α-cyclisation of tertiary amines: Synthesis of some novel annelated quinolines via a three-component reaction under solvent-free conditions

Article abstract of DOI:10.1055/s-2006-951477

Synthesis of some novel classes of quinolizine-, indolizine- and pyrido-1,4-oxazine-fused quinoline derivatives via a three-component reaction under solvent-free conditions by exploring the 'tertiary amine effect' reaction strategy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951477

LETTER
2593
a-Cyclisation of Tertiary Amines: Synthesis of Some Novel Annelated
Quinolines via a Three-Component Reaction under Solvent-Free Conditions
S
I
ynthesi
p
s of
N
ovel
A
s
nnelate
d
Q
i
uinoli
t
ne
s
a Devi, Biswajita Baruah, Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 14 June 2006
(
c)
O
Abstract: Synthesis of some novel classes of quinolizine-, indoliz-
ine- and pyrido-1,4-oxazine-fused quinoline derivatives via a three-
component reaction under solvent-free conditions by exploring the
(b)
N
N
N
O
‘tertiary amine effect’ reaction strategy.
Camptothecin
OH O
Key words: quinolines, pyrimidines, tertiary amine effect, solvent-
free reaction, multicomponent reaction
Figure 1
1
0
11
such as camptothecin, luotonin A, 22-hydroxy-
a-Cyclisation of tertiary amines is a mechanistically in-
12
13
acuminatine or nothapodytine (Figure 1).
triguing and synthetically useful cyclisation which has not
1
4
received much attention. Certain tertiary anilines or enam- As a result of our continued interest in the development
ines and enamine esters undergo such cyclisation leading of highly expedient methods and syntheses of diverse
to annelated pyrrolidines. Suchitzky and Meth-Cohn1 heterocyclic compounds of biological significance we
have coined the term ‘tertiary amine effect’ to describe report here the preparation of some novel classes of
such processes which have been further developed by quinolizine-, indolizine- and pyrido-1,4-oxazine-fused
2
Reinhoudt and Verboom.
quinoline derivatives via a three-component reaction
under solvent-free conditions by exploring the ‘tertiary
amine effect’ reaction strategy (Schemes 1 and 2).
Development of new solid-phase (solvent-free) reactions
and transferring solution-phase reactions to the solid
phase are subjects of recent interest in the context of gen-
erating libraries of molecules for the discovery of biolog-
ically active leads and also for the optimisation of potent
R1
R1
CHO
Cl
Me
DMF, POCl3
N
H
O
N
3
drug candidates. Multi-component reactions (MCRs) by
2a–c
1
virtue of their convergence, productivity, facile execution
and generally high yield of products have attracted con-
siderable attention from the point of view of combinatori-
1a: R = H
1b: R1 = Me
c: R1 = OMe
1
4
al chemistry. The first MCR was described by Strecker in
2
5
R CH2CN
1
850 for the synthesis of amino acids. However, in the
2
4
4
a: R = CN
R1
R1
CN
R2
CHO
past decade there have been tremendous developments in
three- and four-component reactions and great efforts
have been and still are being made to find and develop
2
b: R = CO2Et
+
H
N
N
Cl
N
N
X
6
2a–c
new MCRs.
5a–j
X
Quinoline and its annelated derivatives are well known by
synthetic as well as biological chemists. Compounds with
3a: X = -CH2-CH2-
3b: X = -CH2-
3c: X = -OCH2-
this ring system have found wide application as drugs and
7
pharmaceuticals. Therefore, large efforts have been di- Scheme 1
rected towards the synthetic manipulation of quinolines to
find more useful compounds. As a result, a number of
compounds have been obtained with diverse biological
O
Y
8
z
activities some of which are used as potent drugs. In this
Y
6a: Y = NMe; Z = CO
6b: Y = O; Z = CMe2
R1
regard the [b]-annelation of quinolines gave access to a
O
+
O
Y
9
z
huge number of new quinoline derivatives, besides
providing novel approaches for the synthesis of alkaloids
R1
CHO
Cl
Y
O
N
N
N
H
N
2
X
7a–d
3
a: X = -CH2-CH2-
SYNLETT 2006, No. 16, pp 2593–2596
Advanced online publication: 22.09.2006
0
4
.1
0
.2
0
0
6
X
3b: X = -CH2-
DOI: 10.1055/s-2006-951477; Art ID: D16906ST
Scheme 2
©
Georg Thieme Verlag Stuttgart · New York

2
594
I. Devi et al.
LETTER
Simple acetanilides 1 were taken as starting materials in We then studied the reactivity pattern of 2 and 3 with
our reaction strategy. 2-Chloro-3-formyl quinolines 2 highly active cyclic b-diamide (Barbituric acids) or cyclic
were prepared from acetanilides 1 by modifying the b-dilactone (Meldrum’s acid) 6 under solvent-free condi-
1
5
existing method (Scheme 2). Thus acetanilide 1a on tions (Scheme 2). As expected the dimethyl barbituric
treatment with the Vilsmeier reagent (DMF/POCl ) gave acid and Meldrum’s acid 6 underwent ring closure in
3
1
6
2
-chloro-3-formyl quinoline (2a) in excellent yields. In shorter reaction times to afford the product 7 with the
1
7
a simple three-component reaction equimolar amounts spirocyclic ring system in excellent yields (Table 2).
