Regio- and stereoselective synthesis of 1-benzopyrano[2,3-b]pyrrolo[2,3-d] pyridines: A microwave-accelerated intramolecular [3+2] cycloaddition reaction of azomethine ylide

Article abstract of DOI:10.1002/jhet.567

Figure represented. Regio- and stereoselective syntheses of tetracyclic compounds having chromone, pyrrolidine, and piperidine rings have been accomplished by an intramolecular [3+2] cycloaddition reaction involving azomethine ylide. The reactions were ca

Full text of DOI:10.1002/jhet.567

July 2011
Regio- and Stereoselective Synthesis of 1-Benzopyrano[2,3-
b]pyrrolo[2,3-d]pyridines: A Microwave-Accelerated
Intramolecular [3þ2] Cycloaddition Reaction of
Azomethine Ylide
763
Sourav Maiti,a T. M. Lakshmykanth,b Suman Kalyan Panja,a
Ranjan Mukhopadhyay,c Ayan Datta,b* and Chandrakanta Bandyopadhyaya*
aDepartment of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara,
Kolkata 700 118, West Bengal, India
bSchool of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram,
Kerala, India
cChemistry Division (CSIR), Indian Institute of Chemical Biology, Jadavpur 700 032,
West Bengal, India
*E-mail: ayan@iisertvm.ac.in or kantachandra@rediffmail.com
Received April 21, 2010
DOI 10.1002/jhet.567
Published online 1 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
Regio- and stereoselective syntheses of tetracyclic compounds having chromone, pyrrolidine, and pi-
peridine rings have been accomplished by an intramolecular [3þ2] cycloaddition reaction involving azo-
methine ylide. The reactions were carried out thermally as well as by irradiation with microwave. The
latter process accelerates the reaction. The selectivities were investigated by density functional theory
computation.
J. Heterocyclic Chem., 48, 763 (2011).
INTRODUCTION
cells [23]. Some naturally occurring chromone-based
alkaloids such as schumanniophytine and isoschuman-
niophytine were found to possess antiviral activity
[24,25]. [3þ2] Cycloaddition reaction involving azome-
thine ylide for the synthesis of pyrrolidine moiety has
been studied by ultrasonication [26], microwave irradia-
tion [27] in addition to classical heating condition. How-
ever, reports on intramolecular cycloaddition reaction
involving azomethine ylide, assisted by microwave irra-
diation or by ultrasonication, are few [28].
Intramolecular 1,3-dipolar cycloaddition reaction is an
effective method for double annulation in a single-step
reaction [1]. Intramolecular nitrone–olefin cycloaddition
reaction has been widely used for the synthesis of com-
plex heterocyclic compounds including alkaloids [2,3],
modified nucleosides [4], b-lactam antibiotics [5], and
natural products [6]. O-Allylated salicylaldehyde [7,8],
4-allylamino-3-formyl-a-pyrone [9], and 2-allylamino-3-
formylchromone [10] have been used in intramolecular
[3þ2] nitrone–olefin cycloaddition reaction for the syn-
thesis of isoxazolidines fused with different heterocycles
[11–15]. Analogous pyrrolidine derivatives, which may
be obtained by azomethine ylide–olefin cycloaddition,
possess antiviral [16] and local anesthetic activities [17].
Some of them are potential antileukemic and anticonvul-
sant agents [18]. Benzopyranopyridines or pyrrolidines
act as selective dopamine D3 receptor antagonist
[19,20], can bind with DNA [21], and have potential
antiplatelet activities [22]. Compounds having piperidine
substructures display spasmolytic activity and potent cy-
totoxicity toward human Molt 4/C8 and CEM T-lym-
phocytes as well as Murine P 388 and L 1210 leukemic
2-Alkyl/arylamino-3-formylchromone 3 has become
an attractive building block for the synthesis of various
heterocycles. Synthesis of 3 was achieved directly from
3-formylchromone 1 [29] or by the rearrangement of
nitrone 2 [30,31]. Use of 3 as a synthon has drawn
attention markedly in this decade [32–38]. In most of
the cases, 3 was further alkylated and nucleophilic sub-
stitution reactions were studied using suitable nucleo-
philes [32–34]. Recently, we have reported deformyla-
tive Mannich reaction [39] on 3 for the synthesis of bis-
chromones [36], reactions of different amines with 3
[37], and conversion of 3 into chromeno[2,3-b]pyridines
with various substituents at their 3-position [38]. Many
C
V
2011 HeteroCorporation

764
S. Maiti, T. M. Lakshmykanth, S. K. Panja, R. Mukhopadhyay, A. Datta, and C. Bandyopadhyay Vol 48
Table 1
Synthesis of 1-benzopyrano[2,3-b]pyrrolo[2,3-d]pyridines using [3þ2] cycloaddition reaction.
