Microwave-assisted synthesis of substituted: 2-(benzylthio)imidazo[1,2a] pyrimidin-5-ones

Article abstract of DOI:10.1021/cc900176x

A microwave-assisted solid-phase synthesis of 2-(benzylthio)imidazo[1,2a] pyrimidin-5-ones has been developed. Using microwave irradiation, the reaction time was significantly reduced from a few days to 80 min. A representative set of 10 2-(benzylthio)-6,7-substituted-imidazo[1,2a]pyrimidin-5-ones was prepared. These compounds were subsequently N-alkylated and formylated in good yields.

Full text of DOI:10.1021/cc900176x

286
J. Comb. Chem. 2010, 12, 286–291
Microwave-Assisted Synthesis of Substituted
2-(Benzylthio)imidazo[1,2a]pyrimidin-5-ones
Chai Hoon Soh and Yulin Lam*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3, Singapore 117543
ReceiVed NoVember 15, 2009
A microwave-assisted solid-phase synthesis of 2-(benzylthio)imidazo[1,2a]pyrimidin-5-ones has been
developed. Using microwave irradiation, the reaction time was significantly reduced from a few days to 80
min. A representative set of 10 2-(benzylthio)-6,7-substituted-imidazo[1,2a]pyrimidin-5-ones was prepared.
These compounds were subsequently N-alkylated and formylated in good yields.
4-one 3a (R1) H, R2) C2H5, Scheme 1) using a conventional
Introduction
heating procedure4c that involves condensing ethyl 3-oxo-
Imidazo[1,2a]pyrimidin-5-ones constitute an interesting
class of heterocycles that possess diverse biological activi-
ties,1 and this structural motif is also present in phosphodi-
esterase inhibitors2 and benzodiazepine receptor ligands,1a
as well as gonadotrophin-releasing hormone antogonists.3
The structural feature of the imidazo[1,2-a]pyrimidine
nucleus is related to the purine and benzimidazole ring
systems, and there have been reports on 2-benzylthiobenz-
imidazole, 8-benzylthiopurine, and other benzylthio hetero-
cyclic analogs which have demonstrated stronger biological
activity than the parent compounds.4 The paucity of informa-
tion on 2-benzylthio derivatives of imidazo[1,2a]pyrimidin-
5-ones prompted us to initiate a study on the synthesis of
this class of compounds. Since the synthesis would involve
multistep reactions, which limits the synthesis of large
number of compounds if performed using solution-phase
methodology, a solid-phase approach would offer a good
pathway to a large number of these analogues. However a
major drawback of solid-phase reactions is their heteroge-
neous nature, which often results in a nonlinear kinetic
behavior and slow reaction time.5 Microwave applications
in synthesis have allowed for reaction acceleration, while
minimizing decomposition,6 and the literature also cites an
increasing number of examples of microwave-mediated
heterocyclization.7 We were thus interested to design a
synthetic strategy which would provide an expedient
preparation of 2-(benzylthio)imidazo[1,2a] pyrimidin-
5(1H)-ones 1. Herein, we describe a simple and efficient
microwave-mediated procedure for the solid-phase syn-
thesis (SPS) of 1.
pentanoate 2a with thiourea in the presence of NaOEt/EtOH
under reflux. The reaction was monitored by TLC and found
to be completed after 24 h. The crude mixture was purified
by flash chromatography (CH2Cl2/MeOH ) 30:1) to provide
3a in 75% yield. To facilitate the rapid synthesis of 3a, we
explored microwave irradiation (Table 1) and found that
compound 3a was obtained in the highest yield (83%) when
the reaction was performed in EtOH/DMF mixture at 130
°C for 30 min. S-Benzylation of 3a with benzyl bromide in
EtOH under microwave irradiation4c for 10 min at 100, 110,
and 120 °C gave 2-(benzylthio)-6-ethylpyrimidin-4-one 4 in
90%, 96%. and 90% yields, respectively. Attempts to alkylate
the N3-position of 4 with chloroacetonitrile (10 equiv) did
not provide the desired compound 5. A more reactive
bromoacetonitrile was used instead, and the reaction with 4
in the presence of TEA at 100 °C was monitored with TLC
and found to be completed after 24 h. Alkylation occurred
at two sites giving compound 5 and the O-alkylated product
Scheme 1. Solution-Phase Synthesis
Results and Discussion
Table 1. Microwave-Assisted Synthesis of 3
entry
solvent
temp (°C)
time (min)
yield (%)
Solution-Phase Synthesis. Prior to the SPS, preliminary
solution-phase studies were carried out to survey the requisite
reaction conditions and establish the modifications for the
solid-phase synthesis. For comparison purpose, we began our
investigation by synthesizing 6-ethyl-2-mercaptopyrimidin-
1
2
3
4
5
6
8
EtOH
EtOH
120
120
130
130
130
140
140
10
20
10
20
30
10
20
10
32
46
69
83
75
70
EtOH/DMFa
EtOH/DMFa
EtOH/DMFa
EtOH/DMFa
EtOH/DMFa
* To whom correspondence should be addressed. E-mail: chmlamyl@
nus.edu.sg. Fax: (65)-6779-1691.
a EtOH/DMF ) 10:1.
