One-pot synthesis of 2H-quinolizine and 1H-pyrido[1,2-a]qinoline derivatives by using dialkylcarbodiimides

Article abstract of DOI:10.14233/ajchem.2013.13772

Reaction of the zwitter ions generated from pyridine and dialkylacetylene dicarboxylate with electron-deficient dialkylcarbodiimides lead to substituted 2H-quinolizines.

Full text of DOI:10.14233/ajchem.2013.13772

Asian Journal of Chemistry; Vol. 25, No. 7 (2013), 4111-4112
http://dx.doi.org/10.14233/ajchem.2013.13772
NOTE
One-Pot Synthesis of 2H-Quinolizine and 1H-Pyrido[1,2-a]qinoline
Derivatives by Using Dialkylcarbodiimides
1
1
1
1
S.S. GHAFOURI , M. AMIR AFSHARI , N. SAEEDI , H. DJAHANIANI2,* and B. MOHTAT
1Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran
2Department of Chemistry, East Tehran Branch, Islamic Azad University, P.O. Box 1866113118, Tehran, Iran
*Corresponding author: Fax: +98 21 33594337; E-mail: jahanbani.ho@gmail.com
(Received: 20 March 2012;
Accepted: 30 January 2013)
AJC-12770
Reaction of the zwitter ions generated from pyridine and dialkylacetylene dicarboxylate with electron-deficient dialkylcarbodiimides lead
to substituted 2H-quinolizines.
Key Words: 2H-Quinolizine, Synthesis, Zwitter ion, Electron-deficient.
Quinolizines are of considerable interest due to their wide-
spread occurrence in natural products, particularly in the field
of alkaloids1. A large variety of nitrogen heterocycles are
known to form zwitter ionic species on addition of activated
olefins or acetylenes. The earliest work in the area was reported
by Diels and Alder and their study2 and subsequently the
structure elucidation of Acheson3 showed that pyridine reacts
smoothly with dimethyl acetylene dicarboxylate (DMAD) to
form 4H-quinolizine.
meter operating at an ionization potential of 70 eV. IR spectra
were measured on a Shimadzu IR-460 spectrometer. 1H and
13C NMR spectra were measured on a BrukerAvance DRX-
300 spectrometer using CDCl3 as applied solvent and TMS as
internal standard at 300 and 75 MHz, respectively.
To a stirred solution of dimethyl acetylenedicarboxylate
(0.48 mL, 4 mmol) and pyridine (0.16 g, 2 mmol) in 10 mL
CH2Cl2 was added drop wise at -10 ºC over 10 min dicyclo-
carbodiimide (DCC) (0.41 g, 2 mmol). The reaction mixture
was then allowed to warm up to room temperature and stand
for 24 h. The solvent was removed under reduced pressure
and the residual products were purified by recrystallized from
diethyl ether as yellow powder; yield: 0.44 g (55 %), m.p. 154
ºC. IR (KBr, νmax, cm-1): 1740, 1715 and 1666 (3 C=O), 1632
(C=N). 1H NRM δ 1.21-1.96 (m, 10H, 5CH2), 3.43-3.51 (m,
1H, CHN), 3.91 (s, 3H, OCH3), 3.97 (s, 6H, 2OCH3), 7.51 (t,
1H, J = 7.0 Hz, CH), 8.01 (t, 1H, J = 8.6 Hz, CH), 8.83 (d, 1H,
J = 9.1 Hz, CH), 9.46 (d, 1H, J = 7.1 Hz, CH) ppm. 13C NMR
δ 24.8 (2CH2), 25.5 (CH2), 33.6 (2CH2), 49.4 (CHN), 52.2
(OCH3), 52.5 (2OCH3), 103.9 (C), 115.0 (C), 118.8 (CH),
124.8 (CH), 129.6 (CH), 138.1 (CH), 145.3 (C), 146.8 (C),
156.6 (N-C=N), 163.9 (C=O), 164.5 (C=O), 165.9 (C=O) ppm.
Anal. calcd. (%) for C21H24N2O6 (400): C, 62.99; H, 6.04; N,
7.00; Found (%): C, 63.08; H, 5.98; N, 7.15.
Herein we report the reaction of pyridine with dialkyl-
acetylene dicarboxylates 1 in the presence of dialkylcarbodi-
imides 2 in dry dichloromethane at ambient temperature to
produce 4H-quinolizine-1,2,3,4-tetracarboxylate (Scheme-I).
CO2R'
CO2R'
CO2R'
+
CO2R'
NR
CH2Cl2
r.t
2
+
R
N
C
N
R
+
N
N
CO2R'
R'
N
CO2R'
CO2R'
R'
CO2R'
CO2R'
R
1
2
4
R
3
a
Me
Et
a
a
Cyclohexyl
Cyclohexyl
Me
Et
b
b
c
Cyclohexyl
Cyclohexyl
tBu
tBu
c
Scheme-I
Chemicals were purchased from Fluka and used without
further purification. Melting points were measured on an
Electrothermal 9100 apparatus. Elemental analyses for C, H
and N were performed using a Heraeus CHN-O-Rapid analyzer
and the results agreed favorably with the calculated values.
Mass spectra were recorded on a Finnigan MAT 8430 spectro-
Triethyl 2-(cyclohexylimino)-2H-quinolizine-1,3,4-
tricaboxylate (4b):Yellow powder; yield: 0.51 g (58 %), m.p.
165 ºC. IR (KBr, νmax, cm-1): 1741, 1710 and 1666 (3C=O),
1
1619 (C=N). H NMR δ 1.08-1.96 (m, 10H, 5CH2), 1.19 (t,
3H, J = 7.1 Hz, CH3), 1.35 (t, 3H, J = 7.1 Hz, CH3), 1.38 (t,