Entry
R1
R2
R3
R4
Conditions
Product
Yield (%)
Mp (ꢀC)
1
2
H
Me
H
Ph
Ar
Ph
Ar
Ph
Ph
Ar
Ph
Ph
Ar
Ar
Ar
Ph
Ar
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
MeOH/heat/30 h
PhCH3/heat/26 h
PhCH3/TsOH/heat/36 h
PhCH3/heat/28 h
PhCH3/heat/25 h
PhCH3/heat/26 h
DMF/Et3N/3.5 h
MW/4 min
–
6a
–
–
64
–
–
198–200
–
3
4
H
H
H
6b
6c
6d
6a
6d
6c
6b
6a
6e
6f
65
56
55
30
60
62
62
62
75
81
70
71
182–184
168–170
162–164
198–200
162–164
168–170
182–184
198–200
Semisolid
Semisolid
Semisolid
Semisolid
5
Me
H
Me
H
Me
H
Me
Me
H
H
6
7
H
H
8
9
H
H
MW/5 min
MW/5 min
MW/3 min
10
11
12
13
14
15
H
H
Ph
Ph
Ph
Ph
PhCH3/heat/25 h
PhCH3/heat/25 h
MW/3 min
Me
H
6e
6f
MW/3 min
Ar stands for 4-MeC6H4; MW stands for microwave irradiation.
attempts for the intramolecular nitrone–olefin cycloaddi-
tion reaction using N-allyl-N-arylamino-3-formylchro-
mone (4) led to nitrone–amide rearrangement. However,
intramolecular [3þ2] cycloaddition was accomplished
only under cold condition using MeNHOH as nitrone
precursor [10]. Our recent interest on azomethine ylides
[40,41] prompted us to generate azomethine ylide on 4.
Earlier reports on the reaction of sarcosine (5) with 1
revealed that azomethine ylide derived from 1 and 5
underwent [3þ2] cycloaddition and electrocyclic ring
closure reactions [40,42–44]. We report herein the
results of intramolecular [3þ2] cycloaddition reactions
involving azomethine ylide derived from 4 and 5 under
various conditions.
RESULTS AND DISCUSSION
On heating an equimolar mixture of 4 (R3 ¼ R4 ¼ H)
and 5 in methanol under reflux for 30 h produced no
suitable result (Table 1, entry 1), but produced 6 (R3 ¼
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Regio- and Stereoselective Synthesis of 1-Benzopyrano[2,3-b]pyrrolo[2,3-d]pyridines:
A Microwave-Accelerated Intramolecular [3þ2] Cycloaddition Reaction of Azomethine Ylide
765
Scheme 2
molecular [3þ2] cycloaddition reaction to give 6. Struc-
1
ture of 6 was supported by its mass spectrum. H-NMR
spectrum of 6 showed the disappearance of vinylic as
well as aldehydic protons of 4. The stereochemistry of
C/D ring juncture of 6 deserves special mention. Litera-
ture survey revealed that reduced form of pyrano[4,3-
b]pyrrole system exhibited trans-fusion with J-values
10–12 Hz and corresponding cis-fusion with J-values 5–
1
7 Hz in their H-NMR spectra [11,15,45–47]. However,
a recent report claimed that reduced form of pyri-
dino[4,3-c]isoxazole in the trans-fused condition exhib-
1
ited negligible coupling (broad singlet) [10]. In the H-
NMR spectrum of 6, C11bAH appears around d 3.7 (for
6a–6d) and around d 4.3 (for 6e, 6f) with a small cou-
pling constant (J ¼ 3–5 Hz), which supports cis-fusion
1
[15,45–47]. H NOESY experiments on 6a exhibited a
very strong cross peak between protons C3aAH and
C11bAH. This corroborates the cis-fusion. The CAH
attachments were established with the help of 1H–13C
correlation spectroscopy. Irradiation of proton at C11b
showed NOE enhancement of the signal for the proton
at C3b, which further supports the cis-fusion.
The probable modes of approaches of the 1,3-dipolar
azomethine ylide and olefin moieties in the intermediate
7 were considered (Scheme 2). Of the four probable
approaches (A–D), A or B and C or D can produce two
different regiomers 6 and 8, respectively.
