Metal-free cascade synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones

Article abstract of DOI:10.1039/d1ra04319f

A convenient metal-free synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones has been developed. In this procedure, various structural 2-aminopyrimidines, as well as 4,5-dihydroisoxazol-5-ols and pyrazoles were synthesized in moderate to excellent yields. A plausible mechanism was also proposed for the cascade reaction. This method represents an effective strategy towards the synthesis of unsymmetrical 2-aminopyrimidines.

Full text of DOI:10.1039/d1ra04319f

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Metal-free cascade synthesis of unsymmetrical 2-
aminopyrimidines from imidazolate enaminones†
Cite this: RSC Adv., 2021, 11, 24247
*
*
Xue Cui,‡ Jianting Ma,‡ Tingting Zeng, Junyu Xu, Youbin Li and Xuesong Wang
A convenient metal-free synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones has
been developed. In this procedure, various structural 2-aminopyrimidines, as well as 4,5-dihydroisoxazol-
5-ols and pyrazoles were synthesized in moderate to excellent yields. A plausible mechanism was also
proposed for the cascade reaction. This method represents an effective strategy towards the synthesis of
unsymmetrical 2-aminopyrimidines.
Received 4th June 2021
Accepted 5th July 2021
DOI: 10.1039/d1ra04319f
rsc.li/rsc-advances
Recently, enaminones15 have emerged as important building
blocks for the construction of versatile 1,2,3-triazoles, pyridines,
indoles and pyrroles.16 However, a method for the synthesis of
unsymmetrical 2-aminopyrimidines from enaminones with
guanidines has not been reported. Herein, we designed a metal-
free strategy for the synthesis of 2-aminopyrimidines from
imidazolate enaminones via a cascade sequence (Scheme 1c).
Introduction
Pyrimidines are important heterocyclic structural motifs, exist
in numerous drug molecules and exhibit a wide range of bio-
logical activities, such as antineoplastic,1 antibacterial,2 anti-
HIV,3 antiviral4 and antitubercular.5 As illustrated in Fig. 1,
examples of leading commercial drugs based on the pyrimidine
scaffold include Imatinib,6 Pyrimethamine7 and Rosuvastatin.8
Moreover, pyrimidines are the essential building blocks in DNA
and RNA,9 and have also found important application in
materials chemistry10 and agricultural chemistry.11 For these
reasons, the development of efficient methodologies for the
synthesis of pyrimidines continues to be of great signicance.12
Conventionally, the most popular approaches to the
construction of 2-aminopyrimidine moiety consist of: (a)
transition-metal-catalyzed amination of 2-Cl or 2-Br-
pyrimidines (Scheme 1a);13 or (b) condensation of guanidines
with 1,3-dicarbonyl compounds or their synthetic equivalents
(Scheme 1b).14 Nevertheless, methodologies based on
transition-metal-catalyzed reactions limits their potential
application in the pharmaceutical industry owing to the
contamination of heavy metals, while routes based on
condensation reactions usually require multistep routes to
synthesize the unsymmetrical 2-aminopyrimidines, and
considerable disadvantages like harsh reaction conditions or
poor functional-group tolerance are associated with these
processes.14a–c Therefore, a practical and efficient method for
the synthesis of unsymmetrical 2-aminopyrimidine is still of
considerable.
Results and discussion
At the outset of the study, the condensation of 3-(1H-imidazol-1-
yl)-1,3-diphenylprop-2-en-1-one (E/Z) 1a and guanidine
Fig. 1 Selected pyrimidine-containing drugs.
Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan
Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou
Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical
University, Haikou 571199, P. R. China. E-mail: wxuesong18@163.com; liyoubinli@
sohu.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra04319f
Scheme
aminopyrimidine.
1 Strategies for the synthesis of unsymmetrical 2-
‡ X. Cui and J. Ma contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
However, other solvents, such as EtOH, CH3CN, THF, DCE
and H2O led to no reaction or lower yield (entries 10–14). When
other enaminones A–G were subjected to the metal-free cascade
reaction, the desired product 3a could also be successfully
attained, albeit in decreased yields (entries 15–21). On the basis
of the above results, the optimized conditions for the reaction
comprise the base by 4.0 equiv. K2CO3 at 60 ꢀC in DMF to
furnish the single 2-aminopyrimidine 3a in 94% yield (Table 1,
entry 7).
Entry
Substrate
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
A
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOH
NaOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
DMSO
NMP
EtOH
CH3CN
THF
DCE
H2O
DMF
35
80
82
78
42
36
94
92
89
60
56
42
38
n.d.c
92
89
79
85
83
87
54
With the optimized reaction conditions in hand, the gener-
ality and scope of the metal-free cascade reactions were inves-
tigated as illustrated in Table 2. Interestingly, a wide range of
substrates were well tolerated under the cascade reaction
conditions, affording the corresponding unsymmetrical 2-ami-
nopyrimidines (3a–3u) in 58–96% yields. Generally, imidazolate
enaminones with electron-donating substituents (–Me, –n-Bu &
–OMe) (entries 2–9) provided the corresponding products in
higher yields than those bearing electron-withdrawing groups
(–F, –Cl, –Br, –CN & –COOMe) (entries 10–18). As for regioiso-
meric substrates, imidazolate enaminones with substituents in
Ar-R1 (entries 2, 6, 10 & 15) could be transformed into the cor-
responding 2-aminopyrimidines products in similar yields as
those with substituents in Ar-R2 (entries 3, 7, 11 & 16). A
signicant inuence of steric hindrance on this reaction was
observed. For instance, the ortho-substituted substrates led to
lower yield than the para-substituted substrates (entries 2 & 5,
10 & 12). Notably, alkyl enaminones with cyclopropyl or t-butyl
could also participate in this reaction, albeit giving lower yield
of the product (entries 19, 20 & 21). Moreover, imidazolate
enaminones possessing thiophenyl and naphthyl ring were also
tested (entries 22, 23 & 24). Additionally, other representative
guanidine analogues, such as benzimidamide 1,1-dime-
thylguanidine, were well-tolerated (entries 25 & 26).
