Novel dual use of formamide-POCl3 mixture for the efficient, one-pot synthesis of condensed 2 H-pyrimidin-4-amine libraries under microwave irradiation

Article abstract of DOI:10.1080/00397911.2011.607934

The novel dual use of formamide-POCl3 mixture for the incorporation of a C-N fragment to form the pyrimidine nucleus and its subsequent chlorination in an efficient, one-pot synthesis of potentially bioactive condensed 2H-pyrimidin-4-amine libraries under

Full text of DOI:10.1080/00397911.2011.607934

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Novel Dual Use of Formamide-POCl3
Mixture for the Efficient, One-Pot
Synthesis of Condensed 2H-Pyrimidin-4-
amine Libraries Under Microwave
Irradiation
Kishore S. Jain a , Muthu K. Kathiravan a , Jitender B. Bariwal a
Pratip K. Chaskar a , Santosh S. Tompe a & Nikhilesh Arya a
,
a Department of Pharmaceutical Chemistry (PG), Sinhgad Institute of
Pharmaceutical Sciences, Pune, Maharashtra, India
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Kishore S. Jain, Muthu K. Kathiravan, Jitender B. Bariwal, Pratip K. Chaskar,
Santosh S. Tompe & Nikhilesh Arya (2013): Novel Dual Use of Formamide-POCl3 Mixture for the
Efficient, One-Pot Synthesis of Condensed 2H-Pyrimidin-4-amine Libraries Under Microwave
Irradiation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:5, 719-727
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Synthetic Communications1, 43: 719–727, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.607934
NOVEL DUAL USE OF FORMAMIDE-POCl3 MIXTURE
FOR THE EFFICIENT, ONE-POT SYNTHESIS OF
CONDENSED 2H-PYRIMIDIN-4-AMINE LIBRARIES
UNDER MICROWAVE IRRADIATION
Kishore S. Jain, Muthu K. Kathiravan, Jitender B. Bariwal,
Pratip K. Chaskar, Santosh S. Tompe, and Nikhilesh Arya
Department of Pharmaceutical Chemistry (PG), Sinhgad Institute of
Pharmaceutical Sciences, Pune, Maharashtra, India
GRAPHICAL ABSTRACT
Abstract The novel dual use of formamide-POCl3 mixture for the incorporation of a C-N
fragment to form the pyrimidine nucleus and its subsequent chlorination in an efficient,
one-pot synthesis of potentially bioactive condensed 2H-pyrimidin-4-amine libraries under
microwave irradiation (MWI) is reported. The one-pot microwave-assisted synthetic pro-
tocol is high-yielding, ecofriendly, rapid, and novel as well as eliminates intermittent work-
ups. The protocol can be adapted for the library synthesis of series of a condensed
pyrimidines.
Keywords Condensed 2H-pyrimidin-4-amines; MWI; one-pot synthesis
INTRODUCTION
Organic synthesis by microwave irradiation (MWI) is an invaluable technology
for drug discovery applications as it reduces reaction time, which makes it ideal for
rapid reaction scouting and optimization, allowing rapid synthesis of large number of
new chemical entities (NCEs) and their libraries.[1–3] Pyrimidines and condensed
pyrimidines have exhibited diverse biological activites.[4] A variety of condensed
Received April 30, 2011.
Address correspondence to Kishore S. Jain, Department of Pharmaceutical Chemistry, P. G.
Research Centre, Sinhgad Institute of Pharmaceutical Sciences, S. No. 44=1, Vadgaon (Bk), Off
Sinhgad Road, Pune 411041, Maharastra, India. E-mail: drkishorsjain@gmail.com
719

