A convenient synthesis of 3-polyfluoroalkyl pyrazoles and 6-polyfluoroalkyl pyrimidines from β-polyfluoroalkyl enaminones

Article abstract of DOI:10.1016/S0022-1139(97)00027-4

3-Polyfluoroalkyl pyrazoles and 6-polyfluoroalkyl pyrimidines can be easily synthesized from the reactions of hydrazine monohydrate or amidine respectively with β-polyfluoroalkyl enaminones which are prepared by the nucleophilic substitution of the anion of a methyl ketone with N-aryl polyfluoroalkyl imidoyl iodides.

Full text of DOI:10.1016/S0022-1139(97)00027-4

Journal of Fluorine Chemistry 84 (1997) 65–67
A convenient synthesis of 3-polyfluoroalkyl pyrazoles and
6-polyfluoroalkyl pyrimidines from b-polyfluoroalkyl enaminones
Hong-Bin Yu, Wei-Yuan Huang U
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 4 December 1996; accepted 27 February 1997
Abstract
3-Polyfluoroalkyl pyrazoles and 6-polyfluoroalkyl pyrimidines can be easily synthesized from the reactions of hydrazine monohydrate or
amidine respectively with b-polyfluoroalkyl enaminones which are prepared by the nucleophilic substitution of the anion of a methyl ketone
with N-aryl polyfluoroalkyl imidoyl iodides. q 1997 Elsevier Science S.A.
Keywords: Polyfluoroalkyl enaminone; Pyrazole; Pyrimidine; Imidoyl iodide
1. Introduction
Fluorinated heterocyclic compounds have attracted much
attention because of their unique biological andphysiological
activities [1]. Among them, fluorinated pyrazoles [2] and
Scheme 1.
pyrimidines [3] have been shown to possess high biological
fluoroalkyl pyrimidines (7) in good yields under the amine–
aniline exchange.
activities as herbicides, fungicides, insecticides, analgesics,
antipyretics and anti-inflammatories. Therefore, develop-
ment of new methodologies for the synthesis of fluorinated
pyrazoles and pyrimidines has attracted growing interest.
These methods include the synthesis of ring-fluorinatedcom-
pounds [4] and of pyrazoles [5] or pyrimidines [6] with a
perfluoroalkyl group. On the other hand, enaminones are
established as synthetic intermediates, particularly in heter-
ocyclic chemistry [7]. Because the most general method for
the synthesis of enaminones is the reaction betweenammonia
or a primary or secondary amine and a 1,3-diketone or 3-
keto-ester [8], there are not many reports on their use as b-
dicarbonyl equivalents for the synthesis of heterocycles
[9,10]. These researches are based on an unusual amine
group exchange of tertiary enaminones with hydroxylamine
or amidines. However, the amine exchange of aryl enami-
nones has not been reported so far. In addition, the research
on b-polyfluoroalkyl enaminone derivatives (3) is also lim-
ited in the literature. Herein we describe a convenient syn-
thetic route using b-polyfluoroalkyl enaminones (3) for the
production of 3-polyfluoroalkyl pyrazoles (4) and 6-poly-
The b-polyfluoroalkyl enaminones (3) were prepared by
nucleophilic substitution of N-aryl polyfluoroalkyl imidoyl
iodides [11] with the carbanion of an a-methyl ketone
(Scheme 1 and Table 1). The reaction was completed during
15 min with sodium hydride as a base in dried DMF or THF
at room temperature under nitrogen. The mixture wasworked
up to give product 3, which existed as the enaminone rather
than the imine structure presumably because of the thermo-
dynamic stability of the b-amino a,b-unsaturated ketone
moiety [12]. For entries 8 and 9, the yields were not satis-
factory because of the deterioration of compound 1. A lower
temperature only prolonged the reaction time and did not
improve the yields.
Treatment of 3 with an excess of hydrazine monohydrate
at 60 8C in ethanol proceeded smoothly to affordtwoproducts
4 and 5 (Scheme 2 and Table 1). Spectral data of 4 indicated
the absence of arylamino-group and there is a single peak of
one proton at 6.5–6.9 ppm. It was identified as a 3-polyfluo-
1
roalkyl 5-substituted pyrazole by H NMR, 13C NMR, 19F
NMR, MS, IR and elemental analyses. Product 5 was shown
to be p-toluidine (5a) or p-anisidine (5b).
U Corresponding author. E-mail: wyhuang@pub.sioc.ac.cn
0022-1139/97/$17.00 q 1997 Elsevier Science S.A. All rights reserved
PII S0022-1139(97)00027-4

