Synthesis of uracil derivatives and their alkylation: An approach to peptide non-nucleic acid monomers

Article abstract of DOI:10.1007/s00706-010-0280-x

N³-substituted 5-acetyluracils derived from corresponding N ³-substituted 5-acetylcytosines are versatile functional precursors that allow the introduction of various aliphatic, aromatic, carbocyclic, and carbamoyl functionalities at N¹-position. A series of 1,3-disubstituted 5-acetyluracils were synthesized by alkylation at N ¹-position. For the introduction of carbamoyl functionalities a convergent approach is studied, leading to N-arylacetamide derivatives; the linear approach furnished peptide non-nucleic acid monomers by replacement of active ester with amino acid esters in good yields.

Full text of DOI:10.1007/s00706-010-0280-x

Monatsh Chem (2010) 141:451–459
DOI 10.1007/s00706-010-0280-x
ORIGINAL PAPER
Synthesis of uracil derivatives and their alkylation: an approach
to peptide non-nucleic acid monomers
•
Madhukar N. Jachak Dilip R. Birari
•
•
•
Raghunath B. Toche Maruti G. Ghagare
Sandeep M. Bagul
Received: 5 July 2009 / Accepted: 23 February 2010 / Published online: 23 April 2010
Ó Springer-Verlag 2010
Abstract N3-substituted 5-acetyluracils derived from
corresponding N3-substituted 5-acetylcytosines are versa-
tile functional precursors that allow the introduction of
various aliphatic, aromatic, carbocyclic, and carbamoyl
functionalities at N1-position. A series of 1,3-disubstituted
5-acetyluracils were synthesized by alkylation at N1-posi-
tion. For the introduction of carbamoyl functionalities a
convergent approach is studied, leading to N-arylacetamide
derivatives; the linear approach furnished peptide non-
nucleic acid monomers by replacement of active ester with
amino acid esters in good yields.
synthesis of uracil derivatives 2 and studied their alkylation
with alkyl halide/analide/amino acids/esters. Previously we
have reported the synthesis of 4-aryl/4-aminopyrimidines
and studied their N1-alkylation reactions [22, 23].
Results and discussion
Nucleobases exist in different tautomeric forms in an
equilibrium, which is strongly dependent on the interaction
of these molecules with their environment [24–29].
Knowledge regarding this tautomerization in different
environments can provide insight into the influence of
solvent effects on molecular stability. It has also been
studied experimentally [30–32] and theoretically [33–35]
that cytosine exists primarily in two most stable tautomeric
forms, i.e., the aminooxo form (canonic form) and am-
inohydroxo form. The existence of a small amount of the
iminooxo form has been shown experimentally and theo-
retically also (Scheme 1).
Keywords Uracil ꢀ Amino acid ꢀ N1-alkylation ꢀ
Peptide non-nucleic acid monomer ꢀ Spectroscopy
Introduction
Heterocycles such as pyrimidines [1–5] and [1-2,4]triaz-
olo[1,5-a]pyrimidines [6] have been the subject of
chemical and biological studies due to their interesting
pharmacological activities such as antipyretic [7, 8], anal-
gesic [9, 10], anti-inflammatory [11, 12], potential
herbicidal [13], fungicidal [14, 15, 16], and leishmanicidal
[17, 18]. N3-substituted 5-acetyluracils could be accessed
either by cyclization of ureidomethylene-acetoacetate [19,
20] or by reaction of 1,3-oxazine-2,4-diones with amides
[21]. In this work we have developed a novel route towards
In a previous communication we described preparation
of cytosine derivatives 1a–1e having the acetyl group at
5-position and different substituents at N3-position [36]. In
this work we decided to study the amount of the iminooxo
form by converting the cytosine derivatives to uracil
derivatives 2 by an acidic hydrolysis method.
Thus, the 5-acetyluracil derivatives 2a–2e were obtained
in 76–88% yield from corresponding 5-acetylcytosines
1a–1e (Scheme 2) on treatment with 80% aqueous acetic
acid at reflux temperature. Compounds 2a–2e were
characterized by spectral and analytical methods. As an
example the 1H nuclear magnetic resonance (NMR) of
compound 2d showed appearance of a D2O exchangeable
broad singlet at 12.09 ppm. Two distinct peaks at 160.9
and 150.5 ppm for two amide carbonyls and 193.3 ppm for
M. N. Jachak (&) ꢀ D. R. Birari ꢀ R. B. Toche ꢀ
M. G. Ghagare ꢀ S. M. Bagul
Department of Chemistry, Organic Chemistry Research Center,
K.T.H.M. College, Gangapur Road, Nashik 422 002,
Maharashtra, India
e-mail: mn_jachak@hotmail.com
123

452
M. N. Jachak et al.
H
H
N
biological activities. Hence we have chosen 2d for alkyl-
ation reactions. Thus compound 2d was reacted with
alkyl halides to obtain N1-substituted compounds 4a–4j
(Scheme 3) in refluxing acetonitrile using a mildly basic
medium in 75–90% yield. Compounds 4a–4j were char-
acterized by infrared (IR), 1H and 13C NMR, and elemental
analysis. It was found that the broad singlet present in
compound 2d for NH proton at 12.0 ppm disappeared, and
the presence of two signals at 160.5 and 150.5 ppm for
amide carbonyls and one acetyl carbonyl carbon at
193.5 ppm indicated that only N-alkylated product was
obtained under these conditions.
H
H
N
H
N
N
N
N
H
O
N
O
H
N
H
O
N
H
Iminooxo form
Aminoxo form
(canonic)
Aminohydroxo form
Scheme 1
O
NH
O
O
The introduction of a carbamoyl functionality at N1-
position was achieved by alkylation of 2d with 2-bromo-N-
arylacetamide. Thus, compounds 6a–6g were obtained by
treating 2d with 2-bromo-N-arylacetamides 5a–5g in
presence of a mild base in an aprotic polar solvent such as
DMF in 75–95% yield (Scheme 4). Some workers have
noted O-alkylation in carbostyrils [59] under these reaction
conditions using crown ethers as phase-transfer catalyst. It
was also observed that, on substitution at N1-position, the
UV maximum was shifted to 292 nm when compound 2d
was substituted with a 2-methylpropyl moiety (com-
pound 4d), whereas substitution at N1-position with
N-arylacetamides showed an UV absorption peak at
286 nm (compound 6f).
