Sonogashira alkynylation

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

Non-Sonogashira alkynylation procedures have also been employed with pyrimidines, and selective replacement of the 4- and 6-chlorine atoms of 2,4,6-trichloropyrimidine 258 was able to be achieved using potassium (1-hexyn-l-yl)-trifluoroborate 257 <2002JOC8416>. 

SCHEME 41. Comparison of the Negishi alkynylation and the Sonogashira alkynylation... 

For a related study of the Sonogashira alkynylation reporting significantly different results, see ... 

Castro-Stephens reaction Heck alkynylation Sonogashira alkynylating... 

Contrasting results were observed in the Pd-catalyzed alkynylation with alkylzincs versus the Sonogashira alkynylation. For example, reaction of iodopyrazine with ethyl-3-bromozinc-propynate (20) provided the coupled product alkynylpyrazine 21 [18]. However, the corresponding Sonogashira reaction of iodopyrazine with propynoate provided 21 in only 37% yield [18]. 

The Sonogashira alkynylation has been successfully extended to the thiophene series to synthesize the alkynylthiophenes ( 1). This method has been used to prepare 2,5-di(2-thienylethynyl)-thiophene (602) (Scheme 137). Conjugated enynes (603) have also been prepared by this method <92TL4229>. 

The Pd-catalyzed cross-coupling with alkynylzincs appears to be considerably more general than the Sonogashira alkynylation. However, the operational simplicity may favor the latter in most of those cases where both are comparably satisfactory. On the other hand, there have been an increasing number of cases where the alkynylzinc reaction is decidedly more favorable than the Sonogashira reaction. 

Since Pd-catalyzed alkynylation with prefonned alkynylmetals is generally somewhat more involved than the Sonogashira alkynylation, the use of the former protocol has to be duly justified. The following differences between the two protocols are worth noting. 

In addition to Zn, B, and Sn—three metal countercations that were found to be highly satisfactory for alkynylafiorf —the Sonogashira alkynylation protocol (Sect IIL2X1) has also proved to be generally tqtpUcable to this case. Some representative examples of Pd-catalyzed conjugate substitution with alkynylmetals and terminal alkynes are summarized in Table 3. 

Muller and coworkers [63] developed a nice domino process in which a termination of an intramolecnlar arylation of an alkyne was achieved by a Sonogashira alkynylation. The transformation could even be carried on using an intramolecnlar cycloaddition. Treatment of a mixture of 109 and 110 in the presence of catalytic amonnts of PdCl2(PPh3)2 and Cul in toluene/bntyronitrile/triethylamine at reflux led to hitherto unknown spiro compounds 111 in up to 86% yield (Scheme 8.28). 

Tsuji proved the usefulness of this building block in the synthesis of less strained phenylacetylene macrocycles [29, 33]. Sonogashira alkynylation, Glaser-Ellington... 

Scheme 3.38 Pd-catalyzed Sonogashira alkynylation and Negishi alkynylation.

Scheme 42). Then, Sonogashira alkynylation permitted the preparation of the corresponding 2-(l-alkynyl)phenylphosphonates 199a—k using palladium and copper catalysts. 

Pinto etal. [52] have reported a consecutive three-component synthesis of oxin-doles that proceeds in the sense of a Sonogashira alkynylation-carbopalladation-CH activation-cyclization sequence, furnishing 3-(diarylmethylene)oxindoles 31 in moderate to good yields (Scheme 12.20). 

Alkynones [62] and 1,3-diaryl propenones (chalcones) [63] are reactive three-carbon building blocks that can be transformed into five-, six-, and seven-membered heterocycles with bifunctional nucleophiles in the sense of Michael addition and cyclocondensation. Therefore, a catalytic access to ynones [64] and enones [65] by Sonogashira alkynylation turned out to be a versatile entry to consecutive multicomponent syntheses of heterocycles. This reactivity-based concept has been considerably developed by the Muller group in the past decade. In several reviews, the major advancements of this one-pot methodology have been summarized [66]. Therefore, only very recent conceptual achievements with respect to sequentially Pd-catalyzed processes [7] will be considered here. 

Z)-I-Bromo-4-trimethylsUyl-I-buten-3-yne (14). There have been a few papers reporting the synthesis of the Z isomer of 1. The most reasonable one appears to be that shown in eq 3. Since its cross-coupling and other synthetically useful reactions have not been adequately investigated, its synthetic utility remains largely unknown, although the Sonogashira alkynylation appears to proceed weU, as indicated in eq 3. ... 

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