Nickel-catalyzed C-H alkylations: Direct secondary alkylations and trifluoroethylations of arenes

Article abstract of DOI:10.1002/anie.201309584

A versatile nickel catalyst allowed for C-H alkylations of unactivated arenes with challenging secondary alkyl bromides and chlorides. The high catalytic efficacy also set the stage for direct secondary alkylations of indoles as well as C-H trifluoroethylations with ample substrate scope. In an absence of activation: A robust nickel(II) catalyst enabled secondary alkylations of unactivated aryl C-H bonds with secondary alkyl bromides and chlorides with ample substrate scope. Based on this system the first C-H trifluoroethylations of arenes with unactivated C-H bonds could be carried out (see scheme; Q=8-quinolinyl). Copyright

Full text of DOI:10.1002/anie.201309584

Angewandte
Chemie
DOI: 10.1002/anie.201309584
À
C H Activation
Hot Paper
À
Nickel-Catalyzed C H Alkylations: Direct Secondary Alkylations and
Trifluoroethylations of Arenes**
Weifeng Song, Sebastian Lackner, and Lutz Ackermann*
Table 1: Optimization of nickel-catalyzed secondary alkylation.[a]
À
Abstract: A versatile nickel catalyst allowed for C H alkyl-
ations of unactivated arenes with challenging secondary alkyl
bromides and chlorides. The high catalytic efficacy also set the
À
stage for direct secondary alkylations of indoles as well as C H
trifluoroethylations with ample substrate scope.
À
C
H activation has emerged as an increasingly viable tool
Entry
Catalyst
Ligand
Base
Yield [%]
for improving the step-economy in organic synthesis.[1] While
various useful methods for catalytic direct arylations have
been developed during the past few years, significantly more
[b]
1
2
3
4
5
6
7
8
Ni(OTf)2
[Ni(acac)2]
[Ni(cod)2]
Ni(OTf)2
PPh3
–
–
–
–
–
–
PPh3
IPrHCl
Xantphos
DME
BDMAE
L-proline
TMEDA
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
Na2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Na2CO3
Cs2CO3
NaOAc
LiOtBu
LiOtBu
LiOtBu
–
10
52
33
–
40
55
30
–
20
60
70
22
45
–
À
challenging C H bond alkylations with unactivated alkyl
halides continue to be scarce.[2] Indeed, only few methods for
direct alkylations with primary alkyl halides are thus far
NiCl2
[(diglyme)NiBr2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
[(DME)NiCl2]
available.[2a–j] C H Functionalizations with secondary alkyl
À
halides are even more difficult because of their reluctance to
undergo oxidative additions onto transition metals and the
pronounced tendency of the thus formed alkyl metal com-
plexes to undergo undesired b-hydride eliminations.[2,3] As
9
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
a direct consequence, secondary C H alkylations[4] on arenes
À
are currently largely limited to very recently developed
ruthenium-[5] and cobalt-catalyzed transformations.[6]
In recent years, bidentate auxiliaries have attracted
–
–
71
76
86[d]
considerable attention owing to their unique potential for
[7]
À
the activation of otherwise inert C H bonds. Since the
seminal studies by Daugulis,[8] a variety of reactions utilizing
À
auxiliary-assisted C H bond transformations have been
[a] Reaction conditions: 1a (0.50 mmol), 2a (1.0 mmol), [Ni] (10 mol%),
ligand (20 mol%), base (2.0 equiv), solvent (1.0 mL), 1608C, 20 h; yields
of isolated product. [b] PPh3 (20 mol%), 89% of re-isolated 1a. [c] 1,4-
Dioxane (1.0 mL). [d] PhMe (1.0 mL). [e] BDMAE (40 mol%). OTf=tri-
fluoromethane sulfonate, acac=acetylacetonate, Q=8-quinolinyl,
BDMAE=bis(2-dimethylaminoethyl)ether, DME=dimethoxyethane.
Optimized system highlighted in bold.
developed,[9] including a very recent nickel-catalyzed direct
C H alkylation with primary alkyl halides.[10] In consideration
of the key challenges associated with the use of secondary
À
À
alkyl halides in C H activation chemistry, we became
À
attracted by devising direct C H alkylations of arenes with
unactivated secondary alkyl halides. We report herein robust
nickel(II) catalysts that allow for expedient secondary
alkylations with both alkyl bromides and chlorides. It is
À
further noteworthy that unprecedented C H trifluoroethyl-
We initiated our studies by exploring reaction conditions
for the envisioned direct alkylation of benzamide 1a with
bromocyclohexane (2a; Table 1). At the outset, we observed
ations[11,12] of arenes are achieved with the inexpensive
nickel(II) catalyst.
À
that the nickel catalyst previously used for C H transforma-
tions with primary alkyl halides[10] was completely ineffective
[*] M. Sc. W. Song, M. Sc. S. Lackner, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
À
for the desired secondary C H alkylation (entry 1). After
considerable optimizations we found that among a set of
nickel precursors [(DME)NiCl2] was most suitable (entries 2–
7). Thereafter, we explored various stabilizing ligands, with
BDMAE and DME furnishing particularly effective catalysts
(entries 8–14). As to the nature of the base and the solvent,
the most effective C H secondary alkylation was accom-
plished with LiOtBu (entries 15–17) in toluene (entries 18–
20).
