Synthesis of cytosine derivatives and study of their alkylation under mild conditions

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Organic Preparations and Procedures
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Synthesis of Cytosine Derivatives and
Study of their Alkylation under Mild
Conditions
Dilip R. Birari a , Maruti G. Ghagare a , Muddassar A. Kazi a , Sandeep
M. Bagul a , Bhausaheb K. Ghotekar a , Raghunath B. Toche a
Madhukar N. Jachak a
&
a Organic Chemistry Research Centre, Department of Chemistry ,
KTHM College , Nashik, 422002, M. S., India
Published online: 20 Nov 2009.
To cite this article: Dilip R. Birari , Maruti G. Ghagare , Muddassar A. Kazi , Sandeep M. Bagul ,
Bhausaheb K. Ghotekar , Raghunath B. Toche & Madhukar N. Jachak (2009) Synthesis of Cytosine
Derivatives and Study of their Alkylation under Mild Conditions, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 41:6, 515-532
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Organic Preparations and Procedures International, 41:515–532, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903324390
Synthesis of Cytosine Derivatives and Study of their
Alkylation under Mild Conditions
Dilip R. Birari, Maruti G. Ghagare, Muddassar A. Kazi,
Sandeep M. Bagul, Bhausaheb K. Ghotekar, Raghunath B. Toche,
and Madhukar N. Jachak
Organic Chemistry Research Centre, Department of Chemistry, KTHM College,
Gangapur Road, Nashik 422002, (M. S.), India
The isolation of cytosine from the hydrolysis of calf thymus tissue in 1894 and its structure
determination in 1903,1 followed by its first synthesis from 2-ethylthiopyrimidin-4(3H)-one
are a few of the first important steps of current nucleotide chemistry. Cytosine derivatives
have gained paramount importance in the pharmaceutical sphere, particularly in cases
where no vaccination is available and prompt medical treatment is required. Hence these
derivatives are widely used as antiviral,2 anti-neoplastic,3–5 and anti-AIDS agents.6
Cytosine derivatives have been synthesized through various processes. One of the most
frequently used involves the conversion of uracil into 2,6-dichloropyrimidine, followed by
monoaminolysis to a mixture of chloropyrimidinamines. These chloropyrimidinamines are
converted into mixtures of methoxypyrimidinamines by treatment with sodium methoxide.
Isolation of the desired components is accomplished by taking advantage of the different
solubility of the individual components in dioxane followed by acid hydrolysis of iso-
lated methoxypyrimidinamines into cytosine.7 Another route starts with the conversion of
2-thiouracil into dithiouracil followed by its aminolysis into 2-thiocytosine, which upon
heating with aqueous chloroacetic acid or warming in DMSO containing a little sulfuric
acid leads to cytosine.8 Most of the synthetic endeavors towards the preparation of cytosine
involve the corresponding thio analogues.9 This suggests that there is a need for the devel-
opment of alternative efficient, commercially viable approaches towards the synthesis of
cytosine derivatives.
Several pyrimidine derivatives have recently emerged as the integral backbone
of calcium channel blockers, antihypertensive agents and antagonists.10–14 We previ-
ously reported the synthesis of 4-aryl/4-aminopyrimidines,15, 16 fused pyrimidines17 and
pyrazolo-[3,4-b]pyridines.18 Heterocycles such as pyrazoles,19–22 pyrimidines23–26 and 1,2,4
triazolo-[1,5-a] pyrimidines27 have been the subject of chemical and biological studies
Received March 20, 2009; in final form September 3, 2009.
Address correspondence to Madhukar N. Jachak, Organic Chemistry Research Centre,
Department of Chemistry, KTHM College, Gangapur Road, Nashik 422002, (M. S.), India. E-mail:
mn jachak@hotmail.com
515

516
Jachak et al.
Figure 1
due to their interesting pharmacological properties such as antipyretic,28, 29 analgesic,30
anti-inflammatory,31 potential herbicidal,32 fungicidal33, 34 and leishmanicidal activity.35, 36
Recently diethyl ethoxymethyl-enemalonate (EMME) and 2-ethoxymethylene-3-
oxobutanenitrile (Figure 1) have been used as attractive building blocks for the synthesis
of biologically relevant heterocyclic or carbocyclic compounds.37–42
Pyrimidines and triazines can easily be accessed by reaction of EMME with aliphatic or
aromatic amidines.43 Similarly pyrazoles, pyrimidines and bicyclic triazolopyrimidines are
readily synthesized by reaction of 2-ethoxymethylene-3-oxobutanenitrile with hydrazines,
amidines and aminotriazoles respectively.44 Stimulated by these findings, we explored
the application of 2-dimethyaminomethylene-3-oxobutanenitrile (1) a synthetic equiva-
lent of EMME and 2-ethoxymethylene-3-oxobutanenitrile where the two ester groups in
EMME are replaced by ketone and nitrile moieties and the ethoxy group is replaced by
the dimethylamino moiety (2-ethoxymethylene-3-oxobutanenitrile). We now report an ef-
ficient, commercially viable synthesis of some novel cytosines and studied their alkylation.
A previous communication16 described the one-pot synthesis of ureidopropeneni-
triles from benzoylacetonitrile, triethyl orthoformate and urea (and substituted ureas).
Considering the biological activities of cytosine derivatives, we undertook the synthe-
sis of new cytosine derivatives having an acetyl group at the 5-position. Thus, treat-
ment of 3-oxobutanenitrile, obtained by acid hydrolysis of β-aminocrotononitrile,45 with
dimethylformamide dimethyl acetal (DMF-DMA) furnished 2-dimethyaminomethylene-
3-oxobutanenitrile (1). Condensa-tion of 1 with urea or substituted ureas (2a–f) furnished
open-chain ureidopropenitriles 3 in 50–80% yields (Scheme 1). Compounds 3 were char-
acterized by spectral and analytical data (Tables 1 and 2).
Scheme 1
It is to be noted that the protons attached to nitrogen and the olefinic carbon in
1
compound 3 showed doubling of signals in H NMR. This type of doubling of signals

