50 Years of Zweifel Olefination: a Transition-Metal-Free Coupling

SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2017, 49, 3323–3336 short review 3323 en

Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review

50 Years of Zweifel Olefination: A Transition-Metal-Free Coupling

Roly J. Armstrong 0000-0023-7590-61X Varinder K. Aggarwal* 0000-0030-3446-430

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

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

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

Abstract The Zweifel olefination is a powerful method for the stereoselective synthesis of alkenes. The reaction proceeds in the absence of a transition-metal catalyst, instead taking place by iodination of vinyl boronate complexes. Pioneering studies into this reaction were reported in 1967 and this short review summarizes developments in the field over the past 50 years. An account of how the Zweifel olefination was modified to enable the coupling of robust and air-stable boronic esters Varinder K. Aggarwal (right) studied chemistry at Cambridge Univer- is presented followed by a summary of current state of the art develop- sity and received his Ph.D. in 1986 under the guidance of Dr Stuart ments in the field, including stereodivergent olefination and alkynyla- Warren. After postdoctoral studies (1986–1988) under Professor Gil- tion. Finally, selected applications of the Zweifel olefination in target- bert Stork, Columbia University, he returned to the UK as a Lecturer at oriented synthesis are reviewed. Bath University. In 1991, he moved to Sheffield University, where he 1 Introduction was promoted to Professor in 1997. In 2000, he moved to Bristol Uni- 2.1 Zweifel Olefination of Vinyl Boranes versity where he holds the Chair in Synthetic Chemistry. He was elected 2.2 Zweifel Olefination of Vinyl Borinic Esters Fellow of the Royal Society in 2012. 2.3 Extension to Boronic Esters Roly J. Armstrong (left) graduated with an MSci in Natural Sciences 3.1 Introduction of an Unsubstituted Vinyl Group from Pembroke College, Cambridge (2011) spending his final year 3.2 Coupling of α-Substituted Vinyl Partners working in the laboratory of Professor Steven Ley. He subsequently 3.3 Syn Elimination moved to Merton College, Oxford to carry out a DPhil under the super- 4 Zweifel Olefination in Natural Product Synthesis vision of Professor Martin Smith (2011–2015) working on asymmetric 5 Conclusions and Outlook counterion-directed catalysis. In October 2015, he joined the group of Professor Varinder Aggarwal at the University of Bristol as a postdoctor- Key words Zweifel olefination, coupling, boronic esters, alkenes, al research associate. transition-metal-free, enantiospecific

1 Introduction of secondary and tertiary (chiral) boronates remains prob- lematic.3 Furthermore, the high cost and toxicity of the pal- The stereocontrolled synthesis of alkenes is a topic that ladium complexes required to catalyze these processes also has attracted a great deal of attention owing to the preva- detract from the appeal of this methodology.4 lence of this motif in natural products, pharmaceutical The Zweifel olefination represents a powerful alterna- agents and materials.1 Of the many olefination methods tive to the Suzuki–Miyaura reaction, enabling the coupling that exist, the Suzuki–Miyaura coupling represents a highly of vinyl metals with enantioenriched secondary and tertia- convergent method to assemble alkenes (Scheme 1, a).2 ry boronic esters with complete enantiospecificity (Scheme However, although the coupling of vinyl halides with pri- 1, b).5 The reaction is mediated by iodine and base and pro- mary and sp2 boronates takes place effectively, the coupling ceeds with no requirement for a transition-metal catalyst.

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Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review

This process is based upon pioneering studies reported in R' BH R' 2 I2, NaOH R' 1967 by Zweifel and co-workers on the iodination of vinyl R B R R' R THF THF/H2O boranes. This short review summarizes the key contribu- 12 tions made over the last 50 years that have enabled this anti transformation to evolve into an efficient and atom-eco- I2 iodination NaOH elimination nomical method for the coupling of boronic esters. Recent 1,2-metallate I OH OH I rearrangement B contributions to the field are described including the devel- B R' R R' R opment of Grignard-based vinylation, stereodivergent ole- R' R' fination and alkynylation processes. Finally, selected exam- 34 Me ples of Zweifel olefination in target-oriented synthesis are selected products: Cy Cy reviewed to highlight the utility of this methodology. Cy Cy Me Me 2a; 83 % yield 2b; 75 % yield 2c; 77 % yield 2d; 70 % yield (a) Suzuki–Miyaura Coupling 99:1 Z/E 92:8 Z/E 85:15 Z/E R1 X cat. Pd(0) R1 R3 + R3 B(pin) Scheme 2 Zweifel olefination: iodination of vinyl boranes R2 R2

(b) Zweifel Olefination with very high levels of E-selectivity. Chiral non-racemic 1 1 3 R M I2 R R Transition-Metal Free boranes could be transformed with complete stereospeci- 3 + R B(pin) Stereospecific ficity. 2 NaOMe 2 R R Enantiospecific

R' Scheme 1 Olefination of boronic esters R'2BH BrCN, CH2Cl2 B R R R R' R' THF then workup 2.1 Zweifel Olefination of Vinyl Boranes 56with aq. NaOH syn BrCN bromination In 1967, Zweifel and co-workers reported that vinyl elimination CN boranes 1, obtained by hydroboration of the corresponding CN Br Br B R' B R' alkynes, could be treated with sodium hydroxide and R R' 1,2-metallate rearrangement R R' iodine, resulting in the formation of alkene products 2 7 8 6 (Scheme 2). Intriguingly, although the intermediate vinyl selected products: Me Me nBu nBu boranes were formed with high E-selectivity, after addition nBu Cy of iodine, Z-alkenes were produced. A reaction with a dia- Me stereomerically pure secondary borane afforded the cou- 6a; 69 % yield 6b; 68 % yield 6c; 75 % yield Me 96:4 E/Z 93:7 E/Z 98:2 E/Z pled product, 2d, as a single anti diastereoisomer, indicating that the process proceeds with retention of configuration.7 Scheme 3 Synthesis of E-alkenes using cyanogen bromide Mechanistically, this reaction is thought to proceed by acti- vation of the π bond with iodine along with complexation A related syn elimination process was reported by Levy of sodium hydroxide to form a zwitterionic iodonium inter- and co-workers (Scheme 4).11 In this case, a vinyl lithium mediate 3. This species is poised to undergo a stereospecific reagent was prepared by lithium–halogen exchange and 1,2-metalate rearrangement resulting in the formation of a then combined with a symmetrical trialkylborane resulting β-iodoborinic acid 4. In the presence of sodium hydroxide, in formation of boronate complex 9. Treatment of this inter- this intermediate then undergoes anti elimination to afford mediate with iodine resulted in stereospecific iodination to the resulting Z-alkene product.8 produce β-iodoborane 10. The enhanced electrophilicity of Because vinyl borane intermediates could only be ac- this species (compared to β-iodoborinic acids such as 4) en- cessed by hydroboration of alkynes, the iodine-mediated abled a syn elimination to occur, generating the corre- Zweifel coupling was initially limited to the synthesis of Z- sponding trisubstituted alkene 11 with high levels of ste- alkenes.9 However, Zweifel and co-workers subsequently reocontrol. Although the substrate scope of the process is reported an elegant strategy for the complementary syn- wide, the method was limited to the use of symmetrical tri- thesis of E-alkenes (Scheme 3).10 This transformation was alkyl boranes. achieved by reacting dialkyl vinyl borane 5 with cyanogen Brown and co-workers demonstrated that the Zweifel bromide under base-free conditions. Following stereospe- olefination can also be applied to the synthesis of alkynes cific bromination, a boranecarbonitrile intermediate 8, was (Scheme 5).12 In this case, monosubstituted alkynes were formed, a species that was sufficiently electrophilic to un- deprotonated to form lithium acetylides, which were react- dergo syn elimination. A variety of boranes underwent this ed with trialkylboranes to form alkynylboronate complexes transformation, forming alkenes 6a–c in high yields and 12. Addition of iodine triggered a 1,2-metallate rearrangement to generate β-iodoboranes 13, which spontaneously

