Multicomponent synthesis of polysubstituted dihydroquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.07.008

A series of new poly-functionalized dihydroquinoline derivatives (26 examples) were synthesized via three-component reactions of aldehydes (1 equiv) and 1-arylethylidenemalononitriles (2 equiv) in ethylene glycol using NaOH as a base promoter under microwave irradiation. During these reaction processes, the domino construction of dihydroquinoline skeleton with concomitant formation of two new cycles was readily achieved in a one-pot operation and in an intermolecular manner.

Full text of DOI:10.1016/j.tetlet.2012.07.008

Tetrahedron Letters 53 (2012) 5071–5075
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Tetrahedron Letters
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Multicomponent synthesis of polysubstituted dihydroquinoline derivatives
⇑
⇑
Yan Yu, Man-Su Tu, Bo Jiang , Shu-Liang Wang, Shu-Jiang Tu
School of Chemistry and Chemical Engineering and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 211116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new poly-functionalized dihydroquinoline derivatives (26 examples) were synthesized via
three-component reactions of aldehydes (1 equiv) and 1-arylethylidenemalononitriles (2 equiv) in
ethylene glycol using NaOH as a base promoter under microwave irradiation. During these reaction
processes, the domino construction of dihydroquinoline skeleton with concomitant formation of two
new cycles was readily achieved in a one-pot operation and in an intermolecular manner.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 24 April 2012
Revised 28 June 2012
Accepted 3 July 2012
Available online 20 July 2012
Keywords:
Microwave (MW)-assisted synthesis
Polysubstituted hydroquinoline
Multicomponent domino reactions
Heterocyclic compounds embedded with nitrogen are prevalent
in nature and present in numerous natural products and pharma-
ceutical leads. Among the nitrogen heterocycles, the partially
hydrogenated quinoline derivatives are important motifs, for being
widely found in many natural products, many of them displaying
biological activities1 such as psychotropic,2 anti-allergenic,3 anti-
inflammatory,4 and estrogenic activities.5 Owing to their biological
importance, the synthesis of these derivatives attracted the atten-
tion of synthetic chemists, and hence, many synthetic strategies
are dedicated to get accesses to these frameworks. Skraup reac-
tion,6 Bischler–Napieralski synthesis,7 and Povarov’s reaction8 are
a few well-known synthetic protocols employed for the preparation
of tetrahydro/dihydroquinoline derivatives. Very recently, many
methodologies for the synthesis of polyhydroquinolines have been
developed; most of them involved Lewis acid-catalyzed cascade
cyclization of anilines,9 ruthenium-catalyzed ring-closing
metathesis,10 copper11 rhodium(I)-12, silver-,13 or gold(I)-catalyzed
coupling of anilines14, Diels–Alder intramolecular addition of 1,2,4-
triazines,15 and palladium-catalyzed cycloadditions of benzoxazin-
anones.16 However, the substrate availability, cost, stoichiometric
amount of additives, and functional group tolerance are some
limitations of the current methods for dihydroquinolines’ synthesis.
Moreover, during most of these reaction processes only the
construction of pyridine skeleton was achieved through benzannu-
lation reaction. Therefore, a simple and novel method for synthesiz-
ing polyhydroquinoline, especially the simultaneous formation of
phenyl and pyridine rings in one-pot operation, is highly desirable
and has practical benefits.
On the other hand, the development of new methodologies
aimed at improving synthetic efficiency is an important goal in
contemporary organic synthesis. Multicomponent domino
reactions (MDRs), which involve several bond-forming reactions
in a one-pot manipulation, represent an attractive strategy in the
facile assembly of molecular architecture.17 Such reactions are able
to create combinatorial libraries of complex and diverse structures
in efficient fashion by virtue of their convergent nature.