of 2-chloro-3-formyl quinoline (2a), piperidine (3a) and
malononitrile (4a) were treated at 110–120 °C in the
absence of solvent for five hours. The solid material ob-
tained on cooling the reaction mixture and after work-up
afforded compound 5a in good yield. The structure of the
compound was determined from the spectroscopic data
A reasonable mechanism for the reaction is outlined in
Scheme 3. The base 3 initially catalyses the condensation
of 2 and 4, and then substitutes the chloro group to give
compound [A]. Then compound [A] undergoes a 1,5-hy-
dride shift under thermolytic conditions to generate a 1,6-
dipole [B], which subsequently underwent intramolecular
cyclisation to give the product 5.
and elemental analysis. The IR spectrum exhibited a sharp
–
1
band at 2217 cm confirming the presence of the CN
1
The formation of compound 5 was established by per-
forming the reaction stepwise (Scheme 4). In a simple
experimental procedure equimolar amounts of 2-chloro-
3-formyl quinoline (2a), piperidine (3a) and potassium
carbonate were reacted in DMF under refluxing condi-
tions, which after work-up afforded the product 8a in high
functionality. The H NMR spectra showed the absence of
the aldehyde proton and the presence of a methylene
group at d = 5.30 ppm as a singlet. The mass spectrum
+
revealed a strong molecular ion peak at 289 (M + H) .
With suitable conditions established for the three-compo-
nent reaction, compounds 5b–j were synthesised by util-
ising 2a–c with various secondary amines 3a–c and alkyl
nitriles 4a and 4b (Table 1). The use of less reactive ethyl
cyanoacetate requires a longer reaction time to give
comparatively a lower yield of the cyclised product. The
structures of the compounds were ascertained from their
spectroscopic data and elemental analysis.
18
yield. The structure of the compound was ascertained by
spectroscopy. Then compound 8a was treated with mal-
ononitrile (4a) in the presence of a catalytic amount of 3a
to afford the Knoevenagel product 9 in excellent yields,19
which under thermolytic conditions in the absence of sol-
vent afforded the cyclised product 5a in excellent yield.20
Table 1 Synthesis of Novel Annelated Quinoline Derivatives 5
Product
R1
R2
X
Time (h)
Temp (°C)
110–120
110–120
110–120
110–120
110–120
110–120
110–120
110–120
110–120
110–120
Mp (°C)
169–170
174–175
164–165
147–148
191–192
203–204
183–184
161–162
210–211
218–219
Yield (%)
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
H
Me
CN
CN
(CH2)2
CH2
CH2
5
5
6
6
5
6
6
5
5
5
54
57
52
45
58
60
55
45
51
58
Me
OMe
H
CO Et
(CH )
2
2 2
H
CN
CN
CN
CH2
Me
OMe
H
CH2
g
h
i
CH2
CO Et
CH2
2
H
CN
CN
OCH2
OCH2
j
Me
Table 2 Synthesis of Novel Annelated Quinoline Derivatives 7
Product
R1
X
Y
Z
Time (h)
Temp (°C)
110–120
110–120
110–120
110–120
110–120
110–120
Mp (°C)
Yield (%)
7
7
7
7
7
7
a
b
c
d
e
f
H
(CH2)2
(CH2)2
(CH2)2
CH2
NMe2
NMe2
NMe2
NMe2
NMe2
O
C=O
C=O
C=O
C=O
C=O
CMe2
4
148–149
175–176
139–140
170–171
185–186
165–166
62
59
57
54
52
55
Me
OMe
H
4
4
5
5
4
Me
H
CH2
CH2
Synlett 2006, No. 16, 2593–2596 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Annelated Quinolines
2595
H
N
References and Notes
2
R1
CHO
Cl
R CH2CN
R1
R2
CN
(
1) Suschitzky, H.; Meth-Cohn, O. Adv. Heterocycl. Chem.
972, 14, 211.
4
X
1
H
N
N
N
Cl
(2) Verboom, W.; Reinhoudt, D. N. Recl. Trav. Chim. Pay-Bas
1990, 109, 311.
