Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization

Abstract

Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon-carbon or carbon-heteroatom.

Keywords: intramolecular cyclization; medium-sized heterocycles; transition-metal catalysis.

Figure 1

Examples of natural and bioactive compounds containing a medium-sized heterocycle.

Scheme 1

Schematic representation of an intramolecular Heck reaction accessing medium-sized heterocycles.

Scheme 2

Synthesis of benzo[d]azocines by reductive cyclocarbopalladation of alkynes.

Scheme 3

Synthesis of azocino[cd]indoles by reductive cyclocarbopalladation of alkynes.

Scheme 4

Synthesis of dibenzoazocines by reductive cyclocarbopalladation of alkynes.

Scheme 5

Pd-catalyzed reductive cyclization of bromoenynamides.

Scheme 6

Pd-catalyzed reductive cyclization to access thiazocine and thiazonine derivatives.

Scheme 7

Pd-catalyzed reductive cyclization to access thiazecine and thiazaundecine derivatives.

Scheme 8

Pd-catalyzed cyclization–allenylation–amination to access tetrahydro-2-benzoxocine.

Scheme 9

Intramolecular Sonogashira reaction to access medium-sized O,S-heterocycles.

Scheme 10

Synthesis of medium-sized N-polyheterocycles by a Pd-catalyzed intramolecular N-arylation–C–H activation–aryl–aryl bond-forming domino reaction.

Scheme 11

Synthesis of benzoxazocines by intramolecular Pd-catalyzed N-arylation.

Scheme 12

Synthesis of 9-membered N-heterocycle by intramolecular Pd-catalyzed N-arylation.

Scheme 13

Synthesis of 8-membered N,N-heterocycles by Pd-catalyzed oxidative cis-aminopalladation.

Scheme 14

Synthesis of 8-membered N-heterocycles by Pd-catalyzed cyclizations of bromoallenes.

Scheme 15

Synthesis of 8- or 9-membered N-heterocycles by Pd-catalyzed heteroannulation of 1,2-dienes.

Scheme 16

Synthesis of 8-membered N-heterocycles by Pd-catalyzed intramolecular carbonylation.

Scheme 17

Synthesis of medium-sized O-heterocycles by Pd-catalyzed cyclization of allendiols.

Scheme 18

Synthesis of medium-sized O,S-heterocycles by Pd-catalyzed cyanosulfenylation.

Scheme 19

Synthesis of 8-membered heterocycles by Pd-catalyzed cyclization of bromoallenes.

Scheme 20

Synthesis of 9-membered N,O-heterocycles by Pd-catalyzed [5 + 4] formal cycloaddition.

Scheme 21

Synthesis of 8-membered N,O-heterocycles by Pd-catalyzed [5 + 3] formal cycloaddition.

Scheme 22

Synthesis of 8- to 11-membered heterocycles by Pd-catalyzed [n + 2] formal cycloaddition.

Scheme 23

Stereoselective synthesis of biaryl-containing medium-sized heterocycles via an intramolecular copper-mediated C–C bond formation.

Scheme 24

Synthesis of 8- to 9-membered heterocycles by Cu-catalyzed cyclization involving Sn amino protocol (SnAP) reagents.

Scheme 25

Synthesis of bridged aza-[n.2.1]-indolyl medium-sized heterocycles by copper-catalyzed hydroamination–Friedel–Crafts domino process.

Scheme 26

Synthesis of a sultam skeleton via Cu-catalyzed intramolecular N-Arylation.

Scheme 27

Synthesis of medium N-heterocycles via Cu-catalyzed intramolecular N-arylation.

Scheme 28

One-pot synthesis of medium-sized N-heterocycles via S_N2 reaction followed by Cu-catalyzed intramolecular N-arylation.

Scheme 29

Synthesis of a benzoxazocine by Cu-catalyzed N-vinylation.

Scheme 30

Asymmetric synthesis of medium-sized N,O-heterocycles via copper-catalyzed intramolecular hydroamination.

Scheme 31

Copper-catalyzed intramolecular O-arylation to access dibenzoxazocines and oxazonines.

Scheme 32

Gold-catalyzed cyclization of alkynylindole.

Scheme 33

Gold-catalyzed alkyne hydroarylation of propargyl amide derivatives.

Scheme 34

Gold-catalyzed cascade reactions of aniline derivatives.

Scheme 35

Gold-catalyzed cascade reactions of indole derivatives.

Scheme 36

Gold-catalyzed cascade reactions for the construction of ten- and eleven-membered rings.

Scheme 37

Gold(I)-catalyzed cycloisomerization of vinylidenecyclopropane-enes.

Scheme 38

Synthesis of benzoxocines by gold(I)-catalyzed 8-endo-dig cyclization.

Scheme 39

Synthesis of 8- and 9-membered ring ethers and amines by gold(I)-catalyzed cascade reaction.

Scheme 40

Ag(I)- and Au(I)-catalyzed hydroalkoxylation of alkynoic acids.

Scheme 41

Au(I)-catalyzed hydroalkoxylation for oxazocenone synthesis.

Scheme 42

Ag(I)-catalyzed 8-endo-dig cyclization for quinazolinone-fused 8-membered heterocycle synthesis.

Scheme 43

Au(I)-catalyzed cyclization of 2-alkynyl-N-propargylanilines.