Catalyst-free tandem Michael addition-cyclization reactions in aqueous media for the synthesis of benzimidazo[1,2-a]pyrimidinone derivatives

Article abstract of DOI:10.1007/s11426-010-4033-9

The catalyst-free reactions of Baylis-Hillman alcohols (1a-i) with 2-aminobenzimidazole (2) in THF-H₂O (1:4) were developed for the convenient and greener synthesis of benzimidazo[1,2-a]pyrimidinone derivatives (3a-i). The pesticidal activities of 3a-i were examined to investigate a new biological activity of the imidazo[1,2-a]pyrimidinone-type compounds.

Full text of DOI:10.1007/s11426-010-4033-9

SCIENCE CHINA
Chemistry
July 2010 Vol.53 No.7: 1492–1496
doi: 10.1007/s11426-010-4033-9
• ARTICLES •
Catalyst-free tandem Michael addition-cyclization reactions
in aqueous media for the synthesis of
benzimidazo[1,2-a]pyrimidinone derivatives
REN ChuanLi, WANG Yan, WANG Dong, CHEN YongJun & LIU Li*
Beijing National Laboratory (BNLMS), CAS Key Laboratory for Molecular Recognition and Function; Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
Received March 22, 2010; accepted June 13, 2010
The catalyst-free reactions of Baylis-Hillman alcohols (1a–i) with 2-aminobenzimidazole (2) in THF-H2O (1:4) were devel-
oped for the convenient and greener synthesis of benzimidazo[1,2-a]pyrimidinone derivatives (3a–i). The pesticidal activities
of 3a–i were examined to investigate a new biological activity of the imidazo[1,2-a]pyrimidinone-type compounds.
aqueous media, Baylis-Hillman alcohol, 2-aminobenzimidazole, pesticidal activity
erocyclic compounds, which subsequently transform to their
derivatives.
1 Introduction
There has been growing interest in studying organic re-
actions in aqueous media [12–14]. The use of water is due
to its natural abundance as well as the inherent advantages
of using water as a solvent. It was observed in numerous
reports that water played a significant role for the accelera-
tion of the reaction. Recently, the efficient synthesis of het-
erocyclic compounds in aqueous media through multi-steps
in a one-pot process has also been of much interest [15, 16].
However, to our knowledge, there are few reports on the
aqueous synthesis of fused heterocyclic compounds through
tandem multi-step reactions without any catalysts and addi-
tives in a one-pot process.
To continue our interest in aqueous organic synthesis
[17–19] and the synthesis of biologically active heterocyclic
compounds [20, 21], herein, we report catalyst-free Michael
addition-cyclization tandem reactions of Baylis-Hillman
alcohols with 2-aminobenzoimidazole in aqueous media
(THF/H2O = 1:4), which was applied to the synthesis of
benzimidazo[1,2-a]pyrimidinone derivatives in a one-pot
process. In order to evaluate new biological activities, ex-
cept pharmaceutical activity, possessed by imidazo[1,2-a]
Imidazo[1,2-a]pyrimidines are significant compounds in
pharmaceutical chemistry [1–3]. Among them, benzimidazo
[1,2-a]pyrimidinone and its derivatives have attracted con-
siderable attention due to their various biological activities
[4–6]. Although several approaches have been used in the
synthesis of benzimidazo[1,2-a]pyrimidinones [6–9], search-
ing for new types of substrates to enhance the diversity and
new synthetic methods to synthesize benzimidazo[1,2-a]
pyrimidinone compounds is still required.
Because the three chemospecific groups, the hydroxyl,
double bond and carbonyl group, exist closely in one mole-
cule, the Baylis-Hillman alcohol is useful in a lot of special
chemical transformations through appropriate tuning of
these groups. The Baylis-Hillman adducts were illustrated
as valuable precursors for the synthesis of heterocycles and
many biologically active molecules [10, 11]. The combina-
tion of 2-aminobenzimidazole with Baylis-Hillman alcohols
may be an efficient and convenient method to prepare het-
*Corresponding author (email: lliu@iccas.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
www.springerlink.com

REN ChuanLi, et al. Sci China Chem July (2010) Vol.53 No.7
1493
pyrimidinone-type compounds, the test of pesticidal activity
was conducted.
X-80. The final concentration was 100 and 500 mg/L, re-
spectively. The tender radish seedlings were dipped into the
prepared solution for enough time and dried at room tem-
perature naturally. Then the 3rd-instar larvae of P. Xylos-
tella were placed onto the treated radish seedlings in petri
dishes. Treated larvae were held under the conditions given
in the bioassay. The test for against T. cinnabarinus was
carried out by treatment of the broad bean leaf covered by
mite T. cinnabarinus with the prepared solution for 5 s.
