Vicinal Diboration of Alkyl Bromides via Tandem Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01481

Vicinal diboration of alkyl bromides via tandem catalysis is reported. The reported reaction exhibits a broad substrate scope, good functional group compatibility, and regioselectivity. Moreover, it shows good practicality due to the easy accessibility of alkyl bromides in combination with diverse transformations of diboronates. Mechanism study indicates that terminal alkenes are generated selectively through nickel-catalyzed dehydrohalogenation of alkyl bromides followed by base/MeOH promoted diboration process to provide 1,2-diboration products.

Full text of DOI:10.1021/acs.orglett.9b01481

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Vicinal Diboration of Alkyl Bromides via Tandem Catalysis
Xiao-Xu Wang,† Lei Li,† Tian-Jun Gong, Bin Xiao, Xi Lu,* and Yao Fu*
Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui
Province Key Laboratory of Biomass Clean Energy, iChEM, University of Science and Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: Vicinal diboration of alkyl bromides via tandem
catalysis is reported. The reported reaction exhibits a broad
substrate scope, good functional group compatibility, and
regioselectivity. Moreover, it shows good practicality due to the
easy accessibility of alkyl bromides in combination with diverse
transformations of diboronates. Mechanism study indicates that
terminal alkenes are generated selectively through nickel-catalyzed
dehydrohalogenation of alkyl bromides followed by base/MeOH
promoted diboration process to provide 1,2-diboration products.
rganoboron compounds are fundamental and versatile
1
Ointermediates in synthetic chemistry. These compounds
strike a good balance between stability and reactivity. They are
easy to handle due to good air and moisture stability and can
be conveniently transformed under mild reaction conditions.2
Among boron family compounds, vicinal diboronates are
indispensable, providing an efficient synthetic module for the
expedient synthesis of complex molecules through C−B
transformation approaches.3 For the creation of vicinal
diboronates, pioneer works focused on diboration of alkenes
and alkynes catalyzed by diverse transition-metal catalysts.4
Further, hydroxyl-directed diboration of alkenyl alcohols5a and
unidirectional homologation of diborylmethane5b have also
6a,b
́
been reported. Recent progress was made by Fernandez,
Huang,6c and Song6d in base-catalyzed diboration of alkenes or
alkynes. On the other hand, alkyl (pseudo)halides are also
easily accessible and abundant feedstock starting materials and
proved to be a good choice to access alkylboron compounds
(Figure 1a, left).7,8 Despite these successes, a new design
principle capable of directly obtaining vicinal diboronates from
alkyl (pseudo)halides would be practical (Figure 1a, right).
Over the past decade, nickel-catalyzed cross-coupling of
alkyl electrophiles, especially alkyl halides, enjoyed great
success in virtue of efficient retardation of undesired β-H
elimination.9 Most recently, such a previously avoided event
was skillfully utilized as a desired process. For example, chain-
walking functionalization was realized through dehydrohaloge-
nation alkene generation, then successive insertion and
migration of C−C double bond, and finally functionalization
at a remote site (Figure 1b, pathway I).10 As part of our
ongoing interest in developing alkyl halide conversion
reactions and alkene functionalization strategies,11 we set out
to achieve the regioselective vicinal diboration of alkyl halides,
taking advantage of designed β-H elimination and alkene bis-
boronation (Figure 1b, pathway II). Herein, we report the
vicinal diboration of alkyl bromides via tandem catalysis as an
alternative method for preparing 1,2-diboronates. A variety of
Figure 1. Boronation of alkyl (pseudo)halides and reaction design of
vicinal diboration of alkyl bromides via tandem catalysis. FG =
functional group. B2pin2 = bis(pinacolato)diboron. Ts = tosyl.
primary, secondary, and tertiary alkyl bromides could be easily
diboronated with good regioselectivity. From the point of view
of easy accessibility of alkyl bromides and diverse trans-
Received: April 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01481
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formations of diboronates, this reaction might find many
applications in synthetic chemistry.
We commenced the study with the preparation of 1,2-
diborylalkane 2 through proposed vicinal diboration of primary
alkyl bromide 1 (Table 1). On the basis of our previously
of reactivity in our reaction system (entry 7). Without the
addition of NEt3 or MeOH, lower yields were provided
(entries 8 and 9). Alkyl iodine 8 was also a good substrate in
this transformation (entry 10), but alkyl tosylate 9 was
unreactive under the current reaction conditions (entry 11). It
should be pointed out that 1,1-diboration was not observed in
most conditions (also see Scheme 5 for more explanation).
