New application of Pictet-Spengler reaction leading to the synthesis of an unusual seven-membered heterocyclic ring system

Article abstract of DOI:10.1021/jo050384h

A novel strategy for the Pictet-Spengler reaction is reported. Our strategy involves reaction of arylamines, linked to the N-1 of disubstituted imidazoles, with aldehydes in the presence of p-TsOH. The iminium ion generated in situ undergoes C-C bond form

Full text of DOI:10.1021/jo050384h

New Application of Pictet-Spengler
Reaction Leading to the Synthesis of an
Unusual Seven-Membered Heterocyclic
Ring System†
Bijoy Kundu,* Devesh Sawant, Pankaj Partani, and
Amit P. Kesarwani
FIGURE 1. Typical acid-catalyzed Pictet-Spengler reaction.
Division of Medicinal Chemistry, Central Drug Research
Institute, Lucknow 226001, India
bijoy_kundu@yahoo.com
Received March 1, 2005
FIGURE 2. Typical base-catalyzed Pictet-Spengler reaction.
contrast, alkaline catalyst is used for Pictet-Spengler
reaction involving His/histamine derived from imidazoles
(Figure 2).3d,e
A careful survey of the literature revealed that Pictet-
Spengler reaction has never been applied to arylamines
linked to an activated aromatic nucleus. This prompted
us to explore the use of arylamines linked to either N or
C as a possible substrate for the Pictet-Spengler reac-
tion.
The motivation stemmed from the fact that iminium
ion derived from aromatic amine will facilitate C-C bond
formation more than aliphatic amine since enhancement
of the electrophilic nature of the iminium intermediate
has been reported to be a driving force for cyclization.5
A novel strategy for the Pictet-Spengler reaction is reported.
Our strategy involves reaction of arylamines, linked to the
N-1 of disubstituted imidazoles, with aldehydes in the
presence of p-TsOH. The iminium ion generated in situ
undergoes C-C bond formation with the C-5 of the imida-
zoles to furnish triazabenzoazulenes as a novel heterosys-
tem. Our strategy differs from conventional Pictet-Spengler
reaction since the latter utilizes only aliphatic amines in
which the amine functionality is linked to a C instead of N
of the activated aromatic moiety.
To begin with, we focused our attention on arylamines
linked to the N-1 of imidazole and recently reported a
modified strategy for Pictet-Spengler reaction on the
solid phase leading to the synthesis of imidazoquinoxa-
lines with three-point diversity.6 This led us to believe
that our modified strategy for the Pictet-Spengler reac-
tion can be applied for the synthesis of a variety of
heterosystems of medicinal significance. This is in con-
For the last ∼100 years, the Pictet-Spengler reaction1
has been widely used for C-C bond formation in ring
systems referred to as tetrahydro-â-carbolines (THBCs)
and tetrahydroisoquinolines (THIQs). However, despite
being an attractive strategy, its application is limited to
only the following three amine prototypes: Trp/tryp-
tamine,2 His/histamine,3 and dopamine/tyramine.2
A
typical Pictet-Spengler reaction involves condensation
of an aldehyde with amine (Trp or dopamine) to form an
imine, which is often activated by Bronsted acids.4 Final
cyclization between a sufficiently reactive aromatic moi-
ety and activated iminium ion results in a new carbon-
carbon bond, forming a heterocyclic ring (Figure 1). In
(4) (a) Gonzalez, J. F.; Cuesta, E.; Avendano, C. Tetrahedron 2004,
60, 6319-6326. (b) Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron
Lett. 2003, 44, 543-547. (c) Cutter, P. S.; Miller, R. B.; Schore, N. E.
Tetrahedron 2002, 58, 1471. (d) Singh, K.; Deb, P. K.; Venugopalan,
P. Tetrahedron 2001, 57, 7939-7949. (e) Cox, E. D.; Hamaker, L. K.;
Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J. M. J.
Org. Chem. 1997, 62, 44-61. (f) Kametani, T.; Iida, H.; Shinbo, M.;
Endo, T. Chem. Pharm. Bull. 1968, 16, 949-952. (g) Kametani, T.;
Kigasawa, K.; Hiiragi, M.; Ishimaru, H. J. Chem. Soc. C 1971, 2632-
2634. (h) Stuart, K.; Woo-Ming, R. Heterocycles 1975, 3, 223-264. (i)
Von Strandtmann, M.; Puchalski, C.; Shavel, J. J. Med. Chem. 1964,
7, 141-146. (j) Brown, R. T.; Chapple, C. L. J. Chem. Soc., Chem.
