Stereospecific ring opening of cyclopropanes : a route tofunctionalized medium sized ringsCitation for published version (APA):Loozen, H. J. J. (1976). Stereospecific ring opening of cyclopropanes : a route to functionalized medium sizedrings. Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR144464
DOI:10.6100/IR144464
Document status and date:Published: 01/01/1976
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STEREOSPECIFIC
RING OPENING
OF CYCLOPROPANES
· A ROUTE TO FUNCTIONALIZED
MEDIUM SIZED RINGS
HUBERT LOOZEN
STEREOSPECIFIC RING OPENING OF CYCLOPROPANES
A ROUTE TO FUNCTIONALIZED MEDIUM
SIZED RINGS
PROEFSCHRIFT
TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL EINDHOVEN, OP GEZAG VAN DE RECTOR MAGNIFICUS, PROF. DR. P.VAN DER LEEDEN, VOOR EEN COMMISSIE AANGEWEZEN DOOR HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP
DINSDAG 26 OKTOBER 1976 TE 16.00 UUR
DOOR
HUBERT LOOZEN
GEBOREN TE HEERLEN
DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR
DE PROHOTOREN
PROF.DR. H.H. BUCK
EN
PROF.DR. TH.J. DE BOER
Aan mvn ouders Aan Fia
CONTENTS
In troduction
Chapter I
Chapter IJ
Ch-zpter JIJ
Solvolytic ring expansions I-1 Mechanistic backgrounds of the sal
volysis of cyclopropyl derivatives I-2 Silver perchlorate promoted ring ex
pansions of some geminal dibromo
cyclopropanes I-3 Experimental sectien
References and notes
7
12
Non-solvolytic ring expansions 25
II-1 Silver tosylate promoted ring enlarge
ment of geminal dibromocyclopropanes
II-2 Silver nitrate promoted ring expan
sions of geminal dibrornocyclopropanes
II-3 Influences of nucleophilicity and
ring size in the aleoholysis of sorne
dibrornocyclopropanes
II-4 Structure assignments II-5 Experimental section
Raferences and notes
Stereosele~tive synthesis of gerninal endo
iodo-exo-bromo-cyclopropanes
III-1 Introduetion
III-2 Iodination of endo-lithio-exo-bromo
cyclopropanes
45
Chapter IV
Summary
Samenvatting
III-3 Silver fluoride as an effective catalyst in ring expansions of geminal dihalocyclopropanes
III-4 Experimental section
References and notes
Bishomoaromatic interaction in the disrota- 67 tory ring opening of cyclopropyl carbenoids
IV-1 Introduetion IV-2 Lithiation of geminal dibromocyclo
propanes IV-3 Backgrounds of the ring opening of
cycloprópylidenes
IV-4 Behaviour of cyclopropylidenes attached to polyenes
IV-5 Experimental section References and notes
94
96
Curriculum Vitae 98
Dankwoord 99
INTRODUCTION
The important influence of steroids in the dynamics of the living organism has been accepted now for several decades. An important and fascinating achievement in chemistry was the elucidation of the metabolic pathway by which steroids are built up from the simple precursor acetic acid.
--N 3 y~~oP206-
Geranyl- ~ pyrophosphate ~
--- ----
""-, Farnesylpyrophosphate
Squalene
Lanosterol 7
In the biogenesis of steroids, especially the conversion of
squalene into the tetracyclic larrosterol constitutes a problem
of outstanding interest. In this polycyclization reaction only one tetracyclic product is formed from an a-chiral precursor.
It was assumed that an enzyme folds the squalene molecule in
such a conformation that the cyclization results in one stereo
isomer only (the tetracyclic lanosterol). Experiments under
non-enzymatic conditions showed that the methyl substitution pattern in squalene determines the formation of carbenium
ion centers during the cyclization and therefore is respon
sible for the formation of products having a five-membered
C-ring. This contrasts with the formation of a six-membered
C-ring exclusively in the enzymatle reaction. The stereo
chemistry of larrosterol determines the mode of folding for
2,3-epoxysqualene (first product formed before the cyclization
to lanosterol). From model studies it can be deduced that a
chair-boat-chair folding must be involved (leading references
have been cited below 1- 4 ).
\::'-------- ~~ ....... ---·~ l,
'
0 ) ...... ,/'
In order to gain more insight in the influences of conformation
on the nature of the products originati~g from cyclization re
actions, the synthesis of molecules which contain a part of the
squalene chain in a fixed conformation, was started.
8
n = 2,3 R:: H,C~
Preparatien of nine- or ten-membered rings (n=2 and 3 respec
tively) containing two trans double bands and an unsaturated
C-5 side chain at an allylic position seemed to be an attractive approach for the aims above. At this stage attention
was focused on the typical chemistry of medium sized rings.
In a relatively simple straight forward sequence such a molecule, containing a nine-membered basic skeleton, was
made accessible in the following way 5•
. H Br
c:x·~ AgClOt. ------5% aq. acetone
tosy !chloride ~H ~···oH
------pyridine, 0°
8r
- 5%-H:!SDt_-Clfs OH
Buli, THF;-1.5°
~H ~···oros
Br
2,1. ,l. -trimethyloxa-zoline, Buli,THF. -70"
9
However, several fundamental problems remained unclear in such an approach. Reduction of bramine from a trans double bond with retention of contiguration proved to be rather
cumbersome. Purthermare the control of stereochemistry was
lost completely in the reaction of the oxazoline with the
2-bromocyclonona-1,6-dien-3-yltosylate, whereas the eluci
dation of the stereochemistry with the aid of pure spectroscopie techniques seemed to be hampered by the fact that we
are dealing with a rather scarcely explored area of these particular cyclic systems. Best outlook for the final achieve
ment of a straight forward synthesis seemed to be incorporated in the development of new synthetic methods in this field,
which allow the facile and stereocontrolled introduetion of interesting functionality and which provide a profound in
sight in the elementary nature of reactivity in cyclic structures.
JO
Rq-erences
1. W.S. JOHNSON, Acc. Chem. Res., l• 1 (1968)
2. E.E. van TAMELEN, Acc. Chem. Res., ~. 152 (1975)
3. D. ARIGONI, Pure Appl. Chem. (IUPAC), !l, 219 (1975)
4. E.E. van TAMELEN, Acc. Chem. Res., l• 111 (1968)
5. H.J.J. LOOZEN, unpublished results.
11
CHAPTER I
solvolytic nng expansions
I-1 Meohanistic backgrounds of the solvolysis of
cyclopropyl derivatives
One of the most used ways in constructing medium sized rings consists of rupture of the bond between the bridge-head
carbon atoms of bicyclic systems 1 • In this way cyclic structures containing n+3 carbon atoms can be obtained from bicyclo[ n. 1. O] al kanes.
The property of a variety of cyclopropyl systems to undergo
a- rapid solvolytic ring opening to allylic derivatives is
commonly used as the basic element of such ring expansions.
The presence of a good leaving group at Cn+ 3 of the cyclopropane part of the molecule is a prerequisite. As such monohalo- and geminal dihalocyclopropanes represent
a favourite class of compounds for effecting such ring
expansions; the more so because they are readily accessible.
12
x
"'0<-~ . Rt. Solv
The arrangement of the substituents attached to the double bond is, of course, dependent upon the mode of ring opening of the cyclopropyl cation.
Since the announcement of Woodward and Hoffmann's rules of conservation of orbital symmetry 2
• 3 , several profound
investigations concerning the characteristic elements of the solvolytic ring opening of cyclopropane derivatives appeared
in the literature 4 13 , Solvolytic rate measurements of a
series of substituted cyclopropyl halides and cyclopropyl
tosylates were indicative for the following mechanistic
features.
1. Ring opening proceeds in a disrotatory manner, as can be
predicted from Woodward-Hoffmann rules for a two electron
system (cyclopropyl cation).
2. Substituents which are arranged cis to the leaving group
rotate inward and those which are trans to the leaving
group rotate outward. This latter condition implicates that the departure of the
leaving group and the ring opening praeeed concertedly and not as separate processes.
13
-x (exol ..!:)-k, :--1~
"A From these considerations it becomes clear that the ring expansion of ais-bicyclo[n.1.0lalkanes may lead to cyclic olefins, containing n+3 carbon atoms, exhibiting a cis or a trans geometry, depending on the original orientation of the leaving group.
-x ( endo) _______ ,_ Solv
~.,H ~Solv
_______ ,..,.. Solv
When the exo group is lost the final geometry will be trans. Endo leaving results in a cis arrangement. This solvolytic behaviour of cyclopropanes, annulated to cyclic structures, has received wide spread experimental support 1 ~- 28 •
It has been established quite recently 29 - 35 that silver perchlorate assisted solvolytic ring opening of geminal dibromocyclopropanes, annulated to seven-, eight- and nine membered rings, proceeds with loss of the more accessible exo bromine atom. The products arising from such reactions should necessarily have the trans geometry.
14
A further remarkable selectivity in this ring opening reaction results from the fact that the nucleophile enters concertedly
at the same side of the incipient allylic system from which the exo halogen atom is released, thus leading to one single
diastereoisomer only. This latter phenomenon has been observed
befare in the salvolysis studies performed by Parham et al·
on 1,1-dichloro-2,3-dipropylcyclopropanes 11• Schematically
this can be visualized as follows:
Ag+
r
2) Solv
It should be mentioned that the endo halogen atom is lost
preferentially in those compounds where the expanded ring would become too small to accommodate a trans double bond.
Then cis compounds are formed as a matter of course 36,
As an illustrative example the different rates of the
salvolysis of 7-endo-chloronorcarane, 7-exo-chloronorcarane and 7,7-dichloronorcarane are given:
~l ~\
H
k=1.4x1o-6 sec- 1 -7 1 k=4.5x10 sec
J,j
In order to elaborate a well-set up synthesis, leading to the target compounds, mentioned in the introduction, the develop
ment of novel approaches for the introduetion of interesting functionality with control of stereochemistry was required.
As such an intensive examinatien of ring expansions in medium
sized rings seemed to be a logical beginning.
I-2 SiZveP pepchZorate promoted ring expansions of
some geminaZ dibromocycZopropanes
As substrates for the silver ion catalysed ring expansion
reactions the dibromides 1-4 were selected. They were readily
accessible by the reaction of the corresponding olefins with dibromocarbene according to the original procedure of Doering
and Hoffmann 37•
H Br
(j:' CD
H Br
~~ ®
r-~r CJ'~Br
These compounds, upon reaction with an excess of silver
perchlorate, according to the method of Reeseet aZ. 29 ,
afforded the trans allylic alcohols 5-8 as the main products.
cqc cq< . . ~" ~OH '()H -Br
H Br Br
G) (i) G)
16
Whereas the ring opening of 1 and 3 afforded only S and 7 in a smooth reaction, the ring opening of 2 and of 4 gave
besides the expected products 6 and 8 reproducible amounts of a side product (ca. 20% in both cases). These products
could be separated by column chromatography. Their microanalyses proved to be consistent with those of the concomi
tantly formed trans alcohols. The possibility that these
by-products might be the trans isoroers 9 and 10 could be
ruled out easily. It has been established that both trans
cyclonenene and trans-cyclodecene (which are optically active
molecules) are optically labile at room temperature 38 • 39 •
The explanation for this behaviour is based on the fact that
the olefinic hydragen can rotate through the loop of the ring
with a relatively low activation energy:
~ E "' 20 kcal/mol
(Yl ... oH
~ t:
E n.11kcal/mol
@) Br
From these values it can be seen that bath 6 and 8 exist at
room temperature as two rapidly equilibrating diastereoisomers. This intra molecular isomerization process can be re
cognized by nmr. The 1H-nmr spectrum displays a double doublet
at ê 4.02 (J=11 and 4 Hz) and a multiplet at ê 4.54 for the
methine protons, and two double doublets at ê 6.03 (J=10 and
6 Hz) and at,ê 6.21 (J=10 and 7 Hz) for the olefinic proton.
For the equilibrium 8 t 10 the activation energy is so small
that at room temperature 8 and 10 are not distinguishable.
17
The spectrum displays only one double doublet for the methine proton at 6 4.17 10 and 5 Hz) and a triplet at 6 6.26 (J= 8 Hz) for the olefinic hydrogen. With all these considerations in mind the side products from the ring opening of 2 and of 4 must be the cis alcohols 11 and 12 respectively.
®
~OH
~Br
® From the back-ground hitherto known, there are two possibili
ties to explain the formation of such cis products. The first possibility, an isomerization of the diastereoisomerie mixture of 6 and 8 under the reaction conditions, could be ruled out easily. Stirring of 6 and 8 with silver perchlorate in aqueous acetone did not yield 11 and 12 respectively. Another possibility is based on mechanistic considerations. In case that besides the exo halogen also the endo halogen is expelled in 2 and 4, then 11 and 12 would be formed:
AgCl04 -----· 5o;. aq.acetone
This explanation seems, for the moment, not unrealistic, because it has been demonstrated that 9-endo-bromobicyclo[6.1.0)nonane actually undergoes, though very slowly, ring opening with silver perchlorate 29 • As such the ring expansion of. 2 and 4 might be regarded as an ordinary competition of "exo leaving" VB. "endo leaving".
18
~
Table I
Salvolysis of geminal dibromocyclopropanes
with AgCl04 in 5% aqueous acetone1
Substroles Products' Mp, °C • 'field,% NMR dato (CDCI 3), 6 values
(j~· o::x 76 4,17 (dd, 1, methine H, J=9 and 6 Ez)
tlH 6 • 11 ( dd, 1 , o 1 e fin E, J = 11 and 5 Hz)
G) @ Sr
dZ~ OH
11: 4.75 (m, 1, methine Hl,
CQ< ~r 6.18 (t, 1, alefin H, J=11 Hz)
72-74 2 73 6: 4.02 (dd, methine H, J=8 and 4 Hz) H (cis) 4.55 (m, methine H)
0 @72 Br
@ 28 6.03 (dd, alefin H, J=10 and 6 Hz) 6.40 (dd, alefin H, J=10 and 7 Hz)
d Cq< 4.16 (dd, 1, methine H, J=10 and 5 Hz)
\ "Br
84-86' 65 5.37 (m, 2, alefin H) ' H
5.87 (t, 1, alefin H, J=7.5 Hz) @ cv Br
12: 4.82 (t, 1, methine H, J=8 Hz)
(\)( c::c 5.98 (dd, 1, alefin H, J=12 and 6 Hz) d Br 48-so• 71 8: 4.42 (dd, 1, methine H, J=9 and 4 Hz) (cis) 6.23 (t, 1, alefin H, J=7.5 Hz) OH
G) @77 Br
@ 23
l Reactions were carried out with initial 1 molar concentrations of silver perchlorate. 2) Crystallized from petroleum ether (60/80). 3) Crystallized from diisopropyl ether. 4) Yields arebasedon crude isolated rnatorials (purity > 95~). 5) Satisfactory analytica! data were obtained for the new products (~ 0.3~ for C and H).
I-3 Experimental seation
General. Starting materials 1-4 were prepared by a modification of the classica! procedure from the corresponding olefins and dibromocarbene• 0 • Cyclononene, required for the preparation of 4 was obtained from 2 by conversion with methyllithium in ether to the cyclonona-1,2-diene and subsequent reduction with sodium in ammonia- 1
• The solvolytic ring expansion reaction is exemplified with the salvolysis of 2 and 4. A survey of the products obtained in the salvolysis reactions of 1-4 is given in Table I.
