Solvent-free synthesis of 2-(phenylamino)-4-(trifluoromethyl)-1,6- dihydropyrimidine derivatives catalyzed by sulfamic acid

Article abstract of DOI:10.1002/jhet.912

A series of 2-(phenylamino)-4-(trifluoromethyl)-1,6-dihydropyrimidine derivatives were synthesized efficienly via the reaction of aryl aldehyde, ethyl 4,4,4-trifluoro-3-oxobutanoate and 1-phenylguanidine carbonate catalyzed by sulfamic acid under solvent-free conditions. This protocol has the advantages of mild condition, high yields and environmentally benign procedure.

Full text of DOI:10.1002/jhet.912

September 2012 Solvent‐Free Synthesis of 2‐(Phenylamino)‐4‐(trifluoromethyl)‐1,6‐
1033
dihydropyrimidine Derivatives Catalyzed by Sulfamic Acid
Shide Shen, Weihua Yang, Chenxia Yu, Tuanjie Li and Changsheng Yao
a
b
b
b
b
*
aXuzhou Institute of Architectural Technology, Xuzhou, Jiangsu 221116, People’s Republic of China
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology on
Medical Plant, Xuzhou, Jiangsu 221116, People’s Republic of China
*
E-mail: csyao@xznu.edu.cn
Received January 10, 2011
DOI 10.1002/jhet.912
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
A series of 2‐(phenylamino)‐4‐(trifluoromethyl)‐1,6‐dihydropyrimidine derivatives were synthesized effi-
cienly via the reaction of aryl aldehyde, ethyl 4,4,4‐trifluoro‐3‐oxobutanoate and 1‐phenylguanidine carbon-
ate catalyzed by sulfamic acid under solvent‐free conditions. This protocol has the advantages of mild
condition, high yields and environmentally benign procedure.
J. Heterocyclic Chem., 49, 1033 (2012).
INTRODUCTION
or eliminated, so the costs of waste treatment are also re-
duced. An additional attractive feature is the operational sim-
plicity [14,15]. To continue our work on the synthesis of
functionalized pyrimidine derivatives via Biginelli reaction
[16], we shall report herein an efficient, solventless prepara-
tion of ethyl 6‐aryl‐2‐(phenylamino)‐4‐(trifluoromethyl)‐1,6‐
dihydropyrimidine‐5‐carboxylates using sulfamic acid
(NH2SO3H, SA) as catalyst (Scheme 1).
The fluorine‐containing organic compounds are of great
importance to the pharmaceutical and agrochemical indus-
tries, because of their unique properties such as the increased
membrane permeability, enhanced hydrophobic binding and
stability against metabolic oxidation. And the trifluoromethyl
group (CF3) as a functionalized structural moiety were often
introduced into diverse classes of bioactive organic molecules
to modify their physical, chemical, and physiological proper-
ties [1–6]. Therefore, the development of synthetic methods
for trifluoromethylated compounds is very significant to both
organofluorine chemistry and organic synthetic chemistry [7].
On the other hand, pyrimidine is the representative of the
most prevalent nitrogen‐containing heterocycles found in nat-
ural products, such as amino acid derivatives (willardiine and
tingitanine), vitamins (vitamin B1), antibiotics (bacimethrin,
sparsomycin, and bleomycin), alkaloids (heteromines,
crambescins, manzacidins, variolins, meridianins, psammo-
pemmins etc.), and toxins. Thus, many efforts have been
devoted to the synthesis and biological research of these
pyrimidine derativets [8].
2‐Arylamino‐6‐arylpyrimidine derivatives have diverse
biological activities such as inhibition of VEGFR‐2 and
cyclin dependent kinase 1 (CDK1) [9], antiproliferative
activity [10] and herbicidal activity [11]. The synthesis of 6‐
trifluoromethylated aromatized derivatives of 2‐arylamino‐6‐
arylpyrimidine and their bioactivity, such as the selective
inhibition of cyclooxygenase‐2 and acting as amyloid beta
modulator were well documented [12,13]. However, to the
best of our knowledge, the synthesis method of 1,6‐dihy-
drogenated 4‐trifluoromethyl‐2‐arylamino‐6‐arylpyrimidine
derivatives has not been developed. Solvent‐free reaction
processes are not only environmentally benign, but also eco-
nomically beneficial because toxic wastes can be minimized
RESULTS AND DISCUSSION
Initially, several conventional acid catalysts and phase‐
transfer catalyst were screened via the reaction of benzaldehyde
(1a), ethyl 4,4,4‐trifluoro‐3‐oxobutanoate (2) and 1‐
phenylguanidine carbonate (3) using H2SO4, FeCl3·6H2O,
MgSO4, TEBA (triethylbenzylammonium chloride),
SnCl2·2H2O and SA as catalyst (10% mol) (Table 1). As
shown in Table 1, SA is the favourable catalyst for this
reaction from the viewpoint of yield and reaction time.
