Ethynylation reaction

AGE2731). (Product 146 during its synthesis, unlike analog 95a, does not suffer acid hydrolysis of the N-methylanilino group after the aza-Diels-Alder reaction.) Ethynyl enol 147 is isolated in a very small 5deld the corresponding (2S)-ferf-butyldimethylsilyloxymethyl compound exists in its tautomeric 1-keto form. 

The Ci3-ketone /-ionone (2) is built up in five stages (5 + 4—from the starting materials acetone (3) and acetylene (4), with sigmatropic rearrangements playing a key role (Scheme 1). The process comprises four basic reactions, ethynylation, partial hydrogenation, reaction with wo-propenyl methyl ether (9) and rearrangement, which can be carried out inexpensively [11]. 

Butynediol. Butynediol, 2-butyne-l,4-diol, [110-65-6] was first synthesized in 1906 by reaction of acetylene bis(magnesium bromide) with paraformaldehyde (43). It is available commercially as a crystalline soHd or a 35% aqueous solution manufactured by ethynylation of formaldehyde. Physical properties are Hsted in Table 2. 

Secondary acetylenic alcohols are prepared by ethynylation of aldehydes higher than formaldehyde. Although copper acetyUde complexes will cataly2e this reaction, the rates are slow and the equiUbria unfavorable. The commercial products are prepared with alkaline catalysts, usually used in stoichiometric amounts. 

Methylbutynol. 2-Methyl-3-butyn-2-ol [115-19-5] prepared by ethynylation of acetone, is the simplest of the tertiary ethynols, and serves as a prototype to illustrate their versatile reactions. There are three reactive sites, ie, hydroxyl group, triple bond, and acetylenic hydrogen. Although the triple bonds and acetylenic hydrogens behave similarly in methylbutynol and in propargyl alcohol, the reactivity of the hydroxyl groups is very different. 

Ethynylation. Base-catalyzed addition of acetylene to carbonyl compounds to form -yn-ols and -yn-glycols (see Acetylene-DERIVED chemicals) is a general and versatile reaction for the production of many commercially useful products. Finely divided KOH can be used in organic solvents or Hquid ammonia. The latter system is widely used for the production of pharmaceuticals and perfumes. The primary commercial appHcation of ethynylation is in the production of 2-butyne-l,4-diol from acetylene and formaldehyde using supported copper acetyHde as catalyst in an aqueous Hquid-fiHed system. 

The ethynylation reaction takes place at 10—40°C and 2 MPa (20 atm) and hquid ammonia is the solvent. The methylbutynol is converted into methylbutenol by selective hydrogenation and then is dehydrated over alumina at 250—300°C. Polymerization-grade isoprene is obtained. 

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). 

The Michael addition of nucleophiles to the carbon—carbon double bond of maleimide has been exploited ia the synthesis of a variety of linear polymers through reaction of bismaleimide with bisthiols (39). This method has been used to synthesize ethynyl-terminated imidothioether from the reaction of 4,4 -dimercaptodiphenyl ether [17527-79-6] and A/-(3-ethynylphenyl)maleimide (40). The chemical stmcture of this Michael addition imide thermoset is as follows ... 

With an activated C—C triple bond two successive additions can occur if the intermediate alkene is reactive enough. DMAD and 3,5-dimethylpyrazole give an initiaj fumarate (255) which reacts further at the other end to form regioselectively the succinates (256). On the other hand, methyl ethynyl ketone reacts twice at the same carbon atom with pyrazole to form 1,1-pyrazolylbutanone (258) (68ZC458). The probable intermediate, a pyrazolide vinylogue (257), can be prepared from methyl chlorovinyl ketone and pyrazole, in a reaction which is similar to acetylation (Section 4.04.2.1.3(x)). 

Imidazole, 2-ethyl-1 -(o-nitrophenyl)-cyclization, S, 431 Imidazole, 4-ethyl-2-phenyl-oxidation, S, 405 Imidazole, ethynyl-Michael addition, S, 437 Imidazole, 4-ethynyl-2-phenyl-synthesis, S, 494 Imidazole, 1-formyl-reactions, S, 452 Imidazole, 2-formyl-mass spectra, S, 360 Imidazole, 4-formyl-synthesis, S, 475-476 Imidazole, 2-formyl-1,5-dimethyl-mass spectra, S, 360 3-oxide... 

