Bischler-Napieralski synthesis of some new pyrazole-fused β-carbolines

Article abstract of DOI:10.1515/znb-2002-1120

3-(4-Acylaminopyrazol-5-yl)-4-methylindoles (13a,b), under Bischler-Napieralski reaction conditions, undergo cyclization at the pyrrolic carbon-2 with ultimate formation of the corresponding pyrazolo[3,4:5′,6′]pyrido[3,4-b]indoles (14a,b) as evidenced by

Full text of DOI:10.1515/znb-2002-1120

Bischler-Napieralski Synthesis of Some New Pyrazole-Fused ꢀ-Carbolines
Kayed A. Abu-Safieha, Mustafa M. El-Abadelaha, Salim S. Sabria,
Wolfgang Voelterb, Cäcilia M. Mössmerc, and Markus Stroebelec
a
Chemistry Department, Faculty of Science, Jordan University, Amman, Jordan
b
Abteilung für Physikalische Biochemie, Physiologisch-chemisches Institut der Universität
Tübingen, Hoppe-Seyler Straße 4, D-72076 Tübingen, Germany
c
Institut für Anorganische Chemie auf der Morgenstelle 18, Universität Tübingen,
D-72076 Tübingen, Germany
Reprint requests to Prof. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de
or to Prof. M. M. El-Abadelah. E-mail: mustelab@ju.edu.jo
Z. Naturforsch. 57b, 1327Ð1332 (2002); received August 21, 2002
Bischler-Napieralski Reaction, Directed Cyclization, Pyrazolopyridoindoles
3-(4-Acylaminopyrazol-5-yl)-4-methylindoles (13a,b), under Bischler-Napieralski reaction
conditions, undergo cyclization at the pyrrolic carbon-2 with ultimate formation of the corre-
sponding pyrazolo[3,4:5Ј,6Ј]pyrido[3,4-b]indoles (14a,b) as evidenced by crystal structure
analysis of 14a.
Introduction
were cited in the literature [7Ð9]. Examples of
these condensed tetracyclic aza-heterocycles (pyr-
azolopyridoindoles) are confined to compounds 3
possessing pepsin-inhibiting and antiulcerogenic
activity [7], the δ-carboline 4, showing in vitro an-
xiolytic activity [8], and γ-carboline 5 [9].
Quite recently we have reported that 3-(4-acyl-
amino-1,3-dimethylpyrazol-5-yl)indoles 6, under
Bischler-Napieralski reaction conditions, under-
went regioselective cyclization at C-4 of the indole
nucleus to deliver the corresponding pyrazolo-
[3Ј,4Ј:6,7]azepino[5,4,3-cd]indoles (7) (Scheme 1)
[10].
The ꢀ-carboline ring system is among the most
commonly encountered alkaloid frameworks in
the terrestrial environment [1, 2], and also occurs
in compounds derived from a variety of marine
species. [2, 3]. The Harmala alkaloids 1a,b were
the first marine derived ꢀ-carbolines to be re-
ported in 1980 from Noctiluca miliaris [4]. Re-
cently, several manzamines 2, exhibiting antitumor
activity, have been reported from different marine
sponge genera [3, 5].
Currently, there is a wealth of research work ori-
ented toward the synthesis and bioassay of various
ꢀ-carboline derivatives [6]. We became interested
in pyrazole-fused carbolines for which limited data
Scheme 1.
0932Ð0776/2002/1100Ð1327 $06.00 ” 2002 Verlag der Zeitschrift für Naturforschung, Tübingen · www.znaturforsch.com
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1328
K. A. Abu-Safieh et al. · Bischler-Napieralski Synthesis of Some New Pyrazole-Fused ꢀ-Carbolines
In this context, we wish to report herein on the 4-methylindolylmagnesium chloride (9) [11], pre-
use of 4-methylindole (8) in the synthesis of the pared in situ from methylmagnesium iodide and
new model 1,3,10-trimethylpyrazolo[3Ј,4Ј:5,6]py- 4-methylindole (8).
rido[3,4-b]indoles 14a,b (Scheme 2) via the Bisch-
ler-Napieralski route.
The spectral (MS, NMR) and microanalytical
data are in conformity with the assigned structures
11Ð14, and are given in the Experimental Part.
