Full text of DOI:10.1080/00397911.2018.1479761

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Highly efficient one-pot synthesis of fused
pyrimidones from 2-heteroaryl amines
and Morita–Baylis–Hillman carbonates via
intermolecular cyclocondensation
Surendra Babu Inturi, Biswajit Kalita & A. Jafar Ahamed
To cite this article: Surendra Babu Inturi, Biswajit Kalita & A. Jafar Ahamed (2018): Highly efficient
one-pot synthesis of fused pyrimidones from 2-heteroaryl amines and Morita–Baylis–Hillman
carbonates via intermolecular cyclocondensation, Synthetic Communications
To link to this article: https://doi.org/10.1080/00397911.2018.1479761
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https://doi.org/10.1080/00397911.2018.1479761
Highly efficient one-pot synthesis of fused pyrimidones
from 2-heteroaryl amines and Morita–Baylis–Hillman
carbonates via intermolecular cyclocondensation
Surendra Babu Inturia,b, Biswajit Kalitaa and A. Jafar Ahamedb
b
aMedicinal Chemistry Division, Jubilant Biosys Ltd., Bangalore, India; Post Graduate and Research
Department of Chemistry, Jamal Mohamed College (Autonomous) affiliated to Bharathidasan University,
Tiruchirappalli, India
ABSTRACT
ARTICLE HISTORY
Received 11 April 2018
A highly selective and efficient cyclocondensation reaction for con-
struction of various 3-substituted-2H-pyrido[1,2-a]pyrimidin-2-ones
and related fused pyrimidones from allylic carbonates and 2-hetero-
aryl amines has been developed. The transformation involves one-pot
sequential aza-Michael addition, intramolecular acyl substitution, and
[1,3]-H shift. The method is catalyst free, eco-friendly, scalable, and
completes within a short reaction time, with no work-up, no column
purification, and demonstrate a broad functional group tolerance.
KEYWORDS
Cyclocondensation; fused
pyrimidones; green
chemistry; 2-heteroaryl
amines; MBH carbonates
GRAPHICAL ABSTRACT
Introduction
Pyrimidine is an important structural motif and has appeared as one of the key
pharmacophores in many bioactive molecules including DNA and RNA.[1–2] The fused
pyrimidone derivatives are one of the most promising and widely used heteroaromatic
compounds across multiple therapeutic areas and target classes[3] due to their unprece-
dented biological importance and have shown a wide range of biological activities that
have led to the development of many marketed drugs.[4] These derivatives, in particular,
have been reported as G protein signaling (RGS) protein regulators,[5] anticancer
CONTACT Biswajit Kalita
Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560022, Karnataka, India; A. Jafar Ahamed
yahoo.co.in Post Graduate and Research Department of Chemistry, Jamal Mohamed College (Autonomous), affiliated
Biswajit.kalita@jubilantbiosys.com
Medicinal Chemistry Division, Jubilant Biosys Ltd, #96,
agjafar@
to Bharathidasan University, Tiruchirappalli 620020, Tamil Nadu, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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S. B. INTURI ET AL.
Figure 1. Selected biologically active compounds.
agents,[6] HIV integrase inhibitors,[7] estrogen-related receptors (ERR) agonists,[8] anti-
coccidial agents,[9] aldose reductase inhibitors,[10] and antimalarial agents.[11] A few of
the biologically active fused pyrimidones were exemplified in Figure 1.[3e,9] Because of
their usefulness and importance, synthesis of this class of fused pyrimidones is one of
the most attractive areas in organic and medicinal chemistry for several years.
The Morita–Baylis–Hillman (MBH) adducts are synthetically important synthons
for constructing a wide range of densely functionalized cyclic and heterocyclic skele-
tons.[12] Consequently, several methods were known to synthesize fused pyrimidones
over the years.[13] Notably, Basavaiah et al. and the other leading groups have
reported the synthesis of 3-substituted-2H-pyrido[1,2-a]pyrimidin-2-ones and related
fused pyrimidones in a one-pot protocol from 2-aminopyridine and MBH derived
acetates at room temperature under solvent and solvent-free conditions.[14]
Satyanarayana et al. have reported the solvent-free microwave assisted reaction to
synthesize this class of fused pyrimidones using the same starting materials.[15]
Recently, Alsharif et al. reported hexafluoroisopropanol (HFIP) mediated synthesis of
3-substituted-2H-pyrido[1,2-a]pyrimidin-2-ones from MBH alcohols and 2-aminopyri-
dines under thermal condition.[16]
Although these methods are efficient to form 3-substituted-2H-pyrido[1,2-a]pyrimi-
din-2-ones and related fused pyrimidones, however, these reactions involve in long reac-
tion time and the use of microwaves irradiations that impose a limitation on scalability.
HFIP is a corrosive and hazardous liquid. Guided by the reactivity of the MBH carbo-
nates and its affinity for cyclocondensation, we sought to develop a one-pot reaction
strategy that would fulfill the large scope of this class of compound synthesis with a
broad substrate variety.
In this study, we report a novel methodology that employs a variety of allylic carbo-
nates in a one-pot reaction system to give a diverse range of 3-substituted-2H-pyr-
ido[1,2-a]pyrimidin-2-ones and related fused pyrimidones in good to excellent yields.
To the best of our knowledge, use of allylic carbonates in the synthesis of this class of
fused heterocycles has never been previously reported.
Results and discussion
We initially began our investigation reaction between pyridin-2-amine (1) and ethyl
2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl)acrylate (2a) in 1,4-dioxane at room tem-
perature (Table 1, entry 1). To our delight, the desired product 3a was obtained in 20%
yield over a period of 16 h along with 50% of ethyl 2-(phenyl(pyridin-2-ylamino)methyl)-
1
acrylate(4) (confirmed by H & 13C NMR, see supporting information), which is possible
via nucleophilic allylic amination of MBH carbonate 2a. Our study began by screening of
solvents such as ACN, THF, DMF, and EtOH (Table 1, entries 2–5). The optimization

