Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with tert-butyl Grignard reagents

Article abstract of DOI:10.1016/j.cclet.2018.12.027

A ligand-free nickel-catalyzed Kumada cross-coupling of aryl bromides and tert-butyl Grignard reagents led to the formation of a series of tert-butyl aryls in moderate to good yields, excellent tBu/iBu ratios, and good functional group compatibility. A radical coupling process is indicated and a mechanism with a Ni(I)-Ni(III) catalytic cycle is proposed.

Full text of DOI:10.1016/j.cclet.2018.12.027

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CCLET 4764 No. of Pages 4
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with
tert-butyl Grignard reagents
b,
Zhenghan Wua, Tengda Sib, Guangqing Xub, Bin Xua, , Wenjun Tang
*
*
a
Department of Chemistry, Shanghai University, Shanghai 200444, China
b
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A ligand-free nickel-catalyzed Kumada cross-coupling of aryl bromides and tert-butyl Grignard reagents
led to the formation of a series of tert-butyl aryls in moderate to good yields, excellent tBu/iBu ratios, and
good functional group compatibility. A radical coupling process is indicated and a mechanism with a Ni
(I)-Ni(III) catalytic cycle is proposed.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 10 November 2018
Received in revised form 19 December 2018
Accepted 24 December 2018
Available online xxx
Keywords:
Ligand free
Kumada cross-coupling
Tert-Butyl arenes
Nickel catalysis
Metal-catalyzed cross-coupling reactions are among the most
versatile and important transformations that have found numer-
ous applications in organic synthesis [1]. Although major activities
are related to the formation of C(sp2)ÀÀC(sp2) bonds, recent
advances in transition metal catalysis have enabled the employ-
ment of C(sp3) nucleophiles and electrophiles for cross-coupling to
form all-carbon quaternary centers [2]. As a part of our ongoing
efforts in exploring aryl-alkyl cross-coupling, we have recently
reported a Pd-catalyzed Suzuki reaction, allowing the cross-
coupling of acyclic secondary alkylboronic acids and aryl bromides
to form tertiary carbons in high yields and excellent selectivities
[3]. Further research is directed on nickel-catalyzed cross-coupling
of tertiary alkyl nucleophiles and aryl halides to form aryl-
substituted all-carbon quaternary centers. However, only a few
reports of Pd- or Ni-catalyzed cross-couplings employing tertiary
alkyl nucleophiles were available and the majority led to the
exclusive formation of the isomerization side-products [4] due to
rapid β-hydride elimination. Among some notable examples,
Kumada and co-workers [5] described a nickel-catalyzed coupling
of tertiary alkyl Grignard reagents with β-bromostyrene. Biscoe [6]
and Glorius [7] reported respectively the Ni-catalyzed Kumada
cross-couplings of tertiary alkyl magnesium halides and aryl
bromides by using N-heterocyclic carbenes (NHC) as supporting
ligands (Scheme 1). Nevertheless, high loadings of catalysts and
ligands are necessary in their reports, which hampered the
practicality and applications of such methods. We herein report
that the cross-coupling proceed under ligand-free conditions even
at a lower loading of nickel. Herein, we detailed our results on
efficient Ni-catalyzed cross-couplings of tertiary alkyl Grignard
reagents with aryl bromides.
We looked into the Ni-catalyzed cross-coupling of tBuMgCl and
2-bromonaphthalene (1a). The yields and proportions of the
potential products (2a-3a) were readily analyzable by gas
chromatography. The reactions were conducted at 0 ꢀC for
30 min in THF with 10 mol% NiCl2 in the absence of a phosphorus
or NHC ligand. We were pleased that the desired cross-coupling
product 2a was obtained in 53% yield with a 2a/3a ratio of 5:1.
Various nickel precursors were investigated and NiCl2 (H2O)1.5
Á
proved to be best in terms of yield (Table 1, entries 2–5).
Employment of PdCl2 instead of NiCl2 gave no desired product
(entry 6). We thus selected NiCl2 (H2O)1.5 as the nickel precursor
Á
for further optimization. When the Ni loading decreased to 2 mol%,
we found that a good yield maintained while the 2a/3a selectivity
was further improved (entries 7 and 8). By reducing the reaction
temperature to -10 ꢀC and increasing the Ni loading to 2.5 mol%, the
cross-coupling product 2a was afforded in 70% yield with a 2a/3a
ratio of 25:1 (entry 9). Further addition of K2CO3 or KOtBu did not
result in an improved yield (entries 10 and 11). No formation of the
product was observed in the absence of a nickel catalyst.
The substrate scope of the Ni-catalyzed coupling of aryl
bromides with tertiary alkyl magnesium halides was explored.
As can be seen in Scheme 2, both electron-rich (2b and 2c) and
* Corresponding authors.
E-mail addresses: xubin@shu.edu.cn (B. Xu), tangwenjun@sioc.ac.cn (W. Tang).
https://doi.org/10.1016/j.cclet.2018.12.027
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z. Wu, et al., Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with tert-butyl Grignard
reagents, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2018.12.027

