Hydrolysis with acetylides

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

Hydrolysis with mild acid leads to selective reversal of the silyl cyanohydrin formation, thus revealing the ketone at C17. Condensation of that function with lithium acetylide proceeds as in all cases noted earlier to give the 17a-ethynyl-17/3-hydroxy intermediate 31-2 (Scheme 4.31). Treatment of that intermediate with acid then leads to hydrolysis of the ketal at position 3. The transient intermediate hydroxy ketone quickly loses water so as to form an olefin at C4 and thus mifepristone (31-3). 

From an investigation of various Michael acceptors, it has emerged that ethoxymethylidene malonates are suitable for addition-elimination reactions with acetylides to give diacids (426) after hydrolysis and elimination. Upon heating in a-dichlorobenzene, these acids cyclise to give ylidenebutenolides (427)Chromium carbonyl complexes of acetylenes have been used to prepare 2-methoxyfurans and... 

Treatment of dimethylketene with ethoxyacetylene and related compounds affords 3>ethoxycydobutenones. Hydrolysis with acid then leads to cyclobutane-1,3-diones, the solution structures of which have been studied by n.m.r. In contrast diphenylketene reacts with the silylynamine (138) to give the butenyne (139). The reaction between nitrones and copper acetylides in pyridine gives rise to cis- and /raw-azetidinones. Deuteriation and isomerization studies indicate that... 

Both chlorines of 1,1-dichloroethylene (340) react stepwise with different terminal alkynes to form the unsymmetrical enediyne 341 [250]. The coupling of the dichloroimine 342 with tin acetylide followed by hydrolysis affords the dialkynyl ketone 343[2511. The phenylthioimidoyl chloride 344 undergoes stepwise reactions with two different tin acetylides to give the dialkynylimine 345[252],... 

The interaction of (10) with vinylmagnesiiim chloride yields, after hydrolysis of the ketal group, 46% of the 3a-vinyl-l7-ketone (11b) and 7% of the 3j5-vinyl-17-ketone (12b). Ethynylation of (10) with potassium acetylide in dimethylformamide or with acetylene and potassium t-amyloxide in t-amyl alcohol-ether gives only the 3a-ethynyl derivative (11c) in 63% and 74% yields, respectively. ... 

Oppenauer oxidation of the enol ether (34) affords the corresponding 17 ketone (37) (the enol ether is stable to the basic oxidation conditions). This ketone affords the corresponding 17a-ethynyl compound on reaction with metal acetylides. Hydrolysis of the enol ether under mild conditions leads directly... 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

Oppenauer oxidation of the enol ether (34) affords the corresponding 17 ketone (37) (the enol ether is stable to the basic oxidation conditions). This ketone affords the corresponding 17a-ethynyl compound on reaction with metal acetylides. Hydrolysis of the enol ether under mild conditions leads directly to ethynodrel (39), an orally active progestin. This is the progestational component of the first oral contraceptive to be offered for sale. Treatment of the ethynyl enol ether with strong acid leads to yet another oral progestin employed as a contraceptive, norethindrone (40). ° In practice these and all other so-called combination contraceptives are mixtures of 1-2% mestranol... 

The compound in which the 3-keto group is reduced to a hydrocarbon interestingly still acts as an orally active progestin. The preparation of this compound starts with the hydrolysis of dihydrobenzene (13-2) to afford 19-nortestosterone (15-1). Reaction with ethane-1,2-thiol in the presence of catalytic acid leads to the cyclic thioacetal (15-2). Treatment of this intermediate with Raney nickel in the presence of alcohol leads to the reduced desulfurized derivative (15-3). The alcohol at 17 is then oxidized by any of several methods, such as chromic acid in acetone (Jones reagent), and the resulting ketone (15-4) treated with hthium acetylide. There is thus obtained the progestin lynestrol (15-5) [18]. 

Use of chiral cyclopropylethynyllithium derivatives permits the elegant selective synthesis of labeled chiral vinylcyclopropanes, for stereochemical studies of the thermal vinyl cyclopropane-cyclopentene rearrangement237. Thus, reductive elimination of (1 S,trans)-(2,2-dibromoethenyl)-l-methylcyclopropane with BuLi in pentane, followed by hydrolysis of the lithium acetylide, afforded (15,/ram)-2-ethynylmethylcyclopropane (equation 157). 

Reaction of aliphatic aldehydes with alkali acetylides in liquid ammonia gives the carbinols in very small amounts, even when the aldehyde is added to a strongly cooled solution of lithium acetylide. The predominant reaction presumably is formation of the enolate and the aldol condensation product As shown on p. 21, a suspension of LiOCH in THF can be obtained by gradually replacing the ammonia of an ammoniacal solution of the acetylide by THF. The lithium acetylide obtained in this way probably thanks its stability to the complexed ammonia. In the procedure described below, butanal is added to the suspension to give the acetylenic carbinol in a reasonable yield. Since this compound is rather volatile, it is essential to remove the greater part of the THF, before the hydrolysis is carried out. The main solvent which then has to be removed in the isolation procedure is the diethyl ether, used for the extractions. During the addition of the aldehyde, acetylene is introduced to suppress the formation of the diol RCH(OH)C=CCH(OH)R. 

For the preparation of the second component 421 of the cockroach pheromone Burgsthaler et al. 228) also used a Wittig reaction. Lithium acetylide is alkylated with the two halides 414 and 416 and the resulting alkynyl bromide 417 converted into the phosphonium salt. Olefination of the corresponding ylide with 9-bromo-2-nonanone 418 gives a (Z)/( )-mixture of olefin 419 which is converted into the pheromone 3,ll-dimethyl-29-hydroxynonacosan-2-one 421 by aeetoaeetate synthesis, hydrogenation, hydrolysis, and decarboxylation 228) (Scheme 73). 

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