0-halogenoketones

A variation of Hantzsch s synthesis, using thioureas in conjunction with a-diazoketones in place of a-halogenoketones, has proved to be generally applicable. In this manner, King and MUler (310) obtained 2-amino-4-phenylthiazole in 67% yield. A wide range of 4-substituted 2-aIkyl (or aryl) aminothiazoles and 2-arylimino-3,4-diarylthiazolines have been prepared by Hampel and Muller (627, 665, 666). 

The comparatively ready accessibility of selenocarboxamides has encouraged the use of this procedure for the synthesis of selenazoles (1889LA(250)294). Reaction of the a-chloro-carbonyl compound (73) with the selenocarboxamide (74) provided a ready synthesis of a variety of substituted selenazoles (75). Useful variations of this general procedure are described in detail in Chapter 4.20, and particularly attractive is the reaction of hydrogen selenide with a mixture of a nitrile and the a-halogenoketone to afford the selenazole (48YZ191, 79S66). 

Amidines and related systems such as guanidines react with a-halogenoketones to form imidazoles. a-Hydroxyketones also take part in this reaction to form imidazoles, and a variety of substituents can be introduced into the imidazole nucleus by these procedures. Reaction of the a-halogenoketone (73) with an alkyl- or aryl-substituted carboxamidine (76) readily gave the imidazole (77) (01CB637, 48JCS1960). Variation of the reaction components that successfully take part in this reaction process is described in Chapter 4.08. 

Oxazoles are also obtained by the reaction of a-halogenoketones (78) with primary amides (the Bliimlein-Lewy synthesis), and this method is particularly appropriate for oxazoles containing one or more aryl groups as in (79). Formamide may also be used in this process, resulting in a free 2-position in the oxazole, and when a urea derivative (80) is used, 2-aminooxazoles (81) are formed (80ZOR2185, 78IJC(B)1030, 78JIC264). Numerous applications of these procedures are described in Chapter 4.18. 

Scheme 3 illustrates two general annulation procedures, one with the a-halogenoketone moiety incorporated in a cyclic system leading to C—C fused systems. The other, with the heteroatoms already incorporated in a heterocycle, results in a product with a heteroatom at a fusion point. 

The latter approach is illustrated by the conversion of the 2-thiazolethione (90) into the thiazolo[2,3-6]thiazolylium salt (92) by reaction with the a-halogenoketone. The intermediate (91) may be isolated, and strong acid was required to effect the final cyclization (77HC(30-1)1). A wide variety of [5,5] fused systems are prepared in this way, and variations of this approach are discussed in Chapter 4.36. 

In contrast to the above, the reaction of a heterocyclic thione with an a-halogenoketone (Scheme 3) has been widely exploited as a route to [5,6] ring-fused systems with a heteroatom at a ring fusion point. 

The difficulties encountered in the synthesis of 2-alkyl- and 2-aryl-substituted selenazoles lie principally in the preparation of the corresponding selenoamides. In this respect, a method is worthy of note in which the use of selenoamides is dispensed with. For this, a nitrile, a hydrogen selenide, and an a-halogenoketone are reacted together in the presence of a condensation catalyst. Phosphorus oxychloride, alone or mixed with zinc chloride or phosphorus trichloride, is specially suitable. The yields of the corresponding 2-alkylseIenazoles are up to a maximum of 25%,... 

By condensation of selenourea with dibromodiacetyl as the -halogenoketone. Backer and Bos were able to prepare 2,2 -diamino-4,4 -biselenazole (3). 

Methylphenyl-n-propylphosphine reacts with halogenoketones to give ketophosphonium salts (36) with retention of configuration at phos-... 

Some systems have been obtained by a modification of the above procedure in which propargyl bromide replaces the cr-halogenoketone. Table II summarizes the systems that have been prepared by the Tschitschibabin reaction, together with the preparative route used. However, certain difficulties are encountered with this method. The syntheses of imidazo[l,2-6]-s-triazoles and imidazo[l,2-d]tetrazoles have been reported,20813 but repetition of this work more recently209 has cast doubt on these results. 5-Aminotetrazole was found to react with arylacyl bromides to give products shown to be AT-substituted tetrazoles 203 and not imidazol 1,2-rf]tetrazoles (204) as previously suggested.20813... 

Generally speaking, 2-aminothiazoles, -oxazoles, and N-substituted imidazoles react with or-halogenoketones more easily than NH compounds, though 2-amino-4,5-dimethyloxazole and 3-amino-l-methyl-4-phenylpyrazole are reported214 not to undergo the Tschitschibabin reaction. 

Some of the simple condensations of a-ketoesters with a-halogenoketones suffer from the disadvantage that mixtures of furans may result. Nakanishi used this reaction in condensing chloroacetaldehyde with ethyl acetoacetate in the presence of pyridine to give the known 2-methyl-3-furoate in 55% yield during the synthesis of an insecticide (70MI31200). 

The construction of the furan ring in a Feist-Benary type reaction starting from 4-hydroxy-6-methylpyran-2-one (66) has also proved to be useful for the synthesis of furo[3,2-c]pyridines (Scheme 14) (75JHC461, cf. 71BSF4041). Quite recently the synthesis of the hitherto unknown furo[3,2-c]pyridin-3-ols has been described (79LA371). 4-Hydroxypyridine-3-carboxylates (e.g. 69), which are available from diketene and /3-aminocrotonic esters, react with a-halogenoketones in the presence of potassium carbonate to give compounds of type 70. 

Water addition to the carbonyl group of aldehydes and ketones has been known for a long time. a-Halogenoketones react with water to form tetrahedral adducts (reaction 23). 

The condensation of an a-halogenoketone with ammonia yields both 2,5- and 2,6-disubstituted pyrazines via the dihydropyrazines [Eq. (3)]. For example, when ai-chloroacetophenone is heated with alcoholic ammonia, 2,5- and 2,6-diphenylpyrazines are formed in about equal amounts.121... 

Recently Zbiral and Stroh reported that treatment of a-azido-ketones (obtained generally by reaction of the a-halogenoketone with sodium azide) with triphenylphosphine is a convenient route to 2,5-disubstituted pyrazines (Scheme 5). Thus, 2,5-diphenyl-, 2,5-bis(4-methoxyphenyl)-, and 2,5-diisopropylpyrazine have been obtained in 75, 45, and 44% yield, respectively. The intermediate P-iV-ylide undergoes intermolecular condensation to give a 2,5-dihydropyrazine which is subsequently aromatized.122... 

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