Synthesis of dihydrobenzoheterocycles through Al(OTf)3-mediated cascade cyclization and ionic hydrogenation

Article abstract of DOI:10.1021/jo501824z

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corres

Full text of DOI:10.1021/jo501824z

Article
pubs.acs.org/joc
Synthesis of Dihydrobenzoheterocycles through Al(OTf) ‑Mediated
3
Cascade Cyclization and Ionic Hydrogenation
Yulin Tian, Xiaojian Wang,* Qiong Xiao, Chenbin Sun, and Dali Yin*
†
,‡
,†,‡
†
‡
,†,‡
†
‡
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, and Beijing Key Laboratory of Active Substances
Discovery and Drugability Evaluation, Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China
*
S Supporting Information
ABSTRACT: A facile and versatile synthesis of dihydrobenzoheterocycles via
Al(OTf) -mediated cascade cyclization and ionic hydrogenation has been
3
developed. The reaction is applicable to a wide range of substrates with various
functional groups to afford the corresponding products in good yields.
INTRODUCTION
Six- and seven-membered dihydrobenzoheterocycles are
Et SiH (2.0 equiv) in CH CN at room temperature, the
3 3
■
desired product was observed and isolated in 55% yield after
2 h (Table 1, entry 1). Encouraged by this result, we
1
privileged scaffolds that have been found in a wide variety1
examined optimal conditions to obtain more satisfactory
of natural products and bioactive important molecules.
results (Table 1). Changing CH CN to other solvents such as
Among them, heterocycles with two heteroatoms in 1,4-
distance such as dihydro-1,4-benzoxazepinones and dihydro-
3
CH Cl , CH NO , DMF, and THF led to lower yields (Table
2
2
3
2
1
, entries 2−5). When the temperature was raised to 80 °C,
1
(
,4-benzoxazines are known to possess high biological activity
2
the yield of 2a was increased to 85% and the reaction time for
Figure 1). In the past few decades, the development of
complete conversion was shortened to 30 min (Table 1, entry
methods for the preparation of such types of compounds has
attracted remarkable attention in the synthetic community.
Ionic hydrogenation has been considered to be an efficient
method for the reduction of ketones, alcohols, and imines.
Recently, our group has developed a cascade cyclization and
ionic hydrogenation strategy to synthesize a vast array of
3
6
). Screening of Lewis and Brønsted acids indicated that
Al(OTf) displayed the highest reaction activity toward the
3
4
formation of 2a (Table 1, entries 6−14).
With the optimal conditions in hand, we examined the
scope and limitation of this cascade reaction to assemble 3,4-
dihydro-1,4-benzoxazepin-5(2H)-one (Table 2). Both methyl
lactams from ketoamides using the Et SiH/Lewis acid
3
5
(
2a−c) and aryl groups (2d−k) were introduced into the 3-
system. This method provided an important way to form
position of the dihydrobenzoxazepin-5(2H)-one scaffold
successfully. The formation of 3-aryl-substituted products
took longer time than for 3-methyl-substituted products,
perhaps because of steric hindrance from the aryl groups. The
reaction was found to be tolerant to electron-donating groups
(2b,e−f), electron-withdrawing groups (2j), and halides
(2c,g−i) as well as a heterocyclic group (2k) and generated
the target products in good to excellent yields. Interestingly, a
tricyclic compound, 6,7,8,9,9a,10-hexahydro-1,4-dibenzoxaze-
pin-11(5aH)-one (2l), could be efficiently synthesized using
this cascade reaction and is the important motif found in6
various natural products and pharmaceutical compounds.
the intramolecular N−C bond, especially the amide N−C
bond in N-heterocycles. Based on this cascade reaction,
structural diverse N-substituted lactams such as pyrrolidi-
nones, piperidones, isoindolinones, and oxazolidinone were
readily assembled from different kinds of building blocks in
good yields. To continue our efforts on this project, we
applied this strategy to the construction of dihydrobenzohe-
terocycles, such as dihydro-1,4-benzoxazepinones, dihydro-1,4-
benzoxazines and other related heterocycles (Scheme 1).
RESULTS AND DISCUSSION
■
Initially, 2-(2-oxopropoxy)benzamide (1a) was chosen as a
model substrate to investigate the reaction conditions for
construction of 3,4-dihydro-1,4-benzoxazepin-5(2H)-one (2a).
Received: August 7, 2014
To our delight, in the presence of Al(OTf) (0.5 equiv) and
Published: September 24, 2014
3
©
2014 American Chemical Society
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Figure 1. Representative examples of dihydrobenzoheterocycles.
Scheme 1. Strategies for the Construction of N-
Heterocycles
Next, we extended our work to construct another seven-
membered dihydrobenzoheterocycle, 4,5-dihydro-1,4-benzox-
azepin-3(2H)-one (4), from 2-(2-acetylphenoxy)acetamide
(
3) (Scheme 2) in a manner similar to that observed with
the preparation of 2. Two target molecules were successfully
obtained in moderate yields, indicating that the method is
noteworthy for its utility in preparing versatile seven-
membered dihydrobenzoheterocycles with high efficiency.
