A novel three-component reaction: Synthesis of some complex annelated quinolines from simple acetanilides and via intramolecular 1,3-dipolar cycloaddition of azide to nitrile

Article abstract of DOI:10.1055/s-2007-982568

Synthesis of a novel class of tetrazolo[4′,5′:1,6]pyrido[2,3-d] quinolines from simple acetanilides and via intramolecular 1,3-dipolar cycloaddition of azides to nitriles using a three-component one-pot protocol is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982568

LETTER
1873
A Novel Three-Component Reaction: Synthesis of Some Complex Annelated
Quinolines from Simple Acetanilides and via Intramolecular 1,3-Dipolar
Cycloaddition of Azide to Nitrile
S
B
ynthesis of Com
i
plex-
A
s
nnelated Q
w
uinolines ajita Baruah, Mohit L. Deb, Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 9 March 2007
ments in three- and four-component reactions and great
Abstract: Synthesis of a novel class of tetrazolo[4¢,5¢:1,6]pyri-
do[2,3-d]quinolines from simple acetanilides and via intra-
molecular 1,3-dipolar cycloaddition of azides to nitriles using a
three-component one-pot protocol is reported.
efforts have been and continue being made to find and
develop new MCRs.10
11
As part of our continued interest on quinolines and de-
Key words: quinolines, acetanilides, multicomponent reaction, velopment of highly expedient methods for the synthesis
cyano-stabilised carbanion, intramolecular 1,3-dipolar cycloaddi-
tion reactions
of diverse heterocyclic compounds of biological impor-
tance, we report herein the synthesis of a novel class of
tetrazolo[4¢,5¢:1,6]pyrido[2,3-d]quinolines from simple
acetanilides by intramolecular 1,3-dipolar cycloaddition
Quinoline and its annelated derivatives have wide of azides to nitriles using a three-component one-pot
1
applications as drugs and pharmaceuticals. Therefore, protocol under mild conditions (Scheme 1).
considerable efforts have been directed towards the
preparation and synthetic manipulation of quinolines and
a number of compounds have been obtained with diverse
biological activities some of which are used as potent
R1
R1
CHO
Cl
Me
DMF + POCl3
N
H
O
N
2
drugs. In this regard the [b]-annelation of quinolines
1
1
1
1
a R = H
2a–c
gives access to a range of derivatives besides providing
novel approaches to the synthesis of alkaloids such as
1
b R = Me
1
c R = OMe
3
4
5
camptothecin, luotonin A, 22-hydroxyacuminatine, or
6
2
R CH2CN
nothapodytine (Figure 1).
R1
a R2 = CO2Et
2
3
N
[
c]
3b R = CN
CHO
b]
Cl
O
C R2 = CONH2
3
R2
N
N
N
N
[
R1
CHO
Cl
N
N
N
Et3N
6
O
+
DMF
N
camptothecin
50 °C
NaN3
R2
OH O
R1
4
Figure 1
2a–c
N
N
N
N
N
The attack of cyanide-stabilised carbanions on azide func-
tions leading to 1,2,3-triazoles is a well-established con-
version in organic synthesis. In an extensive study, the
carbanion derived from diethyl acetonedicarboxylate can
5a–i
7
8
Scheme 1
also be employed in this reaction process, and the triazoles Acetanilides 1 were chosen as the parent molecules in our
resulting from the reaction undergo base-catalysed reaction strategy (Scheme 1). The 2-chloro-3-formyl
intramolecular condensation at the ortho substituent to quinolines 2 were prepared from acetanilides 1 by our
own reported method.1 Thus acetanilide (1a) on treat-
ment with Vilsmeier reagent gave 2-chloro-3-formyl
quinoline (2a) in excellent yield. In the three-component
reaction12 equimolar amounts of 2a, ethyl cyanoacetate
1b
give well-funtionalised triazolo[1,5-a]quinolines.
One-pot multicomponent reactions (MCRs), by virtue of
their convergence, ease of execution and generally high
yields of products have attracted considerable attention.9
(
3a), and sodium azide (4) were treated at 50 °C in the
In the past decade there have been tremendous develop-
presence of a catalytic amount of triethylamine for four
hours using DMF as solvent. The solid compound ob-
tained on pouring the reaction mixture into water and
workup afforded the product 5a in good yield. The
structure of the compound was ascertained from the
SYNLETT 2007, No. 12, pp 1873–1876
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982568; Art ID: D08007ST
2
4
.0
7
.2
0
0
7
©
Georg Thieme Verlag Stuttgart · New York

