Difluoromethyl phenyl sulfone, a difluoromethylidene equivalent: Use in the synthesis of 1,1-difluoro-1-alkenes

Article abstract of DOI:10.1002/anie.200460815

A nucleophilic substitution-elimination reaction strategy in which difluoromethyl phenyl sulfone is used as a selective difluoromethylidene equivalent allows the facile synthesis of 1,1-difluoro-1-alkenes from primary alkyl halides (see scheme).

Full text of DOI:10.1002/anie.200460815

Angewandte
Chemie
Fluorinated Alkenes
Difluoromethyl Phenyl Sulfone, a
Difluoromethylidene Equivalent: Use in the
Synthesis of 1,1-Difluoro-1-alkenes**
G. K. Surya Prakash,* Jinbo Hu, Ying Wang, and
George A. Olah
1,1-Difluoro-1-alkenes are unique compounds with unusually
high electrophilicity from the gem-difluorovinyl group, and
recently have drawn many synthetic and theoretical endeav-
ors.[1] gem-Difluorovinyl functionality has been known to act
as a bioisostere for aldehydes and ketones,[2] and it is critical
to many biologically active molecules such as enzyme
inhibitors[1,3] and pesticides.[4] 1,1-Difluoro-1-alkenes are
also useful synthetic precursors for the preparation of other
fluorinated compounds and polymers.[5] Although several
different methods for the preparation of 1,1-difluoro-1-
alkenes have been disclosed in the literature including the
Wittig reaction using difluoromethylene ylides,[6] we now
report an efficient method for the transformation of readily
available primary alkyl halides into 1,1-difluoro-1-alkenes
(Scheme 1).
Scheme 1. Preparation of 1,1-difluoro-1-alkenes from primary alkyl
halides.
One can envision a nucleophilic substitution–elimination
strategy for this transformation, that is, a fluorine-bearing
À
nucleophile (such as CF3 ) substitutes the halogen atom of the
alkyl halide followed by an a,b-elimination (ÀHF or others).
However, while alkyl halides can readily react with various
carbon nucleophiles (mostly by SN2 reactions) to form
carbon–carbon bonds, their nucleophilic substitution reac-
tions with fluorine-bearing carbon nucleophiles are generally
difficult due to their unmatched hard–soft nature.[7] In
addition, although fluorinated organocopper reagents
(RfCu) can be used to couple with aryl, vinyl, benzyl, and
allyl halides, their reactions with simple alkyl halides are not
effective.[8]
[*] Prof. Dr. G. K. S. Prakash, Dr. J. Hu, Y. Wang, Prof. Dr. G. A. Olah
Loker Hydrocarbon Research Institute and
Department of Chemistry
University of Southern California
University Park, Los Angeles, CA 90089-1661 (USA)
Fax: (+1)213-740-6270
E-mail: gprakash@usc.edu
[**] Support of our work by Loker Hydrocarbon Research Institute is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 5203 –5206
DOI: 10.1002/anie.200460815
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Communications
Table 1: Optimization of the reaction conditions for the nucleophilic substitution of 1 with alkyl halides
and triflates.
The possible solution to this
problem is to introduce a proper
auxiliary functional group connect-
ing to the fluorinated carbon nucle-
ophile to increase its softness, since
the alkyl halide is a soft electro-
phile. Furthermore, the proper
auxiliary group should be easily
removed or transformed into other
functional groups afterwards. The
benzenesulfonyl group (PhSO2) is
one of the choices, for its softness
and its varying chemical reactivi-
ties (so-called “chemical chame-
leon”).[9] Difluoromethyl phenyl
sulfone (1) is the ideal compound
for this purpose, due to its easy
generation of the (benzenesulfo-
nyl)difluoromethyl anion 2 after
the deprotonation of its CF2H
group (Scheme 2).[10] Difluoro-
methyl phenyl sulfone can be read-
Run
1 (equiv)
3 (equiv)
Base (equiv)
Solvent
T [8C]
t [h]
Yield of
4 [%][a]
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
n-C5H11Br (2.1)
n-C5H11Br (2.1)
n-C5H11Br (2.1)
n-C5H11Br (4.0)
n-C5H11I (4.0)
n-C5H11Br (10.0)
n-C2H5I (4.0)
n-C2H5I (4.0)
tBuOK (1.0)
tBuOK (1.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
NaOH (25.0)[b]
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
DMF
DMF
DMF
DMF
DMF
CH2Cl2
DMF
THF
À50–25
À50–25
À50–25
À50
1.0
16.0
1.0
1.0
1.0
20.0
1.0
1.0
1.0
1.0
34
29
52
61
85
0[c]
65
0[d]
0[d]
0[e]
0[e]
À50
25
À50
À50
2-iodobutane (4.0)
CF3SO3CH3 (4.0)
CF3SO3CH3 (4.0)
DMF
DMF
THF
À50
10
11
À50
À50
1.0
[a] Yields were determined by 19F NMR spectroscopy using PhOCF3 as an internal standard. [b] 50 wt%
aqueous NaOH solution was used, with the catalytic amount of phase-transfer agent Aliquat 336.
