The Intramolecular Povarov Tool in the Construction of Fused Nitrogen-Containing Heterocycles

Abstract

Nitrogen heterocycles are part of the structure of natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs. For this reason, heterocyclic compounds are one of today's most desirable synthetic targets and the Povarov reaction is a powerful synthetic tool for the construction of highly functionalized heterocyclic systems. This process involves an aromatic amine, a carbonyl compound, and an olefin or acetylene to give rise to the formation of a nitrogen-containing heterocycle. This review illustrates advances in the synthetic aspects of the intramolecular Povarov reaction for the construction of intricate nitrogen-containing polyheterocyclic compounds. This original review presents research done in this field, with references to important works by internationally relevant research groups on this current topic, covering the literature from 1992 to 2022. The intramolecular Povarov reactions are described here according to the key processes involved, using different combinations of aromatic or heteroaromatic amines, and aliphatic, aromatic, or heteroaromatic aldehydes. Some catalytic reactions promoted by transition metals are detailed, as well as the oxidative Povarov reaction and some asymmetric intramolecular Povarov processes.

Keywords: Fused nitrogenated heterocycles; Intramolecular; Povarov reaction; [4 + 2]-cycloaddition.

Fig. 1

A Some marketed synthetic THQs and QUINs and their application. B Some bioactive THQs and QUINs from natural sources

Scheme 1

First example described by Povarov

Scheme 2

Intramolecular Povarov reaction

Scheme 3

Scope of intramolecular Povarov reaction

Scheme 4

Mechanistic approaches to form trans- and cis-adducts 17

Scheme 5

Synthesis of octahydroacridines 21 by using Lewis or Brønsted acids

Scheme 6

Synthesis of (octahydroacridine)chromium tricarbonyl complexes 25

Scheme 7

Synthesis of octahydroacridines 28 and/or amines 29 with molecular sieves as activating agents

Scheme 8

Synthesis of octahydroacridines 31 using bismuth(III) chloride as catalyst

Scheme 9

Synthesis of octahydroacridines 32 using a solid-supported catalyst

Scheme 10

Synthesis of octahydroacridine derivatives 34 using a solid-supported catalyst and thio-functionalized anilines

Scheme 11

Synthesis of octahydroacridine derivatives 36 with a solid-supported catalyst and thio-functionalized aldehydes

Scheme 12

Synthesis of octahydroacridines 39 catalyzed by different solid acid catalysts

Scheme 13

Synthesis of bis-octahydroacridines 46–48

Scheme 14

Solid-phase synthesis of octahydroacridine 55

Scheme 15

Synthesis of octahydroacridines 57 by fluorous phase synthesis

Scheme 16

Synthesis of octahydroacridines 63 by using selenium- and tellurium-based ionic liquids

Scheme 17

Synthesis of octahydroacridines 21 with ionic liquids

Scheme 18

Synthesis of cyclopenta[b]quinolines 70 and 71

Scheme 19

Preparation of octahydrobenzo[c]acridines 73

Scheme 20

Synthesis of cyclopenta[c]acridine derivatives 76

Scheme 21

Synthesis of quinolines 80 condensed to a steroid skeleton

Scheme 22

Synthesis of heterocycles 85 from steroid-derived aldehydes

Scheme 23

Synthesis of pyrano[4,3-b]quinolines 88 from O-allyl carbohydrate-derived aldehydes

Scheme 24

Synthesis of furo[3,2-h][1,6]naphthyridines 91 from N-allyl carbohydrate-derived aldehydes

Scheme 25

Quinoline-fused lactones 94 obtained by intramolecular Povarov reaction

Scheme 26

Intramolecular Povarov reaction with glyoxylic 95 or glyoxamide-derived aldehydes 96

Scheme 27

InCl₃-catalyzed intramolecular Povarov reaction for the preparation of pyrroloquinolines 101

Scheme 28

Ytterbium triflate-catalyzed Povarov reaction with N-cinnamoyl-α-aminoaldehydes

Scheme 29

BiCl₃-promoted intramolecular Povarov reaction with N-(prenylaminomethyl)cinnamaldehyde

Scheme 30

Synthesis of fused benzo[b]pyrrolo[1,2-h][1,7]naphthyridines 111

Scheme 31

Intramolecular Povarov reaction of l-proline-derived aldehydes

Scheme 32

Synthesis of fused bis-benzopyrrolo[1,7]naphthyridine derivatives 118 and 119

Scheme 33

Synthesis of fused benzo[g]quinolino[2,3-a]quinolidines 122

Scheme 34

Synthesis of fused benzo[b]isoquinolino[2,3-h][1,7]naphthyridines 125 and 126

Scheme 35

Synthesis of quinoline-fused lactones 131

Scheme 36

Synthesis of pyrrolo[3,4-b]quinolines 133

Scheme 37

Synthesis of benzo[b]pyrrolo[1,2-h][1,7]naphthyridine derivative 137

Scheme 38

Synthesis of luotonin A analogs via intramolecular Povarov reaction

Scheme 39

Synthesis of fused benzo[b]isoquinolino[2,3-h][1,7]naphthyridines 142

Scheme 40

2-Prenylated benzaldehyde as carbonyl component in the BiCl₃-promoted intramolecular Povarov reaction

Scheme 41

Synthesis of polycyclic compounds 150 through previous allylation followed by intramolecular Povarov reaction

Scheme 42

Synthesis of indeno[1,2-b]quinolines through reaction of aromatic amines and o-propargylbenzaldehydes

Scheme 43

Synthesis of dibenzo[a,c]acridines using FeCl₃

Scheme 44

Synthesis of polysubstituted tetrahydrochromeno[4,3-b]quinolines 159 using different catalytic conditions

Scheme 45

Synthesis of benzochromeno[4,3-b]quinoline derivatives 161 and 162

Scheme 46

Preparation of chromeno[4,3-b]quinolines via intramolecular aza-Diels–Alder reaction

Scheme 47

Synthesis of trans-fused tetrahydrochromeno[4,3-b]quinolines from nitrobenzenes 167

Scheme 48

Intramolecular aza-Diels–Alder cyclization using O-cinnamyl- and O-cinnamoylsalicylaldehydes

Scheme 49

Solid-phase preparation of polysubstituted tetrahydrochromeno[4,3-b]quinolines 178 extended to solid phase

Scheme 50

Preparation of bis-tetrahydrochromeno[4,3-b]quinolines using different reaction conditions

Scheme 51

Synthesis of chromeno[4,3-b]quinolines promoted by I₂/DMSO system

Scheme 52

Efficient synthesis of 6H-chromeno[4,3-b]quinolines through CuI/La(OTf)₃ promoted intramolecular Povarov reaction

Scheme 53

Copper-catalyzed intramolecular domino synthesis of 6H-chromeno[4,3-b]quinolines in green conditions

Scheme 54

Synthesis of halogenated chromenoquinolines and thiochromenoquinolines via Cu-catalyzed cascade reaction

Scheme 55

Synthesis of chromenoquinoline-COF_TAPB-BPTA 200

Fig. 2

Other amines used to synthetize chromenoquinoline-based covalent organic frameworks (COF)

Scheme 56

Preparation of hexahydrodibenzo[b,h][1,6]naphthyridines catalyzed by BiCl₃ as Lewis acid

Scheme 57

Preparation of 1,6-naphthyridines via tandem intramolecular aza-Diels–Alder reaction/oxidative aromatization

Scheme 58

Synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridine derivatives via copper catalyzed reaction

Scheme 59

Synthesis of pyrrolizino[1,2-b]quinolines 215 by InCl₃ promoted-intramolecular Povarov reaction

Scheme 60

Lewis acid-catalyzed intramolecular Povarov reaction for the synthesis of indolo-annulated pyrroloquinolines

Scheme 61

Synthesis of quinoline-annulated heterocycles by InCl₃-assisted intramolecular Povarov reaction

Scheme 62

Pyrazole-annulated sulfur heterocycles by intramolecular Povarov reaction catalyzed by BiCl₃ or InCl₃

Scheme 63

Pyrazole-annulated sulfur heterocycles by bis-intramolecular Povarov reaction catalyzed by InCl₃

Scheme 64

Combination of visible-light-photoredox and Brønsted acid-catalyzed intramolecular Povarov reaction for the preparation of indolizino[1,2‑b]quinolin-9(11H)‑ones

Scheme 65

Intramolecular Povarov reaction in the preparation of benzopyrimido[4,5-h][1,6]naphthyridine libraries

Scheme 66

Tandem acid-catalyzed intramolecular Povarov reaction/visible-light photoredox for the synthesis of the precursor of 10-hydroxycamptothecin and irinotecan

Scheme 67

Synthesis of chromenoacridine derivatives through intramolecular Povarov reaction

Scheme 68

Synthesis of chromenonaphthyridines via TPP-induced intramolecular Povarov reaction

Scheme 69

Synthesis of pyrano and thiopyranoquinolines through InCl₃/silica gel supported catalyzed intramolecular Povarov reaction

