An efficient method for the synthesis of gem-difluoroolefins

Article abstract of DOI:10.1016/j.tetlet.2016.12.070

A series of gem-difluoroolefin derivatives were synthesized in moderate to good yields by the reaction of α,α-difluoro-β-carbonyl benzothiazol-2-yl sulfones (DFBTs) with various carbon nucleophiles. Using dl-proline as organocatalyst, the reaction of DFBT with acetone gave a tertiary alcohol, which could be further converted to the corresponding difluoroolefin by LDA.

Full text of DOI:10.1016/j.tetlet.2016.12.070

Accepted Manuscript
An efficient method for the synthesis of gem-difluoroolefins
Chun-Ru Cao, Song Ou, Min Jiang, Jin-Tao Liu
PII:
S0040-4039(16)31725-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.070
TETL 48482
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
25 October 2016
22 December 2016
23 December 2016
Please cite this article as: Cao, C-R., Ou, S., Jiang, M., Liu, J-T., An efficient method for the synthesis of gem-
difluoroolefins, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.070
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An efficient method for the synthesis of gem-
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difluoroolefins
Chun-Ru Cao, Song Ou, Min Jiang and Jin-Tao Liu*
A series of gem-difluoroolefin derivatives were synthesized in moderate to good yields by the reaction of α,α-difluoro-β-
carbonyl benzothiazol-2-yl sulfones (DFBTs) with various carbon nucleophiles. Using dl-proline as organocatalyst, the
reaction of DFBT with acetone gave a tertiary alcohol, which could be further converted to the corresponding difluoroolefin
by LDA.

1
Tetrahedron Letters
An efficient method for the synthesis of gem-difluoroolefins
Chun-Ru Cao, Song Ou, Min Jiang and Jin-Tao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of gem-difluoroolefin derivatives were synthesized in moderate to good yields by
the reaction of α,α-difluoro-β-carbonyl benzothiazol-2-yl sulfones (DFBTs) with various
carbon nucleophiles. Using dl-proline as organocatalyst, the reaction of DFBT with
acetone gave a tertiary alcohol, which could be further converted to the corresponding
difluoroolefin by LDA.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
α,α-difluoro-β-carbonyl benzothiazol-2-yl sulfone
nucleophile
gem-difluoroolefin
organocatalysis
The introduction of fluorine atom may modulate physical and
electronic properties of a molecule, which further reflects on the
reactivity and bioactivity of fluorinated organic compounds.1
Because of their high hydrophobicity, metabolic activity and
bioavailability, fluorinated compounds have recently attracted
significant interest and became very important synthetic targets
in labs and industries.2 Among various fluorinated structural
moieties, the gem-difluoroolefin unit plays an important role in
many biologically active compounds such as potential
mechanism-base inhibitors because it is highly electrophilic and
the fluorine atom(s) can be replaced by nucleophiles through an
addition-elimination process.3 Furthermore, gem-difluoroolefins
are also useful precursors in organic synthesis.4 So far, most
methods for the synthesis of gem-difluoroolefins involved the
Wittig-type reaction of aldehydes or ketones.5 It was also
reported that difluoromethyl phenyl sulfone could be used to
prepare gem-difluoroolefins via classical Julia reaction.6 Due to
their important applications, the development of efficient and
practical methods for the synthesis of gem-difluoroolefins is still
a hot research topic currently.
reactions of bromodifluoromethyl ketones S-1 with 1.5 equiv of
2-mercaptobenzothiazole in the presence of triethylamine were
easily preformed, and the corresponding benzothiazolyl sulfone
derivatives S-2 were obtained in high yields. Subsequent
oxidation of S-2 under mild conditions afforded the expected
DFBTs 1. As shown in Table 1, ɑ,ɑ-difluoro-β-carbonyl
benzothiazol-2-yl sulfones containing both aryl and alkyl
substituents were prepared in good yields.
Table 1. Preparation of -difluoro-β-carbonyl sulfones (DFBTs)
Yield (step 1, %)a Yield (step 2, %)b Product 1
Entry
R
Recently, we reported a novel one-pot method for the synthesis
of tetrasubstituted olefins and monofluoroolefins via a modified
Julia olefination process.7 In this approach, a series of carbon
nucleophiles reacted with β-carbonyl benzothiazol-2-yl sulfones
to give the corresponding β-alkoxysulfone intermediates, which
underwent facile Smiles rearrangement8 and spontaneous
elimination to afford tetrasubstituted alkenes.9 In continuation of
the study on the application of this olefination reaction, we
further synthesized a series of ɑ,ɑ-difluorintaed sulfones and
investigated their reaction with various nuclephiles. The results
are reported in this paper.
87
93
90
92
83
86
75
85
61
81
81
65
1a
1b
1c
1d
1e
1f
1
2
3
4
5
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-CF3C6H4
C6H5(CH2)3
6
a
Yields were determined based on the weight of crude product
after workup and removal of solvent; b Isolated yields.
Our initial work started with the preparation of ɑ,ɑ-difluoro-β-
carbonyl benzothiazol-2-yl sulfones (DFBTs). Gratefully, the

