Synthesis of 2-aminophenols and heterocycles by Ru-catalyzed C-H mono- and dihydroxylation

Article abstract of DOI:10.1021/ol400437a

A novel and efficient synthesis of 2-aminophenols, 2-aminobenzene-1,3- diols, and heterocycles through Ru-catalyzed C-H mono- and dihydroxylation of anilides has been developed with a new directing group strategy. The reaction demonstrates excellent reactivity, regioselectivity, good functional group tolerance, and high yields.

Full text of DOI:10.1021/ol400437a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of 2‑Aminophenols and
Heterocycles by Ru-Catalyzed CꢀH
Mono- and Dihydroxylation
Xinglin Yang,† Gang Shan,† and Yu Rao*
MOE Key Laboratory of Protein Sciences, Department of Pharmacology and
Pharmaceutical Sciences, School of Medicine and School of Life Sciences, Tsinghua
University, Beijing 100084, China
yrao@mail.tsinghua.edu.cn
Received February 15, 2013
ABSTRACT
A novel and efficient synthesis of 2-aminophenols, 2-aminobenzene-1,3-diols, and heterocycles through Ru-catalyzed CꢀH mono- and
dihydroxylation of anilides has been developed with a new directing group strategy. The reaction demonstrates excellent reactivity,
regioselectivity, good functional group tolerance, and high yields.
2-Aminophenol and 2-aminobenzene-1,3-diol derivatives1
are highly valuable building blocks for synthesis, medicinal
chemistry, and materials science. By far the most prevalent
strategies for preparing 2-aminophenol and 2-aminobenzene-
1,3-diol are using the classic sequential nitrationꢀreduction
protocols.2 However, these methods usually suffer from one
or more serious limitations including poor regioselectivity,
harsh reaction conditions, low yields, and tedious reaction
procedures. Therefore, the development of a general, mild,
and practical approach to 2-aminophenol and 2-aminoben-
zene-1,3-diol derivatives still remains an important challenge.
Direct functionalization of CꢀH bonds by a transition
metal has emerged as a powerful method for organic
synthesis in recent years.3 Since in most cases of CꢀH
activation the existing functional group within a substrate
is unsuitable to achieve efficient intramolecular delivery of
a catalyst or reagent, various directing groups (DGs) have
been widely used to achieve the desired regioselectivity.4 In
multistep synthesis, those DGs need to be removed for
further chemical manipulations. However, some DGs are
nonremovable and deprotections of many special DGs
require quite harsh conditions, which will seriously limit
the scope and practicality of those methodologies. Hence,
in comparison with common directing group approaches,
a double-functional DG strategy which can serve as not
only a readily cleavable coordinating group but also an
essential structural component for complex molecule
synthesis would be highly desirable.
† These authors contributed equally.
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r
10.1021/ol400437a
XXXX American Chemical Society

