An efficient Rh/O2 catalytic system for oxidative C-H activation/annulation: Evidence for Rh(I) to Rh(III) oxidation by molecular oxygen

Article abstract of DOI:10.1021/ja404414q

A novel and efficient Rh/O₂ catalytic system has been developed and shown to catalyze highly efficient oxidative C-H activation/annulation reactions, producing a broad range of isoquinolinium salts with high turnover numbers (up to 740). Mechanistic studies provided strong evidence of facile oxidation of Rh(I) to Rh(III) by molecular oxygen facilitated by acid.

Full text of DOI:10.1021/ja404414q

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Communication
An Efficient Rh/O2-Catalytic System for Oxidative C-H Activation/
Annulation: Evidence for Rh(I) to Rh(III) Oxidized by Molecular Oxygen
Guoying Zhang, Lei Yang, Yanyu Wang, Yinjun Xie, and Hanmin Huang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja404414q • Publication Date (Web): 06 Jun 2013
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An Efficient Rh/O2-Catalytic System for Oxidative C-H Activa-
tion/Annulation: Evidence for Rh(I) to Rh(III) Oxidized by Mo-
lecular Oxygen
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Guoying Zhang, Lei Yang, Yanyu Wang, Yinjun Xie, and Hanmin Huang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, P. R. China
Supporting Information Placeholder
to lower atom economy and reduced the appeal of rhodi-
ABSTRACT: A novel and efficient Rh/O2-catalytic sys-
um-catalyzed oxidative couplings and hindered large-
tem has been developed and shown to catalyze highly
scale applications. Hence, efficient method enables O2 as
efficient oxidative C-H activation/annulation reactions,
a sole oxidant to sustain the Rh-catalytic cycle would
producing a broad range of isoquinolinium salts in high
circumvent the need for stoichiometric metal oxidant,
TON (740). Mechanistic studies provide evidence to
and thereby provide an important C-H functionalization
strongly support that molecular oxygen could facilely
oxidize the Rh (I) to Rh(III) facilitated by acid.
protocol for synthesis of isoquinolinium salts. Herein, we
describe a novel Rh/O2 catalytic system that is efficient
for the oxidative coupling of 2-aryl pyridines and alkynes.
Mechanistic studies have disclosed that oxygen acts as a
sole oxidant in the present reaction to efficiently promote
the Rh(I) to Rh(III).
Transition-metal-catalyzed oxidative C-H bond function-
alization has emerged as a powerful tool for the step-
economical construction of C-C bonds in modern organic
Scheme 1. Rh-catalyzed Oxidative Annulation
under Molecular Oxygen
chemistry. Mechanistically, the metal-mediated oxidative
C-H functionalization is usually initiated from higher
oxidation state of the metal catalyst and ended in lower
oxidation state.1 As a result, stoichiometric oxidants are
generally required to sustain the catalytic cycle. Conse-
quently, varieties of oxidants, such as peroxide, metal
oxidant are used in such process, thus resulting in the
generation of undesired waste, especially when metal
oxidants are used. One attractive approach to circumvent
this problem is using O2 as a sole oxidant, in which only
water is produced as a co-product.2 Indeed, O2 has been
successfully used as a sole oxidant for some transition
metal catalyzed C-H activation reactions.2-3 However, to
the best of our knowledge, the Rh-catalyzed oxidative C-
H functionalization with O2 as a sole oxidant has never
been reported.4
With these considerations in mind, an annulation re-
action between 2-phenylpyridine 1a and 1,2-
diphenylethyne 2a in CH3OH at 120 oC was chosen as the
model reaction to investigate the optimized reaction
conditions. [{Cp*RhCl2}2] was firstly used as catalyst
precursor for searching the optimal oxidant (Table 1,
entries 1-7). The combined oxidants system consisted of
stoichiometric Cu(OTf)2 and catalytic amount of AgOTf
(4 mol%) could readily promote the reaction to afford the
desired product 3aa in high yield under argon atmos-
phere (Table 1, entry 1). The structure of 3aa was con-
firmed to contain a pyridoisoquinolinium cation and an
OTf anion by single-crystal X-ray analysis.9 With stoichi-
ometric AgOTf alone, the reaction could also give high
yield (Table 1, entry 2). These results suggested that both
Cu(OTf)2 and AgOTf were suitable as oxidants for this C-
H functionalization. However, the reaction virtually
stopped with stoichiometric Cu(OTf)2 as oxidant, which
indicated that the reaction was most likely initiated with
the cationic Cp*Rh(III) species formed in situ by reaction
of [{Cp*RhCl2}2] with AgOTf. To our delight, almost
quantitative yield (99% yield) was obtained when O2 was
served as terminal oxidant and the reaction was conduct-
ed in the presence of one equivalent of HOTf with cata-
lytic amount of AgOTf as an additive (Table 1, entry 4).
