Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs

Abstract

In nucleophilic phosphine catalysis, tertiary phosphines undergo conjugate additions to activated carbon-carbon multiple bonds to form β-phosphonium enolates, β-phosphonium dienolates, β-phosphonium enoates, and vinyl phosphonium ylides as intermediates. When these reactive zwitterionic species react with nucleophiles and electrophiles, they may generate carbo- and heterocycles with multifarious molecular architectures. This article describes the reactivities of these phosphonium zwitterions, the applications of phosphine catalysis in the syntheses of biologically active compounds and natural products, and recent developments in the enantioselective phosphine catalysis.

Scheme 1

Phosphine-catalyzed reactions at an early stage.

Scheme 2

Phosphine-initiated general base catalysis.

Scheme 3

Phosphine-mediated Michael additions of alcohols and water to activated alkenes.

Scheme 4

Aldol reaction through oxaphospholidine-stabilized enol ether.

Scheme 5

Preparation of bicyclic cross-conjugated bis-enones. Condition A: Me₃P (5 equiv) in 2-methylbutan-2-ol. Condition B: Bu₃P (1 equiv) in 2,2,2-trifluoroethanol.

Scheme 6

Mechanism of Michael-interfered aza-MBH reaction.

Scheme 7

Construction of 2,5-dihydropyrrole derivatives.

Scheme 8

Proposed MBH–Michael pathway.

Scheme 9

Preparation of xanthenone derivatives.

Scheme 10

Stepwise γ-umpolung addition.

Scheme 11

Proposed mechanism for phosphine-catalyzed γ-umpolung addition.

Scheme 12

Preparation of γ-substituted 2-butenoates.

Scheme 13

Formation of dihydropyrroles via intramolecular γ-umpolung addition. ^a Reaction performed without additives.

Scheme 14

Proposed β'-umpolung addition mechanism.

Scheme 15

Formation of functionalized acrylates.

Scheme 16

Synthesis of acrylate derivatives. ^a Reaction conducted using Ph₃P. ^b Reaction conducted at room temperature.

Scheme 17

Synthesis of piperazines via γ-umpolung–Michael addition.

Scheme 18

Proposed mechanism for mixed double-Michael [4+1] annulation.

Scheme 19

Mixed double-Michael addition with allenoates. ^a 10 mol % catalyst was used. ^b dr = 1:1

Scheme 20

Proposed mechanism for γ-umpolung–Michael reaction.

Scheme 21

Synthesis of cyclopentenes derivatives.

Scheme 22

Proposed reaction mechanism for Lu’s [3 + 2] annulation.

Scheme 23

Lu’s [3+2] annulation with alkenes.

Scheme 24

Synthesis of diquinanes through intramolecular [3 + 2] annulation.

Scheme 25

Preparation of functionalized dihydrocoumarins.

Scheme 26

Formation of polysubstituted cyclopentenes and dihydropyrroles.

Scheme 27

Synthesis of cyclopentenes using phenyl allenone.

Scheme 28

Total synthesis of (–)-hinesol.

Scheme 29

Total synthesis of (±)-hirsutene.

Scheme 30

Total synthesis of (+)-geniposide.

Scheme 31

Preparation of functionalized dihydropyrroles.

Scheme 32

Kwon’s synthesis of tetrasubstituted dihydropyrroles.

Scheme 33

Synthesis of functionalized 2-aryl and 2-alkyl dihydropyrroles.

Scheme 34

Formal synthesis of (±)-allosecurinine.

Scheme 35

Formal synthesis of (+)-trachelanthamidine.

Scheme 36

Enantioselective total synthesis of (+)-ibophyllidine.

Scheme 37

Proposed mechanism for azomethine imine–allene [3 + 2] annulation.

Scheme 38

Formation of tetrahydropyrazolopyrazolone derivatives. ^a Me₃P was used as catalyst.

Scheme 39

Proposed mechanism for Kwon’s [4 + 2] annulation.

Scheme 40

Formation of densely functionalized tetrahydropyridines using Kwon’s [4+2] annulation. ^a 3 equivalents of Na₂CO₃ were added.

Scheme 41

Formal synthesis of (±)-alstonerine.

Scheme 42

Synthesis of the skeletal framework of reserpine.

Scheme 43

Total synthesis of (±)-hirsutine.

Scheme 44

Synthesis of functionalized cyclohexenes through allene–alkene [4 + 2] annulation.

Scheme 45

Synthesis of functionalized dihydropyrans.

Scheme 46

Synthesis of dioxanes, 2-pyranones, and dihydro-2-pyranones via phosphine catalysis.

Scheme 47

Synthesis of dioxane derivatives through phosphine catalysis.

Scheme 48

Phosphine-catalyzed formation of 2-pyranones.

Scheme 49

Formation of various dihydro-2-pyranones.

Scheme 50

Preparation of functionalized dihydrobenzofuran.

Scheme 51

Synthesis of aminochromans.

Scheme 52

Synthesis of hydroxychromans.

Scheme 53

Preparing functionalized aminochromans and hydroxychromans.

Scheme 54

Isomerization of alkynes through nucleophilic addition.

Scheme 55

Isomerization of activated alkynes. ^a Reaction performed in xylene as the solvent.

Scheme 56

Proposed phosphine-catalyzed Michael addition of alkynes.

Scheme 57

Phosphine-initiated Michael addition of alcohols. ^a Reaction was completed within 30 min.

Scheme 58

Preparation of functionalized acrylates.

Scheme 59

Proposed mechanism of α-umpolung addition.

Scheme 60

Formation of α-aminoacrylates.