For a critical understanding of the mechanistic path-
ways for the regio- and stereoselective formation of the
various possible products, a detailed density functional
theory (DFT) computation was performed at the
B3LYP/6-31þG(d) level [48–50]. All the calculations
were performed in Gaussian 03 suite of program [51].
Geometry optimization was performed on all the struc-
tures without any symmetry constraints for locating the
minimum energy structures as well as the transition-state
geometries. Additional frequency calculations were per-
formed on all the geometries to confirm the absence of
any imaginary frequencies in the harmonic vibrational
modes for the minimum energy structures and one imag-
inary mode corresponding to the saddle—points in the
transition states (TSs). The reactive intermediate 7
(Scheme 1) can exist in two isomeric forms A or B
R4 ¼ H) in 64% yield when heated in toluene for 26 h
(entry 2; Scheme 1). Addition of TsOH in the above
reaction mixture showed adverse effect and no suitable
product was isolated (entry 3). Compound 6 with differ-
ent substituents was synthesized by heating 4 (R3 ¼ R4
¼ H) and 5 in freshly distilled toluene for 25–30 h
(entries 4–6). Use of DMF as solvent in the presence of
Et3N shortens the reaction time markedly but isolated
yield of 6 was poor (entry 7). When an equimolar mix-
ture of 4 and 5 was irradiated by microwave, surpris-
ingly, it yielded 6 within 3–5 min in moderate to good
yields (entries 8–11). Compound 4 (R3 ¼ H, R4 ¼ Ph)
produced 6 (R3 ¼ H, R4 ¼ Ph) in better yield both by
classical heating (entries 12 and 13) and by microwave-
induced cycloaddition reaction (entries 14 and 15).
Although microwave irradiation does not improve the
yield, it shortens the reaction time markedly. When
the above reactions were performed under sonication,
the reactions were not complete even after 40 h.
The structure of compound 6 was established on the
basis of IR, 1H-NMR, 13C–NMR, and mass spectral
analysis. Formation of 6 may be rationalized as follows:
compound 4 reacts with 5 to produce an azomethine
ylide intermediate 7 (Scheme 1), which undergoes intra-
Figure 1. Model structures for DFT calculation.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

766
S. Maiti, T. M. Lakshmykanth, S. K. Panja, R. Mukhopadhyay, A. Datta, and C. Bandyopadhyay Vol 48
Figure 2. Exothermicity (DG) and free energies for activation (DG‡; in kcal/mol) of the various pathways leading to different products. [Color
figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(Scheme 2), which are designated by M1 and M2,
respectively, in the model (Fig. 1), which keep the
active reaction site similar to that of the experimental
molecules.
ing azomethine ylide. This led to a one-pot regio- and
stereoselective synthesis of hitherto unreported chro-
mone-fused pyrrolidino-piperidines in moderate yields.
The selectivities have been supported by DFT
calculations.
M1 having cis relationship between CH2ꢁ and chro-
monyl moiety is more stable than M2, where the relation-
ship is trans by 3.1 kcal/mol (Fig. 2). Although the low
energy intermediate (M1) can produce two regiomers cis-
P1 and product cis-P2 via the TSs TSI (DG‡ ¼ 8.7 kcal/
mol) and TS III (DG‡ ¼ 19.4 kcal/mol), respectively, the
high energy intermediate (M2) can produce only trans-
P1 via TS II (DG‡ ¼ 19.5 kcal/mol). An attempt to get an
energy-minimized structure of the model compound cor-
responding to 8D (Scheme 2), the corresponding cis-iso-
mer (cis-P2) was obtained, hence, the possibility of get-
ting other regiomer from M2 was ruled out. The energy
profile diagram (Fig. 2) explains the preferable formation
of cis-isomer via the TS TSI and this finding corroborates
the results of the spectral analysis. So, both kinetic and
thermodynamic preferences for the regio- and stereose-
lective synthesis of 6 may be predicted.
EXPERIMENTAL
General. The recorded melting points are uncorrected. IR
spectra were recorded in KBr on a Beckman IR 20a, 1H-
NMR/13C-NMR spectra on a Bruker 300 MHz/75 MHz spec-
trometer in CDCl3 unless stated otherwise, mass spectra on a
Qtof micro YA 263 instrument, and elemental analysis on a
Perkin–Elmer 240c elemental analyzer. Light petroleum refers
to the fraction with 60–80ꢀC. All chemicals used are of com-
mercial grade and are used as such.
