Copper-Catalyzed Reductive Cross-Coupling of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides

Article abstract of DOI:10.1002/chem.201405223

A copper-catalyzed reductive cross-coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost-effective construction of aryl-alkyl and alkyl-alkyl C=C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo- or heterocycles, such as 2,3-dihydrobenzofuran and benzochromene derivatives.

Full text of DOI:10.1002/chem.201405223

DOI: 10.1002/chem.201405223
Communication
&
Organic Synthesis
Copper-Catalyzed Reductive Cross-Coupling of Nonactivated Alkyl
Tosylates and Mesylates with Alkyl and Aryl Bromides
Jing-Hui Liu,[a, b, c] Chu-Ting Yang,[a] Xiao-Yu Lu,[a] Zhen-Qi Zhang,[a] Ling Xu,[a] Mian Cui,[a]
Xi Lu,[a] Bin Xiao,[a] Yao Fu,*[a] and Lei Liu*[a, b, c]
Abstract: A copper-catalyzed reductive cross-coupling re-
action of nonactivated alkyl tosylates and mesylates with
alkyl and aryl bromides was developed. It provides a practi-
cal method for efficient and cost-effective construction of
aryl–alkyl and alkyl–alkyl CÀC bonds with stereocontrol
from readily available substrates. When used in an intra-
molecular fashion, the reaction enables convenient access
to various substituted carbo- or heterocycles, such as 2,3-
dihydrobenzofuran and benzochromene derivatives.
Transition-metal-catalyzed CÀC bond cross-coupling has been
established as an indispensable tool in modern organic synthe-
sis.[1] While most catalytic cross-coupling reactions occur be-
tween organometallic reagents and organic halides,[2] direct re-
Scheme 1. Transition-metal-catalyzed reductive cross-coupling of nonactivat-
ed organic halides or pseudohalides.
ductive cross-coupling of two organic halides sometimes ex-
hibits practical advantages as it avoids the prior preparation
and handling of sensitive or expensive organometallic re-
agents.[3] Recent examples (Scheme 1) for catalytic reductive
cross-coupling between two organic halides[4] include Co-cata-
lyzed coupling of aryl bromides with alkyl halides,[5] Pd-[6] and
Fe-catalyzed[7] aryl–alkyl couplings, and Ni-catalyzed reductive
cross-coupling of alkyl halides with aryl or alkyl halides.[8–9]
These reactions have been shown to be efficient for the aryl–
alkyl couplings,[4–8] but the reductive cross-coupling between
two alkyl halides is usually more challenging due to the homo-
coupling of each alkyl halide reactant.[10–11] To improve the
scope of reductive cross-coupling reactions, new catalyst sys-
tems need to be examined. Although copper has been shown
to be an efficient catalyst in the coupling reactions of alkyl hal-
ides and pseudohalides,[12] Cu-catalyzed reductive cross-cou-
pling between two nonactivated organic halides or between
an organic halide and a pseudohalide has not been investigat-
ed.[13]
Herein, we report a potentially general Cu catalyst system
for the reductive cross-coupling of nonactivated alkyl halides
and pseudohalides with alkyl and aryl bromides. This reaction
expands the concept and scope of both catalytic reductive
cross-coupling reactions and Cu-catalyzed cross-coupling reac-
tions. It also exhibits some unique features as compared to the
previous Co, Pd, Fe, and Ni-catalyzed reductive cross-coupling
reactions. Not only the alkyl–aryl coupling is readily achievable
with the Cu catalyst, but also the cross-coupling between a pri-
mary or secondary alkyl bromide and a primary or secondary
alkyl-OTs/OMs can now take place smoothly to afford the alkyl-
alkyl products. Compared to the Cu-catalyzed cross-coupling
of alkyl halides and pseudohalides with Grignard reagents,[12]
the present reaction avoids the trouble of prior preparation of
Grignard reagents, which proves critical for the reactions in-
volving some sensitive functional groups (e.g. ester, amide) as
well as intramolecular reductive cross-coupling.[14]
[a] J.-H. Liu,+ C.-T. Yang,+ X.-Y. Lu, Z.-Q. Zhang, L. Xu, M. Cui, X. Lu, B. Xiao,
Prof. Dr. Y. Fu, Prof. Dr. L. Liu
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (P. R. China)
E-mail: fuyao@ustc.edu.cn
lliu@mail.tsinghua.edu.cn
[b] J.-H. Liu,+ Prof. Dr. L. Liu
State Key Laboratory for Oxo Synthesis
and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, 730000 Lanzhou (P. R. China)
[c] J.-H. Liu,+ Prof. Dr. L. Liu
Department of Chemistry, Tsinghua University
Beijing 100084 (P. R. China)
[+] These authors contributed equally to this work.