Thus, their MS spectra display the correct M+ for
which the measured HRMS data are in good
agreement with the calculated values. Assign-
ments of the 1H NMR signals to the different pro-
tons are straightforward, and 13C-signal assign-
ments are based on DEPT and 2D (COSY,
HMBC, HMQC) experiments; these experiments
showed different correlations that helped in the
full assignments of hydrogens and carbons. It is
worth noting that the doublet, belonging to 2-H of
the indole ring in the 1H NMR spectra of 13a,b, is
Results and Discussion
In the present study, we have utilized 3-[(4-(N-
acetyl)amino-1,3-dimethylpyrazol-5-yl]-4-methyl-
indoles 13a,b (Scheme 2) as substrates in the cycli-
zation step under Bischler-Napieralski reaction
conditions. We envisaged that incorporation of a
substituent, such as a methyl group, at C-4 of the
indole nucleus would act as a blockage therein,
and thence would direct ring closure solely at C-2
of the pyrrole ring. This anticipation has been real-
ized with ultimate production of the correspond-
ing pyrazolo-ꢀ-carbolines 14a,b (Scheme 2).
1
absent in the H NMR spectra of 14a,b. Further-
more, C-2 in 13a,b is identified as tertiary in the
13C NMR (DEPT) spectra, while it is quaternary
(C-5a) in 14a,b, indicating that ring closure has
taken place at C-2 of the indole nucleus. Eventu-
ally, the spectral data of the target compounds
14a,b are compatible with the pyrazolo-ß-carbo-
line structure as determined for 14a by X-ray crys-
tal structure measurements.
Compounds 13a,b were obtained by direct acy-
lation of 3-(4-amino-1,3-dimethylpyrazol-5-yl)-4-
methylindole (12) with the respective acid chloride
in the presence of triethylamine. The synthon 12
was produced by reduction, using tin and HCl in
the conventional manner, of 3-(1,3-dimethyl-4-
nitropyrazol-5-yl)-4-methylindole (11). The latter
precursor was, in turn, prepared by the reaction of
5-chloro-1,3-dimethyl-4-nitropyrazole (10) with
Scheme 2.
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K. A. Abu-Safieh et al. · Bischler-Napieralski Synthesis of Some New Pyrazole-Fused ꢀ-Carbolines
1329
a Finnigan MAT TSQ-70 spectrometer at 70 eV;
ion source temperature = 200 ∞C. Microanalyses
were performed at the Microanalytical Laboratory
of the Inorganic Chemistry Institute, Tübingen
University.
X-Ray Crystal Structure Determination of 14a
An X-ray crystal structure of 14a has been per-
formed. The molecular structure of 14a is shown
in Fig. 1 and selected bond lengths and angles are
given in Table 1. The crystallographic data confirm
the proposed pyrazolo-ꢀ-carboline structure for
14a.
3-(1,3-Dimethyl-4-nitropyrazol-5-yl)-4-methyl-
indole (11)
A
solution of 4-methylindole (8) (3.00 g,
23 mmol) in dry diethyl ether (20 ml) was stirred
with magnesium (0.61 g, 25 mmol) and methyl
iodide (3.55 g, 25 mmol) at 22∞ C for 20 min. To
the resultant solution of 4-methylindolylmagne-
sium iodide (9) was added dropwise a solution of
5-chloro-1,3-dimethyl-4-nitropyrazole (10) (1.34 g,
7.6 mmol) in dry diethyl ether (30 ml). The result-
ing reaction mixture was stirred for 4 h and then
treated with water (100 ml). The ether layer was
separated and the aqueous layer extracted with
ether (2 ¥ 100 ml). The combined organic extracts
were dried (anhydrous Na2SO4) and the solvent
was evaporated; the residue was dissolved in
CH2Cl2 and precipitated using petroleum ether to
give a yellowish solid which was soaked in petro-
leum ether to remove unreacted 4-methylindole.
