New approach to 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones via base-induced chloroform elimination from 4-trichloromethyl-1,2,3,4- tetrahydropyrimidin-2-ones

Article abstract of DOI:10.1016/j.tet.2010.06.058

A four-step method for the synthesis of 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones has been developed. The reaction of readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]ureas with sodium enolates of α-arylsulfonylketones followed by heterocyclization-dehydration of the oxoalkylureas formed gave 5-arylsulfonyl-4-trichloromethyl-1,2,3,4- tetrahydropyrimidin-2-ones. The latter, in the presence of strong bases, eliminate CHCl₃ to give the target compounds.

Full text of DOI:10.1016/j.tet.2010.06.058

Tetrahedron 66 (2010) 7219e7226
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New approach to 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones via
base-induced chloroform elimination from 4-trichloromethyl-1,2,3,4-
tetrahydropyrimidin-2-ones
*
Anastasia A. Fesenko, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow State Academy of Fine Chemical Technology, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2010
Received in revised form 1 June 2010
Accepted 21 June 2010
Available online 25 June 2010
A four-step method for the synthesis of 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones has been
developed. The reaction of readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]ureas with sodium
enolates of
a-arylsulfonylketones followed by heterocyclizationedehydration of the oxoalkylureas
formed gave 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones. The latter, in the
presence of strong bases, eliminate CHCl3 to give the target compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
5-Arylsulfonyl-1,2,3,4-tetrahydropyrimidin-
2-ones
5-Arylsulfonyl-1,2-dihydropyrimidin-2-
ones
Ureidoalkylation
Aromatization
1. Introduction
1,2,3,4-tetrahydropyrimidin-2-ones.5a The majority of their syn-
theses are highly specific and suffer from low yields of target
Recently, we have developed a new approach to 5-acyl-1,2-
dihydropyrimidin-2-ones via NaH-induced chloroform elimination
from the respective 4-trichloromethyl-1,2,3,4-tetrahydropyr-
imidin-2-ones.1 Due to the simplicity and efficiency of the synthesis
we decided to extend its scope to the preparation of pyrimidin-2-
ones with C(5)eS bonds (e.g., 1; Fig. 1). The latter are of considerable
interest since some of them possess antibacterial,2 antiviral,3
bronchodilator, and antiulcer activities.4 Nevertheless, compounds
1 remain hitherto practicallyunknownwith fewexamples described
in the literature.2e5 These examples include hydrolysis of appro-
priate 2-functionalized pyrimidines,2,3,5b condensation reactions of
(CeCeCþNeCeN)-type,4,5b,5c and oxidation of corresponding
products.
Thus, the development of a general approach to the synthesis of
compounds particularly 5-arylsulfonyl-substituted 1,2-dihy-
dropyrimidin-2-ones is important. In this article we describe their
synthesis using base-induced aromatization of 5-arylsulfonyl-4-
trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones.
1
2. Results and discussion
2.1. Synthesis of trichloromethyl-substituted oxoalkylureas
5-Arylsulfonyl-substituted 4-trichloromethyl-1,2,3,4-tetrahy-
dropyrimidin-2-ones were prepared according to our methodology
based on the ureidoalkylation of enolates of
ketones.1,6 Readily available
-acetoxy-substituted (trichloroethyl)
ureas 2a and b were used as ureidoalkylation reagents.1 Sodium
enolates of ketones bearing the arylsulfonyl group at -position
a-functionalized
a
a
generated in situ by treating the corresponding CH-acids 3aed
with an equivalent amount of NaH reacted with ureas 2a and
b (MeCN or THF, rt, 4e9 h) to give products of nucleophilic sub-
stitution of the acetoxy group, sulfones 4aee, in 76e90% yield
(Scheme 1, Table 1).
Figure 1. Structures of 1,2-dihydropyrimidin-2-ones 1 with C(5)-S bonds.
* Corresponding author. E-mail address: shutalev@orc.ru (A.D. Shutalev).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.058

7220
A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
the protons for major diastereomers is anti for NHeCH and gauche
for CHeCH moieties (3JNH,CH¼9.5e9.6 Hz, 3JCH,CH¼1.5e1.8 Hz).
We optimized the geometry of both isomers for 4a and d using
semiempirical methods AM1 and PM6.7 The data obtained showed
that the conformation of (R
*
*
,S )-4a and d with an antiegauche
orientation of the protons in NHeCHeCH moiety was more stable
than that with an antieanti orientation and vice versa for (R
*
*
,R
,R
*
*
)-4a
)-4a
and d. The most stable conformations for (R ,S )- and (R
*
*
with an anti orientation of bulky CCl3 and PhSO2 groups are shown
in Figure 2. In case of major diastereomer formation of intra-
molecular hydrogen bond between the proton of NH-group and
oxygen of carbonyl group becomes possible.
Thus,fromquantummechanicalcalculationsand1HNMRdatawe
conclude that major diastereomers of 4a and d have the (R
*
,S )- and
*
minor (R ,R )-configurations. The corresponding diastereomers of
*
*
compounds 4b, c, and e have the same configurations, which is clear
from comparison of their 1H NMR spectra with those for 4a and d.
Scheme 2 illustrates a supposed mechanism, which explains the
high diastereoselectivity of the reaction of 2a and b with sodium
enolates of 3aed.
Scheme 1. Synthesis of oxoalkylureas 4aee.
Table 1
Reaction of ureas 2a and b with sodium enolates of 3aed at rt
Entry Starting material Solvent Reaction Product Diastereomer ratioa Yieldb
time (h)
(%)
(R
*
,S
*
)-4/(R
*
*
,R )-4
1
2
3
4
5
6
7
2a
2a
2a
2b
2b
2b
2b
3a
3a
3b
3b
3c
3d
3d
MeCN
THF
4
4.5
5
8
4
4a
4a
4b
4c
4d
4e
4e
95:5
88:12
91:9
88
76
85
88
85
86
90
MeCN
MeCN
MeCN
MeCN
THF
97:3
85:15
85:15
86:14
9
6.5
a
According to 1H NMR data of crude products.
For isolated compounds.
b
IR, 1H, and 13C NMR spectra indicated that compounds 4aee
existed only in acyclic form both in solid state and in DMSO-d6
solution. Their cyclic isomers 5aee (Scheme 1) were not detected
by spectroscopic methods.
Reactions of 3aed with 2a and b proceeded with high diaster-
eoselectivity to give sulfones 4aee in 70e94% diastereomeric ex-
cesses (Table 1). The polarity of the solvent had a slight effect on
diastereoselectivity (entry 1 vs entry 2; entry 6 vs entry 7). N-Acyl-
substituted urea 2b reacted with enolate of 3b with higher dia-
stereoselectivity compared with urea 2a (entry 3 vs entry 4).
Based on the values of vicinal couplings of protons in the
NHeCHeCH moiety, we have concluded that the minor
diastereomers of 4aee in DMSO-d6 solution exist in a conformation
with an antieanti orientation of the named protons
(3JNH,CH¼10.1e10.8 Hz, 3JCH,CH¼8.8e9.0 Hz), while the orientation of
Scheme 2. Probable pathway of reaction between 2a and b and sodium (Z)-enolates of
3aed.
Nucleophilic addition of enolates of a-arylsulfonylketones to N-
acylimines 7 resulting from the base-induced elimination of AcOH
fromstartingureas2aandbaccordingtoanE1cBmechanism(via6)is
the principal stage of this pathway.8,9 This addition can be considered
as an aza-analog of aldol reactions between preformed enolates and
acylimines.10 The enolate also plays the role of base and regenerates
Figure 2. Optimized geometry of (R
*
,S
*
)-4a (a) and (R
*
*
,R )-4a (b) (PM6, Mopac 2009).

