Some Aspects of the Chemistry of Alkynylsilanes

In amongst the considerable chemistry of acetylenes there lies some unique chemistry of alkynylsilanes (silylacetylenes) some of which is reviewed herein. This unique character is exemplified not only in the silyl protection of the terminal C–H of acetylenes, but also in the ability of the silyl group to be converted into other functionalities after reaction of the alkynylsilane and to its ability to dictate and improve the regioselectivity of reactions at the triple bond. This, when combined with the possible subsequent transformations of the silyl group, makes their chemistry highly versatile and useful. 1 Introduction 2 Safety 3 Synthesis 4 Protiodesilylation 5 Sonogashira Reactions 6 Cross-Coupling with the C–Si Bond 7 Stille Cross-Coupling 8 Reactions at the Terminal Carbon 9 Cross-Coupling with Silylethynylmagnesium Bromides 10 Reactions of Haloethynylsilanes 11 Cycloaddition Reactions 11.1 Formation of Aromatic Rings 11.2 Diels–Alder Cyclizations 11.3 Formation of Heterocycles 11.4 Formation of 1,2,3-Triazines 11.5 [2+3] Cycloadditions 11.6 Other Cycloadditions 12 Additions to the C≡C Bond 13 Reactions at the C–Si Bond 14 Miscellaneous Reactions


Review Syn thesis
conditions. The desilylation protocols are, in general, highly tolerant of other functional groups with the notable exception of silyl-protected alcohols. The reader will note several examples in this review where the silyl group basically provides a protective function, but has further synthetic potential. A further advantage of the terminal silylacetylenes is that the presence of the silyl group, for both steric and electronic reasons, can often influence the regio-and stereochemistry of reactions at the C≡C bond. This is most often reflected in cyclization reactions and it bears remembering that the regioselectively placed silyl group has the potential to be another group including hydrogen. Finally, the trimethylsilyl group has its own reactivity in the final product of a reaction at the C≡C bond. These often result in the generation of a vinylsilane unit, which can be further reacted under a number of conditions including protiodesilylation to the parent alkene. 2 Examples of these aspects of the chemistry are to be found throughout the review.

Safety
A report of an explosion using (trimethylsilyl)acetylene in an oxidative coupling under Glaser-Hay conditions was published. 3 After a thorough investigation the cause of the explosion was attributed to static electricity between the syringe needle used to introduce the copper catalyst and a digital thermometer inside the flask and not the thermal instability of the silane. It is interesting to note that the trimethylsilyl group can impart stability to alkynyl systems. A good example of this is 1,4-bis(trimethylsilyl)buta-1,3diyne, which shows excellent thermal stability compared to that of the parent buta-1,3-diyne.

Synthesis
A well-known and often used approach to silylacetylenes is via the straightforward acid-base metalation, typically with RMgX or n-BuLi (the base), of a terminal acetylene (the acid) followed by reaction with an appropriate chlorosilane or related reactive organosilane. As a specific example, 1-(triisopropylsilyl)prop-1-yne was prepared by lithiation of propyne followed by reaction with triisopropylsilyl triflate (Scheme 1). 4 The direct trimethylsilylation of a terminal alkyne can be carried out in a single step with the combination of LDA and TMSCl at low temperature. This was applied to the synthesis of 1, which was used in a synthesis of complanadine A (Scheme 2). 5 Marciniec and co-workers have demonstrated the direct silylation of terminal acetylenes using an iridium carbonyl catalyst and iodotrimethylsilane in the presence of Hünig's base. 6 The yields are excellent and the process works well for diynes and is tolerant of OH and NH 2 groups, albeit these end up as their trimethylsilylated derivatives in the final product (Scheme 3).

Scheme 3 Ir-catalyzed direct trimethylsilylation of terminal alkynes
A direct dehydrogenative cross-coupling of a terminal alkyne and a hydrosilane provided a convenient and simple route to silylacetylenes. Thus, reaction of a terminal acetylene and a silane with a catalytic amount of NaOH or KOH gave the desired silylacetylene in high yield with expulsion of hydrogen. The reaction of a variety of acetylenes with dimethyl(phenyl)silane showed excellent general reactivity for

Protiodesilylation
Because trialkylsilyl groups are very commonly used to protect the terminal C-H of an acetylene, protiodesilylation back to the parent acetylene is an important transformation. This can be accomplished under a number of mild reaction conditions. Among these is the simple reaction of (trimethylsilyl)acetylene derivatives with K 2 CO 3 /MeOH or, for more hindered silanes, TBAF/THF. Examples of these are to be found throughout this review. The selective protiodesilylation of (trimethylsilyl)acetylene group in the presence of an (triisopropylsilyl)acetylene group with K 2 CO 3 / THF/MeOH illustrates the potential for selective protection/deprotection (Scheme 5). 8

Sonogashira Reactions
Of the many reactions at the terminal C-H of simple silylacetylenes, the Sonogashira reaction stands among the most important, where it has proved to be a very important synthetic entry into arylacetylenes and conjugated enynes. 10 These approaches typically make use of the Pdcatalyzed protocols employed in most cross-coupling reactions. The Au-catalyzed use of silylacetylenes in Sonogashira cross-coupling reactions has been reviewed. 11 Under the standard Sonogashira reaction conditions the C-Si bond does not react thus providing excellent protection of this position along with adding more desirable physical properties. Moreover, it provides an excellent entry into a variety of substituted silylacetylenes. Though the silyl group nicely provides protection of a terminal position in the Sonogashira cross-coupling, 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.

