Catalyst-free synthesis of alkyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxylate derivatives on water

Article abstract of DOI:10.1016/j.tet.2014.02.084

An environmentally friendly and effective method to construct 4H-pyrido[1,2-a]pyrimidin-4-one, which are ubiquitous structural units in a number of biologically active compounds has been developed. In this process, the reaction using water as the solvent in absence of catalyst under the mild conditions makes transformations very green, practical, and attractive.

Full text of DOI:10.1016/j.tet.2014.02.084

Tetrahedron 70 (2014) 2761e2765
Contents lists available at ScienceDirect
Tetrahedron
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Catalyst-free synthesis of alkyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate derivatives on water
,
,
,
,
,b
Hao Yan a b, Ying Ma a b, Yuanjun Sun c, Chao Ma a b, Yuling Wang a b, Xiaoyu Ren a
,
Guosheng Huang a
,b,
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, China
c Jin chuan Group Co., Ltd, Jinchang 737104, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally friendly and effective method to construct 4H-pyrido[1,2-a]pyrimidin-4-one, which
are ubiquitous structural units in a number of biologically active compounds has been developed. In this
process, the reaction using water as the solvent in absence of catalyst under the mild conditions makes
transformations very green, practical, and attractive.
Received 10 November 2013
Received in revised form 20 February 2014
Accepted 27 February 2014
Available online 10 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst-free
Green chemistry
Heterocycles
Cycloaddition
On water
Pyrido[1,2-a]pyrimidines
1. Introduction
Heterocyclic compounds1 as important building blocks have
been applied in medical science,2,3 natural products synthesis4 as
well as many functional materials.5 Recently, our group have re-
ported several strategies of imidazo[1,2-a]pyridine6 heterocycle
derivatives from readily available aminopyridines and nitroalkenes
(Scheme 1, A, B).7 The Michael addition intermediates of amino-
pyridines and nitroalkenes involved the pyridine nitrogen in
a regioselective 5-exo-trig fashion to give the cyclization products.
Encouraged by these progresses, we continued our interest for
synthesizing some other building blocks. Fortunately, we explored
2-aminopyridines and dialkyl ethylenedicarboxylates to produce
alkyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate derivatives
(Scheme 1, C).
Scheme 1. Strategies for heterocycles synthesis.
The pyrido[1,2-a]pyrimidines, in particular, 4H-pyrido[1,2-a]
pyrimidin-4-one, are being increasingly motif to study,8 because of
their valuable biologically properties,9 tremendous applications in
medicinal and drug synthesis.10 They are widely used in clinical
treatment of many diseases (Scheme 2), such as seganserin (an
antihypertensive, I),11 barmastine (the antiallergic agent, II),12
pemirolast (an antiallergic agent, III),12b pirenperone (the tran-
quilizer, IV),13 and lusaperidone (the antidepressant, V).14
Consequently, many efforts have been devoted to the con-
struction of their preparation. To the best of our knowledge, several
strategies for the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-one
have been reported.15 However, they suffered from one or more
shortcomings in terms of applicabilities and reaction conditions.
* Corresponding author. Tel./fax: þ86 0931 8912582; e-mail address: hgs@lzu.
edu.cn (G. Huang).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.084

2762
H. Yan et al. / Tetrahedron 70 (2014) 2761e2765
reaction conditions (Table 1). In this preliminary experiment, the
reaction was carried out without catalyst at room temperature for
6 h on 30 mL water. To our delight, the desired product methyl 4-
oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (3aa) was ob-
tained with the yield of 82%. The structure of (3aa) through an X-
ray crystal analysis was confirmed unambiguously (Fig. 1). We ex-
pected that the reaction yield could be improved by reagent con-
trol, and then different solvents were screened. First, the reaction
was conducted in toluene, we could not get desirable product, even
if for 12 h (Table 1, entries 2 and 3). The corresponding neat (sol-
vent-free) reaction or in MeOH, expected product was still not
obtained (Table 1, entries 7 and 5). While in DMF and miscible
solvent (Acetone and H2O), the product was isolated, in spite of
lower yields than water (Table 1, entries 4 and 6). Thus, water as
a suspension in improving the reaction efficiency. In order to fur-
ther improve the reaction efficiency, different catalysts were in-
vestigated. When the reactions were catalyzed by different copper
salts (Table 1, entries 8e11, entries 13 and 14) and palladium salt
(Table 1, entry 12), catalysts failed to ameliorate the yields. Pro-
longing the reaction time did not increase the yield (Table 1, entry
16), while shorter reaction time reduced the yield in 78% (Table 1,
entry 15). Raising the reaction temperature to 50 ꢀC or higher (Table
1, entries 17e19) did not promote the yield obviously, but it could
shorten the reaction time. Considering developing an economic
and eco-friendly reaction system, the room temperature was
clearly the most appropriate. When the reaction was carried out
under an atmosphere of nitrogen, the yield was slightly decreased
(Table 1, entry 20). The similar effect to air was observed under the
atmosphere of oxygen (Table 1, entry 21). Thus, air was chosen as
gas atmosphere for its low cost, and convenience. With a series of
detailed investigations mentioned above, the reaction conditions
were eventually identified (Table 1, entry 1).
