Synthesis of chiral 4,4-disubstituted-dihydropyridazines

In this paper, a novel general route to the stereospecific synthesis of chiral dihydropyridazines relying on the stereospecific formation of 1,4-diones is presented. The chirality is provided through the application of bicyclic lactams to the synthesis of the required diones. Treatment of the diones with hydrazine produces the pyridazine targets. In this report, the synthesis of four chiral 6-phenyl-4,4-disubstituted-1,4-dihydropyridazines is also presented.

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(3S,6S,7aS)-Tetrahydro-6-methyl-3-(1-methylethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC16H21NO2[α]D22.2=+37.1 (c 1.7, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S,6S,7aS)

(3S,6R,7aS)-Tetrahydro-6-methyl-3-(1-methylethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC17H23NO2[α]D22.2=+41.2 (c 1.7, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S,6R,7aS)

(3S,6S,7aS)-Tetrahydro-6-(2-propenyl)-6-methyl-3-(1-methylethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC19H25NO2[α]D21.6=+2.5 (c 1.44, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S,6S,7aS)

(3S,6S,7aS)-Tetrahydro-6-butyl-6-methyl-3-(1-methylethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC20H29NO2[α]D20.6=+4.5 (c 1.7, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S,6S,7aS)

(3S,6S,7aS)-Tetrahydro-6-methyl-3-(1-methylethyl)-6-(2-methylpropyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC20H29NO2[α]D20.7=+6.9 (c 1.5, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S,6S,7aS)

(3S)-3-Methyl-3-(2-propenyl)-1-phenyl-1,4-octanedioneC18H24O2[α]D20.6=+36.8 (c 0.7, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S)

(3S)-3-Methyl-3-(2-phenylmethyl)-1-phenyl-1,4-octanedioneC22H24O2[α]D20.6=-20.6 (c 2.8, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S)