Efficient benzylic and aliphatic C-H oxidation with selectivity for methylenic sites catalyzed by a bioinspired manganese complex

Article abstract of DOI:10.1021/ol4037083

A benzimidazole-based nonheme manganese complex efficiently catalyzes benzylic, aliphatic C-H as well as tertiary C-H oxidation with hydrogen peroxide as the oxidant in the presence of acetic acid as additive. ¹⁸O labeling experiments suggest the reaction may proceed via a high-valent manganese-oxo intermediate.

Full text of DOI:10.1021/ol4037083

Letter
pubs.acs.org/OrgLett
Efficient Benzylic and Aliphatic C−H Oxidation with Selectivity for
Methylenic Sites Catalyzed by a Bioinspired Manganese Complex
Duyi Shen,†,‡ Chengxia Miao,† Shoufeng Wang,† Chungu Xia,† and Wei Sun*,†
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, 730000, PR China
‡University of Chinese Academy of Sciences, Beijing, 100049, PR China
S
* Supporting Information
ABSTRACT: A benzimidazole-based nonheme manganese complex
efficiently catalyzes benzylic, aliphatic C−H as well as tertiary C−H
oxidation with hydrogen peroxide as the oxidant in the presence of
acetic acid as additive. 18O labeling experiments suggest the reaction
may proceed via a high-valent manganese-oxo intermediate.
can mediate the methylene oxidation under mild conditions
and lower catalyst loadings.8
irect oxidation and functionalization of C−H bonds
Dunder mild conditions is an appealing methodology
toward the complex molecule synthesis and the elaboration of
simple hydrocarbon feedstocks into value-added hydroxyl and
carbonyl compounds.1 Biological C−H bond functionalization
is primarily performed by iron-containing enzymes that utilize
dioxygen as the terminal oxidant, such as methane mono-
oxygenase (MMO) and Rieske dioxygenase.2 Inspired by these
metal enzymes, a variety of biomimetic catalytic models
involving transition metals had been developed and applied
to catalyze C−H bond oxidation during the past decades.3
Bioinspired nonheme iron complexes, containing tetradentate
N4 ligands, such as the tripodal TPA (TPA = tris(2-
pyridylmethyl)amine) and linear MEP (MEP = N,N′-
dimethyl-N,N′-bis(2-pyridylmethyl)ethylene-1,2-diamine), can
perform stereospecific alkane hydroxylation using H2O2 as the
oxidant.4 These extensive studies involving nonheme iron
catalysts have provided key insights into the mechanisms about
the alkane C−H oxidation. In 2007, White and co-workers
reported that the [Fe(S,S-PDB)(CH3CN)2](SbF6)2 (PDB =
N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine) catalyst catalyzes
the hydroxylation of complex organic molecules with syntheti-
cally useful yields, but in the presence of acetic acid.5 Costas et
al. demonstrated that the Fe-MCPP complex can efficiently
oxidize C−H bonds under lower catalyst loadings.6 Later,
White applied the same iron catalyst to achieve the methylene
oxidation of a broad range of hydrocarbons.7 Recent work by
Despite previous advances in the oxidations of C−H bond-
catalyzed nonheme iron catalysts, the efficiency of catalysts
need to be further improved from the viewpoint of synthetic
use. In the course of our investigations with nonheme catalysts
for the enantioselective epoxidation of olefins, manganese
complexes generally display higher turnover numbers (TONs)
than those of iron complexes.9−11 Most significantly, one of the
manganese complexes (S-PEB-Mn, Figure 1) based on ligands
Figure 1. Previous reported nonheme Mn complexes.
with chiral diamine derived from proline and two benzimida-
zoles as sp2 nitrogen units can efficiently catalyze the
asymmetric epoxidation of olefins, even in a 0.01 mol %
catalyst loading.9d Despite the fact that nonheme Mn catalyzed
C−H oxidations with H2O2 have been less investigated,12 Nam
et al. reported that Bn-TPEN-Mn(IV)-oxo complex shows high
reactivity in oxidation of C−H bond of ethylbenzene.13
Bryliakov et al. reported the aminopyridine manganese
Costas et al. showed that [Fe-(Me,MePytacn)]2+ Me,MePytacn =
(
1-(6-methyl-2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclono-
nane), pinene-containing nonheme iron catalysts and analogues
Received: December 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol4037083 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
complexes (Figure 1) demonstrate excellent efficiency and
stereospecificity in the oxidation of aliphatic C−H bonds with
acetic acid as the additive.14 Herein, we report a manganese
complex that can catalyze the selective oxidation of secondary
C−H groups and tertiary C−H groups by using H2O2 as the
oxidant in the presence of acetic acid.