Synthesis of Cytosine Derivatives and Study of their Alkylation
517
has already been reported and discussed in the literature.46 Cyclization of 3a and 3b using
triethylamine in acetonitrile yielded 5-acetylcytosine derivatives 4a and 4b in 43–47%
yields (Scheme 2). However, 3c–f could not be cyclized to 5-acetylcytosines under these
conditions. Hence 3c–f were cyclized to 4c-f using a strong base such as t-BuOK in ethanol
at reflux temperature in 75–85% yields (Scheme 2). Treatment of 3a and 3b with sodium
methoxide in MeOH furnished 5a and 5b respectively, in 77–78% yields (Scheme 2). The
presence of the hydroxy group in 5 was detected by the FeCl3 color test for phenol and
confirmed by 13C NMR.
Scheme 2
It is interesting to note that treatment of 3a and 3b with AcOH yielded the 5-cyano-
pyrimidines 6a,b in 40–48% yields; however, this cyclization failed to occur with 3c–f.
Compounds 4–6 were characterized by IR, mass spectra, 1H NMR and 13C NMR (Table 2).
In a manner analogous to 4a, compound 4g (R = H, R1 = CH2Ph) was prepared from
3-dimethylamino-2-formyl-acrylonitrile47–49 a useful synthon for the synthesis of various
heterocycles. The N-alkylation of 4a and 4g was studied. Of the several alkylation conditions
tested, including bases such as sodium bicarbonate, potassium carbonate, sodium carbon-
ate, triethylamine, t-BuOK in solvents such as acetonitrile, dimethylformamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, toluene, the combination of DMF and K2CO3 proved
to be superior and scalable. Thus reaction of compounds 4a and 4g (1.05 equiv) with 7
proceeded smoothly (monitored by TLC) and furnished exclusively N(1) alkylated prod-
ucts 8a–n in 60–95% yields. Neither O-alkylated nor N-imino alkylated products were
obtained. The presence of the imine nitrogen in 4a and 4g was established by N-alkylation
with 2-bromo-N-phenyacetamides (7) (Scheme 3). Compounds 8a–n were characterized
by spectral and analytical data (Tables 1 and 2).

518
Jachak et al.
Scheme 3
Under similar conditions, the alkylation of cytosine 4g with alkyl halides 9a–e gave,
after quenching in ice-cold water, solids which were recrystallized from ethanol. Clean
monoalkylation of 4g occurred to afford 10a–e in 78–90% yields. Thus selectivity of the
alkylation at the N(1) position and not at the imino nitrogen was confirmed by spectroscopic
analysis (Scheme 4, Table 2).
Scheme 4
The feasibility of our approach was tested by reaction of a known cytosine, 5-
fluorocytosine 11, with a slight excess of different anilides (7) (1.05 mmole) in DMF/K2CO3
at room temperature for 8–12 h; the sole products 12a–g obtained were characterized by IR,
Mass, 1H NMR and 13C NMR, which showed that the alkylation was at N(1) nitrogen and
not at the imino nitrogen. No by-products were detected when the reaction was monitored
by TLC (Scheme 5).
In summary, we have reported a simple and convenient method to synthesize some
novel cytosine derivatives. We have reported a new series of N(1) alkylated-3-benzyl-
4-imino-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (4g) and 3-benzyl-4-imino-
2-oxo-1,2,3,4-tetrahydro-5-acetylpyrimidine (4a) by a simple, convenient and scalable
method. This transformation could be of importance to synthetic and combinatorial chemists
to generate a library of cytosine derivatives.
Experimental Section
Melting points were determined on a Buchi melting point apparatus, Mod. B-545 and
1
are uncorrected. The H (300 MHz) and 13C (75 MHz) NMR spectra (Table 2) were

Synthesis of Cytosine Derivatives and Study of their Alkylation
519
Scheme 5
recorded on a Varian XL-300MHz spectrometer. Chemical shifts are reported in parts
per million (δ ppm) relative to tetramethylsilane (TMS), and multiplicities are given as
s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). The solvents for NMR
spectra were DMSO-d6 and CDCl3 unless otherwise stated. Infrared spectra were taken on
a Thermo Electron Corporation Nicolet 380 FTIR instrument as potassium bromide pellets
unless otherwise stated. Mass spectra were recorded on Shimadzu GC-MS QP 2010A mass
spectrometer with an ionization potential of 70 eV (Table 2). All reactions were monitored
by thin layer chromatography, carried out on 0.2 mm silica gel 60 F254 (Merck) plates
using UV light (254 and 366 nm) for detection. Common reagent grade chemicals were
either commercially available or used without further purification or prepared by standard
literature procedures.
Synthesis of 3-Oxobutanenitrile
β-Aminocrotononitrile (10.0 g, 0.12 mol) was slurried in water (12.5 mL) and conc.
hydrochloric acid (12.5 mL) was added dropwise below 15◦C within 1 h. The reaction
mixture was then heated to 80◦C for 2 h. After completion of reaction (TLC check,
chloroform:methanol 9:1), the reaction mixture was cooled to room temperature and diluted
with ethyl acetate (100 mL). The insoluble materials were filtered through hyflo supercel,
the biphasic clear filtrate was separated, and the aqueous layer was extracted twice with
ethyl acetate (100 mL × 2). The combined ethyl acetate extracts were washed with saturated
sodium chloride solution and the organic layer was dried over sodium sulfate. The solvent
was removed under reduced pressure to afford crude 3-oxobutanenitrile as a light brown
oil (9.0 g, 90%), which was used in the next step for the synthesis of compound 1.
Synthesis of Dimethylaminomethylene-3-oxobutanenitrile (1)
The crude, 3-oxobutane- nitrile (9.0 g, 0.11 mol) obtained above, was dissolved in dimethyl-
formamide dimethyl acetal (20 mL) at 25◦C and stirred for 30 min. The reaction mixture was
then heated to 70–80◦C and maintained for 1 h. After completion of reaction (TLC check,
chloroform: methanol, 9:1), the reaction mixture was cooled to room temperature and the
excess dimethylformamide dimethyl acetal was distilled to give dark brown oil. The crude
oil was purified by column chromatography on silica gel (elution with dichloromethane)

