Accelerated Hantzsch electrospray synthesis with temporal control of reaction intermediates

Abstract

Complex chemical reactions can occur in electrosprayed droplets on the millisecond time scale. The Hantzsch synthesis of 1,4-dihydropyridines was studied in this way using on-line mass spectral analysis to optimize conditions and characterize the product mixture. Changing the distance between the nanospray source and the MS inlet allowed exploration of reaction progress as a function of droplet time-of-flight. Desolvation of the charged microdroplets is associated with transformation from starting material to intermediates and eventually to product as the distance is increased. Results of the on-line experiments require a termination step that discontinuously completes the desolvation process and allows the generated gaseous ions to be used to characterize the state of the system at a particular time. The intermediates seen correspond to those known to occur in the bulk solution-phase reaction. Off-line collection of the sprayed reaction mixture allowed the recovery of 250 mg h^-1 of desired reaction product from a single sprayer, permitting characterization by NMR and other standard methods. A thin film version of the accelerated reaction is described and it could be controlled through the temperature of the collection surface.

Scheme 1. Knoevenagel condensation product (4) reacts with the enamine ester (6) via a Michael addition to form 7, which undergoes proton transfers and intramolecular enamine formation to give 9. In a separate step, dehydrogenation yields the pyridine (10). All species are shown in their charged forms where appropriate.

Fig. 1. Extent of reaction as a function of distance (l) between the MS inlet and the spray source. The data are accounted for by desolvation to give smaller, more rapidly reacting droplets. * denotes known impurities thought to be from the guiding tube.

Fig. 2. Chronograms showing relative abundances of compounds 3, 5, and 7 as the temperature is increased from room temperature to 80 °C (∼3 min) at l = 30 cm.

Fig. 3. Progress of the off-line cold surface reaction at various distances between the ESI source and the collection surface under conditions where reaction at the surface is minimized by operating at low temperature.

Fig. 4. On-line reaction (l = 100 cm) at various ion transfer capillary temperatures. Spectra on the right are expansions showing 9 and 10. Note that 9 and 10 occur as protonated, sodiated, and potassiated forms. The signal at m/z 282 is due to background.