One-pot synthesis of pyrimidines via cyclocondensation of β-bromovinyl aldehydes with amidine hydrochlorides

Article abstract of DOI:10.1002/hlca.201000264

A series of pyrimidines were prepared by cyclocondensation of β-bromovinyl aldehydes with amidine hydrochlorides in the presence of Et₃N in excellent yields (74-95%).

Full text of DOI:10.1002/hlca.201000264

Helvetica Chimica Acta – Vol. 94 (2011)
487
One-Pot Synthesis of Pyrimidines via Cyclocondensation of b-Bromovinyl
Aldehydes with Amidine Hydrochlorides
by Shengjiao Yan1), Yajuan Tang1), Fuchao Yu, and Jun Lin*
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of
Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091,
P. R. China (phone: þ 868715033215; e-mail: linjun@ynu.edu.cn)
A series of pyrimidines were prepared by cyclocondensation of b-bromovinyl aldehydes with
amidine hydrochlorides in the presence of Et3N in excellent yields (74 – 95%).
Introduction. – As part of our interest in the development of simple and efficient
procedures to synthesize various N-containing heterocycles with potential bioactivities
[1], we report herein an efficient method, based on cyclocondensation of b-bromovinyl
aldehydes 1 with amidine hydrochlorides 2, for the rapid construction of a library of
pyrimidines.
Results and Discussion. – Initially, an easily available starting material, b-
bromovinyl aldehyde 1a, was reacted with 0.83 equiv. of 4-(trifluoromethyl)benzami-
dine hydrochloride (2a) in 1,4-dioxane, catalyzed by Et3N and at reflux for 8 h,
successfully affording the pyrimidine 3a in good yield (85%; Scheme; Table, Entry 1).
The product was identified by spectroscopic data and high-resolution mass spectrom-
etry.
Encouraged by this result, we explored the scope and limitations of cyclo-
condensation reactions involving various b-bromovinyl aldehydes 1 with a number of
amidine hydrochlorides 2 (Table, Entries 1 – 22). The results revealed that b-
bromovinyl aldehydes with various substituents were all good substrates for the
cyclocondensation reaction (Table, Entries 1 – 22). The reactions usually only took 6 –
8 h at reflux in 1,4-dioxane in the presence of Et3N and gave the target compounds in
good yields.
Scheme. Synthesis of Pyrimidines
The structures of the b-bromovinyl aldehydes 1 have modest influence on the
reactivity and yields, so we cannot derive a general rule on the group effects of the
1
)
These authors contributed equally to this article.
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Table. Synthesis of Pyrimidines
Entry
1
2
3
R
R1
R2
Yield [%]a)
M.p. [8] (lit. m.p.)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2f
2g
2b
2c
2d
2g
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
4-CF3ꢀC6H4
4-ClꢀC6H4
Ph
85
92
93
92
74
79
84
94
83
93
77
81
86
95
88
91
80
95
93
89
85
91
208 – 210
116 – 120 (115 – 117) [2]
71.5 – 73.5 (74 – 75) [2]
86 – 87 (91 – 94) [3]
58 – 61 (61 – 62) [4]
56 (54 – 54.5) [3]
217 – 221
147 – 152
69 – 72
153 – 154.6
90 – 92 (80 – 90) [5]
95 – 97 (91 – 93) [6]
190 – 190.5
74 – 75.6
102 – 104 (109.5 – 110) [3]
114 – 116.5
70 – 72.5 (79 – 79.5) [3]
208 – 209.5
159 – 163
50 – 52 (52 – 53) [7]
149 – 152
95 – 96.5
4-MeꢀC6H4
H
Me
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
4-CF3ꢀC6H4
4-ClꢀC6H4
Ph
4-MeꢀC6H4
H
Me
4-CF3ꢀC6H4
4-ClꢀC6H4
Ph
4-MeꢀC6H4
Me
Pyridin-4-yl
4-ClꢀC6H4
Ph
3s
3t
3u
3v
4-MeꢀC6H4
Pyridin-4-yl
a) Yields of isolated products, based on amidine hydrochlorides 2.
substrates 1 (Table, Entries 1 – 6 vs. 7 – 12, and 13 – 18 vs. 19 – 22, resp.). On the contrary,
the structures of the amidine hydrochlorides 2 can contribute to the reactivity and
yields. Thus, the aryl-substituted amidine hydrochlorides always lead to good-to-
excellent yields (83 – 95%; Table, Entries 1 – 4, 7 – 10, 13 – 16, and 18 – 22), whereas the
alkyl-substituted amidine hydrochlorides usually give good yields (74 – 81%; Table,
Entries 5, 6, 11, 12, and 17).
