A straightforward preparation of fluorine-containing 1,2-dihydropyrimidines and pyrimidines with 2,2-dihydropolyfluoroalkylaldehydes

Article abstract of DOI:10.1016/j.tet.2007.04.010

The reactions of 2,2-dihydropolyfluoroalkylaldehydes with ammonia and enol ethers or carbonyl compounds are described. In the presence of zinc chloride, all reactions took place readily in THF at 50 °C to give fluorine-containing 1,2-dihydropyrimidines in

Full text of DOI:10.1016/j.tet.2007.04.010

Tetrahedron 63 (2007) 5643–5648
A straightforward preparation of fluorine-containing
1,2-dihydropyrimidines and pyrimidines with
2,2-dihydropolyfluoroalkylaldehydes
Xian-Jin Yang,a,b Li-Si Zhangb and Jin-Tao Liua,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
bLaboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science
and Technology, Shanghai 200237, China
Received 13 December 2006; revised 3 April 2007; accepted 3 April 2007
Available online 12 April 2007
Abstract—The reactions of 2,2-dihydropolyfluoroalkylaldehydes with ammonia and enol ethers or carbonyl compounds are described. In the
presence of zinc chloride, all reactions took place readily in THF at 50 ꢀC to give fluorine-containing 1,2-dihydropyrimidines in moderate
to good yields. Dehydrogenation of the resulting fluorine-containing 1,2-dihydropyrimidines with tetrachloro-1,4-benzoquinone (TCBQ)
or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room temperature afforded the corresponding fluorine-containing pyrimidines in
good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and the reaction of perfluoroalkyl iodides with amines and
ethyl vinyl ether in the presence of sodium dithionite gave
the corresponding perfluoroalkylated enaminoketones.6
However, when ammonia was used instead of amine to react
with perfluorobutyl iodide (1a) and ethyl vinyl ether, a new
compound was obtained along with the desired product
(Scheme 1). Spectral analyses and X-ray crystallography
showed that it was 2-methyl-4-heptafluoropropyl-1,2-di-
hydropyrimidine 2a (Fig. 1).7
The ability of fluorine atom to enhance biological and thera-
peutic activities of certain organic compounds has led to
a widespread interest in selective introduction of fluorine
atom and fluoroalkyl groups into organic molecules, espe-
cially those heterocyclic compounds which have potential
biological activities.1 It is known that 1,2-dihydropyrimidine
and pyrimidine are important heterocyclic moieties in both
natural and synthetic compounds with biological proper-
ties.2 Accordingly many methods have been developed for
their synthesis.3 However, fluorine-containing 1,2-dihydro-
pyrimidines, which may have potential biological activities
are less studied.4 In this paper we report a convenient
synthesis of fluorine-containing 1,2-dihydropyrimidines and
pyrimidines from 2,2-dihydropolyfluoroalkylaldehydes.5
From the structure of 2a, it was supposed that this by-
product was formed by the reaction of 1a with 2 equiv of
ethyl vinyl ether and 2 equiv of ammonia. To confirm this
hypothesis, different amounts of ethyl vinyl ether were
tested in the presence of excess ammonia. As shown in Table
1, the yield of 2a increased gradually with the addition of
more ethyl vinyl ether, but it did not change obviously
when more than 2 equiv of ethyl vinyl ether was used.
Similar results were obtained with other perfluoroalkyl
iodides (Table 1). In all reactions, the yields of 2 were rela-
tively low.
2. Results and discussion
Recently, it was found in our laboratory that both the reac-
tion of 2,2-dihydropolyfluoroalkylaldehydes with amines
It is known that the reaction of perfluoroalkyl iodides and
ethyl vinyl ether initiated by sodium dithionite affords 2,2-
dihydropolyfluoroalkylaldehydes (3). Referring to the above
results, we proposed that compound 3 was involved in the
reaction as an intermediate. In the presence of sodium
dithionite, 1 reacted with ethyl vinyl ether first to give 3,
which reacted with another ethyl vinyl ether and ammonia
Keywords: 2,2-Dihydropolyfluoroalkylaldehyde; Fluorine-containing 1,2-
dihydropyrimidine; Fluorine-containing pyrimidine; Ammonia; Zinc
chloride.
