N-substituted ureas and thioureas in Biginelli reaction promoted by chlorotrimethylsilane: Convenient synthesis of N1-alkyl-, N1-aryl-, and N1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thi)ones

Article abstract of DOI:10.1055/s-2007-965881

The classical Biginelli reaction has been extended by the use of N-substituted ureas and thioureas. A set of N1-alkyl-, N1-aryl-, and N1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thi)ones was readily prepared in excellent yield when chlorotrimethylsilane in

Full text of DOI:10.1055/s-2007-965881

PAPER
417
N-Substituted Ureas and Thioureas in Biginelli Reaction Promoted by
Chlorotrimethylsilane: Convenient Synthesis of N1-Alkyl-, N1-Aryl-, and
N1,N3-Dialkyl-3,4-Dihydropyrimidin-2(1H)-(thi)ones
Synthesis of
N
e
-Substitute
r
d 3, 4-D
i
g
e
H
)-(
y
thi)one
s
V. Ryabukhin,a,b Andrey S. Plaskon,a,b Eugeniy N. Ostapchuk,a Dmitriy M. Volochnyuk,*a,c
Andrey A. Tolmachevb
a
Enamine Ltd, 23 A. Matrosova St, Kyiv, 01103, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
National Taras Shevchenko University, 62 Volodymyrska St, Kyiv-33, 01033, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv-94, 02094, Ukraine
b
c
Received 10 October 2006; revised 7 November 2006
ed the synthetic versatility of numerous 1,3-dicarbonyl
compounds, including b-keto esters, b-keto amides, cyclic
b-diketones, and b-keto phosphonates.7 N-Unsubstituted
ureas and thioureas are predominantly used in the reac-
Abstract: The classical Biginelli reaction has been extended by the
use of N-substituted ureas and thioureas. A set of N1-alkyl-, N1-
aryl-, and N1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thi)ones
was readily prepared in excellent yield when chlorotrimethylsilane
in N,N-dimethylformamide was used as promoter and water scaven- tion. Therefore, N1-aryl-substituted DHPMs are very
scantily represented in the literature.8,9 This may be be-
ger.
cause the N-aryl- and N,N-dialkylureas as well as the cor-
responding thioureas involved in the Biginelli reaction
lead to a complex mixture of products containing a negli-
gible amount of the corresponding dihydropyrimi-
dones.3a,10 N-Alkylureas provide higher yields of the
target compounds. Moreover, they usually are obtained by
the alternative method based on selective alkylation of
N1-unsubstituted analogues under Mitsunobu-type condi-
tions.10 N1,N3-dialkyl-DHMPs,11 including N1,N3-di-
methyl derivatives,12 could be prepared in several steps by
alkylation. The same approach to N-aryl-DHMPs by ary-
lation of N1,N3-unsubstituted DHMPs has been described
in only one paper, and leads exclusively to N3-arylated
products.13
Key words: Biginelli reaction, heterocycles, Lewis acid, multi-
component reaction, parallel synthesis
Derivatives of dihydropyrimidinones (DHPMs) have
widespread pharmacological activities, and are regarded
as one of the most important groups of druglike scaffolds.1
The Biginelli reaction is ranked as one of the most power-
ful tools for the facile synthesis of these scaffolds. The
classical Biginelli reaction involves the one-pot cyclocon-
densation of an aldehyde, a b-keto ester, and a urea under
highly acidic conditions (Scheme 1).2,3
R
We have developed an alternative approach to N1-substi-
tuted DHMPs, and this approach is based on the regiose-
lective cyclocondensation of a-chlorobenzyl isocyanates
with ethyl N-alkyl- or N-aryl-b-aminocrotonates.14 Since
the approach did not allow the variation of substituents at
N1 and C4, we became interested in extending the Bigi-
nelli reaction by optimizing the reaction conditions by us-
ing various substituted ureas and thioureas. At the same
time our synthetic group developed the use of chlorotri-
methylsilane as a promoter and water scavenger.15 Silanes
with good active groups such as halogen or triflate have
been applied successfully as condensation agents for the
Biginelli reaction.16 In these reactions, unsubstituted ureas
and thioureas are used; however, any marked advantage
of the silanes over Lewis acids4 was not demonstrat-
ed.16b,d–f Nevertheless, the N,N-dimethylformamide–
acetonitrile–chlorotrimethylsilane system broadens the
scope of the reaction to cyclic mono- and dicarbonyl com-
pounds.16 On the basis of these considerations and prelim-
inary results,17 the silanes were chosen as promising
condensing agents for this reaction. Initially we used the
previously described procedures,16a,b,e which are quite
complicated, and gave yields lower than 20–25%.
H+, EtOH
CO2Et
Me
NH2
NH2
R
+
+
CO2Et
Me
O
HN
O
H
O
O
N
H
Scheme 1
Over the last two decades, more efficient conditions have
been found for the Biginelli reaction, in which Lewis
acids such as BF3·OEt2, LaX3 (X = Cl, OTf), Yb(OTf)3,
InX3 (X = Cl, Br), ZrCl4, BiX3 (X = Cl, OTf), LiX (X =
Br, ClO4), Mn(OAc)3, CAN, FeCl3·6H2O, NiCl2·6H2O,
RuCl3, and SmI2 are used as catalysts.4 Microwave
exposure5 as well as solid-phase and fluoro-phase
techniques6 facilitating this synthesis have also become
increasingly widespread. Also, in recent decades, the
scope of the original Biginelli reaction, shown in
Scheme 1, has been extended by variation of the 1,3-di-
carbonyl building blocks. Many groups have demonstrat-
SYNTHESIS 2007, No. 3, pp 0417–0427
Advanced online publication: 12.01.2007
x
x
.
x
x
.2
0
0
7
DOI: 10.1055/s-2007-965881; Art ID: P11606SS
© Georg Thieme Verlag Stuttgart · New York

418
S. V. Ryabukhin et al.
PAPER
Two reactions, between N-phenylurea (1e) or N-phenyl-
thiourea (2e), benzaldehyde (3a), and ethyl acetoacetate
(4), were chosen for optimization (Scheme 2, Figures 1–4).