10.1021/cc900176x  2010 American Chemical Society
Published on Web 02/04/2010

Substituted 2-(Benzylthio)imidazo[1,2a]pyrimidin-5-ones
Table 2. Microwave-Assisted Synthesis of 5a
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 287
Scheme 2. SPS of Substituted
2-(Benzylthio)Imidazo[1,2-a]pyrimidin-5-ones
entry
solvent
temp (°C)
time (min)
yieldb (%)
5/6
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH/DMF
EtOH
EtOH
100
100
120
120
120
120
130
80
10
20
10
15
20
30
20
20
20
16
50
43
70
74
70
69
35
1:5
1:1
1:1
2:1
3:1
3:1
2:1
1:2
70
a TEA as base. b Yield of compound 5.
Table 3. Conventional and Microwave-Assisted Synthesis of
1aa
entry
base/thiolb
method
temp (°C)
time
18 h
18 h
18 h
18 h
18 h
10 min
10 min
20 min
30 min
yieldc (%)
1
2
3
4
5
6
7
8
9
4.5:5
1:1
2:2
9:10
4.5:5
4.5:5
4.5:5
4.5:5
4.5:5
heat
heat
heat
heat
heat
MW
MW
MW
MW
40b
40b
40b
40b
60b
60
50
40
40
41
10
21
40
33
esters were used to generate a representative set of 10
members of compound 1 in 35-46% overall yield (purities
of >95% by NMR), indicating an average yield of at least
70% for each step of the reaction (Figure 1).
12
61
59
To increase the diversity of compound 1, we explored the
N-alkylation of 1 using alkyl, benzyl, and allyl bromides and
sodium hydride as a base. Generally, the reaction proceeded
readily at 0 °C and provided both the N1- and N8-alkylated
regioisomers, 9i and 9ii, respectively, whose assignments
were confirmed by NOESY NMR experiments. For example
in the NOESY spectrum of compound 9ai, a clear interaction
between the 1-benzylic protons (-NCH2Ph) and 2-thiol
benzylic protons (-SCH2Ph) protons were observed, while
9aii showed a clear interaction between the 7-methyl protons
(-CH3) and the 8-benzylic protons (-NCH2Ph). Interestingly,
the alkylation preferably occurred on the N8-position with
the exception of cyclopentyl bromide where only the
formation of the N1 isomer was observed (Figure 1) and
confirmed using X-ray crystallography. This may be at-
tributed to the bulkiness of the sec-bromide, which also
provided no product when the reaction was carried out at 0
°C. Hence with cyclopentyl bromide, the reaction mixture
was heated to 80 °C, and the reaction was found to be
completed within 3 h.
a tBuOH as solvent. b The equivalents of base and thiol used were
calculated with respect to compound 5. c Temperature of water bath.
6 in 60% and 39% yields, respectively. When the same
reaction was heated in the microwave at 120 °C (Table 2,
entry 5), complete conversion was observed within 20 min
and compounds 5 and 6 was obtained in 74% and 25%
yields, respectively. Attempts to further increase the propor-
tion of 5 by varying the base (DBU, NaOEt, and TEA/KI
(cat)) did not result in any improvement in the regioselec-
tivity.
Synthesis of 2-(benzylthio)-7-ethylimidazo[1,2-a]pyrimi-
din-5(8H)-one 1a was first carried out by adapting a reported
conventional heating procedure.8 The reaction between 5 and
benzyl thiol at 40 °C for 18 h with t-butanol as solvent and
potassium tert-butoxide as a base resulted in the formation
of the 1a in 41% yield (Table 3, entry 1). Varying the base:
benzyl thiol ratio did not increase the yield of 1a (Table 3,
entries 1-4). However when the reaction was carried out
under microwave irradiation at 40 °C, it was found to be
completed after 20 min and 1a obtained in 61% yield.
