Microwave-assisted synthesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)- ones catalyzed by DBU in aqueous medium

Article abstract of DOI:10.1039/c2gc16469h

A clean green, efficient and facile protocol was developed for the synthesis of a series of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones in water with good yield by the reaction of 2-amino-nicotinonitriles with carbonyls catalyzed by DBU under microwave i

Full text of DOI:10.1039/c2gc16469h

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PAPER
Microwave-assisted synthesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-
ones catalyzed by DBU in aqueous medium†
Liupan Yang, Daxin Shi, Shu Chen, Hongxin Chai, Danfei Huang, Qi Zhang and Jiarong Li*
Received 17th November 2011, Accepted 4th January 2012
DOI: 10.1039/c2gc16469h
A clean green, efficient and facile protocol was developed for the synthesis of a series of 2,3-
dihydropyrido[2,3-d]pyrimidin-4(1H)-ones in water with good yield by the reaction of 2-amino-
nicotinonitriles with carbonyls catalyzed by DBU under microwave irradiation. The DBU–H2O system
can be recycled five times without activity loss.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), which is nor-
mally regarded as a non-nucleophilic, strong tertiary amine base
Introduction
Nowadays, the development of cleaner and more benign chemi-
cal processes to prepare new biologically active molecules has
become one of the most exciting research endeavours for the
chemistry community.1 As part of the concept of green chem-
istry, microwaves and water have received substantial interest in
recent years.2 Microwave irradiation, which has proved to be a
clean, fast and convenient energy source, has taken an undeni-
able role in chemical laboratory practice.3 Similarly, water, as
nature’s reaction medium, has advantages of being non-
flammable, non-hazardous, non-toxic, and non-exhaustible that
make it an ideal reaction media in synthetic chemistry. With a
very high dielectric constant and intermediate values for tangent
delta and the dielectric loss, water is also a medium microwave-
absorbing solvent.4 Because of the above properties, the use of
water as solvent combined with microwave irradiation for
heating has recently received a considerable interest in green
chemistry.5
2,3-Dihydropyrido[2,3-d]-pyrimidin-4(1H)-ones are a class of
fused heterocycles which possess a wide range of biological
properties and have been assigned as privileged structures in
drug development.6 The traditional synthetic approach towards
2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones employed the
condensation of aldehyde with 2-amino-nicotinamides, which
were always hydrolysed from the corresponding o-aminonitri-
les.6d,e,7 However, these procedures suffer from several draw-
backs such as tedious synthetic routes, time-consuming
experimental procedures, as well as use of toxic reagents. Thus,
the development of environmentally benign, high-yielding, and
clean syntheses of 2,3-dihydropyrido[2,3-d]-pyrimidin-4(1H)-
ones still remains a highly desired goal in organic synthesis.
has been widely used as an effective catalyst in many organic
transformations in recent years.8 Compared to traditionally used
basic catalysts (NaOH or KOH), DBU has advantages of less
corrosion for equipment, fewer amounts of residues generated as
well as excellent reusability. Interestingly, researches also
showed that the catalytic activity of DBU improved considerably
in the presence of water.9 o-Aminocyanopyridines exhibit unique
reactivity because neighbouring group interaction of cyano
group and electron-donating amino group can give a variety of
additional heterocyclic compounds.10 Inspired by the catalytic
potential of DBU and continuing our interest in the development
of efficient methods for the construction of important hetero-
cyclic skeletons using o-aminonitriles as starting material,11
herein we report a rapid, efficient and convenient procedure for
the synthesis of 2,3-dihydro-pyrido[2,3-d]-pyrimidin-4(1H)-ones
derivatives via condensation of 2-amino-nicotinonitriles and
various carbonyl compounds catalyzed by DBU under micro-
wave irradiation in water (Scheme 1).
Results and discussion
Initially, 2-amino-nicotinonitrile (1a) and cyclohexanone (2b)
were chosen as model substrates to find a green and effective
solvent for the reaction. As shown in the Table 1, the reaction
was performed in cyclohexanone, THF, methanol, CH3CN,
CH2Cl2, dioxane and water (entries 1–7). Gratifyingly, we found
that the reaction using water as the solvent resulted in higher
yields than those using other solvents as well as less use of DBU
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing, 100081, China. E-mail: jrli@bit.edu.cn; Fax: +86
(10)68918012
†Electronic supplementary information (ESI) available. CCDC 792400,
854865, 854866. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2gc16469h
Scheme 1 Synthesis of 2,3-dihydropyrido[2,3-d]-pyrimidin-4(1H)-
ones.
