Revisiting the reaction of β-chloroacroleins with 2-aminophenol: a new observation

Article abstract of DOI:10.1016/j.tet.2007.10.101

The reaction of β-chloroacrolein with 1 equiv of 2-aminophenol in DMF proceeds smoothly to afford 11-hydroxy derivative of chromenoquinoline in good yield. This single pot method allows for a rapid access to a variety of chromenoquinolines or oxepinoquinolines depending on the nature of β-chloroacrolein used. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. A plausible mechanism for this reaction has been proposed. The reaction seemed to proceed via a chloroimine species, whose intermediacy has been established, followed by the construction of the fused quinoline ring.

Full text of DOI:10.1016/j.tet.2007.10.101

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 582e589
www.elsevier.com/locate/tet
Revisiting the reaction of b-chloroacroleins with 2-aminophenol:
a new observation
a,c
Rabin Bera , G. Dhananjaya , Shambu Nath Singh , B. Ramu , Sai Uday Kiran ,
a
a
a
b
a
P. Rajender Kumar , K. Mukkanti , Manojit Pal
c
b, ,y
*
a
Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500049, Andhra Pradesh, India
Chemistry, Discovery Research, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500049, Andhra Pradesh, India
b
c
Chemistry Division, Institute of Science and Technology, JNT University, Kukutpally, Hyderabad-500072, Andhra Pradesh, India
Received 27 July 2007; received in revised form 16 October 2007; accepted 26 October 2007
Available online 1 November 2007
Abstract
The reaction of b-chloroacrolein with 1 equiv of 2-aminophenol in DMF proceeds smoothly to afford 11-hydroxy derivative of chromeno-
quinoline in good yield. This single pot method allows for a rapid access to a variety of chromenoquinolines or oxepinoquinolines depending on
the nature of b-chloroacrolein used. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. A
plausible mechanism for this reaction has been proposed. The reaction seemed to proceed via a chloroimine species, whose intermediacy has
been established, followed by the construction of the fused quinoline ring.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: b-Chloroacroleins; 2-Aminophenol; Chromenoquinoline; Oxepinoquinoline
1
. Introduction
derived from I (Fig. 1). The new chromenoquinolines II
were initially designed via changing the connectivity between
chromene and quinoline moiety. However, since the earlier
work on I was limited to the effect of substituents on D and
Drugs that modulate the transcriptional activity of human
progesterone receptor (hPR) play important role in medicine,
and over the years hPR agonists have been used therapeuti-
1
cally. Due to the undesirable side effects caused by all the ste-
roidal hRP modulators, a polynuclear heterocyclic framework
such as chromenoquinoline (I, Fig. 1) has been designed and
identified as an effective pharmacophore for the development
of better nonsteroidal hPR agonists. Additionally, this class of
compounds has shown glucocorticoid receptor agonist and an-
2
a
C ring, hence we focused on modifying the A and B ring
also followed by the expansion of C ring as shown in Figure 1.
We presumed that these compounds containing 8-hydroxyqui-
2
b
noline moiety might be useful for conducting structureeac-
tivity relationship (SAR) studies related to the compound I and
that some of them might show the similar pharmacological
properties to I. Additionally, the substituent, e.g., hydroxyl
group present on the quinoline ring might help in further func-
tionalization of II and III.
2
3
tagonist activity and androgen receptor antagonist activity.
Based on these reports that this framework can be utilized
for the development of potential drugs, we became interested
in the synthesis of substituted 6H-chromeno[4,3-b]quinolines
Whilst a large number of methods are known for the con-
struction of quinoline rings, only a few have been reported
for chromenoquinolines. These include (i) condensation of
(
II) and 6,7-dihydrobenzo[2,3]oxepino[4,5-b]quinolines (III)
4
aec
2
(
2
-aminobenzaldehyde with chroman-4-one,
(ii) heating
200 C) or irradiation of phenyl-[3-(phenylimino-methyl)-
H-chromen-4-yl]-amine hydrochloride, and (iii) treatment
ꢀ
4d
4e
*
Corresponding author. Tel.: þ91 40 23045439; fax: þ91 40 23045438.
E-mail address: manojitpal@rediffmail.com (M. Pal).
Present address: New Drug Discovery, R&D Center, Matrix Laboratories
4
f
y
of N-phenyl-2-prop-2-ynyloxy-benzamide with POCl3. On
the other hand, 6,7-dihydro-benzo[2,3]oxepino[4,5-b]quinolines
Limited, Bollaram, Andhra Pradesh 502 325, India.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.101

R. Bera et al. / Tetrahedron 64 (2008) 582e589
583
chromene
Ar
Change of connectivity
O
O
O
between chromene and
quinoline moiety
Expansion of
ether ring
D
C
Z
Z
N
B
A
N
N
H
HO
III
HO
quinoline
I
II
Figure 1. Design of new chromenoquinolines and oxepinoquinolines.
can be obtained via condensation of 1-(2-amino-phenyl)-eth-
anone hydrochloride with 3,4-dihydro-2H-benzo[b]oxepin-5-
ꢀ
4g
one at high temperature (140 C). Many of these processes,
however, suffer from disadvantages, such as the use of excess
reagents, longer reaction time, and the low yields of products.