Cumulative mortalities were determined after 3 days of
treatment. Larvae and mites were considered dead if ap-
pendages did not move when prodded with a brush pen. All
treatments were repeated four times.
2 Experimental
2.1 General information
IR spectra were recorded with a Perkin-Elmer 782 IR spec-
1
trometer. H NMR and 13C NMR spectra were obtained
with a Bruker DMX-300 (300 MHz) spectrometer. Chemi-
cal shifts are given in ppm relative to tetramethylsilane
(TMS) and the center of the multiplet of DMSO was de-
fined as 39.53 ppm for 13C NMR spectra. HRMS (ESI)
spectra were measured on a JEOL JMS-DX303. Melting
points were measured with a Beijing-Taike X-4 apparatus
and are uncorrected. Unless otherwise noted, all reagents
were obtained from commercial suppliers and were used
without further purification.
2.4 Spectroscopic data for the products
3a. A white solid, m.p. = 206–208 °C (decom.); FT-IR
1
(KBr): 3414, 3054, 1689, 1526, 1458, 1238 cm1; H NMR
According to the previously reported procedure [22], the
Baylis-Hillman alcohols (1a–i) were prepared.
(300 MHz, DMSO-d6):  3.28 (m, 1H), 3.97–4.27 (m, 2H),
5.09–5.27 (m, 1H), 5.76–5.93 (m, 1H), 6.85–7.50 (m, 8H),
11.53 (s, 1H); 13C NMR (75MHz, DMSO-d6):  36.9, 46.6,
69.8, 108.6, 117.1, 120.6, 121.2, 125.9, 127.1, 127.9, 128.1,
133.0, 142.8, 147.6, 168.6; HRMS (ESI): m/z calcd for
C17H15N3O2Cl (M++1): 328.0845, found 328.0847.
2.2 Typical procedure for the synthesis of benzimidazo
[1,2-a]pyrimidinone
To a solution of Baylis-Hillman alcohol (1a) (45 mg, 0.2
mmol) in the co-solvent THF/H2O (4:1) (1.2 mL) was added
2-aminobenzimidazole 2 (27 mg, 0.2 mmol), followed by
stirring at 50 °C for 24 h. After cooled to room temperature,
the solvent was removed under reduced pressure to give an
oil residue. The crude product was purified by flash chro-
matography on silica gel (eluent: CH2Cl2/CH3OH/aq. NH3 =
100:2:1) to afford the product 3a as a white solid (58 mg,
89%).
3b. A White solid, m.p. = 225–227 °C (decom.); FT-IR
1
(KBr): 3382, 3056, 1678, 1510, 1457, 1223 cm1; H NMR
(300 MHz, DMSO-d6):  3.27(m, 1H), 3.96–4.25 (m, 2H),
5.07–5.27 (m, 1H), 5.87–5.90 (m, 1H), 6.91–6.97 (m, 1H),
7.06–7.12 (m, 2H), 7.15–7.24 (m, 1H), 7.24–7.34 (m, 2H),
7.38–7.45 (m, 2H), 8.27 (m, 1H), 11.50 (s, 1H); 13C NMR
(75MHz, DMSO-d6):  37.0, 46.7, 69.2, 108.7, 114.7, 115.0,
117.1, 120.6, 121.2, 127.9, 128.0, 133.0, 141.7, 147.6,
168.5; HRMS (ESI): m/z calcd for C17H15N3O2F (M++1):
312.1141, found 312.1143.
According to the same procedure, the fused heterocyclic
compounds (3b–i) were synthesized.
3c. A white solid, m.p. = 231–233 °C (decom.); FT-IR
Three-component one-pot reaction procedure: To a solu-
tion of 4-nitrobenzaldehyde 4 (48 mg, 0.2 mmol) and methyl
acrylate 5 (54 L, 0.6 mmol) in 5 mL of 1,4-dioxane/water
(1:1, V/V) was added DABCO (22.4 mg, 0.2 mmol). The
reaction mixture was stirred for 24 h at room temperature
until 4 was consumed in TLC analysis. 2-Aminobenzimi-
dazole 2 (80 mg, 0.6 mmol,) was added to the reaction
mixture, followed by stirring for 24 h at 50 °C. After cooled
to room temperature, the solvent was removed under re-
duced pressure and the residue was purified by flash chro-
matography on silica gel (eluent: CH2Cl2/CH3OH/aq. NH3 =
100:2:1) to afford 3c (35 mg, 52%).
