Synthesis of diverse fused pyrazoles through palladium-mediated heteroarylation of heteroarene C-H bonds

Article abstract of DOI:10.1002/ejoc.201200401

A facile and efficient synthesis of new fused pyrazoles through the Pd(OAc)₂-mediated heteroarylation of heteroarene C-H bonds in Morita-Baylis-Hillman derivatives of 4-iodopyrazolecarbaldehydes is described.

Full text of DOI:10.1002/ejoc.201200401

FULL PAPER
DOI: 10.1002/ejoc.201200401
Synthesis of Diverse Fused Pyrazoles through Palladium-Mediated
Heteroarylation of Heteroarene C–H Bonds[‡]
Maloy Nayak[a] and Sanjay Batra*[a]
Keywords: Palladium / Nitrogen heterocycles / Heteroarylation / Morita–Baylis–Hillman / Synthetic methods
A facile and efficient synthesis of new fused pyrazoles
through the Pd(OAc)2-mediated heteroarylation of heteroar-
ene C–H bonds in Morita–Baylis–Hillman derivatives of 4-
iodopyrazolecarbaldehydes is described.
tion of our work, we envisaged that palladium-promoted
intramolecular heteroarylation of MBH derivatives of 4-
iodopyrazolecarbaldehydes would not only allow access to
several unknown fused pyrazole systems but would also en-
hance the scope of the intramolecular heteroarylation strat-
egy (Figure 1). A literature survey revealed that Kim et al.
have successfully accomplished the synthesis of diverse
Introduction
Transition-metal-catalyzed direct (hetero)arylation of
heteroarene C–H bonds in an intramolecular fashion repre-
sents a powerful tool for the construction of a variety of
fused-ring heteroarenes.[1] As described by Lautens et al.,
direct arylation of heteroarenes could be achieved through
either electrophilic substitution reactions, Heck-type reac-
tions or cross-coupling reactions.[1a] Although there are sev-
eral procedures for the intramolecular direct arylation of
heteroarenes, frequently the tether approach is adopted, be-
cause it is considered to be robust and proceeds with great
regioselective control owing to the limited degree of free-
dom. Analysis of reported examples reveals that the use of
halogenated benzene as the coupling partner in these reac-
tions is common, whereas there are fewer examples illustrat-
ing the participation of halogenated heteroarenes. It is
widely reported that halogenated pyrazoles are excellent
building blocks for accessing new chemical entities in-
corporating a pyrazole nucleus.[2] As part of one of our re-
search programs, we have also established 4-iodopyrazole
derivatives to be convenient starting substrates for prepar-
ing diverse fused-pyrazoles. We have successfully demon-
strated that the cross-coupling reactions of 4-iodopyrazole-
carbaldehydes or their Morita–Baylis–Hillman (MBH) de-
rivatives under different conditions results in the synthesis
of pyrazolo[4,3-b]pyridin-5-ones, pyrazolo[4,3-b]pyridines,
pyrazolo-fused benzodiazepines and benzoxazepines,
pyrazolo[4,3-d]pyrimidines and pyrazolo[4,3-d]pyrimidin-
7(6H)-ones.[3] Fused pyrazoles are of great significance in
medicinal chemistry, because compounds bearing such
cores display a variety of biological activities.[4] In continua-
Figure 1. Retrosynthetic analysis for the synthesis of fused pyr-
azoles.
[‡] CDRI Communication No. 8525
[a] Medicinal and Process Chemistry Division, CSIR – Central
Drug Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405, -2623938
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200401.
Figure 2. Different heteroarylation strategies. TBAB = tetrabut-
ylammonium bromide.
Eur. J. Org. Chem. 2012, 3677–3683
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3677

M. Nayak, S. Batra
FULL PAPER
benzazepines by using a similar protocol under ligandless
conditions, whereas Ila and co-workers have reported the
synthesis of fused pyrazoles through intramolecular Heck
heteroarylation of 1,3-disubstituted 5-(2-bromoanilino)pyr-
azole (Figure 2).[5,6] In both the studies 2-bromobenzene
was tethered to the heterosystem, and ligandless conditions
were employed. We decided to proceed to investigate the
utility of iodopyrazoles for this methodology. Herein, we
disclose a facile efficient synthesis of new fused pyrazole
derivatives employing intramolecular palladium-mediated
direct arylation of pyrrole, indole and imidazole nuclei
on derivatives generated from MBH adducts of 4-iodo-
pyrazolecarbaldehydes.
Results and Discussion
In the first phase of the study we investigated the strategy
with the heteroarylation of allylpyrroles that can be readily
prepared from primary allylamines. We commenced our
studies with the stereoselective synthesis of primary allyl-
amines 2a–i from MBH acetates 1a–i of 4-iodo-3-pyrazole-
carbaldehydes according to the reported procedure.[3c] Be-
cause (E) stereochemistry on the substrates is required for
the anticipated intramolecular heteroarylation, we per-
formed the studies with derivatives generated from acrylates
only. Treatment of these primary allylamines 2a–i with 2,5-
dimethoxytetrahydrofuran and AcOH/H2O in CH2Cl2 at
65 °C for 4–5 h afforded allyl pyrroles 3a–i in 67–73% yields
stereoselectively as (E) isomers (Scheme 1). It is worthwhile
to note that direct reaction of pyrrole with MBH acetate
leads to allylpyrrole in minor yield only.[7] With the required
compounds for the palladium-mediated reactions in hand,
we carried out an optimization study to determine suitable
conditions for the intramolecular arylation reaction
(Table 1). We screened the reaction of 3a as the model sub-
strate under different conditions for intramolecular het-
eroarylation. Initially, the reaction of 3a was performed
with Pd(OAc)2 (10 mol-%) and K2CO3 (2 equiv.) in N,N-
dimethylformamide (DMF) at 90 °C for 12 h (Table 1, En-
try 1), which successfully resulted in the isolation of the de-
sired methyl 1,2-diphenyl-2,6-dihydropyrazolo[4,3-c]pyr-
rolo[1,2-a]azepine-5-carboxylate (5a) in 37% yield. Next,
PPh3 (20 mol-%) was added as the ligand, and the reaction
was carried out under similar conditions. In the presence of
PPh3, the reaction was complete in 2 h, and the yield of 5a
increased to 93% (Table 1, Entry 2). To investigate the effect
Scheme 1. Reagents and conditions: (i) NH3/MeOH, room temp.,
30 min. (ii) 2,5-Dimethoxytetrahydrofuran (1.5 equiv.), AcOH,
H2O, CH2Cl2, 60 °C, 4–5 h. (iii) Imidazole (1.2 equiv.), K2CO3
(1.5 equiv.), DMF, room temp., 3 h. (iv) Indole (1.2 equiv.), KOH
(1.5 equiv.), DMF, 0 °C, 6–8 h. (v) Pd(OAc)2 (0.1 equiv.), PPh3
(0.2 equiv.), K2CO3 (2.0 equiv.), 90 °C, 2 h.
