Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 13, 2006
Douglass Taber
University of Delaware

Best Synthetic Methods: Carbon-Carbon Bond Formation

Carbon-carbon bond formation is central to organic synthesis. In the ideal, a homologation method will start with a common functional group, and proceed under mild conditions using non-toxic reagents. These standards are exemplified by the conversion of aryl bromides to nitriles reported (J. Org. Chem. 2005, 70, 1508. DOI: 10.1021/jo0481250) by Steven A. Weissman of Merck Rahway. Note that this reaction proceeds without supporting phosphine ligands for the Pd catalyst.

Jieping Zhu of the Insitut de Chimie at Gif-sur-Yvette has developed (J. Am. Chem. Soc. 2005, 127, 6926. DOI: 10.1021/ja0511220) an elegant procedure for the one-carbon homologation of aldehydes and ketones to the corresponding amide. The most efficient alternatives would have taken at least three steps.

Takeshi Takeda of the Tokyo University of Agriculture and Technology has found (Tetrahedron Lett. 2005, 46, 3157. DOI: 10.1016/j.tetlet.2005.03.062) that an N-aryl amide such as 6 can be efficiently homologated to the corresponding amines by Ti-mediated reductive condensation with a thioacetal.

The Wittig reaction, a staple of organic synthesis, is far from atom efficient. Andrew F. Parsons of the University of York has created (Org. Lett. 2005, 7, 1597. DOI: 10.1021/ol050292e) a promising alternative. Free radical addition of diethyl thiophosphite to a terminal alkene proceeds smoothly. The product phosphonothioate 11 is readily deprotonated with s-BuLi, and the resulting anion condenses smoothly with ketones to give alkenes.

Sulfoxides can also be used to homologate aldehydes and ketones. István Markó of the Université Catholique de Louvain has described (Org. Lett. 2005, 7, 2373. DOI: 10.1021/ol050649e) an optimized procedure based on SmI2 reduction of the benzoylated adduct. As with Julia-Lythgoe homologation, the products from aldehydes are predominantly E.

Transition metal catalyzed o-activation of aromatic C-H bonds has become a practical method for organic synthesis. In a recent advance, Bekir Çetinkaya of Ege University, Turkey has found (Tetrahedron Lett. 2005, 46, 2273. DOI: 10.1016/j.tetlet.2005.02.023) that the imidazolium ligand 18 activates the Pd sufficiently that even aryl chlorides can be used to o-arylate benzaldehydes. Aryl bromides lead to the doubly arylated products.

Nicholas E. Leadbetter of the University of Connecticut recently reported a “Pd-free” Suzuki coupling. He has now (J. Org. Chem. 2005, 70, 161. DOI: 10.1021/jo048531j) found that these reactions were indeed Pd catalyzed - the commercial Na2CO3 used in the reactions was found to contain 20 to 50 parts per billion Pd. Indeed, the couplings did not proceed with Pd-free K2CO3, but worked smoothly on addition of 100 ppb Pd(OAc)2. This corresponds to a turnover number of 1,250,000.

D. F. Taber, Org. Chem. Highlights 2006, March 13.