Aerobic oxidation of PdII to PdIV by active radical reactants: Direct C-H nitration and acylation of arenes via oxygenation process with molecular oxygen

Article abstract of DOI:10.1021/cs502126n

A Pd-catalyzed aerobic oxidative C-H nitration and acylation of arenes with simple and readily available tert-butyl nitrite (TBN) and toluene as the radical precursors has been developed. Molecular oxygen is employed as the terminal oxidant and oxygen source to initiate the active radical reactants. Many different directing groups such as pyridine, pyrimidine, pyrazole, pyridol, pyridylketone, oxime, and azo groups can be employed in these novel transformations. The Pd^II/Pd^IV catalytic cycle through a radical process is the most likely pathway for these oxidative C-H nitration and acylation reactions.

Full text of DOI:10.1021/cs502126n

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Article
The Aerobic Oxidation of PdII to PdIV by Active Radical
Reactants: Direct C-H Nitration and Acylation of Arenes
via Oxygenation Process with Molecular Oxygen
Yu-Feng Liang, Xinyao Li, Xiaoyang Wang, Yuepeng Yan, Peng Feng, and Ning Jiao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/cs502126n • Publication Date (Web): 12 Feb 2015
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The Aerobic Oxidation of PdII to PdIV by Active
Radical Reactants: Direct C-H Nitration and
Acylation of Arenes via Oxygenation Process with
Molecular Oxygen
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Yu-Feng Liang,† Xinyao Li,† Xiaoyang Wang,† Yuepeng Yan,† Peng Feng,† and Ning Jiao*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai
200062, China
ABSTRACT. A Pd-catalyzed aerobic oxidative C-H nitration and acylation of arenes with
simple and readily available tert-butyl nitrite (TBN) and toluene as the radical precursors has
been developed. Molecular oxygen is employed as the terminal oxidant and oxygen source to
initiate the active radical reactants. Many different directing groups such as pyridine, pyrimidine,
pyrazole, pyridol, pyridylketone, oxime, and azo groups, can be employed in these novel
transformations. PdII/PdIV catalytic cycle through a radical process is the most likely pathway for
these oxidative C-H nitration and acylation reactions.
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KEYWORDS. C-H functionalization, Oxygen, Nitration, Acylation, Palladium, Radicals,
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Regioselectivity.
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INTRODUCTION:
Palladium-catalyzed C-H functionalization of organic substrates have been developed over the
past decades as powerful and versatile tools in synthetic organic chemistry.1-2 Among them, the
catalytic cycle between PdII and PdIV is one of the major pathway, in which a number of oxidants
such as K2S2O8, TBHP, BQ, DDQ, PIDA etc. have been widely employed (Scheme 1a). On
behalf of the green and sustainable chemistry, molecular oxygen is considered as an ideal
oxidant and offers attractive academic and industrial prospects.3-4 Therefore, the development of
Pd-catalyzed oxidative C-H functionalization with molecular oxygen as oxidant is highly
desirable. Although many protocols have been achieved on this topic under Pd/O2 conditions,
they were almost limited to oxidative Heck type reactions with Pd0/PdII catalytic cycle.4-5 It is
well known that O2 could oxidize Pd0 to PdII based on the standard electrode potential, but can
hardly oxidize PdII to high-valent Pd species under ordinary conditions.6 Therefore, only a few
examples that palladium-catalyzed aerobic oxidation formation of C-N,7 C-C,8 and C-O9 bond
were reported through a reductive elimination process from high-valent Pd intermediates.
Despite the significances of these reactions, the mechanism for the direct oxidation of PdII to
high-valent Pd species is still unclear yet. More recently, Stahl7a and Sanford9a developed a
significant palladium-catalyzed aerobic oxidative C-H functionalization, in which the PdII
intermediates were probably oxidized to PdIV through single electron transfer (SET) process
(Scheme 1b). Inspired by these reactions and our efforts on the aerobic oxidative C-H bond
functionalization,10 we hypothesized that the active radical partner generated in situ could
oxidize PdII to PdIV, and the subsequent reductive elimination may enable the C-H
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functionalization with this radical precursor, providing new strategy for aryl C-H
functionalization (Scheme 1c).
