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Kharasch-Sosnovsky Reaction

22 October 2008 - Named reactions

What: Kharasch-Sosnovsky Reaction: copper catalysed allylic oxidation using an organic peroxide.
Who: reported by M. S. Kharasch and George Sosnovsky in 1958 ((DOI) DOI). In the original publication the reactants are cyclohexene and t-butyl perbenzoate with cuprous bromide and the reaction product is cyclohex-1-en-3-yl benzoate:

Why: many reagents react with alkenes to form dihydroxy derivatives. Free-radical based methods suffer from poor regioselectivity. One alternative method is selenium oxide based allylic oxidation.
Asymmetric: An early chiral catalysis system (1965) is based on t-butyl hydroperoxide and a chiral tartaric acid (Denney et al. DOI).Two almost identical adapted methods were reported in 1995 and based on a bisoxazoline ligand (Gokhale et al. DOI , Andrus et al. DOI). The compound (S)-cyclohexenyl benzoate thus obtained is a key intermediate in leukotriene B4 total synthesis.
Mechanism: (review: DOI). The reaction mechanism devised by Beckwith et al (DOI) contains the following steps:

Cu(I) cleavage of the perester to a Cu(II) species and t-butyloxy radical. Radical proton exchange between allylic position cyclohexene and tBuOH. Recombination of allyl radical with Copper acetate species forming a Cu(III) intermediate and finally pericyclic reductive elimination to product and regeneration of Cu(I).
In a recent mechanistic in-silico analysis the radical intermediates are skippped in favor of a direct reaction with pre-coordinated alkene and a RCOOCu(III)OR catalyst (Mayoral et al. DOI)
Deployment: Mukaiyama Taxol total synthesis step 44 to 45 is a variation.
Organic syntheses: OS 5:70

Named reactions: Nieuwland catalyst

23 June 2008 - OrgChem

The Nieuwland catalyst is a mixture of copper(I) chloride and potassium chloride or ammonium chloride in water used together with acetylene to form a mixture of vinylacetylene and divinylacetylene.

This reaction was first reported in 1931 by organic chemist / botanist / Catholic priest Julius Nieuwland (DOI). Vinylacetylene paved the way for the development of the first synthetic rubber neoprene through its hydrochloric acid adduct chloroprene.

The reaction is hazardous: the formation of explosive copper acetylide lurks and DVA itself as already noted by Nieuwland himself can neither be distilled nor handled without explosions varying in degree from rapid decompositions to violent detonations

The purpose of potassium chloride is to allow the concentration of the copper salt to be increased. The reaction mechanism has recently been re investigated (Tachiyama et al. DOI). In it, copper first forms a copper - acetylene pi complex and then an organocopper sigma complex with expulsion of a proton. This step is the rate-determining step as evidenced by a 4.7 kinetic isotope efect. This complex and another pi complex then dimerize in a step that still needs elucidation.

Sigma complexes of copper with acetylene can also be found in the Sonogashira coupling and the Cadiot-Chodkiewicz coupling.

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Named reactions: Frater - Seebach alkylation

14 June 2008 - OrgChem

The Fráter-Seebach alkylation is the stereoselective alkylation of chiral beta-hydroxy esters using superbases such as LDA or LiHMDS. This organic reaction was first reported by G. Fráter in 1979 (DOI DOI).

In the original Fráter publication the starting material is ethyl acetoacetate 1, stereoselectively converted to the beta-hydroxy ester 2 with Baker's yeast, converted to the dianion 3 with LDA and finally alkylated with iodomethane in HMPA to 4.

In the key step of this enolate alkylation the lithium ion present in the base coordinates to both oxygen atoms, effectively shielding one of the faces of the enolate complex. In this sense the reaction is an early example and predating the concept of memory of chirality.

Dieter Seebach in 1980 reported on a related reaction: the diastereoselective alkylation of an malic acid ester ( DOI) with the newly formed alkyl group in an anti relationship to the alcohol.