Encouraged by the above results, we turned our attention
to the preparation of 3,4-dihydro-1,4-benzoxazine (Table 3), a
six-membered dihydrobenzoheterocycle which is a common
7
structure in bioactive molecules. The most common method
to synthesize this compound is the reduction of the CN
8
double bond in 2H-1,4-benzoxazine, or the tandem reductive
9
cyclization of nitro compounds (Scheme 3). In our study,
when N-Boc-2-(2-oxo-2-substituted ethoxy)aniline (e.g., 5a)
was used as the substrate in the Al(OTf) /Et SiH system, the
3
3
Boc group was removed and the reaction proceeded very
quickly (10 min) to afford the 3,4-dihydro-2H-1,4-benzoxazine
(
e.g., 6a). The result indicated that a one-pot reaction
including removal of Boc group, intramolecular cyclization,
and ionic hydrogenation had taken place. We found that a
variety of functional groups including electron-donating
groups (6b,c) and electron-withdrawing groups (6g,k) were
well tolerated. Of note, compounds with halogen substitutions
Table 1. Optimization of Reaction Conditions ,
ab
(
6d−f,i,j), especially chloro and bromo, could be synthesized
successfully in good yields but were difficult to prepare under
catalytic hydrogenation conditions. The thienyl ring can also
be easily introduced to the 3-position of the dihydro-1,4-
benzoxazine scaffold (6l). Moreover, three other dihydroben-
zoheterocycles with different scaffolds, 3-methyl-3,4-dihydro-
entry
acid
solvent
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
AlCl3
CH CN
rt
12
12
12
12
12
0.5
1
55
0
3
CH Cl
rt
2
2
2
H-1,4-benzothiazine (6m), 2-methyl-1,2,3,4-tetrahydroqui-
noxaline (6n), and 2-methyl-2,3-dihydro-1,4-benzoxazepin-
(1H)-one (6o), were easily achieved using the corresponding
CH NO
rt
38
trace
trace
85
68
23
12
0
3
2
DMF
THF
rt
5
rt
substrates under standard conditions.
CH CN
80
80
80
80
80
80
80
80
80
3
For the formation of dihydro-1,4-benzoxazepinones, two
reaction pathways are possible. One way is ketone reduction
to the alcohol initially and then direct amination with
assistance from a Lewis acid to form 3,4-dihydro-1,4-
benzoxazepin-5(2H)-one. The other way is ketone cyclization
with assistance from a Lewis acid and then reduction of the
imine intermediate by ionic hydrogenation. In our study, the
alcohol product was not observed during the reaction process.
Furthermore, when 2-(2-hydroxy-2-phenylethoxy)benzamide
(7d) was treated with Al(OTf) (0.5 equiv) in CH CN at 80
CH CN
3
SnCl4
CH CN
4
3
TiCl4
CH CN
4
3
1
1
1
1
1
0
1
2
3
4
ZnCl2
CH CN
4
3
FeCl3
CH CN
4
trace
0
3
SnCl2
CH CN
4
3
BF ·Et O
CH CN
1
64
22
3
2
3
CF COOH
3
CH CN
4
3
a
The reaction was performed using 1a (1.0 equiv), Lewis or Brønsted
acid (0.5 equiv), and Et SiH (2.0 equiv) in solvent. Isolated yield.
b
3
3
3
°
C, no target product was observed, which did not support
the reduction−direct amination procedure. On the other
hand, when 2-(2-oxo-2-phenylethoxy)benzamide (1d) was
Furthermore, it was found that the benzodiazepin-5-one
scaffold can also be constructed based on this method, as 3-
phenyl-3,4-dihydro-1H-1,4-benzodiazepin-5(2H)-one (2m)
was readily achieved from 2-((2-oxo-2-phenylethyl)amino)-
benzamide in moderate yield.
treated first with Al(OTf) (0.5 equiv), the imine intermediate
3
3-phenyl-1,4-benzoxazepin-5(2H)-one (8d) was isolated,
which can be reduced by Al(OTf) /Et SiH to give target
3
3
product 2d (Scheme 4). On the basis of the above results, the
formation of 3,4-dihydro-1,4-benzoxazepin-5(2H)-one deriva-
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Table 2. Synthesis of 3,4-Dihydrobenzoxazepin-5(2H)-ones ,
a b
a
All reactions were performed using 1 (1.0 equiv), Al(OTf) (0.5 equiv), and Et SiH (2.0 equiv) in CH CN at reflux for the corresponding time.
Isolated yield.
3
3
3
b
Scheme 2. Synthesis of 4,5-Dihydro-1,4-benzoxazepin-
CONCLUSIONS
■
,
a b
3
(2H)-ones
In summary, we have developed a facile and versatile
Al(OTf) -mediated cascade cyclization and ionic hydro-
3
genation reaction which allows access to a variety of
dihydrobenzoheterocycles including 3,4-dihydro-1,4-benzoxa-
zepin-5(2H)-one (2a−l), 3,4-dihydro-1H-1,4-benzodiazepin-
5
(2H)-one (2m), 4,5-dihydro-1,4-benzoxazepin-3(2H)-one
(
4a,b), 3,4-dihydro-2H-1,4-benzoxazine (6a−l), 3,4-dihydro-
H-1,4-benzothiazine (6m), 1,2,3,4-tetrahydroquinoxaline
6n), and 2,3-dihydro-1,4-benzoxazepin-5(1H)-one (6o).
2
(
a
The relevant reaction mechanism was explored to verify a
cascade cyclization and reduction pathway. This method is
attractive for its tolerance of a wide range of functional
groups, ease of preparation of nitrogen-containing precursors,
mild reaction conditions, and high efficiency and has immense
potential application in organic synthesis.
All reactions were performed using 3 (1.0 equiv), Al(OTf) (0.5
3
b
equiv), and Et SiH (2.0 equiv) in CH CN at reflux for 8 h. Isolated
yield.
3
3
tives may proceed through a cascade cyclization and reduction
pathway (Scheme 5).
