Metal-free TEMPO-catalyzed oxidative C-C bond formation from Csp 3-H bonds using molecular oxygen as the oxidant

Article abstract of DOI:10.1039/c2cc30684k

An efficient TEMPO-catalyzed oxidative C-C bond formation with two Csp ³-H bonds using molecular oxygen as the oxidant has been developed. The novel transformation provides a new strategy for the TEMPO-O₂ catalysis to construct C-C bonds. The advantages of this method include: (1) relatively mild and neutral conditions; (2) simplicity and safety of operation; (3) a stoichiometric amount of dangerous oxidants, any transition metals, additives, even solvent, is not required.

Full text of DOI:10.1039/c2cc30684k

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COMMUNICATION
Metal-free TEMPO-catalyzed oxidative C–C bond formation from
Csp3–H bonds using molecular oxygen as the oxidantw
Bo Zhang,a Yuxin Cuia and Ning Jiao*ab
Received 31st January 2012, Accepted 15th March 2012
DOI: 10.1039/c2cc30684k
An efficient TEMPO-catalyzed oxidative C–C bond formation
with two Csp3–H bonds using molecular oxygen as the oxidant
has been developed. The novel transformation provides a new
strategy for the TEMPO–O2 catalysis to construct C–C bonds.
The advantages of this method include: (1) relatively mild and
neutral conditions; (2) simplicity and safety of operation; (3) a
stoichiometric amount of dangerous oxidants, any transition
metals, additives, even solvent, is not required.
TEMPO–O2 catalytic system for C–C bond formation, the use
of organomagnesium compounds as the substrates may limit the
further application of such a method. In recent years, the cross
dehydrogenative coupling of C–H bonds for C–C bond formation
has become a powerful strategy.6 However, the direct C–C coupling
from Csp3–H bonds using molecular oxygen as the oxidant is still a
challenging task.7,8 Herein, we describe an unprecedented TEMPO-
catalyzed cross-coupling reaction for C–C bond formation from
two different Csp3–H bonds using molecular oxygen as the oxidant
under mild and neutral conditions (b, Scheme 1).
The construction of C–C bonds is one of the most useful and
fundamental processes in organic synthesis. Recently, the utiliza-
tion of a TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) radical
as a mild organic oxidant for C–C bond formation has attracted
considerable attention.1 In the reported methods, the introduction
of a stoichiometric amount of TEMPO, functionalized starting
materials, or transition metal was usually required. Therefore, the
development of a more environmentally benign and catalytic
oxidation process for C–C bond formation is highly desirable.
On behalf of green and sustainable chemistry,2 molecular
oxygen has been considered as an ideal oxidant, and received
considerable attention in modern oxidative chemistry.3 Although
TEMPOH can be reoxidized to a TEMPO radical by O2, the
mild TEMPO-catalyzed oxidative reactions employing molecular
oxygen as the oxidant are rarely reported.4,5 Recently, Studer
and coworkers disclosed a TEMPO-catalyzed homocoupling
reaction of various organomagnesium compounds for C–C
bond formation using molecular oxygen as the terminal oxidant
(a, Scheme 1).4 Despite its significant breakthrough in the
Acridine derivatives are important skeletons which display a
range of distinctive biological activities.9 As part of our
continuing interest in TEMPO assisted aerobic oxidation,10
we want to try the TEMPO catalyzed C–C bond coupling reaction
with Csp3–H. The study was initiated by investigating the reaction
of 10-methyl-9,10-dihydroacridine 1a with nitromethane 2a in the
presence of 10 mol% of TEMPO at room temperature under 1
atmosphere of O2. Fortunately, the desired coupling product 3aa
was obtained in 47% yield (Table 1, entry 1). Encouraged by this
Table 1 Optimization of reaction conditionsa
Entry Catalyst (mol%) Temp/1C Time/h Yield of 3aab (%)
1
2
TEMPO (10)
TEMPO (10)
NHPI (10)
TEMPO (10)
TEMPO (5)
TEMPO (10)
—
CH3SO3H (10)
TFA (10)
—
RT
40
40
40
40
60
60
40
40
40
40
40
36
36
36
36
36
18
18
62
62
13
13
13
47
90
71
56
64
92
Trace
20
43
11
0
3
4c
5
6
7
8
9
Scheme 1 TEMPO-catalyzed oxidative C–C bond formation using
10d
11e
12f
oxygen as the oxidant.
—
—
36
a State Key Laboratory of Natural and Biomimetic Drugs,
Peking University, Xue Yuan Rd. 38, Beijing 100191, China.
E-mail: jiaoning@bjmu.edu.cn; Fax: +86 010 8280 5297;
Tel: +86 010 8280 5297
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mL), catalyst
(0.02 mmol), stirred at the appointed temperature under O2 (1 atm).
b
d
Isolated yields. c The reaction was carried out in air. DDQ (1.0 eq.) was
b Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, East China Normal University, Shanghai 200062, China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc30684k
employed instead of TEMPO as the oxidant under Ar. e CAN (2.0 eq.) was