To find the best catalyst loading, the aforementioned re-
action was run in 1 mmol scale of substrate using different
amounts of catalyst (Table 2). Table 2 shows that 10% mol
amount of SA was enough to push the solvent‐free reaction
forward. Moreover, the optimal temperature for the reac-
tion was found to be 90°C (Table 3).
Under the optimized reaction conditions, a series of 1,6‐
dihydrogenated 4‐trifluoromethyl‐2‐arylamino‐6‐arylpyrimi-
dine derivatives were synthesized (Table 4). As shown in Table
4, this methodology can be applied to aromatic aldehydes either
with electron‐withdrawing groups (such as a nitro group,
halide) or electron‐donating groups (such as a methoxy group)
with moderate to excellent yields under the same conditions.
Therefore, we conclude that the electronic nature of substi-
tuents of the aromatic aldehyde has no significant effect on
the reaction.
© 2012 HeteroCorporation

1034
S. Shen, W. Yang, C. Yu, T. Li, and C. Yao
Vol 49
Table 4
SA catalyzed the synthesis of compound 4.
Scheme 1
Time
(h)
Yielda
(%)
Entry Product
Ar
Mp (°C)
1
2
3
4
5
6
7
8
4a
4b
4c
C6H5
4‐BrC6H4
2,4‐Cl2C6H3
9
9
8
9
9
8
8
7
7
8
7
81
87
76
84
87
85
78
77
86
80
90
146–148
145–147
194–196
178–180
154–156
146–147
136–138
180–182
161–162
192–194
197–198
4d 3,4,5‐(MeO)3C6H2
4e
4f
4g
4h
4i
3,4‐(MeO)2C6H3
3‐NO2C6H4
2‐FC6H4
Table 1
Catalyst optimization for the synthesis of 4a under solvent‐free media.
2‐ClC6H4
3‐FC6H4
3‐ClC6H4
3‐BrC6H4
9
10
11
Entry
Catalyst
Temp. (°C)
Time (h)
Yielda (%)
4j
4k
1
2
3
4
5
6
H2SO4
FeCl3·6H2O
MgSO4
TEBA
SnCl2·2H2O
SA
90
90
90
90
90
90
10
10
10
10
10
9
54
65
60
72
55
81
aIsolated yield.
aIsolated yield.
Table 2
The effect of catalyst loading on reaction under solvent‐free media.
Entry
Catalyst (%)
Temp. (°C)
Time (h)
Yielda (%)
1
2
3
4
5
0
5
10
15
20
90
90
90
90
90
9
9
9
9
9
Trace
60
81
80
80
aIsolated yield.
Figure 1. The crystal structure of 4c.
Table 3
Temperature optimization for the synthesis of 4a under solvent‐free media.
was condensed with 1‐phenylguanidine carbonate 3 to af-
ford intermediate 5. The active methylene of 2 reacted with
the electrophilic C N bond to give intermediate 6. The fol-
lowing isomerization and cyclization by the nucleophilic
attack of NH2 group on carbonyl group, which was more
reactive than the ester group, afforded intermediate 8 and
its’ isomerism, 9 and 10. Final products 4 were obtained
via the dehydration of 9. The previous reports showed that
Biginelli reaction involving the fluorinated 1,3‐dicarbonyl
compounds as building blocks often gave the undehydrated
products and the dehydrated compounds were obtained under
drastic condition [23–29]. Here, the possible driving force of
dehydration was the formation of highly conjugated system.
Moreover, other dehydrated products including 11, 12, 13,
and 14 could not be obtained, which may be attributed to
the short conjugated chain in these compounds.
Entry
Temp. (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
30
50
70
80
90
9
9
9
9
9
9
9
Trace
28
33
65
81
100
110
80
80
aIsolated yield.
All of the synthesized compounds were characterized by
elemental analysis, FTIR, 1H NMR and 19F NMR. To fur-
ther elucidate the structure of products, a single crystal of
compound 4c was prepared and its structure was deter-
mined by X‐ray diffraction (Fig. 1) [17].