Conclusions. – We have developed a procedure for simple synthesis of a variety of
potentially bioactive pyrimidines. By this method, a diverse pyrimidine library was
rapidly constructed with good-to-excellent yields by simply refluxing a reaction mixture
of b-bromovinyl aldehydes and the amidine hydrochlorides, catalyzed by Et3N. The
one-pot conditions and the mild reaction conditions render this method an attractive
alternative for the synthesis of this type of N-containing heterocycles.
The authors wish to acknowledge the financial supports from NSFC (No. 30860342 and 20762013)
and NSFYN (No. 2009cc017 and 2008cd063).
Experimental Part
General. Compounds 1a – 1d were synthesized according to [8], and 2a – 2g were purchased from
Aldrich. All novel compounds were fully characterized by spectroscopic analysis. All chemicals and
solvents were used as received without further purification unless otherwise stated. Column

Helvetica Chimica Acta – Vol. 94 (2011)
489
chromatography (CC): silica gel (SiO2; 200 – 300 mesh). The reactions were monitored by TLC using
silica gel GF254. M.p.: XT-4A melting-point apparatus; uncorrected. IR Spectra: FT-IR Thermo Nicolet
Avatar 360; KBr pellets. NMR Spectra: Bruker DRX500 (1H: 500 MHz, 13C: 125 MHz); chemical shifts
(d) in ppm, and J values in Hz; CDCl3 as solvent. HR-MS: Agilent LC/Msd TOF instrument.
General Procedure for the Preparation of Pyrimidines 3a – 3v. A 25-ml round-bottom flask was
charged with b-bromovinyl aldehyde 1 (1.2 mmol), 1,4-dioxane (6 ml), and Et3N (1.5 ml), then, the soln.
was added to the amidine hydrochloride 2 (1.0 mmol), and the mixture was heated at reflux. The
resulting soln. was stirred for 6 – 8 h 1 was completely consumed. The reaction was quenched by the
addition of H2O (25 ml), and then AcOEt (25 ml) was added. The org. phase was washed with H2O (3 ꢁ
8 ml), dried (Na2SO4), concentrated, and purified by CC (petroleum ether/AcOEt 10 :1) to afford the
final product.
4-Phenyl-2-[4-(trifluoromethyl)phenyl]pyrimidine (3a). M.p. 208 – 2108. IR: 3432, 2569, 2333, 1633,
1520, 1374, 1324, 1115, 1068, 873. 1H-NMR: 7.26 – 7.28 (m, 1 arom. H); 7.47 (d, J ¼ 7.3, 2 arom. H); 7.74 –
7.83 (m, 4 arom. H); 8.41 – 8.44 (m, 1 arom. H); 8.79 – 8.81 (m, 3 arom. H). 13C-NMR: 126.0; 126.3; 128.7;
129.4; 129.6; 129.6; 129.9; 130.7; 139.6; 143.3; 170.9; 172.9. HR-MS (TOF-ESþ): 302.1040 ([M þ 2 H]þ,
C17H13F3Nþ2 ; calc. 302.1020).
4-(4-Chlorophenyl)-2-[4-(trifluoromethyl)phenyl]pyrimidine (3g). M.p. 217 – 2218. IR: 3435, 2573,
2328, 2190, 1649, 1396, 825. 1H-NMR: 7.21 – 7.82 (m, 7 arom. H); 8.31 – 8.77 (m, 3 arom. H). 13C-NMR:
123.2; 125.4; 125.7; 126.0; 128.5; 130.3; 134.1; 135.0; 136.6; 139.5; 141.7; 170.9; 172.6. HR-MS (TOF-ESþ):
334.0491 (Mþ, C17H10ClF3Nþ2 ; calc. 334.0485).