9
10
11
12
13
14
15
16
17
18
19
20
21
B
C
D
E
F
G
DMF
DMF
DMF
DMF
DMF
DMF
Subsequently, hydroxylamine hydrochloride 2b and hydra-
zine hydrate 2c were also tolerated in the cascade reaction
system and furnished the product 3,5-diphenyl-4,5-
dihydroisoxazol-5-ol 3ab and 3,5-diphenyl-1H-pyrazole 3ac in
91% and 96% yields, respectively (Scheme 2a and b).17 However,
when imidazolate enaminones 1e0 and 1e involved to react with
hydroxylamine hydrochloride 2b and phenylhydrazine 2d, the
single products 4,5-dihydroisoxazol-5-ol 3e0b and pyrazole 3ed
were obtained in 75% and 82% yields, respectively (Scheme 2c
and d).17 It's suggested that the imidazole is replaced by
hydroxylamine or hydrazine in the rst step of the reaction,
while the condensations of hydroxylamine or hydrazine with
the carbonyl group do not occurs.
Base on the above results, the mechanistic pathways of this
cascade metathesis were proposed and presented in Scheme 3.
The initial step of the reaction involved the formation of
intermediate H from 3-(1H-imidazol-1-yl)-1,3-diphenylprop-2-
en-1-one (E/Z) 1a via the substitution procedure followed by
the released one molecular of imidazole (path a). Conversely,
the condensation of carbonyl group with guanidine was not
observed in the rst step of the reaction (path b). Then ther-
mally inducing the transformation of intermediate H gave the
desired unsymmetrical 2-aminopyrimidine 3a.
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), and base (2.0
b
mmol) in 3 mL of solvent at 60 ꢀC for 12 h under air. Isolated yield
c
based on 1a. n.d. ¼ no detected. DMF ¼ N,N-dimethylformamide,
DMSO ¼ dimethyl-sulfoxide, NMP ¼ 1-methylpyrrolidin-2-one, DCE ¼
1,2-dichloroethane, THF ¼ tetrahydrofuran.
hydrochloride 2a was chosen as a model reaction to screen the
reaction parameters (Table 1). To our delight, the desired
product 3a was obtained in 35% yield when the cascade reaction
was conducted at 60 ꢀC in the presence of 4.0 equiv. K2CO3
(based on 1a) in toluene for 12 h (entry 1). The yield was
improved to 80% when the transformation was conducted with
1,4-dioxane instead of toluene (entry 2). Further studies focused
on screening of versatile base (entries 3–6). In the presence of
a medium-strength base, such as Cs2CO3 and K3PO4, the reac-
tion furnished 3a in 82% and 78%, respectively (entries 3 & 4).
Other strong bases, including NaOH and NaOtBu, provided 3a
in acceptable yields (entries 5 & 6). Further investigation showed
that this transformation was highly solvent dependent (entries
7–14). The yield was improved to 94% by switching the solvent
1,4-dioxane to DMF, while no deviations were observed between
DMF, DMSO and NMP (entries 7–9).
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Table 2 Scope of substratesa
Table 2 (Contd.)
Yieldb (%)
Entry
Yieldb (%)
Entry
1
2
3
4
5
6
7
8
R1 ¼ H, R2 ¼ H, 1a
3a
3b
94 (90)c
95
92
90
80
96
92
88
90
80
78
63
81
80
81
77
75
R1 ¼ 4-Me, R2 ¼ H, 1b
R1 ¼ H, R2 ¼ 4-Me, 1b0
R1 ¼ 3-Me, R2 ¼ H, 1c
R1 ¼ 2-Me, R2 ¼ H, 1d
R1 ¼ 4-OMe, R2 ¼ H, 1e
R1 ¼ H, R2 ¼ 4-OMe, 1e0
R1 ¼ 3-OMe, R2 ¼ H, 1f
R1 ¼ H, R2 ¼ 4-n-Bu, 1g
R1 ¼ 4-F, R2 ¼ H, 1h
R1 ¼ H, R2 ¼ 4-F, 1h0
R1 ¼ 2-F, R2 ¼ H, 1i
25
1a
1a
88
3c
3d
3e
3f
3g
3h
9
26
90
10
11
12
13
14
15
16
17
18
3i
3j
3k
3l
R1 ¼ 3-Cl, R2 ¼ H, 1j
R1 ¼ H, R2 ¼ 4-Cl, 1k
R1 ¼ 4-Br, R2 ¼ H, 1l
R1 ¼ H, R2 ¼ 4-Br, 1l0
R1 ¼ 4-CN, R2 ¼ H, 1m
a
b
c
Under the optimized conditions.
performed at 10 mmol scale.