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Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review

R R2 i. nBuLi, THF 2 2 R R R I2, THF I B R R I B R3 3 2 R R R R syn R3 ii. R3B Li then workup R3 R elimination 9 with NaOH/H2O2 10 11

selected products: Et Me nPr Et Et Et Et Et nHex Et Et nPr Ph 11a 11b; 80 % yield 11c; 87 % yield 11d; 38 % yield 66 % yield >95:5 Z/E >95:5 E/Z >97:3 E/Z

Scheme 4 Olefination of symmetrical trialkylboranes underwent elimination to form alkyne products. This pro- ful when the borane is challenging to access or expensive. cess represents a convenient alternative to the alkylation of One solution to this problem would be to employ a mixed lithium acetylides with alkyl halides and has been success- borane in which one (or two) of the boron-bound groups fully employed in total synthesis.13 demonstrates a low migratory aptitude (e.g., thexyl).14 However, in practice, determining which group will migrate 2.2 Zweifel Olefination of Vinyl Borinic Esters has proved to be non-trivial and highly substrate-depen- dent. For example, Zweifel and co-workers showed that The transformations described in the previous section treatment of divinylalkylborane 15 (obtained by double hy- suffer from an inherent limitation in that only one of the al- droboration of 1-hexyne with thexylborane) with iodine kyl groups present in the borane starting materials is incor- resulted in competitive migration of both the sp2 and thexyl porated into the alkene product. This is particularly waste- groups leading to a mixture of the desired product 16 along with 17 (Scheme 6).15 They overcame this problem by treat- R ing the intermediate divinylalkylborane 15 with trimethyl- i. nBuLi, THF Li R I2 I B R amine oxide, resulting in selective oxidation of the B–C R' R' B R R' R thexyl ii. R3B R THF/Et2O R' R bond to afford borinic ester 18. Due to the low migratory 12 13 14 aptitude of an alkoxy ligand on boron,16 addition of iodine selected products: and sodium hydroxide now led to selective formation of nBu nBu nBu Cy nBu Ph Ph Ph Z,E-diene 16. Although this allowed control over which 14a; 96 % yield 14b; 99 % yield 14c; 98 % yield 14d; 95 % yield group migrated, the method was limited to the synthesis of Scheme 5 Alkynylation of boranes symmetrical dienes.

(a) Problem: competitive thexyl group migration n Me Me Bu Me nBu Me BH Me Me 2 I , NaOH nBu Me B 2 Me Me nBu Me + (2 eq.) nBu nBu THF Me Me THF/H2O 15 16 17 ratio 16/17 = 52:48 (b) Solution: selective oxidation to a borinic ester nBu nBu nBu Me Me3NO Me Me I2, NaOH B B Me n n n Bu Me THF Bu O THF/H2O Bu Me Me Me 15 18 16; 65 % yield 98:2 Z,E:isomers anti I iodination NaOH 2 elimination nBu 1,2-metallate I OThex rearrangement B B nBu OH nBu OThex I OH nBu Scheme 6 Diene synthesis by Zweifel olefination of boranes or borinic esters

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2 Br OMe R BHBr·SMe2 NaOMe I2, NaOMe 1 B B R R 1 2 1 2 R R R R 2 Et2O Et2O/MeOH MeOH R 19 20 21 selected products: nPr Cy nHex nPr nPr Et nPr nHex 21a; 74 % yield 21b; 69 % yield 21c; 62 % yield 21d; 68 % yield >99:1 Z/E >99:1 Z/E >99:1 Z/E >99:1 Z/E

Scheme 7 Synthesis of Z-alkenes from vinyl borinic esters

A more general approach to the iodination of vinyl O R2Li Li O I , NaOH borinic esters was later reported by Brown and co-workers 2 R1 B B O 17 R1 O R1 R2 R2 (Scheme 7). In this case, non-symmetrical vinyl borinic Et2O THF/H2O esters 20 were obtained by hydroboration of alkynes with 22 23 24 anti alkylbromoboranes followed by methanolysis of the result- I 2 iodination NaOH elimination ing bromoborane intermediates 19. Addition of sodium 1,2-metallate I O methoxide and iodine led to alkene products 21a–d in good I O rearrangement B B O R1 O R1 yields and very high levels of Z-selectivity. R2 R2 selected products: Me Ph 2.3 Extension to Boronic Esters nBu Ph 24a; 30 % yield 24b; 65 % yield

Although the use of borinic esters significantly expand- Scheme 8 Zweifel olefination of vinyl boronic esters ed the potential of the Zweifel olefination, there were still significant problems with this approach, most notably as- sociated with the high air sensitivity of the borane starting Evans and co-workers’ strategy also began with forma- materials. In contrast to boranes, boronic esters are air- and tion of a vinyl boronate complex (Scheme 9).20 In contrast moisture-stable materials which can be readily prepared to Matteson’s approach, this intermediate was accessed by via a wide range of methods.18 Evans and Matteson inde- reacting E-vinyl lithium reagent 26a (prepared by lithium– pendently recognized the potential of boronic esters as sub- halogen exchange) with secondary alkyl boronic ester 25. strates for Zweifel olefination communicating independent Treatment of the resulting vinyl boronate complex 27a with studies almost simultaneously.19,20 iodine and sodium methoxide resulted in formation of Matteson’s coupling process began with the synthesis of alkene 28a in 75 % yield (>96:4 Z/E). When a Z-vinyl lithium a vinyl boronate complex 23 by addition of an organolithi- precursor 26b was employed, alkene 28b was obtained in um reagent to a vinyl boronic ester 22 (Scheme 8).19 This in- 58 % yield with very high E-selectivity. The flexibility de- termediate was treated with iodine and sodium hydroxide, rived from the ability to form identical vinyl boronate com- resulting in iodination followed by 1,2-metallate rearrange- plexes by either reacting a vinyl boronic ester with an or- ment to form a β-iodoboronic ester which underwent anti ganolithium or a vinyl lithium with a boronic ester is a par- elimination to form the corresponding Z-alkene. This reac- ticularly appealing feature of the Zweifel olefination. tion could be carried out with alkyl or aryl lithium reagents Brown and co-workers subsequently extended this and the coupled products 24a and 24b were formed in methodology to enable the synthesis of trisubstituted moderate to good yields. alkenes (Scheme 10).17c,21 By reacting various trisubstituted