Yield of 11: 1.65 g (80%), m.p. 178Ð179∞ C. Ð MS:
m/z (%) = 270 (94) [M+], 253 (87), 239 (100), 208
(76), 170 (63), 152 (76), 139 (26). Ð HRMS: calcd.
for C14H14N4O2: 270.11165, found 270.11450. Ð 1H
NMR (300.13 MHz, CDCl3): δ = 2.12 (s, 3H,
4-CH3), 2.64 (s, 3H, 3Ј-CH3), 3.61 (s, 3H, NÐCH3),
6.94 (d, J = 7.7 Hz, 1H, 5-H), 7.18 (dd, J = 7.7,
8.1 Hz, 1H, 6-H), 7.24 (d, J = 2.7 Hz, 1H, 2-H),
7.30 (d, J = 8.1 Hz, 1H, 7-H), 8.58 (s , 1H, NÐH).
Fig. 1. ORTEP Plot (50% probability level for ellipsoids
of thermal vibrations) of the molecular structure of 14a.
˚
Table 1. Selected bond lengths (A) and angles (∞) for 14a.
N(1)ÐN(2)
N(1)ÐC(10c)
N(2)ÐC(3)
C(3)ÐC(3a)
1.386 (3) N(1)ÐC(10c)ÐC(10b)
135.2 (2)
1.374 (3) C(10a)ÐC(10b)ÐC(10c) 139.6 (2)
1.314 (3) C(10)ÐC(10a)ÐC(10b) 136.5 (2)
Ð
13C NMR (75.47 MHz, CDCl3): δ = 14.3
1.424 (3) N(1)ÐC(10c)ÐC(3a)
C(3a)ÐC(10c) 1.404 (3) N(1)ÐN(2)ÐC(3)
106.2 (2)
107.9 (2)
109.8 (2)
106.1 (2)
(3Ј-CH3), 18.4 (4-CH3), 37.3 (NÐCH3), 102.4
(C-3), 109.6 (C-7), 122.4 (C-5), 123.3 (C-6), 125.1
(C-2), 125.4 (C-3a), 130.0 (C-3Ј), 132.7 (C-4), 136.1
N(4)ÐC(3a)
N(4)ÐC(5)
C(5a)ÐC(5)
C(5a)ÐC(10b) 1.419 (3) N(4)ÐC(5)ÐC(5a)
C(10b)ÐC(10c) 1.421 (3) N(6)ÐC(5a)ÐC(5)
N(6)ÐC(5a)
1.359 (3) N(2)ÐC(3)ÐC(3a)
1.335 (3) C(3)ÐC(3a)ÐC(10c)
1.421 (3) N(4)ÐC(3a)ÐC(3)
127.7 (2) (C-7a), 138.9 (C-5Ј), 146.2 (C-4Ј). Ð C14H14N4O2
120.0 (2)
127.4 (2)
116.7 (2)
(270.29): calcd. C 62.21, H 5.22, N 20.73; found
C 62.10, H 5.35, N 20.51.
1.382 (3) C(5)ÐN(4)ÐC(3a)
3-(4-Amino-1,3-dimethylpyrazol-5-yl)-4-methyl-
indole (12)
Experimental Section
A mixture of 3-(1,3-dimethyl-4-nitropyrazol-5-
5-Chloro-1,3-dimethyl-4-nitropyrazole was pur- yl)-4-methylindole (11) (1.35 g, 5.0 mmol), tin
chased from Maybridge, U. K. 4-Methylindole (8) granules (3.0 g) in ethanol (10 ml) and conc. HCl
and phosphorous oxychloride were purchased (20 ml) was refluxed (water bath) for 2 h. The re-
from Acros. Melting points (uncorrected) were de- sulting acidic solution was cooled and basified with
termined on a Gallenkamp melting point appara- 40% aqueous NaOH. This cold basic solution was
tus. NMR spectra were recorded on a Bruker extracted with CH2Cl2 (3 ¥ 50 ml). The combined
WM-400 or a Bruker DPX-300 spectrometer using dichloromethane extracts were dried (anhydrous
TMS as internal reference. Mass spectra (EI) and Na2SO4), and the solvent was removed in vacuo.