A plausible reaction pathway was proposed based on the
mechanism research of Biginelli reaction (Scheme 2)
[18–22]. Firstly, one molecule of aromatic aldehyde 1
In summary, we have developed a simple protocol to
synthesize 1,6‐dihydrogenated and 4‐trifluoromethylated
derivatives of 2‐arylamino‐6‐arylpyrimidine catalyzed by
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Solvent‐Free Synthesis of 2‐(Phenylamino)‐4‐(trifluoromethyl)‐1,6‐dihydropyrimidine
1035
Derivatives Catalyzed by Sulfamic Acid
Scheme 2
1325, 1271, 1167, 1111, 1037, 938, 824, 751, 700, and 668
cm−1 1H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.11 (t, J =
;
7.2 Hz, 3H, OCH2CH3), 4.03 (q, J = 7.2 Hz, 2H, OCH2CH3),
5.43 (d, J = 3.2 Hz, 1H, CH), 6.98 (t, J = 7.2 Hz, 1H, ArH),
7.25–7.32 (m, 5H, ArH), 7.36–7.40 (m, 2H, ArH), 7.48 (d, J =
8.0 Hz, 2H, ArH), 7.68 (d, J = 3.2 Hz, 1H, NH), 9.12 (s, 1H,
NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm): −65.2 (CF3);
Anal. calcd. For C20H18F3N3O2: C, 61.69; H, 4.66; N, 10.79.
Found: C, 61.75; H, 4.54; N, 10.94.
Ethyl 6‐(4‐bromophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4b). IR (KBr, υ, cm−1): 3292,
2990, 2944, 1668, 1592, 1578, 1540, 1467, 1372, 1324, 1268, 1230,
1209, 1167, 1109, 1039, 1009, 938, 830, 752, 703, and 691; 1H NMR
(400 MHz, DMSO‐d6) (δ, ppm): 1.12 (t, J = 7.2 Hz, 3H, OCH2CH3),
4.03 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.41 (d, J = 3.2 Hz, 1H, CH),
6.99 (t, J = 7.2 Hz, 1H, ArH), 7.25–7.30 (m, 4H, ArH), 7.47 (d,
J = 8.0 Hz, 2H, ArH), 7.59 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 3.2
Hz, 1H, NH), 9.20 (s, 1H, NH); 19F NMR (376.33 MHz, CDCl3)
(δ, ppm): −65.1 (CF3); Anal. calcd. For C20H17BrF3N3O2: C, 51.30; H,
3.66; N, 8.97. Found: C, 51.42; H, 3.56; N, 8.84.
Ethyl 6‐(2,4‐dichlorophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4c). IR (KBr, υ, cm−1): 3379,
3343, 3234, 3181, 3103, 3061, 2984, 2938, 2898, 2868, 1659, 1567,
1481, 1371, 1304, 1176, 1048, 943, 906, 866, 845, 816, 795, 758, 736,
717, 695, and 669; 1H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.07 (t,
J = 7.2 Hz, 3H, OCH2CH3), 4.00 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.81
(s, 1H, CH), 6.97 (t, J = 6.8 Hz, 1H, ArH), 7.24–7.30 (m, 3H, ArH),
7.48–7.52 (m, 3H, ArH), 7.68 (t, J = 2.0 Hz, 1H, ArH), 7.79 (s, 1H,
NH), 8.98 (s, 1H, NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm):
−65.0 (CF3); Anal. calcd. For C20H16Cl2F3N3O2: C, 52.42; H, 3.52; N,
9.17. Found: C, 52.55; H, 3.44; N, 9.22.
SA under solvent‐free media. Particularly, valuable fea-
tures of this method include good yields of the products,
environmental friendliness, and straightforward procedure.
Ethyl 2‐(phenylamino)‐4‐(trifluoromethyl)‐6‐(3,4,5‐
trimethoxyphenyl)‐1,6‐dihydropyrimidine‐5‐carboxylate (4d). IR
(KBr, υ, cm−1): 3304, 3183, 2940, 2839, 1672, 1574, 1503, 1464, 1422,
EXPERIMENTAL
1
Common reagents and materials were purchased from com-
mercial sources and purified by recrystallization or distillation.