Review Syn thesis
Modest yields of symmetrical 1,4-diarylbuta-1,3-diynes resulted from the Sonogashira reaction of an aryl bromide and (trimethylsilyl)acetylene followed by treatment with NaOH/MeCN. The reaction sequence was the combination of the 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, CO 2 H, and CHO functional groups (Scheme 8). 13

Scheme 8 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 (trimethylsilyl)acetylene and (triethylsilyl)acetylene reacted without loss of the silyl group. The key to the success of the reaction proved to be the sterically hindered ligand 7 (Scheme 9). 14 Scheme 9 Copper-free Sonogashira cross-coupling [3-Cyanopropyl(dimethyl)silyl]acetylene (CPDMSA, 8) was prepared and utilized in the synthesis of arene-spaced diacetylenes. The purpose of this particular silylacetylene was twofold, firstly it could be selectively deprotected in the presence of the (triisopropylsilyl)acetylene group and, secondly, it provided polarity allowing for a facile chromatographic separation of the key intermediates in the syntheses of the diethynylarenes (Scheme 10). The arene groups were introduced via Sonogashira cross-coupling. 15 In a good example of the use of (trimethylsilyl)acetylene as a precursor to 1,2,4,5-tetraethynylbenzene, 1,2,4,5tetraiodobenzene was reacted with (trimethylsilyl)acetylene under Sonogashira conditions to give 1,2,4,5tetrakis[(trimethylsilyl)ethynyl]benzene. The trimethylsilyl groups were then converted into bromides with NBS in greater than 90% over the two steps. 1,2,4,5-Tetrakis(bromo-ethynyl)benzene was subsequently reacted with cyclohexa-1,4-diene to give 2,3,6,7-tetrabromoanthracene (Scheme 11). 16

Scheme 11
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 into an aryl halide was reported. These worked well for both (trimethylsilyl)acetylene and (triethylsilyl)acetylene (Scheme 12). 17 In an interesting and useful approach, (trimethylsilyl)acetylene was cross-coupled with aryl iodides, bromides, and triflates in the presence of an amidine base and water. If water was omitted until the second stage of the reaction, i.e. reaction at the C-Si terminus, the result was the synthesis of unsymmetrical diarylacetylenes (Scheme 13). 18 The Sonogashira reaction of (trimethylsilyl)acetylene with 2,6-dibromo-3,7-bis(triflyloxy)anthracene was inves-

Review Syn thesis
tigated 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, however, result in a synthetic approach to the desired anthracene difuran. Success was realized via the Sonogashira cross-coupling of (trimethylsilyl)acetylene with 2,6-diacetoxy-3,7dibromoanthracene followed by desilylative cyclization. The thiofuran analogue, anti-ADT, was prepared via crosscoupling of 9 with (trimethylsilyl)acetylene, iodine cyclization, and reduction. A Suzuki-Miyaura cross-coupling and protiodesilylation gave the phenyl-substituted anti-ADT 10.

Review Syn thesis 6 Cross-Coupling with the C-Si Bond
Hatanaka and Hiyama were the first to report the crosscoupling of (trimethylsilyl)acetylenes. 22 This they accomplished with cross-coupling with β-bromostyrene to form conjugated enynes with TASF promotion. It bears mentioning that under the same conditions (trimethylsilyl)ethenes were cross-coupled in high yield with aryl and vinyl iodides (Scheme 17).

Scheme 17 Conjugated enynes from (trimethylsilyl)acetylenes
Tertiary 3-arylpropargyl alcohols reacted with bis(trimethylsilyl)acetylene under Rh catalysis to give the hydroxymethyl-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 into the alkylidene-dihydrofuran. The alkylidene-dihydrofurans thus prepared exhibited fluorescent properties (Scheme 18). 23

Scheme 18 Silyl Sonogashira cross-coupling of propargyl alcohols
Seeking a practical entry into 1,4-skipped diynes as potential precursors to polyunsaturated fatty acids, the Syngenta group investigated the cross-coupling of 1-aryl-or 1alkyl-2-(trimethylsilyl)acetylene derivatives with propargyl chlorides. Under the best conditions the reaction of a (trimethylsilyl)acetylene 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, a requirement in other copper-catalyzed coupling protocols. The reaction failed with nitrogen-containing groups on the silylacetylene. The reaction proceeded well with 1-phenyl-2-(tributylstannyl)acetylene (70%) and 4-phenyl-1-(trimethylgermyl)but-1-yne (90%) (Scheme 19). 24 Denmark and Tymonko demonstrated the cross-coupling of alkynyldimethylsilanols with aryl iodides under promotion with potassium trimethylsilanolate (Scheme 20). 25 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 hept-1-yne, hept-1-ynyldimethylsilanol, and 1-(trimethylsilyl)hept-1-yne under the potassium trimethylsilanolate promotion conditions showed the hept-1-ynyldimethylsilanol to be considerably faster than hept-1-yne and the 1-(trimethylsilyl)hept-1-yne 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 advantages of using iodoarenes. 25 The TBAFpromoted cross-coupling of alkynylsilanols with aryl iodides had previously been shown. 26