2-Bromo-3-hydroxycyclonon-1-ene (6, 11) To a solution of 5.64 g (0.02 mol) of 2 in 50 ml of 5% aqueous acetone was added a solution of 5.36 g (0.026 mol) of silver perchlorate in 25 ml of 5% aqueous acetone. The mixture was stirred for 1 hr at ambient temperature and monitored with tlc. After addition of 50 ml of saturated sodium chloride solution stirring was prolonged for an additional 5 min. The precipitate was filtered. The filtrate was diluted with 200 ml of water and extracted with ether. Upon washing, drying and evaporation of the organic phase 3.19 g (73%) of the product was left as a colorless oil. The product consisted of two components. Chromatography (silica gel; chloroform-2% methanol as eluent) afforded 0.89 g of the cis alcohol 11 (Rf 0.29) and 2.29 g of the diastereoisomerie mixture of trans alcohols 6 and 9 (Rf 0.22). The cis alcohol was recrystallized from petroleum ether: mp 72-74°; nmr (CDC1 3) o 4.75 (m, 1, methine H), 6.18 (t, 1, olefin H, J= 11Hz). Anal. Calcd for C9H15Br0: C, 49.31; H, 6.84. Found: C, 49.29; H, 6.80.
2-Bromo-3-hydroxycyclodec-1-ene (8, 12) A solution of 5.92 g (0.02 mol) of 4 and 5.36 g (0.026 mol) of silver perchlorate in 75 ml of 5% aqueous acetone was stirred for 3 hr at room temperature. Work-up in a similar manner as described above afforded 3.21 g (71%) of the product.
20
Chromatography over silica gel (chloroform-2% methanol) as
eluent afforded 2.55 g of trans alcohol 8 (Rf 0.38) as a colourless oil: nmr (CDC1 3) ó 4.18 (dd, 1, methine H, J= 9
and 5 Hz), 6.24 (t, 1, alefin H, J= 9 Hz). The other component (0.75 g, Rf 0.44) was the cis alcohol 12 mp 48-50° (petroleum ether); nmr (CDC1 3) o 4.82 (t, 1, methine H, J= 8 Hz), 5.98 (dd, 1, alefin H, J= 12 and 6 Hz). Anal. Calcd for c10H17Br0: C, 51.50; H, 7.29. Found: C, 51.62; H, 7.31.
21
Re_[erences and notes
1. C.D. GUTSCHE and D. REDMORE, "Advances in Alicyclic Chemistry"; Carbocyclic Ring Expansion Reactions, Academie Press, New York, 1968
2. R.B. WOODWARD and R. HOFFMANN, J. Amer. Chem. Soc.,
8 ' 395 (1965) 3. R.B. WOODWARD and R. HOFFMANN, "The Conservation of
Orbital Symmetry", Verlag Chemie G.m.b.H., Weinheim, 1970
4. C.H. DE PUY, L.G. SNACK, J.W. HAUSSERand W. WIEDEMANN, J. Amer. Chem. Soc., JU, 400.6 (1965)
5. L. SKATTEB~L, J. Org. Chem., ll• 1554 (1966)
6. C.H. DE PUY, L.G. SNACK and J.W. HAUSSER, J. Amer. Chem. Soc., , 3343 (1966)
7. P.v.R. SCHLEYER, G.W. VAN DINE, U. SCHÖLLKOPF and J.PAUST,
J. Amer. Chem. Soc.,~. 2868 (1966) 8. J.W. HAUSSERand N.J. PINKOWSKI, J. Amer. Chem. Soc.,
~. 6981 (1967)
9. W.E. PARHAM, K.S .. YONG, J. Org. Chem., ~. 3947 (1968)
10. J.A. LANDGREBE and L.W. BECKER, J. Org. Chem., 33, 1173,
(1968)
11. W.E. PARHAM and K.S. YONG. J. Org. Chem., ~. 683 (1970)
12. P.v.R. SCHLEYER, W.F. SLIWINSKI, G.W. VAN DINE, U. SCHÖLLKOPF, J. PAUST, K. FELLENBERGER, J. Amer. Chem. Soc., Qi, 125 (1972)
13. W.F. SLIWINSKI, T.M. SU and P.v.R. SCHLEYER, J. Amer. Chem. Soc., 94, 133 (1972
14. S.J. CRISTOL, R.M. SEQUEIRA, C.H. DE PUY, J. Amer. Chem. Soc., !U_, 4007 (1972)
15. G.H. WHITHAM and M. WRIGHT, Chem. Comm., 294 (1967)
16. U. SCHÖLLKOPF, K. PELLENBERGERand M. PATSCH, Tetr. Lett.,
3639 (1967)
17. M.S. BAIRD and C.B. REESE, Tetr. Lett., 1379 (1967)
18. W. PARHAM and R.J. SPERLEY, J. Org. Chèm., ~. 924
(1967)
19. W.E. PARHAM and R.J. SPERLEY, J. Org. Chem., ~. 926
(1967)
20. C.W. JEFFORD and W. WOJNAROWSKI, Tetr. Lett., 199 (1968)
21. W.E. PARHAM, F.M. PARHAM, J.F. DOOLEY and M.K. MEILAHN, J. Org. Chem., ~. 3651 q968)
22. D.T. CLARK and G. SMALE, Chem. Comm., 868 (1969)
23. M.S. BAIRD and CrB. REESE, J. Chem. Soc. (C), 1808 (1969)
24. M.S. BAIRD, D.G. LINDSAY and C.B. REESE, J. Chem. Soc. (C), 1173 (1969)
25. D.B. LEDLIE and E.A. NELSON, Tetr. Lett., 1175 (1969)
26. S.R. SANDLER, J. Org. Chem. , ~. 3876 (1966)
27. S.R. SANDLER and P.S. SKELL, J. Amer. Chem. Soc., ~. 2024 (1958)
28. E.E. SCHWEIZER and W.E. PARHAM, J. Amer. Chem. Soc.,~. 4085 (1960)
29. C.B. REESE and A. SHAW, J. Amer. Chem. Soc., 2 2566
(1970)
30. C.B. REESE and A. SHAW, Chem. Comm., 1365 (1970)
31. C.B. REESE and A. SHAW, Chem. Comm., 1367 (1970)
32. D. DUFFIN and J.K. SUTHERLAND, Chem. Comm., 626 (1970)
33. M.S. BAIRD and C.B. REESE, Tetr. Lett., 4637 (1971)
34. G.H. WHITHAM and M. WRIGHT, J. Chem. Soc. (C), 1173
(1969)
35. C.B. REESE and A. SHAW, J. Chem. Soc., ( Perkin I) ' 2422 (1975)
36. P.M. WARNER, R.C. LA ROSE, R.F. PALMER, c. LEE, D.O. ROSS and J.C. CLARDY, J. Amer. Chem. Soc. , 9 7,
5507 (1975). See also references 1 2 ' 1 3' 1 4, 26' 27
and 28
2S
37. W.E. DOERING and A.K. HOFFMANN, J. Amer. Chem. Soc., ~. 6162 (1954)
38. A.C. COPE, K. BANHOLZER, H. KELLER, B.A. PAWSON, J.J. WHANG and H.J.S. WINKLER, J. Amer. Chem. Soc., !I, 3644 (1965)
39. G. BINSCH and J.D. ROBERTS, J. Amer. Chem. Soc., !I• 5157 (1965)
40. L. SKATTEB~L, Acta Chem. Scand., !l, 1683 (1963) 41. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~' 3518
(1961)
24
CHAPTER IJ
Non-solvolytic rzng expansions
II-1 SiZver tosyZate promoted ring enZargement of
geminaZ dibromoayaZopropanes
The reactions described in the preceding section are always performed by reacting halocyclopropanes, with or without silver salts, in solvents such as methanol, ethanol, aqueous acetone or acetic acid. Therefore they may be classified as solvolytic ring opening reactions 1 • The role of the silver ion consists in facilitating the formation of a cyclopropyl cation by withdrawal of the halogen atom. Based on steric considerations it is self-evident that complexation will occur preferentially at the exo iite. The products ari
sing from such solvolytic ring opening reactions are generally allyl ethers, allyl alcohols or allyl esters when these reactions are carried out in alcohols, aqueous solvents or acids respectively. With regard to the synthesis of the target compounds the question was raised if the scope of this reaction could be extended such that interesting functionality could be introduced at the allylic position in one step and with control of stereochemistry. The use of silver tosylate in a neutral solvent seemed to be a good choice 2 -~. The silver ion
induces the ring opening whereby the intermediate allylic cation should be captured by the tosylate anion; thus giving a direct entry to allylic tosylates. The substrates 1-4 were used again as representative model compounds.
25
H Br
d'"' ~c ~IBr
CD 0 H Br
c:i"' . H Br
c:Jt:'Bc 0 0
Upon treatment of 1 and 3 with two equivalents of silver tosylate in refluxing acetonitrile trans-2-bromo-3-tosyloxycyclooct-1-ene (13) and trans,ais-2-bromo-3-tosyloxycyclonona-1,6-diene (14) were formed respectively.
@ ®
The configurations of these tosylates could be confirmed easily by independent synthesis from the corresponding aleohals with tosyl chloride in pyridine. It is obvious that the
formation of 13 and 14 underlies the samebasic features as the solvolytic reactions outlined in Chapter I. Again the
ring expansion of 2 and 4 with silver tosylate afforded ring expanded tosylates. However, they proved to have cis double bands. Via synthesis from the corresponding alcohols they were identified as ais-2-bromo-3-tosyloxycyclonon-1-ene (15)
and ais-2-bromo-3-tosyloxycyclodec-1-ene (16) respectively. The formation of exclusively cis products from the ring
opening of 2 and 4 is rather curieus. They are nat formed by isomerization from the trans tosylates 17 and 18.
26
® This could be checked easily by control experiments. Formation of 15 and 16 by expelling the endo bramine atom from 2 and 4 is highly improbable, as there is no reason that complexing of the exo bramine would become unfavourable. Conclusive evidence is obtained from the fact that 9-endo
bromobicyclo[6.1.0)nonane (19) is unreactive towards silver tosylate 5
•
Obviously the ring opening of 2 and 4 leads to a strained transient trans cation which isomerizes rapidly to a ~is cation befare reacting with the weakly nucleöphilic tosylate anion. In contrast, the ring opening of 1 and 3 leads ëxclusively to trans tosylates 13 and 14 because full development of a free trans cation would require a too unfavourable geometry. Therefore these reactions praeeed completely concerted (a survey of the tosylates is given in Table II). The model description presented above seems to be quite "realistic, but it deserves to be supported by more experimental evidence. Therefore a more profound investigation was undertaken.
27 '
Table II
React10n of gem,nal dibromoc_yclopropanes
with AgOTos m acetonitrile
Substroles Produels l Mp,°C Yîeld.~ó 2 NMR dol a I CDCt3 ,, b volues
Cl IBr 6.10 (dd, 1, alefin H, J=11 and 5 Hz)
a::;>( os
80-82 85 4.92 (t, 1, methine H, J=8 Hz) 2.42 (s, 3, CH 3)
CD @ Br 3
2i OT os 6.04 (t, 1, alefin H, J=8 Hz)
~IBr (j-Br 91-93 93 5.52 (dd, 1, methine H, J=10 and 5 Hz)
2.40 (s, 3,
® H Sr 5. 85 (t' 1, alefin H, J=8 Hz)
d/Br ccx 5.27 (m, 2, H cis double bond) 89-91 89 4.85 (dd, 1, methine H, J=10 and 6 Hz)
OTos 2.39 (s, 3,
0 @ Br
eX .. C::XOTos 5.75 (rn, 2, alefin IJ and methine Ü) 108-111 81 2.41 (s, 3, CH 3)
Br
0 ®
1) Satisfactory analytica! data were obtained (~ 0.3% for C and H).
2) Yields are hased upon isolated crude material (purity > 95%). ~
II-2 Bilver nitrate promoted ring expansions of
geminal dibromoeyelopropanes
The geminal dibromocyclopropanes 1-4 react rapidly with silver tosylate giving either trans or cis products. In order
to prove this tendency a series of ring enlargement reactions
with silver nitrate 6 • 7 was carried out under similar conditions as described for the silver tosylate promoted ring expansions. The substrates 1 and 3 gave the trans allylic nitrates 20 and 21 respectively.
The identity of 20 was proved by synthesis from the parent
alcohols with acetyl nitrate in acetic anhydride-methylene chloride mixture 8 • The structure of 21 could be established
by reduction with lithium aluminohydride in refluxing THF to
trans,eis-2-bromocyclonona-1,6-diene (22) 9,
10•
cq<" 0 cq<" AcN03 , 0 ... . "OH AcfJ CH2Ct2 "ON02
® Br @ Br
Q:,X" LiAlH4, THF Q:{<" . ... . "ON02
reflu x "H
@ Br @ Br
1 LiAIH4 ,0' ether
(9<" ' OT os
@ Br
29
Upon reaction of 2 with silver nitrate in acetonitrile ois-
2-bromocyclonon-1-en-3-ylnitrate (23) was formed as sole product. This could be confirmed by nitrating the cis alcohol 11 .
The ring opening of 4 with silver nitrate seemed, according to tic, to afford a single isomer. However, the 1H-nmr spectrum revealed a 1:1 mixture of ois-and tPans-2-bromocyclodec-1-en-3-ylnitrate 24 and 25 respectively.
The isomers 24 and 25 were not separable by chromatography
and could only be obtained by synthesis from their parent alcohols. The formation of both the trans and cis isomer 24 and 25 may be explained readily by assuming a competition between attack of the nitrate anion and isomerization of the trans cation into the cis cation. This contrasts with the re
action of 4 with silver tosylate which leads exclusively to the cis tosylate 16. Apparently the nitrate anion is a better nucleophile than the tosylate anion. The formation of only a cis nitrate 23, in the ring opening of 2, is probably the result of such a severe strain in the intermediate cation that isomerization occurs far more rapidly than attack of the
nitrate anion. A survey is given in Table III.
~
Substrot es
d (Î)
~~ 0
cY: -~ w~
®
cY: ®
Table III
Reaction of geminal dibromocyclopropanes
with AgN03 in aceotonltrile
Praducts trotio)
~:02 @) Br
~NOz
~Br
@
~H ~~NO:z @) Br
WH @ 50 Br '6N0:2
cyç:o2
@ 65H
c:x::02 @so
dNOz @3S
l Yield,0/o Time,hr
71
78
62
83 3
72 0.5
NMR dato I CDCl3 I, 6 vol u es
6.37 (t, 1, alefin H, J•B Hz)
5. 76 (t, 1, mcthine H, J•B Hz]
6.33 (t, 1, alefin H, J=9 Hz) 5.86 (m, 1, methlne fl)
6.08 (dd, 1, olefln H, J•8 and 6 Hz]
5.35 (m, 2, cis double bond) 5.14 0•, 1, mcthine H]
~: 6.37 (t, 1, alefin H, J=8 Hz) 5. 21 (t, 1, methine H, J=7 Hz)
cis 5.82-6.32 (m, 2, alefin H and
methine H)
~: 4.72-5.28 (m, 1, methine H) 5.36-6.03 (m, 2, alefin H)
cis 5.20-6.08 (m, 3, methine H + alefin H) 13c (ppm downfield to external TMS)
trans: 86.8 methine C cis 82.9 mothine C
1) Yields were based on pure isolated products after chromatography.
2) Satisfactory analytical data were obtained (~ 0.3~ for C, ll and N).
With regard to the previously presented data it is clear that two factors control the cis or trans geometry of the products formed after ring opening, viz. the strain in the incipient trans cation (ring size) and the nucleophilicity of the anion. If the ring size imposes severe restrictions on the formation of a free transient trans cation, then the production of trans products is favoured, without regard to the nature of the nucleophile. Larger rings allow the formation of a transient
trans cation, which can isomerize to a more stabie cis cation, thus leading to cis products. The extent to which such an isomerization takes place is clearly dependent on the nucleophilicity.
II-J InfZuenaee of nuaZeophiZiaity and ring eize in the
aZcoholysis of some dibromoaycZopropanee
It has become clear in the preceding section that the ring expansion products all originate from the same kind of a disrotatory ring opening of the cyclopropane ring. The extent to which cationic character may be ascribed to the transition state is clearly dependent on the ring size. The experiments carried out with a series of geminal dibromo
cyclopropanes show that 9,9-dibromobicyclo[6.1 .Oinonane (2) is the smallest ring in the series which obviously possesses the property of undergoing ring opening in a semi-concerted way i.e. via a more or less free transient cation. There is no reason to assume why the solvolytic reactions should exhibit a different behaviour towards nucleophilicity than the reactions performed under non-solvolytic conditions. So, a series of solvolytic ring expansions was carried out with 2 which clearly demonstrate the effect of nucleophilicity on the cis/trans ratio of the products formed.
