Decarboxylation Barton method

An alternative method is the deoxygenation of the anomeric carboxylic acid 52, producing 55 [27], The functionalized precursor, in particular the O-acyl-thiohydroxamate ester 54, which is formed in situ after exposure of the carboxylic acid 52 to the salt 53, is decarboxylated by the Barton method. 

The basic transformation that underlies the Barton method is outlined in Scheme 45, steps 1 and 2.152 Thermolysis in refluxing toluene or photolysis with a sunlamp rapidly converts a thiohydroxamate ester (32) to the decarboxylated pyridyl sulfide (33). This pyridyl sulfide is formed by addition of an alkyl radical R to the thiohydroxamate (32) followed by fragmentation of (34) as indicated. In the planning of addition reactions by the Barton method, it is usually assumed that the addition step 1 is rate limiting. However, there is now evidence that step 1 may sometimes be reversible and step 2 may be rate limiting.153... 

The Liu synthesis of Aa-methyl-A18-isokoumidine (137) (214) starts from L-tryptophan (138), which was transformed to intermediate 139 in six steps. The Dieckmann condensation of 139 afforded the /3-ketoester 140. Oxidative free radical cyclization of /3-ketoester 140, initiated with Mn(0Ac)3, H20/Cu/(0Ac)2 H2O, followed by the removal of the Na-protecting group, led almost quantitatively to 141. Hydrolysis and decarboxylation using the Barton method afforded, via compound 142, intermediate 143. Treatment of 143 with (CH3)2S = CH2/dimethyl sulfoxide (DMSO) THF yielded the epoxy derivative 144, which was reduced with A1H2C1 in THF to the, not yet naturally found, jVa-methyl-A18-isokoumidine (137) (Scheme 12). 

Substituent exchange in the 1,2,4-triazine ring is an extensively studied reaction, as in other systems. As earlier mentioned, the introduction of a hydrogen atom into the 1,2,4-triazine ring can be achieved by oxidation of hydrazino-l,2,4-triazines (306), as was shown for 3-hydrazino and 5-hydrazino compounds. Another method is by the decarboxylation of carboxylic acids (307). This reaction was used by Paudler and Barton for the preparation of the parent 1,2,4-triazine (1) by decarboxylation of the 3-carboxylic acid (66JOC1720), but decarboxylation of 5- and 6-carboxylic acids are also well-documented reactions. 

Loss of a carbon atom from the precursor need not always result. Barton and Crich have introduced a related procedure based on the chemistry of mixed oxalates, an example of which is provided in Scheme 49.159 Double decarboxylation is involved in the decomposition of oxalate precursors, such as (39). Unfortunately, there are indications that this method may to be limited to tertiary alcohols one secondary alcohol derived mixed oxylate did not fragment completely to the alkyl radical. 

Stereochemistry in radical reactions for organic synthesis has not been studied very extensively, because mild or low temperature-promoted radical reaction methods are extremely limited and the stereoselectivity in radical reactions is generally rather poor. Recently, however, stereoselective organic synthesis with radical reactions has become popular, since mild radical reaction methods such as the Barton decarboxylation, Et3B-initiated Bu3SnH reaction, etc. have been developed. Normally, low temperature-initiated radical reactions induce high stereoselectivity. 

The a-arylation of ketones, such as cyclohexanone, can be achieved using different methods. A convenient route by Pinhey et al.89), reacts cyclohexanone-2-carboxylic esters with aryllead triacetates in pyridine. The protection of the P-carboxylic ester prevents a,a-di- or even higher arylations in a -positions. The ester group can be removed by basic hydrolysis and mild thermal decarboxylation or by heating in wet dimethylsulfoxide with sodium chloride (120-180 °C)90). Barton et al. 91) have found a similar a-arylation route using the less electrophilic triphenylbismuth carbonate. In both cases probably the lead- or bismuth-enolates, respectively, are the first inter-... 

