Synthesis of optically active 1,4-benzoxazine derivatives using palladium-catalyzed coupling kinetic resolution

Article abstract of DOI:10.1016/j.tetasy.2011.06.005

A novel coupling kinetic resolution has been developed by employing commercially available reagents, such as Pd(OOCCF₃) ₂-(S)-BINAP, which is a simple and convenient protocol that enables the formation of a highly important, novel cl

Full text of DOI:10.1016/j.tetasy.2011.06.005

Tetrahedron: Asymmetry 22 (2011) 948–954
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journal homepage: www.elsevier.com/locate/tetasy
Synthesis of optically active 1,4-benzoxazine derivatives
using palladium-catalyzed coupling kinetic resolution
⇑
R. Koteshwar Rao, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel coupling kinetic resolution has been developed by employing commercially available reagents,
such as Pd(OOCCF3)2–(S)-BINAP, which is a simple and convenient protocol that enables the formation
of a highly important, novel class of optically active trans-1,4-benzoxazine derivatives and optically
active trans-recovered starting materials with moderate selectivity (s).
Received 4 April 2011
Accepted 2 June 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
ever, all the aforementioned methods are achiral methodologies
and provide racemic 1,4-benzoxazine derivatives. As a result
Developing novel methods to synthesize chiral molecules has
become an important pursuit for synthetic organic chemists. Dif-
ferent enantiomers generally exhibit different biological activities.
In biological systems, enzymes catalyze the reactions with excel-
lent selectivity for the synthesis of a single enantiomer. These
natural catalysts have inspired chemists to develop a variety of
non-enzymatic synthetic catalysts, which can catalyze the reac-
tions with excellent selectivity.1
development of a novel chiral method is highly desirable.
In order to devise a more efficient and simple chiral catalyst
system for the synthesis of optically active trans-1,4-benzoxazines,
we explored a novel kinetic resolution11 method based on a cou-
pling reaction (coupling kinetic resolution) by the use of simple
and commercially available palladium as a metal source with the
support of chiral chelating ligand (Scheme 1).
For the past few years, great advances have been made in the
development of cross-coupling methodology.2 The leading applica-
tion of cross-coupling chemistry, in particular C–N bond-forming
reactions, are important in medicinal chemistry, pharmaceutical
companies and in academic laboratories.
Organic compounds containing 1,4-benzoxazine and phenoxa-
zine moieties have attracted interest due to their biological activi-
ties.3 Generally, 1,4-benzoxazine compounds are synthesized via a
multistepprocess, suchas thecyclocondensationof o-aminophenols
withsuitabledihaloderivatives,4 cyclocondensationof o-aminophe-
coupling kinetic resolution
Ts
NH
Ts
NH
Ts
N
*
*
Pd catalyst
chiral ligand
*
*
+
R
O
O
O
n
n
n
X
R
X
R
optically active
product
( )
optically active
recovered starting material
nols with a-halo-acyl bromides followed by carbonyl group reduc-
tion with BH3,5 and alkylation of o-nitrophenol with a haloester
followed by reductive cyclization.6 Alternatively, these 1,4-benzox-
azine moieties can be made via a ring opening of an epoxide with o-
halosulfonamides followed by cyclization7 or ring opening of an
epoxide with o-aminophenols followed by cyclocondensation.8
As part of our ongoing research towards copper catalyzed cou-
pling chemistry,9 we have very recently developed a domino reac-
tion, as an alternative to the conventional multistep process to
prepare a 1,4-benzoxazine skeleton in a single process from readily
available o-iodophenols and aziridines using a copper-catalyzed
domino ring opening followed by a Goldberg cyclization.10 How-
Scheme 1. Proposed scheme for the coupling kinetic resolution.
2. Results and discussion
In our initial studies, the palladium catalyzed coupling kinetic
resolution was carried out using trans-N-(2-(2-iodophenoxy)-
cyclohexyl)-4-methylbenzenesulfonamide ( )-1 in the presence
of 5 mol % of Pd(OAc)2 and 10 mol % of (S)-BINAP in toluene at
110 °C. The reaction provided 10% ee and 58% isolated yield for
the recovered starting material (+)-1 and 16% ee, 36% yield for
the corresponding product 4 (Table 1, entry 1).
In general, lowering the reactivity of the starting material, in-
creased the selectivity. Hence, the more reactive iodo-starting
material ( )-1 was replaced by the corresponding less reactive
⇑
Corresponding author.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.005

R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
949
Table 1
Selection of starting material for the coupling kinetic resolution
Ts
Ts
Ts
N
Pd(OAc)2 (5 mol%)
(S)-BINAP (10 mol%)
NH
NH
*
*
*
+
*
Cs2CO3
toluene, 110 °C
O
O
O
(+)-4
( )-trans
X
X
( )-1: X = I
( )-2: X= Br
( )-3: X = Cl
Entry
Substrate
Time (h)
Recovered starting material
Product
Conversion (C) (%)
Selectivity factor (s)
eea (%)
Yieldb (%)
eea (%)
Yieldb (%)
1
2
3
( )-1
( )-2
( )-3
8
7
48
10
34
02
58
42
81
16
26
10
36
55
13
38.5
56.7
16.8
1.5
2.3
1.2
a
%Ee were calculated using HPLC chiral columns.
Isolated yield.
b
bromo-starting material ( )-2. As expected, replacing trans-( )-1
with ( )-2 increased the enantiomeric excess up to 34% ee for
the recovered starting material and 26% ee for the product with a
selectivity of 2.3 (entry 2). However, decreasing the reactivity fur-
ther by using the corresponding chloro precursor ( )-3 reduced the
selectivity to 1.2 (entry 3).
