Rearrangement of o-nitrobenzaldehyde in the Hantzsch reaction

Article abstract of DOI:10.3390/60800683

The reaction of 5-hydroxy-2-nitrobenzaldehyde with ethyl acetoacetate in ammonia gave the two expected isomeric 1,4- and 1,2-dihydropyridines resulting from the normal Hantzsch reaction. However, the combination of 2-nitrobenzaldehyde with ethyl acetoacet

Full text of DOI:10.3390/60800683

Molecules 2001, 6, 683-693
molecules
ISSN 1420-3049
http://www.mdpi.org
Rearrangement of o-Nitrobenzaldehyde in the Hantzsch
Reaction†
E. Angeles1, H. Santillán1, I. Menconi1, I. Martínez1, A. Ramírez1, A. Velázquez1, R. López-
Castañares2 and R. Martínez3,*.
1
Laboratorio de Química Medicinal, Facultad de Estudios Superiores Cuautitlán, Universidad
Nacional Autónoma de México; E-mail: angeles@servidor.unam.mx.
2
Facultad de Química, Universidad Autónoma del Estado de México.
3
Instituto de Química, Universidad Nacional Autónoma de México, Apartado Postal 70-213,
Coyoacán, México, D.F. CP 04510, México.
† Contribution No. 1736 from the Instituto de Química, UNAM
* Author to whom correspondence should be addressed; E-mail: robmar@servidor.unam.mx .
Received: 13 December 2000; in revised form 6 June 2001 / Accepted: 16 July 2001 /Published: 21
July 2001
Abstract: The reaction of 5-hydroxy-2-nitrobenzaldehyde with ethyl acetoacetate in
ammonia gave the two expected isomeric 1,4- and 1,2-dihydropyridines resulting from
the normal Hantzsch reaction. However, the combination of 2-nitrobenzaldehyde with
ethyl acetoacetate under the same conditions yielded four products: the two normal
isomeric dihydropyridines and two tricyclic compounds. When we attempted to
independently synthesize the two tricyclic compounds by reductive cyclization of 4-(2-
nitrophenyl)-2,6-dimethyl-3,5-dicarbetoxy-1,4-dihydropyridine and 2-(2-nitrophenyl)-
4,6-dimethyl-3,5-dicarbetoxy-1,2-dihydropyridine with tin (II) chloride in hydrochloric
acid media, we obtained instead an indole and a quinoline derivative, respectively.
Keywords: Hantzsch reaction, cyclization, indole derivatives, quinoline derivatives

Molecules 2001, 6
684
Introduction
Dihydropyridine derivatives display a broad spectrum of medicinal activities, mainly as
antihypertensive and antiarrhythmic drugs. They are also used as starting materials for cycloaddition
and electrophilic reactions [1-4]. Recently we reported the preparation of 4-substituted-2-cyclo-
hexenones by reductive cyclization of Hantszch esters using sodium and ethanol as the solvent [5]. As
a part of our drug design program [6], we were interested in the preparation of 1,4-dihydropyridines 1
and 2 [8] and the evaluation of their antihypertensive properties, since they are structurally similar to
Nifedipine (3). In this paper we describe the attempted synthesis of 1 and 2 using the Hantzsch reaction
of 5-hydroxy-2-nitrobenzaldehyde (4) and 2-nitrobenzaldehyde (5), respectively. We also describe
here the results of the reductive cyclization of the 1,4-dihydropyridines 1 and 2 and the 1,2-
dihydropyridines 6 and 7 with tin (II) chloride in hydrochloric acid.
Results and Discussion
Our approach to the synthesis of compounds 1 and 2 was based on the Hantzsch method. To this
end a study was undertaken of the reaction of 5-hydroxy-2-nitrobenzaldehyde 4 with ethyl acetoacetate
in ammonia. The reaction gave the isomeric 1,4- and 1,2-dihydropyridine products 1 (48%) and 6
(20%) resulting from the normal Hantzsch reaction (Scheme 1).
R1
NO2
O
O
R1 R2
OH Et
R2
R2
1
2
3
O
O
H
H
Et
Me
N
H
CHO
HO
O
NO2
O
O
NH4OH
NO2
6
+
1 +
∆
O
HO
O
NH
O
4
O
Scheme 1

