Synthesis of 3-(pyrimidinyl)pyrrole derivatives

Article abstract of DOI:10.3987/COM-09-11881

Alkylation of 4,6-dimethyl-2-pyrimidineacetonitrile and 2,6-dimethyl-4-pyrimidineacetonitrile with chloroacetic acid anilides was shown to give 5-amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-arylpyrrol-2-ones and 5-amino-4-(2,6-dimethyl-4-pyrimidiny

Full text of DOI:10.3987/COM-09-11881

HETEROCYCLES, Vol. 81, No. 3, 2010
611
HETEROCYCLES, Vol. 81, No. 3, 2010, pp. 611 - 623. © The Japan Institute of Heterocyclic Chemistry
Received, 8th December, 2009, Accepted, 29th January, 2010, Published online, 1st February, 2010
DOI: 10.3987/COM-09-11881
SYNTHESIS OF 3-(PYRIMIDINYL)PYRROLE DERIVATIVES
Igor Yu. Nestorak,a,b Anton V. Tverdokhlebov,*a,b Andrey A. Tolmachev,a,b
and Yulian M. Volovenkob
a
Enamine Ltd., Alexandra Matrosova str. 23, 01103, Kiev, Ukraine; e-mail:
atver@univ.kiev.ua
b Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033, Kiev,
Ukraine
Abstract
–
Alkylation of 4,6-dimethyl-2-pyrimidineacetonitrile and
2,6-dimethyl-4-pyrimidineacetonitrile with chloroacetic acid anilides was shown
to give 5-amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-arylpyrrol-2-ones
and
5-amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-arylpyrrol-2-ones,
respectively. Corresponding isomeric compounds, 5-amino-4-pyrimidinyl-
2,3-dihydropyrrol-3-ones were obtained by Claisen condensation of the
mentioned pyrimidineacetonitriles with N-Boc -aminoacids imidazolides
followed by removal of the protecting group accompanied with simultaneous ring
closure.
INTRODUCTION
Over the last 5 years among 3-(2- and 4-pyrimidinyl)pyrrole derivatives the substances with promising
pharmacological properties were found.1-3 Thus, CDK inhibitors,1 HIV integrase inhibitors,2 and selective
GSK-3 inhibitors3 all reaching nanomolar activity level were discovered. Of course, it caused increasing
interest in these scaffolds. However, to date there are at about 10 papers only devoted to the preparation
of various pyrimidinylpyrroles.1-5 The different approaches were used, namely pyrimidine ring formation
from the suitably substituted pyrroles,1,4 pyrrole ring construction on the basis of properly substituted
pyrimidines,2 and finally, cross-coupling reactions between pyrrole and pyrimidine derivatives.3,5
Nevertheless, all the methods had some shortcomings. The first one provided quite limited products
diversity thus being disadvantageous for medicinal chemistry, whereas the latter two required hardly
available pyrimidine derivatives so making the whole synthesis very laborious.
Applications of different hetarylacetonitriles for preparation of various heterocycles including pyrroles
were widely studied in our laboratory.6,7 Continuing these researches we have turned our attention to the

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isomeric pyrimidineacetonitriles 1 and 5 (Scheme 1). They were obtained in good yields from the
corresponding 2- and 4-chloro dimethylpyrimidines using slightly modified protocol developed by Atwal
with co-workers.8 The sequence included hetarylation of tert-butyl cyanoacetate followed by removal of
the ester group by acidic hydrolysis with simultaneous decarboxylation. So, utility of the nitriles 1, 5 for
the synthesis of pyrimidinylpyrrole derivatives has been examined and the results obtained are reported
herein.
RESULTS AND DISCUSSION
Alkylation of malononitrile and ethyl cyanoacetate with chloroacetic acid anilides was known to give
5-aminopyrrol-2-one derivatives.9 Usually K2CO3 or triethylamine were used in this reaction as the bases.
However application of this procedure to the nitriles 1, 5 afforded unsatisfactory results. Nevertheless in
the presence of the stronger base, potassium tert-butoxide desired pyrroles 2a-d and 6a-d were obtained
in 50-60 % yields. Apparently the reaction occurred through initial alkylation of the methylene group
followed by the intramolecular addition of the secondary amide to the nitrile.
Further we attempted to prepare pyrrol-3-one derivatives 4, 8, the isomers of compounds 2, 6. It should
be noted that Claisen type acylation of malononitrile and alkyl cyanoacetates with aminoacids esters is
well documented.10 Moreover, in case of malononitrile direct carbonyldiimidazole assisted acylation was
reported.11 We have collated the both approaches and carried out Claisen type acylation with acid
imidazolides. Thus, treatment of the Boc-protected anilinoacetic acids imidazolides generated in situ as
O
N
N
O
Cl
Ar
Cl
Ar
N
N
H
N
N
N
N
N
H
N
t-BuOK
t-BuOK
H2N
H2N
CN
CN
1
5
N
N
O
Ar
O
O
O
Ar
Ar
Ar
2 a-d
6 a-d
N
N
N
N
N
N
Boc
Boc
t-BuOK
t-BuOK
N
N
HCl
HCl
N
N
H
N
H
N
N
N
O
O
O
O
H2N
H2N
CN
CN
Boc
Boc
N
N
N
N
Ar
Ar
3 a-d Ar
Ar
8 a-d
4 a-d
7 a-d
Scheme 1. Ar = a: Ph; b: 4-ClC6H4; c: 4-MeOC6H4; d: 4-MeC6H4.