After selecting bromo derivative ( )-2 as the starting material
for the coupling kinetic resolution, we started our optimization
process by changing several parameters. Initially, we screened sev-
eral chiral ligands and the results are summarized in Table 2.
Among them, (S)-BINAP provided a maximum selectivity (s = 2.3)
for the coupling kinetic resolution (Table 2, entry 1). When chiral
palladium carbene catalyst 5 was used alone, there was no reac-
tion, whereas the chiral palladium carbene catalyst 5 in combina-
tion with PPh3 catalyzed the coupling reaction but without any
selectivity (entry 6). However, the chiral palladium carbene cata-
lyst 5 in combination with (S)-BINAP provided an improved selec-
tivity of 3.2 (entry 7). This observation clearly shows that the (S)-
BINAP is important for the coupling kinetic resolution to give good
selectivity.
The coupling kinetic resolution was further optimized by
changing the palladium source and the results are summarized in
Table 3. Although several palladium salts catalyzed the coupling
kinetic resolution reaction, the Pd(OOCCF3)2 turned out to be the
optimal palladium salt in terms of selectivity (s = 3.7) (Table 3, en-
try 4). The reaction was further optimized by changing the solvents
and bases to increase the efficiency of the coupling kinetic resolu-
tion. Among all the solvents examined, toluene provided the best
results in terms of selectivity. The selectivity factor in the case of
dioxane is only 1.7 while the reaction in DMF lowered the selectiv-
ity further to 1.2. The reaction in acetonitrile and in THF did not
provide any selectivity. Among the bases K2CO3, K3PO4, Na2CO3
and Cs2CO3 screened, the Cs2CO3 continued to be the optimal base
for the coupling kinetic resolution as it provided the maximum
selectivity of 3.7 at 68.3% conversion in toluene using Pd(OOCCF3)2
(5 mol %)–(S)-BINAP (10 mol %).
Using the aforementioned optimized reaction conditions, we
initiated our investigation into the scope of the chiral palladium
catalyzed coupling kinetic resolution and the results are summa-
rized in Table 4. The starting material trans-N-(2-(2-bromophen-
oxy)cyclohexyl)-4-methylbenzenesulfonamide ( )-2 provided
a
Table 2
Screening of Chiral Ligands for the coupling kinetic resolution
Ts
NH
Ts
NH
Ts
N
Pd(OAc)2 (5 mol%)
chiral ligand (10 mol%)
+
Cs2CO3
O
O
O
toluene, 110 °C
( )-trans-2
Br
Br
Entry
Ligands
Time (h)
Recovered starting material
Product
Conversion C (%)
Selectivity factor (s)
eea (%)
Yieldb (%)
eea (%)
Yieldb (%)
1
2
3
4
5
6
7
(S)-BINAP
L1
L2
L3
Catalyst 5
Catalyst 5 PPh3
Catalyst 5 (S)-BINAP
7
48
48
48
48
4.5
5
34
—
—
—
—
42
—
26
—
—
—
—
55
—
56.7
<5%
No rxn
No rxn
No rxn
38.0
2.3
—
—
—
—
>99
>99
>99
62
72
O
00
00
00
33
19
00
12
00
48
—
3.2
20.0
PPh2
PPh2
N
N
N
Pd
N
N
N
N
O
I
I
O
PPh2
N
L2
N
L1
L3
catalyst 5
a
% Ee were calculated using HPLC chiral columns.
Isolated yield.
b

950
R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
Table 3
Screening of palladium salts for the coupling kinetic resolution
Ts
NH
Ts
NH
Ts
N
Pd salt (5 mol%)
(S)-BINAP (10 mol%)
+
Cs2CO3
toluene,110 °C
O
O
O
( )-trans-2
Br
Br
Entry
Pd salts
Time (h)
Recovered starting material
Product
Conversion C (%)
Selectivity factor (s)
eea (%)
Yieldb (%)
eea (%)
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
Pd2dba3
Pd(OOCCF3)2
Pd(acac)2
K2PdCl4
Pd(OOCCF3)2
Pd(OOCCF3)2
7
72
7.5
3.5
3.5
72
4
34
52
53
69
41
39
96
48
42
9
26
6
55
72
81
62
51
45
85
53
56.7
10.3
82.8
68.3
51.3
48.8
88.9
55.8
2.3
3.4
1.9
3.7
3.3
3.4
3.6
3.5
13
32
43
42
10
40
11
32
39
41
12
38
3 h 10 min
a
% Ee were calculated using HPLC chiral columns.
Isolated yield.
b
maximum selectivity of 3.7 with 69% ee for the recovered starting
material and 32% ee for the product (entry 1). When the ring size
was altered, the selectivity of the reaction was slightly reduced
(entries 2 and 6). When electron withdrawing groups were present
on the aromatic ring, a small reduction in selectivity (entries 3 and
5) was observed, while electron-donating groups reduced the
selectivity further (entries 4 and 7). The enantiomerically enriched
recovered starting material can be further reacted with an achiral
palladium complex to obtain the other enantiomer of the cyclized
product.
