Intramolecular γ‐Hydroxylations of Nonactivated CH Bonds with Copper Complexes and Molecular Oxygen

Abstract

Copper(I) complexes incorporating the isomeric bidentate ligands IMPY (iminomethyl-2-pyridines) or AMPY (aminomethylene-2-pyridines) are quite unusual in their ability to bind and activate molecular oxygen. Using these complexes, hydroxylations of nonactivated CH, CH2, or CH3 groups in the gamma-position in relation to the imino-nitrogen atom, and with a specific orientation of one H atom with respect to the binuclear Cu-O species, can be achieved in synthetically useful yields. Through mechanistic studies employing conformationally well-defined molecules (for example, cyclic isoprenoids), coupled with solid-state X-ray structure analyses and force-field calculations, we postulate a seven-membered transition state for this reaction in which six atoms lie approximately in a plane. This plane is defined by the positions of the lone pairs on the nitrogen atoms, as well as the copper and the oxygen atoms. For a successful hydroxylation, one hydrogen atom should be located close to this plane. Prediction of the stereochemical course of these reactions is possible based on a simple geometrical criterion. The convenient introduction of IMPY and AMPY groups as auxiliaries into oxo and primary amino compounds and the simple hydrolysis after the hydroxylation procedure has allowed the synthesis of 3-hydroxy-1-oxo and 3-hydroxy-1-amino compounds. If desired, the 3-hydroxy-1-IMPY and -1-AMPY compounds can be reduced with NaBH4 to obtain 3-hydroxy-1-aminomethylpyridines. For a successful hydroxylation procedure, the method employed for the synthesis of the CuI complexes is very important. Starting either from CuI salts or from CuII salts with a subsequent reduction with benzoin/triethylamine may turn out to be the better way, depending on the ligand and the molecular structure.

Steroids as chiral model compounds for selective reactions with metals

“…In the case of the hydrolytic work-up procedure, the iminomethylpyridine (IMPY ligand) and the iminoethylpyridine ligand play an auxiliary role and can be simply removed after the hydroxylation procedure [44,45]. Conformational analysis by X-ray analysis and MMFF94 force field calculations for IMPY compound 42 indicate that a seven-membered ring with six atoms nearly in a plane (Fig.…”

“…Surprisingly, and in contrast to the results obtained with compound 42 (method B 50%, method A 29%), hydroxylation with method A [starting with copper(I) salts] resulted in better yields (34% for 60 and 31% for 64). In the case of (1R)-IMPY-camphor, we could isolate the stable c-hydroxylated IMPY-compound (64), which could be hydrolyzed to the (1R)-10-hydroxy-camphor (65) [45]. Reaction of the IMPY-compound 59 gave an interesting dependence of the stereoselectivity from the Scheme 17.…”

“…A C-ring conformation with a twist-boat form (Fig. 5B) will allow the hydroxylation in the 12a-position [45].…”

“…8.3. c-Hydroxylations with aminomethylenepyridino ligands (AMPY ligands) [45] In addition to the iminomethylpyridino ligands (IMPY ligands), we became interested in the isomeric aminomethylenepyridino ligands (AMPY ligands) [45]. These compounds are also simple to prepare by condensation of primary amines with pyridine-2-carboxaldehyde (Scheme 19).…”

“…Hydrolysis of the AMPY group after hydroxylation opens a route to 1,3-primary amino alcohols [45]. Scheme 19.…”