General and green synthesis of C-6 sulfonylmethyl 4-aryl-3,4- dihydropyrimidinones in water

Article abstract of DOI:10.1080/00397910802654682

A simple, inexpensive, and green reaction permitting the synthesis of new C-6 arylsulfonylmethyl 4-aryl-3,4-dihydropyrimidinones in water by S-alkylation of 6-bromomethyl 3,4-dihydropyrimidinones 2 with benzenesulfinic acid anions 3 is reported. The requi

Full text of DOI:10.1080/00397910802654682

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General and Green Synthesis of
C-6 Sulfonylmethyl 4-Aryl-3,4-
dihydropyrimidinones in Water
Zheng-Jun Quan a , Qiang-Bing Wei a , Dong-Dong Ma
a , Yu-Xia Da a , Xi-Cun Wang a & Mao-Sen Shen b
a Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu, China
b Jing Tai Second Middle School, Baiyin, Gansu,
China
Version of record first published: 12 May 2009.
To cite this article: Zheng-Jun Quan , Qiang-Bing Wei , Dong-Dong Ma , Yu-Xia Da , Xi-
Cun Wang & Mao-Sen Shen (2009): General and Green Synthesis of C-6 Sulfonylmethyl
4-Aryl-3,4-dihydropyrimidinones in Water, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:12, 2230-2239
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Synthetic Communications1, 39: 2230–2239, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654682
General and Green Synthesis of C-6
Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones
in Water
Zheng-Jun Quan,1 Qiang-Bing Wei,1 Dong-Dong Ma,1 Yu-Xia Da,1
Xi-Cun Wang,1 and Mao-Sen Shen2
1Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou,
Gansu, China
2Jing Tai Second Middle School, Baiyin, Gansu, China
Abstract: A simple, inexpensive, and green reaction permitting the synthesis
of new C-6 arylsulfonylmethyl 4-aryl-3,4-dihydropyrimidinones in water by
S-alkylation of 6-bromomethyl 3,4-dihydropyrimidinones 2 with benzenesulfinic
acid anions 3 is reported. The required 6-bromomethyldihydropyrimidone pre-
cursors 2 were readily prepared using an organic solid brominating reagent.
Keywords: Bromination, 3,4-dihydropyrimidinones (DHPMs), dioxane dibro-
mide, water
INTRODUCTION
In recent years, green chemistry has become increasing important, which
has the objective of creating new products, industrial and laboratory pro-
cesses, and services that achieve social and economic progress without
environmental detriment. The use of water as a medium in organic reac-
tions has advantages because it is inexpensive, nontoxic, nonflammable,
environmentally benign, and readily available. The isolation of organic
Received August 22, 2008.
Address correspondence to Xi-Cun Wang, Gansu Key Laboratory of Polymer
Materials, College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu 730070, China. E-mail: wangxicun@nwnu.edu.cn
2230

C-6 Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones
2231
Scheme 1. Synthesis of C-6 bromo-DHPMs.
products can be performed by simple phase separation. This feature has
stimulated the development of useful procedures for organic transforma-
tions in water.[1,2]
Research on 3,4-dihydropyrimidin-2(1H)-ones (DHPMs, Scheme 1)
synthesized via the one-pot, three-component Biginelli condensation[3]
has surged rapidly because of the pharmacological properties associated
with many derivatives of this privileged heterocyclic core.[4–6] Strategies
for the synthesis of the DHPM nucleus have varied from a one-step to
a multistep approach, but the methods for the peripheral elaboration
are scarce[3] or of limited synthetic scope.
A careful examination of the current literature has revealed that few
elaborations of C-6 of 4-aryl-6-methyl-DHPMs has been described.[3]
Generally, the functionalization of the C-6 methyl group is through
bromination (invariably plagued by gem-dibromination) and subsequent
reaction with some nucleophiles.[7] 6-Halomethyl-DHPMs are also con-
venient starting materials for the synthesis of fused pyrimidines, such
as furo[3,4-d]pyrimidines, pyrrolo[3,4-d]pyrimidines, and pyrimido[4,5-d]
pyrimidines.[8] Recently, C-6 functionalized 4-aryl-3,4-dihydropyrimidi-
nones were prepared through metalation of the C-6 methyl group and
subsequent reaction with electrophilic reagents.[9] To the best of our
knowledge, elaboration of C-6 DHPMs through reactions of the C-6
bromo-DHPMs with sulfonyl anions is unprecedented. In the context
of our interest in the synthesis of functionalized DHPM derivatives,[10]
we became interested in combining sulfonyl group with the DHPM core.
Scheme 2. Synthesis of C-6 Sulfonylmethyl 4-aryl-3,4-dihydropyrimidinones
4a: R1 ¼ H, R2 ¼ H; 4b: R1 ¼ H, R2 ¼ CH3; 4c: R1 ¼ 2-Cl, R2 ¼ H; 4d: R1 ¼ 2-
Cl, R2 ¼ CH3; 4e: R1 ¼ 2,4-Cl2, R2 ¼ H; 4f: R1 ¼ 2,4-Cl2, R2 ¼ CH3; 4g: R1 ¼ 4-
Cl, R2 ¼ H; and 4h: R1 ¼ 4-Cl, R2 ¼ CH3.

