Direct noncatalytic electrophilic trifluoroacetylation of electron-rich pyrazoles

Article abstract of DOI:10.1055/s-0033-1340840

Electron-rich N-substituted pyrazoles smoothly reacted with trifluoroacetic anhydride in pyridine to form the corresponding trifluoromethyl ketones in good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340840

1254▌
PAPER
paper
Direct Noncatalytic Electrophilic Trifluoroacetylation of Electron-Rich
Pyrazoles
Trifluoroacetylation of Electron-Rich Pyrazoles
Dmytro V. Yarmoliuk,a,1 Viatcheslav V. Arkhipov,b,1 Maksym V. Stambirskyi,b,1 Yurii V. Dmytriv,b
Oleg V. Shishkin,c Andrei A. Tolmachev,a,b Pavel K. Mykhailiuk*a,b
a
Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska str. 64, 01601 Kyiv, Ukraine
Fax +389(44)2351273; E-mail: Pavel.Mykhailiuk@gmail.com
b
Enamine Ltd., Oleksandra Matrosova Street, 23, 01103 Kyiv, Ukraine
c
STC, Institute for Single Crystals, National Academy of Science of Ukraine, 60 Lenina Ave., 61001 Kharkiv, Ukraine
Received: 17.01.2014; Accepted: 29.01.2014
effectively influences the pKa of the neighboring function-
al groups, the compound lipophilicity, solubility, confor-
mational preferences, and hydrolytic and metabolic
stabilities.4 Therefore, elaboration of practical, robust
methods to prepare novel trifluoromethylated building
blocks on a large scale from common starting materials is
of interest to both academia and industry.5
Abstract: Electron-rich N-substituted pyrazoles smoothly reacted
with trifluoroacetic anhydride in pyridine to form the corresponding
trifluoromethyl ketones in good yields.
Key words: trifluoromethyl group, trifluoroacetyl group, fluorine,
pyrazole, building blocks
Recently, our colleagues trifluoroacetylated 1,3-azoles
with trifluoroacetic anhydride in pyridine.6 The formed 2-
(trifluoroacetyl)-1,3-azoles were subsequently used to
prepare novel drug-like compounds.7 We wanted to ex-
pand this methodology to the pharmacologically relevant
pyrazole core.8 Indeed, 4-trifluoroacetylated pyrazoles
have already attracted attention in medicinal projects, ag-
Fluorinated compounds have played an important role in
chemistry: ~20% of all pharmaceuticals and agrochemi-
cals contain at least one fluorine atom.2,3 This is because
the incorporation of fluorine, trifluoromethyl groups, or
other fluorinated fragments into organic molecules signif-
icantly changes their physicochemical and biological
properties. For example, the trifluoromethyl substituent
HO
R2
N
CF3
R3
R2
Br/I
R3
N
R1
R2
O
CF3
N
(CF3CO)2O
N
N
NH
R1
R1
EtO
[O] ref. 12
[O]
BuLi
ref. 11
ref. 13
a
O
R2
O
O
R2
CF3
Cl
NH
H2N
R2
O
CF3
R3
CF3
NH
R1
N
N
R3
ref. 10
ref. 14
ref. 15
R3
N
R1
O
R1
O
ref. 17
this work
R2
O
R2
O
H2N
CN
CF3
(CF3CO)2O
N
R3
N
R1
N
R1
Scheme 1 Chemical approaches to 4-(trifluoroacetyl)pyrazoles.10–15 a Synthon for a tricarbonyl compound.
SYNTHESIS 2014, 46, 1254–1260
Advanced online publication: 18.02.2014
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4
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DOI: 10.1055/s-0033-1340840; Art ID: SS-2014-M0047-OP
© Georg Thieme Verlag Stuttgart · New York

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Trifluoroacetylation of Electron-Rich Pyrazoles
1255
rochemistry, and coordination chemistry.9 Scheme 1 distillation (Scheme 2). We were also very pleased to find
summarizes the key synthetic approaches to 4-(trifluoro- that the procedure was reproducible upon scaling up: 80
acetyl)pyrazoles.10–15 Though functionalization of pyr- grams of the product were easily prepared in one synthesis
azole at C4 by electrophilic substitution is known in the run.
literature,16 unexpectedly, direct incorporation of the tri-
fluoroacetyl group into pyrazole core has scant coverage.
