1-Alkyl -ones, reaction with ammonia

There has been little systematic study of the chemistry of 1,4-oxazepines. Vigorous acid hydrolysis cleaves the amide linkage in (369 R1=Ph, R2 = H) and recyclization gives 2-o-hydroxyphenyl-5-phenyloxazoline and l,2,3,4-tetrahydro-l,8-dihydroxy-3-phenyl-isoquinoline. The l,4-benzoxazepin-5-one (353) can be alkylated at N but on treatment with triethyloxonium fluoroborate it is converted to 5-ethoxy-3-phenyl-l,4-benzoxazepine — one of the very few examples of a fully unsaturated 1,4-oxazepine ring. This product is isomerized to l-ethoxy-4-hydroxy-3-phenylisoquinoline when boiled in methanol. The 4,l-benzoxazepine-2,5-diones (348) are converted to quinazolines by reaction with ammonia. The dihydro-l,4-oxazepin-5-one (343) can be acetylated at nitrogen and bromi-nated at the 6-position. 

Carboxylic acid dianions have also been alkylated by reaction with aziridines to give novel y-amino substituted acids in good yields508. Methoxybenzoic acids have also been alkylated in a reductive process by reaction with lithium in ammonia followed by treatment with an alkyl halide. The product formed in this one-pot reaction is an alkylated cyclohexa-2,5-diene carboxylic acid507. 

Aromatic aldehydes and ketones can be alkylated and reduced in one reaction vessel by treatment with an alkyl- or aryllithium, followed by lithium and ammonia and then by ammonium chloride." ... 

Because silylation with HMDS 2/TCS 14 in acetonitrile at ambient temperature converts the unreactive a-chloroketone moiety of 743 into an /Z-mixture of reactive alkyl 4-chloro-3-trimethylsilyloxycrotonates 746a, b [230, 231] which can be isolated and distilled, if humidity is excluded, silylation of 743a, b in the presence of ami dine salts such as 745 gives the desired ethyl or methyl imidazole(4,5)-acetates 748a, b via IMz and 747b. The reaction of formamidine acetate with 746a,b affords 745 (with R=H) in up to 70% yield [232, 233] (Scheme 5.79). As side reactions one must, e.g., take into account the reaction of 746 with ammonia to give 755 which subsequently dimerizes to the pyrazine 756, as discussed in Section 5.5.3. 

So the reaction of an alkyl halide with NaSH or Na2S cannot usually be made to stop after one alkylation as the anion of the first product is at least as nucleophilic as HS or S2. This is obvious in reactions with Na2S. Less obviously with NaSH the first reaction 18 gives the thiol 19 but this is in equilibrium with RS- and a second displacement 20 gives the sulfide 21. We shall see shortly how to get round this problem. A more important example—the failure of the alkylation of ammonia to give a useful amine synthesis—has chapter 8 to itself. 

This strategy chapter is rather different. We shall look at one class of starting material—alkynes or acetylenes—and see what special jobs they can do in synthesis. In particular, we shall see how they can solve some problems we have already met. Acetylene itself 3 is readily available and its first important property is that protons on triple bonds are much more acidic than most CH protons. Acetylene forms a genuine anion 4 with sodium in liquid ammonia, a lithium derivative 1 with BuLi and a Grignard reagent 2 by reaction with a simple alkyl Grignard such as EtMgX. 

The reaction of the salt 308 with alkyl halides in base gave the corresponding 2-alkylthiothieno[3,4-d]pyrimidin-4(3//)-ones 369. Heating the latter with ammonia or amines afforded 2-amino(or substituted amino)thieno[3,4-d]pyrimidin-4(3//)-ones 370 (90EUP404356). When 2-methylthiothieno[3,4-d]pyrimidin-4(3//)-one 360 was heated with o-tolu-idine at 200°C, displacement of the 2-methylthio group afforded compound 372 (91MIP1). 

Cyclopropen-1-yl sodium derivatives are also readily prepared. Thus reaction of cyclopropene with one equivalent of sodium amide in liquid ammonia leads to 1-sodiocyclopropene which is alkylated by haloalkanes 77,78 reacts with ketones to produce tertiary alcohols and opens epoxides to produce 2-cyclopropenyl-ethanols in moderate to good yields79). Moreover, on reaction with two equivalents of base followed by haloalkane, 1,2-dialkylated species are obtained sequential reactions can also be used to produce unsymmetrically substituted cyclopropenes78). Reaction with a deficiency of sodium amide can also cause addition of the cyclopro-penyl anion to unreacted cyclopropene, leading to products derived from the 2-cyclo-propylcydopropen-l-yl anion and to 1,2-dicyclopropylcyclopropene 77). 

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