A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

Article abstract of DOI:10.1016/j.tet.2007.08.024

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetyl

Full text of DOI:10.1016/j.tet.2007.08.024

Tetrahedron 63 (2007) 11135–11140
A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]-
pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and
4H-pyrazino[1,2-a]pyrimidines
a
a
Mehdi Adib,a, Mohammad Hosein Sayahi, Hakimeh Ziyadi,
*
Hamid Reza Bijanzadehb and Long-Guan Zhuc
aSchool of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
bDepartment of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
cChemistry Department, Zhejiang University, Hangzhou 310027, PR China
Received 11 May 2007; revised 9 July 2007; accepted 8 August 2007
Available online 14 August 2007
Abstract—A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyr-
azino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylene-
dicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the
reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively
confirms the structure of the obtained bridgehead bicyclic 6–6 heterocyclic compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cyclizations, classified on the basis of the number of ring
atoms in each of the components being cyclized.2,4
Multi-component reactions (MCRs) have become a signifi-
cant part of today’s arsenal of methods in combinatorial
chemistry.1 MCRs, leading to interesting heterocyclic scaf-
folds, are particularly useful for the construction of diverse
chemical libraries of ‘drug-like’ molecules. The isocya-
nide-based MCRs are especially important in this area.1b,c
There are several methods reported in the literature for the
preparation of pyrimido[1,2-a]pyrimidine and pyrazino[1,2-
a]pyrimidine ring system. The most common synthetic routes
involve [3+3] ring closure of 2-aminopyrimidines and 2-ami-
nopyrazines with a variety of bifunctional electrophiles.3,7,8
Bridgehead nitrogen heterocycles are ofinterest because they
constitute an important class of natural and non-natural prod-
ucts, many of which exhibit useful biological activity. The in-
terest in bicyclic 6–6 systems stems from the occurrence of
saturated and partially saturated pyrido[1,2-a]pyrimidines,
pyrimido[1,2-a]pyrimidines, and pyrazino[1,2-a]pyrim-
idines in many biologically active compounds and natural
products.2–6
The diverse pharmacological activities of the three fused bi-
cyclic 6–6 heterocycles encouraged us to develop a concise
synthetic route to these heterocyclic compounds.
2. Results and discussion
As part of our current studies on the design of new routes
for the preparation of biologically active heterocyclic com-
pounds,9 we report herein a simple synthesis of functional-
ized 4H-pyrido[1,2-a]pyrimidines,4a 4H-pyrimido[1,2-a]-
pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines using
simple starting materials from [1+2+3] atom fragments by
formation of three bonds. Thus, a mixture of an isocyanide
1, a dialkyl acetylenedicarboxylate 2, and an N-(2-hetero-
aryl)amide 3 or 5 undergoes a smooth 1:1:1 addition reaction
in dry CH2Cl2 at ambient temperature to produce 2-amino-
4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylates 4a–j in
83–92% yields (Scheme 1), 2-amino-4H-pyrimido[1,2-
To date, the most common synthetic methods reported for
the preparation of pyrido[1,2-a]pyrimidine ring systems in-
volve: (i) transformation of an existing heterocycle and (ii)
Keywords: 4H-Pyrido[1,2-a]pyrimidines; 4H-Pyrimido[1,2-a]pyrimidines;
4H-Pyrazino[1,2-a]pyrimidines; Three-component synthesis; Acetylenic
esters; Isocyanides.
* Corresponding author. Tel./fax: +98 21 66495291; e-mail: madib@
khayam.ut.ac.ir
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.024

11136
M. Adib et al. / Tetrahedron 63 (2007) 11135–11140
R"
R"
_
CH2Cl2
+
R
+
C
CO2R' +
C
C
N
R'O2C
N
NHCOR"' r.t., 24 h
N
N
R
N
CO2R'
4
R'O2C
COR"'
1
2
3
4 R
R'
R"
R"'
% Yield
a Cyclohexyl Me
H
CO2Et
92
88
90
85
83
89
85
b Cyclohexyl Et
H
CO2Et
c Cyclohexyl Me 7-Me CO2Et
d Cyclohexyl Et
7-Me CO2Et
e Cyclohexyl Me
H
H
H
OEt
CO2Et
CO2Et
t
f
Bu
Me
Et
t
g Bu
Scheme 1.
a]pyrimidine-3,4-dicarboxylates, and 2-amino-4H-pyr-
azino[1,2-a]pyrimidine-3,4-dicarboxylates 6a–j in 79–94%
yields (Scheme 2).
The isolated azino[1,2-a]pyrimidines 6a–g were character-
ized on the basis of their elemental analyses and IR, H
1
NMR, and 13C NMR spectra. The nature of these compounds
as 1:1:1 adducts was apparent from the mass spectra, which
displayed molecular ion peaks at the appropriate m/z values.
The 1H NMR spectrum of 6a consisted of multiplet signals
for the 11 protons of the cyclohexyl ring and the five protons
of the ethoxy function (d 1.04–2.15 and 4.04–4.26 ppm).
Three single sharp lines were observed for the two CH3O
(d 3.70 and 3.74 ppm) and methine (d 6.08 ppm) groups.
Three characteristic doublet of doublets (d 6.87, 7.90, and
8.76 ppm; J¼6.6, 4.0, and 2.1 Hz) were seen for the three
mutually coupling CHs in positions 6, 7, and 8 of the bicyclic
ring. The 1H-decoupled 13C NMR spectrum of 6a showed 21
distinct resonances, in agreement with the suggested struc-
ture. Partial assignments of these resonances are given in
Section 4.
