Ligand-free copper-catalyzed efficient one-pot access of benzo[b]pyrido[3,2-f][1,4]oxazepinones through O-heteroarylation-Smiles rearrangement-cyclization cascade

Article abstract of DOI:10.1039/c4ra11128a

Efficient synthesis of a library of novel benzopyrido[1,4]oxazepinones was accomplished by Cs₂CO₃-mediated one-pot coupling of N-substituted-o-chloronicotinamides and o-halogenated phenols using cuprous oxide catalysis in DMF at 120 °C through an O-heteroarylation-Smiles rearrangement-cyclization cascade (16 examples). The C-N bond construction process is biased in favour of Smiles rearrangement allowing regioselective generation of these tricyclic molecular architectures essentially free from Goldberg-N-arylation products in good to excellent yields.

Full text of DOI:10.1039/c4ra11128a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Ligand-free copper-catalyzed efficient one-pot
access of benzo[b]pyrido[3,2-f][1,4]oxazepinones
through O-heteroarylation-Smiles rearrangement-
cyclization cascade†
Cite this: RSC Adv., 2014, 4, 55640
a
Nemai C. Ganguly, Pallab Mondal,a Sushmita Roya and Partha Mitrab
*
Efficient synthesis of a library of novel benzopyrido[1,4]oxazepinones was accomplished by Cs2CO3-
mediated one-pot coupling of N-substituted-o-chloronicotinamides and o-halogenated phenols using
cuprous oxide catalysis in DMF at 120 ꢀC through an O-heteroarylation-Smiles rearrangement-
cyclization cascade (16 examples). The C–N bond construction process is biased in favour of Smiles
rearrangement allowing regioselective generation of these tricyclic molecular architectures essentially
free from Goldberg-N-arylation products in good to excellent yields.
Received 24th September 2014
Accepted 23rd October 2014
DOI: 10.1039/c4ra11128a
www.rsc.org/advances
continuation of our interest in the construction of structurally and
functionally diversied targets with a privileged heterocyclic
core,15 we embarked on synthesis of [1,4]oxazepinones that share
pyridine and benzene/naphthalene substructures, the former
being connected to the carbonyl ank to its secondary amide core.
Deconstruction of a conceived target 3a reveals N-benzylated-o-
chloronicotinamide (1a) and 1-bromo-2-naphthol (2a) as building
blocks assuming Smiles rearrangement-based exchange of rela-
tionship of OH and Br of 2a onto 3a (Scheme 1).
1a is readily accessible from 2-chloronicotinic acid which
served as a versatile intermediate for synthesis of a number of
agrochemicals and pharmaceuticals including the anti-HIV drug
nevarapine.16 Notwithstanding the reluctance of aryl chlorides
towards Ullmann etherication,17 the labile nature of chlorine in
2-chloropyridine is expected to favour nucleophilic displacement
process. However, subsequent N-arylation of 4a can deliver two
regioisomeric products 3a0 and 3a depending on direct Goldberg
reaction18 or Smiles rearrangement19-based coupling. The
successful entry to 3a hinges on nding out suitable reaction
conditions that preclude Goldberg reaction and biased in favour
of Smiles rearrangement. The proposed reaction pathway leading
to 3a is depicted in Scheme 2. Both O- and N-arylations are
feasible under base-mediated copper-catalysis and, therefore, can
be integrated in a one-pot synthetic operation. Copper-catalyzed
Introduction
Benzo- and heteroaryl-fused [1,4]oxazepinones exhibit a broad
and diverse range of biological properties. Dibenzoxazepinones,
particularly those with a pendant N-substituent, are endowed with
HIV-1 RT inhibition,1 anti-cancer,2 anti-tumor3 and anti-inam-
matory4 activities. Several CNS-active compounds showing anti-
depressant,5 anti-psychotic activities6 and b-secretase inhibitors7
feature this privileged heterocyclic motif. Installation of hetero-
cyclic substructures at this scaffold profoundly modulate its bio-
logical space. The heteroaryl-annulated oxazepinones showed
anticonvulsant,8 antimicrobial,9 anti-ischemic10 and integrin
antagonism activities.11 The promising biological prole attracted
considerable synthetic interest in [1,4]oxazepinones and several
initiatives are reported to generate collections of these
compounds for biological screening. Dibenzoxazepinones were
accessed from substituted ortho-bromophenols and secondary
benzamides under ligand-assisted copper catalysis.12 In another
approach functionalised N-benzylsalicylamides and 1,2-diuor-
onitrobenzene were utilized as reaction partners under K2CO3-
mediated transition metal free one-pot process to synthesize these
compounds.13 These methods basically rely on domino C–O and
regioselective C–N bond formations via Smiles rearrangement. A
good number of biologically relevant heterocycles14 have been
synthesized using Smiles rearrangement in a key step. In
aDepartment of Chemistry, University of Kalyani, Kalyani 741235, India. E-mail:
nemai_g@yahoo.co.in; Fax: +91-33-25828282
bDepartment of Inorganic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700032, India
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic data, copies of the 1H NMR and 13C NMR spectra of all nal
products. CCDC 994880 and 994881. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ra11128a
Scheme 1 Deconstruction of target structure 3a.
