An efficient one pot three component synthesis of fused pyridines via electrochemical approach

Article abstract of DOI:10.1016/j.tetlet.2016.10.111

A convenient and economical method is developed for the synthesis of pyrido[2,3-d]pyrimidine derivatives by electrochemically induced condensation of various aromatic aldehydes, dimedone or malononitrile and 6-amino uracil. The reaction is carried out in

Full text of DOI:10.1016/j.tetlet.2016.10.111

Accepted Manuscript
An efficient one pot three component synthesis of fused pyridines via electro-
chemical approach
Abhishek Upadhyay, Laxmi Kant Sharma, Vinay K. Singh, Rana Krishna Pal
Singh
PII:
S0040-4039(16)31444-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.111
TETL 48281
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 September 2016
25 October 2016
28 October 2016
Please cite this article as: Upadhyay, A., Kant Sharma, L., Singh, V.K., Krishna Pal Singh, R., An efficient one pot
three component synthesis of fused pyridines via electrochemical approach, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.111
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Graphical Abstract
An efficient one pot three component
synthesis of fused pyridines via
electrochemical approach
Leave this area blank for abstract info.
Abhishek Upadhyay, L. K. Sharma, Vinay K. Singh, Rana Krishna Pal Singh*
O
O
O
CN
CN
H
H
O
R2
O
N
N
O
O
O
O
R2
O
CN
N
R2
O
N
R3
NH2
N
N
NH2
N
N
3
R3
R3
EtOH, NaBr
EtOH, NaBr

2
Tetrahedron Letters
journal homepage: www.els evier.com
An efficient one pot three component synthesis of fused pyridines via electrochemical
approach
Abhishek Upadhyay, Laxmi Kant Sharma, Vinay K. Singh, Rana Krishna Pal Singh*
Electrochemical laboratory of green synthesis, Department of Chemistry, University of Allahabad, Allahabad -211002, India
∗ Corresponding author. Tel.: +91 532 2465287; fax: +91 532 2460533; E-mail address: rkp.singh@rediffmail.com (R.K.P. Singh)
ARTICLE INFO
ABSTRACT
A convenient and economical method is developed for the synthesis of pyrido[2,3-d]pyrimidine
derivatives by electrochemically induced condensation of various aromatic aldehydes, dimedone
or malononitrile and 6-amino uracil. The reaction is carried out in an undivided cell, at a constant
current in the presence of NaBr as supporting electrolyte and ethanol as solvent.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction,
Electrosynthesis
Atom economy
6-amino uracil
Dimedone
Malononitrile
Multicomponent reactions have been recently recognized as a
powerful tool in synthetic organic chemistry. They allow one-pot
reaction in which three or more reactants are combined together
decreased energy requirements and reduced waste production,
and the ability to perform a wide range of precisely tuned
oxidation and reduction reaction. As a part of our ongoing efforts
towards synthesis of medicinally important compound,17 we
developed a convenient and environmentally friendly method for
multicomponent synthesis of pyrido[2,3-d]pyrimidine-6-
carbonitrile derivatives and 8,9-dihydro-1,3,8,8-tetramethyl 5-
phenylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,7H)-trione
derivatives by the electrochemical transformation using 6-
aminouracil, various aromatic aldehydes, malononitrile or
dimedone as starting material in an undivided cell at 40 oC under
a constant current density.
to form
a
new desired compound in sort duration.
Multicomponent reactions (MCRs) play an important role in
atom economy and green chemistry.1 These reactions
dramatically reduce the generation of chemical waste and the
cost. MCR strategies offer significant advantages over
conventional linear type synthesis.2 It provide powerful dais to
access diversity as well as complexity in few reaction steps. The
conventional multi-step synthesis of compounds involve
purification of compounds after each individual step,3 which
leads to two main disadvantages, synthetic inefficiency and the
production of large amount of waste.
The derivatives of 6-amino uracil have received considerable
attention over the last few years due to their vast range of
biological and pharmacological properties such as, antimicrobial,
Cl
O
O
NH2
N
N
H
N
NH2
NH2
4
antibacterial,5 antifungal,6 antiallergic,7 anti-inflammatory,8
N
O
N
N
10
analgesic,9 antihypertensive and antitumor.11 The synthesis of
N
N
pyrido[2,3-d]pyrimidine derivatives has been explored
extensively in recent years. Various methods such as using
microwave,12 magnesium oxide,13 diammonium hydrogen
phosphate (DAHP),14 bismuth(III)-nitrate pentahydrate15 and
palladium-catalyzed oxidative coupling16 have been reported.
However, conventional methods for the synthesis of these
products suffer from various drawbacks such as harsh reaction
conditions, prolonged reaction time, low yield, use of toxic
organic solvents, expensive reagents and catalysts. Therefore
simple, efficient and environmentally benign approaches for
synthesis of pyrido[2,3-d]pyrimidine are desirable.
eEF-2K inhibitors
(IC50 = 420 mM)
Anti tumor activity
IC50 = 3.74 µg/mL; MCF7
OH
O
O
NH
O
NH
OH
NH
N
CF3
N
H2N
N
N
N
O
N
N
H
NH2
Folic acid
PTP1B inhibitor
Figure 1. Several biologically active pyrido[2,3-d]pyrimidine
In electrochemistry electron serve as sole reagent hence there
is no need of acid, base or catalyst, electrogenerated base (EGB)
promote reactions in good yields. Electrosynthesis have many
advantages with atom economy, mild reaction conditions,
compounds.