Meanwhile, controlled reactions were conducted to explore
possible pathways to understand the mechanism of assembling
dihydro-1,4-benzoxazines. When N-Boc-2-(2-oxo-2-phenyl-
EXPERIMENTAL SECTION
■
General Information. Melting points were determined on a
microscope melting point apparatus. NMR spectra were recorded on
a 400 MHz NMR spectrometer. Chemical shifts are referenced to
the residual solvent peak and reported in ppm (δ scale), and all
coupling constant (J) values are given in hertz. ESI-HRMS data were
measured on an orbitrap mass spectrometer. Flash column
chromatography was performed with 230−400 silica. All the solvents
and reagents were obtained from commercial sources and used
without further purification.
ethoxy)aniline (5h) was treated with Al(OTf) (0.5 equiv)
3
in CH CN at 80 °C, 3-phenyl-2H-1,4-benzoxazine (9h) was
3
rapidly formed, which can be easily reduced by Al(OTf)3/
Et SiH to afford target product 6h (Scheme 4). The results
3
indicated that a sequential Boc removal, condensation, and
reduction process occurred to furnish 3,4-dihydro-2H-1,4-
benzoxazine derivatives (Scheme 5).
General Procedure for Synthesis of Dihydrobenzohetero-
cycles (2a−m, 4a,b, 6a−o). To a solution of 1 or 3 or 5 (1.0
mmol) in CH CN (5 mL) were added Et SiH (2.0 mmol) and
3
3
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Table 3. Synthesis of 3,4-Dihydrobenzoxazines ,
a b
a
b
All reactions were performed using 5 (1.0 equiv), Al(OTf) (0.5 equiv), and Et SiH (2.0 equiv) in CH CN at reflux for 10 min. Isolated yield.
3
3
3
c
The reaction was stirred for 1 h.
Scheme 3. Most Common Methods To Synthesize 3,4-Dihydro-1,4-benzoxazines
Scheme 4. Investigation of the Reaction Mechanism
Al(OTf) (0.5 mmol) at room temperature. The reaction mixture
The residue was purified by silica gel flash column chromatography
to afford the desired product.
3
was heated at reflux for the corresponding time and then
concentrated under vacuum. The residue was diluted with EtOAc,
washed with brine, dried over Na SO , filtered, and concentrated.
3-Methyl-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one (2a).
Yield: 85% (150 mg); (CH Cl /EtOAc = 4:1, R = 0.40); white
2
4
2
2
f
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Scheme 5. Proposed Pathway for the Synthesis of Dihydrobenzoheterocycles
1
solid; mp: 142−144 °C; H NMR (400 MHz, acetone) δ 7.92 (d, J
132.9, 132.7, 129.2, 127.0, 123.3, 122.2, 120.4, 76.1, 56.8, 20.2; ESI-
+
=
7.8 Hz, 1H), 7.46−7.39 (m, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.01 (d,
HRMS m/z calcd for C H NO [M + H] 254.1176, found
16
16
2
J = 8.2 Hz, 1H), 4.26 (dd, J = 11.3, 2.5 Hz, 1H), 4.22−4.09 (m,
254.1172.
13
1
H), 3.78−3.73 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H); C NMR (100
3-(4-Methoxyphenyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-
MHz, acetone) δ 167.4, 156.2, 132.7, 131.7, 124.9, 122.4, 120.8, 77.7,
one (2f). Yield: 70% (188 mg); (CH Cl /EtOAc = 4:1, R = 0.50);
2
2
f
+
1
4
1
7.3, 15.5; ESI-HRMS m/z calcd for C H NO [M + H]
yellow solid; mp: 95−97 °C; H NMR (400 MHz, acetone) δ 8.11
(d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.33 (d, J
= 8.6 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H),
6.92 (d, J = 8.7 Hz, 2H), 4.86−4.78 (m, 1H), 4.56 (dd, J = 11.8, 7.9
1
0
12
2
78.0863, found 178.0861.
-Methoxy-3-methyl-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-
one (2b). Yield: 86% (178 mg); (CH Cl /EtOAc = 4:1, R = 0.38);
light yellow solid; mp: 87−89 °C; H NMR (400 MHz, acetone) δ
.98 (d, J = 8.9 Hz, 1H), 7.49 (s, 1H), 6.67 (d, J = 8.9 Hz, 1H), 6.50
s, 1H), 4.27 (dd, J = 11.6, 1.8 Hz, 1H), 4.15 (dd, J = 11.6, 7.9 Hz,
H), 3.83 (s, 3H), 3.77−3.74 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H);
NMR (100 MHz, acetone) δ 166.7, 163.5, 158.2, 134.0, 115.7, 109.1,
04.0, 76.8, 55.0, 47.8, 16.2; ESI-HRMS m/z calcd for C H NO
8
2
2
f
1
13
Hz, 1H), 4.36 (dd, J = 11.8, 2.4 Hz, 1H), 3.78 (s, 3H); C NMR
7
(100 MHz, acetone) δ 166.8, 159.6, 157.0, 132.9, 132.6, 129.9, 128.4,
(
1
1
23.5, 122.3, 120.5, 114.0, 76.3, 56.4, 54.7; ESI-HRMS m/z calcd for
13
C
+
C H NO [M + H] 270.1125, found 270.1120.
16
16
3
3
-(4-Fluorophenyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
1
[
11
14
3
(2g). Yield: 78% (200 mg); (CH Cl /EtOAc = 4:1, R = 0.52);
2
2
f
+
M + H] 208.0968, found 208.0967.