There are several specific examples in recent patents on
the trifluoroacetylation of pyrazoles activated by a (sub-
O
(CF3CO)2O (1.1 equiv)
CF3
py
N
stituted) amino function.17 Mostly, these reactions were
performed in the presence of aluminum trichloride as a
catalyst. In this work, therefore, we report on direct mild
non-catalytic trifluoroacetylation of electron-rich N-sub-
stituted pyrazoles with trifluoroacetic anhydride in pyri-
dine.
N
r.t., 12 h
84%
N
N
Me
1a
Me
2a
Scheme 2 Synthesis of ketone 2a
Given the simplicity and efficiency of this protocol, we
next studied its scope (Table 1). Pyrazoles 1b–f bearing
three electron-donating groups smoothly reacted to afford
products 2b–f in 62–91% yield. Aminopyrazole 1g gave
bis-trifluoroacetylated ketone 2g when using excess tri-
fluoroacetic anhydride. While disubstituted pyrazole 1h
also gave product 2h at room temperature, mono-substi-
tuted pyrazoles 1i–k showed low conversion (30–40%).
We obtained the corresponding products 2i–k in good
yields, however, by performing the reaction under heating
with two equivalents of trifluoroacetic anhydride.
We selected the model pyrazole 1a to validate the sug-
gested transformation, because it contained three elec-
tron-rich methyl groups that maximally facilitate the
electrophilic reaction. In fact, treating a solution of 1a in
pyridine at 0 °C with trifluoroacetic anhydride (2.0 equiv)
followed by stirring the reaction mixture at room temper-
ature for 12 hours completed the transformation. More-
over, we found that the amount of trifluoroacetic
anhydride can be reduced to 1.1 equivalents without af-
fecting the reaction conversion. The product 2a was iso-
lated from the reaction mixture in 84% yield by
Table 1 Synthesis of Ketones 2a–k
Entry
Substrate
Product
(CF3CO)2O (equiv) Temp
Time (h)
Yield (%)
COCF3
N
N
N
1
1.1
1.1
1.1
r.t.
r.t.
r.t.
12
84
N
Me
Me
1a
2a
COCF3
N
N
N
N
2
3
12
12
74
81
OMe
OMe
1b
2b
COCF3
N
N
N
N
Ph
Ph
1c
2c
COCF3
N
N
N
N
4
1.1
r.t.
12
91
1d
2d
© Georg Thieme Verlag Stuttgart · New York
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V. V. Arhipov et al.
PAPER
Table 1 Synthesis of Ketones 2a–k (continued)
Entry
Substrate
Product
(CF3CO)2O (equiv) Temp
Time (h)
Yield (%)
COCF3
N
N
N
OMe
OMe
N
5
1.1
r.t.
12
62
1e
2e
COCF3
N
N
N
N
6
7
8
9
1.1
4.0
1.1
2.0
r.t.
12
12
12
6
94
74
90
54
Ph
Ph
1f
2f
COCF3
N
N
N
NH2
NHCOCF3
N
r.t.
Ph
Ph
1g
2g
COCF3
COCF3
COCF3
N
N
N
N
r.t.
Me
Me
1h
2h
N
N
N
N
reflux
Me
Me
1i
2i
N
N
N
N
N
10
11
2.0
2.0
reflux
reflux
6
67
92
1j
2j
COCF3
N
N
N
6
1k
2k
The reaction, however, did not work for pyrazoles bearing The structure of product 2f was confirmed by an X-ray
the electron-withdrawing substituents: substrates 3 and 4 diffraction study (Figure 2).18
(Figure 1) remained unchanged.