Very recently, we have developed a series of multicomponent
domino reactions (MDRs) that provided an easy access to multiple
functionalized ring structures of chemical and pharmaceutical
interest.18,19 During our continuous efforts on the development
of useful multi-component domino reactions, herein, we would
like to report another highly efficient approach to multi-function-
alized dihydroquinolines through multi-component reaction under
mild conditions (Scheme 1). This reaction was achieved from the
available starting materials such as aldehydes and 2-arylethylid-
enemalononitrile in the presence of NaOH under microwave irradi-
ation. The great aspect of the present domino reaction is shown by
the fact that the simultaneous construction of two new rings including
phenyl and pyridine rings was readily achieved via base-promoted
multi-component reaction in a one-pot operation, and two cyano
groups of compound 2 were converted into two amine groups in an
intermolecular manner.
Ethylidenemalononitriles are versatile and readily obtainable
reagents, and their chemistry has received considerable attention
in recent years.20 It has been reported that when a mixture of aryl-
aldehydes and aryl ethylidenemalononitriles was refluxed in etha-
nol, five examples of aromatized quinolines were produced in
26–50% yields, accompanied by the byproducts of 1,3-diarylallylid-
enemalononitriles.21 Due to its limited substrate scope and low
yields of products, we reasoned that the reaction may be improved
⇑
Corresponding authors. Tel./fax: +86 516 83500065.
E-mail addresses: jiangchem@jsnu.edu.cn (B. Jiang), laotu@jsnu.edu.cn (S.-J. Tu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.008

5072
Y. Yu et al. / Tetrahedron Letters 53 (2012) 5071–5075
Table 1
R
Optimization of reaction conditions
Ar
N
R
O
Entry
Base
T/°C
Time/min
Yielda (%)
1
NC
Ar
Ar
Base
MW
1
2
3
4
5
6
K2CO3
Piperidine
DMAP
Et3N
NaOEt
NaOH
100
100
100
100
100
100
20
20
20
15
15
15
15
27
Trace
38
57
+
H2N
Ar
NC
CN
NC
CN
CN
2
3
2
78
Scheme 1. The three-component domino reaction of 1 with 2.
a
Isolated yield
polysubstituted dihydroquinoline 3b in 78% yield, instead of
aromatized quinolines reported in the literature. The structure of
3b was characterized on the basis of their spectra and analytical
data. Furthermore, the structural elucidation was unequivocally
determined by X-ray diffraction of single crystals that were ob-
by screening appropriate reaction conditions. In an initial study,
phenylethylidenemalononitrile (2a, 2.2 equiv) as a substrate was
employed to subject with 4-chlorobenzaldehyde (1b, 1.0 equiv)
in ethylene glycol at 100 °C using NaOH (0.5 equiv) as a base under
microwave heating. The reaction proceeded smoothly to yield
Figure 1. X-ray structure of 3e.23
Figure 2. X-ray structure of 3k.23

Y. Yu et al. / Tetrahedron Letters 53 (2012) 5071–5075
5073
tained by slow evaporation of the solvent, as in the case of 3e
(Fig. 1) and 3k (Fig. 2).
Encouraged by the above reported satisfactory results, we next
optimized this reaction condition including the solvents and bases.
As shown in Table 1, the same reaction of 1a with 2b was
investigated using a variety of bases (0.5 equiv), such as K2CO3,
NaOH, Et3N, piperidine, NaOEt, and N,N-dimethyl-4-aminopyridine
(DMAP) under microwave (MW) irradiation at 100 °C. The reaction
scarcely proceeded in the presence of K2CO3, piperidine, and DMAP.