Our study began with the reaction between (3-bromopro-
pyl)benzene (1) and bromocyclohexane (2a) (Scheme 2). We
used CuI as the catalyst, tetramethylethylenediamine (TMEDA)
as the ligand, LiOMe as the additive, and Mg powder as the re-
ductant. A moderate yield (54%) of the cross-coupling product
(3a) was obtained. We also observed the formation of homo-
coupling products (4 and 5) in significant quantities. Subse-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405223.
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observed (entry 13). Finally, when 3-phenylpropyl
methanesulfonate was used to replace 1a, the reduc-
tive cross-coupling can also proceed smoothly to
give 3a in slightly better yields (94% GC yield and
89% isolated yield, entry 14).
With the optimized conditions in hand, we investi-
gated the scope of the Cu-catalyzed reductive cross-
coupling reaction (Table 2). Cross-coupling of secon-
dary alkyl bromides and primary alkyl bromides with
Scheme 2. Cu-catalyzed reductive cross-coupling of two alkyl bromides. GC yields with
benzophenone as the internal standard. TMEDA=N,N,N’,N’-tetramethylethylenediamine.
Table 1. Copper-catalyzed cross-coupling under various conditions.
Table 2. Substrate scope of reductive alkyl-alkyl cross-coupling.[a]
Entry Cat. (10% mol) Li Salt (1 equiv) Additive T [8C] Yield [%][a]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuI
CuI
–
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiCl
LiOtBu
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
TMEDA
TMEDA
PPh3
DPPP
DPPE
0
25
0
0
0
0
0
0
0
0
0
0
0
0
52
48
27
81
69
82
89 (82[b]
65
33
80
trace
trace
trace
94 (89[b]
DPPB
DPPM
DPPM
DPPM
DPPM
DPPM
DPPM
DPPM
DPPM
)
)
9
10
11[c]
12[d]
13
14[e]
CuI
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), Mg powder
(0.5 mmol), Cu catalyst (10 mol%), ligand (20 mol%), Li salt (0.25 mmol) in
0.5 mL THF for 24 h under Ar. Yields (average of two runs) were determined
by GC analysis with benzophenone as the internal standard. [b] Isolated
yields. [c] Zn powder was added to replace Mg. [d] Mn powder was added
to replace Mg. [e] 3-Phenylpropyl methanesulfonate was used to replace 1a.
quent optimizations failed to suppress the homocoupling of
either alkyl bromide. As a result we changed one substrate to
an alkyl pseudohalide (1a in Table 1). In the first trial, the yield
of the cross-coupling product was 52% (Table 1, entry 1), but
we observed much less homocoupling products (Supporting
Information). Encouraged by this observation, we systematical-
ly screened the reaction conditions. First, an increase of the
temperature from 0 to 258C slightly lowered the yield
(entry 2). A change of the ligand from TMEDA to PPh3 was not
helpful (entry 3). We were then surprised to find that a biden-
tate phosphine ligand DPPP (1,3-bis(diphenylphosphino)pro-
pane) can dramatically improve the yield to 81% (entry 5).
After more bidendate phosphine ligands including DPPE (1,2-
bis(diphenylphosphino)ethane), DPPB (1,4-bis(diphenylphos-
phino)butane), and DPPM (bis(diphenylphosphino)methane)
were examined (entries 5-7), we concluded that DPPM gave
the optimal result (89% GC yield and 82% isolated yield). Fur-
ther changes of Li salts, Cu catalysts, or other reductants did
not improve the reaction (entries 8–12). In a control experi-
ment without adding any Cu catalyst, no cross-coupling was
[a] Reaction conditions: alkyl-OTs/OMs (0.25 mmol), alkyl-Br (0.5 mmol),
Mg (0.5 mmol), CuI (10 mol%), LiOMe (0.25 mmol), DPPM (20 mol%), THF
(0.5 mL), 08C for 24 h under Ar. Isolated yields. [b] Reactions were carried
out at RT. [c] Alkyl-Br (3 equiv) and Mg powder (3 equiv) were added.