More importantly, none of these processes appeared to be suit-
able for the synthesis of both II and III. Thus, development of
an appropriate and general, but cost effective process, for the
preparation of II and III was highly desirable. Due to our con-
tinued interest in the design and synthesis of polynuclear het-
5
erocyclic compounds of potential biological interest, we have
recently reported the Pd-mediated synthesis of furoquinolines
5
d
via construction of the fused furan ring. Herein, we report
a very simple and single pot synthesis of hydroxy derivatives
of various 6H-chromeno[4,3-b]quinolines and 6,7-dihydroben-
zo[2,3]oxepino[4,5-b]quinolines via construction of the fused
quinoline moiety using b-chloroacroleins and 2-aminophenol
as synthetic precursors (Scheme 1).
1
Figure 2. H NMR (in DMSO-d
6
) spectra of 6H-chromeno[4,3-b]quinoline-11-
ol (3a).
ꢁ
1
and a broad peak at 3364 cm in IR spectra due to the phe-
nolic OH], the product isolated after usual work up and puri-
fication was identified as 6H-chromeno[4,3-b]quinoline-11-ol
2
. Results and discussion
(3a, C H NO ). This was supported by the molecular struc-
ture of 2-bromo-6H-chromeno[4,3-b]quinolin-11-ol (3e) being
confirmed by X-ray analysis (Fig. 3).
16 11 2
Recently, condensation followed by cyclization of hetero-
cyclic b-chloroaldehydes with 2-aminophenol has been stud-
7
ied, which led to the formation of 1,5-benzoxazepines in
6
We were delighted to isolate the chromenoquinoline deriva-
tive where the fused quinoline ring seemed to have formed via
an unprecedented pathway under the reaction condition stud-
ied (see later for mechanistic discussion). Thus, encouraged
by these results we then decided to assess the generality and
scope of this one-pot process. A variety of 2-aminophenols
(2) were employed in this reaction and a range of 6H-chro-
meno[4,3-b]quinoline derivatives (3aef) were synthesized
good yields. Accordingly, we reacted 4-chloro-2H-chro-
mene-3-carboxaldehyde (1a) with 1.1 equiv of 2-aminophenol
ꢀ
(
reaction mixture at 120 C for 4 h. To our surprise, the corre-
2a) in DMF (5 mL) at 25 C for 1.0 h followed by heating the
ꢀ
sponding 1,5-benzoxazepine (3aa) was not isolated from the
1
reaction mixture (Scheme 2). Based on analytical data [ H
1
3
(
Fig. 2) and C NMR, Mass {m/z 250.3 (Mþ1, 100%)},
O
(CH2)n
O
H N
(
CH2)
2
n
H
1. DMF, 25 °C, 1h
. 120 °C, 2-4 h
Z
+
2
N
Z
HO
X
Cl
O
HO
X
1
2
3
Scheme 1. Reaction of b-chloroacroleins with 2-aminophenol.
O
O
O
H N
2
1
. DMF, 25 °C, 1h
X
H
+
N
2. 120 °C, 2-4 h
N
O
HO
Cl
O
HO
1a
2a
3a
3
aa
Scheme 2. Reaction of 4-chloro-2H-chromene-3-carboxaldehyde (1a) with 1.1 equiv of 2-aminophenol (2a).

