Rhodium-Catalyzed Reaction of Azobenzenes and Nitrosoarenes toward Phenazines

Article abstract of DOI:10.1021/acs.orglett.9b00502

A rhodium-catalyzed annulative reaction between azobenzenes and nitrosoarenes has been developed, leading to a series of phenazines in moderate to good yields. This procedure proceeds with sequential chelation-assisted addition of aryl C-H to nitrosoarenes and ring closure by electrophilic attack of azo group to aryl. During this transformation, the azo group served as not only a traceless directing group but also a building block in the final products.

Full text of DOI:10.1021/acs.orglett.9b00502

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Reaction of Azobenzenes and Nitrosoarenes
toward Phenazines
Yan Xiao, Xiaopeng Wu, Hepan Wang, Song Sun, Jin-Tao Yu, and Jiang Cheng*
School of Petrochemical Engineering, and Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Changzhou
University, Changzhou 213164, P.R. China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed annulative reaction be-
tween azobenzenes and nitrosoarenes has been developed,
leading to a series of phenazines in moderate to good yields.
This procedure proceeds with sequential chelation-assisted
addition of aryl C−H to nitrosoarenes and ring closure by
electrophilic attack of azo group to aryl. During this
transformation, the azo group served as not only a traceless directing group but also a building block in the final products.
henazines are ubiquitous in natural products1 and
Table 1. Selected Results for Screening the Optimized
Reaction Conditions
a
2
Pbioactive compounds, which show antibacterial,
anti-
fungal,3 antiviral,4 and antitumor5 activities (Scheme 1). The
synthetic pathways starting from ortho-difunctionalized sub-
strates, such as the Beirut reaction,6 the Buchwald−Hartwig
amination,7 and Chen’s procedure,8 allow facile access to
phenazine frameworks. However, they often suffer from a
multistep process to prepare the starting material in the case of
accessing polysubstituted phenazines. Alternatively, the
annulation between 2 equiv of monofunctionalized starting
material features rapid construction of products with chemical
diversity and complexity. However, the traditional Wohl−Aue
reaction required harsh reaction conditions.9 Recently,
Ellmann reported an efficient method toward phenazine by
the rhodium-catalyzed annulation of aldehydes and azides.10
Nitrosoarenes are versatile building blocks in organic
synthesis.11 Previously, we developed a Rh(III)-catalyzed
bilateral cyclization of aldehydes with nitrosoarenes toward
unsymmetrical acridines proceeding with C−H functionaliza-
tion enabled by a transient directing group.12 Herein, we
b
yield
(%)
entry
catalyst
additive (equiv)
solvent
1
2
3
4
5
6
[Cp*RhCl2]2
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
23
nr
nr
[RuCl2(p-cymene)2]2
[Cp*Co(CO)I2]
[Cp*Rh(OAc)2]2
[Cp*Rh(MeCN)3X2]
[Cp*RhCl2]2
14
18
25
e
c
7
[Cp*RhCl2]2
CH3CN 41
8
9
10
11
12
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
THF
dioxane
DCE
DCE
DCE
nr
nr
55
63
nr
Zn(OTf)2 (1)
Zn(OTf)2 (1)
CF3SO3H (1)
[Cp*RhCl2]2
c
13
14
15
[Cp*RhCl2]2/AgSbF6 Zn(OTf)2 (1)
AcOH (5)
[Cp*RhCl2]2/AgSbF6 Cu(OAc)2 (1)
AcOH (5)
DCE
DCE
50 ,68,
d
71
Scheme 1. Representative Phenazines Compounds
45
[Cp*RhCl2]2/AgSbF6 MgSO4 (1)AcOH DCE
50
(5)
a
Reaction conditions: azobenzene 1a (0.1 mmol), nitrosobenzene 2a
(0.15 mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), AcOH (5
equiv), other indicated additives (0.1 mmol), solvent (2.0 mL), N2
b
(1.0 atm.), at 120 °C for 24 h, in a sealed Schlenk tube. Isolated
c
d
e
yield. 100 °C. 140 °C. X = SbF6.
report the rhodium-catalyzed reaction of nitrosoarenes and
azobenzenes13,14 toward phenazines, proceeding with the
Received: February 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Scope of substituted nitrosobenzenes. (a) Reaction
conditions: (E)-1,2-di-m-tolyldiazene 1j (0.1 mmol), substituted
nitrosobenzenes 2 (0.15 mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6
(20 mol %), Zn(OTf)2 (1 equiv), AcOH (5 equiv), DCE (2.0 mL),
N2 (1.0 atm), at 140 °C for 24 h, in a sealed Schlenk tube. (b)
Isolated yield.
Figure 1. Scope of substituted azobenzenes. (a) Reaction conditions:
substituted azobenzenes 1 (0.1 mmol), nitrosobenzene 2a (0.15
mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Zn(OTf)2 (1
equiv), AcOH (5 equiv), DCE (2.0 mL), N2 (1.0 atm.), at 140 °C for
24 h, in a sealed Schlenk tube. (b) Isolated yield.
sequential directing group-assisted C−H functionalization and
catalytic annulation.
Scheme 2. H/D Exchange of Azobenzenes and Kinetic
Isotopic Experiments
We initiated our work by exploring the reaction of
azobenzene 1a (0.1 mmol) and nitrosobenzene 2a (0.15
mmol) in the presence of [Cp*RhCl2]2 (5 mol %) and AgSbF6
(20 mol %) in MeOH at 120 °C in a sealed tube for 24 h
(Table 1). To our delight, the annulation product phenazine
3aa was isolated in 23% yield (entry 1). On the contrary, the
reaction resulted in poor or no conversion in the absence of
either AgSbF6 or [RhCp*Cl2]2. [RuCl2(p-cymene)2]2 and
[Cp*Co(CO)I2] were ineffective for this transformation
(entries 2 and 3), while [Cp*Rh(OAc)2]2 (14%) and
[Cp*Rh(MeCN)3(SbF6)2] (18%) decreased the reaction
efficiency (entries 4 and 5). During the solvent screening,
dichloroethane (DCE, 55%) was superior to MeOH (23%),
DMF (25%), and MeCN (41%, entries 6, 7, and 10). However,
THF and dioxane inhibited the reaction (entries 8 and 9). The
yield was improved in the presence of Zn(OTf)2 (63%, entry
11). Moreover, in the presence of Zn(OTf)2 (1 equiv) and
AcOH (5 equiv), the yield further improved to 68% (entry
13). When AcOH was replaced by triflic acid, the product
could not be detected (entry 12). Therefore, AcOH plays an
important role in this transformation. Meanwhile, Cu(OAc)2
and MgSO4 along with AcOH had little effect on the reaction
(entries 14 and 15). The reaction temperature had some effect
on the reaction efficiency (71%, 140 °C; 50%, 100 °C). Finally,
the optimized reaction conditions were selected as follows:
azobenzene 1 (0.1 mmol), nitrosobenzenes 2 (0.15 mmol),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Zn(OTf)2 (0.1
mmol), and AcOH (5 equiv) in DCE (2.0 mL) at 140 °C for
24 h under an inert atmosphere (N2).
To study the scope of the C−H activation bilateral
cyclization process, we initially conducted the reactions of
various azobenzenes 1 with nitrosobenzene 2a under the
optimized conditions (Figure 1). Notably, some azobenzenes
with electron-donating groups such as methyl (3da, 61%),
isopropyl (3ea, 71%), tert-butyl (3fa, 75%), and methoxy (3ga,
56%) at the para-position worked in good to moderate yields.
However, azobenzenes possessing electron-withdrawing groups
B
DOI: 10.1021/acs.orglett.9b00502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have demonstrated a facile procedure
starting from azobenzenes and nitrosobenzenes to access
phenazine analogues. This procedure allowed the rapid access
of a series polysubstituted phenazine. Preliminary mechanistic
studies indicated that a sequential chelation-assisted addition
of aryl C−H to nitrosobenzenes and the ring closure by
electrophilic attack of azo group to aryl and aromatization
process was involved.
Scheme 3. Tentative Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00502.
Experimental procedures along with copies of spectra
(PDF)
AUTHOR INFORMATION
■
provided the corresponding products in relatively low yields
(3ba, 45%; 3ha, 37%). Meanwhile, this procedure was also
applicable for multisubstituted azobenzenes (3ia, 58%).
Disappointingly, the ortho-substituted analogues (3ka and
3la) did not work under the reaction conditions.
Corresponding Author
*E-mail: jiangcheng@cczu.edu.cn.
ORCID
Song Sun: 0000-0002-9974-6456
Jin-Tao Yu: 0000-0002-0264-9407
Jiang Cheng: 0000-0003-2580-1616
Next, the substrate scope of nitrosobenzenes 2 was
investigated by the reaction of substituted nitrosobenzenes
with 1j (Figure 2). Various nitrosobenzenes 2 including those
bearing both electron-donating (methyl, tert-butyl and
methoxy) and electron-withdrawing groups (chloro, bromo)
were all well tolerated, affording the corresponding products
3ja−ji with yields ranging from 53% to 79%. Notably, some
nitrosobenzenes with electron-withdrawing groups such as
bromo (3jd, 79%) and chloro (3je, 75%) at the para-position
proceeded in good yields, while those with methyl (3jb, 69%)
and tert-butyl (3jc, 67%) provided the products in relatively
low yields. Typically, the compatibility of halogen-containing
substrates provided facile handles for potentially further
functionalizations. Moreover, multisubstituted nitrosobenzenes
also access phenazine analogues (3jf, 65%). In the cases of
meta-substituted nitrosobenzenes, 3jg and 3ji were isolated in
moderate yields (53−69%). Disappointingly, the ortho-
substituted analogues (3jj and 3jk) failed to work under the
reaction conditions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21572025, 21602019, and 21672028), “Innovation &
Entrepreneurship Talents” Introduction Plan of Jiangsu
Province, Natural Science Foundation of Jiangsu Province
(BK20171193), the Key University Science Research Project
of Jiangsu Province (15KJA150001), Jiangsu Key Laboratory
of Advanced Catalytic Materials & Technology (BM2012110),
and Advanced Catalysis and Green Manufacturing Collabo-
rative Innovation Center for financial support. S.S. thanks the
Young Natural Science Foundation of Jiangsu Province
(BK20150263) for financial support.
The test of KIE on azobenzenes was failed since the H/D
exchange of azobenzenes was confirmed (Scheme 2, eqs 1).
This result indicated the cleavage of ortho-C−H in
azobenzenes was reversible. Meanwhile, the inter- and
intramolecular KIE for nitrosobenzene were both found to
be 1.5 (Scheme 2, eqs 2 and 3). Thus, the cleavage of the C−H
bond in nitrosobenzene was unlikely to be the rate-
determining step during this transformation.
A proposed mechanism is outlined in Scheme 3. First,
azobenzene undergoes directed ortho C−H bond cleavage
leading to metallacycle B. Then, the coordination and
migratory insertion of newly formed Rh−C bond into the
NO group takes place to form rhodacycle C. Second, the
protonolysis of rhodacycle C produces hydroxylamine D, along
with the regeneration of Rh(III) species to enter the catalytic
cycle. Third, intermediate F is formed via the sequential
alkylation of D by DCE and release of chloroethanal.15 Finally,
in the presence of proton, the intramolecular electrophilic
aromatic substitution of F forms G, which encounters the
aromatization leading to phenazine 3aa and aniline.
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DOI: 10.1021/acs.orglett.9b00502
Org. Lett. XXXX, XXX, XXX−XXX