Isolated yield.
Reaction
3m
R1 ¼ H, R2 ¼ 4-COOMe, 1n 3n
72
19
20
21
22
23
24
66
58
72
65
60
96
Scheme 2 The synthesis of isoxazole and pyrazole.
Scheme 3 Plausible mechanism.
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4-Phenyl-6-(m-tolyl)pyrimidin-2-amine (3c). 118 mg, 90%
yield; yellow liquid, mp 134–138 ꢀC. IR (KBr) n 3309, 3186, 1635,
Conclusions
In conclusion, we have developed a convenient metal-free 1366, 768 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.05 (m, 2H), 7.87
method for the synthesis of unsymmetrical 2-amino- (s, 1H), 7.83 (d, J ¼ 8.0 Hz, 1H), 7.49 (m, 3H), 7.44 (s, 1H), 7.38 (t,
pyrimidines from imidazolate enaminones and guanidine J ¼ 8.0 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 1H), 5.32 (s, 2H), 2.45 (s, 3H);
hydrochloride. Imidazolate enaminones with electron-donating 13C NMR (100 MHz, CDCl3) d 166.4, 166.1, 163.6, 138.4, 137.8,
and electron-withdrawing groups provided 2-aminopyrimidines 137.7, 131.2, 130.4, 128.7, 128.6, 127.7, 127.1, 124.2, 104.4, 21.5.
in moderate-to-excellent yields. The steric effect on this reaction HRMS m/z (ESI) calcd for C17H15N3, (M + Na)+ 284.1158; found,
was also observed. Moreover, the plausible mechanism was 284.1159.
proposed base on the synthesis of 5-hydroxy-4,5-
dihydroisoxazoles and pyrazoles in the cascade reaction yield; white solid, mp 134–136 C. IR (KBr) n 3299, 3186, 1629,
system. This method represents an effective strategy towards 1356, 764 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.02 (m, 2H), 7.49–
4-Phenyl-6-(o-tolyl)pyrimidin-2-amine (3d). 105 mg, 80%
ꢀ
the synthesis of unsymmetrical 2-aminopyrimidines.
7.43 (m, 4H), 7.36–7.28 (m, 3H), 7.15 (s, 1H), 5.30 (s, 2H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3) d 169.3, 165.6, 163.2, 138.9,
137.5, 135.7, 130.9, 130.5, 129.1, 128.9, 128.8, 127.1, 126.0,
108.0, 20.2. HRMS m/z (ESI) calcd for C17H15N3, (M + Na)+
284.1158; found, 284.1160.
Experimental
General information
4-(4-Methoxyphenyl)-6-phenylpyrimidin-2-amine
(3e).
Unless otherwise stated, all reagents were used directly without
further purication. Silica gel was purchased from Qing Dao
Hai Yang Chemical Industry Co. All melting points were deter-
mined on a Beijing Science Instrument Dianguang Instrument
Factory XT4B melting point apparatus and uncorrected. 1H and
13C NMR spectra were measured on a 400 MHz Bruker spec-
trometer (1H 400 MHz, 13C100 MHz), using CDCl3 as the solvent
with tetramethylsilane (TMS) as the internal standard at room
temperature. HRMS-ESI spectra were equipped with an ESI
133 mg from 1e, 96% yield; 127 mg from 1e0, 92% yield; pink
solid, mp 150–152 ꢀC (lit.12 152 ꢀC). IR (KBr) n 3326, 3196, 1538,
1361, 822 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.04 (d, J ¼ 8.0 Hz,
4H), 7.49 (m, 3H), 7.41 (s, 1H), 7.00 (d, J ¼ 8.0 Hz, 2H), 5.24 (s,
2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d 166.0, 165.6,
163.5, 161.6, 137.9, 130.3, 130.1, 128.7, 128.6, 127.1, 114.1,
103.5, 55.4.
4-(3-Methoxyphenyl)-6-phenylpyrimidin-2-amine
(3f).
122 mg, 88% yield; yellow solid, mp 136–138 C (lit.12 139–140
ꢀC). IR (KBr) n 3450, 3314, 1567, 1356, 768 cmꢂ1; 1H NMR (400
MHz, CDCl3) d 8.05 (m, 2H), 7.62 (m, 2H), 7.53–7.38 (m, 5H),
7.03 (m, 1H), 5.29 (s, 2H), 3.90 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 166.3, 166.0, 163.6, 160.0, 139.2, 137.7, 130.5, 129.8,
128.8, 127.1, 119.5, 116.4, 112.2, 104.4, 55.4.
ꢀ
ꢀ
source and a TOF detector. PE is petroleum ether (60–90 C).
Typical procedure for the preparation of 4,6-
diphenylpyrimidin-2-amine (3a)
A suspension of 3-(1H-imidazol-1-yl)-1,3-diphenylprop-2-en-1-
one (E/Z) 1a (0.5 mmol, 137.0 mg), guanidine hydrochloride 2
(1.0 mmol, 95.5 mg) and K2CO3 (2.0 mmol, 276.4 mg) in DMF (3
mL) was stirred at 60 ꢀC for 12 h. Aer 1a was exhausted
completely (monitored by TLC), it was cooled down to room
temperature and saturated aqueous brine (10 mL) was added.
