Substitution of two fluorine atoms in a trifluoromethyl group: Regioselective synthesis of 3-fluoropyrazoles

Article abstract of DOI:10.1002/anie.201206946

Replacing the fluorine: 3-Fluorinated pyrazoles were regioselectively synthesized by sequential substitution reactions of 2-trifluoromethyl-1-alkenes (see scheme). S_N2'-type reactions of 2-trifluoromethyl-1-alkenes with deprotonated tert-butoxy

Full text of DOI:10.1002/anie.201206946

Angewandte
Chemie
DOI: 10.1002/anie.201206946
Heterocycle Formation
Substitution of Two Fluorine Atoms in a Trifluoromethyl Group:
Regioselective Synthesis of 3-Fluoropyrazoles**
Kohei Fuchibe, Masaki Takahashi, and Junji Ichikawa*
Fluorine atoms in vinylic and allylic positions are highly
versatile substituents.[1] Among the compounds bearing these
fluorine atoms, 2-trifluoromethyl-1-alkenes and 1,1-difluoro-
1-alkenes are attractive as building blocks for organic
syntheses.[2] Because these fluoroalkenes are electron-defi-
cient, they inherently react with nucleophiles instead of
electrophiles. 2-Trifluoromethyl-1-alkenes are subjected to
nucleophilic attack at the carbon atom in the position g with
respect to the fluorine substituents (Scheme 1A).[2] Succes-
alkenes at the vinylic CF2 carbon atom (Scheme 1B).[2] This
substitution provides monofluorinated and non-fluorinated
alkenes through an addition–elimination process (SNV reac-
tion).[4] Both substitutions have been useful in organic
syntheses.[5–9]
On the basis of the concept of combining these two
substitutions, we adopted a simple method of constructing
fluorinated ring systems using bifunctional nucleophiles (XH-
YH, Scheme 1C). In the proposed ring constructions, SN2’-
type reactions of 2-trifluoromethyl-1-alkenes would proceed
with one of the nucleophilic centers (XH-) to give the
corresponding 1,1-difluoro-1-alkenes, and the 1,1-difluoro-1-
alkenes formed would then be subjected to intramolecular
SNV reactions with the other nucleophilic moiety (-YH), to
give ring-fluorinated cyclic compounds. In this sequence, the
substitution of two fluorine atoms in a trifluoromethyl group
could be used to construct two bonds, which would promote
an unprecedented ring formation.
Herein, we report a simple method for the synthesis of 3-
fluoropyrazoles using hydrazines as bifunctional nucleophiles.
Pyrazoles bearing fluoroalkyl groups have been synthesized
for their use in agrochemicals and pharmaceuticals.[10] In
contrast, methods for the synthesis of ring-fluorinated pyr-
azoles have not been extensively studied and have not been
well developed to date.[11–13]
SN2’-type reactions of trifluoromethylstyrene 1a with
substituted hydrazines were examined (Table 1). When meth-
Table 1: SN2’-type reactions of trifluoromethylstyrene 1a.[a]
Scheme 1. Background and concept of our ring construction.
sive elimination of fluoride ions proceeds, which is caused by
migration of the double bond, resulting in the formation of
1,1-difluoro-1-alkenes (SN2’-type reaction).[3] On the other
hand, nucleophilic substitution occurs in the 1,1-difluoro-1-
Entry
R
Base
Conditions
Yield [%]
1
2
3
4
5
6
Me
Ac
Bz
Ts
nBuLi
NaH
NaH
nBuLi
NaH
nBuLi
À788C, 2 h
reflux, 4.5 h
558C, 24 h
À78 to 08C, 3 h
08C, 1 h
66 (55:45)[b]
11[c]
[*] Dr. K. Fuchibe, M. Takahashi, Prof. J. Ichikawa
Division of Chemistry, Faculty of Pure and Applied Sciences,
University of Tsukuba
–
–
Boc, 2a[d]
Ph, 2b
92, 3a
À608C, 2 h
75,[c] 3e; 6,[c] 4e
Tsukuba, Ibaraki 305-8571 (Japan)
E-mail: junji@chem.tsukuba.ac.jp
Homepage: http://www.chem.tsukuba.ac.jp/junji/index.html
[a] THF=tetrahydrofuran. [b] The regioisomeric ratio was determined by
19F NMR spectroscopy. The regiochemistry was not assigned. [c] Yield as
determined by 19F NMR spectroscopy. [d] 2a (1.8 equiv.) and NaH
(1.8 equiv.).