[c] Unreacted 1 and a small amount of the by-product PhSO2CF2SPh were observed. [d] A messy product
mixture was observed. [e] Starting material 1 was recovered.
(Table 1, runs 10, 11), which may be due to the fast reaction
between DMF, alkyl triflate, and tBuOK to form the dialkyl
acetal of DMF.[13]
Following optimization of the reaction conditions, a
variety of alkyl-substituted gem-difluoromethyl phenyl sul-
Scheme 2. Generation of (benzenesulfonyl)difluoromethide from
fones 4 were prepared in good yields (Table 2). Various
primary alkyl iodides with different chain lengths were able to
be substituted with (benzenesulfonyl)difluoromethide (in situ
generated from 1) and tBuOK (Table 2, entries 1–6). Sub-
stituted alkyl iodides also behave in the similar way, which
leads to the formation of structurally diverse gem-difluori-
nated sulfones (Table 2, entries 7–12). Alkyl-substituted
difluoromethyl sulfones themselves are a group of useful
compounds used as nonlinear optical materials.[14] The known
available method for their preparation is by the a-fluorination
of sulfoxides bearing a-hydrogen atoms by elemental fluorine
difluoromethyl phenyl sulfone and a base.
ily prepared from sodium thiophenoxide and chlorodifluoro-
methane followed by oxidation.[10,11] The nucleophilic addi-
tion of 1 with carbonyl compounds in the presence of a base
has been demonstrated.[10b,c] Recently, we have reported the
synthetic application of 1 as a difluoromethyl anion equiv-
alent (“CF2HÀ”)[12] as well as a selective difluoromethylene
À
dianion equivalent (“ÀCF2 ”).[10c] Herein, we disclose another
significant synthetic application of 1 as a difluoromethylidene
=
equivalent (“ CF2”), which enables a novel synthesis of 1,1-
difluoro-1-alkenes from primary alkyl halides using an
Table 2: Preparation of substituted difluoromethyl sufones 4 from 1
(1 equiv), alkyl iodides (4 equiv), and tBuOK (2 equiv) in DMF at À508C
for 1 h.
unprecedented
approach.