To optimize the reaction conditions, the solvent, the reac-
tion time, and the amount of chlorotrimethylsilane were
varied. We encountered problems in monitoring these re-
actions by HPLC–MS (Figure 1). The chromatograms of
the reaction mixtures were rather complicated, and the
peak with the molecular weight of the supposed product
was not observed. However, treatment of the reaction
mixtures with water resulted in the precipitation of solids,
which in most cases appeared to be the target product. The
chromatogram of the reaction mixture containing com-
pounds 2e, 3a, and 4 in the presence of four equivalents
chlorotrimethylsilane in N,N-dimethylformamide solu-
tion after 48 hours at room temperature, and the chromato-
gram of the same reaction mixture after its treatment with
water are shown in Figure 1 (top and bottom, respective-
ly). The main peak (99%) at m/z = 353 corresponds to
[M + 1] of product 6ea. The appearance of the chromato-
grams can be rationalized by the assumption that various
polysilylated derivatives of 6ea are present in the reaction
mixture, and that they either do not ionize or have m/z
peaks corresponding to [M + 1] above 353. It should be
noted that the first chromatogram does not contain peaks
of the starting materials. On the basis of these results, fur-
ther monitoring of the reactions was by HPLC–MS of the
precipitates formed after treatment of the reaction mix-
tures with water. It is worth noting that in the mother li-
quor (H2O–DMF, ca. 10:1) the product was found in trace
amounts.
Figure 1 HPLC chromatograms of the reaction mixture of 2e, 3a,
and 4 in DMF in the presence of TMSCl (4 equiv) at r.t. after 48 h
(top) and of the precipitate that formed after dilution of the reaction
mixture with 10 volume of H2O (bottom)
The optimal reaction conditions were found to consist of
N,N-dimethylformamide solution, 48 hours at room tem-
perature, and the presence of four equivalents chlorotri-
methylsilane. Under these conditions, the model reaction
with N-phenylurea (1e) gave the final product 5ea in 95%
yield and in 86% purity. N-Phenylthiourea (2e) produced
better results: the desired DHPM 6ea formed in 97%
yield, with a homogeneity of the crude product of 99%.
When the reaction mixtures are heated, the yields de-
crease significantly, and many side processes take place.
building blocks 1, 2, and 3 used in the Biginelli reaction
are shown in Figures 2–4.
R3
R2
TMSCl
(4 equiv)
R2
X
CO2Et
Me
NH
CO2Et
Me
R3
N
+
H
+
X
NH
R1
DMF, r.t., 48 h
O
O
N
R1
1, 2
3
4
5, 6
1, 5 X = O
2, 6 X = S
In addition, the influence of the silane leaving group was
studied under the optimized conditions. Chloro-, bromo-,
and iodotrimethylsilanes were examined. Iodotrimethylsi-
lane was generated in situ from chlorotrimethylsilane and
sodium iodide in N,N-dimethylformamide solution.16e
More active and expensive silanes do not have any advan-
tage in the reaction. While under analogous conditions
iodotrimethylsilane gave comparable results, those of bro-
motrimethylsilane were worse, and the purity of the crude
products decreased. It can probably be explained by the
higher reactivity of bromo- and iodotrimethylsilane to-
wards the ester functions in the starting ethyl acetoacetate
(4) and the final DHPMs 5ea and 6ea.
Scheme 2
NH2
NH2
NH
NH2
NH2
O
NH
Me
O
O
NH
Ph
O
NH
1a
1b
1c
1d
NH2
NH
NH2
Me
O
NH
O
O
NH
NH
Me
1e
1f
1g
Cl
This optimized procedure was used in the parallel synthe-
sis of an array of DHPMs from ethyl acetoacetate (4) and
various substituted (aryl, alkyl, symmetrical dialkyl)
ureas 1, thioureas 2, and aldehydes 3 (Scheme 2). The
Figure 2 The urea building blocks 1a–g used in the Biginelli reac-
tion
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Substituted 3,4-Dihydropyrimidin-2(1H)-(thi)ones
419
NH2
NH2
NH
NH2
NH
Ph
mixture exists in an equilibrium with its protonated salt 11
(Scheme 3). The formation of this type of intermediate in
the reaction between urea or thiourea and an aldehyde in
the presence of chlorotrimethylsilane has been described
previously.18 The next step, the addition of silylated ace-
toacetate 13 to this imine 10 affords intermediate 14. Fi-
nally, 6-exo-trig cyclization followed by elimination of
bis(trimethylsilyl) ether leads to the 3,4-dihydropyrimi-
din-2(1H)-(thi)one products. In the case of symmetrical
dialkyl(thio)ureas, a key intermediate is, most probably, a
compound of type 17 (Scheme 3). The formation of simi-
lar types of compounds in the presence of chlorotrimeth-
ylsilane has been described previously.19 As we use an
excess of chlorotrimethylsilane in the reaction mixtures,
intermediates of types 17 and 18 could be present. Most
probably, these compounds are shown in the HPLC–MS
spectra, but when the reaction mixtures are poured into
water, only final products 16 form.
S
NH
S
S
2a
2b
2c
OMe
NH2
NH
NH2
NH
Me
S
NH
S
S
NH
Me
O
2d
2e
2f
Figure 3 The thiourea building blocks 2a–f used in the Biginelli
reaction
Cl
OMe
CHO
NMe2
CHO
The structures of the new substances were confirmed by
1H NMR, 13C NMR, and IR spectroscopy, mass spectrom-
etry, and elemental analysis (Table 2). The 1H NMR spec-
tra of N1-aryl-substituted 3,4-dihydropyrimidin-2(1H)-
(thi)ones have an interesting feature. The signals for the
ortho protons of the substituent at N1 are broad and struc-
turally unresolved owing to hindered rotation about N1–
C(ipso). To confirm the structures of these compounds,
we tried obtain NOE correlations between the C6-methyl
group and the ortho protons of the N1-aryl group so that
dihydrothiazine and dihydrooxazine systems could be ex-
cluded (Figure 5).20 Unfortunately, due to strong broaden-
ing of the signals for the ortho protons (e.g., Dn1/2 ~ 95 Hz
for 6ec), satisfactory NOE correlations could be obtained
only at 100 °C (Figure 5). Broadening of signals was also
observed for the alkyl group on N1. For example, at room
temperature the methylene group of the N1-benzyl deriv-
ative 6cb exhibited two broad and structurally unresolved
signals (Dn1/2 ~ 95 Hz) and good NOE correlation for this
compound was obtained only at 80 °C (Figure 5).