* Corresponding author. Tel.: +86 21 54925188; fax: +86 21 64166128;
e-mail: jtliu@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.010

5644
X.-J. Yang et al. / Tetrahedron 63 (2007) 5643–5648
CF2CF2CF3
N
O
Na2S2O4/NaHCO3
+
+
H2N
CF2CF2CF3
CF3CF2CF2CF2I
CH2=CHOC2H5
+ NH3
CH3CN/H2O
N
H
1a
2a
Scheme 1.
Table 1. The reaction of 1 with ethyl vinyl ether and ammoniaa
RF
Na2S2O4/NaHCO3
N
+ NH3
CH =CHOC H
2 5
RFCF2I +
2
CH3CN/H2O
N
H
1a-c
2a-c
Entry
1 (RF)
Ethyl vinyl
ether/1 (mol)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
1a (C3F7)
1a (C3F7)
1a (C3F7)
1a (C3F7)
1b (ClC3F6)
1b (ClC3F6)
1c (CF3)
1.2:1
1.5:1
2.0:1
2.5:1
1.2:1
2.0:1
1.5:1
2.0:1
2a
2a
2a
2a
2b
2b
2c
2c
8
18
25
25
7
27
19
28
1c (CF3)
a
Reaction conditions: 1 (1 mmol), sodium dithionite (9 mmol), sodium
dicarbonate (8 mmol), aqueous ammonia solution (25%, 5 mL).
Isolated yields based on 1.
b
Table 2. The reaction of 3 with ammonia and ethyl vinyl ethera
RF
N
RFCF2CH2CHO
+
CH2=CHOC2H5 + NH3
N
H
3
2
Figure 1. Crystal structure of 2a.
Entry
3 (RF)
Condition
Product
Yieldb (%)
1
2
3
4
5
6
3a (C3F7)
3a (C3F7)
3a (C3F7)
3a (C3F7)
3c (CF3)
NH3 (aq)
NH3 (g)
ZnCl2, NH3 (aq)
ZnCl2, NH3 (g)
ZnCl2, NH3 (g)
ZnCl2, NH3 (g)
2a
2a
2a
2a
2c
2b
31
34
51
71
61
72
to afford the final product 2 (Scheme 2). Compound 3 is an
important intermediate in organic synthesis and has been
used for the preparation of many fluorine-containing com-
pounds.6a,8 To make the reaction simple and improve the
yield of 2, the reaction of 3 with ammonia and ethyl vinyl
ether was then studied. It was found that 2 was obtained as
expected and the yield could be improved significantly by
the addition of anhydrous zinc chloride. Gaseous ammonia
gave higher yields than aqueous ammonia. The results are
summarized in Table 2.
3b (ClC3F6)
a
Reaction conditions: 3 (1 mmol), ethyl vinyl ether (1.5 mmol), and excess
ammonia in THF (20 mL) at 50 ꢀC.
Isolated yields based on 3.
b
good yields (Scheme 3). The results are listed in Table 3.
It was interesting that spiral products 2h and 2i were
obtained from 1-cyclohexenyl trimethylsilyl ether 4e in
reasonable yields, while the reaction of 1-cyclopentyl trime-
thylsilyl ether 4f with 3 and ammonia was very complicated
Under similar conditions, trimethylsilyl enol ethers 4 could
also react with 3 and ammonia to give the corresponding
4-perfluoroalkyl-1,2-dihydropyrimidines in moderate to
RF
CH2=CHOC2H5/NH3
N
CH2=CHOC2H5
RFCF2CH2CHO
RFCF2I
Na2S2O4/NaHCO3
N
H
1
3
2
Scheme 2.

X.-J. Yang et al. / Tetrahedron 63 (2007) 5643–5648
Table 4. The reaction of 3 with ammonia and carbonyl compoundsa
5645
and no desired product was isolated, probably due to the
strong angle tension of compound 4f.
Entry
3
Carbonyl compound
Product
Yieldb (%)
1
2
3
4
5
6
7
8
3c
3a
3c
3a
3b
3a
3a
3a
3a
3a
3a
3b
5a (CH3CHO)
5a (CH3CHO)
5b (C3H7CHO)
5b (C3H7CHO)
5b (C3H7CHO)
5c ((CH3)2CHCHO)
5d (CH3COCH3)
5e (CH3COC2H5)
5f (CH3COC3H7)
5g (PhCOCH3)
5h
2c
2a
2d
2e
2j
2k
2f
2l
2m
2n
2h
2i
63
74
61
64
63
65
75
63
62
10
77
77
RF
ZnCl2
N
+
+
+
+
R1CH=C(R2)OSiMe3
RFCF2CH2CHO
NH3
R2
R1
N
H
3a-c
4a-d
2c-g
9
OSiMe3
RF
10
11
12
N
ZnCl2
+
RFCF2CH2CHO
NH3
5h
N
H
a
Reaction conditions: 3 (1 mmol), 5 (1.5 mmol), ZnCl2 (1 mmol), and
excess ammonia in THF (20 mL) at 50 ꢀC.