2,4-Bis(4-chlorophenyl)pyrimidine (3h). M.p. 147 – 1528. IR: 3471, 2925, 2855, 2338, 1586, 1392, 1092,
789. 1H-NMR: 7.11 – 7.22 (m, 6 arom. H); 7.36 (d, J ¼ 5.2, 1 arom. H); 7.89 (d, J ¼ 8.3, 2 arom. H); 8.30 (d,
J ¼ 8.3, 2 arom. H); 8.52 (d, J ¼ 5.2, 1 arom. H). 13C-NMR: 114.7; 128.8; 129.0; 129.8; 130.4; 135.4; 136.4;
137.0; 137.3; 158.4; 162.8; 163.6. HR-MS (TOF-ESþ): 301.0299 ([M þ H]þ, C6H11Cl2Nþ2 ; calc. 301.0294).
4-(4-Chlorophenyl)-2-phenylpyrimidine (3i): M.p. 69 – 728. IR: 3434, 2924, 2571, 2348, 1636, 1546,
1393, 1089. 1H-NMR: 7.54 – 7.57 (m, 6 arom. H); 8.20 – 8.23 (m, 2 arom. H); 8.86 – 8.89 (m, 2 arom. H);
9.24 – 9.27 (m, 1 arom. H). 13C-NMR: 114.6; 128.7; 128.9; 129.6; 129.9; 131.2; 135.8; 137.6; 138.1; 158.4;
163.1; 165.1. HR-MS (TOF-ESþ): 267.0689 ([M þ H]þ, C16H12ClNþ2 ; calc. 267.0684).
4-(4-Chlorophenyl)-2-(4-methylphenyl)pyrimidine (3j). M.p. 153 – 154.68. IR: 3434, 2578, 2312, 1553,
1489, 1435, 1374. 1H-NMR: 2.45 (s, Me); 7.33 (d, J ¼ 7.8, 2 arom. H); 7.49 – 7.52 (m, 3 arom. H); 8.16 (d,
J ¼ 8.0, 2 arom. H); 8.46 (d, J ¼ 8.0, 2 arom. H); 8.81 (d, J ¼ 5.1, 1 arom. H). 13C-NMR: 21.9; 114.3;
128.7; 129.2; 129.6; 129.8; 135.4; 135.9; 137.5; 141.5; 158.4; 163.0; 165.2. HR-MS (TOF-ESþ): 281.0848
([M þ H]þ, C17H14ClNþ2 ; calc. 281.0840).
4-(4-Methylphenyl)-2-[4-(trifluoromethyl)phenyl]pyrimidine (3m). M.p. 190 – 190.58. IR: 3438, 2577,
2337, 1635, 1509, 1387, 1323, 820. 1H-NMR: 2.42 (s, Me); 7.25 – 7.27 (m, 2 arom. H); 7.63 (d, J ¼ 7.9, 1 arom.
H); 7.77 – 7.81 (m, 3 arom. H); 8.34 – 8.38 (m, 1 arom. H); 8.74 – 8.77 (m, 3 arom. H). 13C-NMR: 21.9;
125.2; 125.4; 126.0; 128.7; 129.6; 130.2; 132.9; 134.2; 139.6; 141.2; 143.3; 170.7; 173.0. HR-MS (TOF-
ESþ): 353.0652 ([M þ K]þ, C18H13F3KNþ2 ; calc. 353.0662).
2-(4-Chlorophenyl)-4-(4-methylphenyl)pyrimidine (3n). M.p. 74 – 75.68. IR: 3426, 2573, 2345, 1604,
1
1488, 1398, 1328, 1271. H-NMR: 2.34 (s, Me); 6.16 – 6.52 (m, 1 arom. H); 7.09 – 7.13 (m, 2 arom. H);
7.37 – 7.48 (m, 4 arom. H); 7.98 – 8.01 (m, 3 arom. H). 13C-NMR: 21.6; 126.1; 127.0; 127.8; 128.1; 129.1;
129.5; 129.8; 133.9; 135.8; 138.2; 140.1; 160.5. HR-MS (TOF-ESþ): 281.0834 ([M þ H]þ, C17H14ClN2þ ;
calc. 281.0840).
