Recent advances in dibenzo[b,f][1,4]oxazepine synthesis

Introduction

Three isomeric forms of dibenzoxazepine systems are possible – dibenz[b,f][1,4]oxazepine (DBO) 1, dibenz[b,e][1,4]oxazepine 2, and dibenz[c,f][1,2]oxazepine 3 (Figure 1).

Figure 1

Isomeric forms of dibenzoxazepine systems.

Among tricyclic isomers 1–3, the DBO ring system 1 is of particular interest because it is found in many physiologically active compounds. Compounds containing chemotype 1 include antidepressants [1], analgesics [2], calcium channel antagonists [3], a histamine H₄ receptor agonist [4], a non-nucleoside HIV-1 reverse transcriptase inhibitor [5], and a lachrymatory agent [6]. This review provides synthetic chemists with an update on the progress in the synthesis of DBO derivatives.

Synthetic strategies to DBOs

In a report by Ghafarzadeh et al. [7], DBO derivatives 6 were synthesized in short reaction time in yields of 78–87% (Scheme 1). Substituted 2-chlorobenzaldehydes 4 were allowed to react with substituted 2-aminophenols 5 under basic conditions in a microwave oven. The simplicity of the reaction and a short reaction time make this method attractive from a practical standpoint.

Scheme 1

Microwave-induced formation of DBO derivatives 6.

Sang et al. [8] reported a protocol for the one-pot synthesis of indole/benzimidazole-fused DBOs 9 via copper catalysis (Scheme 2). The reaction involves a copper initiated C-N and C-O coupling of 2-halophenols 7 and 2-(2-halophenyl)-1H-indoles 8 in one pot. Use of easily available aryl chlorides enhances the practical application of this method. Notably, this transformation involves a Smiles rearrangement (1,5-hydrogen shift) leading to the observed regioselectivity.

Scheme 2

Synthesis of indole/benzimidazole-fused DBOs 9 via copper catalysis.

Khlebnikov et al. [9] reported synthesis of novel DBO derivatives – dibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepines 18 (Scheme 3). The synthesis involves reaction of imines 10 with dichlorocarbene to afford 2,2-dichloroaziridines 12 through intermediate 11. gem-Dichloroaziridines isomerize to imidoylchlorides in the presence of Lewis acids, which are also well-known catalysts for Friedal-Crafts acylation. Hence, treating 12 with AlCl₃ leads to domino reactions – azirdine ring opening followed by Friedal-Crafts acylation – to afford oxazepines 14. Compounds 14 were treated with LiAlH₄ to afford aziridinobenzooxazepines 15. Heating compounds 15 in anhydrous toluene or under solvent-free conditions in presence of dipolarophiles 17 at 140°C furnished the target dibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepines 18 in yields of 71–97% from 15.

Scheme 3

Synthesis of dibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepines 18 via formation of aziridines followed by 1,3-dipolar cycloaddition of dibenzoxazepinium ylides 16 with alkenes 17.

Gijsen et al. [10] reported a series of substituted DBOs (Scheme 4) as potent TRPA1 receptor antagonists. The synthesis involves a benzamide formation from anilines 19 and benzoic acids 20, followed by an intramolecular S_NAr to install the tricyclic scaffold 22. Reduction of cyclic amides 22 gave the brominated 10,11-dihydro-DBOs 23, which were transformed in two steps to the target DBOs 25.

Scheme 4

Synthesis of DBO derivatives 25 by benzamide formation followed by intramolecular S_NAr.

Fakhraian and Nafary [11] investigated conditions for a two-step, one-pot preparation of 28 (Scheme 5). The best result (89% yield) was obtained when 2-aminophenol 26 was first dissolved in PEG(300) at 50°C, and after addition of 2-fluorobenzaldehyde 27, the solution was stirred for 10 h at 50°C to facilitate Schiff base formation, followed by addition of potassium carbonate and continuing the reaction for 10 h at 100°C. Jorapur et al. [12] also reported the same conversion using PEG(400) instead with the best yield of 89%.

Scheme 5

Synthesis of DBO derivatives 28 from 2-aminophenol 26 and 2-fluorobenzaldehyde 27 using PEG300 and potassium carbonate.

In a novel method to synthesize DBO derivatives developed by Gutch and Acharya [13], 2-aminophenol 26 was condensed with substituted 2-chlorobenzaldehydes 29. The condensed products 30 were converted to the potassium salts 31, which, in turn, were cyclized in dimethyl sulfoxide (DMSO) at 120°C to afford target DBOs 32 in yields of 68–72% (Scheme 6).

Scheme 6

Synthesis of DBO derivatives 32 from 2-aminophenol 26 and substituted 2-chloroacetaldehyde 29.