Table 1. Screening the Reaction Conditions
The S-PMB ligand (L1) could be prepared easily in good
yield according to the previous method for the synthesis of S-
PEB ligand (Figure 2).9c,d The crystal structure of S-PMB-
b
entry
catalyst
oxidant
AcOH/equiv
yield
1
C1
C1
C1
none
C1
C1
C1
C1
C2
C3
H2O2
0
6
NR
48
2
H2O2
c
3
H2O2
14
14
−
0
68
4
H2O2
NR
60
5
AcOOH
m-CPBA
PhIO
6
trace
NR
trace
15
7
0
8
tBuOOH
H2O2
0
9
14
14
10
H2O2
6
a
Reaction conditions: 3.5 equiv of oxidant diluted with 0.5 mL of
CH3CN was delivered by syringe pump over 30 min to a stirred
solution of catalyst C1 (2.0 × 10−3 mmol, 0.5 mol %), HOAc (5.6
mmol), and substrate (0.4 mmol) in 1.0 mL of CH3CN at rt under Ar
b
c
atmosphere. GC yield with nitrobenzene as an internal standard. 1%
yield of α-methylbenzyl alcohol and 6% yield of α-methylbenzyl
acetate as the byproducts.
Figure 2. Ligand S-PMB (L1) and crystal structure of the
corresponding nonheme manganese complex S-PMB-Mn(OTf)2
(C1).
After the optimized conditions were identified, a series of
derivatives of ethylbenzene containing different substituted
groups on the aromatic ring were subjected to the oxidation
reactions catalyzed by the Mn complex C1. Most of the tested
substrates gave the corresponding ketone in >60% yields
(Table 2, entries 1−3; Table S1, Supporting Information (SI),
entries 1−4). Only oxidation of 4-ethylbiphenyl resulted in a
23% yield of ketone, an additional 5% is acetic ester byproduct
(Table S1 (SI), entry 4). In the case of oxidation of toluene,
trace amount of benzyl alcohol and benzaldehyde were
observed (Table S1 (SI), entry 5). Other benzylic compounds
with bulkier groups were also explored; the reaction provided
the benzophenone in a 70% yield for the oxidation of
diphenylmethane (Table 2, entry 4). An enhanced yield was
afforded for the oxidation of 1,2-diphenylethane because of the
substrate having both identical benzylic sites (Table 2, entry 6).
Oxidation of the benzylic sites in cycloalkanes bearing aromatic
rings was also accomplished. The oxidation of 1,2,3,4-
tetrahydronaphthalene occurs preferentially at one of the
both benzylic sites with a 51% yield of ketone and a 10%
yield of acetic ester with two equiv of H2O2 (Table 2, entry 7).
On the other hand, 51% yield of 1,4-naphthoquinone was
obtained through the desaturation reaction by using of 6.0
equiv of H2O2 (Table S1 (SI), entry 9). Xanthene could be
transformed into carbonyl compound in a 55% yield and an
additional 10% yield of acetic ester (Table 2, entry 8).
Furthermore, oxidation of cyclohexane under optimized
conditions afforded cyclohexanone in 61% yield together with
4% yield of cyclohexanol (Table 2, entry 10). On the other
hand, oxidation at the C3 site was mainly observed in the case
of tert-butylcyclohexane because of the steric influence; a total
49% yield of C3 and C4 ketones were formed (Table 2, entry
12, C3/C4 = 3.7/1).
Mn(OTf)2 (C1) shows a slightly distorted octahedral
manganese center in a cis-α conformation, in which the two
benzimidazole rings are trans to each other and the two triflate
anions are cis to each other.15 The room temperature solution
magnetic moment determined using the method of Evans is 6.1
μB for manganese complex, consistent with high-spin (S = 5/2)
manganese(II).16
The manganese complex C1 was tested as catalyst (0.5 mol
%) for the ethylbenzene oxidation in acetonitrile at room
temperature. H2O2 (3.5 equiv) was added to a reaction tube
under argon over a period of 30 min by using a syringe pump.
