Technical Library

The Ru-catalyzed hydroacylation of 4-methoxybenzaldehyde with trimethylsilylpropyne gave a mixture of isomeric trimethylsilyl dienol ethers 47 and 48.52

The reaction of a tertiary amine with methyl trimethylsilylpropynoate gave addition of the amine to the triple bond and the formation of an allenoate ion. This, in the presence of an aldehyde, gave predominantly bis addition of the aldehyde resulting in two products 49 and 50. When the aldehyde was an aliphatic group addition at the C-H terminus of the triple bond occurred to give 51. No reaction occurred with ethyl 3-methylpropionate indicating that the trimethylsilyl group was necessary.

Scheme 43. Aldehyde addition to an alkynylsilane

Ethynyltrimethylsilanes were reacted under nickel 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-(1-pyrollidino)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. Only phenylethynyltrimethylsilane and p-anisylethynyltrimethylsilane were reported to give mixtures of (Z) and (E) alkylidene isomers. Two additional examples were presented, where the PhMe2Si and t-BuMe2Si acetylenes were reacted, albeit in lower yield. Two dialkylacetylenes failed to react indicating that the presence of the TMS group is necessary for the reaction.53

Scheme 44. Decarbonylative addition to an alkynylsilane

The torquoselective olefination of alkynoates was accomplished. The silylalkynoates gave excellent selectivity for the (E)-enyne formed. Silver catalyzed cyclization of the resulting enynes was carried out to give either the 5-exo tetronic acid derivatives or the 6-endo pyrones. The TES-silylated tetronic acid 52 was stereoselectively converted to the corresponding iodide 53, which was in turn subjected to phenylation via a Suzuki cross-coupling and to ethynylation via Sonogashira cross-coupling.54

Scheme 45. Addition to silylpropynoates

A series of silylated propargylic alcohols was prepared via the straightforward reaction of the lithiated ethynylsilane and a variety of aldehydes and ketones. These were subjected to conditions for the Meyer-Schuster rearrangement in the preparation of acylsilanes. The reaction of the propargyl alcohols derived from aromatic aldehydes underwent the rearrangement in good yield under either of two catalyst systems, p-TSA•H2O/n-Bu4•ReO4 or Ph3SiOReO3. The p-TSA•H2O/n-Bu4•ReO4 system did not work for electron donating aryl systems, though the Ph3SiOReO3 catalyst worked well for these. Aliphatic aldehydes failed with the exception of that obtained from pivaldehyde. The reactions from the propargylic alcohols prepared from diaryl ketones showed mixed pathways.55

Scheme 46. Rearrangement and oxidation of silylpropargyl alcohols

A one-step hydroiodation of ethynylsilanes to the vinyl iodide, highly useful substrates for crosscoupling applications, was found to occur upon treatment of the ethynylsilane with trimethyliodosilane. The reaction sequence of a Sonogashira cross-coupling of ethynyltrimethylsilane and an aryl halide followed by the hydroiodation resulted in a facile synthesis of α-iodostyrene derivatives. In the end the reaction resulted in the Markovnikov addition of HI to the triple 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.56

Scheme 47. Iodination of alkynylsilanes

A three-component with methyl trimethylsilylpropiolate, an amine and an imine is directed by both the ester and the trimethylsilyl moieties. The reaction involves a 1,4-silyl shift. When applied to salicyl imines chromenes were generated. This reaction was shown to proceed through the aminal 54, which could be trapped with allyltrimethylsilane or the TMS-enol ether of acetophenone.57

Scheme 48. Reaction of silylpropynoates with imines

A variety of 1-silylethynyl aldehydes and ketones, prepared via a silylation, deprotection, oxidation sequence, were converted to the silyl-1,3-dithianes, which are useful synthons via their potential for Anion Relay Chemistry (ARC).58 Although 8 different R3Si groups showed good results, the dithiation did not occur when R3Si was sterically hindered as with TBDPS, TIPS, (t-)Bu2HSi, or i-Pr2HSi.59

Scheme 49. Dithiation of silylpropynals

The LAH reduction of the 4-silylbutyn-2-ones provided the 4-silylbuten-2-ol in good yields and high Z:E ratios.60