Solid-Phase Synthesis. With the solution-phase pathway
evaluated, we proceeded to synthesize 1 via microwave-
assisted SPS. To explore a one-pot synthesis of resin 7
(Scheme 2) from ꢀ-keto ester 2, thiourea (3 equiv) was
treated with an equal amount of 2 to provide 5,6-disubsti-
tuted-2-mercaptopyrimidin-4-one 3, which was immediately
reacted under microwave-irradiation with bromomethyl resin
at 100 °C for 10 min to yield resin 7, whose formation was
amenable to KBr FTIR monitoring for the appearance of a
strong CdN stretch at 1670 cm-1. Resin 7 was then treated
with bromoacetonitrile (10 equiv) in the presence of TEA
(10 equiv) in a DMF/ethanol mixture to afford resin 8, which
according to FTIR analysis showed a CN stretch at
2220-2260 cm-1. Subsequent reaction of resin 8 with benzyl
thiol and t-butoxide as base under microwave irradiation at
40 °C resulted in self-cyclization with concomitant cleavage
of the solid-support to give product 1. To illustrate the
generality of this microwave-assisted reaction, various ꢀ-keto
Following N-alkylation, we examined the formylation of
compounds 1 and 9 under Vilsmeier condition (POCl3/DMF,
100 °C).3a When the reaction was carried out with
compound 9ai via conventional heating, the reaction was
found to be completed after 5 h and formylation was
observed to occur on the C6 position to give compound
10ai in 67% yield. However under microwave irradiation,
complete conversion was observed after 10 min and 10ai
was obtained in 82% yield (Figure 1). When the microwave-
assisted formylation was applied to compound 1e where
the C6 proton is absent, formylation was observed to occur
on the C3 position to afford 11ei in 90% yield. This
suggests that the C6 position is a more reactive site for
electrophilic aromatic substitution.
In summary, we have described the first example of a SPS
route to 2-(benzylthio)imidazo[1,2a] pyrimidin-5(1H)-ones.
Using microwave irradiation, we have shown that the total

288 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Soh and Lam
Figure 1. Library of substituted 2-(benzylthio)imidazo[1,2-a]pyrimidin-5-ones. For compound 1, the yields reported refer to the overall
yield, which is based on the bromomethyl resin loading. For compounds 9-11, the yields reported refer to the yields of the alkylation or
formylation reactions.
reaction time for the SPS could be shortened from a couple
of days to 80 min.
on Finnigan MAT 95/XL-T spectrometer under electron
impact (EI) or electrospray ionization (ESI) techniques.
Synthesis of 2-(Benzylthio)-6-ethylpyrimidin-4(3H)-one
4. Thiourea (2.2 mmol, 1.1 equiv) was added to a mixture
of ethyl 3-oxopentanoate (2 mmol, 1 equiv.) and 21 wt %
NaOEt in EtOH (8 mmol, 4 equiv.) in EtOH/DMF (10:1,
20 mL). The reaction mixture was heated under microwave
irradiation to 130 °C for 30 min. Benzyl bromide (2.4 mmol,
1.2 equiv) was then added, and the reaction mixture was
heated under microwave irradiation to 110 °C for another
10 min. The crude mixture was purified by flash chroma-
tography (eluent MeOH/CH2Cl2 ) 1:30) to provide 4 in 79%
overall yield. 1H NMR (300 MHz, DMSO-d6): δ 7.41-7.39
(m, 2H, ArH), 7.28-7.25(m, 3H, ArH), 5.96(s, 1H, -CH),
4.44(s, 2H,-CH2Ph), 2.53(q, 2H, -CH2CH3, J ) 7.7 Hz),
1.22 (t, 3H, -CH2CH3, J ) 7.7 Hz). HRMS (ESI, M + H)
Calcd for C13H14N2OS: 246.0827; found 246.0827.
Synthesis of 2-(2-(Benzylthio)-4-ethyl-6-oxopyrimidin-
1(6H)-yl) acetonitrile 5. Bromoacetonitrile (20 mmol, 10
equiv) was added to a reaction mixture of TEA (20 mmol,
10 equiv) and 2-(benzylthio)-6-ethylpyrimidin-4(3H)-one, 4
(2 mmol, 1equiv), using EtOH as solvent. The reaction
mixture was heated at 120 °C using microwave irradiation,
monitored with TLC, and was found to be completed after
Experimental Section
General Procedures. Bromomethyl resin was purchased
from Tianjin Nankai Hecheng Science and Technology Co.
(100-200 mesh, 1.5 mmol/g, 1% divinylbenzene cross-
linking). All other chemical reagents were purchased from
Aldrich, Merck, Lancaster, or Fluka and were used without
further purification. The microwave-assisted reactions were
performed using the Biotage Initiator microwave synthesizer
at 300 W. Analytical TLC was carried out on precoated plates
(Merck silica gel 60, F254) and visualized with UV light or
stained with ninhydrin. Flash column chromatograph was
performed with silica (Merck, 70-230 mesh).
