Decarboxylative rearrangement

EPR spectroscopy is usually used to calibrate the clock (i.e., to determine kc). The method described here uses EPR to detect the two radicals. These are the parent (R1 ) and the product (R2 ) of its reaction, be it cyclization, decarbonylation, decarboxylation, rearrangement, or whatever. The radical R1 is produced photochemi-cally in the desired inert solvent by steady and usually quite intense light irradiation of the EPR cavity. Typically, R1 and R2 attain steady-state concentrations of 10-8 to 10 6 M. 

Asymmetric decarboxylative rearrangement (Carroll rearrangement) of allyl a-acetamido-/3-ketocarboxylates, catalysed by a palladium complex modified with a chiral phosphine ligand, has been reported to give optically active /,5-unsaturated a-amino ketones with up to 90% ee (Scheme 92).135 The mechanism for the Carroll rearrangement is shown in Scheme 93. 

Pinhey utilized the decarboxylative rearrangement of 2 to the nor-alkyl pyridyl sulfide 3, oxidation to the corresponding sulfoxide and thermal elimination sequence in a simple transformation of podocarpic acid 4 into useful synthons 5 (for example, in vitamin D3 synthesis) for steroid CD-ring systems, as shown in Scheme l.8... 

A mild, but indirect, approach to oxidative decarboxylation involves a modification of the 0-acyl thiohydroxamate decarboxylative rearrangement (Section 5.4.6.1). An 0-acyl selenohydroxamate is photolyzed to give a noralkyl-2-pyridyl selenide which, after ozonolysis to the selenoxide, undergoes syn elimination to the alkene (equation IS). 

Hnally, a useful, although not strictly a radical, meAod of effecting decarboxylative oxygenation is Ae so-called carboxy inversion reaction. The activated acid is transformed into a mixed all l aryl diacyl peroxide which suffers decarboxylative rearrangement to Ae alkyl ester of the aryl acid. This reaction is particularly useful as it takes place wiA retention of configuration at the migrating center (equation... 

The simple photolytic or thermal decomposition of 0-acyl thiohydroxamates in benzene or pyridine as solvent yields the product of decarboxylative rearrangement, and not alkylbenzenes or alkylpyridines. However, photolysis in dichioromethane in the presence of protonated heteroaromatic bases results in the formation of alkylated heterocycles in good yield, as illustrated in equation (57). The great advantage of this latter method lies in the fact that the base to be alkylated is not used as the reaction solvent, which evidently permits the use of a much wider range of bases as trapping agents. 

Barton, D.H.R., Bridon, D., Fernandez-Picot, 1., and Zard, S.Z. 1987. The invention of radical reactions Part XV Some mechanistic aspects of the decarboxylative rearrangement of thiohydroxamic esters. Tetrahedron 43, 2733-2740. 

The oxidation of 1,4-dicarboxylic acids with LTA in benzene results in double decarboxylation with the formation of a double bond (equation 16). Similarly, the pyrolysis of the di-r-butyl peroxy esters of 1,4-dicarboxylic acids in high boiling solvents leads to the formation of double bonds (equation 17). The method is especially useful in so far as 1,4-diacids are readily available from Diels-Alder reactions using derivatives of mtdeic and fumaric acid as the dienophile. Apparently, application of the 0-acyl thiohydroxamate method to 1,4-diacids does not result in the formation of double bonds but rather in the product of double decarboxylative rearrangement (Section S.4.6.1). ... 

The electrochemical rearrangement of paraconic acids (CIV) [Eq. (52)], y-carboxy-3-lactones (CVI) [Eq. (53)] [168], and /6-keto carboxylic acid ethylene acetals (CVIII) [Eq. (54)] [169,170] has been known to proceed smoothly. y-Keto carboxylic acids (CX) and acetals (CXII) undergo decarboxylative rearrangement to afford esters (CXI and XCIII) as in Eqs. (55) and (56) [171,172]. 

