Preparation of 2-alkenylperhydro-1,3-benzoxazines and application for 2-isoxazolines synthesis

Various 2-substituted-N-benzyl-4,4,7-trimethyl-trans-octahydro-1,3-benzoxazines 2 were prepared from the condensation of (−)-8-benzylaminomenthol 1 derived from (+)-pulegone, with acrolein, crotonaldehyde, cinnamaldehyde, 2(E)-N,N-diisopropyl-4-oxobut-2-enamide, ethyl (2E)-4-oxobut-2-enoate, and 2-furaldehyde in 71–96% yield. The 1,3-dipolar cycloaddition with aceto- and benzonitrile oxide gave the corresponding 2-isoxazoline cycloadducts. The origin of the stereoselectivity (4′S, 5′S-cycloadducts up to 64% de) arises from the cycloaddition of the dipole to the top of the Re,Re-alkene face of dipolarophile 2.

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(−)-(1′E)-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyl-2-(prop-1′-enyl)octahydro-2H-1,3-benzoxazineC21H31NODe = 100%[α]D23=-31.3 (c 0.193, CH2Cl2)Source of chirality: (+)-pulegone

(−)-(2E)-[(2S,7R,9R,10S)-Ethyl -3-[3-(benzyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl]-prop-2-enoateC23H33NO3De = 100%[α]D23=-69.0 (c 0.114, CH2Cl2)Source of chirality: (+)-pulegone

(−)-(2E)-3-[(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl]-N,N-diisopropylprop-2-enamideC27H42N2O2De = 100%[α]D23=-65.1 (c 0.45, CH2Cl2)Source of chirality: (+)-pulegone

(−)-(2S,7R,9R,10S)-3-(Benzyl)-2-(2′-furyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazineC22H29NO2De = 100%[α]D23=-24.6 (c 0.74, CH2Cl2)Source of chirality: (+)-pulegone

(−)-(1′E)-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyl-2-[2′-phenylethenyl]octahydro-2H-1,3-benzoxazineC26H33NODe = 100%[α]D23=-63.5 (c 0.66, CH2Cl2)Source of chirality: (+)-pulegone

(+)-(2S,5′S,7R,9R,10S)-3-(Benzyl)-2-[3′-phenyl-4,5-dihydroisoxazol-5′-yl]-4,4,7-trimethyloctahydro-2H-1,3-benzoxazineC27H34N2O2De = 56%[α]D23=+13.4 (c 0.264, CH2Cl2)Source of chirality: (+)-pulegone

(+)-(2S,3R,5′S,7R,9R,10S)-3-(Benzyl)-2-[3′-methyl-4,5-dihydroisoxazol-5′-yl]-4,4,7-trimethyloctahydro-2H-1,3-benzoxazineC22H32N2O2De = 50%[α]D22=+29.3 (c 0.161, MeOH)Source of chirality: (+)-pulegone

Ethyl (+)-(2S,4′S,5′S,7R,9R,10S)-5-[3-(benzyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl]-3-phenyl-4,5-dihydroisoxazole-4-carboxylateC30H38N2O4[α]D23=+81.0 (c 0.09, CH2Cl2)Source of chirality: (+)-pulegone

(+)-(2S,4′S,5′S,7R,9R,10S)-4-[3-(Benzyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl]-N,N-diisopropyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamideC34H47N3O3[α]D23=+248.3 (c 0.202, CH2Cl2)Source of chirality: (+)-pulegone

(−)-(2S,4′R,5′R,7R,9R,10S)-3-(Benzyl)-2-[(3′,5′-diphenyl-4,5-dihydroisoxazol-4-yl)]-4,4,7-trimethyloctahydro-2H-1,3-benzoxazineC33H38N2O2[α]D23=-146.7 (c 0.31, CH2Cl2)Source of chirality: (+)-pulegone