Molecules 2001, 6
685
The proposed structures of all products were confirmed by analytical and spectral data and by
comparison with melting points reported in previous work [7,8]. The analytical and spectral data of 6
were consistent with the 1,2-dihydro isomeric system in which the resonance of the hydrogen attached
1
to esters groups produces different shifts in the H-NMR spectrum. The combination of 2-
nitrobenzaldehyde 5 with ethyl acetoacetate yielded interesting results. Separation of the products
using column chromatography yielded the normal isomeric dihydropyridines 2[8] and 7 as crystalline
solids in 35% and 20% yields, and the compounds 8 and 9 in yields of 15% and 20%, respectively
(Scheme 2).
NO2
O
CHO
O
O
NO2
O
NH
O
NH4OH
+
2 +
7
∆
O
5
O
+
OH
O
NH
O
N
O
O
O
O
+
+
N
8
N
9
Scheme 2
Careful examination of the spectral and analytical data of compounds 8 and 9 indicated that they
are the ethyl esters of 5,6-dihydro-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid
and 5,6-dihydro-6-hydroxy-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid. Kim [9]
has reported that refluxing of 4-(2-aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic
acid diethyl ester 10 in toluene gave four compounds: 8, 11, 12 and 13 (Scheme 3). He also reported
that catalytic hydrogenation in the presence of palladium-charcoal of 2,6-dimethyl-4-(2-nitrophenyl)-
3,5-pyridinedicarboxylic acid diethyl ester 14, followed by treatment of the crude product with boiling
pyridine, afforded a mixture of 8 and 9 in a ratio of approximately 1:1. To the best of our knowledge
isolation of compounds 8 and 9 from a Hantzsch reaction has not been described in the literature.

Molecules 2001, 6
686
R1
O
NH2
O
O
O
∆
8 + 11 + 12 + 13
Toluene
N
H
10
NH2
O
H
N
O
Me
NH
CO2Et
O
O
R
Me
N
CO2Me
12
N
R = CO2Et
H
11
13
NO2
O
O
O
O
H2/Pd/C
8
9
+
Py/∆
N
14
Scheme 3
The formation of compounds 8 and 9 can be explained by an in situ intramolecular oxidation-
reduction reaction of compound 2 (Scheme 4), since it is well known that the dihydropyridine moiety
behaves as a reductive system [10-12] and the nitrophenyl framework could act as an oxidizing agent
[13]. We presume that one of the first steps could be the formation of the N-OH intermediates 15 and
subsequent cyclization gives compound 8. The total reduction of the nitro group to amine 16, and its
subsequent cyclization with one of the ethyl ester groups, gives compound 9. With the aim of testing
the above statement compound 2 was treated with tin (II) chloride in hydrochloric acid [14-16].

Molecules 2001, 6
687
NHOH
O
O
8
O
O
NO2
O
O
N
15
O
O
N
H
NH2
O
O
9
O
O
2
N
16
Scheme 4
Unexpectedly the compound that was obtained in 40 % yield was proven to be 17 (Scheme 5). The
structure of 17 was confirmed by comparing its melting point and spectral data with literature data
[17,18].
R
NO2
R
O
O
SnCl2
HCl
O
O
O
CO2Et
N
H
N
H
1 R = OH
2 R = H
18
17
Scheme 5
This prompted us to also investigate the behavior of 4-(5-hydroxy-2-nitrophenyl)-1,4-dihydro-
pyridine 1 towards tin (II) chloride in acid media conditions, and this time the corresponding indole
derivative 18 was obtained in 56% yield. Starting from 1 and 2 the following mechanistic pathway