General procedure for the synthesis of 2-[N-aryl-N-ally-
lamino]-4-oxo-4H-1-benzopyran-3-carboxaldehyde (4a–f). A
mixture of 3 (4 mmol), anhydrous K2CO3 (2 g), NaI (50 mg),
and 9 [8 mmol for (R3 ¼ R4 ¼ H) and 6 mmol for (R3 ¼ H;
R4 ¼ Ph)] in dry acetonitrile (100 mL) was heated under
reflux with stirring for 9 h. The reaction mixture was filtered
hot and the residue was washed with acetonitrile. All the
washings and the filtrate were mixed together and solvent was
removed under reduced pressure. The residue was purified by
column chromatography over silica gel using 10% ethyl ace-
tate in benzene as eluent to produce white crystalline solid 4.
6-Methyl-2-[N-(4-methylphenyl)-N-(prop-2-enyl)]amino-4-
oxo-4H-1-benzopyran-3-carboxaldehyde (4a). Yield 80%,
CONCLUSIONS
In conclusion, we have reported a microwave-acceler-
ated intramolecular [3þ2] cycloaddition reaction involv-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Regio- and Stereoselective Synthesis of 1-Benzopyrano[2,3-b]pyrrolo[2,3-d]pyridines:
A Microwave-Accelerated Intramolecular [3þ2] Cycloaddition Reaction of Azomethine Ylide
767
mp 164–166ꢀC; IR (KBr) mmax: 2910, 1680, 1665, 1614, 1590
Method B: A well-ground mixture of 4 (1 mmol) and 5 (1.1
cmꢁ1 1H-NMR: d 2.33 (s, 3H), 2.44 (s, 3H), 4.56 (brs, 2H),
;
mmol) in a small conical flask was irradiated in a domestic
microwave oven (Bajaj 1700MT, operating frequency 2450
MHz, 1200 W) with full capacity for 3–5 min. Absence of 4
in the reaction mixture was monitored by TLC. The resultant
mixture was dissolved in CHCl3. The CHCl3 solution was
washed with water and dried over Na2SO4, and compound 6
was isolated by column chromatography as described above.
1,9-Dimethyl-2,3,4,5,3a,11b-hexahydro-5-(4-methylphenyl)-1-
benzopyrano[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-one (6a). Yield
64%, mp 198–200ꢀC; IR (KBr) mmax: 3050, 2783, 1650, 1613,
5.22 (brd, J ¼ 11.4 Hz, 1H), 5.27 (brd, J ¼ 20.1 Hz, 1H),
5.92–6.01 (m, 1H), 7.08–7.20 (m, 5H), 7.42 (brd, J ¼ 7.8 Hz,
1H), 7.98 (brs, 1H), 9.98 (s, 1H). Anal. Calcd for C21H19NO3:
C, 75.66; H, 5.74; N, 4.20. Found: C, 75.80; H, 5.65; N, 4.10.
[N-(4-Methylphenyl)-N-(prop-2-enyl)]amino-4-oxo-4H-1-
benzopyran-3-carboxaldehyde (4b). Yield 77%, mp 116–
118ꢀC; IR (KBr) mmax: 2985, 1676, 1660, 1615, 1510 cmꢁ1
;
1H-NMR: d 2.34 (s, 3H), 4.59 (d, J ¼ 4.8 Hz, 2H), 5.23 (brd,
J ¼ 10.8 Hz, 1H), 5.29 (brd, J ¼ 20.7 Hz, 1H), 5.91–6.01 (m,
1H), 7.05–7.20 (m, 4H), 7.25 (brd, J ¼ 8.4 Hz, 1H), 7.37–7.42
(m, 1H), 7.59–7.64 (m, 1H), 8.20 (brd, J ¼ 7.5 Hz, 1H), 9.99
(s, 1H). Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N,
4.39. Found: C, 75.08; H, 5.22; N, 4.28.
1546 cmꢁ1 1H-NMR: d 1.44–1.47 (m, 1H), 2.12–2.19 (m, 1
;
H), 2.25–2.27 (m, 1H), 2.39 (s, 3H), 2.40 (s, 3H), 2.41–2.44
(m, 1H), 2.51 (s, 3H), 3.12–3.17 (m, 1H), 3.44 (dd, J ¼ 12.0,
5.7 Hz, 1H), 3.68 (d, J ¼ 4.5 Hz, 1H), 3. 85 (t, J ¼ 11.4 Hz,
1H), 6.91 (d, J ¼ 8.1 Hz, 1H), 7.19–7.27 (m, 5H), 7.95 (brs,
1H); 13C-NMR: d 20.8, 21.0, 26.4, 32.8, 40.8, 53.6, 53.9, 58.4,
95.1, 115.9, 122.6, 125.2, 125.8 (2 C), 129.6 (2 C), 132.6,
134.0, 136.6, 139.3, 150.9, 159.0, 175.5; mass m/z 361 (M þ
Hþ). Anal. Calcd for C23H24N2O2: C, 76.64; H, 6.71; N, 7.77.