high resolution data (HRMS) were obtained using The resulting solid was recrystallized from
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1330
K. A. Abu-Safieh et al. · Bischler-Napieralski Synthesis of Some New Pyrazole-Fused ꢀ-Carbolines
CH2Cl2Ðpetroleum ether (b.p. 40Ð60∞ C) to af- following the same procedure and experimental
ford a white solid. Yield of 7: 1.06 g (88%), m.p. conditions describrd above for 13a. Yield of 13b:
219Ð220∞ C. Ð MS: m/z (%) = 240 (100) [M+], 208 0.57 g (67%), m.p. 214Ð215 ∞C (dec.). Ð MS: m/z
(6), 198 (11), 171 (12), 157 (41), 130(10). Ð HRMS: (%) = 282 (100) [M+], 240 (82), 222 (21), 208 (12),
calcd. for C14H16N4: 240.13750, found 240.13657. Ð 155 (28), 115 (7). Ð HRMS: calcd. for C16H18N4O:
1H NMR (300.13 MHz, CDCl3): δ = 2.22 (s, 3H, 282.14806, found 282.14862. Ð H NMR (400.14
1
3Ј-CH3), 2.27 (s, 3H, 4-CH3), 2.55 (br s, 2H, NH2), MHz, DMSO-d6): δ = 1.80 (s, 3H, CH3CO), 2.04
3.55 (s, 3H, NÐCH3), 6.92 (d, J = 7.3 Hz, 1H, 5-H), (s, 3H, 3Ј-CH3), 2.11 (s, 3H, 4-CH3), 3.40 (s, 3H,
7.17 (dd, J = 7.3, 8.2 Hz, 1H, 6-H), 7.21 (d, J = NÐCH3), 6.76 (d, J = 7.5 Hz, 1H, 5-H), 7.02 (dd,
2.6 Hz, 1H, 2-H), 7.31 (d, J = 8.2 Hz, 1H, 7-H), J = 7.5, 8.0 Hz, 1H, 6-H), 7.24 (d, J = 2.5 Hz, 1H,
8.64 (br s , 1H, NÐH). Ð 13C NMR (75.47 MHz, 2-H), 7.27 (d, J = 8.0 Hz , 1H, 7-H), 8.83 (s , 1H,
CDCl3): δ = 11.1 (3Ј-CH3), 18.1 (4-CH3), 36.6 NÐH), 11.40 (s, 1H, NHCO). Ð 13C NMR (100.62
(NÐCH3), 104.5 (C-3), 109.2 (C-7), 121.8 (C-5), MHz, DMSO-d6): δ = 11.7 (3Ј-CH3), 18.0 (4-CH3),
122.9 (C-6), 125.0 (C-3Ј), 125.1 (C-2), 126.2 (C-5Ј), 22.5 (CH3CO), 36.4 (NÐCH3), 102.3 (C-3), 109.7
126.3 (C-3a), 131.0 (C-4), 136.4 (C-7a), 137.0 (C-7), 117.7 (C-4Ј), 120.7 (C-5), 121.7 (C-6), 125.8
(C-4Ј). Ð C14H16N4 (240.29): calcd. C 69.97, (C-3a), 126.1 (C-2), 129.4 (C-4), 134.4 (C-5Ј), 136.2
H 6.71, N 23.31; found C 69.58, H 6.67, N 23.07.
(C-7a), 143.0 (C-3Ј), 168.9 (NHCO). Ð C16H18N4O
(282.35): calcd. C 68.06, H 6.43, N 19.84; found
C 68.13, H 6.29, N 19.79.
