C-H bond functionalization. Some strategies.

As creating a new covalent bond usually requires the presence of either an heteroatom or a unsaturation in the carbon backbone, H attached to C is not considered a functional group. However, selective introduction of new functionalities directly through transformation of C-H bonds unlocks opportunities for different synthetic strategies. Let's focus on three of them that are real alternatives to longer and/or less mild classical procedures.

Intramolecular Radical Reactions

Over unactivated alkyl C-H bonds in complex substrates, regioselectivity is classically achieved by exploiting structural proximity between the high energy radical (transiently generated), and the alkyl group, resulting in intramolecular H abstraction. May be amazing to notice that, in this field, the earlier work by Hoffman started in the 1800 on the hydrolysis of haloamines to functionalise methyl groups. This reaction is know today as the Hoffman-Loffler-Freitag reaction.

Another (not so) earlier work is the photolysis of a nitrite ester as a means for converting an isolated methyl group into an oxime in one step. Although with a low yield, is a demonstration of the potential of C-H functionalization.

Intramolecular Transition Metal-Catalyzed Carbene and Nitrene Insertion

Carbenes can also serve as reactive intermediates for C-H functionalization. In contrast to carbenes, the corresponding transition metals carbenoids readily available by decomposition of diazocarbonyl substrates offer more control over the reaction course. In particular, the introduction of Rh dimeric catalysts has became a powerful tool, in which, for instance, diazocarbonyl substrates can be converted in one step to cyclic ketones, lactones and lactams by means of regioselective C-C bond formation at the alkyl site. These strategies provide a unique and straightforward strategy for preparation of valuable cyclic products.

C-N bond formation at an isolated alkyl site, achieved by transition metal-catalyzed nitrene insertion, can be formally viewed as a nitrene insertion, a process analogous to the carbene derivative. Cyclization of carbamate or sulfamate substrates is achieved with dimeric Rh, an oxidant and a base in a mild, regio and stereoselective process.

Both, carbene and nitrene insertion reactions may be an elegant synthesis for natural products or advanced intermediates.

Directed Metallation

Directed metallation entails the use of a suitable heteroatomic function to direct a metal complex. The resulting metallacycle serves as intermediate to C-C or C-X bond formation. Palladium metallacycles (palladacycles) are versatile catalyst to choice, as well as its Pt, Ru and Rh analogs. Other examples include the almost classical ortho-lithiation of arenes (stoichiometric in this case), and the Friedel-Crafts alkylation, which can have its catalytic alternative and perhaps with reversed regioselectivity, depending on the case.

Science, 312, 2006, 67