55640 | RSC Adv., 2014, 4, 55640–55648
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Scheme 2 Plausible reaction route to benzopyrido[1,4]oxazepinone 3a.
isolation of the tricyclic product 3a in 40% exclusive yield (entry
1, Table 1). Addition of 5 mol% of CuI to the above reaction
mixture substantially improved the reaction performance and a
decent 77% yield in shorter reaction time (3 h) was accom-
plished revealing the implication of Cu(I) catalyst (entry 2). A few
other copper sources such as CuBr, Cu(OAc)2, Cu(OTf)2 and
Cu2O were screened at identical catalyst level (5 mol%) (entries
3–6). Copper triate was least effective and cuprous oxide sur-
passed all delivering 85% yield (entry 6). Optimization of cata-
lyst concentration revealed that lowering it to 2 mol% resulted
in erosion of yield to 62% (entry 7). On the other hand, its
increment to 10 mol% as also the use of an excess of base (4 mol
Scheme 3 Structures of regioisomeric products 3l and 3l0 formed via
Smiles rearrangement and Goldberg N-arylation respectively.
methods are cost effective than its Pd-, Ni-variants and several equiv.) did not improve the yield (entries 8 and 9). Encouraged
methods are available that utilize copper sources at low catalyst by the reported promotion of N-arylation by nitrogen and
levels under mild conditions, with and without ligands,20,21 as also oxygen ligands such as diamines and b-diketones,18b we
in bimetallic form (Fe–Cu).21 Herein, we disclose our results explored the effect of ligand additives on the reaction outcome.
of Cs2CO3-mediated ligand-free copper-catalyzed synthesis of Performing the reaction in the presence of 10 mol% of diben-
benzo[b]pyrido[3,2-f][1,4]oxazepinones using N-substituted-2- zoylmethane (dbm) or acetylacetone did not signicantly affect
chloronicotinamides and o-halogenated naphthols/phenols as the reaction outcome (entries 10 and 11). Plausibly, in-built
coupling partners (Scheme 3).
ligating ability of pyridine moiety accounts for the insensi-
tivity of the protocol towards additional ligands. A few other
bases (K2CO3, K3PO4 and DBU) were also screened; K2CO3 and
DBU gave poor results whereas K3PO4 proved more effective
affording 3a in 76% yield (entries 12–14). Replacing DMF with
acetonitrile provided 32% sole yield of 4a in a sluggish reaction
(8 h; entry 15). The reaction in toluene was similarly interrupted
in the O-heteroarylation stage. But remarkably 90% yield of 4a
was scored in a rapid and efficient reaction (entry 16).
To assess the scope and generality of the protocol, an
assortment of N-substituted-2-chloronicotinamides (1a–d) were
reacted with ortho-halogenated phenols under optimized reac-
tion conditions [5 mol% Cu2O, Cs2CO3 (2 mol equiv.), DMF at
120 ꢀC] to build a library of this novel class of compounds.
These results are exhibited in Table 2. The o-bromophenol (2b)
reacted much slowly compared to its naphthol counterpart (2a);
however, the regioselectivity of N-arylation could not be ascer-
tained in this case in absence of any ring substituent.
Results and discussion
First, 2-chloronicotinic acid was converted to its acid chloride
by oxalyl chloride in DMF–CH2Cl2 followed by treatment with
benzylamine in the presence of triethylamine to give N-benzyl-2-
chloronicotinamide (1a). For preliminary survey, an assembly of
1a and 1-bromo-2-naphthol (2a) was submitted to a set of basic
reaction conditions. Cs2CO3 was the base of choice in view of its
proven competence for promoting both C–O and C–N cross
coupling reactions17c,22 The mild base is compatible with DMF
primarily due to its appreciable solubility and this combination
is reported to effectively mediate several Smiles rearrangement-
based entry to heterocycles.14d,e,h The results of these exploratory
experiments are presented in Table 1. Initially, a mixture of 1a
and 2a in 1 : 1.1 molar ratio was heated with Cs2CO3 (2 mol
equiv.) in DMF at 120 ꢀC without any catalyst resulting in
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 55640–55648 | 55641

View Article Online
RSC Advances
Paper
Table 1 Optimization experiments for coupling of 1a and 2a
Yieldb (%)
Entry
Catalyst (mol%)
Additive (mol%)
Base
Solvent
Timea (h)
3a
4a
1
2
3
4
5
6
7
8
—
Cul (5)
—
—
—
—
—
—
—
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCNd
PhMed
5
3
3
5
5
3
3
3
3
3
3
5
3
3
8
3
40
77
72
57
55
85
62
83
84
81
75
45
76
20
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
10
32
90
CuBr (5)
Cu(OAc)2 (5)
Cu(OTf)2 (5)
Cu2O (5)
Cu2O (2)
Cu2O (10)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
c
9
—
10
11
12
13
14
15
16
dbm (10)
Acetylacetone (10)
—
—
—
—
—
K3PO4
DBU
Cs2CO3
Cs2CO3
a
Reactions were performed on 1 millimolar scale; reaction conditions: 1a and 2a (1 : 1.1 ratio), base (2 equiv.), copper catalyst, solvent (3 mL), 120
ꢀC. Refers to isolated yield aer chromatographic purication. c 4 mol equiv. of Cs2CO3 was used. Reactions were performed under reuxing
b
d
condition.
