A modified synthetic approach to optically pure benzoxazepines from amino acid precursors using intramolecular buchwald-hartwig C-O bond-formation reaction

Article abstract of DOI:10.1055/s-0030-1258406

Palladium-catalyzed intramolecular aryl etherification reaction using bulky binaphthylphosphane ligand is shown to be a convenient method for the synthesis of seven-membered heterocycles. Application of this methodology to a naturally occurring proteinoge

Full text of DOI:10.1055/s-0030-1258406

PAPER
585
A Modified Synthetic Approach to Optically Pure Benzoxazepines from
Amino Acid Precursors Using Intramolecular Buchwald–Hartwig C–O
Bond-Formation Reaction
Synthesis of
Optic
e
allyPure
B
b
enzoxazepine
l
s
eena Bhattacharya, Ashok Behera, Sandip K. Hota, Partha Chattopadhyay*
Department of Chemistry, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India
Fax +91(33)24735197; E-mail: partha@iicb.res.in
Received 15 November 2010
low yields of reaction products. Another synthetic route13
developed by Vinsova et al. described unexpected and
poor formation of benzoxazepine moiety through esterifi-
cation of biologically active salicylanilides with some N-
Abstract: Palladium-catalyzed intramolecular aryl etherification
reaction using bulky binaphthylphosphane ligand is shown to be a
convenient method for the synthesis of seven-membered heterocy-
cles. Application of this methodology to a naturally occurring pro-
teinogenic L-amino acid has led to the synthesis of optically active protected amino acids. Therefore a better procedure for
benzoxazepine ring systems of versatile biological importance.
the synthesis of optically pure benzoxazepines remains to
be established.
Key words: amino acids, palladium, ligand, etherification, chiral
benzoxazepines
In continuation of our project for the synthesis of chiral
medium ring heterocycles from carbohydrate precur-
sors,14 we designed the synthesis of biologically active
optically pure 1,4-benzoxazepines using L-amino acids as
cheap and useful chiral synthon. In this article, we report
a short and efficient synthetic route of this class of com-
pounds in excellent yield and good purity applying in-
tramolecular aryl etherification15 strategy.
A wide variety of benzo-fused medium ring heterocycles
containing nitrogen and oxygen atoms form the core
structural motif of common natural products endowed
with a broad range of medicinal values.1 These structures
represent a class of molecules, which are capable of bind-
ing to multiple receptors with high affinity and acting as
good antagonist.2 Benzannulated seven-membered rings
have significant antinociceptive properties3 and are fre-
quently used as antidepressants.4 Abundance of a large
number of CNS active novel seven-membered oxa-aza
heterocycles5 support their huge potency in neuro diseases
and these are of great pharmacological demand due to
their properties as enzyme inhibitors, analgesics, and an-
titussives.6 Among them, 1,4-benzoxazepines are well
known for their enormous antitumor activities in breast
cancer cells7 as well as for excellent anti-inflammatory8
and antithrombotic9 activities. Also, 1,4-benzoxazepine
derivatives were established for squalene synthase inhibi-
tory and cholesterol biosynthesis inhibitory activities.10
Hence, the development of a simple and modified route to
synthesize seven-membered fused heterocycles has be-
come a challenging area for synthetic organic chemists.
Initially we planned to protect the NH2 and CO2H group
of naturally abundant amino acids. Condensation with a-
bromobenzyl bromides should then lead successfully to
N-benzylation and the esterified CO2H group was to be
smoothly reduced to alcohol. The product was expected to
function as a substrate for an intramolecular Buchwald–
Hartwig aryl etherification reaction leading to the chiral
benzoxazepines. In actual practice different L-amino acids
1 were first reacted with p-toluenesulfonyl chloride (2)
and aqueous NaOH; subsequent acidification with con-
centrated HCl afforded16 N-tosylamino acids
3
(Scheme 1). These N-protected amino acids were then
converted17 to their methyl esters 4 by treatment with p-
toluenesulfonic acid in anhydrous MeOH under refluxing
condition. N-Alkylation of the products 4 with appropri-
ately substituted 2-bromobenzyl bromides 5 afforded18
the respective bromobenzyl-N-tosylamino acid methyl es-
ters 6a–g in 70–73% yields (Table 1). There was a choice
of reagents for this particular step. Primarily, NaH in an-
hydrous DMF was employed at 0 °C to room temperature
(Table 1, entry 1) furnishing the required product in short
time but in low yield. So the reaction condition was
changed to K2CO3 in anhydrous acetone at room temper-
ature (Table 1, entries 2 and 4) to get a somewhat better
yield. But the best result was recorded by changing the
solvent to anhydrous acetonitrile. Lithium borohydride
(LiBH4) reduction of 6a–g in anhydrous THF under reflux
for 14–20 hours then gave the corresponding alcohols19
7a–g as thick oils in 75–78% yields (Table 2).
Although several approaches to the synthesis of benzo-
and dibenzoxazepines using Pd-mediated intramolecular
aryl etherification, aryl amination, carbonylation, or other
methods have been reported in the literature,11 application
of these methodologies to the preparation of chiral ben-
zannulated heterocycles are scarce. Recently, Panda et al.
reported12 the synthesis of chiral benzoxazepines from
natural amino acids using intramolecular Mitsunobu ap-
proach of C–O bond formation reaction. But this method
requires a lengthy sequence of reactions and provides only
SYNTHESIS 2011, No. 4, pp 0585–0592
x
x
.
x
x
.2
0
1
1
Advanced online publication: 12.01.2011
DOI: 10.1055/s-0030-1258406; Art ID: P17110SS
© Georg Thieme Verlag Stuttgart · New York
In order to develop a facile aryl etherification methodolo-
gy through intramolecular Pd-induced cyclization, we