Table 1. Results of the optimization study for the heteroarylation
of allylpyrrole.[a]
Entry Ligand
Base
Solvent Temp. Time Yield[b]
[°C]
[h]
[%]
1
2
3
4
5
6
7
8
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NEt3
DMF
DMF
DMSO
MeCN
toluene
DMF
90
90
90
80
90
90
90
90
2
2
2
4
3
2
4
3
37
93
78
56
34
67
72
57
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
DMF
DMF
NaOH
[a] Reactions were performed with Pd(OAc)2 (0.1 equiv.), PPh3
of solvent, we performed the reaction in DMF, dimethyl (0.2 equiv.), K2CO3 (2.0 equiv.). [b] Isolated yields after column
chromatography.
sulfoxide (DMSO), acetonitrile (MeCN) and toluene and
found that DMF was the most effective medium (Table 1,
Entries 2–5). Amongst the different bases, K2CO3 per-
formed the best, although the other bases were also success- the diversity of the fused pyrazoles that could be obtained
ful, albeit in lower yields (Table 1, Entries 5–8). by using this method. Allylimidazoles 4a,b and allyl indoles
With a successful protocol in hand, we wanted to expand
The generality of the reaction sequence was investigated 7a–c,g were prepared from MBH acetates by using reported
with other allylpyrrole derivatives 3b–i (Table 2, Entries 1– procedures (Scheme 1).[8] Treatment of these substrates with
9) prepared by making changes at position 1 and 5 of the Pd(OAc)2 in the presence of ligand and base afforded the
pyrazole nucleus. Under the optimized conditions all sub- corresponding fused pyrazoles 6a–b and 8a–c,g in excellent
strates reacted efficiently to furnish respective products 5b– yields (Table 2, Entries 10–15). Theoretically, two isomeric
i in excellent yields.
cyclization products may arise from the coupling reaction
3678
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3677–3683

Fused Pyrazoles through Heteroarylation of Heteroarene C–H Bonds
Table 2. Scope of heteroarylation[a] of the substrates derived from by activation of either the C–H bond at C-2 of the imid-
MBH acetates of 4-iodopyrazole-3-carbaldehydes.
azole or the C–H bond at C-5. Interestingly, the reaction
was regioselective for C-2, which was confirmed by the ab-
sence of a signal in the 1H NMR spectrum at δ = 8.70 ppm
(in 6a from 4a) attributed to the proton at the C-2 posi-
tion.[9]
To further extend the scope of the protocol, starting all-
ylpyrroles 11a–c and allyl indoles 13a–b were prepared from
the MBH acetates 9a–c of 4-iodo-5-pyrazolecarbaldehydes
(Scheme 2). Treatment of 11a–c and 13a–b with Pd(OAc)2
and PPh3 in the presence of base in DMF under similar
conditions resulted in 12a–c and 14a–b in 86–89% yields,
respectively (Table 3).
Scheme 2. Reagents and conditions: (i) NH3/MeOH, room temp.,
30 min. (ii) 2,5-Dimethoxytetrahydrofuran (1.5 equiv.), AcOH,
H2O, CH2Cl2, 60 °C, 4–5 h. (iii) Indole (1.2 equiv.), KOH
(1.5 equiv.), DMF, 0 °C, 6–8 h. (iv) Pd(OAc)2 (0.1 equiv.), PPh3
(0.2 equiv.), K2CO3 (2.0 equiv.), 90 °C, 2.
Conclusion
We have demonstrated the use of MBH derivatives of 4-
iodopyrazolecarbaldehydes for the synthesis of new fused
pyrazoles through heteroarylation of heteroarene C–H
bonds. The protocol is attractive, because it works with a
wide variety of substrates and does not require any special
conditions. Excellent yields of the annulated pyrazoles are
an important feature of this protocol. More work showcas-
ing the utility of the halogenated pyrazoles for the synthesis
of different fused pyrazoles through transition-metal-based
reactions is underway in our laboratory, which will be re-
ported soon.
Experimental Section
[a] Reactions were performed with Pd(OAc)2 (0.1 equiv.), PPh3
General: Melting points were determined in capillary tubes with a
Precision melting point apparatus containing silicon oil. IR spectra
(0.2 equiv.), K2CO3 (2.0 equiv.), 90 °C, 2 h. [b] Isolated yields after
column chromatography.
Eur. J. Org. Chem. 2012, 3677–3683
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3679

M. Nayak, S. Batra
FULL PAPER
Table 3. Scope of heteroarylation[a] of the substrates derived from
MBH acetates of 4-iodopyrazole-5-carbaldehydes.
ArH), 7.22–7.30 (m, 7 H, ArH), 7.39–7.41 (m, 3 H, ArH), 7.73 (s,
1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 45.0, 52.4, 71.2,
107.5, 121.6, 124.6, 128.1, 128.7, 129.0, 129.4, 130.2, 130.3, 131.3,
139.6, 144.8, 148.2, 167.6 ppm. MS (ES+): m/z = 509.9 [M+ + 1].
HRMS: calcd. for C24H21IN3O2 [MH]+ 510.0678; found 510.0675.
Methyl (E)-3-(4-Iodo-1,3-diphenyl-1H-pyrazol-5-yl)-2-(1H-pyrrol-1-
ylmethyl)prop-2-enoate (11a): 71% as a colorless oil (197 mg from
250 mg). R = 0.61 (hexanes/EtOAc, 90:10, v/v). IR (neat): ν
=
˜
f
max
1722 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3
H, CO2Me), 4.76 (s, 2 H, CH2), 6.03 (t, J = 2.0 Hz, 2 H, ArH),
6.43 (t, J = 1.9 Hz, 2 H, ArH), 7.38–7.49 (m, 9 H, ArH and =CH),
7.92–7.94 (m, 2 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
47.0, 53.1, 65.3, 109.0, 121.5, 124.1, 128.8, 128.88, 128.94, 129.3,
129.9, 130.5, 132.5, 135.6, 140.0, 140.2, 154.2, 166.3 ppm. MS
(ES+): m/z = 510.0 [M+ + 1]. HRMS: calcd. for C24H21IN3O2
[MH]+ 510.0678; found 510.0688.
1
General Procedure for the Synthesis of Compounds 4a–b as Exem-
plified for 4a: To a stirred solution of compound 1a (500 mg,
0.99 mmol) in DMF (5 mL), imidazole (81 mg, 1.20 mmol) and
K2CO3 (206 mg, 1.49 mmol) were added at room temperature, and
the reaction was continued for 3 h. Thereafter, ethyl acetate
(20 mL) and water (20 mL) were added, and the layers were sepa-
rated. The aqueous layer was further extracted with ethyl acetate
(2ϫ15 mL), the organic layers were combined, washed with brine
(20 mL), dried with anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography of the crude product on silica
gel (hexanes/EtOAc, 50:50) afforded pure 4a as a white solid
(432 mg, 85%).