Two interesting features are seen in the crystal phase of
ketone 2f: first, the phenyl and pyrazole rings are not
coplanar, as the N(2)–N(1)–C(Ph)–C(Ph) torsion angle is
–48.2(3)°. The twist is probably due to a steric repulsion
N
between the phenyl ring and the methyl group at the C5 at-
N
N
Cl
N
om, which is confirmed by presence of shortened intramo-
lecular contact C(13)···C(5) 3.19 Å, H(13c)···C(5) 2.75 Å,
H(13c)···C(4) 2.67 Å (the van der Waals radii sum19 is
3.42 Å for the C–C contact and 2.87 Å for the H–C). Sec-
ond, the carbonyl group is not coplanar to the pyrazole
Ph
Me
3
4
Figure 1 Compounds that failed to give the trifluoroacetyl deriva-
tives
Synthesis 2014, 46, 1254–1260
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Trifluoroacetylation of Electron-Rich Pyrazoles
1257
Solvents were purified according to standard procedures. Column
chromatography was performed using Kieselgel Merck 60 (230–
1
400 mesh). H, 19F, and 13C NMR spectra were recorded at 499.9
MHz, 470.3 MHz, and 124.9 MHz referenced to TMS (1H, 13C) or
CFCl3 (19F) as internal standards. Mass spectra were recorded either
on GC/MS instrument by electronic ionization (EI) or on LC/MS in-
strument by chemical ionization (CI).
2,2,2-Trifluoro-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanone
(2a), Typical Procedure
To a solution of pyrazole 1a (50.0 g, 0.45 mol) in pyridine (200 mL,
2.6 mol) cooled to 0 °C (CF3CO)2O (69.5 mL, 0.50 mol) was added
dropwise. The mixture was stirred at r.t. for 12 h. H2O (1000 mL)
was added. The formed suspension was washed with CH2Cl2 (3 ×
500 mL). The organic layer was dried (Na2SO4), filtered, and evap-
orated under vacuum. The residue was purified by vacuum distilla-
tion (bp 107–110 °C/26.7 mbar) to afford pure 2a (78.6 g, 0.38
mmol, 84%) as a yellowish liquid.
Figure 2 Molecular structure of compound 2f according to XRD.
Thermal ellipsoids are shown at 30% probability level. Atoms: C,
grey; N, blue; O, red; F, yellow. Hydrogen atoms are omitted for clar-
ity.
ring with the O(1)–C(11)–C(2)–C(1) torsion angle being
13.7(4)°. In this case, steric repulsion between trifluoro-
acetyl group and methyl substituents at C(1) and C(3)
seems to be involved [the shortened intramolecular con-
tacts O(1)–C(10) 2.95 Å (the van der Waals radii sum is
3.00 Å), C(13)···C(12) 3.31 Å (3.42 Å), H(13b)···C(12)
2.86 Å (2.87 Å), H(13b)···F(2) 2.45 Å (2.57 Å)].
1H NMR (500 MHz, CDCl3, TMS): δ = 3.65 (s, 3 H), 2.35 (s, 3 H),
2.22 (s, 3 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 174.2 (q, 2JC,F = 37.5 Hz),
150.4 (s), 146.6 (s), 116.2 (q, 1JC,F = 287.5 Hz), 112.5 (s), 35.7 (s),
13.8 (s), 11.6 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –74.3 (s).
MS: m/z = 207 [M + 1]+.
To study the reactivity of the carbonyl group in the syn-
thesized ketones, several representative reactions on the
simplest pyrazole 2i were performed (Scheme 3).
2,2,2-Trifluoro-1-[1-(2-methoxyethyl)-3,5-dimethyl-1H-pyr-
azol-4-yl]ethanone (2b)
Following the typical procedure for 2a from 1b gave 2b as a yellow-
ish liquid; yield: 1.2 g (74%).
HO
1H NMR (500 MHz, CDCl3, TMS): δ = 4.22 (t, J = 5.0 Hz, 2 H),
3.70 (t, J = 5.0 Hz, 2 H), 3.27 (s, 3 H), 2.51 (s, 3 H), 2.41 (s, 3 H).
NO2
HO
CF3
CF3
13C NMR (125 MHz, CDCl3 TMS): δ = 175.3 (q, 2JC,F = 36.5 Hz),
150.7 (s), 147.8 (s), 115.8 (q, 1JC,F = 288.7 Hz), 112.2 (s), 70.3 (s),
56.6 (s), 48.5 (s), 13.7 (s), 11.4 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.3 (s).
MS: m/z = 251 [M + 1]+.
N
NaBH4
MeOH
r.t.
DBU, MeNO2
CH2Cl2, r.t.
N
N
N
Me
O
Me
6
94%
93%
5
CF3
CO2Et
N
PhMgCl
THF, r.t.
N
1-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2,2-trifluoroeth-
anone (2c)
Following the typical procedure for 2a from 1c gave 2c as a yellow-
ish liquid; yield: 14.2 g (81%).