employed instead of TEMPO as the oxidant under Ar. f PIDA (2.0 eq.)
was employed instead of TEMPO as the oxidant under Ar.
c
4498 Chem. Commun., 2012, 48, 4498–4500
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result, we decided to screen the reaction conditions. Gratifyingly,
when the reaction was performed at 40 1C, the yield of 3aa was
improved to 90% (Table 1, entry 2). However, another aminoxyl
radical precursor NHPI (N-hydroxy-phthalimide) exhibited
lower efficiency than TEMPO in this transformation (Table 1,
entry 3). When the reaction was carried out in air, the yield was
decreased to 56% (entry 4). Lowering the catalytic amount of
TEMPO to 5 mol% decreased the yield to 64% (entry 5). It is
noteworthy that higher reaction temperature can accelerate the
reaction and produce 3aa in 92% yield (Table 1, entry 6). Only
a trace amount of the desired product 3aa was obtained in the
absence of a TEMPO catalyst (entry 7, Table 1). When a
strong acid such as CH3SO3H or TFA was employed as the
catalyst,8 the results were unsatisfactory in view of the low yields
and long reaction time (Table 1, entries 8 and 9). Other stoichio-
metric oxidants such as 2,3-dichloro-5,6-dicyano-benzoquinone
(DDQ), ammonium nitrate (CAN), phenyliodonium diacetate
(PIDA) were also investigated, the reactions did not execute
well under these conditions (Table 1, entries 10–12).
We then investigated the scope of 9,10-dihydroacridine
(Table 3). Initially, the alkyl substituents on the nitrogen of
the 9,10-dihydroacridine backbone were examined. Besides
methyl, ethyl and propyl were compatible under the reaction
conditions. They provided the desired products in excellent yields
(3ba: 88% and 3ca: 81%). Moreover, the benzyl substituents on
the nitrogen containing electron-rich or electron-deficient groups
were tolerant, affording the desired products 3da–3ha with
excellent yields (73–91%, Table 3). When phenyl substituents
on the nitrogen were employed, satisfactory yields were obtained
(3ia–3la, 68–90%, Table 3). It was noteworthy that the products
3ia–3la contained the triphenylamine unit which was widely applied
in the photoelectric material and hole-transporting material.11
Thus, this class of compounds could have some potential
performance. Interestingly, employing 9,10-dihydroacridine
without N-substituents led to the desirable product 3ma and
the aromatization product 4 in 43% and 57% yield, respectively
(Table 3). Unfortunately, diphenylmethane and its derivatives
did not work under these conditions (see ESIw).
With the optimized conditions in hand, we applied this
strategy to the aerobic oxidative C–C bond formation of
9,10-dihydroacridine 1 with a variety of nucleophilic Csp3–H
substrates 2 (Table 2). When nitroethane and 1-nitropropane
were used as the nucleophiles, the desired products 3ab and 3ac
were obtained in excellent yields (97%, Table 2). Intriguingly,
some cyclic ketones smoothly underwent this transformation
generating the desired products 3ad–3af in moderate to good
yields (37–88%, Table 2). Compared to the reported method,8
3ad could be obtained under 1 atm of molecular oxygen with
shorter reaction time by this protocol. In addition, the noncyclic
ketones also provided the desired products with a low yield which
was attributed to the formation of 10-methylacridin-9(10H)-one 5
(for example 3ag). Notably, malonate and malononitrile could be
used to construct C–C bonds, affording 3ah-3di with good to
excellent yields (76–98%, Table 2).
In addition, when the reaction was carried out in the
absence of nucleophiles 2, the reaction of 1a in CH3CN at
80 1C under 1 atmosphere of O2 quantitatively produced
the oxidation product 5 (eqn (1)). To the best of our knowledge,
the oxidative reaction of benzyl C–H using molecular oxygen
as the oxidant has been achieved by the use of NHPI and O2,
however TEMPO has no catalytic activity in the transformation.12
This chemistry realized the oxidation of benzyl C–H for the first
time by the TEMPO and O2 catalytic system (eqn (1)).
To gain some mechanistic insights into this TEMPO-catalyzed
aerobic oxidative C–C coupling reaction, the intermolecular kinetic
isotopic effects (KIEs) were measured through a competition
Table 3 TEMPO-catalyzed aerobic oxidative C–C coupling of
9,10-dihydroacridines 1 with nitromethane 2aa,b
Table 2 TEMPO-catalyzed aerobic oxidative C–C coupling of
9,10-dihydroacridines 1 with various carbon nucleophiles 2a,b
a
Reaction conditions: see entry 6, Table 1. b Isolated yields. c The reaction
a
b
c
was carried out at 80 1C. d Reaction conditions: 1 (0.2 mmol), 2i (1.0 mmol),
TEMPO (0.02 mmol) in DCE 0.3 mL, stirred at 80 1C under O2 (1 atm).
Reaction conditions: see entry 6, Table 1. Isolated yields. 2a (1.0 mL)
was used.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4498–4500 4499

