Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

Abstract

This review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review.

Keywords: bioactive molecules; cyclocondensations; dipolar cycloaddition; microwave irradiation; multicomponent reactions.

Figure 1

Representative examples of bioactive benzazepines.

Scheme 1

Heck reaction leading to 2-benzazepines.

Figure 2

Representative examples of bioactive 5,6,7,8-tetrahydrodibenzo[c,e]azocine.

Scheme 2

Suzuki-Miyaura reaction/A³ coupling sequence leading to 2- and 3-benzazepines.

Figure 3

Representative examples of bioactive 3-benzazepines.

Scheme 3

Synthesis of 3-benzazepines through Heck intramolecular reaction.

Scheme 4

A³ coupling/Pd-catalyzed cyclization sequence leading to 3-benzazepines.

Scheme 5

Mechanistic study of the 3-benzazepines synthesis reported by Peshkov and co-workers [16].

Scheme 6

MW-assisted synthesis of 3-benzazepines and indalones with a potential activity against CNS disorders.

Figure 4

Relevant examples of bioactive benz[b]oxepines.

Scheme 7

One-pot, multi-component reaction leading to pentacyclic pyrano[4,3-b]oxepines.

Scheme 8

Mechanistic study of the benz[b]oxepines synthesis reported by Jiang and co-workers [22].

Scheme 9

Synthetic route to ptaeroxilin involving a MW-assisted Claisen rearrangement step.

Figure 5

Relevant examples of bioactive dibenz[b,f]oxepines.

Scheme 10

Two MW-assisted synthesis of functionalized dibenzoxazepines.

Figure 6

Relevant examples of bioactive dibenzo[b,f]thiepines.

Scheme 11

Synthesis of dibenzo[b,f]thiepines by means of a Pd-catalyzed double C-S bond formation.

Figure 7

Relevant examples of bioactive benzodiazepines.

Scheme 12

Intramolecular condensation of diketones in water and under polystyrene sulfonic acid leading to 1,2-diazepines.

Scheme 13

Synthetic route to 1,3-diazepines via cyclo-dehydration of aminoamides.

Scheme 14

Solvent-free synthesis of 1,4-diazepines through Retro Diels-Alder and intramolecular enamine formation.

Scheme 15

One-pot, three components reaction leading to pyrrole-fused 1,3-diazepines.

Scheme 16

Mechanistic study of the pyrrole-fused 1,3-diazepines synthesis reported Liang et al. [42].

Scheme 17

MW-synthesis of 2-ferrocenyl-7-hydroxy-5-phenethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones.

Scheme 18

Green synthesis of 1,4-benzodiazepines.

Scheme 19

One-pot three-component reaction sequence leading to 2,4-disubstituted benzodiazepines.

Scheme 20

Two step synthesis of benzodiazepinones via an Ugi 4-components reaction and intramolecular cyclization.

Scheme 21

Synthesis of benzo[f]azulen-1-ones and isoindole-fused furo[1,4]diazepines in aqueous media.

Scheme 22

Cu(I)-catalysed domino three-component reaction leading to indole-fused 1,4-diazepines.

Scheme 23

Mechanistic study of the indole-fused 1,4-diazepine synthesis reported by Fujii and Ohno [52].

Figure 8

Relevant examples of bioactive pyrrolo[1,4]benzodiazepine-2,5-diones.

Scheme 24

Benzodiazepinone synthesis through a reduction-double cyclization sequence of 1,3-ketonamides.

Figure 9

Relevant examples of bioactive dibenzothiazepines.

Scheme 25

MW-assisted RCM affording benzo-fused dibenzothiazepines and dibenzoxathiepines.

Scheme 26

Copper-assisted C-S bond formation leading to series of dihydrodibenzo[b,f][1,4]-thiazepine-11-carboxamides.

Scheme 27

Mechanistic study of the C-S bond formation reported by Saha et al. [57].

Scheme 28

MW-assisted three-component reaction in water affording benzo[e][1,4]thiazepin-2(1H,3H,5H)-ones.

Scheme 29

Mechanistic study of the benzo[e][1,4]thiazepin-2(1H,3H,5H)-ones syntheses reported by Tu et al. [58].

Scheme 30

Solvent-free multicomponent reaction affording 1,4-thiazepines.

Figure 10

Examples of representative oxazepines.

Scheme 31

Synthetic route to triazolo-fused benzoxazepinones and benzoxazepines via successive Passerini reaction and [1,3]-dipolar cycloaddition.

Scheme 32

One-pot, green synthesis of triazolobenzoxazepines through Sonogashira azide-alkyne cycloadditions.

Scheme 33

Oxazepines synthesis via Ugi 4-component reaction and intramolecular O-arylation.

Figure 11

Representative examples of bioactive benzotriazepines.

Scheme 34

Synthesis of benzotriazepines and indazoles.

Scheme 35

Mechanistic study of the benzotriazepines and indazoles synthesis reported Dong et al. [70].

Scheme 36

Green procedure for the synthesis of fused triazepines on a solid support.

Scheme 37

Green procedure for 1,2,4-triazepine synthesis in ionic liquid as solvent.

Scheme 38

Solvent free synthesis of thiadiazepines.

Scheme 39

Green synthesis of thiadiazepines.

Scheme 40

Green synthesis and solvent free synthesis of thiadiazepines.

Scheme 41

MW-assisted synthesis of 20-membered cyclic peptidomimetics.

Scheme 42

Example of peptidomimetic cyclization through a MW-assisted thioester bond formation.

Scheme 43

MW-assisted SPPS and on-resin cyclization of 7-mer peptides.

Scheme 44

Example of peptide cyclization through MW-assisted RCM.

Scheme 45

Synthesis of a 10-mer cyclic through on-resin MW-assisted RCM.

Scheme 46

Synthesis of biphenomycin B via a Pd(0) C-C bond formation.

Scheme 47

Peptide cyclization through an on-resin Glaser reaction.

Scheme 48

MW-assisted chain-to-tail cyclization of peptoïds.

Scheme 49

MW-assisted synthesis of (−)-rhazinilam derivatives.

Scheme 50

MW-assisted synthesis of Steganacin and 8-aza-Steganone.

Scheme 51

Synthesis of buflavine analogues through a Suzuki-Miyaura cross-coupling and MW-activated RCM sequence.

Scheme 52

MW-assisted Ullmann coupling leading to macrocyclic diaryl ethers.

Figure 12

Relevant examples of macrocyclic diaryl ethers as natural compounds.

Scheme 53

MW-assisted synthesis of metallophthalocyanine.

Scheme 54

MW-assisted synthesis of metal-free phthalocyanine polymer.

Scheme 55

MW-assisted synthesis of phthalonitriles and zinc (II) phthalocyanines.

Scheme 56

First example of a MW-activated calix-type synthesis.

Scheme 57

MW-assisted synthesis of 24- or new 72-membered chiral macrocyclic Schiff bases.

Scheme 58

Green synthesis of calix[4]arenes.

Scheme 59

Green synthesis of calix[4]resorcinarenes.

Figure 13

The large scope of the MW-assisted macrocyclisations.