A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines via dual C(sp3)-H/C(sp 2)-H functionalizations

Article abstract of DOI:10.1039/c4ob01256a

A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines has been developed through dual C(sp ³)-H/C(sp²)-H functionalizations. The synthetic method has the advantages of high yields, good compatibility of functional groups and mild reaction conditions, although very unreactive alkanes were involved in the reaction. A plausible mechanism through both copper-catalyzed and DTBP mediated pathways has also been proposed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01256a

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A cascade alkylarylation reaction of
2-isocyanobiphenyls with simple alkanes for
6-alkyl phenanthridines via dual C(sp3)–H/
C(sp2)–H functionalizations†
Cite this: DOI: 10.1039/c4ob01256a
Received 17th April 2014,
Accepted 20th June 2014
DOI: 10.1039/c4ob01256a
www.rsc.org/obc
Zhi-Qiang Zhu,a Tian-Tian Wang,a Peng Baia and Zhi-Zhen Huang*a,b
A cascade alkylarylation reaction of 2-isocyanobiphenyls with to undergo a cascade alkylarylation reaction with alkanes to
simple alkanes for 6-alkyl phenanthridines has been developed give oxindoles via dual C(sp3)–H/C(sp2)–H functionalizations.5a
through dual C(sp3)–H/C(sp2)–H functionalizations. The synthetic In view of the significance of alkane C–H functionalizations,
method has the advantages of high yields, good compatibility of and as a continuation of our studies on C–H bond functionali-
functional groups and mild reaction conditions, although very zations,6 we carried out the investigation on C–H functionali-
unreactive alkanes were involved in the reaction. A plausible zations of simple alkanes.
mechanism through both copper-catalyzed and DTBP mediated
Phenanthridines are biologically important compounds
that exist in nature and are useful as drugs or drug candidates
in medicinal chemistry.7,8 These heterocycles show different
biological activities, such as antibacterial, antitumoral, cyto-
toxic, and antileukemic activity.8 Recently, a cascade reaction
of radical addition to 2-isocyanobiaryls followed by aromatic
substitution has become a main strategy for the synthesis of
6-substituted phenanthridine derivatives (Scheme 1).9 Very
recently, a couple of cascade reactions of 2-isocyanobiaryls via
C–H activations for 6-substituted phenanthridine derivatives
were reported (Scheme 2).10,11 In 2013, Studer’s group reported
that 2-isocyanobiaryls participated in a cascade reaction with
aldehydes to give 6-aroylated phenanthridine derivatives in the
presence of FeCl3 as a catalyst and TBHP as an oxidant.10 In
2014, Ji and Cheng et al. have independently developed a facile
cascade reaction of 2-isocyanobiaryls with ethers for 6-alkyl
phenanthridine derivatives via dual C(sp3)–H/C(sp2)–H func-
tionalizations, the C(sp3)–H bonds of which are active.11 To
the best of our knowledge, the cascade alkylarylation reaction
of 2-isocyanobiaryls with simple alkanes possessing inactive
C(sp3)–H bonds leading to 6-alkyl phenanthridine derivatives
pathways has also been proposed.
Carbon–carbon bond formations by direct C–H functionaliza-
tions are of fundamental interest in modern synthetic organic
chemistry, as it can potentially lead to more efficient synthesis
with a reduced number of synthetic operations.1 Among
various C–H bonds, the functionalization of active sp3 C–H
bonds, such as α-C–H bonds of amines, ethers, benzylic and
allylic C–H bonds, has received great attention in recent
years.1,2 By contrast, the studies on direct C–H functionaliza-
tions of simple alkanes for the formation of C–C bonds are
much fewer. However, these are important and challenging
tasks because aliphatic C–H bonds are ubiquitous in organic
compounds and are among the least reactive bonds. In the
past few years, new progress has been made in C–H functionali-
zations of alkanes for C–C bond formation.3–5 For example, in
2008 Li et al. developed a novel coupling reaction of 2-arylpyri-
dines with simple cycloalkanes for C–C bond formation using
the ruthenium complex as a catalyst and TBHP as an oxidant.3a
In 2013, Antonchick and co-workers reported an efficient coup-
ling reaction of quinolines with simple alkanes in the presence
of [bis(trifluoroacetoxy)iodo]benzene and NaN3.4a In 2014,
Liu’s group disclosed that under the catalysis of Cu2O and in
the presence of dicumyl peroxide, N-arylacrylamides were able
aDepartment of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028,
P. R. China. E-mail: huangzhizhen@zju.edu.cn; Fax: +86-0571-8880-7077;
Tel: +86-0571-8795-1352
bState Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin,
300071, P. R. China. E-mail: huangzz@nju.edu.cn
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data and the spectra of 1H NMR, 13C NMR MS and
HRMS for products. See DOI: 10.1039/c4ob01256a
Scheme 1 The cascade reaction of 2-isocyanobiaryls for 6-substituted
phenanthridine derivatives.
