Copper-catalyzed/promoted cross-coupling of gem -diborylalkanes with nonactivated primary Alkyl halides: An alternative route to alkylboronic esters

Article abstract of DOI:10.1021/ol503111h

The first copper-catalyzed/promoted sp³-C Suzuki-Miyaura coupling reaction of gem-diborylalkanes with nonactivated electrophilic reagents is reported. Not only 1, 1-diborylalkanes but also some other gem-diborylalkanes can be coupled with nonactivated primary alkyl halides, offering a new method for sp³C-sp³C bond formation and, simultaneously, providing a new strategy for the synthesis of alkylboronic esters.

Full text of DOI:10.1021/ol503111h

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed/Promoted Cross-coupling of gem-Diborylalkanes
with Nonactivated Primary Alkyl Halides: An Alternative Route to
Alkylboronic Esters
Zhen-Qi Zhang,† Chu-Ting Yang,† Lu-Jun Liang,† Bin Xiao,*,† Xi Lu,† Jing-Hui Liu,† Yan-Yan Sun,†
Todd B. Marder,‡ and Yao Fu*,†
†Anhui Province Key Laboratory of Biomass Clean Energy Department of Chemistry, University of Science and Technology of China,
Hefei 230026, China
‡Institut fur Anorganische Chemie, Julius-Maximilians-Universitat Wurzburg, Am Hubland, 97074 Wurzburg, Germany
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S
* Supporting Information
ABSTRACT: The first copper-catalyzed/promoted sp3-C Suzuki−Miyaura coupling
reaction of gem-diborylalkanes with nonactivated electrophilic reagents is reported.
Not only 1, 1-diborylalkanes but also some other gem-diborylalkanes can be coupled
with nonactivated primary alkyl halides, offering a new method for sp3C−sp3C bond
formation and, simultaneously, providing a new strategy for the synthesis of
alkylboronic esters.
uzuki−Miyaura cross-coupling represents an efficient
philes. However, only a few functional groups were reported in
their paper (Scheme 1b).8
1
3
Sstrategy for the formation of sp C−C bonds.
In the
Herein we report the first Cu-catalyzed/promoted sp3-carbon
Suzuki−Miyaura cross-coupling of gem-diborylalkanes with
nonactivated primary alkyl halides (Scheme 1c). This reaction
provides an efficient method for constructing saturated C−C
bonds, and an alternative synthesis of alkylboronic esters with a
wider range of functional groups,9,10 and we also present a
synthesis of 1,1-diborylalkanes on gram scale.11
past few decades, great progress has been achieved in the cross-
coupling reactions between aryl boronate esters and alkyl/aryl
electrophiles. In contrast, the coupling of alkylboron reagents
with alkyl electrophiles has rarely been reported. As early as
1992, Suzuki et al. found that alkyl 9-BBN reagents react with
alkyl iodides in the presence of a Pd-catalyst.2 Thereafter, Fu et
al. developed a Pd-catalyzed coupling reaction of alkyl 9-BBN
reagents with more inert alkyl electrophiles.3 Meanwhile, a Ni-
catalyst has also been found to be efficient for the cross-
coupling of secondary alkyl halides with alkyl 9-BBN reagents.4
Recently, our group reported the first Cu-catalyzed cross-
coupling reaction of alkyl 9-BBN reagents with primary alkyl
electrophiles.5 It is noteworthy that the 9-BBN reagents used in
previous studies are highly reactive species, and thus issues
surrounding their preparation (e.g., functional group protec-
tion) and purification limit their applications in organic
synthesis.6
Recently, Shibata et al. successfully realized the coupling
between a series of novel alkylboron compounds (1,1-
diborylalkanes) and aryl/benzyl/allyl halides with the aid of a
Pd-catalyst (Scheme 1a),7 whereas the Suzuki−Miyaura
reaction of unactivated alkyl electrophiles with gem-dibor-
ylalkanes remains challenging. Lately, Morken et al. described a
metal-free reaction of gem-diborylalkanes and alkyl electro-
On the basis of our previous studies10a on the Cu-catalyzed
borylation of primary/secondary alkyl halides and pseudoha-
lides, we first attempted the synthesis of 1,1-diborylalkanes with
the same catalyst system. We found that the reaction occurred
smoothly for the preparation of diborylmethane, while 1 equiv
of a Cu source was required for the preparation of other 1,1-
diborylalkanes. Importantly, these methods enable convenient
gram scale synthesis, and the resulting diboryl compounds are
readily available for exploring their subsequent transformations.