The mixture was stirred for 10 min and then was extracted by
EtOAc (3 ꢁ 10 mL). The combined organic layers were dried
over Na2SO4. Aer ltration, removal of the solvent gave
a residue, which was puried by a column chromatography
(silica gel, PE/EtOAc ¼ 5/1) to afford 3a as light yellow solid;
116 mg, 94% yield; mp 118–120 ꢀC (lit.12 118 ꢀC). IR (KBr) n 3307,
4-(4-Butylphenyl)-6-phenylpyrimidin-2-amine (3g). 136 mg,
90% yield; yellow solid, mp 90–94 ꢀC. IR (KBr) n 2957, 1565,
1531, 1364, 768 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.05 (m, 2H),
7.98 (d, J ¼ 12.0 Hz, 2H), 7.51–7.45 (m, 4H), 7.31 (d, J ¼ 8.0 Hz,
2H), 5.22 (s, 2H), 2.68 (t, J ¼ 8.0 Hz, 2H), 1.64 (m, 2H), 1.38 (m,
2H), 0.94 (t, J ¼ 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.3,
166.1, 163.6, 145.8, 137.9, 135.1, 130.4, 128.9, 128.7, 127.1,
127.0, 104.1, 35.5, 33.5, 22.3, 13.9. HRMS m/z (ESI) calcd for
C
20H21N3, (M + Na)+ 326.1628; found, 326.1630.
4-(4-Fluorophenyl)-6-phenylpyrimidin-2-amine (3h). 106 mg
from 1h, 80% yield; 103 mg from 1h0, 78% yield; white solid, mp
130–132 ꢀC (lit.12 132 ꢀC). IR (KBr) n 3333, 3207, 1639, 1228,
768 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.09–8.04 (m, 4H), 7.50
(t, J ¼ 4.0 Hz, 3H), 7.42 (s, 1H), 7.18 (t, J ¼ 8.0 Hz, J ¼ 12.0 Hz,
2H), 5.23 (s, 2H); 13C NMR (100 MHz, CDCl3) d 166.4, 165.6,
164.4 (d, J ¼ 249.0 Hz), 163.5, 137.6, 133.8 (d, J ¼ 3.0 Hz), 130.5,
129.1 (d, J ¼ 8.0 Hz), 128.8, 127.1, 115.8 (d, J ¼ 1.0 Hz), 103.9.
4-(2-Fluorophenyl)-6-phenylpyrimidin-2-amine (3i). 84 mg,
1
3192, 1629, 1365, 763 cmꢂ1; H NMR (400 MHz, CDCl3) d 8.05
(m, 4H), 7.52–7.46 (m, 7H), 5.24 (s, 2H); 13C NMR (100 MHz,
CDCl3) d 166.2, 163.6, 137.8, 130.4, 128.8, 127.1, 104.3.
A similar procedure was used for the preparation of products
3b–3t & 3ab–3ed
4-Phenyl-6-(p-tolyl)pyrimidin-2-amine (3b). 124 mg from 1b,
95% yield; 120 mg from 1b0, 92% yield; yellow solid, mp 125–
127 ꢀC (lit.12 128 ꢀC). IR (KBr) n 3314, 3202, 1569, 1365,
770 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.05 (m, 2H), 7.96 (d, J ¼
8.0 Hz, 2H), 7.49 (m, 3H), 7.45 (s, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H),
5.22 (s, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) d 166.1,
166.1, 163.6, 140.8, 137.9, 134.9, 130.4, 129.5, 128.7, 127.1,
127.0, 104.0, 21.4.
ꢀ
63% yield; yellow solid, mp 123–126 C. IR (KBr) n 3323, 1630,
1358, 759 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.05 (m, 3H), 7.56
(d, J ¼ 4.0 Hz, 1H), 7.50–7.42 (m, 4H), 7.29 (d, J ¼ 8.0 Hz, 1H),
7.19 (dd, J ¼ 8.0 Hz, J ¼ 8.0 Hz, 1H), 5.22 (s, 2H); 13C NMR (100
MHz, CDCl3) d 166.1, 163.5, 162.1 (d, J ¼ 2.0 Hz), 161.1 (d, J ¼
250.0 Hz), 137.6, 131.6 (d, J ¼ 9.0 Hz), 130.6 (d, J ¼ 2.0 Hz),
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130.5, 128.8, 127.2, 125.9 (d, J ¼ 11.0 Hz), 124.5 (d, J ¼ 4.0 Hz), (KBr) n 3448, 3320, 1580, 1346, 769 cmꢂ1; H NMR (400 MHz,
116.4 (d, J ¼ 23.0 Hz), 108.3 (d, J ¼ 11.0 Hz). HRMS m/z (ESI) CDCl3) d 8.05–8.00 (m, 2H), 7.78 (d, J ¼ 4.0 Hz, 1H), 7.51–7.47
calcd for C16H12FN3, (M + Na)+ 288.0907; found, 288.0909.
(m, 4H), 7.36 (s, 1H), 7.15 (t, J ¼ 4.0 Hz, 1H), 5.32 (s, 2H); 13C
4-(3-Chlorophenyl)-6-phenylpyrimidin-2-amine (3j). 114 mg, NMR (100 MHz, CDCl3) d 166.2, 163.5, 160.7, 143.2, 137.7, 130.6,
81% yield; white solid, mp 118–120 ꢀC (lit.12 118 ꢀC). IR (KBr) n 129.3, 128.9 (2C), 128.3, 127.2 (2C), 127.1, 102.6.