2232
Z.-J. Quan et al.
Compounds containing sulfonyl groups themselves have long been a
research focus as a result of their biological importance and chemical
applications.[11] Arylsulfonyl substitutents have been used as protecting
groups for oxygen and nitrogen functionalities.[12]
Thus we report here a practical, inexpensive, and green method for
the preparation of C-6 arylsulfonylatedmethyl DHPM derivatives
through a S-alkylation reaction of 6-bromomethyl-DHPM with sodium
salt of arylsulfinic acid in the presence of PEG-400 in water (Scheme 2).
RESULTS AND DISCUSSION
To prepare the C-6 arylsulfonylatedmethyl DHPM libraries of type 4, it
was necessary to first develop procedures for the rapid generation of
C-6-bromomethyl DHPMs 2. There are several reports in the literature
describing the bromination of DHPMs 2 with elemental bromine.[13]
All of these procedures require careful, dropwise addition of bromine
at subambient temperatures to the DHPM to avoid overbromination
of the corresponding gem-dibromo derivative. Recently, Kappe et al.[7]
reported a bromination of DHPM involving a polymer-supported
brominating reagent under flow-through conditions.
In an endeavor to gradually change the current working practices to
greener alternatives and to meet environmental demands,[14] an environ-
mentally favorable protocol for the preparation of various organic
ammonium tribromides (OATB) and some of its applications was dis-
closed recently.[15] Organic brominating reagents including ammonium
tribromides and dioxane dibromide (DDB) are preferable because of
the hazards associated with bromine. The other advantages of OATB
are that it is crystalline, is easy to handle, and maintains the desired stoi-
chiometry. Our initial experiments utilizing n-tetrabutylammonium tri-
bromide (TBATB) for the bromination of DHPM 1a, using chloroform
or 1,2-dichloroethane as a solvent, provided the bromomethyl intermedi-
ate 2a (after stirring in an ice bath for an additional 6 h) in 85% yield.
However, when we prepared TBATB, it was difficult to release the
remaining bromine from the mixture, and TBATB was unstable. In an
attempt to obtain better control of the selectivity in this crucial bromina-
tion step, we also explored the use of DDB. When using DDB as bromi-
nating reagent, we were able to achieve efficient brominations in 88%
yield using dioxane as solvent at room temperature for 5 h.
Then we examined the S-alkylation reaction of the simple 6-
bromomethyl-5-ethoxycarbonyl-4-phenyl-3,4-dihydropyrimidinone 2a with
sodium salt of benzenesulfinic acid 3a at different reaction temperatures
using various catalysts and solvents to determine optimal conditions for

