Regioselective synthesis of fused oxazepinone scaffolds through one-pot smiles rearrangement tandem reaction

Article abstract of DOI:10.1021/co2001058

The paper describes a convenient and facile methodology for the regioselective synthesis of fused oxazepinone scaffolds. This process is an efficient construction of the oxazepinone scaffold by a one-pot coupling/Smiles rearrangement/cyclization approach.

Full text of DOI:10.1021/co2001058

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Regioselective Synthesis of Fused Oxazepinone Scaffolds through
One-Pot Smiles Rearrangement Tandem Reaction
Yanli Liu,† Chunxiao Chu,† Aiping Huang,† Chunjing Zhan,† Ying Ma,† and Chen Ma*,†,‡
†School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P.R. China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, P.R. China
S Supporting Information
b
ABSTRACT: The paper describes a convenient and facile methodology for the
regioselective synthesis of fused oxazepinone scaffolds. This process is an
efficient construction of the oxazepinone scaffold by a one-pot coupling/Smiles
rearrangement/cyclization approach. This transition metal-free process has
potential applications in the synthesis of biologically and medicinally relevant
compounds.
KEYWORDS: one-pot, coupling/Smiles rearrangement/cyclization process,
fused oxazepinone scaffolds
’ INTRODUCTION
A one-step synthetic route, without transition metal catalyst,
would be a very useful improvement. The Smiles rearrangement
has become a powerful method in pharmaceutical, biomedical,
and optical chemistry.15 Herein, we report an effective regiose-
lective synthesis of fused oxazepinone scaffolds via Smiles
rearrangement tandem reaction by the reaction of commercially
available N-substituted salicylamides with substituted benzenes
or pyridines (Scheme 1).
One of the main challenges in medicinal chemistry is the
design and synthesis of biologically active molecules. Combina-
torial chemistry1 has emerged as a useful tool for the synthesis of
biological compounds.
Fused oxazepinone derivatives have attracted considerable
attention owing to their promising biological activities, such as
anticancer,2 anti-HIV,3 antidepressant,4 and antitumor5 activities.
They also show a wide range of pharmacological and neurochem-
ical activities as potential central nervous system agents,6 potential
atypical antipsychotics,7 β-secretase inhibitors,8 histone deacety-
lase inhibitors,9 and muscarinic cholinergic receptors.10 Among
them, Sintamil(I)4 and its derivatives were reported as antide-
pressants. Ioxapine7 was reported for its potential clozapine-like
properties.
’ RESULTS AND DISCUSSION
To study the range of the reaction, various N-substituted
salicylamides were reacted with 1,2-difluoro-4-nitrobenzene,
with the results shown in Table 1. Both the N-alkyl and N-aryl
salicylamides produced the corresponding products with good to
excellent yields (Table 1, entries 1À12).
A variety of compounds 2 were then studied under the same
reaction conditions, with the results in Table 2. When 1b was
reacted with benzenes possessing electron-withdrawing groups,
such as nitro, nitrile, halogen, and trifluoromethyl, the desired
products 4bÀi were generated in good to excellent yields
(Table 2, entries 1À8).
Moreover, reactions of 1b with 2j under the same conditions
produced the corresponding pentacyclic heterocycle product 4j
with 60% yield (entry 9). As 1b was reacted with an electron-
donating group, such as methyl 2l and acetamide 2m, and the
corresponding products 4lÀm were generated with moderate
yields (entries 11À12). It is noteworthy that the yield of the
reaction with a benzene ring having an electron-withdrawing
group is higher than that with an electron-donating group.
As a result, various methods have been developed to synthe-
size fused oxazepinone scaffolds, including intramolecular aro-
matic substitutionin2-hydroxyanilines ofortho substitutedbenzoic
acids (X = F, Cl, NO2),11 the reaction of 2-(2-halophenoxy)-
phenylamines and 2-(2-halophenoxy)pyridine-3-amines with car-
bon monoxide under pressure using palladium catalysts,12 the
heating of xanthen-9-one oximes with phosphorus pentachloride
via Beckmann rearrangement,13 and the intramolecular cyclocar-
bonylation of substituted 2-(2-iodophenoxy)anilines.14 How-
ever, these methods are not ideal because they either involve
multiple steps or use a transition metal catalyst.
