Stereodivergent hydrodefluorination of: Gem -difluoroalkenes: Selective synthesis of (Z)- and (E)-monofluoroalkenes

Article abstract of DOI:10.1039/c7cc05225a

We have developed a novel approach for the stereodivergent hydrodefluorination of gem-difluoroalkenes using copper(i) catalysts to obtain stereodefined monofluoroalkenes. Both (Z)- and (E)-terminal monofluoroalkenes were obtained by the hydrodefluorination of gem-difluoroalkenes in the presence of copper(i) catalysts and diboron or hydrosilane, respectively, with high stereoselectivity. DFT calculations were conducted to elucidate the stereoselectivity.

Full text of DOI:10.1039/c7cc05225a

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Stereodivergent Hydrodefluorination of gem-Difluoroalkenes:
Selective Synthesis of (Z)- and (E)-Monofluoroalkenes
Received 00th January 20xx,
Accepted 00th January 20xx
Ryoto Kojima, Koji Kubota and Hajime Ito*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We have developed a novel approach for the stereodivergent selectivity (up to 99% yield, E/Z = 95:5). However, no Z-
hydrodefluorination of gem-difluoroalkenes using copper(I) selective hydrodefluorination of gem-difluoroalkenes has been
catalysts to obtain stereodefined monofluoroalkenes. Both (Z)- reported to date.9
and (E)-terminal monofluoroalkenes were obtained by
Herein, we report the copper(I)-catalyzed stereodivergent
hydrodefluorination of gem-difluoroalkenes in the presence of hydrodefluorination of gem-difluoroalkenes to provide (Z)- and
copper(I) catalysts and diboron or hydrosilane, respectively, with (E)-terminal monofluoroalkenes (Scheme 1). We have been
high stereoselectivity. DFT calculations were conducted to studying the copper(I)-catalyzed reactions of diboron10–12 and
elucidate the stereoselectivity.
hydrosilanes,13,14 and envisioned that the regioselective
addition of borylcopper(I) and copper(I)-hydride and
subsequent stereoselective β-elimination of the Cu–F moiety
could achieve a stereodivergent hydrodefluorination of gem-
difluoroalkenes.15 By considering the transition state of the
elimination of the Cu-F moiety of the adduct formed between
the borylcopper(I) species and the gem-difluoroalkenes
(Scheme 1a), the steric repulsion between the bulky B(pin) and
the aromatic group (Ar) may result in the Z product after
deborylation. Contrary, the electronic repulsion between the
aromatic group (Ar) and F group in the elimination transition
state of the copper(I)-hydride adducts would give the
corresponding E-product (Scheme 1b).8g
Terminal monofluoroalkenes are important structural motifs in
materials1 and medicinal chemistry2 due to the unique
properties of fluorine.3 The bioactivity of monofluoroalkenes
varies widely according to their stereochemistry. For instance,
Sayre and co-workers reported that an inhibitor for bovine
plasma amine oxidase (BPAO) with a (Z)-β-monofluoroalkene
structure exhibited
a 10-fold effective inhibition ability
compared with its E-stereoisomer on the basis of the IC50
values.4 Thus, their stereodefined synthesis is very important.5
Our
research
focuses
on
the
stereodivergent
hydrodefluorination of gem-difluoroalkenes, which are easily
available from the corresponding carbonyl compounds. This is
expected to be a powerful method for the preparation of
stereodefined terminal monofluoroalkenes with both Z- and E-
configurations from one synthetic intermediate.6-8
A
major challenge in achieving a stereodivergent
hydrodefluorination of gem-difluoroalkenes is the selective
cleavage of one of the two terminal C–F bonds under mild
conditions. Carbon-fluorine bond is the strongest single bond
known, and its cleavage often requires harsh conditions. The
bond energy difference between the two C–F bonds is very
small. Cao and co-workers reported an E-selective
hydrodefluorination of gem-difluoroalkenes using a selective
reduction with Red-Al®.8g This reaction provides the
corresponding (E)-monofluoroalkenes in high yield with good E
Scheme 1. Copper(I)-catalyzed selective defluorination of gem-difluoroalkenes
(this work).
