Synthesis of polysubstituted 5-aminopyrimidines from α-azidovinyl ketones and amidines

Article abstract of DOI:10.1016/j.tet.2011.01.062

A simple and direct synthesis of polysubstituted 5-aminopyrimidines from a-azidovinyl ketones and amidines in the present of base was developed. The reactions were performed under mild conditions in good to excellent yields. Additionally a possible mechan

Full text of DOI:10.1016/j.tet.2011.01.062

Tetrahedron 67 (2011) 2676e2680
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Synthesis of polysubstituted 5-aminopyrimidines from
amidines
a-azidovinyl ketones and
*
Miao Hu, Jianwei Wu, Yaohong Zhang, Fangli Qiu, Yongping Yu
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and direct synthesis of polysubstituted 5-aminopyrimidines from
a-azidovinyl ketones and
Received 2 December 2010
Received in revised form 14 January 2011
Accepted 21 January 2011
Available online 27 January 2011
amidines in the present of base was developed. The reactions were performed under mild conditions in
good to excellent yields. Additionally a possible mechanism of 1,4-Michael addition is proposed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a
-Azidovinyl ketones
Amidines
Polysubstituted 5-aminopyrimidines
1, 4-Michael addition
Rearrangement
1. Introduction
Recently, by exploiting vinyl azides including a-azidovinyl ke-
tones, novel synthetic approaches toward nitrogen-containing
Pyrimidines represent an important class of heterocycles1 and
their structural framework is a key constituent of numerous natural
biologically active compounds.2 These compounds have been
shown to possess antitumor,3 anti-inflammatory,4 anti-viral,5
antiproliferative activities,6 as well as the potential to inactivate
human DNA repair.7 Furthermore, several pyrimidines are used in
polymer and supramolecular chemistry.8,9 5-Aminopyrimidine
derivatives, in particular, exhibit various important pharmacologi-
cal activities, such as anti-anoxic and anti-lipid peroxidation
activities to ameliorate brain ischemic damage.10 In addition, the 5-
aminopyrimidine substructures are useful for treating a disorder,
disease or a condition of a subject, which is responsive to activation
of Kv7 channels.11
Polysubstituted pyrimidines have been synthesized using vari-
ous procedures based on classical condensation reactions between
CeCeC and NeCeN12 or cross-coupling reactions.13 It is worth-
while to note that the direct syntheses of 5-aminopyrimidines are
rare in literature. The most common method for the preparation of
5-aminopyrimidines employs the reduction from 5-nitro-
pyrimidines with multiple steps.14,15 In this regard, the de-
velopment of synthetic methods, which enable a facile access to
polysubstituted 5-aminopyrimidines is desirable.
heterocycles have emerged from the literature.16e18 Our attention
was drawn to the potential chemical reactivity of a-azidovinyl ke-
tones as a three-atom unit including one nitrogen to synthesize
heterocycles.17 Our previous work have developed a domino ap-
proach to synthesize pyrrolo[1,2-a]pyrazine from vinyl azides and
2-pyrrolecarbaldehyde.19 Herein, we report a simple, straightfor-
ward and efficient methodology to prepare structurally diverse 5-
aminopyrimidines from
a-azidovinyl ketones and amidines.