-Chloro-3-methyl-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
2c). Yield: 82% (173 mg); (CH Cl /EtOAc = 4:1, R = 0.43); white
1
yellow solid; mp: 135−137 °C; H NMR (400 MHz, acetone) δ
.17 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.48−7.41 (m, 3H), 7.15−
7.11 (m, 3H), 6.96 (d, J = 8.2 Hz, 1H), 4.95−4.92 (m, 1H), 4.64
7
8
(
2
2
f
1
solid; mp: 143−145 °C; H NMR (400 MHz, acetone) δ 7.92 (s,
1
3
(
dd, J = 12.0, 7.1 Hz, 1H), 4.41 (dd, J = 12.1, 2.2 Hz, 1H);
C
1
1
1
H), 7.57 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz,
NMR (100 MHz, acetone) δ 166.7, 163.5, 161.1, 157.2, 133.00,
132.86, 129.2, 122.2, 120.3, 115.3, 115.1, 75.6, 56.5; ESI-HRMS m/z
H), 4.30 (dd, J = 11.5, 2.3 Hz, 1H), 4.19 (dd, J = 11.3, 8.5 Hz,
H), 3.88−3.73 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H); C NMR (100
MHz, acetone) δ 165.7, 155.1, 132.5, 131.2, 126.9, 125.7, 122.7, 77.5,
13
+
calcd for C H NO F [M + H] 258.0925, found 258.0923.
15
13
2
+
3-(4-Chlorophenyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
4
2
7.5, 15.7; ESI-HRMS m/z calcd for C H NO Cl [M + H]
10 11 2
(
2h). Yield: 75% (204 mg); (CH Cl /EtOAc = 4:1, R = 0.52);
2
2
f
12.0473, found 212.0473.
-Phenyl-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one (2d).
Yield: 75% (179 mg); (CH Cl /EtOAc = 4:1, R = 0.55); white
1
yellow solid; mp: 94−96 °C; H NMR (400 MHz, acetone) δ 8.20
d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.46−7.37 (m, 5H), 7.13 (t, J =
7.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.96−4.94 (m, 1H), 4.67 (dd,
3
(
2
2
f
1
solid; mp: 89−91 °C; H NMR (400 MHz, DMSO) δ 8.61 (d, J =
1
3
J = 12.2, 6.8 Hz, 1H), 4.43 (dd, J = 12.2, 2.0 Hz, 1H); C NMR
100 MHz, acetone) δ 166.4, 157.3, 137.7, 133.04, 133.01, 128.8,
28.5, 122.46, 122.36, 122.1, 120.2, 75.1, 56.5; ESI-HRMS m/z calcd
5
7
1
.3 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H),
.37−7.22 (m, 5H), 7.12 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.2 Hz,
H), 4.79 (t, J = 5.1 Hz, 1H), 4.64 (dd, J = 12.1, 6.4 Hz, 1H), 4.32
(
1
+
dd, J = 12.1, 1.9 Hz, 1H); 13C NMR (100 MHz, acetone) δ 166.7,
for C H NO Cl [M + H] 274.0629, found 274.0625.
(
15 13
2
3
-(4-Bromophenyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
1
7
2
57.2, 138.4, 132.92, 132.82, 128.6, 127.8, 127.1, 123.0, 122.1, 120.4,
5.8, 57.1; ESI-HRMS m/z calcd for C H NO [M + H]
40.1019, found 240.1015.
-(p-Tolyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one (2e).
Yield: 72% (182 mg); (CH Cl /EtOAc = 4:1, R = 0.55); yellow
+
(2i). Yield: 71% (225 mg); (CH Cl /EtOAc = 4:1, R = 0.58); yellow
2
2
f
1
5
14
2
1
solid; mp: 97−99 °C; H NMR (400 MHz, acetone) δ 8.19 (d, J =
.0 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 6.8
8
3
Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.95 (d,
J = 8.1 Hz, 1H), 4.94−4.92 (m, 1H), 4.67 (dd, J = 12.2, 6.7 Hz,
1H), 4.42 (dd, J = 12.2, 1.9 Hz, 1H); 13C NMR (100 MHz, acetone)
δ 166.5, 157.2, 138.1, 133.06, 133.02, 131.5, 129.2, 122.4, 122.1,
2
2
f
1
syrup; H NMR (400 MHz, acetone) δ 8.13 (d, J = 8.0 Hz, 1H),
7
7
4
.61 (s, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H),
.20−7.09 (m, 3H), 6.96 (d, J = 8.1 Hz, 1H), 4.85−4.83 (m, 1H),
.58 (dd, J = 11.9, 7.6 Hz, 1H), 4.37 (dd, J = 11.9, 2.2 Hz, 1H), 2.30
121.2, 120.2, 75.1, 56.6; ESI-HRMS m/z calcd for C15
+ H] 318.0124, found 318.0124.
H13NO
Br [M
2
s, 3H); 13C NMR (100 MHz, acetone) δ 166.8, 157.1, 137.5, 135.2,
+
(
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3
-(4-(Trifluoromethyl)phenyl)-3,4-dihydrobenzo[f ][1,4]oxazepin-
115.60, 115.48, 70.4, 44.9, 20.0, 17.0; ESI-HRMS m/z calcd for
+
5
0
(2H)-one (2j). Yield: 68% (208 mg); (CH Cl /EtOAc = 4:1, R =
C H NO [M + H] 164.1070, found 164.1067.