At the beginning of our investigations, we explored dif-
ferent ortho-substituted benzoyl groups, including 2-fluoro-
benzoyl, 2,6-difluorobenzoyl, 2,6-dichlorobenzoyl, 2.4,6-
trifluorobenzoyl, pentafluorobenzoyl, etc., as potential
directing groups under previously reported hydroxylation
reaction conditions. It was found that all these DGs
(1aꢀ1g) were efficient in providing the desired monohy-
droxylation products. To our delight, three benzoyl groups
including 1b, 1c, and 1g showed promising results, produc-
ing both mono- and dihydroxylation products in signifi-
cant amounts respectively (Scheme 1). In parallel, a variety
ofcommon removable DGs were usedascomparison tests.
Among them, trifluoroacetyl1h, methylcarbamate1k, and
imide 1m groups can provide monohydroxylation prod-
ucts, but none or only a trace amount of the corresponding
dihydroxylation products can be observed with these DGs
(1hꢀ1m) by LC-MS analysis.
Figure 1. A new strategy for 2-aminophenol and heterocycle
synthesis.
Recently, Ru(II) catalysts have been successfully em-
ployed in CꢀH hydroxylation of benzoates, benzamides,
and ketones5,6 through weak coordination.7 In our con-
tinuous studies of developing new methods for functiona-
lized 2-aminophenol and heterocycle synthesis, we en-
visioned that an ortho-substituted benzoyl group might
serve as an ideal double-functional DG in Ru(II)-catalyzed
regioselective CꢀH hydroxylation of anilides and the
ensuing heterocycle synthesis with the following presump-
tions. (1) Compared with a benzoate ester (a very weak
coordinating group), a benzamide group having stronger
coordinating ability may feasibly facilitate both the ortho-
selective CꢀH mono- and dihydroxylation8 reaction of
anilides under suitable conditions to provide 2-amino-
phenol and 2-aminobenzene-1,3-diol derivatives. (2) Besides
removal from hydroxylated products, the directing group
(ortho-substituted benzoyl part) itself can be further uti-
lized in the synthesis of heterocycles such as dibenzoxaze-
pines and benzoxazoles. Herein we report the first example
of the synthesis of 2-aminophenols and heterocycles
through Ru(II)-catalyzed CꢀH mono- and dihydroxylation
of anilides with a double-functional DG strategy (Figure 1).
Scheme 1. Screening of Various Directing Groups
Based on the preliminary results of these DGs, com-
pound 1b containing a 2,6-difluorobenzoyl group was
selected for further model study. Then, as shown in Table 1,
optimization of the mono- and dihydroxylation of 1b was
performed. After an extensive testing including varied co-
oxidants, the ratio of TFA/TFAA, additives, etc., it was
(5) Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874.
(6) For Ru-catalyzed CꢀH oxygenation with amide, ketone as a
directing group: (a) Thirunavukkarasu, V. S.; Hubrich, J.; Ackermann,
L. Org. Lett. 2012, 14, 4210. (b) Thirunavukkarasu, V. S.; Ackermann,
L. Org. Lett. 2012, 14, 6206. (c) Yang, F.; Ackermann, L. Org. Lett.
2013, 15, 718.
(7) For CꢀH activation through weak coordinations, see: (a) Engle,
K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (b)
Wang, D.-H.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387. (c) Zhang,
Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 6097. (d)
Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2011, 133, 7222. (e) Giri, R.; Chen, X.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2005, 44, 2122.
(8) For some representative examples of Pd-catalyzed CꢀH oxygen-
ation, see: (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 12790. (b) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7,
4149. (c) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654. (d)
Powers, D. C.; Xiao, D. Y.; Geibel, M. A. L.; Ritter, T. J. Am. Chem.
Soc. 2010, 132, 14530. (e) Emmert, M. H.; Cook, A. K.; Xie, Y. J.;
Sanford, M. S. Angew. Chem., Int. Ed. 2011, 50, 9409. (f) Huang, C.;
Ghavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
2011, 133, 17630. (g) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem.,
Int. Ed. 2012, 52, 13070. (h) Mo, F.; Trzepkowski, L.; Dong, G. Angew.
Chem., Int. Ed. 2012, 52, 13075.
9
noticed that co-oxidant K2S2O8 was generally superior
over other oxidants with a remarkably higher level of
efficiency. Interestingly, when (NH4)2S2O8 was used, only
dihydroxylation product 1b00 can be observed (entry 10). It
was found that a ratio of TFA/TFAA of ∼3:1 is most
suitable for the reaction and the amount of co-oxidants is
the dominating factor for mono- or dihydroxylation se-
lectivity. For instance, the monohydroxylation reaction
will proceed to completion to provide 1b0 with 1.2 equiv of
K2S2O8 (entry 13). In contrast, when higher amounts of
(9) For bystanding persulfate and Fþ oxidants, see: (a) Engle, K. M.;
Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 1478.
(b) Wang, X.; Lu, Y.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132,
12203. (c) Vickers, C.; Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010, 12, 2511. (d)
Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. (e)
Wang, X.; Leow, D.; Yu., J. J. Am. Chem. Soc. 2011, 133, 13864.
B
Org. Lett., Vol. XX, No. XX, XXXX

