Synthesis of 5-polyfluoroalkyl-4-(p-tolyl-sulfonyl)pyrazoles and 4-polyfluoroalkyl-5-(p-tolylsulfonyl)pyrimidines from 1-dimethylamino-2-(p- tolylsulfonyl)-polyfluoro-1-alken-3-ones

Article abstract of DOI:10.1007/s10593-007-0140-8

1-Dimethylamino-2-(p-tolylsulfonyl)polyfluoro-1-alken-3-ones were obtained from hydrates of 3,3,3-trifluoro-1-(p-tolylsulfonyl)-2-propanone and 3,3,4,4,5,5-hexafluoro-1-(p-tolylsulfonyl)-2-pentanone under conditions of the Vilsmeier-Haack-Arnold reaction.

Full text of DOI:10.1007/s10593-007-0140-8

Chemistry of Heterocyclic Compounds, Vol. 43, No. 7, 2007
SYNTHESIS OF 5-POLYFLUOROALKYL-4-(p-TOLYL-
SULFONYL)PYRAZOLES AND 4-POLYFLUOROALKYL-
5-(p-TOLYLSULFONYL)PYRIMIDINES FROM
1-DIMETHYLAMINO-2-(p-TOLYLSULFONYL)-
POLYFLUORO-1-ALKEN-3-ONES
O. S. Kanishchev, Yu. P. Bandera, V. M. Timoshenko,
E. B. Rusanov, S. A. But, and Yu. G. Shermolovich
1-Dimethylamino-2-(p-tolylsulfonyl)polyfluoro-1-alken-3-ones were obtained from hydrates of
3,3,3-trifluoro-1-(p-tolylsulfonyl)-2-propanone and 3,3,4,4,5,5-hexafluoro-1-(p-tolylsulfonyl)-2-penta-
none under conditions of the Vilsmeier-Haack-Arnold reaction. The analogous reaction of
3,3-difluoro-1-(p-tolylsulfonyl)-2-propanone hydrate leads to 3-chloro-1-dimethylamino-4,4-difluoro-
2-(p-tolylsulfonyl)-1,3-butadiene. The feasibility of using 1-dimethylamino-2-(p-tolylsulfonyl)-
polyfluoro-1-alken-3-ones in reactions with nitrogen binucleophiles has been demonstrated for the
regioselective synthesis of pyrazoles and pyrimidines. The structure of 1-phenyl-4-(p-tolylsulfonyl)-
5-trifluoromethyl-1H-pyrazole was confirmed by X-ray diffraction structural analysis.
Keywords: 1-arylsulfonyl-1,1-dihydropolyfluoro-2-alkanone, enaminone, pyrazole, pyrimidine,
Vilsmeier-Haack-Arnold reaction, X-ray diffraction structural analysis.
Fluoropyrazoles and fluoropyrimidines display a variety of strong biological activities [1-5], which has
led to work to develop new methods for the synthesis of such heterocyclic compounds.
The synthetic approaches for the heterocyclic pyrazole system have been studied extensively. The most
common approach involves a reaction, in which the three-carbon fragment of a β-dicarbonyl compound or its
synthetic equivalent is condensed with the diatomic N–N fragment of hydrazine or its derivative. A problem
with this approach is the regioselectivity of the reaction using asymmetric starting compounds since a mixture of
N-substituted pyrazoles is formed in most cases [6]. The similar reaction of β-dicarbonyl compounds with a
binucleophile possessing an N–C–N fragment leads to the formation of pyrimidines and is also frequently used
for the design of these heterocycles [7].
In the present work, we studied the feasibility of using 1-dimethylamino-2-(p-tolylsulfonyl)-
polyfluoro-1-alken-3-ones 2a,b, which are the synthetic equivalents of a new type of β-dicarbonyl compounds,
namely, 1-arylsulfonyl-2-oxopolyfluoroalkanals 1a,b for the regioselective synthesis of fluoropyrazoles and
fluoropyrimidines. Monoenamines of various 1,3-dicarbonyl compounds (amide vinylogs) have found common
use in the synthesis of many heterocyclic systems [8].
