Mitsunobu amines

In the synthesis of 3-fluoroamino acid 256 (Scheme 9.55), fluorination of alcohol 251 (R2 = H) with morpho-DAST afforded the desired alcohol only in low yield (10-25%). The same reaction of trimethylsilyl ether 251 (R2 = TMS) improved the yield (50%). The Mitsunobu amination of the secondary hydroxyl group in 254 successfully gives 255 in 89% yield. Starting from 250, several fluorinated a- and P-amino acids 257-259 have been prepared [31]. 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

An asymmetric synthesis of phosphonylated thiazolines has been described. The phosphonodithioacetate 46 was aminated with a chiral amino alcohol 47 to give the phosphonylated thioamide 48 in good yield. This was then cyclised using a Mitsunobu procedure to give the chiral thiazoline phosphonate 49 in good yields under mild conditions. Homer-Wadsworth-Emmons reaction of these phosphonylated thiazolines gave chiral vinylic thiazolines 50 <00S1143>. 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

Transformation of a primary amine to a secondary amine using 2,4-dinitro-benzenesulfonyl chloride and an alcohol. Also known as Fukuyama-Mitsunobu procedure. 

Introduction of a halogen atom into the amine component is not possible, but an alternative solution is represented by the use of ethanolamines 26, performing the cyclization under Mitsunobu or Mitsunobu-like conditions to give ketopiperazines. These compounds have been observed as side products in reactions promoted by... 

Reduction of the ester (100) with sodium borohydride gives the alcohol (101) which is converted to the primary amine (102) under Mitsunobu conditions, and the tertiary amine (103) via its mesylate (Scheme 24) <92JMC3691>. 

Both intermediates 43a and 43b were converted to the final molecule duloxetine (3), as described in Scheme 14.11. Therefore, route A involved direct transformation of the (5)-chloroalcohol 43a into the corresponding iodide, followed by amination and etherification. In contrast, route B consisted of Mitsunobu inversion of (R)-chloroalcohol 43b... 

Eine weitere Variante der Mitsunobu-Reaktion verwendet als Amin-Quelle Phosphorsau-re-tert.-butyloxycarbonylamid-diethylester. Auf diese Weise lassen sich ebenfalls aus Alkoholen primare aliphatische Amine in guten Ausbeuten herstellen1. 

Bifunctionally tagged Mitsunobu reagents 21 and 22, quaternary ammonium carbonate resin 65, tetrafluorophthalic anhydride (as a solution-phase linking reagent), and amine-functionalized resin 2 were used in a three-step solution-phase synthesis of a series of substituted hydroxypiperidines.39 No further purification (e.g., liquid-phase extraction or chromatography) was required, and products were isolated in good yields and purities. 

In another purine library synthesis, Schultz and co-workers attached a 6-aminomethylaniline side chain to the PAL linker1718 via reductive amina-tion (Scheme 5). Alkylation at the 9-position was achieved using Mitsunobu conditions and an SwAr reaction was used to functionalize the 2-position with amines. The final cleavage of the aniline was achieved using 90%... 

An oxidizing agent. Useful for the dealkylation of amines and the conversion of pyrimidines to purines. It is most often associated with triphenylphosphine (TPP) in the Mitsunobu reaction. Examples ... 

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