Multicomponent cyclocondensations of β-ketosulfones with aldehydes and aminoazole building blocks

Article abstract of DOI:10.3987/COM-07-S(U)19

The multicomponent reaction of methylsulfonylacetone (or α-methylsulfonylacetophenone) with aromatic aldehydes and aminoazoles (or urea) under microwave irradiation to yield 5,8-dihydroimidazolo[1,2-a]pyrimidines and 4,7-dihydro[1,2,4]triazolo[l,5-a]pyrimidines was studied. The influence of the type of aminoazole building block on the reactivity was established. In addition, an unusual reaction pathway for the Biginelli-type condensation of methylsulfonylacetone with aldehydes and urea leading to non-classical Hantzsch-type dihydropyridines was found.

Full text of DOI:10.3987/COM-07-S(U)19

HETEROCYCLES, Vol. 73, 2007
469
HETEROCYCLES, Vol. 73, 2007, pp. 469 - 480. © The Japan Institute of Heterocyclic Chemistry
Received, 18th June, 2007, Accepted, 26th July, 2007, Published online, 27th July, 2007. COM-07-S(U)19
MULTICOMPONENT CYCLOCONDENSATIONS OF
β-KETOSULFONES WITH ALDEHYDES AND AMINOAZOLE
BUILDING BLOCKS
Eugene S. Gladkov,a,b* Valentin A. Chebanov,a Sergey M. Desenko,a Oleg V.
Shishkin,a Svetlana V. Shishkina,a Doris Dallinger,b and C. Oliver Kappeb*
a State Scientific Institution “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Lenin Ave, 60, Kharkiv, Ukraine, 61001,
gladkov@isc.kharkov.com
b Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute
of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz,
Austria, oliver.kappe@uni-graz.at
Abstract – The multicomponent reaction of methylsulfonylacetone (or α-
methylsulfonylacetophenone) with aromatic aldehydes and aminoazoles (or urea)
under microwave irradiation to yield 5,8-dihydroimidazolo[1,2-a]pyrimidines and
4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines was studied. The influence of the
type of aminoazole building block on the reactivity was established. In addition,
an unusual reaction pathway for the Biginelli-type condensation of
methylsulfonylacetone with aldehydes and urea leading to non-classical Hantzsch-
type dihydropyridines was found.
INTRODUCTION
Partially hydrogenated pyrimidines and azolopyrimidines play an important role in medicinal chemistry.
Some of these nitrogen-containing heterocycles (Figure 1) are known as mitotic kinesin Eg5 inhibitors,
cardiovascular vasodilators, calcium channel blocking agents, potassium channel inhibitors and
openers.1,2 One of the most facile synthetic routes to dihydroazolopyrimidines is based on the Biginelli-
or Hantzsch-type cyclocondensation of aldehydes with aminoazoles and CH-acidic compounds. There is
ample precedent in the literature for the synthesis of fused azolopyrimidines by treatment of 3-amino-
1,2,4-triazole, 5-aminotetrazole and 5-aminopyrazoles with aldehydes and acetoacetic acid derivatives,
pyruvic acids or cyclic β-diketones.2-4

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The known pharmacological activity of heterocycles containing both a sulfone and azolopyrimidine
moiety (Figure 1)2 stimulated our interest in the multicomponent reaction of β-ketosulfones with aromatic
aldehydes and aminoazoles containing a guanidine fragment or with urea.5 We here report on microwave-
assisted6 one-pot multicomponent cyclocondensations involving aromatic aldehydes containing
substituents with different electronic nature, acyclic β-ketosulfones and aminoazoles such as 2-
aminobenzimidazole (3) and 3-amino-1,2,4-triazole (4).
Figure 1. Selected examples of biologically active dihydropyrimidines.1,2
F
F
OH
Br
N
Br
O
O
F
O
O
O
S
N
N
N
EtO
NH
N
O
N
N
S
N
N
H
N
S
N
N
H
H
H
RESULTS AND DISCUSSION
In the course of our investigations we found that the microwave-assisted three-component condensation
of benzimidazole 3, methylsulfonylacetone (1a) or α-methylsulfonylacetophenone (1b), and the
appropriate aromatic aldehyde 2 in DMF at 135 °C for 30 minutes led to the formation of the
corresponding 5,8-dihydroimidazolo[1,2-a]pyrimidines 5a-l (see Scheme 1 and Table 1). Applying the
same reaction conditions for the triazole building block 4 the corresponding 4,7-dihydro[1,2,4]tri-
azolo[1,5-a]pyrimidines 6a-i were isolated in moderate to excellent yields (Scheme 1, Table 1). The
purification step consists of simple product precipitation by addition of acetone. The reaction with 5-
aminotetrazole was unsuccessful. Although a variety of different reaction conditions were tested, only
unreacted starting materials could be isolated. An explanation for this unreactivity could be the decrease
in nucleophilicity comparing 3-amino-1,2,4-triazole and 2-aminobenzimidazole with 5-aminotetrazole.