32
As typical reagents for such an experiment the following alcohols were chosen with decreasing nucleophilicity in the order methanol > ethanol > iso-propanol > t-butanol.
The reactions were carried out with initial concentrations
of lM of silver perchlorate at 40°. The results are summarized in Table IV.
Table IV
Aleoholysis of 9,9- dibromobicyclo[6.1.0]nonone
OR c:J-.,. ~ ~··~aR
@) Br
@
R Cis,% Trans,%
0 CH3 10 90
(§) C2H5 39 61
CS) iso-c3H7 53 47
@ i·C4Hg 64 36
S3
The results which are achieved with these solvolytic ring
expansions are self explanatory. A rather drastic increase
in cis products is observed with decreasing nucleophilicity
of the solvent. Obviously the influence of nucleophilicity
is in both solvolytic and non-solvolytic reactions an important factor in determining the cis/trans ratios. Alternative
ly the ring opening reactions of 9,9-dibromobicyclo[6.1.0)
non-4-ene (3) and 8,8-dibromobicyclo[5.1.0)octane (1) should
give trans products exclusively, even if solvolyzed in the
solvent with the lowest nucleophilicity viz. t-butanol. Indeed, reaction of 1 and 3 with silver perchlorate in t-butanol at 40° afforded only trans t-butyl ethers.
H Br
lj·~ CD
_____ ,.,.
. AgCl04-t-C4HgOH
40~ 10 min
H Br
~~, ----·
0
... (f;i'VH ~·''OH
pTSA, 0 Br
toluene
The configurational constitution of 28 and 29 was determined
readily by cleavage of the ether linkage by treatment with p-toluenesulfonic acid in refluxing toluene for 10 minutes.
This led to the formation of the known alcohols 5 and 7 (see
Chapter I). The formation of 5 from 28 was accompanied by
some isomerization to the cis alcohol, a phenomenon which is
not unusual if we consider the strain at the double bond.
34
The two isomers could be separated by application of column chromatography. The result obtained by alcoholysing 10,10-
dibromobicyclo(7.1.0ldecane (4) in t-butanol is in full agreement with the hypothesis that nucleophilicity and ring size determine the final cis/trans ratio. Upon treatment of 4 for 10 minutes at 40° with a 1M solution of silver perchlorate in
t-butanol, a mixture of two t-butoxy ethers was obtained, viz.
80% of the trans isomer (31) and 20% of the cis isomer (30).
The transient trans cation in the ten-membered ring is much less tained with strain and consequently the propensity to
isomerization is strongly diminished.
H Br
~' trans I eis N 80/20
The reaction of 9-exo-bromobicyclo[6.1.0lnonane (32) with
silver perchlorate in t-butanol affords in a very rapid re
action mainly trans-3-t-butoxycyclonon-1-ene (33) which con
tained about 10% of the related cis compound (34).
® trans/cis N 90/10
35
The considerable differences between the cis/trans ratios in the products arising from 9,9-dibromobicyclo[6.1.0lnonane (2)
and 9-exo-bromobicyclo[6.1 .Olnonane (32) at first glance seem
rather unexpected. Probably this discrepancy can be explained
in a quite simple way if we consider the stereochemistry of
the cation in question (Fig. I).
Figure I
The difference in transition state between the monobromo
derivative (32) and the dibromo derivative (2) is only the
presence of a bulky bromine atom in the cation formed in the
ring opening of 2. Apparently increased stability arising
from the interaction of the pn-electrons of the bromine atom
with the n-electrons of the allylic cation is of minor impartanee with respect to the steric influence of the bromine
atom in the transition state. Therefore the enhanced propensity to isomerization in the ring opening of 2 might be due
to a severe trans-annular interaction between the bramine
atom and the methylene hydragen at c7. Ring opening of 32 with silver nitrate, alternatively, gave a 2:1 mixture of trans
and cis nitrate 35 and 36 respectively. This observation fits
well with the hypothesis that the configuration of the product will be dependent on the relative nucleophilicity of the anion.
The influence of unfavourable steric interactions in the for
mation of anomalous products has been observed earlier in the
dihalocarbene addition to norbornene 11 - 1 ~.
. H Br
~''" + ...
@ trans 1 cis cv 65/35
II-4 StPuctuPe assignments
The contiguration of products 26a-d and 27a-d arising
from the ring expansion of 2 were determined with the aid of
their 1H- and 13c- nmr spectra (see Table V). In the proton spectrum the trans products 27a-d exist as two rapidly equi
librating diastereoisomers (rotation of the trans double bond
through the loop of the ring 15 •16
). Their spectra display
typical double doublets for the olefinic region. The methine
part of the spectrum shows a characteristic double doublet and a lower field multiplet. The corresponding cis structures
26a-d can be detected readily by their typical olefinic tri
plet and by the signal of the methine proton; a multiplet which resonates always at lower field than the methine protons
of the trans diastereoisomers. These observations are in good
agreement with recently reported data for similar compounds 17 , 18 •
An additional and valuable methad of determining the contigu
ration of the product consisted in comparison of the 13c-nmr
spectra. Of importance is the resonance of the allylic carbons.
One of these, to which the alkoxy subsituent is attached may readily be found.
37
For the cis isomer this latter allylic carbon resonates generally at 5-10 ppm upfield relative to the allylic signal
of the corresponding trans diastereoisomers 19,
In this way the mixtures 30/31 and 33/34, as well as the
mixtures of trans- and cis-cyclonon-1-en~3-ylnitrate (36 and 35) were analyzed unambiguously. The structural assign
ments of the two trans compounds 28 and 29 were made in
accordance with their 1H-nmr spectra20 • The coupling constants were in good agreement with the values measured in analogous compounds.
Compound
26a, 27a
26b' 27b
26c, 27c
26d, 27d
29
28
30' 31
33, 34
Tabl e V
1H-nmr values
(CC1 4 solutions)
3.91 and 3.47 (m and dd,
methine H-3, trans, J~s and
10 Hz), 4.20 (rn, methine H-3,
cis)
3.62 and 4.02 (m and dd, methine
H-3, trans, J•S.S and 1 0 Hz),
4.35 (m, methine H-3, cis)
4.11 (rn, methine H-3, trans),
4.40 (rn, methine H-3, cis),
6.20 (t, J=9 Hz, olefin H-1, cis)
3.72 and 4.07 (rn and dd, trans t
J methine H-3, J=5 and 10 Hz),
4.41 (m, cis, methine H), 6.02
(t, alefin ll-1, J=9 Hz, cis)
5.78 (t. 1, H-1, J=8 Hz), 5.19 (m, 2. H-5 and ll-6). 3.84 (m, 1, rnethine H-3)
5.99 (dd, 1, H-1, J=11 and 4. 5
3.96 (t' 1, H-3 1 J=B Hz)
6.24 (t. J=8 Hz, trans·, H-1), 5.82 (dd, H-1, cis, J=12 and 6
4.49 (m, H- 3 ~ cis) ,
3.99 (m, H-3, trans)
3.59 (m, methine H, trans),
4.06 (m, methine H, cis)
5. 21 (m, olefin H)
Hz),
Hz),
13c-nmr, ppm downfield to
external TMS in c2Br2F4
56.9
85.9
, 79.2 (C-:i, cis),
87.2 (C-3, trans)
64.7 (CH3
-ç_H20), 77.4 (C-3,
cis), 84.1 and 85.4 (C-3, trans)
69.2 ( (CH 3 ) 2f.), 74.2 (C-3, cis), 81.3 and 82.7 (C-3, trans)
70.4 (C-3, cis), 74.7
( (CH3 ) 3
f_), 78.1 and 79.3
(C-3, trans)
75.1 (f_(CH3
)3), 78.7 (C-3,
trans)
69.2 (C-3, cis), 75.0 (f.(CH3) 3) 77.6 (C-3, trans)
68.9 (C-3, cis),
73.9 (f_(CH 3 ) 3), 75.9 (C-3, trans)
1) Only the most significant signals were tabulated, because in the methine region
the slgnals are often overlapped by alcoxy protons, whereas in the olefinic
region the protons of cis and trans structures coincide.
39
II-5 Experimental seation
General. The starting materials 1-4 were prepared
according to known procedures by the reaction o~ dibromocarbene with the appropriate olefins 21 . 9-endo-Bromobicyclo[6.1.0]-
nonane (19) was obtained from reduction of 2 with tri-n-butyltinhydride22·23. The isomerie 9-exo-bromobicyclo[6.1.0]nonane (32) was synthesized from 2 by reduction of the dibromide 2 with dimsyl anion in DMS0 24 . Silver tosylate was prepared from silver oxide and p-toluenesulfonic acid, according to the procedure of Kornblum et al. 25 . Cyclononene, required for the preparation of 4 was obtained from 9,9-dibromobicyèlo[6.1.0l
nonane (2) by conversion to cyclonona-1,2-diene and subsequent reduction 26 . 1H-Nmr spectra were measured on a Varian T-60 spectrometer and 13c-nmr spectra were obtained on a Varian HA-100 apparatus at 25.12 Mc/s. A typical experimental procedure for the preparation of the tosylates is exemplified with the synthesis of 14. The ring expansion reaction with silver nitrate is illustrated with the preparation of 23. The aleoholysis reactions were performed at 40°, starting with an initial 1M concentration of silver perchlorate. A typical experiment is illustrated by the preparation of 28.
2-Bromo-3-tosyloxycyclonona-trans,ais-1 ,5-diene (14) To a solution of 2.80 g (0.01 mol) of 3 in 10 ml of acetonitrile was added a solution of 3.10 g (0.011 mol) of silver tosylate in 15 ml acetonitrile. The mixture was stirred with gentie reflux for 2 hr. After cooling and addition of an equal
vo~ume of ether the precipitate was filtered and the filtrate evaporated to dryness. The resulting gummy product was chromatographed through a short silica gel column and afforded 3.3 g (89%) of white crystalline tosylate 14. Recrystallization from
diisopropyl ether gave analytica! material; mp 89-91°. Anal.
Calcd for c 16H19Brü3S: C, 51.75; H, 5.12. Found: C, 51.64; H, 5.12.
40
cis-2-Bromocyclonon-1-en-3-ylnitrate (23)
A solution of 2.82 g (0.01 mol) of 9,9-dibromobicyclo[6.1.0l
nonane (2) and 3.33 g (0.02 mol) of silver nitrate in 20 ml of acetonitrile was refluxed with stirring for 4 hr (progress
of the reaction was monitored by tlc). After cooling the re
action mixture was poured onto 100 ml of saturated sodium chloride solution and 75 ml of ether. Stirring was continued
for 10 minutes and the mixture was filtered through Celite.
The organic layer was separated from some tlc immobile mate
rial by chromatography through a short silica gel column,
using pentane as eluent. Upon bulb to bulb distillation 1.86
g (78%) of 23 was obtained as a colourless oil. Nmr data are presented in the Table; ir (neat) cm- 1 2930, 2860, 1630, 1460,
1440, 1360, 1320, 1290, 1270, 1160, 1020, 1005, 970, 962, 946,
920, 890, 845, 750. Anal. Calcd for c9H14N0 3Br: C, 40.91;
N, 5.30. Found: C, 40.99; H, 5.36; N, 5.19.
Product 23 was obtained also by nitration of cis-2-bromocyclo
non-1-en-3-ol as follows. To 3 ml of acetic anhydride was added
265 mg (1.1 mmol) of Cu(N03) 2 .3H20.After the appearance of the
typical precipitate of cupric acetate the mixture was stirred
for an additional 15 minutes and then cooled to 0°. A solution
of 210 mg (1 mmol) of cis-2-bromocyclonon-1-en-3-ol (11) in 2 ml of methylene chloride was added in 1 minute. The mixture
was stirred for an additional 5 minutes and then poured on
20 ml of water. After neutralization with solid sodium bicar
bonate the product was extracted with ether. The oil which
remained after evaporation of the organic phase was chromato
graphed over a short silica gel column (pentane as eluent) and
afforded 240 mg (91%) of 23.
trans-2-Bromo-3-t-butoxycyclooct-1-ene (28)
Toa solution of 4.14 g (0.02 mol) of silver perchlorate in
20 ml of t-butanol c~ 15 g) was added at 40° with vigorous
stirring 2.68 g (0.01 mol) of 1. Precipitation of silver
bromide began immediately. After 20 minutes the starting
bromide had disappeared (as evidenced by the thin layer chro
matogram; Merck silicagel plates, benzene as eluent). 41
Then 20 ml of saturated sodium chloride solution were added. The mixture was stirred for about 5 minutes and filtered
through Celite. After dilution with 100 ml of water the product was extracted twice with ether. Upon washing, drying
and evaporation of the solvent 2.16 g (83%) of pure 28 remained as a colourless oil. The nmr data are presented in
Table V. A solution of 1.3 g (0.005 mol) of 28 in 10 ml of toluene,
containing about 100 mg of p-toluenesulfonic acid was re
fluxed for 10 minutes. The mixture was washed twice with 10% sodium bicarbonate solution and once with water. After drying
and evaporation of the organic phase 0.75 g (74%) of a 3:2
mixture of trans and cis alcohol was obtained. These two alcohols were separated by column chromatography (silica gel
chloroform-2% methanol as eluent); Rf (cis alcohol) 0.35; Rf (trans alcohol) 0.29. Nmr (CDC1 3) for the trans alcohol 5:
ó 4.18 (dd, 1, methine H-3, J 10 and 5 Hz), 6.11 (dd, 1, ole
fin H-1, J 10.5 and 4.5 Hz). Nmr (CDC1 3) for the cis isomer: ó 4.71 (dd, 1, methine H-3, J 10 and 5 Hz), 6.21 (t, 1, olefin H-1, J 8.5 Hz).
trans,ais-2-Bromocyclonona-1,6-diene (22) To a suspension of 0.8 g (0.021 mol) of lithium aluminohydride
in 10 ml of dry THF was added with stirring a solution of 2.62
g (0.01 mol) of 7 in 5 ml of THF. No reaction took place 27•
Then the mixture was refluxed for 0.5 hr. After work up in the
usual manner the resulting oil was chromatographed through a
short silica gel column, using pentarre as eluent. Upon bulb to
bulb distillation 0.7 g (35%) of 22 was obtained; bp 67-70°
(1 mm). Nmr (CDC1 3) ó 5.67 (m, 1, H-1 olefin), 5.37 (m, 2, H-6
and H-7 olefin).
This compound proved to be identical with an authentic sample prepared by reduction of the corresponding tosylate.
42
Rf!ferences and notes
1. A. STREITWIESER, Jr., "Solvolytic Displacement Reactions",
McGraw-Hill, Inc., New York 1962
2. N. KORNBLUM, W.J. JONES and G.J. ANDERSON, J. Amer. Chem.
Soc.,~. 4113 (1959)
3. W.D. EMMONS and H.F. FERRIS, J. Amer. Chem. Soc., 7
2257 (1953)
4. H.M.R. HOFFMANN, J. Chem. Soc., 6748 (1965)
5. The 9-exo-bromobicyclol6.1.0lnonane reacts within 5 minutes
completely with silver tosylate under the common reaction
conditions. Though a crude tosylate could be isolated, the
purification failed.
6. Y. POCKER and P.N. KEVILL, J. Amer. Chem. Soc.,~. 4760
(1965)
7. N. KORNBLUM and D.E. HARDIES, J. Amer. Chem. Soc.,~.
1707 (1966)
8. Acetylnitrate was prepared by modifying a known method;
T. SATO, T. AKIMAand K. UNO, J. Chem Soc. (C), 891 (1973)
9. The nitrate 21 could be prepared actually by reaction of
the parent alcohol with acetyl nitrate, but this reaction
suffers from giving a lot of side products, probably
arising from the addition of acetyl nitrate to the double
bondor from trans-annular reactions.
