Metal and Solvent-Free Synthesis of 2H-Pyrido[1,2-a]pyrimidin-2-ones Catalyzed by Elemental Sulfur

Article abstract of DOI:10.1002/ejoc.201901356

The efficiency of elemental sulfur for the synthesis of 2H-pyrido[1,2-a]pyrimidin-2-ones has been demonstrated. This strategy involves coupling of 2-aminopyridines and β-oxo esters under neat condition in the absence of external oxidant. The reaction does not require pre-functionalization of the substrates, thus making it an alternate approach for the synthesis of 2H-pyrido[1,2-a]pyrimidin-2-ones. The reaction was tolerant to several substituted 2-aminopyridines and β-oxo esters.

Full text of DOI:10.1002/ejoc.201901356

DOI: 10.1002/ejoc.201901356
Communication
Metal-Free Cyclization
Metal and Solvent-Free Synthesis of 2H-Pyrido[1,2-a]pyrimidin-
2-ones Catalyzed by Elemental Sulfur
Thangavel Pavithra,[a] E. Sankari Devi,[a] Subbiah Nagarajan,[b] Vellaisamy Sridharan,[c] and
C. Uma Maheswari*[a]
Abstract: The efficiency of elemental sulfur for the synthesis of reaction does not require pre-functionalization of the sub-
2H-pyrido[1,2-a]pyrimidin-2-ones has been demonstrated. This strates, thus making it an alternate approach for the synthesis
strategy involves coupling of 2-aminopyridines and ꢀ-oxo esters of 2H-pyrido[1,2-a]pyrimidin-2-ones. The reaction was tolerant
under neat condition in the absence of external oxidant. The to several substituted 2-aminopyridines and ꢀ-oxo esters.
Introduction
Fused N-heterocycles are among the most widely studied het-
erocycles owing to their applications in pharmaceutical,[1] agro-
chemical,[2] and materials industries.[3] Among these N-hetero-
cycles, 2H-pyridopyrimidinone scaffold is more privileged due
to their remarkable biological properties such as antidepress-
ant, antiallergic, antipsychotic, antiulcerative, and antihyperten-
sive activities,[4] and are found in several marketed drugs.[5]
They have been reported as anticancer agents,[6] estrogen-
related receptors (ERR) agonists,[7] G protein signaling (RGS)
protein regulators,[8] HIV integrase inhibitors,[9] efflux pump in-
hibitors,[10] anticoccidial agents,[11] and antimalarial agents.[12]
Figure 1 depicts structure of few biologically active fused pyr-
idopyrimidinones.
Figure 1. Biologically active fused pyridopyrimidinones.
Several methods have been reported in the literature for the
synthesis of 4H-pyrido[1,2-a]pyrimidin-4-one scaffold due to
their vast applications, but development of synthetic proce-
of this scaffold can be ascribed to the relative lack of synthetic
flexibility for their construction. Jaenicke et al.[17] carried out
the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones from readily
dures for the construction of its regioisomer, 2H-pyrido[1,2-a]-
available 2-aminopyridine and ꢀ-oxo esters, but there were no
pyrimidin-2-one is rather limited. A well-known procedure for
reports on the synthesis of its regioisomer employing the same
the synthesis of this class of compounds remain the coupling
starting materials. Consequently, we envisioned to utilize mild,
of Baylis–Hillman adduct or its derivatives with 2-aminopyrid-
environmentally benign, non-hygroscopic elemental sulfur as
catalyst for the construction of 2H-pyrido[1,2-a]pyrimidin-2-
ones from 2-aminopyridines and ꢀ-oxo esters by replacing the
existing strategies which employs activated Baylis–Hillman ad-
ines.[13] Other methods to construct this skeleton involves treat-
ment of 2-aminopyridines with alkynoate esters[14] or aryl
malonates,[15] or by cyclization of N-(1,3-dioxobutyl)-2-amino-
pyridines (Scheme 1).[16] The major limitation for the synthesis
ducts, microwave assistance, and added reagents.
