Copper-catalyzed cross-coupling reactions of non-activated primary, secondary or tertiary alkyl chlorides with phenylmagnesium bromide

Article abstract of DOI:10.1016/j.tetlet.2016.12.013

Efficient copper-catalyzed cross-coupling reactions of non-activated alkyl chlorides, including primary, secondary, and tertiary alkyl chlorides, with phenyl Grignard reagents were achieved. Preparation of phenylmagnesium bromide in 2-methyltetrahydrofuran is critical for the success of the reaction. This protocol expands the synthetic toolbox for the construction of C[sbnd]C bonds of non-activated primary, secondary, and tertiary alkyl chlorides via copper-catalyzed cross-coupling.

Full text of DOI:10.1016/j.tetlet.2016.12.013

Accepted Manuscript
Copper-catalyzed cross-coupling reactions of non-activated primary, secondary
or tertiary alkyl chlorides with phenylmagnesium bromide
Chuanzhou Tao, Lei Sun, Bin Wang, Zhou Liu, Yadong Zhai, Xiulian Zhang,
Dahua Shi, Weiwei Liu
PII:
S0040-4039(16)31635-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.013
TETL 48425
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 September 2016
1 December 2016
3 December 2016
Please cite this article as: Tao, C., Sun, L., Wang, B., Liu, Z., Zhai, Y., Zhang, X., Shi, D., Liu, W., Copper-catalyzed
cross-coupling reactions of non-activated primary, secondary or tertiary alkyl chlorides with phenylmagnesium
bromide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.013
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Copper-catalyzed cross-coupling reactions of non-
activated primary, secondary or tertiary alkyl
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chlorides with phenylmagnesium bromide
Chuanzhou Tao, Lei Sun, Bin Wang, Zhou Liu, Yadong Zhai, Xiulian Zhang, Dahua Shi, Weiwei Liu

2
Tetrahedron Letters
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Copper-catalyzed cross-coupling reactions of non-activated primary, secondary
or tertiary alkyl chlorides with phenylmagnesium bromide
a,b∗
a
a
a
a
a
a,b
a,b
Chuanzhou Tao , Lei Sun , Bin Wang , Zhou Liu , Yadong Zhai , Xiulian Zhang , Dahua Shi , Weiwei Liu
a
School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China
Jiangsu Marine Resources Development Research Institute, Lianyungang 222005, P. R. of China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Efficient copper-catalyzed cross-coupling reactions of non-activated alkyl chlorides, including
primary, secondary, and tertiary alkyl chlorides, with phenyl Grignard reagents were achieved.
Preparation of phenylmagnesium bromide in 2-methyltetrahydrofuran is critical for the success
of the reaction. This protocol expands the synthetic toolbox for the construction of C−C bonds
of non-activated primary, secondary, and tertiary alkyl chlorides via copper-catalyzed cross-
coupling.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
copper-catalyzed
non-activated alkyl chlorides
cross-coupling
1
5
Due to high energy barrier to oxidative addition and
unproductive β-H elimination, alkyl halides constitute a more
difficult class of electrophiles than the corresponding aryl or
vinyl halides in transition metal-catalyzed C−C cross-coupling
2
catalytic amount of Cu(OTf) . In 2012, Liu et al. made a major
advance and achieved CuI/TMEDA/LiOMe catalyzed cross-
coupling non-activated secondary alkyl bromides or tosylates
16
with alkyl Grignard reagents. Lately, Kambe et al. reported a
copper catalyst system for non-activated secondary alkyl iodides
with 1,3-butadiene as additive. Nonetheless, these alkyl
electrophilic coupling partners were limited to alkyl iodides,
bromides, or tosylates. Secondary or tertiary alkyl chlorides are
still challenging substrates in copper-catalyzed C-C cross-
coupling reactions, which are among the most useful starting
materials due to their low cost and easy availability. Very
recently, Xu and Fu reported copper-catalyzed allylation of
secondary alkyl halides with allyl boron esters, where in a few
cases activated secondary benzylic alkyl chlorides were used.
Non-activated secondary or tertiary alkyl chlorides still remained
difficult in the copper-catalyzed C-C cross-coupling reactions.
1
reactions. Compared to primary alkyl halides, secondary or
tertiary alkyl halides are much more difficult because of the
2
added steric hindrance. Nevertheless, some significant progress
3
4
has been made in the past few years, such as nickel, iron,
5
6
palladium and cobalt-catalyzed alkyl−aryl and alkyl−alkyl
cross-coupling reactions. Alkyl chlorides are abundant industrial
7
feedstocks, however, they are challenging substrates in metal-
17
catalyzed C-C cross-coupling reactions due to their inherently
high carbon-chlorine bond strength. Considerable effort has been
devoted to achieving useful cross-coupling reactions with
8
primary alkyl chlorides, however, cross-coupling reactions of
9
secondary alkyl chlorides remained rare. Recently, Fe-catalyzed
4
cross-couplings of non-activated alkyl chlorides were reported,
Herein, we demonstrate a copper catalyzed process for C−C
cross-coupling reactions of non-activated alkyl chlorides,
involving secondary, tertiary and primary alkyl chlorides. With
copper as catalyst, and 2-methyltetrahydrofuran as Grignard
reagent’s solvent, non-activated alkyl chlorides, especially
secondary and tertiary alkyl chlorides, were successfully coupled
with phenyl magnesium bromide under ligand-free and additive-
free conditions. To the best of our knowledge, this is the first
time that copper catalyst system has been employed to C−C
cross-coupling of non-activated secondary or tertiary alkyl
chlorides with aryl Grignard reagents. Easy accessibility of the
reagents and the convenient reaction conditions make this
protocol highly practically appealing. Moreover, this method
in which cross-coupling reactions of various secondary and
tertiary alkyl chlorides with aryl Grignard reagents were
achieved.
10
11
In the case of copper catalyst system for secondary alkyl
12
halides, the precedents were focused on activated alkyl halides.
When referred to non-activated secondary or tertiary alkyl
halides, the successful examples were rare. Seminal report is
13
Burns’ catalyst (CuBr/LiSPh/LiBr/THF), which was used to
catalyze cross-coupling of non-activated secondary alkyl
14
tosylates with alkyl Grignard reagents. Then, Oshima et al.
demonstrated a cross-coupling of tertiary alkyl bromides with
cyclopentadienyl magnesium bromide in the presence of a

