50 Years of Zweifel Olefination: A Transition-Metal …...Warren. After postdoctoral studies...

3323

R. J. Armstrong, V. K. Aggarwal Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2017, 49, 3323–3336short reviewen

50 Years of Zweifel Olefination: A Transition-Metal-Free CouplingRoly J. Armstrong 0000-0002-3759-061X Varinder K. Aggarwal* 0000-0003-0344-6430

School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, [email protected]

Dedicated to Professor Herbert Mayr on the occasion of his 70th birthday

Received: 15.05.2017Accepted after revision: 16.05.2017Published online: 11.07.2017DOI: 10.1055/s-0036-1589046; Art ID: ss-2017-z0328-sr

License terms:

Abstract The Zweifel olefination is a powerful method for the stereo-selective synthesis of alkenes. The reaction proceeds in the absence of atransition-metal catalyst, instead taking place by iodination of vinyl bo-ronate complexes. Pioneering studies into this reaction were reportedin 1967 and this short review summarizes developments in the fieldover the past 50 years. An account of how the Zweifel olefination wasmodified to enable the coupling of robust and air-stable boronic estersis presented followed by a summary of current state of the art develop-ments in the field, including stereodivergent olefination and alkynyla-tion. Finally, selected applications of the Zweifel olefination in target-oriented synthesis are reviewed.1 Introduction2.1 Zweifel Olefination of Vinyl Boranes2.2 Zweifel Olefination of Vinyl Borinic Esters2.3 Extension to Boronic Esters3.1 Introduction of an Unsubstituted Vinyl Group3.2 Coupling of α-Substituted Vinyl Partners3.3 Syn Elimination4 Zweifel Olefination in Natural Product Synthesis5 Conclusions and Outlook

Key words Zweifel olefination, coupling, boronic esters, alkenes,transition-metal-free, enantiospecific

1 Introduction

The stereocontrolled synthesis of alkenes is a topic thathas attracted a great deal of attention owing to the preva-lence of this motif in natural products, pharmaceuticalagents and materials.1 Of the many olefination methodsthat exist, the Suzuki–Miyaura coupling represents a highlyconvergent method to assemble alkenes (Scheme 1, a).2However, although the coupling of vinyl halides with pri-mary and sp2 boronates takes place effectively, the coupling

of secondary and tertiary (chiral) boronates remains prob-lematic.3 Furthermore, the high cost and toxicity of the pal-ladium complexes required to catalyze these processes alsodetract from the appeal of this methodology.4

The Zweifel olefination represents a powerful alterna-tive to the Suzuki–Miyaura reaction, enabling the couplingof vinyl metals with enantioenriched secondary and tertia-ry boronic esters with complete enantiospecificity (Scheme1, b).5 The reaction is mediated by iodine and base and pro-ceeds with no requirement for a transition-metal catalyst.

Varinder K. Aggarwal (right) studied chemistry at Cambridge Univer-sity and received his Ph.D. in 1986 under the guidance of Dr Stuart Warren. After postdoctoral studies (1986–1988) under Professor Gil-bert Stork, Columbia University, he returned to the UK as a Lecturer at Bath University. In 1991, he moved to Sheffield University, where he was promoted to Professor in 1997. In 2000, he moved to Bristol Uni-versity where he holds the Chair in Synthetic Chemistry. He was elected Fellow of the Royal Society in 2012.Roly J. Armstrong (left) graduated with an MSci in Natural Sciences from Pembroke College, Cambridge (2011) spending his final year working in the laboratory of Professor Steven Ley. He subsequently moved to Merton College, Oxford to carry out a DPhil under the super-vision of Professor Martin Smith (2011–2015) working on asymmetric counterion-directed catalysis. In October 2015, he joined the group of Professor Varinder Aggarwal at the University of Bristol as a postdoctor-al research associate.

Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3323–3336

http://orcid.org/0000-0002-3759-061X

http://orcid.org/0000-0003-0344-6430

3324


This process is based upon pioneering studies reported in1967 by Zweifel and co-workers on the iodination of vinylboranes. This short review summarizes the key contribu-tions made over the last 50 years that have enabled thistransformation to evolve into an efficient and atom-eco-nomical method for the coupling of boronic esters. Recentcontributions to the field are described including the devel-opment of Grignard-based vinylation, stereodivergent ole-fination and alkynylation processes. Finally, selected exam-ples of Zweifel olefination in target-oriented synthesis arereviewed to highlight the utility of this methodology.

Scheme 1 Olefination of boronic esters

2.1 Zweifel Olefination of Vinyl Boranes

In 1967, Zweifel and co-workers reported that vinylboranes 1, obtained by hydroboration of the correspondingalkynes, could be treated with sodium hydroxide andiodine, resulting in the formation of alkene products 2(Scheme 2).6 Intriguingly, although the intermediate vinylboranes were formed with high E-selectivity, after additionof iodine, Z-alkenes were produced. A reaction with a dia-stereomerically pure secondary borane afforded the cou-pled product, 2d, as a single anti diastereoisomer, indicatingthat the process proceeds with retention of configuration.7Mechanistically, this reaction is thought to proceed by acti-vation of the π bond with iodine along with complexationof sodium hydroxide to form a zwitterionic iodonium inter-mediate 3. This species is poised to undergo a stereospecific1,2-metalate rearrangement resulting in the formation of aβ-iodoborinic acid 4. In the presence of sodium hydroxide,this intermediate then undergoes anti elimination to affordthe resulting Z-alkene product.8

Because vinyl borane intermediates could only be ac-cessed by hydroboration of alkynes, the iodine-mediatedZweifel coupling was initially limited to the synthesis of Z-alkenes.9 However, Zweifel and co-workers subsequentlyreported an elegant strategy for the complementary syn-thesis of E-alkenes (Scheme 3).10 This transformation wasachieved by reacting dialkyl vinyl borane 5 with cyanogenbromide under base-free conditions. Following stereospe-cific bromination, a boranecarbonitrile intermediate 8, wasformed, a species that was sufficiently electrophilic to un-dergo syn elimination. A variety of boranes underwent thistransformation, forming alkenes 6a–c in high yields and

with very high levels of E-selectivity. Chiral non-racemicboranes could be transformed with complete stereospeci-ficity.

Scheme 3 Synthesis of E-alkenes using cyanogen bromide

A related syn elimination process was reported by Levyand co-workers (Scheme 4).11 In this case, a vinyl lithiumreagent was prepared by lithium–halogen exchange andthen combined with a symmetrical trialkylborane resultingin formation of boronate complex 9. Treatment of this inter-mediate with iodine resulted in stereospecific iodination toproduce β-iodoborane 10. The enhanced electrophilicity ofthis species (compared to β-iodoborinic acids such as 4) en-abled a syn elimination to occur, generating the corre-sponding trisubstituted alkene 11 with high levels of ste-reocontrol. Although the substrate scope of the process iswide, the method was limited to the use of symmetrical tri-alkyl boranes.