2
Tetrahedron
With the desired substrates 1 in hand, we next studied their
Encouraged by the above results, we continued to investigate
the reaction of 1a with acetone in the presence of LDA (lithium
diisopropylamide). As expected, difluoroolefin 5a was formed in
65% yield (determined by the 19F NMR). When 2,2'-bipyridine,
BINAP ((±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) or
HMPA (hexamethylphosphoramide) was used as additive, the
yield of 5a could be improved to 84%, 75% and 87%,
respectively. Therefore, we chose HMPA as the additive to
further study the reaction of DFBTs with acetone (Scheme 2).
olefination reaction with nucleophiles. Previous study showed
that alkynyl lithiums were effective nucleophiles for this reaction,
affording the corresponding conjugated enynes in good to
excellent yields.7 Therefore, the reaction of trimethylsilylethynyl
lithium 2a with 1a was examined firstly by using the Barbier
procedure.10 However, the desired product 3a was not observed
and a great amount of decomposed products were detected in the
19F NMR spectrum of the reaction mixture. Fortunately,
optimization of reaction conditions showed that the
decomposition of 1a could be suppressed when 1.5 equiv of 2,2'-
bipyridine was added to the reaction mixture,7b and difluoroolefin
3a was obtained in 82% yield (Scheme 1).
Scheme 2. The reaction of DFBT 1a with acetone
Scheme 1. The reaction of DFBT 1a with ethynyl lithium
Using the optimized conditions, the scope of DFBT was
studied and the results are summarized in Table 3. It was found
that the electronic property of DFBT had some influence on the
yield of the reaction. When electron-donating groups such as
methyl and methoxy were introduced to the benzene ring, good
yields were obtained (Table 3, entries 1-3). However, the reaction
of 1d with a chloro substituent gave the corresponding product
5d in much lower yield (53%, entry 4), and only 36% yield of
difluoroolefin 5e was obtained in the case of 1e containing a
trifluoromethyl substituent (entry 5).
Next, the scope of DFBT 1 and alkynyl lithium 2 were
examined. As shown in Table 2, the reaction of alkynyl lithiums
bearing aryl-, silyl- or alkyl-substitution proceeded well to give
the corresponding conjugated difluorinated enynes 3 in good
yields (Table 2, entries 1-3). For alkynyl lithium 2d with an ester
substituent, the reaction gave difluoroolefin 3d in only 26% yield,
possibly due to the high reactivity of COOEt group to Lithium
diisopropylamide (entry 4). In the case of DFBTs, it was found
that lower yield was obtained with electron-rich DFBT (1a vs. 1c,
entries 1 and 8). Furthermore, no desired product was observed in
the reaction of alkyl-substituted DFBT 1f (entry 10).
Table 3. The reaction of 1 with acetone
Table 2. The reaction of DFBTs with alkynyl lithiums
Entrya
R
Yield (5, %)b
5a, 75 (87)c
5b, 71
1
1
2
3
4
5
C6H5
1a
1b
1c
1d
1e
Entrya
1, R1
2, R2
Yield (3, %)b
3a, 82
3b, 74
3c, 82
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-CF3C6H4
1
2
1a, C6H5
2a, TMS
2b, C6H5
2c, nC4H9
2d, CO2Et
2a, TMS
2b, C6H5
2c, nC4H9
2a, TMS
2a, TMS
2a, TMS
5c, 66
1a, C6H5
5d, 53
5e, 36d
3
1a, C6H5
3d, 26c
a
4
1a, C6H5
Reaction conditions: 1 (1.0 equiv), acetone (10.0 equiv), LDA (2.0
equiv), HMPA:THF = 1:10 (V:V) at -78 ℃ for 3h; b Isolated yield; c
Yield in parenthesis was determined by 19F NMR; d Determined by 19
F NMR.
5
1b, 4-MeC6H4
1b, 4-MeC6H4
1b, 4-MeC6H4
1c, 4-MeOC6H4
1d, 4-ClC6H4
1f, C6H5(CH2)3-
3e, 85
6
3f, 65
7
3g, 82
3h, 45
3i, 87
Under similar conditions, we also studied the reaction of
DFBT 1a with some other potential carbon nucleophiles. As
shown in Table 4, when phenyl methyl ketone and
cyclohexanone were used, the reaction worked successfully to
afford difluoroolefin products 5f and 5g in 56% and 37% yield,
respectively (Table 4, entries 2-3). Ethyl acetate and N,N-
dimethylacetamide could also react with 1a to give the
corresponding difluoroolefin products 5h and 5i in moderate
yields (entries 4 and 5). It is worth mentioning that the reaction
of nitromethane with 1a occurred well and difluoroolefin 5j was
obtained in 69% yield (entry 6).
8
9
10
3j, -c
a
Reaction conditions: 1 (0.5 mmol), 2,2'-bipyridine (0.75 mmol), 2
(1.0 mmol) and LDA (0.75 mmol) in THF (5.0 mL) at -78 oC for 3 h.
b Isolated yields. c Determined by 19F NMR.

