Tandem dual C(sp3)-H/C(sp2)-H functionalization: A radical cyclization of 2-isocyanobiphenyl with ether to 6-alkylated phenanthridine

Article abstract of DOI:10.1007/s11426-014-5118-7

A simple and efficient radical coupling of 2-isocyanobiphenyl with ethers was developed, providing a variety of 6-alkylated phenanthridines. Both cyclic and acyclic ethers are suitable substrates for this transformation, which comprised the functionalization of two C-H bonds: the sp³ C-H of ether and sp² C-H of phenyl group. The kinetic isotope effect (KIE) revealed that the cleavage of sp³ C-H bond would be involved in the rate-determining step.

Full text of DOI:10.1007/s11426-014-5118-7

SCIENCE CHINA
Chemistry
August 2014 Vol.57 No.8: 1172–1175
doi: 10.1007/s11426-014-5118-7
• COMMUNICATIONS •
Tandem dual C(sp3)−H/C(sp2)−H functionalization: a radical
cyclization of 2-isocyanobiphenyl with ether to 6-alkylated
phenanthridine
PAN ChangDuo1, HAN Jie1 & ZHU ChengJian1,2*
1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received March 6, 2014; accepted March 19, 2014; published online June 23, 2014
A simple and efficient radical coupling of 2-isocyanobiphenyl with ethers was developed, providing a variety of 6-alkylated
phenanthridines. Both cyclic and acyclic ethers are suitable substrates for this transformation, which comprised the functional-
ization of two C–H bonds: the sp3 C–H of ether and sp2 C–H of phenyl group. The kinetic isotope effect (KIE) revealed that
the cleavage of sp3 C−H bond would be involved in the rate-determining step.
C–H functionalization, domino reaction, phenanthridine, 2-isocyanobiphenyl, ether
motifs [4]. Recently, it was reported that phenanthridine
1 Introduction
skeleton could be formed through C-radical addition to
2-isocyanobiphenyls with subsequent homolytic aromatic
substitution [5]. However, the development of simple and
efficient method to access phenanthridine is still the pursuit
of organic chemists.
Phenanthridine is an important skeleton present in many
natural products and is of great interest in medicinal chem-
istry due to their remarkable biological activities, such as
antitumor, antimicrobial, and antiviral (Figure 1(a)) [1].
Some members in this family also demonstrated optoelec-
tronic properties and are receiving growing attention in ma-
terial research [2]. As a consequence, a number of efficient
and selective synthetic protocols have been developed for
their synthesis [3]. Among many possible approaches to the
phenanthridine scaffold, intramolecular cyclization via C–C
or C–N bond formation of an ortho-functionalized biaryl
precursor to construct the central ring are particularly at-
tractive in virtue of ready accessibility of starting material
by cross-coupling reaction. Homolytic aromatic substitution
by an aryl radical and related process has been demonstrat-
ed as an efficient approach for the construction of biaryl
Functionalization of unreactive C(sp3)–H bonds is one of
the most challenging issues in synthetic chemistry and con-
tinues to attract intensive efforts [6]. Tetrahydrofuran (THF)
and 1,4-dioxane are important chemical raw materials. Such
five- and six-membered ring moieties are widely present in
natural organic substances and medicinal compounds (Fig-
ure 1(b)) [7]. Therefore, introduction of these simple ether
molecules into complex organic compounds is very valua-
ble in synthetic chemistry [8]. Due to their chemical inert-
ness, direct sp3 C–H bond functionalization of ethers is a
challenging task. As a matter of fact, ethers can produce
radicals under certain reaction conditions [9]. We postulate
that radical A encounters radical acceptor aryl isonitrile can
form imidoyl radical B, which then undergoes intramolecu-
lar homolytic aromatic substitution to afford 6-alkylated
Dedicated to Professor Qian Changtao on the occasion of his 80th birthday.
*Corresponding author (email: cjzhu@nju.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2014
chem.scichina.com link.springer.com