584
R. Bera et al. / Tetrahedron 64 (2008) 582e589
in situ at low temperature in the initial step, (b) followed by
the construction of fused quinoline ring at elevated tempera-
ture in the next step to afford the observed product 3. A plau-
sible mechanism showing the formation of compound 3 from
a 4-chloroimine is depicted in Scheme 4. To prove the inter-
mediacy of 4-chloroimine, the reaction of 1a with 2a was
ꢀ
carried out in DMF at 25 C for 1.0 h where the corresponding
4-chloroimine (4) was isolated in 75% yield (Scheme 5). The
spectral data of the solid product (mp 156e157 C) obtained
was found to be identical in all respects as reported earlier
ꢀ
ꢀ
6
lit. mp 156e158 C). It is interesting to note that the reaction
(
of 1a with 2 equiv of aniline in chloroform at room tempera-
ture afforded the corresponding enaminoimine in 80% yield,
ꢀ
which on pyrolysis (200 C) furnished 6H-chromeno[4,3-b]-
4
a
quinoline. Since the formation of enaminoimine was not ob-
served in the present case perhaps due to the use of lesser
quantity (1.0 equiv) of 2a, the intermediacy of enaminoimine
can be ruled out. Moreover, isolation of 6H-chromeno[4,3-b]-
quinoline-11-ol (3a) in 80% yield from compound 4 when
ꢀ
heated at 120 C for 4 h (Scheme 4) clearly suggests that the
reaction proceeds via a chloroimine intermediate. Thus, once
generated in situ the chloroimine undergoes intermolecular cy-
cloaddition at elevated temperature as shown in Scheme 3. The
fused tetrahydro pyrimidine intermediate (X-1) formed then
collapsed to chroman-4-ylideneamine species (X-2), which
as a result of intra-molecular rearrangement followed by aro-
matization furnish 3 with the regeneration of chloramine
9
,10
thereby completing the reaction cycle.
. Conclusions
In conclusion, the reaction of b-chloroacroleins with 2-ami-
3
nophenols in DMF was investigated, which yielded chromeno-
quinolines and oxepinoquinolines thereby providing an easy
method for the synthesis of these compounds. Contrary to
Figure 3. X-ray crystal structure of 3e (ORTEP diagram). Displacement ellip-
soids are drawn at 50% probability level for non-hydrogen atoms.
6
(
2
Table 1) in good yields. As evident from Table 1, all the
-aminophenols participated in this reaction smoothly and
the earlier report no 1,5-benzoxazepine derivative was iso-
lated under the present reaction conditions. The single step
procedure described here could be attractive as it is simple,
easy to handle, and does not involve the use of expensive re-
agents or catalysts. The process is also free from the use of ex-
cess 2-aminophenol or photochemical conditions and found to
be general for the synthesis of quinoline based polynuclear
heterocycles. Therefore, the process may prove to be a power-
ful tool in the direct synthesis of chromenoquinoline/oxepino-
quinolines based agents of potential pharmacological interest,
preparation of which via other route may require lengthy syn-
thetic procedure. Moreover, this design may be applicable to
generate diversity-based library of polynuclear heterocyclic
compounds.
the yields of the products were remarkably similar irrespective
of the presence of electron donating/withdrawing groups on
the aniline ring (entry 1 vs entries 3e5, Table 1). No other sig-
nificant side products including 1,5-benzoxazepine were iso-
lated. Generally, all the reactions were carried out in DMF
ꢀ
6
at 120 C instead of refluxing DMF. However, the use of
other solvents, e.g., ethanol was investigated and found to be
less effective in terms of yield of the product (entry 2, Table
1). The methodology was extended successfully to prepare
the hydroxy derivatives of 6,7-dihydrobenzo[2,3]oxe-
pino[4,5-b]quinoline (3gei) in good yields (entry 8e10, Table
1
). Thus b-chloroacroleins appeared to be useful synthetic pre-
cursors for the preparation of 6H-chromenoquinolines (3aef)
and 6,7-dihydrobenzo[2,3]oxepino[4,5-b]quinolines (3gei).
All the b-chloroacroleins (1) were readily prepared from the
corresponding ketones by a VilsmeiereHaackeArnold reac-
tion according to Scheme 3. All the 2-aminophenols used
are commercially available.
4. Experimental
4.1. General
8
Unless stated otherwise, reactions were monitored by thin
layer chromatography (TLC) on silica gel plates (60 F254),
visualizing with ultraviolet light or iodine spray. Flash
Mechanistically, the present two-step reaction in a single
pot seems to proceed via (a) generation of a 4-chloroimine

R. Bera et al. / Tetrahedron 64 (2008) 582e589
585
Table 1
Synthesis of 6H-chromeno quinolines (3aef) and 6,7-dihydrobenzo[2,3]oxepino[4,5-b]quinolines (3gei)
a
b
Products (3)
c
Yield (%)
Entry
b-Chloroacroleins (1)
Aminophenols (2)
O
1
H N
79
2
3a
HO
N
d
2
2a
30
69
HO
O
H N
2
3
b
3
4
5
6
HO
F
N
2b
O
HO
F
H
Cl
O
1
a
O
H N
2
3c
70
65
71
66
HO
Cl
N
2c
HO
Cl
O
H N
2
3
d
HO
NO2
N
2d
HO
NO2
O
H N
2
Br
3e
HO
N
2e
HO
O
H
Br
b
Cl
O
1
O
H N
2
Br
3f
7
HO
F
N
HO
2f
F
O
O
H N
2
7
7
8
HO
3g
CHO
N
Cl
2g
1c
HO
(continued on next page)

586
R. Bera et al. / Tetrahedron 64 (2008) 582e589
Table 1 (continued)
b
Products (3)
c
Yield (%)
Entry
b-Chloroacroleins (1)
Aminophenols (2)
O
H N
2
3h
N
9
77
HO
F
HO
2h
F
O
H N
2
10
3i
74
HO
Cl
N
2i
HO
Cl
a
b
c
d
ꢀ
ꢀ
All the reactions were carried out by using 1 (1.0 equiv), 2 (1.1 equiv), DMF at 25 C for 1 h, and then at 120 C for 2e4 h.
