Catalyst-free synthesis of (E)-2-alkenylquinoline derivatives via C(sp3)-H functionalization of 2-methylquinolines

Article abstract of DOI:10.1016/j.tetlet.2014.10.079

This Letter described a facile approach to synthesize (E)-2-alkenylquinoline derivatives via C(sp³)-H functionalization of 2-methylquinolines under catalyst-free conditions. A variety of electronically and sterically diverse 2-methyl quinoline and aromatic aldehydes were well tolerated.

Full text of DOI:10.1016/j.tetlet.2014.10.079

Accepted Manuscript
3
Catalyst-Free Synthesis of (E)-2-Alkenylquinoline Derivatives via C(sp )-H
Functionalization of 2-Methylquinolines
Zhuzhou Shao, Lubin Xu, Liang Wang, Huaili Zhao, Jian Xiao
PII:
S0040-4039(14)01773-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.079
TETL 45308
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
31 August 2014
30 September 2014
14 October 2014
Please cite this article as: Shao, Z., Xu, L., Wang, L., Zhao, H., Xiao, J., Catalyst-Free Synthesis of (E)-2-
3
Alkenylquinoline Derivatives via C(sp )-H Functionalization of 2-Methylquinolines, Tetrahedron Letters (2014),
doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.079
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Catalyst-Free Synthesis of (E)-2-Alkeny-
quinoline Derivatives via C(sp3)-H Functionalization of 2-Methylquinolines
Zhuzhou Shao, Lubin Xu, Liang Wang, Huaili Zhao, Jian Xiao*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
3
Catalyst-Free Synthesis of (E)-2-Alkenylquinoline Derivatives via C(sp )-H
Functionalization of 2-Methylquinolines
Zhuzhou Shao, Lubin Xu, Liang Wang, Huaili Zhao, Jian Xiao*
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266109, China
ARTICLE INFO
ABSTRACT
Article history:
Received
This letter described a facile approach to synthesize (E)-2-alkenylquinoline derivatives via
C(sp )-H functionalization of 2-methylquinolines under catalyst-free condition. A variety of
3
Received in revised form
Accepted
electronically and sterically diverse 2-methyl quinoline and aromatic aldehyes were well
tolerated.
Available online
2
014 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst-Free
Olefination
C(sp3)-H Activation
2
2
-Methylquinolines
-Alkenylquinoline
Nitrogen-containing aromatic heterocycles (azaarenes) are
diminish the application of these methods. Recent progress has
witnessed the use of transition metals as Lewis acids for direct
activation of 2-alkylazarenes. In this context, Huang group
ubiquitous in a large number of biologically active substances
1
9
such as pharmaceuticals, agrochemicals and natural products.
Among them, 2-alkenylquinoline cores are privileged structural
motifs and spread over a variety of bioactive molecules such as
reported an iron-catalyzed olefination of 2-substituted azaarenes,
which furnished (E)-2-alkenylated azaarenes through tandem
addition of 2-methylazaarenes to N-sulfonyl imines and
2
3
4
chimanine B (1), VUF 5017 (2), L-660,711 (3), and LY290154
5
9f
(
4) (Figure 1). Moreover, 2-alkenylquinoline itself contains an
elimination of amide (Scheme 1a). Subsequently, Wang et al
embedded imine and alkene, which might be exploited as a
versatile synthetic precursor to access a wide range of
functionalized heterocycles. Therefore, direct olefination of
reported a catalyst-free synthesis of (E)-alkenylazaarene via
similar tandem approach which afforded the corresponding (E)-2-
alkenylquinolines as the dominant isomers in moderate to
6
9
o
quinolines has great significance in organic synthesis and great
efforts have been devoted to develop efficient methods to
excellent yields (Scheme 1b). The (E)-2-alkenylquinolines
could also be facilely accessed via tandem addition and
dehydration of 2-methyquinolines and aldehydes in the presence
7
construct such motifs.
9
p
of La(Pfb) (Scheme 1c).
3
Figure 1 Biologically active 2-alkenlyazaarene derivatives.
Transition-metal-catalyzed cross-coupling reactions of
activated quinolines provides one of the most reliable approaches
8
to prepare the 2-alkenylquinolines. However, the noble metal
catalysts and prefunctionalized substrates, e.g. alkenyl halides
and borates are always required as coupling partners, which
Scheme 1 Synthesis of 2-alkenylquinolines.