During the course of reaction we screen several solvents and
found that ethanol solvent at current density of 10 mA/cm2 (I =
50 mA, electrode surface = 5 cm2) promote the reaction of
benzaldehyde, malononitrile or dimedone and 6-aminouracil to
pyrido[2,3-d]pyrimidine or pyrimido[4,5-b]quinoline efficiently at
40oC. We applied different amount of current for the same
reaction and found that at 10 mA/cm2 current densities (when
0.77 F/mol of electricity had been passed), the yield of reaction
O
O
O
H
H
O
CN
electrolysis
N
N
N
H
CN
CN
O
50 mA, ROH or MeCN,
NaBr
N
N
NH2
H3C
NH2
CH3
4
3
1
2
R = Et, Me, n-Pr
Scheme 1. Synthesis of 7-amino-1,2,3,4-tetrahydro-1methyl-2,4-
dioxo-5-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile.
was
excellent.
Combination
of
Acetonitrile
and
tetrabutylammonium perchlorate (Bu4NClO4) show maximum
yield. Acetonitrile is more expensive rather than ethanol and has
a modest toxicity in small doses. It can be metabolized to
produce hydrogen cyanide, which has toxic effects.20 In general
Bu4NClO4 is commonly used as PTC (phase transfer catalyst).
When we used Bu4NClO4 as an electrolyte, we found excellent
yield
O
O
O
H3C
O
O
electrolysis
N
N
O
H3C
O
N
H
50 mA, ROH or MeCN,
NaBr
N
N
H3C
NH2
O
CH3
8
6
7
9
R = Et, Me, n-Pr
Scheme 2. Synthesis of 8,9-dihydro-1,3,8,8-tetramethyl-5-
phenylpyrimido[4,5-b]quinoline-2,4,6-(1H, 3H, 7H)-trione.
2EtO
H2
2EtOH
2e
At cathode :
O
O
Three component compounds related to scheme 1 and 2
were prepared by several methods,19 which require large amounts
of oxidants. In situ purification produce large amounts of
undesired waste so developing greener and efficient procedure is
still an important need. Our investigation is based on the
electrochemically induced transformation of aryl aldehydes,
malononitrile or dimedone and 6-aminouracil into Pyrido[2,3-
d]pyrimidines under optimum reaction conditions (current
density 10 mA/cm2, 0.77 F/mol passed electricity, 40oC, EtOH)
by electrolysis in an undivided cell. The synthetic pathway is
shown in Scheme 1 and 2.
EtOH
CH
In solution
H
Ar
CH
Ar
OH
1
EtO
CH2
CH
Ar
-H2O
NC
NC
2
When
CH2
Ar
Ar
C
N
C
N
I
O
When
CH2
HN
3
O
N
CH3
NH2
O
O
O
Ar
C
N
CN
HN
C
N