1H NMR and 13C NMR spectra were measured at 298 K
on a Bruker ACF 300 or AMX 500 Fourier Transform
spectrometer. Chemical shifts were reported in δ (ppm),
relative to the residual undeuterated solvent which was used
an internal reference. The signals observed were described
as s (singlet), d (doublet), t (triplet), and m (multiplet). The
number of protons (n) for a given resonance was indicated
as nH. All Infrared (IR) spectra were recorded on a Bio-
Rad FTS 165 spectrometer. Mass spectra were performed

Substituted 2-(Benzylthio)imidazo[1,2a]pyrimidin-5-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 289
20 min. The crude mixture was purified by flash chroma-
tography (eluent EA/Hex ) 1:10) to obtain 5 in 74% yield.
1H NMR (300 MHz, DMSO-d6): δ 7.47-7.44 (m, 2H, ArH),
7.35-7.25 (m, 3H, ArH), 6.67 (s, 1H, -CH), 5.27 (s, 2H,
-CH2CN), 4.46(s, 2H, -CH2Ph), 2.66 (q, 2H, -CH2CH3, J
) 7.7 Hz), 1.19 (t, 3H, -CH2CH3, J ) 7.7 Hz). HRMS (ESI,
M + H) Calcd for C15H15N3NaOS: 308.0834; found 308.0834.
Synthesis of 2-(Benzylthio)-7-ethylimidazo[1,2a]pyrimi-
din-5(1H)-one 1a. Benzyl thiol (5 mmol, 5 equiv) was added
into a stirring solution of potassium tert-butoxide (4.5 mmol,
4.5 equiv) in t-butanol (10 mL). After it was stirred for 30
min, compound 5 (1 mmol, 1 equiv) was added; the reaction
mixture was heated under microwave irradiation to 40 °C,
and the reaction was found to be completed after 20 min
(monitored by TLC). The crude mixture was purified by flash
chromatography (eluent MeOH/CH2Cl2 ) 1:30) to provide
130.9 (×2), 128.4 (×2), 128.3 (×2), 112.4, 95.2, 59.6, 19.0.
HRMS (ESI, M + H) Calcd for C14H13N3OS: 272.0858;
found 272.0857.
2-(Benzylthio)-7-propylimidazo[1,2a]pyrimidin-5(1H)-
1
one 1c. H NMR (300 MHz, CD3OD): δ 7.31 (s, 1H,-CH),
7.26-7.25 (m, 5H, ArH), 5.71 (s, 1H, -CH-), 4.13 (s, 2H,
-CH2-), 2.58 (t, 2H, -CH2CH2CH3, J ) 8.0 Hz), 1.73 (q,
2H, -CH2CH2CH3, J ) 7.7 Hz), 1.00 (t, 3H, -CH2CH2CH3,
J ) 7.7 Hz). 13C NMR (75 MHz, DMSO-d6): δ 156.4, 143.7,
137.8, 129.0 (×2), 128.6 (×2) 128.4, 127.0, 106.8, 98.2,
94.4, 36.6, 34.8, 21.3, 13.3. HRMS(ESI, M + H) Calcd for
C16H17N3NaOS: 322.099; found 322.0985.
2-(Benzylthio)-7-tert-butylimidazo[1,2-a]pyrimidin-5(1H)-
one 1d. 1H NMR (300 MHz, CD3OD): δ 7.30 (s, 1H, -CH),
7.26-7.22 (m, 5H, ArH), 5.91 (s, 1H, -CH-), 4.14 (s, 2H,
-CH2-), 1.33 (s, 9H, -C(CH3)3) 13C NMR (75 MHz,
DMSO-d6): δ 171.8, 166.8, 161.4, 160.5, 136.5, 128.8, 128.4
(×2), 127.3 (×2), 103.3, 45.1, 36.8, 35.4, 28.3 (×3). HRMS
(ESI, M + H) Calcd for C17H19N3NaOS: 336.1147; found
336.1141.
1
1a in 61% yield. H NMR (300 MHz, CD2Cl2): δ 7.37(s,
1H, -CH), 7.25-7.20 (m, 5H, ArH), 5.65(s, 1H, -CH), 4.07
(s, 2H, -CH2), 2.81(q, 2H, -CH2CH3, J ) 7.6 Hz), 1.28 (t,
3H, -CH2CH3, J ) 7.7 Hz). 13C NMR (75 MHz, CD2Cl2):
δ 142.7, 137.5, 134.9 (×2), 134.5 (×2), 133.7,131.5, 123.2,
123.1, 118.2, 104.4, 50.5, 46.8, 28.3. HRMS (ESI, M + H)
Calcd for C15H15N3NaOS: 308.0834; found 308.0834.
