C-H activation/functionalization catalyzed by simple, well-defined low-valent cobalt complexes

Article abstract of DOI:10.1021/ja512728f

A facile C-H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe₃)₄ as catalyst we have developed an efficient and simple protocol for the C-H/hydroarylation of alkynes wit

Full text of DOI:10.1021/ja512728f

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Communication
C–H activation/functionalization catalyzed by
simple, well-defined low valent cobalt complexes
Brendan J. Fallon, Etienne Derat, Muriel Amatore, Corinne Aubert,
Fabrice Chemla, Franck Ferreira, Alejandro Pérez-Luna, and Marc Petit
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Jan 2015
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C–H activation/functionalization catalyzed by simple, well-
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Brendan J. Fallon, Etienne Derat, Muriel Amatore, Corinne Aubert, Fabrice Chemla, Franck Ferreira,
Alejandro PerezꢀLuna, Marc Petit*
UPMC UNIV Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, 75252 Paris
Cedex 05, France.
Supporting Information Placeholder
Furthermore it is difficult to gain mechanistic insight due tothe
complex reaction mixture.
ABSTRACT: A facile C–H activation and functionalization
of aromatic imines is presented using lowꢀvalent cobalt cataꢀ
lysts. Using Co(PMe3)4 as catalyst we have developed an
efficient and simple protocol for the C–H/hydroarylation of
alkynes with an anti selectivity. Deuteriumꢀlabeling experiꢀ
ments, DFT calculations coupled with the use of a wellꢀ
defined catalyst have for the first time shed light on the elusive
black box of cobalt catalyzed C−H functionalization.
Scheme 1. Hydroarylation of alkynes via directed C−H
activation.
The last decade has seen a rapid development in the field of
C–H bond functionalization, and within this area orthoꢀ
directed C–H bond cleavage has proven to be a broadly appliꢀ
cable strategy for the regioselective functionalization of othꢀ
erwise unreactive C–H bonds.1 While much work focused on
secondꢀrow transition metals such as palladium, ruthenium
and rhodium2 (Scheme 1, a) there is an obvious need to develꢀ
op alternatives using the more naturally abundant and cheaper
firstꢀrow transition metals.3 Pioneering work in 1955 by Muꢀ
rahashi demonstrated the ability of cobalt to participate in C–
H functionalization.4 Some notable contributors to this field
include Klein who demonstrated that the use of stoichiometric
electronꢀrich cobalt(I) species, particularly MeCo(PMe3)4,
were capable of promoting cyclometalation of aromatic subꢀ
strates such as aryl ketones, imines and thioketones at low
temperatures (–70 oC).5 Despite these cobalt complexes
demonstrating their potential utility in ortho C−H functionaliꢀ
zation, no catalytic activity was reported. Kisch reported a
series of antiꢀadditions of diarylacetylenes into C−H bonds of
azobenzenes catalyzed by HCo(N2)(PPh3)3 or HCo(H2)(PPh3)3.
Unfortunately this reaction had a very limited scope and the
mechanism remains ambiguous.6 The last five years has seen
an explosion of interest in C–H functionalization catalyzed by
We reasoned that wellꢀdefined electronꢀrich cobalt catalysts
could offer the possibility to achieve C–H functionalization
without reducing agents or additives and thus allow us to
address some of these issues. Based on recent results pubꢀ
lished within our laboratory on the dimerization of arylacetyꢀ
lenes via a C–H activation/hydroalkynylation pathway using
Co(PMe3)4 and HCo(PMe3)4 we postulated these catalysts
could have the potential to participate in the C–H activaꢀ
tion/functionalization of aromatic imines.10, 11 Table 1 summaꢀ
rizes our initial screening of reaction conditions. We chose
imine 1a and diphenylacetylene 2a as our model substrates.
No conversion was observed at rt for Co(PMe3)4, HCo(PMe3°)4,
or HCo(N2)(PPh3)3 (Entries 1ꢀ3). Heating the reaction to 80 C
using HCo(PMe3)4 and Co(PMe3)4, product 3aa could be
isolated in 50 and 60% yield respectively (Entries 4ꢀ5). Much
to our surprise however, and in sharp contrast with Yoshikai’s
results, 3aa was isolated exclusively as the (Z)ꢀisomer, as
determined by Xꢀray crystallography (see SI). Increasing the
reaction temperature to 110 °C in toluene showed no signifiꢀ
cant improvement in yield (Entry 6). On switching from therꢀ
mal to microwave conditions a reduction of the reaction time
was observed (Entry 7). Using the catalyst previously reported
by Kish (Entry 9) a very low yield of 10% was achieved furꢀ
ther emphasizing the specificity of this catalyst to hydroarylaꢀ
tion of azobenzenes.