2
2
f
10 14
1
.57); light yellow solid; mp: 141−143 °C; H NMR (400 MHz,
6-Methoxy-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6c).
acetone) δ 8.24 (d, J = 6.8 Hz, 1H), 7.82 (s, 1H), 7.72 (d, J = 8.2
Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.13 (t,
J = 7.6 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.08 (m, 1H), 4.77 (dd, J
Yield: 90% (161 mg); (PE/EtOAc = 15:1, R = 0.21); brown
f
1
solid; mp: 47−49 °C; H NMR (400 MHz, acetone) δ 6.56 (d, J =
8.6 Hz, 1H), 6.19 (s, 1H), 6.09 (d, J = 9.5 Hz, 1H), 5.00 (s, 1H),
4.14−4.03 (m, 1H), 3.64 (s, 3H), 3.62−3.58 (m, 1H), 3.47−3.44 (m,
1H), 1.12 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, acetone) δ
154.6, 137.6, 135.0, 116.0, 102.1, 100.5, 70.3, 54.6, 45.0, 17.0; ESI-
=
12.3, 6.2 Hz, 1H), 4.48 (d, J = 12.3 Hz, 1H); 13C NMR (100
MHz, acetone) δ 166.5, 157.4, 143.6, 133.24, 133.22, 133.09, 129.3
q, J = 31.9 Hz), 127.8, 125.3 (q, J = 3.8 Hz), 124.4 (q, J = 269.6
Hz), 122.0, 120.2, 74.8, 56.9; ESI-HRMS m/z calcd for
(
+
HRMS m/z calcd for C H NO [M + H] 180.1019, found
10
14
2
+
C H NO F [M + H] 308.0893, found 308.0889.
6
180.1016.
1
13
2 3
3
-(Thiophene-2-yl)-3,4-dihydrobenzo[f ][1,4]oxazepin-5(2H)-one
6-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6d).
(
2k). Yield: 72% (176 mg); (CH Cl /EtOAc = 4:1, R = 0.58);
2
2
f
Yield: 88% (146 mg); (PE/EtOAc = 15:1, R = 0.30); brown
f
1
1
yellow solid; mp: 83−85 °C; H NMR (400 MHz, acetone) δ 8.11
d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.38 (d, J
solid; mp: 30−32 °C; H NMR (400 MHz, acetone) δ 6.66−6.57
(
=
(m, 1H), 6.35 (d, J = 10.4 Hz, 1H), 6.22 (t, J = 8.6 Hz, 1H), 5.32 (s,
1H), 4.18−4.09 (m, 1H), 3.70−3.59 (m, 1H), 3.54−3.42 (m, 1H),
1.14 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, acetone) δ 158.9,
156.6, 139.4, 135.7, 116.1, 102.4, 102.2, 100.9, 100.6, 70.1, 44.7, 16.8;
5.1 Hz, 1H), 7.12 (t, J = 7.6 Hz, 2H), 7.03−6.96 (m, 2H), 5.25−
5
.08 (m, 1H), 4.67 (dd, J = 11.9, 7.0 Hz, 1H), 4.52−4.39 (m, 1H);
1
3
C NMR (100 MHz, acetone) δ 166.3, 156.9, 141.3, 133.0, 132.7,
+
1
26.9, 125.6, 125.4, 123.0, 122.3, 120.5, 75.5, 52.7; ESI-HRMS m/z
calcd for C H NO S [M + H] 246.0583, found 246.0580.
ESI-HRMS m/z calcd for C H NOF [M + H] 168.0819, found
9
11
+
13
12
2
168.0817.
6
,7,8,9,9a,10-Hexahydrodibenzo[b,f ][1,4]oxazepin-11(5aH)-one
6-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6e).
(
2l). Yield: 84% (182 mg); (CH Cl /EtOAc = 4:1, R = 0.55); white
Yield: 92% (168 mg); (PE/EtOAc = 15:1, R = 0.32); yellow
2
2
f
f
1
1
solid; mp: 231−233 °C; H NMR (400 MHz, DMSO) δ 8.27 (s,
solid; mp: 60−62 °C; H NMR (400 MHz, acetone) δ 6.64 (d, J =
1
7
1
1
H), 7.60 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.16 (t, J =
.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.05 (td, J = 10.7, 4.1 Hz,
H), 3.08−3.00 (m, 1H), 2.01−1.92 (m, 2H), 1.69−1.59 (m, 2H),
8.4 Hz, 1H), 6.61 (s, 1H), 6.48 (d, J = 8.5 Hz, 1H), 5.31 (s, 1H),
4.22−4.11 (m, 1H), 3.73−3.61 (m, 1H), 3.56−3.42 (m, 1H), 1.15
(dd, J = 6.4, 0.9 Hz, 3H); 13C NMR (100 MHz, acetone) δ 142.1,
135.9, 125.2, 116.9, 116.4, 113.9, 70.2, 44.6, 16.8; ESI-HRMS m/z
13
.44−1.22 (m, 3H), 1.16−1.06 (m, 1H); C NMR (100 MHz,
+
DMSO) δ 168.8, 153.8, 133.0, 130.4, 128.7, 123.8, 122.8, 88.4, 54.4,
1.3, 30.0, 24.1, 23.9; ESI-HRMS m/z calcd for C H NO [M +
calcd for C H NOCl [M + H] 184.0524, found 184.0525.
9
11
3
6-Bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6f).
13
16
2
+
H] 218.1176, found 218.1173.
-Phenyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (2m).
Yield: 52% (123 mg); (CH Cl /EtOAc = 4:1, R = 0.50); light
Yield: 85% (193 mg); (PE/EtOAc = 15:1, R = 0.32); yellow
f
1
3
solid; mp: 73−75 °C; H NMR (400 MHz, acetone) δ 6.75 (s, 1H),
2
2
f
6.63−6.58 (m, 2H), 5.30 (s, 1H), 4.22−4.10 (m, 1H), 3.73−3.61 (m,
1
13
yellow solid; mp: 162−164 °C; H NMR (400 MHz, acetone) δ
1H), 3.55−3.41 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H); C NMR (100
8
1
3
.17 (d, J = 8.0 Hz, 1H), 7.35−7.23 (m, 6H), 7.15 (t, J = 7.3 Hz,
MHz, acetone) δ 142.6, 136.4, 119.4, 117.4, 116.8, 112.6, 70.2, 44.6,
+
H), 6.69−6.85 (m, 2H), 5.98 (s, 1H), 4.80 (t, J = 5.2 Hz, 1H),
16.8; ESI-HRMS m/z calcd for C H NOBr [M + H] 228.0019,
9
11
13
.85−3.72 (m, 1H), 3.60 (dd, J = 13.6, 3.3 Hz, 1H); C NMR (100
found 228.0020.