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Scheme 1. Strategies for Palladium-catalyzed C-H Functionalization
Herein, we report an efficient Pd(OAc)2 catalyzed aerobic oxidative C-H nitration and
acylation of arenes via a radical pathway (Scheme 1d). In this chemistry: 1) A radical process is
reasonably involved in this aerobic catalytic cycle between PdII and PdIV species; 2) Simple and
commercial available TBN and toluene are employed respectively as the radical precursors in
these novel aerobic oxidative C-H nitration and acylation reactions. 3) Many kinds of directing
groups (e.g. pyridine, pyrimidine, pyrazole, pyridol, pyridylketone, oxime, and azo groups) can
be used in this direct transformation with broad substrate scope under mild conditions; 4)
Environmentally benign molecular oxygen is employed as both oxidant and reagent.
RESULTS AND DISCUSSION:
According to this hypothesis, it is pre-requisite to find an aerobic oxidative pathway to generate
active radicals, and will be very attractive to start from simple starting materials via dioxygen
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activation,3-4 which would enable the direct oxygenation process using molecular oxygen as the
oxygen source. It is known that the commercial available TBN can decompose into NO radical
and tBuO radical by heating, and then the NO radical could be directly oxidized by O2 to
generate NO2 radical (Scheme 2a).11 On the other hand, on the basis of NHPI (N-
hydroxyphthalimide) catalyzed aerobic oxygenation reactions,12 we envisioned that PINO
(phthalimido-N-oxyl) radical could be smoothly generated with molecular oxygen and the
benzoyl radical can be produced from very simple toluene via single electron transfer (SET)
processes (Scheme 2b). If the above proposed active N-radical and C-radical could be
successfully generated in PdII-catalysis, the following relay of oxidation of PdII-intermediate to
PdIV species and reductive elimination would occur to afford new C-N and C-C bond. In these
cases, Pd-catalyzed ortho nitration and acylation of arenes with dioxygen as the terminal oxidant
could be realized.
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Scheme 2. (a) The Aerobic Oxidative Generation of tBuO Radical and NO2 radical; (b) The
Aerobic Oxidative Generation of PINO Radical and Benzoyl Radical.
Aromatic nitro compounds are important synthetic intermediates for the generation of
pharmaceuticals, dyes, explosives, and materials.13 The classical electrophilic nitration of
arenes14-15 is widely used for the synthesis of nitroarenes. Evidently, these methods suffer from
some disadvantages of poor regioselectivity and limited functional group tolerance under harsh
conditions such as strong acidic systems. In order to prepare nitroarenes at the specific position,
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transition-metal catalyzed coupling type nitration of aryl halides,16 aryl boronic acids17 and other
prefunctionalized arenes18 have been developed. Alternatively, inspired by the development of
directed C-H bond functionalization with a directing group, the synthesis of nitroarenes via direct
C-H bond nitration has been an attractive topic.19 Despite the significances on the specific
nitration position of these methodologies, the employment of expensive nitrite salts such as
AgNO2 as the nitro source and the additional stoichiometric oxidants such as peroxides,
hypervalent iodine oxidants and toxic metal salts, limited their application.
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More recently, simple and readily available nitro source has been employed in the synthesis of
nitroarenes.20-21 Buchwald and coworkers developed an elegant protocol for the regioselective
nitration of prefunctionalized aryl chlorides, triflates, and nonaflates with NaNO2 as a simple
nitro source.20 Alternatively, Li et al. reported a significant Rh-catalyzed C-H nitration of arenes
with NaNO2 assisted by an expensive hypervalent iodine oxidant.21a Therefore, although lots of
nitration approaches have been developed in the past decades,16-21 it is still very attractive to
develop better methodologies with: 1) environmentally benign oxidant, such as molecular
oxygen; 2) broad scope of directing groups in the C-H bond nitration reaction.