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 01094 Kiev; Ukraine; e-mail:
sherm@bpci.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1052-1058,
July, 2007. Original article submitted October 13, 2006.
0009-3122/07/4307-0887©2007 Springer Science+Business Media, Inc.
887

O
O
SO Tol-
p
SO Tol-
2
p
2
RF
RF
H
O
H
NMe2
1a,b
2a,b
1, 2 a RF = H(CF2)3, b RF = CF3
Enaminones 2a,b were obtained by the Vilsmeier-Haack-Arnold reaction [9] from 1-arylsulfonyl-
1,1-dihydropolyfluoro-2-alkanone hydrates 3a,b [10]. This reaction proceeds at room temperature. The use of
ketosulfone hydrate 3c under analogous conditions leads to
a
mixture of reaction products.
HO OH
DMF / POCl3
SO Tol-
p
2
2a,b
RF
3a,b
3 a RF = H(CF2)3, b RF = CF3
OH
O
HO
HF2C
OH
p
p
SO2Tol-
NMe2
SO2Tol-
NMe2
Cl
SO Tol-
F2C
HF2C
p
2
3c
5
F
F
NMe2
p-TolSO2
4
Heating this mixture to 100°C permitted the isolation of aminodiene 4 as a pure product. Aminodiene 4 is
apparently formed as the result of the chlorination of the enolic form of intermediate keto sulfone 5.
Fig. 1. General view of a molecule of 6d. Selected bond lengths and angles: C(5)–N(1) 1.443(2),
N(1)–C(1) 1.352(2), N(1)–N(2) 1.356(2), N(2)–C(3) 1.371(3), S(1)–C(2) 1.757(2), S(1)–O(1) 1.4251(16),
S(1)–O(2) 1.4345(17), S(1)–C(11) 1.755(2) Å; C(5)N(1)C(1) 129.04(16),
C(5)N(1)N(2) 119.2(16), N(1)N(2)C(3) 105.33(17)°.
888

Pyrazoles 6a-g were obtained by adding the corresponding hydrazine to a solution of enaminone 2a,b in
acetonitrile. The reaction is complete in 2 h at room temperature. This reaction is conveniently monitored by
19F NMR spectroscopy of the reaction mixture and the spectra show signals only for one of the two possible
regioisomers 6. The structure of 6d was unequivocally demonstrated by X-ray diffraction structural analysis. A
general view of a molecule of 6d and the major bond lengths and angles are shown in Fig. 1. The central
pyrazole ring C(1)C(2)C(3)N(2)N(1) is virtually planar; the deviation from the mean square plane does not exceed
0.005 Å. Steric hindrance forces benzene rings C(5)–C(10) and C(11)–C(16) to be twisted almost orthogonally to the
central benzene ring; the corresponding dihedral angles are 80.68° and 74.48°.
O
SO Tol-
p
RNHNH2
2
RF
2a,b
RNH
N
H
7
OH
SO Tol-
RF
p
SO Tol-
p
2
2
RF
R
N
N
– H2O
R
N
N
H
6a–g
6 a RF = H(CF2)3, R = Ph, b RF = H(CF2)3, R = 2-ClC6H4, c RF = H(CF2)3, R = Me,
d RF = CF3, R = Ph, e RF = CF3, R = 2-ClC6H4, f RF = CF3, R = Me, g RF = H(CF2)3, R = H
The formation of only one regioisomer suggests that the first step features transamination of enaminone 2
with subsequent intramolecular nucleophilic attack of the carbonyl group carbon by the second nitrogen atom in
intermediate 7, leading to loss of a water molecule and formation of heterocycle 6 [11].
Pyrimidines 8a-c were obtained using salts of the corresponding amidines as the N–C–N fragment.
