Facile synthesis of tricyclic oxazino- or oxazepino-fused tetrahydroquinolines via intramolecular reductive amidation

Article abstract of DOI:10.1055/s-0030-1260056

Reductive cyclization of -(8-quinolyloxy)alkyl esters by zinc in acetic acid is shown to constitute a convenient methodology for the synthesis of oxazino- or oxazepino-fused tetrahydroquinolines. It is operationally simple, requires a short reaction time, and provides excellent yields. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260056

PAPER
2079
Facile Synthesis of Tricyclic Oxazino- or Oxazepino-Fused
Tetrahydroquinolines via Intramolecular Reductive Amidation
Oxazino- or
O
h
xazepino-Fu
y
a
roquinoline
m
s
al Mondal,a Arindam Maity,a Subhendu Naskar,a Rupankar Paira,a Abhijit Hazra,a Krishnendu B. Sahu,a
Pritam Saha,a Saktipada Das,b Sukdeb Banerjee,a Nirup B. Mondal*a
a
Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research,
4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
Fax +91(33)24735197; E-mail: nirup@iicb.res.in
Department of Chemistry, University of Kalyani, Kalyani 741325, India
b
Received 11 January 2011; revised 21 April 2011
based on fused quinolines,12,13 we became interested in
developing the synthesis of tetrahydroquinolines. In this
communication, we describe a facile methodology for the
construction of fused tricyclic tetrahydroquinolines by re-
ductive amidation of w-(8-quinolyloxy)alkyl esters,
brought about by zinc in acetic acid. The attractiveness of
the methodology lies in the operational simplicity, forma-
tion of structurally unique molecules, short reaction times,
and excellent yields.
Abstract: Reductive cyclization of w-(8-quinolyloxy)alkyl esters
by zinc in acetic acid is shown to constitute a convenient methodol-
ogy for the synthesis of oxazino- or oxazepino-fused tetrahydro-
quinolines. It is operationally simple, requires a short reaction time,
and provides excellent yields.
Key words: reductive amidation, intramolecular amidation, w-(8-
quinolyloxy)alkyl ester, fused tetrahydroquinoline, zinc
Important pharmaceuticals often possess heterocyclic
moieties as their building blocks.1 The extensive use of
heterocyclic compounds may be attributed to the wide
range of reaction types available that facilitate subtle
structural modifications in the heterocyclic compounds
allowing easy entry to compound libraries.2–4 Investiga-
tions towards understanding the reactivity of heterocyclic
compounds are, therefore, gaining significance, especial-
ly expedient syntheses leading to N-heteroaromatics,
which are potent inhibitors of lymphocyte apoptosis5 and
often form the framework of DNA intercalating agents.6,7
Tetrahydroquinoline and its derivatives, which possess a
variety of biological activity and are used as pharmaco-
logical agents,8 pesticides,9 antioxidants,10 and corrosion
inhibitors,11 form a special group among them. As a con-
tinuation of our interest in the development of methodol-
ogies for the preparation of potent bioactive molecules
The investigation was initiated with 8-hydroxyquinoline,
which was reduced by using zinc in concentrated hydro-
chloric acid14 (Scheme 1) to prepare the substrate 8-hy-
droxy-1,2,3,4-tetrahydroquinoline. To achieve the goal,
we felt the necessity of a specific reactant that would com-
bine with 8-hydroxy-1,2,3,4-tetrahydroquinoline to pro-
duce our desired tricyclic oxazino- and oxazepino-fused
tetrahydroquinoline systems in a single step. Easily avail-
able and cost-effective haloacyl chlorides were chosen as
the model reactant as they would act both as acylating and
alkylating agents in the presence of suitable organic or in-
organic bases (Scheme 1, Route A). We performed reac-
tions using different bases and different solvents to
establish the optimum conditions (Table 1).
Using tetrahydrofuran as the solvent, we performed dif-
ferent reactions systematically with a number of bases like
triethylamine, aqueous sodium hydroxide, potassium car-
route A
ClCOCH2Cl
THF, K3PO4
N
N
H
OH
OH
Cl
O
Zn, AcOH
2
2
K2CO3, dry acetone
45 min, r.t.
92%
N
N
N
reflux
94%
EtO
OH
O
O
O
O
1a
route B
2a
Scheme 1 Synthesis of tricyclic oxazino-fused tetrahydroquinoline through two different pathways
SYNTHESIS 2011, No. 13, pp 2079–2084
x
x.
x
x
.