Brown and co-workers demonstrated that the Zweifelolefination can also be applied to the synthesis of alkynes(Scheme 5).12 In this case, monosubstituted alkynes weredeprotonated to form lithium acetylides, which were react-ed with trialkylboranes to form alkynylboronate complexes12. Addition of iodine triggered a 1,2-metallate rearrange-ment to generate β-iodoboranes 13, which spontaneously

I2

NaOMe

R3 B(pin)

R2

R1 M+

R2

R1 R3 Transition-Metal Free

Stereospecific

Enantiospecific

(b) Zweifel Olefination

R3 B(pin)

R2

R1 X+

R1 R3

(a) Suzuki–Miyaura Coupling

cat. Pd(0)

R2

Scheme 2 Zweifel olefination: iodination of vinyl boranes

RR'2BH

THF

I2, NaOH

THF/H2OR

B

selected products:

Cy

MeCy

Me

CyCy

2a; 83 % yield 2b; 75 % yield99:1 Z/E

2c; 77 % yield92:8 Z/E

2d; 70 % yield85:15 Z/E

1 2

R'

R'

Me

R'R

RB R'OH

R'

I

1,2-metallaterearrangement

RBOHI

R'R'

iodinationantielimination

3 4

I2 NaOH

RR'2BH

THF

BrCN, CH2Cl2

then workup with aq. NaOH

RB

selected products:

Cy

6a; 69 % yield96:4 E/Z

5 6

R'

R'

R'

RB R'CN

R'

Br

1,2-metallaterearrangement R

BCN

Br R'

R'8

BrCN

R

brominationsynelimination

nBu

6b; 68 % yield93:7 E/Z

nBuMe Me

MeMe

nBu

6c; 75 % yield98:2 E/Z

7


3325


underwent elimination to form alkyne products. This pro-cess represents a convenient alternative to the alkylation oflithium acetylides with alkyl halides and has been success-fully employed in total synthesis.13

2.2 Zweifel Olefination of Vinyl Borinic Esters

The transformations described in the previous sectionsuffer from an inherent limitation in that only one of the al-kyl groups present in the borane starting materials is incor-porated into the alkene product. This is particularly waste-

ful when the borane is challenging to access or expensive.One solution to this problem would be to employ a mixedborane in which one (or two) of the boron-bound groupsdemonstrates a low migratory aptitude (e.g., thexyl).14

However, in practice, determining which group will migratehas proved to be non-trivial and highly substrate-depen-dent. For example, Zweifel and co-workers showed thattreatment of divinylalkylborane 15 (obtained by double hy-droboration of 1-hexyne with thexylborane) with iodineresulted in competitive migration of both the sp2 and thexylgroups leading to a mixture of the desired product 16 alongwith 17 (Scheme 6).15 They overcame this problem by treat-ing the intermediate divinylalkylborane 15 with trimethyl-amine oxide, resulting in selective oxidation of the B–Cthexylbond to afford borinic ester 18. Due to the low migratoryaptitude of an alkoxy ligand on boron,16 addition of iodineand sodium hydroxide now led to selective formation ofZ,E-diene 16. Although this allowed control over whichgroup migrated, the method was limited to the synthesis ofsymmetrical dienes.

Scheme 4 Olefination of symmetrical trialkylboranes

I2, THF

then workup with NaOH/H2O2

selected products:

11

BR

I R

10

IR3

i. nBuLi, THF

ii. R3B

BR3 R

RR

Li

9

RR3

R synelimination

R2R2

R2

R3

R2

11a66 % yield

nHex

Et

Et

Me

11b; 80 % yield>95:5 Z/E

Et

nPrEt

11d; 38 % yield>97:3 E/Z

Ph

EtEt

11c; 87 % yield>95:5 E/Z

nPr

EtEt

Scheme 5 Alkynylation of boranes

I2

THF/Et2O

selected products:

14

BR

I R

13

i. nBuLi, THF

ii. R3BBR

RRLi

12

R

14a; 96 % yield

R' R'R'

R' R

nBu nBu

14b; 99 % yield

nBu Cy

14c; 98 % yield

nBu Ph

14d; 95 % yield

Ph Ph

Scheme 6 Diene synthesis by Zweifel olefination of boranes or borinic esters

nBu

THF

I2, NaOHnBu

B

15 16

BH2

MeMeMe

Me(2 eq.)

Me MeMe

Me

nBu

(a) Problem: competitive thexyl group migration

nBu

nBu

+ nBu

MeMe Me

Me

17

(b) Solution: selective oxidation to a borinic ester

I2, NaOH

THF/H2O

18 16; 65 % yield98:2 Z,E:isomers

nBu

nBu

nBuB

Me MeMe

Me

nBu

Me3N O

nBuB

nBu

OMe

MeMeMe

15

nBuB

nBu

OThexI OH


nBu

I

nBu

BOThex

OH

antieliminationiodinationI2 NaOH

THF

THF/H2O

ratio 16/17 = 52:48


3326


A more general approach to the iodination of vinylborinic esters was later reported by Brown and co-workers(Scheme 7).17 In this case, non-symmetrical vinyl borinicesters 20 were obtained by hydroboration of alkynes withalkylbromoboranes followed by methanolysis of the result-ing bromoborane intermediates 19. Addition of sodiummethoxide and iodine led to alkene products 21a–d in goodyields and very high levels of Z-selectivity.

2.3 Extension to Boronic Esters

Although the use of borinic esters significantly expand-ed the potential of the Zweifel olefination, there were stillsignificant problems with this approach, most notably as-sociated with the high air sensitivity of the borane startingmaterials. In contrast to boranes, boronic esters are air- andmoisture-stable materials which can be readily preparedvia a wide range of methods.18 Evans and Matteson inde-pendently recognized the potential of boronic esters as sub-strates for Zweifel olefination communicating independentstudies almost simultaneously.19,20

Matteson’s coupling process began with the synthesis ofa vinyl boronate complex 23 by addition of an organolithi-um reagent to a vinyl boronic ester 22 (Scheme 8).19 This in-termediate was treated with iodine and sodium hydroxide,resulting in iodination followed by 1,2-metallate rearrange-ment to form a β-iodoboronic ester which underwent antielimination to form the corresponding Z-alkene. This reac-tion could be carried out with alkyl or aryl lithium reagentsand the coupled products 24a and 24b were formed inmoderate to good yields.

Scheme 8 Zweifel olefination of vinyl boronic esters

Evans and co-workers’ strategy also began with forma-tion of a vinyl boronate complex (Scheme 9).20 In contrastto Matteson’s approach, this intermediate was accessed byreacting E-vinyl lithium reagent 26a (prepared by lithium–halogen exchange) with secondary alkyl boronic ester 25.Treatment of the resulting vinyl boronate complex 27a withiodine and sodium methoxide resulted in formation ofalkene 28a in 75 % yield (>96:4 Z/E). When a Z-vinyl lithiumprecursor 26b was employed, alkene 28b was obtained in58 % yield with very high E-selectivity. The flexibility de-rived from the ability to form identical vinyl boronate com-plexes by either reacting a vinyl boronic ester with an or-ganolithium or a vinyl lithium with a boronic ester is a par-ticularly appealing feature of the Zweifel olefination.

Brown and co-workers subsequently extended thismethodology to enable the synthesis of trisubstitutedalkenes (Scheme 10).17c,21 By reacting various trisubstituted

Scheme 7 Synthesis of Z-alkenes from vinyl borinic esters

R1

R2BHBr·SMe2

Et2O

NaOMe

Et2O/MeOHR1

B

selected products:

Cy

21a; 74 % yield>99:1 Z/E

19 20

R2

Br I2, NaOMe

MeOHR1

BR2

OMeR

R2

nPr

21b; 69 % yield>99:1 Z/E

nPr

nPr

Et

21c; 62 % yield>99:1 Z/E

nPr

21

nHex

21d; 68 % yield>99:1 Z/E

nHex

R2Li

Et2OR1

B

22


iodinationantielimination

O

O

R1B

23

OO

R2

Li I2, NaOH

THF/H2O

R1

R2

24

R1B O

O

R2

IR1

B O

O

R2

I

selected products:

24a; 30 % yield 24b; 65 % yield

MenBu

PhPh

NaOHI2

Scheme 9 Zweifel olefination of vinyl lithiums with boronic esters

OTBS

C5H11Li

25

I2, NaOMe

THF/MeOH

Et

B(OMe)2

TBSO C5H11

Et

TBSO

C5H11

Et

B(OMe)2OTHP

H11C5

I2, NaOMe

THF/MeOH

Et

C5H11

OTHP

Et

B(OMe)2

OTHP

C5H11

Li

27a 28a; 75 % yield>96:4 Z/E

27b 28b; 58 % yield>99:1 E/Z

26a

26b

THF

THF


3327


vinyl boronic esters (29) with organolithium nucleophiles,a range of products was prepared in good to excellentyields. Notably, heteroaromatic groups could be introduced(in 31b) and alkyl Grignard reagents could be used in placeof organolithium reagents (in 31d).