Table 1a Optimization of reaction conditions for synthesis of
pyrido[2,3-d]pyrimidine 40oC.a
O
O
N
N
CH3
7
NH2
HN
O
4
O
N
NH2
Ar
CH3
Aromatization
I'
O
O
O
O
O
H
Ar
O
Ar
H
O
CN
N
O
O
N
electrolysis
N
N
H
CN
8
N
CN
H
HN
CN
CN
O
N
NH2
HN
O
C
50 mA, ROH or MeCN,
NaBr
N
N
NH2
O
N
NH2
N
H
NH
NH
Ar
O
O
H3C
NH2
CH3
CH3
CH3
Ar
II
4
O
3
1
2
R = Et, Me, n-Pr
O
O
N
Current
density
(mA/cm2)
Electricit Yieldb
Electro-
lyte
Solv-
I
Time
(min)
N
O
N
NH2
-y
(%)
ent
(mA)
O
N
N
H
O
O
Aromatization
Passed
(F/mol)
II'
H3C
O
N
O
N
CH3
N
O
Ar
O
N
O
N
Ar
O
Ar
O
H
H
N
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
KBr
EtOH
EtOH
EtOH
EtOH
MeOH
MeOH
5
1
210
150
80
25
25
25
25
25
25
25
25
25
0.65
1.39
1.24
0.77
1.16
0.77
0.77
0.52
0.77
0.77
0.77
0.52
60
65
70
90
70
80
75
92
40
42
90
92
9
N
O
NH
OH
O
N
NH
O
O
N
N
H
OH
15
25
50
75
50
3
Scheme 3. A plausible mechanism for the formation of pyrido[2,3-
d] pyrimidine 4 and pyrimido[4,5-b]quinoline 9 compounds.
The proposed mechanism is depicted in Scheme 3. Alcohol
deprotonation at the cathode leads to the formation of an alkoxide
anion. Subsequent reaction between the alkoxide anion and
malononitrile gives rise to a malononitrile anion. The aldehyde
reacts with malononitrile anion or with 5,5-dimethyl-1,3-
cyclohexanedione anion followed by elimination of water to
afford intermediate I or I’. The olefin intermediate undergoes
Michael addition with 6-amino-1-methyluracil followed by
intramolecular cyclization to give corresponding intermediate II
or II’. This intermediate undergoes oxidation to give final
product 4 or 9.
The electrolysis performed under the optimum conditions
(current density 10 mA/cm2, 0.77 F/mol electricity passed at
40oC, EtOH) for 30 min and results are summarized in Table 2. It
was observed that aromatic aldehydes having electron
withdrawing or donating groups reacts with malononitrile to
give product in excellent yield.
5
10
15
10
10
10
10
10
10
10
n-PrOH 50
MeCN
EtOH
EtOH
50
50
50
50
50
KI
Bu4NClO4 EtOH
Bu4NClO4 MeCN
aGeneral procedure: 6-amino uracil (2 mmol), benzaldehyde (2 mmol),
malononitrile (2.4 mmol), electrolyte (0.5 mmol), EtOH (30 mL), iron
cathode (5 cm2), graphite anode (5 cm2) .
bYield of isolated product.