Scheme 2. Known biologically active compounds containing 4H-pyrido[1,2-a]pyr-
imidin-4-one core.
For instance, most of them were limited due to high temperature,16
high pressure,16b,17 or the presence of catalyst,18 therefore, a mild
and practical procedure is desirable. In recent years, environmental
issues have received increasing attentions. Developing benign and
environmental transformations have been positioned high on the
agenda of synthetic chemists. A large number of endeavours mainly
focus on efficient conversion with green solvent. As we known,
water is an ideal solvent owing to its safe, abundant and sustain-
able. With the development of green chemistry ideology,19 using
water as medium has drawn much attention.20 Herein, we wish to
report the first work for the synthesis of alkyl 4-oxo-4H-pyrido[1,2-
a]pyrimidine-2-carboxylate from 2-aminopyridines and dialkyl
ethylenedicarboxylates on water.
2. Results and discussions
Initially, 2-aminopyridine (1a) and dimethyl acetylenedi-
carboxylate (2a) were used as the model substrates to optimize the
Table 1
Optimization of reaction conditions with 2-aminopyridine 1a and dimethyl acety-
lenedicarboxylate 2aa
Entry
Catalyst
T(ꢀC)
t(h)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
None
None
None
None
None
None
None
CuI
CuBr
CuCl
Cu(OAc)2
Pd(OAc)2
CuCl
Cu(OAc)2
None
None
None
None
None
None
None
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
80
80
rt
6
6
12
6
6
6
6
6
6
6
6
6
2
2
4
8
4
H2O
82
0
0
15
0
70
0
60
64
70
71
65
75
78
78
82
82
83
83
70
82
Fig. 1. The crystal structure of 3aa.
Toluene
Toluene
DMF
MeOH
Actone/H2O (1:1)
Neat
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Having established the optimal reaction conditions, the scope of
the substrates was examined (Table 2). In most cases, the reactions
of 2-aminopyridines and dialkyl acetylenedicarboxylate were pro-
ceeded smoothly, and the yields were moderate to good, up to 97%
(Table 2, entry 16). It was observed that the nature of the sub-
stituent on the pyridine ring had some influence on the yields of the
products. As illustrated in Table 2, 2-aminopyridines containing
electron-rich groups resulted in higher yields than electron-
deficient ones (Table 2, entries 2e4, 12, 15 and 16, vs entries 6e9,
18e20). 2-aminopyridines substituted with methyl at 5-position
gave products in highest yields (Table 2, entries 4 and 16). After
further investigation, we found that the product yields of diethyl
acetylenedicarboxylate were slightly higher than dimethyl acety-
lenedicarboxylate, which perhaps was attributed to the electronic
effects (Table 2, entries 15e18, 20 vs entries 3e6, 9). Unfortunately,
when 6-substituted 2-aminopyridines were subjected to the re-
action system, no separable product was formed, which could be
due to the great steric effects of 6-substituted groups on the pyri-
dine rings. Furthermore, when 2-aminopyrimidine was tested,
9
10
11
12
13
14
15
16
17
18
19
20c
21d
rt
50
80
98
rt
2.5
1.5
6
H2O
H2O
rt
6
a
Reaction conditions: 1a (0.32 mmol), 2a (0.38 mmol), catalyst-free, on 30 mL
water for 6 h in air.
b
Isolated yield.
