Thermal cyclization of 3-arylamino-3-(2-nitrophenyl)-propenal Schiff base hydrochlorides followed by triethyl phosphite mediated deoxygenation: A facile synthesis of quindolines

Article abstract of DOI:10.1016/j.tetlet.2005.11.007

A simple and useful method for the synthesis of various 2-substituted quindolines starting from 2-nitroacetophenone is described.

Full text of DOI:10.1016/j.tetlet.2005.11.007

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 377–379
Thermal cyclization of 3-arylamino-3-(2-nitrophenyl)-propenal
Schiff base hydrochlorides followed by triethyl phosphite
mediated deoxygenation: a facile synthesis of quindolines
Bishnupada Dutta, Surajit Some and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 23 August 2005; revised 24 October 2005; accepted 2 November 2005
Available online 18 November 2005
Abstract—A simple and useful method for the synthesis of various 2-substituted quindolines starting from 2-nitroacetophenone is
described.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion of 2-substituted quindolines 2 starting from 2-nitro-
acetophenone 3 (Scheme 1). Two important steps
involved in the synthesis are: regioselective thermal
cyclization of enaminoimine hydrochloride 5 and gener-
ation of a nitrene intermediate followed by insertion into
a sp2 C–H bond.
Cryptolepine 1a is an important indoloquinoline alkal-
oid found in Cryptolepis sanguinolenta (Lind.), a shrub
used in traditional medicine for the treatment of malaria
as well as for a number of other diseases1–3 in central
and west Africa.
Thus, when 2-nitroacetophenone 3 was treated with
POCl3 in DMF, it underwent a Vilsmeier–Haack reac-
tion to produce the b-chlorocinnamaldehyde 4,10 with
the nitro group remaining intact. The chloroaldehyde
4 upon reaction with 2.2 equiv of aniline in 2 N ethan-
olic HCl at 0 °C produced the corresponding enamino-
imine hydrochloride 5a in very good yield. Thermal
cyclization of 5a at 200–250 °C produced 2-(2-nitro-
phenyl)quinoline 6a as the major isolable product. The
desired quindoline 2a was synthesized by heating 6a
with triethyl phosphite (TEP) at 160 °C. This step
involves intramolecular annulation through a nitrene
intermediate.9
7
6
5
N
4
CH3
7
6
8
3
4
5
8
N
9
3
N
R
2
10
9
H
1
11
N
10
R
2
2a (R=H), 2b (R=CH3)
2c (R=Br), 2d (R=I)
1
11
1a (R=H), 1b (R=CH3)
1c (R=Br), 1d (R=I)
Fichter and Boehringer first synthesized cryptolepine in
1906 before its isolation from natural sources.4 Later on
it was synthesized by various other groups,5–8 of which
the preparation by methylation of quindoline by Holt
and Petrow (1947)8a deserves special mention. There
are many synthetic methods available for the construc-
tion of tetracyclic indoloquinolines8 and quindolines.9
We also synthesized various 2-substituted quindolines
2b–d following the above mentioned procedure.
The experimental results are summarized in Table 1.
Cryptolepines 1a–d could be obtained from quindolines
2a–d by heating with methyl iodide in acetone in the
presence of BaO and KOH.5
To develop a general method for the synthesis of various
2-substituted cryptolepines 1, we undertook the prepara-
In conclusion we have developed a simple method for
the synthesis of various 2-substituted quindolines from
easily accessible starting materials.
Keywords: Quindoline; Cryptolepine.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222
282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.007

378
B. Dutta et al. / Tetrahedron Letters 47 (2006) 377–379
NO2
NO2
i
Cl
CH3
3
4
O
H
CHO
ii
NO2
NO2
iii
NH
CH
R
N
.HCl
R
H
N
R
6a (R=H), 6b (R=CH3)
6c (R=Br), 6d (R=I)
5a (R=H), 5b (R=CH3)
5c (R=Br), 5d (R=I)
iv
N
v
cryptolepines (1a-d)
N
H
R
2a (R=H), 2b (R=CH3)
2c (R=Br), 2d (R=I)
Scheme 1. Reagents and conditions: (i) POCl3, DMF, 0 °C, 1 h then 80 °C, 4 h, 80%; (ii) 2 N ethanolic HCl, arylamine, 0 °C; (iii) heat, 200–250 °C,
5 min; (iv) P(OEt)3, reflux, 4 h; (v) BaO, KOH, acetone, reflux, then CH3I reflux, 4 h.
Table 1.
Entry
Yield of compound 5 (%)
Yield of compound 6 (%)
Yield of compound 2 (%)
Yield of compound 1 (%)
1
2
3
4
5a (92)
5b (88)
5c (91)
5d (90)
6a (40)
6b (37)
6c (41)
6d (35)
2a (70)
2b (75)
2c (68)
2d (72)
1a (71)
1b (70)
1c (65)
1d (73)
Typical experimental procedure for thermal cyclization
of 5: In a test tube the propenal Schiff base hydrochlo-
ride 5 was heated at 200–250 °C for 5 min in a pre-
heated salt bath. In the cooler part of the test tube,
arylamine hydrochloride was deposited. The residue at
the bottom of the test tube was then cooled, washed
with cold water and dissolved in benzene (caution: car-
cinogenic). The organic layer was washed well with
water, dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The crude prod-
uct 6 thus obtained was purified by column chromato-
graphy over silica gel using hexane–ethyl acetate (5:1)
as eluent.
2. Selected spectroscopic data
2.1. Compound 6b
1H NMR (CDCl3, 200 MHz): d 2.54 (s, 3H), 7.45–7.59
(m, 4H), 7.63–7.67 (m, 2H), 7.93–7.96 (m, 2H), 8.10–
8.14 (d, 1H, J = 8.4 Hz). 13C NMR (CDCl3, 50 MHz):
d 21.59, 120.42, 124.39, 126.35, 127.16, 129.18, 131.54,
132.23, 132.55, 135.84, 136.08, 136.99, 146.51, 149.20,
154.53.
ESI MS for C16H12N2O2 [M], [M+H]+ = 265.09.
Anal. Calcd for C16H12N2O2: C, 72.72; H, 4.54; N,
10.60. Found: C, 72.49; H, 4.51; N, 10.71.
Typical experimental procedure for nitrene insertion: In
a 5 mL round-bottomed flask, 2-(2-nitrophenyl)quino-
line (0.4 mmol) was heated with triethyl phosphite
(2 mL) for 4 h. The excess triethyl phosphite was
removed by distillation and the crude product was puri-
fied by column chromatography over silica gel using
hexane–ethyl acetate (3:1) as eluent.
2.2. Compound 2a
1
Yellow solid, mp 250–251 °C (lit.7a mp 249–251 °C). H
NMR (DMSO-d6, 200 MHz): d 11.39 (s, 1H, NH), 8.42
(d, 1H, J = 8.4 Hz), 8.29 (s, 1H), 8.19 (d, 1H,

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Acknowledgements
Financial support from CSIR (New Delhi) is gratefully
acknowledged. B.P.D. thanks CSIR (New Delhi) and
S.S. thanks UGC (New Delhi) for their fellowships.
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