2
0
1
1
Advanced online publication: 19.05.2011
DOI: 10.1055/s-0030-1260056; Art ID: N10711SS
© Georg Thieme Verlag Stuttgart · New York

2080
S. Mondal et al.
PAPER
bonate, tripotassium phosphate etc. (Table 1). In all cases was reacted with zinc (1 equiv) in acetic acid at room tem-
moderate yields (45–50%) were obtained, attended by the perature for one hour, when 36% of the desired product 2a
formation of inseparable complex mixtures. Strong bases was obtained. Increasing the proportion of zinc to four
tended to produce more complex mixtures; in some cases, equivalents afforded the tricyclic fused tetrahydroquino-
yields were marginally better such as when tripotassium line 2a in an excellent yield (92%) when the reaction was
phosphate was used as base (entry 6). Thereafter attempts performed for one hour at room temperature (Scheme 1,
were made to study the effectiveness of the solvent and route B)). However, the use of higher amounts of zinc was
successive reactions were performed in dichloromethane, found to severely lower the yield of the product. This
N,N-dimethylformamide, dioxane, and toluene, but no might be due to the coagulation of the reaction mixture.
significant improvement of the yield was observed.
In order to investigate the general applicability of the
Therefore, we opted for the alternative of using halo esters methodology, we employed differently substituted 8-
and reacted 8-hydroxyquinoline with ethyl bromoacetate quinolyloxy derivatives, viz. 5-chloro, 5,7-dichloro, and
in refluxing dry acetone in presence of potassium carbon- 5,7-dibromo as the alkyl ester components and performed
ate to obtain ethyl (8-quinolyloxy)acetate (1a), a stepping reactions as for the protocols adopted for 1a. In all cases
stone for the synthesis of the desired tricyclic fused quin- the tricyclic tetrahydroquinolines 2a–n were isolated in
oline (Scheme 1, Route B). Attention was then focused on excellent yield (Table 2). It is noteworthy that slightly
selecting a suitable reagent that will act both as a reducing lower yields were obtained in case of dichloro and dibro-
and a cyclizing agent. Thus, taking ethyl (8-quinolyl- mo derivatives, which might be due to solubility prob-
oxy)acetate (1a) as the substrate, we tested the efficacy of lems. When the reaction was extended to 2-methyl-8-
some of the widely used reagents reported in the literature quinolyloxyalkyl ester derivative(s), we were disappoint-
for the reduction of quinolines or 8-hydroxyquinolines, ed to note that the expected tricyclic tetrahydroquinoline
including NaBH4,15 Zn(BH4)2,16 Zn/formic acid,17 and Sn/ was not obtained in a pure form. The behavior of this sub-
HCl.18
strate may be attributed to steric factors which hamper the
reduction process.20
Table 1 Synthesis of Tricyclic Oxazino-Fused Tetrahydroquinoline
Similar experimental procedure was applied for the syn-
thesis of seven-membered fused tricyclic oxazepinotet-
rahydroquinolines 2i–n and the products were again
obtained in excellent yields (Table 2). The marginal de-
crease in the overall yield of the product on moving from
six-membered to seven-membered ring system might be
attributed to the increase in ring strain in the latter cases.
2a Using Chloroacyl Chloride with Different Bases (Scheme 1, Route
A)a
Entry
Base
Time (h)
Yieldb (%)
1
Et3N
8
3
50
52
40
50
45
58
47
50
2
NaOH
K2CO3
Cs2CO3
Na2HPO4
K3PO4
K2SO3
KOAc
The products were characterized by NMR and mass spec-
troscopic analysis. In 1H NMR, the protons of the
ArOCH2 group usually generated a singlet at d = 4.59–
4.69 ppm in the six-membered (unsubstituted) ring sys-
tem, whereas a triplet was found in the higher homologues
3
7
4
4
5
10
12
9
6
7
8
7
a THF as solvent.
b Isolated yield after flash column chromatography.
When the reaction was performed with sodium borohy-
dride in methanol–water at different temperatures (r.t. to
reflux), only the reduction of ester to alcohol was ob-
served. On the other hand, reaction with zinc borohydride
resulted in the reduction of both the ester group and the
heterocyclic ring of quinoline producing the 2-(1,2,3,4-
tetrahydro-8-quinolyloxy)ethanol without a trace of the
cyclized product. Then the reaction was tried with zinc in
formic acid and tin in hydrochloric acid. In both the cases
simultaneous reduction as well as cyclization took place
to produce the targeted product, but with low yield. Thus
both were considered unsatisfactory.
