Coupling of Trifluoroacetaldehyde N-Triftosylhydrazone with Organoboronic Acids for the Synthesis of gem-Difluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.9b03740

The synthesis of alkyl gem-difluoroalkenes remains a difficult task in organic synthesis. Here, we report a general and efficient approach for tackling this problem by gem-difluoroolefination of trifluoroacetaldehyde N-triftosylhydrazone with organoboronic acids. This protocol is operationally simple, free of transition metals, and suitable for a broad range of organoboronic acids. Moreover, the utility of the products was demonstrated by further conversion of the gem-difluorovinyl group.

Full text of DOI:10.1021/acs.orglett.9b03740

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Coupling of Trifluoroacetaldehyde N‑Triftosylhydrazone with
Organoboronic Acids for the Synthesis of gem-Difluoroalkenes
Yu Ma,†,‡ Bhoomireddy Rajendra Prasad Reddy,† and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The synthesis of alkyl gem-difluoroalkenes remains a
difficult task in organic synthesis. Here, we report a general and efficient
approach for tackling this problem by gem-difluoroolefination of
trifluoroacetaldehyde N-triftosylhydrazone with organoboronic acids.
This protocol is operationally simple, free of transition metals, and
suitable for a broad range of organoboronic acids. Moreover, the utility
of the products was demonstrated by further conversion of the gem-
difluorovinyl group.
gem-Difluoroalkenes are ubiquitous structural units in bio-
logically active molecules, pharmaceuticals, agrochemicals, and
organic materials (Figure 1).1 They are also important motifs
Figure 2. Coupling strategies for the synthesis of gem-difluoroalkenes
using diazo compounds.
Figure 1. Biologically active molecules containing a gem-difluorovinyl
moiety.
or an aryl ring. In addition, homodimerization and cyclo-
propanation yield the side products. Recently, Wang and co-
workers reported a seminal coupling reaction of trifluorodiazo-
in the design of mechanism-based enzyme inhibitors1c,2 and
ethane (CF3CHN2) and arylboronic acids leading to gem-
difluoroalkenes (Figure 2a).5g However, this method required
the direct use of toxic and explosive CF3CHN2. A survey of the
chemistry of gem-difluoroalkenes revealed that alkyl gem-
difluoroalkenes were more abundant in biologically active
compounds than aryl gem-difluoroalkanes (Figure 1).1 Never-
theless, the synthesis of alkyl gem-difluoroalkenes remains a
difficult task in organofluorine chemistry. As part of our
continued interest in the room-temperature decomposition of
are known to act as bioisosteres of carbonyl groups.3
Moreover, gem-difluoroalkenes are versatile building blocks in
organic synthesis.4 Consequently, a number of elegant
methods for their synthesis have been developed. Among
these, the construction of gem-difluoroalkenes from diazo
compounds has attracted considerable attention in recent
years.5 For instance, Wang, Hu, and others demonstrated a
cross-carbene type coupling of diazo compounds with
difluorocarbene precursors to access gem-difluoroalkenes
(Figure 2a).5a−f Despite their versatility, these methodologies
are viable for only diazo compounds bearing at least one EWG
Received: October 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
N-sulfonylhydrazones, we recently disclosed a nontoxic and
bench-stable trifluoroacetaldehyde N-triftosylhydrazone
(TFHZ-Tfs) as a CF3CHN2 surrogate, which afforded
CF3CHN2 in situ under basic conditions. In addition,
TFHZ-Tfs was successfully employed in the gem-difluoroolefi-
nation of X−H bonds (X = N, O, S, or Se).6 Encouraged by
these results, we envision that gem-difluoroolefination of
trifluoroacetaldehyde N-sulfonylhydrazones with organobor-
onic acids might be possible. An investigation of this
hypothesis led to the development of a highly efficient
transition metal free gem-difluoroolefination of TFHZ-Tfs
with organoboronic acids, which represents a novel method for
accessing alkyl and aryl gem-difluoroalkenes (Figure 2b).
We started our study using TFHZ-Tfs and biphenyl ethyl
boronic acid (1e) as standard substrates. As shown in Table 1,
for obtaining gem-difluoroalkenes in high yield (entries 11−
13). When the ammonium salts were replaced with LiCl, the
reaction failed to provide the desired product (entry 14). The
use of TFHZ-Ts or TFHZ-Ns as a substitute for TFHZ-Tfs
resulted in lower yields (entry 15 or 16, respectively). When 1e
was subjected to the method reported by Wang et al.,5g the
product was delivered in a lower yield (entry 17). Presumably,
the slow release of CF3CHN2 from TFHZ-Tfs may favor the
gem-difluoroolefination in the case of alkylboronic acids. We
thus selected the reaction conditions listed in entry 11 of Table
1 as the optimum conditions for the subsequent assessment of
the substrate scope.
