An unusual rearrangement following cyclization of 2-anilino-2-ethoxy-3-oxothiobutanoic acid with aliphatic 1,3- as well as 1,4-diamine leads to zwitterionic derivatives of 2-hydroxypropanoic acid. Moreover, with aromatic 1,2-diamines, fused heterocyclic systems such as pteridine, quinoxaline, and pyrido[2,3-b]pyrazine are obtained.
Fully saturated piperazin-3-one and quinoxalin-3-one derivatives were prepared by reactions of 2-anilino-2-ethoxy-3-oxothiobutanoic acid anilide with aliphatic 1,2-diamines. An unusual ring expansion of the intermediate 1,3-diazines leads to 1,4-diazines. Moreover, quinoxalin-3-one derivatives from chiral trans-1,2-diaminocyclohexane were obtained with diastereoselectivity >95%.
New convenient methods for the synthesis of 1,2,3-thiadiazole, 1,3,4-thiadiazine, and 1,2,5-triazepine derivatives are reported. In the heterocyclization process, the reactivity of 1-thia-4-aza-1,3-butadiene system of syn-2-phenylhydrazono-3-oxothiobutanoic acid anilides was exploited.The structure and chemistry of the 1,2,3-thiadiazole system have been under active investigation for years. 1-3 Its derivatives are useful in the treatment of hyperproliferative disorders including tumor growth and angiogenesis, and lymphoproliferative symptoms. 4 Moreover, derivatives of this system are applied in the treatment and/or prevention of morbid states mediated by oxytocin, including premature labour and dysmenorhea. 5 The 1,2,3-thiadiazole moiety is crucial for the antibacterial activity of new carbapenems 6 as well as for the efficacy of some pesticides. 7 The biological activity of 1,2,5-triazepines 8 has received less attention than the corresponding benzofused system.Recently, we have reported 9,10 the synthesis of 1,3-and 1,4-diazines which used the C-2 disubstituted thioanilides of 3-oxobutanoic acid 1 (X = S) 11 in heterocyclization reactions with various diamines. We have found that good leaving groups at C-2 of compound 1 offer an entry to formation of six-and seven-membered rings by treatment with binucleophiles. The reaction includes the initial nucleophilic attack of the nitrogen atoms of aliphatic 1,3-or 1,4-diamines on C-2 of compounds 1, followed by a novel sigmatropic rearrangement. On the other hand, the reactions of 1 with aliphatic 1,2-diamines lead to 1,4-diazines by ring expansion of the intermediate 1, 3-diazines. 12 In order to develop synthetic applications of thioanilides 1a-c in closing heterocyclic rings we have transformed them into phenylhydrazones 2a-c by treatment with phenylhydrazine (Scheme 1). The nucleophilic attack of the amino group of phenylhydrazine took place exclusively on the C-2 position of 2-anilino-2-methoxy-3-oxothiobutanoic acid anilides 1a-c.In contrast, the reaction of 2-anilino-2-methoxy-3-oxobutanoic acid anilide 3a (X = O), under similar conditions, exclusively provided osazone 4a (Scheme 1).Compounds 2a-c can appear in two isomeric forms corresponding to Z or E configuration of the 1-thia-4-aza-1,3-butadiene system. In solution, spectral data confirm the structure of the molecules of 2a-c as shown in Scheme 1 as the unique reaction product. X-ray analysis of 2a was carried out to prove the configuration in the solid state and precisely determine the molecular geometry. 14 A perspective view of molecule of 2a with the crystallographic atom numbering is presented in Figure 1. The central framework of the molecule, consisting of heteroatoms (S1, O1, N1-N3) and carbon atoms C1-C4, is quite flat. None of these atoms deviates from the least-squares plane passing through the heteroatoms by more than 0.1 Scheme 1Downloaded by: Chinese University of Hong Kong. Copyrighted material.
S y n t h e s i s o f 3 , 4 -D i h y d r o -2 H -p y r i d o [ 1 , 2 -a ] [ 1 , 3 , 5 ] t r i a z i n -2 -o n e sAbstract: A convenient method leading to fused pyrido[1,2-a] [1,3,5]triazine-2-ones is described. It consists in a one-pot, two-step reaction of N-(2¢-pyridinyl)benzoylacetamide with nitrosobenzenes. On the other hand, N-(2¢-pyridinyl)acetoacetamide provides a C-2 condensation/addition product with nitrosobenzene. N-(2¢-Pyridinyl)benzoylthioacetamide and N-(2¢-pyridinyl)acetothioacetamide with nitrosobenzene undergo oxidative heterocyclisation leading to [1,2,4]thiadiazolo[2,3-a]pyridine derivatives.The interest in the pyrido[1,2-a][1,3,5]triazine system arises from its wide biological activity, 1,2 which comes from its antagonistic effect upon 5-HT 2 and 5-HT 2a serotonin receptors. Such influence can result in: mediating coronary blood flow, 1a decreasing mean arterial blood pressure, 1b and the anti-thrombotic effect 1c in mammals. Other disorders, for whose prophylactic or therapeutic treatment pyrido[1,2-a][1,3,5]triazine derivatives can be used, are those involving airway constriction in human or animals: asthma, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, 2 and various psychotic conditions including schizophrenia, depression, anorectic or bulimic eating disorders, and anxiety in humans. 2c Since 1952, when a possible approach to this system was mentioned for the first time, 3a several general methods of synthesis of pyrido[1,2-a][1,3,5]triazines have been invented, mostly leading to their oxo derivatives.Cyclodimerisation of iso(thio)cyanates leads to pyrido[1,2-a][1,3,5]triazine-2,4-di(thi)ones. 3b-d The other methods include: reaction of isocyanates 4a or active esters of imidodicarbonic 4b or carbonic 4c acid with 2-aminopyridine or other amidines and cyclisation of (thio)urea derivatives 3a or their reaction with isothiocyanate. 4d Pyrido[1,2-a][1,3,5]triazine-4-ones can be obtained from urea derivatives, 5a,b e.g. by their cyclisation, 5a or reaction of aryl isocyanates and unsymmetrical carbodiimides containing 2¢-pyridine ring. 5c,d There are only a few examples of the syntheses of pyrido[1,2-a][1,3,5]triazine-2-(thi)ones known. 3d,6
