Micelle enabled C(sp2)-C(sp3) cross-electrophile coupling in waterviasynergistic nickel and copper catalysis

Article abstract of DOI:10.1039/d1cc02885e

A robust and sustainable C(sp²)-C(sp³) cross-electrophile coupling was developedvianickel/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields on a very large scale.

Full text of DOI:10.1039/d1cc02885e

Volume 57
Number 62
11 August 2021
Pages 7587–7720
ChemComm
Chemical Communications
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COMMUNICATION
Ning Ye, Bin Wu, Fabrice Gallou et al.
Micelle enabled C(sp2)–C(sp3) cross-electrophile coupling in
water via synergistic nickel and copper catalysis

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Micelle enabled C(sp2)–C(sp3) cross-electrophile
coupling in water via synergistic nickel and
copper catalysis†
Cite this: Chem. Commun., 2021,
57, 7629
Received 1st June 2021,
Accepted 30th June 2021
Ning Ye, *a Bin Wu, *a Kangming Zhao,‡a Xiaobin Ge,‡a Yu Zheng,a
Xiaodong Shen,a Lei Shi,a Margery Cortes-Clerget,b Morgan Louis Regnier,b
b
b
DOI: 10.1039/d1cc02885e
Michael Parmentier
and Fabrice Gallou
*
rsc.li/chemcomm
A robust and sustainable C(sp2)–C(sp3) cross-electrophile coupling of the terminal (hetero)aryl alkenes and alkyl halides under
was developed via nickel/copper synergistic catalysis under micellar aqueous micellar conditions that addressed these issues in the
conditions. This protocol provided a general method to access alkylated specific reported case.15 With the aim to derive an even more
arenes with good to excellent yields on a very large scale.
general and robust sustainable catalytic system, herein, we
report a Ni/Cu co-catalyzed C(sp2)–C(sp3) cross-electrophile
Metal catalyzed C(sp2)–C(sp3) bond formation reactions are coupling under micellar conditions, in water as the bulk
widely applied in academia and the industrial area.1,2 Although medium (Scheme 1).
the traditional cross coupling reaction is carried out using pre-
With this objective in mind, our investigation started with
formed organometallic reagents as the coupling partner,3 there the coupling of ethyl 4-bromobenzoate (1a) and iodocyclohex-
is increasing interest in cross-electrophile coupling which ane (2a) as model substrates (Table 1). Brief variations of the
serves as an alternative method to forge C(sp2)–C(sp3) standard conditions led us to the best conditions of 2.5 mol%
bonds.4–11 In 2010, Weix reported the first general nickel- Ni(OAc)2ꢀ4H2O, 3 mol% of 3,4,7,8-tetramethyl-1,10-phenan-
catalyzed cross-electrophile coupling of aryl halides with unac- throline (L1), 0.75 mol% of copper oxide, and zinc as the
tivated alkyl halides.12 This seminal report generated high
expectations and several follow-up efforts to further extend
and improve the methodology. Nevertheless tedious operations
are still required to ensure high quality in the end product, due
to the extent of side-reactions, and the high amount of residual
components inherent to such transformations. In addition,
such chemistry tends to happen in the flagged reprotoxic polar
aprotic solvents, such as DMA, DMF or NMP. Meanwhile,
chemistry-in-water technology has become more and more
popular owing to the demand of the environmental foot-
print.13 Lipshutz’s group reported aryl–alkyl cross coupling
using micelle enabled Pd catalysis.14 This work sheds light on
the further development of related chemistry in terms of
sustainability. In collaboration with Lipshutz, we also revisited
the methodology to make it more amenable for large scale
production and reported the iron-catalyzed reductive couplings
a Chemical & Analytical Development, Suzhou Novartis Technical Development Co., Ltd,
Changshu, Jiangsu 215537, China. E-mail: ning.ye@novartis.com,
bin-3.wu@novartis.com
b Chemical & Analytical Development, Novartis Pharma AG, Basel 4056, Switzerland.
E-mail: fabrice.gallou@novartis.com
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc02885e
Scheme 1 Synthesis of alkylated arenes via cross-electrophile couplings.
Chem. Commun., 2021, 57, 7629–7632 | 7629
‡ These authors contributed equally to this work.
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Table 1 Standard and control reactions
well for the reaction and the yields varied from 67–75%, as
shown in entries 15–17. To our delight, this reaction could also
be performed at room temperature, producing the desired
product 3aa in 81% yield (entry 18). 2-Me-THF is selected as
the best co-solvent as other common solvents such as THF,
acetone and MeCN yielded more modest results (entries 19–21).
A lower yield was observed compared with the micellar condi-
tions (entry 22) when only water was used in addition to
challenging physical operations.
Entry
Reaction conditiona
Yieldb (%)
While we still do not have enough unambiguous mecha-
nistic evidence of the actual role of the synergistic effect of
copper, and are currently actively working on elucidating it, we
proposed the following dual catalytic cycles depicted as
Scheme 2 based on key literature precedents.16–18 Nickel is
assumed to have the expected role in oxidative addition and
reductive elimination, while copper could facilitate the trans-
metalation of the alkyl species to nickel.19,20 Nickel and copper
catalytic cycles should be matched well in order to deliver the
desired compound in a good manner. We are currently inves-
tigating the mechanistic aspects of the process and will share
more insights in due course.
With these best conditions in hand, the scope and limita-
