The addition of acetylenes

The simplest method for the addition of a 2-carbon fragment to a 17-keto steroid while retaining an oxygen function at C-17 is via reaction with acetylene or a substituted acetylene e.g., ethoxyacetylene, chloroacetylene). Since the resulting acetylenic carbinol (which is usually obtained in excellent yield) can in turn be hydrated, reduced, rearranged, and oxidized, this reaction offers considerable synthetic possibilities. 

The reaction can be performed under a variety of conditions. Origin-aiiyi2o,i26,234 acetylene and potassium in liquid ammonia were used. Subsequently, this was simplified by the use of potassium r-amylate in r-amyl alcohol and later this system was found to react selectively at C-17 in the presence of an A-ring a,j5-unsaturated ketone. A closer investigation of these reaction conditions revealed the formation of a small amount (2-3 %) of the disubstituted acetylene this can be avoided by reacting the 17-keto steroid with acetylenedimagnesium bromide in ether-tetrahydrofuran (see chapter 10.) 

Sodium chloroacetylide in liquid ammonia will also react selectively at C-17 in the presence of a 3-keto-A group. 

With higher homologs e.g., propynyl, butynyl), 3j5-hydroxyandrost-5-en-17-one does not react well with the alkyne and potassium r-butoxide, or with the lithium alkyne in tetrahydrofuran. However, satisfactory results are obtained by use of the alkynylmagnesium bromide in tetrahydrofuran,  

Both sodium acetylide in xylene (Air Reduction Corporation) and lithium acetylide-ethylenediamine complex (Foote Mineral Co.) are now commercially available, and have been used successfully for the ethynylation of 17-keto steroids. 

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The name ethynylation was coined by Reppe to describe the addition of acetylene to carbonyl compounds (8). 

Although stoichiometric ethynylation of carbonyl compounds with metal acetyUdes was known as early as 1899 (9), Reppe s contribution was the development of catalytic ethynylation. Heavy metal acetyUdes, particularly cuprous acetyUde, were found to cataly2e the addition of acetylene to aldehydes. Although ethynylation of many aldehydes has been described (10), only formaldehyde has been catalyticaHy ethynylated on a commercial scale. Copper acetjlide is not effective as catalyst for ethynylation of ketones. For these, and for higher aldehydes, alkaline promoters have been used. 

A two-carbon ring expansion of cyclic ketones was achieved by the addition of acetylenic esters and diesters to the enamine derivatives of the ketones, and reported almost simultaneously from several laboratories (337-343). The intermediate bicyclic adduct could be isolated in some cases. 

Sakakura and coworkers reported the catalytic action of iron(lll) triflate for the addition of acetylenes to olefins without the need for an inert gas atmosphere (Scheme 30) [43]. 

The primary hydroxymethyl group of lupinine 6 was studied with regard to the addition of acetylene in basic systems to give the vinylated product 111 (Equation 7). As compared with aliphatic amino alcohols, the vinylation of lupinine required more drastic conditions <2004RCB242>. 

Dimethylethynyl carbinol has usually been prepared by the addition of acetylene to the sodium derivative of acetone,3 4 5 6 7>8 but potassium metal9 and sodium ethoxide10 have also been used. The above method is based upon that described by Sung Wou-seng.3 A more recent method uses potassium hydroxide, calcium carbide, and acetone.11... 

The 7-azaquadricyclane (77), like its precursor (12), shows evidence in the NMR spectrum of restricted rotation about the N-CO bond. All the 7-heteroquadricyclanes, 76-79, are thermolabile, and they rearrange very readily to the corresponding azepines (80) or oxepin (81). (In another instance the 7-oxabicyclo[4.1.0] valence-bond tautomer was obtained instead. ) In appropriate conditions the addition of acetylenic esters (methyl propiolate and dimethyl acetylene-dicarboxylate) competes successfully with the isomerization and gives the ca o-tricyclic adducts 82 or 83. " °... 

Compounds with Metal—Metal Bonds. Additions of compounds with metal-metal bonds to acetylenes are rare. Perhaps the addition of acetylenes to cobalt octacarbonyl (29) should be considered an insertion reaction even though the metal-metal bond is not broken since the acetylene finally is bonded to both metal atoms. 

The only reaction in which a chromene appears to react as a heterodiene and not like a styrene is the addition of acetylene dicarboxylate to lapachenol, followed by thermal decomposition of the adduct (Scheme 10).254 The ready photodimerization of a chromene has been reported recently. 255 (See also cannabicyclol, Section V,B.)... 

The addition of acetylenic esters to anilinoimidazolines (197) gives the imidazopyrimidines 198.155 A thorough investigation of the addition... 