The presence of an additional electron-withdrawing p-chloro Hz, 1H, H-5) respectively. The most downeld one-proton
substituent in the bromophenol component 2c helped rate doublet signal at d 8.75 (d, J ¼ 8.4 Hz) was assigned to H-80 of
enhancement and attainment of relatively high yields (entries 3 the naphthalene ring that is peri to the ether oxygen bridge. Of
and 10, Table 2). In contrast, the presence of p-Me/-OMe groups the other two peri-proton signals that appeared relatively upeld
afforded lower yields and required longer exposures (entries 4 from the rest viz, d 7.36 (d, J ¼ 8.8 Hz, 1H, H-30), d 7.51 (t, J ¼ 7.6
and 5). In case of sterically congested 2-bromo-6-methylphenol Hz, H-60) and d 7.65 (t, J ¼ 7.6 Hz, H-70), the one due to H-40
(2f), the yield plummeted to 35% in a sluggish reaction (6 h) corresponded to d 7.69 (d, J ¼ 8.8 Hz, 1H) and was shied
which might be attributed to steric impediment to the nucleo- upeld from H-50 signal at d 7.80 (1H, d, J ¼ 8 Hz) due to the
philic attack of the phenoxide ion during etherication (entry presence of electron-releasing ether oxygen at its para position.
6). 2-Bromo-3-hydroxypyridine (2g) was also well-tolerated and Notably, the regioisomeric Goldberg N-arylation product 3l0
proved to be an efficient phenol partner (entries 7 and 8). lacks analogous peri-proton in para relationship to oxygen. This
Expectedly, the activating effect of electron-withdrawing pyri- discrimination of the three peri-proton signals in term of
dine moiety facilitates the Smiles rearrangement. 1-Iodo-2- chemical shi was observed to a general feature in 1H-NMR
naphthol (2h) and o-iodophenols (2i and 2j), to our surprise, spectra of all products embodying a naphthalene moiety. The
responded well providing excellent yields of corresponding 13C-NMR spectra and HRMS data were also supportive of their
target structures, despite the poor activation level of iodine assigned structures.
towards Smiles rearrangement event (entries 13–15).
The structure of two representative products 3c and 3i were
Conversely, 2-nitro-3-hydroxypyridine (2k) was found to be a unambiguously conrmed by their single crystal XRD studies.
rather reluctant partner (entry 16).
The corresponding ORTEP diagrams are depicted below (Fig. 1).
To gain an insight into the mechanistic scenario of the reac-
The 1H-NMR spectra of the tricyclic products allowed
assignment of their structures as 3a–l. A representative product tions, N-benzyl-2-(1-bromonaphthalen-2-yloxy)nicotinamide (4a)
3l, for example, exhibited discrete signals in the aromatic range was separately prepared by treatment of a mixture of N-benzyl-2-
for nine protons of which pyridine ring protons appeared at chloronicotinamide (1a) and 1-bromo-2-naphthol (2a) in the
characteristic positions23 at d 8.40 (dd, J ¼ 4.8, 1.6 Hz, 1H, H-6), presence of 5 mol% of Cu2O and Cs2CO3 (2 mol equiv.) in
d 8.30 (dd, J ¼ 7.2, 1.6 Hz, 1H, H-4) and d 7.22 (dd, J ¼ 7.2, 4.8 toluene at reux (entry 16, Table 1). It was then exposed to
55642 | RSC Adv., 2014, 4, 55640–55648
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 2 Reactions of N-substituted-2-chloronicotinamide and o-halogenated phenols under copper-catalyzed basic conditions
Entry
Secondary amide
o-Halogenated phenol
Producta
Time (h)
Yieldb (%)
1
3
85
2
3
1a
1a
6
3
72
90
4
5
6
1a
1a
5
6
6
78
65
35
1a
1a
7
8
3
3
93
90
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 55640–55648 | 55643

View Article Online
RSC Advances
Paper
Table 2 (Contd.)
Entry
Secondary amide
o-Halogenated phenol
Producta
Time (h)
Yieldb (%)
9
1b
3
78
10
11
3
3
85
80
1c
12
3
82
13
14
15
1a
1a
1a
3
2
3
88
90
82
55644 | RSC Adv., 2014, 4, 55640–55648
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 2 (Contd.)
Entry
Secondary amide
o-Halogenated phenol
Producta
Time (h)
Yieldb (%)
16
1a
10
77
a
The products were characterized by their spectral features (FTIR, 1H and 13C-NMR, MS) and XRD analysis. b Refers to isolated yields aer column
chromatographic purication.
Scheme 4 Control experiment for the N-arylation step.
Cs2CO3 in DMF without copper catalyst at 120 ꢀC to afford 3a in
86% yield in 2.5 h (Scheme 4).
This result is consistent with intermediacy of 4a on route to
the target compound 3a and also demonstrated that N-arylation
event did not necessarily require support of copper catalysis.
Cesium carbonate plays crucial facilitatory role in both
heteroarylation and Smiles rearrangement. The greater
solubility of the cesium phenoxide or phenolate–copper complex
compared to its potassium/sodium counterpart in organic
solvents24 is particularly important for etherication process.
