Lithium alkynides

The synthetic utility of the alkyne/B-X-9-BBN adducts has also been explored.152 (Z)-l-Alkynyl-2-halo-1-alkenes are the result of lithium alkynide action on these latter boranes (Scheme 76).157 The adducts resulting from the treatment of alkynes with B-X-9-BBN have been shown to be labile under protic conditions. However the decomposition has been harnessed and is an efficient preparation of 2-halo-1 -alkenes.158... 

The synthesis of unsymmetrical derivatives has been reported, which involves stepwise treatment of an alkenyldialkylborane with lithium alkynide followed by boron trifluoride. Protonolysis of the intermediate affords in a good yield the iso-merically pure unsymmetrical (Z, )-dicnc (Eq. 83) U1). 

In addition, conjugate addition of lithium alkynides and thermally unstable lithium carbenoids, which is very difficult to achieve in organocopper chemistry, is realized with this amphiphilic conjugate alkylation system (Sch. 98). 

Although lithium cuprates bearing two alkynic ligands notoriously resist transfer of this group, when admixed with an equal amount of the lithium alkynide (i.e. 3RC CLi Cul) exclusive 1,2-addition occurs with cyclic enones. While prior efforts to effect this chemistry in strictly ethereal solvents (diox-ane) have been unsuccessful, use of HMPA (- 20%) as cosolvent now leads to efficient couplings in these cases. The initial products may be isolated as such, or oxidatively worked up to provide, in the case of (73), the rearranged material (74 Scheme 11). 

Alkynylation of oxiranes or oxetanes with lithium alkynides is effectively carried out in the presence of BF3 OEt2 at -78 C. The use of BF3 gives better results than TiCU, SnCU or AlCU. The reaction takes place stereospecifically with anti opening, and the attack generally occurs at the less hindered site. Several functional groups such as halogens, acetals or certain esters survive the reaction conditions (Scheme 16). 100-102... 

The mechanistic aspects of this Lewis acid promoted reaction have been examined by low temperature NMR studies, and reaction of the lithium alkynides with the Lewis acid activated epoxides is indicated. The order of the addition of the reagents does not affect the product yields provided that the reaction is carried out at -78 C addition of BF3-OEt2 to a mixture of an epoxide and an alkynide or addition of an epoxide to a mixture of an alkynide and BF3-OEt2 are both possible. The transmetalation between RLi and BF3 which produces unreactive organoboron compounds is shown to be very slow at this temperature. - ... 

Jacobi s synthesis of ( )-paniculide-A involves an intramolecular Diels-Alder reaction of the alkynic ketone (31). This compound was prepared in >90% yield (Scheme 9) by acylation of a lithium alkynide with the A7-methoxy-A7-methylamide (30). Addition of the anion to other derivatives related to (30) such as an acid chloride, a trifluoroacetic mixed anhydride, an acyl imidazole, S-(2-pyridyl) thiolates and a mixed carbonic anhydride (from ethyl chloroformate) led to either bis-addition or to proton abstraction. Notice should be made of the stability exhibited by the A7-methoxy-A7-methylamide group while the oxa-zole moiety was being introduced. ... 

The fust important test of this methodology came in Hanessian s investigation of the spiroketal portion of avermectin Bu- This highly convergent approach incorporates all the oxidation levels and functionality required for carbons C(15)-C(28), except for the necessity of alkyne to alkene conversion. The lithium alkynide was prepared at -78 C and then mixed with boron trifluoride etherate under the conditions of Yamaguchi (Scheme 19). (Direct condensation of the lithium salt and lactone lead to substantial amounts of a, -unsaturated lactone.) Addition of the lactone in stoichiometric amounts to the solution of the modified alkynide led to the formation of the desired hemiketal in acceptable yield. Further improvements could be obtained by the recycling of starting material. ... 

The highly reactive carbonyl of lactone (60), an intermediate in the synthesis of forskolin, was easily converted to propargyl ketone (61) by addition of the lithium alkynide as shown in equation (48). It is possible that the intermediate ketal alkoxide was not stable in solution because of ring strain however, no multiple addition products were reported, nor was there any Michael addition of the alkoxide to the resulting ynone. 

Tin(n) triflate mediated cross aldol reactions between a-bromo ketone (124 Scheme 56) and aldehydes afford iyn-a-bromo-P-hydroxy ketones (125) with high stereoselectivity. The resulting halohydrins are converted to the corresponding (Z)-2,3-epoxy ketones (126). Chiral aldehyde (127) reacts with lithium alkynide (128) followed by mesylation and base treatment to give chirally pure ( )-epoxide (129). The initially formed alkoxide anion should be trapped in situ by mesylation, otherwise partial racemization takes place owing to benzoate scrambling (Scheme 56). ... 