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K. S. JAIN ET AL.
Figure 1. Microwave-assisted synthesis of 2-amino-3-carbethoxy-4,5-disubstitutedthiophenes I, 2-
substituted condensedthienof2,3-d]pyrimidines Ia, and 2H-4-substituted anilinothieno[2,3-d] pyrimidines Ib.
2H-pyrimidin-4-amines have been reported[5–10] to exhibit receptor tyrosine kinase
inhibitory activity and hold potential for the development of antiproliferative and
antitumour drugs.
Earlier, we reported a novel methodology for the microwave-assisted synthesis
of 2-amino-3-carbethoxy-4,5-disubstitutedthiophenes I[11] and rapid cyclocondensa-
tion of these derivatives with various aliphatic nitriles under MWI (Ia).[12] Further,
we have also reported a MWI-based three-step synthesis of condensed 2H-4-substi-
tutedanilinothieno[2,3-d] pyrimidines Ib.[13] (Fig. 1) Our recent endeavors involving
green chemical techniques of synthesis are focused on converting multistep syntheses
into simple one-pot multicomponent reactions (MCRs).
In the present study we report a MWI-based, rapid, and one-pot protocol
adaptable to the parallel synthesis of this type of condensed 2H-pyrimidin-4-amines
(Ib) with improved yields. In all we report the one-pot synthesis of thirty-five such
derivatives. The main attraction of this protocol is short reaction time and elimin-
ation of the intermittent workup procedures to isolate the intermediates, thus
directly leading to the target compounds.
RESULTS AND DISCUSSION
The starting materials, thiophene o-aminoesters 1-4[11] and pyrazole
o-aminoesters 5,6[14] were synthesized as per reported methods. In the next step
the o-aminoester substrate was cyclocondensed with formamide either through con-
ventional heating under reflux or under MWI to afford the corresponding condensed
2H-4-hydroxypyrimidine. The subsequent steps involve the chlorination of the
4-hydroxy function with POCl3 to form the corresponding condensed 4-chloropyri-
midine and finally the nucleophilic displacement of 4-chloro substituent with various
amines using iso-propanol as the solvent. The latter two steps of the synthesis can be
done through the conventional protocol or under MWI. The drawback of this meth-
odology as far as high-throughtput parallel library synthesis is concerned is that it
involves intermittent workup and isolation of the intermediates. This affects the
speed and overall yield of the throughput.
Our aim was to develop a protocol by which both cyclocondensation of
formamide with the o-aminoester substrate as well as subsequent chlorination of
the condensed pyrimidin-4-one could be coupled in a single step (Scheme 1).

FORMAMIDE-POCl3 MIXTURE
721
Scheme 1. Protocol for one-pot synthesis of condensed 2H-4-anilinopyrimidines.
Combination of dimethylformamide (DMF) with POCl3, SOCl2, and SO2Cl2 under
varying conditions from ice cold (0–5 ꢀC) to 60 ꢀC leads to a complex, referred as
Vilsmier–Hack reagent.[15–17] Any group or site susceptible to formylation in the sub-
strate is the limiting factor for chlorination under these conditions. Because, the
transient 2H-pyrimidin-4(3H)-one intermediate did not have any such site suscep-
tible to formylation, the adaptation of Vilsmier-Hack conditions appeared to be
attractive. We have replaced DMF with formamide in this reagent. Thus, use of
the combination of formamide–POCl3 appeared to be more attractive. This has been
achieved by a novel dual use of formamide-POCl3 mixture in proper stoichiometry
and under suitable reaction conditions. This mixture, besides serving as a variant
of Vilsmier–Hack reagent, also can provide the C-N component from HCONH2
for the cyclocondensation reaction to form the condensed 2H-pyrimidin-4-one.
Further, the stoichiometry of POCl3 can be manipulated to afford the subsequent
chlorination. The HCONH2-POCl3 mixture was prepared under ice-cold conditions
and added to the reaction flask containing the o-aminoester substrate, and then the
reaction mixture was subjected to MWI. After the formation of condensed 2H-
4-chloropyrimidine, the reaction mixture was washed with n-hexane. The residue
was further treated in the same flask with a solution of appropriate aromatic amine
in i-PrOH, without isolation, and subjected to MWI afford the target compounds
(1a–e to 7a–e) in good yield (Table 1).
This protocol provides some distinct advantages over the conventional
method: reducing the reaction time from 2–12 h to just a few minutes, employing
very mild reaction conditions (40 W), and using minimal quantity of the chlorinating
agent, due to which the intermediate, condensed 4-chloro-2-substitutedpyrimidine, is
formed in good yield and purity. Further, the intermediate 4-chloropyrimidine is not
isolated but is directly converted to the final product, thus avoiding intermittent
workup and isolation, as well as leading to improved overall yields.
The protocol was explored for the synthesis of a library of compounds (1a–e to
7a–e). (Table 1). It has been observed that aniline underwent the nucleophilic

