SYNTHESIS AND CHEMISTRY OF (TRIALKYLSILYL)VINYLKETENES
byDAWN MARIE BENNETT
B. A., ChemistryBoston University, 1994
SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIALFULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
June 1999
© 1999 Massachusetts Institute of TechnologyAll Rights Reserved
Signature of Author................................ -.... .... .............
Department of ChemistryMay 19, 1999
C ertified by ............................................. ......... ........Rick L. DanheiserThesis Supervisor
A ccepted by............................ ........ ...............................Dietmar Seyferth
Department Committee on Graduate Studies
7%9;;" TUTE
M.I.T. I VWV
I LIBRARIES
This doctoral thesis has been examined by a committee of the Department of
Chemistry as follows:
Professor Stephen L. Buchwald.............. ....... ... ....
Chair
Professor Rick L. Danheiser........ ............. .......----
Thesis Supervisor
Professor Gregory C. Fu ............................ ---..........--
2
Acknowledgments
I would like to thank my family, friends, and colleagues for their unwavering supportthroughout my graduate school career. First and foremost, I must express my gratitude to myadvisor, Professor Rick Danheiser, for providing me with the opportunity to learn in hislaboratory. I promise to always remember that "criticism makes you stronger!" I am alsoindebted to my undergraduate advisor, Professor Warren Giering of Boston University, forinspiring me to pursue my love of chemistry at the highest possible level.
I wish to thank the National Science Foundation for a predoctoral fellowship from1994-1997. Also, thanks are due to Jeff Simpson and Mark Wall of the InstrumentationFacility (Spec Lab!!) as well as to Kevin Shea for their patience with me on the NMRmachines over the years.
I consider myself fortunate to have had such excellent co-workers over the past fiveyears and I would like to thank all Danheiser group members past and present for theircontributions to my intellectual growth. I would especially like to thank the current groupmembers for their support while I've been writing this thesis and for not teasing me too muchabout my Diet Coke addiction.
I would like to thank both Jason Diffendal and Matt Martin for helping me to sort outall kinds on computer snafus and for being such good sports about all the Star Wars jokes.Christophe Mellon has provided valuable discussions about chemistry (and life) and I wishhim the best in Cantata! Kevin Shea has helped me numerous times with NMR experimentsand has been a great resource for discussing ketene chemistry and Italian restaurants. I wouldlike to thank Greg Dudley for his last-minute help with MacSpartan calculations even thoughit meant he had to suffer through missing a day of group clean-up (Keanu Reeves rules!). Ialso wish to thank Dana Buske, Chris, Greg, and that blue guy for making my last night ofthesis writing so memorable! Best wishes to Ralf Demuth, Yoshi, Rob Niger, and ouryoungest group member, Dave Amos (TABOO!).
I would like to express my appreciation to Jason, Kevin, Matt, Greg, and Jeremy forproofreading this dissertation on extremely short notice. Special thanks are due to Greg whograciously accepted proofreading duties for the longest chapter plus all the associatedexperimentals! Most of all, I would like to thank Rick for reading each chapter in minutedetail and providing useful writing tips at the same time.
Thank you to my dear friend Elizabeth for all your sane advice on life and love whenthe world seemed upside down. I consider myself incredibly fortunate to have you as myfriend. Mint chocolate chip always!
To the members of the women's group (you know who you are), thank you from thebottom of my heart for helping me to recognize my own strengths. I will carry a part of eachof you with me forever.
Rob Lea, I wish you were still on this earth to share this happy moment with me. Ithink of you often and know you have found peace in heaven.
I have been truly blessed with a wonderful family. This thesis would have beenimpossible without the support of my Mom, Dad, and brother, Craig. Of course the recentaddition to my "family", Wile E., has helped immensely, too! I love you all dearly and can'tfind appropriate words to express my sincere gratitude for all of your kindness and support.
3
To my family
4
SYNTHESIS AND CHEMISTRY OF (TRIALKYLSILYL)VINYLKETENES
byDawn M. Bennett
Submitted to the Department of Chemistryon May 19, 1999 in partial fulfillment of the
requirements for the Degree of Doctor of Philosophy
ABSTRACT
The properties of silylketenes differ dramatically from those of ketenes. New
strategies for the synthesis of (trialkylsilyl)vinylketenes ("TAS-vinylketenes") were explored.
These robust vinylketenes undergo highly regioselective [4+2] cycloadditions in which the
ketene carbonyl dominates in controlling the regiochemical course of the reaction. TAS-
Vinylketenes have been shown to undergo Diels-Alder reactions with activated olefinic and
azcetylenic dienophiles. These vinylketenes also participate in a hetero [4+2] version of the
reaction in which carbonyl and imino dienophiles react with TAS-vinylketenes to afford
substituted (6)-lactones and lactams. TAS-Vinylketenes also react in a [4+1] annulation to
afford cyclopentenones.
Thesis supervisor: Rick L. Danheiser
Title: Professor of Chemistry
5
Table of Contents
Part I
Synthesis and Chemistry of (Trialkylsilyl)vinylketenes
Chapter 1
Introduction and Background: Vinylketenes and (Trialkylsilyl)ketenes
Chapter 2
Synthetic Approaches to Substituted TAS-Vinylketenes
Chapter 3
Applications of TAS-Vinylketenes as Dienes in the Diels-AlderReaction: Synthesis of Carbocyclic Compounds
Chapter 4
Applications of TAS-Vinylketenes as Dienes in the Hetero Diels-AlderReaction: Synthesis of Heterocyclic Compounds
Chapter 5
TAS-Vinylketenes as Four-Carbon Components in a New [4 + 1]Annulation Strategy
Part II
Experimental Section
General Procedures
Materials
Chromatography
Instrumentation
Experiments and Spectra
6
8
34
53
68
100
113
114
114
114
115
116
PART I
Synthesis and Chemistry of (Trialkylsilyl)vinylketenes
7
CHAPTER 1
INTRODUCTION AND BACKGROUND: VINYLKETENES AND
(TRIALKYLSILYL)KETENES
Introduction
The utility of ketenes in organic synthesis is well-established.' Studies in the
laboratory of Staudinger2 nearly one hundred years ago led to the first general methods for the
synthesis of alkyl- and arylketenes. Staudinger also examined the participation of ketenes in
addition reactions with nucleophiles as well as their dimerization and polymerization
reactions. Since his pioneering work, ketene chemistry has flourished and now includes
studies in theoretical, mechanistic, and synthetic areas.
Vinylketenes (a,P-unsaturated alkenylketenes) were believed to be intermediates in
chemical reactions as early as 1941 . Although these ketenes are difficult to isolate, a variety
of methods exist for generating them in situ for use in synthetic reactions. Vinylketenes have
the capacity to function as versatile four-carbon building blocks for the assembly of a variety
of carbocyclic systems. [2+2] Cycloadditions of vinylketenes are especially valuable
transformations which can serve as triggering steps for pericyclic cascades leading to the
formation of six- and eight-membered carbocyclic compounds (vide infra).
My research has focused on the chemistry of (trialkylsilylvinylketenes ("TAS-
vinylketenes"). We expected that these compounds would be more stable than vinylketenes,
allowing them to express their underlying reactivity as electron-rich conjugated dienes and
participate as four-carbon components in Diels-Alder and related cycloadditions. As
background to our work, this chapter includes a review of the synthesis and reactions of
vinylketenes, followed by a discussion of silylketenes, including their properties, common
1. For reviews of ketene chemistry, see: (a) Tidwell, T. T. Ketenes; Wiley: New York, 1991. (b) The
Chemistry ofKetenes, Allenes, and Related Compounds; Patai, S., Ed.; John Wiley and Sons: New
York, 1980 and references cited therein. (c) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159.(d) Schaumann, E.; Scheiblich, S. In Methoden der organischen Chemie (Houben Weyl); Kropf, H.,Schaumann, E., Eds.; George Thieme: Stuttgart, 1993; Vol. E15/3, pp 2818-2880, 2933-2957.
2. (a) Staudinger, H. Chem. Ber. 1905, 38, 1735. (b) Staudinger, H.; Ott, E. Chem. Ber. 1908, 41,2208. (c) Staudinger, H.; Anthes, E.; Schneider, H. Chem. Ber. 1913, 46, 3539.
3. Smith, L. I.; Hoehn, H. H. J. Am. Chem. Soc. 1941, 63, 1181.
8
methods of preparation, and utility in organic synthesis. The remaining chapters will detail
our investigations of the synthesis and reactions of TAS-vinylketenes.
Generation of Vinylketenes
Three synthetically significant methods for the generation of vinylketenes have been
reported to date: (1) the dehydrohalogenation of a,p-unsaturated acid chlorides, (2) the
electrocyclic ring opening of cyclobutenones, and (3) the photochemical Wolff rearrangement
of a,p-unsaturated diazo ketones. In addition, several other methods have been used to
prepare particular vinylketenes. Most vinylketenes cannot be isolated due to their tendency to
dimerize and polymerize, and therefore are usually generated in situ and immediately reacted
with a ketenophile.
Dehydrohalogenation of acid chlorides has been used as a method for the generation
of vinylketenes since 1966 when Payne first discovered that reaction of 3-methyl-2-butenoyl
chloride with trimethylamine forms isopropenylketene. 4 Although this ketene itself is
unstable, it can be trapped by reaction with ethyl vinyl ether or isolated as the ketene dimer.
In subsequent years, a variety of vinylketenes have been prepared via the
dehydrohalogenation method5 including the isolable vinylketene 2 which Wuest found could
be purified by distillation (24 *C, 0.01 mm Hg, eq 1).5k
00 C11 Et3N 1
160 C, 8h
benzene
sealed tube
1 62% 2
4. Payne, G. B. J. Org. Chem. 1966, 31, 718.5. For examples of the generation of vinylketenes via dehydrohalogenation, see: (a) Gelin, R.; Gelin, S.;
Dohnazon, R. Tetrahedron Lett. 1970,3657. (b) Hickmott, P. W.; Miles, G. J.; Sheppard, G.; Urbani,
R.; Yoxall, C. T. J. Chem. Soc., Perkin Trans. 1 1973, 1514. (c) Rey, M.; Roberts, S.; Dieffenbacher,
A.; Dreiding, A. S. Helv. Chim. Acta 1970, 53,417. (d) Rey, M.; Dunkelblum, E.; Allain, R.;Dreiding, A. S. Helv. Chim. Acta 1970, 53,2159. (e) Dondoni, A. Heterocycles 1980, 1547. (f)Wuest, J. D. Tetrahedron 1980, 36,2291. (g) Huston, R.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta
1982, 65,451. (h) Jackson, D. A.; Rey, M.; Dreiding, A. S. HeIv. Chim. Acta 1983, 66,2330. (i)Danheiser, R. L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37, 3943. (j) Danheiser, R. L.;
Gee, S. K.; Sard, H. J. Am. Chem. Soc. 1982, 104, 7670. (k) Wuest, J. D.; Madonik, A. M.; Gordon,
D. C. J. Org. Chem. 1977, 42, 2111.
9
One major drawback of the dehydrohalogenation route to vinylketenes is the
production of an amine hydrochloride byproduct which is known to catalyze the
polymerization of ketenes. 6 In addition, this salt can cause isomerization of the 0,y-double
bonds of 2-vinylcyclobutanoneS 5h (products of [2+2] reactions of vinylketenes with olefins)
into conjugation with the carbonyl group.
The electrocyclic ring opening of cyclobutenones is a second general method for the
synthesis of vinylketenes. This process can occur under either thermal7 or photochemical8
conditions. In 1956, Jenny and Roberts discovered that heating optically active 2,4-dichloro-
3-phenylcyclobutenone results in racemization (eq 2).9 They proposed that this reaction
involves reversible formation of chloroketenes 4 via electrocyclic ring opening of the
cyclobutenone. In the presence of ethanol the ketene can be trapped as the ethyl ester 5,
providing evidence in support of a vinylketene intermediate.
C1 0 CHC 3 C C,0 C 0
' 1X100 C EtOH H OEt (2)Ph CI Ph CI / Ph
H H
3 4 5
Photochemical conditions can also effect the electrocyclic cleavage of cyclobutenones.
For example, methylprenylketene is generated via the photochemically induced electrocyclic
6. For examples, see: (a) Brady, W. T.; Waters, 0. H. J. Org. Chem. 1967, 32, 3703. (b) Hansford, W.E.; Sauer, J. C. Org. React. 1946, 3, 108.
7. For examples of thermal electrocyclic ring opening to generate vinylketenes, see: (a) Bellus, D.; Ernst,B. Angew. Chem., Intl. Ed Engl. 1988, 27, 797. (b) Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. Top.Curr. Chem. 1986, 133, 83. (c) Moore, H. W.; Yerxa, B. R. In Advances in Strain in OrganicChemistry, Halton, B., Ed.; Jai Press: London, 1995, pp 81-162. (d) Marvell, E. N. In ThermalElectrocyclic Reactions, Academic Press: New York, 1980, pp 124-190. (e) Moore, H. W.; Decker,0. H. W. Chem. Rev. 1986, 86, 821.
8. For examples of photochemical electrocyclic ring opening to generate vinylketenes, see: (a) Barton, D.H. R. Helv. Chim. Acta 1959, 42, 2604. (b) Baldwin, J. E.; McDaniel, M. C. J. Am. Chem. Soc.1968, 90, 6118. (c) Chapman, 0. L.; Lassila, J. D. J. Am. Chem. Soc. 1968, 90, 2449. (d) Arnold, D.R.; Hedaya, E.; Merritt, V. Y.; Karnischky, L. A.; Kent, M. E. Tetrahedron Lett. 1972, 3917. (e)Huisgen, R.; Mayr, H. J. Chem. Soc., Chem. Commun. 1976, 55. (f) Mayr, H.; Huisgen, R. J. Chem.Soc., Chem. Commun. 1976, 57.
9. (a) Jenny, E. F.; Roberts, J. D. J. Am. Chem. Soc. 1956, 78, 2005. (b) Silversmith, E. F.; Kitahara, Y.;Roberts, J. D. J. Am. Chem. Soc. 1958, 80,4088. (c) Silversmith, E. F.; Kitahara, Y.; Caserio, M. C.;Roberts, J. D. J. Am. Chem. Soc. 1958, 80, 5840.
10
ring opening of 2,4,4-trimethylcyclobutenone. This vinylketene then undergoes [2+2]
cycloaddition with ethyl vinyl ether to afford a mixture of stereoisomeric cyclobutenones (eq
3 ).8f One advantage of this route is that vinylketenes can be generated at room temperature.
In our laboratory, Kollol Pal studied the generation of vinylketenes by irradiation of
cyclobutenones and in fact was able to observe the formation of several vinylketenes in good
yield by 'H NMR spectroscopy. 0
0 hv ro D O0 +0c tEto
(3)
6 7 8 9
72: 28
The advantages of the electrocylic ring opening for the generation of vinylketenes are
clear. This mild, efficient method produces no amine salt that can cause undesirable side
reactions. Also, because this is an intramolecular process requiring no reagents, the
vinylketene can be generated in very low concentration thus reducing the rate of dimerization.
A third method for the generation of ketenes, the photochemical Wolff rearrangement
of a,p-unsaturated diazo ketones, is useful for two reasons: the reaction can be run at room
temperature, and the only byproduct is nitrogen." In 1964, Roedig reported that irradiation of
diazo ketone 10 results in formation of vinylketene intermediate 11 which can be trapped by
reaction with N-(phenyl)benzaldimine to afford P-lactam 12 (eq 4).12 We have investigated
the generation of vinyl- and arylketene intermediates via the photochemical Wolff
rearrangement of a-diazo ketones in the context of the aromatic annulation strategy developed
in our laboratory.' 3
10. Pal, K., Ph. D. Thesis, Massachusetts Institute of Technology, Cambridge, MA, 1987, pp. 69-77.11. For reviews of the photo Wolff rearrangement, see: (a) Regitz, M.; Maas, G. Diazo Compounds -
Properties and Synthesis; Academic Press: New York, 1986. (b) Doyle, M. P.; McKervey, M. A.; Ye,T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley: New York,1998. (c) Zollinger, H. Diazo Chemistry II: Aliphatic, Inorganic, and Organometallic Compounds;VCH: New York, 1995.
12. Roedig, A.; Fahr, E.; Aman, H. Chem. Ber. 1964, 97, 77.13. Danheiser, R. L.; Brisbois, R. G.; Kowalcyzk, J. J.; Miller, R. F. J. Am. Chem. Soc. 1990, 112, 3093.
11
0 N2 hv M0C C! h O
A CO 2Me benzene MeO 2C CN PhN MoO2C NPh
Cl ' CI -N2 CI1 CI Ph 28% CCI Ph
CI CI CI
10 11 12
Another method for the generation of vinylketenes involves the photolysis or
thermolysis of alkenylcarbene metal complexes.14 In this process, metal-ketene complexation
suppresses undesired side reactions such as dimerization. These metal-ketene complexes can
undergo nucleophilic addition, cycloaddition with alkenes, and intramolecular cyclization.
For example, reaction of cobalt complex 13 and 3-hexyne at 25 *C results in the formation of
cobalt-vinylketene complex 14;1' addition of sodium methoxide then yields ester 15 in 54%
yield (eq 5).
Ph Et --=-- Et Et C>Co(CO)SnPh3 Ph 3Sn(OC)2Co-
MeO benzene rt Ph
13 35% 14 OMe
NaOMeMeOH (5)
54%
0Et OMe
15 Et) PhOMe
In summary, three synthetically significant methods for the generation ofvinylketenes
have found use in recent years: (1). the dehydrohalogenation of acid chlorides, (2) the
electrocyclic ring opening of cyclobutenones, and (3) the photo Wolff rearrangement of
14. For reviews on alkenylcarbene metal complexes, see: (a) Hegedus, L. S. In Advances in Metal
Carbene Chemistry; Schubert, U., Ed.; Klumer Academic Publishers: Boston, 1989, pp 199-210, 233-246. (b) D~tz, K. H. New J. Chem. 1990, 14, 433.
15. Wulff, W. D.; Gilbertson, S. R.; Springer, J. P. J Am. Chem. Soc. 1986, 108, 520.
12
unsaturated a-diazo ketones. Other pyrolytic and thermolytic methods also can be used for
the preparation of specific ketenes. 16
Reactions of Vinylketenes
Vinylketenes participate in a variety of reactions including nucleophilic addition and
[2+2] and [4+2] cycloadditions. A brief summary of these reactions follows.
Nucleophilic addition of water, alcohols, amines, and carboxylic acids to vinylketenes
affords acids, esters, amides, and anhydrides. Nucleophiles trap vinylketenes very efficiently,
and this process is often cited as evidence that a ketene was generated in a reaction. For
example, in our laboratory Kollol Pal confirmed the intermediacy of a vinylketene generated
by the electrocyclic ring opening of 2,3-dimethylcyclobutenone by carrying out the reaction in
the presence of t-butylamine to afford amides 17 and 18 (eq 6).
o hv 00t-BuNH2 Nt-Bu + Nt-Bu (6)
100% A616 17 18
Vinylketenes have found their greatest utility reacting with alkenes and alkynes in
[2+2] cycloadditions leading to 2-vinylcyclobutanones and -cyclobutenones.!'" In
particular, our research group has extensively employed these cycloadditions as triggering
steps for pericyclic cascades that lead to the formation of 3-cyclohexenols, cyclooctadienones,
and highly substituted phenolic compounds (Scheme 1). In these reactions, vinylketenes
function as electron-deficient 2n components in the key [2+2] cycloaddition step.
16. See ref la, pp 52-149.17. For examples, see refs 5dh,ij, 8f, and 13.18. Danheiser, R. L.; Nishida, A.; Savariar, S.; Trova, M. P. Tetrahedron Lett. 1988, 4917.
13
Scheme 1
Rz REREO_ H' RE OH
D Rz [1,3) Sigmatropic ERearrangement Rz
D D
0 1 [3,31C"0 Sigmatropic
b 1,3-Dienes Rearrangement
Acetylenes R 1 0O 1) 4e~ Electrocyclic OHAceyleesCleavage R'
1 2 2) 69- ElectrocyclicR---- R R2 12)eClosure R2
3) Tautomerization
Scheme 1 outlines three strategies for the synthesis of carbocyclic compounds
developed in our laboratory based on vinylketenes. The first strategy (pathway a) provides a
method for the synthesis of substituted 3-cyclohexenols.5 i In this annulation, generation of
the vinylketene by dehydrohalogenation of an a,p-unsaturated acid chloride followed by a
[2+2] cycloaddition with an electron-rich alkene affords a 2-vinylcyclobutanone intermediate.
Addition of a nucleophile with subsequent alkoxy-accelerated [1,3] sigmatropic
rearrangement then yields a 3-cyclohexenol.
Pathway b illustrates a [4+4] strategy for the synthesis of eight-membered
carbocycles. 5i In this method, generation of the vinylketene occurs by either 1,4-
dehydrohalogenation of an acid chloride or the thermal electrocyclic ring opening of a
cyclobutenone. [2+2] Cycloaddition of the vinylketene with a 1,3-diene yields a 2,3-
divinylcyclobutanone intermediate. Subsequent [3,3] sigmatropic rearrangement results in
formation of the 2,6-cyclooctadienone.
The aromatic annulation strategy described in pathway c is a powerful method for the
preparation of highly substituted phenolic compounds. 13,18 We have demonstrated the utility
of this strategy by developing direct synthetic routes to a variety of natural products, including
14
Dan Shen diterpenoid quinones,' 9 maesanin, 2 0 aegyptinones A and B, salvilenone,2 2 and
bergapten.2 Irradiation of an a-diazo ketone triggers a photochemical Wolff rearrangement
to produce a vinylketene which then reacts with an acetylene in a regiospecific [2+2]
cycloaddition. Continued irradiation or thermolysis effect the 4n electrocyclic opening of the
resulting 4-vinylcyclobutenone generating a dienylketene. The penultimate 67c
electrocyclization is followed by tautomerization to yield the aromatic product.
Although vinylketenes have a proclivity to undergo [2+2] cycloadditions, a few
examples of direct [4+2] cycloadditions of these compounds do exist,24 including cases
involving dimerization of vinylketenes. For example, reaction of two molecules of
vinylketene 19 affords the a-pyrones 20 and 21 resulting from a [4+2] cycloaddition (eq 7 ).5d
Generating vinylketenes in low concentrations in the presence of an excess of ketenophile
helps to prevent this undesired dimerization.
0 Et3N CW0 0 0
CICHC13 ''0 0 0 (C d3 is--I+ (7)rt
19 KI20 21
34% 31%
As summarized above, vinylketenes have been well-documented as intermediates in a
variety of reactions and their participation in [2+2] cycloadditions has been extensively
exploited in organic synthesis. If this normal reaction pathway could be suppressed,
vinylketenes might express their underlying reactivity as electron-rich conjugated dienes for
other useful tranformations. Based on the fact that silylketenes are remarkably more stable
19. (a) Danheiser, R. L.; Casebier, D. S.; Loebach, J. L. Tetrahedron Lett. 1992, 33, 1149. (b) Danheiser,R.L.; Casebier, D. S.; Firooznia, F. J. Org. Chem. 1995, 60, 8341.
20. Danheiser, R. L.; Cha, D. D. Tetrahedron Lett. 1990, 31, 1527.21. Danheiser, R. L.; Casebier, D. S.; Huboux, A. H. J. Org. Chem. 1994, 59, 4844.22. Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116,9471.23. Danheiser, R. L.; Trova, M. P. Synlett 1995, 573.24. For examples, see: (a) Day, A. C.; McDonald, A. N.; Anderson, B. F.; Bartczak, T. J.; Hodder, 0. J. R. J.
Chem. Soc., Chem. Commun. 1973,247. (b) Rees, C. W.; Somanathan, R.; Storr, R. C.; Woolhouse, A. D.J. Chem. Soc., Chem. Commun. 1976, 125. (c) Berge, J. M.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta1982, 65,2230. (d) Collumb, D.; Doutheau, A. Tetrahedron Lett. 1997, 38, 1397.
15
that most other ketenes, we hypothesized that silylvinylketenes might exhibit the stability of
silylketenes, thus reducing their eagerness to participate in [2+2] reactions. In order to
understand the basis for this hypothesis, it is first necessary to review the synthesis and
chemistry of (trialkylsilyl)ketenes.
(Trialkylsilyl)ketenes
Silylketenes25 exhibit completely different properties from most other ketenes. The
remarkably stable parent compound (trimethylsilyl)ketene can be stored at room
temperature for several years without decomposition. In fact, this TAS-ketene can even be
purified by distillation at 82 *C. As will become apparent later in this chapter, TAS-ketenes
resist dimerization and undergo reactions at a much slower rate than their alkylketene
counterparts.
The silyl substituent has an extraordinary ability to stabilize ketenes and suppress their
natural tendency to dimerize and undergo [2+2] cycloadditions. Originally, TAS-ketenes
were believed to exist as a tautomeric mixture of (trimethylsilyl)ketene and
trimethylsilyloxyacetylene, accounting for their unusual stability. Spectroscopic studies later
showed that this was not true and that only the ketene structure is present.
Currently, the amazing stability of TAS-ketenes is believed to result from
hyperconjugative electron a-7t donation from the C-Si bond into the in-plane carbonyl 7r*-
orbital, a reasonable supposition considering that the power of the C-Si bond as a
hyperconjugative electron donor has been well documented. Also, Tidwell has proposed
that -the stability of TAS-ketenes is due to the electron-releasing ability of the electropositive
25. For a review on silylketenes, see: Pommier, A.; Kocienski, P.; Pons, J.-M. J. Chem. Soc., PerkinTrans. 1 1998, 2105.
26. Loebach, J. L.; Danheiser, R. L. In Encyclopedia ofReagentsfor Organic Synthesis; Paquette, L. A.,Ed.; Wiley: New York, 1995, pp 5266-5268.
27. For a discussion, see: (a) Patai, S. The Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z.,Eds; Wiley: New York, 1989. (b) Weber, W. P. Silicon Reagentsfor Organic Synthesis; Springer-Verlag:Berlin, 1983. (c) Colvin, E. W. Silicon in Organic Synthesis; Butterworths: London, 1981. (d) Fleming, I.In Comprehensive Organic Synthesis; Jones, D. N., Ed.; Pergamon: New York, 1979; Vol. 3, pp 541-686.
(e) Armitage, D. A. In Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon: New
York, 1982; Vol. 2, pp 1-203.
16
silicon group, allowing for a donation. The carbonyl group is rendered less electrophilic and,
as a result, less reactive toward nucleophilic addition reactions and cycloadditions.28
MeSi , Me3Si® _9C=O =-
H 2 1 H
A trimethylsilyl group attached to the C-2 of a ketene results in an upfield shift of the
13 C NMR resonance of C-1 as a result of partial sp character at C-1, providing some evidence
for silicon acting as a a-t donor in (trialkylsilyl)ketenes. The phenomenon of a-n donation
by silicon is well documented in other areas of silicon chemistry.
Alternatively, Runge has suggested that TAS-ketene stability is due to back-donation
from the ketene n-system to the d-orbitals of the silicon atom, resulting in a partial Si-C
double bond.29 Any major contribution by such a resonance form (see below) should result in
a longer C-C bond and shorter C-O bond. Ab initio molecular orbital calculations confirmed
that the C=O and C=C bond lengths of (trimethylsilyl)ketene are almost the same as the C=O
and C=C bonds of methylketene and therefore Runge's proposed structures probably do not
contribute significantly to TAS-ketene stability.
GMe 3 Si> M Me 3Si
>=C=0 =C= o 01 g C=H ZH
H
Generation of (Trialkylsilyl)ketenes
Silylketenes have been prepared by a wide variety of methods including the
thermolysis of alkoxyalkynes, dehydration of silylacetic acids, Wolff rearrangement of x-
diazo ketones, electrocyclic ring opening of cyclobutenediones, and reaction of lithiated
28. For a discussion, see ref Ia and the following: (a) Greg, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem.
Soc. 1991, 113, 6021. (b) Allen, A. A.; Egle, I.; Janoschek, R.; Liu, H. W.; Ma, J.; Marra, R. M.; Tidwell,T. T. Chem. Lett. 1996, 45.
29. Runge, W. Prog. Phys. Org. Chem. 1981, 13,315.
17
silyldiazomethane with carbon monoxide. Shchykovskaya achieved the first synthesis of
(trimethylsilyl)ketene in 1965 by pyrolysis of an alkoxy(trialkylsilyl)acetylene, the most
commonly used procedure for the preparation of TAS-ketenes to date.3 0 Heating
ethoxy(trimethylsilyl)ethyne 22 at 120 *C results in liberation of ethylene, affording ketene 23
in 90% yield (eq 8). Initially, Shchukovskaya believed that the mechanism of the reaction
proceeds via an isomerization, but in 1975 Ruden reported that the reaction actually occurs
via a retro-ene 6-membered transition state.3 1
H H
120 *C H -C2H4 Me 3SiMe 3Si ---- OEt 0 ' C C=0 (8)
22 [ Me 3Si - 0 90% 23
Subsequent studies have shown that (trimethylsilyl)ketene (23) can be generated at
lower temperatures by the thermal decomposition of t-butoxy(trimethylsilyl)ethyne 24.
Heating alkyne 24 at temperatures as low as 50 *C resulted in the slow elimination of 2-
methylpropene. Nearly instantaneous conversion to (trimethylsilyl)ketene occurs at higher
temperatures (100-110 *C). The large t-butoxy group shields the triple bond and helps to
prevent side reactions (such as polymerization and nucleophile attack) that commonly occur
when the silylketene is generated from the less hindered ethoxy derivative 22. Therefore,
preparation of silylketenes from 24 can occur in the presence of nucleophiles which
subsequently react with the ketene. For example, (trimethylsilyl)ketene (generated by
pyrolysis of 24) in the presence of diphenylamine, afforded amide 25 in quantitative yield (eq
9). Unfortunately, the t-butoxy derivative 24 requires several steps to prepare whereas a one-
step procedure yields ethoxy derivative 22 from commercially available ethoxyacetylene.