Methyl (E)-2-[(1H-Imidazol-1-yl)methyl]-3-(4-iodo-1,5-diphenyl-1H-
pyrazol-3-yl)prop-2-enoate (4a): 85% as a white solid (432 mg from
500 mg). M.p. 210–212 °C. Rf = 0.40 (hexanes/EtOAc, 50:50, v/v).
IR (KBr): ν
= 1714 (CO2Me) cm–1. 1H NMR (300 MHz,
˜
max
CDCl3): δ = 3.93 (s, 3 H, CO2Me), 5.66 (s, 2 H, CH2), 7.21–7.28
(m, 5 H, ArH), 7.37–7.42 (m, 6 H, ArH), 7.49 (s, 1 H, ArH), 7.92 (s,
1 H, =CH), 8.70 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 45.7, 53.2, 71.7, 119.8, 121.8, 124.9, 125.2, 128.7, 128.9, 129.1,
129.7, 129.8, 130.3, 134.6, 134.9, 139.2, 146.2, 147.4, 166.7 ppm.
MS (ES+): m/z = 511.0 [M+ + 1]. HRMS: calcd. for C23H20IN4O2
[MH]+ 511.0631; found 511.0643.
[a] Reactions were performed with Pd(OAc)2 (0.1 equiv.), PPh3
(0.2 equiv.), K2CO3 (2.0 equiv.), 90 °C, 2 h. [b] Isolated yields after
column chromatography.
were recorded with a Perkin–Elmer’s RX I FTIR spectrophotome-
1
ter. H and 13C NMR spectra were recorded either with a Bruker
General Procedure for the Synthesis of Compounds 7a–c,g and 13a,b
as Exemplified for 7a: To a stirred solution of compound 1a
(500 mg, 0.99 mmol) in DMF (5 mL), indole (140 mg, 1.20 mmol)
and KOH (84 mg, 1.49 mmol) were added, and the reaction was
allowed to continue at room temperature for 6 h. After completion
of the reaction, ethyl acetate (20 mL) and water (20 mL) were
added, and the layers were separated. The aqueous layer was fur-
ther extracted with ethyl acetate (2ϫ15 mL). The organic layers
were combined, washed with brine (20 mL), dried with anhydrous
Na2SO4 and concentrated under vacuum. Column chromatography
of the crude product on silica gel (hexanes/EtOAc, 5:95) furnished
pure 7a as a white solid (418 mg, 75%).
DPX-200 or a Bruker Avance DRX-300 FT spectrometer with
TMS as an internal standard. ESMS data were recorded with a
MICROMASS Quadro-II LCMS system. HRMS data were re-
corded as EI-HRMS with an Agilent 6520 Q-TOF, LC-MS/MS
mass spectrometer.
General Procedure for the Synthesis of Compounds 3a–i and 11a–
c as Exemplified for 3a: To a solution of compound 2a (250 mg,
0.54 mmol) in CH2Cl2 (10 mL), 2,5-dimethoxytetrahydrofuran
(0.084 mL, 0.65 mmol), AcOH (2 mL) and water (3 mL) were
added simultaneously, and the reaction mixture was heated at 60 °C
for 4 h. The reaction mixture was then diluted with water (20 mL),
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2ϫ15 mL), the organic layers were combined and
washed with brine (20 mL), dried with anhydrous Na2SO4 and con-
centrated under vacuum. Column chromatography of the crude
product on silica gel (hexanes/EtOAc, 5:95) furnished pure 3a as a
white solid (202 mg, 73%).
Methyl
(E)-2-[(1H-Indol-1-yl)methyl]-3-(4-iodo-1,5-diphenyl-1H-
pyrazol-3-yl)prop-2-enoate (7a): M.p. 178–180 °C. Rf = 0.49 (hex-
anes/EtOAc, 90:10, v/v). IR (KBr): νmax = 1716 (CO2Me) cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, CO2Me), 5.77 (s, 2 H,
CH2), 6.45 (d, J = 2.6 Hz, 1 H, ArH), 7.03–7.18 (m, 4 H, ArH),
7.24–7.26 (m, 3 H, ArH), 7.29–7.32 (m, 2 H, ArH), 7.37–7.42 (m,
4 H, ArH), 7.50 (d, J = 7.7 Hz, 1 H, ArH), 7.59 (d, J = 7.4 Hz, 1
Methyl (E)-3-(4-Iodo-1,5-diphenyl-1H-pyrazol-3-yl)-2-(1H-pyrrol-1-
ylmethyl)prop-2-enoate (3a): M.p. 159–160 °C. Rf = 0.56 (hexanes/ H, ArH), 7.78 (s, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ
EtOAc, 90:10, v/v). IR (KBr): ν
= 1710 (CO2Me) cm–1. 1H
= 42.7, 52.5, 71.2, 101.1, 110.6, 119.2, 120.7, 121.3, 124.7, 128.2,
128.6, 128.8, 129.1, 129.2, 129.5, 129.6, 130.0, 130.1, 130.4, 131.5,
˜
max
NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H, CO2Me), 5.52 (s, 2 H,
CH2), 6.08 (t, J = 1.9 Hz, 2 H, ArH), 6.94 (t, J = 1.9 Hz, 2 H, 136.7, 139.6, 145.0, 148.4, 167.7 ppm. MS (ES+): m/z = 560.0 [M+
3680
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3677–3683

Fused Pyrazoles through Heteroarylation of Heteroarene C–H Bonds
+ 1]. HRMS: calcd. for C28H23IN3O2 [MH]+ 560.0835; found
560.0833.
166.4 ppm. MS (ES+): m/z = 416.2 [M+ + 1]. HRMS: calcd. for
C24H19ClN3O2 [MH]+ 416.1166; found 416.1169.
Methyl (E)-2-[(1H-Indol-1-yl)methyl]-3-(4-iodo-1,3-diphenyl-1H-
pyrazol-5-yl)prop-2-enoate (13a): 71% as a white solid (198 mg from
250 mg). M.p. 172–174 °C. Rf = 0.48 (hexanes/EtOAc, 90:10, v/v).
Methyl 1-(4-Fluorophenyl)-2-phenyl-2,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylate (5d): 89 % as a yellow solid
(135 mg from 200 mg). M.p. 215–216 °C. Rf = 0.39 (hexanes/
1
IR (KBr): ν
= 1712 (CO2Me) cm–1
.