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9 and 10). For further screening of the amount of DTBP, it was
found that 3.5 eq. DTBP was the best, increasing the yield of
3a to 75% (Table 1, entry 11). Effects of the temperature and
the amount of cyclohexane on the reaction were also investi-
gated, and the best yield could be obtained when the reaction
was performed at 120 °C in 5 mL cyclohexane for 0.2 mmol
biarylisonitrile (Table 1, entries 12–14, also see SI†). In the
absence of Cu2O, the yield of 3a decreased remarkably, but
still was 68% (Table 1, entry 15). This result suggested that the
reaction possibly underwent both copper-catalyzed and metal-
free pathways.
After screening the reaction conditions, it can be concluded
that the optimized reaction should be performed using 5 mol%
Cu2O and 3.5 eq. DTBP at 120 °C. Under the optimized reac-
tion conditions, a variety of 2-isocyanobiaryls 1a–l were
employed to react with cyclohexane 2a (Table 2). It was found
that a broad range of 2-isocyanobiaryls 1a–l could undergo the
cascade reaction with cyclohexane 2a smoothly, affording the
desired alkylarylated products 3aa–la in the yields of 71–78%
(Table 2). The cascade reaction seems to be not sensitive to
electronic effects in benzene rings without isocyano groups,
and electron-donating groups on the benzene rings of 2-isocyano-
phenyls 1aa–fa led to similar yields of 3aa–fa with that of
electron-withdrawing groups on the benzene rings of 1ga–ia
(Table 2, compare 3aa–fa with 3ga–ia). Similarly, both an elec-
tron-donating group and an electron-withdrawing group on
the benzene rings attached by isocyano groups in 2-isocyano-
Scheme 2 The cascade reaction of 2-isocyanobiaryls for 6-substituted
phenanthridine derivatives via dual C–H functionalizations.
has remained unknown. Herein, we wish to present our recent
results on a cascade reaction of 2-isocyanobiaryls with simple
alkanes for 6-alkyl phenanthridine derivatives via dual C(sp3)–
H/C(sp2)–H functionalizations.
Initially, 2-isocyanobiphenyl 1a and cyclohexane 2a were
chosen as model substrates to explore and optimize the
cascade alkylarylation reaction. When the reaction was per-
formed in the presence of 5 mol% CuCl and 2 eq. TBHP under
air at 110 °C, we were pleased to find that the desired 6-cyclo-
hexyl phenanthridine 3a formed in 38% yield (Table 1, entry1).
Then, other copper catalysts were examined in the reaction.
Among these copper salts, Cu2O is the most efficient for the
yield (Table 1, compare entries 1–4 with entry 5, also see SI†).
Using other peroxides led to similar yields, and di-tert-butyl
peroxide (DTBP) proved to be the best (Table 1, compare
entries 5–7 with entry 8). No desired reaction occurred when
K2S2O8 or O2 was employed as an oxidant (Table 1, entries
Table 2 Reaction scope of 1a–l with 2aa,b
Table 1 Screening of reaction conditionsa
Entry
[M]
Oxidant
T(°C)
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBPB
DCP
DTBP
K2S2O8
O2
DTBP
DTBP
DTBP
DTBP
DTBP
110
110
110
110
110
110
110
110
110
110
110
90
38
45
20
42
52
58
56
63
—
CuBr2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
—
9
10
11c
12c
13c
14c
15d
—
75
Trace
82
80
68
120
130
120
a Reaction conditions: 1a (0.2 mmol), 2a (5 ml), catalyst (5 mol%),
oxidant (2 equiv.), air, 110 °C, 24 h. b Isolated yield. c 3.5 eq. oxidant. a Reaction conditions: 1 (0.2 mmol), 2a (5 ml), Cu2O (5 mol%), DTBP
d In the absence of transition-metal catalyst.