We then decided to exploit zinc in acetic acid for this pur-
Figure
1
ORTEP diagram of 8,10-dichloro-6,7-dihydro-5H-
pose.19 In this endeavor, ethyl (8-quinolyloxy)acetate (1a)
[1,4]oxazino[2,3,4-ij]quinolin-3(2H)-one (2c)
Synthesis 2011, No. 13, 2079–2084 © Thieme Stuttgart · New York

PAPER
Oxazino- or Oxazepino-Fused Tetrahydroquinolines
2081
2i–n. Another extra two proton triplet resonating at d =
3.79 ppm was present in the spectrum of the seven-mem-
bered fused tetrahydroquinolines 2m–n as would be ex-
pected. Again a noticeably downfield one-proton triplet
resonating at d = 5.57 ppm indicates the presence of the
bromide substituent in the oxazepino ring in case of 2m,n.
The reduction of the pyridine ring (along with the form-
ation of amide bond) caused a major upfield shift in the
13C NMR of C8 of the benzenoid ring from d = 153.5 ppm
in 1a to d = 144.4 ppm in 2a. The molecular structure of
2c was unambiguously determined by single-crystal X-
ray analysis. ORTEP representation of the molecular
structure showing the atomic numbering schemes is
shown in Figure 1.
Zn, AcOH
••
N
H
••
N
N
H
O
O
O
O
EtO2C
EtO2C
1a
I
EtO
Zn(OAc)2
II
– Zn(OAc)2
– EtOH
N
N
O
N
H
[AcOH]
O
O
O
EtO
EtO
H
O
O
2a
OAc
A plausible pathway for the reaction is outlined in
Scheme 2. It is presumed that the formation of fused
oxazino- and oxazepino-fused tetrahydroquinolines 2a–n
from w-(8-quinolyloxy)alkyl esters (shown for 1a) pro-
ceeded through the intermediate 1,2,3,4-tetrahydro-8-
quinolyloxy alkyl ester I which underwent intramolecular
(AcO)Zn
III
Zn(OAc)
IV
Scheme 2 Plausible reaction pathway leading to fused tetrahydro-
quinoline 2a
Table 2 Synthesis of Fused Tetrahydroquinolines Using Zinc in Acetic Acid (Scheme 1, Route B)
R1
R1
Zn, AcOH
r.t., 45–65 min
N
R2
N
R2
X
O
O
O
n
EtO2C
n
X
1
2
Substrate
Time (min)
Product
Yielda (%)
R1
R1
1a R1 = R2 = H
45
45
45
45
2a
2b
2c
2d
92
91
86
84
1b R1 = Cl, R2 = H
1c R1 = R2 = Cl
1d R1 = R2 = Br
R2
N
O
R2
N
O
EtO2C
O
R1
R1
1e R1 = R2 = H
1f R1 = Cl, R2 = H
1g R1 = R2 = Cl
1h R1 = R2 = Br
45
45
45
45
2e
2f
2g
91
90
85
83
R2
N
O
R2
N
2h
O
EtO2C
O
R1
R1
1i R1 = R2 = H
1j R1 = Cl, R2 = H
1k R1 = R2 = Cl
1l R1 = R2 = Br
65
65
65
65
2i
90
90
82
81
2j
2k
2l
R2
N
R2
N
O
O
EtO2C
O
R1
R1
1m R1 = R2 = H
65
65
2m
2n
89
88
1n R1 = Cl, R2 = H
R2
N
R2
N
O
EtO2C
O
O
Br
Br
a Isolated yield after column chromatography.
Synthesis 2011, No. 13, 2079–2084 © Thieme Stuttgart · New York

2082
S. Mondal et al.
PAPER
8-Chloro-6,7-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-3(2H)-
one (2b)
White crystals; yield: 203 mg (91%); mp 125–126 °C.
1H NMR (600 MHz, CDCl3): d = 2.00 (m, 2 H, CH2), 2.84 (t, J = 6.6
Hz, 2 H, CH2), 3.87 (t, J = 6.0 Hz, 2 H, CH2), 4.59 (s, 2 H, CH2),
6.77 (d, J = 8.4 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 20.4 (CH2), 24.7 (CH2), 38.9
(CH2), 67.2 (CH2), 115.1 (CH), 123.4 (CH), 123.6 (C), 126.5 (C),
127.3 (C), 143.2 (C), 163.2 (C=O).
amide formation. The Lewis acid nature of zinc(II) facili-
tates the formation of the intermediate zinc complex II,
which allows the reaction to occur at room temperature.
To the best of our knowledge, this is the first report of the
preparation of fused tetrahydroquinolines using zinc/
acetic acid.
In summary, we have demonstrated a synthesis of tricy-
clic oxazino- and oxazepino-fused tetrahydroquinolines.