1H NMR (300 MHz, EtOAc, 80:20, v/v). IR (KBr): ν
= 1711 (CO2Me) cm–1. H
˜
˜
max
max
CDCl3): δ = 3.73 (s, 3 H, CO2Me), 5.35 (s, 2 H, CH2), 6.50 (s, 1
H, ArH), 7.15–7.20 (m, 3 H, ArH), 7.30–7.36 (m, 5 H, ArH), 7.51
NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, CO2Me), 4.96 (s, 2 H,
CH2), 5.57 (dd, J1 = 1.5, J2 = 3.5 Hz, 1 H, ArH), 6.03 (t, J =
(s, 4 H, ArH), 7.65 (d, J = 7.3 Hz, 1 H, ArH), 7.72 (s, 3 H, =CH 3.1 Hz, 1 H, ArH), 6.69 (s, 1 H, ArH), 7.06 (t, J = 8.6 Hz, 2 H,
and ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.7, 52.7, 70.3,
ArH), 7.27–7.32 (s, 7 H, ArH), 8.02 (s, 1 H, =CH) ppm. 13C NMR
102.1, 109.7, 119.9, 121.3, 122.1, 125.4, 125.9, 127.3, 128.3, 128.6,
(50 MHz, CDCl3): δ = 44.9, 52.6, 107.3, 108.5, 116.1, 116.5, 117.1,
128.7, 128.9, 129.6, 130.4, 132.2, 136.3, 137.3, 139.2, 152.7, 122.1, 125.2, 125.5, 125.9, 128.2, 128.6, 129.1, 132.5, 132.6, 135.6,
167.0 ppm. MS (ES+): m/z = 560.0 [M+ + 1]. HRMS: calcd. for
138.4, 139.3, 145.2, 160.7, 166.4 ppm. MS (ES+): m/z = 400.3 [M+
+ 1]. HRMS: calcd. for C24H19FN3O2 [MH]+ 400.1461; found
400.1446.
C28H23IN3O2 [MH]+ 560.0835; found 560.0845.
General Procedure for the Synthesis of Compounds 5a–i, 6a,b, 8a–
c,g, 12a–c and 14a,b as Exemplified for 5a: To a solution of com-
pound 3a (250 mg, 0.49 mmol) in DMF (4 mL), Pd(OAc)2 (11 mg,
Methyl 1-(4-Methoxyphenyl)-2-phenyl-2,6-dihydropyrazolo[4,3-
c]pyrrolo[1,2-a]azepine-5-carboxylate (5e): 90% as a yellow solid
0.059 mmol), PPh3 (26 mg, 0.098 mmol) and K2CO3 (136 mg, (172 mg from 250 mg). M.p. 157–158 °C. Rf = 0.40 (hexanes/
1
0.98 mmol) were added, and the reaction mixture was heated at
80 °C under nitrogen for 12 h. Thereafter, water (50 mL) and ethyl
acetate (25 mL) were added, and the reaction mixture was filtered
through a Celite pad, and the layers were separated. The aqueous
layer was further extracted with ethyl acetate (2ϫ20 mL), and the
combined organic layers were washed with brine (25 mL), dried
with anhydrous Na2SO4 and concentrated under vacuum. Column
chromatography of the crude product on silica gel (hexanes/EtOAc,
5:95) gave pure 5a as a yellow solid (174 mg, 93%).
EtOAc, 80:20, v/v). IR (KBr): ν
= 1712 (CO2Me) cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 3.86 (s, 3 H,
CO2Me), 4.96 (s, 2 H, CH2), 5.61 (d, J = 1.9 Hz, 1 H, ArH), 6.02
(t, J = 2.9 Hz, 1 H, ArH), 6.67 (s, 1 H, ArH), 6.87 (d, J = 8.6 Hz,
2 H, ArH), 7.21 (d, J = 8.6 Hz, 2 H, ArH), 7.31 (s, 5 H, ArH),
8.02 (s, 1 H, =CH) ppm. 13C NMR (50 MHz, CDCl3): δ = 45.0,
52.6, 55.4, 107.2, 108.4, 114.5, 116.9, 121.8, 122.0, 125.1, 126.0,
127.9, 128.3, 129.0, 131.9, 135.8, 139.4, 139.6, 145.1, 160.2,
166.5 ppm. MS (ES+): m/z = 412.3 [M+ + 1]. HRMS: calcd. for
C25H22N3O3 [MH]+ 412.1661; found 412.1655.
Methyl 1,2-Diphenyl-2,6-dihydropyrazolo[4,3-c]pyrrolo[1,2-a]-
azepine-5-carboxylate (5a): 93 % as a yellow solid (174 mg from
250 mg). M.p. 210–211 °C. Rf = 0.40 (hexanes/EtOAc, 80:20, v/v).
Methyl 1-(4-Nitrophenyl)-2-phenyl-2,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylat (5f): 89 % as a yellow solid
IR (KBr): ν
= 1707 (CO2Me) cm–1
.
1H NMR (300 MHz, (171 mg from 250 mg). M.p. 181–182 °C. Rf = 0.37 (hexanes/
˜
max
1
CDCl3): δ = 3.86 (s, 3 H, CO2Me), 4.97 (s, 2 H, CH2), 5.57 (d, J
EtOAc, 80:20, v/v). IR (KBr): ν
= 1707 (CO2Me) cm–1. H
˜
max
= 2.1 Hz, 1 H, ArH), 6.01 (t, J = 3.1 Hz, 1 H, ArH), 6.67 (s, 1 H, NMR (300 MHz, CDCl3): δ = 3.87 (s, 3 H, CO2Me), 4.98 (s, 2 H,
ArH), 7.30–7.37 (m, 10 H, ArH), 8.03 (s, 1 H, =CH) ppm. 13C CH2), 5.56 (dd, J1 = 1.5, J2 = 3.6 Hz, 1 H, ArH), 6.04 (dd, J1 =
NMR (75 MHz, CDCl3): δ = 44.9, 52.6, 107.3, 108.5, 117.0, 121.9,
2.8, J2 = 3.5 Hz, 1 H, ArH), 6.72 (t, J = 1.0 Hz, 1 H, ArH), 7.24–
125.1, 125.7, 127.9, 128.4, 128.96, 128.99, 129.1, 130.0, 130.6, 7.26 (m, 2 H, ArH), 7.35–7.37 (m, 3 H, ArH), 7.51 (d, J = 8.8 Hz,
135.7, 139.46, 139.51, 145.1, 166.4 ppm. MS (ES+): m/z = 382.1
[M+ + 1]. HRMS: calcd. for C24H20N3O2 [MH]+ 382.1556; found
382.1546.
2 H, ArH), 8.02 (s, 1 H, =CH), 8.20 (d, J = 8.8 Hz, 2 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 44.9, 52.7, 107.8, 108.8,
117.7, 122.5, 124.2, 124.7, 125.3, 128.7, 129.1, 129.4, 131.6, 135.1,
136.5, 136.8, 138.9, 145.6, 148.0, 166.2 ppm. MS (ES+): m/z =
427.3 [M+ + 1]. HRMS: calcd. for C24H19N4O4 [MH]+ 427.1406;
found 427.1396.
Methyl 1-(4-Methylphenyl)-2-phenyl-2,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylate (5b): 91 % as a yellow solid
(137 mg from 200 mg). M.p. 206–207 °C. Rf = 0.40 (hexanes/
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1707 (CO2Me) cm–1. H
Methyl 2-Methyl-1-phenyl-2,6-dihydropyrazolo[4,3-c]pyrrolo[1,2-
a]azepine-5-carboxylate (5g): 92% as a yellow solid (164 mg from
250 mg). M.p. 220–221 °C. Rf = 0.30 (hexanes/EtOAc, 80:20, v/v).
