Ecofriendly synthesis of substituted pyridine and pyrido[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1007/s11172-005-0440-z

An environmentally benign novel one-pot synthesis of pyridines and pyrido[2,3-d]pyrimidines from chalcones and malononitrile was described. In the reaction under neat conditions using microwave irradiation, enhancement in the reaction rate and high yields

Full text of DOI:10.1007/s11172-005-0440-z

Russian Chemical Bulletin, International Edition, Vol. 54, No. 6, pp. 1523—1526, June, 2005
1523
Ecofriendly synthesis of substituted pyridine and pyrido[2,3ꢀd]pyrimidine
derivatives
M. Kidwai,ꢀ R. Thakur, and S. Rastogi
Department of Chemistry, University of Delhi, 110007 Delhi, India.
Fax: (911 1) 2766 6235. Eꢀmail: kidwai_chemistry@yahoo.co.uk; rubythakur1511@yahoo.co.in
An environmentally benign novel oneꢀpot synthesis of pyridines and pyrido[2,3ꢀd]pyrimidiꢀ
nes from chalcones and malononitrile was described. In the reaction under neat conditions
using microwave irradiation, enhancement in the reaction rate and high yields were observed.
Key words: pyridines, pyrido[2,3ꢀd]pyrimidine derivatives, microwave irradiation, supꢀ
ported catalysts, neat reaction conditions.
The increasing environmental consciousness throughꢀ
out the world has trigged the search for new products and
processes that are compatible with the ecofriendly enviꢀ
ronment. The strict legislative restrictions on pollution
exposure has enforced the application of solventꢀfree conꢀ
ditions in practice.1 In this endeavor, inorganic solid supꢀ
ports such as zeolites, alumina, bentonite, montmorilloꢀ
nite Kꢀ10 clay, etc. are strikingly appealing, because the
reaction can be performed in "dry media."2—4 Furthemore,
the usage of solid supports in conjunction with microꢀ
waves5,6 leads to higher yield and reaction rate enhanceꢀ
ment.7 The minute observation of the usage of solid supꢀ
ports reveals that an appreciable amount of solvent is
required for the adsorption of the reactants and desorpꢀ
tion of products. An alternative solventꢀfree approach is
the "neat reaction" technique. This has made a landmark
as it aims at the complete elimination of solvent from the
reaction. These solventless reactions proved to be adꢀ
vantageous for environmental reasons especially when
coupled with microwaves, since they provide an opportuꢀ
nity to conduct various transformations more efficiently
and expeditiously.
Results and Discussion
In the present paper we are reporting a facile and rapid
synthesis (Scheme 1) of 4,6ꢀdisubstituted 2ꢀaminoꢀ3ꢀ
cyanopyridines 4a—f and 5,7ꢀdisubstituted 3ꢀphenylꢀ
pyrido[2,3ꢀd]pyrimidineꢀ2,4(1H,3H )ꢀdiones 6a—f withꢀ
Scheme 1
Pyridines generate a widespread interest due to diverse
pharmacological activities.8,9 Pyrimidines owing to their
natural occurrence in human genetic material are espeꢀ
cially important as antiinfective agents.10—12 Thus fused
pyrido[2,3ꢀd]pyrimidine derivatives are associated with
numerous biological activities,13—16 viz., antitumor17 and
anticonvulsant.18 This is responsible for the abiding interꢀ
est in this class of compounds.
Various conventional methods are known for the synꢀ
thesis of pyrido[2,3ꢀd]pyrimidineꢀ2,4(1H,3H )ꢀdiones
starting from 6ꢀaminouracil,19 6ꢀiminoꢀ1,3ꢀdialkylꢀ
uracil,20,21 and arylidene derivatives of barbituric acids.22
All these procedures are not readily accessible, since they
demand synthesis even at the precursor stage and require
long reaction time and appreciable amount of solvent.
Reagents and conditions: A. µν, 3.1—5.1 min, clay Kꢀ10 (Aꢀ1) or
neutral Al2O3 (Aꢀ2); B. µν, 4.2—5.9 min, clay Kꢀ10 (Bꢀ1) or
basic Al2O3 (Bꢀ2); C. µν, 1.5—2.3 min (after addition of
NH4OAc), clay Kꢀ10; D. µν, 2.8—4.3 min.