520
Jachak et al.
Table 1
Yield, mps, and Elemental Analyses of Compounds
Elemental Analysis (Found)
Cmpd
Yield (%)
mp (◦C)
C
H
N
1
84
76
80
76
63
50
67
43
47
75
88
76
85
78
77
48
40
60
80
78
96
74
91
92
86
89
91
87
85
92
88
78
90
82
88
88
83
65–66
60.85 (60.85)
64.19 (64.02)
65.35 (65.30)
47.06 (47.23)
50.29 (50.35)
53.03 (52.79)
62.87 (62.82)
64.19 (63.99)
65.35 (65.30)
47.06 (47.26)
50.29 (50.46)
53.03 (53.23)
62.87 (62.82)
64.19 (64.44)
65.35 (65.47)
69.32 (69.53)
70.28 (70.08)
55.18 (55.43)
63.95 (63.82)
67.68 (67.52)
58.82 (59.04)
53.91 (54.15)
56.64 (56.62)
53.96 (54.05)
54.26 (54.39)
63.15 (63.38)
67.01 (67.31)
57.91 (58.20)
53.02 (53.27)
55.70 (55.43)
60.53 (60.29)
65.36 (65.19)
67.35 (67.50)
67.35 (67.19)
68.21 (68.00)
62.63 (62.48)
48.58 (48.80)
7.30 (7.25)
5.39 (5.42)
5.88 (6.02)
4.61 (4.60)
5.43 (5.60)
6.12 (6.03)
4.84 (4.83)
5.39 (5.15)
5.88 (6.02)
4.61 (4.71)
5.43 (5.26)
6.12 (6.34)
4.84 (4.83)
5.39 (5.13)
5.88 (5.95)
4.88 (4.77)
5.48 (5.24)
3.79 (4.06)
4.86 (4.95)
5.68 (5.79)
4.23 (4.14)
3.54 (3.36)
4.07 (4.08)
4.06 (4.16)
3.47 (3.58)
4.50 (4.68)
5.36 (5.57)
3.89 (4.16)
3.24 (3.50)
3.74 (3.49)
4.32 (4.47)
5.88 (6.07)
6.71 (6.49)
6.71 (6.45)
7.07 (7.29)
4.43 (4.55)
3.40 (3.57)
20.28 (20.25)
17.27 (17.46)
16.33 (16.54)
27.44 (27.37)
25.14 (25.30)
23.19 (22.94)
18.33 (18.26)
17.27 (17.48)
16.33 (16.56)
27.44 (27.66)
25.14 (24.86)
23.19 (23.42)
18.33 (18.26)
17.27 (17.06)
16.33 (16.51)
18.66 (18.43)
17.56 (17.84)
11.70 (11.55)
14.21 (14.13)
14.35 (14.60)
13.06 (13.25)
10.93 (11.16)
12.58 (12.32)
11.99 (12.07)
12.05 (12.31)
14.73 (14.97)
14.88 (15.16)
13.51 (13.73)
11.24 (11.49)
12.99 (12.81)
14.12 (14.25)
16.33 (16.50)
14.73 (14.50)
14.73 (14.61)
14.04 (14.26)
15.38 (15.00)
18.88 (19.11)
3a
3b
3c
3d
3e
145–146
164–165
196–198
200–201
199–200
224–225
215–216
220–221
218–219
225–226
164–165
113–114
195–196
197–198
211–212
220–221
145–146
158–160
186–187
230–231
168–170
130–131
168–170
115–117
112–114
170–172
185–187
194–196
125–127
113–115
116–118
105–107
94–96
3f
4a
4b
4c
4d
4e
4f
5a
5b
6a
6b
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
10a
10b
10c
10d
10e
12a
112–114
155–158
288–290

Synthesis of Cytosine Derivatives and Study of their Alkylation
521
Table 1
Yield, mps, and Elemental Analyses of Compounds (Continued)
Elemental Analysis (Found)
Cmpd
Yield (%)
mp (◦C)
C
H
N
12b
12c
12d
12e
12f
86
87
85
85
89
79
297–298
278–280
288–290
253–255
240–242
235–237
42.82 (43.06)
51.43 (51.32)
56.52 (56.74)
45.80 (46.04)
42.22 (42.49)
43.53 (43.79)
2.49 (2.27)
3.60 (4.45)
4.74 (4.95)
2.88 (3.01)
2.28 (2.47)
2.74 (2.87)
15.36 (15.50)
19.99 (20.20)
20.28 (20.10)
17.80 (18.00)
14.07 (14.26)
16.92 (17.14)
12g
to afford light yellow oil, which was triturated with hexane to yield a yellow solid. It was
crystallized from isopropyl alcohol (12.6 g, 84%), mp. 65–68◦C, lit.50 mp. 68◦C.
Synthesis of 2-Acetyl-3-uredopropenenitriles 3a–f. General Procedure
To a solution of 1 (10.0 g, 0.074 mol) and urea/substituted ureas 2a–f (0.079 moles) in
ethanol (250 mL), was added 7.5 mL conc. hydrochloric acid and the reaction mixture
was heated to 60–65◦C for 3 h. After completion of the reaction (TLC check, chloroform:
methanol, 9:1), the solvent was evaporated to dryness under reduced pressure. The resulting
solid obtained was stirred in cold ethanol (25 mL), collected, dried and recrystalized from
methanol: chloroform (3:2). All the compounds were obtained as colorless solids.
Synthesis of 5-Acetyl-3,4-dihydro-4-iminopyrimidin-2(1H)-one Derivatives 4a, b.
General Procedure
To a solution of 3a or 3b (0.004 mol) in acetonitrile (20 mL) was added triethylamine
(1.2 mL), and the mixture was refluxed for 24–30 h. After completion of reaction (TLC
check, chloroform: methanol, 9:1), the solvent was evaporated to dryness under reduced
pressure. The resulting solid was stirred in cold ethanol (10 mL), collected, dried and
recrystalized from methanol:chloroform (3:2). Compounds 4a and 4b were obtained as
pale yellow solids.
Synthesis of 5-Acetyl-3,4-dihydro-4-iminopyrimidin-2(1H)-one Derivatives 4c–f.
General Procedure
A solution of 3c–f (0.0021 mol) and sodium tert-butoxide (0.28 g, 0.0025 mol) in ethanol
(10 mL) was refluxed for 5–6 hrs. After completion of reaction (TLC check, chloro-
form:methanol, 9:1). The solvent was removed under reduced pressure and the oily residue
obtained was treated with acetic acid to adjust pH up to 6.5. The solids obtained were
collected, washed with ethanol and crystallized from ethanol.