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Table 1 Solvent screening for the synthesis of compound 3b under
Table 2 Synthesis of pyridopyrimidinone derivatives from 1a and
microwave irradiationa
various carbonyl compoundsa
Amount of
DBU (equiv)
Time
(minute)
Entry Ketone/Aldehyde Product
1
Time (min) Yield (%)b
Entry
Solvent
Yield (%)
5
75
1
2
3
4
5
6
7
8
9
Cyclohexanone
THF
MeOH
CH3CN
CH2Cl2
Dioxane
H2O
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
10
10
10
10
10
10
5
10c
No reaction
20b
40b
2
3
97
23b
30b
97c
H2O
H2O
5
5
97c
3
4
5
5
5
5
89
85
85
0.5
77c
a Reaction conditions: 2-amino-nicotinonitrile (1 mmol), solvent (1 ml).
b Isolated yield after purification by column chromatography. c Isolated
yield by filtration and recrystallization.
and reaction time (entries 7–8). The function of water is shown
in the possible mechanism (Scheme 2). Firstly, DBU reacts with
equimolar amount of water and changes to DBU–H2O complex
which can transform into a second resonance structure I with
Brønsted basic properties.9c The key intermediate II is formed
by addition of the amino group of the o-aminonitrile onto the
carbonyl of the cyclohexanone and subsequent intramolecular
nucleophilic attack of hydroxyl group to the nitrile group results
in the cyclized pyrido[2,3-d]oxazine III (Pinner reaction12),
which subsequently rearranges to afford the final product
(Dimroth rearrangement).13 The role of I in the reaction is to
activate the hydroxyl group of intermediate II to form an alkox-
ide anion which makes the nucleophilic reaction easier own to
its stronger nucleophilicity.
With these results in hand, we surveyed the scope of this reac-
tion by subjecting a series of carbonyl compounds 2a–o to react
with 2-amino-nicotinonitrile 1a and the results are presented in
Table 2. The method underwent well for all cyclic and branched
ketone substrates tested (entries 1–8). However, different cyclic
ketones have certain effect on this reaction because they exhibit
distinct steric hindrance and ring tension. The conversion of
6
7
5
5
83
90
8
5
82
9
5
5
84
93
10
11
5
5
93
90
12b
13
5
87
14
15
5
5
93
92
a Reaction conditions: 2-amino-nicotinonitrile (1 mmol), carbonyl
compounds (1.3 mmol), water (1 ml). b Isolated yields after filtration
and recrystallization.
Scheme 2 Possible mechanism for the formation of 3b catalyzed by
DBU.
946 | Green Chem., 2012, 14, 945–951
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Table 3 Synthesis
of
spiro-cyclohexane-pyridopyrimidinone
o-aminonitriles with cyclohexanone gave the highest yield and
consumed lowest time (entry 2). All linear ketones tested gave
the corresponding pyrido[2,3-d]pyrimidin-4(1H)-ones in good to
excellent yields (entries 4–8) after 5 minutes. Even poorly reac-
tive aromatic ketones, for example, acetophenone and 2-acetyl-
pyridine were successfully cyclized to give good yields of the
fused ring systems 3i–j (entries 9–10). Encouraged by these
exciting results, subsequently, we investigated the reaction of 2-
amino-nicotinonitrile 1a with a range of aromatic aldehydes with
different substituents ranging from electron-donating group to
electron-withdrawing group. All the aromatic aldehydes tested
performed well in this reaction. A range of 2-aryl substituted
2,3-dihydropyrido[2,3-d]-pyrimidin-4(1H)-ones have been con-
venient synthesized in high yields (entries 11–15).
To extend further scope of this methodology, a set of substi-
tuted 2-amino-nicotinonitriles were investigated and the results
obtained are summarized in Table 3. 2-Amino-nicotino-nitriles
bearing electron-donating or electron-withdrawing groups in C-5
and C-6 position (entries 2–3) were tolerated affording excellent
yields of the corresponding 1′H-spiro[cyclohexane-1,2′-pyrido
[2,3-d]pyrimidin]-4′(3′H)-ones. Furthermore, fully-substituted 2-
amino-nicotinonitriles also performed well (entries 4–7) and
indicated a certain influence of steric factors on the reaction
outcome. Interestingly, symmetrical 1′H,9′H-spiro[cyclohexane-
1,2′-1,8′-pyrido[2,3-d:6,5-d′]dipyrimidine]-4′,6′(3′H,7′H)-dione
was also obtained by the cyclocondensation of 2,6-diamino-pyri-
dine-3,5-dicarbonitrile with cyclohexanone under the catalysis of
DBU in good yields (entry 8). Usually, this skeleton was
afforded by several steps from barbituric acid or 6-amino-uracil14
as starting material.
derivatives from 2b and various 2-amino-nicotinonitrilesa
Time
(min)
Yield
(%)b
Entry o-Aminonitriles
Product
1
3
97
2
3
4
5
94
5
93
62
10
5
10
66
6
7
10
10
63
64
We examined the recyclability of the catalyst and solvent. The
product 3b can be separated from the reaction mixture by simple
filtration. This allows quick recovery for reuse in the next run.