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Table 1. Optimization of reaction conditionsa.
Entry
Solvent
Temperature (ꢀC)
Time
Yield 3a/4 (%)b
1
2
3
4
5
6
7
8
9
1,4-dioxane
MeCN
THF
DMF
EtOH
EtOH
MeOH
i-PrOH
–
25
25
25
25
25
65
65
65
65
16 h
16 h
16 h
16 h
5 h
15 min
15 min
15 min
15 min
20/50
40/25
46/20
25/15
85/trace
94/0
75/0
78/0
60/0
aReaction conditions: 1 (0.5 mmol), 2a (0.53 mmol), solvent (0.8 mL), 25–65 ꢀC, under air.
bIsolated yields based on 1.
The significance of bold value indicates the best optimized condition and was taken forward.
results are summarized in Table 1. From these screening results, we found that under an
un-optimized condition, ethanol was superior to all other solvents that we had tested giv-
ing 85% yield of the corresponding 3-benzyl-2H-pyrido[1,2-a]pyrimidin-2-one (3a) along
with trace of 4 (Table 1, entry 5). Based on these initial outcomes, we planned to further
optimize the reaction condition to reduce the reaction time and to improve yield. It was
noteworthy to mention that increasing the reaction temperature up to 65 ꢀC, the desired
product 3a was achieved in 94% isolated yield within 15 min (Table 1, entry 6). During the
course of the reaction, product 3a was precipitated which was then diluted with diethyl
1
ether (4 mL) and filtered to get the pure product 3a confirmed by H, 13C NMR, and MS
that match with the reported literature values.14a The reaction proceeded less efficiently in
other solvents such as methanol and isopropyl alcohol (Table 1, entries 7 and 8). A reduc-
tion in yield of 3a was observed while removing solvent from the reaction (Table 1, entry
9). Thus, the optimized reaction condition was established as: 1 (1 equiv.) and 2a (1.05
equiv.) in EtOH at 65 ꢀC for 15 min (Table 1, entry 6).
With the optimized condition in hand, we decided to evaluate the efficiency and ver-
satility of this methodology. As shown in Table 2, this was generalized using various
aromatic, heteroaromatic, and aliphatic aldehyde derived MBH carbonates as electro-
philes (2a–2p) with 2-aminopyridine (1). A range of functional groups was tolerated
with good to excellent yields and selectivity. It was found that halogen, electron-donat-
ing groups (EDG), and electron-withdrawing groups (EWG), such as p-Br, p-MeO,
p-CF3, m-Cl, m-CN, o-F, o-Cl, and o-Me were very well tolerated under the reaction
condition, leading to the corresponding products 3b–3i in 70–98% yields.
Polysubstituted allylic carbonates 2j and 2k gave the corresponding cycloadducts 3j and
3k in yields of 75 and 87%, respectively. Also, other heterocycles like pyridine (2l), N-
methyl pyrazole (2m), thiophene (2n), and thiazole (2o) at R were very well tolerated to
give desired products (3l–o) in excellent yields (70–82%). It is noteworthy to mention
that several MBH carbonates having heteroaryls (2l–o) worked highly efficiently under
the reaction condition and provide first-in-class examples in this area. In addition, the