1
3486, 3320, 1638, 1360, 771 cmꢂ1; H NMR (400 MHz, CDCl3)
4-Phenyl-6-(thiophen-3-yl)pyrimidin-2-amine (3r). 76 mg,
d 8.06–8.01 (m, 3H), 7.92 (d, J ¼ 8.0 Hz, 2H), 7.54–7.38 (m, 6H), 60% yield; yellow solid, mp 114–116 ꢀC (lit.12 113–115 ꢀC). IR
5.54 (s, 2H); 13C NMR (100 MHz, CDCl3) d 166.6, 146.7, 163.7, (KBr) n 3432, 3347, 1568, 1376, 770 cmꢂ1; H NMR (400 MHz,
1
139.6, 137.6, 134.9, 130.7, 130.4, 130.1, 128.9 (2C), 127.4, 127.2 CDCl3) d 8.09 (d, J ¼ 4.0 Hz, 1H), 8.05–8.01 (m, 2H), 7.69–7.78 (d,
(2C), 125.3, 104.2.
J ¼ 4.0 Hz, 1H), 7.51–7.47 (m, 3H), 7.41 (t, J ¼ 4.0 Hz, 1H), 7.33
4-(4-Chlorophenyl)-6-phenylpyrimidin-2-amine (3k). 112 mg, (s, 1H), 5.35 (s, 2H); 13C NMR (100 MHz, CDCl3) d 166.4, 163.7,
80% yield; yellow solid, mp 158–160 ꢀC (lit.12 160 ꢀC). IR (KBr) n 161.7, 140.8, 137.8, 130.6, 128.9 (2C), 127.2 (2C), 126.6, 126.3,
3318, 3195, 1634, 1360, 768 cmꢂ1; H NMR (400 MHz, CDCl3) 126.3, 104.2.
1
d 8.06–8.00 (m, 4H), 7.51–7.45 (m, 5H), 7.42 (s, 1H), 5.26 (s, 2H);
13C NMR (100 MHz, CDCl3) d 166.5, 164.9, 163.6, 137.6, 136.6, 142 mg, 96% yield; yellow solid, mp 115–118 C (lit.12 113–115
136.1, 130.6, 129.0, 128.8, 128.4, 127.1, 103.9.
ꢀC). IR (KBr) n 3328, 3208, 1645, 805 cmꢂ1; 1H NMR (400 MHz,
4-(Naphthalen-2-yl)-6-phenylpyrimidin-2-amine
(3s).
ꢀ
4-(4-Bromophenyl)-6-phenylpyrimidin-2-amine (3l). 132 mg CDCl3) d 8.18–8.09 (m, 3H), 7.99–7.88 (m, 3H), 7.59 (s, 1H), 7.55–
from 1l, 81% yield; 126 mg from 1l0, 77% yield; yellow solid, mp 7.51 (m, 5H), 5.48 (s, 2H); 13C NMR (100 MHz, CDCl3) d 166.4,
170–174 ꢀC (lit.12 171–172 ꢀC). IR (KBr) n 3302, 3192, 1633, 1360, 166.2, 163.8, 137.9, 135.1, 134.5, 133.3, 130.6, 129.0, 128.9 (2C),
765 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.05 (m, 2H), 7.95 (d, J ¼ 128.6, 127.8, 127.3 (2C), 127.2, 126.6, 124.3, 104.6.
8.0 Hz, 2H), 7.62 (d, J ¼ 8.0 Hz, 2H), 7.50 (m, 3H), 7.43 (s, 1H),
2,4,6-Triphenylpyrimidine (3t). 136 mg, 88% yield; yellow
5.20 (s, 2H); 13C NMR (100 MHz, CDCl3) d 166.5, 164.9, 163.6, solid, mp 186–188 ꢀC. IR (KBr) n 2858, 1559, 1354, 760 cmꢂ1; 1H
137.6, 136.6, 131.9, 130.6, 128.8, 128.6, 127.1, 125.0, 103.9.
NMR (400 MHz, CDCl3) d 8.75 (d, J ¼ 8.0 Hz, 2H), 8.31 (d, J ¼
4-(2-Amino-6-phenylpyrimidin-4-yl)benzonitrile
102 mg, 75% yield; white solid, mp 184–186 ꢀC. IR (KBr) n 3469, CDCl3) d 164.7, 164.5, 138.1, 137.5, 130.8, 130.6, 128.9, 128.5,
3119, 2322, 1612, 767 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.16 (d, 128.4, 127.3, 110.3.
