Direct Nucleophilic S_N1‐Type Reactions of Alcohols

Abstract

In 2005, the ACS Green Chemistry Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the development of green chemistry and green engineering in the pharmaceutical industry. The Roundtable has established a list of key research areas including the direct nucleophilic reactions of alcohols. The substitution of activated alcohols is a frequently used approach for the preparation of active pharmaceutical ingredients. Alcohols are transformed into the reactive halides or sulfonate esters, thereby allowing their reaction with nucleophiles. Although the direct nucleophilic substitution of an alcohol should be an attractive process, as one of the byproducts from the reaction yields water, hydroxide is a poor leaving group that hinders the reaction. Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved through an SN1 reaction with catalytic amounts of Brønsted or Lewis acids. In this review, the approaches leading to a greener process are examined in detail, and the advances achieved to date in this important transformation are presented.

Exploring the Reactivity of α‐Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]‐Wittig Rearrangement and the Mechanistic Proposal Revisited

“…The direct nucleophilic substitution of -activated alcohols to build CX or CC bonds is nowadays a wellestablished methodology that avoids the transformation of hydroxyl groups into the corresponding halides or sulfonates for reacting with nucleophiles. [32] Different Lewis and Brønsted acidcatalyzed procedures have been developed in the last years for this reaction, which in the case of using aromatic groups as the nucleophilic partner could be considered catalytic FriedelCrafts reactions. [33] Taking advantage of our previous experience in this field, [34] we decided to use a simple Brønsted acid like 2,4-dinitrobenzenesulfonic acid (DNBSA) as catalyst for attempting the cyclization of a selection of alcohols 11.…”

Alkylation of Oxazolones and Related Heterocycles through an SN1 Reaction

“…We expanded the reaction scope by employing other interesting scaffolds such as pyrazolones or oxindoles, affording the final alkylated products in excellent yields. [19] Experimental Section General Procedure: Bis[4-(dimethylamino)phenyl]methanol (41 mg, 0.15 mmol, 1 equiv. ), the desired oxazol-5(4H)-one (0.225 mmol, 1.5 equiv.…”

Ferric chloride-catalyzed decarboxylative alkylation of β-keto acids with benzylic alcohols

“…Based on our experimental results, we propose the following reaction pathways for the catalytic decarboxylative alkylation of β-keto acids with benzylic alcohols (Scheme 1). Alcohol 2 is subjected to iron-catalyzed carbon-oxygen bond cleavage to give benzyl cation 7 [31−34], which reversibly reacts with alcohol 2 to generate ether 4 as an intermediate [21,35,36]. Benzyl cation 7 couples with β-keto acid 1 to give β-keto acid 5 via carbon-carbon bond-formation and β-keto ester 8 via carbon-oxygen bond-formation.…”