The benzoyl peroxide-promoted functionalization of simple alkanes with 2-aryl phenyl isonitrile

Article abstract of DOI:10.1039/c4cc03304c

The benzoyl peroxide (BPO)-promoted phenanthridinylation of simple alkanes with isonitrile is developed via C(sp³)-H and C(sp²)-H bond cleavage. This procedure is featured by dual C-C bond formation proceeding with the addition of an

Full text of DOI:10.1039/c4cc03304c

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The benzoyl peroxide-promoted functionalization
of simple alkanes with 2-aryl phenyl isonitrile†
Wanxing Sha,a Jin-Tao Yu,a Yan Jiang,a Haitao Yanga and Jiang Cheng*ab
Cite this: Chem. Commun., 2014,
50, 9179
Received 3rd May 2014,
Accepted 24th June 2014
DOI: 10.1039/c4cc03304c
www.rsc.org/chemcomm
The benzoyl peroxide (BPO)-promoted phenanthridinylation of simple target organic compound is a highly desired goal for organic
alkanes with isonitrile is developed via C(sp3)–H and C(sp2)–H bond chemists.
cleavage. This procedure is featured by dual C–C bond formation
The unique property of isonitrile inspired us to test the
proceeding with the addition of an alkyl radical to isonitrile followed reaction of isonitrile with simple alkanes, proceeding through
by radical aromatic cyclization.
a radical pathway. Herein, we wish to report our study on the
sequential addition of alkyl radical/intramolecular cyclization
The direct and selective functionalization of the sp3 C–H bond of isonitrile. Such a similar strategy has been developed for the
constitutes a long standing goal in synthetic organic chemistry synthesis of 6-substituted phenanthridine,11 which is widely
because of its high bond-dissociation energy (BDE) and low found in natural and pharmaceutical compounds.12 Compared
polarity. As a result, the chelating group assisted sp3 C–H bond with Yu’s procedure,13 it involves (1) transition-metal free
functionalization and the activation of the sp3 C–H bond, reaction conditions; (2) the employment of a simple alkane
which was benzylic or adjacent to the oxygen or nitrogen atom, rather than an alkyl bromide.
have been well developed in the past few years.1 The function-
The first glimpse of success was obtained by using the
alization of simple alkanes remains more practicable because reaction of 2-phenyl phenyl isonitrile and cyclohexane with the
they are major constituents of petroleum and natural gas.2 combination of FeCl2 and TBHP as the model reaction at 100 1C,
In 2008, Li reported the Ru-catalyzed oxidative coupling of which provided 6-cyclohexanyl phenanthridine in 28% yield
2-aryl pyridine with cycloalkanes.3 Bettinger, Ochiai and (Table 1, entry 1). Replacing TBHP with other oxidants, such as
Hartwig described the conversion of inactive alkane to amine
and amide, respectively.4 Recently, Antonchick developed the
direct oxidative cross-coupling of alkanes with heteroarenes and
Table 1 Selected results for optimal reaction conditionsa
(thio)chromones.5 Fokin reported a highly efficient enantio-
selective C–H insertion of azavinyl carbenes into inactive alkanes.6
The C–H bond of alkanes is prone to be functionalized via
a radical pathway under certain reaction conditions.7 Very
recently, Wei reported the copper-catalyzed alkenylation of
Entry
Metal
Peroxide
T/1C
Yieldb (%)
alkanes.8 Meanwhile, the cascade radical functionalization
of the inactive C–H bond attracted much attention.9 Liu
developed free-radical cascade alkylarylation of alkenes with
simple alkanes leading to oxindoles.10 However, the functiona-
lization of simple alkanes toward diversity and complexity of a
1
2
3
4
5
6
7
8
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
CuCl2
CuI
—
—
—
—
TBHP
H2O2
DTBP
K2S2O8
BPO
BPO
BPO
BPO
BPO
BPO
—
100
100
100
100
100
100
100
100
80
28
o1
o5
o1
67
25
o1
75(76)c
69
74
o1
a School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, and Jiangsu Province Key Laboratory of Fine
Petrochemical Engineering, Changzhou University, 1 Gehu Road, Changzhou,
213164, P. R. China. E-mail: jiangcheng@cczu.edu.cn
9
10
11
120
100
b State Key Laboratory of Coordination Chemistry, Nanjing University,
a
Reaction conditions: 1a (0.2 mmol), peroxide (2.2 equiv.) (DTBP =
di-tert-butyl peroxide, TBHP = tert-butyl hydroperoxide, BPO = benzoyl
22 Hankou Road, Nanjing, 210093, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03304c
peroxide), and cyclohexane (2.0 mL) under air for
tube. Isolated yield. N2.
4 h, sealed
b
c
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Scheme 2 Proposed mechanism.
Scheme 1 Preliminary mechanistic study.
DTBP, H2O2, and K2S2O8, resulted in no reaction (Table 1, entries 2–4).
To our delight, the yield dramatically increased to 67% by using