The unactivated aryl chlorides are poor reaction partners of
phenols as the cleavage of C–Cl bond in rate determining step of
Ullmann process17a is not very facile. But this cleavage is greatly
facilitated in 2-chloropyridine because electron-decient nature
Fig. 1 ORTEP diagrams of 3c and 3i, respectively. Ellipsoids are drawn
at the 50% probability level.
of pyridine enables it to support the developing negative charge
Scheme 5 Plausible mechanism for the formation of 3a.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 55640–55648 | 55645

View Article Online
RSC Advances
Paper
due to nucleophilic attack of oxyanion. The success of the Hz, 1H), 7.35–7.28 (m, 6H), 7.16 (d, J ¼ 8.8 Hz, 1H), 7.09 (dd, J ¼
domino sequence is crucially dependent on the nature of 8.8, 2.4 Hz, 1H), 5.31 (s, 2H); 13C NMR (100 MHz, CDCl3): d
solvent used. The superior performance of toluene providing 164.9, 163.7, 152.2, 151.9, 143.0, 136.3, 132.9, 131.9, 128.9,
ether 4a (entry 16, Table 1) is substantiated by literature prec- 127.5, 126.8, 126.5, 123.8, 123.0, 122.5, 120.9, 52.5; IR (KBr):
edence.17c However, the apolar nature of toluene did not allow it 1652, 1594, 1491, 1427, 1383, 1323, 1288, 1219, 1084, 817 cmꢂ1
;
to generate and stabilize the conjugate anion of the weak HRMS (ESI) m/z: calcd for C19H13ClN2O2Na [M + Na]+: 359.0564.
secondary amide base that is essentially required for Smiles Found 359.0563.
rearrangement.25 The polar aprotic solvent DMF outperforms
Oxazepinone 3a. Brown liquid; 1H NMR (400 MHz, CDCl3): d
others because, in addition to its supportive role in ether- 8.76 (d, J ¼ 8 Hz, 1H), 8.43 (dd, J ¼ 4.8, 2 Hz, 1H), 8.34 (dd, J ¼
ication, it strongly stabilizes the nitrogen anion 4a0 and the 7.6, 1.6 Hz, 1H), 7.76 (d, J ¼ 8.4 Hz, 1H), 7.64 (t, J ¼ 8 Hz, 1H),
subsequent Meisenheimer complex 4a00 (Scheme 5). Acetonitrile 7.60 (d, J ¼ 9.2 Hz, 1H), 7.51 (t, J ¼ 8 Hz, 1H), 7.38–7.35 (m, 3H),
proved ineffective for coupling of relatively inactivated phenol 7.32–7.20 (m, 4H), 5.43 (s, 2H); 13C NMR (100 MHz, CDCl3): d
partner, 1-bromo-2-naphthol (2a) in our case. Similar failure 165.6, 164.7, 151.6, 146.9, 142.8, 136.7, 132.3, 129.6, 128.8,
was previously observed for analogous coupling of N-chlor- 127.7, 127.6, 127.4, 127.3, 127.0, 126.9, 126.1, 122.7, 122.1,
oacetamides with bromophenol.14a Recent DFT studies for 121.8, 120.7, 52.0; IR (KBr): 3063, 2926, 2852, 1649, 1592, 1459,
analogous S–N type Smile rearrangement suggest that this route 1422, 1341, 1220, 1100, 815, 752 cmꢂ1; HRMS (ESI) m/z: calcd
has much lower activation energy barrier than direct nucleo- for C23H17N2O2 (M + H)+: 353.1290. Found: 353.1219.
1
philic displacement route (Goldberg N-arylation)14h,i and,
Oxazepinone 3b. Off-white solid; m.p. 102–104 C; H NMR
ꢀ
therefore, energetically favoured over the latter. The following (400 MHz, CDCl3): d 8.43 (d, J ¼ 4 Hz, 1H), 8.33 (d, J ¼ 7.2 Hz,
mechanistic pathway is proposed for formation of 3a.
1H), 7.43 (d, J ¼ 7.6 Hz, 1H), 7.33–7.23 (m, 7H), 7.18–7.10 (m,
2H), 5.34 (s, 2H); 13C NMR (100 MHz, CDCl3): d 165.2, 164.1,
151.9, 151.7, 142.9, 136.7, 134.2, 128.8, 127.3, 127.1, 126.8,
126.3, 123.1, 122.6, 122.1, 121.2, 52.7; IR (KBr): 3058, 2923,
Conclusions
To summarize, one-pot coupling of readily accessible building 2852, 1646, 1591, 1568, 1421, 1392, 1222, 1190, 984, 791, 759
blocks viz. N-substituted-o-chloronicotinamides and o-haloge- cmꢂ1; HRMS (ESI) m/z: calcd for: C19H15N2O2 (M + H)+:
nated naphthols/phenols in the presence ofꢀCs2CO3 (2 equiv.) 303.1133. Found: 303.1142.
and Cu2O (5 mol%) catalyst in DMF at 120 C provided facile
Oxazepinone 3d. Pale yellow liquid; 1H NMR (400 MHz,
regioselective entry to hitherto unprecedented benzo[b]pyrido CDCl3): d 8.42 (dd, J ¼ 4.4, 2 Hz, 1H), 8.31 (dd, J ¼ 7.6, 2 Hz, 1H),
[3,2-f][1,4]oxazepinones through
O-heteroarylation-Smiles 7.32–7.23 (m, 7H), 7.11 (d, J ¼ 8 Hz, 1H), 6.92 (d, J ¼ 8 Hz, 1H),
rearrangement-cyclization cascade. It represents rare cases of 5.31 (s, 2H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3): d 165.2,
Smiles rearrangement using unactivated o-bromo- and -iodo- 164.2, 151.8, 151.6, 142.9, 137.6, 136.8, 131.4, 128.7, 127.3,
phenols without the support of electron-withdrawing groups. 127.0, 126.8, 122.9, 122.7, 122.1, 121.4, 52.5, 20.6; IR (KBr):
The present optimized protocol delivered a new library of the 3031, 2921, 1646, 1592, 1509, 1425, 1386, 1323, 1221, 1029, 801
designed tricyclic targets (16 examples) of potential biological cmꢂ1; HRMS (ESI) m/z: calcd for C20H17N2O2 (M + H)+: 317.1290.
relevance in good to excellent yields and its scope has been Found: 317.1290.