The same observations regarding the reactivity characteristics for these aminoazoles have already been
reported before.7
The structures of compounds 5a-l and 6a-i were established by elemental analysis, MS-spectrometry and
1
NMR-spectroscopy (see Experimental Part). The H NMR spectra of heterocycles 5a-l and 6a-i exhibit
the following signals: characteristic resonances for the aromatic rings (6.5–8.0 ppm), a singlet for the Ar-
CH proton (~ 6.5 ppm), a broad singlet for the amino group (10.0-11.5 ppm) and signals for other
functional groups, including the SO2CH3 functionality at ~ 2.7 ppm. The formation of the isomeric
products resulting from condensation at the N1 rather than at the N3 position of the dihydropyrimidine

HETEROCYCLES, Vol. 73, 2007
471
1
ring can be excluded based on H NMR spectra. In related structural cases8 the NH protons are shifted
upfield by 2-3 ppm. Additionally, the absence of a coupling between the methine and the NH-group
strongly corraborates the formation of isomers 5 and 6.
H
N
Ar
O
S
Me
NH2
3
N
N
O
R1
N
H
DMF, MW, 135 °C, 30 min
N
O
O
O
Me
5a-l (27-97%)
S
R1
+
Ar
H
NH
N
Ar
O
S
O
Me
R1 = Me: 1a
R1 = Ph: 1b
2
NH2
N
N
4
N
N
O
DMF, MW, 135 °C, 30 min
R1
N
H
6a-i (46-95%)
Scheme 1. Biginelli-type multicomponent reactions.
Table 1. Synthesis of 5,8-dihydroimidazolo[1,2-a]pyrimidines 5a-l and 4,7-dihydro[1,2,4]tri-
azolo[1,5-a]pyrimidines 6a-i.
Entry
Diamine
R1
Ar
Yield [%]a
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
95
97
85
90
85
73
65
70
65
55
47
27
80
95
70
92
88
46
60
52
45
4-Cl-Ph
4-MeO-Ph
4-Me-Ph
4-F-Ph
2-MeO-Ph
Ph
4-Cl-Ph
4-MeO-Ph
2-MeO-Ph
4-Br-Ph
3-MeO-Ph
Ph
4-Cl-Ph
4-MeO-Ph
4-Me-Ph
4-F-Ph
5j
5k
5l
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
4-MeO-Ph
2-MeO-Ph
a Yields refer to isolated yields of pure compound.

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The investigation of the classical three-component Biginelli reaction involving equimolar amounts of urea,
β-ketosulfone 1a and aldehydes 2 under the same reaction conditions as described above (135 °C, 45 min)
was another objective of the present work. However, when methylsulfonylacetone 1a was employed as
CH-acidic building block the anticipated Biginelli dihydropyrimidines 7 (Figure 3) were not obtained.
According to MS-spectra and elemental analysis the isolated compounds contained two equivalents of
ketosulfones, one equivalent of aldehyde and ammonia. This composition would correspond to classical
Hantzsch dihydropyridines such as 8 (Figure 3). The formation of Hantzsch-type dihydropyridines as
reaction products could be expected according to literature data.9 However, the presence of two doublets
at ~4.4 and 4.9 ppm (J ~ 5.6–6.0 Hz) and a doublet of doublets at 3.9 ppm in the 1H NMR spectra allowed
us to reject this hypothesis.
Figure 3. Biginelli and Hantzsch reaction products.
O
O
Ar
Ar
O
S
Me
Me
Me
S
S
NH
O
O
O
R1
N
H
N
H
Me
O
Me
8
7
The structures of the synthesized compounds were established with the aid of X-ray diffraction analysis.
