Stereoselective Synthesis of Z Fluoroalkenes through Copper-Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water

Article abstract of DOI:10.1002/anie.201708224

A copper catalytic system was established for the stereoselective hydrodefluorination of gem-difluoroalkenes through C?F activation to synthesize various Z fluoroalkenes. H₂O is used as the hydrogen source for the fluorine acceptor moiety. This mild catalytic system shows good-functional group compatibility, accepting a range of carbonyls as precursors to the gem-difluoroalkenes, including aliphatic, aromatic, and α,β-unsaturated aldehydes and even ketones. It serves as a powerful synthetic method for the late-stage modification of complex compounds.

Full text of DOI:10.1002/anie.201708224

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Stereoselective Synthesis of Z-Fluoroalkenes by Copper-
Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water
Authors: Zhuangzhi Shi, Jiefeng Hu, Xiaowei Han, and Yu Yuan
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708224
Angew. Chem. 10.1002/ange.201708224
Link to VoR: http://dx.doi.org/10.1002/anie.201708224
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10.1002/anie.201708224
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C-F Activation
Stereoselective Synthesis of Z-Fluoroalkenes by Copper-Catalyzed
Hydrodefluorination of gem-Difluoroalkenes with Water
Jiefeng Hu+, Xiaowei Han+, Yu Yuan, and Zhuangzhi Shi*
Dedicated to Professor Qi-Lin Zhou on the occasion of his 60th birthday
Abstract: A copper-catalytic system has been established for the
stereoselective hydrodefluorination of gem-difluoroalkenes via C-F
activation to synthesize various Z-fluoroalkenes. H2O is first used as
a hydrogen source for the fluorine acceptor moiety. This mild
catalytic system shows good functional group compatibility bearing
substrates from aliphatic, aromatic and α,β-unsaturated aldehydes
and even ketones that can be served as a powerful synthetic tool for
late-stage modification of complex compounds.
from aldehydes to complement the present method.
Alkenes with a fluorine substituent are commonly occurring
structural motifs which are not only used as powerful intermediates
for synthesis of fluorine containing compounds,[1] but also widely
found in medicines, agrochemicals and materials.[2] Moreover, the
terminal fluoro-olefin group is a useful functionality in the design of
mechanism-based enzyme inhibitors.[3] Since the potency of these
inhibitors often depends on the geometry of the olefins, their Z/E
stereoisomers often exhibit different bioactivities.[4] In this context,
considerable effort has been paid to develop methods that can lead
to stereodefined fluoro-olefins. However, most methods reported so
far produce mixtures of E and Z isomers, which are often difficult to
separate.[5] Although some stereoselective methods have been
developed, most of them mainly generate the E-fluoroalkenes.[6] E-
alkenes are usually lower in energy and thus generated preferentially.
Undoubtedly, the implicit challenge of a strategy accessing the
selectivity of acyclic Z-fluoroalkenes is evident.
The synthetic protocols for Z-fluoroalkenes are limited.[7] One
available route entails multi-step sequences demanding prior
stereoselective synthesis of the toxic alkenylstannanes, followed by
conversion of the C-Sn units to C–F bonds.[8] Methods for
preparation of 1,2-disubstituted Z-alkenyl fluorides with high
stereoselectivity are far less common. One opportunity is the
conventional Wittig olefination reaction of aldehydes with a
Figure 1. Synthesis of Z-fluoroalkenes.
Hydrodefluorination (HDF) is a promising way to access partially
fluorinated building blocks from readily available perfluorinated
substrates via C-F activation, where hydrosilane R3SiH is usually
used as a hydrogen source.[11] Herein, we disclose a highly
stereoselective method to construct di- or tri-substituted Z-
fluoroalkenes by a Cu-catalyzed regioselective HDF of gem-
difluoroalkenes[12] using water as the hydrogen source (Figure 1c).
Our route employing cheap aldehydes or ketones, fluorine and
hydrogen sources using earth-abundant metal as the catalyst can be
operated without considering the Z/E configuration of the substrates
and intermediates.