1
ꢀ
demonstrated for a range of electronically and sterically
Oxazepinone 3e. Pale yellow solid; m.p. 84–86 C; H NMR
discriminated substrates. The use of inexpensive air-stable (400 MHz, CDCl3): d 8.42 (dd, J ¼ 4.4, 2 Hz, 1H), 8.33 (dd, J ¼ 7.6,
cuprous oxide catalyst, operational simplicity and ease of 2 Hz, 1H), 7.32–7.24 (m, 6H), 7.13 (d, J ¼ 9.2 Hz, 1H), 6.95 (d, J ¼
isolation of products are the notable advantages of the method. 2.8 Hz, 1H), 6.67 (dd, J ¼ 8.8, 2.8 Hz, 1H), 5.29 (s, 2H), 3.75 (s,
3H); 13C NMR (100 MHz, CDCl3): d 165.1, 158.3, 153.0, 151.5,
142.9, 136.8, 128.7, 127.3, 127.0, 126.9, 126.8, 123.7, 122.2,
Experimental
Typical procedure for the synthesis of oxazepinone 3c
121.4, 112.9, 106.9, 55.7, 52.5; IR (KBr): 3063, 2935, 1646, 1590,
1507, 1460, 1416, 1392, 1296, 1215, 1100, 798 cmꢂ1; HRMS (ESI)
To a stirring solution of N-benzyl-2-chloronicotinamide (1a) m/z: calcd for C20H17N2O3 (M + H)+: 333.1239. Found: 333.1235.
(246 mg, 1.00 mmol) and 1-bromo-4-chlorophenol (2c) (210 mg,
Oxazepinone 3f. Pale yellow solid; m.p. 148–150 ꢀC; 1H NMR
1.01 mmol) in DMF (3 mL) were added Cu2O (7 mg, 0.05 mmol) (400 MHz, CDCl3): d 8.36 (dd, J ¼ 4.8, 2 Hz, 1H), 8.24 (dd, J ¼ 7.6,
and cesium carbonate (650 mg, 2.00 mmol). Then the reaction 2 Hz, 1H), 7.33–7.24 (m, 6H), 7.23–7.21 (m, 1H), 7.13 (t, J ¼ 8 Hz,
ꢀ
mixture was heated at 120 C for 3 hours. Aer completion of 1H), 7.07 (d, J ¼ 7.6 Hz, 1H), 5.76 (d, J ¼ 14.8 Hz, 1H), 4.46 (d, J ¼
the reaction (monitored by TLC), the reaction mixture was 14.8 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): d 166.1,
cooled to room temperature and extracted with EtOAc (3 ꢁ 10 165.0, 155.4, 151.3, 142.4, 136.5, 134.8, 133.1, 129.1, 128.5,
mL). The combined organic layer was washed with brine water 127.8, 127.6, 127.5, 122.1, 121.7, 119.7, 53.5, 19.6; IR (KBr):
(2 ꢁ 5 mL), dried over MgSO4, and evaporated under reduced 3023, 1639, 1591, 1459, 1431, 1397, 1321, 1213, 1096, 953, 782
pressure to give the crude product. It was puried by column cmꢂ1; HRMS (ESI) m/z: calcd for C20H17N2O2 (M + H)+: 317.1290.
chromatography on silica gel using EtOAc–light petrol (1 : 9) as Found: 317.1298.
eluent to afford the desired product 3c as off-white solid (302
Oxazepinone 3g. Dark brown solid; m.p. 138–140 ꢀC; 1H
1
ꢀ
mg, 90%). m.p. 210–212 C; H NMR (400 MHz, CDCl3): d 8.45 NMR (400 MHz, CDCl3): d 8.52 (dd, J ¼ 4.4, 1.6 Hz, 1H), 8.35 (dd,
(dd, J ¼ 4.8, 2 Hz, 1H), 8.33 (dd, J ¼ 7.6, 2 Hz, 1H), 7.44 (d, J ¼ 2.4 J ¼ 7.6, 2 Hz, 1H), 8.15 (d, J ¼ 4.4 Hz, 1H), 7.60 (dd, J ¼ 8, 1.2 Hz,
55646 | RSC Adv., 2014, 4, 55640–55648
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
1H), 7.35–7.24 (m, 6H), 7.15 (dd, J ¼ 8, 4.8 Hz, 1H), 5.32 (s, 2H);
13C NMR (100 MHz, CDCl3): d 164.9, 162.2, 156.5, 152.5, 145.3,
142.7, 136.0, 132.3, 129.2, 129.0, 127.7, 126.8, 122.6, 122.5,
120.4, 52.4; IR (KBr): 3065, 1645, 1592, 1414, 1393, 1323, 1215,
1185, 743 cmꢂ1; HRMS (ESI) m/z: calcd for C18H14N3O2 (M + H)+:
304.1086. Found: 304.1080.
N-Benzyl-2-(1-bromonaphthalen-2-yloxy)nicotinamide (4a).