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613
usual with the nitriles 1, 5 in the presence of potassium tert-butoxide furnished crude derivatives 3a-d and
7a-d (80-90% purity) in 75-90% yields. Compounds 3a and 7a were purified by chromatography and
completely characterized as the representative examples. However, the purification procedure appeared
not to be obligatory, since the crude compounds 3, 7 were converted successfully into the target pyrroles
4a-d, 8a-d by means of deprotection with hydrochloric acid and simultaneous cyclization at the expense
of intramolecular addition of the liberated amine to the nitrile. Also it should be mentioned that the
similar Claisen condensation of N-protected proline imidazolides with certain methylene compounds of
non-nitrile nature was reported previously.12
Moreover, the method was successfully extended to the synthesis of pyrroles 10 and 12 (Scheme 2)
starting from the common aminoacids set. Thus, acylation of the nitriles 1, 5 with N-Boc aminoacids
imidazolides in the presence of potassium tert-butoxide yielded crude compounds 9a-e, 11a-e. Again,
derivatives 9a, 11a were purified by chromatography and characterized as representative samples.
Nevertheless, similarly to the previous case the purification was not needed, and treatment of crude
compounds 9, 11 with hydrochloric acid led to the pyrroles 10a-e, 12a-e in 50-65% overall yields based
on the nitriles 1, 5.
The structures of the prepared pyrimidinylpyrroles 2, 4, 6, 8, 10, 12 were confirmed by 1H and 13C NMR
data. According to the spectral data all pyrroles 2-12 in DMSO-d6 solutions exist entirely in the
amino-oxo form. Neither keto-enol nor amine-imine tautomerisms were observed. Noteworthy, there was
significant difference in the amino group signal shape of 2-oxo and 3-oxo isomers 2, 6 and 4, 8, 10, 12,
respectively.
Scheme 2.

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Thus, in the spectra of pyrrol-2-ones 2, 6 the habitual two-proton singlet of the amino group was present
at 7.0-7.5 ppm. At the same time in the spectra of pyrrol-3-ones 4, 8, 10, 12 the amino group signals
appeared as two separate one-proton singlets at 7.7-8.0 and 9.5-9.8 ppm. This magnetical
non-equivalence of the amino group protons is caused by the strong vinylogous amide-like conjugation
between amino and carbonyl moieties in the compounds 4, 8, 10, 12, which evidently is absent in the
isomeric derivatives 2, 6. The same effect was observed previously by us7 and other researchers10 for
close related cyclic enaminones.
To resume, pyrimidineacetonitriles 1, 5 have been shown to be suitable precursors for various
pyrimidinylpyrrole derivatives, the substances of potential pharmacological interest. The several
approaches elaborated provide high diversity of the available products favorable for medicinal chemistry.
Moreover, Claisen condensation with acid imidazolides has been worked out. It seems to be helpful
alternative for the typical reaction with esters.
EXPERIMENTAL
Chloroacetic acid anilides were prepared according to the described procedure.13 N-Boc aminoacids were
either commercially available or obtained as reported.14 Other reagents were commercially available and
were used without extra purification. All melting points were determined in open capillary tubes in a
Thiele apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Unity plus 400
1
13
spectrometer (400 MHz for H and 100 MHz for C) in DMSO-d6, CDCl3 or CF3COOD solutions.
Chemical shifts () are given in ppm downfield from internal Me4Si. J values are in Hz. The purity of all
compounds obtained was checked by 1H NMR and LC/MS on an Agilent 1100 instrument.
Pyrimidineacetonitriles 1, 5. General Procedure: Step A. Powdered K2CO3 (3.00 g, 22 mmol) was
added to a solution of the corresponding chlorodimethylpyrimidine (1.43 g, 10 mmol) and tert-butyl
cyanoacetate (1.55 g, 11 mmol) in anhydrous DMF (25 mL) and the mixture was stirred at 120 C for 6 h.
The solvent was evaporated in vacuo, the residue was dissolved in water (30 mL) and acidified with 20%
hydrochloric acid (4 mL). The solid precipitated was filtered and recrystallized from aqueous EtOH to
give -cyano-4,6-dimethyl-2-pyrimidineacetic acid tert-butyl ester (1.78 g, 72%, mp 198 C) or
-cyano-2,6-dimethyl-4-pyrimidineacetic acid tert-butyl ester (1.90 g, 77%, mp 184 C).
Step B. Conc. hydrochloric acid (9 mL) was added to a solution of compounds prepared on previous step
(2.47 g, 10 mmol) in EtOH (40 mL) and the mixture obtained was refluxed for 40 min. The solvent was
removed in vacuo, and the residue was dissolved in water (30 mL). K2CO3 (1.50 g, 11 mmol) was added
to this solution and then the water was evaporated to dryness in vacuo. The residue was treated with Et2O
(30 mL), the inorganic materials were filtered off and washed with Et2O (3 x 20 mL). Combined ethereal

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615
filtrate and washings were evaporated in vacuo yielding pure nitriles 1, 5 as oily materials, which
solidified quickly.
4,6-Dimethyl-2-pyrimidineacetonitrile (1): (1.29 g, 88%). Mp 79 C, lit.,15 mp 71 C. The spectra were
in complete agreement with the published data.15
2,6-Dimethyl-4-pyrimidineacetonitrile (5): (1.15 g, 78%). Mp 60 C. 1H NMR (DMSO-d6)  = 2.42 (s,
3H, CH3), 2.55 (s, 3H, CH3) 4.17 (s, 2H, CH2), 7.20 (s, 1H, 5-H). 13C NMR (DMSO-d6)  = 23.5 (CH3),
25.1 (CH3), 25.3 (CH2), 116.1 (5-C), 117.2 (CN), 159.6 (4-C), 167.1 (6-C), 167.7 (2-C). Anal. Calcd for
C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.25; H, 6.20; N, 28.50.
