A facile BPO-mediated ortho -hydroxylation and benzoylation of N -alkyl anilines for synthesis of 2-benzamidophenols

Article abstract of DOI:10.1021/ol501293c

A facile benzoyl peroxide (BPO) mediated ortho-hydroxylation and benzoylation of N-alkyl anilines for the synthesis of 2-benzamidophenols has been developed. The reaction tolerates a wide range of functional groups and is a good method for the straightfor

Full text of DOI:10.1021/ol501293c

Letter
pubs.acs.org/OrgLett
A Facile BPO-Mediated ortho-Hydroxylation and Benzoylation of
N‑Alkyl Anilines for Synthesis of 2‑Benzamidophenols
Zhi-Jing Zhang, Xue-Jing Quan, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: A facile benzoyl peroxide (BPO) mediated
ortho-hydroxylation and benzoylation of N-alkyl anilines for
the synthesis of 2-benzamidophenols has been developed. The
reaction tolerates a wide range of functional groups and is a
good method for the straightforward synthesis of valuable 2-benzamidophenols in good yields under mild conditions.
2-Aminophenol and their derivatives are valuable chemicals and
have been widely applied in organic synthesis to synthesize
various pharmaceutical heterocyclic compounds and dyes.1
Conventionally, 2-aminophenols were synthesized by nitration
of phenols sequential with reduction of the nitro group.2
However, the nitration step involves poor regioselectivity to
form 2- or 4-nitro phenol isomers under harsh conditions.
Although an enzyme catalyzed method was also available for
the synthesis of 2-aminophenols, it was limited in substrate
scope.3 Therefore, a novel, practical and mild protocol for the
straightforward synthesis of 2-aminophenols remains highly
desirable.
Recently, transition metal catalyzed chelation assisted C−H
bond functionalization has become a very active area of
research. Pd- or Ru-catalyzed ortho-acyloxylation or ortho-
hydroxylation of a variety of aromatic substrates for the
synthesis of substituted phenols has been developed by several
groups.4−6 Ru-catalyzed ortho-hydroxylation and ortho-benzox-
ylation of anilides has also been developed for the synthesis of
2-aminophenol derivatives.7 In 2012, we developed a Pd-
catalyzed carbonylation of N-alkyl anilines for the synthesis of
isatoic anhydrides.8 The nitrogen atom of N-alkyl anilines was
first discovered to be a directing group in Pd-catalyzed ortho
C−H carbonylation (Scheme 1, eq 1). Inspired by this work,
we hypothesized that Pd-catalyzed ortho C−H bond hydrox-
ylation of the N-alkyl anilines might provide an alternative
route to synthesize 2-aminophenols. However, after extensive
research, a transition-metal-free ortho-hydroxylation of the N-
alkyl anilines by benzoyl peroxide (BPO) was found to
synthesize 2-benzamidophenols straightforwardly (Scheme 1,
eq 2).
Transition-metal-free oxidative ortho hydroxylation of ani-
lines was actually investigated in the 1950s.9 However, the
narrow substrate scope and low yield make the reaction less
applicable in organic synthesis. In this paper, we have improved
the synthetic method and developed an efficient BPO-mediated
ortho-hydroxylation and benzoylation of N-alkyl anilines for the
synthesis of 2-benzamidophenols. The reaction tolerates a wide
range of functional groups and gives the corresponding 2-
benzamidophenols in good yields under mild conditions.
We began our study by investigating the Pd-catalyzed ortho-
hydroxylation of N-methyl aniline 1a. Initially, a variety of
common oxidants were screened in the reaction, but no
reaction occurred. Delightedly, when BPO was used as the
oxidant, an unexpected but valuable 2-benzamidophenol 2a was
observed in 26% yield (Table 1, entry 1). The structure of 2a
was confirmed by X-ray diffraction analysis. However, further
investigation indicated that the Pd(OAc)2 catalyst plays no role
in the reaction (Table 1, entries 2−3). It was a simple BPO-
mediated ortho-hydroxylation and benzoylation of N-methyl
aniline (Table 1, entries 4−5). This interesting result prompted
us to optimize the reaction conditions in order to develop a
synthetically useful process for the direct synthesis of
substituted 2-benzamidophenols from simple N-alkyl anilines.
Therefore, various solvents such as CH3CN, toluene, DMSO,
MeOH, t-BuOH, glycol, and poly(ethylene glycol) (PEG) were
screened to examine if they improved the reaction efficiency
(Table 1, entries 6−12). PEG600 was found to be the most
effective solvent in the reaction, affording the 2-benzamido-
phenol 2a in 47% yield. To further improve the reaction
efficiency, bases which may neutralize the benzoic acid
byproduct in the reaction were screened (Table 1, entries
13−19). NaOAc gives the best result to afford 2a in 62%
yield.10 Other bases are less effective than NaOAc.
Scheme 1. Transformations of N-Methyl Aniline
Received: May 6, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. BPO-Mediated ortho-Hydroxylation and
Benzoylation of N-Methyl Anilines for Synthesis of 2-
a
Benzamidophenols
entry
catalyst
oxidant
BPO
base
solvent
yield (%)
1
