A free radical cascade cyclization of isocyanides with simple alkanes and alcohols

Article abstract of DOI:10.1021/ol501461u

A copper-catalyzed free-radical cascade cyclization of isocyanides with simple alkanes and alcohols was developed, which allowed convenient access to various alkyl-substituted phenanthridines.

Full text of DOI:10.1021/ol501461u

Letter
pubs.acs.org/OrgLett
A Free Radical Cascade Cyclization of Isocyanides with Simple
Alkanes and Alcohols
Zejiang Li, Fenghua Fan, Jie Yang, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: A copper-catalyzed free-radical cascade cyclization of
isocyanides with simple alkanes and alcohols was developed, which
allowed convenient access to various alkyl-substituted phenanthridines.
Scheme 1. Strategies for Preparation of Alkyl-Substituted
Phenanthridines
he strategy for C−C bond formation through C−H bond
Tfunctionalization has drawn much attention in recent
years.1 Among them the free-radical-promoted (sp3) C−H
bond activation forming C−C bonds represents one of the
most efficient methods.2,3 In recent decades, Li and co-workers
have explored a series of efficient methods for C(sp3)−C(sp3)
bond formation using simple alkanes through the cross-
dehydrogenative-coupling (CDC) reactions.4 Recently, a
valuable PhI(OCOCF3)/NaN3-promoted oxidative cross-cou-
pling reaction of heteroarenes with simple alkanes has been
developed by Antonchick and Burgmann.5In addition, several
protocols for C(sp3)−C(sp2) bond construction with innate sp3
C−H bonds via free-radical addition−elimination processes
have been developed by us6 and others.7 Very recently, we have
reported a free-radical addition/cyclization of N-arylacrylamides
with simple alkanes, which allowed highly efficient access to
alkylated oxindoles.8 Although considerable advances in this
field have been made, more efficient and versatile strategies for
C−C bond formation by direct selective functionalization of
unactived C−H bond would be highly desirable.
The skeleton of phenanthridines is widely found in
pharmaceutical and bioactive compounds,9 which draw much
attention from synthetic chemists.10 In 2012, Chatani and co-
workers reported a Mn(III)-promoted oxidative cyclization of
isocyanides with organoboron reagents, which provided an
efficient strategy for preparation of aryl- and alkyl-substituted
phenanthridines.11 Very recently, a valuable approach to 6-
alkylated phenanthridines using isocyanides and electron-
deficient bromides by means of photoredox catalysis has been
developed by Yu and co-workers.12 Of particular interest in the
C−C bond formation via direct selective C−H bond
activation,13 we began to reason that a free-radical-initiated
cascade reaction14 of isonitriles with simple alkanes would
concisely synthesize various 6-alkylated phenanthridines using
the strategy of C−H activation/C−C bond formation (Scheme
1) and the problems of regioselectivity would be solved by this
strategy. To the best of our knowledge, the systhesis of 6-alkyl
phenanthridines by using isonitriles with simple alkanes has
never been reported. Herein, we report a Cu-catalyzed free
radical cascade cyclization of isocyanides with alkanes and
alcohols, which allows for convenient access to a series of 6-
alkylated phenanthridine and its derivatives by selective
functionalization of unactivated (sp2)C−H and (sp3)C−H
bonds.
To test the hypothesis, the reaction of 2-isocyano-5-methyl-
1,1′-biphenyl (1a) with cyclohexane was carried out. It can be
seen from Table 1 that the radical initiator is important to the
reaction. Initiated by dicumyl peroxide (DCP), the desired
product 6-cyclohexyl-2-methylphenanthridine (2a) was ob-
tained in 53% yield without any catalyst (entry 1). It was found
that the CuF2 was better than other salts including CuBr, CuI,
Cu2O, CuO, CuCl2, and copper powder (entries 2−8). Other
radical initiators such as tert-butyl hydroperoxide (TBHP), di-
tert-butyl peroxide (DTBP), and BPO proved to be less
efficient than DCP (entries 9−11). The addition of 2 and 10
mL of cyclohexane as the solvent led to the isolation of the
product 2a in 58% and 41% yields, respectively (entries 12 and
13). Variation of the amount of the radical initiator and catalyst
Received: May 20, 2014
Published: June 10, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Modification of the Typical Reaction Conditions
Table 2. Copper-Catalyzed Radical Cascade Reaction of
a
Isocyanides with Simple Alkanes
radical initiator
(equiv)
solvent
(mL)
b
entry catalyst (mol %)
yield (%)
1
−
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
5
5
5
5
5
5
5
5
5
5
5
2
10
5
5
5
5
5
5
53
2
CuBr (5)
58
3
CuI (5)
56
4
Cu (5)
35
5
Cu2O (5)
CuO (5)
CuCl2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (2)
CuF2 (10)
CuF2 (5)
CuF2 (5)
55
6
60
7
57
8
68 (30)
35
c
9
TBHP
10
11
12
13
14
15
16
17
18
19
DTBP
25
BPO
13
DCP (3)
DCP (3)
DCP (2)
DCP (1)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
58
41
63
58
55
65
d
e
60
−
a
Reaction conditions: isocyanide (1 equiv, 0.25 mmol), radical
initiator (3 equiv, 0.75 mmol), cyclohexane as solvent, 110 °C
(measured temperature of the oil bath), 7 h, unless otherwise noted.
b
c
d
e
Isolated yields. TBHP (in decane). 120 °C. 80 °C.