5-Amino-2,3-dihydropyrrol-2-ones 2a-d, 6a-d. General Procedure: Potassium tert-butoxide (0.59 g,
5.3 mmol) was added to a stirred solution of nitrile 1, 5 (0.90 g, 6.1 mmol) and appropriate chloroacetic
acid amide (5.0 mmol) in anhydrous THF (10 mL) and the mixture was stirred at reflux for 10 min. The
solvent was evaporated in vacuo, the residue was triturated with water (70 mL), filtered and washed with
water. Recrystallization from dioxane – i-propanol (1:1, v/v) mixture afforded derivatives 2a-d, 6a-d.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-phenylpyrrol-2-one (2a): (0.87 g, 62%). Mp
197 C. 1H NMR (DMSO-d6)  = 2.28 (s, 6H, 2CH3), 3.41 (s, 2H, CH2), 6.56 (s, 1H, 5-HPyrim), 7.11 (br s,
13
2H, NH2), 7.34 (d, J = 7.0, 2H, 2,6-HAr), 7.47 (t, J = 7.0, 1H, 4-HAr), 7.54 (t, J = 7.0, 2H, 3,5-HAr). C
NMR (DMSO-d6)  = 24.3 (2CH3), 35.7 (CH2), 81.0 (4-C), 111.6 (5-CPyrim), 128.4 (3,5-CAr), 128.9
(4-CAr), 129.9 (2,6-CAr), 133.1 (1-CAr), 152.1 (4,6-CPyrim), 164.0 (2-CPyrim), 165.4 (5-C), 174.8 (2-C=O).
Anal. Calcd for C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.69; H, 5.94; N, 19.82.
5-Amino-1-(4-chlorophenyl)-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydropyrrol-2-one (2b): (0.99 g,
63%). Mp 175 C. 1H NMR (DMSO-d6)  = 2.29 (s, 6H, 2CH3), 3.41 (s, 2H, CH2), 6.56 (s, 1H, 5-HPyrim),
13
7.16 (br s, 2H, NH2), 7.38 (d, J = 7.4, 2H, 2HAr), 7.60 (d, J = 7.4, 2H, 2HAr). C NMR (DMSO-d6)  =
24.3 (2CH3), 35.7 (CH2), 81.2 (4-C), 111.7 (5-CPyrim), 129.9 (2,6-CAr), 130.3 (3,5-CAr), 132.1 (4-CAr),
133.4 (1-CAr), 151.9 (4,6-CPyrim), 164.0 (2-CPyrim), 165.0 (5-C), 174.7 (2-C=O). Anal. Calcd for
C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80; Cl, 11.26. Found: C, 61.21; H, 4.73; N, 17.62; Cl, 11.30.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-(4-methoxyphenyl)pyrrol-2-one (2c): (0.81 g,
1
52%). Mp 176 C. H NMR (DMSO-d6)  = 2.27 (s, 6H, 2CH3), 3.38 (s, 2H, CH2), 3.80 (s, 3H, OCH3),
13
6.53 (s, 1H, 5-HPyrim), 7.07 (m, 4H, 2HAr, NH2), 7.24 (d, J = 8.6, 2H, 2HAr). C NMR (DMSO-d6)  =
24.3 (2CH3), 35.6 (CH2), 55.9 (OCH3), 80.7 (4-C), 111.2 (5-CPyrim), 111.4 (3,5-CAr), 125.6 (1-CAr), 129.9
(2,6-CAr), 152.6 (4,6-CPyrim), 159.6 (4-CAr), 164.1 (2-CPyrim), 165.1 (5-C), 175.0 (2-C=O). Anal. Calcd for
C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.70; H, 5.85; N, 17.86.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-(4-methylphenyl)pyrrol-2-one (2d): (0.90 g,
1
61%). Mp 167 C. H NMR (DMSO-d6)  = 2.27 (s, 6H, 2CH3), 2.36 (s, 3H, CH3), 3.39 (s, 2H, CH2),

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6.54 (s, 1H, 5-HPyrim), 7.07 (br s, 2H, NH2), 7.19 (d, J = 7.0, 2H, 2HAr), 7.33 (d, J = 7.0, 2H, 2HAr). C
NMR (DMSO-d6)  = 21.2 (CH3), 24.3 (2CH3), 35.6 (CH2), 80.8 (4-C), 111.5 (5-CPyrim), 128.2 (3,5-CAr),
130.4 (2,6-CAr), 130.5 (4-CAr), 138.4 (1-CAr), 152.3 (4,6-CPyrim), 164.0 (2-CPyrim), 165.3 (5-C), 174.8
(2-C=O). Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03. Found: C, 69.31; H, 6.34; N, 19.25.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-phenylpyrrol-2-one (6a): (0.80 g, 57%). Mp
1
212 C. H NMR (DMSO-d6)  = 2.24 (s, 3H, CH3), 2.39 (s, 3H, CH3), 3.38 (s, 2H, CH2), 6.39 (s, 1H,
13
5-HPyrim), 7.35 (d, J = 7.5, 2H, 2,6-HAr), 7.49 (m, 3H, 4-HAr, NH2), 7.56 (t, J = 7.5, 2H, 3,5-HAr). C
NMR (DMSO-d6)  = 24.1 (CH3), 26.4 (CH3), 34.4 (CH2), 79.0 (4-C), 108.5 (5-CPyrim), 128.4 (3,5-CAr),
129.1 (4-CAr), 130.0 (2,6-CAr), 132.8 (1-CAr), 152.8 (4-CPyrim), 161.8 (6-CPyrim), 164.1 (2-CPyrim), 165.2
(5-C), 174.4 (2-C=O). Anal. Calcd for C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.42; H, 5.70;
N, 19.89.