The recyclability of DBU–H2O is tested by a five-run recycling
experiment (Table 4). All reactions were completed in 3 min and
afforded yields of 93–97%, the catalyst showed no substantial
reduction in activity after reused for five times.
All the products were characterized by ESI spectra, IR spectra,
1H NMR spectra, 13C NMR spectra and elemental analyses. The
structures of 3a, 4b and 4e have also been confirmed by X-ray
crystallographic analysis.
8
5
87
a Reaction conditions: 2-amino-nicotinonitrile (1 mmol), carbonyl
compounds (1.3 mmol), water (1 ml). b Isolated yields after filtration
and recrystallization.
Conclusion
In summary, we have developed an efficient method for the syn-
thesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones under
microwave irradiation in aqueous media. 1,8-Diazabicyclo[5.4.0]
undec-7-ene (DBU) showed high catalytic activity in this reac-
tion and without loss of its catalytic activity after reused for
several times. Furthermore, this method offers significant advan-
tages of time efficiency, ease of manipulation and atom
economy.
Table 4 Recycling of the DBU and solvent
Experimental
Run
1
2
3
4
5
Melting points were determined using XT4 microscope melting
point apparatus (uncorrected). The microwave reactor “Initiator”
(manufactured by Biotage, formerly Personal Chemistry) was
Yield (%)
97
95
94
94
93
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1′H-Spiro[cycloheptane-1,2′-pyrido[2,3-d]pyrimidin]-4′(3′H)-one
(3c)
used in all reactions. Infrared (IR) spectra were recorded on a
1
Perkin Elmer FT-IR spectrophotometer with KBr pellets. H and
13C NMR spectra were recorded at a Bruker 400 (400 MHz)
spectrometer with TMS as the internal standard. Mass spectra
were recorded on a ZAB-HS mass spectrometer using ESI ioniz-
ation. Elemental analyses were performed on an Elementar Vario
EL.
White solid; m.p. 272 °C; IR (KBr, v, cm−1): 3220, 3170, 2924,
1
1667, 1608, 1444; H NMR (400 MHz, DMSO-d6) (δ, ppm):
1.50 (8H, s, CH2), 1.90 (4H, d, J = 7.6, CH2), 6.65 (1H, m, J =
12.0, pyridine-H), 7.60 (1H, s, NH), 7.84 (1H, t, J = 7.2, pyri-
dine-H), 8.12 (1H, t, J = 4.4, pyridine-H), 8.26 (1H, s, NH); 13
C
The starting materials 2-amino-3-cyanopyridine (1a) and 5-
bromo-2-amino-3-cyanopyridine (1b) are commercially avail-
NMR (100 MHz, DMSO-d6) (δ, ppm): 21.27 (2C), 29.84 (2C),
42.10 (2C), 72.27, 109.23, 113.60, 135.82, 153.19, 157.34,
162.79; ESI-MS (m/z) = 232.1 ([M + H]+); Anal. Calcd for
C13H17N3O: C, 67.51; H, 7.41; N, 18.17%. Found: C, 67.40; H,
6.44; N, 17.91%.
able.
2-Amino-6-(dimethylamino)-pyridine-3,5-dicarbonitrile
and 2,6-diaminopyridine-3,5-dicarbonitrile were synthesized
from 2-chloropyridine-3,5-dicarbonitriles using a standard meth-
odology reported by Samadi.15 The fully substituted 2-amino-
pyridine-3-carbonitriles (1d–g) were conveniently synthesized
from a three-component reaction using commercial cyclic
ketones, aldehyde and malononitrile according to a reported
methodology.10d
2,2-Dimethyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3d)
White solid; sublimation; IR (KBr, v, cm−1): 3221, 3167, 2922,
1
1675, 1613, 1431; H NMR (400 MHz, DMSO-d6) (δ, ppm):
1.41 (6H, s, CH3), 6.66 (1H, m, J = 12.0, pyridine-H), 7.47 (1H,
s, NH), 7.87 (1H, m, J = 9.2, pyridine-H), 8.12 (1H, t, J = 6.8,
pyridine-H), 8.16 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)
(δ, ppm): 30.07 (2C), 67.22, 108.99, 113.81, 136.03, 153.39,
157.72, 162.95; ESI-MS (m/z) = 178.0 ([M + H]+); Anal. Calcd
for C9H11N3O: C, 61.00; H, 6.26; N, 23.71%. Found: C, 61.23;
H, 6.32; N, 23.81%.