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iron and cobalt.7, Of particular interest is the cobalt based
quaternary system consisting of CoBr2, P(3ꢀClC6H4)3, neopenꢀ
tylꢀmagnesium bromide and pyridine developed by Yoshikai
to promote the addition of internal alkynes to aromatic imines
through chelationꢀassisted C–H activation (Scheme 1, b).9
Despite these impressive results the use of bimetallic comꢀ
binations as catalytic systems for direct C–H functionalization
suffers limitations; the nature of the active catalytic species
and the precise role of additives remain largely unknown.
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Table 1. Optimization of reaction conditionsa
ran smoothly on gramꢀscale with an identical yield to the
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standard reaction conditions (Entry 4). Substrates bearing a
methyl group in meta position (Entry 6) showed complete
selectivity for the less hindered ortho position which could be
expected based on sterics, while substrates bearing a methoxy,
fluoro and cyano group in the same position (Entries 7ꢀ9)
reacted preferentially at the more hindered ortho position.
Presumably this is due to the secondary directing effect previꢀ
ously reported for cobalt, ruthenium and iridium catalysis.12
A
similar secondary group effect was observed for the methꢀ
ylenedioxy product (Entry 10). The imine derived from 2ꢀ
acetonaphthone also participated in the reaction to afford the
desired product in good yield and reasonable regioselectivity
of 75/25 for both catalysts (Entry 11). Imines derived from
propiophenone and tetralone also yielded the desired comꢀ
pound (Entries 12ꢀ13).
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Table 3. Scope of the alkynes
Further exploration of solvents and reaction temperature led to
the optimal conditions of 1 h at 170 °C (MW) with Co(PMe3)4
(Entry 12). Only a small decrease in yield was observed on
switching to thermal conditions in a sealed tube showing no
significant microwave effect (Entry 14).
Table 2. Scope of the arylꢀiminea
Having explored the scope of the reaction in terms of imine
variation we then focused on other acetylenes (Table 3). Interꢀ
estingly, nonꢀdiarylic acetylenes proved to be much more
active thus lower catalyst loadings and reaction times were
possible. The reaction of TMS protected phenylacetylene with
a variety of paraꢀsubstituted imines proceeded in moderate to
good yields (Entries 1ꢀ4). The insertion showed complete anti-
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stereoselectivity and regioselectivty which was proven by H
NMR after removal of the TMS protecting group by TBAF
(see SI). As seen previously with the addition of diphenylaꢀ
cetylene, metaꢀfluoro substituted imines preferentially reacted
in the more hindered position (Entry 5). We chose imine 1d as
the model substrate for the proceeding reactions due to the
ease at which we could follow the reaction by 1H NMR. Para
and metaꢀsubstituted TMSꢀprotected phenylacetylene reacted
in moderate to good yields with the same regioꢀ and stereoꢀ
selectivity as seen before (Entries 6ꢀ9). TMS protected
pentyne (Entry 10) produced a modest yield of 45 % with
reasonable stereoselectivity of addition (89/11). Due to stabilꢀ
ity issues, the product 3dh of 1ꢀphenylꢀ1ꢀpentyne addition
could not be isolated purely as the imine derivative but instead
With our optimal conditions in hand, we sought to explore
the potential scope of the hydroarylation reaction on a variety
of imines and diphenylacetylene 2a (Table 2). The reaction
proceeded in good yields for paraꢀsubstituted imines (Entries
1ꢀ5). Electronꢀdonating (e.g., OMe), neutral and electronꢀ
withdrawing groups (e.g., F) were all tolerated. The reaction
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was hydrolyzed by 3M HCl (see SI) to afford the correspondꢀ barrier with Co(PMe3)4 is found to be smaller than with
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ing ketone in 50% yield with a lower regioselectivity of the
addition (Entry 11). Next the reactivity of 4ꢀoctyne was exꢀ
plored. It proved to be the most active of all substrates but the
regioselectivity of the C–H activation was difficult to control.
The C–H functionalized product was isolated in 96% yield as
a (70/30) mixture of monoꢀ and dialkenylated compounds
(Entry 12). Finally for this series the bisꢀbutyl substituted
diphenylacetylene was shown to efficiently undergo addition
(Entry 13). It is worth mentioning that using HCo(PMe3)4 as
catalyst allows the formation of same compounds in slightly
lower yields.
HCo(PMe3)4 which is in line with the experimental observaꢀ
tions.