MHz, acetone) δ 168.4, 148.3, 141.3, 133.8, 131.8, 128.3, 127.2,
26.6, 117.6, 116.5, 116.3, 58.2, 52.1; ESI-HRMS m/z calcd for
3-Methyl-7-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]-
1
oxazine (6g). Yield: 87% (188 mg); (PE/EtOAc = 15:1, R = 0.30);
f
+
1
C H N O [M + H] 239.1179, found 239.1176.
5
5
Yield: 60% (106 mg); (CH Cl /EtOAc = 4:1, R = 0.46); white
yellow solid; mp: 63−65 °C; H NMR (400 MHz, acetone) δ 6.99
1
15
2
-Methyl-4,5-dihydrobenzo[f ][1,4]oxazepin-3(2H)-one (4a).
(d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.71 (d, J = 8.3 Hz, 1H), 5.72 (s,
1H), 4.29−4.18 (m, 1H), 3.80−3.67 (m, 1H), 3.58−3.56 (m, 1H),
2
2
f
1
13
solid; mp: 152−154 °C; H NMR (400 MHz, acetone) δ 7.39−7.23
1.18 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, acetone) δ 142.6,
(
4
m, 3H), 7.17 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.79−
138.1, 125.1 (q, J = 267.8 Hz), 118.3 (q, J = 4.1 Hz), 117.8 (q, J =
32.2 Hz), 113.9, 112.7 (q, J = 3.8 Hz), 70.1, 44.7, 16.7; ESI-HRMS
13
.74 (m, 1H), 4.54−4.36 (m, 2H), 1.64 (d, J = 6.9 Hz, 3H);
C
+
NMR (100 MHz, acetone) δ 157.7, 136.8, 129.4, 126.47, 126.45,
24.7, 121.0, 72.5, 48.2, 20.2; ESI-HRMS m/z calcd for C H NO
2
m/z calcd for C H NOF [M + H] 218.0787, found 218.0785.
10
11
3
1
[
3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6h). Yield: 90%
10
12
+
1
M + H] 178.0863, found 178.0860.
-Methoxy-5-methyl-4,5-dihydrobenzo[f ][1,4]oxazepin-3(2H)-
one (4b). Yield: 68% (140 mg); (CH Cl /EtOAc = 4:1, R = 0.45);
(190 mg); (PE/EtOAc = 15:1, R = 0.50); yellow oil; H NMR (400
f
7
MHz, acetone) δ 7.44 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H),
7.34−7.27 (m, 1H), 6.81−6.68 (m, 3H), 6.57 (t, J = 7.5 Hz, 1H),
5.37 (s, 1H), 4.49 (d, J = 7.8 Hz, 1H), 4.29−4.17 (m, 1H), 4.02−
3.83 (m, 1H); 13C NMR (100 MHz, acetone) δ 143.4, 140.2, 134.9,
128.5, 127.8, 127.1, 121.2, 117.7, 116.0, 115.3, 70.5, 53.7; ESI-HRMS
2
2
f
1
white solid; mp: 148−150 °C; H NMR (400 MHz, acetone) δ 7.32
(
s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.91−6.82 (m, 2H), 4.80−4.65
m, 1H), 4.45−4.33 (m, 2H), 3.79 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H);
C NMR (100 MHz, acetone) δ 170.5, 156.6, 151.2, 137.9, 121.7,
(
1
3
+
m/z calcd for C H NO [M + H] 212.1070, found 212.1076.
14
14
1
13.6, 112.1, 72.7, 55.0, 48.3, 20.0; ESI-HRMS m/z calcd for
3-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (6i).
Yield: 88% (215 mg); (PE/EtOAc = 15:1, R = 0.49); brown oil;
+
C H NO [M + H] 208.0968, found 208.0965.
f
11
14
3
1
3
-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6a). Yield: 92%
H NMR (400 MHz, acetone) δ 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J
= 7.5 Hz, 2H), 6.78−6.72 (m, 3H), 6.58 (t, J = 7.4 Hz, 1H), 5.44 (s,
1H), 4.53 (d, J = 6.5 Hz, 1H), 4.23 (dd, J = 10.5, 1.4 Hz, 1H), 3.93
(dd, J = 9.9, 8.3 Hz, 1H); 13C NMR (100 MHz, acetone) δ 143.4,
139.3, 134.6, 132.9, 128.9, 128.5, 121.3, 117.8, 116.0, 115.3, 70.2,
1
(
137 mg); (PE/EtOAc = 15:1, R = 0.35); brown oil; H NMR (400
f
MHz, acetone) δ 6.66−6.63 (m, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.50
(
1
t, J = 7.5 Hz, 1H), 4.94 (s, 1H), 4.22−4.06 (m, 1H), 3.70−3.63 (m,
13
H), 3.51−3.40 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); C NMR (100
+
MHz, acetone) δ 143.5, 134.6, 120.9, 117.3, 115.9, 114.9, 70.4, 44.9,
1
53.1; ESI-HRMS m/z calcd for C H NOCl [M + H] 246.0680,
14
13
+
6.9; ESI-HRMS m/z calcd for C H NO [M + H] 150.0913, found
found 246.0677.
9
12
1
50.0912.
,6-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (6b). Yield:
3-(4-Bromophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (6j).