The reaction was performed under N2 atmosphere.
The reaction was performed under O2 atmosphere.
c
d

H. Yan et al. / Tetrahedron 70 (2014) 2761e2765
2763
Table 2
acetylenedicarboxylate on water. Reactions were performed at
room temperature in air, which made the process economical,
available and practical. The procedure is suitable for many sub-
strates and proceeds in moderate to good yields. We predict that
this simple and environmentally friendly route to synthesize alkyl
4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate derivatives has
great potential in future medicinal chemistry.
Synthesis of alkyl 4-oxo-4H-pyrido[1,2-a]pyrimidines derivatives from 2-
aminopyridines and dialkyl ethylenedicarboxylatesa
4. Experimental section
4.1. General remarks
Entry
R1/X
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1a
1b
1c
1d
1e
1f
H/C
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
3aa
3ba
3ca
3da
d
82
60
74
83
d
3-Me/C
4-Me/C
5-Me/C
6-Me/C
5-F/C
Column chromatography was carried out on silica gel. 1H NMR
spectra were recorded on 400 MHz in CDCl3 and 13C NMR spectra
were recorded on 100 MHz in CDCl3 using TMS as internal standard.
All new compounds were further characterized by HRMS or MS.
Copies of their 1H NMR and 13C NMR spectra were provided. All
melting points were determined without correction. Commercially
available reagents and solvents were used without further
purification.
3fa
3ga
3ha
3ia
d
45
71
39
47
d
4-Cl/C
5-Cl/C
9
5-Br/C
6-Br/C
3-BnO/C
4-COOEt/C
H/C
3-Me/C
4-Me/C
5-Me/C
6-Me/C
5-F/C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3ka
3la
3ab
3bb
3cb
3db
d
40
72
82
35
86
97
d
4.2. Typical procedure for the preparation of alkyl 4-oxo-4H-
pyrido[1,2-a]pyrimidine-2-carboxylate derivatives
3fb
3gb
3ib
d
52
53
50
d
A flask was charged with 1 (0.32 mmol) and water (30 mL). Then
2 (0.38 mmol) was added to the reaction system. The reaction was
stirred at room temperature for 6 h in air. Then the reaction was
extracted with CH2Cl2 (20 mL) and dried over anhydrous Na2SO4.
After the solvent was evaporated in vacuo, the residues were pu-
rified by column chromatography, eluting with petroleum ether
(PE)eEtOAc to afford pure 3.
1g
1i
1j
1k
1l
1m
4-Cl/C
5-Br/C
6-Br/C
3-BnO/C
4-COOEt/C
H/N
Et
Et
Me
3kb
3lb
d
15
56
d
a
Reaction conditions: 1a (0.32 mmol), 2a (0.38 mmol), catalyst-free, in 30 mL
water for 6 h under air.
4.2.1. Methyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate
(3aa). Yellow solid: mp 168e170 ꢀC. 1H NMR (400 MHz, CDCl3):
even if the temperature reached the boiling point of the solvent, no
desired product was achieved.
d
9.10 (d, J¼7.2 Hz, 1H), 7.91e7.89 (m, 2H), 7.34e7.30 (m, 1H), 7.19 (s,
1H), 4.05 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
164.6, 157.9, 151.5,
On the basis of the results obtained, a mechanism is proposed
and summarized in Scheme 3. The initial step includes the coupling
of substrate 1 and 2 to generate Michael addition intermediate 4.
Subsequently, electron transfer and intramolecular nucleophilic
attack involving the pyridine nitrogen in a regioselective 6-endo-
trig fashion lead to intermediate 5, which undergoes elimination
R2OH to provide the cyclization product 3.
151.0, 136.9, 127.09, 127.07, 116.5, 105.2, 53.1 ppm; HRMS (ESI) calcd
for C10H9N2O3 [MþH]þ: 205.0608; found: 205.0603.
4.2.2. Methyl 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3ba). Yellow solid: mp 175e177 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.99 (d, J¼7.2 Hz, 1H), 7.68 (d, J¼6.8 Hz, 1H),
7.17e7.14 (m, 2H), 4.01 (s, 3H), 2.69 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 165.2, 158.9, 151.2, 150.9, 136.3, 135.7, 125.4, 116.1, 105.3,
53.1,18.2 ppm; HRMS (ESI) calcd for C11H11N2O3 [MþH]þ: 219.0764;
found: 219.0767.
