Ru(II)-catalyzed ortho-C-H amination of arenes and heteroarenes at room temperature

Article abstract of DOI:10.1021/ol402515s

The Ru(II)-catalyzed ortho-C-H amination directed by a weakly coordinating amide auxiliary with O-benzoyl hydroxylamines at room temperature has been achieved. This reaction is compatible with heterocycles including pyrazole, thiophene, benzothiophene, furan, benzofuran, and indole.

Full text of DOI:10.1021/ol402515s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ru(II)-Catalyzed ortho-CꢀH Amination
of Arenes and Heteroarenes at Room
Temperature
Ming Shang,† Shao-Hang Zeng,† Shang-Zheng Sun,† Hui-Xiong Dai,*,† and
Jin-Quan Yu*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China,
and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037, United States
hxdai@sioc.ac.cn; yu200@scripps.edu
Received September 2, 2013
ABSTRACT
The Ru(II)-catalyzed ortho-CꢀH amination directed by a weakly coordinating amide auxiliary with O-benzoyl hydroxylamines at room temperature
has been achieved. This reaction is compatible with heterocycles including pyrazole, thiophene, benzothiophene, furan, benzofuran, and indole.
Aryl- and heteroarylamines are ubiquitous among phar-
maceuticals, agrochemical, and organic materials.1 There-
fore, development of efficient synthetic methodologies
toward the construction of CꢀN bonds has attracted con-
siderable attention. Among these methods, the Buchwaldꢀ
Hartwig amination reaction of aryl halides with amines
has been most extensively studied and practiced in both
academic and industrial settings.2 Inspired by a number
of seminal reports on Pd-catalyzed intramolecular CꢀH
amination reactions,3 Pd-catalyzed intermolecular amina-
tion of CꢀH bonds has been developed as an alternative
method for preparing arylamines (Scheme 1).4,5 This new
approach could prove especially valuable when access to
certain aryl halides in a synthetic sequence are challenging.
For example, Pd-catalyzed ortho-CꢀH amination4 has
recently been used to perform a late-stage diversification
of an advanced intermediate affording novel analogues of
hongoquercin A.6 While Pd-catalyzed CꢀH amination
using electrophilic N-benzoyloxyamines allows for the
introduction of a wide range of secondary amines onto
simple benzamide substrates, further development of this
approach using other transition metal catalysts7ꢀ9 could
improve the scope and practicality of this CꢀH amination
† Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ The Scripps Research Institute.
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Amino
Group Chemistry, From Synthesis to the Life Sciences; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2007.
(2) For recent reviews, see: (a) Hartwig, J. F. Acc. Chem. Res. 2008,
41, 1534. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,
47, 6338.
(4) For Pd-catalyzed intermolecular CꢀH amination with alkyla-
mines, see: Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 7652.
(3) For examples of intramolecular Pd-catalyzed CꢀH amination
reactions, see: (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 14560. (b) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 14058. (c) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias,
M.; Beck, E. M.; Gaunt, M. J. Am. Chem. Soc. 2008, 130, 16184. (d) Mei,
T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. (e)
(5) For Pd-catalyzed intermolecular CꢀH amidation, see: (a) Thu,
H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (b) Ng,
K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010, 132, 12862. (c)
Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem. Soc. 2011,
133, 1466. (d) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am.
Chem. Soc. 2011, 133, 1694. (e) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.;
Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (f) Sun, K.; Li, Y.; Xiong, T.;
Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694.
€
Neumann, J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed.
2009, 48, 6892. (f) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
3676. (g) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7. (h)
He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012,
134, 3.
(6) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu,
J.-Q.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 7458.
r
10.1021/ol402515s
XXXX American Chemical Society