Et Et Li C5H11 B(OMe)2 26a OTBS I2, NaOMe TBSO THF THF/MeOH TBSO C5H11 C5H11 Et 27a 28a; 75 % yield >96:4 Z/E

B(OMe)2 Et Et 25 I2, NaOMe THF B(OMe) C5H11 OTHP 2 THF/MeOH C5H11 OTHP 26b H11C5 Li OTHP 27b 28b; 58 % yield >99:1 E/Z

Scheme 9 Zweifel olefination of vinyl lithiums with boronic esters

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23 1 1 stereocontrolled synthesis of (+)-faranal (Scheme 11). In R O R3Li R O I , MeOH 2 3 B B R this process, vinyl lithium was prepared in situ from tetra- O O R1 Et O Li R3 then aq. NaOH 2 R2 2 R2 R vinyltin by tin–lithium exchange and was then reacted with 29 30 31 enantioenriched secondary boronic ester 32. The resulting selected products: vinyl boronate complex was treated with iodine and sodi- S Me Ph Cl Ph um methoxide, thus promoting 1,2-metallate rearrange- nBu nBu nBu Me nBu nBu Me nBu ment and elimination affording alkene 33. This key inter- 31a; 80 % yield 31b; 81 % yield 31c; 76 % yield 31d; 64 % yield mediate was directly subjected to hydroboration and oxida- i >97:3 E/Z >97:3 E/Z >97:3 E/Z (with PrMgCl); >97:3 E/Z tion to provide alcohol 34 in 69 % yield with very high Scheme 10 Zweifel olefination of trisubstituted vinyl boronic esters diastereoselectivity. Oxidation with PCC completed the synthesis of (+)-faranal in 76 % yield. It was subsequently shown that the vinyl lithium ap- vinyl boronic esters (29) with organolithium nucleophiles, proach could be also be applied to the enantiospecific cou- a range of products was prepared in good to excellent pling of trialkyl tertiary boronic esters (Scheme 12, a)24 and yields. Notably, heteroaromatic groups could be introduced benzylic tertiary boronic esters25 (Scheme 12, b). It is note- (in 31b) and alkyl Grignard reagents could be used in place worthy that in these cases despite the sterically congested of organolithium reagents (in 31d). nature of the boronic ester starting materials, the coupled The methods shown in Schemes 8–10 represented a sig- products were obtained in excellent yields. The double vi- nificant advance upon the early work on the Zweifel olefi- nylation of primary–tertiary 1,2-bis(boronic esters) has also nation of boranes and borinic esters. However, at the time been achieved using this approach (Scheme 12, c).26 Using the potential of the method was not fully realized owing to four equivalents of vinyl lithium, diene 37 was obtained in the paucity of methods available for the preparation of bo- 77 % yield. ronic esters. Consequently, only a handful of studies involving Zweifel olefination were published over the following (a) Synthesis of α-(tertiary trialkyl) alkenes 22 n n three decades. In recent years, the huge increase in meth- Bu B(pin) i. Li Et2O/THF Bu n n ods available for the enantioselective synthesis of boronic Pr Me ii. I2 Pr Me esters has led to a renaissance in chemistry based upon the iii. NaOMe, Et2O/THF/MeOH 35; 72 % yield 100 % e.s. Zweifel olefination. Several new studies into the process (b) Synthesis of α-(tertiary benzylic) alkenes have been reported along with elegant reports employing i. THF Zweifel olefination in total synthesis. These results are de- Me B(pin) Li Me PMP Ph PMP Ph scribed in the following sections. ii. I2, NaOMe, THF/MeOH 36; 92 % yield 100 % e.s. 3.1 Introduction of an Unsubstituted Vinyl Group (c) Synthesis of dienes B(pin) i. Li Et2O/THF PMP B(pin) PMP The introduction of a vinyl group into a target molecule Me ii. I2 Me is commonly required in synthesis owing to the prevalence iii. NaOMe, Et2O/THF/MeOH 37; 77 % yield of this motif in natural products and as a valuable handle Scheme 12 Applications of Zweifel olefination with vinyl lithium (pre- for further functionalization. The first report describing the pared from tetravinyltin); PMP = p-methoxyphenyl; e.s. = enantiospeci- introduction of an unsubstituted vinyl group by Zweifel ole- ficity fination was published by Aggarwal and co-workers in their

Me Me

i. R B(pin) nBuLi Me Me 32 Me Sn Li R THF/Et O hexanes 2 Me ii. I2, THF/Et2O/MeOH iii. NaOMe 33

Et Me Me O PCC Me Me OH i. 9-BBN R Me ii. H2O2/NaOH Me Me (+)-faranal; 76 % yield 34; 69 % yield 94:6 d.r.

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

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Vinylation under Zweifel conditions represents a powerful strategy for the synthesis of alkenes. However, the ne- O B(pin) MgCl (1.0-4.0 eq.) B O B cessity of preparing vinyl lithium in situ from the corre- or sponding toxic stannane or volatile vinyl bromide detracts PMP Me solvent R Me R Me from the appeal of the process. In contrast, stable THF solu- 42 43 44 δB = 35 ppm δB = 8 ppm δB = –13 ppm tions of vinylmagnesium chloride or bromide are commer- 27 I2, NaOMe cially available. Aggarwal and co-workers have studied eq. RMgCl solvent ratio 42/43/44 yield 45a THF/MeOH the Zweifel olefination of tertiary boronic ester 38 with vi- 1.0THF >67:0:<33 37 % nylmagnesium bromide in THF.25 Monitoring the reaction 4.0THF 0:0:100 96 % 11 1.21:1 THF/DMSO 0:100:0 89 % R Me by B NMR spectroscopy revealed that with one equivalent 45a of vinylmagnesium bromide, the expected vinyl boronate selected examples: complex 39 was not observed and instead a mixture of un- NBoc Me reacted boronic ester 38 and trivinyl boronate complex 40 OTBS PMP Me CO2Et was formed (Scheme 13). The latter species originates from 45a; 89 % yield 45b 45c 45d 45e over-addition of vinylmagnesium bromide promoted by the 100 % e.s. 78 % yield 95 % yield 74 % yield 68 % yield 2+ high Lewis acidity of the Mg counterion. Upon addition of Scheme 14 Zweifel olefination of boronic esters with vinylmagnesium an excess of vinylmagnesium bromide (4 eq.), trivinyl boro- chloride in THF/DMSO; R = (CH2)2PMP nate complex 40 was obtained exclusively, and after addition of I2 followed by NaOMe, the coupled product 41a was obtained in good yield. These conditions were successfully ceeds effectively with a range of primary, secondary and ar- applied to the synthesis of a series of benzylic tertiary sub- omatic boronic esters. Notably, the use of the mild Grignard strates 41a–d. The reaction is ineffective at forming very reagent allows chemoselective coupling to occur in the hindered alkenes such as 36, although this product could be presence of reactive functional groups such as carbamates synthesized efficiently with vinyl lithium. (in 45b) and ethyl esters (in 45d). Although good yields of product were obtained with unhindered tertiary boronic esters (in 45e), in general, the Zweifel vinylation of tertiary MgBr B(pin) O (1.0–4.0 eq.) B O MgBr B boronic esters is best achieved either with four equivalents Et Ph Et Et of vinylmagnesium halide in THF or with vinyl lithium. Me THF Ph Ph Me Me In summary, there are currently three methods avail- 38 39 40 O δB = 32 ppm δB = 5–8 ppm O δB = –13 ppm able to introduce an unsubstituted vinyl group by Zweifel not observed Mg I2, THF/MeOH olefination (Scheme 15). For aromatic, primary and unhin- then NaOMe dered secondary boronic esters, the desired boronate com- eq. RMgBr ratio 38/40 yield 41a plex can be formed efficiently using 1.2 equivalents of vi- 1.0 70:30 26 % Et nylmagnesium halide in 1:1 THF/DMSO. For the majority of 4.0 0:100 66 % Ph Me tertiary boronic esters it is recommended to employ four 41a selected examples: equivalents of vinylmagnesium halide in THF (to form the Et trivinyl boronate complex), although with extremely hin- Et Et Me Ph dered tertiary boronic esters, the best results are obtained Ph Ph PMP PMP Me Me Me Cl Me with vinyl lithium. 41a; 66 % yield 41b; 79 % yield 41c; 62 % yield 41d; 79 % yield 36 100 % e.s. 100 % e.s. 100 % e.s. 100 % e.s. not observed increasing steric hindrance Scheme 13 Zweifel olefination of tertiary boronic esters with vinylmagnesium bromide in THF B(pin) B(pin) B(pin) B(pin) B(pin) B(pin) ArB(pin) R R R R Me R R R Ar Ar R R R Ar