A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
7221
after the addition stage. The reaction of 2a and b with the sodium (Z)-
enolates of 3aed11,12 proceeds similarly to aldol additions via six-
member chair-like transition states TS-1 and TS-2 resulting from
nucleophilic attack of 8aed on Si or Re face of N-acylimines 7, re-
9bed (entry 2 vs entry 4; entries 3, 6, and 7). Benzoyl-containing
ureas 4aec react significantly slower comparing with acetyl-con-
taining ureas 4d and e (entries 1, 2, and 4 vs entries 5and 8). Ap-
parently, cyclization of N-deacylated ureas 4a, b, f, and g into the
corresponding hydroxypyrimidines 5, which is affected by elec-
trophilicity of carbonyl group and steric bulk of R1, is the rate-de-
termining step of compounds 9aed formation.
spectively. TS-2 resulting in minor (R
*
,R )-isomers is less stable than
*
TS-1 because of a steric 1,3-diaxial repulsion between CCl3 group and
R1 in TS-2. According to the proposed mechanism, the diaster-
eoselectivity of the reaction increases with increasing the steric bulk
ofR1, whichisconfirmedbydatapresentedinTable 1 (entries4and5).
Thus, under optimal conditions reflux of 4aee in BuOH in the
presence of 2e4 equiv of p-TsOH led to the smooth formation of
pyrimidines 9aed in 63e93% yields.
The specific feature of 1H NMR spectra of 6-phenyl-substituted
compounds 9a and b in DMSO-d6 solutions is strong broadening of
signals of meta- and especially ortho-protons of 6-Ph ring. The same
broadening was observed for meta- and ortho-carbon atoms in 13C
NMR spectra of 9a and b, which can be explained by hindered ro-
2.2. Synthesis of 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-
tetrahydropyrimidin-2-ones
Tetrahydropyrimidines 9aed were obtained by the reflux of
ureas 4aee in alcohols (EtOH, n-BuOH) in the presence of p-TsOH
(1e4 equiv) (Scheme 3, Table 2).
0
tation around C(6)eC(1 ) bond.
2.3. Synthesis of 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones
Treatment of tetrahydropyrimidines 9aed with strong bases in
aprotic solvents resulted in the formation of the corresponding 1,2-
dihydropyrimidines 10aed (Scheme 4).
Scheme 4. Synthesis of 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 10aed.
Scheme 3. Synthesis of 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-
2-ones 9aed.
Target pyrimidines 10aed were obtained by the reaction of
9aed (rt, MeCN, 1.2e3.3 h) with NaH (1.1 equiv) in 80e98% yields.
The rate of elimination decreased with a decrease in the base
strength. When compound 9d was treated with DBU (2.1 equiv)
in MeCN, aromatization completed in 5 days and led to formation
of 10d in 96% yield. Reaction of 9c with sodium malonate in
MeCN did not proceed at rt and was complete only after reflux for
1 h, resulting in 10c in 85% yield. Compound 9d being treated
with NaH (1.1 equiv) in THF (rt, 2 h) gave compound 10d in 90%
yield.
Formation of compounds 9a and b from 4a and b proceeds via
heterocyclization of intermediate hydroxypyrimidines 5a and
b followed by dehydration. In case of N-acetylureas 4cee, the first
step is N-deacylation into corresponding ureas 4b, f, and g followed
by cyclization into hydroxypyrimidines 5b, f, and g and fast de-
hydration into tetrahydropyrimidines 9bed. The data presented in
Table 2 show that the result of the reaction depends on the struc-
ture of the starting compounds and reaction conditions. The rate of
pyrimidine 9 formation increases with increasing reaction tem-
perature (entry 7 vs entry 8) and quantity of p-TsOH (entry 3 vs
entry 4; entry 6 vs entry 7). N-deacylation of 4cee proceeds much
faster than subsequent transformation of obtained 4b, f, and g into
Transformation of 9aed into 10aed proceeds via elimination of
chloroform from 9aed. Proton abstraction from the more acidic
Table 2
Transformation of 4aee into 9aeda
Entry
Starting
material
Solvent
Molar ratio
of 4:p-TsOH
Reaction
time (h)
Product(s)
Molar ratio of
Isolated yield
of 9 (%)
products, 9:4b
1
2
3
4
5
6
7
8
4a
4b
4c
4c
4d
4e
4e
4e
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
EtOH
1:4.0
1:4.0
1:3.1
1:4.0
1:2.0
1:1.1
1:2.1
1:2.0
31
25
5
18
2
26
16.5
2
9a
d
63
75
d
72
93
d
d
92
9b
d
9bþ4bc
28:72
d
9b
9c
d
9dþ4gd
9dþ4gd
9d
68:32
80:20
d
EtOH
n-BuOH
a
Reflux in alcohols in the presence of p-TsOH.
According to 1H NMR data.
Diastereomer mixture, 85:15.
b
c
d
Diastereomer mixture, 84:16.

7222
A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
N
(1)eH group13 in 9aed followed by CCl3-anion elimination from
hydride (60% suspension in mineral oil) was washed with dry
hexane, dried in vacuum desiccator prior to use. All other reagents
and solvents were purchased from commercial sources and used
without additional purification.
11aed leads to formation of 10aed (Scheme 5).
IR spectra (in Nujol or hexachlorobut-1,3-diene) were recorded
with a Bruker Equinox 55/S or Bruker Vector 22 spectrophotome-
ters. Band characteristics in IR spectra are defined as very strong
(vs), strong (s), medium (m), weak (w), and shoulder (sh). NMR
spectra were recorded using a Bruker DPX 300 spectrometer at
300.13 (1H) and 75.48 (13C) MHz as solutions in DMSO-d6. 1H NMR
chemical shifts are referenced to the residual proton signal for
DMSO-d6 (2.50 ppm). 13C NMR chemical shifts are reported to the
carbon signal for DMSO-d6 (39.50 ppm). Multiplicities are reported
as singlet (s), doublet (d), triplet (t), quartet (q), some combination
of these, and multiplet (m).
Scheme 5. Base-induced transformation of 9aed into 10aed.
The structure of compounds 10aed was confirmed by IR, 1H, and
13C NMR spectra. The specific characteristic of the IR spectra of
these compounds in solid state is that the NH-stretching vibrations
appear as broad and intense bands in an unusual long-wave region
(2400e3300 cmꢀ1), which can be explained by formation of strong
intermolecular hydrogen bonds of NeH/N]C type.
Thin-layer chromatography (TLC) was performed on silica gel
plates Kieselgel 60 F254 (Merck) in chloroformemethanol (9:1, v/v)
and chloroformemethanol (5:1, v/v) as solvent systems. Plates
were visualized with iodine vapor or UV light.
13C NMR spectra of 10aed in DMSO-d6 solutions demonstrated
an extreme broadening of the signals of C(4), C(6), and the carbon
atom of group R1 directly bound to pyrimidine ring, suggesting an
exchanging process. Presumably, there are three tautomeric forms
10aed, 12aed, and 13aed in DMSO-d6 (Scheme 6).
Allyields refertoisolated, spectroscopicallyand TLC purematerial.
4.2. N-[(1,1,1-Trichloro-4-oxo-4-phenyl-3-phenylsulphonyl)
but-2-yl]urea (4a)
To
a mixture of NaH (0.218 g, 9.09 mmol) and phenyl-
sulfonylacetophenone 3a (2.361 g, 9.07 mmol) was added anhy-
drous MeCN (16 mL) and the resulted suspension was stirred upon
cooling in ice bath for 9 min. To the obtained suspension was added
2a (2.266 g, 9.08 mmol) and MeCN (4.8 mL) and the reaction mix-
ture was stirred for 4 h 15 min at rt. The solvent was removed under
vacuum, to a solid residuewas added a saturated aqueous solution of
NaHCO3 until adense suspension formed, and themixturewas left in
water bath (temperature of bath 35 ꢁC) for 2 h. Upon cooling to 0 ꢁC,
the precipitate was filtered, washed with ice-cold water, light petrol,
dried, washed with cold Et2O (3ꢂ10 mL), and dried to give 3.602 g
Scheme 6. Tautomeric equilibrium of 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones.