On the basis of the above hypothesis, we initiated our investigation by exploring the nitration
of 2-phenylpyridine 1a with simple, readily available TBN22 and O2 as nitro source using
o
Pd(OAc)2 as catalyst. When the reaction was conducted in DCE at 80 C, the ortho-nitration
product 2a was indeed isolated in 31% yield (entry 1, Table 1). Solvent screening showed that
PhCl is a very suitable solvent for this transformation providing the product 2a in 74% yield
(entry 6). Whereas the reactions in other solvents such as CH3CN, tAmyl-OH, CH3NO2 and
toluene showed low efficiency (entries 2-5). The reaction catalyzed by PdCl2 or PdTFA2 gave
lower yield than that catalyzed by Pd(OAc)2 (entries 7-8). The reaction under air instead of pure
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molecular oxygen performed well but produced 2a with a slightly lower yield (entry 9). However,
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the yield of 2a declined dramatically when the reaction temperature decreased to 60 C (entry
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10). The reaction proceeded well in the dark, which indicated that the nitration is not initiated by
photoirradiation (entry 11). As a control, no product 2a was detected in the absence of Pd(OAc)2
catalyst (entry 12). When NaNO2, NaNO3, and NO2 gas were used respectively as nitro source
instead of TBN, the nitration product was not obviously obtained (entries 13-14).
Table1. Optimization of the Reaction Conditionsa
aReaction conditions: 1a (0.3 mmol), catalyst (10 mol%), TBN (2.0 equiv), solvent (1 mL),
o
b
c
stirred at 80 C under O2 (1 atm) for 24 h. Isolated yields. The reaction was carried out under
air (1 atm). d he reaction was carried out at 60 oC. e he reaction was carried out in dark. NaNO3
f
or NaNO2 was used as nitro source instead of TBN. gNO2 gas was used as nitro source instead of
TBN.
As shown in Table 2, a range of 2-arylpyridines underwent this ortho-nitration very well with
TBN and dioxygen. It was found that either an electron-donating group, such as alkyl, alkoxy,
phenyl, or electron-withdrawing group, such as halogen, trifluoromethyl, ethoxycarbonyl, nitro,
at the 4-position (2b-2j), 2-position (2k-2m), or 3-position (2n-2p) of the phenyl ring was
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compatible in this procedure leading to the corresponding nitration products in moderate to good
yields. Consistent with previous Pd-catalyzed C-H functionalization studies,2 the nitration of
meta-substituted 2-arylpyridines occurred selectively at the less hindered position of the aromatic
ring (2n-2p).
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Table 2. Substrate Scope of Nitration of 2-Arylpyridines with TBN and Dioxygena
aStandard conditions: 1 (0.3 mmol), Pd(OAc)2 (10 mol%), TBN (2.0 equiv), PhCl (1 mL), at 80
oC under O2 (1 atm) for 24 h. Isolated yields. b3.0 equiv of TBN was employed at 100 oC.
It is noteworthy that pyrimidine and pyrazole rings were also effective directing groups in this
transformation (4a-4f, Table 3). Moreover, phenyl(pyridin-2-yl)methanone was also tolerant to
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provide the nitration product 4g in moderate yield. Significantly, the sp3 C-H bond of 8-
methylquinoline reacted with 1.0 equiv of TBN and afforded benzyl nitro compound 4h in
moderate yield. Interestingly, the reaction conditions were equally applicable to 2-
aryloxypyridine substrates (4i-4q).
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Table 3. Substrate Scope of Nitration with TBN and Dioxygen Directed by Other Pyridine
Groupsa
DG
DG
Pd(OAc)2 (10 mol%)
PhCl, 100 oC, 24 h
H
NO2
N
O
O
R
R
O
2 (1atm)
3
TBN
4
product
entry
product
N
yield
entry
yield
NO2
O
N
R
N
R1
R2
NO2
4a (79%)
4b (63%)
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2
3
4
R = H
R = 2-CH3
R = 3-OCH3
R1 = H, R2 = H
4i
9
(75%)
4c
(58%)
R1 = H, R2 = 4-CH3
R1 = H, R2 = 4-OCH3
R1 = H, R2 = 4-I
4j (57%)
4k (68%)
4l (56%)
4m (57%)
4n (69%)
4o (73%)
4p (59%)
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R = 3-CH3
N
4d (55%)
OCH3
5
4e (78%)
N
NO2
R1 = H, R2 = 3-CH3
R1 = H, R2 = 2-CH3
R1 = 5-CH3, R2 = H
R1 = 3-CH3, R2 = H
N
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4f (61%)
4g (69%)
N
NO2
O
NO2
7
NO2
N
N
O
17
4q (69%)
N
8a
4h
(56%)
O2N
aStandard conditions: 3 (0.3 mmol), Pd(OAc)2 (10 mol%), TBN (3.0 equiv), PhCl (1 mL), at 100
oC under O2 (1 atm) for 24 h. Isolated yields. b1.0 equiv of TBN was employed at 80 oC.
