Unexpected simultaneous synthesis of trisubstituted quinolines and acylhydrazones under catalyst-free conditions

Article abstract of DOI:10.1080/00397911.2017.1310249

Trisubstituted quinolines and acylhydrazones were unexpectedly prepared from a reaction of N′-((2-aminophenyl)(phenyl)methylene)benzohydrazides with acetylenic esters. Using of N′-((2-aminophenyl)(phenyl)methylene)benzohydrazides led to obtain not only qu

Full text of DOI:10.1080/00397911.2017.1310249

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Unexpected Simultaneous Synthesis of
Trisubstituted Quinolines and Acylhydrazones
Under Catalyst-Free Conditions
Tahere Hosseyni Largani, Gholamhassan Imanzadeh, Nader Noroozi Pesyan
& Ertan Şahin
To cite this article: Tahere Hosseyni Largani, Gholamhassan Imanzadeh, Nader Noroozi
Pesyan & Ertan Şahin (2017): Unexpected Simultaneous Synthesis of Trisubstituted Quinolines
and Acylhydrazones Under Catalyst-Free Conditions, Synthetic Communications, DOI:
10.1080/00397911.2017.1310249
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1310249
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Date: 10 April 2017, At: 21:40

Unexpected Simultaneous Synthesis of Trisubstituted Quinolines and
Acylhydrazones Under Catalyst-Free Conditions
Tahere Hosseyni Largani1, Gholamhassan Imanzadeh1, Nader Noroozi Pesyan2, Ertan
Şahin3
1Department of Chemistry, Faculty of Basic Science, University of Mohaghegh Ardabili,
Ardabil, Iran, 2Department of Chemistry, Faculty of Science, Urmia University, Urmia,
Iran, 3Department of Chemistry, Faculty of Science, Atatürk University, Erzurum,
Turkey
Corresponding author: Gholamhassan Imanzadeh. E-mail: Imanzad2000@yahoo.com
Abstract
Ttrisubstituted quinolines as well as acylhydrazones were unexpectedly prepared from a
reaction of N'-((2-aminophenyl)(phenyl)methylene)benzohydrazides with acetylenic
esters. Using of N'-((2-aminophenyl)(phenyl)methylene)benzohydrazides led to obtain
not only quinoline, but also a second pharmaceutical important product acylhydrazone.
Notably, excellent yields, operational simplicity, short reaction times, and the avoidance
of the use of catalysts make this approach an attractive complementary method to
produce quinoline-2,3-dicarboxylates. The crystal structure of 5a was determined using
single crystal X-ray crystallography. The results showed that crystal packing diagram of
5a are of two pairs of molecules that have two independent alternate intermolecular 1D-
polymeric H-bonds between two perpendicular molecules.
GRAPHICAL ABSTRACT
1

KEYWORDS: Quinoline-2,3-dicarboxylate; Acylhydrazone; Unexpected simultaneous
synthesis; X-ray crystallography; Catalyst free
1. INTRODUCTION
Among nitrogen-containing heterocycles, quinolines have received special attention
because of their abundance in a variety of naturally occurring products and medicinally
active compounds.[1] A great number of quinoline-based compounds exhibit a broad
range of physiological and biological properties such as antimalarial,[2] antitumor,[3] anti-
infective,[4] and anti-inflammatory.[5] In agrochemicals,[6] quinoline is a substructure of
many herbicides, fungicides, and insecticides. Synthesis of substituted quinolines have
been reported using various mechanisms and strategies: Conrad−Limpach−Knorr,[7,8]
Skraub−Doebner−Von Miller,[9−11] Frielaender,[12,13a,b] halogen mediated,[14] copper
catalyzed[15] and ultrasonic-assisted[16a,b] or miscellaneous.[10,17]
Ring-substituted quinolines have a broad range of applications in medicinal, bioorganic,
and industrial chemistry as well as in the field of synthetic organic chemistry.[18] Also, the
4-substituted quinolinecarboxylic acid/ester analogues of these compounds have been
found to possess various biological activities like antiparasitic[19] antibacterial[20]
2

antimycobacterial[21] and antiprotozoal[22] activities. Amongst these analogues 4-
substituted quinoline-2,3-dicarboxylates show antiallergic properties[23] and are widely
used in the synthesis of bioactive compounds like Benzo[c][2,7]naphthyridines[24] and
dihydroxypyridazinoquinolines.[20]
Although there are few reports in the literature for the preparation of 4-substituted
quinoline-2,3-dicarboxylates, many of these methods suffer from harsh reaction
conditions,[25, 26] long reaction times,[27] low yields,[28] difficulties in workup, and usage
of expensive or moisture sensitive catalysts.[29, 30] In view of these drawbacks, the
reaction could be further explored and refined to overcome some of these shortcomings
under mild reaction conditions.
Acylhydrazones are one of the most important Schiff bases and have been well
documented to possess important pharmacological activities,[31a,b] such as antitumor,[32]
antibacterial[33] antiviral and antimalarial[31b] effects. Due to the pharmacophoric character
of acylhydrazone, this group framework [34] has been widely exploited in the design of
new bioactive compounds with different pharmacological profiles.[31a]
In this context, for the first time we present herein an improved methodology that allows
simultaneous, simple, and fairly efficient catalyst free synthesis of quinoline-2,3-
dicarboxylates and acylhydrazones via the reaction of N'-((2-
aminophenyl)(phenyl)methylene)-4-nitrobenzohydrazides with acetylenic esters in
toluene at 110 °C.
3