A plausible reaction pathway is described in Scheme 2. Initially,
the oxidative coupling takes place at the aryl-bromide bond of ( )-
2 with the chiral palladium catalyst; the selectivity is due to the
diastereomeric transition state pair. The faster reacting enantiomer
of ( )-2 reacts first and produces intermediate 6 followed by nucle-
ophilic displacement to give intermediate 7. Intermediate 7, upon
reductive elimination releases the desired enantiomerically en-
riched product (+)-4 and simultaneously regenerates the palla-
dium(0) catalyst for the next cycle. When the reaction was
stopped before completion, the fast reacting enantiomer of the
( )-2 was converted into the product and slow reacting enantiomer
of the ( )-2 starting material remained in the reaction mixture in
an enantiomerically enriched form.
dried over sodium wire (vacuum distillation). Reactions were per-
formed by using Aldrich Stirrer, Thin-layer chromatography (TLC)
was performed using Merck Silica Gel 60 F254 pre-coated plates
(0.25 mm) and visualized by UV fluorescence quenching. Silica
gel (particle size 100–200 mesh) purchased from SRL India was
used for chromatography. 1H and 13C NMR spectra were recorded
on a Bruker 400 MHz instrument. 1H NMR spectra were reported
relative to Me4Si (d 0.0 ppm) or residual CHCl3 (d 7.26 ppm). 13C
NMR were reported relative to CDCl3 (d 77.16 ppm). FTIR spectra
were recorded on a Nicolet 6700 spectrometer and are reported
in frequency of absorption (cmꢀ1). High resolution mass spectra
(HRMS) were recorded on Q-Tof Micro mass spectrometer. The
enantiomeric excess (%ee) was determined by Shimadzu HPLC sys-
tems using Daicel chemical industries Ltd ChiralPAK AS-H column
and ChiralPAK AD-H columns.
The selectivity factor (s) was determined using the following
equation.13
ln½ð1 ꢀ CÞð1 ꢀ eeRSMÞꢁ
ðsÞ ¼ ðkfast=kslowÞ ¼
ln½ð1 ꢀ CÞð1 þ eRSMÞꢁ
eeRSM
C ¼ Conversion ¼
eeRSM þ eeproduct
eeRSM ¼ enantiomeric excess of recovered starting material
3. Conclusion
4.1.1. Typical experimental procedure for the synthesis of
starting materials
In conclusion, a novel coupling kinetic resolution has been
developed by employing commercially available (S)-BINAP–
Pd(OOCCF3)2. This simple and convenient protocol enables us to
access both enantiomers of a novel class of highly important opti-
cally active 1,4-benzoxazine derivatives and optically active trans-
recovered starting materials with moderate selectivity factors (s).
7-Tosyl-7-azabicyclo[4.1.0]heptane (1.004 g, 4.0 mmol), o-bro-
mophenol (464
taken under a nitrogen atmosphere in a 20 mL reaction tube
equipped with septum. To this reaction mixture, toluene
lL, 4.0 mmol) and Cs2CO3 (1.955 g, 6.0 mmol) were
a
(8.0 mL) was added and heated at 110 °C for 12 h. After completion
of the reaction (the reaction progress was monitored by TLC), the
reaction mixture was allowed to cool, toluene was evaporated un-
der rotavapor and the crude reaction mixture was purified directly
using column chromatography on silica gel using ethyl acetate/
hexane as eluents to afford trans-N-(2-(2-bromophenoxy)cyclo-
hexyl)-4-methylbenzenesulfonamide ( )-2, 1.69 g (99%). The cor-
responding ( )-1 and ( )-3 starting materials were synthesized
using a similar procedure.
4. Experimental
4.1. General information
All reactions were carried out in reaction tubes under a nitrogen
atmosphere. Ligands, palladium salts and Cs2CO3 were purchased
from Aldrich Chemical Company and used without further purifi-
cation. Ligands L1 and L3 and catalyst 5 were prepared using liter-
ature procedures.12 The starting materials for the coupling kinetic
resolution were made by using aziridines and substituted o-brom-
ophenols. Toluene was purchased from SRL Chemicals, India and
4.1.2. Typical experimental procedure for the palladium
catalyzed coupling kinetic resolution reaction
At first, Pd(OOCCF3)2 (4.2 mg, 0.0125 mmol), (S)-BINAP
(15.6 mg, 0.025 mmol), ( )-2 (106 mg, 0.25 mmol) and Cs2CO3

R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
951
Table 4
Scope of the palladium catalyzed coupling kinetic resolution
Ts
NH
Ts
NH
Ts
N
Pd(OOCCF3)2 (5 mol%)
(S)-BINAP (10 mol%)
*
*
*
*
R
+
Cs2CO3
toluene, 110 °C
O
n
O
O
n
n
Br
Br
R
R
Entry
Ligands
Time (h)
Recovered starting material
Product
Yieldb (%)
Conversion C (%)
Selectivity factor (s)
eea (%)
Yieldb (%)
eea (%)
32
Ts
NH
1
3.5
69
32
62
68.3
35.5
35.7
38.1
33.9
18.9
53.6
30.0
3.7
2.9
2.6
2.0
2.8
2.8
2.1
2.9
O
Br
Ts
NH
2
3
4
5
6
7
8
27
22
20
16
20
10
28
18
58
61
56
53
67
42
63
40
36
26
39
43
24
42
35
30
36
31
16
49
23
O
Br
Ts
NH
Cl
3 h 50 min
O
Br
Br
Br
Ts
NH
OMe
Ph
3 h 50 min
O
Ts
NH
4
O
Ts
NH
4
O
Br
Ts
NH
OMe
Me
24
6.5
O
Br
Ts
NH
O
Br
a
% Ee were calculated using HPLC chiral columns.
Isolated yield.
b
(163 mg, 0.5 mmol) were taken under a nitrogen atmosphere in a
10 mL reaction tube equipped with a septum. To this reaction
mixture, toluene (2.2 mL) was added and heated at 110 °C for
3.5 h. After completion of the reaction (the reaction progress was
monitored by TLC), the reaction mixture was allowed to cool, the
toluene was evaporated under rotavapor and the crude reaction
mixture was purified directly using column chromatography on
silica gel using ethyl acetate/hexane as eluents to afford (+)-
trans-10-tosyl-2,3,4,4a,10,10a-hexahydro-1H-phenoxazine 53 mg
in 62%, and the starting material recovered (+)-2 as 34 mg (32%)
(Table 4, entry1).