To investigate the scope of other directing groups in this C-H nitration reaction, we next
examined several different arenes containing oxime groups (Table 4). When acetophenone O-
methyl oxime 5a was tested under the standard nitration conditions, ortho-nitrated product 6a
was isolated in 44% yield. The yield could be improved to 65% when 10 mol% of tetrabutyl
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ammonium bromide (TBAB) was added as an additive into the reaction.23 Acetophenoneoximes
bearing both electron-donating (Me, OMe, tBu) and electron-withdrawing (Br, F) substitutents
were successfully converted into the corresponding ortho-nitrated products (6b-6g). An ortho-
methyl-substituted aryloxime was also tolerant in this transformation to afford the nitration
product (6h). Additionally, when alkylphenone, benzaldehyde, and diarylketone O-methyl
oximes were examined, the transformation still proceeded well to afford the desired products (6i-
6p).
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Table 4. C-H Bond Nitration with TBN and Dioxygen Directed by a Oxime Groupa
aStandard conditions: 5 (0.3 mmol), Pd(OAc)2 (10 mol%), TBAB (10 mol%), TBN (1.5 equiv),
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b
PhCl (1 mL) at 80 C under O2 (1 atm) for 24 h. Isolated yields. The reaction was carried out
with 3.0 equiv of TBN at 100 oC.
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The scope of the reaction with regard to azoarenes was then explored (Table 5).24 The
azoarenes with electron-donating groups proceeded faster than those with electron-withdrawing
groups (8a-8j). When the reaction was performed with 3.0 equiv of TBN at 100 oC, the electron-
deficient azoarenes can produce the desired products in moderate to excellent yields (8d-8f, 8h-
8i). Furthermore, we also examined the electronic effect of substitutents on the regioselectivity
of the ortho-nitration of unsymmetrical azoarenes. The results indicated that the ortho-nitration
reactions occurred mainly on the electron-rich aryl rings (8k-8l).
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Table 5. C-H Bond Nitration with TBN and Dioxygen Directed by a Azo Groupa
R2
R2
Pd(OAc)2 (10 mol%)
TBAB (10 mol%)
N
N
N
N
N
O
O
PhCl, 80 oC, 24 h
NO2
8
R1
R1
O
2 (1 atm)
7
TBN
product
entry
product
yield
entry
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yield
R
N
N
N
N
8j (80%)
8k (64%)
R
NO2
NO2
8a (72%)
8b (60%)
8c (42%)
8d (72%)
8e (89%)
1
R = H
R = CH3
R = OCH3
R = Cl
2
CN
3
4b
N
N
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12
5b
6b
R = CF3
NO2
8f (82%)
R = OCF3
R
N
N
R
N
N
NO2
NO2
8l + 8l',
(75%) (1.5:1)
8g (72%)
8h (41%)
7
8b
R = CH3
R = F
F
N
N
N
N
NO2
9b
8i (45%)
F
NO2
aStandard conditions: 7 (0.3 mmol), Pd(OAc)2 (10 mol%), TBAB (10 mol%), TBN (1.5 equiv),
o
b
PhCl (1 mL) at 80 C under O2 (1 atm) for 24 h. Isolated yields. The reaction was carried out
with 3.0 equiv of TBN at 100 oC.
Hence, our hypothesis was proved reasonable by these positive results. Encouraged by this
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successful radical nitration reaction, then we carried out the aerobic oxidative radical acylation
project (Scheme 1d and Scheme 2b). As expected, under 1 atm of O2, the reaction of 1a with
toluene (9a) as both the acylation reagent and solvent using 10 mol % Pd(OAc)2 and 20 mol %
NHPI as cocatalyst at 80 oC gave the acylation product aryl ketone (10a) in 80% yield with trace
amount of dibenzoylated product formation (Eq. 1).25 Aryl ketones are important structural units
and synthetic precursors in natural products, pharmaceutical compounds, and functional
materials.26 The present acylation reaction provides a simple route for ortho acylation of arenes
with molecular oxygen as the terminal oxidant and oxygen source to afford aryl ketones.