4.2.3. Methyl 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3ca). Yellow solid: mp 183e185 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.98 (d, J¼7.6 Hz, 1H), 7.68 (s, 1H), 7.13 (s, 1H),
7.12e7.09 (m, 1H), 4.03 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 165.0, 158.3, 152.0, 151.2, 149.4, 126.6, 125.5, 119.3, 104.6,
53.3, 21.5 ppm; HRMS (ESI) calcd for
219.0764; found: 219.0761.
C
11H11N2O3 [MþH]þ:
4.2.4. Methyl 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3da). Yellow solid: mp 197e198 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.91 (s, 1H), 7.82 (d, J¼8.8 Hz, 1H), 7.72 (d,
Scheme 3. Proposed reaction mechanism.
J¼8.8 Hz, 1H), 7.17e7.15 (m, 1H), 4.03 (s, 3H), 2.49 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 164.8, 157.9, 151.3, 150.0, 139.8, 127.2, 126.6,
124.7, 105.0, 53.2, 18.3 ppm; HRMS (ESI) calcd for C11H11N2O3
3. Conclusion
[MþH]þ: 219.0764; found: 219.0770.
In summary, we have demonstrated a catalyst-free and green
protocol for the synthesis of alkyl 4-oxo-4H-pyrido[1,2-a]pyrimi-
dine-2-carboxylate derivatives from 2-aminopyridines and dialkyl
4.2.5. Methyl 7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3fa). Yellow solid: mp 200e202 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
9.02e8.99 (m,1H), 7.94 (d d, J¼9.6 Hz, J¼5.2 Hz,

2764
H. Yan et al. / Tetrahedron 70 (2014) 2761e2765
1H), 7.79e7.75 (m, 1H), 7.22 (s, 1H), 4.04 (s, 3H); 13C NMR (100 MHz,
CDCl3):
NMR (100 MHz, CDCl3): d 164.4, 158.3, 152.4, 151.2, 149.2, 126.5,
d
164.7, 157.7 (d, J¼2.0 Hz), 155.9, 153.5, 151.6, 149.3,
125.4, 119.2, 104.4, 62.3, 21.4, 14.1 ppm; HRMS (ESI) calcd for
129.7e129.3 (m), 113.7 (d, J¼41.0 Hz), 105.4, 53.5 ppm; HRMS (ESI)
C
12H13N2O3 [MþH]þ: 233.0921; found: 233.0925.
calcd for C10H8FN2O3 [MþH]þ: 223.1013; found: 223.0510.
4.2.14. Ethyl 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
4.2.6. Methyl 8-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3db). Yellow solid: mp 148e150 ꢀC. 1H NMR
carboxylate (3ga). Yellow solid: mp 195e197 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.91 (s, 1H), 7.83 (d, J¼9.2 Hz, 1H), 7.72 (d,
(400 MHz, CDCl3):
d
9.00 (d, J¼7.6 Hz, 1H), 7.87 (d, J¼2.0 Hz, 1H),
J¼9.2 Hz, 1H), 7.16 (s, 1H), 4.49 (q, J¼7.2 Hz, 2H), 2.49 (s, 3H), 1.45 (t,
7.21 (d d, J¼7.6 Hz, J¼2.4 Hz, 1H), 7.17 (s, 1H), 4.03 (s, 3H); 13C NMR
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 164.3,158.1,151.7,150.0,
(100 MHz, CDCl3):
d
164.5, 157.8, 152.2, 151.1, 144.4, 128.2, 125.5,
139.7, 127.1, 126.7, 124.7, 105.0, 62.4, 18.3, 14.0 ppm; HRMS (ESI)
118.1, 106.0, 53.4 ppm; HRMS (ESI) calcd for C10H8ClN2O3 [MþH]þ:
calcd for C12H13N2O3 [MþH]þ: 233.0921; found: 233.0920.
239.0218; found: 239.0213.
