A facile synthesis of substituted pyridines and pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1002/jhet.5570420622

A facile, solvent free, ecofriendly approach for the synthesis of 2-amino-3(ethylcarboxy)-4,6-disubstituted pyridine 4 and pyrazolo[3,4-b] pyridines 6 is herein described employing neat reaction conditions under microwave irradiation. This solventless met

Full text of DOI:10.1002/jhet.5570420622

A Facile Synthesis of Substituted Pyridines and Pyrazolo[3,4-b]pyridines
Sep-Oct 2005
1181
M. Kidwai*, R. Thakur and S. Saxena
Department of Chemistry, University of Delhi, Delhi-110007, India
Telefax: 91 11 27666235; E-mail: kidwai_chemistry@yahoo.co.uk
Received October 11, 2004
A facile, solvent free, ecofriendly approach for the synthesis of 2-amino-3(ethylcarboxy)-4,6-disubsti-
tuted pyridine 4 and pyrazolo[3,4-b]pyridines 6 is herein described employing neat reaction conditions under
microwave irradiation. This solventless methodology is environmentally benign as it completely eliminates
the use of solvent from the reaction procedure. The observed reaction rate enhancement and high yield of
products are due to the neat reaction conditions coupled with microwaves (MWs).
J. Heterocyclic Chem., 42, 1181 (2005).
Industrial chemistry in the new millennium is widely
adopting the concept of "Green Chemistry" [1] to meet the
fundamental scientific challenges of protecting the human
health and environment while maintaining commercial
viability. One of the advances in this area where substan-
tial progress has been made is the microwave assisted [2-
4] solid supported synthesis [5-7]. But this technique does
not meet the ecofriendly goal of clean synthesis as an
appreciable amount of solvent, is required for the adsorp-
tion of reactants and elution of products. The "neat reac-
tion" technique is an alternative solvent free approach in
which the reaction is carried out in the absence of solvent,
support and catalyst. Further coupling of this solventless
synthesis with MWs has the associated benefits of shorter
reaction time, uniform heating and better yield in compari-
son to conventional heating.
The basic skelton of chalcones which possess α,β-
unsaturated carbonyl group is useful as the starting
material for the synthesis of various heterocyclic com-
pounds of physiological importance viz. pyrazoline [8],
pyridines [9], pyrimidine [10] and isooxazoline [11].
The presence of enone functionality in chalcone moiety
confers biological activity [12-13]. The importance of
pyridines and fused pyridine as calcium antagonists
[14] and hypertensives [15] are well known. Also the
interest in the synthesis of condensed pyrazoles has
recently revived [16-18] because of their wide variety
of biological and pharmacological properties [19-20].
Therefore in view of our ongoing program towards
green synthesis [21], it was thought worthwhile to syn-
thesize 2-amino-3(ethylcarboxy)-4,6-disubstituted
pyridines 4a-f and pyrazolo[3,4-b]pyridines derivatives
6a-f under neat reaction condition.
Table 1
Comparison of Reaction Time and Yield for 4a-f and 6a-f
1
2
Compd.
No.
R
R
Reaction time (min's") / Yield (%)
Solid support*
MWI
Neat MWI
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
C H
4-MeO-C H
4-MeO-C H
2-Furyl
C H
8'50" / 84
7'40" / 88
9'20" / 82
7'20" / 81
7'10" / 86
7'30" / 80
6'50" / 81
7'10" / 83
7'00" / 82
7'20" / 84
6'30" / 80
6'40" / 86
3'50" / 92
2'40" / 94
3'40" / 91
2'50" / 93
3'20" / 89
3'00" / 95
3'50" / 93
4'00" / 91
4'20" / 92
3'40" / 96
4'40" / 93
4'50" / 96
6
5
6
5
5
C H
6
4
4
6
3,4-(CH ) C H
6
3 2
6
3
Methyl
3-Indolyl
4-Br-C H
6
4
4
Benzo[1,3] dioxol-3-yl
C H
4-Br-C H
6
C H
C H
6
6
5
6
5
5
4-MeO-C H
4MeO-C H
2-Furyl
3-Indolyl
6
4
3,4-(CH ) C H
6
4
3 2
6
3
Methyl
4-Br-C H
6
4
Benzo[1,3] dioxol-3-yl
4Br-C H
6 4
* From 4a-f – Support used is neutral alumina; From 6a-f – Support used is basic alumina.

