Asymmetric Synthesis of 4,1-Benzoxazepine-2,5-Diones — Effect of the Halogen of (2S)-α-Haloacids

Novel chiral 4,1-benzoxazepine-2,5-diones have been unusually synthesized in a single step by exploiting the chiral pool methodology. Substituted anthranilic acids afford N-acylanthranilic acids and (3R)-3-alkyl-4,1-benzoxazepines-2,5-dione upon coupling with α-chloroacids or α-bromoacids, respectively.


Introduction
The benzoxazepines belongs to the heterocycles class of compounds, which are obligatory components of biologically important molecules such as nucleic acids, hormones and therapeutic drugs. The benzoxazepine scaffolds are very versatile and of therapeutic use in many important fields. They have acquired tremendous importance in recent years owing to their wide applications in the OPEN ACCESS medicinal and pharmaceutical industry. For example, benzoxazepines have shown anti-tumor [1,2], anti-HIV [3], and tranquilizing activities [4], among a long list of other effects. Most of the conventional synthesis methods reported in literature produce racemic/achiral syntheses of 4,1-benzoxazpine. Leptit et al. reported the synthesis of 4,1-benzoxazepine by N-alkylation of 2-amino benzhydrol, followed by cyclization in the presence of ethanolic Na solution to yield 5-phenyl-1,3,5-trihydro-4,1benzoxazepine-2-ones [5]. Bergman et al., reported N-alkylation of N-methylanthranilic acid with an α-chloroacid followed by intramolecular cyclization to afford 4,1-benzoxazepine-3,5-dione [6]. Yar et al., reported a single step synthesis of 4,1-benzoxazepine in which N-tosyl-1,3-aminoalcohols were treated with bromoethylsulfonium salts, via vinyl sulfonium salt formation, which upon intramolecular cyclization afforded 4,1-benzoxazepines [7]. Because of the variety of their biological activities, these are heterocycles of intense chemical and biological significance.
Asymmetric synthesis is acquiring greater significance in pharmaceutical industry because of the wider application of enantiopure drugs. Mostly medicines used are racemic modifications of two enantiomers and side-effect of these medicines is being found due to presence of the vestigial enantiomers [8,9]. Asymmetric synthesis of thus heterocycles attracting greater attention in synthetic chemistry. The accessibility of drug for a community depends on the cost as well. A more efficient drug with high purchase value may not be accessible for all economical levels. This can be avoided by using inexpensive starting materials, especially, those from natural sources. Our methodology employs the chiral pool strategy that involves the use of absolutely enantiopure starting materials, which can be obtained easily from natural resources and tailors a/several chiral centre(s) in a target molecule with up to 100% stereoselectivity. The natural amino acids are inexpensive and readily available chiral starting materials. Many strategies reported in the literature are inspired by chiral pool methodology which makes use of naturally occurring chiral amino acids [10,11]. Our previous work also involved chiral pool strategy which employs inexpensive (S)-amino acids as starting materials to afford (3R)-4,1-benzoxazepines in high ee (up to 81%) [12].
The reaction of anthranilic acid 1a-e with α-chloroacids 3a-b and 3d affords (3S)-N-acylanthranilic acids 6b-g. When the reaction mixture was poured into ice chilled H 2 O the compounds 6a-c precipitated out as white solids that were purified by crystallization from EtOAc, whilst 6d-g were purified by column chromatography. However, under such conditions the coupling of 1a and 1c-e with (S)-2-bromopropanoic acid 3c affords either (3R)-4,1-benzoxazepines 4a-c as a major product in most cases or (3S)-N-acylanthranilic acid 6a after transhalogenation. The Br atom is a good leaving group and it is replaced by a Cl ion (transhalogenation), because chlorine ion is present in the reaction mixture resulting in the formation of (R)-2-chloropropanoic acid which upon coupling with anthranilic acids gave a mixture of both Cl-and Br-substituted products. Scheme 1. Synthesis of N-acylanthranilic acids 6a-g and benzoxazepines 4a-d.    The coupling of 1c-e with 3c affords the unusual (3R)-4,1-benzoxazepines 4a-c in the majority of the cases. The Br is replaced by either the O of the COOH group in N-acylanthranilic acid or with the Cl ion to afford 4,1-benzoxazepine directly or the Cl-substituted N-acylanthranilic acid, respectively. The coupling of 1a with 3c afforded the Cl-substituted N-acylanthranilic acid 6a exclusively. In this case, the Br is replaced by the Cl ion during the acid halide formation of (S)-2-bromopropanoic acid 3c with SOCl 2 .