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CCLET 4764 No. of Pages 4
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Z. Wu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
delighted that the coupling could also occur on 1-bromonaph-
thalene, leading to the formation of 2f in a moderate yield,
indicating the tolerance of certain steric hindrance of the reaction
on substrate. The coupling was also compatible with large aromatic
systems such as anthracene (2g and 2t), phenanthrene (2h), and
triphenylene (2s). para- and meta-Substituted bromo benzenes
also gave coupling products in moderate to excellent yields and
good tBu/iBu ratios (2i-2q). No coupling product was observed
with ortho-methyl bromo benzene as the substrate, possible due to
steric hindrance. When a heteroaryl bromide was employed in this
reaction, we were pleased that a quinoline product (2r) was
formed in a satisfactory yield (80%). A pyridine derivative 4-
bromo-2,6-lutidine could also be employed to provide the
coupling product in 50% yield with a tBu/iBu ratio of 4:1.
To demonstrate the practicality of this method, the coupling was
performedatagramscale. Inthepresenceof2.5 mol%NiCl2 (H2O)1.5,
Á
thereactionwascompletein30 minandthecouplingproduct2awas
obtainedin62%isolatedyieldwithatBu/iBuratioof15:1(Scheme3).
To shed light on the mechanism of this transformation, the
following experiments were implemented. Under similar reaction
conditionswithadditionaladditionofTEMPOorDMPO(2equiv.),little
or no coupling product was obtained (Scheme 4). When para-methyl
bromobenzene (1u) was employed as the substrate, a significant
amount of the homo-coupling product 2u' was formed in 40% yield.
When 1-bromo-2-(but-3-en-1-yl)benzene (1v) was employed as
the substrate, a cyclization product 2v was formed. These experi-
ments indicated a possible radical process during the coupling.
On the basis of Louie’s proposal [8] as well as our own
investigations, we proposed a mechanism of the ligand-free
nickel-catalyzed cross-coupling of aryl bromides with tert-butyl
Grignard reagent illustrated in Scheme 5. Reduction of Ni(II)
species by Grignard reagent forms a tBu-Ni(I) species A. Oxidative
addition of aryl bromide to A affords a Ni(III) species B, which
undergoes a normal reductive elimination pathway to form the
cross-coupling product tBu-Ar and Ni(I)-X species E.
Scheme 1. Kumada coupling of tertiary alkyl Grignard reagents.
electron-deficient (2d and 2e) naphthalene products were isolated
in moderate to good yields and excellent tBu/iBu ratios (10-25:1).
Functional groups such as ester (2e,2j, and 2k), pyrrole (2 m),
sulfonyl group (2i), and trifluoromethoxy group (2p) were well
tolerable under the reaction conditions. The method also displayed
good chemo-selectivity on aryl bromide over aryl chloride or
fluoride as indicated by selective preparation of products 2d and 2o
in decent yields. Thus, chloro- and fluoro-aryl substituted hydro-
carbons bearing all-carbon quaternary centers could be easily
formed, which were viable for further derivatization. We were
Table 1
Optimization of the Ni-catalyzed cross-coupling of tBuMgCl and 2-Bromonaphthlene
.
Entry
Variation from the condition
none
yield (%)a
2a:3aa
1
2
3
4
5
6
7
8
9
10
53
70
57
46
42
–
5:1
8:1
9:1
8:1
10:1
–
NiCl2 (H2O)1.5 (10 mol%)
Á
Ni(OTf)2 (10 mol%)
Ni(acac)2 (10 mol%)
Ni(OAc)2
PdCl2 (instead of NiCl2)
Á
(H2O)4 (10 mol%)
NiCl2
NiCl2
NiCl2
NiCl2
Á
Á
Á
Á
(H2O)1.5 (5 mol%)
68
70
70
47
11:1
18:1
25:1
8:1
(H2O)1.5 (2 mol%)
(H2O)1.5 (2.5 mol%),-10 ꢀ
(H2O)1.5 (2.5 mol%),
C
À10 ꢀC, K2CO3 (0.4 equiv.)
11
NiCl2
Á
(H2O)1.5 (2.5 mol%),
27
6:1
À10 ꢀC; KOtBub
toluene instead of THF
no nickel
12
13
68
–
8:1
–
a
Yields and selectivity determined by GC.
Please cite this article in press as: Z. Wu, et al., Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with tert-butyl Grignard
reagents, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2018.12.027