1, 4, 6
R1
R2
a
b
c
d
e
f
4ꢀMeOC6H4
2ꢀFuryl
3ꢀIndolyl
Benzo[1,3]dioxolꢀ5ꢀyl
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
Ph
Ме
4ꢀBrC6H4
4ꢀBrC6H4
Ph
4ꢀMeOC6H4
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1479—1482, June, 2005.
1066ꢀ5285/05/5406ꢀ1523 © 2005 Springer Science+Business Media, Inc.

1524
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
Kidwai et al.
out solvent or on a solid support under microwave irraꢀ
diation from α,βꢀunsaturated carbonyl compounds of the
chalcone type. Moreover, we have studied the influence
of different solid supports under microwave irradiation for
the synthesis of the above pyridine and pyrido[2,3ꢀd]pyriꢀ
midine derivatives and developed the oneꢀpot synthesis
of 6a—f.
The reported synthesis of 5,7ꢀdisubstituted 3ꢀphenylꢀ
pyrido[2,3ꢀd]pyrimidineꢀ2,4(1H,3H )ꢀdiones 6 starting
from chalcone and malononitrile23 is a twoꢀstep reacꢀ
tion performed in ethanol or dioxane during 22—24 h.
Thereby 4,6ꢀdisubstituted 2ꢀaminoꢀ3ꢀcyanopyridines 4
were formed as intermediates, and the final products 6
were obtained in a very low yield. In an attempt to
"greenify" the synthetic procedure and increase its rate
and yield, experiments were done under microwave irraꢀ
diation. The aboveꢀmentioned conventional procedure is
modified by using chalcones and their heterocyclic anaꢀ
logs on solid supports (montmorillonite clay Kꢀ10 or aluꢀ
mina); after microwave irradiation for several minutes,
4,6ꢀdisubstituted 2ꢀaminoꢀ3ꢀcyanopyridines 4a—f were
obtained in 79—82% yields (see Scheme 1, method А;
Table 1).
pot synthesis of pyrido[2,3ꢀd]pyrimidines 6a—f on a
solid support using chalcones 1, malononitrile (2),
NH4OAc (3), and PhNCO (5) (see Scheme 1, method С).
In an improved method, compounds 1, 2, and 3 were
adsorbed on clay Kꢀ10 and irradiated. Upon intermediꢀ
ates 4 formation (TLC examination), a solution of PhNCO
(5) was added and further irradiated under microwaves.
Thus, products 6a—f were obtained directly without elutꢀ
ing in the middle of the process. This is attributed to the
dual nature24 of Kꢀ10 montmorillonite clay, which can
act as both cyclizing and condensing agent.25 In continuꢀ
ation to our interest in the development of environmenꢀ
tally benign protocol,26—28 we carried out the neat synꢀ
thesis of 5,7ꢀdisubstituted 3ꢀphenylpyrido[2,3ꢀd]pyriꢀ
midineꢀ2,4(1H,3H)ꢀdiones 6a—f without solvent (see
Scheme 1, method D). In this method, neat reactants 1,
2, 3, and 5 were mixed without using any solid support or
solvent and irradiated. To our surprise, products 6 were
obtained in excellent yields (see Table 1) with not much
change in the reaction time, when compared with the
oneꢀpot solidꢀsupported synthesis.