CHO
3a
CHO
3b
3c
3d
CO2Me
NO2
CF3
OCHF2
CHO
CHO
CHO
CHO
3g
3e
3f
3h
S
S
F
Cl
F
F
CHO
CHO
CHO
CHO
3i
3j
3k
3l
Figure 4 The aldehyde building blocks 3a–l used in the Biginelli
reaction
The reaction was generally run according to an estab-
lished procedure in which a 1:1:1:4 molar ratio of urea 1
(thiourea 2), aldehyde 3, acetoacetate 4, and chlorotrime-
thylsilane was used as a solution in N,N-dimethylforma-
mide. The reactions were completed in 24–48 hours at
room temperature. Then the reaction mixture was diluted
with 3 volumes of water, and the amorphous precipitate
that had formed was triturated in an ultrasonic bath for an
hour, yielding a crude product. The crude product 5 or 6
was isolated by simple filtration, washed with a small
amount of propan-2-ol, and crystallized from an appropri-
ate solvent. The total yields of the isolated products were
between 73% and 97%, with high purities indicated by
HPLC (Table 1). The aldehydes that can be used in the re-
action are limited, and are similar to those suitable for the
synthesis of benzimidazoles.15d
In conclusion, an efficient solution-phase procedure for
the combinatorial synthesis of libraries of N1-substituted
3,4-dihydropyrimidin-2(1H)-ones and 3,4-dihydropyrim-
idine-2(1H)-thiones in solution was developed. For the
first time, a simple convenient procedure for the synthesis
of N1-aryl-3,4-dihydropyrimidin-2(1H)-ones and N1-
aryl-3,4-dihydropyrimidine-2(1H)-thiones was presented.
All investigated reactions were used for the preparation of
small libraries. In the majority of cases, the final products
were obtained in high purity (>90%) or purification could
be done by simple crystallization. The results provide fur-
ther confirmation of the scope and generality of the ap-
plied approach to 3,4-dihydropyrimidin-2(1H)-ones and
3,4-dihydropyrimidine-2(1H)-thiones. Over the last year,
over 2500 analogues have been synthesized in our labora-
tories (www.enamine.net) by parallel-synthesis methods.
The reaction most probably proceeds by the mechanism
proposed for the Biginelli-type reactions in the presence
of chlorotrimethylsilane.16a–c The first key step is forma-
tion of iminium intermediate 10, which in the reaction
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

420
S. V. Ryabukhin et al.
PAPER
X
X
X
COOEt
9
Ar
Ar
Ar'
O
Ar
OTMS
Ar'
N
H
N
N
NHTMS
H
13
H
COOEt
HN
10
X
Ar'
O
NH
Ar
TMSCl
Ar'
7
TMSCl
Ar
14
X
COOEt
N
H
N+
H
N
H
NH2
8
O
12
11
TMSCl
Ar'
Ar'
S
COOEt
TMSCl
HN
COOEt
Me
HN
N+
Ar'
N
H
X
N
OTMS
– TMS2O
Me
X
N
17
Ar
Ar
16
15
TMSCl
TMSCl
H2O
H2O
Ar'
Ar'
COOEt
COOEt
TMSCl
TMS-N
X
TMS-N
X
N
N
OTMS
– TMS2O
Ar
Ar
17
18
Scheme 3
Cl
OMe
6cb
6ec
COOEt
HN
COOEt
weak NOE (80 °C)
HN
2.01, s
Me
2.39, s
S
N
Me
S
N
NOE (100 °C)
H
at 80 °C: 6.06, d, 2JHH = 15.6
at r.t.: br, Dn1/2 ~ 45 Hz
H
H
H
at 100 °C: 7.15,
d, 3JHH = 7.2
strong NOE (80 °C)
at 80 °C: 5.18, d, 2JHH = 15.6
at r.t.: br, Dn1/2 ~ 45 Hz
at r.t.: 7.15, br,
Dn1/2 ~ 95 Hz
Figure 5 Significant 1H NMR data (400 MHz, DMSO-d6) for 3,4-dihydropyrimidine-2(1H)-thiones 6ec and 6cb
Table 1 Yield and Purification Data of 3,4-Dihydropyrimidin-2(1H)-ones and 3,4-Dihydropyrimidine-2(1H)-thionesa
Reagent 1 or 2 Reagent 3
Product
No
Yield
Purity
Crystalliza- Yieldd
tion solvent (%)
(crude)b (%) (crude)c (%)
1a
3b
5ab
97
93
88
EtOH
89
O
N
NH
Cl
N
COOEt
1a
3d
5ad
81
i-PrOH
78
O
N
NH
COOEt
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Substituted 3,4-Dihydropyrimidin-2(1H)-(thi)ones
421
Table 1 Yield and Purification Data of 3,4-Dihydropyrimidin-2(1H)-ones and 3,4-Dihydropyrimidine-2(1H)-thionesa (continued)
Reagent 1 or 2 Reagent 3
Product
No
Yield
Purity
Crystalliza- Yieldd
tion solvent (%)
(crude)b (%) (crude)c (%)
O
N
1a
3f
5af
96
89
EtOH
88
NH
COOEt
NO2
1a
1b
1c
3l
5al
94
96
97
92
90
90
EtOH
88
86
86
O
N
NH
S
COOEt
3b
3b
5bb
5cb
EtOAc–
n-hexane
O
N
NH
Cl
COOEt
NH
i-PrOH
O
N
Cl
COOEt
1d
1e
1e
1f
1f
1f
3e
3a
3g
3a
3f
5de
5ea
5eg
5fa
5ff
96
95
96
95
96
96
89
86
84
88
88
84
EtOAc–
n-hexane
80
84
82
87
87
81
O
N
NH
COOMe
COOEt
NH
Et2O
O
N
COOEt
Et2O
O
N
CF3
NH
COOEt
MeOH
MeOH
i-PrOH
O
NH
Cl
Cl
N
COOEt
O
N
NH
COOEt
Cl
NO2
3i
5fi
O
N
NH
Cl
F
COOEt
1g
3e
5ge
96
85
EtOAc–
n-hexane
83
O
N
N
COOMe
COOEt
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