586
D. Bhattacharya et al.
PAPER
R1
R1
R1
O
S
NaOH, H2O
PTSA, anhyd MeOH
90 °C, reflux, 20 h
+
Cl
HN
Ts
COOH
HN
Ts
COOMe
H2N
COOH
r.t., overnight
O
1a–e
L-amino acid
4a–e
3a–e
2
Br
Br
K2CO3, anhyd MeCN
r.t., 14 h
R2
5a,b
O
Br
Br
OH
R1
COOMe
N
R1
LiBH4, anhyd THF
reflux, 14–20 h
Pd2(dba)3, K2CO3, KOt-Bu
R1
R2
R2
R2
N
N
( )-BINAP, anhyd toluene
reflux, 17 h
Ts
Ts
Ts
8a–g
66–73%
7a–g
75–78%
6a–g
70–73%
Scheme 1 Synthesis of optically pure 1,4-benzoxazepine moieties
Table 1 Benzylation of N-Protected Amino Acid Ester
Table 2 Reduction of Substituted Bromobenzyl Ester
base
solvent
LiBH4, anhyd THF, reflux
+
4a–e
5a,b
6a–g
6a–g
7a–g
Entry Substrate R1
R2
H
Time (h) Product Yield (%)a
Entry Substrate R1
R2
Base
Solvent ProductYield
(anhyd)
(%)a
58b
64
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
Me
20
18
17
17
16
14
14
7a
7b
7c
7d
7e
7f
76
77
78
78
77
75
78
1
2
3
4
5
6
7
8
9
4a
4a
4a
4b
4b
4c
4d
4e
4e
Me
Me
Me
i-Pr
i-Pr
i-Bu
s-Bu
Bn
H
H
H
H
H
H
H
H
NaH
DMF
6a
i-Pr
i-Bu
s-Bu
Bn
H
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
acetone 6a
MeCN 6a
acetone 6b
MeCN 6b
MeCN 6c
MeCN 6d
MeCN 6e
MeCN 6f
MeCN 6g
H
71
H
66
H
73
Bn
OMe
OMe
72
6g
i-Pr
7g
71
a Isolated yield.
72
Bn
OMe K2CO3
OMe K2CO3
71
ligand was found to be ( )-BINAP and toluene was more
effective as solvent than DMF. Therefore, the appropriate
reaction condition includes 10 mol% Pd2(dba)3 as catalyst,
7 mol% ( )-BINAP as ligand, 2 equivalents each of
K2CO3 and t-BuOK, and toluene (10 L/mol) as solvent un-
der reflux.
10 4b
i-Pr
70
a Isolated yield.
b Reaction conditions: 0 °C to r.t., 7 h.
tested the reagent system – Pd2(dba)3/( )-BINAP/t-BuOK
+ K2CO3 – in toluene as reported by Rogers et al.11c,15
However, as no reaction took place (based on TLC) even
after 18 hours of heating at 90 °C, the reaction mixture
was allowed to reflux gently for 17 hours when the reac-
tant was entirely consumed. Usual workup followed by
column chromatographic purification gave the desired cy-
clic products 8 in 66–73% yields. Deprotection of tosyl
group can easily be performed in different ways.12,20
The assigned structures of the benzoxazepine derivatives
8a–g were rationalized by 1H NMR as well as 13C NMR,
mass, and IR spectroscopy. The benzylic methylene pro-
tons attached to N resonated between d = 4.47–4.79 as
doublets. The only proton on the chiral center was detect-
ed as a multiplet between d = 4.02–4.26. The signals for
OCH2 protons adjacent to the chiral center appeared at d
= 3.68–3.92. For compounds 8f and 8g, the methoxy pro-
tons signal showed up as a singlet at d = 3.76. The cyclic
structure was also confirmed by a single crystal X-ray
analysis21–23 of 8g (Figure 1).
In order to optimize the reaction condition, we have ex-
plored other reported reagent systems. By screening a va-
riety of bases we found the combination of K2CO3 and t-
BuOK as the most efficient base for cyclization including
Cs2CO3 and t-BuONa (Table 3, entries 2 and 3). Pd(OAc)2
as an alternative source of Pd also furnished the desired
cyclic ether but less efficiently (Table 3, entry 2) and
Pd(PPh3)4 was not at all a good choice. The most versatile
The present strategy thus establishes transition-metal-
catalyzed cycloetherification as a suitable synthetic tool
for the preparation of optically active benzoxazepines by
exploiting the supremacy of L-amino acids as chiral syn-
thon. A probable mechanism of intramolecular aryl
Synthesis 2011, No. 4, 585–592 © Thieme Stuttgart · New York

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Synthesis of Optically Pure Benzoxazepines
587
Table 3 Optimization of the Intramolecular Palladium-Catalyzed Cycloetherification Reaction
Pd cat., ligand, base, solvent, Δ
7a–g
8a–g
Entry
1
Substrate
7a
Base
Catalyst
Ligand
Solvent
THF
Producta
8a
Yield (%)b
K2CO3
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
–
NRc
55d
51e
69f
59g
48h
73i
72i
73i
72i
66i
73i
2
7a
Cs2CO3
( )-BINAP
DPPF
toluene
toluene
toluene
toluene
DMF
8a
3
7a
t-BuONa
8a
4
7a
K2CO3 + t-BuOK
t-BuOK
( )-BINAP
xantphos
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
8a
5
7b
8b
6
7b
K2CO3 + t-BuOK
K2CO3 + t-BuOK
K2CO3 + t-BuOK
K2CO3 + t-BuOK
K2CO3 + t-BuOK
K2CO3 + t-BuOK
K2CO3 + t-BuOK
8b
7
7b
toluene
toluene
toluene
toluene
toluene
toluene
8b
8
7c
8c
9
7d
8d
10
11
12
7e
8e
7f
8f
7g
8g
a b-Elimination products (5–10%) were detected in all cases.
b Isolated yield.
c Reaction conditions: Pd(PPh3)4 (10 mol%), K2CO3 (3 equiv), toluene (10 L/mol), reflux, overnight.
d Reaction conditions: Pd(OAc)2 (10 mol%), ( )-BINAP (7 mol%), Cs2CO3 (5 equiv), toluene (10 L/mol), reflux, 16 h.
e Reaction conditions: Pd2(dba)3 (10 mol%), DPPF (7 mol%), t-BuONa (4 equiv), toluene (10 L/mol), reflux, 17 h.
f Reaction conditions: Pd2(dba)3 (10 mol%), ( )-BINAP (7 mol%), K2CO3 (2 equiv), t-BuOK (2 equiv), toluene (10 L/mol), reflux, 18 h.
g Reaction conditions: Pd2(dba)3 (10 mol%), xantphos (7 mol%), t-BuOK (4 equiv), toluene (10 L/mol), reflux, 19 h.
h Reaction conditions: Pd2(dba)3 (10 mol%), ( )-BINAP (7 mol%), K2CO3 (2 equiv), t-BuOK (2 equiv), DMF (10 L/mol), 110 °C, 14 h.
i Reaction conditions: Pd2(dba)3 (10 mol%), ( )-BINAP (7 mol%), K2CO3 (2 equiv), t-BuOK (2 equiv), toluene (10 L/mol), reflux, 17 h.