2
X
(
(
3) Tanaka, T.; Toda, F. Chem. Rev. 2000, 100, 1025.
4) (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366.
(b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
3
R2
R1
R2
CN
R1
–
CN
X
+
N
N
N
N
(5) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
X
(
6) (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
A
B
R1
CN
R2
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,
N
N
X
5
4
3, 6293. (f) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das,
Scheme 3
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.
The structure of the compound was determined from the
physical and spectroscopic data. Similarly compounds 5e,
Lett. 2003, 5, 1205.
5
i and 7a were prepared by the stepwise reaction and then
(
7) (a) Elderfield, R. C. In Heterocyclic Compounds, Vol. 4;
Elderfield, R. C., Ed.; John Wiley Inc.: London, 1960, Chap.
characterised.
1
, 1. (b) Wright, C. W.; Addac-Kyereme, J.; Breen, A. G.;
Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek, Y.; Kendrick,
H.; Phillips, R. M.; Pollet, P. L. J. Med. Chem. 2001, 44,
3187. (c) Sahu, N. S.; Pal, C.; Mandal, N. B.; Banerjee, S.;
Raha, M.; Kundu, A. P.; Basu, A.; Ghosh, M.; Roy, K.;
Bandyopadhyay, S. Bioorg. Med. Chem. 2002, 10, 1687.
CNCH2CN
CHO
N
CHO
N
H 3a
4a
K2CO3
N
Cl
N
(
d) Bringmann, G.; Reichert, Y.; Kane, V. Tetrahedron
N
H
2a
8a
2004, 60, 3539. (e) Kournetsov, V. V.; Mendez, L. Y. V.;
Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141.
8) Antimalarial Drugs II; Peters, W.; Richards, W. H. G., Eds.;
Springer Verlag: Berlin, 1984.
CN
CN
CN
CN
(
N
N
N
N
(9) Meth-Cohn, O. Heterocycles 1993, 35, 359.
(
(
10) (a) Rigby, J. H.; Danca, D. M. Tetrahedron Lett. 1997, 38,
4969. (b) Leue, S.; Miao, W.; Kanazawa, A.; Genisson, Y.;
Garcon, S.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1
9
a
5a
Scheme 4
2001, 2903. (c) Comin, D. L.; Nolan, J. M. Org. Lett. 2001,
3, 1611.
11) (a) Toyata, M.; Komori, C.; Ihara, M. Heterocycles 2002, 56,
In conclusion we have reported the synthesis of some
novel classes of quinolizine-, indolizine- and pyrido-1,4-
oxazine-fused complex quinoline derivatives via a novel
three-component reaction under solvent-free conditions
by exploring the ‘tertiary amine effect’ reaction strategy.
Product formation in the three-component reactions was
established by performing the reactions stepwise. Spiro-
cyclic compounds such as the cyclic b-diamide (uracil de-
rivative) possess a wide range of biological activity and
the b-dilactone (Meldrum’s acid) is transformable to other
functionality and hence there is further scope for molecu-
lar manipulation of these products. This cost-efficient,
environment-friendly and operationally very simple pro-
cedure for the synthesis of tetracyclic angularly annelated
quinolines from easily available starting materials render
this method a valuable addition to quinoline chemistry.
101. (b) Chavan, S. P.; Sivappa, R. Tetrahedron Lett. 2004,
45, 3113. (c) Chavan, S. P.; Sivappa, R. Tetrahedron 2004,
60, 9931. (d) Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe,
H.; Takeuchi, Y. Synlett 2003, 847.
(12) Ma, Z.; Lee, D. Y. Z. Tetrahedron Lett. 2004, 45, 6721.
(13) Carles, L.; Narkunan, K.; Penlou, S.; Rousset, L.; Bouchu,
D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304.
(
14) (a) Devi, I.; Bhuyan, P. J. Synlett. 2004, 283. (b) Devi, I.;
Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 8625. (c) Devi, I.;
Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 7727. (d)Deb,M.
L.; Bhuyan, P. J. Tetrahedron 2005, 46, 6453.
15) Meth-Cohn, O.; Narine, B.; Tarowski, B. Tetrahedron Lett.
1979, 33, 3111.
(
(16) Compound 2a: POCl
wise via dropping funnel to DMF (2.7 mL, 34.65 mmol) at
–5 °C. The mixture was stirred for about 5 min. Acetanilide
1a; 1.42 g, 10.37 mmol) was then added to the reaction
mixture and the resulting solution was heated for 8 h (75–
0 °C). The reaction mixture was cooled to r.t. and then
(9 mL, 98.28 mmol) was added drop-
3
0
(
8
poured into crushed ice with stirring. A pale-yellow precipi-
Acknowledgment
tate appeared at once, which was filtered, washed with H O
2
The authors thank the Department of Science & Technology, India,
for financial support.
and dried. The crude compound was then recrystallised from
EtOAc. Yield: 80% (1.62 g); mp 142–143 °C. Similarly
compounds 2b–d were synthesised and characterised.