2. RESULTS AND DISCUSSION
In continuation of our interest aza-Michael reaction,[35a-c] we planned to synthesize
compound 3 (R = CH3, X = H, Y = NO2, Z = H) from the reaction between N'-((2-
aminophenyl)(phenyl)methylene)-4-nitrobenzohydrazide 1 (X = H, Y = NO2, Z = H, 1
mmol) and dimethyl acetylenedicarboxylate 2 (R = CH3, 2 mmol). However, when this
model reaction was conducted under argon atmosphere in the toluene solvent at 110 °C,
two compounds were obtained as reaction products that the spectroscopic data of each of
them were inconsistent with expected structure 3. The structures of the products were
deduced from their IR, 1HNMR and 13CNMR. Surprisingly, the data were in good
agreement with the structures of unexpected products quinoline-2,3-dicarboxylate 4 (R =
CH3, X = H) and acylhydrazone 5 (R = CH3, Y = NO2, Z = H) (Scheme 1).
The reaction was also repeated with one equivalent of 2 under the same conditions.
However, after 8 h a mixture of 4, 5 and unreacted 1 was the only product of reaction and
even the prolonged time (24 h) did not lead to completion of this reaction. Based on these
results a plausible mechanism can be suggested to this reaction as represented in Scheme
2.
First, Michael addition of 1 to acetylenic ester 2 produces intermediate 6. This
intermediate undergoes a cyclization reaction to 7. Loss of a hydrazide molecule from 7,
leads to formation of quinoline 4. The addition of intermediate 8 to ester 2 affords
product 5.
4

In order to optimize the model reaction conditions, firstly, the effect of ethanol and
toluene was investigated as protic and aprotic solvents, respectively, at different reaction
temperatures. It was found that the best results were obtained in toluene at 110 °C (Table
1, entry 4).
To survey the scope of the reaction, these optimal conditions were applied for the
simultaneous synthesis of trisubstituted quinolines and acylhydrazones derivatives.
Different N'-((2-aminophenyl)(phenyl)methylene)-4-benzohydrazides 1 were reacted
with acetylenic esters 2 and the results are presented in Table 2. It was found that
different substitutions on aromatic ring did not significantly affect the products yield and
the reaction time.
3. CONCLUSION
In conclusion, we have described here the first improved methodology that allows
simultaneous, simple, and fairly efficient catalyst free synthesis of quinoline-2,3-
dicarboxylates and acylhydrazones. This novel catalyst free reaction is attractive in terms
of excellent yields, operational simplicity, short reaction times, and mild reaction
conditions. For further investigation of compound 5a, the crystal structure of 5a is shown
in Fig. 1. Crystal packing diagram of 5a constitute two pairs of molecules that have two
independent alternate intermolecular 1D-polymeric H-bonds between two perpendicular
molecules Fig. 2.
4. EXPERIMENTAL
5

4.1. General
All acetylene dicarboxylates, 2-aminobenzophenons and hydrazides were purchased from
Merck and used without further purification. The progress of the reactions was followed
by TLC using silica gel SILIG/UV 254 plates. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded on a Bruker 400 MHz instrument. FT-IR spectra were
recorded on a Perkin-Elmer RX-1 instrument. Elemental analysis for C, H, and N were
performed using a Heraeus CHN-O-Rapid analyzer. The melting points were determined
in open capillaries with a Stuart Melting Point Apparatus and are uncorrected.
4.2. General Procedure For The Synthesis N'-((2-
Aminophenyl)(Phenyl)Methylene)Benzohydrazides (1a-G)
A mixture of 2-aminobenzophenons (1 mmol) and hydrazides (1 mmol) was refluxed in
ethanol (10 mL) in the presence of p-toluenesulfonic acid (10 mol%) for 6 h. The
progress of reaction was monitored by TLC. At the end of the reaction, the precipitate
was collected by filtration and recrystallized from ethanol.
4.2.1. N'-((2-Aminophenyl)(Phenyl)Methylene)-4-Nitrobenzohydrazide
(1a)
Orange crystalline solid (0.320 g, 89 % yield); m.p. 234-235 °C; IR (KBr) νmax/cm-1:
3412 and 3340 (NH2), 3234 (NH), 3058 (Csp2-H), 1676 (C=O), 1637 (C=N); Anal. Calcd.
For C20H16N4O3: C, 66.66; H, 4.48; N, 15.55. Found: C, 66.53; H, 4.55; N, 15.61.
6

