Oxidative arylamination of 1,3-dinitrobenzene and 3-nitropyridine under anaerobic conditions: the dual role of the nitroarenes

1,3-Dinitrobenzene and 3-nitropyridine react with lithium arylamides under anaerobic conditions to produce N -aryl-2,4-dinitroanilines and N -aryl-5-nitropyridin-2-amines, respectively, in 8-42% yields.


Introduction
The importance of aromatic and heteroaromatic amines is generally known 1 .The most common method for their preparation is nucleophilic aromatic substitution of halide or other nucleofugal groups under conventional 2 or catalytic conditions 3 .In cases of electron-deficient substrates, such as azines and nitroarenes, the nucleophilic aromatic substitution of hydrogen (S H N ), 4 including its oxidative 5 and vicarious 6 versions, is an attractive alternative to the above methods.This methodology does not require any preliminary introduction of a classical leaving group into an aromatic substrate and need not expensive catalysts or ligands.Mechanistically, the oxidative S H N -amination consists of σ H -adduct formation and its subsequent oxidative rearomatization (Scheme 1).
In the presence of KMnO4 electron-deficient azines and nitroarenes can be smoothly aminated by potassium amide in a liquid ammonia or liquid ammonia itself.5a In our previous reports we have shown that an alkylamine/AgPy2MnO4 system is very efficient for the oxidative alkylamination of fused azines, 5b 3-nitropyridine 5c , 1,3-dinitrobenzene and nitronaphthalenes 5d .In the course of this study, we have been interested in the S H N -arylamination of aromatic substrates.Unfortunately, the oxidative amination and alkylamination procedure is not suitable for arylamination because of the low nucleophilicity and high sensitivity arylamines towards oxidation.This is why S H N -arylamination reactions are still rare.The majority of these are intramolecular and are performed using mild oxidants such as sulfur, chloranil, nitrobenzene. 7In some cases, oxidation of σ H -complexes with the oxygen in air was observed. 8When nitroarenes were used as substrates, the NO2 group itself was often found to be an acceptor of hydride ion. 9 Similarly, for the amination of azaheterocycles, the ring C=N bond can intercept hydride ion.8b To date, only a few intermolecular oxidative arylamination reactions have been reported.5azacinnoline, 10 3-X-1,2,4-triazines (X = SMe, SBu t , OMe) 11 and 2-X-3-nitropyridines (X = H, Cl) 12 were found to be suitable substrates.In all cases, the reaction was carried out with anilines 10 or hetarylamines [10][11][12] in the presence of a strong base.Thus, to be performed the reaction needs metal arylamide as a nucleophile.Interaction of 5-azacinnoline with arylamines demanded 20 days for completion with crucial access to the air.Arylamination of 1,2,4-triazines proceeded without external oxidant under an inert atmosphere.Obviously, the substrate itself served here as a hydride ion acceptor.3-Nitropyridines reacted with 2-, 3-or 4-aminopyridines in the presence of LiHMDS (or LDA) in THF without isolation of the reaction mixture from the air oxygen.The use of nitrobenzene as a co-solvent has been shown to improve the yield of the arylamination product.Here we wish to report on the direct arylamination of 3-nitropyridine and 1,3dinitrobenzene by reacting with lithium aryl(hetaryl)amides under anaerobic conditions.