Scheme 28
Stille cross-coupling of 1-(tributylstannyl)-2-(trimethylsilyl)acetylene 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 25 was subjected to a Stille crosscoupling with 1-(tributylstannyl)-2-(trimethylsilyl)acetylene (17) to give the ethynylarene 26 in 91% yield. This compared favorably with a three-step sequence (Scheme 29). 35

Scheme 31 Asymmetric ethynylation of an aldehyde
The aldehyde 27 was reacted with (trimethylsilyl)acetylene under Carreira conditions to give a single diastereomer of 28, which was O-silylated followed by protiodesilylation of the TMS group. This material was carried forth in a synthesis of hyptolide and 6-epi-hyptolide (Scheme 32). 38

Scheme 32 Diastereoselective ethynylation of an aldehyde in a synthesis of hyptolide
In keeping with the common use of silylacetylenes as surrogates for the simple ethynyl organometallics, an 'in situ' process for the ethynylation of aldehydes was developed. In this chemistry a combination of ZnBr 2 , TMSOTf, and Hünig's base was used to generate the ethynylzinc reagent in situ and, along with a silylating agent, it was reacted with the aldehyde to generate the doubly silylated propargyl alcohol, which was O-deprotected with dilute hydrochloric acid (Scheme 33). 39  This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Review Syn thesis Scheme 33 'In situ' ethynylation of aldehydes
The aminomethylation of terminal alkynes was applied to a variety of acetylene derivatives including a single example with (triethylsilyl)acetylene, which provided the triethylsilylated propargyl amine in good yield. This was subsequently protiodesilylated and the resulting propargyl amine converted into a mixed bis(aminomethyl)alkyne in a 49% yield over three steps (Scheme 34). 40 (Triisopropylsilyl)acetylene was employed in a Ni-catalyzed, three-component reaction of the ethynylsilane, an alkyne, and norbornene. A variety of norbornene derivatives were reacted with good success. When (triisopropylsilyl)acetylene was used as the sole acetylene reactant, the bis(triisopropylsilyl)-1,5-enyne was produced. One example with a bicyclo[2.2.2]octene gave the corresponding product in only 12% yield when reacted with (triisopropylsilyl)acetylene (Scheme 35). 41 (Trimethylsilyl)acetylene could be directly alkylated to give 1-(trimethylsilyl)dodec-1-yne in modest yield. The yield of this sole silicon example was comparable to the direct alkylation of other terminal alkynes (Scheme 36). 42

Cross-Coupling with Silylethynylmagnesium Bromides
In a useful synthetic approach to alkynylsilanes (triisopropylsilyl)ethynylmagnesium bromide was cross-coupled with anisoles (23 examples 42-94% yield). In the cross-coupling of either 4-fluoroanisole or 4-cyanoanisole, the coupling of the F or CN substituent was favored over that of the methoxy group. The trimethylsilyl enol ether of cyclohexanone cross-coupled, as did 4,5-dihydrofuran. In one exam-  4 4-I-C 6 H 4 -Bu (73%)

Review Syn thesis
ple the TIPS group was removed with TBAF/H 2 O and the resulting acetylene cross-coupled in a Sonogashira reaction to the diarylacetylene (Scheme 37). 43 The bromomagnesium reagents of (triisopropylsilyl)acetylene (32) and (tert-dimethylsilyl)acetylene were cross-coupled with primary and secondary alkyl iodides and bromides in a Sonogashira-type reaction employing the iron complex 33. The reaction was tolerant of ester, amide, and aryl bromide groups (6 examples, 69-92% yield, 2 examples with TBS, both 83% yield). The free radical nature of the reaction was shown by the cross-coupling/cyclization of 34 (Scheme 38). 44 The synthesis of 2-alkylated ethynylsilanes was accomplished via a FeBr 2 -catalyzed coupling reaction between a silylethynylmagnesium bromide reagent and a primary or secondary alkyl halide. This nicely broadens the scope of entries into 2-alkylated ethynylsilanes (Scheme 38). 45

Scheme 43 Ethynylation of glycals
The advantages of the selective chemistry of different silyl groups was applied to the synthesis of tris(biphenyl-4yl)silyl (TBPS) terminated polyynes. Based on the findings that bulky groups on the termini of polyynes provide stability and calculations showing the TBPS group to have over twice the radius of the TIPS group, this group was investigated in the synthesis and stability of TBPS-terminated polyynes. The synthesis of the polyynes started with the reaction of lithium (trimethylsilyl)acetylide with tris(biphenyl-4-yl)chlorosilane. Selective protiodesilylation gave the

Cycloaddition Reactions
Silylacetylenes, like many alkynes, undergo an extensive variety of cycloaddition reactions. In many cases based on electronic and steric factors the silyl group can impart useful regio-and stereoselectivities in addition to the ability to chemically transform the silyl group to other useful functionalities.