expands the concept and scope of copper-catalyzed cross-
coupling reactions in a fundamental sense.
11–14). However, the yield is slightly lower for cuprous catalyst
Cu(OTf) and the yield is 52% (entry 15).
2
We began our investigation with cyclohexyl chloride 1a as
model substrate to test different solvents for Grignard reagent
Table 1). It was found that the conversion of 1a is 6% and yield
of product 2a is 1% when THF was used as the solvent for
The above results show that CuI/Toluene is an efficient
combination for cross-coupling phenyl magnesium bromide with
alkyl chlorides. To test the scope of this method, we examined a
variety of substrates (Table 2). We found that non-activated
secondary alkyl chlorides can be smoothly coupled with phenyl
magnesium bromide 2b to afford excellent yields (entries 1–5).
For instance, cyclohexyl chloride can give an isolated yield of
75% (entry 1), and cyclopentyl chloride can generate 71% yield
(entry 2). Similarly, the yield for (3-chlorobutyl)benzene is 74%,
and the yield for 2-chlorobutane is 78%. The yield of activated
secondary alkyl chlorides (chloromethylene)dibenzene is slightly
low (entry 5, 66% yield).
(
phenylmagnesium bromide. Even when the temperature was
o
increased to 80 C, the coupling reaction only generate 3%
product with 14% conversion. However, when the solvent was
changed to 2-MeTHF (2b), we observed dramatic improvement.
o
Under 80 C, the yield was increased to 65%, and the conversion
was 100%.
a
Table 1 optimizing the solvent of phenyl Grignard reagents.
Table 3 copper-catalyzed cross-coupling non-activated alkyl chlorides with
a
phenylmagnesium bromide
o
b
b
Entry PhMgBr Temp.( C) 1a Con.(%)
3a Yield(%)
1
2
3
2a
2a
2b
65
80
80
6
14
100
1
3
65
b
Entry
1
1
3
Yield (%)
75
a
Reaction conditions: 1a 0.5mmol,
concentration of PhMgBr is 1.0 mol/L, reaction time is 18h. GC yield.
2 1.1-1.2 mmol, CuI 10mol%,
b
1
a
3
a
a
Table 2 optimizing copper-catalyzed cross-coupling conditions.
2
3
4
71
74
1
b
3b
3c
b
Entry
Catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
Solvent
2-MeTHF
THF
Yield (%)
65
1
2
3
4
5
6
7
8
9
1c
62
63
70
77
74
77
80
4
79
71
68
75
73
52
Dioxane
c
78
t
Bu OMe
i
1d
Cl
3d
3e
Pr
2
O
Hexane
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
5
6
66
78
Ph
Ph
1
e
c
10
11
12
13
14
15
CuI
CuBr
CuCl
CuCl
CuBr
Cu(OTf)
2
1f
3
f
2
2
a
c
Reaction conditions: 1a 0.5 mmol, 2b 1.1-1.2 mmol (C = 2.9 mol/L in 2-
MeTHF), catalyst 10mol%, solvent 1.0 mL, temperature 80 C, 18h. GC
7
8
9
38
o
b
1g
3g
c
yield. CuI purity is 99.998%.
71
70
67
Subsequently, using phenylmagnesium bromide 2b which was
made in 2-Me-THF as coupling partner, different reaction
solvents were examined (Table 2, entries 1–8). It was found that
good yields of the desired products were obtained in 2-MeTHF
THF and dioxane (entry 1–3). Interestingly, solvents with more
steric hindrance are better for the coupling reaction, and we can
get higher yields of the designed product (entries 4, 5). We
speculate the weak coordination of these solvents is the reason.
Therefore, we turned to some low polar solvents such as hexane,
benzene and toluene (entries 6–8). Delightfully, the yield was
further improved to 80% when toluene was used (entry 8).
Copper is critical for the conversion, and only 4% of 3a were
detected in the absence of CuI (entry 9). Additionally, when the
CuI with high purity was used, the same catalytic activity was
observed, and 79% yield was obtained (entry 10). Next, we
screened the copper sources with different valences. Gratifyingly,
1
h
3h
Cl
8
1
i
3
i
10
1
j
3j
a
Reaction conditions: 1 1.0 mmol, 2b 2.2-2.4 mmol (C = 2.9 mol/L in 2-
MeTHF), CuI 10 mol%, toluene 2.0 mL, temperature 80 C, 18h. Isolated
yield. GC yield.
o
b
c
Furthermore, the method can be applied to the coupling of
non-activated tertiary alkyl chlorides. Although the yield of
tert-butyl chloride is only 38%, 1-chloroadamantane can be
coupled with phenylmagnesium bromide to give an excellent
isolated yield of 78%. Finally, non-activated primary alkyl
chlorides were tested, and dodecyl chloride can be converted
12
2 2
CuBr, CuCl, CuBr and CuCl all gave excellent yields (entries