522
Jachak et al.
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
1
3469, 2241,
1711, 1667
2.42(s, 3H,-CH3), 3.20(s,
3H,-NCH3), 3.4(s, 3H,
-NCH3), 7.78(s, 1H,CH).
20.11, 24.67,
108.37, 114.86
154.0, 194.9
138[M]+, 123,
95, 81, 42.
3a
3334, 3308,
2222, 1726,
1667, 1544
2.32(s, 3H, CH3), 4.45(t, 2H, 26.4, 48.9, 89.4, 243[M]+, 144,
CH2), 7.30(m, 5H, Ar-H),
8.40 & 8.00 (d, 1H, olefinic
CH, J = 12.3 & 9.9 Hz),
8.78 & 7.68(t, 1H, NH, J =
5.3 Hz & 9.3 Hz), 11.42 &
10.31(d, 1H, NH, J = 12.3
Hz & 9.9 Hz).
119.3, 126.2,
127.1, 127. 8,
128.2, 128.8,
141.7, 150.2,
151.7, 195.2.
110, 95, 68,
43.
3b
3312, 3278,
2219, 1725,
1669, 1561
2.32(s, 3H, CH3), 2.78(t, 2H, 26.3, 38.1, 42.9, 257[M]+, 144,
CH2, J = 4.8 Hz), 3.45(dt,
89.5, 115.6,
110, 95, 68,
43
2H, CH2, J = 6.0 Hz, & J = 125.4, 126.3,
4.8 Hz), 7.23 (m, 5H,
126.5, 128.3,
128.6, 140.4,
150.2, 151.3,
Ar-H), 8.40 & 8.00(d, 1H,
olefinic CH, J = 12.6 &
12.9 Hz), 8.79 & 7.70(t, 1H, 195.5.
NH, J = 6.0 Hz & 4.8 Hz),
11.32 & 10.21(d, 1H, NH, J
= 12.6 Hz & 12.9 Hz).
3c
3371, 3212,
2219, 1739,
1670, 1552
2.30(s, 3H, CH3), 6.70 (bs,1H, 25.6, 98.2, 115.0, 153[M]+, 144,
NH), 7.70(bs, 1H, NH), 8.02 155.2, 164.7,
& 8.40(d, 1H, olefinic CH, J 194.5
= 12.9 Hz)10.20 & 11.30(d,
110, 95, 68,
43.
1H, NH, J = 12.9 Hz).
3d
3317, 3276,
2218, 1711,
1661, 1573
2.3 (s, 3H, CH3), 2.7(d, 3H, J 26.2, 28.2, 88.9, 167[M]+, 110,
= 4.5Hz, CH3), 8.20 and
7.11 (bq, 1H, NH, J = 4.5
and 4.2 Hz), 8.4 and 8.0 (d,
1H, olefinic CH, J = 11.1
and 12.6 Hz), 11.4 and 10.3
(d, 1H, NH, J = 10.5 Hz).
115.6, 151.2,
152.1, 195.5,
95, 58, 43.
3e
3325, 3198,
2219, 1723,
1666, 1554
1.07(t, 3H, CH3), 2.30(s, 3H, 14.1, 26.3, 40.6, 181[M]+, 144,
CH3), 3.17(dq, 2H, CH2),
8.10 (d, 1H, olefinic CH, J
= 12.3 Hz, & 13.2 Hz),
8.32(t, 1H, NH), 11.37 &
10.23 (d, 1H, NH, J = 12.6
Hz).
88.7, 119.4,
150.1, 151.6,
195.3.
115, 106,
91, 44.

Synthesis of Cytosine Derivatives and Study of their Alkylation
523
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
3f
3296, 3224,
2218, 1721,
1671, 1544
2.32(s, 3H, CH3),
35.5, 89.2, 118.2, 229[M]+, 137,
7.50–7.47(m, 5H, Ar-H), 8.
40 & 8.10(d, 1H, olefinic
CH, J = 2.9 Hz &
124.6, 125.1,
125.1, 127.1,
127.6, 137.4,
151.2, 152.2,
195.3.
119, 110, 95,
77, 68, 43.
12.3 Hz), 9.57(s,1H, NH),
11.5 & 10.25(d, 1H, NH, J
= 12.3 Hz and 12.9 Hz)
4a
4b
3405, 3134,
1671, 1575,
1370
2.42(s, 3H, CH3), 5.18(s, 2H, 26.6, 44.5, 101.5, 243[M]+, 242,
N-CH2), 7.36–7.15 (m, 5H,
Ar-H), 8.79 (s, 1 H, olefinic
CH), 8.50(bs, 1H, NH),
10.0(bs, 1H, NH).
126.8, 127.2,
127.8, 128.2,
129.3, 138.4,
143.4, 150.1,
152.4, 197.2.
159, 138,
106, 91, 77,
55, 43.
3403, 3144,
1670, 1570,
1376
2.40(s, 3H, CH3), 2.80(t, 2H, 26.1, 36.2, 45.0, 257[M]+, 166,
CH2, J = 5.4 Hz), 4.10 (t,
2H, N-CH2, J = 5.3 Hz),
7.26–7.29
119.2, 125.4,
126.8, 128.3,
128.5, 130.2,
140.5, 154.2,
157.7, 195.2.
137, 104,
95, 77.
(m, 5H, Ar -H), 8.57 (bs,
1H, NH), 8.72(s, 1H,
olefinic, CH), 10.05(bs, 1H,
NH).
4c
3527, 3469,
3282, 3131,
1711.
3527, 3469,
3282, 3131,
1711, 1667
2.37(s, 3H, CH3), 8.72(s, 1H, 29.4, 99.2, 154.6, 153[M]+, 139,
olefinic CH), 8.57 (bs, 1H,
NH), 9.90 (bs, 2H, NH2).
2.40(s, 3H,-CH3), 3.22(s, 3H, 26.1, 29.4, 99.2, 167 [M]+,
N-CH3), 8.69(s,1H, olefinic
CH), 8.42(bs, 1H, NH),
9.80(bs, 1H, NH).
1.10(t, 3H, CH3), 2.40(s, 3H, 15.0, 26.1. 38.4, 181[M]+, 153,
CH3), 3.93(q, 2H, CH2),
8.69(s, 1H, olefinic
CH),10.05(bs, 2H, NH2).
2.42(s, 3H, CH3), 7.42–7.32 26.3, 115.2,
157.1, 164.2,
195.3.
124, 110,
95, 57, 44.
4d
154.6, 157.1,
164.2, 195.3.
152, 139,
124, 110,
95, 57, 44.
4e
4f
3325, 3198,
2219, 1723,
1666,
119.2, 140.1,
154.6, 157.1,
195.3
138, 83.
3527, 3469,
3282, 3131,
1711, 1667
229[M]+, 186,
171, 143,
77, 44.
(m, 5H, Ar-H), 7.82 (s, 1H,
olefinic CH), 8.42 (bs, 1H,
NH). 9.8(bs, 1H, NH).
119.4, 120.1,
125.1, 130.2,
131.2 134.2,
140.1, 150.1,
165.2, 198.4
(Continued on next page)

