Dearomatization of 3,5-dinitropyridines – an atom-efficient approach to fused 3-nitropyrrolidines

An efficient and convenient one-step method for the synthesis of decahydrodipyrrolo[3,4-b :3',4'- d ]pyridine derivatives was developed on the basis of 1,3-dipolar cycloaddition of unstabilized N -methyl azomethine ylide with 2-substituted 3,5-dinitropyridines. This novel heterocyclic system contains two 3-nitropyrrolidine fragments fused to a partially saturated pyridine ring. Such types of compound, as follows from the literature, can be considered as potential nitric oxide donors .


Introduction
5][6] Conversion of commercially available aromatics into functionalized alicyclic derivatives is widely used as a strategy for the creation of valuable synthetic products.Among dearomatization methods, 1,3-dipolar cycloaddition is of particular interest.[9][10] The present work extends our ongoing research [11][12][13][14][15][16] on the application of the dearomatization methodology to the synthesis of novel nitrogen-oxygen systems 17,18 -potential NO donors containing two or more pharmacophoric fragments.Since the 1980s, when the unique role of NO in the regulation of numerous physiological and pathophysiological processes was discovered, this small molecule has been of exceptional interest. 19,20Search for new types of NO-donors is one of the actively developing areas of medical chemistry; many papers have been published on the investigation of NO-releasing activity of different classes of compound. 21,22For example, recent research shows 3-nitropyrrolidine fused with benzoazoles to be potential NO-donors. 23This class of compound is quite limited and therefore insufficiently studied.In addition, the pyrrolidine moiety (including fused pyrrolidines) is considered as a "privileged" structural fragment and a key component of efficient organocatalysts, 24 enzyme inhibitors, 25 etc.
Our group has extensive experience in the synthesis of condensed 3-nitropyrrolidines via dearomative 1,3dipolar cycloaddition.Earlier [26][27][28][29] we reported on the first example of [3+2]-cycloaddition of N-methyl azomethine ylide 1 to the benzene ring of a number of m-dinitro-benzohetarenes 2. This resulted in annulation of two pyrrolidine rings to the benzene ring and the formation of polycycles 3 (Scheme 1).
To the best of our knowledge, this reaction constitutes the only example of an uncomplexed pyridine that behaves as a two-electron component in a pericyclic cycloaddition process with azomethine ylides.However, it was found that similar reaction of 3-nitropyridine or its N-oxide with N-benzyl azomethine ylide mainly resulted in the recovery of unconsumed starting material. 9

Results and Discussion
Taking into account the above-mentioned results we studied [3+2]-cycloaddition of ylide 1 to 2-substituted 3,5-dinitropyridines.The starting 2-substituted 3,5-dinitropyridines were synthesized from commercially available 2-chloro-3,5-dinitropyridine 5 (Scheme 3).The chlorine atom in this compound can easily be substituted with a variety of nucleophiles. 30 Compounds 6a-e were studied in reactions with the unstabilized azomethine ylide 1, which was generated in situ from N-methylglycine and paraformaldehyde (Scheme 1).In all cases the products of double cycloaddition of the dipole to aromatic C=C-NO2 fragments were isolated.(Scheme 4)

Scheme 4. [3+2]-Cycloaddition of N-methyl azomethine ylide to 2-substituted 3,5-dinitropyridines
In contrast to 2-unsubstituted 3,5-dinitropyridine 2 (Scheme 2), the C=N-bond in compounds 6a-e is unreactive towards azomethine ylide.This result represents the first synthesis of derivatives of novel heterocyclic system -decahydrodipyrrolo[3,4-b:3',4'-d]pyridine.It should be noted that hydrogenated pyrrolo [3,4-c]pyridine core is an important scaffold since compounds of this class possess antibacterial 32 , and anticancer activity 33,34 as well as cognition activating properties. 35he structures of compounds 7a-e were confirmed by NMR-spectroscopy and HRMS data, as well as X-ray diffraction study (for compounds 7a,b,e).It was found that addition of two molecules of the dipole occurs from the opposite sides of the pyridine ring.A similar situation was observed earlier in the case of m-dinitrobenzohetarenes, 26 Scheme 1.The formation of cycloaddition products 7a-e was found to be diastereoselective.In case of compounds 7a,b,e, the crystal and molecular structure (Figures 1 and 2) confirmed the expected cis-addition of the dipole.
In all three compounds studied by X-ray diffraction the annelated five-membered rings and corresponding nitro groups are located on opposite sides of the central heterocyclic fragment.Due to certain steric hindrance, the six-membered rings in 7a and 7b have an envelope conformation with atom C5 (Figs. 1 and 2) shifted by 0.520(2) and 0.473(2) Å from the mean plane of the remaining atoms.Only in 7e is the conformation of the central ring close to a half-chair conformation, characteristic of cyclohexene.
Interestingly, the conformation of the annelated rings adjacent to the nitrogen atom N1 is a perfect envelope with atom C11 out of the plane, and the conformation of the second cycle is intermediate between an envelope and a half-chair.As expected, the nitrogen atoms of the five-membered rings are significantly pyramidalized.Bond lengths and angles in the three compounds are typical to values for related fragments of known substances.The maximal difference is observed for bond N1-C1 that is by ~0.013 Å longer in sulfurcontaining molecules.All interactions between molecules in crystal are of weak van der Waals type.It is worth noting that compounds 7e and 7a differ in only one atom (oxygen and sulfur), but they have completely different crystal packing.This fact can be explained by different orientation of the phenyl substituent relative to the central ring: the corresponding torsions N1-C2-O1-C13 and N1-C2-S1-C13 are equal to -34.26(1) and 24.47(1)° and have different signs.

Experimental Section
General.All chemicals were of commercial grade and used directly without purification.Melting points were measured on a Stuart SMP 20 apparatus. 1H and 13 C NMR spectra were recorded on a Bruker AM-300 spectrometer (at 300,13 and 75,13 MHz, respectively) in DMSO-d6 or CDCl3 with TMS as internal standard.HRMS spectra were recorded on a Bruker micrOTOF II mass spectrometer using ESI.All reactions were monitored by TLC analysis using ALUGRAM SIL G/UV254 plates, which were visualized by UV light.X-ray.Data collection for all samples was performed on a Bruker APEX DUO diffractometer equipped with CCD detector (graphite-monochromated MoKα radiation, λ = 0.71073 Å or CuKα radiation, λ =1.54178 Å).Frames were integrated using the Bruker SAINT software package 36 by a narrow-frame algorithm.A semiempirical absorption correction was applied with the SADABS 37 program using the intensity data of the equivalent reflections.The structures were solved with direct methods and refined by the full-matrix least-squares technique against F2hkl in anisotropic approximation with SHELX 38 software package.Hydrogen atoms were placed in calculated positions and refined in riding model with Uiso(Hm) = 1.2Ueq(Cm) for methyl groups and Uiso(H) = 1.2Ueq(C) for all other hydrogen atoms.Detailed crystallographic information is provided in Supplementary material.Structures were deposited to Cambridge Structural Database, CCDC 1550123-1550125 contain the supplementary crystallographic data for this paper.These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif , or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033.

Figure 1 .
Figure 1.General view of molecules 7a (left) and 7e (right) in the crystal.Anisotropic displacement parameters are drawn with 50% probability.

Figure 2 .
Figure 2. General view of molecule 7b in the crystal.Anisotropic displacement parameters are drawn with 50% probability.