5-Amino-1-(4-chlorophenyl)-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydropyrrol-2-one (6b): (0.77 g,
49%). Mp 217 C. 1H NMR (DMSO-d6)  = 2.24 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.37 (s, 2H, CH2), 6.40
(s, 1H, 5-HPyrim), 7.37 (d, J = 8.5, 2H, 2HAr), 7.53 (br s, 2H, NH2), 7.60 (d, J = 8.5, 2H, 2HAr). 13C NMR
(DMSO-d6)  = 24.1 (CH3), 26.4 (CH3), 34.4 (CH2), 79.2 (4-C), 108.5 (5-CPyrim), 130.0 (2,6-CAr), 130.4
(3,5-CAr), 131.7 (4-CAr), 133.6 (1-CAr), 152.5 (4-CPyrim), 161.8 (6-CPyrim), 164.2 (5-C), 165. (2-CPyrim),
174.3 (2-C=O). Anal. Calcd for C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80; Cl, 11.26. Found: C, 61.14; H,
4.81; N, 17.67; Cl, 11.46.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-(4-methoxyphenyl)pyrrol-2-one (6c): (0.76 g,
49%). Mp 180 C. 1H NMR (DMSO-d6)  = 2.23 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.34 (s, 2H, CH2), 3.80
(s, 3H, OCH3), 6.37 (s, 1H, 5-HPyrim), 7.07 (d, J = 8.0, 2H, 2HAr), 7.23 (d, J = 8.0, 2H, 2HAr), 7.41 (br s,
2H, NH2). 13C NMR (DMSO-d6)  = 24.1 (CH3), 26.3 (CH3), 34.3 (CH2), 55.9 (OCH3), 78.8 (4-C), 108.3
(5-CPyrim), 115.2 (3,5-CAr), 125.2 (1-CAr), 129.9 (2,6-CAr), 153.3 (4-CPyrim), 159.8 (4-CAr), 161.8 (6-CPyrim),
163.9 (5-C), 165.1 (2-CPyrim), 174.7 (2-C=O). Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05.
Found: C, 65.73; H, 5.64; N, 18.10.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-(4-methylphenyl)pyrrol-2-one (6d): (0.82 g,
56%). Mp 188 C. 1H NMR (DMSO-d6)  = 2.24 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.39 (s, 3H, CH3), 3.35
(s, 2H, CH2), 6.37 (s, 1H, 5-HPyrim), 7.20 (d, J = 7.0, 2H, 2HAr), 7.33 (d, J = 7.0, 2H, 2HAr), 7.43 (br s, 2H,
13
NH2). C NMR (DMSO-d6)  = 21.3 (CH3), 24.1 (CH3), 26.4 (CH3), 34.3 (CH2), 78.9 (4-C), 108.4
(5-CPyrim), 128.3 (3,5-CAr), 130.1 (4-CAr), 130.5 (2,6-CAr), 138.6 (1-CAr), 153.0 (4-CPyrim), 161.8 (6-CPyrim),
164.1 (5-C), 165.2 (2-CPyrim), 174.5 (2-C=O). Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03.
Found: C, 69.40; H, 6.14; N, 19.22.
tert-Butyl (3-cyano-3-pyrimidinyl-2-oxopropyl)carbamates 3a-d, 7a-d, 9a-e, 11a-e. General

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Procedure: Carbonyldiimidazole (1.62 g, 10 mmol) was added to a stirred solution of appropriate N-Boc
aminoacid (10 mmol) in anhydrous MeCN (20 mL) and the stirring was continued until CO2 evolution
had ceased (at about 40 min). Then the corresponding nitrile 1, 5 (1.47 g, 10 mmol) and potassium
tert-butoxide (2.24 g, 20 mmol) were added sequentially and the mixture was stirred at reflux for 1 h.
Upon cooling the solvent was evaporated in vacuo, the residue was dissolved in water (30 mL) and
acidified with acetic acid (2.00 g, 33 mmol) causing separation of a brownish oil, which slowly solidified
being left overnight. It was filtered and dried yielding crude derivatives 3a-d, 7a-d, 9a-e, 11a-e employed
in further step. The representative compounds 3a, 7a, 9a, and 11a were purified by column
chromatography on silica gel using 4:1 v/v hexane – EtOAc mixture as eluent.
[3-Cyano-3-(4,6-dimethyl-2-pyrimidinyl)-2-oxopropyl]phenylcarbamic acid, tert-butyl ester (3a):
(2.85 g, 75%). Mp 149 C. 1H NMR (CDCl3)  = 1.45 (s, 9H, t-Bu), 2.48 (s, 3H, CH3), 2.54 (s, 3H, CH3),
4.83 (s, 2H, CH2), 6.63 (s, 1H, 5-CPyrim), 7.16 (m, 1H, 4-HAr), 7.27 - 7.30 (m, 4H, 2,3,5,6-HAr), 12.16 (s,
13
1H, NH...O). C NMR (DMSO-d6)  = 22.2 (2CH3), 27.8 (3CH3, t-Bu), 55.6 (CH2), 74.4 (Ct-Bu), 79.8
(C-CN), 113.2 (5-CPyrim), 118.6 (CN), 125.3 (4-CAr), 125.9 (2,6-CAr), 128.3 (3,5-CAr), 143.0 (1-CAr),
153.6 (4,6-CPyrim), 159.9 (COO), 172.7 (2-CPyrim), 190.3 (C=O). Anal. Calcd for C21H24N4O3: C, 66.30; H,
6.36; N, 14.73. Found: C, 66.45; H, 6.20; N, 14.93.