Very recently, an improved procedure for coupling un- MgX MgX Li (1.2 eq.) (4.0 eq.) (2 eq.) hindered boronic esters with vinylmagnesium chloride has 1:1 THF/DMSO THF THF been reported (Scheme 14).28 As with tertiary boronic esters, it was observed that addition of vinylmagnesium chlo- Scheme 15 Summary of the best methods for boronate complex formation for the Zweifel vinylation of various boronic esters; R = alkyl ride to a THF solution of secondary boronic ester 42 result- group ed in over-addition to form trivinyl boronate complex 44. However, if the reaction was carried out in a 1:1 THF/DMSO mixture,29 over-addition was completely suppressed and 3.2 Coupling of α-Substituted Vinyl Partners only mono-vinyl boronate complex 43 was obtained. After addition of iodine and sodium methoxide, the coupled In addition to the synthesis of alkyl-substituted alkenes, product 45a was obtained in 89 % yield. This process pro- the Zweifel olefination has also been applied to the cou-

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Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review pling of vinyl partners α-substituted with a heteroatom. the corresponding alkynes 50. Coupling of a wide range of The coupling of lithiated ethyl vinyl ether 46 (readily pre- secondary and tertiary boronic esters was achieved in ex- pared by deprotonation of ethoxyethene with tBuLi) with a cellent yields with complete enantiospecificity. tertiary boronic ester proceeded smoothly to provide enol In 2014, an interesting intramolecular variant of the ether 47, which was hydrolyzed under mild conditions to Zweifel olefination for the construction of four-membered form 48 (Scheme 16, a).25,30 This process represents a novel ring products was reported (Scheme 18).32 In this process, method for the conversion of boronic esters into ketones. 51, which possesses both a boronic ester and a vinyl bro- This methodology has also been extended to the enantio- mide, was treated with tert-butyllithium resulting in che- specific synthesis of vinyl sulfides (Scheme 16, b).28 moselective lithium–halogen exchange followed by sponta- A related strategy for the alkynylation of boronic esters neous cyclization to form cyclic vinyl boronate complex 52. has recently been reported by Aggarwal and co-workers Upon treatment with iodine and methanol this species un- (Scheme 17).31 In contrast to the successful alkynylation re- derwent stereospecific ring contraction to provide β-iodo- actions of trialkyl boranes discussed previously (Scheme boronic ester 53. Elimination of this intermediate gave exo- 5),12,13 boronic esters undergo reversible boronate complex cyclic alkene 54 in 63 % yield. It is particularly noteworthy formation with lithium acetylides. This means that addition that this challenging Zweifel olefination occurs in good of electrophiles does not result in coupling, but instead yield despite the highly strained nature of the exomethy- leads to direct trapping of the acetylide and recovery of the lene cyclobutene product. boronic ester. A solution to this problem was developed in which vinyl bromides or carbamates were lithiated at the 3.3 Syn Elimination α-position with LDA and then reacted with boronic esters in a Zweifel olefination. Treatment of the resulting vinyl Aggarwal and co-workers have reported a method for bromides or carbamates with base (TBAF for bromides and the synthesis of allylsilanes through a lithiation– tBuLi or LDA for carbamates) triggered elimination to form borylation–Zweifel olefination strategy (Scheme 19).33 In this process, silaboronate 56 was homologated with config- urationally stable lithium carbenoids 55 to provide α-silyl-

(a) Synthesis of ketones from boronic esters Et Me i. Et Me aq. Et Me t EtO BuLi EtO Li (pin)B Ph EtO NH4Cl O Ph Ph ii. I THF 2 Me 46iii. NaOMe 47 48; 66 % yield THF/MeOH 100 % e.s. (b) Synthesis of vinyl sulfides Me i. Me n PhS BuLi·TMEDA PhS Li (pin)B PMP PhS PMP THF ii. I2, NaOMe THF/MeOH 49; 91 % yield 100 % e.s.

Scheme 16 Synthesis of ketones and vinyl sulfides by Zweifel olefination

Br Li CbO Li R or R' X B O R' Li O R–B(pin) O B O boronate complex R X = Br, OCb formation direct I Zweifel I , MeOH iodination 2 olefination 2

TBAF for X = Br R' I + R–B(pin) X R tBuLi for X = OCb R elimination 50 selected examples with X = Br: selected examples with X = OCb:

Me Me Ph CO tBu Me Ph Me Ph 2 Ph Me 2 Me Cl 50a; 81 % yield 50b; 68 % yield 50c; 89 % yield 50d; 87 % yield 100 % e.s. 100 % e.s. 100 % e.s. 100 % e.s.

i Scheme 17 Alkynylation of enantioenriched boronic esters; Cb = C(O)N Pr2

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Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review boronic esters 57, which were then subjected to Zweifel anti B(pin) olefination to obtain allylsilane products 58. Notably, it was elimination R1 H R1 2 necessary to carry out the Zweifel olefination without sodi- R H R2 I I um methoxide owing to the instability of the allylsilane B(pin) Z-alkene products under basic conditions. The substrate scope of the R1 R2 process was wide and a range of allylsilanes was prepared IB(pin) in high yields and with excellent levels of enantioselectivity. R2 syn R1 R1 R2 Interestingly, with a hindered α-silylboronic ester, E-crotyl- elimination H H silane 58d was obtained as a single geometrical isomer, but E-alkene Z-crotylsilane 58c was formed in slightly reduced selectivi- Scheme 20 Rationalization for reduced Z/E selectivity with bulky ty (95:5 Z/E). boronic esters To rationalize the reduced selectivity observed in the formation of Z-crotylsilane 58c, it was postulated that as branched), increasing formation of the E-isomer was ob- the boronic ester becomes more hindered, the transition served, up to 90:10 Z/E in the case of menthol-derived state for anti elimination becomes disfavored due to a steric alkene 60c. clash between the bulky R1 and R2 substituents (Scheme