10. C.B. REESE and A. SHAW, Chem. Comm., 787 (1972)
11. W.R. MOORE, W.R. MOSER and J.E. LaPRADE, J. Org. Chem.,
' 2200 (1963)
12. R.C. DeSELMS and C.M. COMBS, J. Org. Chem., ~. 2206 (1963)
13. C.W. JEFFORD and R.T. MEDARY, Tetr., ~. 4123 (1967)
14. C.W. JEFFORD, S. MAHAJAN, J. WASLYN and B. WAEGEL, J. Amer.
Chem. Soc.,~. 345 (1965)
43
15. A.C. COPE, K. BANHOLZER, H. KELLER, B.A. PAWSON, J.J. WHANG and H.J.S. WINKLER, J. Amer. Chem. Soc., !I• 3644 (1965)
16. G. BINSCH and J.D. ROBERTS, J. Amer. Chem. Soc., !I• 5157 (1965)
17. C.B. REESE and A. SHAW, J. Chem. Soc., (Perkin I), 2422
(1975) 18. C.B. REESE and A. SHAW, Chem. Comm., 1365, 1367 (1970) 19. J.W. de HAAN and L.J.M. van de VEN, Org. Magn. Resonance,
~. 147 (1972) and references cited herein 20. The trans-2-bromo-3-t-butoxycyclooct-1-ene (28) isomerizes
spontaneously on standing for several days 21. L. SKATTEB~L, Acta Chem. Scand., 12, 1683 (1963) 22. M.S. BAIRD and C.B. REESE, J. Chem Soc. (C), 1808 (1969) 23. D. SEYFERTH, H. YAMAZAKI, D.L. ALLESTON, J. Org. Chem.,
~. 703 (1963) 24. C.L. OSBORN, T.C. SHIELDS, B.A. SHOULDERS, C.G. CARDENAS
and P.D. GARDNER, Chem. Ind., 766 (1965) 25. N. KORNBLUM, W.J. JONES and G.J. ANDERSON, J. Amer. Chem.
Soc., .§_1, 4113 (1959) 26. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~. 3518
( 1961) 27. Normally this reaction should afford the corresponding
alcohol. See: L.M. SOFFER, C.W. PAROTTA and J. DI DOMENICO, J. Amer. Chem. Soc., .z.!, 5301 (1952)
44
GRAPTER !//
stereoselective synthesis rif geminal endo-iodo-exo-bromocyc lopropanes
III-1 Introduetion
In the preceding chapter it has been discussed how the configuration of the product is determined by both ring size and nucleophilicity of the solvent (solvolytic ring expansion) or the anion (non-solvolytic ring expansion). The following
general rules are now available. 1. If the expanded ring would become too small to accommodate
a trans double bond, then the endo halogen atom is lost. This always leads to cis products via a disrotatory ring opening. Some representative examples are presented below.
H
Ckr ;
r
H
®
AgOAc-HOAc
re flux - Br- ( endo)
AgOAc-HOAc
re flux -Cl- (endo)
ö-OAc
Br
l {ref. 1) -
(ref. 2 I
45
2. In ring expansions leading to enlarged rings which can bear a trans double bond, but in which the geometry of the en
larged system does not allow the existence of a free trans
cation, the exo halogen atom is lost. The nucleophile enters concertedly with the ring opening and the product formed
does have a trans geometry. These reactions display two-fold
stereospecificity. The r opening proceeds in a stereo-electronic controlled way 3 •~ and the attack of the nucleo
phile at the incipient allylic centre implies an inversion
of configuration 5 • So only one diastereoisomer is formed. A representative example is given below.
H ~
~ ~a~.
H~H ~OH Br
------------
5°/o aq.acetone
3. Another important class of bicyclic systems actually exhi-
46
bits opening via free cationic intermediates. Now two
pathways exist for product formation. If the cation is
trapped immediately the products will have a trans geometry.
From molecular models it is obvious that the steric builcl-
up of such a cation will not allow the formation of both
diastereoisomers one would expect. As such, the final stereo
selectivity of these reactions might be similar to the situ
ation presented for the fully conceited reaction.
If the cation does not react immediately with the solvent or an anion then isomerization to a cis cation may occur.
Generally this occurs preferentially in the presence of
weak nucleophiles such as No;, t-C4H90H, TosO • The products will show now a cis double bond arrangement.
AgOTos
The formation of either cis or trans products is encountered only in two extreme cases. A reasonably stabilized trans cation reacting with a hard nucleophile leads to a trans
configuration, whereas a trans cation which exhibits strong propensity towards trans+cis isomerization reacts with a weak nucleophile under formation of a cis product.
In practice these extreme prerequisites will seldom be encountered and in most cases hitherto known mixtures of cis
and trans products are formed. Representative examples are
e.g. the ring opening of 10,10-dibromobicyclo[7.1.0)decane (4) with silver nitrate and the t-butanolysis of 9,9-dibromobicyclo[6.1.0lnonane (2).
H Br
cj::~ d~r (R%" AgCI04 + !-C4HgOH - crt-c H - 4 9
0 @ Br 8 H Br
c:x~r AgN03 w:ON02 -~H + C~CN ~ ., Br
0 @ "'oNo2 ® Br
47
Only in the case of very weak nucleophilic anions like the tosylate anion, the ring expansion of 2 and 4 results in cis products exclusively.
III-2 Iodination of endo-Zithio-exo-bromocyaZopropanes
In a similar way the synthesis of a vinyl iodide has been described by ring opening of a geminal diiodocyclopropane precursor 6 (41, 42).
@
The examples of diiodocyclopropanes described in the literature are scanty, because these compounds are in most cases too unstable to be isolated or disproportionate rapidly at room temperature. Some efforts directed towards the synthesis of functionalized nine-membered systems bearing a trans vinyl iodide moiety, were rewarded with very moderate success due to the extreme instability of the prerequisite geminal diiodocyclopropanes 7
• 8 • As it is to be expected that mixed dihalocyclopropanes are more stáble precursors than the corresponding diiodo derivatives different chemical routes for their preparatien will be discussed. Synthesis of these hitherto unknown substrates by stereoselective addition of iodobromocarbene to cyclic olefins seemed to be less promising, with regard to the results of a variety of mixed carbene additions to cyclic olefins 9 - 15 • Köbrich et aZ. 16 found that upon treatment of 7,7-dichloronorcarane with n-butyl
lithium at -95° a reasonably stable mixture of endo- and exo isomers of 7-lithio-7-chloronorcarane was obtained.
48
Recently Hiyama et aZ. 11, showed that the corresponding 7,7-
dibromonorcarane could be lithiated stereoselectively at -95°
leading to 7-endo-lithio-7-exo-bromonorcarane. Subsequent addition of methyl iodide afforded the corresponding 7-endo
methyl-7-exo-bromonorcarane (43).
1) Buli, THF, -95°
2lCH3I, -95° -H
CK, H
@)
Based on the above mentioned considerations it was to be expected that iodination of such a lithiate would afford the
corresponding endo-iodo-exo-bromo derivative. This method had
been used for the precursor 9,9-dibromobicyclo[6.1.0lnonane (2). Treatment of 2 with one equivalent of n-butyllithium at -95° results indeed in the specific formation of 9-endo-lithio-9-exo-bromobicyclo[6.1.0lnonane. This was evidenced by a
quenching experiment with methyl iodide (see Chapter IV).
Upon treatment of this lithiate with iodine in THF at -95°
a single isomer was isolated which proved to be structure 44.
@
This compound displayed a typical 13c-nmr resonance at 4.1 ppm
downfield to TMS ( fBri, see Table VI). With the aid of simple silver ion promoted ring expansions the stereochemistry of 44
was determined as 9-endo-iodo-9-exo-bromobicyclo[6.1.0lnonane
(see Scheme I).
49
On treatment of 44 with a molar excess of silver perchlorate
in 10% aqueous acetone a mixture of the diastereoisomers of
trans-2-iodo-3-hydroxycyclonon-1-ene (45) and cis-2-iodo-3-hydroxycyclonon-1-ene (46) was obtained (approximate ratio
45/46 ~ 75/25). Close examination of the crude cis product
revealed the presence of about 20% of cis-2-bromo-3-hydroxy
cyclonon-1-ene (11). The presence of this product may readily
be explained by assuming some competition of a mo4e of ring
opening in which the endo iodine atom is expelled. This side reaction is not unexpected since the endo site now holds a
much better leaving group 18 • The ring expansion of 44 with
silver tosylate gave, as expected, cis-2-iodo-3-tosyloxycyclo
non-1-ene (47) only. lts identity could be established by
synthesis from the corresponding cis-2-iodo-3-hydroxycyclo
non-1-ene (46).
Scheme I
H Br I
d~ Ag+ w H20 O::X" ---- .
' OH
@ @I
OT os ' OH
C)-1 TosO- w-1 HzO ... Cj-1 @ @
50
In a similar way as outlined for the preparation of 44 the compounds 1, 2, 37 and 48 were converted into their corres
ponding geminal endo-iodo-exo-bromo derivatives 50, 44, 49
and 51 respectively (see Table VI).
Same final remarks should be made with regard to the iodination of the lithiates. Attempts to synthesize 6-endo-iodo-6-
exo-bromobicyclo[3.1.0lhexane (53) from the corresponding dibromo derivative (52) met with failure. Presumably this
lithiate disproportionates at -95° via an intermediate
allene 19 • 20 •
d"Bc Buli, THF a·'" ... [0] -95°
...
@) + I ' '
~·'"' dimers
® Another interesting observation is the fact that 9,9-dibromo
bicyclo[6.1.0]non-4-ene (3) could not be converted into the corresponding 9-endo-iodo-9-exo-bromobicyclo[6.1.0lnon-4-ene.
The lithiate derived from 3 proved to decompose instantaneous
ly into the corresponding allene (54) even at -95° as evidenced by an attempt to quench this lithiate with water.
H Br
c}(·' 0
1)8uLi,-95° ------
~' 51
Table VI
GE>m1nal ~- bro mo- E>ndo- iodocyclopropanE>s
Substra!E>s Produc ts 1 YiE>ld,% Bp(mm].Mp{°C I spE>ctro ( ppm val u es
H Br d' èt'' I 77 69-72 (0.01) 10.0 (CBri), 29.4, 33.9, 35.0,
36.2
CD @ H Br
c!l C:X'Br H''I 82 77-79 (0.02) 4.3 (CBri), 27.9, 29.3, 31.4,
34.7
® @
ä H ar
'Br 0~1fi 102-103 2 2.3 (CBri), 27.2, 28.3, 32.8,
90 33.1, 34.2, 34.5, 81.7, 82.2, 0
-J---o''~~. -1- < H 108.4 "' 0 @
H
~' (tl.' 69 71-75 (0.05) 11.3 (CBri), 21.7, 25.5, 29.4 , 1 'ar
@H @)H
1) Satisfactory elemental analyses were obtained (~ 0.3\ for C and H) for all products. 2) Crystallized from 95% ethanol.
3) Spectra obtained from neat products; except 51 which was measured as a 30t salution in CDC1 3 • ~
This phenomenon is discussed in detail in the next Chapter.
The silver ion assisted salvolysis of 49 is worth recording
since 7,7-dihalobicyclo[4.1.0lheptanes are prone to undergo ring expansion by expelling the endo halogen atom 18 • Upon
heating 49 with silver acetate in acetic acid for several
hours only ais-2-bromo-3-acetoxycyclohept-1-ene (38) was isolated in 74\ yield.
This synthesis of endo-iodo-exo-bromocyclopropanes is a hither
te unprecedented approach which permits the stereoselective
introduetion of the elements of iodobromocarbene into an olefinic system via an indirect way. Finally it is noteworthy
to comment that in contrast to the diiodocyclopropanes, the
corresponding endo-iodo-exo-bromocyclopropanes show indeed a high stability. Even on standing at room temperature for seve
ral weeks no disproportienation could be detected.
III-3 SiZver fluoride as an effeative oataZyst in ring
expansions of geminaZ dihaZooyaZopropanes
The ring expansions which have been presented in the
preceding section can be characterized as follows. If the ring size and the relative nucleophilicity of Nu
are known (either solvent or anion) it must be possible to
make rather accurate forecasts which products (and in which ratios) are formed (see Scheme II).
--X, Nu
coneerled
r-t~ , \/"'"~'\
y Nu
------·
' Nu Nu
--Y, Nu
isomerisation _ ~+ .. _, H H
y
One interesting set of experiments with silver fluoride is finally described. Treatment of 9,9-dibromobicyclo[6.1.0]non-
4-ene (3) with two equivalents 21 of silver fluoride gives via
a disrotatory ring opening with concomitant attack of the
fluoride anion at the incipient allylic centre trans,eis-2-
bromo-3-fluorocyclonona-1 ,6-diene (55). Details have been pre
sented in Table VII.
54
AgF, CH3CN
reflux, 3hr - ~H ~~F tf?l Br ~
The 1H-nmr spectrum displayed a typical double doublet coup ling pattern for the allylic hydragen (J 10 and 6 Hz) and a
geminal F-H coupling of 46 Hz. The olefinic proton adjacent
to the bramine atom resonates as a lower field triplet (J 8
Hz). This is in good agreement with the observations made upon reaction of 3 and a number of nucleophiles under silver
ion assisted ring opening. The dibromides 2 and 4 gave mixtures of cis and trans products upon reaction with silver
fluoride in acetonitrile.
H Br
c:z,~ F
AgF,CH3CN ~ ----=--- V-rBr eq; 0 @) Br
cis/trans C\l 60/40
cis/ trans C\l 20/80
The cis and trans products could be separated by column chroma
tography in both cases. The less polar compounds proved to be
the trans isomers. Structure assignment of 56 and 57 can be made readily.
55
The trans isomer 57 displays at room temperature the typical pattern of two equilibrating diastereoisomers (57a, b)
~H ~-,,.F
Br
8 - ~F ~--.,H
Sr
The methine part consistsof a multiplet at ö 5.17 and a double doublet (J= 10 and 5 Hz) at ó 4.82 which are both split by
a characteristic geminal F-H coupling (J= 47Hz). The methine
part of the cis fluoride shows only a double doublet at ö 5.54
(J= 10 and 5 Hz; JFH= 47Hz). Further it is recognized that the methine proton of the cis fluoride (56) resonates at lower
field than the methine protons of the trans diastereoisomers
(57a, b). This is in agreement with similar observations made in numerous compounds. A comparison of the formation of cis
and trans fluorides (56, 57) with the results achieved under
non-solvolytic conditions with other silver salts shows that increasing nucleophilicity produces an increase in the percentage of trans product (compare the silver fluoride cata
lyzed ring expansions with the silver nitrate reaction).
The formation of mainly trans-2-bromo-3-fluorocyclodec-1-ene
(59) upon reacting 4 with silver fluoride is fully consistent with the postulates and deserves no further comments. The
structure assignment was based on the observation mentioned
earlier that the methine proton for 58 resonates at lower field than that in 59.
Attempts to synthesize 2-bromo-3-fluorocyclohept-1-ene (60) by the reaction of 7,7-dibromobicyclo[4.1.0]heptane (37) with
silver fluoride resulted in recovery of starting material, as
37 is a typical system which is prone to undergo ring opening
with release of the endo halogen atom.
56
It seemed much prom1s1ng to choose 7-endo-iodo-7-exo-bromobi
cyclo[4.1.0]heptane (49) as a substrate, thereby favouring the ring expansion by a better leaving group at the endo site (I-). Upon refluxing of 49 for 6 hours with a two-fold molar excess of silver fluoride a ZOt yield of 60 was obtained.