1H-phenoxazine (Table 4, entry 1). White solid, mp 104–106 °C
(lit.7 104–105 °C), Rf 0.63 (10% ethyl acetate/hexanes);
½
a 2D5
ꢁ
¼ þ13:7 (c 1.3, CHCl3); IR (CDCl3): 2932, 2861, 1593, 1485,
1453, 1352, 1255, 1164, 1057, 809, 733, 660 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 1.12–1.26 (m, 1H), 1.27–1.41 (m, 2H), 1.42–
1.54 (m, 1H), 1.66–1.76 (m, 2H), 1.98–2.07 (m, 1H), 2.25 (s, 3H),
2.53–2.62 (m, 1H), 3.30 (ddd, J = 11.0, 10.6 and 4.0 Hz, 1H), 3.42
(ddd, J = 11.0, 10.5 and 3.2 Hz, 1H), 6.62 (dd, J = 7.6 and 1.6 Hz,
1H), 6.87–6.98 (m, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz,
2H), 7.71 (dd, J = 8.0 and 1.6 Hz, 1H); 13C NMR (100 MHz): d 21.7,
24.1, 24.7, 32.0, 33.6, 65.5, 81.0, 117.2, 122.2, 126.3, 126.4, 127.6,
127.9, 129.4, 133.5, 144.0, 152.9; MS (ESI, m/z): 344 [MH]+; HRMS:
calcd for C19H22NSO3, [MH]+ 344.1320, found 344.1316. The enan-
tiomeric excess (% ee) was determined to be 32% by HPLC using a
4.1.3. Spectroscopic data for the products
4.1.3.1.
(+)-trans-4a,10a-10-Tosyl-2,3,4,4a,10,10a-hexahydro-

952
R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
Ts
Br
NH
O
2
( )-
Ts
NH
*
*
selective
oxidative addition
O
2
(+)-
Br
Cs2CO3
Ts
N
PdL*
reductive
recovered
elimination
*
*
optically active
starting material
O
(+)-4
Ts
N
coupling
kinetic
optically active
trans-product
resolution
Ts
L*
O
L*
Pd
N
Pd
L*
L*
Br
O
nucleophilic
6
7
displacement
Scheme 2. A plausible mechanistic explanation.
ChiralPAK AS-H column (4% i-PrOH/hexanes, 0.4 mL/min); tR (min-
or, 27.4 min), tR (major, 30.6 min).
1216, 1168, 1057, 815, 730, 666 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d 1.10–1.49 (m, 5H), 1.66–1.77 (m, 1H), 1.98–2.08 (m, 1H), 2.27 (s,
3H), 2.55–2.64 (m, 1H), 3.27 (t, J = 10.0 Hz, 1H), 3.41 (t, J = 10.8 Hz,
1H), 3.74 (s, 3H), 6.49–6.58 (m, 2H), 7.05 (d, J = 7.2 Hz, 2H), 7.21 (d,
J = 8.4 Hz, 2H), 7.33 (s, 1H); 13C NMR (100 MHz): d 21.7, 24.2, 24.7,
32.0, 33.7, 56.0, 65.5, 81.3, 111.1, 112.4, 117.5, 127.6, 128.4, 129.4,
133.5, 144.0, 146.8, 154.5; MS (ESI, m/z): 374 [MH]+; HRMS: calcd
for C20H24NO4S, [MH]+ 374.1426, found 374.1432. The enantio-
meric excess (% ee) was determined to be 26% by HPLC using a
ChiralPAK AD-H column (10% i-PrOH/hexanes, 0.8 mL/min); tR
(minor, 11.7 min), tR (major, 13.7 min).
4.1.3.2. (+)-trans-3a,9a-9-Tosyl-1,2,3,3a,9,9a-hexahydrobenz-o-
[b]cyclopenta[e][1,4]oxazine (Table 4, entry 2)10. White solid,
mp 140–142 °C, Rf 0.67 (10% ethyl acetate/hexanes);
½
a 2D5
ꢁ
¼ þ29:4 (c 1.3, CHCl3); IR (CDCl3) 2963, 2882, 1592, 1482,
1352, 1290, 1243, 1165, 1093, 811, 733, 660 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 1.59–1.70 (m, 1H), 1.78–2.11 (m, 4H), 2.36
(s, 3H), 2.50–2.60 (m, 1H), 3.30–3.38 (m, 1H), 3.85–3.94 (m, 1H),
6.78 (dd, J = 7.6 and 1.6 Hz, 1H), 6.91–7.03 (m, 2H), 7.17 (d,
J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 8.06, (dd, J = 8.4 and
1.6 Hz, 1H); 13C NMR (100 MHz): d 18.5, 21.7, 25.6, 28.4, 63.1,
80.4, 118.1, 121.9, 123.4, 125.5, 127.4, 127.8, 129.7, 133.9, 144.3,
149.4; MS (ESI, m/z): 352 [MNa]+; HRMS: calcd for C18H19NO3NaS,
[MNa]+ 352.0983, found 352.0980. The enantiomeric excess (% ee)
was determined to be 40% by HPLC using a Chiralcel OJ column
(10% i-PrOH/hexanes, 0.8 mL/min); tR (major, 12.2 min), tR (minor,
14.1 min).