The one-pot three-component condensation reactions were
carried out by first mixing acetylenic ester 2 and N-(2-heter-
oaryl)amide 3 or 5 in dry CH2Cl2. Then, a solution of isocya-
nide 1 in dry CH2Cl2 was added to the reaction mixture. The
reaction proceeded smoothly at ambient temperature and
was complete within 24 h to afford the corresponding pyr-
ido[1,2-a]pyrimidines 4 or azino[1,2-a]pyrimidines 6. The
1H NMR spectra of the crude products clearly indicated
the formation of fused system 4 or 6. Any product other
than 4 or 6 could not be detected by NMR spectroscopy.
The structures of the pyrido[1,2-a]pyrimidines 4a–g were
confirmed by IR, 1H, and 13C NMR spectroscopy, mass spec-
trometry, and elemental analysis. The mass spectrum of 4a
displayed the molecular ion (M+) peak at m/z 445, which
was consistentwith the 1:1:1 adduct of cyclohexyl isocyanide,
dimethyl acetylenedicarboxylate, and ethyl 2-oxo-2-(2-pyri-
Single-crystal X-ray analysis of 4a conclusively confirmed
the structure of the isolated products. An ORTEP diagram
of 4a is shown in Figure 1.10
1
dylamino)acetate. The H NMR spectrum of 4a exhibited
three sharp singlets, arising from the two CH3O (d 3.64 and
3.69 ppm) and methine (d 6.01 ppm) groups along with the
characteristic signals with appropriate chemical shifts and
coupling constants for the 16 protons of the ethoxy and cyclo-
hexyl functions, as well as the characteristic multiplets for
the four protons of the diene moiety of the pyridine ring.
The 1H-decoupled 13C NMR spectrum of 4a showed 22 dis-
tinct resonances, in agreement with the proposed structure.
A mechanistic rationalization for this reaction is provided in
Scheme 3 (exemplified by 4). On the basis of the well-estab-
lished chemistry of isocyanides,1b,c,11 it is reasonable to as-
sume that the pyrido[1,2-a]pyrimidines 4 result from initial
addition of isocyanide to acetylenic ester and subsequent
protonation of the 1:1 zwitterionic adduct 7 by N-(2-pyridyl)-
amide 3, followed by conjugate addition of anion 9 from the
pyridine nitrogen to the a,b-unsaturated nitrilium ion 8 to
Y
Y
X
X
_
CH2Cl2
+
R
+
R'O2C
C
C
CO2R' +
N
C
N
NHCOCO2Et
N
N
r.t., 24 h
R
N
CO2R'
6
R'O2C
COCO2Et
1
2
5
6
R
R'
X
Y
% Yield
a
b
c
d
e
f
Cyclohexyl
Me
N
CH
CH
CH
CH
CH
N
94
90
89
83
79
91
89
Cyclohexyl
Et
N
t
Bu
Me
Et
N
t
Bu
N
1,1,3,3-tetramethylbutyl
Cyclohexyl
Et
N
Me
Et
CH
CH
g
Cyclohexyl
N
Scheme 2.

M. Adib et al. / Tetrahedron 63 (2007) 11135–11140
11137
4. Experimental
4.1. General
Dimethyl- and diethyl acetylenedicarboxylates, tert-butyl-,
cyclohexyl- and 1,1,3,3-tetramethylbutyl isocyanides, 2-
aminopyridines, 2-aminopyrimidine, and 2-aminopyrazine,
ethyl chloroglyoxalate, and ethyl chloroformate were ob-
tained from Merck (Germany) and Fluka (Switzerland) and
were used without further purification. N-(2-Heteroaryl)-
amides 3 and 5 were prepared according to the procedure.12
Melting points were measured on an Electrothermal 9100 ap-
paratus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN-O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer
1
operating at an ionization potential of 20 eV. H and 13C
NMR spectra were measured with Bruker DRX-500
AVANCE (at 500.1 and 125.8 MHz) and Bruker DRX-300
(at 300.1 and 75.5 MHz) spectrometers using CDCl3 solvent
with TMS as an internal standard. IR spectra were recorded
on a Shimadzu IR-460 spectrometer. Chromatography col-
umns were prepared from Merck silica gel 60 mesh.
Figure 1. Molecular structure of 4a, with 50% probability displacement
ellipsoids, H atoms with arbitrary radii.
4.2. General procedure
form ketenimine intermediate 10. Ketenimine may undergo
intramolecular cyclization to bicyclic zwitterion 11, which
undergo rearrangement to afford the fused heterocyclic sys-
tem 4.
To a magnetically stirred solution of the appropriate N-(2-
heteroaryl)amide, 3 or 5 (1 mmol) and the appropriate
acetylenic ester (1 mmol) in dry CH2Cl2 (6 mL) was added
dropwise
a solution of the appropriate isocyanide
(1 mmol) in dry CH2Cl2 (2 mL) at 25 ꢀC over 10 min. The
reaction mixture was then stirred for 24 h. The solvent was
removed and the residue was purified by column chromato-
graphy using hexane–ethyl acetate (1:2) as eluent. The sol-
vent was removed and the product was crystallized from
1:1 hexane–ethyl acetate.
CO2R'
C
E
E
R"
_
E
E
_
C +
+
H
3
R N
_
C
C
C
N
NCOR"'
+
+
RN
RN
CO2R'
9
7
8
4.2.1. Dimethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate
(4a). Yellow crystals, mp 167–169 ꢀC, yield: 0.41 g, 92%.
