Fluorohalogenation of gem-Difluoroalkenes: Synthesis and Applications of α-Trifluoromethyl Halides

Article abstract of DOI:10.1002/chem.201905445

A novel strategy for 1,2-dihalogenation of alkenes is reported that occurs through a sequential nucleophilic halide addition and electrophilic halogenation. By trapping the in situ generated unstable α-trifluoromethyl carbanion intermediates derived from the nucleophilic fluoride addition to electron-poor gem-difluoroalkenes, this fluorohalogenation of gem-difluoroalkenes with electrophilic haloalkynes affords various useful α-trifluoromethyl halides in high yields. A pesticidal active compound and various attractive trifluromethylated molecules could be smoothly synthesized from these obtained α-trifluoromethyl halides.

Full text of DOI:10.1002/chem.201905445

A Journal of
Accepted Article
Title: Fluorohalogenation of gem-Difluoroalkenes: Synthesis and
Applications of α-Trifluoromethyl Halides
Authors: Huanfeng Jiang, Chi Liu, Chuanle Zhu, Yingying Cai, Zhiyi
Yang, Hao Zeng, and Fulin Chen
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Fluorohalogenation of gem-Difluoroalkenes: Synthesis and
Applications of α-Trifluoromethyl Halides
Chi Liu,[a] Chuanle Zhu,*[a] Yingying Cai,[a] Zhiyi Yang,[a] Hao Zeng,[a] Fulin Chen,[a] and Huanfeng
Jiang*[a]
Dedication ((optional))
[a]
C. Liu, Dr. C. Zhu, Y. Cai, Z. Yang, H. Zeng, F. Chen, Prof. Dr. H. Jiang
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, P. R. China
E-mail: cechlzhu@scut.edu.cn; jianghf@scut.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A novel strategy for 1,2-dihalogenation of alkenes is
reported that occurs via sequential nucleophilic halide addition and
electrophilic halogenation. By trapping the in situ generated unstable
α-trifluoromethyl carbanion intermediates derived from the
nucleophilic fluoride addition to electron-poor gem-difluoroalkenes,
this fluorohalogenation of gem-difluoroalkenes with electrophilic
haloalkynes affords various useful α-trifluoromethyl halides in high
yields.
A pesticidal active compound and various attractive
trifluromethylated molecules could be smoothly synthesized from
these obtained α-trifluoromethyl halides.
1,2-Dihalogenation of alkenes is a frontier in organic chemistry,[1]
because the synthesized vicinal dihalides not only represent a
large component of natural organohalogens but also might serve
as progenitors to useful artificially halogenated compounds.[2]
The reported strategies for 1,2-dihalogenation of alkenes are
mainly focused on activating the electron-rich alkene substrate
either by a halenium ion,[3] and / or by an electrophilic transition-
metal[4] or main group electrophile,[5] via a halonium or π-
complex or -iranium ion, and then followed by an outer sphere
attack of a halide ion (Scheme 1, a). On the other hand, 1,2-
dihalogenation of the electron-poor alkenes is quite challenging
and still underdeveloped, probably related to their intrinsic
electrophilic property.[6] Inspired by it, we envisioned that if the
nucleophilic addition of electron-poor alkene substrate with a
halide ion could happen firstly, and subsequently followed by the
process of electrophilic halogenation. This strategy might
become a useful protocol for the 1,2-dihalogenation of electron-
poor alkenes and construct valuable halogenated compounds
(Scheme 1, b). However, owing to the favored β-halogen
elimination process of β-halogenated carbanion, this novel
strategy is quite challenge and still unreported.
Trifluoromethyl group is a privileged moiety in pharmaceutical
and agrochemical research because of its positive influence on
the metabolic stability, lipophilicity, and cell-membrane
permeability of potential drugs.[7] Consequently, the
development of novel and efficient methods for the introduction
of trifluoromethyl group into biologically active molecules has
particularly gained much attention.[8] Electron-poor gem-
difluoroalkenes are readily available, useful and versatile
synthons. It was found that the regioselective nucleophilic
fluoride addition of these substrates could generate the α-
trifluoromethyl-alkylsilver intermediates[9] with AgF or unstable α-
trifluoromethyl carbanion[10] for the preparation of various
Scheme 1. 1,2-Dihalogenation of Alkenes.
trifluoromethylated compounds. Inspired by it, we hypothesized
that the in situ generated α-trifluoromethyl carbanion
intermediates derived from nucleophilic fluoride addition to gem-
difluoroalkenes might be captured by electrophilic halogen
sources (Scheme 1, c). Thus, this fluorohalogenation protocol of
electron-poor gem-difluoroalkenes would lead to the efficient
construction of useful α-trifluoromethyl halides.[11-12] Especially,
this strategy has potential advantages for the preparation of
[18F]CF3 labled α-trifluoromethyl halides.[13] However, because of
the spontaneous proton abstraction quenching or β-fluoride
elimination tendency of the in situ generated unstable α-
trifluoromethyl carbanion, its compatibility with the oxidative
electrophilic halogen sources is the main challenge in this
reaction.
