Cobalt-catalyzed C-H cyanation of arenes and heteroarenes

Article abstract of DOI:10.1002/anie.201409247

Carboxylate assistance proved to be the key for the success of efficient cobalt(III)-catalyzed C-H cyanations. Thus, an in situ generated cationic cobalt complex was identified as a versatile catalyst for the site-selective synthesis of various aromatic a

Full text of DOI:10.1002/anie.201409247

Angewandte
Chemie
DOI: 10.1002/anie.201409247
À
C H Activation
Hot Paper
À
Cobalt-Catalyzed C H Cyanation of Arenes and Heteroarenes**
Jie Li and Lutz Ackermann*
Abstract: Carboxylate assistance proved to be the key for the
toluenesulfonamide (NCTS; 2).[14] In this context it is note-
worthy that direct cyanations with 2 have thus far only been
accomplished with significantly more expensive rhodium[15–18]
or ruthenium[19] catalysts.[20] Within our program on carbox-
À
success of efficient cobalt(III)-catalyzed C H cyanations.
Thus, an in situ generated cationic cobalt complex was
identified as a versatile catalyst for the site-selective synthesis
of various aromatic and heteroaromatic nitriles with ample
substrate scope.
[21,22]
À
ylate-assisted C H activations,
we report on unprece-
À
dented cobalt-catalyzed C H cyanations which are accom-
plished through carboxylate assistance,[22] and provide expe-
dient access to diversely decorated benzonitriles with ample
scope (Scheme 1).
B
enzonitriles are key structural motifs in numerous impor-
tant drugs, agrochemicals, and natural products.[1–3] The cyano
group also serves as one of the most useful functional groups
in organic synthesis, and can be easily transformed into
substituted amines, ketones, or aldehydes.[4] The most
common procedures for the synthesis of aryl nitriles rely on
classical approaches, including the Sandmeyer[5] or the Rosen-
mund–von Braun reaction.[6,7] These transformations face
severe limitations, such as the use of (super)stoichiometric
amounts of mostly toxic metal cyanides and harsh reaction
conditions. Alternatively, in recent years, transition-metal-
catalyzed cyanations of aryl halides or boronic acids have
been elegantly developed by the groups of Beller, Buchwald,
Gelman, and others.[8] Despite its practical importance, this
strategy requires prefunctionalized substrates, the prepara-
tion of which calls for tedious functional-group interconver-
sions and leads to undesired waste formation.
We initiated our studies by varying reaction conditions for
À
the envisioned C H cyanation of substrate 1a (Table 1).
Initial experiments indicated [Cp*CoI2(CO)][23] to be an
efficient catalyst in the presence of cocatalytic amounts of
AgSbF6 and NaOAc (entry 1), while other cobalt sources
were found to be less effective (entries 2–5). These results are
indicative of the in situ generation of cationic cobalt(III)
acetate[22] catalysts. Among a representative set of acetate
additives, KOAc provided optimal results. Notably, omission
À
Functionalizations of unactivated C H bonds provide
a means for improving the step- and atom-economy in organic
synthesis.[9] While most advances in C H activation chemistry
À
À
Scheme 1. Cobalt-catalyzed C H cyanation.
have been accomplished with expensive second-row transi-
tion-metal catalysts, largely based on rhodium, palladium, or
ruthenium complexes, more naturally abundant first-row
transition-metal compounds have witnessed considerable
recent attention.[10] Particularly, inexpensive cobalt cata-
lysts,[11–13] including high-valent [Cp*CoIII] derivatives,[13c,d]
have in the past few years been identified as increasingly
viable tools for the site-selective functionalization of unac-
[a]
À
Table 1: Optimization of cobalt-catalyzed C H cyanation.