2. Results and discussion
First, the coupling of (Z)-2-azido-3-(4-bromophenyl)-1-(4-
chlorophenyl) prop-2-en-1-one with formamidine acetate was
selected as the model reaction to optimize the reaction conditions
(Table 1). Initially we found out that the use of a 1:1 ratio of for-
mamidine acetate to base at 25 ꢀC in DMF gave a very low con-
version to the desired product. But when the ratio was 1:2, the
conversion was much higher. As shown in Table 1, six bases were
tested (entries 1e6), and Cs2CO3 was first used as base source
(entry 1). Increase of the basicity only led to trace amount of the
target product (entry 4). When Na2CO3 or Et3N was employed,
decreased yields of 50% and 35% were obtained, respectively (en-
tries 5 and 6). However, we were pleased to find that K2CO3 was the
most effective base with a highly improved chemical yield of 96%
(entry 2). The effect of solvents was also investigated (Table 1, en-
tries 7e11). The employment of polar solvents, such as EtOH,
* Corresponding author. Tel.: þ86 0571 88208450; fax: þ86 0571 88205450;
e-mail address: yyu@zju.edu.cn (Y. Yu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.062

M. Hu et al. / Tetrahedron 67 (2011) 2676e2680
2677
Table 1
Optimization of reaction conditionsa
Table 2
Reactions of various a
-azidovinyl ketones with amidinesa
R3
O
K2CO3, DMF
r.t, 24h
H2N
NH
N
N
Yieldb (%)
R1
R2
+
Entry
Base
Solvent
T (ꢀC)
R3
R1
R2
N3
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
DBU
t-BuOK
Na2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DCM
EtOH
Dioxane
CH3CN
Toluene
DMF
25
25
25
25
25
25
25
25
25
25
25
40
67
96
75
Trace
50
35
Trace
36
43
55
NH2
3
1
2
Entry
R1
R2
R3
H
Product 3 Yieldb (%)
1
3a
95
96
77
74
81
73
96
96
81
70
77
66
56
82
76
75
70
9
Br
10
11
12
n.r.
80
2
CH3 3b
Br
Br
a
Reaction conditions:
a-azidovinyl ketone(0.2 mmol), formamidine acetate
(0.24 mmol), base(0.48 mmol), 2 mL solvent under N2 atmosphere, 24 h, rt.
3c
4
Ph
H
3c
b
Isolated yield. The most successful entry is highlighted in bold.
3d
Br
dioxane, and CH3CN (entries 8, 9, and 10) led to dramatically de-
creased yields. Only trace of the desired product was observed
when DCM was used (entry 7). Meanwhile, there was no reaction
when the nonpolar solvent toluene was utilized (entry 11). The
reaction was also accessed at a higher temperature (Table 1, entry
5
CH3 3e
Br
6c
7
Ph
H
3f
Br
12), and it gave a reduced yield, probably due to the instability of a-
azidovinyl ketones in the reaction conditions. Therefore, the opti-
mal reactivity was obtained in DMF at 25 ꢀC when K2CO3 was
employed (96%, Table 1, entry 2).
3g
Cl
Cl
Cl
Cl
Br
Based on the optimized reaction conditions, we next examined
8
CH3 3h
Br
the reaction for a range of a-azidovinyl ketones with amidines. The
a
-azidovinyl ketones were readily prepared according to reports by
Knittel,20 Gilchrist,21 and Patonay.22
9c
10
11
12
13
14
15
16d
17d
Ph
H
3i
3j
Br
As shown in Table 2, analog compounds were synthesized when
R3 was either hydrogen or methyl, and the desired final product was
achieved with relatively similar yields (for example, 3a and 3b, 3g
and 3h). However, when R3 was phenyl group, the final yields were
generally lower than the other analogs (3c and 3a, 3b). R1 with
electrophilic groups on the aromatic ring were converted into the
corresponding products with good efficiency (3h and 3d). When R1
was 4-methoxyphenyl group, the reactions were relatively sluggish,
requiring a higher temperature (Table 2, entries 16e18). When R2
was 4-methoxyphenyl group, the reactions (Table 2, entries 10e13)
were not so compatible, probably due to their low activities. Higher
yields were also achieved when the R2 functionality was an aromatic
ring containing an electron-withdrawing group (3g and 3j, 3m and
3o, 3p, 3q, and 3r). Especially, heteroaryl motifs such as thiophene
(3m, 3n, 3o) were successfully incorporated. These results indicated
that the nucleophilicity of the C-1 and C-3 of
played an important role in the entire process.
A possible reaction mechanism for the reaction process is pro-
posed in Scheme 1. Our strategy relies on intermolecular Michael
addition of amidine 2 to the a-azidovinyl ketone 1 in the presence
of base. Consecutive elimination of dinitrogen of the active in-
termediate I affords II, followed by subsequent intramolecular
nucleophilic attack to the carbonyl group. Dehydration of cyclized
intermediate III and further rearrangement of IV provide the de-
sired product 3.