20). This allows the usually less favorable syn elimination Bn B(pin) Bn Li (pin)B Bn I2, NaOMe pathway to compete, resulting in the formation of small R1 R2 THF R1 R2 THF/MeOH R1 R2 amounts of the E-isomer. 59 60 Similar behavior has been observed in the Zweifel olefi- Me Me selected examples: Me H nation of hindered secondary boronic esters with alkenyl- i Bn Me Pr Bn lithiums (Scheme 21).34 As the boronic ester becomes more Me H 3 sterically encumbered (for example, benzylic or β- Me Ph H H Me 60a; 81 % yield TBSO 60b; 67 % yield 60c; 64 % yield 100 % e.s.; 96:4 Z/E H >95:5 d.r.; 92:8 Z/E >95:5 d.r.; 90:10 Z/E Bn Scheme 21 Reduced Z/E selectivity with bulky boronic esters

tBuLi boronate complex MeO Br formation Me Li Me In these cases, Aggarwal and co-workers have shown B B(pin) THF Ar Me B(pin) (pin) that iodine can be replaced with PhSeCl resulting in the for- Ar Me 35 51 52 mation of β-selenoboronic esters (Scheme 22). Because the selenide is a poorer leaving group than the correspond- I2 iodination THF/MeOH ing iodide, treatment of these intermediates with sodium methoxide led exclusively to anti elimination providing the MeO Me 1,2-metallate coupled products 60a–c as a single Z-isomer in all cases.34 elimination Me rearrangement I I Me Ar Ar B It was also demonstrated that β-selenoboronic esters (pin) Me (pin)B (obtained by selenation of vinyl boronate complexes) could 54; 63 % yield 53 100 % e.s. be directly treated with m-CPBA resulting in chemoselective oxidation of the selenide to give the corresponding Scheme 18 Construction of an exomethylene cyclobutene by an intra- selenoxide (Scheme 23, a).34 A novel syn elimination then molecular Zweifel olefination; Ar = 2-MeO-4-MeC6H3 occurred in which the selenoxide oxygen atom attacked a boron atom instead of a hydrogen atom, providing E-

1 2 s R R BuLi·(–)-sp Li Li·(–)-sp Si–B(pin), 56 B(pin) 2 1 Et2O R R R OCb lithiation R OCb borylation Si R THF, then Si R 55 57 I2, THF/MeOH 58 68-69 % yield selected examples: Me Me Me Me

Si Ph Si Ph Si iPr Si iPr 58a; 84 % yield 58b; 94 % yield 58c; 80 % yield 58d; 80 % yield 97:3 e.r.; >96:4 Z/E 97:3 e.r.; >96:4 E/Z 96:4 e.r.; 95:5 Z/E 96:4 e.r.; >96:4 E/Z

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

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Bn B(pin) Bn Li (pin)B Bn i. PhSeCl, THF

1 2 1 2 R R THF R R ii. NaOMe R1 R2 59THF/MeOH 60 anti PhSeCl selenation NaOMe elimination 1,2-metallate R1 R2 SePh rearrangement (pin)B Bn (pin)B Bn R1 R2 SePh

selected examples: Me Me Me H i Bn Me Pr Bn Me H 3

Me Ph H H Me 60a; 63 % yield TBSO 60b; 70 % yield 60c; 55 % yield H 100 % e.s.; >98:2 Z/E >95:5 d.r.; >98:2 Z/E >95:5 d.r.; >98:2 Z/E Bn Scheme 22 Highly Z-selective olefination of sterically hindered boronic esters

(a) Syn elimination of β-selenoboronic esters Li 2 2 R i. PhSeCl, THF 1 1 R (pin)B R R —Bpin) R2 THF R1 ii. m-CPBA, THF selenation; syn PhSeCl 1,2-migration elimination

R1 R1 R2 m-CPBA R2 (pin)B (pin)B SePh oxidation SePh O

(b) Stereodivergent olefination

i. tBuLi i. tBuLi R2 ii. R3–B(pin) Br ii. R3–B(pin) R3 R1 R1 R1 3 2 2 61 R iii. I2, NaOMe R iii. PhSeCl 62 R or PhSeCl, NaOMe iv. m-CPBA

Bn Me Me Me Me Me PMP Bn PMP PMP PMP 2 2 2 Me 2 Me Me 61a; 80 % yield 62a; 74 % yield 61b; 95 % yield 62b; 83 % yield >98:2 Z/E; 100 % e.s. >98:2 E/Z; 100 % e.s. >98:2 Z/E; 100 % e.s. 96:4 E/Z; 100 % e.s. OTBS OTBS Me TBDPSO TBDPSO OPMB Me Me Me Me Me Me OPMB 61c; 48 % yield 62c; 52 % yield 98:2 Z/E; >95:5 d.r. Me 98:2 E/Z; >95:5 d.r.

Scheme 23 Stereodivergent olefination of boronic esters

alkenes with high selectivity. In conjunction with the clic vinyl lithium reagents with boronic esters (Scheme Zweifel olefination (or its PhSeCl-mediated analogue) this 24).28 In this case, the cyclic β-iodoboronic ester intermedi- represents a stereodivergent method where either isomer ates 63 cannot undergo bond rotation and therefore must of a coupled product can be obtained from a single isomer undergo a challenging syn elimination. It was found that of vinyl bromide starting material (Scheme 23, b). The sub- this elimination could be promoted by adding an excess of strate scope of both processes is broad and a range of di- sodium methoxide (up to 20 eq.). Using this methodology, a and trisubstituted alkenes was prepared including 61c range of five- and six-membered cycloalkene products 64 which represents the C9–C17 fragment of the natural prod- were prepared in high yields and with complete stereospec- uct discodermolide. ificity, including glycal 64b and abiraterone derivatives In some cases, the ability to carry out syn elimination of such as 64c. β-iodoboronic esters is also desirable. For example, very recently Aggarwal and co-workers reported a coupling of cy-