4
Tetrahedron
In our studies we performed a three component reaction
Table 3 Electrochemical transformation of aromatic aldehyde,
dimedone and 6-amino-1,3-dimethyluracil into 8,9-dihydro-
using aromatic aldehyde (2 mmol), malononitrile or dimedone
(2.4 mmol) and 6-aminouracil (2 mmol), NaBr (0.5 M) in
ethanol (25mL). The electrolysis was carried out in an undivided
cell equipped with graphite rods (5 cm2) as anode and Fe (5 cm2)
as cathode at 40°C under constant current density 10 mA/cm2 (I
= 50 mA). The progress of the reaction was monitored by thin-
layer chromatography. After electrolysis (30 min), the mixture
was filtered and solvent was evaporated under vacuum. The
residue was purified by recrystallization from EtOH to furnish
the desired product. In this protocol we use graphite as anode and
iron as cathode. The reason being graphite is inexpensive, inert
having high sublimation temperature while iron electrode is low
cost, having high conductivity.
1,3,8,8-tetramethyl-5-phenylpyrimido[4,5-b]
2,4,6(1H, 3H, 7H)-trione derivatives.a b
quinoline
R1
O
O
O
H3C
O
electrolysis
N
N
O
H3C
O
N
O
H
R1
50 mA, EtOH, NaBr
N
N
H3C
NH2
O
CH3
6a-6e
9a-9e
7
8
Entry
1
Aryl
Product
Time (min.) Yieldc mp (0C)
(%)
OH
CHO
25
30
25
25
30
88
92
92
93
90
298-300
299-301
220-222
287-289
281-283
Table 2 Electrochemical transformation of aromatic aldehyde,
malononitrile and 6-amino uracil into pyrido[2,3-d]pyrimidine
derivatives.a b
O
O
H3
H3
H3
H3
H3
C
O
N
N
N
N
N
OH
N
N
6a
CH3
9a
OCH3
CHO
2
3
4
5
O
O
O
R2
O
O
electrolysis
N
N
R2
O
CN
C
O
OCH3
N
H
CN
CN
O
R1
6b
N
N
50 mA, EtOH, NaBr
CH3
N
N
NH2
R3
NH2
9b
NO2
R3
CHO
1a - 1h
3
2
4a - 4h
R3 = CH3 , R2 = H
R3 = R2 = CH3
O
O
O
O
C
O
Time (min.) Yieldc mp (0C)
(%)
NO2
Entry
1
Aryl
Product
N
N
6c
CH3
9c
Cl
CHO
CHO
25
90
299-301
O
H
N
CN
O
1a
C
O
O
N
N
NH2
Cl
N
N
CH3
6d
CH3
4a
9d
Br
OCH3
CHO
2
3
4
5
6
30
30
30
25
20
92
93
93
92
90
300-303
300-302
298-300
298-300
296-298
CHO
O
N
H
O
CN
O
OCH3
N
C
O
1b
N
NH2
Br
CH3
N
N
6e
4b
NO2
CH3
CHO
9e
a For the experimental procedure, see supporting information..
O
bAll compounds are known and were characterized by comparison of their
spectral data with those reported in the literature.22, 23
cYields of isolated pure compounds 9a – 9e.
H
O
CN
NO2
N
1c
N
N
NH2
CH3
4c
CHO
NO2
O
NO2
In conclusion, we have developed an efficient, fast and simple
method for the one-pot synthesis of pyrido[2,3-d]pyrimidine-6-
carbonitrile derivatives and 8,9-dihydro-1,3,8,8-tetramethyl5-
phenylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,7H)-trione
H
O
CN
N
1d
N
N
NH2
CH3
4d
Cl
CHO
C
l
derivatives. The use of inexpensive starting materials, non-
hazardous reaction conditions, high yields and separation of
products through simple filtration avoiding column
chromatography are some significant features of present strategy
which make this an attractive protocol for synthesis of fused
O
Cl
H
O
CN
N
Cl
1e
N
N
NH2
OH
CH3
4e
CHO
O
OH
H
O
CN
N
pyridines.
1f
N
N
NH2
CH3
4f
Cl
Acknowledgments
CHO
7
8
20
25
90
92
300-302
301-303
O
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. A. Upadhyay is grateful to
H3
C
CN
N
Cl
O
N
N
NH2
1g
CH3
the UGC, for financial support. V.K.S. is also grateful to the
UGC, New Delhi, for the award of a DS Kothari postdoctoral
fellowship.
4g
CHO
NO2
O
NO2
H3
C
CN
N
1h
O
N
N
NH2
CH3
4h
a For the experimental procedure, see supporting information..
bAll compounds are known and were characterized by comparison of their
20, 21
spectral data with those reported in the literature.12,
cYields of isolated pure compounds 4a – 4h.