1
874
B. Baruah et al.
LETTER
Table 1 Synthesis of Compound 5 via the Three-Component Reaction
Product
R1
R2
Temp (°C)
Time (h)
Mp (°C)
205
Yield (%)
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
H
CO Et
60
60
60
60
60
60
50
50
50
4
4
4
4
4
4
2
2
2
80
83
86
74
76
78
56
57
60
2
Me
OMe
H
CO Et
210
2
CO Et
196
2
CONH2
CONH2
CONH2
CN
167
Me
OMe
H
173
187
g
h
i
182
Me
OMe
CN
179
CN
175
1
spectroscopic data and elemental analysis. The H NMR The absence of compound 6 rules out the other possible
spectrum showed the absence of the aldehyde proton and reaction path as shown in Scheme 3.
the presence of the ethyl group of the ester and a proton at
d = 7.26 ppm. The IR spectrum showed the absence of the
R1
CHO
R1
CHO
2
R CH2CN
cyanide group, which evidenced its involvement in the cy-
cloaddition reaction. The mass spectrum revealed a strong
3
+
NaN3
+
N
Cl
N
N3
peak at 316 [M + Na]. Although there was the possibility
of the formation of compound 6 via a reaction route as
shown in Scheme 3, no such compound was formed. With
suitable conditions established for the three-component
reaction a series of compounds 5a–i was synthesised by
utilizing various 2-chloro-3-formyl quinolines 2a–c with
alkyl nitriles 3a–c and sodium azide (4). The structures of
the compounds were determined from their spectroscopic
data and elemental analysis (Table 1). Electron-donating
groups at the 4-position of the acetanilides 1 (or the 6-po-
sition of the quinoline 2) were found to enhance the
formation of the product 5.
2
4
R1
R1
CHO
N
NH2
∆
R2
N
N
N
R2
N
N
N
N
N
6
Scheme 3
The path of the reaction and hence the proposed mecha-
nism was established by performing the reaction stepwise
Scheme 4). First we reacted the 2-chloro-3-formyl
quinoline (2a) with ethyl cyanoacetate (3a) in the pres-
ence of piperidine at room temperature, which gave the
Knoevenagel product [A] in quantitative yield. In order
to introduce the azido group at the 2-position of the
quinoline molecules, the compound [A] was treated with
NaN in DMF at 50 °C with stirring. However, the inter-
A reasonable mechanism for the reaction is outlined in
Scheme 2. The reaction occurs via initial Knoevenagel
condensation of 2 and 3 in the presence of triethylamine
to give intermediate [A] which then reacts with sodium
azide to give the intermediate [B]. This undergoes an
intramolecular 1,3-dipolar cycloaddition to the pendant
cyano group of the sterically favoured quinoline deriva-
tive to afford the desired product 5 (Scheme 2).
(
13
14
3
mediate [B] (Scheme 2) could not be isolated but spon-
taneously underwent intramolecular cycloaddition to the
cyanide group to produce the product 5a. The compound
was comparable in all respects to the compound obtained
from the three-component reaction. Although there was
the possibility of the formation of compound [C] no such
compound was found in the reaction mixture. However,
when we tried to introduce the azide group before the
Knoevenagel condensation the azide group underwent in-
tramolecular cycloaddition to the imine bond in the first
step to give the product [D]. Hence in the next step we
obtained simply the Knoevenagel condensation product
R1
CHO
R1
R2
2
R CH
2
CN
+
CN
N
Cl
N
Cl
2
3
[A]
NaN
toluene
3
,
R1
R2
R1
2
R
∆
∆
CN
N
N
3
N
N
N
N
N
[B]
5
[
C] instead of 5.
Scheme 2
Synlett 2007, No. 12, 1873–1876 © Thieme Stuttgart · New York

