Facile synthesis of 2-alkenylazaarenes via dehydrative coupling of 2-methylazaarenes with aldehydes ‘on water’

Article abstract of DOI:10.1016/j.tetlet.2016.08.065

A catalyst-free dehydrative coupling of 2-methylazaarenes with aldehydes ‘on water’ has been developed for efficient synthesis of (E)-2-alkenylazaarenes. The challenging addition/dehydration of aliphatic aldehyde was successfully implemented using water as a solvent. A variety of 2-methylazaarenes, aromatic and aliphatic aldehydes were well tolerated.

Full text of DOI:10.1016/j.tetlet.2016.08.065

Accepted Manuscript
Facile Synthesis of 2-Alkenylazaarenes via Dehydrative Coupling of 2- Meth-
ylazaarenes with Aldehydes “on Water”
Shiheng Fu, Liang Wang, Haoxun Dong, Junqiang Yu, Lubin Xu, Jian Xiao
PII:
S0040-4039(16)31092-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.065
TETL 48036
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 June 2016
17 August 2016
20 August 2016
Please cite this article as: Fu, S., Wang, L., Dong, H., Yu, J., Xu, L., Xiao, J., Facile Synthesis of 2-Alkenylazaarenes
via Dehydrative Coupling of 2- Methylazaarenes with Aldehydes “on Water”, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.08.065
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Facile Synthesis of 2-Alkenylazaarenes via Dehydrative Coupling of 2-
Methylazaarenes with Aldehydes “on Water”
Shiheng Fu,a Liang Wang,a,c Haoxun Dong,a Junqiang Yu,b Lubin Xua and Jian Xiaoa,c*

1
Tetrahedron Letters
Facile Synthesis of 2-Alkenylazaarenes via Dehydrative Coupling of 2-
Methylazaarenes with Aldehydes “on Water”
Shiheng Fu,a Liang Wang,a,c Haoxun Dong,a Junqiang Yu,b Lubin Xua and Jian Xiaoa,c*
a College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266109, China
b Rongcheng Entry-Exit Insepection and Quarantine Bureau, Weihai 264300, China
c Hubei Key Laboratory of Drug Synthesis and Optimization, Jingchu University of Technology, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A catalyst-free dehydrative coupling of 2-methylazaarenes with aldehydes “on water” has been
developed for efficient synthesis of (E)-2-alkenylazaarenes. The challenging
addition/dehydration of aliphatic aldehyde was successfully implemented by using water as a
solvent. A variety of 2-methylazaarenes, aromatic and aliphatic aldehydes were well tolerated.
2014 Elsevier Ltd. All rights reserved.
Available online
Keywords:
On water
Olefination
C(sp3)-H functionalization
2-Methylazaarene
2-Alkenylazaarene
The use of water as a reaction medium in organic synthesis
has emerged as an attractive research area since the pioneering
works of Breslow1 and Sharpless.2 Owing to the fascinating
advantages of water over traditional organic solvents,3 various
type of “in water” or “on water” reactions are completely in
conformity with the standpoint of green chemistry and the
development of green protocols for the synthesis of highly
functionalized bio-active motifs in aqueous medium is highly
desirable.4 In addition to the environmental issue, the unique
physical and chemical properties such as high dielectric constant,
strong ability to form hydrogen bonds and amphoteric nature can
not only dramatically accelerate the rate of the reaction but also
positively influence the reactivity and selectivity of chemical
reactions. Therefore, the current challenges in organic synthesis
might be tackled by using water as solvent. The tandem
nucleophilic addition/dehydration of aldehydes or ketones
represented an important methodology towards the green
synthesis of a variety of valuable vinylogous compounds as water
is the only by-product. In contrast to traditional dehydrative
coupling of aldehydes in organic solvents, this type of reaction
“on water” was undisputably fascinating.
and efficient methods to synthesize 2-alkenylazaarenes. Although
direct olefination of azaarenes has been developed to construct
such motifs,7 expensive and toxic noble metals and high
temperatures are always necessary.
2-Alkenylazaarenes motif can be frequently found in an
ocean of biologically active molecules as antagonist,
antiproliferative, antiviral and antimicrobial agents such as
Chimanine B I, VUF5017 III, CGS23113 II, Montelukast IV, L-
Figure 1 Biologically active 2-alkenlyazaarene derivatives.
Recently, a number of efficient methods through direct
C(sp3)–H functionalization of 2-alkylazaarenes has been
developed.8-11 For example, an iron or lanthanide catalyst has
been used for olefination of 2-alkylazaarenes with aldehydes.9
The similar transformation could also be accomplished with
aldimines as electrophiles under catalyst-free condition only
using toluene as solvent.10 The oxidative olefination of 2-
660,711
V
and VI (Figure 1).5 More interestingly, 2-
alkenylazaarenes contain embedded imines and alkenes, which
can be employed as versatile synthetic precursors to access a
variety of functionalized azaarenes.6 Considering the importance
of 2-alkenylazaarenes, it is highly desirable to develop simple