IR (KBr) (nmax/cmꢁ1): 1742, 1730, 1672, and 1640
(C]O), 1564, 1487, 1396, 1330, 1219, 1146, 1094, 989,
770. MS, m/z (%): 445 (M+, 6), 417 (4), 386 (98), 372
(13), 344 (18), 304 (28), 290 (27), 230 (90), 205 (100),
170 (22), 78 (21), 55 (16). Anal. Calcd for C22H27N3O7
(445.47): C, 59.32; H, 6.11; N, 9.43. Found: C, 59.1; H,
R"
R"
E
O
..
COR"'
NR
+
N
N
N
N
R"'
4
_
N
R
E
E
.
E
10
11
E = CO2R'
1
6.3; N, 9.2%. H NMR (500.1 MHz, CDCl3): d 1.02–2.13
Scheme 3.
[3H, t, J¼7.0 Hz, OCH2CH3; 10H, m, CH(CH2)5], 3.64
and 3.69 (6H, 2s, 2OCH3), 3.99–4.25 [3H, m, OCH2CH3
and NCH(CH2)5], 6.01 (1H, s, NCH), 6.76 (1H, dd, J¼6.6,
6.2 Hz, CH), 7.13 (1H, d, J¼8.3 Hz, CH), 7.38 (1H, d,
J¼6.2 Hz, CH), 7.56 (1H, dd, J¼8.3, 6.6 Hz, CH). 13C
NMR (125.8 MHz, CDCl3): d 13.8 (OCH2CH3), 25.7,
26.1, 26.1, 28.6, and 32.0 (5CH2), 51.6 and 52.9 (2OCH3),
56.8 [NCH(CH2)5], 61.4 (NCH), 62.3 (OCH2), 87.3
(N2C]C), 114.5, 123.8, 137.0, and 139.1 (4CH), 152.7
and 153.5 (2C), 161.9, 162.4, 164.8, and 168.2 (4C]O).
3. Conclusion
In summary, we have developed a new, one-pot, and
three-component synthesisof 2-amino-4H-pyrido[1,2-a]pyr-
imidines-3,4-dicarboxylates, 2-amino-4H-pyrimido[1,2-a]-
pyrimidine-3,4-dicarboxylates, and 2-amino-4H-pyrazino-
[1,2-a]pyrimidine-3,4-dicarboxylates of potential synthetic
and pharmacological interest. The good yields of the prod-
ucts, the mild reaction conditions, and the use of simple
starting materials are the main advantages of this method.
The reactions were performed under neutral conditions and
the substances were mixed without any activation or modifi-
cation. The simplicity of this method makes it an interesting
alternative to other approaches.
4.2.2. Diethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate
(4b). Yellow crystals, mp 152 ꢀC, yield: 0.42 g, 88%. IR
(KBr) (nmax/cmꢁ1): 1744, 1729, 1678, and 1639 (C]O),
1618, 1566, 1481, 1404, 1335, 1234, 1211, 1138, 1094,
1030, 808, 770. MS, m/z (%): 473 (M+, 8), 400 (100), 383

11138
M. Adib et al. / Tetrahedron 63 (2007) 11135–11140
(32), 354 (30), 337 (45), 318 (47), 272 (31), 255 (80), 227
(75), 199 (40), 172 (25), 121 (31), 78 (65), 55 (20). Anal.
Calcd for C24H31N3O7 (473.53): C, 60.88; H, 6.60; N,
8.87. Found: C, 60.7; H, 6.8; N, 8.6%. 1H NMR
(500.1 MHz, CDCl3): d 1.00–2.09 [9H, 3t, J¼7.1 Hz,
3OCH2CH3; 10H, m, CH(CH2)5], 3.95–4.26 [7H, m,
3OCH2CH3 and NCH(CH2)5], 5.97 (1H, s, NCH), 6.70
(1H, dd, J¼6.7, 6.5 Hz, CH), 7.08 (1H, d, J¼8.8 Hz, CH),
7.37 (1H, d, J¼6.5 Hz, CH), 7.50 (1H, dd, J¼8.8, 6.7 Hz,
CH). 13C NMR (125.8 MHz, CDCl3): d 13.7, 13.8, and
14.1 (3OCH2CH3), 25.5, 25.9, 26.0, 28.4, and 32.0
(5CH2), 56.4 [NCH(CH2)5], 60.5 (OCH2), 61.4 (NCH),
62.1, and 62.2 (2OCH2), 88.6 (N2C]C), 113.9, 123.6,
136.9, and 138.6 (4CH), 152.5 and 152.8 (2C), 161.6,
162.2, 164.3, and 167.6 (4C]O).
(%): 417 (M+, 3), 386 (65), 344 (11), 304 (17), 290 (17),
230 (100), 205 (71), 170 (16), 78 (17), 55 (9). Anal. Calcd
for C21H27N3O6 (417.46): C, 60.42; H, 6.52; N, 10.07.
