Brønsted Acid‐Catalyzed Nucleophilic Substitution of Alcohols

Abstract

Abstract:Simple Brønsted acids such as p-toluenesulfonic acid monohydrate (PTS) or polymer-bound p-toluenesulfonic acid efficiently catalyze the direct nucleophilic substitution of the hydroxy group of allylic and benzylic alcohols with a large variety of carbon-and heteroatom-centered nucleophiles. Reaction conditions are mild, the process is conducted under an atmosphere of air without the need for dried solvents, and water is the only side product of the reaction.Keywords: alcohols; C À C coupling; nucleophilic substitution; supported catalysts; synthetic methodsThe construction of C À C bonds is a fundamental reaction in organic synthesis and coupling reactions between reactive nucleophiles (NuH) and halides (RX) or related species are one of the most used strategies. In this context, direct substitution of the hydroxy group in alcohols by nucleophiles could be considered as an ideal process because of the wide availability of the starting materials and the generation of H 2 O as the only side product. However, the main limitation of this strategy is that an excess of sulfuric acid, polyphosphoric acid, [1] or a stoichiometric amount of a Lewis acid [2] is required, and so the range of possible nucleophiles is limited. Therefore, the development of catalytic versions of this reaction remains as a major objective of the modern organic chemistry (Scheme 1). Recent advances in this field are based on the use of transition metal complexes as catalysts. Remarkable are the Ru-, [3] Re-, [4] and Au-catalyzed [5] propargylation of nucleophiles with propargylic alcohols, the Tsuji-Trost reaction of allylic alcohols with active methylene compounds, [6] the reaction of secondary benzylic alcohols with different nucleophiles catalyzed by La, Sc, or Hf salts, [7] and the Fe-, or Au-catalyzed arylation of benzylic alcohols.[8] In addition, InCl 3 has emerged as a powerful catalyst to perform direct nucleophilic substitution of allylic and benzylic alcohols. [9] Although the catalytic activation of alcohols is thought to be difficult due to the poor leaving ability of the OH group, we have recently found that simple Brønsted acids like p-toluenesulfonic acid monohydrate (PTS) catalyze the direct nucleophilic substitution of propargylic alcohols.[10] Herein we report a strategy involving simple Brønsted acid-catalyzed activation of allylic and benzylic alcohols as a method for the direct formation of new C À C and C À heteroatom bonds from carbon (active methylene compounds, aromatic and heteroaromatic compounds), nitrogen, sulfur, and oxygen nucleophiles and alcohols. Surprisingly, the Brønsted acid-catalyzed direct substitution of allylic alcohols has not been reported in the literature and so no systematic study has so far been performed. Moreover, in some recent papers this reaction has been reported not to proceed at all. [9b] Despite all these negative forewarnings, we decided to investigate the reaction of allylic alcohol 1a as a model substrate with selected nucleophiles 2-8 under PTS-catalyzed conditions (Sche...

Direct Nucleophilic SN1‐Type Reactions of Alcohols

“…[26] The use of PTSA was applied to the synthesis of bicyclo[3.1.0]hexanes. [27,28] In addition, an efficient one-pot propargylation/cycloisomerization tandem process catalyzed by PTSA was developed for the synthesis of substituted oxazole derivatives, starting from propargylic alcohols and amides. [29] An interesting approach to performing the reaction in the presence of a Brønsted acid involved the use of ionic liquids.…”

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

“…[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. Satisfactory results were obtained for starting compounds 11a,c,g,h bearing tertiary highly activated hydroxyl groups, which led to the corresponding dihydrobenzofuran derivatives 12a,c,g,h in high yield (Scheme 8).…”

Direct Substitution of the Hydroxy Group at the Allylic/propargylic Position with Carbon‐ and Heteroatom‐ centered Nucleophiles Catalyzed by Yb(OTf)3

“…However, in the p-toluenesulfonic acid catalytic system the reaction of allylic alcohols 1b and 1c with thiol afforded the product as a mixture of regioisomers. 16 n-BuSH was also suitable substrate for the substitution of cinnamyl alcohol and gave the desired product in an 87% yield (Table 3, Entry 12), despite that the reaction rate was decreased. Examples of direct substitution of the hydroxy group in alcohols by thiols are rare, to the best of our knowledge, the present result represents the first example of such reaction catalyzed by lanthanide complexes.…”