Commun. 1973, 886-888. (k) Srinivasan, N.; Ganesan, A. J. Chem.
Soc., Chem. Commun. 2003, 916-917. (l) Tsuji, R.; Nakagawa, M.;
Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177-180. (m) Jiang,
W.; Sui, Z.; Chen, X. Tetrahedron Lett 2002, 43, 8941-8945. (n) Wang,
H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685-4693. (o)Yamada, H.;
Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakgawa,
M. J. Org. Chem. 1998, 63, 6348-6354. (p) Waldmann, H.; Schmidt,
G.; Jansen, M.; Geb, J. Tetrahedron 1994, 50, 11865-11884. (q) Feng,
X.; Lancelot, J. C.; Gillard, A. C.; Landelle, H.; Rault, S. J. Heterocycl.
Chem. 1998, 35, 1313-1316. (r) Grigg, R.; MacLachlan, W. S.;
MacPherson, D. T.; Sridharan, V.; Suganthan, S.; Pett, M. T.; Zhang,
J. Tetrahedron 2000, 56, 6585-6594. (s) Ducrot, P.; Rabhi, C., Thal,
C. Tetrahedron 2000, 56, 2683-2692.
* Corresponding author. Tel: +91-0522-2212411-18, ext 4383.
Fax: +91-0522-2223405, 2223938.
† CDRI Communication No. 6705.
(1) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-
2036.
(2) For reviews, see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem.
Rev. 2004, 104, 2311-2352. (b) Nielsen, T. E.; Diness, F.; Meldal, M.
Curr. Opin. Drug. Discuss. Dev. 2003, 6, 801-814. (c) Cox, E. D.; Cook,
J. Chem. Rev. 1995, 95, 1797-1842. (d) Whaley, W. M.; Govindachari,
T. R. Org. React. 1951, 6, 151-190.
(3) (a) Beke, G.; Szabo, L. F.; Podanyi, B. J. Nat. Prod. 2002, 65,
649-655. (b) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996,
37, 4865-4868. (c) Kametani, T.; Koizumi, M.; Okui, K.; Nishii, Y.;
Ono, M. J. Med. Chem. 1972, 15, 203-204. (d) Stocker, F. B.; Fordice,
M. W.; Larson, J. K.; Thorstenson, J. H. J. Org. Chem. 1966, 31, 2380-
2383. (e) Heyl, D.; Harris, S. A.; Folkers, K. J. Am. Chem. Soc. 1948,
70, 3429-3431. (f) Kametani, T.; Fukumoto, K. Heterocycles 1975, 3,
311-318.
10.1021/jo050384h CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/13/2005
J. Org. Chem. 2005, 70, 4889-4892
4889

SCHEME 1. Novel Strategy for Pictet-Spengler
trast to the conventional Pictet-Spengler reaction that
furnishes either THBC/THIQ or tetrahydroimidazopy-
ridines.
Reactiona
In this paper, we describe a new application of our
strategy based on the Pictet-Spengler reaction that led
to the synthesis of an unusual seven-membered hetero-
cyclic skeleton: triazabenzoazulenes. Seven-membered
azulenes are an important group of therapeutic agents
with CNS activity.7 To the best of our knowledge, this is
the first report of this type of approach in the Pictet-
Spengler reaction.
The synthetic strategy for triazabenzoazulene 4 with
three-point diversity is depicted in Scheme 1. In the first
instance, we decided to synthesize imidazoles 3 with aryl-
NH2 originating from N-1 of the ring. This was carried
out by treating 2,4 disubstituted imidazoles 1 with
o-nitrobenzyl bromide in the presence of NaH to get 2.
The resulting N-1 linked aryl nitro was then reduced to
NH2 functionality via catalytic hydrogenation to give 3.