Found: C, 76.80; H, 6.80; N, 7.69.
6-Methyl-4-oxo-2-[N-(phenyl)-N-(prop-2-enyl)]amino-4H-
1-benzopyran-3-carboxaldehyde (4c). Yield 75%, mp 162–
164ꢀC; IR (KBr) mmax: 3010, 1690, 1665, 1610, 1500 cmꢁ1
;
1H-NMR: d 2.45 (s, 3H), 4.61 (d, J ¼ 3.9 Hz, 2H), 5.23 (brd,
J ¼ 10.2 Hz, 1H), 5.29 (brd, J ¼ 17.7 Hz, 1H), 5.93–6.02 (m,
1H), 7.15 (d, J ¼ 8.4 Hz, 1H), 7.23–7.26 (m, 3H), 7.34–7.39
(m, 2H), 7.43 (brd, J ¼ 8.4 Hz, 1H), 7.99 (brs, 1H), 9.99 (s,
1H). Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N, 4.39.
Found: C, 75.10; H, 5.29; N, 4.30.
2,3,4,5,3a,11b-Hexahydro-1-methyl-5-(4-methylphenyl)-1-
benzopyrano[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-one (6b). Yield
65%, mp 182–184ꢀC; IR (KBr) mmax: 3010, 2920, 1640, 1612
cmꢁ1 1H-NMR: d 1.26–1.38 (m, 1H), 1.65–1.75 (m, 1H),
;
4-Oxo-2-[N-(phenyl)-N-(prop-2-enyl)]amino-4H-1-benzo-
pyran-3-carboxaldehyde (4d). Yield 75%, mp 132–134ꢀC
(lit. [35] mp 110–111ꢀC); IR (KBr) mmax: 3005, 1685, 1660,
2.30–2.41 (m, 1H), 2.41 (s, 3H), 2.43–2.53 (m, 1H), 2.78 (s,
3H), 3.52–3.62 (m, 2H), 4.20–4.28 (m, 2H), 7.01 (d, J ¼ 7.8
Hz, 1H), 7.26–7.29 (m, 4H), 7.43–7.46 (m, 2H), 8.11 (brd, J
¼ 6.9 Hz, 1H). Anal. Calcd for C22H22N2O2: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.39; H, 6.31; N, 7.94.
1640, 1515 cmꢁ1; H-NMR: d 4.62 (d, J ¼ 5.4 Hz, 2H), 5.24
1
(d, J ¼ 10.5 Hz, 1H), 5.30 (d, J ¼ 17.0 Hz, 1H), 5.92–6.04
(m, 1H), 7.22–7.27 (m, 4H), 7.35–7.43 (m, 3H), 7.63 (dt, J ¼
7.2, 1.2 Hz, 1H), 8.20 (dd, J ¼ 7.8, 1.2 Hz, 1H), 10.00 (s,
1H). Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59.
Found: C, 74.66; H, 4.84; N, 4.45.
1,9-Dimethyl-2,3,4,5,3a,11b-hexahydro-5-phenyl-1-benzo-
pyrano[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-one (6c). Yield
62%, mp 168–170ꢀC; IR (KBr) mmax: 3007, 2910, 1650, 1620
cmꢁ1 1H-NMR: d 1.42–1.52 (m, 1H), 2.10–2.20 (m, 1H),
;
6-Methyl-2-[N-(4-methylphenyl)-N-(3-phenylprop-2(E)-enyl)
amino]-4-oxo-4H-1-benzopyran-3-carboxaldehyde (4e). Yield
75%, mp 178–80ꢀC; IR (KBr) mmax: 3050, 1682, 1640, 1520,
2.28–2.29 (m, 1H), 2.40 (s, 3H), 2.40–2.50 (m, 1H), 2.50 (s,
3H), 3.11–3.17 (m, 1H), 3.46–3.51 (m, 1H), 3.71 (d, J ¼ 3.9
Hz, 1H), 3. 88 (t, J ¼ 11.7 Hz, 1H), 6.91 (d, J ¼ 8.4 Hz, 1H),
7.23–7.27 (m, 1H), 7.29–7.34 (m, 3H), 7.41–7.46 (m, 2H),
7.96 (brs, 1H). Anal. Calcd for C22H22N2O2: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.40; H, 6.48; N, 7.98.