R
O
R
O
80% aq. AcOH
Reflux
N
N
N
H
N
H
R =
a
b
c
d
e
CH3
1a-1e
2a-2e
CH2CH3
C6H5
CH2C6H5
CH2CH2C6H5
Scheme 2
acetyl carbonyl in 13C NMR confirmed the formation of
uracil 2d by hydrolysis of the corresponding cytosine 1d.
The ultraviolet (UV) spectrum showed two peaks at 405
and 385 nm. The rest of the spectral and analytical data are
given in the ‘‘Experimental’’ section.
Uracil derivative 2d was further N-linked with amino
acid esters 10a–10d. This involved a multistep synthesis of
11 (Scheme 5). Thus, compound 2d was reacted with ethyl
2-bromoacetate to obtain compound 7, which on basic
hydrolysis yielded acid 8. Compound 8 was then trans-
formed into an active ester 9 using N-hydroxysuccinimide
in presence of a dehydrating agent such as N,N0-dic-
ylohexylcarbodiimide (DCC). Replacement of the active
ester with ethyl esters of amino acids 10a–10d in refluxing
Tetrahydrofuran (THF) furnished the desired key inter-
mediates of peptide non-nucleic acid monomers 11a–11d
in 60–65% yield. The uracils substituted by amino acids at
N1-position have been reported by Dewar et al. [60, 61],
however their uracils are different from ours. Alternatively
compounds 11 were synthesized directly by base-catalyzed
condensation of 8 with ethyl esters of corresponding amino
acids using N-[(1H-benzotriazol-1-yl)(dimethylamino)methy-
lene]-N-methylmethanaminium tetrafluoroborate N-oxide
(TBTU) as peptide coupling reagent in 75–80% yield.
N1-Alkyl derivatives in the uracil family are of interest
because of their inherent bioactivity [37–39] or their use as
starting materials for synthesis of oligonucleotides [40, 41],
polymeric analogues of nucleic acids [42, 43], and non-
nucleoside reverse-transcripted inhibitors [44]. However,
chemoselective alkylations are a critical step and afford
mixtures of N- and O-alkylated derivatives [45–48]. Much
chemical effort has been applied to control N1-regioselec-
tivity by use of 2,4-dialkoxypyrimidines [49, 50] or their
silyloxy analogues [51–53], but little attention has been
given to the conditions for selective N1-alkylation. Liter-
ature data showed that the N/O-alkylation ratio decreases
with increasing hardness of the alkylating agent, supporting
the hypothesis of Hard Soft Acids and Bases (HSAB)
[54, 55] control in the N/O-chemoselection. Therefore we
felt that the HSAB principle could be used to drive the
N1-chemoselectivity in uracil in the presence of a mild
base. The generated uracil anion can be considered as an
ambident nucleophile operating in a polar aprotic solvent
(MeCN or N,N-dimethylformamide (DMF)). The N1 atom
is softer than the oxygen atom and attacks the soft carbon
atom of the alkylating agent in an SN2 mechanism. It was
noted [56–58] that uracils with a carbonyl group at
N1-position and benzyl at N3-position showed remarkable
The latter approach is advantageous as TBTU serves the
purpose of in situ active ester formation and dehydration.
Both unreacted (if any) compounds (2d or 10a–10d) can be
safely removed by acidic or basic washing along with the
byproduct urea giving the pure key intermediates of pep-
tide nucleic acids with superior yields at lower temperature
and lesser reaction time. All compounds 11a–11d were
characterized by spectral and analytical methods.
123

Synthesis of uracil derivatives and their alkylation
453
Scheme 3
O
O
O
O
R-X (X = I, Br, Cl)
N
3a-3j
N
K2CO3 , Acetonitrile
Reflux
N
R
O
N
H
O
2d
4a-4j
R =
a
b
c
CH3
CH2CH3
CH2CH2CH3
d
e
f
g
h
i
Isobutyl
2-Hydroxyethyl
Allyl
Cyclopentyl
Isopentyl
CH2COOCH2CH3
j
CH2CH2COOCH3
Scheme 4
O
O
O
O
O
Ar
Br
N
H
N
N
5a-5g
N
O
O
N
H
O
K2CO3, DMF, R.T.
2d
6a-6g
HN
Ar
Ar =
a
b
c
d
e
f
4-Chloro-3-(trifluoromethyl)phenyl
4-Fluorophenyl
4-Methylphenyl
2-Chloro-6-fluorophenyl
2,5-Bis(trifluoromethyl)phenyl
2,4-Dichlorophenyl
g
4-Chlorophenyl
Conclusion
using the HOSLI CH-Analyzer; the results were in agree-
ment with calculated values.
We have reported a simple and convenient method to syn-
thesize some novel uracil derivatives. This transformation
could be of importance to synthetic and combinatorial
chemists to generate an interesting library of substituted
uracils which could exhibit applications in pharmacological
activities.
General procedure for synthesis of 2a–2e
A magnetically stirred solution of 1 (4.12 mmol) in 10 cm3
80% aqueous acetic acid was heated to 110 °C and main-
tained for 20–25 h [thin-layer chromatography (TLC)
check, CHCl3:MeOH 9:1]. The reaction mixture was then
filtered through Celite, evaporated completely, and tritu-
rated with diisopropylether. The solid residue was
recrystallized from ethanol to give 2 as pale yellow solids
in 76–88% yield.
Experimental
Melting points: Gallenkamp melting point apparatus. IR
1
spectra (KBr-compression mould): Shimadzu IR-408; H
5-Acetyl-3-methylpyrimidine-2,4(1H,3H)-dione
(2a, C7H8N2O3)
NMR (300 MHz). 13C-NMR (75 MHz) spectra: Varian
XL-300, dimethyl sulfoxide (DMSO)-d6, CDCl3, tetra-
methylsilane (TMS). Mass spectra: Shimadzu GC–MS QP
2010A mass-spectral instrument with ionization potential
of 70 eV. Elemental analyses (C, H, N, S) were conducted
Yield 88%; m.p.: 218–220 °C; IR (KBr): vꢀ = 3,325, 1,711,
1
1,667, 1,605 cm-1; H NMR (DMSO-d6): d = 11.89 (bs,
1H, NH), 8.19 (s, 1H, C6H), 3.22 (s, 3H, N–CH3), 2.41 (s,
3H, CH3) ppm; 13C NMR (DMSO-d6): d = 195.3, 164.2,
123

454
M. N. Jachak et al.
O
O
O
O
O
N
Scheme 5
O
Br
N
N
O
N
H
O
K2CO3, DMF, R.T.