Adopting the optimized conditions obtained above (Table 1,
entry 11), we next investigated the substrate scope of the gem-
difluoroolefination of TFHZ-Tfs with alkylboronic acids
(Scheme 1). Straight-chain alkylboronic acids with various
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. gem-Difluoroolefination of TFHZ-Tfs with
a
Alkylboronic Acids
b
entry
base
additive
solvent
PhCF3
T (°C) yield of 2e (%)
1
2
3
4
5
6
7
8
K2CO3
t-BuOLi
t-BuOK
t-BuONa
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
−
−
−
−
−
−
−
−
100
100
100
100
100
100
100
100
100
100
100
80
120
100
100
100
100
trace
30
trace
25
36
0
0
trace
80
PhCF3
PhCF3
PhCF3
PhCF3
1,4-dioxane
DMSO
toluene
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
9
NH4OAc
NH4I
NH4Cl
NH4Cl
NH4Cl
LiCl
NH4Cl
NH4Cl
NH4Cl
10
11
12
13
14
88
c
95 (90)
trace
82
0
38
54
37
d
15
e
16
f
17
a
Reaction conditions: 1e (0.25 mmol), TFHZ-Tfs (0.625 mmol, 2.5
equiv), base (2.0 mmol, 8.0 equiv), and additive (1.0 mmol, 4.0
b
1
equiv) in 5 mL of solvent for 36 h under Ar. Determined by H
NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
c
d
a
standard. Isolated yield in parentheses. Reaction conducted with
Reaction conditions: 1 (0.25 mmol), TFHZ-Tfs (0.625 mmol, 2.5
equiv), LiOH (2.0 mmol, 8.0 equiv), and NH4Cl (1.0 mmol, 4.0
e
f
TFHZ-Ts. Reaction conducted with TFHZ-Ns. Reaction conducted
directly with CF3CHN2 using Wang’s method.5g
equiv) in 5 mL of trifluorotoluene at 100 °C for 36 h under Ar. Yields
b
are of isolated products. Reaction conditions: 1o (6.0 mmol),
TFHZ-Tfs (15.0 mmol, 2.5 equiv), LiOH (48.0 mmol, 8.0 equiv), and
NH4Cl (24.0 mmol, 4.0 equiv) in 100 mL of trifluorotoluene at 100
°C for 48 h under Ar.
the reaction gave desired product 2e in very low yields when
carbonate and various tert-butoxides were used as the base
(entries 1−4). With LiOH in place of carbonate and tert-
butoxides, a slight increase in the yield was observed (entry 5).
The use of nonfluorinated solvents had a detrimental effect on
the reaction outcome (entries 6−8). Notably, the addition of
NH4OAc or NH4I as an additive significantly improved the
yield (entries 9 and 10). The best yield (95%) was achieved by
employing NH4Cl as an additive (entry 11). The judicious
optimization of the temperature showed that 100 °C is crucial
chain lengths were quite compatible with this method and
were converted to 2a−2d in 79−90% yields. It is worth
mentioning that long-chain aliphatic gem-difluoroalkene frame-
works are found in notable bioactive compounds (Figure
1).1a−d Alkylboronic acids featuring a phenyl group at the
terminal carbon of their alkyl chain were successfully converted
B
DOI: 10.1021/acs.orglett.9b03740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to the desired products with high yields (2f−2j). Alkylboronic
acids containing a variety of functional groups at the terminal
carbon, such as ether, sulfide, sulfone, sulfonamide, and
halogens, also proved to be suitable reaction partners, leading
to the desired products 2k−2p in 62−85% yields. Moreover,
alkylboronic acids holding 2-thienyl, 2-naphthyl, and styrene
moieties at the terminal carbon reacted smoothly to form the
desired products in good yields (2q−2s). In addition to
alkylboronic acids, alkenylboronic acids were also competent
substrates, furnishing products 2t−2v in moderate yields under
identical reaction conditions.
87% yield. Naphthyl boronic acids smoothly participated in the
reaction and delivered the corresponding products in good
yields (4p and 4q). Furthermore, we tested a boronic acid
containing a fluorene ring, and it gave 4r in 86% yield.
Interestingly, boronic acids bearing dibenzo-fused heterocycles
could also be employed to construct gem-difluoroalkenes
without any difficulties (4s and 4t).