1
Identified by H NMR, IR, and MS.
Isolated yields.
Ethanol was used as a solvent.
O
chemical shifts (d) are relative to tetramethylsilane (TMS,
d¼0.0) as internal standard and expressed in parts per million.
Spin multiplicities are given as s (singlet), d (doublet), t (trip-
let), and m (multiplet) as well as br (broad). Coupling con-
stants (J ) are given in hertz. Infrared spectra were recorded
on a FTIR spectrometer. Melting points were determined using
a Buchi melting point B-540 apparatus and are uncorrected.
MS spectra were obtained on a mass spectrometer. Chromato-
graphic purity by HPLC was determined by using area normal-
ization method and the condition specified in each case:
O
O
(
CH )
(
CH2)n POCl3
DMF
2 n
H
Z
Z
Cl
O
Scheme 3. Preparation of b-chloroacroleins (1).
chromatography was performed on silica gel (60e120 mesh)
13
1
using distilled petroleum ether and ethyl acetate. H and
C
NMR spectra were determined in DMSO-d solution using
6
2
00 and 400, and 50 MHz spectrometers, respectively. Proton
O
OH
N
Z
Cl
X
X
Cl
O
Z
O
N
N
HO
N
X
OH
Z
OH
Cl
HO
N
O
Z
X
Cl
X
O
3
X-1
X
HO
N
X
Z
HO
X
H
HO
Z
HO
N
X
N
N
O
Z
O
O
Z
Cl
X-3
O
Cl
X-2
Z
Scheme 4. Proposed reaction mechanism.

R. Bera et al. / Tetrahedron 64 (2008) 582e589
587
O
H
O
H N
2
120 °C, 2-4 h
DMF, 25 °C, 1h
Cl
3a
H
+
N
HO
Cl
O
4
HO
1a
2a
Scheme 5. Preparation of 4-chloroimine (4) followed by 3a.
column, mobile phase (range used), flow rate, detection wave-
length, and retention times. All the reagents used are commer-
cially available except b-chloroacroleins that were prepared
1.0 mL/min; UV 220 nm, retention time 18.1 min; HRMS:
calcd for C H NO F 266.0617, found 266.0612.
1
6
9
2
8
according to a known procedure.
4.2.3. 9-Chloro-6H-chromeno[4,3-b]quinolin-11-ol (3c)
Light yellow solid; R 0.62 (25% ethyl acetate/n-hexane);
f
ꢀ
1
4
.2. Synthesis of 6H-chromenoquinolines (3aef) and
,7-dihydrobenzo[2,3]oxepino[4,5-b]quinolines (3gei):
mp 150e152 C; H NMR (DMSO-d , 400 MHz) d 9.96 (br
6
6
general procedure
s, 1H, eOH), 8.75 (dd, J¼7.5, 1.4 Hz, 1H), 8.36 (s, 1H),
7.55 (d, J¼8.4 Hz, 1H), 7.50e7.43 (m, 1H), 7.20e7.17 (m,
ꢁ
1
H), 7.01e7.04 (m, 2H), 5.52 (s, 2H); IR (cm , KBr) 3378,
1
1
3
To a solution of the 4-chloro-2H-3-chromenecarboxalde-
hyde (2.57 mmol) in DMF (5 mL) was added 2-aminophenol
1603, 1583, 1108; m/z (ES mass) 284.2 (Mþ1, 100%); C
NMR (DMSO-d , 200 MHz) d 157.1, 152.7, 147.0, 138.5,
132.4, 128.1, 127.1, 126.8, 126.4, 125.3, 122.1, 122.1,
118.7, 117.1, 111.5, 67.4 (CH ); HPLC: 99.64%, Column:
Luna C18 (2) (150ꢂ4.6 mm), mobile phase A: 0.05% TFA
in water, mobile phase B: 0.05% TFA in acetonitrile, gradient
(T/%B)¼0/35, 25/80, 35/80, 36/35; flow: 1.0 mL/min; UV
220 nm, retention time: 21.3 min; HRMS calcd for
C H NO Cl 284.0478, found 284.0477.
6
ꢀ
(
280 mg, 2.57 mmol) at 25 C under a nitrogen atmosphere.