Isolated yields based on 3.
3a,b
4e
2h,i
b
OSiMe3
RF
N
complicated and no desired product or very low yield was
obtained (Table 4, entry 10).
RFCF2CH2CHO
+
NH3
N
H
3
4f
RF
Scheme 3.
O
ZnCl2
N
R1
R2
+
+
+
+
NH3
RFCF2CH2CHO
R1
R2
Table 3. The reaction of 3 with ammonia and trimethylsilyl enol ethera
N
H
Entry
3
R1CH]C(R2)OSiMe3
Product
Yieldb (%)
5a-g
3a-c
2
1
2
3
4
5
6
7
3c
3c
3a
3a
3b
3a
3b
4a (R1¼H, R2¼H)
4b (R1¼Et, R2¼H)
4b (R1¼Et, R2¼H)
4c (R1¼H, R2¼Me)
4d (R1¼Me, R2¼Me)
4e
2c
2d
2e
2f
2g
2h
2i
59
54
61
70
45
70
71
O
RF
N
ZnCl2
RFCF2CH2CHO
NH3
N
H
3a,b
2h,i
5h
4e
Scheme 4.
a
Reaction conditions: 3 (1 mmol), 4 (1.5 mmol), ZnCl2 (1 mmol), and
excess ammonia in THF (20 mL) at 50 ꢀC.
Isolated yields based on 3.
b
A possible mechanism was proposed for the reaction of 3
with 5 and ammonia as shown in Scheme 5. The reaction
of 3 with ammonia gave intermediate A. Under basic condi-
tions A underwent hydrolyzation to give intermediate B,
which reacted further with ammonia to afford intermediate
C. Subsequent condensation of C and 5 followed by the ad-
dition of NH to C]N double bond resulted in the formation
of the final product. As a proof, the key intermediate, 4-
amino-1,1,1-trifluoro-3-buten-2-one (6) was isolated from
the reaction of 3c and ammonia. Furthermore, 6 was allowed
to react with 5a and ammonia in the presence of ZnCl2 under
similar conditions and 2c was obtained in moderate yield
(Scheme 6). The precise role of ZnCl2 in this reaction was
not very clear. It was tentatively believed that it activated
the reaction substrate by coordination with oxygen atom
Considering the similarity of carbonyl compounds and their
corresponding trimethylsilyl enol ethers in chemical proper-
ties, reactions of 3 with ammonia and aldehydes or ketones
in the presence of zinc chloride were investigated next. As
shown in Table 4, both aliphatic aldehydes and ketones
reacted readily with 3 and ammonia to give the desired prod-
ucts in good yields, providing a more convenient method to
synthesize these fluorine-containing 1,2-dihydropyrim-
idines. Again the reaction of cyclohexanone (5h) with 3
and ammonia gave the corresponding spiral products in
good yields and no desired product was obtained in the
case of cyclopentanone (Scheme 4). The reaction of aro-
matic aldehydes or ketones under similar conditions was
H2O
- 2HF
NH3
NH3
RFCF2CH2CHO
RF
NH2
RF
NH2
F
O
F
3
A
B
RF
R1COR2
N
RF
N
RF
NH2
R1
R2
N:
R1
NH
N
H
H
R2
C
2
Scheme 5.

5646
X.-J. Yang et al. / Tetrahedron 63 (2007) 5643–5648
CF3
Dehydrogenation of these fluorine-containing 1,2-dihydro-
pyrimidines with tetrachloro-1,4-benzoquinone (TCBQ) or
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room
temperature afforded perfluoroalkylated pyrimidines.
NH2
O
ZnCl2/ THF
N
CH CHO
+
+
NH3
3
CF3
N
H
6
2c
Scheme 6.
