Synthesis of nitroaryl derivatives of glycine via oxidative nucleophilic substitution of hydrogen in nitroarenes

Carbanion of ethyl N (1,3 dithiolan 2 ylidene)glycinate adds to activated nitroarenes mostly in para position to the nitro group. Subsequent oxidation of the resulting σ H adducts with DDQ gave respective α­nitroarylated glycine derivatives in moderate yields. The reaction of esters of chiral alcohols such as (-)-menthol or (-)-8-phenylmenthol proceeds with a moderate or high diastereoselectivity leading to enantiomerically enriched nitroarylglycines.


Introduction
Synthesis of unnatural amino acids is of substantial interest since they are valuable intermediates in the construction of pharmaceutically important products such as peptidomimetics, enzyme inhibitors, etc. 1,2 Of particular interest are arylglycines because they are components of many pharmaceuticals e.g.Plavix 3a , Cefprosil 3b or Vancomycin, 3c etc.
Although there are numerous methods of synthesis of arylglycines 4 , those that contain the nitro group in orto or para position are not much known.Synthesis of such nitroarylated glycines are reported via the Strecker reaction, 5 and the base-induced Smiles rearrangement of Nnitrophenylsulfonyl amino acids. 6n a few earlier papers we reported synthesis of some α-nitroaryl-α-amino acids via oxidative nucleophilic substitution of hydrogen (ONSH) in nitroarenes with carbanions of protected esters of amino acids.The ONSH reaction, a two-stage process, comprises addition of nucleophilic agents such as carbanions to nitroarenes in the ortho or para position, in relation to the nitro group, occupied by hydrogen to form σ H adducts and their subsequent oxidation by an external oxidant. 7Since the addition is a reversible process and the nucleophiles (carbanions) are sensitive to oxidation, the ONSH proceeds satisfactorily only when the addition equilibrium is shifted to the adduct due to high nucleophilicity of carbanions and high electrophilicity of nitroarenes.Following this methodology, we have synthesized the α-nitroaryl derivatives of alanine, 8a proline, 8b serine 8a,8c , threonine 8c and phosphoglycine.8d In this paper we report an application of this methodology for synthesis of C-nitroarylglycines.

Results and Discussion
We have chosen ethyl N-(diphenylmethylene)glycinate 1a and ethyl N-(1,3-dithiolane-2-ylidene)glycinate 1b for the precursors of protected glycine carbanions.Similar derivatives of alanine were successfully used in the ONSH reaction in nitroarenes in our early work.8a The protected glycine esters 1a and 1b were obtained according to the literature procedures. 9,10reliminary experiments in which carbanion of 1a generated by treatment of 1a with t-BuOK in THF/DMF mixture at low temperature was reacted with nitrobenzene and 3-cyanonitrobenzene and subsequently oxidized with DDQ gave negative results.No ONSH products were found in the reaction mixtures.It appears that the nucleophilicity of the carbanion of 1a is too low to form the σ H adduct in a sufficient degree, even with highly electrophilic 3-cyanonitrobenzene.
Somewhat similar situation was observed earlier in ONSH with carbanion of protected alanine.The reaction proceeded satisfactorily with nitrobenzenes containing electron-withdrawing substituents but not with the less electron-deficient nitrobenzenes.8a Due to the presence of the methyl group the nucleophilicity of the carbanion of the analogously protected alanine ester is higher than that of 1a.On the other hand the carbanion of 1b exhibited higher nucleophilicity than that of 1a and formed σ H adducts to nitrobenzene derivatives that contain electron-withdrawing substituents.The carbanion of protected alanine esters due to their tertiary character added to nitrobenzenes only in the para position, whereas the secondary carbanion of 1b can react with such nitroarenes in both ortho and para positions.
Thus, when a solution of 1b and 4-chloronitrobenzene in a mixture of THF/DMF at -78 ºC was treated with t-BuOK and after a few minutes DDQ was added, the expected product of ONSH 4a was obtained in a reasonable yield of 45%.It shall be stressed that no traces of a product of nucleophilic substitution of chlorine, S N Ar were detected in the reaction mixture.Under similar conditions a series of nitrobenzene derivatives were reacted with 1b to form products of ONSH, mainly in the para position.The reaction with 2-chloro, 2-bromo-and 2cyanonitrobenzene gave two isomeric ONSH products in positions 4-and 6-, whereas 3-chloroand 3-bromonitrobenzene reacted exclusively in position 4 (Table 1).In all the cases, yields of the ONSH products were only moderate; however, taking into account the availability of the starting materials and the simplicity of the procedures this synthesis of nitroarylated glycines is of practical value.We observed serious difficulties in the separation of the isomeric ONSH products due to small differences in R f in TLC and column chromatography; thus the products were isolated and purified as mixtures o-and p-nitroarylglycinates.The composition of the mixtures was determined on the basis of 1 H NMR.
The products of the ONSH reaction in nitroarenes can be converted into N-formyl derivatives of nitroarylated glycine esters via typical procedure described in our previous paper.8a This possibility was exemplified by hydrolysis of 3a to give ethyl N-formyl-α-(2-chloro-4nitrophenyl)glycinate 3e in 60% yield (Scheme 1).
In order to explore possibilities of synthesis of enantiomerically enriched nitroarylglycines we have attempted the ONSH reaction with protected glycine esters of chiral alcohols.We expected that the chiral auxiliary could promote diastereoselective addition of the carbanions to nitroaromatic rings.For this purpose, we obtained N-Boc protected glycine esters of (-)-menthol and (-)-8-phenylmenthol.These compounds upon deprotection and the reaction with carbon disulfide and 1,2-dibromoethane were converted into the desired N-(1,3-dithiolane-2ylidene)glycinates 1c and 1d, respectively (Scheme 2).