4.1.3.5. (+)-trans-4a,10a-8-Phenyl-10-tosyl-2,3,4,4a,10,10a-hexa-
hydro-1H-phenoxazine (Table 4, entry 5). White solid, mp 109–
111 °C, Rf 0.68 (10% ethyl acetate/hexanes); ½a D25
¼ þ8:7 (c 0.3,
ꢁ
CHCl3); IR (CDCl3): 2931, 2861, 1600, 1482, 1353, 1268, 1166,
1059, 818, 703, 664 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.16–
;
1.30 (m, 2H), 1.30–1.45 (m, 2H), 1.45–1.58 (m, 2H), 1.69–1.79
(m, 2H), 2.03–2.11 (m, 1H), 2.26 (s, 3H), 2.57–2.66 (m, 1H), 3.36
(ddd, J = 10.8, 10.6 and 4.0 Hz, 1H), 3.46 (ddd, J = 11.0, 10.6 and
3.6 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.21
(d, J = 8.0 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H),
7.55 (d, J = 7.6 Hz, 2H), 8.0 (d, J = 2.0 Hz, 1H); 13C NMR
(100 MHz): d 21.7, 24.1, 24.7, 32.0, 33.6, 65.4, 81.1, 117.4, 124.7,
124.9, 127.0, 127.2, 127.7, 128.1, 128.9, 129.5, 133.6, 135.3,
140.4, 144.1, 152.2; MS (ESI, m/z): 420 [MH]+; HRMS: calcd for
4.1.3.3. (+)-trans-4a,10a-8-Chloro-10-tosyl-2,3,4,4a,10,10a-hexa-
hydro-1H-phenoxazine (Table 4, entry 3)10. White solid; mp
117–119 °C Rf 0.52 (10% ethyl acetate/hexanes); ½a D25
¼ þ67:0 (c
ꢁ
2.0, CHCl3); FTIR (neat): 2925, 2858, 1593, 1478, 1345, 1259,
1166, 1050, 887, 814, 667 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
1.28–1.57 (m, 4H), 1.74–1.85 (m, 2H), 2.07–2.20 (m, 1H), 2.35 (s,
3H), 2.62–2.71 (m, 1H), 3.36 (ddd, J = 10.6, 10.5 and 4.0 Hz, 1H),
3.48 (ddd, J = 10.6, 10.5 and 3.2 Hz, 1H), 6.61–6.66 (m, 1H), 6.96–
7.01 (m, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.81
(d, J = 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.7, 24.0, 24.6,
31.9, 33.5, 65.2, 81.1, 118.2, 125.9, 126.0, 126.9, 127.6, 128.9,
129.6, 133.5, 144.3, 151.2; MS (ESI, m/z): 400 [MNa]+; HRMS: calcd
for C19H20NO3SClNa, [MNa]+ 400.0750, found 400.0743. The enan-
tiomeric excess (% ee) was determined to be 36% by HPLC using a
ChiralPAK AS-H column (15% i-PrOH/hexanes, 0.8 mL/min); tR
(minor, 9.0 min), tR (major, 10.1 min).
C
25H26NO3S, [MH]+ 420.1633, found 420.1652. The enantiomeric
excess (% ee) was determined to be 39% by HPLC using a ChiralPAK
AS-H column (15% i-PrOH/hexanes, 0.8 mL/min); tR (minor,
11.1 min), tR (major, 15.7 min).
4.1.3.6. (ꢀ)-trans-(5a,11a,Z)-12-Tosyl-6,7,10,11,11a,12-hexahyd-
ro-5aH-benzo[b]cycloocta[e][1,4]oxazine (Table 4, entry 6)10
.
White solid, mp 97–99 °C, Rf 0.60 (10% ethyl acetate/hexanes);
¼ ꢀ12:0 (c 0.6, CHCl3); IR (CDCl3): 2923, 2856, 1595, 1483,
1348, 1253, 1157, 1092, 812, 750, 662 cmꢀ1 1H NMR (400 MHz,
½ ꢁ
a 2D5
;
CDCl3): d 1.20–1.35 (m, 1H), 1.55–1.77 (m, 1H), 1.82–1.95 (m,
1H), 2.01–2.31 (m, 4H), 2.35 (s, 3H), 3.64–3.73 (m, 1H), 4.32–
4.42 (m, 1H), 5.61–5.75 (m, 2H), 6.76 (d, J = 7.6 Hz, 1H), 7.05 (t,
J = 7.6 Hz, 3H), 7.10–7.19 (m, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.59 (d,
J = 7.6 Hz, 1H); 13C NMR (100 MHz): d 21.7, 22.8, 29.8, 33.8, 34.0,
4.1.3.4. (+)-trans-8-Methoxy-10-tosyl-2,3,4,4a,10,10a-hexahy-
dro-1H-phenoxazine (Table 4, entry 4). White solid, mp 88–
90 °C, Rf 0.61 (10% ethyl acetate/hexanes); ½a D25
¼ þ10:9 (c 0.2,
ꢁ
CHCl3); IR (CDCl3): 2934, 2863, 1602, 1499, 1455, 1354, 1264,

R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
953
62.5, 85.2, 117.4, 123.1, 127.2, 127.9, 128.6, 128.7, 129.3, 129.4,
129.5, 136.0, 143.6, 153.6; MS (ESI, m/z): 392 [MNa]+; HRMS: calcd
for C21H23NO3NaS, [MNa]+ 392.1296, found 392.1291. The enantio-
meric excess (% ee) was determined to be 43% by HPLC using a
ChiralPAK AS-H column (15% i-PrOH/hexanes, 0.8 mL/min); tR
(minor, 9.5 min), tR (major, 10.6 min).
