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Abstract-A new asymmetric synthesis of 2-substituted chiral chromanes has been achieved. The key step is the intramolecular conjugate addition of a phenolic nucleophile on a a,b-unsaturated ester catalyzed by Cinchona alkaloids. The high ee's obtained with cinchonine and its derivatives have been rationalized by ab initio quantum chemistry calculations of transition state structures. Ó 2004 Elsevier Ltd. All rights reserved.Functionalized chromanes possess potentially useful biological properties.1 In the scope of a research program, we developed earlier the synthesis of 2,6-disubstituted-chromanes from 6-substituted chromanones 2 ( Fig. 1).Although high overall yields of racemic material were obtained, this approach suffered from the need to perform an optical resolution in the last step of the synthesis.In order to improve the productivity of the process without having to develop a new route, we sought to utilize a chiral base in the Wittig-oxa-Michael step (Fig. 2). The results of those efforts are reported herein. Initially very low enantioselectivities (ca. 28% ee with cinchonine) were obtained in a tandem process by heating a mixture of lactol 1, phosphorane, and cinchonine to 80-100°C. In this temperature range, we observed that the phosphorane alone was able to catalyze the cyclization thus competing with the chiral catalyst. Therefore, we modified the procedure and performed the reaction sequentially: (i) the Wittig step was carried out at ambient temperature (ii) the remaining phosphorane and the triphenylphosphine oxide by-product were removed by silica gel treatment, and (iii) the chiral

The two structural isomers, 4 and 5, of 1‐substituted‐4‐iminomethyl‐1,2,3‐triazoles are interconvertible when heated in dimethyl sulfoxide at 80°. The equilibrium position depends on the electronic properties of the R‐substituent, favoring 5 for R = alkyl, benzyl and anisyl, and 4 for p‐chlorophenyl and p‐nitrophenyl. An interesting application is the synthesis of 1‐alkyl‐1,2,3‐triazole‐4‐carbaldehydes from 1‐phenyl‐1,2,3‐triazole‐4‐carbaldehyde by Scheme I. The hydrazones 4ij and the oxime 4k do not rearrange due to an unfavorable Z‐configuration around the C  N bond, whereas the acyloximino derivative 4m is converted into the nitrile 11. The structures of the products have been fully characterized by 13C nmr spectroscopy and the mechanistic details of the rearrangement are discussed.

A scalable process has been developed for the synthesis of trans-2-methylcyclopropanecarboxylic acid via the stereoselective cyclopropanation of ethyl crotonate with dimethylsulfoxonium methylide (Corey's ylide). This well-known reaction is generally low yielding and very challenging to scale up as it involves highly reactive reagents. A design of experiment (DoE) allowed us to quickly define the optimal ranges for the reaction parameters. A very significant increase of the yield was obtained by adding the ylide to ethyl crotonate in DMSO at 80 °C in anhydrous conditions. In view of a scale-up at a multikilogram scale, several experiments were then performed combining Process Analytical Technologies (PAT) and Calorimetry (Dynamic DSC, Adiabatic Reaction Calorimetry and Vent Sizing Package). For safety reasons at high temperatures on large scale the reaction was also evaluated in a continuous flow reactor. Thanks to these studies, we were able to develop an efficient process avoiding the hazardous accumulation of the thermally unstable dimethylsulfoxonium methylide.

We report herein a short and efficient synthesis of (R,R)-2-methylcyclopropanecarboxylic acid via a Horner−Wadsworth−Emmons reaction involving commercially available (S)-propylene oxide and triethylphosphonoacetate (TEPA). The TEPA/base/propylene oxide stoichiometry was found critical to achieve high yields. We therefore studied the TEPA anion formation and stability using in situ IR spectroscopy. The reaction yield is strongly influenced by the counterion and solvent, whereas high diastereoselectivities are always obtained. Under the best experimental conditions (HexLi/MeTHF/150 °C), crude (R,R)-2-methylcyclopropanecarboxylic acid is obtained in 85−90% yield with >98% trans selectivity.