One-pot synthesis of 2-aryl-1,2-fused pyrimidones

Article abstract of DOI:10.1007/s12039-017-1244-z

A facile and versatile method for the synthesis of alicyclic fused pyrimidones from aminoacrylates and lactams in the presence of phosphorous oxychloride is described. The results suggest that this method is widely applicable except for cyclobutyl fused s

Full text of DOI:10.1007/s12039-017-1244-z

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-017-1244-z
REGULAR ARTICLE
One-pot synthesis of 2-aryl-1,2-fused pyrimidones
SAMIKANNU RAMESHa, PON SARAVANAKUMARa, RAMASAMY DURAISAMYa,
ARVIND MATHURb and PIRAMA NAYAGAM ARUNACHALAMa,∗
aBiocon Bristol-Myers Squibb Research Center, Syngene International Pvt. Ltd., Biocon Park,
Plot No. 2 &3, Bommasandra–Jigani Road, Bangalore 560 100, India
bResearch and Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, USA
Email: pn.arunachalam@syngeneintl.com
MS received 22 September 2016; revised 8 December 2016; accepted 29 January 2017
Abstract. A facile and versatile method for the synthesis of alicyclic fused pyrimidones from aminoacrylates
and lactams in the presence of phosphorous oxychloride is described. The results suggest that this method
is widely applicable except for cyclobutyl fused systems. This method gives better yield than the method of
condensing aminopyrrolidines with the beta keto esters.
Keywords. Alicyclic fused pyrimidone; aminoacrylates; lactams; phosphorus oxychloride; cyclisation.
1. Introduction
the aminoacrylates were successfully condensed with,
either the open chain alkyl chlorimines derived from
the amides,6 or with the cyclised alkyl chloramines
derived from the lactams which are same as the ones
mentioned in our current study,7 to form the substituted
4-pyrimidones in good yields. The latter example,
though resembled our present work, used phosphorous
oxychloride as a solvent, was not an exhaustive one,
and covered no more than four examples. In addition
to these examples, we also came across an example in
which 3-aminothiophene-2-esters were condensed with
lactams in the presence of phosphorous oxychloride.8
Even though this example was not directly related to
our present work; it did confirm the requirement of a
chlorinating reagent such as phosphorous oxychloride
to effect the condensation. These literature examples
led us to think that the treatment of a lactam with the
calculated quantity of phosphorous oxychloride in a
suitable solvent would generate a cyclized chlorimine
which could be reacted in situ with the aminoacrylates
2 to give the desired pyrimidone intermediates 3 as
shown in the Scheme 3. This enabled us to synthesise a
wide range of fused pyrimidones which were all hith-
erto not reported. Indeed, when we treated pyrrolidin-
2-one (1a, n = 1) with phosphorous oxychloride, it did
result in the formation of the corresponding cyclized
chlorimine,9 intermediate A as evidenced by the
GCMS of the reaction mixture. To confirm the reaction
pathway, we carried out the addition of ethyl 3-amino-
3-(2-chloro-5-nitrophenyl) acrylate, 2a, to this reactive
intermediate at ambient temperature and followed the
reaction by LCMS. Over a couple of hours, this resulted
Pyrrolopyrimidinone derivatives are ubiquitously found
across a range of bioactive molecules. For example,
TLR-9 antagonists takes advantage of the fused core
structure of pyrrolopyrimidinone. This takes care of
the selective corticotrophin-releasing factor-1 (CRF)
receptor antagonism.1 4
In the course of our drug discovery program, we
were interested in the rapid synthesis of 2-aryl substi-
tuted tetrahydropyrrolo[1,2-a] pyrimidone derivatives
as key templates (Figure 1). Initially we attempted to
synthesize these targets through the condensation of
the beta keto esters with the corresponding 2-amino-
3,4-tetrahydropyrrole derivatives as reported in the
literature.5 This is shown in Scheme 1. However, this
methodology required very long duration (72 h) for
the synthesis of 2-amino-3,4-tetrahydropyrrole deriva-
tive that too with a poor yield of 10%, besides, poorer
yield for the condensation step itself (8%).
We thought that a faster approach to the substituted
fused pyrimidones 3 could be achieved by interchang-
ing the reacting groups of both the reactants. That is to
react a lactam 1 with an aminoacrylate 2 as shown in
Scheme 2.
To support this view and to find a suitable reaction
condition, keeping lactams as substrates, we searched
the literature without much success. Broader search of
the literature keeping the substituted pyrimidones as tar-
get molecules, led us to a couple of examples in which
∗For correspondence