Pd(Br)L
Br
OH
R
OH
R
L / Pd
N
N
Ts
Ts
L = ligand
R = alkyl or aryl side chain
base
L
Pd O
R
NTs
Figure 1 ORTEP diagram of compound 8g
β-hydride
reductive
elimination
etherification15,24 for the synthesis of benzoxazepines has
been outlined in Scheme 2.
elimination
In conclusion, we have demonstrated an easy and im-
proved synthesis of enantiomerically pure 1,4-benzox-
azepines from naturally abundant L-amino acids using
intramolecular C–O bond formation reaction as a key
step. This is a unique approach of aryl etherification ex-
tending the feasibility of the Buchwald–Hartwig strategy
using suitably designed starting materials. The fairly
smooth and short reaction procedures, ease of purifica-
tion, and good yield of reaction products open more op-
portunities for further development.
O
H
H
O
R
R
NTs
N
Ts
Scheme 2 Proposed mechanism of intramolecular aryl etherifica-
tion in the synthesis of seven-membered ring
Synthesis 2011, No. 4, 585–592 © Thieme Stuttgart · New York

588
D. Bhattacharya et al.
PAPER
Reactions at r.t. or ambient temperature generally imply a tempera-
ture of 25 °C. Some reagents were obtained from commercial
sources and used without purification. The solvents used were of
technical grade, and freshly distilled prior to use. 1H (300 MHz, 600
MHz) and 13C (75 MHz, 150 MHz) NMR spectra were recorded us-
ing CDCl3 as solvent and TMS as internal standard on Bruker DPX
300 MHz and Bruker DRX 600 MHz NMR instruments at ambient
temperature. Chemical shifts are stated in parts per million in d
scales. Optical rotations were measured on a Jasco P-1020 Polarim-
eter. IR spectra were recorded on a Jasco FTIR Model-410, using
KBr pellets or in neat condition. Mass spectra were measured most-
ly in ESIMS (+) and some in EIMS mode. DI-EIMS were recorded
on a GCMS-Shimadzu-QP5050A and ESIMS were done on a Wa-
ters Micromass Q-TOF microTM Mass Spectrometer. X-ray crystal-
lographic data of single crystals were collected on Bruker Kappa
Apex II with Mo-Ka radiation (l = 0.71073Å). TLC was per-
formed on precoated plates (0.25 nm, silica gel 60 F254). Organic ex-
tracts were dried over anhyd Na2SO4. Column chromatography and
flash chromatography were carried out using commercial grade sil-
ica gel (100–200 mesh). Petroleum ether (PE) used refers to the
fraction boiling in the range 60–80 °C.
13C NMR (75 MHz, CDCl3): d = 19.3 (CH3), 20.1 (CH3), 21.5
(CH3), 28.7 (CH), 48.8 (CH2), 51.2 (CH3), 65.9 (CH), 122.3 (C),
127.2 (CH), 127.7 (2 CH), 128.5 (CH), 129.4 (2 CH), 130.2 (CH),
132.3 (CH), 136.2 (C), 137.0 (C), 143.7 (C), 170.7 (C).
MS (ESI): m/z = 476, 478 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C20H24BrNO4S: C, 52.87; H, 5.32; N, 3.08. Found:
C, 53.09; H, 5.53; N, 3.29.
2-[(2-Bromobenzyl)(toluene-4-sulfonyl)amino]-4-methylpen-
tanoic Acid Methyl Ester (6c)
White crystalline solid; mp 118–120 °C; Rf = 0.52 (PE–EtOAc,
4:1); [a]D25 –20.49 (c 0.30, CHCl3).
IR (KBr): 3059, 2958, 2921, 2868, 1942, 1737, 1593, 1440, 1346,
1201, 1160, 1028 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.58 (d, J = 5.7 Hz, 3 H), 0.87 (d,
J = 5.4 Hz, 3 H), 1.26–1.38 (m, 1 H), 1.46–1.50 (m, 1 H), 2.44 (s, 3
H), 3.38 (s, 3 H), 4.57–4.62 (m, 2 H), 4.68–4.79 (m, 1 H), 7.12 (t,
J = 7.5 Hz, 1 H), 7.31–7.36 (m, 3 H), 7.49 (d, J = 8.1 Hz, 1 H),
7.72–7.79 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 21.6 (CH3), 21.7 (CH3), 22.2
(CH3), 24.7 (CH), 39.2 (CH2), 48.9 (CH2), 51.8 (CH3), 58.2 (CH),
122.3 (C), 127.5 (CH), 127.6 (2 CH), 128.7 (CH), 129.5 (2 CH),
130.2 (CH), 132.4 (CH), 136.4 (C), 137.1 (C), 143.7 (C), 171.4 (C).
Bromobenzyl(toluene-4-sulfonyl)amino Acid Methyl Esters
6a–g; General Procedure
To a magnetically stirred solution of compound 4a–e (5.26 mmol)
in anhyd MeCN (30 mL) at r.t. was added K2CO3 (1.45 g, 10.52
mmol) and sonicated for 20 min. The suspension was stirred for 10
min at r.t. and the respective 2-bromobenzyl bromide 5a,b (0.98
mL, 6.31 mmol) was added and again sonicated for 10 min. The
mixture was then stirred for 14 h at r.t. under dry condition and ex-
tracted with CH2Cl2 (3 × 30 mL). The organic layer was dried
(Na2SO4) and evaporated. The residue was washed with PE (2–3 ×
20 mL) to remove excess 2-bromobenzyl bromide and subjected to
column chromatography over silica gel (eluent: PE–EtOAc, 7:1) to
afford pure solid product.
MS (ESI): m/z = 490, 492 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C21H26BrNO4S: C, 53.85; H, 5.59; N, 2.99. Found:
C, 53.66; H, 5.38; N, 3.20.
2-[(2-Bromobenzyl)(toluene-4-sulfonyl)amino]-3-methylpen-
tanoic Acid Methyl Ester (6d)
White crystalline solid; mp 136–137 °C; Rf = 0.50 (PE–EtOAc,
4:1); [a]D25 –28.58 (c 0.50, CHCl3).
IR (KBr): 3071, 2961, 2873, 1734, 1595, 1440, 1340, 1199, 1157,
1110, 1018 cm–1.