BPO (Table 1, entry 5).14 CuCl2 and CuI were found to be less
effective or ineffective for this transformation (Table 1, entries 6
and 7). The blank experiment confirmed that FeCl2 was not
essential for this transformation (Table 1, entry 8). Although O2
may inhibit the radical reaction, the yield did not increase under
N2 (Table 1, entry 8). The yield slightly decreased at 80 1C and a
comparable yield was obtained at 120 1C (Table 1, entries 9
and 10). A further study revealed that no reaction took place in
the absence of BPO (Table 1, entry 11).
More experiments were conducted to gain some insight into the
reaction. Firstly, the inter- and intra-molecular kinetic isotope effects
of the arene C–H bond were tested and the KH/KD was found to be
nearly 1.0 and 1.0, respectively (eqn (1) and (2), Scheme 1). These
results implied that (1) the cleavage of the arene C–H bond was not
the rate-determining step; (2) either the radical or electrophilic
aromatic substitution pathway was involved in this transformation.15
However, a large kinetic isotope effect (KH/KD = 6.1–8.1) was detected
for the sp3 C–H bond in cyclohexane, which confirmed the slow
cleavage of the sp3 C–H bond (eqn (3), Scheme 1). Finally, 1.0
equivalent of TEMPO was added and the reaction was inhibited,
which strongly supported the radical pathway (eqn (4), Scheme 1).
Based on these experimental results, the proposed mechanism
is outlined in Scheme 2. Initially, the benzoyl radical is formed by
the homolytic cleavage of BPO. Then the formed benzoyl radical
abstracts one H of cyclohexane to form a cyclohexanyl radical. This
Fig. 1 Substrate scope of isonitrile. a Reaction conditions: 1 (0.2 mmol),
BPO (ca. 0.44 mmol), cyclohexane (2.0 mL), 100 1C, 4 h. b Determined by
1H NMR spectroscopy.
The substrate scope of isonitrile was studied, as shown in
step is the rate-determining step as confirmed by the KIE. Next, the Fig. 1. As expected, all substrates smoothly underwent the
addition of the cyclohexanyl radical to isonitrile produces another reaction. This procedure tolerated some functional groups, such
radical intermediate 5. Subsequently, the intramolecular radical as fluoro, chloro, trifluoromethyl, acetyl, cyano and methoxy-
cyclization of intermediate 5 takes place to form radical inter- carbonyl, which were applicable to further potential function-
mediate 6. Finally, the benzoyl radical abstracts one H from alization. Since a radical cyclization pathway was involved in
intermediate 6 to form phenanthridine.
this transformation, as expected, the reaction efficiency was not
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decreased by the electron-withdrawing groups attached in the
cyclized phenyl ring. For example, 3da, 3ea and 3fa were all
isolated in good yield. However, moderate yields were obtained
for 3ga, 3ha and 3ia, which may be at least partly due to
potential side reaction derived from the substituted groups.
For the isonitrile possessing a meta-methyl on the cyclized
phenyl ring, 3la was isolated in 73% yield with 3 : 2 selectivity,
where the less hindered isomer was the main product.
Next, the substrate scope of alkanes was studied, as shown
in Fig. 2. Once again, cyclopentane, cycloheptane and cyclo-
octane worked well, providing the desired products 3ab, 3ac,
3ad and 3af in 67%, 80%, 81% and 30% yields, respectively.
Particularly, hexane took part in the reaction, leading to the 2-
and 3- functionalized products 3ae (1 : 1) in total 62% yield.
In conclusion, we have developed the BPO-promoted phen-
anthridinylation of simple alkanes with isonitrile.16 The procedure
involves dual C–C bond formation via dual C–H bond cleavage. The
cleavage of the sp3 C-H bond is the rate-determining step in this
transformation.
We thank the National Natural Science Foundation of China
(no. 21272028 and 21202013), ‘‘Innovation & Entrepreneurship
Talents’’ Introduction Plan of Jiangsu Province, the Natural Science
Foundation of Zhejiang Province (no. R4110294), State Key Labora-
tory of Coordination Chemistry of Nanjing University, Jiangsu Key
Laboratory of Advanced Catalytic Materials & Technology, Jiangsu
Province Key Laboratory of Fine Petrochemical Engineering, and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions for financial support.
13 H. Jiang, Y. Cheng, R. Wang, M. Zheng, Y. Zhang and S. Yu, Angew.
Chem., Int. Ed., 2013, 52, 13289–13292.
14 BPO is stabilized by water, containing ca. 60% of BPO in weight as
assayed by 1H NMR.
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Notes and references
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Chem. Commun., 2014, 50, 9179--9181 | 9181