[**] We acknowledge the Grants-in-Aid for Scientific Research on
Innovative Areas “Organic Synthesis Based on Reaction Integration.
Development of New methods and Creation of New Substances”
(No. 2105) for financial support. We also thank Tosoh F-TECH, Inc.
for the generous gift of2-bromo-2,2,2-trifluoroprop-1-ene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206946.
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ylhydrazine was used, the corresponding substitution prod-
ucts 3 were obtained as a roughly 1:1 mixture of regioisomers
in terms of the hydrazine nitrogen atoms (66% yield, entry 1).
SN2’-type reactions with acetyl (Ac), benzoyl (Bz), and p-
toluenesulfonyl (Ts, tosyl) hydrazines were tested without
success (entries 2–4). However, tert-butoxycarbonyl (Boc)
hydrazine 2a regioselectively gave 1,1-difluoro-1-alkene 3a,
which is the desired SN2’-type product with a Boc group on the
inner nitrogen, in 92% yield (entry 5). Phenylhydrazine 2b
was also subjected to the regioselective SN2’-type reaction
using treatment with butyllithium at À608C to give 3e in 75%
yield (entry 6) with a small amount of the overreaction
product 4e (6%).[14]
The difluoroalkenes 3 formed were tosylated without
purification on their terminal nitrogen atom to give tosylhy-
drazides 5a–h in excellent yield. Hydrazides 5 were expected
to afford aromatized 3-fluoropyrazoles directly through
intramolecular SNV reactions and elimination of p-toluene-
sulfinic acid.
When tosylhydrazide 5a was treated with NaH
(2.2 equiv.) in refluxing THF, ring closure proceeded to give
the cyclized product, dihydropyrazole 6a in 10% yield and
the desired aromatized 3-fluoropyrazole 7a in 11% yield
(Table 3, entry 1). The yield of the desired 7a was remarkably
Table 3: Cyclization and elimination reactions of 5a.
Similarly, several 2-trifluoromethyl-1-alkenes 1 were sub-
jected to SN2’-type reactions with Boc- and arylhydrazines 2 to
form difluorostyrenes 3, the tosylation of which gave the
corresponding tosylhydrazides 5 (Figure 1 and Table 2). The
Entry
Base
Solvent[a]
Conditions
6a [%][b]
7a [%][b]
1
2
3
4
5
6
NaH
NaH
NaH
NaH
LHMDS
KH
THF
reflux, 9 h
RT, 12 h
RT, 12 h
RT, 5 h
RT, 20 h
RT, 6.5 h
10
4
11
32
HMPA
DMA
DMF
DMF
DMF
13
12[c]
6
68
86[c]
47
8[c]
56[c]
[a] HMPA=hexamethylphosphoramide; DMA=N,N-dimethylaceta-
mide; DMF=dimethylformamide. [b] Yield as determined by 19F NMR
spectroscopy. [c] Yield of the isolated product.
Figure 1. List of substrates.
rates of the SN2’-type reactions were significantly affected by
the substituent: the electron-donating methoxy group on 1b
decreased the rate of the SN2’-type reaction (7 hours, 95%
yield, entry 2) and the electron-withdrawing bromo- and
trifluoromethyl groups on 1c and 1d increased the rate of the
reaction (0.5 hours each, 72% and 79% yields, entries 3 and
4, respectively). Tolylhydrazines 2c and 2d, each bearing an
electron-donating methyl group, gave the corresponding SN2’-
type products 3 f and 3g in 80% and 88% yields, respectively
(entries 6 and 7), while 2e bearing an electron-withdrawing
trifluoromethyl group gave 3h in 32% yield (entry 8).
improved to 86% by conducting the reaction in DMF as
opposed to other solvents (entries 2–4). Lithium hexamethyl-
disilazide (LHMDS) and KH were found to be less effective
as bases for the reaction than NaH (entries 5 and 6).[15]
Ring closure and elimination reactions completed our
sequential synthesis of 3-fluoropyrazoles (Table 4). Boc-
hydrazides 5a–d were treated with NaH in DMF to give the
corresponding 3-fluorinated N-Boc-pyrazoles 7a–d in 55–
86% yields (entries 1–4). Arylhydrazides 5e–h also afforded
the corresponding 3-fluorinated N-arylpyrazoles 7e–h in 96–
98% yields (entries 5–8). These products 7 and 6 were
obtained as single regioisomers.[16]
Table 2: Regioselective SN2’-type reaction and tosylation.