30. Shchukovskaya, L. L.; Pal'chik, R. I.; Lazarev, A. N. Dokl. Akad Nauk SSSR (Engi. Transl) 1965, 164,
357.31. Ruden, R. A. J. Org. Chem. 1974, 39, 3607.32. Valenti, E.; Pericas, M. A.; Serratosa, F. J. Org. Chem. 1990, 55, 395.
18
Ph 2NHCHC13 0
50-55 *C, 11 h (Me3SI -= Ot-Bu 100 Me3Si -- NPh2 (9)100% N~ 2
24 25
Substituted (trialkylsilyl)ketenes can be prepared by a related method, the thermal
rearrangement of trialkylsilyloxyacetylenes.33 Treatment of 1-methoxy-3-methyl-i-butyne
with trimethylsilyl iodide affords intermediate 1-(trimethylsilyloxy)-3-methyl-i-butyne.
Rearrangement to the corresponding isopropyl-substituted ketene 28 occurs at room
temperature (eq 10).33a Synthesis of the parent (trimethylsilyl)ketene can occur via a similar
rearrangement in which reaction of ketene, trimethylsilyl triflate, and triethylamine affords
(trimethylsiloxy)acetylene as an intermediate which undergoes 1,3-silicon transfer at room
temperature to afford (trimethylsilyl)ketene in 63% yield. 4
i-Pr OM Me3SiI = OSiMe M 3SI >C=O (10)CH 3CN i-Pr
rt, 30 min 90%26 27 28
Lutsenko reported another pyrolytic method for the generation of (TAS)ketenes. 5
Heating (triethylsilyl)acetic anhydride affords (triethylsilyl)ketene in 80% yield (eq 11).
Condensation of two molecules of (triethylsilyl)acetic acid produces the necessary anhydride.
The requisite silylacetic acids can presumably be prepared in one step by the conversion of
acetic acid to the dianion by treatment with LDA followed by silylation with two equivalents
of the desired silyl chloride.36 Dehydrohalogenation of acid chlorides also forms TAS-
ketenes, but this method generally gives only low yields of the desired product?7
33. (a) Sakurai, H.; Shirahata, A.; Sasaki, K.; Hosomi, A. Synthesis 1979, 740. (b) Efinova, I. V.; Kazankova,M. A.; Lutsenko, I. F. J. Gen. Chem. USSR (Engi. Trans.) 1985, 55, 1465. (c) Pons, J.-M.; Kocienski, P.Tetrahedron Lett. 1989, 30, 1833.
34. Uhlig, W.; Tzschach, A. Z. Chem. 1988, 28, 409.35. Kostyuk, A. S.; Dudukina, 0. V.; Burlachenko, G. S.; Baukov, Yu. I.; Lutensko, I. F. JGen. Chem. USSR
(Engl. Transi.) 1969, 39, 441.36. Tsuge, 0.; Kanemasa, S.; Suzuki, T.; Matsuda, K. Bull. Chem. Soc. Jpn. 1986, 59, 2851.
19
0 0 A Et3Si C=O(11)Et 3SK~i,,k 0..J.SiEt3 80% H
29 30
In 1989, Olah reported an efficient preparation of silylketenes by the dehydration of
silyl acetic acids.38 Treatment of commercially available (trimethylsilyl)acetic acid 31 with
dicyclohexylcarbodiimide (DCC) in the presence of catalytic triethylamine affords
(trimethylsilyl)ketene in 63% yield (eq 12). However, all attempts in our laboratory to
accomplish the synthesis of (trimethylsilyl)ketene according to this procedure have thus far
been unsuccessful. Other (TAS)acetic acid precursors for this new approach to TAS-ketenes
can be prepared as mentioned above.
DCC
cat. Et3N
Me0Si . H C= (12)
63% H31 23
In 1985, Maas reported an extremely facile synthesis of TAS-ketenes by the Wolff
rearrangement of a-silyl-a-diazo ketones under photochemical conditions or with transition
metal catalysis. 3 9 Irradiation of a-diazo ketone 32 affords silylketene 33 in 94% yield (eq
13). Alternatively, treatment of 32 with copper triflate (4 mol% in benzene, 20 *C) results in
Wolff rearrangement, producing the desired ketene 33 in 93% yield. The requisite a-silyl-a-
diazo ketone can be prepared via silylation of an a -diazo ketone, thus allowing access to a
variety of aryl- and alkyl-substituted silylketenes.
37. Lutensko, I. F.; Baukov, Yu. I.; Kostyuk, A. S.; Savelyeva, N. I.; Krysina, V. K. J. Organomet. Chem.1969, 17, 241.
38. Olah, G. A.; Wu, A.; Farooq, 0. Synthesis 1989,568.39. (a) Maas, G.; Brackmann, R. J. Org. Chem. 1985, 50,2801. (b) Brtckmann, R.; Schneider, K.;
Maas, G. Tetrahedron 1989, 45,5517.
20
Ph XyN2Si(i-Pr)h
hvbenzenert 1.5h
94%
32
(i-Pr)3Si>-C=O
Ph
33
In recent years, Tidwell has done extensive studies on the preparation of
bis(trialkylsilyl)ketenes via the electrocyclic ring opening of cyclobutenediones under both
thermal and photochemical conditions.40 Reaction of bis(t-butyldimethyl-silyl)acetylene 34
with dichloroketene (generated from trichloroacetyl chloride with zinc-copper couple) affords
dichlorocyclobutenone 35. Hydrolysis with concentrated sulfuric acid yields the
cyclobutenedione 36 which undergoes a facile electrocyclic ring opening to produce bisketene
37 in excellent yield (Scheme 2).
Scheme 2
CC13CCOCIZn-Cu
Et 2O:DME
84%
34
A or hvCDC13
92%
t-BuMe2Si 0
9CIt-BuMe2Si C135
H2SO455 *C
44%
t-BuMe2Si 0
t-BuMe2Si 0
36
40. For recent reports on the synthesis and chemistry of bis(trialkylsilylketene), see: (a) Allen, A. D.; Liu,R.; Ma, J.; McAllister, M. A.; Tidwell, T. T.; Zhao, D.-C. Acc. Chem. Res. 1995, 28,265. (b) Allen,A. D.; Liu, R.; Ma, J.; McAllister, M. A.; Tidwell, T. T.; Zhao, D.-C. Pure Appi. Chem. 1995, 67,777. (c) Allen, A. D.; Colomvakos, J. D.; Egle, I.; Liu, R.; Ma, J.; Marra, R. M.; McAllister, M. A.;Tidwell, T. T. Can. J. Chem. 1996, 74,457. (d) Zhao, D.-C.; Tidwell, T. T. J. Am. Chem. Soc. 1992, 114,10980. (e) Zhao, D.-C.; Allen, A. D.; Tidwell, T. T. J. Am. Chem. Soc. 1993, 115, 10097.
21
(13)
t-BuMe2Si
III
t-BuMe2Si
t-BuMe 2Si XC :C SiMe 2t-Bu
37
Recently, Murai reported a remarkably efficient route to bis(silyl)- and
stannyl(silyl)ketenes by the reaction of lithiated (trimethylsilyl)diazomethane with carbon
monoxide, followed by trapping with a silyl chloride, silyl triflate, or stannyl chloride.4' Thus,
treatment of (trimethylsilyl)diazomethane with n-butyllithium followed by exposure to carbon
monoxide (1 atm) affords acyllithium intermediate 39. Extrusion of dinitrogen produces the
lithiated silylketene 40 which is trapped with triethylsilyl trifluoromethanesulfonate to
produce the bis(silyl)ketene 41 in 85% yield. Efforts to trap lithiated silylketene 40 with alkyl
halides or a proton source were unsuccessful.
Scheme 3
n-BuLi LiTHE Li COo
.0SI/=N2 TH ' ) N2 ,O 0= N2Me 3Si Me 3Si 3938 39
-N 2
00 Et3SiOTf 9C ofC
Me 3SSi SiEt3 Mo 3Si Li
41 40
Reactions of (Trialkylsilyl)ketenes
Silylketenes undergo a diverse assortment of reactions and the rich area of silylketene
chemistry has been extensively investigated. The remainder of this chapter will briefly
summarize the participation of TAS-ketenes in nucleophilic addition reactions as well as
[2+2] and [4+2] cycloadditions. Also, the formation of allenes, cyclopropanones, and
cyclobutanones from TAS-ketenes will be reviewed.
(1) Nucleophilic Addition
TAS-Ketenes readily undergo nucleophilic addition with a variety of compounds
including water, alcohols, amines, and certain carbon nucleophiles. Hydration of
41. Kai, H.; Iwamoto, K.; Chatani, N.; Murai, S. J Am. Chem. Soc. 1996, 118, 7634.
22
(trimethylsilyl)ketene under neutral conditions occurs at a significantly slower rate than the
addition of water to comparable alkylketenes. However, under acidic or basic conditions, the
rate of silylketene hydration is faster than that of alkylketenes.42 ,43 This interesting rate
difference is believed to result from silicon's unique ability to stabilize both a negative charge
a to the silicon (basic hydration conditions) and to stabilize a positive charge P to the silicon
(acidic hydration conditions).44
Other oxygen nucleophiles also react at a much faster rate with alkylketenes than with
TAS-ketenes. However, under appropriate conditions, simple alcohols do add to
(trimethylsilyl)ketene to afford esters in excellent yield.45 Alcohols also combine with the
more hindered (t-butyldimethylsilyl)ketene, although at a slightly reduced rate. TAS-Ketenes
react with sterically hindered alcohols very slowly unless a Lewis acid that can catalyze the
reaction is present. For example (eq 14), addition of n-butanol to TMS-ketene occurs rapidly
at -10 OC,30 but reaction of t-butanol with 23 is much slower (CC14 , 48 h, rt, 80%) unless
catalyzed by a Lewis acid (BF 3-OEt 2, 5 min, rt, 93%).31
t-BuOH0 BF 3-OEt n-BuOH
M e3S i -.-,A 1* rt 5 min Me 3Si C=o -10 C 0 Me3SIkOn-B. (14)Ot-Bu 93% H 85%
43 23 42
Zinc halides effectively catalyze the addition of alcohols to (trimethylsilyl)ketenes.46
Many functional groups tolerate the presence of this mild Lewis acid, including carbonyl
groups, acetals, olefins, and epoxides that would be sensitive to other Lewis acids such as
BF 3-OEt 2. Kita has thus found that zinc chloride catalyzes the addition of a-hydroxy ketones
42. Allen, A. D.; Tidwell, T. T. Tetrahedron Lett. 1991, 32, 847.43. For other studies on the hydration of silylketenes, see refs 30, 40e and the following: (a) Vodolazskaya, V.
M.; Baukov, Yu. I. J. Gen. Chem. USSR (Engl. Transl.) 1973, 43, 2076. (b) Ponomarev, S. V. Angew.Chem., Int. Ed Engl. 1973, 12,675.
44. Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc. 1991, 113, 6021.45. For examples of the reaction of silylketenes with alcohols, see refs 30, 31, 40e, 43a and the following:
(a) Ando, W.; Sekiguchi, A.; Migita, T.; Kammula, S.; Green, M.; Jones, M., Jr. J. Am. Chem. Soc.1975, 97, 3818. (b) Knauss, E. E.; Coutts, R. T.; Kazakoff, C. W. J. Chromatogr. Sci. 1976, 14, 525.(c) Ponomarev, S. V.; Erman, M. B.; Gervits, L. L. J. Gen. Chem. USSR (Engl. Transl.) 1972, 42,462.
46. Kita, Y.; Sekihachi, J.-i.; Hayashi, Y.; Da, Y.-Z. ; Yamamoto, M.; Akai, S. J. Org. Chem. 1990, 55,1108.
23
to (trimethylsilyl)ketene to afford functionalized a-silylacetates (eq 15), compounds that are
difficult to prepare by traditional methods. Yamamoto reported that a naturally occurring
lipase isolated from Rhizopusjaponicus also catalyzes this transformation.47
0 ZnC 2, CH 2C2 0)> c=0 + Ph)Y OH rt 45 mn Ph < O SiMe3 (15)
H Me 91% Me O
23 44 45
As mentioned earlier, TAS-ketenes react rapidly with amines to form amides.48
Ruden reported the quantitative conversion of (trimethylsilyl)ketene to the corresponding
amide 46 upon addition of diisopropylamine at room temperature (eq 16).31 Bromine also
adds to (trimethylsilyl)ketene to produce bromo(trimethylsilyl)acetylbromide. 30 In addition,
alkoxy(tributyl)tins combine with TAS-ketenes to afford a-stannyl esters.49
i-Pr2NHMeS C= Me3Si P (16)
H 100% M SA NiP)
23 46
Taylor reported a convenient one-pot preparation of coumarins based on the addition
of salicylaldehyde salts to TAS-ketenes.50 Condensation of o-acyl phenol 47 with ketene 23
affords a-silylcarboxylate 48, and subsequent cyclization and elimination yields coumarin 49
in 92% yield (eq 17).
47. Yamamoto, Y.; Ozasa, N.; Sawada, S. Chem. Express 1993, 8, 305.48. For examples of the reaction of silylketenes with amines, see refs 30, 31, and the following: Coutts, R.
T.; Jones, G. R.; Benderly, A.; Mak, A. L. C. J. Chromatogr. Sci. 1979, 17, 350.49. (a) Akai, S.; Tsuzuki, Y.; Matsuda, S.; Kitagaki, S.; Kita, Y. J. Chem. Soc., Perkin Trans. 1 1992,
2813. (b) Akai, S.; Tsuzuki, Y.; Matsuda, S.; Kitagaki, S.; Kita, Y. Synlett 1991, 911.50. Taylor, R. T.; Cassell, R. A. Synthesis 1982, 672.
24
Na O1
CHO Me 3Si H
47 23
DMF 0rt 2h N O
92% CHO SiMe 3
48 49
The addition of carbon nucleophiles to TAS-ketenes has also received considerable
attention. Organolithium reagents add to substituted TAS-ketenes; subsequent addition of
acid results in formation of a ketone, whereas treatment with a trialkylsilyl chloride affords a
silyl enol ether. For example, treatment of bis(trimethylsilyl)ketene with n-butyllithium
followed by acidic workup affords ketone 51.51 Alternatively, addition of n-butyllithium to
ketene 52 followed by trapping with trimethylchlorosilane produces the vinyl silyl ether 53 as
a single stereoisomer (eq 18).
1. n-BuLi, THFMe 3Si >C=O rt 8h NoMe 3Si 2. H30+
50 85%
1. n-BuLi, Et 20-78 *C 1h
2. Me 3SiCI-78 *C to rt 12 h
78%
0Me 3Si Y'knn-Bu
SiMe3
51
Me3Si OSiMe3
Et n-Bu
53
When a TAS-ketene containing a proton at C2 is treated with strongly basic
organolithium reagents, only proton abstraction results (no nucleophilic addition is
observed).53 Kita reported that the resulting lithiated silylketene can react with a
(trialkylsilyl)chloride at low temperature to afford bis(trialkylsilyl)ketenes in excellent yield.54
In the presence of a less basic organocerium reagent, nucleophilic addition to TAS-ketenes
51 . Woodbury, R. P.; Long, N. R.; Rathke, M. W. J. Org. Chem. 1978, 43,376.52. Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. T. J. Am. Chem. Soc. 1985, 107, 5391.53. See ref 51 and the following: Sullivan, D. F.; Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1977,
42, 2038.
25
(17)
Me 3Si
Et
52
(18)
occurs, forming an enolate. 5 For example, addition of BuCeC 2 to (t-
butyldimethylsilyl)ketene affords enolate 55 which can be trapped with either aqueous
ammonium chloride or an alkyl halide to afford 56 and 57 (eq 19).
NH 4CI 0t-BuMe
2Si Bu_[ 091%t-BuMe2Si BuCeC 2 t-BuMe2Si 0 561C=0 N >=( (19)
H H Bu
54 55 Mel t-BuMe2SIy 0BHMPA Y,
Me76%
57
Enamines can react as ketenophiles, combining with silylketenes to form 1,3-diones. 56
For example, Shioiri reported that addition of enamine 58 to (t-butyldimethylsilyl)ketene 54 at
room temperature followed by hydrolysis of the imine during silica gel chromatograpy affords
dione 59 in 70% yield (eq 20).
1. PhH 0 0t-BuMe 2Si N rt, 18 h Sit-BuMe2H= + (5~ ~ IJ~(20)
H 2. Si02
70%54 58 59
(2) Cycloadditions of TAS-Ketenes
Because of the stabilizing effect of silicon substituents on ketenes, TAS-ketenes
undergo [2+2] cycloadditions only with very reactive, electron-rich olefms. In 1974, Zaitseva
reported the addition of 1,1 -diethoxyethene to (trimethylsilyl)ketene to afford the [2+2]
cycloadduct.57 Brady later reported that (trimethylsilyl)ketene reacts with tetramethoxyethene
54. Akai, S.; Kitagaki, S.; Naka, T.; Yamamoto, K.; Tsuzuki, Y.; Matsumoto, K.; Kita, Y. J. Chem. Soc.,Perkin Trans. 1 1996, 1705.
55. Kita, Y.; Matsuda, S.; Kitagaki, S.; Tsuzuki, Y.; Akai, S. Synlett 1991, 401.56. Takaoka, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 1005.57. Zaitseva, G. S.; Baukov, Yu. I.; Mal'tsev, V. V.; Lutsenko, I. F. J. Gen. Chem. USSR (Engi. Transl.) 1974,
44, 1389.
26
to form cyclobutanone 61.58 Treatment of ketene 23 with the bulkier alkene 62 results only in
addition to the ketene (without subsequent ring closure) to yield acyclic ester 63 (eq 21).' 9
MoO OMe60
MoO OMeMe3Si
90*C 2h a MeI OMe
65% MeO OMe
61Me3Si (21)
H MoO OSiMo3 62 M0 3Si OSiMe323 H OSiMO3 H' CO 2SMe3
rt 24 h MeO
95% 63
In 1975, Zaitseva reported the first [2+2] cycloaddition of a TAS-ketene and an
aldehyde. Reaction of (trimethylsilyl)ketene with benzaldehyde in the presence of BF 3-OEt2
affords a 2:1 mixture of cis- and trans-4-phenyl-3-trimethylsilyloxetan-2-one (64) in 65%
yield (eq 22).60 Due to the decreased reactivity of TAS-ketenes in [2+2] cycloadditions, these
reactions usually require catalysis by Lewis acids. Since Zaitseva's discovery, this [2+2]
approach has become a common method for the synthesis of P-lactones. 61 Recent
developments in the area of oxetanone synthesis include the use of bulky Lewis acids for
preparation of exclusively cis-substituted P-lactones62 and chiral Lewis acids for the
formation of enantiomerically enriched products.63 Silylketenes do not participate in [2+2]
reactions with ketones.
58. Brady, W. T.; Saidi, K. J Org. Chem. 1980, 45, 727.59. Brady, W. T.; Saidi, K. J. Org. Chem. 1990, 55, 4215.60. Zaitseva, G. S.; Vinokurova, N. G.; Baukov, Yu. I. J. Gen. Chem. USSR (Engl. Transl.) 1975, 45, 1372.61. For a review on the synthesis of P-lactones via the [2+2] reaction of TAS-ketenes and carbonyl
compounds, see ref 25 and references cited therein.62. Maruoka, K.; Concepcion, A. B.; Yamamoto, H. Synlett 1992, 31.63. For a recent example, see: Dymock, B.; Pons, J.-M.; Kocienski, P. J. Chem. Soc., Chem. Commun. 1996,
1053.
27
PhCHOcat. BF 3-OEt
65%
Me 3Si 0
Ph
64
Although the well-known Staudinger reaction of ketenes and imines is an extremely
useful method for the synthesis of P-lactams, few examples of silylketene participation in this
type of reaction have been reported.64 In 1976, Brady reported the first [2+2] reaction of a
TAS-ketene with an imine. Reaction of bromo(trimethylsilyl)ketene 66 (generated in situ by
dehydrohalogenation of 65) with N-(t-butyl)benzaldimine provided P-lactam 67 in 56% yield
(eq 23).64a
N.,t-BuEt3N Me3S
Pheptane 3Br C= Ph H
reflux 16 h -56%
66
t-Bu 0'N
Ph! SiMe3Br
67
Schubert later reported the reaction of ethoxy(triphenylsilyl)ketene 69 (generated in
situ from metal complex 68) with N-(methyl)benzaldimine which produces a 74:16 mixture of
cis and trans-substituted P-lactams 70 and 71 (eq 24).64' At about the same time, Zaitseva
reported that (trimethylsilyl)ketene reacts with N-alkylsulfonyl chloralimines.64c
64. (a) Brady, W. T.; Owens, R. A. Tetrahedron Lett. 1976, 1553. (b) Kron, J.; Schubert, U. J. Organomet.Chem. 1989, 373, 203. (c) Novikova, 0. P.; Livantsova, L. I.; Zaitseva, G. S. J. Gen. Chem. USSR (Engl.Transi.) 1989, 59, 2350. (d) Zaitseva, G. S.; Novikova, 0. P.; Livantsova, L. I.; Petrosyan, V. S.; Baukov,Yu. I. J. Gen. Chem. USSR (Engl. Transi.) 1991, 61, 1268.
28
Me 3Si >
H
23
(22)
MOSi -)ABr
Br
65
(23)
(CO) 5MC(OEt)SiPh3
M = Cr, Mo, W
68
Et2O
-M(CO) 6
Me, 0N
P h /SiMe 3H OEt
7074%
Ph 3Si>=
EtO69IPh
)=N-MeH
Me 0N
PhXf I/EtH SiMe3
7116%
Usually TAS-ketenes do not participate in formal [4+2] cycloaddition reactions, but a
few examples have been reported. Shioiri recently described the reaction of (t-
butyldimethylsily)ketene with an electron-rich 1,3-diene. 65 Experimental evidence was
obtained suggesting that this reaction proceeds via a stepwise mechanism. Thus, addition of
diene 72 to ketene 54 affords a betaine intermediate (73) that can be trapped as the ester 74 by
addition of water. Increasing the time or temperature of the reaction results in cyclization to
afford the dihydropyranone 75 which subsequently isomerizes to pyranone 76 (Scheme 4).
Scheme 4
t-BuMe2Si OSiMO3C=0 +
H Oh.~.IIEO3
54 72
benzenereflux 3 d
a OSiMe3t-BuMe2SI OSiMe
73
'-Q COSiMe3
74
t-BuMe2 Si I An0 0
76
t-BuMe 2Si 0 077%
75
65. Ito, T.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1993, 34, 6583.
29
(24)
In 1996, Aoyama and Shioiri reported another example of a TAS-ketene undergoing a
[4+2] cycloaddition.66 Reaction of (trimethylsilyl)ketene with acylisocyanate 77 affords the
[4+2] adduct, 78. Subsequent reaction with dimethylacetylene dicarboxylate and expulsion of
carbon dioxide then yields 2-pyridone 79 in nearly quantitative yield in an extremely efficient
one-pot procedure (eq 25).
0
R N=C=0 +
77 IMO 3SI
H R = (p-N0 2)C6 H4
23
o-dichlorobenzenereflux 3 h
0
[OMe 3SiO N R
78
.IDMAD3h
99%
CO 2MeCO2Me
O N RH
79
(3) Formation of Allenes, Cyclopropanones, and Cyclobutanones
Olefmation of (trimethylsilyl)ketene with stabilized phosphorus ylides has been used
for the preparation of allenes.67 For example, reaction of ylide 80 with (trimethylsilyl)ketene
at -5 'C affords allenic ester 81 in 85% yield (eq 26). Reaction of (trimethylsilyl)ketene with
unstabilized phosphorus ylides results only in formation of complex mixtures of products.
Combination of a variety of phosphorus ylides (such as Ph3P=C(Ph)(Et)) with
bis(trialkylsilyl)ketenes gives reasonable yields of silylallenes.
66. (a) Takaoka, K.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1996, 37, 4973. (b) Takaoka, K.; Aoyama, T.;Shioiri, T. Tetrahedron Lett. 1996, 37, 4977.
67. See ref 25 and Kita, Y.; Tsuzuki, Y.; Kitagaki, S.; Akai, S. Chem. Pharm. Bull. 1994, 42, 233.
30
(25)
H
MeSPh 3 P C2Et Me 3Si HHO iC=O 80 HC== (26)H H CO 2Et
CH 2CI2, -5 *C23 85% 81
Silyl-substituted ketenimines can also be prepared using organophosphorous
chemistry. Barbaro and co-workers described the reaction of (trimethylsilyl)ketene with
[bis(trimethylsilyl)methylimino]triphenylphosphorane 82 at room temperature, affording
ketenimine 83 in moderate yield (eq 27).68 Another aza-Wittig-type reaction serves as a key
step in Molina's total synthesis of aaptamine in which treatment of a functionalized
iminophosphorane with (trimethylsilyl)ketene affords a silylketenimine intermediate.69
,CH(SiMe 3)2
Me 3Si Ph3P=N 82 Me 3Si (2)CH(SiMe)
H Et2O, 25*C H
23 42% 83
Zaitseva found that reaction of TAS-ketenes with diazomethane produces
cyclopropanones or cyclobutanones.70 The outcome of the reaction depends greatly on the
amount of diazomethane used. Treatment of (trimethylsilyl)ketene with one equivalent of
diazomethane at 130 *C results in exclusive formation of 2-(trimethylsilyl)-cyclopropanone
84. The cyclopropanone product can react with a second equivalent of diazomethane to
afford the ring expansion products 85 and 86 as a mixture of isomers. The cyclobutanones
can be obtained directly by treatment of 23 with two equivalents of diazomethane at -78 *C
(Scheme 5).
68. Barbaro, G.; Battagliz, A.; Giogianni, P.; Guerrini, A.; Seconi, G. J. Org. Chem. 1995, 60, 6032.69. Molina, P.; Vida, A.; Varquero, I. Synthesis 1996, 1199.70. (a) Zaitseva, G. S.; Bogdanova, G. S.; Baukov, Yu. I.; Lutsenko, I. F. J. Organomet. Chem. 1976, 121, Cl-
C22. (b) Zaitseva, G. S.; Bogdanova, G. S.; Baukov, Yu. I.; Lutsenko, I. F. J. Gen. Chem. USSR (Engl.Trans.) 1978, 48, 111.
31
1 equiv CH 2N2 M0 3Si-130 C
50%
Et 2
2 equiv CH 2N2 Me 3SiEt2 , -78 C
90% 85
84
quiv CH 2N2), -78 *C
0
Me 3Si 86
40: 60
(Trimethylsilyl)diazomethane also combines with TAS-ketenes in [2+1]
cycloadditions.7 1 Brady reported that (diethylmethylsilyl)ketene 87 reacts smoothly with
TMS-diazomethane to afford exclusively the cis-substituted cyclopropanone 88 (eq 2 8 ).',a
Reaction of TMS-diazomethane with (trimethylsilyl)ketene and other
(trimethylsilyl)arylketenes have also been reported.7 lb" Concurrent with our work (see
Chapter 5), Tidwell reported the [4+1] reaction of bis(trialkylsilylketenes) with TMS-
diazomethane. This reaction will be discussed in detail in Chapter 5.
Et 2MeSi
H
Me 3SiCHN 2Et2 O
-10 *C to rt
90%87
Et 2MeSi > 0Me3Si
88
(28)
Our laboratory reported the first synthesis and isolation of a silylvinylketene several
years ago. Since then, we have been interested in developing new routes to substituted TAS-
vinylketenes and systematically investigating their utility in organic synthesis. Chapter 2
71. (a) Brady, W. T.; Cheng, T. C. J. Organomet. Chem. 1977, 137,287. (b) Zaitseva, G. S.; Kisim, A.N.; Fedorenko, E. N.; Nosova, V. M.; Livantsova, L. I.; Baukov, Yu. I.; Lorberth, J. J. Gen. Chem.
USSR (Engl. Transi.) 1987, 57, 1836. (c) Zaitseva, G. S.; Lutsenko, I. F.; Kisin, A. V.; Baukov, Yu. I.;Lorberth, J. J. Organomet. Chem. 1988, 345, 253.
72. Colomvakos, J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J. J. Org. Chem. 1996, 61,9522.
32
Scheme 5
Me 3Si
H
23
O
discusses new approaches for the synthesis TAS-vinylketenes, and Chapters 3-5 present our
results on TAS-vinylketene reactivity in [4+2] and [4+1] cycloadditions.
33
CHAPTER 2
SYNTHETIC APPROACHES TO SUBSTITUTED TAS-VINYLKETENES
Synthesis of (Trimethylsilyl)vinylketene by Dehydrohalogenation
One of the most widely used methods for the preparation of TAS-vinylketenes
involves the dehydrohalogenation of acid chlorides. Indeed, this approach has been used for
the synthesis of vinylketenes as discussed in Chapter 1. Several years ago our laboratory
reported the first synthesis of (trimethylsilyl)vinylketene (92) by this method, according to the
route outlined in Scheme 6.7 Treatment of 1-(trimethylsilyl)propyne (89) with
diisobutylaluminum hydride and methyllithium affords a vinylalanate intermediate75 that
subsequently reacts with carbon dioxide to form (Z)-2-(trimethylsilyl)-2-butenoic acid (90).
The potassium salt of 90 reacts with oxalyl chloride to afford acid chloride 91 that is used in
the next step without purification. Addition of 91 to a pentane solution of triethylamine
followed by heating at reflux (15 to 24 h) yields (trimethylsilyl)ketene. Purification by
distillation (25 *C, 1 mmHg) affords the ketene (92) as a yellow-green liquid (Scheme 6).
(Trimethylsilyl)vinylketene is moderately stable and can be stored in solution at 0 0C for 1-2
weeks without appreciable decomposition.