Scheme 50. LAH reduction of silylpropargyl alcohols

The β-silyl effect to stabilize β-cationic intermediates was employed in the regioselective addition of ICl to ethynylsilanes. The diastereoselectivity of the addition is the opposite that found for the reaction of ICl with the simple terminal alkyne. The Z:E selectivity is higher with aryl-substituted ethynylsilanes, though the Z selectivity of the alkyl-substituted ethynylsilanes increases with an increase in the size of the silyl group.61

Scheme 51. Iodochlorination of alkynylsilanes

The addition of the halogens to ethynyltrimethylsilane 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 a 9:1 E:Z mixture.62

Scheme 52. Halogenation of alkynylsilanes

The reaction of Weinreb amides with internal acetylenes under promotion via 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 the TMS-terminated alkynes the yields were comparable to those of other alkynes investigated, though with slightly lower regioselectivity.63

Scheme 53. Reaction of Weinreb amide with alkynylsilanes

The syn addition of two aryl groups from an arylboronic acid to an internal alkyne resulted in the formation of 1,2-diaryl tetrasubstituted olefins. In the single silicon example the reaction of ethyl trimethylsilylpropiolate with p-tolylboronic acid under Pd catalysis formed the trisubstituted corresponding vinylsilane via the addition of two equivalents of the p-tolyl group. The reaction provided a route to a highly substituted β-trimethylsilyl-α,β-unsaturated ester.64

The highly regio- and stereoselective addition of a boronic acid to alkynylsilanes was reported. The reaction occurred under mild conditions and in high yields. Interesting points found were that 1-hexynyltriethylsilane was more regioselective than 1-hexynyltrimethylsilane, 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 to their corresponding iodide and bromide. In the case of the iodide this could be done in a two-step, one-pot reaction sequence, whereas with the bromide two independent steps were required. In a further extrapolation of the chemistry the region- and stereoselective synthesis of (Z)-1-(4-tolyl)-2-(4-anisyl)styrene 55 was accomplished in 3 steps from phenylethynyltrimethylsilane. The (E)-isomer was prepared starting from 4-tolylethynyltrimethylsilane. The reaction was also possible with the addition of a vinylboronic acid giving a dienylsilane.65

Scheme 54. Addition of a boronic acid to alkynylsilanes

The Oshima group reported the syn-hydrophosphination of terminal and internal alkynes. With aryl terminal alkynes the regioselectivity was approximately 9:1 and with ethynyltriethylsilane, 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 sulfides.66

Scheme 55. Hydrophosphination of an alkynylsilane

A chiral NHC catalyst was employed in the enantioselective conjugate addition of trimethylsilylalkynes to 3-substituted cyclopentenones and 3-substituted cyclohexenones. Thus, the alkynylsilane was reacted with diisobutylalane to form the 1-trimethylsilylvinylaluminum reagent, which was then reacted with the enone under catalysis with the chiral NHC complex 56. In the reactions with the cyclopentenones up to 10% of addition of the isobutyl group from aluminum was observed. This increased to up to 33% in the case of the cyclohexenones reacted. The er values were excellent ranging from 92.5:7.5 to 98.5:1.5. Of considerable importance the resulting vinylsilanes were further reacted. Oxidation with m-chloroperbenzoic acid gave the ketone. NCI converted it to the vinyl iodide and protiodesilylation to the parent olefin. This chemistry was applied to a short synthesis of riccaardiphenol B 57.67

Scheme 56. Hydroalumination of alkynylsilanes and asymmetric vinylation of enones

The reaction of indoles with halophenylethynyltrimethylsilanes under copper (I) catalysis gave addition of the indole to the triple bond and, under the basic conditions, protiodesilylation to form the corresponding olefin 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 4-bromophenylethynyltrimethylsilane and 4-iodoanisole a 50% yield of addition to the triple bond and only 6% reaction of the iodophenyl bond was observed.68

Scheme 57. Hydroamination of alkynylsilanes in presence of aryl halides

The hydrosilylation of various propiolate esters was carried out and served to prepare α-silylated-α,β-unsaturated esters in good yields. When this reaction was done with trimethylsilylpropiolate esters the product formed was the (E)-α,β-bis(silyl)acrylate. Other similar systems such as an ynone and a sulfone gave good addition products.69