Synlett 2006, No. 16, 2593–2596 © Thieme Stuttgart · New York

2
596
I. Devi et al.
LETTER
(
17) Three-Component Synthesis: 2-Chloro-3-formyl quinoline
2a) (1.92 g, 10 mmol) was mixed thoroughly with freshly
yellow solid appeared, which was allowed to settle for 2 h
under ice cooling. The precipitate was filtered under reduced
pressure, dried in a hot-air oven and finally purified by
(
distilled piperidine (3a; 0.991 g, 11.66 mmol) and
malononitrile (4a; 0.660 g, 10 mmol) in a round-bottom
flask. The reaction mixture was allowed to fuse at 110–
column chromatography (CHCl –hexane). Yield: 87.5%
3
(2.1 g); light yellow crystals; mp 84–85 °C. IR: 2935.1,
–
1 1
120 °C for 5 h. The progress of the reaction was monitored
2851.2, 1690.7 cm . H NMR (60 MHz, CDCl ): d = 1.5–
3
by TLC and after its completion the product was separated
1.7 (CH , 6 H), 3.1–3.3 (CH , 4 H), 6.9–7.6 (Ph, 5 H), 8.2
2
2
and purified by preparative TLC (CHCl –hexane, 2:1) to
(CH, 1 H), 9.8 (CHO, 1 H).
3
give 5a. Yield: 540 mg (54%); brown solid; mp 169–170 °C.
(19) Compound 9a: Compound 8a (1.2 g, 5 mmol) and
malononitrile (4a; 0.33 g, 5 mmol) were added to hexane (5
mL) and the resulting solution was stirred at r.t. To this
solution piperidine (1 drop) was added and stirring was
continued for 90 min. After completion of the reaction
(monitored by TLC) the solvent was evaporated to dryness.
The orange solid was further purified by column
–
1 1
IR (CHCl ): 2945, 2854, 2225 cm . H NMR (300 MHz,
3
CDCl ): d = 1.25–1.79 (m, 4 H, CH ), 2.10–2.33 (m, 2 H,
3
2
CH ), 2.79–2.84 (t, 1 H, CH), 3.54–3.73 (m, 2 H, CH ), 5.3
2
2
1
3
(
s, 2 H, CH ), 7.26–7.75 (m, 5 H, Ar). C NMR (CDCl ):
2
3
d = 23.79 (C-10), 24.68 (C-11), 30.12 (C-7), 36.74 (C-9),
3
1
1
1
7.11 (C-12), 45.55 (C-8), 60.06 (C-8a), 112.51 (C-5),
13.63 (CN), 114.75 (CN), 123.84 (C-4), 123.92 (C-2),
27.22 (C-3), 127.36 (C-6), 130.45 (C-6a), 137.03 (C-12b),
chromatography using (CHCl –hexane). Yield: 88.5% (1.24
3
g); orange crystals; mp 127–129 °C. IR: 2938, 2851, 2229
+
–1 1
47.89 (C-5a), 152.96 (C-1a). MS: m/z = 289 (M + H) .
cm . H NMR (60 MHz, CDCl ): d = 1.5–1.8 (CH , 4 H),
3
2
Similarly compounds 5b–j and 7a–f were synthesised and
characterised.
3.1–3.3 (CH , 4 H), 7.0–7.8 (Ph, 5 H), 8.5 (CH, 1 H). Yield:
2
1.24 g (88.5%). Similarly compounds 9b and 9c were
synthesised and characterised.
(
18) Compound 8a: 2-Chloro-3-formyl quinoline (2a; 1.92 g, 10
mmol) was mixed thoroughly with freshly distilled
piperidine (3a; 0.991 g, 11.66 mmol) and K CO (1.469 g,
(20) Compound 5a: Compound 9a (1 g, 3.47 mmol) was allowed
to fuse at 110–120 °C for 5 h. The conversion was monitored
by TLC. The new compound was separated by preparative
2
3
1
1.66 mmol) in DMF (50 mL). The resulting mixture was
allowed to reflux for 7 h. After completion of the reaction
monitored by TLC), the mixture was cooled to r.t. and
poured into crushed ice under continuous stirring. A light-
TLC (CHCl –hexane, 2:1) to give a brown solid. Similarly
3
(
compounds 5e, 5i and 7a were synthesised and
characterised.
Synlett 2006, No. 16, 2593–2596 © Thieme Stuttgart · New York