˜
max
NMR (300 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3), 3.86 (s, 3 H,
CO2Me), 4.96 (s, 2 H, CH2), 5.60 (dd, J1 = 1.6, J2 = 3.7 Hz, 1 H,
ArH), 6.02 (dd, J1 = 2.7, J2 = 3.7 Hz, 1 H, ArH), 6.67 (dd, J1 =
1.7, J2 = 2.4 Hz, 1 H, ArH), 7.13–7.20 (m, 4 H, ArH), 7.30 (s, 5
H, ArH), 8.03 (s, 1 H, =CH) ppm. 13C NMR (50 MHz, CDCl3): δ
= 21.4, 44.8, 52.4, 107.1, 108.3, 116.8, 121.7, 125.0, 125.7, 126.7,
IR (KBr): ν
= 1695 (CO2Me) cm–1 1H NMR (300 MHz,
.
˜
max
CDCl3): δ = 3.82 (s, 3 H, CO2Me), 3.85 (s, 3 H, NCH3), 4.89 (s, 2
H, CH2), 5.54 (dd, J1 = 1.5, J2 = 3.4 Hz, 1 H, ArH), 5.98 (t, J =
3.1 Hz, 1 H, ArH), 6.63 (s, 1 H, ArH), 7.42–7.44 (m, 2 H, ArH),
127.7, 128.2, 128.8, 129.5, 130.3, 135.6, 139.0, 139.5, 144.9, 7.49–7.50 (m, 3 H, ArH), 7.94 (s, 1 H, =CH) ppm. 13C NMR
166.3 ppm. MS (ES+): m/z = 396.3 [M+ + 1]. HRMS: calcd. for
(50 MHz, CDCl3): δ = 37.8, 44.9, 52.5, 106.5, 108.3, 115.9, 121.7,
126.2, 127.2, 129.2, 129.5, 129.8, 130.3, 135.8, 140.2, 143.3,
166.5 ppm. MS (ES+): m/z = 320.2 [M+ + 1]. HRMS: calcd. for
C19H18N3O2 [MH]+ 320.1399; found 320.1400.
C25H22N3O2 [MH]+ 396.1712; found 396.1706.
Methyl 1-(4-Chlorophenyl)-2-phenyl-2,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylate (5c): 90 % as a yellow solid
(172 mg from 250 mg). M.p. 185–186 °C. Rf = 0.41 (hexanes/ Methyl 2-Methyl-1-(4-methylphenyl)-2,6-dihydropyrazolo[4,3-c]-
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1705 (CO2Me) cm–1. H
pyrrolo[1,2-a]azepine-5-carboxylate (5h): 90 % as a yellow solid
˜
max
NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, CO2Me), 4.96 (s, 2 H,
CH2), 5.59 (d, J = 2.0 Hz, 1 H, ArH), 6.03 (t, J = 3.0 Hz, 1 H,
ArH), 6.69 (s, 1 H, ArH), 7.23–7.29 (m, 4 H, ArH), 7.32–7.35 (m,
(163 mg from 250 mg). M.p. 243–245 °C. Rf = 0.31 (hexanes/
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1698 (CO2Me) cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 3.80 (s, 3 H,
5 H, ArH), 8.01 (s, 1 H, =CH) ppm. 13C NMR (50 MHz, CDCl3): CO2Me), 3.84 (s, 3 H, NCH3), 4.88 (s, 2 H, CH2), 5.57 (t, J =
δ = 44.9, 52.6, 107.4, 108.6, 117.1, 122.1, 125.2, 125.3, 128.2, 128.4,
1.7 Hz, 1 H, ArH), 5.98 (t, J = 3.0 Hz, 1 H, ArH), 6.62 (s, 1 H,
128.6, 129.2, 129.4, 131.9, 135.3, 135.5, 138.1, 139.3, 145.3, ArH), 7.31 (s, 4 H, ArH), 7.93 (s, 1 H, =CH) ppm. 13C NMR
Eur. J. Org. Chem. 2012, 3677–3683
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3681

M. Nayak, S. Batra
FULL PAPER
(75 MHz, CDCl3): δ = 21.6, 37.7, 45.0, 52.5, 106.5, 108.3, 115.9,
121.6, 126.4, 126.9, 127.1, 129.9, 130.2, 135.9, 139.5, 140.3, 143.3,
166.5 ppm. MS (ES+): m/z = 334.3 [M+ + 1]. HRMS: calcd. for
C20H20N3O2 [MH]+ 334.1556; found 334.1558.
Methyl 1-(4-Chlorophenyl)-2-phenyl-2,6-dihydropyrazolo[4Ј,3Ј:3,4]-
azepino[1,2-a]indole-5-carboxylate (8c): 89 % as a yellow solid
(140 mg from 200 mg). M.p. 228–230 °C. Rf = 0.40 (hexanes/
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1696 (CO2Me) cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 3.90 (s, 3 H, CO2Me), 5.19 (s, 2 H,
CH2), 5.90 (s, 1 H, ArH), 7.05 (t, J = 7.4 Hz, 1 H, ArH), 7.21 (d,
J = 7.3 Hz, 1 H, ArH), 7.28–7.38 (m, 9 H, ArH), 7.42 (d, J =
7.9 Hz, 1 H, ArH), 7.59 (d, J = 8.2 Hz, 1 H, ArH), 8.06 (s, 1 H,
=CH) ppm. 13C NMR (50 MHz, CDCl3): δ = 40.3, 52.7, 99.7,
109.4, 116.4, 120.0, 120.5, 121.9, 125.3, 128.0, 128.4, 129.3, 129.5,
130.2, 132.0, 135.5, 135.6, 136.0, 139.1, 139.9, 146.2, 166.4 ppm.
MS (ES+): m/z = 466.3 [M+ + 1]. HRMS: calcd. for C28H21ClN3O2
[MH]+ 466.1322; found 466.1300.
Methyl 2-Methyl-2,6-dihydropyrazolo[4,3-c]pyrrolo[1,2-a]azepine-5-
carboxylate (5i): 91% as a yellow solid (119 mg from 200 mg). M.p.
100–102 °C. R = 0.29 (hexanes/EtOAc, 80:20, v/v). IR (KBr): ν
˜
f
max
= 1708 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 3.84 (s,
3 H, CO2Me), 3.99 (s, 3 H, NCH3), 4.83 (s, 2 H, CH2), 6.17–6.22
(m, 2 H, ArH), 6.69 (s, 1 H, ArH), 7.58 (s, 1 H, ArH), 7.91 (s, 1
H, =CH) ppm. 13C NMR (50 MHz, CDCl3): δ = 39.6, 44.9, 52.5,
105.8, 108.6, 118.2, 122.2, 126.1, 126.8, 127.1, 135.5, 143.9,
166.5 ppm. MS (ES+): m/z = 244.3 [M+ + 1]. HRMS: calcd. for
C13H14N3O2 [MH]+ 244.1086; found 244.1076.