1H NMR (500 MHz, CDCl3, TMS): δ = 7.34–7.28 (m, 3 H), 7.13 (d,
J = 7.5 Hz, 2 H), 5.29 (s, 2 H), 2.47 (s, 6 H).
PO(OEt)2
NaH, THF
Me
2i
HO
97%
79%
CO2Et
CF3
N
CF3
N
Me
13C NMR (125 MHz, CDCl3 TMS): δ = 175.4 (q, 2JC,F = 35.1 Hz),
N
N
150.6 (s), 146.6 (s), 134.7 (s), 128.6 (s), 127.8 (s), 126.4 (s), 115.5
7
1
5
Me
(q, JC,F = 280.4 Hz), 112.8 (s), 52.7 (s), 14.6 (q, JC,F = 3.8 Hz),
8
11.6 (s).
Scheme 3 Reactions of compound 2i
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.2 (s).
MS: m/z = 283 [M + 1]+.
Condensation of compound 2i with nitromethane using
DBU as the base smoothly afforded the corresponding
product 5 in 93% yield. Reduction of the carbonyl group
with sodium borohydride provided alcohol 6 in 94%
yield. Addition of the Grignard reagent to 2i gave alcohol
7. The Horner–Wadsworth–Emmons reaction of 2i led to
alkene 8.20
1-(1-tert-Butyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2,2-trifluoro-
ethanone (2d)
Following the typical procedure for 2a from 1d gave 2d as a yellow-
ish liquid; yield: 14.2 g (91%); bp 95–97 °C/0.53 mbar.
1H NMR (500 MHz, CDCl3, TMS): δ = 2.70 (s, 3 H), 2.40 (s, 3 H),
1.68 (s, 9 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 176.3 (q, 2JC,F = 36.3 Hz),
147.4 (s), 147.0 (s), 116.3 (q, 1JC,F = 288.7 Hz), 114.2 (s), 61.5 (s),
29.9 (s), 14.3 (s), 14.2 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.0 (s).
MS: m/z = 249 [M + 1]+.
We have developed an easy practical method for trifluo-
roacetylation of electron-rich pyrazoles at C4. The reac-
tion is performed in pyridine with trifluoroacetic
anhydride as an acylating agent. Di- and trisubstituted
pyrazole reacted at room temperature, while monosubsti-
tuted required heating.21
© Georg Thieme Verlag Stuttgart · New York
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V. V. Arhipov et al.
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1-(1-Ethyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone (2j)
Following the typical procedure for 2a from 1j using (CF3CO)2O (2
equiv) at reflux for 6 h gave 2j as a yellowish liquid; yield: 8.2 g
(67%); bp 104–106 °C/13.3 mbar.
1-(1-tert-Butyl-5-methoxy-3-methyl-1H-pyrazol-4-yl)-2,2,2-tri-
fluoroethanone (2e)
Following the typical procedure for 2a from 1e gave 2e as a yellow-
ish liquid; yield: 3.1 g (62%).
1H NMR (500 MHz, CDCl3, TMS): δ = 3.99 (s, 3 H), 2.35 (s, 3 H),
1.56 (s, 9 H).
1H NMR (500 MHz, CDCl3, TMS): δ = 7.99 (s, 1 H), 7.79 (s, 1 H),
4.05 (q, J = 7.5 Hz, 2 H), 1.29 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 173.3 (q, 2JC,F = 36.3 Hz),
159.2 (s), 146.6 (s), 116.4 (q, 1JC,F = 283.5 Hz), 102.5 (s), 62.4 (s),
60.1 (s), 28.8 (s), 15.1 (s).
13C NMR (125 MHz, CDCl3 TMS): δ = 174.1 (q, 2JC,F = 36.4 Hz),
141.3 (s), 133.5 (s), 116.1 (q, 1JC,F = 288.8 Hz), 115.1 (s), 47.5 (s),
14.3 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.2 (s).
MS: m/z = 265 [M + 1]+.
19F NMR (375 MHz, CDCl3, CFCl3): δ = –76.2 (s).
MS: m/z = 193 [M + 1]+.
1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoroeth-
anone (2f)
Following the typical procedure for 2a from 1f gave 2f as a yellow-
ish solid; yield: 140.0 g (94%); bp 85–87 °C/0.53 mbar; mp 48 °C.
