Synthesis and Characterization of Enantiomerically Pure Menthylamines and Their Isocyanates

Abstract

E n a n t i o m e r i c a l l y P u r e M e n t h y l a m i n e s a n d T h e i r I s o c y a n a t e s Abstract: A synthetic protocol for optically pure (-)-menthylamine, (-)-8-methylmenthylamine, and the novel (-)-8-phenylmenthylamine is presented including a detailed characterization of these compounds and their isocyanates.Enantiomerically pure a-chiral amines 1 are important building blocks and auxiliaries in synthetic organic chemistry. 1 Several methodologies are established for the enantioselective synthesis of these compounds. 2 If very bulky substituents on the a-stereogenic center are involved, common procedures like the conversion of enantiopure sulfinimines suffer from low yields and are consequently less attractive. 3 For our supramolecular investigations, achiral amines with far-projecting substituents (R 2 ) larger than tert-butyl groups (e.g. 2) were required. The chiral information should be addressed by steric means in the vicinity of the nitrogen. In addition, the rigidity of the cyclohexane skeleton will provide conformational stability with locating the substituents appropriately and resulting in different steric demands on both sides of the nitrogen. 4 All these molecular features are excellently combined in 3 ( Figure 1).Optically pure menthylamine or 8-substituted derivatives 3 seemed to be the compounds of choice since an ex chiral pool synthesis can be exploited and should be feasible on a multi-gram scale. 8-Substituted (-)-menthol derivatives are widely used auxiliaries e.g. in the Diels-Alder reaction. 5 In contrast, the corresponding menthylamines are either not known or only sparingly described in the literature. 6,7 We describe a reliable protocol for the synthesis of enantiopure menthyl-, 8-methylmenthyl-, and 8-phenylmenthylamine, as well as their isocyanates, including the full analytical characterization. All transformations can be applied to multi-gram quantities.The synthesis of the parent menthylamine started directly with the commercially available (-)-menthone. For the 8-substituted derivatives the corresponding menthones had to be prepared first. Therefore, we used (+)-pulegone (4) and installed the appropriate moiety by cuprate addition, providing 5b/c (Scheme 1). 8 Employment of (+)-pulegone in practical grade (92%) is recommended since the impurities and the by-products of the 1,4-addition are easily removed after the transformation. The 1,2-addition occurred in a side reaction forming the intermediate alcohols, which undergo elimination upon work-up. The menthanones 5b/c were purified by a single distillation and consisted of an epimeric mixture due to the configurationally labile a-carbon. Subsequent oxime formation (Scheme 2) was performed under standard conditions. 9 Analytically pure product was only obtained after column chromatography on silica yielding 6a-c as colorless crystals. At the beginning, the eluent contains pure (E)-oxime; only the last 20% of the eluent consists of an E/Z-mixture. Therefore, all analytical data refer to the (E)-oxime. While the m...

Nms‐Amides: An Amine Protecting Group with Unique Stability and Selectivity

“…Additional references cited within the Supporting Information. [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]…”

Construction and Optimization of a Biocatalytic Route for Menthone Amination

“…Currently, all the synthetic pathways of (+)-neomenthylamine rely on chemical methods with terpenoids initial reactants such as (−)-menthone (Wallach 1891;Kozlov et al 1981;Kozlov 1982;Schopohl et al 2003). A conventional way was to convert (−)-menthone by reductive amination under Leuckart-Wallach conditions (Kitamura et al 2002), which could obtain all the neomenthylamines isomers.…”

“…Subsequently, dielectrically controlled resolution (DCR) of racemic neomenthol by (R, R)-tartaric acid and electrochemical synthesis with mercury pool cathode were both used to produce optical pure (+)-neomenthylamine stereoselectively (Schopohl et al 2003;Kulisch et al 2011;Schmitt et al 2014;Reinscheid and Reinscheid 2016). In recent reports, hydrogenation of menthone oxime to amines via gold catalysts has excellent yields in high temperature.…”