4
S. B. INTURI ET AL.
Table 2. Substrate scope of diverse MBH carbonatesa,b
.
aReaction conditions: 1 (0.5 mmol) and 2a–p (0.53 mmol) in EtOH (0.8 mL) at 65 ꢀC for 15 min.
bIsolated yields based on 1.
cThis reaction was performed on a 1.0 g scale.
dReaction was continued at 65 ꢀC for 4 h.
scope of this methodology worked well with cycloalkyl MBH carbonate (2p) giving the
desired fused pyrimidine compound (3p) in 65% yield. The reaction performed on a 1 g
scale with 2f was reproducible and yielded 95% of 3f.
To further explore the synthetic potential of this protocol, several substituted 2-ami-
nopyridines (1a–1k), 3-aminopyridazines (1l and 1m) and 8-aminonapthridine (1n)
based substrates as nucleophiles were investigated under the optimized reaction condi-
tion. The results of our studies are summarized in Table 3. Importantly, the pyridine
ring bearing halogen substituents such as F (1h) and Br (1d, 1i) groups were compatible
with this reaction, leading to the corresponding fused pyrimidones 5h, 5d, and 5i in
60–74% yields, which provide an access for further modifications. 2-Aminopyridine ring
bearing EDG (–Me, –OMe) reacted efficiently with electrophile (2a) to give the desired
products 5a–5c, 5f and 5g in 68–90% yields, respectively. Subsequently, EWG (–COOEt,
–COOMe) on 2-aminopyridine ring (1e and 1j) could react with MBH carbonate (2a)
smoothly to generate the desired products 5e and 5j in moderate yields. Disubstituted

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Table 3. Substrate scope of 2-heteroaryl aminesa,b
.
aReaction conditions: 1a–n (0.5 mmol) and 2a (0.53 mmol) in EtOH (0.8 mL) at 65 ꢀC for 15 min.
bIsolated yields based on 1.
2-aminopyridine (1k) was converted to the desired product 5k in 70% yield.
Furthermore, the reaction of substituted 3-aminopyridazine as nucleophile (1l and 1m)
with allylic carbonate (2a) proceeded very well and generated the desired products 5l
and 5m in 72 and 70% yields, respectively. It is worth noting that 1,7-naphthyridin-8-
amine (1n) can be tolerated in this reaction affording product (5n) in 45% yield.
The advantage of the described method compared to the reported ones in the litera-
ture was summarized in Table 4. The careful comparison between the yields derived
from using MBH acetates[14a,b,15] versus MBH carbonates revealed that the Boc group
facilitated the reaction in a much better way than the acetate group.
To further evaluate the scope of this reaction, diversely substituted nucleophiles
(1e, 1i, 1k, 1l, and 1o) with the MBH derived Michael acceptors (2l–o) were examined
under the standard condition as shown in Table 5. Particularly these derivatives
(Table 5, 6a–h) can be used as excellent precursors for bioactive molecules.