The incomplete reaction was observed using Et3N or NaOEt as a
Table 2
Syntheses of 5,6-dihydroquinolines22
Entry
Product 3a
R
Time (min)
Yieldb (%)
1
2
3a
3b
4-Fluorophenyl (1a)
4-Chlorophenyl (1b)
12
15
83
82
3
4
3c
3d
4-Bromophenyl (1c)
4-Methoxyphenyl (1d)
15
15
86
75
R
NC
H2N
N
CN
3a-3k
5
6
3e
3f
4-Tolyl (1e)
2,4-Dichlorophenyl (1f)
20
15
82
81
Cl
7
8
9
3g
3h
3i
3,4-Dichlorophenyl (1g)
2,3-Dimethoxyphenyl (1h)
Thien-2-yl (1i)
15
15
15
83
78
86
R
NC
H2N
N
CN
Cl
3l-3r
10
11
3j
3k
Furan-2-yl (1j)
Isopropyl (1k)
15
16
81
82
Br
12
13
14
15
3l
4-Fluorophenyl (1a)
4-Chlorophenyl (1b)
4-Bromophenyl (1c)
4-Tolyl (1e)
8
10
10
15
84
85
86
78
3m
3n
3o
R
NC
H2N
N
CN
Br
3s-3w
16
17
3p
3q
3,4-Dichlorophenyl (1g)
Thien-2-yl (1i)
15
10
83
80
CH3
18
19
20
3r
3s
3t
Picoline-4-yl (1l)
4-Chlorophenyl (1b)
4-Bromophenyl (1c)
15
8
10
74
85
84
R
NC
H2N
N
CN
CH3
3x-3y
OCH3
21
22
3u
3v
4-Methoxyphenyl (1d)
2,4-Dichlorophenyl (1f)
15
10
87
80
23
24
25
26
3w
3x
3y
3z
3,4-Dichlorophenyl (1g)
4-Chlorophenyl (1b)
4-Bromophenyl (1c)
4-Chlorophenyl (1b)
10
20
20
20
86
76
82
75
R
NC
H2N
N
CN
OCH3
3z
Reagents and conditions: NaOH (0.5 equiv), 110 oC, ethylene glycol, microwave heating.
Isolated yield.
a
b

5074
Y. Yu et al. / Tetrahedron Letters 53 (2012) 5071–5075
O
NC
Ar
CN
H
NC
A2
CN
NC
A2
CN
-OH
H
R
H2O
O-
R
-
OH
-H2O
CH2
2
NC
CN
Ar
NC
CN
Ar
NC
CN
H
NC
Ar
CN
NC
Ar
CN
H2C
OH
R
Ar
R
R
B
A
H
OH
CN
H
HO
H
N
N
C
Ar
N
R
CN
Ar
NC
H2N
N
H2N
NC
Ar
NC
Ar
Ar
Ar
H
R
-OH
CN
R
C
3
D
Scheme 2. The possible mechanism of formation of 5, 6-dihydroquinolines.
base catalyst. Subsequently, the reaction catalyzed by NaOH was
performed and repeated many times in different solvents including
EtOH (67%), DMF (54%), and 1,4-dioxane (70%) in a sealed vessel
under microwave irradiation for 15 min. The best yield of product
3b (82%) was obtained in ethylene glycol as the reaction tempera-
ture was increased to 110 °C.
intramolecular second cyclization (C to D), and isomerization (D
to 3).
In conclusion, we have described a three-component domino
heterocyclization reaction (aldehydes and 2-arylethylidenemalon-
onitriles) as a method for annulation of 5,6-dihydroquinolines,
with concomitant formation of four new
r bonds in one-pot
With this result in hand, we went on to study the scope of the
methodology. Using the optimized reaction conditions, a variety
of structurally diverse aldehydes were investigated, and a series
of new 5,6-dihydroquinolines were afforded in good yields, with
two cyano groups in positions 3 and 8 of the dihydroquinoline nu-
cleus, respectively. As shown in Table 2, at the beginning, we made
a search for the aldehyde substrate scope, 2-phenylethylidenemal-
ononitriles 2a were used as model substrates (Table 2, entries 1–
11), and the results indicated that aromatic aldehydes bearing
either electron donating or electron withdrawing functional
groups such as bromo, chloro, or methoxyl were able to affect
the synthesis of compound 3. The bulkily o-substituted aldehydes
1f and 1g were converted into the corresponding 5,6-dihydroquin-
olines 3f and 3g in 81% and 78% yields, respectively. Furthermore,
thiophene-2-carbaldehyde and alkaline-sensitive furan-2-carbal-
dehyde (Table 2, entries 9–10) still displayed high reactivity under
this standard condition, providing the corresponding thien-2-yl
and furan-2-yl substituted dihydroquinoline (3i and 3j). Aliphatic
aldehyde such as isobutyraldehyde was also suitable for this reac-
tion (Table 2, entry 11). Additionally, functional groups like bro-
mide and chloride were well tolerated. These functional groups
provide ample opportunity for further functional group manipula-
tions, for example, by modern cross-coupling reactions.
manner. The reaction proceeds by domino [4 + 1 + 1]/[4 + 2] het-
erocyclization obtaining 5,6-dihydroquinolines in good yields,
showing that the synthetic route allows us to build blocks of 5,6-
dihydroquinoline derivatives with a wide diversity in substituents.