Elemental sulfur has myriad properties and are often em-
ployed as catalyst to carry out numerous redox transforma-
[a] Department of Chemistry, School of Chemical and Biotechnology,
SASTRA Deemed University,
tions.[18] A number of transition metal free catalysis for the syn-
thesis of heterocycles can be achieved by employing sulfur as
the catalyst.[19–21] When equivalent amount of elemental sulfur
was used for transformations, it acts as a building block result-
ing in the formation of S-heterocycles or incorporation of sulfur
in the final product.[22] Moreover, it can act as oxidant similar
to oxygen and it is non-volatile, non-hygroscopic and amor-
phous solid, thus easy to handle.[23] Another important facet of
elemental sulfur is that it can act as both oxidant and reductant
and can exist in variable oxidation states.
Thanjavur, 613401, India
E-mail: umamaheswaric@scbt.sastra.edu
uma.cchem@gmail.com
[b] Department of Chemistry, National Institute of Technology-Warangal,
Warangal, 506004, India
[c] Department of Chemistry and Chemical Sciences, Central University of
Jammu,
Rahya-Suchani (Bagla), District-Samba, Jammu-181143, J&K, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901356.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
Temp
[°C]
Yield [%][b]
3a
3a′
1
2
3
4
5
6
7
8
I2
S
S
S
S
S
S
S
MeOH
MeOH
DMF
DMSO
Toluene
DCB
DCE
–
–
–
–
–
–
–
–
–
65
65
37
63
NR
NR
NR
NR
43
96
41
85
92
72
90
67
46
NR
–
–
–
16
91
36
–
–
–
120
120
120
120
120
120
120
120
120
120
120
100
80
9
InCl3
Yb(OTf)3
FeCl3
AlCl3
CAN
S
10
11
12
13
14
15
16
–
–
–
trace
trace
–
S
–
120
[a] Reaction conditions: Ethyl acetoacetate (1.0 mmol), 2-aminopyridine
(1.0 mmol), catalyst (5 mol-%), solvent (1 mL), 2 h. [b] Isolated yield.
Scheme 1. Strategies for the construction of 2h-pyrido[1,2-a]pyrimidin-2-
ones.
temperature is lowered, the product yield decreases considera-
bly along with trace amount of 3a′ (entries 14 and 15). In the
absence of catalyst and solvent, the reaction failed to deliver
the product completely (entry 16).
Results and Discussion
In order to arrive at suitable reaction conditions, initial optimi-
zation studies were carried out employing ethyl acetoacetate
(1a) and 2-aminopyridine (2a) as model substrates (Table 1).
Instead of BiCl3 as catalyst for the synthesis of 4H-pyrido-
[1,2-a]pyrimidin-4-ones as reported by Jaenicke,[17] we envis-
aged that I2 can act as mild Lewis acid and can be employed
for the coupling of 1a and 2a. When the reaction was per-
formed with I2 in methanol under reflux, we observed the for-
mation of 2H-pyrido[1,2-a]pyrimidin-2-one instead of its regio-
isomer (entry 1).
To explore the scope of this reaction, differently substituted
2-aminopyridine were treated with various ꢀ-oxo esters under
the optimized reaction condition (Table 2). When 2-aminopyr-
idine was treated with ethyl acetoacetate or methyl acetoacet-
ate, the desired product 3a was obtained in excellent yield of
96 %. Next, 2-aminopyridine variations were varied with ethyl
acetoacetate, and when an electron releasing methyl group is
present in 3rd, 4th and 5th position of 2-aminopyridine, the cor-
responding products were obtained in excellent yields (3b–3d).