Scheme 6
1. DIBAL-MeLi 0
- SiMe3 Et20-hexane O Me3SI OH2. C0 2
89 90
KOH, MeOH1.1 equiv (COC) 2pentane, cat. DMF
0 *C to rt, 1.5 h
0.9 equiv Et 3NMeSiNC, pentane, reflux Me Si
C 15-24 h M3S C11
39-50%92 overall yield 91
73. Danheiser, R. L.; Sard, H. J. Org. Chem. 1980, 45, 4810.74. (a) Eisch, J. J.; Damasevitz, G. A. J. Org. Chem. 1976, 41, 2214. (b) Uchida, K.; Utimoto, K.; Nozaki, H.
J. Org. Chem. 1976, 41, 2215.75. Zweifel, G.; Steele, R. B. J. Am. Chem. Soc. 1967,89,2754.
34
Unfortunately, the limited thermal stability of this vinylketene restricts the scope of its
reactions. We expected that substituted TAS-vinylketenes would be more stable.
Unfortunately, although dehydrohalogenation of the aP-unsaturated chloride 91 provides
convenient access to (trimethylsilyl)vinylketene, this strategy is not well-suited for the
synthesis of more highly substituted TAS-ketenes. In some cases the requisite precursors are
not available, and regiochemical ambiguities can arise in dehydrohalogenation (1,4-
elimination) reactions involving p,p-disubstituted-a,p-unsaturated carboxylic acid derivatives
(eq 29).
R3Si C R3Si C" R3Si C"C00_ + (29)
R R2 R R2 R1 R2
Recent studies in our laboratory have demonstrated that the photochemical Wolff
rearrangement provides an efficient method for the synthesis of vinylketenes.13 In these
transformations, the vinylketene is not isolated, but is trapped in situ with an alkyne, initiating
a cascade of pericyclic reactions leading ultimately to the formation of a highly substituted
aromatic system. Maas and co-workers have shown that saturated TAS-ketenes can be
generated in a similar fashion by the Wolff rearrangement of a-silyl-a-diazo ketones.39 The
efficiency of these processes suggested that the rearrangement of a'-silyl-a'-diazo-a,P-
unsaturated ketones (94) might provide the basis for a new route to TAS-vinylketenes (eq 30).
1 R3SiOTf R1 0 N RSi C R3SiR N2 i-Pr2EtN 2 hv R1 (30)
R 3 R
93 94 95
35
Synthesis of Substituted TAS-Vinylketenes by Photochemical Wolff Rearrangement
The requisite a-diazo ketone precursors (93) were all prepared using the
"detrifluoroacetylative" diazo transfer strategy previously developed in our laboratory.76
Thus, treatment of methyl ketone 96 with 1.1 equivalents of lithium hexamethyldisilazide in
THF at -78 *C produces a lithium enolate, which is acylated by exposure to 1.2 equivalents of
trifluoroethyl trifluoroacetate at -78 *C. Treatment of the resulting a-trifluoroacetyl ketone
(97) with 1.5 equiv of MsN3 in the presence of 1.0 equivalents of water and 1.5 equivalents of
Et3N in acetonitrile (25 *C, 4 h) affords the desired diazo ketone 98 in 75-79% yield after
chromatographic purification (eq 31). It should be noted that a'-diazo-a,P-unsaturated
ketones generally cannot be prepared by addition of diazomethane to acyl chlorides because
of competing side reactions involving dipolar cycloadditions to the conjugated double bond."
0 .1 L0 0 1.5 equiv MsN31. 1.1 equiv LiHMDS 1.0 equiv H20 N
THF, -78 C CF3 1.5 equiv Et 3N N2
2. 1.2 equiv TFETFA CH 3CN, rt 4 h-78 *C, 5-10 min
75-79%96 97 98
Silylation of the diazo ketones was accomplished using a modification of the method
of Mass and co-workers. 78 In this procedure, diazo ketones are treated with a silyl triflate
reagent and diisopropylethylamine to afford the a-silyl-a-diazo ketone. As reported by Maas,
the silylated a-diazo ketones have a tendency to undergo protodesilylation during their
preparation and isolation caused by the presence of acidic trialkylammonium triflate
byproducts. Jennifer Loebach of our laboratory found that this problem can be minimized by
employing a solvent system consisting of equal parts Et2O and hexane. 9 The ammonium
76. (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959. (b)Danheiser, R. L.; Miller, R. F.; Brisbois, R. G. Organic Syntheses; Wiley: New York; 1998; Collect. Vol.
IX, 197.77. For a discussion and examples, see: (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis;
Academic Press: New York, 1986, pp 498-499. (b) Fink, J.; Regitz, M. Synthesis 1985, 569. (c) Itoh, M.;
Sugihara, A. Chem. Pharm. Bull. 1969, 17, 2105. (d) Regitz, M.; Menz, F.; Liedhegener, A. Justus
Liebigs Ann. Chem. 1970, 739, 174. (e) Harmon, R. E.; Sood, V. K.; Gupta, S. K. Synthesis 1974, 577. (f)Rosenquist, N. R.; Chapman, 0. L. J. Org. Chem. 1976, 41, 3326 and references therein.
78. See ref 39 and the following: Bruckmann, R.; Maas, G. Chem. Ber. 1987, 120,635.79. (a) Loebach, J. L., Ph. D. Thesis, Massachusetts Institute of Technology, Cambridge, MA 1995. (b)
Loebach, J. L.; Bennett, D. B.; Danheiser, R. L. J. Org. Chem. 1998, 63, 8380.
36
salts have reduced solubility in this medium, and the desired silylation products are obtained
in 10-30% higher yield as compared to reaction in Et2O alone. A variety of a'-trialkylsilyl-
c'-diazo-a,P-enones can be prepared in good yield by employing this protocol (Scheme 7).
Diazo ketones 100-102 were isolated as yellow to orange oils that can be stored in solution at
0 *C for several days without significant decomposition. Because a wider range of silyl
chloride reagents are available as compared to silyl triflates, we briefly examined the
suitability of silyl chlorides as substitutes for triflates in the silylation reaction. As a model
case, the reaction of chlorotriethylsilane with diazo ketone 98 was examined under the
standard silylation conditions (1.0 equiv i-Pr2EtN, Et2O:hexane, 0 *C to rt). Unfortunately,
this reaction afforded none of the desired product even after stirring for several days at room
temperature. Apparently, silyl chlorides are insufficiently reactive to effect the desired
transformation.
Scheme 7
0 R3SiOTf, i-Pr2EtN 0
RI N2 Et2 -hexane R0_0C toi
_t1
99 R',R2= (CH 2)4 R3= (i-Pr)3 100 75%
98 RI = R2 = CH 3 R3 =(i-Pr)3 101 86-89%
98 Ri= R2 =CH3 R3 = Et3 102 70-84%
Recently we have been interested in preparing TAS-vinylketenes with alkoxy- or
phenyl-substituted silyl groups. We anticipated that these particular silyl groups would permit
useful synthetic transformations following cycloaddition. The silyl triflates necessary for the
synthesis of these desirable TAS-vinylketenes were not readily available. However, these
highly reactive and extremely moisture sensitive compounds have been prepared previously
by treatment of the requisite silyl chloride with triflic acid80 or by reaction of the silyl chloride
with silver triflate.8 1 Alternatively, treatment of an aryl- or allylsilane with triflic acid results
80. Corey, E. J.; Cho, H.; Racker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455.
81. Riediker, M.; Graf, W. Helv. Chim. Acta 1979, 62, 205.
37
in displacement of the phenyl or allyl group, affording a silyl triflate product.82 We first
prepared an aryl-substituted silyl triflate using the strategy outlined in eq 32. Reaction of
dichlorodiphenylsilane with 2.4 equivalents of ethylmagnesium bromide afforded the desired
silane 103 in excellent yield,83 and addition of an equimolar amount of triflic acid then
generated the desired silyl triflate 104 and benzene, which can be removed by distillation. The
crude triflate reagent (104) was used for silylation reactions without further purification.
2.4 equiv EtMgBr
Ph 2SiC12 Et 2O, reflux 4 h - Ph2M2 1.0 equiv TfOH PhEt2SIOTf (32)
87% 103 -PhH 104
Reaction of diazo ketone 98 with approximately one equivalent of the unpurified
diethyl(phenyl)silyl trifluoromethanesulfonate 104 under the standard silylation conditions
affords the desired silyl diazo ketone 105 in 56-74% yield (eq 33, not optimized).
PhEt 2SiOTf, i-Pr2EtNN2 E20-hexane N
0 C to rt, 1-2 h 10N 2 (33)SIEt2Ph
56-74%98 105
Unfortunately, synthesis of the alkoxy-substituted silyl triflate 107 was not
straightforward (Scheme 8). Dichlorodiethylsilane, when treated with isopropanol in
refluxing benzene, affords the alkoxysilyl chloride 106 in 75% yield after distillation.84
(Chloride 106, as expected, was not sufficiently reactive to effect silylation of diazo ketone
98). Reaction of chloride 106 with silver triflate afforded a mixture of products that could not
be separated by distillation. By a second route, dichlorodiethylsilane reacts with two
equivalents of silver triflate to afford the ditriflate 107 in 61% yield after distillation.
82. (a) Matyjaszewski, K.; Chen, Y. L. J. Organomet. Chem. 1988, 340, 7. (b) Uhligh, W. J. Organomet.Chem. 1993, 452, 29.
83. Kipping, C. J. Chem. Soc. 1927, 107.84. McCusker, P. A.; Greene, C. E. J. Am. Chem. Soc. 1948, 70,2807.
38
Unfortunately, subsequent treatment with isopropanol and base afforded a mixture of products
that decomposed upon attempted distillation.
Scheme 8
1.0 equiv i-PrOHbenzene, reflux 1.0 equiv AgOTf
5 min CH2C 2, rt 2 hEt2Si(Oi-Pr)CI
75% 106 A OTfEM2=1~2 Et2S 1 -\ 2.0 equiv AgOTf 1.0 equiv i-PrOH Et 2 Oi-Pr
CH 2C12 Et2SI(OTf)2 Et3 N 107
61% 108
An alternate route to 107 which was not investigated experimentally is outlined in eq
34. Treatment of dichlorodiethylsilane with an equimolar amount of isopropanol followed by
addition of allylmagnesium bromide was expected to afford intermediate 109, and subsequent
displacement of the allyl group with triflic acid was then anticipated to produce the desired
compound 107.
1) i-PrOH .O(I-Pr) 1.0 equiv TfOHEt 2 SiC2 - - - - - - - - - - - - - - Et2S - 107 (34)
2) . MgBr109
With efficient routes to a variety of a-trialkylsilyl-L-diazo ketones in hand, we were
able to carry out a systematic investigation of their conversion to the desired TAS-
vinylketenes. Initial studies by Loebach found that Wolff rearrangement occurred upon
irradiation at 300 nm using a Rayonet RPR-100 photochemical reactor at 30-35 *C (Scheme
9). Better yields were obtained in the synthesis of more highly substituted vinylketenes,
possibly because of the greater stability of the diazo ketone precursors.
39
Scheme 9
0*0hv (300 nm) R3Si C*
R1 N2 benzene imp-R2) SiR3 R
12R
100 R ,R2= (CH 2)4, R3= (i-Pr)3 110 70-74%101 R1 = R2 = CH 3, R3= (i-Pr)3 111 74-87%102 Ri = R2 = CH 3, R3 = Et3 112 59%
105 R1 = R2 = CH 3, R3 = Et 2 Ph 113 64%
TAS-Vinylketenes exhibit a number of interesting spectral characteristics. The
following page outlines the spectral features of the diethyl(phenyl)silyl-substituted ketene 113
(Figure 1). The IR spectrum of TAS-vinylketene 113 shows the expected strong diagnostic
stretch near 2100 cm-1 resulting from the symmetric stretching modes of the ketene backbone
(C=C=O). The 'H NMR spectrum is relatively uninformative because TAS-vinylketenes do
not contain a proton on the ketene double bond that would be diagnostic of the structure.
However, the 13C NMR spectrum has two notable features. As expected, the C-1 (C=C=0)
carbons of TAS-vinylketenes are extensively deshielded and give a low field signal near 185
ppm. The C-2 carbon (C=C=O) exhibits an unusually high field signal near 20 ppm, resulting
from contribution of the resonance structure illustrated below.
40
0 R3SR 3 Si C ______G
C
Figure 1. Spectral Characteristics of
(E)-2-(1-Methyl-1-propenyl)-2-(diethyl(phenyl)silyl)ketene (113)
IR (film): 3360, 2440, and 2060
'H NMR (500 MHz, CDCl3):
7.53-7.57 (m, 2H) 0.90-1.04 (m)
7.32-7.39 (m, 3H) Ph,SI C0
1.80 (s) H3C H 4.96
CH 3 1.51
(q, J= 6.8 Hz)
(d, J= 6.8 Hz)
I'If t
i 6 7 6 5 4 3
13C NMR (125 MHz, CDCl3):
226 200 180 i6 i48 126 1600 80 6 40 20 pPM
41
Li2 1 I ppe
7.9
136.2,135.1, Ph 4.8 o130.1, 128.6 S25.0 184.8
1123.8
19.2 H3C 119.3
CH 3
14.6
I .
cm~I
Maas previously reported the application of the transition-metal catalyzed Wolff
rearrangement for the preparation of saturated alkyl(TAS)ketenes, 39 and we hoped that this
method might be applicable for the synthesis of TAS-vinylketenes. Treatment of silylated a-
diazo ketone 100 with a 0.04 to 0.2 equivalents of CuOTf results in formation of the desired
ketene 110 (eq 35). Unfortunately, the yield of this reaction (22-26%) compares poorly with
the excellent yield (89%) obtained by the photochemically induced Wolff rearrangement of
the same diazo ketone, and this method was not pursued further.
cat. CuOTf (i-Pr)3Si C0
benzeneI(i-Pr)3 rt, 1-2.5 h (35)
22-26%100 110
Substituted TAS-vinylketenes are remarkably robust compounds, in dramatic contrast
to typical vinylketenes. The triisopropyl derivative (111) was recovered unchanged after
heating in C6D6 at 80 *C for four days, although some decomposition of the
(triethylsilyl)vinylketene 112 was observed after heating at this temperature for 10 h. Also
notable is the observation that these ketenes can be purified by conventional silica gel
chromatography without any detectable decomposition.
We were interested in preparing 3-alkoxy-substituted TAS-vinylketenes because these
electron-rich compounds are expected to exhibit increased reactivity in cycloaddition
reactions. As discussed earlier, TAS-vinylketenes are easily prepared by the photochemically
induced Wolff rearrangement of a'-trialkylsilyl-a'-diazo-a,p-enones. We expected that
application of this protocol to a-alkoxy-a'-trialkylsilyl-a'-diazo-a,p-enones might provide a
route to the desired alkoxy-substituted vinylketenes.
Dr. Yutaka Ukaji of our laboratory investigated this approach as outlined in Scheme
10. Lithiation of 3,4-dihydro-2H-pyran (114) with n-butyllithium followed by treatment with
N,N-dimethylacetamide afforded the aP-unsaturated methyl ketone 115 as previously
reported by Boeckman.85 Application of our standard diazo transfer conditions provided
85. Boeckman, R. K.; Bruza, K. J. Tetrahedron 1981, 37, 3997.
42
diazo ketone 116 in moderate yield. Subsequent silylation with triisopropylsilyl
trifluoromethanesulfonate in the presence of diisopropylethylamine provided silyl diazo
ketone 117 in 58% yield after purification by silica gel chromatography. Unfortunately,
irradiation of 117 in a degassed benzene solution yielded none of the desired ketene 118. It is
possible that alkoxy-substituted TAS-vinylketene 118 is an exceptionally sensitive compound
and may have formed under the photochemical conditions and then decomposed or
polymerized.
Scheme 10
1) n-BuLi, THF0 to 50 C
2) H3CCONMe 2 1
32-49%
0
115
R3SI C"
118
1) LiHMDS, THF-78 *C thenTFETFA
2) MsN 3H20, Et 3NCH 3CN, rt
46%
hv (300 nm)benzene
00 N2
116
(i-Pr)3SiOTfi-Pr2EtN
Et 2O:hexane0 0C to rt
58%
0
0 N2
SiR3
117
Synthesis of Substituted TAS-Vinylketenes by Electrocylic Cleavage of Cyclobutenones
In our previous studies on the application of vinylketenes in annulation routes to six-s8
and eight-5imembered rings, our laboratory has shown that the electrocyclic ring opening of
cyclobutenones provides an especially attractive method for the generation of these reactive
species. It therefore appeared likely that 2-trialkylsilylcyclobutenones might afford TAS-
vinylketenes in good yield upon heating. Advantages of this method include the fact that no
byproducts are formed and the reaction is reversible. In fact, Tidwell has recently shown that
86. See refs 5i, 13, and the following: Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672.
43
0
114
V
A
silylated bisketenes can be generated in a similar fashion by the thermal or photochemical
ring opening of cyclobutenediones (see Scheme 2).
Our plan for the preparation of cyclobutenone precursors to TAS-vinylketenes called
for the [2+2] cycloaddition of dichloroketene with an activated alkyne followed by reductive
dechlorination. It is important to note that in order to obtain the requisite 2-silyl substituted
cyclobutenone, the alkyne must contain a donating substituent (such as an alkoxy or phenyl
group) to direct the regiochemical course of the reaction. In the case of
(trialkylsilyl)acetylenes with only alkyl substituents, mixtures of regioisomeric cycloadducts
are generally obtained. Earlier, in attempts to prepare (trimethylsilyl)vinylketene via this
method, Sard discovered that the [2+2] cycloaddition of (trimethylsilyl)acetylene with
dichloroketene affords almost exclusively the undesired P-silylcyclobutenone 120 (eq 36).87
Me3Si CC13COCI Me 3Si 0 0Zn(Cu)
' i Et2 O, reflux /Ci .J /CI
H9 C Me 3Si Cl
67% 119 120
1:99
Scheme 11 outlines the application of this strategy to the synthesis of TAS-
vinylketene 127. Addition of dichloroketene to the phenyl-substituted
(trialkylsilyl)acetylenes 121 and 122 provides the desired dichlorocyclobutenones 123 and
124 in high yield. The structure of compound 124 (a single regioisomer as determined by 300
MHz 'H NMR analysis) was assigned based on the known powerful directing effect of phenyl
groups in the [2+2] cycloadditions of ketenes and also by knowledge of the 13C NMR
spectrum of the previously characterized cyclobutenone 123 (Figure 2).86
87. Danheiser, R. L.; Sard, H. Tetrahedron Lett. 1983, 24, 23.
44
R3Si
IIIPh
121 (R= Me)122 (R = Et)
R3Si X o
Ph M
127 (R = Me)
CC13COCIZn(Cu)
Et2O, 35 c
benzene60 *C, 4.5 h
37%
R3Si 0
Ph iPh C1
123 (R = Me) 86-95%124 (R = Et) 92%
ZnAcOH-TMEDA
EtOH0 to 25 0C
R3Si 0
Ph
125 (R = Me) 64-74%126 (R = Et) 55%
150.7
Me 3Si 10182.9
180.,5
Ph /1/Cl91.2
123
149.8
EtASi1 183.4
PhC191.0
124
Dechlorination of 4,4-dichlorocyclobutenones does not proceed smoothly under
conventional conditions, but can be accomplished in good yield by employing the protocol
developed independently in our laboratory88 and that of Dreiding. 89 Upon heating in benzene
at 60 'C for 4.5 h, 125 undergoes smooth conversion to the desired TAS-vinylketene 127. As
expected, this (trimethylsilyl)vinylketene proved less stable to chromatography than the
triethyl- and triisopropylsilyl derivatives 110-112 and could only be obtained in 37% yield
after purification on Florisil. For this reason, it ultimately proved advantageous to generate
the ketenes from cyclobutenones 125 and 126 in situ for various cycloadditions rather than to
subject these sensitive compound to isolation and purification. Chapters 3 and 4 discuss the
"in situ generation" of TAS-vinylketenes from cyclobutenones 125 and 126 in detail.
88. (a) Danheiser, R. L.; Savariar, S. Tetrahedron Lett. 1987, 28, 3299. (b) Danheiser, R. L.; Savariar, S.; Cha,D. D. Organic Syntheses; Wiley: New York, 1993; Collect. Vol. VIII, pp 82-86.
89. Ammann, A. A.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1987, 70, 321.
45
Scheme 11
Figure 2
Interestingly, in several reactions where cyclobutenone 125 was heated at elevated
temperatures (110-150 *C), a butenolide side product was isolated. We believe that this
byproduct results from reaction of TAS-vinylketene 127 with diradical oxygen. A related
reaction of oxygen with a bisketene has been previously reported by Tidwell,90 and a similar
mechanism may be operative in our examples. Scheme 12 outlines the mechanism we
propose for formation of butenolide byproduct 129. Addition of oxygen to ketene 127
followed by reaction with a second ketene molecule affords diradical intermediate 128. After
intersystem crossing, 128 can undergo cyclization to afford two molecules of butenolide 129.
After bubbling air through a refluxing toluene solution of cyclobutenone 125 for 18 h, the
butenolide (129) was isolated in 42% yield following purification by silica gel
chromatography.
Scheme 12
Me 3Si 0 toluene, reflux 002 48 h MeSI 3
be 3 0
Ph 42% 5125 Ph129
Me 3Si C0
Ph: 127
Ph02
0 . Me 3Si 0 Ph
M0 3Si M0 3Si C
t PhSiePh Ph 128 0
A variety of spectral data was collected and analyzed in order to substantiate the
structural assignment of 129. The 1H NMR spectrum exhibits a singlet at 4.94 ppm
corresponding to the two C-5 protons on the butenolide ring. The IR spectrum of 129 shows a
strong carbonyl stretching frequency at 1745 cm-1 indicative of the a,p-unsaturated lactone.
Further proof for the structure of 129 was obtained from a 13C NMR DEPT experiment. The
90. Zhao, D.-C.; Tidwell, T. T. J. Am. Chem. Soc. 1992, 114, 10980.
46
C-5 carbon appears as a methylene group at a characteristic resonance of 73.7 ppm. Also, the
carbonyl resonance is observed at 176.9 ppm and the two butenolide alkenyl carbons appear
at 174.0 ppm (C-4) and 133.4 ppm (C-3). The C-4 carbon is deshielded by conjugation with
the carbonyl group and therefore appears downfield in the 13C NMR spectrum.
We have shown that TAS-vinylketenes form easily by the electrocyclic ring opening
of 2-silylcyclobutenones and we therefore believed it would be possible to access alkoxy-
substituted TAS-vinylketenes (131) by this method (Scheme 13).76 One factor motivating our
interest in alkoxy-substituted TAS-cyclobutenones is the potential utility of these compounds
as synthetic intermediates. Addition of R to the carbonyl of 130 followed by hydrolysis
should provide an avenue to a wide array of substituted cyclobutanones (132) that could then
undergo electrocyclic ring opening to TAS-vinylketenes (133). Three methods were explored
for the formation of the requisite 3-alkoxy-2-(trialkylsilyl)cyclobutenones.
Scheme 13
A or hv R3Si C
R3Si 0 RO13113
RO 1)R + R3Si 0 R3Si C130 2) H30 A or hv R
R132 133
The first method we investigated involved the [2+2] cycloaddition of dichloroketene
with an alkoxysilane (eq 37). (Trimethylsilyl)ethoxyacetylene (22)' underwent smooth [2+2]
cycloaddition with dichloroketene (generated via dehalogenation of trichloroacetyl chloride)
to afford the desired cyclobutenone 134 in excellent yield. The next step in our scheme
required the reductive dechlorination of a 4,4-dichlorocyclobutenone, which is considerably
more difficult than in the case of the corresponding saturated derivatives, though it can be
accomplished using procedures developed independently in our laboratory and that of
Dreiding (vide supra). Unfortunately, the reductive dechlorination of 134 was unsuccessful
91. Ruden, R. A. J. Org. Chem. 1974, 39, 3607.
47
using the standard conditions and we were forced to abandon this approach. We suspect that
zinc coordination to the neighboring ethoxy group may prevent the desired reductive
dechlorination from occurring.
Me 3Si CC13COCI Me 3Si o Zn, EtOH Me3S 0
11 Zn(Cu) -I Ac0H-TMEDA4, (37Et 2O, reflux /CI
EtO EtO C1 EtO86%
22 134 135
Zaitseva has reported that reaction of TAS-ketenes with ketene acetals affords 3,3-
dialkoxy-2-(trialkylsilyl)cyclobutanones in 48-49% yield.57 Our second strategy for the
synthesis of 3-alkoxy-2-(trialkylsilyl)cyclobutenones was based on this precedent. We
anticipated that cyclobutanone 140 produced by the Zaitseva reaction might undergo
elimination in the presence of ZnCl2 to give the desired 2-silylcylobutenone 141 (Scheme 14).
We hoped that the regiochemistry of this elimination reaction could be controlled by
employing the procedure of Scheeren which allowed him to regioselectively deprotonate
cyclobutanone 136 at the more hindered position. Scheeren found that situ trapping with
(trimethylsilyl)chloride affords silyl enol ether 137, while without ZnCl2, the alternative
isomer 138 is isolated (eq 38). In our case, in the absence of a trapping agent, we expected to
observe elimination of ethoxide to provide the desired cyclobutenone 141 upon treatment of
140 with Et3N-ZnCl2.
Scheme 14
EtASi>C=0
H H 30 80 O*A _Et3Si 0 RA3 I 0
+ -(--Ir ------ ON-EtO 3> EtO EtO )
tEtOEtO139 140 141
48
OSiMe3 0 ZnC12 OSiMe3Et3N, Me3SCf EtN, Me 3SiCIrt 25 h rt 25 h (38)
Et Et Et4 IiEt EtO Et90% 90%
138 136 137
Zaitseva reported the preparation of our target intermediate (140) in 48% yield via the
reaction of diethylketene acetal (139, synthesized by dehydrobromination of
bromoacetaldehyde diethylacetal in t-BuOK/t-BuOH)92 and (triethylsilyl)ketene without
solvent at 80 *C. Unfortunately, in our hands, attempts to repeat Zaitseva's procedure
afforded none of the desired product 140. The reaction was attempted using freshly distilled
reagents, and a variety of solvents, temperatures, and reaction times were investigated, but in
no case could [2+2] cycloadduct be detected by 'H NMR. We have been unable to account
for these results.
Our third method investigated the generation of alkoxy-substituted TAS-vinylketenes
from squaric acid derivatives (Scheme 15). Liebeskind has extensively studied the chemistry
of squaric acid and its derivatives, reporting that addition of organolithium reagents to
diisopropylsquarate followed by treatment with catalytic amounts of acid is the best available
procedure for the preparation of squaric acid derivatives. 93 We found that reaction of
diisopropyl squarate (142) with dimethylphenylsilyllithium in THF at -78 *C followed by
treatment with concentrated aqueous HCl affords silyl-substituted cyclobutendione 144 in 84-
86% yield.
92. McElvain, S. M.; Kundiger, D. Organic Syntheses; Wiley: New York, 1955; Collect. Vol. III, pp 506-509.93. Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J. Org. Chem. 1988, 53, 2482.
49
i-PrO 0
i-PrO 0
142
PhMe 2SiLi i-PrO OH PTHF SiMe 2Ph conc. HCI
-78 *C, 30 mn iPr 84-86%
143
hMe2Si 0
i-PrO O
144
H
PhMe2Si 0
i-PrO H
145
Liebeskind also reported that selective reduction of the more reactive carbonyl group
of squaric acid derivatives occurs smoothly upon addition of lithium tri-(tert-
butoxy)aluminum hydride at reduced temperatures. 94 We studied the reduction of
cyclobutendione 144 with a variety of hydride reagents, as summarized in Table 1. Of the
reagents investigated, only the lithium tri-(t-butoxy)aluminum hydride successfully reduced
cyclobutenedione 144, but the reaction required a large excess of the hydride reagent (entry
6). Although this route appeared feasible, we were discouraged by the multiple steps required
to access the desired cyclobutenone intermediate and therefore this route was not studied
further.
94. (a) Edwards, J. P.; Krysan, D. J.; Liebeskind, L. S. J. Org. Chem. 1993, 58, 3942. (b) Krysan, D. J.;Gurski, A.; Liebeskind, L. S. J. Am. Chem. Soc. 1992, 114, 1412.
50
Scheme 15
PhMe 2Si 0- PhMe2S! 0
)q 90H
i-PrO i-PrO H
144 145
Conditions
i-Bu 2AlH, CH 2C12, -78 *C, 1 h
Li s-Bu3BH , THF, 0 'C, 5 min
NaBH 4, i-PrOH, rt, 5 min
LiAl(t-BuO) 3H, THF, 0 *C to rt, 2 days
LiAl(t-BuO) 3H, THF, -78 *C to rt, 2 days
LiAl(t-BuO) 3H, THF, -40 *C, 45 min
Red-Al, Et2O, 0 *C, 2 h
Complex mixture
Complex mixture
Complex mixture
No reaction observed
No reaction observed
-30%
Complex mixture
Alternative Routes to TAS-Vinylketenes: Preliminary Studies
Currently in our laboratory, Kevin Shea is investigating the preparation of TAS-vinyl-
and alkynylketenes via the cross coupling reactions of stannyl- and halo(silylketenes) as
outlined in Scheme 16. Murai previously reported a synthesis of
tributylstannyl(trimethylsilyl)ketene 146 from (trimethylsilyl)diazomethane as discussed in
Chapter 1. We expect that ketene 146 may undergo Stille-type reactions with alkenyl- and
alkynyl halides. Alternatively, reaction of bromo(trialkylsilyl)ketenes6 4a (148) with alkenyl-
or alkynylstannanes should afford unsaturated ketene products as well. This method would
allow efficient access to a wide array of unsaturated TAS-ketenes (147), including the elusive
TAS-alkynylketenes.