4. Experimental section
4.1. General experimental methods
and the coordination of zinc ion with both oxygen of car-
bonyl group and ammonia facilitated the formation of inter-
mediate C. Other Lewis acids such as FeCl3, AlCl3, and
BF3$Et2O were also tried in the reaction, only BF3$Et2O
gave comparable yield (Table 5).
Melting points were uncorrected. IR spectra were taken on
a Perkin–Elmer Jeol 983 spectrophotometer. 1H NMR spec-
tra were recorded on a Bruker AM300 (300 MHz) spectro-
meter with TMS as internal standard. 19F NMR spectra
were recorded on a Bruker AM300 (282 MHz) spectrometer
with CFCl3 as external standard. Mass spectra were taken on
an HP 5989A spectrometer. High-resolution mass data were
obtained on a Finnigan MAT 8430 spectrometer. Column
chromatography was performed using silica gel H, particle
size 10–40 mm.
Table 5. The effect of Lewis acids on the reactiona
Entry
3
5
Lewis acid
Products
Yieldb (%)
1
2
3
4
5
3a
3a
3a
3a
3a
5b
5b
5b
5b
5b
—
2e
2e
2e
2e
2e
31
64
33
37
57
ZnCl2
AlCl3
FeCl3
BF3$Et2O
4.2. The reaction of 1 with ethyl vinyl ether and
ammonia
a
Reaction conditions: 3 (1 mmol), 5 (1.5 mmol), Lewis acid (1 mmol), and
excess ammonia in THF (20 mL) at 50 ꢀC.
Isolated yields based on 3.
To a mixture of 1 (10 mmol), ethyl vinyl ether (15 mmol),
acetonitrile (25 mL), and water (25 mL), was added a mix-
ture of sodium dithionite (9 mmol) and sodium dicarbonate
(8 mmol) in portion under stirring at 0 ꢀC. After addition the
mixture was stirred at 0 ꢀC for 10 min. Aqueous ammonia
solution (25%, 5 mL) was added and the resulting mixture
was stirred for 2 h at room temperature and 2 h at 50 ꢀC.
After the reaction was complete (monitored by 19F NMR),
the mixture was extracted with ethyl acetate (3ꢁ30 mL),
the combined organic layer was washed with water and dried
over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the crude product was purified by
column chromatography (ethyl acetate and petroleum ether)
to give compound 2.
b
Compound 2 was very easy to be converted into the cor-
responding pyrimidine. Taking 2e and 2j as examples,
treatment of 2e and 2j with tetrachloro-1,4-benzoquinone
(TCBQ) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) at room temperature for 24 h gave perfluoroalkylated
pyrimidines 7 in good yields. The results are summarized
in Table 6.
Table 6. Dehydrogenation of 2 with TCBQ or DDQa
RF
RF
4.2.1. 2-Methyl-4-heptafluoropropyl-1,2-dihydropyrim-
idine (2a). White solid, mp: 79–81 ꢀC. IR (KBr): 3153,
3018, 2946, 2857, 1613, 1545, 1495, 1354, 1287, 1221,
N
N
N
H
C3H7
N
C3H7
1
1186, 1118 cmꢂ1. H NMR (CDCl3): d 6.92 (1H, d, J¼
2e,j
7e,j
6.6 Hz), 5.39 (1H, d, J¼6.6 Hz), 4.92 (1H, q, J¼6.3 Hz),
4.20 (1H, br s), 1.58 (3H, d, J¼6.3 Hz). 19F NMR (CDCl3):
d ꢂ80.7 (3F, m), ꢂ117.7 (2F, m), ꢂ127.1 (2F, m). EIMS
(m/z, %): 265 (M++1, 2), 264 (M+, 13), 249 (M+ꢂCH3,
100), 69 (CF+3, 36). Anal. Calcd for C8H7F7N2: C, 36.37; H,
2.67; N, 10.60. Found: C, 36.51; H, 2.87; N, 10.38.
Entry
2
Reagent
Condition
Product
Yieldb (%)
1
2
3
4
2e
2j
2e
2j
TCBQ
TCBQ
DDQ
MeCN, rt, 24 h
MeCN, rt, 24 h
CH2Cl2, rt, 24 h
CH2Cl2, rt, 24 h
7e
7j
7e
7j
78
83
85
82
DDQ
a
Reaction conditions: 2 (10 mmol), TCBQ or DDQ (15 mmol), and solvent
(50 mL) at room temperature.
Isolated yields based on 2.