Given the advantages of potassium fluoride (KF) in
nucleophilic fluorination such as low-cost, abundant, safe and
easy to handle,[14] the initial experiment of this
fluorohalogenation of electron-poor gem-difluoroalkene 1a was
carried out with N-bromosuccinimide (NBS) in the presence of
o
KF in DMF at 50 C under N2 (Table 1, entry 1). Although the
yield was very poor, the desired fluorobromination product 5a
could be detected by GC-MS analysis. Other oxidative
electrophilic halogen sources such as 1,3-dibromo-5,5-
dimethylhydantoin (DBDMH), Br2, N-chlorosuccinimide (NCS),
and N-iodosuccinimide (NIS) have also been tried, however, no
corresponding fluorohalogenation products (5a, 6a, and 7a)
were obtained (Table 1, entries 2-5). We thought that the
suitable electrophilic halogen source might be the key to the
1
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Table 1. Optimization of the reaction conditions.[a]
obtained in 89% yield under open air and undried DMF (Table 1,
entry 21).[10a, 12] Additionally, chloroalkyne 3a and iodoalkyne 3b
were also used to capture the in situ generated unstable α-
trifluoromethyl carbanion. The fluorochlorination product 6a was
not obtained in isolatable yield (Table 1, entry 22), however, the
fluoroiodonation product 7a was isolated in 61% yield (Table 1,
entry 23).
Under the optimized reaction conditions, the scope of gem-
difluoroalkenes in this fluorobromination reaction was examined.
Owing to their highly volatile property, selected α-trifluoromethyl
bromides were isolated and illustrated in Scheme 2. Electron
neutral naphthyl gem-difluoroalkenes promisingly gave products
5a-b in high yields. α-Trifluoromethyl bromides 5c-l with
electron-withdrawing substituents such as 3-methoxyl, fluoro,
bromo, iodo, trifluoromethyl, formic ester, cyano, sulfonyl, and
nitro groups on the phenyl ring were all isolated in good to high
yields. Furthermore, 3-benzo[b]thiophenyl bearing gem-
difluoroalkene delivered product 5m in 63% yield. gem-Difluoro-
1,3-diene was also found to be a suitable substrate, providing
1,2-fluorobrominated product 5n in reasonable yield. Double
fluorobromination of gem-difluoroalkene afforded symmetric α-
trifluoromethyl bromide 5o in 50% isolated yield, which has
ample potential for polymer synthesis. Significantly, trichloro
substituted α-trifluoromethyl bromide 5q was isolated in 63%
yield, which is a key intermediate for the synthesis of pesticidal
active compound.[19]
Entry
X+
F-
Solvent
Product
Yield (%)[b]
1
NBS
DBDMH
Br2
NCS
NIS
2a
KF
KF
DMF
DMF
5a
5a
5a
6a
7a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
6a
7a
< 2%
2
0
3
KF
DMF
0
4
KF
DMF
0
5
KF
DMF
0
6
KF
DMF
63 (50)
7
2a
LiF
DMF
0
8
2a
NaF
CsF
CuF
AgF
(n-Bu)4NF
KF
DMF
0
9
2a
DMF
32
10
2a
DMF
0
11
2a
DMF
0
12
2a
DMF
16
13[c]
14[c]
15[c]
16[c]
17[c]
18[c]
19[c]
20[c]
21[d]
22[c]
23[c]
2a
DMF
91 (81)
2a
KF
DMSO
MeCN
1.4-dioxane
THF
90
2a
KF
53
2a
KF
0
2a
KF
0
2a
KF
DCE
0
0
2a
KF
cyclohexane
toluene
DMF
2a
KF
0
2a
KF
89
3a
KF
DMF
<5
4a
KF
DMF
78 (61)
[a] Unless otherwise noted, all reactions were carried out with 1a (0.2 mmol),
‘X+’ (2 equiv), ‘F-’ (2 equiv), and solvent (4 mL) in a 25 mL Schlenk tube at 50
oC for 12 h under N2. [b] The yields were determined by 19F NMR spectroscopy
of the crude product with PhCF3 as an internal standard. The numbers in the
parentheses were isolated yields. [c] With 18-crown-6 (2.5 equiv) as additives.