Initial studies involved the evaluation of the selective HDF of 1,1-
difluorotridec-1-ene 1a (Table 1). In the presence of 10 mol% CuCl2,
10 mol% Xantphos, 3.0 equiv LiOtBu, and 3.0 equiv B2pin2, at 40
oC under an Ar atmosphere in DMA, we observed a defluorinated
product, 1-fluorotridec-1-ene (2a) after 24 h in GC-MS, albeit in
trace amount (entry 1). We suspected that the generated hydrogen
atom in the product may come from residual water in solvent. To
our delight, when 3.0 equiv H2O was added as a proton source in
this system, the yield of 2a was dramatically increased to 25% yield
and the product was formed with sole Z selectivity (entry 2). To
improve the result, we evaluated several copper salts and observed
more promising results (entries 3-6). The largest increase in reaction
efficacy was found with catalytic CuTc, furnishing the desired HDF
product in 81% yield. Under these conditions, B2nep2 was proven
better than B2Pin2 improving 2a to 90% yield (entry 7). However,
decreasing the B2nep2 load to 2.0 equiv resulted in lower yield
(entry 8). Other hydrogen sources such as methanol, acetic acid
were found unsuccessful in this transformation (entries 9-10).
Notably, other bases such as KOtBu were completely ineffective for
this reaction (entry 11). Finally, with control experiments run either
in the absence of Xantphos ligand, B2nep2, or copper catalyst, the
reaction was unsuccessful (entries 12-14).
fluorine-containing
phosphoranium
salt.
However,
the
stereoselectivity of this method is difficult to control and the
construction of 2-aryl substituted Z-fluoroalkenes is completely
failed (Figure 1a).[9] Very recently, Hoveyda and coworkers reported
an important breakthrough for the highly Z-selective synthesis of
these olefins from Z-bromofluoroethene by Mo-catalyzed olefin
cross-metathesis (CM) reactions (Figure 1b).[10] Inherently, both of
routes are feasible for conversion of the ready available starting
materials including aldehydes and olefins. However, disadvantages
of the current route from aldehydes are obvious. Thus, there is a
great need for strategies that can efficiently deliver Z-fluoroalkenes
[]
Jiefeng Hu,[+] Xiaowei Han,[+] and Prof. Dr. Zhuangzhi Shi
State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, China
E-mail: shiz@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/zzshi/
Xiaowei Han,[+] Prof. Dr. Yu Yuan
College of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou 225002, China
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification
number(s) for the author(s) for this article can be found under
http://www.angewandte.org.
To evaluate the utility of this HDF reaction, a series of gem-
difluoroalkenes derived from aliphatic aldehydes were tested first
(Table 2). Substrates with aryl groups (1b-1f) or heteroaryl moieties
(1g-1j) didn’t hinder the C-F activation process affording the
corresponding products 2b-2j in 71-92% yields. Versatile functional
1
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10.1002/anie.201708224
Angewandte Chemie International Edition
Table 1. Reaction Development.[a]
Table 2. HDF of gem-Difluoroalkenes from Aliphatic Aldehydes.[a]
Additive
(equiv)
[b]
Entry
Cat [Cu]
Base
[H]
Yield (%)
1
2
CuCl2
CuCl2
CuF2
LiOtBu
LiOtBu
LiOtBu
B2pin2 (3)
-
trace
25
B2pin2 (3)
B2pin2 (3)
B2pin2 (3)
B2pin2 (3)
B2pin2 (3)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
AcOH
H2O
H2O
H2O
H2O
3
36
4
CuBr•Me2S LiOtBu
45
5
CuI
LiOtBu
LiOtBu
62
6
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuCl2
81
[c]
7
LiOtBu B2nep2 (3)
90 (88)
78
8
LiOtBu
LiOtBu
LiOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
B2nep2 (2)
B2nep2 (3)
B2nep2 (3)
B2nep2 (3)
B2nep2 (3)
-
9
trace
trace
trace
0
10
11
[d]
12
13
0
14
B2nep2 (3)
0
[a]Conditions: 1a (0.20 mmol), 10 mol% of copper salts, 10 mol% of
Xantphos, 3.0 equiv of base, 2.0-3.0 equiv of borylating agents, 3.0
o
equiv of H source, in 1.0 mL solvent at 40 C, 12 h. [b]Determined
by GC analysis. [c]Isolated yield. [d]Without ligand.