Scheme 70

Cyclization of N-allyl naphthyridones into luotonin A analogs using amide-activating reagents

Scheme 71

Povarov reaction in the preparation of antiproliferative tetrahydropyranochromeno[4,3-b]quinolines

Scheme 72

Tandem intramolecular Povarov reaction/visible light-promoted dehydrogenation for the construction of substituted luotonin A derivatives

Scheme 73

O-Propargylated 8-formyl chromenones as carbonyl components in the CuFe₂O₄-promoted intramolecular Povarov reaction

Scheme 74

Synthesis of decarbonyl analogs of the anticancer alkaloid luotonin A by BF₃·OEt₂-assisted intramolecular Povarov reaction

Scheme 75

Intramolecular Povarov reaction in the formal synthesis of camptothecin

Scheme 76

Intramolecular Povarov reaction in the total synthesis of luotonin A

Scheme 77

Cyclization of N-propargyl naphthyridones into luotonin A analogs using amide-activating reagents

Scheme 78

Intramolecular Povarov reaction using 2-aminopyrrole under microwave conditions

Scheme 79

Povarov reaction of citronellal and 3-aminocarbazole

Scheme 80

Hetero-Diels–Alder reaction of 5-amino-3-methylisoxazole in the synthesis of annulated tetrahydropyridines

Scheme 81

Intramolecular Povarov reaction using 2-aminopyrrole and 2-aminopyrazole under microwave conditions

Scheme 82

Intramolecular Povarov reaction of aromatic aldehydes and 3-aminocarbazole

Scheme 83

Synthesis of chromeno[4,3-b][1,5]naphthyridines and chromeno[4,3-b][1,5]naphthyridin-6-ones

Scheme 84

Synthesis of thiazolino-2-pyridone-based polyheterocycles capable of modulating and binding to α-synuclein and amyloid-β fibrils

Scheme 85

Synthesis of quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-ones

Scheme 86

Intramolecular Povarov reaction using 2-aminopyrrole or 2-aminopyrazole and alkyne-tethered aldehydes

Scheme 87

Synthesis of chromeno[4,3-b][1,5] and [1,8]naphthyridines using alkyne-tethered aldehydes

Scheme 88

Intramolecular Povarov reaction involving 5-amino-1,3-dimethyl uracil for the preparation of chromenopyrido[3,2-d]pyrimidines

Scheme 89

Intramolecular Povarov reactions in the synthesis of isoellipticine fused with dihydrochromene derivatives

Scheme 90

Synthesis of quinolino[1,5]naphthyridines and quinolino[1,8]naphthyridines

Scheme 91

Synthesis of isomeric ellipticine derivatives by means of intramolecular Povarov reaction of heteroaromatic aldehydes and heteroaromatic amines

Scheme 92

Intramolecular Povarov reaction of iminium ions for the synthesis of octahydroacridines

Scheme 93

BiCl₃-catalyzed intramolecular cationic Povarov reaction for the construction of octahydroacridines

Scheme 94

Intramolecular cationic Povarov reaction catalyzed by TFA in the preparation of pyrroloquinolinones

Scheme 95

Synthesis of diazacyclopenta[a]phenalenone by intramolecular cationic Povarov approach

Scheme 96

Intramolecular Povarov reaction in the preparation of benzopyrimido[4,5-h][1,6]naphthyridine libraries

Scheme 97

Catalytic radical cation salt induced C_sp3–H oxidation for the construction of quinoline-fused lactones

Scheme 98

Catalytic radical cation salt induced C_sp3–H oxidation for the construction of quinoline-fused lactams

Scheme 99

Oxone promoted intramolecular dehydrogenation followed by Povarov cyclization for the construction of quinoline-fused lactones and lactams

Scheme 100

TRIP-catalyzed enantioselective organocatalytic intramolecular Povarov reaction

Scheme 101

Asymmetric intramolecular Povarov reaction for the preparation of enantiomerically enriched tetrahydrochromeno[4,3-b]quinolines and hexahydrodibenzo[b,h][1,6]naphthyridines

Scheme 102

Enantioselective intramolecular Povarov reaction with secondary anilines

Scheme 103

Enantioselective intramolecular Povarov reaction with indoline derivatives

Scheme 104

Enantioselective intramolecular Povarov reaction with two-substituted indoline derivatives

Scheme 105

Enantioselective organocatalytic one-pot domino Michael/intramolecular Povarov reaction with malononitriles

Scheme 106

Enantioselective organocatalytic one-pot domino Michael/intramolecular Povarov reaction with indolinones