4
Tetrahedron
with a good yield (71%) under the standard conditions (entry
). Likewise, satisfactory isolated yields were obtained for decyl
chloride (entry 9, 70% yield) and (3-chloropropyl)benzene (entry
0, 67% yield). It is noteworthy that this protocol for primary
alkyl chlorides is efficient without using any ligands, such as
8
1
11a
11b
diene, alkyne
.
Nevertheless, when we extend Grignard reagent to other
arylmagnesium bromide, the cross-coupling reactions were not
yet successful. Couplings (4-chlorophenyl)magnesium bromide
or (4-methoxyphenyl)magnesium bromide with cyclohexyl
chloride or dodecyl chloride failed, and the starting materials
were recovered (Scheme 1).
Scheme 3 the proposed mechanism of copper-catalyzed cross-coupling of
non-activated chlorides.
To conclude, we have demonstrated copper-catalyzed alkyl–
aryl cross-coupling reactions between non-activated alkyl
chlorides and phenyl Grignard reagents. The non-activated alkyl
chlorides involved various primary, secondary, and tertiary alkyl
chlorides. The direct phenylation proceeds efficiently in the
presence of copper as catalyst, and phenylmagnesium bromide
made in 2-methyltetrahydrofuran as corresponding coupling
partner. Considering the less costly nature of alkyl chlorides, the
method described in the present report may be valuable for
industrial-scale applications. Moreover, this method expands the
synthetic toolbox for the construction of C−C bonds between
non-activated primary, secondary, and tertiary alkyl chlorides
through copper-catalyzed cross-coupling.
Scheme
magnesium bromide.
1 copper-catalyzed cross-coupling dodecyl chloride with aryl
Notably, in the present catalytic system, non-activated alkyl
chlorides showed higher activity than the corresponding
bromides or tosylates (Scheme 2). When the catalytic system was
applied to non-activated alkyl bromides or tosylates, phenylation
yield is only 4% for cyclohexyl bromide and 7% for cyclohexyl
tosylates, which are values significantly lower than cyclohexyl
chloride. Dodecyl halides were selected to compare the activity
between alkyl bromides and chlorides. We found that an alkyl
chloride showed more reactive to cross-coupling with phenyl
magnesium bromide 2b, and less reactive to eliminate to yield
the alkene. 75% coupling product was obtained with 24% alkene.
However, the corresponding alkyl bromide was difficult to
couple, and only 43% phenylation product was obtained with
Acknowledgments
We are grateful to National Science Foundation of China
(
(
21402062), Natural Science Foundation of Jiangsu Province
BK20130404, BK20141246), Scientific and Technological
54% elimination. This observation will be synthetically useful for
Research Project of Lianyungang (CG1303), Jiangsu Key
Laboratory of Marine Pharmaceutical Compound Screening
the design of site-selective sequential cross-coupling reactions.
(2015HYB11), and the Project Funded by the Priority Academic
CuI 10mol%
X
MgBr
Program Development of Jiangsu Higher Education Institutions.
Toluene
2
b
X = Cl
Br
OTs
80%, 3a
4%, 3a
7%, 3a
References and notes
CuI 10mol%
Toluene
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