Noncatalytic electrophilic oxyalkylation of 3-aminopyrazoles with 2-(trifluoroacetyl)-1,3-azoles

Article abstract of DOI:10.1055/s-0029-1218657

2-(Trifluoroacetyl)-1,3-azoles reacted with 3-aminopyrazoles to give the corresponding trifluoromethyl-substituted alcohols. The conditions required for the reaction and the yields of the products were highly dependent on the electronic nature of the both

Full text of DOI:10.1055/s-0029-1218657

PAPER
1195
Noncatalytic Electrophilic Oxyalkylation of 3-Aminopyrazoles with
2-(Trifluoroacetyl)-1,3-azoles
Electrophilic
O
a
xyalkylatio
v
n
of 3-Amin
e
opyrazolesl V. Khodakovskiy,a,b Pavel K. Mykhailiuk,*a,b Dmitriy M. Volochnyuk,a,c Andrey A. Tolmacheva,b
a
b
c
Enamine Ltd., Oleksandra Matrosova Street 23, 01103 Kyiv, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kyiv, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, 02660 Kyiv-94, Ukraine
Fax +380(44)2351273; E-mail: Pashamk@gmx.de
Received 1 December 2009; revised 8 December 2009
From a range of available representative ketones 1,6a we
selected 2-(trifluoroacetyl)-1-methyl-1H-imidazole (1a;
Figure 1), which shows a relatively low activity of the car-
bonyl group, and the much more reactive 2-(trifluoro-
acetyl)-1,3-benzothiazole (1b) as model compounds, and
we examined their C-oxyalkylation reactions with 3-ami-
nopyrazoles 2–16 (Figure 2) to give the corresponding tri-
fluoromethylated alcohols 2a–16a and 2b–16b,
respectively (Scheme 1 and Table 1).
Abstract: 2-(Trifluoroacetyl)-1,3-azoles reacted with 3-aminopy-
razoles to give the corresponding trifluoromethyl-substituted alco-
hols. The conditions required for the reaction and the yields of the
products were highly dependent on the electronic nature of the both
the 1,3-azole and the 3-aminopyrazole units.
Key words: heterocycles, alkylations, fluoro compounds, alcohols,
aminopyrazoles
The replacement of hydrogen by fluorine is a method that
is widely used to improve the pharmacological character-
istics of organic compounds.1 Moreover, many commer-
cially available pharmaceuticals containing contain
fluorine, although fluorine rarely occurs in natural prod-
ucts.2 The trifluoromethyl group, in particular, is one of
the most attractive functional groups in organic chemistry,
and the incorporation of this group into organic com-
pounds remains a topic of growing interest.3 Commercial-
ly available trifluoromethyl ketones, such as hexa-
fluoroacetone and trifluoropyruvate, are highly valuable
building blocks that are frequently used to prepare tri-
fluoromethyl-containing compounds.4 However, despite
the considerable potential of both hexafluoroacetone and
trifluoropyruvate,4 the chemistry of other trifluoroacetyl
ketones has received little attention.5
N
N
NH2
NH2
N
N
N
N
NH2
N
NH2
N
H
HO
NC
Me
3
2
4
5
N
N
N
N
N
NH2
NH2
NH2
NH2
N
N
N
N
N
O
S
6
7
8
9
N
N
NH2
NH2
N
N
N
N
N
NH2
Cl
We recently began a project aimed at the synthesis and ap-
plication of various trifluoroacetyl 1,3-azoles (1;
Figure 1).6 We have already shown that derivatives of in-
dole, pyrrole, furan, thiophene, 1,3-thiazole, and 1,2-
oxazole react smoothly with ketones 1 to form the corre-
sponding trifluoromethyl-substituted alcohols.6d,e We
now report an extension of this strategy to another elec-
tron-rich aromatic system, 3-aminopyrazole.7
NH2
N
N
10
11
12
13
N
N
NH2
N
N
N
N
NH2
NH2
N
N
NH
N
A1
A2
N
N
F3C
F3C
F3C
N
N
N
X
S
O
O
O
Me
14
15
16
1
1a
1b
Figure 2 Substituted 3-aminopyrazoles 2–16
Figure 1 2-(Trifluoroacetyl)-1,3-azoles (1): 2-(trifluoroacetyl)-1-
methyl-1H-imidazole (1a), and 2-(trifluoroacetyl)-1,3-benzothiazole
(1b)
The reaction proceeded smoothly when mixtures of the re-
actants were heated in toluene (Table 1). In most cases,
the transformations of azole 1a required longer reaction
times than 1b. For example, the products 3a, 6a, and 7a
were obtained by heating the reaction mixture at 100 °C
SYNTHESIS 2010, No. 7, pp 1195–1199
x
x
.