This procedure allows a great deal of synthetic flexibility
and offers the possibility of synthesizing newer hetero-
aromatic systems having potential biological activity. The
novelty of this methodology lies in the operational sim-
plicity, use of readily available starting materials, and en-
vironmentally friendly mild reaction conditions.
MS (ESI): m/z = 224 [M + H]+, 248 [M + 2 + Na]+.
HRMS: m/z [M + Na]+ calcd for C11H10NClO2Na: 246.0298; found:
246.0310.
8,10-Dichloro-6,7-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-
3(2H)-one (2c)
White crystals; yield: 221 mg (86%); mp 171–172 °C.
1H NMR (600 MHz, CDCl3): d = 1.99 (m, 2 H, CH2), 2.81 (t, J = 6.6
Hz, 2 H, CH2), 3.87 (t, J = 6.0 Hz, 2 H, CH2), 4.69 (s, 2 H, CH2),
7.09 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 20.2 (CH2), 24.6 (CH2), 39.0
(CH2), 67.3 (CH2), 119.8 (C), 122.3 (C), 123.9 (CH), 127.2 (C),
127.3 (C), 139.4 (C), 162.8 (C=O).
Melting points were determined with a capillary melting point ap-
paratus and are uncorrected. NMR spectra were taken on a Bruker
600 DPX spectrometer operating at 600 MHz (1H) and 150 MHz
(13C), with TMS as an internal standard. Mass spectra and HRMS
(positive mode) were obtained using an LC-ESI-Q-TOF micro mass
spectrometer. All chromatographic purifications were performed on
silica gel (60–120 mesh) (E. Merck India Ltd., Mumbai). TLC was
performed on pre-coated silica gel 60 F254 aluminum sheets (E.
Merck, Germany) using different solvent systems and the spots
were visualized either under UV torch or on heating after spraying
with Liebermann–Burchard soln. Organic solvents used for the
chemical synthesis and also for chromatography were of analytical
grade (E. Merck, India). 8-Hydroxyquinoline derivatives and ethyl
bromoacetate were purchased from Aldrich Chemical Ltd (USA).
MS (ESI): m/z = 258 [M + H]+, 282 [M + 2 + Na]+, 284 [M + 4 +
Na]+.
HRMS: m/z [M + Na]+ calcd for C11H9NCl2O2Na: 279.9908; found:
279.9909.
8,10-Dibromo-6,7-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-
3(2H)-one (2d)
White amorphous; yield: 308 mg (84%); mp 184–185 °C.
Fused Tetrahydroquinolines 2a–n; General Procedure
1H NMR (600 MHz, CDCl3): d = 1.99 (m, 2 H, CH2), 2.78 (t, J = 6.6
Hz, 2 H, CH2), 3.87 (t, J = 6.0 Hz, 2 H, CH2), 4.69 (s, 2 H, CH2),
7.42 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 20.5 (CH2), 27.6 (CH2), 39.0
(CH2), 67.3 (CH2), 108.5 (C), 117.3 (C), 124.6 (C), 127.3 (C), 129.5
(CH), 141.0 (C), 162.7 (C=O).
8-Hydroxyquinoline derivative (1 mmol) was dissolved in anhyd
acetone in a 250 mL round-bottomed flask and treated with K2CO3.
The mixture was stirred at r.t. for ~10 min and then brought to re-
flux. The desired bromoacetate or -propionate was added to the
stirred soln under reflux and stirring was continued for 4–5 h. After
completion of the reaction (TLC), the mixture was evaporated to
dryness under vacuum. The residue was mixed with H2O and ex-
tracted with EtOAc. The organic extract was evaporated to dryness
to give crude w-(8-quinolyloxy)alkyl esters 1a–n. The w-(8-
quinolyloxy)alkyl ester (1 mmol) was dissolved in AcOH (10 mL)
in a 250 mL round-bottomed flask and treated with Zn dust (4
equiv). The mixture was stirred at r.t. for ~45–65 min. After com-
pletion of the reaction (TLC), the mixture was neutralized with
NaHCO3 soln and extracted with EtOAc. The EtOAc extract was
evaporated to dryness and the residue was column chromato-
graphed (silica gel, 60–120 mesh, hexane–EtOAc) to yield the fused
tetrahydroquinolines 2a–n. Further crystallization was carried out
(CHCl3–hexane).
MS (ESI): m/z = 368 [M + H]+, 392 [M + 2 + Na]+, 394 [M + 4 +
Na]+.
