Asymmetric synthesis of 4,1-Benzoxazepine-2,5-Diones -Effect of the halogen of (2S)-A-Haloacids

Article abstract of DOI:10.3390/molecules19010139

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 a-chloroacids or a-bromoacids, respectively.

Full text of DOI:10.3390/molecules19010139

Molecules 2014, 19, 139-148; doi:10.3390/molecules19010139
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Asymmetric Synthesis of 4,1-Benzoxazepine-2,5-Diones —
Effect of the Halogen of (2S)-α-Haloacids
Syeda Laila Rubab 1, Bushra Nisar 1, Abdul Rauf Raza 1,*, Nisar Ullah 2,*
and Muhammad Nawaz Tahir 3
1
Ibn-e-Sina Block, Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan;
E-Mails: xahrachemist@gmail.com (S.L.R.); b.nisacapri@gmail.com (B.N.)
2
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261,
Saudi Arabia
3
Department of Physics, University of Sargodha, Sargodha 40100, Pakistan;
E-Mail: dmntahir_uos@yahoo.com
* Authors to whom correspondence should be addressed;
E-Mails: roofichemist2012@gmail.com (A.R.R.); nullah@kfupm.edu.sa (N.U.);
Tel.: +92-48-600-7432 (A.R.R.); Fax: +92-48-923-0799 (A.R.R.);
Tel.: +96-63-860-7527 (N.U.); Fax: +96-63-860-4277 (N.U.).
Received: 28 November 2013; in revised form: 12 December 2013 / Accepted: 16 December 2013 /
Published: 23 December 2013
Abstract: 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.
Keywords: (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones; asymmetric synthesis; α-chloroacids;
α-bromoacids; anthranilic acid; chiral pool methodology
1. 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

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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-4,1-
benzoxazepine-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].
2. Results and Discussion
This strategy involved chiral pool methodology in which chiral substrates are coupled with
achiral anthranilic acids to afford chiral 4,1-benzoxazepine-2,5-diones. We planned to synthesize
4,1-benzoxazepines in two steps, which involve the coupling of α-haloacids with various anthranilic
acids followed by intramolecular cyclization to afford the corresponding 4,1-benzoxazepine-2,5-
diones. For this purpose (−)-(S)-2-chloroacids or (−)-(S)-2-bromoacids 3a–c were prepared in high
ee (95%–98%) via diazotization of naturally occurring (+)-(S)-amino acids [13]. The coupling of
α-chloroacids 3a–b with 1a–e afforded N-acylanthranilic acid as expected, but the use of α-bromoacid
3c resulted in the formation of seven member ring compounds 4a–c in most cases (Scheme 1 and Table 1).
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 H2O 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

Molecules 2014, 19
141
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.
O
O
O
N
R2
W X Y C3
6
5
W
X
W
X
Cl
O
3
OH
O
R
b
4a Br H Br
4b H H Me
R
R
R1
+
+
7
NH2
O
N
9
4c Cl H Me R
4d H Cl H
H
O
2a-c R = OH
Y
Y
X
a
S
R
R1 R2
5a X = (R)-Cl
5b X = (S)-Br
W X Y
c
3a Cl Bn Cl
3b Cl iPr Cl
3c Cl Me Br
3d Cl iBu Cl
1a H Cl H
1b Br H H
1c Br H Br
1d H H Me
1e Cl H Me
W
COOH
O
6a 6b 6c 6d 6e 6f 6g
W
X
H
H
Br Br
H
H
Br
H
R1
2'
X
N
Cl Cl
H
H
Cl Cl
H
R1 Me iPr Bn iPr iBu Bn iBu
Cl
C2'
R
S
S
S
S
S
S
Reagents and Conditions: (a) SOCl2 (1.5 eq), DMF (1 drop); (b) dropwise addition of 3 to 1, DMF, 0 °C;
(c) K2CO3, DMF, 80 °C (3 h).
Table 1. The %yield and specific rotations of 4a–d, 5 and 6a–g.