1182
M. Kidwai, R. Thakur and S. Saxena
Vol. 42
reaction as checked by TLC, the reaction mixture was cooled and
the sticky product so obtained was titurated with chilled
methanol. The product 4a was separated, collected by filtration
and washed with cold ethanol and recrystalized from ethanol.
The reaction was also persued over neutral alumina in an alu-
mina bath [23] (solid support MWs) wherein the product was
obtained on elution with ethanol. This compound 4a had m.p. –
The synthesis of 2-amino-3(ethylcarboxy)-4,6-disubsti-
tuted pyridine 4a-f was carried out by subjecting the reac-
tants chalcone 1, ethylcyanoacetate 2 and ammonium
acetate 3 adsorbed over neutral alumina [22a] to MWI for
about 8-10 minutes (Table 1). This solid supported synthe-
sis is further modified to a relatively clean, efficient and
economical procedure by utilizing the neat reaction tech-
nique in which 1, 2 and 3 were condensed in the absence of
support and solvent. To our surprise, excellent yield of
products were obtained within just a few minutes (Table 1)
of MWI. Further, the use of heterocyclic chalcones led to
the synthesis of new pyridine derivatives.
-1
1
144-145 °C. IR (KBr) in cm , 1656 (C≡N), 3445 (N-H); H
NMR (DMSO-d ): δ 1.12 (t, 3H, CH ), 4.01 (brs, 2H, NH), 4.31
6
3
(q, 2H, OCH ), 7.21-7.98 (m, 11H, Ar-H).
2
+
Anal. Calcd. for C H N O (M : m/e 318): C, 75.45; H,
20 18
2 2
5.66; N, 8.79. Found: C, 75.38; H, 5.42; N, 8.72.
2-Amino-4(4-methoxyphenyl)-6-phenyl-3-(ethylcarboxy)pyri-
This technique was further extended for the synthesis of
4,6-disubstituted-1,2-dihydropyrazolo[3,4-b]pyridin-3-one
dine (4b).
-1
This compound has m.p. – 298-299 °C. IR (KBr) in cm ; 1650
(C=N), 3440 (N-H); H NMR (CDCl ): δ 1.08 (t, 3H, CH ), 3.73
(s, 3H, OCH ), 4.21 (q, 2H, OCH ), 4.95 (brs, 2H, NH), 6.83-
7.99 (m, 10H, Ar-H).
Anal. Calcd. for C H N O (M : m/e 348): C, 72.41; H,
5.74; N, 8.04. Found: C, 72.39; H, 5.79; N, 8.10.
1
6a-f. The reaction of 4a-f with NH OH.HCl 5, gave the
2
3
3
required product 6a-f in very good yield (Table 1) within 3-
5 min of MWI. Few drops of base i.e. pyrrolidine was used
to trap the HCl released by hydroxylamine hydrochloride.
For comparative study 6a-f was also synthesized from 4a-f
and 5 over basic alumina [22b] (Table 1).
3
2
+
21 20
2 3
2-Amino-4(4-methoxyphenyl)-6-(3,4-dimethylphenyl)-3(ethyl-
The structural assignment of 4a-f and 6a-f was based on
spectral and analytical data. The molecular formulae were
confirmed by elemental analysis and mass spectroscopy
carboxy)pyridine (4c).
-1
This compound has m.p. – 158-159 °C. IR (KBr) in cm ; 1660
1
(C=N), 3449 (N-H); H NMR (DMSO-d ): δ 1.02 (t, 3H, CH ),
6
3
+
(M /m/e). In conclusion, a novel environmentally benign
2.35 (s, 6H, 3,4-CH -Ar), 3.74 (s, 3H, OCH ), 4.20 (q, 2H,
3
3
OCH ), 4.98 (brs, 2H, NH), 6.82-7.68 (m, 8H, Ar-H).
methodology for the synthesis of pyridine and pyra-
zolo[3,4-b]pyridin-3-one has been developed, keeping
modernization and simplification of classical procedure,
avoiding volatile and toxic organic solvent. This neat reac-
tion under MWs not only gave excellent yield of products
with lesser reaction time but is also devoid of hazardous
solvents and reagents.
2
+
Anal. Calcd. for C H N O (M : m/e 376) C, 73.40; H,
23 24
2 3
6.38; N, 7.44. Found: C, 73.88; H, 6.29; N, 7.48.
2-Amino-4(2-furyl)-6-methyl-3(ethylcarboxy)pyridine (4d).