2,4-Bis(4-methylphenyl)pyrimidine (3p). M.p. 114 – 116.58. IR: 3432, 2565, 2310, 1555, 1408, 817, 779.
1H-NMR: 2.42 (s, 2 Me); 7.29 – 7.32 (m, 4 arom. H); 7.51 (d, J ¼ 5.0, 1 arom. H); 8.11 (d, J ¼ 7.7, 2 arom.
H); 8.46 (d, J ¼ 7.7, 2 arom. H); 8.76 (d, J ¼ 5.0, 1 arom. H). 13C-NMR: 21.9; 22.2; 114.3; 127.5; 128.7;
129.7; 130.1; 134.7; 135.7; 141.3; 141.7; 158.1; 164.2; 165.0. HR-MS (TOF-ESþ): 261.1390 ([M þ H]þ,
C18H17Nþ2 ; calc. 261.1386).
4-(4-Methylphenyl)-2-(pyridin-4-yl)pyrimidine (3r). M.p. 208 – 209.58. IR: 3438, 3034, 2916, 2351,
2202, 1627, 1509, 1372. 1H-NMR: 2.40 (s, Me); 7.1 – 7.9 (m, 4 arom. H); 8.18 – 8.85 (m, 6 arom. H).
13C-NMR: 22.0; 122.6; 128.8; 129.2; 129.8; 130.8; 141.5; 143.4; 144.0; 151.3; 170.6; 173.4. HR-MS (TOF-
ESþ): 248.1190 ([M þ H]þ, C16H14Nþ3 ; calc. 248.1182).

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Helvetica Chimica Acta – Vol. 94 (2011)
2-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinazoline (3s). M.p. 159 – 1638. IR: 3448, 2932, 2850, 1607,
1494, 1335, 1273, 1175, 1086. 1H-NMR: 1.60 – 1.70 (m, 2 CH2); 2.20 – 2.68 (m, 2 CH2); 6.33 (s, 1 arom. H);
7.34 (br. s, 2 arom. H); 7.96 (br. s, 2 arom. H). 13C-NMR: 22.5; 25.0; 25.4; 26.4; 121.7; 128.8; 129.0; 129.2;
134.0; 137.4; 138.1; 160.0. HR-MS (TOF-ESþ): 245.0835 ([M þ H]þ, C14H14ClNþ2 ; calc. 245.0840).
5,6,7,8-Tetrahydro-2-(4-methylphenyl)quinazoline (3u). M.p. 149 – 1528. IR: 3426, 2935, 2850, 2569,
1683, 1626, 1540, 1419, 1084. 1H-NMR: 1.85 – 1.86 (m, CH2); 1.91 – 1.93 (m, CH2); 2.41 (s, Me); 2.71 – 2.76
(m, CH2); 2.91 – 2.94 (m, CH2); 7.27 (d, J ¼ 7.8, 2 arom. H); 8.26 (d, J ¼ 7.8, 2 arom. H); 8.43 (s, 1 arom.
H). 13C-NMR: 21.7; 22.8; 26.0; 32.6; 39.1; 127.9; 128.2; 129.6; 135.7; 140.6; 157.4; 162.5; 166.5. HR-MS
(TOF-ESþ): 225.1396 ([M þ H]þ, C15H17Nþ2 ; calc. 225.1386).
5,6,7,8-Tetrahydro-2-(pyridin-4-yl)quinazoline (3v). M.p. 95 – 6.58. IR: 3315, 2935, 1642, 1537, 1420,
1087, 922, 771. 1H-NMR: 1.86 – 1.89 (m, CH2); 1.92 – 1.97 (m, CH2); 2.78 – 2.90 (m, CH2); 2.93 – 2.96 (m,
CH2); 8.24 (d, J ¼ 5.4, 2 arom. H); 8.48 (s, 1 arom. H); 8.73 (d, J ¼ 5.4, 2 arom. H). 13C-NMR: 22.5; 22.6;
26.0; 32.4; 122.2; 130.0; 145.8; 150.7; 157.7; 160.3; 167.0. HR-MS (TOF-ESþ): 212.1191 ([M þ H]þ,
C13H14Nþ3 ; calc. 212.1182).
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Received July 8, 2010