Ketones in liquid ammonia

In contrasi to many acetylenes RCsCH, chloroacetylene can be successfully coupled with ketones in liquid ammonia via the lithium compound [80,85], The excellent yield in the reaction with acetone indicates that practically no formation of enolate occurs. Similar good results have been obtained with lithiated ethynyl thioethers, (LiCsCSR), lithiated enyne thioethers, (LiCsCCH=CHSR), lithiated 1,3-diynes (RC=CC=CLi), and lithiated aiylacetylenes (LiCsCAryl)[2], A possible explanation for the small extent of enolization of the ketone is that all these acetylides are less basic due to some stabilization of the anion. 

MIGNONAC REACTION. Formation of amines by catalytic hydrogenation of aldehydes and ketones in liquid ammonia and absolute ethanol in [he presence of a nickel catalyst. 

The synthesis of indoles by the photoinduced substitution reaction of o-haloanilines (22) with carbanions derived from aliphatic ketones in liquid ammonia is an important example of the SRN1 reaction followed by a spontaneous ring closure in the reaction media in moderate to excellent yield (53%-100%) [1]. Although the enolate anions of aromatic ketones do not react in liquid ammonia with 22, they will cyclize to indoles in DM SO under photoinitiation (Scheme 10.44) [60, 61]. 

Such a mediator was successfully used [163] to obtain 2,5-dihydro-l//-imidazoles from ketones in liquid ammonia. 

Reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia exhibit characteristics consistent with a radical chain mechanism for substitution (8UOC294). 

Methylpyrazine reacts with sodamide in liquid ammonia to generate the anion, which may be alkylated to give higher alkylpyrazines (Scheme 10) (61JOC3379). The alkylpyrazines have found extensive use as fiavouring and aroma agents (see Section 2.14.4). Condensation reactions with esters, aldehydes and ketones are common, e.g. methyl benzoate yields phenacylpyrazine in 95% yield, and reactions of this type are summarized in Scheme 11. 

BIRCH hOCKEL - BENKESER Reduction Reduction ol aromatics, unsaturated ketones coniugated dienes by alkali metals in liquid ammonia or amines... 

A more fundamental issue than that of adventitious proton donors is the intrinsic stability of ketone enolate salts in liquid ammonia. Even... 

Reaction of the 17-keto compound (54) with potassium acetylide in liquid ammonia gives the 17a-ethynylandrost-5-ene-3) ,I7)5-dioI (55). ° Similar results have been obtained with A-ring aromatic 17-ketones. ... 

Ethynylation of the totally synthetic racemic 18-methyl-17-ketone (63) with acetylene and potassium t-butoxide in t-butanol-toluene or with alkali metal acetylide in liquid ammonia gives a low yield of rac-18-methyl-17a-ethynyl-3-methoxyestra-l,3,5(10)-trien-17/ -ol (64). 

The preparation of 17j -hydroxy-4a-methyl-5a-androstan-3-one (3) which cannot be obtained by direct alkylation or via formyl or oxalyl ketones was achieved by Schaub in 40% yield by the Stork " alkylation procedure. As discussed in the introduction this method proceeds by trapping the A -enolate (2), obtained from (1) and lithium in liquid ammonia, with methyl iodide. 

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.)... 

The largest industrial use of LiC2H is in the production of vitamin A, where it effects ethynyl-ation of methyl vinyl ketone to produce a key tertiary carbinol intermediate. The acetylides and dicarbides of the other alkali metals are prepared similarly. It is not always necessary to prepare this type of compound in liquid ammonia and, indeed, further substitution to give the bright red perlithiopropyne Li4C3 can be effected in hexane under reflux ... 

Methylation of the ketone occurs from the loss crowded underside to give enone (36) which is reduced to saturated ketone (37) by lithium in liquid ammonia. 

More convenient synthetic access to 15 is provided by the sequence in Figure 13 (68). Alkylation of the potassium salt of 2,6-dimethoxy-1,4-cyclohexadiene with 2-(2-naphthyl)ethy1 bromide in liquid ammonia followed by mild acidic hydrolysis generated the diketone (16). Cyclization of 16 in polyphosphoric acid took place smoothly in the desired direction to afford the partially saturated ketone which underwent dehydrogenation with DDQ to 15. 

The bimolecular reduction of ketones to pinacols by magnesium may involve ketyls as intermediates, the bivalence of magnesium favoring the bimolecular reduction product. Ketyl formation with sodium in liquid ammonia eventually leads to the reduction of the ketone to the alcohol. The corresponding pinacol is also cleaved to the alcohol under the same conditions.128... 

Simple synthesis of ( )-17-epiyohimbol (73) has been reported by Mori et al. (214). yV-Benzyloctahydroindolo[2,3-a]quinolizinone (126), prepared according to the procedure of Novdk and Szdntay (97) was coverted to the corresponding pyrrolidine enamine, which was treated with methyl vinyl ketone to give N-benzylyohimbenone (379). Reduction of 379 with sodium in liquid ammonia... 

The use of lithium in liquid ammonia to reduce enones is a well-known, well-established procedure which has seen widespread use. The nucleophilic character of the -carbon is clear, and has been demonstrated in many ways. For example, reduction of enone 253 leads to displacement of tosylate and formation of the tricyclic ketone 254 [68,69]. It is interesting to note that the yield for formation of 254 is a function of the nature of the reducing agent. For example, using Li/NH3, a 45% yield is obtained, while with lithium dimethylcuprate, it is 96% [70], and via cathodic reduction, 98%. 

Similar stereoselectivity was noticed in reductions of ketones by alkali metals in liquid ammonia and alcohols. 4-rerr-Butylcyclohexanone gave almost exclusively the more stable equatorial alcohol, norcamphor 68-91% of the less stable e cfo-norborneol, and camphor a mixture of bomeol and isoborneol [860],... 

Electron-transfer initiation from other radical-anions, such as those formed by reaction of sodium with nonenolizable ketones, azomthines, nitriles, azo and azoxy compounds, has also been studied. In addition to radical-anions, initiation by electron transfer has been observed when one uses certain alkali metals in liquid ammonia. Polymerizations initiated by alkali metals in liquid ammonia proceed by two different mechanisms. In some systems, such as the polymerizations of styrene and methacrylonitrile by potassium, the initiation is due to amide ion formed in the system [Overberger et al., I960]. Such polymerizations are analogous to those initiated by alkali amides. Polymerization in other systems cannot be due to amide ion. Thus, polymerization of methacrylonitrile by lithium in liquid ammonia proceeds at a much faster rate than that initiated by lithium amide in liquid ammonia [Overberger et al., 1959]. The mechanism of polymerization is considered to involve the formation of a solvated electron ... 

Reaction of o-iodobenzenesulfonamide 265 with the potassium enolate of ketones 266 in liquid ammonia under photochemical conditions affords 1,2-benzothiazine 1,1-dioxides 267 in excellent yield (Scheme 37) <2005JOC9147>. While a variety of other ketone substrates have been investigated for this reaction, those containing /3-hydrogens afford significant amounts of benzenesulfonamide by dehalogenation of the starting material 265. 

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