O
2d
7
O
1. THF/H2O
2N NaOH
2. 2N HCl
O
O
O
N
O
O
N
OH
N
O
O
N
O
O
N
O
O
O
9
DCC, DCM
N
8
OH
O
N
N
N
_
+
BF4
amino acid ester
amino acid ester
N
10a-10d
O
10a-10d
Hünig base
N
THF Reflux
TBTU
O
O
N
O
O
N
O
O
N
O
O
N
N
N
N
N
O
O
O
O
O
N
O
O
O
O
H
O
H
O
H
O
HN
HN
HN
O
O
O
O
H
HO
11a
11b
11c
11d
Amino acid ester 10
L-Phenyl alanine ethyl ester
L-Proline ethyl ester
L-Tyrosine ethyl ester
L-Norvaline ethyl ester
a
b
c
d
159.3, 157.1, 154.6, 99.2, 29.4, 26.1 ppm; EIMS: m/z
(%) = 168 (M?, 12), 152 (3), 139 (4), 124 (6), 110 (18), 95
(12), 57 (19), 44 (100).
d = 12.82 (bs, 1H, NH), 7.82 (s, 1H, C6H), 7.37–7.14 (m,
5H, Ar–H), 2.42 (s, 3H, CH3) ppm; 13C NMR (DMSO-
d6): d = 198.3, 165.2, 150.2, 140.1, 134.2, 131.2, 130.2,
125.1, 119.4, 115.2, 26.5 ppm; EIMS: m/z (%) = 230
(M?, 9), 186 (2), 137 (4), 119 (100), 110 (25), 77 (32),
44 (9).
5-Acetyl-3-ethylpyrimidine-2,4(1H,3H)-dione
(2b, C8H10N2O3)
Yield 76%; m.p.: 266–268 °C; IR (KBr): vꢀ = 3,282, 1,723,
1
1,666, 1,612 cm-1; H NMR (DMSO-d6): d = 11.85 (bs,
5-Acetyl-3-benzylpyrimidine-2,4(1H,3H)-dione
(2d, C13H12N2O3)
1H, NH), 8.24 (s, 1H, C6H), 3.93 (q, 2H, J = 6.8 Hz,
CH2), 2.42 (s, 3H, CH3), 1.10 (t, 3H, J = 6.8 Hz, CH3)
ppm; 13C NMR (DMSO-d6): d = 195.3, 157.1, 154.6,
140.1, 119.2, 38.4, 26.1, 15.0 ppm; EIMS: m/z (%) = 182
(M?, 17), 153 (23), 138 (25), 83 (38), 43 (58), 31 (100).
Yield 84%; m.p.: 156–158 °C; IR (KBr): vꢀ = 3,134, 1,724,
1,671, 1,608, 1,575 cm-1
;
1H NMR (DMSO-d6):
d = 12.09 (bs, 1H, NH), 8.10 (s, 1H, C6H), 7.29–7.25
(m, 5H, Ar–H), 4.97 (s, 2H, N–CH2), 2.45 (s, 3H, CH3)
ppm; 13C NMR (DMSO-d6): d = 193.3, 160.9, 150.5,
146.8, 136.7, 128.2, 127.4, 127.0, 110.6, 43.1, 30.2 ppm;
EIMS: m/z (%) = 244 (M?, 33), 153 (3), 132 (26), 106
(15), 91 (100), 70 (28), 65 (23), 43 (34), 31 (52).
5-Acetyl-3-phenylpyrimidine-2,4(1H,3H)-dione
(2c, C12H10N2O3)
Yield 85%; m.p.: 145–147 °C; IR (KBr): vꢀ = 3,285,
1,711, 1,667,1,615, 1,561 cm-1 1H NMR (DMSO-d6):
;
123

Synthesis of uracil derivatives and their alkylation
455
5-Acetyl-3-(2-phenylethyl)pyrimidine-2,4(1H,3H)-dione
(2e, C14H14N2O3)
(m, 2H, CH2), 0.90 (t, 3H, J = 6.4 Hz, CH3) ppm; 13C
NMR (DMSO-d6): d = 193.5, 160.5, 150.4, 136.8, 127.5,
110.7, 51.2, 43.9, 30.3, 21.7, 10.5 ppm; EIMS: m/z
(%) = 286 (M?, 26), 271 (11), 243 (2), 195 (3), 154
(14), 132 (15), 112 (11), 91 (100), 77 (13), 65 (23), 43 (28).
Yield 81%; m.p.: 172–175 °C; IR (KBr): vꢀ = 3,190, 1,726,
1,685, 1,635, 1,434 cm-1
;
1H NMR (DMSO-d6):
d = 11.98 (bs, 1H, NH), 8.05 (s, 1H, C6H), 7.28–7.21
(m, 5H, Ar–H), 3.99 (t, 2H, J = 6.0 Hz, NCH2), 2.82 (t,
2H, J = 6.0 Hz, CH2), 2.45 (s, 3H, CH3) ppm; 13C NMR
(DMSO-d6): d = 193.5, 160.8, 150.3, 146.5, 138.4, 128.5,
128.4, 126.3, 110.6, 41.3, 33.0, 30.3 ppm; EIMS: m/z
(%) = 258 (M?, 5), 138 (3), 104 (100), 91 (9), 82 (5), 65
(5), 43 (9).
5-Acetyl-3-benzyl-1-(2-methylpropyl)pyrimidine-
2,4(1H,3H)-dione (4d, C17H20N2O3)
Yield 83%; m.p.: 92–94 °C; IR (KBr): vꢀ = 1,731, 1,669,
1,627, 1,605, 1,559 cm-1; 1H NMR (DMSO-d6): d = 8.49
(s, 1H, C6H), 7.33 (m, 5H, Ar–H), 5.00 (s, 2H, N–CH2),
3.72 (d, 2H, J = 6.2 Hz, N–CH2), 2.50 (s, 3H, CH3), 1.92
(m, 1H, CH), 0.81 (d, 6H, J = 6.8 Hz, 2CH3) ppm; 13C
NMR (DMSO-d6): d = 193.5, 160.5, 150.5, 136.8, 127.4,
110.6, 56.2, 43.9, 30.3, 27.5, 19.2 ppm; EIMS: m/z
(%) = 300 (M?, 80), 285 (15), 244 (10), 168 (17), 124
(20), 106 (28), 91 (100), 82 (18), 65 (18), 41 (30).