x
x
.2
0
1
0
Advanced online publication: 29.01.2010
DOI: 10.1055/s-0029-1218657; Art ID: Z26009SS
© Georg Thieme Verlag Stuttgart · New York

1196
P. V. Khodakovskiy et al.
PAPER
for one hour, whereas the corresponding alcohols 3b, 6b,
and 7b were obtained within 30 minutes at the same tem-
perature. The electronic nature of the 3-aminopyrazoles
also affects the outcome of the reaction; for instance, re-
placing electron-donating alkyl groups at the N-atom in 3-
aminopyrazoles 3–10 by electron-withdrawing phenyl or
pyridyl substituents (compounds 11–14) resulted in
marked increases in the reaction time to two hours in the
case of 1a and one hour in the case of 1b. Moreover, 3-
aminopyrazoles 15 and 16, which contain much more
electron-withdrawing pyrimidine and benzoimidazole
moieties, respectively, failed to react with 1a. With 1b,
the products 15b and 16b were, however, obtained in 62%
and 60% yields, respectively, by heating the appropriate
reaction mixtures for two hours at 100 °C.
Table 1 Syntheses of Trifluoroacetyl-Substituted Alcohols 2a–16a
and 2b–16ba
Azole
2
Ketone
1a
Time (h)
Product
2a
Yield (%)
42
52
76
74
88
92
93
59
61
69
68
64
79
65
75
70
78
64
73
0
1
2
1b
1a
1
2b
3
1
3a
3
1b
1b
1b
1a
0.5
0.5
0.5
1
3b
4
4b
5
5b
6
6a
6
1b
1a
0.5
1
6b
N
F3C
7
7a
1a
N
OH
7
1b
1b
1b
1b
1a
0.5
0.5
0.5
0.5
2
7b
toluene
heat
Me
NH2
N
8
8b
N
2a–16a
R
9
9b
NH2
N
N
N
F3C
10
11
11
12
13
14
14
15
15
16
16
10b
11a
11b
12a
13b
14a
14b
15a
15b
16a
16b
R
S
OH
1b
2–16
toluene
heat
NH2
N
1b
1a
1
N
2b–16b
R
2
Scheme 1 Synthesis of trifluoroacetyl-substituted alcohols 2a–16a
and 2b–16b from 3-aminopyrazoles and 2-(trifluoroacetyl)-1,3-
azoles 1a and 1b
1b
1a
1
2
1b
1a
1
In summary, we have developed a very simple and effi-
cient one-step procedure for preparing the trifluoroacetyl-
substituted alcohols 2a–16a and 2b–16b from N-substi-
tuted derivatives of 3-aminopyrazole and 2-trifluoro-
acetyl-1,3-azoles. The necessary reaction conditions and
yields of products depend markedly on the electronic na-
tures of both the 1,3-azole and 3-aminopyrazole compo-
nents.
4
1b
1a
2
62
0
4
1b
2
60
a The reactions were all performed in toluene at 100 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.39 (s, 3 H), 3.37 (s, 3 H),
Ketones 1a and 1b were synthesized as previously reported.6a The
1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance
500 spectrometer at 499.9, 124.9, and 470.3 MHz, respectively.
Chemical shifts are reported in ppm downfield from TMS (1H and
13C) or CFCl3 (19F) as internal standards. Mass spectra were record-
ed on an Agilent 1100 LCMSD SL instrument by atmospheric pres-
sure chemical ionization (APCI).
4.47 (br s, 3 H), 6.84 (s, 1 H), 7.18 (s, 1 H), 7.42 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.51, 33.98, 73.50 (q,
2JCF = 30.6 Hz), 96.71, 123.99, 125.68, 126.10 (q,
1JCF = 287.1 Hz), 140.02, 144.26, 152.35.
19F NMR (470 MHz, DMSO-d6): d = –76.65.
MS (APCI): m/z = 276 [M + 1].
Trifluoroacetyl Alcohols; General Procedure
A mixture of an appropriate trifluoromethyl ketone (1 mmol), 3-
aminopyrazole (1 mmol), and toluene (2 mL) was stirred at 100 °C
for the time shown in Table 1. The mixture was then cooled to r.t.,
and the resulting crystalline solid was filtered off. The product on
the filter was washed with CCl4 and recrystallized (i-PrOH).