[3-Cyano-3-(2,6-dimethyl-4-pyrimidinyl)-2-oxopropyl]phenylcarbamic acid, tert-butyl ester (7a):
(3.19 g, 84%). Mp 134 C. 1H NMR (CDCl3)  = 1.46 (s, 9H, t-Bu), 2.47 (s, 3H, CH3), 2.62 (s, 3H, CH3),
4.76 (s, 2H, CH2), 6.88 (s, 1H, 5-HPyrim), 7.19 (m, 1H, 4-HAr), 7.32 (m, 4H, 2,3,5,6-HAr), 10.17 (s, 1H,
NH...O). 13C NMR (DMSO-d6)  = 22.0 (2CH3), 27.8 (3CH3, t-Bu), 56.9 (CH2), 78.2 (Ct-Bu), 79.5 (C-CN),
108.3 (5-CPyrim), 116.7 (CN), 125.2 (4-CAr), 126.0 (2,6-CAr), 128.2 (3,5-CAr), 143.1 (1-CAr), 154.2
(6-CPyrim), 158.7 (COO), 167.6 (4-CPyrim), 168.3 (2-CPyrim), 189.5 (C=O). Anal. Calcd for C21H24N4O3: C,
66.30; H, 6.36; N, 14.73. Found: C, 66.15; H, 6.56; N, 14.59.
[3-Cyano-3-(4,6-dimethyl-2-pyrimidinyl)-2-oxopropyl]carbamic acid, tert-butyl ester (9a): (2.49 g,
82%). Mp 167 C. 1H NMR (CDCl3)  = 1.47 (s, 9H, t-Bu), 2.49 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.36 (s,
13
2H, CH2), 5.21 (s, 1H, NHBoc), 6.64 (s, 1H, 5-HPyrim), 9.98 (s, 1H, NH...O). C NMR (DMSO-d6)  =
22.1 (2CH3), 28.2 (3CH3, t-Bu), 45.9 (CH2), 74.3 (Ct-Bu), 77.9 (C-CN), 113.1 (5-CPyrim), 118.7 (CN),
155.7 (4,6-CPyrim), 159.9 (COO), 178.9 (2-CPyrim), 191.0 (C=O). Anal. Calcd for C15H20N4O3: C, 59.20; H,
6.62; N, 18.41. Found: C, 59.07; H, 6.60; N, 18.57.
[3-Cyano-3-(2,6-dimethyl-4-pyrimidinyl)-2-oxopropyl]carbamic acid, tert-butyl ester (11a): (2.40 g,
79%). Mp 131 C. 1H NMR (CDCl3)  = 1.47 (s, 9H, t-Bu), 2.46 (s, 3H, CH3), 2.61 (s, 3H, CH3), 4.31 (s,
13
2H, CH2), 5.19 (s, 1H, NHBoc), 6.87 (s, 1H, 5-HPyrim), 10.79 (s, 1H, NH...O). C NMR (DMSO-d6)  =
21.8 (2CH3), 28.2 (3CH3, t-Bu), 47.1 (CH2), 74.2 (Ct-Bu), 77.8 (C-CN), 107.7 (5-CPyrim), 117.3 (CN),

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156.3 (6-CPyrim), 158.3 (COO), 166.6 (4-CPyrim), 169.2 (2-CPyrim), 189.7 (C=O). Anal. Calcd for
C15H20N4O3: C, 59.20; H, 6.62; N, 18.41. Found: C, 59.30; H, 6.51; N, 18.50.
5-Amino-2,3-dihydropyrrol-3-ones 4a-d, 8a-d, 10a-e, 12a-e. General Procedure: Conc. hydrochloric
acid (3 mL) was added to a solution of the crude compounds 3, 7, 9, 11 (2.5 mmol) in EtOH (30 mL) and
the mixture was heated at reflux for 1h. After cooling it was evaporated to dryness in vacuo, the residue
was triturated with the mixture of anhydrous dioxane (10 mL) and ether (20 mL), filtered and washed
with ether affording compounds 4a-d, 8a-d, 10a-e, 12a-e as hydrochlorides. These salts were dissolved in
water (5 mL) and treated with 10% aqueous K2CO3 solution (5 mL). The precipitate formed was filtered,
washed with water and dried to give derivatives 4, 8, 10, 12. The yields of compounds 4, 8, 10, 12 given
below are calculated on the basis of the nitriles 1, 5 through the two-step sequence.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-phenylpyrrol-3-one (4a): (0.41 g, 59%). Mp
221 C. 1H NMR (DMSO-d6)  = 2.35 (s, 6H, 2CH3), 4.10 (s, 2H, CH2), 6.76 (s, 1H, 5-HPyrim), 7.31 (t, J =
7.0, 1H, 4-HAr), 7.48 (m, 4H, 2,3,5,6-HAr), 7.71 (s, 1H, NH), 9.67 (s, 1H, NH). 13C NMR (CF3COOD)  =
23.8 (2CH3), 59.6 (2-CH2), 91.0 (4-C), 116.4 (5-CPyrim), 125.6 (2,6-CAr), 130.5 (4-CAr), 131.0 (3,5-CAr),
133.8 (1-CAr), 154.9 (2-CPyrim), 162.2 (4,6-CPyrim), 164.4 (5-C), 193.1 (3-C=O). Anal. Calcd for
C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.50; H, 5.85; N, 19.93.