Molecules 2001, 6
688
leading to the indole compounds 17 and 18 can be formulated (Scheme 6). It starts with the reduction
of the 2-nitro group to the nitroso functionality. This suffers a nucleophilic attack at C-3 on the
dihydropyridine moiety mediated by a Michael type addition of water to C-2 of the same moiety. The
pyridine unit undergoes a ring opening reaction facilitated by the loss of a water molecule from the
nitrogen of the incipient indole group. Subsequent decarboxylation and isomerization processes lead to
the indole compounds.
R2
R2
R2
NO2
R
N
R
O
+
O H
N
R
2
R
SnCl /HCl
R
R
+
+
2
H
+
-H
N
H
N
H
N
H
OH
H2O
-
H2O
R2
R2
O
R2
O
O
O
+
N
R
H2O
-EtOH
N
N
-AcNH
2
O
HO
HO
R
H
R
H
N
N
HO
H2O
O
O
-CO2
R2
R2
R= -CO2Et R2=H
17
N
N
R= -CO2Et R2=OH 18
R
R
HO
O
Scheme 6
In order to provide evidence for this proposed mechanism the reduction reaction was studied using
the 1,2-dihydropyridines 6 and 7 (Scheme 7). Treatment of 7 with tin (II) chloride in acid media
afforded a mixture of quinoline compounds 12 and 19 instead of the expected indole. The major
product from this reaction exhibited spectral data consistent with structure 12 [9].

Molecules 2001, 6
689
R
NO2
O
O
O
R
O
O
O
NH
O
+
SnCl2
HCl
N
N
O
O
7
6
R = H
R = OH
12
20
19
Scheme 7
The spectral and melting point data of the minor product (72-74 oC) indicated it to be 19, a product
not described in the literature. However, when the 1,2-dihydropyridine 6 reacted under similar
conditions it gave the substituted 6-hydroxyquinoline 20 as the only product. Kim [9] has reported that
treatment of 4-(2-aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester
10 with ethanol pretreated with hydrogen chloride gas gave the quinoline 12 and proposed a plausible
mechanism for this conversion that involves the intermediate 21 (Scheme 8). Considering these
observations we propose a similar mechanism to explain the conversion of 1,2-dihydropyridines 6 and
7 into quinoline derivatives (Scheme 8). In addition, Hazard has reported the electrochemical
transformation of Nifedipine into a mixture of indole and quinoline compounds [17].
EtO2C
NH2
NH
O
O
H
EtOH
HCl (g)
12
O
O
CO2Et
N
N
21
10
Scheme 8
Conclusions
The Hantszch reaction of 5-hydroxy-2-nitrobenzaldehyde gave the expected 1,4- and 1,2
dihydropyridines. However, the same reaction with 2-nitrobenzaldehyde gave four compounds: the

