Iron-Catalyzed Diborylation of Unactivated Aliphatic gem-Dihalogenoalkenes: Synthesis of 1,2-Bis(boryl)alkanes

Article abstract of DOI:10.1021/acs.orglett.1c01967

Herein, we report the first example of iron-catalyzed defluoroborylation of unactivated gem-difluoroalkenes, gem-dichloroalkenes, and gem-dibromoalkenes, providing the 1,2-bis(boryl)alkanes in moderate to good yield. This transformation has high regiosele

Full text of DOI:10.1021/acs.orglett.1c01967

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Letter
Iron-Catalyzed Diborylation of Unactivated Aliphatic gem-
Dihalogenoalkenes: Synthesis of 1,2-Bis(boryl)alkanes
Shangsheng Zhou,# Yu Pu,# Zhengli Liu, Xiaoming Zhang, Jiang Zhu,* and Zhang Feng*
Cite This: Org. Lett. 2021, 23, 5565−5570
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ABSTRACT: Herein, we report the first example of iron-catalyzed
defluoroborylation of unactivated gem-difluoroalkenes, gem-dichlor-
oalkenes, and gem-dibromoalkenes, providing the 1,2-bis(boryl)-
alkanes in moderate to good yield. This transformation has high
regioselectivity, wide substrate scope, and excellent functional
group compatibility. Preliminary mechanistic studies indicate that
double β-F elimination is involved in the catalytic cycle, and the
1,1-diborylated alkenes might be intermediates in this iron-
catalyzed 1,2-diborylation reaction.
Scheme 1. Transition-Metal-Catalyzed the Transformation
of gem-Difluoroalkenes
ron catalysts have been widely employed in organic
Isynthesis due to their advantages of nontoxicity, low cost,
and abundance.1 In addition, the different properties of iron
catalysis in organic reactions make it more attractive than other
transition metals.2 For instance, palladium always exhibits a
two-electron pathway in cross-coupling reactions, while iron
initiates these transformations through one-electron transfer.3
Usually, many unpredictable reactions are discovered by the
one-electron transfer pathway, thus highlighting the superiority
of iron catalysis.3 In our previous work,4 we found different
reactivities of iron catalysis. Fortunately, in the recent
defluorosilylation of unactivated aliphatic gem-difluoroalkenes,4
iron catalysis showed different reactivity from copper,
palladium, and nickel. The gem-disilylated alkenes were
afforded via iron catalysis, while other transition metals
provided the E-selective silylated fluoroalkenes (Scheme 1).
In 2017, borylation of gem-difluoroalkenes by copper was
reported by the Hosoya and Cao groups, respectively, where
the E-selective borylated compounds were delivered.5,6 Since
then, other E-selective borylation reactions have been
reported,7 and the main products are the monoborylated
fluoroalkenes. Shi and co-workers reported an interesting work
in 20188 in which the 1,2-diborylated, 1,1,2-triborylated, and
1,1,1,2-tetradiborylated compounds were obtained. Inspired by
our recent iron-catalyzed defluorosilylation reaction,4d we
wondered whether the defluoroborylation via iron catalysis has
specific reaction properties. Therefore, as part of our
continuing interest in iron catalysis,9 we herein explore iron-
catalyzed defluoroborylation of unactivated aliphatic gem-
difluoroalkenes.10
catalyzed by iron. After evaluating iron sources, we found
that 1,2-diborylated product 3a was obtained using unactivated
Received: June 13, 2021
Published: July 7, 2021
With these considerations in mind, we began our
investigation on the borylation of gem-difluoroalkenes
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 5565−5570
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aliphatic gem-difluoroalkene 1a as the substrate. In addition,
this reaction could not provide the triborylated and
tetraborylated compounds, which were produced via copper
catalysis reported by the Shi group.8 1,2-Bis(boryl)alkanes are
an important class of synthons that have attracted much
attention due to their versatile transformation. Several
important methods for the synthesis of 1,2-bis(boryl)alkanes
from alkenes or alkynes have been reported.11 Although
significant progress has been developed, the iron-catalyzed
synthesis of 1,2-bis(boryl)alkanes is still attractive.