524
Jachak et al.
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
5a
3148, 1682,
1564, 1288
2.42(s, 3H, CH3), 5.10(s, 26.6, 40.2, 125.0,
243[M]+, 242,
226, 183,
159, 138,
2H, N-CH2), 7.31–7.34
(m, 5H, Ar-H), 8.72(s,
1H, olefinic CH),
126.8, 127.2,
127.4, 128.2,
128.6, 145.3,
149.4, 154.2,
164.4, 198.2
106, 91.
9.92(s, 1H, NH),
11.2(s,1H,OH).
5b
3405, 3143,
1671, 1575,
1366, 1287
2.49(s, 3H, CH3), 2.80(t, 27.1, 31.2, 40.1,
257[M]+, 166,
137, 104,
95, 77.
2H, CH2, J = 7.5 Hz),
4.20(t, 2H, N-CH2, J =
7.8 Hz), 7.20–7.34 (m,
5H, Ar-H), 8.82(s, 1H,
olefinic CH), 10.42(bs,
1H, NH), 11.60(s, 1H,
OH).
126.8, 127.4,
127.8, 128.1,
128.4, 128.6,
139.5, 148.3,
153.2, 167.7, 198.2
6a
6b
3415, 3134,
2240,
1.71(s, 3H, CH3), 5.18 (s, 16.6, 48.5, 54.5,
225[M]+, 183,
159, 138,
106, 91.
2H, N-CH2), 7.06–7.50
(m, 5H, Ar-H), 8.79(s,
1H, ArH).
97.6, 120.9, 126.8,
127.0, 128.2,
129.3, 141.5 155.0,
160.0, 164.7.
3453, 3150,
2242, 1670,
1570, 1376
1.78(s, 3H, CH3), 2.82 (t, 20.1, 33.7, 50.02,
2H, CH2, J = 5.4 Hz), 58.4, 95.4, 117.8,
239[M]+, 166,
137, 104,
95, 77.
4.15 (t, 2H, N-CH2, J = 127.1, 128.0,
6.0 Hz), 7.10–7.60(m,
5H, Ar-H), 8.60(s, 1H,
ArH).
128.4, 128.8,
130.2, 140.5,
145.2, 154.2.
8a
3464, 3268,
3196, 3122,
3075, 1696,
1658, 1597
2.50(s, 3H, CH3). 4.84(s, 30.2, 44.3, 52.8,
477(M-1),
278, 221,
195, 133, 91,
77, 65, 43.
NCH2), 5.00(s, 2H,
-N CH2), 7.26(m, 5H,
ArH), 7.29–7.70 (m,
3H, ArH) 8.15 (bs, 1H,
NH), 8.59(s, 1H,
115.1, 117.7,
120.2, 123.2,
124.1, 126.2,
126.4, 127.0,
127.2, 127.7,
128.5, 132.5,
137.1, 141.2,
150.0, 151.8,
160.4, 165.5, 198.2
olefinic CH),
10.85(bs,1H,NH).