Formation of Aromatic Rings
The tricyclization of alkynes to aromatic rings has long been recognized, as has the use of silylacetylenes in this practice. Silyl-protected arylacetylenes reacted with 2-(phenylethynyl)benzaldehyde under acid catalysis to produce the 2-aryl-3-silylnaphthalene in good yield. The TMSprotected arylalkynes resulted in the formation of 2-arylnaphthalene with protiodesilylation taking place under the reaction conditions. However, the more hindered TES-, TBS-, and TIPS-protected derivatives gave the corresponding 3silylnaphthalenes allowing for the ICl ipso iodination of the silyl group to provide the iodonaphthalene for further elaboration via cross-coupling chemistry. The chemistry was applied to the synthesis of several highly encumbered polyaromatic systems (Scheme 45). 54

Scheme 45 Cyclization to aromatic rings from arylacetylenes
The Rh-catalyzed reaction of (trimethylsilyl)acetylenes with cyclobutenols gave 1,2,3,5-tetrasubstituted benzenes with the trimethylsilyl group regioselectively positioned in the 2-position. No conversions of the trimethylsilyl group were carried out in this work (Scheme 46). 55

Scheme 46 Cyclobutenol to a TMS-substituted arene
Methyl 3-(trimethylsilyl)propynoate was successfully employed in the synthesis of 2H-quinolizin-2-ones. In this approach the trimethylsilyl group conveniently served the purpose of protecting the acidic hydrogen of the parent terminal acetylene (Scheme 47). 56

Scheme 47 Quinolizin-2-ones from methyl 3-(trimethylsilyl)propynoate
The cationic rhodium catalyst [Rh(cod) 2 ]BF 4 /BIPHEP brought about the cyclotrimerization of (trimethylsilyl)acetylene and unsymmetrical electron-deficient acetylenes. Unfortunately, neither the stoichiometry nor the regioselectivity of the cyclization was optimal. Larger silyl groups tended to favor the addition of one of the silylacetylene moieties and two of the electron-deficient alkynes, whereas increasing the steric bulk of the electron-deficient

Review Syn thesis
alkyne resulted in the reaction of two equivalents of the silylacetylene. (Triisopropylsilyl)acetylene failed to react. Protiodesilylation of a mixture of regioisomers was able to simplify the reaction mixture, but reaction with ICl gave a synthetically challenging mixture of isomers in modest yield (Scheme 48). 57

Scheme 49 Homocyclization of ethyl 3-(trimethylsilyl)propynoate
Complete regioselection in the formation of 2-aryl-1,3,5-tris(silyl)benzene was realized in the Pd-catalyzed reaction of two equivalents of a terminal alkyne, including (trimethylsilyl)acetylene, and an equivalent of a β-iodo-βsilylstyrene. The nature of the silylstyrene proved crucial as trialkylsilyl (TMS, TES, TBS, Me 2 BnSi) groups gave poor yields and the phenylated silyl groups gave better yields, with the β-Ph 2 MeSi-substituted styrene proving optimal. Selective electrophilic substitution of the 5-(trimethylsilyl) group, para relative to the aromatic substituent, proved possible. In a demonstration of the potential synthetic utility of the highly silylated systems, a number of conversions of the silyl groups were carried out including protiodesilylation, acylation, iodination, and Denmark cross-coupling. It is noteworthy that the iododesilylation of 48 was selective for the formation of 49 and that iododesilylation of a phenyl group from the Ph 2 MeSi group did not occur. Comparable selectivity was noted in the acetylation of 48 to 4phenylacetophenone (Scheme 50). 59

Scheme 51 Diels-Alder cyclization of silylacetylenes with 1,3-dienes
The synthesis of aryl and vinyl iodides has taken on increased importance due to their facility as electrophilic partners in various cross-coupling reactions. Building on the Diels-Alder chemistry of butadienes with (trimethylsilyl)acetylenes, the Hilt group devised an efficient route to highly substituted aryl iodides wherein the TMS group served nicely to define the regiochemistry and provide the iodide functionality. The complete reaction sequence could be carried out in a single flask although considerable effort was placed on the oxidation/iodination step. For example, ICl/CH 2 Cl 2 gave only 5% of the iodide 54, NIS/MeCN gave modest yields of the iodide in 5 cases, but the reaction was very slow and product decomposition led to purification difficulties. The combination of H 2 O 2 /ZnI 2 gave modest yields, but again in a slow reaction that required further oxidation with DDQ for completion. Finally, the use of tertbutyl hydroperoxide with ZnI 2 and K 2 CO 3 was found to give high yields of the desired iodides (Scheme 52). 61 Scheme 52 Diels-Alder cyclization to cyclic 1,4-dienes

Review Syn thesis
Under strong base catalysis, 1-aryl-2-silylacetylenes were converted into oxasilacyclopentenes upon reaction with aldehydes or ketones. The reaction required that the silyl moiety contain a Si-H bond [SiHMe 2 , SiH(i-Pr) 2 , SiHPh 2 ]. Among the catalysts investigated KOt-Bu was clearly superior, with fluoride ion sources tending to give more of the product of direct alkynylation of the carbonyl. Silylalkynylation of the carbonyl followed by base-catalyzed intramolecular hydrosilylation of the C≡C bond is proposed. 4-Methoxyphenyl-and 2-tolyl-substituted (dimethylsilyl)acetylenes on reaction with cyclohexanone gave only alkynylation of the ketone, but 4-fluorophenyl-and 4-(trifluoromethyl)phenyl-substituted (dimethylsilyl)acetylenes gave good yields of their respective oxasilacyclopentenes (8 examples, 48-87% yields). The oxasilacyclopentene 64 was shown to have synthetic utility as it could be oxidized, epoxidized, and cross-coupled all in good yield (Scheme 54). 63