3-[4-(4Ј-Chlorobenzoyl)amino-1,3-dimethyl-
pyrazol-5-yl]-4-methylindole (13a)
p-Chlorobenzoyl chloride (0.24 g, 1.37 mmol)
was added to a solution of 12 (0.29 g, 1.26 mmol)
in dry benzene (20 ml),followed by addition of tri-
ethylamine (2 ml). The resulting mixture was re-
fluxed (oil bath, 90 ∞C) for 4 h. The solvent was
5-(4-Chlorophenyl)-1,3,10-trimethyl-1H,6H-
pyrazolo[3Ј,4Ј:5,6]pyrido[3,4-b]indole (14a)
This compound was prepared by heating at re-
then evaporated in vacuo, and the solid residue flux (oil bath) a solution of 13a (0.3 g, 0.8 mmol)
soaked in water (40 ml), filtered and finally and POCl3 (3 ml) in dry acetonitrile (20 ml) for
washed with petroleum ether to give a white solid. 3 h. The resulting mixture was subjected to vac-
Yield of 13a: 0.40 g (86%), m.p. 205Ð207∞ C. Ð uum distillation to remove excess acetonitrile and
MS: m/z (%) = 378 (90) [M+], 239 (100), 224 (24), POCl3. The residue was cooled, basified with 5%
222 (60), 208 (19), 156 (17), 155 (38), 139 (56), aqueous NaOH, then extracted with CH2Cl2 (3 ¥
111 (27). Ð HRMS: calcd. for C21H19ClN4O: 50 ml) to give a yellowish-green solid. Yield of 14a:
1
378.12474, found 378.12942. Ð H NMR (400.14 0.18 g (63%). The crude product was purified on
MHz, DMSO-d6): δ = 2.07 (s, 3H, 3Ј-CH3), 2.12 (s, silica gel plates, eluting with MeOH:CHCl3 (2:98
3H, 4-CH3), 3.44 (s, 3H, NÐCH3), 6.76 (d, J = v/v) to furnish the title compound as a yellowish
7.5 Hz, 1H, 5-H), 6.99 (dd, J = 7.5, 8.0 Hz, 1H, solid, m.p. 239Ð240∞ C. Ð MS: m/z (%) = 360 (100)
6-H), 7.24 (d, J = 8.0 Hz, 1H, 7-H), 7.28 (br s, 1H, [M+], 345 (6), 304 (6), 268 (9), 180 (10), 162 (15),
2-H), 7.51 (d, J = 8.5 Hz, 2H, 3Љ-H/5Љ-H), 7.87 (d, 134 (7). Ð HRMS: calcd. for C21H17 Cl N4:
1
J = 8.5 Hz, 2H, 2Љ-H/6Љ-H), 9.47 (s , 1H, NÐH), 360.11417, found 360.11752 . Ð H NMR (400.14
11.37 (s, 1H, NHCO). Ð 13C NMR (100.62 MHz, MHz, CDCl3): δ = 2.75 (s, 3H, 10-CH3), 3.08 (s,
DMSO-d6): δ = 11.5 (3Ј-CH3), 18.0 (4-CH3), 36.5 3H, 3-CH3), 4.15 (s, 3H, NÐCH3), 7.19 (d, J =
(NÐCH3), 102.2 (C-3), 109.7 (C-7), 117.2 (C-4Ј), 7.0 Hz, 1H, 9-H), 7.40 (d, J = 7.7 Hz, 1H, 7-H),
120.7 (C-5), 121.6 (C-6), 125.7 (C-3a), 126.1 (C-2), 7.47 (dd, J = 7.0, 7.7 Hz, 1H, 8-H), 7.53 (d, J =
128.3 (C-3Љ/C-5Љ), 128.9 (C-5Ј), 129.3 (C-4), 129.4 8.5 Hz, 2H, 3Љ-H/5Љ-H), 7.85 (d, J = 8.5 Hz, 2H,
(C-2Љ/C-6Љ), 132.9 (C-1Љ), 135.2 (C-7a), 136.1(C-4Љ), 2Љ-H/6Љ-H), 8.88 (s, 1H, NÐH). Ð 13C NMR
143.1 (C-3Ј), 165.3 (NHCO). Ð C21H19ClN4O (100.62 MHz, CDCl3): δ = 11.5 (3-CH3), 25.5
(378.88): calcd. C 66.58, H 5.05, Cl 9.36, N 14.79; (10-CH3), 41.4 (NÐCH3), 109.0 (C-7), 112.7
found C 66.71, H 5.06, Cl 9.24, N 14.59.
(C-10b), 121.0 (C-10a), 123.1 (C-9), 127.4 (C-8),
129.5 (C-3Љ/C-5Љ), 129.8 (C-2Љ/C-6Љ), 133.5 (C-10),
134.0 (C-10c), 134.8 (C-3), 134.9 (C-4Љ), 135.7
(C-5a), 136.9 (C-1Љ), 139.9 (C-6a), 140.0 (C-5),
146.0 (C-3a). Ð C21H17 Cl N4 (360.85): calcd.