diboron 2a, a 63% yield was provided (Table 1, entry 9). Other
solvents were also investigated, and this reaction proceeded
well in ether solvents (for details, see the Supporting
Information). Dioxane could provide the desired product in
47% yield, and THF was the best choice (Table 1, entries 9
and 10). Some additives as proton resources were added to
improve the efficiency of this conversion (Table 1, entries 11−
13; for details, see the Supporting Information). When
methanol was used as the additive, 68% yield was obtained
using JohnPhos as the ligand (Table 1, entry 12). Gratifyingly,
the best result (85% yield upon 1H NMR) was provided when
tert-butyl alcohol was used (Table 1, entry 13), and only 64%
of the isolated yield was obtained due to the instability of alkyl
1,2-bis(boronates) 3a in our catalytic system. Control
experiments demonstrated the importance of additive, and
only 53% yield was obtained in the absence of tert-butyl
alcohol (Table 1, entry 14). Only the moderate yield was
provided without ligands, and no desired product was observed
in the absence of the iron catalyst, which demonstrated the
necessity of iron catalysts (Table 1, entries 15 and 16). Some
transition metals, such as copper, palladium, and nickel
sources, were also tested, but no desired product was observed
(for details, see the Supporting Information).
After establishing the optimized reaction conditions, we set
out to evaluate the scope of the iron-catalyzed diborylation of
gem-difluoroalkenes. As shown in Table 2, various unactivated
aliphatic gem-difluoroalkenes could undergo this transforma-
tion smoothly, and the corresponding products were afforded
in moderate isolated yields. Substrates containing an aromatic
ring at the carbon chain performed this diborylation well,
affording the desired products in moderate yields. Gratifyingly,
this reaction showed excellent functional group tolerance. For
instance, CF3, F, Cl, Br, OBn, carboxylate, TIPS, and
carbamate were well-tolerated in this catalytic system (3d,
3e, 3i, 3j, 3n, 3o, 3r, 3s, and 3t). gem-Difluoroalkenes with a
fluoro or chloro group on the aromatic ring reacted well, and
58% yield was delivered (3i, 3j). In addition, substrates bearing
a chloro or bromo group underwent this transformation
smoothly, and the diborylated products were obtained in
moderate yields (3n, 3o). The saturated linear substrate could
also perform this diborylation, and 56% yield was obtained
(3u). The heteroaromatic ring could be tolerated as well, and
the desired product was produced in 60% yield (3m).
Substrates with a substituted alkyl group near the gem-
difluoroalkenyl group performed this conversion well, and the
diborylated products were generated in moderate yields (3k,
3l). The excellent value of this iron-catalyzed 1,2-diborylation
reaction was further exhibited in its application in biomole-
cules. Citronellol, myrac aldehyde, and diacetone-D-glucose-
derived gem-difluoroalkenes performed this transformation
smoothly, as shown in Table 2, and the alkenyl group could
be well-tolerated, affording the desired 1,2-diborylated
products in moderate yields (3v, 3w, 3x).
Encouraged by these results, other iron salts were tested in
the presence of dppp (Table 1, entries 1−4; for details, see the
Table 1. Representative Results for the Optimization of the
a
Iron-Catalyzed Defluoroborylation of 1a
b
yield
entry
[Fe]
ligand
dppp
dppp
dppp
dppp
Xantphos
Mephos
TMEDA
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
solvent
additive
(%)
1
2
3
4
5
6
7
8
Fe(acac)3
Fe(OAc)2
Fe(OTO3
FeBr2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
THF
28
50
12
46
36
50
40
60
63
47
61
c
9
c
10
l1
c
MeOH
(2.0 equiv)
MeOH
(2.0 equiv)
t-BuOH
(5.0 equiv)
c
12
Fe(OAc)2
Fe(OAc)2
JohnPhos
JohnPhos
JohnPhos
THF
THF
68
d
13
85 (64)
d
14
Fe(OAc)2
Fe(OAc)2
THF
THF
53
63
d
15
t-BuOH
(5.0 equiv)
t-BuOH
(5.0 equiv)
d
16
JohnPhos
THF
0
a
Reaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0
equiv), bis(pinacolato)diboron 2a (0.5 mmol, 2.5 equiv), [Fe] (0.02
mmol, 0.1 equiv), ligand (0.1−0.2 equiv), t-BuONa (0.55 mmol, 2.75
b
1
equiv), solvent (1.5 mL), 70 °C, 12 h. Determined by H NMR
using mesitylene as an internal standard. The isolated yield is shown
in parentheses. bis(pinacolato)diboron 2a (0.6 mmol, 3.0 equiv), t-
BuONa (0.7 mmol, 3.5 equiv). bis(pinacolato)diboron 2a (0.8
c
d
mmol, 4.0 equiv), t-BuONa (0.6 mmol, 3.0 equiv).