NMR spectra were measured on a Bruker DPX 400, Data for
1H are reported as follows: chemical shift (ppm), multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad),
coupling constant (Hz), integration and number. 19F NMR
(376.33 MHz) was recorded on a Varian VXR‐unity 400 spec-
trometer with CFCl3 as an internal standard. Infrared (IR) spectra
were recorded on a TENSOR 27 spectrophotometer in KBr pallet
and are reported in terms of frequency of absorption (cm−1).
Elemental analyzes were performed on Perkin‐Elmer 240 II
elementary analyzer. Melting points were determined in open
capillaries and are uncorrected. The single crystal diffraction data
were gathered on a SMART CCD 1000 area diffractometer.
General procedure for the synthesis of ethyl 6‐aryl‐2‐
(phenylamino)‐4‐(trifluoromethyl)‐1,6‐dihydropyrimidine‐5‐
carboxylate (4a–4k). The mixture of sulfamic acid (0.1 mmol),
1‐phenylguanidine carbonate (1.0 mmol), aryl aldehydes (1.0
mmol), and ethyl 4,4,4‐trifluoro‐3‐oxobutanoate (1.0 mmol) was
triturated together in an agate mortar for 5 min. Then the
mixture was kept at 90°C for a certain time (monitored by
TLC). The result mixture was cooled to room temperature,
washed with water and recrystallized from ethanol (95%) to
give the pure product 4. A similar procedure was used in
preparing the following compounds.
1373, 1229, 1125, 1042, 1013, 933, 832, 805, 756, 700, and 670; H
NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.14 (t, J = 7.2 Hz, 3H,
OCH2CH3), 3.65 (s, 3H, OCH3), 3.74 (s, 6H, 2× OCH3), 4.03 (q,
J = 7.2 Hz, 2H, OCH2CH3), 5.39 (d, J = 3.2 Hz, 1H, CH), 6.62 (s, 2H,
ArH), 6.99 (t, J = 7.2 Hz, 1H, ArH), 7.26 (t, J = 8.0 Hz, 2H, ArH),
7.46 (d, J = 7.2 Hz, 2H, ArH), 7.70 (d, J = 3.2 Hz, 1H, NH), 9.13
(s, 1H, NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm): −63.8 (CF3);
Anal. calcd. For C23H24F3N3O5: C, 57.62; H, 5.05; N, 8.76. Found: C,
57.74; H, 5.12; N, 8.64.
Ethyl 6‐(3,4‐dimethoxyphenyl)‐2‐(phenylamino)‐4‐
(trifluoromethyl)‐1,6‐dihydropyrimidine‐5‐carboxylate (4e). IR
(KBr, υ, cm−1): 3303, 3179, 2940, 1681, 1574, 1514, 1463, 1372,
1
1231, 1040, 949, 913, 858, 812, 765, 752, 700, and 669; H NMR
(400 MHz, DMSO‐d6) (δ, ppm): 1.13 (t, J = 6.8 Hz, 3H,
OCH2CH3), 3.73 (s, 6H, 2× OCH3), 4.03 (q, J = 6.8 Hz, 2H,
OCH2CH3), 5.37 (d, J = 3.2 Hz, 1H, CH), 6.80–6.82 (m, 1H, ArH),
6.92–7.02 (m, 3H, ArH), 7.25 (t, J = 8.0 Hz, 2H, ArH), 7.46 (d,
J = 7.6 Hz, 2H, ArH), 7.63 (d, J = 3.2 Hz, 1H, NH), 9.08 (s, 1H,
NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm): −65.2 (CF3); Anal.
calcd. For C22H22F3N3O4: C, 58.79; H, 4.93; N, 9.35. Found: C,
58.86; H, 5.04; N, 9.26.
Ethyl 6‐(3‐nitrophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4f). IR (KBr, υ, cm−1):
3290, 3086, 2989, 1668, 1606, 1592, 1530, 1498, 1465, 1372,
1325, 1269, 1227, 1171, 1127, 1041, 1018, 946, 897, 819, 771,
751, and 696; 1H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.07 (t, J
= 6.8 Hz, 3H, OCH2CH3), 4.06 (q, J = 6.8 Hz, 2H, OCH2CH3),
5.61 (d, J = 3.2 Hz, 1H, CH), 7.01 (t, J = 7.2 Hz, 1H, ArH), 7.27
Ethyl 6‐phenyl‐2‐(phenylamino)‐4‐(trifluoromethyl)‐1,6‐
dihydropyrimidine‐5‐carboxylate (4a). IR (KBr, υ, cm−1):
3299, 3184, 3029, 2989, 2941, 1670, 1575, 1498, 1466, 1372,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Shen, W. Yang, C. Yu, T. Li, and C. Yao
Vol 49
(t, J = 8.0 Hz, 2H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.70–7.77
(m, 2H, ArH), 7.90 (d, J = 3.2 Hz, 1H, NH), 8.18 (dd, J1 = 1.2
Hz, J2 = 5.6 Hz, 2H, ArH), 9.33 (s, 1H, NH); 19F NMR (376.33
MHz, CDCl3) (δ, ppm): −63.5 (CF3); Anal. calcd. For
C20H17F3N4O4: C, 55.30; H, 3.94; N, 12.90. Found: C, 55.42; H,
3.82; N, 12.78.
