Switchable 2,2,2-trifluoroethylation and gem-difluorovinylation of organoboronic acids with 2,2,2-trifluorodiazoethane

Article abstract of DOI:10.1002/ejoc.201402597

The transition-metal-free 2,2,2-trifluoroethylation and gem-difluorovinylation of arylboronic acids were developed. By employing different reaction conditions, these transformations provide both (2,2,2-trifluoroethyl)arenes and gem-difluorovinylarenes fro

Full text of DOI:10.1002/ejoc.201402597

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402597
Switchable 2,2,2-Trifluoroethylation and gem-Difluorovinylation of
Organoboronic Acids with 2,2,2-Trifluorodiazoethane
Guojiao Wu,[a] Yifan Deng,[a] Chaoqiang Wu,[a] Xi Wang,[a] Yan Zhang,[a] and
Jianbo Wang*[a]
Keywords: Boron / Fluorine / Diazo compounds / Trifluoroethylation / gem-Difluorovinylation
The transition-metal-free 2,2,2-trifluoroethylation and gem-
difluorovinylation of arylboronic acids were developed. By
employing different reaction conditions, these transforma-
tions provide both (2,2,2-trifluoroethyl)arenes and gem-di-
fluorovinylarenes from arylboronic acids and 2,2,2-trifluoro-
diazoethane. The operation is simple and scalable with good
functional group tolerance.
Introduction
Fluorinated organic molecules have found important ap-
plications in various fields including pharmacy and materi-
als.[1] The development of new methods for introducing
fluorinated moieties has attracted great attention.[2] In par-
ticular, trifluoromethylation has been extensively studied in
recent years.[3] In contrast, related 2,2,2-trifluoroethylation
remains largely unexplored, regardless of the fact that tri-
fluoromethyl-containing molecules also have various appli-
cations.[4] McLoughlin and Thrower in 1969 reported the
Cu0-mediated 2,2,2-trifluoroethylation of iodobenzene with
trifluoroethyl iodide (Scheme 1, a, path i).[5] In 2012, the
Pd0-catalyzed 2,2,2-trifluoroethylation of trifluoroethyl iod-
ide with organoboronic acids and esters was developed by
Hu[6] and Zou.[7] Trifluoromethylation of benzyl halides
represents an alternative approach towards aromatic 2,2,2-
trifluoroethylation.[8] For example, trifluoromethylation has
been recently achieved via a [CuCF3] species generated from
copper powder and the Umemoto regent by Shibata and
co-workers (Scheme 1, a, path ii).[8g]
On the other hand, gem-difluoroalkenes (CF2 = CHAr)
as another important class of fluorinated organic com-
pounds also have potential applications in various
fields.[9–11] However, currently only few methods are avail-
able for introducing gem-difluorovinyl groups into arenes.
Traditional methods for preparing gem-difluoroalkenes in-
clude the Wittig reaction,[12] the Julia reaction[13]
(Scheme 1, b, path iii), and transition-metal-catalyzed cross-
Scheme 1. Methods for the synthesis of trifluoroethylated and di-
fluorovinylated arenes.
coupling reactions (Scheme 1, b, path iv).[14] In general,
these methods suffer from some drawbacks, such as sub-
strate scope, tedious transformations, and expensive transi-
tion-metal catalysts. Hence, the development of an effective
strategy for the gem-difluorovinylation of arenes that can
largely avoid these drawbacks is highly desirable.
Herein, we report a novel method to access both 2,2,2-
trifluoroethylated and gem-difluorovinylated arenes in a
switchable manner from organoboronic acids and 2,2,2-tri-
fluorodiazoethane (Scheme 1, c). This reaction proceeds
under transition-metal-free conditions and uses trifluorodi-
azoethane as the fluorinating agent. The preparation of tri-
fluorodiazoethane was first reported in the 1940s from am-
monium salts.[15] However, this reagent did not arouse at-
tention until it was recently used as a valuable CF3-contain-
ing reagent.[16] We previously reported the metal-free reac-
tion of diazo compounds with boronic acids.[17] This type
[a] Beijing National Laboratory of Molecular Sciences (BNLMS)
and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry,
Peking University,
Beijing 100871, China
E-mail: wangjb@pku.edu.cn
http://www.chem.pku.edu.cn/physicalorganic/home.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402597.