To confirm this suggestion we performed ab initio calculations
(B3LYP/6-31þþG**
)
14 for 10a, 12a, 13a and 10c, 12c, 13c. According
(88.3%) of 4a as a mixture of (R
*
,S
*
)- and (R
*
*
,R )-diastereomers, 95:5.
to these calculations, 13a is the most stable tautomer in the gas
phase, followed by 12a and 10a in the order of increasing energy
(0.5 and 0.7 kcal/mol, respectively). Analogously, the hydroxy form
13c is favorable, while the tautomers 10c and 12c are less stable (0.4
and 1.4 kcal/mol, respectively). Thus, the computations clearly
demonstrate the insignificant difference in energy of all three
tautomeric forms 10aed, 12aed, and 13aed.15
After three crystallization from EtOH the diastereomeric ratio
changed to 98:2. Mp 172.5e173 ꢁC (decomp., EtOH). 1H NMR of
major diastereomer (DMSO-d6) d: 8.00e8.06 (2H, m, C(2)H and C(6)H
in PhC]O), 7.86e7.92 (2H, m, C(2)H and C(6)H in PhSO2), 7.69e7.81
(2H, m, C(4)H in PhC]O and PhSO2), 7.55e7.66 (4H, m, C(3)H and
C(5)H in PhC]O and PhSO2), 6.89 (1H, d, J 9.6 Hz, NH), 6.29 (2H, br s,
NH2), 6.13 (1H, d, J 1.7 Hz, CHeSO2), 5.53 (1H, dd, J 9.6, 1.7 Hz,
CHeCCl3).1H NMR of minor diastereomer (DMSO-d6)
d: 6.86 (1H, d, J
3. Conclusion
10.6 Hz, NH), 6.17 (2H, br s, NH2), 5.85 (1H, d, J 8.8 Hz, CHeSO2), 5.75
(1H, dd, J 10.6, 8.8 Hz, CHeCCl3). Signals of other protons overlap
with proton signals of major isomer. 13C NMR of major diastereomer
We have developed a new four-step approach to the synthesis of
5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones. Starting
trichloromethyl-substituted oxoalkylureas were prepared using
(DMSO-d6) d: 191.8 (C]O in PhC]O), 157.2 (NeC]O), 137.0 (C(1) in
PhC]O), 136.1 (C(1) in PhSO2), 135.0 (C(4) in PhSO2), 134.7 (C(4) in
PhC]O), 129.5 (C(2) and C(6) in PhC]O), 129.3 (C(2) and C(6) in
PhSO2),129.2 (C(3) and C(5) in PhSO2),128.9 (C(3) and C(5) in PhC]O),
ureidoalkylation of sodium enolates of a-arylsulfonyl-substituted
ketones with readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]
ureas. High diastereoselectivity of this reaction was explained in
terms of aza-analog of aldol condensation. Hetero-
cyclizationedehydration of resulted oxoalkylureas in the presence
of p-TsOH gave 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahy-
dropyrimidin-2-ones. The key step of the synthesis was the aro-
matization of the latter compounds induced by strong bases, which
proceeds via elimination of chloroform and led to smooth formation
of the target 5-arylsulfonyl-substituted dihydropyrimidin-2-ones.
102.3 (CCl3), 64.4 and 63.5 (NeCHeCHeSO2). IR (Nujol)
3503 (s), 3470 (s), 3383 (br s), 3337 (s), 3192 (m) ( NH),1711 (s),1679
(vs),1662 (s) (amide-I and C]O in Bz),1605 (s) ( CC in Ph),1535 (s)
(amide-II), 1496 (s) ( CC in Ph), 1338 (s) (nas SO2), 1154 (s) (ns SO2),
751 (vs) ( CH in Ph). Anal. Calcd for C17H15Cl3N2O4S: C, 45.40; H,
n :
, cmꢀ1
n
n
n
n
d
3.36; N, 6.23%. Found: C, 45.31; H, 3.34; N, 6.21%.
When THF was used instead of MeCN (rt, 4 h 30 min), 4a was
obtained in 76.4% yield as a mixture of (R
,S
* *
)- and (R
*
,R )-di-
*
astereomers, 88:12.
4. Experimental section
4.1. General
4.3. N-[(1,1,1-Trichloro-4-oxo-4-phenyl-3-tosyl)but-2-yl]urea
(4b)
Acetonitrile was dried by distillation from P2O5 and then from
CaH2. THF was dried over KOH pellets and then over Na. Sodium
Compound 4b (2.696 g, 85.0%) as a mixture of (R
*
,S
*
)- and (R
*
,
R
*
)-diastereomers (91:9) was prepared (analogously to 4a) from 2a

A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
7223
(1.714 g, 6.87 mmol), p-tosylacetophenone 3b (1.877 g, 6.84 mmol),
4.5. N-Acetyl-N0-[(1,1,1-trichloro-4-oxo-3-phenylsulfonyl)
and NaH (0.164 g, 6.84 mmol) in MeCN (16 mL) (rt, 4 h 45 min).
After crystallization from EtOH the diastereomeric ratio changed to
92:8. Mp 205e205.5 ꢁC (decomp., EtOH). 1H NMR of major di-
pent-2-yl]urea (4d)
Compound 4d (3.745 g, 84.6%) as a mixture of (R
*
,S
*
)- and (R ,
*
astereomer (DMSO-d6)
d
: 7.99e8.05 (2H, m, C(2)H and C(6)H in Ph),
R )-diastereomers (85:15) was prepared (analogously to 4a) from
*
7.77 (2H, m, AA0 part of AA0XX0 spin system, Jortho 8.3 Hz, C(2)H and
C(6)H in 4-MeC6H4), 7.70e7.77 (1H, m, C(4)H in Ph), 7.55e7.63 (2H,
m, C(3)H and C(5)H in Ph), 7.43 (2H, m, XX0 part of AA0XX0 spin
system, Jortho 8.3 Hz, C(3)H and C(5)H in 4-MeC6H4), 6.89 (1H, d, J
9.6 Hz, NH), 6.30 (2H, br s, NH2), 6.09 (1H, d, J 1.7 Hz, CHeSO2), 5.49
(1H, dd, J 9.6, 1.7 Hz, CHeCCl3), 2.40 (3H, s, CH3). 1H NMR of minor
2b (2.789 g, 9.67 mmol), phenylsulfonylacetone 3c (1.896 g,
9.56 mmol), and NaH (0.229 g, 9.56 mmol) in MeCN (19 mL) (rt, 3 h
40 min). Mp 213.5e214 ꢁC (decomp., EtOH). 1H NMR of major di-
astereomer (DMSO-d6) d: 10.58 (1H, br s, NH), 9.73 (1H, br d, J
9.5 Hz, NH), 7.61e7.91 (5H, m, Ph), 5.54 (1H, d, J 1.5 Hz, CHeSO2),