The reaction gave no product in the absence of acetic acid
(Table 1, entry 1). To our delight, the reaction provided
acetophenone in 48% yield by using 6.0 equiv of acetic acid as
the additive (Table 1, entry 2). After optimization, best result
(68% yield of acetophenone, Table 1, entry 3) was obtained
when the acetic acid was increased to 14.0 equiv with respect to
the substrate. These reaction conditions were adopted by
Costas et al. in the epoxidation of olefins10,11 and Bryliakov et
al. in the oxidation of unactivated aliphatic C−H bonds.14 It
should be noted that α-methylbenzyl alcohol (1% yield) and α-
methylbenzyl alcohol acetate (6% yield) were observed on the
basis of the GC and GC−MS analysis. These results also
indicate the formation of acetophenone by further oxidation of
α-methylbenzyl alcohol.12e Various oxidants, such as AcOOH,
PhIO, m-CPBA, and tBuOOH, were tested in the oxidation
reaction; only AcOOH as the oxidant led to a comparable result
(Table 1, entries 5−8). Other manganese complexes, S-PMPP-
Mn(OTf)2 (C2) and R,R-MCP-Mn(OTf)2 (C3)17 were also
tested, but both proved not to be efficient ones (Table 1,
entries 9, 10).
B
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Organic Letters
Letter
Table 2. Scope of the Oxidation of Benzylic and Aliphatic
C−H Bonds
Scheme 1. Oxidation of Adamantane and cis-4-Methyl-
cyclohexyl-1-pivalate
a
under the standard oxidation conditions shows a KIE value of
3.9, which indicates that the C−H cleavage is the rate-limiting
step (see SI). Isotopic labeling experiments were also carried
out to reveal the reaction mechanism. Under standard
conditions, oxidation of ethylbenzene in the presence of 20
equiv of H218O resulted in 13.3% of 18O incorporation into
acetophenone (see SI). The high-valent manganese-oxo species
may be involved in the catalytic process, since oxygen exchange
between the high-valent manganese-oxo species and labeled
water could take place via tautomerism.4h,18 Despite the use of
AcOOH or H2O2/AcOH as the oxidant showing similar
reactivity in the oxidations mediated by nonheme catalysts, the
specific role of acetic acid has not yet been clarified.9−11
A
control experiment was performed under the standard reaction
conditions but without substrate; 700 equiv of H2O2 was added
to the reaction system in CD3CN (1.0 equiv of Mn complex C1
and 2800 equiv of acetic acid). After 30 min, no detectable
AcOOH was observed on the basis of the 13C NMR spectrum
(see SI).19 It suggests that acetic acid may serve as a key
additive to promote fast O−O heterolysis of MnIII−OOH
intermediates.20
In summary, a bioinspired manganese complex based on the
ligand with a more rigid diamine derived from proline and two
benzimidazoles was successfully applied to the benzylic and
aliphatic C−H oxidation under mild conditions. The present
nonheme manganese catalyst exhibits good performance in the
oxidation of secondary benzylic, aliphatic C−H bonds as well as
tertiary C−H groups and provides oxidation products in
synthetically valuable yields. Further investigations into the
mechanism and applications of this nonheme system are
currently underway in our laboratory.
a
Reaction conditions: 3.5 equiv of oxidant diluted with 0.5 mL of
CH3CN was delivered by syringe pump over 30 min to a stirred
solution of catalyst C1 (2.0 × 10−3 mmol, 0.5 mol %), HOAc (5.6
mmol), and substrate (0.4 mmol) in 1.0 mL of CH3CN at rt under Ar
atmosphere. Isolated yield (GC yields in the parentheses). With 2.0
equiv of H2O2 as oxidant, 10% yield acetic ester as a byproduct. 10%
b
c
d
e
f
ASSOCIATED CONTENT
yield acetic ester as a byproduct. 4% yield of alcohol. 5% yield of
alcohol.
■
S
* Supporting Information
Procedures for C−H bond catalytic oxidation reactions,
characterization of Mn complex C1 and the products, NMR
copies of the products, and crystal data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
The oxidation of adamantine was also examined by using 1.3
equiv of H2O2, which gave 1-adamantanol as the main product
in 40% yield (Scheme 1(I); 2-adamantanol and 2-adamanta-
none were obtained in 3.5% yield, totally). The hydroxylation
occurs at the more electron-rich tertiary C−H groups, and it
indicates that the catalytic system possess an electrophilic
nature. We also chose cis-4-methylcyclohexyl-1-pivalate as a
substrate to evaluate the capability of complex C1 to
stereospecific hydroxylates tertiary C−H bonds. As expected,
the catalyst exhibits a good selectivity for tertiary C−H bonds
with excellent retention of configuration (Scheme 1(II)).6
To gain further insights into this reaction, we measured the
kinetic isotope effect (KIE) in the oxidation of cyclohexane by
using excess substrate and limited H2O2. The competing
experiment of cyclohexane and the deuterated cyclohexane
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wsun@licp.cas.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (No. 21073210, 21133011, and 21103206) for financial
support.
C
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Letter
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