In this context, several 1,1-diborylalkanes, 1a−1c (Scheme 2a;
for details, see Supporting Information (SI)), have been
synthesized. However, limited availability of 1,1-dibromoal-
kanes limits the synthesis of different types of 1,1-
Scheme 2. Synthesis Methods of gem-Diborylalkanes
Scheme 1. sp3-C Suzuki−Miyaura Coupling Reaction
Received: October 24, 2014
© XXXX American Chemical Society
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Letter
diborylalkanes, but one can efficiently synthesize a variety of
1,1-diborylalkanes with different substituents from diboryl-
methane using the slightly improved method previously
reported by Matteson and Moody.11b Thus, we prepared a
series of 1,1-diborylalkanes (1d−1h) (Scheme 2b; for details,
see SI).
Subsequently, we examined the cross-coupling reaction of
1,1-diborylalkanes with primary alkyl halides. The diboryl-
methane and n-hexyl bromide were first selected as the model
substrates (Table 1). Similar to our previous study, CuI (10%),
electrophilic reagents. It was found that 10% CuI, LiOMe, and
40 °C (entry 17, or even rt, entry 18) are appropriate for the
couplings of alkyl iodide, and the optimal conditions for alkyl-
OTs were the same as those for alkyl bromide (entry 24). What
is more important is that the necessity for copper in our
reaction conditions was confirmed by the results showing
without CuI the reaction does not occur (entry 12) or yields
only a small yield of product (entry 20).
As shown in Scheme 3, diborylmethane can react with a
variety of alkyl electrophiles. Many synthetically important
Table 1. Various Conditions for the Reaction of n-Hexyl
Bromide and Diborylmethane
Scheme 3. Substrate Scope for the Reaction of Primary
Electrophiles with Diborylmethane
a
a
entry
X
y (mmol)
base (equiv)
temp (°C) yield (%)
1
2
3
4
5
Br
0.15
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.15
0.15
0.15
0.15
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
LiOMe (2)
LiOMe (3)
LiOMe (3)
LiOMe (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
LiOMe (2)
LiOMe (2)
LiOMe (2)
t-BuOLi (2)
LiOMe (3)
t-BuOLi (3)
LiOMe (3)
LiOMe (3)
LiOMe (3)
t-BuOLi (3)
t-BuOLi (3)
t-BuOLi (3)
60
60
80
40
60
60
60
60
60
60
60
60
60
40
25
40
40
25
25
40
60
60
60
60
23
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
38
10
35
58
e
6
53
be
,
7
8
9
25
f
36
b
c
70
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
85(80)
91(84)
trace
58
bc
,
d
I
66
I
65
I
66
I
87(81)
84(80)
64
I
I
a
Reactions were carried out under the conditions shown, using alkyl
d
c
b
I
12
bromides as substrates, and all yields are isolated yields. The
OTs
OTs
OTs
OTs
8
reactions were carried out under the optimal condition for the reaction
of alkyl iodide and diboryl-methane: 10 mol % CuI, 3 equiv of MeOLi,
45
c
49
0.5 mL DMF and 40 °C; and all yields are isolated yields. The
bc
,
reaction was carried out using 1 equiv of tetrabutylammonium iodide.
78(72)
d
e
a
Alkyl iodide was used as a substrate. Alkyl OTs was used as a
All reactions are carried out under 0.1 mmol scale, 10 mol % CuI, and
in 0.5 mL of DMF. The yields were determined by GC (average of two
f
substrate. AllylOPO(OEt)2 was used as a substrate.
b
c
GC runs). 1 equiv of tetrabutylammonium iodide was added. 20 mol
% CuI was used. CuI was not used. The solvent is THF. The
d
e
f
functional groups, including acetal 2ac, terminal olefin 2ad, and
TBS-protected alcohol 2ae are tolerated. In addition, alkyl
esters (2af) and aryl esters (2ag) are good substrates for this
reaction. Aryl cyanide (2ai) and phthalic imide (2ah) give
moderate yields. The heterocyclic compounds (2aj, 2ak) also
give moderate yields under the same conditions, whereas the
yield of 2ak is relatively lower due to elimination of side
products. In addition, amino acid derivatives also react with 1a
to give the desired products 2al. Substrates 2am, 2an, 2ao, 2ap
were examined to explore the chemoselectivity of this reaction.
We found that the activity of alkyl bromide and tosylate is
higher than that of aryl bromide, and the activity of alkyl
bromide is higher than that of aryl and alkyl chloride.
Moreover, activated alkyl electrophiles are also good substrates
(2aq, 2ar).
solvent is DMSO.