The X-ray study of a single crystal of compound 9d demonstrated that it was 6-methyl-5-methylsulfonyl-
2-methylsulfonylmethyl-4-(4-methylphenyl)-1,4-dihydropyridine (Scheme 2, Figure 4). The
dihydropyridine ring adopts an asymmetric boat conformation. Deviations of the N(1) and C(3) atoms
from the mean plane of remaining atoms of the ring are -0.15 Å and -0.32 Å, respectively. The N(1)-C(1)
bond (1.362(4) Å) is somewhat shortened and the C(1)-C(2) bond (1.351(4) Å) is slightly elongated
compared to equivalent N(1)-C(5) and C(4)-C(5) bonds (1.383(4) Å and 1.320(4) Å, respectively). This
redistribution of electron density in the dihydropyridine ring can be caused probably by the conjugation
between the lone pair of the nitrogen atom and the methylsulfonyl group. The repulsion between the
methyl substituent and the neighboring atoms (the shortened intramolecular contacts H(8b)… S(1) 2.89 Å
(the van der Waals radii sum10 is 3.01 Å), H(8c)…H(1N) 2.28 Å (2.34 Å)), probably results in some
twisting of the C(1)-C(2) double bond (the C(8)-C(1)-C(2)-S(1) torsion angle is 6.9(4)°). The phenyl
substituent has a pseudoaxial orientation and it is turned almost perpendicular to the average plane of the
heterocycle (the C(1)-C(2)-C(3)-C(10) and C(2)-C(3)-C(10)-C(11) torsion angles are 96.9(3)° and
115.3(3)°, respectively).

HETEROCYCLES, Vol. 73, 2007
473
Figure 4. Molecular structure (X-ray diffraction data) of 6-methyl-5-methylsulfonyl-2-
methylsulfonylmethyl-4-(4-methylphenyl)-1,4-dihydropyridine (9d).
Surprisingly, based on our findings from the X-ray diffraction analysis, the multicomponent reaction of β-
ketosulfone 1a, aromatic aldehydes 2 and urea yielded unusual Hantzsch dihydropyridines 9a-d (Scheme
2), which were formed after elimination of ammonia from urea and participation of the methyl group as
CH-acid center instead of the more reactive methylene.11 However, the yields in these reactions were
rather poor, an no exact investigation on the mechanism of this interesting transformation has been
performed.
O
2
O
Ar
Me
Ar
H
S
O
O
DMF
O
H2N
Me
Me
O
+
S
S
O
Me
MW, 135 °C, 45 min
N
H
Me
O
O
1a
H2N
9a-d
(13-35%)
Scheme 2. Synthesis of dihydropyridines via Hantzsch-type reaction.
Table 2. Isolated Yields of Dihydropyridines 9a-d.
Entry
Ar
Yield [%]
9a
9b
9c
9d
Ph
13
25
35
20
4-Cl-Ph
4-MeO-Ph
4-Me-Ph

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Performing the reaction with two equivalents of β-ketosulfone 1a, one equivalent of the appropriate
aldehyde and urea allowed an improvement of the target compound yields, but still remained insufficient
(Table 2). No positive result neither in an enhancement of the yield nor in obtaining the expected
dihydropyrimidine structure of the isolated compounds was achieved when the solvents (methanol,
ethanol, acetic acid or their mixtures), catalyst type (no catalyst, HCl, Yb(OTf)3), temperature (70–
160 °C) or heating conditions (MW in sealed vials, MW in open vials, conventional heating) were varied.
Only dihydropyridines 9a-d together with starting materials and unidentified byproducts could be
detected by HPLC in the reaction mixture.
In conclusion, microwave-assisted multicomponent reactions of methylsulfonylacetone or α-
methylsulfonylacetophenone with various aromatic aldehydes and aminoazoles or urea were studied.
Rapid procedures for the synthesis of 5-methylsulfonyl-5,8-dihydroimidazolo[1,2-a]pyrimidines and 5-
methylsulfonyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines were developed. An influence of the nature
of the aminoazole building block on the reactivity was established: the yields of the target
dihydropyrimidines decreased from 2-aminobenzimidazole to 3-amino-1,2,4-triazole, while 5-
aminotetrazole did not react at all. Additionally, an unusual direction of the Biginelli reaction of
methylsulfonylacetone with aldehydes and urea leading to non-classical Hantzsch-type 6-methyl-5-
methylsulfonyl-2-methylsulfonylmethyl-4-aryl-1,4-dihydropyridines was found.
EXPERIMENTAL
Melting points of all synthesized compounds were determined with a Kofler or Gallenkamp melting point
13
apparatus. The NMR spectra were recorded in DMSO-d6 at 360 MHz (90,5 MHz for C) with a Bruker
AMX-360 and at 200 MHz with a Varian Mercury VX-200 spectrometer. The MS spectra were measured
on a GC-MS Varian 1200L (ionizing voltage 70 eV) instrument or on a Hewlett-Packard LC/MSD 1100
series instrument in the atmospheric pressure chemical ionization (positive APCI) mode. Elemental
analysis was realized on EuroVector EA-3000.
