Alcohols reaction with diisopropyl azodicarboxylate

Various p-amino thiols are synthesized from the corresponding P-amino alcohols 1 by activation of the hydroxy group to form a tosylate intermediate 2 and then conversion into a thioester 3 5 or direct thioacetylation of the hydroxy group of 1 using the Mitsunobu reaction with diisopropyl azodicarboxylate, triphenylphosphine, and thiolacetic acid as reagents (Scheme l). 6,7 The thioesters 3 are then hydrolyzed and the corresponding disulfide derivatives 4 are produced by iodine oxidation. 7 ... 

Imino ethers and 2-alkoxybenzthiazolium salts prepared from chiral alcohols react with carboxylic acids to give the esters of the corresponding inverted rdcohols (Scheme 39).7ic.72d,73,75a reaction of a chiral alcohol with a carboxylic acid, DEAD and PhsP affords the ester of the inverted alcohol (Scheme 44). 2 Diisopropyl or dimethyl azodicarboxylate can be used instead of DEAD. Little difference between these reagents has been reported. ... 

This reaction was initially reported by Fukuyama and co-workers in 1995. It is a two-step conversion of primary amines into secondary amines via ortho-nitrobenzenesulfonation in conjunction with the Mitsunobu Reaction and subsequent removal of the o-nitrobenzenesulfonyl group by thiophenol. Therefore, this reaction is generally known as the Fukuyama amine synthesis. In addition, it is also referred to as the Fukuyama-Mitsunobu A -alkylation," Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama-Mitsunobu Reaction. In this reaction, the o-nitrobenzenesulfonyl-protected amine is alkylated with alcohol in the presence of PPhs and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection occurs in a very mild condition (almost neutral ). The o-nitrobenzenesulfonyl group is simply called the Fukuyama sulfonamide protecting groupThis reaction has become a versatile method... 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

Resin 23 was first swollen in CH2CI2 and, in a manner that parallels the route employed in the solution-phase synthesis, was reacted with a selected benzylsulfonyl chloride and t-BuOLi as a base to afford the corresponding sulfonamide resin 28, containing the first diversity element R. The sulfonamide resin 28 was then reacted under Mitsunobu conditions (PPha (triphenyl phosphine), DIAD (diisopropyl azodicarboxylate), THE, room temperature) with the appropriate alcohols. This process efficiently produced resin 29 and introduced the second diversity element R. Cyclization reaction of resin 29 was promoted by sodium hydride in DMF and led to the formation of the desired thiazolo[4,5-c] [l,2]thiazine resin 30. Treatment of resin 30 with mCPBA in CH2CI2 generated the resin-bound cyclic sulfonamide 31. Finally, the thiazolo[4,5-c][l,2]thiazine derivatives 5 were formed and cleaved from the resin (in a traceless manner" ) by treatment of resin 31 with the corresponding amines (R R" N diversity elements) in respectable yields (34 examples, from 11% to 29% for seven linear steps starting with Merrifield resin 1, Table 10.4). 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

---