X
H2NC=NH
O
SO Tol-
p
2
RF
X
2a,b
HN
N
H
RF
N
RF
N
OH
SO Tol-
p
p
SO2Tol-
2
N
X
X
N
H
8a–c
8 a RF = H(CF2)3, X = NH2, b RF = CF3, X = NH2, c RF = H(CF2)3, X = Me
889

EXPERIMENTAL
1
The H, 19F, and 13C NMR spectra were taken on a Varian VXR-300 spectrometer at 300, 282, and
1
75 MHz, respectively, for solutions in CDCl3 (2a,b, 4, and 6a-g) and in DMSO-d6 (8a-c) with TMS (for the H
and 13C NMR spectra) and C6F6 (δ = -162.9 ppm relative to CCl3F for the 19F NMR spectra) as the internal
standard. The mass spectra were taken on an Agilent 1100 Series mass spectrometer equipped with an
Agilent LC\MSD SL dimonomatrix and mass-selective detector. Atmospheric pressure chemical ionization
(APCI) was used. The IR spectra were taken on a UR-20 spectrometer. Silica gel 60A 70-230 was used for the
column chromatography. All the solvents were initially dried and distilled according to standard procedures.
Enaminones 2a,b. (General Method). A sample of DMF (6 ml) was added to POCl3 (2.8 ml,
30 mmol) and the complex was stirred for 1 h. Then, a solution of keto sulfone hydrate 3a,b (5 mmol) in DMF
(6 ml) was added, stirred for 2 h at 20°C, and poured onto ice. The crystalline precipitate was filtered off,
washed with water, and dried. The resultant enaminones were used in the subsequent syntheses without further
purification. Analytical samples were obtained by crystallization.
1-Dimethylamino-4,4,5,5,6,6-hexafluoro-2-(p-tolylsulfonyl)hex-1-en-3-one (2a) was obtained in 88%
yield; mp 118-120°C (1:4 hexane–ether). IR spectrum (neat), ν, cm-1: 1610 (C=C), 1660 (C=O). 1H NMR
3
2
spectrum, δ, ppm (J, Hz): 8.26 (1H, s, CH=N); 7.28 and 7.75 (4H, dd, JHH= 8.0, C6H4); 6.16 (1H, tt, JHF = 53.0,
3JHF = 6.0, HCF2); 3.44 (3H, s, NCH3); 3.04 (3H, s, NCH3); 2.42 (3H, s, CH3). 19F NMR spectrum, δ, ppm (J, Hz):
-118.14 (2F, m, CF2); -133.56 (2F, m, CF2); -133.42 (2F, dm, JFH = 53.0, HCF2). Mass spectrum, m/z: 404 [M]+.
Found, %: C 44.53; H 3.74; N 3.77; S, 8.07. C15H15F6NO3S. Calculated, %: C 44.67; H 3.75; N 3.47; S 7.95.
1-Dimethylamino-4,4,4-trifluoro-3-(p-tolylsulfonyl)but-1-en-3-one (2b) was obtained in 82% yield;
1
mp 155-157°C (methanol). H NMR spectrum, δ, ppm (J, Hz): 8.16 (1H, s, CH=N); 7.25 and 7.73 (4H, dd,
3JHH = 8.0, C6H4); 3.42 (3H, s, NCH3); 2.92 (3H, s, NCH3); 2.40 (3H, s, CH3). 19F NMR spectrum, δ, ppm: -73.04 (s,
CF3).
3-Chloro-1-dimethylamino-4,4-difluoro-2-(p-tolylsulfonyl)-1,3-butadiene (4). A sample of POCl3
(2.8 ml, 30 mmol) was added to DMF (6 ml) and the complex was stirred for 1 h. Then, a solution of
ketosulfone hydrate 3c (1.24 g) in DMF (6 ml) was added, maintained for 2 h at 100°C, cooled, and poured onto
ice. The crystalline precipitate was filtered off, washed with water, and dried to give 4 in 75% yield;
mp 114-116°C (9:1 hexane–ether). 1NMR spectrum, δ, ppm (J, Hz): 7.51 (1H, s, CH=N); 7.26 and 7.72 (4H, dd,
3JHH = 8.0, C6H4); 3.09 (6H, s, N(CH3)2); 2.41 (3H, s, CH3). 19F NMR spectrum, δ, ppm (J, Hz): -80.41 (1F, d,
2
JFF = 16.0, CF); -83.27 (1F, d, JFF = 16.0, CF). 13C NMR spectrum, δ, ppm (J, Hz): 155.45 (dd, JCF = 290.0,
4
2JCF = 296.0, CF2); 150.39 (d, JCF = 2.5, =CH); 142.93 (s, C(Ar)CH3); 139.78 (s, C(Ar)SO2); 129.40 (s, C(Ar)H);
127.28 (s, C(Ar)H); 94.91 (s, =C–SO2); 84.48 (dd, 2JCF = 29.0, 2JCF = 40.0, =C–Cl); 47.37 (br., CH3N); 37.45 (br.,
CH3N); 21.54 (s, CH3(Ar)). Mass spectrum, m/z: 322 [M]+. Found, %: C 48.66; H 4.26; Cl 11.21; N 4.38; S 10.15.