Received: June 18, 2011
Revised:
July 13, 2011
Published: July 18, 2011
r
2011 American Chemical Society
547
dx.doi.org/10.1021/co2001058 ACS Comb. Sci. 2011, 13, 547–553
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ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 1. Synthesis of Fused Oxazepinone Scaffolds
Table 2. Reaction of N-Ethyl Salicylamide 1b with
Various 2a
Table 1. Reaction of N-Substituted Salicylamides with 1,
2-Difluoro-4-nitrobenzenea
entry
R2
product
time/h
yieldb (%)
1
Me (1a)
3a
3b
3c
3d
3e
3f
1
2
1
1
1
1
1
1
1
1
4
1
93
96
87
96
87
88
83
71
82
80
79
97
2
Et (1b)
3
Pr (1c)
4
i-Pr (1d)
5
c-Hex (1e)
Bn (1f)
6
7
Ph (1 g)
3g
3h
3i
8
4-MePh (1 h)
4-OMePh (1i)
4-FPh (1j)
4-ClPh (1k)
4-BrPh (1 L)
9
10
11
12
3j
3k
3l
a Reaction conditions: 1.2 mmol 1aÀl, 1 mmol 2a, 3 mmol K2CO3,
10 mL of DMF, 80 °C, 1À4 h. b Isolated yield.
Furthermore, the reaction of a variety of functional N-benzyl
salicylamides with 1,2-difluoro-4-nitrobenzene was then investi-
gated, with the results shown in Table 3. Reactions of N-benzyl
salicylamide containing an electron-donating substitutent 5a
with 2a gave the corresponding product 6a with 88% yield
(Table 3, entry 1). N-benzyl salicylamide bearing a halogen
atom, such as 5b, was successfully utilized to give rise to the
desired product 6b with 90% yield (entry 2). N-benzyl-3-hydro-
xy-2-naphthamide 5c and N-benzyl-1-hydroxy-2-naphthamide
5d were converted into the desired products 6cÀd with 92%
and 50% yield (entries 3À4).
On the basis of reported Smiles rearrangement chemis-
try and our experimental results, a plausible reaction mechan-
ism is presented in Scheme 2. The reaction of 1aÀl with 2a
yielded compound 7aÀl. Compound 7aÀl could proceed
in two paths (I and II). Path I would afford the direct
intramolecular nucleophilic substitution product 9aÀl. Path
II would lead to compound 3aÀl via Smiles rearrange-
ment. However, 9aÀl was not detected. Therefore, Imido
nitrogen in compound 8aÀl underwent intramolecular nucleo-
philic attack on the carbonium (para position to the nitro
group). Migration of the spiro-oxygen, proceeding through the
a Reaction conditions: 1.2 mmol 1b, 1 mmol 2, 3 mmol K2CO3, 10 mL of
DMF, 80 °C, 1À6 h. b Isolated yield.
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RESEARCH ARTICLE
“Meisenheimer Complex” 10aÀl, with intramolecular nucleo-
philic displacement of fluoride anion by an oxygen anion of
compound 11aÀl yielded the desired cyclization product
3aÀl.
In support of the proposed mechanism, compound 12
was reacted with 2a under the same conditions as above. In
this instance, no reaction took place, even when the tem-
perature was up to 110 °C (Scheme 3). This result indi-
cates that the amide group in N-substituted salicylamides
cannot serve as the nucleophilic reaction center. It is im-
portant to note that the reaction was performed via Smiles
rearrangement.
Table 3. Reaction of Functional N-Benzyl Salicylamide with
1,2-Difluoro-4-nitrobenzenea
Additionally, the result can be unambiguously supported by
the molecular structure of 4d being confirmed by X-ray analysis
(Figure 1).
Scheme 3. Reaction of 12 with 2a
a Reaction conditions: 1.2 mmol 5, 1 mmol 2a, 3 mmol K2CO3, 10 mL of
DMF, 80 °C, 1À10.5 h. b Isolated yield.
Figure 1. X-ray crystal structure of 4d.
Scheme 2. Plausible Reaction Mechanism
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RESEARCH ARTICLE
’ CONCLUSION
21.37. HRMS calcd for C16H14N2O4, 298.0954; found,
298.1026.
In conclusion, a variety of fused oxazepinone derivatives were
systematically obtained in moderate to excellent yields via a Smiles
rearrangement tandem reaction. Of particular importance, the
described chemistry is a transition metal-catalyst-free process,
and therefore a green method for the construction of these
important heterocyclic compounds, which exhibits a wide range
of applications in medicinal chemistry. Further studies on its
application in the synthesis of biologically relevant compounds
are currently in progress.