1423 cmꢁ1; H-NMR: d 2.33 (s, 3H), 2.44 (s, 3H), 4.71 (d, J ¼
1
5.7 Hz, 2H), 6.31 (td, J ¼ 15.9, 5.7 Hz, 1H), 6.57 (d, J ¼ 15.9
Hz, 1H), 7.10–7.20 (m, 5H), 7.23–7.33 (m, 5H), 7.41 (dd, J ¼
8.4, 1.5 Hz, 1H), 7.98 (brs, 1H), 10.01 (s, 1H). Anal. Calcd for
C27H23NO3: C, 79.20; H, 5.66; N, 3.42. Found: C, 79.35; H,
5.53; N, 3.32.
2,3,4,5,3a,11b-Hexahydro-1-methyl-5-phenyl-1-benzopyrano
[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-one (6d). Yield 60%,
mp 162–164ꢀC; IR (KBr) mmax: 3054, 2930, 1660, 1613, 1546
4-Oxo-2-[N-(phenyl)-N-(3-phenylprop-2(E)-enyl)amino]-4H-
1-benzopyran-3-carboxaldehyde (4f). Yield 75%, mp 142–
144ꢀC (lit. [35] mp 117–118ꢀC); IR (KBr) mmax: 3058, 1675,
cmꢁ1 1H-NMR: d 1.42–1.52 (m, 1H), 2.11–2.21 (m, 1H),
;
1633, 1515, 1428 cmꢁ1; H-NMR: d 4.76 (d, J ¼ 6.0 Hz, 2H),
1
2.24–2.29 (m, 1H), 2.41–2.50 (m, 1H), 2.50 (s, 3H), 3.11–3.16
(m, 1H), 3.49 (dd, J ¼ 11.7, 5.5 Hz, 1H), 3.70 (d, J ¼ 4.5 Hz,
1H) 3.89 (t, J ¼ 11.7 Hz, 1H), 7.01 (brd, J ¼ 8.4 Hz, 1H),
7.27–7.36 (m, 4H), 7.42–7.47 (m, 3H), 8.17 (dd, J ¼ 7.8, 0.9
Hz, 1H). Anal. Calcd for C21H20N2O2: C, 75.88; H, 6.06; N,
8.43. Found: C, 75.95; H, 5.98; N, 8.34.
6.32 (td, J ¼ 15.6, 6.0 Hz, 1H), 6.59 (d, J ¼ 15.6 Hz, 1H),
7.27–7.42 (m, 12H), 7.62 (brt, J ¼ 7.5Hz, 1H), 8.20 (brd, J ¼
7.8 Hz, 1H), 10.03 (s, 1H). Anal. Calcd for C25H19NO3: C,
78.72; H, 5.02; N, 3.67. Found: C, 78.60; H, 4.92; N, 3.58.
General procedure for the synthesis of 1-benzopyr-
ano[2,3-b]pyrrolo[2,3-d]pyridines (6a–f). Method A: A mix-
ture of 4 (1 mmol) and 5 (1 mmol) was heated under reflux in
freshly distilled toluene (15 mL) for several hours (Table 1).
The progress of the reaction was monitored by TLC. Solvent
from the reaction mixture was removed under reduced pres-
sure. The residual mass was dissolved in CHCl3, the organic
extract was washed with water, dried over Na2SO4, and chro-
matographed over silica gel (100–200) using 10% methanol in
ethyl acetate to afford 6a–6d as a white crystalline solid, and
6e and 6f were obtained as a semisolid mass when eluted with
1:1 benzene–ethyl acetate mixture.
1,9-Dimethyl-2,3,4,5,3a,11b-hexahydro-5-(4-methylphenyl)-
3-phenyl-1-benzopyrano[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-
one (6e). Yield 75%, semisolid mass; IR (KBr) mmax: 3014,
1
2910, 1672, 1610, 1556 cmꢁ1; H-NMR: d 0.86–0.88 (m, 1H),
2.40 (s, 6H), 2.42–2.48 (m, 1H), 2.62 (s, 3H), 2.99–3.05 (m,
1H), 3.62–3.73 (m, 2H), 4.01 (t, J ¼ 11.4 Hz, 1H), 4.28 (d, J
¼ 5.1 Hz, 1H), 6.92 (d, J ¼ 8.4 Hz, 1H), 7.17–7.31 (m, 10H),
7.96 (brs, 1H); 13C-NMR: d 20.8, 21.0, 40.7, 42.1, 46.6, 52.7,
59.6, 63.5, 93.7, 116.1, 122.3, 125.2, 125.8 (2 C), 126.8, 127.4
(2 C), 128.7 (2 C), 129.8 (2 C), 133.0, 134.3, 136.9, 138.9,
143.2, 151.0, 159.4, 175.8; mass m/z 437 (M þ Hþ), 459 (M
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