To further assess the utility of the described gem-
difluoroolefination, we performed a series of synthetic
manipulations of the gem-difluorovinyl group (Scheme 3).
a
The results presented above prompted us to investigate the
scope of arylboronic acids (Scheme 2). Delightfully, in this
Scheme 3. Synthetic Applications of 2c
Scheme 2. gem-Difluoroolefination of TFHZ-Tfs with
a
Arylboronic Acids
a
Reaction conditions: (a) 2c (0.2 mmol), CuTc (10 mol %),
Xantphos (10 mol %), t-BuOLi (0.6 mmol, 3.0 equiv), and B2nep2
(0.6 mmol, 3.0 equiv) in DMA (1.0 mL) at 40 °C for 16 h under Ar;
(b) 2c (0.5 mmol), PhMgBr (3.0 equiv), and NiCl2(dppp) (4 mol %)
in THF (2.5 mL) at rt for 1 h under Ar; (c) 2c (0.2 mmol), EtSH (0.4
mmol, 2.0 equiv), and Cs2CO3 (0.6 mmol, 3.0 equiv) in DMF (2.0
mL) at rt for 15 h; (d) 2c (0.3 mmol, 2.0 equiv), 2-iodoanisole (0.15
mmol), [allylPdCl]2 (2.5 mol %), XPhos (10 mol %), and AgF (0.18
mmol, 1.2 equiv) in cyclohexane (1.0 mL) at 80 °C for 12 h under N2.
For example, gem-difluoroalkene 2c readily underwent Cu-
catalyzed hydrodefluorination to produce Z-fluoroalkene 5 in
72% yield (Scheme 3a).4f Also, 2c smoothly underwent a
double cross-coupling with Grignard reagents in the presence
of a Ni catalyst (Scheme 3b).7 Upon treatment with thiols, the
compound underwent direct nucleophilic substitution to
produce α-fluorovinyl thioether 7 in 78% yield with excellent
Z selectivity (Scheme 3c).8 Moreover, we were pleased to find
that 2c could readily undergo a Pd-catalyzed fluoroarylation to
deliver 8 in 83% yield (Scheme 3d).4i
On the basis of the aforementioned results and previous
reports,5g,6,9 we proposed a possible reaction mechanism
(Scheme 4). Initially, CF3CHN2 (I) is generated from TFHZ-
Tfs under basic conditions. Thereafter, nucleophilic addition of
CF3CHN2 (I) to the electron-deficient boron atom of the
boronic acid afforded a tetracoordinate boronate intermediate
(II). The subsequent 1,2-shift of the carbon ligand from boron
to carbon followed by elimination of N2 afforded intermediate
a
Reaction conditions: 3 (0.3 mmol), TFHZ-Tfs (0.75 mmol, 2.5
equiv), LiOH (1.8 mmol, 6.0 equiv), and NH4Cl (0.9 mmol, 3.0
equiv) in 4.5 mL of trifluorotoluene at 100 °C for 12 h under Ar.
Yields are of isolated products.
Scheme 4. Proposed Reaction Mechanism
case the base and additive loading could be reduced to 6.0 and
3.0 equiv, respectively, and the reaction was complete within
12 h. Initially, we studied the effect of the substituents on the
benzene ring of arylboronic acids. The electronic properties,
position, and number of substituents on the benzene ring have
very little influence on the gem-difluoroalkene formation, and
the corresponding products were furnished in good to high
yields (4a−4n, 70−94% yields). Similarly, 1,3-benzodioxole-5-
boronic acid was used in the reaction to provide product 4o in
C
DOI: 10.1021/acs.orglett.9b03740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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A novel transition metal free gem-difluoroolefination of
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access alkyl gem-difluoroalkenes, which were previously
challenging to prepare. Moreover, the reaction is suitable for
a wide range of organoboronic acids, and the utility of the
products was established by further transformations of the gem-
difluorovinyl group. In view of the bench-stable and nontoxic
TFHZ-Tfs reagent, ready availability of boronic acids, and
biological significance and versatile transformations of gem-
difluoroalkenes, this method would find wide applications in
organic synthesis.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03740.
Experimental procedures and copies of spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bixh507@nenu.edu.cn.
ORCID
Xihe Bi: 0000-0002-6694-6742
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (21871043 and
21961130376), the Department of Science and Technology
of Jilin Province (20180101185JC and 20190701012GH), and
the Fundamental Research Funds for the Central Universities
(2412019ZD001).
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He, L. Org. Biomol. Chem. 2017, 15, 3863.
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1667. (b) Li, H.; Zhang, Y.; Wang, J. Synthesis 2013, 45, 3090.
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