1
Found: C, 60.4; H, 6.5; N, 9.9%. H NMR (300.1 MHz,
CDCl3): d 1.02–2.15 [3H, t, J¼7.1 Hz, OCH2CH3; 10H,
m, CH(CH2)5], 3.68 and 3.72 (6H, 2s, 2OCH3), 3.95–4.30
[3H, m, OCH2CH3 and NCH(CH2)5], 6.03 (1H, s, NCH),
6.80 (1H, dd, J¼6.7, 6.4 Hz, CH), 7.18 (1H, d, J¼8.8 Hz,
CH), 7.39 (1H, d, J¼6.4 Hz, CH), 7.59 (1H, dd, J¼8.8,
6.7 Hz, CH). 13C NMR (75.5 MHz, CDCl3): d 13.9
(OCH2CH3), 25.6, 26.0, 26.1, 28.5, and 32.0 (5CH2), 51.8
and 53.0 (2OCH3), 56.8 [NCH(CH2)5], 61.5 (NCH), 62.3
(OCH2), 87.3 (N2C]C), 114.6, 123.8, 136.9, and 139.2
(4CH), 152.6 and 161.9 (2C), 162.3, 164.8, and 168.1
(3C]O).
4.2.3. Dimethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-7-methyl-4H-pyrido[1,2-a]pyrimidine-3,4-di-
carboxylate (4c). Yellow crystals, mp 155–157 ꢀC, yield:
0.41 g, 90%. IR (KBr) (nmax/cmꢁ1): 1743, 1730, 1677, and
1643 (C]O), 1567, 1490, 1433, 1390, 1220, 1140, 1096,
1012, 970. MS, m/z (%): 459 (M+, 7), 400 (75), 372 (18),
318 (25), 258 (33), 233 (100), 92 (22), 57 (9). Anal. Calcd
for C23H29N3O7 (459.50): C, 60.12; H, 6.36; N, 9.14. Found:
4.2.6. Dimethyl 2-[tert-butyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate
(4f). Yellow crystals, mp 160 ꢀC, yield: 0.37 g, 89%.
IR (KBr) (nmax/cmꢁ1): 1745, 1729, 1684, and 1659
(C]O), 1632, 1566, 1490, 1430, 1391, 1323, 1221, 1194,
1138, 1099, 1010, 959, 771. MS, m/z (%): 419 (M+, 3),
360 (20), 304 (97), 290 (17), 230 (100), 205 (20), 170
(12), 78 (18), 57 (7). Anal. Calcd for C20H25N3O7
(419.43): C, 57.27; H, 6.01; N, 10.02. Found: C, 57.1; H,
1
C, 60.1; H, 6.4; N, 9.1%. H NMR (500.1 MHz, CDCl3):
1
d 1.02–2.13 [3H, t, J¼7.1 Hz, OCH2CH3; 10H, m,
CH(CH2)5], 2.21 (3H, s, CH3), 3.66 and 3.69 (6H, 2 s,
2OCH3), 4.05–4.25 [3H, m, OCH2CH3 and NCH(CH2)5],
5.96 (1H, s, NCH), 7.09 (1H, d, J¼8.7 Hz, CH), 7.14
(1H, s, CH), 7.43 (1H, d, J¼8.7 Hz, CH). 13C NMR
(125.8 MHz, CDCl3): d 13.8 (OCH2CH3), 17.4 (CH3),
25.7, 26.0, 26.1, 28.5, and 32.0 (5CH2), 51.5 and 52.8
(2OCH3), 56.7 [NCH(CH2)5], 61.3 (NCH), 62.5 (OCH2),
86.3 (N2C]C), 123.5 (CH), 124.6 (C), 134.5 and 141.5
(2CH), 151.5 and 153.8 (2C), 161.9, 162.4, 164.8, and
168.3 (4C]O).
6.1; N, 10.1%. H NMR (500.1 MHz, CDCl3): d 1.20 (3H,
t, J¼7.1 Hz, OCH2CH3), 1.43 [9H, s, C(CH3)3], 3.61 and
3.69 (6H, 2s, 2OCH3), 4.05 and 4.17 (2H, 2dq, ABX3 system,
3
2J¼10.6 Hz and J¼7.1 Hz, OCHAHBCH3), 5.99 (1H, s,
NCH), 6.71 (1H, dd, J¼6.7, 6.1 Hz, CH), 7.05 (1H, d,
J¼8.9 Hz, CH), 7.36 (1H, d, J¼6.1 Hz, CH), 7.50 (1H, dd,
J¼8.9, 6.7 Hz, CH). 13C NMR (125.8 MHz, CDCl3):
d 13.7 (OCH2CH3), 28.0 [C(CH3)3], 51.4 and 52.8
(2OCH3), 60.3 [C(CH3)3], 61.0 (NCH), 62.1 (OCH2), 91.7
(N2C]C), 114.2, 123.6, 136.8, and 138.9 (4CH), 152.3
and 152.7 (2C), 161.4, 162.2, 164.5, and 168.0 (4C]O).
