Iodine-Catalyzed Direct C-H Alkenylation of Azaheterocycle N-Oxides with Alkenes

Article abstract of DOI:10.1021/acs.orglett.6b03399

An efficient and regioselective alkenylation of azaheterocycle N-oxides with alkenes catalyzed by iodine under metal- and external oxidant-free reaction conditions has been developed. A variety of (E)-2-styrylazaheterocycles have been produced in moderate

Full text of DOI:10.1021/acs.orglett.6b03399

Letter
pubs.acs.org/OrgLett
Iodine-Catalyzed Direct C−H Alkenylation of Azaheterocycle
N‑Oxides with Alkenes
Zhenhao Zhang,† Chao Pi,† Heng Tong,‡ Xiuling Cui,*,† and Yangjie Wu*,†
†Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China
‡Henan Textiles Quality Testing and Inspecting Institutes, Zhengzhou 450000, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and regioselective alkenylation of
azaheterocycle N-oxides with alkenes catalyzed by iodine
under metal- and external oxidant-free reaction conditions has
been developed. A variety of (E)-2-styrylazaheterocycles have
been produced in moderate to excellent yields. The mech-
anistic exploration indicated that the N-oxide group played
dual roles as both the directing group and an internal oxidant
in this catalytic cycle.
irect C−H bond activation has attracted great interest in
contamination of the products, which is particularly significant in
Dorganic synthesis as the most efficient and straightforward the pharmaceutical industry12 and advanced functional materi-
als.13 Therefore, C−H activation reactions under metal-free
conditions are highly desirable.14
method to build C−C and C-heteroatom bonds.1 The high bond
energy, weak reactivity, and poor regioselectivity of the C−H
bond have led to very harsh reaction conditions. Transition
metal-catalyzed C−H functionalization through cyclometalation
has become an ideal strategy to overcome these substantial
challenges.2 For instance, the transition-metal catalyzed oxidative
Heck reaction has been widely used to create functionally diverse
and structurally complicated compounds.3 Generally, an external
oxidant is required to regenerate the active catalytic species,
which would provide a stoichiometric amount of the reduced
external oxidant as waste and reduce the overall “greenness”
of the process. Our group has previously developed a novel
alkenylation of quinoline N-oxides catalyzed by palladium in
which the N-oxides served as an oxidizing directing group
(ODG) and additional oxidants were avoided (Scheme 1a).4 The
clear advantages of ODGs, which serve as both directing group
and oxidant, thereby simplifying reaction systems and making
reactions more concise and efficient, have attracted interest
in C−H activation. Further progress has been achieved by
the Yu,5 Ackermman,6 Hartwig,7 Li,8 Shi,9 Glorius,10 and other
groups.11 However, the use of transition metals may cause potential
Iodine has concurrently been developed as a newly emerging
nonmetal catalyst due to its low toxicity, convenient after-
treatment, and ease of removal, and it has emerged as one of the
most active research topics in organic synthesis.15 Our interest in
clean cross-dehydrogenative coupling reactions under external
oxidant-free conditions spurred us to test the feasibility of iodine-
catalyzed oxidative alkenylation.14d,16 Herein, we embarked on
the development of a highly efficient and selective iodine-
catalyzed direct alkenylation of azaheterocycle N-oxides with
alkenes as part of our continuing work. In this transformation, the
substrate scope was successfully extended to low activity alkenes,
and the N−O group served as an oxidizing directing group and
avoided the use of a metal catalyst (Scheme 1b).
The condensation of quinoline N-oxide 1a and styrene 2a was
chosen as an initial model reaction to screen various reaction
parameters (Table 1). In an initial attempt, 1a was treated with
2a in the presence of I2 (10 mol %) in toluene at 120 °C under air
for 22 h. As a result, the desired dehydrogenative coupling
product 3aa was formed in 57% yield (Table 1, entry 1). The
molecular structure of product 3aa was confirmed by single
crystal X-ray diffraction analysis (SI, Figure S1) and NMR
spectra. Next, various solvents were screened (entries 2−6).
Among them, DCM gave the best results to afford 3aa in 83%
yield. Decreasing the reaction time to 5 h gave the same result
(entry 7). Pleasingly, 2 mol % I2 was sufficient for this trans-
formation, affording the coupling product 3aa in 83% yield
(entries 8−11). No target product was observed in the absence
of iodine (entry 12) and in the presence of KI instead of I2.
Scheme 1. Oxidative Alkenylation Reaction under External
Oxidant-Free Conditions
Received: November 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03399
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Letter
Table 1. Optimization of the Reaction Conditions for
Quinoline N-Oxide 1a with Styrene 2a