Therefore, the aerobic oxidative nitration and acylation of arenes via dioxygen activation are
successfully achieved through the proposed active radical oxidation strategy.
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Followed these results, the acylation reaction by combination of toluene and molecular oxygen
(Eq. 1) was also expanded to 2-arylpyridines and other arenes with different directing groups
(Tables 6-8). For the 2-arylpyridines substrates (Table 6), the benzene rings with electron-
donating and electron-withdrawing groups proceeded smoothly to give 10a-10d in good to
excellent yields. The reaction of benzo[h]quinoline and 2-arylpyrimidine were also examined
and the excellent yields of products 10e-10g were obtained. 2-Phenoxypyridine could be
benzoylated to generate 10h in moderate yield (Table 6).
Table 6. Acylation Reaction with Pyridine Groupsa
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R
R
Pd(OAc)2 (10 mol%)
CH3
NHPI (20 mol%)
80 oC, 24 h
N
O
N
O
2 (1atm)
Ph
1 or 3
9a
10
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Ph
Cl
N
O
N
O
N
O
N
O
Ph
Ph
Ph
Ph
10a: 80%
(5%)b
10b: 84%
(12%)b
10c: 78%
10d: 70%
(4%)b
H3CO
N
N
N
N
O
N
N
O
O
O
O
Ph
10f
Ph
Ph
Ph
: 62%
(35%)b
10e: 96%
10g: 83%
10h: 43%
aStandard conditions: 1 or 3 (0.5 mmol), Pd(OAc)2 (10 mol%), NHPI (20 mol%), toluene 9a (1
mL) at 80 C under O2 (1 atm) for 24 h. Isolated yields. In some cases, diacylation occurred.
The number in the parentheses is the yield of diacylation product.
o
b
Table 7. Acylation Reaction of O-methyl Oximes with Toluenea
aStandard conditions: 5 (0.5 mmol), Pd(OAc)2 (10 mol%), NHPI (20 mol%), toluene 9a (1 mL)
at 80 oC under O2 (1 atm) for 24 h. Isolated yields. bAt 100 oC.
Subsequently, the acylation reaction of O-methyl oximes was investigated (Table 7). Under
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the optimized acylation reaction conditions (See the Supporting Information), various substitutes
at the para-position of the aryl ring were tolerated well to provide the products 11a-11f in
moderate to good yields. The electron-rich substrates generally provided superior efficiencies to
electron-deficient substrates. The acylation of meta-substituted acetophenone O-methyl oximes
were favored at the less hindered ortho-position, to produce the corresponding products 11g-11i.
An ortho-fluorine-substituted acetophenone O-methyl oxime gave the product in moderate yield
(11j). Moreover, O-methyl oximes which derived from alkylphenone and diarylketone were also
converted to the corresponding products (11k-11q). 4-Chromanone O-methyl oxime, with a
bicyclic scaffold, reacted smoothly (11r). It is noted that the reaction of 5a in 20 mmol scale
afforded 11a in 78% yield, which demonstrates the potential application in synthesis.
We next tested the scope of the toluene derivatives as the simple acyl source (Table 8). p-
Xylene, o-xylene, m-xylene could reacted well to generate the products 11s-11u in good yields.
The reaction only occurred on one methyl group, with the other methyl group remaining intact.
Electron-donating 4-methoxy-toluene gave slightly lower yield (11v). Furthermore, halo groups
(Cl, Br) on aromatic rings were compatible (11w-11x), offering versatile synthetic functionality
for further transformation. Multiple substituted toluenes smoothly executed this reaction with
moderated yields (11y-11z).
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Table 8. Scope of Toluene Derivatives as the Source of Acyla
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aStandard conditions: 5a (0.5 mmol), Pd(OAc)2 (10 mol%), NHPI (20 mol%), toluene
derivatives 9 (1 mL) at 80 oC under O2 (1 atm) for 24 h. Isolated yields.