4.2.2. 2-Methyl-4-(3-chloro-1,1,2,2,3,3-hexafluoro-
propyl)-1,2-dihydropyrimidine (2b). Colorless oil. IR
(film): 3148, 3016, 2942, 2844, 1612, 1544, 1495, 1133,
b
1120 cmꢂ1. H NMR (CDCl3): d 6.92 (1H, d, J¼6.3 Hz),
1
3. Conclusions
5.39 (1H, d, J¼6.3 Hz), 4.90 (1H, q, J¼6.0 Hz), 3.62 (1H,
br s), 1.57 (3H, d, J¼6.3 Hz). 19F NMR (CDCl3): d ꢂ67.3
(2F, m), ꢂ115.1 (2F, m), ꢂ121.1 (2F, m). EIMS (m/z, %):
280 (M+, 12), 265 (M+ꢂMe, 100). Anal. Calcd for
C8H7ClF6N2: C, 34.24; H, 2.51; N, 9.98. Found: C, 34.47;
H, 2.54; N, 10.04.
In summary, a convenient method has been developed for the
synthesis of perfluoroalkylated 1,2-dihydropyrimidines and
pyrimidines. In the presence of zinc chloride, a series of
carbonyl compounds and enol ethers reacted readily with
2,2-dihydropolyfluoroalkylaldehydes and ammonia under
mild conditions to give the corresponding perfluoroalkylated
1,2-dihydropyrimidines in moderate to good yields.
4.2.3. 2-Methyl-4-trifluoromethyl-1,2-dihydropyrim-
idine (2c). White solid, mp: 59–61 ꢀC. IR (KBr): 3149,

X.-J. Yang et al. / Tetrahedron 63 (2007) 5643–5648
5647
3020, 2983, 2955, 1615, 1546, 1501, 1448, 1388, 1350,
1H NMR (CDCl3): d 6.75 (1H, d, J¼5.7 Hz), 5.13 (1H, d,
J¼5.7 Hz), 4.20 (1H, br s), 1.95–1.61(2H, m), 1.38 (3H,
s), 0.92 (3H, t, J¼6.3 Hz). 19F NMR (CDCl3): d ꢂ67.4
(2F, m), ꢂ116.8 (2F, m), ꢂ121.2 (2F, m). EIMS (m/z, %):
308 (M+, 2), 293 (M+ꢂMe, 13), 279 (M+ꢂEt, 100). Anal.
Calcd for C10H11ClF6N2: C, 38.91; H, 3.59; N, 9.08. Found:
C, 38.74; H, 3.42; N, 8.99.
1
1313, 1222, 1193, 1133, 1094, 1069, 742 cmꢂ1. H NMR
(CDCl3): d 6.93 (1H, d, J¼6.6 Hz), 5.37 (1H, d, J¼
6.6 Hz), 4.82 (1H, q, J¼6.0 Hz), 3.62 (1H, br s), 1.57 (3H,
d, J¼6.0 Hz). 19F NMR (CDCl3): d ꢂ71.8 (3F, m). EIMS
(m/z, %): 164 (M+, 22), 149 (M+ꢂMe, 100). Anal. Calcd
for C6H7F3N2: C, 43.91; H, 4.30; F, 34.73; N, 17.07. Found:
C, 43.95; H, 4.32; F, 34.78; N, 17.01.
4.3.5. 2-Heptafluoropropyl-1,5-diazaspiro[5.5]undeca-
1,3-diene (2h). White solid, mp: 71–73 ꢀC. IR (KBr):
3277, 2942, 1628, 1535, 1352, 1247, 1197, 1116, 892,
4.3. The reaction of 3 with ammonia and ethyl vinyl
ether
1
737 cmꢂ1. H NMR (CDCl3): d 6.79 (1H, d, J¼5.4 Hz),
A mixture of 3 (1 mmol) and ZnCl2 (1 mmol) in THF
(10 mL) was stirred under ammonia atmosphere for 2 h at
room temperature. Then a solution of ethyl vinyl ether
(1.5 mmol) in THF (10 mL) was added dropwise. The result-
ing mixture was stirred at 50 ꢀC under ammonia atmosphere
for a few hours (monitored by 19F NMR). After cooling,
20 mL water was added and the solution was extracted
with ethyl acetate (3ꢁ10 mL). The combined organic layer
was washed with water and dried over anhydrous Na2SO4.