768
S. Maiti, T. M. Lakshmykanth, S. K. Panja, R. Mukhopadhyay, A. Datta, and C. Bandyopadhyay Vol 48
þ Naþ). Anal. Calcd for C29H28N2O2: C, 79.79; H, 6.46; N,
6.42. Found: C, 79.71; H, 6.52; N, 6.36.
[24] Houghton, P. J.; Woldemariam, T. Z.; Mahmood, N. J
Pharm Pharmacol 1994, 46, 1061.
[25] Houghton, P. J.; Woldemariam, T. Z.; Khan, A. I.; Mah-
mood, N. Antivir Res 1994, 25, 235.
3,5-Diphenyl-2,3,4,5,3a,11b-hexahydro-1-methyl-1-benzo-
pyrano[2,3-b]pyrrolo[2,3-d]pyridine-11H-11-one (6f). Yield
81%, semisolid mass; IR (KBr) mmax: 3010, 2920, 1680, 1615
[26] Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett
2007, 48, 6809.
1
cmꢁ1; H-NMR: d 0.86–0.88 (m, 1H), 2.43 (brs, 1H), 2.64 (s,
[27] Ramesh, E.; Kathiresan, M.; Raghunathan, R. Tetrahedron
Lett 2007, 48, 1835.
3H), 2.91–3.08 (m, 1H), 3.61–3.70 (m, 2H), 4.03 (t, J ¼ 11.0
Hz, 1H), 4.21 (brs, 1H), 7.02 (brd, J ¼ 8.1 Hz, 1H), 7.25–7.46
(m, 12H), 8.19 (brd, J ¼ 7.2 Hz, 1H). Anal. Calcd for
C27H24N2O2: C, 79.39; H, 5.92; N, 6.86. Found: C, 79.48; H,
5.83; N, 6.76.
[28] Ramesh, E.; Raghunathan, R. Tetrahedron Lett 2008, 49, 1125.
[29] (a) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Banerjee, S. J
Chem Res Synop 2003, 459; (b) Bandyopadhyay, C.; Sur, K. R.; Patra,
R.; Banerjee, S. J Chem Res Miniprint 2003, 847.
[30] Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett
1998, 39, 6547.
Acknowledgments. The authors gratefully acknowledge CSIR,
New Delhi [project no. 01(2206)/07/EMR-II] for financial assis-
tance; IICB, Jadavpur for spectral analysis; and finally the college
authority for providing research facilities. Ayan Datta thanks
DST-Fast Track scheme for partial funding.
[31] Ghosh, T.; Bandyopadhyay, C. Tetrahedron Lett 2004, 45, 6169.
[32] Singh, G.; Singh, L.; Ishar, M. P. S. Tetrahedron 2002, 58, 7883.
[33] Sattofattori, E.; Anzaldi, M.; Balbi, A.; Artali, R.; Bomb-
ieri, G. Helv Chim Acta 2002, 85, 1698.
[34] Singh, G.; Singh, G.; Ishar, M. P. S. Synlet 2003, 256.
[35] Singh, G.; Singh, G.; Ishar, M. P. S. Helv Chim Acta 2003,
86, 169.
REFERENCES AND NOTES
[36] Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Tetrahedron
Lett 2009, 50, 3966.
[1] Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
[2] Confalone, P. N.; Huie, E. M. Org React 1988, 36, 1.
[3] Carruthers, W.; Coggins, P.; Weston, J. B. J Chem Soc Per-
kin Trans 1 1990, 2323.
[37] Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Indian J Chem
B 2009, 48, 1447.
[38] Maiti, S.; Panja, S. K.; Bandyopadhyay, C. J Heterocycl
Chem 2010, 47, 973.
[4] Rong, J.; Roselt, P.; Plavec, J.; Chattopadhyay, J. Tetrahe-
dron 1994, 50, 4921.
[39] Panja, S. K.; Maiti, S.; Drew, M. G. B.; Bandyopadhyay, C.
Tetrahedron 2009, 65, 1276.
[5] Ihara, M.; Takahashi, M.; Fukumoto, K.; Kametani, T.
J Chem Soc Chem Commun 1988, 9.