(3m). 8.0 Hz, 4H), 8.02 (s, 1H), 7.60–7.53 (m, 9H); 13C NMR (100 MHz,
J ¼ 8.0 Hz, 2H), 8.06–8.03 (m, 2H), 7.78 (d, J ¼ 8.0 Hz, 2H), 7.53–
N,N-Dimethyl-4,6-diphenylpyrimidin-2-amine (3u). 124 mg,
7.49 (m, 3H), 7.45 (s, 1H), 5.40 (m, 2H); 13C NMR (100 MHz, 90% yield; yellow solid, mp 124–126 C. IR (KBr) n 3325, 1632,
CDCl3) d 167.0, 164.0, 163.8, 142.0, 137.3, 132.6 (2C), 130.9, 1363, 766 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.14 (m, 4H), 7.52–
129.0 (2C), 127.8 (2C), 127.2 (2C), 118.6, 113.9, 104.5. HRMS m/z 7.46 (m, 6H), 7.37 (s, 1H), 3.36 (s, 6H); 13C NMR (100 MHz,
(ESI) calcd for C17H12N4, (M + Na)+ 295.0954; found, 295.0951. CDCl3) d 165.0, 162.9, 138.5, 130.2, 128.6, 127.1, 101.0, 37.0.
Methyl 4-(2-amino-6-phenylpyrimidin-4-yl)benzoate (3n). HRMS m/z (ESI) calcd for C18H17N3, (M + Na)+ 298.1315; found,
110 mg, 72% yield; light yellow solid, mp 156–158 ꢀC. IR (KBr) n 298.1317.
ꢀ
3386, 3103, 1645, 762 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 8.16–
3,5-Diphenyl-4,5-dihydroisoxazol-5-ol (3ab). 102 mg, 86%
8.03 (m, 6H), 7.50–7.46 (m, 4H), 5.47 (s, 2H), 3.94 (m, 3H); 13C yield; white solid, mp 163–165 C (lit.17 161–163 C). IR (KBr) n
ꢀ
ꢀ
NMR (100 MHz, CDCl3) d 165.8, 165.7, 164.0, 162.8, 140.9, 136.5, 3378, 3298, 1597, 1363, 761 cmꢂ1; H NMR (400 MHz, CDCl3)
1
130.7, 129.7, 129.1 (2C), 127.9 (2C), 126.24 (2C), 126.19 (2C), d 7.71–7.65 (m, 4H), 7.44–7.38 (m, 6H), 3.68 (d, J ¼ 20.0 Hz, 1H),
103.6, 51.4. HRMS m/z (ESI) calcd for C18H15N3O2, (M + Na)+ 3.49 (d, J ¼ 16.0 Hz, 1H), 3.20 (s, 1H); 13C NMR (100 MHz,
328.1056; found, 328.1058.
CDCl3) d 157.4, 140.7, 130.4, 129.2, 129.0, 128.8, 128.6, 126.8,
4-Cyclopropyl-6-phenylpyrimidin-2-amine (3o). 70 mg from 125.6, 107.7, 49.0.
1o, 66% yield; 61 mg from 1o0, 58% yield; white solid, mp 122–
3,5-Diphenyl-1Hꢀ-pyrazole (3ac). 99 mg, 90% yield; white
1
126 C. IR (KBr) n 2968, 1523, 1510, 1346, 770 cmꢂ1; H NMR solid, mp 198–200 C (lit.17 201–203 C). IR (KBr) n 2830, 1461,
(400 MHz, CDCl3) d 7.97–7.94 (m, 2H), 7.45 (t, J ¼ 4.0 Hz, 3H), 685 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 11.35 (s, 1H), 7.72 (d, J ¼
6.88 (s, 1H), 5.16 (s, 2H), 1.94–1.88 (m, 1H), 1.12–1.08 (m, 2H), 8.0 Hz, 4H), 7.41–7.37 (m, 4H), 7.35–7.31 (m, 2H), 6.83 (s, 1H);
1.03–0.98 (m, 2H); 13C NMR (100 MHz, CDCl3) d 173.5, 164.5, 13C NMR (100 MHz, CDCl3) d 128.9, 128.2, 125.6, 100.1.
ꢀ
ꢀ
163.3, 137.7, 130.1, 128.6 (2C), 127.0 (2C), 105.5, 29.6, 17.0, 10.1.
3-(4-Methoxyphenyl)-5-phenyl-4,5-dihydroisoxazol-5-ol
HRMS m/z (ESI) calcd for C13H13N3, (M + Na)+ 234.1002; found, (3e0b). 101 mg, 75% yield; white solid, mp 130–132 ꢀC (lit.17 130–
1
132 C). IR (KBr) n 3369, 3300, 1611, 1373, 775 cmꢂ1; H NMR
ꢀ
234.1000.
4-(tert-Butyl)-6-phenylpyrimidin-2-amine (3p). 82 mg, 72% (400 MHz, CDCl3) d 7.64 (m, 4H), 7.39 (m, 3H), 6.92 (d, J ¼
ꢀ
yield; yellow solid, mp 98–102 C. IR (KBr) n 2937, 1545, 1503, 8.0 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J ¼ 16.0 Hz, 1H), 3.46 (d, J ¼
1388, 778 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 7.98–7.95 (m, 2H), 16.0 Hz, 1H), 3.26 (s, 1H); 13C NMR (100 MHz, CDCl3) d 161.3,
7.48–7.45 (m, 3H), 7.06 (s, 1H), 5.23 (s, 2H), 1.34 (s, 9H); 13C 157.0, 140.8, 128.9, 128.5 (2C), 128.3 (2C), 125.6 (2C), 121.8,
NMR (100 MHz, CDCl3) d 179.7, 165.6, 163.1, 138.2, 130.1, 128.6 114.2 (2C), 107.4, 55.4, 49.2.