All microwave-assisted experiments were carried out in a Discover single-mode microwave instrument
from CEM producing controlled irradiation at 2450 MHz.
X-ray diffraction study. Сrystals of 9d are monoclinic. At the 293 K a = 5.503(3), b = 18.423(2), c =
16.758(9) Å, β = 93.06(4)°, V = 1697(1) Ǻ3, Mr = 355.46, Z = 4, space group P21/n, dcalc= 1.392 g/сm3, µ
–1
(MoKα) = 0.333 mm , F(000) = 752. Intensities of 10636 reflections (2978 independent, Rint = 0.062)
were measured on the «Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD
detector, ω-scans, 2Θmax = 50°). The structure was solved by direct method using SHELXTL package.12
Positions of hydrogen atoms were located from electron density difference maps and refined by “riding”

HETEROCYCLES, Vol. 73, 2007
475
model with Uiso = nUeq of non-hydrogen atom bonded with given hydrogen atom (n = 1.5 for methyl
groups and n = 1.2 for other hydrogen atoms). The hydrogen atom participated in the hydrogen bond was
refined in isotropic approximation. Full-matrix least-squares refinement against F2 in anisotropic
approximation using 2940 reflections was converged to wR2 = 0.080 (R1 = 0.042 for 1414 reflections with
F>4σ(F)), S = 0.771). Atomic coordinates and crystallographic parameters have been deposited at the
Cambridge Crystallographic Data Centre (CCDC 649116).
Starting α-methylsulfonylacetophenone 1b was obtained by a known method.13
Preparation of methylsulfonylacetone 1a. 2.50 g (0.245 mol) of sodium methanesulfinate was dissolved
in 20 mL of ethanol and 2.25 g (0.245 mol, 1.94 mL) of chloroacetone was added into the mixture. After
refluxing for 2 h and cooling, the reaction mixture was poured onto 200 mL of ice-water, extracted with
chloroform (3 x 50 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the
resulting sulfone was precipitated from a chloroform solution by addition of hexane. Sulfone 1a was
obtained in 73% yield (2.43 g). Mp 53-54 oC (lit., 54).14
General procedure for the preparation of 5,8-dihydroimidazolo[1,2-a]pyrimidines 5a-l and 4,7-
dihydro[1,2,4]triazolo[1,5-a]pyrimidines 6a-i. A mixture of aminoazole 3 or 4 (1.0 mmol), β-
ketosulfone 1a or 1b (1.0 mmol) and the appropriate aldehyde 2 (1.0 mmol) in 1.0 mL of DMF was
o
irradiated at 135 C for 30 min in a 25 mL round-bottom flask with a short air condenser under open-
vessel conditions. After cooling, 10 mL of acetone were added and the reaction mixture was refluxed for
2-3 min. After cooling to rt, the mixture was kept at -5 oC overnight. The formed precipitate was filtered,
washed with MeOH and dried at 50 °C in the drying oven to give the target dihydroazolopyrimidine.
When it was necessary the product additionally was crystallized from DMF-MeOH (1:2).
1
5a H NMR (DMSO-d6, 360 MHz): δ 2.43 (s, 3H), 2.62 (s, 3H), 6.49 (s, 1H), 6.96 (t, J = 7.6 Hz, 1H),
13
7.05 (t, J = 7.6 Hz, 1H), 7.30 (m, 5H), 7.42 (d, J = 7.6 Hz, 2H), 11.07 (bs, 1H). C NMR (DMSO-d6,
90.6 MHz): δ 17.8, 44.9, 55.6, 106.9, 110.5, 117.4, 120.9, 122.5, 127.9, 128.9, 129.2, 131.8, 140.9, 142.6,
145.7, 146.1. Anal. Calcd for C18H17N3O2S (%): C, 63.70; H, 5.05; N, 12.38. Found: C, 63.71; H, 4.99; N,
12.45. MS: Calcd MS for [M+1]+ 340.10. Found: 340.6 (M+1, 96), 260.5 (100), 184.6 (29), 135.5 (10).
Mp 295-296 oC (with decomposition).