-1
This compound has m.p. – 192-193 °C. IR (KBr) in cm ; 1658
1
(C=N), 3440 (N-H); H NMR (CDCl + CD OD): δ 1.12 (t, 3H,
3
3
CH ), 3.10 (s, 3H, CH ), 4.12 (q, 2H, OCH ), 4.76 (brs, 2H, NH),
3
3
2
6.60 (s, 1H, Ar-H), 7.71 (d, 1H, furan C H), 6.31 (m, 2H, furan
5
C -C -H).
3
4
EXPERIMENTAL
+
Anal. Calcd. for C H N O (M : m/e 234): C, 63.41; H,
13 14
2 3
5.69; N, 11.38. Found: C, 63.36; H, 5.58; N, 11.30.
Melting points were determined on a Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were recorded on
a Perkin-Elmer FT IR-1710 spectrophotometer. H NMR were
2-Amino-4(3-indolyl)-6-(4-bromophenyl)3-(ethylcarboxy)pyri-
dine (4e).
1
-1
recorded on a Bruker Avance Spectrospin 300 (300 MHz) instru-
ment using TMS as an internal standard and CD OD/CDCl /
This compound has m.p. – 185-186 °C. IR (KBr) in cm ; 1662
1
(C=N), 3441 (N-H); H NMR (CDCl + CD OD): δ 1.23 (t, 3H,
CH ), 4.05 (q, 2H, OCH ), 4.25 (brs, 2H, N-H), 7.02-7.83 (m,
3
3
3
3
DMSO as a solvent. Elemental analysis was performed on a
Heraeus CHN Rapid Analyser. EI mass spectra were recorded on
a JEOL-JHS-DX 303 mass spectrometer. Microwave irradiation
was carried out in a Kenstar Microwave Oven, Model No. OM
9925E (2450 MHz, 800 W). The temperature of the reaction was
measured through an AZ, Mini Gun Type, Non-Contact IR
Thermometer, Model No. 8868. The purity of compounds was
verified on silica gel coated Al plates (Merck). The synthesis of
2-amino-4,6-diphenyl-3(ethylcarboxy)pyridine 4a is representa-
tive of general procedure employed for 4a-f.
3
2
9H, Ar-H), 10.1 (brs, 1H, N-H indole).
+
Anal. Calcd. for C H BrN O (M : m/e 435.9): C, 60.56; H,
22 18
3 2
4.12; N, 9.63. Found: C, 60.49; H, 4.23; N, 9.71.
2-Amino-4(benzo[1,3]dioxol-3-yl)-6-(4-bromophenyl)-3(ethyl-
carboxy)pyridine (4f).
-1
This compound has m.p. – 252-253°C. IR (KBr) in cm ; 1665
1
(C=N), 3450 (N-H); H NMR (DMSO-d ): δ 1.18 (t, 3H, CH ),
6
3
4.08 (q, 2H, OCH ), 4.35 (brs, 2H, N-H), 5.82 (s, 2H, CH -piper-
2
2
onal), 7.21-7.45 (m, 8H, Ar-H).
2-Amino-4,6-diphenyl-3(ethylcarboxy)pyridine (4a).
+
Anal. Calcd. for C H BrN O (M : m/e 440.9); C, 57.15; H,
21 17
2 4
Equimolar amount of benzalacetophenone (chalcone) 1 and
ethylcyanoacetate 2 (0.005 mole) were condensed with 0.40 mole
of ammonium acetate in a 250 ml Erlenmeyer flask. The reaction
mixture was irradiated for the specified time inside the
microwave oven (Table 1). Progress of reaction was monitored
through TLC at an interval of 30 seconds. On completion of
3.85; N, 6.35. Found: C, 57.12; H, 3.79; N, 6.40.
4,6-Diphenyl-1,2-dihydropyrazolo[3,4-b]pyridine-3-one (6a).
Equimolar amount of 4a (prepared above) and hydroxylamine
hydrochloride was mixed in 100 ml Erlenmeyer flask. To the
above reaction mixture few drops of pyrrolidine was added in

Sep-Oct 2005
A Facile Synthesis of Substituted Pyridines and Pyrazolo[3,4-b]pyridines
1183
order to remove the excess of HCl. The reaction mixture was
irradiated for 2-4 min inside the microwave oven. Progress of
reaction was monitored through TLC. On completion of reac-
tion, the flask was cooled the product was extracted from
methanol and recrystallized from methanol. The reaction was
also persued over basic alumina (solid support MW) in place of
pyrrolidine where product was obtained on elution with ethanol.