(dd, J = 8.2 and 1.2 Hz, 1H), 7.18–7.26 (m, 3H), 7.49 (dd, J = 7.6
and 1.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz): d
21.4, 21.5, 29.7, 31.2, 59.3, 84.2, 113.0, 115.1, 122.2, 127.3, 128.4,
129.8, 133.4, 136.8, 143.6, 153.8; MS (ESI, m/z): 432 [MNa]+;
HRMS: calcd for
C
18H20NO3SNaBr, [MNa]+ 432.0245, found
432.0259; The enantiomeric excess (% ee) was determined to be
22% by HPLC using a ChiralPAK AD-H column (15% i-PrOH/hexanes,
1 mL/min); tR (minor, 7.7 min), tR (major, 9.3 min).
4.1.3.7. (+)-trans-3a,9a-7-Methoxy-9-tosyl-1,2,3,3a,9,9a-hexahy-
drobenzo[b]cyclopenta[e][1,4]oxazine (Table 4, entry 7). White
solid, mp 103–105 °C, Rf 0.64 (10% ethyl acetate/hexanes);
4.1.3.11.
(ꢀ)-trans-N-(2-(2-Bromo-4-chlorophenoxy)cyclohe-
½
a 2D5
ꢁ
¼ þ48:7 (c 1.0, CHCl3); IR (CDCl3): 2924, 1608, 1496, 1356,
xyl)-4-methylbenzenesulfonamide (Table 4, entry 3). White so-
lid, mp 98–100 °C, Rf 0.35 (20% ethyl acetate/hexanes);
1267, 1215, 1168, 1097, 952, 733, 668 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d 1.49–1.61 (m, 1H), 1.73–1.90 (m, 3H), 1.91–2.02 (m,
1H), 2.29 (s, 3H), 2.44–2.54 (m, 1H), 3.21–3.31 (m, 1H), 3.73 (s,
3H), 3.76–3.86 (m, 1H), 6.49 (dd, J = 8.8 and 2.8 Hz, 1H), 6.62 (d,
J = 8.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H),
7.61 (d, J = 2.8 Hz, 1H); 13C NMR (100 MHz): d 18.5, 21.7, 25.5,
28.6, 56.0, 63.1, 80.8, 108.1, 111.7, 118.4, 127.8, 129.7, 133.9,
143.4, 144.3, 154.3; MS (ESI, m/z): 360 [MH]+; HRMS: calcd for
½
a 2D5
ꢁ
¼ ꢀ21:1 (c 3.5, CHCl3); IR (CDCl3): 3275, 2936, 2863, 1592,
1467, 1321, 1272, 1153, 1091, 1040, 811, 734, 665 cmꢀ1 1H
;
NMR (400 MHz, CDCl3): d 1.17–1.34 (m, 3H), 1.38–1.54 (m, 2H),
1.59–1.69 (m, 1H), 1.8–1.89 (m, 1H), 2.04–2.15 (m, 1H), 2.32 (s,
3H), 3.19–3.28 (m, 1H), 4.03–4.11 (m, 1H), 5.29 (d, J = 5.6 Hz,
1H), 6.70 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 8.8 and 2.8 Hz, 1H), 7.16
(d, J = 8.0 Hz, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz): d 21.6, 22.1, 22.5, 28.3, 29.8, 54.6, 78.8,
114.2, 116.5, 126.8, 127.2, 128.3, 129.8, 133.0, 137.2, 143.5,
152.4; MS (ESI, m/z): 480 [MNa]+; HRMS: calcd for C19H21NO3NaS-
ClBr, [MNa]+ 480.0012, found 480.0020; The enantiomeric excess
(% ee) was determined to be 20% by HPLC using ChiralPAK AD-H
column (15% i-PrOH/hexanes, 1 mL/min); tR (minor, 8.3 min), tR
(major, 11.1 min).
C
19H22NO4S, [MH]+ 360.1270, found 360.1261. The enantiomeric
excess (% ee) was determined to be 24% by HPLC using a ChiralPAK
AS-H column (15% i-PrOH/hexanes, 0.8 mL/min); tR (minor,
14.4 min), tR (major, 19.8 min).
4.1.3.8. (+)-trans-7-Methyl-9-tosyl-1,2,3,3a,9,9a-hexahydrobenz-
o[b]cyclopenta[e][1,4]oxazine (Table 4, entry 8). White solid,
mp 118–121 °C, Rf 0.64 (10% ethyl acetate/hexanes);
½
a 2D5
ꢁ
¼ þ16:9 (c 0.2, CHCl3); IR (CDCl3): 2924, 1599, 1496, 1354,
4.1.3.12. (+)-trans-N-(2-(2-Bromo-4-methoxyphenoxy)-cyclohe-
xy-l)-4-methylbenzenesulfonamide (Table 4, entry 4). White
solid, mp 93–95 °C, Rf 0.35 (20% ethyl acetate/hexanes);
1257, 1167, 1096, 814, 761, 665 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d 1.48–1.61 (m, 1H), 1.72–1.91 (m, 3H), 1.91–2.02 (m, 1H), 2.34 (s,
3H), 2.28 (s, 3H), 2.41–2.51 (m, 1H), 3.21–3.30 (m, 1H), 6.59 (d,
J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H),
7.37 (d, J = 8.0 Hz, 2H), 7.79 (s, 1H); 13C NMR (100 MHz): d 18.5,
21.1, 21.7, 25.6, 28.4, 63.1, 80.4, 117.6, 123.7, 126.1, 127.0, 127.8,
129.6, 131.3, 134.0, 144.2, 147.2; MS (ESI, m/z): 343 [M]+; HRMS:
calcd for C19H21NO3S, [MH]+ 343.1242, found 343.1242. The enan-
tiomeric excess (% ee) was determined to be 42% by HPLC using a
ChiralPAK AD-H column (15% i-PrOH/hexanes, 1 mL/min); tR (ma-
jor, 8.8 min), tR (minor, 10.8 min).
