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Monday, September 12, 2005
Douglass Taber
University of Delaware

Best Synthetic Methods: Functionalization of Aromatic and Heteroaromatic Rings

Aromatic and heteroaromatic rings are the heart of pharmaceutical design. It is often less expensive to purchase a ring than to build it, so efficient methods for the selective functionalization of preformed aromatic rings are important.

In general, aromatic halogenation proceeds to give the para product. Jallal M. Gnaim of the The Triangle Regional R&D Center, Kfar-Qari, Israel, has developed (Tetrahedron Lett. 2004, 45, 8471. DOI: 10.1016/j.tetlet.2004.09.102) a procedure that selectively converts phenols such as 1 into the ortho chlorinated product 2. Meta substitution is even more elusive. William R. Roush, now at Scripps Florida, prepared (J. Org. Chem. 2004, 69, 4906. DOI: 10.1021/jo049426c) the valuable meta brominated phenol 4 by perbromination followed by selective reduction.

A common application of aryl halides is Pd-mediated coupling to form C-C bonds. Graham Meek of Chirotech Technology Ltd., Cambridge, UK has found (Tetrahedron Lett. 2004, 45, 9277. DOI: 10.1016/j.tetlet.2004.10.063) that the enamide 6 participates efficiently in Heck coupling. The product 7 is an excellent substrate for enantioselective hydrogenation, to give 8.

For some applications, it is useful to put a substrate on a solid support. Linkers that can be converted directly to desired functionality (“traceless”) are particularly valuable. Andrew M. Cammidge of the University of East Anglia and A. Ganesan of the University of Southampton independently (Chem. Commun. 2004, 1914, DOI: 10.1039/b408021a; 1916, DOI: 10.1039/b408166h) developed the polymeric sulfonyl chloride 9. The derived phenyl sulfonates are useful partners for transition-metal mediated cross coupling.

Direct alkylation of an unfunctionalized aromatic ring is usually much less expensive than cross coupling, even with an aryl chloride. This is not, however, usually a useful way to attach a linear chain, as such chains rearrange too readily under Lewis acid conditions. Chuan He of the University of Chicago has found (J. Am. Chem. Soc. 2004, 126, 13596. DOI: 10.1021/ja046890q) an Au catalyst that mediates the direct alkylation of an aromatic ring such as 12 with a straight chain triflate, without rearrangement, to give 13.

The functionalization of heteroaromatics is also important. Chi-Ming Che of the University of Hong Kong has found (Org. Lett. 2004, 6, 2405. DOI: 10.1021/ol049232j) that in situ oxidation of sulfonamide in the presence of a Ru porphyrin catalyst leads to a species that effects electrophilic amination of heteroaromatics such as 14, to give 15.

Heterocycles are often sufficiently electron rich that oxidative addition and subsequent coupling can be carried out even on chlorides. Iodides are, nonetheless, much more reactive. Morris Robbins of Brigham Young University has shown (Org. Lett. 2004, 6, 2917. DOI: 10.1021/ol048987n) that Finkelstein exchange of the heteroaryl chloride 16 proceeds readily at -40C. The product iodide 17 is an efficient substrate for SNAr, Sonogashira and Suzuki-Miyaura reactions. For instance, the Sonogashira reaction on 17 proceeded in 20 min at room temperature, to give 18. Under the same conditions, the chloride 16 did not react.

D. F. Taber, Org. Chem. Highlights 2005, September 12.