ꢀ
The resulting solution was stirred at 25 C for 1.0 h under a ni-
trogen atmosphere. The resulting reaction mixture was then
2
ꢀ
stirred at 120 C for 2e4 h. After completion of the reaction
(
as indicated by TLC, mobile phase: 20% ethyl acetate/petro-
leum ether), solvent was removed under reduced pressure and
the residue was purified by column chromatography using
light petroleum ether/ethyl acetate to furnish the desired
product.
1
6
11
2
4.2.4. 9-Nitro-6H-chromeno[4,3-b]quinolin-11-ol (3d)
Light yellow solid; R 0.55 (25% ethyl acetate/n-hexane);
f
ꢀ
1
4
.2.1. 6H-Chromeno[4,3-b]quinolin-11-ol (3a)
mp 270e272 C; H NMR (DMSO-d , 400 MHz) d 10.63
6
Light yellow solid; R 0.50 (25% ethyl acetate/n-hexane);
(br s, 1H, eOH), 8.74 (dd, J¼7.8, 1.6 Hz, 1H), 8.45 (s, 1H),
8.42 (d, J¼2.4 Hz, 1H), 7.4 (d, J¼2.4 Hz, 1H), 7.5e7.46 (m,
1H), 7.23e7.2 (m, 1H), 7.07 (dd, J¼8.1, 0.8 Hz, 1H), 5.49
f
ꢀ
1
mp 139e140 C; H NMR (DMSO-d , 400 MHz) d 9.65 (br
6
s, 1H, eOH), 8.74 (dd, J¼7.8, 1.9 Hz, 1H), 8.15 (s, 1H),
ꢁ
1
,
ꢁ1
7
.44e7.37 (m, 3H), 7.19e7.02 (m, 3H), 5.43 (s, 2H); IR (cm
(d, J¼1.1 Hz, 2H); IR (cm , KBr) 3401, 1607, 1573, 1491,
1
3
KBr) 3364, 1604, 1567; m/z (ES mass) 250.3 (Mþ1, 100%);
1335, 1121; m/z (ES mass) 293.1 (Mꢁ1, 100%); C NMR
1
3
C NMR (DMSO-d , 200 MHz) d 156.9, 153.2, 146.3,
(DMSO-d , 200 MHz) d 157.5, 154.4, 148.7, 145.3, 140.7,
6
6
1
1
37.9, 131.9, 131.4, 128.1, 127.3, 126.2, 125.5, 122.7, 122.1,
17.6, 117.1, 111.3, 67.5 (CH ); HPLC 99.74%, column:
133.7, 133.1, 127.3, 126.8, 126.6, 122.3, 122, 117.2, 114.3,
104.5, 67.3 (CH ); HRMS: calcd for C H N O 293.0562,
found 293.0565.
2
2
16 9 2 4
ZORBAX XDB-C8 (150ꢂ4.6 mm), mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in acetonitrile, gra-
dient (T/%B)¼0/15, 25/90, 30/90, 31/35; flow: 1.0 mL/min;
UV 215 nm, retention time 19.44 min; HRMS: calcd for
C H NO 250.0868, found 250.0866.
4.2.5. 2-Bromo-6H-chromeno[4,3-b]quinolin-11-ol (3e)
Light yellow solid; R 0.54 (25% ethyl acetate/n-hexane);
f
ꢀ
1
1
6
12
2
mp 182e184 C; H NMR (DMSO-d , 400 MHz) d 9.89 (br
6
s, 1H, -OH), 8.99 (d, J¼2.7 Hz, 1H), 8.16 (s, 1H), 7.56e
7.53 (m, 1H), 7.43 (t, J¼8.1 Hz, 1H), 7.37 (dd, J¼8.3, 1.3 Hz,
1H), 7.11 (d, J¼1.3 Hz, 1H), 7.09e7.0 (m, 1H) 5.46 (s, 2H);
4
.2.2. 9-Fluoro-6H-chromeno[4,3-b]quinolin-11-ol (3b)
Cream solid; R 0.56 (25% ethyl acetate/n-hexane); mp
f
ꢀ
1
ꢁ1
1
1
7
5
42e144 C; H NMR (DMSO-d , 200 MHz) d 10.26 (br s,
IR (cm , KBr) 3363, 1610, 1559; m/z (ES mass) 327.8
6
þ
13
H, eOH), 8.72 (dd, J¼7.8, 1.9 Hz, 1H), 8.13 (s, 1H),
(M , 50%), 329.8 (Mþ2, 50%); C NMR (DMSO-d6,
200 MHz) d 155.9, 153.4, 144.9, 137.9, 134.1, 131.5, 128.4,
128.3, 127.7, 124.9, 124.5, 119.3, 117.5, 114.2, 111.5, 67.6
.46e7.38 (m, 1H), 7.20e7.15 (m, 2H), 7.06e6.96 (m, 2H),
ꢁ
1
.43 (s, 2H); IR (cm , KBr) 3351, 1638, 1608, 1122; m/z (ES
1
3
mass) 268.4 (Mþ1, 100%); C NMR (DMSO-d , 200 MHz)
(CH ); HPLC 98.8%, column: ZORBAX XDB-C8 (150ꢂ
6
2
d 160.5, 156.8, 155.3, 145.8, 135.6, 131.9, 131.1, 128.2,
1
4.6 mm), mobile phase A: 0.05% TFA in water, mobile phase
B: 0.05% TFA in acetonitrile, gradient (T/%B)¼0/15, 25/90,
30/90, 31/35; flow: 1.0 mL/min; UV 215 nm, retention time:
22.98 min; HRMS calcd for C H NO Br 325.9817, found
26.6, 126.1, 122.5, 122.1, 117.0, 101.6, 100.9, 67.4 (CH2);
HPLC: 98.47%, column: Luna C18 (2) (150ꢂ4.6 mm), mobile
phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in
acetonitrile, gradient (T/%B)¼0/35, 25/80, 35/80, 36/35; flow
1
6
9
2
325.9817.