We found that the copper(I)-catalyzed reaction with
diboron proceeded with perfect Z-selectivity (E/Z=1:>99,
Scheme 1a). Furthermore, we found that the stereoselectivity
of the defluorination of gem-difluoroalkenes could be
drastically switched by swapping the diboron reagent for a
hydrosilane (E/Z= from 90:10 to >99:1, Scheme 1b) for the first
time. The DFT calculations suggested the stereoselectivity was
determined at the defluorination steps.
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We first investigated the optimal conditions for the resulted in no reaction (entry 2). The results with other ligands
selective hydrodefluorination of gem-difluoroalkenes by using were inferior to that with the dppp ligand (entries 3–6).
a copper(I)/diboron catalytic system. The reaction of 1a with
bis(pinacolato)diboron (1.2 equiv) in the presence of
CuCl/Xantphos (5 mol%), Na(O-t-Bu) (1.0 equiv), and MeOH
(1.0 equiv) in THF (1.0 mL) at 30°C provided (Z)-2a in high yield
with perfect Z selectivity, and the defluoroborylated product
(Z)-3a was not observed (Table 1, entry 1). The reaction was
also conducted without a ligand, which gave trace amount of
the product with a low conversion of the substrate (entry 2).
We also evaluated other ligands and found the inferior results
(entries 3–6). In all of the reactions, no other by-products
except for 3a were observed, and the mass balance was
Table 2. Substrate scope of the Z-selective defluorination of gem-difluoroalkenesa
unreacted 1a
.
We also tested
a
gem-difluoroalkene
was
(R=CH2CH2Ph) and found borylation product (Z)-
3
obtained in a moderate yield (70%) as the major product.
Table 1. Optimization of the reaction conditions for the Z-selective synthesisa
aReagents and conditions: CuCl (0.025 mmol), Xantphos (0.025 mmol), 1 (0.5
mmol), bis(pinacolato)diboron (0.6 mmol), Na(O-t-Bu) (0.5 mmol) and MeOH (0.5
mmol) in THF (1.0 mL) at 30°C. Yields of isolated products are reported. Yields
determined by 1H NMR analysis are shown in parentheses. The E/Z ratios of the
products were determined by 1H NMR and GLC analyses. b10 mol % of CuCl and
Xantphos were used.
entry
1
2
ligand
Xantphos
none
yield of 2a (%)b
yield of 3a (%)b
96
2
0
2
Table 3. Optimization of the reaction conditions for the (E)-selective synthesisa
3
4
5
6
PPh3
IPr·HCl
dppp
1
9
31
36
45
38
9
dppbz
12
entry
1
2
ligand
dppp
none
yield of 2a (%)b
E/Z c
95:5
–
aConditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1a (0.5 mmol),
bis(pinacolato)diboron (0.6 mmol), alcohol (0.5 mmol) and Na(O-t-Bu) (0.5 mmol)
in THF (1.0 mL). bNMR yield.
96
0
3
4
5
6
IPr·HCl
PPh3
9
–
35
30
70
90:10
92:8
93:7
The optimized conditions were used for further evaluation
of the substrate scope of this reaction (Table 2). Aryl gem-
difluoroalkenes bearing electron donating- and withdrawing-
groups at the para position underwent the defluorination
dppbz
Xantphos
aConditions: CuOAc (0.025 mmol), ligand (0.025 mmol), 1a (0.5 mmol), PhMe2SiH
(1.0 mmol) and NaOTMS (1.0 mmol) in THF (0.5 mL). bNMR yield. cE/Z ratio was
determined by GLC analysis.
reaction to give the desired product (Z)-2b–e in good yields
and with excellent Z selectivity (76–93%, Z only). Cyano
substituted and sterically hindered gem-difluoroalkene (1f and
With the optimized conditions in hand, we examined the
scope of the selective defluorination with various gem-
difluoroalkenes using the copper(I)/hydrosilane catalyst
system (Table 4). Electron rich and deficient aryl gem-
difluoroalkenes underwent the reaction to give the
1g
)
showed low reactivity toward this Z-selective
28%, (Z)-2g n.d.]. Tetra-
hydrodefluorination [(Z)-2f
:
:
substituted gem-difluoroalkene 1h also reacted to provide the
corresponding monofluoroalkene (Z)-2h in low yield and with
excellent Z selectivity (16%, Z only). The reaction of hetero-
aryl-substituted gem-difluoroalkene 1i proceeded smoothly to
give the desired product (Z)-2i in good yield with excellent
selectivity (61%, Z only). Substrates with other π-system (1j
and 1k) gave the corresponding defluorinated products (Z)-2j
and (Z)-2k in high yields (73% and 71%, respectively).