Scheme 58. Hydrosilylation of functional alkynylsilanes

Bis(trimethylsilyl)-1,3-butadiyne underwent carbomagnesiation of one of the triple bonds with arylmagnesium bromide reagents. The resulting vinylmagnsium bromide intermediate could be further reacted, including cross-coupling to form various substituted silylated enynes. Phenyl-(trimethysilyl)butadiyne underwent the carbomagnesiation at the phenyl substituted triple bond.70

Scheme 59. Addition of Grignard reagents to alkynylsilanes

Kimura and coworkers reported on the nickel-catalyzed, four-component coupling of internal acetylenes, 1,3-butadiene, dimethylzinc, and carbon dioxide. The reaction of the TMS-substituted alkynes gave lower yields and poorer regioselectivity than those of alkyl- or aryl-substituted alkynes.71

Scheme 60. Four-component coupling involving an alkynylsilane

The three-component coupling of acetylenes, vinyloxiranes and dimethylzinc was reported to give 2-vinyl-5,6-unsaturated alcohols. The bis(trimethylsilyl)acetylene and ethynyltrimethylsilane gave lower yields than trimethylsilylpropyne and alkyl- or arylalkynes. In a similar manner vinylcyclopropanes were reacted to provide the 1,4-dienes.72

Scheme 61. Alkylative three-component coupling of an alkynylsilane with a vinyloxiranes

The reaction of ethynylsilane 58 with ruthenium catalyzed addition of acetic acid gave a mixture of the desired enol acetate 59 along with 60. A longer reaction time gave 60 in good yield. Although 59 was the initial desired intermediate it was 60 that was in fact carried forward in a synthesis of Clavosolide A.73

Scheme 62. Hydroacetation of an alkynylsilane

An iron-catalyzed imine-directed C2-alkenylation of indole with internal alkynes produced the 2-alkenylated derivative in good yield and regioselectivity. Terminal acetylenes did not react under the conditions employed. This was, however, circumvented by the use of a TMS-terminated acetylene, which was reacted with high regioselectivity forming the C2-Cvi bond beta to the TMS group. These conditions also proved useful for the formation of C2-Csp3 bonds when the reaction was carried out with olefins. Here again the reaction did not occur with terminal olefins.74

Scheme 63. Coupling of an alkynylsilane with an α,β-unsaturated imine

The dibal-H addition to 1-trimethylsilylpropyne followed by conversion to the lithium alanate and reaction with formaldehyde resulted in vinylsilane 61. This was in turn used to generated vinylsilane 62 and, from that, vinyliodide 63, which was then converted in two steps to norfluorocurarine 64.75

Scheme 64. Dibal-H addition to propargylTMS and further reaction to norfluorocurarine

A study on the iododesilylation of a series of vinylsilanes wherein the silyl group was TIPS, TBS, and TBDPS was carried out. 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 the vinylTBDPS. Four different sources of I+, N-iodosuccinimide (NIS), N-iodosaccharin (NISac), 1,3-diodo-5,5-dimethylhydantoin (DIH), and bis(pyridine)iodonium tetrafluoroborate (Ipy2BF4) were investigated with comparable results for each. The success of the reaction depended on the solvent system including hexafluoroisopropanol. The reaction was tolerant of epoxides, olefins, esters, TIPS ethers, and a TIPS acetylene.76

Scheme 65. Iodination of vinylsilanes, readily available from alkynylsilanes

Bis-(trimethylsilyl)butadiyne was reacted with MeLi•LiBr to prepare the mono-lithiated diyne, which was reacted in a Sonogashira cross-coupling with o-iodoaniline.77