1
Methyl 2-Methyl-1-phenyl-2,6-dihydropyrazolo[4Ј,3Ј:3,4]azepino-
[1,2-a]indole-5-carboxylate (8g): 91% as a yellow solid (135 mg
Methyl 9,10-Diphenyl-5,9-dihydroimidazo[1,2-a]pyrazolo[4,3-c]-
azepine-6-carboxylate (6a): 78 % as a yellow solid (146 mg from
250 mg). M.p. 178–180 °C. Rf = 0.28 (hexanes/EtOAc, 50:50, v/v).
from 200 mg). M.p. 195–196 °C. Rf = 0.32 (hexanes/EtOAc, 80:20,
1
v/v). IR (KBr): ν
= 1706 (CO2Me) cm–1. H NMR (300 MHz,
˜
max
CDCl3): δ = 3.87 (s, 3 H, NCH3), 3.88 (s, 3 H, CO2Me), 5.11 (s, 2
H, CH2), 5.83 (s, 1 H, ArH), 7.00 (t, J = 7.5 Hz, 1 H, ArH), 7.18
(t, J = 7.1 Hz, 1 H, ArH), 7.36 (d, J = 7.7 Hz, 1 H, ArH), 7.48–
7.55 (m, 6 H, ArH), 7.98 (s, 1 H, =CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 37.9, 40.4, 52.6, 98.9, 109.4, 115.3, 119.8, 120.3, 121.6,
128.5, 129.0, 129.4, 129.6, 129.8, 130.4, 132.8, 135.8, 136.1, 142.0,
144.4, 166.5 ppm. MS (ES+): m/z = 370.2 [M+ + 1]. HRMS: calcd.
for C23H20N3O2 [MH]+ 370.1556; found 370.1541.
IR (KBr): ν
= 1710 (CO2Me) cm–1 1H NMR (300 MHz,
.
˜
max
CDCl3): δ = 3.89 (s, 3 H, CO2Me), 5.03 (s, 2 H, CH2), 6.48 (s, 1
H, ArH), 7.26–7.48 (m, 11 H, ArH), 8.07 (s, 1 H, =CH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 42.6, 52.8, 113.7, 114.2, 125.0, 126.2,
127.4, 128.2, 129.1, 129.6, 129.9, 130.2, 135.9, 139.2, 139.4, 140.3,
144.6, 166.1 ppm. MS (ES+): m/z = 383.2 [M+ + 1]. HRMS: calcd.
for C23H19N4O2 [MH]+ 383.1508; found 383.1510.
Methyl 10-(4-Methylphenyl)-9-phenyl-5,9-dihydroimidazo[1,2-a]-
pyrazolo[4,3-c]azepine-6-carboxylate (6b): 80% as a yellow solid
Methyl 1,3-Diphenyl-3,6-dihydropyrazolo[4,3-c]pyrrolo[1,2-a]-
azepine-5-carboxylate (12a): 89% as a yellow solid (167 mg from
250 mg). M.p. 161–162 °C. Rf = 0.45 (hexanes/EtOAc, 80:20, v/v).
(151 mg from 250 mg). M.p. 160–161 °C. Rf = 0.27 (hexanes/
1
= 1708 (CO2Me) cm–1. H
IR (KBr): ν
= 1705 (CO2Me) cm–1 1H NMR (300 MHz,
.
EtOAc, 50:50, v/v). IR (KBr): ν
˜
max
˜
max
NMR (300 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 3.88 (s, 3 H,
CO2Me), 5.03 (s, 2 H, CH2), 6.49 (s, 1 H, ArH), 7.17 (s, 4 H, ArH),
7.32 (s, 5 H, ArH), 7.46 (s, 1 H, ArH), 8.06 (s, 1 H, =CH) ppm.
13C NMR (50 MHz, CDCl3): δ = 21.5, 42.6, 52.8, 113.7, 125.0,
125.4, 126.0, 126.3, 127.3, 128.1, 129.1, 129.9, 130.0, 136.0, 136.7,
139.3, 139.6, 140.4, 144.5, 166.1 ppm. MS (ES+): m/z = 397.2 [M+
+ 1]. HRMS: calcd. for C24H21N4O2 [MH]+ 397.1665; found
397.1653.
CDCl3): δ = 3.84 (s, 3 H, CO2Me), 5.02 (s, 2 H, CH2), 6.10 (d, J
= 2.0 Hz, 1 H, ArH), 6.17 (t, J = 3.0 Hz, 1 H, ArH), 6.75 (s, 1 H,
ArH), 7.43–7.47 (m, 4 H, ArH), 7.53–7.64 (m, 4 H, ArH), 7.70 (s, 1
H, =CH), 7.85 (d, J = 5.4 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 44.9, 52.7, 108.3, 109.1, 117.7, 121.5, 124.3, 125.7,
126.6, 128.1, 128.5, 128.9, 129.6, 129.9, 132.9, 134.0, 139.1, 150.0,
165.7 ppm. MS (ES+): m/z = 382.3 [M+ + 1]. HRMS: calcd. for
C24H20N3O2 [MH]+ 382.1556; found 382.1556.
Methyl 1,2-Diphenyl-2,6-dihydropyrazolo[4Ј,3Ј:3,4]azepino[1,2-a]-
indole-5-carboxylate (8a): 92 % as a yellow solid (142 mg from
200 mg). M.p. 200–201 °C. Rf = 0.41 (hexanes/EtOAc, 80:20, v/v).
Methyl 1-(4-Methylphenyl)-3-phenyl-3,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylate (12b): 88% as a yellow solid
(166 mg from 250 mg). M.p. 201–202 °C. Rf = 0.44 (hexanes/
IR (KBr): ν
= 1710 (CO2Me) cm–1 1H NMR (300 MHz,
.
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1714 (CO2Me) cm–1. H
˜
max
˜
max
CDCl3): δ = 3.90 (s, 3 H, CO2Me), 5.19 (s, 2 H, CH2), 5.87 (s, 1
H, ArH), 7.03 (t, J = 7.0 Hz, 1 H, ArH), 7.21 (t, J = 7.1 Hz, 1 H,
ArH), 7.33–7.36 (m, 11 H, ArH), 7.58 (d, J = 7.9 Hz, 1 H, ArH),
8.07 (s, 1 H, =CH) ppm. 13C NMR (50 MHz, CDCl3): δ = 40.3,
52.7, 99.7, 109.4, 119.9, 120.5, 121.8, 125.2, 128.2, 129.1, 129.5,
130.0, 130.6, 132.3, 135.1, 135.7, 136.0, 139.4, 141.3, 146.0,
166.5 ppm. MS (ES+): m/z = 432.3 [M+ + 1]. HRMS: calcd. for
C28H22N3O2 [MH]+ 432.1712; found 432.1711.