5.27 (1H, dd, J 9.5, 1.5 Hz, CHeCCl3), 2.52 (3H, s, CH3 in CHeAc), 1.98
diastereomer (DMSO-d6)
d
: 7.90e7.95 (2H, m, C(2)H and C(6)H in
(3H, s, CH3 in NHeAc). 1H NMR of minor diastereomer (DMSO-d6)
d:
Ph), 7.26 (2H, m, XX0 part of AA0XX0 spin system, Jortho 8.3 Hz, C(3)
H
10.72 (1H, br s, NH), 9.19 (1H, br d, J 10.7 Hz, NH), 7.61e7.9 (5H, m,
signals overlap with proton signals of major isomer, Ph), 5.65 (1H,
dd, J 10.7, 8.8 Hz, CHeCCl3), 5.50 (1H, d, J 8.8 Hz, CHeSO2), 2.38 (3H,
s, CH3 in CHeAc), 2.01 (3H, s, CH3 in NHeAc). 13C NMR of major
and C(5)H in 4-MeC6H4), 6.84 (1H, d, J 10.1 Hz, NH), 6.18 (2H, br s,
NH2), 5.78 (1H, d, J 8.8 Hz, CHeSO2), 5.73 (1H, dd, J 10.1, 8.8 Hz,
CHeCCl3), 2.29 (3H, s, CH3). Signals of other protons overlap with
proton signals of major isomer. 13C NMR of major diastereomer
diastereomer (DMSO-d6) d: 199.9 (C]O in CHeAc), 171.9 (C]O in
(DMSO-d6)
d
: 191.9 (C]O in PhC]O), 157.2 (NeC]O), 145.8 (C(4) in
NHeAc), 153.4 (C]O in urea), 135.8 (C(1) in Ph), 135.2 (C(4) in Ph),
129.5 (C(2) and C(6) in Ph), 129.2 (C(3) and C(5) in Ph), 100.7 (CCl3),
68.1 (CHeSO2), 63.3 (CHeNH), 34.9 (CH3 in CHeAc), 23.5 (CH3 in
4-MeC6H4), 137.1 (C(1) in Ph), 134.6 (C(4) in Ph), 133.3 (C(1)
in 4-MeC6H4), 129.8 (C(3) and C(5) in 4-MeC6H4), 129.5 (C(2) and C(6)
in Ph), 129.2 (C(2) and C(6) in 4-MeC6H4), 128.9 (C(3) and C(5) in Ph),
102.4 (CCl3), 64.4 and 63.5 (NeCHeCHeSO2), 21.2 (CH3 in Ts). IR
NHeAc), 21.2 (CH3 in Ts). IR (Nujol)
3067 (m) ( NH), 1718 (s) ( C]O in CHeAc), 1694 (vs) (amide-I),
1583 (w) ( CC in Ph), 1538 (vs) (amide-II), 1496 (m) (
1316 (s) (nas SO2), 1155 (vs) (ns SO2), 743 (s), 682 (s) (
n
, cmꢀ1: 3239 (br s), 3139 (br s),
n
n
(Nujol)
NH), 1683 (vs) (amide-I and
C6H4), 1494 (s) (amide-II), 1335 (m) (nas SO2), 1131 (m) (ns SO2), 803
(m) ( CH in C6H4), 742 (s) ( CH in Ph). Anal. Calcd for
n
, cmꢀ1: 3437 (s), 3374 (m), 3315 (m), 3248 (w), 3204 (m) (
n
n
n
CC in Ph),
n
C]O in Bz), 1594 (m) (
n
CC in Ph and
d CH in Ph).
Anal. Calcd for C14H15Cl3N2O5S: C, 39.13; H, 3.52; N, 6.52%. Found: C,
39.44; H, 3.63; N, 6.59%.
d
d
C18H17Cl3N2O4S: C, 46.62; H, 3.70; N, 6.04%. Found: C, 46.55; H,
4.04; N, 6.18%.
4.6. N-Acetyl-N0-[(1,1,1-trichloro-4-oxo-3-tosyl)pent-2-yl]urea
(4e)
Compound 4e (2.250 g, 90.0%) as a mixture of (R
*
,S
*
)- and (R
*
,
4.4. N-Acetyl-N0-[(1,1,1-trichloro-4-oxo-4-phenyl-3-tosyl)but-
R
*
)-diastereomers (86:14) was prepared (analogously to 4a) from
2-yl]urea (4c)
2b (1.746 g, 5.99 mmol), p-tosylacetone 3d (1.196 g, 5.63 mmol),
and NaH (0.136 g, 5.65 mmol) in THF (10 mL) (rt, 6 h 28 min). When
MeCN was used instead of THF (rt, 8 h 42 min), 4e was obtained in
Compound 4c (3.745 g, 88.1%) as a mixture of (R
)-diastereomers (97:3) was prepared (analogously to 4a) from 2b
(2.453 g, 8.41 mmol), p-tosylacetophenone 3b (2.305 g,
*
,S
*
)- and (R
*
,
R
*
85.6% yield as a mixture of (R
Mp 224.5e225 ꢁC (decomp., EtOH). 1H NMR of major diastereomer
(DMSO-d6) : 10.54 (1H, br s, NH), 9.71 (1H, br d, J 9.5 Hz, NH), 7.75
(2H, m, AA0 part of AA0XX0 spin system, Jortho 8.4 Hz, C(2)H and C(6)
*
,S
*
)- and (R
*
,R
*
)-diastereomers, 85:15.
8.40 mmol), and NaH (0.202 g, 8.40 mmol) in MeCN (21 mL) (rt, 7 h
44 min). After crystallization from EtOH the diastereomeric ratio
changed to 98:2. Mp 233e233.5 ꢁC (decomp., EtOH). 1H NMR of
d
H
in 4-MeC6H4), 7.48 (2H, m, XX0 part of AA0XX0 spin system, Jortho
8.4 Hz, C(3)H and C(5)H in 4-MeC6H4), 5.48 (1H, d, J 1.5 Hz, CHeSO2),
5.25 (1H, dd, J 9.5,1.5 Hz, CHeCCl3), 2.52 (3H, s, CH3 in CHeAc), 2.44
(3H, s, CH3 in 4-MeC6H4), 1.98 (3H, s, CH3 in NeAc). 1H NMR of
major diastereomer (DMSO-d6) d: 10.64 (1H, br s, NH in NHeAc),
9.90 (1H, br d, J 9.5 Hz, NH), 8.02e8.07 (2H, m, C(2)H and C(6)H in
Ph), 7.70e7.76 (1H, m, C(4)H in Ph), 7.67 (2H, m, AA0 part of AA0XX0
spin system, Jortho 8.4 Hz, C(2)H and C(6)H in 4-MeC6H4), 7.54e7.61
(2H, m, C(3)H and C(5)H in Ph), 7.41 (2H, m, XX0 part of AA0XX0 spin
system, Jortho 8.4 Hz, C(3)H and C(5)H in 4-MeC6H4), 6.17 (1H, d, J
1.8 Hz, CHeSO2), 5.59 (1H, dd, J 9.5, 1.8 Hz, CHeCCl3), 2.39 (3H, s,
CH3 in Ts), 2.02 (3H, s, CH3 in NHeAc). 1H NMR of minor di-
astereomer (DMSO-d6)
br d, J 10.2 Hz, NH), 7.92e7.97 (2H, m, C(2)H and C(6)H in Ph), 7.24
(2H, m, XX0 part of AA0XX0 spin system, Jortho 8.3 Hz, C(3)H and C(5)
minor diastereomer (DMSO-d6) d: 10.70 (1H, br s, NH), 9.21 (1H, br
d, J 10.8 Hz, NH), 7.69 (2H, m, AA0 part of AA0XX0 spin system, Jortho
8.4 Hz, C(2)H and C(6)H in 4-MeC6H4), 7.45 (2H, m, XX0 part of
AA0XX0 spin system, Jortho 8.4 Hz, C(3)H and C(5)H in 4-MeC6H4), 5.63
(1H, dd, J 10.8, 8.8 Hz, CHeCCl3), 5.41 (1H, d, J 8.8 Hz, CHeSO2), 2.41
(3H, s, CH3 in 4-MeC6H4), 2.37 (3H, s, CH3 in CHeAc), 2.02 (3H, s,
d: 10.80 (1H, br s, NH in NHeAc), 9.52 (1H,
CH3 in NeAc). 13C NMR of major diastereomer (DMSO-d6)