Supporting Information). Fe(OAc)2 exhibited good efficiency,
providing the desired product 3a in 50% yield (Table 1, entry
2). Poor yields were obtained using high-valent iron salts, such
as Fe(acac)3 or Fe(OTf)3 (Table 1, entry 1 and entry 3).
Subsequently, when Fe(OAc)2 was used as the catalyst, other
ligands were carefully screened. The bidentate or monodentate
phosphine ligands and nitrogen-based ligands could promote
this transformation smoothly (Table 1, entries 5−8; for details,
see the Supporting Information). The moderate yield was
obtained using tri(o-tolyl)phosphine as the ligand (Table 1,
entry 8). By slightly increasing the loading of bis(pinacolato)-
In the previous work,8 the unactivated gem-dibromoalkenes
were not suitable for copper-catalyzed borylation. Encouraged
by the results of the iron-catalyzed 1,2-diborylation of
unactivated gem-difluoroalkenes, we wondered whether the
fluorine group was necessary for our developed protocol.
Therefore, according to the literature, the unactivated gem-
dibromoalkene 1a′ and gem-dichloroalkene 1a′′ were synthe-
sized to perform this conversion. As shown in Scheme 2, the
1
excellent yields determined by H NMR were observed, but
moderate isolated yields were obtained due to the instability of
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a
Table 2. Scope of the Iron-Catalyzed Diborylation of Unactivated gem-Difluoroalkenes
a
Reaction conditions (unless otherwise specified): gem-difluoroalkenes (0.2 mmol, 1.0 equiv), bis(pinacolato)diboron 2a (0.8 mmol, 4.0 equiv), t-
b
BuONa (0.6 mmol, 3.0 equiv), Fe(OAc)2 (0.02 mmol, 0.1 equiv), JohnPhos (0.04 mmol, 0.2 equiv), THF (1.5 mL), 70 °C, 12 h. The yield
determined by H NMR using mesitylene as an internal standard is shown in parentheses.
1
transformation through the functionalization of C−B bond.
Thus, this protocol could offer an excellent synthetic route for
the diversification of gem-difluoroalkenes. Additionally, 3a
could be directly converted into 1,2-diol derivative 6 in
excellent yield (Scheme 2).13
Scheme 2. Iron-Catalyzed Diborylation of Unactivated gem-
Dibromoalkenes and gem-Dichloroalkenes and
Transformation of 1,2-Bis(boryl)alkane 3a
Next, radical inhibition experiments were conducted to
understand the mechanism of this iron-catalyzed 1,2-
diborylation reaction (Scheme 3A). This transformation was
almost completely suppressed when the radical scavenger
TEMPO (100 mol %) was used as an additive. The addition of
radical inhibitor BHT (100 mol %) under the standard
reaction conditions provided the desired product in 50% yield.
On the basis of these results, the free-radical pathway could not
be excluded in this catalytic system. During our evaluation of
reaction conditions, we found that this reaction could also
proceed smoothly without t-BuOH as a proton source, and a
1
moderate yield (53% yield upon H NMR) was obtained. In
order to determine the source of protons in the 1,2-diborylated
products, deuterium-labeling experiments were carried out
(Scheme 3B). When d8-THF was used as the solvent, this 1,2-
diborylation reaction proceeded well in the presence of t-
BuOH, and no deuterated desired product was obtained.
Interestingly, when t-BuOD was employed as an additive under
standard reaction conditions, the deuterated 1,2-diborylated
product 3a′ was afforded in 42% yield. The structure of the
deuterated product 3a′ was inconsistent with the copper-
catalyzed 1,2-diborylation,8 which suggested that iron-
catalyzed defluoroborylation proceeded in a different pathway.