C-6 Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones
2233
Table 1. Reaction of 2a with 3a under different conditions
Entry Catalyst
Solventa
Temperature (ꢀC) Yield (%)b
1
2
3
4
5
6
7
PEG-400 H2O
100
100
100
100
70
85
78
75
82
80
85
63
TBAB
K2CO3
18-C-6
H2O
H2O
H2O
PEG-400 Acetone
PEG-400 Acetone=H2O (V=V: 1=1)
H2O
100
100
—
aReaction conditions: a mixture of 1 equiv. of 2a with 2 equiv. of 3a was heated
under reflux condtions for 24 h.
bIsolated yield.
C-6 sulfonylmethyl DHPM 4a (Scheme 2). The results are shown in Table 1.
We found that treatment of 1 equiv. of 2a with 2 equiv. of 3a in the
presence of a catalytic amount of PEG-400 in reflux water gave C-6
sulfonylated methyl substituted DHPM 4a in 85% yield after 24h
(entry 1). When this reaction was carried out in acetone, however, 4a was
obtained in a lesser yield, 80% (entry 5). Increasing the amount of
the sodium salt of sulfinic acid or enhancing the reaction time did not
increase the yield in any significant way. The use of these optimal experi-
mental conditions for the reactions of different 6-bromo-DHPMs 2 and
arylsulfinic acid anions 3a,b afforded good yields of DHPM derivatives
4b–h, presenting an arylsulfonylmethyl group in position C-6 of the DHPM
nucleus.
In summary, the present synthetic method is a simple, efficient,
inexpensive, and green protocol for new functionalized 3,4-dihydropyri-
midinone derivatives via S-alkylation reaction in water in good yields.
The required 6-bromomethyldihydropyrimidone precursors 2 were
readily prepared using an organic solid brominating reagent. The proto-
col described herein allows for creation of structural diversity to produce
‘‘druglike’’ molecule for biological screening.
EXPERIMENTAL
All reagents were obtained commercially and used without further puri-
fication. Melting points were determined on an XT-4 electrothermal
micromelting-point apparatus and are uncorrected. NMR spectra were
recorded at 400 (1H) and 100 (13C) MHz, respectively, on a Varian
Mercury Plus-400 instrument using dimethyl sulfoxide (DMSO-d6) as
solvent and tetramethylsilane (TMS) as internal standard. Mass spectra

2234
Z.-J. Quan et al.
were recorded on a ZAB-HS spectrometer. Elemental analyses were
performed on a Carlo-Erba 1106 Elemental Analysis instrument.
Compounds 1 were prepared by following the reported method.[16]
General Preparation for Brominating Dihydropyrimidone 2
A mixture of dihydropyrimidinone 1 (2 mmol) and dioxane dibromide
(2.2 mmol) in dioxane (5 mL) was stirred for 5 h at rt. The reaction mix-
ture was washed with aqueous sodium thiosulfate and aqueous sodium
hydrogensulfite, and the solvent was removed to give the crude product,
which was recrystallized in ethanol.
General Preparation for C-6 Arylsulfonylatedmethyl DHPMs 4
Bromomethyldihydropyrimidine 2 (1.00 mmol) and four drops of PEG-
400 were added to a solution of sodium salt of arylsulfinic acid
(2.0 mmol) 3. After the mixture was stirred at 100ꢀC for 24 h, the mixture
was cooled to rt. The solid was filtered and washed with acetone and
water; the resulting product was purified by recrystallized from DMF
and ethanol (DMF–EtOH ¼ 1:1).
Data
Compound 4a
Mp 231–233ꢀC; yield 85%. 1H NMR (400 MHz, DMSO) d: 9.20 (br, 1H,
NH), 7.90 (br, 1H, NH), 7.71 (d, J ¼ 7.6 Hz, 2H, ArH), 7.53 (t,
J ¼ 7.6 Hz, 1H, ArH), 7.38–7.23 (m, 7H, ArH), 5.15 (s, 1H, CH), 4.84
(s, 2H, CH2), 3.98 (q, J ¼ 6.8 Hz, 2H, CH2O), 0.99 (t, 3H, J ¼ 6.8 Hz,
CH3). 13C NMR (100 MHz, DMSO) d: 166.4, 151.6, 144.2, 140.1,
130.8, 129.6, 129.2, 129.5, 128.8, 128.4, 124.8, 107.6, 61.2, 54.1, 51.8,
13.9. Anal. calcd. for C20H20N2O5S: C, 59.99; H, 5.03; N, 7.00; found:
C, 60.19; H, 5.14; N, 6.88. MS (FAB) m=z: 400 (Mþ).
Compound 4b
Mp 235–237ꢀC; yield 87%. 1H NMR (400 MHz, DMSO) d: 9.20 (br, 1H,
NH), 7.78 (br, 1H, NH), 7.65 (d, J ¼ 7.6 Hz, 2H, ArH), 7.45 (t,
J ¼ 7.6 Hz, 2H, ArH), 7.35–7.21 (m, 5H, ArH), 5.15 (s, 1H, CH), 4.82