d: 200.0
H
(C]O in CHeAc),171.8 (C]O in NHeAc), 153.3 (C]O in urea),146.0
(C(4) in 4-MeC6H4), 133.0 (C(1) in 4-MeC6H4), 129.8 (C(3) and C(5) in
4-MeC6H4), 129.2 (C(2) and C(6) in 4-MeC6H4), 100.7 (CCl3), 68.1
(CHeSO2), 63.4 (CHeNH), 34.8 (CH3 in CHeAc), 23.4 (CH3 in
in 4-MeC6H4), 5.99 (1H, d, J 9.0 Hz, CHeSO2), 5.93 (1H, dd, J 10.2,
9.0 Hz, CHeCCl3), 2.26 (3H, s, CH3 in Ts), 2.07 (3H, s, CH3 in NHeAc).
Signals of other protons overlap with proton signals of major iso-
mer. 13C NMR of major diastereomer (DMSO-d6)
d
: 191.3 (C]O in
NHeAc), 21.2 (CH3 c Ts). IR (Nujol)
3064 (m) ( NH), 1719 (s) ( C]O in CHeAc), 1696 (s) (amide-I),
1602 (w) ( CC in C6H4), 1536 (s) (amide-II), 1496 (w) ( CC in C6H4),
1325 (s) (nas SO2), 1155 (vs) (ns SO2), 797 (s) ( CH in C6H4). Anal.
n
, cmꢀ1: 3229 (br s), 3141 (br s),
PhC]O), 171.9 (C]O in NHeAc), 153.3 (C]O in urea), 146.1 (C(4) in
4-MeC6H4), 136.9 (C(1) in Ph), 134.7 (C(4) in Ph), 132.9 (C(1) in 4-
MeC6H4), 129.8 (C(3) and C(5) in 4-MeC6H4), 129.3 (C(2) and C(6) in
Ph), 129.1 (C(2) and C(6) in 4-MeC6H4), 129.0 (C(3) and C(5) in Ph),
100.7 (CCl3), 63.6 and 63.5 (NeCHeCHeSO2), 21.2 (CH3 in Ts). IR
n
n
n
n
d
Calcd for C15H17Cl3N2O5S: C, 40.60; H, 3.86; N, 6.31%. Found: C,
40.37; H, 3.95; N, 6.32%.
(Nujol)
(amide-I and
(amide-II), 1505 (m) (
(m) (ns SO2), 805 (s) (
n
, cmꢀ1: 3237 (m), 3129 (m) (
C]O in Bz), 1594 (m) ( CC in Ph and C6H4), 1531 (s)
CC in Ph and C6H4), 1323 (s) (nas SO2), 1130
CH in C6H4), 745 (s) ( CH in Ph). Anal. Calcd
n NH), 1692 (vs), 1674 (s)
n
n
4.7. 4-(Trichloromethyl)-6-phenyl-5-phenylsulphonyl-1,2,3,4-
tetrahydropyrimidin-2-one (9a)
n
d
d
for C20H19Cl3N2O5S: C, 47.49; H, 3.79; N, 5.54%. Found: C, 47.27; H,
3.84; N, 5.60%.
A solution of 4a (3.038 g, 6.18 mmol) and p-TsOH$H2O (4.701 g,
24.72 mmol) in n-BuOH (20 mL) was heated to reflux under stirring

7224
A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
for 31 h, and solvent was then removed in vacuum. To a residue was
added saturated aqueous solution of NaHCO3 (10 mL) and light
petrol (20 mL), and the obtained mixture was neutralized by solid
NaHCO3 to pH 8 under stirring. Upon cooling to 0 ꢁC, the precipitate
was filtered, washed with ice-cold water, light petrol, dried, washed
with cold Et2O (3ꢂ10 mL), and dried to give 1.832 g (62.6%) of 9a. Mp
for 2 h and then solvent was removed in vacuum. The obtained res-
idue was triturated with light petrol (2ꢂ20 mL), the liquid layer was
decanted and saturated aqueous solution of NaHCO3 was added (to
pH 8), to the obtained suspension was added light petrol (10 mL).
Upon cooling to 0 ꢁC, the precipitate was filtered, washed with ice-
coldwater, lightpetrol,coldEt2O(3ꢂ10 mL), anddriedtogive6.939 g
278.5 ꢁC (decomp., EtOH).1H NMR (DMSO-d6)
d
: 10.36 (1H, s, N(1)H),
(92.9%) of 9c. Mp 251.5 ꢁC (decomp., EtOH). 1H NMR (DMSO-d6)
d:
9.05 (1H, d, J 5.2 Hz, N(3)H), 7.39e7.47 (2H, m, C(4)H in 6-Ph and
PhSO2), 7.20e7.27 (2H, m, C(3)H and C(5)H in PhSO2), 7.04e7.09 (2H,
10.21 (1H, s, N(1)H), 8.93 (1H, d, J 5.0 Hz, N(3)H), 7.58e7.71 (5H, m, Ph),
5.06 (1H, d, J 5.0 Hz, 4H), 1.89 (3H, s, 6-CH3). 13C NMR (DMSO-d6)
d:
m, C(2)H and C(6)H in PhSO2), 6.70e7.30 (4H, m, very br signals, C(2)
and C(6)H, C(3)H and C(5)H in 6-Ph), 5.28 (1H, d, J 5.2 Hz, 4H).13C NMR
(DMSO-d6) : 154.1 (C(2)),151.0 (C(6)),142.5 (C(1) in PhSO2),132.3 (C(4)
H
153.4 (C(2)),151.2 (C(6)),143.7 (C(1) in Ph),132.9 (C(4) in Ph),129.4 (C(2)
andC(6) in Ph),126.1 (C(3) and C(5) in Ph),104.9 (CCl3),102.6 (C(5)), 66.3
d
(C(4)), 17.6 (6-CH3). IR (Nujol)
3087 (w), 3063 (w) ( CH in Ph),1718 (s),1685 (s) (amide-I),1618 (s) (n
n n NH),
, cmꢀ1: 3284 (br s), 3168 (m) (
in PhSO2), 131.2 (C(4) in 6-Ph),130.6 (C(1) in 6-Ph),130.2 (very br, C(2)
and C(6) in 6-Ph),128.5 (C(2) and C(6) in PhSO2),127.8 (br, C(3) and C(5)
in 6-Ph), 126.3 (C(3) and C(5) in PhSO2), 104.8 (CCl3), 104.6 (C(5)), 66.0
n
C]C),1289 (s) (nas SO2),1137 (s) (ns SO2), 758 (s), 689 (s) (d CH in Ph).
(C(4)). IR (Nujol)
(vs) (amide-I), 1612 (s) (
759 (s), 685 (s) ( CH in Ph). Anal. Calcd for C17H13Cl3N2O3S: C, 47.30;
n
, cmꢀ1: 3288 (m), 3234 (m), 3129 (m) (
n
NH), 1711
4.10. 4-(Trichloromethyl)-6-methyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one (9d)
n
C]C), 1294 (s) (nas SO2), 1142 (s) (ns SO2),
d
H, 3.04; N, 6.49%. Found: C, 47.32; H, 3.30; N, 6.49%.
