Copper-catalyzed cascade preparation of dihydropyrimidin-4-ones from N -(Prop-2-yn-1-yl)amides and azides

Article abstract of DOI:10.1021/jo401094j

Dihydropyrimidin-4-ones were efficiently synthesized from copper catalyzed reaction between N-(prop-2-yn-1-yl)amides and sulfonylazides under mild conditions in moderate to excellent yields (up to 96% yields). The cascade process involves the copper-catal

Full text of DOI:10.1021/jo401094j

Note
pubs.acs.org/joc
Copper-Catalyzed Cascade Preparation of Dihydropyrimidin-4-ones
from N‑(Prop-2-yn-1-yl)amides and Azides
Jinjin Wang, Jing Wang, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: Dihydropyrimidin-4-ones were efficiently synthe-
sized from copper catalyzed reaction between N-(prop-2-yn-1-
yl)amides and sulfonylazides under mild conditions in moderate to
excellent yields (up to 96% yields). The cascade process involves
the copper-catalyzed alkyne−azide cycloaddition, the formation of
ketenimine intermediate, the intramolecular nucleophilic addition
of ketenimine, and subsequent rearrangement.
ihydropyrimidinones (DHPMs) are an important class of
heterocycles in medicinal chemistry due to their diverse
D
pharmacological activities.1−4 Among these compounds,
dihydropyrimidin-4-ones have attracted attention extensively
in the past decade. A number of dihydropyrimidin-4-ones have
been found to be non-nucleoside HIV-1 inhibitors.5−7
Moreover, several dihydropyrimidin-4-ones, such as risperidone
(Risperdal) and paliperidone (9-hydroxy-risperidone, Invega),
are currently used for the treatment of schizophrenia.8,9
Traditional methods leading to dihydropyrimidin-4-one skel-
eton include the condensation between β-amino amides and
aldehydes,10,11 and the reaction of amidines with methyl
acrylates.10 The three-component coupling of Meldrum’s acid,
aldehydes, and guanidine carbonate could afford 2-amino-
dihydropyrimidin-4-ones, yet in relatively lower yields.12,13
In recent years, the copper-catalyzed azide−alkyne cyclo-
addition (CuAAC) has been developed to form keteni-
mines,14,15 which shine light on the development of multi-
component approaches to a variety of principal heterocyclic
compounds.15−19 In our previous study, a number of efficient
three-component20−24 and four-component reactions25−27
were successfully achieved by intermolecular trapping of the
ketenimine intermediates generated through CuAAC mecha-
nism. However, there are few examples presenting the
intramolecular trapping of ketenimine.28 Consequently, we
were interested in integrating terminal alkyne and nucleophilic
amide into one starting material molecule, such as N-(prop-2-
yn-1-yl)amides 1, and expected that the terminal alkyne group
could react with tosyl azide to generate reactive ketenimine A in
CuAAC conditions and the intramolcular amide could function
as a trapping unit to attack central carbon of the resulting
ketenimine to give heterocyclic compounds B and/or B′
(Figure 1). Herein, we would like to report the results of this
effort.
Figure 1. Our preliminary consideration.
(Table 1, entry 1). The structure of 3a was established by single
crystal analysis.29 Encouraged by this result, we investigated the
reaction conditions and the results are summarized in Table 1.
After screening seven solvents, acetonitrile was found to be the
optimal in comparison to other widely used solvents, such as
dichloromethane (DCM), dichloroethane (DCE), tetrahydro-
furan (THF), N,N-dimethylforamide (DMF), dimethyl sulf-
oxide (DMSO), toluene, and 1,4-dioxane (Table 1, entries 1−
8). Adding the molecular sieve could prompt this trans-
formation to increase the yield (Table 1, entry 9). When tested
the catalysts, most of Cu(I) catalysts offered slightly lower
yields in comparison to CuI except for Cu2O, which did not
facilitate the reaction (Table 1, entries 10−14). Additionally,
pyridine (2 equiv) was found to be the optimal in comparison
to other bases, such as K2CO3, Cs2CO3, and triethylamine.
DABCO and DBU did not work for this transformation (Table
1, entries 15−21). Optimal reaction temperature and reaction
time were found to be 70 °C and 1 h, respectively (Table 1,
entry 24).