Synthesis of Cytosine Derivatives and Study of their Alkylation
525
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
393(M-1),
8b
3455, 3266,
2.36(s, 3H,-CH3), 4.65 (s,
2H, N-CH2), 5.13(s, 2H,
-CH2), 7.25(m, 7H, Ar-H), 120.5, 121.1, 126.0, 111, 91,
7.58(m, 2H, Ar-H), 126.8, 127.4, 128.2, 77, 43.
8.50(bs, 1H, -NH), 9.63(s, 128.4, 134.5, 137.1,
26.2, 43.3, 51.8,
112.2, 115.3, 115.7, 242, 133,
3147, 3115,
3075, 1697,
1657
1H, = CH), 10.68 (bs,
149.2, 153.2, 156.2,
159.2, 165.2, 196.2
26.2, 45.3, 55.8, 389(M-1),
114.2, 115.8, 115.6, 242, 106,
121.5, 122.4, 125.8, 91, 77, 65,
1H,-NH).
8c
3451, 3274,
3149, 3111,
3077, 1691,
1654,
2.24(s, 3H, CH3), 2.36(s,
3H,CH3), 4.65(s, 2H,
N-CH2), 5.13(s, 2H,
-CH2), 7.10(d, 2H, J = 8.1 126.0, 127.2, 127.8, 43.
Hz, Ar-H), 7.25(m, 5H, 129.4, 135.5, 139.1,
Ar-H), 7.46(d, 2H, J = 8.1 148.2, 154.2, 158.2,
Hz, Ar-H), 8.51(bs,
160.2, 165.2, 198.2
1H,-NH), 9.62(s, 1H, =
CH), 10.30(bs, 1H,-NH).
2.30(s, 3H,-CH3), 4.74(s,
2H, N-CH2), 5.14(s, 2H,
-CH2), 7.20(m, 5H, Ar-H), 118.4, 122.4, 126.6, 106, 91,
7.46(m, 3H, ArH), 127.2, 127.8, 128.5, 77, 65, 43.
8.54(bs,1H, -NH), 9.60 (s, 128.8, 131.2, 132.4,
8d
8e
3457, 3280,
3144, 3118,
3078, 1695,
1654
28.2, 45.8, 53.6, 427(M-1),
113.5, 116.6, 115.2, 242, 145,
1H, = CH), 10.15(bs, 1H,
144.2, 149.4, 153.2,
160.5, 168.3, 195.8
-NH).
3485, 3288,
3145, 3110,
1690, 1655,
1591
2.32(s, 3H, -CH3), 4.82 (s, 26.2, 44.8, 54.6,
2H, N-CH2), 5.19(s, 2H, 114.2, 115.8, 117.2, 285, 257,
-CH2), 7.17(m, 5H, Ar-H), 121.8, 123.8, 124.2, 132, 124,
7.52(m, 3H, Ar-H), 124.9, 125.8, 129.2, 91, 82, 65,
8.56(bs, 1H, -NH), 9.65(s, 133.1, 133.8, 134.2, 43.
511(M-1),
1H = CH), 10.22 (bs, 1H,
138.2, 141.4, 148.8,
150.9, 151.3, 158.5,
166.8, 192.2
NH).
8f
3485, 3288,
3145, 3110,
3085, 1690,
1655,
2.36(s, 3H, -CH3) 4.76(s,
2H, N-CH2), 5.13 (s, 2H,
-CH2), 7.23(m, 5H, Ar-H), 127.2, 128.8, 129.6, 133, 123,
7.42(d, 1H, J = 8.7 Hz
Ar-H), 7.68(s, 1H,Ar-H)
7.78(d, 1H, J = 8.4 Hz,
Ar-H), 8.51(bs, 1H,-NH),
9.60(s, 1H, = CH), 10.05
(bs,1H,-NH).
26.9, 43.5, 51.3,
116.9, 124.2, 126.8, 242, 161,
443(M-1),
130.6, 131.2, 131.9, 106, 91,
133.5, 137.1, 141.2, 77, 65, 43.
148.1, 149.3, 151.9,
153.5, 168.8, 198.1.
(Continued on next page)

526
Jachak et al.
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
8g
3489, 3281,
3156, 3115,
3089, 1698,
1659,
2.36(s, 3H,-CH3), 4.66(s, 26.9, 43.7, 51.5,
410[M-1], 242,
123, 106, 91,
77, 65, 43.
2H, N-CH2), 5.13(s, 2H,
-CH2), 7.26 (m, 5H,
54.3, 106.9,
120.2, 126.9,
126.9, 127.0,
127.5, 128.6,
Ar-H), 7.38(d, 2H, J =
8.7 Hz, Ar-H), 7.60(d,
2H, J = 8.7 Hz), 8.51(bs, 128.8, 131.2,
1H, -NH), 9.60(s, 1H =
131.1, 131.9,
135.6, 137.8,
149.8, 153.9,
165.2, 195.8.
44.2, 52.1, 107.1,
117.5, 117.6,
120.6, 123.8,
124.3, 126.5,
126.9, 127.1,
128.1, 128.3,
132.2, 135.9,
137.7, 148.7,
153.8, 156.1,
165.4, 188.6
43.6, 51.8, 108.1,
115.3, 115.6,
120.8, 120.9,
126.9, 127.3,
128.1, 134.7,
136.9, 149.3,
153.2, 155.3,
156.5, 159.6,
164.9, 188.9.
20.6, 43.7, 51.8,
108.2, 119.1,
127.0, 127.4,
128.2, 129.3,
132.7, 135.9,
137.0, 149.4,
153.4, 155.4,
164.8, 189.0
CH), 10.50(bs, 1H, NH).
8h
3285, 3063,
2927, 1673,
1599, 1482
4.79(s, 2H, CH2), 5.18(s,
2H, CH2), 7.16–7.26 (m,
5H, Ar-H), 7.68-.81 (m,
3H,Ar-H), 8.18(s, 1H,
CH), 8.53(bs, 1H, NH),
9.52(s, 1H, CHO),
464[M]+
10.01(bs, 1H, NH)
8i
3468, 3287,
3162, 2770,
2720, 1699
4.66(s, 2H, CH2), 5.11(s,
2H, CH2), 7.12–7.58 (m,
9H, Ar-H), 8.24(s, 1H,
CH), 9.22(bs, 1H, NH),
9.44 (s, 1H, CHO),
380[M]+
10.44(bs, 1H, NH)
8j
3320, 3280,
3032, 1830,
1679, 1540
2.24(s, 3H, CH3), 4.65(s,
2H, CH2), 5.11(s, 2H,
CH2), 7.12(d, J = 9 Hz,
2H, Ar-H), 7.16–7.27(m,
5H, Ar-H), 7.44(d, J = 9
Hz, 2H, Ar-H),
376[M]+
8.22(s,1H, CH),
9.22(bs,1H,NH), 9.44(s,
1H, CHO),10.30(bs,1H,
NH)

Synthesis of Cytosine Derivatives and Study of their Alkylation
527
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
414[M]+
8k
3340, 3277, 4.74(s, 2H, CH2), 5.11(s,
2960, 1675, 2H, CH2), 7.18–7.53(m,
43.7, 51.4, 108.3,
115.3, 122.7, 125.5,
127.0, 127.2, 127.4,
128.2, 129.1, 129.2,
132.1, 137.0, 149.3,
153.4, 156.3, 159.7,
165.6, 189.1
43.7, 51.7, 108.2,
120.9, 121.3, 123.6,
124.5, 124.9, 125.9,
127.0, 127.4, 128.2,
128.5, 132.8, 133.3,
135.7, 136.9, 149.4,
153.2, 155.3, 167.0,
189.1
1649, 1583
8H, Ar-H), 8.26 (s, 1H,
CH), 9.20(bs, 1H, NH),
9.43(s,1H, CHO), 10.25
(bs,1H, NH)
8l
3350, 3281, 4.75(s, 2H, CH2), 5.11(s,
3052, 2847, 2H, CH2), 7.18–7.26(m,
498[M]+
1681, 1643
5H, Ar-H), 7.84(d, J = 6
Hz, 1H, Ar-H), 7.88(s,
1H, Ar-H), 8.01(d, J = 6
Hz, 1H, Ar-H), 8.22(s,
1H, CH), 9.20(bs,1H,
NH), 9.44(s,1H, CHO),
10.33(bs, 1H, NH)
8m
8n
3320, 3246, 4.77(s, 2H, CH2), 5.12(s,
3033, 2810, 2H, CH2), 7.21–7.27(m,
1671, 1582
43.6, 51.6, 93.2,
431[M+1
]
108.1, 126.8, 127.0,
127.2, 127.5, 128.0,
128.9, 129.5, 133.3,
136.9, 149.2, 153.2,
155.3, 165.8, 188.9
5H, Ar-H), 7.68–7.72(m,
3H, Ar-H), 8.27(s, 1H,
CH), 9.21(bs, 1H, NH),
9.43(s, 1H, CHO),
10.11(bs, 1H, NH)
3469, 3282, 4.68(s, 2H, CH2), 5.13(s,
3131, 1711, 2H, CH2), 7.19–7.37(m,
43.0, 51.1, 108.2,
115.0, 115.1, 120.5,
121.9, 126.5, 127.7,
128.2, 132.1, 136.1,
146.9, 153.0, 155.2,
157.2, 158.1, 164.7,
188.5
396[M]+
1667, 1556
5H, Ar-H), 7.39(d, J =
6.9 Hz, 2H, Ar-H),
7.60(d, J = 6.9 Hz, 2H,
Ar-H), 8.25(s, 1H, CH),
9.24(bs, 1H, NH), 9.45(s,
1H, CHO), 10.52(bs, 1H,
NH)
10a 3298, 2995, 1.27(t, J = 6.0 Hz, 3H,
14.2, 43.4, 44.7,
257[M]+
2971, 1697, CH3), 3.85(q, J = 6.0 Hz, 108.2, 126.7, 127.3,
1672, 1646
2H, CH2), 5.13(s, 2H,
CH2), 7.20–7.31(m, 5H,
Ar-H), 8.29(s, 1H, CH),
9.12(bs, 1H, NH), 9.43(s,
1H, CHO)
128.0, 137.1, 148.9,
153.3, 152.2, 188.7
(Continued on next page)

528
Jachak et al.
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
10b 3296, 3037, 0.92(t, J = 5.4 Hz, 3H,
13.6, 19.2, 30.6, 43.5, 285[M]+
49.2, 108.1, 126.7,
127.3, 128.0, 137.1,
149.1, 153.3, 154.4,
188.8
2957, 2863, CH3), 1.26(m, 2H, CH2),
1694, 1655
1.67(m, 2H, CH2), 3.79(t,
J = 5.4 Hz, 2H, CH2),
5.12(s, 2H, CH2),
7.19–7.28(m, 5H, Ar-H),
8.26(s, 1H, CH), 9.12(bs,
1H, NH), 9.42(s, 1H,
CHO)
10c
3294, 3037, 0.96(d, J = 6.4 Hz, 6H,
19.4, 27.7, 43.5, 56.0, 285[M]+
108.0, 126.7, 127.2,
2953, 2873, 2CH3), 2.01(m, 1H, CH),
1665, 1647
3.62(d, J = 6.4 Hz, 2H,
CH2), 5.13(s, 2H, CH2),
7.19–7.28(m, 5H, Ar-H),
8.25(s, 1H, CH), 9.13(bs,
1H, NH), 9.43(s, 1H,
CHO)
128.0, 137.1, 149.3,
153.2, 154.6, 188.9
10d 3298, 3037, 0.88(t, J = 6.2 Hz, 3H,
13.9, 21.8, 28.0, 28.2, 299[M]+
43.5, 49.4, 108.1,
2960, 1695, CH3), 1.23–1.32(m, 4H,
1666, 1649
2CH2), 1.67(m, 2H,
CH2), 3.79(t, J = 6.2 Hz,
2H, CH2), 5.12(s, 2H,
CH2), 7.20–7.28(m, 5H,
Ar-H), 8.26(s, 1H, CH),
9.12(bs, 1H, NH), 9.42(s,
1H, CHO)
126.7, 127.3, 128.0,
137.1, 149.1, 153.3,
154.4, 188.8
10e
3308, 3028, 5.11(s, 2H, CH2), 5.13(s,
1708, 1683, 2H, CH2), 7.18–7.27(m,
43.6, 52.0, 108.6,
364[M]+
123.6, 126.7, 127.2,
128.0, 128.4, 136.9,
143.7, 146.8, 149.1,
153.1, 154.4, 188.9
1517,
5H, Ar-H), 7.64(d, J =
9.0 Hz, 2H, Ar-H),
8.24(d, J = 9.0 Hz, 2H,
Ar-H), 8.46(s, 1H, CH),
9.22(bs, 1H, NH),
9.46(bs, 1H, CHO)
12a 3482, 3440, 4.45(s, 2H, CH2), 7.38(d, J 51.4, 120.4, 126.8,
296[M]+
3228, 3195, = 9.0 Hz, 2H, Ar-H),
128.6, 131.2, 131.6,
133.7, 136.8, 137.5,
154.1, 157.8, 166.1
1689
7.48(bs, 1H, NH), 7.61(d,
J = 9.0 Hz, 2H, Ar-H),
7.71(bs, 1H, NH), 7.94(d,
1H, CH), 10.37(bs, 1H,
NH)

Synthesis of Cytosine Derivatives and Study of their Alkylation
529
Table 2
IR, 1H NMR, 13C NMR, and Mass Spectra of Compounds (Continued)
Cmpd IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Mass Spectra
364[M]+
12b 3549, 3436, 4.47(s, 2H, CH2), 7.52(bs, 51.3, 115.1, 121.8,
3258, 3191, 1H, NH), 7.74(d, J = 9.6
125.1, 128.3, 131.0,
131.9, 133.5, 136.0,
137.8, 154.7, 157.5,
166.5
3058, 1697
Hz, 1H, Ar-H), 7.75(bs,
1H, NH), 8.78(d, J = 2.4
Hz, 1H, Ar-H), 7.93(d,
1H, CH), 8.18(d, J = 2.4
Hz, 1H, Ar-H), 10.70(bs,
1H,NH)
12c
3475, 3430, 4.44(s, 2H, CH2),
3269, 3218, 7.12–7.18(m, 2H, Ar-H),
51.3, 115.4, 120.6,
131.6, 133.6, 135.0,
136.8, 154.1, 156.2,
157.8, 159.4, 165.9
280[M]+
3079, 1689
7.47(bs, 1H, NH),
7.56–7.60(m, 2H, Ar-H),
7.70(bs, 1H, NH), 7.94(d,
1H, CH), 10.28(bs,
1H,NH)
12d 3462, 3444, 2.19(s, 3H, CH3), 4.44(s,
20.5, 51.3, 118.8,
276[M]+
3290, 3281, 2H, CH2), 7.12(d, J = 9.0 129.0, 131.2, 131.6,
3078, 1685
Hz, 2H, Ar-H), 7.46(d, J
= 9.0 Hz, 2H, Ar-H),
7.68(bs, 2H, NH2),
7.93(d, 1H, CH),
132.1, 133.6, 136.1,
136.8, 154.1, 157.7,
165.6
10.13(bs, 1H, NH)
3472, 3440, 4.55(s, 2H, CH2),
3285, 3078, 7.26–7.53(m, 3H, Ar-H),
12e
12f
51.7, 115.4, 122.9,
125.2, 128.6, 131.4,
132.0, 136.8, 157.5,
159.5, 164.2, 166.3
314[M]+
398[M]+
1697, 1612
7.55(bs, 1H, NH),
7.71(bs, 1H, NH), 7.96(d,
1H, CH), 10.02(bs, 1H,
NH)
3402, 3269, 4.54(s, 2H, CH2), 7.47(bs, 51.1, 121.0, 124.4,
3108, 3020, 1H, NH), 7.71(bs, 1H,
126.8, 127.2, 128.4,
131.4, 133.7, 134.0,
136.2, 139.0, 154.1,
157.6, 167.8
1687, 1650
NH), 7.78–8.12(m, 3H,
Ar-H), 8.26(d, 1H, CH),
10.10(bs, 1H, NH)
12g 3549, 3495, 4.55(s, 2H, CH2), 7.43(d, J 51.2, 126.3, 126.5,
331[M+1
]
3306, 3059, = 9.0 Hz, 1H, Ar-H),
127.4, 128.8, 129.1,
131.5, 133.7, 136.8,
154.1, 157.7, 166.7
1693, 1627
7.56(bs, 1H, NH), 7.67(s,
1H, Ar-H), 7.70(bs, 1H,
NH), 7.78(d, J = 9.0 Hz,
1H, Ar-H), 7.94(d, 1H,
CH), 9.92(bs, 1H, NH)

530
Jachak et al.
Synthesis of 1-(3-Benzyl-1, 4-dihydro-2-hydroxy-4-iminopyrimidin-5-yl)ethanone 5a–b.
General Procedure
To a solution of 3a or 3b (0.0102 mol) in methanol (50 mL), sodium methoxide (0.66 g,
0.0124 mol) was added and refluxed for 6–8 h. After completion of reaction (TLC check,
chloroform:methanol, 9:1), the solvent was removed under reduced pressure and the residue
obtained was dissolved in cold water and acidified with acetic acid to yield pale yellow
solid. Compounds 5a and 5b were crystallized from ethanol.
Synthesis of 1-Benzyl-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carbonitrile 6a, b.
General Procedure
A solution of 3a or 3b (0.004 mol) in acetic acid (10 mL) was refluxed for 24–30 h. After
completion of reaction (TLC check, chloroform: methanol, 9:1), acetic acid was removed
under reduced pressure and the residue obtained was dissolved in ethyl acetate (10 mL)
and washed with a saturated sodium chloride solution. The organic layer were dried over
sodium sulfate and evaporated under reduced pressure to give 6a–b as pale yellow solids,
which were recrystalized from ethanol.
Synthesis of (5-Acetyl-3-benzyl-3, 4-dihydro-4-imino-2-oxopyrimidin-1-(2H)-yl)-N-
phenylacetamide (8a–n and 12a–g). General Procedure
To a magnetically stirred suspension of 4a or 4g or 11 (2.1 mmol) and K2CO3 (0.28 g,
2.1 mmol) in DMF (4 mL) was added 7a–g (2.2 mmol). This suspension was further
stirred at room temperature for 9–12 hrs (TLC check, chloroform:methanol, 9:1) and the
reaction mixture was then quenched in ice-cold water. The colorless solid obtained was
collected, washed with water, dried and the solid residue obtained was recrystalized from
dichloromethane:heptane (2:8) to give 8a–n and 12a–g.
General Procedure for the Synthesis of 10a–e
A suspension of 4g (0.5 g, 2.1 mmol), K2CO3 (0.3 g, 2.1 mmol) and alkyl halides 9a–e
(2.2 mmol) in DMF (4 mL) was stirred at room temperature for 6–8 h (TLC monitoring,
mobile phase:chloroform:methanol, 9:1). Reaction mass was then quenched in ice-cold
water, solid obtained was collected, washed with water, dried and was recrystalized with
ethanol to give 10a–e in 78–90% yield.
Acknowledgements
Authors thanks to CSIR and UGC, New Delhi, India, for financial support. Thanks to Dr.
V. B. Gaikwad, Principal, KTHM College, Nashik, for facilities.
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