66
H.-B. Yu, W.-Y. Huang / Journal of Fluorine Chemistry 84 (1997) 65–67
Table 1
Synthesis of b-polyfluoroalkyl enaminones and their conversion into 3-polyfluoroalkyl 5-substituted pyrazoles
Entry
Ar, n, X, 1
R, 2
Solvent
3, yield (%)a
4, yield (%)a
1
2
3
4
5
6
7
8
9
p-CH3C6H4, 2, Cl, 1a
p-CH3OC6H4, 2, Cl, 1b
p-CH3OC6H4, 4, Cl, 1c
p-CH3OC6H4, 1, F, 1d
p-CH3OC6H4, 2, Cl, 1b
p-CH3OC6H4, 4, Cl, 1c
p-CH3OC6H4, 1, F, 1d
p-CH3OC6H4, 2, Cl, 1b
p-CH3OC6H4, 2, Cl, 1b
Ph 2a
Ph 2a
Ph 2a
Ph 2a
2-furan 2b
2-furan 2b
2-furan 2b
t-Bu 2c
CH3 2d
THF
THF
THF
THF
THF
THF
THF
DMF
DMF
3aa 67
3ba 77
3ca 68
3da 72
3bb 56
3cb 64
3db 73
3bc 42
3bd 11
4a 93
4a 95
4b 86
4c 90
4d 79
4e 50
4f 72
4g 71
4h 72
aIsolated yields.
Scheme 2.
Table 2
ethanol or THF did not give satisfactory results. Thus, the b-
polyfluoroalkyl enaminones served as b-dicarbonyl equiva-
lents, the bifunctional N-nucleophile attacked theb-polyfluo-
roalkyl enaminones on the carbonyl carbon followed by ring
closure with the cleavage of one molecule of aryl amine. The
reaction was mild and clean and the yield was satisfactory. It
provides a new usage of b-polyfluoroalkyl enaminones in the
synthesis of polyfluoroalkyl pyrazoles or pyrimidines.
Synthesis of 6-polyfluoroalkyl pyrimidines from b-polyfluoroalkyl
enaminones
Entry
Enaminone 3
Amidine 6
Reaction time
(h)
7, yield
(%)a
1
2
3
4
5
6
7
8
9
3ba
3ca
3da
3ba
3ca
3da
3bb
3cb
3db
3bb
3cb
3db
R9'Ph 6a
R9'Ph 6a
R9'Ph 6a
R9'CH3 6b
R9'CH3 6b
R9'CH3 6b
R9'Ph 6a
R9'Ph 6a
R9'Ph 6a
R9'CH3 6b
R9'CH3 6b
R9'CH3 6b
12
12
12
20
20
20
12
12
12
20
20
20
7a 90
7b 93
7c 96
7d 96
7e 94
7f 70
7g 98
7h 98
7i 80
7j 70
7k 84
7l 71
2. Typical experimental procedure
Preparation of 3ca. A flask fitted with a nitrogen inlet was
charged with acetophenone (528 mg, 4.4 mmol), sodium
hydride (176 mg, 60% dispersion in mineral oil, 4.4 mmol)
and 8 ml anhydrous THF. The mixture was stirred at room
temperature for 20 min. Then N-(p-methoxyphenyl) v-
chloro-octafluorobutyl imidoyl iodide [11] (1.98 g, 4.0
mmol) in 2 ml dry THF was added with a syringe during 2
min and the resulting mixture was stirred for 15 min. After
work-up in the usual way the crude product was purified by
flash column chromatography on silica gel (petroleum ether
(b.p. 60–90 8C):ethyl acetate 20:1) to give 3ca as yellow
crystals (1.33 g, 68%), m.p. 100–102 8C. 1H NMR (90 MHz,
CDCl3) 12.73 (br.s. 1H, NH), 8.05–6.85 (m, 9H, Ar–H),
6.40 (s, 1H, C_CH), 3.90 (s, 3H, CH3O) ppm; 19F NMR
(56.4 Hz, CDCl3, CFCl3 as the external standard) 67.1 (m,
10
11
12
All reactions were carried out at 80 8C.
aIsolated yields.
Furthermore, treatment of 3 with 1.5 equivalent of benza-
midine hydrochloride (6a) in the presence of 4.0 equivalents
of potassium carbonate in 1,4-dioxane resulted in the for-
mation of a 2-phenyl 4-substituted 6-polyfluoroalkyl pyrim-
idine in 80%–90% overall yields after 12 h (Scheme 2). For
acetamidine hydrochloride (6b), the reaction time was
longer and the yield was comparatively lower than for ben-
zamidine (Table 2). Dioxane was a good solvent whereas