1
(KBr): 3373, 3052, 1667, 1521, 1456, 1348 cm1; H NMR
(300 MHz, DMSO-d6):  3.40(m, 1H), 3.98–4.34(m, 2H),
5.15–5.50 (m, 1H), 6.17–6.18 (m, 1H), 7.06–7.09 (m, 1H),
7.28–7.38 (m, 1H), 7.52–7.72 (m, 1H), 7.97–8.26 (m, 1H),
11.60 (s, 1H); 13C NMR (75MHz, DMSO-d6):  36.9, 46.3,
69.0, 108.8, 117.1, 120.6, 121.3, 123.3, 127.4, 133.0, 141.6,
146.7, 147.5, 150.8, 168.1; HRMS (ESI): m/z calcd for
C17H13N4O4 (M++1): 339.1086, found 339.1087.
3d. A white solid, m.p. = 211–213 °C (decom.); FT-IR
1
(KBr): 3378, 3051, 1671, 1523, 1456, 1351 cm1; H NMR
(300 MHz, DMSO-d6):  3.42 (m, 1H), 4.01–4.29 (m, 2H),
5.25–5.50 (m, 1H), 5.75–6.19 (m, 1H), 7.04–7.11 (m, 2H),
7.26–7.45 (m, 2H), 7.64–7.69 (m, 1H), 7.85–7.92 (m, 1H),
8.11–8.17 (m, 1H), 8.27 (m, 1H), 11.60 (s, 1H); 13C NMR
(75MHz, DMSO-d6):  36.9, 46.3, 68.7, 108.9, 117.1, 120.6,
120.8, 121.3, 122.1, 129.6, 132.8, 133.0, 141.6, 145.3,
147.5, 147.8, 168.2; HRMS (ESI): m/z calcd for
C17H13N4O4 (M++1): 339.1086, found 339.1087.
2.3 Test of pesticidal activity
The toxicity of test compounds (3a–3i) to 3rd-instar larvae
of Plutella xylostella and the mite of Tetranychus cinna-
barinus were examined by dipping assay [23, 24]. Each
sample (0.001 g) was individually dissolved in DMF and
suspended in distilled water containing surfactant Triton
3e. A white solid, m.p. = 204–206 °C (decom.); FT-IR

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REN ChuanLi, et al. Sci China Chem July (2010) Vol.53 No.7
Table 1 Solvent effect on the reaction of 1a with 2 a)
(KBr) 3360, 3055, 1671, 1523, 1456, 1340 cm1; H NMR
(300 MHz, DMSO-d6)  3.34 (m, 1H), 4.11 (m, 1H), 4.28
(m, 1H), 5.86 (m, 1H), 6.14 (m, 1H), 7.10 (m, 2H), 7.30 (m,
1H), 7.41 (m, 1H), 7.59 (m 1H), 7.82 (m, 1H), 7.91 (m, 1H),
8.03 (m, 1H), 11.60 (s, 1H); 13C NMR (75MHz, DMSO-d6)
 37.3, 45.4, 65.1, 108.8, 117.1, 120.6, 121.2, 124.3, 128.6,
129.3, 133.0, 133.5, 138.1, 141.7, 147.2, 147.6, 168.0;
HRMS (ESI): m/z calcd for C17H13N4O4 (M++1): 339.1086,
found 339.1087.
1
Entry
Solvent
C2H5OH/H2O (1:4)
dioxane/H2O (1:4)
CH3CN/H2O (1:4)
CH2Cl2/H2O (1:4)
THF/H2O (1:4)
THF/H2O (1:1)
THF
Yield (%)b)
1
2
3
4
5
6
7
8
71
74
78
84
89
80
71
55
3f. A white solid, m.p. = 223–225 °C (decom.); FT-IR
1
(KBr): 3470, 3080, 1671, 1517, 1456, 1388 cm1; H NMR
(300 MHz, DMSO-d6):  2.16–2.31 (m, 3H), 3.93–4.22 (m,
2H), 4.99–5.25 (m, 1H), 5.72–5.76 (m, 1H), 6.95–6.97 (m,
1H), 7.04–7.17 (m, 4H), 7.19–7.41 (m, 3H), 11.49 (s, 1H);
13C NMR (75MHz, DMSO-d6):  21.0, 37.3, 47.1, 70.2,
109.0, 117.4, 121.1, 121.7, 126.3, 128.8, 133.1, 136.5,
138.8, 142.0, 147.8, 168.9; HRMS (ESI): m/z calcd for
C18H17N3O2 (M++1): 308.1394, found 308.1393.