corresponding products, (E)-2b
with high E selectivities (48–94%, E/Z 90:10–99:1). Reaction
with gem-difluoroalkenes bearing cyano group 1f
–e in moderate to high yields
a
a
( )
afforded only a trace amount of the defluorinated product. A
sterically congested, mesityl group-substituted gem-
difluoroalkene 1g showed low reactivity (20%, E/Z >99:1). This
hydrodefluorination was also applied to tetra-substituted gem-
difluoroalkene 1h to give the corresponding product (E)-2h in
Next, we conducted the E-selective hydrodefluorination
using the copper(I)/hydrosilane catalytic system. We found
that the reaction of gem-difluoroalkene 1a with PhMe2SiH (2.0
equiv) in the presence of CuOAc/dppp (5 mol%), NaOTMS (2.0
equiv) in THF at –20°C afforded the (E)-monofluoroalkene, (E)-
2a, in high yield with excellent E selectivity (Table 3, entry 1,
96%, E/Z = 95:5). The reaction of 1a in the absence of ligand
high yield with perfect
E selectivity (81%, E/Z >99:1).
Heteroaryl gem-difluoroalkenes 1i did not provide the
defluorinated product. The reaction of 1l afforded the desired
defluorinated product (E)-2l in high yield and E selectivity
(85%, E/Z 94:6).
2 | J. Name., 2012, 00, 1-3
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We next conducted several mechanistic experiments to followed by a copper(I)-catalyzed proto-deborylation to give
support the proposed reaction mechanism. Z-Selective the product (Z)-2 187
DFT calculations (ωB97XD/cc-pVDZ) of
.
defluorination of 1a under the optimized conditions with model structures were conducted to elucidate the
B2(pin)2 using MeOD instead of MeOH gave (Z)-2a’, bearing a stereoselectivity-determining step (Figure S1, p. S22 in SI). The
deuterium at the β-position (D 91%) [(Z)-2a’: 86%, Z only, activation barrier for the transition state for the Z-isomer is
Scheme 2].16 We also conducted the mechanistic experiment +3.02 kcal/mol lower in energy than that for the E-isomer. This
regarding the deborylation step (Scheme 3). The difference in the activation barrier can be attributed to steric
monofluoroalkenyl boronate ester (Z)-3a was synthesized congestion between the B(pin) group and the phenyl group of
separately and treated with Na(O-t-Bu) and MeOH in the the substrate.
presence or absence of the copper(I) catalyst. With the
copper(I) catalyst, the deborylated product was obtained in
good yield (64%). In contrast, only a trace amount of the
desired product was obtained without the copper(I) catalyst.
These results revealed that the deborylation proceeds through
a copper(I)-catalyzed transmetallation/protonation pathway.17
Table
4. Substrate scope of the E-selective defluorination of gem-
difluoroalkenesa
Figure 1. Proposed reaction mechanism for selective defluorination using the
copper(I)/diboron system
We also conducted an additional mechanistic experiment
to support the proposed reaction mechanism. The E-selective
defluorination reaction with use of PhMe2SiD instead of
PhMe2SiH provided the corresponding β-deuterated product,
(E)-2a’ with excellent regio- and E-selectivity (Scheme 4). This
suggests that the current defluorination proceeds via the
regioselective addition of copper(I)-hydride to the substrate,
followed by β-fluorine elimination of the alkylcopper(I)
intermediate.
aReagents and conditions: CuOAc (0.025 mmol), dppp (0.025 mmol), 1 (0.5
mmol), PhMe2SiH (1.0 mmol) and NaOTMS (1.0 mmol) in THF (0.5 mL) at 0°C.
Yields of isolated products are reported. Yields determined by 1H NMR analysis
are shown in parentheses. The E/Z ratios of the products were determined by 1
H
NMR analyses. bTHF (1.0 mL) was used; 10 mol % of CuOAc and dppp were used.
Scheme 4. Deuterium labelling experiment for the E-selective synthesis
Scheme 2. Deuterium labelling experiment about Z-selective synthesis
Scheme 3. Mechanistic study of the deborylation step
A
proposed reaction mechanism for the Z-selective
defluorination using the copper(I)/diboron system is shown in
Figure 1. Copper(I) alkoxide would initially react with
diboron to afford the borylcopper(I) species The
coordination of the gem-difluoroalkene to species would
result in the formation of the π-complex , which would
undergo an insertion reaction to give the alkylcopper(I)
A
B
.