2-[(2-Bromobenzyl)(toluene-4-sulfonyl)amino]propionic Acid
Methyl Ester (6a)
1H NMR (300 MHz, CDCl3): d = 0.47 (br s, 3 H), 0.75 (d, J = 4.2
Hz, 3 H), 0.91–0.96 (m, 1 H), 1.52–1.59 (m, 2 H), 2.43 (s, 3 H), 3.31
(s, 3 H), 4.21 (d, J = 9.3 Hz, 1 H), 4.65 (d, J = 17.7 Hz, 1 H), 5.14
(d, J = 17.7 Hz, 1 H), 7.11–7.13 (m, 1 H), 7.29–7.31 (m, 3 H), 7.49
(d, J = 6.9 Hz, 1 H), 7.71 (d, J = 6.3 Hz, 2 H), 7.82 (d, J = 7.5 Hz, 1
H).
White crystalline solid; mp 115–118 °C; Rf = 0.53 (PE–EtOAc,
4:1); [a]D25 –28.15 (c 0.50, CHCl3).
IR (KBr): 3064, 2976, 1740, 1596, 1450, 1342, 1198, 1161, 1029,
902, 846, 816 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (d, J = 7.2 Hz, 3 H), 2.43 (s,
3 H), 3.43 (s, 3 H), 4.55–4.72 (m, 3 H), 7.11 (t, J = 7.2 Hz, 1 H),
7.31 (d, J = 7.2 Hz, 3 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.68–7.74 (m, 3
H).
13C NMR (75 MHz, CDCl3): d = 10.5 (CH3), 15.4 (CH3), 21.5
(CH3), 26.4 (CH2), 35.0 (CH), 48.7 (CH2), 51.2 (CH3), 64.5 (CH),
122.3 (C), 127.4 (CH), 127.7 (2 CH), 128.6 (CH), 129.5 (2 CH),
130.4 (CH), 132.4 (CH), 136.1 (C), 137.3 (C), 143.7 (C), 171.0 (C).
13C NMR (75 MHz, CDCl3): d = 16.6 (CH3), 21.5 (CH3), 49.0
(CH2), 52.0 (CH3), 55.4 (CH), 122.1 (C), 127.5 (3 CH), 128.7 (CH),
129.6 (2 CH), 129.6 (CH), 132.4 (CH), 136.5 (C), 137.0 (C), 143.7
(C), 171.4 (C).
MS (ESI): m/z = 490, 492 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C21H26BrNO4S: C, 53.85; H, 5.59; N, 2.99. Found:
C, 54.07; H, 5.80; N, 3.18.
MS (ESI): m/z = 448, 450 [M + Na] + for 79Br, 81Br.
2-[(2-Bromobenzyl)(toluene-4-sulfonyl)amino]-3-phenylpropi-
onic Acid Methyl Ester (6e)
Anal. Calcd for C18H20BrNO4S: C, 50.71; H, 4.73; N, 3.29. Found:
C, 50.94; H, 4.99; N, 3.05.
White crystalline solid; mp 130–133 °C; Rf = 0.49 (PE–EtOAc,
4:1); [a]D25 –14.08 (c 0.24, CHCl3).
2-[(2-Bromobenzyl)(toluene-4-sulfonyl)amino]-3-methylbutyr-
ic Acid Methyl Ester (6b)
IR (KBr): 3062, 3034, 2948, 2926, 1734, 1440, 1346, 1160, 1091,
1021 cm–1.
White crystalline solid; mp 132–133 °C; Rf = 0.52 (PE–EtOAc,
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 2.79 (dd, J = 6.2,
13.6 Hz, 1 H), 3.06 (dd-like, 1 H), 3.28 (s, 3 H), 4.65 (d, J = 17.4
Hz, 1 H), 4.79–4.85 (m, 2 H), 7.02–7.11 (m, 3 H), 7.18–7.23 (m, 4
H), 7.30 (d, J = 8.1 Hz, 2 H), 7.52 (dd, J = 8.1, 12.3 Hz, 2 H), 7.72
(d, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 36.7 (CH2), 49.0
(CH2), 51.7 (CH3), 60.8 (CH), 122.2 (C), 126.8 (CH), 127.4 (CH),
127.6 (2 CH), 128.4 (2 CH), 128.7 (CH), 129.0 (2 CH), 129.6 (2
4:1); [a]D25 –34.46 (c 0.46, CHCl3).
IR (KBr): 3067, 2970, 1737, 1595, 1468, 1439, 1347, 1295, 1203,
1158, 1112, 1022 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (d, J = 6.3 Hz, 6 H), 1.88–
1.96 (m, 1 H), 2.43 (s, 3 H), 3.32 (s, 3 H), 4.16 (d, J = 9.6 Hz, 1 H),
4.61 (d, J = 17.7 Hz, 1 H), 5.04 (d, J = 18.0 Hz, 1 H), 7.10 (t, J = 7.2
Hz, 1 H), 7.29 (d, J = 7.2 Hz, 3 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.70–
7.74 (m, 3 H).
Synthesis 2011, No. 4, 585–592 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Pure Benzoxazepines
589
CH), 129.9 (CH), 132.3 (CH), 136.0 (C), 136.3 (C), 136.4 (C),
143.8 (C), 170.3 (C).
IR (neat): 3527, 2926, 1730, 1597, 1441, 1335, 1156, 1091, 1019,
907, 848, 815, 751 cm–1.
MS (ESI): m/z = 524, 526 [M + Na]+ for 79Br, 81Br.
1H NMR (300 MHz, CDCl3): d = 0.90 (d, J = 6.9 Hz, 3 H), 2.44 (s,
3 H), 3.30 (d, J = 6.3 Hz, 2 H), 4.06 (q, J = 6.6 Hz, 1 H), 4.43 (d,
J = 16.8 Hz, 1 H), 4.63 (d, J = 16.8 Hz, 1 H), 7.13 (t, J = 7.0 Hz, 1
H), 7.33 (d, J = 8.1 Hz, 3 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.76 (d,
J = 8.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 14.1 (CH3), 21.5 (CH3), 46.9
(CH2), 56.0 (CH), 64.6 (CH2), 122.2 (C), 127.1 (2 CH), 127.9 (CH),
129.0 (CH), 129.8 (CH), 129.9 (2 CH), 132.6 (CH), 137.2 (C),
137.4 (C), 143.6 (C).
Anal. Calcd for C24H24BrNO4S: C, 57.37; H, 4.81; N, 2.79. Found:
C, 57.11; H, 5.08; N, 2.55.
2-[(2-Bromo-5-methoxybenzyl)(toluene-4-sulfonyl)amino]-3-
phenylpropionic Acid Methyl Ester (6f)
White crystalline solid; mp 126–128 °C; Rf = 0.47 (PE–EtOAc,
4:1); [a]D25 –34.46 (c 0.50, CHCl3).