1-(5-Amino-3-methyl-1H-pyrazol-4-yl)-1-(1,3-benzothiazol-2-
yl)-2,2,2-trifluoroethanol (2b)
Yield: 52%; mp 172–173 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.70 (s, 3 H), 3.90–5.90 (br s,
3 H), 7.50 (dd, J = 8.0, 7.0 Hz, 1 H), 7.56 (dd, J = 8.0, 7.0 Hz, 1 H),
8.10 (d, J = 8.0 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.32 (br s, 1 H).
1-(5-Amino-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoro-1-(1-
methyl-1H-imidazol-2-yl)ethanol (2a)
Colorless solid; yield: 42%; mp > 250 °C.
13C NMR (125 MHz, DMSO-d6): d = 12.22, 76.63 (q,
1
2JCF = 30.2 Hz), 97.93, 122.79, 123.97, 125.70 (q, JCF = 288.0
Hz), 126.49, 126.90, 135.53, 140.47, 152.04, 172.25.
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Electrophilic Oxyalkylation of 3-Aminopyrazoles
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19F NMR (470 MHz, DMSO-d6): d = –75.89.
MS (APCI): m/z = 329 [M + 1].
1H NMR (500 MHz, DMSO-d6): d = 2.20 (s, 3 H), 3.44 (s, 3 H),
4.90 (br s, 2 H), 5.00 (s, 2 H), 5.98 (s, 1 H), 6.09 (s, 1 H), 6.85 (s, 1
H), 6.88 (s, 1 H), 7.18 (s, 1 H), 7.42 (s, 1 H).
1-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-2,2,2-trifluoro-1-(1-
methyl-1H-imidazol-2-yl)ethanol (3a)
Colorless solid; yield: 76%; mp >235 °C (dec).
13C NMR (125 MHz, DMSO-d6): d = 13.70, 34.43, 44.20, 73.34 (q,
2JCF = 30.2 Hz), 97.57, 106.98, 109.31, 124.46, 125.62 (q,
1JCF = 288.0 Hz), 125.96, 137.45, 143.71, 144.91, 148.85, 151.65.
1H NMR (500 MHz, DMSO-d6): d = 1.25 (s, 3 H), 3.37 (s, 3 H),
3.42 (s, 3 H), 4.95 (br s, 2 H), 6.86 (s, 1 H), 7.19 (s, 1 H), 7.49 (s, 1
H).
19F NMR (470 MHz, DMSO-d6): d = –76.91.
MS (APCI): m/z = 356 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 12.27, 34.01, 34.28, 73.46 (q,
2JCF = 30.6 Hz), 94.41, 123.98, 125.77, 126.13 (q,
1JCF = 286.7 Hz), 144.01, 144.02, 146.40.
1-{5-Amino-1-[(5-methyl-2-furyl)methyl]-1H-pyrazol-4-yl}-1-
(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (6b)
Colorless solid; yield: 59%; mp 174–175 °C.
19F NMR (470 MHz, DMSO-d6): d = –77.06.
1H NMR (500 MHz, DMSO-d6): d = 2.19 (s, 3 H), 5.03 (s, 2 H),
5.34 (s, 2 H), 5.98 (s, 1 H), 6.19 (s, 1 H), 7.29 (s, 1 H), 7.50 (dd,
J = 8.0, 7.0 Hz, 1 H), 7.56 (dd, J = 8.0, 7.0 Hz, 1 H), 8.08 (d, J = 8.0
Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.29 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.74, 44.14, 75.91 (q,
2JCF = 30.2 Hz), 97.46, 107.02, 109.95, 122.78, 123.70, 125.13 (q,
1JCF = 288.0 Hz), 126.22, 126.92, 134.97, 137.40, 145.28, 148.59,
151.82, 153.23, 172.32.
MS (APCI): m/z = 290 [M + 1].
1-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-1-(1,3-benzo-
thiazol-2-yl)-2,2,2-trifluoroethanol (3b)
Colorless solid; yield: 74%; mp >245 °C (dec).