General procedure for synthesis of 4a–4j
To a suspension of 0.2 g 2d (0.82 mmol) and 0.135 g
anhydrous potassium carbonate (0.98 mmol) in 10 cm3
acetonitrile, 3 (0.85 mmol) was added at room temperature
and refluxed for 6–8 h (TLC check, CHCl3:MeOH,
9.5:0.5). The reaction mixture was then filtered through
Celite, and the filtrate was evaporated completely. The
solid residue was recrystallized from ethanol to give 4a–4h
as colorless crystals in 75–90% yield. It was observed that
compounds 4i and 4j were obtained as oils which solidified
on standing.
5-Acetyl-3-benzyl-1-(2-hydroxyethyl)pyrimidine-
2,4(1H,3H)-dione (4e, C15H16N2O4)
Yield 79%; m.p.: 130–132 °C; IR (KBr): vꢀ = 1,733,
1
1,667, 1,625, 1,602, 1,556 cm-1; H NMR (DMSO-d6):
d = 8.40 (s, 1H, C6H), 7.30 (m, 5H, Ar–H), 5.00 (s, 2H,
N–CH2), 3.91 (bs, 2H, O–CH2), 3.60 (bs, 2H, N–CH2),
2.52 (s, 3H, CH3) ppm; 13C NMR (DMSO-d6): d = 193.5,
160.7, 151.3, 136.7, 127.6, 110.0, 58.2, 52.3, 43.9,
30.3 ppm; EIMS: m/z (%) = 288 (M?, 28), 273 (11),
156 (4), 132 (15), 124 (11), 106 (9), 91 (100), 82 (13), 65
(18), 43 (32).
5-Acetyl-3-benzyl-1-methylpyrimidine-2,4(1H,3H)-dione
(4a, C14H14N2O3)
Yield 88%; m.p.: 123–125 °C; IR (KBr): vꢀ = 1,733, 1,665,
1,622, 1,612, 1,558 cm-1; 1H NMR (DMSO-d6): d = 8.51
(s, 1H, C6H), 7.32 (m, 5H, Ar–H), 5.05 (s, 2H, N–CH2),
3.41 (s, 3H, N–CH3), 2.51 (s, 3H, CH3) ppm; 13C NMR
(DMSO-d6): d = 193.3, 161.2, 152.6, 137.2, 128.5, 110.2,
44.2, 37.4, 30.1 ppm; EIMS: m/z (%) = 258 (M?, 25), 243
(10), 167 (5), 153 (3), 126 (16), 104 (6), 91 (100), 77 (12),
65 (18), 42 (23).
5-Acetyl-3-benzyl-1-(2-propenyl)pyrimidine-2,4(1H,3H)-
dione (4f, C16H16N2O3)
Yield 88%; m.p.: 84–86 °C; IR (KBr): vꢀ = 1,735, 1,657,
1,624, 1,612, 1,566 cm-1; 1H NMR (DMSO-d6): d = 8.40
(s, 1H, C6H), 7.30 (m, 5H, Ar–H), 5.90 (m, 1H, CH), 5.20
(m, 2H, olefinic CH2), 5.00 (s, 2H, N–CH2), 4.53 (m, 2H,
N–CH2), 2.52 (s, 3H, CH3) ppm; 13C NMR (DMSO-d6):
d = 193.5, 160.5, 150.3, 149.9, 136.6, 132.4, 127.5, 118.4,
111.0, 51.2, 43.9, 30.3 ppm; EIMS: m/z (%) = 284 (M?,
29), 269 (6), 243 (3), 200 (5), 171 (2), 152 (11), 138 (34),
110 (10), 91 (100), 77 (15), 65 (31), 41 (36).
5-Acetyl-3-benzyl-1-ethylpyrimidine-2,4(1H,3H)-dione
(4b, C15H16N2O3)
Yield 70%; m.p.: 96–98 °C; IR (KBr): vꢀ = 1,734, 1,662,
1,622, 1,605, 1,561 cm-1; 1H NMR (DMSO-d6): d = 8.52
(s, 1H, C6H), 7.31 (m, 5H, Ar–H), 5.03 (s, 2H, N–CH2),
3.93 (q, 2H, J = 6.4 Hz, N–CH2), 2.51 (s, 3H, CH3), 1.23
(t, 3H, J = 6.4 Hz, CH3) ppm; 13C NMR (DMSO-d6):
d = 193.4, 160.6, 150.3, 136.7, 128.3, 110.8, 45.2, 43.8,
30.2, 14.0 ppm; EIMS: m/z (%) = 272 (M?, 40), 257 (12),
243 (7), 167 (5), 132 (18), 98 (20), 91 (100), 77 (15), 65
(20), 43 (30).
5-Acetyl-3-benzyl-1-cyclopentylpyrimidine-2,4(1H,3H)-
dione (4g, C18H20N2O3)
Yield 87%; m.p.: 94–96 °C; IR (KBr): vꢀ = 1,734, 1,668,
1,622, 1,602, 1,566 cm-1; 1H NMR (DMSO-d6): d = 8.31
(s, 1H, C6H), 7.31 (m, 5H, Ar–H), 5.00 (s, 2H, N–CH2),
4.80 (m, 1H, CH), 2.50 (s, 3H, CH3), 2.00 (m, 2H, CH2),
1.82 (m, 4H, 2CH2), 1.63 (m, 2H, CH2) ppm; 13C NMR
(DMSO-d6): d = 193.4, 160.2, 150.4, 147.0, 136.7, 127.6,
110.9, 59.8, 44.0, 30.5, 30.2, 23.6 ppm; EIMS: m/z
(%) = 312 (M?, 27), 244 (23), 229 (8), 202 (12), 180
(3), 153 (5), 132 (15), 112 (14), 106 (28), 91 (100), 65 (17),
41 (36).
5-Acetyl-3-benzyl-1-propylpyrimidine-2,4(1H,3H)-dione
(4c, C16H18N2O3)
Yield 75%; m.p.: 108–110 °C; IR (KBr): vꢀ = 1,732, 1,664,
1,624, 1,612, 1,559 cm-1; 1H NMR (DMSO-d6): d = 8.50
(s, 1H, C6H), 7.32 (m, 5H, Ar–H), 5.00 (s, 2H, N–CH2),
3.83 (t, 2H, J = 6.4 Hz, N–CH2), 2.51 (s, 3H, CH3), 1.74
123

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M. N. Jachak et al.
