Enantioselective Friedel–Crafts reactions of ethenetricarboxylates and substituted pyrroles and furans and intramolecular reaction of benzene derivatives

Compared to enantioselective Friedel–Crafts reactions of indoles, reactions of alkylidene malonates with monocyclic aromatic compounds generally proceed with low enantioselectivity. The Friedel–Crafts reactions of ethenetricarboxylates 1 and monocyclic heteroaromatic compounds, such as substituted pyrroles and furans were investigated. The reaction of 1 with 2,4-dimethylpyrrole in the presence of a chiral bisoxazoline–copper(II) complex (10 mol %) in tetrahydrofuran at room temperature gave alkylated products in up to 72% ee. The reaction of 1 with 2-substituted furans gave alkylated products in 46–62% ee. The absolute stereochemistry of the furan Friedel–Crafts product 7e was determined by transformation to the known 2,3-dimethylbutyric acid. The intramolecular reaction of benzene derivatives gave cyclized products up to 56% ee.

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1-tert-Butyl 2,2-diethyl 1-(5-butylfuran-2-yl)ethane-1,2,2-tricarboxylateC21H32O7Ee = 58%[α]D22=-59 (c 1.02, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]Absolute configuration: (R)

1-tert-Butyl 2,2-diethyl 1-(3,5-dimethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC19H29NO6Ee = 72%[α]D30=-75 (c 1.06, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC17H25NO6Ee = 29%[α]D32=-20 (c 0.96, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(1-ethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC19H29NO6Ee = 10%[α]D23=-15 (c 1.55, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(1-phenyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC23H29NO6Ee = 10%[α]D21=+10 (c 1.80, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(1-phenyl-1H-pyrrol-3-yl)ethane-1,2,2-tricarboxylateC23H29NO6Ee = 66%[α]D14=-76 (c 0.15, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(5-ethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC19H29NO6Ee = 45%[α]D26=-40 (c 0.99, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(5-benzyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC24H31NO6Ee = 41%[α]D24=-37 (c 1.02, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(3-phenyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC23H29NO6Ee = 66%[α]D23=-99 (c 0.50, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(4-phenyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC23H29NO6Ee = 12%[α]D27=+11 (c 0.22, CHCl3)Source of chirality: (+)-2,2′-isopropylidenebis[(4R)-4-benzyl-2-oxazoline]

1-tert-Butyl 2,2-diethyl 1-[3-(4′-chlorophenyl)-1H-pyrrol-2-yl]ethane-1,2,2-tricarboxylateC23H28ClNO6Ee = 50%[α]D22=-77 (c 1.23, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-[4-(4′-chlorophenyl)-1H-pyrrol-2-yl]ethane-1,2,2-tricarboxylateC23H28ClNO6Ee = 28%[α]D26=-13 (c 0.20, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-dibenzyl 1-(3,5-dimethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC21H32O4Ee = 38%[α]D26=-35 (c 1.00, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1,2,2-Triethyl 1-(3,5-dimethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC17H25NO6Ee = 63%[α]D21=-96 (c 1.24, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-(4-Bromobenzyl) 2,2-diethyl 1-(3,5-dimethyl-1H-pyrrol-2-yl)ethane-1,2,2-tricarboxylateC22H26BrNO6Ee = 48%[α]D23=-38 (c 0.54, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

Diethyl 2-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-2-(piperidin-1-yl)ethyl]malonateC20H30N2O5Ee = 71%[α]D27=-118 (c 1.08, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

Diethyl 2-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-2-phenylethyl]malonateC21H25NO5Ee = 41%[α]D22=-83 (c 1.68, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

Diethyl 2-[(3,5-dimethyl-1H-pyrrol-2-yl)(phenyl)methyl]malonateC20H25NO4Ee = 47%[α]D19=-10 (c 0.56, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

1-tert-Butyl 2,2-diethyl 1-(furan-2-yl)ethane-1,2,2-tricarboxylateC17H24O7Ee = 9%[α]D28=-8 (c 0.31, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]

1-tert-Butyl 2,2-diethyl 1-(5-methylfuran-2-yl)ethane-1,2,2-tricarboxylateC18H26O7Ee = 46%[α]D24=-52 (c 0.95, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]

1-tert-Butyl 2,2-diethyl 1-(5-ethylfuran-2-yl)ethane-1,2,2-tricarboxylateC19H28O7Ee = 60%[α]D30=-63 (c 1.07, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]

1-tert-Butyl 2,2-diethyl 1-(5-propylfuran-2-yl)ethane-1,2,2-tricarboxylateC20H30O7Ee = 57%[α]D28=-62 (c 1.48, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]

1-tert-Butyl 2,2-diethyl 1-(4,5-dimethylfuran-2-yl)ethane-1,2,2-tricarboxylateC19H28O7Ee = 27%[α]D22=-29 (c 1.01, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

(S)-2-(Hydroxymethyl)-3-(5-butylfuran-2-yl)butane-1,4-diolC13H22O4Ee = 62%[α]D17=-5.8 (c 1.35, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]Absolute configuration: (S)

(R)-2-Butyl-5-(1,2-dimethypropyl)furanC13H22OEe = 62%[α]D16=-6.3 (c 0.66, CHCl3)Source of chirality: (−)-2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole]Absolute configuration: (R)

Diethyl 2-(1,2,3,4-tetrahydro-6,8-dimethoxy-2-oxonaphthalen-1-yl)malonateC19H24O7Ee = 48%[α]D31=+90 (c 0.75, CHCl3)Source of chirality: (+)-2,2′-isopropylidenebis[(4R)-4-benzyl-2-oxazoline]

Diethyl 2-(5,7-dimethoxy-3-oxochroman-4-yl)malonateC18H22O8Ee = 20%[α]D26=+38 (c 1.19, CHCl3)Source of chirality: (S,S)-(−)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline)

Diethyl 2-(6,8-bis(benzyloxy)-1,2,3,4-tetrahydro-2-oxonaphthalen-1-yl)malonateC31H32O7Ee = 56%[α]D30=+109 (c 0.85, CHCl3)Source of chirality: (+)-2,2′-isopropylidenebis[(4R)-4-benzyl-2-oxazoline]