3
Yield: 82% (237 mg); (PE/EtOAc = 15:1, R = 0.49); yellow
f
1
1
9
4% (153 mg); (PE/EtOAc = 15:1, R = 0.35); brown oil;
H
solid; mp: 57−59 °C; H NMR (400 MHz, acetone) δ 7.55 (d, J =
8.4 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 6.78−6.72 (m, 3H), 6.58 (t, J
= 7.4 Hz, 1H), 5.45 (s, 1H), 4.52 (d, J = 7.3 Hz, 1H), 4.24 (dd, J =
10.6, 2.4 Hz, 1H), 3.93 (dd, J = 10.0, 8.2 Hz, 1H); C NMR (100
MHz, acetone) δ 143.4, 139.8, 134.5, 131.5, 129.2, 121.3, 121.0,
f
NMR (400 MHz, acetone) δ 6.53 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H),
6
3
3
.31 (d, J = 8.0 Hz, 1H), 4.82 (s, 1H), 4.13−4.06 (m, 1H), 3.67−
.59 (m, 1H), 3.45−3.41 (m, 1H), 2.12 (s, 3H), 1.11 (d, J = 6.4 Hz,
H); 13C NMR (100 MHz, acetone) δ 141.4, 134.2, 129.9, 117.9,
1
3
9
683
dx.doi.org/10.1021/jo501824z | J. Org. Chem. 2014, 79, 9678−9685

The Journal of Organic Chemistry
Article
1
1
17.8, 116.0, 115.3, 70.1, 53.1; ESI-HRMS m/z calcd for
as a yellow solid. mp: 135−137 °C; H NMR (400 MHz, acetone) δ
8.07 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 6.9 Hz, 2H), 7.59 (t, J = 7.5
+
C H NOBr [M + H] 290.0175, found 290.0176.
14
13
13
3
-(4-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]-
Hz, 3H), 7.21−7.06 (m, 2H), 5.80 (s, 2H); C NMR (100 MHz,
acetone) δ 193.0, 160.1, 134.6, 134.3, 133.8, 133.7, 128.8, 127.9,
121.3, 116.0, 113.1, 101.8, 70.6; ESI-HRMS m/z calcd for
oxazine (6k). Yield: 84% (234 mg); (PE/EtOAc = 15:1, R = 0.45);
yellow solid; mp: 62−64 °C; H NMR (400 MHz, acetone) δ 7.69
f
1
+
(
dd, J = 18.2, 8.3 Hz, 4H), 6.80−6.73 (m, 3H), 6.60 (t, J = 7.4 Hz,
C H NO [M + H] 238.0863, found 238.0860.
15
12
2
1
4
1
H), 5.53 (s, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.34−4.22 (m, 1H),
General Procedure for Synthesis of 3-Phenyl-2H-benzo[b]-
[1,4]oxazine (9h). To a solution of 5h (327 mg, 1.0 mmol) in
CH CN was added Al(OTf) (237 mg, 0.5 mmol) at room
temperature. The reaction mixture was heated to reflux for 10 min
and then concentrated. The residue was diluted with EtOAc, washed
13
.07−3.92 (m, 1H); C NMR (100 MHz, acetone) δ 145.2, 143.4,
34.4, 129.3 (q, J = 31.8 Hz), 127.9, 125.3 (q, J = 3.8 Hz), 124.5 (q,
3
3
J = 269.5 Hz), 121.4, 117.9, 116.1, 115.3, 70.0, 53.4; ESI-HRMS m/z
calcd for C H NOF [M + H] 280.0944, found 280.0941.
+
15
13
3
3
-(Thiophene-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (6l).
with brine, dried over Na
residue was purified by silica gel flash column chromatography (PE/
EtOAc = 15:1, R = 0.65) to afford the desired product (186 mg,
2 4
SO , filtered, and concentrated. The
Yield: 80% (173 mg); (PE/EtOAc = 15:1, R = 0.49); yellow
f
1
solid; mp: 55−57 °C; H NMR (400 MHz, acetone) δ 7.38 (d, J =
f
1
5
6
=
.1 Hz, 1H), 7.14 (d, J = 2.7 Hz, 1H), 7.01 (t, J = 4.3 Hz, 1H),
89% yield) as a white solid. mp: 100−102 °C; H NMR (400 MHz,
acetone) δ 8.05 (d, J = 8.0 Hz, 2H), 7.54−7.52 (m, 3H), 7.38 (d, J =
7.7 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.92
(d, J = 8.0 Hz, 1H), 5.19 (s, 2H); 13C NMR (100 MHz, acetone) δ
58.9, 146.7, 135.4, 134.0, 131.1, 128.6, 128.5, 127.6, 126.5, 122.1,
15.4, 62.5; ESI-HRMS m/z calcd for C H NO F [M + H]
.74−6.72 (m, 3H), 6.59 (t, J = 8.9 Hz, 1H), 5.54 (s, 1H), 4.85 (d, J
13
7.2 Hz, 1H), 4.33−4.22 (m, 1H), 4.04−3.99 (m, 1H); C NMR
(
1
100 MHz, acetone) δ 143.9, 143.5, 134.0, 126.7, 125.0, 124.7, 121.4,
18.2, 116.1, 115.5, 70.7, 49.8; ESI-HRMS m/z calcd for C H NOS
1
1
2
12
12
+
+
[
M + H] 218.0634, found 218.0633.
-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (6m). Yield: 83%
11 13
2
10.0925, found 210.0927.
