Preparation of chiral bipyridine bis-N-oxides by oxidative dimerization of chiral pyridine N-oxides

The direct preparation of chiral 2,2′-bipyridine bis-N-oxides has been developed. The method involves two stages, first, the deprotonation of substituted chiral pyridine N-oxides and second, the oxidative dimerization of the resulting 2-lithiopyridine N-oxides. Optimization of the reaction conditions led to the selection of LiTMP in THF for the deprotonation and molecular iodine as the oxidant. The corresponding 2-iodopyridine N-oxide is invariably formed as a by-product. A series of 11 chiral pyridine N-oxides was prepared that bear substituents at the C(2) and C(5) positions. Oxidative dimerization of these mono-N-oxides proceeded in 33–77% yield. In all cases, the dimerization was highly diastereoselective for the formation of the P-configuration of the chiral axis.

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(R)-1-[2-(5-Methylpyridyl)]-2,2-dimethylpropanolC11H17NO (177.25)Er = 97.8/2.2[α]D24=+28.4 (c 0.89, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)

(R)-5-Methyl-1-(1-butyloxy-2,2-dimethylpropyl)pyridineC15H25NO (235.37)Er = 97.8/2.2[α]D24=+37.8 (c 0.67, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)

(R)-5-Methyl-1-(1-butyloxy-2,2-dimethylpropyl)pyridine N-oxideC15H25NO2 (251.37)Er = 97.8/2.2[α]D24=+87.5 (c 0.535, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC30H48N2O4 (500.72)Er >99.9/0.1[α]D24=-39.7 (c 1.03, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(M)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC30H48N2O4 (500.72)Er >99.9/0.1[α]D24=+129.5 (c 0.74, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (M)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′- bis-(1-(2,4,6-trimethyl)benzyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC42H59N2O4 (653.43)Er >99.9/0.1[α]D24=-101.7 (c 1.27, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-(2,4,6-triisopropyl)benzyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC54H80N2O4 (822.62)Er >99.9/0.1[α]D24=-42.3 (c 0.50, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-(1-naphthylmethoxy-2,2-dimethylpropyl))-2,2′-bipyridine bis-N-oxideC44H49N2O4 (669.37)Er >99.9/0.1[α]D24=-80.9 (c 1.54, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-(naphthylmethoxy-2,2-dimethylpropyl))-2,2′-bipyridine bis-N-oxideC44H49N2O4 (669.37)Er >99.9/0.1[α]D24=-61.4 (c 1.80, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2-methyl-2-phenylpropyl)-2,2′-bipyridine bis-N-oxideC28H44N2O4 (472.66)Er >99.9/0.1[α]D24=+39.7 (c 0.67, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2-methyl-2-phenylpropyl)-2,2′-bipyridine bis-N-oxideC40H52N2O4 (624.42)Er >99.9/0.1[α]D24=+27.5 (c 1.01, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2,2-diethylbutyl)-2,2′-bipyridine bis-N-oxideC30H48N2O4 (584.88)Er >99.9/0.1[α]D24=-30.7 (c 1.34, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dibromo-6,6′-bis-(1-butyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC28H42Br2N2O4 (629.16)Er >99.9/0.1[α]D24=-29.9 (c 0.28, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)

(P)-(R,R)-3,3′-Dimethyl-6,6′-bis-(1-butyloxy-2,2-dimethylpropyl)-2,2′-bipyridine bis-N-oxideC32H57N2O4 (529.40)Er >99.9/0.1[α]D24=-39.4 (c 0.89, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (P)-(R,R)