[d] THF (0.3 mL) was added. [e] Reactions were carried at 708C. [f] Diaste-
reomeric mixture. Cbz=benzyloxycarbonyl. PMP=4-methoxyphenyl.
primary alkyl pseudohalides can be successfully achieved (3a–
o). More importantly, the Cu-catalyzed reaction can be readily
applied to more challenging yet synthetically useful transfor-
mations, that is, the reductive cross-coupling between two sec-
ondary alkyl electrophiles (3p–w). Both cyclic (3a–j, 3p–v) and
acyclic (3k–m, 3w) alkyl bromides can be smoothly converted
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in the reaction with good to excellent yields. A variety of syn-
thetically relevant functional groups including ether (e.g. 3e),
ester (3h), olefin (3o), amide (3 f–h), sulfonamide (3t), aryl flu-
orine (3i), aryl chloride (3s), furan (3j), and piperonyl (3r) can
be tolerated. Remarkably, bromocyclopropane (3v), which was
shown to be a problematic reactant in Ni-catalyzed alkyl–alkyl
reductive cross-coupling,[8c] is a good substrate in the Cu-cata-
lyzed reaction. Furthermore, an alkyl bromide with a chloroar-
ene moiety (3m) can participate in the reaction without affect-
ing the aryl chloride group. This particular example illustrates
the special power of the reductive cross-coupling process, be-
cause it would be difficult to prepare the corresponding alkyl
Grignard reagent in which the alkyl bromide group has to be
selectively activated over the aryl chloride group.[15] Finally, re-
actions of alkyl bromides with a sensitive group (e.g. amide)[16]
(3 f, 3g) also proceed smoothly. Even when both the coupling
partners contain groups (e.g. ester) sensitive to the Grignard
reagent, the desired reductive cross-coupling product can be
obtained in 40% yield (3h). Extension of the reductive cross-
coupling reaction to a tertiary alkyl bromide was also investi-
gated (3x). The yield was modest (25%) under unoptimized
conditions.
Table 3. Substrate scope of reductive alkyl-aryl cross-coupling.[a]
[a] Reaction conditions: alkyl-OTs/OMs (0.25 mmol), Aryl-Br (0.5 mmol),
Mg (0.5 mmol), CuI (10 mol%), LiOMe (0.25 mmol), DPPM (20 mol%), THF
(0.5 mL), room temperature for 24 h under Ar. Isolated yields. PMP=4-
methoxyphenyl.
A gram-scale reaction (1.14 g scale, Scheme 3) was conduct-
ed to evaluate the efficiency of the new catalyst system in
Scheme 3. A gram-scale reductive cross-coupling reaction.
Scheme 4. Modification of an estradiol. The Cu-catalyzed reductive cross-
coupling step was conducted at 708C under conditions shown in Table 3.
PMP=4-methoxyphenyl.
preparative organic synthesis. In this experiment, the Cu-cata-
lyzed reductive cross-coupling reaction could proceed equally
well in comparison to the smaller scale experiments and afford
3l in 78% isolated yield under slightly modified conditions.
The scope of the Cu-catalyzed reductive cross-coupling reac-
tion was not limited to aliphatic substrates. Aryl bromides
were also suitable reaction partners. As depicted in Table 3,
phenyl bromide was converted to the product 7a in 87% iso-
lated yield. Aryl bromides bearing electron-donating (e.g. 7b)
or -withdrawing (e.g. 7e) substituents at the p-position gave
rise to the coupling products in good to excellent yields. A
substituent at the m-position showed no significant effect on
the reaction (7g, 7h), whereas the ortho-substitution led to
a lower yield (7d). Notably, the ester group (7c) was compati-
ble with the reaction. The aryl chloride substitution also could
be tolerated (7 f), which provided opportunities for further
transformation through cross-coupling reactions. Also of note,
the reaction of the alkyl tosylate equipped with a terminal
monosubstituted alkene gave the desired product 7d without
formation of any isomerization[8b] or cyclization[8d] byproduct,
which indicated that the Cu-catalyzed reductive cross-coupling
reaction proceeded through a nonradical process.
verted 3,17-dimethoxy estradiol to its alkylated derivative 8 by
a simple bromination step followed by Cu-catalyzed reductive
cross-coupling. The desired product was obtained in 47% iso-
lated yield, which indicated the potentiality of the new reac-
tion as a useful tool for the late-stage functionalization of com-
plex molecules in modern medical chemistry studies. The
avoidance of preparing sensitive organometallic reagents is an
important advantage of this CÀC bond formation process.
