Synthesis of Trisubstituted Alkenes

The other methods which involve organoboranes for the synthesis of trisubstituted alkenes employ either trialkyl(l-alkynyl)boratesl36) or trialkyl(l-alkenyl) bora- 

These results indicate a mechanism analogous to that involved in the formation of a.v-disubstituted alkenes is operative (Eq. 77)I38). 

The procedure still suffered from the disadvantage that only one of the R group was utilized. However, the recent development of hydridation procedure makes it possible 

HBBr2 SMe2 R1BBr2 SMe2 - R1BHBr SMe2 R-C CR i 

Zweifel and his co-workers have also introduced a stereospecific synthesis of trisubstituted alkenes (Eq. 75) although it has limitations of the use. 

Unfortunately, the Zweifel s hydroboration procedure suffers from the same dis-adventage as his synthesis of cis and trans alkenes. It requires R2BH as a reagent. Application of the new synthesis of RjBH via hydridation of R2BX made the procedure general for essentially all R groups available through hydroboration (Eq. 76) 

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Of greater potential practical significance, however, are the note193 and full papers194,195 in which Fabre, Julia and Verpeaux describe a new stereoselective synthesis of trisubstituted alkenes in which vinyl sulphones are attacked by Grignard reagents in the presence of iron or nickel catalysts (equations 82-84). 

Synthesis of Trisubstituted Alkenes via Olefin Cross-Metathesis, A. K. Chatter-JEE, R.H. Grubbs, Org. Lett. 1999, 1,... 

Trisubstituted alkenes.9 A stereoselective synthesis of trisubstituted alkenes uses (E)-alkenyl sulfoxides (1)>U as the starting material. These are reduced to the corresponding sulfides (2)," which undergo coupling with Grignard reagents in the presence of complexes of nickel chloride and phosphines as catalyst.12 The products (3) are obtained in steroisomeric purity of > 99%. 

Brown et al.3 have now extended the Zweifel synthesis to a stereospecific synthesis of trisubstituted alkenes from an internal alkyne (equation III). Evidently a similar mechanism is involved franr-addition of I+ and OC H 3 followed by trans-elimination of I and BROCH3 resulting in tram-orientation of the two alkyl groupsof the alkyne. 

Fig. 14.48. Ireland-CLaisen rearrangement of two 0-allyl-0-sityl ketene acetals. Trans-selective synthesis of disubsti-tuted and F-selective synthesis of trisubstituted alkenes.

Fig. 11.43. Claisen-Ireland rearrangement of two O-allyl-O-silyl ketene acetals. 7ran.v-sclective synthesis of disubstituted and E-selective synthesis of trisubstituted alkenes.

Various functionalized alkynes can be submitted to carbocupration reactions, such as alkoxyalkynes,150 alkynyl carbamates,151 acetylenic orthoesters,152 and thioalkynes.153 The carbocupration of orthoesters, for example, 204, has been used to prepare a-substituted esters of the type 206 by acidic hydrolysis of the adduct 205 (Scheme 51).152 This allows the formation of regioisomers that are not accessible by copper-mediated addition to acetylenic esters. A stereoselective synthesis of trisubstituted alkenes has been described by Normant et al.lSd> starting from phenylthio-acetylene 207. Carbocupration with lithium di- -butylcuprate affords the intermediate 208 which, upon addition of /z-butyllithium, undergoes a 1,2-metalate rearrangement to the vinylcuprate 209. The latter can be trapped with various electrophiles, for example, ethyl propiolate, providing product 210 with complete regio- and stereocontrol. 

Table 16 Synthesis of Trisubstituted Alkenes 1 (CF3CH20)2POCH(Me)CO2R in THF with KHMDS and 18-Ctown-6 ...

The Homer reaction can be applied to the synthesis of trisubstituted alkenes. As in the case of HWE reactions, the yield obtained by adding a disubstituted phosphine oxide to an aldehyde is frequently higher than that obtained by adding an anion to a ketone. This methodology was applied to the synthesis... 

The Julia coupling has also been successfully utilized for the synthesis of more complex alkenes. There are limitations to the application of the method to tri- and tetra-substituted alkenes, since the addition of the sulfone anion to a highly substituted ketone forms a -alkoxy sulfone that is difficult to trap and isolate. There is a tendency for highly substituted p-alkoxy sulfones to revert back to the ketone sulfone. There have been several recent examples of the synthesis of trisubstituted ( )-alkenes worthy of note. 

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

Tago, K., Kogen, H. Bis(2,2,2-trifluoroethyl) bromophosphonoacetate, a Novel HWE Reagent for the Preparation of (E)-a-Bromoacrylates A General and Stereoselective Method forthe Synthesis of Trisubstituted Alkenes. Org. Lett. 2000, 2, 1975-1978. 

Like hydroalumination and hydrozirconation, hydroboration of alkynes also provides a convenient and Stereospecific route to alkenyl metal reagents. However, initial attempts to achieve palladium-catalyzed cross-coupling of alkenylboranes with alkenyl halides were unsuccessful, due to the poor carbanionic character of these reagents. Later, Suzuki discovered that the desired transformation could be effected in the presence of an alkoxide or hydroxide base weaker bases, such as sodium acetate or triethylamine, were not generally effective. The reaction is suitable for the preparation of ( , )-, ( ,Z)- and (Z,Z)-dienes. Since reactions of alkenylboronates are higher yielding than those of alkenylboranes, the recent availability of (Z)-l-alkenylboronates " substantially improves the Suzuki method for the preparation of (Z)-alkenes. An extension of the methodology to the synthesis of trisubstituted alkenes has also been reported. " ... 

Wipf, P, Xiao, J. and Geib, S. J. (2005) Imine additions of internal alkynes for the synthesis of trisubstituted ( )-alkene and cyclopropane peptide isosteres. Adv. Synth. Catal., 347, 1605-1613. 

A. B. (2002) A Synthesis of trisubstituted alkenes by a Ru-catalyzed addition. Chemistry - A European Journal, 8, 2341-2349. 

The rearrangement of compounds B is an important method for the stereoselective synthesis of trisubstituted alkenes of known geometry (Table 3, p 3330). Simple ally] vinyl ethers provide EjZ ratios of approximately 90 10 (Tabic 3, entries 1 — 5)308,309, while the rearranged product of the transvinylation derivative of 2-methoxypropene and 2-methyl-l-penten-3-ol contains less than 1 % of the (Z)-alkene309. 

Other coupling partners to organozinc reagents include heterocyles such as 2-methylthiobenzothiazole, alkenyl aryl iodonium triflates (alkenyl group transfer for synthesis of trisubstituted alkenes), and aryl heteroaryl ethers. " Improved nickel-catalyzed cross-coupling conditions between oz-rto-substituted aryl iodides-nonaflates and alkyl-zinc iodides in. solution and in the solid phase have been defined. ... 

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