Molecules 2001, 6
690
two isomeric dihydropyridines and two tricyclic compounds that we propose arise from an in situ
oxidation-reduction reaction. Likewise, the reaction of 1,4- and 1,2-dihydropiridines with tin (II)
chloride in hydrochloric acid gave derivatives of indole and quinoline, respectively.
Acknowledgments
We are grateful to C. Contreras, B. Quiróz, H. Rios, L. Velasco and F.J. Peréz for their help in
obtaining the IR, NMR and mass spectral data and to C. Pérez and D. Jiménez for their technical
assistance. We thank also to DGAPA, UNAM and CONACyT for financial support.
Experimental
General
All melting points are uncorrected. The IR spectra were recorded on a Nicolet FT-55X
1
spectrophotometer. The H-NMR spectra were determined on a Varian FT-200 and Varian FT-300S
instruments. All NMR spectra were obtained with the pulse sequence included with the spectrometer's
software and, unless specified otherwise, were determined in deuterochloroform solutions containing
tetramethylsilane as the internal standard. Chemical shifts (δ) are expressed in ppm downfield from the
reference peak. Mass spectra were recorded on a Jeol SX-102 mass spectrometer using the direct inlet
system with an ionization energy of 70 eV, an emission current of 100 µA and and ion source
temperature of 150 oC.
Synthesis of 4-(5-hydroxy-2-nitrophenyl)-1,4-dihydropyridine (1) + 2-(5-hydroxy-2-nitro-phenyl)-4,6-
dimethyl-1, 2-dihydropyridine-3,5-dicarboxylic acid diethyl ester (6).
A mixture of 5-hydroxy-2-nitrobenzaldehyde (5g, 0.30 mole), ethyl acetoacetate (7.8g ,0.60 mole)
and 30% ammonium hydroxide (25 mL) in ethanol (250 mL) was stirred under reflux for 2 h. The
solution was concentrated (rotary evaporator) to afford a solid residue. This mixture was then
separated by column chromatography (silica gel, hexane/ ethyl acetate gradient) into compounds 1
(5.57 g, 48%) and 6 (2.32g, 20%); m.p. 206-208°C (hexane/ethyl acetate); IR (CHCl3 film) νmax/cm-1:
3346, 3240, 1701, 1656; 1H-NMR: 10.3 (s, 1H, OH), 7.96 (d, J=6.0Hz, 1H, H3*), 6.97 (d, J=6.0Hz 1H,
H6*), 6.80 (dd, J=6.0, J=1.8 Hz, 1H, H4*), 6.52 (d, J=2.5 Hz, 1H, NH), 6.18 (d, J=2.5 Hz, 1H, H2),
4.20 (q, J=9.4 Hz, 2H, H10), 4.0 (q, J=9.4 Hz, 2H, H13), 2.51 (s, 3H, H7), 2.14 (s, 3H, H8), 1.28 (t,
13
J=9.4 Hz, 3H, H14), 1.06 t, J=9.4 Hz, 3H, H11); C-NMR: 167.2 (C=O, C9), 165.0 (C=O,C12), 163
(C5*), 154.5 (C6), 148.3 (C4), 139.8 (C2*), 138.5 (C3), 127.0 (C3*), 116.4 (C6*), 114.7 (C4*), 107.0
(C1*), 102.2 (C5), 59.0 (C13), 58.8 (C10), 50.2 (C2), 20,8 (C7), 18.6 (C8), 13.8 (C14), 13.4 (C11);
M.S. IE m/z (%)= 390 (15, M+), 373 (18) , 345 (30), 299 (100).