4a
50
4b
78
4c
66
4d
57
5 §
32
6a
67
6b
86
6c
70
6d
71
6e
68
6f
67
6g
46
% Yield
c *
0.5
0.2
0.2
0.2
0.3
0.5
0.6
1.0
1.0
1.0
1.0
0.2
[α]D
+12.0 +80.0 +67.9 +54.0 –19.0 +80.0 +16.9 +17.0 +32.0 +16.2 +35.2 +23.3
(°C)
(30) (30)
(30) (30) (23) (30) (30) (30) (30) (25) (25)
(26)
* MeOH, taken in g/100 mL unit and measured in a cell of 1 dm length; § mixture of both 5a and 5b (82:18).
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 SOCl2.
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
SOCl2 (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
SOCl2 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).

Molecules 2014, 19
Scheme 2. Mechanism showing the formation of 6-chloro-2-(1'-haloethyl-8-methyl-3,1-
142
benzoxazine-4-one 5a–b.
O
O
O
Cl
Cl
O
Cl
Cl
O
O
-H+
-Cl-
N
N
H
N
H
X
X
X
5a-b
X = (S)-Br/ (R)-Cl
Figure 1. A part of (a) LR EIMS showing the predominance of 5a molecular ions; (b) the
1H-NMR elaborating the level of predominance of Cl-substituted benzoxazinone 5a over
Br-substituted benzoxazinone 5b.
H7 (2 Cl)
H5 (2 Cl)
(b)
(a)
[M]+. with two Cl
(9:6:1)
H5 (Cl & Br)
H7 (Cl & Br)
[M]+. with Cl & Br
(6:9:2)
m/z
7.5
8.0
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 C2 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
1
in 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 (K2CO3) 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].

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143
Figure 2. The ORTEP diagram of; (a) 4c; (b) 4a.
(b)
(a)
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
1
4d that was purified by column chromatography. The 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.
3. Experimental
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
1
13
size, Merck) were used for purification. The H-NMR and 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.
Representative procedure for the synthesis of 4a–c, 5a–b and 6a–g: A mixture of (S)-2-bromopropanoic
acid (5 mmol, 2 eq), SOCl2 (7.5 mmol, 2.5 eq) and catalytic amount of DMF (1 drop) was heated at
60 °C for 30 min. The resulting 2-haloacid chlorides 3a–d, without further purification, was slowly
added dropwise to a stirred chilled solution of 5-cholo-3-methylanthranilic acid (1e) (2.5 mmol, 1 eq)
and Et3N (2.5 mmol, 1 eq) in DMF (2 mL) at 0 °C. The reaction mixture was stirred overnight at room
temperature. An excess of H2O was added and extracted with EtOAc (3 × 15 mL). The combined

Molecules 2014, 19
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organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure till a
brownish liquid was obtained. This crude product was subjected to column chromatography on silica
gel that afforded 5 (200 mg, 32%) and/or 4 (390 mg, 66%), both as white solids, by elution with 2%
and 5% EtOAc in n-hexane.
(3R)-7,9-Dibromo-3-methyl-4,1-benzoxazepine-2,5-dione (4a): Rf: 0.75 (EtOAc/n-hexane 3:7),
[α]3D0 = +12.0 (c 0.5, MeOH); MP: 165 °C; H-NMR (300 MHz, CD3OD): δ (ppm) 2.60 (3H, d,
1
J = 6.9 Hz, CH3), 4.35 (1H, q, J = 6.9 Hz, H3), 7.70 (1H, d, J = 1.5 Hz, H8), 7.94 (1H, d, J = 1.8 Hz,
H6); IR (KBr): ύmax (cm−1) 1697 (a broad signal of OC=O and NC=O); UV-Vis (MeOH): λmax 304 nm
(log ε = 3.21670 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 351, 349, 347 (6, 12, 6 in 1:2:1
ratio) [M]+•, 279, 277 and 275 (39, 77 and 40 in 1:2:1 ratio) [M-C3H4O2, A]+•, 251, 249 and 247 (8, 17
and 9 in 1:2:1 ratio) [A-CO]+•, ESI MS (m/z) for C10H7Br2NO3: 373.8649, 371.8669 and 369.8690
found for 373.8645 [M+4+Na], 371.8665 [M+2+Na] and 369.8686 [M+Na] in 1:2:1.