1
5b H NMR (DMSO-d6, 360 MHz): δ 2.44 (s, 3H), 2.73 (s, 3H), 6.54 (s, 1H), 6.98 (t, J = 7.2 Hz, 1H),
7.06 (t, J = 7.2 Hz, 1H), 7.37 (m, 4H), 7.45 (d, J = 8.6 Hz, 2H), 11.07 (bs, 1H). Anal. Calcd for
C18H16ClN3O2S (%): C, 57.83; H, 4.31; N, 11.24. Found: C, 57.78; H, 4.30; N, 11.32. MS: Calcd MS for
[M+1]+ 374.07. Found: 373.9 (M+1, 100), 294.1 (80). Mp 302 oC (with decomposition).

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HETEROCYCLES, Vol. 73, 2007
5c 1H NMR (DMSO-d6, 360 MHz): δ 2.41 (s, 3H), 2.61 (s, 3H), 3.68 (s, 3H), 6.43 (s, 1H), 6.86 (d, J = 8.4
Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 7.30 (m, 4H), 11.13 (s, 1H). 13C NMR (DMSO-
d6, 90.6 MHz): δ 17.8, 45.0, 55.5, 56.0, 107.0, 110.5, 114.5, 117.4, 120.8, 122.4, 129.2, 131.8, 132.9,
142.6, 145.7, 159.6. Anal. Calcd for C19H19N3O3S (%): C, 61.77; H, 5.18; N, 11.37. Found: C, 61.84; H,
o
5.20; N, 11.45. MS: Calcd MS for [M+1]+ 370.11. Found: 370.2 (M+1, 100), 290.1 (57). Mp 290 C
(with decomposition).
5d 1H NMR (DMSO-d6, 360 MHz): δ 2.21 (s, 3H), 2.42 (s, 3H), 2.61 (s, 3H), 6.44 (s, 1H), 6.96 (t, J = 7.6
13
Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 7.31 (m, 4H), 10.98 (bs, 1H). C NMR
(DMSO-d6, 90.6 MHz): δ 17.9, 21.1, 45.0, 56.3, 106.9, 110.5, 117.4, 120.9, 122.4, 127.8, 129.7, 131.8,
138.0, 138.3, 142.6, 145.7, 146.0. Anal. Calcd for C19H19N3O2S (%): C, 64.57; H, 5.42; N, 11.89. Found:
C, 64.49; H, 5.42; N, 11.75. MS: Calcd MS for [M+1]+ 354.12. Found: 354.4 (M+1, 100), 274.3 (69). Mp
302 oC (with decomposition).
1
5e H NMR (DMSO-d6, 360 MHz): δ 2.43 (s, 3H), 2.69 (s, 3H), 6.53 (s, 1H), 6.97 (t, J = 7.6 Hz, 1H),
7.06 (t, J = 7.6 Hz, 1H), 7.16 (m, 2H), 7.35 (dd, J = 8.0 Hz, 2H), 7.49 (dd, J = 8.0 Hz, 2H), 11.06 (bs, 1H).
Anal. Calcd for C18H16FN3O2S (%): C, 60.49; H, 4.51; N, 11.76. Found: C, 60.37; H, 4.50; N, 11.60. MS:
Calcd MS for [M+1]+ 358.09. Found: 357.9 (M+1, 100), 277.8 (33). Mp 296 oC (with decomposition).
5f 1H NMR (DMSO-d6, 360 MHz): δ 2.08 (s, 3H), 2.40 (s, 3H), 3.74 (s, 3H), 6.63 (s, 1H), 6.97 (m, 4H),
7.18 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 10.93
(bs, 1H). Anal. Calcd for C19H19N3O3S (%): C, 61.77; H, 5.18; N, 11.37. Found: C, 61.87; H, 5.23; N,
o
11.42. MS: Calcd MS for [M+1]+ 370.11. Found: 370.2 (M+1, 100), 290.1 (32). Mp 286-287 C (with
decomposition).
5g 1H NMR (DMSO-d6, 360 MHz): δ 2.45 (s, 3H), 6.68 (s, 1H), 7.04 (m, 2H), 7.39 (m, 5H), 7.56 (m, 7H),
11.21 (bs, 1H). Anal. Calcd for C23H19N3O2S (%): C, 68.81; H, 4.77; N, 10.47. Found: C, 68.41; H, 4.70;
N, 10.53. MS: Calcd MS for [M+1]+ 402.12. Found: 402.6 (M+1, 100), 322.5 (57). Mp 261-262 oC.