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G. Wu, Y. Deng, C. Wu, X. Wang, Y. Zhang, J. Wang
SHORT COMMUNICATION
of transformation follows a simple pathway that includes the basis of 19F NMR spectroscopy (Table 1, entry 11).
the coordination of the electron-rich diazo carbon atom to Given that the crude product contained a small amount of
the electron-deficient boron center, which is followed by a gem-difluoroalkene, which was inseparable from 3a by silica
1,2-shift of the carbon ligand from boron to carbon to form gel column chromatography, the crude material was treated
a C–C bond (Scheme 1, d).[18–20] Thus, if the diazo substrate with KF in DMSO at 100 °C to convert the gem-difluoro-
is CF3CHN2, intermediate I is expected to be formed, alkene byproduct into separable compounds. In this way,
which undergoes subsequent protonation or β-F elimi- 2,2,2-trifluoroethylated product 3a was isolated in 71%
nation to achieve 2,2,2-trifluoroethylation or gem-difluoro- yield.
vinylation (Scheme 1, c).
With the optimized conditions, we studied the substrate
scope for this direct 2,2,2-trifluoroethylation reaction. As
shown in Table 2, a series of arylboronic acids were submit-
ted to the reaction under the optimized conditions. The cor-
responding (2,2,2-trifluoroethyl)arenes were obtained in
moderate to good yields. The reaction proceeded smoothly
with arylboronic acids bearing halide substituents and gave
corresponding 2,2,2-trifluoroethylated products 3a–c, 3q 3r,
and 3s. Notably, even an iodo substituent on the aromatic
ring was tolerated in the reaction (see product 3c), which is
beneficial for subsequent transformations. Notably, inter-
Results and Discussion
At first, 2,2,2-trifluorodiazoethane (2) was prepared
from 2,2,2-trifluoroethylammonium chloride (2Ј) in dif-
ferent solvents according to the method reported Carreira
and co-workers.[16e–16i] Then, we investigated the reaction
of (p-chlorophenyl)boronic acid with CF3CHN2 in different
solvents. In toluene and 1,2-dichloroethane (DCE), ex-
pected 2,2,2-trifluoroethylated product 3a was formed in 20
and 12% yield, respectively, on the basis of 19F NMR spec-
troscopy (Table 1, entries 1 and 2). In polar solvents, such
as THF, dioxane, MeCN, MeOH, and DMF, product 3a
was not obtained (Table 1, entry 3). To further optimize the
reaction, a variety of additives were screened (Table 1, en-
tries 4–8), and KF as a weaker base was identified as an
effective additive (Table 1, entry 8). Replacing KF with
NH4F or NH4Cl further improved the yield (Table 1, en-
tries 9 and 10). Finally, we found that a one-pot reaction
directly using 2Ј worked well and gave 3a in 80% yield on
Table 2. The scope of the 2,2,2-trifluoroethylation reaction.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Additive
(4 equiv.)
Yield [%][b]
1
2
3
4
5
6
7
8
PhMe/H2O, 20:1
DCE/H2O, 20:1
PS[c]/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
PhMe/H2O, 20:1
–
–
–
20
12
–
–
45
20
31
61
K2CO3
iPr2NH
LiOtBu
CsF
KF
9
NH4F
NH4Cl
NH4Cl
72
10
75
11[d]
80 (71)[e]
[a] If not otherwise noted, the reaction was performed with 1a
(0.22 mmol), 2 (0.55 mmol) in solvent (1 mL). [b] The yield was
determined by 19F NMR spectroscopy by using PhCF3 as an in-
ternal standard. [c] PS = polar solvents, including THF, dioxane,
MeCN, MeOH, and DMF. [d] One-pot reaction with the use of
2Ј (0.88 mmol). [e] The yield of the isolated product obtained by
treatment of the crude product with KF in DMSO at 100 °C for
10 h is given in parentheses.
