A convenient three-component reaction for the construction of multifunctional 6-fluoroalkyl-1,2,3,4-tetrahydropyrimidines

Article abstract of DOI:10.1016/j.jfluchem.2005.08.015

β-Fluoroalkylenaminoketones were prepared and their reaction with primary amines and formaldehyde were studied. Multifunctional 6-fluoroalkyl-1,2,3,4-tetrahydropyrimidines were synthesized conveniently from the three-component reaction in good yields unde

Full text of DOI:10.1016/j.jfluchem.2005.08.015

Journal of Fluorine Chemistry 126 (2005) 1539–1542
www.elsevier.com/locate/fluor
A convenient three-component reaction for the construction of
multifunctional 6-fluoroalkyl-1,2,3,4-tetrahydropyrimidines
*
Yun Lin, Jin-Tao Liu , Fu-Lu Zhao
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 22 June 2005; received in revised form 29 August 2005; accepted 30 August 2005
Available online 13 October 2005
Abstract
b-Fluoroalkylenaminoketones were prepared and their reaction with primary amines and formaldehyde were studied. Multifunctional 6-
fluoroalkyl-1,2,3,4-tetrahydropyrimidines were synthesized conveniently from the three-component reaction in good yields under mild conditions.
# 2005 Elsevier B.V. All rights reserved.
Keywords: b-Fluoroalkylenaminoketone; Fluoroalkylated 1,2,3,4-tetrahydropyrimidine; Primary amine; Formaldehyde
1. Introduction
investigated. The results of this three-component reaction are
reported in this paper.
The ability of fluorine atom to enhance biological and
therapeutic activities of certain organic compounds has led to
widespread interest in selective introduction of fluorine atom
and fluoroalkyl groups into organic molecules [1–5], especially
those heterocyclic compounds which have potential biological
activities. 1,2,3,4-Tetrahydropyrimidine ring is an important
moiety in both natural and synthetic organic compounds, and
many compounds containing it show interesting biological
activities [6–12]. Accordingly many methods have been
developed for the synthesis of various 1,2,3,4-tetrahydropyr-
imidines [13]. However, the synthesis of fluoroalkylated
1,2,3,4-tetrahydropyrimidines is less studied [14] and their
biological activities remain unexplored. Therefore, it is our
interest to develop synthetic methodologies for those fluorine-
containing heterocycles which might have unique properties by
the introduction of fluoroalkyl groups.
2. Results and discussion
b-Fluoroalkylenaminoketones (1) were prepared from
commercial available fluoroalkyl iodides as shown in Scheme
1 [15].
The reaction of 1b with methylamine and formaldehyde was
firstcarriedoutinrefluxingacetonitrilewith amole ratioof1:2:4.
It was found that the reaction was very slow and only trace
product was formed after 24 h. Then the amount of methylamine
and formaldehyde was increased. With a ratio of 1:8:18 (1/
methylamine/formaldehyde), the reaction was completed in
10 h. After workup, a light yellow solid was obtained. Spectral
and elemental analysis showed that it was the expected product,
6-chlorodifluoromethyl-5-tert-butylcarbonyl-3-methyl-1-phe-
nyl-1,2,3,4-tetrahydropyrimidine (3ba) (Scheme 2).
Recently, it was found in our laboratory that the reaction of
fluorine-containing enaminoketones or 3-fluoroalkylanili-
noacrylic acid esters with primary amines and formaldehyde
could afford multifunctional 1,2,3,4-tetrahydropyrimidines
under mild conditions [14]. To explore the scope of this
procedure further, b-fluoroalkylenaminoketones were prepared
and their reaction with primary amines and formaldehyde were
To find suitable conditions, the reaction of 1b, methylamine
and formaldehyde under various conditions was investigated.
As shown in Table 1, the yield of 3ba was influenced by the
ratio of three reactants and better result was obtained when
more methylamine and formaldehyde were used. Solvent and
temperature also played important roles in the reaction. When
the reaction was carried out in DMF at 110 8C, the reaction time
was fantastically shortened, and much less methylamine and
formaldehyde were needed for a satisfactory conversion of 1b.
Increasing temperature further made the reaction more
* Corresponding author. Tel.: +86 21 54925188; fax: +86 21 64166128.