5-Acetyl-3-benzyl-1-(3-methylbutyl)pyrimidine-2,4(1H,3H)-
dione (4h, C18H22N2O3)
J = 3.0 Hz, Ar–H), 7.78 (dd, 1H, J = 3.0, 3.0 Hz, Ar–H),
7.70 (d, 1H, J = 9.0 Hz, Ar–H), 7.29 (m, 5H, Ar–H), 5.03
(s, 2H, CH2), 4.83 (s, 2H, N–CH2), 2.32 (s, 3H, CH3) ppm;
13C NMR (DMSO-d6): d = 193.4, 165.7, 160.4, 151.3,
150.5, 137.7, 132.2, 128.2, 127.4, 126.9, 124.3, 123.8,
120.7, 117.6, 110.7, 52.1, 44.0, 30.5 ppm; EIMS: m/z
(%) = 481 (M ? 2, 5), 479 (M?, 15), 285 (22), 257 (14),
132 (12), 124 (33), 91 (100), 82 (21), 65 (7), 43 (17).
Yield 84%; m.p.: 98–100 °C; IR (KBr): vꢀ = 1,731, 1,667,
1,625, 1,602, 1,556 cm-1; 1H NMR (DMSO-d6): d = 8.51
(s, 1H, C6H), 7.30 (m, 5H, Ar–H), 5.01 (s, 2H, N–CH2),
3.90 (t, 2H, J = 5.4 Hz, N–CH2), 2.51 (s, 3H, CH3), 1.52
(m, 3H, CH and CH2), 0.90 (d, 6H, J = 6.2 Hz, 2CH3)
ppm; 13C NMR (DMSO-d6): d = 193.5, 160.5, 150.5,
150.2, 136.7, 127.5, 110.8, 48.3, 43.9, 37.2, 30.3, 25.2,
22.2 ppm; EIMS: m/z (%) = 314 (M?, 33), 299 (9), 258
(3), 223 (27), 205 (6), 182 (8), 132 (10), 106 (14), 91 (100),
65 (12), 41 (22).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-(4-fluorophenyl)acetamide
(6b, C21H18FN3O4)
Yield 83%; m.p.: 265–267 °C; IR (KBr): vꢀ = 3,266, 1,718,
1
1,697, 1,657, 1,602, 1,542 cm-1; H NMR (DMSO-d6):
Ethyl 2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimi-
din-1(2H)-yl)acetate (4i, C17H18N2O5)
d = 10.45 (bs, 1H, NH), 8.55 (s, 1H, C6H), 7.56 (m, 2H,
Ar–H), 7.25 (m, 7H, Ar–H), 5.01 (s, 2H, N–CH2), 4.77 (s,
2H, N–CH2), 2.49 (s, 3H, –CH3) ppm; 13C NMR (DMSO-
d6): d = 193.7, 164.9, 160.9, 159.8, 156.6, 151.5, 150.6,
136.5, 134.8, 128.4, 127.5, 121.0, 115.7, 110.7, 52.1, 44.2,
30.6 ppm; EIMS: m/z (%) = 395 (M?, 11), 285 (14), 257
(9), 152 (7), 132 (7), 124 (35), 111 (11), 91 (87), 82 (17),
65 (8), 44 (25), 32 (100).
Yield 92%; m.p.: 32–34 °C; IR (KBr): vꢀ = 1,733, 1,667,
1,625, 1,602, 1,558 cm-1; 1H NMR (DMSO-d6): d = 8.51
(s, 1H, C6H), 7.36–7.15 (m, 5H, Ar–H), 5.20 (s, 2H, N–
CH2), 4.63 (s, 2H, N–CH2), 4.17 (q, 2H, J = 6.2 Hz, O–
CH2), 2.41 (s, 3H, CH3), 1.22 (t, 3H, J = 6.2 Hz, CH3)
ppm; 13C NMR (DMSO-d6): d = 194.4, 167.3, 160.3,
153.3, 149.9, 145.9, 136.9, 128.2, 127.8, 108.7, 62.5, 50.3,
44.8, 26.8, 14.3 ppm; EIMS: m/z (%) = 330 (M?, 12), 315
(3), 198 (4), 132 (17), 91 (100), 65 (18), 43 (27).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-(4-methylphenyl)acetamide
(6c, C22H21N3O4)
Methyl 3-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimi-
din-1(2H)-yl)propionate (4j, C17H18N2O5)
Yield 88%; mp 261–263 °C; IR (KBr): vꢀ = 3,274, 1,725,
1
1,691, 1,654, 1,591, 1,536 cm-1; H NMR (DMSO-d6):
Yield 95%; m.p.: 32–35 °C (n-pentane); IR (KBr):
vꢀ = 1,735, 1,662, 1,635, 1,612, 1,548 cm-1 1H NMR
;
d = 10.27 (bs, 1H, NH), 8.56 (s, 1H, C6H), 7.28 (d, 2H,
J = 5.4 Hz, Ar–H), 7.28 (m, 5H, Ar–H), 7.12 (d, 2H,
J = 8.4 Hz, Ar–H), 5.02 (s, 2H, CH2), 4.78 (s, 2H, N–CH2),
2.48 (s, 3H, CH3), 2.24 (s, 3H, CH3) ppm; 13C NMR (DMSO-
d6): d = 193.4, 164.5, 160.4, 151.4, 150.5, 136.4, 135.8,
132.5, 129.1, 128.2, 127.4, 118.9, 110.5, 51.9, 44.0, 30.5,
20.5 ppm; EIMS: m/z (%) = 391 (M?, 12), 285 (10), 257
(6), 124 (39), 107 (58), 91 (100), 82 (18), 65 (8), 43 (15).