NMR (300 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3), 3.81 (s, 3 H,
CO2Me), 4.99 (s, 2 H, CH2), 6.10 (dd, J1 = 1.6, J2 = 3.7 Hz, 1 H,
ArH), 6.15 (t, J = 3.2 Hz, 1 H, ArH), 6.72 (t, J = 2.1 Hz, 1 H,
ArH), 7.23 (d, J = 8.0 Hz, 2 H, ArH), 7.42 (t, J = 7.2 Hz, 1 H,
ArH), 7.53 (t, J = 7.7 Hz, 2 H, ArH), 7.58–7.61 (m, 2 H, ArH),
7.67 (s, 1 H, =CH), 7.72 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.5, 44.9, 52.6, 108.2, 109.0, 117.6, 121.4,
124.3, 125.8, 126.5, 128.0, 128.7, 129.2, 129.6, 129.90, 129.94,
133.9, 138.4, 139.2, 150.0, 165.6 ppm. MS (ES+): m/z = 396.3 [M+
+ 1]. HRMS: calcd. for C25H22N3O2 [MH]+ 396.1712; found
396.1714.
Methyl 1-(4-Methylphenyl)-2-phenyl-2,6-dihydropyrazolo[4Ј,3Ј:3,4]-
azepino[1,2-a]indole-5-carboxylate (8b): 90 % as a yellow solid
(140 mg from 200 mg). M.p. 240–241 °C. Rf = 0.41 (hexanes/
1
EtOAc, 80:20, v/v). IR (KBr): ν
= 1704 (CO2Me) cm–1. H
Methyl 1-(4-Chlorophenyl)-3-phenyl-3,6-dihydropyrazolo[4,3-c]-
pyrrolo[1,2-a]azepine-5-carboxylate (12c): 87% as a yellow solid
˜
max
NMR (300 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 3.90 (s, 3 H,
CO2Me), 5.19 (s, 2 H, CH2), 5.91 (s, 1 H, ArH), 7.03 (t, J = 7.1 Hz,
1 H, ArH), 7.16–7.25 (m, 5 H, ArH), 7.33–7.41 (m, 6 H, ArH), EtOAc, 80:20, v/v). IR (KBr): ν
(166 mg from 250 mg). M.p. 150–151 °C. Rf = 0.44 (hexanes/
1
= 1708 (CO2Me) cm–1. H
˜
max
7.58 (d, J = 8.3 Hz, 1 H, ArH), 8.07 (s, 1 H, =CH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 21.7, 40.3, 52.7, 99.6, 109.4, 116.2, 119.8,
120.4, 121.7, 125.3, 126.5, 128.1, 128.5, 129.1, 129.9, 130.4, 132.5,
135.7, 136.0, 139.5, 141.5, 146.0, 166.5 ppm. MS (ES+): m/z =
NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, CO2Me), 4.99 (s, 2 H,
CH2), 6.09 (s, 1 H, ArH), 6.17 (s, 1 H, ArH), 6.73 (s, 1 H, ArH),
7.38–7.41 (m, 3 H, ArH), 7.54–7.57 (m, 4 H, ArH), 7.66 (s, 1 H,
=CH), 7.80 (d, J = 6.9 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz,
446.3 [M+ + 1]. HRMS: calcd. for C29H24N3O2 [MH]+ 446.1869; CDCl3): δ = 44.9, 52.8, 108.3, 109.2, 121.2, 121.7, 124.3, 125.4,
found 446.1869.
126.9, 128.3, 128.8, 129.7, 130.1, 131.4, 134.2, 134.5, 139.1, 148.7,
3682
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3677–3683

Fused Pyrazoles through Heteroarylation of Heteroarene C–H Bonds
165.6 ppm. MS (ES+): m/z = 416.2 [M+ + 1]. HRMS: calcd. for
[3] a) S. Nag, M. Nayak, S. Batra, Adv. Synth. Catal. 2009, 351,
2715–2723, and references cited therein; b) M. Nayak, S. Batra,
Adv. Synth. Catal. 2010, 352, 3431–3437; c) M. Nayak, N. Ras-
togi, S. Batra, Eur. J. Org. Chem. 2012, 1360–1366; d) M.
Nayak, S. Batra, RSC Adv. 2012, 2, 3367–3373.
C24H19ClN3O2 [MH]+ 416.1166; found 416.1167.
Methyl 1,3-Diphenyl-3,6-dihydropyrazolo[4Ј,3Ј:3,4]azepino[1,2-a]-
indole-5-carboxylate (14a): 87 % as a yellow solid (134 mg from
200 mg). M.p. 211–212 °C. Rf = 0.46 (hexanes/EtOAc, 80:20, v/v).
[4] a) L. Yet, in Comprehensive Heterocyclic Chemistry (Eds.: A. R.
Katrizky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor),
Pergamon, London, 2008, vol. 4, chapter 4.01, p. 1; b) J. El-
guero, P. Goya, N. Jagerovic, A. M. S. Silva, “Pyrazoles as
Drugs: Facts and Fantasies” in Targets in Heterocyclic Systems
(Eds.: O. A. Attanasi, D. Spinelli), Italian Society of Chemistry,
Roma, 2002, vol. 6, pp. 52–98; c) R. L. Dow, P. A. Carpino, D.
Gautreau, J. R. Hadcock, P. A. Iredale, D. Kelly-Sullivan, J. S.
Lizano, R. E. O’Connor, S. R. Schneider, D. O. Scott, K. M.
Ward, ACS Med. Chem. Lett. 2012, 3, 397–401; d) T. Reddy,
K. S. Kumar, C. L. T. Meda, A. Kandale, D. Rambabu, G.
Rama Krishna, C. Hariprasad, V. V. Rao, S. Venkataiah, C. M.
Reddy, A. Naidu, P. K. Dubey, K. V. L. Parsa, M. Pal, Bioorg.
Med. Chem. Lett. 2012, 22, 3248–3255; e) S. Bondock, W.
Khalifa, A. A. Fadda, Eur. J. Med. Chem. 2011, 46, 2555–2561;
f) M. S. Christodoulou, S. Liekens, K. M. Kasiotis, S. A. Har-
outounian, Bioorg. Med. Chem. 2010, 18, 4338–4350; g) S. Kor-
tagere, W. J. Welsh, J. M. Morrisey, T. Daly, I. Ejigiri, P. Sinnis,
A. B. Vaidya, L. W. Bergman, J. Chem. Inf. Model. 2010, 50,
840–849; h) M. Herdemann, I. Heit, F.-U. Bosch, G. Quintini,
C. Scheipers, A. Weber, Bioorg. Med. Chem. Lett. 2010, 20,
6998–7003; i) R. L. Dow, P. A. Carpino, J. R. Hadcock, S. C.
Black, P. A. Iredale, P. DaSilva-Jardine, S. R. Schneider, E. S.
Paight, D. A. Griffith, D. O. Scott, R. E. O’Connor, C. I.
Nduaka, J. Med. Chem. 2009, 52, 2652–2655; j) G. Ouyang,
X.-J. Cai, Z. Chen, B.-A. Song, P. S. Bhadury, S. Yang, L.-H.