422
S. V. Ryabukhin et al.
PAPER
Table 1 Yield and Purification Data of 3,4-Dihydropyrimidin-2(1H)-ones and 3,4-Dihydropyrimidine-2(1H)-thionesa (continued)
Reagent 1 or 2 Reagent 3
Product
No
Yield
Purity
Crystalliza- Yieldd
tion solvent (%)
(crude)b (%) (crude)c (%)
1g
3f
5gf
94
86
EtOAc–
n-hexane
82
O
N
N
COOEt
NO2
2a
2a
3b
3h
6ab
6ah
97
87
88
89
EtOAc–
n-hexane
85
78
S
N
NH
Cl
COOEt
EtOAc–
n-hexane
F
F
S
N
O
NH
COOEt
NH
2a
2b
2c
3k
3b
3b
6ak
6bb
6cb
88
93
93
90
85
91
EtOAc–
n-hexane
77
81
88
S
N
S
COOEt
EtOAc–
n-hexane
S
N
NH
Cl
Cl
O
COOEt
i-PrOH
S
N
NH
COOEt
2c
3c
3f
6cc
6df
89
85
91
90
EtOAc–
n-hexane
85
73
S
N
NH
OMe
COOEt
2d
EtOAc–
n-hexane
S
N
NH
NO2
COOEt
NH
O
2e
2e
2e
3a
3b
3c
6ea
6eb
6ec
97
97
94
99
99
98
–
–
–
97
97
94
S
N
COOEt
S
N
NH
Cl
COOEt
S
N
NH
OMe
COOEt
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Synthesis of N-Substituted 3,4-Dihydropyrimidin-2(1H)-(thi)ones
423
Table 1 Yield and Purification Data of 3,4-Dihydropyrimidin-2(1H)-ones and 3,4-Dihydropyrimidine-2(1H)-thionesa (continued)
Reagent 1 or 2 Reagent 3
Product
No
Yield
Purity
Crystalliza- Yieldd
tion solvent (%)
(crude)b (%) (crude)c (%)
2e
2e
3h
6eh
93
94
93
EtOH
90
F
F
S
N
O
NH
COOEt
F
3j
6ej
88
i-PrOH
84
S
N
NH
F
COOEt
2f
2f
3c
3g
6fc
6fg
90
91
88
87
EtOAc–
n-hexane
81
79
S
N
N
N
O
COOEt
CF3
EtOAc–
n-hexane
S
N
COOEt
a Satisfactory microanalysis data were obtained for all products, with C 0.33, H 0.45, N 0.25.
b Yield of crude material obtained after dilution of the reaction mixture with 3 volumes H2O and collection of the precipitate by filtration.
c Homogeneity of the crude products by reversed-phase HPLC.
d Yield of pure, isolated product.
Table 2 Melting Point, 1H NMR Spectroscopy, and MS Data of 3,4-Dihydropyrimidin-2(1H)-(thi)ones 5 and 6a
Compd Mpb (°C)
1H NMR (400 MHz, DMSO-d6): dc
m/zd
5ab
5ad
5af
125–126
127–128
129–130
117–118
150–151
152–153
107–108
1.17 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.50 (s, 3 H, CH3), 3.13 (s, 3 H, NCH3), 4.04 (q, 3JHH = 7.1 Hz, 2 309
H, OCH2CH3), 5.16 (d, 3JHH = 3.9 Hz, 1 H, CH), 7.21 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.26 (d, 3JHH = 8.7 Hz,
2 H, CH), 7.93 (d, 3JHH = 3.9 Hz, 1 H, NH)
1.18 (t, 3JHH = 7.2 Hz, 3 H, OCH2CH3), 2.51 (s, 3 H, CH3), 2.89 (s, 6 H, N(CH3)2), 3.13 (s, 3 H, NCH3), 318
4.03 (q, 3JHH = 7.2 Hz, 2 H, OCH2CH3), 5.06 (d, 3JHH = 3.7 Hz, 1 H, CH), 6.59 (d, 3JHH = 8.6 Hz, 2 H,
CH), 7.01 (d, 3JHH = 8.6 Hz, 2 H, CH), 7.64 (d, 3JHH = 3.7 Hz, 1 H, NH)
1.19 (t, 3JHH = 7.2 Hz, 3 H, OCH2CH3), 2.54 (s, 3 H, CH3), 3.14 (s, 3 H, NCH3), 4.08 (q, 3JHH = 7.1 Hz, 2 320
H, OCH2CH3), 5.30 (d, 3JHH = 3.8 Hz, 1 H, CH), 7.56 (t, 3JHH = 7.8 Hz, 1 H, CH), 7.63 (d, 3JHH = 7.8 Hz,
1 H, CH), 8.08 (d, 3JHH = 7.8 Hz, 1 H, CH), 8.11 (s, 1 H, CH), 8.12 (d, 3JHH = 3.8 Hz, 1 H, NH)
5al
1.25 (t, 3JHH = 7.2 Hz, 3 H, OCH2CH3), 2.39 (s, 3 H, CH3), 2.47 (s, 3 H, CH3), 3.12 (s, 3 H, NCH3), 4.11 295
(q, 3JHH = 7.2 Hz, 2 H, OCH2CH3), 5.30 (d, 3JHH = 3.9 Hz, 1 H, CH), 6.52 (m, 1 H, CH), 6.61 (d, 3JHH
3.4 Hz, 1 H, CH), 7.93 (d, 3JHH = 3.9 Hz, 1 H, NH)
=
5bb
5cb
5de
1.22 (t, 3JHH = 7.2 Hz, 3 H, OCH2CH3), 1.48 (m, 2 H, CH2), 1.63 (m, 1 H, CH), 1.84 (m, 3 H, CH2+CH), 363
2.07 (m, 2 H, CH2) 2.46 (s, 3 H, CH3), 4.07 (m, 3 H, OCH2CH3+NCH), 5.10 (d, 3JHH = 4.2 Hz, 1 H, CH),
7.19 (d, 3JHH = 8.6 Hz, 2 H, CH), 7.24 (d, 3JHH = 8.6 Hz, 2 H, CH), 7.80 (d, 3JHH = 4.2 Hz, 1 H, NH)
1.15 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.40 (s, 3 H, CH3), 3.05 (s, 3 H, NCH3), 4.02 (q, 3JHH = 7.1 Hz, 2 385
H, OCH2CH3), 4.78 (d, 1 H, 2JHH = 17.1 Hz, CH), 5.12 (d, 1 H, 2JHH = 17.1 Hz, CH), 5.22 (d, 3JHH = 3.6
Hz, 1 H, CH), 7.04 (d, 3JHH = 7.5 Hz, 2 H, CH), 7.16–7.26 (m, 7 H, CH), 8.09 (d, 3JHH = 3.9 Hz, 1 H, NH)
1.15 (t, 3JHH = 7.0 Hz, 3 H, OCH2CH3), 2.48 (s, 3 H, CH3), 3.85 (s, 3 H, COOCH3), 4.04 (m, 2 H,
OCH2CH3), 4.22 (dd, 2JHH = 17.7 Hz, 1 H, 3JHH = 4.4 Hz, CH), 4.47 (dd, 2JHH = 17.7 Hz, 1 H, 3JHH = 4.4
Hz, CH), 5.00 (d, 3JHH = 16.9 Hz, 1 H, CH), 5.08 (d, 3JHH = 10.4 Hz, 1 H, CH), 5.26 (d, 3JHH = 3.6 Hz, 1
H, CH), 5.80 (m, 1 H, CH), 7.34 (d, 3JHH = 8.2 Hz, 2 H, CH), 7.90 (d, 3JHH = 8.2 Hz, 2 H, CH), 8.01 (d,
3JHH = 3.6 Hz, 1 H, NH)
359
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

