Rhenium-catalyzed C-H aminocarbonylation of azobenzenes with isocyanates

Article abstract of DOI:10.1039/c5ob01121c

The first C-H aminocarbonylation of azobenzenes with isocyanates is achieved by using rhenium-catalysis, which provides an expedient and atom-economical access to varied o-azobenzamides from readily available starting materials. The reaction efficiency can be enhanced by the catalytic use of sodium acetate via accelerated C-H bond activation.

Full text of DOI:10.1039/c5ob01121c

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Rhenium-catalyzed C–H aminocarbonylation of
azobenzenes with isocyanates†
Cite this: DOI: 10.1039/c5ob01121c
Received 4th June 2015,
Accepted 5th June 2015
Xiaoyu Geng and Congyang Wang*
DOI: 10.1039/c5ob01121c
www.rsc.org/obc
The first C–H aminocarbonylation of azobenzenes with iso-
cyanates is achieved by using rhenium-catalysis, which provides an
expedient and atom-economical access to varied o-azobenza-
mides from readily available starting materials. The reaction
efficiency can be enhanced by the catalytic use of sodium acetate
via accelerated C–H bond activation.
Because of the unique azo motif and conjugated characteri-
stics, aromatic azo compounds find wide applications in
industries as dyes and pigments.1 Also, the light-driven revers-
ible isomerization between the cis and trans forms renders
them extremely suitable for supermolecular recognition,
photochemical molecular switches, light-driven molecular
motors, biosensors, pharmaceuticals, and so on.2 Specifically,
the o-azobenzamide skeleton is often found as a key structural
unit in biologically active molecules such as photomodulated
deoxyribozymes for RNA cleavage, photoswitchable peptidomi-
metic inhibitors of α-chymotrypsin, and antiproliferative
agents (Scheme 1A).3 In general, the o-azobenzamide core is
constructed either through the amide bond formation by tra-
ditional condensation reactions of o-azobenzoic acid deriva-
tives with amines (path a, Scheme 1B), or through the azo
bond formation by manipulation of o-nitro/-aminobenzamides
(path b).3,4 Of note, both these approaches require 1,2-bisfunc-
tionalized arenes as starting materials and often result in the
formation of undesired waste byproducts. In principle, a more
atom-economical way to build this unit is the direct ortho-C–H
bond addition of azobenzenes to isocyanates (path c,
Scheme 1C). However, as far as we are aware, this direct C–H
bond aminocarbonylation process is unprecedented for azo-
benzenes though other types of C–H bond transformations of
azobenzenes have been reported recently.5 As our continuous
Scheme 1 Bioactive o-azobenzamides and their synthetic approaches.
interest in rhenium-catalysis,6,7 herein we report the first C–H
aminocarbonylation of azobenzenes with isocyanates by using
rhenium-catalysis (Scheme 1C).8 Thus, varied o-azobenza-
mides are accessed from readily available starting materials in
an expedient and atom-economical manner. Importantly, only
mono-C–H functionalized products are formed through a
regioselective C–C bond formation, which circumvents the
homocoupling issue in the synthesis of unsymmetrical azo-
arenes with traditional methods.4
At the outset, we examined the model reaction of azoben-
zene 1a with p-bromophenyl isocyanate 2i (Table 1).9 No pro-
ducts were observed in the absence of catalysts (entry 1). To
our delight, with 5 mol% of Re2(CO)10 the C–H aminocarbony-
lated product 3ai was obtained in 60% NMR yield (entry 2).
Variations on solvents showed that toluene was the best
(entries 3–6).9 Further tuning of the ratio of the starting
materials and reaction temperature demonstrated that higher
yield of 3ai could be achieved at 130 °C with excess of 1a
(entries 7–11). A slightly higher concentration and longer reac-
tion time led to the best results among the conditions tested
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China. E-mail: wangcy@iccas.ac.cn
†Electronic supplementary information (ESI) available: Experimental details,
characterization data and NMR spectra for all new compounds, and X-ray data.
CCDC 1055707 for 3an. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c5ob01121c
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Table 1 Optimization of reaction conditionsa
Entry Cat. (5 mol%) 1a/2i Solvent
T (°C) Yield of 3aib (%)
c
1
2
3
4
5
6
7
8
—
1/2.5 Toluene
1/2.5 Toluene
1/2.5 DCE
1/2.5 CCl4
1/2.5 CH3CN
150
150
150
150
150
0
60
46
0
0
55
32
54
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
Re2(CO)10
ReBr(CO)5
Mn2(CO)10
Ru3(CO)12
Rh(PPh3)3Cl
Pd(OAc)2
1/2.5 1,4-Dioxane 150
1/1
Toluene
150
150
140
130
120
130
130
130
130
130
130
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
2.5/1 Toluene
9
69
72
10
11
12d
13d
14d
15d
16d
17d
0
Scheme 2 Substrate scope for isocyanates. Reaction conditions: 1a
(1.25 mmol), 2 (0.5 mmol), Re2(CO)10 (0.025 mmol), toluene (2.5 mL),
130 °C, 48 h. a Isolated yields are shown. b NaOAc (20 mol%). c 1H NMR
yield without NaOAc.
77 (75)e
0
0
7
0
0
a Reaction conditions unless otherwise noted: 1a (0.2 mmol), 2i
(0.5 mmol), catalyst (0.01 mmol), solvent (2 mL), 24 h. b Yields
determined by 1H NMR analysis. c No catalyst. d Toluene (0.2 M), 48 h.
e Isolated yield on 0.5 mmol scale, 1a was recovered in 70% isolated
yield. DCE = 1,2-dichloroethane.
and 3ai was obtained in 75% isolated yield (entry 12).
Rhenium, manganese, and ruthenium carbonyls and other
transition metal catalysts displayed very low reactivity, if any at
all (entries 13–17).9 Of note, no bis-C–H functionalized pro-
ducts such as 4ai and 5ai were detected during the entire
screening process, which showcased the excellent chemo-
selectivity in this reaction.
With the optimized conditions in hand, we first investi-
gated the reaction scope with regard to isocyanates (Scheme 2).
It turned out that both electron-donating and -withdrawing
substituents on the aromatic ring of isocyanates were tolerated
affording products 3aa–j smoothly. Importantly, a wide range
of functional groups such as OMe, OCF3, CF3, F, Cl, Br, and I
remain intact under the reaction conditions allowing for
further synthetic transformations. The ortho-substituted
phenyl isocyanates showed rather sluggish reactivity upon the
sole catalysis of Re2(CO)10. However, the addition of a catalytic
amount of NaOAc dramatically accelerated the reaction giving
o-azobenzamide 3ak–l in good yields. meta-Substituted phenyl
isocyanates as well as 2-naphthalenyl isocyanate were all amen-
able to these conditions leading to products 3am–o without
difficulty. The structure of 3an was unambiguously confirmed
by single-crystal X-ray diffraction analysis. Pleasingly, aliphatic
isocyanates, no matter linear, cyclic or benzylic, also reacted
well with 1a to give the corresponding products 3ap–r in syn-
thetically useful yields.
Scheme 3 Substrate scope for azobenzenes. Reaction conditions: 1
(1.25 mmol), 2h (0.5 mmol), Re2(CO)10 (0.025 mmol), NaOAc (0.1 mmol),
toluene (2.5 mL), 130 °C, 24 h. a Isolated yields are shown. b Ratio in the
crude reaction mixture determined by GC-MS.
donating groups gave products in higher yields than those of
azobenzenes bearing electron-withdrawing groups (3bh–fh).
Meanwhile, ortho-methyl and -methoxyl azobenzenes were also
suitable substrates despite the enhanced steric hindrance
(3gh–ih). meta-Disubstituted azobenzene delivered product 3jh
in good yield. When meta-monosubstituted azobenzene was
used, the sterically more accessible C–H bond was functiona-
lized with excellent regioselectivity (3kh). Unsymmetrical azo-
Next, we examined the substrate scope of azobenzenes
(Scheme 3). It was found that azobenzenes with para electron-
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Scheme 4 Probe the possible reaction intermediate. a 1H NMR yield.
b Isolated yield.
benzene containing a bulky mesityl group on the N-atom
showed high reactivity in the reaction (3lh). Again, the
sterically less congested C–H bond in the unsymmetrical
azobenzene
was
regio-specifically
amino-carbonylated
affording a single product (3mh).
To get insight into the reaction mechanism, we performed
the stoichiometric reaction of Re2(CO)10 with azobenzene 1a
(Scheme 4a). Gratifyingly, rhenacycle A was isolated in 6%
yield by sublimation. The addition of NaOAc to the reaction
doubled the yield of A indicating the acceleration effect of
NaOAc for Re-promoted C–H activation.7e The stoichiometric
reaction of A with isocyanate 2i was then conducted and
product 3ai was formed in 57% isolated yield (Scheme 4b).
Furthermore, it was shown that A did catalyze the reaction of
azobenzene 1a and isocyanate 2i affording 3ai in comparable
yield (Scheme 4c). Collectively, these results suggested the
involvement of rhenacycle A in the catalytic reaction.
Scheme 5 Deuterium-labeling experiments.
To further probe the nature of the C–H activation step, the
deuterium-labeling experiments were carried out. When fully
deuterated azobenzene 1a-d10 was employed in the reaction,
partial deuterium-loss was detected in both the recovered start-
ing material and the product (Scheme 5a), which implied that
a reversible deprotonation/protonation equilibrium existed in
Scheme 6 Competition experiments.
formation of products from azobenzene 1f and isocyanate 2f,
the C–H activation step. To verify this assumption, azobenzene both containing an electron-withdrawing group, were favored
1a was treated with one equivalent of D2O under the catalysis
in the reaction, which might be ascribed to the easier deproto-
of Re2(CO)10 and NaOAc. As expected, 35% D-incorporation
native C–H activation and the higher affinity to nucleophilic
was observed at the ortho positions of 1a. Interestingly, almost attack for 1f and 2f, in comparison with 1b and 2b,
no D/H scrambling was detected for 1a when the reaction was
conducted in the absence of NaOAc. Meanwhile, only a very
respectively.
Based on the above results, a plausible reaction mechanism
small amount of deuterium-loss was found when 1a-d10 was is proposed in Scheme 7. Initially, rhenacycle A is generated
subjected to the reaction conditions without NaOAc. These
results suggested that NaOAc accelerated the deprotonation/
from 1a and Re2(CO)10 with or without the assistance of
NaOAc. The ligand exchange of CO with isocyanate 2a gives
protonation equilibrium in both directions. Furthermore, the intermediate B followed by a migratory insertion leading to the
kinetic isotope effect (KIE) experiments were performed by
using two parallel reactions and the KIE value was determined
formation of a seven-membered rhenacycle C or D. Protona-
tion of C/D gives the target product 3aa and forms the
to be 2.07 (Scheme 5b), which indicated that the C–H bond rhenium species E, which facilitates the C–H bond cleavage of
cleavage might be involved in the rate-limiting step.
1a regenerating rhenacycle A. The existence of NaOAc may
accelerate the deprotonative C–H activation step of 1a and the
In addition, the competition experiments between two
different azobenzenes and isocyanates bearing electronically protonation step of species C/D, thus acting as a proton
varied groups were tested (Scheme 6). It turned out that the
shuttle in the reaction.
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Scheme 7 A plausible mechanism.
Scheme 8 Synthetic transformations of o-azobenzamides.
Finally, the exemplified synthetic transformations of
product 3 are shown in Scheme 8. o-Azobenzamide 3aa could
be easily reduced by Zn/NH4Cl to afford hydrazine 6aa in 92%
yield.9 Also, the second C–H bond acylation reaction of 3aa
with benzaldehyde was achieved by using palladium catalysis5f
to give unsymmetrical azoarene 7aa, which is difficult to
access via traditional methods.4
In conclusion, we have developed the first C–H aminocarbo-
nylation of azoarenes with isocyanates by using rhenium-
catalysis. This protocol provides an expedient, operationally
practical, and chemo- and regioselective approach to mono-
C–H functionalized o-azobenzamides with high atom-
economy. Mechanistic studies revealed a deprotonative C–H
activation pathway and identified a five-membered rhenacycle
as the key reaction intermediate.
Financial support from the National Basic Research
Program of China (973 Program) (no. 2011CB808600) and the
National Natural Science Foundation of China (21322203,
21272238, 21472194) are gratefully acknowledged.
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