With the optimized reaction conditions, we sought to
examine the substrate scope of alkyl bromides with different
functional groups. As shown in Scheme 1, a variety of
a
Table 1. Optimization of Reaction Conditions
a
Scheme 1. Substrate Scope of Primary Alkyl Bromides
a
b
Isolated yield for 0.2 mmol scale reaction. Isolated yield for 0.5
mmol scale reaction. Nap = naphthyl.
unactivated primary alkyl bromides could be easily diboro-
nated with moderate to good isolated yields (37−65%).
Although there are remote π-system in substrates, terminal
vicinal diboranates were obtained as single products (2, 10).
Substrates with different chain lengths also performed well in
this transformation (11−14). Further, the four-membered ring
was well-tolerated, and no ring opening side product was
observed (15). A variety of functional groups could be readily
accommodated, including ether (16, 17), cyano (18), alkyl
chloride (19), and even unprotected alcoholic hydroxyl group
(20). In addition, the toleration of amide (21) and
ethoxycarbonyl group (22) indicated that the diboration
reaction could be conducted without unexpected trans-
esterification.14
a
GC yield. 4,4′-Carbonylbis(toluene) was used as an internal
b
standard. Standard conditions: 5 mol % Ni(COD)2, 5 mol % Cy-
XantPhos, 2.0 equiv B2pin2, 1.0 equiv LiOMe, 0.5 equiv NEt3, 5.0
equiv MeOH, 1.1 mL PhMe/2-Me-THF (v:v = 10:1) under Ar at 100
°C for 24 h. Isolated yield. Recovery of 8. Recovery of 9. COD =
cis,cis-1,5-cyclooctadiene. THF = tetrahydrofuran. Cy = cyclohexyl.
c
d
e
Subsequent studies revealed that this diboration reaction has
broad substrate scope with respect to the alkyl bromides. As
illustrated in Scheme 2, a wide range of secondary and tertiary
alkyl bromides was successfully converted to the desired
products. Substrates with different chain lengths (2, 10, 12, 16,
23−25, 28−30) smoothly delivered the desired products in
moderate to good yields. Cyclic alkyl bromides, such as six-
and seven-membered rings (26, 27) also performed well in this
transformation and produced vicinal diboronates in onefold
syn-configuration. In addition, representative substrate (27)
was conveniently prepared in gram-scale (see the Supporting
Information for more details).
reported nickel-catalyzed synthesis of 1,1-diboronates,11b we
were pleased to obtain the desired product 2 with 70% GC
yield and 60% isolated yield in the presence of Ni(COD)2 and
Cy-XantPhos, modified with MeOH and NEt3 (entry 1). In the
absence of nickel catalysts, diboration could not proceed with
84% alkyl bromide recovered (entry 2). Ligand effects were
systematically screened (see Supporting Information for more
details), for example, monodentate phosphine (entry 3), other
bidentate phosphines (entries 4 and 5), and nitrogen ligands
(entry 6) were much less effective. Cy-XantPhos might be the
only appropriate ligand, providing good reactivity and
selectivity for terminal alkene generation.12,13 Cesium carbo-
nate showed high efficiency for diboration reactions in
previous works;6a,b however, it showed almost complete loss
To better highlight the practicability of our diboration
protocol, we exploited its application in the modification of
natural products. Lithocholic acid 31 was esterified, reduced by
B
DOI: 10.1021/acs.orglett.9b01481
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of Secondary and Tertiary Alkyl
Bromides
Scheme 4. Mechanistic Experiments
a
a
Isolated yield for 0.2 mmol scale reaction.
content) was used to furnish single diboration product 39 in
30% yield with 80% deuterium content (Scheme 4, eq 4). The
formation of single diboronates 36 and 39 indicates that β-H
of alkylnickel species eliminates in a regioselective manner to
generate terminal alkene. Followed by syn-addition of
bisboronates to terminal alkene, vicinal diboronate was
obtained. The different yields might be rationalized in terms
of isotope effects. Finally, (2-bromoethyl)benzene (41) could
also be converted to the desired product (42) smoothly under
our standard reaction conditions, in which a styrene
intermediate might be formed (Scheme 4, eq 5).
a
b
Isolated yield for 0.2 mmol scale reaction. syn-/anti- > 20:1.
c
Isolated yield for 8.0 mmol scale. Bz = benzoyl.
lithium aluminohydride, brominated, and then followed by our
diboration reaction under standard conditions, after which 32
was obtained with a moderate yield (50%) (Scheme 3, eq 1).
a
Scheme 3. 1,2-Diboration of Natural Products
In our reaction design, alkene intermediate 4a would be
generated, followed by diboration process to access 1,2-
diboronate. The transformation of 4a with or without nickel
catalysts supported our hypothesis (entries 3 and 4, Scheme
5). The approximate results indicated that nickel might not be
involved in diboration process. Previously, we reported the
nickel-catalyzed synthesis of 1,1-diborylalkanes from terminal
alkenes (entry 5, Scheme 5).11b However, new transformation
with alkyl halides shows almost entirely 1,2-diboration
selectivity under very similar reaction conditions and went
a
Scheme 5. Mechanism Studies on Regioselectivity
a
Isolated yield for 0.2 mmol scale reaction. (i) SOCl2, MeOH; (ii)
LiAlH4, THF; (iii) NBS, PPh3, CH2Cl2; (iv) standard conditions. (v)
Standard conditions, 10 mol % Ni(COD)2, 10 mol % L1; vi) NaBO3·
4H2O, THF/H2O (v/v = 1:1). Bn = benzyl.