4112 Ghafouri et al.
Asian J. Chem.
3H, J = 7.1 Hz, CH3), 3.37-3.45 (m, 1H, CH), 4.14 (q, 2H, J =
7.1 Hz, OCH2), 4.39 (q, 2H, J = 7.1 Hz, OCH2), 4.44 (q, 2H,
J = 7.1 Hz, OCH2), 7.37 (t, 1H, J = 7.3 Hz, CH), 7.98 (t, 1H,
J = 8.9 Hz, CH), 8.65 (d, 1H, J = 8.9 Hz, CH), 9.54 (d, 1H,
J = 7.4 Hz, CH) ppm. 13C NMR δ = 13.3 (CH3), 13.4 (CH3),
13.8 (CH3), 24.3 (2CH2), 25.0 (CH2), 33.2 (2CH2), 49.0 (CHN),
61.6, (OCH2), 61.8 (OCH2), 61.9 (OCH2), 104.0 (C), 114.8
(C), 118.6 (CH), 124.7 (CH), 129.5 (CH), 137.7 (CH), 145.7
(C), 148.9 (C), 156.7 (N-C=N), 164.2 (C=O), 165.0 (C=O),
165.2 (C=O) ppm. Anal. calcd. (%) for C24H30N2O6 (442): C,
62.67; H, 6.51; N, 6.96; Found (%): C, 62.23; H, 6.70; N,
7.12. MS (EI, 70 eV): m/z (%) = 442 (M+, 5), 346 (90), 316
(90), 242 (100), 170 (60).
calcd. (%) for C25H26N2O6 (450): C, 66.66; H, 5.82; N, 6.22;
Found (%): C, 66.74; H, 5.68; N, 6.15.
The reactions proceeded spontaneously in CH2Cl2 and
1
were completed within a few hours. The H and 13C NMR
spectra of the crude products clearly indicated the formation
of 3 and 4. The structures of compounds 4a-c were deduced
from their elemental analyses and their IR, 1H and 13C NMR
spectra.
Although the mechanistic details of the reaction are not
clearly known, a plausible rationalization may be advanced to
explain the product formation. Presumably, the zwitter ion 5
formed from pyridine and the acetylenic compound4-7 adds to
the dicyclocarbodiimide to furnish intermediate 6, which then
adds to another molecule of acetylenic ester to produce 7. This
intermediate undergoes cyclization to furnish the fused
structure 8. Intermediate 8 is converted to 9 by recyclization
and then by elimination of 10, the product 4 is produced
(Scheme-II).
Tri(tert-butyl) 2-(cyclohexylimino)-2H-quinolizine-
1,3,4-tricaboxylate (4c): Yellow powder; yield: 0.50 g (48
%), m.p. 157-159 ºC. IR (KBr, νmax, cm-1): 1739, 1712 and
1660 (3C=O), 1625 (C=N). 1H NMR δ = 1.21-1.95 (10 H, m,
5 CH2), 1.57 (s, 9H, CMe3), 1.62 (s, 9H, CMe3), 1.64 (s, 9H,
CMe3), 3.34-3.42 (m, 1H, CH), 7.51 (t, 1H, J = 6.7 Hz, Hz,
CH), 7.94 (t, 1H, J = 8.6 Hz, CH), 8.75 (d, 1H, J = 9.0 Hz,
R
CO2R'
N
13
2
+
+
C
N
R
+
CH), 9.48 (d, 1H, J = 7.1 Hz, CH) ppm. C NMR δ = 24.9
_
N
N
N
+
+