Almost simultaneously, papers by Schmid et al.509 and by Gotthardt and Reiter510 appeared on the photoaddition of DMAD to sydnones the last authors also used propiolic and phenylpropiolic esters. Ohta et al.511 showed that similar reactions could be carried out with 3-alkyl-4-phenylsydnones, and other papers on the addition of acetylenic esters to sydnones have appeared.512-514... 

Heavy metal acetylides, particularly cuprous acetylide (CuC CH), catalyze the addition of acetylene (HC=CH) to aldehydes (RCH=0). 

The reactions (21) and (22) are particularly important. The first one leads to the main products. The second one emphasizes the formation of acetylene, further involved in the formation of other impurities, such as benzene and vinyl-acetylene. The third and the fourth reactions explain the formation of light unsaturated hydrocarbons. In the presence of free radicals they may produce a variety of higher molecular species, some unsaturated as butadiene (reaction (25)) and chloroprene (reaction (26)). The chloroprene, formed by the addition of acetylene to vinyl-chloride, is highly undesired. 

The work is based on the idea of W. Reppe of applying the acetylene chemistry developed by him to the synthesis of terpenes. The 2-methylbutyn-2-ol (40, see page 14) formed by the addition of acetylene to acetone (39) was intended, as the C5 building block, as the starting point for terpene syntheses. A C5 building block appeared to be small enough to ensure the required flexibility for terpenoid vitamins and carotenoids and the extensive area of terpenoid flavors and fragrances. 

Consiglio and Morandini and co-workers (67) have investigated the stereochemistry involved in the addition of acetylenes to chiral ruthenium complexes. Reaction of propyne with the separated epimer of the chiral ruthenium phosphine complex 34 at room temperature results in the chemo- and stereospecific formation of the respective propylidene complex 64. An X-ray structure of the product (64) proves that the reaction proceeds with retention of configuration at the ruthenium center. The identical reaction utilizing the epimer with the opposite configuration at ruthenium (35) also proceeded with retention of configuration at the metal center, proving that the stereospecificity of the reaction in not under thermodynamic control [Eq. (62)]. 

Tertiary unsaturated alcohols, obtained by the addition of acetylenic or vinylic Grignard reagents to polyhaloacetoncs, react mainly in an S i -type reaction to yield rearranged products... 

Reactions of alkynes with benzimidazole are also electrophilic processes. Thus, 1-vinyl-benzimidazole and 1,3-divinylbenzimidazolinone are formed by the addition of acetylene in aqueous dioxane at 160 and 200 °C to benzimidazole and benzimidazolinone, respectively. There is rather more complication involved in the reactions of such alkynes as dimethyl-acetylene dicarboxylate (DMAD) (see Section 4.07.1.8) with not only products of Af-alkylation, but also the formation of tricyclic products involved. 

Both conditions are fulfilled for the addition of acetylene leading to 6 and for the addition of formaldehyde leading to 8. Further experimental work is necessary to prove the statements of this theoretical investigation. 

An attractive alternative procedure for the preparation of 1-ethynylcyclohcxanol which gives yields of 80-90% employs the potassium salt of ferf.-amyl alcohol to effect the addition of acetylene to cyclohexanone. This condensation has been brought about by a suspension of sodium amide in ether 7.8.9.10.11 and by potassium hydroxide in ether. 1-Ethynylcylclohexanol has also been prepared by the action of acetylene on the sodium enolate of cyclohexanone. The procedure described here is essentially that of Campbell, Campbell, and Kby. ... 

Under the influence of the angular methyl group the addition of acetylene occurs from the a-side, giving the opposite configuration at C-17 to that required for the corticosteroids, but the rearrangement of the diastereomeric methanol adducts of the derived allenic sulfoxide is also forced to proceed at the a-side, leading finally to the correct configuration. The elaboration of the required side chain in (17) can easily be accomplished. 

In contrast to olefins, the addition of acetylenes to LCoD shows clear trans addition as in eq 26. 

Vitamin A synthesis. The addition of acetylene to methyl vinyl ketone is a key step in Isler s technical synthesis of vitamin A. The resulting carbinol (2) under... 

Methylhept-2-en-6-one, usually referred to simply as methylhep-tenone, is a useful synthon for the total synthesis of terpenes. One early synthesis of this intermediate employed the Carroll reaction, the substrate for which is prepared by the addition of acetylene to acetone and subsequent partial hydrogenation to 2-methylbut-3-en-2-ol, as shown in Scheme 4.5. Addition of acetylene to methylheptenone gives dehydrolinalool, which can be hydrogenated to linalool using a Lindlar catalyst. 

Silaaromatics also are excellent partners in Diels-Alder cycloadditions, acting either as dienes or as dienophiles. Thus, the addition of acetylene and bis(trifluoromethyl)acetylene to silabenzenes is one of the best documented trapping procedures290,314,320,326,327. This reaction has been reported to fail only in the case of the sterically quite hindered 1,4-di-tm-butyl-1 -silabenzene312. 

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