With the optimized reaction conditions in hand, we
investigated the substrate scope of N-(prop-2-yn-1-yl)amides
and sulfonylazides, respectively. As shown in Table 1, both
aromatic amides (1a-1h and 1k-1m) and aliphatic amides (1j
and 1n) worked for this cascade reaction to afford the
corresponding products 3a-3h and 3j-3n in yields varied from
20% to 96%. Electronic effect of substituents on the phenyl ring
In our primary experiment, we selected N-(prop-2-yn-1-
yl)amide 1a as starting material for the model reaction with
tosyl azide and obtained dihydropyrimidin-4-one 3a in 30%
isolated yield when the reaction was carried out in the presence
of CuI and triethylamine in dichloromethane at 30 °C for 2.5 h
Received: May 18, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401094j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Screening of the Reaction Conditions
b
c
d
entry
catalyst
base/equiv
solvent
DCM
temp °C
4 Å MS
time (h)
yield (%)
1
CuI
TEA/2
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
50
70
reflux
-
2.5
2.5
2.0
1.3
3.5
2.0
1.8
2.0
2.0
4.0
72.0
5.0
4.0
3.0
1.0
7.7
2.0
1.3
3.5
3.5
2.0
5.0
2.0
1.0
0.7
30
35
12
16
11
13
6
2
CuI
TEA/2
DCE
-
3
CuI
TEA/2
THF
-
4
CuI
TEA/2
DMF
-
5
CuI
TEA/2
DMSO
Toluene
1,4-Dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
-
6
CuI
TEA/2
-
7
CuI
TEA/2
-
8
CuI
TEA/2
-
38
46
31
0
9
CuI
TEA/2
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuCl
Cu2O
CuCN
CuBr
CuOTf
CuI
TEA/2
TEA/2
TEA/2
27
37
40
45
0
TEA/2
TEA/2
K2CO3/2
DABCO/2
DBU/2
CuI
CuI
0
CuI
CsCO3/2
Pyridine/2
Pyridine/1
Pyridine/3
Pyridine/2
Pyridine/2
Pyridine/2
Pyridine/2
30
47
35
34
0
CuI
CuI
CuI
CuI
CuI
52
57
54
CuI
CuI
a
b
c
Reaction conditions: 1a (0.5 mmol); 2a (0.5 mmol); solvent (2 mL). Entries 9−25: 4 Å MS (100 mg). Reaction time was determined on the
d
basis of the disappearance of substrate by tracking with TLC. Isolated yield.
a
of R1 in 1 was apparent. Only substituents with moderate
electron-donating property facilitated the reaction and afforded
dihydropyrimidine-4-ones in good yields (Table 2, entry 3).
Cinnamamide (1i) furnished 3i in 50% yield. Two methyl
groups attached on propargylic amine were found to be
significant in increasing the yield by comparing two pairs: 1c
and 1k (Table 2, entries 3 and 11), 1g and 1l (Table 2, entries
Table 2. Substrate Scope of N-(Prop-2-yn-1-yl)amides
reaction time
3 (yield,
%)
b
c
entry
1(R1/R2/R3)
(h)
7 and 12).
As listed in Table 3, both aromatic sulfonyl azides (2a-2e)
and aliphatic sulfonyl azide (2f) reacted with N-(prop-2-yn-1-
yl)amides (1a-1d) in the presence of CuI to produce 3c and
3o−3v in yields varied from 30% to 81%.
1
1a (4-MeOC6H4/H/H)
1b (Ph/H/H)
1
3a (57)
3b (76)
3c (79)
3d (53)
3e (59)
3f (32)
3g (20)
3h (69)
3i (50)
3j (21)
3k (96)
3l (38)
3m (53)
3n (68)
2
1
3
1c (4-MeC6H4/H/H)
1d (4-ClC6H4/H/H)
1e (2-ClC6H4/H/H)
1f (3-ClC6H4/H/H)
1g (4-BrC6H4/H/H)
1h (2-naphthalenyl/H/H)
1i (PhCHCH/H/H)
1j (c-C6H11/H/H)
1.5
2.2
6
4
Based on the investigation of reaction conditions and
substrate scope, a possible mechanism is postulated as shown
in Scheme 1. Terminal alkyne 1 first reacts with sulfonylazide
2a in the presence of Cu(I) to afford ketenimine intermediate
A via an expected copper-catalyzed alkyne−azide cycloaddition,
following by Dimorth rearrangement. The electron-deficient
central carbon of ketenimine A might be intramolecularly
attacked by oxygen of the amide to form B. Theoretical
calculation supported the prior formation of six-membered ring
B instead of four-membered ring B′ due to the ring strain.
