Cyclizations of Silylalkynes

The tricyclization of alkynes to aromatic rings has long been known as has the use of silylacetylenes in this practice.⁴⁰

Silyl-protected arylacetylenes reacted with o-phenylethynylbenzaldehyde under acid catalysis to produce the 2-aryl-3-silylnaphthalene in good yield. The TMS-protected arylalkynes resulted in the 2-arylnaphthalene with protiodesilylation taking place under the reaction conditions. However, the more hindered TES, TBS, and TIPS-protected derivatives gave the corresponding 3-silylnaphthalenes allowing for the ICl ipso iodination of the silyl group to provide the naphthyl iodide for further elaboration via cross-coupling chemistry. The chemistry was applied to the synthesis of several highly encumbered polyaromatic systems.⁴¹

The rhodium-catalyzed reaction of trimethylsilylacetylenes 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, however.⁴²

Methyl trimethylsilylpropynoate 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.⁴³

The cationic rhodium catalyst, [Rh(cod)₂]BF₄/BIPHEP, brought about the cyclotrimerization of ethynyltrimethylsilane with 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 alkyne resulted in the reaction of two equivalents of the silylacetylene. Ethynyltriisopropylsilane 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.⁴⁴

The cyclotrimerization of ethyl trimethylsilylpropynoate gave the single regioisomers 28 in 92% yield.⁴⁵

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 ethynyltrimethylsilane, and an equivalent of a β-iodo-β-silyl styrene. The nature of the silylstyrene proved crucial as the trialkylsilyl (TMS, TES, TBS, Me₂BnSi) groups gave poor yields, and the phenylated silyl groups giving better yields with the β-Ph₂MeSi-substituted styrene proving to be optimal. Selective electrophilic substitution of the 5-trimethylsilyl, para position 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 a Denmark cross-coupling. It is noteworthy that the iododesilylation of 29 is selective for the formation of 30 and that iododesilylation of a phenyl group from the Ph₂MeSi group does not occur. Comparable selectivity was noted in the acetylation of 29 to acetophenone 31, which could be desilylated to 4-phenylacetophenone in good yield.⁴⁶

1-Trimethylsilylacetylenes were shown to provide excellent regiochemical control in the cobalt-catalyzed Diels-Alder reaction with 1,3-dienes. In the un-substituted case various Si-substituted ethynylsilanes were reacted with 2-methyl-1,3-butadiene under cobalt catalysis. It turned out that the regioselectivity was highly dependent on the accompanying ligand employed with CoBr₂(mesitylpyridin-2-yl-methyleneamine) favoring the meta regioisomers 32 after DDQ oxidation to the aromatic derivative. On the other hand, the use of CoBr₂(1,2-bis-diphenylphosphinoethane) favored the para isomer 33. In addition a number of alkynyltrimethylsilanes were reacted with 2-methyl-1,3-butadiene. Here the yields were very high, but the regioselectivity was less than that observed with the simple ethynylsilanes. Of particular interest was the result from the reaction of 1-trimethylsilylpropargyl acetate with Danishefsky’s diene, 2-trimethylsilyloxy-1,3-butadiene 36.⁴⁷

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 ethynyltrimethylsilanes 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/CH₂Cl₂ gave only 5% of the iodide 38, 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 H₂O₂/ZnI₂ gave modest yields, but again in a slow reaction that required further oxidation with DDQ for completion. Finally, the use of tert-butylhydroperoxide with ZnI₂ and K₂CO₃ was found to give high yields of the desired iodides.⁴⁸

A series of 1,4-disubstituted-1,2,3-triazines 42 was prepared in a one-pot, three-step sequence involving first a Sonogashira preparation of an arylethynyltrimethylsilane from ethynyltrimethylsilane, reaction with an alkyl azide and, finally, deprotection of the 5-trimethylsilyl group.⁴⁹

Arylethynyltrimethylsilanes, readily formed via a Sonogashira reaction from ethynyltrimethylsilane, reacted with sodium azide and an alkyl bromide in a three-step, one-pot sequence to yield a desilylated 1-alkyl-4-aryl-1,2,3-triazole 43 or 44. The reaction took place via initial deprotection of the trimethylsilyl group followed by the [3+2] click cycloaddition. This represents a safe and scalable process for the formation of 1,4-disubstituted 1,2,3-triazoles.

The reaction of alkynyltrimethylsilanes with CuBr/Et₃N served to directly prepare the alkynylcopper reagent without prior desilylation. The resulting copper reagent underwent reaction with various azides to form the 1,2,3-triazenes 45 in excellent yield. When the reaction was carried out with ethynyltrimethylsilane or ethynyltriisopropylsilane the reaction occurred at the C-H terminus. TIPS and TBS-terminated acetylenes failed to react.⁵⁰

The dichloropyridazine 46 was converted to the [1,2,3]triazole-fused pyrazinopyridazindione 47 in a three-step sequence with ethyl trimethylsilylpropynoate. The TMS group is lost in the last step of the sequence, but provides the desired regioselectivity in the azide click step of the sequence.⁵¹