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[**] Support by the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement no. 307535 and the Chinese Scholarship Council
(fellowship to W.S.) is gratefully acknowledged. We also thank
Grigory Shevchenko for the synthesis of starting materials.
À
With the optimized catalytic system in hand, we probed its
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309584.
À
scope in the C H functionalization of diversely decorated
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The inexpensive nickel catalyst was not limited to the
functionalization of arenes 1, but heterocyclic indoles 5 served
À
as valuable substrates for the secondary C H bond alkylation
as well (Scheme 3). Both cyclic and acyclic alkyl bromides 2
delivered the desired products 6 with high catalytic efficacy.
À
Scheme 3. Secondary C H alkylations of indoles 5.
Approximately 30% of all agrochemicals and 20% of all
pharmaceuticals contain fluorine, including top-selling anti-
depressant fluoxetine (Prozac).[11] Fluorine uniquely affects
the properties of organic molecules, and thus enhances
solubility, bioavailability, and metabolic stability as compared
to the nonfluorinated analogues. Therefore, there is a signifi-
cant demand for selective syntheses of fluorinated organic
molecules.[11] Thus, it is noteworthy that the versatile nickel
catalyst also enabled challenging direct trifluoroethylation[12]
reactions (Scheme 4). Indeed, the trifluoroethylation through
À
Scheme 1. Scope of nickel-catalyzed secondary C H alkylations.
amides 1 with secondary alkyl bromides 2 (Scheme 1). To our
delight, a variety of electrophilic functional groups was well
tolerated by the versatile nickel catalyst to deliver the desired
products 3 with excellent selectivities for the mono-substi-
tuted form. The transformations of meta-substituted sub-
strates 1h and 1i resulted in highly site-selective direct
À
À
alkylations, exclusively occurring at the less-hindered C H
chelation-assisted C H cleavage was realized with commer-
cially available trifluoroethyl iodide (7) under otherwise
bonds. Notably, a,b-unsaturated amide 1k proved to be
a viable substrate for the secondary alkylation reaction on
alkenes as well. Cyclic alkyl bromides 2b–d with different ring
size afforded the corresponding mono-substituted products
3ab–ad in good yields. Intriguingly, the alkylation with exo-2-
bromonorbornane (2e) delivered product 3ae with retention
of the configuration. Moreover, acyclic secondary alkyl
bromides 2 f–i were found to be amenable to the nickel-
identical reaction condition.
À
catalyzed C H functionalization, proceeding without the
formation of any isomerized or rearranged side-products.
Likewise, significantly less-reactive secondary alkyl chlor-
ides 4 turned out to be viable electrophiles (Scheme 2).
À
Scheme 4. Nickel-catalyzed C H trifluoroethylations.
In light of the unique reactivity profile of the nickel
catalyst, we became interested in probing its mode of action.
To this end, competition experiments between differently
substituted arenes 1 revealed substrates with electron-with-
drawing groups to be preferentially converted (Scheme 5).
À
These findings show that the acidity of the C H bond being
cleaved is clearly important.
Additionally, we performed studies with isotopically
labeled substrate [D]5-1b, revealing a considerable H/D
exchange, exclusively in the ortho-positions of the re-isolated
À
Scheme 2. C H alkylations with secondary alkyl chlorides 4.
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Scheme 5. Intermolecular competition experiments.
substrate [D]n-1b and product [D]n-3ba arenes (Scheme 6).
This finding provided strong support for the occurrence of
À
a reversible C H bond metalation event.
Scheme 6. Direct secondary alkylation with labeled arene [D]5-1b.
In conclusion, we have developed a first nickel-catalyzed
À
C H arene alkylation with challenging secondary alkyl
À
halides. Thus, a robust nickel(II) catalyst enabled C H
activations with cyclic and acyclic alkyl bromides and
chlorides with ample substrate scope. Preliminary mechanis-
À
tic studies indicated the C H metalation to be reversible in
À
nature, and identified the acidity of the C H to be cleaved to
be of importance. Notably, the versatile nickel(II) catalyst
also formed the basis for unprecedented trifluoroethylations
À
of unactivated C H bonds.
Experimental Section
PhMe (1.0 mL) was added to a mixture of benzamide (1a; 131 mg,
0.50 mmol), bromocyclohexane (2a; 163 mg, 1.00 mmol), [(DME)-
NiCl2] (11 mg, 10.0 mol%), BDMAE (32 mg, 40 mol%), and LiOtBu
(80 mg, 1.00 mmol). Thereafter, the reaction mixture was stirred
under N2 at 1608C for 20 h. At ambient temperature, the crude
product was purified by column chromatography on silica gel (n-
hexane/EtOAc 20:1) to yield 3aa as a white solid (148 mg, 86%).
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Received: November 4, 2013
Published online: January 31, 2014
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À
Keywords: auxiliary assistance · C H activation · nickel ·
secondary alkylation · trifluoroethylation
.
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