722
K. S. JAIN ET AL.
Table 1. Physical data of condensed 2H-pyrimidin-4-amines (1a–e to 7a–e)
Target compounds
Compound
R1
R2 Yield (%) Melting point (ꢀC) Reaction time (min)
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
H
H
H
Cl
Br
F
89
83
81
87
81
83
81
84
86
83
97
88
94
82
88
87
85
83
92
80
86
81
88
89
84
81
87
81
82
83
89
87
90
92
87
176–178
136–138
154–156
167–169
136–138
173–174
145–147
162–164
168–170
146–148
184–186
160–162
190–192
183–185
193–195
242–244
145–147
139–140
180–182
130–132
170–172
142–144
158–160
152–154
162–163
181–183
156–158
169–171
174–176
169–171
248–250
253–257
255–258
250–252
247–248
40
45
45
50
45
35
40
50
50
45
40
45
50
45
50
40
45
45
40
50
40
45
50
55
45
50
45
55
55
45
40
45
40
50
35
H
H
Cl
H
F
H
Cl
Br
F
H
H
H
Cl
H
F
H
Cl
Br
F
H
H
H
Cl
H
F
H
Cl
Br
F
H
H
H
Cl
H
F
H
Cl
Br
F
H
H
H
Cl
H
F
H
Cl
Br
F
H
H
H
Cl
H
F
Cl
H
F
Cl
H
Cl
CH3
F
H
displacement reaction at
a
faster rate than the amines bearing an
electron-withdrawing group(EWG). The reaction, however, tolerates a variety of
functional groups and is applicable to amines containing EWG. The increase in

FORMAMIDE-POCl3 MIXTURE
723
Scheme 2. Plausible mechanism for the one-pot reaction.
bulkiness of the substituents in the o-aminoesters substrate has no significant effect
on the rate of reaction. The overall yield is better than those reported so far (80–97%)
in a shorter time (35–55 min). The process is amenable to scale up and can be gain-
fully employed to synthesize a library of condensed pyrimidine analogs.
A plausible mechanism of the one-pot reaction is as follows: initially the first
mole of POCl3 reacts with formamide and results in the formation of Vilsmier–
Hack-type reagent. POCl3 acts as a Lewis acid and results in the formation of imi-
dyl halide, which facilitates nucleophilic attack of amine to give intermediate i. The
second mole of POCl3 reacts with ester and converts it into acid chloride ii,
increasing the electrophility of the carbonyl carbon. The intramolecular cyclization
reaction between the acid chloride and amidine amino group results in the forma-
tion of the condensed 2H-pyrimidin-4(3H)-one iii. The third mole of POCl3
converts the 4-hydroxy into the 4-chloro derivative iv. The mechanism is depicted
in Scheme 2.
EXPERIMENTAL
All reagents and chemicals were of LR grade, purchased from standard ven-
dors, and used as received. Microwave synthesizer (Qustron Technologies Corp.,
Canada; model-Pro M) with monomode open vessel was used for the synthesis.
1
The H NMR spectra were recorded in CDCl3 using a NMR Varian Mercury YH
300-MHz spectrometer, and chemical shifts are given in units as per million, down-
field from tetramethylsilane (TMS) as an internal standard. Mass spectra were
obtained on a Shimadzu GCMS-QP2010 spectrometer. Elemental analyses were
obtained using a flash EA 1112 Thermofinnigan instrument. The ultraviolet absorp-
tion spectra were determined in methanol on a Jasco V-530, UV-visible double-beam
spectrophotometer. The infrared (IR) spectra of the synthesized compounds were
recorded on Perkin-Elmer Spectrum BX Fourier transform (FT-IR) in potassium
bromide discs.