3
Table 4. The reaction of 1a with carbon nucleophiles 4
Entry a
1
Product
Yield (%)b
75
Scheme 4. Transformation of 6a to gem-difluoroolefin 5a
4
5
5a
In summary, an efficient synthetic method for the synthesis of
gem-difluoroolefins was developed through the reaction of -
difluoro-β-carbonyl benzothiazol-2-yl sulfones with various
carbon nucleophiles. Terminal alkynes, methyl ketones, ethyl
acetate, N,N-dimethylacetamide and nitromethane are all suitable
precursors of carbon nucleophiles for this reaction, and a series of
gem-difluoroolefin derivatives were prepared in moderate to
good yields. In the proline-catalyzed reaction of DFBT and
acetone, the tertiary alcohol intermediate was isolated and could
be further converted to the corresponding difluoroolefin product
in the presence of lithium reagent.
2
3
56
37
5f
5g
4
5
6
43
51
69
5h
5i
Acknowledgments
5j
Financial support from the National Natural Science
Foundation of China (No. 21572257 and 21502213) is gratefully
acknowledged.
a
Reaction conditions: 1a (1.0 equiv), 4 (10.0 equiv), LDA (2.0
equiv), HMPA:THF = 1:10 (V:V) at -78 ℃ for 3h; b Isolated yield.
Supplementary data
Proline is an important compound in organocatalysis,11 which
emerged as a very rapidly growing area in modern organic
synthesis because of its environmental friendliness.12 To make
the olefination reaction more mild and practical, we tried the
reaction of 1a with acetone using proline as the organocatalyst.
However, when 1a was treated with 10.0 equiv of acetone in the
presence of 30 mol% dl-proline at room temperature, unexpected
tertiary alcohol 6a was isolated in 97% yield (Scheme 3). It is
obvious that alcohol 6a formed by the addition of acetone to 1a
was too stable under the reaction conditions to undergo the Smile
rearrangement. When unfluorinated sulfone or monofluorinated
sulfone was used under similar conditions, no reaction occured
and all of starting materials were recovered.
Supplementary data associated with this article can be found,
in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.201x.xx.xxx.
References and notes
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Scheme 3. The reaction of 1a with acetone catalyzed by dl-
proline
We proposed that tertiary alcohol 6a would transform to
difluoroolefin 5a in the presence of a stronger base. So several
bases were tested and the results are shown in Scheme 4. Weak
bases such as K2CO3 or Et3N failed to promote any olefination
reaction, resulting in full recovery of the starting material.
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when LDA was used (Scheme 4). These results provided further
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10. Typical Barbier procedure: β-carbonyl sulfone 1a (0.5 mmol) and
trimethylsilylethynyl (2.0 mol) were dissolved in THF (5 mL). To the
solution was added LDA (0.75 mL, 1.0 M in THF) at -78 oC. The
resulting mixture was stirred at -78 oC for 3 hour.
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5
Research highlights:
Synthesis of gem-difluoroolefins via olefination
reaction was investigated.
A series of gem-difluoroolefin derivatives were
seperated in moderate to good yields.
A tertiary alcohol as intermediate in this
methodology was obtained.