Scheme 55 Cyclization of a silylated skipped diyne with a nitrile
Whereas the Ru-catalyzed reaction of an internal alkyne, carbon monoxide, and an enone produced hydroquinones in a [2+2+1+1]-cycloaddition reaction, (trimethylsilyl)acetylenes reacted in a [3+2+1] fashion to form an αpyrone, wherein the carbonyl and α-carbon of the enone provided three atoms. The resulting 3-(trimethylsilyl)-2Hpyran-2-ones were not elaborated further (Scheme 56). 65,66 The reaction of 1-(methoxydimethylsilyl)-2-phenylacetylene with propanenitrile oxide, generated in situ from 1-nitropropane and phenyl isocyanate, gave a mixture of 4and 5-silylated isoxazoles favoring formation of the 4-silyl isomer. Acid hydrolysis of this mixture allowed isolation of the pure 4-dimethylsilanol derivative in 49% overall yield. In a similar manner the 'in situ' generated benzonitrile oxide reacted to give, after hydrolysis, the corresponding 4-silanol products. These silanols were subjected to Denmark cross-coupling protocols to take advantage of the position of the silyl group to introduce aryl substituents at the 4-position of the isoxazole. Unfortunately, in addition to the

Scheme 62 Cyclization of (trimethylsilyl)acetylene derivatives with azetidinones
In an approach to complanadine A and various lycodine derivatives the Siegel group, 1,4-bis(trialkylsilyl)buta-1,3diynes were used in a [2+2+2] cycloaddition strategy. Thus, the key intermediate cyanoalkyne 75 was prepared on a gram scale and reacted with three different 1,4-bis(trialkylsilyl)buta-1,3-diynes; 1,4-bis(trimethylsilyl)buta-1,3-diyne gave the best yield of the 2-alkynylated pyridine 76 when the reaction was carried out with CpCo(CO) 2 as catalyst. A small amount of the (trimethylsilyl)ethynyl group was protiodesilylated upon silica gel chromatography and 76 was cleanly protiodesilylated upon treatment with TBAF/THF to 77. Trimethylsilylation of the terminal alkyne 77 then provided alkynylsilane 78, which was subjected to the CpCo(CO) 2 -catalyzed [2+2+2] cycloaddition with 75. This provided the undesired 2,2′-bipyridine derivative in a modest 43% yield. After considerable study and effort it was found that modification of the cyanoalkyne 75 to the Nformyl-cyanoalkyne 79 and reaction with 78 with added triphenylphosphine and under very dilute 5 mM conditions gave an acceptable yield of the desired 2,3-bipyridyl structure 80, which was protiodesilylated and deprotected to complanadine A (Scheme 63). In model studies several 1aryl-2-(trimethylsilyl)acetylenes were reacted with 75 to give the 2-aryl-3-(trimethylsilyl) cycloaddition products in low to modest yields. In none of these cases was the trimethylsilyl group reacted further. A facile conversion of 75 into lycodine was presented wherein the cycloadditions was carried out with bis(trimethylsilyl)acetylene followed by protiodesilylation and deprotection in a 24% overall yield (Scheme 63). 5,74 1,4-Bis(trimethylsilyl)buta-1,3-diyne is thermally stable and, therefore, serves as an excellent substitute for the thermally sensitive buta-1,3-diyne. It was employed in a [2+2+2] cyclization with the alkynyl nitrile 75. The reaction was extended to 1-aryl-2-(trimethylsilyl)acetylenes, wherein the trimethylsilyl group dictated the regioselectivity to place the trimethylsilyl group on the 3-position of the
With the exception of ethyl 3-(trimethylsilyl)propynoate, the regioselectivity was very high. 1H-Inden-1-ones were also formed via the reaction of 2-bromophenylboronic acid, a (trimethylsilyl)acetylene, and paraformaldehyde, although the reaction took longer and required a higher temperature (Scheme 65). 80 Benzoyltrimethylsilanes reacted with (trimethylsilyl)acetylenes under Au catalysis to form indan-1-ones. Mechanistic studies showed that a migration of the acylsilyl group to the C≡C bond occurred to form the 2-(trimethylsilyl)indan-1-one; the trimethylsilyl group was lost upon workup. On the other hand the more sterically hindered and stable benzoyl(tert-butyl)dimethylsilane gave the 2-(tert-butyldimethylsilyl)-substituted indanone. The reaction proceeds through the formation of the interesting 2-(trimethylsilyl)-substituted silyl enol ether (Scheme 66). 81

Review Syn thesis
ethynylation of the C≡C bond as the predominant pathway. The silylfulvene was reductively complexed with Rh(III) to give the rhodium dimer 93 (Scheme 68). 83

