Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 19, 2012
Tristan H. Lambert
Columbia University

New Methods for C-N Ring Construction

The reduction of pyridines offers an attractive approach to piperidine synthesis, and now Toshimichi Ohmura and Michinori Suginome of Kyoto University have developed (J. Am. Chem. Soc. 2012, 134, 3699. DOI: 10.1021/ja3002953) a rhodium-catalyzed hydroboration of pyridines, including the reaction of 1 to produce 3. Timothy J. Donohoe at the University of Oxford has found (Org. Lett. 2011, 13, 2074. DOI: 10.1021/ol200478p) that pyridinium silanes 4 undergo intramolecular hydride transfer by treatment with TBAF to produce dihydropyridones (e.g. 5) with good diastereoselectivity.

Enantioselective amination of allylic alcohols has proven challenging, but Ross A. Widenhoefer at Duke University has reported (Angew. Chem. Int. Ed. 2012, 51, 1405. DOI: 10.1002/anie.201107877) that a chiral gold catalyst can effect such intramolecular cyclizations with good enantioselectivity, as in the synthesis of 7 from 6. Alternatively, Masato Kitamura at Nagoya University has developed (Org. Lett. 2012, 14, 608. DOI: 10.1021/ol203218d) a ruthenium catalyst that operates at as low as 0.05 mol% loading for the conversion of substrates like 8 to 9. Efforts to replace transition metal catalysts with alkaline earth metal-based alternatives has been gaining increasing attention, and Kai C. Hultzsch at Rutgers University has found (Angew. Chem. Int. Ed. 2012, 51, 394. DOI: 10.1002/anie.201105079) that the magnesium complex 12 is capable of catalyzing intramolecular hydroamination (e.g. 10 to 11) with high enantioselectivity. Meanwhile, a stereoselective Wacker-type oxidation of tert-butanesulfinamides such as 13 to produce pyrrolidine derivatives 14 has been disclosed (Org. Lett. 2012, 14, 1242. DOI: 10.1021/ol3000519) by Shannon S. Stahl at the University of Wisconsin at Madison.

Though highly desirable, Heck reactions have rarely proven feasible with alkyl halides due to competitive β-hydride elimination of the alkyl palladium intermediates. Sherry R. Chemler at the State University of New York at Buffalo has demonstrated (J. Am. Chem. Soc. 2012, 134, 2020. DOI: 10.1021/ja211272v) a copper-catalyzed enantioselective amination-Heck-type cascade (e.g. 15 and 16 to 17) that is thought to proceed via radical intermediates. David L. Van Vranken at the University of California at Irvine as reported (Org. Lett. 2012, 14, 3233. DOI: 10.1021/ol301385g) the carbenylative amination of N-tosylhydrazones, which proceeds through η3-allyl Pd intermediates constructed via carbene insertion. This chemistry was applied to the two step synthesis of caulophyllumine B from vinyl iodide 18 and N-tosylhydrazone 19.

As part of the development of a piperidine chiron for the Veratrum alkaloids, Douglass F. Taber at the University of Delaware reported rearrangement of the bromohydrin 20 to pyrrolidine 22 in the presence of allenyl stannane 21 (J. Org. Chem. 2012, 77, 4235. DOI: 10.1021/jo2026228). Speaking of rearrangements, the interconversion of isomeric starting materials can sometimes pose a problem for selective synthesis, but Jeffrey Aubé at the University of Kansas has shown (J. Am. Chem. Soc. 2012, 134, 6528. DOI: 10.1021/ja300369c) that an equilibrating mixture of 23 and 24 (four total isomers) leads to a 10:1 stereoselectivity for the formation of 25 via intramolecular Schmidt reaction.

An effective dipeptide-based phosphine catalyst 29 has been reported (Angew. Chem. Int. Ed. 2012, 51, 767. DOI: 10.1002/anie.201106672) by Yixin Lu at the National University of Singapore for the [3+2] cycloaddition of imines 26 and allenoates 27 to produce enantioenriched dihydropyrroles 28. Meanwhile, a remarkable rhodium-catalyzed cascade involving C-H activation, electrocyclization, and reduction (e.g. 30 to 31) has been developed (J. Am. Chem. Soc. 2012, 134, 4064. DOI: 10.1021/ja2119833) by Robert G. Bergman at the University of California at Berkeley and Jonathan A. Ellman, now at Yale University.

For nitrogen heterocycle synthesis, the cyclization of linear precursors via C-H amination offers a potentially powerful strategy. Gong Chen at the Pennsylvania State University has now shown (J. Am. Chem. Soc. 2012, 134, 3. DOI: 10.1021/ja210660g) that azetidines such as 33 can be prepared via palladium-catalyzed C-H amination of 32. The key to this chemistry is the use of coordinating protecting groups such as the picolinamide shown.

Finally, Erick M. Carreira at ETH Zürich has reported (Org. Lett. 2012, 14, 66. DOI: 10.1021/ol2028459) azaspiro[3.3]heptanes (e.g. 36) as novel building blocks for drug discovery, which may be synthesized from precursor bromoalcohols 35. Notably, the proper choice of base and solvent are critical to the desired oxetane formation, in that the use of potassium tert-butoxide in THF leads to selective Grob-type fragmentation to produce the 3-methylene azetidine 34 instead.

T. H. Lambert, Org. Chem. Highlights 2012, November 19.