Brown liquid; 1H NMR (400 MHz, CDCl3): d 8.69 (dd, J ¼ 7.6, 1.6
Hz, 1H), 8.32 (s, 1H), 8.21 (dd, J ¼ 4.8, 1.6 Hz, 1H), 7.90 (d, J ¼
8.8 Hz, 1H), 7.68 (d, J ¼ 7.6 Hz, 1H), 7.79 (d, J ¼ 8.4 Hz, 1H),
7.58–7.47 (m, 3H), 7.38–7.27 (m, 5H), 7.18 (dd, J ¼ 7.6, 4.8 Hz,
1H), 4.74 (d, J ¼ 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
163.5, 160.4, 150.1 (2C), 142.5, 138.2, 134.0, 131.4, 129.8, 128.8,
127.9, 127.6, 127.5 (2C), 126.8, 125.8, 121.6, 119.6, 118.5, 116.8,
44.0; IR (KBr): 3420, 3060, 2924, 2853, 1656, 1590, 1531, 1511,
1417, 1303, 1244, 1156, 963, 755 cmꢂ1; HRMS (ESI) m/z: calcd
for C23H17BrN2O2Na (M + Na)+: 455.0365. Found: 455.0385.
Oxazepinone 3h. Pale yellow liquid; 1H NMR (400 MHz,
CDCl3): d 8.50 (dd, J ¼ 4.8, 2 Hz, 1H), 8.31 (dd, J ¼ 7.6, 2 Hz, 1H),
8.21 (dd, J ¼ 4.4, 1.6 Hz, 1H), 7.79 (dd, J ¼ 8, 1.6 Hz, 1H), 7.32
(dd, J ¼ 7.6, 4.8 Hz, 1H), 7.26 (dd, J ¼ 8, 4.4 Hz, 1H), 6.09–5.99
(m, 1H), 5.34–5.30 (m, 2H), 4.67 (dd, J ¼ 3.6, 1.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 164.3, 162.1, 156.1, 152.4, 145.1,
142.7, 132.6, 132.1, 129.5, 122.7, 122.4, 120.4, 117.7, 52.1; IR
(KBr): 3079, 3010, 2924, 2852, 1654, 1592, 1415, 1318, 1215,
1100, 761 cmꢂ1; HRMS (ESI) m/z: calcd for C14H12N3O2 (M + H)+:
254.0929. Found: 254.0937.
Acknowledgements
SR is thankful to UGC, New Delhi, India for nancial assistance
by way of research fellowship. We are grateful to DST-FIST and
UGC-SAP programmes for providing infrastructural facilities to
the Department of Chemistry, University of Kalyani.
1
ꢀ
Oxazepinone 3i. Off-white solid; m.p. 104–106 C; H NMR
(400 MHz, CDCl3): d 8.79 (d, J ¼ 8.4 Hz, 1H), 8.45 (dd, J ¼ 4.8,
2 Hz, 1H), 8.33 (dd, J ¼ 7.2, 2 Hz, 1H), 7.83 (d, J ¼ 8 Hz, 1H),
7.72–7.67 (m, 2H), 7.56 (t, J ¼ 8 Hz, 1H), 7.51 (d, J ¼ 8.8 Hz, 1H),
7.30–7.27 (m, 1H), 6.14–6.05 (m, 1H), 5.40 (d, J ¼ 17.2 Hz, 1H),
5.30 (d, J ¼ 10.4 Hz, 1H), 4.81 (d, J ¼ 5.2 Hz, 2H); 13C NMR (100
MHz, CDCl3): d 165.1, 164.6, 151.5, 146.5, 142.7, 133.0, 132.2,
129.8, 127.7, 127.6, 127.3, 126.9, 126.1, 122.7, 122.1, 121.8,
120.6, 117.4, 51.6; IR (KBr) nmax: 3054, 2921, 2851, 1644, 1630,
1591, 1425, 1396, 1313, 1219, 1097, 1012, 804 cmꢂ1; HRMS (ESI)
m/z: calcd for C19H15N2O2 (M + H)+: 303.1133. Found: 303.1126.
Notes and references
1 S. Vilar, L. Santana and E. Uriarte, J. Med. Chem., 2006, 49,
1118–1124.
2 Eur. Patent 000463, 2005.
3 M. Binaschi, A. Boldetti, M. Gianni, C. A. Maggi, M. Gensini,
M. Bigioni, M. Parlani, A. Giolitti, M. Fratelli, C. Valli,
M. Terao and E. Garattini, ACS Med. Chem. Lett., 2010, 1,
411–415.
4 J. K. Chakrabarti and T. A. Hicks, Eur. J. Med. Chem., 1987,
22, 161–163.
1
ꢀ
Oxazepinone 3j. Off-white solid; m.p. 132–134 C; H NMR
(400 MHz, CDCl3): d 8.39 (d, J ¼ 2.8 Hz, 1H), 8.25 (d, J ¼ 7.2 Hz,
1H), 7.45 (s, 1H), 7.29–7.19 (m, 3H), 4.12 (q, J ¼ 6.8 Hz, 2H), 1.34
(t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 164.3, 163.6,
152.6, 151.6, 142.8, 132.8, 131.7, 126.6, 123.7, 123.1, 122.4,
121.3, 44.2, 13.6; IR (KBr): 3061, 2939, 1649, 1628, 1591, 1460,
1437, 1371, 1337, 1220, 1166, 1044, 898, 803 cmꢂ1; HRMS (ESI)
m/z: calcd for C14H12ClN2O2 (M + H)+: 275.0587. Found:
275.0584.