Although a detailed mechanistic picture needed further ex-
ploration, several experiments were conducted to provide in-
sights into the mechanism of the Cu-catalyzed reductive cross-
coupling reaction. When the reaction was conducted in the ab-
sence of
a copper catalyst (Table 1, entry 13) and was
quenched within 30 min, a rapid consumption of alkyl bromide
2a was observed.[17] This finding may indicate the intermediacy
of an in situ generated Grignard reagent from alkyl bromide.
Next, a chiral alkyl tosylate 9 was subjected to the reaction,
leading to formation of 10 in 50% yield (Scheme 5). Chiral
HPLC and X-ray crystallography analysis of 10 showed that the
reaction occurred with complete inversion of configuration.
Based on these experiments, we proposed that the reaction
proceeded by initial formation of the Grignard reagent which
To test the application of the new reductive cross-coupling
reaction to complex bioactive molecules (Scheme 4), we con-
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cross-coupling reactions. We also
demonstrate that the Cu-cata-
lyzed method is amenable to
the late-stage functionalization
of complex bioactive molecules
and gram-scale preparative or-
ganic synthesis. In addition, a cat-
alytic intramolecular reductive
cyclization reaction can be ap-
plied to the synthesis of 2,3-di-
hydrobenzofuran and benzo-
Scheme 5. Cross-coupling with a chiral substrate and X-ray analysis of the product. The ee % value was deter-
mined by chiral HPLC analysis.
then reacted with the Cu catalyst, producing an organocopper
intermediate to cause SN2 substitution of alkyl pseudohalides.
To further demonstrate the usefulness of this new reaction,
intramolecular cyclization reactions were carried out using aryl
bromides bearing a side-chain alkyl tosylate group. Such com-
pounds were known to be difficult substrates in the prepara-
tion of Grignard reagents.[18] As depicted in Table 4, various
chromene derivatives. Our further study on extension of this
methodology to more challenging substrates (e.g. cross-cou-
pling with tertiary alkyl halides and cyclization of larger ring
systems) is currently in progress.
Acknowledgements
This study was supported by the “863” Program of the Ministry
of Science and Technology (2012AA02A700), the National Basic
Research Program of China (973 program, No. 2013CB932800),
and NSFC (Nos. 21221062, 91313301, and 21225207).
Table 4. Intramolecular reductive coupling/cyclization reactions.[a]
Keywords: catalysis · CÀC bond formation · copper · cross-
coupling · cyclization
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cross-coupling reaction of nonactivated alkyl pseudohalides
with alkyl and aryl bromides. This reaction proceeds under
mild conditions and tolerates various synthetically useful func-
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a powerful new tool for the construction of aryl–alkyl and
alkyl–alkyl CÀC bonds. It provides an important alternative to
previously reported Fe-, Co-, Pd-, and Ni-catalyzed reductive
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Received: September 11, 2014
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COMMUNICATION
CÀC bond formation: A copper-cata-
lyzed reductive cross-coupling reaction
of nonactivated alkyl tosylates and me-
sylates with alkyl and aryl bromides was
developed. This reaction can be used to
construct aryl–alkyl and alkyl–alkyl CÀC
bonds with stereocontrol from readily
available substrates. Intramolecular cyc-
lization reactions also enable access to
various substituted 2,3-dihydrobenzo-
furan and benzochromene derivatives.
&
Organic Synthesis
J.-H. Liu, C.-T. Yang, X.-Y. Lu, Z.-Q. Zhang,
L. Xu, M. Cui, X. Lu, B. Xiao, Y. Fu,* L. Liu*
&& – &&
Copper-Catalyzed Reductive Cross-
Coupling of Nonactivated Alkyl
Tosylates and Mesylates with Alkyl
and Aryl Bromides
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!