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S. B. INTURI ET AL.
Table 4. Yield comparison between MBH acetates and MBH carbonates.
MBH acetate/
MBH carbonate/
Entry
Compound
Yield (literature reported) (%)
Yield (current method) (%)
1
2
3
4
5
6
3a
3b
3c
3i
5a
5i
7714a
8614b
5614a
7914a
8615
94
89
84
96
90
74
6814b
Table 5. Substrate scope of diverse 2-heteroaryl amines and MBH carbonatesa,b
.
aReaction conditions: 1e, i, k, l, o (0.5 mmol) and 2l–o (0.53 mmol) in EtOH (0.8 mL) at 65 ꢀC for 15 min.
bIsolated yields based on 1.
cThis reaction was performed on a 1.0 g scale.
These results indicate that the reaction underwent smoothly to generate the desired
fused pyrimidone products 6a–h in excellent yields.
In Scheme 1, it is proposed that the Michael addition of pyridine nitrogen of 2-ami-
nopyridine (1) onto the olefinic double bond of allylic carbonate (2) generates the
transient intermediate A, which undergoes an elimination of carbon dioxide and
tert-butanol via intermediate B to give the iminopyridine acrylate C. A subsequent intra-
molecular acyl substitution followed by 1,3-hydrogen shift would give the desired fused
pyrimidone G.

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7
Scheme 1. Proposed reaction pathway for the formation of fused pyrimidones.
Conclusion
In summary, we have developed a highly efficient one-pot cyclocondensation reaction
for synthesis of structurally diverse 3-substituted-2H-pyrido[1,2-a]pyrimidin-2-ones and
related fused pyrimidone derivatives. The reaction is environmentally benign, operation-
ally simple, cost-effective, diverse, and have broad functional group tolerance giving
good to excellent yields and selectivity. Importantly, the reaction can be readily scaled
up to gram quantities, offering good practicality.
Experimental
General experimental methods
All chemicals and solvents were purchased from commercial suppliers and used without
further purification. Solvents were used without drying. The MBH carbonates 2 were
synthesized according to the reported procedure.[17] 1H and 13C NMR spectra were
recorded at 400 and 100.5 MHz on Varian NMR spectrometer with DMSO-d6 as solvent.
Chemical shifts were reported in d ppm using residual solvent protons as internal stand-
1
ard (d 2.48 ppm for DMSO-d6 in H-NMR and d 40.0 ppm for DMSO-d6 in 13C-NMR).
Coupling constants (J) were reported in Hz and refer to apparent peak multiplicity. The
peak splitting patterns were indicated as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet; dd, doublet of doublets; td, triplet of doublets; and tt, triplet of triplets.
High resolution mass spectra were obtained on WATERS Q-TOF Premier-HAB213
spectrometer in ESI mode. Melting points were recorded using Buchi melting point
apparatus and temperatures were uncorrected. Thin layer chromatography was per-
formed on aluminum plates coated with silica gel 60 with F254 indicator.
General procedure for the synthesis of compounds 3a–3p, 5a–5n, and 6a–6h
To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate
(0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 ꢀC for 15 min. During the

8
S. B. INTURI ET AL.
course of the reaction, product was precipitated which was then diluted with diethyl
ether (4 mL) and filtered to get the pure product.
In case of 3p, reaction was continued to stir at 65 ꢀC for 4 h. After this time, ethanol
was evaporated under reduced pressure; the obtained solid was diluted with diethyl
ether (2 mL) and filtered to get the pure product.
3-Benzyl-2H-pyrido[1,2-a]pyrimidin-2-one (3a)[14a]
1
White solid; Yield: 111 mg, 94%; M.p.: 219–221 ꢀC (lit: 218–220 ꢀC); H NMR (400 MHz,
DMSO-d6): d 8.19 (s, 1H), 8.14 (d, J ¼ 6.4 Hz, 1H), 7.63 (tt, J ¼ 6.8, 2.0 Hz, 1H),
7.30–7.25 (m, 4H), 7.21– 7.16 (m, 1H), 7.13 (d, J ¼ 9.2 Hz, 1H), 6.91 (td, J ¼ 6.4, 0.8 Hz,
1H), 3.72 (s, 2H); 13C NMR (100.5 MHz, DMSO-d6): d 167.6, 151.1, 139.2, 136.8, 136.6,
134.4, 129.3, 128.7, 127.9, 126.6, 122.9, 113.0, 34.1. ESI-MS [M þ H]þ m/z 237.1. All
other characterization data and spectra of compounds are given in supplementary data.
Acknowledgments
The authors sincerely thank the Senior Management of Jubilant Biosys Ltd. for providing the
facilities to conduct this research work and also thankful to the Management of Jamal
Mohamed College.
Disclosure statement
The authors declare no competing financial interest.
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