An analogy between the imidazole derivative 3 (Scheme
1) and histamine (Figure 2) can be drawn from the fact
that whereas in the former an aromatic amine function-
ality originates from N-1, in the latter, an aliphatic amine
originates from the C-4. Further, in both the substrates,
the C-5 that is involved in C-C bond formation is
adjacent to the N-1 on one side and C-4 on the other side,
which is considered to be a prerequisite for Pictet-
Spengler reaction. Encouraged by these similarities, we
then proceeded to study the utility of derivative 3 as an
amine component for Pictet-Spengler reaction. In the
first instance we treated imidazole derivative 3 with
potassium hydroxide at reflux as described elsewhere for
histamine.3d However, this failed in the formation of
carbon-carbon bond between the imine and C-5 of
imidazole. This led us to carry out the Pictet-Spengler
reaction under a variety of reaction conditions such as
acid-catalyzed and neutral conditions in order to optimize
the cyclization via C-C bond formation.
a Reaction conditions: (a) NaH, DMF, 30 min, rt; (b) Pd-C, H2,
2 h; (c) p-TsOH, toluene, 125 °C, 18 h.
TABLE 1. Ratio of Imine and Triazabenzoazulene (4)
Formed during Pictet-Spengler Reaction of 3 with
p-Ethoxybenzaldehyde under Acidic and Neutral
Conditions (Scheme 1)
Accordingly, we treated imidazole derivative 3 with
p-ethoxybenzaldehyde in the presence of 5% TFA, 33%
HBr, Yb(OTf)3, acetic acid, and p-TsOH in the presence
of methanol, toluene, and DCM as solvents. The best
result was obtained when the Pictet-Spengler reaction
was carried out in the presence of pTsOH in toluene at
reflux for 18 to 20 h (Table 1). The completion of the
reaction was monitored by TLC. In the initial stages of
the reaction, the TLC exhibited a bright yellow spot due
iminea triazabenzo-
conditions
(%)
azulenea (%)
5% TFA, DCM, rt, 16 h
87
23
0
41
78
80
33
83
13
0
100
0
23
0
p-TsOH (0.1 equiv), MeOH, rt, 16 h
p-TsOH (0.1 equiv), toluene, reflux, 18 h
33% HBr in AcOH, EtOH, reflux, 2 h
Yb(OTf)3, DCM, rt, 16 h
25% AcOH in DCM, rt, 12 h
MeOH, reflux, 12 h
toluene, reflux, o/n
0
10
(5) (a) Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Nu, G.
S.; Yamanaka, E.; Hutchkins, L.; DiPierro, M.; Cook, J. M. J. Org.
Chem. 1979, 44, 535-545. (b) Sandrin, J.; Soerens, D.; Mokry, P.; Cook,
J. M. Heterocycles 1977, 6, 1133-1139. (c) Dai, W. M.; Zhu, H. J.; Hao,
X. J. Tetrahedron Lett 1996, 37, 5971-5974. (d) Czerwinski, K. M.;
Deng, L.; Cook, J. M. Tetrahedron Lett. 1994, 33, 4721-4724. (e) Zhang,
L. H.; Bi, Y. Z.; Yu, F. X.; Menzia, G.; Cook, J. M. Heterocycles 1992,
34, 517-547. (f) Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M.
J. Org. Chem. 1981, 46, 164-168. (g) Jawdosiuk, M.; Cook, J. M. J.
Org. Chem. 1984, 49, 2699-2701. (h) Bonnet, D.; Ganesan A. J. Comb.
Chem. 2002, 4, 546-548. (i) Wang, H.; Ganesan, A. Org Lett 1999, 1,
1647-1649. (j) Zawadzka, A.; Leniewski, A.; Maurin, J. K.; Wojta-
siewicz, K.; Czarnocki, Z. Org. Lett. 2001, 3, 997-999. (k) Gremmen,
C.; Wanner, M. J.; Koommen, G. J. Tetrahedron Lett. 2001, 42, 8885-
8888. (l) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen G. J.
Org. Lett. 2000, 2, 1955-1958.
a As evident by HPLC (C18 reversed-phase column; 250 × 4.6
mm; 10 µm).
to the formation of Schiff base, which gradually disap-
peared and resulted in a new colorless spot probably due
to the formation of 4.