588
R. Bera et al. / Tetrahedron 64 (2008) 582e589
4
.2.6. 2-Bromo-9-fluoro-6H-chromeno[4,3-b]-
s, 1H, eOH), 8.44 (s, 1H), 8.09 (dd, J¼7.8, 1.9 Hz, 1H),
7.6e7.48 (m, 2H), 7.39e7.32 (m, 1H), 7.21e7.08 (m, 2H),
quinolin-11-ol (3f)
ꢁ
13
1
Light yellow solid; R 0.56 (25% ethyl acetate/n-hexane);
4.57 (t, J¼6.3 Hz, 2H), 3.09 (t, J¼6.3 Hz, 2H); IR (cm
,
C
f
ꢀ
1
mp 203e205 C; H NMR (DMSO-d , 400 MHz) d 10.43 (s,
KBr) 3310, 1600; m/z (ES mass) 298.3 (Mþ1, 100%);
6
1
2
7
3
1
H), 8.97 (d, J¼2.4 Hz, 1H), 8.1 (s, 1H), 7.54 (dd, J¼8.6,
NMR (DMSO-d , 200 MHz) d 156.0, 154.9, 152.8, 138.0,
6
.4 Hz, 1H), 7.19 (d, J¼2.7 Hz, 1H), 7.17 (d, J¼2.7 Hz, 1H),
133.3, 132.8, 131.4, 131.3, 131.1, 127.3, 125.1, 124.2,
122.1, 118.2, 111.2, 75.9 (CH ), 31.8 (CH ); HRMS: calcd
ꢁ
1
.01e6.98 (m, 2H), 5.45 (d, J¼0.8 Hz, 2H); IR (cm , KBr)
2
2
þ
359, 3069, 1641, 1615, 1125; m/z (ES mass) 346.0 (M ,
for C H NO Cl 298.0635, found 298.0644.
17 13 2
1
3
00%), 347.9 (Mþ2, 100%); C NMR (DMSO-d , 200 MHz)
6
d 160.8, 155.8, 155.5, 144.4, 135.6, 134.2, 131.3, 128.6, 128.3,
26.2, 124.4, 119.4, 114.3, 101.8, 100.9, 67.6 (CH ); HPLC:
Acknowledgements
1
2
9
A: 0.05% TFA in water, mobile phase B: 0.05% TFA in ace-
9.1%, column: Luna C18 (2) (150ꢂ4.6 mm), mobile phase
The authors thank Dr. V. Dahanukar and Mr. A. Mukherjee
for their encouragement and the analytical group for spectral
data. Mr. R.B. thanks CPS-DRL, Hyderabad, India for allow-
ing him to pursue this work as a part of his Ph.D. program.
tonitrile, gradient (T/%B)¼0/35, 25/80, 35/80, 36/35; flow:
1.0 mL/min; UV 220 nm, retention time: 22.3 min; HRMS:
calcd for C H NO FBr 344.9801, found 344.9813.
1
6
8
2
References and notes
4
quinoline-12-ol (3g)
.2.7. 6,7-Dihydrobenzo[2,3]oxepino[4,5-b]-
1
2
. (a) The Pharmacological Basis of Therapeutics, 8th ed.; Gilman, A. G.,
Rall, T. W., Nies, A. S., Taylor, P., Eds.; Pergamon: New York, NY,
1990; Chapter 58, pp 1397e1412; (b) Savouret, J. F.; Chauchereau, A.;
Misrahi, M.; Lescop, P.; Mantel, A.; Bailly, A.; Milgrom, E. Hum. Reprod.