4.2.4. Diethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-7-methyl-4H-pyrido[1,2-a]pyrimidine-3,4-di-
carboxylate (4d). Yellow crystals, mp 147 ꢀC, yield: 0.41 g,
85%. IR (KBr) (nmax/cmꢁ1): 1744, 1728, 1674, and 1641
(C]O), 1568, 1489, 1421, 1337, 1229, 1130, 1096, 1032,
847, 623. MS, m/z (%): 487 (M+, 5), 414 (84), 386 (24),
332 (31), 258 (38), 233 (100), 205 (22), 186 (10), 92 (17),
55 (8). Anal. Calcd for C25H33N3O7 (487.55): C, 61.59; H,
4.2.7. Diethyl 2-[tert-butyl(2-ethoxy-2-oxoacetyl)amino]-
4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate (4g). Yel-
low crystals, mp 110–111 ꢀC, yield: 0.38 g, 85%. IR (KBr)
(nmax/cmꢁ1): 1738, 1675, 1657, and 1640 (C]O), 1574,
1492, 1393, 1319, 1232, 1193, 1142, 1093, 1024, 964,
773. MS, m/z (%): 447 (M+, 2), 374 (22), 318 (100), 244
(43), 216 (24), 172 (13), 78 (17), 57 (8). Anal. Calcd for
C22H29N3O7 (447.49): C, 59.05; H, 6.53; N, 9.39. Found:
1
1
6.82; N, 8.62. Found: C, 61.6; H, 6.9; N, 8.5%. H NMR
C, 59.0; H, 6.6; N, 9.4%. H NMR (500.1 MHz, CDCl3):
(500.1 MHz, CDCl3): d 0.96–2.02 [9H, 3t, J¼7.1 Hz,
3OCH2CH3; 10H, m, CH(CH2)5], 2.15 (3H, s, CH3), 3.90–
4.20 [7H, m, 3OCH2CH3 and NCH(CH2)5], 5.91 (1H, s,
NCH), 7.01 (1H, d, J¼8.8 Hz, CH), 7.17 (1H, s, CH), 7.37
(1H, d, J¼8.8 Hz, CH). 13C NMR (125.8 MHz, CDCl3):
d 13.6, 13.8, and 14.0 (3OCH2CH3), 17.2 (CH3), 25.5,
25.8, 25.9, 28.3, and 32.0 (5CH2), 56.3 [NCH(CH2)5], 60.3
(OCH2), 61.2 (NCH), 62.0 and 62.2 (2OCH2), 87.6
(N2C]C), 123.1 (CH), 124.3 (C), 134.6 and 141.4 (2CH),
151.3 and 153.0 (2C), 161.6, 162.2, 164.3, and 167.8
(4C]O).
d 1.11, 1.21, and 1.28 (9H, 3t, J¼7.1 Hz, 3OCH2CH3),
1.45 [9H, s, C(CH3)3], 4.00–4.30 (6H, m, 3OCH2), 5.96
(1H, s, NCH), 6.66 (1H, dd, J¼6.7, 6.5 Hz, CH), 7.04 (1H,
d, J¼8.9 Hz, CH), 7.32 (1H, d, J¼6.5 Hz, CH), 7.47 (1H,
dd, J¼8.9, 6.7 Hz, CH). 13C NMR (125.8 MHz, CDCl3):
d 13.7, 13.8, and 14.2 (3OCH2CH3), 28.1 [C(CH3)3], 60.3
[C(CH3)3], 60.7 (OCH2), 61.1 (NCH), 62.2 and 62.3
(2OCH2), 93.4 (N2C]C), 113.5, 123.5, 136.7, and 138.4
(4CH), 151.7 and 152.2 (2C), 161.4, 162.1, 164.3, and
167.6 (4C]O).
4.2.8. Dimethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate
(6a). Yellow crystals, mp 189 ꢀC, yield: 0.42 g, 94%.
IR (KBr) (nmax/cmꢁ1): 1744, 1721, 1691, and 1676
(C]O), 1620, 1568, 1491, 1412, 1325, 1225, 1121, 1096,
1012, 805. MS, m/z (%): 446 (M+, 10), 387 (60), 373 (23),
4.2.5. Dimethyl 2-[cyclohexyl(ethoxycarbonyl)amino]-
4H-pyrido[1,2-a]pyrimidine-3,4-dicarboxylate (4e). Yel-
low crystals, mp 158–159 ꢀC, yield: 0.35 g, 83%. IR (KBr)
(nmax/cmꢁ1): 1749, 1729, 1720, 1668, and 1637 (C]O),
1625, 1568, 1493, 1393, 1331, 1219, 1144, 1097. MS, m/z

M. Adib et al. / Tetrahedron 63 (2007) 11135–11140
11139
345 (35), 305 (48), 291 (35), 259 (20), 231 (100), 206 (83),
171 (15), 79 (30), 55 (23). Anal. Calcd for C21H26N4O7
(446.46): C, 56.50; H, 5.87; N, 12.55. Found: C, 56.4; H,
5.9; N, 12.4%. 1H NMR (300.1 MHz, CDCl3): d 1.04–2.15
[3H, t, J¼7.1 Hz, OCH2CH3; 10H, m, CH(CH2)5], 3.70
and 3.74 (6H, 2s, 2OCH3), 4.04–4.26 [3H, m, OCH2CH3
and NCH(CH2)5], 6.08 (1H, s, NCH), 6.87 (1H, dd, J¼6.6,
4.0 Hz, CH), 7.90 (1H, dd, J¼6.6, 2.1 Hz, CH), 8.76 (1H,
dd, J¼4.0, 2.1 Hz, CH). 13C NMR (75.5 MHz, CDCl3):
d 13.8 (OCH2CH3), 25.3, 26.0, 26.1, 28.6, and 31.4
(5CH2), 52.0 and 53.3 (2OCH3), 57.5 [NCH(CH2)5], 61.6
(NCH), 62.3 (OCH2), 90.2 (N2C]C), 111.3 and 146.6
(2CH), 152.8 and 153.3 (2C), 161.6 and 162.1 (2C]O),
163.9 (CH), 164.3 and 167.8 (2C]O).
1161, 1118, 1092, 1013, 968, 700. MS, m/z (%): 448 (M+,
4), 391 (13), 375 (29), 347 (8), 319 (100), 273 (12), 245
(89), 217 (37), 173 (14), 130 (12), 79 (19), 57 (8). Anal.
