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The Sonogashira reaction has proven to be a very important synthetic entry into aryl alkynes and conjugated enynes.6 These approaches typically make use of the Pd-catalyzed or Pd/Cu-catalyzed protocols employed in most cross-coupling reactions. The Au-catalyzed use of alkynylsilanes in Sonogashira cross-coupling has been reviewed.7
Of the many reactions at the terminal C-H of the simple alkynylsilanes, the Sonogashira reaction stands among the most important. Under the standard Sonogashira reaction conditions the C-Si bond does not react, providing excellent protection of this position along with adding more desirable physical properties. Moreover, it provides an excellent entry into a variety of substituted alkynylsilanes. Though the silyl group nicely provides protection of a terminal position in the Sonogashira crosscoupling, under modified conditions wherein the silyl group is activated, a Sonogashira-type conversion at the C-Si bond is possible, thus providing an alternative to a two-step protiodesilylation/Sonogashira sequence.

In an example of the use of the TMS group as a protecting group eventually leading to an unsymmetrically arylated system, trimethylsilylbutadiyne was coupled with aryl iodide 3 to diyne 4, which was protiodesilylated and further cross-coupled to 5, a potential hepatitis C NS5A inhibitor.8,9

Scheme 4. Sonogashira cross-coupling sequence employing desilylation

Modest yields of symmetrical1,4-diaryl-1,3-butadiynes resulted from the Sonogashira reaction of an aryl bromide and ethynyltrimethylsilane followed by treatment with NaOH in MeCN. The reaction sequence combined a Sonogashira cross-coupling and a Glaser coupling in a two-step single-flask operation. The second step did not require the further addition of catalyst. The reaction was tolerant of HO, CO2H, and CHO functionalities.10

Scheme 5. Sonogashira arylation and homocoupling without prior desilylation

The Beller group developed a copper-free protocol for the Sonogashira reaction with the more available and less costly aryl chlorides. Both ethynyltrimethyl- and ethynyltriethylsilane reacted without loss of the silyl group. The key to the success of the reaction proved to be the sterically hindered ligand 6.11

Scheme 6. Copper-free Sonogashira cross-coupling

The ethynylsilane (CPDMSA) 7 with the 3-cyanopropyl moiety was prepared and utilized in the synthesis of arene-spaced diacetylenes. The purpose of this particular ethynylsilane was two-fold, firstly it could be selectively deprotected in the presence of the ethynyl-TIPS group and, secondly, it provided polarity allowing for a facile chromatographic separation of the key intermediates in the syntheses of the diethynyl arenes. The arene groups were introduced via Sonogashira cross-coupling.12

Scheme 7. Sonogashira cross-coupling and selective protiodesilylation

In a good example of the use of ethynyltrimethylsilane as a precursor to the 1,2,4,5-tetraethynylbenzene, 1,2,4,5-tetraiodobenzene was reacted with ethynyltrimethylsilane under Sonogashira conditions to give 1,2,4,5-tetrakis(trimethylsilylethynyl)benzene. The trimethylsilyl groups were then converted to bromides with NBS in greater than 90% over the two steps. The tetrakis(bromoethynyl)benzene was reacted with 1,4-cyclohexadiene to give 2,3,6,7-tetrabromoanthracene.13

Scheme 8. Formation of 1,2,4,5-tetrakis(bromoethynyl)benzene

In related chemistry the direct ethynylation of tautomerizable heterocyclics under Sonogashira conditions without the need for conversion of the heterocyclic to an aryl halide was reported. These worked well for ethynyltrimethylsilane and ethynyltriethylsilane.14

Scheme 9. Direct Sonogashira ethynylation of tautomerizable heterocycles

In an interesting and useful approach, ethynyltrimethylsilane cross-coupled with aryl iodides, bromides and triflates in the presence of an amidine base and water. If water was held out until the second stage of the reaction, i.e. reaction at the C-Si terminus, the result was the synthesis of unsymmetrical diarylacetylenes.15

Scheme 10. Symmetrical and unsymmetrical diarylation of ethynyltrimethylsilane

The Sonogashira reaction of ethynyltrimethylsilane with 2,6-dibromo-3,7-ditriflatoanthracene was investigated as an intermediate in a route to anthra[2,3-b:6,7-b’]-difuran (anti-ADT). In this reaction the Sonogashira cross-coupling occurred selectively at the triflate leaving the bromine groups available. This route did not result in a synthetic approach to the desired anthracene difuran. Success was realized via the Sonogashira cross-coupling of ethynyltrimethylsilane with 2,6-dibromo-3,7-diacetatoanthracene followed by desilylative cyclization. The thiofuran analog, anti-ADT, was prepared via cross-coupling of 8 with ethynyltrimethylsilane, I2 cyclization and reduction. A Suzuki-Miyaura cross-coupling and protiodesilylation gave the phenyl-substituted anti-ADT 2. In an analogous manner the anti-diselenophene 10 was prepared from 9 in 62% yield over three steps.16

Scheme 11. Sonogashira cross-coupling in the synthesis of thiophenes and selenophenes

The relatively simple and economical catalyst system of FeCl3 and N,N´-dimethylethylenediamine was used in the synthesis of arylethyltriethylsilanes. The reaction conditions were not mild requiring 135 °C and 72 h for completion.17

Scheme 12. Sonogashira cross-coupling with iodopyridine

The Sonogashira reaction of several terminal alkynes with o-nitrofluorobenzene gave the o-alkynylnitrobenzene. The use of ethynyltriethylsilane gave a considerably higher yield than other terminal alkynes. The TES group was not further reacted in this study.18