HRMS: m/z [M + Na]+ calcd for C11H9NBr2O2Na: 367.8898; found:
367.8850.
2-Methyl-6,7-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-3(2H)-
one (2e)
White crystals; yield: 185 mg (91%); mp 110–111 °C.
1H NMR (600 MHz, CDCl3): d = 1.56 (d, J = 2.4 Hz, 3 H, CH3),
1.98 (t, J = 6.0 Hz, 2 H, CH2), 2.80 (t, J = 6.0 Hz, 2 H, CH2), 3.79
(m, 1 H, CH2), 3.91 (m, 1 H, CH2), 4.64 (m, 1 H), 6.69 (d, J = 7.8
Hz, 1 H), 6.88 (m, 1 H), 6.82 (d, J = 7.2 Hz, 1 H).
6,7-Dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-3(2H)-one (2a)
White crystals; yield: 174 mg (92%); mp 85–86 °C.
13C NMR (150 MHz, CDCl3): d = 16.4 (CH3), 20.9 (CH2), 26.3
(CH2), 41.8 (CH2), 73.2 (CH), 114.8 (CH), 122.3 (C), 122.5 (CH),
123.8 (CH), 125.4 (C), 142.9 (CH), 149.6 (C), 165.7 (C=O).
MS (ESI): m/z = 204 [M + H]+, 226 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C12H13NO2Na: 226.0844; found:
1H NMR (600 MHz, CDCl3): d = 1.98 (m, 2 H, CH2), 2.81 (t, J = 6.0
Hz, 2 H, CH2), 3.87 (t, J = 6.0 Hz, 2 H, CH2), 4.61 (s, 2 H, CH2),
6.79 (m, 2 H), 6.88 (m, 1 H).
13C NMR (150 MHz, CDCl3): d = 20.8 (CH2), 26.5 (CH2), 39.8
(CH2), 67.3 (CH2), 114.5 (CH), 122.7 (CH), 123.2 (CH), 124.9 (C),
125.7 (C), 144.4 (C), 163.5 (C=O).
226.0870.
8-Chloro-2-methyl-6,7-dihydro-5H-[1,4]oxazino[2,3,4-ij]quino-
lin-3(2H)-one (2f)
MS (ESI): m/z = 190 [M + H]+, 212 [M + Na]+.
White crystals; yield: 213 mg (90%); mp 119–121 °C.
1H NMR (600 MHz, CDCl3): d = 1.56 (d, J = 6.6 Hz, 3 H, CH3),
1.98 (m, 2 H, CH2), 2.83 (t, J = 6.0 Hz, 2 H, CH2), 3.73 (m, 1 H,
HRMS: m/z [M + Na]+ calcd for C11H11NO2Na: 212.0687; found:
212.0667.
Synthesis 2011, No. 13, 2079–2084 © Thieme Stuttgart · New York

PAPER
Oxazino- or Oxazepino-Fused Tetrahydroquinolines
2083
CH2), 3.96 (m, 1 H, CH2), 4.60 (m, 1 H), 7.13 (d, J = 9.0 Hz, 1 H),
7.21 (d, J = 8.4 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 16.4 (CH3), 20.6 (CH2), 24.7
(CH2), 39.2 (CH2), 73.1 (CH), 115.4 (CH), 117.0 (C), 123.4 (CH),
126.8 (C), 127.1 (C), 142.5 (C), 165.6 (C=O).
13C NMR (150 MHz, CDCl3): d = 23.8 (CH2), 25.0 (CH2), 35.7
(CH2), 41.4 (CH2), 74.5 (CH2), 121.2 (C), 125.7 (CH), 127.4 (CH),
128.0 (C), 131.0 (C), 149.3 (C), 166.9 (C=O).
MS (ESI): m/z = 239 [M + H]+, 263 [M + 2 + Na]+.
HRMS: m/z [M + Na]+ calcd for C12H12ClNO2Na: 260.0454; found:
MS (ESI): m/z = 238 [M + H]+, 260 [M + Na]+.
260.0479.
HRMS: m/z [M + Na]+ calcd for C12H12ClNO2Na: 260.0454; found:
260.0473.
9,11-Dichloro-2,3,7,8-tetrahydro-4H,6H-[1,4]oxazepino[2,3,4-
ij]quinolin-4-one (2k)
White crystals; yield: 222 mg (82%); mp 140–141 °C.
8,10-Dichloro-2-methyl-6,7-dihydro-5H-[1,4]oxazino[2,3,4-
ij]quinolin-3(2H)-one (2g)
Yellow amorphous; yield: 230 mg (85%); mp 102–103 °C.
