Rearrangements of o-Nnitrobenzaldehydes in the Hhantzsch Rreaction†

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.


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][2][3][4]. Recently we reported the preparation of 4-substituted-2-cyclohexenones 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 1,2dihydropyridines 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).

Scheme
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 to esters groups produces different shifts in the 1 H-NMR spectrum. The combination of 2nitrobenzaldehyde 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).

Scheme 3
The formation of compounds 8 and 9 can be explained by an in situ intramolecular oxidationreduction reaction of compound 2 (Scheme 4), since it is well known that the dihydropyridine moiety behaves as a reductive system [10][11][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][15][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].

Scheme 5
This prompted us to also investigate the behavior of 4-(5-hydroxy-2-nitrophenyl)-1,4-dihydropyridine 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 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.

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].

Scheme 7
The spectral and melting point data of the minor product (72-74 o C) 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].

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 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.

General
All melting points are uncorrected. The IR spectra were recorded on a Nicolet FT-55X spectrophotometer. The 1 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 o C.