10-Cyclohexyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one
(3e). Pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.10À8.11
(d, 1H, J = 2.7 Hz), 8.02À8.06 (dd, 1H, J = 2.7, 9 Hz), 7.80À7.83
(dd, 1H, J = 1.5, 7.5 Hz), 7.50À7.53 (d, 1H, J = 8.7 Hz),
7.42À7.48 (m, 1H), 7.19À7.26 (m, 2H), 4.26À4.30 (m, 1H),
0.81À2.11 (m, 10H). 13C NMR (75 MHz, CDCl3) δ 165.75,
160.17, 155.46, 145.21, 141.10, 133.71, 132.43, 126.61, 125.92,
125.16, 120.60, 119.42, 117.34, 63.14, 31.54, 26.41, 25.54.
HRMS calcd for C19H18N2O4, 338.1267; found, 338.1338.
10-Benzyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one (3f).
1
Pale yellow oil. H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H,
’ EXPERIMENTAL PROCEDURES
J = 2.56 Hz), 7.90À7.93 (dd, 2H, J = 2.28, 9 Hz), 7.50À7.55
(m, 1H), 7.27À7.33 (m, 8H), 5.37 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ 166.02, 159.74, 153.54, 144.92, 141.20, 136.17,
134.36, 132.55, 128.95, 127.62, 126.68, 126.11, 125.76, 123.17,
121.14, 119.86, 117.56, 52.53. HRMS calcd for C20H14N2O4,
346.0954; found, 346.1023.
General Experimental Procedure for the Synthesis of
(3aÀl), (4bÀm), (6aÀd). Representative Procedure for the Synth-
esis of 10-Ethyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one (3b).
To a solution of N-ethyl salicylamide (150 mg, 0.9 mmol) in dry
dimethylformamide (DMF, 10 mL) were added 1,2-difluoro-
4-nitrobenzene (120 mg, 0.8 mmol) and K2CO3 (310 mg, 2.3
mmol), then the mixture was stirred for 1 h at 80 °C (oil bath), and
then H2O (30 mL) was added and the mixture was extracted with
EtOAc (3 Â 25 mL) . The combined organic layers were washed
with sat. brine (2 Â 20 mL), dried over MgSO4, filtered, and
evaporated in vacuo. The crude product was purified by column
chromatography on silica gel (PE/EtOAc = 5:1) to afford the
desired product 3b as a pale yellow oil (207 mg, 96%).
7-Nitro-10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one (3g).
1
Pale yellow oil. H NMR (300 MHz, CDCl3) δ 8.19À8.20
(d, 1H, J = 2.7 Hz), 7.93À7.96 (dd, 1H, J = 1.8, 5.7 Hz),
7.84À7.88 (dd, 1H, J = 2.4, 9 Hz), 7.49À7.59 (m, 3H),
7.33À7.47 (m, 3H), 7.29À7.31 (m, 2H), 6.87À6.90 (d, 1H,
J = 9 Hz). 13C NMR (100 MHz, CDCl3) δ 165.56, 159.55,
152.90, 144.61, 141.85, 141.15, 134.48, 132.63, 129.87, 129.05,
128.56, 126.16, 126.00, 125.59, 120.82, 119.98, 117.73. HRMS
calcd for C19H12N2O4, 332.0797; found, 332.0885.
10-Methyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one
1
(3a). White crystal, mp 158À163 °C H NMR (300 MHz,
7-Nitro-10-(p-tolyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one
1
CDCl3) δ 8.15 (d, 1H, J = 2.7 Hz), 8.08À8.12 (dd, 1H, J = 2.7, 9
Hz), 7.89À7.92 (dd, 1H, J = 1.8, 9 Hz), 7.50À7.56 (m, 1H),
7.34À7.37 (d, 1H, J = 9 Hz), 7.26À7.31 (m, 2H), 3.63 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 165.76, 159.57, 152.86, 144.74,
142.26, 134.33, 132.56, 125.98, 125.31, 122.40, 121.27, 119.86,
117.56, 37.02. HRMS calcd for C14H10N2O4, 270.0641; found,
270.0721.