C-6 Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones
2235
(s, 2H, CH2), 3.76 (q, J ¼ 6.8 Hz, 2H, CH2O), 2.31 (s, 3H, CH3), 0.99 (t,
3H, J ¼ 6.8 Hz, CH3). 13C NMR (100 MHz, DMSO) d: 165.1, 151.0,
144.3, 141.5, 134.6, 131.8, 130.1, 129.8, 129.5, 129.1, 127.9, 106.1, 60.8,
58.6, 51.5, 21.2, 13.6. Anal. calcd. for C21H22N2O5S: C, 60.85; H, 5.35;
N, 6.76; found: C, 70.02; H, 5. 22; N, 6.89. MS (FAB) m=z: 414 (Mþ).
Compound 4c
Mp 229–230ꢀC; yield 87%. 1H NMR (400 MHz, DMSO) d: 9.24 (br, 1H,
NH), 8.29 (br, 1H, NH), 7.86 (d, J ¼ 7.6 Hz, 2H, ArH), 7.75 (d, J ¼
7.2 Hz, 1H, ArH), 7.63 (t, J ¼ 7.6 Hz, 2H, ArH), 7.29–7.42 (m, 4H, ArH),
4.92 (s, 2H, CH2), 5.61 (s, 1H, CH), 3.66 (q, J ¼ 7.2 Hz, 2H, CH2O), 0.90
(t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, DMSO) d: 164.2, 150.5,
145.0, 141.9, 139.3, 134.9, 132.6, 129.8, 129.6, 129.5, 128.7, 128.3,
126.8, 103.8, 59.8, 54.3, 51.2, 13.6. Anal. calcd. for C20H19ClN2O5S: C,
55.24; H, 4.40; N, 6.44; found: C, 55.14; H, 4.31; N, 6.31. MS (FAB)
m=z: 434 (Mþ), 436 (Mþ þ 2).
Compound 4d
Mp 222–224ꢀC; yield 90%. 1H NMR (400 MHz, DMSO) d: 9.25 (br, 1H,
NH), 7.82 (br, 1H, NH), 7.74–7.72 (m, 2H, ArH), 7.43–7.28 (m, 6H,
ArH), 5.62 (s, 1H, CH), 4.97 (d, J ¼ 13.6 Hz, 1H, CH2), 4.85 (d,
J ¼ 13.6 Hz, 1H, CH2), 3.67 (q, J ¼ 6.8 Hz, 2H, CH2O), 2.31 (s, 3H,
CH3), 0.90 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, DMSO) d:
164.0, 150.9, 144.9, 140.9, 138.8, 135.8, 131.7, 129.8, 129.6, 129.5,
129.0, 128.4, 127.9, 103.2, 59.8, 55.6, 51.5, 21.2, 13.7. Anal. calcd. for
C21H21ClN2O5S: C, 56.18; H, 4.72; N, 6.24; found: C, 56.00; H, 4.83;
N, 6.14. MS (FAB) m=z: 448 (Mþ), 450 (Mþ þ 2).
Compound 4e
Mp 225–227ꢀC; yield 80%. 1H NMR (400 MHz, DMSO) d: 9.24 (br, 1H,
NH), 8.29 (br, 1H, NH), 7.85 (d, J ¼ 7.6 Hz, 2H, ArH), 7.71–7.68 (m, 1H,
ArH), 7.62 (t, J ¼ 7.6 Hz, 2H, ArH), 7.44–7.25 (m, 3H, ArH), 5.60 (s,
1H, CH), 4.85 (s, 2H, CH2), 3.67 (q, J ¼ 7.2 Hz, 2H, CH2O), 0.91 (t,
J ¼ 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, DMSO) d: 164.0, 150.3,
145.2, 140.8, 139.2, 135.0, 133.5, 130.7, 130.2, 129.5, 128.8, 128.3,
127.9, 103.2, 59.8, 52.7, 51.5, 13.6. Anal. calcd. for C20H18Cl2N2O5S:
C, 51.18; H, 3.87; N, 5.97; found: C, 51.32; H, 3.79; N, 6.08. MS
(FAB) m=z: 468 (Mþ), 470 (Mþ þ 2).

