Efficient one-pot synthesis of 2-oxo-1,9a-dihydro-2H-pyrido[1,2-a] pyrimidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.12.082

Pyridines react smoothly with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce dialkyl 2-oxo-1,9a-dihydro-2H-pyrido[1,2-a] pyrimidine 3,4-dicarboxylates in excellent yields.

Full text of DOI:10.1016/j.tetlet.2003.12.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1803–1805
Efficient one-pot synthesis of 2-oxo-1,9a-dihydro-2H-pyrido-
[1,2-a]pyrimidine derivatives
Mehdi Adib,* Hossine Yavari and Mehdi Mollahosseini
Department of Chemistry, Faculty of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Received 15 September 2003; revised 1 December 2003; accepted 12 December 2003
Abstract—Pyridines react smoothly with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce dialkyl 2-oxo-
1,9a-dihydro-2H-pyrido[1,2-a]pyrimidine 3,4-dicarboxylates in excellent yields.
Ó 2003 Elsevier Ltd. All rights reserved.
The development of simple synthetic routes for widely
used organic compounds from readily available reagents
is one of the major tasks in organic synthesis.1 Bridge-
head nitrogen heterocycles are of interest because they
constitute an important class of natural and unnatural
products, many of which exhibit useful biological
activity.2;3 The interest in bicyclic 6–6 systems with one
ring junction and one extra nitrogen atom, stems from
the appearance of saturated and partially saturated
pyrido[1,2-a]pyrimidine ring systems in many biologi-
cally active compounds and natural products,3–9 some of
which are key intermediates for the synthesis of rutae-
carpine alkaloids, some have characteristic pharmaco-
logical properties such as analgesic antiallergic,
antiasthmatic and antipsychotic agents, and some are
neutral hydrogen chloride acceptors in organic synthe-
sis.3
was added slowly. The reactions proceeded spontane-
ously in CH2Cl2 and were complete within a few
hours.15
The 1H NMR spectrum of 4a exhibited15 two single
sharp lines readily recognized as arising from methoxy
protons (d 3.82 and 3.97) along with four multiplets for
the protons of an electron rich diene and an allylic
proton as well as characteristic multiplets for the aro-
matic protons. The 1H decoupled 13C NMR spectrum of
4a showed 16 distinct resonances in agreement with the
structure of the product.
Although we have not established the mechanism of this
reaction between pyridines and acetylenic esters in the
presence of isocyanates in an experimental manner, a
possible explanation is proposed in Scheme 2. The first
step may involve addition of the pyridine to the acetyl-
enic ester and formation of the 1:1 adduct 5. Subsequent
nucleophilic attack of the adduct to the isocyanate
would yield bidentate anions 6 and 7. The observed
product is formed from the intramolecular addition of
the nitrogen to the pyridinium moiety.
As part of our current studies on the development of
new routes in heterocyclic synthesis,10–14 in this letter, we
wish to report that pyridines 1 undergo a smooth reac-
tion with dialkyl acetylenedicarboxylates 2 in the pres-
ence of isocyanates 3 in dry dichloromethane at ambient
temperature to produce functionalized 2-oxo-1,9a-di-
hydro-2H-pyrido[1,2-a]pyrimidines 4 in 85–98% yields
(Scheme 1).
The 13C NMR spectrum was used to distinguish the
isolated product from the other possible structure 8.
Thus, the 13C NMR spectrum of the isolated product
exhibited a methine carbon resonance at about d 70 ppm
for C9aH. The chemical shift for the methine carbon in 8
would be expected to appear at about d 80 ppm.16
The reactions were carried out by first mixing the pyr-
idine and the isocyanate and then the acetylenic ester
An alternative possible structure, 1-oxo-2,4a-dihydro-
1H-pyrido[1,2-c]pyrimidine 9 (Scheme 3), which fits the
analytical data, can be readily ruled out. This structure
would be derived from initial addition of the pyridine to
Keywords: Pyridines; Acetylenic esters; Isocyanates; 2-Oxo-1,9a-dihy-
dro-2H-pyrido[1,2-a]pyrimidine derivatives.
* Corresponding author. Fax: +98-21-6495291; e-mail: madib@
khayam.ut.ac.ir
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.082