424
S. V. Ryabukhin et al.
PAPER
Table 2 Melting Point, 1H NMR Spectroscopy, and MS Data of 3,4-Dihydropyrimidin-2(1H)-(thi)ones 5 and 6a (continued)
Compd Mpb (°C) 1H NMR (400 MHz, DMSO-d6): dc
m/zd
5ea
5eg
5fa
5ff
88–89
1.12 (t, 3JHH = 7.0 Hz, 3 H, OCH2CH3), 2.02 (s, 3 H, CH3), 4.05 (q, 3JHH = 7.0 Hz, 2 H, OCH2CH3), 5.28 337
(d, 3JHH = 3.7 Hz, 1 H, CH), 7.21 (d, 3JHH = 7.6 Hz, 2 H, CH), 7.30 (m, 1 H, CH), 7.39 (m, 5 H, CH), 7.45
(m, 2 H, CH), 8.13 (d, 3JHH = 3.7 Hz, 1 H, NH)
139–140
172–173
201–202
0.97 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.16 (s, 3 H, CH3), 3.92 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.74 405
(d, 3JHH = 3.9 Hz, 1 H, CH), 7.29 (d, 3JHH = 7.8 Hz, 2 H, CH), 7.41 (m, 2 H, CH), 7.48 (m, 3 H, CH), 7.70
(d, 3JHH = 7.8 Hz, 1 H, CH), 7.72–7.78 (m, 2 H, CH+NH)
1.07 (t, 3JHH = 7.0 Hz, 3 H, OCH2CH3), 2.50 (s, 3 H, CH3), 4.06 (m, 2 H, OCH2CH3), 5.28 (d, 3JHH = 3.5 371
Hz, 1 H, CH), 7.09–7.17 (m, 3 H, CH), 7.24 (m, 1 H, CH), 7.33 (m, 3 H, CH), 7.39 (d, 3JHH = 8.7 Hz, 2
H, CH), 8.09 (d, 3JHH = 3.8 Hz, 1 H, NH)
1.20 (t, 3JHH = 7.2 Hz, 3 H, OCH2CH3), 2.54 (s, 3 H, CH3), 4.09 (q, 3JHH = 7.2 Hz, 2 H, OCH2CH3), 5.41 416
(d, 3JHH = 3.5 Hz, 1 H, CH), 7.21 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.45 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.67 (t,
3JHH = 8.1 Hz, 1 H, CH), 7.80 (d, 3JHH = 8.1 Hz, 1 H, CH), 8.15 (d, 3JHH = 8.1 Hz, 1 H, CH), 8.25 (s, 1 H,
CH), 8.34 (d, 3JHH = 3.5 Hz, 1 H, NH)
5fi
190–191
110–111
1.08 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.54 (s, 3 H, CH3), 3.97 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.98 423
(d, 3JHH = 3.5 Hz, 1 H, CH), 7.10 (t, 3JHH = 8.7 Hz, 1 H, CH), 7.21 (m, 3 H, CH), 7.29 (m, 1 H, CH), 7.43
(d, 3JHH = 8.4 Hz, 2 H, CH), 7.99 (d, 3JHH = 3.5 Hz, 1 H, NH)
5ge
1.21 (t, 3JHH = 7.0 Hz, 3 H, OCH2CH3), 2.47 (s, 3 H, CH3), 2.81 (s, 3 H, CH3), 3.21 (s, 3 H, CH3), 3.85 (s, 347
3 H, COOCH3), 4.05 (q, 3JHH = 7.0 Hz, 2 H, OCH2CH3), 5.25 (s, 1 H, CH), 7.30 (d, 3JHH = 8.3 Hz, 2 H,
CH), 7.91 (d, 3JHH = 8.3 Hz, 2 H, CH)
5gf
121–122
86–87
1.24 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.50 (s, 3 H, CH3), 2.84 (s, 3 H, CH3), 3.23 (s, 3 H, CH3), 4.08 (q, 334
3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.35 (s, 1 H, CH), 7.58 (m, 2 H, CH), 8.06–8.12 (m, 2 H, CH)
6ab
1.16 (t, 3JHH = 7.2 Hz, 3 H, NCH2CH3), 1.21 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.56 (s, 3 H, CH3), 4.02 339
(q, 3JHH = 7.2 Hz, 1 H, CH), 4.11 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 4.63 (q, 3JHH = 7.2 Hz, 1 H, CH),
5.16 (d, 3JHH = 4.3 Hz, 1 H, CH), 7.20 (d, 3JHH = 8.5 Hz, 2 H, CH), 7.28 (d, 3JHH = 8.5 Hz, 2 H, CH), 9.63
(d, 3JHH = 4.3 Hz, 1 H, NH)
6ah
6ak
6bb
6cb
101–102
111–112
141–142
119–120
1.11 (t, 3JHH = 7.0 Hz, 3 H, NCH2CH3), 1.24 (t, 3JHH = 6.9 Hz, 3 H, OCH2CH3), 2.55 (s, 3 H, CH3), 4.00 371
(m, 2 H, OCH2CH3), 4.15 (m, 1 H, CH), 4.52 (m, 1 H, CH), 5.51 (d, 3JHH = 3.8 Hz, 1 H, CH), 6.97 (t,
2JHF = 76.3 Hz, 1 H, OCHF2), 7.12–7.22 (m, 3 H, CH), 7.30 (m, 1 H, CH), 9.28 (d, 3JHH = 3.8 Hz, 1 H, NH)
1.14 (t, 3JHH = 6.7 Hz, 3 H, NCH2CH3), 1.24 (t, 3JHH = 6.9 Hz, 3 H, OCH2CH3), 2.51 (s, 3 H, CH3), 3.62 311
(m, 1 H, CH), 3.84 (m, 1 H, CH), 4.10 (m, 2 H, OCH2CH3), 5.40 (d, 3JHH = 3.4 Hz, 1 H, CH), 6.87 (m, 2
H, CH), 7.14 (m, 1 H, CH), 7.89 (d, 3JHH = 3.4 Hz, 1 H, NH)
1.19 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.57 (s, 3 H, CH3), 3.24 (s, 3 H, OCH3), 3.40 (m, 1 H, CH), 3.48 369
(m, 1 H, CH), 4.00 (m, 1 H, CH), 4.08 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.04 (d, 3JHH = 15.4 Hz, 1 H,
CH), 5.14 (d, 3JHH = 4.3 Hz, 1 H, CH), 7.26 (s, 4 H, CH), 9.80 (d, 3JHH = 4.3 Hz, 1 H, NH)
1.19 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.45 (s, 3 H, CH3), 4.10 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.08 401
(d, 2JHH = 17.0 Hz, 1 H, CH), 5.26 (d, 3JHH = 4.4 Hz, 1 H, CH), 6.16 (d, 2JHH = 17.0 Hz, 1 H, CH), 6.97