51
Table I
Entry
1
2
3
4
5
6
7
Results
1.2
1.2
1.6
1.2
2.3
5.0
1.2
equiv
equiv
equiv
equiv
equiv
equiv
equiv
n-BuLi;CO;Bu 3SnCI
Me3SiCHN 2
X R'
C R2
Me 3Si SnBu3
146
0 Br2; 0C Et 3N
R3Si H R3Si Br148
R3Si C -
R3Sn.., R'
I R'R2 R
147
We have developed efficient methods for the synthesis of TAS-vinylketene and
continue to investigate new, improved routes to these compounds. In what kind of
synthetically significant reactions do these novel compounds participate? The remainder of
this thesis explores this provocative question. Chapters 3 and 4 detail the [4+2]
cycloadditions of TAS-vinylketenes, and Chapter 5 presents the application of these
compounds in a novel [4+1] annulation strategy for the synthesis of cyclopentenones.
52
Scheme 16
CHAPTER 3
APPLICATION OF TAS-VINYLKETENES AS DIENES IN THE DIELS-ALDER
REACTION: SYNTHESIS OF CARBOCYCLIC COMPOUNDS 95
Substituted cyclohexenones are important synthetic targets and are most commonly
prepared via the Robinson annulation. In recent years, considerable research has been
directed toward the development of alternative routes to cyclohexenones based on the Diels-
Alder reaction. Most of these methods have been based on the application of highly
functionalized dienes as 47t components, 96 and depending on the choice of diene, routes to
cyclohexenones with electron-withdrawing groups at C-4, C-5, and C-6 are now available.
Danishefsky has developed an elegant route to cyclohexenones in which oxygen
substituted dienes participate in [4+2] cycloadditions with electron-deficient dienophiles.97
The oxygen substituents impart a high degree of reactivity and regiospecificity on the dienes
which combine with activated dienophiles to produce cyclohexene intermediates. Subsequent
treatment of the enol ether with acid hydrolyzes the vinylogous hemiketal to produce
substituted cyclohexenones. Note that this methodology produces cyclohexenones in which
the dienophile activating (W) group ends up at the C-4 position of the cyclohexenone ring.
OR OR
WJ7 W +
RO - RO
Even moderately reactive dienophiles undergo cycloadditions with these unhindered,
electron-rich dienes. For example, 2-methylcyclohexenone reacts with Danishefsky's diene at
200 *C to afford the substituted cyclohexanone intermediate 151. Exposure of the reaction
mixture to a 3:1 THF:0.005 N HCl solution then produces the cis-fused cyclohexenone 152 in
95. Portions of this chapter are published in ref 79b.96. (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley: New York, 1990. (b) Petrzilka,
M.; Grayson, J. I. Synthesis 1981, 753. (c) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400.
53
47% yield (eq 39). Subsequently, Danishefsky reported the synthesis of chiral l-alkoxy-3-
trimethylsilyloxy-1,3-dienes for asymmetric Diels-Alder reactions. 98' 99 In a related method,
Rawal has reported that chiral l-amino-3-silyloxy-1,3-dienes participate in Diels-Alder
reactions with a,p-unsaturated aldehydes and esters to afford substituted cyclohexenones in
high ee.100
HMe3S!O xylene Me 3SiO
+ 200 *C 20 h
47%OMe 0 MoO 0
149 150 151
I HCI (39)
H
00
152
Trost has investigated a novel Diels-Alder approach for the preparation of
cyclohexenones in which 2-alkoxy-3-thio-substituted dienes undergo [4+2] cycloadditions
with electron-poor dienophiles to afford cycloadducts that can be converted to
cyclohexenones by enol ether hydrolysis, oxidation of the sulfide to a sulfoxide, and thermal
elimination. This methodology generates cyclohexenones in which the dienophile W-group is
ultimately found at the C-5 position of the new ring.' Trost has employed this approach for
the synthesis of carvone (156) as illustrated in Scheme 17.
97. (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807. (b) Danishefsky, S.; Kitahara, T. J.
Org. Chem. 1975, 40, 538.98. (a) Bednarski, M.; Danishefsky, S. J Am. Chem. Soc. 1983, 105, 6968. (b) Danishefsky, S.; Bednarski,
M.; Izawa, T.; Maring, C. J. Org. Chem. 1984, 49, 2290. (c) Bednarski, M.; Danishefsky, S. J. Am.
Chem. Soc. 1986, 108, 7060.99. For other examples of chiral alkoxy dienes, see: (a) Trost, B. M.; O'Krongly, D.; Belletire, J. L. J. Am.
Chem. Soc. 1980, 102, 7595. (b) Lubineau, A.; Queneau, Y. J. Org. Chem. 1987, 52, 1001. (c) Gupta, R.
C.; Larsen, D. S.; Stoodley, R. J.; Slawin, A. M. Z.; Williams, D. J. J. Chem. Soc., Perkin Trans. 1 1989,739. (d) Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 7630. (e) Boehler, M.
A.; Konopelski, J. P. Tetrahedron 1991, 47, 4519.100. Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165.101. Trost, B. M.; Vladuchick, W. C.; Bridges, A. J. J. Am. Chem. Soc. 1980, 102, 3554.
54
Oy W RO ZQW RO + W
Scheme 17
0 0MeO A 2h MeO
PhS 75% PhS
153 154 (4:1 regioisomers)155
1) Ph 3P=CH 2 , THF2) HCO 4, aq CH 3CN3) NaH, Mel, THF4) mCPBA5) (MeO) 3P, A
21%
carvone 0156
A third objective of interest in this area of Diels-Alder based cyclohexenone synthesis
has been the development of vinylketene equivalents capable of participating as diene
components in [4+2] cycloadditions. In contrast to the Diels-Alder strategies summarized
above, these reactions would produce cyclohexenones in which the dienophile W-group
would appear at the C-6 position of the new cyclohexenone ring. Unfortunately, the tendency
of vinylketenes to form only [2+2] cycloadducts with alkenes (eq 40) and the intrinsic
instability of these ketenes generally precludes their direct use as [4+2] enophiles, as
discussed in Chapter 1.24
55
W 0, W
[2+2] C + [+ (40)
Vinylketene acetals have found use as vinylketene surrogates; however, the scope of
this methodology is somewhat limited because of the sensitivity of these compounds and the
fact that the s-cis conformation required for cycloaddition is usually disfavored in these Z-
substituted dienes. Substitution by an electron-donating alkoxy- or silyloxy-group at C-3
dramatically increases the reactivity of vinylketene acetals, and these activated dienes readily
participate in [4+2] cycloadditions with a variety of dienophiles.C"lO 2 For example, the
oxygenated diene 157 combines rapidly with dimethylacetylene dicarboxylate (DMAD) in
refluxing benzene to afford substituted phenol 159 in 89% yield (eq 41).
OMe CO 2Me benzene OH
+ 80 *C 30 min- OP CO2Me (41)
Me 3SiO CO2Me 89% HO CO2 Me
157 158 159
In 1980, our laboratory reported that (trimethylsilyl)vinylketene participates as a
reactive enophile in [4+2] cycloadditions with standard electron-deficient Diels-Alder dienes.
This chemistry is summarized later in this section. Several years later, Ghosez reported that
N-silylated silylvinylketenimines can function in a similar manner as vinylketene equivalents
in Diels-Alder reactions with olefinic and acetylenic dienophiles.103 In an example of this
interesting cycloaddition, ketenimine 160 combines smoothly with methyl acrylate at 150 'C,
and subsequent protodesilylation with potassium fluoride in refluxing methanol yields
dihydroaniline 162 (eq 42). Hydrolysis to the cyclohexenone 163 can then be effected using
1.2 N HCl. Ketenimine 160 also reacts in [4+2] cycloadditions with methyl crotonate,
various acetylenic esters, and napthoquinones.
102. Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.103. Differding, E.; Vandevelde, 0.; Roekins, B.; Van, T. T.; Ghosez, L. Tetrahedron Lett. 1987, 28, 397.
56
Si(i-Pr)h,N 1)150*C NH2(i-Pr)Si C CO 2Me 2) KF-MeOH (i-PrhSi C02MO
70%
160 161 162
1.2 N HCICCi 4
(42)
70%
0(i-Pr)hSi CO 2Me
163
[4+2] Cycloadditions of TAS-Vinylketenes
Several years ago, our laboratory reported the first synthesis and isolation of
(trimethylsilyl)vinylketene (92)." As expected, 92 fails to engage in typical ketene [2+2]
cycloadditions and instead participates as a diene component in [4+2] cycloadditions with
electron-deficient alkenes and alkynes. The ketene carbonyl group is predicted to donate
electron density into the diene system (see resonance hybrid, below), activating this system
for [4+2] cycloadditions with standard electron-deficient dienophiles.
6 OR3Si CRSI C
The trimethylsilyl group confers only a weak directing effect on Diels-Alder reactions
of 1- and 2-(trimethylsilyl)-1,3-dienes 10 4 and is not expected to contribute significantly to the
regiochemical course of TAS-vinylketene reactions. As mentioned above, the carbonyl
oxygen of the vinylketene is predicted to function as an electron-donor substituent and
104. (a) Fleming, I.; Percival, A. J. Chem. Soc., Chem. Commun. 1976, 681. (b) Fleming, I.; Percival, A. J.Chem. Soc., Chem. Commun. 1978, 178. (c) Jung, M. E.; Gaede, B. Tetrahedron 1979, 35, 621. (d) Batt,D. G.; Ganem, B. Tetrahedron Lett. 1978, 3323. (e) For a review on the application of silyl-substitutedconjugated dienes in synthesis, see: Luh, T.-Y.; Wong, K.-T. Synthesis 1993, 349.
57
therefore is expected to control the regiochemical outcome of these cycloadditions. In fact,
early experiments by Howard Sard in our laboratory confirmed the expectation that [4+2]
cycloadditions with TAS-vinylketenes would be highly regioselective.7 3 For example, methyl
propiolate (164) reacts smoothly with (trimethylsilyl)vinylketene (92) to afford 3-
(trimethylsilyl)salicylate (165) as a single regioisomer (eq 43). Note also that the cycloadduct
undergoes facile protodesilylation when treated with trifluoroacetic acid at room temperature
to yield 166.
, CO toluene OHMe3Si C 2 95 "C 63 h Me3Si CO2Me
+ |
45%92 164 165
TFA, CH 2Cl225 *C 24h (43)
78%
OH
CO 2 Me
166
(Trimethylsilyl)vinylketene also reacts with olefins such as diethyl fumarate and N-
phenylmaleimide to afford cyclohexenones. Unfortunately, the scope of these reactions is
restricted by the limited thermal stability of this vinylketene (which begins to decompose at
temperatures above 95 *C), and ketene 92 does not undergo cycloadditions with less reactive
dienophiles in satisfactory yield.
Originally, substituted TAS-vinylketenes were not available by the
dehydrohalogenation route. However, development of the photo Wolff rearrangement of a-
silyl-a-diazo ketones made the more robust, substituted ketenes available. We expected that
these derivatives would engage in [4+2] cycloadditions with a broader range of substrates
than (trimethylsilyl)ketene, providing a useful synthetic route to highly substituted
cyclohexenones and phenols. We therefore undertook a systematic investigation of Diels-
Alder reactions of these substituted TAS-vinylketenes, focusing on the scope and
58
stereochemical course of the process. Initial experiments by Jennifer Loebach of our
laboratory confined the feasibility of these reactions and, subsequently, my research goal has
been to extend the scope of this interesting methodology by investigating the use of different
substituted TAS-vinylketenes, other reactive dienophile partners (including heterodienophiles,
see Chapter 4), and Lewis acid catalysts.
The relative reactivity of different TAS-vinylketenes was explored initially by
examining their cycloadditions with the reactive dienophile, dimethyl acetylenedicarboxylate
(DMAD). In a typical reaction, a degassed toluene solution of TAS-vinylketene 111 and 1.0
equiv of DMAD was heated at 150 *C for 16 h in a threaded Pyrex tube sealed with a Teflon
cap. Concentration and purification by chromatography on silica gel provided the expected
phenol 167 in nearly quantitative yield (eq 44). Protodesilylation of this cycloadduct
proceeded readily (80% yield) upon exposure to 20 equiv of TFA in dichloromethane at room
temperature for 2 h.
'0 CO 2Me 150 C OH(+-Pr)3Si C toluene 16 h (i-Pr)3 Si , CO 2Me
+I ICO 2Me 98% CO 2Me
111 158 167
20 equiv TFACH2CI2 0rt 2 h
80%
OH
CO 2MO
CO2M.
168
Interestingly, cycloaddition with the corresponding triethylsilyl derivative 112
afforded a mixture of products tentatively assigned as the silyl ether 169 and phenol 170 (eq
45). In this case, the acidity of the phenolic product apparently promotes desilylation of the
cycloadduct at the elevated reaction temperature. This process is not as facile in the case of
the triisopropysilyl derivative 111 because of the steric bulk of the silyl group.
59
EtS "*0 C 2Me 150 0C OSEt3 OHEt3SirC,0 CO2Metoluene 16 h CO02Me O CO 2Me
+ C02| + C0M (45)
CC2Me
112 158 169 170
29% 20%
Further experiments investigated by Loebach confirmed that a wide range of
substituted TAS-vinylketenes would react with DMAD. As discussed in Chapter 2,
cyclobutenones undergo 4n-electrocyclic ring opening to afford TAS-vinylketenes. We were
interested in using this method to generate ketenes in situ from cyclobutenones for reaction
with DMAD. As illustrated in eq 46, heating 2-silylcyclobutenones 125 and 126 in toluene at
reflux in the presence of DMAD affords phenols 171 and 172 in good yield. Presumably,
cyclobutenones 125 and 126 undergo an in situ electrocyclic ring opening to generate TAS-
vinylketenes which then react in [4+2] cycloadditions. Lower yields of the desired phenols
were obtained when the reactions were conducted at higher temperatures and butenolide side
products were isolated (see Chapter 2 for a discussion). It is interesting to note that in both
cases, none of the rearranged products (akin to 169 and 170) were observed.
R3Si o toluene 2. R0 C2Me OH3 reflux 42-55 h R3 RSi CO2Me
Ph Ph X CO2 Me Ph CO2Me
125 (R = Me) 158 171 (R = Me) 63%
126 (R = Et) 172 (R = Et) 55%
The scope of TAS-vinylketene cycloadditions encompasses other reactive dienophiles
such as ethyl cyanoacrylate, nitroethylene, and cyanoallene. Since ethyl cyanoacrylate bears
two electron-withdrawing groups, the cycloadditions of this dienophile were not informative
with regard to the stereochemical course of the Diels-Alder reactions of TAS-vinylketenes.
Simple acrylate derivatives proved insufficiently reactive, so we turned our attention to
reactions of nitroalkenes. TAS-Vinylketene 111 combines with nitroethylene in a
regioselective Diels-Alder reaction, but because of the high acidity of the doubly activated a'
60
proton in the cycloadduct, the product is expected to undergo equilibration. Therefore, the
identity of the major product does not necessarily provide insight into the stereochemical
course of the cycloaddition stop. No such ambiguity is associated with the reaction of 2-
nitropropene with ketene 111 (eq 47), and indeed this cycloaddition produces a single
cycloadduct in 35% yield whose structure was established by Loebach as 174 by analysis of
'H NMR coupling constant data and an NOE study.
0 toluene O(i-PraSi C"' N02 reflux 116 h (i-Pr)3 Si N02
+ y/CH 3 (47)35%
CH3
111 173 174
This result indicates that as in other Diels-Alder reactions, cycloadditions involving
TAS-vinylketenes follow the Alder endo rule and prefer transition states in which the
dienophile activating group adopts an endo orientation (175) relative to the diene system (eq
48). Disappointingly, vinylketene 111 failed to react with less reactive dienophiles such as
N-phenylmaleimide and chloroacrylonitrile; in each case, complex mixtures of products were
obtained.
0 2N
(i-Pr)Si C=0 endo , 174 (48)
175
Other work by Loebach established that monoactivated allenes are excellent partners
for [4+2] cycloadditions with TAS-vinylketenes, providing access to phenolic products that
could otherwise be produced only by cycloadditions with less reactive acetylene dienophiles.
For example, addition of cyanoallene to TAS-vinylketene 111 in toluene at 150 *C gave a
single product in good yield, which NOE studies revealed to be not the expected o-
(triisopropylsilyl)phenol, but rather the isomeric silyl ether 178 (Scheme 18). Isomerization
61
of the presumed initial cycloadduct 175 to 178 may proceed via the intermediacy of the a-
silyl ketone 177. 1,3-Silyl shifts of a-silyl ketones to form silyl enol ethers are well-known
processes.105
Scheme 18
.0(i-Pr)3Si C'
[4+2]cycloaddition
0R3Si CN
I -
H2C=C=: CNH
150 "Ctoluene 31 h
67%
0RASi CN
(i-Pr)hSiOCN
178
1, 3-silylshift
0R3Si CN
I
- 175 176 177
We anticipated that other reactive allenes might also participate in cycloadditions with
TAS-vinylketenes and so we next examined the reaction of acetylallene with the vinylketene
generated in situ by electrocyclic ring opening of 125. Thus, a degassed toluene solution of
acetylallene (179) and cyclobutenone 125 was heated at reflux for 20 h, and the desired
cycloadduct was isolated in 37-45% yield (eq 49). None of the silyloxy product resulting
from. 1,3-silyl rearrangement was observed as in the cyanoallene case. Disappointingly,
reaction of acetylallene with the triisopropylsilyl-substituted ketene 111 led to even lower
yields (25-26%) of the phenolic product.
105. See: Munschauer, R.; Maas, G. Angew. Chem., Int. Ed. Engl. 1991, 30, 306 and references therein.
62
o [ 0 OH OMe3Si 0 toluee Me 3Si Me 3SI+ ~reflux 20h (9
Ph ' J437-45%9)
L125 179 180 181
The acetylallene for this study was prepared in two steps by the method of Buono (eq
50).10 First, reaction of 2,4-pentanedione 182 with triphenylphosphine-bromine in
dichloromethane affords a mixture of (E/Z)-2-bromo-4-oxo-2-pentene 183 and a
triphenylphosphine oxide hydrobromide salt, which is precipitated by the addition of ether.
After concentration of the filtrate, the resulting vinyl bromide 183 is used directly in the next
step without further purification. Dehydrobromination of 183 occurs upon treatment with
triethylamine in ether. The solvent is removed by distillation and pure acetylallene (179) is
isolated in 59-65% yield following careful distillation at reduced pressure. The colorless
liquid (bp 62 *C, 80 mmHg) polymerizes readily and must be stored over a small amount of
hydroquinone to inhibit this undesired reaction.
(000 0 PPh3-Br2 Br 0Et3N If<(0
57-65%overall
182 183 179
Rigby has reported the application of the [4+2] cycloadditions of vinyl isocyanates
and benzyne107 as a useful method for the preparation of phenanthridinones (eq 51).'O8 We
expected that this highly reactive acetylene species might react with TAS-vinylketenes in
good yield to afford interesting polycyclic products.
106. (a) Buono, G. Synthesis 1981, 872. (b) Constantieux, T.; Buono, G. Org. Synth., in press.107. For reviews on the preparation and [4+2] cycloadditions of arynes, see: (a) Gilchrist, T. L. In The
Chemistry ofFunctional Groups; Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1983, pp383-419. (b)Hart, H. In The Chemistry of Triple-Bonded Functional Groups, Supplement 12; Wiley: New York, 1994,pp 1017- 1134.
63
0NH 2 Pb(OAc)
4 C 1N% CH 2CI 2 rt N HN(
N I:5 .C a x (51)N 58%
184 185 186 187
Benzyne can be generated by a variety of methods. Rigby obtained the best results
with Diels-Alder reactions of vinyl isocyanates when the benzyne was generated by Pb(OAc) 4
oxidative decomposition of 1-aminobenzotriazole (184). With this method for benzyne
preparation, reaction can occur over a broad range of temperatures (-78 *C to 55 *C).
However, side reactions sometimes occur in the presence of the lead tetraacetate, a powerful
oxidizing agent, and acetic acid is a byproduct of the reaction. Generation of benzyne with
lead tetraacetate is believed to proceed through a nitrene intermediate (188, eq 52).
Fragmentation of the ortho-fused benzene derivative expels two molecules of nitrogen, lead
diacetate, and acetic acid, none of which compete for benzyne.
NH 2 N:I I
N Pb(OAc)4 N (
// N - -,*-.-/ (52)N Pb(OAC) 2 N - 2N2
2 AcOH184 188 186
1-Aminobenzotriazole (184) is commercially available but is quite expensive, so for
our study this benzyne precursor was prepared by amination of benzotriazole according to the
procedure of Campbell and Rees (eq 53).109 Thus, treatment of triazole 189 with
hydroxylamine-o-sulfonic acid in aqueous potassium hydroxide affords 1-aminobenzotriazole
in 13% yield (lit. 38%).
64
108. (a) Rigby, J. H.; Holsworth, D. D.; James, K. J. Org. Chem. 1989, 54, 4020. (b) Rigby, J. H.; Holsworth,D. D. Tetrahedron Lett. 1991, 32, 5757.
109. Campbell, C. D.; Rees, C. W. J Chem. Soc. C 1969, 742.
H
NN
N
189
NH 2OSO 3H
aq KOH
13%
NH2
NN
N
184
Unfortunately, attempted reaction of TAS-vinylketene 190 with benzyne (generated as
described above by the lead tetraacetate method) led only to unreacted starting material and
the benzyne dimer biphenylene (192, eq 54). Apparently, reaction of TAS-vinylketenes with
benzyne occurs more slowly than benzyne dimerization.
Et 3S
Ph
190
OH
+ 0 'a i (,Et3Si )
186 191
192
In an attempt to expand the scope of the [4+2] cycloadditions of TAS-vinylketenes to
include dienophiles of low reactivity, the application of Lewis acids as catalysts for the
reaction was examined. It should be noted that Lewis acids have found considerable use as
catalysts for [2+2] cycloadditions of TAS-ketenes with aldehydes." Unfortunately, attempts
to promote the cycloaddition of vinylketene 111 with methyl acrylate or DMAD using either
Me2AlCl or BF 3-OEt2 at various temperatures proved unsuccessful (see Table 2). In all cases,
extensive decomposition of 111 was observed and none of the desired cycloadduct was
detected.
110. See ref 58 and the following: Brady, W. T.; Saidi, K. J. Org. Chem. 1979, 44, 733.
65
(53)
Et3Si V
184Pb(OAC)4
CH 2C2
reflux
38%126
(54)
Attempted Lewis Acid Catalysis of Diels-Alder Cycloadditions of TAS-Vinylketenes
Entry
1
Ketene
111
E
2 111
3 111
4 111
5 111
6 111
ienophile Conditions
DMAD 1.0 equiv Me2AlClCH2CL2, 0 *C to rt
DMAD 1.0 equiv Me2A1ClCH2Cl2, -78 *C to rt
DMAD 0.1 equiv BF3-OEt2CH2Cl 2, 0 'C to rt
DMAD 0.1 equiv BF 3-OEt2
CH2 Cl 2 , -78 *C to rt
methyl 1.0 equiv Me2AlClacrylate CH2 Cl 2, 0 *C
methyl 0.1 equiv BF 3-OEt2acrylate CH2Cl 2, 0 'C
Result
rapid decompositionof the ketene
rapid decompositionof the ketene
rapid decompositionof the ketene
rapid decompositionof the ketene
rapid decompositionof the ketene
rapid decompositionof the ketene
TAS-vinylketenes bearing electron-donating substituents are expected to exhibit
increased reactivity in [4+2] cycloadditions, expanding the scope of this methodology to
include less activated dienophiles. Our initial attempts to prepare 3-alkoxy TAS-vinylketenes
have thus far been unsuccessful (as discussed in Chapter 2), however, further studies are
planned to explore this important area.
R3Si C 0.
RO
We have shown that TAS-vinylketenes undergo highly regioselective [4+2]
cycloadditions with reactive olefinic and acetylenic dienophiles to produce highly substituted
cyclohexenones and phenols. The ketene carbonyl dominates in controlling the regiochemical
course of the reaction and the stereochemical course of these cycloadditions follows the Alder
66
Table 2
Entry
endo rule. The syntheses of oxygen and nitrogen heterocycles via the hetero Diels-Alder
reactions of TAS-vinylketenes is described in Chapter 4.
67
CHAPTER 4
APPLICATION OF TAS-VINYLKETENES AS DIENES IN THE DIELS-ALDER
REACTION: SYNTHESIS OF HETEROCYCLIC COMPOUNDS
The hetero Diels-Alder reaction is an extremely important method for the synthesis of
heterocyclic compounds."1 A wide variety of heterodienophiles participate in [4+2]
cycloadditions, including carbonyl compounds, imines, iminium salts, and azo- and nitroso
compounds. This methodology often allows the rapid construction of complex molecules
from simple starting materials and has been applied for the synthesis of many heterocyclic
natural products. In recent years, asymmetric versions of hetero Diels-Alder reactions have
also been reported.
As discussed in the preceding chaper, we have shown that TAS-vinylketenes take part
in [4+2] cycloadditions with olefins and acetylenes, and we anticipated that carbonyl
compounds and imines might also function as dienophiles providing efficient routes to
interesting heterocycles. This chapter describes the results of our investigation of the hetero
Diels-Alder reactions of TAS-vinylketenes, including a discussion of the scope,
stereochemical course, and mechanism of the process.
Diels-Alder Reactions with Carbonyl Dienophiles: Background
In 1949, Gresham and Stedman reported the first example of the oxa Diels-Alder
reaction of a carbonyl dienophile with a conjugated diene.1 1 2 Specifically, heating 2,4-
dimethyl-1,3-butadiene and formaldehyde affords 5,6-dihydropyran 194 in 60% yield (eq 55).
Unfortunately, similar reactions of diene 193 with higher aldehydes leads only to low yields
of products.
111. For reviews on the hetero Diels-Alder reaction, see: (a) Tietze, L. F.; Kettschau, G. Top. Curr. Chem.
1997, 189, 1. (b) Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;Pergamon Press: Oxford, 1991; Vol. 5, pp 401-449. (c) Boger, D. L. In Comprehensive OrganicSynthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 451-512. (d) Boger,D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic Press: San
Diego, 1987. (e) Waldmann, H. Synthesis 1994, 535.112. Gresham, T. L.; Stedman, T. R. J. Am. Chem. Soc. 1949, 71, 737.
68
0+ H ) H
193
A6,
60%
(55)
194
Later findings confirmed that simple 1,3-dienes react best with electron-deficient
carbonyl compounds. For example, diethyl oxomalonate (196) combines with 2-methyl-1,3-
butadiene to afford the pyran cycloadduct 197 in 80% yield (eq 56).113 Less reactive carbonyl
compounds will participate in [4+2] cycloadditions in the presence of Lewis acid catalysts or
under the application of high pressure.
-Ic +
195
0
EtO2C CO 2Et
196
CH 3CN130 *C 4 h
80%
(56)
CC2Et197
Vinylketene equivalents such as 198 have been shown to undergo Lewis-acid
catalyzed Diels-Alder reactions with aldehydes. For example, as illustrated in eq 57, electron-
rich diene 198 and amino aldehyde 199 combine in the presence of diethylaluminum chloride
to afford a 92:8 mixture of lactones 200 and 201.1 14
OSIMe3 0 EtAICI 0
OMe + H i-Pr 2 0-l i-Pr
MeO NHBoc 67-83% MeONHBoc
198 199 200
0
+0 -Pr (57)MeO&
MHBoc201
92: 8
113. Bonjouklian, R.; Ruden, R. J. Org. Chem. 1977, 42, 4095.
69
Diels-Alder Reactions of TAS-Vinylketenes with Carbonyl Dienophiles
We anticipated that TAS-vinylketenes would participate in oxa Diels-Alder reactions
with activated carbonyl compounds to afford aP-unsaturated 8-valerolactones. The proposed
oxa Diels-Alder reaction of TAS-vinylketenes was initially investigated by examining
cycloadditions with the highly reactive and commercially available oxadienophile diethyl
oxomalonate. In a typical reaction, an acetonitrile solution of silylketene 111 and 1.5 equiv of
diethyl oxomalonate (196) was heated at reflux for 15 minutes. Concentration and
purification by chromatography on silica gel afforded the desired a,P-unsaturated 6-
valerolactone 202 in 94% yield (eq 58). As shown in previous studies (Chapter 3), the ketene
carbonyl functions as an electron-donor substituent and directs the regiochemical course of
the reaction.
0(i-Pr)hSi C.0 CH 3CN (i-Pr)3SI
0 reflux 15 min 0 (58)A3 2 CO 2Et
EtO2C CO2Et 94% Ha CO 2Et
111 196 202
1H NMR spectral data supports the structural assignment for compound 202 and
includes a diagnostic resonance at 3.21 ppm (quartet) that corresponds to proton Ha on the
lactone ring. The IR spectrum contains a strong carbonyl stretching frequency at 1715 cm1
due to the lactone carbonyl. In addition, the 13C NMR spectrum exhibits characteristic
resonances for the aP-unsaturated lactone carbonyl carbon at 168.9 ppm, two alkenyl
carbons (166.6 and 122.0 ppm), and the C-2 carbon at 85.0 ppm.
The reaction of oxomalonate 196 with the cyclohexenyl TAS-ketene 110 also
proceeds smoothly to afford lactone 203 in 77% yield (eq 59). With this more sterically
hindered ketene, the reaction rate is slower and requires two hours in refluxing acetonitrile to
reach completion.
70
114. (a) Midland, M. M.; Afonso, M. M. J. Am. Chem. Soc. 1989, 111,4368. (b) Midland, M. M.; Koops, R.W. J. Org. Chem. 1990, 55, 4647. (c) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 5058.
0(i-Pr)3Si C"0 CH3CN (i-Pr)3SI
+ Oreflux 2 h 0 (59)
Et02C AC02Et 77% C2Et
110 196 203
TAS-Vinylketenes generated by the electrocyclic ring opening of cyclobutenones also
participate in oxa Diels-Alder reactions. For example, addition of oxomalonate 196 to a
refluxing acetonitrile solution of cyclobutenone 126 affords the predicted cycloadduct 205 in
excellent yield (eq 60).
Et3SI CH 3CN E C~ 1960 Et3SI%.
