Catalytic Phosphorus(V)-Mediated Nucleophilic Substitution Reactions: Development of a Catalytic Appel Reaction

Abstract

Catalytic phosphorus(V)-mediated chlorination and bromination reactions of alcohols have been developed. The new reactions constitute a catalytic version of the classical Appel halogenation reaction. In these new reactions oxalyl chloride is used as a consumable stoichiometric reagent to generate the halophosphonium salts responsible for halogenation from catalytic phosphine oxides. Thus, phosphine oxides have been transformed from stoichiometric waste products into catalysts and a new concept for catalytic phosphorus-based activation and nucleophilic substitution of alcohols has been validated. The present study has focused on a full exploration of the scope and limitations of phosphine oxide catalyzed chlorination reactions as well as the development of the analogous bromination reactions. Further mechanistic studies, including density functional theory calculations on proposed intermediates of the catalytic cycle, are consistent with a catalytic cycle involving halo- and alkoxyphosphonium salts as intermediates.

Simple unprecedented conversion of phosphine oxides and sulfides to phosphine boranes using sodium borohydride

“…A very wide variety of all conceiveable reducing agents has been employed but none are problem-free. 1c Although hydride reagents have attracted some 20 recent attention, 2 at present silane reagents are the most commonly used, both in the laboratory and industrially. 4 A significant point in their favour is that, with care and with much process development, they can usually be made to stereospecifically reduce optically active phosphine oxides.…”

“…13 We also studied an enantiomerically enriched P-stereogenic case, (S)-methylphenylo-tolylphosphine oxide (of 93% ee). 20 Disappointingly, this gave racemic phosphine borane under a variety of reaction conditions. 22 It was our strong suspicion that this racemisation was induced by the presence of the chloride counter ion of the chlorophosphonium salt.…”

A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions

“…Two protocols for carrying out Appel reactions that are catalytic in phosphine oxide have been reported recently. 21,22,23 In the process of Denton and co-workers, oxalyl chloride reacts with the oxide to give chlorophosphonium 90 salt (vide infra), which in turn reacts with alcohol to give alkoxyphosphonium salt, resulting in alkyl chloride and regenerating phosphine oxide. Denton et.…”

“…Denton and co-workers 21,22 have used a sequence 60 based on the treatment of phosphine oxide with oxalyl chloride as the basis for their catalytic Appel reactions. They reported that their protocol was less efficient for reactions involving secondary alcohols.…”

An Efficient Conversion of Alcohols to Alkyl Bromides Using Pyridinium Based Ionic Liquids: A Green Alternative to Appel Reaction

“…Other notable synthetic procedures are the Mitsunobo reaction [3], the reaction of 2,4,6-trichloro- [1,3,5]-triazine (TCT) in DMF followed by addition of CH2Cl2 solution of the reactant alcohol [4], the reaction of alcohol with 2,3-trichloro-5,6-dicyanobenzo-quinone in the presence of triphenyl phosphine, CH2Cl2 and a phase transfer catalyst [5]. ROMP-gel supported triphenyl-phosphine [6], phosphorus(V) mediated nucleophilic substitution reaction [7] and finally the use of fluorous phosphine [8] besides others. The previously reported procedures suffer from the use of toxic and expensive reagents and further the use of triphenylphosphine makes product recovery difficult and time consuming specially due to the in situ formation of the phosphane oxide.…”