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...
The mechanism of the novel dimethyldioxirane (DMD) oxidation of sigma(H) adducts (Meisenheimer complexes) generated from nitroarenes and carbanions was elucidated. The proposed mechanism, which is akin to that of the oxidative Nef reaction, is supported by the isolation of the cyclohexadienone intermediate and the lack of a primary kinetic isotopic effect. Protic solvents (H(2)O, MeOH) enhance the reactivity of DMD through intermolecular hydrogen bonding.
p-Nitroaryl)diarylmethanes are readily prepared via vicarious nucleophilic substitution of hydrogen in nitroarenes with carbanions of diarylmethyl p-chlorophenyl sulfide. These carbanions are efficient reagents for introduction of diarylmethyl substituents in the para position of nitroarenes via the VNS reaction. The reaction does not proceed ortho to the nitro group due to steric hindrances on the addition step.
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