½
a 2D5
ꢁ
¼ þ13:3 (c 0.3, CHCl3); IR (CDCl3): 3277, 2936, 2862, 1601,
1487, 1446, 1270, 1212, 1152, 1089, 1033, 808, 737, 666 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.12–1.41 (m, 4H), 1.46–1.58 (m,
1H), 1.59–1.69 (m, 1H), 1.81–1.91 (m, 1H), 2.16–2.27 (m, 1H),
2.33 (s, 3H), 3.10–3.20 (m, 1H), 3.69 (s, 3H), 3.89 (ddd, J = 8.4, 8.2
and 3.6 Hz, 1H), 5.15 (d, J = 3.2 Hz, 1H), 6.66–6.75 (m, 2H), 6.99
(d, J = 2.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz): d 21.6, 22.6, 22.9, 28.8, 30.3, 55.6, 56.0,
79.8, 114.0, 114.6, 118.4, 118.6, 127.7, 137.1, 143.4, 147.4, 154.9;
MS (ESI, m/z): 454 [MH]+; HRMS: calcd for C20H25NO4SBr, [MH]+
454.0688, found 454.0671; The enantiomeric excess (% ee) was
determined to be 16% by HPLC using a ChiralPAK AD-H column
(15% i-PrOH/hexanes, 1 mL/min); tR (minor, 8.8 min), tR (major,
10.9 min).
4.1.3.9. (+)-trans-N-(2-(2-Bromophenoxy)cyclohexyl)-4-methyl-
benzenesulfonamide (Table 4, entry 1). White solid, mp 89–
91 °C, Rf 0.35 (20% ethyl acetate/hexanes); ½a D25
¼ þ33:7 (c 0.2,
ꢁ
CHCl3); IR (CDCl3): 3276, 2927, 2858, 1586, 1469, 1321, 1276,
1154, 1090, 1036, 813, 743, 667 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d 1.13–1.49 (m, 3H), 1.28–1.42 (m, 1H), 1.44–1.54 (m, 1H), 1.69–
1.78 (m, 1H), 1.93–2.02 (m, 1H), 2.23–2.33 (m, 1H), 2.4 (s, 3H),
3.24–3.32 (m, 1H), 4.16 (ddd, J = 7.8, 7.8 and 3.6 Hz, 1H), 5.09 (d,
J = 4.4 Hz, 1H), 6.82–6.87 (m, 2H), 7.21 (ddd, J = 8.0, 7.9 and
1.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.50 (dd, J = 8.2, 1.6 Hz,, 1H),
7.77 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz): d 21.7, 22.3, 22.7,
28.5, 29.9, 55.0, 78.5, 113.8, 116.0, 122.8, 127.4, 128.5, 129.8,
133.7, 137.1, 143.5, 153.5; MS (ESI, m/z): 424 [MH]+; HRMS: calcd
for C19H23NO3SBr, [MH]+ 424.0582, found 424.0581. The enantio-
meric excess (% ee) was determined to be 69% by HPLC using a
ChiralPAK AD-H column (15% i-PrOH/hexanes, 1 mL/min); tR (min-
or, 9.5 min), tR (major, 12.3 min).
4.1.3.13. (+)-trans-N-(2-(3-Bromobiphenyl-4-yloxy)cyclohexyl)-
4-methylbenzenesulfonamide (Table 4, entry 5). White solid,
mp 131–134 °C, Rf 0.35 (20% ethyl acetate/hexanes); ½a D25
¼ þ5:0
ꢁ
(c 0.2, CHCl3); IR (CDCl3): 3245, 2936, 1597, 1475, 1266, 1154,
1088, 1043, 815, 734, 666 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
1.21–1.36 (m, 3H), 1.41–1.58 (m, 2H), 1.62–1.72 (m, 1H), 1.88–
1.98 (m, 1H), 2.11–2.26 (m, 1H), 2.31 (s, 3H), 3.21–3.30 (m, 1H),
4.09–4.18 (m, 1H), 5.18 (d, J = 4.4 Hz, 1H), 6.84 (dd, J = 8.4 and
1.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.23–7.29 (m, 1H), 7.31–7.38
(m, 3H), 7.41–7.46 (m, 2H), 7.66 (t, J = 2.0 Hz, 1H), 7.71 (dd,
J = 8.0 and 1.6 Hz, 2H); 13C NMR (100 MHz): d 21.7, 22.3, 22.7,
28.6, 29.9, 55.0, 78.7, 114.1, 116, 126.9, 127.0, 127.4, 127.5,
129.0, 129.8, 132.1, 136.1, 137.1, 139.4, 143.5, 152.8; MS (ESI, m/
z): 522 [MNa]+; HRMS: calcd for C25H26NO3NaBrS, [MNa]+
522.0714, found 522.0721; The enantiomeric excess (% ee) was
determined to be 20% by HPLC using chiralcel OD-H column (15%
i-PrOH/hexanes, 1 mL/min); tR (major, 9.5 min), tR (minor,
10.8 min).
4.1.3.10. (ꢀ)-trans-N-(2-(2-Bromophenoxy)cyclopentyl)-4-me-
thyl-benzenesulfonamide (Table 4, entry 2). White solid, mp
94–96 °C, Rf 0.35 (20% ethyl acetate/hexanes); ½a D25
¼ ꢀ22:9 (c
ꢁ
3.5, CHCl3); IR (CDCl3): 3262, 2960, 1586, 1471, 1438, 1279,
1154, 1089, 813, 747, 665 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
1.39–1.49 (m, 1H), 1.68–1.91 (m, 3H), 1.96–2.07 (m, 1H), 2.11–
2.22 (m, 1H), 2.38 (s, 3H), 3.65–3.71 (m, 1H), 4.59–4.63 (m, 1H),
4.89 (d, J = 6.0 Hz, 1H), 6.82 (ddd, J = 7.6, 7.6 and 1.2 Hz, 1H), 6.87
4.1.3.14.