nucleophilic
substitution–elimination
The nucleophilic substitution of difluoromethyl phenyl
sulfone 1 with alkyl bromides, alkyl iodides, and alkyl triflates
were examined, to produce alkylated difluoromethyl sulfone
3, with careful modifications of the reaction conditions
(Table 1). The reactions were typically performed under an
argon atmosphere, and a base was added to a mixture of 1 and
3. The best product yield was obtained when one equivalent
of 1 was treated with four equivalents of primary alkyl iodide
and two equivalents of tBuOK as a base in DMF at À508C for
1 h (Table 1, run 5). Primary alkyl bromides are also suitable
for the reaction but with somewhat lower yields (Table 1,
runs 1–4). A secondary alkyl halide, however, did not give the
anticipated product (Table 1, run 9), indicating that the
reaction proceeds by a typical SN2 pathway. Methyl triflate
did not react with 1 either to give the expected product
Entry
RCH2I
RCH2CF2SO2Ph (4)
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
CH3(CH2)6I
CH3(CH2)4I
CH3(CH2)3I
CH3(CH2)2I
CH3CH2I
CH3(CH2)6CF2SO2Ph (4a)
CH3(CH2)4CF2SO2Ph (4b)
CH3(CH2)3CF2SO2Ph (4c)
CH3(CH2)2CF2SO2Ph (4d)
CH3CH2CF2SO2Ph (4e)
CH3CF2SO2Ph (4 f)
Ph(CH2)3CF2SO2Ph (4g)
Ph(CH2)4CF2SO2Ph (4h)
Ph(CH2)5CF2SO2Ph (4i)
Ph(CH2)6CF2SO2Ph (4j)
Ph2CH(CH2)2CF2SO2Ph (4k)
PhO(CH2)3CF2SO2Ph (4l)
PhO(CH2)4CF2SO2Ph (4m)
79
80
84
73
62
42
71
52
59
50
37
71
60
CH3I
Ph(CH2)3I
Ph(CH2)4I
Ph(CH2)5I
Ph(CH2)6I
Ph2CH(CH2)2I
PhO(CH2)3I
PhO(CH2)4I
[a] Yield of isolated product.
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Chemie
with low yields (10 ~ 20%).[15] Our current methodology
possesses many advantages such as convenience, safety, cost,
and efficiency.
substitued difluoromethyl sulfones are highly efficient in their
facile transformations into 1,1-difluoro-1-alkenes by base-
induced eliminations. Difluoromethyl phenyl sulfone acts as a
difluoromethylidene equivalent. This new methodology
promises to be a highly useful synthetic tool for many other
potential applications.
During the preparation of alkyl-substituted difluoro-
methyl sulfones 4, the formation of a small amount of 1,1-
difluoro-1-alkenes as by-products was observed. This is due to
the high acidity of the a-hydrogen atom of the difluoro-
methylene group, which allows the easy deprotonation by
tBuOK to generate a new carbanion species 5 (Scheme 3).
Intermediates 5 readily undergo b-elimination to eliminate
the benzenesulfonyl group (rather than a fluorine atom) to
afford 1,1-difluoro-1-alkenes 6. The benzenesulfonyl group is
Received: May 27, 2004
Keywords: alkenes · fluorination · elimination · fluorine ·
.
nucleophilic substitution
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from À208C to room temperature.
Entry RCH2CF2SO2Ph (4)
RCH CF2 (6)
Yield [%][a]
=
=
1
2
3
4
5
6
Ph(CH2)3CF2SO2Ph
Ph(CH2)4CF2SO2Ph
Ph(CH2)5CF2SO2Ph
Ph(CH2)6CF2SO2Ph
Ph(CH2)2CH CF2 (6a)
85
71
82
80
84
55
=
Ph(CH2)3CH CF2 (6b)
=
Ph(CH2)4CH CF2 (6c)
=
Ph(CH2)5CH CF2 (6d)
=
Ph2CH(CH2)2CF2SO2Ph Ph2CHCH2CH CF2 (6e)
=
p-MeO-C6H4-
p-MeO-C6H4-(CH2)3CH
CF2 (6 f)
PhO(CH2)2CH CF2 (6g)
(CH2)4CF2SO2Ph
PhO(CH2)3CF2SO2Ph
PhO(CH2)4CF2SO2Ph
=
7
8
88
87
=
PhO(CH2)3CH CF2 (6h)
[a] Yield of isolated product.
[7] The nucleophilic substitution reaction of CF3À (generated in situ
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attempted by us with no success. However, the nucleophilic
trifluoromethylation of primary alkyl triflates was successful
using TMS-CF3 and fluoride. See: D. V. Sevenard, P. Kirsch, G.-
V. Roschenthaler, V. N. Movchun, A. A. Kolomeitsev, Synlett
2001, 379.
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In conclusion, the unprecedented nucleophilic substitu-
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(generated in situ from difluoromethyl phenyl sulfone and a
base) with primary alkyl halides (preferentially primary alkyl
iodides) have been developed, which demonstrates the
efficient carbon–carbon bond formation between a fluori-
nated carbanion and primary alkyl halides. The new alkyl-
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Communications
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