groups such as ether (2k), cyclohexane (2l), chlorine (2m), fluorine
(2n), nitrile (2o), different amides (2p-2r), ester (2s), or acetal (2t)
were well tolerated. Particularly, diene substrates with either cis or
trans-configuration such as 1u and 1v could also be effectively
converted to the desired Z-fluoroalkenes 2u and 2v respectively in
good yields.
[a]Conditions: 0.20 mmol of 1, 10 mol% of CuTc, 10 mol% of
Xantphos, 3.0 equiv of LiOtBu, 3.0 equiv of B2nep2, 3.0 equiv of
H2O in 1.0 mL DMA at 40 oC, 16 h, under Ar; Isolated yield.
Table 3. HDF of gem-Difluoroalkenes from Aromatic Aldehydes.[a]
An array of 2-aryl substituted Z-fluoroalkenes can also be
prepared in good yields with sole stereoselectivity utilizing the
present protocol (Table 3). Compared to B2nep2 used in above
aliphatic substrates, the utilization of B2pin2 had showed better
reactivity with aromatic compounds (e.g. 4a). A wide range of 2-
aryl substituted gem-difluoroalkenes that incorporate ether (4a-4d),
ester (4e), amine (4f), F (4g), Cl (4h), Br (4i), CF3 (4j), CF2 (4k),
and cyano (4l) groups at the ortho, meta, and para positions of
benzene motif were readily tolerated. Naphthalene (4m) and
heterocycles including benzofuran (4n), pyridine (4o), and
quinolone (4p) were also shown to exhibit high levels of reactivity.
These examples indicate that the Z-stereoselectivity of the reaction
is not sensitive to the electronic nature or position of the substituents
on the benzene ring.
We were also pleased to see that this method could be applied to
some more challenging substrates. For example, this approach
allowed the C–F activation of 1,1-difluorobuta-1,3-dienes 5a-5c in
64-78% yields, thus providing a method to synthesize conjugated
terminal Z-fluoroalkenes (Scheme 1). Moreover, a ketone-derived
difluoroalkene 7[13] bearing a para-bromo atom was successfully
transformed into trisubstituted Z-fluoroalkene 8 in moderated yield
with sole stereoselectivity as well (Scheme 2).
[a]Conditions: 0.20 mmol of 3, 10 mol% of CuTc, 10 mol% of
Xantphos, 3.0 equiv of LiOtBu, 3.0 equiv of B2pin2, 3.0 equiv of
H2O in 1.0 mL DMA at 40 oC, 16 h, under Ar; Isolated yield.
[b]Using B2nep2 instead of B2Pin2.
A major benefit of this mild and highly stereoselective C−F
activation procedure is the tolerance of a range of functional units
commonly found in biologically active molecules (Scheme 3). For
example, cyclamal (9a) with α-branched methyl group, proceeded
readily and stereoselectively to produce 11a after gem-
2
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10.1002/anie.201708224
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Scheme 1. HDF of gem-Difluoroalkenes from α,β-Unsaturated
Aldehydes.
Scheme 2. HDF of gem-Difluoroalkene 8 from Ketone 7'.
difluoroolefination. (R)-(+)citronellal (9b)[14] with a chiral center,
could be subjected to this method to produce the Z-fluoroalkene 11b
in 79% isolated yield. Hydroxycitronellal (9c) with a 5-hydroxy
group could also be tolerated (92% yield). α-Linolenic acid (12a)[15]
with three cis configuration could be transformed smoothly to
provide gem-difluoroalkene 13a, which was in turn converted into
the product 14a in 85% yield with complete Z-configuraton. Finally,
synthesis of a complex molecule 14b was also successful from
lithocholic acid analog 12b by the sequence of reduction and gem-
difluoroolefination, followed by stereoselective HDF reaction in
good yield.