Pd(OAc)2
Pd(OAc)2
THF
26
0
2
THF
3
BPO
TBHP
DTBP
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
THF
33
0
4
THF
5
THF
0
6
CH3CN
toluene
DMSO
MeOH
t-BuOH
glycol
24
22
29
23
39
35
47
48
46
56
62
37
51
29
7
8
9
10
11
12
13
14
15
16
17
18
19
PEG600
PEG600
PEG600
PEG600
PEG600
PEG600
PEG600
PEG600
K2CO3
Na2CO3
KOAc
NaOAc
LiOAc
CsOAc
NaOH
a
Reaction conditions: N-methylaniline 1a (0.2 mmol), oxidant (1.5
equiv), base (1.0 equiv) in solvent (2 mL) at 80 °C, 20 h. Isolated
yields. BPO = benzoyl peroxide, DTBP = di-tert-butyl-peroxide,
PEG600 = The average molecular mass of poly(ethylene glycol) is
600.
a
Reaction conditions: 1 (0.2 mmol), BPO (1.5 equiv), NaOAc (1.0
equiv) in PEG600 (2 mL) at 80 °C, 20 h. Isolated yields.
With the optimized conditions in hand, the scope of the
reaction was investigated (Scheme 2). This BPO-mediated
ortho-hydroxylation and benzoylation reaction displayed high
functional-group tolerance and proved to be a facile and general
protocol for the synthesis of substituted 2-benzamidophenols.
N-Methyl anilines substituted with electron-donating groups,
such as methyl and methoxyl, or electron-withdrawing groups,
such as fluoro, chloro, bromo, iodo, acetyl, and ethoxycarbonyl,
all gave the corresponding 2-benzamidophenols 2b−2o in good
to high yields, thus implying that the electronic nature of the
substrates has little influence on the reaction. A single isomer
was obtained when 2- or 4-substituted N-methyl anilines were
used as the substrates. 3-Substituted N-methyl anilines
produced two isomers of the 2-benzamidophenols, such as
the examples listed in the gridline in Scheme 2. It should be
noted that the steric hindrance of the substrates plays a role in
the reaction. A less sterically hindered isomer, such as 2c, 2f,
and 2i, was formed as the major product in the reaction.
Similarly, the slightly lower yields of 2b, 2e, and 2g may be
assumed to be due to the steric hindrance of ortho-methyl or
ortho-methoxyl on the N-methyl anilines. Additionally, when N-
methylnaphthalen-1-amine was used as the substrate, 1-
benzamidonaphthalen-2-ol 2p was also obtained in 77% yield.
Furthermore, anilines with a different substituent on the
nitrogen atom were investigated to extend the reaction scope
(Scheme 3). It was found that anilines with ethyl, isobutyl, allyl,
benzyl, or furfuryl on the nitrogen atom were all tolerated in
the reaction to give the corresponding 2-benzamidophenols
2q−2u in high yields. Cyclic substrates, such as tetrahydro-
quinoline, were also tolerated to afford the desired (8-hydroxy-
Scheme 3. BPO-Mediated ortho-Hydroxylation and
Benzoylation of N-Alkyl Anilines for Synthesis of 2-
a
Benzamidophenols
a
Reaction conditions: 1 (0.2 mmol), BPO (1.5 equiv), NaOAc (1.0
equiv) in PEG600 (2 mL) at 80 °C, 20 h. Isolated yields.
B
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3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone 2v in 46%
yield. In addition, diphenylamine was also tolerated in the
reaction to give the desired N-(2-hydroxyphenyl)-N-phenyl-
benzamide 2w in 53% yield. However, no reaction occurred
when N-acetyl aniline, N,N-dimethylaniline, or simple aniline
was employed as the substrate.9a−d
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oxidation of N-methyl aniline 1 by BPO produces a radical
cation A. Deprotonation and radical migration of A generates a
radical intermediate B.9b Rapid coupling of radical intermediate
B with a free radical forms an intermediate C. Rearomatization
of intermediate C sequential with a 1,4-benzoyl shift through a
5-exo-trig cycle intermediate D gives 2-benzamidophenol 2.
In summary, a facile and efficient BPO-mediated ortho-
hydroxylation and benzoylation of N-alkyl anilines for the
synthesis of 2-benzamidophenols was developed. The reaction
employs readily available N-alkyl anilines as the starting
materials and tolerates a wide range of functional groups.
The reaction provides a practical protocol for the straightfor-
ward synthesis of a variety of valuable 2-benzamidophenols in
good yields under mild conditions. Further studies of the
reaction scope and mechanism are underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral data for all
products, and X-ray data of 2a and 2c′. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guanzhh@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (21272183 and
21002077) and Fund of the Rising Stars of Shanxi Province
(2012KJXX-26).
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C
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(e) Venkateswarlu, V.; Kumar, K. A. A.; Balgotra, S.; Reddy, G. L.;
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(10) The reaction conversion was very good. 2-Benzamidophenol 2a
was isolated as the main product, together with the N,N′-dimethyl-
hydrazobenzene byproduct and a small amount of complex colored
mixtures. A similar result was observed in Schemes 2 and 3. See:
Edward, J. T. J. Chem. Soc. 1956, 222.
D
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