(DMSO-d6): d = 8.50 (s, 1H, C6H), 7.36–7.15 (m, 5H, Ar–
H), 5.21 (s, 2H, N–CH2), 3.99 (t, 2H, J = 6.0 Hz, N–CH2),
3.66 (s, 3H, O–CH3), 2.80 (t, 2H, J = 6.0 Hz, CH2), 2.40
(s, 3H, CH3) ppm; 13C NMR (DMSO-d6): d = 193.4,
171.3, 160.3, 153.4, 149.2, 145.7, 136.3, 128.4, 127.2,
108.5, 62.5, 50.3, 41.6, 33.4, 30.2 ppm; EIMS: m/z
(%) = 330 (M?, 28), 315 (5), 244 (58),198 (5), 153
(5),132 (28),112 (14), 91 (100), 65 (15), 43 (24).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-(2-chloro-6-fluorophenyl)acetamide
(6d, C21H17ClFN3O4)
General procedure for synthesis of 6a–6g
Yield 96%; m.p.: 275–277 °C; IR (KBr): vꢀ = 3,118, 1,715,
To a suspension of 0.5 g 2d (2.1 mmol) and 0.3 g anhy-
drous potassium carbonate (2.1 mmol) in 10 cm3 DMF, 5
(2.2 mmol) was added and stirred for 2–3 h at room tem-
perature (TLC check, CHCl3:MeOH, 9:1). The reaction
mixture was then quenched in ice-cold water, and the
precipitated solid was filtered off, washed with water,
dried, and recrystallized from DMF:H2O 1:5 to give 6a–6g
as a white solids in 70–95% yield.
1
1,695, 1,654, 1,611, 1,538 cm-1; H NMR (DMSO-d6):
d = 10.22 (bs, 1H, NH), 8.63 (s, 1H, C6H), 7.46 (m, 8H,
Ar–H), 5.04 (s, 2H, CH2), 4.91 (s, 2H, N–CH2), 2.48 (s,
3H, CH3) ppm; 13C NMR (DMSO-d6): d = 193.4, 165.3,
160.4, 151.3, 136.4, 130.9, 128.8, 127.4, 125.7, 115.4,
110.6, 51.7, 44.0, 30.5 ppm; EIMS: m/z (%) = 431
(M ? 2, 4), 429 (M?, 12), 285 (24), 257 (15), 132 (12),
124 (37), 91 (100), 82 (23), 65 (8), 43 (18).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-[4-chloro-3-(trifluoromethyl)phenyl]acetam-
ide (6a, C22H17ClF3N3O4)
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-[2,5-bis(trifluoromethyl)phenyl]acetamide
(6e, C23H17F6N3O4)
Yield 82%; m.p.: 197–199 °C; IR (KBr): vꢀ = 3,268, 1,723,
1
1,696, 1,658, 1,597, 1,545 cm-1; H NMR (DMSO-d6):
Yield 74%; m.p.: 224–226 °C; IR (KBr): vꢀ = 3,288, 1,712,
1
1,690, 1,655, 1,591, 1,534 cm-1; H NMR (DMSO-d6):
d = 10.85 (bs, 1H, NH), 8.59 (s, 1H, C6H), 8.15 (d, 1H,
123

Synthesis of uracil derivatives and their alkylation
457
d = 10.32 (bs, 1H, NH), 8.59 (s, 1H, C6H), 8.02 (d,
J = 9.0 Hz, 1H, Ar–H), 7.91 (s, 1H, Ar–H), 7.85 (d,
J = 9.0 Hz, 1H, Ar–H), 7.28 (m, 5H, Ar–H), 5.04 (s, 2H,
CH2), 4.90 (s, 2H, N–CH2), 2.50 (s, 3H, CH3) ppm; 13C
NMR (DMSO-d6): d = 193.4, 166.8, 160.4, 151.4, 150.5,
136.5, 135.6, 133.1, 128.2, 127.7, 125.8, 124.8, 123.4,
121.1, 120.7, 110.6, 51.8, 44.0, 30.5 ppm; EIMS: m/z
(%) = 513 (M?, 28), 498 (2), 285 (6), 257 (9), 132 (24),
124 (37), 91 (100), 82 (27), 65 (9), 43 (22).
7.36–7.15 (m, 5H, Ar–H), 5.22 (s, 2H, N–CH2), 4.63 (s,
2H, N–CH2), 4.17 (q, 2H, J = 6.4 Hz, O–CH2), 2.41 (s,
3H,CH3), 1.23 (t, 3H, J = 6.4 Hz, CH3) ppm; 13C NMR
(DMSO-d6): d = 194.4, 167.3, 160.3, 153.3, 149.9, 145.9,
136.9, 128.2, 127.8, 108.7, 62.5, 50.3, 44.8, 26.8,
14.3 ppm; EIMS: m/z (%) = 330 (M?, 12), 315 (3), 198
(4), 132 (17), 91 (100), 65 (18), 43 (27).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)acetic acid (8, C15H14N2O5)
Compound 7 (6.4 g, 0.19 mol) was dissolved in 65 cm3
tetrahydrofuran and treated with 11.6 cm3 2 N NaOH
solution (0.23 mol). The reaction mixture was heated to
50 °C for 4–5 h (TLC check, CHCl3:MeOH, 9:1), and
tetrahydrofuran was evaporated under reduced pressure.
The aqueous residue was acidified with 2 N HCl to pH 1–2.
The product was extracted twice with 25 cm3 ethyl acetate;
washed with saturated sodium chloride solution, the
extracts were dried over sodium sulfate, filtered, and
evaporated under reduced pressure to obtain a colorless
solid. Yield 90%; m.p.: 35–37 °C; IR (KBr): vꢀ = 3,542,
1,725, 1,635, 1,619, 1,612, 1,514 cm-1; 1H NMR (CDCl3):
d = 8.80 (s, 1H, C6H), 7.36–7.15 (m, 5H, Ar–H), 5.20 (s,
2H, N–CH2), 4.62 (s, 2H, N–CH2), 2.43 (s, 3H, CH3) ppm;
13C NMR (DMSO-d6): d = 195.8, 168.4, 154.8, 152.1,
148.5, 135.3, 127.8, 104.4, 59.4, 50.8, 44.7, 30.7,
27.0 ppm; EIMS: m/z (%) = 302 (M?, 12), 287 (3), 170
(5), 132 (12), 106 (8), 91 (70), 82 (14), 65 (17), 43 (100),
31 (65).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-(2,4-dichlorophenyl)acetamide
(6f, C21H17Cl2N3O4)
Yield 91%; m.p.: 254–256 °C; IR (KBr): vꢀ = 3,285, 1,722,
1
1,687, 1,645, 1,581, 1,531 cm-1; H NMR (DMSO-d6):
d = 10.11 (bs, 1H, NH), 8.60 (s, 1H, C6H), 7.75 (m, 2H,
Ar–H), 7.40 (d, 1H, J = 8.4 Hz, Ar–H), 7.28 (m, 5H, Ar–
H), 5.03 (s, 2H, CH2), 4.91 (s, 2H, N–CH2), 2.51 (s, 3H,
CH3) ppm; 13C NMR (DMSO-d6): d = 193.3, 165.8,
160.4, 151.4, 136.4, 133.3, 129.4, 128.9, 127.4, 126.7,
110.6, 51.9, 44.0, 30.5 ppm; EIMS: m/z (%) = 449
(M ? 4, 9), 447 (M ? 2, 4), 445 (M?, 13), 285 (32),
257 (20), 132 (18), 124 (39), 110 (5), 91 (100), 82 (20), 65
(8), 43 (11).