(3R)-3,9-Dimethyl-4,1-benzoxazepine-2,5-dione (4b): Rf: 0.65 (EtOAc/n-hexane 3:7), [α]3D0 = +80.0
(c 0.2, MeOH); MP: 190 °C; 1H-NMR (300 MHz, CDCl3): δ (ppm) 1.83 (3H, d, J = 6.9 Hz, CH3), 2.27
(3H, s, Ar-CH3), 4.55 (1H, q, J = 6.9 Hz, H3), 7.24 (1H, t, J = 7.5 Hz, H7), 7.49 (1H, d, J = 7.5 Hz, H8),
13
7.90 (1H, d, J = 7.8 Hz, H6), 9.56 (1H, s, NH); C-NMR (75 MHz, CDCl3): δ (ppm) 18.8 (Ar-CH3),
22.8 (C1'), 55.9 (C3), 126.2 (C9), 126.3 (C7), 129.3 (C8), 129.4 (C5a), 136.5 (C6), 136.6 (C9a), 168.0,
170.6 (C2 and C5); IR (KBr): ύmax (cm−1) 1697 (a broad signal of OC=O and NC=O); UV-Vis
(MeOH): λmax 294 nm (log ε = 3.32135 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 205 (72)
[M]+•, 133 (100) [M-C3H4O2, A]+•, 105 (100) [A-CO]+•, ESI MS (m/z) for C11H11NO3: 228.0636 found
for 228.0631 [M+Na].
(3R)-7-Chloro-3,9-dimethyl-4,1-benzoxazepine-2,5-dione (4c): Rf: 0.61 (EtOAc/n-hexane 3:7);
[α]3D0 = +67.9 (c 0.2, EtOAc); MP: 187 °C; H-NMR (300 MHz, CD3OD): δ (ppm) 1.73 (3H, d,
1
J = 6.9 Hz, H1'), 2.26 (3H, s, Ar-CH3), 4.67 (1H, q, J = 6.9 Hz, H3), 7.50 (1H, broad s, H8), 7.76 (1H, d,
13
J = 2.4 Hz, H6); C-NMR (75 MHz, CD3OD): δ (ppm) 18.2 (Ar-CH3), 22.1 (C1'), 55.7 (C3), 129.4
(C8), 129.8 (C5a), 135.0 (C6), 135.6 (C7), 168.0, 170.6 (C2 and C5); IR (KBr): ύmax (cm−1) 3362 (N-H),
1693 (a broad signal of OC=O and NC=O); UV-Vis (MeOH): λmax 306 nm (log ε = 3.25701 L cm−1 M−1);
LR EIMS: m/z in amu (% abundance) 241, 239 (13, 37 in 1:3 ratio) [M]+•, 169, 167 (29, 100 in 1:3
ratio) [M-(3-methyloxirane-2-one), A]+•, 141, 139 (31, 90 in 1:3 ratio) [A-CO]+•; ESI MS (m/z) for
C11H10ClNO3: 264.0217 and 262.0246 found for 264.0214 [M+2+Na] and 262.0242 [M+Na] in 1:3 ratio.
(1'R)-6-Chloro-2-(1'-chloroethyl)-8-methyl-3,1-benzoxazine-4-one (5a): Rf: 0.87 (EtOAc/n-hexane
3:7); [α]2D3 = −19.0 (c 0.3, EtOAc); MP: 129 °C; H-NMR (300 MHz, CDCl3): δ (ppm) 2.04 (3H, d,
1
J = 6.9 Hz, H2'), 2.53 (3H, s, Ar-CH3), 4.82 (1H, q, J = 6.9 Hz, H1'), 7.61 (1H, broad s, H7), 8.00 (1H,
broad s, H5), IR (KBr): ύmax (cm−1) 1764 (lactonic OC=O), 1528 (C=N); UV-Vis (MeOH): λmax 326 nm
(log ε = 3.96534 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 261, 259 and 257 (2.5, 16 and 24
in 1:6:9 ratio) [M with 2 Cl]+•, 224, 222 (22, 63 in 1:3 ratio) [M-•Cl]+, 196, 194 (31, 100 in 1:3 ratio)
[M-H3CC·(H)Cl]+; ESI MS (m/z) for C11H9Cl2NO2: 283.9849, 281.9878 and 279.9908 found for
283.9846 [M+4+Na], 281.9875 [M+2+Na] and 279.9905 [M+Na] in 1:6:9 ratio.