(2CH2), 25.5 (CH2), 33.8 (2CH2), 27.9 (CMe3), 28.1 (CMe3),
28.2 (CMe3), 49.4 (CHN), 81.2 (C), 82.8 (C), 83.2 (C), 103.9
(C), 115.0 (C), 118.8 (CH), 124.8 (CH), 129.6 (CH), 138.1
(CH), 145.3 (C), 145.7 (C), 156.6 (N-C=N), 162.1 (C=O),
164.3 (C=O), 164.8 (C=O) ppm. Anal. calcd. (%) for
C30H42N2O6 (526): C, 68.42; H, 8.04; N, 5.32; Found (%): C,
68.49; H, 7.98; N, 5.26
CO2R'
NR
_
C
R'O2C
R'O2C
R'O2C
2
NR
1
CO2R'
5
6
R
N
CO2R'
CO2R'
CO2R'
_
_
H
CO2R'
NR
10
CO2R'
R
4
CO2R'
N
N
N
+
CO2R'
NR
N
N
R'O2C
R'O2C
CR'O2C
R'O2C
R
CO2R'
R'O2C
NR
NR
Trimethyl 1-(cyclohexylimino)-1H-pyrido-[1,2-a]-
quinoline-2,3,4-tricaboxylate (11): Yellow powder; yield:
0.54 g (60 %), m.p. 162 ºC. IR (KBr, νmax, cm-1): 1738, 1714
8
7
9
Scheme-II
1
and 1660 (3 C=O), 1624 (C=N). H NMR δ: 0.87-1.36 (m,
Quinoline and isoquinoline were employed to react with
dimethyl acetylenedicarboxylates1 and dicyclohexylcarbo
diimde 2 under above conditions produce trimethyl 3-(cyclo-
hexylimino) 3H-pyrido[1,2-a]quinoline-1,2,4-tricarboxylates
11 and trimethyl 2-(cyclohexylimino) 2H-pyrido[2,1-
a]isoqunoline-1,3,4-tricarboxylates 12, respectively (Scheme-
III).
10H, 5CH2), 3.58-3.76 (m, 1H, CHN), 3.88 (s, 3H, OCH3),
3.94 (s, 6H, 2OCH3), 6.87 (dt, 1H, J = 6.7 Hz and J = 1.0 Hz,
CH), 7.70 (dt, 1H, J = 8.6 Hz and J = 1.3 Hz, CH), 7.85 (d,
1H, J = 9.4 Hz, CH), 8.01 (dd, 1H, J = 7.8Hz and J = 1.5 Hz,
CH), 8.15 (d, 1H, J = 8.6 Hz, CH), 8.25 (d, 1H, J = 9.4 Hz,
CH) ppm. 13C NMR δ: 24.4 (2CH2), 25.6 (CH2), 31.1 (2CH2),
49.8 (CHN), 51.8 (OCH3), 52.8 (2OCH3), 104.3 (C), 118.2
(C), 120.3 (C), 126.2 (CH), 126.8 (CH), 129.3 (CH), 129.7
(CH), 129.9 (CH), 131.3 (C), 131.9 (C), 133.4 (C), 137.9 (CH),
155.2 (N-C=N), 162.7 (C=O), 163.6 (C=O), 165.7 (C=O) ppm.
Anal. calcd. (%) for C25H26N2O6 (450): C, 66.66; H, 5.82; N,
6.22; Found (%): C, 66.58; H, 5.78; N, 6.17.
CO2Me
CO2Me
N
N
CO2Me
N
N
MeO2C
MeO2C
CO2Me
Trimethyl 4-(cyclohexylimino)-4H-pyrido[2,1-a]-
isoquinoline-1,2,3-tricaboxylate (12):Yellow powder; yield:
0.58 g (65 %), m.p. 178 ºC. IR (KBr, νmax, cm-1): 1739, 1720
11
12
Scheme-III
1
and 1665 (3C=O), 1619 (C=N). H NMR δ: 1.01-1.84 (m,
REFERENCES
10H, 5CH2), 3.54-3.65 (m, 1H, CHN), 3.90 (s, 3H, OCH3),
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