(3.5 equiv.), air, 120 °C, 24 h. b Isolated yield.
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phenyls 1ja–la resulted in satisfactory yields of 3ja–la. When
1d was employed instead of 1a, two isomers of o-arylation 3da
and p-arylation 3da′ products were isolated in 47% and 31%
yields, respectively. Although cyclohexane 2a is unreactive as a
reactant, the cascade alkylarylation reaction tolerates a range
of functional groups, such as fluoro, chloro, trifluoromethyl,
methoxy and methyl groups.
To further examine the scope of alkanes, the optimized
reaction conditions were applied to other alkanes 2b–g. We
were pleased to find that cyclopentane 2b, cycloheptane 2c,
cyclooctane 2e and cyclodecane 2f also worked well and all
gave the desired products 3ab–3ae in good yields (Table 3).
When adamantane 2f was used in the reaction, the mixture of
two alkylated isomers 3af and 3af′ was obtained through ter-
tiary C–H bond and secondary C–H bond activations, respect-
ively. When acyclic alkane, hexane 2g was employed in the
reaction, a mixture of alkylated regioisomers 3ag was also
obtained. Highly selective C(sp3)–H functionalization at the
2-position of the 6-hexyl group in 3ag was observed. Although
either steric hindrance or C–H abundance in the 3-position of
isopentane 2h is more beneficial for C–H functionalization as
compared to those in the 2-position, the C–H functionalization
in the 2-position is much more than that in the 3-position of
the product 3ah. It is obvious that the free radical stabilities,
Scheme 3 Plausible mechanism.
which at 3 °C is more stable than 2 °C, played a powerful role
in the C(sp3)–H functionalization of isopentane 2h.
When a radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyl-
oxy (TEMPO), was added into the reaction system, the cascade
reaction was completely suppressed. This result suggests that
the mechanism may undergo a radical pathway. Based on the
literature,9a,10 a plausible mechanism is depicted in Scheme 3.
Initially a tert-butoxyl radical generated by either Cu(I)-catalysis
or decomposition of DTBP by heating may abstract an α-hydro-
gen atom of cyclohexane 2a to form the cyclohexyl radical 4.12
Then the radical addition of 4 to 2-isocyanobiphenyl 1a gives
the imidoyl radical 5. Intramolecular aromatic substitution of
5 generates the cyclohexadienyl radical 6. Subsequently, the
radical 6 takes away an electron by either a Cu(II) or a tert-
butoxyl radical to form the cyclohexadienyl cation 7 with
regenerating Cu(I) or generating the tert-butoxyl anion. Finally,
deprotonation of 7 results in the desired 6-cyclohexyl phenan-
thridine 3a.
Table 3 Reaction scope of 1a–c with 2b–ga,b
Conclusions
In summary, we have developed a cascade alkylarylation reac-
tion of 2-isocyanobiphenyls 1 with simple alkanes 2 for 6-alkyl
phenanthridines 3 via dual C(sp3)–H/C(sp2)–H functionaliza-
tions. The synthetic method has the advantages of high yields
and good compatibility of functional groups although very
unreactive alkanes were involved in the reaction. A plausible
mechanism through both copper-catalyzed and DTBP
mediated pathways has also been proposed. Further studies on
other azaarene involved reactions with alkanes and related
mechanisms are currently underway in our laboratory.
Acknowledgements
We gratefully thank MOST of China (973 program 2011
CB808600) and the National Natural Science Foundation of
China (No. 21372195) for financial support.
a Reaction conditions: 1 (0.2 mmol), 2a (5 ml), Cu2O (5 mol%), DTBP
(3.5 equiv.), air, 120 °C, 24 h. b Isolated yield. c 10 eq. adamantine in
EtOAc (5 ml). d 130 °C. e 130 °C, 5 equiv. DTBP, 48 h.
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