Mitsunobu esterification reaction

Furthermore, the apphcabihty in a Mitsunobu esterification reaction and a Diels-Alder reaction was proven (Scheme 10.13). The polymer-bound benzyl alcohol (70) was reacted with 4-acetamidophenol in the presence of the Mitsunobu reagent to give phenyl ether (71) in quantitative yield. It was released from the polymeric support in high yield. 

Camp, D., Jenkins, I. D. The mechanism of the Mitsunobu esterification reaction. Part I. The involvement of phosphoranes and oxyphosphonium salts. J. Org. Chem. 1989, 54, 3045-3049. 

In the Mitsunobu esterification reaction, an alcohol can be converted to a carboxylate ester as indicated in (12.338). Conversions to an azide, an iodide and other compounds has also been carried out with this kind of reaction involving Ph3P -i- EtOOCN=NCOOEt. 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

Transesterification under strongly basic reaction conditions has been used to acy-late support-bound alcohols with alkyl esters (Entry 10, Table 13.12). For sensitive acids, the Mitsunobu reaction is a particularly mild method of esterification. This reaction gives high yields with support-bound primary aliphatic alcohols and proceeds under essentially neutral reaction conditions (Experimental Procedure 13.4). Mitsunobu esterification of PEG with /V-Fmoc amino acids has also been reported [172]. 

Carbonates,4 Alcohols can be converted into the carbonates, ROCOOR, by reaction with CO, in THF under conditions of Mitsunobu esterification. Isolated yields (five examples) are in the range 40-80%. 

There are two problems. Enolates of primary amides are not very practical as the NH protons are more acidic than the CH protons. The solution is to use the nitrile and hydrolyse it later to the amide. A more serious problem is that the Sn2 reaction we want to use to couple the two together will go with inversion and that will give the biologically inactive enantiomer of darifenacin. The solution is a double inversion. Protection of the amine by tosylation 67 is followed by tosylation of the alcohol with inversion using a Mitsunobu-style reaction. This unusual esterification goes reliably with inversion.20... 

The reaction of an alcohol and a carboxylate anion with diethyl azodicarbox-ylate EtOOCN=NCOOEt and PhsP is called the Mitsunobu esterification reac-tion. This reaction can also be considered as an 8 2. Other Mitsunobu catalysts are available, " and a polymer-bound phosphine has been used. A renewable phosphine ligand has been developed. Note that other functional groups, including azides and thiocyanates can be generated from alcohols using Mitsunobu conditions. 

Carboxylic acids can be attached to these linkers using methods of ester bond formation such as carbodiimide/DMAP [23] and acid chloride/base. For the loading of N-protected-a-amino acids in particular, an array of different methods has been developed to minimize enantiomerizahon and dipeptide formation during the esterification reaction. These include the use of MSNT/N-methylimidazole [24], mixed anhydrides generated with 2,6-dichlorobenzoyl chloride [25], esters of 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene [26] and acid fluorides [27]. Phenols and N-protected hydroxylamines have been immobilized using the Mitsunobu reaction [28, 29], The latter are particularly useful for the preparation of hydroxamates [29, 30],... 

Intramolecular coupling of 120 having an aryl iodide group and a vinylstannane group accomplished the total synthesis of (-)-zealarenone (99) (Scheme 19) [77]. The first total synthesis of macrolactin A (124) was efficiently accomplished based on the Stille reaction of 122 for both stereospecific construction of the diene moieties and closure of the 24-membered macrocyclic ring [78]. The key precursor 122 was synthesized via two Stille couplings and Mitsunobu esterification. An alternative route to the dimethyl ether 125 was reported by cyclization of 123, which was prepared by the Stille and Suzuki couplings followed by DCC-DMAP esterification... 

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. 

The synthesis of the second building block [62] for meropenem starts from trans-hydroxyproline. First, the amino acid is protected on both, the amino and the carboxyl group. By reaction with thioacetic acid m a Mitsunobu esterification, the thiol ftmction is introduced, and the carboxyl group is then selectively deprotected with trifluoroacetic add. The dimethylamino-group is introduced with the aid of isopropyl chloroformate, and the thiol acetate is finally hydrolysed with aqueous sodium hydroxide. 

Finally, because benzoic acid is an excellent partner in the Mitsunobu reaction, benzoate formation with inversion has been used to prepare protected variants of relatively rare carbohydrates from readily available precursors. Thus, Mitsunobu esterification at the 3- and 6-positions in methyl (3-D-glucopyranoside proceeded with inversion of the C-3 configuration to provide an efficient synthesis of methyl 3-D-allopyranoside after Zemplen methanolysis (Figure 2.49). The a-anomer was reactive only at the 6-position (to maintain the gluco-configuration) under the same conditions [67]. 

Solid-supported triphenylphosphine, first reported by Havens et al. in 1983 for an esterification reaction, has found extensive applications in Mitsunobu chemistry. For example, the preparation of aryl ethers from amino alcohols has been carried out interestingly, addition of triethylamine led to better conversion in some cases. " More recently, Pelletier et al. prepared a series of primary amines by reaction of a primary alcohol in the presence of (Boc)2NH, TBAD and solid-supported TPP. Typical reported yields were in excess o l5% ... 

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