(brs, 1H, N-H), 5.82 (s, 2H, CH -piperonal), 7.21-7.45 (m, 8H,
2
Ar-H), 8.06 (d, 1H, N-H).
+
Anal. Calcd. for C H BrN O (M : m/e 409.9). C, 55.62; H,
19 12
3 3
2.92; N, 10.24. Found: C, 55.70; H, 2.98; N, 10.29.
Acknowledgement.
The authors M. Kidwai, R. Thakur and S. Saxena are thankful to
University Grants Commission, India for the financial assistance.
-1
This compound 6a had m.p. – 142-143 °C. IR (KBr) in cm ;
1
1631 (C=O), 3373 (NH); H NMR (CDCl ): δ 4.10 (brs, 1H, N-
3
H), 7.21-7.98 (m, 11H, Ar-H), 8.01 (d, 1H, N-H).
REFERENCES AND NOTES
+
Anal. Calcd. for C H N O (M : m/e 287): C, 75.26; H,
18 13
3 1
4.52; N, 14.63. Found: C, 75.22; H, 4.49; N, 14.58.
[1] F. Bigi, L. Chesini, R. Maggi and G. Sartori, J. Org. Chem.,
64, 1033 (1999).
[2] R. S. Varma, Green Chemistry, 1, 43045 (1999).
[3] P. Hermkens, H. Ottenheijm and D. Rees, Tetrahedron, 53,
5643 (1997).
4-(4-methoxyphenyl)-6-phenyl-1,2-dihydropyrazolo[3,4-b]pyri-
dine-3-one (6b).
This compound was prepared according the method described
above for compound 6a and has m.p. – 197-198 °C. IR (KBr) in
[4] J. Rebek, D. Brown and S.J. Zimmerman, J. Am. Chem. Soc.,
97, 454 (1995).
[5] M. Kidwai, R. Venkataramanan, R.G. Garg and K.R.
Bhushan, J. Chem. Research(S), 586 (2000).
[6] M. Kidwai, P. Sapra, K.R. Bhushan and P. Misra, Synthesis,
10, 1509 (2001).
[7] M. Kidwai, R. Venkataramanan and B. Dave, J. Heterocyclic.
Chem., 39, 1045 (2002).
[8] M. Ankhiwaler and M.V. Hathi, J. Indian Chem. Soc., 71, 587
(1994).
[9] A. M. Van Leusen and J.W. Terpstra, Tetrahedron Lett., 22,
5097 (1981).
[10] D. J. Brown, Comprehensive Heterocyclic Chemistry, Boulton
McKillop, 3, 150 (1984).
[11] S. A. Lang, Y. I. Lin, Comprehensive Heterocyclic Chemistry,
Boulton McKillop, 6, 27 (1984).
[12] R. Li, G. L. Kenyon, F. E. Cohen, X. Chen B. Gong, J. N.
Dominguez, E. Davidson, G. Miller, R. E. Miller, E. O. Nuzum, P. J.
Rosenthal and J. H. McKerrow, J. Med. Chem., 38, 5031 (1995).
[13] J. C. Onyilagha, B. Malhotra, M. Elder, J. Christopher and G.
H. N. Towers, J. Plant Pathol., 19, 133 (1997); Chem. Abstr., 127, 157896
(1997).
[14] G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D.
Dimarco, J. Gougoutas, A. Hedberg, M. Malley, J. P. McCarthy, R. Zhang
and S. Moreland, J. Med. Chem., 38, 119 (1995).
-1
1
cm ; 1634 (C=O), 3373 (N-H); H NMR (CDCl ): δ 3.73 (s, 3H,
3
OCH ), 4.02 (brs, 1H, N-H), 6.83-7.9 (m, 10H, Ar-H), 8.10 (d,
3
1H, N-H).
+
Anal. Calcd. for C H N O (M : m/e 317): C, 71.92; H,
19 15
3 2
4.73; N, 13.24. Found: C, 71.98; H, 4.79; N, 13.18.
4-(4-Methoxyphenyl)-6-(3,4-dimethylphenyl-1,2-dihydropyra-
zolo[3,4-b]pyridin-3-one (6c).
This compound was prepared according the method described
above for compound 6a and has m.p. – 207-208 °C. IR (KBr) in
-1
1
cm ; 1632 (C=O), 3375 (N-H); H NMR (CD OD + CDCl ): δ
3
3
2.35 (s, 6H, CH ), 3.74 (s, 3H, OCH ), 4.21 (brs, 1H, N-H), 6.82-
3
3
7.68 (m, 8H, Ar-H), 8.06 (d, 1H, N-H).