Novel nonchelation phenomena are observed with a steroidal a-hydroxy aldehyde. The reaction of a lithium or magnesium alkynide with the aldehyde gives the (20/7,22J )-diastereomer predominantly, the formation of which was explained by Cram s cyclic model. When BFa-OEtj is added to the lithium alkynide prior to the addition of the aldehyde, the stereoselectivity is inverted, and the (20/ ,225)-isomer is obtain as the principal product. Transformation of a-alkoxy aldehyde to the boron ate complex is suggested. Other l wis acids, such as B(OMe)3, AICI3, etc., are less effective (equation 29). ... 

Thiazolines activated with an equivalent of BF3 readily react with a wide range of organometals, giving rran -4,S-disubstituted thiazoles stereoselectively. Alkyllithiums, Grignard reagents, lithium alkynides, nitronates, ester and ketone enolates have been employed as the nucleophile. Stereocontrolled construction of three contiguous asymmetric centers is performed with a lithiated isothiocyanatoacetate, and the product is successfully transformed to (+)-biotin (Scheme 27). 

Activation of the G=N moiety by the addition of BF3 0Et2 has increased the scope of organometallic additions (Table 2). Akiba and coworkers have shown that lithium alkynides treated with BF3 OEt2 add to substituted aldimines (entry 1, Table BF3 complexes of organocopper and di-... 

Rapoport found that 5-(2-pyridyl) thioates such as (28) did not function as selective acylating agents, and sutetantial amounts of tertiary alcohol were formed through overaddition (equadon 16). Presumably, the tetrahedral intermediate, derived from nucleophilic addition to the S-(2-pyridyl) thioate, was not a stable entity in the reaction mixture. As will be discussed shortly, the lability of these intermediates had been recognized previously. The novel dimethylpyrazolide moiety of substrate (29) also did not confer any additional stability to the tetrahedral intermediate and tertiary alcohol was the major product (equation 16). Tertiary amides, such as those derived from pyrrolidine or dimethylamine, were reactive towards lithium alkynides in the presence of BFa, but analysis of the product indicated that it had undergone substantial racenuzation. ... 

Lithium alkynides in tetrahydrofuran or dioxane often give substitution products with secondary haloalkanes, while alkynide Grignard reagents do not usually react with haloalkanes except in the presence of other metals such as cobalt and copper. Substitution of iodine or bromine for chlorine in the halo-alkane often leads to an increased yield of the alkylation product and alkanesulfonates may give greater yields than haloalkanes. Scheme 1 illustrates examples of alkylation of haloalkanes and alkyl sulfates with alkynides of Group I metals. 

Treatment of lithium alkynides with aluminum trichloride leads to tri(ethynyl)aluminum intermediates, which on treatment with haloalkanes give the corresponding disubstituted acetylenes. " The reaction is successful with tertiary haloalkanes and a variety of alkynes have been prepared (Scheme 9). An interesting variation of this method has been reported by Trost and Ghadri who reacted a diethylethynylalumin-um with an allyl sulfone in the the presence of the Lewis acid aluminum trichloride. When the allyl sulfone was part of a six-membered ring, then the alkyne was introduced exclusively in a pseudo axial orientation (Scheme 10). 

Trost and Martin have used the dimethylsulfoxonium ion to provide a leaving group. Thus, a cis addition of DMTSF to alkenes flrst led to adducts of the type (15), which then reacted with lithium alkynides in the presence of diethylaluminum chloride to give the trans adduct (Scheme 28). The reaction is presum to involve the episulfonium ion, which then ensures the observed stereospecificity. The reaction is also regiospecific, the anti-Markovnikov addition being illustrated by the second example in Scheme 28. The adducts can be converted to alkanes with Raney nickel and to alkenes by sulfoxide formation and elimination. 

Butadiyne has also been alkylated through the lithium alkynide. Thus, Holmes and Jones treated bis(trimethylsilyl)buta-l,3-diyne with MeLi in the presence of lithium bromide and obtained the monolithium alkynide, which was then alkylated in HMPA (Scheme 30). If the lithium alkynide was complexed with ethylenediamine then DMSO could be used as solvent. In addition, Himbert and Feustel prepared the lithium derivative of l-A A(-dialkylbuta-l,3-diyne by treatment of 4- -dialkyl-l,l,2-trichlorobut-l-en-3-yne with butyllithium. The lithium salt was not isolated but was alkylated to the l-alkyl-4-lV-di-alkylbuta-l,3-diyne (Scheme 31). 

The (Z)-alkynylhaloalkenes (7) can be synthesized in relatively good yields from 1 -alkynes in a regio-and stereo-selective manner, following haloboration with Br-9-BBN and subsequent treatment with lithium alkynides and iodine (Scheme... 

---