H2O
Reaction temperature: 50 °C; time: 24 h; b) based on 1H NMR analysis.
3g. A white solid, m.p. = 175–177 °C (decom.); FT-IR
1
(KBr): 3393, 3054, 1674, 1525, 1456, 1312 cm1; H NMR
the best result (entry 5). For THF used alone, the reaction
yield was relatively low (71%, entry 7) and the product was
a more complex mixture in terms of H NMR analysis. The
(300 MHz, DMSO-d6):  3.15 (m, 1H), 4.16 (m, 1H), 4.35
(m, 1H), 5.20–5.62 (m, 1H), 5.93–6.11 (m, 1H), 6.75–7.95
(m, 8H), 11.58 (s, 1H); 13C NMR (75MHz, DMSO-d6): 
36.9, 46.2, 65.1, 108.8, 117.1, 120.6, 121.2, 125.4, 125.5,
127.9, 129.2, 132.4, 133.0, 141.6, 141.8, 147.5, 167.9;
HRMS (ESI): m/z calcd for C18H13N3O2F (M++1): 362.1106,
found 362.1101.
1
increase of THF amount in the co-solvent to THF-H2O=1:1
resulted in the decrease of the yield (entry 6). The results
indicate that under the aqueous reaction conditions, water
could play a role in enhancing the reaction rate. However,
the use of water alone would lead to the increase of
by-products and decrease of the yield notably (entry 8),
which is probably attributed to water-insolubility of the
substrates and heterogeneity of the reaction system. The
reaction temperature influenced the reaction remarkably: at
room temperature or in refluxing the reaction products were
very complicated.
The Baylis-Hillman alcohols bearing various aryl sub-
stituents (1a–h) and furyl group (1i) were employed in the
reactions with 2 at 50 °C for 24 h in THF-H2O (1:4, V/V)
without any catalysts and additives to give benzimidazo
[1,2-a]pyrimidinone compounds (3a–i) in good to excellent
yields (74%–95%) (Scheme 1, Table 2). The substituent
effect of the aromatic ring has no apparent impact on the
reaction. Phenyl (1h), phenyl with electron-withdrawing
groups (1a–b, 1g) or electron-donating groups (1f) could
afford good yields (entries 1–2, 6–8). However, furyl or
nitro substituted substrates resulted in relatively low yields
due to the decomposition of substrates (1c–e, 1i) through
the retro-Morita-Baylis-Hillman reaction under heating
conditions (entries 3–5, 9).
3h. A white solid, m.p. = 233–235 °C (decom.); FT-IR
1
(KBr): 3390, 3064, 1665, 1515, 1458, 1334 cm1; H NMR
(300 MHz, DMSO-d6):  3.26 (m, 1H), 3.97 (m, 1H), 4.19
(m, 1H), 5.28 (m, 1H), 5.80 (m, 1H), 7.01–7.16 (m, 2H),
7.19–7.33 (m, 2H), 7.33–7.52 (m, 4H), 11.53 (s, 1H); 13C
NMR (75 MHz, DMSO-d6):  36.9, 46.6, 69.8, 108.6, 117.1,
120.6, 121.2, 125.9, 127.1, 128.1, 133.0, 141.7, 142.8,
147.6, 168.6; HRMS (ESI): m/z calcd for C17H16N3O2
(M++1): 294.1234, found 294.1237.
3i. A yellow solid, m.p. = 206–208 °C (decom.); FT-IR
1
(KBr) 3434, 3054, 1685, 1522, 1456, 1384 cm1; H NMR
(300 MHz, DMSO-d6)  3.39 (m, 1H), 4.04–4.34 (m, 2H),
5.09–5.25 (m, 1H), 5.98–5.99 (m, 1H), 6.23–7.64 (m, 7H),
11.55 (s, 1H); 13C NMR (75 MHz, DMSO-d6)  37.4, 44.2,
64.6, 106.8, 108.8, 110.3, 117.1, 120.6, 121.3, 133.0, 141.7,
142.2, 147.5, 155.2, 169.1; HRMS (ESI): m/z calcd for
C15H14N3O2(M++1): 284.1026, found 284.1029.
3 Results and discussion
Initially, the reactions of Baylis-Hillman alcohol (1a, R =
4-ClC6H4) with 2-aminobenzoimidazole 2 were carried out
o
in various solvents at 50 C for 24 h to give the fused het-
erocyclic product (3a) in good to excellent yields (Table 1).