Results and Discussion
Note, for arylamination of 3-nitropyridines 12 , 2-, 3-or 4-aminopyridines were solely used as nucleophiles.Checking the feasibility of a similar approach for other aryl-and hetarylamides was our initial goal.We have also yet to answer if this reaction is possible under anaerobic conditions.
At first, we studied reaction of 3-nitropyridine 1 with 2-aminopyridine under modified experimental procedure (Scheme 2, Table 1).Lithium arylamide was prepared by treating 2aminopyridine (1.1 mmol) with butyl lithium (1.2 mmol, 1.6M solution in hexane) in anhydrous THF at -78 to -70 о С under argon.Solution of 3-nitropyridine 1 (1 mmol) in THF was subsequently added.The reaction mixture was stirred for 16-19 h with gradual warming to room temperature.After extraction and flash column chromatography 5-nitro-N-(pyridin-2-yl)pyridin-2-amine 2a was obtained in 19% yields (Table 1, Entry 1).Increased amounts of 2aminopyridine and BuLi led to 2a in higher yields (Table 1, Entries 2-4).The use of 1.6 equiv of arylamine and 1.7 equiv of BuLi was optimal and gave an even better yield of 2a compared with the published 11 procedure.Upon arylamination of 1 with quinolin-2-amine or aniline similar results were observed (Table 1, Entries 10,11,13,14).The corresponding N-aryl-5-nitropyridin-2amines 2b and 2c were obtained in 34-37% yields.The procedure was also suitable for amination of 1 with phenylamidine yielding compound 2d (Table 1, Entry 16).The use of nitrobenzene as a co-solvent, as has been shown 12 , improves the yield of the arylamination product due to its ability to accept a hydride ion from σ H -adduct and thus, facilitate the rearomatization step.To check this observation, we carried out the reaction of 3nitropyridine 1 with 2-aminopyridine using nitrobenzene as an additive.Indeed, this additive provided higher yields of 2a (Table 1, Entries 5-7).The use of 1.1 equiv of nitrobenzene was found to be optimal.Addition of nitrobenzene assisted also the reaction of 1 with phenylamidine (Table 1, Entry 17).At the same time, its influence on the reactions with other aryl(hetaryl)amines was not essential (Table 1, Entries 12 and 15).
To verify the hypothesis of oxidation with nitrobenzene, we carried out the reaction of 1 with 2-aminopyridine in the presence of 1,2-or 1,3-dinitrobenzene as soon as their oxidative ability is certainly higher.However, 1,2-dinitrobenzene additive gave less yield of 2a (Table 1, Entry 8) than in the reference experiment with nitrobenzene (Table 1, Entry 6).Interestingly, when the reaction of 3-nitropyridine 1 with 2-aminopyridine was carried out in the presence of 1,3-dinitrobenzene 3, the arylamino derivatives 2a and 4a were obtained in 13 and 28% yields, respectively (Table 1, Entry 9).This indicated that 1,3-dinitrobenzene is more reactive towards amides comparing with 3-nitropyridine.As a second part of our work, we examined the arylamination of 1,3-dinitrobenzene 3 using the optimized reaction conditions developed for 1.The results are collected in Scheme 3 and Table 2.As shown in Table 2, the nature of the arylamine affects the reaction.Evidently, if the NHacidity of arylamine is high, the corresponding N-anion is formed easier.On the other hand, the greater the NH-acidity of arylamine, the lower the nucleophilicity of the corresponding N-anion.The steric accessibility of the N-nucleophilic center should be also taken into account.The sum of these factors is responsible for yields of the arylamination products 4. Indeed, as it follows from Table 2 and data on the NH-acidity of arylamines, the highest yields of 4 were obtained upon using of 2-and 4-aminopyridines having middle pKa values (Table 2, Entries 1,2).The presence of a substituent in the position ortho to the amino group of arylamine makes difficult the nucleophilic attack and, perhaps, oxidation of the arylamino- H -complex.That is why compounds 4g and 4i were obtained in low yields (Table 2, Entries 7,9).The greater steric hindrance of the peri-amino group may cause reduction in the yield switching from 4c to 4d (Table 2, Entries 3,4).
The developed procedure was also suitable for amination of 3 with benzamide yielding compound 4m (Table 2, Entry 13).a NH-Acidity in DMSO. 13t should be mentioned that the reactions of 3-nitropyridine and 1,3-dinitrobenzene with aryl(hetaryl)amides were carried out under anaerobic conditions.Thus, one can conclude that the substrate itself acts here as the oxidant accepting a hydride ion from anionic  H -complex (Scheme 4).That is why the yields of the arylamination products 2 and 4 did not exceed 42%.In addition, when 2-aminothiazole was used as a nucleophile, the arylamino derivative 4l was obtained together with 3-nitroaniline 5 (the reduction product of 3) (Table 2 RNH Li The structures of compounds 2 and 4 were characterized by UV, IR, 1 H NMR, 13 C NMR, mass spectroscopy and in two cases (compounds 4a and 4k) single crystal X-ray diffraction analysis.The X-ray data indicate the presence of intramolecular hydrogen bond of the N-H….O type with the length range 1.856-1.898Å (Figures 1A and 2).Interestingly, the six-membered cycle of 4a closed by intramolecular hydrogen bond is not planar: the dihedral angle between the O-N-O and H-N-C planes is ~12 o (Figure 1B).Molecule 4k adopts a spiral-like shape: the dihedral angle between the planes of the neighbouring benzene rings is ~33-35 o (Figure 2).
A -ORTEP plots for X-ray crystal structure of 4a with crystallographic numbering scheme (two independent molecules in the unit cell; the length of intramolecular hydrogen bond is marked in red) Bview on the molecule 4a, showing that the cycle closed by intramolecular hydrogen bond is not planar (Cgrey, Nblue, Ored, Hwhite)