(3h). White crystal, mp 185À187 °C. H NMR (400 MHz,
CDCl3) δ 8.18À8.19 (d, 1H, J = 2.44 Hz), 7.92À7.95 (dd, 1H,
J = 1.48, 8.04 Hz), 7.84À7.87 (dd, 1H, J = 2.44, 9.04 Hz),
7.54À7.58 (m, 1H), 7.27À7.33 (m, 6H), 6.90À6.92 (d, 1H,
J = 9.04 Hz), 2.43 (s, 3H). 13C NMR (400 MHz, CDCl3) δ
165.71, 159.56, 152.85, 144.55, 142.00, 138.64, 138.51, 134.37,
132.66, 130.52, 128.67, 126.13, 126.08, 125.48, 120.75, 119.91,
117.74, 21.23. 13C NMR (75 MHz, CDCl3) δ 165.71, 159.56,
153.85, 144.55, 142.00, 138.64, 138.51, 134.37, 132.66, 130.52,
128.67, 126.13, 126.08, 125.48, 120.75, 119.91, 117.74, 21.23.
HRMS calcd for C20H14N2O4, 346.0954; found, 346.1042.
10-(4-Methoxyphenyl)-7-nitrodibenzo[b,f][1,4]oxazepin-
10-Ethyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one (3b).
Pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.14À8.15(d, 1H,
J = 2.7 Hz), 8.07À8.11 (dd, 1H, J = 2.4, 9 Hz), 7.84À7.87 (dd, 1H,
J = 1.8, 7.8 Hz), 7.43À7.54 (m, 2H), 7.23À7.30 (m, 2H),
4.09À4.23 (q, 2H, J = 7.2 Hz), 1.39À1.44 (t, 3H, J = 6.9 Hz).
13C NMR (100 MHz, CDCl3) δ 165.48, 159.61, 153.71, 144.75,
141.36, 134.03, 132.27, 126.14, 125.98, 122.82, 121.23, 119.66,
117.65, 44.71, 13.75. HRMS calcd for C15H12N2O4, 284.0797;
found, 284.0876.
7-Nitro-10-propyldibenzo[b,f][1,4]oxazepin-11(10H)-one (3c).
Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.14À8.15 (d, 1H,
J = 2.7 Hz), 8.07À8.10 (dd, 1H, J = 2.4, 9 Hz), 7.84À7.87 (dd, 1H,
J = 1.5, 7.5 Hz), 7.48À7.53 (m, 1H), 7.41À7.44 (d, 1H, J = 9 Hz),
7.24À7.30 (m, 2H), 4.11À4.16 (t, 2H, J = 6.9 Hz), 1.71À1.83 (m,
2H), 0.94À0.99 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3)
δ 165.68, 159.76, 154.11, 144.85, 141.28, 133.99, 132.35, 126.11,
125.99, 123.35, 121.16, 119.64, 117.73, 50.58, 21.24, 11.09. HRMS
calcd for C16H14N2O4, 298.0954; found, 298.1031.
1
11(10H)-one (3i). White crystal, mp 128À132 °C. H NMR
(300 MHz, CDCl3) δ 8.18À8.19 (d, 1H, J = 2.7 Hz), 7.92À7.95
(dd, 1H, J = 1.8, 8.1 Hz), 7.85À7.89 (dd, 1H, J = 2.7, 9 Hz),
7.53À7.59 (m, 1H), 7.27À7.34 (m, 4H), 7.01À7.05 (m, 2H),
6.91À6.94 (d, 1H, J = 9 Hz), 3.87 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 165.87, 159.57, 159.39, 152.75, 144.52, 142.12,
134.39, 133.76, 132.67, 129.99, 126.12, 126.02, 125.42, 120.76,
119.91, 117.75, 115.08, 55.56. HRMS calcd for C19H14N2O5,
362.0903; found, 362.0991.
10-(4-Fluorophenyl)-7-nitrodibenzo[b,f][1,4]oxazepin-11-
1
(10H)-one (3j). White crystal, mp 82À85 °C. H NMR (400
MHz, CDCl3) δ 8.20À8.21 (d, 1H, J = 2.48 Hz), 7.92À7.95 (dd,
1H, J = 1.6, 8.04 Hz), 7.88À7.91 (dd, 1H, J = 2.52, 9.04 Hz),
7.56À7.60 (m, 1H), 7.31À7.40 (m, 4H), 7.19À7.24 (t, 2H,
J = 8.32 Hz), 6.88À6.90 (d, 1H, J = 9.04 Hz). 13C NMR (100
MHz, CDCl3) δ 165.65, 163.35, 160.87, 159.58, 152.97, 144.76,
141.67, 136.96, 134.60, 132.69, 130.86, 126.21, 125.71, 120.87,
120.00, 117.86, 116.75. HRMS calcd for C19H11FN2O4,
350.0703; found, 350.0704.