Samikannu Ramesh et al.
in the formation of the adduct B as evidenced by the
LCMS analysis of the crude reaction mixture. Though
the intermediate B could not be isolated for further
analysis due to its instability, upon heating at 90◦C it
was smoothly converted to 3aa. Based on these obser-
vations, it is clear that the nucleophilic attack of the
aminoacrylates on the cyclic chloro intermediate A, fol-
Figure 1. 2-aryl substituted tetrahydropyrrolo[1,2-a] lowed by the intramolecular condensation at the ester
pyrimidone.
group at higher temperature resulted in the formation of
pyrimidone derivatives 3aa as illustrated in Scheme 3.
This approach is attractive since a variety of
aminoacrylates 2 could be easily synthesized via decar-
boxylative Blaise reaction from the arylnitriles,10 16 and
can be condensed with lactams 1 of various ring sizes in
the presence of phosphorous oxychloride. Using about
2.0 equivalents of phosphorus oxychloride instead of a
large excess, ensures that a wider range of lactams with
sensitive substitutions such as ester groups as in exam-
ple 1b also can be successfully derivatized. As such,
this methodology had the potential for synthesizing a
large number of examples since we do not need to iso-
late the cyclic chlorimines which are not very stable as
shown in Scheme 4.
Scheme 1. Synthesis of fused pyrimidones via β-keto ester.
2. Experimental
2.1 Materials and instrumentation
Melting points were recorded on Buchi melting point B-545
apparatus. 1H NMR and 13C NMR spectra were recorded on
a 300/400-MHz Bruker DRX-400 instrument and DMSO-d6,
Scheme 2. Retrosynthesis of fused pyrimidone.
Scheme 3. Possible reaction pathway for the synthesis of fused pyrimidones.
Scheme 4. General scheme for the preparation of 2-aryl-1,2-fused pyrimidones.