1H NMR (500 MHz, DMSO-d6): d = 1.54 (s, 3 H), 3.45 (s, 3 H),
5.23 (s, 2 H), 7.50 (dd, J = 7.2 Hz, 1 H), 7.56 (dd, J = 7.6, 7.2 Hz, 1
H), 8.11 (d, J = 7.6 Hz, 1 H), 8.13 (d, J = 7.2 Hz, 1 H), 8.30 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –76.77.
13C NMR (125 MHz, DMSO-d6): d = 13.94, 34.33, 76.60 (q,
2JCF = 30.2 Hz), 95.42, 122.80, 123.99, 125.79 (q,
1JCF = 288.0 Hz), 126.56, 126.94, 135.52, 144.20, 146.48, 151.93,
172.21.
MS (APCI): m/z = 409 [M + 1].
1-{5-Amino-1-[(5-methyl-2-thienyl)methyl]-1H-pyrazol-4-yl}-
2,2,2-trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethanol (7a)
Colorless solid; yield: 61%; mp 185–186 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.36 (s, 3 H), 3.43 (s, 3 H),
4.94 (br s, 2 H), 5.16 (s, 2 H), 6.61 (m, 1 H), 6.74 (m, 1 H), 6.85 (s,
1 H), 6.87 (s, 1 H), 7.18 (s, 1 H), 7.40 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 15.36, 34.43, 45.95, 73.30 (q,
2JCF = 30.2 Hz), 97.53, 124.45, 125.14, 125.60 (q,
1JCF = 288.0 Hz), 125.92, 126.36, 137.58, 137.68, 139.70, 143.71,
144.63.
19F NMR (470 MHz, DMSO-d6): d = –76.32.
MS (APCI): m/z = 343 [M + 1].
1-[5-Amino-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]-1-
(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (4b)
Colorless solid; yield: 88%; mp 233–234 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.54 (s, 3 H), 3.65 (m, 2 H),
3.85 (m, 2 H), 4.97 (m, 1 H), 5.17 (s, 2 H), 7.51 (dd, J = 8.0, 6.0 Hz,
1 H), 7.57 (dd, J = 8.0, 6.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 8.14
(d, J = 8.0 Hz, 1 H), 8.27 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.08, 49.45, 60.43, 76.64 (q,
2JCF = 30.2 Hz), 95.46, 122.81, 123.98, 125.78 (q,
1JCF = 288.0 Hz), 126.55, 126.93, 135.51, 144.51, 146.71, 151.96,
172.20.
19F NMR (470 MHz, DMSO-d6): d = –76.93.
MS (APCI): m/z = 372 [M + 1].
1-{5-Amino-1-[(5-methyl-2-thienyl)methyl]-1H-pyrazol-4-yl}-
1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (7b)
Colorless solid; yield: 69%; mp 209–210 °C.
19F NMR (470 MHz, DMSO-d6): d = –75.95.
1H NMR (500 MHz, DMSO-d6): d = 2.35 (s, 3 H), 5.19 (s, 2 H),
5.41 (s, 2 H), 6.60 (s, 1 H), 6.81 (m, 1 H), 7.30 (s, 1 H), 7.49 (dd,
J = 8.0, 7.0 Hz, 1 H), 7.56 (dd, J = 8.0, 7.0 Hz, 1 H), 8.08 (d, J = 8.0
Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.35 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 15.36, 45.82, 75.92 (q,
2JCF = 31.0 Hz), 97.37, 122.79, 123.69, 125.13, 125.14 (q,
1JCF = 288.0 Hz), 126.21, 126.92, 134.98, 137.22, 137.61, 139.97,
145.06, 153.22, 172.43.
MS (APCI): m/z = 373 [M + 1].
3-{5-Amino-4-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-hy-
droxyethyl]-3-methyl-1H-pyrazol-1-yl}propanenitrile (5b)
Colorless solid; yield: 92%; mp 195 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.56 (s, 3 H), 2.90 (t, J = 6.5
Hz, 2 H), 4.08 (t, J = 6.5 Hz, 2 H), 5.40 (br s, 2 H), 7.51 (dd, J = 8.0,
6.5 Hz, 1 H), 7.57 (dd, J = 8.0, 6.5 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1
H), 8.14 (d, J = 8.0 Hz, 1 H), 8.31 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.14, 17.58, 42.28, 76.58 (q,
2JCF = 30.2 Hz), 95.42, 119.06, 122.83, 123.99, 125.73 (q,
1JCF = 288.0 Hz), 126.59, 126.96, 135.52, 145.52, 146.57, 151.93,
172.06.