Additions to the C≡C Bond
The Ru-catalyzed hydroacylation of 4-methoxybenzaldehyde with 1-(trimethylsilyl)prop-1-yne gave a mixture of isomeric trimethylsilyl dienol ethers 94 and 95. 84 The reaction of a tertiary amine with methyl 3-(trimethylsilyl)propynoate gave addition of the amine to the C≡C bond and the formation of an allenoate ion. This, in the presence of an arylaldehyde, gave predominantly bis-addition of the aldehyde resulting in two products 96 and 97; aliphatic aldehydes gave addition at the C-H terminus of the C≡C bond to give 98. No reaction occurred with ethyl but-2-ynoate indicating that the trimethylsilyl group was essential (Scheme 69). 85 Scheme 69 Aldehyde addition to an alkynylsilane (Trimethylsilyl)acetylenes were reacted under Ni catalysis with phthalimides to give decarbonylation and alkylidenation of one of the carbonyl groups. Although the reaction appears to be potentially general, all but two of 11 examples were with N-(pyrrolidino)phthalimide. The use of a catalytic amount of the strong and sterically demanding methylaluminum bis-(2,6-di-tert-butyl-4-methylphenoxide) (MAD) was crucial in the success of the reaction. In the absence of MAD the major products were isoquinolones. Various 1-alkyl and 1-aryl-substituted (trimethylsilyl)acetylenes were utilized and gave the E-isomer as the product, but only 1-phenyl-2-(trimethylsilyl)acetylene and 1-(4-methoxyphenyl)-2-(trimethylsilyl)acetylene gave mixtures of Zand E-isomers. Two additional examples of reactions where the silyl groups were PhMe 2 Si and TBS were successful, albeit in lower yield. Two internal alkynes failed to react indicating that the presence of the TMS group is necessary for the reaction (Scheme 70). 86,87 Scheme 70 Decarbonylative addition to a silylacetylene The olefination of ynolates was accomplished with 3-silylpropynoates giving excellent selectivity for the E-enyne. Ag-catalyzed cyclization of the resulting enynes was carried out to give either the 5-exo-tetronic acid derivatives or the 6-endo-pyrones. The triethylsilyl-tetronic acid 99 was stereoselectively converted into the corresponding iodide 100, which was in turn subjected to phenylation via a Suzuki cross-coupling and to ethynylation via Sonogashira crosscoupling (Scheme 71). 88

Scheme 71 Addition to silylpropynoates and reaction of the resulting vinylsilanes
A series of silylated propargylic alcohols was prepared via the straightforward reaction of a lithiated silylacetylene and a variety of aromatic and aliphatic aldehydes and ketones. These silylated propargylic alcohols were then subjected to the Meyer-Schuster rearrangement to give acylsilanes; propargyl alcohols derived from aromatic aldehydes underwent the rearrangement in good yield under catalysis with either PTSA·H 2 O/n-Bu 4 N·ReO 4 or Ph 3 SiOReO 3 . The PTSA·H 2 O/n-Bu 4 N·ReO 4 system did not work for electron-donating aryl systems, though the Ph 3 SiOReO 3 catalyst worked well for these. Propargyl alcohols derived from ali-

Review Syn thesis
phatic aldehydes failed to give acylsilanes with the exception of pivaldehyde. Propargylic alcohols derived from diaryl ketones gave either indanones or acylsilanes (Scheme 72). 89

Scheme 72 Rearrangement and oxidation of silylpropargyl alcohols
A one-step hydroiodination of 1-aryl-2-silylacetylenes to the vinyl iodide, highly useful substrates for cross-coupling applications, was found to occur upon treatment of the 1-aryl-2-silylacetylenes with iodotrimethylsilane. The reaction sequence of a Sonogashira cross-coupling of (trimethylsilyl)acetylene and an aryl halide followed by the hydroiodination resulted in a facile synthesis of α-iodostyrene derivatives; the reaction resulted in the Markovnikov addition of HI to the C≡C bond. It was further found that the terminal acetylene itself would undergo the reaction as well. More hindered silyl groups gave a lower yield of the vinyl iodide (Scheme 73). 90 A three-component with methyl 3-(trimethylsilyl)propynoate, an amine, and an imine is directed by both the ester and the trimethylsilyl moieties. The reaction involves a 1,4-silyl shift. When salicyl imines were used as substrates the products were chromenes. This reaction was shown to proceed through the aminal 101, which could be trapped with allyltrimethylsilane or the TMS enol ether of acetophenone (Scheme 74). 91

Scheme 74 Reaction of 3-silylpropynoates with imines
A variety of 3-silylpropynals and silylethynyl ketones, prepared via a silylation, deprotection, oxidation sequence, were converted into 2-silyl-1,3-dithianes, which are useful synthons via their potential for anion relay chemistry (ARC). 92 Although 8 different silyl groups showed good results, the dithiation did not occur when the silyl was sterically hindered, as with TBDPS, TIPS, t-Bu 2

Review Syn thesis
The lithium aluminum hydride reduction of 4-silylbut-3-yn-2-ones provided the 4-silylbut-3-en-2-ol in good yields and high E/Z ratios (Scheme 76). 94 The β-silyl effect to stabilize β-cationic intermediates was employed in the regioselective addition of ICl to silylacetylenes. The diastereoselectivity of the addition is the opposite of that found for the reaction of ICl with the simple terminal alkyne. The Z/E selectivity is higher with arylsubstituted silylacetylenes, though the Z selectivity of alkylsubstituted silylacetylenes increases with an increase in the size of the silyl group (Scheme 77). 95

Scheme 77 Iodochlorination of silylacetylenes
The addition of the halogens to (trimethylsilyl)acetylene in the absence of light produced the E isomer, which could be equilibrated to a mixture of both stereoisomers. In the cases of the E-dichloride or E-dibromide the equilibration was brought about by exposure to light in the presence of a trace of bromine. In the case of the E-diiodide, prolonged refluxing in cyclooctane produced an E/Z mixture of 9:1 (Scheme 78). 96