2
Tetrahedron
With great interest in manipulation of azaarenes via
C(sp )-H functionalization, our group reported the first Brønsted
Under the optimized conditions, the substrate scope was
examined and the results were listed in Scheme 2. A variety of
electronically and sterically diverse 2-methyl quinolines and
aromatic aldehydes were well-tolerated. When methyl (3ba) or
bromine (3ca) was introduced to the 2-methylquinoline or
aromatic aldehydes, the yields were decreased to some extent. 1-
methylisoquinoline was also ideal substrate for this reaction
(3da, 3dg). Remarkably, the electronic characteristic of
aldehydes had important influence on the yields. The yields were
not much influenced by the steric hindrance of aromatic aldehyde
since 2, or 3 or 4-methyl benzaldehyde gave similar yields (3ab,
3ac, 3ad). Remarkably, when the aromatic aldehydes were
substituted with electron-withdrawing groups, such as nitro group
(3ag, 3ah) or fluorine (3af, 3al), chlorine (3ai, 3am) and bromine
(3aj, 3ak, 3dg), the analogous products were furnished in good
to excellent yield. Whereas if the aromatic aldehydes were
substituted with electron-donating groups (3ae), or comparatively
electron-rich aldehydes (3an, 3ao) the yields were inferior to
those of electron-poor aldehydes. The results could be
rationalized that the carbonyl group of electron-poor aldehyde
could be more readily attacked by the enamine generated from 2-
methylquinoline via tautomerization. Aliphatic aldehydes were
also investigated, whereas no desired product was observed.
Notably, when thiophene-2-carbaldehyde was subjected to the
optimized condition, in addition to the desired olefination
product (3ao), the adduct (4ao) was also observed.
3
3
acid-catalyzed sp C−H functionalization of 2-methylazaarenes,
providing a facile synthetic approach of biologically important
1
0a
azaarene-substituted 3-hydroxy-2-oxindoles in one step. On the
basis of that, recently we have successfully achieved a facile
catalyst-free tandem Michael addition/decarboxylation sp C-H
3
activation of 2-alkylazaarenes with (thio)coumarin-3-carboxylic
acids for the efficient construction of azaarene-substituted 3,4-
1
0b
dihydro-(thio)coumarins. As a continuation of development of
efficient and green methods to construct biologically active
9
j,10
molecules,
(
herein we reported the catalyst-free synthesis of
3
E)-2-alkenylquinoline derivatives via tandem C(sp )-H
functionalization of 2-methylquinolines/dehydration with
aldehydes in which water was the sole side product (1d). The
catalyst-free condition and only water as side product is highly
desirable and environmentally valuable.
a
Table 1. Optimization Studies
b
Entry
Solvent
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
THF
DMF
EtOH
DCE
Temp./℃
80
100
120
140
Yield /%
c
1
2
3
4
5
6
7
8
9
0
Trace
c
53
89
67
36
140
140
140
140
c
Trace
78 (13)
73 (20)
140
a
Reactions were conducted with 1a (1.0 mmol), 2a (0.5 mmol) in 2 mL
b
solvent, 48 h. Isolated yield of 3aa, and values in parentheses are isolated
c
yields of 4aa. The reaction time was 72 h.
Initially, 2-methylquinoline 1a and benzaldehyde 2a were
chosen as the model substrates and subjected to the reactions
under the catalyst-free conditions (Table 1). The reaction did not
proceed at 80℃ and almost no reaction at 100℃. To our delight,
this reaction proceeded smoothly at 120℃ in 1,4-dioxane and the
desired product (E)-3aa was obtained in 53% yield (Table 1,
entry 3). When the temperature was elevated to 140℃, the yield
was increased to 89% (Table 1, entry 4). The configuration of
(
comparison of the H NMR spectra of products with previous
E)-3aa was unambiguous established via coupling constants and
1
9
f,9o,9p,7d-q
literatures.
Subsequently, other solvents were also
examined, whereas no better result was achieved and the
employment of DMF merely resulted in trace product (Table 1,
entries 5-9). Notably, a small amount of by-product 4aa was
obtained when ethanol or 1, 2-dichloroethane were exploited as
solvent (Table 1, entries 8 and 9). From the results mentioned
above, it could be concluded that the polarity of solvent had
considerable influence on the reaction and the employment of the
nonprotonic solvent with comparatively strong polarity such as
THF and DMF was detrimental to the yield (Table 1, entry 6, 7).
However, the protonic polar solvent was beneficial to this
reaction such as EtOH (Table 1, entry 8). In terms of solvents
with weak polarity, such as toluene and DCE, led to much higher
yields (Table 1, entries 5, 9). Basically, the by-product 4aa was
furnished via Michael addition of 1a to 3aa in which 3aa can be
considered as a Michael acceptor.
Scheme 2 Substrate scope of 2-alkylazaarenes and arylaldehydes
Intriguingly, when the aromatic aldehyde 2p and 2q were
subjected to the standard condition, in addition to the desired
olefination product 3p and 3q, the alcohol product 5p and 5q
prior to dehydration were also obtained in 20% and 35% yield
respectively, even the reaction time was prolonged to 72h
(Scheme 3). Surprisingly, the results remained unchanged even
in the presence of 20 mol% TfOH.

3
C bond with this green approach are in due course in our
laboratory.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 21102142), the Outstanding Young Scientist Award
Foundation of Shandong Province (No. BS2013YY002,
BS2011YY007) and Qingdao Special Research Foundation of
Science and Technology (14-2-4-70-jch). Financial supports
from Talents of High Level Scientific Research Foundation (No.
Scheme 3 The reaction of 2-methylquinoline with 2p and 2q.
631223, 631009) of Qingdao Agricultural University is also
gratefully acknowledged.
These phenomena might be rationalized as follows: The
aromatic groups of aldehdyes 2p and 2q, i.e. 4-formylphenyl and
4
-pyridyl are electron-deficient ones. The dehydration process
consists of three steps, i.e. protonation of the hydroxyl group,
elimination of H O and deprotonation of the carbocationic
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(
E)-configured 3 is finally afforded.
3
Scheme 5 Mechanism for sp functionalization of 2-alkylazaaenes.
Conclusions
In summary, we have developed a facile catalyst-free
protocol to synthesize (E)-2-alkenylquinoline derivatives for the
first time. This approach offers organic chemists a novel atom-
3
economic pathway to directly functionalize sp C-H bond of 2-
8
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4
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