Compound 9d (2.346 g 92.3%) was prepared (analogously to 9c)
from 4e (3.051 g, 6.79 mmol) and p-TsOH$H2O (2.619 g,
13.77 mmol) in n-BuOH (26 mL) (reflux, 2 h). Mp 256e256.5 ꢁC
4.8. 4-(Trichloromethyl)-6-phenyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one (9b)
(decomp., EtOH). 1H NMR (DMSO-d6)
d: 10.17 (1H, d, J 1.8 Hz, N(1)H),
8.91 (1H, dd, J 5.0,1.8 Hz, N(3)H), 7.66 (2H, m, AA0 part of AA0XX0 spin
system, Jortho 8.3 Hz, C(2)H and C(6)H in 4-MeC6H4), 7.41 (2H, m, XX0
part of AA0XX0 spin system, Jortho 8.3 Hz, C(3)H and C(5)H in
4-MeC6H4), 5.04 (1H, d, J 5.0 Hz, 4H), 2.38 (3H, s, CH3 in 4-MeC6H4),
Method A:
A solution of 4b (2.328 g, 4.60 mmol) and
p-TsOH$H2O (3.498 g, 18.39 mmol) in n-BuOH (17 mL) was heated
to reflux under stirring for 25 h, and solvent was then removed in
vacuum. To an oily residue was added saturated aqueous solution of
NaHCO3 (pH 8), and the resulting mixture was stirred until com-
plete crystallization. Upon cooling to 0 ꢁC, the precipitate was fil-
tered, thoroughly washed with ice-cold water, light petrol, dried,
washed with cold Et2O (3ꢂ5 mL), and dried to give 1.530 g (74.8%)
1.89 (3H, s, 6-CH3). 13C NMR (DMSO-d6)
d: 153.1 (C(2)), 151.3 (C(6)),
143.3 (C(4) in 4-MeC6H4), 141.0 (C(1) in 4-MeC6H4), 129.8 (C(3) and
C(5) in 4-MeC6H4), 126.2 (C(2) and C(6) in 4-MeC6H4), 104.9 (CCl3),
103.0 (C(5)), 66.3 (C(4)), 21.0 (CH3 c Ts), 17.6 (6-CH3). IR (Nujol)
cmꢀ1: 3222 (br s), 3084 (br s) (
NH), 1726 (s) (amide-I), 1625 (s) (
C]C), 1598 (w), 1491 (w) ( CC in C6H4), 1293 (s) (nas SO2), 1146 (s)
ns SO2), 809 (s) ( CH in C6H4). Anal. Calcd for C13H13Cl3N2O3S: C,
n,
n
n
of 9b. Mp 234e234.5 ꢁC (decomp., AcOEt). 1H NMR (DMSO-d6)
d
:
n
10.31 (1H, s, N(1)H), 9.00 (1H, d, J 5.2 Hz, N(3)H), 7.40e7.47 (1H, m,
C(4)H in 6-Ph), 7.18e7.31 (2H, m, br signals, C(3)H and C(5)H in 6-Ph),
6.85e7.17 (2H, m, very br signals, C(2)H and C(6)H in 6-Ph), 7.03 (2H,
m, AA0 part of AA0XX0 spin system, Jortho 8.3 Hz, C(2)H and C(6)H in
4-MeC6H4), 6.93 (2H, m, XX0 part of AA0XX0 spin system, Jortho
8.3 Hz, C(3)H and C(5)H in 4-MeC6H4), 5.27 (1H, d, J 5.2 Hz, 4H), 2.28
(
d
40.70; H, 3.42; N, 7.30%. Found: C, 40.92; H, 3.51; N, 7.54%.
4.11. 4-Phenyl-5-phenylsulphonyl-1,2-dihydropyrimidin-2-
one (10a)
(3H, s, CH3 in 4-MeC6H4). 13C NMR (DMSO-d6)
d
: 153.9 (C(2)), 151.0
To a mixture of NaH (0.037 g, 1.54 mmol) and 9a (0.665 g,
1.40 mmol) was added anhydrous MeCN (10 mL) and the resulted
suspension was stirred in an ice bath for 3 min. The obtained so-
lution was stirred for 7 min at rt and then precipitation occurred.
The resultant suspension was stirred for additional 1 h 45 min at rt,
and solvent was removed in vacuum. To a dry residue was added
H2O (2 mL), the obtained suspension was neutralized with 2%
aqueous solution of HCl to pH 7. Upon cooling to 0 ꢁC, the pre-
cipitate was filtered, washed with ice-cold water, light petrol, and
dried to give 0.406 g (92.5%) of 10a. Mp 245.5e246.5 ꢁC (EtOH). 1H
(C(6)), 142.5 (C(4) in 4-MeC6H4), 139.8 (C(1) in 4-MeC6H4), 131.1 (C(4)
in Ph),130.7 (C(1) in Ph),130.1 (very br, C(2) and C(6) in Ph),128.9 (C(3)
and C(5) in 4-MeC6H4), 127.7 (br, C(3) and C(5) in Ph), 126.3 (C(2) and
C(6) in 4-MeC6H4), 104.9 (C(5)), 104.8 (CCl3), 66.0 (C(4)), 20.9 (CH3
Ts). IR (Nujol)
, cmꢀ1: 3399 (s), 3293 (sh), 3239 (br s), 3128 (s) (
NH), 1712 (vs) (amide-I), 1612 (s) (
in Ph and C6H4), 1301 (s) (nas SO2), 1145 (s) (ns SO2), 821 (s) (
C6H4), 763 (s), 695 (s) ( CH in Ph). Anal. Calcd for C18H15Cl3N2O3S:
c
n
n
n
C]C), 1597 (m), 1494 (m) (
n
CC
CH in
d
d
C, 48.50; H, 3.39; N, 6.29%. Found: C, 48.47; H, 3.26; N, 6.26%.
Method B: A solution of 4c (4.909 g, 9.70 mmol) and p-TsOH$H2O
(7.386 g, 38.82 mmol) in n-BuOH (30 mL) was heated to reflux
under stirring for 18 h and then solvent was removed in vacuum. To
an oily residue was added saturated aqueous solution of NaHCO3
(10 mL) and H2O (40 mL), the resulted mixture was triturated upon
cooling, and the aqueous layer was decanted. To the obtained res-
idue was added saturated aqueous solution of NaHCO3 (5 mL) and
the mixture was allowed to stand overnight at rt. The resulted solid
was triturated until fine suspension formed, upon cooling to 0 ꢁC,
the precipitate was filtered, thoroughly washed with ice-cold wa-
ter, light petrol, dried, washed with cold Et2O (2ꢂ10 mL), and dried
to give 3.183 g (72.0%) of 9b.
NMR (DMSO-d6) d: 13.04 (1H, br s, NH), 8.85 (1H, s, 6H), 7.53e7.61
(1H, m, C(4)H in PhSO2), 7.40e7.47 (1H, m, C(4)H in 4-Ph), 7.35e7.40
(4H, m, C(2)H and C(6)H, C(3)H and C(5)H in PhSO2), 7.25e7.31 (2H, m,
C(3)H and C(5)H in 4-Ph), 7.04e7.08 (2H, m, C(2)H and C(6)H in 4-Ph).
13C NMR (DMSO-d6)
d: 170.7 (very br, C(4)), 155.0 (C(2)), 154.5 (very
br, C(6)), 140.4 (C(1) in PhSO2), 134.9 (very br, C(1) in 6-Ph), 133.4 (C(4)
in PhSO2),129.9 (br, C(4) in 4-Ph),129.0 (C(2) and C(6) in PhSO2),128.1
(br, C(2) and C(6) in 4-Ph), 127.5 (C(3) and C(5) in 4-Ph), 127.1 (C(3) and
C(5) in PhSO2), 117.2 (C(5)). IR (Nujol)
2661 (m), 2626 (m) ( NH), 1687 (vs) (amide-I), 1596 (vs) (
C]N), 1517 (s) (amide-II), 1308 (s) (nas SO2), 1147 (vs) (ns SO2), 766
(s), 691 (s) ( CH in Ph). Anal. Calcd for C16H12N2O3S: C, 61.53; H,
n
, cmꢀ1: 3064 (m), 2725 (m),
C]C,
n
n
n
d
3.87; N, 8.97%. Found: C, 61.47; H, 3.85; N, 8.91%.