10-Isopropyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one
1
(3d). Pale yellow oil. H NMR (400 MHz, CDCl3) δ 8.12
(d, 1H, J = 2.6 Hz), 8.04À8.07 (dd, 1H, J = 2.6, 8.88 Hz),
7.84À7.86 (dd, 1H, J = 1.6, 7.64 Hz), 7.50À7.52 (d, 1H, J = 8.96
Hz), 7.45À7.49 (m, 1H), 7.22À7.31 (m, 2H), 4.70À4.77 (m,
1H), 1.58À1.59 (d, 6H, J = 6.56 Hz). 13C NMR (100 MHz,
CDCl3) δ 165.62, 160.07, 155.09, 145.17, 140.97, 133.82,
132.41, 126.51, 125.92, 124.57, 120.69, 119.49, 117.43, 54.20,
10-(4-Chlorophenyl)-7-nitrodibenzo[b,f][1,4]oxazepin-11-
1
(10H)-one (3k). White crystal, mp 186À189 °C. H NMR
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RESEARCH ARTICLE
(400 MHz, CDCl3) δ 8.20 (d, 1H, J = 2.36 Hz), 7.92À7.94
(dd, 1H, J = 1.36, 8.04 Hz), 7.87À7.90 (dd, 1H, J = 2.44, 9.04
Hz), 7.55À7.60 (m, 1H), 7.49À7.51 (d, 2H, J = 8.52 Hz),
7.32À7.35 (m, 4H), 6.87À6.89 (d, 1H, J = 9 Hz). 13C NMR
(100 MHz, CDCl3) δ 165.47, 159.58, 153.10, 144.86, 141.47,
139.53, 134.65, 134.47, 132.70, 130.37, 130.08, 126.24, 125.66,
125.45, 120.89, 120.02, 117.89. HRMS calcd for C19H11Cl-
N2O4, 366.0407; found, 366.0474.
(100 MHz, CDCl3) δ 165.78, 160.01, 149.69, 147.28, 143.98,
141.99, 133.97, 132.46, 126.21, 125.62, 119.71, 115.87, 43.78,
13.64. HRMS calcd for C14H12N2O2, 240.0899; found, 240.1005.
10-Ethyl-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one (4g).
1
Pale yellow oil. H NMR (400 MHz, CDCl3) δ 8.14 (d, 1H,
J = 2.56 Hz), 8.07À8.10 (dd, 1H, J = 2.56, 9 Hz), 7.84À7.86 (dd,
1H, J = 1.32, 7.64 Hz), 7.45À7.51 (m, 2H), 7.24À7.29 (m, 2H),
4.17À4.23 (q, 2H, J = 7.08 Hz), 1.41À1.44 (t, 3H, J = 7.08 Hz).
13C NMR (100 MHz, CDCl3) δ 165.46, 159.56, 153.64, 144.70,
141.33, 134.03, 132.22, 126.11, 125.95, 122.84, 121.24, 119.66,
117.60, 44.71, 13.73. HRMS calcd for C15H12N2O4, 284.0797;
found, 284.0880.
9-Chloro-10-ethyldibenzo[b,f][1,4]oxazepin-11(10H)-one
(4h). White crystal, mp 80À83 °C. 1H NMR (400 MHz, CDCl3)
δ 7.81À7.83 (dd, 1H, J = 6.16, 7.68 Hz), 7.36À7.40 (m, 1H),
7.10À7.27 (m, 5H), 4.62À4.71 (m, 1H), 3.60À3.69 (m, 1H),
1.17À1.21 (t, 3H, J = 7.12 Hz). 13C NMR (100 MHz, CDCl3)
δ 166.75, 161.33, 159.21, 133.16, 132.40, 131.84, 130.69, 127.82,
127.76, 126.99, 125.66, 119.72, 119.66, 44.42, 13.38. HRMS
calcd for C15H12ClNO2, 273.0557; found, 273.0629.