Scheme 66. Lithiation and reaction of bis(trimethylsilyl)butadiyne

Pan and coworkers were able to conjugate add alkynyl groups to acrylate derivatives via the reaction of the trimethylsilylalkyne under InCl3 catalysis. Silyl moieties other than that of the TMS group were not investigated. The reaction worked best for alkynes with a strongly electron donating aryl group attached. Thus, 4-CN, 4-CO2Me and 4-CF3-substituted arylalkynes failed to react. In direct comparison of the TMS-terminated alkyne and the H-terminated the yields were better with the TMS derivatives. Chlorobenzene was found to be the best solvent and Et3N the best base. Bis(trimethylsilylethynyl)benzene 65 could be reacted to furnish the mono- or di-substituted γ,δ-ethynyl ester. The reaction was also occurred with methylvinyl ketone as the acceptor.78

This protocol compares well with the conjugate addition of terminal alkynes to acrylates catalyzed with Ru3(CO)12/bis(triphenylphosphine)iminium chloride79 and with Pd(OAc)2.80

Scheme 67. Ethynylation of α,β-unsaturated esters with alkynyltrimethylsilanes

β-Amino enone 66 was converted in a two-step, single-pot sequence to enol ether 67 via reaction with trimethylsilylpropargyllithium in 51% overall yield. Propargylmagnesium bromide gave a 40% yield of 67. Enol ether 67 was carried on in a synthesis of 7-hydroxycopodine.81

Scheme 68. Reaction of trimethylsilylpropargyllithium with an iminium salt

Trialkylsilylethynylcyclopropanols were ring expanded to alkylidene cyclobutanones under the promotion of ruthenium catalyst 68. Interestingly, the favored stereoisomer was the (Z)-isomer. Similar results were obtained with the electron deficient alkynyl cyclopropanols. On the other hand, alkylethynylcyclopropanols reacted to give expansion to cyclopentenones. Stabilization of a β-carbocation in the silyl-substituted examples, and a favored Michael addition in the electron deficient examples help explain the formation of the four-membered ring in these cases.82

Scheme 69. Rearrangement of silylethynylcyclopropanols

Trimethylsilylpropynal was nicely used in a convenient synthesis of ethynyl-β-lactone 69. Propynal did not undergo the requisite chemistry to this key synthon. The silylated enantiomerically enriched β-lactone 1 has been applied to synthetic approaches to leustroducsin B and the protiodesilylate ethnyl lactone 70 to (-)-murictacin, (-)-Japonilure, and (-)-Eldamolide.83,84,85

Scheme 70. Synthesis of silylethynyl-β-lactone

Corey and Kirst were the first to report on the synthesis and utility of lithio(trimethylsilyl)propyne 71. The direct lithiation occurred with BuLi/TMEDA in 15 minutes. The reagent reacted with primary alkyl halides in diethyl ether to form the desired alkyne with only small amounts of the isomeric allene, a common side product found with propargylmagnesium chloride reagent.86

Corey and Rucker followed this work up with propynyltriisopropylsilane 72, which was readily lithiated to give the more sterically encumbered TIPS propargyllithium reagent. This was converted via lithium reagent to the bis(triisopropyl)propyne 74 in quantitative yield. Reaction of 73 with cyclohexenone gave 1,4-addition in THF/HMPA and 1,2-addition in THF. Bis-TIPS reagent 77 was reacted with n-BuLi/THF to give lithiated 78, which was reacted with aldehydes in a Peterson reaction to form an enynes.87

Trimethylsilylpropargyllithium 71 was used to introduce the propargyl group onto epoxy geranyl chloride. The yield was 85% over three steps from geraniol. The TMS group was removed with TBAF and the enyne carried on to the triterpene limonin.88

Trimethylsilylpropargyllithium 71 was reacted with lactone 75 followed by mesylation/elimination to give enynes 76 and 77 in good yield. The TMS group was removed with AgNO3/EtOHaq en route to stereoisomers of bis(acetylenic) enol ether spiroacetals of artemisia and chrysanthemum.89

Scheme 71. Formation and reactions of silylpropargyllithium reagents

Fu and Smith demonstrated the enantioselective nickel-catalyzed, Negishi cross-coupling arylation of racemic trimethylsilylpropargylic bromides. The yields and the ee values were excellent. The protocol was applied to the synthesis of 79 which had been shown to be a precursor to pyrimidine 80, an inhibitor of dihydrofolate reductase.90

Scheme 72. Asymmetric arylation of trimethylsilylpropargyl bromides