(2C), 127.0 (2C), 103.4, 37.3, 29.3 (3C). HRMS m/z (ESI) calcd for
13H13N3, (M + Na)+ 250.1315; found, 250.1317.
5-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole
(3ed).
C
133 mg, 82% yield; white solid, mp 78–80 ꢀC (lit.17 77–79 ꢀC). IR
4-Phenyl-6-(thiophen-2-yl)pyrimidin-2-amine (3q). 84 mg, (KBr) n 2826, 1458, 676 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 7.95
65% yield; yellow solid, mp 137–140 ꢀC (lit.12 208–210 ꢀC). IR (d, J ¼ 8.0 Hz, 2H), 7.47–7.31 (m, 8H), 7.22 (d, J ¼ 8.0 Hz, 2H),
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6.86 (d, J ¼ 8.0 Hz, 2H), 6.79 (s, 1H), 3.81 (s, 3H); 13C NMR (100 12 (a) P. K. Agarwal, S. K. Sharma, D. Sawant and B. Kundu,
MHz, CDCl3) d 159.5, 151.8, 144.2, 140.2, 133.1, 130.0 (2C), 128.8
(2C), 128.6 (2C), 127.9, 127.3, 125.7 (2C), 125.2 (2C), 122.9,
113.9, 104.6, 55.2.
Tetrahedron, 2009, 65, 1153–1161; (b) A. Nimkar,
M. M. V. Ramana, R. Betkar, P. Ranade and B. Mundhe,
New J. Chem., 2016, 40, 2541–2546; (c) Q.-Z. Chen,
Z.-C. Ding, Y.-L. Ma, Z.-D. Wang and Z.-P. Zhan,
Heterocycles, 2012, 85, 1891–1896; (d) L. Rong, H. Han,
H. Wang, H. Jiang, S. Tu and D. Shi, J. Heterocycl. Chem.,
2009, 46, 152–157; (e) L. Rong, H. Ji, S. Xia, S. Yin, Y. Shi
and S. Tu, J. Heterocycl. Chem., 2012, 49, 696–699; (f)
G. Chakraborty, R. Sikari, R. Mondal, S. Mandal and
N. D. Paul, Asian J. Org. Chem., 2020, 9, 431–436; (g)
S. Saikia and R. Borah, ChemistrySelect, 2019, 4, 8751–8756.
13 (a) D. R. Carver, A. P. Komin, J. S. Hubbard and J. F. Wolfe, J.
Org. Chem., 1981, 46, 294–299; (b) S. Jaime-Figueroa, Y. Liu,
J. M. Muchowski and D. G. Putman, Tetrahedron Lett., 1998,
39, 1313–1316; (c) M. K. Elmkaddem, C. Fischmeister,
C. M. Thomas and J.-L. Renaud, Chem. Commun., 2010, 46,
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by Hainan Provincial Nature Science
Foundation of China (Nos. 820QN264 & 2019RC214) and
Fundamental Research Funds of Hainan Medical University
(No. XRC180009).
´
´
925–927; (d) P. Benderitter, J. X. de Araujo Junior,
M. Schmitt and J. J. Bourguignon, Tetrahedron, 2007, 63,
12465–12470; (e) S. Tumkevicius, J. Dodonova, I. Baskirova
and A. Voitechovicius, J. Heterocycl. Chem., 2009, 46, 960–
964.
Notes and references
1 (a) M. M. Gineinah, M. N. A. Nasr, S. M. I. Badr and W. M. El-
Husseiny, Med. Chem. Res., 2013, 22, 3943–3952; (b)
D. B. Longley, D. P. Harkin and P. G. Johnston, Nat. Rev.
Cancer, 2003, 3, 330–338.
2 (a) S. N. Pandeya, D. Shriram, G. Nath and E. D. Clercq, Il
Farmaco, 1999, 54, 624–628; (b) O. Moukha-chaq and
R. C. Reynolds, ACS Comb. Sci., 2014, 16, 232–327; (c)
Q. Chen, X. Zhu, L. Jiang, Z. Liu and G. Yang, Eur. J. Med.
Chem., 2008, 43, 595–603.
3 (a) J. Kim, J. Kwon, D. Lee, S. Jo, D. Park, J. Choi, E. Park,
J. Y. Hwang, Y. Ko, I. Choi, M. K. Ju, J. Ahn, J. Kim,
S.-J. Han, T.-H. Kim, J. Cechetto, J. Nam, S. Ahn,
P. Sommer, M. Louzzi and J. Lee, Bioorg. Med. Chem. Lett.,
2014, 24, 5473–5477; (b) C. E. Mackewicz, A. Landay,
H. Hollander and J. A. Levy, Clin. Immunol. Immunopathol.,
1994, 73, 80–87.
4 G. Smolin, M. Okumoto, S. Feiler and D. Condon, Am. J.
Ophthalmol., 1981, 91, 220–225.
5 R. A. Gupta and S. G. Kaskhedikar, Med. Chem. Res., 2013, 22,
3863–3880.
6 H. Joensuu and S. Dimitrijevic, Ann. Med., 2001, 33, 451–455.
7 C. O. Obonyo and E. A. Juma, Malar. J., 2012, 11, 2–11.
8 M. Hanefeld, Int. J. Clin. Pract., 2001, 55, 399–405.
9 E. V. Koroleva, K. N. Gusak and Z. V. Ignatovich, Russ. Chem.
Rev., 2010, 79, 655–681.
