Elaboration of the oxazepine ring system via cuI/L-proline-catalyzed intramolecular aryl amination

Article abstract of DOI:10.1055/s-2008-1078506

A two-step approach for assembling oxazepines is described, which started from 2-aminophenols and substituted 2-bromobenzyl bromides and used CuI/L-proline-catalyzed coupling reaction as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078506

LETTER
1833
Elaboration of the Oxazepine Ring System via CuI/L-Proline-Catalyzed
Intramolecular Aryl Amination
E
laboration of th
e
e
O
xazepi
i
ne Ring Syste
G
m
uo,a,1 Ben Li,b,1 Wenlong Huang,a Gang Pei,b Dawei Ma*c
a
Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, P. R. of China
Shanghai Institute of Biological Chemistry & Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
319 Yueyang Lu, Shanghai 200031, P. R. of China
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: madw@mail.sioc.ac.cn
b
c
Received 13 April 2008
O
1. O-alkylation
2. Fe/HCl reduction
HO
Abstract: A two-step approach for assembling oxazepines is de-
scribed, which started from 2-aminophenols and substituted 2-bro-
mobenzyl bromides and used CuI/L-proline-catalyzed coupling
reaction as the key step.
Br
+
3. Pd(dba)2, P(t-Bu)3
N
Br
O2N
H
1a
2
6a
Key words: cross-coupling, aryl bromide, ethers, oxazepines
Scheme 2
The oxazepine moiety has been found in many pharma-
ceutically important compounds.2,3 The typical method
for elaboration of this tricyclic system is based on a five-
step route as depicted in Scheme 1.3 The key step is a cop-
per-catalyzed intramolecular coupling of amide 4 to the
corresponding cyclization product 5. Obviously, if a met-
al-catalyzed intramolecular aryl amination of 3a to 6a
worked well, the formation and saponification steps
would be avoided. Recently, Rogers and co-workers re-
ported that this goal could be reached by employing
Pd(dba)2/P(t-Bu)3 as a catalytic system (Scheme 2).4
Herein, we wish to describe that an inexpensive CuI/L-
proline catalytic system can be used for the same transfor-
mation,5,6 thereby giving a practical approach to assess
substituted oxazepines.7
could proceed smoothly in a mixed solvent at 0 °C to af-
ford 3a in 81% yield.8 This success allows further short-
ening of the previous five-step procedure to two steps
because reduction of nitro group was omitted. Next, we
explored the possible reaction conditions for CuI/L-pro-
line-catalyzed cyclization. Initially, our standard condi-
tions for aryl amination5 were used (Table 1, entry 1), and
it was found that after 60 hours only 30% desired product
was isolated. Changing solvents to DMF, toluene, and di-
oxane gave worse results (entries 2–4). However, switch-
ing base to triethylamine provided a better yield (entry 7),
although K2CO3 and K3PO4 still gave poor yields of the
product (entries 5 and 6). Further attempts revealed that
DABCO was a better base for this reaction, providing 3a
in 58% yield after 48 hours (entry 8). The best yield was
obtained by using DMSO–water as a mixed solvent (entry
9). Adding L-proline was essential for coupling because
no product was isolated if it was absent (entry 10).
As shown in Scheme 3, we started our attempts by modi-
fication of the preparation of cyclization precursors. We
found that etherification by directly using 2-aminophenol
O
Na2CO3, DMSO
HO
O
DMF, H2O, 0 °C
Br
1. O-alkylation
2. Fe/HCl reduction
HO
+
Br
+
81%
Br
H2N
H2N
Br
Br
O2N
H2N
Br
1a
7a
3a
1a
2
3a
O
10 mol% CuI, 20 mol% L-proline
base, solvent, 90 °C
O
O
Cu-catalyzed
coupling
N
N-formylation
H
6a
N
R
HN
Br
H
Scheme 3
O
5: R = CHO
6a: R = H
4
hydrolysis
After the optimized reaction conditions were obtained,9
we explored the scope and limitations of this method by
varying the bromides and phenols. As shown in Table 2,
all examined substrates gave good yields in the etherifica-
tion step. However, the yields of the intramolecular cou-
pling step were found to be highly dependent on the
Scheme 1
SYNLETT 2008, No. 12, pp 1833–1836
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078506; Art ID: W05708ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1834