Molecules 2014, 19
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(1'S)-2-(1'-Bromoethyl)-6-chloro-8-methyl-3,1-benzoxazine-4-one (5b): Rf: 0.87 (EtOAc/n-hexane
3:7); [α]2D3 = −19.0 (c 0.3, EtOAc); MP: 129 °C; H-NMR (300 MHz, CDCl3): δ (ppm) 1.95 (3H, d,
1
J = 6.6 Hz, H2'), 2.24 (3H, s, Ar-CH3), 4.51 (1H, q, J = 6.9 Hz, H1'), 7.45 (1H, broad s, H7), 7.86 (1H,
broad s, H5), IR (KBr): ύmax (cm−1) 1761 (lactonic OC=O), 1528 (C=N); UV-Vis (MeOH): λmax 326 nm
(log ε = 3.96534 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 305, 303 and 301 (1.9, 7.4 and
5.5 in 2:9:6 ratio) [M with Br and Cl]+•, 224, 222 (22, 63 in 1:3) [M-•Br]+, 196, 194 (31, 100 in 1:3
ratio) [M-H3CC•(H)Br]+; ESI MS (m/z) for C11H9BrClNO2: 327.9352, 325.9373 and 323.9402 found
for 327.9350 [M+4+Na], 325.9370 [M+2+Na] and 323.9400 [M+Na] in 2:9:6 ratio.
(2'R)-4-Chloro-2-(2'-chloropropanamido)benzoic acid (6a): The product (0.39 g, 67%) was
precipitated out when reaction mixture was poured into ice chilled H2O. Rf: 0.56 (EtOAc/n-hexane
3:7); [α]3D0 = +80.0 (c 0.5, EtOAc); MP: 187 °C; H-NMR (400 MHz, CDCl3): δ (ppm) 1.82 (3H, d,
1
J = 7.2 Hz, H3'), 4.54 (1H, q, J = 7.2 Hz, H2'), 7.15 (1H, dd, J = 8.4, 1.6 Hz, H5), 8.07 (1H, d,
J = 8.8 Hz, H6), 8.82 (1H, d, J = 1.5 Hz, H3), 11.7 (1H, s, NH); IR (KBr): ύmax (cm−1) 1678 (OC=O),
1583 (NC=O); UV-Vis (MeOH): λmax 306 nm (log ε = 3.950121 L cm−1 M−1); LR EIMS: m/z in amu
(% abundance) 265, 263 and 261 (2, 11 and 21 in 1:6:9 ratio) [M]+•, 200, 198 (15, 45 in 1:3 ratio)
[M-H3CC•(H)Cl, A]+, 182, 180 (45, 100) [A-H2O]+.
(2'S)-4-Chloro-2-(2'-chloro-3'-methylbutanamido)benzoic acid (6b): Rf: 0.45 (EtOAc/n-hexane 3:7),
[α]3D0 = +16.9 (c 0.6, MeOH); MP: 178 °C; 1H-NMR (300 MHz, CDCl3): 1.00 (3H, d, J = 6.3 Hz, CH3),
1.09 (3H, d, J = 6.6 Hz, H4'), 2.55 (1H, m, H3'), 4.35 (1H, d, 4.5 Hz, H2'), 7.13 (1H, dd, J = 8.7, 1.5 Hz,
H5), 8.06 (1H, d, J = 8.6 Hz, H6), 8.83 (1H, d, J = 1.5 Hz, H3), 11.78 (1H, s, NH); IR (KBr):
ύmax (cm−1) 3500 (O-H), 3383 (N-H), 1666 (OC=O), 1595 (NC=O); UV-Vis (MeOH): λmax 336 nm
(log ε = 3.01872 L cm−1 M−1). ESI MS (m/z) for C12H13Cl2NO3: 316.0111, 314.0140 and 312.0170
found for 316.0108 [M+4+Na], 314.0136 [M+2+Na] and 312.0167 [M+Na] in 1:6:9 ratio.