3
1
(
136 mg); (PE/EtOAc = 15:1, R = 0.52); brown oil; H NMR (400
f
MHz, acetone) δ 6.88 (d, J = 7.7 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H),
ASSOCIATED CONTENT
■
6
.56−6.45 (m, 2H), 5.17 (s, 1H), 3.73−3.58 (m, 1H), 2.95−2.87 (m,
* Supporting Information
S
13
1H), 2.80−2.71 (m, 1H), 1.27 (d, J = 6.3 Hz, 3H); C NMR (100
Copies of H NMR, 13C NMR, and HRMS spectra of
compounds 2a−m, 4a,b, 6a−o, 7d, 8d, and 9h. This material
is available free of charge via the Internet at http://pubs.acs.
org.
1
MHz, acetone) δ 142.7, 126.8, 125.2, 116.8, 115.0, 114.6, 46.8, 31.7,
+
2
1
1.5; ESI-HRMS m/z calcd for C H NS [M + H] 166.0685, found
9 12
66.0683.
-Methyl-1,2,3,4-tetrahydroquinoxaline (6n). Yield: 75% (111
2
1
mg); (PE/EtOAc = 4:1, R = 0.30); yellow solid; mp: 48−50 °C; H
f
AUTHOR INFORMATION
Corresponding Authors
NMR (400 MHz, acetone) δ 6.46−6.34 (m, 4H), 4.60 (s, 2H), 3.40
■
(
6
s, 1H), 3.28 (d, J = 10.7 Hz, 1H), 2.97−2.88 (m, 1H), 1.12 (d, J =
.2 Hz, 3H); 13C NMR (100 MHz, acetone) δ 134.1, 133.8, 117.5,
*E-mail: wangxiaojian@imm.ac.cn.
1
17.3, 113.63, 113.47, 48.0, 45.2, 19.2; ESI-HRMS m/z calcd for
*
E-mail: yindali@imm.ac.cn.
+
C H N [M + H] 149.1073, found 149.1071.
9
13
2
Notes
2
-Methyl-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-one (6o).
The authors declare no competing financial interest.
Yield: 79% (139 mg); (PE/EtOAc = 2:1, R = 0.33); yellow solid;
mp: 64−66 °C; H NMR (400 MHz, acetone) δ 7.67 (d, J = 8.0 Hz,
f
1
ACKNOWLEDGMENTS
1
7
1
H), 7.26 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.69 (t, J =
.5 Hz, 1H), 5.74 (s, 1H), 4.35 (d, J = 12.7 Hz, 1H), 4.27 (dd, J =
2.7, 6.0 Hz, 1H), 3.93−3.84 (m, 1H), 1.26 (d, J = 6.6 Hz, 3H);
■
We are grateful to the National Natural Science Foundation
of China (no. 81102322), PUMC Youth Fund (no.
3320140011), and PUMC Graduate Innovation Fund
13
C
NMR (100 MHz, acetone) δ 170.2, 146.6, 133.8, 133.6, 118.5, 117.0,
3
114.2, 69.7, 52.5, 18.2; ESI-HRMS m/z calcd for C H NO [M +
10
12
2
(
No.31038).
+
H] 178.0863, found 178.0861.
General Procedure for Synthesis of 2-(2-Hydroxy-2-
REFERENCES
phenylethoxy)benzamide (7d). To a solution of 1d (255 mg,
1
■
.0 mmol) in MeOH was added NaBH4 (75 mg, 2.0 mmol)
portionwise. The reaction mixture was stirred at room temperature
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S.; Sabbah, M.; Wightman, D.; Nguyen, I. T.; Sanselme, M.; Besson,
T.; Briere, J. F.; Oudeyer, S.; Levacher, V. J. Org. Chem. 2013, 78,
8191. (e) Chouhan, G.; Alper, H. Org. Lett. 2010, 12, 192.
for 2 h and then concentrated. The residue was diluted with EtOAc,
washed with 1 N HCl, saturated aq NaHCO , and brine, and then
3
dried over Na SO . After filtration and concentration, the residue was
2
4
purified by silica gel flash column chromatography (CH Cl /MeOH
2
2
=
25:1, R = 0.42) to afford the desired product (215 mg, 84% yield)
f
1
as a yellow oil. H NMR (400 MHz, acetone) δ 8.04 (d, J = 7.7 Hz,
1
7
H), 7.94 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H),
.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 6.8 Hz, 1H), 7.17 (d, J = 8.4
Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.78 (s, 1H), 5.23−5.19 (m, 1H),
.14 (d, J = 4.1 Hz, 1H), 4.40 (dd, J = 9.7, 3.4 Hz, 1H), 4.28−4.15
m, 1H); 13C NMR (100 MHz, acetone) δ 166.2, 157.3, 141.6,
32.7, 131.7, 128.3, 127.6, 126.3, 122.5, 120.9, 113.5, 74.3, 71.6; ESI-
5
(
1
+
HRMS m/z calcd for C H NO [M + H] 258.1125, found
15
16
3
258.1120.
General Procedure for Synthesis of 3-Phenylbenzo[f][1,4]-
oxazepin-5(2H)-one (8d). To a solution of 1d (255 mg, 1.0 mmol)
in CH CN was added Al(OTf)3 (237 mg, 0.5 mmol) at room
3
temperature. The reaction mixture was heated to reflux for 8 h and
then concentrated. The residue was diluted with EtOAc, washed with
brine, dried over Na SO , filtered, and concentrated. The residue was
2
4
purified by silica gel flash column chromatography (CH Cl /EtOAc
́
(f) Herrero, S.; García-Lopez, M. T.; Cenarruzabeitia, E.; Río, J. D.;
Herranz, R. Tetrahedron 2003, 59, 4491. (g) Field, G. F.; Zally, W. J.;
2
2
=
10:1, R = 0.58) to afford the desired product (80 mg, 34% yield)
f
9
684
dx.doi.org/10.1021/jo501824z | J. Org. Chem. 2014, 79, 9678−9685

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