4.2.15. Ethyl 7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3fb). Yellow solid: mp 192e194 ꢀC. 1H NMR
4.2.7. Methyl 7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3ha). Yellow solid: mp 194e196 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
9.01e8.99 (m,1H), 7.94 (d d, J¼9.6 Hz, J¼5.2 Hz,
(400 MHz, CDCl3):
d
9.11 (d, J¼2.4 Hz, 1H), 7.84 (d, J¼9.2 Hz, 1H),
1H), 7.79e7.75 (m, 1H), 7.22 (s, 1H), 4.50 (q, J¼7.2 Hz, 2H), 1.45 (t,
7.78e7.76 (m, 1H), 7.24 (s, 1H), 4.04 (s, 3H); 13C NMR (100 MHz,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 164.1, 157.9, 155.9,
CDCl3):
d
164.6, 157.3, 151.7, 149.8, 138.3, 128.3, 125.6, 125.2, 106.3,
153.5, 151.8, 149.2, 129.6e129.3 (m), 113.6 (d, J¼41.0 Hz), 105.3, 62.7,
53.5 ppm; HRMS (ESI) calcd for C10H8ClN2O3 [MþH]þ: 239.0218;
14.2 ppm; LC-MS: 236.
found: 239.0216.
4.2.16. Ethyl 8-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
4.2.8. Methyl 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3gb). Yellow solid: mp 114e116 ꢀC. 1H NMR
carboxylate (3ia). Yellow solid: mp 198e199 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
9.00 (d, J¼7.6 Hz, 1H), 7.88 (d, J¼2.0 Hz, 1H),
(400 MHz, CDCl3):
d
9.21 (d, J¼2.0 Hz, 1H), 7.88e7.85 (m, 1H), 7.77
7.19 (d d, J¼7.6 Hz, J¼2.4 Hz, 1H), 7.17 (s, 1H), 4.49 (q, J¼7.2 Hz, 2H),
(d, J¼9.2 Hz, 1H), 7.23 (s, 1H), 4.03 (s, 3H); 13C NMR (100 MHz,
1.45 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 164.0, 157.9,
CDCl3):
d
164.6, 157.2, 151.7, 149.8, 140.4, 128.3, 127.6, 112.3, 106.4,
152.6, 151.1, 144.3, 128.2, 125.6, 118.1, 105.9, 62.7, 14.1 ppm; HRMS
53.5 ppm; HRMS (ESI) calcd for C10H8BrN2O3 [MþH]þ: 282.9713;
(ESI) calcd for C11H10ClN2O3 [MþH]þ: 253.0374; found: 253.0377.
found: 282.9710.
4.2.17. Ethyl 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
4.2.9. Methyl 9-(benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3ib). Yellow solid: mp 174e176 ꢀC. 1H NMR
carboxylate (3ka). Yellow solid: mp 139e141 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
9.20 (d, J¼2.0 Hz, 1H), 7.6 (d d, J¼9.2 Hz,
(400 MHz, CDCl3):
J¼6.8 Hz, 2H), 7.41e7.38 (m, 3H), 7.22 (s,1H), 7.11e7.05 (m, 2H), 5.39
(s, 2H), 4.01 (s, 3H); 13C NMR (100 MHz, CDCl3):
165.1, 158.4, 151.9,
d
8.71 (d d, J¼6.0 Hz, J¼2.4 Hz, 1H), 7.49 (d,
J¼2.0 Hz, 1H), 7.77 (d, J¼9.2 Hz, 1H), 7.22 (s, 1H), 4.49 (q, J¼7.2 Hz,
2H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 164.0,
d
157.3, 152.0, 149.8, 140.3, 128.3, 127.5, 112.2, 106.3, 62.7, 14.1 ppm;
HRMS (ESI) calcd for C10H10BrN2O3 [MþH]þ: 296.9869; found:
296.9867.
150.9, 145.9, 135.1, 128.8, 128.4, 127.1, 119.4, 115.7, 114.6, 106.2, 71.9,
53.3 ppm; HRMS (ESI) calcd for C17H15N2O4 [MþH]þ: 311.1026;
found: 311.1022.