2
Tetrahedron
Initially, the reaction of valeraldehyde 1a and 2-
methylquinoline 2a was carried out in toluene at 80℃ and
moderate yield could be obtained (Table 1, entry 1). The desired
product was also observed in alcoholic solvents, albeit with
lower yields (Table 1, entries 2-3). However, no reaction
occurred in other solvents such as DMF and DMSO (Table 1,
entries 4-6). Consistent with our proposal, this reaction
proceeded smoothly in water and afforded the product 3a in 74%
yields (Table 1, entry 7). The higher temperature did not benefit
the yields and the employment of excessive aldehydes was
critical to the good yield of this transformation (Table 1, entries
8-10). Hence, water was identified as the optimal solvent in
terms of reaction efficiency and benignity as well as the cost.
Afterwards, a variety of sterically and electronically diverse
substrates were examined to investigate the generality of this
transformation under the optimal condition (Scheme 1). The
reaction of 2-methylquinoline and with aliphatic aldehydes such
as butyraldehyde and isovaleraldehyde could give the
corresponding products in moderate to good yields (3a-3f).
alkylazaarenes with N-alkylanilines in the presence of DDQ or
with dimethylformamide (DMF) mediated by TBHP have also
been explored.11 However, all these methods suffered from the
use of organometallic compounds, organic solvents, prepared
imines and harsh conditions. Furthermore, in most cases,
aromatic aldehydes were employed as electrophiles, and in
contrast, comparatively less investigation was conducted on
aliphatic aldehydes despite that 2-alkenylazaarenes with alkyl
group are important such as Chimanine B.9b,10 Although the work
of Zhou9b and Wang10 showed the sporadic examples of aliphatic
aldehydes, the yields were low and not satisfied.
During our research interest in C(sp3)-H functionalization of
azaarenes,11 our group reported the first organocatalytic C(sp3)–H
functionalization of 2-alkylazaarenes and followed by that, the
catalyst-free C(sp3)-H functionalization of 2-alkylazaarenes were
also achieved by the rational substrate design.12a-c As a
continuation of that, we developed a facile catalyst-free protocol
to synthesize 2-alkenylquinolines in good yields via C(sp3)-H
functionalization of 2-alkylazaarenes with aromatic aldehydes in
dioxane, whereas the employment of aliphatic aldehydes still
remained elusive.11c Keeping the challenges in mind and inspired
by our “on water” reactions,13 we envisaged that this issue might
be addressed by the hydrophobic effect and emulsions of aqueous
Scheme 1 Synthesis of 2-alkenylquinolines
solutions. Herein, we would like to report our new catalyst-free
synthesis
of
(E)-2-alkenylazaarenes
via
C(sp3)-H
functionalization of 2-alkylazaarenes with aldehydes “on water”.
Considering that water is the most inexpensive and
environmentally benign reaction medium, together with the
catalyst-free condition and only water as side product, this
process is highly desirable and environmentally valuable for
direct synthesis of (E)-2-alkenylazaarenes.
Table 1. Optimization Studiesa
Entry
Solvent
Yield (%)
T [℃]
1
2
3
4
5
6
toluene
MeOH
i-PrOH
DMF
1,4-dioxane
DMSO
80
80
80
80
80
80
52
46
21
NR
NR
NR
7
8
H2O
H2O
80
90
74
72
9
10
H2O
H2O
100
120
68
65
Scheme 2 Substrate scope of 2-alkylazaarenes and aldehydes.
Reactions were conducted with 1a (10 mmol for aliphatic aldehyede
and 5 mmol for aryl aldehyde), 2a (1 mmol) in 5 mL H2O, 36 h.
a Reactions were conducted with 1a (5 mmol), 2a (0.5 mmol) in 5
mL H2O, 36 h.

3
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methylquinoxaline, aliphatic aldehydes and 2-methylquinoline
were less-than-ideal substrates, with which only moderate yields
could be achieved (3a-3d). In addition to the desired products,
much of the substrates remained intact. Meanwhile, trace side
products were indeed observed. Subsequently, a multitude of
diverse 2-methylquinolines and aromatic aldehydes were tested.
Electron-deficient or electron-rich aromatic aldehydes were well
tolerated to furnish the analogous products in good yield (3g-3z).
When aromatic aldehydes were substituted with electron-rich
groups such as methoxyl group (3n), the yields were superior to
those of electron-poor aldehydes such as fluorine (3h) and nitro-
group substituted ones (3l). 1-Methylisoquinoline and the
quinoxaline ring were also good substrates for this reaction,
furnishing the desired product in good yields (3r-3y). In addition
to phenyl aldehydes, furanyl aldehyde also worked very well
(3z). At last, formaldehyde, acetophenone, and cyclohexanone
were subjected to the reaction under the standard condition,
aiming to access 2-vinylquinoline, trisubstituted alkenes or
tertiary alcohols, whereas no transformation could be observed
and all the reactants remained intact.
Conclusions
In summary, we have developed a facile catalyst-free protocol to
synthesize (E)-2-alkenylquinolines “on water”. The challenging
addition/dehydration of aliphatic aldehyde was successfully
implemented by using water as a solvent. Compared with the
traditional methods, the advantages of using water as solvent and
only water as side product render this methodology atom-
economic and environmentally friendly to access (E)-2-
alkenylquinoline derivatives, which can be further employed as
synthetic precursors to build an army of functionalized
heterocycles. Further development of green methods for C(sp3)-H
functionalization of azaarenes “on water” are ongoing in our
laboratory.
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Acknowledgments
12. (a) Niu, R.; Xiao, J.; Liang, T.; Li, X. Org. Lett .2012, 14, 676. (b) Xu, L.;
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Wang, L.; Xiao, J.; Loh, T.-P. ChemChatChem. 2014, 6, 1183. (f) Xiao,
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Green Chem. 2015, 18, 1032.
We are grateful to the National Natural Science Foundation of
China (Nos. 21102142). Financial supports from Talents of High
Level Scientific Research Foundation (Nos. 6631112323,
6631115015) of Qingdao Agricultural University and Open
Project Program of Hubei Key Laboratory of Drug Synthesis and
Optimization, Jingchu University of Technology (Nos.
OPP2015YB01 and OPP2015ZD02) are also appreciated.
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Highlights
 Synthesis of 2-alkenylazaarenes via reaction of 2-methylazaarenes with aldehydes.
 The aliphatic aldehyde problem was harnessed by using water as a solvent.
 Water as solvent and no catalyst render this method atom-economic and green.