Scheme 61

Synthesis of functionalized alkylidene phthalans via Michael–Heck reaction. ^a Major Z-phthalan isolated.

Scheme 62

Total syntheses of 3-deoxyisoochracinic acid, isoochracinic acid, and isoochracinol.

Scheme 63

Syntheses of oxazolidines, thiazolidines, and pyrrolidines via mixed double-Michael additions.

Scheme 64

Phosphine-catalyzed mixed double-Michael addition. ^a Reaction performed at rt. ^b Reaction performed in the absence of AcOH/NaOAc. ^c Reaction performed in the absence of AcOH/NaOAc at rt.

Scheme 65

Proposed mechanism for the formation of tetrahydrofurans.

Scheme 66

Synthesis of tetrahydrofurans through Michael–Michael annulation.

Scheme 67

Formation of functionalized quinolines.

Scheme 68

Plausible mechanism for γ-butenolide formation.

Scheme 69

Synthesis of γ-butenolides from MBHADs.

Scheme 70

Proposed mechanism for MBHAD–alkene [3 + 2] annulation.

Scheme 71

Synthesis of cyclopentenes via MBHAD–alkene [3 + 2] annulation. ^a 1.5 eq. K₂CO₃ employed as additive. ^b Reaction performed at rt.

Scheme 72

Intramolecular MBHAD–alkene [3+2] annulation.

Scheme 73

Preparation of dihydropyrroles from MBHADs.

Scheme 74

Suggested mechanism for the formation of 3-amino-2,3-dihydrobenzofurans.

Scheme 75

Preparation of 3-amino-2,3-dihydrobenzofuran derivatives.

Scheme 76

Asymmetric formation of cyclopentenes using phosphabicyclo[2.2.1]heptane. ^a Reaction performed at 0 °C. ^b Reaction performed in toluene at 0 °C

Scheme 77

Asymmetric formation of cyclopentenes, catalyzed by Gladiali’s phosphepine 118.

Scheme 78

Asymmetric formation of cyclopentenes using FerroPHANE 119. ^a Reaction performed in acetone.

Scheme 79

Asymmetric formation of cyclopentenes, catalyzed by (R,R)-DIPAMP.

Scheme 80

Asymmetric formation of spirocyclopenteneoxindoles, catalyzed by (+)-Ph-BPE. ^a Yield and ee of the major diastereoisomer. ^b Dr 3.7:1:0.7:0.04. ^c Dr 2:1:0.2:0.2. ^d Reaction performed with 20 mol % 121 at −20 °C.

Scheme 81

Asymmetric formation of tetrahydropyridines, catalyzed by Gladiali’s phosphepine 118.

Scheme 82

Asymmetric formation of γ-substituted enoates catalyzed by the phosphabicyclo[2.2.1]heptane 122.

Scheme 83

Asymmetric formation of γ-substituted acrylamides catalyzed by the phosphinamine 123.

Scheme 84

Asymmetric formation of γ-substituted enoates, catalyzed by TangPhos.

Scheme 85

Asymmetric formation of γ-substituted enoates, catalyzed by the phosphepine 125.

Scheme 86

Asymmetric formation of γ-substituted acrylates and acrylamides, catalyzed by the phosphepine 126.

Scheme 87

Asymmetric formation of γ-amino acrylates and acrylamides, catalyzed by the spirophosphepine 127.

Scheme 88

Asymmetric formation of tetrahydropyrans and tetrahydrofurans, catalyzed by the spirophosphepine 127.

Scheme 89

Asymmetric formation of pyrrolidines and 2,3-dihydroindoles, catalyzed by the spirophosphepine 127. ^a Reaction performed with 50 mol % of 2,4- dimethoxyphenol. ^b Reaction performed with 20 mol % of 2-fluoro-6-methoxyphenol.

Scheme 90

Asymmetric formation of β-lactones, catalyzed by Josiphos.

Scheme 91

Asymmetric formation of β-lactams using BINAPHANE. ^a Reaction performed with 15 mol % of 130

Scheme 92

Asymmetric formation of cyclopentenes, catalyzed by the phosphinyl alanine 131.

Scheme 93

Asymmetric formation of cyclopentenes using N-acyl amino phosphine.

Scheme 94

Asymmetric formation of cyclopentenes, catalyzed by the chiral dipeptide phosphine 133.

Scheme 95

Asymmetric formation of dihydropyrroles, catalyzed by the chiral phosphinothiourea 134.

Scheme 96

Asymmetric formation of dihydropyrroles, catalyzed by the chiral dipeptide phosphine 55.

Scheme 97

Asymmetric formation of cyclopentenes, catalyzed by the chiral thiourea phosphine 135.

Scheme 98

Asymmetric formation of spirocyclopenteneoxindoles, catalyzed by the chiral dipeptide phosphine 136.

Scheme 99

Asymmetric formation of tetrahydropyridines, catalyzed by the N-acyl amino phosphine 132.

Scheme 100

Asymmetric formation of cyclohexenes, catalyzed by the chiral dipeptide phosphine 137.

Scheme 101

Asymmetric formation of cyclohexenes, catalyzed by the N-acyl amino phosphine 138.

Scheme 102

Asymmetric formation of spirocyclohexeneoxindoles, catalyzed by the chiral dipeptide phosphine 55.

Scheme 103

Asymmetric formation of 3,3-disubstituted oxindoles, catalyzed by the chiral dipeptide phosphine 139.

Scheme 104

Asymmetric formation of γ-butenolides, catalyzed by the chiral binaphthyl phosphine 140.

Scheme 105

Asymmetric formation of 3,3-disubstituted phthalides, catalyzed by the chiral dipeptide phosphine 141.