À
tivated C H bonds, yet almost exclusively leading to alkyla-
tions, alkenylations, and arylations.[11–13] Considering the
practical importance of aryl cyanides, we were attracted to
Entry
[Co]
Additive A
Additive B
Yield [%][b]
À
devising reaction conditions for the first cobalt-catalyzed C
H cyanations with the readily available N-cyano-N-phenyl-p-
1
2
3
4
5
6
7
8
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[CoI2]
[Co(acac)2]
[Cp*CoCl2]2
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
–
AgSbF6
AgOAc
AgSbF6
AgSbF6
AgSbF6
AgSbF6
–
AgSbF6
AgSbF6
AgSbF6
AgSbF6
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
AgOAc
KOAc
–
83
0
0
0
[*] M. Sc. J. Li, Prof. Dr. L. Ackermann
30
66
0
33
0
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
9
10
11
KOAc
KOAc
KOAc
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
90
[**] Generous 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 Scholar-
ship Program (fellowship to J.L.) is gratefully acknowledged.
93[c]
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), [Cp*CoI2(CO)]
(2.5 mol%), additive A (5.0 mol%), additive B (5.0 mol%), DCE
(2.0 mL), 1208C, 16 h. [b] Yield of isolated product. [c] 2 (1.5 mmol).
DCE=1,2-dichloroethane, Cp*=C5Me5.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409247.
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of either of the catalystꢀs components resulted in significantly
reduced yields of the desired product 3a (entries 6–10). A
À
C H cyanation with an excess 2 furnished the monocyanated
arene 3a as the sole product (entry 11), thereby highlighting
the excellent chemoselectivity of the cobalt(III) catalyst.
With the optimized cobalt(III) catalyst in hand, we tested
its substrate scope with various N-heteroarylarenes
À
(Scheme 2). The chelation-assisted C H cyanation of the
[a]
À
Scheme 3. Cobalt-catalyzed C H cyanation of the indoles 1.
[Cp*CoI2(CO)] (5.0 mol%), AgSbF6 (10 mol%), KOAc (10 mol%).
ents, such as bromo or amido groups, were efficiently
cyanated, and should allow the synthesis of serotonin
derivatives in a step-economical fashion. Substitution on the
aromatic moiety of the substrates 4 was generally well
À
tolerated by the C H functionalization catalyst (5a–f). Like-
wise, the sterically more congested 3-substituted indole 4g
delivered the desired cyanated product 5g with an excellent
yield upon isolation. Even the sensitive ketone functionality
on the tetrahydroindole 4h remained untouched by the cobalt
catalyst.
The versatile cobalt catalyst was not restricted to cyana-
À
tions on the indole heterocycle. Indeed, the direct C H
functionalization of pyrroles (6; Scheme 4a) and thiophenes
(8; Scheme 4b) occurred with excellent levels of efficacy and
positional selectivity as well.
Intrigued by the outstanding catalytic activity of the
cobalt catalyst through mechanistically unusual carboxylate
assistance, we sought to unravel the mode of action. To this
end, intermolecular competition experiments between the
differently substituted arenes 1 highlighted a slight preference
À
Scheme 2. Substrate scope of cobalt-catalyzed C H cyanation.
meta-disubstituted arenes 1a–c proceeded with excellent
levels of site selectivity at the less sterically hindered position.
Importantly, the cobalt catalyst displayed a remarkable
chemoselectivity wherein a number of valuable electrophilic
groups, such as esters or ketones, were well tolerated. The
fluoro substituent in the substrate 1g featured a considerable
secondary directing group effect,[12,24] thus leading to the site-
selective formation of 3g as the sole product. A variation of
the substitution pattern on the Lewis-basic pyridine moiety
proved to be viable, but did not significantly alter the catalytic
efficacy. We were pleased to observe that synthetically useful
heterocycles, such as pyridines (py), pyrimidine (pym), and
pyrazole, could be utilized as the selectivity ensuring entities.
In contrast, arenes displaying oximes or esters have thus far
not been suitable substrates.
À
in the C H cyanation for the more electron-rich substrate 1b
(Scheme 5).