Scheme 13. Sonogashira cross-coupling with o-nitrofluorobenzene

Hatanaka and Hiyama were the first to report the cross-coupling of alkynyltrimethylsilanes. This they accomplished with cross-coupling with β-bromostyrene to form conjugated enynes with TASF promotion. It bears mentioning that under the same conditions vinyltrimethylsilanes were cross-coupled in high yield with aryl and vinyl iodides.19

Scheme 14. Conjugated enynes from TMS-alkynes

3-Aryl-tert-propargyl alcohols reacted with bis(trimethylsilyl)acetylene under Rh catalysis to give the enyne regio- and stereoselectively with loss of benzophenone and one equivalent of the starting arylethynyl group as its TMS-substituted derivative. Under Pd catalysis this silylated enyne could be cross-coupled with an aryl iodide, which was converted to the alkylidene dihydrofuran, which showed fluorescent properties.20

Scheme 15. Silyl Sonogashira cross-coupling of propargyl alcohols

Seeking a practical entry into 1,4-skipped diynes as potential precursor to polyunsaturated fatty acids, the Syngenta group investigated the cross-coupling of alkyltrimethylsilanes with propargyl chlorides. Under the best conditions the reaction of an alkynyltrimethylsilane with a propargyl chloride gave the 1,4-skipped diyne under promotion with fluoride ion and CuI catalysis. The method avoids the need for protiodesilylation to the parent acetylene that is required in other copper catalyzed coupling protocols. The reaction failed with nitrogen containing groups on the alkynylsilane. The reaction proceeded well with phenylethynyltri-n-butyltin (70%) and phenethylethynyltrimethylgermanium (90%).21

Scheme 16. Cross-coupling approach to 1,4-skipped diynes

Denmark and Tymonko demonstrated the cross-coupling of alkynyldimethylsilanols with aryl iodides with potassium trimethylsilanolate promotion. This protocol avoids the typical necessity of fluoride ion promotion and the associated disadvantages of cost and low tolerance for silicon-based protecting groups. The alkynylsilanols were prepared in a two-step reaction sequence. Interestingly, a direct comparison of the reaction rates of 1-heptyne, heptynyldimethylsilanol, and heptynyltrimethylsilane under the potassium trimethylsilanolate promotion conditions showed the heptynyldimethylsilanol to be considerably faster than 1-heptyne and the heptynyltrimethylsilane to be unreactive. This strongly suggests a role of the silanol group in the cross-coupling. A similar experiment with TBAF promotion showed all three to react with the silanol derivative being the fastest. Under the same conditions 4-bromotoluene gave a 25% conversion showing the need for the iodoarene.22 The TBAF-promoted cross-coupling of alkynylsilanols with aryl iodides had previously been shown.23

Scheme 17. Formation of ethynylsilanols and their cross-coupling with aryl iodides

The bis(trimethylsilyl)enyne 11 was nicely prepared via a Suzuki cross-coupling with bromoethynyltrimethylsilane. The ethynylsilane 11 cross-coupled with aryl iodides in a sila-Sonogashira reaction to provide the silylated conjugated enyne 12. Similar cross-coupling reactions with vinyl iodides led to 1,5-dien-3-ynes 13. Cyclic vinyl triflates also reacted well to form the 1,5-dien-3-ynes 14.24

Scheme 18. Suzuki cross-coupling with bromoethynyltrimethylsilane and cross-coupling of the alkynyltrimethylsilane

Ethynyltrimethylsilane was deprotonated and reacted with tributylchlorotin to give the stannylated ethynylsilane 15 in good yield.25

Scheme 19. Synthesis of tri-n-butylstannylethynyltrimethylsilane

Tributylstannylethynyltrimethylsilane 15 was prepared directly from ethynyltrimethylsilane and tributylmethoxytin in 49% isolated yield.26

Scheme 20. Alternative synthesis of tri-n-butylstannylethynyltrimethylsilane

The bis(silyl)enyne 17 was prepared by cross-coupling tri-n-butylstannylethynyltrimethylsilane with vinyl iodide 16 in 75% yield. In another approach to this end in the same paper vinylstannane 18 reacted with bromoethynyltrimethylsilane and bromoethynyltriisopropylsilane to give the bissilylated conjugated enynes in good yield.27

Scheme 21. Stille cross-coupling reactions

The alkynylation of anomeric position of the benzyl-protected glucose derivatives 19 was accomplished with tributylstannylethynyltrimethylsilane.28

Scheme 22. sp3-sp cross-coupling of 18 with a sugar derivative

Tri-n-butylstannylethynyltrimethylsilane was cross-coupled with 20 and found to be tolerant of a ketal, and a cyclopropene. The TMS group was removed along with deacetoxylation of the ester upon treatment with K2CO3/MeOH.29

Scheme 23. Stille cross-coupling showing functional group tolerance

Tributylstannylethynyltrimethylsilane was cross-coupled with the highly substituted aryl bromide 21 in a synthesis of (+)-kibdelone A. The TMS group was removed in 93% yield with AgNO3•pyridine in aqueous acetone.30

Scheme 24. Stille cross-coupling of 15 with highly-substituted aryl bromide

Similarly to the Sonogashira reaction of ethynyltrimethylsilane where the cross-coupling occurs at the C-H bond the cross-coupling of tributylstannylethynyltrimethylsilane occurs at the C-Sn bond rather than the C-Si bond. This was employed in the synthesis of the indole piece of sespendole.31

Scheme 25. Stille cross-coupling with a highly-substituted aryl triflate

In an approach to the synthesis of Lactonamycins, a model glycine was prepared wherein a critical step was the addition of an ethynyl group onto a highly substituted arene. Thus, bromoarene 22 was subjected to a Stille cross-coupling with tributylstannylethynyltrimethylsilane to give the ethynylarene 23 in 91% yield. This compared favorably with a three-step sequence.32

Scheme 26. Selective Stille cross-coupling