(2'S)-5-Bromo-2-(2'-chloro-3'-phenylpropanamido)benzoic acid (6c): Rf: 0.14 (EtOAc/n-hexane 3:7),
[α]3D0 = +17.0 (c 1.0, MeOH); MP: 110 °C; H-NMR (500 MHz, CD3OD): 3.21 (1H, dd, J = −14.0,
1
3'
3'
8.0 Hz, Hα ), 3.43 (1H, dd, J = −14.0, 8.0 Hz, Hβ ), 4.69 (1H, dd, J = 8.0, 6.0 Hz, H2'), 7.17-7.24 (5H,
m, Ph), 7.63 (1H, dd, J = 9.0, 2.5 Hz, H4), 8.11 (1H, d, J = 2.5 Hz, H6), 8.48 (1H, d, J = 9.0, H3);
13C-NMR (125 MHz, CD3OD) δ (ppm): 42.46 (C3'), 62.29 (C2'), 116.76 (C1''), 119.97 (C1), 123.08
(C4''), 128.18 (C3), 129.45, 130.54 (C3'' and C2''), 134.92 (C4), 137.47 (C5), 137.71 (C6), 140.58 (C2),
169.23 (NC=O), 169.57 (OC=O); IR (KBr): ύmax (cm−1) 3028 (O-H), 2916 (N-H), 1709 (OC=O), 1531
(NC=O); UV-Vis (MeOH): λmax 317 nm (log ε = 3.56741 L cm−1 M−1); LR EIMS: m/z in amu (%
abundance) 385, 383, 381 (1, 5, 3 in 2:9:6 ratio) [M]+•, 226, 224 (16, 15 in 1:1 ratio) [M-•CH2(Cl)Bn
and H2O, A]+, 217, 215 (53, 52 in 1:1) [M-•CH2(Cl)Bn and CO]+, 198, 196 (56, 56) [A-CO]+.
(2'S)-5-Bromo-2-(2'-chloro-3'-methylbutanamido)benzoic acid (6d): Rf: 0.45 (EtOAc/n-hexane 3:7),
[α]3D0 = +32.0 (c 1.0, MeOH); MP: 178 °C; 1H-NMR (300 MHz, CDCl3): 1.00 (3H, d, J = 6.3 Hz, CH3),
1.09 (3H, d, J = 6.6 Hz, H4'), 2.55 (1H, m, H3'), 4.35 (1H, d, 4.5 Hz, H2'), 7.13 (1H, dd, J = 8.7, 1.5 Hz,
H4), 8.06 (1H, d, J = 8.6 Hz, H3), 8.83 (1H, d, J = 1.5 Hz, H6), 11.78 (1H, s, NH); IR (KBr):
ύmax (cm−1) 3500 (O-H), 3383 (N-H), 1666 (OC=O), 1595 (NC=O); UV-Vis (MeOH): λmax 336 nm

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(log ε = 3.01872 L cm−1 M−1); ESI MS (m/z) for C12H13BrClNO3: 359.9615, 357.9644 and 355.9665
found for 359.9612 [M+4+Na], 357.9642 [M+2+Na] and 355.9663 [M+Na] in 2:9:6 ratio.