[a] If not otherwise noted, the reaction conditions are as follows:
ArB(OH)2 (0.5 mmol), PhMe/H2O = 20:1 (2.5 mL), 24 h; upon
completion of the reaction, the crude product was treated with KF
in DMSO (3 mL) at 100 °C. All reported yields refer to yields of
the isolated products after column chromatography. [b] One-pot re-
action under conditions A. [c] Under conditions B. [d] HCO2NH4
was used as an additive instead of NH4Cl. [e] NH4SCN was used
as an additive instead of NH4Cl.
2
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Switchable 2,2,2-Trifluoroethylation and gem-Difluorovinylation
mediate I would be oxidized to the alcohol with electron- submitted to the reaction with 2. The reaction afforded cor-
rich boronic acids under oxidative conditions. responding gem-difluoroalkenes 4 in moderate to good
The reaction seemed to be slightly affected by electronic yields, along with the formation of a small amount of
effects. The 2,2,2-trifluoroethylation reaction proceeded (2,2,2-trifluoroethyl)arenes as the byproducts. The func-
smoothly for substrates bearing both electron-withdrawing tional group tolerance is similar to that of the correspond-
and -donating substituents. For arylboronic acids bearing ing 2,2,2-trifluoroethylation reaction.
electron-withdrawing substituents, such as ester (see 1g),
Table 3. gem-Difluorovinylation of arylboronic acids with 2,2,2-tri-
ketone (see 1h and 1i), and nitro groups (see 1j), the reac-
tion afforded the corresponding trifluoroethylated prod-
ucts; however, the yields varied depending on the substitu-
ents. The yields for arylboronic acids bearing electron-do-
nating substituents, such as tert-butyl (see 1k), methoxy (see
1l), and methyl (see 1p), showed modest fluctuation. No-
tably, a free hydroxy group was compatible with the reac-
tion, and desired product 3m was obtained in good yield.
The yields could be improved by using HCO2NH4 as an
additive instead of NH4Cl if arylboronic acids bearing elec-
tron-donating substituents in the para position of the aro-
matic ring were used as substrates (see 3k and 3l), whereas
NH4SCN as the additive enhanced the yield with aryl-
boronic acids bearing electron-withdrawing groups in the
meta position (see 3i and 3j).
fluorodiazoethane.[a]
To demonstrate the practical usefulness of this reaction,
gram-scale experiments were performed with the aryl-
boronic acids 1c and 1g. As shown in Equations (1) and (2),
the reaction proceeded smoothly to afford corresponding
2,2,2-trifluoroethylated products 3c and 3g in good yields.
Given that difluoroalkenes were observed as byproducts
in this reaction, we next conceived that a useful method
for the synthesis of difluoroalkenes may be developed by
[a] Reaction conditions: ArB(OH)2 (0.5 mmol), PhCF3 (2.5 mL),
24 h, 100 °C, yields of the isolated products are given, and the ratio
was obtained by H NMR spectroscopy. [b] HCO2K was used in-
1
modulating the reaction conditions to enable fluoride elimi- stead of (LiOH + NH4Cl).
nation[21] from intermediate I (shown in Scheme 1, c) to be-
come the major reaction pathway. Considering that basic
conditions can hinder protonation and are thus conducive
to the formation of the β-trifluoroethyl carbanion, the ad-
dition of base additives was examined. Through extensive
Conclusions
screening, LiOH was identified as the base that could afford
In summary, a transition-metal-free method for direct
a satisfactory yield of the desired difluoroalkenes, whereas 2,2,2-trifluoroethylation and gem-difluorovinylation by the
other bases such as Mg(OH)2, Ca(OH)2, and KOH gave reaction of arylboronic acids with 2,2,2-trifluorodiazo-
complex mixtures. Notably, this gem-difluorovinylation ethane has been developed. The transformation is switch-
method is not compatible with the one-pot reaction as de- able: under weak acidic conditions, 2,2,2-trifluoroethylation
scribed for conditions A in Table 2.