K2S2O8 (3.0ꢀ4.0 equiv) were used, dihydroxylation prod-
uct 1b00 became the major product (entry 17). We found
that 2.5% equiv amount of [Ru(p-cymene)Cl2]2 was
enough to effectively promote the reaction. A control
reaction showed that omission of the Ru catalyst resulted
in complete inactivity of this catalytic system. Typically
both mono- and dihydroxylation reaction will proceed to
completion within 12 h at 70ꢀ90 °C with 1.2 or 3.0 equiv of
K2S2O8 respectively. To the best of our knowledge, this
represents the first example of Ru(II) catalyzed mono- and
dihydroxylation of anilides.
can be smoothly prepared in satisfactory yields by using
3.0ꢀ4.0 equiv of K2S2O8. It is notable that all of the
reactions demonstrated excellent regioselectivity and re-
activity. Moreover, all dihydroxylation and most mono-
hydroxylation products either are very difficult or need
extra, tedious steps to be prepared with traditional methods.
Table 1. Optimization of the Reaction Conditions
a Conversion ratio by LC-MS. b Isolated yield. c Ru catalyst (5%);
DG = 2,6-difluorobenzoyl.
With the optimal conditions in hand, we next set out to
explore the scope for this new hydroxylation reaction. As
displayed in Figure 2, a variety of anilides were smoothly
transformed into the corresponding monohydroxylated
products in good to excellent yields. The scope of the
substituents was found to be very broad. The ortho-,
meta-, and para-substituted aryl groups, as well as the
electron-withdrawing and -donating functional groups
(halides, CF3, ester, methyl, methoxyl, etc.) were well
tolerated. For example, satisfactory yields were observed
withsubstrateswhich containstrong electron-withdrawing
groups, such as F and CF3 (2, 5, 8, 12, 19, 20), especially for
22 and 24 which have two electron-withdrawing groups.
All meta-substituted substrates gave only one regioiso-
meric product (such as 8ꢀ13) due to steric discrimination.
It is noteworthy to point out that the synthesis of 25 is very
challenging due to high steric hindrance and the electron-
poor property of the precursor compound. Besides sec-
ondary benzamides, we were delighted to find that tertiary
benzamides can also be successfully converted to the
desired ortho-hydroxylated products (26ꢀ29). In addition,
the scope of CꢀH dihydroxylation via this transformation
was testedas well. As shown in Figure2, we were pleased to
find that the desired dihydroxylation compounds (30ꢀ38)
Figure 2. Subtrate scope of CꢀH mono- and dihydroxylation.
To prove both the practicality and effectiveness of this
method in the large-scale synthesis, we prepared mono-
and dihydroxylation products 4, 5, 1b0, 1b00, 1h, and 34 on a
gram-scale under the optimized conditions in good yields
(Figure 3). It was found the large-scale reactions can be
smoothly promoted with a verysmall amount of the Ru(II)
catalyst loading (1% for mono- and 2% for dihydro-
xylation). Remarkably, we were very pleased to observe
that even 0.1% [Ru(p-cymene)Cl2]2 can efficiently catalyze
the synthesis of compound 4in a yield of 54%. It is noteworthy
that this protocol was conducted without the need for air- or
moisture-proof conditions. In comparison with conventional
approaches, the current method is advantageous for rapid
access to these types of molecules because of its operational
simplicity and broad availability of starting materials.
To verify the synthetic utility of the new directing
groups, two types of important heterocycles were prepared
with mono- and dihydroxylation products containing
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthesis of Dibenzoxazepine and Benzoxazolea
Figure 3. Gram-scale synthesis.
DGs. As illustrated in Scheme 2, a variety of dibenzox-
azepines (39ꢀ43, 46) and benzoxazoles (44, 45) were readily
synthesized with corresponding mono- and dihydro-
xylation compounds via nucleophilic aromatic substitu-
tion and intramolecular dehydration respectively. It is
worth mentioning that43 and 44 containing a free hydroxy
group are challenging heterocycles by traditional synthetic
approaches. Moreover, the halides from DGs can be
further utilized for ensuing chemical manipulations. For
example, 20,40-fluoride atoms from 42 can readily undergo
nucleophilic aromatic substitution to construct a wide range
of carbonꢀcarbon and carbonꢀheteroatom bonds. Using
known transformations,10 46 can be further transformed
into new Cl-containing analogues of representative anti-
depressant drugs Ioxapine and Amoxapine. Considering
the easy availability of the building blocks, this method
potentially can provide a convenient approach to novel
dibenzoxazepine and benzoxazole analogues for early
drug discovery.
a Conditions: (a) K2CO3 or NaOH, DMF or acetone, 100 °C, 2ꢀ3 h;
(b) p-TsOH H2O, p-xylene, 140 °C, 12 h; isolated yield.
3
Scheme 3. Removal of Directing Groupa
Finally, we showed that this amide directing group can
be easily removed from both mono- and dihydroxylation
products toprovidecorresponding 2-aminophenols47ꢀ49
and 2-aminobenzene-1,3-diol 50 in good to excellent yields
(Scheme 3). It should be pointed out that catechols and
resorcinols can be readily accessed from these products by
Sandemyer reactions.
In summary, a unique and practical directing group
strategy has been developed for the synthesis of a broad
range of 2-aminophenols and 2-aminobenzene-1,3-diols
by Ru-catalyzed CꢀH mono- and dihydroxylation of
easily accessible anilides. The reaction demonstrates
excellent reactivity, regioselectivity, good functional
group tolerance, and high yields. The synthetic utilities
of DGs have been well demonstrated in the facial
removal of DGs and ensuing synthesis of heterocycles.
Further studies into developing new directing group
a Conditions: (a) NH2NH2 xH2O, 100 °C, 3ꢀ4 h.
3
strategies and the scope of this reaction are in progress
in our laboratory.
Acknowledgment. This work was supported by the na-
tional ‘973’ grant from the Ministry of Science and Tech-
nology (Grant No. 2011CB965300), National Natural
Science Foundation of China (Grant No. 21142008), and
Tsinghua University 985 Phase II funds and Tsinghua
University Initiative Scientific Research Program. We
thank Mrs. L. Ma for her help in our studies.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Smits, R.; Herman, D. L.; Stegink, B.; Bakker, R. A.; de Esch,
I. J. P.; Leurs, R. J. Med. Chem. 2006, 49, 4512.
The authors declare no competing financial interest.
D
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