(2'S)-4-Chloro-2-(2'-chloro-3'-methylpentanamido)benzoic acid (6e): Rf: 0.15 (EtOAc/ n-hexane 3:7),
[α]2D5 = +16.2 (c 1.0, MeOH); MP: 126 °C; H-NMR (600 MHz, CD3OD): 0.96 (3H, d, J = 6.6 Hz,
1
CH3), 0.98 (3H, d, J = 6.6 Hz, H5'), 1.85–1.98 (3H, m, H3' and H4'), 4.51 (1H, dd, J = 9.6, 4.8 Hz, H2'),
13
7.18 (1H, dd, J = 8.4, 1.8 Hz, H5), 8.06 (1H, d, J = 8.4 Hz, H6), 8.69 (1H, d, J = 1.8, H3); C-NMR
(125 MHz, CD3OD) δ (ppm): 21.56 (Me), 23.06 (C5'), 26.52 (C4'), 45.44 (C3'), 60.48 (C2'), 116.42 (C1),
120.97 (C5), 124.53 (C3), 133.99 (C6), 141.13 and 142.81 (C2 and C4), 170.39 (NC=O), 170.44
(OC=O); IR (KBr): ύmax (cm−1) 3221 (O-H), 3120 (N-H), 1640 (OC=O), 1550 (NC=O); UV-Vis
(EtOAc): λmax 307 nm (log ε = 3.44321 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 307, 305
and 303 (0.1, 1.2 and 2.1 in 1:6:9 ratio) [M]+•, 251, 249 and 247 (6, 45 and 77 in 1:6:9 ratio) [M-C4H8,
A]+•, 200, 198 (3, 7 in 1:3) [A-•CH2Cl, B]+, 182, 180 (37, 80) [B-H2O, C]+, 173, 171 (29, 100)
[B-CO]+, 155, 153 (17, 52) [C-CO]+.
(2'S)-4-Chloro-2-(2'-chloro-3'-phenylpropanamido)benzoic acid (6f): Rf: 0.17 (EtOAc/n-hexane 1:1),
[α]2D5 = +35.2 (c 1.0, MeOH); MP: 121 °C; H-NMR (500 MHz, CD3OD): 3.23 (1H, dd, J = −14.0,
1
3'
3'
7.5 Hz, Hα ), 3.44 (1H, dd, J = −14.0, 6.0 Hz, Hβ ), 4.71 (1H, dd, J = 7.5, 6.0 Hz, H2'), 7.15 (1H, dd,
J = 8.5, 2.0 Hz, H5), 7.19-7.26 (5H, m, Ph), 8.01 (1H, d, J = 8.5 Hz, H6), 8.66 (1H, d, J = 2.0, H3);
13C-NMR (125 MHz, CD3OD) δ (ppm): 42.43 (C3'), 62.24 (C2'), 116.35 (C1''), 120.91 (C5), 124.55 (C3),
128.12 (C4''), 129.47, 130.57 (C3'' and C2''), 133.91 (C6), 137.45 (C1), 141.04 (C4), 142.56 (C2), 169.46
(NC=O), 170.18 (OC=O); IR (KBr): ύmax (cm−1) 3221 (O-H), 3001 (N-H), 1670 (OC=O), 1543
(NC=O); UV-Vis (MeOH): λmax 306 nm (log ε = 3.09876 L cm−1 M−1). LR EIMS: m/z in amu
(% abundance) 304, 302 (9, 31 in 1:3 ratio) [M-•Cl]+, 182, 180 (25, 8) [M-•CH2(Cl)Bn and H2O, A]+.
(2'S)-5-Bromo-2-(2'-chloro-3'-methylpentanamido)benzoic acid (6g): Rf: 0.12 (EtOAc/n-hexane 3:7),
[α]2D6 = +23.3 (c 0.2, MeOH); MP: 118 °C; H-NMR (500 MHz, CD3OD): 0.96 (3H, d, J = 6.5 Hz,
1
CH3), 0.98 (3H, d, J = 6.0 Hz, H5'), 1.84–1.97 (3H, m, H3'and H4'), 4.51 (1H, dd, J = 9.0, 5.0 Hz, H2'),
13
7.69 (1H, dd, J = 9.0, 2.5 Hz, H4), 8.17 (1H, d, J = 2.5 Hz, H3), 8.53 (1H, d, J = 9.0, H6); C-NMR
(125 MHz, CD3OD) δ (ppm): 21.59, 23.06 (CH3 and C5'), 25.53 (C4'), 45.49 (C3'), 60.53 (C2'), 116.75
(C1), 119.97 (C5), 123.20 (C4), 135.02 (C3), 137.87 (C6), 140.89 (C2), 169.76 (NC=O), 170.26
(OC=O); IR (KBr): ύmax (cm−1) 3259 (O-H), 3044 (N-H), 1685 (OC=O), 1531 (NC=O); UV-Vis
(MeOH): λmax 310 nm (log ε = 3.23921 L cm−1 M−1); LR EIMS: m/z in amu (% abundance) 351, 349
and 347 (4, 12 and 11) [M]+•, 226, 224 (62, 43) [M-·CH2(Cl)Bn and H2O, A]+, 217, 215 (99, 100)
[M-·CH2(Cl)Bn and CO]+, 199, 197 (61, 60) [A-CO]+.
