Monday, October 9, 2006
Douglass Taber
University of Delaware
Preparation of Benzene Derivatives
Benzene derivatives lie at the heart of pharmaceutical chemistry. While most are prepared from pre-existing benzene rings, direct assembly of the benzene ring can allow access to substitution patterns that are not otherwise easily prepared. Akio Saito and Yuji Hanzawa of the Showa Pharmaceutical University in Tokyo recently described (Tetrahedron Lett. 2006, 47, 891. DOI: 10.1016/j.tetlet.2005.11.155) the Diels-Alder cyclization of esters such as 1. The reaction proceeded at room temperature using a cationic Rh catalyst, in hexafluoroisopropanol (HFIP) solvent. The adduct 2 tended to aromatize, so the cyclization was most conveniently worked up with DDQ, to give 3.
Simple aromatic halogenation could be considered to be “C-H activation”. What sets apart recent developments in the field of aromatic C-H activation is the ability to direct reactivity to particular sites on the benzene ring. This selectivity is illustrated by the recent work (J. Am. Chem. Soc. 2006, 128, 7416. DOI: 10.1021/ja060232j) of Zhangjie Shi of Peking University (known in China as Beida). Pd-catalyzed oxidation converts acetanilide 4 specifically into the ortho chlorinated 5. The para product is not observed. Bromides can be prepared this way also.
Benzene derivatives can also be halogenated by stoichiometric metalation. Paul Knochel of the Universität München has found (Angew. Chem. Int. Ed. 2006, 45, 2958. DOI: 10.1002/anie.200504024) that a 1:1 mixture of iPr2NMgCl•LiCl and 2,2,6,6,-tetramethylpiperidine worked particularly well. Exposure of the ester 6 to these conditions followed by the addition of I2 gave the iodide 7. Note that the aromatic bromide is not eliminated, even though these are strongly basic conditions.
C-H activation can also be used to oxygenate benzene rings. Melanie S. Sanford of the University of Michigan has developed (Org. Lett. 2006, 8, 1141. DOI: 10.1021/ol0530272) a Pd-mediated protocol to incorporate an acetoxy group or a methoxy group adjacent to an aryl ketone, protected as the methoxime. The bulk oxidant is the inexpensive Oxone®.
Friedel-Crafts acylation could also be classified as “C-H activation”. Again, the difference comes in the observed regioselectivity. Thus, the observation by Richard C. Larock of Iowa State (J. Org. Chem. 2006, 71, 3551. DOI: 10.1021/jo060220g) that the Pd-mediated condensation of 11 with 12 leads to a 52 : 48 ratio of 13 and 14 suggests that this reaction is probably proceeding by electrophilic addition to the benzene ring.
In contrast, the Ru-catalyzed condensation of the aryl oxazoline 15 with aryl tosylates such as 16, developed by Lutz Ackermann of the Universität München (Angew. Chem. Int. Ed. 2006, 45, 2619. DOI: 10.1002/anie.200504450), does proceed with high regiocontrol. Other heterocycles, including 2-pyridyls, also direct well.
Pd-mediated activation can be effective even on scale. The cyclization of 18 to 19 was the key step in the preparation of the phospholipase sPLA2 inhibitor LSN426891 (20) recently described (Tetrahedron Lett. 2006, 47, 1351. DOI: 10.1016/j.tetlet.2005.12.043) by Scott A. May of Lilly Process.
D. F. Taber, Org. Chem. Highlights 2006, October 9.
URL: https://www.organic-chemistry.org/Highlights/2006/09October.shtm
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