Energy difference between B and B′ was calculated to be 9.25
kJ/mol when R referred to phenyl group (1b) (see Table S1;
Calculated with Spartan’10 by density functional method at
B3LYP/6-31G* level). Extension calculation for the potential
energies of B and B′ when R referred to 4-methoxyphenyl (1a),
5
6
3
7
4
8
2
9
1
10
11
12
13
14
2
1k (4-MeC6H4/Me/Me)
1l (4-BrC6H4/Me/Me)
1m (4-MeC6H4/R2,R3= -(CH2)5-)
1n (Me/H/Ph)
4
1
1.3
1.3
a
Reaction conditions: 1 (0.5 mmol); 2a (0.5 mmol); 4 Å MS (100
mg); Acetonitrile (2 mL). Reaction time was determined on the basis
of the disappearance of substrate by tracking with TLC. Isolated yield.
b
c
B
dx.doi.org/10.1021/jo401094j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
sodium azide.32 With the diverse pharmacological activities of
dihydropyrimidinones, our method shall find its applications in
medicinal chemistry.
a
Table 3. Substrate Scope of Azides
EXPERIMENTAL SECTION
■
General Considerations. Infrared spectra were obtained on a
1
reaction time
3 (yield
FTIR spectrometer. H NMR spectra were recorded on 500 or 400
b
c
entry
1 (R1)
2 (R4)
(h)
%)
MHz spectrometer, referred to the internal solvent signals (0 for TMS
in CDCl3 or 2.5 for the residue of DMSO). The following
abbreviations were used to describe peak patterns where appropriate:
b = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. Coupling constants were reported in Hertz (Hz). 13C NMR
were recorded on 125 or 100 MHz spectrometer, referred to the
internal solvent signals (77.27 for CDCl3 or 40.0 for DMSO-d6). High
resolution mass spectra (HRMS) were performed on an electron
ionization time-of-flight (EI-TOF) mass spectrometer. Melting points
were measured with micromelting point apparatus.
General Procedure for the Synthesis of Dihydropyrimidin-4-
ones 3. To a solution of N-(prop-2-yn-1-yl)amides (0.5 mmol),
sulfonyl azide (0.6 mmol), 4 Å MS (100 mg), and CuI (0.05 mmol) in
MeCN (1.5 mL) protected by argon was added a solution of pyridine
(1 mmol) in MeCN (0.5 mL) via syringe, and the mixture was reacted
at 70 °C (oil bath) for a certain period of time which was determined
by TLC. After filtrated, the reaction mixture was then diluted with
CH2Cl2 (10 mL), washed with dilute hydrochloric acid, water, and
brine, dried over anhydrous Na2SO4, and evaporated in vacuum. The
residue was subject to silica gel column chromatography with EA/Pet
(1:3, v/v) as eluent to give products 3.
1
2
3
4
1c (4-MeC6H4) 2a (4-MeC6H4)
1.5
1.7
1.3
2.5
3c (79)
3o (47)
3p (81)
3q (42)
1b (Ph)
2b (4-MeOC6H4)
1c
2b
1a (4-
MeOC6H4)
2c (Ph)
5
6
1c
1c
2c
1
2
3r (71)
3s (49)
2d (2-
naphthalenyl)
7
8
9
1c
2e (4-ClC6H4)
2e
3
3t (37)
3u (30)
3v (42)
1d (4-ClC6H4)
2
1c
2f (Me)
1.5
a
Reaction conditions: 1 (0.5 mmol); 2a (0.5 mmol); 4 Å MS (100
mg); Acetonitrile (2 mL). Reaction time was determined on the basis
of the disappearance of substrate by tracking with TLC. Isolated yield.
b
c
Scheme 1. Proposed Mechanism for the Formation of 3
2-(4-Methoxyphenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (3a). Unknown compound, a white powder (103 mg, 0.29 mmol,
57%); mp 161.8−162.5 °C; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J
= 8.0 Hz, 2H), 7.59 (d, J = 8.5 Hz 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.91
(d, J1 = 9.0 Hz, 2H), 3.86 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 2.52 (t, J =
6.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.0,
161.9, 154.3, 145.9, 136.3, 129.6, 129.3, 126.7, 113.9, 55.6, 43.5, 34.4,
22.0; IR (KBr) v 2991, 2859, 1734, 1637, 1606, 1511, 1361, 1259,
1184, 1147, 1102, 823, 685 cm−1; HRMS (EI-TOF) calcd for
C18H18N2O4S (M+), 358.0987; found, 358.0985.
2-Phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (3b). Un-
known compound, a light yellow powder (125 mg, 0.38 mmol, 76%);
1
mp 163.0−164.2 °C; H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.5
Hz, 2H), 7.62−7.56 (m, 2H), 7.48 (m, 1H), 7.40 (m, 2H), 7.32 (d, J =
8.0 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.45 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.8, 154.7, 146.0, 136.4,
136.1, 131.0, 129.6, 129.6, 128.6, 127.6, 43.6, 34.2, 22.0; IR (KBr) v
2959, 1736, 1640, 1449, 1370, 1282, 1252, 1191, 1169, 1151, 1102,
1084, 1002, 809, 771, 699, 686, 671 cm−1; HRMS (EI-TOF) calcd for
C17H16N2O3S (M+), 328.0882; found, 328.0878.