5-Amino-1-(4-chlorophenyl)-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydropyrrol-3-one (4b): (0.49 g,
62%). Mp 247 C. 1H NMR (DMSO-d6)  = 2.32 (s, 6H, 2CH3), 4.06 (s, 2H, CH2), 6.74 (s, 1H, 5-HPyrim),
13
7.45 (d, J = 7.5, 2H, 2HAr), 7.52 (d, J = 7.5, 2H, 2HAr), 7.80 (s, 1H, NH), 9.65 (s, 1H, NH). C NMR
(CF3COOD)  = 24.7 (2CH3), 59.7 (2-CH2), 90.9 (4-C), 116.5 (5-CPyrim), 127.1 (2,6-CAr), 131.2 (3,5-CAr),
132.3 (1-CAr), 137.1 (4-CAr), 154.8 (2-CPyrim), 163.2 (4,6-CPyrim), 167.0 (5-C), 189.3 (3-C=O). Anal. Calcd
for C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80; Cl, 11.26. Found: C, 61.00; H, 4.51; N, 17.70; Cl, 10.99.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-(4-methoxyphenyl)pyrrol-3-one (4c): (0.48 g,
1
62%). Mp 213 C. H NMR (DMSO-d6)  = 2.34 (s, 6H, 2CH3), 3.80 (s, 3H, OCH3), 4.01 (s, 2H, CH2),
6.74 (s, 1H, 5-HPyrim), 7.05 (d, J = 8.5, 2H, 2HAr), 7.37 (d, J = 8.5, 2H, 2HAr), 7.48 (s, 1H, NH), 9.50 (s,
1H, NH). 13C NMR (CF3COOD)  = 22.8 (2CH3), 55.4 (OCH3), 59.7 (2-CH2), 90.7 (4-C), 116.2
(5-CPyrim), 116.4 (3,5-CAr), 127.1 (1-CAr), 127.5 (2,6-CAr), 154.5 (2-CPyrim), 154.7 (4-CAr), 159.8
(4,6-CPyrim), 164.5 (5-C), 199.9 (3-C=O). Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05.
Found: C, 65.70; H, 5.75; N, 17.86.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-(4-methylphenyl)pyrrol-3-one (4d): (0.36 g,
49%). Mp 244 C. 1H NMR (DMSO-d6)  = 2.33 (s, 9H, 3CH3), 4.04 (s, 2H, CH2), 6.74 (s, 1H, 5-HPyrim),
13
7.29 (d, J = 7.5, 2H, 2HAr), 7.33 (d, J = 7.5, 2H, 2HAr), 7.61 (s, 1H, NH), 9.60 (s, 1H, NH). C NMR
(CF3COOD)  = 19.32 (CH3), 22.7 (2CH3), 59.4 (CH2), 90.7 (4-C), 116.04 (5-CPyrim), 125.1 (3,5-CAr),

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130.7 (4-CAr), 131.2 (2,6-CAr), 141.5 (1-CAr), 154.6 (2-CPyrim), 155.3 (4,6-CPyrim), 164.1 (5-C), 191.5
(3-C=O). Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03. Found: C, 69.30; H, 6.20; N, 19.10.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-phenylpyrrol-3-one (8a): (0.44 g, 63%). Mp
251 C. 1H NMR (DMSO-d6)  = 2.33 (s, 3H, CH3), 2.47 (s, 3H, CH3), 4.21 (s, 2H, CH2), 7.34 (t, J = 6.8,
13
1H, 4-HAr), 7.49 (m, 4H, 2,3,5,6-HAr), 7.93 (s, 1H, NH), 8.04 (s, 1H, 5-HPyrim), 9.70 (s, 1H, NH). C
NMR (CF3COOD)  = 18.3 (CH3), 20.7 (CH3), 58.5 (2-CH2), 97.8 (4-C), 115.0 (5-CPyrim), 125.5 (3,5-CAr),
130.7 (4-CAr), 130.9 (2,6-CAr), 133.0 (1-CAr), 159.7 (6-CPyrim), 162.0 (2-CPyrim), 164.0 (5-C), 164.8
(4-CPyrim), 188.6 (3-C=O). Anal. Calcd for C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.33; H,
5.64; N, 19.90.
5-Amino-1-(4-chlorophenyl)-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydropyrrol-3-one (8b): (0.45 g,
57%). Mp 244 C. 1H NMR (DMSO-d6)  = 2.34 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.21 (s, 2H, CH2), 7.49
13
(d, J = 8.5, 2H, 2HAr), 7.56 (d, J = 8.5, 2H, 2HAr), 8.03 (m, 2H, 5-HPyrim, NH), 9.68 (s, 1H, NH). C
NMR (CF3COOD)  = 18.2 (CH3), 20.7 (CH3), 58.6 (2-CH2), 97.3 (4-C), 114.5 (5-CPyrim), 127.0 (3,5-CAr),
131.1 (2,6-CAr), 131.6 (4-CAr), 137.3 (1-CAr), 159.3 (6-CPyrim), 161.9 (2-CPyrim), 164.0 (5-C), 165.1
(4-CPyrim), 189.4 (3-C=O). Anal. Calcd for C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80; Cl, 11.26. Found:
C, 60.95; H, 4.83; N, 17.80; Cl, 11.47.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-(4-methoxyphenyl)pyrrol-3-one (8c): (0.42 g,
1
54%). Mp 239 C. H NMR (DMSO-d6)  = 2.32 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
4.12 (s, 2H, CH2), 7.05 (d, J = 9.0, 2H, 2HAr), 7.39 (d, J = 9.0, 2H, 2HAr), 7.73 (s, 1H, NH), 8.02 (s, 1H,
5-HPyrim), 9.51 (s, 1H, NH). 13C NMR (CF3COOD)  = 18.3 (CH3), 20.7 (CH3), 55.3 (OCH3), 58.8