19F NMR (470 MHz, DMSO-d6): d = –76.81.
MS (APCI): m/z = 425 [M + 1].
1-[5-Amino-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-1-(1,3-
benzothiazol-2-yl)-2,2,2-trifluoroethanol (8b)
Colorless solid; yield: 68%; mp 168–169 °C.
19F NMR (470 MHz, DMSO-d6): d = –76.00.
1H NMR (500 MHz, DMSO-d6): d = 5.22 (s, 2 H), 5.45 (s, 2 H),
6.90 (d, J = 8.0 Hz, 1 H), 7.28 (dd, J = 8.0, 4.5 Hz, 1 H), 7.35 (s, 1
H), 7.50 (dd, J = 8.0, 7.0 Hz, 1 H), 7.56 (dd, J = 8.0, 7.0 Hz, 1 H),
7.74 (dd, J = 8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.16 (d, J = 8.0
Hz, 1 H), 8.34 (br s, 1 H), 8.52 (d, J = 4.5 Hz, 1 H).
MS (APCI): m/z = 382 [M + 1].
1-{5-Amino-1-[(5-methyl-2-furyl)methyl]-1H-pyrazol-4-yl}-
2,2,2-trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethanol (6a)
Colorless solid; yield: 93%; mp 217–219 °C (sublimation).
13C NMR (125 MHz, DMSO-d6): d = 52.79, 75.94 (q,
2JCF = 31.0 Hz), 97.76, 121.81, 122.81, 123.02, 123.73, 125.14 (q,
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P. V. Khodakovskiy et al.
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1-[5-Amino-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]-
1JCF = 288.0 Hz), 126.25, 126.95, 135.01, 137.52, 137.87, 146.12,
149.51, 153.24, 157.40, 172.34.
2,2,2-trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethanol (12a)
Colorless solid; yield: 70%; mp > 250 °C.
19F NMR (470 MHz, DMSO-d6): d = –76.81.
1H NMR (500 MHz, DMSO-d6): d = 1.36 (s, 3 H), 2.34 (s, 3 H),
3.46 (s, 3 H), 5.06 (s, 2 H), 6.90 (s, 1 H), 7.23 (s, 1 H), 7.27 (d,
J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.70 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.46, 21.01, 34.03, 73.53 (q,
2JCF = 30.6 Hz), 95.51, 123.58, 124.15, 125.89, 126.11 (q,
1JCF = 286.7 Hz), 129.99, 136.22, 136,74, 143.76, 146.33, 146.51.
MS (APCI): m/z = 406 [M + 1].
1-[5-Amino-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1-(1,3-
benzothiazol-2-yl)-2,2,2-trifluoroethanol (9b)
Colorless solid; yield: 64%; mp 175–176 °C.
1H NMR (500 MHz, DMSO-d6): d = 5.19 (s, 2 H), 5.47 (s, 2 H),
7.30–7.39 (m, 2 H), 7.46–7.60 (m, 3 H), 8.09 (d, J = 8.0 Hz, 1 H),
8.15 (d, J = 8.0 Hz, 1 H), 8.33 (br s, 1 H), 8.40 (s, 1 H), 8.46 (d,
J = 3.0 Hz, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –76.61.
MS (APCI): m/z = 366 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 48.16, 75.91 (q,
2JCF = 30.2 Hz), 97.66, 122.80, 123.72, 123.94, 125.13 (q,
1JCF = 288.0 Hz), 126.24, 126.93, 133.44, 135.02, 135.65, 137.94,
145.78, 148.96, 149.17, 153.23, 172.28.
1-[5-Amino-1-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-1-
(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (13b)
Colorless solid; yield: 78%; mp 245–246 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.63 (s, 3 H), 5.54 (s, 2 H),
7.39 (d, J = 8.0 Hz, 1 H), 7.46–7.61 (m, 4 H, 3 × CH, OH), 7.63 (s,
1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.55 (br s,
1 H).
19F NMR (470 MHz, DMSO-d6): d = –76.81.
MS (APCI): m/z = 406 [M + 1].
1-[5-Amino-1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-1-(1,3-
benzothiazol-2-yl)-2,2,2-trifluoroethanol (10b)
Colorless solid; yield: 79%; mp 180–181 °C.