Scheme 4. Mechanistic Studies.
desired product 4b was not detected (Scheme 4c). Surprisingly, the
addition of catalytic amount of substrate 1a to the above reaction, 4b
was generated in 82% with sole stereoselectivity (Scheme 4d).
Moreover, the addition of a fluoride ion, LiF to the system can carry
out the HDF process (49%) as well (Scheme 4e). These results
suggest that Z-fluorinated vinylboronate esters should be visible
intermediates in reactions and a new formed copper species, CuF is
likely to be formed during C–F cleavage process which could
transfer the boronate esters to Z-fluoroalkenes. Finally, we noted
that reduction of 3b with LiAlH4 afforded the E-alkene 4b' as the
major product (4b:4b' = 2:98, Scheme 4f). [
]
6c, 6g
Figure 2. Proposed Catalytic Cycle.
Scheme 3. Late-Stage Modification of Natural-Product-Derived
gem-Difluoroalkenes.
On the basis of the above experimental results, a mechanism has
been proposed as shown in Figure 2. The reaction of the precatalyst
CuTC with LiOtBu forms the catalytically active species A. This
complex can easily undergo transmetalation with boron source
(B2pin2 or B2nep2) generating intermediate B, followed by cis
insertion of gem-difluoroalkene I to generate the species C.
Subsequent cis β-F elimination[12b,e,i,17a ] of the stable conformation
D delivers the key vinylboronate ester intermediate II and a CuF-
like species E. This copper species can undergo another step of
transmetalation with intermediate II then furnishes a stereoselective
vinyl copper complex F. Hydrolysis of F can furnish the Z-
fluoroalkene III regenerating the copper catalyst. The steric effect
plays a critical role and the interplay between the R-substituent from
Several experiments were conducted to provide insight about the
potential mechanism of this transformation (Scheme 4). When the
reaction of 1a was conducted with D2O under standard reactions, D
label nearly full incorporated into 2a (84% yield, 99% D). This
observation confirmed water as the sole source of the hydrogen
atom in the product (Scheme 4a). Using diethoxymethylsilane
(DEMS) with substrate 3b instead of B2pin2 and H2O, a common
hydride source in CuH chemistry,[16] we observed a mixture of
isomers 4b and 4b' (56:44), which ruled out the CuH-catalyzed
process (Scheme 4b). We further employed Z-fluorinated
vinylboronate ester 15[17] under standard conditions, however, the
3
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10.1002/anie.201708224
Angewandte Chemie International Edition
gem-difluoroalkene and bulky boryl group (D vs D') controls the
remarkable stereodivergence.
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In summary, we have developed an efficient copper-catalytic
system, which is capable of activating C–F bonds of gem-
difluoroalkenes from aldehydes and ketones using water as
hydrogen source via HDF process to produce various Z-
fluoroalkenes. Sole Z-stereoselectivity was observed in all cases.
Given the widespread carbonyl group and its precursors in
chemicals, we anticipate that this strategy will simplify the synthesis
and structural elaboration of Z-fluoroalkene targets for research in
chemistry, biology and medicine.
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Acknowledgments
We are grateful to Mr. Pan Gao in our group for reproducing the
results of 2f, 2q and 4h. We also thank the “1000-Youth Talents
Plan”, and NSF of China (Grant 2167020084, 21401099) for
financial support.
Keywords: copper ·fluorine ·HDF ·water ·Z-alkenes
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4
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
C-F Activation
Jiefeng Hu, Xiaowei Han, Yu Yuan, and
Zhuangzhi Shi* ___ Page – Page
Stereoselective
Fluoroalkenes by Copper-Catalyzed
Hydrodefluorination of gem-
Difluoroalkenes with Water
Synthesis
of
Z-
Two-Minus-One: A copper-catalytic system has been established for HDF of gem-
difluoroalkenes of carbonyl compounds with water via C-F activation. This route
employing cheap aldehydes or ketones, fluorine and hydrogen sources using earth-
abundant metal as the catalyst can be operated without considering the Z/E
configuration of the substrates and intermediates to construct di- or tri-disubstituted
Z-fluoroalkenes with highly stereoselectivity.
5
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