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Since the pioneering studies on Zweifel olefination re- sis was the vinylation of the bridgehead tertiary boronic es- ported by Evans and Matteson, the method has been signifi- ter in 68. Formation of the trivinyl boronate complex with cantly developed such that a wide range of functionalized excess vinylmagnesium bromide in THF followed by addi- alkene products can now be obtained. The final section of tion of iodine and sodium methoxide produced alkene 69, this short review showcases selected examples where which was employed without purification in a subsequent Zweifel olefination has been used in complex molecule syn- sequence of oxidative cleavage and Horner–Wadsworth– thesis.36 Emmons olefination to form 70 in a yield of 67 % over four steps. Morken and Blaisdell have reported an elegant stereose- 4 Zweifel Olefination in Natural Product lective synthesis of debromohamigeran E that employs a Synthesis Zweifel coupling of an α-substituted vinyl lithium (Scheme 27).39 Cyclopentyl boronic ester 72 was prepared from 1,2- Aggarwal and co-workers recently reported an 11-step bis(boronic ester) 71 in 42% yield by a highly selective hy- total synthesis of the alkaloid (–)-stemaphylline employing droxy-directed Suzuki–Miyaura coupling. This intermedi- a tandem lithiation–borylation–Zweifel olefination strategy ate was then subjected to Zweifel coupling with isopro- (Scheme 25).37 Pyrrolidine-derived boronic ester 65 was penyllithium (synthesized by Li–Br exchange) to form 73 in homologated with a lithium carbenoid to afford boronic es- 93 % yield. Completion of the synthesis of debromohamigeran ter 66 in 58 % yield and 96:4 d.r. A subsequent Zweifel olefi- E required four further steps including hydrogenation of the nation with vinyl lithium (synthesized in situ from tetra- alkene to an isopropyl group. vinyltin) gave alkene 67 in 71 % yield. Notably, these two A short enantioselective total synthesis tatanan A was steps could be combined into a one-pot operation, directly reported by Aggarwal and co-workers, which employs a providing 67 in 70 % yield. The alkene was later employed in stereospecific alkynylation reaction (Scheme 28).40 Boronic a ring-closing-metathesis–reduction sequence to form the ester 74 (synthesized by a diastereoselective Matteson ho- core 5-7 ring system of (–)-stemaphylline. mologation) was subjected to Zweifel olefination with lithi- A recent formal synthesis of the complex terpenoid nat- ated vinyl carbamate. Treatment of the resulting vinyl car- ural product solanoeclepin A has been reported by Hiems- bamate 75 with LDA resulted in elimination to form alkyne tra and co-workers (Scheme 26).38 A key step in this synthe-

R syn X Li i. R—B(pin), THF X X R B(pin) elimination ii. NaOMe (3-20 eq.) n n I n I2, THF/MeOH n = 0,1 63 64

selected examples: OTIPS Me Me O Me PMP PMP O 64b PMP TIPSO 49 % yield H 64a TIPSO 64d >95:5 d.r. H H 98 % yield 64c 79 % yield TBSO 100 % e.s. 86 % yield 100 % e.s.

Scheme 24 Synthesis of cycloalkenes via a challenging syn elimination

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

SiO Me OTIB SiO Me H i. Li SiO Me H Li·(–)-sp Et2O/THF (pin)B N N N Et2O then Boc (pin)B Boc ii. I2 Boc CHCl3, reflux iii. NaOMe 65 66; 58 % yield 67; 71 % yield 96:4 d.r. THF/Et2O/MeOH

O O Me steps H Me N (–)-stemaphylline

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

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MgBr i. I2 Me Me Me (4 eq.) THF/MeOH O B(pin) O B O H H H O THF O ii. NaOMe O OBn OBn TBSO TBSO OBn TBSO 68 69 i. cat. OsO4, NMO ii. NaIO4

iii. (EtO)2OP CO2Et NaH OH O H CO2H CO2Et Me Me O H steps O H Me Me O OMe O HO O TBSO OBn solanoeclepin A 70; 67 % (4 steps)

Scheme 26 Formal synthesis of solanoeclepin A

76 in 97 % yield with complete diastereospecificity. This

Me alkyne was converted into the trisubstituted alkene of Me O Me Me tatanan A in two further steps. Me O O Me (pin)B OH A collaborative study on the synthesis of ladderane nat- O OTf ural products was recently published by the groups of Boxer, (pin)B OTBS Me Pd(OAc)2 (2.5 mol %) (pin)B 41 RuPhos (3 mol %) Me Gonzalez-Martinez and Burns (Scheme 29). A key inter- 71 aq. KOH, THF/PhMe mediate in these studies was the unusual lipid tail [5]-lad- then TBSCl 72; 42 % yield deranoic acid. This compound was prepared from meso- Me i. Et2O alkene 77 by a sequence involving copper-catalyzed de- Li ii. I2, Et2O/MeOH symmetrizing hydroboration (95 % yield, 90 % ee) followed iii. NaOMe by Zweifel olefination with vinyl lithium reagent 79 (3:1 Me Me OH Me O E/Z). It was found that carrying out the Zweifel olefination Me O with N-bromosuccinimide rather than iodine was critical to CO2H Me steps Me OTBS CO2H achieve efficient coupling. Following silyl deprotection, the Me Me Me coupled product 80 was obtained in 88 % yield as an incon- debromohamigeran E 73; 93 % yield (2.1 g) sequential mixture of Z/E isomers. Hydrogenation of the alkene followed by Jones oxidation of the primary alcohol completed the first catalytic enantioselective synthesis of [5]-ladderanoic acid. Scheme 27 Enantioselective synthesis of debromohamigeran E

OMe MeO Li OCb Et Ar Et Ar THF OMe Et OMe OCb LDA Ar Ar B(pin) then I2 Me THF Me Me THF/MeOH MeO 75 76; 97 % yield 74 OMe 100 % d.s. OMe MeO

steps MeO Et OMe OMe

Me Me MeO OMe OMe tatanan A OMe

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

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Hoveyda and co-workers have employed a similar strat- H H H H Cu(MeCN)4PF6 (10 mol %) (pin)B H H H H (R)-DM-SEGPHOS (11 mol %) egy to synthesize the antitumor agent herboxidiene

t 43 B2(pin)2, NaO Bu, (Scheme 31). In this case, Z-vinyl boronic ester 83 was H H H H H H H H MeOH/THF prepared as a single stereoisomer by a Cu-catalyzed boryla- 77 78; 95 % yield; 90 % e.e. tion–allylic substitution reaction. Boronic ester 83 was then i. 79, Et2O/THF OTBS ii. NBS converted into trisubstituted alkene 84 in a Zweifel olefina- 5 Li iii. NaOMe tion with methyllithium. The resulting alkene was obtained 79 (3:1 E/Z) THF/Et2O/MeOH iv. HF·pyr, THF as a single E-isomer in 70 % yield and could be converted

O OH into herboxidiene in five steps. H H H H H H H H H H i. H2, Ra-Ni A stereocontrolled synthesis of (–)-filiformin has been HO 5 5 reported by Aggarwal and co-workers involving an intra- ii. CrO3/H2SO4 H H H H H H H H molecular Zweifel olefination (Scheme 32).32 Intermediate [5]-ladderanoic acid 80; 88 % yield 85 (synthesized in high stereoselectivity by lithiation– Scheme 29 Zweifel olefination in the synthesis of [5]-ladderanoic acid borylation) was converted into cyclic boronate complex 86 by in situ lithium–halogen exchange. Addition of iodine and Negishi and co-workers have employed a Zweifel olefi- methanol brought about the desired ring contraction to nation in the synthesis of the side chain of (+)-scyphostatin provide exocyclic alkene 87 in 97 % yield. Deprotection of (Scheme 30).42 In this case, a boronate complex was formed the phenolic ether followed by acid-promoted cyclization between vinyl boronic ester 81 (prepared in 7 steps from al- and bromination completed the synthesis of (–)-filiformin. lyl alcohol) and methyllithium. After addition of iodine and NaOH followed by silyl deprotection, trisubstituted alkene 82 was obtained in 76 % yield. The very high stereoselectiv- 5 Conclusions and Outlook ity obtained in this reaction (>98:2 E/Z) is particularly noteworthy and represents a significant improvement upon Fifty years have passed since the first report by Zweifel previous synthetic approaches toward this fragment. and co-workers on the iodine-mediated olefination of vinyl boranes. Since then, this process has evolved into a robust