Thereafter, we exploited the use of the pyrimidine group
for the direct cyanation of the biologically active indole[25]
derivatives 4[26] by a removable directing group approach
(Scheme 3). Interestingly, indoles bearing various 5-substitu-
À
Scheme 4. Cobalt-catalyzed C H cyanation of the heteroarenes 6 and
8.[a] 21% of the 2,4-dicyanated product also isolated.
2
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Scheme 5. Competition experiment between different arenes 1.
Scheme 8. a) Removal of directing group. b) Cobalt-catalyzed one-pot
synthesis of the carboxylic acid 10a. DMSO=dimethylsulfoxide.
desired product 3, while proto-demetalation regenerates the
catalytically active cobalt(III) carboxylate catalyst A.
To illustrate the unique potential of the cobalt(III)-
catalyzed cyanation protocol, we removed the directing
group on the indole 5a (Scheme 8a),[26] and devised a reaction
sequence which resulted in the formal direct carboxylation of
Scheme 6. Cobalt-catalyzed H–D exchange on the arene 1a.
[29]
À
The use of a deuterated cosolvent clearly indicated
a significant H–D exchange solely occurring in the ortho po-
sition of 1a (Scheme 6a). Accordingly, cobalt-catalyzed C H
unactivated C H bonds.
Thus, a one-pot procedure ini-
À
tiated by the cobalt-catalyzed C H cyanation, along with
a facile base-mediated saponification, delivered the desired
carboxylic acid 10 in high yield (Scheme 8b).
À
cyanations with isotopically labeled substrates led to a minor
kinetic isotope effect (KIE) of kH/kD ꢀ 1.0 and kH/kD ꢀ 1.1 for
the inter- and intramolecular KIE, respectively (Sche-
À
Finally, we exploited the cobalt-catalyzed C H cyanation
for the synthesis of the decorated indoles 11–13 (Scheme 9).
Particularly, the high-yielding preparation of the 2-tetrazolyl-
derivative 13 should prove instrumental for the design of
novel bioactive drugs.
me 6b).[27] This data is in agreement with the C H metalation
À
step not being rate-determining. Moreover, a Hammett plot
correlation[28] (sm) was indicative of a change in the rate-
determining reaction step depending on the substitution
pattern of the arene.[27]
Based on our mechanistic studies, we propose the catalytic
À
cycle to initiate by a reversible C H metalation, thus yielding
the cyclometalated complex
B
(Scheme 7). Subsequent
coordination and insertion of 2 furnish the key intermediates
C and D, respectively. Finally, b elimination provides the
À
Scheme 9. Cobalt-catalyzed C H activation towards substituted
indoles.[27]
In summary, we have reported on the first cobalt-
À
catalyzed cyanation of unactivated C H bonds. Thus, car-
boxylate assistance led to a highly active cationic cobalt(III)
catalyst for the direct cyanation of arenes and heteroarenes
with ample scope. The optimized catalytic system tolerated
various functional groups and proved applicable to removable
directing groups. Mechanistic studies revealed an effective
cobalt catalyst for the site-selective ortho deuteration of
À
heteroarylarenes by reversible C H activation. The develop-
ment of related cobalt(III)-catalyzed transformations, such as
halogenations, is currently ongoing in our laboratories and
will be reported in due course.
Scheme 7. Proposed catalytic cycle.
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Received: September 18, 2014
Revised: October 25, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · cobalt · cyanides · heterocycles ·
synthetic methods
.
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4
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Angewandte
Chemie
Communications
À
C H Activation
As directed: The title reactions were
accomplished with in situ generated
cobalt(III) carboxylate complexes for
J. Li, L. Ackermann*
&&&& — &&&&
À
highly efficient C H activations. The
À
Cobalt-Catalyzed C H Cyanation of
Arenes and Heteroarenes
direct cyanation proved viable with
removable directing groups and dis-
played a broad substrate scope and mild
reaction conditions.
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