With slightly electron withdrawing halogens (F, Cl, Br or I)
Elemental sulfur in similar lines, was used for several oxid- present in the 5th position of 2-aminopyridine, the yield of the
ative transformations and we predicted the use of sulfur for the desired products decreased slightly (3e–3h). Similar trend was
synthesis of this scaffold, and when the reaction was performed observed with 3-hydroxy-2-aminopyridine (3i). When the reac-
using sulfur as catalyst in methanol as solvent, 63 % of 2H-pyr- tion was performed with other heterocyclic amines like 2-
ido[1,2-a]pyrimidin-2-one was observed within 2 h (entry 2). In aminothiazole, the reaction was marginally sluggish and the
order to increase the reaction temperature, thereby yield of the product was obtained in moderate yield (3j). Instead of ethyl
desired product, variation of solvents was performed. The reac- acetoacetate, when ethyl 3-oxo-3-phenylpropanoate was used
tion doesn't proceed with polar solvents like DMF or DMSO at as the substrate along with 2-aminothiazole the yield of the
120 °C (entries 3 and 4). When the reaction was performed with desired product decreased substantially to 10 % after 5 h (3k).
non-polar solvents like toluene and dichlorobenzene, the amide Variations of ꢀ-oxo esters were then performed with 2-amino-
(3a′) was observed as the major product (entries 5 and 6). When pyridine and the product yield was good to excellent with tri-
DCE was used as solvent for the reaction, almost equal amounts fluoromethyl and n-propyl ꢀ-oxo esters (3l and 3m) and moder-
of 3a and 3a′ were formed (entry 7). Under neat conditions, in ate with ethyl 3-oxo-3-phenylpropanoate after prolonging for
the presence of sulfur (5 mol-%) as catalyst, the desired product 5 h (3n). Then substituents at both 2-aminopyridines and ꢀ-oxo
was observed in almost quantitative yield (entry 8). Then, sev- esters were varied simultaneously. When 2-amino 3-hydroxyl-
eral Lewis acids were varied and the reaction gave moderate to pyridine was coupled with n-propyl and trifluoromethyl-substi-
good yields with almost all catalysts (entries 9–13). But elemen- tuted ꢀ-oxo esters, the expected products were obtained in
tal sulfur is chosen because of its environmentally benign na- good and moderate yields respectively (3o and 3p). Finally,
ture as compared to other metal catalysts. When the reaction when ethyl 3-oxohexanoate was treated with different methyl-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
substituted 2-aminopyridines, the corresponding products were philicity of carbonyl carbon of the ester, facilitating the nucleo-
attained in excellent yield (3q–3s).
philic attack of the amino group of 2 resulting in the formation
of intermediate I. Subsequent removal of ethanol from I yields
the intermediate amide 3a′ which was observed during the
course of the reaction. Oxidative cyclization of intermediate
3a′ gave intermediate II, followed by dehydration to give inter-
mediate III. Oxidation of the intermediate III results in the for-
mation of the desired product 3a.
Table 2. Substrate scope.[a]
Conclusions
In conclusion, we have demonstrated the efficiency of elemen-
tal sulfur as catalyst for the construction of 2H-pyrido[1,2-a]pyr-
imidin-2-ones from readily available starting materials, 2-amino-
pyridines and ꢀ-oxo esters. This reaction efficiently replaces ex-
isting strategies and does not employ pre-functionalization of
the substrates, microwave assistance or added reagents or sol-
vents, thus making it an alternate approach for the synthesis of
2H-pyrido[1,2-a]pyrimidin-2-ones. The reaction scope includes
various substituted ꢀ-oxo esters, 2-aminopyridines, and 2-
aminothiazoles (Scheme 3).
Scheme 3. Plausible mechanism.
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), sulfur (5 mol-%), 120 °C,
2 h. Isolated yields are reported.
Experimental Section
Since the 2H-pyrido[1,2-a]pyrimidin-2-one are very useful
and shows remarkable bio-activity, the feasibility of the present
catalytic system on gram scale was examined for the synthesis
of 7-bromo-4-methyl-2H-pyrido[1,2-a]pyrimidine-2-one (3g).
Reaction of ethyl acetoacetate and 2-amino-5-bromopyridine
under optimized reaction condition was performed in gram-
scale to give the desired product in 79 % yield (Scheme 2).