L. Guo et al.
LETTER
Table 1 CuI-Catalyzed Intramolecular Aryl Amination of 3a under
ether delivered the coupling product 6c10 in 80% yield af-
ter 24 hours (entry 2). These results indicated that an ad-
ditional electron-withdrawing group in the aryl bromide
part was favorable for the coupling reaction, which was
consistent with our previous observation for intermolecu-
lar aryl amination.5 The orientation of the electron-with-
drawing group in the aryl bromide part also influenced the
coupling process, as evident from that the 2-bromo-3-
(tert-butoxycarbonyl)benzyl bromide derived ether
showed good conversion in 24 hours (entry 3), while the
2-bromo-4-acylbenzyl bromide derived ether required 48
hours to provide the satisfactory conversion (entry 4).
From naphthalene-embodied bromide 1f, tetracyclic com-
pound 6f11 was obtained in 61% overall yield (entry 5).
Various Conditionsa
Entry Base
Solvent
Time
(h)
Yield
(%)c
1
2
Na2CO3
DMSO
60
60
60
60
60
60
72
48
48
48
30
12
8
Na2CO3
DMF
3
Na2CO3
toluene
4
Na2CO3
dioxane
DMSO
0
5
K2CO3
20
0
6
K3PO4
DMSO
7
Et3N
DMSO
65b
58b
78b,d
0b,d,e
We then checked the influence of electronic properties in
2-aminophenol part to the coupling process. It was found
that introduction of an additional electron-donating group
could facilitate this reaction, because 4-chloro-2-ami-
nophenol derived ether gave low conversion (entry 6),
while 4-methyl-2-aminophenol derived ether provided the
desired product 6h12 in good yield (entry 7). The orienta-
tion of the electron-donating group in 2-aminophenol also
played an important role for promoting the reaction, as an
excellent coupling yield observed in a shorter reaction
time when 3-methyl-2-aminophenol derived ether was
employed (compare entries 7–9). This phenomenon was
easily understandable because the additional electron-do-
nating groups could enhance the nucleophilicity of the
amine.
8
DABCO·6H2O
DABCO·6H2O
DABCO·6H2O
DMSO
9
DMSO–H2O
DMSO–H2O
10
a Reaction conditions: 3a (0.5 mmol), CuI (0.05 mmol), L-proline (0.1
mmol), base (2 mmol), DMSO (4 mL), 90 °C.
b 5 mmol of base was added.
c Isolated yield.
d 1 mL of water was added.
e Without addition of L-proline.