E P I reflux 15 h E C 196 Et00.. CO 2 Et (60)
[L Ph J 92% Ph CO 2 Et
126 204 205
As expected, unactivated carbonyl compounds such as pivaldehyde do not participate
in cycloaddition reactions with TAS-vinylketenes. Lewis acids have found considerable use
as catalysts for [2+2] cycloadditions of TAS-ketenes with aldehydes and we hoped that Lewis
acids might promote the oxa Diels-Alder reaction of TAS-vinylketenes.106 Unfortunately,
attempts to promote the cycloaddition of vinylketene 111 with pivaldehyde using ZnCl2
proved unsuccessful, resulting only in slow decomposition of the ketene; none of the desired
cycloadduct was observed. Previous attempts to catalyze Diels-Alder reactions of TAS-
vinylketenes with other Lewis acids gave similarly disappointing results (see Chapter 3).
Finding effective conditions for protodesilylation of the lactone cycloadducts required
a substantial amount of investigation. A variety of acidic conditions were explored for the
protodesilylation of lactone 202 (Table 3), but none resulted in clean removal of the
triisopropylsilyl group. However, protodesilylation of the triethylsilyl derivative 205
proceeds more easily. Thus, treatment of lactone 205 with 5 equivalents of methanesulfonic
acid in refluxing dichloromethane affords the desired lactone 206 in quantitative yield (entry
6, eq 61).
71
Protodesilylation of a-Silylcyclopentenones
EiEResult
no reaction, recoveredstarting material in 88% yield
no reaction
complex mixture
no reaction
complex mixture
100%
Cycloadditions with Imino Dienophiles: Background
In addition to carbonyl compounds, we were also interested in exploring the utility of
imines as dienophiles in [4+2] cycloadditions with TAS-vinylketenes. An enormous amount
of research has been devoted to the study of electron-deficient imines such as N-sulfonyl and
N-acylimines as well as iminium salts as dienophiles in the Diels-Alder reaction. These [4+2]
cycloaditions comprise an important strategy for the synthesis of nitrogen heterocycles.
Neutral imines generally react in [4+2] cycloadditions only with highly activated
dienes in the presence of a Lewis acid catalyst. Grieco has demonstrated that iminium salts
react with dienes in intermolecular [4+2] cycloadditions.115 The iminium salts are generated
in aqueous solution by the reaction of a primary amine with aqueous formaldehyde or by the
115. (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768. (b) Grieco, P. A.; Larsen, S. D.;Fobare, W. F. Tetrahedron Le#. 1986,27, 1975.
72
ritry Lactone
1 202
2 202
3 202
4 205
5 205
6 205
0Et3SI 0
Ph C02CO 2Et
205
Conditions
20 equiv TFACH 2Cl2, rt, 48 h
15 equiv MsOHMeOH, rt, 24 h
5 equiv TBAFTHF, rt, 1 h
20 equiv TFACH 2Cl2, rt, 5 days
1 equiv TBAFTHF, rt, 30 min
5 equiv MsOHCH2Cl2, reflux, 15 h
5.0 equiv MsOHCH2C 2
reflux 15 h
Et100%
0
Ph CO 2EtCO 2Et
Table 3
206
(61)
reaction of an aldehyde with an ammonium chloride solution. Unfortunately, iminium ions
derived from higher aldehydes are generally much less reactive.
Unactivated imines were of particular interest to our group as heterodienophiles for
Diels-Alder reactions with TAS-vinylketenes. Simple, uncharged imines are usually not
reactive as heterodienophiles in Diels-Alder cycloadditions unless partnered with reactive,
electron-rich dienes in the presence of a Lewis acid.' 16 For example, Brassard's oxygenated
diene 198 (a vinylketene equivalent) combines with chiral imine 207 with the aid of a Lewis
acid to form the lactam 208 in good yield (eq 62).117
OMe
OSiMe3 +
MeO 1
198
i-Pr
N Y1CO2t-Bu
Ph H
207
Et2AICICH 2CI2
-78 C to rt
84%
95% d.e.
o CO 2t-Bu
N I-Pr
MeOL74Ph
208
Danishefsky employed the imino Diels-Alder reaction as a key step in the total
synthesis of ipalbidine (Scheme 19).118 Reaction of vinylketene equivalent 210 with 1-
pyrroline in the presence of BF 3-OEt 2 affords the lactam intermediate 212. Reduction of the
lactam carbonyl and subsequent dehydration provides ipalbidine (213) in 78% yield.
116. For recent reviews on the imino Diels-Alder reaction, see ref 11 lb and: Boger, D. L.; Weinreb, S. M.
Hetero Diels-Alder Methodology in Organic Synthesis; Academic Press: Orlando, 1987; pp 35-71.
117. Waldmann, H.; Braun, M.; Drager, H. Tetrahedron: Asymmetry 1991, 2, 1231.
118. Danishefsky, S. J.; Vogel, C. J. Org. Chem. 1986, 51, 3915.
73
(62)
Scheme 19
LDA, THF-HMPT
CI2Et t-BuMe 2SiCI OSt-BuMe2 + No
MeO ~100% MeO / OEt
209 210 211
BF 3-Et 2O, CH 2C 2-78 OC to rt
40-45%
N 1) LiAIH 4-AIC 3 NN 2) BBr3, CH 2C 2 N
MO 78% Meo 0
ipalbidine213
We envisioned that the [4+2] cycloadditions of TAS-vinylketenes with imines might
provide another direct route to substituted 5,6-dihydro-2(lIH)-pyridones (a,p-unsaturated 3-
valerolactones).
It is well known that imines of the type R2C=NH are generally not stable.
Benzophenone imine (Ph2C=NH), however, is stable and is commercially available, and we
hoped that this ketimine would react in [4+2] cycloadditions with TAS-vinylketenes.
Unfortunately, when ketene 111 was heated with benzophenone imine in refluxing
acetonitrile, only a complex mixture of inseparable. products was obtained and none of the
desired lactam cycloadduct could be observed in the 1H NMR spectrum.
. Unlike N-H substituted imines, N-(trimethylsilyl)imines are quite stable under
anhydrous conditions. These imines are easily prepared and some can even be purified by
distillation at reduced pressure. Note that the cycloadduct derived from an N-
(trimethylsilyl)imine is expected to undergo protodesilylation under very mild conditions (e.g.
aqueous workup or silica gel chromatography) to afford the same products that would have
resulted from cycloaddition of the unstable imines of the type R2C=NH.
Few examples of [4+2] cycloadditions of N-(trimethylsilyl)imines have been reported
to date. Barluenga has reported that N-(trimethylsilyl)imines react as dienophiles in ZnCl 2 -
74
catalyzed [4+2] cycloadditions with 2-amino-1,3-dienes to afford tetrahydropyridones and 4-
piperidinones.119 For example, reaction of N-(trimethylsilyl)benzaldimine 215 with the
electron-rich chiral diene 214 affords enamine 216 which is converted on silica gel to the
enantiomerically enriched tetrahydropyridone 217 (eq 63). As suggested above, in these
reactions N-silylimines function as masked forms of the elusive imines of ammonia. Most
imines that are not substituted at nitrogen rapidly trimerize to the corresponding triazines.
OMe
ZnC " 1)NaHCO 3
NiMe3 THF N 2) SiO 2
Ph H 0Nme Ph 70%
82% e.e.
215 216
OMe
' NH
0 V Ph
217
The reaction of imines with ketenes has been exploited extensively for the synthesis of
P-lactams in the well known Staudinger reaction. N-(Trimethylsilyl)imines have also been
employed as participants in these [2+2] cycloadditions. In 1977, Birkofer described that
addition of N-(trimethylsilyl)benzophenone imine to diphenylketene affords the acyclic
intermediate 220 in quantitative yield; none of the P-lactam product was observed (Scheme
20). Heating N-(trimethylsilyl)benzaldimine with diphenylketene at 160 *C and subsequent
hydrolysis of the N-trimethylsilyl group provides P-lactam 222 in poor yield.2
119. (a) Barluenga, J.; Aznar, F.; Valdds, C.; Cabal, M.-P. J. Org. Chem. 1993, 58, 3391. (b) Barleunga, J.;
Aznar, F.; Valdds, C.; Martin, A. An. Quim. 1993, 115. (c) Barluenga, J.; Aznar, F.; Vald6s, C.; Martin,
A.; Garcia-Granda, S.; Martin, E. J. Am. Chem. Soc. 1993, 115,4403.
75
OMe
+
N
OMe
214
(63)
N' SIMe benzene+ reflux 30 min
100%
219
N'SiMe3 xylenePh H 160 C
1 12%
215
Me 3SiON
Ph /PhPh Ph
220
C
Ph Ph
218
0
Ph Ph
218
Panunzio reported that the [2+2] cycloadditions of ketenes (generated in situ from an
acid chloride) with N-(trimethylsilyl)imines is a useful method for the direct preparation of N-
H substituted azetidinones. For example, reaction of N-(trimethylsilyl)imine 224 with the
ketene derived from acid chloride 225 affords the acyclic azadiene intermediate 226 which
can be observed by analysis of the crude reaction mixture. Upon heating in refluxing toluene
for 6 h, cyclization occurs to afford exclusively the trans-substituted [-lactams 227 and 228 in
59% yield as a 80/20 mixture of the anti and syn isomers (Scheme 21).121
76
Scheme 20
0 SiMe0 N *Se3 H20
Ph f~Ph Ph
221
0NH
Ph ffPh Ph
222
120. Birkofer, L.; Schramm, J. Liebigs Ann. Chem. 1977, 760.121. Bandini, E.; Maretili, G.; Spunta, G.; Panunzio, M. Synlett. 1996, 1017.
Scheme 21
OSi(i-Pr)3 LiHMDSH heptane 0 *C
0
223
OSi(i-Pr)3H
N, SmN4SiMe
224
00 0
Ph 225
Et3N, 0 *Ctuen ~
0 rO OSI(i-Pr)3
PhNH
0 80:;227
20-
(i-Pr)3S1O
Ph N , N- ePh OSIlMe3
226
toluenereflux
59%
0 -O OSi(i-Pr)3
PhN H
0228
Panunzio found that syn selectivity can be obtained in the [2+2] cycloadditions of N-
(trimethysilyl)imines with ketenes by appending an alkoxy substituent on the ketene. For
example, reaction of imine 215 with the ketene derived from acid chloride 229 affords the cis-
substituted P-lactam 231 in 81% yield.122 Panunzio postulates that the cis-diastereoselectivity
results from the formation of a weak electrostatic bond between the imine carbon and the
ether oxygen. This interaction stabilizes the azadiene intermediate 230. A similar
electrostatic interaction had previously been proposed in an example of the classical
Staudinger reaction of an alkoxy-substituted ketene with an N-alkyl imine. 23
SiMe3
Ph" H
215
0Ph y0%)
CI229
Et3 N, 0 'Ctoluene
81%[.Bn
0, +H'Ph I
NMe 3SiO
230
BnO \Ph
0)NH
231
122. Bacchi, S.; Bongini, A.; Panunzio, M.; Villa, M. Synlett 1998, 843.123. Bose, A. K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron Lett. 1972, 4091.
77
(64)
Imino Diels-Alder Reactions with TAS-Vinylketenes
We anticipated that N-(trimethylsilyl)imines might participate as dienophiles in Diels-
Alder reactions. Described in the following section is our systematic investigation of the
imino Diels-Alder reactions of TAS-vinylketenes, including our studies of the scope,
stereochemical course, and mechanism of the process.
Reactions with N-(Trimethylsilyl)benzaldimine
To test the feasibility of the proposed silylimine [4+2] cycloadditions, we initially
examined the reaction of TAS-vinylketenes with the easily prepared N-
(trimethylsilyl)benzaldimine. To our immense delight, we found that the combination of
silylketene 111 and 1.5 equivalents of imine 215 in refluxing acetonitrile provides the desired
cycloadduct (tentatively assigned as the N-silyl isomer 232) and no catalyst is needed to
promote the reaction! The bond to silicon is easily hydrolyzed from the crude product 232
during purification on silica gel to afford lactam 233 in excellent yield (eq 65). Similarly, in
subsequent cases, protodesilylation of the initial crude products occurs during silica gel
chromatography.
,0 CH3CN 0(i-Pr)3Si C NSiMe 3 reflux 1.5 h (i-Pr)Sai NSiMe3
Ph H Ph
111 215 232
Si02 (65)79-83%
0(i-Pr)3Si NH
Ph
233
78
The N-(trimethylsilyl)benzaldimine substrate (215) was prepared using the procedure
of Hart (eq 66).124 Thus, treatment of benzaldehyde with lithium hexamethyldisilylamide in
hexane affords the desired silyl imine 215 in 90% yield (lit. 89%) after distillation at reduced
pressure. This yellow liquid can be stored at 0 *C indefinitely under anhydrous conditions.
Note that this reaction proceeds via a heteroatom variant of the Peterson olefination,
presumably via the four-membered transition state 234.
Li hexane+ 0 C to rt 10 min
Me 3SI 'SiMe 390%
LiO- ;SiMe 3
Ph H SiM03 ]234-234
'I-Me 3SiOLi (66)
NSiMe 3
Ph H
215
'H NMR spectral data supports the structural assignment of compound 233, including
a resonance at 4.77 ppm due to the C-6 proton and a multiplet at 2.21 ppm corresponding to
the C-5 proton. The N-H proton is observed as a broad singlet at 5.51 ppm. These
assignments are consistent with data previously reported by Marson for the related lactam 235
in which the C-5 and 6 substituents are trans rather than cis (Figure 3).114
124. Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289.
79
0
Ph AH
5.51 (br s)
0+(i-Pr)3Si H
PhH
Hb CHa4
4.77 (d, J= 3.6 Hz)
5.62 (br s)
0
NH56Ph2 "H
3 aH3C Hb 1 a
14.28 (dd, J= 11 and 7 Hz)2.59 (in)
235
Proof of the cis-stereochemistry of 233 was obtained from 'H NMR coupling constant
data and an NOE study (Figure 4). The proton at C-6 (Ha) is assigned to be on the same side
of the ring as proton Hb due to the observed equatorial-axial coupling constant (Jab = 3.6 Hz).
Also, irradiation of Ha results in a 9% enhancement of Hb, providing further confirmation that
Ha and Hb are on the same side of the ring. Although the trans isomer was not available for
comparison of NOE data, later NOE studies on an analogous compound support this
assignment.
Figure 4
Irradiate
9% +H3C Ha Si(i-Pr)3
Hb NHC Ph 'H3C
233
0%
'IH3C Ha Si(i-Pr)3
Hb tN.
H3C
Irradiate
80
Figure 3
2.21 (m)
233
The same cycloaddition was run with 1.0 equiv of imine 215 rather than 1.5 equiv as
in eq 65. However, in this case the time for the reaction to reach completion increased from
1.5 h to 3 h and the yield decreased slightly to 72%. Therefore, in most of the [4+2]
cycloadditions examined subsequently, a slight excess of imine was employed.
The rate of the [4+2] reaction was found to be noticeably faster in acetonitrile than in
toluene. Reactions in toluene were only approximately 50% complete by TLC analysis after
the same period of time in which the acetonitrile based reactions were finished. This increase
in rate in the more polar solvent suggests that the mechanism of the reaction proceeds via a
transition state involving more charge separation than the ground state (vide infra). We later
discovered that the hetero Diels-Alder reactions of TAS-vinylketenes proceed rapidly and at a
lower temperature in the absence of solvent. For example, ketene 112 combines with imine
215 (1.5 equiv) at room temperature in two hours (no solvent) to afford the cis-substituted
lactam 236 in 76% yield (eq 67). Again, an NOE study confirmed the cis assignment of the
substituents on this triethylsilyl-substituted lactam: irradiation of the C-6 proton resulted in a
6% enhancement of the neighboring C-5 proton.
0EtNSi C 0 no solvent EtSI Et 3i ,SiMe 3 rt 2 h; (67
+ N 0 X 6(67)A Si02 5 6
Ph H 7.Ph76%
112 215 236
The Diels-Alder reactions of N-(trimethylsilyl)benzaldimine and two other TAS-
vinylketenes were explored. Silylketene 110 undergoes cycloaddition with imine 215 to
afford the exo-substituted product 237 (as identified by an NOE study) in 91% yield (eq 68).
Irradiation of the C-1 proton (Ha) results in no enhancement of the C-8a proton (Hb).
However, one C-8 proton (He) exhibits a 7% enhancement, confirming the trans assignment
of lactam 237 (Figure 5).
81
CH 3CNN 'SiMO3 reflux 25 h;
Ph H Si0 2
91%
215
0(i-Pr)3S* NH
. Ph8
237
Assuming that these reactions follow a concerted cycloaddition mechanism, it would
appear that the steric effect of the cyclohexenyl substitutent in ketene 110 leads to a
preference for the transition state in which the phenyl group is exo (238, eq 69), whereas the
less hindered ketenes 111 and 112 prefer the transition state in which this group has the endo
orientation.
Me3Si,N
(i-Pr)3Si -.Ph
H
exo 237 (69)
238
82
(i-Pr)3Si C"O
110
Figure 5
(68)
7% Irradiate
H Ha SI(i-Pr)3
NHd Ph'HHb
t 2370%
[4+2] Cycloaddition of silylimine 215 with the TAS-vinylketene generated via in situ
electrocyclic ring opening of cyclobutenone 126 also was successful and afforded the lactone
239 in 84% yield after purification by column chromatography (eq 70).
SIM CH 3CNPN 0SIM3 reflux 45 min;
Ph ) H Si0 2
84%
215
0EtASi H
Ah[:Ph
239
(2) Reactions with N-(Trimethylsilyl)cinnamaldimine
Clearly, the imino Diels-Alder reactions of TAS-vinylketenes have a broad scope with
respect to the ketene. We next were interested in investigating the scope of the reaction with
regard to imino dienophiles. We began this study with a reaction of a vinyl-substituted imine,
N-(trimethylsilyl)cinnamaldimine (240), which was prepared according to the procedure of
Colvin.12 5 Treatment of commercially available (and pleasantly aromatic) cinnamaldehyde
with LiHMDS followed by trapping with chlorotrimethylsilane affords imine 240 as a yellow
liquid in 59% yield (lit. 95%) after distillation at reduced pressure.
Reaction of TAS-vinylketenes 111 and 110 with aldimine 240 occurs almost
instantaneously at room temperature. Under these solvent-free conditions, the cycloadducts
241 and 242 were obtained in 78% and 73% yield, respectively (Scheme 22).
125. Colvin, E. W.; McGarry, D.; Nugent, M. J. Tetrahedron 1988, 44, 4157.
83
Et 3SI 0
Ph
126
(70)
no solvent+ MO3S I N rt 15min;
SiO 2
78%240 Ph
no solvent+ MO3S I N rt 10min;
H SiO2
Ph 73%240
0(i-Pr)3Si NH
156
Ph241
0(i-Pr)3Si NH
181
Ph242
Support for the sterochemical assignments for the cis isomer 241 and the trans isomer
242 was obtained by NOE experiments. Irradiation of the C-6 proton (Ha) of 241 resulted in a
9% enhancement of the corresponding C-5 proton (Hb), indicating that the two protons have a
cis orientation. However, irradiation of the C-1 proton (Ha) of 242 resulted in no
enhancement of the C-8a proton (Hb) and instead showed an 8% enhancement of H0 , thereby
indicating that the lactam ring is trans-substituted (Figure 6).
Figure 6
9% Irradiate
I Ha Si(i-Pr)3HbH3C N 0
H3C HPh
241
8% Irradiate
He Ha Si(i-Pr)3
Hd Hb | H
t Ph
0% 242
84
Scheme 22
(i-Pr)3Si
111
110
(3) Reactions with N-(Silyl)ketimines
To further investigate the scope of this interesting cycloaddition, we next turned our
attention from aldimines to ketimines. Would this class of more highly substituted imines be
effective partners for cycloadditions with TAS-vinylketenes? We first undertook a study of
the reaction of TAS-vinylketenes with N-(trimethylsilyl)benzophenone imine (219), prepared
via the procedure of Rochow.126 Addition of benzonitrile to an ethereal solution of
phenyllithium and subsequent treatment with chlorotrimethylsilane affords the N-silyl imine
219 in 77% yield (lit. 55%) after purification by distillation at reduced pressure (eq 71).
PhLi, Et2Ort 15 min;
Ph-C=N Me 3SiCI
rt 22 h
243 77%
,'S!Me3NSIO
Ph Ph
219
We were delighted to discover that ketimine 219 reacts with ketene 111 to afford the
lactam 244 in 79% yield (eq 72). This cycloaddition proceeds at a significantly slower rate
(refluxing CH 3CN, 18 h) than the comparable reaction with aldimine 215 (refluxing CH3CN,
15 min), probably due to the increased steric demands of 219.
(i-Pr)3S! C
111
M03Si, I+ M3 hN
Ph Ph
219
CH 3CNreflux 18 h;
Si0 2
79%
0(i-Pr)3S1 NH
Ph
244
The cyclohexenyl-substituted ketene 110 also combines smoothly with imine 219
(refluxing acetonitrile, 24 h) to provide the desired lactam 245 in 66% yield (eq 73).
126. Chan, L.-H.; Rochow, E. G. J. Organomet. Chem. 1967, 9,-231.
85
(71)
(72)
(i-Pr)3 Si C 0
110
Me3SiN
Ph Ph
219
Silylketenimines were also studied as potential heterodienophiles in Diels-Alder
reactions with TAS-vinylketenes. Silylketenimines 247 and 249 were prepared by the method
of Watt. 127 Thus, treatment of the requisite nitrile with lithium diisopropylamide and
subsequent trapping with t-butyldimethylchlorosilane affords the ketenimine products in
excellent yields (Scheme 23). Unfortunately, reaction of these imines with ketene 111
afforded only a complex mixture of products.
Scheme 23
LDA, THF-78 *C;
t-BuMe 2SiCI-78 *C to rt 25 h
91%
Ph>
H3C Sit-BuMe2
247
G- C=N
248
LDA, THF-78 *C;
t-BuMe2SiCI '=NiSit-BuMe2-78 *C to rt 16 h
84% 249
(4) Reaction with Alkyl-Substituted N-(Silyl)Imines
In all successful cases thus far, the azadienophile component has had one or more
stabilizing phenyl substitutents. We next investigated the reaction of TAS-vinylketenes with
alkyl-subsituted N-silylimines, which are notably less stable than the aromatic-substituted
derivatives. In 1987, Cainelli reported the preparation of enolizable N-(trimethylsilyl)imines
127. Watt, D. Synth. Commun. 1974, 4, 127.
86
CH 3CNreflux 24 h;
SiO 2
66%
0(i-Pr)3S" NH
PhPh
245
(73)
Ph>
H3C
246
which must be generated and trapped in situ at temperatures of -30 *C or below."' For
example, addition of isobutyraldehyde to a -30 *C solution of LiHMDS generates N-
(trimethylsilyl)isobutyraldimine (250, eq 74).
SLiHMDS N.SiM0 3
THF -40 0CH H (74)
250
Attempts to use this procedure for in situ reactions with TAS-vinylketenes led to
disappointing results. Generation of the imine by the aforementioned procedure and
subsequent addition of ketene 111 at -78 0C followed by slow warming to room temperature
afforded a complex mixture of inseparable products. At low temperatures, the vinylketene
and imine probably do not undergo cycloaddition and as the temperature increases, the imine
likely isomerizes to the more stable enamine which may react with the ketene by alternative
pathways initiated by nucleophilic addition.
In contrast to this result, we have found that nonenolizable alkyl-substituted imines
serve as good partners for [4+2] cycloadditions with TAS-vinylketenes. Reaction of
pivaldehyde with LiHMDS at ambient temperature affords N-(trimethylsilyl)pivaldimine
251115 in 46-48% yield after distillation at reduced pressure. Treatment of ketene 110 with
imine 251 using our standard cycloaddition conditions (CH 3CN, reflux, 24 h) afforded none
of the desired lactam product. However, heating the reaction mixture in a sealed tube at 110
*C for 90 h did provide the desired cycloadduct in 56% yield (eq 75). This imine appears to
slowly decompose at these elevated temperatures, and therefore it was necessary to utilize
three equivalents of the dienophile which were added in two portions of 1.5 equiv each.
128. (a) Cainelli, G.; Giacomini, M.; Panunzio, M.; Martelli, G.; Spunta, G. Tetrahedron Lett. 1987, 28, 5369.
(b) Cainelli, G.; Giacomini, D.; Galletti, P.; Gaiba, A. Synlett 1996, 657.
87
(i-Pr)3Si C' 0
110
Me3Si'N
H t-Bu
251
0CH 3CNI
110C 90h (i-Pr)3 S* NHSiO2 -I8a~
t-Bu8.
56%252
Not surprisingly, the combination of hindered ketene 110 with the sterically
encumbered imine 251 results in formation of the trans-substituted product. This
stereochemistry was confirmed by an NOE study in which irradiation of the C-1 proton (Ha)
results in a 5% enhancement of one C-8 proton (He). No enhancement of the C-8a proton
(Hb) is observed, confirming the trans assignment (Figure 7).
Figure 7
5% Irradiate
H Ha Si(i-Pr)h
Hd H H0Hb H
t0% 252
(5) Reactions with N-Alkyl-Substituted Imines
. We next chose to study the cycloadditions of N-alkyl imines and TAS-vinylketenes.
This class of imines is generally prepared by addition of an amine to an aldehyde or ketone.
For example, treatment of benzaldehyde with methylamine in refluxing benzene with water
separation via a Dean-Stark trap provides N-methyl benzaldimine (253) in 89% yield (lit. 87-
95%, eq 76).129
129. Moffett, R. B. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, pp 605-608.
88
(75)
benzene
H2N-CH3 + 0 5 *C to reflux NCH3 (76)Ph H Dean-Stark Ph H
89%253
Reaction of ketene 111 with N-alkyl imine 253 does proceed successfully, but affords
an inseparable 3:1 mixture of diastereomeric lactams 254 and 255 in 71% yield (eq 73).
2530 CH 3CN00
(i-PrhSi C'' 120 0C 42 h (i-Pr)3S H3 (i-Pr)3SI CH36 N 6 W(77)
71% Ph Ph
111 254 3:1 255
SYBYL Calculations of the ground state energy of the cis and trans-substituted
lactams 254 and 255 were performed in an attempt to determine which conformational isomer
has a lower ground state energy for each product. For the modeling studies, the
triisopropylsilyl group of lactams 254 and 255 was replaced with a proton in order to simplify
the calculations and because the silyl group probably does not significantly influence the
difference in ground state energies of lactams 254 and 255. These molecular modeling
studies indicate that for the cis-substituted lactam, it is conformer 255a (with the phenyl
group in the equatorial position) which is the thermodynamically most stable conformation.
The difference in energy between 255a and 255b (AG = 1.46 kcal/mol) should result in
approximately a 90:10 ratio of conformational isomers. The trans-substituted lactam 254
slightly favors a conformation in which the phenyl group adopts an equatorial position (254a).
The small difference in energy between 254a and 254b (AG = 0.388 kcal/mol) indicates that
compound 254 exists as approximately a 2:1 ratio of conformational isomers 254a and 254b.
89
H3C Ha Si(i-Pr)3H3C N>
I Ph *CH3Hb P
4.205 kcal/mol
254a
H3C C H3 (-P)
Hb I rP*
Ph
majorcycloadduct
H3 C Ha S1(1-Pr) 3
Hb N
I3 Ph CH3
3.451 kcal/mol
255a
minorcycloadduct
4.593 kcal/mol
254b
Hb IHHCH Si(i-Pr)h
Ph H
4.914 kcal/mol
255b
The identity of the major cycloadduct was confirmed by an NOE study (Figure 8).
Irradiation of the C-5 methyl group of the major isomer (254, favored conformation shown)
results in a 5% enhancement of the proton at C-6, confirming that these two groups reside on
the same side of the ring (trans-substituted). However, irradiation of the C-6 proton (Ha) of
the minor isomer gives a 7% enhancement of the C-5 proton (Hb). Thus, the minor isomer
does in fact have both protons on the same side of the ring (cis-substituted). Although no
enhancement of Ha is expected upon irradiation of the C-5 methyl group, a 3% enhancement
is in fact observed, but this value is not considered to be a significant NOE enhancement.
Figure 8
Irradiate
7% 4H3C Ha Si(i-Pr)3
Hb? N, 0
HC Ph CH3
minor isomer
255
3%
1H3C Ha SI(i-Pr)3
Hb? N,C6
HCPh CH3HC0
IIrradiate
90
5%
Irradiate 4H3C a Si(i-Pr)h
H3 C-tN.wPh CH 3
Hbmajor isomer
254
In order to determine experimentally which isomer is the thermodynamically favored
product, we investigated the base-induced isomerization of the mixture of products. Thus,
treatment of the 75:25 (trans:cis) mixture of isomers 254 and 255 with potassium t-butoxide
in t-butanol results in isomerization to provide predominately the cis-substituted isomer in a
72:28 cis:trans ratio (eq 78), indicating that the cis isomer is the thermodynamically favored
product in agreement with our molecular modeling calculations. In fact, based on the
calculated difference in energies between 254a and 255a (AG = 0.754) we would predict to
observe a similar ratio of approximately 75:25.
0 0(i-Pr)3Si ,CH 3 (i-Pr)3Si ,CH 3 KOt-Bu
N + N t-BuOH5II 5 6 W 254 + 255 (78)
Ph rt 18h
28: 72254 255
75:25
Unfortunately, other more hindered alkyl-substituted imines did not participate in
[4+2] cycloadditions with TAS-vinylketenes. For example, reaction of ketene 111 with
enantiomerically enriched imine 258 (prepared from benzaldehyde and (S)-a-methyl-
benzylamine) at 125 to 150 *C afforded mostly unreacted ketene and imine starting materials.
None of the desired cycloadduct was observed by 'H NMR. Reaction of 2-phenyl-1-pyrroline
2590 with ketene 111 (CH 3CN, 110 *C, 35 h) also gave disappointing results, providing a
complex mixture of products.