General procedure for the synthesis of 3 and 4
The microwave reactor “Initiator” (manufactured by Biotage, for-
merly Personal Chemistry) was used in all reactions: A solution
of corresponding 2-amino-nicotinonitriles (1 mmol), carbonyl
compounds (1.3 eq), DBU (1 mmol) and water (1 ml) were
added in a 5 ml tube, sealed and heated to 100 °C. After com-
pletion of the reaction as indicated by TLC, the mixture was
cooled to room temperature and the precipitate was isolated by
filtration and then purified by crystallization from proper solvent
to provide the pure target products.
2-Ethyl-2-methyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one
(3e)
White crystal; m.p. 221–222 °C; IR (KBr, v, cm−1): 3220, 3191,
1
2942, 1681, 1611, 1434; H NMR (400 MHz, CDCl3) (δ, ppm):
1.01 (3H, t, J = 14.8, CH3), 1.55 (3H, s, CH2), 1.81 (2H, m, J =
22.0, CH3), 5.61 (1H, s, NH), 6.39 (1H, s, NH), 6.73 (1H, m, J
= 12.0, pyridine-H), 8.11 (1H, m, J = 8.8, pyridine-H), 8.17
(1H, d, J = 4.0, pyridine-H); 13C NMR (100 MHz, CDCl3) (δ,
ppm): 8.44, 29.01, 35.10, 69.97, 106.25, 110.10, 137.37,
153.41, 156.37, 161.75; ESI-MS (m/z) = 192.1 ([M + H]+);
Anal. Calcd for C10H13N3O: C, 62.81; H, 6.85; N, 21.97%.
Found: C, 62.70; H, 6.84; N, 21.80%.
1′H-Spiro[cyclopentane-1,2′-pyrido[2,3-d]pyrimidin]-4′(3′H)-one
(3a)
White crystal; m.p. 265 °C; IR (KBr, v, cm−1): 3271, 3168,
1
2922, 1644, 1600, 1420; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 1.67–1.83 (8H, d, C4H8), 6.65–6.69 (1H, m, J = 12.0, pyr-
idine-H), 7.61 (1H, s, NH), 7.85–7.88 (1H, d, J = 7.2, pyridine-
H), 8.12 (1H, s, pyridine-H), 8.30 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 22.47 (4C), 77.09, 109.47,
113.78, 136.02, 153.09, 158.03, 163.22; ESI-MS (m/z) = 204.1
([M + H]+); Anal Calcd for C11H13N3O: C, 65.01; H, 6.45; N,
20.68%. Found: C, 65.06; H, 6.47; N, 20.50%.
2-Methyl-2-propyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one
(3f)
White solid; m.p. 183–184 °C; IR (KBr, v, cm−1): 3219, 3176,
1
2959, 1675, 1611, 1453; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 0.93 (3H, t, J = 14.8, CH3), 1.42 (2H, m, J = 11.2, CH2),
1.46 (3H, s, CH3), 1.71 (2H, m, J = 22.8, CH2), 6.71 (1H, m, J
= 12.4, pyridine-H), 7.50 (1H, s, NH), 7.92 (1H, m, J = 9.2, pyr-
idine-H), 8.16 (1H, s, NH), 8.18 (1H, m, J = 11.2, pyridine-H);
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 14.46, 17.08, 69.41,
108.60, 113.38, 135.81, 153.27, 157.77, 162.98; ESI-MS (m/z)
= 206.2 ([M + H]+); Anal. Calcd for C11H15N3O: C, 64.37; H,
7.37; N, 20.47%. Found: C, 64.03; H, 7.32; N, 20.19%.
1′H-Spiro[cyclohexane-1,2′-pyrido[2,3-d]pyrimidin]-4′(3′H)-one
(3b)
White crystal; m.p. 263 °C; IR (KBr, v, cm−1): 3221, 3172,
1
2927, 1675, 1607, 1437; H NMR (400 MHz, CDCl3) (δ, ppm):
1.43–1.52 (2H, m, J = 36.0, CH2), 1.59–1.65 (4H, m, J = 24.0,
CH2), 1.78–1.92 (4H, m, J = 56.0, CH2), 5.43 (1H, s, NH), 6.15
(1H, s, NH), 6.75 (1H, m, J = 12.4, pyridine-H), 8.10 (1H, m, J
= 8.8, pyridine-H), 8.17 (1H, d, J = 4.0, pyridine-H); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 21.33 (2C), 23.95, 38.12 (2C),
67.81, 109.03, 114.38, 136.47, 152.69, 155.98, 162.83; ESI-MS
(m/z) = 218.1 ([M + H]+); Anal. Calcd for C12H15N3O: C,
66.34; H, 6.96; N, 19.34%. Found: C, 66.13; H, 6.99; N,
19.22%.
