Triphenylphosphine—Diisopropyl azodicarboxylate

THIOL ESTERS Chlorodiphenylphosphine. Diphenylphosphinyl azide. Polyphosphate ester. Sodium borohydride. 2,4,6-Trichlorobenzyl chloride. Triphenylphosphine-Diisopropyl azodicarboxylate-Thiolacetic acid. 

Hydroxymethyl-1,4-benzodioxin (137) obtained in 80% yield by reduction of ethyl 1,4-benzo-dioxin-2-carboxylate (39) with lithium aluminum hydride in refluxing ether <91TL5525> reacted with zinc azide bis-pyridine complex under Mitsunobu conditions (triphenylphosphine, diisopropyl azodicarboxylate) to yield exclusively compound (138) in 75% yield. Otherwise, (137) was first reacted with zinc iodide under the same conditions until complete transformation of the starting material into the mixture of regioisomers (139) and (140) excess of dry piperidine was then added to the crude reaction medium to yield the alkenic analogue (141) of Piperoxan <89TL1637>. 

The mechanistic pathway" " can be divided into three steps 1. formation of the activating agent from triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) 2. activation of the substrate alcohol 1 3. a bimolecular nucleophilic substitution (Sn2) at the activated carbon center. 

The 3-methyl- and 3-phenyl-l,2,3-oxadiazolinium salts 96 and 97 are capable of oxidizing thiols to disulfides <1995MI817>. New dihydro-1,2,3-benzoxadiazoles, prepared by the reaction of 1,2-benzoquinones with diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in the presence of triphenylphosphine (Section 5.03.9.4), have been shown to undergo catalytic hydrogenolysis to give phenols (Equation 12) <20050L5139>. 

A one-pot procedure for the conversion of alcohols into alkylamines is by treatment of the former with hydrazoic acid in the presence of triphenylphosphine and diisopropyl azodicarboxylate addition of triphenylphosphine to the resulting azide gives an hninophosphorane, which is hydrolysed to the alkylamine by water (equation 8)35. 

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-... 

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 ... 

The C-2 hydroxyl derivative with the unnatural configuration (2-Epi-Sl or 62) was synthesized using Mitsunobu conditions of triphenylphosphine (PPI13), diisopropyl azodicarboxylate (DIAD), and 4-nitrobenzoic acid as the nucleophile, which was subsequently hydrolyzed with K2C03 in MeOH to afford 62 in 64% yield over two steps [34]. Compounds 57 and 2-epi-Sl have been exploited as common intermediates in diversification of the C-2 position. Hydroxyl 57 has been utilized... 

A modified Mitsunobu procedure in which 63 is first treated with the preformed complex 68 (prepared by reaction of triphenylphosphine and diisopropyl azodicarboxylate) and then cesium thioacetate leads to significant racemization [17]. However, if the free acid is reacted instead with an appropriate thioacid (rather than the ester and a cesium salt), optical yields improve significantly. Thus, thioacetylation of (S)-l can be accomplished by treating it with 68 followed by the addition of thioacetic acid in THF to provide in 48% yield (5)-2-(acet-ylthio)-2-phenylacetic acid (69) with 84% ee after recrystallization. The low yield is due in part to the unavoidable formation to the extent of at least 50% of a viscous, polymeric material. The reaction is complete in minutes, however, and proceeds with retention of configuration. Presumably this is a result of a double inversion mechanism that passes through an a-lactone. Interestingly, the corresponding reaction with lactic acid does occur with inversion [18]. 

One such strategy exploits 142 for construction of the heterodiene 149, derived from azide 148, in which the stereochemistry of the intramolecular Diels—Alder cycloadducts is controlled by the configuration of the dienophile olefin. Treatment of 142 with diphenylpho-sphoryl azide in the presence of diisopropyl azodicarboxylate and triphenylphosphine affords the epoxy azide 148 with inversion of chirality. This is then converted in six steps to the heterodiene intermediate 149, which undergoes an intramolecular cycloaddition to fiimish a single adduct that is subsequently converted to 150. Transformation of 150 into 151 in seven steps completes the synthesis [59] (Scheme 36). 

With triphenylphosphine and diisopropyl azodicarboxylate, various ether end groups can be attached, e.g., methoxy groups with methanol, 2-methoxyethoxy end groups with ethylene glycol mono methyl ether, etc. 

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. 

A very mild method for the preparation of isocyanates from primary amines (RNH2) and carbon dioxide (CO2) involves the use of a Mitsunobu zwitterion generated from either diisopropyl azodicarboxylate (DIAD) or di-tert-butyl azodicarboxylate and triphenylphosphine or tri-n.-butylphosphine. 

Perfluoroalkylated fatty acid 6-esters of sucrose and aa-trehalose were prepared by a reaction of sucrose or a,a-trehalose with a perfluoroalkylated acid, Rf(CH2)rtCOOH (Rf = C4F9, C6F 3, or CgFi7, n = 2, 4, 10) in the presence of triphenylphosphine and diisopropyl azodicarboxylate in j/V,iV-dimethylformamide [262]. The surfactants were used to prepare fluorochemical emulsions intended as intravascular oxygen carriers (see Section 10.4). 

The Mitsunobu Reaction. A mixture of triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) is generally used however, diisopropyl azodicarboxylate (DIAD) is cheaper and works just as well. The overall reaction enables the replacement of the hydroxyl group of an alcohol by a nucleophile X (eq 1). 

The combination of DEAD and TPP has been utilized most often as the condensation reaction system, but dimethyl, diisopropyl, and di-r-butyl azodicarboxylates (6) can also be used instead of DEAD the azodicarboxamide (7) has been used as well. Triphenylphosphine can be substituted by a variety of trivalent phosphorus compounds, including substituted triarylphosphines and trialky Iphosphines. ... 

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