3-[4-(N-Acetyl)amino-1,3-dimethylpyrazol-5-yl]-
4-methylindole (13b)
This compound was prepared from acetyl chlo- C 69.90, H 4.75, Cl 9.82, N 15.53; found C 69.73,
ride (0.24 g, 3.1 mmol) and 12 (0.72 g, 3.0 mmol), H 4.52, Cl 9.73, N 1544.
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K. A. Abu-Safieh et al. · Bischler-Napieralski Synthesis of Some New Pyrazole-Fused ꢀ-Carbolines
1331
1,3,5,10-Tetramethyl-1H, 6H-pyrazolo[3Ј,4Ј:5,6]-
pyrido[3,4-b]indole (14b)
(8), c = 1262.60 (9) pm, α = 85.819 (8)∞, ꢀ = 64.807
(8)∞, γ = 87.510 (8)∞, V = 1.7631 (2) nm3, Z = 2,
Dcalc = 1.359 g/cm3. Data collection was made at
20 ∞C, on a STOE-IPDS diffractometer. 10867 Re-
flections were collected within the scan range θ =
3.25Ð22.98∞ using Mo-Kα radiation (λ = 71.073
pm). The unit cell parameters for the data collec-
tion were obtained using the setting angles of 7837
(θ = 55∞) reflections. The structure was solved by
direct methods using the program SHELXS-97
[12]. All non-hydrogen atoms were refined aniso-
tropically by a full-matrix least-squares procedure
based on F2 using all unique data with SHELXL-
97 [13]. The hydrogen atoms have been found in
the difference Fourier map and were refined iso-
This compound was prepared from compound
13b (0.43 g, 1.5 mmol) and phosphorous oxychlo-
ride (4 ml) in acetonitrile (30 ml), following the
same procedure and experimental conditions de-
scribed above for 14a. Yield of 14b: 0.22 g (crude)
(56%), m.p. 211Ð213∞ C (dec.). Ð MS: m/z (%) =
264 (100) [M+], 222 (15), 208 (11), 182 (18), 132
(12). Ð HRMS: calcd. for C16H16N4: 264.13750,
found 264.13625. Ð 1H NMR (400.14 MHz,
DMSO-d6): δ = 2.53 (s, 3H, 10-CH3), 2.82 (s, 3H,
5-CH3), 2.96 (s, 3H, 3-CH3), 4.00 (s, 3H, NÐCH3),
7.09 (d, J = 7.0 Hz, 1H, 9-H), 7.43 (dd, J = 7.0,
8.0 Hz, 1H, 8-H), 7.51(d, J = 8.0 Hz, 1H, 7-H),
12.02 (s, 1H, NÐH). Ð 13C NMR (100.62 MHz,
DMSO-d6): δ = 11.1 (3-CH3), 20.7 (5-CH3), 22.6
(10-CH3), 41.3 (NÐCH3), 109.6 (C-7), 109.8
(C-10b), 120.0 (C-10a), 122.0 (C-9), 126.6 (C-8),
132.5 (C-10), 133.0 (C-10c), 133.5 (C-3), 133.6
(C-5a), 139.9 (C-6a), 140.0 (C-5), 144.1 (C-3a). Ð
C16H16N4 (264.33): calcd. C 72.70, H 6.10, N 21.20;
found C 72.52, H 6.21, N 21.35.
tropically. This resulted in R values R1/wR2
=
0.0619/0.0655 for all data and 0.0299/0.0590 for re-
flections with I > σ [Rint = 0.038] and 605 variable
parameters; GOF = 1.003, largest peak and hole
in final Fourier difference map were 0.17 and
3
˚
Ð0.13 e/A , respectively.
Supplementary material
Further information on the crystal structure de-
termination and X-ray data of compound 14a can
be ordered from the Cambridge Crystallographic
Data Center (E-mail: deposit@ccdc.cam.au.uk)
under the depository number CCDC 163856.
Crystal structure determination of 14a
Crystals (light yellow needles) were obtained by
allowing a hot solution of 14a in ethanol/water
(4:1, v/v) to stand at ambient temperature for 60
h; crystal dimensions: 0.28 ¥ 0.12 ¥ 0.24 mm. Crys-
tal data for C21H17ClN4: FW = 360.84; triclinic;
Acknowledgements
We wish to thank the BMBF (Bonn, Germany)
¯
space group P1, with a = 1230.46 (8), b = 1257.60 for financial support.
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