Addition of terminal alkynes to aldehyde

The same authors have also reported the application of green solvents in additions of terminal alkynes to aldehydes in the presence of Zn(OTf)2 and l,8-diazabicyclo[5,4,0]-7-undecene (DBU, Scheme 109).287 The reactions proceeded very slowly, but afforded desirable alcohols 195 in moderate to good yields. 

Carreira and co-workers developed a highly efficient enantioselective addition of terminal alkynes to aldehydes giving propargyl alcohols by the mediation of zinc tri-flate and N-methylephedrine [17]. This reaction serves as a convenient and powerful synthetic route to a wide variety of enantioenriched allenes via propargyl alcohols. Dieter and Yu applied this alkynylation to the asymmetric synthesis of allenes (Scheme 4.12) [18]. Reaction of phenylacetylene with isobutyraldehyde afforded the propargyl alcohol in 80% yield with 99% ee, which was mesylated to 49 in quantitative yield. Reaction of 49 with the cyanocuprate 50 afforded the desired allene 51 with 83% ee. 

Recent Developments in Enantioselective Addition of Terminal Alkynes to Aldehydes... 

Interestingly, the first catalytic version of such nucleophilic additions of alkynyl silvers to aldehydes has been described." Indeed, silver chloride in the presence of tricyclohexylphosphine and mild bases such as ethyldiisopropylamine catalyzed the addition of terminal alkynes to aldehydes in good to high yields (Table 10.5). The reaction proved to be almost insensitive to electronic effects however, alkyla-cetylenes were less reactive than arylacetylenes. The solvent had a dramatic effect on the reaction course. Control experiments with preformed phenylethynylsilver showed that both phosphine and water activated the silver acetylide. 

Application of this catalyst system to propargyl alcohols provides a, 3-unsaturated aldehydes (Equation 1.17) and ketones (Equation 1.18) [18]. The ease of accessibility of the substrates by simple addition of terminal alkynes to aldehydes followed by this redox isomerization constitutes a highly chemoselective and atom economic strategy to these unsaturated carbonyl compounds. The chemoselectivity problems of the direct aldol condensation and the poor atom economy of olefination methods make this new strategy the most efficient and reliable approach to these units. 

The best e.e. values reported to date were achieved by Carreira et al. by direct addition of terminal alkynes to aldehydes in the presence of (+)-A(-methylephedrine as chiral ligand. In several cases the e.e. has been 98%. This method was very general for both aU-phatic and aromatic aldehydes, the alkyne component was flexible, and the reaction conditions were very short. This method involves in situ generation of zinc alkynylide by mixing alkyne, Iriethyl amine, and Zn(OTf)2. Another very intriguing feature is that the method is very general and not substrate dependent (Table 21.4). 

A simpler preparation of catalytic chiral indium complex based on BINOL ligand were reported by Shibasaki et al. in their asymmetric alkynylation of aldehydes [317]. InBrs was the Lewis acid of choice and the authors proposed a dual role for this bifunctional catalyst, both in activating the alkyne triple bond and the carbonyl moiety. These characteristics, and the inclusion of the chiral BINOL ligand into the In(III) center, had allowed the asymmetric addition of terminal alkynes to aldehydes with just the addition of a mild amine base (Figure 8.150). Positive nonlinear effect was observed with BINOL of varying optical enrichment, and thus the active catalytic species was expected by the authors to be most likely bimetallic in nature. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The Cu(I)-catalyzed direct addition of terminal alkynes to imines generated in situ from aldehydes and amines affords synthetically useful propargylamines. This metal-catalyzed carbon-carbon bond formation is best performed in toluene but water is also a convenient solvent. While the achiral process is mediated by the bimetallic catalytic system RuCls/CuBr, CuOTf in conjunction with chiral bis(oxazolines) has been found optimal for enantioselective additions (eq 119). 

The high synthetic utility of alcohols 38 stems from the fact that terminal alkynes are among the most versatile functional groups for the further elaboration of a carbon skeleton. Asymmetric synthesis of alcohols 38 from aldehydes with the concurrent formation of the two stereogenic C atoms has been accomplished mainly by two methods. The first features synthesis of chiral nonracemic allenylmetal compounds from the corresponding chiral nonracemic propargyl alcohols and addition of the former to aldehydes [26] and the second method in-... 

The following compounds with H—C and II—M bonds undergo oxidative addition to form metal hydrides. This is examplified by the reaction of 6, which is often called ortho-metallation, and occurs on the aromatic C—H bond at the ortho position of such donar atoms as N, S, 0 and P. Reactions of terminal alkynes and aldehydes are known to start by the oxidative addition of their C—H bonds. Some reactions of carboxylic acids and active methylene compounds are explained as starting with oxidative addition of their O—H and C—H bonds. 

Corey introduced the use of a 1 1 CsF/CsOH salt to effect the in-situ activation of trimethylsilyl alkyne and subsequent addition to aldehydes (Eq. 2) [8]. The use of catalytic quantities of CsOH to effect the addition of terminal acetylenes to ketones in DMSO/THF or THF has also been documented (Eq. 3) [9]. 

Oxidation of the vinylborane (using basic hydrogen peroxide) gives a vinyl alcohol (end), resulting from anti-Markovnikov addition of water across the triple bond. This end quickly tautomerizes to its more stable carbonyl (keto) form. In the case of a terminal alkyne, the keto product is an aldehyde. This sequence is an excellent method for converting terminal alkynes to aldehydes. 

Asymmetric addition of alkynylzinc reagents to aldehydes has been developed with A-methylephedrine (or other chiral amino alcohol) as the chiral ligand. The alkynylzinc reagent is prepared in situ from the terminal alkyne and this allows use of the metal salt (zinc triflate) as a catalyst in substoichiometric amount (1.145). 

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