Synthesis of 4-unsubstituted 3-fluoropyrazoles was also
accomplished by using 2-silylated trifluoromethylalkenes
(Scheme 2). Although the parent, 2-unsubstituted 3,3,3-tri-
fluoropropene was not a suitable substrate for the SN2’-type
reaction with hydrazines,[17] 2-silylated trifluoropropene 1e
was readily subjected to SN2’-type reactions with Boc- and
phenylhydrazines, 2a and 2b.[3a] Desilylation occurred during
cyclization to give 3-fluoropyrazoles 7i and 7j in high yields.
To elucidate the cyclization mechanism, we performed
several experiments. When the isolated dihydropyrazole 6c
was treated with NaH, 7c was not obtained [Eq. (1)]. This
suggests that the formation of fluoropyrazoles 7 proceeds
Entry
1
2
Conditions[a]
3 [%][b]
5 [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1a
1a
2a
2a
2a
2a
2b
2c
2d
2e
A, 1 h
A, 7 h
A, 0.5 h
A, 0.5 h
B, 2 h
B, 2 h
B, 2 h
B, 2 h
97, 3a
95, 3b
72, 3c
79, 3d
76, 3e
80, 3 f
88, 3g
32,[d] 3h
96 [89], 5a
99 [88], 5b
98 [72], 5c
quant. [69], 5d
92 [63], 5e
96 [57], 5 f
83 [73], 5g
94 [30], 5h
[a] Condition A: 2a, NaH (1.8 equiv.), THF, 08C. Condition B: 2b–e,
nBuLi (1.8 equiv.), THF, À78 to À558C. [b] Yield as determined by
19F NMR spectroscopy. [c] Yield as determined by 19F NMR spectroscopy
for tosylation step. Yield of the isolated product over two steps is shown
in square brackets. [d] À988C.
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Table 4: Synthesis of 3-fluoropyrazoles.[a]
Entry
5
t [h]
7 [%]
6 [%]
1
5a
5
86, 7a
12, 6a
2
3
5b
5c
72
14
85, 7b
55, 7c
–
20, 6c
4
5
6
7
8
5d
5e
5 f
14
6
56, 7d
98, 7e
98, 7 f
96, 7g
97, 7h
23, 6d
Scheme 3. Plausible mechanism for pyrazole formation.
–
–
–
–
10 (Scheme 3c).[20] Azomethine imines are normally prepared
from hydrazine derivatives and aldehydes and have been used
mainly in 1,3-dipolar cycloadditions to prepare pyrazolidines
and dihydropyrazoles.[21] The pyrazole ring formation ach-
ieved in this study provides a novel use for azomethine imines
in organic synthesis.
Thus, we have achieved substitution of two fluorine atoms
in a trifluoromethyl group by combining two substitutions of
allylic and vinylic fluorine atoms, which allows the regiose-
lective synthesis of 3-fluoropyrazoles: 1) the SN2’-type reac-
tion of 2-trifluoromethyl-1-alkenes with lithio- or sodio-
hydrazines gave 1,1-difluoro-1-alkenes and 2) the cyclization
of tosylated 1,1-difluoro-1-alkenes afforded 3-fluoropyrazoles
in good to excellent yield. We hypothesize that the cyclization
process proceeds via azomethine imine intermediates, which
will potentially promote the use of azomethine imines in
organic synthesis.
6
5g
5h
6
6
[a] Conditions: 5, NaH (2.2 equiv.), DMF, RT.
Experimental Section
Synthesis of tosylhydrazide 5a (Condition A): Sodium hydride
(43 mg, 1.8 mmol) was added to a THF (2.0 mL) solution of a-
trifluoromethylstyrene (1a, 172 mg, 1.00 mmol) and Boc-hydrazine
(2a, 239 mg, 1.80 mmol) at 08C. After the mixture was stirred for 1 h
at 08C, phosphate buffer (pH 7) was added to quench the reaction.
Organic materials were extracted with ethyl acetate three times. The
combined extracts were washed with brine and dried over anhydrous
sodium sulfate. After removal of the solvent under reduced pressure,
the residue was transferred to a reaction flask with ethyl acetate for
the following tosylation step. Ethyl acetate was removed under
vacuum and the residue was azeotropically dehydrated with pyridine
under reduced pressure three times to give crude 3a.