4-methylphenyl (1c), or 4-chlorophenyl (1d) further supported
that the formation of B was prior to the formation of B′. B is
unstable with an imidic anhydride substructure, which under-
goes a ring-opening to form intermediate C. As a result, the
thermodynamically stable product 3 is constructed via an
intramolecular nucleophilic addition. Also, this could be
explained by the calculated result. The energy difference
between B and 3b (R = Ph) was calculated to be 27.98 kJ/mol
and 3b is more stable. Similar results were observed for the
cases where R is 4-methoxyphenyl (3a), 4-methylphenyl (3c),
or 4-chlorophenyl (3d) (see Table S1).
In conclusion, we developed an efficient method for the
preparation of dihydropyrimidin-4-ones from N-(prop-2-yn-1-
yl)amides and sulfonyl azides. The cascade reaction underwent
copper-catalyzed alkyne−azide cycloaddition, formation and
intramolecular nucleophilic addition of ketenimine, and
subsequent rearrangement in a single step. Moreover, the
starting materials, propargylamides, could be easily prepared
from propargylic alcohols via Ritter reaction30 or from
propargylamines via aminolysis of acid chlorides,31 while
sulfonylazides could be obtained from sulfonylchlorides and
2-(p-Tolyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (3c). Un-
known compound, a white powder (136 mg, 0.40 mmol, 79%); mp
1
176.0−177.0 °C; H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz,
2H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.0
Hz, 2H), 3.70 (t, J = 6.3 Hz, 2H), 2.52 (t, J = 6.3 Hz, 2H), 2.45 (s,
3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.9, 154.6,
145.9, 141.4, 136.2, 133.7, 129.6, 129.3, 127.5, 43.5, 34.2, 22.0, 21.8; IR
(KBr) v 2916, 1744, 1634, 1361, 1279, 1185, 1106, 811, 685 cm−1;
HRMS (EI-TOF) calcd for C18H18N2O3S (M+), 342.1038; found,
342.1042.
2-(4-Chlorophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(3d). Unknown compound, a white powder (96 mg, 0.26 mmol, 53%);
1
mp 171.5−172.7 °C; H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.4
Hz, 2H), 7.59−7.54 (m, 2H), 7.41−7.36 (m, 2H), 7.33 (d, J = 8.2 Hz,
2H), 3.72 (t, J = 6.4 Hz, 2H), 2.53(t, J = 6.4 Hz, 2H), 2.46 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 170.5, 153.7, 146.2, 137.1, 136.0,
134.9, 129.7, 129.5, 129.0, 128.8, 43.6, 34.1, 22.0; IR (KBr) v 2971,
1730, 1637, 1595, 1371, 1277, 1185, 1168, 1152, 1088, 1003, 822, 690
cm−1; HRMS (EI-TOF) calcd for C17H15ClN2O3S (M+), 362.0492;
found, 362.0489.
C
dx.doi.org/10.1021/jo401094j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2-(2-Chlorophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(3e). Unknown compound, a white powder (107 mg, 0.29 mmol,
59%); mp 115.0−116.6 °C; 1H NMR (500 MHz, CDCl3) δ 7.57−7.54
(m, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.39−7.36 (m, 2H), 7.18 (d, J = 7.2
Hz, 2H), 3.86 (t, J = 5.5, 2H), 2.67 (t, J = 5.5, 2H), 2.42 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 170.1, 151.6, 145.8, 134.9, 134.3, 132.5,
131.9, 131.0, 129.3, 129.2, 129.1, 127.0, 43.8, 34.1, 22.0; IR (KBr) v
3282, 2925, 1732, 1599, 1546, 1438, 1370, 1281, 1224, 1142, 1084,
938, 811, 751, 683 cm−1; HRMS (EI-TOF) calcd for C17H15ClN2O3S
(M+), 362.0492; found, 362.0492.
2-(4-Bromophenyl)-6,6-dimethyl-3-tosyl-5,6-dihydropyrimi-
din-4(3H)-one (3l). Unknown compound, a white powder (84 mg,
0.19 mmol, 38%); mp 143.5−144.0 °C; 1H NMR (500 MHz, CDCl3)
δ 7.87 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4
Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 2.47 (s, 2H), 2.46 (s, 3H), 1.31 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 170.1, 150.0, 146.2, 136.1,
135.6, 131.7, 130.1, 129.5, 129.1, 124.9, 54.5, 45.5, 27.5, 22.0; IR
(KBr) v 2969, 2929, 1728, 1636, 1591, 1360, 1273, 1175, 1083, 1010,
815, 667 cm−1; HRMS (EI-TOF) calcd for C19H19BrN2O3S (M+),
434.0300; found, 434.0305.