1
5h H NMR (DMSO-d6, 360 MHz): δ 2.52 (s, 3H), 6.73 (s, 1H), 6.90 (dd, 2H), 7.09 (m, 4H), 7.50 (m,
7H), 11.2 (bs, 1H). Anal. Calcd for C23H18ClN3O2S (%): C, 63.37; H, 4.16; N, 9.64. Found: C, 63.11; H,
4.34; N, 9.62. MS: Calcd MS for [M+1]+ 436.08. Found: 436.3 (M+1, 95), 356.2 (100). Mp 250 oC.
1
5i H NMR (DMSO-d6, 360 MHz): δ 2.57 (s, 3H), 3.93 (s, 3H), 6.64 (s, 1H), 6.93 (d, J = 8.5 Hz, 2H),
7.04 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.52 (m, 7H), 10.30 (bs, 1H). Anal. Calcd
for C24H21N3O3S (%): C, 66.80; H, 4.91; N, 9.74. Found: C, 66.59; H, 4.85; N, 9.88. MS: Calcd MS for
[M+1]+ 432.13. Found: 432.1 (M+1, 65), 352.3 (100). Mp 257 oC.
1
5j H NMR (DMSO-d6, 360 MHz): δ 2.33 (s, 3H), 3.79 (s, 3H), 6.77 (s, 1H), 7.00 (m, 4H), 7.23 (d, J =
7.6 Hz, 1H), 7.31 (m, 2H), 7.49 (m, 5H), 7.65 (d, J = 7.6 Hz, 1H), 11.16 (bs, 1H). Anal. Calcd for
C24H21N3O3S (%): C, 66.80; H, 4.91; N, 9.74. Found: C, 66.66; H, 4.84; N, 9.87. MS: Calcd MS for

HETEROCYCLES, Vol. 73, 2007
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[M+1]+ 432.13. Found: 432.1 (M+1, 100), 352.3 (65). Mp 254-255 oC.
5k 1H NMR (DMSO-d6, 360 MHz): δ 2.52 (s, 3H), 6.71 (s, 1H), 7.02 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.4
Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.54 (m, 9H), 11.32 (bs, 1H). Anal. Calcd for
C23H18BrN3O2S (%): C, 57.51; H, 3.78; N, 8.75. Found: C, 57.45; H, 3.70; N, 8.77. MS: Calcd MS for
[M+1]+ 480.03. Found: 480.1 (M+1, 100), 402.1 (37), 322.3 (51). Mp 261 oC.
5l 1H NMR (DMSO-d6, 360 MHz): δ 2.55 (s, 3H), 3.74 (s, 3H), 6.66 (s, 1H), 7.06 (m, 5H), 7.35 (m. 2H),
7.50 (m, 6H), 11.35 (bs, 1H). Anal. Calcd for C24H21N3O3S (%): C, 66.80; H, 4.91; N, 9.74. Found: C,
66.72; H, 4.83; N, 9.80. MS: Calcd MS for [M+1]+ 432.13. Found: 432.1 (M+1, 56), 352.3 (100). Mp
242-243 oC.
6a 1H NMR (DMSO-d6, 360 MHz): δ 2.39 (s, 3H), 2.69 (s, 3H), 6.31 (s, 1H), 7.30 (m, 5H), 7.68 (s, 1H),
13
11.06 (bs, 1H). C NMR (DMSO-d6, 90.6 MHz): δ 17.7, 44.9, 60.1, 106.5, 127.8, 129.0, 129.1, 141.1,
146.4, 147.4, 150.8. Anal. Calcd for C13H14N4O2S (%): C, 53.78; H, 4.86; N, 19.30. Found: C, 53.65; H,
4.90; N, 19.17. MS: Calcd MS for [M+1]+ 291.08. Found: 291.4 (M+1, 41), 211.6 (100). Mp 298-299 oC.
1
6b H NMR (DMSO-d6, 360 MHz): δ 2.38 (s, 3H), 2.77 (s, 3H), 6.33 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H),
7.40 (d, J = 8.3 Hz, 2H), 7.67 (s, 1H), 11.25 (bs, 1H). Anal. Calcd for C13H13ClN4O2S (%): C, 48.07; H,
4.03; N, 17.25. Found: C, 48.20; H, 4.07; N, 17.30. MS: Calcd MS for [M+1]+ 325.04. Found: 325.3
(M+1, 22), 245.2 (100). Mp 282-283 oC.