Me Me i. MeLi, Et2O, and practical method for the enantiospecific coupling of ii. I2, MeOH Me Me Me Me Me boronic esters with vinyl metals. Recent contributions have Me OH Me OTBS iii. aq. NaOH B(pin) significantly expanded the generality of the process, en- iv. TBAF 82; 76 % yield 81 >98:2 E/Z abling the efficient coupling of a wide range of different

OH O alkenyl partners and allowing increasingly precise control Me Me Me Me HO steps over the stereochemical outcome of the transformation. Me NH O Rapid progress in enantioselective boronic ester synthesis (+)-scyphostatin O combined with the extensive applications of chiral alkenes bode well for the continued development and application of Scheme 30 Construction of the side chain of (+)-scyphostatin the Zweifel olefination in synthesis.

(EtO) OPO Me OMe 2 OMe B (pin) , KOtBu, THF Me 2 2 (pin)B Me CuCl (5 mol %) Me OBOM Me OBOM Et 83; 76 % yield Ph NN Me >98:2 d.r.; >98:2 Z/E (5 mol %) PF6 HO Et i. MeLi, THF ii. I2, THF/MeOH

Me OMe OMe O steps Me Me O Me Me Me OBOM CO2H Me Me Me Me OH herboxidiene 84; 70 % yield >98:2 E/Z

Scheme 31 Total synthesis of herboxidiene; BOM = benzyloxymethyl

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tBuLi MeO Br MeO Li MeO Me Me Me B(pin) B(pin) B(pin) THF Me Me Me Me Me Me 85 86

I2 i. NaSEt THF/MeOH Me ii. TFA MeO Br Me Me iii. Br2

Me O Me Me Me (-)-filiformin 87; 97 % yield

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

Funding Information (10) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem. Soc. 1972, 94, 6560. We thank EPSRC (EP/I038071/1) and the European Research Council (11) LaLima, N. J.; Levy, A. B. J. Org. Chem. 1978, 43, 1279. (advanced grant 670668) for financial support.EPSRC E(P0I/380711/E)uropean Research Coun lci 6(70668) (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 Acknowledgment esters, see: (a) Negishi, E.; Lew, G.; Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 22, 874. (b) Suzuki, A.; Miyaura, N.; We are grateful to Dr Eddie Myers and Dr Adam Noble for helpful dis- Abiko, S.; Itoh, M.; Midland, M. M.; Sinclair, J. A.; Brown, H. C. cussions and suggestions during the preparation of this manuscript. J. Org. Chem. 1986, 51, 4507. (c) Naruse, M.; Utimoto, K.; Nozaki, H. Tetrahedron 1974, 30, 2159. (d) Naruse, M.; Utimoto, K.; References Nozaki, H. Tetrahedron Lett. 1973, 14, 2741. (e) Pelter, A.; Drake, R. A. Tetrahedron Lett. 1988, 29, 4181. (f) Sikorski, J. A.; Bhat, N. (1) (a) Stereoselective Alkene Synthesis, In Topics in Current Chemis- G.; Cole, T. E.; Wang, K. K.; Brown, H. C. J. Org. Chem. 1986, 51, try,;■V o.■l?■■ Wang, J., Ed.; Springer: Heidelberg, 2012. (b) Williams, J. 4521. (g) Canterbury, D. P.; Micalizio, G. C. J. Am. Chem. Soc. M. J. Preparation of Alkenes: A Practical Approach; Oxford Uni- 2010, 132, 7602. versity Press: Oxford, 1996. (c) Negishi, E.; Huang, Z.; Wang, G.; (14) (a) Aggarwal, V. K.; Fang, G. Y.; Ginesta, X.; Howells, D. M.; Zaja, Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474. M. Pure Appl. Chem. 2006, 78, 215. (b) Slayden, S. W. J. Org. (2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. Chem. 1981, 46, 2311. (c) Slayden, S. W. J. Org. Chem. 1982, 47, (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. 2753. Int. Ed. 2001, 40, 4544. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. (15) Zweifel, G.; Polston, N. L.; Whitney, C. C. J. Am. Chem. Soc. 1968, Angew. Chem. Int. Ed. 2005, 44, 4442. (d) Jana, R.; Pathak, T. P.; 90, 6243. Sigman, M. S. Chem. Rev. 2011, 111, 1417. (e) Suzuki, A. Angew. (16) (a) Tripathy, P. B.; Matteson, D. S. Synthesis 1990, 200. (b) Elliott, Chem. Int. Ed. 2011, 50, 6722. (f) Li, J.; Ballmer, S. G.; Gillis, E. P.; M. C.; Smith, K.; Jones, D. H.; Hussain, A.; Saleh, B. A. J. Org. Fujii, S.; Schmidt, M. J.; Palazzolo, A. M. E.; Lehmann, J. W.; Chem. 2013, 78, 3057. Morehouse, G. F.; Burke, M. D. Science 2015, 347, 1221. (17) (a) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 3806. (g) Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329. (b) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 5407. (3) (a) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, (c) Brown, H. C.; Basavaiah, D.; Kulkarni, S. U.; Bhat, N. G.; 1082. (b) Wang, C.-Y.; Derosa, J.; Biscoe, M. R. Chem. Sci. 2015, 6, Prasad, J. V. N. V. J. Org. Chem. 1988, 53, 239. 5105. (c) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. (18) (a) For a review see: Collins, B. S. L.; Wilson, C. M.; Myers, E. L.; Rev. 2015, 115, 9587. (d) Lee, J. C. H.; McDonald, R.; Hall, D. G. Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, in press; DOI: Nat. Chem. 2011, 3, 894. 10.1002/anie.201701963. For selected recent examples, see: (4) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219. (b) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Science (5) For other review articles which discuss Zweifel olefination, see: 2016, 354, 1265. (c) Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; (a) Matteson, D. S. Chem. Rev. 1989, 89, 1535. (b) Matteson, D. S. Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Science 2016, J. Organomet. Chem. 1999, 581, 51. (c) Scott, H. K.; Aggarwal, V. 351, 70. (d) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, K. Chem. Eur. J. 2011, 17, 13124. (d) Leonori, D.; Aggarwal, V. K. D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, Acc. Chem. Res. 2014, 47, 3174. (e) Sandford, C.; Aggarwal, V. K. M.; Baran, P. S. Science 2017, in press; DOI: 10.1126/sci- Chem. Commun. 2017, 53, 5481. ence.aam7355. (6) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem. Soc. (19) (a) Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem. 1976, 110, 1967, 89, 3652. 25. (b) Matteson had previously described this work in a review (7) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem. article: Matteson, D. S. Synthesis 1975, 147. Soc. 1971, 93, 6309. (20) (a) Evans, D. A.; Thomas, R. C.; Walker, J. A. Tetrahedron Lett. (8) Matteson, D. S.; Liedtke, J. D. J. Am. Chem. Soc. 1965, 87, 1526. 1976, 17, 1427. (b) Evans, D. A.; Crawford, T. C.; Thomas, R. C.; (9) For the synthesis of trisubstituted alkenes, see: Brown, H. C.; Walker, J. A. J. Org. Chem. 1976, 41, 3947. Basavaiah, D.; Kulkarni, S. U. J. Org. Chem. 1982, 47, 171. (21) Brown, H. C.; Bhat, N. G. J. Org. Chem. 1988, 53, 6009.