The Fráter procedure (almost identical to the original) was most recently employed in the total synthesis of 35-deoxy amphotericin B methyl ester (Carreira et al. 2008 DOI):

Kemp elimination

28 May 2008 - Named reactions

Name : Kemp elimination
What : Ring-opening reaction of a benzisoxazole by a base. The reaction product is a alpha-cyanophenol (See benzonitrile, phenol)
Year: 1973
Literature: DOI DOI DOI.

Researchers before Kemp have noted decomposition of certain oxazoles substituted at position 3 but Kemp was the first to attach a mechanism to it.
Mechanism: E2 elimination. Main evidence: general base catalysis, large KIE for D/H at 3-position, large leaving group dependence.
Main characteristics: irreversible reaction, highly exothermic, reaction rate strongly depends on base strength and solvent type. Large rate-acceleration with a carboxylic acid as 3-substituent accompanied by loss of carboxylic acid.

The Kemp reaction is occasionally used as a probe for bases for example BSA (DOI) and most recently in 2008 (DOI) with a set of different amines and an ionic liquid solvent. Interestingly in this particular research not the base strength but the base shape carries weight. For example, the reactivity of dibutylamine (acyclic) is 5 times that of pyrrolidine (cyclic) even though their base strength is comparable. The researchers attribute this effect to a degree of pre-ordering for this particular solvent.

The HLF-CRB reaction

25 May 2008 - Named reactions

The Hofmann-Löffler-Freytag reaction is over 100 years old but still inspires. This reaction is the earliest example of C-H bond activation and involves migration of an halogen atom in a haloamine along an alkyl chain following by ring closure.

The Baran lab has now introduced a HLF variation allowing for the synthesis of a 1,3-diol from the corresponding mono-ol (DOI) illustrated here with the conversion of menthol to isopulegol hydrate.

Basically what happens is carbamate formation with the isocyanate of trifluoroethylamine, bromination at nitrogen with acetylhypobromite, photochemical migration of bromine from nitrogen to tertiary carbon (requires the CF3 group), ring-closing reaction and imine formation with silver carbonate and finally hydrolysis with potassium carbonate.

Be aware of a long list of limitations: the method only works with benzylic or tertiary carbon positions, other functional groups such as alkene, amine, alcohol, carboxylic acid are not permitted. The method uses stoichiometric amounts of silver carbonate and unusual solvents trifluorotoluene and tetrabromomethane. Atom economy is poor as the oxygen donor is a heavy trifluoromethyl functionalized isocyanate.

Newman-Kwart rearrangement

03 May 2008 - Named reactions

Name : Newman-Kwart rearrangement
What : rearrangement reaction of O-aryl N,N-dialkyl thiocarbamate to S-aryl N,N-dialkyl thiocarbamate
Year: 1966
Literature: DOI DOI

Why: Convert phenols to thiophenols
Preceded by: Schonberg rearrangement

Kwart and Evans improved yields of the Schonberg reaction by letting the reaction take place in the gas phase or by replacing an alkoxy group in the thiocarbonate by a alkylamino group (thiocarbamate). Hydrolysis by sodium hydroxide yielded the mercaptan. Kwart also speculated on the direct desulfurization (Raney Nickel) of the carbamate to the hydrocarbon effectively opening a method for removing aromatic hydroxyl groups.

A year later Newman pretty much did the same.
The Kwart rearrangement was investigated in 2008 by a group of AstraZeneca researchers (DOI) who gave it a full microwave kinetic treatment. The reaction is promoted by electron-withdrawing groups at the aromatic para position and the entropy of activation is found to be strongly negative. These findings confirm a ipso substitution reaction mechanism with a four-membered transition state as in structure A.

The group also unearthed a competing bimolecular reaction path at higher reactant concentrations (reaction carried out in dichlorobenzene) with a corresponding 8-membered TS.

Schonberg rearrangement

02 May 2008 - Named reactions

Name : Schonberg rearrangement

What : rearrangement reaction O,O-diaryl-thiocarbonate to O-aryl,S-aryl thiocarbonate
Year: 1930
Literature: DOI DOI
Why: Convert phenols to thiophenols
Made obsolete by: Newman-Kwart rearrangement