The structures of compounds 4a—f and 6a—f were
proved from IR and 1H NMR spectra (Table 2). The
IR spectra of pyridines 4 contain vibrations of the conjuꢀ
gated nitrile group (2180—2230 cm–1) and amino group
of the enaminonitrile fragment (three bands at
3100—3440 cm–1). Their 1H NMR spectra exhibit a
broadened singlet at δ 7.25—7.55 belonging to the NH2
group. The IR spectra of pyridopyrimidines 6 contain a
band at 1600—1630 cm–1 corresponding to the carbonyl
In the second step, compounds 4a—f were condensed
with phenyl isocyanate (5), adsorbed over Kꢀ10 montmoꢀ
rillonite clay or alumina (see Scheme 1, method B), and
irradiated under microwaves to afford the final 5,7ꢀdisubꢀ
stituted 3ꢀphenylpyrido[2,3ꢀd]pyrimidineꢀ2,4(1H,3H )ꢀ
diones 6a—f in 82—89% yields (see Table 1). Further, the
formation of both intermediates 4a—f and the final cyꢀ
clized products 6a—f prompted us to carry out the oneꢀ
1
group of amides. Their H NMR spectra have one signal
Table 1. Reaction time (t) and yields of pyridine derivatives 4a—f and pyrido[2,3ꢀd]pyrimidine derivatives 6a—f
Comꢀ
pound
R1
R2
Method A
Method B
Bꢀ1a Bꢀ2c
Method C a Method D
Aꢀ1a
Aꢀ2b
t/min (yield (%))
4a
4b
4c
4d
4ꢀMeOC6H4
2ꢀFuryl
3ꢀIndolyl
Benzo[1,3]diꢀ
oxolꢀ5ꢀyl
Ph
Me
4ꢀBrC6H4
4ꢀBrC6H4
4.2 (79)
4.1 (80)
3.7 (76)
3.1 (78)
4.8 (78)
4.5 (82)
4.2 (74)
4.6 (75)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4e
4f
6a
6b
6c
6d
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
4ꢀMeOC6H4
2ꢀFuryl
3ꢀIndolyl
Benzo[1,3]diꢀ
oxolꢀ5ꢀyl
Ph
3.9 (81)
4.1 (84)
4.8 (82)
5.1 (83)
—
—
5.6 (79)
5.1 (82)
4.7 (77)
4.2 (79)
—
—
5.9 (73)
5.6 (79)
4.9 (75)
4.8 (72)
—
—
8.6 (84)
6.4 (88)
7.1 (85)
6.8 (82)
—
—
4.1 (97)
3.4 (96)
4.2 (94)
2.8 (95)
4ꢀMeOC6H4
Ph
Me
4ꢀBrC6H4
4ꢀBrC6H4
—
—
—
—
—
—
—
—
6e
6f
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
Ph
—
—
—
—
4.6 (83)
5.8 (87)
5.1 (76)
6.0 (82)
7.4 (85)
8.2 (89)
4.3 (96)
3.5 (93)
4ꢀMeOC6H4
a Montmorillonite clay Kꢀ10.
b Neutral Al2O3.
c Basic Al2O3.

Pyridine and pyridopyrimidine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
1525
Table 2. Physicochemical, spectral, and analytical data for compounds 4a—f and 6a—f
Comꢀ M.p.
pound /°C
Found
Calculated
Molecular
formula
IR,
ν/cm–1
1H NMR (CDCl3 + DMSOꢀd6),
(%)
δ
C
H
—
N
—
4a 176—17723b
4b 169—171
—
—
2182 (C≡N),
3110 (NH)
2198 (C≡N),
3120 (NH)
3.73 (s, 3 H, OMe); 6.83—7.01 (m, 10 H,
H arom.); 7.25 (br.s, 2 H, NH)
2.55 (s, 3 H, Me); 6.31 (dd, 2 H, furyl);
6.90—7.00 (m, 2 H, H arom.); 7.32 (br.s,
2 H, NH)
66.14 4.38 21.24
66.33 4.52 21.10
C11H9N3O
4c 246—248
61.59 3.32 14.21
61.71 3.34 14.39
C20H13BrN4
2230 (C≡N),
3312 (NH)
6.81 (d, 1 H, H(2) of indole); 7.28 (br.s,
2 H, NH); 7.01—7.88 (m, 9 H, H arom.);
10.10 (s, 1 H, NH of indole)
4d 215—217
4e 159—160
51.52 3.15 10.48
55.88 3.04 10.66
72.48 5.20 12.59
72.50 5.13 12.68
69.58 5.42 11.48
69.80 5.26 11.63
74.12 4.48 09.82
74.10 4.51 09.97
67.63 4.18 13.25
67.71 4.07 13.16
C19H12BrN3O2 2210 (C≡N),
5.86 (s, 2 H, ОCH2О); 6.79—7.88 (m, 8 H,
H arom.); 7.35 (br.s, 2 H, NH)
3.71 (s, 6 H, OMe); 6.71—7.31 (m, 9 H,
H arom.); 7.46 (br.s, 2 H, NH)
3.60 (s, 9 H, OMe); 7.11—7.40 (m, 8 H,
H arom.); 7.55 (br.s, 2 H, NH)
3.73 (s, 3 H, OMe); 6.13 (s, 1 H, NH of
pyrimidine); 6.83—7.99 (m, 15 H, H arom.)