2,2-Diethyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3g)
White crystal; m.p. 221–222 °C; IR (KBr, v, cm−1): 3219, 3176,
1
2959, 1675, 1611, 1452; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 0.84 (6H, t, J = 14.8, CH3), 1.60 (4H, m, J = 55.2, CH2),
948 | Green Chem., 2012, 14, 945–951
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6.56 (1H, m, J = 12.0, pyridine-H), 7.30 (1H, s, NH), 7.90 (1H,
m, J = 8.4, pyridine-H), 7.91 (1H, s, NH), 8.06 (1H, m, J = 6.4,
pyridine-H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 8.17
(2C), 34.24 (2C), 72.46, 108.11, 112.87, 135.55, 153.14,
158.24, 163.23; ESI-MS (m/z) = 206.1 ([M + H]+); Anal. Calcd
for C11H15N3O: C, 64.37; H, 7.37; N, 20.47%. Found: C, 64.58;
H, 7.31; N, 20.39%.
ppm): 5.82 (1H, s, CH), 6.69–6.72 (1H, m, J = 12.4 Hz, pyri-
dine-H), 7.33–7.44 (5H, m, J = 45.6, ArH), 7.89–7.91 (1H, t, J
= 7.2, pyridine-H), 8.51 (1H, s, NH), 8.15–8.16 (1H, m, J = 6.4,
pyridine-H), 8.61 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)
(δ, ppm): 65.79, 110.13, 114.44, 126.94 (2C), 129.02, 129.12
(2C), 142.94, 153.62, 158.19, 163.51; ESI-MS (m/z) = 226.1
([M + H]+); Anal. Calcd for C13H11N3O: C, 69.32; H, 4.92; N,
18.66%. Found: C, 69.21; H, 4.91; N, 18.54%.
2-Isopropyl-2-methyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-
one (3h)
2-(4-Chlorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-
one (3l)
White crystal; m.p. 233–234 °C; IR (KBr, v, cm−1): 3273, 3168,
2967, 1675, 1609, 1426; H NMR (400 MHz, DMSO-d6) (δ,
1
White solid; m.p. 290 °C; IR (KBr, v, cm−1): 3211, 3170, 3036,
1687, 1606, 1437; H NMR (400 MHz, DMSO-d6) (δ, ppm):
1
ppm): 0.86–0.89 (6H, d, J = 12.8, CH3), 1.15 (3H, s, CH3),
1.85–1.92 (1H, m, J = 27.6, CH), 6.58–6.61 (1H, m, J = 12.4,
pyridine-H), 7.47 (1H, s, NH), 7.80–7.82 (1H, m, J = 9.6, pyri-
dine-H), 8.07–8.09 (1H, m, J = 6.4, pyridine-H), 8.11 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 13.86, 16.49,
28.79, 69.08, 105.78, 109.58, 136.87, 152.91, 155.78, 161.14;
ESI-MS (m/z) = 206.2 ([M + H]+); Anal. Calcd for C11H15N3O:
C, 64.37; H, 7.37; N, 20.47%. Found: C, 64.33; H, 7.34; N,
20.20%.
5.84 (1H, s, CH), 6.70–6.73 (1H, m, J = 12.4, pyridine-H),
7.44–7.47 (4H, m, J = 13.6, ArH), 7.89–7.91 (1H, m, J = 9.2,
pyridine-H), 8.00 (1H, s, NH), 8.15–8.16 (1H, m, J = 6.8, pyri-
dine-H), 8.60 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 65.17, 110.10, 114.64, 128.97 (2C), 129.12 (2C), 133.61,
136.47, 141.80, 153.70, 158.10, 163.48; ESI-MS (m/z) = 260.2
([M + H]+); Anal. Calcd for C13H10ClN3O: C, 60.12; H, 3.88;
N, 16.18%. Found: C, 59.92; H, 4.02; N, 15.44%.
