Ethynylations, trimethylsilylacetylene

Ethynylations. Trimethylsilylacetylene (TMS A) is one of the most versatile building blocks in organic synthesis to introduce a C2 moiety. These ethynylations with TMSA proceed via the terminal end of TMSA, yielding protected acetylenes with an easily removable TMS-protecting group. The deprotection can be accomplished with mild bases or fluoride source (in many cases TBAF) to obtain another reactive terminal acetylene. 

Reaction of an acid chloride with trimethylsilylacetylene produces an a,P-ethynyl ketone, which on treatment with substituted hydrazines yields a mixture of 1,5- and 1,3-substituted pyrazoles (34). The ratio is dependent on the reaction conditions (eq. 3). 

In 1980 Sonogashira reported a convenient synthesis of ethynylarenes - the Pd-catalyzed cross-coupfing of bromo- or iodoarenes with trimethylsilylacetylene followed by protiodesilylation in basic solution [15]. Prior to this discovery, formation of terminal acetylenes required manipulation of a preformed, two-carbon side chain via methods that include halogenation/dehydrohalogenation of vinyl- and acetylarenes, dehalogenation of /1,/1-dihaloalkenes, and the Vils-meier procedure [ 14]. With the ready availability of trialkylsilylacetylenes, the two-step Sonogashira sequence has become the cornerstone reaction for the construction of virtually all ethynylated arenes used in PAM and PDM synthesis (vide infra). 

Halopyridines, like simple carbocyclic aryl halides, are viable substrates for Pd-catalyzed crosscoupling reactions with terminal acetylenes in the presence of Pd/Cu catalyst. The Sonogashira reaction of 2,6-dibromopyridine with trimethylsilylacetylene afforded 2,6-bis(trimethylsilyl-ethynyl)pyridine (130), which was subsequently hydrolyzed with dilute alkali to provide an efficient access to 2,6-diethynylpyridine (131) [106]. Extensions of the reactions to 2-chloropyridine, 2-bromopyridine, and 3-bromopyridine were also successful albeit at elevated temperatures [107]. 

Iodobenzothiazole was coupled with trimethylsilylacetylene to give adduct 93 which was readily desilylated to furnish 2-ethynyl-l,3-benzothiazole (94) [52],... 

Trimethylsilylacetylene has been prepared by silylation of a variety of ethynyl metal derivatives.2"10 The most useful methods are the silylation of ethynylmagnesium bromide and chloride.2,7,10 The use of ethynylmagnesium bromide has been reported to suffer from complicating side reactions,2 and the results obtained in our hands were unreliable. 

Stereocontrolled ethynylation of methyl 2,3,4-tri-O-benzyl-a-D-g/Hco-hexodialdo-l,5-pyranoside (52) with a Grignard reagent formed from trimethylsilylacetylene, followed by a multistep procedure afforded the aminouronic acid 53, the a-amino acid on which miharamycin A is based.168 Uronic acid derivatives have also been produced by the Wittig reaction on the aldehydic side chain of dialdofuranose compounds.169... 

Monosubstitution of acetylene itself to prepare terminal alkynes is not easy. Therefore, trimethylsilylacetylene (134) is used as a protected acetylene. After the coupling, the silyl group is removed by the treatment with fluoride anion. The hexasubstitution of hexabromobenzene (135) with 134 afforded hexaethynylbenzene (136) after desilylation in total yield of 28%. The product was converted to tris(benzocyclobutadieno)benzene (137) using a Co catalyst (see Section 7.2.1). Hexabutadiynylbenzene was prepared similarly [60], As another method, terminal alkynes 139 are prepared in excellent yields by the coupling of commercially available ethynyl Grignard (138) or ethynylzinc bromide with halides, without protection and deprotection [61]. 