2.55 (s, 3 H, Me); 6.11 (s, 1 H, NH of
pyrimidine); 6.31 (dd, 2 H, furyl);
3400 (NH)
C20H17N3O2
C21H19N3O3
C26H19N3O3
C18H13N3O3
2280 (C≡N),
3300 (NH)
2220 (C≡N),
3210 (NH)
1610 (C=O),
3100 (NH)
1625 (C=O),
3120 (NH)
4f
126—129
6a 224—226
6b 228—229
7.01—7.62 (m, 7 H, H arom.)
6c 239—240
60.62 3.36 11.25
60.71 3.15 11.04
C27H16BrN4O2 1620 (C=O),
3110 (NH)
6.40 (s, 1 H, NH of pyrimidine); 6.81 (d,
1 H, H(2) of indole); 7.02—7.83 (m, 13 H,
H arom.); 10.10 (s, 1 H, NH of indole)
5.90 (s, 2 H, ОCH2О); 6.60 (s, 1 H, NH of
pyrimidine); 6.72—7.88 (m, 13 H, H arom.)
3.71 (s, 6 H, OMe); 6.21 (s, 1 H, NH of
pyrimidine); 6.71—7.92 (m, 14 H, H arom.)
3.62 (s, 9 H, OMe); 6.66 (s, 1 H, NH of
pyrimidine); 7.11—7.63 (m, 13 H, H arom.)
6d 252—254
60.63 3.23 08.38
60.71 3.11 08.17
C26H16BrN3O4 1614 (C=O),
3130 (NH)
6e 150—15123a
—
—
—
—
1630 (C=O),
3140 (NH)
1624 (C=O),
3148 (NH)
6f
120—12223a
—
—
—
—
given in the δ scale relative to Me4Si as internal reference. Elꢀ
emental analyses were performed using a Heraeus CHNꢀRapid
analyzer. The melting points (uncorrected) were determined on
a Thomas Hoover Melting Point apparatus. The purity of comꢀ
pounds and the reaction course were monitored by TLC on
aluminum plates coated with silica gel (Merck) using ethanol as
eluent.
The following solid supports were used: montmorillonite
clay Kꢀ10 (Fluka, 200 20 m2 g–1), neutral and basic aluminas,
(Brockmann activity grade I (Aldrich), ∼150 mesh, 58 Å,
155 m2 g–1).
at δ 6.11—6.66 characteristic of the NH fragment of the
pyrimidinedione ring.
Thus, we have developed facile, economical, and
ecofriendly synthetic procedures for the synthesis of
4,6ꢀdisubstituted 2ꢀaminoꢀ3ꢀcyanopyridines 4 and
5,7ꢀdisubstituted 3ꢀphenylpyrido[2,3ꢀd]pyrimidineꢀ
2,4(1H,3H )ꢀdiones 6 under microwave irradiation using
solventꢀfree techniques. All the reactions under neat conꢀ
ditions gave excellent yields with reduced reaction time
when compared with solidꢀsupport synthesis. This keeps
modernization and simplification of classical procedures
toward green synthesis.
4,6ꢀDisubstituted 2ꢀaminoꢀ3ꢀcyanopyridines 4a—f
Experimental
Solidꢀsupported synthesis (general procedure А). Montmoꢀ
rillonite clay Kꢀ10 (15 g) (method Aꢀ1) or neutral Al2O3 (20 g)
(method Aꢀ2) was added to a solution of chalcone 1 (0.05 mol),
malononitrile (2) (0.05 mol) and ammonium acetate (3)
(0.4 mol) in ethanol (10 mL) with constant stirring (see Table 1).