After removal of solvent, the crude product was purified
by column chromatography (ethyl acetate and petroleum
ether) to give 2.
5.21 (1H, d, J¼5.4 Hz), 1.80–1.40 (10H, m). 19F NMR
(CDCl3): d ꢂ80.6 (3F, m), ꢂ118.1 (2F, m), ꢂ127.1 (2F,
m). EIMS (m/z, %): 318 (M+, 17), 275 (100). Anal. Calcd
for C12H13F7N2: C, 45.29; H, 4.12; N, 8.80. Found: C,
45.28; H, 4.05; N, 8.64.
4.3.6. 2-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-1,5-di-
azaspiro[5.5]undeca-1,3-diene (2i). White solid, mp: 70–
72 ꢀC. IR (KBr): 3223, 2940, 1625, 1537, 1496, 1305,
1198, 1125, 812 cmꢂ1. 1H NMR (CDCl3): d 6.73 (1H, d, J¼
5.4 Hz), 5.21 (1H, d, J¼5.4 Hz), 1.90–1.40 (10H, m). 19F
NMR (CDCl3): d ꢂ67.3 (2F, m), ꢂ116.8 (2F, m), ꢂ121.2
(2F, m). EIMS (m/z, %): 336 (M++2, 7), 334 (M+, 21), 275
(100). Anal. Calcd for C12H13ClF6N2: C, 43.06; H, 3.92;
N, 8.37. Found: C, 42.93; H, 4.08; N, 7.99. ESI-HR calcd
for C12H13N2ClF6Na+: 357.0563. Found: 357.0564.
The procedure for the reaction of 3 with ammonia and 4 or
5 was similar to the above one.
4.3.1. 2-Propyl-4-trifluoromethyl-1,2-dihydropyrimidine
(2d). Colorless oil. IR (film): 3207, 3039, 2964, 1629, 1542,
1467, 1325, 1191, 1142, 1095, 744 cmꢂ1. 1H NMR (CDCl3):
d 6.92 (1H, d, J¼6.6 Hz), 5.34 (1H, d, J¼6.6 Hz), 4.71 (1H,
t, J¼5.1 Hz), 4.55 (1H, br s), 1.86–1.81 (2H, m), 1.51–1.42
(2H, m), 0.96 (3H, t, J¼6.2 Hz). 19F NMR (CDCl3): d ꢂ71.7
(3F, m). EIMS (m/z, %): 192 (M+, 5), 149 (M+ꢂPr, 100), 123
(M+ꢂCF3, 2). Anal. Calcd for C8H11F3N2: C, 50.00; H, 5.77;
F, 29.66; N, 14.58. Found: C, 50.17; H, 5.88; F, 28.67; N,
14.18.
4.3.7. 2-Propyl-4-(3-chloro-1,1,2,2,3,3-hexafluoro-
propyl)-1,2-dihydropyrimidine (2j). White solid, mp:
45–47 ꢀC. IR (KBr): 3217, 2966, 1626, 1572, 1539, 1467,
1309, 1184, 1126, 990, 837 cmꢂ1 1H NMR (CDCl3):
.
d 6.89 (1H, d, J¼6.6 Hz), 5.32 (1H, d, J¼6.6 Hz), 4.79 (1H,
t, J¼6.3 Hz), 1.87–1.80 (2H, m), 1.50–1.43 (2H, m), 0.96
(3H, t, J¼6.2 Hz). 19F NMR (CDCl3): d ꢂ67.4 (2F, m),
ꢂ116.2 (2F, m), ꢂ121.2 (2F, m). EIMS (m/z, %): 309
(M++1, 15), 308 (M+, 8), 265 (M+ꢂC3H7, 100). Anal. Calcd
for C10H11ClF6N2: C, 38.91; H, 3.59; N, 9.08. Found: C,
39.20; H, 3.56; N, 8.91.
4.3.2. 2-Propyl-4-heptafluoropropyl-1,2-dihydropyrim-
idine (2e). White solid, mp: 44–46 ꢀC. IR (KBr): 3218,
2966, 1626, 1572, 1537, 1462, 1302, 1181, 1128, 837 cmꢂ1
.