N Ph
Ph H Ph
258 259
130. A sample of this imine was kindly provided by Marcus Hansen. For details on the preparation of thiscompound, see: Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Maryanoff, B. E. Organic Syntheses
1997, 75, pp 215-222.
91
(6) Cycloadditions with Other Azadienophiles
In the next phase of our study, we turned our attention to investigating electron-rich
and electron-deficient imine derivatives as partners in Diels-Alder reactions with TAS-
vinylketenes. First, electron-rich heteroatom-substituted imines such as amidines were
studied. Visiting scientist Iwao Okamoto examined the [4+2] cycloadditions of these
nucleophilic imines without success. For example, treatment of ketene 111 with amidine 260
at room temperature resulted in some disappearance of the starting material but no
cycloadduct could be observed by 'H NMR (eq 79). Preliminary experiments have been
carried out to survey the possible utility of other azadienophiles, however these compounds
(shown in Figure 9) also resulted in no reaction with ketene 111.
.0 0(i-Pr)3SI C' Me (i-Pr)3SI ,Me
+N (79)
Me 2N H
111 260 261
Figure 90
N'NM2 N Ph N11i1
Ph H Me 2N H 0
262 263 264
Electron-deficient imine derivatives also do not participate in [4+2] cycloadditions
with TAS-vinylketenes. Addition of glyoxylate 268 to ketene 111 in refluxing acetonitrile for
22 h afforded none of the desired product. Preparation of this imine was accomplished by a
two-step procedure as described by Colvin (Scheme 24).12' First, silylation of glycine methyl
ester hydrochloride by treatment with base and then a silyl chloride affords the N-silylamine
266. Subsequent chlorination of 266 with t-butyl hypochlorite followed by base induced
elimination forms the imine 268.
92
Scheme 24
1) Et 3N, DMAP
2) t-BuMe 2SiC
26%
,SiMe 2t-BuN DBU
MeO 2C H 77%
268
H% NSiMe 2t-Bu
'Co2Me
266
'It-BuOCI
C1. ,SiMe 2 t-BuN
CO2Me
267
Mechanism of Imino Diels-Alder Reactions
What is the mechanism of the Diels-Alder reaction of TAS-vinylketenes and imines?
One can envision alternate pathways ranging from a Diels-Alder concerted mechanism to a
true stepwise process, as illustrated in Scheme 25. In the stepwise process, the imine would
first add to the ketene to afford an acyclic intermediate that would then undergo electrocyclic
closure to afford the lactam.
Scheme 25
[R3SI Ci
+ N
RASI G..0R'N R
Concerted
R a RR3SI 8+/R
Asynchronousconcerted
R331 R
Np
L Stepwise
IR3S N 0R
I93
H eNH3CI
CO2Me
265
]
Marson has reported a convenient method for the formation of the 5,6-dihydro-2(1IH)-
pyridone ring system by a [5+1] condensation of a 3-alkenamide with an aldehyde or ketone
that occurs via an intermediate similar to the one proposed above for the stepwise mechanism
for the [4+2] cycloaddition. 3 1 For example, amide 269 and benzaldehyde combine in the
presence of polyphosphoric ester (PPE) to form intermediate 270 which cyclizes to afford
exclusively the trans-substituted lactam 235 in 63% yield (eq 80). Recall that our related
[4+2] cycloaddition of ketene 111 with imine 215 affords only the cis-substituted product
233.
PPE [ O-P 0
NH2 + 0 35*C 24h IrO H (80)
H .1k Ph Ph - :Ph
269 270 235
With respect to the stepwise mechanism (which would involve nucleophilic attack of
the imine on the ketene), it is important to note that amines are much more nucleophilic than
imines. In order to examine whether a stepwise mechanism is feasible, we first studied the
nucleophilic addition of amines to (TAS)ketenes. We found that diethylamine adds rapidly to
(triisopropylsilyl)ketene at room temperature (CH 3CN, 20 min). TAS-Vinylketenes also react
quickly with diethylamine, however the rate of this addition is slower than the addition of
amine with TAS-ketenes. For example, TAS-vinylketene 112 reacts with diethylamine in
acetonitrile when heated at 50 *C for 20 min to afford a mixture of isomers (271-273) that
result from nucleophilic addition of the amine to the TAS-vinylketene (eq 81). Because
nucleophilic addition to TAS-vinylketenes does occur under conditions comparable to those
employed in our imine cycloadditions, we cannot immediately rule out the possibility of a
stepwise mechanism in the [4+2] cycloaddition in which the imine would act as a nucleophile
and attack the ketene, followed by cyclization in a second step.
131. Marson, C. M.; Grabowska, U.; Fallah, A. J. Org. Chem. 1994, 59, 291.
94
Et 2 NH 0
______ Et3SI NEt 2 +CH 3CN +
50 *C 20min
112 271
0Et3SI N R2
272
0Et3S1 NEt2 (81)
273
Also relevant to the mechanism question are the [2+2] cycloadditions of ketenes with
imines. It is well-established that alkyl- and aryl-ketenes react with imines to form P-lactams
in a process commonly known as the Staudinger reaction.132 In a typical example, acid
chloride 274 undergoes in situ dehydrohalogenation to form methylketene which
subsequently reacts with imine 275 to afford the cis-substituted P-lactam 276 in good yield
(eq 82).133 The stereochemical outcome of these [2+2] cycloadditions is sometimes difficult
to predict and depends greatly on the structure of the imine and ketene, the solvent, base,
mode of ketene generation, and temperature as well as other factors.
H COPh
WA
Et 3N
80-90%
275
COPh
0N0 R e
276
The Bose reaction, a variation of the Staudinger reaction in which an aminoketene
reacts with an imine, affords 3-amino-substituted P-lactams. For example, combination of an
amino-substituted ketene (generated in situ from anhydride 277) reacts with imine 278 in a
[2+2] cycloaddition to form 3-amino-2-azetidinone 280 after hydrolysis (eq 83).34
132. For a review of the formation of P-lactams by [2+2] cycloaddition, see: (a) The Organic Chemistry of D-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; Ch. 6, pp 295-368. (b) Dugat, D.; Just, G.; Sahoo, S.Can. J. Chem. 1987, 65, 88.
133. (a) Paloma, C.; Aizpura, J. M.; Lopez, M. C.; Aurrekoetxea, N.; Oiarbide, M. Tetrahedron Lett. 1990, 31,6425. (b) Paloma, C.; Ontoria, J. M.; Odriozola, J. M.; Aizpurua, J. M.; Ganboa, I. J. Chem. Soc., Chem.Commun. 1986, 161.
134. Sain, B.; Baruah, J. N.; Sandhu, J. S. J. Heterocyci. Chem. 1984, 21, 257.
95
Et 3Si C-
0 cl
274
(82)
0OOEt Ph H RHN Ph H21 PhRHN + Oyt P EtN PTSA (83)
0 0 N N0 NDMB 0 DMB DMB
277 278 279 280R = -C(CH)CHCO(OEt)
The mechanism of these important [2+2] cycloadditions has been the subject of
intense scrutiny and the reactions are generally believed to proceed via a stepwise mechanism.
In fact, experiments have been reported in which the intermediate zwitterion was trapped with
ethanol. 35 The substitutents on the ketene presumably determine the direction of attack by
the imine based on steric considerations. Because the trans conformation of the imine is
preferred, formation of the zwitterionic intermediate and subsequent conrotatory ring closure
generally affords the cis-substituted P-lactams.
As mentioned previously, [2+2] cycloadditions of ketenes and N-
(trimethylsilyl)imines are known to proceed via a stepwise mechanism because often the
acyclic intermediate can be observed spectroscopically or, in some cases, isolated. In these
examples, addition of a TAS-ketene to an imine first generates a characterizable acyclic
intermediate that, upon heating, cyclizes to an azetidinone. Surprisingly, no reactions of
(trialkylsilyl)ketenes with N-(trimethylsilyl)imines have been reported to date. We believed
that the rate of such a reaction would provide an important value for comparison with our
[4+2] cycloadditions of (trialkylsilyl)vinylketenes with N-(trimethylsilyl)imines. In fact, we
found that heating (triisopropylsilyl)ketene (281) with N-(trimethylsilyl)benzaldimine 215 at
70 'C resulted in slow reaction and was only approximately 30% complete (by TLC analysis)
after 3 days. However, when the reaction temperature was increased to 140 'C for 3 h, we
were able to isolate the [2+2] adduct 283 in 72% yield (eq 84).
2150 no solvent 0 SiMes3C1 140 *C 3 ha (O %+,SiMe3 N (4
A~ N(i-Pr)3S1 H 72% (i-Pr)hSi Ph (i-Pr)3S' Ph
281 282 283
96
Presumably, this [2+2] reaction proceeds by a stepwise mechanism as do known
reactions of TAS-imines with ketenes. The initially formed trans, cis-zwitterionic compound
isomerizes to zwitterionic intermediate 282 which then undergoes conrototory ring closure to
afford the trans-substituted P-lactam 283. Since the conrotatory ring closure in this
cycloaddition affords the trans-substituted P-lactam, we would expect (and in fact do observe)
formation of the cis-substituted product from the disrotatory ring closure in the [4+2]
cycloaddition of ketene 111 with imine 215 (eq 65).
Because the [4+2] cycloadditions of imines with TAS-vinylketenes are much faster
than the related stepwise [2+2] cycloaddition of imines with TAS-ketenes it is possible that
the TAS-vinylketene reactions are proceeding via a completely different mechanism, a
concerted process. As noted earlier, the reactions proceed at a faster rate in polar than in non-
polar solvents, and thus the reaction would follow an asynchronous concerted mechanism in
which a significant separation of charge occurs in the transition state (Figure 10). This
charged intermediate would be stabilized by the presence of a polar solvent.
Figure 10
8 *0R3SI #"-SiM03
'N 8S
R
Further investigations are underway in our laboratory to determine the mechanism of
the [4+2] cycloaddition and to explain the interesting stereochemical observations made in the
studies described in this chapter.
Protodesilylation of Lactam Cycloadducts
Multiple attempts were made to protodesilylate the triisopropylsilyl-substituted
lactams 233 and 252 (Table 4). Although some of these conditions effectively removed the
triisopropylsilyl group, the desired product could not be isolated in >95% purity (entries 1, 5,
6).
135. Moore, H. W.; Hernandez, L.; Chambers, R. J. Am. Chem. Soc. 1978, 100, 2245.
97
Table 4
Entry
1
2
3
4
Table 5 details our attempts to protodesilylate the triethylsilyl-substituted lactams 239
and 236 which cleaved more readily than the triisopropylsilyl derivatives. Clean removal of
the triethylsilyl-group can be accomplished by treatment with 5 equiv of methanesulfonic acid
in refluxing dichloromethane (entries 3 and 4, eq 85).
Table 5 Protodesilylation of (Triethylsilyl)-Substituted Lactams
Entry Cycloadduct Conditions Result
1 239 20 equiv TFA 14% yield; 239 wasCH 2 C 2 , rt 25h recovered in 86% yield
2 239 5 equiv TBAF no reactionTHF, rt 3 days
3 239 5 equiv MsOH 55% yield of 245CH 2Cl 2 , reflux 4 h
4 236 5 equiv MsOH 83% yield of 285CH 2C 2, reflux 6 h
98
5
6
7
8
9
Protodesilylation of
Cycloadduct
233
233
233
233
233
233
252
252
252
(Triisopropylsilyl)-Substituted Lactams
Conditions Result
20 equiv TFA complete conversionCH 2C12, rt 20 h to 246, <95% purity
5 equiv TBAF complex mixtureTHF, reflux 1 h
1.1 equiv CsF no reactionCH 3CN, reflux 20 h
20 equiv MsOH no reactionMeOH, reflux 4 h
20 equiv MsOH complete conversionCH 2Cl 2, reflux 1.5 h to 246, <95% purity
5 equiv MsOH complete conversionCH 2Cl 2, reflux 17 h to 246, <95% purity
10% aq. HCl no reactionTHF, rt 2 h
oxalic acid no reactionMeOH, rt 22 h
1.1 AlCl 3 no reactionCH 2C 2, rt
MsOHCH2C12
Et 3Si NH reflux 4 h HI NHPh Ph 55% Ph Ph
239 284(85)
o MsOHEt 3Si CH 2C12
NH reflux 6 h NH
Ph 83% Ph
236 285
Conclusion
We have shown that TAS-vinylketenes participate in oxa and imino Diels-Alder
reactions with a variety of heterodienophiles. As shown in previous work, the ketene
carbonyl dominates in controlling the regiochemical course of these reactions. Particularly
interesting is the stereochemical course of these cycloadditions: with less hindered dienes the
endo product is obtained and with more bulky vinylketenes the exo product forms.
Investigations are ongoing to determine whether the mechanism of the imino [4+2]
cycloaddions proceeds via a stepwise mechanism or an asynchronous concerted transition
state which is stabilized in the presence of a polar solvent. Overall, we have shown that TAS-
vinylketenes function as interesting four-carbon dienes in Diels-Alder cycloadditions to afford
X, P-unsaturated 6-valerolactones and -lactams.
99
CHAPTER 5
TAS-VINYLKETENES AS FOUR-CARBON COMPONENTS
IN A NEW [4+1] ANNULATION STRATEGY
Introduction
The invention of new methods for the construction of five-membered rings continues
to be a problem of considerable importance in organic synthesis.136 Many biologically active
natural products incorporate a cyclopentenone ring as a major structural feature and
cyclopentyl systems serve as valuable synthetic intermediates in routes to many classes of
compounds. Five-membered rings can be synthesized by a variety of different methods,
including the Nazarov cyclization,'3 7 the Pauson-Khand cyclization of olefins with alkynes,13 8
[3+2] coupling reactions,139 the [3+2] annulation,'40 intramolecular aldol condensations, and
vinylcarbene insertion into C-H bonds.14' Only a few [4+1] annulation strategies have been
reported to date, one example being the methodology base on oxyanion and carbanion-
accelerated vinylcyclopropane rearrangements developed in our laboratory.142 43 This
chapter outlines our work on the stereoselective [4+1] annulation strategy for the synthesis of
136. For reviews, see: (a) Paquette, L. A. Top. Curr. Chem. 1984, 199, 1. (b) Ramaiah, M. Synthesis 1984,529. (c) Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89, 1467.
137. (a) Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B.M.; Fleming, I., Eds.; Pergamon Press:New York, 1990; Vol. 5, p 751. (b) Habermas, K. L.; Denmark, S. E. In Organic Reactions; Paquette, L.A., Ed.; Wiley: New York, 1994; Vol. 45, pp 1-158.
138. (a) Schore, N. E. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:New York, 1990; Vol. 5, p 1037. (b) Schore, N. E. In Organic Reactions; Paquette, L. A., Ed., Wiley:New York, 1991; Vol. 40, pp 1-90.
139. (a) Noyori, R.; Shimizu, F.; Fukuta, K.; Takaya, H.; Hayakawa, Y. J. Am. Chem. Soc. 1977, 99, 5196. (b)Noyori, R.; Yakoyama, K.; Hayakawa, Y. J. Am. Chem. Soc. 1973, 95, 2722.
140. (a) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992, 57, 6094. (b) Danheiser, R. L.;Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1981, 103, 1604. (c) Danheiser, R. L.; Carini, D. J.; Fink, D.M.; Basak, A. Tetrahedron 1983, 39,935. (d) Danheiser, R. L.; Fink, D. M. Tetrahedron Lett. 1985, 26,2513. (e) Danheiser, R. L.; Takahashi, T.; Bert6k, B.; Dixon, B. R. Tetrahedron Lett. 1993, 34, 3845.
141. (a) Karpf, M.; Huguet, J.; Dreiding, A. S. Helv. Chim. Acta 1982, 65, 13. (b) Williamson, B. L.;Tykwinski, R. R.; Stang, P. J. Am. Chem. Soc. 1994, 116, 93.
142. Reviewed in: Bronson, J. J.; Danheiser, R. L. Charge-Accelerated Small Ring Rearrangements. InComprehensive Organic Synthesis; Paquette, L. A., Ed.; Pergamon Press: Oxford, U. K., 1991; Vol. 5, pp999-1035. A related intramolecular [4+1] annulation based on thermal vinylcyclopropane rearrangementshas been developed by Hudlicky; see: Hudlicky, T.; Reed, J. W. Rearrangements of Vinylcyclopropanesand Related Systems. In Comprehensive Organic Synthesis; Paquette, L. A., Ed.; Pergamon Press:Oxford, U. K., 1991; Vol. 5, pp 899-970.
143. Rigby recently reported a [4+1] heteroannulation based on the addition of dimethoxycarbene to vinylisocyanates; see: Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996, 118, 12848.
100
substituted cyclopentenones based on the reaction of TAS-vinylketenes with nucleophilic
"carbenoid" reagents such as sulfur ylides and diazo compounds (eq 86).144
40 0R3Si C"0 *LRSW
RI + LR3 RSK? 440 (86)
2 R' R2
(L = leaving group)
[4+11 Annulations with Sulfur Ylides and Diazo Compounds
Our plan for the application of TAS-vinylketenes to the synthesis of five-membered
rings called for their reaction with nucleophilic carbenoid reagents to generate dienolate
species that would then cyclize to the desired cyclopentenones. Several classes of carbanionic
nucleophiles are known to add smoothly to simple silylketenes (including
(trimethylsilyl)ketene itself), 145 and we therefore anticipated that TAS-vinylketenes would
participate in the proposed [4+1] annulation provided that carbenoid reagents of suitable
reactivity could be identified.
Among the several classes of carbenoid reagents we have examined, sulfur ylides146
and diazo compounds have thus far proved most effective for the desired [4+1] annulation.
Concurrently with our studies, Tidwell has found that diazo compounds add to silylated
bisketenes in a related process to produce cyclopentene-1,3-diones and 5-methylene-2(5H)-
furanones.147 As illustrated in eq 87, reaction of bisketene 286 with diazomethane affords a
mixture of dione 287 (22%) and furanone 288 (63%). Reactions of bisketene 286 with
(trimethylsilyl)diazomethane and phenyldiazomethane (PhCHN2) provide only substituted
cyclopentene-1,3-dione products.
144. Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9690.145. For examples, see refs 31, 52, and 55.146. Reviewed in: Trost, B. M.; Melvin, L. S. Sulfur Ylides; Academic Press: New York, 1975.147. Colomvakos, J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J. J. Org. Chem. 1996, 61,
9522.
101
Me 3Si C-O
Me3SXC"O%
CH 2N2 _
Et2Ort 2 h
286
0
Me 3Si
Me 3Si 0
28722%
+ M 3Si
Me 3Si CH 2
28863%
Jennifer Loebach of our laboratory initially investigated the new [4+1] annulation
strategy of TAS-vinylketenes with sulfur ylides and diazomethane compounds (Table 6). In
a typical reaction, addition of 1.05 equiv of dimethylsulfonium methylide to ketene 111 in 1:1
THF-DMSO at 0-25 *C for 1.5 h gives the desired cyclopentenone 289 in 75% yield after
chromatographic purification (entry 1). Dimethyloxosulfonium methylide also combines with
111 to produce cyclopentenone 289, though in lower yield (entry 2). Diazomethane reacts
with TAS-vinylketene 111 in a similar fashion to afford the cyclopentenone product in
excellent yield (entry 3). Protodesilylation of annulation product 289 was readily achieved by
exposure to methanesulfonic acid in methanol at 25 *C for 3 h to afford 3,4-
dimethylcyclopentenone in 95% yield (eq 88).
Table 6
(i-Pr)3S j Cr1 0S(P-Pr)3Si
111 289
Carbenoidreagent
G)i G
Me 2S- CH 2
CH 2N2
Conditions
1:1 THF-DMSO0 to 25 *C 1.5 h
1:1 THF-DMSO0 to 25 *C 1.5 h
CH2C3-120 to 25 C 3 h
Yield
75%
43%
96%
102
(87)
Entry
1
2
3
0 20 equiv MsOH 0(i-Pr)3Si MeOH rt 3 h (88)
95%
289 290
Optimizing conditions for the addition of the analogous isopropyl sulfur ylide proved
to be nontrivial. Initially, reaction of diphenylsulfonium isopropylide (291) with ketene 111
was attempted using our standard conditions (0 *C to rt, 1 h) and resulted in formation of the
desired product, but the cyclopentenone 292 could not be isolated in >95% purity. Attempts
to protodesilylate the crude product and then isolate and purify the resulting 3,4,5,5-
tetramethylcyclopentenone also were unsuccessful. Effective removal of the triisopropylsilyl
group from cyclopentenone 292 occurs in the presence of 5 equiv of TBAF (refluxing THF, 3
h) but, unfortunately, the desired product is not stable to silica gel purification and also could
not be isolated in >95% purity. Therefore, we returned to the [4+1] annulation step in an
attempt to obtain pure cyclopentenone 292 directly. It occurred to us that the isopropylide
291 is probably less stable than the methylide derivative previously studied (Table 7, entry 1).
In fact, when ylide 291 was generated at a lower temperature (-20 *C versus 0 *C) smooth
reaction with TAS-vinylketene 111 ensued to afford the desired cyclopentenone 292 in 57%
yield after chromatographic purification (eq 89).
G 0i0 Ph 2S-CMe2 291
THF (i-Pr)3S! (89)-20 *C to rt
57%111 292
Diphenylisopropyl sulfonium fluoroborate (the precursor to ylide 291) was prepared
by the method of Nadeau. Reaction of diphenyl sulfide and isopropyl iodide in the presence
of silver fluoroborate (0 *C to rt, 2.5 h) afforded 18-31% yield (lit. 55%) of the ylide
precursor 295 as a crystalline white solid.148 Treatment of this sulfonium salt with t-BuLi in a
148. Nadeau, R. G.; Hanzlik, R. P. Methods Enzymol. 1969, 15, 347.
103
50% THF-DMSO solution at -20 *C provides the bright yellow ylide 291 which must be used
immediately to avoid decomposition (eq 90).
GBF4/ AgBF 4 P / n-BuLi PG(
Ph2S + I-( - 1 Ph 2 S ~ Ph2S (90)0 Ctort THF -20 *C
293 294 18-31% 295 296
Commercially available (trimethylsilyl)diazomethane1 49 also reacts with TAS-
vinylketene 111 to afford the trans-substituted cyclopentenone 296 (eq 91). However, all
attempts to employ higher diazoalkanes and substituted TMS-diazomethanes in the [4+1]
annulation have been unsuccessful; in each case no significant reaction occurred and the TAS-
vinylketene was recovered unchanged. Fortunately, substituted sulfur ylides are more
nucleophilic and do react with TAS-vinylketenes in the desired fashion, providing access to
highly substituted cyclopentenones in good yield.
00 M03SiCHN2 0(i-Pr)3Si C CH 2C2 25C (i-Pr)3S1 .K SiMe3 (91)
32 h
84-92%111 296
Scheme 26 outlines several alternative pathways to account for the mechanistic course
of our [4+1] annulation. Addition of a carbenoid reagent to the vinylketene should be highly
stereoselective due to the shielding effect of the bulky trialkylsilyl group and should result in
the formation of the (Z)-enolate 297. Cyclization of this intermediate could produce the five-
membered ring product directly, although the planar structure of the dienolate system in 297
may not allow it to achieve an arrangement in which the R electrons are suitably situated for
direct backside displacement of the leaving group. An alternative pathway involves
ionization to produce the 2-oxidopentadienylic cation 298, which can then undergo
149. (a) Seyferth, D.; Dow, A. W.; Menzel, H.; Flood, T. C. J. Am. Chem. Soc. 1968, 90, 1080. (b) Shioiri, T.;Aoyama, T.; Mori, S. Organic Syntheses; Wiley: New York, 1993; Collect. Vol. 8, pp 612-615.
104
conrotatory 4n electrocyclic closure to generate the cyclopentenone product. Pentadienyl
cation electrocyclic ring closures are involved in the mechanism of the Nazarov cyclization,150
and epoxidation of vinylallenes produces cyclopentenones via electrocyclization of 2-
oxidopentadienylic cations analogous to 298.1 A similar mechanism is believed to occur in
the biosynthetic pathway for prostanoid synthesis by marine organisms in which conversion
of an allene oxide intermediate (300) to the cyclopentenone product (302) occurs via a 4n
electrocyclic closure of pentadienyl cation 301 (Scheme 27). A third pathway, proceeding via
the cyclopropanone intermediate 299 (either formed by direct internal displacement or
ionization and subsequent electrocyclic closure), cannot be excluded, particularly in view of
the finding that diazomethane adds to (trimethylsilyl)ketene to generate (trimethylsilyl)-
cyclopropanone in good yield.70
Scheme 26
internaldisplacement
0G
R3Si C-0-7 CH2L -3' I *
C297
ionization
0
299
ectrocyclic)ening
0
R3Si
298
[1,31sigmatropic
rearrangement
4;relectrocyclic
closure
direct internal displacement
150. For a review, see ref 137b.151. Kim, S. J.; Cha, J. K. Tetrahedron Lett. 1988, 29, 5613 and references therein.
105
R3SI
Scheme 27
OP0 CO 2H CO 2H
N.n-C 5H11 . - n-C5H11
300 301
0_
302 - C02Hpreclavuone A -
n-C5 H11
A notable feature of annulations involving substituted carbenoid reagents is the
exclusive formation of trans-4,5-substituted cyclopentenones. The stereochemical outcome of
the reactions of substituted sulfur ylides and diazo compounds is consistent with a mechanism
involving stereospecific conrotatory electrocyclic ring closure if one assumes that ionization
of the initial dienolate intermediate occurs to generate a 2-oxidopentadienylic cation 298 with
the C-1 substitutent cis to the oxygen atom to minimize nonbonded interactions. If a
mechanism involving concerted electrocyclization is indeed operative, then [4+1] annulations
beginning with TAS-vinylketenes with Z-substituted alkenyl groups should afford cis-4,5-
substituted cyclopentenones. Studies are underway in our laboratory to test this hypothesis.
Loebach found that both a-halocarbanions and "nitrenoid" equivalents (such as mesyl
azide) were ineffective as reagents for [4+1] annulations with TAS-vinylketenes. The
following sections describe other potential carbenoid reagents we explored to expand the
utility of this interesting annulation process.
[4+1] Annulation with Acetylides
In 1994, Jacobi reported the synthesis of methylenecyclopentenones in three steps
from enones via cyclization of an intermediate enynone with catalysis by c-tocopherol
106
(vitamin E).15 2 For example, enynone 304 (prepared from 303 as outlined in Scheme 28)
underwent cyclization to methylenecyclopentenone 306 upon heating at 125 *C in the
presence of a catalytic amount of Vitamin E. The enynones do not undergo cyclization in the
absence of a catalyst and the mechanism of the reaction is believed to proceed by a reductive
radical cyclization.
Scheme 28
200 *C 12 hvitamin E
55%
306
methylenomycin
OH
305
0
We hoped that acetylides might function as carbenoid reagents in [4+1] annulations
with TAS-vinylketenes to afford methylenecyclopentenones (309) in a single step.
Nucleophilic addition of an acetylide to the ketene carbonyl could afford intermediate 308
which might then undergo cyclization to the cyclopentenone 309 (eq 92).
R3Si , "
307
Li
R 3Si
R308
0
R3Si
309
(92)
Thus, treatment of ketene 111 with phenylacetylide 310 at -78 *C followed by slow
warming to -5 *C, addition of 1 equiv of BHT, and then heating at 50 'C for 35 min affords
152. (a) Jacobi, P. A.; Briehnann, H. L.; Cann, R. 0. J. Org. Chem. 1994, 59, 5305. (b) Jacobi, P. A.;Armacost, L. M.; Brielmann, H. L.; Cann, R. 0.; Kravitz, J. I.; Martinelli, M. J. J. Org. Chem. 1994 59,5292.
107
0
H
303
1) Li --
2) MnO 2
40%
0
304I
MeH OI M O
Me~ 0Me 3
vitamin E
the cyclopentenone 311 in 69-75% yield after chromatographic purification (eq 93).
Unfortunately, without addition of BHT the reaction gives only poor yields of the desired
cycloadduct. Therefore, the reaction probably proceeds via a radical mechanism (as described
by Jacobi) rather than by a carbanionic sequence of addition/cyclization in which the acetylide
functions as a carbenoid reagent. Other acetylides (such as trimethylsilylacetylide and -
C=CH) add to TAS-vinylketene 111, but only uncyclized addition products were observed to
form in these reactions by 1H NMR spectroscopy.
(i-Pr)3Si C"0 -78 *C to rt 0
+ ( Ph 2 h a (i-Pr)3 Si -- Ph (93)BHT
69-75%111 310 311
Samarium Iodide-Mediated [4+1] Annulations
Previous work by Loebach established that a-halocarbanions were ineffective as
carbenoid reagents in the [4+1] annulation. Recently, Inanaga reported that coupling of
carbonyl compounds with diiodomethane aided by SmI2 affords iodohydrins. For example,
reaction of benzylacetone (312) with diiodomethane in the presence of SmI 2 (room
temperature, 3 min) affords the iodo alcohol 313 in 96% yield (eq 94).
0 SM12 OH
+ CH212 S Phd (94)THF rt CH 213 min
312 96% 313
We hoped to employ a similar procedure for a [4+1] annulation with TAS-
vinylketenes to afford cyclopentenones (eq 95). Unfortunately, however, no observable
reaction occurred upon treatment of a THF solution of ketene 111 and diiodomethane with
SmI2.
108
0 -0(i-PrhSi Cj CH2I (i-Pr)3 Se H
SM12 N 'H \ipr~ (95)
111 314 289
Synthetic Elaboration of Cyclopentenones
As mentioned previously, silylcyclopentenone 289 can be protodesilylated in the
presence of methanesulfonic acid. We were interested in investigating other possible
synthetic transformations of the silyl group such as conversion to a halide which would
provide access to useful synthetic intermediates for cross-coupling and other reactions.
Negishi previously reported that trimethylsilyl-substituted cyclopentenones can be
converted to the x-bromo enones by treatment with N-bromosuccinimide.15 For example,
treatment of bicycle 315 with 2.5 equiv of NBS in DMF affords the bromo-substituted
compound 316 in 75% yield (eq 96).