4.3. General Procedure For The Synthesis Of Dialkyl 4-Phenylquinoline-2,3-
Dicarboxylates (4a–D) And Dialkyl 2-(2-Benzoylhydrazono)Succinates (5a–G)
A mixture of acetylenic esters 2 (2 mmol) and N'-((2-
aminophenyl)(phenyl)methylene)benzohydrazides 1 (1 mmol) was refluxed under argon
atmosphere in toluene (5 mL) for 8h. The progress of reaction was monitored by TLC. At
the end of the reaction, the solvent was removed under reduced pressure, and produced an
oil, which was purified by column chromatography and prep TLC plates (20×20 cm)
(Eluent hexane/ethyl acetate 4:1) to give dialkyl 4-phenylquinoline-2,3-dicarboxylates 4
and dialkyl 2-(2-benzoylhydrazono)succinates 5.
4.3.1. Dimethyl 4-Phenylquinoline-2,3-Dicarboxylate (4a)
White solid (0.289 g, 90 % yield); m.p. 124-126 °C; 1H NMR (400 MHz, CDCl3): δ 8.34
(d, J = 8.8 Hz, 1H), 7.81–7.86 (m, 1H), 7.60–7.66 (m, 2H), 7.51 (t, J = 3.2 Hz, 3H), 7.36–
7.38 (m, 2H), 4.10 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.6, 164.5,
147.1, 146.1, 143.8, 133.5, 130.0, 129.8, 129.6, 128.3, 128.2, 127.8, 127.7, 127.3, 126.6,
126.2, 125.6, 52.5, 51.5; IR (KBr) νmax/cm-1: 3069 (Csp2-H), 2994 (Csp3-H), 1746 and
1725 (C=O); Anal. Calcd. For C19H15NO4: C, 71.02; H, 4.71; N, 4.36. Found: C, 71.00;
H, 4.70; N, 4.38.
4.3.2. Dimethyl 2-(2-(4-Nitrobenzoyl)Hydrazono)Succinate (5a)
Yellow crystalline solid (0.288 g, 89 % yield); m.p. 146-149 °C; 1H NMR (400 MHz,
CDCl3): δ 13.60 (s, N-H, 1H), 8.35 (d, J = 7.6 Hz, 2H), 8.10 (d, J = 7.6 Hz, 2H) 3.91 (s,
3H), 3.73 (s, 5H); 13C NMR (100 MHz, CDCl3): δ 168.8, 127.8, 123.1, 52.1, 51.4, 38.2;
7

IR (KBr) νmax/cm-1: 3246 (NH), 3052 (Csp2-H), 2959 (Csp3-H), 1734 and 1674 (C=O);
Anal. Calcd. For C13H13N3O7: C, 48.30; H, 4.05; N, 13.00. Found: C, 48.21; H, 3.99; N,
12.94; m/z 324 (M + H)+.
ACKNOWLEDGMENT
The authors are grateful to University of Mohaghegh Ardabili for the financial support
and the laboratories of Tehran, Tabriz and Atatürk Universities for analyzing the
products.
SUPPORTING INFORMATION
Detailed procedures and spectral characterization data for all compounds reported herein
can be accessed on the publisher’s website.
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11

Table 1. Optimization the model reaction conditionsa.
Entry
Solvent
Temp (°C)
Time (h)
Yeild (%)b
4a
5a
1
2
3
4
Ethanol
Ethanol
Toluene
Toluene
rt
20
20
20
8
NR
NR
Trace
<25
89
100
rt
Trace
<30
110
90
aReaction conditions: N'-((2-aminophenyl)(phenyl)methylene)-4-nitrobenzohydrazide (1
mmol), dimethyl acetylenedicarboxylate (2 mmol).
bIsolated yield.
12

Table 2. Synthesis of quinoline-2,3-dicarboxylates 4 and acyl hydrazones 5a.
Entry
X
Y
Z
R
Product 4 Yield
Product 5 Yield
(%)b
(%)b
1
2
3
4
5
6
7
8
9
H
NO2
NO2
NO2
NO2
NH2
NH2
Cl
H
H
H
H
H
H
H
H
Cl
CH3
4a
90
89
91
90
89
90
89
86
87
5a
5b
5a
5b
5c
5c
5d
5e
5f
90
89
90
88
90
89
90
90
89
H
CH2CH3 4b
CH3 4c
CH2CH3 4d
Cl
Cl
H
CH3
CH3
CH3
4a
4c
4a
Cl
H
H
H
CH2CH3 4b
CH3 4a
H
Cl
aReaction conditions: N'-((2-aminophenyl)(phenyl)methylene)benzohydrazides (1 mmol),
acetylenic esters (2 mmol), 5 mL of toluene, 8 h, at 110 °C.
bIsolated yield.
13

Scheme 1. The unexpected synthesis of quinoline-2,3-dicarboxylates and acylhydrazones
14

Scheme 2. Proposed mechanism.
15

Figure 1. ORTEP diagram of 5a.
16

Figure 2. Crystal packing diagram of 5a.
17