+
Anal. Calcd. for C H N O (M : m/e 345); C, 73.04; H,
21 19
3 2
5.50; N, 12.17. Found: C, 73.10; H, 5.55, N, 12.20.
4-(2-Furyl)-6-methyl-1,2-dihydropyrazolo[3,4-b]pyridin-3-one
(6d).
This compound was prepared according the method described
above for compound 6a and has m.p. – 210-211 °C. IR (KBr) in
-1
1
cm ; 1630 (C=O), 3370 (N-H), H NMR (CD OD + CDCl ): δ
3
3
3.10 (s, 3H, CH ), 4.10 (brs, 1H, N-H), 6.60 (s, 1H, Ar-H), 7.71
3
[15] J. L. Archibald, G. Bradley, A. Opaklo, T. J. Ward, J. C.
White, C. Ennis, N. B. Shapperson, J. Med. Chem., 33, 646 (1990).
[16] M. H. Elnagdi, M. R. H. El Moghayar and G. E. H. Elgemie,
Adv. Heterocyclic. Chem., 41, 319 (1987).
[17] M. H. Elnagoli, M. R. H. Elmoghayar and K. U. Sadek, Adv.
Heterocyclic. Chem., 48, 223 (1990).
(d, 1H, furan C -H), 6.31 (m, 2H, furan C -C -H), 8.05 (d, 1H,
5
3
4
N-H).
Anal. Calcd. for C H N O (M : m/e 215); C, 61.39; H, 41.8;
+
11
9 3 2
N, 19.53. Found: C, 61.30; H, 4.21; N, 19.49.
4-(3-Indolyl)-6-(4-bromophenyl)-1,2-dihydropyrazolo[3,4-
[18] M. N. Elnagdi, N. H. Taha, F. M. Abd El Ali, R. M. Abdel-
Motaleb and F. F. Mahmoud, Collect. Czech. Commun., 53, 1089 (1988).
[19] C. R. Hardy, Adv. Heterocyclic. Chem., 36, 343 (1984).
[20] R. E. Orth, J. Pharm. Sci., 57, 537 (1968) and references cited
therein.
b]pyridine-3-one (6e).
This compound was prepared according the method described
above for compound 6a and has m.p. – 182-183 °C. IR (KBr) in
-1
1
cm ; 1630 (C=O), 3372 (N-H); H NMR (CDCl + CD OD): δ
3
3
[21a] M. Kidwai, S. Saxena, R. Mohan and R. Venkataramanan, J.
Chem. Soc. Perkin Trans. 1, 16, 1845 (2002); [b] M. Kidwai, R. Mohan,
Canadian J. Chem., 82, 427 (2004); [c] M. Kidwai, Ruby, S. Rastogi,
Indian J. Chem., 43B, 423 (2004); [d] M. Kidwai, S. Rastogi, Ruby, S.
Saxena, Zeitschrift fur Naturforscung, 59B, 606 (2004).
[22a] Aluminium oxide neutral, Brockmann I (Adrich Chem. Co.,
4.03 (brs, 1H, N-H), 7.02-7.83 (m, 9H, Ar-H), 8.12 (d, 1H, N-H),
10.10 (brs, 1H, N-H indole).
+
Anal. Calcd. for C H BrN O (M : m/e 404.9); C, 59.27; H,
20 13
4
3.21; N, 13.83. Found: C, 59.30; H, 3.25; N, 13.90.
4-(Benzo[1,3]dioxol-3-yl)-6(4-bromophenyl)-1,2-dihydropyra-
zolo[3,4-b]pyridine-3-one (6f).
2
Cat No. 19, 997.4, ~ 150 mesh, 58 Å surface area 155 m /g) was used; [b]
Aluminium oxide basic, Brockmann I (Aldrich Chem. Cat. No. 19, 944-3,
This compound was prepared according the method described
2
~ 150 mesh, 58 Å, surface area 155 m /g) was used.
above for compound 6a and has m.p. – 126-127 °C. IR (KBr) in
[23] G. Bram, A. Loupy and M. Majdoub, Tetrahedron, 46, 5167
(1990).
-1
1
cm ; 1632 (C=O), 3374 (N-H); H NMR (DMSO-d ): δ 4.20
6