Synthesis of Heterocyclic Systems by the Reaction of Zwitterionic Compounds with Isocyanates and Thiophosgene

Abstract

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

Synthesis of Saturated Imidazolidin[1,5-a]- and Thiazolidin[3,4-a]perhydroquinoxalin-4-one and Imidazolidin[1,5-a]piperazin-4-one Derivatives. Ring Contraction of Perhydroquinoxalin-4-one to Perhydrobenzimidazolin-2-one

“…14 Studies on the synthesis of fully saturated heterocyclic systems have been our subject of interest. 15,16 In previous work 17 we have described a novel ring expansion of 1,3-diazines to 1,4-diazines resulting in piperazin-3-one and perhydroquinoxalin-3-one derivatives (Scheme 1).…”

New Tricyclic Ring Systems of Fused 1,4-Diazepines

“…7 A rare O-bridged azepine skeleton is present in molecules of interesting zoanthamine alkaloids such as zoanthamine, 8 which have been isolated from the polyps of marine zoanthis. Our recent work has focused on synthetic applications of zwitterionic compounds 2-10 [9][10][11][12] (Figure 1), which we obtained as a result of an unusual rearrangement during reactions of 2-anilino-2methoxy-3-oxothiobutanoic acid anilide derivatives 1 with various aliphatic 1,3-and 1,4-diamines. Scheme 1 shows an example of the reaction.…”

“…This mechanism and complexity of the reactions is discussed more extensively in our previous work. 9 We have already found [10][11][12] that the compounds 2-10 are important synthetic precursors, capable of reacting both with electrophiles and nucleophiles. The reactions led to novel, highly functionalised, saturated, or partially saturated heterocyclic systems.…”

Synthesis, oxidation and dehydrogenation of cyclicN,O- andN,S-Acetals. II . Transformation ofN,S-acetals: 3-Acylbenzothiazolines and -thiazolidines

“…Treatment with ceric salts transforms thiophenols and aromatic nitriles into 2-arylbenzothiazoles [23], sulfides into sulfoxides [24]. Treatment of 7-phenylimino-1,4-thiazepine-3-ones or 1,4-thiazepine-3,7-diones with equimolar amount of CAN has been reported to give 4-oxothiazolidine-2-acetic acid derivatives via ring contraction [25]. CAN, with the ability to effect selective one-electron oxidation of a susceptible heteroatom, transforms cephalosporins via subsequent formation of a sulfur-stabilized carbocation into 2-alkoxycephalosporins with intact cephem skeleton [26] or in a lower yield, with ring-contraction and subsequent cleavage of the lactam ring, into thiazole derivatives [27].…”