1804
M. Adib et al. / Tetrahedron Letters 45 (2004) 1803–1805
R
N
R
CH2Cl2
r.t., 2 h
R"
R"
N
+
N
C
O
R'O2C
C
C
CO2R'
+
N
O
R'O2C
CO2R'
1
2
3
4
4
R
H
H
CH3
CH3
H
H
H
R'
R"
% Yield
98
95
92
85
90
96
95
95
a
b
c
d
e
f
CH3 C6H5
C2H5 C6H5
CH3 C6H5
C2H5 C6H5
CH3 Cyclohexyl
CH3 3,4-Cl2C6H3
C2H5 Cyclohexyl
C2H5 3,4-Cl2C6H3
g
h
H
Scheme 1.
R
R
R
R
N
1
CO2R'
C
+
N
+
N
_
+
N
R"
_
N
C
O
+
NR"
O
(3)
C
_
R'O2C
R'O2C
R'O2C
O
NR"
CO2R'
CO2R'
CO2R'
CO2R'
2
5
6
7
R
R
N
R"
N
O
N
NR"
O
R'O2C
R'O2C
CO2R'
CO2R'
8
4
Scheme 2.
R
N
CO2CH3
CO2CH3
CO2CH3
CO2R'
N
N
O
CO2R'
CH3O2C
N
CO2CH3 CH3O2C
R"
CO2CH3
CO2CH3
9
10
11
Scheme 3.
the isocyanate, followed by cycloaddition of the adduct
to the acetylenic ester. However, when pyridine and
phenyl isocyanate were mixed under the reaction con-
ditions, the reactants were recovered unchanged. Any
product resulting from the nucleophilic attack of pyr-
1
idine onto the isocyanate was not detected by H and
13C NMR spectroscopy. In addition, when pyridine,
phenyl isocyanate and dimethyl acetylenedicarboxylate

M. Adib et al. / Tetrahedron Letters 45 (2004) 1803–1805
1805
8. Djerrari, B.; Essassi, E. M.; Fifani, J.; Garrigues, B.
Comptes Rendus Chimie 2002, 5, 177.
9. Mellor, J. M.; Merriman, G. D.; Rataj, H.; Reid, G.
Tetrahedron Lett. 1996, 37, 2615.
10. Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin
Trans. 1 2002, 21, 2343.
11. Yavari, I.; Adib, M.; Jahani-Moghaddam, F.; Bijanzadeh,
H. R. Tetrahedron 2002, 58, 6901.
were mixed all at once, 9aH-quinolizine 10 and its 4H
isomer 1117 (Scheme 3) were formed under the reaction
conditions whilst phenyl isocyanate was recovered
unchanged. Consequently, the isolated product 4 is
formed from the initial attack of the pyridine on the
acetylenic ester.
In summary, the present method carries the advantage
that, not only is the reaction performed under neutral
conditions, but the substances can be mixed without any
activation or modification. The simplicity of the present
procedure makes it an interesting alternative to other
approaches. The procedure described here provides an
acceptable one-pot method for the preparation of
functionalized 2-oxo-1,9a-dihydro-2H-pyrido[1,2-a]pyr-
imidines.
12. Yavari, I.; Adib, M.; Sayahi, M. H. Tetrahedron Lett.
2002, 43, 2927.
13. Yavari, I.; Adib, M.; Hojabri, L. Tetrahedron 2002, 58,
6895.
14. Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin
Trans. 1 2002, 13, 1517.
15. The procedure for the preparation of dimethyl 2-oxo-1-
phenyl-1,9a-dihydro-2H-pyrido[1,2-a]pyrimidine 3,4-dicarb-
oxylate 4a is described as an example. To a magnetically
stirred solution of phenyl isocyanate (0.119 g, 1 mmol) and
pyridine (0.079 g, 1 mmol) in dry CH2Cl2 (5 mL) was
added dropwise a mixture of dimethyl acetylenedicarb-
oxylate (0.142 g, 1 mmol) in CH2Cl2 (2 mL) at )5 °C over
10 min. The reaction mixture was allowed to warm to
room temperature and stirred for 2 h. The solvent was
removed under reduced pressure and the residue was
crystallized from 2:1 hexane–ethyl acetate. The product 4a
was obtained as yellow crystals, mp 117–119 °C, 0.33 g,
yield 98%. IR (KBr) (mmax/cmꢀ1): 1739, 1695, 1668, 1525,
1255. MS, m=z (%): 340 (Mþ, 10). Anal. Calcd for
C18H16N2O5 (340.34): C, 63.5; H, 4.7; N, 8.2. Found: C,
Acknowledgements
This research was supported by the Research Council of
the University of Tehran as a research project (514/4/
626).
References and notes
1
63.4; H, 4.8; N, 8.2. H NMR (500 MHz, CDCl3): d 3.82
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