Reductive monoalkylation of nitro aryls in one-pot Magne O. Sydnes a, * , Masaki Kuse b , Minoru Isobe a, c a Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan b Chemical Instrument Division, RCMS, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan c Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan article info Article history: Received 4 April 2008 Received in revised form 21 April 2008 Accepted 21 April 2008 Available online 24 April 2008 Keywords: One-pot Nitro aryls Reductive monoalkylation Benzylation Pd/C abstract The scope of the serendipitous reductive monoalkylation of ethyl (4-methoxy-3-nitrophenyl) acetate taking place during reduction of the nitro functionality to the corresponding primary amine when treated with hydrogen (1 atm) over Pd/C (10%) in ethanol is investigated. Upon prolonged reaction time the reaction conducted in ethanol and methanol yields significant amount of the corresponding secondary amines, while when performed in n-butanol and i-propanol it only resulted in the formation of a small amount of the corresponding secondary amines. Further development of the reductive monoalkylation reaction provided conditions that facilitate conversion of a range of different nitro aryls in one-pot to the corresponding secondary benzyl amino aryls in mostly good to excellent yields. This is accomplished by using hydrogen (1 atm) over Pd/C (10%) as reducing agent and benzaldehyde as the benzyl source combined with a stepwise reaction sequence. This chemistry was further extended to the formation of substituted benzyl amino aryls. The yields of the latter products varied dramatically depending on the substitution patterns associated with the benzaldehyde. However, by altering the reaction conditions it was possible to improve the yields of the benzylated products. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction One-pot reactions, where several steps are performed in the same reaction vessel, are gaining popularity as we strive towards conducting our profession in a more sustainable fashion. 1 De- velopment of such reactions is therefore of paramount importance as chemists aim at minimizing reagent and solvent use, as well as reducing isolation steps. Compounds containing a nitro group are valuable substrates in organic synthesis. 2 In particular, nitro aryls are important due to their ready formation from a range of aromatic starting materials 3 and their easy conversion to aromatic amines. 4 Primary aryl amines are in its place vital starting materials for numerous products of great importance, such as pharmaceuticals. 5 Often these aryl amines are taken through several steps where the use of protection groups is essential in order to secure the desired outcome. In a recent com- munication we reported a simple one-pot procedure for reductive monoalkylation of nitro aryls using aliphatic aldehydes as alkyl source and H 2 (1 atm) over Pd/C (10%) as reducing agent (Scheme 1). 6,7 This procedure afforded exclusively the secondary amines even when excess amount of aldehyde was used. Herein we report on the further development of this chemistry for the synthesis of benzyl protected aryl amines and substituted benzyl aryl amines. 2. Results and discussion 2.1. Solvent effects Recently we reported that secondary amine 4a was formed in a reasonable yield (41%) together with the desired primary amine 2a (47%) when the reduction of nitro aryl 1a was run for a pro- longed period of time (48 h) in ethanol (Scheme 1). 6 However, upon NH 2 R 1 2 R N R 1 2 R R 3 2 3 NO 2 R 1 2 R 1 NHR 4 R 1 2 R 4 R 3 CHO, EtOH, rt H 2 , Pd/C (10%), Scheme 1. General outline of the one-pot reductive monoalkylation reaction (intermediates are shown; amine 2 and imine 3). * Corresponding author. Tel.: þ81 52 789 4186. E-mail address: sydnes@nuagr1.agr.nagoya-u.ac.jp (M.O. Sydnes). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.04.077 Tetrahedron 64 (2008) 6406–6414