(m, 2 H, CH), 7.18 (m, 3 H, CH), 7.21 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.29 (d, 3JHH = 8.7 Hz, 2 H, CH), 9.96
(d, 3JHH = 4.4 Hz, 1 H, NH)
6cc
99–100
1.19 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.43 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3), 4.09 (q, 3JHH = 7.1 Hz, 2 397
H, OCH2CH3), 5.10 (d, 2JHH = 16.9 Hz, 1 H, CH), 5.22 (d, 3JHH = 4.1 Hz, 1 H, CH), 6.16 (d, 2JHH = 16.9
Hz, 1 H, CH, 6.81 (d, 3JHH = 9.0 Hz, 2 H, CH), 7.00 (m, 2 H, CH), 7.14 (d, 3JHH = 9.0 Hz, 2 H, CH), 7.18
(m, 3 H, CH), 9.83 (d, 3JHH = 4.4 Hz, 1 H, NH)
6dfc
159–160
1.21 (m, 3 H, OCH2CH3), 1.49 (m, 1 H, CH), 1.68 (m, 1 H, CH), 1.89 (m, 2 H, CH), 2.60 (s, 3 H, CH3) 406
and 2.62* (s, 3 H, CH3), 3.50–3.70 (m, 2 H, CH), 3.79–3.99 (m, 2 H, CH), 4.12 (m, 2 H, OCH2CH3), 5.11*
(m, 1 H, CH) and 5.22 (d, 3JHH = 6.8 Hz, 1 H, CH), 5.28 (d, 3JHH = 4.1 Hz, 1 H, CH) and 5.34* (d, 3JHH
4.1 Hz, 1 H, CH), 7.52 (d, 3JHH = 8.0 Hz, 1 H, CH) and 7.57* (d, 3JHH = 8.0 Hz, 1 H, CH), 7.72 (t, 3JHH
=
=
8.0 Hz, 1 H, CH), 8.09 (d, 3JHH = 8.0 Hz, 1 H, CH), 8.17* (d, 4JHH = 1.3 Hz, 1 H, CH) and 8.19 (d,
4JHH = 1.3 Hz, 1 H, CH), 9.91 (d, 3JHH = 4.1 Hz, 1 H, NH) and 10.01* (d, 3JHH = 4.1 Hz, 1 H, NH)
6ea
116–117
1.21 (t, 3JHH = 7.0 Hz, 3 H, OCH2CH3), 2.06 (s, 3 H, CH3), 4.11 (m, 2 H, OCH2CH3), 5.32 (d, 3JHH = 4.1 353
(116–118)9a Hz, 1 H, CH), 7.11 (br s, Dn1/2 = 47.2 Hz, 2 H, CH), 7.27 (m, 1 H, CH), 7.33–7.41 (m, 7 H, CH), 9.88 (d,
3JHH = 4.1 Hz, 1 H, NH)
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Substituted 3,4-Dihydropyrimidin-2(1H)-(thi)ones
425
Table 2 Melting Point, 1H NMR Spectroscopy, and MS Data of 3,4-Dihydropyrimidin-2(1H)-(thi)ones 5 and 6a (continued)
Compd Mpb (°C) 1H NMR (400 MHz, DMSO-d6): dc
m/zd
6eb
6ec
6eh
6ej
158–159
1.23 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.07 (s, 3 H, CH3), 4.09 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.32 387
(d, 3JHH = 4.1 Hz, 1 H, CH), 7.14 (br s, Dn1/2 = 14.2 Hz, 2 H, CH), 7.37–7.45 (m, 7 H, CH), 9.90 (d,
3JHH = 4.1 Hz, 1 H, NH)
135–136
1.22 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.06 (s, 3 H, CH3), 3.80 (s, 3 H, OCH3), 4.12 (q, 3JHH = 7.1 Hz, 2 383
(140–142)9a H, OCH2CH3), 5.26 (d, 3JHH = 4.1 Hz, 1 H, CH), 6.90 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.15 (br s, Dn1/2 = 16.3
Hz, 2 H, CH), 7.29 (d, 3JHH = 8.7 Hz, 2 H, CH), 7.40 (m, 3 H, CH), 9.81 (d, 3JHH = 4.1 Hz, 1 H, NH)
147–148
1.07 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.03 (s, 3 H, CH3), 4.00 (m, 2 H, OCH2CH3), 5.67 (d, 3JHH = 3.5 419
(153–154)9b Hz, 1 H, CH), 7.19–7.31 (m, 3 H, CH), 7.24 (t, 2JHF = 75.4 Hz, 1 H, OCHF2), 7.35 (t, 3JHH = 7.6 Hz, 1 H,
CH), 7.38–7.47 (m, 4 H, CH), 7.51 (d, 3JHH = 7.6 Hz, 1 H, CH), 9.84 (d, 3JHH = 3.5 Hz, 1 H, NH)
190–191
1.17 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.08 (s, 3 H, CH3), 4.04 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.81 389
(d, 3JHH = 3.5 Hz, 1 H, CH), 7.05 (t, 3JHH = 8.2 Hz, 2 H, CH), 7.24 (br.d, 3JHH = 8.2 Hz, 1 H, CH), 7.31
(br d, 3JHH = 8.2 Hz, 1 H, CH), 7.37–7.44 (m, 2 H, CH), 7.47 (m, 2 H, CH), 9.74 (d, 3JHH = 3.5 Hz, 1 H,
NH)
6fc
6fg
93–94
1.29 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.49 (s, 3 H, CH3), 3.37 (s, 3 H, NCH3), 3.54 (s, 3 H, NCH3), 3.75 335
(s, 3 H, OCH3), 4.16 (q, 3JHH = 7.1 Hz, 2 H, OCH2CH3), 5.45 (s, 1 H, CH), 6.81 (d, 3JHH = 8.7 Hz, 2 H,
CH), 7.04 (d, 3JHH = 8.7 Hz, 2 H, CH)
147–148
1.17 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 2.49 (s, 3 H, CH3), 3.29 (s, 3 H, NCH3), 3.67 (s, 3 H, NCH3),
3.97–4.14 (m, 2 H, OCH2CH3), 5.89 (s, 1 H, CH), 7.47 (d, 3JHH = 8.0 Hz, 1 H, CH), 7.52 (t, 3JHH = 8.0
Hz, 1 H, CH), 7.66 (m, 2 H, CH)
373
a The equipment, instruments, and conditions used are given in the experimental section.
b Melting points are uncorrected; literature values are given in parentheses.
c Signals marked by asterisks (*) are of minor diastereomers.
d The m/z peak corresponding to [M + 1] determined by MS (APCI).