The solvent was then evaporated, and the residue was
taken up in EtOAc and washed twice with water. The
organic layer was dried over Na2SO4 and evaporated to
dryness. The crude product so obtained was purified by
silica gel column chromatography using 20-40% EtOAc-
hexane to give the title compound 4. The final compound
was characterized using NMR and ESMS. However, for
comparative studies, the Schiff base was also isolated and
(6) Kundu, B.; Sawant, D.; Chhabra, R. J. Comb. Chem. 2005, 7,
317-321.
(7) (a) Pokk, P.; Zharkovsky, A. J. Physiol. Pharmacol. 1997, 48,
253-61. (b) Hashimoto, K.; Inoue, O.; Goromaru, T.; Yamasaki, T. Int.
J. Rad. Appl. Instrum. B. 1988, 15, 637-44.
4890 J. Org. Chem., Vol. 70, No. 12, 2005

TABLE 2. ESMS of Compounds Based on 4
entry
product
R1
R2
R3
% isolated yield
ESMS (M + H)
1
2
4a(i)
CH2C6H4-p-OMe
CH2C6H4-p-OMe
CH2C6H4-p-OMe
CH2C6H4-p-OMe
CH2C6H4-p-OMe
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
C6H4-p-OMe
C6H4-p-OMe
C6H4-p-OMe
C6H4-p-OMe
C6H4-p-OMe
OC2H5
NO2
H
81
85
82
80
87
76
80
79
75
78
79
81
88
82
77
502.87
503.93
458.87
493.04
472.87
395.93
397.13
352.07
386.13
366.00
545.13
546.13
501.07
536.93
515.00
4a(ii)
4a(iii)
4a(iv)
4a(v)
4b(i)
3
4
Cl
5
CH3
OC2H5
NO2
H
6
7
4b(ii)
4b(iii)
4b(iv)
4b(v)
4c(i)
4c(ii)
4c(iii)
4c(iv)
4c(v)
C6H5
8
C6H5
9
C6H5
Cl
10
11
12
13
14
15
C6H5
CH3
OC2H5
NO2
H
CH2NHCOC6H5
CH2NHCO C6H5
CH2NHCO C6H5
CH2NHCO C6H5
CH2NHCO C6H5
Cl
CH3
1
ArH), 7.26-7.17 [m (o), 4H, ArH], 6.87 (d, 2H, J ) 8.7 Hz, ArH),
4.09 (s, 2H, CH2), 3.79 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3,
25 °C) δ 157.4, 147.2, 133.7, 130.1, 129.1, 128.1, 125.5, 123.7,
113.4, 56.4, 33.0; IR (KBr) νmax 3434.6 (br, NH), 1605.2. Mass
(ES+): m/z 265 (M+ + 1). Anal. Calcd for C17H16N2O: C, 77.25;
H, 6.10; N, 10.60. Found: C, 77.34; H, 6.08; N, 9.89.
General Procedure for N-Alkylation of Imidazoles 2.
Imidazole 1a (1.32 g, 5.0 mmol) was treated with NaH (0.13 g
in 60% oil, 5.5 mmol) in DMF (10 mL) at rt for 15 min. Then
o-nitrobenzyl bromide (1.14 g, 5.3 mmol) was added portionwise
over a period of 5 min. The reaction was monitored by TLC, and
after the completion of the reaction, the mixture was poured in
ice-cold water (50 mL) and was extracted with EtOAc (2 × 25
mL). The EtOAc layer was washed with water (2 × 10 mL) and
brine solution (1 × 10 mL). The organic layers were combined,
dried over anhydrous Na2SO4, and evaporated to obtained yellow
residue that after column chromatography on silica gel with
hexane/EtOAc (20:80, v/v) as eluent afforded 1.70 g (85%) of 2a
as a yellow solid.
characterized by H NMR after quenching the reaction
1
within 2 h. The H NMR of the Schiff base exhibited
characteristic signals due to the Schiff base proton at
around 8.4 ppm and the C-5 proton of imidazole at
around 7 ppm, whereas the cyclic product 4 exhibited
disappearance of these two protons and emergence of a
new signal at around 6.0 ppm due to the methine. The
scope and limitation of our strategy was examined by
utilizing three 2,4 disubstituted imidazoles8 and five
aldehydes. In all cases, the title compounds were obtained
in excellent yields (75-88%) and were characterized
using NMR, LC-MS, and HPLC. The structure and
ESMS of 15 compounds based on 4 have been sum-
marized in Table 2.