Molecules 2001, 6
691
Synthesis of 2,6-Dimethyl 4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester
(2) + 4,6-Dimethyl 2-(2-nitrophenyl)-1,2-dihydropyridine-3,5-dicarboxylic acid diethyl ester (7) + 5,6-
Dihydro-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid ethyl ester (8) and 5,6-
Dihydro-6-hydroxy-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid ethyl ester (9).
A mixture of 2-nitrobenzaldehyde (10g, 0.066 mole), ethyl acetoacetate (17.2g, 0.122 mole) and
30% ammonium hydroxide (30mL) in ethanol (60 mL) was stirred under reflux for 2 h. The solution
was concentrated (rotary evaporator) to afford a solid mixture. This mixture was then separated by
column chromatography (silica gel, hexane/ethyl acetate gradient) into 2 [8] (8.6 g, 35%), 8 [9] (2.94 g,
15%), 9 [9] (4.1 g, 20%) and 7 (4.90g, 20%), m.p. 158-160 °C; IR (CHCl3 film) νmax/cm-1: 3450 (NH),
1
1710 (C=O), 1650 (C=O); H-NMR: 8.29-7.35 (m, Ar-H, 4H), 4.35 (q, J=7.4 Hz, 2H, H10), 4.09 (q,
J=7.4 Hz, 2H, H9), 2.51 (s, 3H, H13), 2.21 (s, 3H, H14), 1.65 (s, 1H, NH), 1.35 (t, J=7.4 Hz, 3H, H11),
13
0.95 (t, J=7.4 Hz, 3H, H12); C-NMR: 166.3 (C=O, C7), 164.0 (C=O, C8), 122-140 (C-Ar), 62.0,
(C2), 61.0 (C9, C10), 31 (C13), 27.2 (C14), 14.2 (C11), 13.4 (C12).
Reaction of 2,6-Dimethyl 4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (2)
with Tin (II) Chloride in Hydrochloric Acid.
A solution of 1,4-dihydropyridine 2 (1.0 g, 0.0026 mol) in ethanol (25 mL) was added to a solution
of tin (II) chloride (5.4 g, 0.018 mole) in 30% hydrochloric acid (7 mL) at 5 °C. The reaction was
allowed to warm to room temperature and then heated to reflux for 5 h. The solution was neutralized
with a 10% sodium bicarbonate solution and extracted with ethyl acetate (10 mL × 3). The organic
layer was dried (anhydrous sodium sulfate), filtered, and concentrated to afford crude product, which
was purified by recrystallization from ethyl acetate/hexane to give 3-(2-oxopropyl)-1H-indole-2-
carboxylic acid ethyl ester (17) (0.21 g, 40%); m.p. 114-116 °C; IR (KBr pellet) νmax/cm-1: 3337 (N-
H), 1724 (C=O), 1674 (C=O); 1H-NMR: 8.92 (sbr, 1H, N-H), 7.6 (ddd, J= 1.0 Hz, J= 8.0 Hz, 1H, H7),
7.38-7.10 (m, 3H, H4,H5, H6), 4.40 (q, J= 14.2 Hz, 2H, H9), 4.21 (s, 2H, H11), 2.18 (s, 3H, CH ),
3
1.41 (t, J= 14.2 Hz 3H, H10); 13C-NMR: 206.1 (C12), 161.8 (C8), 135.8 (Ca), 127.9 (Cb), 125.9 (C6),
124.2 (C2), 120.7 (C4), 120.5 (C5), 116.5 (C3), 111 (C7), 61.0 (C9), 40.3 (C11), 29.1 (C13), 14.2
(C10); MS m/z (%), 245 (50, M+), 202 (100 ) [ M-C H O], 156 ( 90) [M-C H O ]
2 3
4 9 2
Reaction of 2,6-Diethyl 4-(5-hydroxy-2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl
ester (1) with Tin (II) Chloride in Hydrochloric Acid.
A solution of 1,4-dihydropyridine 1 (1.0 g, 0.0025 mol) in ethanol (25 mL) was added to a solution
of tin (II) chloride (5.4 g, 0.018 mole) in 30% hydrochloric acid (7mL) at 5 °C. The reaction was
allowed to warm to room temperature, and then heated to reflux for 5 h.. The solution was neutralized
with a 10% sodium bicarbonate solution and extracted with ethyl acetate (10 mL × 3). The organic