10-(4-Bromophenyl)-7-nitrodibenzo[b,f][1,4]oxazepin-11-
1
(10H)-one (3l). White crystal, mp 203À205 °C. H NMR
(300 MHz, CDCl3) δ 8.20 (d, 1H, J = 2.4 Hz), 7.87À7.95 (m,
2H), 7.64À7.67 (d, 2H, J = 8.7 Hz), 7.55À7.61 (m, 1H),
7,26À7.35 (m, 4H), 6.87À6.90 (d, 1H, J = 9 Hz). 13C NMR
(75 MHz, CDCl3) δ 165.41, 159.57, 153.11, 144.86, 141.40,
140.05, 134.66, 132.07, 132.69, 130.68, 126.24, 125.63, 125.47,
122.51, 120.90, 120.02, 117.90. HRMS calcd for C19H11-
BrN2O4, 409.9902; found, 409.9973.
10-Ethyl-7-fluorodibenzo[b,f][1,4]oxazepin-11(10H)-one (4b).
Pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.83À7.86 (dd,
1H, J = 1.8, 7.8 Hz), 7.41À7.46 (m, 1H), 7.20À7.28 (m, 2H),
7.14À7.17 (dd, 1H, J = 0.6, 8.1 Hz), 6.98À7.01 (dd, 1H, J = 2.7,
8.4 Hz), 6.88À6.94 (m, 1H), 4.09À4.16 (q, 2H, J = 6.9 Hz),
1.32À1.3 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3) δ
165.82, 161.18, 160.35, 158.71, 155.62, 155.51, 133.31, 132.13,
131.83, 131.22, 131.19, 126.83, 125.57, 123.99, 123.89, 119.58,
112.89, 112.67, 109.27, 109.03, 44.38, 13.71. HRMS calcd for
C15H12FNO4, 257.0852; found, 257.0937
10-Ethyl-7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-
1
(10H)-one (4i). White crystal, mp 58À61 °C. H NMR (400
MHz, CDCl3) δ 7.85À7.87 (dd, 1H, J = 1.56, 7.72 Hz), 7.54
(s, 1H), 7.41À7.47 (m, 3H), 7.19À7.25 (m, 2H), 4.15À4.20
(q, 2H, J = 7.08 Hz), 1.37À1.40 (t, 3H, J = 7.08 Hz). 13C NMR
(100 MHz, CDCl3) δ 165.72, 160.10, 154.21, 138.30, 133.66,
132.21, 128.10, 127.77, 127.36, 126.50, 125.65, 124.66, 123.29,
122.82, 122.78, 122.74, 122.71, 121.95, 119.62, 119.24, 119.20,
119.17, 119.13, 44.39, 13.70. HRMS calcd for C16H12NO2F3,
307.0820; found, 307.0958.
11-Ethyl-3-(trifluoromethyl)benzo[f]pyrido[3,2-b][1,4]oxazepin-
1
10(11H)-on (4c). Pale yellow oil. H NMR (400 MHz, CDCl3)
δ 8.44 (d, 1H, J = 0.96 Hz), 7.79À7.81 (dd, 1H, J = 1.64, 7.8 Hz),
7.67 (d, 1H, J = 1.96 Hz), 7.38À7.43 (m, 1H), 7.11À7.20 (m, 2H),
4.23À4.29 (q, 2H, J = 7 Hz), 1.30À1.33 (t, 3H, J = 7 Hz). 13C NMR
(100 MHz, CDCl3) δ 164.08, 157.69, 150.32, 146.52, 140.75,
140.71, 140.67, 140.63, 132.96, 131.60, 125.89, 125.86, 125.82,
125.79, 125.12, 124.95, 123.25, 123.18, 122.91, 122.58, 122.24,
120.48, 118.39, 41.60, 12.69. HRMS calcd for C15H11F3N2O2,
308.0773; found, 309.0870.
1
4j: White crystal, mp 210À212 °C. H NMR (400 MHz,
CDCl3) δ 7.82À7.84 (dd, 2H, J = 1.24, 7.76 Hz), 7.42À7.46
(m, 2H), 7.15À7.24 (m, 6H), 4.08À4.13 (q, 4H, J = 6.88 Hz),
1.35À1.38 (t, 6H, J = 7.08 Hz). 13C NMR (100 MHz, CDCl3) δ
165.80, 160.23, 152.00, 133.47, 132.62, 132.24, 126.60, 125.58,
119.60, 116.99, 114.38, 44.62, 13.84. HRMS calcd for
C24H20N2O4, 400.1423; found, 400.1495.
