Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

Abstract

The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made during the last years in achieving efficiently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes developed between 2013 and early 2017.

Keywords: Michael addition; asymmetric synthesis; nitroalkenes; organocatalysis.

Scheme 1

Catalytic cycle of the conjugate addition of aldehydes and ketones to nitroalkenes promoted by primary or secondary chiral amines.

Scheme 2

Asymmetric addition of aldehydes to nitroalkenes catalyzed by l-proline-related organocatalysts.

Figure 1

Results obtained using some l-prolinamide organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2.

Figure 2

Results obtained using some peptide-derived organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2.

Scheme 3

Asymmetric addition of aldehydes to α,β-disubstituted nitroalkenes catalyzed by proline-containing tripeptides and further transformation to lactams.

Scheme 4

Synthesis of precursor of isoprostanes using organocatalyst 13.

Scheme 5

Asymmetric synthesis of cis-disubstituted dehydroazulenones using organocatalyst 13.

Scheme 6

Asymmetric cascade reaction leading to cyclohexenes organocatalyzed by 13.

Figure 3

Supported organocatalysts for the asymmetric Michael addition of aldehydes to nitroalkenes leading to nitroaldehydes 2.

Figure 4

Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2.

Scheme 7

Asymmetric anti-selective Michael addition of aldehydes to nitroalkenes.

Scheme 8

Asymmetric synthesis leading to the atropurpuran A-ring.

Scheme 9

Asymmetric organocatalytic Michael addition of isobutyraldehyde to nitroalkenes.

Figure 5

Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric addition of isobutyraldehyde to nitroalkenes leading to nitroaldehyde 34b.

Figure 6

Results obtained using C2-diamine-derived organocatalysts in the asymmetric addition of isobutyraldehyde to nitroalkenes leading to nitroaldehydes 34.

Figure 7

Results obtained using primary-amine thioureas and squaramides as organocatalysts in the asymmetric addition of isobutyraldehyde to nitroalkenes leading to nitroaldehydes 34.

Scheme 10

Asymmetric organocatalytic addition of aldehyde-derived silyl-enol ethers to nitroalkenes.

Scheme 11

Asymmetric organocatalytic Michael addition of cyclohexanone to nitroalkenes organocatalyzed by ionic-liquid 45.

Figure 8

Results obtained using some pyrrolidine-based organocatalysts in the Michael reaction of ketones to β-nitrostyrenes.

Figure 9

Pyrrolidine-based organocatalysts containing a fluorine atom at the ring in the Michael addition of ketones to nitroalkenes.

Figure 10

Pyrrolidine-based organocatalysts containing an additional stereogenic center in the conjugate addition of ketones to nitroolefins.

Figure 11

Pyrrolidine-based organocatalysts containing an additional stereogenic center linked by a heterocyclic ring.

Figure 12

Results obtained using pyrrolidine-based organocatalysts with a diamine backbone in the preparation of nitroketone 46.

Scheme 12

Michael addition of cyclohexanone to β-nitrostyrene organocatalyzed by resin- immobilized 58.

Figure 13

Results obtained using pyrrolidine-based thiourea organocatalysts in the Michael addition of ketones to nitroalkenes.

Scheme 13

Michael addition of aryl methyl ketones to nitrostyrenes organocatalyzed by chiral cyclohexane-1,2-diamine-thiourea derivatives.

Scheme 14

Desymmetrization of prochiral 3-substituted cyclobutanones organocatalyzed by 67.

Scheme 15

Michael addition of β-aryl-α-ketophosphonates to nitroalkenes organocatalyzed by thiourea 69.

Scheme 16

Michael addition of trifluoromethyl α-fluorinated gem-diols to nitroolefins organocatalyzed by Takemoto’s thiourea organocatalyst.

Scheme 17

Sequential Michael addition-diastereoselective amino reductive cyclization processes.

Scheme 18

Asymmetric organocatalyzed Michael addition of β-tetralones to nitroolefins.

Scheme 19

Organocatalyzed Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroolefins under continuous flow chemistry.

Figure 14

Phosphoroamide-type organocatalysts used in the Michael addition of 2-hydroxy-1,4-naphthoquinone to trans-β-nitrostyrene leading to 80.

Figure 15

1,2-Diaminocyclohexane-based organocatalysts used in the Michael addition of acetone (85, 86) and aryl methyl ketones (86) to trans-β-nitroolefins.

Scheme 20

Construction of cyclohexanes with six vicinal stereogenic centers through a Michael/Michael/Henry process.

Figure 16

Simple chiral amine organocatalysts used in the Michael addition of ketones to trans-β-nitrostyrenes.

Scheme 21

Asymmetric organocatalyzed addition of 1-acetylcycloalkenes to β-nitroolefins.

Scheme 22

Organocatalyzed bisvinylogous 1,4-addition of cyclic 2,5-dienones to β-nitroolefins.

Scheme 23

Asymmetric dearomatization of 2-naphthols through an organocatalyzed conjugate addition to nitroethylene.