1H NMR (500 MHz, DMSO-d6): d = 5.20 (s, 2 H), 5.44 (s, 2 H),
7.04 (m, 2 H), 7.38 (s, 1 H), 7.50 (dd, J = 8.0, 6.5 Hz, 1 H), 7.56 (dd,
J = 8.0, 6.5 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.16 (d, J = 8.0 Hz,
1 H), 8.34–8.57 (m, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 14.14, 76.64 (q,
2JCF = 30.2 Hz), 97.08, 122.02, 122.91, 123.21, 124.08, 125.73 (q,
1JCF = 288.0 Hz), 126.72, 126.77, 127.06, 131.26, 133.90, 135.53,
140.33, 146.91, 147.64, 151.90, 171.55.
19F NMR (470 MHz, DMSO-d6): d = –75.93.
MS (APCI): m/z = 439 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 49.50, 75.91 (q,
2JCF = 30.2 Hz), 97.65, 122.49, 122.81, 123.72, 125.17 (q,
1JCF = 288.0 Hz), 126.24, 126.94, 135.05, 138.15, 146.16, 146.95,
150.05, 153.25, 172.41.
1-(5-Amino-3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-2,2,2-tri-
fluoro-1-(1-methyl-1H-imidazol-2-yl)ethanol (14a)
Colorless solid; yield: 64%; mp 218 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.36 (s, 3 H), 3.47 (s, 3 H),
6.66 (s, 2 H), 6.91 (s, 1 H), 7.24 (m, 2 H), 7.73 (s, 1 H), 7.79 (d,
J = 8.5 Hz, 1 H), 7.92 (dd, J = 8.5 Hz, 1 H), 8.39 (d, J = 4.0 Hz, 1
H).
19F NMR (470 MHz, DMSO-d6): d = –76.79.
MS (APCI): m/z = 406 [M + 1].
1-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluo-
ro-1-(1-methyl-1H-imidazol-2-yl)ethanol (11a)
Colorless solid; yield: 65%; mp 247 °C.
13C NMR (125 MHz, DMSO-d6): d = 12.59, 34.03, 73.56 (q,
2JCF = 30.2 Hz), 94.29, 113.49, 120.36, 124.16, 125.95, 126.20 (q,
1JCF = 287.6 Hz), 139.40, 143.60, 147.18, 148.47, 148.68, 154.40.
1H NMR (500 MHz, DMSO-d6): d = 1.35 (s, 3 H), 3.46 (s, 3 H),
5.16 (br s, 2 H), 6.91 (s, 1 H), 7.25 (s, 1 H), 7.32 (t, J = 7.0 Hz, 1 H),
7.47 (dd, J = 8.0, 7.0 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.75 (s, 1
H).
13C NMR (125 MHz, DMSO-d6): d = 12.48, 34.06, 73.54 (q,
2JCF = 30.6 Hz), 95.75, 123.52, 124.19, 125.89, 126.12 (q,
1JCF = 286.7 Hz), 126.85, 129.59, 139.22, 143.71, 146.49, 146.85.
19F NMR (470 MHz, DMSO-d6): d = –76.77.
MS (APCI): m/z = 353 [M + 1].
1-(5-Amino-3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-1-(1,3-
benzothiazol-2-yl)-2,2,2-trifluoroethanol (14b)
Colorless solid; yield: 73%; mp 184–185 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.66 (s, 3 H), 6.93 (s, 2 H),
7.25 (dd, J = 8.0, 4.0 Hz, 1 H), 7.53 (dd, J = 8.0, 7.0 Hz, 1 H), 7.59
(dd, J = 8.0, 7.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.93 (dd, J = 8.0
Hz, 1 H), 8.15 (m, 2 H), 8.40 (d, J = 4.0 Hz, 1 H), 8.45 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –76.92.
MS (APCI): m/z = 352 [M + 1].
1-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-(1,3-ben-
zothiazol-2-yl)-2,2,2-trifluoroethanol (11b)
Colorless solid; yield: 75%; mp 237 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.63 (s, 3 H), 5.39 (br s, 2 H),
7.34 (t, J = 7.3, 7.2 Hz, 1 H), 7.48 (dd, J = 8.0, 7.5 Hz, 1 H), 7.51–
7.63 (m, 5 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H),
8.52 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.32, 76.67 (q,
2JCF = 30.2 Hz), 95.26, 113.65, 120.51, 122.87, 124.11, 125.84 (q,
1JCF = 288.0 Hz), 126.68, 127.02, 135.56, 139.78, 147.18, 148.54,
148.82, 151.92, 154.35, 171.62.