10-Ethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-
10-Ethyldibenzo[b,f][1,4]oxazepin-11(10H)-one (4k). White
crystal, mp 92À95 °C. 1H NMR (400 MHz, CDCl3) δ 7.83À
7.85 (dd, 1H, J = 1.52, 7.68 Hz), 7.38À7.43 (m, 1H), 7.29À7.31
(dd, 1H, J = 1.6, 7.92 Hz), 7.24À7.26 (dd, 1H, J = 1.76, 7.64 Hz),
7.10À7.21 (m, 4H), 4.13À4.18 (q, 2H, J = 6.92 Hz), 1.36 (t, 3H,
J = 7.08 Hz). 13C NMR (100 MHz, CDCl3) δ 166.13, 160.73,
154.78, 134.85, 133.21, 132.04, 127.07, 126.38, 125.80, 125.22,
123.07, 121.59, 119.64, 44.24, 13.81. HRMS calcd for C15H13-
NO2, 239.0946; found, 239.1026.
10-Ethyl-9-methyldibenzo[b,f][1,4]oxazepin-11(10H)-one
(4l). White crystal, mp 70À75 °C. 1H NMR (400 MHz, CDCl3)
δ 7.79À7.82 (dd, 1H, J = 1.68, 7.68 Hz), 7.34À7.38 (m, 1H),
7.06À7.19 (m, 4H), 7.00À7.02 (dd, 1H, J = 1.24, 7.08 Hz),
4.64À4.73 (m, 1H), 3.21À3.29 (m, 1H), 2,30 (s, 3H),
1.17À1.27 (t, 3H, J = 7.08 Hz). 13C NMR (100 MHz, CDCl3)
δ 167.35, 161.75, 158.37, 135.27, 133.24, 132.90, 131.54, 128.37,
127.44, 127.18, 125.27, 119.75, 118.40, 44.72, 19.90, 13.25.
HRMS calcd for C16H15NO2, 253.1103; found, 253.1186.
N-(10-Ethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-
7-yl)acetamide (4m). White crystal, mp 170À173 °C. 1H NMR
(400 MHz, CDCl3) δ 7.81À7.83 (dd, 1H, J = 1.56, 7.72 Hz),
7.60À7.61 (d, 1H, J = 1.88 Hz), 7.39À7.44 (m, 2H), 7.15À7.24
(m, 4H), 4.10À4.15 (q, 2H, J = 6.72 Hz), 2.17 (s, 3H), 1.34
(s, 3H), 13C NMR (100 MHz, CDCl3) δ 168.47, 166.20, 160.52,
155.01, 136.37, 133.27, 131.92, 130.47, 126.94, 125.34, 123.21,
1
7-carbonitrile (4d). White crystal, mp 161À164 °C. H NMR
(400 MHz, CDCl3) δ 7.84À7.86 (dd, 1H, J = 1.56, 7.76 Hz),
7.56À7.57 (d, 1H, J = 1.8 Hz), 7.47À7.51 (m, 2H), 7.39À7.41
(d, 1H, J = 8.44 Hz), 7.19À7.28 (m, 2H), 4.14À4.19 (q, 2H,
J = 7.08 Hz), 1.38À1.41 (t, 3H, J = 7.08 Hz). 13C NMR (100
MHz, CDCl3) δ 165.55, 159.74, 154.03, 139.76, 133.91, 132.29,
129.75, 126.25, 125.89, 125.69, 123.54, 119.57, 117.47, 109.41,
44.50, 13.76. HRMS calcd for C16H12N2O2, 264.0899; found,
264.1162.
10-Ethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-
1
9-carbonitrile (4e). White crystal, mp 120À122 °C. H NMR
(400 MHz, CDCl3) δ 7.84À7.87 (dd, 1H, J = 1.56, 7.72 Hz),
7.51À7.53 (d, 2H, J = 7.92 Hz), 7.42À7.47 (m, 1H), 7.24À7.30
(m, 2H), 7.16À7.18 (d, 1H, J = 8.08 Hz), 4.82À4.89 (m, 1H),
3.80À3.89 (m, 1H), 1.23À1.26 (t, 3H, J = 7.12 Hz). 13C NMR
(100 MHz, CDCl3) δ 165.97, 160.84, 157.76, 137.72, 133.56,
132.26, 131.32, 127.50, 126.52, 126.35, 126.01, 119.52, 116.25,
109.98, 45.52, 13.59. HRMS calcd for C16H12N2O2, 264.0899;
found, 264.1005.