IR (KBr): 3064, 3029, 2997, 2951, 2833, 1938, 1735, 1593, 1468,
1436, 1345, 1295, 1265, 1215, 1165, 1117, 1090, 1047, 1017 cm–1.
MS (ESI): m/z = 420, 422 [M + Na]+ for 79Br, 81Br.
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 2.83 (dd, J = 7.0,
14.0 Hz, 1 H), 3.13 (dd, J = 8.1, 14.1 Hz, 1 H), 3.35 (s, 3 H), 3.63
(s, 3 H), 4.59 (d, J = 17.4 Hz, 1 H), 4.75 (d, J = 17.4 Hz, 1 H), 4.83
(t-like, J = 7.7 Hz, 1 H), 6.65 (dd, J = 3.0, 8.7 Hz, 1 H), 7.02–7.04
(m, 3 H), 7.19–7.21 (m, 3 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.36 (d,
J = 8.7 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 2 H).
Anal. Calcd for C17H20BrNO3S: C, 51.26; H, 5.06; N, 3.52. Found:
C, 51.46; H, 4.89; N, 3.30.
N-(2-Bromobenzyl)-N-(1-hydroxymethyl-2-methylpropyl)-4-
methylbenzenesulfonamide (7b)
Thick oil; Rf = 0.31 (PE–EtOAc, 4:1); [a]D25 –4.08 (c 0.6, CHCl3).
13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 36.6 (CH2), 49.2
(CH2), 51.8 (CH3), 55.2 (CH3), 60.8 (CH), 112.5 (C), 114.7 (CH),
115.6 (CH), 126.7 (CH), 127.6 (2 × CH), 128.4 (2 × CH), 128.8
(2 × CH), 129.6 (2 × CH), 132.9 (CH), 136.1 (C), 136.4 (C), 137.2
(C), 143.8 (C), 159.0 (C), 170.4 (C).
IR (neat): 3537, 2962, 1598, 1466, 1440, 1334, 1155, 1092, 1021,
884, 814, 754 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.56 (d, J = 6.6 Hz, 3 H), 0.86 (d,
J = 6.3 Hz, 3 H), 1.79–1.81 (m, 1 H), 2.45 (s, 3 H), 3.40–3.47 (m, 2
H), 3.71 (d, J = 9.6 Hz, 1 H), 4.52 (d, J = 16.8 Hz, 1 H), 4.70 (d,
J = 16.8 Hz, 1 H), 7.15 (t, J = 7.2 Hz, 1 H), 7.28–7.38 (m, 3 H), 7.51
(d, J = 7.8 Hz, 1 H), 7.82 (dd, J = 7.5, 20.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 20.1 (CH3), 20.4 (CH3), 21.4
(CH3), 28.0 (CH), 48.2 (CH2), 62.0 (CH2), 66.8 (CH), 122.5 (C),
127.4 (2 × CH), 127.6 (CH), 129.0 (CH), 129.6 (2 × CH), 130.3
(CH), 132.5 (CH), 136.8 (C), 137.4 (C), 143.5 (C).
MS (ESI): m/z = 554, 556 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C25H26BrNO5S: C, 56.39; H, 4.92; N, 2.63. Found:
C, 56.14; H, 5.11; N, 2.39.
2-[(2-Bromo-5-methoxybenzyl)(toluene-4-sulfonyl)amino]-3-
methylbutyric Acid Methyl Ester (6g)
White crystalline solid; mp 137 °C; Rf = 0.50 (PE–EtOAc, 4:1);
MS (ESI): m/z = 448, 450 [M+ + Na] for 79Br, 81Br.
[a]D25 +9.88 (c 0.20, CHCl3).
Anal. Calcd for C19H24BrNO3S: C, 53.52; H, 5.67; N, 3.29. Found:
C, 53.29; H, 5.42; N, 3.48.
IR (KBr): 2969, 1736, 1594, 1438, 1347, 1158, 1022 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.85 (dd, J = 6.8, 9.4 Hz, 6 H),
1.92–2.00 (m, 1 H), 2.43 (s, 3 H), 3.34 (s, 3 H), 3.76 (s, 3 H), 4.18
(d, J = 9.9 Hz, 1 H), 4.55 (d, J = 17.4 Hz, 1 H), 5.00 (d, J = 17.7 Hz,
1 H), 6.67 (dd, J = 2.8, 8.6 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 3 H), 7.36
(d, J = 8.7 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 2 H).
N-(2-Bromobenzyl)-N-(1-hydroxymethyl-3-methylbutyl)-4-
methylbenzenesulfonamide (7c)
Sticky oil; Rf = 0.28 (PE–EtOAc, 4:1); [a]D +10.22 (c 0.50,
CHCl3).
25
13C NMR (75 MHz, CDCl3): d = 19.3 (CH3), 20.1 (CH3), 21.5
(CH3), 28.6 (CH), 48.8 (CH2), 51.3 (CH3), 55.3 (CH3), 66.0 (CH),
112.6 (C), 115.0 (CH), 115.2 (CH), 127.6 (2 × CH), 129.4
(2 × CH), 132.9 (CH), 136.2 (C), 137.8 (C), 143.7 (C), 158.8 (C),
170.7 (C).
IR (neat): 3533, 3062, 2956, 2872, 1921, 1597, 1465, 1441, 1333,
1156, 1091, 1026 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.69 (dd, J = 6.4, 11.8 Hz, 6 H),
1.16–1.45 (m, 2 H), 1.84 (s, 1 H), 2.46 (s, 3 H), 3.28–3.34 (m, 1 H),
3.43 (br s, 1 H), 3.88 (br s, 1 H), 4.64 (dd, J = 16.8, 45.9 Hz, 2 H),
7.16 (t, J = 7.5 Hz, 1 H), 7.34–7.45 (m, 3 H), 7.52 (d, J = 7.8 Hz, 1
H), 7.78–7.85 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 21.6 (CH3), 22.3 (CH3), 22.6
(CH3), 24.7 (CH), 38.2 (CH2), 47.4 (CH2), 58.7 (CH), 63.4 (CH2),
122.3 (C), 127.4 (2 CH), 127.9 (CH), 129.1 (CH), 129.8 (2 CH),
130.1 (CH), 132.6 (CH), 137.2 (C), 137.5 (C), 143.7 (C).
MS (ESI): m/z = 506, 508 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C21H26BrNO5S: C, 52.07; H, 5.41; N, 2.89. Found:
C, 51.88; H, 5.18; N, 3.12.