Molecules 2001, 6
692
layer was dried (anhydrous sodium sulfate), filtered, and concentrated to afford crude product, which
was purified by recrystallization from ethyl acetate/hexane to afford 3-(2-oxopropyl)-5-hydroxy-1H-
indole-2-carboxylic acid ethyl ester (18), m.p. 154-156 °C; yield 0.313 g (56 %). IR (KBr pellet)
ν
max/cm-1: 3550 (OH), 3337 (N-H), 1720 (C=O), 1680 (C=O); 1H-NMR: 8.92 (sbr, 1H, N-H), 7.6 (ddd,
J= 1.0 Hz, J= 8.0 Hz, 1H, H7), 7.38-7.10 (m, 3H, H4, H5, H6), 4.40 (q, J= 14.2 Hz, 2H, H9), 4.21 (s,
2H, H11), 2.18 (s, 3H, CH ), 1.41 (t, J= 14.2 Hz 3H, H10); 13C-NMR: 206.1 (C12), 161.8 (C8), 135.8
3
(Ca), 127.9 (Cb), 125.9 (C6), 124.2 (C2), 120.7 (C4), 120.5 (C5), 116.5 (C3), 111 (C7), 61.0 (C9),
40.3 (C11), 29.1 (C13), 14.2 (C10).
.
Reaction of 4,6-Dimethyl 2-(2-nitrophenyl)-1,2-dihydropyridine-3,5-dicarboxylic acid diethyl ester (7)
with Tin (II) Chloride in Hydrochloric Acid.
A solution of 1,2-dihydropyridine 7 (1.0 g, 0.0026 mol) in ethanol (25 mL) was added to a solution of
tin (II) chloride (5.4 g, 0.018 mole) in 30% hydrochloric acid (7 mL) at 5 °C. The reaction was allowed
to warm to room temperature, and then heated to reflux for 5 h. The solution was neutralized with a
10% sodium bicarbonate solution and extracted with ethyl acetate (10 mL × 3). The organic layer was
dried (anhydrous sodium sulphate), filtered, and concentrated to afford crude product, which was
purified by column chromatography and then recrystallized from ethyl acetate/hexane to give 2-
methyl- quinoline-3-carboxylic acid ethyl ester (12), m.p. 74-76 °C (lit [18, 19] 70-72 °C) and 6-
hydroxy-2-methyl-oxyquinoline-3-carboxylic acid ethyl ester (19), 0.3 g (54%); m.p. 98-100 °C; IR
1
(KBr pellet) νmax/cm-1: 1716 (C=O); H-NMR: 8.8 (d, J= 1.2 Hz, 1H, H ), 8.26 (s, 1H, H4), 7.9-7.6 (m,
8
3H, H5, H6, H7), 4.45 (q, J= 14.1 Hz, 2H, H11), 2.96 (s, 3H, H9), 1.46 (t, J= 14.1 Hz, 3H, H12); 13C-
NMR: 165.3 (C=O, C10), 146.3 (C2), 142.3 (Ca), 132.3 (C4), 129.0 (C6), 128.4 (C7), 127.6 (C5),
127.0 (C3), 126.0 (Cb), 119.9 (C8), 62 (C11), 15.8 (C9), 14.2 (C12); MS m/z (%), 231 (75, M+), 214
(15) [M-OH], 186 (100) [M-45].
Reaction of 2-(5-Hydroxy-2-nitrophenyl)-4,6-dimethyl-1,2-dihydropyridine-3,5-dicarboxylic acid
diethyl ester (6) with Tin (II) Chloride in Hydrochloric Acid
A solution of 1,2-dihydropyridine 6 (1.0 g, 0.0025 mol) in ethanol (25 mL) was added to a solution
of tin (II) chloride (5.4g, 0.018 mole) in 30% hydrochloric acid (7 mL) at 5 °C. The reaction was
allowed to warm to room temperature, and then heated to reflux for 5 h.. The solution was neutralized
with a 10% sodium bicarbonate solution and extracted with ethyl acetate (10 mL × 3). The organic
layer was dried (anhydrous sodium sulphate), filtered, and concentrated to afford crude product, which
was purified by column chromatography and then by recrystallization from hexane/ethyl acetate to
give 6-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester (20), yield 0.35 g (60 %); m.p.153-155
°C; IR (KBr pellet) νmax/cm-1= 3431, (OH), 1725 (C=O); 1H-NMR (CDCl3+DMSO): 9.56 (s, 1H, OH),
9.56 (s, 1H, H4), 7.8 (d, J=9 Hz, 1H, H8), 7.4 (dd, J=2.7 Hz, J=9 Hz, 1H, H7), 7.15 (d, J=2.7Hz, 1H,

Molecules 2001, 6
693
13
H5), 4.42, (q, J=14.3Hz, 2H, ester CH2), 2.9 (s, 3H, CH3- 2), 1.45 (t, J=14.3Hz, 3H, ester CH3); C-
NMR (CDCl3 +DMSO): 166.1 (C=O, C10), 155 (C6), 154 (C2), 143 (Ca), 137.5 (C4), 128.9 (C8),
126.4 (C3), 123.7 (C7), 123.4 (Cb), 108.5 (C5), 60.6 (C10), 24.6 (C12), 13.7 ( C11); MS m/z (%), 231
(100, M+), 216 [M-15] (4), 202 [M-C2H5] (20), 186 [M-OEt] (45).
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Sample availability: Available from the authors.
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