Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 27, 2006
Douglass Taber
University of Delaware

Pd-Mediated Arylation of Aromatic and Heteroaromatic Rings

Usually, aryl-aryl bonds are formed by the coupling of two functionalized aromatic carbons. Having both of the aromatic carbons functionalized is not always necessary. It is sometimes possible to directly arylate an aromatic ring, replacing a C-H bond with a C-C bond.

The intermolecular arylation works particularly well with electron rich heteroaromatics. For instance, Atsunori Mori of the Tokyo Institute of Technology has shown (Org. Lett. 2005, 7, 5083. DOI: 10.1021/ol052063y) that bromothiophene 1 couples with aryl iodides such as 2 under Pd catalysis to give the arylated thiophene 3.

Pyridines themselves are not sufficiently reactive, but Keith Fagnou of the University of Ottawa has found (J. Am. Chem. Soc. 2005, 127, 18020. DOI: 10.1021/ja056800x) that the corresponding N-oxides couple efficiently. The product N-oxides are easily hydrogenated to deliver the substituted pyridine 7. In a competition experiment, the 4-nitropyridine oxide was shown to be more reactive than the 4-methoxy pyridine oxide.

Dalibor Sames of Columbia University has developed conditions (J. Am. Chem. Soc. 2005, 127, 8050. DOI: 10.1021/ja043273t) for the direct arylation of indoles. By modulating the reaction conditions, arylation can be directed either towards C-2, to give 10, or toward C-3, to give 11. Note that although three related papers from the group were recently withdrawn (J. Am. Chem. Soc. 2006, 128, 3102. DOI: 10.1021/ja0699586, DOI: 10.1021/ja069957d, DOI: 10.1021/ja069956l), the work cited here was not affected.

Professor Fagnou has also demonstrated (Org. Lett. 2005, 7, 1857. DOI: 10.1021/ol050501v) the design of Pd catalysts that activate even aryl chlorides for cyclization. Carbocycles, cyclic ethers and amines, and lactams such as 13 are formed efficiently in this intramolecular reaction.

Direct intramolecular arylation is a method for specific homologation. In the course of a total synthesis (Angew. Chem. Int. Ed. 2005, 44, 3899. DOI: 10.1002/anie.200500466) of riccardin C (17), David C. Harrowven of the University of Southampton constructed the ester 14. Pd-mediated cyclization proceeded with a modest (5:2) preference for the para product 15.

Direct arylation can also be used for the construction of larger rings. Dirk Trauner of the University of California at Berkeley employed (Org. Lett. 2005, 7, 5207. DOI: 10.1021/ol052033v) Pd-mediated cyclization of 18 to 19 as the key step in the synthesis of rhazinilam (20).


D. F. Taber, Org. Chem. Highlights 2006, March 27.