The reaction mixture was airꢀdried at room temperature, placed
in an alumina bath,29 and subjected to microwave irradiation for
4.2—5.1 min (method Aꢀ1) or 3.1—4.2 min (method Aꢀ2). Upon
completion of the reaction as followed by TLC at an interval of
Microwave irradiation was carried out on
a
KenstarꢀОM9925E microwave oven (2450 MHz, 800 W). The
temperature of the reaction mixture was measured with a nonꢀ
contact miniꢀgunꢀtype IR thermometer (model 8868). IR specꢀ
tra were recorded on a Perkin—Elmer FTIRꢀ1710 spectrophoꢀ
1
tometer using KBr pellets. H NMR spectra were obtained on a
Hitachi Rꢀ600 spectrometer (300 MHz); chemical shifts are

1526
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
Kidwai et al.
30 s, the mixture was cooled to room temperature, and products
4a—f were extracted with ethanol (3×15 mL). Removal of the
solvent in vacuo yielded products 4a—f, which were recrystalꢀ
lized from petroleum ether.
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(b) M. Nettekoven and F. Hoffmann, Synlett, 2001, 12, 1917.
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57, 1961.
5,7ꢀDisubstituted 3ꢀphenylpyrido[2,3ꢀd]pyriꢀ
midineꢀ2,4(1H,3H)ꢀdiones 6a—f
Solidꢀsupported synthesis from intermediates 4 (general proꢀ
cedure B). Clay Kꢀ10 (10 g) (method Bꢀ1) or basic Al2O3 (15 g)
(method Bꢀ2) was added to an equimolar mixture of compounds
4a—f (prepared by method А) and phenyl isocyanate (5) with
constant stirring (see Table 1). The reaction mixture was
airꢀdried, placed in an alumina bath,29 and irradiated for
4.2—5.8 min (method Bꢀ1) or 4.8—6.0 min (method Bꢀ2). Upon
completion of the reaction (TLC monitoring), the mixture was
cooled to room temperature, and reaction products 6 were exꢀ
tracted with ethanol (3×10 mL). Removal of the solvent in vacuo
afforded products 6a—f, which were recrystallized from ethanol.
Solidꢀsupported synthesis from reactants 1—3, and 5 (genꢀ
eral procedure С ). Montmorillonite clay Kꢀ10 (10 g) was added
to a mixture of compounds 1 and 2 (0.05 mol each), ammonium
acetate (3) (0.4 mol), and ethanol (10 mL) at room temperaꢀ
ture. The reaction mixture was thoroughly mixed and dried in
air. Then it was placed in an alumina bath29 and subjected
to microwave irradiation. Upon intermediates 4 formation
(1.5—2.3 min, TLC monitoring), a solution of phenyl isocyanꢀ
ate (5) (0.05 mol) was adsorbed over the solid support, and the
mixture was further irradiated. Upon completion of the reacꢀ
tion, the mixture was cooled, the product was extracted with
ethanol (3×10 mL), and the solvent was removed in vacuo. Prodꢀ
ucts 6a—f were recrystallized from ethanol.
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Oneꢀpot neat (solventꢀfree) synthesis of compounds 6a—f
(general procedure D). Equimolar amounts of compounds 1, 2,
and 5 (0.05 mol each) and ammonium acetate (3) (0.4 mol)
were mixed in a 250ꢀmL Erlenmeyer flask. The reaction mixture
was irradiated for 2.8—4.3 min. Progress of the reaction was
monitored by TLC examination at an interval of 30 s. Upon
reaction completion, the resulting sticky mass was triturated
with cold methanol. Solid products 6a—f formed were filtered
off, washed with cold ethanol, and recrystallized from ethanol.
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This work was financially supported by the University
Grants Commission (New Delhi, India).
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Received February 13, 2004;
in revised form July 6, 2004