General Procedure for Preparation of Resin 7. Thiourea
(3 equiv) was added to the respective ꢀ-keto-ester (3 equiv)
and 21% v/v NaOEt in EtOH (12 equiv) in EtOH/DMF (10/
1, 20 mL). The reaction mixture was heated microwave
irradiation to 130 °C for 30 min. Bromomethyl resin (loading
1.5 mmol/g) was swollen in DMF for 30 min and then added
to the reaction mixture. The reaction was heated under
microwave irradiation at 110 °C for another 10 min. After
which, the mixture was filtered, and the resin was washed
sequentially with DMF (20 mL × 2), H2O (20 mL × 2),
EtOH (20 mL × 2), CH2Cl2 (20 mL × 2), and ether (20 mL
× 2) and dried overnight in a vacuum oven at 40 °C to afford
resin 7.
General Procedure for Preparation of Resin 8. Resin
7 was swollen in DMF for 30 min. Thereafter, a solution of
bromoacetonitrile (10 equiv) and TEA (10 equiv) in ethanol
(30 mL) was added. The reaction mixture was heated under
microwave irradiation at 120 °C for 20 min. The resin was
then filtered, washed with DMF (20 mL × 2), EtOH (20
mL × 2), and CH2Cl2 (20 mL × 2), and dried overnight in
a vacuum oven at 40 °C to afford resin 8.
2-(Benzylthio)-6,7-dimethylimidazo[1,2-a]pyrimidin-
5(1H)-one 1e. 1H NMR (300 MHz, DMSO-d6): δ 7.33-7.28
(m, 6H, ArH + -CH), 4.20 (s, 2H, -CH2-), 2.29 (s, 3H,
-CH3), 1.93 (s, 3H, -CH3). 13C NMR (75 MHz, DMSO-
d6): δ 156.8, 147.7, 142.8, 138.0, 134.5, 128.6 (×2), 128.3
(×2), 127.0, 106.3, 100.6, 38.9, 38.7, 36.6. HRMS (ESI, M
+ H) Calcd for C15H17N3OS: 286.1014; found 286.1015.
2-(Benzylthio)-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-
1
5(1H)-one 1f. H NMR (300 MHz, CD3OD): δ 7.26-7.20
(m, 6H, ArH + -CH), 4.12 (s, 2H, PhCH2-), 2.55 (q, 2H,
-CH2CH3, J ) 7.3 Hz), 2.40 (s, 3H, -CH3), 1.08 (t, 3H,
-CH2CH3, J ) 7.3 Hz). 13C NMR (75 MHz, CD3OD): δ
156.5, 146.9, 142.6, 138.0, 128.6 (×2), 128.3 (×2), 128.1,
127.0, 107.1, 106.3, 36.5, 18.0, 17.0, 13.4. HRMS (ESI, M
+ H) Calcd C16H18N3OS: 300.1171; found 300.1171.
2-(Benzylthio)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-7-
1
methylimidazo[1,2-a]pyrimidin-5(1H)-one 1g. H NMR
(300 MHz, DMSO-d6): δ 12.62 (bs, 1H, -NH), 7.35 (s, 1H,
-CH-), 7.30-7.28 (m, 5H, ArH), 4.20 (s, 2H, -CH2-),
3.65 (t, 2H, -CH2CH2-, J ) 6.3 Hz), 2.62 (t, 2H,
-CH2CH2-, J ) 6.6 Hz), 2.34 (s, 3H, -CH3), 0.81 (s, 9H,
-SiC(CH3)3), -0.06 (s, 6H, -Si(CH3)2). 13C NMR (75 MHz,
DMSO-d6): δ 156.6, 142.7, 142.6, 137.9, 128.6 (×2), 128.3
(×2), 127.0, 106.5, 102.2, 61.2, 36.5, 38.7, 28.3, 25.7, 17.9,
17.6 (×2), -5.5 (×3). HRMS (ESI, M + H) Calcd for
C22H32N3O2SSi: 430.1984; found 430.1984.