All chemicals were obtained from commercial sources and used
without further purification. DMF was freshly distilled and dried by
standard methods, and monitoring of the H2O content in solvents
(all solvents <0.05%, usually 0.02% H2O) was performed using a
Mettler Toledo DL31 KF Titrator. All solvents for crystallization
were used without additional purification. Melting points were mea-
bath for 1 h. The precipitate that formed was filtered and washed
with a small amount of i-PrOH. The product was purified by recrys-
tallization from an appropriate solvent. A further 5–10% of the
product could be collected if the mother liquor was evaporated un-
der reduced pressure and the residue was treated with a small
amount of i-PrOH or Et2O. The residue was recrystallized from the
same solvent described above. The yields, purities, crystallization
solvents, melting points, 1H NMR spectroscopy, and [M + 1] peaks
of the APCI-MS data for products 5 and 6 are collected in Tables 1
and 2. Further IR, MS, and 13C NMR spectroscopy data are given
below. Please note that 13C NMR peaks marked by asterisks (*) are
of minor diastereomers.
1
sured on a Buchi melting point apparatus and are uncorrected. H
NMR and NOE spectra (400 MHz) were recorded on a Varian Mer-
cury-400 spectrometer, and 13C NMR spectra (125 MHz) were re-
corded on a Bruker Avance drx 500 spectrometer; DMSO-d6 was
used as solvent and TMS as internal standard. IR spectra of samples
prepared in KBr discs were recorded on a Nexus-470 spectrometer.
EI-MS (70 eV) spectra were obtained on an MX-1321 instrument
by direct inlet. HPLC-MS was carried out on a system consisting of
an Agilent 1100 Series high-pressure liquid chromatograph
equipped with a diode matrix and an Agilent LC\MSD SL mass-se-
lective detector. HPLC-MS parameters: column: Zorbax SB-C18,
1.8 mm, 4.6 mm × 15 mm; solvents: MeCN–H2O, 95:5 with 0.1%
TFA, H2O with 0.1% TFA; eluent flow: 3 mL·s–1; injected sample
volume: 1 mL; UV detector: l = 215, 254, 265 nm; ionization meth-
od: chemical ionization under atmospheric pressure (APCI); ioniza-
tion mode: simultaneous scanning of positive and negative ions in
the m/z range 80–1000. HPLC-MS data showed that all the synthe-
sized compounds were >98% pure. A BRANSON 2510E-MT ultra-
sonic bath was used.
3,4-Dihydropyrimidin-2(1H)-one 5ab
13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.5, 30.2, 52.4, 60.1,
102.5, 128.5, 128.9, 132.4, 143.5, 151.4, 153.4, 165.9.
MS (EI, 70 eV): m/z (%) = 310 (3), 309 (2), 308 (9) [M+], 281 (10),
279 (27), 235 (20), 197 (100), 169 (18), 151 (14), 56 (54), 32 (18),
31 (9).
3,4-Dihydropyrimidin-2(1H)-one 5bb
13C NMR (125 MHz, DMSO-d6): d = 14.6, 17.1, 25.3, 25.5, 29.7,
30.5, 51.6, 57.2, 60.2, 105.2, 128.2, 128.9, 132.3, 142.9, 152.0,
153.4, 165.9.
MS (EI, 70 eV): m/z (%) = 364 (3), 363 (1), 362 (7) [M+], 267 (9),
265 (32), 251 (19), 221 (20), 184 (11), 183 (100), 155 (14), 137
(13), 42 (22), 41 (30).
3,4-Dihydropyrimidin-2(1H)-ones 5 and 3,4-Dihydropyrimi-
dine-2(1H)-thiones 6; General Procedure
Ethyl acetoacetate (4; 4 mmol), the appropriate aldehyde 3 (4
mmol), and the appropriate urea 2 or thiourea 3 (4.4–5.2 mmol)
were placed in a 15-mL ace pressure tube and dissolved in DMF (10
mL). TMSCl (24 mmol) was added dropwise to the soln. The tube
was thoroughly sealed and allowed to stand at r.t. in an ultrasonic
bath for 1 h and was then left to stand at r.t. for 1–3 d. The mixture
was poured into H2O (20–30 mL) and was left at r.t. in an ultrasonic
3,4-Dihydropyrimidin-2(1H)-one 5de
13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.1, 44.5, 52.6, 52.9,
60.2, 102.7, 115.8, 127.0, 129.2, 129.9, 135.4, 149.7, 150.7, 152.8,
165.9, 166.4.
MS (EI, 70 eV): m/z (%) = 358 (8) [M+], 329 (22), 285 (13), 224 (9),
223 (100), 195 (6), 42 (7), 41 (66), 39 (6), 32 (24).
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

426
S. V. Ryabukhin et al.
PAPER
3,4-Dihydropyrimidin-2(1H)-one 5fa
MS (EI, 70 eV): m/z (%) = 388 (13), 387 (46) [M+], 359 (11), 357
(29), 313 (17), 277 (11), 275 (100), 247 (11), 118 (52), 77 (59), 51
(11).
IR (KBr): 3600–3200 (br, NH), 3107, 2983, 2929, 1711 (C=OCOOEt),
1687, 1630, 1490, 1404, 1342, 1215 (C–O), 1086, 1016, 833, 760,
698, 669 cm–1.
3,4-Dihydropyrimidine-2(1H)-thione 6ec
13C NMR (125 MHz, DMSO-d6): d = 14.5, 18.5, 53.6, 60.3, 104.4,
126.8, 128.0, 129.1, 129.4, 132.2, 133.1, 137.1, 144.3, 148.9, 152.3,
165.9.
MS (EI, 70 eV): m/z (%) = 372 (5), 371 (4), 370 (15) [M+], 343 (10),
341 (30), 297 (20), 295 (39), 294 (22), 293 (100), 211 (20), 152
(33), 127 (25), 111 (25), 77 (14), 45 (16), 44 (15), 43 (25).