reaction. Herein, we report the Ru-catalyzed ortho-CꢀH
amination of benzamides with N-benzoyloxyamines at
room temperature (Scheme 1), demonstrating the superior
reactivity of our weakly coorindating directing group with
Ru(II) catalysts. The scope of this reaction is substantially
broader than our Pd-catalyzed CꢀH amination reaction4
with respect to heteroarenes, which typically inhibit CꢀH
activation.
acetone was also a suitable solvent which is not commonly
used in Pd-catalyzed CꢀH activation (Table 1, entry 4).
We also found that the oxidant is not required for this
reaction [see the Supporting Information]. Extending the
reaction time to 36 h afforded a mixture of mono- and
diproduct in44% yield with a 3.4:1 mono/di ratio (entry 6).
Attempts to further improve the yield by extending the
reaction time was not successful (entry 7).
The strong coordination of nitrogen atoms in either the
aminating reagents or products to the Pd center could
be problematic for developing CꢀH amination activa-
tion reactions assisted by σ-chelation of simple functional
groups. We have recently developed an efficient electron-
deficient amide auxiliary for CꢀH activation of carboxylic
acid substrates. The origin of the observed reactivity of this
auxiliary stems from (a) in situ generation of the imidate
allowing for optimum orientation between the directing
atom and the target CꢀH bond required for facile CꢀH
cleavage and (b) the weakly bound arylpalladium inter-
mediates being highly reactive toward electrophilic or
nucleophilic reaction partners used for functionalizations.
In light of recent progress in Ru(II)-catalyzed CꢀH func-
tionalizations,10 we began to investigate whether this auxil-
iary can be exploited to develop a Ru(II)-catalyzed CꢀH
amination reaction, which will complement our Pd(II)-
catalyzed CꢀH amination reaction in terms of practical
operation and scope. Thus, we were pleased to find that
CꢀH amination of N-arylbenzamide substrate 1a with
2 equiv of N-benzoyloxyamines 2a proceeded in the presence
of 10 mol % [RuCl2(p-cymene)]2 and 2 equiv of K2CO3 in
CH3CN to give the desired amination product 3a in 22%
yield (Table 1, entry 3).
We were surprised to find that the yield increased to
69% (mono/di = 1.7:1) by running the reaction under Ar
(entry 8). To our delight, the yield was further improved to
82% (mono/di = 2.4:1) when the reaction concentration
was increased by 2-fold (entry 9). The use of 3 equiv of
aminating reagent 2a afforded the product 3a in 92% yield
(mono/di = 2:1) (entry 10). Finally, switching 2a to aminat-
ing reagent N-chloroamines 6 decreased the yield to 25%
(entry 12). The use of 5 mol % [RuCl2(p-cymene)]2 gave a
mixture of mono- and diamination products in 54% yield.
Table 1. Optimization of Reaction Conditionsa
time
(h)
yield
(%)b
entry
[Ru]
amine solcent
1
2
3
4
5
6
7
RuH2(PPh3)4
2a
2a
2a
2a
2a
2a
2a
CH3CN
CH3CN
CH3CN
acetone
acetone
acetone
acetone
18
18
18
18
6
0
RuH2(CO)(PPh3)3
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
0
22
23
16
Scheme 1. Transition-Metal-Catalyzed CꢀH Amination with
36
48
34 þ 10(di)
35 þ 12(di)
Electrophilic Amination Reagent
8c
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
2a
2a
2a
acetone
acetone
acetone
36
36
36
44 þ 25(di)
58 þ 24(di)
60 þ 32(di)
9c,d
10c,e [RuCl2(p-cymene)]2
11c,f [RuCl2(p-cymene)]2
2a
6
acetone
acetone
36
36
42 þ 11(di)
25 þ 6(di)
12c
[RuCl2(p-cymene)]2
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [RuCl2-
(p-cymene)]2 (10 mmol %), K2CO3 (0.4 mmol), solvent (1 mL), air, rt.
b Yield determined by 1H NMR analysis of crude reaction mixture using
CH2Br2 as an internal standard. c Ar. d 1a (0.2 mmol), 2a (0.4 mmol). e 1a
(0.2 mmol), 2a (0.6 mmol). f 1a (0.2 mmol), 2a (0.3 mmol).
(8) For examples of Cu(II)-catalyzed CꢀH amination reactions with
amides and anilides, see: (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (b) Uemura, T.; Imoto, S.;
Chatani, N. Chem. Lett. 2006, 35, 842. (c) Brasche, G.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 1932. (d) Wang, Q.; Schreiber, S. L.
Org. Lett. 2009, 11, 5178. (e) Kawano, T.; Hirano, K.; Satoh, T.; Miura,
M. J. Am. Chem. Soc. 2010, 132, 6900. (f) Wang, H.; Wang, Y.; Peng, C.;
Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217. (g) Cho, S. H.;
Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (h) Tran, L. D.;
Roane, J.; Daugulis, O. Angew. Chem., Int. Ed. 2013, 52, 6043.
(9) For a cobalt-catalyzed CꢀH amination of azoles via acid-promoted
nucleophilic attack, see: Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew.
Chem., Int. Ed. 2010, 49, 9899.
To improve this reaction, we tested other Ru catalylsts
and found they were not reactive (Table 1, entries 1, 2). An
extensive screening of reaction parameters showed that
(7) For Rh-catalyzed CꢀH amination reactions: (a) Ng, K.-H.;
Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272. (b) Grohmann, C.; Wang,
H.; Glorius, F. Org. Lett. 2012, 14, 656.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Ru-Catalyzed CꢀH Amination of Arenes Scopea,b
Scheme 3. Ru-Catalyzed CꢀH Amination of Heteroarenes
Scopea,b
a Reaction conditions: 4aꢀ4n (0.2 mmol), 2a (0.6 mmol), [RuCl2-
(p-cymene)]2 (10 mmol %), K2CO3 (0.4 mmol), acetone (1 mL), Ar, rt,
36 h. b Isolated yield.
Scheme 4. Possible Reaction Pathways with Ru(II) Catalyst
yields. Brominated arenes were also compatible in this
reaction, albeit giving lower yields (3k, 3l). Amination of
arene containing an ortho-CF3 group afforded 3m in 71%
yield. Phenyl-substituted arenes also afforded the desired
products in 89% and 52% yields with the ortho-substituted
substrate being more reactive (3n and 3o). A naphthalene
substrate was aminated to give 3p in excellent yield (94%).
Tetrasubstituted arylamines were obtained in good yields
using trisubstituted arenes as substrates (3q and 3r). Next,
we examined the scope of the amine partners. Various
secondary (hetero)cyclic N-benzoyloxyamines containing
the ester and Boc protecting group was successfully incor-
porated into arene substrates in 40ꢀ98% yields (3sꢀ3v).
However, this reaction is largely limited to six-membered
amines. For instance, pyrrolidine is not compatible and
amination with diethyl amine gave the desired product in
20% yield.
a Reaction conditions: 1a-1v (0.2 mmol), 2aꢀ2e (0.6 mmol), [RuCl2-
(p-cymene)]2 (10 mmol %), K2CO3 (0.4 mmol), Acetone (1 mL), Ar, rt,
36 h. b Isolated yield.
With these optimized conditions in hand, we surveyed
the substrate scope of this amination reaction (Scheme 2).
Amination of arenes bearing methyl substitution at ortho-,
meta-, and para-positions gave the desired products in
94%, 81%, and 94% yields respectively (3bꢀ3d). Sterically
bulky t-Bu- and electron-donating MeOꢀ substituents on
arenes were also tolerated (3e and 3f). Amination of
fluorinated and chlorinated arenes proceeded smoothly
to give the corresponding products (3gꢀ3j) in 40ꢀ69%
Considering the importance of heteroaryl amines in
medicinal chemistry, we examined the compatibility of
this amination protocol with a number of heterocyclic
substrates. We were pleased to find that amination of
(10) Recent reviews on ruthenium(II)-catalyzed CꢀH bond functio-
nalization: (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744. (b)
Ackermann, L. Acc. Chem. Res. 2013, 46, DOI:10.1021/ar3002798. (c)
Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879. (d) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211.
Org. Lett., Vol. XX, No. XX, XXXX
C