2-(3-Chlorophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
2-(p-Tolyl)-3-tosyl-1,3-diazaspiro[5.5]undec-1-en-4-one
(3m). Unknown compound, a white powder (108 mg, 0.26 mmol,
53%); mp 141.6−142.5 °C; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J
= 8.3 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.19
(d, J = 7.9 Hz, 2H), 2.45 (s, 3H), 2.44 (s, 2H), 2.39 (s, 3H), 1.83−1.72
(m, 4H), 1.62 (s, 1H), 1.51 (m, 2H), 1.45−1.30 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.5, 145.0, 145.8, 140.7, 135.8, 134.6, 130.1,
129.3, 129.1, 127.5, 56.4, 44.7, 36.4, 25.8, 22.2, 22.0, 21.7; IR (KBr) v
2928, 2855, 1738, 1637, 1372, 1297, 1172, 1082, 677, 665 cm−1;
HRMS (EI-TOF) calcd for C23H26N2O3S (M+), 410.1664; found,
410.1664.
2-Methyl-6-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(3n). Unknown compound, a white powder (117 mg, 0.34 mmol,
68%); mp 167.0−168.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J
= 8.3 Hz, 2H), 7.39−7.33 (m, 6H), 7.32−728 (m, 1H), 4.74−4.60 (m,
1H), 2.77 (dd, J1 = 17.3, J2 = 3.8 Hz, 1H), 2.60 (d, J = 1.7 Hz, 3H),
2.53−2.48 (m, 1H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
169.4, 151.0, 145.9, 140.4, 136.1, 129.8, 129.2, 129.1, 128.0, 126.7,
56.4, 40.8, 24.5, 22.0; IR (KBr) v 3067, 2992, 1737, 1667, 1597, 1362,
1204, 1170, 1087, 1031, 938, 841, 750, 702, 679 cm−1; HRMS (EI-
TOF) calcd for C18H18N2O3S (M+), 342.1038; found, 342.1033.
3-((4-Methoxyphenyl)sulfonyl)-2-phenyl-5,6-dihydropyrimi-
din-4(3H)-one (3o). Unknown compound, a white powder (81 mg,
0.23 mmol, 47%); mp 169.0−171.0 °C; 1H NMR (500 MHz, CDCl3)
δ 7.90 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.4 Hz,
1H), 7.40 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H),
3.73 (t, J = 6.3 Hz, 2H), 2.55 (t, J = 6.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 170.8, 164.5, 154.7, 136.5, 132.0, 130.9, 130.3, 128.5,
127.6, 114.1, 56.0, 43.6, 34.2; IR (KBr) v 2971, 1728, 1635, 1595,
1450, 1360, 1281, 1269, 1198, 1163, 1087, 1019, 840, 777, 698, 683
cm−1; HRMS (EI-TOF) calcd for C17H16N2O4S (M+), 344.0831;
found, 344.0827.
(3f). Unknown compound, a white powder (59 mg, 0.16 mmol, 32%);
1
mp 184.2−185.9 °C; H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.4
Hz, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.37−7.33
(m, 3H), 3.77 (t, J = 6.5 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H), 2.46 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 153.5, 146.2, 138.0,
135.8, 134.5, 131.0, 130.0, 129.8, 129.5, 127.6, 126.0, 43.7, 34.2, 22.0;
IR (KBr) v 3073, 2965, 2906, 2854, 1723, 1633, 1593, 1414, 1359,
1263, 1174, 1112, 1007, 813, 791, 733, 677 cm−1; HRMS (EI-TOF)
calcd for C17H15ClN2O3S (M+), 362.0492; found, 362.0499.
2-(4-Bromophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(3g). Unknown compound, a white powder (40 mg, 0.10 mmol, 20%);
1
mp 180.0−181.5 °C; H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.2
Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.33 (d, J
= 8.1 Hz, 2H), 3.71 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 6.3 Hz, 2H), 2.46
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 153.9, 146.2, 136.0,
135.4, 131.8, 129.7, 129.5, 129.2, 125.5, 43.6, 34.1, 22.0; HRMS (EI-
TOF) calcd for C17H15BrN2O3S (M+), 405.9987; found, 405.9994.
2-(Naphthalen-2-yl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(3h). Unknown compound, a white powder (130 mg, 0.34 mmol,
69%); mp 162.5−163.7 °C; 1H NMR (500 MHz, CDCl3) δ 7.90−7.86
(m, 3H), 7.83 (d, J = 8.3 Hz, 2H), 7.76 (dd, J1 = 8.6, J2 = 1.6 Hz, 1H),
7.70 (d, J = 7.8 Hz, 1H), 7.57−7.48 (m, 2H), 7.3 (d, J = 8.0 Hz, 2H),
3.81 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 171.0, 154.8, 145.9, 136.2, 134.6, 133.7,
132.5, 129.6, 128.9, 128.7, 128.1, 127.6, 126.9, 124.7, 43.8, 34.5, 22.0;
IR (KBr) v 3057, 2922, 2862, 1741, 1637, 1358, 1280, 1145, 1182,
1096, 1000, 814, 665 cm−1; HRMS (EI-TOF) calcd for C21H18N2O3S
(M+), 378.1038; found, 378.1039.