Miyata et al. [14] investigated the domino reaction of tricyclic alkoxyamine 33 with ethylmagnesium bromide to afford DBO 35 as the minor product (23%) (Scheme 7) and 11-ethyl-10,11-dihydrodibenzo[b,f][1,4]oxazepine 34 as the major product. Changing the EtMgBr stoichiometry from 3 to 4 equiv or using other Grignard reagents (PhMgBr, allylMgBr, vinylMgBr) gave rise only to products analogous to 34 in 81–94% yields. The reaction involves a domino elimination-rearrangement-addition sequence from the N-alkoxy(arylmethyl)amine A in the presence of organometallic reagents to afford the target product D.

Scheme 7

Synthesis of DBO 35 via domino elimination-rearrangement-addition sequence from the N-alkoxy(arylmethyl)amines.

Xing et al. [15] established a general and efficient one-pot synthesis of highly functionalized DBOs via microwave-assisted one-pot Ugi four-component reaction (U-4CR) and intramolecular O-arylation (Scheme 8). The protocol involves heating a solution of 2-aminophenols 36, aldehydes 37, benzoic acids 38, and isocyanates 39 in methanol to 80°C for 20 min in a microwave reactor to furnish intermediates 40. Compounds 41 (eight examples, 81–94% yields) were prepared by selecting six substituted 2-aminophenols, two isocyanides in combination with 2-bromobenzaldehyde, and 2-chloro-5-nitrobenzoic acid. Synthesis of compounds 42 was not as efficient and was influenced by the pKa of benzoic acids. Four different benzoic acids were used to synthesize four examples of framework 42 (17–49% yields), with increasing acidity of benzoic acids leading to improved yields.

Scheme 8

Synthesis of DBOs 41 and 42 via microwave-assisted one-pot U-4CR and intramolecular O-arylation.

Intramolecular amidation of compounds 41 to assemble novel classical conjugates 43 was accomplished (Scheme 9). These reactions are catalyzed by Pd(OAc)₂-BINAP catalyst system.

Scheme 9

Palladium-catalyzed intramolecular amidation of 41 to afford novel conjugate compound 43.

Abramov et al. [16] used known reactions of activated nucleophilic substitution to facilitate novel protocols for synthesis of structurally diverse cyano-substituted DBOs. As shown in Scheme 10, 2-(5-phenyl-4H-1,2,4-triazol-3- yl)phenol 45, in the presence of potassium carbonate, undergoes deprotonation generating the corresponding phenoxide, which undergoes a reaction with 4-bromo-5-nitrophthalonitrile 44 to afford the intermediate product 46. A potassium carbonate-induced intramolecular substitution of a nitro group in 46 leads to cyclocondensed product 47. Similarly, 44 undergoes a reaction with 3-(5-phenyl-4H-1,2,4-triazol-3-yl)-2-naphtol 48 to afford cyclocondensed product 49.

Scheme 10

Synthesis of potassium carbonate-induced formation of DBOs 47 and 49.

Heating equimolar quantities of highly reactive substrate 44 and hydrazonamide of 5-bromo salicylic acid 50 in DMF in the presence of potassium carbonate gave product 51 in 56% yield (Scheme 11). Bifunctional nucleophiles such as 52 and 54 undergo cyclocondensation with 44 in the presence of potassium carbonate to afford corresponding DBOs 53 (84% yield) and 55 (72% yield), respectively.

Scheme 11

Synthesis of potassium carbonate-induced formation of DBOs 51, 53, and 55.

Matloubi et al. [17] reported a novel synthesis of 11-[C¹⁴]-clozapine 61 (Scheme 12) with a marked improvement in yield (6–23%) over a previous report [18]. The synthesis involves coupling 2-aminobenzonitrile 56 with 1,4-dichloro-2-nitrobenzene 57 in the presence of base to afford 58. The best results were obtained using Cs₂CO₃. The nitrile 58 was then hydrolyzed to amide 59 with basic hydrogen peroxide in 90% yield. Compound 59 was reduced with stannous chloride and acetic acid to afford key diazepine-11-one 60 in 86% yield. Conversion of 60–61 was carried out as reported by Fryer et al. [19].

Scheme 12

Novel synthesis of 11-[¹⁴C]-clozapine 61 from 2-amino benzonitrile 56 and 1,4-dichloronitrobenzene 57.

Conclusions

We have highlighted recent advances in the preparation of DBO derivatives. Twelve synthetic methods to the DBO ring system have been described. The reported methods include cyclocondensation with two precursors, copper catalysis, 1,3-dipolar cycloaddition, domino elimination-rearrangement-addition sequence, and a U-4CR reaction. The synthetic methods presented in this review are relevant to medicinal and pharmaceutical chemistry and can be used for development of novel DBO derivatives of pharmacological significance.