AgF, CH3CN
-----''-----• 6 hr. reflux
1) AgPF5,
CH3CN, reflux 0.5 hr
2JH2D
®
As by-product the N-(2-bromocyclohept-1-en-3-yl)-acetamide
(61) was isolated, probably formed by a competitive Ritter reaction 22 • Upon using silver hexafluorophosphate (AgPF6) the amide 61 could even be obtained as a single product in
65% yield. The methad presented above constitutes a novel and facile approach in introducing fluorine stereospecifically in organic molecules with simultaneous ring enlargement. As such this constitutes not only an alternative approach for ring enlargement,
but also it is a valuable extension of the arsenal of methods to introduce fluorine in organic compounds 23 -
36• Under circum
stances activatien of a cyclopropane unit by introduetion of
a better leaving group may be a useful technique.
57
Whereas 7,7-dibromobicyclo[4.1.0]heptane (37) displays only
moderate reactivity towards silver nitrate, the corresponding
7-endo-iodo-7-exo-bromobicyclo[4.1.0]heptane (49) could be
converted within 10 minutes to the 2-bromocyclohept-1-en-3-ylnitrate (62) in excellent yield.
58
AgN03 , CH3CN
10 mm. rel lux -
~
Substroles
d' 1/Br
H
CY:,, H 0 H Br
~tBr
H cy.;r '/I
H
@
Table VII
Reaction of gem•nol diholocyclopropanes
with AgF acetonilrile
Product s 3 [ra t1o )11
Yield,%1 Rt 2 NMR dato ! CDCt 3 I, Ó va lues
d-~ cqçH 36
@)4oBr 60
O:XH 33 F
@ Br
CÇ{H c:x: .. 41 ' Br ~
@so 20
F
(j-~ 20
@
56: 6.25 (t
0.29(c) (dd, 1'
0.33(t) JHF=47 57: 6.07 (d
4.82 an
0.16 55: 5.88 [t
5. 29 (m
4.80 (d
58: 6.07 (d 0.22(c) 5.59 (d
0.29(t) JHF=47 59: 6.37 (t
4. 90 (t
JHF=47
0.25 60: 6.46 (t
2 Hz),
4 7 Hz)
, 1, alefin H, J=9 llz], 5.
methine H, J=10 and 5 Hz],
Hz
d, J=10 and 6 Hz)
d 5.17 1, m and dd, J•10
Hz
, olcfin 11, J=8 Hz)
, 1 , olefin H5 and H6 )
d, 1, methine, 11, J=10 and
d, 1, olefin H, J•10.5 and
d, 1, mcthine !!, J=9 and 6
lz
, 1, alefin H, J=R Hz)
, methinc H, J=7 Hz
lz
, 1, alefin J=6 Hz,
5.11 (m, 1, methine H,
1) Yields are based on pure products, isolated after chromatography. 2) Rf values wcre measured on Merck
silicagel plates, using hexane as eluent. 3) Satisfactory analytica! data were obtained (! 0.3\ for C
and H). 4) Product ratlos were determined on the basis of isolated yields after chromatography and wcre consistent with ratios estimated from the nmr spectra of thc mixtures.
III-4 Experimental seation
GeneraZ. The dibromides 1-4 and 37 were prepared by
a documented method 37 • Cyclononene, required for the prepa
ration of 4 was synthesized from 2 in a two-step sequence 38•
Silver fluoride was purchased from Merck A.G. (Darmstadt).
Silver hexafluorophosphate was obtained from Alfa Inorganics (Beverly, Mass.). 13C-Nmr spectra were measured on a Varian HA-100 apparatus at 25.12 Hc/s. Helting points are uncorrec
ted. A typical experimental iodination procedure is outlined
for the preparation of 44 from 2. The preparation of the
fluorides is illustrated by the synthesis of 56 and 57.
9-endo-Iodo-9-exo-bromobicyclo[6.1.0]nonane (44)
To a salution of 2.82 g (0.01 mol) of 2 in 15 ml of THF
(freshly distilled from LiAlH4) was added dropwise with stir
ring at -95° 5.4 ml (0.01 mol) of a 15% salution of butyllithium in hexane. After stirring for 10 minutes a salution
of 2.79 g (0.011 mol) of iodine in 5 ml of THF was introducedat such a rate to maintain the temperature below -80°.
After stirring for an additional 10 minutes the mixture was
allowed to reach room temperature. Upon addition of 100 ml of water the product was extracted twice with 50 ml portions
of ether. After washing, drying and evaporation of the solvent the residual oil was chromatographed through a short silica gel column (hexane as eluent) and was finally distilled under reduced pressure. This afforded 2.69 g (82%) of 44; bp 77-79°
(0.02). 13c-Nmr data are presented in Table VI. Anal. Calcd
for C9H14Brl: C, 32.83; H, 4.25. Found: C, 33.09; H, 4.33.
60
2-Bromo-3-fluorcyclonon-1-ene (56, 57) To a salution of 2.82 g (Q.01 mol) of 2 in 20 ml of aceton
itrile was added 2.52 g (0.02 mol) of silver fluoride. The mixture was stirred with gentie reflux, while monitoring the reaction by tlc. After 3 hours the reaction.mixture was caol
ed and poured onto 100 ml of saturated NaCl solution. Then 50 ml ether were added and stirring was prolonged for 10
minutes. Upon removal of the silver salts by filtration, the organic layer was separated and washed twice with water. The
residue, which remained after drying and evaporation of the
solvent, was taken up in hexane and filtered through a short florisil column. This gave 795 mg (39%) of a mixture of ais
and trans-2-bromo-3-fluorocyclonon-1-ene (56 and 57 respectively). An analytica! sample was obtained from evaporative bulb to bulb distillation. Anal. Calcd for c9H14BrF: C, 48.87;
H, 6.33. Found: C, 48.57; H, 6.30. The individual isomers were obtained by chromatography through silicagel, using hexane as eluent (see Table VII).
trans-4,5-Dihydroxy-9,9-dibromo-ais-bicyclo[6.1.0Jnonane, acetonide (48) Toa stirred salution of 1.82 g (0.01 mol) of the acetonide of 1 ,2-trans-dihydroxycyclooct-5-ene 39 • 40 , 12.65 g (0.05 mol) of bromoform and ZOO mg of benzyldimethylcetylammonium chloride was added at 50° 4 g of 50% aqueous NaOH (0.05 mol). The mixture was stirred for 24 hours at 55-60° and then di
luted with 100 ml of water. The product was extracted twice
with ether. The residue which left after washing, drying and
evaporating of the solvent was treated with 95% ethanol at an ice bath. The white solid obtained was collected and once
recrystallized from 95% ethanol and gave 2.19 g (62%) of 48; mp 85-86°. Nmr (CDC1 3) ó 1.38 (s, 6, CH3), 3.40-4.20 (m, 2, C~(O)-C~(O)-). Anal. Calcd for c12H18 Br 2o2 : C, 40.67; H, 5.08. Found: C, 40.51; H, 5.09.
61
2-Iodo-3-hydroxycyclonon-1-ene (45a, b and 46)
To a solution of 830 mg (4 mmol) of silver perchlorate in 4 ml of 10% aqueous acetone was added with stirring 658 mg
(2 mmol) of 44. Precipitation of silver bromide started immediately. Stirring was prolonged for 1.5 hours while monotering
the reaction progress with tlc. Upon addition of 10 ml of sa
turated· sodium chloride solution and 15 ml of ether the mix
ture was stirred for additional 10 minutes. After removal of
the precipitates the organic phase was washed twice with
water. Upon drying and evaporation of the solvent a mixture of 45a, b and 46 (3:1, according to 1H-nmr) left as an oil. Chromatography (silica gel; chloroform as eluent) afforded
96 mg of cis-2-iodo-3-hydroxycyclonon-1-ene (46) Rf 0.35, mp (hexane) 66-68° and 325 mg of a diastereoisomerie mixture
of trans-2-iodo-3-hydroxycyclonon-1-ene (45a, b, Rf 0.31). Nmr (CDC1 3) for 46: o 0.85-2.40 (m, 12, ring methylene H),
1.87 (s, 1, OH), 4.04 (m, 1, methine H), 6.51 (t, 1, alefin
H). Nmr (CDC1 3) for 45a, b: o 0.75-2.60 (m, 12, methylene H), 2.36 (s, 1, OH), 3.49 and 4.67 (m, 1, methine H), 6.02 and
6.41 (tand m, 1, alefin H, J 8 Hz), Anal. Calcd for C9H15 ro (7): C, 40.60: H, 5.64. Found: C, 40.52; H, 5.71.
cis-2-Iodo-3-tosyloxycyclonon-1-ene (47) A salution of 658 mg (2 mmol) of 44 and 1.12 g (4 mmol) of silver tosylate in 4 ml of acetonitrile was refluxed for 15
minutes. To the caoled mixture was added with stirring 15 ml
of ether and 10 ml of saturated sodium chloride solution.
After filtratien of the precipitates the organic layer was separated and washed twice with water. The product obtained
was chromatographed through a short silica gel column (benzene I
as eluent). This gave 657 mg (78%) of tosylate 47 as a white
crystalline solid; mp (hexane) 59-60°. Anal. Calcd for
c16H21 ro 3s: C, 45.72; H, 5.04.
62
Found: C, 45.87; H, 5.09. Nmr (CDC1 3): ö 2.40 (s, 3, CH3), 5.02 (dd, 1, methine H, J 11 and 5 Hz), 6.40 (t, 1, alefin H, J 9 Hz). The product was identical with an authentic
sample of 47 prepared by tosylation of cis alcohol 46 with
p-toluenesulfonylchloride in pyridine.
cia-2-Bromo-3-acetoxycyclohept-1-ene (38)
A mixture of 301 mg (1 mmol) of 37, 334 mg (2 mmol) of silver
acetate and 2 ml of acetic acid was heated for 10 hours at
100°. The product was poured onto 20 ml of water and neutralized with portions of solid sodium bicarbonate. After extraction with ether, washing, drying and evaparatien the crude
38 left as an oil. Upon chromatography (Si02-CHC1 3) 184 mg
(78%) of pure 38 were isolated (identical with a sample prepared from 7,7-dibromobicyclo[4.1.0lheptane). Nmr (CDC1 3)
ö 2.10 (s, 3, CH 3), 5.57 (m, 1, methine H), 6.43 (t, 1, alefin H, J 7 Hz).
N-(2-bromocyclohept-1-en-3-yl)-acetamide (61)
A salution of 602 mg (2 mmol) of 49 and 1. 01 g ( 4 mmol) of
AgPF 6 in 5 ml of dry acetonitrile was refluxed with stirring
for 0.5 hour. The product was poured onto a stirred mixture
of 20 ml of saturated NaCl salution and 20 ml of ether. After 10 minutes the silver salts were filtered and the orga
nic layer was separated. Upon washing, drying and evapora
tien of the solvent a solid was obtained. Recrystallization
from benzene-pet.ether gave 300 mg (65%) of 61; mp 106-107°.
Anal. Calcd for c9H14BrNO: C, 46.55; H, 6.03; N, 6.03. Found: C, 46.55; H, 6.05; N, 5.90. Nmr (CDC1 3) ö 2.02 (5, 3, CH 3),
4.81 (m, 1, methine H), 6.30 (t, 1, alefin H, J 6 Hz), 6.77
(m, 1, NH); ir (KBr) vco 1650 cm- 1 .
63
Rejerences and notes
1. P.S. SKELL and S.R. SANDLER, J. Amer. Chem. Soc.,~. 2024 (1958)
2. S.J. CRISTOL, R.M. SEQUEIRA and C.H. DePUY, J. Amer.
Chem. Soc.,~. 4008 (1965) 3. R.B. WOODWARD and R. HOFFMANN, J. Amer. Chem. Soc.,
~. 395 (1965) 4. C.H. DePUY, R.G. SNACK and J.W. HAUSER, J. Amer. Chem.
Soc.,~. 3343 (1966) 5. C.B. REESE and A. SHAW, J. Chem. Soc. (Perkin I), 2422
(1975) 6. M.S. BAIRD, Chem. Comm., 197 (1974) 7. J.P. OLIVER and U.V. RAO, J. Org. Chem., ll, 2696 (1966) 8. P. WEYERSTAHL and R. MATHIAS, Angew. Chem., ~. 42 (1974) 9. P. WEYERSTAHL, R. MATHIAS and G. BLUME, Tetr. Lett., 611
(1973)
10. R.A. MOSS and F.G. PILKIEWICZ, Synth., 209 (1973)
11. D. SEYFERTH and S.P. HOPPER, J. Organomet. Chem., ~. 77 (1973)
12. D. SEYFERTH and C.K. HAAS, J. Organomet. Chem., ~. C-33 (1972)
13. H. DAHL, F. NERDELand P. WEYERSTAHL, Ann., 755, 40
(1972) 14. M. SCHLOSSER, G. HEINZ and LE VAN CHAN, Ber., 104, 1921
(1971) 15. T. ANDO, H. HOSAKA, H. YAMANAKA and W. FUNASAKA, Bull.
Chem. Soc. Jap., Q, 2013 (1969)
16. G. KÖBRICH and W. GOYERT, Tetr., ~. 4327 (1968) 17. K. KITATANI, T. HIYAMA and H. NOZAKI, J. Amer. Chem. Soc.,
~. 949 (1975)
64
18. W.F. SLIWINSKI, T.M. SU and P.v.R. SCHLEYER, J. Amer. Chem. Soc., 94, 133 (1972)
19. W.R. MOORE and W.R. MOSER, J. Amer. Chem. Soc., 5469 (1970)
ZO. L.A. PAQUETTE, G. ZON and R.T. TAYLOR, J. Org. Chem., 39, 2677 (1974)
21. For the interconversion of halogen with fluorine normally an undesirable complex formation of the type AgF.AgX takes place. Therefore excess of silver fluoride is usually required. See: R.D. Chambers, "Fluorine in Organic Chemistry", Wiley and Sons, Inc., New York, 1973, pg 38.
22. The formation of an amide has been observed also in the silver tosylate promoted ring opening of 1-fluoro-1-iodo-2-phenylcyclopropane in acetonitrile. See: P. WEYERSTAHL, R. MATHIAS and G. BLUME, Tetr. Lett., 611 (1973).
23. G.A. OLAH, M. NOJIMA and I. KEREKES, Synth., 487, 779 and 786 ( 1973)
24. L.N. MARKOVSKIJ, V.E. PASHINNIK and A. V. KIRSANOV, Synth., 787 (1973)
25. G.A. OLAH and J. WELCH, Synth., 652 (1974) 26. D. LANOINI, F. MONTANARI and F. ROLLA, Synth., 428 (1974) 27. G. PARGES and A. KERGOMAROL, Bull. Soc. Chim. France,
3647 (1969) 28. G.L. GRADY, Synth., 255 (1971) 29. L.O. HALLand J.F. MANVILLE, Can. J. Chem., ±l• 361
(1969) 30. L.O. HALLand D.L. JONES, Can. J. Chem., ~. 2902 (1971) 31. G. BARTOLI, A. LATROFA, F. NASO and P.E. TOOESCO, J. Chem.
Soc. (Perkin I), 2671 (1972) 32. G.A. BOSWELL Jr., J. Org. Chem., 3699 (1968) 33. M. ZUPAN and A. POLAK, Chem. Comm., 845 (1973) 34. M.J. ROBINS and S.R. NAIK, Chem Comm., 18 (1972) 35. M. SCHLOSSER and G. HEINZ, Ber., 102, 1944 (1969)
65
36. A. BOWERS, P.G. HOLTON, E. DENOT, M.C. LOZA and R. URQUIZA, J. Amer. Chem. Soc.,~' 1050 (1962)
37. L. SKATTEB~L, Acta Chem. Scand., !I, 1683 (1963) 38. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~
3518 (1961)
39. P. YATES, C.G. LAVARS and P.H. McCABE, Can. J. Chem.,
~. 1548 (1972) 40. J.M. MciNTOSH, Can. J. Chem., ~. 2152 (1972)
CHAPTER IV
Bishomoaromatic interaction in the disrotatory rzng opening qJ cyclopropyl carbenoids
IV-1 Introduation
In the general introduction, presented at the outset of
this thesis target compounds have been presented.
n = 2, 3
R= H, CH3
In order to achieve the ultimate synthesis of these compounds several individual basic problems had to be solved befare a straight forward synthesis would become feasible. An answer
to a part of the questions raised at the beginning of this
work has been given in the preceding chapters.