5 (a) K. Nagarajan, J. David, Y. S. Kulkarni, S. B. Hendi,
S. J. Shenoy and P. Upadhyaya, Eur. J. Med. Chem., 1986,
´
21, 21–26; (b) J.-F. F. Liegeois, F. A. Rogistert, J. Bruhwyler,
J. Damas, T. P. Nguyen, M.-O. Inarejos, E. M. G. Chleide,
M. G. A. Mercier and J. E. Delarget, J. Med. Chem., 1994, 37,
519–525.
1
ꢀ
Oxazepinone 3k. Off-white solid; m.p. 132–134 C; H NMR
(400 MHz, CDCl3): d 8.77 (d, J ¼ 8.4 Hz, 1H), 8.40–8.39 (m, 1H),
8.27 (d, J ¼ 7.6 Hz, 1H), 7.81 (d, J ¼ 8 Hz, 1H), 7.70 (d, J ¼ 8.8 Hz,
1H), 7.66 (t, J ¼ 8 Hz, 1H), 7.53 (t, J ¼ 7.6 Hz, 1H), 7.43 (d, J ¼ 8.8
Hz, 1H), 7.23 (dd, J ¼ 4.8, 7.2 Hz, 1H), 4.26 (s, 2H), 1.38 (t, J ¼ 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3): d 165.1, 164.7, 151.3, 147.2,
142.6, 132.2, 129.3, 127.8, 127.6, 127.3, 126.9, 126.1, 122.7,
122.1, 122.0, 120.8, 43.6, 13.8; IR (KBr): 3061, 2939, 1649, 1628,
6 Y. Liao, B. J. Venhuis, N. Rodenhuis, W. Timmerman and
¨
H. Wikstrom, J. Med. Chem., 1999, 42, 2235–2244.
7 T.-H. Al-Tel, R. A. Al-Qawasmeh, M. F. Schmidt, A. Al-Aboudi,
S. N. Rao, S. S. Sabri and W. Voelter, J. Med. Chem., 2009, 52,
6484–6488.
8 X.-Q. Deng, C.-X. Wei, F.-N. Li, Z.-G. Sun and Z.-S. Quan, Eur.
J. Med. Chem., 2010, 3080–3086.
9 M. Sridhara, K. R. V. Reddy, J. Keshavayya, P. S. K. Goud,
B. C. Somashekar, P. Bose, S. K. Peethambara and
S. K. Gaddam, Eur. J. Med. Chem., 2010, 4983–4989.
10 (a) K. Kamei, N. Maeda, R. Ogino, M. Koyama, M. Nakajima,
T. Tatsuaka, T. Ohno and T. Inoue, Bioorg. Med. Chem. Lett.,
2001, 11, 595–598; (b) K. Kamei, N. Maeda, K. Nomura,
M. Shibata, R. Katsuragi-Ogino, M. Koyama, M. Nakajima,
T. Inoue, T. Ohno and T. Tatsuoka, Bioorg. Med. Chem.,
2006, 14, 1978–1992.
1591, 1460, 1437, 1371, 1337, 1220, 1166, 1044, 898, 803 cmꢂ1
;
HRMS (ESI) m/z: calcd for C18H15N2O2 (M + H)+: 291.1133.
Found: 291.1127.
1
ꢀ
Oxazepinone 3l. Off-white solid; m.p. 162–164 C; H NMR
(400 MHz, CDCl3): d 8.75 (d, J ¼ 8.4 Hz, 1H), 8.40 (dd, J ¼ 4.8, 1.6
Hz, 1H), 8.30 (dd, J ¼ 7.2, 1.6 Hz, 1H), 7.80 (d, J ¼ 8 Hz, 1H), 7.69
(d, J ¼ 8.8 Hz, 1H), 7.65 (t, J ¼ 7.6 Hz, 1H), 7.51 (t, J ¼ 7.6 Hz,
1H), 7.36 (d, J ¼ 8.8 Hz, 1H), 7.22 (dd, J ¼ 7.2, 4.8 Hz, 1H), 3.65
(s, 3H); 13C NMR (100 MHz, CDCl3): d 165.4, 164.5, 151.5, 145.8, 11 (a) Y. Liu, Y. Ma, C. Zhan, A. Huang and C. Ma, Synlett, 2012,
142.8, 132.1, 130.6, 127.6, 127.4, 126.8, 126.2, 122.6, 122.0,
121.4, 120.2, 36.6; IR (KBr): 3051, 2995, 2922, 1651, 1635, 1595,
255–258; (b) H. Fukui, S. Ikegami, M. Watanuki,
T. Maruyama, Y. Sumita and K. Inoguchi, WO 0155121, 2001.
1478, 1417, 1342, 1304, 1223, 1115, 1037, 799 cmꢂ1; HRMS (ESI) 12 M. O. Kitching, T. E. Hurst and V. Snieckus, Angew. Chem.,
m/z: calcd for C17H13N2O2 (M + H)+: 277.0977. Found: 277.0980.