E-mail address: jtliu@mail.sioc.ac.cn (J.-T. Liu).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.08.015

1540
Y. Lin et al. / Journal of Fluorine Chemistry 126 (2005) 1539–1542
Scheme 1.
Scheme 2.
complex. Therefore, an optimized condition was chosen for this
three-component reaction as follows: in DMF at 110 8C with a
mole ratio of 1:3:6.5 (1b:CH3NH2:HCHO).
tetrahydropyrimidines. Using this method, a series of novel
multifunctional 6-fluoroalkyl-1,2,3,4-tetrahydropyrimidines
were synthesized from easily available starting materials for
the first time.
Using the optimized conditions, various b-fluoroalkylena-
minoketones and primary amines were examined. As shown in
Table 2, aliphatic primary amines reacted readily with 1 and
formaldehyde to give the desired product in good yields. The
length and bulkiness of primary amine had little influence on the
reaction. However, the reaction was very complicated when
aromatic amines such as aniline and para-methoxy aniline were
used and no expected cyclic products were obtained. The
electron charge of the aromatic group in enaminoketones had
little influence on the reaction. Enaminoketones containing
either electron-rich or electron-deficient aromatic ring gave
satisfactory results.
3. Experimental
3.1. General
Melting points were uncorrected. IR spectra were taken on a
1
Perkin-Elmer Jeol 983 spectrophotometer. H NMR spectra
were measured on a Bruker AM300 (300 MHz) spectrometer
using TMS as internal standard. 19F NMR spectra were taken on
a Bruker AM300 (282 MHz) spectrometer using CFCl3 as
external standard. Mass spectra were obtained on a Hewlett–
Packard HP-5989A spectrometer. Column chromatography
was performed on silica gel H, particle size 10–40 mm.
In conclusion, the three-component reaction of b-fluoroalk-
ylenaminoketone, primary amine and formaldehyde was
achieved under mild conditions, providing a convenient method
for the synthesis of fluoroalkylated multifunctional 1,2,3,4-
Table 2
The reaction of 1 with primary amines and formaldehydea
Entry
1
Time (h)
Rf
R1
R2
Product
Yield
(%)b
Table 1
The reaction of 1b with methylamine and formaldehyde under different
conditionsa
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
2
3
3
3
3
4
4
5
3
3
4
5
4
CF3
Ph
Me
Et
3aa
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cb
3cc
3cd
3da
85
83
80
84
85
80
80
80
82
80
78
80
79
CF3
Ph
Entry
Solvent
1b:CH3NH2:
HCHO
Temperature
Time
(h)
Yield
(%)b
3
CF3
Ph
n-Pr
t-Bu
Me
Et
(8C)
4
CF3
Ph
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
DMF
1:2:4
Reflux
Reflux
Reflux
80
24
17
10
9
Trace
78
5
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
Ph
1:4:9
6
Ph
1:8:18
1:8:18
1:4:9
87
7
Ph
n-Pr
t-Bu
Me
Et
90
8
Ph
DMF
80
15
2.5
3
81
9
p-OMe-Ph
p-OMe-Ph
p-OMe-Ph
p-OMe-Ph
p-Br-Ph
DMF
1:4:9
110
90
10
11
12
13
DMF
1:3:6.5
1:2:4
110
88
n-Pr
t-Bu
Me
DMF
110
10
2
50
DMF
1:3:6.5
140
Complex
a
a
All reactions were carried out with 1 (1 mmol) in solvent (5 mL).
Determined by 19F NMR.
All reactions were carried out with 1 (1 mmol) in DMF (5 mL).
Isolated yields based on 1.
b
b

Y. Lin et al. / Journal of Fluorine Chemistry 126 (2005) 1539–1542
1541
3.2. Typical procedure for the synthesis of 6-fluoroalkyl-
1,2,3,4-tetrahydropyrimidines (3)
Anal. Calcd. for C20H27F3N2O: C, 65.20; H 7.39, N, 7.60.
Found: C, 65.08; H, 7.45; N, 7.49.