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Z. Wu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
Scheme 2. Ni-catalyzed cross-coupling of tBuMgCl and Aryl bromides. Unless otherwise stated, the reactions were performed in THF under 4 equiv. tBuMgCl at -10 oC for 30
min in the presence of 2.5 mol% NiCl2
(H2O)1.5; isolated yield was given; ratio determined by 1H NMR spectroscopy.
Á
Scheme 3. Gram-scale of Ni-catalyzed cross-coupling.
Scheme 5. Proposed mechanism.
In summary, we have developed a ligand-free Ni-catalyzed
coupling of tert-butyl Grignard reagent and aryl bromides that
have shown moderate to good yield with good to excellent tBu/iBu
ratios. This process allows facile and efficient construction of aryl-
substituted hydrocarbons with all-carbon quaternary centers at a
low nickel loading. A radical coupling process is indicated and a
mechanism with a Ni(I)-Ni(III) catalytic cycle is proposed. Further
mechanistic investigation is ongoing in our laboratory.
Scheme 4. Mechanistic investigation.
Transmetallation of E with tert-butyl Grignard reagent regenerates
tBu-Ni(I) species and completes the catalytic cycle. When an
electron-rich aryl bromide such as 1 u is employed, the normal
pathway of reductive elimination slows down and the undesired
pathway of reductive elimination to eliminate tBuBr takes place to
form Ar-Ni(I) (C), which could further react with ArBr to form Ni
(III) species D and lead to the formation of homocoupling side-
product Ar-Ar by reductive elimination.
Acknowledgments
We are grateful to the Strategic Priority Research Program of the
Chinese Academy of Sciences (No. XDB20000000), CAS (No.
QYZDY-SSW-SLH029), National Natural Science Foundation of
China (Nos. 21725205, 21432007, 21572246), STCSM-
18520712200, and K.C. Wong Education Foundation.
Please cite this article in press as: Z. Wu, et al., Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with tert-butyl Grignard
reagents, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2018.12.027

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Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
cclet.2018.12.027.
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Please cite this article in press as: Z. Wu, et al., Ligand-free nickel-catalyzed Kumada couplings of aryl bromides with tert-butyl Grignard
reagents, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2018.12.027