electronic nature of the reactants. The 2-bromo-5-meth-
oxybenzyl bromide derived ether gave only 35% yield of
the desired product 6b after 48 hours (entry 1), while the
2-bromo-5-(tert-butoxycarbonyl)benzyl bromide derived
Table 2 Assembly of Oxazepines via Etherification and Subsequent CuI/L-Proline-Catalyzed Coupling of 2-Aminophenols and Substituted
2-Bromobenzyl Bromidesa
Entry
1
Bromide
2-Aminophenol
Product
Time (h)b
48
Yield (%)c of
etherification/coupling
84/35d
R
HO
O
Br
R
Br
H2N
N
H
1b: R = OMe
7a
6b: R = OMe
2
3
1c: R = CO2t-Bu
6c: R = CO2t-Bu
24
24
80/80
70/81
O
Br
Br
N
H
CO2t-Bu
CO2t-Bu
1d
6d
4
5
48
48
65/63
82/75
O
Br
MeOC
Br
N
H
1e
MeOC
6e
O
Br
Br
N
H
1f
6f
Synlett 2008, No. 12, 1833–1836 © Thieme Stuttgart · New York

LETTER
Elaboration of the Oxazepine Ring System
1835
Table 2 Assembly of Oxazepines via Etherification and Subsequent CuI/L-Proline-Catalyzed Coupling of 2-Aminophenols and Substituted
2-Bromobenzyl Bromidesa (continued)
Entry
6
Bromide
2-Aminophenol
Product
Time (h)b
72
Yield (%)c of
etherification/coupling
83/40d
HO
O
Br
Br
H2N
R
N
H
R
1a
7b: R = Cl
6g: R = Cl
7
8
7c: R = Me
6h: R = Me
72
72
68/73
72/66
Me
HO
Me
O
N
H2N
H
7d
HO
6i
6j
9
24
75/93
O
H2N
Me
7e
N
H
Me
10
11
1e
1c
7c
48
24
88/63
78/92
O
N
H
Me
MeOC
6k
7e
O
R
N
H
Me
6l: R = CO2t-Bu
6m: R = OMe
12
13
1b
1e
7e
7c
24
24
75/90
77/65
O
N
H
Me
CO2t-Bu
6n
14
1e
7e
24
74/71
O
N
H
CO2t-Bu
Me
6o
a Reaction conditions: Etherification step: 2-aminophenol (21 mmol), substituted 2-bromobenzyl bromide (10 mmol), Na2CO3 (40 mmol), DMF
(20 mL), DMSO (20 mL), H2O (2 mL), 0 °C. Coupling step: etherification product (0.5 mmol), CuI (0.05 mmol), L-proline (0.1 mmol),
DABCO·6H2O (5 mmol), DMSO (4 mL), H2O (1 mL), 90 °C.
b For coupling step.
c Isolated yield.
d About 20% coupling precursor was recovered.
Starting from substituted 2-bromobenzyl bromides and 2- overcome the poor conversion problem caused by the
aminophenols, several disubstituted oxazepines were as- electron-rich aryl bromide (compare entries 1 and 12).
sembled (entries 10–14). Noteworthy was that an ether
In conclusion, we have developed a two-step approach for
derived from 2-bromo-5-methoxybenzyl bromide and 3-
the assembly of substituted oxazepines. Some functional
methyl-2-aminophenol produced 6m13 in 90% yield (en-
groups like ester, ketone, methoxy, and chloride could be
introduced at the different positions of the oxazepine ring
try 12), indicating that the more reactive amine could
system by choosing suitable substrates. The cheap catalyt-
Synlett 2008, No. 12, 1833–1836 © Thieme Stuttgart · New York

1836
L. Guo et al.
LETTER
46, 2598. (e) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844.
(f) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007,
72, 5337. (g) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115.
(8) Typical Procedure for Etherification
ic system and easy operation in this method are remark-
able. Thus, it may find applications in elaboration of
designed biological molecules.
To a flask containing 2-aminophenol (21 mmol) and Na2CO3
(40 mmol) was added DMF (20 mL), DMSO (20 mL), and
H2O (2 mL). At 0 °C a solution of 2-bromobenzyl bromide
(10 mmol) in DMF (5 mL) was added dropwise. After the
mixture was stirred for about 4 h, it was filtered. The filtrate
was partitioned between EtOAc and H2O. The organic phase
was separated, and the aqueous layer was extracted with
EtOAc. The combined organic phase was washed with H2O
and brine, dried over Na2SO4, and concentrated. The residual
oil was loaded on a silica gel column and eluted with 1:10
EtOAc–PE to afford the etherification product.
Acknowledgment
The authors are grateful to the Chinese Academy of Sciences, Na-
tional Natural Science Foundation of China (grant 20321202 &
20572119) for their financial support.
References and Notes
(1) These authors contributed equally to this paper.
