Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio-/or Diastereoselective N‑Alkylation of Amines by Alcohols via Oxidation/ Imine-Iminium Formation/Reductive Amination: A Pragmatic Synthesis of Octahydropyrazinopyridoindoles and Higher Ring Analogues Imran A. Khan and Anil K. Saxena* Laboratory No. 101, Medicinal and Process Chemistry Division (MPC), CSIR-Central Drug Research Institute (CDRI), Chattar Manzil Palace, Lucknow, Uttar Pradesh 226-001, India * S Supporting Information ABSTRACT: A mild step and atom-economical nonepimeriz- ing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/ reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen- transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues. ■ INTRODUCTION The reductive amination reaction remains one of the most powerful and widely utilized transformations available to practitioners of chemical synthesis in the modern era. 1 Conventionally, the N-alkylation of amines is achieved either by their alkylation with the alkylating agents or by the addition of the nucleophiles or radicals on imines. 2 The most commonly used method for the preparation of secondary and tertiary amines is the substitution of alkyl halides by amines in the presence of a base. 3 However, in this process polyalkylation often occurs, which leads to a mixture of products along with undesired inorganic waste. Moreover, several alkyl halides are toxic and unnatural. The use of accessible, reasonable, and less hazardous reagents such as alcohols instead of alkyl halides for N-alkylation of amines is considered as a better alternative approach with high atom-efficiency leading to the formation of water as a byproduct. The “borrowing hydrogen strategy (hydrogen autotransfer)”, has allowed the direct use of alcohols as alkylating agents. This process has been applied to the formation of C-N bonds, 4 and the use of SiO 2 5 and Al 2 O 3 6 as catalysts has been reported; however, under these conditions both the yields and the selectivities (monoalkylation versus bis- alkylation) are poor. The best known conditions involve transition-metal-based catalysts, including heterogeneous and homogeneous processes. When the reaction is performed with heterogeneous catalysts 3d such as nickel, 7 copper, 8 platinum, ruthenium, 9 palladium, 10 gold, 11 silver, 12 or iron 13 the yields are good to excellent, but generally the main drawback is the need for harsh conditions such as high temperature which can be unfavorable for highly sensitive compounds. The landmark advancement in the field of understanding iminium activation through LUMO lowering activation phenomenon by MacMil- lan 1c-k and more importantly Brønsted acid catalyzed imine activation concepts by Rueping 1l-t added key reasons for major success in the reaction associated with fields like “highly regulated cascade”. 1l Taylor et al. reported a mild one-pot oxidation/imine iminium formation/reduction sequence for the conversion of benzylic, allylic, or propargylic alcohols to amines using MnO 2 (as oxidant), a polymer-supported cyanoborohydride (as reductant), and acetic acid (as additive). 14 The homogeneous catalysts 3 such as ruthenium 15 or iridium 16 catalysts offered good yields of monoalkylated amines. However, the major drawbacks were the high temperature and a long reaction time except under microwave irradiation along with the epimeriza- tion of optically active alcohols that are involved in the N- alkylation of amines. 14b Recently, N-alkylation of amines by direct nucleophilic substitution at the sp 3 carbon atom of alcohols was reported using iron and amino acid catalysts but again at elevated temperature with long reaction times. 17 Our recent research endeavors on developing effective method- ologies for useful organic transformations 18 to construct Received: June 20, 2013 Article pubs.acs.org/joc © XXXX American Chemical Society A dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX-XXX