4.9. 4-(Trichloromethyl)-6-methyl-5-phenylsulphonyl-
1,2,3,4-tetrahydropyrimidin-2-one (9c)
4.12. 4-Phenyl-5-tosyl-1,2-dihydropyrimidin-2-one (10b)
A solution of 4d (8.558 g, 19.92 mmol) and p-TsOH$H2O (7.574 g,
39.82 mmol) in n-BuOH (50 mL) was heated to reflux upon stirring
Compound 10b (0.353 g, 79.6%) was prepared (analogously to
10a) from 9b (0.620 g, 1.36 mmol) and NaH (0.037 g, 1.54 mmol) in

A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
7225
MeCN (4.6 mL) (rt, 1 h 30 min). Mp 225.5e226 ꢁC (MeCN). 1H NMR
(DMSO-d6) : 12.99 (1H, br s, NH), 8.82 (1H, s, 6H), 7.42e7.48 (1H,
Supplementary data
d
m, C(4)H in Ph), 7.27e7.33 (2H, m, C(3)H and C(5)H in Ph), 7.25 (2H, m,
AA0 part of AA0XX0 spin system, Jortho 8.5 Hz, C(2)H and C(6)H in 4-
MeC6H4), 7.19 (2H, m, XX0 part of AA0XX0 spin system, Jortho 8.5 Hz,
C(3)H and C(5)H in 4-MeC6H4), 7.06e7.11 (2H, m, C(2)H and C(6)H in
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.058.
Ph), 2.32 (3H, s, CH3). 13C NMR (DMSO-d6)
d: 170.2 (very br, C(4)),
References and notes
155.0 (C(2)), w154.7 (very br, C(6)), 144.0 (C(4) in 4-MeC6H4), 137.6
(C(1) in 4-MeC6H4), 134.8 (very br, C(1) in 6-Ph), 129.8 (br, C(4) in
4-Ph), 129.4 (C(3) and C(5) in 4-MeC6H4), 128.1 (br, C(2) and C(6) in 4-
Ph),127.4 (br, C(3) and C(5) in 4-Ph),127.2 (C(2) and C(6) in 4-MeC6H4),
1. Fesenko, A. A.; Solovyev, P. A.; Shutalev, A. D. Tetrahedron 2010, 66, 940e946.
2. Caldwell, W. T.; Sayin, A. N. J. Am. Chem. Soc. 1952, 74, 4314e4317.
3. Schroeder, A. C.; Bardos, T. J. J. Med. Chem. 1981, 24, 109e112.
4. Lipinski, C. A.; Stam, J. G.; Pereira, J. N.; Ackerman, N. R.; Hess, H.-J. J. Med. Chem.
1980, 23, 1026e1031.
5. (a) Mamaev, V. P.; Dubovenko, Z. D. Khim. Geterotsikl. Soedin. 1970, 6, 541e545
[Chem. Heterocycl. Compd. (Engl. Transl.) 1970, 6, pp 501e504]; (b) Arukwe, J.;
Keilen, G.; Undheim, K. Acta Chem. Scand., Ser. B 1988, 42, 530e536; (c) Hafez,
A. A. A. Collect. Czech. Chem. Commun. 1993, 58, 2222e2226.
6. (a) Shutalev, A. D.; Kuksa, V. A. Khim. Geterotsikl. Soedin. 1997, 33, 105e109
[Chem. Heterocycl. Compd. (Engl. Transl.) 1997, 33, pp 91e95]; (b) Shutalev, A. D.
Khim. Geterotsikl. Soedin. 1997, 33, 1696e1697 [Chem. Heterocycl. Compd. (Engl.
Transl.) 1997, 33, pp 1469e1470]; (c) Shutalev, A. D.; Kishko, E. A.; Sivova, N. V.;
Kuznetsov, A. Y. Molecules 1998, 3, 100e106; (d) Fesenko, A. A.; Shutalev, A. D.
Tetrahedron Lett. 2007, 48, 8420e8423; (e) Fesenko, A. A.; Cheshkov, D. A.;
Shutalev, A. D. Mendeleev Commun. 2008, 18, 51e53.
117.6 (C(5)), 21.0 (CH3). IR (Nujol)
2730 (br s), 2669 (br s) ( NH), 1700 (vs) (amide-I), 1657 (vs) (
C), 1609 (vs) ( C]N),1514 (s) (amide-II),1492 (m) ( CC in C6H4 and
Ph), 1315 (s) (nas SO2), 1154 (vs) (ns SO2), 816 (s) ( CH in C6H4), 768
(s), 698 (s) ( CH in Ph). IR (hexachlorobut-1,3-diene)
, cmꢀ1: 3158
(br s), 3067 (vs), 3007 (br s), 2951 (br s), 2921 (s), 2866 (br s), 2743
(br s), 2673 (br s) ( NH). Anal. Calcd for C17H14N2O3S: C, 62.56; H,
n
, cmꢀ1: 3157 (br s), 3064 (br s),
C]
n
n
n
n
d
d
n
n
4.32; N, 8.58%. Found: C, 62.25; H, 4.44; N, 8.67%.
7. The PM6 and AM1 calculations were carried out using the Mopac 2009 (James J.P.
Stewart, Stewart Computational Chemistry, Version 9.211W, http://openmopac.
net/index.html) and WinMopac programs (Version 7.21, http://www.psu.ru/
science/soft/winmopac/index_e.html), respectively.
4.13. 4-Methyl-5-phenylsulphonyl-1,2-dihydropyrimidin-2-
one (10c)
8. It was stated,16 that N-acylimines form as an intermediate in the reactions of
amidoalkylation of various nucleophiles in basic media with amidoalkylating
reagents derived from primary amides.
Compound 10c (0.618 g, 97.9%) was prepared (analogously to
10a) from 9c (1.038 g, 2.81 mmol) and NaH (0.074 g, 3.09 mmol) in
MeCN (10 mL) (rt, 3 h 20 min). Mp 247 ꢁC (decomp., EtOH). 1H NMR
9. For reviews on
a-halogenated imino compounds, see: (a) De Kimpe, N.;
Schamp, N. Org. Prep. Proced. Int. 1979, 11, 115e199; (b) De Kimpe, N.; Verhé, R.;
De Buyck, L.; Schamp, N. Org. Prep. Proced. Int. 1980, 12, 49e180.
10. For reviews on aldol reactions, see: (a) Mahrwald, R. Aldol Reactions; Springer:
Dordrecht, 2009; (b) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004; Vols. 1 and 2.
11. The preference of sodium (Z)-enolates formation from 3aed in MeCN was
demonstrated by NMR spectroscopy as followed. A solution of 3c (13.5 mg, 0.