Transformation of 2-aryl-1,2-fused pyrimidones derivatives
CDCl3, CD3OD as solvents, wherever applicable, with δ 2.17–2.52 (m, 2 H, -CH2), 3.26 (t, J=7.9 Hz, 2 H,
tetramethylsilane (TMS) as an internal standard. Liquid -CH2), 4.10–4.33 (m, 2 H, -CH2), 6.66 (s, 1 H, -Ar-H),
Chromatography Mass Spectrometry (LC-MS) data were 7.82 (d, J=9.1 Hz, 1 H, -Ar-H), 8.18–8.38 (m, 1 H, -Ar-
recorded on Agilent Technologies 1200 series.
H), 8.48 (d, J=2.6 Hz, 1 H, -Ar-H); 13C NMR (75 MHz,
CD3OD): δ 168.05, 163.75, 161.88, 140.30, 139.74, 133.30,
127.29, 126.74, 113.99, 34.13, 20.27; (LCMS m/z (ESI);
292[M+H]+; Anal. Calcd for C13H10ClN3O3: C, 53.53; H,
3.46; N, 14.41%. Found: C, 53.63; H, 3.59; N, 14.49%.
Results for the remaining compounds are given in
Supplementary Information
2.2 Typical procedure exemplified by the synthesis of
2-(2-chloro-5-nitrophenyl)-7,8-dihydropyrrolo[1,2-a]
pyrimidin-4(6H)-one (Table 1, Entry 1, 3aa)
A mixture of (ethyl 3-amino-3-(2-chloro-5-nitrophenyl)
acrylate (200 mg, 0.739 mmol) (2a), 1,2-dichloroethane (5 mL),
pyrrolidin-2-one (1a) (62.9 mg, 0.739 mmol), POCl3 (0.2 mL,
1.5 mmol) was taken in a round bottom flask and stirred
at 90◦C for 12 h under nitrogen. After completion of the
reaction, as monitored by the LCMS, the reaction mixture
was cooled to room temperature. It was quenched with 10%
sodium bicarbonate solution and extracted with ethyl acetate
(3 × 25 mL). The combined organic layers were washed
with brine, dried over sodium sulphate, and concentrated on
a rotary evaporator. The crude product was purified by ISCO
chromatography on silica gel to give the pure product.
3. Results and Discussion
To optimize the reaction condition, we screened the
amounts (in equivalents) of substrates and reagents as
well as the reaction temperature. The best condition
observed was as follows: 2-pyrrolidone (1a) (1 equiv.)
and ethyl 3-amino-3-(2-chloro-5-nitrophenyl)acrylate
(2a) (1 equiv.) in the presence of 2 equiv. of phospho-
rous oxychloride in ethylene dichloride was heated at
90◦C for 12 h to afford the 2-(2-chloro-5-nitrophenyl)-
7,8-dihydropyrrolo[1,2-a]pyrimidin-4(6H)-one 3aa in
68% isolated yield (Table 1 Entry 1). With the above
result in hand, we examined the reaction scope. As
shown in Table 1, aryl amino acrylates, with both
2.3 Spectral data of selected compounds
2.3a 2-(2-chloro-5-nitrophenyl)-7,8-dihydropyrrolo[1,2-a]
pyrimidin-4(6H)-one (3aa): Light brown solid, 147 mg,
68% Yield; M.p.184◦C;1H NMR (300 MHz, CD3OD): the electron donating as well as electron withdrawing
Table 1. One pot synthesis of 2-Aryl-1,2-fused pyrimidones.
Entry
Lactam= (1a–e)
R (2a–e)
Product (3a–k)
Yield (%)a
M.p.(◦C) Found/Reported
1
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1e
2a (2-Cl,5-NO2C6H3)
2b (C6H5)
3aa
3ab
3ac
3ad
3ba
3cb
3ce
3cf
68
35
57
38
40
53
40
53
41
58
88
56
45
40
42
45
47
48
46
56
71
51
36
40
32
184.0
2
162.5/161.017
3
2c (4-Cl,2-F-C6H3)
2d (7-azaindole)
2a (2-Cl,5-NO2-C6H3)
2b (C6H5)
168.8
4
181.0
5
143.0
6
128.2/(382 45;B.p./◦C)18
7
2e (4-F-C6H4)
153.1
8
2f (4-Br-C6H4)
141.1
9
2g (4-COCH3-C6H4)
2h (2-F-C6H4)
3cg
3ch
3ca
3cc
3ci
141.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
138.2
2a (2-Cl,5-NO2C6H3)
2c (4-Cl,2-F-C6H3)
2i (3,4-F-C6H3)
2j (4-py)
182.3
159.1
164.7
3cj
165.9/(407 55;B.p./◦C)19
2d (7-azaindole)
2b (C6H5)
2e (4-F-C6H4)
2g (4-COCH3-C6H4)
2h (2-F-C6H4)
2c (4-Cl,2-F-C6H3)
2a (2-Cl,5-NO2C6H3)
2i (3,4-F-C6H3)
2k (2-pyrimidin)
2d (7-azaindole)
2a (2-Cl-5-NO2C6H3)
3cd
3db
3de
3dg
3dh
3dc
3da
3di
178.0
134.2/(396 45;B.p./◦C)20
130.8/(392 52;B.p./◦C)20
128.5
120.9
153.2
192.8
118.5
143.7
153.5
175.3
3dk
3dd
3ea
=
(1a) pyrrolidin-2-one; (1b) ethyl 5-oxopyrrolidine-2-carboxylate; (1c) piperidin-2-one; (1d) azepan-2-one; (1e) 3,4-
dihydroisoquinolin-1(2H)-one.a Isolated yield.

Samikannu Ramesh et al.
valuable support and, Jianqing Li, Richard Rampulla and Bei
Wang of Bristol Myers Squibb for logistic help.
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Figure 2. 2-aryl substituted tetrahydropyrrolo[1,2-a]
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Acknowledgements
Authors thank Department of Discovery Analytical Services
of Biocon Bristol-Myers Squibb Research Center for their
Copper(I) carboxylates, (Ph
3P)2CuO2C(CH2)nCOOH.

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