Some Items of Interest to Process R&D Chemists and Engineers

Abstract

Crafts alkylation of aromatic compounds is one of the important organic transformations. A report (Org. Lett. 2013, 15, 5912) described an intramolecular Friedel−Crafts reaction of aziridinium ions for the synthesis of 4-substituted tetrahydroquinolines. Treatment of enantiopure β-haloamines with AlCl 3 provided, via aziridinium ion intermediates, enantiomerically enriched 4-substituted tetrahydroisoquinolines. Both the formation and ring-opening of aziridinium ions are identified as key steps in these transformations. The bromide in β-bromoamines proved to be the leaving group of choice as using the β-chloroor β-iodoamine substrates led to a lower yield and ee. In addition this intramolecular Friedel−Crafts reaction was quite sensitive to the N-substitution.■ PALLADIUM-CATALYZED AZIRIDINE RING-OPENING Aziridine ring-opening by carbon nucleophiles requires, in general, organometallic nucleophiles in the presence of strong Lewis acid. Those reaction conditions are poorly compatible with functional groups. A mild Pd-catalyzed aziridine ringopening reaction with aryl boronic acid as the nucleophile was developed (J. Am. Chem. Soc. 2013, 135, 18347). Exposure of the aziridine to a mixture of arylboronic acid, Pd(dba) 2 , P(Np) 3 , and Cs 2 CO 3 in the presence of m-chlorophenol (4 equiv) as an additive gave the desired β-aryl-substituted amine product. This ring-opening is highly regioselective and compatible with diverse functionality in the aryl boronic acids, including alkyl, alkoxy, ketone, amide, hydroxyl, nitro, etc. The reaction is hypothesized to proceed through three intermediates, A, B, and C. As the ring-opened intermediates, B and C, are susceptible to the β-hydride elimination, the use of an m-chlorophenol additive is critical for the success of the transformation in preventing the β-hydride elimination side reaction. The key role of the m-chlorophenol additive is presumably to minimize the lifetime of these two species by careful control of the protonolytic equilibrium and the rate of transmetalation.

Schmidt Reaction of Ketones in DME Solution in a Continuous-Flow Microreactor

“…The productivity of continuous-flow microreactor could be further enhanced by prolonging the operation time, extending the tube-length, or by parallel operation of several identical reactors without disturbing the reaction parameters. , Two simple scale-up experiments for 3a by prolonging operation time and doubling the substrate concentration were performed. These indicated that the output of the reactor system could be enlarged to gram-scale easily by prolonging operation time.…”

“…To solve the remaining problems, the reaction could be run in an enclosed small space, such as a continuous-flow microreactor, in which the loss of reagents and the danger of explosion could be minimized. In the last two decades, continuous-flow microreactor systems have attracted increasing interest from synthetic chemists due to their dramatic advantages over traditional batch reactors in heat and mass transfer, time control, and safety . Its tremendous surface-to-volume ratio enables a rapid heat transfer and an exact temperature control.…”