The ready accessibility of the starting materials, the broad compat-
ibility of aldehyde substrates, and the generality of this process
make the reaction highly valuable in view of the synthetic and
material importance of heterocycles of this type, and its applica-
tion was in progress in our laboratory. Features of this strategy in-
clude the mild condition, convenient one-pot operation, short
reaction periods of 8–20 min, and excellent regioselectivity.
Acknowledgments
We are grateful for financial support from the National Science
Foundation of China (21072163 and 21102124), the Priority
Academic Program Development (PAPD) of Jiangsu Higher Educa-
tion Institutions, Science Foundation in Interdisciplinary Major
Research Project of Xuzhou Normal University (No. 09XKXK01),
the NSF of Jiangsu Education Committee (11KJB150016), and Jiang-
su Science and Technology Support Program (No. BE2011045), and
Doctoral Research Foundation of Xuzhou Normal Univ. (XZNU, No.
10XLR20).
To further expand the scope of ethylidenemalononitrile sub-
strates, different aldehydes were used as model substrates and
examined various ethylidenemalononitriles including 4-chloro-
phenyl 2b, 4-bromophenyl 2c, 4-tolyl 2d, and 4-methoxyphenyl
2e. In all these cases, the reactions proceeded smoothly to give
the corresponding 5,6-dihydroquinolines in good yields of 74–
87%(Table 2, entries 12–26). Indeed, the protocol provides a
straightforward pathway to construct highly functionalized 5,6-
dihydroquinolines.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
008.
References and notes
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NaOH powder (0.5 mmol), and ethylene glycol (1.5 mL) were mixed and stirred
at room temperature for 3 min. Then the mixture was heated for a given min at
110 °C under microwave irradiation. Upon completion, monitored by TLC, the
reaction mixture was cooled to room temperature. The resulting suspension
was neutralized with diluted hydrochloric acid solution. Then the mixture was
stirred at room temperature for 5 min. The solid product was collected by
Büchner filtration and washed with water and EtOH (95%), and subsequently
dried and recrystallized from EtOH (95%) to give the pure product 3(3a-z). 2-
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(3e):Yellow solid; mp 228–231 °C; IR (KBr, m
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6.72 (t, J = 7.6 Hz, 2H, ArH), 3.99 (d, J = 6.8 Hz, 1H, CH2), 3.45 (q, J1 = 18.0 Hz,
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Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402–4421; (e)
Ganem, B. Acc. Chem. Res. 2009, 42, 463–472; (f) Li, G.; Wei, H. X.; Kim, S. H.;
(11) Å, b = 12.1912(14) Å, c = 13.4424(15) Å, a
= 68.94(10)o, b = 80.576(2)o,
c
= 65.95(10)o,V = 1390.3(3) Å3, Mr = 511.61, Z = 2, k = 0.71073 Å,
l (Mo
a
K ) = 0.076 mmÀ1, F(000) = 540, R1 = 0.0470, wR2 = 0.0948. Crystal data for 3k
(CCDC-888773): C26H22N4, crystal dimension 0.14 Â 0.10 Â 0.07 mm, Triclinic,
space group P-1, a = 8.4068(8) Å, b = 11.5024(11) Å, c = 12.7902(12) Å,
a
= 73.3320(10)o,
b = 74.5650(16)o,
c
= 79.293(6)o,
V = 1134.04(19) Å3,
(Mo K ) = 0.069 mmÀ1
l , F(000) = 412,
a
Mr = 390.48, Z = 2, k = 0.71073 Å,
R1 = 0.1152, wR2 = 0.2027.