Nickel-Catalyzed C?H Chalcogenation of Anilines

Article abstract of DOI:10.1002/chem.201603092

The C?H thiolation of aniline derivatives was accomplished with a versatile nickel(II) catalyst under ligand-free conditions. The robust nature of the nickel catalysis system was reflected by the C?H thiolation with a good functional group tolerance and an ample scope, employing anilines possessing removable directing groups. The widely applicable nickel catalyst also allowed for aniline C?H selenylations, while mechanistic studies provided strong support that the rate-determining step is the C?H activation.

Full text of DOI:10.1002/chem.201603092

A Journal of
Accepted Article
Title: Nickel-Catalyzed CH Chalcogenation of Anilines
Authors: Thomas M u¨ ller; Lutz Ackermann
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To be cited as: Chem. Eur. J. 10.1002/chem.201603092
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Nickel-Catalyzed C‒H Chalcogenation of Anilines
[
a]
[a]
Thomas Müller and Lutz Ackermann *
Abstract: The C‒H thiolation of aniline derivatives was
accomplished with a versatile nickel(II) catalyst under ligand-free
conditions. The robust nature of the nickel catalysis regime was
reflected by C‒H thiolation with good functional group tolerance and
ample scope, employing anilines possessing removable directing
groups. The widely applicable nickel catalyst also allowed for aniline
C‒H selenylations, while mechanistic studies provided strong
support for rate-determining C‒H activation.
Figure 1. Bioactive drugs derived from 2-aminothiophenes.
2-Aminothiophenols and their selena-analogs are integral
structural motifs of various bioactive compounds, and represent
powerful intermediates in the synthesis of valuable heterocycles
of interest to medicinal chemistry, material sciences and
Our study was initiated by probing various reaction conditions for
[
1]
the envisioned C‒H thiolation of pyrimidyl aniline 1a (Table 1
pharmaceutical industries. For instance, 2-aminothiophenols
provide expedient access to among others substituted
phenothiazines, dibenzothiazepines, and benzothiazoles, which
constitute key scaffolds of various antipsychotic, antidepressant
[
11]
and Table S-1 in the Supporting Information).
Orienting
optimization studies indicated that previously employed nitrogen
and phosphorus ligands proved ineffective in the nickel-
catalyzed aniline C‒H thiolation regime (Table 1, entries 1‒5).
[2]
and immunosuppressive agents (Figure 1). The traditional
syntheses of 2-aminothiophenols are largely based on the
interconversion of prefunctionalized starting materials, leading to
lengthy synthetic operations, along with undesired by-product
formation. During the past decade step-economical C‒H
functionalizations have emerged as a transformative platform,
Thus, among
(DME)NiCl ] and Ni(OTf)
stark contrast to our previous studies,
significantly more pronounced effect than did ligands (entry 6‒
a
set of representative nickel precursors,
[
2
2
provided the best performance. In
[9a,b]
additives exerted a
12), with optimal results being accomplished with MnO
2
(entry
[3]
13‒15). Control experiments confirmed that a nickel catalyst was
avoiding the use of prefunctionalized substrates. In this context,
C‒H chalcogenations have gained considerable momentum,
predominantly relying on the use of precious 4d transition
essential for the C‒H thiolation catalysis (entry 13).
[
a]
[
4]
Table 1. Establishing the nickel-catalyzed C–H thiolation of aniline 1.
metals. In light of the economic benefits associated with 3d
transition metal complexes, recent focus has however shifted
[5]
towards the use of earth-abundant base metal catalysis, with
considerable advances being realized in nickel-catalyzed C‒H
[
6]
activations.
Despite the undisputable progress in nickel-
[
7]
catalyzed C‒H thiolation, the previously established methods
were largely restricted to electron-deficient benzamide
[
8]
derivatives bearing bidentate directing groups. Within our
[
9]
program on nickel-catalyzed C‒H transformations, we have
now developed unprecedented nickel-catalyzed C‒H
entry
[Ni]
ligand
additive
yield (%)
1
2
3
4
5
6
7
8
9
NiCl
2
DtBEDA
DtBEDA
DtBEDA
–
24
14
31
26
31
chalcogenations of aniline derivatives, on which we report herein.
Notable features of our findings include (i) the use of a mono-
dentate pyrimidyl group, (ii) expedient C‒H thiolations and
selenylations of electron-rich anilines, (iii) ligand-free, user-
Ni(acac)
2
–
[(DME)NiCl
[(DME)NiCl
2
]
]
–
2
PPh
3
–
[
10]
Ni(OTf)
Ni(OTf)
Ni(OTf)
Ni(OTf)
Ni(OTf)
Ni(OTf)
Ni(OTf)
2
2
2
2
2
2
2
DtBEDA
DtBEDA
–
friendly nickel(II) catalysis, and (iv) a removable
group approach.
directing
[
[
[
[
[
b]
b]
b]
b]
b]
Zn(OTf)
2
2
50
35
24
18
73
91
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
Zn(OTf)
2 5
V O
FeCl
3
1
0
1
MnO
MnO
2
2
1
1
2
3
4
5
Ni(OTf)
2
PCy
3
MnO
MnO
2
2
68
–
1
1
1
–
–
–
–
[
a]
T. Müller, Prof. Dr. L. Ackermann
Ni(OTf)
2
MnO
MnO
2
96
89
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität
[
c]
Ni(OTf)
2
2
Tammannstraße 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[a]
Reaction conditions: 1a (0.5 mmol), 2a (1.2 equiv), [Ni] (10 mol %), ligand (20 mol %),
LiOtBu (2.0 equiv), additive (1.0 equiv) 1,4-dioxane (1.5 mL), 120 °C, 18 h; yields of
[b]
[c]
isolated products.
0.5 equiv additive.
2
Ni(OTf) (2.5 mol %). DtBEDA = di-tert-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author

