# Rhodium-Catalyzed Homogeneous Asymmetric Hydrogenation of Naphthol Derivatives.
> ロジウム触媒による均一系不斉水素化：ナフトール誘導体から光学純粋テトラヒドロナフトールの合成


## Abstract

Asymmetric hydrogenation of naphthol derivatives to produce 1,2,3,4-tetrahydronaphthols has long been hindered by strong aromaticity and the difficulty of controlling chemo-, regio-, and enantioselectivity simultaneously. This study demonstrates the first homogeneous asymmetric hydrogenation of naphthol derivatives using tethered rhodium-diamine catalysts, achieving yields up to 98% and enantioselectivities exceeding 99% ee across a broad substrate scope. Mechanistic investigations combining experimental and computational methods established that the fluorinated solvent HFIP (1,1,1,3,3,3-hexafluoroisopropanol) is critical for both reactivity and selectivity. The reduction of 1-naphthol proceeds through a cascade sequence: dearomative tautomerization, followed by 1,4-hydride addition, and then 1,2-hydride addition. A synergistic activation model was proposed in which HFIP facilitates simultaneous activation of the hydrogen molecule and the naphthol substrate in the presence of base, with the transiently formed keto tautomer rapidly intercepted by Rh(III)-H before diffusing out of the solvent cage. This methodology enables efficient access to chiral intermediates relevant to pharmaceutical synthesis, including the first enantioselective preparation of optically pure Nadolol.

### Mechanism

HFIP synergistically activates both the hydrogen molecule and the naphthol substrate in the presence of base. The transiently generated keto tautomer undergoes sequential dearomative tautomerization, 1,4-hydride addition, and 1,2-hydride addition, with the Rh(III)-H species trapping the fleeting intermediate within the solvent cage.

## Bibliographic

- **Authors**: Zhang S, Long L, Li Z, He YM, Li SC, Chen H, et al.
- **Journal**: J Am Chem Soc
- **Year**: 2025 (2025-02-12)
- **PMID**: [39879104](https://pubmed.ncbi.nlm.nih.gov/39879104/)
- **DOI**: [10.1021/jacs.4c15673](https://doi.org/10.1021/jacs.4c15673)
- **Study type**: other
- **Delivery route**: not specified
- **Effect reported**: not assessed

## Delivery context

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

## Safety notes

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)

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> **Cite as**: H2 Papers — PMID 39879104. https://h2-papers.org/en/papers/39879104
> **Source**: PubMed PMID [39879104](https://pubmed.ncbi.nlm.nih.gov/39879104/)