Benzenesulfonamides 7a–g; General Procedure
To a magnetically stirred solution of compound 6a–g (1.545 mmol)
in anhyd THF (20 mL) was added LiBH4 (67 mg, 3.09 mmol) and
refluxed for 14–20 h at 90 °C under dry conditions. The reaction
was monitored by TLC and the mixture was extracted with EtOAc
(3 × 30 mL). The combined organic layers were dried (Na2SO4) and
evaporated to afford the crude product. The purification of the crude
material was performed by column chromatography over silica gel
(eluent: PE–EtOAc, 5:1) to furnish the pure compound as a sticky
oil.
MS (ESI): m/z = 462, 464 [M+ + Na] for 79Br, 81Br.
Anal. Calcd for C20H26BrNO3S: C, 54.55; H, 5.95; N, 3.18. Found:
C, 54.31; H, 6.16; N, 3.34.
N-(2-Bromobenzyl)-N-(1-hydroxymethyl-2-methylbutyl)-4-
methylbenzenesulfonamide (7d)
Thick oil; Rf = 0.29 (PE–EtOAc, 4:1); [a]D25 – 5.81 (c 0.50, CHCl3).
IR (neat): 3536, 2963, 2926, 1596, 1464, 1326, 1156, 1091, 1018
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.60 (d, J = 3.9 Hz, 3 H), 0.77 (d,
J = 6.6 Hz, 3 H), 0.88–0.99 (m, 1 H), 1.26 (br s, 1 H), 1.43 (br s, 1
H), 2.44 (s, 3 H), 3.41–3.58 (m, 2 H), 3.69 (d, J = 10.0 Hz, 1 H),
4.59 (dd, J = 16.8, 27.6 Hz, 2 H), 7.13 (t, J = 6.9 Hz, 1 H), 7.32 (d,
N-(2-Bromobenzyl)-N-(2-hydroxy-1-methylethyl)-4-methyl-
benzenesulfonamide (7a)
Thick oil; Rf = 0.30 (PE–EtOAc, 4:1); [a]D +21.47 (c 0.16,
25
MeOH).
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J = 7.8 Hz, 3 H), 7.50 (d, J = 7.8 Hz, 2 H), 7.76 (d, J = 8.1 Hz, 2 H),
7.84 (d, J = 7.2 Hz, 1 H).
112.6 (C), 114.6 (CH), 116.1 (CH), 127.5 (2 CH), 129.6 (2 CH),
133.1 (CH), 137.6 (C), 137.8 (C), 143.6 (C), 159.2 (C).
13C NMR (75 MHz, CDCl3): d = 11.2 (CH3), 15.8 (CH3), 21.5
(CH3), 26.3 (CH2), 34.8 (CH), 48.4 (CH2), 62.0 (CH2), 65.6 (CH),
122.6 (C), 127.5 (2 CH), 127.8 (CH), 129.0 (CH), 129.7 (2 CH),
130.5 (CH), 132.6 (CH), 136.9 (C), 137.6 (C), 143.6 (C).
MS (ESI): m/z = 478, 480 [M + Na]+ for 79Br, 81Br.
Anal. Calcd for C20H26BrNO4S: C, 52.63; H, 5.74; N, 3.07. Found:
C, 52.87; H, 5.58; N, 2.87.
MS (ESI): m/z = 462, 464 [M + Na]+ for 79Br, 81Br.
Benzoxazepines 8a–g; General Procedure
To a magnetically stirred solution of compound 7a–g (0.8 mmol) in
anhyd toluene (10 mL/mol substrate) were added Pd2(dba)3 (0.073
g, 10 mol%), ( )-BINAP (0.035 g, 7 mol%), t-BuOK (0.179 g, 1.6
mmol), and K2CO3 (0.221 g, 1.6 mmol) and the reaction mixture
was heated at 90 °C for 16–18 h under N2. The crude mixture was
passed through a bed of silica gel. The solvent was evaporated and
the residue was extracted with CH2Cl2 (4 × 50 mL). The combined
organic layers were washed with H2O (4 × 50 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure to
give the crude product, which was purified by column chromatog-
raphy over silica gel (eluent: PE–EtOAc, 8:1) to furnish the pure cy-
clized product.
Anal. Calcd for C20H26BrNO3S: C, 54.55; H, 5.95; N, 3.18. Found:
C, 54.28; H, 5.77; N, 2.93.
N-(1-Benzyl-2-hydroxyethyl)-N-(2-bromobenzyl)-4-methylben-
zenesulfonamide (7e)
Sticky oil; Rf = 0.28 (PE–EtOAc, 4:1); [a]D25 –25.02 (c 0.9, CHCl3).
IR (neat): 3529, 3064, 3029, 2926, 1598, 1494, 1443, 1334, 1156,
1093, 1027, 888, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 2.57–2.72 (m, 2 H),
3.33–3.42 (m, 2 H), 4.02–4.06 (m, 1 H), 4.63 (d, J = 17.1 Hz, 1 H),
4.76 (d, J = 17.1 Hz, 1 H), 6.96 (d, J = 5.4 Hz, 2 H), 7.17 (br s, 4
H), 7.29–7.38 (m, 4 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.74–7.81 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 21.6 (CH3), 36.0 (CH2), 48.2
(CH2), 62.1 (CH2), 62.2 (CH), 122.4 (C), 126.6 (CH), 127.3 (2 CH),
128.0 (CH), 128.6 (2 CH), 128.9 (2 CH), 129.2 (CH), 129.9 (2 CH),
130.1 (CH), 132.7 (CH), 137.1 (C), 137.3 (C), 137.4 (C), 143.7 (C).
3-Methyl-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydroben-
zo[f][1,4]oxazepine (8a)
White solid; mp 111 °C; Rf = 0.58 (PE–EtOAc, 4:1); [a]D25 +14.6 (c
0.10, CHCl3).
IR (neat): 2923, 2853, 1601, 1491, 1457, 1334, 1262, 1156, 1092,
757 cm–1.
MS (ESI): m/z = 496, 498 [M + Na]+ for 79Br, 81Br.