1H NMR (600 MHz, CDCl3): d = 1.60 (d, J = 3.6 Hz, 3 H, CH3),
1.98 (m, 2 H, CH2), 2.80 (t, J = 6.6 Hz, 2 H, CH2), 3.78 (t, J = 6.0
Hz, 1 H, CH2), 3.93 (m, 1 H, CH2), 4.72 (q, J = 6.6 Hz, 1 H), 7.09
(s, 1 H).
1H NMR (600 MHz,CDCl3): d = 1.95 (m, 2 H, CH2), 2.72 (t, J = 6.6
Hz, 2 H, CH2), 2.79 (t, J = 6.6Hz, 2 H, CH2), 3.79 (t, J = 6.0 Hz, 2
H, CH2), 4.68 (t, J = 6.6 Hz, 2 H, CH2), 7.58 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 22.6 (CH2), 25.2 (CH2), 35.8
(CH2), 41.5 (CH2), 73.9 (CH2), 125.8 (CH), 126.4 (C), 128.3 (C),
129.1 (C), 136.3 (C), 143.2 (C), 169.7 (C=O).
13C NMR (150 MHz, CDCl3): d = 16.4 (CH3), 20.4 (CH2), 24.5
(CH2), 39.3 (CH2), 73.6 (CH), 121.9 (C), 123.8 (CH), 126.1 (C),
127.9 (C), 138.7 (C), 142.7 (C), 165.2 (C=O).
MS (ESI): m/z = 272 [M + H]+, 294 [M + Na]+, 296 [M + 2 + Na]+,
298 [M + 4 + Na]+.
HRMS: m/z [M + Na]+ calcd for C12H11Cl2NO2Na: 294.0064;
found: 294.0034.
MS (ESI): m/z = 272 [M + H]+, 296 [M + 2 + Na]+, 298 [M + 4 +
Na]+.
9,11-Dibromo-2,3,7,8-tetrahydro-4H,6H-[1,4]oxazepino[2,3,4-
ij]quinolin-4-one (2l)
White amorphous; yield: 291 mg (81%); mp 130–131 °C.
HRMS: m/z [M + Na]+ calcd for C12H11Cl2NO2Na: 294.0064;
found: 294.0089.
8,10-Dibromo-2-methyl-6,7-dihydro-5H-[1,4]oxazino[2,3,4-
ij]quinolin-3(2H)-one (2h)
Yellow amorphous; yield: 298 mg (83%); mp 136–137 °C.
1H NMR (600 MHz, CDCl3): d = 1.94 (m, 2 H, CH2), 2.71 (t, J = 6.6
Hz, 2 H, CH2), 2.76 (t, J = 6.6 Hz, 2 H, CH2), 3.79 (t, J = 6.0 Hz, 2
H, CH2), 4.67 (t, J = 6.6 Hz, 2 H, CH2), 7.59 (s, 1 H).
1H NMR (600 MHz, CDCl3): d = 1.59 (d, J = 3.6 Hz, 3 H, CH3),
1.98 (t, J = 6.0 Hz, 2 H, CH2), 2.77 (t, J = 6.6 Hz, 2 H, CH2), 3.78
(m, 1 H, CH2), 3.91 (m, 1 H, CH2), 4.71 (m, 1 H), 7.42 (s, 1 H).
13C NMR (150 MHz, CDCl3,): d = 22.9 (CH2), 28.2 (CH2), 35.8
(CH2), 41.5 (CH2), 73.7 (CH2), 115.5 (C), 119.4 (C), 130.7 (C),
131.5 (CH), 136.4 (C), 144.8 (C), 169.7 (C=O).
13C NMR (150 MHz, CDCl3): d = 16.4 (CH3), 20.7 (CH2), 27.5
(CH2), 39.2 (CH2), 73.6 (CH), 108.8 (C), 110.8 (C), 117.2 (C),
124.3 (C), 129.3 (CH), 140.3 (C), 165.2 (C=O).
MS (ESI): m/z = 360 [M + H]+, 384 [M + 2 + Na]+, 386 [M + 4 +
Na]+.
HRMS: m/z [M + Na]+ calcd for C12H11Br2NO2Na: 381.9054;
found: 381.9083.
MS (ESI): m/z = 360 [M + H]+, 384 [M + 2 + Na]+, 386 [M + 4 +
Na]+.
3-Bromo-2,3,7,8-tetrahydro-4H,6H-[1,4]oxazepino[2,3,4-
ij]quinolin-4-one (2m)
White crystals; yield: 250 mg (89%); mp 134–135 °C.