(E)-2-Styryl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (3i). Un-
known compound, a white powder (88 mg, 0.25 mmol, 50%); mp
117.1−118.6 °C; 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.3 Hz,
2H), 7.51−7.45 (m, 3H), 7.41−7.35 (m, 5H), 6.88 (d, J = 15.7 Hz,
1H), 3.67 (t, J = 6.4 Hz, 2H), 2.51 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 170.3, 151.5, 146.0, 137.3, 136.5,
3-((4-Methoxyphenyl)sulfonyl)-2-(p-tolyl)-5,6-dihydropyri-
midin-4(3H)-one (3p). Unknown compound, a yellow powder (145
1
mg, 0.40 mmol, 81%); mp 163.9−164.5 °C; H NMR (500 MHz,
135.5, 129.9, 129.7, 129.1, 129.1, 127.9, 122.1, 43.0, 33.8, 22.0; IR
(KBr) v 3315, 2847, 1739, 1636, 1607, 1535, 1362, 1175, 1086, 758,
667 cm−1; HRMS (EI-TOF) calcd for C19H18N2O3S (M+), 354.1038;
found, 354.1035.
CDCl3) δ 7.92 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.21 (d, J
= 7.3 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 3.89 (s, 3H), 3.70 (s, 2H),
2.53 (s, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.9,
164.5, 154.7, 141.3, 133.8, 132.0, 130.4, 129.2, 127.5, 114.1, 56.0, 43.5,
34.3, 21.7; IR (KBr) v 2961, 2845, 1741, 1630, 1593, 1499, 1359,
1271, 1188, 1059, 1086, 1010, 838, 825, 686 cm‑1; HRMS (EI-TOF)
calcd for C18H18N2O4S (M+), 358.0987; found, 358.0998.
2-Cyclohexyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (3j).
Unknown compound, a yellow powder (35 mg, 0.10 mmol, 21%);
1
mp 115.9−117.0 °C; H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.2
Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 3.55 (t, J = 6.2 Hz, 2H), 3.03 (t, J =
10.9 Hz, 1H), 2.46 (s, 3H), 2.40 (t, J = 6.2 Hz, 2H), 1.83 (d, J = 12.1
Hz, 2H), 1.74 (d, J = 12.4 Hz, 2H), 1.68 (d, J = 11.2 Hz, 1H), 1.37−
1.15 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 170.9, 160.2, 145.7,
136.6, 129.8, 128.8, 44.2, 42.5, 31.6, 26.2, 26.1, 21.9; IR (KBr) v 3354,
3067, 2923, 2855, 1745, 1645, 1581, 1542, 1365, 1175, 1081, 852, 665
cm−1; HRMS (EI-TOF) calcd for C17H22N2O3S (M+), 334.1351;
found, 334.1357.
6,6-Dimethyl-2-(p-tolyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (3k). Unknown compound, a white powder (179 mg, 0.48 mmol,
96%); mp 130.1−132.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J
= 8.3 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.19
(d, J = 7.9 Hz, 2H), 2.47 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 1.31 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 170.4, 150.7, 145.9, 140.7,
135.8, 134.4, 131.1, 129.4, 129.1, 127.4, 54.2, 45.6, 27.5, 22.0, 21.7; IR
(KBr) v 2975, 2927, 1727, 1624, 1366, 1274, 1233, 1168, 1084, 814,
696, 668 cm−1; HRMS (EI-TOF) calcd for C20H22N2O3S (M+),
370.1351; found, 370.1357.
2-(4-Methoxyphenyl)-3-(phenylsulfonyl)-5,6-dihydropyrimi-
din-4(3H)-one (3q). Unknown compound, a white powder (72 mg,
0.21 mmol, 42%); mp 151.1−152.6 °C; 1H NMR (500 MHz, CDCl3)
δ 7.99 (dd, J1 = 8.4, J2 = 1.0 Hz, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.58−
7.56 (m, 1H), 7.53 (m, 3H), 6.93−6.87 (m, 2H), 3.85 (s, 3H), 3.69 (t,
J = 6.4 Hz, 2H), 2.53 (t, J = 6.3 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 170.9, 161.9, 154.9, 139.3, 134.6, 129.4, 129.3, 129.0, 128.8,
113.9, 55.6, 43.5, 34.4; IR (KBr) v 2972, 1736, 1634, 1611, 1514, 1362,
1267, 1173, 1082, 1021, 826, 724, 688 cm−1; HRMS (EI-TOF) calcd
for C17H16N2O4S (M+), 344.0831; found, 344.0836.
3-(Phenylsulfonyl)-2-(p-tolyl)-5,6-dihydropyrimidin-4(3H)-
one (3r). Unknown compound, a white powder (117 mg, 0.36 mmol,
71%); mp 152.6−154.2 °C; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J
= 7.8 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.54−7.48 (m, 4H), 7.20 (d, J
= 8.0 Hz, 2H), 3.71 (t, J = 6.4 Hz, 2H), 2.53 (t, J = 6.4 Hz, 2H), 2.40
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.8, 154.5, 141.4, 139.2,
134.6, 133.6, 129.4, 129.2, 128.9, 127.5, 43.5, 34.2, 21.7; IR (KBr) v
3328, 3068, 2920, 1738, 1635, 1561, 1365, 1281, 1172, 1146, 1085,
D
dx.doi.org/10.1021/jo401094j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1006, 811, 724, 685 cm−1; HRMS (EI-TOF) calcd for C17H16N2O3S
(M+), 328.0882; found, 328.0886.
(4) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971.
3-(Naphthalen-2-ylsulfonyl)-2-(p-tolyl)-5,6-dihydropyrimi-
din-4(3H)-one (3s). Unknown compound, a white powder (92 mg,
0.24 mmol, 49%); mp 175.0−176.2 °C; 1H NMR (500 MHz, CDCl3)
δ 8.46 (s, 1H), 7.96 (m, 4H), 7.69 (m, 1H), 7.63 (m, 1H), 7.50 (d, J =
7.8 Hz, 2H), 7.18 (d, J = 7.7 Hz, 2H), 3.73 (t, J = 6.1 Hz, 2H), 2.53 (t,
J = 6.1 Hz, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.8,
154.6, 141.4, 135.9, 135.8, 133.6, 132.0, 131.8, 130.0, 130.0, 129.3,
128.2, 128.0, 127.7, 123.5, 43.6, 34.3, 21.8; IR (KBr) v 3337, 3053,
2917, 1729, 1646, 1373, 1349, 1284, 1199, 1176, 1150, 1102, 1071,
1008, 817, 758, 689 cm−1; HRMS (EI-TOF) calcd for C21H18N2O3S
(M+), 378.1038; found, 378.1040.
(5) Mai, A.; Sbardella, G.; Artico, M.; Ragno, R.; Massa, S.;
Novellino, E.; Greco, G.; Lavecchia, A.; Musiu, C.; La Colla, M.;
Murgioni, C.; La Colla, P.; Loddo, R. J. Med. Chem. 2001, 44, 2544.
(6) Mugnaini, C.; Alongi, M.; Togninelli, A.; Gevaiya, H.; Brizzi, A.;
Manetti, F.; Bernardini, C.; Angeli, L.; Tafi, A.; Bellucci, L.; Corelli, F.;
Massa, S.; Maga, G.; Samuele, A.; Facchini, M.; Clotet-Codina, I.;
Armand-Ugon, M.; Este, J. A.; Botta, M. J. Med. Chem. 2007, 50, 6580.
(7) Rotili, D.; Tarantino, D.; Artico, M.; Nawrozkij, M. B.; Gonzalez-
Ortega, E.; Clotet, B.; Samuele, A.; Este, J. A.; Maga, G.; Mai, A. J. Med.
Chem. 2011, 54, 3091.
(8) Gahr, M.; Kolle, M. A.; Schonfeldt-Lecuona, C.; Lepping, P.;
̈
̈
3-((4-Chlorophenyl)sulfonyl)-2-(p-tolyl)-5,6-dihydropyrimi-
din-4(3H)-one (3t). Unknown compound, a white powder (68 mg,
0.19 mmol, 37%); mp 164.3−165.9 °C; 1H NMR (500 MHz, CDCl3)
δ 7.92 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.0
Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 3.73 (t, J = 6.2 Hz, 2H), 2.56 (t, J =
6.3 Hz, 2H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.9,
154.2, 141.6, 141.4, 137.5, 133.5, 131.1, 129.3, 129.3, 127.5, 43.6, 34.3,
21.8; IR (KBr) v 3107, 2917, 1736, 1640, 1578, 1362, 1281, 1171,
1090, 1009, 816, 755, 668 cm−1; HRMS (EI-TOF) calcd for
C17H15ClN2O3S (M+), 362.0492; found, 362.0488.
Freudenmann, R. W. Drug Des. Devel. Ther. 2011, 5, 125.
(9) Riva, R.; Banfi, L.; Castaldi, G.; Ghislieri, D.; Malpezzi, L.;
Musumeci, F.; Tufaro, R.; Rasparini, M. Eur. J. Org. Chem. 2011, 231.
(10) Kunio, I.; Yoshiko, K.; Yuji, H. J. Heterocyclic Chem. 2005, 42,
583.
(11) Dzhavakhishvili, S. G.; Gorobets, N. Y.; Shishkina, S. V.;
Shishkin, O. V.; Dedenko, S. M.; Groth, U. M. J. Comb. Chem. 2009,
11, 508.
(12) Ostras, K. S.; Gorobets, N. Y.; Desenko, S. M.; Musatov, V. I.
Mol. Divers. 2006, 10, 483.
(13) Mirza-Aghayan, M.; Baie Lashaki, T.; Rahimifard, M.;
Boukherroub, R.; Tarlani, A. A. J. Iran. Chem. Soc. 2011, 8, 280.
(14) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(15) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
(16) Lu, P.; Wang, Y. Chem. Soc. Rev. 2012, 41, 5687.
(17) Kim, S. H.; Park, S. H.; Choi, J. H.; Chang, S. Chem.Asian J.
2011, 6, 2618.
(18) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009, 13, 1766.
(19) Lu, P.; Wang, Y. G. Synlett 2010, 2, 165.
(20) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517.
(21) Cui, S. L.; Wang, J.; Wang, Y. G. Tetrahedron 2008, 64, 487.
(22) Shen, Y.; Cui, S. L.; Wang, J.; Chen, X. P.; Lu, P.; Wang, Y. G.
Adv. Synth. Catal. 2010, 352, 1139.
(23) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2007, 9, 5023.
(24) Li, Y.; Hong, D.; Zhu, Y. X.; Lu, P.; Wang, Y. G. Tetrahedron
2011, 67, 8086.
2-(4-Chlorophenyl)-3-((4-chlorophenyl)sulfonyl)-5,6-dihy-
dropyrimidin-4(3H)-one (3u). Unknown compound, a yellow
1
powder (57 mg, 0.15 mmol, 30%); mp 157.3−159.2 °C; H NMR
(500 MHz, CDCl3) δ 7.95−7.91 (m, 2H), 7.55−7.50 (m, 4H), 7.41−
7.37 (m, 2H), 3.75 (t, J = 6.4 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 170.5, 153.4, 141.7, 137.3, 134.8, 131.0,
129.5, 129.0, 43.7, 34.1; IR (KBr) v 3103, 2970, 2921, 2858, 1736,
1641, 1578, 1489, 1364, 1280, 1181, 1153, 1095, 1013, 879, 821, 679
cm−1; HRMS (EI-TOF) calcd for C16H12Cl2N2O3S (M+), 381.9946;
found, 381.9940.
3-(Methylsulfonyl)-2-(p-tolyl)-5,6-dihydropyrimidin-4(3H)-
one (3v). Unknown compound, a yellow powder (56 mg, 0.21 mmol,
42%); mp 124.4−126.5 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J
= 8.0 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 3.82 (t, J = 6.3 Hz, 2H), 3.46
(s, 3H), 2.68 (t, J = 6.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 153.6, 141.3, 133.6, 129.5, 126.9, 44.4, 43.6, 34.2,
21.7; IR (KBr) v 3308 (m), 3203, 1739, 1635, 1538, 1411, 1185, 1168,
1139, 1102, 1008, 820), 759 cm−1; HRMS (EI-TOF) calcd for
C12H14N2O3S (M+), 266.0725; found, 266.0727.
(25) Song, W. Z.; Lu, W.; Wang, J.; Lu, P.; Wang, Y. G. J. Org. Chem.
2010, 75, 3481.
(26) Song, W. Z.; Lei, M.; Shen, Y.; Cai, S. Y.; Lu, W.; Lu, P.; Wang,
Y. G. Adv. Synth. Catal. 2010, 352, 2432.
(27) Wang, J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y. G. Chem. Commun.
2011, 47, 3275.
(28) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163.
(29) For ORTEPs of compound 3a, please see the Supporting
Information. CCDC 943090 (3a) contains supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all new compounds and
crystallographic information (CIF file) for compound 3a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
(30) Messina, F.; Botta, M.; Corelli, F.; Schneider, M. P.; Fazio, F. J.
Org. Chem. 1999, 64, 3767.
(31) Beccalli, E. M.; Borsini, E.; Broggini, G.; Palmisano, G.;
Corresponding Author
*E-mail: pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Notes
Sottocornola, S. J. Org. Chem. 2008, 73, 4746.
(32) McElwee-White, L.; Dougherty, D. A. J. Am. Chem. Soc. 1984,
106, 3466.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21272204, 21032005).
REFERENCES
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E
dx.doi.org/10.1021/jo401094j | J. Org. Chem. XXXX, XXX, XXX−XXX