Barton Esterification Reductive Decarboxylation. O-Acyl thiohydroxamates or Barton esters are useful precursors of carbon-centered radicals via thermolysis or photolysis. Several different methods are available for converting carboxylic acids into Barton esters (eq 1). These reactions generally proceed via the attack of a 2-mercaptopyridine-N-oxide salt on an activated carboxylic acid that has either been preformed (acid chloride, mixed anhydride) or generated in situ (with 1,3-dicyclohexylcarbodiimide or tri-n-butylphosphine + 2,2 -dithiodipyridine-l,r-dioxide). However, HOTT has the distinct advantages of (1) being easy to prepare and handle without the need for any special precautions, (2) facilitates efficient Barton esterification of carboxylic acids, and (3) simplifies subsequent work-up and purifications by avoiding the need to remove by-products like 1,3-dicyclohexylurea. 

Barton made two interesting applications of the lead tetraacetate-iodine method. One effects smooth decarboxylation of primary and secondary carboxylic acids to I he corresponding iodides, as in the examples formulated. A 5% suspension of lead tetraacetate in carbon tetrachloride is stirred and irradiated with a tungsten lamp. The carboxylic acid is added, followed by iodine until the color persists. If... 

An excellent alternative to the classical Hunsdiecker reaction and its variants, which totally avoids the use of heavy metal salts and potent electrophilic reagents, consists of the simple photolysis or thermolysis of Barton esters in refluxing bromotri-chloromethane for the bromides or tetrachloromethane for the chlorides [4], The analogous decarboxylative iodination can also be achieved using iodoform as the reagent in a benzene/cyclohexene solvent system (Scheme 5). For the cases of vinylic and aromatic acids, where the usual problems of chain efficiency are encountered, the addition of azobisisobutyronitrile (AIBN) is also required [10]. Nevertheless, since this method can operate on both electron-rich and electron-poor aromatic systems, and moreover does not suffer from the competitive electrophilic aromatic bromination found with electron rich aromatics under normal Hunsdiecker conditions, this route to synthetically useful aryl iodides and bromides should find widespread application. 

The fundamental steps in the PTOC-thiol method are illustrated in Fig. 4 [10]. The radical source is one of Barton s PTOC esters or a related thiohydroxamic acid derivative [11, 12] these are made from the corresponding carboxylic acids. The acyloxyl radicals produced in the initiation step rapidly decarboxylate to give the radical of interest. This radical reacts with a hydrogen atom donor, a thiol in this... 

The last and the seventh synthesis of chaetomellic acid A was reported in 1997 by the Samadi group from CNRS, France [81]. This one step synthesis involves a Barton radical decarboxylation and gave 77% overall yield (Scheme 8). The method requires preparation of a thiohydroxamic ester of the corresponding alkyl acid followed by in-situ irradiation in the presence of citraconic anhydride and silica gel chromatography. The last intermediate in this synthesis is similar to the synthesis reported by Branchaud and Slate [75,76]. 

Many new methods for the preparation of alkanes by reductive removal of functional groups have been reported during the year. Barton and his co-workers have presented a new radical decarboxylation for the conversion of carboxylic acids into hydrocarbons. Following esterification with /ran5-9-hydroxy-10-phenylthio-(or -10-chloro-)9,10-dihydrophenanthrene, a primary, secondary, or tertiary carboxylic acid is smoothly reduced under neutral conditions by tri-n-butylstannane and a radical initiator (e.g. Scheme 1). Formation of phenanthrene... 

Next, alcohol 35 was transformed into 36 by reductive dehydroxylation via the nonisolated intermediate xanthate. Hydrolysis of the ester group in 35 to form 30 was followed by decarboxylation to generate 37 by using an improved Barton s method employed with HOTT (5-(l-oxido-2-pyr-idinyl) 1,1,3,3-tetramethylthiouronium hexafluorophos-phate) [35]. Treatment of 37 with TBAF furnished alcohol, which was converted into the proposed structure of paesslerin A by using scandium-catalyzed acetylation. Unfortunately, comparisons of the H- and C-NMR data of the synthetic compound with those reported for the natural product revealed that the substances are not identical. The 2D-NMR data for synthetic 29 are fiiUy consistent with the structure of the target. The result clearly demonstrates that a revision of the structure of natural paesslerin A is required (Scheme 4.17). 

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