Scheme 78 Halogenation of (trimethylsilyl)acetylene
The reaction of Weinreb amides with internal acetylenes promoted by a Kulinkovich-type titanium intermediate gave α,β-unsaturated ketones in modest yield. The reaction conditions were mild with activation of the titanium promoter as the last step at room temperature. With TMSterminated acetylenes, the yields were comparable to those of other alkynes investigated, though with slightly lower regioselectivity (Scheme 79). 97

Scheme 79 Reaction of Weinreb amide with silylacetylenes
The syn addition of two aryl groups from an arylboronic acid to an internal alkyne resulted in the formation of 1,2disubstituted 1,2-diarylethenes. In the single example using a silylacetylene, the reaction of ethyl 3-(trimethylsilyl)propynoate with p-tolylboronic acid under Pd catalysis gave the highly substituted ethyl 2,3-di(p-tolyl)-3-(trimethylsilyl)propenoate via the addition of two equivalents of the ptolyl group (Scheme 80). 98,99 The highly regio-and stereoselective addition of a boronic acid to silylacetylenes occurred under mild conditions and in high yields. Interesting points were that 1-(triethylsilyl)hex-1-yne was more regioselective than (trimethylsilyl)hex-1-yne, which gave a mixture of isomeric vinylsilanes indicating that the steric effect of the silyl group plays a role, and extended reaction times gave reduced stereoselectivity. The resulting arylated vinylsilanes could be converted into their corresponding iodide or bromide. In the case of the iodide this was performed in a twostep, one-pot reaction sequence, whereas the bromide required two independent steps. In a further extrapolation of

Scheme 80 Addition of boronic acids to alkynylsilanes
The Oshima group reported the syn-hydrophosphination of terminal and internal alkynes. With arylacetylenes the regioselectivity was approximately 9:1 and with (triethylsilyl)acetylene, the sole silicon example, it was 94:6, slightly less than that with alkylacetylene substrates, which showed a 100:0 regioselectivity all placing the phosphine on the terminal position. The products were isolated as their phosphine sulfides (Scheme 81). 101 A chiral NHC catalyst was employed in the enantioselective conjugate addition of 1-(trimethylsilyl)alk-1-ynes to 3substituted cyclopentenones and 3-substituted cyclohexen-ones. Thus, the 1-(trimethylsilyl)alk-1-yne was reacted with diisobutylaluminum hydride to form the 1-(trimethylsilyl)vinylaluminum reagent, which was then reacted with the enone, catalyzed by the chiral NHC complex 103. In reactions with the cyclopentenones, up to 10% of addition of the isobutyl group from aluminum was observed; this increased to up to 33% for cyclohexenones. The er values were excellent, ranging from 92.5:7.5 to 98

Review Syn thesis
importance, the resulting vinylsilanes were further reacted. Oxidation with m-chloroperbenzoic acid gave the ketone. NCI converted it into the vinyl iodide and protiodesilylation to the parent alkene. This chemistry was applied to a short synthesis of riccardiphenol B (104) (Scheme 82). 102 The reaction of indoles with 1-(halophenyl)-2-(trimethylsilyl)acetylenes under Cu(I) catalysis gave addition of the indole to the C≡C bond and, under the basic conditions, protiodesilylation to form the corresponding alkene as a mixture of stereoisomers. Very little amination of the aryl halogen bond occurred. In fact, a control experiment wherein indole was reacted with a mixture of 1-(4-bromophenyl)-2-(trimethylsilyl)acetylene and 4-iodoanisole a 50% yield of addition to the C≡C bond and only 6% reaction of the iodophenyl bond was observed (Scheme 83). 103

Scheme 88 Hydroacetation of a silylacetylene
An iron-catalyzed imine-directed 2-vinylation of indole with internal alkynes produced the 2-vinylated derivative in good yield and regioselectivity. Terminal acetylenes did not react under the conditions employed. This deficiency was circumvented by the use of a (trimethylsilyl)acetylene, which reacted with high regioselectivity forming the C2-C vinyl bond β to the TMS group. These conditions also proved useful for the formation of C2-Csp 3 bonds when the reaction was carried out with alkenes (Scheme 89); again the reaction did not occur with terminal alkenes. 109

Scheme 89
Coupling of a (trimethylsilyl)acetylene with an α,β-unsaturated imine The addition of DIBAL-H to 1-(trimethylsilyl)prop-1yne followed by conversion into the lithium aluminate and reaction with formaldehyde resulted in vinylsilane 110. This was in turn used to generated vinylsilane 111 and, from that, vinyl iodide 112, which was then converted in two steps into norfluorocurarine (113) (Scheme 90). 110

Reactions at the C-Si Bond
A study on the iododesilylation of a series of vinylsilanes wherein the silyl group included TIPS, TBS, and TBDPS was carried out. 111 This was the first report of the iododesilylation of a vinylsilane with sterically hindered silyl moieties. Interestingly, it was found that the rate of the reaction with TIPS or TBS groups was about the same, but that of TIPS was faster than that of TBDPS. Four different sources of I + , Niodosuccinimide (NIS), N-iodosaccharin (NISac), 1,3-diodo-5,5-dimethylhydantoin (DIH), and bis(pyridine)iodonium tetrafluoroborate (Ipy 2 BF 4 ) were investigated with comparable results for each. The success of the reaction depended on the solvent system with 1,1,1,3