2-(Benzylthio)-6,7-cyclopenyllimidazo[1,2-a]pyrimidin-
5(1H)-one 1h. 1H NMR (500 MHz, DMSO-d6): δ 12.8-12.9,
(bs, 1H, -NH), 7.29-7.22 (m, 5H, -ArH-), 4.19 (s, 2H,
-CH2-), 2.87-2.84 (m, 2H, -CH2CH2CH2-), 2.66-2.63 (m,
2H, -CH2CH2-), 2.07-2.01 (m, 2H, -CH2CH2CH2-). 13C
NMR (75 MHz, DMSO-d6): δ 154.4, 144.4, 137.7, 133.6,
128.6 (×2), 128.3 (×2), 127.0, 107.5, 106.7, 37.0, 32.1, 26.5,
21.6 (×2). HRMS (ESI, M - H) Calcd for C16H14N3OS:
296.0858; found 296.0844.
General Procedure for Preparation of 2-(Benzylthio)-
imidazo[1,2a]pyrimidin-5(8H)-one 1. Benzyl thiol (5 equiv)
was first added into a stirring solution of potassium tert-
butoxide (4.5 equiv) in t-butanol (10 mL) and stirred for 30
min. Resin 8 was swollen in THF for 30 min and added to
the reaction mixture. The reaction mixture was heated under
microwave irradiation to 40 °C for 20 min. The resin was
filtered and washed with methanol (20 mL × 2) and CH2Cl2
(20 mL × 2). The washings were combined with the filtrate,
concentrated to dryness and purified by column chromatography.
2-(Benzylthio)-7-methylimidazo[1,2-a]pyrimidin-5(1H)-
7-(N,N-Di-tert-butoxycarbonyl)-2-(benzylthio)-6-phe-
1
nylimidazo[1,2-a]pyrimidin-5(1H)-one 1i. H NMR (300
1
one 1b. H NMR (300 MHz, DMSO-d6): δ 13.10 (bs, 1H,
MHz, CD3OD): δ 7.46 (s, 1H, -CH), 7.36-7.24 (m, 10H,
ArH), 4.18 (s, 2H, -CH2-), 1.33 (s, 18H, -2Boc). 13C NMR
(75 MHz, DMSO-d6): δ 154.0, 151.9, 149.7, 144.2, 139.7,
136.5, 131.6, 130.8, 130.4, 129.7 (×2), 129.6, 129.5, 129.2,
NH), 7.79 (s, 1H, -CH), 7.33-7.21 (m, 5H, ArH), 5.74 (s,
1H, -CH), 4.65 (s, 2H, -CH2-), 2.34 (s, 3H, -CH3). 13C
NMR (75 MHz, DMSO-d6): δ 156.7, 153.4, 143.5, 138.5,

290 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Soh and Lam
128.8, 112.9, 112.6, 97.9, 87.4, 85.9, 78.1, 77.7 (×2), 77.3,
40.6, 40.1, 35.1, 28.7, 28.4. HRMS (ESI, M + H) Calcd for
C29H32N4OS: 54.2093; found 548.091.
-ArH), 5.95-5.88 (m, 2H, -CH + -CHdCH2-), 5.25 (d,
1H, -CHdCH2), 5.12 (d, 1H, -CHdCH2), 4.77-4.76 (m,
2H, -CH2CHdCH2), 3.95 (s, 2H, -CH2-), 2.41 (s, 3H,
-CH3). 13C NMR (75 MHz, CDCl3): δ 162.0, 155.8, 144.9,
135.7, 131.1, 128.9, 128.7, 128.4, 128.2, 124.8, 118.8, 112.5,
99.6, 45.3, 41.5, 29.6, 23.2. HRMS (ESI, M + H) Calcd for
C17H17N3OS: 312.1171; found 312.1170.
7-Amino-2-(benzylthio)-6-phenylimidazo[1,2-a]pyrimi-
din-5(1H)-one 1j. 1H NMR (300 MHz, DMSO-d6): δ
7.38-7.24(m, 11H, -ArH), 4.17(s, 2H, -CH2-), 1.60(s,
2H, -NH2). 13C NMR (75 MHz, DMSO-d6): δ 157.9, 144.9,
137.2, 134.1, 131.2, 131.0, 130.7 (×2), 129.4, 128.8 (×2),
128.5 (×2), 128.4, 127.3 (×2), 126.4, 110.4, 90.4. HRMS
(ESI, M + H) Calcd for C19H16N4OS: 348.1045; found
348.1044.
General Procedure for Alkylation of N1- and N8-
Substituted 2-(Benzylthio)Imidazo[1,2a]pyrimidin-5(8H)-
one 9i and 9ii. Sodium hydride (10 mmol, 2 equiv) was
dissolved in DMF (5 mL) and added dropwise at 0 °C to a
mixture of the respective bromide (7.5 mmol, 1.5 equiv) and
compound 1 (5 mmol, 1equiv) in DMF. The reaction was
monitored by TLC and found to be completed after 3hrs.