resulted in a slightly lower yield of the product (entries 14−17).
The yield of 2a decreased with rising temperature (entry 18).
However, no product was observed when the reaction was
conducted at 80 °C (entry 19). Finally, the desired product 2a
along with a byproduct 2-methylphenanthridine (2a′) were
isolated in 68% and 30% yields, respectively, under the typical
reaction conditions: 1 equiv of isocyanide, 5 mol % CuF2, 3
equiv of DCP, 5 mL of alkanes, 110 °C.
a
With the optimized conditions in hand, we next studied the
scope of the reaction of isocyanides with alkanes (Table 2). It
can be seen from Table 2 that the desired 6-alkylated
phenanthridines are isolated in moderate to good yields
through the radical cascade cyclization of various 2-isocyano-
1,1′-biphenyls and derivatives with simple alkanes. Gratifyingly,
the isocyanides bearing either electron-donating or -with-
drawing groups in the biphenyl core all resulted in nearly
quantitative overall yields of the 6-cyclohexyl substituted
phenanthridines 2 and the 6-hydrogen substituted phenan-
thridines (2a−2n). Other cycloalkanes such as cycloheptane
and cyclooctane also acted as effective substrates in this system
(2o and 2p). In the case of acyclic alkanes, high overall yields of
the 6-alkyl-phenanthridines as well as the 2a′ were obtained
(2q and 2r). No alkylation occurred at the C1 position of the
acyclic alkanes although the deviations of the bond dissociation
energies (BDE) do not exceed 1.0 kcal mol−1.15
Reaction conditions: isocyanide (0.25 mmol), DCP (0.75 mmol),
CuF2 (0.0125 mmol), 5 mL of alkane as solvent, 110 °C (measured
b
temperature of the oil bath), 7 h, sealed tube. Isolated yields of the
desired products and 2a′ (in parentheses).
the desired products 3 and the byproducts 3′ in good to
excellent overall yields under the typical conditions (Table 3,
3a−3l). Notably, although relatively low yields of the desired
products were isolated, other alcohols such as 2-butanol,
cyclopropanol, and cyclohexanol can also act as effective
substrates in this system (3m−3o). The conservation of the
hydroxyl group allows versatile synthesis of complex products.
We then studied the possible mechanism for this reaction.
When TEMPO was added into the system, the reaction was
completely inhibited and no desired product was observed.
Additionally, we also studied the initial intermolecular
competing kinetic isotope effect (KIE) of this reaction. It was
found that the rate-determining step would be the sp3 C−H
bond cleavage since a significant initial KIE (20% conversion)
was observed with kH/kD = 6.7 (Scheme 2).
As a continuation of our studies on the free-radical initiated
α-hydroxy-sp3 C−H bond activation of alcohols,6,13a we next
turned our attention to the 6-alkylation of isocyanides with
simple alcohols by using this strategy. As illustrated in Table 3,
free-radical cascade cyclization of various 2-isocyano-1,1′-
biphenyls and derivatives with ethanol and isopropanol gave
A plausible mechanism for this reaction is proposed (Scheme
3). The cumyloxyl radical would be formed through homolysis
of the O−O bond in DCP with the assistance of Cun. Hydrogen
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none.8,16 Further hydrogen-atom transfer from the alkyl radical
and α-hydroxy-carbon-centered radical would generate the
corresponding alkene and ketone, respectively. Addition of the
alkyl radical to the biphenyl isocyanide 1 leads to the imidoyl
radical intermediate A. Subsequently cyclization of A to the
benzene unit would form radical B, which is oxidized by the
Cun+1 species to afford the phenanthridine and regenerates the
Cun species. Alternatively, a carbocation would be formed via
oxidation of the radical A by Cun+1 species, followed by
intramolecular electrophilic aromatic substitution (SEAr)
generating the product, which is also another possible pathway.
The byproducts 2a′ and 3′ would be formed through a free
radical addition/cyclization cascade of the H-atom with the
isocyanides.
Table 3. Copper-Catalyzed Radical Cascade Reaction of
Isocyanides with Simple Alcohols
a
In summary, an efficient Cu-catalyzed free-radical addition/
cyclization of isocyanides with simple alkanes and alcohols has
been developed. It provides a convenient method for
preparation of 6-alkyl-substituted phenanthridine and its
derivatives via selective functionalization of unactivated
(sp3)C−H and (sp2)C−H bonds. Further studies on C−C
bond formation through selective sp3 C−H bond functionaliza-
tion of simple alkanes and alcohols are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liuzhq@lzu.edu.cn.
Notes
a
Reaction conditions: isocyanide (0.20 mmol), DCP (0.6 mmol),
Cu2O (0.01 mmol), 4.95 mL of alcohol, and 0.05 mL of H2O as the
The authors declare no competing financial interest.
mixture solvent, unless otherwise noted, N2, 110 °C (measured
b
temperature of the oil bath), 11 h, sealed tube. 5 mL of alcohol as
ACKNOWLEDGMENTS
c
■
solvent. Isolated yields of the desired products and 3′ (in
parentheses).
This project is supported by the National Science Foundation
of China (No. 21272096) and the Fundamental Research
Funds for the Central Universities (lzujbky-2014-58).
Scheme 2. KIE Studies
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