To a solution of 1 (1 mmol) in DMF (5 mL), were added
3.2.5. 5-tert-Butylcarbonyl-6-chlorodifluoromethyl-3-
methyl-1-phenyl-1,2,3,4-tetrahydropyrimidine (3ba)
Light yellow solid: mp 55–57 8C; IR (KBr): n 3062, 3040,
2976, 2849, 1687, 1639, 1595, 1495, 1181, 1154, 1136, 1114,
896, 699 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.27–7.31 (2H,
m), 7.15–7.19 (3H, m), 3.90 (2H, s), 3.35 (2H, s), 2.29 (3H, s),
1.29 (9H, s); 19F NMR (282 MHz, CDCl3): d À48.11 (s). EIMS
(70 eV) m/z (%): 342 [M+] (5), 214 (100), 57 (21). Anal. Calcd.
for C17H21ClF2N2O: C, 59.66; H, 6.17; N, 8.17. Found: C,
59.61; H, 6.25; N, 7.98.
primary amines
2
(3 mmol) and 37% formaldehyde
(6.5 mmol). The mixture was stirred at 110 8C for 2–5 h
(monitored by TLC or 19F NMR). After completion of the
reaction, the mixture was cooled to room temperature, diluted
with water and extracted with Et2O. The organic layer was
washed with saturated NaCl solution and dried over anhydrous
Na2SO4. The residue obtained after evaporation of the solvent
was purified by flash chromatography on silica gel eluting with
petroleum-ethyl acetate to give 3.
3.2.1. 5-tert-Butylcarbonyl-3-methyl-1-phenyl-6-
trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3aa)
Light yellow liquid. IR (film): n 3062, 2975, 1695, 1646,
3.2.6. 5-tert-Butylcarbonyl-6-chlorodifluoromethyl-3-
ethyl-1-phenyl-1,2,3,4-tetrahydropyrimidine (3bb)
Light yellow liquid. IR (film): n 3064, 2974, 1695, 1638,
1
1596, 1492, 1370, 1183, 1158, 1135, 865, 767, 699 cmÀ1; H
1
1597, 1494, 1180, 1153, 1129, 896, 761, 699 cmÀ1; H NMR
NMR (300 MHz, CDCl3): d 7.28–7.33 (2H, m), 7.14–7.17 (3H,
m), 3.92 (2H, s), 3.35 (2H, s), 2.29 (3H, s), 1.26 (9H, s); 19F
NMR (282 MHz, CDCl3): d À60.71 (s); EIMS (70 eV) m/z (%):
326 [M+] (23), 269 (53), 57 (100). Anal. Calcd. for
C17H21F3N2O: C, 62.56; H, 6.49; N, 8.58. Found: C, 62.53;
H, 6.59; N, 8.34.
(300 MHz, CDCl3): d 7.26–7.36 (2H, m), 7.14–7.20 (3H, m)
3.99 (2H, s), 3.41 (2H, s), 2.49 (2H, q, J = 7.2 Hz), 1.29 (9H, s),
0.95 (3H, t, J = 7.2 Hz); 19F NMR (282 MHz, CDCl3): d
À47.68 (s); EIMS (70 eV) m/z (%): 356 [M+] (4), 299 (18), 214
(100). Anal. Calcd. for C18H23ClF2N2O: C, 60.59; H, 6.50; N,
7.85. Found: C, 60.56; H, 6.28; N, 7.82.
3.2.2. 5-tert-Butylcarbonyl-3-ethyl-1-phenyl-6-
trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3ab)
Light yellow liquid. IR (film): n 3062, 2974, 1694, 1645,
3.2.7. 5-tert-Butylcarbonyl-6-chlorodifluoromethy-1-
phenyl-3-propyl-1,2,3,4-tetrahydropyrimidine (3bc)
Light yellow liquid. IR (film): n 3064, 2968, 1694, 1638,
;
1597, 1494, 1479, 1193, 1133, 912, 699 cmÀ1 1H NMR
1
1597, 1493, 1369, 1159, 1135, 1071, 990, 763, 699 cmÀ1; H
NMR (300 MHz, CDCl3): d 7.28–7.33 (2H, m), 7.14–7.17 (3H,
m), 4.04 (2H, s), 3.43 (2H, s), 2.50 (2H, q, J = 7.2 Hz), 1.29
(9H, s), 0.95 (3H, t, J = 7.2 Hz); 19F NMR (282 MHz, CDCl3):
d À60.44 (s). EIMS (70 eV) m/z (%): 340 [M+] (25), 283 (100),
227 (79), 57 (44). Anal. Calcd. for C18H23F3N2O: C, 63.51; H,
6.81; N, 8.23. Found: C, 63.43; H, 6.83; N, 8.03.
