Rhodium-catalyzed direct addition of aryl C-H bonds to nitrosobenzenes at room temperature

Article abstract of DOI:10.1021/ol403187t

An unprecedented Rh-catalyzed direct addition of aryl C-H bonds to nitrosobenzenes has been developed under very mild reaction conditions (room temperature). The reaction is highly step-, atom-, and redox-economic and compatible with air and water to N-selectively provide a variety of N-diarylhydroxylamines in good to excellent yields. More importantly, this process may provide a new direction for C-N bond formation through direct C(sp²)-H functionalization.

Full text of DOI:10.1021/ol403187t

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6302–6305
Rhodium-Catalyzed Direct Addition of Aryl
CÀH Bonds to Nitrosobenzenes at Room
Temperature
Bing Zhou,* Juanjuan Du, Yaxi Yang, Huijin Feng, and Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, PR China
zhoubing2012@hotmail.com; ycli@mail.shcnc.ac.cn
Received November 5, 2013
ABSTRACT
An unprecedented Rh-catalyzed direct addition of aryl CÀH bonds to nitrosobenzenes has been developed under very mild reaction conditions
(room temperature). The reaction is highly step-, atom-, and redox-economic and compatible with air and water to N-selectively provide a variety of
N-diarylhydroxylamines in good to excellent yields. More importantly, this process may provide a new direction for CÀN bond formation through
direct C(sp2)ÀH functionalization.
Catalytic site-selective CÀH bond functionalizations
have emerged as a powerful tool for the atom-economical
formation of CÀC and CÀheteroatom bonds.1 While
transition-metal-catalyzed arylations of alkene and alkyne
derivatives have been well studied,2 analogous additions
across polar multiple bonds are rare.
Recently, nitrosobenzene has emerged as an attractive
electrophilic source of nitrogen or oxygen in nitroso-aldol
reactions to afford aminoxylation or hydroxyamination
products.3 However, to the best of our knowledge, no
example of direct addition of aryl CÀH bond to nitroso-
benzene (NdO bonds) has been reported, although this is
an attractive and direct method for installing nitrogen or
oxygen into aromatic rings. In recent years, {Cp*RhIII}
complexeshavebeenrecognizedasa promisingcatalystfor
aryl CÀH bond activation and subsequent addition to
polar CdN and CdO groups.4 Inspired by these works
and other Rh(III)-catalyzed arene CÀH bond fuctional-
izations,2,5À7 herein we report the first example of
Rh-catalyzed direct addition of aryl CÀH bond to NdO
bonds without any undesirable waste under very mild
reaction conditions (room temperature). Compared with
traditional addition of organometallic reagents, such as
Grignard reagents, to nitrosobenzenes, this process is
highly step-, atom- and redox-economic, and compatible
with air and water to N-selectively afford synthetically
important N-arylhydroxylamines.8
2-Phenylpyridine (1a) and methyl 4-nitrosobenzoate
(2a) were selected as model substrates (Table 1). While
no coupling occurred when [RhCp*Cl2]2 (2.5 mol %) was
used as a catalyst, addition of a halide abstractor (10 mol %),
AgSbF6, for example, could catalyze the reaction to give
the hydroxyl amine 3ain 20% yield (entry 2). The prepared
RhIII precursor [RhCp*(CH3CN)3](SbF6)2 gave higher
yields (entry 3).The presence of base completely inhibited
the addition reaction (entries 4 and 5), whereas the addi-
tion of an acid such as PivOH and 1-AdCO2H can
significantly effect this addition reaction (entries 8 and 9),
affording 3a in good yield. A screen of the solvents gave
DCE asanoptimalone (entry 10), and the best resultfor 3a
was obtained by using [RhCp*(CH3CN)3](SbF6)2 catalyst,
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CÀH Activation; Springer: Berlin, 2010.
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D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
r
10.1021/ol403187t
Published on Web 11/25/2013
2013 American Chemical Society