C13H14ClF2NO2S. Calculated, %: C 48.52; H 4.39; Cl 11.02; N 4.35; S, 9.97.
5-Polyfluoroalkyl-4-(p-tolylsulfonyl)pyrazoles 6a-g (General Method). Corresponding hydrazine
(1 mmol) was added to a solution of 2a,b (1 mmol) in acetonitrile (7 ml) and stirred for 2 h at 20°C. The reaction
mixture was filtered and the filtrate was evaporated at 50°C (10-15 mm Hg). The residue was crystallized.
5-(1,1,2,2,3,3-Hexafluoropropyl)-1-phenyl-4-(p-tolylsulfonyl)-1H-pyrazole (6a) was obtained in
88% yield; mp144-146°C (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 8.18 (1H, s, HC=N); 7.33 and 7.86 (4H, dd,
3JHH = 8.0, C6H4); 7.36-7.56 (5H, m, C6H5); 6.24 (1H, tt, 2JHF = 52.0, 3JHF = 6.0, HCF2); 2.46 (3H, s, CH3). 19F NMR
spectrum, δ, ppm (J, Hz): -103.71 (2F, m, CF2); -129.61 (2F, m, CF2); -138.74 (2F, dm, JFH = 52.0, HCF2). 13C NMR
spectrum, δ, ppm (J, Hz): 144.89 (s, C(Py)SO2); 142.15 (s, CH=N); 138.70 (s, C(Ar)CH3); 138.47 (C(Ar)SO2); 130.59 (t,
J
CF = 32.5, C(Py)CF2); 130.48 (s, C(Ph)H); 129.85 (s, C(Ar)H); 128.67 (s, C(Ar)H); 127.91 (s, C(Ph)H); 127.23 (s, C(Ph)H);
2
112.52 (tm, JCF = 253.0, HCF2CF2CF2); 109.60 (tt, JCF = 258.5, JCF =32.0, HCF2CF2CF2); 107.67 (tt, JCF = 253.0,
2JCF = 29.5, HCF2CF2CF2); 21.60 (s, CH3(Ar)). Mass spectrum, m/z: 449.2 [M]+. Found, %: C 50.88; H 3.11; N 6.32;
S 7.22. C19H14F6N2O2S. Calculated, %: C 50.89; H 3.15; N 6.25; S 7.15.
890

1-(2-Chlorophenyl)-5-(1,1,2,2,3,3-hexafluoropropyl)-4-(p-tolylsulfonyl)-1H-pyrazole
(6b)
was
1
obtained in 83% yield; mp 113-115°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 8.23 (1H, s, CH=N); 7.36
and 7.85 (4H, dd, 3JHH = 8.0, C6H4); 7.38-7.54 (4H, m, 2-ClC6H4); 6.28 (1H, tt, 2JHF = 51.7, HCF2); 2.46 (3H, s,
CH3). 19F NMR spectrum, δ, ppm (J, Hz): FA -103.95, FB -108.85 (2F, AB, JFF = 297.0, CF2); FA -129.58,
FB -130.25 (2F, AB, JFF =285.0, CF2); -138.53 (2F, m, HCF2).