References
1. (a) Zhou, Y. J.; Chen, D. S.; Li, Y. L.; Liu, Y.; Wang, X. S.
ACS Comb. Sci. 2013, 15, 498; (b) Azizi, N.; Aryanasab, F.;
Saidi, M. R. Org. Lett. 2006, 23, 5275.
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Clark, A. M. J. Pharm. Sci. 1995, 84,661.
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Nogueras, M.; de la Torre, J. M.; Sortino, M.; Zacchino, S.
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Rodriguez, L.; J. Med. Chem. 1984, 27, 1253.
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Barocelli, E. Eur. J. Med. Chem. 2005, 40, 155.
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Syropyatov, B. Y.; Kolla, V. E. and Konshin, M. E. Pharm.
Chem. J. 1991, 25, 248.
11. (a) Insuasty, B.; Becerra, D.; Quiroga, J.; Abonia, R.;
Nogueras, M. and Cobo, J. Eur. J. Med. Chem. 2013, 60, 1;
(b) Ellingboe, J. W.; Princeton, N. J.; Chem. Abstr. 1996, 124,
176.
12. Abdolmohammadi S.; Balalaie, S. Int. J. Org. Chem. 2012, 2,
7.
13. (a) Seifi, M.; Sheibani, H. Catal. Lett. 2008, 126, 275; (b)
Sheibani, H.; Seif, M.; Bazigar, A. Synth. Commun. 2009, 39,
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14. Abdolmohammadi, S. and Balalaie, S. Int. J. Org. Chem.
2012, 2, 7.
15. Naik, R. R. T.; Naik, B. S. H. Mol. Diversity, 2008, 12, 139.
16. Hirota, K.; Kuki, H. and Maki, Y. Heterocycles, 1994, 37,
563.
17. (a) Singh, S.; Sharma, L. K.; Saraswat, A.; Siddiqui, I. R.;
Kehri, H. K.; Singh, R. K. P. RSC Adv. 2013, 3, 4237; (b)
Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.;
Shireen; Waseem, M. A.; Singh, R. K. P. Synlett 2013, 2586;
(c) Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.;
Shireen; Waseem, M. A.; Abumhdi, A. A. H.; Srivastava, A.;
Pragati, Rai; Singh, R. K. P. Asian J. Org. Chem. 2013, 2,
519. (d) Singh, V. K.; Sharma, L. K.; Singh, R. K. P.
Tetrahedron Lett. 2016, 57, 407. (e) Sharma, L. K.; Singh, S.;
Singh V. K.; Singh, R. K. P. J. Indian Chem. Soc. 2016, 93,
827. (f) Sharma, L. K.; Saraswat, A.; Singh, S.; Singh, R. K.
P. Proceedings of NASI, 2015, 85, 29.
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6
Tetrahedron
Graphical Abstract
Leave this area blank for abstract info.
An efficient one pot three component
synthesis of fused pyridines via
electrochemical approach
Abhishek Upadhyay, L. K. Sharma, Vinay K. Singh, Rana Krishna Pal Singh*
O
O
O
CN
CN
H
H
O
R2
O
N
N
O
O
O
O
R2
O
CN
N
R2
O
N
R3
NH2
N
N
NH2
3
N
N
R3
R3
EtOH, NaBr
EtOH, NaBr

Highlights
• Electro-induced condensation of aldehydes,
dimedone or malononitrile and 6-amino
uracil.
•
EGB promots reaction in presence of NaBr
as supporting electrolyte and ethanol as
solvent.
•
Small amount of current was used as energy
source in the place of conventional heating.