0636 mmol) in MeCN-d3 (0.5 mL) was added to a 5 mm NMR tube charged
with NaH (2.3 mg, 0.0958 mmol). The obtained mixture was shaken carefully
until the evolution of gas ceased. Assignment of the (Z)-configuration of the
generated Na-enolate was based on the NOE effect observed between the
(DMSO-d6) d: 12.81 (1H, very br s, NH), 8.75 (1H, s, 6H), 7.94e7.99
(2H, m, C(2)H and C(6)H in Ph), 7.70e7.76 (1H, m, C(4)H in Ph),
7.60e7.68 (2H, m, C(3)H and C(5)H in Ph), 2.33 (3H, s, 4-CH3). 13C
NMR (DMSO-d6)
(C(2)), 140.9 (C(1) in Ph), 133.8 (C(4) in Ph), 129.7 (C(2) and C(6) in Ph),
127.1 (C(3) and C(5) in Ph), 116.0 (C(5)), 21.0 (br, 4-CH3). IR (Nujol)
cmꢀ1: 3164 (m), 3083 (sh), 3064 (s), 2774 (br s), 2687 (br s), 2574
(m) ( NH), 1713 (vs) (amide-I), 1664 (s) ( C]C, C]N), 1589 (s),
1578 (s) (amide-II), 1314 (s) (nas SO2), 1165 (vs) (ns SO2), 735 (s), 688
(s) ( CH in Ph). Anal. Calcd for C11H10N2O3S: C, 52.79; H, 4.03; N,
d: 167.4 (very br, C(4)), 158.0 (very br, C(6)), 155.1
n
,
n
n
n
a
-proton (3.3% enhancement after irradiation of the vicinal CH3) and the
methyl protons in its 1H NMR NOE difference spectrum. (Z)-Configuration of
the enolate of 3c was also confirmed by the value of vicinal coupling con-
stant of 13Ce1H in 13CH3eC]CeH moiety, which equals 2.0 Hz in proton
coupled 13C NMR spectra. The expected constant value for (E)-enolate is
5 Hz.17
d
11.19%. Found: C, 52.82; H, 4.12; N, 10.96%.
4.14. 4-Methyl-5-tosyl-1,2-dihydropyrimidin-2-one (10d)
12. Semiempirical calculations using PM67 method demonstrated that (Z)-eno-
lates of compounds 3aed are thermodynamically more stable than
(E)-enolates.
Compound 10d (0.901 g, 97.8%) was prepared (analogously to
10a) from 9d (1.338 g, 3.49 mmol) and NaH (0.092 g, 3.84 mmol) in
MeCN (20 mL) (rt, 1 h 15 min). Mp 265e265.5 ꢁC (decomp., EtOH).
14
13. According to ab initio calculations (B3LYP/6-31þþG**
)
the anion 11c is more
stable (10.0 kcal/mol) than the anion resulted from N(3)-H deprotonation in the
gas phase.
1H NMR (DMSO-d6)
d: 12.78 (1H, very br s, NH), 8.72 (1H, s, 6H), 7.84
14. The ab initio calculations were carried out using the Gaussian 03 program
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision E.01; Gaussian:
Wallingford, CT, 2004.
(2H, m, AA0 partofAA0XX0 spin system, Jortho 8.3 Hz, C(2)HandC(6)H in
4-MeC6H4), 7.44 (2H, m, XX0 part of AA0XX0 spin system, Jortho 8.3 Hz,
C(3)H and C(5)H in 4-MeC6H4), 2.39 (3H, s, CH3 in Ts), 2.32 (3H, s,
4-CH3). 13C NMR (DMSO-d6)
d: 167.3 (br, C(4)), 157.7 (br, C(6)), 155.3
(C(2)), 144.3 (C(4) in 4-MeC6H4), 138.1 (C(1) in 4-MeC6H4), 130.1 (C(3)
and C(5) in 4-MeC6H4), 127.1 (C(2) and C(6) in 4-MeC6H4), 116.3 (C(5)),
21.0 (CH3 in Ts), 21.0 (br, 4-CH3). IR (Nujol)
(m), 3022 (m), 3006 (m), 2746 (s), 2689 (s), 2646 (m) (
1695 (vs) (amide-I), 1672 (s) ( C]C), 1612 (s) ( C]N), 1545 (s)
(amide-II),1316 (s) (nas SO2),1156 (vs) (ns SO2), 818 (s) ( CH in C6H4).
IR (hexachlorobut-1,3-diene)
, cmꢀ1: 3092 (m), 3066 (m), 3026 (m),
3009 (w), 2971 (m), 2950 (m), 2926 (m), 2846 (br vs), 2830 (s), 2755
(br vs), 2693 (br vs), 2649 (m) ( NH). Anal. Calcd for C12H12N2O3S: C,
n
, cmꢀ1: 3090 (m), 3064
NH),1708 (s),
n
n
n
d
n
15. For the prototropic tautomerism of six-membered heterocycles, see (a)
Katritzky, A. R.; Lagowski, J. M. In Adv. Heterocycl. Chem.; Katritzky, A. R.,
Ed.; Academic: New York, 1963; Vol. 1, pp 339e437; (b) Elguero, J.; Ka-
tritzky, A. R.; Denisko, O. V. In Adv. Heterocycl. Chem.; Katritzky, A. R., Ed.;
Academic: San Diego, 2000; Vol. 76, pp 1e84; (c) Rauhut, G. In Adv. Het-
erocycl. Chem.; Katritzky, A. R., Ed.; Academic: San Diego, 2001; Vol. 81,
n
54.53; H, 4.58; N, 10.60%. Found: C, 54.44; H, 4.52; N, 10.39%.
Acknowledgements
ꢀ
pp 1e105; (d) Stanovnik, B.; Tisler, M.; Katritzky, A. R.; Denisko, O. V. In Adv.
Heterocycl. Chem.; Katritzky, A. R., Ed.; Academic: San Diego, 2001; Vol. 81,
pp 253e303; (e) Stanovnik, B.; Tisler, M.; Katritzky, A. R.; Denisko, O. V. In
Adv. Heterocycl. Chem.; Katritzky, A. R., Ed.; Elsevier: Amsterdam, 2006; Vol.
91, pp 1e134.
We thank Dr. Andrei Guzaev (AM Chemicals LLC, Oceanside, CA,
USA) for helpful discussions. We are also grateful to Dmitry A.
Cheshkov for 1H NMR NOE difference experiments.
ꢀ

7226
A.A. Fesenko, A.D. Shutalev / Tetrahedron 66 (2010) 7219e7226
16. (a) Zaugg, H. E. Synthesis 1970, 49e73; (b) De Kimpe, N.; Verhé, R.; De Buyck, L.;
Dejonghe, W.; Schamp, N. Bull. Soc. Chim. Belg. 1976, 85, 763e779; (c) Ko-
bayashi, T.; Ishida, N.; Hiraoka, T. J. Chem. Soc., Chem. Commun. 1980, 736e737;
(d) Zaugg, H. E. Synthesis 1984, 85e110; (e) Zaugg, H. E. Synthesis 1984,
181e212; (f) Hamon, D. P. G.; Massy-Westropp, R. A.; Razzino, P. Tetrahedron
1992, 48, 5163e5178; (g) Petrini, M.; Torregiani, E. Synthesis 2007, 159e186; (h)
Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2008, 73, 940e947; (i)
7 mg, 0.1125 mmol) in DMSO-d6 (0.5 mL). The values of vicinal coupling
constants 13Ce1H of 13CH3eC]CeH moiety of obtained enolates in proton
coupled 13C NMR spectra were 1.7 and 4.9 Hz correspondingly. Based on the
relationship between this constant and dihedral angle CeC]CeH we con-
clude that major stereoisomer has (Z)-configuration and minor (E)-configu-
ration.18 Assignment of the (Z)-configuration of the major stereoisomer was
also based on the NOE effect observed between the
a-proton (5.1% en-
ꢁ
ꢁ
Mazurkiewicz, R.; Pazdzierniok-Holewa, A.; Orlinska, B.; Stecko, S. Tetrahedron
Lett. 2009, 50, 4606e4609.
hancement after irradiation of the vicinal CH3) and the methyl protons in its
1H NMR NOE difference spectrum.
17. Mixture of stereoisomeric Na-enolates 3c (in 86:14 ratio) was prepared as
described above11 by the reaction of 3c (16.2 mg, 0.0763 mmol) with NaH (2.
18. Pretsch, E.; Büllmann, P.; Affolter, C. Structure Determination of Organic Com-
pounds; Springer: Berlin, Heidelberg, 2000.