LETTER
Synthesis of Complex-Annelated Quinolines
1875
R1
R2
(3) (a) Rigby, J. H.; Danca, D. M. Tetrahedron Lett. 1997, 38,
969. (b) Leue, S.; Miao, W.; Kanazawa, A.; Genisson, Y.;
Garcon, S.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1
4
CN
N
N
2001, 2903. (c) Comin, D. L.; Nolan, J. M. Org. Lett. 2001,
N
N
3, 1611.
2
R2
R CH2CN
R1
(
4) (a) Toyata, M.; Komori, C.; Ihara, M. Heterocycles 2002, 56,
101. (b) Chavan, S. P.; Sivappa, R. Tetrahedron Lett. 2004,
NaN3,
DMF
[C]
3
∆
CN
4
5, 3113. (c) Chavan, S. P.; Sivappa, R. Tetrahedron 2004,
N
Cl
R2
R1
60, 9931. (d) Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe,
H.; Takeuchi, Y. Synlett 2003, 847.
[A]
(
(
5) Ma, Z.; Lee, D. Y. Z. Tetrahedron Lett. 2004, 45, 6721.
6) Carles, L.; Narkunan, K.; Penlou, S.; Rousset, L.; Bouchu,
D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304.
2
N
N
N
N
N
5
a–h
NaN3,
toluene
(7) (a) Tennant, G. J. Chem. Soc. C 1966, 2290. (b)Sutherland,
D. R.; Tennant, G. J. Chem. Soc., Perkin Trans. 1 1974, 534.
(c) Westerlund, C. J. Heterocycl. Chem. 1980, 17, 1765.
(d) Lauria, A.; Patella, C.; Diana, P.; Barraja, P.;
R1
CHO
R1
R2
2
R CH2CN
CN
∆
3
N
N
N
N
N
N
N
Montalbano, A.; Cirrincione, G.; Dattolo, G.; Almerico, A.
M. Tetrahedron Lett. 2006, 47, 2187.
N
[D]
[C]
(
8) Smalley, R. K.; Teguiche, M. Synthesis 1990, 654.
(9) (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366.
b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
Scheme 4
(
S. D.; Keating, T. A. Acc. Chem. Rev. 1996, 29, 123.
10) (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestiopolov,
A. A.; Rodinovskaya, I. A.; Niazimbetova, Z. I.; Evans, D.
H. Org. Lett. 2002, 423. (b) List, B.; Castello, C. Synlett
(
In conclusion we have reported the synthesis of a novel
class of complex quinoline derivatives from simple
acetanilides by exploiting the intramolecular 1,3-dipolar
cycloaddition of azides to nitriles using a three-compo-
nent one-pot protocol under mild conditions. The pathway
for formation of the products in the three-component
process was established by performing the reaction step-
wise. This very simple protocol for the synthesis of
tetracyclic angularly annelated quinolines from readily
available starting materials is a valuable addition to
quinoline chemistry. This is the first example of this type
of reaction, which can be explored for the synthesis of
various complex heterocyclic compounds. Further study
of the reaction is in progress.
2001, 1687. (c) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org.
Chem. 2001, 66, 4427. (d) Bagley, M. C.; Cale, J. W.;
Bower, J. Chem. Commun. 2002, 1682. (e) Cheng, J. F.;
Chen, M.; Arthenius, T.; Nadzen, A. Tetrahedron Lett. 2002,
43, 6293. (f) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das,
J.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6485. (g) Bertozzi,
F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3309.
(
4
h) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett. 2003, 5,
35. (i) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org.
Lett. 2003, 5, 1205.
(
(
11) (a) Kalita, P. K.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett.
2006, 47, 7779. (b) Devi, I.; Baruah, B.; Bhuyan, P. J.
Synlett 2006, 2593. (c) Deb, M. L.; Bhuyan, P. J.
Tetrahedron Lett. 2007, 48, 2159. (d) Deb, M. L.; Bhuyan,
P. J. Tetrahedron Lett. 2005, 46, 6453. (e) Devi, I.; Bhuyan,
P. J. Synlett 2004, 283. (f) Devi, I.; Bhuyan, P. J.
Tetrahedron Lett. 2004, 45, 8625. (g) Devi, I.; Bhuyan, P.
J. Tetrahedron Lett. 2004, 45, 7727.
Acknowledgment
The authors thank the Department of Science & Technology, India,
for financial support.
12) Three-Component Reaction
To a mixture of 2-chloro-3-formylquinoline (2a, 192 mg,
1
mmol), ethyl cyanoacetate (3a, 140 mg, 1.24 mmol) and
References and Notes
NaN (4, 80 mg, 1.24 mmol) in DMF (10 mL) were added
3
(
1) (a) Elderfield, R. C. In Heterocyclic Compounds, Vol. 4;
two drops of water. A catalytic amount (1–2 drops) of Et N
3
Elderfield, R. C., Ed.; John Wiley Inc.: New York / London,
was then added to the reaction mixture and it was allowed to
stir for 4 h at 50–60 °C. After completion of the reaction, the
1960, Chap. 1, 1. (b) Wright, C. W.; Addac-Kyereme, J.;
Breen, A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek,
mixture was cooled to r.t. and poured into H O under
2
Y.; Kendrick, H.; Phillips, R. M.; Pollet, P. L. J. Med. Chem.
continuous stirring. A brown solid precipitated that was
2001, 44, 3187. (c) Sahu, N. S.; Pal, C.; Mandal, N. B.;
shown to be almost totally pure 5a. However, it was further
Banerjee, S.; Raha, M.; Kundu, A. P.; Basu, A.; Ghosh, M.;
Roy, K.; Bandyopadhyay, S. Bioorg. Med. Chem. 2002, 10,
purified by preparative TLC using EtOAc–hexane (3:7); mp
1
205 °C, yield 234 mg (80%). H NMR (CDCl ): d = 1.43 (t,
3
1687. (d) Bringmann, G.; Reichert, Y.; Kane, V.
3 H), 4.32 (q, 2 H), 7.26 (s, 1 H), 7.60–8.05 (m, 4 H), 8.63
1
3
Tetrahedron 2004, 60, 3539. (e) Kournetsov, V. V.;
Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005,
(s, 1 H). C NMR (CDCl ): d = 14.50 (CH ), 61.20
3
3
(CH C=O), 112.55 (C-5), 123.75 (C-4), 124.00 (C-2),
2
9
, 141.
126.20 (C-7), 127.45 (C-3), 127.70 (C-6), 131.00 (C-6a),
136.20 (C-11b), 138.36 (C-8), 145.12 (C-8a), 146.67 (C-5a),
(
2) Antimalarial Drug II; Peters, W.; Richards, W. H. G., Eds.;
+
Springer Verlag: Berlin / Heidelberg / New York / Tokyo,
151.25 (C-1a), 171.75 (C=O). MS: m/z = 316 [M + Na] . IR
–
1
1984.
(CHCl ): 2923.70, 2852.60, 1742.80 cm . Anal. Calcd for
3
C N O H : C, 61.43; H, 3.75; N, 23.89. Found: C, 61.43;
1
5
5
2
11
H, 3.82; N, 23.95.
Synlett 2007, No. 12, 1873–1876 © Thieme Stuttgart · New York