(300 MHz, CDCl3): d 7.26–7.32 (2H, m), 7.14–7.20 (3H, m),
3.97 (2H, s), 3.41 (2H, s), 2.38 (2H, t, J = 7.2 Hz), 1.30–1.36
(2H, m), 1.29 (9H, s), 0.75 (3H, t, J = 7.2 Hz); 19F NMR
(282 MHz, CDCl3): d À47.72 (s); EIMS (70 eV) m/z (%): 370
[M+] (10), 214 (100), 57 (72). Anal. Calcd. for C19H25ClF2N2O:
C, 61.53; H, 6.79; N, 7.55. Found: C, 61.56; H, 6.99; N, 7.35.
3.2.3. 5-tert-Butylcarbonyl-1-phenyl-3-propyl-6-
trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3ac)
3.2.8. 3-tert-Butyl-5-tert-butylcarbonyl-6-chlorodifluoro-
methyl-1-phenyl-1,2,3,4-tetrahydropyrimidine (3bd)
Light yellow solid: mp 64–66 8C; IR (KBr): n 3062, 2974,
1684, 1630, 1595, 1493, 1479, 1366, 1289, 1181, 1133, 1124,
887, 696 cmÀ1; 1H NMR (300 MHz,CDCl3): d 7.26–7.29 (2H,
m), 7.16–7.18 (3H, m), 3.95 (2H, s), 3.47 (2H, s), 1.27 (9H, s),
0.93 (9H, s); 19F NMR (282 MHz, CDCl3): d À48.53 (s); EIMS
(70 eV) m/z (%): 384 [M+] (4), 214 (100), 57 (38). Anal. Calcd.
for C20H27ClF2N2O: C, 62.41; H, 7.07; N, 7.28. Found: C,
62.62; H, 7.30; N, 7.00.
Light yellow liquid. IR (film): n 3061, 2968, 1693, 1647,
1597, 1493, 1479, 1465, 1367, 1297, 1180, 1158, 1136, 927,
699 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.26–7.32 (2H, m),
7.11–7.17 (3H, m), 4.04 (2H, s), 3.42 (2H, s), 2.38 (2H, t,
J = 7.5 Hz), 1.27–1.37 (2H, m), 1.26 (9H, s), 0.74 (3H, t,
J = 7.2 Hz,); 19F NMR (282 MHz, CDCl3): d À60.42 (s); EIMS
(70 eV) m/z (%): 354 [M+] (16), 297 (44), 226 (55), 57 (100).
Anal. Calcd. for C19H25F3N2O: C, 64.39; H, 7.11; N, 7.90.
Found: C, 4.28; H, 7.08; N, 7.86.
3.2.9. 5-tert-Butylcarbonyl-6-chlorodifluoromethyl-3-
methyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidine
(3ca)
3.2.4. 5-tert-Butylcarbonyl-1-phenyl-3-tert-butyl-6-
trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3ad)
Light yellow solid: mp 54–55 8C; IR (KBr): n 3061, 2955,
1693, 1644, 1597, 1492, 1360, 1199, 1181, 1164, 1128, 917,
753, 698 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.26–7.32 (2H,
m), 7.11–7.17 (3H, m), 3.94 (2H, s), 3.46 (2H, s), 1.27 (9H, s),
0.92 (9H, s); 19F NMR (282 MHz, CDCl3): d À61.61 (s); EIMS
(70 eV) m/z (%): 330 [M+] (3), 368 (13), 226 (100), 283 (60).
Light yellow liquid. IR (film): n 3041, 2972, 1693, 1637,
1584, 1509, 1464, 1183, 1153, 1125, 1068, 902, 836, 794 cmÀ1
;
1H NMR (300 MHz,CDCl3): d 7.12–7.16 (2H, m), 6.82–6.86
(2H, m), 3.78–3.81 (5H, m), 3.31 (2H, s), 2.30 (3H, s), 1.28 (9H,
s); 19F NMR (282 MHz, CDCl3): d À47.30 (s); EIMS (70eV) m/
z (%): 372 [M+] (6), 244 (100), 57 (84). Anal. Calcd. for

1542
Y. Lin et al. / Journal of Fluorine Chemistry 126 (2005) 1539–1542
C18H23ClF2N2O2: C, 57.99; H, 6.22; N, 7.51. Found: C, 57.85;
H, 6.31; N, 7.48.