The methods shown in Schemes 8–10 represented a sig-nificant advance upon the early work on the Zweifel olefi-nation of boranes and borinic esters. However, at the timethe potential of the method was not fully realized owing tothe paucity of methods available for the preparation of bo-ronic esters. Consequently, only a handful of studies involv-ing Zweifel olefination were published over the followingthree decades.22 In recent years, the huge increase in meth-ods available for the enantioselective synthesis of boronicesters has led to a renaissance in chemistry based upon theZweifel olefination. Several new studies into the processhave been reported along with elegant reports employingZweifel olefination in total synthesis. These results are de-scribed in the following sections.

3.1 Introduction of an Unsubstituted Vinyl Group

The introduction of a vinyl group into a target moleculeis commonly required in synthesis owing to the prevalenceof this motif in natural products and as a valuable handlefor further functionalization. The first report describing theintroduction of an unsubstituted vinyl group by Zweifel ole-fination was published by Aggarwal and co-workers in their

stereocontrolled synthesis of (+)-faranal (Scheme 11).23 Inthis process, vinyl lithium was prepared in situ from tetra-vinyltin by tin–lithium exchange and was then reacted withenantioenriched secondary boronic ester 32. The resultingvinyl boronate complex was treated with iodine and sodi-um methoxide, thus promoting 1,2-metallate rearrange-ment and elimination affording alkene 33. This key inter-mediate was directly subjected to hydroboration and oxida-tion to provide alcohol 34 in 69 % yield with very highdiastereoselectivity. Oxidation with PCC completed the syn-thesis of (+)-faranal in 76 % yield.

It was subsequently shown that the vinyl lithium ap-proach could be also be applied to the enantiospecific cou-pling of trialkyl tertiary boronic esters (Scheme 12, a)24 andbenzylic tertiary boronic esters25 (Scheme 12, b). It is note-worthy that in these cases despite the sterically congestednature of the boronic ester starting materials, the coupledproducts were obtained in excellent yields. The double vi-nylation of primary–tertiary 1,2-bis(boronic esters) has alsobeen achieved using this approach (Scheme 12, c).26 Usingfour equivalents of vinyl lithium, diene 37 was obtained in77 % yield.

Scheme 12 Applications of Zweifel olefination with vinyl lithium (pre-pared from tetravinyltin); PMP = p-methoxyphenyl; e.s. = enantiospeci-ficity

Scheme 10 Zweifel olefination of trisubstituted vinyl boronic esters

R3Li

Et2O

29

R3Li

I2, MeOH

then aq. NaOH R2

31

selected products:

31a; 80 % yield>97:3 E/Z

R2 R2

R3R1

31b; 81 % yield>97:3 E/Z

R1

nBu

PhnBu

nBu

nBu

S

31c; 76 % yield>97:3 E/Z

Me

PhCl

31d; 64 % yield(with PrMgCl); >97:3 E/Z

nBu

nBu

Me

Me

i

30

R1OB

O

OB

O

Scheme 11 Introduction of an unsubstituted vinyl group with vinyl lithium: stereoselective synthesis of (+)-faranal; R = (CH2)2CHCMeEt; pin = pinaco-lato

R

Me

MeB(pin)

Me

Sn

nBuLi

hexanesLi

THF/Et2Oii. I2, THF/Et2O/MeOH

iii. NaOMe

R

Me

Me

Me

33

i. 9-BBN

ii. H2O2/NaOH

Me

Me

Me

34; 69 % yield94:6 d.r.

OH

Me

Et Me

Me

Me O

(+)-faranal; 76 % yield

R

32

PCC

i.

(a) Synthesis of α-(tertiary trialkyl) alkenes

nPr Me

B(pin)nBu Lii.

ii. I2iii. NaOMe, Et2O/THF/MeOH

nPr Me

nBu

35; 72 % yield100 % e.s.

(b) Synthesis of α-(tertiary benzylic) alkenes

PMP Ph

B(pin)Me

Et2O/THF

PMP Ph

Me

(c) Synthesis of dienes

36; 92 % yield100 % e.s.

B(pin)B(pin)

PMPMe

PMPMe

37; 77 % yield

Lii.

ii. I2, NaOMe, THF/MeOH

Lii. Et2O/THF

ii. I2iii. NaOMe, Et2O/THF/MeOH

THF


3328


Vinylation under Zweifel conditions represents a power-ful strategy for the synthesis of alkenes. However, the ne-cessity of preparing vinyl lithium in situ from the corre-sponding toxic stannane or volatile vinyl bromide detractsfrom the appeal of the process. In contrast, stable THF solu-tions of vinylmagnesium chloride or bromide are commer-cially available.27 Aggarwal and co-workers have studiedthe Zweifel olefination of tertiary boronic ester 38 with vi-nylmagnesium bromide in THF.25 Monitoring the reactionby 11B NMR spectroscopy revealed that with one equivalentof vinylmagnesium bromide, the expected vinyl boronatecomplex 39 was not observed and instead a mixture of un-reacted boronic ester 38 and trivinyl boronate complex 40was formed (Scheme 13). The latter species originates fromover-addition of vinylmagnesium bromide promoted by thehigh Lewis acidity of the Mg2+ counterion. Upon addition ofan excess of vinylmagnesium bromide (4 eq.), trivinyl boro-nate complex 40 was obtained exclusively, and after addi-tion of I2 followed by NaOMe, the coupled product 41a wasobtained in good yield. These conditions were successfullyapplied to the synthesis of a series of benzylic tertiary sub-strates 41a–d. The reaction is ineffective at forming veryhindered alkenes such as 36, although this product could besynthesized efficiently with vinyl lithium.

Very recently, an improved procedure for coupling un-hindered boronic esters with vinylmagnesium chloride hasbeen reported (Scheme 14).28 As with tertiary boronic es-ters, it was observed that addition of vinylmagnesium chlo-ride to a THF solution of secondary boronic ester 42 result-ed in over-addition to form trivinyl boronate complex 44.However, if the reaction was carried out in a 1:1 THF/DMSOmixture,29 over-addition was completely suppressed andonly mono-vinyl boronate complex 43 was obtained. Afteraddition of iodine and sodium methoxide, the coupledproduct 45a was obtained in 89 % yield. This process pro-

ceeds effectively with a range of primary, secondary and ar-omatic boronic esters. Notably, the use of the mild Grignardreagent allows chemoselective coupling to occur in thepresence of reactive functional groups such as carbamates(in 45b) and ethyl esters (in 45d). Although good yields ofproduct were obtained with unhindered tertiary boronicesters (in 45e), in general, the Zweifel vinylation of tertiaryboronic esters is best achieved either with four equivalentsof vinylmagnesium halide in THF or with vinyl lithium.