2-Methyl-2-phenyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one
(3i)
2-(4-Fluorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-
one (3m)
White crystal; m.p. > 300 °C; IR (KBr, v, cm−1): 3206, 3170,
White solid; m.p. 293–294 °C; IR (KBr, v, cm−1): 3213, 3164,
1
2992, 1670, 1603, 1447; H NMR (400 MHz, DMSO-d6) (δ,
1
3031, 1688, 1607, 1447; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 1.68 (3H, s, CH3), 6.62–6.65 (1H, m, J = 12.4, pyridine-
H), 7.19–7.23 (1H, t, J = 14.4, ArH), 7.29–7.33 (2H, t, J = 15.2,
ArH), 7.49–7.51 (2H, d, J = 7.6, ArH), 7.78–7.80 (1H, t, J =
7.6, pyridine-H), 8.13–8.15 (1H, m, J = 6.8, pyridine-H), 8.48
(1H, s, NH), 9.01 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)
(δ, ppm): 30.27, 69.76, 109.56, 113.63, 124.96 (2C), 127.19,
128.02 (2C), 135.55, 147.43, 152.85, 157.35, 163.30; ESI-MS
(m/z) = 240.1 ([M + H]+); Anal. Calcd for C14H13N3O: C,
70.28; H, 5.48; N, 17.56%. Found: C, 70.08; H, 5.47; N,
17.52%.
ppm): 5.85 (1H, s, CH), 6.71–6.72 (1H, d, J = 4.8, pyridine-H),
7.19–7.24 (2H, t, J = 16.8, ArH), 7.47 (2H, s, ArH), 7.89–7.91
(1H, t, J = 6.4, pyridine-H), 7.97 (1H, s, NH), 8.15–8.16 (1H,
m, J = 2.0, pyridine-H), 8.57 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 64.58, 113.88, 115.80, 115.29, 128.44,
128.53, 135.73, 138.33, 152.96, 157.46, 160.78, 162.77, 163.21;
ESI-MS (m/z)
= 244.1 ([M +
H]+); Anal. Calcd for
C13H10FN3O: C, 64.19; H, 4.14; N, 17.28%. Found: C, 64.17;
H, 4.12; N, 17.35%.
2-(p-Tolyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3n)
White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3211, 3164,
2-Methyl-2-(pyridin-2-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4
(1H)-one (3j)
1
White crystal; m.p. 241–242 °C; IR (KBr, v, cm−1): 3180, 3094,
3027, 1660, 1609, 1432; H NMR (400 MHz, DMSO-d6) (δ,
1
ppm): 2.27 (3H, s, CH3), 5.77 (1H, s, CH), 6.69–6.70 (1H, d, J
= 4.8, pyridine-H), 7.16–7.18 (2H, d, J = 7.2, ArH), 7.30–7.32
(2H, d, J = 8.0, ArH), 7.87–7.92 (2H, t, J = 20.0, pyridine-H),
8.13 (1H, s, NH), 8.53 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 20.66, 64.92, 109.49, 113.67, 126.17 (2C),
128.87 (2C), 135.62, 137.54, 139.30, 152.84, 157.50, 162.83;
ESI-MS (m/z) = 238.0 ([M − H]−); Anal. Calcd for C14H13N3O:
C, 70.28; H, 5.48; N, 17.56%. Found: C, 70.11; H, 5.64; N,
17.69%.
2976, 1677, 1606, 1447; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 1.72 (3H, s, CH3), 6.62–6.66 (1H, m, J = 12.4, pyridine-
H), 7.23–7.26 (1H, t, J = 11.6, pyridine-H), 7.49–7.52 (1H, t, J
= 12.0, pyridine-H), 7.75–7.81 (2H, t, J = 24.0, pyridine-H),
8.11–8.12 (1H, d, J = 4.0, pyridine-H), 8.17 (1H, s, pyridine-H),
8.51 (1H, s, NH), 8.78 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 28.45, 70.58, 109.51, 113.77, 119.12,
122.68, 135.53, 136.92, 148.68, 152.81, 157.33, 163.15, 164.03;
ESI-MS (m/z) = 239.1 ([M − H]−); Anal. Calcd for C13H12N4O:
C, 64.99; H, 5.03; N, 23.32%. Found: C, 64.79; H, 5.01; N,
23.18%.
2-(4-Methoxyphenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-
one (3o)
2-Phenyl-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3k)
White solid; m.p. 278–279 °C; IR (KBr, v, cm−1): 3203, 3169,
White solid; m.p. 261–263 °C; IR (KBr, v, cm−1): 3213, 3164,
3103, 1684, 1607, 1443; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 3.73 (3H, s, CH3), 5.77 (1H, s, CH), 6.69–6.70 (1H, d,
Green Chem., 2012, 14, 945–951 | 949
1
1
3031, 1687, 1610, 1447; H NMR (400 MHz, DMSO-d6) (δ,
This journal is © The Royal Society of Chemistry 2012

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J = 12.4, pyridine-H), 6.67–6.70 (2H, m, J = 12.4, ArH),
7.32–7.35 (2H, t, J = 11.6, ArH), 7.87–7.89 (1H, t, J = 7.2, pyri-
dine-H), 7.89 (1H, s, NH), 7.87–7.89 (1H, m, J = 6.8, pyridine-
H), 8.48 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 55.83, 65.50, 110.17, 114.39 (2C), 128.30 (2C), 134.84,
136.36, 153.56, 158.27, 159.94, 163.57; ESI-MS (m/z) = 256.2
([M + H]+); Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N,
16.46%. Found: C, 65.77; H, 5.14; N, 16.33%.