724
K. S. JAIN ET AL.
Synthesis of Starting Materials
The starting material o-aminoester substrates were prepared as per reported
methods.[11–13] To synthesize the variant of the Vilsmier–Hack reagent, 2.8 ml of
POCl3 was added to an ice-cold stirred solution of 1.2 ml formamide dropwise over
10 min. After stirring for 30 min, the reagent was used for further study.
General Procedure for One-Pot Synthesis of Condensed
2h-Pyrimidin-4-amine Derivatives (1a–e to 7a–e)
Appropriate o-aminoester (1–7) (0.01 mol) was taken in the reaction vessel, to
which an ice-cold mixture of POCl3-formamide was added. The reaction vessel was
removed from the ice bath, allowed to attain room temperature (rt), and subjected to
MWI at 40 W for 10–12 min. The formation of the corresponding condensed 2H-
4-chloropyrimidine intermediate was confirmed by thin-layer chromatography
(TLC). The reaction mixture was washed with n-hexane (2 ꢁ 10 mL). Thereafter, a
solution of the appropriate aniline (0.02 mol) in isopropyl alcohol (20 mL) was added
to the reaction mixture, and the reaction mixture was further subjected to MWI at
40 W for 30–44 min. After the completion of the reaction (by TLC), the reaction mix-
ture was poured onto an ice-cold water mixture (50 mL). The precipitated solid was
filtered and air dried. The crude product was purified by crystallization to give the
desired products (1a–e to 7a–e). (Table 1)
Representative Data
Compound 1a. Mp 176–178 ꢀC; yield: 89%; UV (MeOH)=nm: 304.6, IR KBr,
1
t=cmꢂ1: 3430.60 (NH), 2925 (C–H), 1598 (N N); H NMR (CDCl3, 300 MHz): d
=
ppm ¼ 1.91 (d, 4H, J ¼ 9.31 Hz, CH2 at 6 & 7), 2.82 (s, 2H, CH2 at 5), 3.03 (s, 2H,
CH2 at 8), 7.07–7.37 (m, 3H, Ar–H), 7.24 (s, 1H, NH at 4), 7.61 (d, 2H, J ¼ 9.0 Hz,
Ar–H), 8.41 (s, 1H, CH at 2); EIMS (70 eV, m=z) 281 (Mþ), 266, 252, 236, 204, 190.
Anal. calcd. for C16H15N3S: C, 68.30; H, 5.37. Found: C, 68.11; H, 5.18.
Compound 1e. Mp 136–138 ꢀC; yield: 81%; UV (MeOH)=nm: 303; IR KBr,
cmꢂ1 3385 (NH), 2942 (C–H), 1491 (N N), 722 (C–Cl); 1H NMR (CDCl3,
=
300 MHz,): d ppm 1.92 (d, 4H, J ¼ 9.28 Hz, CH2 at 6 & 7), 2.83 (s, 2H, CH2 at 5),
3.01 (s, 2H, CH2 at 8), 7.01–7.11 (m, 1H, Ar–H), 7.60 (s, 1H, NH at 4), 7.86–7.95
(m, 2H, Ar–H), 8.45 (s, 1H, CH at 2); EIMS (70 eV, m=z) 333 (Mþ), 318, 304,
288, 204, 190. Anal. calcd. for C16H13ClFN3S: C, 57.57; H, 3.93. Found: C, 57.31;
H, 3.81.
Compound 2c. Mp 162–164 ꢀC; yield: 84%; UV (MeOH)=nm: 308; IR KBr,
1
cmꢂ1: 3412 (NH), 2915 (C–H), 1558 (C–H): H NMR (CDCl3, 300 MHz): d ppm
2.46 (s, 3H, CH3 at 5), 2.58 (s, 3H, CH3 at 6), 7.08–7.47 (m, 3H, Ar–H), 7.50–7.67
(m, 2H, Ar–H), 8.48 (s, 1H, CH at 2); EIMS (70 eV, m=z) 334 (Mþ), 318, 302,
178, 163. Anal. calcd. for C14H12BrN3S: C, 50.31; H, 3.62. Found: C, 50.00; H, 3.50.
Compound 3b. Mp 160–162 ꢀC; yield: 88%; UV (MeOH)=nm: 248; IR KBr,
cmꢂ1: 3448 (NH), 2925 (C–H), 765 (C–Cl); 1H NMR (CDCl3, 300 MHz): d ppm 7.18
(s, 1H, CH at 6), 7.26–7.52 (m, 8H, Ar–H), 7.41 (s, 1H, NH at 4), 7.97 (s, 1H, CH at