Scheme 2
The ONSH reaction of 1c with 3-chloronitrobenzene under standard conditions (treatment of a solution of the nitroarene and 1c in THF/DMF at -78 °C with t-BuOK followed by oxidation with DDQ) gave the expected product of substitution in the para position 3c in 46% yield.The 1 H NMR spectrum of this product indicates the presence of two diastereomers, observed as two sets of signals in ratio 2:1.Particularly diagnostic was the signal of the α-proton of the arylglycine that appeared as two singlets at 5.44 ppm of the major diastereomer and at 5.42 ppm for the minor one.Under the same conditions the reaction 1d with 3-chloronitrobenzene gave, according to the 1 H NMR spectrum, a single diastereomer 3d in a good yield of 66%.The signal of the proton in the α-position appeared as a singlet at 4.92 ppm.

Scheme 3
In order to clarify the origin of the diastereoselectivity, 3d was treated with t-BuOK in THF at 0°C so as to induce epimerization.The solution became immediately deep-blue indicating a formation of the nitrobenzylic carbanion.The 1 H NMR spectrum of the product, isolated upon acidification and standard isolation procedure, shows presence of the additional set of signals that can be assigned to the second diastereomer.A new α-proton signal at 5.35 ppm appeared, whereas in the pure diastereomer 3d the same proton has the chemical shift of 4.92 ppm.Such an outcome suggests that the configuration of the new chiral center in 3d was fixed at the addition stage.
These results imply that it is possible to obtain enantiomerically enriched p-nitroarylglycines using the procedure presented in this paper.

Experimental Section
General.The carbanion precursors 1a 9 and 1b 10 were obtained according to the standard literature procedures.The syntheses of 1c and 1d were performed in the following way:

General procedure for oxidative nucleophilic substitution of hydrogen in nitroarenes
To a stirred solution of 1b (1.0 mmol) and nitroarene 2 -12 (2.0 mmol) in THF (10 mL) and DMF (2 mL) at -78°C under argon a solution of t-BuOK in THF (1.3 mL, 1.0 M) was added dropwise.The dark mixture was stirred for further 30 min, treated then with DDQ (1.2 mmol) in THF (1 mL).After 5 min the cooling bath was removed and the mixture was allowed to reach room temp.and treated with acidified water.The products were extracted and finally isolated by column chromatography on silica-gel (hexane/ethyl acetate).