The crude mixture was purified by flash chromatography
(eluent EA/Hex ) 1:8) to yield 2 products, N1-substituted-
2-(benzylthio)imidazo[1,2a]pyrimidin-5(8H)-one 9i and N8-
substituted-2-(benzylthio)imidazo[1,2a]pyrimidin-5(8H)-
one 9ii.
1-Benzyl-2-(benzylthio)-7-methylimidazo[1,2-a]pyrimi-
din-5(1H)-one 9ai. 1H NMR (300 MHz, acetone-d6): δ 7.41
(s, 1H, -CH), 7.34-7.15 (m, 10H, -ArH-), 5.72 (s, 1H,
-CH), 5.24 (s, 2H, -CH2N-), 3.88 (s, 2H, -CH2S-), 2.03
(t, 3H, -CH3). 13C NMR (75 MHz, CD3OD): δ 153.7, 139.1,
137.6, 136.8, 130.0, 129.8, 129.6, 129.3, 128.6, 128.0, 127.4,
113.0, 110.6, 99.3, 98.6, 50.7, 46.7, 41.7, 38.7, 24.6, 19.3.
HRMS (ESI, M + H) Calcd for C21H19N3NaOS: 384.1147;
found 384.1141.
8-Allyl-2-(benzylthio)-7-methylimidazo[1,2-a]pyrimidin-
1
5(8H)-one 9cii. H NMR (500 MHz, CDCl3): δ 7.25-7.18
(m, 7H, -ArH), 6.02-5.95 (m, 1H, -CHdCH2), 5.72 (s,
1H, -CH), 5.30 (d, 1H, -CHdCH2), 5.12 (d, 1H,
-CHdCH2), 5.00-4.99 (m, 2H, -CH2CHdCH2), 4.20 (s,
2H, -CH2), 2.41 (s, 3H, -CH3). 13C NMR (75 MHz,
acetone-d6): δ 130.6 (×2), 130.4 (×2), 130.1, 129.8, 129.2,
128.5, 112.8, 99.3, 49.5, 45.5, 42.4, 38.7, 23.1, 19.7, 11.9.
HRMS (ESI, M + H) Calcd for C17H17N3OS: 312.1171;
found 312.1169.
2-(Benzylthio)-1-cyclopentyl-7-methylimidazo[1,2-a]py-
1
rimidin-5(1H)-one 9di. H NMR (500 MHz, CDCl3): δ
7.40-7.26 (m, 6H, -ArH), 5.93 (s, 1H, -CH-), 4.11 (s,
2H, -CH2-), 2.62 (s, 3H, -CH3), 2.22 (s, 4H, -C5H9), 2.04
(s, 3H, -C5H9), 1.80 (s, 2H, -C5H9). 13C NMR (75 MHz,
CDCl3): δ 156.4, 153.6, 141.4, 134.4, 129.2, 129.0, 128.8,
128.7, 127.3, 111.8, 100.2, 59.4, 41.4, 30.9, 30.0, 29.7, 25.2,
25.0, 20.8. HRMS (ESI, M + H) Calcd for C19H21N3NaOS:
362.1303; found 362.1301.
Synthesis of 2-(Benzylthio)-7-methyl-5-oxo-1,5-dihy-
droimidazo[1,2-a]pyrimidine-6-carbaldehyde 10ai. Phos-
phoryl trichloride (20 mmol, 10 equiv) was added to a
solution of compound 9ai (2 mmol, 1 equiv) in DMF (10
mL). The reaction mixture was heated under microwave
irradiation at 100 °C, monitored, and found to be completed
in 10 min. The product was isolated with flash chromatog-
raphy using EA/Hex 1:5 as eluent and 10ai was obtained in
82% yield. 1H NMR (300 MHz, CD3OD): δ 10.29 (bs, 1H,
-CHO), 7.59 (s, 1H, -CH-), 7.36-7.06 (m, 10H, ArH),
5.30 (s, 2H, -CH2SPh), 3.77 (s, 2H, -CH2NPh), 2.70 (s,
3H, -CH3). 13C NMR (75 MHz, DMSO-d6): δ 188.1, 168.5,
157.7, 146.2, 136.3 (×2), 135.5, 129.0, 128.7 (×2), 128.5
(×2), 127.9 (×2), 127.7, 127.2 (×2), 125.4, 112.6, 107.1,
45.4, 24.7. HRMS (ESI, M + H) Calcd C22H20N3O2S:
390.1276; found 390.1276.