5-(1,1,2,2,3,3-Hexafluoropropyl)-1-methyl-4-(p-tolylsulfonyl)-1H-pyrazole (6c) was obtained in 68%
1
yield; mp 124-126°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 8.09 (1H, s, CH=N); 7.31 and 7.80 (4H, dd,
2
3
19
3JHH = 8.0, C6H4); 6.30 (1H, tt, JHF = 52.0, JHF = 6.0, HCF2); 3.99 (3H, s, NCH3); 2.42 (3H, s, CH3). F NMR
spectrum, δ, ppm (J, Hz): -107.59 (2F, m, CF2); -132.28 (2F, m, CF2); -138.32 (2F, dm, 2JFH = 52.0, HCF2). 13C
NMR spectrum, δ, ppm (J, Hz): 144.63 (s, C(Py)SO2); 138.56 (t, JCF = 31.5, C(Py)CF2); 138.33 (s, C(Ar)CH3);
2
136.58 (s, CH=N); 129.69 (C(Ar)H); 127.72 (s, C(Ar)H); 125.27 (s, C(Ar)SO2); 112.20 (tt, JCF = 252.0, JCF = 30.5,
HCF2CF2CF2); 110.33 (tm, JCF = 263.0, JCF = 33.0, HCF2CF2CF2); 108.04 (tt, JCF = 253.5, JCF = 29.0,
HCF2CF2CF2); 40.18 (s, NCH3); 21.53 (s, CH3(Ar)).
2
2
1-Phenyl-4-(p-tolylsulfonyl)-5-trifluoromethyl-1H-pyrazole (6d) was obtained in 68% yield;
mp 116°C (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 8.19 (1H, s, CH=N); 7.36 and 7.88 (4H, dd, 3JHH = 8.0,
C6H4); 7.38-7.56 (5H, m, C6H5); 2.45 (3H, s, CH3). 19F NMR spectrum, δ, ppm: -55.49 (s, CF3).
1-(2-Chlorophenyl)-4-(p-tolylsulfonyl)-5-trifluoromethyl-1H-pyrazole (6e) was obtained in
1
63% yield; mp 93-95°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 8.22 (1H, s, CH=N); 7.36 and 7.88 (4H,
3
dd, JHH = 8.0, C6H4); 7.38-7.57 (4H, m, 2-ClC6H4); 2.45 (3H, s, CH3). 19F NMR spectrum, δ, ppm: -57.32 (s,
CF3).
1-Methyl-4-(p-tolylsulfonyl)-5-trifluoromethyl-1H-pyrazole (6f) was obtained in 61% yield;
1
mp 162-164°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 8.04 (1H, s, CH=N); 7.31 and 7.82 (4H, dd,
3JHH = 8.0, C6H4); 3.97 (3H, s, NCH3); 2.45 (3H, s, CH3). 19F NMR spectrum, δ, ppm: -61.56 (s, CF3).
5-(1,1,2,2,3,3-Hexafluoropropyl)-4-(p-tolylsulfonyl)-1H-pyrazole (6g). Hydrazine sulfate (1 mmol)
and K2CO3 (2 mmol) were added to a solution of enaminone 2a (1 mmol) in acetonitrile (7 ml), heated at reflux
with stirring for 8 h, filtered, and evaporated to dryness. The residue was purified by chromatography using ethyl
acetate as the eluent to give pyrazole 6g in 55% yield as a yellow oil, Rf 0.9 (Silufol UV-254 plate, ethyl acetate
1
as eluent, developed with iodine vapor). H NMR spectrum, δ, ppm (J, Hz): 11.53 (1H, br. s, NH); 8.30 (1H, s,
CH=N); 7.31 and 7.80 (4H, dd, 3JHH = 8.0, C6H4); 6.29 (1H, tt, 2JHF = 52.5, 3JHF = 6.0, HCF2); 2.46 (3H, s, CH3).
2
19F NMR spectrum, δ, ppm (J, Hz): -107.32 (2F, m, CF2); -131.94 (2F, m, CF2); -138.14 (2F, dm, JFH = 52.5,
HCF2).
4-Polyfluoroalkyl-5-(p-tolylsulfonyl)pyrimidines 8a-c (General Method). Guanidine hydrochloride
(in the case of 8a,b) or acetamidine hydrochloride (in the case of 8c) (1 mmol) and K2CO3 (2 mmol) were added
to a solution of enaminone 2a,b in acetonitrile (7 ml). The reaction mixture was heated at reflux with stirring for
2 h, cooled, and treated as in the above procedure.
