A β-enaminone-initiated multicomponent domino reaction for the synthesis of indoloquinolizines and benzoquinolizines from acyclic precursors.
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.
Departmento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid (Spain).
Padmakar A
PA
Suryavanshi
Vellaisamy
V
Sridharan
J Carlos
JC
Menéndez
D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D002563:Cerium / Q000737:chemistry; D003500:Cyclization; D009566:Nitrates / Q000737:chemistry; D054837:Quinolizidines / Q000138:chemical synthesis* / Q000737:chemistry; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D014363:Tryptamines / Q000737:chemistry
D000447:Aldehydes; D000588:Amines; D009566:Nitrates; D054837:Quinolizidines; D011807:Quinolizines; D014363:Tryptamines; D002563:Cerium; C049049:1,2,3,4,6,7,12,12b-octahydroindolo(2,3-a)quinolizine; C006568:ammonium nitrate
Pictet-Spengler reactions; acyliminium cations; domino reactions; multicomponent reactions; β-enaminones