In summary we have for the first time demonstrated
a new application of Pictet-Spengler reaction leading to
the synthesis of an unusual seven membered ring 1) by
changing the position of amine functionality in the
imidazole ring and 2) by using aromatic amine instead
of aliphatic amine. Further studies are in progress with
Pictet-Spengler reaction on arylamines linked to the
carbon of an activated aromatic nucleus.
2-(4-Methoxybenzyl)-1-(2-nitrobenzyl)-4-phenyl-1H-imi-
1
dazole (2a): 85%; yellow solid; mp 148-150 °C; H NMR (300
MHz, CDCl3, 25 °C) δ 8.11 (dd, 1H, J ) 3.9 Hz, ArH), 7.84 (d,
2H, J ) 7.5 Hz, ArH), 7.48-7.40 [m (o), 4H, ArH], 7.28 (t, 1H,
J ) 7.2 Hz, ArH), 7.18 (s, 1H, ArH), 7.01 (d, 2H, J ) 8.4 Hz,
ArH), 6.66 (d, 2H, J ) 8.7 Hz, ArH), 6.56 (dd, 1H, J ) 3.3 Hz,
ArH), 5.40 (s, 2H, CH2), 4.05 (s, 2H, CH2), 3.74 (s, 3H, CH3); 13
C
NMR (75 MHz, CDCl3, 25 °C) δ 158.4, 148.1, 146.9, 140.9, 134.3,
134.0, 132.8, 130.1, 129.5, 128.8, 128.6, 128.3, 128.1, 127.0, 125.2,
124.9, 116.7, 114.3, 114.1, 55.3, 47.6, 33.3; IR (KBr) νmax 1606,
1524, 1331 (NO2); mass (ES+) m/z 400 (M+ + 1).
Experimental Section
General Considerations. See the Supporting Information.
General Procedure for Synthesis of Imidazole 1a. Ce-
sium carbonate (1.02 g, 3.125 mmol) was added to a solution of
4-methoxyphenylacetic acid (1.04 g, 6.25 mmol) in methanol (25
mL). The reaction mixture was stirred for 1 h, the solvent was
evaporated, phenacyl bromide (1.24 g, 6.25 mmol) and dimeth-
ylformamide (20 mL) were added, and the mixture stirred
overnight. The reaction mixture was evaporated to dryness
under reduced pressure and xylene (30 mL) added to the residue.
The cesium bromide salt was filtered, ammonium acetate (10
g) added to the filtrate, and the reaction mixture refluxed for
1.5 h using a Dean-Stark apparatus. After cooling, the reaction
was diluted with ice-water and ethyl acetate (200 mL). The
organic phase was washed with a saturated solution of sodium
bicarbonate (100 mL) followed by brine (50 mL), dried over
sodium sulfate, filtered, and evaporated to dryness under
reduced pressure. Purification was carried out on a silica gel
column to afford 0.40 g (24%) as a light cream powder: mp 148-
150 °C.
General Procedure for the Reduction of Nitro Group
3. A mixture of compound 2a (1.50 g, 3.75 mmol) and Pd-C (100
mg) in methanol (10 mL) was subjected to hydrogenation in the
Parr assembly at 35 psi at room temperature. The reaction was
allowed to continue for 3 h. Thereafter, the catalyst was removed
by vacuum filtering the reaction mixture through a Celite bed
with methanol. The filtrate was evaporated to obtain an oily
residue, which was taken up in EtOAc (2 × 20 mL) and washed
with water (20 mL). The organic layers were evaporated in vacuo
to obtain the crude oil, which was recrystallized in ethanol to
obtain 1.10 g (80%) of 3a as a white solid.
2-[2-(4-Methoxybenzyl)-4-phenylimidazol-1-ylmethyl]-
phenylamine (3a): 80%; white solid; mp 177-179 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ 7.73 (d, 2H, J ) 7.5 Hz, ArH), 7.33
(t, 2H, J ) 7.5 Hz, ArH), 7.25-7.12 [m (o), 4H, ArH], 6.49 (s,
1H, ArH), 6.84 [t (o), 3H, J ) 8.7 Hz, ArH], 6.74 (t, 1H, J ) 7.5
Hz, ArH), 6.64 (d, 1H, J ) 8.1 Hz, ArH), 4.73 (s, 2H, CH2), 4.13
(s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.28 (s, 2H, NH); 13C NMR (75
MHz, DMSO-d6, 25 °C) δ 158.6, 147.5, 144.7, 140.3, 134.3, 129.7,
129.6, 129.0, 128.7, 126.7, 124.8, 119.7, 119.0, 116.5, 115.5, 114.3,
55.4, 47.3, 33.2; IR (KBr) νmax 3461 (br, NH),1647, 1601; mass
(ES+) m/z 370 (M+ + 1).
2-(4-Methoxybenzyl)-4-phenyl-1H-imidazole (1a): 24%;
1
pale yellow solid, mp 148-150 °C; H NMR (300 MHz, CDCl3,
25 °C) δ 7.67 (d, 2H, J ) 7.5 Hz, ArH), 7.36 (t, 2H, J ) 7.5 Hz,
(8) Liiberatore, A.-M.; Schulz, J.; Pommier, J.; Barthelemy, M.-A.;
Huchet, M.; Chabrier, P.-E.; Bigg, D. Bioorg. Med. Chem. Lett. 2004,
14, 3521-3523.
General Procedure for Pictet-Spengler Reaction 4. A
mixture of imidazole-linked amine 3a (0.1 g, 0.27 mmol),
J. Org. Chem, Vol. 70, No. 12, 2005 4891

p-ethoxybenzaldehyde (0.40 g, 0.27 mmol), and p-tolylsulfonic
acid (0.005 g, 0.02 mmol) was refluxed in toluene for 16 h.
Toluene was evaporated in vacuo, and the residue so obtained
was dissolved in ethyl acetate (25 mL). The organic layer was
washed with water (2 × 10 mL) and brine solution (1 × 10 mL).
The organic layers were combined and dried over anhydrous Na2-
SO4 and evaporated to obtained yellow residue that after column
chromatography on silica gel with hexane/EtOAc (40:60, v/v) as
eluent afforded 0.11 g (81%) of 4a(i) as white solid.
10-(4-Ethoxyphenyl)-3-(4-methoxybenzyl)-1-phenyl-9,10-
dihydro-4H-2,3a,9-triazabenzo[f]azulene [4a(i)]: 81%; white
solid; mp 190-192 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 7.66
(d, 2H, J ) 7.2 Hz, ArH), 7.38 (t, 2H, J ) 7.2 Hz, ArH), 7.30-
7.23 [m (o), 3H, ArH], 7.04-6.99 [t (o), 3H, J ) 8.4 Hz, ArH),
6.82 (d, 2H, J ) 8.7 Hz, ArH), 6.75 (d, 2H, J ) 8.4 Hz, ArH),
6.60 (d, 1H, J ) 7.8 Hz, ArH), 6.44 (t, 1H, J ) 7.5 Hz, ArH),
6.32 (d, 1H, J ) 6.9 Hz, ArH), 5.95 (d, 1H, J ) 6.6 Hz, CH), 4.86
(brd, 1H, J ) 7.2 Hz, NH), 4.55 (d, 1H, J ) 15.3 Hz, CH2), 4.32
(d, 1H, J ) 15.6 Hz, CH2), 4.14 (q, 2H, J ) 6.3 Hz, CH2), 3.98
(q, 2H, J ) 6.9 Hz, CH2), 3.75 (s, 3H, OCH3), 1.38 (t, 3H, J )
6.0 Hz, CH2); 13C NMR (75 MHz, CDCl3, 25 °C) δ 158.4, 158.2,
145.4, 145.2, 137.2, 134.8, 134.6, 129.9, 129.4, 129.2, 129.0, 128.6,
127.5, 127.1, 126.8, 118.1, 117.3, 114.9, 114.2, 63.5, 55.3, 51.5,
48.0, 33.0, 14.8; IR (KBr) νmax 3431 (br, NH), 1597. Anal. Calcd
for C33H31N3O2: C, 79.01; H, 6.23; N, 8.31. Found: C, 79.14; H,
6.32; N, 8.39.