[d] Under open air and undried DMF.
success of this transformation. Owing to the sp hybridization of
the triple bond and the adjacent halogen atom, haloalkynes
exhibit rich and tunable reactivity in synthetic chemistry,[15] and
which were used to capture the in situ generated aryl
carbanion.[16] Inspired by it, bromoalkyne 2a was then examined
to capture the in situ generated unstable α-trifluoromethyl
carbanion (Table 1, entry 6). To our delight, the desired
fluorobromination product 5a was isolated in 50% yield, while
the product of fluoride nucleophilic addition to bromoalkyne 2a
was completely undetectable.[17] Next, different nucleophilic
fluoride sources, such as LiF, NaF, CsF, CuF, AgF, and (n-
Bu)4NF were investigated, and no superior results were obtained
(Table 1, entries 7-12). Furthermore, an additive of 18-crown-6
improved the yield of 5a to 91% (Table 1, entry 13).[18] Different
solvents such as DMSO, MeCN, 1,4-dioxane, THF, 1,2-
dichloroethane (DCE), cyclohexane, and toluene were then
screened (Table 1, entries 14-20), however, the yields of 5a was
not further improved. We believed that the strong polar aprotic
solvent might help to stabilize the α-trifluoromethyl carbanion
intermediates. This reaction is not air sensitive, because 5a was
Scheme 2. Isolated α-trifluoromethyl bromides. Reaction conditions: 1 (0.2
mmol), 2a (0.4 mmol), KF (0.4 mmol), DMF (4 mL). [a] Average isolated yield
of two parallel runs. [b] 19F-NMR yields. [c] 2a (2 equiv) and 1-(bromoethynyl)-
4-nitrobenzene (2 equiv) at room temperature. [d] 2a (4 equiv). [e] 4-
(bromoethynyl)benzonitrile (2 equiv) at room temperature.
Intrigued by this unique protocol, a 5 mmol scale reaction
of fluorobromination of gem-difluoroalkene 1a was carried
2
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bromo, and iodo groups, and electron-donating groups such as
methyl, and methylthio groups on the phenyl ring all could
undergo this one pot, three steps transformation smoothly,
providing the corresponding α-trifluoromethyl N-1-triazoles in
moderate to high yields (9c-k). 3-Benzo[b]thiophene substituted
gem-difluoroalkene also gave the desired product 9l in 70%
yield. Next, the scope of bromoalkynes 2 was investigated with
gem-difluoroalkene 1a as the reaction partner. In general,
bromoalkynes with electron-donating and electron-withdrawing
groups on the para-, meta-, and ortho-position of the phenyl ring
all could give the desired α-trifluoromethyl N-1-triazoles in
moderate to high yields (9m-9ab). Significantly, product 9q was
proved to be crystalline, thus its structure was determined by
means of X-ray crystallographic analysis.[22] Bromoalkynes
derived from 2-ethynylnaphthalene and 3-ethynylthiophene were
also found to be good substrates, delivering the corresponding
products in good yields (9ac and 9ad). It is also worth
mentioning that this one pot, three steps transformation is not
sensitive to the steric hindrance effect, because these α-
trifluoromethyl N-1-triazoles ortho-substitution groups were
obtained in reasonable yields (9b, 9e, 9j, 9o, 9u, and 9x).
Scheme 3. Synthetic application of 5a. a) (TMS)3SiH, AIBN, anhydrous
toluene, 80 oC, 12 h. b) AgSbF6, benzene, 80 oC, 1 h. c) Phenylboronic acid,
(3-(trifluoromethyl)but-3-en-1-yn-1-yl)benzene, Ni(NO3)2·6H2O, 4,4-di-tert-butyl
bipyridine, K2CO3, 1,4-dioxane, 80 oC, 72 h. d) NaN3, 70 oC, 8 h. e) (TMS)3SiH,
H2O, 30 oC, 12 h. f) AgNO3, EtOH, 80 oC, 12 h. g) (TMS)3SiH, TEMPO, H2O,
80 oC, 12 h. h) KSCN, 18-crown-6, CH3CN, 100 oC, 24 h. i) (PhS)2, In, DCE,
reflux, 12 h. j) (PhSe)2, In, DCE, reflux, 12 h. k) PPh3, DCM, 130 oC, 4 d.