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process, by subjecting a mixture of the substrates 1a and
[D2]–1a (1 : 1) to the standard conditions.
(c) T. Vogler and A. Studer, Synthesis, 2008, 1979; (d) J. Piera
and J.-E. Backvall, Angew. Chem., Int. Ed., 2008, 47,
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50, 2.
´
2 For reviews on green and sustainable chemistry see: (a) I. T. Horvath
¨
ð1Þ
and P. T. Anastas, Chem. Rev., 2007, 107, 2169; (b) P. Anastas and
N. Eghbali, Chem. Soc. Rev., 2010, 39, 301.
3 For some reviews, see: (a) S. S. Stahl, Angew. Chem., Int. Ed., 2004,
43, 3400; (b) T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem.
Rev., 2005, 105, 2329; (c) M. S. Sigman and D. R. Jensen, Acc. Chem.
The intermolecular kinetic isotopic effect (kH/kD = 4.0)
(eqn. 2) indicates that the cleavage of the benzyl C–H bond is
involved in the rate-determining step.
Res., 2006, 39, 221; (d) J. Piera and J.-E. Backvall, Angew. Chem., Int.
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Ed., 2008, 47, 3506; (e) K. M. Gligorich and M. S. Sigman, Chem.
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ð2Þ
4 For the C–C bond coupling, see: M. S. Maji, T. Pfeifer and
A. Studer, Angew. Chem., Int. Ed., 2008, 47, 9547.
5 For other transformations using the TEMPO–O2 catalytic system,
see: (a) Y.-X. Chen, L.-F. Qian, W. Zhang and B. Han, Angew.
Chem., Int. Ed., 2008, 47, 9330; (b) M. Zhang, C. Chen, W. Ma and
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The mechanism of this transformation is not clear yet.13 We
have tried to synthesize some intermediates such as hydroperoxyl
or hydroxyl intermediates, but failed due to the instability of these
compounds. The benzyl cations may not be involved in this
transformation, because the corresponding ketone 5 (499% yield)
was obtained in the absence of a nucleophile. More detailed
studies are needed to understand the mechanism.
In summary, we have developed an efficient TEMPO-catalyzed
oxidative C–C bond formation with two Csp3–H bonds using
molecular oxygen as the oxidant. The novel transformation
not only provides a simple and efficient approach to modify
9,10-dihydroacridine derivatives at the 9 position under mild and
neutral conditions, but also discovers a new strategy for the
TEMPO–O2 catalysis to construct C–C bonds. The advantages
of this method include: (1) relatively mild and neutral conditions;
(2) simplicity and safety of operation; (3) a stoichiometric amount
of dangerous oxidants, any transition metals, additives, even
solvent, is not required. These advantages make this protocol
very practical. Further studies on the scope, the mechanism, and
the synthetic applications are ongoing in our laboratory.
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8 More recently, by using strong acids such as CH3SO3H as organo-
catalysts, Klussmann and co-workers realized the significant aerobic
oxidative cross-coupling of Csp3–H bonds not adjacent to a nitrogen
atom. In some cases, high pressure (6.0 bar) is required. Only
ketones were used as the nucleophilic Csp3–H partners. See:
´
A. Pinter, A. Sud, D. Sureshkumar and M. Klussmann, Angew.
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H. Paulıkova, J. Plsıkova, Z. Vantova
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, D. Sabolova
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, J. Ungvarsky´ ,
and J. Imrich, Bioorg.
Financial support from National Basic Research Program
of China (973 Program) (Grant No. 2009CB825300) and
National Science Foundation of China (No. 21172006) is
greatly appreciated. We thank Guolin Wu in this group for
reproducing the results of 3ae and 3la.
´
´
´
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Med. Chem., 2011, 19, 1790; (b) X. Luan, C. Gao, N. Zhang,
Y. Chen, Q. Sun, C. Tan, H. Liu, Y. Jin and Y. Jiang, Bioorg. Med.
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13 We thank the referee’s kind suggestions. For a plausible mecha-
nistic discussion, please see ESIw.
Notes and references
1 For some reviews, see: (a) R. A. Sheldon and I. W. C. E. Arends, Adv.
Synth. Catal., 2004, 346, 1051; (b) R. A. Sheldon, I. W. C. E. Arends,
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c
4500 Chem. Commun., 2012, 48, 4498–4500
This journal is The Royal Society of Chemistry 2012