FORMAMIDE-POCl3 MIXTURE
725
2); EIMS (70 eV, m=z): 372 (Mþ), 262, 245, 226, 172. Anal. calcd for C18H11Cl2N3S:
C, 58.07; H, 2.98. Found: C, 57.91; H, 2.97.
Compound 4d. Mp 180–182 ꢀC; yield: 92%; UV(MeOH)=nm: 383; IR KBr,
cmꢂ1: 2926 (C–H), 1689 (COO), 3173 (NH), 1372 (C–F); 1H NMR (CDCl3,
300 MHz): d ppm 1.41 (t, 3H, COOCH2CH3 at 6, J ¼ 7.0 Hz), 2.96 (s, 3H, CH3 at
5), 4.37–4.42 (m, 2H, COOCH2CH3 at 5), 7.27 (s, 1H, NH at 4), 8.07 (s, 1H, CH
at 2); EIMS (70 eV, m=z) 331 (Mþ), 239, 211. Anal. calcd. for C15H12FN3O2S: C,
56.77; H, 3.81. Found: C, 56.45; H, 3.74.
Compound 5e. Mp 162–163 ꢀC; yield: 83%; UV (MeOH)=nm: 306; IR KBr,
1
cmꢂ1: 3391 (NH), 2922 (C–H), 1585 (N N); H NMR (CDCl3, 300 MHz): d ppm
=
2.45 (s, 3H, at 3), 7.02–7.82 (m, 5H, Ar–H at 1), 8.35 (d, 1H, Ar–H, J ¼ 7.2 Hz),
8.61 (s, 1H, Ar–H at 2), 8.83 (s, 1H, NH at 4); EIMS (70 eV, m=z)385 (Mþ), 370,
353, 338, 334, 256. Anal. calcd. for C18H13ClFN5S: C, 56.03; H, 3.40. Found: C,
55.87; H, 3.25.
Compound 6d. Mp 174–176 ꢀC; yield: 82%; UV (MeOH)=nm: 248; IR KBr,
cmꢂ1: 3301 (NH), 2365 (C–H), 1584 (N N), 975 (C–F); 1H NMR (CDCl3,
=
300 MHz): d ppm 7.21–8.23 (m, 9H, Ar–H), 8.61 (s, 1H, Ar–H at 5), 8.24 (s, 1H,
Ar–H at 2), 12.22 (s, 1H, NH at 4); EIMS (70 eV, m=z): 304 (Mþ), 304, 212. Anal.
calcd. for C17H12FN5: C, 66.88; H, 3.96. Found: C, 66.67; H, 3.69.
Compound 7d. Mp 250–252 ꢀC; yield: 92%; UV (MeOH)=nm: 260; IR KBr,
cmꢂ1: 3023(N–H); 2963 (C–H); 1556 (C C), 804 (C–Cl); 1H NMR (CDCl3,
=
300 MHz): d ppm 2.45 (s, 6H, CH3 at 6 & 7), 7.17 (s, 1H, Ar–H at 3) 8.20 (s, 1H,
Ar–H), 8.57 (s, 1H, Ar–H at 2), 9.0 (s, 1H, Ar–H at 2), 9.8 (s, 1H, NH at 2); EIMS
(70 eV, m=z) 333 (Mþ), 316, 302, 188. Anal. calcd. for C16H13ClFN3O2: C, 57.58; H,
3.93. Found: C, 57.60; H, 4.02.
CONCLUSION
This synthetic protocol involves the MWI-assisted transformation of a variety
of o-aminoester substrates (1–7), involving its cyclocondensation and further chlori-
nation with formamide-POCl3 mixture and subsequent nucleophilic displacement
reaction with a substituted aniline, to afford the corresponding condensed 2H-
pyrimidin-4-amines (1a–e to 7a–e) in mere 35–55 min and in excellent yields and
purity (Scheme 1). This novel synthetic protocol under MWI irradiation takes place
one pot and can be adapted to rapid parallel library synthesis. Further, work is in
progress employing substrates bearing a variety of o-aminoesters with aromatic as
well as aliphatic amines containing electron donating groups and EWGs.
ACKNOWLEDGMENTS
The authors acknowledge the contributions of M. N Navale, president, and
S. M. Navale, secretary, Sinhgad Technical Education Society, Pune, for providing
encouragement, facilities to carry out the synthetic work, and basic spectroscopic
analysis. The spectral and elemental analyses were done at the Department of

726
K. S. JAIN ET AL.
Chemistry, Saurashtra University, Rajkot, Gujarat, India, and the Department of
Chemistry University of Pune, India, respectively.
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