2.15 (t, 2H, CH2), 2.78 (t, 2H, CH2), 5.30 (s, 1H, NH), 7.01 (d,
J = 84.0, 2H, ArH), 7.33 (d, J = 84.0, 2H, ArH), 7.36 (s, 1H,
NH); 13C NMR (100 MHz, CDCl3) (δ, ppm): 21.7 (2C), 22.7,
22.9, 24.6, 26.4, 33.2, 38.1 (2C), 67.2, 105.6, 122.4, 128.0 (2C),
128.7 (2C), 132.5, 137.7, 151.3, 154.8, 160.7, 163.3; ESI-MS
(m/z) = 382.2 ([M + H]+); Anal. Calcd for C22H24ClN3O: C,
69.19; H, 6.33; N, 11.00%. Found: C, 68.71; H, 6.45; N,
10.75%.
6′-Bromo-1′H-spiro[cyclopentane-1,2′-pyrido[2,3-d]pyramidin]-
4′(3′H)-one (4b)
5′-(4-Fluorophenyl)-3′,6′,7′,8′-tetrahydrospiro[cyclohexane-1,2′-
cyclopenta[5,6]pyrido[2,3-d]pyrimidin]-4′(1′H)-one (4f)
Light yellow crystal; m.p. 258 °C; IR (KBr, v, cm−1): 3274,
Yellow solid; m.p. 267–270 °C; IR (KBr, v, cm−1): 3406, 3181,
3058, 2927, 1656, 1602, 1568, 1509; 1H NMR (400 MHz,
CDCl3) (δ, ppm): 1.30–1.78 (m, 10H, CH2), 1.97–2.05 (m, 2H,
CH2), 2.56 (t, 2H, CH2), 2.90 (t, 2H, CH2), 5.48 (s, 1H, NH),
7.02–7.18 (m, 4H, ArH), 7.50 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 21.67 (2C), 22.67, 24.56, 29.32,
35.00, 37.83 (2C), 67.14, 104.73, 114.40, 114.61, 127.90,
129.19, 129.27, 148.00, 157.39, 160.72, 163.16, 163.78, 168.65;
1
3175, 2927, 1677, 1610, 142; H NMR (400 MHz, DMSO-d6)
(δ, ppm): 1.30–1.33 (2H, t, J = 10.4, CH2), 1.57–1.59 (4H, d, J
= 4.4, CH2), 1.70–1.73 (4H, t, J = 9.6, CH2), 7.79 (1H, s, NH),
7.92 (1H, d, J = 2.4, pyridine-H), 8.24 (1H, d, J = 2.4, pyridine-
H), 8.35 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6) (δ,
ppm): 21.04 (2C), 24.91, 38.22 (2C), 68.46, 106.83, 110.93,
137.59, 153.42, 156.08, 161.88; ESI-MS (m/z)
= 226.1
([M + H]+); Anal. Calcd for C12H14BrN3O: C, 48.67; H, 4.76;
N, 14.19%. Found: C, 48.88; H, 4.78; N, 14.06%.
ESI-MS (m/z)
= 352.3 ([M +
H]+); Anal. Calcd for
C21H22FN3O: C, 71.77; H, 6.31; N, 11.96%. Found: C, 71.90;
H, 6.45; N, 12.00%.
7′-(Dimethylamino)-4′-oxo-3′,4′-dihydro-1′H-spiro[cyclohexane-
1,2′-pyrido[2,3-d]pyrimidine]-6′-carbonitrile (4c)
5′-(4-Fluorophenyl)-6′,7′,8′,9′-tetrahydro-1′H-spiro[cyclohexane-
1,2′-pyrimido[4,5-b]quinolin]-4′(3′H)-one (4g)
White crystal; m.p. > 300 °C; IR (KBr, v, cm−1): 3280, 3204,
2927, 2202, 1635, 1604, 1396; H NMR (400 MHz, DMSO-d6)
1
(δ, ppm): 1.25–1.36 (2H, d, J = 44.0, CH2), 1.82–1.86 (8H, d, J
= 39.2, CH2), 3.22 (6H, d, 2 × CH3), 7.85 (1H, s, pyridine-H),
7.96 (1H, s, NH), 8.08 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm): 20.56 (2C), 24.44, 38.23 (2C), 40.15 (2C),
68.01, 78.97, 99.42, 120.09, 143.93, 156.62, 160.21, 161.23;
ESI-MS (m/z) = 284.2 ([M − H]−); Anal. Calcd for C15H19N5O:
C, 63.14; H, 6.71; N, 24.54%. Found: C, 63.11; H, 6.70; N,
24.24%.