HRMS: m/z [M + Na]+ calcd for C12H11Br2NO2Na: 381.9054;
found: 381.9025.
2,3,7,8-Tetrahydro-4H,6H-[1,4]oxazepino[2,3,4-ij]quinolin-4-
one (2i)
White crystals; yield: 183 mg (90%); mp 121–122 °C.
1H NMR (600 MHz, CDCl3): d = 1.94 (m, 2 H, CH2), 2.71 (t, J = 6.6
Hz, 2 H, CH2), 2.75 (t, J = 6.6 Hz, 2 H, CH2), 3.79 (t, J = 6.0 Hz, 2
H, CH2), 4.68 (t, J = 6.6 Hz, 2 H, CH2), 7.15 (d, J = 9.0 Hz, 1 H),
7.20 (d, J = 8.4 Hz, 1 H), 7.54 (m, 1 H).
1H NMR (600 MHz, CDCl3): d = 1.91 (m, 2 H, CH2), 2.65 (t, J = 6.6
Hz, 2 H, CH2), 2.82 (t, J = 6.6 Hz, 2 H, CH2), 5.00 (d, J = 3.6 Hz, 2
H, CH2), 5.57 (t, J = 2.4 Hz, 1 H, CH2), 6.60 (d, J = 9.0 Hz, 1 H),
6.72 (d, J = 8.4 Hz, 1 H), 7.20 (m, 1 H).
13C NMR (150 MHz, CDCl3): d = 23.4 (CH2), 25.6 (CH2), 35.9
(CH2), 38.2 (CH2), 74.6 (CH2), 123.4 (CH), 125.6 (CH), 127.0
(CH), 129.2 (C), 131.5 (C), 147.9 (C), 168.9 (C=O).
13C NMR (150 MHz, CDCl3): d = 22.5 (CH2), 27.0 (CH2), 36.7
(CH2), 42.0 (CH2), 75.2 (CH2), 122.7 (CH), 123.4 (C), 125.7 (CH),
126.9 (CH), 137.0 (C), 143.4 (C), 168.9 (C=O).
MS (ESI): m/z = 282 [M + H]+, 306 [M + 2 + Na]+.
HRMS: m/z [M + Na]+ calcd for C12H12BrNO2Na: 303.9949; found:
303.9920.
MS (ESI): m/z = 204 [M + H]+, 226 [M + Na]+.
3-Bromo-9-chloro-2,3,7,8-tetrahydro-4H,6H-[1,4]oxazepi-
no[2,3,4-ij]quinolin-4-one (2n)
White crystals; yield: 277 mg (88%); mp 156–157 °C.
HRMS: m/z [M + Na]+ calcd for C12H13NO2Na: 226.0844; found:
226.0810.
9-Chloro-2,3,7,8-tetrahydro-4H,6H-[1,4]oxazepino[2,3,4-
ij]quinolin-4-one (2j)
White crystals; yield: 214 mg (90%); mp156–157 °C.
1H NMR (600 MHz, CDCl3): d = 1.95 (m, 2 H, CH2), 2.82 (t, J = 6.6
Hz, 2 H, CH2), 2.91 (t, J = 6.0 Hz, 2 H, CH2), 3.79 (t, J = 6.0 Hz, 2
H, CH2), 4.61 (t, J = 6.6 Hz, 2 H, CH2), 7.13 (d, J = 9.0 Hz, 1 H),
7.21 (d, J = 8.4 Hz, 1 H).
1H NMR (600 MHz, CDCl3): d = 1.90 (m, 2 H, CH2), 2.68 (t, J = 6.6
Hz, 2 H, CH2), 2.87 (t, J = 6.6 Hz, 2 H, CH2), 4.99 (d, J = 3.6 Hz, 2
H, CH2), 5.50 (t, J = 2.4 Hz, 1 H), 6.79 (d, J = 9.0 Hz, 1 H), 7.45 (d,
J = 8.4 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 23.6 (CH2), 25.8 (CH2), 35.6
(CH2), 38.9 (CH2), 75.4 (CH2), 123.2 (C), 126.9 (CH), 127.8 (CH),
130.1 (C), 132.4 (C), 147.8 (C), 169.2 (C=O).
MS (ESI): m/z = 316 [M + H]+, 340 [M + 2 + Na]+, 342 [M + 4 +
Na]+.
Synthesis 2011, No. 13, 2079–2084 © Thieme Stuttgart · New York

2084
S. Mondal et al.
PAPER
HRMS: m/z [M + Na]+ calcd for C12H11ClBrNO2Na: 337.9559;
found: 337.9570.