Rearrangement. Transformation of 2-aIkenols to 3-amino-l-aUcenes can be performed via decarboxylative rearrangement of the derived carbamates, the iridium complex of 2B possesses activity for endowing chirality to the amines. When crotyl (J-ketoalkanoate and homologues are exposed to the iridium complex of 2A in the presence of DBU, rearrangement and decarboxylation occur, forming optically active l-aIken-5-ones. ... 

Decarboxylated rearranged ketone (CXVIII) C23H33 06 Amorphous + 150 69 ... 

In terms of generation and manipulation of O-acyl thiohydroxamates it is important to recognize that, in the absence of any other reagents, decarboxylative rearrangement to alkyl-2-pyridyl sulfides can occur (Scheme 7). This is the simplest free-radical reaction of Barton esters and is of preparative utility in its own right. A series of crossover experiments demonstrated that the only mechanism which oper-... 

The decarboxylative rearrangement of a considerable variety of 0-acyl thiohy-droxamates has been an ongoing interest within the Barton group and has led to a tuneable series of alkyl radical triggers which can be preselected to require either a normal tungsten lamp or a medium-pressure mercury lamp for activation [14, 15]. The reaction conditions for decarboxylative rearrangement of some representative derivatives are shown in Scheme 9. 

The decarboxylative rearrangement of 0-acyl thiohydroxamates is thus a very convenient method for the preparation of useful alkyl-2-pyridyl sulfides and functions well irrespective of the nature, primary, secondary, or tertiary of the intermediate alkyl radical. Some representative examples are collected in Scheme 10,... 

The congeneric 0-acyl esters of iV-hydroxypyridine-2-selenone can also be prepared since the corresponding selenohydroxamic acid is readily available by treatment of 2-bromopyridine-iV-oxide with sodium borohydride and selenium. As shown in Scheme 11, this variant of the decarboxylative rearrangement, when followed by ozonolysis and subsequent selenoxide elimination, provided a useful route to optically pure L-vinylglycine from a protected glutamic acid derivative [16]. 

Scheme 10. Decarboxylative rearrangement of 0-acyl thiohydroxamates to alkyl-2-pyridyl sulfides...

The reactions of disulfides, diselenides or ditellurides with O-acylthiohydroxamates provide an efficient method for the synthesis of unsymmetrical thio-, seleno-, and telluroethers respectively (Scheme 12). In this instance, low-temperature tungsten lamp photolysis is the best preparative method since competing decarboxylative rearrangement to alkyl pyridyl sulfides is problematic under thermal conditions [17]. 

In practice, since the decarboxylative rearrangement to alkyl pyridyl sulfides is the competing reaction, electron-withdrawing terminal alkenes have proven to be the most efficient traps [29]. Addition to electron-deficient alkynes is however only moderately effective. The Barton group have studied this facet of O-acyl thio-hydroxamate chemistry in considerable detail over the years, and some examples of the extensive range of richly functionalized adducts which can be produced are collected in Scheme 30. 

Decarboxylative rearrangement. Trimethylsilyl benzoates undergo this radical reaction with XeFj in CHjClj. Interestingly, the reaction in MeCN does not proceed with rearrangement, and the main products are arenes derived from aryl radicals. 

The common reaction mechanisms of chemical degradation of pharmaceutical compounds include hydrolysis, oxidation, isomerization/epimerization, decarboxylation, rearrangement, dimerization/polymerization, photolysis, and reactions with excipients and salt forms. Examples are shown in Table 7.6 Interested readers should consult reference books on drug stability for more information on degradation pathways [13, 22]. 

At pH 7.4 metal ions promote the non-decarboxylative pathway to the acid 2, most likely by enhancing the acidity of the H-2 proton (87BBA203). Notably, however, at pH 5.5, aluminium ions promote the rapid decarboxylative rearrangement of dopachrome leading to 5,6-dihydroxyindole 1 rather than the acid 2 (03MI1689). 

The presence of certain metal ions, especially Cu, Fe, Zn etc., in melanin biosynthesis, however, accelerates the non-decarboxylating rearrangement of dopachrome leading to the formation of DHICA rather than DHI (50, 190). 

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