5-Ethylbenzo[f]pyrido[3,4-b][1,4]oxazepin-6(5H)-one (4f).
1
Pale yellow oil. H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H),
8.38À8.39 (d, 1H, J = 5.44 Hz), 7.84À7.86 (dd, 1H, J = 1.76,
8.24 Hz), 7.45À7.50 (m, 1H), 7.20À7.25 (m, 3H), 4.12À4.17
(q, 2H, J = 7.08 Hz), 1.39À1.42 (t, 3H, J = 7.08 Hz). 13C NMR
551
dx.doi.org/10.1021/co2001058 |ACS Comb. Sci. 2011, 13, 547–553

ACS Combinatorial Science
RESEARCH ARTICLE
119.77, 116.84, 112.90, 44.18, 24.50, 13.75. HRMS calcd for
C17H16N2O3, 296.1161; found, 296.1230.
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J = 2.56, 9 Hz), 7.72À7.74 (dd, 1H, J = 1.2, 7.76 Hz), 7.39À7.41
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J = 7.64 Hz), 5.38 (s, 2H), 2.57 (s, 3H). 13C NMR (100 MHz,
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130.18, 129.14, 128.94, 127.60, 126.66, 125.88, 125.63, 123.06,
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10-Benzyl-2-chloro-7-nitrodibenzo[b,f][1,4]oxazepin-11(10H)-
one (6b). White crystal, mp 155À157 °C. 1H NMR (300 MHz,
CDCl3) δ 8.10À8.11 (d, 1H, J = 2.4 Hz), 7.95À7.99 (dd, 1H,
J = 2.4, 9 Hz), 7.89À7.90 (d, 1H, J = 2.4 Hz), 7.47À7.51 (dd, 1H,
J = 2.7, 8.4 Hz), 7.23À7.37 (m, 7H), 5.36 (s, 2H). 13C NMR (75
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134.14, 132.19, 131.69, 129.01, 127.76, 127.05, 126.65, 123.32,
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13-Benzyl-3-nitrobenzo[b]naphtho[2,3-f][1,4]oxazepin-12-
(13H)-one (6c). White crystal, mp 189À192 °C. 1H NMR (400
MHz, CDCl3) δ 8.52 (s, 1H), 8.21 (d, 1H, J = 2.6 Hz),
7.92À7.96 (m, 2H), 7.84À7.86 (d, 1H, J = 8.24 Hz), 7.72
(s, 1H), 7.58À7.62 (m, 1H), 7.49À7.53 (m, 1H), 7.28À7.38
(m, 6H), 5.43 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 166.18,
156.20, 153.23, 145.04, 141.29, 136.17, 136.00, 134.48, 130.90,
129.12, 128.99, 127.65, 127.22, 126.68, 136.50, 125.17, 123.14,
121.13, 117.83, 116.38, 52.81. HRMS calcd for C24H16N2O4,
396.1110; found, 396.1192.
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1
one (6d). Pale yellow oil. H NMR (400 MHz, CDCl3) δ
8.59À8.61 (d, 1H, J = 8.32 Hz), 8.23 (d, 1H, J = 2.56 Hz),
7.95À7.98 (dd, 1H, J = 2.56, 9 Hz), 7.87À7.91 (t, 3H, J = 7.72 Hz),
7.70À7.75 (t, 2H, J = 8.4 Hz), 7.68À7.70 (t, 1H, J = 6.88 Hz),
7.26À7.38 (m, 6H), 5.45 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
166.47, 156.58, 153.67, 144.81, 141.66, 136.78, 136.16, 129.09,
129.00, 128.03, 127.77, 127.69, 126.80, 125.57, 125.43, 123.09,
122.64, 121.22, 120.67, 117.53, 53.41. HRMS calcd for C24H16-
N2O4, 396.1110; found, 396.1191.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: chenma@sdu.edu.cn.
Funding Sources
We are grateful to the National Science Foundation of China
(No. 20872079), the Natural Science Foundation of Shandong
Province (2009ZRB019YA), IIFSDU (No. 2010TS052), and the
State Key Laboratory of Natural and Biomimetic Drugs of Peking
University (K20090205) for financial support of this research.
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