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Syn thesis R. J. Armstrong, V. K. Aggarwal Short Review

(22) For selected applications of Zweifel reactions of boranes and (30) For a related example involving trialkylboranes, see: Levy, A. B.; borinic esters, see: (a) Abatjoglou, A. G.; Portoghese, P. S. Tetra- Schwartz, S. J.; Wilson, N.; Christie, B. J. Organomet. Chem. 1978, hedron Lett. 1976, 17, 1457. (b) Kulkarni, U. U.; Basavaiah, D.; 156, 123. Brown, H. C. J. Organomet. Chem. 1982, 225, C1. (c) Basavaiah, (31) Wang, Y.; Noble, A.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. D.; Brown, H. C. J. Org. Chem. 1982, 47, 1792. (d) Mikhailov, B. Int. Ed. 2016, 55, 4270. M.; Gurskii, M. E.; Pershin, D. G. J. Organomet. Chem. 1983, 246, (32) Blair, D. J.; Fletcher, C. J.; Wheelhouse, K. M. P.; Aggarwal, V. K. 19. (e) Hyuga, S.; Takinami, S.; Hara, S.; Suzuki, A. Tetrahedron Angew. Chem. Int. Ed. 2014, 53, 5552. Lett. 1986, 27, 977. (f) Benmaarouf-Khallaayoun, Z.; Baboulene, (33) (a) Aggarwal, V. K.; Binanzer, M.; de Ceglie, M. C.; Gallanti, M.; M.; Speziale, V.; Lattes, A. J. Organomet. Chem. 1986, 306, 283. Glasspoole, B. W.; Kendrick, S. J. F.; Sonawane, R. P.; Vázquez- (g) Wang, K. K.; Dhumrongvaraporn, S. Tetrahedron Lett. 1987, Romero, A.; Webster, M. P. Org. Lett. 2011, 13, 1490. For related 28, 1007. (h) Ichikawa, J.; Sonoda, T.; Kobayashi, H. Tetrahedron examples see: (b) Bhat, N. G.; Lai, W. C.; Carroll, M. B. Tetrahe- Lett. 1989, 30, 6379. (i) Hoshi, M.; Masuda, Y.; Arase, A. J. Chem. dron Lett. 2007, 48, 4267. (c) Meng, F.; Jang, H.; Hoveyda, A. H. Soc., Perkin Trans. 1 1990, 12, 3237. (j) Brown, H. C.; Iyer, R. R.; Chem. Eur. J. 2013, 19, 3204. Mahindroo, V. K.; Bhat, N. G. Tetrahedron: Asymmetry 1991, 2, (34) Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K. 277. (k) Brown, H. C.; Mandal, A. K. J. Org. Chem. 1992, 57, 4970. Angew. Chem. Int. Ed. 2017, 56, 786. (l) Periasamy, M.; Bhanu Prasad, A.; Suseela, Y. Tetrahedron (35) Armstrong, R. J.; Sandford, C.; García-Ruiz, C.; Aggarwal, V. K. 1995, 51, 2743. (m) Yang, D. Y.; Huang, X. J. Organomet. Chem. Chem. Commun. 2017, 53, 4922. 1996, 523, 139. (n) Hoshi, M.; Tanaka, H.; Shirakawa, K.; Arase, (36) For other examples of Zweifel olefination in synthesis, see: A. Chem. Commun. 1999, 627. (o) Smith, K.; Balakit, A. A.; El- (a) Man, H.-W.; Hiscox, W. C.; Matteson, D. S. Org. Lett. 1999, 1, Hiti, G. A. Tetrahedron 2012, 68, 7834. 379. (b) Fletcher, C. J.; Blair, D. J.; Wheelhouse, K. M. P.; (23) Dutheuil, G.; Webster, M. P.; Worthington, P. A.; Aggarwal, V. K. Aggarwal, V. K. Tetrahedron 2012, 68, 7598. (c) Shoba, V. M.; Angew. Chem. Int. Ed. 2009, 48, 6317. Thacker, N. C.; Bochat, A. J.; Takacs, J. M. Angew. Chem. Int. Ed. (24) Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem. 2016, 55, 1465. (d) Casoni, G.; Myers, E. L.; Aggarwal, V. K. Syn- Soc. 2013, 135, 16054. thesis 2016, 48, 3241. (e) Chakrabarty, S.; Takacs, J. M. J. Am. (25) (a) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche- Chem. Soc. 2017, 139, 6066. Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem. Int. Ed. (37) Varela, A.; Garve, L. K. B.; Leonori, D.; Aggarwal, V. K. Angew. 2011, 50, 3760. (b) Shimizu, M. Angew. Chem. Int. Ed. 2011, 50, Chem. Int. Ed. 2017, 56, 2127. 5998. (38) Kleinnijenhuis, R. A.; Timmer, B. J. J.; Lutteke, G.; Smits, J. M. M.; (26) Blair, D. J.; Tanini, D.; Bateman, J. M.; Scott, H. K.; Myers, E. L.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Chem. Eur. J. Aggarwal, V. K. Chem. Sci. 2017, 8, 2898. 2016, 22, 1266. (27) Linstrumelle, G.; Alami, M. Vinylmagnesium Bromide, In e-EROS (39) Blaisdell, T. P.; Morken, J. P. J. Am. Chem. Soc. 2015, 137, 8712. Encyclopedia of Reagents for Organic Synthesis; John Wiley & (40) Noble, A.; Roesner, S.; Aggarwal, V. K. Angew. Chem. Int. Ed. Sons: Chichester, 2001. 2016, 55, 15920. (28) Armstrong, R. J.; Niwetmarin, W.; Aggarwal, V. K. Org. Lett. (41) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A. M.; 2017, 19, 2762. Smith, M. W.; Moss, F. R.; Smith, M. D.; Vahala, R.; Gonzalez- (29) For related use of DMSO to promote boronate complex forma- Martinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016, tion with vinyl Grignard reagents, see: (a) Lovinger, G. J.; 138, 15845. Aparece, M. D.; Morken, J. P. J. Am. Chem. Soc. 2017, 139, 3153. (42) Xu, S.; Lee, C.-T.; Rao, H.; Negishi, E. Adv. Synth. Catal. 2011, 353, (b) Edelstein, E. K.; Namirembe, S.; Morken, J. P. J. Am. Chem. Soc. 2981. 2017, 139, 5027. (43) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature 2014, 513, 367.

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