Pan CD, et al. Sci China Chem August (2014) Vol.57 No.8
Table 1 Screening for optimal reaction conditions a)
1173
phenanthridine (Scheme 1). In this way, difunctionalization
of sp3 C–H and sp2 C–H could be achieved. Herein, we re-
port a new oxidative 1,2-alkylarylation of 2-isocyanobi-
phenyl, through which an aryl C(sp2)–H bond and a
C(sp3)–H bond adjacent to an oxygen atom can be activated
for the selective synthesis of functionalized phenanthri-
dines.
Entry
1
[M]
–
Ligand
Radical initiator Yield(%) b)
–
TBHP c)
25
48
2
–
–
DTBP
3
–
–
Dicumyl peroxide
DDQ
31
0
2 Results and discussion
4
–
–
5
FeCl3
FeCl2
CuI
–
DTBP
58
52
50
43
75
66
40
46
Initially, we examined the reaction of biarylisonitrile (1a)
with 1,4-dioxane (2a) in the presence of a radical initiator.
Fortunately, the desired product 6-(1,4-dioxan-2-yl)phen-
anthridine 3aa was obtained in 25% yield using TBHP as
the radical initiator (Table 1, entry 1). The reaction yield
was increased to 48% in the presence of DTBP, while no
product was detected using DDQ. We attempted to promote
the yields by adding inorganic salts, such as FeCl3, FeCl2,
CuI. To our delight, 3aa was isolated in 58% yield when 5
mol% of FeCl3 was subjected to the procedure (Table 1,
entry 5). Next, we explored the benefits from some ligands,
such as DBU, DABCO, 2,2-dipyridine and TMDEA. Grati-
fyingly, the yield increased significantly to 75% when DBU
was used as a ligand (Table 1, entry 9). With several rounds
of optimization, the optimal reaction conditions were ac-
complished by using FeCl3 (5 mol%), DBU (10 mol%) and
DTBP (2 equiv) at 110 oC under N2 (Table 1, entry 9).
6
–
–
DTBP
7
DTBP
8
Bu4NI
FeCl3
FeCl3
FeCl3
FeCl3
–
DTBP
9
DBU
DTBP
10
11
12
DABCO
2,2-dipyridine
TMDEA
DTBP
DTBP
DTBP
a) Reaction conditions: 1a (0.2 mmol), [M] (5 mol%), ligand (10 mol%),
oxidant (0.4 mmol) and 2a (1 mL) under N2 atmosphere for 12 h at 110 oC;
b) isolated yield; c) TBHP (anhydrous, 5M in decane) = tert-butyl hydro-
genperoxide, DTBP = di-tert-butyl peroxide, TMDEA = tetramethylethyl-
enediamine, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DBU =
1,8-diazabicyclo[5.4.0]undec-7-ene, DABCO = 1,4-diazabicyclo[2.2.2]octane.
under the oxidative conditions. The isocyanides 1bh bear-
ing either electron-donating or electron-withdrawing sub-
stituents on 4-position of the aromatic ring all underwent
smoothly to provide the corresponding 6-(1,4-dioxan-2-yl)
phenanthridines 3ba3ha in moderate to good yields. To
investigate the regioselectivity of the cyclization, we studied
meta-substituted biphenyls (1j). This reaction resulted in
poor regioselectivity, and both isomers 3ja and 3'ja were
isolated in 30% and 38% yields, respectively. Subsequently,
we studied the effect of substituents on the aromatic ring
attached to isocyanide. As expected, the corresponding
6-(1,4-dioxan-2-yl)phenanthridines 1ks were afforded
upon oxidative cyclization of isocyanides with 1,4-dioxane
in good yields.
To explore the substrate scope of this protocol, the opti-
mized reaction conditions were applied to a series of
2-isocyanobiaryl compounds. As shown in Table 2, various
functional groups such as methoxy, chloro, fluoro, trifluo-
romethoxy and trifluoromethyl groups were well tolerated
Encouraged by the above results, we further investigated
the scope of ethers. Cyclic ethers such as THF (2b), 1,3-
dioxolane (2c) and tetrahydro-2H-pyran (2d) were also
good partners (Table 3, 3ab3ad). Gratifyingly, moderate
yields were obtained when acyclic ethers such as diethyl
ether (2e), tert-butyl methyl ether (2f) and 1,2-dimetho-
xyethane (2g) were subjected to the procedure. Two isomers
3ag and 3'ag were isolated in 44% and 31% yields, respec-
tively when 1,2-dimethoxyethane was tested.
Figure 1 Phenanthridine and ether moieties in biologically active com-
pounds.
To understand the mechanism for difunctionalization of a
2-isocyanobiphenyls, some isotopic experiments were car-
ried out. A mixture of substrates 1a and 1a' in a 1:1 ratio
was used to determine the intermolecular kinetic isotope
effect (KIE) (Scheme 2, Eq. (1)). The result demonstrated
that there is no kinetic isotope effect (kH/kD = 1) in intermo-
lecular experiments, suggesting that the arylation step may
Scheme 1 Our strategy via radical cyclization.