A mechanistic reaction path has been outlined which prediets the stereochemistry of the products arising from ring expansion reactions with a variety of silver salts. In this way
it has become possible to synthesize interesting functiona
lized precursors for the prerequisite model compounds.
Furthermore, an elegant route has been elaborated which per
mits the stereospecific introduetion of iodine at olefinic
bonds, starting from stabie iodo precursors (endo-iodo-exo
bromocyclopropanes).
67
These latter systems are of particular interest, since it is to be expected that they may be reduced under mild conditions
to the parent olefinic systems with retension of stereochemistry. To convert stereoselectively a variety of the corresponding trans-2-bromo-3-hydroxycycloalk-1-enes to the trans-3-
hydroxycyc~oalk-1-enes proved to be rather cumbersome and was
always accompanied by extensive isomerization 1•
2•
So, on treatment of both ais-2-bromo-3-hydroxycyclonon-1-ene (11) and trans-2-bromo-3-hydroxycyclonon-1-ene (6) witheither
Li-NH3-t-C4H90H, Na-C 2H50H or Li-ethylenediamine always ais-3-
hydroxycyclonon-1-ene (63) was obtained.
frYH ~%H ® Br
dissolving metal
/
OH
Cj
Apparently the reduction proceeds through intermediate radi
cals which, upon progress of the reaction, give the stable cis olefin.
68
~L-yH \../" Y "tJu
Br
~H ~ 0 OU --------
t
'
An alternative approach to trans-cycloalkenes (I) or trans-2-
methylcycloalkenes (II) would entail the ring opening of the corresponding ezo-bromobicycloalkanes (III) or the ezo-bromoendo-methylbicycloalkanes (IV).
~r u ~'H @)
H Br Ag•
~"' _______ ,_
®
H
<;i.;> H H
~ H H
H
~Sol' ____ ,... H H
CH3
ÇJy.so\' .... H H
@
69
The approach presented above hings on the accessibility of the cyclopropane precursors. Therefore an investigation in
this typical area was obvious.
IV-2 Lithiation geminaZ dibromoayatopropanes
Geminal dihalo compounds have been shown to produce
carbenoid species on treatment with organo lithiums 3 •
In the specific instanee of 1,1-dibromocyclopropanes the
transient carbenes generally disproportionate readily. Host
commonly allenes are formed via a conrotatory ring opening
of the four-electron species~- 11 •
conrota t ory -------- , __ /
~-----,
An alternative, often competative, mode of reaction of the
carbenoid species is the insertion inC-H bonds 12 - 20 •
Though it is difficult to derive rules from literature, it
becomes clear that insertion reactions occur predominately
in highly substituted cyclopropylidenes with great preferenee
for tertiary C-H bonds. Illustrative is the following example 1 ~.
70
(80%)
+
120% I
It has been found quite recently that carbenoid species do have slight stability at very low temperatures. Under these
circumstances they behave like anions and are readily alkylatable21-23. In conneetion with the presented work aiming
at the synthesis of the model systems, this behaviour of
carbenoid species might be applied in an elegant way to
achieve an entry into methylated olefins. To this end the
recently described method of Hiyama et aZ. was employed,
which permits the stereoselective synthesis of endo-methyl
exo-bromocyclopropanes by lithiation and subsequent methylation of geminal dibromocyclopropanes.
R~1 R Br
, "' ' • Br H ::.
H
Buli
THF, -95°
R~1 Br
, _. '-' • "'L· H :. I
H
____ ,_ R~1 R Li
" ;.-' . B H ~ r H
71
The formation of the endo-lithio compounds is proposed to occur via an initia! e~o-lithio derivative which isomerizes to the more stabie endo-lithio derivative. The authors showed that these compounds are excellent precursors for specifically
substituted olefins.
~"' H ~ Br
H
AgOAc- HOAc --~----------,--
Treatment of 1-e~o-bromo-1-endo-methyl-trans-2-phenylcyclopro
pane (64) with silver acetate in acetic acid leads to E-Smethylcinnamylacetate (65). With these considerations in mind the methad of Hiyama et aZ. was applied to 9,9-dibromobicyclo[ 6.1.0lnonane (2) and to the acetonide of 4,5-trans-dihydroxy-9,9-dibromo-ais-bicyclo[6.1.0lnonane (48) as representative models.
Upon treatment of 2 with one equivalent of butyllithium in dry THF at -95° and after subsequent addition of excess of methyliodide at -95° one single isomer was obtained in essen
tially quantitative yield. The 1H-nmr spectrum revealed a sharp singlet at o 1.63 (CDC1 3) forthemethyl group. Furthermore this compound reacted within 5 minutes with an excess of silver tosylate, a reagent which is very sensitive towards e~o
bromocyclopropanes (see Chapter I). With the help of the latter reaction the structure of the compound has tentatively
assigned as 9-e~o-bromo-9-endo-methyl-ais-bicyclo[6.1.0lnonane (66). In an identical way 48 was converted to the corresponding endo-methyl derivative 67 in 92% yield. The 1H-nmr
spectrum showed again the presence of one isomer, with a sharp singlet at o 1.63 (CDC1 3).
72
H Br
~''''Br o~H +o~@
------ (77%)
1) Buli, THF,-95°
2) CH3I ,-95°
(92 %)
However, on treatment of 9,9-dibromo-ais-bicyclo[6.1.0lnon-4-
ene (3) with butyllitium and methyliodide under identical conditions, the allene 54 was obtained as the sole product.This
was established unambiguously from its 1H-nmr and ir speetral data 2 ~- 26 •
1) Buli, THF,-95° -
It is worth recording here that a similar anomalous behaviour
of 3 has been observed in the reduction of this dibromide with
dimsyl anion in DMS0 27• The dibromides 2 and 48 can be reduced
easily to their corresponding exo-bromo derivatives 68 and 69
respectively. In contrast, reduction of 3 with this reagent
affords only the allene 54.
73
H Br
c::i"' --------
NoH - DMSO. room temperoture
---------------
These reduction reactions are believed to praeeed via carbe
noid species. It is most likely that the presence of the double bond at c4 5 in 3 might be a crucial factor in this
' anomalous behaviour. In order to get more insight in this problem a related system was used which bare a cyclopropane
unit insteadof a double bond at c4 , 5 .
Treatment of i0,10-dibromo-cis,cis-tricyclo[7.1 .o.o 4' 6 Jdecane
(70) with butyllithium and methyliodide at -95° afforded the corresponding allene 71 and no trace of the methylated product.
H Br
H~''Br H,,~H
H H
@
Buli, CH3I
THF,-95°
H
-~ H
® It is interesting to note that the strained 9,9-dibromo-trans
bicyclo[6.1.0]nonane (72) proved to be stable under the con
ditions described above and could be converted smoothly to
9-methyl-9-bromo-trans-bicyclo[6.1.0]nonane (73) without allenic impurities.
74
q., Br
@
1)BuLi, THF,-95°
2)CH31 ,-95° -
Whereas allene formation may be regarcled as a common reaction at elevated temperatures (> -30°), its formation at such a low
temperature must be regarcled as rather surprising.
IV-J Backgrounds of the ring opening of oyolopropylidenea
Upon consiclering the ability of cyclopropyliclenes to undergo alkylation reactions, they can be regarcled as anions at such low ternperatures. The preferrecl mode of ring opening of such species, leading to allenes, will be conrotatory
basedon orbital symrnetry considerations 28 • 29 • This has been
confirmed by extended Hüokel 30 , ab initio 31 and MIND0/2 32
calculations. A representative exarnple would be the highly
stereospecific ring opening of 9-endo-deuterio-9-exo-chloro
ois-bicyclo!6.1.0]nona-2,4,6-triene (74) with potassiurn in THF leading to oia,oia,oia,trana cyclononatetraenyl anion (75)33,34.
K, THF, -30° 0
-----------------
®
75
The stereochemistry of the anion 75 is indicative for the conrotatory nature of the ring opening. However, the deuterium atom does exhibit pseudo-scrambling by topomerization. Upon warming, the more stable all cis anion is formed. Based
on steric considerations, the conrotatory mode of ring ope
ning seems to be an unfavourable process at very low temperatures for the carbenoids derived from 2, 3, 48 and 70, and even for 72 in which the cyclopropane unit is fused in a favourable trans manner. The conrotatory mode of ring opening 72 at low temperatures is restricted, because the system has
to pass through an initially strained trans,trans allylic geometry. Th1s explanation, basedon steric considerations, can
be supported by an experiment carried out by Winatein et al.
and Paquette et aZ. 35-
40• Treatment of eis-bicyclol6.1.0]nona-
2,4,6-tri~ne (76) with potassium in glyme at -80° gave a nonclassica! anion 77, whereas the corresponding trans-bicyclo-
6.1.0 nona-2,4,6-triene (78), upon treatment with potassium
under similar conditions, gave the classica! anion 79. The ring opening of 78 would lead to an unfavourable strained eia,trans
cyclononatetraenyl radical anion.
d< ,,,,H
non- c lassi cal "H -
H
@ K , glyme, -80° ®
H H
0< classica! -H
H
@ ®
76
The ring opening of 2, 3, 48 and 70 by an alternative disrotatory movement seems to be more attractive but in fact this is a forbidden process. Therefore it is most likely now that the rapid mode of ring opening of 3 and 70 is due to a bishomoaromatic interaction between the cyclopropylidene moiety and the double bond or the WaZsh type orbitals of the cyclopropane unit at c4 , 5 respectivelyq 0 • Extension of the electronic system of the cyclopropylidene by two electrons in
this way leads to an aromatic transition state, favouring a disrotatory ring opening.
Br
Br
Further evidence for this explanation can be quoted from recent literature on bicyclo[3.2.1locta-2,6-diene systemsql-qq.
A particular example which is worth recording, and which by its nature has close similarity to the problem mentioned afore, is the base-catalyzed rearrangement of 3-bromobicyclo[3.2.1]octa-2,6 diene (80) to endo-6-ethynylbicyclo[3.1.01hex-2-ene (81) 45 • In this reaction the intermediacy of a homoconjugated carbene has been suggested.
77
d:>-sr t- c,u..Jï- t:f:>_.---------._ - ~ '!I" • - - -· Br !-C4HgOH -------
------
I• f
The model for the rapid ring opening of the cyclopropylidenes derived from 3 and 70 suggests an interaction through space
over a relatively large distance. Therefore it was obvious that a further requirement might be some flexibility in the
bicyclo[6.1.0)nonane skeleton which allows bending of the
double bond (in 3) and of the cyclopropane (in 70) towards the cyclopropylidene system. An example in this series which
doesnotmeet this requirement is 9,9-dibromo-cis-bicyclo-
[ 6.1.0)nona-2,4,6-triene (82) in which the double bond at
c4,5 is tightly fixed.
1)Buli, THF,-95° -------------
78
Indeed, upon treatment of 82 with butylithium and methyl iodide at -95° only 9-endo-methyl-9-exo~bromo-cis-bicyclo [6.1.0lnona-2,4,6-triene 83 was formed. Some experiments carried out at higher temperatures showed that the lithiate
derived from 82 proved to be stable up to -45°. Above this temperature decomposition to an undefinable mixture of
products took place. The lithiate derived from 2 proved to
undergo ring opening at an appreciable rate at -40°, leading to the corresponding allene.
IV-4 Behaviour of cyclopropylidenes attached to polyenes
In the preceding section it has been shown that cyclo propylidenes disproportionate readily at temperatures above
-40° to allenes or insertion products. At very low temperature
(< -80°) the carbenoid species display a remarkable stability,
except in those cases where favourable electronic interactions facilitate the mode of ring opening (a suitably located double bondor a cyclopropane unit).
------·-
For these cases an "apparent" vialation of Woodward-Hoffmann
rules is observed. A prerequisite for such interactions seems
to be the close proximity and correct position of the double
bond. An example drawn from the literature is the reaction
of 9,9-dibromo-cis-bicyclo[6.1 .O]non-2-ene (84) with methyllithium. The product from this reaction is not the allene
but the insertion products arising from a relatively "stable"
carbenoid (85 and 86)46
79
H
Q{ 8 8 CH3Li. ether +
z -40° Br H
@ @ ®
It would be of special interest to see if interactions be-tween cyclopropylidenes and double bonds would be present in relatively flexible systems, viz. cyclopropylcarbenoids substituted with a polyenic system. This attempt seemed not to be much proruising with regard to some literature data now available, but synthetically it seemed challenging enough to try. Compound 87 was chosen as a model and submitted to the action of butyllithium and methyl iodide at low temperature in order to see if an alkylation could be brought about, leading to 88.
Both 87 and 88 were not known in literature and preparation via selective cyclopropanation of the corresponding triene was considered as the most attractive approach. For the preparation of 87 as starting compound 2-methyl-3-buten-2-ol (89) was used (see Scheme III). Treatment of 89 with vinylethyl ether and a catalytic amount
of phosphoric acid for 3 hours at 160° led via a Claisen re
arrangement to 5-methylhex-4-en-1-al (90)' 7 in 481 yield.
80
Co ....
(<oH
@)
+ ~0~
ÇU" @ ?-P~J· THF,-40°
çó @
cot. H3P04
160°
Cr03. 2 Pyr. HCI
CH2CI 2
q" r--MgBr
~ THF, -20°
@) ® I
CH ( OC2H5J3cH3 cot. c2H5COOH, 130°
' ço LiAIH4 WOC2Hs I ether, 0°
@) ®
Upon reacting this aldehyde with vinylmagnesium bromide at
-20° in dry THF a smooth conversion to 3-hydroxy-7-methylocta-
1,6-diene (91) was achieved in essentially quantitative yield.
The crude product was treated with ethyl orthoacetate and a
catalytic amount of propionic acid. This gave via an orthoes
ter Claisen rearrangement the E-9-methyldeca-4,8-dienoic acid,
ethyl. ester (92) in 74% yield 4 8•
4 9• Reduction of this ester
with lithium aluminohydride gave quantitatively the corres
ponding alcohol 93. Subsequent oxidation with pyridine chloro
chromate50 in methylene chloride afforded the aldehyde E-9-
methyldeca-4,8-dienal (94) in 62% yield. Reaction of this
aldehyde with the ylide derived from isopropyltriphenylphos
phonium iodide at -40° in THF gave the required 2,10-dimethyl
dodeca-2,6,10-triene (95) as a colourless liquid in 82% yield.
The cyclopropanation was attempted with the aid of phase
transfer catalysis 51 . As a catalyst S-hydroxyethyldimethyl
benzylammonium hydroxide was chosen 52 . This catalyst has been
documented to give selectively mono adducts e.g. in the re
action of cyclododecatriene with chloroform. Treatment of 95
with an excess of bramofarm and 50% aqueous sodium hydroxide
at 50° in the presence of the catalyst gave a mixture of mono
and biscyclopropanated product 87 and 96 in a ratio of about
60/40. This ratio remained unaltered upon changing the reaction
conditions. The use of other catalysts, such as e.g. benzyl
dimethylcetylammonium bromide, did nat imprave the result.
82
CHBr3 ,50% -NaOH
soa. :;N_.....oH +
Br
(',I J</··,,s, • LyV ar
@) ai=
Br
''''Br
mono/ bis rv 60/40
The two products could be separated by means of column chroma
tography. The biscyclopropanated product proved to be only
terminally substituted. This result may, to all probability,
be ascribed to a strong steric factor. Treatment of 87 with
butyllithium and methyl iodide at -95° gave a mixture of two
isomerie methylated products to which the structures 88 and
97 have been assigned, based on the observation that an endo
methyl group resonates at higher field than the corresponding
exo-methyl derivative 21•
··~ +
........ ':... ' , Br
The formation of bath the endo and the exo derivative may be
explained by the higher degree of substitution of the cyclo
propane unit, which decreases the energy difference between the endo lithio and the exo-lithio derivative and thus gives
rise to the formation of product mixtures. It is self-evident
that there may still be a preferenee for the formation of 88.