PivOH and DCE solvent at room temperature for 4 h
(entry 14). A control experiment revealed that no product
was observed in the absence of rhodium(III) complex
(entry 15). Notably, this catalytic addition reaction can
be performed with excellent efficiency in the presence of a
lower catalyst loading (1 mol %) by simply lengthening the
reaction time to 12 h (entry 16). The regioselectivity of this
addition reaction was confirmed by the single-crystal
X-ray crystallography of compound 3a.9
Table 1. Optimization of Rh-Catalyzed Direct Addition Reactiona
With the optimized reaction conditions, the scope of this
amination reaction was investigated (Scheme 1). Evalua-
tion of substituted 2-arylpyridines showed that introduc-
tion of various electron-rich, electron-poor, and halogen
groups at the para (3bÀg), meta (3h and 3i), and ortho (3j)
positions of the phenyl ring were all well tolerated. For
3-substituted derivatives, functionalization occurred
exclusively para to the substitutions to afford products 3h
and 3i in high yields. In particular, the 2-Me derivative (3j)
entry
catalyst (2.5 mol %)
additive
solvent 3a (%)
1
(Cp*RhCl2)2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
0
20
35
0
2
(Cp*RhCl2)2/AgSbF6
[Cp*Rh(CH3CN)3](SbF6)2
3
4
[Cp*Rh(CH3CN)3](SbF6)2 Cs2CO3
[Cp*Rh(CH3CN)3](SbF6)2 PivOK
[Cp*Rh(CH3CN)3](SbF6)2 Cu(OAc)2
[Cp*Rh(CH3CN)3](SbF6)2 AcOH
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
5
0
6
27
45
72
60
82
54
65
44
90
0
7
8
9
[Cp*Rh(CH3CN)3](SbF6)2 1-AdCO2H PhCl
10
11
12
13
14b
15
16c
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
PivOH
DCE
THF
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PhMe
CH3OH
DCE
DCE
[Cp*Rh(CH3CN)3](SbF6)2 PivOH
DCE
87
a 1a (0.2 mmol), 2a (0.24 mmol), catalyst (0.005 mmol), additive
(0.2 mmol), and solvent (1 mL) at 40 °C for 4 h. Yield of isolated product.
1-AdCO2H = 1-adamantanecarboxylic acid. b The reaction is carried out at
room temperature. c 1.0 mol % of catalyst was used; reaction time =12 h.
also showed excellent reactivity, thus showing high toler-
ance for steric hindrance. Moreover, the present addition
reaction showed excellent functional group tolerance. For
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data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. X-ray structure of 3a:
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Org. Lett., Vol. 15, No. 24, 2013
6303