2-(5-Acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimidin-
1(2H)-yl)-N-(4-chlorophenyl)acetamide
(6g, C21H18ClN3O4)
Yield 92%; m.p.: 233–235 °C; IR (KBr): vꢀ = 3,281, 1,724,
1
1,698, 1,659, 1,593, 1,529 cm-1; H NMR (DMSO-d6):
d = 10.50 (bs, 1H, NH), 8.57 (s, 1H, C6H), 7.57 (d, 2H,
J = 6.6 Hz, Ar–H), 7.38 (d, 2H, J = 6.8 Hz, Ar–H), 7.28
(m, 5H, Ar–H), 5.02 (s, 2H, -CH2), 4.78 (s, 2H, N–CH2),
2.48 (s, 3H, CH3) ppm; 13C NMR (DMSO-d6): d = 193.4,
165.0, 165.0, 160.4, 151.4, 150.4, 137.3, 136.4, 127.5,
120.5, 110.6, 52.1, 44.0, 30.5 ppm; EIMS: m/z (%) = 413
(M ? 2, 3), 411 (M?, 9), 285 (12), 257 (5), 127 (11), 124
(39), 110 (6), 91 (100), 82 (16), 65 (7), 43 (13).
2,5-Dioxo-1-pyrrolidinyl 2-(5-acetyl-3-benzyl-3,4-dihydro-
2,4-dioxopyrimidin-1(2H)-yl)acetate (9, C19H17N3O7)
N-Hydroxysuccinimide (0.41 g, 3.6 mmol) was added
slowly under stirring to a solution of 1.0 g 8 (3.3 mmol)
in 20 cm3 dry tetrahydrofuran at 0 °C. Then a solution of
0.74 g N,N’-dicylohexylcarbodiimide (3.6 mmol) in 5 cm3
dichloromethane was added at 0–5 °C dropwise under
stirring, which formed white crystalline N,N0-dicyclohex-
ylurea. The mixture was stirred at 0–5 °C for 14–15 h and
then filtered to remove the urea byproduct. The filtrate was
evaporated completely and redissolved in dichloromethane.
The solution was again filtered to remove the insoluble
material and evaporated completely to obtain a viscous oil,
which was purified by column chromatography, eluting
with dichloromethane. The desired fractions were collected
and evaporated under reduced pressure to obtain a colorless
solid. Yield 35%; m.p.: 32–35 °C; IR (KBr): vꢀ = 1,815,
1,786, 1,747, 1,663, 1,623, 1,597 cm-1; 1H NMR (DMSO-
d6): d = 7.62 (s, 1H, C6H), 7.33 -7.21 (m, 5H, Ar–H), 5.31
(s, 2H, N–CH2), 4.53 (s, 2H, N–CH2), 3.80 (s, 4H, 2CH2),
2.31 (s, 3H, CH3) ppm; 13C NMR (CDCl3): d = 194.5,
167.8, 153.3, 149.9, 145.9, 136.8, 128.2, 108.7, 53.2, 50.1,
44.8, 26.7 ppm; EIMS: m/z (%) = 399 (M?, 2), 181 (8),
Ethyl 2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrimi-
din-1(2H)-yl)acetate (7, C17H18N2O5)
To a suspension of 5 g 2d (0.20 mol) and 3.3 g anhydrous
potassium carbonate (0.024 mol) in 100 cm3 DMF, 4.0 g
ethyl 2-bromoacetate (0.024 mol) was added and stirred for
3 h at room temperature (TLC check, CHCl3:MeOH, 9:1).
The reaction mixture was then quenched in ice-cold water
and extracted twice with 50 cm3 ethyl acetate. The ethyl
acetate layer was washed with saturated sodium chloride
solution and dried over sodium sulfate. The solvent was
evaporated under reduced pressure. On trituration in n-
pentane at 5–10 °C a white precipitate was obtained,
filtered, and dried under reduced pressure. Yield 92%;
m.p.: 32–34 °C; IR (KBr): vꢀ = 1,733, 1,667, 1,625, 1,602,
1,558 cm-1; 1H NMR (DMSO-d6): d = 8.52 (s, 1H, C6H),
123

458
M. N. Jachak et al.
157 (4), 144 (28), 115 (19), 106 (22), 91 (100), 77 (16), 65
(17).
Ar–H), 5.02 (s, 2H, N–CH2), 4.81 (s, 2H, N–CH2), 4.29
(dd, 1H, J = 8.4, 8.0 Hz, CH), 4.21 (q, 2H, J = 7.1 Hz,
ester O–CH2), 3.11 (m, 2H, ring CH2), 2.42 (m, 5H, ring
CH2, acetyl CH3), 2.10 (m, 2H, ring CH2), 1.29 (t, 3H,
J = 7.1 Hz, ester CH3) ppm; 13C NMR (DMSO-d6):
d = 193.7, 171.5, 167.7, 162.3, 154.6, 151.4, 136.4,
128.4, 126.5, 114.6, 65.7, 61.2, 53.9, 49.6, 46.9, 28.9,
24.7, 14.1 ppm; EIMS: m/z (%) = 427 (M?, 14), 285 (54),
257 (12), 142 (38), 124 (42), 91 (100), 43 (36).
General procedure for synthesis of 11a–11d
Method A
To a suspension of 0.5 g 8 (0.002 mol) and 0.64 g TBTU
(0.002 mol) in 20 cm3 dichloromethane, 10 (0.002 mol) was
added at room temperature. To this was added a solution of
0.774 g N,N-diisopropylethylamine (0.006 mol) in 10 cm3
dichloromethane dropwise at room temperature. The reac-
tion mixture was stirred for 2 h (TLC check, CHCl3:MeOH,
8:2). The reaction mass was then washed twice with 20 cm3
water followed by 20 cm3 1% phosphoric acid, 20 cm3 sat-
urated sodium bicarbonate solution, and finally with 20 cm3
saturated sodium chloride solution. The dichloromethane
layer was dried over sodium sulfate, filtered, and evaporated
under reduced pressure to obtain 11 in 78–90% yield.