Furthermore, other suspected intermediates were synthesized
to perform this transformation under standard reaction
conditions. To our delight, both monoborylated fluoroalkene
7 and the 1,1-diborylated alkene 8 could undergo this 1,2-
products, 1,2-bis(boryl)alkanes in our catalytic system. These
results indicate that our iron-catalyzed diborylation reaction
exhibits more general reactivity, not only for gem-difluor-
oalkenes but also for gem-dichloroalkenes and gem-dibromoal-
kenes. This 1,2-diborylation reaction could be carried out on a
1 g scale, providing the corresponding product 3a in 60% yield
(Scheme 2). Subsequently, the 1,2-bis(boryl)alkane 3a could
undergo Suzuki cross-coupling reactions with organoboronic
esters and afforded the secondary alkylboronic esters (4, 5)
instead of primary alkylboronic esters in moderate to good
yields (Scheme 2).12 It is worth noting that the resulted
alkylboronic esters 4 and 5 could also undergo the downstream
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excellent functional group tolerance. Moreover, the products
1,2-diborylated alkanes could be further converted into other
functional molecules, thus providing excellent opportunities for
the diversification of gem-difluoroalkenes.
Scheme 3. Mechanistic Studies
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01967.
Experimental data and copies of 1H NMR and 13C NMR
spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Zhang Feng − Sichuan Key Laboratory of Medical Imaging,
North Sichuan Medical College, Nanchong, Sichuan 637000,
P.R. China; Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P.R.
China; orcid.org/0000-0001-7776-8200;
Email: fengzh@cqu.edu.cn
Jiang Zhu − Sichuan Key Laboratory of Medical Imaging,
North Sichuan Medical College, Nanchong, Sichuan 637000,
P.R. China; orcid.org/0000-0001-7437-2956;
Email: zhujiang@nsmc.edu.cn
Authors
diborylation, providing the corresponding deuterated product
in comparable yield (Scheme 3C). The 1,2-diborylated alkene
9 could also perform this transformation,14 but no deuterated
product 3a′ was observed. These results indicated that
compounds 7 and 8 might be the intermediates of this
reaction.
According to these mechanistic studies, a proposed pathway
for the iron-catalyzed 1,2-diborylation was provided, as shown
in Scheme 4. First, the iron−borane complex I was generated
Shangsheng Zhou − Sichuan Key Laboratory of Medical
Imaging, North Sichuan Medical College, Nanchong, Sichuan
637000, P.R. China
Yu Pu − Sichuan Key Laboratory of Medical Imaging, North
Sichuan Medical College, Nanchong, Sichuan 637000, P.R.
China
Zhengli Liu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P.R.
China
Scheme 4. Proposed Mechanism
Xiaoming Zhang − Sichuan Key Laboratory of Medical
Imaging, North Sichuan Medical College, Nanchong, Sichuan
637000, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01967
Author Contributions
#S.Z. and Y.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
and then inserted into the gem-difluoroalkene 1a. Subse-
quently, the monoborylated fluoroalkene 7 was formed
through β-F elimination,4d which performed the second
borylation reaction to afford the 1,1-diborylated alkene 8.
Finally, the critical compounds 7 and 8 underwent further
transformations to obtain the desired 1,2-diborylated product,
but the mechanism of this process is still unclear.
In conclusion, we have developed an efficient iron-catalyzed
protocol for the 1,2-diborylation of unactivated gem-difluor-
oalkenes. This reaction exhibits a wide range of substrates and
We are grateful for the financial support from NSFC (No.
21801029, 81671675), the Fundamental Research Funds for
the Central Universities (No. 2020CDJQY-A043), Sichuan
Key Laboratory of Medical Imaging (North Sichuan Medical
College, No. SKLMI201901), Strategic Cooperation of
Science and Technology between Nanchong City and North
Sichuan Medical College (Nos. 19SXHZ0441, 19SXHZ0227),
Chongqing Postdoctoral Science Foundation (No.
cstc2019jcyj-bshx0057), China Postdoctoral Science Founda-
tion (No. 2020M673121), Natural Science Foundation of
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Science Foundation of Sichuan (No. 2021YJ0413).
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