DMF, and LiOMe were used as the catalyst, solvent, and base,
respectively. However, only 23% GC yield has been gained
(entry 1). Adjusting the reaction temperature and increasing
the amount of diborylmethane were found to have little
influence on the GC yield (<40%, entries 2−4). We next tried
to replace LiOMe with t-BuOLi and found that the yield
improved to ∼60% (entry 5).12 Meanwhile, use of THF or
DMSO as solvent results in slightly lower yields (entries 6−8).
Significantly, increasing the catalyst loading to 20% or the
addition of tetrabutylammonium iodide gives better results
(entries 9−10). Accordingly, a 91% GC yield and an 84%
isolated yield have been obtained in the presence of 20% CuI
and 1 equiv of the additive tetrabutylammonium iodide (entry
11). In addition to alkyl bromide, we also tried some other
Unfortunately, the reaction conditions for diborylmethane
failed when other substituted 1,1-diborylalkanes were used (the
B
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Letter
yield is very low). Therefore, we examined the reaction of 1,1-
diborylalkane 1b and n-hexyl iodide to reoptimize the reaction
conditions. Interestingly, the reaction is very sensitive to the
catalyst loading and base. An 89% GC yield was obtained using
1 equiv of CuI and 4 equiv of base (see SI).
Under the newly obtained optimized conditions, we
examined the scope of the 1,1-diborylalkanes (Scheme 4).
Electrophiles such as alkyl iodides (3b, 3c, 3h), alkyl bromides
(3d, 3e, 3g), or OTs (3a, 3f, 3i) all coupled smoothly with 1b,
1d, 1e, 1f under these conditions.
Finally, when 6-bromo-1-hexene was used as a substrate, the
terminal olefin was retained, and no cyclized product was
detected (Scheme 6, eq 1). Meanwhile, only 3% of the ring-
Scheme 6. Selectivity in Ring Closing/Ring Opening
Experiments
Scheme 4. Substrate Scope for the Reaction of Primary
a
Electrophiles with 1,1-Diborylalkanes
opening product was detected when cyclopropylmethyl bro-
mide was used as the substrate (eq 2). The results are opposed
to what would be expected for a radical mechanism usually seen
with Ni chemistry.14,15
In summary, we report the first copper catalyzed/promoted
Suzuki−Miyaura cross-coupling of gem-diborylalkanes with
nonactivated primary alkyl electrophiles. The reaction can
proceed smoothly in the presence of CuI, t-BuOLi, and DMF.
Generally, 10−20 mol % CuI is adequate for the reaction of the
diborylmethane, while 1 equiv of CuI and 4 equiv of base (t-
BuOLi) are required for the couplings of substitued 1,1-
diborylalkanes. Furthermore, tertiary alkylboronic esters can be
obtained using 3 equiv of CuI and 8 equiv of t-BuOLi. A radical
mechanism has been excluded,16 and the previously reported
SN2 mechanism seems to be more plausible.5 Further study on
ligand effects is ongoing in our laboratory.
a
Reactions were carried out under the conditions shown, and all yields
are isolated yields. b 1b was used as the substrate. c 1f was used as the
substrate. d 1e was used as the substrate. e 1d was used as the substrate.
In addition to synthesizing unactivated primary and
secondary alkylboronic esters, we also attempted to synthesize
tertiary alkylboronic esters. Thus, we reacted diborylalkane 1i
or 1j (see SI) with an alkyl halide and successfully obtained the
desired products (4a−4e) (Scheme 5). The reaction requires 3
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectra data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Scheme 5. Synthesis of Tertiary Alkylboronic Ester
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fuyao@ustc.edu.cn.
*E-mail: binxiao@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the 973 Program (2012CB215306), FRFCU
(WK2060190025, WK2060190033, WK2060190029), NSFC
(21325208, 21172209, 21272050, 21302178), CAS (KJCX2-
EW-J02), and SRFDP (20123402130008) for financial support.
a
Reactions were carried out under the conditions shown, and all yields
b
c
are isolated yields. 1i was used as the substrate. 1j was used as the
substrate.
We thank Dr. Andreas Lorbach (Universitat Wurzburg) for
help with the NMR data.
̈
̈
equiv of CuI and 8 equiv of t-BuOLi. If we reduce the loading
of copper, the conversion of gem-diborylalkane is very low, and
the major byproduct is one generated by protodeboronation.
We reoptimized the reaction conditions, and some copper
sources and ligands were examined (for details, see SI), but to
our knowledge, only a few methods have been reported for the
synthesis of tertiary alkylboronic esters, and thus our work
provides a new strategy for the synthesis of these com-
pounds.10c−f,13
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■
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D
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