Light yellow solid; R 0.50 (25% ethyl acetate/n-hexane);
f
ꢀ
1
mp 150e152 C; H NMR (DMSO-d , 400 MHz) d 9.53 (br
6
s, 1H, eOH), 8.23 (s, 1H), 8.06 (dd, J¼7.5, 1.6 Hz, 1H),
1
994, 9, 7.
7
1
6
3
.52e7.42 (m, 2H), 7.4e7.32 (m, 2H), 7.18 (dd, J¼7.8,
. (a) Edwards, J. P.; West, S. J.; Marschke, K. B.; Mais, D. E.; Gottardis,
M. M.; Jones, T. K. J. Med. Chem. 1998, 41, 303; (b) 8-Hydroxyquinoline
is a well known antiseptic with mild fungistatic, bacteriostatic, anthelmin-
tic, and amebicidal action, see: Albert, A.; Hampton, A.; Selbie, F. R.
Br. J. Exp. Pathol. 1954, 35, 75.
.1 Hz, 1H), 7.40 (dd, J¼7.5, 1.6 Hz, 1H), 4.53 (t, J¼
ꢁ
1
.2 Hz, 2H), 3.0 (t, J¼6.2 Hz, 2H); IR (cm , KBr) 3381,
1
3
352, 1601, 1567; m/z (ES mass) 264.1 (Mþ1, 100%);
C
NMR (DMSO-d , 200 MHz) d 155.1, 154.7, 153.2, 137.6,
6
3
4
. Jones, T. K.; Goldman, M. E.; Pooley, C. L. F.; Winn, D. T.; Edwards, J.
P.; West, S. J.; Tegley, C. M.; Zhi, L.; Hamann, L. G.; Davis, R. L.;
Farmer, L. J. PCT Int. Appl. Pub. No. WO 96/19458, 1996.
1
1
34.8, 133.4, 131.9, 130.9 (2C), 127.9, 127.5, 124.1, 122.0,
17.1, 110.9, 75.9 (CH ), 31.7 (CH ); HPLC 99.9%, Column:
2
2
ZORBAX XDB-C8 (150ꢂ4.6 mm), mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in acetonitrile, gra-
dient (T/%B)¼0/15, 25/90, 30/90, 31/35; flow: 1.0 mL/min;
UV 215 nm, retention time: 13.5 min; HRMS: calcd for
C H NO 264.1025, found 264.1017.
. (a) Pfeiffer, V. B. J. Prakt. Chem. 1938, 151, 312; (b) Jacquignon, P.; Goisy,
N. P. J. Chem. Soc., Perkin Trans. 1 1972, 4266; (c) Sabitha, G.; Reddy,
B. V. S. Synth. Commun. 1999, 29, 4403; (d) Balasubramanian, K. K.;
Bindumadhavan, G. V.; Nair, M.; Venugopalan, B. Synthesis 1977, 611;
(
e) Swaminathan, K. S.; Ganesh, R. S.; Venkatachalam, C. S.; Balasubrama-
1
7
14
2
nian, K. K. Tetrahedron Lett. 1983, 24, 3653; (f) Rougeot, P. E.; Moskowitz,
H.; Miocque, M. Tetrahedron Lett. 1983, 24, 2379; (g) Kempter, G.; Zanker,
P.; Zurner, H. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1967, 300, 829.
4
quinoline-12-ol (3h)
.2.8. 10-Fluoro-6,7-dihydrobenzo[2,3]oxepino[4,5-b]-
5. (a) Pal, M.; Veeramaneni, V. R.; Nagabelli, M.; kalleda, S. R.; Misra, P.;
Casturi, S. R.; Yeleswarapu, K. R. Bioorg. Med. Chem. Lett. 2003, 1639;
(b) Padakanti, S.; Veeramaneni, V. R.; Pattabiraman, V. R.; Pal, M.; Yeles-
warapu, K. R. Tetrahedron Lett. 2002, 43, 8715; (c) Swamy, N. K.; Tatini,
L. K.; Babu, J. M.; Annamalai, P.; Pal, M. Chem. Commun. 2007, 1035;
Light yellow solid; R 0.52 (25% ethyl acetate/n-hexane);
f
ꢀ
1
mp 190e192 C; H NMR (DMSO-d , 400 MHz) d 10.16
6
(
br s, 1H, eOH), 8.21 (s, 1H), 8.04 (dd, J¼7.7, 1.8 Hz, 1H),
7
1
6
1
.51e7.47 (m, 1H), 7.36e7.32 (m, 1H), 7.18 (dd, J¼7.8,
(
d) Venkataraman, S.; Barange, K. D.; Pal, M. Tetrahedron Lett. 2006,
.1 Hz, 2H), 6.97 (dd, J¼10.7, 2.7 Hz, 1H), 4.53 (t, J¼
47, 7317; (e) Chaitanya, K. K.; Pal, M.; Huckaby, A.; Kumar, L. S.;
Rajasekhar, B.; Khanna, I.; Pillarisetti, S. R.; Vally, M. K. Abstract no
A107, DRL-13156 e an orally active selective cytokine modulator with
disease modifying activity in arthritis, Presented at the 14th IRA Interna-
tional Conference, October 15e19, 2006, Cambridge, Maryland, USA.