Pyrazole, 3-ethoxycarbonyl-3 (5 ),5-dimethyl-5 (3 )-pyrazol-l-yl-reduction, 5, 260 Pyrazole, ethynyl-reactions, 5, 261 Pyrazole, 4-formyl-IR spectra, S, 201 NMR... 

Pyrrole, 4-ethynyl-2-formyl-3-methyl-synthesis, 4, 222 Pyrrole, formyl-oxidation, 4, 289 reactions, 4, 292 with sulfoxides, 4, 293 synthesis, 4, 223, 274, 287 Pyrrole, 1-formyl-barrier to rotation, 4, 193 Pyrrole, 2-formyl-benzoylation, 4, 220 conformation, 2, 107 4, 193 diacetoxythallium derivative iodination, 4, 216 dipole moment, 4, 194 ketals, 4, 290 protonation, 4, 47 reactions... 

Dj Ethynylation Reaction of acetylene with formaldehyde over a CaCf-supported catalyst. 

The 17a-ethynyl compound (59) has been prepared in 88% yield from estr-4-ene-3,17-dione (58) and acetylene, at 2-3 atm pressure in tetrahydro-furan in the presence of potassium t-butoxide. Presumably the A-ring enone system is protected as the enolate anion during the course of the reaction. 

The direct reaction of androsta-l,4-diene-3,17-dione with acetylene in the presence of potassium t-amyloxide gives the 17a-ethynyl-17j -hydroxyandros-ta-l,4-dien-3-one in only 12% yield. 

Ethynylation of 3j -hydroxy-16a-methyl-5a-androstan-17-one in a mixture of diethylene glycol dimethyl ether and diethylene glycol monoethyl ether in the presence of potassium hydroxide produces two isomeric 17-ethynyl derivatives. This result is not unexpected since molecular models suggest that the steric influence of the 13/ -methyl group is nearly offset by the 16a-methyl group. The presence of a 16a-acetoxy group in the estrone series also leads to the formation of epimeric 17-ethynyl compounds (61) and (62) on reaction with acetylenedimagnesium bromide. 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia " reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for... 

Disubstituted isotellurazoles 1 (4-11%) and bis((3-acylvinyl)tellurides 3 (3-10%) were isolated in very low yields from the reaction mixture as the products of nucleophilic addition of telluride anion to the triple bond of the initial ethynyl ketones (83S824). This method cannot be applied to the synthesis of 3//-isotellurazoles. When a-acetylenic aldehydes were used instead of ethynyl ketones, bis((3-cyanovinyl)tellurides 4 obtained in 14-20% yields were the only products (83S824). 

Diazopropyne reacts similarly with a monosubstituted acetylene to form 3(5)-alkynylpyrazoles (68LA113). Thus, the reaction of diazopropyne with acetylene-carboxylic acid methyl ether results in 5-ethynyl-l//-pyrazole-3-carboxylic acid methyl ether in 48 h in 62% yield. 5-Ethynyl-l//-pyrazole-3,4-dicarboxylic acid dimethyl ester was prepared by reaction of diazopropyne with acetylenedicar-boxylic acid methyl ether (Scheme 10). 

The Favorsky reaction should be considered a general method for producing pyrazolyl-Q -acetylenic alcohols because even the less reactive 4-ethynyl-l,3,5-trimethylpyrazole, additionally deactivated by three donor methyl groups, reacts with acetone (Scheme 61). 

The presence of the aliphatic amino group complicates the course of the reaction. Thus, the oxidative coupling of 4-ethynyl-1,3-dimethyl-5-aminomethylpyrazole in mild conditions (20°C, CuCl, pyridine, O2) leads to only 20% of butadiyne. However, acylic protection eliminates these complications, and 4-ethynyl-1,3-dimethyl-5-(acetyl)aminomethylpyrazole forms a dehydrodimer in 95% yield (Scheme 66) (86TH1). 

The condensation of 4-ethynyl-1,3-dimethyl-5-aminomethylpyrazole with iodo-benzene in the standard conditions of the Heck-Sonogashira reaction caused no complications and the yield of disubstituted acetylene was 87% (86TH1) (Scheme 68). 

TABLE XXn. Ethynyl- and Polyethynylpyrazoles Prepared by Retro-Eavorsky Reaction [69IZV2546 69KGS1055 71IZV1764 72IZV2524 86TH1 88M253]. 

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