To obtain mechanistic insights into the present direct C-H nitration reaction, a series of
experiments for mechanistic study were carried out. The reaction of 1a under Ar atmosphere
only produced 2a in 13% yield with 72% of 1a recovered (Eq. 2). The 2-(2-
nitrosophenyl)pyridine 12 was not detected by GC-MS and in situ NMR in this reaction (Eq. 2),
which illustrated that 12 is not the intermediate of this nitration. When the reaction was
performed under 18O2 atmosphere, three products were obtained (2a-16O2, 2a-18O16O, 2a-18O2,
with the ratio of 1:0.78:0.21) (Eq. 3), which demonstrates that the NO2 radical might be
generated from NO radical through different processes under O2 (Scheme 3). It is known that NO
radical could be directly oxidized by O2 to afford NO2 radical (Scheme 3a and 3b) just as our
design for this reaction (Scheme 2a).11 Alternatively, the disproportionation reaction of NO
radical catalyzed by O2 occurs to give NO2 radical (Scheme 3c).22i,27 Clearly, the oxygen atom of
the generated carbonyl group originates from molecular oxygen in the aerobic acylation reaction
proved by the 18O-labeling experiment (Eq. 4).
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Scheme 3. (a) and (b) The Generation of NO2 Radical Through the Direct Oxidation of NO
Radical with O2, (c) The Generation of NO2 Radical Through the Disproportionation of
NO Radical.
Furthermore, a kinetic isotopic effect (KIE) study was also conducted. The intramolecular
kH/kD of 1a was determined to be 2.23 (Eq. 5) and the intermolecular kH/kD was 3.35 (Eq. 6),
which suggested that the C-H activation should be irreversible. Moreover, the reactions were
completely inhibited in the presence of a radical scavenger such as TEMPO or 1,1-
diphenylethylene (Eq. 7), which indicated that a radical process might be involved in this
transformation.
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On the basis of the above studies and reported literatures,7a,9a a catalytic cycle of this Pd-
catalyzed C-H nitration or acylation is illustrated in Scheme 4. The transformation occurs
probably involving 1) the formation of palladacycle intermediate A by directing group assisted
ortho-selective cyclometalation on the benzene ring of the substrate with Pd(OAc)2; 2) oxidative
addition of active radicals (NO2 and tBuO radiacls for nitration, ArCO and PINO radicals for
acylation) to A provides PdIV intermediate28-29 B; 3) C-N or C-O bond formation through
reductive elimination affords the corresponding products along with the regeneration of the PdII
species.
Scheme 4. Proposed Mechanism
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CONCLUSION :
In conclusion, we have developed Pd-catalyzed aerobic oxidative direct regioselective C-H
nitration and acylation reactions with simple, inexpensive, and readily available tert-butyl nitrite
(TBN) and toluene as the radical precursors. Molecular oxygen is employed as the terminal
oxidant and oxygen source to initiate the active radical reactants. Many different directing groups
such as pyridine, pyrimidine, pyrazole, pyridol, pyridylketone, oxime, and azo, can be employed
in these novel C-H nitration and acylation transformations. The reaction proceeds under mild
conditions and shows a broad substrate scope. These reactions may proceed via a Pd-mediated
radical mechanism through the PdII/PdIV catalytic cycle. Further studies to elucidate the detailed
reaction mechanism are ongoing in our group and we hope to disclose it in the near future.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical data for products, NMR spectra
of products. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
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*E-mail: jiaoning@pku.edu.cn
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Basic Research Program of China (973 Program) (grant No.
2015CB856600) and National Natural Science Foundation of China (Nos. 21325206, 21172006),
and National Young Top-notch Talent Support Program are greatly appreciated. We thank Wujie
Zou in this group for reproducing the results of 4i and 6k.
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(25) It should be noted that in our previous work (ref. 12 h), the hydroxylation took place under
the conditions of PdCl2/NHPI/toluene/100 oC, where as the described acylation occurred instead
o
of hydroxylation under the similar conditions of Pd(OAc)2/NHPI/toluene/80 C. The anion or
ligand in catalyst may have crucial influence on the chemselectivity between the hydroxylation
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and the acylation. The reaction temperature and the concentration of reactants are also influential.
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underway in our group for the deep understanding of these aerobic oxidation reactions.
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