Jin, W. Xue, D.-Y. Hu, S. Zeng, J. Agric. Food Chem. 2008, 56,
10160–10167; k) P. Giovanni, G. Luca, B. Francesca, T. Gior-
gio, M. Patrizia, G. Grazia, G. Fabrizio, C. Massimo, G. Or-
lando, C. Paolo, Org. Biomol. Chem. 2007, 5, 2567–2571; l)
T. V. Herk, J. Brussee, A. M. C. H. van den Nieuwendijk,
P. A. M. van der Klein, A. P. IJzerman, C. Stannek, A. Bur-
meister, A. Lorenzen, J. Med. Chem. 2003, 46, 3945–3951; m)
T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Cater, P. W.
Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha,
J. M. Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. An-
derson, E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Ko-
boldt, W. E. Perkins, K. Seibert, A. W. Vennhuizen, Y. Y.
Zhang, P. Isakson, J. Med. Chem. 1997, 40, 1347–1365; n)
N. K. Terret, A. S. Bell, D. Brown, P. Ellips, Bioorg. Med.
Chem. Lett. 1996, 6, 1819–1824; o) M. Rinaldi-Carmona, F.
Barth, M. Heaulme, D. Shire, B. Calandra, C. Congy, S. Marti-
nez, J. Maruani, G. Neliat, D. Caput, P. Ferrara, P. Soubrie,
J. C. Breliere, G. Le Fur, FEBS Lett. 1994, 350, 240–244; p)
H. A. De Wald, S. Lobbestael, B. P. H. Poschel, J. Med. Chem.
1981, 24, 982–987.
IR (KBr): ν
= 1705 (CO2Me) cm–1 1H NMR (300 MHz,
.
˜
max
CDCl3): δ = 3.85 (s, 3 H, CO2Me), 5.24 (s, 2 H, CH2), 6.39 (s, 1
H, ArH), 7.08 (t, J = 7.4 Hz, 1 H, ArH), 7.23–7.28 (m, 1 H, ArH),
7.43–7.48 (m, 5 H, ArH), 7.51–7.65 (m, 5 H, ArH), 7.72 (s, 1 H,
=CH), 7.86–7.90 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 40.3, 52.8, 100.4, 109.4, 116.9, 120.0, 120.7, 122.0, 124.6, 128.5,
128.7, 128.9, 129.0, 129.7, 129.8, 132.0, 132.6, 135.5, 135.6, 139.0,
151.2, 165.7 ppm. MS (ES+): m/z = 432.4 [M+ + 1]. HRMS: calcd.
for C28H22N3O2 [MH]+ 432.1712; found 432.1712.
Methyl 1-(4-Methylphenyl)-3-phenyl-3,6-dihydropyrazolo[4Ј,3Ј:3,4]-
azepino[1,2-a]indole-5-carboxylate (14b): 86% as a yellow solid
(134 mg from 200 mg). M.p. 197–198 °C. Rf = 0.45 (hexanes/
EtOAc, 80:20, v/v). IR (KBr): ν
= 1696 (CO2Me) cm–1. 1H
˜
max
NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 3.84 (s, 3 H,
CO2Me), 5.23 (s, 2 H, CH2), 6.41 (s, 1 H, ArH), 7.08 (t, J = 7.5 Hz,
1 H, ArH), 7.26 (s, 2 H, ArH), 7.45–7.63 (m, 8 H, ArH), 7.70 (s, 1
H, =CH) 7.77 (d, J = 7.9 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.6, 40.3, 52.8, 100.3, 109.4, 116.8, 120.0, 120.7,
121.9, 124.6, 127.5, 128.4, 128.6, 128.9, 129.4, 129.7, 129.9, 132.1,
135.4, 135.5, 138.8, 139.0, 151.3, 165.7 ppm. MS (ES+): m/z =
446.3 [M+ + 1]. HRMS: calcd. for C29H24N3O2 [MH]+ 446.1869;
found 446.1859.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data for remaining compounds; copies of 1H
and 13C NMR spectra of all compounds.
Acknowledgments
M. N. gratefully acknowledges the financial assistance in the form
of a fellowship from the Council of Scientific and Industrial Re-
search (CSIR), New Delhi. The authors acknowledge the SAIF
Division for providing the spectroscopic and analytical data.
[1] a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174–238; b) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,
36, 1173–1193; c) A. Martins, M. Lautens, J. Org. Chem. 2008,
73, 8705–8710; d) C. Verrier, T. Martin, C. Hoarau, F. Marsais,
J. Org. Chem. 2008, 73, 7383–7386; e) S. J. Hwang, S. H. Cho,
S. Chang, J. Am. Chem. Soc. 2008, 130, 16158–16159; f) F. [5] a) H. S. Lee, S. H. Kim, S. Gowrisankar, J. N. Kim, Tetrahe-
Derridj, J. Roger, F. Geneste, S. Djebbar, H. Doucet, J. Or-
ganomet. Chem. 2009, 694, 455–465; g) F. Bellina, R. Rossi,
Chem. Rev. 2010, 110, 1082–1146.
dron 2008, 64, 7183–7190; b) H. S. Lee, S. H. Kim, T. H. Kim,
J. N. Kim, Tetrahedron Lett. 2008, 49, 1773–1776; c) H. S. Lee,
K. H. Kim, S. H. Kim, J. N. Kim, Tetrahedron Lett. 2012, 53,
497–501.
[2] a) Y. L. Janin, Chem. Rev. 2012, DOI: 10.1021/cr200427q and
references cited therein; b) S. Fustero, M. Sánchez-Roselló, P.
Barrio, A. Simón-Fuentes, Chem. Rev. 2011, 111, 6984–7034
and references cited therein; c) S. Guillou, F. J. Bonhomme,
M. S. Ermolenko, Y. L. Janin, Tetrahedron 2011, 67, 8451–
[6] S. Kumar, H. Ila, H. Junjappa, J. Org. Chem. 2009, 74, 7046–
7051.
[7] S. Nag, S. Madapa, S. Batra, Synthesis 2008, 101–109.
[8] a) M. Nayak, G. Pandey, S. Batra, Tetrahedron 2011, 67, 7563–
7569; b) J. Li, X. Wang, Y. Zhang, Tetrahedron Lett. 2005, 46,
5233–5237.
ˇ
8457; d) G. Vilkauskaite, A. Sacˇkus, W. Holzer, Eur. J. Org.
˙
Chem. 2011, 5123–5133; e) S. Guillou, Y. L. Janin, Chem. Eur.
J. 2010, 16, 4669–4677; f) M. Schnürch, R. Flasik, A. F. Khan,
M. Spina, M. D. Mihovilovic, P. Stanetty, Eur. J. Org. Chem.
2006, 3283–3307.
[9] Q. Liao, L. Zhang, S. Li, C. Xi, Org. Lett. 2011, 13, 228–231.
Received: March 29, 2012
Published Online: May 22, 2012
Eur. J. Org. Chem. 2012, 3677–3683
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3683