SIM03 2.5 equiv NBS Br
o DMF c o (96)
315 75% 316
We anticipated that this transformation would occur at an extremely slow rate for
triisopropylsilyl-substituted cyclopentenones such as 289 as a result of steric hindrance.
However, in preliminary studies we found that the less-hindered triethylsilyl-substituted
cyclopentenone 317 does undergo conversion to the bromo-substituted compound when
treated with 3.5 equiv of N-bromosuccinimide in DMF (room temperature, 54 h), affording
the cyclopentenone 318 in 51% yield (eq 97). Not surprisingly, reaction with this triethylsilyl
compound occurs at a significantly slower rate than with the less hindered triisopropylsilyl-
substituted cyclopentenone 289. Other conditions for more efficient conversion of our
annulation products to vinyl bromides and iodides are under investigation in our laboratory.
153. Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J.Am. Chem. Soc. 1989, 111, 3336.
109
Et 3Si
317
3.5 equiv NBSDMF
rt 40 h
55%
Confirmation of the structural assignment of bromo cyclopentenone 318 was made by
analogy to previously reported spectroscopic data. As expected, the triethylsilyl resonances
of 317 do not appear in the 1H NMR spectrum of 318. Also, the 13C NMR spectrum of bromo
cyclopentenone 318 exhibits similar resonances as reported for bromo cyclopentenone 316
(Scheme 29).
Scheme 29
136.0198.4
1ISiMe3
0
214.6315
136.6
190.6SIEt3
5=0
213.2
317
116.9
187.1
i Br
202.6
316
122.9177.3
Br
200.4
318
Vollhardt reported that iodine monochloride (IC) 15 4 effectively cleaves carbon-silicon
bonds to produce the corresponding iodo compound. For example, treatment of
trimethylsilyl-substituted 319 with 2 equiv of iodine monochloride in carbon tetrachloride
yields the diiodo derivative 320 in 94% yield (eq 98).155 Presumably, iodination of the
154. Brisbois, R. G.; Wanke, R. A. In Encyclopedia ofReagentsfor Organic Synthesis; Paquette, L. A., Ed.;Wiley: New York, 1995; pp 2 8 1 1-2 8 12 .
155. Hillard, R. L.; Vollhardt, P. C. J. Am. Chem. Soc. 1977, 99,4058.
110
0
Br
318
(97)
silicon-substituted double bond affords a P-silicon stabilized cation. Subsequent cleavage of
the silicon group by attack with chloride generates the iodo alkene 320.
2 equiv ICI
1 ,C 0 E (98)E ) SiM03 94%-
319 320
Preliminary small-scale studies for the iodination of triethylsilyl-substituted
cyclopentenones utilizing similar conditions gave promising results. Treatment of
cyclopentenone 317 with 2 equiv of iodine monochloride (room temperature, 40 h) affords the
iodocyclopentenone 321 in -55% yield (not optimized, eq 99).
0 2 equiv ICI 0Et3S 1CH 2C12 I
rt 40 h
317 321
We envision that TAS-cyclopentenones could also undergo another interesting
transformation, the Tamao/Fleming cleavage of an alkoxy-substituted silyl compound to
afford a hydroxyl group.156 Organosilyl groups bearing at least one electronegative
substitutent have been widely used as synthetic equivalents of the hydroxy group. However,
successful conversion of a vinylsilane to the enol occurs only with specifically substituted
silicon groups. Currently, we are working to develop synthetic routes to TAS-vinylketenes
that contain the proper type of silyl group for this transformation. This methodology could
potentially be applied to the total synthesis of the natural product terpestacin (323) which
exhibits potential anti HIV activity (eq 100).157
156. For reviews on the use of silyl groups as synthetic equivalents of hydroxy groups, see: (a) Jones, G. R.;Landais, Y. Tetrahedron 1996,52, 7599. (b) Fleming, I. Chemtracts - Organic Chem. 1996, 9, 1.
157. Oka, M.; limura, S.; Narita, Y.; Furumai, T.; Konishi, M.; Oki, T. J. Org. Chem. 1993, 58, 1875.
ill
0 0
XR2Si HO
------------ ,,- (100)HO / HO
OH OH
322 323X = OR, F, CI terpestacin
Summary
We have described herein new, efficient routes to substituted TAS-vinylketenes via
the electrocyclic ring opening of cyclobutenones and the photochemical Wolff rearrangement
of a-silyl-a-diazo enones. TAS-Vinylketenes are reactive as four-carbon building blocks in
organic synthesis and behave as dienes in Diels-Alder reactions with reactive dienophiles,
activated carbonyl compounds, and imines. These ketenes also participate in [4+1]
cycloadditions with carbenoid reagents to form cyclopentenones. We are continuing to
explore promising new synthetic applications of TAS-vinylketenes for the total synthesis of
natural products and investigations are ongoing in our laboratory to develop other new,
efficient routes to these useful synthetic intermediates.
112
PART II
Experimental Section
113
General Procedures
All reactions were performed in flame-dried glassware under a positive pressure of
nitrogen or argon. Reactions were stirred magnetically unless otherwise indicated except
sealed tube reactions, which were not stirred. Air- and moisture-sensitive liquids and
solutions were transferred via syringe or cannula into reaction vessels through rubber septa.
Reaction product solutions and chromatography fractions were concentrated by using a Btichi
evaporator at ca. 20 mmHg unless otherwise indicated.
Materials
Commercial grade reagents and solvents were used without further purification except
as indicated below.
(a) Distilled under argon or vacuum from calcium hydride:
acetonitrile, benzene, dichloromethane, DMSO, diisopropylethylamine, hexane,
toluene, and triethylamine
(b) Distilled under argon or vacuum from sodium benzophenone ketyl or dianion:
tetrahydrofuran and diethyl ether
(c) Distilled under argon
trichloroacetyl chloride
(d) Other
N-Bromosuccinimide was recrystallized from water. 157 Alkyllithium reagents were
titrated in tetrahydrofuran or hexane at 0 *C using 1-10-phenanthroline as an indicator.15
Chromatography
(a) Analytical thin-layer chromatography (TLC)
Analytical thin-layer chromatography (TLC) was performed on Merck pre-coated
glass-backed 0.25 mm silica gel 60-F-254 plates. Visualization of spots was effected by one
or more of the following techniques: (a) ultraviolet irradiation, (b) exposure to iodine vapor,
157. Virgil, S. C. In Encyclopedia ofReagentsfor Organic Synthesis; Paquette, L. A.; Wiley: Chichester,1995, Vol. 1; pp 768-773.
158. Inorganic Synthesis 1963, 7, 10.
114
and (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed
by heating at ca. 200 'C.
(b) Column chromatography
Column chromatography was performed on ICN silica gel (32-60ptm).
Instrumentation
(a) Melting points
Melting points (mp) were determined with a Fischer-Johns melting point apparatus
and are uncorrected.
(b) Spectrometry
H NMR spectra were measured with Varian XL-300 (300 MHz), Unity-300 (300
MHz), and Unity-500 (500 MHz) instruments. Chemical shifts are expressed in parts per
million (6) downfield from tetramethylsilane (with the CHC13 peak at 7.26 ppm used as a
standard). 13 C NMR spectra were measured with Varian XL-300 (75 MHz), Unity-300 (75
MHz), and Unity-500 (125 MHz) spectometers. Chemical shifts are expressed in parts per
million (d) downfield from tetramethylsilane (with the central peak of CHC13 at 77.0 ppm
used as a standard). Infrared spectra (IR) were obtained using a Perkin Elmer 1320 grating
spectrophotometer.
(c) Elemental analyses
Robertson Laboratory, Inc. of Madison, New Jersey and E+R Microanalytical
Latoratory, Inc. of Parsippany, New Jersey performed elemental anlayses.
115
0
98 N2
98
0N2
SiEt2Ph
105
1-Diazo-1-(diethyl(phenyl)silyl)-3-methyl-3-penten-2-one (105).
A three-necked, 15-mL, round-bottomed flask equipped with a rubber septum, argon
inlet adapter, and glass stopper was charged with diazoketone 98 (0.052 g, 0.419 mmol), 0.8
mL of ether, and 0.8 mL of hexane then cooled at 0 *C. Diisopropylethylamine (0.073 mL,
0.419 mmol) was added followed by diethylphenylsilyl trifluoromethanesulfonate 104 (0.130
g, 0.416 mmol). The resulting solution was stirred for 30 min and then allowed to warm to
room temperature over 30 min. The reaction mixture was filtered through Celite with the aid
of 5 mL of ether and concentrated at reduced pressure to give 0.129 g of a red-orange oil.
Column chromatography on 3 g of silica gel (elution with 0-2.5% EtOAc-hexane) afforded
0.085 g (74%) of diazo ketone 105 as a yellow oil.
IR (film): 2950, 2060, and 1590 cm1
'H NMR (500 MHz, CDC13):
13C NMR (125 MHz, CDC13):
7.55-7.58 (m, 2H), 7.36-7.40 (m, 3H), 6.09 (q, J= 7.0 Hz, 1H), 1.78 (s, 3H), 1.72 (d, J = 7.0 Hz, 3H),1.09 (q, J= 5.8 Hz, 4H), and 1.05 (t, J= 5.8 Hz, 6H)
197.0, 137.4, 135.1, 134.4, 131.5, 130.5, 128.8, 52.3,14.3, 13.6, 7.9, and 4.1
116
wdd 0 Tc* * ~ * P P P i n I I p p9£96
t-
90
0
v 5
0;Y N2
SiEt2Ph
105
PhEt2SI C 0
113
(E)-2-(1-Methyl-1-propenyl)-2-(diethyl(phenyl)silyl)ketene (113).
A solution of diazo ketone 105 (0.194 g, 0.677 mmol) in 6.7 mL of benzene was
placed in a 25-cm vycor tube (15 mm O.D., 13 mm I.D.) fitted with a rubber septum. A
second rubber septum (inverted) was secured with wire to the tube to insure a good seal
and the reaction mixture was degassed (three freeze-pump-thaw cycles at -196 *C, <0.05
mmHg) and then irradiated with 300 nm light for 3 h in a Rayonet reactor. Column
chromatography on 10 g of silica gel (elution with hexane) provided 0.111 g (64%) of
ketene 113 as a yellow oil.
IR (film): 3360, 2440, and 2060 cm 1
'H NMR (500 MHz, CDCl 3): 7.53-7.57 (m, 2H), 7.32-7.39 (m, 3H), 4.96 (q, J= 6.8 Hz, 1H), 1.80 (s, 3H), 1.51 (d, J = 6.8 Hz,3H), and 0.90-1.04 (m, 1OH)
'3C NMR (125 MHz, CDCl3): 184.8, 136.2, 135.1, 130.1,25.0, 19.2, 14.6, 7.9, and 4.8
128.6, 123.8,
118
119.3,
PhEt 2SI C
113
f
LYJ-UI .
9 8 7 6 5 4 p
((
3 2 1 0 ppm4
SiEt3
I I
Ph
0
C+ c
Et3SI 0
Phgc
122 124
4 ,4 -Dichloro-3-phenyl-2-(triethylsilyl)-2-cyclobutenone (124).
A 500-mL, three-necked, round-bottomed flask equipped with a rubber septum,
reflux condenser, and' pressure-equalizing addition funnel was charged with activated
zinc 59 (7.26 g, Ill mmol) and a solution of (triethylsilyl)phenylacetylene' 60 122 (4.01 g,37.0 mmol) in 80 mL of ether. The resulting solution was heated at reflux while a
solution of trichloroacetyl chloride (4.2 mL, 37.0 mmol) in 125 mL of ether was added
dropwise over 3 h. The reaction mixture was heated at reflux for 14 h and was then
allowed to cool to room temperature and filtered. The filtrate was extracted with two
1 00-mL portions of saturated NaHCO 3, two 1 00-mL portions of water, and two 1 00-mL
portions of saturated NaCl, dried over MgSO4, filtered, and concentrated to give 6.67 g of
a red-brown liquid. Column chromatography on 40 g of silica gel (elution with 0-2%
ether-pentane) provided 5.55 g (92%) of cyclobutenone 124 as a yellow oil.
2950 and 1770 cm 1
'H NMR (300 MHz, CDCl3):
13C NMR (75 MHz, CDCl3):
7.91-7.94 (m, 2H), 7.57-7.60 (m, 3H), and 0.85-1.00 (m, 15H)
183.4, 181.9, 149.8, 133.1, 129.9, 129.7, 129.2,91.0, 7.2, and 3.1.
159.Brady, W. T.; Liddell, H. G.; Vaughn, W. L. J. Org. Chem. 1966, 31, 626.160. Jun, C.-H.; Crabtree, R. H. J. Organomet. Chem. 1993, 447, 177.
120
IR (film):
Et 3SI 0
Ph Cl
124
t~J
2
rJL )
[ I19 3 7
2 1 S ppm
5 49 i 7 ppo
Me 3SI 0 M03SI
Ph I PhX
123 125
3 -Phenyl-2-(trimethylsilyl)-2-cyclobutenone (125).
A 50-mL, three-necked, round-bottomed flask equipped with a rubber septum,
25-mL pressure-equalizing addition funnel, and argon inlet adapter was charged with zinc
dust (0.626 g, 9.53 mmol), TMEDA (1.44 mL, 9.53 mmol), and 8 mL of ethanol and then
cooled at 0 "C using an ice-water bath. Acetic acid (0.55 mL, 9.53 mmol) was added
over 2 min, and then a solution of cyclobutenone 123 (0.463 g, 1.64 mmol) in 5 mL of
ethanol was added dropwise via the addition funnel over 12 min. The reaction mixture
was stirred for 15 min, and then the ice-bath was removed and the reaction mixture was
stirred for 3 h at 25 *C. The resulting mixture was filtered through Celite with the aid of
80 mL of 1:1 Et2O:pentane. The filtrate was extracted with 100 mL of 1 M aqueous HCl
solution, 100 mL of water, 80 mL of saturated NaHCO 3, and 80 mL of saturated NaCl
solution, dried over MgSO 4, filtered, and concentrated to give 0.409 g of a yellow liquid.
Column chromatography on 20 g of silica gel (gradient elution with 0-4% EtOAc-
hexane) provided 0.257 g (74%) of 125 as a yellow oil.
IR (film): 2950 and 1785 cm'
'H NMR (300 MHz, CDCl3): 7.59-7.61 (m, 2H), 7.50-7.51 (m, 3H), 3.71 (s, 2H),and 0.32 (s, 9H)
"C NMR (75 MHz, CDC13): 191.0, 176.7, 131.4, 129.2, 128.7, 128.6, 126.4,54.6, and -1.2
HRMS: Calcd For C13HI6OSi: 216.0970Found: 216.0970
122
M03SI 0
Ph
126
3.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 PPM
Et 3Si 0 Et3SI 0
CIPh)I Ph
124 126
3-Phenyl-2-(triethylsilyl)-2-cyclobutenone (126).
A 100-mL, 3-necked, round-bottomed flask equipped with a rubber septum, 50-
mL pressure-equalizing addition funnel, and argon inlet adapter was charged with zinc
dust (1.14 g, 17.5 mmol), TMEDA (2.6 mL, 17.5 mmol), and 13 mL of ethanol and then
cooled at 0 *C using an ice-water bath. Acetic acid (1.00 mL, 17.5 mmol) was added
over 8 min, and then a solution of cyclobutenone 124 (0.99 g, 3.0 mmol) in 16 mL of
ethanol was added dropwise via the addition funnel over 1 h. The reaction mixture was
stirred for 15 min, and then the ice-bath was removed and the reaction mixture was
stirred for 4.5 h at room temperature. The resulting mixture was filtered through Celite
with the aid of 150 mL of 1:1 Et20:pentane. The filtrate was extracted with 50 mL of 1
M aqueous HCl solution, 50 mL of water, 40 mL of saturated NaHCO3, and 40 mL of
saturated NaCl solution, dried over MgSO 4, filtered, and concentrated to give 0.848 g of a
yellow liquid. Column chromatography on 25 g of silica gel (gradient elution with 0-
10% ether-pentane) provided 0.428 g (55%) of 126 as a yellow oil.
IR (film): 2070 and 1740 cm 1
'H NMR (300 MHz, CDCl 3): 7.63-7.66 (m, 2H), 7.51-7.54 (m, 3H), 3.75 (s, 2H),0.99 (t, J =6.8 Hz, 9H), and 0.86 (q, J= 6.8 Hz,6H)
'3C NMR (75 MHz, CDCl3 ): 191.5, 178.1, 147.2, 133.6, 131.4, 129.0, 128.7,52.1, 7.4, and 3.4
HRMS: Calcd For C16H22 OSi: 258.1440Found: 258.1441
124
id~d t £9
9I
0
1
Me 3SI 0
PhX
125
M03SI C40
Ph:
127
2-(1-Phenylethenyl)-2-(trimethylsilyl)ketene (127).
A 25-mL, two-necked, round-bottomed flask equipped with a glass stopper and
reflux condenser was charged with cyclobutenone 125 (0.106 g, 0.497 mmol) in 18 mL
of benzene and then heated at 60 *C for 4.5 h. The resulting mixture was allowed to cool
to room temperature and then concentrated to give 0.113 g of a yellow oil. Column
chromatography (twice) on 2.0 g Florisil (elution with hexane) provided 0.039 g (37%) of
ketene 127 as a pale yellow oil.
2080 and 1740 cm'
'H NMR (300 MHz, CDCl 3):
13C NMR (75 MHz, CDC13):
HRMS:
7.41-7.43 (m, 2H), 7.30-7.40 (m, 3H), 4.98 (s, 2H),and 0.28 (s, 9H)
180.9, 142.7, 139.4, 128.3,26.0, and -0.6
Calcd For C13H16OSi:Found:
128.0, 126.8, 110.9,
216.0970216.0970
126
IR (film):
HddO 0 9 L V
IZ
) 4ldI
SOL-
Me 3Si 0
Ph)ft125
3-Phenyl-2-trimethylsilyl butenolide (129).
A 50-mL, one-necked, round-bottomed flask equipped with a reflux condenser
was charged with cyclobutenone 125 (0.153 g, 0.703 mmol) in 30 mL of toluene. Air
was bubbled through the solution at a rate of about 5 bubbles per second. The reaction
mixture was heated at reflux for 18 h then cooled to room temperature and concentrated
to give 0.213 g of a yellow oil. Column chromatography on 10 g of silica gel (elution
with 0-10% EtOAc-hexane) afforded 0.069 g (42%) of butenolide 129 as a yellow oil.
IR (CDCl3): 2950 and 1740 cm"
'H NMR (300 MHz, CDCl3):
'3 C NMR (75 MHz, CDC13):
7.45-7.46 (m, 3H), 7.29-7.44 (m, 2H), 4.93 (s, 2H),and 0.149 (s, 9H)
176.9, 174.0, 133.4, 130.0, 128.5, 127.9, 127.4,73.7, and -0.97
128
0
Me 3SI
Ph
129
0
M03SI 0
Ph129
K-
:97.0 6.0 5.0 4.0 3.0 2.0 1.0 0. 0 Ppm
O.-A
Me3SI
PhX
OH
Me 3SI CO 2Me
Ph) CO 2MO
125 171
Dimethyl 3-Hydroxy-5-phenyl-4-(trimethylsilyl)phthalate (171).
A 25-mL, two-necked, round-bottomed flask equipped with a glass stopper and
reflux condenser was charged with a solution of cyclobutenone 125 (0.109 g, 0.511
mmol), DMAD (0.063 mL, 0.511 mmol), and 7 mL of toluene. The resulting solution
was heated at reflux for 42 h and then allowed to cool to room temperature.
Concentration of the resulting mixture afforded 0.260 g of an orange oil. Column
chromatography on 26 g of silica gel (elution with 20% EtOAc-hexane) provided 0.116 g
(63%) of phenol 171 as a white solid, mp 51-52 *C.
1740 and 1660 cmn~
'H NMR (300 MHz, CDCl3): 11.21 (s, lH), 7.33-7.35 (m, 3H), 7.22-7.24 (m,2H), 6.79 (s, lH), 3.91 (s, 3H), 3.85 (s, 3H), and-0.04 (s, 9H)
13C NMR (75 MHz, CDCl3 ): 170.0, 169.4, 166.5, 156.0,128.7, 127.9, 127.8, 121.1,0.8
143.0, 135.1, 129.3,106.9, 52.8, 52.5, and
HRMS: Calcd For C19H220 5Si:Found:
130
IR (CC14):
358.1236358.1235
OH
M03SI C0 2Me
Ph): C0 2MO
171
-a
6 4
K
10 B 2 0oPPIV
Et 3Si 0
PhX
OH
Et 3SI CO 2MO
Ph CO 2Me
126 172
Dimethyl 3-Hydroxy-5-phenyl-4-(triethylsilyl)phthalate (172).
A 25-mL, two-necked, round-bottomed flask equipped with a glass stopper and
reflux condenser was charged with a solution of cyclobutenone 126 (0.111 g, 0.429
mmol), DMAD (0.053 mL, 0.429 mmol), and 7 mL of toluene. The resulting solution
was heated at reflux for 55 h and then allowed to cool to room temperature.
Concentration of the resulting mixture afforded 0.167 g of an orange oil. Column
chromatography on 10 g of silica gel (gradient elution with 0-70% benzene-hexane)
afforded 0.095 g (55%) of phenol 172 as a white solid, mp 61-61.5 'C.
1730 and 1660 cm~
'H NMR (300 MHz, CDCl3):
'3C NMR (75 MHz, CDCl3):
HRMS:
11.28 (s, 1H), 7.32-7.36 (m, 5H), 6.79 (s, 1H), 3.93(s, 3H), 3.87 (s, 3H), 0.78 (t, J= 7.8 Hz, 9H), and0.48 (q, J= 7.8 Hz, 6H)
170.1, 169.5, 166.8, 157.2, 143.1, 135.0, 128.7,127.8, 127.7, 127.0, 121.3, 106.6, 52.8, 52.5, 7.8and 4.2
Calcd For C22 H28O5Si:Found:
400.1706400.1707
132
IR (CCL4):
Ndd 0 P 9 9 al
9
HO
v II
I
I
j
o(i-Pr)3S1 C'
111
EtO2C CO 2Et
0(I-Pr)3SI 0
CO 2EtCO 2Et
196 202
3,4-Dimethyl-6-oxo-5-(triisopropylsilyl)-3,6-dihydropyran-2,2-dicarboxylic
diethyl ester (202).
acid
A 10-mL, two-necked, pear-shaped flask equipped with a glass stopper and a
reflux condenser fitted with a rubber septum and an argon inlet needle was charged with
ketene 111 (0.121 g, 0.479 mmol), diethyl ketomalonate (0.110 mL, 0.719 mmol), and
0.43 mL of acetonitrile. The reaction mixture was heated at reflux for 15 min and then
cooled and concentrated at reduced pressure to give 0.280 g of a yellow liquid. Column
chromatography on 14 g of silica gel (elution with 5% EtOAc-hexane) provided 0.191 g
(94%) of lactone 202 as a white solid, mp 69-70 *C.
IR (CH 2C 2): 2930, 2860, and 1715 cm1
'H NMR (300 MHz, CDCl3):
'3C NMR (75 MHz, CDCl3 ):
4.21-4.36 (m, 3H), 4.04-4.36 (m, 1H), 3.21 (q, J=7.2 Hz, IH), 2.12 (s, 3H), 1.47 (sept, J= 7.5 Hz,
3H), 1.32 (t, J= 7.2 Hz, 3H), 1.24 (t, J= 7.2 Hz,3H), 1.13 (d, J= 7.0 Hz, 3H), and 1.04 (d, J= 7.5Hz, 18H)
168.9, 166.6, 164.4, 163.7, 122.0, 85.0, 62.7, 62.5,41.5, 23.3, 19.0, 14.0, 13.7, 12.9, and 12.4
Elemental Analysis: Calcd for C22H 38O6Si:Found:
C, 61.93; H, 8.98C, 62.12; H, 9.05
134
wdd 0I I I I a I I
£ V 9L
I -fl
U
a'b NO 0--- Wova,
0
mw
V/-4
(I-Pr) 3Si C4 0
6110
+
EtO2C CO 2 Et
196
0
(I-Pr)3Si 0
CO2EtCO 2Et
203
3-Oxo-3,5,6,7,8,8a-hexahydro-isochromene-1,1-dicarboxylic acid diethyl ester (203).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 110 (0.208 g, 0.679 mmol), diethyl ketomalonate (0.155 mL, 1.02 mmol), and
0.68 mL of acetonitrile. The tube was tightly sealed with a teflon cap and then heated at
reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated at
reduced pressure to give 0.461 g of an yellow-orange oil. Column chromatography on
10 g of silica gel (elution with 5% EtOAc-hexane) provided 0.250 g (77 %) of lactone
203 as a white solid, mp 79-80 *C.
IR (CDCl3):
'H NMR (300 MHz, CDCl3):
'3C NMR (125 MHz, CDCl3 ):
2930,2850, 1740 and 1710 cm-1
4.24-4.38 (m, 3H), 4.05-4.14 (m, 1H), 3.26 (dd, J=12.0, 3.3 Hz, IH), 2.76 (m, 1H), 2.35 (dt, J= 12.3,4.6 Hz, 1H), 2.10 (m, 1H), 1.82-1.91 (m, 2H), 1.54-1.67 (m, 3H), 1.46 (sept, J = 7.3 Hz, 3H), 1.32 (t, J= 7.3 Hz, 3H), 1.25 (t, J= 7.3 Hz, 3H), and 1.05 (d,J= 7.3 Hz, 18H)
174.1, 167.9, 165.7, 164.6, 122.0, 85.0, 63.9, 63.4,46.8, 37.4, 31.0, 30.5, 26.2, 19.8, 14.8, 14.5, and13.0
136
0
(I.Pr)3S1
C0 2Et
C O02Et
203
7 6 5 A 3 0 1 PPM
+
EtO2C CO2 Et
196
0
Et3Si
Ph CO 2EtCO 2Et
205
6-Oxo-4-phenyl-5-(triethylsilyl)-3,6-dihydropyran-2,2-dicarboxylic acid diethyl ester
(205).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
cyclobutenone 126 (0.115 g, 0.445 mmol), diethyl ketomalonate (196, 0.100 mL, 0.667
mmol), and 0.40 mL of acetonitrile. The tube was tightly sealed with a teflon cap and
heated at reflux for 15 h. The reaction mixture was cooled and concentrated at reduced
pressure to afford 0.250 g of a yellow oil. Column chromatography on 12 g of silica gel
(elution with 10% EtOAc-hexane) provided 0.176 g (92%) of the lactone 205 as a white
solid, mp 63 *C.
IR (film): 2960, 2880, 1735, and 1575 cm 1
'H NMR (300 MHz, CDCl3):
13C NMR (125 MHz, CDCl3):
7.31-7.33 (m, 3H), 7.18-7.21 (m, 2H), 4.24 (q, J=7.3 Hz, 4H), 3.21 (s, 2H), 1.26 (t, J= 7.3 Hz, 6H),0.71 (t, J= 7.9 Hz, 9H), and 0.34 (q, J= 7.8 Hz,6H)
166.3, 164.6, 163.4, 139.9, 129.9, 129.5, 128.2,127.7, 82.8, 63.1, 38.1, 13.9, 7.4 and 4.2
Elemental Analysis: Calcd for C23H320 6Si:Found:
C, 63.86; H, 7.46C, 63.78; H, 7.31
138
Et3SI
PhX
126
0
Et3SI
10COEPhA CO 2Et
205
b-"
3 76 54 32 10Im Ir-l
PPM
0
Et 3SI 0
Ph CO 2EtCO 2Et
205
0
10Ph CO 2Et
CO 2Et
206
6-Oxo-4-phenyl-3,6-dihydropyran-2,2-dicarboxylic acid diethyl ester (206).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
a solution of silyl lactone 205 (0.065 g, 0.151 mmol) in 0.75 mL of CH2Cl 2.
Methanesulfonic acid (0.049 mL, 0.756 mmol) was added rapidly dropwise. The tube
was tightly sealed with a teflon cap and heated at reflux for 15 h. The reaction mixture
was cooled, diluted with 10 mL of CH 2C 2, and washed with 10 mL of saturated NaHCO 3
solution, 10 mL of water, 10 mL of 10% aqueous HCl solution, and 10 mL of saturated
NaCl solution, dried over MgSO 4, filtered, and concentrated at reduced pressure to give
0.060 g of a cloudy brown oil. Column chromatography on 14 g of silica gel (elution
with 20-50% EtOAc-hexane) provided 0.048 g (100%) of the lactone 206 as a white
solid, mp 68.5 *C.
IR (film): 2950,2900, 1705, 1435, and 1360 cm7
'H NMR (500 MHz, CDCl3 ):
'3C NMR (125 MHz, CDCl3):
7.45-7.55 (in, 5H), 6.33 (s, 1H), 4.31 (q, J= 7.1 Hz,4H), 3.48 (s, 2H), and 1.29 (t, J= 7.2 Hz, 6H)
165.9, 161.9, 152.3, 135.2, 131.0, 129.0, 126.1,114.4, 82.9, 63.2, 31.1, and 13.8
Elemental Analysis: Calcd for C17Hi80 6:Found:
C, 64.14; H, 5.70C, 64.25; H, 5.88
140
0
0 CO2Et
Ph CO2Et
206
p
9 8 7 6 5
cf
K
14 3 .2
p.
1 0 ppm
"-A
3 24
MeH , NP
H Ph
0
(I-Pr)3Si NH
Ph
215 233
cis-4,5-Dimethyl-6-phenyl-3-(triisopropylsilyl)- 5,6-dihydro-1H-pyridin-2-one (233).
A 10-mL, two-necked, pear-shaped flask equipped with a glass stopper and a
reflux condenser fitted with a rubber septum and an argon inlet needle was charged with
ketene 111 (0.134 g, 0.531 mmol), imine 215 (0.147 g, 0.829 mmol), and 0.47 mL of
acetonitrile. The reaction mixture was heated at reflux for 1.5 h then cooled to room
temperature and concentrated at reduced pressure to give 0.272 g of a yellow oil.