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To probe the reaction mechanism we initially carried out a
series of experiments using deuteriumꢀlabeled imine 1aꢀd5
(Scheme 2). Firstly, combining an equimolar mixture of 1aꢀd5
and 1d no evidence of H/D crossover in the final products was
observed (Scheme 2a). This unambiguously proves that the
olefinic hydrogen atom is a product of intramolecular hydroꢀ
gen transfer excluding any deprotonation step. Secondly,
competition experiment between an excess of 1aꢀd5 and 1a
compared to 2a was ran to determine the kinetic isotopic effect
(Scheme 2b). Values of 1.4 and 1.7 were obtained respectively
for Co(PMe3)4 and HCo(PMe3)4 in agreement with the KIE
(1.05 and 1.65) of the transition states calculated using the
Bell kinetic theory. However, these values are not significant
enough to suggest that the C–H activation is the rate limiting
step. Thirdly, combining imine 1aꢀd5 with two equivalents of
diphenylacetylene in the presence of 50 mol% of HCo(PMe3)4
under standard reaction conditions, we saw no incorporation
of hydrogen in the final product with 3aaꢀd5 isolated in a 20%
yield as the sole compound (Scheme 2c). Moreover, no eviꢀ
Figure 1. DFT calculated transition state structures for
the C–H activation
Secondly, the structural similarity between the two transiꢀ
tion states can be explained by the fact that the orbital involvꢀ
ing the unpaired electron (namely dz2) in the Co(0) species
shows no interaction with the migrating hydrogen. Nevertheꢀ
less, the cobaltꢀhydrogen distance is shorter in the Co(0) speꢀ
cies. Thirdly, to understand the mechanism of C–H activation,
topological analyses were performed, namely using AIM and
ELF schemes. It appears that, according to AIM, there is a
bonding between cobalt and hydrogen during the transfer.
According to ELF methodology, one electron is always assoꢀ
ciated to the proton during hydrogen transfer (see SI). Thus,
this C–H activation pattern can be designated as a metalꢀ
assisted σ bond metathesis, also termed in a more general way
ligandꢀtoꢀligand hydrogen transfer (LLHT) as coined by Eiꢀ
senstein and Hall.13
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dence of oxidative addition was observed by H NMR when
heating HCo(PMe3)4 in the presence of the imine. From these
observations we postulated that the C–H bond activation and
functionalization proceed in a concerted manner for the hydroꢀ
complex.
Scheme 2. Deuterium labeling and KIE experiments
Putting together the closeness of the KIE values, the same
regioselectivity14 for the naphthalene compound 3ka and the
similarity of the calculated TS, we can propose the following
common catalytic cycle for both catalysts (Scheme 3).15 Ligꢀ
and exchange between trimethylphosphine, the imine and
alkyne leads to the formation of intermediate (I). A concerted
hydrogen transfer via an oxidative pathway generates intermeꢀ
diate (II). Intermediate (II) undergoes a reductive elimination
leading to the formation of intermediate (III). A subsequent
isomerization would account for the observed anti selectivity.
Indeed, we calculated that at 170°C antiꢀ3aa is 2.27 kcal more
stable than syn-3aa, high enough to achieve complete isomeriꢀ
zation. Indeed, the ability of cobalt to participate in the isomꢀ
erization of double bonds is well known.16 Shibata reported a
simple cationic iridiumꢀcatalyzed addition of aryl ketones to
alkynes which allowed us access to the ketone with synꢀ
stereochemistry.17 Introduction of this ketone into our catalytic
system resulted in an isomerization of 55 % to our observed
anti product suggesting that the postꢀ isomerization is a feasiꢀ
ble pathway. Complete isomerization was not observed in this
case presumably due to the weaker anchoring group effect of
ketones compared to imines.11, 18
To further substantiate this claim a series of computational
studies namely, DFT calculations were performed on the key
step of the catalytic process (the C–H activation). The Turboꢀ
mole program was used in conjunction with the B3LYP funcꢀ
tional complemented by an empirical scheme to describe disꢀ
persion and a doubleꢀzeta polarized basis set (see SI). To find
a relevant transition state, it was mandatory to remove three
phosphines from the metallic centre in order to accommodate
simultaneously imine and alkyne. The two catalysts
Co(PMe3)4 and HCo(PMe3)4 were investigated and led to globꢀ
ally similar transition state (TS) structures (Figure 1). It is
noteworthy to mention the following observations. Firstly, the
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(5) (a) Klein, H.ꢀF.; Beck, R.; Flörke, U.; Haupt, H.ꢀJ. Eur. J. In-
Scheme 3. Proposed catalytic cycle
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In conclusion we have demonstrated the utility of simple
wellꢀdefined lowꢀvalent cobalt catalysts to carry out C–H
functionalization without the need for reducing agents or addiꢀ
tives. Moreover, for a wide scope of substrates antiꢀselectivity
was observed for this hydroarylation process. Additionally
deuteriumꢀlabeling studies and computational studies of our
simple catalysts have allowed us to gain greater mechanistic
insight than previously reported for cobalt catalyzed C–H
functionalization.
Ackermann,
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and phyꢀ
sical properties of compounds. This material is available free
of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
marc.petit@upmc.fr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by CNRS, MRES, UPMC and ANR
(ANRꢀ12ꢀBS07ꢀ0031ꢀ 01COCACOLIGHT) which we grateꢀ
fully acknowledge. ED thanks the program ANRꢀ12ꢀBS07ꢀ
0024 (CarBioRed) for computational resources.
(14) In our previous work (ref 10) we observed the same tendency.
(15) Stability of the catalysts was explored (see SI).
(16) Schmidt, A.; Nödling, A.; Hilt, G. Angew. Chem. Int. Ed.
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