Aryl Amines à la Yale and MIT

Aryl Amines à la Yale and MIT

by Dr. John Emsley

WHAT'S HOT IN CHEMISTRY...

Rank	Paper	Citations This Period Jul- Aug 01	Rank Last Period May- Jun 01
1	M. Scholl. et al., "Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands," Organic Lett., 1(6):953-6, 23 September 1999. [Caltech, Pasadena] *281QF	20	2
2	H. Li, et al., "Design and synthesis of an exceptionally stable and highly porous metal-organic framework," Nature, 402(6759):276-9, 18 November 1999. [Arizona St. U., Tempe; U. Michigan, Ann Arbor] *257ZP	14	†
3	A.F. Littke, C. Dai, G.C. Fu, "Versatile catalysts for the Suzuki cross-coupling of arylboronic acids with aryl and vinyl halides and triflates under mild conditions," J. Amer. Chem. Soc., 122(17):4020-8, 3 May 2000. [MIT, Cambridge] *312NZ	14	3
4	J.P. Wolfe, et al. "Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates," J. Org. Chem., 65(4):1158-74, 25 February 2000. [MIT, Cambridge] *289DH	11	†
5	J.F. Hartwig, et al., "Room-temperature palladium-catalyzed amination of aryl bromides and chlorides and extended scope of aromatic C-N bond formation with a commercial ligand," J. Org. Chem., 64(15):5575-80, 23 July 1999. [Yale U., New Haven, CT] *222CU	10	5
6	J.M.L Martin, G. de Oliveira, *"Towards standard methods for benchmark quality ab initio* thermochemistry<197>W1 and W2 theory,"** J. Chem. Phys., 111(5):1843-56, 1 August 1999. [Weizmann Inst. Sci., Rehovot, Israel] *220ZA	10	†
7	B. Lygo, J. Crosby, J.A. Peterson, "Enantioselective alkylation of alanine-derived imines using quaternary ammonium catalysts," Tetrahedron Lett., 40(49):8671-4, 3 December 1999. [U. Salford, U.K.; AstraZeneca, Macclesfield, U.K.] *255JK	10	†
8	W.W. Lukens, "Evaluating pore sizes in mesoporous materials: a simplified standard adsorption method and a simplified Broekhoff-de Boer method," Langmuir, 15(16):5403-9, 3 August 1999. [U. Calif., Santa Barbara] *227KJ	9	†
9	S.-H. Lee, K. Liu, "Exploring the spin-orbit reactivity in the simplest chlorine atom reaction," J. Chem. Phys., 111(14):6253-9, 8 October 1999. [Inst. Atom. Molec. Sci., Taipei, Taiwan] *240TM	9	†
10	G. Schaftenaar, J.H. Noordik, "Molden: a pre- and post-processing program for molecular and electronic structures," J. Comp.-Aid. Molec. Des., 14(2):123-34, February 2000. [Nijmegen U., Netherlands] *279EG	8	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

he current list of Hot Papers in chemistry has two consecutive entries (#4 and #5) on attaching an amine group to an aromatic ring to make an aryl amine, and both report how palladium compounds make excellent catalysts for the formation of these potentially useful compounds. But why should chemists want to attach amine groups to benzene rings?

To answer this we need look no further than the pharmaceutical industry, where aryl amines are intermediates in drug discovery and synthesis, being particularly important in researching drugs that act on the central nervous system. Other manufacturers are also interested in aryl amines, because of their unusual electronic properties with potential applications as light-emitting diodes and conducting polymers; they are also used in the production of agrochemicals and dyes.

Paper #4 comes from a group at Massachusetts Institute of Technology headed by Stephen Buchwald, and the earlier paper #5 comes from a team of chemists at Yale University led by John Hartwig. It is clear that both researchers have been motivated to seek out better palladium catalysts for aryl amination, the object being to find ones that would make the reaction work at room temperature and use the more accessible, but relatively unreactive, aryl chlorides as starting materials. Both have succeeded, albeit by slightly different routes.

Buchwald’s paper gives details of reactions in which various ligand-palladium catalysts were used, with yields of desired product sometimes in excess of 95%, even in those reactions carried out at room temperature. Moreover the ligands are commercially available and air stable. According to Buchwald the commercial potential for these catalyzed reactions has already been patented: "MIT has a broad U.S. patent coverage, in addition to a variety of U.S. and international applications, on the process of palladium and nickel-catalyzed methods for aromatic carbon-nitrogen bond forming processes."

Hartwig’s paper reports a simpler, commercially available ligand, tri-tert-butylphosphine, which also works at room temperature and also produces high yields. According to Hartwig: "This reaction has become one of the most useful coupling processes, and the catalyst system is simple to use, reliable, and relatively inexpensive. The reaction conditions are extremely mild and product separation is trouble-free." He hints that his group have recently found an even easier way to use this ligand, and says they have uncovered the mechanism by which the reaction works.

What is surprising about the research in papers #4 and #5 is the apparent simplicity of the method, but as Buchwald comments: "It takes a lot of work and effort to go from initial results on simple systems to develop methods that work in other people's hands. The easy part is making the initial discovery. The hard part is understanding the system well enough that you can make it general, user friendly and applicable to other chemists’ work."

Among Buchwald’s recent papers, the one he says is of greatest significance is published in Journal of the American Chemical Society (see. A. Klapars, et al.,123[31]:7727-9, 2001), in which he reports a new copper catalyst for carbon-nitrogen bond formation, a method which he says has several advantages when it comes to using heterocycles substrates, and these overcome the previous limitations in the use of palladium catalysts.

Meanwhile Hartwig has also been developing his research, and recent papers from his groups at Yale include one on improved catalysts for the synthesis of oxindoles, (J. Org. Chem., 67: in press) and another which is about the use of room-temperature palladium-based catalysts for the Heck reaction, which is a method of attaching an olefin to a benzene ring (see J.P. Stambuli, et al., J. Am. Chem. Soc., 123[11]:2677-8, 2001).

The work of Hartwig and Buchwald has spurred others to contribute to this area of research. For example, Duncan Macquarrie, Battsengel Gotov and Stefan Toma describe in Platinum Metals Review (45[3]:102, 2001) how the reactions reported in papers #4 and #5 can be made more efficient by having the palladium catalyst immobilized on a solid phase such as silica, which enables it to be easily recovered and reused.

Dr. John Emsley is science writer in residence at the
Department of Chemistry, Cambridge University, U.K.