Scheme 24

Asymmetric addition of 1,3-dicarbonyl compounds to nitroolefins using different organocatalysts.

Figure 17

Organocatalyts employed in the asymmetric addition of 1,3-dicarbonyl compounds to nitroolefins leading to 96.

Scheme 25

Asymmetric addition of malonates and malononitriles onto nitroolefins using organocatalysts 104 and 105.

Figure 18

Calix[4]arene-based organocatalysts for the enantioselective addition of 1,3-diketones and malonates to nitroolefins.

Scheme 26

Asymmetric organocatalyzed addition of malonates and thiomalonates to nitroalkenes in brine.

Scheme 27

Enantioselective Michael addition ‘on water’ using recyclable organocatalyst 112.

Scheme 28

Organocatalyzed enantioselective addition of β-ketoamides to nitroalkenes.

Scheme 29

Organocatalyzed enantioselective addition of β-ketoamides.

Scheme 30

Enantioselective Michael addition of dithiomalonates and 2-oxochroman-3-carboxylate esters organocatalyzed by 102.

Scheme 31

Organocatalyzed enantioselective Michael addition of fluorinated pro-nucleophiles to nitroolefins.

Scheme 32

Organocatalyzed enantioselective Michael addition onto α-hydroxymethylnitroolefins.

Scheme 33

Multicomponent reaction based on the organocatalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroolefins catalyzed by 124.

Scheme 34

Asymmetric Michael addition of α-fluoro-α-nitro esters to nitroalkenes catalyzed by an alkaloid-threonine-thiourea derivative.

Scheme 35

Asymmetric Michael addition of 1-nitropropane to nitroalkenes organocatalyzed by an alkaloid-squaramide derivative.

Scheme 36

Asymmetric organocatalytic conjugate addition of 3-aminooxindoles to nitroolefins.

Scheme 37

Asymmetric organocatalytic conjugate addition of 3-aminooxindoles to nitroolefins.

Figure 19

Organocatalysts employed for the conjugate addition reactions of 3-alkyloxindoles and 3-chlorooxindoles to nitroolefins.

Scheme 38

Asymmetric organocatalyzed conjugate addition of 3-alkylideneoxindoles to nitroolefins.

Scheme 39

Asymmetric organocatalyzed conjugate addition of pyrazolones to four-member heterocycle-containing nitroolefins.

Scheme 40

Organocatalyzed asymmetric conjugate addition of pyrazolones to trifluoromethylated nitroolefins.

Scheme 41

Asymmetric organocatalyzed conjugate addition of oxazolones, thiazolones, oxazolidindiones, and thiazolidindiones to nitroolefins.

Figure 20

Organocatalysts employed in the conjugate addition of oxazolones, thiazolones, oxazolidindiones, and thiazolidindiones to nitroolefins leading to 148.

Scheme 42

Asymmetric organocatalyzed direct vinylogous conjugate addition of deconjugated butenolides to nitroolefins.

Scheme 43

Asymmetric organocatalyzed Conjugate addition of phthalide derivatives to nitroolefins.

Scheme 44

Organocatalytic enantioselective addition of cyclic hemiacetals to nitroolefins.

Scheme 45

Asymmetric aza-Michael addition of acylhydrazines to nitroalkenes by using Takemoto’s thiourea catalyst 73.

Scheme 46

Asymmetric aza-Michael addition of 4-nitrophthalimide to nitroalkenes using an alkaloid-thiourea derivative as organocatalyst.

Scheme 47

Asymmetric aza-Michael addition of benzotriazole to β,β-disubstituted nitroalkenes by using an alkaloid-thiourea derivative.

Scheme 48

Asymmetric cascade aza-Michael/Michael addition for the synthesis of piperidines by using an alkaloid-thiourea derivative.

Scheme 49

Asymmetric oxa-Michael addition of 4-methoxybenzaldehyde oxime to nitroalkenes by using an alkaloid-thiourea derivative.

Scheme 50

Asymmetric cascade oxa-Michael/Michael addition by using an alkaloid-thiourea derivative as organocatalyst.

Scheme 51

Asymmetric sulfa-Michael addition of thioacetic acid to nitroalkenes by using a tertiary amine-thiourea derivative as organocatalyst.

Figure 21

Enantioenriched 1,2-nitrothioesters via addition of thioacids to nitroalkenes organocatalyzed by 74.

Scheme 52

Asymmetric sulfa-Michael addition of thiols to nitroalkenes by using an alkaloid derivative.

Scheme 53

Asymmetric cascade sulfa-Michael/Michael addition leading to chromans by using a cyclohexanediamine-squaramide organocatalyst.

Scheme 54

Asymmetric cascade sulfa-Michael/Michael addition leading to thiochromans by using an alkaloid-thiourea derivative as organocatalyst.

Scheme 55

Asymmetric phospha-Michael addition of diphenylphosphite to nitroalkenes by using a tertiary amine-squaramide derivative as organocatalyst.