4.3.8. 2-iso-Propyl-4-heptafluoropropyl-1,2-dihydropyr-
imidine (2k). White solid, mp: 50–52 ꢀC. IR (KBr): 3215,
1H NMR (CDCl3): d 6.89 (1H, d, J¼6.6 Hz), 5.34 (1H, d,
J¼6.6 Hz), 4.80 (1H, t, J¼6.3 Hz), 4.50–4.00 (1H, br s),
1.91–1.80 (2H, m), 1.52–1.44 (2H, m), 0.98 (3H, t,
J¼6.3 Hz). 19F NMR (CDCl3): d ꢂ80.7 (3F, m), ꢂ117.8
(2F, m), ꢂ127.1 (2F, m). EIMS (m/z, %): 292 (M+, 2), 249
(M+ꢂC3H7, 100). Anal. Calcd for C10H11F7N2: C, 41.11;
H, 3.79; N, 9.59. Found: C, 41.18; H, 3.84; N, 9.44.
1
2941, 1628, 1547, 1501, 1353, 1182, 1121 cmꢂ1. H NMR
(CDCl3): d 6.91 (1H, d, J¼6.3 Hz), 5.31 (1H, d, J¼
6.3 Hz), 4.54 (1H, d, J¼5.7 Hz), 2.24–2.18 (1H, m), 1.04–
0.99 (6H, m). 19F NMR (CDCl3): d ꢂ80.4 (3F, m), ꢂ116.7
(2F, m), ꢂ127.1 (2F, m). EIMS (m/z, %): 292 (M+, 4), 275
(100), 249 (M+ꢂC3H7, 38). Anal. Calcd for C10H11F7N2:
C, 41.11; H, 3.79; N, 9.59. Found: C, 40.98; H, 3.85; N, 9.19.
4.3.3. 2,2-Dimethyl-4-heptafluoropropyl-1,2-dihydropyr-
imidine (2f). White solid, mp: 64–66 ꢀC. IR (KBr): 3217,
4.3.9. 2-Methyl-2-ethyl-4-heptafluoropropyl-1,2-dihy-
dropyrimidine (2l). Colorless oil. IR (film): 3260, 2980,
1
1628, 1548, 1504, 1353, 1182, 1121, 900, 735 cmꢂ1. H
1
NMR (CDCl3): d 6.79 (1H, d, J¼6.3 Hz), 5.22 (1H, d,
J¼6.3 Hz), 4.30–3.90 (1H, br s), 1.46 (6H, s). 19F NMR
(CDCl3): d ꢂ80.7 (3F, m), ꢂ118.6 (2F, m), ꢂ127.3 (2F,
m). EIMS (m/z, %): 278 (M+, 9), 263 (M+ꢂCH3, 100), 144
(13). Anal. Calcd for C9H9F7N2: C, 38.68; H, 3.26; N,
10.07. Found: C, 38.74; H, 3.37; N, 9.91.
1632, 1542, 1230, 1184, 1120 cmꢂ1. H NMR (CDCl3):
d 6.75 (1H, d, J¼5.7 Hz), 5.13 (1H, d, J¼5.7 Hz), 4.20
(1H, br s), 1.95–1.61 (2H, m), 1.38 (3H, s), 0.92 (3H, t,
J¼6.2 Hz). 19F NMR (CDCl3): d ꢂ80.6 (3F, m), ꢂ118.1 (2F,
m), ꢂ127.7 (2F, m). EIMS (m/z, %): 277 (M+ꢂMe, 24), 265
(M+ꢂEt, 100). Anal. Calcd for C10H11F7N2: C, 41.10; H,
3.79; N, 9.58. Found: C, 40.97; H, 3.73; N, 9.46.
4.3.4. 2-Methyl-2-ethyl-4-(3-chloro-1,1,2,2,3,3-hexafluoro-
propyl)-1,2-dihydropyrimidine (2g). Colorless oil. IR
4.3.10. 2-Methyl-2-propyl-4-heptafluoropropyl-1,2-di-
hydropyrimidine (2m). White solid, mp: 48–50 ꢀC. IR
(film): 3264, 2978, 1631, 1542, 1184, 1125, 840, 811 cmꢂ1
.

5648
X.-J. Yang et al. / Tetrahedron 63 (2007) 5643–5648
(KBr): 3238, 3075, 2962, 1624, 1542, 1351, 1231, 1118,
895, 753 cmꢂ1 1H NMR (CDCl3): d 6.75 (1H, d,
d, J¼4.8 Hz), 7.50 (1H, d, J¼4.8 Hz), 2.72 (2H, t,
J¼7.5 Hz), 1.61–1.52 (2H, m), 0.69 (3H, t, J¼7.5 Hz). 19F
NMR (CDCl3): d ꢂ66.8 (2F, m), ꢂ115.3 (2F, m), ꢂ121.4
(2F, m).