Calcd for C21H28N4O7 (448.48): C, 56.24; H, 6.29; N,
12.49. Found: C, 56.0, H, 6.3; N, 12.4%. 1H NMR
(300.1 MHz, CDCl3): d 1.03, 1.18, and 1.32 (9H, 3t,
J¼7.1 Hz, 3OCH2CH3), 1.59 [9H, s, C(CH3)3], 4.03–4.37
(6H, m, 3OCH2CH3), 5.96 (1H, s, NCH), 6.69 (1H, dd,
J¼6.6, 4.0 Hz, CH), 7.79 (1H, dd, J¼6.6, 2.2 Hz, CH),
8.61 (1H, dd, J¼4.0, 2.2 Hz, CH). 13C NMR (75.5 MHz,
CDCl3): d 13.7, 13.9, and 14.4 (3OCH2CH3), 28.1
[C(CH3)3], 60.8 [C(CH3)3], 61.2 (NCH), 61.3, 62.4, and
62.9 (3OCH2), 98.6 (N2C]C), 110.0 and 146.3 (2CH),
150.6 and 152.3 (2C), 160.0 and 162.1 (2C]O), 163.6
(CH), 164.0 and 168.3 (2C]O).
4.2.9. Diethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrimido[1,2-a]pyrimidine-3,4-dicarboxy-
late (6b). Yellow crystals, mp 156 ꢀC, yield: 0.43 g, 90%.
IR (KBr) (nmax/cmꢁ1): 1740, 1684, and 1664 (C]O),
1620, 1566, 1499, 1414, 1304, 1221, 1126, 1016, 804. MS,
m/z (%): 474 (M+, 6), 401 (97), 373 (21), 347 (8), 319
(64), 245 (57), 220 (100), 173 (13), 149 (15), 79 (21), 55
(20). Anal. Calcd for C23H30N4O7 (474.51): C, 58.22; H,
6.37; N, 11.81. Found: C, 58.2; H, 6.5; N, 11.6%. 1H
4.2.12. Diethyl 2-[(2-ethoxy-2-oxoacetyl)(1,1,3,3-tetra-
methylbutyl)amino]-4H-pyrimido[1,2-a]pyrimidine-3,4-
dicarboxylate (6e). Yellow crystals, mp 95 ꢀC, yield:
0.40 g, 79%. IR (KBr) (nmax/cmꢁ1): 1745, 1736, 1728, and
1668 (C]O), 1620, 1572, 1493, 1396, 1377, 1286, 1246,
1213, 1119, 1090, 1022, 797. MS, m/z (%): 504 (M+, 3),
433 (20), 393 (17), 331 (62), 319 (100), 245 (26), 219
(70), 191 (21), 147 (12), 122 (34), 79 (35), 57 (20). Anal.
Calcd for C25H36N4O7 (504.58): C, 59.51; H, 7.19; N,
11.10. Found: C, 59.7, H, 7.3; N, 10.9%. 1H NMR
(300.1 MHz, CDCl3): d 1.03 [9H, s, C(CH3)3], 1.19, 1.23,
and 1.32 (9H, 3t, J¼7.1 Hz, 3OCH2CH3), 1.53 and 1.77
[6H, 2s, C(CH3)2], 2.17 and 2.38 (2H, 2d, AB system,
2J¼14.4 Hz, CHAHB), 4.03–4.35 (6H, m, 3OCH2CH3),
5.89 (1H, s, NCH), 6.66 (1H, dd, J¼6.6, 4.0 Hz, CH), 7.72
(1H, dd, J¼6.6, 2.2 Hz, CH), 8.68 (1H, dd, J¼4.0, 2.2 Hz,
CH). 13C NMR (75.5 MHz, CDCl3): d 13.7, 13.9, and 14.4
(3OCH2CH3), 27.4 and 28.4 [C(CH3)2], 31.5 (CH2), 31.7
[C(CH3)3], 31.8 [C(CH3)3], 61.2 (OCH2), 61.4 (NCH),
62.4 and 62.9 (2OCH2), 66.1 [NC(CH3)2], 99.1 (N2C]C),
109.8 and 146.1 (2CH), 151.0 and 152.1 (2C), 159.8 and
162.1 (2C]O), 163.6 (CH), 164.0 and 168.4 (2C]O).
NMR (300.1 MHz, CDCl3):
d 1.02–2.16 [9H, 3t,
J¼7.1 Hz, 3OCH2CH3; 10H, m, CH(CH2)5], 4.02–4.25
[7H, m, 3OCH2CH3 and NCH(CH2)5], 6.02 (1H, s, NCH),
6.80 (1H, dd, J¼6.6, 4.0 Hz, CH), 7.79 (1H, dd, J¼6.6,
2.1 Hz, CH), 8.73 (1H, dd, J¼4.0, 2.1 Hz, CH). 13C NMR
(75.5 MHz, CDCl3): d 12.4, 12.5, and 12.7 (3OCH2CH3),
23.9, 24.5, 24.6, 27.1, and 30.1 (5CH2), 55.8 [NCH(CH2)5],
59.8 (OCH2), 60.2 (NCH), 60.9 and 61.3 (2OCH2), 89.8
(N2C]C), 109.2 and 144.9 (2CH), 151.3 and 151.6 (2C),
160.1 and 160.6 (2C]O), 162.2 (CH), 162.7 and 165.9
(2C]O).