Review Syn thesis
reacted in a Sonogashira cross-coupling with 2-iodoaniline. The coupling product was reacted with trichloroacetyl isocyanate and this converted into desilylated urea 115 in a single step. The resulting diyne was subjected to a double cyclization to give the pyrimido[1,6-a]indol-1(2H)-one 116 (Scheme 92). 112 Pan and co-workers reported the conjugate addition of alkynyl groups to acrylate derivatives via the reaction of a (trimethylsilyl)acetylene derivative under InCl 3 catalysis. Silyl moieties other than that of the TMS group were not investigated. The reaction worked best for 1-phenyl-2-(trimethylsilyl)acetylene wherein the phenyl group is a strongly electron-donating aryl group. Thus, 4-CN-, 4-CO 2 Me-, and 4-CF 3 -substituted 1-phenyl-2-(trimethylsi-lyl)acetylenes failed to react. A direct comparison of 1-butyl-and 1-phenyl-2-(trimethylsilyl)acetylene with hex-1yne and phenylacetylene, that is, the H-terminated acetylenes, showed that TMS-terminated acetylenes gave better yields. Chlorobenzene was found to be the best solvent and Et 3 N the best base. 1,4-Bis[(trimethylsilyl)ethynyl]benzene (117) reacted with ethyl acrylate to give the mono-or disubstituted γ,δ-ethynyl esters. The reaction was also occurred with methyl vinyl ketone as the acceptor (Scheme 93). 113 This protocol compares well with the conjugate addition of terminal alkynes to acrylates catalyzed by Ru 3 (CO) 12 /bis(triphenylphosphine)iminium chloride and with Pd(OAc) 2 . 114,115 14 Miscellaneous Reactions β-Amino enone 118 was converted in a two-step, single-pot sequence into enol ether 119 via reaction with 3-(trimethylsilyl)propargyllithium in 51% overall yield; using propargylmagnesium bromide gave the corresponding Hterminated product in 40% yield. Enol ether 119 was utilized in a synthesis of 7-hydroxycopodine (Scheme 94). 116 1-[(Trialkylsilyl)ethynyl]cyclopropan-1-ols were ring expanded to 2-alkylidenecyclobutanones in a reaction catalyzed by the Ru catalyst 120. Interestingly, the favored stereoisomer was the Z-isomer. Similar results were ob-

Review Syn thesis
tained with electron-deficient alkynyl cyclopropanols. On the other hand, under the same conditions 1-alk-1-ynylcyclopropan-1-ols underwent ring expansion to cyclopentenones. Stabilization of a β-carbocation in the silyl-substituted examples and a favored Michael addition in the electron-deficient examples helps to explain the formation of the four-membered ring (Scheme 95). 117 3-(Trimethylsilyl)propynal was nicely used in a convenient synthesis of ethynyl-β-lactone 121; propynal did not undergo a corresponding reaction to give 122. The silylated enantiomerically enriched β-lactone 121 was utilized in synthetic approaches to leustroducsin B and the protiodesilylated ethynyl lactone 122 was converted to derivatives of similar structure to the natural products (-)-muricaticin, (-)-japonilure, and (+)-eldanolide. [118][119][120] Scheme 96 Synthesis of silylethynyl-β-lactone Corey and Kirst were the first to report the synthesis and utility of 3-(trimethylsilyl)propargyllithium (123). The direct lithiation of 1-(trimethylsilyl)prop-1-yne occurred using BuLi/TMEDA in 15 minutes. The reagent 123 reacted with primary alkyl halides in diethyl ether to form the desired alkynes with only small amounts of the isomeric allene, a common side product found with propargylmagnesium chloride reagent. 121 Corey and Rucker then utilized 1-(triisopropylsilyl)prop-1-yne (124), which was readily lithiated to give the more sterically encumbered 3-(triisopropylsilyl)propargyllithium (125). Lithium reagent 125 was reacted with cyclohexenones in a 1,2-and 1,4-manner. In addition it was converted into the 1,3-bis(triisopropylsilyl)prop-1-yne (126) in quantitative yield on treatment with triisopropylsilyl triflate. Reaction of 125 with cyclohexenone gave 1,4-addition in THF/HMPA and 1,2-addition in THF. Bis-TIPS reagent 126 reacted with BuLi/THF to give lithiated 126, which reacted with aldehydes in a Peterson reaction to form an enynes (Scheme 97). 4 3-(Trimethylsilyl)propargyllithium (123) was used to introduce the propargyl group into epoxygeranyl chloride in 85% yield over three steps from geraniol. The TMS group was removed with TBAF and the resulting enyne was used in a synthesis of the triterpene limonin (Scheme 97). 122 3-(Trimethylsilyl)propargyllithium (123) reacted with lactone 127 and this was followed by mesylation/elimination to give enynes 128 and 129 in good yield. The TMS group was removed with AgNO 3 /aq EtOH en route to stereoisomers of bis(acetylenic) enol ether spiroacetals of artemisia and chrysanthemum (Scheme 97). 123 Fu and Smith demonstrated the enantioselective Ni-catalyzed, Negishi cross-coupling arylation of racemic 3-(trimethylsilyl)propargyl bromides; the yields and the ee values were excellent. The protocol was applied to the synthesis of 131, a precursor to pyrimidine 132, an inhibitor of dihydrofolate reductase (Scheme 98). 124