Asymmetric synthesis of 3- or 4-alkyl or arylbenzo[c]azepines

Two flexible routes for the stereoselective synthesis of a variety of 3- or 4-alkylated or arylated tetrahydrobenzazepines have been developed. The key steps are the highly diastereoselective metallation/alkylation reaction and 1,2-addition processes applied to stereopure SAMP hydrazones combined with a cyclomethylenation reaction.

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[(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[3-(3,4,5-trimethoxyphenyl)propylidene]amineC18H28N2O4Ee >96%[α]D25=-73.5 (c 1.07, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

N-[3-(3,4-Dimethoxyphenyl)propylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC17H26N2O3Ee >96%[α]D25=-69.8 (c 1.01, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S)

[(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(R)-2-methyl-3-(3,4,5-trimethoxyphenyl)propylidene]amineC19H30N2O4Ee >96%[α]D25=-122.3 (c 1.09, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,2R)

N-[(R)-2-Benzyl-3-(3,4,5-trimethoxyphenyl)propylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC25H34N2O4Ee >96%[α]D25=-52.9 (c 0.83, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,2S)

[(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(R)-2-methoxymethyl-3-(3,4,5-trimethoxyphenyl)propylidene]amineC20H32N2O5Ee >96%[α]D25=-95.9 (c 0.99, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,2R)

N-[(R)-3-(3,4-Dimethoxyphenyl)-2-methylpropylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC18H28N2O3Ee >96%[α]D25=-124.0 (c 0.72, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2R,2S)

N-[(S)-3-(3,4-Dimethoxyphenyl)-2-methylpropylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC18H28N2O3Ee >96%[α]D25=-37.0 (c 1.22, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,2S)

[(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(S)-2-phenyl-3-(3,4,5-trimethoxyphenyl)propylidene]amineC24H32N2O4Ee >96%[α]D25=-86.6 (c 1.10, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,2S)

N-[(S)-2-(2,3-Dimethoxybenzyl)heptylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC22H36N2O3Ee >96%[α]D25=-29.8 (c 1.09, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,2S)

N-[(R)-2-Benzo[1,3]dioxol-5-ylmethyl-4-benzyloxybutylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amineC25H32N2O4Ee >96%[α]D25=-43.2 (c 0.87, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R,2S)

(R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC20H32N2O4Ee >96%[α]D25=-46.8 (c 0.71, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,4R)

(R)-4-Benzyl-7,8,9-trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]azepineC26H36N2O4Ee >96%[α]D25=-37.8 (c 0.72, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R,2S)

(R)-7,8,9-Trimethoxy-4-methoxymethyl-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]azepineC21H34N2O5Ee >96%[α]D25=-44.0 (c 0.61, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R,2S)

(R)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC19H30N2O3Ee >96%[α]D25=-38.8 (c 0.51, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,4R

(S)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC26H36N2O4Ee >96%[α]D25=-32.6 (c 0.58, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S,2S)

(R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC25H34N2O4Ee >96%[α]D25=-58.3 (c 1.75, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,4R)

(S)-6,7-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-4-pentyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC23H38N2O3Ee >96%[α]D25=-48.2 (c 1.0, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,4S)

(R)-8-(2-Benzyloxyethyl)-6-[(S)-2-methoxymethylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]indeneC26H34N2O4Ee >96%[α]D25=-46.6 (c 0.67, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (8R,2S)

(R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC20H32N2O4Ee >96%[α]D25=-43.8 (c 1.25, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,3R)

(R)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC19H30N2O3Ee >96%[α]D25=-50.3 (c 0.31, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2S,3R)

(R)-3-Hexyl-7,8-dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]azepineC24H40N2O3Ee >96%[α]D25=-46.3 (c 0.49, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3R,2S)

(R)-7,8,9-Trimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC14H21NO3Ee >96%[α]D25=-39.4 (c 0.72, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(R)-4-Benzyl-7,8,9-trimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepineC20H25NO3Ee >96%[α]D25=-72.8 (c 0.39, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(R)-7,8,9-Trimethoxy-4-methoxymethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC15H23NO4Ee >96%[α]D25=-44.2 (c 0.41, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(R)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC13H19NO2Ee >96%[α]D25=-56.5 (c 0.63, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(S)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-2-benzo[c]azepineC13H19NO2Ee >96%[α]D25=+53.6 (c 0.52, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S)

(R)-6,7-Dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC19H23NO3Ee >96%[α]D25=+24.3 (c 0.38, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(S)-6,7-Dimethoxy-4-pentyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC17H27NO2Ee >96%[α]D25=-6.8 (c 0.47, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4S)

(R)-8-(2-Benzyloxyethyl)-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta[f]indeneC20H23NO3Ee >96%[α]D25=-12.6 (c 0.61, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (4R)

(R)-7,8,9-Trimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC14H21NO3Ee >96%[α]D25=-81.1 (c 0.54, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3R)

(R)-7,8-Dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepineC13H19NO2Ee >96%[α]D25=-69.7 (c 0.41, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3R)

(3R)-7,8-Dimethoxy-3-hexyl-2,3,4,5-tetrahydro-1H-2-benzazepineC18H29NO2Ee >96%[α]D25=-29.6 (c 0.73, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (3R)