1
B
Figure 2. Proposed reaction mechanism for selective defluorination using the
copper(I)/hydrosilane system
C
We have postulated
a reaction mechanism for the
intermediate
D
. Then syn-elimination from this intermediate
would result in the formation of
D
3
defluorination using the copper(I)/hydrosilane system, which is
via transition state
E
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8
For selected examples of hydrodefluorination of gem-
shown in Figure 2. In this case, the copper(I)-hydride species B’
would be produced initially, and subsequent insertion would
give the alkylcopper(I) intermediate D’, which is similar to that
suggested in the copper(I)/diboron system. The β-fluorine
elimination of D’ via transition state E’ would proceed to give
difluoroalkenes to monofluoroalkenes, see: (a) W. A. Vinson,
K. S. Prickett, B. Spahic and P. R. Ortiz de Montellano, J. Org.
Chem., 1983, 48, 4661–4668; (b) M. Bobek, I. Kavai and E. De
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Landelle, M.-O. Turcotte-Savard, J. Marterer, P. A.
the defluorinated product (E)-
2 as well as generating the
copper(I) fluoride A. DFT calculations (ωB97XD/cc-pVDZ)
(Figure S2, p. S23 in SI) showed that the activation barrier for
the transition state for the E-isomer is +1.21 kcal/mol lower in
energy than that for the Z-isomer.
Champagne and J.-F. Paquin, Org. Lett., 2009, 11, 5406–
5409; (f) H. Zhang, C.-B. Zhou, Q.-Y. Chen, J.-C. Xiao and R.
Hong, Org. Lett., 2010, 13, 560–563; (g) J. Wu, J. Xiao, W. Dai
and S. Cao, RSC Adv., 2015, 5, 34498–34501.
In summary, we have developed a novel stereodivergent
hydrodefluorination of gem-difluoroalkenes for the
preparation of (Z)- and (E)-terminal monofluoroalkenes using
borylcopper(I) and copper(I)-hydride species with excellent
selectivities. This reaction involves the regioselective boryl- or
hydrocupration of gem-difluoroalkenes, followed by
stereoselective fluorine elimination from the resulting
alkylcopper(I) intermediates. Our study is the first example of
the stereodivergent synthesis of (Z)- and (E)-terminal
monofluoroalkenes from the same starting material. Further
studies directed toward the reaction of alkyl gem-
difluoroalkenes are currently underway.
9
This work was presented at the 97th CSJ Annual Meeting,
Yokohama, Japan (March 16–19, 2017). At the same
conference, the Ogoshi and Hosoya group independently
reported copper(I)-catalyzed defluoroborylations of
polyfluoroalkenes including gem-difluoroalkenes. During the
preparation of this paper, Cao and co-workers reported a
related defluoroborylation reaction and showed one
example of deborylation, see: J. Zhang, W. Dai, Q. Liu and S.
Cao, Org. Lett., 2017, doi: 10.1021/acs.orglett.7b01430.
Their reactions require additional reagents (AgNO3, Et3N,
EtOH) for deborylation step. E-reduction with hydrosilane
was only reported by us.
10 Early studies of copper(I)-mediated activation of diboron,
see: (a) H. Ito, H. Yamanaka, J. Tateiwa and A. Hosomi,
Tetrahedron Lett., 2000, 41, 6821–6825; (b) K. Takahashi, T.
Ishiyama and N. Miyaura, Chem. Lett., 2000, 982–983.
11 For selected our studies for copper(I)/diboron catalyst
system, see: (a) H. Ito, C. Kawakami and M. Sawamura, J. Am.
Chem. Soc., 2005, 127, 16034–16035; (b) H. Ito, S. Kunii and
This work was financially supported by the Japanese
Ministry of Education, Culture, Sports, Science and Technology
(MEXT) via the “Program for Leading Graduate Schools” at
Hokkaido University “Ambitious Leaders Program”, and by JSPS
KAKENHI (Grant Nos. 15H03804 and 15K13633).
M. Sawamura, Nat. Chem., 2010, 2, 972–976; (c) K. Kubota,
Y. Watanabe, K. Hayama and H. Ito, J. Am. Chem. Soc., 2016,
138, 4338–4341.
Notes and references
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