No abstract

Potassium and sodium salts of diphenylphosphine add to nitroarenes in the position ortho and para to the nitro group. Subsequent oxidation of s H -adducts with potassium permanganate gave diphenyl(nitroaryl)phosphine oxides.

a-(p-Nitroaryl)alanine and a-(p-nitroaryl)serine alkyl esters are efficiently synthesized via oxidative nucleophilic substitution of hydrogen in nitroarenes with carbanions of protected alanine and serine.Nonproteogenic (unnatural) a-amino acids play an important role in design and synthesis of pharmaceutically interesting molecules, such as peptidomimetics, enzyme inhibitors, and conformationally constrained peptides. 2,3 Hence synthesis of such a-amino acids has recently attracted great attention. 4,5 Particular attention has been directed toward the synthesis of quaternary (a,a-disubstituted) glycine derivatives because they are important components of peptides with special properties. 6 Amongst a variety of quaternary a-amino acids, those bearing a p-nitroaryl substituent in a position are practically unknown, and no direct method of synthesis of such amino acids is reported. According to our knowledge the only reported nitroarylated amino acids were synthesized via base-induced Smiles rearrangement of esters of Nalkyl-N-nitrophenylsulphonyl amino acids 7 or via the Strecker synthesis. 8In this communication we present a general and simple method of synthesis of a-(p-nitroaryl) derivatives of alanine and serine via oxidative nucleophilic substitution of hydrogen (ONSH) in nitroarenes. In our previous papers we have reported that carbanions of 2-phenylalkanenitriles 9 and esters of phenylacetic acid 10 add to nitroarenes in positions para to the nitro group producing anionic s H adducts that are subsequently oxidized by KMnO 4 or DDQ to give the respective nitroarylated nitriles and esters. We expected that similar ONSH procedure with proper carbanionic partners could be applied for the synthesis of nitroarylated amino acids. From a great variety of protected amino acids suitable for generation of carbanions 11,12 we have selected protected alanine and serine esters. For alanine we have chosen the commonly used N-(diphenylmethylene)alanine ethyl ester (1a) 13 and the much less common N-(1,3-dithiolane-2-ylidene)alanine isopropyl ester (1b), readily prepared via the reaction of the ester of alanine, CS 2 and ethylene bromide. 12 As a precursor of the protected serine ester carbanion we have selected 2-phenyl-4-carboethoxy-2-oxazoline (1c). 14 It should be stressed that 1a and 1c have also been widely used for synthesis of a,a-dialkylglycine derivatives via enantioselective phase-transfer-catalyzed (PTC) alkylation. 15,16 Scheme 1 Reagents and conditions: (i) nitroarene (2 equiv), tBuOK (1.5 equiv), THF, DMF, -78 °C; (ii) DDQ (1.2 equiv), -78 °C, then r.t.; (iii) aq HCl, EtOH or H 2 O 2 (10 equiv), HCO 2 H, MeCN, 5 °C to 20 °C.Both of the precursors of alanine carbanions 1a and 1b are sufficiently acidic to be deprotonated by t-BuOK in THF to give carbanions of proper nucleophilicity that add to activated nitroarene rings giving s H adducts that were further oxidized by DDQ to the expected nitroarylated products.Thus treatment of a mixture of nitroarene 2-8 (2 equiv), and carbanion precursor 1a or 1b (1 equiv...

Optically pure (R)-a-(p-nitroaryl)prolines are synthesized via oxidative nucleophilic substitution of hydrogen in nitroarenes using chiral carbanion of L-proline protected as N,Oacetal of pivalaldehyde.Enantiomerically pure unnatural a-amino acids are interesting intermediates for pharmaceutical and agrochemical industries so their synthesis attracts considerable attention. Of particular interest are a-substituted proline derivatives that are used in peptide research for manipulation of conformational flexibility of the peptide chain, 2 as chiral building blocks, 3 efficient organocatalysts, 4 etc.Several methods for asymmetric synthesis of a-substituted prolines are reported. Alkylation and reactions with other electrophiles of the carbanion of proline protected as N,O-acetal of pivalaldehyde proceeds diastereoselectively thus assuring the synthesis of a-substituted prolines with self-reproduction of chirality. 5 Enantioselective introduction of aryl and benzyl groups into position a of N-methyl proline proceeds via Stevens and Sommelett-Hauser rearrangement of N-benzyl-N-methyl ammonium salts of proline tert-butyl ester. 6 Enantiomerically pure a-substituted prolines can be obtained via construction of the pyrrolidine ring in sequence of reactions: monoalkylation of chiral Schiff base of glycine with 1,3-diiodopropane followed by hydrolysis of the resulting imine and subsequent N-alkylation, 7 as well as via cyclization of enantiomerically pure a,w-amino alcohols under Mitsunobu conditions. 8 In this letter we report the synthesis of a-(p-nitroaryl)prolines in enantiomerically pure form via diastereoselective oxidative nucleophilic substitution of hydrogen, ONSH, in nitroarenes with carbanion of protected proline. We have shown previously that carbanions of some protected a-amino acids add to nitroarenes giving anionic s H adducts that after oxidation followed by hydrolytic deprotection produced racemic a-(p-nitroarylated)alanines and serines. 9 For enantioselective synthesis of a-(p-nitroaryl)prolines we have applied the approach developed by Seebach for self-reproduction of chirality, namely used as the carbanion precursor, proline protected as N,O-acetal of pivalaldehyde 1 (Figure 1). It should be noted that reaction of 1 with benzenetricarbonylchromium complex followed by oxidation gave a-phenylproline, product of nucleophilic oxidative arylation in moderate yield. 5Compound 1 was prepared via direct reaction of pivalaldehyde with the trimethylsilyl ester of N-trimethylsilyl-L-proline according to slightly modified literature method. 10 In many reports on reaction of carbanion of 1, its lithium salt generated by action of LDA was utilized. 5,11 Taking into account that addition of carbanions to nitroarenes proceeds satisfactorily when they are in form of loose ion pairs, 12 we used the potassium salt of 1 -generated by reaction of 1 with potassium hexamethyldisilazane (KHMDS) in a mixture of THF-DMF. When 1 and nitrobenzene in THF-DMF mixture was treated at -70°C with KHMDS, and after some time the fo...

Carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate add to nitroarenes to form relatively long-lived sigma(H) adducts that can be oxidized to products of oxidative nucleophilic substitution of hydrogen. By variation of the conditions, o- and p-nitroarylated derivatives of the starting phosphonates can be synthesized regioselectively. It has been proven that addition of carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate to nitroarenes is a fast process and the respective sigma(H) adducts are formed almost quantitatively.