9-Azabicyclo[3.3.1]nonane N-Oxyl: An Efficient Organocatalyst

Basic Information

Chinese common name: 9-Azabicyclo[3.3.1]nonane N-oxyl  

English name: 9-Azabicyclo[3.3.1]nonane N-oxyl  

CAS No.: 31785-68-9  

Molecular formula: C8H14NO•  

Molecular weight: 140.20286  

EINECS No.: 803-697-7  

9-Azabicyclo[3.3.1]nonane N-oxyl (ABNO, CAS No. 31785-68-9) is a stable nitroxyl radical with a bicyclic structure. Compared with the classic TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl), ABNO has significantly lower steric hindrance and therefore exhibits higher reactivity. Its unique bicyclic skeleton fully exposes the nitroxyl radical active site, enabling more efficient interaction with substrate molecules.

1. Key Advantages

Higher reactivity and broader substrate scope

The most prominent advantage of ABNO lies in its unhindered molecular structure. The four methyl groups in TEMPO create significant steric hindrance, limiting its efficiency in oxidizing sterically bulky alcohol substrates. In contrast, the bicyclic skeleton of ABNO fully exposes the active site, allowing efficient oxidation of various alcohols including primary, secondary, allylic, benzylic, and aliphatic alcohols. Under identical conditions, reactions catalyzed by ABNO are usually complete within 1 hour, whereas TEMPO systems require several hours or may not proceed at all. With a catalyst loading of only 0.01 mol%, ABNO affords an 81% product yield, while TEMPO gives only 23%.

Mild reaction conditions and environmental friendliness

ABNO can efficiently catalyze the oxidation of alcohols to the corresponding aldehydes or ketones using oxygen from air as the oxidant at room temperature and atmospheric pressure. The system requires no high temperature or pressure and no stoichiometric chemical oxidants, with water as the only by-product. These features align with the core principles of green chemistry, making it a preferred green chemistry alternative.

Excellent functional group compatibility

The ABNO catalytic system exhibits good tolerance toward various functional groups, enabling selective oxidation in complex molecules containing sensitive functionalities. This property makes it particularly suitable for late-stage functionalization of drug molecules and other fine chemical synthesis scenarios.

2. Representative Applications

Selective catalytic oxidation of alcohols

The core application of ABNO is as a selective oxidation catalyst for alcohols. Combined with Cu(I) salts such as (MeObpy)CuOTf, the catalytic system can efficiently oxidize various primary and secondary alcohols at room temperature under air, achieving isolated yields above 90% within 1 hour. Representative results include: oxidation of benzyl alcohol to benzaldehyde in >99% yield, 1-phenylethanol to acetophenone in 98% yield, cinnamyl alcohol to cinnamaldehyde in 98% yield, and cyclohexanol to cyclohexanone in 94% yield.

An iron/ABNO system with Fe(NO3)3·9H2O can also efficiently catalyze the aerobic oxidation of alcohols at room temperature in air. A Bi(NO3)3/ABNO system has also been reported to achieve efficient conversion of alcohols to carbonyl compounds under mild conditions.

Aerobic oxidation of amines to imines

In 2012, it was reported that ABNO (specifically keto-ABNO) can serve as an efficient catalyst for the aerobic oxidation of amines to imines under mild conditions. The reaction uses oxygen from air as the oxidant and proceeds under mild and operationally simple conditions.

Oxidative coupling of alcohols and amines to synthesize amides

The Cu/ABNO catalytic system enables oxidative coupling of alcohols and amines to directly construct amide bonds. The reaction proceeds at room temperature and is applicable to all four combinations of benzylic/aliphatic alcohols and primary/secondary amines, providing a green and efficient route for amide synthesis.

Oxidative lactonization and oxidative cyclization of diols

The Cu/ABNO system can efficiently catalyze the aerobic oxidative lactonization of both symmetric and sterically hindered unsymmetric diols. In addition, the system can catalyze the oxidative coupling of diols with primary amines to construct N-substituted pyrroles in a single step.

Electrochemical oxidation reactions

ABNO also shows good application prospects in electrochemical oxidation. It can be used for the selective electrochemical Shono-type oxidation of pyrrolidines to prepare pyrrolidinones with high selectivity.

Protein modification and chemical biology

The applications of ABNO and its derivatives have expanded from small-molecule synthesis to protein modification. keto-ABNO can be used for selective oxidative cleavage of serine and selective bioconjugation of tryptophan. ABNOH-linked nucleotides have also been used for bioconjugation and crosslinking studies of DNA.

Preparation of sodium pyruvate

In the synthesis of sodium pyruvate, ethyl pyruvate can be prepared by catalytic oxidation using air as the oxidant, 9-azabicyclo[3.3.1]nonane N-oxyl radical as the catalyst, and sodium nitrite as the co-catalyst, followed by hydrolysis and neutralization to give sodium pyruvate. Under these conditions, the yield of ethyl pyruvate can reach 92%, and the yield of sodium pyruvate can reach 93%.

9-Azabicyclo[3.3.1]nonane N-oxyl(ABNO) has become a highly regarded efficient organocatalyst in organic synthesis, owing to its unhindered molecular structure, excellent catalytic activity, mild reaction conditions, and broad substrate scope. Whether in the selective oxidation of alcohols, conversion of amines to imines, green construction of amide bonds, or cutting-edge fields such as electrochemical oxidation and protein modification, ABNO shows broad application prospects. With the continuous advancement of green chemistry and sustainable catalysis, the application value of ABNO as an efficient and environmentally friendly catalytic tool will continue to be explored and expanded.