6c 1H NMR (DMSO-d6, 360 MHz): δ 2.39 (s, 3H), 2.69 (s, 3H), 3.73 (s, 3H), 6.26 (s, 1H), 6.90 (d, J = 8.3
Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.67 (s, 1H), 11.01 (bs, 1H). 13C NMR (DMSO-d6, 90.6 MHz): δ 17.6,
44.9, 55.6, 59.5, 106.6, 114.5, 129.1, 133.2, 150.7, 159.7. Anal. Calcd for C14H16N4O3S (%): C, 52.49; H,
5.03; N, 17.49. Found: C, 51.87; H, 4.98; N, 17.23. MS: Calcd MS for [M+1]+ 321.09. Found: 321.3
(M+1, 56), 241.5 (100). Mp 281 oC.
6d 1H NMR (DMSO-d6, 360 MHz): δ 2.26 (s, 3H), 2.39 (s, 3H), 2.69 (s, 3H), 6.26 (s, 1H), 7.15 (m, 4H),
7.66 (s, 1H), 10.94 (bs, 1H). Anal. Calcd for C14H16N4O2S (%): C, 55.25; H, 5.30; N, 18.41. Found: C,
55.17; H, 5.22; N, 18.50. MS: Calcd MS for [M+1]+ 305.10. Found: 305.2 (M+1, 94), 225.4 (100). Mp
297 oC.
1
6e H NMR (DMSO-d6, 360 MHz): δ 2.39 (s, 3H), 2.76 (s, 3H), 6.35 (s, 1H), 7.18 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.3 Hz, 2H), 7.68 (s, 1H), 10.84 (bs, 1H). Anal. Calcd for C13H13FN4O2S (%): C, 50.64; H,
4.25; N, 18.17. Found: C, 50.59; H, 4.25; N, 18.25. MS: Calcd MS for [M+1]+ 309.07. Found: 308.8
(M+1, 44), 229.0 (100). Mp 284 oC.
1
6f H NMR (DMSO-d6, 360 MHz): δ 2.47 (s, 3H), 6.50 (s, 1H), 7.46 (m, 10H), 7.72 (s, 1H), 11.23 (bs,
1H). 13C NMR (DMSO-d6, 90.6 MHz): δ 45.7, 60.2, 108.2, 127.9, 128.5, 129.1, 129.4, 129.9, 130.5,
132.9, 141.0, 147.2, 147.6, 151.0. Anal. Calcd for C18H16N4O2S (%): C, 61.35; H, 4.58; N, 15.90. Found:
C, 61.42; H, 4.65; N, 15.95. MS: Calcd MS for [M+1]+ 353.1. Found: 353.0 (M+1, 57), 272.9 (100). Mp

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266 oC.
6g 1H NMR (DMSO-d6, 360 MHz): δ 2.55 (s, 3H), 6.55 (s, 1H), 7.49 (m, 5H), 7.58 (m, 4H), 7.74 (s, 1H),
13
11.27 (bs, 1H). C NMR (DMSO-d6, 90.6 MHz): δ 45.6, 59.5, 107.9, 128.5, 129.4, 129.8, 129.9, 130.6,
132.8, 133.7, 140.1, 147.2, 147.8, 151.1. Anal. Calcd for C18H15ClN4O2S (%): C, 55.88; H, 3.91; N, 14.48.
Found: C, 56.12; H, 3.88; N, 14.70. MS: Calcd MS for [M+1]+ 387.06. Found: 386.9 (M+1, 27), 306.8
(100). Mp 226 oC.
1
6h H NMR (DMSO-d6, 360 MHz): δ 2.48 (s, 3H), 3.75 (s, 3H), 6.46 (s, 1H), 6.97 (d, J = 8.3 Hz, 2H),
7.36 (d, J = 8.3 Hz, 2H), 7.54 (m, 5H), 7.71 (s, 1H), 11.19 (bs, 1H). 13C NMR (DMSO-d6, 90.6 MHz): δ
45.7, 55.6, 59.6, 108.3, 114.7, 128.5, 129.2, 129.8, 130.5, 133.0, 133.1, 147.1, 150.9, 159.9. Anal. Calcd
for C19H18N4O3S (%): C, 59.67; H, 4.74; N, 14.65. Found: C, 59.24; H, 4.83; N, 14.39. MS: Calcd MS for
[M+1]+ 383.11. Found: 383.1 (M+1, 100), 303.3 (76). Mp 270 oC.
1
6i H NMR (DMSO-d6, 360 MHz): δ 2.32 (s, 3H), 3.76 (s, 3H), 6.58 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H),
7.08 (d, J = 8.3 Hz, 1H), 7.38 (m, 2H), 7.45 (m, 5H), 7.65 (s, 1H), 11.09 (bs, 1H). Anal. Calcd for
C19H18N4O3S (%): C, 59.67; H, 4.74; N, 14.65. Found: C, 59.34; H, 4.66; N, 14.25. MS: Calcd MS for
[M+1]+ 383.11. Found: 383.2 (M+1, 39), 303.4 (100). Mp 251-252 oC.