[40] Ghosh, T.; Bandyopadhyay, C. J Chem Res 2007, 190.
[41] Panja, S. K.; Karmakar, P.; Chakraborty, J.; Ghosh, T.;
Bandyopadhyay, C. Tetrahedron Lett 2008, 49, 4397.
[42] Clarke, P. D.; Fitton, A. O.; Kosmirak, M.; Suschitzky, H.;
Suschitzky, J. L. J Chem Soc Perkin Trans 1 1985, 1747.
[43] de la Torre, M. D. L.; Rodrigues, A. G. P.; Tome, A. C.;
Silva, A. M. S.; Cavaleiro, J. A. S. Tetrahedron 2004, 60, 3581.
[44] Figueiredo, A. G. P. R.; Tome, A. C.; Silva, A. M. S.; Cav-
aleiro, J. A. S. Tetrahedron 2007, 63, 910.
[6] Bhattacharjya, A.; Chattopadhyay, P.; McPhail, A. T.;
McPhail, D. R. J Chem Soc Chem Commun 1990, 1508.
[7] Broggini, G.; Folcio, F.; Sardone, N.; Zecchi, G. Tetrahe-
dron 1996, 52, 11849.
[8] Broggini, G.; Zecchi, G. Synthesis 1996, 1280.
[9] Gotoh, M.; Mizui, T.; Sun, B.; Hirayama, K.; Noguchi, M.
J Chem Soc Perkin Trans 1 1995, 1857.
[10] Singh, G.; Ishar, M. P. S.; Gupta, V.; Singh, G.; Kalyan,
M.; Bhella, S. S. Tetrahedron 2007, 63, 4773.
[45] Barr, D. A.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J.;
McMeekin, P.; Sridharan, V. Tetrahedron 1988, 44, 557.
[46] Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy, D. A.;
Malone, J. F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45, 1723.
[47] Najdi, S.; Park, K.-H.; Olmstead, M. M.; Kruth, M. J. Tet-
rahedron Lett 1998, 39, 1685.
[11] Confalone, P. N.; Huie, E. M. J Am Chem Soc 1984, 106,
7175.
[12] Wenkert, D.; Ferguson, S. B.; Porter, B.; Qvarnstorm, A.;
McPhail, A. T. J Org Chem 1985, 50, 4114.
[13] Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J Org Chem
2000, 65, 5498.
[48] Becke, A. D. J Chem Phys 1993, 98, 5648.
[14] Coldham, I.; Crapnell, K. M.; Moseley, J. D.; Robot, R. J
Chem Soc Perkin Trans 1 2001, 1758.
[49] Lee, C.; Yang, W.; Parr, R. G. Phys Rev B 1988, 37, 785.
[50] Hariharan, P. C.; Pople, J. A. Theor Chim Acta 1973, 28,
213.
[15] Novikov, M. S.; Khlebnikov, A. F.; Besidina, O. V.; Kasti-
kov, R. R.; Tetrahedron Lett 2001, 42, 533.
[51] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Bar-
one, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.
A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hase-
gawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dap-
prich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Mallick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Lia-
shenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J.
A. Gaussian 03, Revision C.01; Gaussian, Inc.: Wallingford CT, 2004.
[16] Lundahl, K.; Schutt, J.; Schlatmann, J. L. M. A.; Paerels,
G. B.; Peters, A. J Med Chem 1972, 15, 129.
[17] Kornett, M. J.; Thio, A. P. J Med Chem 1976, 19, 892.
[18] Abou-Gharbia, M. A.; Doukas, P. H. Heterocycles 1979,
12, 637.
[19] Dubuffet, T.; Muller, O.; Simonef, S. S.; Descomhes, J.-J.;
Laubie, M.; Verheuren, T. J.; Lavidle, G. Bioorg Med Chem Lett
1996, 6, 349.
[20] Dubuffet, T.; Newman-Tancerdi, A.; Cussac, D.; Audinot,
V.; Loutz, A.; Millan, M. J.; Lavielle, G. Bioorg Med Chem Lett
1999, 9, 2059.
[21] Guillo, L. A.; Beylot, B.; Vigny, P.; Spassky, A. Photochem
Photobiol 1996, 64, 349.
[22] Guinn, D. E.; Summers, J. B.; Heyman, H. R.; Conway, R.
G.; Rhein, D. A.; Albert, D. H.; Magoc, T.; Carter, G. W. J Med
Chem 1992, 35, 2055.
[23] Kumar, R. R.; Perumal, S. Tetrahedron 2007, 63, 12220.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet