Hantzsch Dihydropyridine (Pyridine) Synthesis.
Recent Strategies for the Synthesis of Pyridine ..
Several aspects of this new continuous flow process are noteworthy. For example, this is the first instance of the synthesis of pyrrole-3-carboxylic acids and pyrrole-3-carboxamides directly from inexpensive commercially available starting materials in a single continuous process without isolating intermediates. As noted previously, the standard in-flask synthesis of these compounds involves multiple reaction steps requiring workup and purification of several intermediates. Second, the HBr generated as a byproduct in the Hantzsch reaction is employed in the flow method to saponify the t-butyl esters in situ to provide the corresponding acids in a one-chip reaction. By way of comparison, we performed the in-flask (batch) synthesis of 1-benzyl-2-methyl-5-phenyl-1H-pyrrole-3-carboxylic acid (, Entry 1) using the optimized conditions we developed for our continuous flow method (see for experimental details). Interestingly, the reaction proceeded as expected to provide the product but in significantly lower yield (40%) than the flow process (65%). Finally, the products can be further manipulated in the final step by coupling diverse amines to generate a variety of amides allowing the introduction of additional structural complexity. To demonstrate the utility of the flow method to generate useful quantities of material for further synthetic manipulation, we scaled up the flow synthesis of 1-benzyl-2-methyl-5-phenyl-1H-pyrrole-3-carboxylic acid (, Entry 1) by approximately 17-fold. Gratifyingly, using the flow method, 850 mg (63% yield) of the compound was efficiently produced in 2.5 h flow time.
One-step synthesis of pyridines and dihydropyridines in …
Tert-butyl esters are versatile protecting groups for carboxylic acids which are stable under basic conditions but can be removed using acid. Typically strong protic acids, such as HCl, H2SO4, HNO3, or TFA, are employed for tert-butyl ester hydrolysis in aqueous or organic solvents. During the Hantzsch pyrrole synthesis HBr is generated as a side product and in our procedure DIPEA is used as a neutralizing agent. We hypothesized that we could take advantage of the strong acid generated in the Hantzsch reaction to saponify the tert-butyl ester formed in the initial product. With this in mind we varied the reaction conditions using different equivalents of DIPEA () and found that the use of 0.5 equiv of DIPEA was optimal to efficiently convert the tert-butyl ester pyrroles to the corresponding acids in situ (, Entry 2).