4.2.18. Ethyl 9-(benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
4.2.10. 8-Ethyl 2-methyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2,8-
carboxylate (3kb). Yellow solid: mp 140e142 ꢀC. 1H NMR
dicarboxylate (3la). Yellow solid: mp 103e104 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.71 (d d, J¼6.4 Hz, J¼2.0 Hz, 1H), 7.51 (d,
(400 MHz, CDCl3):
d
9.09 (d, J¼7.2 Hz, 1H), 8.54 (d, J¼0.8 Hz, 1H), 7.0
J¼7.2 Hz, 2H), 7.42e7.38 (m, 3H), 7.21 (s,1H), 7.11e7.08 (m, 2H), 5.39
(d d, J¼7.2 Hz, J¼1.6 Hz, 1H), 7.28 (s, 1H), 4.47 (q, J¼7.2 Hz, 2H), 4.05
(s, 2H), 4.46 (q, J¼7.2 Hz, 2H), 1.45 (t, J¼7.2 Hz, 3H); 13C NMR
(s, 3H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
164.5,
(100 MHz, CDCl3): d 164.5, 158.5, 151.9, 151.3, 145.9, 135.2, 128.8,
162.9, 157.9, 151.9, 151.1, 138.0, 129.5, 127.8, 114.8, 107.6, 62.6, 53.5,
14.0 ppm; HRMS (ESI) calcd for C13H13N2O5 [MþH]þ: 277.0819;
found: 277.0816.
128.3, 127.1, 119.5, 115.7, 114.6, 106.2, 71.8, 62.4, 14.1 ppm; LC-MS:
324.
4.2.19. Diethyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2,8-dicarboxylate
4.2.11. Ethyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate
(3lb). Yellow solid: mp 124e126 ꢀC. 1H NMR (400 MHz, acetone-
(3ab). Yellow solid: mp 118e120 ꢀC. 1H NMR (400 MHz, CDCl3):
d6):
d
9.08 (d, J¼7.2 Hz,1H), 8.23 (d, J¼1.2 Hz,1H), 7.74e7.72 (m, 1H),
d
9.09 (d, J¼7.2 Hz,1H), 7.92e7.84 (m, 2H), 7.30e7.26 (m,1H), 7.19 (s,
7.03 (s, 1H), 4.48 (q, J¼7.2 Hz, 2H), 4.42 (q, J¼7.2 Hz, 2H), 1.45 (t,
1H), 4.50 (q, J¼7.2 Hz, 2H),1.45 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
J¼7.2 Hz, 3H), 1.41 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
CDCl3):
d
164.3, 158.3, 152.1, 151.3, 136.8, 127.4, 127.3, 116.5, 105.5,
d 164.0, 163.1, 158.1, 152.3, 151.1, 137.9, 129.6, 127.8, 114.8, 107.5,
62.5, 14.1 ppm; GCeMS: 218.
62.74, 62.65, 14.2, 14.1 ppm; HRMS (ESI) calcd for C14H15N2O5
[MþH]þ: 291.0975; found: 291.0972.
4.2.12. Ethyl 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
carboxylate (3bb). Yellow solid: mp 151e152 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.98 (d, J¼7.2 Hz, 1H), 7.68 (d, J¼6.8 Hz, 1H),
Acknowledgements
7.17e7.13 (m, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.69 (s, 3H), 1.45 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
164.6, 158.9, 151.5,
We thank the financial supported by the Fundamental Research
Funds for the Central Universities.
150.9, 136.3, 135.6, 125.4, 116.0, 105.1, 62.2, 18.1, 14.1 ppm; HRMS
(ESI) calcd for C12H13N2O3 [MþH]þ: 233.0921; found: 233.0923.
4.2.13. Ethyl 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-
Supplementary data
carboxylate (3cb). Yellow solid: mp 133e134 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.98 (d, J¼7.2 Hz, 1H), 7.68 (s, 1H), 7.11e7.09 (m,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.084.
2H), 4.48 (q, J¼7.2 Hz, 2H), 2.53 (s, 3H), 1.45 (t, J¼7.2 Hz, 3H); 13C

H. Yan et al. / Tetrahedron 70 (2014) 2761e2765
2765
Vanelle, P. Synthesis 2011, 3115; (f) Kinzel, O. D.; Ball, R. G.; Donghi, M.; Maguire,
C. K.; Muraglia, E.; Pesci, S.; Rowley, M.; Summa, V. Tetrahedron Lett. 2008, 49,
6556.
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