.
J¼5.7 Hz), 5.13 (1H, d, J¼5.7 Hz), 4.12 (1H, br s), 1.89–
0.91 (10H, m). 19F NMR (CDCl3): d ꢂ80.7 (3F, m),
ꢂ117.1 (2F, m), ꢂ127.1 (2F, m). EIMS (m/z, %): 306 (M+,
2), 291 (M+ꢂCH3, 13), 263 (M+ꢂC3H7, 100). Anal. Calcd
for C11H13F7N2: C, 43.14; H, 4.27; N, 9.14. Found: C,
42.86; H, 4.27; N, 9.03.
Acknowledgements
The authors thank the National Natural Science Foundation
of China for financial support (Nos. 20572124 and
20172065).
4.3.11. 2-Methyl-2-phenyl-4-heptafluoropropyl-1,2-dihy-
dropyrimidine (2n). Oil. IR (film): 3398, 3284, 1627, 1537,
1351, 1230, 1120, 935, 765 cmꢂ1 1H NMR (CDCl3):
.
References and notes
d 7.27–7.55 (5H, m), 6.92 (1H, d, J¼6.9 Hz), 5.33 (1H, d,
J¼6.9 Hz), 1.81 (3H, s). 19F NMR (CDCl3): d ꢂ79.7 (3F,
m), ꢂ116.4 (2F, m), ꢂ125.9 (2F, m). EIMS (m/z, %): 340
(M+, 2), 325 (M+ꢂMe, 100). EI-HR calcd for C13H8F7N2:
325.0576. Found: 325.0560.
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structure of 2a in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 233537. Copies of the data can be
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4.4. The isolation of 69
A mixture of 3c (1 mmol) and ZnCl2 (1 mmol) in THF
(10 mL) was stirred under ammonia atmosphere at 50 ꢀC
for 2 h. After cooling, 20 mL water was added and the solu-
tion was extracted with ethyl acetate (3ꢁ10 mL), the com-
bined organic layer was washed with water and dried over
anhydrous Na2SO4. After removal of solvent, the crude
product was purified by column chromatography to give
compound 6. 1H NMR (CDCl3) d: 9.49 (1H, br), 7.30–7.20
(1H, m), 6.27 (1H, br), 5.45 (1H, d, J¼7.2 Hz). 19F NMR
(CDCl3) d: ꢂ77.9 (s).
4.5. The reaction of 6 with ammonia and 5a
A mixture of 6 (1 mmol) and ZnCl2 (1 mmol) in THF
(10 mL) was stirred under ammonia atmosphere for 2 h at
room temperature. Then a solution of 5a (1.5 mmol) in
THF (10 mL) was added dropwise. The resulting mixture
was stirred at 50 ꢀC under ammonia atmosphere for a few
hours (monitored by 19F NMR). After cooling, 20 mL
water was added and the solution was extracted with ethyl
acetate (3ꢁ10 mL). The combined organic layer was
washed with water and dried over anhydrous Na2SO4. After
removal of solvent, the crude product was purified by
column chromatography (ethyl acetate and petroleum
ether) to give 2c.
4.6. The preparation of 7
A mixture of 2 (10 mmol) and DDQ or TCBQ (15 mmol) in
CH2Cl2 or acetonitrile (50 mL) was stirred at room temper-
ature for 24 h. After removal of solvent, the crude product
was purified by column chromatography to give 7.
4.6.1. 2-Propyl-4-heptafluoropropylpyrimidine (7e).10 Oil.
1H NMR (CDCl3): d 8.67 (1H, d, J¼4.8 Hz), 7.25 (1H, d,
J¼4.8 Hz), 2.74 (2H, t, J¼7.5 Hz), 1.60–1.53 (2H, m,
CH2), 0.69 (3H, t, J¼7.5 Hz). 19F NMR (CDCl3): d ꢂ81.2
(3F, m), ꢂ117.4 (2F, m), ꢂ127.4 (2F, m).
4.6.2. 2-Propyl-4-(3-chloro-1,1,2,2,3,3-hexafluoropro-
1
pyl)pyrimidine (7j).9 Oil. H NMR (CDCl3): d 8.91 (1H,