(ꢀ)-trans-N-((Z)-8-(2-Bromo-4-phenoxy)cyclooct-4-
enyl)-4-methylbenzenesulfonamide (Table 4, entry 6). Rf 0.35

954
R. Koteshwar Rao, G. Sekar / Tetrahedron: Asymmetry 22 (2011) 948–954
(20% ethyl acetate/hexanes); ½a D25
ꢁ
¼ ꢀ6:9 (c 0.2, CHCl3); IR (CDCl3):
determined to be 18% by HPLC using a ChiralPAK AD-H column
(15% i-PrOH/hexanes, 1 mL/min); tR (minor, 9.2 min), tR (major,
11.0 min).
3310, 2930, 1586, 1474, 1436, 1274, 1157, 1091, 1035, 815, 747,
666 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.47–1.65 (m, 2H), 1.84–
1.99 (m, 2H), 1.99–2.09 (m, 1H), 2.09–2.21 (m, 1H), 2.30–2.53
(m, 2H), 2.35 (s, 3H), 3.63–3.72 (m, 1H), 4.45 (ddd, J = 7.3, 7.2
and 2.4 Hz, 1H), 5.35 (d, J = 7.2 Hz, 1H), 5.63–5.77 (m, 2H), 6.73
(d, J = 8.4 Hz, 1H), 6.76–6.82 (m, 1H), 7.13–7.20 (m, 1H), 7.22 (d,
J = 8.0 Hz, 2H), 7.46 (dd, J = 7.8 and 1.6 Hz, 1H), 7.72 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz): d 21.5, 21.7, 23.4, 29.9, 32.7, 54.8, 78.6,
113.5, 115.0, 122.8, 127.4, 128.7, 129.8, 130.9, 131.2, 133.8,
137.5, 143.5, 153.5; MS (ESI, m/z): 450 [MH]+; HRMS: calcd for
Acknowledgments
We thank DST (Project No.: SR/S1/OC-06/2008), New Delhi, for
the financial support, and R.K.R. thanks CSIR, New Delhi, for a se-
nior research fellowship.
C
21H25NO3SBr, [MH]+ 450.0739, found 450.0744; The enantiomeric
References
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AD-H column (15% i-PrOH/hexanes, 1 mL/min); tR (minor, 9.5 min),
tR (major, 12.3 min).
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pent-yl)-4-methylbenzenesulfonamide (Table 4, entry 7).
White solid, mp 74–76 °C, Rf 0.35 (20% ethyl acetate/hexanes);
½
a 2D5
ꢁ
¼ ꢀ11:2 (c 1.3, CHCl3); IR (CDCl3): 3245, 2936, 1597, 1475,
1266, 1154, 1088, 1043, 815, 734, 666 cmꢀ1 1H NMR (400 MHz,
;
3. (a) Bourlot, A-S.; Sa´nchez, I.; Dureng, G.; Guillaumet, G.; Massingham, R.;
Monteil, A.; Winslow, E.; Pujol, M. D.; Me´rour, J.-Y. J. Med. Chem. 1998, 41, 3142;
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CDCl3): d 1.31–1.41 (m, 1H), 1.57–1.82 (m, 3H), 1.83–1.92 (m,
1H), 2.02–2.13 (m, 1H), 2.32 (s, 3H), 3.69 (s, 3H), 3.54–3.61 (m,
1H), 4.40–4.45 (m, 1H), 4.89 (d, J = 5.6 Hz, 1H), 6.68 (dd, J = 9.0
and 3.2 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.99 (d, J = 2.8 Hz, 1H),
7.17 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz): d 21.4, 21.6, 29.7, 31.2, 56.0, 59.3, 85.3, 113.8, 113.9,
117.0, 118.7, 127.4, 129.9, 136.9, 143.7, 148.2, 154.6; MS (ESI, m/
z): 440 [MH]+; HRMS: calcd for C19H23NO4SBr, [MH]+ 440.0531,
found 440.0523; The enantiomeric excess (% ee) was determined
to be 28% by HPLC using a ChiralPAK AD-H column (15% i-PrOH/
hexanes, 1 mL/min); tR (minor, 11.3 min), tR (major, 13.3 min).
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13. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Wiley: New York, 1988;
Vol. 18, p 249.
4.1.3.16. (ꢀ)-trans-N-(2-(2-Bromo-4-methylphenoxy)cyclopen-
tyl)-4-methylbenzenesulfonamide (Table 4, entry 8). Rf 0.35
(20% ethyl acetate/hexanes);
(CDCl3): 3264, 2963, 1602, 1489, 1259, 1154, 1090, 810, 734,
668 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.31–1.41 (m, 1H), 1.60–
½
a 2D5
ꢁ
¼ ꢀ19:5 (c 3.5, CHCl3); IR
;
1.83 (m, 3H), 1.87–1.99 (m, 1H), 2.03–2.17 (m, 1H), 2.19 (s, 3H),
2.31 (s, 3H), 3.55–3.63 (m, 1H), 4.45–4.50 (m, 1H), 4.62 (d,
J = 5.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H),
7.15–7.21 (m, 2H), 7.24 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz): d 20.3, 21.4, 21.6, 29.7, 31.2, 59.4, 84.5, 113.0, 115.5,
127.4, 129.0, 129.9, 132.2, 133.8, 136.9, 143.7, 151.8; MS (ESI, m/
z): 446 [MNa]+; HRMS: calcd for C19H22NO3NaBrS, [MNa]+
446.0401, found 446.0410; The enantiomeric excess (% ee) was