Remote intramolecular hydrogen

The transfer of a proton between an acidic and a basic group within the same molecule is often more complex than the process shown in (1). The proton may be transferred along hydrogen-bonded solvent molecules between the acidic and basic groups if these are too remote to permit formation of an intramolecular hydrogen bond. Alternatively, two inter-molecular proton transfers with an external acid or base may be necessary. Tautomerisation of oxygen and nitrogen acids and bases (3) will be described in Section 6. The reactions are usually quite rapid and fast reaction... 

Remote photocyclization of (dibenzylamino)ethyl benzoylacetate. Intramolecular hydrogen abstraction through a ten-membered cyclic transition state. Journal of the Chemical Society, Chemical Communications, 363-364. 

Hydrogen abstraction can occur intramolecularly and is useful for functionalizing rather remote unactivated sites. With freely rotating alkyl systems, there is a great preference for a five- or six-membered cyclic transition state. With rigid or conformationally restricted systems, molecular models are necessary to predict the site of intramolecular hydrogen abstraction. 

Intramolecular hydrogen abstraction by a photochemically generated alkoxyl radical has been employed in remote functionalisation of non-activated carbon atoms,and the stereoisomeric a-iodo epoxides (128) are formed by irradiation of 5-hydroxy-5/3-cholest-3-ene (129) in benzene containing mercury(II) oxide and iodine. 

Intramolecular hydrogen abstraction by excited nitrobenzene derivatives may lead to the introduction of an oxidized functional group in a remote part of the molecule, as previously reported by Scholl and Van De Mark.63 Japanese workers have now extended this reaction to the preparation of some oxidized derivatives of the triterpene dammaranediol.64... 

Photoinduced remote cyclization of amino ketones provides modest yields of mixtures of the cis and trans isomers of oxazocinones (79 R = H, = H, Ph, R = H, Ph R = Me, R = R = Ph) (Scheme 21), resulting from intramolecular hydrogen abstraction by the photoexcited ketone in a ten-membered transition state <85CC363,90JCS(Pl)90l). 

Both substitution and addition reactions can occur intramolecularly. Intramolecular substitution reactions that involve hydrogen abstraction have some important synthetic utility, since they permit functionalization of carbon atoms relatively remote from the initial reaction site. The preference for a six-membered cyclic transition state in the hydrogen-abstraction step imparts considerable selectivity to these intramolecular hydrogen abstractions. An important example of this... 

Many other workers have taken independent advantage of this tendency of radicals to undergo intramolecular hydrogen transfer through 6-membered cyclic transition states to yield highly specific products as in the Barton reaction (20) Most recently, the concept has been extended by Breslow to highly specific substitutions at much more remote sites in the steroid series.(21)... 

Section 12.5 in Part A describes some additional reactions that are of synthetic value and involve intramolecular hydrogen abstraction at unactivated groups. Of particular note is a method, known as the Barton reaction, in which nitrite esters of alcohols are photolyzed. Nearby hydrocarbon groups, including methyl groups, can be functionalized by this method, and the reaction has been applied to remote functionalization in steroids. 

Remote Oxidation.—Remote oxidation reactions generally involve intramolecular hydrogen abstraction. The best known example is the Barton reaction (photolysis of nitrite esters). "- One of the most important applications of this reaction was to the synthesis of aldosterone acetate. The yield of this reaction has been substantially improved (55%) by irradiating the dienone nitrite ester (172) in which the extended conjugation ensures that sufficient separation between C-19 and the 11/3-oxygen atom exists to suppress functionalization at C-19 in favour of attack at C-18. Another recent application of the Barton reaction occurred in the synthesis of perhydrohistrionicotoxin (175), where the key step was the stereoselective formation of the oxime (174) from the nitrite ester (173). °... 

Hasegawa, X, Miyata, K., Ogawa, T., Yoshihara, N., and Yoshioka, M., Remote photocychsation of (dibenzylamino) ethyl benzoylacetate. Intramolecular hydrogen abstraction through a ten-mem-bered cyclic transition state, /. Chem. Soc., Chem. Commun., 363, 1985. 

The billiard reaction, a second intramolecular hydrogen abstraction from a 1,3-diaxially located methyl group by a carbon-centered radical, initially generated by an alkoxyl radical was observed in the remote functionalization of certain triterpenoids and diterpenoids by a thermal hypoiodite reaction with lead tetraacetate-iodine by Wenkert and Milari in 1967. Recent work by Suarez indicates that similar results can be achieved by the photolysis of hypoiodites in the presence of (diacetoxyiodo)benzene-iodine (Scheme 21). Scheme 22 outlines the reaction path. 

The selectivity observed in most intramolecular functionalizations depends on the preference for a six-membered transition state in the hydrogen-atom abstraction step. Appropriate molecules can be constmcted in which steric or conformational effects dictate a preference for selective abstraction of a hydrogen that is more remote from the reactive radical. 

In less repetitive syntheses, it is possible to use remote functional groups as "control elements", a technique which depends more upon the opportunist tactics developed in the course of a synthesis rather than of a premeditated strategy. Such is the case, for instance, of the synthesis of strychnine (i) by Woodward [2], in which after synthesising the intermediate 2 a hydrogen at C(8) must be introduced onto the P-face (4), i.e., onto the most hindered concave face of the molecule (Scheme 8.1). Usually the reduction with a metal hydride would lead to the a-C(8)-H isomer (i.e., the hydride ion will atack from the less hindered face of the molecule), however in the present case the P-OH group at C(21) acts as a control element and, besides the reduction of the amide at C(20), a hydride ion attacks at C(8) from the P-face by an intramolecular transfer of the complex C(21)-0-Al-H (3). 

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