Dark yellow solid; m.p. 294–296 °C; IR (KBr, v, cm−1): 3355,
1
3258, 2930, 1667, 1567, 1509; H NMR (400 MHz, CDCl3) (δ,
ppm): 1.43–1.59 (m, 10H, CH2), 1.74–1.79 (m, 4H, CH2CH2),
2.15 (t, 2H, CH2), 2.77 (t, 2H, CH2), 5.27 (s, 1H, NH),
7.02–7.07 (m, 4H, ArH), 7.65 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 21.67 (2C), 22.49, 22.93, 24.51,
26.45, 33.22, 38.06 (2C), 67.12, 105.77, 114.51, 114.72, 122.53,
128.90, 128.98, 135.06, 135.10, 151.47, 154.88, 160.52, 162.96,
163.50; ESI-MS (m/z) = 366.2 ([M + H]+); Anal. Calcd for
C22H24FN3O: C, 72.31; H, 6.62; N, 11.50%. Found: C, 72.18;
H, 6.80; N, 11.32%.
5′-(4-Chlorophenyl)-3′,6′,7′,8′-Tetrahydrospiro[cyclohexane-1,2′-
cyclopenta[5,6]pyrido[2,3-d]pyrimidin]-4′(1′H)-one (4d)
White solid; m.p. 294–295 °C; IR (KBr, v, cm−1): 3355, 3258,
3079, 2930, 2869, 1668, 1605, 1509; 1H NMR (400 MHz,
CDCl3) (δ, ppm): 1.33–1.77 (m, 10H, CH2), 1.97–2.05 (m, 2H,
CH2), 2.54 (t, 2H, CH2), 2.90 (t, 2H, CH2), 5.45 (s, 1H, NH),
7.12 (d, J = 84, 2H, ArH), 7.32 (d, J = 84, 2H, ArH), 7.51 (s,
1H, NH); 13C NMR (100 MHz, CDCl3) (δ, ppm): 21.68 (2C),
22.64, 24.59, 29.27, 34.97, 37.87 (2C), 67.21, 104.57, 127.73,
127.80 (2C), 128.94 (2C), 132.79, 137.65, 147.76, 157.29,
163.69, 168.72; ESI-MS (m/z) = 368.2 ([M + H])+; Anal. Calcd
For C21H22ClN3O: C, 68.56; H, 6.03; N, 11.42%. Found: C,
68.35; H, 6.35; N, 11.18%.
1′H,9′H-Spiro[cyclohexane-1,2′-1,8′-pyrido[2,3-d:6,5-d′]di-
pyrimidine]-4′,6′(3′H,7′H)-dione (4h)
White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3281, 3186,
1
2926, 1655, 1593, 1495; H NMR (400 MHz, DMSO-d6) (δ,
ppm): 1.26–1.75 (m, 20H, CH2), 7.40 (s, 2H, NH), 7.87 (s, 2H,
NH), 8.03 (1H, s, pyridine-H); 13C NMR (100 MHz, DMSO-d6)
(δ, ppm): 20.77 (4C), 24.56 (2C), 37.98 (4C), 67.67 (2C),
100.03 (2C), 135.83, 158.90 (2C), 162.49 (2C); ESI-MS (m/z) =
354.0 ([M − H]−); Anal. Calcd for C19H25N5O2: C, 64.20; H,
7.09; N, 19.70%. Found: C, 64.14; H, 7.11; N, 19.56%.
5′-(4-Chlorophenyl)-6′,7′,8′,9′-tetrahydro-1′H-spiro
[cyclohexane-1,2′-pyrimido[4,5-b]quinolin]-4′(3′H)-one (4e)
Acknowledgements
White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3428, 3168,
2933, 1707, 1661, 1578, 1491; H NMR (400 MHz, CDCl3) (δ,
ppm): 1.48–1.64 (m, 10H, CH2), 1.76–1.80 (m, 4H, CH2CH2),
950 | Green Chem., 2012, 14, 945–951
This work was supported by the grant of Beijing Institute of
Technology. We are grateful for analytical help of Institute of
Chemistry, Chinese Academy of Sciences.
1
This journal is © The Royal Society of Chemistry 2012

View Article Online
(e) J. M. Khurana, B. Nand and P. Saluja, Tetrahedron, 2010, 66, 5637;
(f) K. Ando and K. Yamada, Green Chem., 2011, 13, 1143.
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