Acknowledgments. The authors are grateful for financial support
by the Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions
(09KJA430003), Natural Science Foundation of Xuzhou City
(XM09B016), Graduate Foundation of Xuzhou Normal
University (09YLB030), and Qing Lan Project (08QLT001).
Ethyl 6‐(2‐fluorophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4g). IR (KBr, υ, cm−1):
3299, 3065, 2994, 2942, 1671, 1611, 1592, 1577, 1499, 1487, 1466,
1373, 1328, 1267, 1169, 1113, 1100, 1038, 939, 833, 753, and 700;
1H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.08 (t, J = 6.8 Hz, 3H,
OCH2CH3), 4.00 (q, J = 6.8 Hz, 2H, OCH2CH3), 5.73 (s, 1H, CH),
6.97 (t, J = 6.8 Hz, 1H, ArH), 7.21–7.26 (m, 5H, ArH), 7.35–7.38
(m, 1H, ArH), 7.48 (d, J = 7.6 Hz, 2H, ArH), 7.72 (s, 1H, NH), 9.02
(s, 1H, NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm): −65.2 (CF3),
−120.4 (Ar–F); Anal. calcd. For C20H17F4N3O2: C, 58.97; H, 4.21;
N, 10.32. Found: C, 58.86; H, 4.16; N, 10.44.
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1,6‐dihydropyrimidine‐5‐carboxylate (4h). IR (KBr, υ, cm−1):
3369, 3242, 3187, 3101, 3065, 3021, 2985, 2937, 1660, 1634, 1569,
1484, 1437, 1400, 1371, 1334, 1304, 1261, 1174, 1147, 1076, 1047,
1
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MHz, DMSO‐d6) (δ, ppm): 1.06 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.98
(q, J = 6.8 Hz, 2H, OCH2CH3), 5.84 (s, 1H, CH), 6.97 (t, J = 7.2 Hz,
1H, ArH), 7.24–7.31 (m, 3H, ArH), 7.34–7.42 (m, 3H, ArH), 7.49
(d, J = 8.0 Hz, 2H, ArH), 7.72 (s, 1H, NH), 8.94 (s, 1H, NH); 19F
NMR (376.33 MHz, CDCl3) (δ, ppm): −63.6 (CF3); Anal. calcd. For
C20H17ClF3N3O2: C, 56.68; H, 4.04; N, 9.91. Found: C, 56.74; H,
4.12; N, 10.02.
Ethyl 6‐(3‐fluorophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4i). IR (KBr, υ, cm−1):
3292, 3174, 2991, 2944, 1671, 1592, 1498, 1486, 1449, 1373, 1229,
1171, 1088, 1040, 952, 910, 880, 843, 810, 789, 779, 751, 717, and
701; 1H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.27 (t, J = 6.8 Hz,
3H, OCH2CH3), 4.06 (q, J = 6.8 Hz, 2H, OCH2CH3), 5.46 (d,
J = 3.2 Hz, 1H, CH), 6.99 (t, J = 7.2 Hz, 1H, ArH), 7.06 (d, J = 10.0
Hz, 1H, ArH), 7.13–7.17 (m, 2H, ArH), 7.27 (d, J = 7.6 Hz, 2H,
ArH), 7.42–7.50 (m, 3H, ArH), 7.78 (d, J = 3.2 Hz, 1H, NH), 9.21
(s, 1H, NH); 19F NMR (376.33 MHz, CDCl3) (δ, ppm): −63.8 (CF3),
−110.6 (Ar–F); Anal. calcd. For C20H17F4N3O2: C, 58.97; H, 4.21;
N, 10.32. Found: C, 58.88; H, 4.14; N, 10.26.