proceeds efficiently, whereas under weak basic conditions
Under the optimized reaction conditions for gem-di- gem-difluorovinylation becomes the major reaction path.
fluorovinylation, the scope of arylboronic acids was Both transformations are performed under mild conditions
studied. As shown in Table 3, a series of boronic acids were and various functional groups are tolerated.
Eur. J. Org. Chem. 0000, 0–0
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G. Wu, Y. Deng, C. Wu, X. Wang, Y. Zhang, J. Wang
SHORT COMMUNICATION
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Experimental Section
Procedure for 2,2,2-Trifluoroethylation under Conditions A: Aryl-
boronic acid (0.5 mmol), 2,2,2-trifluoroethylamine hydrochloride
(2.0 mmol), sodium nitrite (2.5 mmol), and ammonium chloride
(2.0 mmol) were added into a Schlenk tube. Toluene (2.5 mL) and
water (125 µL) were then added. The mixture was stirred at 100 °C
for 24 h. After the mixture had cooled down to room temperature,
the solvent was removed under reduced pressure. DMSO (2.5 mL)
and potassium fluoride (1.0 mmol) were added to the crude prod-
uct. Then, the mixture was heated at 100 °C for 10 h. After the
solution had cooled down to room temperature, water was added,
and the mixture was extracted with DCE. Evaporation of the sol-
vent gave the crude product, which was purified by column
chromatography with silica gel to afford product 3.
[4]
[5]
[6]
Procedure for 2,2,2-Trifluoroethylation under Conditions B: Aryl-
boronic acid (0.5 mmol) and ammonium chloride (2.0 mmol) were
added into a Schlenk tube. Toluene (1 mL), 2,2,2-tirfluorodiazo-
ethane (0.88 m in toluene, 1.5 mL), and water (125 µL) were added.
The mixture was stirred at 100 °C for 24 h. Then the solution was
treated following the same procedure as that described for condi-
tions A.
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Procedure for the gem-Difluorovinylation: Arylboronic acid
(0.5 mmol), ammonium chloride (0.5 mmol), and lithium hydroxide
(1.0 mmol) were added into a Schlenk tube. PhCF3 (1 mL) and
2,2,2-tirfluorodiazoethane (0.88 m in PhCF3, 1.5 mL) were then
added. Then, the mixture was stirred at 100 °C for 24 h. After the
mixture had cooled down to room temperature, the solvent was
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[10]
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[18] For a review on the reaction of diazo compounds with boron
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[19] For related reactions, see: a) J. Barluenga, M. Tomas-Gamasa,
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Received: May 18, 2014
Published Online: ᭿
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5

Job/Unit: O42597
/KAP1
Date: 16-06-14 10:18:35
Pages: 6
G. Wu, Y. Deng, C. Wu, X. Wang, Y. Zhang, J. Wang
SHORT COMMUNICATION
Switchable Transformations
G. Wu, Y. Deng, C. Wu, X. Wang,
Y. Zhang, J. Wang* .......................... 1–6
Switchable 2,2,2-Trifluoroethylation and
gem-Difluorovinylation of Organoboronic
Acids with 2,2,2-Trifluorodiazoethane
The transition-metal-free 2,2,2-trifluoro-
ethylation and gem-difluorovinylation of
arylboronic acids are reported. By em-
ploying different reaction conditions, these
transformations provide both (2,2,2-tri-
fluoroethyl)arenes and gem-difluorovin-
ylarenes from arylboronic acids and 2,2,2-
trifluorodiazoethane. The operation is sim-
ple and scalable with good functional
group tolerance.
Keywords: Boron / Fluorine / Diazo com-
pounds Trifluoroethylation gem-Di-
fluorovinylation
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