8-Benzyl-2-(benzylthio)-7-methylimidazo[1,2-a]pyrimi-
1
din-5(8H)-one 9aii. H NMR (300 MHz, CDCl3): δ 7.41
(s, 1H, -CH), 7.36-7.15 (m, 10H, -ArH), 5.74 (s, 1H,
-CH), 5.62 (s, 2H, -CH2N-), 4.18 (s, 2H, -CH2S-), 2.34
(s, 3H, -CH3). 13C NMR (75 MHz, acetone-d6): δ 130.6,
130.4, 130.3 (×2), 130.1, 129.8, 129.4, 129.2, 129.1, 128.4,
128.1, 128.0, 113.6, 110.0, 99.6, 99.0, 50.8, 45.9, 42.2, 38.5,
19.9. HRMS (ESI, M + H) Calcd for C21H19N3NaOS:
384.1147; found 384.1141.
2-(Benzylthio)-7-methyl-1-propylimidazo[1,2-a]pyrimi-
din-5(1H)-one 9bi. 1H NMR (300 MHz, DMSO-d6): δ 7.31
(s, 1H, -CH), 7.30-7.17 (m, 5H, -ArH-), 5.89 (s, 1H,
-CH), 3.98 (s, 2H, -CH2S-), 3.95 (t, 2H, CH3CH2CH2N-,
J ) 7.6 Hz), 2.38 (s, 3H, -CH3), 1.76 (q, 2H,
CH3CH2CH2N-, J ) 7.6 Hz), 0.92 (t, CH3CH2CH2N-, J
) 7.6 Hz). 13C NMR (75 MHz, DMSO-d6): δ 163.8, 155.6,
145.4, 136.8, 128.9 (×2), 128.5 (×2), 127.5, 124.0, 110.5,
109.2, 97.5, 43.6, 24.2, 21.7, 10.8. HRMS (ESI, M + H)
Calcd for C17H20N3OS: 314.1327; found 314.1326.
Synthesis of 2-(Benzylthio)-6,7-dimethyl-5-oxo-5,8-
dihydroimidazo[1,2a]pyrimidine-3-carbaldehyde 11ei. Phos-
phoryl trichloride (20 mmol, 10 equiv) was added to a
solution of compound 1e (2 mmol, 1equiv) in DMF (10 mL).
The reaction mixture was heated under microwave at 100
°C, monitored, and found to be completed in 10 min. The
product was isolated with flash chromatography using EA/
1
Hex 1:5 as eluent, and 11ei was obtained in 90% yield. H
NMR (500 MHz, DMSO-d6): δ 13.30 (bs, 1H, -CHO),
2-(Benzylthio)-7-methyl-8-propylimidazo[1,2-a]pyrimi-
10.50 (bs, 1H, -NH-), 7.45-7.24 (m, 5H, ArH), 4.44(s,
1
din-5(8H)-one 9bii. H NMR (500 MHz, acetone-d6): δ
2H, -CH2SPh), 2.34(s, 3H, -CH3), 1.99(s, 3H, -CH3). 13
C
7.39-7.21 (m, 6H, ArH + -CH), 5.65 (s, 1H, -CH-),
4.28-4.25 (m, 4H, PhCH2- + -CH2CH2CH3), 2.52 (s, 3H,
-CH3), 1.93-1.85 (m, 2H, -CH2CH2CH3), 1.03 (t, 3H,
-CH2CH2CH3, J ) 4.3 Hz) 13C NMR (75 MHz, DMSO-
d6): δ 165.4, 157.5, 148.5, 138.6, 130.6, 130.1 (×2), 129.2,
125.6, 112.8, 99.3, 45.5, 42.4, 25.1, 25.0, 23.7, 11.9. HRMS
(ESI, M + H) Calcd for C17H20N3OS: 314.1327; found
314.1327.
NMR (125 MHz, DMSO-d6): δ 178.1, 158.5, 152.0, 145.9,
144.8, 137.7, 128.9 (×2), 128.4 (×2), 127.1, 121.1, 121.4,
104.7, 33.6, 16.9, 10.1. HRMS (ESI, M + H) Calcd
C16H15N3O2S: 314.0958; found 314.0955.
Acknowledgment. We thank the A*Star Biomedical
Research Council for financial support of this work (Grant
R-143-000-348-305).
1-Allyl-2-(benzylthio)-7-methylimidazo[1,2-a]pyrimidin-
5(1H)-one 9ci. 1H NMR (500 MHz, CDCl3): δ 7.46 (s, 1H,
-CH), 7.29-7.26 (m, 3H, -ArH), 7.15-7.13 (m, 2H,
1
Supporting Information Available. H and 13C NMR
spectra of compound 1a-1j, 9ai, 9aii, 9bi, 9bii, 9ci, 9cii,

Substituted 2-(Benzylthio)imidazo[1,2a]pyrimidin-5-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 291
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