2-Amino-4-(1,1,2,2,3,3-hexafluoropropyl)-5-(p-tolylsulfonyl)pyrimidine (8a). The reaction mixture
was filtered and the filtrate was evaporated to dryness to give 8a in 95% yield; mp 217-219°C (acetonitrile).
1H NMR spectrum, δ, ppm (J, Hz): 9.14 (1H, s, CH=N); 8.46 (2H, br. s, NH2); 7.41 and 7.78 (4H, dd, 3JHH = 8.0,
2
3
C6H4); 7.32 (1H, tt, JHF = 52.0, JHF = 6.0, HCF2); 2.38 (3H, s, CH3). 19F NMR spectrum, δ, ppm (J, Hz):
-107.05 (2F, m, CF2); -130.39 (2F, m, CF2); -137.02 (2F, dm, 2JFH = 52.0, HCF2). Mass spectrum, m/z: 398 [M]+.
2-Amino-5-(p-tolylsulfonyl)-4-trifluoromethylpyrimidine (8b). The precipitate of 8b formed in the
reaction mixture was filtered off, washed on the filter with water, and dried to give 8b in 84% yield;
mp 260-262°C (acetonitrile). 1H NMR spectrum, δ, ppm (J, Hz): 9.09 (1H, s, CH=N); 8.43 (2H, br. s, NH2); 7.41
and 7.78 (4H, dd, 3JHH = 8.0, C6H4); 2.38 (3H, s, CH3). 19F NMR spectrum, δ, ppm: -64.36 (s, CF3).
2-Methyl-4-(1,1,2,2,3,3-hexafluoropropyl)-5-(p-tolylsulfonyl)pyrimidine (8c). The reaction mixture
was filtered and the filtrate was evaporated to dryness. The residue was crystallized to give 8c in 81% yield;
1
mp 110-112°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 9.68 (1H, s, CH=N); 7.47 and 7.87 (4H, dd,
891

2
3
3JHH =8.0, C6H4); 7.10 (1H, tt, JHF = 51.5, JHF = 6.0, HCF2); 2.84 (3H, s, CH3); 2.40 (3H, s, CH3). 19F NMR
spectrum, δ, ppm (J, Hz): -106.81 (2F, m, CF2); -129.30 (2F, m, CF2); -137.24 (2F, dm, 2JFH= 51.5, HCF2).
X-Ray Diffraction Structural Analysis of a Monocrystal of 6d grown from absolute ethanol
(0.38×0.25×0.20 mm) at room temperature on an automatic Bruker Apex II CCD diffractometer using
MoKα radiation, λ = 0.71069 Å, θmax = 31°, sphere segment -12 ≤ h ≤ 12, -14 ≤ k ≤ 13, -15 ≤ l ≤ 14. We
collected 10,339 reflections (5214 independent reflections, Rint = 0.0197). The unit cell parameters of the triclinic
crystals of 6d are as follows: a = 8.7461(2), b = 10.1910(2), c = 10.5604(2) Å, V = 856.47(3) Å3, M = 435.03,
Z = 2, dcalc = 1.421 g/cm3, µ = 2.32 cm-1, F(000) = 376, space group P-1 (No. 2). The structure was solved by the
direct method and refined by the method of least squares in the full-matrix anisotropic approximation using the
SHELX897 and SHELXL97 programs [12, 13]. A total of 5214 reflections were used in the refinement (3684
reflections with I > 2σ(I) and 232 refined parameters, the number of reflections per parameter was 22.47). All
the hydrogen atoms were found in the electron density difference map and placed in the refinement with fixed
positional
and
temperature
parameters.
The
following
weighting
scheme
was
used:
ω = 1/[σ2(Fo2) + (0.1006P)2 + 0.8932P], where P = (Fo2 + 2Fc2)/3. The final R1 = 0.0544 and wR2 = 0.0766,
GOOF = 0.708. The residual electron density from the Fourier difference map was -0.363 and 0.541 e/Å3. The
full set of X-ray diffraction structural data for 6d was deposited in the Cambridge Crystallographic Data Center
(CCDC 645235).
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