A β‐Enaminone‐Initiated Multicomponent Domino Reaction for the Synthesis of Indoloquinolizines and Benzoquinolizines from Acyclic Precursors

Abstract

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential multicomponent reaction between tryptamine, α,β-unsaturated aldehydes, and β-dicarbonyl compounds affords highly substituted indolo[2,3-a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C-C and two C-N bonds by a domino process comprising initial β-enaminone formation, followed by individual Michael addition, 6-exo-trig cyclization, iminium formation, and Pictet-Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H-2 and H-12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5-bromotryptamine, 3,4-dimethoxyphenylethylamine) prevents the Pictet-Spengler final step and leads to N-indolylethyl or N-phenylethyl-1,4-dihydropyridines, which are cyclized to the corresponding indolo[2,3-a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3-a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers.

Four‐Component Synthesis of β‐Enaminone and Pyrazole through Phosphine‐Free Palladium‐Catalyzed Cascade Carbonylation

“…On the basis of the above observations, we anticipated that the reaction would first undergo the carbonylative Sonogashira coupling and then the Michael addition of an alkynone with an amine would generate the desired product enaminone (Scheme 3). The amine could be used both as a base [c] [Pd(OAc) 2 (bipy)] [d] 2.0 76 7 [c] [Pd(OAc) 2 [a] Reaction conditions: 0.5 mmol iodobenzene, 0.6 mmol phenylacetylene, 1 mol % catalyst, 1.5 mL toluene, P CO = 0.1 MPa, T = 110 8C, t = 4 h; [b] in the Sonogashira coupling and as a substrate in the Michael addition; therefore, increasing the amine amount from 1.5 to 2 mmol could facilitate the carbonylative domino reaction. Meanwhile, the amine substrate could react with the palladium-acyl intermediate to furnish complete the aminocarbonylation reaction.…”

“…[2] As a result, the efficient synthetic methods to form enaminones from readily available starting materials have attracted much attention in the past decades. As shown in path 1 of Scheme 2, the condensation reaction of b-diketones with amines could generate enaminones but the regioselectivity issue of the corresponding products still remain.…”

Pictet–Spengler-Based Multicomponent Domino Reactions to Construct Polyheterocycles

“…In 2013, the group of Menéndez described a sequential multi-component reaction of tryptamines 82, α,β-unsaturated aldehydes 83, and β-dicarbonyl compounds 84 catalyzed by ammonium cerium nitrate (CAN), providing the indoloquinolizines 85 in good yields (►Scheme 20). 86 The process of reaction involved the initial formation of an enamine from the tryptamines and β-dicarbonyl components, followed by Michael addition of α,β-unsaturated aldehyde and 6-exo-trig cyclization to form a vinylimide cation, then a Pictet-Spengler cyclization to access the target products.…”

The Pictet-Spengler Reaction Updates Its Habits

“…Menéndez and coworkers highlighted cerium (IV) ammonium nitrate (CAN) as an excellent catalyst for the fast synthesis of β-enaminones 168 [175] and performed the one-pot, efficient preparation of 1-alkyl-6-ethoxy-1,4,5,6-tetrahydropyridines 169 from acyclic precursors, i.e., primary amines 166, β-dicarbonyl compounds 167, α,β-unsaturated aldehydes 145, and alcohols (as sketched in Scheme 49). The combination of this preparation with a P-S cyclization makes up a domino process that involves the generation of an iminium cation 170 from the tetrahydropyridines 169 and culminates in the direct one-pot preparation of a variety of benzo[a]-or indolo[2,3a]quinolizidines 171 [176]. 1,1,2,2-tetrachloroethane (TCE) and CHCl 3 were alternated as needed, while changing the molecular sieves (MS) from 3 to 4 Å greatly improved the yield, but decreased stereoselectivity.…”