Although several aqueous media provided good yields
(71%–84%, entries 1–4), the THF-H2O (1:4) system showed
Scheme 1

REN ChuanLi, et al. Sci China Chem July (2010) Vol.53 No.7
1495
Table 2 Aqueous synthesis of pyrimidinone derivatives (3a–i) a)
Table 3 Toxicity to T. cinnabarinus and P. xylostella by a dipping assay
of 3a–c and 3i
Entry
B-H Alcohol (R)
1a, 4-ClC6H4
1b, 4-FC6H4
Product (R)
3a, 4-ClC6H4
3b, 4-FC6H4
3c, 4-NO2C6H4
3d, 3-NO2C6H4
3e, 2-NO2C6H4
3f, 4-CH3C6H4
3g, 2-CF3C6H4
3h, C6H5
Yield (%) b)
Mortality of T.
Mortality of P.
xylostella (%) b)
Compound
cinnabarinus (%) a)
1
2
3
4
5
6
7
8
9
89
95
81
77
74
91
90
90
80
3a
3b
3c
3i
100
100
100
100
80
70
90
80
1c, 4-NO2C6H4
1d, 3-NO2C6H4
1e, 2-NO2C6H4
1f, 4-CH3C6H4
1g, 2-CF3C6H4
1h, C6H5
a) Exposed to 500 mg/L; b) exposed to 100 mg/L.
the mortality of P. Xylostella was 100%. However, the rest
of the test compounds caused no morality. The preliminary
results provided a clue for finding a new biological activity
of imidazo[1,2-a]pyrimidine-type compounds.
1i, 2-furyl
3i, 2-furyl
a) In THF/H2O (1:4), reaction temperature: 50 oC, time: 24 h; b) isolated
yield.
Although water and methanol as a cocatalyst could pro-
mote the Baylis-Hillman reaction, it is problematic to per-
form the Baylis-Hillman reaction in aqueous media [25].
The combination of the Baylis-Hillman reaction with sub-
sequent reactions in aqueous media in one pot remains a
challenge. The aqueous synthesis of 3c from 4-nitroben-
zaldehyde (4), methyl acrylate (5) and 2 in a one-pot process
was examined. However, in THF/H2O, the Baylis-Hillman
reaction of 4 with 5 did not work at all, even with the reac-
tion time prolonged to four days. However, the reaction
proceeded smoothly by using 1,4-dioxane/H2O (1:1) as a
reaction medium to afford the product (3c) in 52% yield
(Scheme 2). For smoothly carrying out the Baylis-Hillman
reaction of 4 with 5 in aqueous media the excess of 5 (3 eq.)
and basic promoter DABCO were used, and the corre-
sponding 3 equiv of 2 was employed in the subsequent tan-
dem Michael addition and cyclization in one pot.
4 Conclusions
Benzimidazo[1,2-a]pyrimidinone derivatives were synthe-
sized by the combination of an aqueous Michael reaction of
Baylis-Hillman alcohol and the subsequent cyclization reac-
tion in the absence of catalysts in one pot. The protocol
provides a convenient, simple, and green method for the
synthesis of fused heterocyclic compounds. A new biologi-
cal activity, pesticidal activity, of imidazo[1,2-a]pyrimidinone-
type compounds was evaluated. The test results indicate that
several benzimidazo[1,2-a]pyrimidinone compounds have
moderate activities to T. cinnabarinus and P. Xylostella.
Further studies on the aqueous synthetic method of hetero-
cyclic compounds with biological activities are ongoing in
our group.
A plausible mechanism for the construction of benzimi-
dazo[1,2-a]pyrimidinone by the reaction of Baylis-Hillman
alcohol (1) with 2-aminobenzimidazole (2) was proposed
through a Michael addition followed by an intramolecular
cyclization. Water may enhance the reaction rate by the
promotion of the Michael addition (step 1) through double
activation on both the carbonyl group of the BH alcohol and
the amino group of 2-aminobenzimidazole via hydrogen
bonding interaction [26].
The pesticidal activities of test compounds (3a–3i)
against T. cinnabarinus and P. Xylostella are shown in Ta-
ble 3. At the concentration of 100 mg/L, compounds 3a–c
and 3i gave 80%, 70%, 90% and 80% mortalities for P.
Xylostella, respectively. At the concentration of 500 mg/L,
This work was supported by the National Natural Science Foundation of
China, Ministry of Science and Technology (2009ZX09501-006) and the
Chinese Academy of Sciences.
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