19F NMR (470 MHz, DMSO-d6): d = –75.95.
MS (APCI): m/z = 406 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 14.15, 76.69 (q,
2JCF = 30.6 Hz), 96.54, 122.90, 123.85, 124.08, 125.79 (q,
1JCF = 288.0 Hz), 126.68, 127.04, 127.11, 129.66, 135.55, 138.98,
146.51, 146.92, 151.93, 172.75.
1-[5-Amino-1-(4,6-dimethylpyrimidin-2-yl)-3-methyl-1H-pyra-
zol-4-yl]-1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (15b)
Colorless solid; yield: 62%; mp 187 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.68 (s, 3 H), 2.45 (s, 6 H),
6.84 (s, 2 H), 7.12 (s, 1 H), 7.53 (dd, J = 8.0, 6.5 Hz, 1 H), 7.59 (dd,
J = 8.5, 6.5 Hz, 1 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.0 Hz,
1 H), 8.45 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –76.07.
MS (APCI): m/z = 405 [M + 1].
Synthesis 2010, No. 7, 1195–1199 © Thieme Stuttgart · New York

PAPER
Electrophilic Oxyalkylation of 3-Aminopyrazoles
1199
13C NMR (125 MHz, DMSO-d6): d = 14.36, 23.91, 76.62 (q,
2JCF = 29.8 Hz), 94.91, 116.98, 122.89, 124.11, 125.82 (q,
1JCF = 288.0 Hz), 126.69, 127.02, 135.54, 148.90, 149.30, 151.90,
157.17, 168.60, 171.62.
(3) (a) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
(b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (c) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(d) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189.
(e) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555.
19F NMR (470 MHz, DMSO-d6): d = –75.94.
MS (APCI): m/z = 435 [M + 1].
(4) (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(b) Nenaidenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ.
Chem. Rev. 1999, 68, 437. (c) Bégué, J.-P.; Bonnet-Delpon,
D. Tetrahedron 1991, 47, 3207. (d) Dolenský, B.; Kvíčala,
J.; Paleček, J.; Paleta, O. J. Fluorine Chem. 2002, 115, 67.
(e) Friezer, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.;
Boulet, L.; Côté, B.; Frenette, R.; Girard, M.; Guay, D.;
Huang, Z.; Jones, T. R.; Laliberté, F.; Lynch, J. J.; Mancini,
J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegl, P. K.
S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young, R. N.;
Girard, Y. J. Med. Chem. 2003, 46, 2413. (f) Middleton, L.
J. Am. Chem. Soc. 1964, 86, 4948. (g) Palecek, J.; Paleta, O.
Synthesis 2004, 521. (h) Braun, R. A. J. Org. Chem. 1966,
31, 3828. (i) Ohkura, H.; Berbasov, D. O.; Soloshonok, V.
A. Tetrahedron 2003, 59, 1647.
1-[5-Amino-1-(1H-benzimidazol-2-yl)-3-methyl-1H-pyrazol-4-
yl]-1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (16b)
Colorless solid; yield: 60%; mp 210–211 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.73 (s, 3 H), 7.00 (s, 2 H),
7.17 (m, 2 H), 7.41 (m, 1 H), 7.49–7.63 (m, 3 H), 8.16 (m, 2 H), 8.53
(s, 1 H), 12.78 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.22, 76.50 (q,
2JCF = 30.2 Hz), 95.02, 111.69, 118.16, 122.27, 122.49, 122.92,
1
124.16, 125.75 (q, JCF = 288.0 Hz), 126.73, 127.07, 132.61,
135.50, 141.70, 147.33, 148.38, 150.12, 151.96, 171.43.
19F NMR (470 MHz, DMSO-d6): d = –76.28.
MS (APCI): m/z = 445 [M + 1].
(5) (a) Regel, E.; Buechel, K. H. Liebigs Ann. Chem. 1977, 145.
(b) Kawase, M.; Sakagami, H.; Kusama, K.; Motohashi, N.;
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S.; Maki, Y.; Kimoto, H. J. Fluorine Chem. 1987, 35, 437.
(d) Salvador, R. L.; Saucier, M. Tetrahedron 1971, 27, 1221.
(6) (a) Khodakovskiy, P. V.; Volochnyuk, D. M.; Panov, D. M.;
Pervak, I. I.; Zarudnitskii, E. V.; Shishkin, O. V.;
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Synthesis 2010, No. 7, 1195–1199 © Thieme Stuttgart · New York