Diisobutylaluminum Hydride Reductions Revitalized: A Fast, Robust, and Selective Continuous Flow System for Aldehyde Synthesis

Abstract

A continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction.

Design, synthesis and biological evaluation of GPR55 agonists

“…Alternatively, this reaction was also examined using flow chemistry. It was previously determined that aryl esters were especially difficult to reduce to the aldehyde, 24–25 but using high flow rates (50 mL/min), cold temperatures (−78 °C), and short reaction times (0.037 sec), we were able to obtain a moderate yield of the aldehyde ( 14 ) directly, although with some over-reduction to the alcohol ( 13 ). For simplicity, it was decided to fully convert ester 12 to alcohol 13 and then oxidize it to the aldehyde.…”

“…Following related reports, 24–25 solutions of methyl 6-bromo-2-naphthoate in toluene ( 12 ; 0.1 M) and DIBAL-H in toluene (0.3 M) were added via inhouse built syringe pumps 43 into 0.04 inch internal diameter tubing at a rate of 25 mL/min. Each solution was precooled to −78 °C before mixing by submerging 1.6 feet of steel tubing into a dry ice/acetone bath.…”

Enhanced Reaction Efficiency in Continuous Flow

“…In 2012, our group showed that this multistep batch approach could be avoided by performing the DIBAL reduction of esters to their corresponding aldehydes in the simple continuous flow setup illustrated in Table . It consists of two reactors (R1 and R2) constructed from standard PFA tubing and three precooling loops (P1–P3) submerged in a cooling bath.…”

“…Using the reduction of ethyl hydrocinnamate 1 as an example (Table ), we showed that, at the fastest flow rate ( A 1 =30 mL min −1 ), and thus, shortest residence time ( t R ) examined, essentially full conversion to the corresponding aldehyde 2 was achieved at a constant R1 volume and temperature of −78 °C. This is due to the additional energy provided at high flow rates to mix the streams of DIBAL and ester . Importantly, at all flow rates ( A 1 =5, 10, and 30 mL min −1 ), aldehyde release and over‐reduction are prevented as a result of the rapid in‐line mixing and quenching of the organoaluminum intermediate by methanol.…”

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

“…Worthy of note is the DoE-driven optimization for the partial reduction of esters into aldehydes using diisobutylaluminium hydride (DIBALH) as reducing agent [22]. The work of Webb and Jamison was aimed to avoid the over-reduction to alcohols and the use of cryogenic temperatures combined with the slow addition rate of DIBALH as model reaction.…”