(3R)-8-Chloro-3-methyl-4,1-benzoxazepine-2,5-dione (4d): A mixture of 6a (1 mmol, 1 eq) and
anhydrous K2CO3 (1.5 mmol, 1.5 eq) in DMF (1 mL) was heated at 80 °C for 3 h. Excess of chilled
H2O was added, the mixture was neutralized with dilute HCl (5 mL) and extracted with EtOAc
(2 × 15 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to afford the crude product. It was purified by column chromatography using
5% EtOAc in n-hexane as mobile phase to afford pure 4d. Rf: 0.57 (EtOAc/n-hexane 3:7);
[α]3D0 = +54.0 (c 0.2, MeOH); MP: 134 °C; H-NMR (400 MHz, CDCl3): δ (ppm) 1.61 (3H, d,
1

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J = 6.8 Hz, H1'), 4.79 (1H, q, J = 4.8 Hz, H3), 7.00 (1H, d, J = 1.6 Hz, H9), 7.26 (1H, dd, J = 8.4,
1.6 Hz, H7), 7.92 (1H, d, J = 8.4 Hz, H6), 7.94 (1H, s NH); IR (KBr): ύmax (cm−1) 3262 (N-H), 1707
(a broad signal of OC=O and NC=O); UV-Vis (MeOH): λmax 302 nm (log ε = 3.98631 L cm−1 M−1);
LR EIMS: m/z in amu (% abundance) 227 and 225 (10 and 30 in 1:3) [M]+•, 155 and 153 (30 and 100
in 1:3 ratio) [M-(3-methyloxirane-2-one)]+•, 183 and 181 (3 and 10 in 1:3 ratio) [M-CO]+•.
4. Conclusions
This strategy leads towards the one-pot synthesis of novel (3R)-4,1-benzoxazepines-2,5-diones
exploiting the chiral pool methodology. The use of (S)-2-bromopropanoic acid results in the formation
of (3R)-4,1-benzoxazepines-2,5-diones with chances of racemization due to transhalogenation; on the
other hand the use of (S)-2-chloroacids affords (S)-N-acylanthranilic acids exclusively although
another base mediated step is mandatory to achieve the same product but with high ee [12]. Thus, the
use of (S)-2-chloroacids for such coupling reactions is recommended to achieve high ee for the
synthesis of (3R)-4,1-benzoxazepines-2,5-diones. In future, these (3R)-4,1-benzoxazepines-2,5-diones
shall be available for various biological applications, a few of which are currently under examination.
Acknowledgments
The authors acknowledge the Higher Education Commission (HEC) of Pakistan for generous
support of research fellowship to Syeda Laila Rubab (PIN No. 074-2373-Ps4-426), Bushra Nisar
(074-1727-Ps4-192) and financial support for spectral analysis (NMR and MS) at QAU, Islamabad
and/or ICCBS, University of Karachi, Karachi. We are grateful to the University of Sargodha for the
provision of basic instruments and XRD facility.
Conflicts of Interest
The authors declare no conflict of interest.
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These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
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Tahir, Department of Physics, University of Sargodha, Sargodha, Pakistan.
Sample Availability: Samples of the compounds 4a–d, 5 and 6a–g are available from the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).