Ethyl 2-[[2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyr-
imidin-1(2H)-yl)-1-oxoethyl]amino]-3-(4-hydroxy-
phenyl)propionate (11c, C26H27N3O7)
Method A: yield 88%; method B: 8 h reflux, yield 60%;
m.p.: 43–45 °C; IR (KBr): vꢀ = 3,263, 1,746, 1,685, 1,667,
1,632, 1,602, 1,538 cm-1; 1H NMR (DMSO-d6): d = 10.56
(bs, 1H, NH), 8.61 (s, 1H, C6H), 7.13 (m, 7H, Ar–H), 7.35
(d, 2H, Ar–H), 5.02 (s, 2H, N–CH2), 4.82 (s, 2H, N–CH2),
4.74 (dd, 1H, J = 8.4, 8.0 Hz, CH), 4.27 (q, 2H,
J = 7.0 Hz, ester O–CH2), 3.23 (dd, 1H, J = 5.5, 5.5 Hz,
Bn–Ha), 2.85 (dd, 1H, J = 8.2, 8.3 Hz, Bn–Hb), 2.4 (s, 3H,
acetyl CH3), 1.25 (t, 3H, J = 7.0 Hz, ester CH3) ppm; 13C
NMR (DMSO-d6): d = 194.4, 174.3, 170.8, 162.2, 154.9,
151.5, 141.1, 139.7, 128.8, 127.4, 114.2, 55.1, 53.4, 44.5,
36.4, 25.5 ppm; EIMS: m/z (%) = 517 (M?, 8), 479 (22),
373 (22), 341 (9), 317 (11), 302 (28), 277 (36), 245 (39),
234 (7), 219 (9), 124 (23), 91 (100), 77 (25), 43 (31).
Method B
To a suspension of 0.2 g 9 (0.5 mmol) in 10 cm3 tetrahy-
drofuran, 10 (0.55 mmol) was added and stirred at reflux
temperature for 6–8 h (TLC check, CHCl3:MeOH, 8:2).
The reaction mixture was filtered through Celite, the filtrate
was evaporated under reduced pressure, and the residue
was purified by column chromatography eluting with
dichloromethane to furnish 11 in 60–65% yield.
Ethyl 2-[[2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyr-
imidin-1(2H)-yl)-1-oxoethyl]amino]pentanoate
(11d, C22H27N3O6)
Ethyl 2-[[2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyr-
imidin-1(2H)-yl)-1-oxoethyl]amino]-3-phenylpropionate
(11a, C26H27N3O6)
Method A: yield 78%; method B: 7 h reflux, yield 65%;
Method A: yield 83%; method B: 7 h reflux, yield 62%;
m.p.: 63–65 °C; IR (KBr): vꢀ = 3,258, 1,729, 1,685, 1,654,
m.p.: 36–38 °C; IR (KBr): vꢀ = 3,266, 1,736, 1,697, 1,666,
1,624, 1,615, 1,541 cm-1
;
1H NMR (DMSO-d6):
1,622, 1,605, 1,548 cm-1
;
1H NMR (DMSO-d6):
d = 10.52 (bs, 1H, NH), 8.70 (s, 1H, C6H), 7.26 (m, 5H,
Ar–H), 5.18 (s, 2H, N–CH2), 4.78 (s, 2H, N–CH2), 4.51
(dd, 1H, J = 8.4, 8.0 Hz, CH), 4.21 (q, 2H, J = 7.1 Hz,
ester O–CH2), 2.42 (s, 3H, acetyl CH3), 1.90 (q, 2H,
J = 5.4 Hz, CH2), 1.33 (m, 2H, CH2), 1.29 (t, 3H,
J = 7.1 Hz, ester CH3), 0.90 (t, 3H, J = 5.4 Hz, CH3)
ppm; 13C NMR (DMSO-d6): d = 193.7, 171.5, 170.7,
162.3, 154.6, 151.4, 136.4, 126.7, 114.6, 61.3, 56.1, 55.9,
46.9, 28.9, 18.8, 14.1, 13.8 ppm; EIMS: m/z (%) = 429
(M?, 9) 285 (22), 257 (5), 144 (2), 91 (100), 65 (9), 43 (9).
d = 10.50 (bs, 1H, NH), 8.62 (s, 1H, C6H), 7.33 (m, 5H,
Ar–H), 7.10 (m, 5H, Ar–H), 5.03 (s, 2H, N–CH2), 4.82 (s,
2H, N–CH2), 4.72 (dd, 1H, J = 8.4, 8.0 Hz, CH), 4.20 (q,
J = 7.1 Hz, 2H, ester O–CH2), 3.13 (dd, 1H, J = 5.5,
5.5 Hz, Bn-Ha), 2.91 (dd, 1H, J = 8.2, 8.3 Hz, Bn-Hb),
2.41 (s, 3H, acetyl CH3), 1.22 (t, 3H, J = 7.1 Hz, ester
CH3) ppm; 13C NMR (DMSO-d6): d = 194.7, 174.8,
170.7, 154.6, 162.3, 151.4, 141.6, 139.4, 128.4, 127.5,
114.6, 55.2, 53.6, 44.4, 36.6, 25.7 ppm; EIMS: m/z
(%) = 477 (M?, 27), 404 (8), 285 (58), 257 (62), 233
(29), 176 (52), 148 (67), 124 (53), 104 (61), 91 (100), 82
(67), 65 (54), 43 (58).
Acknowledgments The authors gratefully acknowledge financial
support of this project by UGC, New Delhi, India. Also we thanks
Principal, K.T.H.M. College, Nashik, 422 002 for facilities.
Ethyl 1-[2-(5-acetyl-3-benzyl-3,4-dihydro-2,4-dioxopyrim-
idin-1(2H)-yl)-1-oxoethyl]pyrrolidine-2-carboxylate
(11b, C22H25N3O6)
References
Method A: yield 84%; method B: 6 h reflux, yield 63%;
m.p.: 33–35 °C; IR (KBr): vꢀ = 3,263, 1,726, 1,687, 1,652,
1. Ishibuchi S, Morimoto H, Oe T, Ikebe T, Inoue H, Fukunari A,
Kamezawa M, Yamada I, Naka Y (2001) Bioorg Med Chem Lett
11:879
1,612, 1,595, 1,542 cm-1
;
1H NMR (DMSO-d6):
d = 10.48 (bs, 1H, NH), 8.71 (s, 1H, C6H), 7.36 (m, 5H,
123

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