3.2.13. 1-(4-Bromophenyl)-5-tert-butylcarbonyl-6-
chlorodifluoromethyl-3-methyl-1,2,3,4-
tetrahydropyrimidine (3da)
Light yellow liquid. IR (film): n 2974, 1693, 1638, 1588,
1
1487, 1181, 1152, 1139, 1066, 1008, 900, 852, 768 cmÀ1; H
3.2.10. 5-tert-Butylcarbonyl-6-chlorodifluoromethyl-3-
ethyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidine
(3cb)
Light yellow liquid. IR (film): n 3041, 2972, 1693, 1637,
1584, 1508, 1494, 1479, 1199, 1180, 1127, 920, 899, 836,
791 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.16 (2H, d,
;
J = 9.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 3. 88 (2H, s), 3.78 (3H, s),
3.37 (2H, s), 2.48 (2H, q, J = 7.2 Hz), 1.27 (9H, s), 0.97 (3H, t,
J = 7.2 Hz); 19F NMR (282 MHz, CDCl3): d À46.98 (s); EIMS
(70 eV) m/z (%): 386 [M+] (7), 329 (36), 244 (100). Anal.
Calcd. for C19H25ClF2N2O2: C, 58.99; H, 6.51; N, 7.24; Found:
C, 59.17; H, 6.62; N, 7.20.
NMR (300 MHz, CDCl3): d 7.44 (2H, d, J = 9.0 Hz), 7.05 (2H,
d, J = 9.0Hz), 3.85 (2H, s), 3.33 (2H, s), 2.28 (3H, s), 1.28 (9H,
s); 19F NMR (282 MHz, CDCl3): d 48.46 (s). EIMS (70 eV) m/z
(%): 422 [M+] (8), 379 (27), 292 (73), 57 (100). Anal. Calcd. for
C18H23ClF2N2O2: C, 48.42; H, 4.78; N, 6.64. Found: C, 48.64;
H, 4.97; N, 6.50.
Acknowledgement
We thank the National Natural Science Foundation of China
for financial support (No. 20172065).
References
3.2.11. 5-tert-Butylcarbonyl-6-chlorodifluoromethyl -1-(4-
methoxyphenyl)-3-propyl-1,2,3,4-tetrahydropyrimidine
(3cc)
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(2003) 5763–5772.
Light yellow liquid. IR (film): n 3041, 2966, 1693, 1637,
1584, 1509, 1475, 1465, 1246, 1193, 1180, 1153, 1127, 1034,
1008, 904, 836, 796 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.16
(2H, d, J = 8.7 Hz), 6.83 (2H, d, J = 8.7Hz), 3.84 (2H, s), 3.78
(3H, s), 3.35 (2H, s), 2.37 (2H, t, J = 7.2 Hz), 1.33–1.40 (2H,
m), 1.26 (9H, s), 0.78 (3H, t, J = 7.2 Hz); 19F NMR (282 MHz,
CDCl3): d À47.90 (s); EIMS (70 eV) m/z (%): 400 [M+] (7),
329 (40), 244 (100), 57 (53). Anal. Calcd. for C20H27ClF2N2O2:
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6.80.
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tert-butyl-5-tert-butylcarbonyl-1,2,3,4-tetrahydropyrimidine
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Light yellow liquid. IR (film): n 2972, 1693, 1637, 1610,
1584, 1508, 1478, 1465, 1290, 1247, 1199, 1183, 1129, 1034,
921, 895, 836 cmÀ1; 1H NMR (300 MHz,CDCl3): d 7.14–7.16
(2H, m), 6.79–6.83 (2H, m), 3.85 (2H, s), 3.78 (3H, s), 3.44 (2H,
s), 1.26 (9H, s), 0.94 (9H, s); 19F NMR (282 MHz, CDCl3): d
48.16 (s); EIMS (70 eV) m/z (%): 414 [M+] (7), 329 (37), 244
(100), 57 (14). Anal. Calcd. for C21H29ClF2N2O2: C, 60.79; H,
7.04; N, 6.75. Found: C, 60.62; H, 7.02; N, 6.63.
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