A variety of pyrrolo [3,4-b]hexahydro-1H-1,5-benzodiazepine derivatives have been prepared in a new one-pot reaction from thiophene-2,3-dione as well as pyrrolidinetrione derivatives and trans -(±)-1,2-diaminocyclohexane. The reactivity of 2,3-dicarbonyl fragment of thiophene-2,3-dione was exploited in the synthesis of fused quinoxaline systems.The pharmacological activity of diazepine derivatives 1 in conjunction with their structural variety has made this class of compounds a continuing target on which the utility of novel synthetic methodology is tested. It is known that benzodiazepine derivatives are the most frequently prescribed drugs for the pharmacotherapy of anxiety, epilepsy, convulsive states and emotional disorder. 2 In contrast to benzodiazepine based tranquilizers hexahydrobenzodiazepine derivatives have been selected as promising candidates for potential anticancer drugs 3 and as antagonists of arginine vasopressin. 4 We have been interested in the synthesis and application of polycarbonyl heterocyclic systems 5 as potential building-blocks for the construction of fused heterocyclic compounds. Recently we have described a very effective synthesis of thiophene-2,3-dione derivatives 6 3 based on the reaction of 3-aminovinylthioamides 2 with ethyl oxalyl chloride. Thophene-2,3-dione derivatives were used in the synthesis of fused heterocyclic system such as pyrrolo[3,2-c]pyridine. 6 Knoevenagel condensation of thiophene-2,3-dione derivatives with malononitrile resulted in the ring transformation of thiophene system followed by elimination of sulfur, leading to pyrrolo[3,2-c]pyridine derivatives. In continuation of these efforts we have investigated reactivity of thiophene-2,3-dione towards binucleophiles such as 1,2-diamines.In contrast to our earlier results a nucleophilic amino group of trans-1,2-diaminocyclohexane attacks preferentially the C-2 position of thiophene-2,3-dione 3 leading to the ring opening and transformation to pyrrolidine system. The simultaneous attack of the second amino group on C-6 position results in the transamination and formation of 1,5-diazepine ring (Scheme 1).A conclusion, that the reaction of thiophene-2,3-dione 3 with trans-1,2-diaminocyclohexane 7 provided 1,5-diazepine derivatives 5 (method A) was supported by the re- Scheme 1Downloaded by: University of Liverpool. Copyrighted material.
The reaction of various isocyanates or thiophosgene with zwitterionic pyrimidinylium and 1,3-diazepinylium derivatives has led to the formation of unusually substituted [1,3]oxazolo[3,4-a]pyrimidines and novel heterocyclic system such as [1,3]oxazolo[3,4-a][1,3]diazepine. Oxazolopyrimidine or 1,3-oxazolo[1,4]diazepine moieties are essential in many pharmacologically relevant compounds. Derivatives of 1,3-oxazolo[3,4-a]pyrimidine, such as 2,4-diaza-4-deoxypodophyllotoxin, show significant activity against vincristine-resitant P-388 leukemia, 1 whereas 1,3-oxazolo[3,2-c]pyrimidine derivatives have anti-inflammatory properties. 2 Biological activity of compounds based on the 1,3-oxazolo[3,2-a]pyrimidine moiety is considered to be very significant. 3 Moreover, some derivatives of this system have technical applications 4 in the chemistry of polymers. Some 1,3-oxazolo[3,4-d][1,4]diazepine derivatives have antibacterial activity 5-7 whereas in commercially available drugs, such as mexazolam or oxazolam, the 1,3-oxazolo[3,2-d][1,4]diazepine moiety is present. 8 In this regard, we have now synthesized a series of pharmacologically interesting systems: 1,3-oxazolo[3,4-a]pyrimidines and novel 1,3-oxazolo[3,4-a][1,3]diazepines.At the center of our investigation lie 2-anilino-2-methoxy-3-oxothiobutanoic acid anilides 1, which are readily prepared 9 from 3-oxothiobutanoic acid anilides by the one pot, tandem condensation-addition reaction with nitrosobenzene. The multifunctional compounds 1 have a high synthetic potential.In a recent paper 10 we have described the heterocyclization (at C2) of 2-anilino-2-ethoxy-3-oxothiobutanoic acid anilides 1 with aliphatic 1,3-and 1,4-diamines leading to novel zwitterionic compounds 2 and 3, 11 respectively. Good leaving groups at C2 of compounds 1 facilitate cyclization followed by a novel rearrangement of 3-oxothiobutanoic acid anilides 1 to 2-hydroxythiopropanoic acid zwitterionic derivatives 2 and 3 (Scheme 1). We now wish to report the application of zwitterionic compounds 2 and 3 in the synthesis of saturated fused heterocyclic systems. Treatment of compound 2 or 3 with 2 equivalents of phenyl isocyanate in toluene (100 °C) for 15 minutes furnished a mixture of compounds 4 or 5, respectively, 12 with an equivalent amount of N,N¢-diphenylurea (Scheme 1). Scheme 1 + + toluene / 75 °C toluene / 75 °C 1a Ar = C 6 H 5 1b Ar = C 6 H 4 Cl-p 2 a, b 3 a, b 4 a, b 5 a, b R = Ph, naphthyl, p-chlorophenyl, cyclohexyl
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