Barton modification Hunsdiecker reaction

During the final stages of the asymmetric total synthesis of antimitotic agents (+)- and (-)-spirotryprostatin B, the C8-C9 double bond had to be installed, and at the same time the carboxylic acid moiety removed from C8. R.M. Williams et al. found that the Kochi- and Suarez modified Hunsdiecker reaction using LTA or PIDA failed and eventually the Barton modification proved to be the only way to achieve this goal. After the introduction of the bromine substituent at C8, the C8-C9 double bond was formed by exposing the compound to sodium methoxide in methanol. This step not only accomplished the expected elimination but also epimerized the C12 position to afford the desired natural product as a 2 1 mixture of diastereomers at C12. The two diastereomers were easily separated by column chromatography. 

The fourth modification of the Hunsdiecker reaction, pioneered by Barton, is the use of /-butyl hypoiodide.23 Thus, acid 16 was treated with /-butyl hypoiodide to give the acyl hypoiodite, which underwent white-light photolysis at room temperature to give iodide 17. The reaction works for primary, secondary, and tertiary acids. 

The last, but certainly not the least, is the Barton modification to the Hunsdiecker reaction.24-26 It involves decomposition of thiohydroxamate esters in halogen donor solvents such as CCU, BrCCh, CHI3, or CH2I2 promoted by a source of radical initiation, which could be radical initiator (e.g., 18—>20),24 thermal (e.g., 21—>22),25 or photolytic26 conditions. The Barton modification is highly compatible with most functional groups. For example, under photolytic conditions, acid 23 was converted to acid chloride 24, which, without isolation, was treated with the sodium salt of Z/-hydroxypyridine-2-thione (19) with bromotrichloromethane as solvent to give alkyl bromide 25 in 90% yield.26... 

The classical Hunsdiecker conditions using Ag, and modifications using metals such as Hg, Tl, Pb, and Mn(II), are not very synthetically useful because of the use of toxic metals, requirement of high temperature, and poor yields. As a consequence, many variants of greener chemistry have been developed to replace heavy metals. In addition to Barton s radical approaches, Roy et al. developed a metal-free Hunsdiecker reaction where the acid was treated with A-bromosuccinamide (NBS) and a catalytic amount of LiOAc27 or the phase transfer catalyst (PTC) tetrabutylammonium trifluoroacetate (TBATFA).28-30 As shown below, cinnamic acid 26 was converted to (B-bromostyrene 27 in almost quantitative yield.28 The authors also found that a mixture of 93 7 MeCN/H20 was also a good solvent for the metal-free Hunsdiecker reaction.29 In place of TBATFA, another phase transfer catalyst Select flur was found to be an efficient catalyst for the metal-free Hunsdiecker reaction as well (e.g., 29—>30).31... 

The difficulties inherent in the original Hunsdiecker reaction and its modifications stimulated the development of an additional halo-decarboxylation method that involves treatment of thiohydroxamic esters of carboxylic acids with BrCCls, ICH3 or CH2I2 in the presence of a radical initiator (Route 3, Barton reaction, Figure 10.23). 

Perhaloalkanes serve as bromination or iodination agents in the radical decarbox-ylative halogenation of carboxylic acids. In an interesting modification of the Hunsdiecker-Bodin reaction Barton and coworkers have applied iV-hydroxypyridine-2-thione esters as nonelectrophilic intermediates for the decarboxylative bromination and iodination of primary, secondary and tertiary aliphatic and alicyclic592, as well as aroma-... 

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