From the experiment outlined above it is obvious that in an open-chain system like 87 there does not exist a strong in
teraction between the cyclopropyl lithiate and the nearby
double bond. For such an interaction the presence of a double
bond in a transition state like arrangement seemes to be an
additional ite.
IV-5 Experimentat seotion
Generat. The starting dibromides 2 and 3 were prepared by reaction of the appropriate olefins with dibromocarbene 53
•
9,9-Dibromo-trans-bicyclo[6.1.0]nonane (72) was obtained from trans-cyclooctene 5 ~ by reaction with bromoform and potassium
t-butoxide in pentane 6• The preparatien of 9,9-dibromo-ois
bicyclo[6.1.0]nona-2,4,6-triene (82) was brought about as indicated by VogeZ 55
• The preparatien of the dibromide 48 had been achieved as outlined in Chapter III. Compound 70 had been obtained in 58% yield by the reaction of bicyclo[6.1.0]non-4-ene with dibromocarbene 56 ; bp 83-85° (0.01). Helting points were determined on a Mettier apparatus and are uncorrected. Nmr spectra were recorded on a Varian T-60 spectrometer, using TMS as an internal standard.
3~Hydroxy-ois-cyclonon-1-ene (63) To a solution of 200 mg of lithium in 10 ml of liquefied ammonia was added dropwise with stirring at -40°, a solution of 219 mg (1 mmol) of ois-2-bromo-3-hydroxycyclonon-1-ene (11) and of 200 mg of t-butanol in 2 ml of THF. The mixture was kept for 0.5 hour at -40° and the excess of lithium was destroyed with solid ammonium chloride. After evaporation of ·the ammonia, 10 ml of water and 10 ml of ether were added. The organic layer was separated and washed twice with water.
Upon drying and evaporation of the solvent 116 mg (83%) of 63 left as an oil. The product was identical in all respects with an authentical sample prepared from 9-endo-bromobicyclo[6.1.0]nonane and silver perchlorate in 5% aqueous acetone 57
•
Nmr (CDC1 3) o 0.8-2.3 (m, 12, methylene H), 2.61 (s, 1, OH),
4.54 (m, 1, C!:!OH), 5.49 (m, 2, olefin H).
84
The same product was obtained by reduction of the tPana-2-
bromo-3-hydroxycyclonon-1-ene (6) under identical conditions.
9-exo-Bromo-9-endo-methyl-ais-bicyclo[6.1.0lnonane (66) To a solution of 2.80 g (0.01 mol) of 2 in 15 ml of dry THF (distilled from LiAlH 4) was added dropwise 4 ml of a 20\ solution of butyllithium in hexane at -95° (toluene-liquid nitrogen bath). After stirring for 10 minutes 1.5 ml of methyl
iodide was auded in one portion and after one hour the mixture was gradually warmed to 0°. Then 100 ml of water was added and the product was extracted with ether. Work-up and subsequent
distillation gave 1.5 g (70%) of 66; bp 118-121° (14). Nmr (CDC1 3) ö 1.63 (s, 3, CH 3), 1.60-2.20 (alifatic and cyclopropane H). Anal. Calcd for c10 H17Br: C, 55.30; H, 7.83. Found: C, 55.31; H, 7.89.
4,5-tPana-Dihydroxy-9-exo-bromo-9-endo-methyl-aia-bicyclo[~.1.0]nonane, acetonide (67) Toa solution of 1.7 g (0.005 mol) of 48 in 10 ml of dry THF
was added 2.2 ml of butyllithium salution and 0.7 ml of methyl iodide in a similar way as described for 2. Work-up afforded 1.22 g (92%) of 67 as a white solid; mp [ (i-Pr) 20J70-71°. Nmr (CDC1 3) ö 1.39 (s, 6, CH 3), 1.63 (s, 3, endo CH 3), 3.40-4.35 (m, 2, CH(O)-CH(O)-). Anal. Calcd for c13H21 Br0: C, 53.98; H, 7.27. Found: C, 54.04; H, 7.10.
Cyclonona-1,2,6-triene (54) Toa salution of 2.80 g (0.01 mol) of 3 were added 0.011 mol of butyllithium and excessof methyl iodide at -95°, as described for the synthesis of 66. Work-up gave an oil which, upon examination by tlc, proved to consist of one component
besides some tlc immobile material (silica gel; pentane as eluent). Chromatography gave 0.98 g (81\) of 54; identical with the compound prepared by other routes 2 ~• 25 •
85
Nmr (CDC13
) 6 5.20 (m, 2, allenic H), 5.55 (m, 2, alefin H), 1.25-2.60 (m, 8, other H); ir (neat) v 1958 cm- 1 (allene).
ois-Bicyclo[7.1.0]deca-4,5-diene (71) This compound was prepared in an identical way as described
for 54 from 2.94 g (0.01 mol) of 70. Work-up and chromato
graphy over a short column (silicagel; pentane as eluent) provided 0.89 g (67%) of the allene 71, nmr (CDC1 3) 6 5.27
(m, 2, allenic H), 0.40-2.60 (m, 12, alifatic ringHand cyclopropyl H). Ir (neat) v 1960 cm- 1 (allene). This compound
proved to be thermolabile.
9-exo-Bromo-ois-bicyclo[6.1 .O]nonane (68) 27
To 20 ml of a 1M salution of dimsyl anion in DMSO was added
with stirring 2.8 g (0.01 mol) of 2 at such a rate as to
maintain the temperature at 25 30°. After stirring for an additional 2 hours, 150 ml of water was added and the product was extracted with ether. After washing, drying and evapo
ration of the organic solvent the residue was distilled and
afforded 1.1 g (55%) of 68; bp 105-110° (18).
4,5-trans-Dihydroxy-9-exo-bromo-cis-bicyclo[6.1.0]nonane, acetonide (69)
A salution of dimsyl anion was prepared by dissolving 15 g (ca. 0.5 mol) of sodium hydride (80% dispersion in mineral
oil) in 500 ml of m1s0 (CaH2 dried). In half an hour was added dropwise with stirring at 20° a salution of 60 g (0.17
mol) of 48 in 100 ml of THF. The mixture was stirred for
about 2 hours and poured into 4 l of water. The product was
extracted with ether. The oil which remained after washing,
drying and evaporation of the solvent was treated with 95%
ethanol and afforded 21 g (45%) of 69; mp (95% ethanol) 66-67°.
86
Nmr (CDC1 3) ö 1.40 (s, 6, CH 3), 0.60-2.55 (alifatic and cyclopropyl H), 3.42-4.40 (m, 2, -CH(O)-CH(O)-). Anal. Calcd for
c12 H19 Br0 2 : C, 53.36; H, 6.91. Found: C, 52.44; H, 7.06.
9-Hethyl-9-bromo-trans-bicyclo[6.1 .O]nonane (73) A salution of 2.82 g (0.01 mol) of 72 in 20 ml of THF was
treated at 95° with butyllithium and methyl iodide as de
scribed for 66. Work-up afforded 1.93 g (89%) of 73; bp:
55-60° (0.1). Nmr (CDC1 3) o 1.68 (s, 3, CH3), 1.65-2.40 (other H's). Anal. Calcd for c10H17Br: C, 55.30; H, 7.83.
Found: C, 55.20; H, 7.81.
9-endo-Methyl-9-exo-bromo-cis-bicyclo[6.1.0]nona-2,4,6-triene ( 8 3)
A salution of 1.38 g (0.005 mol) of 82 in 10 ml of THF was
treated with butyllithium and methyl iodide as described for
66. Work-up in the usual way afforded an oil which upon separation of the compounds which had no tlc mobility (silica gel;
pet.ether as eluent), gave 0.89 g (84%) of 83. Nmr (CDC1 3) ö
1.61 (s, 3, endo CH 3), 2.09 (s, 2, cyclopropane CH), 5.62-6.05
(m, 6, olefin H). The compound proved to decompose upon dis-sa
tillation .
3-Hydroxy-7-methylocta-1 ,6-diene (91) To a salution of 2.24 g (0.02 mol) of 5-methylhex-4-en-1-al (90)- 7 in 25 ml of THF was added dropwise with stirring at
-20° a solution of 0.022 mol of vinylmagnesium bromide (prepared by dissolving 10 ml of a 2M salution of vinylmagnesium
bromide in 20 ml of THF). After additional stirring for 1
hour the mixture was poured onto 150 ~1 of 10% ammonium chloride solution and extracted with ether. Upon washing,
drying and evaporation 2.7 g (96%) of pure 91 leftas a colourless oil.
87
Nmr (CDC1 3) o 1.58 (s, 3, CH 3), 1.70 (s, 3, CH 3), 5.16 (m, 3, olefin H), 5.86 (m, 1, olefin H-2).
E~9-Methyldeca-4,8-dienoic acid, ethyl ester (92)
A mixture of 2.80 g (0.02 mol) of 91 and 23 g of ethyl ortho
acetate c~ seven-fold molar excess) containing 300 mg of propionic acid was treated at 130° for 1 hour with continuous
removal of ethanol. After evaporation of the orthoacetate under reduced pressure, the residue was distilled in vacuo
and gave 3.11 g (74%) of 92; bp 108-111°(0.5). Nmr (CDC1 3) o 1.23 (t, 3, CH 3), 1.60 (s, 3, CH 3), 1.69 (s, 3, CH 3), 4.10
(q, 2, CH 2), 5.11 (m, 1, olefin H-8). 5.46 (m, 2, olefin H-4 and H-5).
E-9-Methyldeca-4,8-dien-1-ol (93) Toa suspension of 4.18 g (0.11 mol) of lithium aluminohydride
in 350 ml of dry ether was added with stirring at 0-5° a so
lution of 42.0 g (0.2 mol) of the ester 92 in 150 ml of ether. The mixture was refluxed for 15 minutes and worked up by subsequent addition of 4.2 ml of water, 4.2 ml of 10% sodium
hydroxide and 13 ml of water. Upon filtering the aluminates
over Celite the resulting clear solution was concentrated and the residue was distilled in vacuo. This afforded 30.5 g
(91%) of alcohol 93 as an oil; bp 88-92° (0.1). Nmr (CDC1 3)
o 1.60 (s, 3, CH3), 1.71 (s, 3, CH 3), 3.60 (t, 2, C!:!20H), 5.13 (m. 1, olefin H-8), 5.44 (m, 2, olefin H-4 and H-5).
E-9-Methyldeca-4,8-dien-1-al (94)
Toa suspension of 32.3 g (0.15 mol) of pyridinium chlorochro
mate and 4.10 g (0.15 mol) of sodium acetate in 250 ml of
anhydrous methylene chloride was added with stirring 16.8 g
(0.1 mol) of the alcohol 93 in 30 ml of methylene chloride.
88
After 1 hour 200 ml of ether and 30 g of sodium sulfate were added. The mixture was stirred for an additional 15 minutes and filtered through a short Florisil column. After removal of the solvent the remaining residue was distilled and gave
10.3 g (62%) of 94, bp 82-86° (2). Nmr 1.59 (s, 3, CH3),
1.69 (s, 3, CH 3). 5.09 (m, 1, olefin H-8). 5.42 (m, 2, olefin H-4 and H-5). 9.72 (s, 1, CHO).
2,10-Dimethyldodeca-2,6,10-triene (95) To a suspension of 30.2 g (0.07 mol) of isopropyltriphenylphosphonium iodide in 200 ml of dry THF was added at 20°
under a nitrogen atmosphere 38.5 ml of a 15% solution of butyllithium in hexane. The deep red solution of the ylide
was added dropwise at -40° to a solution of 8.3 g (0.05 mol) of aldehyde 94 in 150 ml of ether, until persistenee of the
red colour. After additional stirring for 10 minutes, the mixture was warmed to room temperature and poured onto 750 ml of pentane. The precipitates were filtered and the solvent was removed in vacuo. The residue was chromatographed through a short Florisil column (pentane as eluent) and subsequently distilled. This gave 6.64 g (82%) of 95 as a colourless liquid, bp 135-136° (18). Nmr (CDC1 3) o 1.57 (s, 6, CH 3), 1.69 (s, 6, CH 3), 5.10 (m, 2, olefin H-3 and H-10). 5.41 (m, 2, olefin
H-6 and H-7).
1,1-Dibromo-2,2-dimethyl-3-(2-methyl-nona-2,6-dien-9-yl)cyclopropane (87)
A mixture of 1.26 g (5 mmol) of bromoform, 400 mg of 50% aqueous sodium hydroxide (5 mmol), 168 mg (1 mmol) of triene 95 and 20 mg of 8-hydroxyethylbenzyldimethylammonium hydroxide
was stirred vigourously at 50° for 20 hours. The reaction
mixture was diluted with 10 ml of water and extracted twice with pentane.
89
The residue which remained upon washing, drying and evapora
tion of the pentane, consisted besides starting material of 2
compounds (Rf 0.50 and 0.38; hexane-3% benzene as eluent). The less polar product proved to be the desired compound 87; 76 mg (21%). The more polar compound was assigned to be 96;
74 mg (14%). The ratio 87/96 ~ 60/40. Nmr for 87 (CDC1 3) 6
1.18 (s, 3, CH3), 1.33 (s, 3, CH 3), 1.58 (s, 3, CH3), 1.67
(s, 3, CH 3), 5.11 (m, 1, olefin H-3'), 5.43 (m, 2, olefin
H-6' and H-7'). Nmr for 96 (CDC1 3) 6 1.18 (s, 6, CH 3), 1.40
(s, 6, CH 3), 5.46 (m, 2, olefin H).
1-Bromo-1-methyl-2,2-dimethyl-3-(2-methyl-nona-2,6-dien-9-yl)cyclopropane (88 and 97)
To a salution of 364 mg (1 mmol) of 87 in 3 ml of THF was
added at -95° a salution of 15% butyllithium in hexane (0.55
ml, ~ 1.1 mmol). Afteranaging period of 10 minutes an excess of methyl iodide (0.2 ml) was added and the mixture
was allowed to stirr for an additional 20 minutes at -95°.
Upon warming to room temperature 10 ml of water and 10 ml of
ether were added. The organic layer was separated, washed twice
and dried. Upon concentrating 252 mg of product (84%) left as
a colourless oil. The tlc showed two components (Rf 0.29 and 0.31, hexane as eluent). Attempts to isolate them by means of
chromatography failed due to decomposition. By means of nmr
the structures have been assigned as 88 and 97. Nmr (CDC13
)
6 endo (88) at 1.42; exo CH 3 (97) at 1.93. Ratio 88/97 ~ 2/1 .