Ethyl 6‐(3‐chlorophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4j). IR (KBr, υ, cm−1):
3287, 3172, 2990, 1667, 1582, 1498, 1466, 1431, 1373, 1207, 1039,
1
942, 910, 876, 837, 802, 773, 750, 717, and 699; H NMR (400
[15] For recent advances, see: (a) Walsh, P. J.; Li, H. M.; de Parrodi, C. A.
Chem Rev 2007, 107, 2503. (b) Hobbs, H. R.; Thomas, N. R. Chem Rev 2007,
107, 2786. (c) Tanaka, K.; Toda, F. Chem Rev 2000, 100, 1025. (d) Sheldon,
R. A. Green Chem 2005, 7, 247. (e) Kranjc, K.; Kocevar, M. Curr Org Chem
2010, 14, 1050. (f) Lv, M.; Xu, H. Comb Chem High Throughput Screen
2010, 13, 293. (g) Shearouse, W. C.; Waddell, D. C.; Mack, J. Curr Opin Drug
Discov Devel 2009, 12, 772. (h) Martins, M. A. P.; Frizzo, C. P.; Moreira,
D. N.; Buriol, L.; Machado, P. Chem Rev 2009, 109, 4140.
MHz, DMSO‐d6) (δ, ppm): 1.12 (t, J = 6.8 Hz, 3H, OCH2CH3), 4.05
(q, J = 6.8 Hz, 2H, OCH2CH3), 5.45 (s, 1H, CH), 7.00 (t, J = 7.2 Hz,
1H, ArH), 7.26–7.33 (m, 4H, ArH), 7.37–7.50 (m, 4H, ArH), 7.78 (s,
1H, NH), 9.22 (s, 1H, NH); 19F NMR (376.33 MHz, CDCl3) (δ,
ppm): −65.2 (CF3); Anal. calcd. For C20H17ClF3N3O2: C, 56.68; H,
4.04; N, 9.91. Found: C, 56.56; H, 4.12; N, 9.75.
Ethyl 6‐(3‐bromophenyl)‐2‐(phenylamino)‐4‐(trifluoromethyl)‐
1,6‐dihydropyrimidine‐5‐carboxylate (4k). IR (KBr, υ, cm−1):
3290, 3172, 2989, 2940, 1667, 1591, 1578, 1531, 1498, 1465, 1428,
1372, 1322, 1265, 1226, 1167, 1125, 1111, 1039, 941, 832, 788,
[16] (a) Yao, C. S.; Lei, S.; Wang, C. H.; Yu, C. X.; Tu, S. J. J
Heterocycl Chem 2008, 45, 1609. (b) Yao, C. S.; Lei, S.; Wang, C. H.;
Li, T. J.; Yu, C. X.; Wang, X. S.; Tu, S. J. J Heterocycl Chem 2010, 47, 26.
[17] The single‐crystal growth was carried out in ethanol at room
temperature. The single crystal diffraction data were gathered on a
SMART CCD 1000 area diffractometer. Crystal data for 4c:
C20H16Cl2F3N3O2, crystal dimension 0.26 × 0.24 × 0.20 mm, orthorhom-
bic, space group P212121, a = 11.0085(15) Å, b = 11.8934(17) Å, c =
15.698(2) Å, V = 2055.4(5) Å3, Mr = 458.26, Z = 4, Dc = 1.481 g cm3,
1
772, 750, and 696; H NMR (400 MHz, DMSO‐d6) (δ, ppm): 1.14
(t, J = 6.8 Hz, 3H, OCH2CH3), 4.07 (q, J = 6.8 Hz, 2H, OCH2CH3),
5.44 (s, 1H, CH), 7.01 (t, J = 5.2 Hz, 1H, ArH), 7.26–7.30 (m, 4H,
ArH), 7.38–7.49 (m, 4H, ArH), 7.77 (s, 1H, NH), 9.21 (s, 1H, NH);
19F NMR (376.33 MHz, CDCl3) (δ, ppm): −64.9 (CF3); Anal. calcd.
For C20H17BrF3N3O2: C, 51.30; H, 3.66; N, 8.97. Found: C, 51.18;
H, 3.56; N, 8.83.
λ = 0.71073 Å, μ (Mokα) = 0.365 mm−1, F(000) = 936, S =1.04, R1
0.037, wR2 = 0.092.
=
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Solvent‐Free Synthesis of 2‐(Phenylamino)‐4‐(trifluoromethyl)‐1,6‐dihydropyrimidine
1037
Derivatives Catalyzed by Sulfamic Acid
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