H3CO
H3CO
H3CO
H3CO
F
CH3 3k
O2N
O2N
Ph
H
3l
S
S
S
3m
CH3 3n
H
H
H
3o
3p
3q
Cl
a-azidovinyl ketones
H3CO
H3CO
Cl
Br
18d
H
3r
59
H3CO
a
Reactions were performed in anhydrous DMF with 1.2 equiv of amidine (2) and
2.4 equiv of K2CO3 under N2 atmosphere at rt for 24 h unless mentioned otherwise.
3. Conclusion
b
Isolated yield.
c
The reaction was performed with 2 equiv of amidine (2) and 4 equiv of K2CO3.
d
The reaction was performed at 50 ꢀC for 24 h.
In conclusion, we have developed a simple, direct, and efficient
method for the synthesis of polysubstituted 5-aminopyrimidines
from readily available a-azidovinyl ketones and amidines in mild

2678
M. Hu et al. / Tetrahedron 67 (2011) 2676e2680
1H), 7.51 (t, J¼7.0, 8.0 Hz, 2H), 7.64 (d, J¼8.5 Hz, 2H), 7.68 (d,
J¼8.5 Hz, 2H), 7.74 (d, J¼7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
25.16, 123.67, 128.46, 129.07, 129.47, 130.24, 132.19, 132.60, 135.73,
136.60, 150.55, 152.43, 157.99; LCeMS (ESI): m/z [MþH]þ: 340.2;
HRMS (ESI): m/z calcd for C17H14N3Br (M)þ: 339.0371. Found:
339.0371.
4.2.3. 4-(4-Bromophenyl)-6-(p-tolyl)pyrimidin-5-amine (3d). Pale
yellow solid (251 mg, 74%); mp: 195.0e197.5 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
2.42 (s, 3H), 4.05 (s, 2H), 7.32 (d, J¼8.0 Hz, 2H), 7.63e7.70
(m, 6H), 8.72 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
21.43, 123.85,
128.32, 129.74, 130.18, 132.20, 133.34, 135.37, 135.46, 149.26, 152.08;
LCeMS (ESI): m/z [MþH]þ: 340.2; HRMS (ESI): m/z calcd for
C17H14N3Br (M)þ: 339.0371. Found: 339.0368.
Scheme 1. Proposed mechanism of 5-aminopyrimidines formation.
4.2.4. 4-(4-Bromophenyl)-2-methyl-6-(p-tolyl)pyrimidin-5-amine
(3e). Pale yellow solid (286 mg, 81%); mp: 188.0e190.5 ꢀC; 1H NMR
(500 MHz, CDCl3)
d 2.41 (S, 3H), 2.68 (s, 3H), 3.85 (s, 2H), 7.31 (d,
conditions to obtain the corresponding products in good yields. The
reaction may be realized by 1,4-Michael addition and subsequent
rearrangement. Furthermore, it satisfies the green-chemistry fea-
tures as only a molecule of nitrogen and water is lost in the whole
process.
J¼8.0 Hz, 2H), 7.62e7.68 (m, 6H); 13C NMR (125 MHz, CDCl3)
d
21.64, 25.36, 123.84, 128.61, 129.94, 130.50, 132.38, 132.84, 133.89,
136.02, 139.79, 150.59, 152.81, 158.16; LCeMS (ESI): m/z [MþH]þ:
354.3; HRMS (ESI): m/z calcd for C18H16N3Br (M)þ: 353.0528.
Found: 353.0536.
4. Experimental section
4.1. General
4.2.5. 4-(4-Bromophenyl)-6-(4-chlorophenyl)pyrimidin-5-amine
(3g). Pale yellow solid (346 mg, 96%); mp: 203.0e205.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
4.04 (s, 2H), 7.50 (d, J¼8.5 Hz, 2H), 7.65e7.70 (m,
J¼8.5, 8.5 Hz, 4H), 7.75 (d, J¼8.5 Hz, 2H), 8.75 (s, 1H); 13C NMR
All solvents were purified according to standard methods prior to
use. Reactions were under an atmosphere of nitrogen unless men-
tioned otherwise. Purification of reaction products were carried out
by chromatography using silica gel (200e300 mesh). Melting points
(125 MHz, CDCl3)
d 124.09, 129.33, 129.90, 130.14, 132.30, 134.67,
135.15, 135.33, 135.80, 149.35, 150.56, 150.59; LCeMS (ESI): m/z
[MþH]þ: 360.1; HRMS (ESI): m/z calcd for C16H11N3ClBr (M)þ:
358.9825. Found: 358.9820.
€
were recorded on a BUCHI B-540 melting point apparatus. NMR
spectra were recorded for 1H NMR at 500 MHz and 13C NMR at
4.2.6. 4-(4-Bromophenyl)-6-(4-chlorophenyl)-2-methylpyrimidin-5-
125 MHz. For 1H NMR, tetramethylsilane (TMS) served as internal
amine (3h). Pale yellow solid (359 mg, 96%); mp: 188.5e191.0 ꢀC;
standard (
d
¼0) and data are reported as follows: chemical shift, in-
1H NMR (500 MHz, CDCl3)
d
2.68 (s, 3H), 3.83 (s, 3H), 7.49 (d,
J¼8.5 Hz, 2H), 7.63e7.67 (m, J¼8.5, 8.5 Hz, 4H), 7.73 (d, J¼8.5 Hz,
2H); 13C NMR (125 MHz, CDCl3)
25.10, 123.83, 129.28, 129.97,
tegration, multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), and coupling constant(s) in hertz. For 13C NMR, TMS
d
(
d
¼0) or CDCl3 ( ¼77.26) was used as internal standard and spectra
d
130.22, 132.24, 132.57, 135.00, 135.49, 135.56, 151.00, 151.23, 158.13;
LCeMS (ESI): m/z [MþH]þ: 374.2; HRMS (ESI): m/z calcd for
C17H13N3ClBr (M)þ: 372.9981. Found: 372.9985.
were obtained with complete proton decoupling. LCeMS and HRMS
data was obtained using ESI ionization. The starting materials 1aer
were prepared according to literature methods.
4.2.7. 4-(4-Chlorophenyl)-6-(4-methoxyphenyl)pyrimidin-5-amine
4.2. General procedure for the synthesis of polysubstituted
5-aminopyrimidines
(3j). Yellow solid (218 mg, 70%); mp: 165.0e167.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
3.86 (s, 3H), 4.04 (s, 2H), 7.03 (d, J¼8.0 Hz, 2H),
7.48 (d, J¼7.5 Hz, 2H), 7.76 (d, J¼7.5 Hz, 4H), 8.71 (s, 1H); 13C NMR
A mixture of
a
-azidovinyl ketone 1 (1.0 mmol), amidine acid 2
(125 MHz, CDCl3) d 55.63, 114.63, 128.85, 129.45, 130.18, 135.30,
(1.2 mmol), and K2CO3 (2.4 mmol) was stirred in anhydrous DMF
(4 mL) at rt under nitrogen overnight. The reaction mixture was
quenched with water (10 mL), and then extracted three times with
EtOAc. The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated. Purification of the crude
product by chromatography (silica gel, eluent PE/EA) to afford 3.
135.53, 135.74, 149.55, 150.10, 160.90; LCeMS (ESI): m/z [MþH]þ:
312.2; HRMS (ESI): m/z calcd for C17H14N3OCl (M)þ: 311.0825.
Found: 311.0825.
4.2.8. 4-(4-Methoxyphenyl)-2-methyl-6-(4-nitrophenyl)pyrimidin-
5-amine (3k). Red solid (259 mg, 77%); mp: 180.0e182.0 ꢀC; 1H
NMR (500 MHz, CDCl3) d 2.70 (s, 3H), 3.87 (s, 3H), 3.91 (s, 2H), 7.05
4.2.1. 4-(4-Bromophenyl)-6-phenylpyrimidin-5-amine
yellow solid (309 mg, 95%); mp: 142.0e144.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
4.05 (s, 2H), 7.47 (t, J¼7.0, 7.5 Hz, 1H), 7.52 (t,
(3a). Pale
(d, J¼8.5 Hz, 2H), 7.75 (d, J¼9.0 Hz, 2H), 8.02 (d, J¼8.5 Hz, 2H), 7.86
(d, J¼8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 25.35, 55.68, 114.74,
d
124.37, 128.71, 130.03, 130.23, 133.00, 143.62, 148.27, 148.78, 153.45,
158.41, 160.97; LCeMS (ESI): m/z [MþH]þ: 337.2; HRMS (ESI): m/z
calcd for C18H16N4O3 (M)þ: 336.1222. Found: 336.1216.
J¼7.0, 8.0 Hz, 2H), 7.64 (d, J¼8.5 Hz, 2H), 7.70 (d, J¼8.5 Hz, 2H), 7.76
(d, J¼7.5 Hz, 2H), 8.72 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 123.88,
128.40, 129.08, 129.67, 130.15, 132.22, 135.38, 135.43, 136.31, 149.29,
150.09, 151.91; LCeMS (ESI): m/z [MþH]þ: 326.2; HRMS (ESI): m/z
calcd for C16H12N3Br (M)þ: 325.0215. Found: 325.0219.
4.2.9. 4-(4-Methoxyphenyl)-6-(thiophen-2-yl)pyrimidin-5-amine
(3m). Yellow solid (159 mg, 56%); mp: 158.0e160.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
7.19e7.21 (m, 1H), 7.54 (d, J¼5 Hz, 1H), 7.75e7.79 (m, 3H), 8.70 (s,
1H); 13C NMR (125 MHz, CDCl3)
55.42, 114.44, 127.63, 128.09,
128.55, 128.96, 130.09, 134.15, 141.37, 144.76, 149.15, 152.57, 160.72;
d
3.89 (s, 1H), 4.29 (s, 2H), 7.05 (d, J¼9.0 Hz, 2H),
4.2.2. 4-(4-Bromophenyl)-2-methyl-6-phenylpyrimidin-5-amine
(3b). Pale yellow solid (326 mg, 96%); mp: 127.5e128.5 ꢀC; 1H NMR
d
(500 MHz, CDCl3)
d
2.69 (S, 3H), 3.85 (s, 2H), 7.46 (t, J¼7.0, 7.5 Hz,

M. Hu et al. / Tetrahedron 67 (2011) 2676e2680
2679
LCeMS (ESI): m/z [MþH]þ: 284.2; HRMS (ESI): m/z calcd for
(d, J¼9.0 Hz, 2H), 8.44 (d, J¼8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
C15H13N3OS (M)þ: 283.0779. Found: 283.0773.
d 55.68, 114.68, 124.29, 127.49, 128.60, 129.10, 129.64, 130.15, 133.85,
138.05, 143.88, 148.36, 148.65, 153.24, 155.75, 161.10; LCeMS (ESI):
m/z [MþH]þ: 399.3; HRMS (ESI): m/z calcd for C23H18N4O3 (M)þ:
398.1379. Found: 398.1372.
4.2.10. 4-(4-Fluorophenyl)-2-methyl-6-(thiophen-2-yl)pyrimidin-5-
amine (3n). Yellow solid (234 mg, 82%); mp: 158.0e161.0 ꢀC; 1H
NMR (500 MHz, CDCl3)
3H), 7.50e7.52 (m, 1H), 7.71e7.74 (m, 3H); 13C NMR (125 MHz,
CDCl3)
128.02, 128.85 (d, J¼221 Hz), 128.92, 130.67 (d, J¼8 Hz), 130.91 (d,
J¼8 Hz), 131.51, 132.50 (d, J¼3 Hz), 141.21, 145.46, 152.10, 157.83,
162.33, 164.31; m/z [MþH]þ: 286.2; HRMS (ESI): m/z calcd for
C15H12N3SF (M)þ: 285.0736. Found: 285.0724.
d 2.66 (s, 3H), 4.05 (s, 2H), 7.16e7.20 (m,
4.4. General procedure for the synthesis of 3p, 3q, 3r
d
25.01, 115.60 (d, J¼22 Hz), 116.08 (d, J¼22 Hz), 127.74,
A mixture of a-azidovinyl ketone 1 (1.0 mmol), amidine acid 2
(1.2 mmol), and K2CO3 (2.4 mmol) was stirred in anhydrous DMF
(4 mL) at 50 ꢀC for 24 h under nitrogen. The reaction mixture was
quenched with water (10 mL), and then extracted three times with
EtOAc. The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated. Purification of the crude
product by chromatography (silica gel, eluent PE/EA) to afford 3.
4.2.11. 4-(4-Chlorophenyl)-6-(thiophen-2-yl)pyrimidin-5-amine
(3o). Yellow solid (218 mg, 76%); mp: 139.0e140.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
2H), 7.53e7.54 (m, 1H), 7.72e7.73 (m, 2H), 7.74e7.76 (m, 1H), 8.67
(s, 1H); 13C NMR (125 MHz, CDCl3)
128.01, 128.41, 129.48, 129.55,
d 4.27 (s, 2H), 7.18e7.20 (m, 1H), 7.48e7.53 (m,
4.4.1. 4-(4-Chlorophenyl)-6-(4-methoxyphenyl)pyrimidin-5-amine
(3p). Yellow solid (233 mg, 75%); mp: 177.5e180.0 ꢀC; 1H NMR
d
130.24, 134.44, 134.93, 136.03, 141.26, 145.54, 149.37, 151.50; LCeMS
(ESI): m/z [MþH]þ: 288.1; HRMS (ESI): m/z calcd for C14H10N3SCl
(M)þ: 287.0284. Found: 287.0282.
(500 MHz, CDCl3)
d
3.86 (s, 3H), 4.05 (s, 2H), 7.03 (d, J¼8.5 Hz, 2H),
7.48 (d, J¼8.5 Hz, 2H), 7.76 (d, J¼8.5 Hz, 4H), 8.71(s, 1H); 13C NMR
(125 MHz, CDCl3)
d 55.64, 114.62, 128.84, 129.45, 130.18, 135.29,
135.55, 135.74, 149.55, 150.09, 152.00, 160.88; LCeMS (ESI): m/z
[MþH]þ: 312.2; HRMS (ESI): m/z calcd for C17H14N3OCl (M)þ:
311.0825. Found: 311.0826.
4.3. General procedure for the synthesis of 3c, 3f, 3i, 3l
A mixture of a-azidovinyl ketone 1 (1.0 mmol), amidine acid 2
(2.0 mmol), and K2CO3 (4.0 mmol) was stirred in anhydrous DMF
(4 mL) at rt under nitrogen overnight. The reaction mixture was
quenched with water (10 mL), and then extracted three times with
EtOAc. The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated. Purification of the crude
product by chromatography (silica gel, eluent PE/EA) to afford 3.
4.4.2. 4-(2-Bromophenyl)-6-(4-methoxyphenyl)pyrimidin-5-amine
(3q). Yellow-brown solid (248 mg, 70%); mp: 190.0e193.0 ꢀC; 1H
NMR (500 MHz, CDCl3)
d
3.77 (s, 5H), 6.94 (d, J¼9.0 Hz, 2H),
7.19e7.24 (m, 1H), 7.33e7.38 (m, 2H), 7.62 (d, J¼8.0 Hz, 1H), 7.69 (d,
J¼8.5 Hz, 2H), 8.64 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 55.40,
114.41, 122.15, 128.25, 128.52, 129.82, 130.75, 130.79, 133.40, 135.64,
137.08, 148.60, 151.12, 151.26, 160.65; LCeMS (ESI): m/z [MþH]þ:
356.2; HRMS (ESI): m/z calcd for C17H14N3OBr (M)þ: 355.0320.
Found: 355.0327.
4.3.1. 4-(4-Bromophenyl)-2,6-diphenylpyrimidin-5-amine (3c). Pale
yellow solid (309 mg, 77%); mp: 192.0e194.0 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
4.05 (s, 2H), 7.38 (t, J¼7.0, 7.5 Hz, 1H), 7.43 (t,
J¼7.5, 7.5 Hz, 2H), 7.49 (t, J¼7.0, 7.5 Hz, 2H), 7.54 (t, J¼7.5, 7.5 Hz),
4.4.3. 4-(4-Methoxyphenyl)-6-phenylpyrimidin-5-amine
7.81 (d, J¼8.5 Hz, 2H), 7.88 (d, J¼8.5 Hz, 2H); 13C NMR (125 MHz,
(3r). Yellow solid (163 mg, 59%); mp: 128.0e130.0 ꢀC; 1H NMR
CDCl3)
d 123.78, 127.28, 128.33, 128.74, 129.00, 130.47, 132.14,
(500 MHz, CDCl3)
7.47 (t, J¼7.0, 7.5 Hz, 1H), 7.53 (t, J¼7.0, 7.5 Hz, 2H), 7.78e7.80 (m,
4H), 8.76 (s, 1H); 13C NMR (125 MHz, CDCl3)
55.41, 114.39, 128.47,
d
3.88 (s, 3H), 4.07 (s, 2H), 7.05 (d, J¼9.0 Hz, 2H),
133.51, 136.02, 136.89, 138.04, 150.38, 152.18, 155.38; LCeMS (ESI):
m/z [MþH]þ: 402.3; HRMS (ESI): m/z calcd for C22H16N3Br (M)þ:
401.0528. Found: 401.0523.
d
128.87, 129.03, 129.49, 129.96, 135.32, 136.65, 149.34, 151.28, 151.40,
160.58; LCeMS (ESI): m/z [MþH]þ: 278.2; HRMS (ESI): m/z calcd for
C17H15N3O (M)þ: 277.1215. Found: 277.1208.
4.3.2. 4-(4-Bromophenyl)-2-phenyl-6-(p-tolyl)pyrimidin-5-amine
(3f). Pale yellow solid (304 mg, 73%); mp: 223.0e225.5 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
2.43 (s, 3H), 4.03 (s, 2H), 7.33 (d, J¼7.5 Hz, 2H),
Acknowledgements
7.38 (d, J¼7.0 Hz, 1H), 7.42 (t, J¼7.0, 7.5 Hz, 2H), 7.65 (d, J¼8.5 Hz,
2H), 7.77e7.80 (m, J¼8.0, 8.5 Hz, 4H), 8.43 (d, J¼7.0 Hz, 2H); 13C
We thank the National Natural Science Foundation of China
(No. 30772652 and No. 90813026) and National key Tech project
for Major Creation of New Drug (No. 2009ZX09501-010).
NMR (125 MHz, CDCl3)
d 21.70, 123.94, 127.52, 128.54, 128.89,
129.41, 129.89, 130.73, 132.33, 133.74, 134.24, 136.33, 138.35, 139.92,
150.40, 152.55, 155.55; LCeMS (ESI): m/z [MþH]þ: 416.2; HRMS
(ESI): m/z calcd for C23H18N3Br (M)þ: 415.0684. Found: 415.0688.
Supplementary data
4.3.3. 4-(4-Bromophenyl)-6-(4-chlorophenyl)-2-phenylpyrimidin-5-
Experimental procedures, characterization data, and copies of 1H
and 13C NMR spectra for all products. Supplementary data associ-
ated with this article can be found in online version at doi:10.1016/
j.tet.2011.01.062. These data include MOL files and InChiKeys of
the most important compounds described in this article.
amine (3i). Pale yellow solid (353 mg, 81%); mp: 240.0e242.5 ꢀC;
1H NMR (500 MHz, CDCl3)
d 4.02 (s, 2H), 7.38e7.44 (m, 3H), 7.52 (d,
J¼8.0 Hz, 2H), 7.68 (d, J¼8.0 Hz, 2H), 7.80 (d, J¼8.5 Hz, 2H), 7.86 (d,
J¼8.0 Hz, 2H), 8.42 (d, J¼7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
123.94, 127.25, 128.37, 129.23, 129.37. 130.19, 130.44, 132.19,
133.43, 135.30, 135.65, 135.78, 137.83, 150.83, 155.48; LCeMS (ESI):
m/z [MþH]þ: 436.2; HRMS (ESI): m/z calcd for C22H15N3ClBr (M)þ:
435.0138. Found: 435.0136.
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