1174
Pan CD, et al. Sci China Chem August (2014) Vol.57 No.8
Table 2 The scope of 2-isocyanobiaryl compounds a)
Table 3 The scope of ethers a)
a) Reaction conditions: 1a (0.2 mmol), FeCl3 (5 mol%), DBU (10 mol%),
o
DTBP (0.4 mmol) and 2 (1 mL) under N2 atmosphere for 12 h at 110 C.
Isolated yield.
Scheme 2 Deuteration experiments.
this oxidative cyclization (Scheme 2, Eq. (2)).
On the basis of the above experimental results, a possible
mechanism (Scheme 3) is proposed. Initially, homolysis of
DTBP is assisted by Fe(II) into a tert-butoxy radical and
Fe(III) [11]. Substrate 2b with C(sp3)H bonds adjacent to
an oxygen atom is readily transformed into radical interme-
diate A in the presence of a tert-butoxy radical. Then, radi-
cal A attacks the N=C bond of 2-isocyanobiaryl 1a to form
the imidoyl radical B, which upon intramolecular cycliza-
tion with an aryl ring gives radical intermediate C. Finally,
a) Reaction conditions: 1 (0.2 mmol), FeCl3 (5 mol%), DBU (10 mol%),
DTBP (0.4 mmol) and 2a (1 mL) under N2 atmosphere for 12 h at 110 oC;
b) isolated yield.
be compatible with either SEAr or free radical mechanism
[10]. When 2.0 equiv. of 2,2,6,6-tetramethylpiperidine ox-
ide (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT)
was added as a radical inhibitor, no desired product was
observed, which supported the free radical mechanism.
However, the KIE result of the experiment between THF 2b
and [D8]THF 2b' (kH/kD = 4) showed that the sp3 C−H bond
cleavage should be involved in the rate-determining step of
Scheme 3 The proposed mechanism.

Pan CD, et al. Sci China Chem August (2014) Vol.57 No.8
1175
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takes place to provide 6-(tetrahydrofuran-2-yl)phenanthri-
dine 3ab.
3 Conclusions
In summary, we have developed a novel cascade radical
bimolecular C−C coupling of 2-isocyanobiaryls with ethers
to afford 6-alkylated phenanthridines. This reaction com-
prised functionalization of two C–H bonds, including the
sp3 C–H of ether and the sp2 C–H of phenyl group. In addi-
tion, cheap and commercially available DTBP was used as
an oxidant for this procedure.
6
This work was supported by the National Natural Science Foundation of
China (21172106, 21074054 and 21372114), the National Basic Research
Program of China (2010CB923303), and the Research Fund for the Doc-
toral Program of Higher Education of China (20120091110010). PAN
ChangDuo is thankful the support of the Natural Science Foundation of
China (21272178).
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ZHU ChengJian was born in Henan, China, in 1966. He obtained his Ph. D. from Shanghai Institute
of Organic Chemistry (CAS) in 1996 under the supervision of Professor Changtao Qian. Then he
worked as a postdoctoral fellow successively in Universite de Bourgogne, University of Oklahoma,
and then University of Houston from 1997 to 2000. He joined Nanjing University as an associate
professor in 2000. Since 2003, he has been a professor at Nanjing University. His present research
interests lie in organometallic chemistry and asymmetric catalysis.