Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

Abstract

Benzo-fused γ-lactam rings such as isoindolin-2-ones and 2-oxindoles are part of the structure of many pharmaceutically active molecules. They can be often synthesized by means of multicomponent approaches and recent contributions in this field are summarized in this review. Clear advantages of these methods include the efficiency in saving raw materials and working time. However, there is still a need of new catalytic systems to allow the enantioselective preparation of these heterocycles by multicomponent reactions.

Keywords: 2-oxindoles; indolin-2-ones; isoindolinones; multicomponent reactions; γ-lactams.

Figure 1

γ-Lactam-derived structures considered in this review.

Figure 2

Alkaloids containing an isoindolinone moiety.

Figure 3

Alkaloids containing the 2-oxindole ring system.

Figure 4

Drugs and biological active compounds containing an isoindolinone moiety.

Figure 5

Drugs and biologically active compounds bearing a 2-oxindole skeleton.

Scheme 1

Three-component reaction of benzoic acid 1, amides 2 and DMSO (3).

Scheme 2

Copper-catalysed three-component reaction of 2-iodobenzoic acids 10, alkynylcarboxylic acids 11 and ammonium acetate (12).

Scheme 3

Proposed mechanism for the formation of methylene isoindolinones 13.

Scheme 4

Copper-catalysed three-component reaction of 2-iodobenzamide 17, terminal alkyne 18 and pyrrole or indole derivatives 19.

Scheme 5

Palladium-catalysed three-component reaction of ethynylbenzamides 21, secondary amines 22 and CO (23).

Scheme 6

Proposed mechanism for the formation of methyleneisoindolinones 24.

Scheme 7

Copper-catalysed three-component reaction of formyl benzoate 29, amines 2 and alkynes 18.

Scheme 8

Copper-catalysed three-component reaction of formylbenzoate 29, amines 2 and ketones 31.

Scheme 9

Non-catalysed (A) and phase-transfer catalysed (B) three-component reactions of formylbenzoic acids 33, amines 2 and 1,3-dicarbonyl derivatives 34.

Scheme 10

Proposed mechanism for the formation of isoindolinones 36.

Scheme 11

Three-component reaction of formylbenzoic acid 33, amines 2 and fluorinated silyl ethers 39.

Scheme 12

Three-component Ugi reaction of 2-formylbenzoic acid (33), diamines 41 and isocyanides 42.

Scheme 13

Non-catalysed (A, B) and chiral phosphoric acid promoted (C) three-component Ugi reactions of formylbenzoic acids 33, amines 2 and isocyanides 42.

Scheme 14

Proposed mechanism for the enantioselective formation of isoindolinones 46.

Scheme 15

Three-component reaction of benzoic acids 33 or 54, amines 2 and TMSCN (52).

Scheme 16

Several variations of the three-component reaction of formylbenzoic acids 33, amines 2 and isatoic anhydrides 56.

Scheme 17

Proposed mechanism for the synthesis of isoindoloquinazolinones 57.

Scheme 18

Three-component reaction of isobenzofuranone 61, amines 2 and isatoic anhydrides 56.

Scheme 19

Palladium-catalysed three-component reaction of 2-aminobenzamides 59, 2-bromobenzaldehydes 62 and CO (23).

Scheme 20

Proposed mechanism for the palladium-catalysed synthesis of isoindoloquinazolinones 57.

Scheme 21

Four-component reaction of 2-vinylbenzoic acids 67, aryldioazonium tetrafluoroborates 68, DABCO·(SO₂)₂ (69) and nitriles 70.

Scheme 22

Plausible mechanism for the formation of isoindolinones 71.

Scheme 23

Three-component reaction of trimethylsilylaryltriflates 77, isocyanides 42 and CO₂ (78).

Scheme 24

Plausible mechanism for the three-component synthesis of phthalimides 79.

Scheme 25

Copper-catalysed three-component reaction of 2-formylbenzonitriles 85, arenes 86 and diaryliodonium salts 87.

Scheme 26

Copper-catalysed three-component reaction of 2-formylbenzonitriles 85, diaryliodonium salts 87 and ketones 89 and 91.

Scheme 27

Proposed mechanism for the formation of 2,3-diarylisoindolinones 88, 89 and 92.

Scheme 28

Palladium-catalysed three-component reaction of chloroquinolinecarbaldehydes 97 with isocyanides 42 and aromatic amines 2.

Scheme 29

Palladium-catalysed three-component reaction of imines 99 with CO (23) and ortho-iodoarylimines 100.

Scheme 30

Palladium-catalysed three-component reaction of amines 2 with CO (23) and aryl iodide 105.

Scheme 31

Three-component reaction of 2-ethynylanilines 109, perfluoroalkyl iodides 110 and carbon monoxide (23).

Scheme 32

Ultraviolet-induced three-component reaction of N-(2-iodoaryl)acrylamides 113, DABCO·(SO₂)₂ (69) and hydrazines 114.

Scheme 33

Proposed mechanism for the preparation of oxindoles 115.

Scheme 34

Three-component reaction of acrylamide 113, CO (23) and 1,4-benzodiazepine 121.

Scheme 35

Multicomponent reaction of sulfonylacrylamides 123, aryldiazonium tetrafluoroborates 68 and DABCO·(SO₂)₂ (69).

Scheme 36

Proposed mechanism for the preparation of oxindoles 124.

Scheme 37

Three-component reaction of N-arylpropiolamides 128, aryl iodides 129 and boronic acids 130.

Scheme 38

Proposed mechanism for the formation of diarylmethylene- and diarylallylideneoxindoles 131 and 132.

Scheme 39

Three-component reaction of cyclohexa-1,3-dione (136), amines 2 and alkyl acetylenedicarboxylates 137.

Scheme 40

Proposed mechanism for the formation of 2-oxindoles 138.