General procedure for the preparation of 6-methyl-5-methylsulfonyl-4-aryl-2-methanesulfonyl-
methyl-1,4-dihydropyridine 9a-d. A mixture of 60 mg (1.0 mmol) of urea, 272 mg (2.0 mmol) of 2-
methylsulfonylacetone (1a) and 1.0 mmol of the appropriate aldehyde 2 in 1.0 mL of DMF was irradiated
o
at 135 C for 45 min in a 25 mL round-bottom flask equipped with a short air condenser under open-
vessel conditions. After cooling, 10 mL of acetone were added and the reaction mixture was refluxed for
2-3 min. After cooling to rt, the mixture was kept at -5 oC overnight. The formed precipitate was filtered,
washed with MeOH and dried at 50 °C in the drying oven to give dihydropyridine products 9a-d. In some
cases the product was additionally recrystallized from DMF-MeOH (1:1).
9a 1H NMR (DMSO-d6, 360 MHz): δ 2.19 (s, 3H), 2.84 (s, 3H), 3.14 (s, 3H), 3.90 (dd, J = 14.6 Hz, J =
24.3 Hz, 2H), 4.48 (d, J = 6.0 Hz, 1H), 4.97 (d, J = 6. Hz, 1H), 7.42 (m, 5H), 8.45 (bs, 1H). Anal. Calcd
for C15H19NO4S2 (%): C, 52.76; H, 5.61; N, 4.10. Found: C, 52.71; H, 5.65; N, 4.11. MS: Calcd MS for
[M+1]+ 342.08. Found: 342.4 (M+1, 100). Mp 204 oC.
9b. 1H NMR (DMSO-d6, 360 MHz): δ 2.21 (s, 3H), 2.56 (s, 3H), 2.87 (s, 3H), 3.91 (dd, J = 37.8 Hz, J =
14.3 Hz, 2H), 4.53 (d, J = 5.6 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 7.25 (d, 2H), 7.37 (d, 2H), 8.53 (bs, 1H).
Anal. Calcd for C15H18ClNO4S2 (%): C, 47.93; H, 4.83; N, 3.73. Found: C, 47.90; H, 4.85; N, 3.77. MS:
Calcd MS for [M+1]+ 376.04. Found: 376.1 (M+1, 12) 296.0 (100). Mp 218-219 oC.
9c 1H NMR (DMSO-d6, 360 MHz): δ 2.18 (s, 3H), 2.44 (s, 3H), 2.88 (s, 3H), 3.71 (s, 3H), 3.90 (dd, J =
41.8 Hz, J = 14.3 Hz, 2H), 4.44 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.6 Hz, 1H), 6.86 (d, 2H), 7.16 (d, 2H),

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8.42 (bs, 1H). 13C NMR (DMSO-d6, 90.6 MHz): δ 18.2, 45.7, 55.5, 57.1, 105.9, 109.1, 114.2, 114.4,
125.7, 129.1, 139.6, 146.2, 158.5. Anal. Calcd for C16H21NO5S2 (%): C, 51.73; H, 5.70; N, 3.77. Found: C,
51.70; H, 5.75; N, 3.81. MS: Calcd MS for [M-1]+ 370.1. Found: 370.2 (M-1, 100). Mp 217 oC.
9d 1H NMR (DMSO-d6, 360 MHz): δ 2.17 (s, 3H), 2.24 (s, 3H), 2.43 (s, 3H), 2.85 (s, 3H), 3.90 (dd, J =
42.8 Hz, J = 14.3 Hz, 2H), 4.45 (d, 1H, J = 6.0 Hz), 4.94 (d, J = 6.0 Hz, 1H), 7.08 (d, 2H), 7,12 (d, 2H),
8.41 (bs, 1H). Anal. Calcd for C16H21NO4S2 (%): C, 54.06; H, 5.95; N, 3.94. Found: C, 54.08; H, 5.99; N,
3.91. MS: Calcd MS for [M+1]+ 356.1. Found: 355.9 (M+1, 29) 276.1 (100). Mp 201-202 oC.
ACKNOWLEDGEMENTS
The present work was supported by an Ernst Mach Grant from the Austrian Academic Exchange Service
(OeAD, Nr. 151-1/2005).
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