Conclusions
In the present paper we have shown that N-aryl-2,4-dinitroanilines and N-aryl-5-nitropyridin-2amines may be easily obtained from 1,3-dinitrobenzene and 3-nitropyridine, respectively, through oxidative nucleophilic substitution of hydrogen, using the metal amides of a range of aryl(hetaryl)amines as reactants.The reaction proceeds under anaerobic conditions.The nitroarene plays the dual role in this reaction acting as the substrate and oxidizing agent.

Experimental Section
General. 1 H NMR spectra were obtained on a Bruker DPX-250 (250 MHz) and Bruker Avance 400 (400 MHz) spectrometers. 13C NMR spectra were recorded on a Bruker DPX-250 (62.9 MHz) and Bruker Avance 400 (100 MHz) spectrometers. 1 H and 13 C NMR chemical shifts are in parts per million relative to Me4Si.Coupling constants are in Hertz.IR spectra were recorded on a Varian Excalibur 3100 FT-IR and Cary 50 Probe spectrometers using Nujol.UV spectra were registered on a FSM-1201 spectrophotometer with CHCl3 as a solvent.Mass spectra were measured on a Finnigan MAT INCOS 50 spectrometer.CHN analysis was accomplished by combustion analysis (Dumas and Pregl method).Melting points were determined in glass capillaries using a PTP device and are uncorrected.Column chromatography was performed on silica gel 60 (70-200 mesh; Merck).All commercial reagents (3-nitropyridine, 1,3dinitrobenzene, aryl-and hetarylamines, BuLi, THF) were purchased from Acros and Aldrich and used without additional purification.Crystallographic data for 4a and 4k (atomic coordinates, bond lengths, bond angles and thermal parameters) have been deposited at the Cambridge Crystallographic Data Centre (CCDC) and allocated the deposition number CCDC 815054 (4a) and CCDC815055(4k). 1 H and 13 C NMR spectra of all 2 and 4 as well as crystallographic data for 4a and 4k are available as supporting information.

General procedure for the synthesis of N-aryl-5-nitropyridin-2-amines (2a-d)
Lithium arylamide was prepared by treating arylamine (1.6 mmol) with butyl lithium (1.7 mmol, 1.6M solution in hexane) in anhydrous THF (4 mL) at -78…-70 о С under argon.Solution of 3nitropyridine 1 (124 mg, 1 mmol) in THF (1 mL) was added dropwise.The resulting mixture was stirred for 16-19 h with gradual warming to room temperature.The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 x 10 mL).The organic extract was dried over MgSO4, concentrated and purified by silica gel chromatography using dichloromethane/methanol (100 : 1) mixture as the eluent.The bright yellow fraction was collected.Subsequent recrystallization of the crude product from heptane or toluene gave 2 in the yield pointed in Table 1.

or 3 as a hydride ion acceptor reduction of 1 or 3 2 or 4 Scheme 4 .
Scheme 4. Mechanism of the compounds 2 and 4 formation.

Figure 1 .
Figure 1.The X-ray crystal structure of 4a.

Figure 2 .
Figure 2. The X-ray crystal structure of 4k (the length of intramolecular hydrogen bond is marked in red).