Another example was the synthesis of C-alkyl glycoside. Our
new reaction was used to modify glycoside to produce
diboron-containing derivative. Brominated C-allyl-D-glucose
derivative 33 was synthesized from tetrabenzyl-protected D-
glucose (see the Supporting Information for more synthetic
details). Under standard conditions, the desired diboration
product was obtained in 42% yield. Using oxidation with
sodium perborate tetrahydrate in a mixture of H2O and THF,
polyhydroxy sugar derivative 34 was delivered with good yield
(81%) (Scheme 3, eq 2). Notably, the two enantiomers could
be well-separated by normal silica gel workup. These
transformations demonstrated high synthetic value of this
newly developed reaction.
A series of experiments was carried out to support our
proposed catalytic cycle (Scheme 4). Deuterated alkyl bromide
35 (97% deuterium content) was employed as starting material
and provided product 36 in 62% yield with 90% deuterium
content (Scheme 4, eq 3), while isomers 37 were not detected.
As a comparison, deuterated compound 38 (84% deuterium
a
GC yield. 4,4′-Carbonylbis(toluene) was used as an internal
b
standard. Literature yield.
C
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Letter
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To fully understand the nature of these transformations, more
mechanism studies on regioselectivity were carried out.
Conditions in ref 11b were performed on alkyl bromide
substrate 1, and we obtained 1,2-diboronate 2 but not the 1,1-
diboronate 3 (entry 2, Scheme 5). We considered that the
influence of in situ formed LiBr or MeOH must be taken into
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(20%) was obtained from alkene 4a (entry 6, Scheme 5).
When MeOH was used as an additive, 1,2-diboronate 2 was
formed as single product (entry 7, Scheme 5). These
observations indicated that the added or in situ formed
MeOH likely enables the alkoxide-promoted 1,2-diboration of
alkenes which favors the 1,2- over the 1,1-product.
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primary, secondary, and tertiary alkyl bromides to furnish a
variety of vicinal diboronates using tandem catalysis. This
reaction presents a broad substrate scope and could be
successfully performed in the presence of many synthetic
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bromides and broad applications of product diboronates with
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01481.
Detailed experimental procedures and spectral data for
all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: luxi@mail.ustc.edu.cn.
*E-mail: fuyao@ustc.edu.cn.
ORCID
Tian-Jun Gong: 0000-0001-5484-8531
Bin Xiao: 0000-0002-1200-6819
Xi Lu: 0000-0002-9338-0780
Yao Fu: 0000-0003-2282-4839
Author Contributions
†X.-X.W. and L.L. contributed equally. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
́
́
́
8703. Ramírez, J.; Corberan, R.; Sanau, M.; Peris, E.; Fernandez, E.
Unprecedented use of silver(I) N-heterocyclic carbene complexes for
the catalytic preparation of 1,2-bis(boronate) esters. Chem. Commun.
2005, 3056−3058. Wen, H.; Zhang, L.; Zhu, S.; Liu, G.; Huang, Z.
Stereoselective Synthesis of Trisubstituted Alkenes via Cobalt-
Catalyzed Double Dehydrogenative Borylations of 1-Alkenes. ACS
Catal. 2017, 7, 6419−6425.
ACKNOWLEDGMENTS
■
We are grateful for the support from the National Key R&D
Program of China (Grant 2017YFA0303502), the National
Natural Science Foundation of China (Grants 21572212,
21732006, 21702200, and 51821006), the Strategic Priority
Research Program of CAS (Grant XDB20000000), and the
Major Program of Development Foundation of Hefei Centre
for Physical Science and Technology (Grant 2017FXZY001).
(5) (a) Blaisdell, T. P.; Caya, T. C.; Zhang, L.; Sanz-Marco, A.;
Morken, J. P. Hydroxyl-Directed Stereoselective Diboration of
Alkenes. J. Am. Chem. Soc. 2014, 136, 9264−9267. (b) Blair, D. J.;
Tanini, D.; Bateman, J. M.; Scott, H. K.; Myers, E. L.; Aggarwal, V. K.
Selective uni- and bidirectional homologation of diborylmethane.
Chem. Sci. 2017, 8, 2898−2903.
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