Column chromatography on 27 g of silica gel (elution with 5% EtOAc-hexane) provided
0.151 g (79%) of lactam 233 as a white solid, mp 197-199 *C.
IR (CDCl3): 3400, 2930, 2850, and 1625 cm~1
'H NMR (300 MHz, CDCl3):
"C NMR (75 MHz, CDCl3):
7.28-7.42 (m, 5H), 5.51 (br s, 1H), 4.77 (d, J= 3.6Hz, IH), 2.21 (m, 1H), 2.10 (s, 3H), 1.53 (sept,J= 7.3 Hz, 3H), 1.12 (d, J= 5.7 Hz, 18H), and 0.82(d, J= 7.1 Hz, 3H)
170.0, 165.9, 138.4, 128.5, 127.6, 126.6, 126.4,58.1,45.0, 23.0, 19.3, 13.0, and 11.0
Elemental Analysis: Calcd for C22H35NOSi:
Found:
C, 73.89; H, 9.86;N, 3.92C, 73.80; H, 9.88;N, 3.84
142
( )'0
+
111
wdd 06 p p I
cez
ISC(Jd-,)
0
-I
J
I t I I a I
Et3Si C'
+
112
Me3SiN
H Ph
0Et 3Si NH
Ph
215 236
cis-4,5-Dimethyl-6-phenyl-3-(triethylsilyl)- 5,6-dihydro-1H-pyridin-2-one (236).
A 5-mL, pear-shaped flask equipped with a reflux condenser fitted with a rubber
septum and an argon inlet needle was charged with ketene 111 (0.160 g, 0.761 mmol) and
imine 215 (0.202 g, 1.14 mmol) then stirred at room temperature for 2 h. The resulting
yellow oil was purified by column chromatography on 10 g of silica gel (elution with 0-
10% EtOAc-hexane) which provided 0.182 g (76%) of lactam 236 as a white solid, mp
155 *C.
IR (CH 2C 2): 2930, 2850, and 1630 cm'1
'H NMR (500 MHz, CDCl3):
'3C NMR (125 MHz, CDCl3 ):
7.28-7.41 (m, 5H), 5.56 (br s, 1H), 4.79 (d, J= 4.0Hz, 1H), 2.22 (m, 1H), 2.08 (s, 3H), 0.97 (t, J= 7.8Hz, 9H), and 0.86 (m, 9H)
171.0, 167.5, 139.4, 129.3, 128.5, 127.3, 127.1,58.9, 44.9, 22.8, 11.7, 8.5, and 5.8
144
wddK I I a Ic vyI I I I p I 0 1 1 1 a I I A a I I I I I I
I ~t* r..[vf
It)
99Z
H NlISC13
s9
Me3SSi
H Ph
0
(i-Pr)3S! NH
/Ph
215 237
trans-1-Phenyl-4-(triisopropylsilyl)-1,5,6,7,8,8a-hexahydro-2H-isoquinolin-3-one
(237).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 110 (0.208 g, 0.679 mmol), imine 215 (0.184 g, 1.04 mmol), and 0.68 mL of
acetonitrile. The tube was tightly sealed with a teflon cap and then heated at reflux for 25
h. The reaction mixture was cooled to room temperature and concentrated at reduced
pressure to give 0.403 g of a yellow oil. Column chromatography on 14 g of silica gel
(elution with 10% EtOAc-hexane) provided 0.256 g (91%) of lactam 237 as a white solid,
mp 211-212 *C.
IR (CDCl3 ): 3400, 2930, 2850, and 1625 cm 1
'H NMR (500 MHz, CDCl3 ):
13C NMR (75 MHz, CDCl3):
7.29-7.41 (m, 5H), 5.43 (br s, 1H), 4.79 (d, J= 5.2Hz, IH), 2.82 (d, J= 11.6 Hz, 1H), 2.25 (m, 2H),2.00 (m, 1H), 1.73 (m, 1H), 1.52 (sept, J= 7.4 Hz,3H), 1.25-1.48 (m, 4H), and 1.12 (d, J= 7.5 Hz,18H)
170.5, 170.3, 138.5, 128.5, 127.7, 126.7, 123.7,57.3, 49.2, 36.9, 30.9, 28.2, 25.9, 19.3, and12.6
Elemental Analysis: Calcd for C24H37NOSi:
Found:
C, 75.14; H, 9.72;N, 3.65C, 75.10; H, 10.01;N, 3.66
146
110
(/-Pr)3Si CV.'
IIII it
'if
HNISC(Jd-I)
0
odd *IUCU Sa
I r
I
)
'-4
now
e i
Et 3Si 0
PhX
126
*1-
Me 3SK .
H Ph
0
Et3Si NH
Ph Ph
215 239
4,6-Diphenyl-3-(triethylsilyl)- 5,6-dihydro-1H-pyridin-2-one (239).
A 10-mL, two-necked, pear-shaped flask equipped with a glass stopper and a
reflux condenser fitted with a rubber septum and an argon inlet needle was charged with
cyclobutenone 126 (0.134 g, 0.518 mmol), imine 215 (0.133 g, 0.778 mmol), and 0.47
mL of acetonitrile. The reaction mixture was heated at reflux for 45 min and then cooled
and concentrated at reduced pressure to give 0.259 g of an yellow oil. Column
chromatography on 25 g of silica gel (elution with 5-20% EtOAc-hexane) provided 0.157
g (84%) of lactam 239 as a white solid, mp 130-131 *C.
IR (film): 3400, 2940,2860, 2220, and 1630 cm 1
'H NMR (300 MHz, CDCl3): 7.29-7.41 (m, 8H), 7.12-7.18 (m, 2H), 5.72 (s, 1H),4.74 (dq, J= 5.1, 1.6 Hz, 1H), 2.80 (m, 2H), 0.81(t, J= 7.6 Hz, 9H), and 0.43 (q, J= 7.6 Hz, 6H)
'3C NMR (125 MHz, CDCl3 ):
Elemental Analysis:
170.7, 162.7, 142.8, 141.6,128.9, 128.7, 128.5, 127.3,
Calcd for C23H29NOSi:
Found:
134.4, 129.6, 129.1,56.0, 43.7, 8.5, and 5.2
C, 75.98; H, 8.04;N, 3.85C, 75.76; H, 7.99;N, 3.77
148
0
Et3SI
I NH
Ph & Ph
239
87 65 4 32 1 0OPpm
MeSi, N
H
240 Ph
0
(i-Pr)3Si NH
Ph241
cis-4,5-Dimethyl-6-styryl-3-(triisopropylsilyl)-5,6-dihydro-1H-pyridin-2-one (241).
A 10-mL, pear-shaped flask equipped with a rubber septum and argon inlet
needle was charged with ketene 111 (0.165 g, 0.654 mmol) and imine 240 (0.135 g,
0.654 mmol). The reaction mixture was stirred at 25 *C for 15 min and then transferred
to a round-bottomed flask with 5 mL of CH2Cl2 and concentrated at reduced pressure to
give 0.321 g of an orange oil. Column chromatography on 12 g of silica gel (elution with
0-10% EtOAc-hexane) provided 0.196 g (78%) of lactam 241 as pale yellow oily solid.
IR (film): 3160, 3040, 2900, 1625, and 1455 cm~1
'H NMR (300 MHz, CDCl3):
'3C NMR (125 MHz, CDCl3):
7.24-7.40 (m, 5H), 6.62 (d, J= 15.8 Hz, IH), 6.16(dd, J= 16.0, 7.8 Hz, 1H), 5.84 (br s, 1H), 4.26 (dd,J= 7.7, 3.9 Hz, 1H), 2.19 (m, 1H), 2.06 (s, 3H),1.50 (sept, J= 7.5 Hz, 3H), 1.07 (d, J= 7.5 Hz,18H), and 1.07 (d, J= 7.0 Hz, 3H)
170.5, 166.9, 136.9, 133.6, 129.4, 128.7, 127.5,127.2, 126.8, 56.8, 44.1, 23.6, 20.0, 13.5, and 11.7
150
-o(i-r)Si C-
+
111
wdd- 0 T
w
-f
S 9L
LI lID II1'
9 6I I
f
4id
HN I~Ji
0
I I t I I --i I I I -- I --- L- I I I L-- I I I I
c
V"
(I-Pr)3SI C
110
Me 3SI , N+ -
H
Ph240
0
(i-Pr)3SINH
Ph242
trans-i-Styryl-4-(triisopropylsilyl)-1,5,6,7,8,8a-hexahydro-2H-isoquinolin-3-one
(242).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 110 (0.199 g, 0.649 mmol) and imine 240 (0.133 g, 0.649 mmol). The reaction
mixture was stirred at 25 *C for 10 min and then transferred to a round-bottomed flask
with 5 mL of CH2Cl2 and concentrated at reduced pressure to give 0.384 g of a yellow-
orange liquid. Column chromatography on 12 g of silica gel (elution with 0-50% EtOAc-
hexane) provided 0.209 g (73%) of lactam 242 as a white solid, mp 162-163 *C.
IR (film): 3400, 2930, 2860, and 1625 cm-1
'H NMR (300 MHz, CDC13):
'3C NMR (75 MHz, CDCl3):
7.28-7.38 (m, 5H), 6.57 (d, J= 15.8 Hz, 1H), 6.20(dd, J= 8.1, 15.8 Hz, 1H), 5.37 (br s, 1H), 4.21 (m,1H), 2.79 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 1.98(m, 1H), 1.84 (m, 2H), 1.50 (sept, J= 7.5 Hz, 3H),and 1.09 (d, J= 7.5 Hz, 18H)
169.6, 169.2, 136.2, 132.6, 128.7, 128.0, 126.5,126.4, 124.6, 55.5, 46.8, 36.3, 29.3, 28.0, 25.5,19.4, and 12.7
Elemental Analysis: Calcd for C26H39NO:
Found:
C, 76.23; H, 9.60;N, 3.42C, 75.97; H, 9.84;N, 3.57
152
0
(I-Pr)3SINH
Ph
242
F 43
9 U7 6 4 3 a 1*
(i-Pr)3SI C
111
.SiMe3
Ph Ph
0
(i-Pr)3S NH P
PhPh
219 244
4,5-Dimethyl-6,6-diphenyl-3-(triisopropylsilyl)-5,6-dihydro-1H-pyridin-2-one (244).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 111 (0.153 g, 0.606 mmol), imine 219 (0.233 g, 0.909 mmol), and 0.60 mL of
acetonitrile. The tube was tightly sealed with a teflon cap and then heated at reflux for 18
h. The reaction mixture was cooled to room temperature and concentrated at reduced
pressure to give an orange oil. Column chromatography on 10 g of silica gel (elution
with 0-10% EtOAc-hexane) provided 0.208 g (79%) of lactam 244 as a white solid, mp
182 *C.
IR (CDCl 3): 2930, 2850, and 1620 cm 1
'H NMR (300 MHz, CDCl3):
'3C NMR (125 MHz, CDCl3 ):
7.24 (m, 11 H), 3.09 (q, J= 6.9 Hz, 1H), 2.13 (s,3H), 1.36 (sept, J= 7.5 Hz, 3H), 0.94 (d, J= 6.9 Hz,3H), 0.85 (d, J= 7.3 Hz, 9H), and 0.82 (d, J= 7.5Hz, 9H)
170.0, 165.5, 146.6, 142.6, 128.4, 128.0, 127.4,126.9, 126.5, 126.4, 125.8, 65.0, 46.5, 23.7, 19.0,14.0, and 12.5
Elemental Analysis: Calcd for C28H39NOSi:
Found:
C, 77.54; H, 9.06;N, 3.23C, 77.87; H, 9.17;N, 3.32
154
ITS 9 S -
W/)
4d
4d
HN
y IOt(Jd-,)0
odd -a2tL
) r
S SMe3
+ Ph kPh
(i-Pr)3Si C'! '
6
110
0
(i-Pr)3Si NH
Ph
Ph
245
1,1-Diphenyl-4-(triisopropylsilyl)-1,5,6,7,8,8a-hexahydro-2H-isoquinolin-3-one
(245).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 110 (0.208 g, 0.679 mmol), imine 219 (0.150 g, 0.489 mmol), and 0.49 mL of
acetonitrile. The tube was tightly sealed with a teflon cap and then heated at reflux for 24
h. The reaction mixture was cooled to room temperature and concentrated at reduced
pressure to give 0.342 g of a yellow-orange oil. Column chromatography on 10 g of
silica gel (elution with 10% EtOAc-hexane) provided 0.149 g (66%) of lactam 245 as a
white solid, mp 237-237.5 *C.
IR (film): 3040, 2930, 2850, and 1630 cm-1
'H NMR (500 MHz, CDCl3 ): 7.14-7.30 (m, 10 H), 7.03 (br s, 1H), 2.99 (dd, J=2.4, 9.1 Hz, 1H), 2.84 (dd, J = 3.1, 11.6 Hz, IH),2.39 (m, 1H), 2.07 (m, 1H), 1.76 (m, 1H), 1.49 (m,3H), 1.33 (sept, J = 7.3 Hz, 3H), 1.13 (d, J = 12.8Hz, IH), 0.87 (d, J= 7.3 Hz, 9H), and 0.80 (dd, J=7.3 Hz, 9H)
13C NMR (75 MHz, CDC13):
Elemental Analysis:
170.4, 170.3, 146.9, 143.2,126.9, 126.6, 126.4, 125.3,31.2, 26.5, 19.0, and 12.5
Calcd for C3oH 41NOSi:
Found:
128.3, 127.9, 127.3,64.3, 51.1, 37.3, 31.5,
C, 78.38; H, 9.01;N, 3.05C, 78.44; H, 9.41;N, 3.03
156
219
udd g 1 3
S3 La 6 I I ..I ..I .I
TI
4d
4d !HN
ISC(Jd-I)
0
odd
rl-
(i-Pr)3Si Cl0
6 +
110
Me 3Si.. N
H t-Bu
251
0
(i-Pr)3Si NH
)< t-Bu
252
trans-1-(1,1-Dimethylethyl)-4-(triisopropylsilyl)-1,5,6,7,8,8a-hexahydro-2H-
isoquinolin-3-one (252).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
ketene 110 (0.162 g, 0.529 mmol), imine 251 (0.165 g, 1.06 mmol), and 0.53 mL of
acetonitrile. The tube was tightly sealed with a teflon cap and heated at reflux for 4 h and
then at 110-110 *C for 65 h. The reaction mixture was cooled to room temperature and
additional imine (0.093 g, 0.53 mmol) was added then heated at 110-130 *C for 23 h.
The reaction mixture was cooled to room temperature and concentrated to give 0.307 g of
a yellow-gray liquid. The reaction mixture was filtered through Celite, rinsing with the
aid of CH2Cl 2 and concentrated at reduced pressure to give 0.187 g of a pale yellow solid.
The solid was washed with heptane to afford 0.115 g (56%) of lactam 252 as a white
solid, mp 235-237 *C.
IR (CH2Cl 2): 2950,2850, and 1630 cm~1
'H NMR (300 MHz, CDCl3 ):
13C NMR (125 MHz, CDCl3):
5.19 (br s, 1H), 3.21 (d, J= 4.1 Hz, 1H), 2.72 (m,1H), 2.25 (m, 2H), 2.00 (m, 2H), 1.80 (m, 1H), 1.47(sept, J= 7.5 Hz, 3H), 1.47 (m, 3H), 1.07 (d, J= 7.1Hz, 18H), and 1.02 (s, 9H)
171.1, 170.4, 124.0, 60.7, 47.2, 37.2, 32.5, 30.8,28.6, 27.3, 26.0, 19.3, and 12.6
Elemental Analysis: Calcd for C22H4iNOSi:
Found:
C, 72.66; H, 11.36;N, 3.85C, 72.59; H, 11.65;N, 3.78
158
0
(I.Pr)3S1NH
252
I-AA
3 7 654 3 21 0OPPM
(i-Pr)3Sj~ - H3C
H Ph
0 0
(i-Pr)3S1 CH3 (i-Pr)3S N CH3
Ph Ph
253 254 255
trans-6-Phenyl-3-(triisopropylsilyl)-1,4,5-trimethyl-5,6-dihydro-1H-pyridin-2-one
(254) and cis-6-Phenyl-3-(triisopropylsilyl)-1,4,5-trimethyl-5,6-dihydro-1H-pyridin-
2-one (255).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
a solution of ketene 111 (0.069 g, 0.273 mmol), 0.27 mL of acetonitrile, and imine 253
(0.050 g, 0.410 mmol). The tube was tightly sealed with a threaded teflon cap and heated
at 120 C for 42 h. The reaction mixture was cooled and concentrated at reduced pressure
to give 0.120 g of an orange oil. Column chromatography on 12 g of silica gel (elution
with 5% EtOAc-hexane) afforded 0.072 g (71%) of a 3:1 mixture of lactams 254 and 255
as a pale yellow oil.
Both isomers:
IR (neat): 2940,2850, and 1615 cm 1
Major isomer (254):
'H NMR (300 MHz, CDCl3 ):
'3C NMR (75 MHz, CDCl 3):
Minor isomer (255):
'H NMR (300 MHz, CDCl3 ):
7.19-7.29 (m, 5H), 4.32 (d, J= 6.1 Hz, IH), 2.90 (q,obscured by the singlet at 2.89 ppm, IH), 2.89 (s,3H), 1.92 (s, 3H), 1.54 (m, 3H), 1.06-1.13 (d, J=7.4 Hz, 18H), and 0.92 (d, J= 7.3 Hz, 3H)
168.9, 160.4, 137.2, 129.0, 128.0, 127.8, 126.1,66.2,40.6, 33.5, 21.7, 19.4, 19.3, and 13.1
7.19-7.29 (m, 5H), 4.19 (s, 1H), 3.03 (s, 3H), 2.35(q, J= 7.0 Hz, 1H), 1.79 (s, 3H), 1.54 (sept, J= 7.4Hz, 3H), 1.30 (d, J= 7.0 Hz, 3H), and 1.00 (d, J=
160
7.4 Hz, 18H)
3C NMR (75 MHz, CDC 3): 167.8, 160.9, 140.3, 128.6, 128.2, 127.4, 127.2,66.7, 45.4, 35.1, 23.5, 19.2, 14.0, and 12.9
161
0 0
(/-Pr)3S N .*CH3 (NPr)3SI N CH3
"Ph Ph
254 255
5 5
F
4 32
v.
6 pp.
t'j
B a 7
.J- -- w , ___j
0
C
(i-Pr)3Si H
281
Me3Si N
H Ph
215
trans-N-(Trimethylsilyl)-4-phenyl-3-(triisopropylsilyl)-azetidin-2-one (283).
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
(triisopropylsilyl)ketene (0.063 g, 0.318 mmol) and imine 215 (0.057 g, 0.321 mmol).
The tube was tightly sealed with a threaded teflon cap and then heated at 70 *C for 20 h
and then at 140 *C for 3 h. The reaction mixture was cooled to give 0.117 g of an orange
oil. Column chromatography on 10 g of silica gel (elution with 0-20% EtOAc-hexane)
afforded 0.085 g (71%) of lactam 283 as a pale yellow oil.
IR (film): 2930, 2850, 2230, 1710, and 1450 cm 1
'H NMR (500 MHz, CDCl3):
'3C NMR (125 MHz, CDCl3):
7.29-7.40 (m, 5H), 4.47 (d, J= 3.1 Hz, 1H), 3.00 (d,J= 3.1 Hz, 1H), 1.26 (sept, J= 7.0 Hz, 3H), 1.09 (d,J = 7.3 Hz, 9H), and 1.05 (d, J = 7.6 Hz, 9H), and0.10 (s, 9H)
176.3, 143.0, 129.3, 128.7, 127.2, 54.6, 52.1, 19.4,11.1, and -0.4
163
23SiMeN
(i-Pr)3Si P" Ph
283
) NlAeIM3
(I-Pr)3S1 Ph
283
b."
f
Al *1~I 9uu u i i ~ p 5 1 1 ,t
3 2
jfj
1 0 -ppm
I
9
0
Et3Si NH
Ph Ph
239
0
NH
Ph Ph
284
4,6-Diphenyl-5,6-dihydro-1H-pyridin-2-one (284)
A flame-dried, threaded Pyrex tube (13 mm O.D., 10 mm I.D.) was charged with
a solution of silyl lactam 239 (0.091 g, 0.250 mmol) in 1.01 mL of CH2Cl 2.
Methanesulfonic acid (0.081 mL, 1.25 mmol) was added. The tube was tightly sealed
with a threaded teflon cap and the reaction mixture was heated at reflux for 4 h. The
reaction mixture was cooled and then diluted with 10 mL of CH2Cl 2 . The organic
portions were separated and washed with 10 mL of saturated NaHCO3 solution, 10 mL of
water, 10 mL of saturated NaCl solution, dried over MgSO4, filtered, and concentrated at
reduced pressure to give 0.095 g of a pale yellow solid. Column chromatography on 14 g
of silica gel (elution with 50-100% EtOAc-hexane) afforded 0.034g (55%) of the lactam
284 as a white solid, mp 182 *C.
IR (CH2 Cl2 ): 3380, 3020,2960, and 1640 cm~
'H NMR (500 MHz, CDCl3):
13C NMR (125 MHz, CDCl3):
7.35-7.51 (m, 10H), 6.37 (s, 1H), 5.65 (br s, 1H),4.86 (dd, J= 5.5, 11.6 Hz, 2H), and 2.96 (m, 1H)
167.5, 149.9, 141.1, 137.3, 129.6, 128.9, 128.7,128.3, 126.4, 125.8, 118.9, 55.7, and 35.7
165
wdd 0 T p S 9 1 6
I I I I~ II * *V
t1Z2)4id H V i d
HN
0
)
0
Et 3Si NH
Ph
236
0
NH
Ph
285
4,5-Dimethyl-6-phenyl-5,6-dihydro-1H-pyridin-2-one (285).
A flame-dried, 25-mL, round-bottomed flask equipped with a reflux condenser
fitted with a rubber septum and argon inlet needle was charged with a solution of silyl
lactam 236 (0.075 g, 0.238 mmol) in 1.2 mL of CH 2C 2. Methanesulfonic acid (0.077
mL, 1.19 mmol) was added and the reaction mixture was heated at reflux for 6 h. The
reaction mixture was cooled, diluted with 10 mL of CH2Cl2, and washed with 10 mL of
saturated NaHCO 3 solution, 10 mL of water, 10 mL of 10% aqueous HCl solution, 10 mL
of saturated NaCl solution, dried over MgSO 4, filtered, and concentrated at reduced
pressure to give 0.087 g of an oily yellow-brown solid. Column chromatography on 8 g
of silica gel (elution with 20-100% EtOAc-hexane) afforded 0.040g (83%) of the lactam
285 as a white solid, mp 170.5 *C.
IR (CH 2Cl2): 3980, 2950, 1655, and 1615 cm 1
'H NMR (500 MHz, CDCl3): 7.29-7.42 (m, 5H), 5.76 (s, 1H), 5.45 (br s, 1H),4.90 (d, J= 4.6 Hz, 1H), 2.29 (m, 1H), 2.00 (s, 3H),and 0.80 (d, J= 7.0 Hz, 3H)
13C NMR (125 MHz, CDCl3 ): 168.6, 159.4, 139.2, 129.5,59.9, 41.4, 22.5, and 12.2
128.8, 127.2, 119.6,
167
T Z £ I U aIFs9£ 9 6 I I I I a I I I I I I I I I I I I I a I I a
00
4td
HN
0
wdd 0
IfI
.p+ - 0
(-Pr) 3Si C Ph 2S- CMe 2 (i-Pr)3Si
111 292
3,4,5,5-Tetramnethyl-2-(triisopropylsilyl)cyclopent-2-en-1-one (292).
A 25-mL, two-necked, round-bottomed flask equipped with an argon inlet
adapter and rubber septum was charged with a solution of ketene 111 (0.140 g, 0.554
mmol) in 5.0 mL of 50:50 THF-DMSO and cooled at -20 'C. A 15-mL, two-necked,
round-bottomed flask equipped with an argon inlet adapter and rubber septum was
charged with diphenylisopropylsulfonium fluoroborate (0.193 g, 0.610 mmol) in 2.5 mL
of THF and cooled at -78 *C with an acetone-dry ice bath. t-BuLi (1.55 M in pentane,
0.38 mL, 0.582 mmol) was added dropwise down the side of the flask over 10 sec. The
resulting bright yellow ylide solution was immediately transferred via cannula over 5 min
to the ketene solution, and the resulting solution was stirred for 30 min at -20 *C. The
cooling bath was removed and the reaction mixture was allowed to warm to room
temperature over 3 h and then diluted with 20 mL of water. The aqueous layer was
separated and extracted with three 20-mL portions of diethyl ether, and the combined
organic phases were washed with 40 mL of saturated NaCl solution, dried over MgSO4,
filtered, and concentrated to give 0.275 g of a yellow oil. Column chromatography on 10
g of silica gel (gradient elution with 0-2.5% EtOAc-hexane) afforded 0.093 g (57%) of
cyclopentenone 292 as a colorless oil.
IR (CDCl3): 2960, 2940, 2860, and 1680 cm-'
'H NMR (500 MHz, CDCl3): 2.45 (q, J= 7.3 Hz, IH), 2.15 (s, 3H), 1.51 (s, 3H),1.51 (sept, J= 7.6 Hz, 3H), 1.07 (d, J= 7.3 Hz, 3H),1.05 (s, 3H), 1.04 (d, J= 7.6 Hz, 18H), and 0.94 (s,3H)
13C NMR (125 MHz, CDCl 3): 217.8, 187.6, 132.2, 53.2, 47.7, 26.4, 20.5, 19.0,
169
18.8, 14.7, and 11.7
HRMS: Calcd For Cl 8H34OSi: 294.2379Found: 294.2378
170
Wdd 0 9
-~~~~~~~~ IT- It II If iriirii
ISC(Jd-I)
0
0(i-Pr)3S! C'.O
+ Li --=-- Ph O (i-Pr)hSi Ph
111 310 311
5-(Phenylmethylene)-3,4-dimethyl-2-(triisopropylsilyl)-2-cyclopentenone (311)
A 25-mL, two-necked, round bottomed flask equipped with a glass stopper and
reflux condenser was charged with phenyl acetylene (0.065 mL, 0.592 mmol) and 3 mL
of THF then cooled at -78 *C. n-BuLi (2.6 M in hexane, 0.23 mL, 0.592 mmol) was
added and the reaction mixture was stirred for 15 min. A solution of ketene 111 (0.136 g,
0.539 mmol) in 1 mL of THF was added dropwise via cannula to the -78 *C solution
over 3 min (1 mL THF rinse). The reaction mixture was stirred at -78 *C for 1.5 h then
warmed to -5 *C over 40 min. BHT (0.133 g, 0.592 mmol) was added and the solution
was allowed to warm to room temperature over 15 min then heated at 50 *C for 35 min.
The reaction mixture was cooled to room temperature and quenched by the addition of 10
mL of saturated NaCl solution. The organic portion was separated and the aqueous layer
was extracted with two 30-mL portions of CH 2Cl2. The organic portions were combined,
dried over Na2SO 4, filtered, and concentrated to give 0.379 g of an orange oil. Column
chromatography on 25 g of silica gel (elution with 0-1% ether-pentane) afforded 0.143 g
(75%) of cyclopentenone 311 as a pale yellow solid, mp 117 *C.
IR (film): 2940,2860, and 1705 cm~
'H NMR (300 MHz, CDCl3 ): 7.54 (d, J= 7.3 Hz, 2H), 7.26-7.43 (m, 4H), 3.73 (q,J= 7.0 Hz, lH), 2.29 (s, 3H), 1.61 (sept, J= 7.5 Hz,3H), 1.24 (d, J= 7.0 Hz, 3H), and 1.09 (d, J= 7.5Hz, 18H)
"C NMR (75 MHz, CDCl3 ): 201.5, 186.3, 139.7, 136.2, 135.2, 130.3, 129.2,128.7, 128.6, 44.7, 18.8, 16.7, 12.0, and 11.8
172
0
(I-Pr)3S1 P
311
-.4
7 6 5 mr~mrlnrFI I II I I
2 1 0
6
98 I I I T
PPM
0 0Et3SI)
Br)4
317 318
2-Bromo-3,4-dimethyl-1-cyclopentenone (318)
A 25-mL, pear-shaped flask equipped with a rubber septum and argon inlet needle
was charged with silylcyclopentenone 317 (0.120 g, 0.535 mmol), N-bromosuccinimide
(0.238 g, 1.34 mmol), and 1.8 mL of DMF and the solution was stirred at room
temperature for 48 h. An additional portion of NBS was added (0.093 g, 0.522 mmol)
and the reaction mixture was stirred for 16 h then quenched by the addition of 10 mL of a
10% aqueous HCl solution. The organic portion was separated and the aqueous portion
was extracted with 3 20-mL portions of ether. The organic portions were combined and
washed with 15 mL of water, 15 mL of saturated NaHCO 3 solution, 15 mL of water, and
15 mL of saturated NaCI solution, then dried over MgSO4, filtered, and concentrated to
afford 0.197 g of a red-orange liquid. Column chromatography on 10 g of silica gel
(elution with 0-10% EtOAc-hexane) afforded 0.051 g (5 1%) of cyclopentenone 318 as a
pale yellow oil.
IR (film): 2930, 1705, and 1610 cmf
'H NMR (500 MHz, CDC 3 ): 2.88 (m, 1H), 2.77 (dd, J= 18.6, 6.4 Hz, 1H), 2.15(s, 3H), 2.14 (dd, J= 18.6, 2.2 Hz, 1H), and 1.25 (d,J= 7.0 Hz, 3H)
'3C NMR (125 MHz, CDC3 ): 200.4, 177.3, 122.9, 41.7, 38.3, 18.8, and 16.8
174
wdd 0 I £ '7 S 9 I II 9 6
I I I I
)J
SKC
Jg
0
Etp9 wdd -0