tions of this cross-electrophile coupling were examined with a
variety of aryl halides (Scheme 3). Besides aryl bromide, the
more reactive aryl iodides could obviously undergo this trans-
formation smoothly to afford the desired product with 94%
yield (3aa, X = I, X0 = I). Cyclohexyl bromide also worked well
under the standard conditions, albeit in a lower yield (3aa,
X = Br, X0 = Br). Aryl halides bearing various functional groups
at the para-position could be prepared in moderate to good
yields (65–85%), including acetyl (3ca), trifluoromethyl (3db),
methoxyl (3eb), cyanide (3fa), formyl (3ha), amide (3ia), sulfonyl
(3ja) and phenyl (3ka) groups. meta and ortho substituted aryl
halides such as 3-bromobenzoate and 2-bromobenzoate also
serve as good candidates in this reaction, affording the desired
coupling product with 76% and 55% yields, respectively
(3ga and 3ma). The reaction of 2-bromonaphthalene with Boc
protected 4-iodo-piperidine successfully resulted in the corres-
ponding product in a 62% yield (3la). Other heterocyclic halides
including indole (3na), carbazole (3oa), benzofuran (3pa), ben-
zothiophene (3qa), 3-coumaranone (3ra), and pyridine (3sa and
3ta) could also be employed to produce the corresponding
coupling products in 59% to 75% yields. Note that this chemistry
could also be implemented to the pharmaceutically relevant
1
2
3
4
5
6
7
8
Without Ni(OAc)ꢀ4H2O
Without zinc
Without L1
0
0
0
Without Cu2O
50
27
60
92(89)
80
68
62
78
79
58
11
67
72
75
81
60
41
32
70
Without 2 wt% TPGS-750-M/H2O
Without 2-Me-THF
Standard conditions
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
L7 instead of L1
L8 instead of L1
CuI instead of Cu2O
CuO instead of Cu2O
Cu(OAc)2 instead of Cu2O
25 1C instead of 45 1C
THF instead of 2-Me-THF
Acetone instead of 2-Me-THF
MeCN instead of 2-Me-THF
Water instead of TPGS-750-M
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
Reaction were performed with 1a (4.38 mmol), 2a (6.58 mmol),
2-Me-THF (10 mL), 2 wt% TPGS-750-M/H2O (10 mL) at 45 1C for 16 h.
b
Yields determined by HPLC using 1,3,5-trimethoxybenzene as an
internal standard. Value within parentheses is isolated yield.
reducing agent in the co-solvent system of 2 wt% TPGS aqueous
solution and 2-Me-THF leading to the full consumption of the
starting material 1a and an 89% isolated yield of the desired
product 3aa (entry 7). This finding on the crucial role of copper
co-catalysis came from originally contaminated aryl bromide
with copper trace. Careful investigations on the challenges we
faced when working with analytically pure aryl bromide that
would not react any longer led us to find out that Cu2O was
essential to the process. Control experiments indicated that
this transformation could not occur in the absence of either
nickel, ligand or zinc (entries 1–3). The catalytic amount of
copper also plays an important role as the yield dropped to 50%
without copper (entry 4).16 The nano-micelle environment was
necessary for the reaction since a low yield was obtained in sole
organic solvent (entry 5). Besides L1, other phenanthroline and
bi-pyridine type ligands also showed effectiveness for this
reaction, albeit in lower yields (11–80%, entries 8–14). Other
copper sources including CuI, CuO and Cu(OAc)2 also worked Scheme 2 Proposed mechanistic cycle for the dual catalysis.
7630 | Chem. Commun., 2021, 57, 7629–7632
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Scheme 4 Substrate scope of alkyl halides.
afforded the desired product 3ab in an 82% yield. Not only
secondary alkyl iodides, but also primary alkyl iodides such as
ethyl 4-iodobutanoate could also be used to give 3ac in a 71%
yield. Isopropyl iodide and cyclopentyl iodide are both active
candidates to produce the corresponding product in 75% and
81% yields, respectively. The presence of both chloride and
iodide in the alkyl partner leads to complete selectivity for
coupling at the iodide (3ae). Alkyl iodide bearing heteroatoms
such as hydropyran (3ah and 3ak) and azetidine (3aj) could also
be well tolerated. Notably, this method was applicable to drug
like analogues, or subsections thereof, as one example shown
in 3al. It is emphasized that the challenging substrate cyclo-
propyl iodide could also act as a good coupling partner under
these micellar conditions and afford the desired product 3am
in 68% yield.
Scheme 3 Substrate scope of aryl halides.
In conclusion, a robust nickel and copper catalysed C(sp2)–
molecules such as 3ua to afford the desired coupling target in a C(sp3) cross-electrophile coupling within aqueous nanoreactors
good yield (55%).21
under very mild conditions has been developed. The present
We next explored the scope of this cross electrophile cou- synergistic approach22 allows the expedient synthesis of a wide
pling by using different alkyl iodides (Scheme 4). As mentioned variety of functionalized adducts with considerable generality,
in Scheme 2, the 4-iodopiperidine derivative reacted well and good-to-excellent yields, cost-efficiency and high chemoselectivity.
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and C(sp3)–C(sp3) cross-electrophile couplings.26
All work described in this paper was funded by Novartis.
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Conflicts of interest
There are no conflicts to declare.
21 B. Wu, S. S. Zhang, T. Hong, Y. Zhou, H. Wang, M. Shi, H. W. Yang,
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7632 | Chem. Commun., 2021, 57, 7629–7632
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