H.-B. Yu, W.-Y. Huang / Journal of Fluorine Chemistry 84 (1997) 65–67
67
2F, CF2Cl), 107.4 (m, 2F, _CCF2), 119.1 (m, 4F, CF2CF2)
ppm; IR (n, cmy1) 2974, 2847, 1618, 1593, 1507, 1206,
1100–1140; MS 489 (Mqq2, 10.46), 487 (Mq, 30.27),
252 (Mq-Cl(CF2)4, 100.00); analysis calculated for
C20H14ClF8NO2 C 49.25, H 2.89, N 2.87, F 31.16; found C
49.28, H 2.80, N 2.73, F 31.18.
with a variety of substitution patterns from b-polyfluoroalkyl
enaminones and hydrazine monohydrate or amidines respec-
tively. This work broadened the utility of b-polyfluoroalkyl
enaminones in organic synthesis and provided a convenient
synthesis for fluoroalkyl heterocycles.
Preparation of 4d. Hydrazine monohydrate (30 mg, 0.62
mmol) was added to a solution of 3bb (100 mg, 0.26 mmol)
in ethanol (3 ml) and the mixture was heated to 60 8C for 2
h with stirring. The cold mixture was then extracted with
diethyl ether (20 ml=3) and the organic layer was washed
with brine followed by drying over Na2SO4. After removal
of the solvent underreducedpressure, theresiduewaspurified
by thin layer chromatography on silica gel (petroleum ether
(b.p. 60–90 8C):ethyl acetate 3:1) to give 4d as colorless
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1
crystals (55 mg, 93%) and 5b. 4d had m.p. 88–90 8C; H
NMR (90 MHz, CDCl3) 7.55 (s, 1H), 6.73–6.49 (m, 3H,
H-furan) ppm; 19F NMR (56.4 Hz, CDCl3, CFCl3 as the
external standard) 70.2 (s, 2F, CF2Cl), 108.8 (s, 2F, CF2)
ppm; 13C NMR (75.4 MHz, CDCl3) 141.95(t, Js29 Hz,
C3), 101.91 (s, C4) ppm; IR (n, cmy1) 3131, 2905, 1631,
1504, 1413, 1263, 1134; MS270(Mqq2, 31.10), 268(Mq,
86.10), 183 (Mq-CF2Cl, 100.00); analysis calculated for
C9H5ClF4N2O C 40.25, H 1.88, N 10.43, F 28.29; found C
40.20, H 1.83, N 10.40, F 28.20.
Preparation of 7a. Benzamidine hydrochloride (6a) (61
mg, 0.39 mmol) and K2CO3 (144 mg, 1.04 mmol) were
added to a stirred solution of 3ba (100 mg, 0.26 mmol) in
dioxane (3 ml). The mixture was stirred for 12 h at a tem-
perature of 80 8C. Then the cold mixture was washed with
saturated aqueous NH4Cl solution and extracted with diethyl
ether (20 ml=3). The organic extracts were dried over
Na2SO4 and evaporated in vacuo. The residue was purified
by flash column chromatography on silica gel (petroleum
ether (b.p. 60–90 8C):ethyl acetate 100:1) to give 7a as
colorless crystals (100 mg, 90%) and 5b. 7a had m.p. 122–
1
123 8C; H NMR (90 MHz, CDCl3) 8.68 (m, 2H, Ph-H),
8.38 (m, 2H, Ph-H), 7.95 (s, 1H, heterocyclic-H), 7.58 (m,
6H, Ph-H); 19F NMR (56.4 Hz, CDCl3, CFCl3 as external
standard) 68.2 (s, 2F, CF2Cl), 113.8 (s, 2F, CF2-ring) ppm;
IR (n, cmy1) 1587, 1572, 1548, 1382, 1367, 1164, 1151,
1087; MS 366(Mq, 100.00); analysis calculated for
C18H11ClF4N2 C 58.95, H 3.02, N 7.64, F 20.72; found C
59.06, H 3.06, N 7.52, F 20.25.
In conclusion, a convenient synthetic method has been
developed for the preparation of pyrazoles or pyrimidines