3-(4-Methoxybenzyl)-10-(4-nitrophenyl)-1-phenyl-9,10-
dihydro-4H-2,3a,9-triazabenzo[f]azulene [4a(ii)]: 85%; yel-
low solid; mp 165-167 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ
8.15 (d, 2H, J ) 8.7 Hz, ArH), 7.64 (d, 2H, J ) 7.2 Hz, ArH),
7.53 (d, 2H, J ) 8.7 Hz, ArH), 7.41 (t, 2H, J ) 6.9 Hz, ArH),
7.32 (d, 1H, J ) 7.2 Hz, ArH), 7.11-7.00 [m (o), 3H, ArH], 6.76
(d, 2H, J ) 8.4 Hz, ArH), 6.66 (d, 1H, J ) 7.8 Hz, ArH), 6.50 (t,
1H, J ) 7.5 Hz, ArH), 6.31 (d, 1H, J ) 6.6 Hz, ArH), 6.05 (s,
1H, CH), 4.86 (brd, 1H, NH), 4.39 (s, 2H, CH2), 4.17 (q, 2H, J )
15.0 Hz, CH2), 3.76 (s, 3H, OCH3); 13C NMR (50 MHz, CDCl3,
25 °C) δ 158.9, 150.8, 147.6, 146.5, 144.9, 138.0, 134.4, 130.4,
129.7, 129.5, 129.2, 127.9, 127.8, 127.6, 126.2, 124.5, 118.5, 118.2,
118.0, 114.6, 55.7, 52.4, 48.3, 33.1; IR (KBr) νmax 3406 (br, NH)
1603, 1513, 1347 (NO2). Anal. Calcd for C31H26N4O3: C, 74.09;
H, 5.21; N, 11.15. Found: C, 73.92; H, 5.33; N, 11.15.
) 6.3 Hz, ArH), 7.47-7.40 [m (o), 3H, ArH], 7.30 (s, 4H, ArH),
7.14(t, 1H, J ) 7.5 Hz, ArH), 6.88 (d, 1H, J ) 7.2 Hz, ArH),
6.74-6.67 [m (o), 2H, ArH], 5.75 (s, 1H, CH), 4.76 (s, 2H, CH2),
2.30 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3, 25 °C) δ 146.1,
145.4, 141.5, 134.0, 133.2, 130.0, 129.6, 129.4, 129.0, 128.9, 128.7,
128.5, 127.7, 127.0, 120.0, 118.7, 118.3, 52.7, 48.5, 29.6; IR (KBr)
νmax 3397 (br, NH), 1597. Anal. Calcd for C24H20ClN3: C, 74.70;
H, 5.22; N, 10.89. Found: C, 74.76; H, 5.19; N, 10.72.
N-[1-(4-Methoxyphenyl)-10-(4-nitrophenyl)-9,10-dihydro-
4H-2,3a,9-triazabenzo[f]azulen-3-ylmethyl]benzamide [4c-
(ii)]: 81%; yellow solid; mp 188-190 °C; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 8.52 (brt, 1H, NH), 8.17 (d, 2H, J ) 8.4 Hz,
ArH), 7.86 (d, 2H, J ) 7.5 Hz, ArH), 7.58 [d (o), 3H, J ) 8.4 Hz,
ArH], 7.48 (t, 1H, J ) 6.9 Hz, ArH), 7.41 [d (overlapped with
CDCl3), 2H, J ) 7.2 Hz, ArH], 7.02 (t, 1H, J ) 7.5 Hz, ArH),
6.93 [t (o), 3H, J ) 8.7 Hz, ArH], 6.74 (d, 1H, J ) 8.1 Hz, ArH),
6.51 (d, 1H, J ) 7.8 Hz, ArH), 6.41 (t, 1H, J ) 7.2 Hz, ArH),
6.03 (d, 1H, J ) 6.9 Hz, CH), 5.05-4.98 [m (o), 2H, CH2], 4.66-
4.52 [m (o), 2H, CH2], 3.82 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 166.5, 158.5, 150.0, 146.5, 144.5, 142.9, 135.8,
133.1, 130.9, 129.6, 128.7, 128.0, 127.6, 126.9, 126.6, 125.9, 125.0,
123.4, 116.9, 116.4, 113.6, 54.6, 50.8, 47.0, 34.8; IR (KBr) νmax
3404 (br, NH), 1647 (CONH), 1698, 1520, 1348 (NO2). Anal.