4.2.10. Dimethyl 2-[tert-butyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrimido[1,2-a]pyrimidine-3,4-dicarboxy-
late (6c). Yellow crystals, mp 186 ꢀC, yield: 0.37 g, 89%.
IR (KBr) (nmax/cmꢁ1): 1748, 1740, 1718, and 1668
(C]O), 1626, 1600, 1512, 1431, 1402, 1382, 1362, 1308,
1282, 1254, 1221, 1126, 1090, 943, 790. MS, m/z (%): 420
(M+, 2), 363 (11), 347 (9), 305 (100), 291 (40), 259 (16),
231 (84), 171 (13), 79 (16), 57 (12). Anal. Calcd for
C19H24N4O7 (420.42): C, 54.28; H, 5.75; N, 13.33. Found:
4.2.13. Dimethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrazino[1,2-a]pyrimidine-3,4-dicarboxy-
late (6f). Orange crystals, mp 148 ꢀC, yield: 0.41 g, 91%.
IR (KBr) (nmax/cmꢁ1): 1749, 1738, 1678, and 1662
(C]O), 1614, 1557, 1481, 1431, 1414, 1335, 1290,
1230, 1204, 1132, 1092, 1055, 1012, 916, 808, 735. MS,
m/z (%): 446 (M+, 2), 401 (83), 373 (7), 319 (45), 301
(11), 245 (55), 220 (100), 173 (13), 83 (16), 55 (14).
Anal. Calcd for C21H26N4O7 (446.46): C, 56.50; H, 5.87;
1
C, 54.3; H, 5.8; N, 13.3%. H NMR (300.1 MHz, CDCl3):
d 1.26 (3H, t, J¼7.1 Hz, OCH2CH3), 1.50 [9H, s,
C(CH3)3], 3.69 and 3.78 (6H, 2s, 2OCH3), 4.12 and 4.23
(2H, 2dq, ABX3 system, 2J¼10.6 Hz and 3J¼7.1 Hz,
OCHAHBCH3), 6.10 (1H, s, NCH), 6.82 (1H, dd, J¼6.6,
4.0 Hz, CH), 7.90 (1H, dd, J¼6.6, 2.1 Hz, CH), 8.72 (1H,
dd, J¼4.0, 2.1 Hz, CH). 13C NMR (75.5 MHz, CDCl3):
d 13.9 (OCH2CH3), 28.1 [C(CH3)3], 51.9 and 53.3
(2OCH3), 60.7 [C(CH3)3], 61.3 (NCH), 62.2 (OCH2), 95.4
(N2C]C), 111.0 and 146.5 (2CH), 151.1 and 152.5 (2C),
161.4 and 162.1 (2C]O), 163.9 (CH), 164.3 and 167.8
(2C]O).
1
N, 12.55. Found: C, 56.5; H, 5.9; N, 12.4%. H NMR
(300.1 MHz, CDCl3): d 1.02–2.13 [3H, t, J¼7.1 Hz,
OCH2CH3; 10H, m, CH(CH2)5], 3.67 and 3.71 (6H, 2s,
2OCH3), 4.01–4.29 [3H, m, OCH2CH3 and NCH(CH2)5],
6.02 (1H, s, NCH), 7.23 (1H, d, J¼4.1 Hz, CH), 7.81
(1H, d, J¼4.1 Hz, CH), 8.54 (1H, s, CH). 13C NMR
(75.5 MHz, CDCl3): d 12.4 (OCH2CH3), 24.0, 24.5, 24.6,
27.2, and 30.4 (5CH2), 50.6 and 51.8 (2OCH3), 55.5
[NCH(CH2)5], 59.6 (NCH), 60.3 (OCH2), 88.4 (N2C]C),
125.9 and 130.1 (2CH), 144.0 (C), 149.2 (CH), 151.4 (C),
160.0, 160.7, 162.8, and 166.0 (4C]O).
4.2.11. Diethyl 2-[tert-butyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrimido[1,2-a]pyrimidine-3,4-dicarboxy-
late (6d). Yellow crystals, mp 138 ꢀC, yield: 0.37 g, 83%.
IR (KBr) (nmax/cmꢁ1): 1736, 1727, 1681, and 1666
(C]O), 1620, 1568, 1487, 1382, 1319, 1294, 1261, 1219,
4.2.14. Diethyl 2-[cyclohexyl(2-ethoxy-2-oxoacetyl)-
amino]-4H-pyrazino[1,2-a]pyrimidine-3,4-dicarboxy-
late (6g). Orange crystals, mp 125 ꢀC, yield: 0.42 g, 89%.

11140
M. Adib et al. / Tetrahedron 63 (2007) 11135–11140
IR (KBr) (nmax/cmꢁ1): 1744, 1680, and 1659 (C]O), 1618,
1574, 1506, 1414, 1377, 1323, 1238, 1138, 1103, 1010.
MS, m/z (%): 474 (M+, 5), 401 (87), 373 (7), 319 (44),
301 (13), 245 (65), 220 (100), 173 (11), 83 (18), 55 (9).
Anal. Calcd for C23H30N4O7 (474.51): C, 58.22; H, 6.37;
Appl. 2006, WO 2006, 24390; Chem. Abstr. 2006, 144,
274545g.
7. Eynde, J. J. V.; Hecq, N.; Kataeva, O.; Kappe, C. O.
Tetrahedron 2001, 57, 1785–1791.
8. Pratap, R.; Kushwaha, S. P.; Goel, A.; Ram, V. J. Tetrahedron
Lett. 2007, 48, 549–553.
