Abstract
An efficient sequential multi-component method for the synthesis of N-arylpyrrole-3-carbaldehydes has been developed. This reaction involved a proline-catalyzed direct Mannich reaction-cyclization sequence between succinaldehyde and in situ generated Ar/HetAr/indolyl-imines, followed by IBX-mediated oxidative aromatization in one-pot operation. The practical utility of this procedure is shown at gram-scale and the synthesis of diverse bioactive fused heterocyclic scaffolds such as pyrroloquinoline, pyrrolo-oxadiazole, dihydro pyrroloquinoline, and pyrrolo-phenanthridine.
Highlights
In continuation to our efforts to utilize using linear dialdehydes,12 for the synthesis of medium-sized N-heterocycles under metal-free conditions,13 we recently developed a two-pot protocol for the direct synthesis of pyrrole-3-carbaldehyde from succinaldehyde and imines (eqn [2], Scheme 1).13b This method resulted in a quick synthesis of pyrrole-3-aldehydes, though, it required the pre-assembled imines and DDQ as a harsh and toxic reagent for oxidative aromatization
We have developed a straight forwarded sequential multicomponent synthesis of substituted N-aryl-pyrrole-3carbaldehydes. This one-pot protocol proceeds through proline-catalyzed Mannich reaction-cyclization sequence between succinaldehyde and imines, in situ generated from Ar/ HetAr/indole-aldehydes with aromatic amines, followed by IBXmediated oxidative aromatization under mild conditions
Synthetic applicability of the developed method was established through; (i) at gramscale synthesis, and (ii) the rapid access to the biologically important natural products analogous like-pyrrolo-quinoline, Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further puri cation
Summary
Medium sized nitrogen heterocycles are privileged scaffolds present in numerous natural and unnatural compounds.1 Among them, the pyrrole core is present in many important classes of natural products and its derivatives have been used as valuable intermediates for the synthesis of many drugs that exhibit interesting biological activities (Fig. 1).2 In addition, functionalized pyrroles have shown wide applications in agrochemicals and avor components, dyes, and functionalized materials.3 Over the past few decades, a number of elegant methods to access functionalized pyrroles have been reported, which includes classical methods,4 cycloadditions,5 multicomponent,6 metal-catalyzed reactions,7 and several others.8 Despite the extensive efforts, the synthesis of C3-functionalized pyrroles is probably the most difficult task and required a special strategy.9 In particular, the regiospeci c synthesis of pyrroles endowed with aldehyde group at C3-position is still very rare.10 Pyrrole-3-carbaldehydes have mainly been synthesized by the use of sterically bulky triisopropylsilyl (TIPS) as protecting group on the nitrogen of pyrrole followed by Vilsmeier–Hacck formylation and deprotection as a multistep process (eqn [1], Scheme 1),10a along with other direct/indirect methods.10b–e these reported approaches have one or more drawbacks, such as the requirement of specially designed substrates, multistep process with low yields, and harsh reaction conditions. Multicomponent reactions allow the rapid construction of novel libraries of pharmaceutically active compounds and marine alkaloids, the development of such protocol is always applauded.14 we report a simple and most rational sequential multicomponent protocol for the synthesis of pyrrole-3-carbaldehydes via in situ imine formation between Ar/HetAr/indole-aldehydes and ArNH2, followed by amine-catalyzed direct Mannich reactioncyclization with succinaldehyde, and IBX-mediated aromatization sequence in one-pot operation (eqn [3], Scheme 1).
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