Similar good results were observed when reactions were
conducted in the presence of CF3CO2Ag/TFA and
Isoquinolinium salts are one of the most valuable
backbones in natural alkaloids and widely utilized in in-
dustrial field, such as dyes, paints, insecticides, as well as
pharmaceuticals.5 Although a number of methods are
available for the synthesis of such compounds, many are
limited by the lack of generality, functional group toler-
ance and lengthy synthetic steps.6 In 2008, Jones devel-
oped a novel reaction towards this kind of compounds
with 2-phenylpyridine, N-benzylidenemethylamine and
DMAD via Rh-mediated C-H activation, in which a stoi-
chiometric amount of [{Cp*RhCl2}2] was required.7 In-
spired by this work, the catalytic oxidative coupling of
alkynes with in situ formed N-benzylidenemethylamines
has been established in the presence of catalytic amount
of rhodium or ruthenium (5-10 mol%).8 However, the
stoichiometric amount of silver salts and copper salts
were still required to sustain the catalytic cycle, which led
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AgOTs/HOTs under aerobic conditions, respectively the phenyl ring were tolerated well. Furthermore, when
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(Table 1, entries 6-7). Further investigation of the rhodi-
um catalyst precursors demonstrated that the cationic
Rh(III) species were effective for this reaction and the
best results could be achieved with Cp*Rh(H2O)3(OTf)2
as the catalyst in the presence of one equivalent of acid
under the aerobic conditions (Table 1, entries 8-11). Con-
trol reactions demonstrated that only trace amount of
the annulation product 3aa was obtained in the absence
of acid, indicating the importance of acid (Table 1, entry
12). Finally, when the catalyst loading was lowered from
1 to 0.2 mol%, the reaction still worked well and gave the
identical high yield of the annulation product (Table 1,
entry 13). Further decreasing the catalyst loading to 0.1
mol%, the desired product 3aa was obtained with 74%
yield in prolonged reaction time under other identical
conditions. Notably, this result represents a TON of 740,
which is among the highest reported for oxidative C-H
activation reaction.10
benzo[h]quinoline and 5-bromobenzo[h]quinoline were
subjected to this procedure, 87% and 71% yield of the
annulation products were isolated, respectively (3na,
3oa), which revealed that the quinoline could functional-
ize as useful direction group for this C-H activation.
Moreover, 1-phenyl-1H-pyrazole could also provide the
desired product 3pa in excellent yield under the stand-
ard conditions. It is worth noting that N-benzylidene-1-
phenylmethanamine derivatives are usable for the pre-
sent reaction, affording the corresponding products 3qa-
3sa in decent yields as well.
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Table 2. Substrate Scope of Rh-catalyzed annula-
tion a
Table 1. Optimization of Reaction Conditions a
With these results in hand, we next investigated the
substrate scope of this transformation. As shown in Ta-
ble 2, for 2-phenylpyridines, a series of functional groups,
such as methyl, methoxyl, trifluoromethoxyl, fluoro and
chloro, contained in the phenyl-ring were compatible
with the present Rh/O2 catalytic system, and the desired
products were isolated in excellent yields (3aa-3ia),
which indicated that the present reaction had a good
functional-group tolerance. The reaction of 2-meta-
tolylpyridine 1g and 1,2-diphenylethyne afforded a single
regioisomer 3ga. However, the reaction of 2-(3-
fluorophenyl)pyridine 1h afforded 3ha as a mixture of
regioisomers in a ratio of 10:1. These results suggest that
the rhodium attacks selectively the sterically less hin-
dered C-H bond of the phenyl ring. In addition to phe-
nylpyridine, the reactions of phenylquinolines also pro-
ceeded well, affording the corresponding products in
good to excellent yields (3ka-3ma). The electron-
donating and electron-withdrawing groups contained in
On the other hand, diarylalkynes containing various
electron-rich and electron-deficient functional groups
reacted smoothly to give the corresponding products in
high yields (3ab-3ag). Typical functional groups such as
methoxyl and halide groups were compatible with the
reaction conditions. The aryl alkyl alkynes such as 2h-2i
were also suitable for this reaction, affording the corre-
sponding products (3ah-3ai) in high yields. Further-
more, the challenging dialkyl alkyne 2j successfully un-
derwent this annulation reaction to provide the desired
product 3aj in 78% yield. The unsymmetrical alkynes
gave the desired products in high yields with moderate
regioselectivity (3af-3ai), revealing that the rhodium
selectively attacked the less hindered position of alkynes.
To gain insight into the reaction mechanism, several
experiments for forming cyclometalated rhodium com-
plexes were conducted. The desired five-membered cy-
clometalated Rh(III) complex 4 was isolated in almost
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quantitative yield, when treating Cp*Rh(H2O)3(OTf)2
with ten equivalents of 1a in CH3OH at 120 C for 10
trials provided evidences that O2 has the ability to oxidize
o
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2
3
4
5
6
7
8
the sandwich type Rh(I) species to the Rh(III) species in
presence of acid even at room temperature. The higher
activity of 5 that is prone to be oxidized by molecular
oxygen in the present aerobic oxidation is partially at-
tributed to the special sandwich structure, in which the
redox potential of the corresponding Rh(I) can be in-
creased by the η4-coordination. Finally, both 4 and 5
could catalyze the aerobic C-H activation/annulation
between 1a and 2a to give 3aa in high yield under the
standard conditions, suggesting the plausible intermedi-
acy of 4 and 5 in the catalytic cycle (Scheme 3, Eqs 5-6).
hours (Scheme 2, top). The structure of 4 was character-
ized by X-ray crystallography9 and high-resolution mass
spectrometry (see the Supporting Information). However,
no any desired rhodium complex was detected when the
same reaction conducted at room temperature for 24
hours. These results indicate that high temperature is
required for the cleavage of C-H bond of the phenyl ring.