2236
Z.-J. Quan et al.
Compound 4f
Mp 248–250ꢀC; yield 83%. 1H NMR (400 MHz, DMSO) d: 9.31 (br, 1H,
NH), 7.90 (br, 1H, NH), 7.90 (d, J ¼ 7.6 Hz, 2H, ArH), 7.75 (s, 1H, ArH),
7.58–7.37 (m, 4H, ArH), 5.60 (s, 1H, CH), 4.86 (s, 2H, CH2), 3.67 (q,
J ¼ 7.2 Hz, 2H, CH2O), 2.30 (s, 3H, CH3), 0.90 (t, J ¼ 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, DMSO) d: 163.9, 150.9, 145.0, 140.1,
139.0, 135.7, 133.1, 132.7, 130.5, 129.8, 128.9, 128.4, 128.1, 102.8, 59.9,
51.4, 51.3, 21.2, 13.7. Anal. calcd. for C21H20Cl2N2O5S: C, 52.18; H,
4.17; N, 5.80; found: C, 52.40; H, 4.09; N, 5.69. MS (FAB) m=z: 482
(Mþ), 484 (Mþ þ 2).
Compound 4g
Mp 221–223ꢀC; yield 88%. 1H NMR (400 MHz, DMSO) d: 9.23 (br, 1H,
NH), 8.12 (br, 1H, NH), 7.86–7.63 (m, 5H, ArH), 7.29–7.23 (m, 4H,
ArH), 5.60 (s, 1H, CH), 5.00 (s, 2H, CH2), 3.66 (q, J ¼ 7.2 Hz, 2H,
CH2O), 0.90 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, DMSO) d:
164.0, 150.5, 145.3, 141.8, 140.5, 135.2, 132.9, 130.5, 130.1, 129.8,
129.3, 127.2, 103.3, 59.8, 54.1, 51.5, 13.7. Anal. calcd. for
C20H19ClN2O5S: C, 55.24; H, 4.40; N, 6.44; found: C, 55.41; H, 4.30;
N, 6.32. MS (FAB) m=z: 434 (Mþ), 436 (Mþþ 2).
Compound 4h
Mp 232–234ꢀC; yield 92%. 1H NMR (400 MHz, DMSO) d: 9.22 (br, 1H,
NH), 7.98 (br, 1H, NH), 7.72 (d, J ¼ 7.6 Hz, 2H, ArH), 7.51 (d, J ¼ 7.6 Hz,
2H, ArH), 7.31–7.21 (m, 4H, ArH), 5.60 (s, 1H, CH), 4.94 (d,
J ¼ 13.6 Hz, 1H, CH2), 4.78 (d, J ¼ 13.6 Hz, 1H, CH2), 3.67 (q, J ¼ 7.2 Hz,
Hz, 2H, CH2O), 2.39 (s, 3H, CH3), 0.90 (t, J ¼ 7.2 Hz, 3H, CH3). 13C
NMR (100 MHz, DMSO) d: 165.1, 151.2, 144.2, 140.9, 139.5, 133.8,
133.1, 130.8, 130.2, 129.6, 129.3, 127.2, 102.5, 60.1, 53.5, 51.2, 21.3,
13.6. Anal. calcd. for C21H21ClN2O5S: C, 56.18; H, 4.72; N, 6.24; found:
C, 56.42; H, 4.86; N, 6.11. MS (FAB) m=z: 448 (Mþ), 450 (Mþ þ 2).
ACKNOWLEDGMENT
We are thankful for the financial support from the Natural Science
Foundation of Gansu Province (3ZS061-A25-019) and the Scientific
Research Fund of Gansu Provincial Education Department (0601-25).

C-6 Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones
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