The catalyst system for the coupling reaction was a Pd(II)-tri-phenylphosphine complex, usually prepared in situ, with excess triphenyl-phospUne and either cuprous iodide or cupric acetate as a co-catalyst. Alternatively, a preformed catalyst mixture prepared from these reagents may be utilized (see Experimental Section). When 2-methyl-3-butyn-2-ol was used as the protected acetylene, the intermediates 5a-d were converted to the corresponding aryl acetylenes 6a-d by a retro-Favorskii-Babayan (8) reaction utilizing potassium r-butoxide in toluene under conditions of slow distillation. In the case of p-iododimethylaniline (3e), trimethylsilylacetylene was used as the ethynyl source. The intermediate (5e) was treated with hydroxide to generate the free aryl acetylene 6e. The syntheses of 6d and 6e are described in the Experimental section below. 

The coupling of /raaf-2,6-diodo-3,7-diphenyltetrathiafulvalene 704 (obtained in 62% yield by metallation of the corresponding diphenyl-TTF with LDA followed by iodination with perfluorohexyl iodide) with trimethylsilylacetylene in the presence of Pd(PPh3)4, Cul, and NEt3 in tetrahydrofuran (THF) afforded symmetrical bis(2-trimethylsilyl)ethynyl-TTF 705 in 70% yield which was then desilylated with aqueous KOFI to give 706 (Scheme 104) <1998S259>. 

Bromo- and 3-iodo-l,2,4-triazines react with nucleophiles in a similar manner, but more easily than their chloro analogues. For example, 3-iodo-5,6-diphenyl-1,2,4-triazine is converted into 3-(2-trimethylsily-l-ethynyl) -5,6-diphenyl-1,2,4-triazine (61) by action of trimethylsilylacetylene (60) (Scheme 39), whereas no reaction between 3-chloro-5,6,-diphenyl-1,2,4-triazine and acetylene (60) has been observed under identical conditions (84H2245). 

In 1983, Yamanaka published smooth ethynylation of several haloazines and -diazines via Sonogashira coupling with trimethylsilylacetylene, using triethylamine as base and solvent, followed by subsequent desilylation with aqueous methanolic potassium hydroxide [81]. Two chloropyridazines were included as substrates in this report namely, 3-chloro-6-methylpyridazine and 4-chloro-3,6-dimethylpyridazine (185). 

Copper Reactants. Application of the Pd/Cu-catalyzed cross-coupling, the Sonogashira reaction, with monosubstituted or protected acetylene gives rise to a variety of ethynyl-heteroarenes (Schenae 27). Reactions with trimethylsilylacetylene or phenylacetylene in... 

A similar approach was used by Knochel and coworkers for the first synthesis of unsubstituted b-SFs-indole (7) (12CEJ10234). They directly used unprotected 2-bromo-5-SF5-aniline (8) in reaction with trimethylsilylacetylene under Sonogashira cross-coupling conditions, which provided SFs-substituted 2-ethynyl(trimethylsilyl)aniline (9). Subsequent cychzation using KH in 1-methyl-2-pyrrolidinone afforded the b-SFs-indole (7) in 83% yield (Scheme 3). 

The monoiodo derivative 74 was then converted to the ethynyl substituted phthalocyanine 76 by reaction with trimethylsilylacetylene ([Pd(PPh3)2Cl2], Cul, EtjN, THF, RT, 24 h) followed by desyUlation of 75 (TBAF, THF, 0 C-rt, 2 h, 65 %). Then 1,3-butadiyn bridged dimer 77 was obtained by copper catalysed Glaser homo-coupling reaction (CuCl, pyridine, rt, 3 days, 75 %) [62],... 

PdCl2(PPli3)2] (53.76 mg, 0.07 mmol, 2 mol %), trimethylsilylacetylene (0.63 mL, 4.42 mmol, 1.2 equiv) and Cul (35.68 mg, 0.18 mmol, 5 mol %) were added to a solution of compound III-79C02Me (1.02 g, 3.68 mmol, 1 equiv) in EtaN (12 mL). The mixture was stirred at room temperature overnight. After removal of solvent under vacuum, 1.01 g of methyl 3-((trimethylsilyl)ethynyl)-l//-indole-l-carboxylate (III-80CO2Me) was isolated (quant.), which was used in the next step without further purification [252]. 

---