(11) Shikhaliev, K. S.; Shmyreva, Z.; Gurova, E. M. Izv. Vyssh.
Uchebn. Zaved., Khim. Khim. Technol. 1989, 32, 85; Chem.
Abstr. 1990, 112, 216659a.
(12) (a) Hashimoto, K.; Okaichi, Y.; Nomi, D.; Miyamoto, H.;
Bando, M.; Kido, M.; Fujimura, T.; Furuta, T.;
Minamikawa, J.-I. Chem. Pharm. Bull. 1996, 44, 642.
(b) Shaaban, M. A.; Ghoneim, K. M.; Kalifa, M. Pharmazie
1997, 32, 90. (c) Collin, J.; Jaber, N.; Lannou, M. I.
Tetrahedron Lett. 2001, 42, 7405.
(13) (a) Dutta, R.; Mandal, D.; Panda, N.; Mondal, N. B.;
Banerjee, S.; Kumar, S.; Weber, M.; Luger, P.; Sahu, N. P.
Tetrahedron Lett. 2004, 45, 9361. (b) Paira, P.; Hazra, A.;
Sahu, K. B.; Banerjee, S.; Mondal, N. B.; Sahu, N. P.;
Weber, M.; Luger, P. Tetrahedron 2008, 64, 4026.
(c) Paira, P.; Paira, R.; Hazra, A.; Naskar, S.; Sahu, K. B.;
Saha, P.; Mondal, S.; Maity, A.; Banerjee, S.; Mondal, N. B.
Tetrahedron Lett. 2009, 50, 4619. (d) Paira, P.; Paira, R.;
Hazra, A.; Sahu, K. B.; Naskar, S.; Saha, P.; Mondal, S.;
Maity, A.; Banerjee, S.; Mondal, N. B. Tetrahedron Lett.
2009, 50, 5505.
Acknowledgment
The authors express their gratitude to the Director, IICB for labora-
tory facilities and the Council of Scientific and Industrial Research
(CSIR) for providing the funding and fellowships to S.M., A.M.,
S.N., R.P., A.H., K.B.S., P.S. We are indebted to Mr. E. Padmana-
ban and Mr. K. Sarkar for recording the spectra and Dr. B. Achari,
Emeritus Scientist, CSIR, for his valuable suggestions.
References
(1) Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112.
(2) Fagnoni, M. Heterocycles 2003, 60, 1921.
(3) Hazos, G.; Riedl, Z.; Kollenz, G. Eur. J. Org. Chem. 2001,
3405.
(4) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.
Tetrahedron 2004, 60, 6239.
(14) Kaufman, D.; Johnson, E.; Mosher, M. D. Tetrahedron Lett.
(5) Barchechath, S. D.; Tawatao, R. I.; Corr, M.; Carson, D. A.;
Cottam, H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1785.
(6) Brana, M. F.; Cacho, M.; Gradillas, A.; Pascual-Teresa, B.;
Ramos, A. Curr. Pharm. Des. 2001, 7, 1745.
(7) Martinez, R.; Chacon-Garcia, L. Curr. Med. Chem. 2005,
12, 127.
(8) White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc.
1994, 116, 1831.
(9) Tsushima, K.; Osumi, T.; Matsuo, N.; Itaya, N. Agric. Biol.
Chem. 1989, 53, 2529.
2005, 46, 5613.
(15) Da Costa, C. S. J.; Pais, K. C.; Fernandes, E. L.; de Oliveira,
P. S. M.; Mendonça, J. S.; De Souza, M. V. N.; Peralta, M.
A.; Vasconcelos, T. R. A. ARKIVOC 2006, (i), 128.
(16) Ranu, B. C.; Jana, U.; Sarkar, A. Synth. Commun. 1998, 28,
485.
(17) Tafel, J. Ber. Dtsch. Chem. Ges. 1894, 27, 825.
(18) Kocian, O.; Ferles, M. Collect. Czech. Chem. Commun.
1978, 43, 1413.
(19) Gauffre, J. C.; Grignon-Dubois, M.; Rezzonico, B.; Léger,
M. J. Org. Chem. 2002, 67, 4696.
(20) Zhuravleva, A. Yu.; Zimichev, V. A.; Zemtsova, N. M.;
Klimochkin, N. Yu. Russ. J. Org. Chem. (Engl. Transl.)
2009, 45, 609.
(10) Nishiyama, T.; Hashiguchi, Y.; Sakata, T.; Sakaguchi, T.
Polym. Degrad. Stab. 2003, 79, 225.
Synthesis 2011, No. 13, 2079–2084 © Thieme Stuttgart · New York