Scheme 2. Substrate Scope of Heteroaromatic N-Oxides with
Alkenes
a
a,b
b
entry
I2 (mol %)
solvent
toluene
time (h)
yield (%)
1
10
10
10
10
10
10
10
15
5
22
22
22
22
22
22
5
57
71
82
62
83
75
83
82
85
83
43
2
1,4-dioxane
MeCN
DCE
3
4
5
DCM
6
7
DCM
DCM
DCM
DCM
DCM
DCM
DCM
8
5
9
5
10
11
12
13
14
15
16
17
18
2
5
1
5
c
0
5
n.d.
d
2
24
24
24
24
5
58
e
2
69
e
2
DCM
DCM
DCM
DCM
67
f
2
58
g
2
66
h
2
5
35
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 mmol), solvent
b
c
(0.5 mL), under air, 120 °C. Isolated yield. n.d. = not detected.
d
e
f
g
h
Sealed container. N2. O2. 2a (1.0 mmol). 2a (0.4 mmol).
a
The transformation was incomplete after 24 h in a sealed
container in air as well as under N2 and O2 atmospheres (entries
13−16). Decreasing the loading of 2a to 1.0 or 0.4 mmol led to
lower yield of 66% and 35%, respectively (entries 17 and 18).
With the optimized conditions set, the substrate scope of this
transformation was investigated (Scheme 2). A range of alkenes
were tested with quinoline N-oxide (1a). Styrenes with electron-
donating and electron-with drawing substituents (such as Me, F,
Cl, Br, and NO2) at the para-position of the benzene ring gave the
desired products in excellent yields (3aa−af). Generally, styrenes
with electron-donating groups gave higher yields than those with
electron-withdrawing groups (3aa−ab vs 3ac−af). The
efficiency of the alkenylation was not significantly affected by
steric hindrance (3aa−ah vs 3ai−ak). For instance, 4-chlorostyr-
ene (2d) gave a similar yield to 2-chlorostyrene (2j). Further-
more, 2-vinylpyridine and 2,3,4,5,6-pentafluorostyrene could
give the corresponding C2-alkenylated products in 66% and 70%,
respectively (3al and 3am). However, aliphatic alkene is not
suitable for this reaction system. For example, no desired product
was observed when vinylcyclohexane was used as a reactant
under the standard reaction conditions.
We next investigated a range of heteroaromatic N-oxides to react
with styrene (2a) under the optimized conditions (Scheme 2).
Electronically and sterically diverse quinoline N-oxides all par-
ticipated smoothly to provide the targets in good to excellent
yields (3ba−sa). A strong electron-withdrawing group such as
5-nitroquinoline (2i) generated the product 3ia in 85% yield.
C8-substituted quinoline N-oxides (2r and 2s) provided the
desired products in 48% (3ra) and 50% (3sa) yields. Isoquinoline
N-oxide (2t), 6-bromoisoquinoline N-oxide (2u), and quinoxa-
line N-oxide (2v) are also suitable for this catalytic system
and generated the desired products in 58%, 62%, and 48% yields
(3ta, 3ua, and 3va). Pyridine oxides instead of quinolone-oxide
could not give the desired product.
Reaction conditions: 1 (0.2 mmol), 2 (2.0 mmol), DCM (0.5 mL),
b
c
120 °C, 5 h, air. Isolated yield. Twenty-four hours.
Compounds containing the 7-chloro-2-styrylquinoline moiety
are always present in leukotriene receptor antagonists.17 To
demonstrate the synthetic utility of this alkenylation reaction, a
gram-scale reaction of 7-chloroquinoline N-oxide (1m) and
styrene (2a) was carried out. As shown in Scheme 3, (E)-7-chloro-
2-styrylquinoline (3ma) was obtained in 75% yield.
Scheme 3. Gram-Scale Reaction of 1m with 2a
To clarify the reaction mechanism, control experiments were
performed (Scheme 4). Addition of the radical scavenger BHT
(2,6-ditert-butyl-4-methylphenol) to the reaction mixture afforded
the target product 3aa in 82% yield (Scheme 4a), suggesting the
impossibility of a radical process. When quinoline was used
instead of quinoline N-oxide as the reactant under the standard
reaction conditions, no desired 3aa was found, which indicated
that the N−O group played an important role in this transforma-
tion (Scheme 4b). Moreover, when a mixture of 5-nitroquinoline
1-oxide 1i and quinoline (1:1) were added to the reaction system,
only 3aa was detected (Scheme 4c), further indicating the crucial
role of N-oxide.
Based on the obtained results and the literature,18 a plausible
reaction mechanism is proposed (Scheme 5). Initially, the oxygen
atom in quinoline N-oxide (1a) was attacked by the iodine, leading
to the formation of quaternary ammonium salt intermediate A.
B
DOI: 10.1021/acs.orglett.6b03399
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Scheme 4. Control Experiments
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly acknowledge partial financial support from the NSF
of China (21572072), the Science and Technology Innovation
Program of the Universities of Henan Province (16HAS-
TIT007), and Zhengzhou University
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03399.
General experimental procedure and characterization data
of the products (PDF)
CIF data of 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cuixl@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
ORCID
Xiuling Cui: 0000-0001-5759-766X
C
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