Calcd for C32H27N5O4: C, 70.45; H, 4.99; N, 12.84. Found: C,
70.44; H, 4.95; N, 12.85.
N-[1-(4-Methoxyphenyl)-10-p-tolyl-9,10-dihydro-4H-2,-
3a,9-triazabenzo[f]azulen-3-ylmethyl]benzamide [4c(v)]:
1
77%; white solid; mp 146-147 °C; H NMR (300 MHz, CDCl3,
25 °C) δ 7.74 (d, 2H, J ) 7.2 Hz, ArH), 7.51 (d, 2H, J ) 8.7 Hz,
ArH), 7.46 (d, 1H, J ) 7.2 Hz, ArH), 7.37 (t, 2H, J ) 7.5 Hz,
ArH), 7.25 [t (overlapped with CDCl3), 2H, ArH], 7.15-7.02 [m
(o), 4H, ArH, NH], 6.95 (d, 1H, J ) 6.9 Hz, ArH), 6.90 (d, 2H, J
) 6.9 Hz, ArH), 6.64 (d, 1H, J ) 7.8 Hz, ArH), 6.50 (t, 1H, J )
7.5 Hz, ArH), 5.93 (d, 1H, J ) 7.2 Hz, CH), 4.98-4.63 [m (o),
5H, 2xCH2, NH], 3.81 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3, 25 °C) δ 167.4, 159.3, 145.5, 143.0, 139.9, 137.6,
137.5, 134.2, 131.9, 130.6, 130.1, 129.6, 129.0, 128.8, 127.9, 127.5,
127.2, 126.2, 118.3, 118.1, 117.7, 114.5, 55.7, 52.1, 48.1, 36.3,
21.3; IR (KBr) νmax 3406 (br, NH), 1648 (CONH), 1605, 1490.
Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89. Found:
C, 77.15; H, 5.82; N, 10.73.
1-Methyl-3,10-diphenyl-9,10-dihydro-4H-2,3a,9-triaza-
benzo[f]azulene [4b(iii)]: 79%; white solid; mp 225-228 °C;
1H NMR (300 MHz, CDCl3, 25 °C) δ 7.52 (d, 2H, J ) 6.3 Hz,
ArH), 7.47-7.24 [m (o), 8H, ArH], 7.14 (t, 1H, J ) 8.1 Hz, ArH),
6.89 (d, 1H, J ) 7.2 Hz, ArH), 6.79-6.66 [m (o), 2H, ArH], 4.83
(s, 1H, CH), 4.78 (s, 2H, CH2), 2.28 (s, 3H, CH3); 13C NMR (75
MHz, CDCl3, 25 °C) δ 146.2, 143.4, 134.1, 130.5, 130.1, 129.7,
129.4, 129.2, 129.1, 128.9, 128.1, 127.7, 126.6, 125.5, 119.8, 118.6,
118.4, 53.2, 48.9, 12.9; IR (KBr) νmax 3474 (br, NH), 1597. Anal.
Calcd for C24H21N3: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.12;
H, 5.89; N, 11.99.
Acknowledgment. D.S. is thankful to CSIR, New
Delhi, for providing a fellowship.
Supporting Information Available: 1H NMR spectra of
compounds 1a, 4a(i)-(v), 4b(i)-(v), and 4c(i)-(v). 13C NMR
spectra of compounds 1a, 4a(i)-(v), 4b(i)-(v), and 4c(i)-
(v). 2-D HSQC NMR spectra of compounds 4a(i) and 4c(ii).
DEPT spectra of compounds 4a(i), 4c(ii), and 4c(iii). LC-
MS profiles of compounds 4a(ii), 4b(iv), and 4c(iii). This
material is available free of charge via the Internet at
http://pubs.acs.org.
10-(4-Chlorophenyl)-1-methyl-3-phenyl-9,10-dihydro-4H-
2,3a,9-triazabenzo[f]azulene [4b(iv)]: 75%; yellow solid; mp
205-207 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 7.52 (d, 2H, J
JO050384H
4892 J. Org. Chem., Vol. 70, No. 12, 2005