(2-CH2), 97.7 (4-C), 114.9 (5-CPyrim), 116.4 (3,5-CAr), 126.4 (1-CAr), 127.5 (2,6-CAr), 159.7 (6-CPyrim),
160.3 (4-CAr), 162.0 (2-CPyrim), 164.0 (4-CPyrim), 165.1 (5-C), 188.7 (3-C=O). Anal. Calcd for
C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.72; H, 5.73; N, 18.03.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-(4-methylphenyl)pyrrol-3-one (8d): (0.41 g,
56%). Mp 230 C. 1H NMR (DMSO-d6)  = 2.32 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.47 (s, 3H, CH3), 4.16
(s, 2H, CH2), 7.30 (d, J = 8.0, 2H, 2HAr), 7.35 (d, J = 8.0, 2H, 2HAr), 7.83 (s, 1H, NH), 8.03 (s, 1H,
5-HPyrim), 9.62 (s, 1H, NH). 13C NMR (CF3COOD)  = 18.1 (CH3), 19.2 (CH3), 20.5 (CH3), 58.3 (2-CH2),
97.7 (4-C), 114.8 (5-CPyrim), 125.0 (3,5-CAr), 129.8 (4-CAr), 131.2 (2,6-CAr), 141.9 (1-CAr), 159.5
(6-CPyrim), 161.8 (2-CPyrim), 163.7 (5-C), 164.5 (4-CPyrim), 188.2 (3-C=O). Anal. Calcd for C17H18N4O: C,
69.37; H, 6.16; N, 19.03. Found: C, 69.40; H, 6.20; N, 18.87.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1H-pyrrol-3-one (10a): (0.30 g, 59%). Mp 283
1
C. H NMR (DMSO-d6)  = 2.31 (s, 6H, 2CH3), 3.55 (s, 2H, CH2), 6.68 (s, 1H, 5-HPyrim), 7.28 (s, 1H,
13
1-H), 7.64 (s, 1H, NH), 8.95 (s, 1H, NH). C NMR (CF3COOD)  = 22.9 (2CH3), 51.6 (2-CH2), 89.9

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(4-C), 115.8 (5-CPyrim), 154.5 (4,6-CPyrim), 160.3 (2-CPyrim), 166.2 (5-C), 194.3 (3-C=O). Anal. Calcd for
C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.74; H, 5.90; N, 27.60.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1-methylpyrrol-3-one (10b): (0.30 g, 55%). Mp
288 C. 1H NMR (DMSO-d6)  = 2.32 (s, 6H, 2CH3), 3.02 (s, 3H, NCH3), 3.61 (s, 2H, CH2), 6.66 (s, 1H,
5-HPyrim), 7.76 (br s, 1H, NH), 9.39 (br s, 1H, NH). 13C NMR (CF3COOD)  = 20.3 (2CH3), 30.2 (NCH3),
58.7 (2-CH2), 91.2 (4-C), 116.4 (5-CPyrim), 154.8 (4,6-CPyrim), 154.9 (2-CPyrim), 164.8 (5-C), 192.8
(3-C=O). Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.78; H, 6.54; N, 25.59.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-2-methyl-1H-pyrrol-3-one (10c): (0.35 g, 64%).
Mp 286 C. 1H NMR (DMSO-d6)  = 1.17 (d, J = 7.0, 3H, CH3), 2.31 (s, 6H, 2CH3), 3.53 (q, J = 7.0, 1H,
2-H), 6.67 (s, 1H, 5-HPyrim), 7.46 (s, 1H, 1-H), 7.59 (s, 1H, NH), 8.96 (s, 1H, NH). 13C NMR (CF3COOD)
 = 14.8 (CH3), 21.9 (2CH3), 58.8 (2-C), 88.3 (4-C), 115.5 (5-CPyrim), 154.6 (4,6-CPyrim), 160.1 (2-CPyrim),
164.8 (5-C), 197.6 (3-C=O). Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.29; H,
6.40; N, 25.58.
3-Amino-2-(4,6-dimethyl-2-pyrimidinyl)-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one (10d): (0.32 g,
53%). Mp 284 C. 1H NMR (DMSO-d6)  = 1.38 (m, 1H, 6-H), 2.00 (m, 3H, 6,7,7-H), 2.33 (s, 6H, 2CH3),
3.29 (m, 2H, 5-CH2), 3.71 (m, 1H, 7a-H), 6.72 (s, 1H, 5-HPyrim), 8.15 (s, 1H, NH), 9.24 (s, 1H, NH). 13C
NMR (CF3COOD)  = 23.7 (2CH3), 25.8 (6-CH2), 27.6 (7-CH2), 44.8 (5-CH2), 70.4 (7a-C), 91.0 (2-C),
115.9 (5-CPyrim), 154.5 (4,6-CPyrim), 161.1 (2-CPyrim), 167.5 (3-C), 196.3 (1-C=O). Anal. Calcd for
C13H16N4O: C, 63.92; H, 6.60; N, 22.93. Found: C, 64.16; H, 6.42; N, 22.77.
5-Amino-4-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-2-benzylpyrrol-3-one (10e): (0.35 g, 48%). Mp
228 C. 1H NMR (DMSO-d6)  = 2.31 (s, 6H, 2CH3), 2.62 (dd, J2 = 13.5, J3 = 8.5, 1H, -HR1), 3.08 (dd,
J2 = 13.5, J3 = 3.0, 1H, -HR1), 3.82 (dd, J3 = 8.5, J3 = 3.0, 1H, 2-H), 6.67 (s, 1H, 5-HPyrim), 7.20 (t, J =
6.5, 1H, 4-HR1), 7.26 (m, 4H, 2,3,5,6-HR1), 7.34 (m, 2H, 1-H, NH), 8.91 (s, 1H, NH). 13C NMR
(CF3COOD)  = 20.4 (2CH3), 37.2 (-CR1), 64.6 (2-C), 89.6 (4-C), 115.9 (5-CPyrim), 127.6 (4-CR1), 128.7
(3,5-CR1), 128.8 (2,6-CR1), 134.3 (1-CR1), 154.9 (4,6-CPyrim), 161.0 (2-CPyrim), 165.4 (5-C), 196.4 (3-C=O).
Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03. Found: C, 69.42; H, 6.07; N, 19.10.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1H-pyrrol-3-one (12a): (0.29 g, 57%). Mp 145
C. 1H NMR (DMSO-d6)  = 2.28 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.66 (s, 2H, CH2), 7.49 (s, 1H, 1-H),
13
7.80 (s, 1H, NH), 7.92 (s, 1H, 5-HPyrim), 8.98 (s, 1H, NH). C NMR (CF3COOD)  = 18.9 (CH3), 21.3
(CH3), 51.5 (2-CH2), 98.4 (4-C), 116.1 (5-CPyrim), 161.2 (4-CPyrim), 162.8 (6-CPyrim), 164.6 (2-CPyrim),
167.3 (5-C), 189.5 (3-C=O). Anal. Calcd for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.87; H,
5.84; N, 27.45.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-1-methylpyrrol-3-one (12b): (0.34 g, 62%). Mp

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285 C. 1H NMR (DMSO-d6)  = 2.28 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.02 (s, 3H, NCH3), 3.72 (s, 2H,
13
CH2), 7.92 (s, 1H, 5-CPyrim), 7.99 (s, 1H, NH), 9.41 (s, 1H, NH). C NMR (CF3COOD)  = 18.4 (CH3),
20.8 (CH3), 30.2 (NCH3), 57.1 (2-CH2), 98.4 (4-C), 115.5 (5-CPyrim), 160.3 (4-CPyrim), 162.2 (6-CPyrim),
163.6 (2-CPyrim), 164.6 (5-C), 186.6 (3-C=O). Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67.
Found: C, 60.39; H, 6.34; N, 25.53.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-2-methyl-1H-pyrrol-3-one (12c): (0.29 g, 54%).
Mp 100 C. 1H NMR (DMSO-d6)  = 1.19 (d, J = 7.0, 3H, 2-CH3), 2.28 (s, 3H, CH3), 2.45 (s, 3H, CH3),
3.66 (q, J = 7.0, 1H, 2-H), 7.73 (s, 1H, 1-H), 7.78 (s, 1H, NH), 7.91 (s, 1H, 5-HPyrim), 8.98 (s, 1H, NH).
13C NMR (CF3COOD)  = 15.9 (2-CH3), 18.5 (CH3), 20.9 (CH3), 58.6 (2-C), 96.5 (4-C), 115.2 (5-CPyrim),
160.1 (4-CPyrim), 162.3 (6-CPyrim), 164.4 (2-CPyrim), 165.7 (5-C), 195.1 (3-C=O). Anal. Calcd for
C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.41; H, 6.67; N, 25.60.
3-Amino-2-(2,6-dimethyl-4-pyrimidinyl)-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one (12d): (0.41 g,
67%). Mp 115 C. 1H NMR (DMSO-d6)  = 1.37 (m, 1H, 6-H), 2.04 (m, 3H, 6,7,7-H), 2.29 (s, 3H, CH3),
2.47 (s, 3H, CH3), 3.29 (m, 2H, 5-CH2) 3.84 (m, 1H, 7a-H), 7.91 (s, 1H, 5-HPyrim), 8.38 (s, 1H, NH), 9.28
(s, 1H, NH). 13C NMR (CF3COOD)  = 18.5 (CH3), 20.9 (CH3), 26.9 (6-CH2), 28.0 (7-CH2), 45.3
(5-CH2), 69.8 (7a-C), 98.8 (4-C), 115.2 (5-CPyrim), 160.0 (4-CPyrim), 162.2 (6-CPyrim), 163.8 (2-CPyrim),
164.2 (3-C), 186.4 (1-C=O). Anal. Calcd for C13H16N4O: C, 63.92; H, 6.60; N, 22.93. Found: C, 63.90; H,
6.65; N, 22.90.
5-Amino-4-(2,6-dimethyl-4-pyrimidinyl)-2,3-dihydro-2-benzylpyrrol-3-one (12e): (0.48 g, 65%). Mp
102 C. 1H NMR (DMSO-d6)  = 2.29 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.72 (dd, J2 = 13.5, J3 = 7.5, 1H,
-HR1), 3.09 (dd, J2 = 13.5, J3 = 3.5, 1H, -HR1), 3.96 (dd, J3 = 7.5, J3 = 3.5, 1H, 2-H), 7.19 (t, J = 7.0,
1H, 4-HR1), 7.23 (m, 4H, 2,3,5,6-HR1), 7.47 (s, 1H, 1-H), 7.58 (s, 1H, NH), 7.91 (s, 1H, 5-HPyrim), 8.88 (s,
1H, NH). 13C NMR (CF3COOD)  = 18.1 (CH3), 20.5 (CH3), 37.4 (-CR1), 63.5 (2-C), 96.8 (4-C), 114.3
(5-CPyrim), 127.8 (4-CR1), 128.6 (3,5-CR1), 128.7 (2,6-CR1), 133.3 (1-CR1), 159.1 (4-CPyrim), 161.7
(6-CPyrim), 163.9 (2-CPyrim), 165.7 (5-C), 192.4 (3-C=O). Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N,
19.03. Found: C, 69.59; H, 6.18; N, 19.18.
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