1H NMR (500 MHz, CDCl3, TMS): δ = 7.52 (m, 3 H), 7.41 (d,
J = 7.5 Hz, 2 H), 2.53 (s, 6 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 175.9 (q, 2JC,F = 36.3 Hz),
151.6 (s), 141.2 (s), 137.9 (s), 129.4 (s), 129.2 (s), 125.8 (s), 116.2
(q, 1JC,F = 287.5 Hz), 113.6 (s), 14.5 (s), 13.1 (s).
1-[1-(1-Ethylpropyl)-1H-pyrazol-4-yl]-2,2,2-trifluoroethanone
(2k)
Following the typical procedure for 2a from 1k using (CF3CO)2O
(2 equiv) at reflux for 6 h gave 2k as a yellowish liquid; yield: 2.3 g
(92%); bp 90–94 °C/0.53 mbar.
1H NMR (500 MHz, CDCl3, TMS): δ = 8.10 (s, 1 H), 8.05 (s, 1 H),
3.98 (m, 1 H), 1.90 (m, 4 H), 0.79 (d, J = 7.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 174.2 (q, 2JC,F = 37.1 Hz),
4
4
141.4 (q, JC,F = 5.0 Hz), 133.3 (q, JC,F = 5.0 Hz), 117.2 (q,
1JC,F = 286.4 Hz), 67.5 (s), 27.5 (s), 10.0.
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.9 (s).
MS: m/z = 270 [M + 1]+.
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.4 (s).
MS: m/z = 235 [M + 1]+.
2,2,2-Trifluoro-N-[3-methyl-1-phenyl-4-(trifluoroacetyl)-1H-
pyrazol-5-yl]acetamide (2g)
Following the typical procedure for 2a from 1g using (CF3CO)2O
(4 equiv) gave 2g as a yellowish oil that crystallized upon standing;
yield: 23.1 g (74%). An analytically pure sample was obtained by
crystallization (CH2Cl2) as a white solid; mp >200 °C.
1,1,1-Trifluoro-2-(1-methyl-1H-pyrazol-4-yl)-3-nitropropan-2-
ol (5)
To a solution of compound 2i (1.00 g, 5.6 mmol) in CH2Cl2 (20 mL)
was added MeNO2 (0.68 g, 11.2 mmol) and DBU (1.20 g, 7.9
mmol). The mixture stirred for 16 h at r.t. 1 M aq HCl (20 mL) was
added. The organic layer was washed with H2O (2 × 10 mL), dried
(MgSO4), and evaporated under vacuum. The product was purified
by column chromatography (EtOAc–hexane, 1:1) to provide pure 5
(1.25 g, 93%) as a white solid; mp 125 °C.
1H NMR (500 MHz DMSO-d6, TMS): δ = 7.82 (d, J = 7.7 Hz, 2 H),
7.44 (t, J = 7.7 Hz, 2 H), 7.29 (t, J = 7.7 Hz, 1 H), 2.32 (s, 3 H).
2
13C NMR (125 MHz, DMSO-d6, TMS): δ = 175.5 (q, JC,F = 35.0
Hz), 158.5 (q, 2JC,F = 31.2 Hz), 154.0 (s), 150.2 (s), 139.9 (s), 128.8
1
1H NMR (500 MHz, DMSO-d6, TMS): δ = 7.86 (s, 1 H), 7.57 (s, 1
H), 7.47 (s, 1 H), 5.17 (d, 3JH,H = 12.0 Hz, 1 H), 5.07 (d, 3JH,H = 12.0
Hz, 1 H), 3.85 (s, 3 H).
13C NMR (125 MHz, DMSO-d6, TMS): δ = 137.8 (s), 130.6 (s),
125.8 (q, 1JC,F = 285.0 Hz), 116.3 (s), 79.4 (s), 73.0 (q, 2JC,F = 30.0
Hz), 39.1 (s).
19F NMR (375 MHz, DMSO-d6, CFCl3): δ = –78.76 (s).
MS: m/z = 240 [M + 1]+.
(s), 126.5 (s), 123.4 (s), 117.2 (q, JC,F = 288.8 Hz), 116.5 (q,
1JC,F = 287.5 Hz), 105.4 (s), 14.8 (s).
19F NMR (375 MHz, DMSO-d6, CFCl3): δ = –72.8 (s), –74.5 (s).