. (a) Sekhar, B. C.; Ramana, D. V.; Ramadas, S. R. J. Heterocycl. Chem.
2001, 38, 383; (b) This process involves isolation of the imino derivative,
ꢁ1
.2 Hz, 2H), 2.98 (t, J¼6.2 Hz, 2H); IR (cm , KBr) 3312,
1
3
604, 1568, 1126; m/z (ES mass) 282.1 (Mþ1, 100%);
C
NMR (DMSO-d , 200 MHz) d 160.6, 155.5, 154.7 (2C),
6
1
1
54.5, 135.2, 134.5, 133.1, 130.9, 130.8, 128.0, 124.1, 121.9,
01.2, 100.3, 75.8 (CH ), 31.7 (CH ); HPLC: 99.5%, column:
6
7
2
2
ꢀ
which was cyclized in refluxing DMF (bp 152.8 C).
. Single crystals suitable for X-ray diffraction of 3e were grown from meth-
anol. The compound crystallizes in triclinic space group P-1 with the unit
Luna C18 (2) (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in acetonitrile, gradient
T/%B)¼0/35, 25/80, 35/80, 36/35; flow: 1.0 mL/min;
(
˚
˚
˚
cell parameters a¼10.841(3) A, b¼11.643(2) A, c¼12.127(3) A, a¼
3
UV 220 nm, retention time: 15.2 min; HRMS calcd for
C H FNO 280.0774, found 280.0771.
ꢀ
ꢀ
ꢀ
˚
83.52(7) , b¼89.004(8) , g¼62.70(5) , V¼1350(6) A and Z¼4. The in-
tensity data was collected on a Rigaku Mercury CCD area detector with
1
7
11
2
˚
graphite monochromated Mo Ka (l¼0.7107 A) radiation. The structure
was solved by direct methods (SIR92) and refined by least squares
method. The residual factors are R
4
.2.9. 10-Chloro-6,7-dihydrobenzo[2,3]oxepino[4,5-b]-
quinoline-12-ol (3i)
Light yellow solid; R 0.60 (25% ethyl acetate/n-hexane);
1
¼0.049 and Rw¼0.1185 for 4576
observed reflections. Due to the change in the conformation of the
‘chromeno’ ring the independent molecules A and B differ, which
is indicated by the difference in the torsion angles C14C15C16O1
f
ꢀ
1
mp 187e189 C; H NMR (DMSO-d , 200 MHz) d 9.93 (br
6

R. Bera et al. / Tetrahedron 64 (2008) 582e589
589
(
ꢁ144.6(5)) and C30C31C32O3 (ꢁ157.1(4)), respectively. The phenolic
10. In an alternative pathway the reaction may proceed via protonated imine
intermediate, which then reacts with a second molecule of the 2-amino-
OH of A showed an intermolecular hydrogen bonding with the hydroxyl
oxygen of B. Crystallographic data (excluding structure factors) for 3e
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 644669.
4
d
phenol by additioneelimination of HCl to form the NeC bond. The
beta-amino imine, when protonated, would be able to undergo ring-
closure and then subsequent aromatization to give compound 3 with
regeneration of the ‘second’ 2-aminophenol molecule. We thank the
reviewer for bringing this to our notice.
8
. (a) Arnold, Z.; Zemlicka, J. Collect. Czech. Chem. Commun. 1959, 24, 2385;
(b) Andrieux, J.; Battioni, J. P.; Giraud, M.; Molho, D. Bull. Soc. Chim. Fr.
1973, 2093.
9
. The intermediacy of 4-arylamino-2H-chromene-3-carbaldehyde has been
proposed during photochemical transformation of 4-chloroimine to chrom-
2
O
O
OH
OH
H
N
2
4
e
N
HCl
enoquinoline. While intermediacy of a similar species cannot be ruled out
in the present case we, however, failed to detect or isolate a corresponding
carbaldehyde intermediate under the condition employed during our syn-
thesis of compound 3. Preparation of this intermediate from 1a for further
studies was also not successful.
3
HN
HO
Cl
X
X
HCl
X