Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications

Abstract

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids. The current review summarizes recent scientific literature on intra- and intermolecular reactions leading to the formation of various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidines, and piperidinones. Moreover, the pharmaceutical applications of synthetic and natural piperidines were covered, as well as the latest scientific advances in the discovery and biological evaluation of potential drugs containing piperidine moiety. This review is designed to help both novice researchers taking their first steps in this field and experienced scientists looking for suitable substrates for the synthesis of biologically active piperidines.

Keywords: amination; annulation; biological activity; cyclization; cycloaddition; hydrogenation; multicomponent reactions; pharmacological activity; piperidines; piperidinones.

Figure 1

Piperidine derivatives scope of this review.

Scheme 1

Main routes to the piperidine cycle synthesis.

Scheme 2

Pyridine derivatives hydrogenation using cobalt- (A), ruthenium- (B) and nickel-based (C) nanocatalysts.

Scheme 3

Iridium-catalyzed asymmetric hydrogenation of pyridinium salts.

Scheme 4

Rhodium- (A) and palladium-catalyzed (B) hydrogenation of fluorinated pyridines.

Scheme 5

Interrupted palladium-catalyzed hydrogenation of pyridine derivatives.

Scheme 6

Hydrogenation of bromopyridine derivatives using palladium catalyst with hydrochloric acid (A) or triethylamine additive (B), and rhodium catalyst (C).

Scheme 7

Chemoselective hydrogenation of pyridine derivatives: one-pot palladium(0)-catalyzed Suzuki–Miyaura/hydrogenation reaction (A), palladium(0)-catalyzed hydrogenation under ambient conditions (B), donepezil precursor synthesis through palladium(0)-catalyzed hydrogenation (C), serotonin reuptake inhibitor precursor synthesis through platinum-catalyzed hydrogenation (D).

Scheme 8

Stereoselective palladium-catalyzed cascade including pyridine hydrogenation.

Scheme 9

Borenium-catalyzed hydrogenation of 2,5- (A) and 2,3-substituted (B) pyridines.

Scheme 10

Hydrosilylation of 1- (A), 2-quinolines (B) and pyridines (C).

Scheme 11

Double reduction of pyridine derivatives using ruthenium(II) (A) and rhodium(I) (B) catalyst, and piperidinone derivatives (C).

Scheme 12

Tofacitinib precursor synthesis: rhodium-catalyzed asymmetric hydrogenation.

Scheme 13

Main scheme of intramolecular cyclization.

Figure 2

Main routes of intramolecular cyclization.

Scheme 14

Intramolecular aminations of N-tethered alkenes: gold(I)-catalyzed oxidative aminoesterification (A), palladium(II)-catalyzed oxidative 6-endo aminoacetoxylation (B), palladium(II)-catalyzed azidation (C), palladium(II)-catalyzed 6-endo diamination (D), palladium(II)-catalyzed aminotrifluoromethanesulfinyloxylation (E), palladium(0)-catalyzed allylic amination (F), palladium(II)-catalyzed hydrofunctionalization (G), cation-induced alkylation/amination (H).

Scheme 15

Intramolecular aza-Michael reactions of N-tethered alkenes: organocatalytic enantioselective synthesis of protected 2,5- (A) and 2,5,5-substituted piperidines (B), base-induced diastereoselective large-scale synthesis of 2,6-trans-piperidine (C), carbene-catalyzed diastereoselective cyclization (D).

Scheme 16

Stereoselective 6-endo-trig cyclisation.

Scheme 17

Intramolecular cyclization of alkene via hydride transfer/cyclization cascade.

Scheme 18

Palladium-catalyzed enantioselective 6-exo aza-heck cyclization.

Scheme 19

Copper(I)-catalyzed radical enantioselective cyclization.

Scheme 20

Light-mediated iridium(III)-catalyzed cyclization.

Scheme 21

Asymmetric MOC cyclization via S_N2-reaction.

Scheme 22

Highly enantioselective nickel-catalyzed intramolecular hydroalkenylation of 1,6-ene-dienes.

Scheme 23

Double highly diastereoselective intramolecular cyclization of 1,3-ene-dienes via a hydride transfer/cyclization cascade.

Scheme 24

Rhodium(I)-catalyzed cycloisomerization of 1,7-ene-dienes.

Scheme 25

Nickel-catalyzed cyclization 1,7-ene-dienes.

Scheme 26

[2 + 2] Intramolecular cycloaddition of 1,7-ene-dienes.

Scheme 27

Carbenium ion-induced intramolecular cyclization.

Scheme 28

Samarium-catalyzed intramolecular radical cyclization of haloalkynals.

Scheme 29

Gold(I)-catalyzed intramolecular dearomatization/cyclization.

Scheme 30

Radical stereoselective cyclization of 1,6-enynes initiated through borane addition (A) and oxidation (B).

Scheme 31

Stereoselective reductive hydroamination.

Scheme 32

Cobalt-catalyzed cyclization.

Scheme 33

Intramolecular radical C–H amination/cyclization through electrolysis (A), copper(I) (B) and copper(II) catalysis (C).

Scheme 34

Way to piperidines through radical-mediated C-H cyanation.

Scheme 35

Palladium-catalyzed azide reduction cyclization.

Scheme 36

Asymmetric synthesis of piperidines by nitro-Mannich/reduction cyclization.

Scheme 37

Local desymmetrization approach to piperidines.

Scheme 38

Intramolecular cyclization/reduction cascade.

Scheme 39

Iron-catalyzed reductive amination.

Scheme 40

Intramolecular amination of organoboronates.

Scheme 41

Hydrogen borrowing annulation of diols (A) and enentioenriched diols (B).

Scheme 42

Diastereoselective [5 + 1] annulation of amines with aldehydes (A,B) and ketoesters (C).

Scheme 43

Amino-ketoester cyclization with aldehydes.

Scheme 44

1,2-Diamination of aldehydes.

Scheme 45

Double reductive aminations via ruthenium(II) catalysis (A), microwave radiation (B) consecutive oxidative ring opening and reductive ring closure (C).

Scheme 46

Aza-Prins cyclizations of homoallylic amines with aldehydes (A) and epoxides (B).

Scheme 47

Aza-Sakurai cyclizations of allylic amines with cyclic ketones (A) and aldehydes (B).

Scheme 48

A [5 + 1] acid-mediated 4-chloropiperidines synthesis.

Scheme 49

Synthesis of N-aryl-substituted azacycles from cyclic ethers.

Scheme 50

Radical-mediated intermolecular annulations through copper(II) catalysis (A) and electrolysis (B).

Scheme 51

Enantiospecific synthesis of 2-substituted piperidine-4-carboxylic acids.

Scheme 52

Piperidine synthesis through palladium(II)-catalyzed (A) and organocatalytic (B) [4 + 2] cycloaddition.

Scheme 53

Piperidine synthesis through [3 + 3] cycloaddition.

Scheme 54

Main scheme of MCRs.

Scheme 55

Pseudo four-component synthesis of cyclic imide.

Scheme 56

Pseudo six-component synthesis of spiropiperidine derivatives.

Figure 3

Synthetic piperidine derivatives in medicine.

Scheme 57

Pseudo six-component synthesis of spiropiperidine derivatives.

Scheme 58

Common cascade mechanism of piperidine cycle formation.

Scheme 59

Stereoselective one-pot pseudo six-component synthesis of poly-substituted piperidines with three (A) and two (B) aromatic substituents.

Scheme 60

Stereoselective one-pot pseudo four-component synthesis of poly-substituted piperidines with two (A) and three (B) aromatic substituents, and example of retro-Knoevenagel condensation (C).

Scheme 61

Stereoselective one-pot pseudo five-component synthesis of poly-substituted piperidinols.

Scheme 62

Water-mediated pseudo three-component synthesis of piperidinols.

Scheme 63

Three-component synthesis of piperidines with the acetylene group.

Scheme 64

Stereoselective one-pot pseudo four-component synthesis of poly-substituted piperidinons via the Michael/Mannich (A) and Knoevenagel/Michael/Mannich cascade (B).

Scheme 65

Pseudo four-component synthesis of poly-substituted piperidinons with naphthalene (A) and benzene (B) substituents.

Scheme 66

Regioselective solvent-free multicomponent synthesis of piperidinons (A) and spiropiperidinones (B).

Figure 4

Pharmacological properties of natural piperidine derivatives.

Figure 5

Structure–activity relationship of piperidine derivatives with anticancer activity [207,214,218,223,224,225,230,231,233,234].

Figure 6

Piperidine derivatives as potential drugs for Alzheimer disease therapy [242,243,244,245,246,247,252,253,254,255,256,257,258].

Figure 7

Piperidine derivatives with antimicrobial activity [260,261,263,264,265,266,267,268,269].

Figure 8

Piperidine derivatives as potential drugs for neuropathic pain disorders [274,275,276,277,279,281,282,283].