A mixture of ꢀ-oxo esters 1 (1.0 mmol), 2-aminopyridines 2
(1.0 mmol), and elemental sulfur (0.05 mmol) was taken in a reac-
tion vial and stirred at 120 °C. Progress of the reaction was moni-
tored by TLC. After the completion of the reaction, water was added
to the mixture and extracted with DCM. The extract was washed
with brine solution and dried with anhydrous Na2SO4. Removal of
the solvent under vacuum afforded the crude product, which was
purified by column chromatography using hexane/ethyl acetate
mixture (90:10).
Acknowledgments
Financial support from the Department of Science and Technol-
ogy, DST, New Delhi for the award of a research grant EMR/
2016/002485/OC and the Council of Scientific and Inductrial Re-
search, CSIR [No. 09/1095(0032)/18-EMR-I] is gratefully acknowl-
Scheme 2. Gram scale synthesis of 3g.
Based on the previous literature reports,[16] we propose a edged.
plausible mechanism. It is well known that depending upon the
reaction condition, sulfur can act as Lewis acid or base and in
the presence of oxygen it can act as Lewis acid. Initially, sulfur
can coordinate with ꢀ-oxo esters 1, which increases the electro-
Keywords: Sulfur · 2H-pyrido[1,2-a]pyrimidin-2-one · 2-
Amino pyridines · ꢀ-Oxo esters · Solvent-free condition
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[1] J. J. Li, in Heterocyclic chemistry in drug discovery, ed., (John Wiley &.
Sons, Hoboken, N. J. 2013, pp. 720).
[2] S. Jeanmart, A. J. Edmunds, C. Lamberth, M. Pouliot, Bioorg. Med. Chem.
[12] a) U. R. Mane, D. Mohanakrishnan, D. Sahal, P. R. Murumkar, R. Giridhar,
M. R. Yadav, Eur. J. Med. Chem. 2014, 79, 422–435; b) U. R. Mane, H. Li, J.
Huang, R. C. Gupta, S. S. Nadkarni, R. Giridhar, P. P. Naik, M. R. Yadav,
Bioorg. Med. Chem. 2012, 20, 6296–6304.
2016, 24, 317–341.
[3] a) D. Chen, S.-J. Su, Y. Cao, J. Mater. Chem. C 2014, 2, 9565–9578; b) M.
Liu, S.-J. Su, M.-C. Jung, Y. Qi, W.-M. Zhao, J. Kido, Chem. Mater. 2012, 24,
3817–3827.
[4] a) C. L. Motta, S. Sartini, L. Mugnaini, F. Simorini, S. Taliani, S. Salerno,
A. M. Marini, F. D. Settimo, A. Lavecchia, E. Novellino, M. Cantore, P. Failli,
M. Ciuffi, J. Med. Chem. 2007, 50, 4917–4927; b) A. R. Katritzky, J. W.
Rogers, R. M. Witek, S. K. Nair, ARKIVOC 2004, 8, 52–60; c) G. C. B. Harri-
man, S. Chi, M. Zhang, A. Crowe, R. A. Bennett, I. Parsons, Tetrahedron
Lett. 2003, 44, 3659–3662.
[13] a) D. Basavaiah, T. Satyanarayana, Tetrahedron Lett. 2002, 43, 4301–4303;
b) S. Satyanarayana, K. P. Kumar, P. L. Reddy, R. Narender, G. Narasimhulu,
B. V. S. Reddy, Tetrahedron Lett. 2013, 54, 4892–4895; c) Z. Alsharif, M. A.
Ali, H. Alkhattabi, D. Jones, E. Delancey, P. C. Ravikumar, M. A. Alam, New
J. Chem. 2017, 41, 14862–14870.
[14] T. A. Alanine, W. R. J. D. Galloway, S. Bartlett, J. J. Ciardiello, T. M. McGuire,
D. R. Spring, Org. Biomol. Chem. 2016, 14, 1031–1038.
[15] S. M. Chichetti, S. P. Ahearn, B. Adams, A. Rivkin, Tetrahedron Lett. 2007,
48, 8250–8252.
