Stereoselective Synthesis of Tetrahydroindolizines through the Catalytic Formation of Pyridinium Ylides from Diazo Compounds

Abstract

Commercially available iron(III) and copper(I) complexes catalyzedm ulticomponent cycloaddition reactions between diazocompounds,pyridines,and electrophilic alkenes to give alkaloid-inspired tetrahydroindolizidines in high yield with high diastereoselectivity.Hitherto,the catalytic formation of versatile pyridinium ylides from metal carbenes has been poorly developed;t he broad utility demonstrated herein sets the stage for the invention of further multicomponent reactions in future.Indolizidines are found in many bioactive alkaloids, [1] whereas their unsaturated indolizine counterparts have valuable photochemical properties. [2,3] Both structures are valued for their therapeutic potential. [4][5][6] Spirooxindoles have also been identified as privileged scaffolds for drug discovery.[7] Efficient and versatile routes toward these structural motifs are therefore highly desirable.Thec onvergent synthesis of tetrahydroindolizidines is possible by 1,3-dipolar cycloaddition of pyridinium ylides with electrophilic alkenes.The resulting products may then be converted into indolizines by oxidation, [8][9][10] or into indolizidines by reduction or other types of functionalization (Scheme 1). [11,12] Ty pically,pyridinium ylides are formed by deprotonation of the corresponding salts,b ut this method produces stoichiometric conjugate-acid waste and usually requires as eparate alkylation step to prepare the pyridinium salts.S uch drawbacks significantly restrict the utility of otherwise versatile synthetic intermediates.In principle,c atalytic reactions that directly transform pyridines into their corresponding ylides under aprotic conditions,a nd in the presence of electrophilic alkenes, open up the prospect of more powerful multicomponent reactions to prepare tetrahydroindolizidines.T he addition of Lewis bases to metal carbenes to form ylides has been widely developed for synthesis, [13][14][15][16][17][18][19][20] but there are few reports of catalyzed reactions of pyridines with diazo compounds. [21,22] Theg eneration of pyridinium ylides in this way has received surprisingly little attention;infact, we could find only asingle example of this type of catalyzed three-component reaction to form an indolizine.[23]Herein, we describe anew,multicomponent reaction that produces highly functionalized tetrahydroindolizidines in good yields with generally excellent diastereoselectivity (Scheme 2). These reactions involve the catalytic generation of pyridinium ylides via metallocarbenes and in situ cycloaddition with electrophilic alkenes.This highly efficient route generates nitrogen as the only by-product. Ther eaction

Recent advances in the iron‐catalysed multicomponent reactions

“…An iron (III)‐catalysed stereoselective synthesis of tetrahydroindolizidines 20 was disclosed by Dowden and co‐workers. [ 38 ] The multicomponent reaction of alkenes, diazo compounds and pyridines resulted in functionalized tetrahydroindolizidines in good yields (Scheme 5). The reaction commenced using 3‐alkenyloxindole, 3‐bromopyridine, and ethyl diazoacetate in presence of various catalysts and [Fe (TPP)Cl] (TPP = tetraphenylporphyrin) was found as the optimum one.…”

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

“…It was worth noting that such a special selectivity was rarely reported for addition to pyridinium salts, especially for the pyridines bearing electron-donating groups. [42][43][44] In view of the high utility of polycyclic N-heterocycles, several other kinds of N-heteroaromatic substrates were explored (Table 4). 3-Methoxy and 6-bromoquinolines could be transformed into the corresponding products 8a-8b, excellent diastereo-and enantioselectivitivities were obtained albeit with lower yields.…”

[3+2]‐Cycloaddition of Catalytically Generated Pyridinium Ylide: A General Access to Indolizine Derivatives

“…In Dowden's work with diazo compounds as carbene precursor for the generation of pyridinium ylides, they also reported an alternative carbene precursor, tosylhydrazone salt 68 (Scheme 21). [27] Under the optimal conditions with extra additive BnEt 3 NCl, the three-component reaction with benzylidene hydrazone salt delivered cycloadduct 69 in 57% yield.…”

“…In 2016, Dowden et al disclosed an iron-and copper-catalyzed reaction of pyridines with diazo compounds and electrophilic alkenes that enable the efficient synthesis of alkaloid-like tetrahydroindolizidines 43 and 44 in good to excellent yields with generally excellent diastereoselectivity (Scheme 14). [27] The formation of cycloadduct 43 a regardless of the Z-or Econfiguration of the starting oxindole 41 a suggests a stepwise mechanism involving 1,4-addition of the pyridinium ylide to the alkenyloxindole via transition state 45, followed by cyclization via transition state 46. The observed anti-configuration of the ester groups at C3' and C2' in the products can be explained by minimized dipole-dipole repulsions between the respective carbonyl groups in transition state 45.…”

“…Beyond the diazo compounds, a variety of reagents, including alkynes, [33] propargyl esters, [34] cyclopropenes, [35] 1,3,5cycloheptatrienes, [4d] and others, [36] have been introduced as the carbene precursors in various transformations. Among these advances, sulfoxonium ylides, [37] enynes, [38] and hydrazone salts [27] have been used as the metal carbene precursors for the catalytic generation of corresponding pyridinium ylides with pyridine derivatives.…”