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(9) Typical Procedure for Coupling
A Schlenk tube was charged with the above ether (0.5
mmol), CuI (0.05 mmol), L-proline (0.1 mmol), and
DABCO·6H2O (5.0 mmol), evacuated, and backfilled with
Ar. Then, DMSO (4 mL) and H2O (1 mL) were added. The
reaction mixture was heated at 90 °C until the starting
material disappeared (monitored by TLC). The cooled
mixture was partitioned between EtOAc and H2O. The
organic phase was separated, and the aqueous layer was
extracted with EtOAc. The combined organic phase was
washed with brine, dried over Na2SO4, and concentrated.
The crude product was purified by column chromatography
on silica gel to provide the coupling product.
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(10) Selected Data for 6c
1H NMR (300 MHz, CDCl3): d = 7.78 (dd, J = 1.8, 8.1 Hz, 1
H), 7.69 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.99
(dd, J = 1.5, 7.8 Hz, 1 H), 6.74 (td, J = 1.8, 7.8 Hz, 1 H), 6.59
(td, J = 1.2, 8.1 Hz, 1 H), 6.46 (dd, J = 1.8, 8.1 Hz, 1 H), 4.31
(s, 2 H), 3.84 (s, 1 H), 1.48 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 165.0, 161.2, 114.3, 138.6, 130.8, 130.4, 129.6,
127.4, 124.4, 121.8, 120.3, 119.4, 118.7, 80.8, 47.1, 28.1.
ESI-MS: m/z = 298.1 [M + H]+. ESI-HRMS: m/z calcd for
C18H20NO3 [M + H]+: 298.1438; found: 298.1432.
(11) Selected Data for 6f
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1H NMR (300 MHz, CDCl3): d = 8.41 (d, J = 8.1 Hz, 1 H),
7.76 (d, J = 8.4 Hz, 1 H), 7.40–7.53 (m, 3 H), 7.31 (dd,
J = 1.2, 7.8 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 6.82 (td,
J = 1.2, 7.2 Hz, 1 H), 6.69 (td, J = 1.5, 7.8 Hz, 1 H), 6.51 (dd,
J = 1.2, 7.8 Hz, 1 H), 4.52 (s, 2 H), 3.75 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 153.3, 144.6, 139.2, 134.2, 127.6,
127.1, 126.6, 126.2, 126.1, 125.8, 124.4, 123.6, 122.0,
121.8, 119.2, 118.8, 46.9. ESI-MS: m/z = 248.1 [M + H]+.
ESI-HRMS: m/z calcd for C17H14NO [M + H]+: 248.1070;
found: 248.1068.
(12) Selected Data for 6h
1H NMR (300 MHz, CDCl3): d = 7.05–7.18 (m, 3 H), 6.97–
6.99 (m, 1 H), 7.00 (d, J = 8.1, 1 H), 6.39 (dd, J = 1.5, 8.1
Hz, 1 H), 6.27 (d, J = 1.2 Hz, 1 H), 4.35 (s, 2 H), 3.56 (s, 1
H), 2.08 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 158.5,
142.9, 138.2, 133.9, 131.7, 128.9, 128.0, 124.1, 121.7,
120.4, 119.9, 118.9, 46.8, 20.5. ESI-MS: m/z = 212.0 [M +
H]+.
(13) Selected Data for 6m
1H NMR (300 MHz, CDCl3): d = 7.02 (dd, J = 4.2, 5.1 Hz, 1
H), 6.91 (d, J = 4.2 Hz, 1 H), 6.59–6.70 (m, 3 H), 6.53 (t,
J = 7.8 Hz, 1 H), 4.45 (s, 2 H), 3.68 (s, 3 H), 1.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 152.4, 145.0, 136.6,
133.1, 125.9, 125.3, 120.9, 119.7, 118.0, 113.2, 113.1, 55.6,
46.3, 17.7. ESI-MS: m/z = 242.0 [M + H]+. ESI-HRMS: m/z
calcd for C15H16NO2 [M + H]+: 242.1179; found: 242.1176.
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Synlett 2008, No. 12, 1833–1836 © Thieme Stuttgart · New York