out under the standard reaction conditions, delivering α-
trifluoromethyl bromide 5a in 78% yield (1.127 g) (Scheme 3,
above). Furthermore, the synthetic applications of these α-
trifluoromethyl bromides were explored with 5a as a model
substrate (Scheme 3, below). The C(sp3)-Br bond of α-
trifluoromethyl bromide 5a has ample potential for further
transformations, which could be smoothly converted to C-H (8a),
C-C (8b and 8c), C-N (8d), C-O (8e, 8f, and 8g), C-S (8h and 8i),
C-Se (8j), and C-Cl (6a) bonds.[20] Especially, the obtained
substituted trifluoroethane derivatives (8a-c), α-trifluoromethyl
azide (8d), alcohol (8e), ether (8f), thiocyanate (8h), sulfane (8i),
selane (8j), and chloride (6a) are very attractive
trifluoromethylated intermediates or building blocks in medicinal
chemistry.
In this fluorohalogenation reaction of gem-difluoroalkenes with
haloalkynes, stoichiometric amount of alkyne byproducts would
be generated just like previous literatures.[16b-d] However,
inspired by the highly efficient nucleophilic azidation of 5a, we
then explored a one pot, three steps transformation for the
construction of α-trifluoromethyl N-1-triazoles
9
via the
processes of fluorobromination of gem-difluoroalkenes,
nucleophilic azidation of the generated α-trifluoromethyl
bromides, and the regioselective Click reaction[21] between the
newly in situ formed α-trifluoromethyl azides and the alkyne
byproducts. Gratifyingly,
a
broad spectrum of gem-
difluoroalkenes 1 and bromoalkynes 2 with different substitution
patterns could be tolerated in this one pot, three steps
transformation, delivering the corresponding α-trifluoromethyl N-
1-triazoles in moderate to high yields (Scheme 3). Firstly, the
scope of gem-difluoroalkenes 1 was examined with bromoalkyne
2a as the reaction partner. 2-Naphthyl or 1-naphthyl substituted
gem-difluoroalkenes afforded the desired products 9a and 9b in
high yields. Both electron-withdrawing groups such as chloro,
Scheme 4. Synthesis of α-trifluoromethyl N-1-triazoles. Reaction conditions:
step 1): 1 (0.2 mmol), 2 (0.4 mmol), KF (0.4 mmol), DMF (4 mL); step 2): NaN3
(0.4 mmol); step 3): CuSO4 (10 mol%), H2O (2 mL), sodium ascorbate (0.1
mmol). [a] Average isolated yield of two parallel runs. [b] At 110 oC for step 1.
[c] At 45 oC for step 3. [d] The Oak Ridge Thermal Ellipsoid Plot of a crystal
structure 9q with thermal ellipsoids set at 50% probability. H atoms were
omitted for clarity.
3
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In summary, we have reported a novel strategy for 1,2-
dihalogenation of alkenes via sequential nucleophilic halide
addition and electrophilic halogenation. By trapping the in situ
generated unstable α-trifluoromethyl carbanion intermediates
derived from the nucleophilic fluorination of electron-poor gem-
difluoroalkenes, this fluorohalogenation of gem-difluoroalkenes
with electrophilic haloalkynes affords various useful α-
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A pesticidal active
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could be smoothly synthesized from these obtained α-
trifluoromethyl halides. Furthermore, a one pot, three steps
transformation was developed via the processes of
fluorobromination of gem-difluoroalkenes with haloalkynes,
nucleophilic azidation of the generated α-trifluoromethyl bromides,
and the regioselective Click reaction between the newly in situ
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Investigation of the asymmetric variants and exploration of this
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Acknowledgements ((optional))
The authors thank the National Program on Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21702064), the Pearl River S&T Nova
Program of Guangzhou (201806010138), and the Fundamental
Research Funds for the Central Universities (2019ZD19) for
financial support.
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Keywords: dihalogenation • alkenes • fluorination • α-
trifluoromethyl carbanion • potassium fluoride
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Entry for the Table of Contents
The fluorohalogenation of gem-difluoroalkene is reported that is initiated by nucleophilic fluorination, and followed by electrophilic
halogenation of the in situ generated unstable α-trifluoromethyl carbanion. The obtained α-trifluoromethyl halides were further
transformed into various useful trifluoromethylated compounds.
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