Int. Ed., 2012, 51, 2925–2929.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 55640–55648 | 55647

View Article Online
RSC Advances
Paper
13 Y. Liu, C. Chu, A. Huang, C. Zhan, Y. Ma and C. Ma, ACS 17 (a) H. Weingarten, J. Org. Chem., 1964, 29, 977–978; (b)
Comb. Sci., 2011, 13, 547–553.
14 (a) S.-D. Cho, Y.-D. Park, J.-J. Kim, S.-G. Lee, C. Ma,
S.-Y. Song, W.-H. Joo, J. R. Falck, M. Shiro, D.-S. Shin and
J. Lindley, Tetrahedron, 1984, 40, 1433–1456; (c)
J. F. Marcoux, S. Doye and S. L. Buchwald, J. Am. Chem.
Soc., 1997, 119, 10539–10540.
Y.-J. Yoon, J. Org. Chem., 2003, 68, 7918–7920; (b) 18 (a) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428–
S. D. Cho, S. Y. Song, Y. D. Park, J. J. Kim, W. H. Joo,
M. Shiro, J. R. Falck, D. S. Shin and Y. J. Yoon, Tetrahedron
2439; (b) E. Racine, F. Monnier, J. P. Vors and M. Taillefer,
Org. Lett., 2011, 13, 2818–2821.
Lett., 2003, 44, 8995–8998; (c) C. Ma, Q. Zhang, K. Ding, 19 (a) W. E. Truce, E. M. Kreider and W. W. Brand, Org. React.,
L. Xin and D. Zhang, Tetrahedron Lett., 2007, 48, 7476–
7479; (d) H. Zuo, L. Meng, M. Ghate, K. H. Hwang,
Y. K. Cho, S. Chandrasekhar, C. R. Reddy and D. S. Shin,
1971, 18, 99; (b) M. Schnurch, R. Flasik, A. F. Khan, M. Spina,
M. D. Mihovilovic and P. Stanetty, Eur. J. Org. Chem., 2006,
3283–3307.
Tetrahedron Lett., 2008, 49, 3827–3830; (e) H. Zuo, Z. B. Li, 20 For reviews, see: (a) S. V. Ley and A. W. Thomas, Angew.
F. K. Ren, J. R. Falck, M. Lijuan, C. Ahn and D. S. Shin,
Tetrahedron, 2008, 64, 9669–9674; (f) A. Huang, Z. Qiao,
X. Zhang, W. Yu, Q. Zheng, Y. Ma and C. Ma, Tetrahedron,
2012, 68, 906–912; (g) C. Zhan, J. Jia, B. Yang, A. Huang,
Chem., Int. Ed., 2003, 42, 5400–5449; (b) H. C. Goodbrandt,
J. Org. Chem., 1999, 64, 670–674; (c) A. Klapars, J. C. Antilla
and S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727–
7729 and references cited therein.
Y. Liu and C. Ma, RSC Adv., 2012, 2, 7506–7512; (h) 21 M. Taillefer, N. Xia and A. Quali, Angew. Chem., Int. Ed., 2007,
Y. Zhao, Y. Wu, J. Jia, D. Zhang and C. Ma, J. Org. Chem., 46, 934–936.
2012, 77, 8501–8506; (i) B. Yang, X. Tan, R. Guo, S. Chen, 22 (a) M. Wolter, G. Nordmann, G. E. Job and S. L. Buchwald,
Z. Zhang, X. Chu, C. Xie, D. Zhang and C. Ma, J. Org.
Chem., 2014, 79, 8040–8048.
15 (a) N. C. Ganguly, S. Roy, P. Mondal and R. Saha, Tetrahedron
Org. Lett., 2002, 4, 973–976; (b) C. C. Malakar,
A. Baskakova, J. Conrad and U. Beifuss, Chem.–Eur. J.,
2012, 18, 8882–8885.
Lett., 2012, 52, 7067–7071; (b) N. C. Ganguly, P. Mondal and 23 M. Hellal and G. D. Cuny, Tetrahedron Lett., 2011, 52, 5508–
S. Roy, Tetrahedron Lett., 2013, 54, 2386–2390; (c) 5511.
N. C. Ganguly, S. Roy and P. Mondal, RSC Adv., 2014, 4, 24 (a) H. E. Zaugg, J. Org. Chem., 1976, 41, 3419–3421; (b)
42078–42086.
W. H. Kwizinga and R. M. Kellogg, J. Chem. Soc., Chem.
Commun., 1979, 286–288; (c) D. D. Hennings, S. Imasa and
V. R. Rawal, J. Org. Chem., 1997, 62, 2–3.
16 (a) V. J. Merluzzi, K. D. Hargrave, M. Labadia, K. Grozinger,
M. Skoog, J. C. Wu, C. K. Shih, K. Eckner, S. Hattox and
J. Adams, et al., Science, 1990, 250, 1411–1413; (b) J. C. Wu, 25 D. M. Schmidt and G. E. Bonvicino, J. Org. Chem., 1984, 49,
T. C. Warren, J. Adams, J. Proudfoot, J. Skiles,
P. Raghavan, C. Perry, I. Potocki, P. R. Farina and
P. M. Grob, Biochemistry, 1991, 30, 2022–2026.
1664–1666.
55648 | RSC Adv., 2014, 4, 55640–55648
This journal is © The Royal Society of Chemistry 2014