14 (a) M. C. Bagley, D. D. Hughes, M. C. Lubinu, E. A. Merritt,
P. H. Taylor and N. C. O. Tomkinson, QSAR Comb. Sci.,
2004, 23, 859–867; (b) E. K. Dora, B. Dash and C. S. Panda,
J.
Heterocycl.
Chem.,
1983,
20,
691–696;
(c)
K. P. Cheremnykh, V. A. Savelyev, M. A. Pokrovskii, D. S
Baev, T. G. Tolstikova, A. G. Pokrovskii and E. E. Shults,
Med. Chem. Res., 2019, 28, 545–558; (d) F. H. Al-Hajjar and
S. S. Sabri, J. Heterocycl. Chem., 1982, 19, 1087–1092; (e)
P. M. Fresneda, P. Molina, S. Delgado and J. A. Bleda,
Tetrahedron Lett., 2000, 41, 4777–4780; (f) A. S. Karpov and
T. J. J. Mueller, Synthesis, 2003, 2815–2826; (g) A. S. Karpov
and T. J. J. Mueller, Org. Lett., 2003, 5, 3451–3454; (h)
S. Goswami, S. Jana, S. Dey and A. K. Adak, Aust. J. Chem.,
2007, 60, 120–123; (i) I. R. Baxendale, S. C. Schou,
J. Sedelmeier and S. V. Ley, Chem.–Eur. J., 2010, 16, 89–94;
(j) R. S. Keri, K. M. Hosamani, R. V. Shingalapur and
M. H. Hugar, Eur. J. Med. Chem., 2010, 45, 2597–2605; (k)
P. M. Fresneda, P. Molina and J. A. Bleda, Tetrahedron,
2001, 57, 2355–2363; (l) H. K. Maurya, M. Hasanain,
S. Singh, J. Sarkar, V. Dubey, A. Shukla, S. Luqman,
F. Khan and A. Gupta, RSC Adv., 2016, 6, 18607–18618.
15 X. Cui, Y. Chen, W. Wang, T. Zeng, Y. Li and X. Wang, Chem.
Pap., 2021, 75, 3625–3634.
¨
10 (a) S. M. Kelly, J. Funfschilling and A. Villiger, Liq. Cryst.,
1994, 16, 813–829; (b) G. Huges, C. Wang, A. S. Batsanov, 16 (a) X. Zhang, X. Cui, W. Wang, T. Zeng, Y. Wang, Y. Tan,
M. Fern, S. Frank, M. R. Bryce, I. F. Perepichka,
A. P. Monkman and B. P. Lyons, Org. Biomol. Chem., 2003,
1, 3069–3077; (c) H. A. Zamani, M. R. Ganjali and N. Sei,
Collect. Czech. Chem. Commun., 2007, 72, 1189–1206; (d)
L.-Y. Lin, C.-H. Tsai, K.-T. Wong, T.-W. Huang, C.-C. Wu,
S.-H. Chou, F. Lin, S.-H. Chen and A.-I. Tsai, J. Mater.
Chem., 2011, 21, 5950–5958.
D. Liu, W. Wang and Y. Li, Asian J. Org. Chem., 2020, 9,
2176–2183; (b) X. Cui, X. Zhang, W. Wang, X. Zhong,
Y. Tan, Y. Wang, J. Zhang, Y. Li and X. Wang, J. Org.
Chem., 2021, 86, 4071–4080; (c) G. Cheng, X. Zeng, J. Shen,
X. Wang and X. Cui, Angew. Chem., Int. Ed., 2013, 52,
13265–13268; (d) J. Shen, D. Cai, C. Kuai, Y. Liu, M. E. Wei,
G. Cheng and X. Cui, J. Org. Chem., 2015, 80, 6584–6589;
(e) J. Shen, G. Cheng and X. Cui, Chem. Commun., 2013, 49,
10641–10643; (f) L. Xu, L. Wu, T. Chen, S. Xu, C. Huang,
Y. Wang, Q. You and J. Shen, ChemistrySelect, 2020, 5, 655–
11 (a) A. Cansev, H. Guelen, Z. M. Kesici, S. Ergin and
M. Cansev, WO2014129996A1, 2014; (b) M. G. Hoffmann,
U. Doeller, M. Bruenjes, H. Dietrich, E. Gatzweiler,
D. Schmutzler and C. H. Rosinger, WO2014086738A1, 2014.
24252 | RSC Adv., 2021, 11, 24247–24253
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
659; (g) R. Bernini, G. Fabrizi, A. Sferrazza and S. Cacchi,
RSC Advances
1966; (c) V. K. Aggarwal, J. de Vicente and R. V. Bonnert, J.
Org. Chem., 2003, 68, 5381–5383; (d) P. Liu, Y. M. Pan,
Y. L. Xu and H. S. Wang, Org. Biomol. Chem., 2012, 10,
4696–4698.
Angew. Chem., Int. Ed., 2009, 48, 8078–8081.
17 (a) X. Wang, Y. Chen, X. Chen, X. Zhang, W. Guan and Y. Li,
Asian J. Org. Chem., 2019, 8, 1479–1483; (b) S. Tang, J. He,
Y. Sun, L. He and X. She, J. Org. Chem., 2010, 75, 1961–
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