In summary, there are currently three methods avail-able to introduce an unsubstituted vinyl group by Zweifelolefination (Scheme 15). For aromatic, primary and unhin-dered secondary boronic esters, the desired boronate com-plex can be formed efficiently using 1.2 equivalents of vi-nylmagnesium halide in 1:1 THF/DMSO. For the majority oftertiary boronic esters it is recommended to employ fourequivalents of vinylmagnesium halide in THF (to form thetrivinyl boronate complex), although with extremely hin-dered tertiary boronic esters, the best results are obtainedwith vinyl lithium.

3.2 Coupling of α-Substituted Vinyl Partners

In addition to the synthesis of alkyl-substituted alkenes,the Zweifel olefination has also been applied to the cou-

Scheme 13 Zweifel olefination of tertiary boronic esters with vinyl-magnesium bromide in THF

Ph

B(pin)

MeEt

MgBr(1.0–4.0 eq.)

Ph

B

MeEt

OO

B = 5–8 ppm39

δ

MgBr

OMg

O

Ph

B

MeEt

B = –13 ppm40

δ

I2, THF/MeOHthen NaOMe

Ph MeEt

not observed

41a

eq. RMgBr ratio 38/40 yield 41a

1.0 70:30 26 %

4.0 0:100 66 %

38B = 32 ppmδ

Ph MeEt

41a; 66 % yield100 % e.s.

selected examples:

Ph MeMe

Et

Cl

41b; 79 % yield100 % e.s.

41d; 79 % yield100 % e.s.

PMP MePh

36not observed

PMP MeEt

41c; 62 % yield100 % e.s.

THF

Scheme 14 Zweifel olefination of boronic esters with vinylmagnesium chloride in THF/DMSO; R = (CH2)2PMP

selected examples:

B(pin) MgCl (1.0-4.0 eq.)

solvent R

BOO

B = 8 ppm43

δ

R

B

B = –13 ppm44

δ42

B = 35 ppmδ

Me Me Me

I2, NaOMeTHF/MeOH

R Me45a

eq. RMgCl ratio 42/43/44 yield 45a

1.0 37 %

4.0 0:0:100 96 %

1.2 0:100:0 89 %

solvent

1:1 THF/DMSO

THF

THF

Me

>67:0:<33

PMP

45a; 89 % yield100 % e.s.

45c95 % yield

MeOTBS

45e68 % yield

CO2Et45d

74 % yield

NBoc

45b78 % yield

orPMP

Scheme 15 Summary of the best methods for boronate complex for-mation for the Zweifel vinylation of various boronic esters; R = alkyl group

R

B(pin)

MeR

B(pin)

R R

B(pin)

R

B(pin)

RR

Ar

B(pin)

RR

Ar

B(pin)

ArRArB(pin)

increasing steric hindrance

MgX(1.2 eq.)

1:1 THF/DMSO

MgX(4.0 eq.)

THF

Li(2 eq.)THF


3329


pling of vinyl partners α-substituted with a heteroatom.The coupling of lithiated ethyl vinyl ether 46 (readily pre-pared by deprotonation of ethoxyethene with tBuLi) with atertiary boronic ester proceeded smoothly to provide enolether 47, which was hydrolyzed under mild conditions toform 48 (Scheme 16, a).25,30 This process represents a novelmethod for the conversion of boronic esters into ketones.This methodology has also been extended to the enantio-specific synthesis of vinyl sulfides (Scheme 16, b).28

A related strategy for the alkynylation of boronic estershas recently been reported by Aggarwal and co-workers(Scheme 17).31 In contrast to the successful alkynylation re-actions of trialkyl boranes discussed previously (Scheme5),12,13 boronic esters undergo reversible boronate complexformation with lithium acetylides. This means that additionof electrophiles does not result in coupling, but insteadleads to direct trapping of the acetylide and recovery of theboronic ester. A solution to this problem was developed inwhich vinyl bromides or carbamates were lithiated at theα-position with LDA and then reacted with boronic estersin a Zweifel olefination. Treatment of the resulting vinylbromides or carbamates with base (TBAF for bromides andtBuLi or LDA for carbamates) triggered elimination to form

the corresponding alkynes 50. Coupling of a wide range ofsecondary and tertiary boronic esters was achieved in ex-cellent yields with complete enantiospecificity.

In 2014, an interesting intramolecular variant of theZweifel olefination for the construction of four-memberedring products was reported (Scheme 18).32 In this process,51, which possesses both a boronic ester and a vinyl bro-mide, was treated with tert-butyllithium resulting in che-moselective lithium–halogen exchange followed by sponta-neous cyclization to form cyclic vinyl boronate complex 52.Upon treatment with iodine and methanol this species un-derwent stereospecific ring contraction to provide β-iodo-boronic ester 53. Elimination of this intermediate gave exo-cyclic alkene 54 in 63 % yield. It is particularly noteworthythat this challenging Zweifel olefination occurs in goodyield despite the highly strained nature of the exomethy-lene cyclobutene product.

3.3 Syn Elimination

Aggarwal and co-workers have reported a method forthe synthesis of allylsilanes through a lithiation–borylation–Zweifel olefination strategy (Scheme 19).33 Inthis process, silaboronate 56 was homologated with config-urationally stable lithium carbenoids 55 to provide α-silyl-

Scheme 16 Synthesis of ketones and vinyl sulfides by Zweifel olefination

(a) Synthesis of ketones from boronic esters

Ph(pin)B

MeEt

EtOtBuLi

THF

EtO Li EtO

ii. I2iii. NaOMeTHF/MeOH

i.

Ph

MeEt aq. NH4Cl

Me

OPh

MeEt

48; 66 % yield100 % e.s.

(b) Synthesis of vinyl sulfides

(pin)BPhSnBuLi·TMEDA

THF

PhS Li PhS

ii. I2, NaOMe THF/MeOH

i.

49; 91 % yield100 % e.s.

Me

PMPMe

PMP

46 47

Scheme 17 Alkynylation of enantioenriched boronic esters; Cb = C(O)NiPr2

R–B(pin)R' Li

RB

OO

R'

I2direct

iodination

R' I + R–B(pin)

Br Li CbO Li

orRB

OOX

I2, MeOH

RX

Zweifelolefination

TBAF for X = BrtBuLi for X = OCb

eliminationR

selected examples with X = Br:

Ph Me

Me

50a; 81 % yield100 % e.s.

50b; 68 % yield100 % e.s.

selected examples with X = OCb:

Ph Me

Me

Me

PhMe

Cl50c; 89 % yield

100 % e.s.50d; 87 % yield

100 % e.s.

PhCO2

tBu2

X = Br, OCbboronate complex

formation

50


3330


boronic esters 57, which were then subjected to Zweifelolefination to obtain allylsilane products 58. Notably, it wasnecessary to carry out the Zweifel olefination without sodi-um methoxide owing to the instability of the allylsilaneproducts under basic conditions. The substrate scope of theprocess was wide and a range of allylsilanes was preparedin high yields and with excellent levels of enantioselectivity.Interestingly, with a hindered α-silylboronic ester, E-crotyl-silane 58d was obtained as a single geometrical isomer, butZ-crotylsilane 58c was formed in slightly reduced selectivi-ty (95:5 Z/E).

To rationalize the reduced selectivity observed in theformation of Z-crotylsilane 58c, it was postulated that asthe boronic ester becomes more hindered, the transitionstate for anti elimination becomes disfavored due to a stericclash between the bulky R1 and R2 substituents (Scheme20). This allows the usually less favorable syn eliminationpathway to compete, resulting in the formation of smallamounts of the E-isomer.

Similar behavior has been observed in the Zweifel olefi-nation of hindered secondary boronic esters with alkenyl-lithiums (Scheme 21).34 As the boronic ester becomes moresterically encumbered (for example, benzylic or β-

branched), increasing formation of the E-isomer was ob-served, up to 90:10 Z/E in the case of menthol-derivedalkene 60c.

Scheme 21 Reduced Z/E selectivity with bulky boronic esters

In these cases, Aggarwal and co-workers have shownthat iodine can be replaced with PhSeCl resulting in the for-mation of β-selenoboronic esters (Scheme 22).35 Becausethe selenide is a poorer leaving group than the correspond-ing iodide, treatment of these intermediates with sodiummethoxide led exclusively to anti elimination providing thecoupled products 60a–c as a single Z-isomer in all cases.34

It was also demonstrated that β-selenoboronic esters(obtained by selenation of vinyl boronate complexes) couldbe directly treated with m-CPBA resulting in chemoselec-tive oxidation of the selenide to give the correspondingselenoxide (Scheme 23, a).34 A novel syn elimination thenoccurred in which the selenoxide oxygen atom attacked aboron atom instead of a hydrogen atom, providing E-

Scheme 18 Construction of an exomethylene cyclobutene by an intra-molecular Zweifel olefination; Ar = 2-MeO-4-MeC6H3

B(pin)

Li

Me

B(pin)Me

Br

Me

MeO

MeO

tBuLi

THF

I2THF/MeOH

54; 63 % yield100 % e.s.

5251

B(pin)

Me

B(pin)

I

Ar

Me

(pin)B

I

iodination


MeAr

MeAr

boronate complexformation

MeAr

elimination

53

Scheme 19 Synthesis of allyl- and crotylsilanes via a lithiation–borylation–Zweifel olefination strategy; Si = SiPhMe2; (–)-sp = (–)-sparteine

R OCb

sBuLi·(–)-spEt2O

lithiation R OCb

Li·(–)-sp Si–B(pin), 56

Si R

B(pin)

R1Li

R2

Si R

R2

R1

55 5768-69 % yield

58

selected examples:

Si

Me

Ph

58a; 84 % yield97:3 e.r.; >96:4 Z/E

Si Ph

58b; 94 % yield97:3 e.r.; >96:4 E/Z

Me

Si iPr

58c; 80 % yield96:4 e.r.; 95:5 Z/E

Si iPr

58d; 80 % yield96:4 e.r.; >96:4 E/Z

Me

THF, then I2, THF/MeOH

borylation

Me

Scheme 20 Rationalization for reduced Z/E selectivity with bulky boronic esters

H

R1

R2

B(pin)I

H

I

R1B(pin)

HR2

I

R1

B(pin)

R2H

antielimination

synelimination

R1R2

R1

R2

Z-alkene

E-alkene

Me Ph

Bn

60a; 81 % yield100 % e.s.; 96:4 Z/E

selected examples:iPr

Me

Bn

60c; 64 % yield>95:5 d.r.; 90:10 Z/E

Me

Me

TBSOH

H

H

HMe

Me

Me

3

H60b; 67 % yield

>95:5 d.r.; 92:8 Z/EBn

Bn Li

R1 R2

B(pin)

R1 R2

Bn

R1 R2

(pin)B Bn I2, NaOMe

THF/MeOH6059

THF


3331


alkenes with high selectivity. In conjunction with theZweifel olefination (or its PhSeCl-mediated analogue) thisrepresents a stereodivergent method where either isomerof a coupled product can be obtained from a single isomerof vinyl bromide starting material (Scheme 23, b). The sub-strate scope of both processes is broad and a range of di-and trisubstituted alkenes was prepared including 61cwhich represents the C9–C17 fragment of the natural prod-uct discodermolide.

In some cases, the ability to carry out syn elimination ofβ-iodoboronic esters is also desirable. For example, very re-cently Aggarwal and co-workers reported a coupling of cy-

clic vinyl lithium reagents with boronic esters (Scheme24).28 In this case, the cyclic β-iodoboronic ester intermedi-ates 63 cannot undergo bond rotation and therefore mustundergo a challenging syn elimination. It was found thatthis elimination could be promoted by adding an excess ofsodium methoxide (up to 20 eq.). Using this methodology, arange of five- and six-membered cycloalkene products 64were prepared in high yields and with complete stereospec-ificity, including glycal 64b and abiraterone derivativessuch as 64c.

Scheme 22 Highly Z-selective olefination of sterically hindered boronic esters

Bn Li

R1 R2

B(pin)

R1 R2

Bn

R1 R2

(pin)B Bn i. PhSeCl, THF

ii. NaOMeTHF/MeOH

R1 R2

(pin)B BnSePh

Bn(pin)BSePh

R1 R2

selenationPhSeCl


NaOMeantielimination

Me Ph

Bn

60a; 63 % yield100 % e.s.; >98:2 Z/E

selected examples:

iPr

Me

Bn

60c; 55 % yield>95:5 d.r.; >98:2 Z/E

Me

Me

TBSOH

H

H

HMe

Me

Me

3

H 60b; 70 % yield>95:5 d.r.; >98:2 Z/E

Bn

59 60THF

Scheme 23 Stereodivergent olefination of boronic esters

R2Li

R2

R1

(pin)BR2 i. PhSeCl, THF

ii. m-CPBA, THF

R2(pin)B

R1

SePh

selenation;1,2-migrationPhSeCl

oxidation

synelimination

R1

R2(pin)B

R1

SePh

m-CPBA

O

(a) Syn elimination of β-selenoboronic esters

R1Br

R2

i. tBuLiii. R3–B(pin)

iii. PhSeCliv. m-CPBA

i. tBuLiii. R3–B(pin)

iii. I2, NaOMeor PhSeCl, NaOMe

MePMP

Bn

61a; 80 % yield>98:2 Z/E; 100 % e.s.

MePMP

62a; 74 % yield>98:2 E/Z; 100 % e.s.

Bn2 2

MePMP

Me

61b; 95 % yield>98:2 Z/E; 100 % e.s.

MePMP

62b; 83 % yield96:4 E/Z; 100 % e.s.

Me2 2

Me Me

R1—Bpin)

Me

MeOPMB61c; 48 % yield

98:2 Z/E; >95:5 d.r.

Me

OTBS

MeTBDPSO

MeMe

OTBS

MeTBDPSO

MeOPMB

62c; 52 % yield98:2 E/Z; >95:5 d.r.

(b) Stereodivergent olefination

THF

61 62R1

R3

R2R1

R2

R3


3332


Since the pioneering studies on Zweifel olefination re-ported by Evans and Matteson, the method has been signifi-cantly developed such that a wide range of functionalizedalkene products can now be obtained. The final section ofthis short review showcases selected examples whereZweifel olefination has been used in complex molecule syn-thesis.36

4 Zweifel Olefination in Natural Product Synthesis

Aggarwal and co-workers recently reported an 11-steptotal synthesis of the alkaloid (–)-stemaphylline employinga tandem lithiation–borylation–Zweifel olefination strategy(Scheme 25).37 Pyrrolidine-derived boronic ester 65 washomologated with a lithium carbenoid to afford boronic es-ter 66 in 58 % yield and 96:4 d.r. A subsequent Zweifel olefi-nation with vinyl lithium (synthesized in situ from tetra-vinyltin) gave alkene 67 in 71 % yield. Notably, these twosteps could be combined into a one-pot operation, directlyproviding 67 in 70 % yield. The alkene was later employed ina ring-closing-metathesis–reduction sequence to form thecore 5-7 ring system of (–)-stemaphylline.