example, the ester (3d) and halogen (3e, 3f and 3i) groups
were highly compatible with this amination reaction,
enabling further synthetic manipulations. The 4-CN deri-
vative gave a relatively low yield of 3g (40%), presumably
because the CN group competitively coordinates to the
Rh(III) center.4a The substrate scope was further extended
to other directing groups, and a variety of pyridinyl
directing groups were investigated first. The steric bulki-
ness on the pyridine ring had quite a limited effect on this
addition reaction (3kÀn). Significantly, the tricyclic benzo-
[h]quinolone (3o) and other N-based heterocycles such as
pyrimidine (3p) also worked well as efficient directing
groups for this addition reaction.
Scheme 2. Substrate scope of nitrosobenzenes.a
Scheme 1. Substrate Scope for the Rh-Catalyzed Addition
Reactiona
a The reactions were performed by heating [RhCp*(CH3CN)3]-
(SbF6)2 (2.5 mol %), substrate 1a (0.2 mmol), 2 (0.24 mmol), PivOH
(0.2 mmol) and DCE (1 mL) for 4 h at room temperature. Isolated yields.
insights for further work on intermolecular CÀN bond-
forming reactions.
To our delight, the present addition reaction is poten-
tially applicable in large-scale synthesis, and the product
was easily isolated by a simple recrystallization process
(eq 1). Treatment of 3a with Zn/AcOH gave the valuable
diarylamine product 4a in 97% yield.11 Notably, the diaryl-
amine product has utility as dyes and functional materials,
as exemplified by Piers’s group as important fluorescent
dyes with large Stokes shifts and high photostability.12
To obtain more mechanistic insight, we carried out
several preliminary mechanistic experiments. First, a cyclo-
metalated Rh(III) complex 5 successfully catalyzed the
addition reaction to provide the hydroxylamine product
3a in 90% yield, indicating the relevancy of CÀH activation
a The reactions were performed by heating [RhCp*(CH3CN)3]-
(SbF6)2 (2.5 mol %), substrate 1 (0.2 mmol), 2a (0.24 mmol), PivOH
(0.2 mmol), and DCE (1 mL) for 4 h at room temperature. Isolated
yields.
The scope of nitrosobenzenes was then examined
(Scheme 2). Other different electron-poor nitrosobenzenes
showed excellent activities (3qÀv). A variety of functional
groups (e.g., trifluoromethyl (3q), nitro (3s and 3v), bromo
(3t), ester (3u), acetyl (3w), and even the electrophilic
carboxaldehyde (3r) groups)10 were well-compatible with
this addition reaction. However, silimar to previous
results,4d,e no desired product was observed when elec-
tron-rich nitrosobenzenes were used. Further efforts are
being made in our laboratory to approach such a goal.
Notably, to date, this is the first example of direct addition
of aryl CÀH bonds to nitrosobenzenes, thus providing
(11) Diarylamine synthesis via CÀH activation: Uemura, T.; Imoto,
S.; Chatani, N. Chem. Lett. 2006, 35, 842.
(12) Araneda, J. F.; Piers, W. E.; Heyne, B.; Parvez, M.; McDonald,
R. Angew. Chem., Int. Ed. 2011, 50, 12214.
(13) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
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2008, 130, 12414. (b) Li, L.; Brennessel, W.; Jones, W. D. Organome-
tallics 2009, 28, 3492.
(10) No any byproduct involving the addition of CÀH bond to
aldehydes was observed (3r).
(15) Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6910.
6304
Org. Lett., Vol. 15, No. 24, 2013

Based on the above experiment, we tentatively propose
the following mechanism (Scheme 3). 2-Phenylpyridine
undergoes Rh-catalyzed ortho-directed CÀH bond activa-
tion to provide a rhodacycle A,14 followed by coordination
and the subsequent nucleophilic addition (or migratory
insertion of NdO) to give OÀRh species C. Protonation of
C delivers the hydroxylamine 3a and the Rh(III) catalyst.15
In summary, we have developed an unprecedented
rhodium-catalyzed addition of aryl CÀH bonds to nitro-
sobenzenes. The reaction is highly step-, atom-, and redox-
economic and can be readily scaled up. Moreover, this
procedure can be carried out under very mild conditions in
the atmospheric environment, providing a variety of
N-arylhydroxylamines in good to excellent yields. The
hydroxylamine products can be easily reduced to provide
valuable diarylamines in excellent yield. More importantly,
this process may provide a new direction for C(sp2)ÀH
activation/CÀN bond formation involving the use of nitroso-
benzenes as the nitrogen source. Studies to expand this
methodology to a wider range of substrates are currently
underway in our laboratories.
Scheme 3. Proposed Mechanism (Ar = 4-COOMe-phenyl)
(eq 3). An intermolecular competitive coupling of 2a with a
1:1 mixture of 1a and 1a-d5 revealed a significant primary
kinetic isotope effect (KIE) of 3.7 at a low conversion. This
KIE value of 3.7 is typical for the CÀH activation processes
(eq 4).13
Acknowledgment. Support of this work by the National
Natural Science Foundation of China (No. 21302200) is
gratefully acknowledged.
Supporting Information Available. Experimental proce-
dures, characterization of products, and copies of 1Hand13C
NMR spectra are provided. The material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 24, 2013
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