Tosyl chloride (515 mg, 2.70 mmol) was added to a pyridine
(2.0 mL) solution of the crude 3a at room temperature. After the
mixture was stirred for 2.5 h at room temperature, phosphate buffer
(pH 7) was added to quench the reaction. The mixture was filtered,
and organic materials were extracted with ethyl acetate three times.
The combined extracts were washed with brine and dried over
anhydrous sodium sulfate. After removal of the solvent under
reduced pressure, the residue was purified by column chromatog-
raphy (hexane/AcOEt 4:1) on silica gel. After removal of the solvent
under reduced pressure, hexane was added to the viscous liquid. The
obtained solid was washed with hexane three times, and tosylhydra-
zide 5a was obtained as a white powder (390 mg, 89%, two steps).
Synthesis of 3-fluoropyrazole 7a: Sodium hydride (24 mg,
1.0 mmol) was added to a DMF (0.9 mL) solution of tosylhydrazide
Scheme 2. Synthesis of 4-unsubstituted 3-fluoropyrazoles.
through a pathway other than the originally assumed SNV
process of 5 (Scheme 3a).[18] One possible alternative is the
pathway involving nitrene intermediates 8 (Scheme 3b).
However, this is not true because the separately-formed
nitrene 8a generated by treating 3a with iodosylbenzene[19]
gave the [2,3]-rearrangement product 9a along with only
a trace amount of 7a [Eq. (2)]. Therefore, we propose that the
cyclization proceeds through azomethine imine intermediates
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5a (200 mg, 0.456 mmol) at room temperature. After the mixture was
stirred for 5 h at room temperature, phosphate buffer (pH 7) was
added to quench the reaction. Organic materials were extracted with
ethyl acetate three times. The combined extracts were washed with
brine and dried over anhydrous sodium sulfate. After removal of the
solvent under reduced pressure, the residue was purified by column
chromatography (hexane/AcOEt 10:1) on silica gel to give fluoro-
pyrazole 7a (104 mg, 86%) and dihydrofluoropyrazole 6a (23 mg,
12%) as colorless liquids.
Ichikawa, K. Sakoda, J. Mihara, N. Ito, J. Fluorine Chem. 2006,
127, 489 – 504; e) K. Sakoda, J. Mihara, J. Ichikawa, Chem.
Commun. 2005, 4684 – 4686.
[10] See for example: a) S. Fustero, R. Romꢂn, J. F. Sanz-Cervera, A.
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Chem. 2008, 73, 3523 – 3529; b) P. J. Skinner, M. C. Cherrier, P. J.
Webb, Y.-J. Shin, T. Gharbaoui, A. Lindstrom, V. Hong, S. Y.
Tamura, H. T. Dang, C. C. Pride, R. Chen, J. G. Richman, D. T.
Connolly, G. Semple, Bioorg. Med. Chem. Lett. 2007, 17, 5620 –
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[11] [3-fluoropyrazoles] a) D. A. Clark, G. P. Lahm, B. K. Smith, J. D.
Barry, D. G. Clagg, Bioorg. Med. Chem. 2008, 16, 3163 – 3170;
b) F. Fabra, J. Vilarrasa, J. Coll, J. Heterocycl. Chem. 1978, 15,
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[12] For our previous synthesis of 3- and 5-fluoropyrazoles based on
substitution and dehydration of 2,2-difluorovinyl ketones, see:
a) J. Ichikawa, M. Kobayashi, Y. Noda, N. Yokota, K. Amano, T.
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Volle, M. Schlosser, Eur. J. Org. Chem. 2000, 823 – 828.
[13] For general reviews on syntheses of nonfluorinated pyrazoles,
see: a) S. Fustero, M. Sꢂnchez-Rosellꢃ, P. Barrio, A. Simꢃn-
Fuentes, Chem. Rev. 2011, 111, 6984 – 7034; b) K. Makino, H. S.
Kim, Y. Kurasawa, J. Heterocycl. Chem. 1999, 36, 321 – 332.
[14] Use of NaH as a base for the reaction of 2b at 08C gave a 41%
yield of 3e and a 20% yield of 4e. It is likely that performing the
reaction at À608C suppressed the overreaction to form 4e as
shown in entry 6 of Table 1.
Received: August 28, 2012
Published online: October 19, 2012
Keywords: cyclization · fluorine · fluoroalkene ·
.
nucleophilic substitution · pyrazole
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[16] X-ray crystal structure analysis of 7c confirmed that 7c has
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