Cyclization with diketene

IV-Substituted derivatives have been prepared by the reaction of IV-methylhydroxylamine with phenylpropiolic esters or acid chlorides (71CPB1389), the cyclization of A"-substituted /3-ketohydroxamic acids or the reaction of phenylhydroxylamine with diketene (Scheme 150) 63GEP1146494). 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

Aliquat is an efficient catalyst for the acetoacetylation of amines by diketene. The initially formed amides react with an excess of the diketene to form, after cyclization of the secondary product, 1-substituted 3-acetyl-4-hydroxy-6-methylpyrid-2-ones [39]. Amides react under similar conditions with diketene to form A-acyl aceto-acetamides, which react further with a second molecule of diketene to yield, after cleavage of the A-acyl group, 3-acetyl-4-hydroxy-6-methylpyrid-2-one [39]. 

Acetyluracil — Ethyl 2-hydroxy-4-methyl-5-pyrimidinecarboxylate (XXXVI), which is prepared by the cyclization of the ureidomethylene derivative of aceto-acetic ester, can be caused to rearrange into 5-acetyluracil (XXXVII) in dilute alkali [304]. Compound (XXXVII) can also be prepared from diketene and ethyl carbamate, followed by treatment with ethyl orthoformate and cyclization with ammonia [305]. 

The second method of forming the oxazin-3-one ring is illustrated by reaction of 363 with diketene 364 followed by diazo exchange, base hydrolysis, and Lewis acid-catalyzed cyclization to give 365 as shown in Scheme 43. This method has been used in fewer reports <1983JOC2675, 1983EPP80117, 1984USP4431167>. 

Diketene is of course a masked form of acetoacetic ester, and as such reacts in much the expected manner with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines, and phenols, for example, give acetoacetanilides and aryl acetoacetates the latter can be cyclized in excellent yield to coumarins while reaction of the former with excess of diketene followed by cyclization gives dioxopyridines (e.g. equation 164). Amidines, ureas, thioureas, S- alkylthioureas and carbodiimides also react with diketene to give pyrimidines e.g. equation 165), although in the case of amidines, S- alkylthioureas and carbodiimides the initially formed products are 1,3-oxazines which are converted into pyrimidines on subsequent treatment with acid or base. 

Reaction of 3-(5-acetoxyhexyl)-6-amino-l-methyluracil with diketene in boiling dichloroethane gave the cyclized pyrido[2,3-,71pyrimidine-2,4,5-trione 501 <2002W02002094824>. Also, reaction of 6-amino-1-phenyluracil with methoxyvinyl cyanide gave 7-amino-tetrahydropyrido[2,3-,7]pyrimidinedione 502 <2001EPP1145716>. The cyano... 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

In another cyclization procedure for the 1,5-benzodiazodne system, the nitriles (296) are converted to the aminodihydrodiazocines (297) (79CPB2589). Attack of nucleophiles on (297) occurs at the N-5—C-6 bond to give the 3,4,5,6-tetrahydrodiazodnes (298) with NaBH4 and the jS-aminoethylquinazolines (301) on hydrolysis. The diazocines (297) behave as typical amidines. Oxidation leads to the amidoximes (300) which on hydrolysis are converted to 2,1-benzisoxazoles (302), and reaction with diketene leads to the fused pyrimidinones (299 and l-methyl-3-one isomer) (79CPB2927). 

Aryl acetoacetates, which may be obtained by the reaction of phenols with diketene, are cyclized on treatment with sulfuric acid (54JCS854). The yields of coumarins are similar to those obtained by a Pechmann reaction on the phenol. 

When diethyl malonate is the diketone component, the ester (135) is first formed, which then cyclizes to the expected (136). Reaction of (131) with diketene gives a mixture of (137) and (138), the latter on acid cyclization also yields (134). This rearrangement is by a 1,3-shift of the acetoacetyl group to give the transient imine followed by cyclization. Similar rearrangements are known. Compound (139), the 7-one isomer of (134), is obtained from the reaction of (131) with a-bromocrotonic acid (76JHC291). 

Furthermore, 6-aminouracils are attacked by oxalyl chloride, diketene, and chlorocarbonylsulfenyl chloride at C-5, followed by cyclization with the amino group to give pyrrolo[2,3-[Pg.153]

AT-Iminopyridines (327) react with diketene to give pyrazolo[l,5-a]pyridines (328) and (329) as shown in Scheme 94. Methyl iodide and sodium ethoxide convert (328) into a mixture of its N- (329) and O-methyl (330) derivatives (75CPB452). Similar cyclizations where ester and nitrile groups stabilize the intermediate carbanion are known (78BCJ251). 

Nitromethylideneimidazolidines (42.14) [synthesized from l-nitro-2,2-bis(methylthio)ethene and ethyienediamines] react at room temperature with diketene (reviews [116, 2018]) to form a new fused pyridinone ring [3816]. The readily available chalcones may be cyclized in hot mineral acid to form a fused pyran-4-one ring in moderate yield [3517]. 

Atnino groups are converted into pyrazole rings on heating the compound with a methyl ketone under acidic conditions an intermediate imine may be involved. 1-Aminopyridinium iodide reacts with diketene to give the aceto-acetylimino ylide which cyclizes under the influence of a base. 

Reaction of 1 with diketene 404 in the presence of sodium hydroxide in tetrahydrofuran gave 2-acetoacetyl dimedone 405. Cyclization of which to the benzopyran-4,5-dione 406 was performed with acid (73CPB1840). 

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