IR (KBr): 3600–3300 (br, NH), 3157, 3007, 2958, 2935, 1705
(C=OCOOEt), 1622, 1595, 1510, 1340, 1248, 1173 (C–O), 1080,
1032, 858, 771, 696, 606 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 14.5, 18.7, 53.0, 55.6, 60.6,
106.3, 114.6, 128.1, 128.8, 135.4, 140.8, 146.5, 159.4, 165.8, 177.5.
MS (EI, 70 eV): m/z (%) = 383 (17), 387 (77) [M+], 353 (57), 322
(25), 310 (16), 309 (78), 276 (16), 275 (96), 118 (93), 77 (100), 51
(14).
3,4-Dihydropyrimidin-2(1H)-one 5gf
IR (KBr): 3095, 2978, 2927, 2860, 1699 (C=OCOOEt), 1674, 1612,
1524 (NO2), 1346 (NO2), 1273, 1205 (C–O), 1171, 1051, 1032, 823,
756, 729, 685 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 14.4, 16.6, 31.1, 34.3, 59.8,
60.3, 101.9, 122.0, 123.3, 131.0, 133.5, 144.0, 148.2, 151.4, 153.1,
165.4.
3,4-Dihydropyrimidine-2(1H)-thione 6fc
13C NMR (125 MHz, DMSO-d6): d = 14.6, 16.8, 38.2, 42.7, 55.6,
60.5, 60.6, 105.7, 114.6, 128.0, 132.1, 147.7, 159.5, 165.5, 179.1.
MS (EI, 70 eV): m/z (%) = 335 (11), 334 (52) [M+], 305 (12), 262
(18), 261 (88), 260 (21), 227 (83), 199 (12), 56 (100), 32 (14), 31
(12).
MS (EI, 70 eV): m/z (%) = 333 (5) [M+], 316 (3), 212 (3), 211 (100),
183 (18), 165 (9), 67 (3), 56 (22), 43 (6), 42 (8).
3,4-Dihydropyrimidine-2(1H)-thione 6ab
Acknowledgment
13C NMR (125 MHz, DMSO-d6): d = 14.0, 14.4, 15.9, 42.3, 51.7,
60.2, 106.0, 128.0, 128.6, 132.3, 141.4, 146.9, 165.2, 177.3.
The authors acknowledge Dr. A. V. Mazepa (Bogatsky Physico-
Chemical Institute, National Academy of Sciences of Ukraine, De-
partment of Molecular Structure), Dr. S. A. Alekseev (Department
of Chemistry, Kyiv National Taras Shevchenko University), A. Y.
Petin and V. V. Polovinko (Enamine Ltd) for spectral measure-
ments and Dr. A. N. Kostyuk for helpful discussions and sugges-
tions for preparation of the manuscript.
MS (EI, 70 eV): m/z (%) = 340 (15), 339 (7), 338 (44) [M+], 309
(21), 267 (13), 265 (40), 228 (10), 227 (100), 199 (24), 171 (9), 70
(32), 42 (96).
3,4-Dihydropyrimidine-2(1H)-thione 6bb
13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.9, 46.8, 52.5, 58.8,
60.7, 71.3, 106.3, 128.8, 129.0, 132.8, 141.7, 148.2, 165.6, 177.8.
MS (EI, 70 eV): m/z (%) = 370 (2), 368 (5) [M+], 310 (23), 283 (18),
282 (9), 281 (50), 237 (17), 200 (13), 199 (100), 59 (23), 42 (12), 31
(13).
References
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(2) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(3) For reviews, see: (a) Kappe, C. O. Tetrahedron 1993, 49,
6937. (b) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
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3,4-Dihydropyrimidine-2(1H)-thione 6cb
IR (KBr): 3356 (NH), 3195, 3032, 2983, 2943, 1697 (C=OCOOEt),
1643, 1525, 1385, 1358, 1215, 1155 (C–O), 978, 862, 827, 715, 646
cm–1.
13C NMR (125 MHz, DMSO-d6): d = 14.4, 16.8, 50.9, 52.0, 60.8,
107.0, 126.7, 127.5, 128.6, 128.9, 129.0, 132.9, 138.1, 141.7, 147.6,
165.6, 178.9.
MS (EI, 70 eV): m/z (%) = 402 (6), 400 (21) [M+], 327 (7), 289 (10),
166 (5), 106 (6), 92 (8), 91 (100), 65 (6).
(g) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
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B. V. S.; Srinivas, R.; Venugopal, C.; Ramalingam, T.
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Reddy, C. S.; Reddy, C. D. Tetrahedron Lett. 2001, 42,
7873. (l) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K.
S.; Prasad, A. R. J. Chem. Soc., Perkin Trans. 1 2001, 1939.
(m) Jun, L.; Yinjuan, B. Synthesis 2002, 466. (n) Salehi, P.;
Dabiri, M.; Zolfigol, M. A.; Fard, M. A. B. Tetrahedron Lett.
2003, 44, 2889. (o) Sabitha, G.; Reddy, G. S. K. K.; Reddy,
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Synthesis 1999, 1799.
3,4-Dihydropyrimidine-2(1H)-thione 6df
13C NMR (125 MHz, DMSO-d6): d = 14.4, 14.5*, 17.0, 25.2*, 25.6,
28.3*, 28.7, 50.7, 52.0*, 52.6, 60.8, 60.9*, 67.4*, 68.0, 77.5*, 78.1,
105.8, 121.5*, 121.8, 123.1*, 123.3, 130.7, 133.5*, 133.8, 144.6,
144.7*, 148.2*, 148.4, 149.0, 165.4, 165.6*, 178.0.
MS (EI, 70 eV): m/z (%) = 405 (0.3) [M+], 322 (20), 321 (27), 304
(27), 292 (29), 248 (10), 199 (100), 85 (47), 84 (22), 43 (47), 42
(15), 41 (11).
3,4-Dihydropyrimidine-2(1H)-thione 6eb
IR (KBr): 3373 (NH), 3188, 3043, 2985, 2929, 2900, 1693
(C=OCOOEt), 1635, 1517, 1404, 1381, 1342, 1248, 1176 (C–O),
1088, 825, 696, 600 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 14.5, 18.8, 53.0, 60.8, 105.5,
128.8, 128.9, 129.4, 133.0, 140.7, 142.1, 147.3, 165.7, 177.8.
Synthesis 2007, No. 3, 417–427 © Thieme Stuttgart · New York

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Synthesis of N-Substituted 3,4-Dihydropyrimidin-2(1H)-(thi)ones
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