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butylethylenediamine
disulfide 2f was identified as a viable substrate likewise, despite
of its remarkable bidentate coordination ability.
Encouraged by these results, we next explored the catalyst’s
versatility in the C‒H thiolation process (Scheme 1). The
optimized protocol was characterized by high levels of positional
selectivities, thereby solely delivering the ortho-thiolated
[
12]
products 3aa‒3na.
The C‒H functionalization with
naphthalene derivative 1i occurred site-selectively at the β-
position, while the peri-C‒H bond remained unchanged. The
conversion of ortho-fluoro-substituted anilines 1a, 1j and 1l
chemo-selectively occurred by C‒H functionalization, while
[
13]
products stemming from C‒F
functionalization were not
observed. C‒H thiolations on meta-decorated arenes 1m and 1n
proceeded preferentially at the less congested C‒H bond. The
robustness of the optimized nickel catalyst was reflected by
tolerating valuable electrophilic functional groups, such as chloro,
bromo and iodo substituents, thus providing a handle for further
diversification. Moreover, the gram-scale synthesis of product
3aa was accomplished in high yields at a significantly reduced
catalyst loading.
Scheme 2. Nickel-catalyzed C–H thiolation with disulfides 2.
The versatility of the optimized nickel catalyst was further
illustrated by allowing for the aniline C‒H selenylation under
otherwise identical reaction conditions. Thus, a variety of aniline
derivatives 1 and diselenides 4 were efficiently converted to the
desired 2-aminoselenophenols
5 (Scheme 3). The C‒H
selenylation proceeded with high positional selectivity and good
tolerance of valuable functional groups.
Scheme 1. Scope of the nickel-catalyzed C–H thiolation of anilines 1, yields of
[
a]
2
isolated products. Ni(OTf) (2.5 mol %).
Subsequently, the scope of viable disulfides 2 was explored
Scheme 2). Indeed, substituents in the para- and the more
(
sterically congested ortho-position were well accepted by the
optimized nickel catalyst. Interestingly, the challenging pyridyl

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The nickel-catalyzed C‒H functionalization was inhibited by the
addition of representative radical scavengers (Scheme 5). These
findings can be rationalized in terms of SET-type processes
being of key relevance.
Scheme 5. Influence of radical scavengers.
Subsequently, we studied the kinetics of the C‒H thiolation
process. Hence, independent experiments with the substrate 1a
and its isotopically labeled [D]
1
-1a revealed a kinetic isotope
effect (KIE) of k /k  5 (Scheme 6), indicating a rate-
H
D
determining C‒H activation.
Scheme 3. C–H Selenation of anilines 1 with diselenide 4, all yields of isolated
[
a]
products. mono/di selectivity in parenthesis.
In consideration of the unique features of the nickel-catalyzed
aniline C‒H chalcogenation, we became attracted to delineating
its mode of action. To this end, we performed intermolecular
competition experiments that highlighted electron-poor anilines
to react preferentially (Scheme 4), thereby rendering an
electrophilic mode of action unlikely to be operative.
Scheme 6. KIE by independent experiments.
Based on our mechanistic findings, we propose a catalytic cycle
to commence by rate-determining C‒H nickelation (Scheme 7).
Then, oxidation by a sulfenyl radical generates a nickel(III)
species that subsequently undergoes reductive elimination. The
active nickel(II) catalyst is proposed to be regenerated by the
action of the disulfide 2, which itself is formed by the action of
Scheme 4. Intermolecular competition experiment.
[
14]
the oxidant MnO
2
.
.

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COMMUNICATION
Acknowledgements
Generous support by the European Research Council under the
European Community’s Seventh Framework Program (FP7
2007–2013)/ERC Grant agreement no. 307535 is gratefully
acknowledged.
Keywords: C‒H activation • mechanism • nickel • selenylation •
sulfenylation
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chalcogenation of aniline derivatives. Thus,
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2
levels of positional control and good chemo-selectivity. The
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thiophenols.
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2

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COMMUNICATION
10.1002/chem.201603092
Thomas Müller, and Lutz Ackermann*
Page No. – Page No.
Nickel-Catalyzed C‒H Chalcogenation
of Anilines
Expedient nickel-catalyzed C‒H thiolations were achieved under ligand-free reaction conditions, which also enabled site-
selective C‒H selenylation with ample scope through a removal directing group strategy.