1
N, 11.81. Found: C, 58.2; H, 6.4; N, 11.7%. H NMR
9. Adib, M.; Sheibani, E.; Mostofi, M.; Ghanbary, K.; Bijanzadeh,
H. R. Tetrahedron 2006, 62, 3435–3438; Adib, M.;
Tahermansouri, H.; Aali Koloogani, S.; Mohammadi, B.;
Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 5957–5960;
Adib, M.; Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.;
Bijanzadeh, H. R. Synlett 2006, 1765–1767; Adib, M.;
Haghighat Jahromi, A.; Tavoosi, N.; Mahdavi, M.;
Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 2965–2967;
Adib, M.; Ghanbary, K.; Mostofi, M.; Bijanzadeh, H. R.
Tetrahedron 2005, 61, 2645–2648.
(300.1 MHz, CDCl3): d 1.03–2.04 [9H, 3t, J¼7.1 Hz,
3OCH2CH3; 10H, m, CH(CH2)5], 4.00–4.35 [7H, m,
3OCH2CH3 and NCH(CH2)5], 5.99 (1H, s, NCH), 7.20
(1H, d, J¼4.0 Hz, CH), 7.76 (1H, d, J¼4.0 Hz, CH), 8.51
(1H, s, CH). 13C NMR (75.5 MHz, CDCl3): d 12.3, 12.4,
and 12.6 (3OCH2CH3), 24.0, 24.5, 24.6, 27.2, and 30.5
(5CH2), 55.3 [NCH(CH2)5], 59.5 (OCH2), 59.8 (NCH),
60.3 and 61.2 (2OCH2), 90.1 (N2C]C), 125.9 and 129.5
(2CH), 143.9 (C), 149.2 (CH), 150.6 (C), 159.8, 160.6,
162.6, and 165.5 (4C]O).
10. Selected X-ray crystallographic data for compound 4a:
C22H27N3O7, triclinic, space group¼P1 (No. 2), a¼
˚
˚
˚
˚
11.353(2) A, b¼13.700(3) A, c¼15.132(3) A, V¼2245.1(7) A3,
Acknowledgements
T¼295(2) K, Z¼4, Dcalcd¼1.318 g cmꢁ3
,
m
(Mo Ka)¼
0.099 mmꢁ1, 17,002 reflections measured, 8265 unique reflec-
tions (Rint¼0.0705), 4016 observed reflections, final R1¼0.074,
wR2¼0.150 and for all data R1¼0.158, wR2¼0.188. CCDC
636589 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
This research was supported by the Research Council of the
University of Tehran as research project (6102036/1/02).
References and notes
ꢀ
1. (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley: Weinheim, 2005; (b) Domling, A. Chem. Rev. 2006,
€
11. Ugi, I. Isonitrile Chemistry; Academic: London, 1971; Ugi, I.
Angew. Chem., Int. Ed. Engl. 1982, 21, 810–819; Walborsky,
H. M.; Periasamy, M. P. The Chemistry of Functional
Groups, Supplement C; Patai, S., Rappaport, Z., Eds.; Wiley:
New York, NY, 1983; Chapter 8.20, pp 835–837; Nair, V.;
Vinod, A. U.; Nair, J. S.; Sreekanth, A. R.; Rath, N. P.
Tetrahedron Lett. 2000, 41, 6675–6679; Nair, V.; Deepthi, A.
Tetrahedron Lett. 2006, 47, 2037–2039.
12. To a magnetically stirred solution of the appropriate acyl chlo-
ride (ethyl chloroglyoxalate or ethyl chloroformate) (0.01 mol)
in dry CH2Cl2 (60 mL) was added a solution of the appropriate
amine (0.02 mol) in a minimum volume of dry CH2Cl2 at
ꢁ5 ꢀC over 2–3 min. The reaction mixture was stirred for
15 min and then warmed up to room temperature and stirred
for 2 h. Then, the solvent was evaporated to 20 mL. The chlo-
ride salt was separated by suction and filtration. The filtrate was
washed with water (2ꢂ30 mL) and dried over anhydrous
sodium sulfate. The solvent was removed and the N-(2-hetero-
aryl)amide was obtained as colorless crystals.
€
106, 17–89; (c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3169–3210.
ꢀ
ꢀ
2. Hermecz, I.; Vasvari-Debreczy, L.; Matyus, P. Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. V. F., Eds.; Pergamon: London, 1996; Chapter
8.23, pp 563–595 and references therein.
ꢀ
ꢀ
3. Vasvari-Debreczy, L.; Hermecz, I.; Matyus, P. Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. V. F., Eds.; Pergamon: London, 1996; Chapter
8.25, pp 633–706 and references therein.
4. (a) The first part of this paper has been published as a prelimi-
nary form: Adib, M.; Sayahi, M. H.; Nosrati, M.; Zhu, L.-G.
Tetrahedron Lett. 2007, 48, 4195–4198; (b) Adib, M.; Yavari,
H.; Mollahosseini, M. Tetrahedron Lett. 2004, 45, 1803–1805.
5. Kappe, C. O.; Kappe, T. Arch. Pharm. 1991, 324, 863–866.
6. Lennig, P.; Stengelin, S.; Klabunde, T.; Gossel, M.; Safar, P.;
Smrcina, M.; Spoonamore, J.; Merriman, G.; Klein, J. T.;
Whiteley, B.; Lanter C.; Bordeau, K.; Yang, Z. PCT Int.