1
876
B. Baruah et al.
LETTER
(13) 2-Chloro-3-formyl quinoline (2a, 384 mg, 2 mmol) was
(14) The condensed product [Aa] (286 mg, 1 mmol) was mixed
mixed with ethyl cyanoacetate (3a, 260 mg, 2.17 mml) in
toluene (10 mL). One drop of piperidine was added and the
reaction mixture was allowed to stir at r.t. for 1 h. The
solvent was evaporated and the yellow solid obtained was
purified by recrystallisation from EtOH.
with NaN (4, 80 mg, 1.24 mmol) in DMF (10 mL) and 2
3
drops of H O were added. The reaction mixture was allowed
2
to stir for 4 h at 50–60 °C. After completion of the reaction
the mixture was cooled to r.t. and poured into H O under
2
continuous stirring. A brown coloured solid which appeared
was filtered and purified by preparative TLC using EtOAc–
hexane (3:7) to furnish 5a (176 mg, 60%).
1
2
Compound [Aa] (R = H, R = CO Et): mp 110 °C, yield
2
1
5
2
(
16 mg (98%). H NMR (CDCl ): d = 1.43 (t, 3 H), 4.43 (q,
H), 7.46–815 (m, 4 H), 8.74 (s, 1 H), 9.05 (s, 1 H). IR
3
–
1
CHCl ): 2226.70, 1730.90 cm .
3
Synlett 2007, No. 12, 1873–1876 © Thieme Stuttgart · New York

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