1H NMR (600 MHz, CDCl3): d = 1.28 (d, J = 3.0 Hz, 3 H), 2.31 (s,
3 H), 3.87 (dd, J = 4.2, 13.2 Hz, 1 H), 3.97 (dd, J = 8.4, 13.2 Hz, 1
H), 4.30–4.34 (m, 1 H), 4.64 (d, J = 17.4 Hz, 1 H), 4.73 (d, J = 16.8
Hz, 1 H), 6.53 (d, J = 7.2 Hz, 1 H), 6.92 (t, J = 7.3 Hz, 1 H), 6.99 (d,
J = 7.8 Hz, 2 H), 7.03–7.05 (m, 1 H), 7.10 (d, J = 7.2 Hz, 1 H), 7.37
(d, J = 8.4 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 16.2 (CH3), 21.2 (CH3), 44.3
(CH2), 54.7 (CH), 74.5 (CH2), 119.6 (CH), 122.7 (CH), 126.5 (C),
127.3 (CH), 128.2 (CH), 128.5 (CH), 129.6 (CH), 137.2 (C), 142.7
(C), 158.5 (C).
Anal. Calcd for C23H24BrNO3S: C, 58.23; H, 5.10; N, 2.95. Found:
C, 57.98; H, 4.89; N, 3.11.
N-(2-Bromo-5-methoxybenzyl)-N-(1-hydroxymethyl-2-phenyl-
ethyl)-4-methylbenzenesulfonamide (7f)
Sticky liquid; Rf = 0.26 (PE–EtOAc, 4:1); [a]D +6.05 (c 0.20,
CHCl3).
25
IR (neat): 3535, 3024, 2924, 1597, 1469, 1333, 1238, 1157, 1094,
1020, 894, 812 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 2.58–2.73 (m, 2 H),
3.36–3.48 (m, 2 H), 3.77 (s, 3 H), 4.04–4.09 (m, 1 H), 4.57 (d,
J = 17.1 Hz, 1 H), 4.70 (d, J = 17.1 Hz, 1 H), 6.72 (dd, J = 3.0, 8.7
Hz, 1 H), 6.97 (d, J = 5.4 Hz, 2 H), 7.18 (br s, 3 H), 7.29–7.34 (m,
3 H), 7.41 (d, J = 8.7 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 36.0 (CH2), 48.2
(CH2), 55.4 (CH3), 62.1 (CH2), 62.3 (CH), 112.5 (C), 114.6 (CH),
116.0 (CH), 126.6 (CH), 127.3 (2 × CH), 128.6 (2 × CH), 128.9
(2 × CH), 129.8 (2 × CH), 133.2 (CH), 137.3 (C), 137.4 (C), 137.9
(C), 143.7 (C), 159.3 (C).
MS (ESI): m/z = 340 [M + Na]+.
Anal. Calcd for C17H19NO3S: C, 64.33; H, 6.03; N, 4.41. Found: C,
64.11; H, 6.27; N, 4.19.
3-Isopropyl-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydroben-
zo[f][1,4]oxazepine (8b)
Crystalline white solid; mp 145–148 °C; Rf = 0.58 (PE–EtOAc,
4:1); [a]D25 –11.16 (c 0.20, CHCl3).
IR (KBr): 3060, 2966, 1581, 1492, 1452, 1399, 1334, 1297, 1263,
1226, 1153 cm–1.
MS (ESI): m/z = 526, 528 [M + Na]+ for 79Br, 81Br.
1H NMR (CDCl3, 300 MHz): d = 1.04 (d, J = 6.0 Hz, 3 H), 1.06 (d,
J = 6.0 Hz, 3 H), 2.10–2.17 (m, 1 H), 2.27 (s, 3 H), 3.79–3.88 (m, 2
H), 4.13 (dd, J = 7.0, 12.8 Hz, 1 H), 4.56 (d, J = 17.1 Hz, 1 H), 4.76
(d, J = 16.8 Hz, 1 H), 6.48 (d, J = 7.8 Hz, 1 H), 6.88–7.03 (m, 4 H),
7.09 (d, J = 6.9 Hz, 1 H), 7.36 (d, J = 7.8 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 19.4 (CH3), 20.0 (CH3), 21.3
(CH3), 28.0 (CH), 45.8 (CH2), 64.0 (CH), 71.6 (CH2), 119.7 (CH),
122.7 (CH), 126.4 (C), 127.3 (CH), 128.4 (CH), 128.6 (CH), 129.5
(CH), 137.1 (C), 142.5 (C), 158.4 (C).
Anal. Calcd for C24H26BrNO4S: C, 57.14; H, 5.20; N, 2.78. Found:
C, 56.93; H, 5.42; N, 2.55.
N-(2-Bromo-5-methoxybenzyl)-N-(1-hydroxymethyl-2-methyl-
propyl)-4-methylbenzenesulfonamide (7g)
Thick oil; Rf = 0.29 (PE–EtOAc, 4:1); [a]D25 +7.14 (c 0.20, CHCl3).
IR (neat): 3534, 2962, 1597, 1470, 1332, 1239, 1155, 1092, 1046,
1014, 890, 814 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.58 (d, J = 6.3 Hz, 3 H), 0.85 (d,
J = 6.3 Hz, 3 H), 1.76–1.81 (m, 1 H), 2.43 (s, 3 H), 3.38–3.51 (m, 2
H), 3.71 (d, J = 12.0 Hz, 1 H), 3.78 (s, 3 H), 4.43 (d, J = 16.8 Hz, 1
H), 4.64 (d, J = 17.1 Hz, 1 H), 6.70 (dd, J = 2.5, 8.6 Hz, 1 H), 7.30–
7.37 (m, 4 H), 7.76 (d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.2 (CH3), 20.6 (CH3), 21.5
(CH3), 28.1 (CH), 48.4 (CH2), 55.5 (CH3), 62.0 (CH2), 67.0 (CH),
MS (ESI): m/z = 368 [M + Na]+.
Anal. Calcd for C19H23NO3S: C, 66.06; H, 6.71; N, 4.05. Found: C,
65.89; H, 6.97; N, 4.27.
3-Isobutyl-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydroben-
zo[f][1,4]oxazepine (8c)
Crystalline white solid; mp 148–149 °C; Rf = 0.61 (PE–EtOAc,
4:1); [a]D25 +9.38 (c 0.20, CHCl3).