90
RCferences and notes
1. H.J.J. LOOZEN, J. Th. RICHTER, unpublished results 2. D. DEVAPRABHAKARA, A. KUf\lAR and A. SINGH, Tetr. Lett.,
3343 (1975) 3. W. KIRMSE, "Carbene Chemistry", 2nd ed, Academie Press,
New York, N.Y., 1971 4. K. KLEVELAND and L. SKATTEB0L, Acta Chem. Scand. (B),
~. 191 (1975) 5. H.S. BAIRD, Chem. Comm., 1145 (1971) 6. A.C. COPE, W.R. HOORE, R.D. BACH and H.J.S. WINKLER,
J. Amer. Chem. Soc., 2, 1243 (1970) 7. E.T. HARQUIS and P.D. GARDNER, Tetr. Lett., 2793 (1966) 8. W.R. HOORE and H.R. WARD, J. Org. Chem., ?:.]_, 4179 (1962) 9. W.v.E. DOERING and P.M. La FLAMME, Tetr., 2, 75 (1958)
10. K.G. UNTCH, D.J. ~~RTIN and N.T. CASTELLUCCI, J. Org. Chem., 30, 1683 (1965)
11. P.D. GARDNER and M. NARAYN1A, J. Org. Chem., ~. 3518 (1961)
12. L.A. PAQUETTE, G. ZON and R.T. TAYLOR, J. Org. Chem., ~. 2677 (1974)
13. D.P.G. HAMHON and V.C. TRENERRY, Tetr. Lett., 1371 (1974) 14. R.B. REINARZ and G. PONKEN, Tetr. Lett., 441 (1974)
15. D.W. BROWN, M.E. HENDRICK and M. JONES, Tetr. Lett., 3951 (1973)
16. W.R. MOORE and J.B. HILL, Tetr. Lett., 4343 (1970) 17. W.R. MOORE and J.B. KING, J. Org. Chem., 36, 77 (1971) 18. W.R. MOORE and J.B. KING, J. Org. Chem~, 36, 1882 (1971) 19. L. SKATTEB0L, Tetr. Lett., 2361 (1970) 20. E.T. MARQUIS and P.D. GARDNER, Chem. Comm., 726 (1966)
21. K. KITATANI, T. HIYN~ and H. NOZAKI, J. Amer. Chem. Soc., Q.l., 949 (1975)
91
22. R.L. LAMBERT and D. SEYFERTH, J. Amer. Chem. Soc., 4, 9248 (1972)
23. E.J. COREY and G.H. POSNER, J. Amer. Chem Soc.,~. 5615 (1968)
24. M.S. BAIRD and C.B. REESE, J. Chem. Soc., (C), 1808 (1969) 25. L. SKATTEB~L, Tetr. Lett., 167 (1961) 26. J.H. WOTIZ and D.E. MANCUSO, J. Org. Chem., ~. 207 (1957) 27. C.L. OSBORN, T.C. SHIELDS, B.A. SHOULDERS, C.G. CARDENAS
and P.D. GARDNER, Chem. Ind., 766 (1965) 28. W.M. JONES and W.J. WILSON, Tetr. Lett., 1587 (1965) 29. W.M. JONES and D.L. KRAUSE, J. Amer. Chem. Soc., 93, 551
(1971) 30. R.B. WOODWARD and R. HOFF~~NN, J. Amer. Chem Soc.,~.
395 (1965) 31. P. MERLET, S.D. PEYERIMHOFF, R.J. BUENKER and S. SHIH
J. Amer. Chem. Soc., 96 959 (1974) 32. H.J.S. DEWAR and S. KIRSCHNER, J. Amer. Chem. Soc., 93,
4290 (1971) 33. G. BOCHE, D. ~~RTENS and W. DANZER, Angew. Chem., , 1003
(1969) 34. G. BOCHE, A. BIEBEREACH and H. WEBER, Angew. Chem., ~.
550 (1975) 35. ~1. OGLIARUSO, R. RIEKE and S. WINSTEIN, J. Amer. Chem. Soc.,
~. 4731 (1966) 36. M. OGLIARUSO, J. Amer. Chem Soc.,~· 7490 (1970) 37. G. MOSHUK, G. PETROWSKI and S. WINSTEIN, J. Amer. Chem.
Soc.,~. 2179 (1968) 38. L.B. ANDERSON, M.J. BROADHURST and L.A. PAQUETTE, J. Amer.
Chem. Soc., 95, 2198 (1973) 39. L.A. PAQUETTE, R.E. WINGARD Jr. and R.K. RUSSELL, J. Amer.
Chem. Soc., 2198 (1973) 40. For a review on the concept of homoaromatic interactions
see: S. WINSTEIN, Quart. Rev. Chem. Soc.,~. 141 (1969) 41. P.K. FREE~~N and T.A. HARDY, Tetr. Lett., 3939 (1971) 42. G.B. TRIMITSIS and A. TUNCAY, J. Amer. Chem. Soc., 7
7193 (1975)
92
43. J.t1. BROWN and L.J. OCCOLOWITZ, J. Chem. Soc. (B), 412 (1968)
44. S. WINSTEIN, M. OGLIARUSO, M. SAKAI and J.M. NICHOLSON, J. Amer. Chem. Soc.,~. 3656 (1967)
45. R.G. BERMAN and V.J. RAJADHYAKSHA, J. Amer. Chem. Soc.,
~. 2164 (1970) 46. C.G. CARDENAS, B.A. SHOULDERS and P.D. GARDNER, J. Org.
Chem., E• 1220 (1967) 47. R. HARBET and G. Saucy, Helv. Chim. Acta,~. 2095 (1967) 48. D.J. FAULKNER and M.R. PETERSEN, Tetr. Lett., 3243 (1969) 49. W.S. JOHNSON, R. WERTHEt~NN, W.R. BARTLETT, T.J. BROCKSOM,
T. LI, D.J. FAULKNER and M.R. PETERSEN, J. Amer. Chem. Soc., ~. 741 (1970)
50. E. J. COREY and W.J. SUGGS, Tetr. Lett., 2647 (1975) 51. E.V. DEHHLOV, Angew. Chem., 187 (1974) 52. T. HIYAMA, H. SAWADA, M. TSUKANAKA and H. NOZAKI, Tetr.
Lett., 3013 (1975) 53. L. SKATTEB0L, Acta Chem. Scand., lZ• 1683 (1963) 54. E. VEDEJS, K.A.J. SNOBLE and P.L. FUCHS, J. Org. Chem.,
~. 1178 (1973) 55. E. VOGEL, Angew. Chem., , 548 (1961) 56. D.I. SCHUSTER and F.T. LEE, Tetr. Lett., 4119 (1965) 57. C.B. REESE and A. SHAW, J. Chem. Soc. (Perkin I), 2422
(1975) 58. Bicyclo[6.1.0]nona-2,4,6-trienes have a very strong
tendency to rearrange upon warming; see S.W. STALEY and T.J. HENRY, J. Amer. Chem. Soc.,~. 1239 (1969) and references cited therein.
SUMMARY
In this thesis several new methods are described which
permit the synthesis of medium sized cycloalkanes with func
tionality at the olefinic and allylic carbon atom, by ring expansions of geminal dihalocyclopropanes under non-solvolytic conditions. The synthesis of medium sized rings via
silver ion assisted ring expansions of geminal dihalocyclo
propanes in solvents, such as acetic acid, aqueous acetone or methanol, proceeds with loss of the more accessible exo halogen atom and has been well documented. This reaction general
ly leads to trans allylic products. The alternate approach, viz. ring expansions under non-solvolytic conditions, has not
been described before.
Treatment of a variety of geminal dibromobicyclo[n.1.0Jalkanes
(n= 5, 6, 7) with silver salts (AgX) in acetonitrile shows that the ring opening may lead to both cis and trans products.
The anion (X-) now replaces the role of the solvent in solvo
lytic reactions. A hypothesis has been developed now that the
nature of the product is dependent on two main factors.
Products which can bear a trans double bond, but which are not able to accommodate a trans,trans allylic cation, are
formed in a reaction in which the nucleophile enters con
comitantly with the ring opening at the same side of the incipient allylic system as where the exo halogen atom is lost.
If the product is actually able to accommodate a trans,trans allylic cation, then two possibilities exist: either attack
of the nucleophile at the transrtrans cation occurs immediately (leading totrans products), or an isomerization toa
cis cation takes place (leading to cis products).
94
Furthermore, a synthesis of geminal endo-iodo-exo-bromocyclo
propanes has been developed, based upon the ability of dibromocyclopropanes to undergo a stereoselective halogen-metal
interconversion with butyllithium at -95°, leading to endo
lithio-exo-bromocyclopropanes. The compounds, obtained by iodination of such stereospecifically generated lithiates
proved to be excellently stable precursors for the stereo-
fic synthesis of cyclic systems hearing a vinyl iodide
moiety, along the lines indicated above. The lithiate derived from 9,9-dibromobicyclo[6.1.0]non-4 ene
is highly unstable, even at -95°, and disproportionates readily to an allene. Responsible for this anomalous behaviour is the presence of the favourably located double bond. A
strong bishomoaromatic interaction favours a rapid disrotatory ring opening. As such this is one of the few examples,
hitherto known in the area of bicyclic systems, in which a
cyclopropyl anion exhibits an apparently forbidden mode of ring opening by homointeraction.
A further investigation shows that these interactions are not
present in cyclopropyl anions substituted with a polyenic
chain. Probably, the presence of a double bond in a transition state like arrangement is a prerequisite.
~MEN~TnNG
In dit proefschrift worden enige nieuwe methoden be
schreven om te komen tot gefunktionaliseerde middelgrote ring systemen, door middel van ring opening van geminale dihalo
cyclopropanen onder niet-salvolytische omstandigheden. De synthese van middelgrote ringen met behulp van zilver zouten
onder salvolytische kondities, in oplosmiddelen zoals bijv.
azijnzuur, methanol of waterige systemen, geschiedt via het
afsplitsen van het meest toegankelijke exo halogeen atoom. Door middel van dit type reaktie worden als regel trans pro
dukten verkregen. De ring openingsreaktie onder niet-solvalytische omstandigheden was tot nu toe niet bestudeerd.
Tijdens de reaktie van geminale dibroombicyclo[n.1.0lalkanen
(n= 5, 6, 7) met zilver zouten (AgX) in acetonitril worden
zowel trans als cis produkten gevormd. Het anion (X-) vervult nu dezelfde rol als het oplosmiddel in de salvolytische reak
tie. Vastgesteld is dat de aard van het produkt afhankelijk
is van een tweetal faktoren. Cyclische produkten, die een trans dubbele band kunnen bevatten, doch geen trans,trans kation, worden gevormd in een ring opening, waarbij het af
splitsen van het exo halogeen atoom gelijktijdig plaatsvindt
met de aanval van het nucleofiel (X-) aan dezelfde kant van
het molecuul. Dit leidt tot trans produkten. Wanneer we te maken hebben met moleculen, die zowel een trans dubbele band
als een trans,trans kation kunnen bevatten, dan kan er ofwel
direkt aanval van het nucleofiel plaatsvinden, ofwel er treedt eerst een isomerisatie naar het cis kation op. In dit
laatste geval worden er cis produkten gevormd.
96
De mate waarin deze cis produkten worden gevormd, is afhankelijk van de spanning in het trans,trans kation (ring grootte) en van de nucleofiele eigenschappen van het anion. Verder wordt in dit proefschrift de synthese van geminale endo-iodo-exo-broomcyclopropanen beschreven. Deze synthese is gebaseerd op de mogelijkheid om stereoselektief endo-lithiöexo-broomcyclopropanen te genereren uit de overeenkomstige dibroom verbindingen en deze vervolgens te joderen bij -95°. Met behulp van deze uitermate stabiele verbindingen kunnen op de wijze, zoals hierboven beschreven, stereospecifiek cyclische systemen worden bereid, die een vinyljodide fragment bevatten. Het lithium derivaat, verkregen uit 9,9-dibroombicycloi6.1.0Jnon-4-een, blijkt zeer instabiel te zijn, zelfs bij -95°. Dit is vermoedelijk het gevolg van een bishomoaromatische interaktie van het cyclopropyl anion met de dubbele band, die een gemakkelijke disroterende ringopening tot gevolg heeft. Het produkt dat hierbij wordt gevormd is het alleen. Tot nu toe zijn van dit type interakties die een schijnbaar verboden ring opening tot gevolg hebben in bi
cyclische systemen weinig voorbeelden bekend. Verder onderzoek aan een cyclopropyl anion, gesubstitueerd met een polyeen doet vermoeden dat de aanwezigheid van een dubbele band in een transition-state achtige positie een voorwaarde is voor interaktie.
97
CURRICULUM VITAE
De auteur werd geboren op 24 augustus 1948 te Heerlen.
Na het behalen van het einddiploma HBS-b aan de HBS St.
Antonius Dr. te Kerkrade, werd in 1966 begonnen met de studie
scheikunde aan de Technische Hogeschool te Eindhoven. Het
kandidaatsexamen werd in 1969 afgelegd. In september 1971
behaalde hij met lof het Ingenieurs diploma, met als afstu
deerrichting Organische Chemie.
Tot medio 1974 werkte hij op de afdeling Organische Chemie
van de Technische Hogeschool te Eindhoven, onder leiding van
Dr. E.P. Godefroi, aan de synthese van heterocyclische ver
bindingen. Het onderzoek met betrekking tot de synthese van
modelstoffen voor biomimetische reakties, dat in dit proef
schrift beschreven is, werd gestart medio 1974 onder leiding
van Prof. Dr. H.M. Buck.
In de periode dat hij werkzaam was op de afdeling Organische
Chemie verschenen van zijn hand een twaalftal wetenschappe
lijke publikaties.
Sinds 1 september 1976 is hij werkzaam als research chemicus
op de Research and Development Laboratories van Organon
International B.V. te Oss.
98
DANKWOORD
Mijn erkentelijkheid zou ik willen uitspreken aan de
docenten Prof. Dr. H.M. Buck en Dr. E.F. Godefroi, die in zeer belangrijke mate hebben bijgedragen tot mijn wetenschappelijke vorming, welke de basis is geweest voor de
totstandkoming van dit proefschrift.
Ik zou mijn dank willen uitspreken tegenover Dr. J.W. de
Haan voor zijn bijdrage met betrekking tot de spectrosco
pische aspekten van mijn werk.
Tenslotte zou ik alle leden van de Vakgroep Organische Chemie willen bedanken. Tijdens mijn werkzaamheden vormden
zij het inspirerende klimaat, waarin mijn wetenschappelijk
werk tot stand gekomen is.
99
STELLINGEN
I De conclusie van OZah et aZ., dat in 1,3-diarylcyclobutenyl
kationen geen homoconjugatie tussen de koolstofatomen c1 en c3 voorkomt, is aanvechtbaar.
G.A. Olah, J.S. Staral, R.J. Spearen G. Liang,
J. Amer. Chem. Soc.,~. 5489 (1975) A.E. van der Hout-Lodder, J.W. de Haan, L.J.M.
van de Ven en H.M. Buck,
Reel. Trav. Chim., ~. 1040 (1973)
2 De beschouwing van Seebaah et aZ., waarin het thioacroleine dianion wordt beschreven als synthon voor allyl carbeen,
is onjuist.
D. Seebach, K.H. Geiss en M. Pohmakotr,
Angew. Chem., ~. 449 (1976)
8 Het toekennen van de structuur van 2,6-exo,exo-dihydroxybicyclo[3.3.1]-9-thianonaan op grond van uitsluitend
infrarood gegevens, is zeer twijfelachtig.
E.D. Weil, K.J. Smith en R.J. Gruber,
J. Org. Chem., ll, 1669 (1966)
4 Het door Massoth en SaaPpieZZo gebruikte model voor reductie van Bi 2o3 met propeen, is onjuist.
F.E. Massoth en D.A. Scarpiello,
J. Cat., ~. 225 (1971)
S Het mechanisme dat door Hiyama et al. wordt voorgesteld voor de vorming van a,B-onverzadigde ketonen uit geminale
dichloorcyclopropanen, is te speculatief.
T. Hiyama, T. Mishima, K. Kitatani en H. Nozaki,
Te t r . Le tt. , 3 2 9 7 ( 19 7 4)
6 De veronderstelling, dat het meten van een optische
draaiing bij de reactie van chloroform met olefinen onder
phase-transfer condities is toe te schrijven aan chirale
inductie, berust op verkeerde interpretatie van de gege
vens. T. Hiyama, H. Sawada, M. Tsukanaka en H. Nozaki, Tetr. Lett., 3013 (1975)
7 Het onderscheid dat Bril maakt tussen het substituanteffect in de B3o6
3- ring en een symmetrisch tri-gesubsti
tueerde benzeen ring van het type c6H3x3 , is uit het oogpunt van mesomeria niet terecht.
T.W. Bril, Proefschrift, Technische Hogeschool Eindhoven
(1976)
8 Aan het gebruik van het voorvoegsel "bio" in wetenschap
pelijke literatuur dient paal en perk te worden gesteld.
H.J.J. Loozen Eindhoven, 26 oktober 1976