The Modified Hunsdiecker Reaction

The Hunsdiecker reaction is the treatment of the dry silver salt of a carboxylic acid with bromine in carbon tetrachloride. Decarboxylation occurs, and the product isolated is the corresponding organic bromide 16). Since dry silver salts are tedious to prepare, a modification of the reaction discovered by Cristol and Firth (77) is now 

CARBON-CARBON BOND FORMATION BY MISCELLANEOUS REACTIONJ 

The preparation of adamantane from readily available starting materials (Chapter 13, Section I) has opened the door to a study of its many substitution products, both from a chemical and a biological point of view (/). Adamantylamine hydrochloride for example, has been found to exhibit antiviral activity. Presented below are several procedures for the preparation of adamantane derivatives. 

Caution Because carbon monoxide is evolved, the reaction should be carried out in a hood. 

A l-Iiter, three-necked, round-bottom flask is equipped with a mechanical stirrer, a thermometer immersed in the reaction mixture, a dropping funnel, and a gas vent. In the flask is placed a mixture of 96% sulfuric acid (25.5 ml, 470 g, 4.8 mole), carbon tetrachloride (100 ml), and adamantane (13.6 g, 0.10 mole), and the mixture is cooled to 15-20° with rapid stirring in an ice bath. One milliliter of 98% formic acid is added and the mixture is stirred until the evolution of carbon monoxide is rapid (about 5 minutes). A solution of 29.6 g (38 ml, 0.40 mole) of t-butyl alcohol in 55 g (1.2 mole) of 98-100% formic acid is then added dropwise to the stirred mixture over 1-2 hours, the temperature being maintained at 15-20°. After stirring for an additional 30 minutes, the mixture is poured onto 700 g of ice, the layers are separated, and the aqueous (upper) layer is extracted three times with lOO-ml portions of carbon tetrachloride. The combined carbon tetrachloride solutions are shaken with 110 ml of 15 A ammonium hydroxide, whereupon ammonium 1-adamantanecarboxylate forms as a crystalline solid. This precipitate is collected by filtration through a fritted glass funnel and washed 

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In a modified procedure the free carboxylic acid is treated with a mixture of mercuric oxide and bromine in carbon tetrachloride the otherwise necessary purification of the silver salt is thereby avoided. This procedure has been used in the first synthesis of [1.1.1 ]propellane 10. Bicyclo[l.l.l]pentane-l,3-dicarboxylic acid 8 has been converted to the dibromide 9 by the modified Hunsdiecker reaction. Treatment of 9 with t-butyllithium then resulted in a debromination and formation of the central carbon-carbon bond thus generating the propellane 10." ... 

Hmtsdiecker Cristol reaction. (I, 657). A detailed procedure for the preparation of l-bromo-3-chlorocyclobutanc by the modified Hunsdiecker reaction has been published. A l-l. three-necked, round-bottomed flask wrapped with aluminum foil to exclude light and equipped with a mechanical stirrer, a reflux condenser, and an addition funnel, is charged with 37 g. (0.17 mole) of red mercuric oxide and 330 ml. 

Bromotrithiatriazepine 8 can also be obtained from the carboxylic acid 6 in 52 % yield by a modified Hunsdiecker reaction involving irradiation of a mixture of the acid, bromine, mer-cury(II) oxide and carbon tetrachloride. The iodo derivative is formed when iodine is employed418... 

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

Modified Hunsdiecker reaction. Primary carboxylic acids are converted into thallium(I) carboxylates by reaction with T12C03. The salts are not isolated, but treated with Br2 (1.5 equiv.) to give primary alkyl bromides (equation I).1... 

This is a modified Hunsdiecker reaction which avoids some of the difficulties associated with the use of heavy metals, i.e. troublesome work up procedures and the need to use an excess of toxic oxidant. For this transformation there is no need to convert the acid into its PhI(02CR)2 derivative, since it is formed in situ using DIB. 

The best yields (51-89%) were for substrates with R1 =H and phenyl rings (R2 and/or R3), especially when containing an electron-donating group. This modified Hunsdiecker reaction was equally successful with DIB conventional methods for this transformation of a,/J-unsaturated acids gave poor results. DIB has also been used for the photochemical halodecarboxylation of acids (Section 4.8.1). 

Tliis procedure, which is a modified Hunsdiecker reaction bused upon the method of Cristol and Firth, results in moderate 1(1 liigli yields of bromides and iodides from aliphatic and alicyclic carboxylic acuds, Carbon tc trachloride is most li cipiciiUy used as the solvent, but others can be einjiloycd. - ... 

The classical Hunsdiecker reaction was utilized in the laboratory of P.J. Chenier for the preparation of a highly strained cyclopropene, tricyclo[3.2.2.0 " ]non-2(4)-ene. The Diels-Alder cycloaddition was used to prepare the bicyclic 1,2-diacid, which surprisingly failed to undergo the Cristol-Firth modified Hunsdiecker reaction, most likely due to the unreactive nature of the diacid mercuric salt. However, the classical conditions proved to work better to afford the bicyclic 1,2-dibromide in modest yield. Treatment of this dibromide with f-BuLi generated the desired strained cyclopropene, which was trapped with diphenylisobenzofuran (DPIBF). 

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 dibromide itself was obtained from the corresponding dicarboxylic acid by a modified Hunsdiecker reaction. This method could also be applied to the generation and trapping of highly strained cyelopropenes such as bicyclo[4.1.0]hept-l(6)-ene, bicyclo[3.1.0]hex-l(5)-ene, and tricyclo[3.2.2.0 ]non-2(4)-ene (2) which was trapped in the presence of 1,3-diphenylisoben-zofuran, although two stereoisomers of the product were reported. ... 

The degradation of carboxylic acids to alkyl halides using mercuric oxide and halogens involves the initial formation of the mercuric salt of the acid, followed by a normal Hunsdiecker reaction of the salt with halogen. The relative insensitivity of the reaction to water is a consequence of the solubility of the mercury salts in the solvent (CC14). There are two limitations tertiary acids are not degraded, and use of iodine as the halogen frequently leads to the ester RCOOR as the major product. The yields in the modified reaction are usually lower than those obtained with the silver salt method.2... 

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