The formation of Cl-substituted N-acylanthranilic acid in 6a was confirmed by the appearance of the molecular ion observed in LR EIMS; the [M] + appeared at 261, 263 and 265 amu in a 9:6:1 ratio that proves the transhalogenation (presence of two Cl) has ocurred. It is observed that a slight excess of SOCl 2 (2 eq) in the acid halide formation step affords benzoxazinones 5a/5b as a side-product along with 4,1-benzoxazepine 4c as major product. It is proposed that N-acylanthranilic acid reacts with SOCl 2 to form the acid halide which undergoes cyclization to the six member benzoxazinones 5a/5b (Scheme 2).
The benzoxazinone is also a mixture of two products 5a/5b (both Cl-and Br-substituted) in which mainly the Cl-substituted benzoxazinone 5a dominates. Transhalogenation was confirmed by the presence of both Cl-and Br-substituted molecular ion signals in 9:6:1 and 6:9:2 respectively, observed in LR EIMS (Figure 1a). The LR EIMS revealed molecular ion signals at 301, 303, 305 and 257, 259, 261 amu which confirm the presence of both Br and Cl atoms at C 2 respectively. It shows that the Cl-substituted product 5a dominates over the Br-substituted product 5b since the signals of the former radical cation show more abundance in the LR EIMS. Each aromatic proton shows a pair of signals of unequal size in 1 H NMR (Figure 1b); the integration of each signal pair revealed the level of predominancy of the Cl-substituted compound 5a (82%) over Br substituted benzoxazinone 5b (18%).
In the case of 6a-g no cyclized product was formed; probably the ease of C-Br bond dissociation is the reason for such behavior (direct cyclization). The Br is a better leaving group than Cl and for cyclization of the Cl substituted N-acylanthranilic acids 6a-g, base (K 2 CO 3 ) catalysis is required to get the cyclized 4,1-benzoxazepines [12]. The formation of 4,1-benzoxazepine in a single step was confirmed by single crystal XRD (Figure 2), which indicates the disappearance of C-Br and the formation of a new C-O bond (1.455 and 1.448 Å in 4c and 4a respectively) [14]. The base mediated the intramolecular cyclization of the N-acylated anthranilic acid 6a, obtained by the coupling of anthranilic acid 1a with acid chlorides 3c, to afford the 4,1-benzoxazepine-2,5-dione 4d that was purified by column chromatography. The 1 H-NMR spectra of the 4,1-benzoxazepine 4d showed no prominent changes as compared to the N-acylated anthranilic acid precursor 6a. A small shift is observed for the proton present at the chiral centre, which appeared slightly downfield (δ = 4.79 ppm) as compared to corresponding precursor acid 6a (δ = 4.45 ppm) due to the electron withdrawing inductive effect of O.

General Information
The pre-coated silica gel (0.25 mm thick layer over Al sheet, Merck, Darmstadt, Germany) TLC plates were used to monitor the reactions. Glass column packed silica gel (0.6-0.2 mm, 60 Å mesh size, Merck) were used for purification. The 1 H-NMR and 13 C-NMR were recorded in the designated solvents on a Bruker AVANCE DPX (300, 400, 500 or 600 MHz) spectrometer (Bruker, Billarica, MA, USA) using TMS as internal standard. The optical rotation was measured on an Atago (AP-300) polarimeter (Atago, Tokyo, Japan). The HR ESI was recorded on a Q-TOF Ultima API instrument (Micromass, Waters, Milford, MA, USA) at the Biomedical Mass Spectrometry Facility (BMSF), UNSW, Sydney (Australia). The single crystal X-Ray data were recorded on a Bruker Kappa APEX 11 CCD diffractometer. The IR and UV/Vis spectra were recorded on a Prestige 21 FTIR spectrometer (Shimadzu, Tokyo, Japan) and a Thermo Spectronic UV-1700 spectrophotometer (Thermo, Waltham, MA, USA), respectively.