MS: m/z = 366 [M + 1]+.
1-(1,5-Dimethyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone (2h)
Following the typical procedure for 2a from 1h gave 2h as a yellow-
ish liquid; yield: 2.5 g (90%); bp 98–100 °C/26.7 mbar.
1H NMR (500 MHz, CDCl3, TMS): δ = 7.90 (s, 1 H), 3.84 (s, 3 H),
2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-4-yl)ethanol (6)
2.59 (s, 3 H).
To a solution of compound 2i (10.0 g, 56 mmol) in MeOH (100 mL)
at –10 °C was added NaBH4 (2.1 g, 56 mmol) in small portions, so
that the temperature did not rise above 0 °C. After the addition, the
mixture was allowed to warm to r.t. with stirring for 3 h. The mix-
ture was diluted with EtOAc (150 mL) and H2O (150 mL). The or-
ganic layer was separated and washed with H2O (2 × 150 mL). The
organic layer was separated, dried (Na2SO4), and evaporated under
vacuum to give pure 6 (9.5 g, 94%) as a white solid; mp 53–55 °C.
13C NMR (125 MHz, CDCl3 TMS): δ = 174.6 (q, 2JC,F = 36.5 Hz),
146.4 (q, JC,F = 5.0 Hz), 140.6 (q, JC,F = 5.0 Hz), 112.9 (s), 35.8
(s), 10.8 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –76.1 (s).
MS: m/z = 193 [M + 1]+.
4
4
2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-4-yl)ethanone (2i)
Following the typical procedure for 2a from 1i using (CF3CO)2O (2
equiv) at reflux for 6 h gave 2i as a yellowish solid; yield: 11.2 g
(54%) ; bp 90–93 °C/26.7 mbar; mp 36 °C.
1H NMR (500 MHz, CDCl3, TMS): δ = 8.04 (s, 1 H), 7.96 (s, 1 H),
3.92 (s, 3 H).
1H NMR (500 MHz, CDCl3, TMS): δ = 7.44 (s, 1 H), 7.43 (s, 1 H),
5.06 (br s, 1 H), 4.96 (q, 3JH,F = 7.5 Hz, 1 H), 3.82 (s, 3 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 138.0 (s), 129.8 (s), 124.6
(q, 1JC,F = 280.0 Hz), 116.4 (q, 3JC,F = 1.3 Hz), 65.5 (q, 2JC,F = 32.5
Hz), 38.7 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –79.7 (d, 3JF,H = 3.8 Hz).
MS: m/z = 181 [M + 1]+.
13C NMR (125 MHz, CDCl3 TMS): δ = 174.2 (q, 2JC,F = 37.5 Hz),
141.8 (s), 135.0 (s), 116.4 (s), 116.3 (q, 1JC,F = 287.5 Hz), 39.5 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –75.6 (s).
MS: m/z = 179 [M + 1]+.
3,3,3-Trifluoro-2-(1-methyl-1H-pyrazol-4-yl)-2-phenylprop-
anol (7)
To a solution of compound 2i (500 mg, 2.8 mmol) in anhyd THF (5
mL) at 0 °C was added a solution of PhMgCl in THF (3.1 mmol, 1.1
Synthesis 2014, 46, 1254–1260
© Georg Thieme Verlag Stuttgart · New York

PAPER
Trifluoroacetylation of Electron-Rich Pyrazoles
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equiv). The mixture was stirred at r.t. for 12 h. The mixture was
evaporated under vacuum, and H2O (1 mL) was added to the resi-
due. The formed suspension was extracted with EtOAc (3 × 2 mL).
The combined organic extracts were dried (Na2SO4), filtered, and
evaporated under vacuum to afford pure 7 (690 mg, 2.7 mmol, 97%)
as a grey solid; mp 114–116 °C.
References
(1) These authors contributed equally to this work.
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1H NMR (500 MHz, CDCl3, TMS): δ = 7.53 (s, 2 H), 7.35–7.31 (2
s, 4 H), 7.23 (s, 1 H), 3.80 (s, 3 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 137.8 (s), 129.5 (s), 128.3
(s), 127.6 (s), 126.9 (s), 124.4 (q, 1JC,F = 281.2 Hz), 121.7 (s), 74.4
(q, 2JC,F = 30.0 Hz), 38.4 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –78.01 (s).
MS: m/z = 257 [M + 1]+.
Ethyl (2E)-4,4,4-Trifluoro-3-(1-methyl-1H-pyrazol-4-yl)but-2-
enoate (8)
To a suspension of NaH (248 mg, 60%, 6.2 mmol) in THF (10 mL)
at 0 °C under stirring was added a solution of (EtO)2P(O)CH2CO2Et
(1.38 g, 6.2 mmol) in THF (3 mL) dropwise. The mixture was vig-
orously stirred at r.t. for 30 min. The mixture was cooled to 0 °C
again, and a solution of 2i (1.0 g, 5.6 mmol) in anhyd THF (5 mL)
was added dropwise. The mixture was additionally stirred at r.t. for
12 h. The solvent was evaporated under vacuum and H2O (5 mL)
was added. The formed suspension was extracted with EtOAc (3 ×
10 mL). The combined organic extracts were dried (Na2SO4) and
evaporated under vacuum to give pure 8 (1.1 g, 4.4 mmol, 79%) as
a viscous oil.
1H NMR (500 MHz, CDCl3, TMS): δ = 7.96 (s, 1 H), 7.75 (s, 1 H),
6.36 (s, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.91 (s, 3 H), 1.28 (t, J = 7.0
Hz, 3 H).
13C NMR (125 MHz, CDCl3 TMS): δ = 164.5 (s), 140.0 (s), 133.1
(q, 2JC,F = 36.5 Hz), 132.2 (s), 122.5 (q, 1JC,F = 281.1 Hz), 118.4 (s),
110.4 (s), 60.8 (s), 38.7 (s), 13.7 (s).
19F NMR (375 MHz, CDCl3, CFCl3): δ = –66.8 (s).
MS: m/z = 249 [M + 1]+.
(6) Khodakovskiy, P. V.; Volochnyuk, D. M.; Panov, D. M.;
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(b) Khodakovskiy, P. V.; Volochnyuk, D. M.; Tolmachev,
A. A. Synthesis 2009, 1099. (c) Khodakovskiy, P. V.;
Mykhailiuk, P. K.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2010, 967. (d) Khodakovskiy, P. V.; Mykhailiuk,
P. K.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis
2010, 979. (e) Khodakovskiy, P. V.; Mykhailiuk, P. K.;
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1633.
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Marchetti, F.; Pettinari, C.; Pettinari, R.; Skelton, B. W.;
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X-ray Diffraction Study
The colorless crystals of 2f (C13H11N2OF3) are orthorhombic. At
293 K a = 25.174(2), b = 25.175(2), c = 8.123(1) Å, V = 5148.3(9)
Ǻ3, Mr = 268.24, Z = 16, space group Fdd2, dcalc = 1.384 g/сm3,
μ(MoKα) = 0.119 mm–1, F(000) = 2208. Intensities of 5809 reflec-
tions (1980 independent, Rint = 0.026) were measured on the «Xcal-
ibur-3» diffractometer (graphite monochromated MoKα radiation,
CCD detector, ω-scanning, 2Θmax = 50°). The structure was solved
by direct method using SHELXTL package.22 Positions of the hy-
drogen atoms were located from electron density difference maps
and refined by ‘riding’ model with Uiso = nUeq of the carrier atom
(n = 1.5 for hydrogen atoms of methyl groups and n – 1.2 for other
hydrogen atoms). Full-matrix least-squares refinement against F2 in
anisotropic approximation for non-hydrogen atoms using 1971 re-
flections was converged to wR2 = 0.092 (R1 = 0.036 for 1477 reflec-
tions with F > 4σ(F), S = 0.997). The final atomic coordinates, and
crystallographic data for molecule 2f have been deposited with the
Cambridge Crystallographic Data Centre, 12 Union Road, CB2
1EZ,
UK
(fax:
+44(1223)336033;
e-mail:
depos-
it@ccdc.cam.ac.uk) and are available on request quoting the depo-
sition numbers CCDC 951419).
Acknowledgement
D.Y. and P.M. are very grateful to Dr. Marian Gorichko for moral
support and helpful discussions during this project.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
© Georg Thieme Verlag Stuttgart · New York
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V. V. Arhipov et al.
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Synthesis 2014, 46, 1254–1260
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