A was then oxidized to Ru(IV) species B by the aminating
reagent which underwent reductive elimination to give the
desired product. The intermediacy of the Ru(IV) species
in CꢀH arylation was previously studied.11 At this stage,
an electrophilic cleavage of the ArꢀRu(II) bond by
the aminating reagents cannot be ruled out.12 In support
of this pathway, we have also characterized the Arꢀ
1
Ru(II)Ln intermediate A by H NMR (Figure 1). Ln is
mostly likely p-cymene(p-isopropyltoluene) and carbonate
or chloride.
In summary, we have developed a Ru-catalyzed inter-
molecular CꢀH amination directed by a weakly coordi-
nating amide auxiliary. This reaction proceeds at room
temperature demonstrating the efficacy of a weakly co-
ordinating directing group with Ru(II) catalysts. This
new catalytic reaction also provides a potential method
for preparing heteroarylamines.
Acknowledgment. We gratefully acknowledge Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, the CAS/SAFEA International Partnership Pro-
gram for Creative Research Teams, and The Recruitment
Program of Global Experts for financial support.
Figure 1. Comparison of 1H NMR of the substrate 1a and
intermediate A.
heteroarenes including pyrazole, thiophene, benzothio-
phene, furan, benzofuran, and indole proceeded smoothly
to givethe corresponding heteroaryl amines in moderate to
good yields (Scheme 3).
Based on a previous Pd-catalyzed CꢀH amination reac-
tion4 and Ru(II)-catalyzed CꢀH functionalizations,10 we
proposed a preliminary pathway for this amination reac-
tion as shown in Scheme 4. First, the arylruthenium(II)
intermediate A was formed in the presence of base K2CO3.
Supporting Information Available. Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
5680. (b) Berman, A. M.; Johnson, J. S. Synlett 2005, 1799. (c) Berman,
A. M.; Johnson, J. S.; Nora, G.; Miller, M. J. Org. Synth. 2006, 83, 31. (d)
Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219. (e) Campbell,
M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521.
(11) (a) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V.
Org. Lett. 2010, 12, 5032. (b) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.;
Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX