Co(acac)2/O2-mediated oxidative isocyanide insertion with 2-aryl anilines: Efficient synthesis of 6-amino phenanthridine derivatives

Article abstract of DOI:10.1021/ol500286x

A novel and efficient protocol for the creation of 6-amino phenanthridine derivatives by Co(acac)₂-catalyzed isocyanide insertion with 2-aryl anilines under an O₂ atmosphere via homolytic aromatic substitution (HAS) type C-H functionalization has been developed. This reaction not only proceeds smoothly utilizing O₂ as the oxidant but also provides a new approach to construct phenanthridine derivatives utilizing readily available 2-aryl anilines with isocyanides instead of 2-isocyanobiaryls with different radical precursors.

Full text of DOI:10.1021/ol500286x

Letter
pubs.acs.org/OrgLett
Co(acac)2/O2‑Mediated Oxidative Isocyanide Insertion with 2‑Aryl
Anilines: Efficient Synthesis of 6‑Amino Phenanthridine Derivatives
Tong-Hao Zhu, Shun-Yi Wang,* Yang-Qing Tao, Tian-Qi Wei, and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A novel and efficient protocol for the creation
of 6-amino phenanthridine derivatives by Co(acac)2-catalyzed
isocyanide insertion with 2-aryl anilines under an O2
atmosphere via homolytic aromatic substitution (HAS) type
C−H functionalization has been developed. This reaction not
only proceeds smoothly utilizing O2 as the oxidant but also
provides a new approach to construct phenanthridine
derivatives utilizing readily available 2-aryl anilines with
isocyanides instead of 2-isocyanobiaryls with different radical
precursors.
henanthridines have attracted much attention, because
they show versatile biological activities such as anti-
aminobenzimidazoles, 2-aminobenzothiazoles, and 2-amino-
benzoxazoles.9
P
bacterial, antitumoral, cytotoxic, and DNA intercalator (Figure
As a continuation of our work on isocyanide insertion
reactions,9,10 herein, we plan to investigate the reaction of
isocyanides with 2-aryl anilines catalyzed by a cobalt salt under
oxidative conditions, which would concisely synthesize 6-amino
phenanthridine derivatives via the formation of an imidoyl
radical intermediate followed by HAS type C−H functionaliza-
tion (Scheme 1). This reaction utilizes readily available 2-aryl
anilines with isocyanides instead of 2-isocyanobiaryls with
1).1,2 Therefore, it is important to develop new methods for the
Scheme 1. Phenanthridines Synthesis by Isocyanide
Insertion
Figure 1. Biologically active phenanthridines.
synthesis of these compounds.3,4 Transition-metal-catalyzed
isocyanide insertion reactions5 and somophilic isocyanide
insertion reactions3,6 have been well developed for the
construction of heterocycles via cascade reactions.7 Recently,
a series of 6-substituted phenanthridines were easily prepared
by radical addition to 2-isocyanobiaryls followed by a homolytic
aromatic substitution (HAS) process.3,8 However, there has
been no report on the construction of 6-amino phenanthridines
utilizing a similar strategy. There are also no reactions of 2-aryl
anilines with isocyanides to construct 6-amino phenanthridines.
More recently, we have developed a cobalt-catalyzed isocyanide
insertion reaction of aromatic amine derivatives to synthesize 2-
Received: January 27, 2014
© XXXX American Chemical Society
A
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Letter
different radical precursors catalyzed by an inexpensive and low
toxicity cobalt salt under oxidation conditions.
Scheme 2. Cobalt-Catalyzed Insertion Reactions of tert-Butyl
Isocyanides 2a with Substituted 2-Phenyl Aniline 1a−k
a
,b
Our initial studies focused on developing a more efficient
catalytic system by investigating the reaction of aniline 1a and
tert-butyl isocyanide 2a as a model system. When the reaction
of 1a and 2a was carried out in toluene at 100 °C without a
catalyst under sealed tube conditions, no desired product was
observed (Table 1, entry 1). To our surprise, the desired N-
Table 1. Optimization of Isocyanide Insertion with 2-Aryl
a
Anilines
b
entry
catalyst (mol %)
temp (°C)
solvent
toluene
yield (%)
1
−
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
130
100
100
0
2
Co(acac)2 (20)
Co(OAc)2 (20)
CoCl2·6H2O (20)
Co(NO3)2·9H2O (20)
CoSO4·7H2O (20)
Co(acac)2 (20)
Co(acac)2 (20)
Co(acac)2 (20)
Co(acac)2 (20)
Co(acac)2 (20)
Co(acac)2 (20)
Co(acac)2 (10)
Co(acac)2 (30)
Co(acac)2 (30)
Co(acac)2 (30)
Co(acac)2 (30)
Co(acac)2 (30)
toluene
toluene
toluene
toluene
toluene
benzene
53
3
trace
trace
trace
trace
39
4
5
6
7
e
8
DMSO
trace
56
9
anisole
10
11
12
13
14
15
16
1,4-dioxane
58
f
DCE
41
g
a
DME
53
Reaction conditions: substituted 2-phenyl aniline 1a−k (0.5 mol),
tert-butyl isocyanide 2a (0.6 mol, 1.2 equiv), Co(acac)2 (30 mol %),
and 1,4-dioxane (3 mL) mixed in a Schlenk tube at 100 °C under O2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
24
63
b
balloon conditions. Isolated yields.
44
43
c
17
d
trace
66
reacted well with tert-butyl isocyanide 2a (Scheme 2), giving
the desired products 3a−k in moderate yields. It is noteworthy
that not only the 2-aryl group bearing electron-donating groups
could offer the desired products in moderate yields but also the
2-aryl group bearing electron-withdrawing groups could afford
the desired products in moderate yields (30%-63%). When 3′-
methylbiphenyl-2-amine 1h was applied to the reaction, a
mixture of the two isomers N-tert-butyl-9-methylphenanthridin-
6-amine 3h and N-tert-butyl-7-methylphenanthridin-6-amine
3h′ in the ratio 3:2 was obtained. 2-(Pyridin-4-yl)aniline could
also react well and lead to the desired product 3i in 49% yield.
It should be noted that 3j could also be observed in 42% yield
with excellent regioselectivity, determined by NMR.
Then, we investigated the subtituent effects on the aniline
aromatic ring. The results are listed in Scheme 3. The 2-aryl
substituted anilines (1l−s) reacted well with tert-butyl
isocyanide 2a, furnishing the desired products 4a−h in
moderate yields. It is worth noting that the reaction of aniline
bearing electron-donating groups (Me, OMe) could lead to the
desired products in 31%−55% yields. When an aniline bearing
an electron-withdrawing group such as NO2 was applied to the
reaction, the desired product 4d could also be obtained in 35%
yield. The reactions of halo-substituted anilines 1l and 1m
afforded the products 4a and 4b in 54% and 57% yields,
respectively. Furthermore, relatively bulky substrate 1p could
also undergo the transformation, generating the desired
product 4e in 31% yield. Unfortunately, when 3-methyl-
biphenyl-2-amine 1q reacted with 2a, only a trace of product
was formed. To our delight, N-(tert-butyl)benzo[c][1,5]naph-
thyridin-6-amine 4h could also be observed in 47% yield by the
18
a
Reaction conditions: biphenyl-2-amine 1a (0.5 mol), tert-butyl
isocyanide 2a (0.6 mol, 1.2 equiv), cobalt catalyst, and solvent (3
mL) mixed in a 25 mL sealed tube with a magnetic stirrer for 12 h.
b
Yields were determined by GC analysis with biphenyl as the internal
c
d
standard. The atmosphere was argon. The O2 balloon was used, and
a Schlenk tube was used instead of a sealed tube. DMSO = dimethyl
sulfoxide. DCE = 1,2-dichloroethane. DME = ethyleneglycol
dimethyl ether.
e
f
g
(tert-butyl)phenanthridin-6-amine 3a could be obtained in 53%
GC-yield by the reaction of 1a and 2a catalyzed by 20 mol %
Co(acac)2 in toluene at 100 °C under sealed tube conditions
(Table 1, entry 2). However, other cobalt salts such as
Co(OAc)2, CoCl2·6H2O, Co(NO3)2·9H2O, and CoSO4·7H2O
could not promote this reaction (Table 1, entries 3−6). The
results of screening for solvent, catalyst loading, and reaction
temperature conditions indicated that 1,4-dioxane, 30 mol %
Co(acac)2, and 100 °C were optimal for this reaction (Table 1,
entries 7−16). When the reaction was carried out under an
argon atmosphere, it was found that almost no desired product
was formed (Table 1, entry 17). This result indicated that O2
was critical for this reaction. To our delight, the reaction of 1a
and 2a catalyzed by 30 mol % Co(acac)2 in 1,4-dioxane at 100
°C could react smoothly under 1 atm of O2 atmosphere (O2
balloon) to afford the desired product 3a in 66% GC-yield
(60% isolated yield) (Table 1, entry 18).
With the optimized conditions in hand, the reaction scope of
the 2-aryl anilines was investigated. The results are summarized
in Schemes 2 and 3. The substituted 2-aryl anilines (1a−k)
B
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Letter
Scheme 3. Cobalt-Catalyzed Insertion Reactions of tert-Butyl
Isocyanides 2a with Substituted 2-Phenyl Aniline 1l−s
Scheme 5. Proposed Mechanism
a
,b
a
Reaction conditions: substituted 2-phenyl aniline 1l−1s (0.5 mol),
tert-butyl isocyanide 2a (0.6 mol, 1.2 equiv), Co(acac)2 (30 mol %),
and 1,4-dioxane (3 mL) mixed in a Schlenk tube at 100 °C under O2
b
balloon conditions. Isolated yields.
reacting with isocyanide 2 to furnish complex A′.14,15 Then, 1a
adds to A′ to give cobalt(II) carbene complex B (Scheme 5,
path II). After the oxidation of B,16 cobalt(III) complex C is
formed, which may be cleaved homolytically to afford the active
imidoyl radical D and the Co(II) catalyst. After the intra-
molecular cyclization of D, further oxidation, and subsequently
deprotonation, the desired phenanthridine is formed.
In conclusion, we have developed a new, simple, and efficient
Co(acac)2-catalyzed cascade isocyanides insertion with 2-aryl
anilines under an O2 atmosphere to construct 6-amino
phenanthridine derivatives in moderate to good yields via
homolytic aromatic substitution (HAS) type C−H functional-
ization. In view of the important biological properties of
phenanthridines, 6-amino substituted phenanthridines have
potential biological properties. The mechanism of this reaction
is different from the mechanisms of the Pd-catalyzed isocyanide
insertion reaction and radical isocyanide insertion reaction, and
further mechanism studies are underway in our laboratory.
reaction of 2-phenylpyridin-3-amine 1k with 2a under the
optimal conditions.
We further studied the reaction of several isocyanides with 1a
under identical conditions. When other secondary or tertiary
aliphatic isocyanides 2b−e were employed, the reactions also
proceeded smoothly to give the desired products in moderate
yields (39%−52%) (Scheme 4). However, the reactions of
primary aliphatic isocyanide n-butyl isocyanide 2f and aromatic
isocyanide 2g failed to give the desired products.
Scheme 4. Cobalt-Catalyzed Insertion Reactions of
Substituted Isocyanides 2b−g with Biphenyl-2-amine 1a
a
,b
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shunyi@suda.edu.cn.
a
Reaction conditions: substituted biphenyl-2-amine 1a (0.5 mol),
isocyanide 2b−g (0.6 mol, 1.2 equiv), Co(acac)2 (30 mol %), and 1,4-
dioxane (3 mL) mixed in a Schlenk tube at 100 °C under O2 balloon
*E-mail: shunjun@suda.edu.cn.
Notes
b
conditions. Isolated yields.
The authors declare no competing financial interest.
Based on the literature reports11−16 and the above results, we
proposed a plausible mechanism via two possible pathways as
shown in Scheme 5. Path I consists of a Co(II) salt reacting
with 1a to give cobalt(II) complex A.11 A undergoes addition
with 212 to provide cobalt(II) carbene complex B13 (Scheme 5,
path I). The other possible pathway involves the Co(II) salt
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (Nos. 21172162, 21372174), the Ph.D. Programs
Foundation of Ministry of Education of China
(2013201130004), the Young National Natural Science
Foundation of China (No. 21202111), the Young Natural
C
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Letter
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(KJS1211), PAPD, and Soochow University for financial
support.
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