A recent formal synthesis of the complex terpenoid nat-ural product solanoeclepin A has been reported by Hiems-tra and co-workers (Scheme 26).38 A key step in this synthe-

sis was the vinylation of the bridgehead tertiary boronic es-ter in 68. Formation of the trivinyl boronate complex withexcess vinylmagnesium bromide in THF followed by addi-tion of iodine and sodium methoxide produced alkene 69,which was employed without purification in a subsequentsequence of oxidative cleavage and Horner–Wadsworth–Emmons olefination to form 70 in a yield of 67 % over foursteps.

Morken and Blaisdell have reported an elegant stereose-lective synthesis of debromohamigeran E that employs aZweifel coupling of an α-substituted vinyl lithium (Scheme27).39 Cyclopentyl boronic ester 72 was prepared from 1,2-bis(boronic ester) 71 in 42% yield by a highly selective hy-droxy-directed Suzuki–Miyaura coupling. This intermedi-ate was then subjected to Zweifel coupling with isopro-penyllithium (synthesized by Li–Br exchange) to form 73 in93 % yield. Completion of the synthesis of debromohamigeranE required four further steps including hydrogenation of thealkene to an isopropyl group.

A short enantioselective total synthesis tatanan A wasreported by Aggarwal and co-workers, which employs astereospecific alkynylation reaction (Scheme 28).40 Boronicester 74 (synthesized by a diastereoselective Matteson ho-mologation) was subjected to Zweifel olefination with lithi-ated vinyl carbamate. Treatment of the resulting vinyl car-bamate 75 with LDA resulted in elimination to form alkyne

Scheme 24 Synthesis of cycloalkenes via a challenging syn elimination

synelimination

selected examples:

64a98 % yield100 % e.s.

X Li

nn = 0,1

i. R—B(pin), THF X

n

B(pin)R

I

X

n

R

Me

PMP

OMe

PMP

TIPSOTIPSO

OTIPS

64b49 % yield>95:5 d.r. HH

H

TBSO64c

86 % yield

64d79 % yield100 % e.s.

OMe

PMP

ii. NaOMe (3-20 eq.) I2, THF/MeOH

63 64

Scheme 25 Stereocontrolled synthesis of (–)-stemaphylline; Si = TBDPS; TIB = 2,4,6-triisoproylbenzoyl

Et2O thenCHCl3, reflux

NBoc

(pin)B

MeOTIB

Li·(–)-spNBoc(pin)B

Me

SiO

SiO H

NBoc

MeSiO HLi

ii. I2iii. NaOMe

THF/Et2O/MeOH

one-pot tandem lithiation–borylation–Zweifel olefination; 70 % yield

N

Me HO

O

Me

(–)-stemaphylline

66; 58 % yield96:4 d.r.

67; 71 % yield

steps

i.Et2O/THF

65


3333


76 in 97 % yield with complete diastereospecificity. Thisalkyne was converted into the trisubstituted alkene oftatanan A in two further steps.

A collaborative study on the synthesis of ladderane nat-ural products was recently published by the groups of Boxer,Gonzalez-Martinez and Burns (Scheme 29).41 A key inter-mediate in these studies was the unusual lipid tail [5]-lad-deranoic acid. This compound was prepared from meso-alkene 77 by a sequence involving copper-catalyzed de-symmetrizing hydroboration (95 % yield, 90 % ee) followedby Zweifel olefination with vinyl lithium reagent 79 (3:1E/Z). It was found that carrying out the Zweifel olefinationwith N-bromosuccinimide rather than iodine was critical toachieve efficient coupling. Following silyl deprotection, thecoupled product 80 was obtained in 88 % yield as an incon-sequential mixture of Z/E isomers. Hydrogenation of thealkene followed by Jones oxidation of the primary alcoholcompleted the first catalytic enantioselective synthesis of[5]-ladderanoic acid.

Scheme 26 Formal synthesis of solanoeclepin A

OBn

Me

H

TBSO

B(pin)

OBn

Me

H

TBSO

O

O

B

MgBr(4 eq.)

i. I2THF/MeOH

ii. NaOMeOBn

Me

H

TBSO

O

O

69

i. cat. OsO4, NMOii. NaIO4

iii. (EtO)2OP CO2Et

OBn

Me

H

TBSO

O

O

70; 67 % (4 steps)

CO2Et

68

O

Me

HO

CO2H

OOMeMe Me

O

OOH

H

H

solanoeclepin A

steps

O

O THF

NaH

Scheme 27 Enantioselective synthesis of debromohamigeran E

debromohamigeran E

Me

O

OMe

Me

OTBS

Me

(pin)B

Me

O

OMe

Me

OTBS

Me

Me

72; 42 % yield

73; 93 % yield (2.1 g)

steps

Me

CO2HCO2H

OHMe

Me

Me

(pin)B

Me

OH

(pin)BPd(OAc)2 (2.5 mol %)

RuPhos (3 mol %)aq. KOH, THF/PhMe

then TBSCl

O

OMe

MeMe

OTf

Li

Me

ii. I2, Et2O/MeOHiii. NaOMe

i.

71

Et2O

Scheme 28 Total synthesis of tatanan A; Ar = 2,4,5-trimethoxyphenyl; d.s. = diastereospecifity

tatanan A

Et

MeB(pin)

OCbLi

Et

Me

OMe

MeOOMe

MeO

OMeMeO

74

THF

then I2THF/MeOH

76; 97 % yield100 % d.s.

steps

Ar

Et

Me

ArOCb LDA

THFAr

Et

Me

Ar

Me

OMeOMe

OMe

OMe

MeOOMe

OMeMeO

OMe

75


3334


Scheme 29 Zweifel olefination in the synthesis of [5]-ladderanoic acid

Negishi and co-workers have employed a Zweifel olefi-nation in the synthesis of the side chain of (+)-scyphostatin(Scheme 30).42 In this case, a boronate complex was formedbetween vinyl boronic ester 81 (prepared in 7 steps from al-lyl alcohol) and methyllithium. After addition of iodine andNaOH followed by silyl deprotection, trisubstituted alkene82 was obtained in 76 % yield. The very high stereoselectiv-ity obtained in this reaction (>98:2 E/Z) is particularly note-worthy and represents a significant improvement uponprevious synthetic approaches toward this fragment.

Hoveyda and co-workers have employed a similar strat-egy to synthesize the antitumor agent herboxidiene(Scheme 31).43 In this case, Z-vinyl boronic ester 83 wasprepared as a single stereoisomer by a Cu-catalyzed boryla-tion–allylic substitution reaction. Boronic ester 83 was thenconverted into trisubstituted alkene 84 in a Zweifel olefina-tion with methyllithium. The resulting alkene was obtainedas a single E-isomer in 70 % yield and could be convertedinto herboxidiene in five steps.

A stereocontrolled synthesis of (–)-filiformin has beenreported by Aggarwal and co-workers involving an intra-molecular Zweifel olefination (Scheme 32).32 Intermediate85 (synthesized in high stereoselectivity by lithiation–borylation) was converted into cyclic boronate complex 86by in situ lithium–halogen exchange. Addition of iodine andmethanol brought about the desired ring contraction toprovide exocyclic alkene 87 in 97 % yield. Deprotection ofthe phenolic ether followed by acid-promoted cyclizationand bromination completed the synthesis of (–)-filiformin.

5 Conclusions and Outlook

Fifty years have passed since the first report by Zweifeland co-workers on the iodine-mediated olefination of vinylboranes. Since then, this process has evolved into a robustand practical method for the enantiospecific coupling ofboronic esters with vinyl metals. Recent contributions havesignificantly expanded the generality of the process, en-abling the efficient coupling of a wide range of differentalkenyl partners and allowing increasingly precise controlover the stereochemical outcome of the transformation.Rapid progress in enantioselective boronic ester synthesiscombined with the extensive applications of chiral alkenesbode well for the continued development and application ofthe Zweifel olefination in synthesis.

[5]-ladderanoic acid

H

H

H

H

H

H

H

H

77

Cu(MeCN)4PF6 (10 mol %)(R)-DM-SEGPHOS (11 mol %)

H

H

H

H

H

H

H

H

(pin)B

i. 79, Et2O/THFii. NBSiii. NaOMe THF/Et2O/MeOHiv. HF·pyr, THF

80; 88 % yield

H H

H

H

H

H

H

H

H

5

OHH H

H

H

H

H

H

H

H

5

O

HOi. H2, Ra-Ni

ii. CrO3/H2SO4

78; 95 % yield; 90 % e.e.

B2(pin)2, NaOtBu, MeOH/THF

LiOTBS

79 (3:1 E/Z)

5

Scheme 30 Construction of the side chain of (+)-scyphostatin

(+)-scyphostatin

Me

B(pin)Me

Me Me

OTBS

i. MeLi, Et2O, ii. I2, MeOH

iii. aq. NaOHiv. TBAF

Me MeMe

Me Me

stepsMe MeMe

Me MeNH

O

HOOH O

O

82; 76 % yield>98:2 E/Z81

OH

Scheme 31 Total synthesis of herboxidiene; BOM = benzyloxymethyl

i. MeLi, THFii. I2, THF/MeOH

Me

OMe

OBOM

Me

Me

OMe

OBOM

Me

Me MeMe

OMe

OH

Me

Me Me

O

MeO

CO2H

Me

herboxidiene 84; 70 % yield>98:2 E/Z

steps

Me

(pin)B

Me

OMe

OBOM

Me

(EtO)2OPO Me

CuCl (5 mol %)

83; 76 % yield>98:2 d.r.; >98:2 Z/E

N NPh

Et

Et

PF6

B2(pin)2, KOtBu, THF

(5 mol %)

HO


3335


Funding Information

We thank EPSRC (EP/I038071/1) and the European Research Council(advanced grant 670668) for financial support.EPSRC (EP/I038071/1)European Research Council (670668)

Acknowledgment

We are grateful to Dr Eddie Myers and Dr Adam Noble for helpful dis-cussions and suggestions during the preparation of this manuscript.

References

(1) (a) Stereoselective Alkene Synthesis, In Topics in Current Chemis-try,;Vol. ■■?■■ Wang, J., Ed.; Springer: Heidelberg, 2012. (b) Williams, J.M. J. Preparation of Alkenes: A Practical Approach; Oxford Uni-versity Press: Oxford, 1996. (c) Negishi, E.; Huang, Z.; Wang, G.;Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474.

(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.Int. Ed. 2001, 40, 4544. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.Angew. Chem. Int. Ed. 2005, 44, 4442. (d) Jana, R.; Pathak, T. P.;Sigman, M. S. Chem. Rev. 2011, 111, 1417. (e) Suzuki, A. Angew.Chem. Int. Ed. 2011, 50, 6722. (f) Li, J.; Ballmer, S. G.; Gillis, E. P.;Fujii, S.; Schmidt, M. J.; Palazzolo, A. M. E.; Lehmann, J. W.;Morehouse, G. F.; Burke, M. D. Science 2015, 347, 1221.(g) Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329.

(3) (a) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54,1082. (b) Wang, C.-Y.; Derosa, J.; Biscoe, M. R. Chem. Sci. 2015, 6,5105. (c) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem.Rev. 2015, 115, 9587. (d) Lee, J. C. H.; McDonald, R.; Hall, D. G.Nat. Chem. 2011, 3, 894.

(4) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219.(5) For other review articles which discuss Zweifel olefination, see:

(a) Matteson, D. S. Chem. Rev. 1989, 89, 1535. (b) Matteson, D. S.J. Organomet. Chem. 1999, 581, 51. (c) Scott, H. K.; Aggarwal, V.K. Chem. Eur. J. 2011, 17, 13124. (d) Leonori, D.; Aggarwal, V. K.Acc. Chem. Res. 2014, 47, 3174. (e) Sandford, C.; Aggarwal, V. K.Chem. Commun. 2017, 53, 5481.

(6) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem. Soc.1967, 89, 3652.

(7) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem.Soc. 1971, 93, 6309.

(8) Matteson, D. S.; Liedtke, J. D. J. Am. Chem. Soc. 1965, 87, 1526.(9) For the synthesis of trisubstituted alkenes, see: Brown, H. C.;

Basavaiah, D.; Kulkarni, S. U. J. Org. Chem. 1982, 47, 171.

(10) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem.Soc. 1972, 94, 6560.

(11) LaLima, N. J.; Levy, A. B. J. Org. Chem. 1978, 43, 1279.(12) Suzuki, A.; Miyaura, N.; Abiko, S.; Itoh, M.; Brown, H. C.; Sinclair,

J. A.; Midland, M. M. J. Am. Chem. Soc. 1973, 95, 3080.(13) For selected examples of alkynylation of boranes and borinic

esters, see: (a) Negishi, E.; Lew, G.; Yoshida, T. J. Chem. Soc.,Chem. Commun. 1973, 22, 874. (b) Suzuki, A.; Miyaura, N.;Abiko, S.; Itoh, M.; Midland, M. M.; Sinclair, J. A.; Brown, H. C.J. Org. Chem. 1986, 51, 4507. (c) Naruse, M.; Utimoto, K.; Nozaki,H. Tetrahedron 1974, 30, 2159. (d) Naruse, M.; Utimoto, K.;Nozaki, H. Tetrahedron Lett. 1973, 14, 2741. (e) Pelter, A.; Drake,R. A. Tetrahedron Lett. 1988, 29, 4181. (f) Sikorski, J. A.; Bhat, N.G.; Cole, T. E.; Wang, K. K.; Brown, H. C. J. Org. Chem. 1986, 51,4521. (g) Canterbury, D. P.; Micalizio, G. C. J. Am. Chem. Soc.2010, 132, 7602.

(14) (a) Aggarwal, V. K.; Fang, G. Y.; Ginesta, X.; Howells, D. M.; Zaja,M. Pure Appl. Chem. 2006, 78, 215. (b) Slayden, S. W. J. Org.Chem. 1981, 46, 2311. (c) Slayden, S. W. J. Org. Chem. 1982, 47,2753.

(15) Zweifel, G.; Polston, N. L.; Whitney, C. C. J. Am. Chem. Soc. 1968,90, 6243.

(16) (a) Tripathy, P. B.; Matteson, D. S. Synthesis 1990, 200. (b) Elliott,M. C.; Smith, K.; Jones, D. H.; Hussain, A.; Saleh, B. A. J. Org.Chem. 2013, 78, 3057.

(17) (a) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 3806.(b) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 5407.(c) Brown, H. C.; Basavaiah, D.; Kulkarni, S. U.; Bhat, N. G.;Prasad, J. V. N. V. J. Org. Chem. 1988, 53, 239.

(18) (a) For a review see: Collins, B. S. L.; Wilson, C. M.; Myers, E. L.;Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, in press; DOI:10.1002/anie.201701963. For selected recent examples, see:(b) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Science2016, 354, 1265. (c) Zhang, L.; Lovinger, G. J.; Edelstein, E. K.;Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Science 2016,351, 70. (d) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters,D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan,M.; Baran, P. S. Science 2017, in press; DOI: 10.1126/sci-ence.aam7355.

(19) (a) Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem. 1976, 110,25. (b) Matteson had previously described this work in a reviewarticle: Matteson, D. S. Synthesis 1975, 147.

(20) (a) Evans, D. A.; Thomas, R. C.; Walker, J. A. Tetrahedron Lett.1976, 17, 1427. (b) Evans, D. A.; Crawford, T. C.; Thomas, R. C.;Walker, J. A. J. Org. Chem. 1976, 41, 3947.

(21) Brown, H. C.; Bhat, N. G. J. Org. Chem. 1988, 53, 6009.

Scheme 32 Synthesis of (–)-filiformin via an intramolecular Zweifel olefination

B(pin)Me

Li

Me Me

B(pin)Me

Me

Me

Me

MeO

Me

MeO

Me

B(pin)Me

Br

Me

MeO

Me

MeO

tBuLi

THF

I2THF/MeOHi. NaSEt

ii. TFAiii. Br2

O Me

MeMe

Me

Br

(-)-filiformin 87; 97 % yield

8685


3336


(22) For selected applications of Zweifel reactions of boranes andborinic esters, see: (a) Abatjoglou, A. G.; Portoghese, P. S. Tetra-hedron Lett. 1976, 17, 1457. (b) Kulkarni, U. U.; Basavaiah, D.;Brown, H. C. J. Organomet. Chem. 1982, 225, C1. (c) Basavaiah,D.; Brown, H. C. J. Org. Chem. 1982, 47, 1792. (d) Mikhailov, B.M.; Gurskii, M. E.; Pershin, D. G. J. Organomet. Chem. 1983, 246,19. (e) Hyuga, S.; Takinami, S.; Hara, S.; Suzuki, A. TetrahedronLett. 1986, 27, 977. (f) Benmaarouf-Khallaayoun, Z.; Baboulene,M.; Speziale, V.; Lattes, A. J. Organomet. Chem. 1986, 306, 283.(g) Wang, K. K.; Dhumrongvaraporn, S. Tetrahedron Lett. 1987,28, 1007. (h) Ichikawa, J.; Sonoda, T.; Kobayashi, H. TetrahedronLett. 1989, 30, 6379. (i) Hoshi, M.; Masuda, Y.; Arase, A. J. Chem.Soc., Perkin Trans. 1 1990, 12, 3237. (j) Brown, H. C.; Iyer, R. R.;Mahindroo, V. K.; Bhat, N. G. Tetrahedron: Asymmetry 1991, 2,277. (k) Brown, H. C.; Mandal, A. K. J. Org. Chem. 1992, 57, 4970.(l) Periasamy, M.; Bhanu Prasad, A.; Suseela, Y. Tetrahedron1995, 51, 2743. (m) Yang, D. Y.; Huang, X. J. Organomet. Chem.1996, 523, 139. (n) Hoshi, M.; Tanaka, H.; Shirakawa, K.; Arase,A. Chem. Commun. 1999, 627. (o) Smith, K.; Balakit, A. A.; El-Hiti, G. A. Tetrahedron 2012, 68, 7834.

(23) Dutheuil, G.; Webster, M. P.; Worthington, P. A.; Aggarwal, V. K.Angew. Chem. Int. Ed. 2009, 48, 6317.

(24) Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem.Soc. 2013, 135, 16054.

(25) (a) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem. Int. Ed.2011, 50, 3760. (b) Shimizu, M. Angew. Chem. Int. Ed. 2011, 50,5998.

(26) Blair, D. J.; Tanini, D.; Bateman, J. M.; Scott, H. K.; Myers, E. L.;Aggarwal, V. K. Chem. Sci. 2017, 8, 2898.

(27) Linstrumelle, G.; Alami, M. Vinylmagnesium Bromide, In e-EROSEncyclopedia of Reagents for Organic Synthesis; John Wiley &Sons: Chichester, 2001.

(28) Armstrong, R. J.; Niwetmarin, W.; Aggarwal, V. K. Org. Lett.2017, 19, 2762.

(29) For related use of DMSO to promote boronate complex forma-tion with vinyl Grignard reagents, see: (a) Lovinger, G. J.;Aparece, M. D.; Morken, J. P. J. Am. Chem. Soc. 2017, 139, 3153.(b) Edelstein, E. K.; Namirembe, S.; Morken, J. P. J. Am. Chem. Soc.2017, 139, 5027.

(30) For a related example involving trialkylboranes, see: Levy, A. B.;Schwartz, S. J.; Wilson, N.; Christie, B. J. Organomet. Chem. 1978,156, 123.

(31) Wang, Y.; Noble, A.; Myers, E. L.; Aggarwal, V. K. Angew. Chem.Int. Ed. 2016, 55, 4270.

(32) Blair, D. J.; Fletcher, C. J.; Wheelhouse, K. M. P.; Aggarwal, V. K.Angew. Chem. Int. Ed. 2014, 53, 5552.

(33) (a) Aggarwal, V. K.; Binanzer, M.; de Ceglie, M. C.; Gallanti, M.;Glasspoole, B. W.; Kendrick, S. J. F.; Sonawane, R. P.; Vázquez-Romero, A.; Webster, M. P. Org. Lett. 2011, 13, 1490. For relatedexamples see: (b) Bhat, N. G.; Lai, W. C.; Carroll, M. B. Tetrahe-dron Lett. 2007, 48, 4267. (c) Meng, F.; Jang, H.; Hoveyda, A. H.Chem. Eur. J. 2013, 19, 3204.

(34) Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K.Angew. Chem. Int. Ed. 2017, 56, 786.

(35) Armstrong, R. J.; Sandford, C.; García-Ruiz, C.; Aggarwal, V. K.Chem. Commun. 2017, 53, 4922.

(36) For other examples of Zweifel olefination in synthesis, see:(a) Man, H.-W.; Hiscox, W. C.; Matteson, D. S. Org. Lett. 1999, 1,379. (b) Fletcher, C. J.; Blair, D. J.; Wheelhouse, K. M. P.;Aggarwal, V. K. Tetrahedron 2012, 68, 7598. (c) Shoba, V. M.;Thacker, N. C.; Bochat, A. J.; Takacs, J. M. Angew. Chem. Int. Ed.2016, 55, 1465. (d) Casoni, G.; Myers, E. L.; Aggarwal, V. K. Syn-thesis 2016, 48, 3241. (e) Chakrabarty, S.; Takacs, J. M. J. Am.Chem. Soc. 2017, 139, 6066.

(37) Varela, A.; Garve, L. K. B.; Leonori, D.; Aggarwal, V. K. Angew.Chem. Int. Ed. 2017, 56, 2127.

(38) Kleinnijenhuis, R. A.; Timmer, B. J. J.; Lutteke, G.; Smits, J. M. M.;de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Chem. Eur. J.2016, 22, 1266.

(39) Blaisdell, T. P.; Morken, J. P. J. Am. Chem. Soc. 2015, 137, 8712.(40) Noble, A.; Roesner, S.; Aggarwal, V. K. Angew. Chem. Int. Ed.

2016, 55, 15920.(41) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A. M.;

Smith, M. W.; Moss, F. R.; Smith, M. D.; Vahala, R.; Gonzalez-Martinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016,138, 15845.

(42) Xu, S.; Lee, C.-T.; Rao, H.; Negishi, E. Adv. Synth. Catal. 2011, 353,2981.

(43) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature 2014, 513, 367.


Date post:	29-Jul-2020
Category:	Documents
Upload:	others
View:	4 times
Download:	0 times

50 Years of Zweifel Olefination: A Transition-Metal …...Warren. After postdoctoral studies...

Documents