Further reaction of 4 with 1,2-diphenylalkyne at room
temperature could quickly lead to formation of air stable
complex 5 in five minutes (Scheme 2, bottom). The
unique sandwich structure of 5 was confirmed by X-ray
crystallography,9 in which the pyridoisoquinolinium
moiety are bound to the rhodium-center through η4-
coordination. These results indicate that the Rh(III)-
Rh(I)-Rh(III) catalytic cycle was most likely involved in
the present catalytic reaction.
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On the basis of the results described above and the
precedented reports,4n, 7 a tentative reaction mechanism
for this aerobic C-H activation/annulation reaction is
exemplified in Figure 1. The initial coordination of 2-
phenylpyridine to the Cp*Rh(H2O)3(OTf)2 and the ortho
C-H bond activation take place to generate the five-
membered rhodacycle complex 4, which is the rate-
limiting step of the reaction.11 After ligand exchange to
form A, the regioselective insertion of alkyne into the
rhodium-carbon bond of intermediate A gives the seven-
membered rhodacycle intermediate B. The subsequent
reductive elimination of B releases the complex 5, which
is re-oxidized by molecular oxygen in the presence of
HOTf to regenerate the active catalyst for the next cata-
lytic cycle and give rise to the desired product 3aa.
Scheme 2. Synthesis of Complex 4 (top) and
complex 5 (bottom)
2+
2(-OTf)
3aa
Ph-Py
Rh
H2O
OH2
OH2
HOTf, H2O
1/2 O2 +2 HOTf
-OTf
N
After confirming that 4 could be facilely converted to 5,
we proceeded to execute a set of experiments for eluci-
dating the catalytic cycle of the present reaction. As
shown in Scheme 3, the final product 3aa together with
Cp*Rh(H2O)3(OTf)2 were obtained when the sandwich
type Rh(I)-complex 5 was treated with HOTf in CH3OH
under O2 atmosphere at room temperature for 20 hours
(Scheme 3, Eq 1). However, the reaction was virtually
stopped when the same reaction was conducted in the
absence of O2 (Scheme 3, Eq 2). In addition, the complex
5 quantitatively converted to the desired product 3aa
with formation of 4 in 6 hours by reaction with one
equivalent of 1a and HOTf under the aerobic conditions.
Rh
Rh
H2O
4
N
Ph
-
Ph
OTf
Ph
Ph
5
-OTf
-OTf
Rh
Ph
Ph
Ph
Ph
N
N
Rh
A
B
Figure 1. Proposed Reaction Pathway
Scheme 3. Preliminary Mechanistic Studies
In summary, we have successfully developed a new
and efficient rhodium-catalyzed protocol for synthesis of
isoquinolinium salts from the reaction between arenes
and alkynes through oxidative C-H bond activation and
annulation. Notably, this rhodium-catalyzed aerobic oxi-
dative C-H activation exhibits high reactivity (up to 740
TON), which represents the first Rh/O2 catalytic system
for highly efficient oxidative C-H activation with lower
catalyst loading. Furthermore, the discovery of the facile
oxidation of Rh(I) to Rh(III) with molecular oxygen
would pave the way for establishing some new and effi-
cient Rh-catalyzed oxidative C-H activation reactions.
Further investigations on application of the Rh/O2 sys-
tem in other oxidative C-H activation reactions are cur-
rently underway in our laboratory.
No reaction occurred when the same reaction was per-
formed in the absence of O2 (Scheme 3, Eqs 3-4). These
3
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Supporting Information. Experimental details and full
spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* hmhuang@licp.cas.cn
9
ACKNOWLEDGMENT
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This research was supported by the Chinese Academy of
Sciences, the National Natural Science Foundation of China
(21222203, 21172226 and 21133011).
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(9) CCDC 932849 (3aa), 932850 (5) and 932851 (4) contain
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Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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tions (Scheme 3) suggested that the C-H cleavage was most
likely involved in the rate-limiting step. See Supporting Infor-
mation for details.
(4) For recent selected examples on Rh-catalyzed oxidative
C-H functionalization, see: (a) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407. (b) Ueura, K.; Satoh, T.; Miura, M. J.
Org. Chem. 2007, 72, 5362. (c) Stuart, D. R.; Bertrand-Laperle,
M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474. (d) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew.
Chem. Int. Ed. 2008, 47, 4019. (e) Guimond, N.; Fagnou, K. J.
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