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Synthesis of Optically Pure Benzoxazepines
591
IR (KBr): 2925, 2857, 1579, 1487, 1454, 1333, 1152, 1090, 1047
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H), 2.99 (dd, J = 4.6,
13.0 Hz, 1 H), 3.12–3.20 (m, 1 H), 3.67–3.71 (m, 1 H), 3.77 (s, 3 H),
4.00 (dd, J = 5.8, 12.8 Hz, 1 H), 4.27–4.28 (m, 1 H), 4.49 (d,
J = 16.8 Hz, 1 H), 4.63 (d, J = 17.1 Hz, 1 H), 6.63 (d, J = 15.9 Hz,
3 H), 7.03 (d, J = 8.1 Hz, 3 H), 7.30–7.41 (m, 6 H).
1H NMR (300 MHz, CDCl3): d = 0.98 (d-like, J = 5.4 Hz, 6 H),
1.31–1.40 (m, 1 H), 1.61–1.71 (m, 1 H), 1.76–1.82 (m, 1 H), 2.29
(s, 3 H), 3.80 (dd-like, J = 4.0, 13.0 Hz, 1 H), 3.93 (dd-like, J = 7.2,
12.9 Hz, 1 H), 4.21 (br s, 1 H), 4.64 (dd, J = 16.8, 41.1 Hz, 2 H),
6.51 (d, J = 7.8 Hz, 1 H), 6.90–7.05 (m, 4 H), 7.11 (d, J = 6.9 Hz, 1
H), 7.37 (d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.4 (CH3), 22.4 (CH3), 23.0
(CH3), 24.3 (CH), 38.8 (CH2), 45.0 (CH2), 56.3 (CH), 73.4 (CH2),
119.7 (CH), 122.7 (CH), 126.6 (C), 127.3 (2 CH), 128.5 (CH),
128.7 (2 CH), 129.6 (CH), 137.1 (C), 142.6 (C), 158.4 (C).
MS (ESI): m/z = 424 [M + H]+, 446 [M + Na]+.
Anal. Calcd for C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found: C,
68.29; H, 6.14; N, 3.05.
3-Isopropyl-7-methoxy-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahy-
drobenzo[f][1,4]oxazepine (8g)
Crystalline white solid; mp 157–158 °C; Rf = 0.56 (PE–EtOAc,
4:1); [a]D25 –8.08 (c 0.20, CHCl3).
MS (ESI): m/z = 360 [M + H], 382 [M + Na]+.
IR (KBr): 2966, 1591, 1500, 1336, 1275, 1211, 1151, 1051, 899,
814 cm–1.
Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.01; N, 3.90. Found: C,
67.04; H, 6.78; N, 4.13.
1H NMR (300 MHz, CDCl3): d = 1.02–1.05 (m, 6 H), 2.18–2.20 (m,
1 H), 2.30 (s, 3 H), 3.70 (d, J = 10.8 Hz, 2 H), 3.76 (s, 3 H), 4.10 (t-
like, J = 6.9 Hz, 1 H), 4.50 (d, J = 16.8 Hz, 1 H), 4.68 (d, J = 16.8
Hz, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 6.57 (dd, J = 2.4, 8.7 Hz, 1 H),
6.64 (s, 1 H), 7.00 (d, J = 7.8 Hz, 2 H), 7.41 (d, J = 8.1 Hz, 2 H).
3-sec-Butyl-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydroben-
zo[f][1,4]oxazepine (8d)
Crystalline white solid; mp 143 °C; Rf = 0.60 (PE–EtOAc, 4:1);
[a]D25 +7.04 (c 0.20, CHCl3).
IR (KBr): 2966, 2927, 2874, 1917, 1600, 1492, 1453, 1384, 1342,
1222, 1155, 1091, 1045, 1007 cm–1.
13C NMR (75 MHz, CDCl3): d = 19.5 (CH3), 20.0 (CH3), 21.4
(CH3), 27.4 (CH), 45.7 (CH2), 55.7 (CH3), 64.0 (CH), 71.8 (CH2),
113.7 (CH), 114.2 (CH), 120.6 (CH), 127.4 (2 CH), 128.2 (C),
128.8 (2 CH), 137.3 (C), 142.7 (C), 152.7 (C), 155.0 (C).
1H NMR (300 MHz, CDCl3): d = 0.97 (dd, J = 7.1, 16.0 Hz, 6 H),
1.15–1.25 (m, 1 H), 1.71–1.79 (m, 1 H), 1.89–1.91 (m, 1 H), 2.27
(s, 3 H), 3.84–3.92 (m, 2 H), 4.10–4.17 (m, 1 H), 4.58 (d, J = 17.1
Hz, 1 H), 4.77 (d, J = 17.1 Hz, 1 H), 6.45 (d, J = 7.8 Hz, 1 H), 6.87–
7.02 (m, 4 H), 7.07 (d, J = 7.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 11.4 (CH3), 15.3 (CH3), 21.3
(CH3), 25.8 (CH2), 35.0 (CH), 46.1 (CH2), 62.8 (CH), 71.3 (CH2),
119.6 (CH), 122.6 (CH), 126.0 (C), 127.3 (2 CH), 128.4 (CH),
128.6 (2 CH), 129.5 (CH), 137.0 (C), 142.5 (C), 158.3 (C).
MS (ESI): m/z = 376 [M + H]+, 398 [M + Na]+.
Anal. Calcd for C20H25NO4S: C, 63.97; H, 6.71; N, 3.73. Found: C,
64.14; H, 6.54; N, 3.98.
Acknowledgment
Financial support from the Department of Science and Technology
(DST), New Delhi, Government of India is gratefully acknowled-
ged. We thank CSIR (India) for financial assistance. Thanks are
also due to Dr. B. Achari, Emeritus Scientist, IICB, for valuable
suggestions.
MS (ESI): m/z = 382 [M + Na]+.
Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.01; N, 3.90. Found: C,
67.06; H, 7.23; N, 3.74.
3-Benzyl-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydroben-
zo[f][1,4]oxazepine (8e)
References
Crystalline colorless solid; mp 153–154 °C; Rf = 0.59 (PE–EtOAc,
4:1); [a]D25 +11.60 (c 0.60, CHCl3).
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13.2 Hz, 1 H), 3.11 (dd, J = 9.0, 13.2 Hz, 1 H), 3.79 (dd, J = 3.6,
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MS (ESI): m/z = 416 [M + Na]+.
Anal. Calcd for C23H23NO3S: C, 70.20; H, 5.89; N, 3.56. Found: C,
69.97; H, 6.07; N, 3.34.
3-Benzyl-7-methoxy-4-(toluene-4-sulfonyl)-2,3,4,5-tetrahy-
drobenzo[f][1,4]oxazepine (8f)
Yellowish white solid; mp 159–160 °C; Rf = 0.55 (PE–EtOAc,
4:1); [a]D25 +5.20 (c 0.15, CHCl3).
IR (KBr): 2948, 1667, 1623, 1506, 1432, 1355, 1121, 1034 cm–1.
Synthesis 2011, No. 4, 585–592 © Thieme Stuttgart · New York

592
D. Bhattacharya et al.
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Synthesis 2011, No. 4, 585–592 © Thieme Stuttgart · New York