[5] a) M. Corena-McLeod, Drugs R&D 2015, 15, 163–174; b) T. Gohda, C. Ra,
C. Hamada, T. Tsuge, H. Kawachi, Y. Tomino, Arzneim.-Forsch. 2008, 58,
18–23.
[6] J. Ni, Q. Liu, S. Xie, C. Carlson, T. Von, K. Vogel, S. Riddle, C. Benes, M. Eck,
T. Roberts, N. Gray, J. Zhao, Cancer Discovery 2012, 2, 425–433.
[7] L. Peng, X. Gao, L. Duan, X. Ren, D. Wu, K. Ding, J. Med. Chem. 2011, 54,
7729–7733.
[8] L. L. Blazer, D. L. Roman, A. Chung, M. J. Larsen, B. M. Greedy, S. M.
Husbands, R. R. Neubig, Mol. Pharmacol. 2010, 78, 524–533.
[9] G. Le, N. Vandegraaff, D. I. Rhodes, E. D. Jones, J. A. V. Coates, L. Lu, X. Li,
C. Yu, X. Feng, J. J. Deadman, Bioorg. Med. Chem. Lett. 2010, 20, 5013–
5018.
[10] M. Askoura, W. Mottawea, T. Abujamel, I. Taher, Libyan J. Med. 2011, 6,
5870–5877.
[11] L. Silpa, A. Niepceron, F. Laurent, F. Brossier, M. Pénichon, C. Enguehard-
Gueiffier, M. Abarbri, A. Silvestre, J. Petrignet, Bioorg. Med. Chem. Lett.
2016, 26, 114–120.
[16] O. P. Suri, K. A. Suri, B. D. Gupta, N. K. Satti, Synth. Commun. 2002, 32,
741–746.
[17] I. I. Roslan, Q.-X. Lim, A. Han, G.-K. Chuah, S. Jaenicke, Eur. J. Org. Chem.
2015, 2015, 2351–2355.
[18] For recent reviews, see: a) T. B. Nguyen, Adv. Synth. Catal. 2017, 359,
1066–1130; b) T. B. Nguyen, Asian J. Org. Chem. 2017, 6, 477–491.
[19] T. B. Nguyen, P. Retailleau, J. Org. Chem. 2019, 84, 5907–5912.
[20] F. Shibahara, R. Sugiura, E. Yamaguchi, A. Kitagawa, T. Murai, J. Org. Chem.
2009, 74, 3566–3568.
[21] Z. Wang, X. Chen, H. Xie, D. Wang, H. Huang, G.-J. Deng, Org. Lett. 2018,
20, 5470–5473.
[22] K. Wang, M. Groom, R. Sheridan, S. Zhang, E. Block, J. Sulfur Chem. 2013,
34, 55–66.
[23] R. Steudel, Top. Curr. Chem. 2003, 230, 81–116.
Received: September 13, 2019
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Metal-Free Cyclization
A simple and efficient method for the
synthesis of 4-methyl-2H-pyrido[1,2-a]-
pyrimidin-2-one from ꢀ-oxo esters and
2-aminopyridine in the presence of
sulfur was demonstrated. In this reac-
tion, inexpensive and readily available
starting materials and catalysts were
employed. The advantages of this
strategy are: (i) A neat, oxidant and
metal free reaction. (ii) The reaction
was tolerant to different ꢀ-oxo esters
and 2-aminopyridines.
T. Pavithra, E. S. Devi, S. Nagarajan,
V. Sridharan, C. U. Maheswari* ...... 1–5
Metal and Solvent-Free Synthesis of
2H-Pyrido[1,2-a]pyrimidin-2-ones
Catalyzed by Elemental Sulfur
DOI: 10.1002/ejoc.201901356
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim