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Discovery and Understanding of Transition-Metal-Catalyzed Aromatic Substitution Reactions Transition-Metal-Catalyzedjohn Aromatic Substitution Reactionsf

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Discovery and Understanding of Transition-Metal-Catalyzed Aromatic Substitution Reactions Transition-Metal-Catalyzedjohn Aromatic Substitution Reactionsf ACCOUNT 1283 Discovery and Understanding of Transition-Metal-Catalyzed Aromatic Substitution Reactions Transition-Metal-CatalyzedJohn Aromatic Substitution ReactionsF. Hartwig* Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8107, USA Fax +1(203)4326144; E-mail: [email protected] Received 5 January 2006 John F. Hartwig was the recipient of the 2004 Thieme–IUPAC Prize. amides derived from secondary amines in the presence of Abstract: This article presents studies on the development of cross- coupling reactions of aryl halides and sulfonates with amines, a palladium catalyst containing a sterically hindered alkoxides, and various enolates. Emphasis is placed on the process aromatic phosphine (Equation 1). Although the scope of of developing new catalysts with mechanistic information gained in this prior work was also narrow, it demonstrated that the author’s laboratory. palladium complexes could catalyze aromatic carbon– 1 Introduction nitrogen bond formation. 2 Early Reaction Development Et 3 New Catalyst Developments R L2PdCl2 R Et 4 Mechanism of the Cross-Coupling Processes Bu3Sn N + Br N + Bu3SnBr only for 5 Mechanism of Oxidative Addition Et Et L = (o-Tol)3P Ref. 7,8 6 Reductive Elimination of Amines 7 Stable Palladium Catalysts for Coupling of Primary Amines Equation 1 8 Guidelines for Catalyst Selection Key words: cross-coupling, palladium, amination, arylation, We were interested in developing methods that would mechanism expand the scope of this process and that would occur without tin reagents. Although we did not anticipate that the process would be as general and widely used as it has 1 Introduction become, we did hope that these advances would create a process that is convenient enough to be useful for organic Nucleophilic aromatic substitution is a fundamental synthesis. We hoped to uncover catalysts that would be organic transformation. However, the scope of the direct more active for the amination process and that could ex- reaction is narrow and the temperature for reaction of pand the scope to encompass primary amines, nitrogen unactivated substrates is high. Mild, direct nucleophilic nucleophiles other than amines, and related nucleophiles, aromatic substitution requires highly electron-deficient such as alkoxides. aryl halides. Thus, alternative uncatalyzed methods have We were also interested in uncovering the elementary re- been studied to develop a net aromatic substitution pro- actions of this catalytic process, including the step of the 1 cess, such as reactions through aryne intermediates or catalytic cycle that forms the carbon–nitrogen bond in the 2,3 reactions occurring by radical nucleophilic substitution. product. If the C–N coupling process followed a mecha- Although these reactions are useful in some contexts, the nism that was analogous to that for conventional C–C scope of these stepwise, uncatalyzed methods is also cross-coupling, then the carbon–nitrogen bond would be narrow and the tolerance for accompanying functional formed by a type of reductive elimination that was un- groups is poor. known when we started our work.9,10 We sought to use My group has sought transition-metal catalysts for nu- this type of mechanistic information on the catalytic pro- cleophilic aromatic substitution reactions that occur with cess to design or select catalysts that would give rise to the both heteroatom nucleophiles and common enolate desired increase in activity and scope of the process. 4–6 nucleophiles. As a result of these efforts, we have Due to the efforts of students and postdocs in my group, developed mild methods to prepare aromatic amines, as well as work by many other groups, including the ex- ethers, sulfides, and a-aryl carbonyl compounds with tensive work of Steve Buchwald’s group at MIT,11,12 the phosphine-ligated palladium catalysts. Our work on scope of this reaction is now extremely broad. Equation 2 metal-catalyzed aromatic substitution, or ‘cross-cou- summarizes the types of catalysts now employed in the pling’, stemmed from work by Kameyama, Kosugi and amination process and an overall view of the scope of the 7,8 Migita from the early 1980’s. These authors reported C–N coupling. With these catalysts, the amination reac- the coupling of electron-neutral aryl bromides with tin tions can be conducted with low loadings of catalyst, and can now be conducted with aromatic bromides, chlorides, SYNLETT 2006, No. 9, pp 1283–1294 01.06.2006 triflates, in some cases with aryl iodides, and most recent- Advanced online publication: 22.05.2006 ly with aryl tosylates. Both primary and secondary amines DOI: 10.1055/s-2006-939728; Art ID: A40606ST © Georg Thieme Verlag Stuttgart · New York undergo this reaction, although the optimal catalyst for 1284 J. F. Hartwig ACCOUNT these two classes of amines is often different. The reaction 2 Early Reaction Development has been adopted for many types of applications, such as the synthesis of aromatic amines and nitrogen hetero- The first synthetic advance was published concurrently by cycles for biological and medicinal applications, synthesis Steve Buchwald’s group and by us13,14 and showed that of sophisticated materials for electronic applications, and the reaction could be conducted with amine nucleophiles synthesis of anionic nitrogen ligands for applications in in the presence of an alkoxide or silylamide base with the both asymmetric catalysis and the synthesis of polyole- catalyst originally used by Kosugi and Migita for the fins. coupling of tin amides. A wide variety of catalysts have now been evaluated for this reaction, and the current Pd/2 L R scope of this reaction is summarized in a broad sense in X X = Cl, Br, I, OTf, OTs N base R' Equation 2. In addition to amines, some other nitrogen + HNRR' 25–80 °C nucleophiles that are useful in synthetic applications Y Y L = hindered monodentate ligands undergo the coupling process with broad scope. For P(o-Tol)3, P(t-Bu)3, Ph5FcP(t-Bu)2 (Q-phos), heterocyclic carbenes, example, the reaction of ammonia equivalents, such as – 15,16 (Biaryl)PR2, OP(t-Bu)2, Solvias metallacycle, Verkade's phosphatranes benzophenone imine and lithium hexamethyldisilyl- or chelating bidentate ligands amide (LiHMDS),17,18 occur in good yield with many DPPF, BINAP, Josiphos ligands, Xantphos aromatic halides. Reactions of benzophenone imines and Broad scope: cyclic secondary, acyclic secondary, primary aliphatic, aromatic amines an alkoxide base are milder than those with the more NH strongly basic LiHMDS and can be conducted with ortho- LiN(SiMe ) H N-N=CPh Ph Ph 3 2 2 2 substituted aryl halides, but the hydrolysis of the aromatic Narrower scope: silylamide products is more facile. Benzophenone hydra- H O O O O Boc N HN O HN zone also reacts with aryl halides with broad scope, and S S H N R R R H N O-t-Bu H N p-Tol HN 2 2 2 Boc the products from these reactions are precursors to a variety of nitrogen heterocycles.19–22 Equation 2 Biographical Sketch John F. Hartwig was born transition-metal complexes. In addition to the Thieme– in 1964 outside of Chicago, He has developed a selec- IUPAC Prize in Synthetic and was raised in upstate tive catalytic functionaliza- Organic Chemistry, Pro- New York. He received a tion of alkanes, a method for fessor Hartwig received the B.A. in 1986 from Princeton formation of arylamines and Leo Hendrik Baekeland University, and a Ph.D. in aryl ethers from aryl halides Award in 2003, the A.C. 1990 from the University of or sulfonates, a method for Cope Scholar Award in California, Berkeley under the direct conversion of car- 1998, the Camille Dreyfus the collaborative direction bonyl compounds to a-aryl Teacher-Scholar Award in of Robert Bergman and carbonyl derivatives, a 1997, a Union Carbide Richard Andersen. After an system for the catalytic ad- Innovative Recognition American Cancer Society dition of amines to vinylare- Award in 1995 and 1996, postdoctoral fellowship nes and dienes, and highly the National Science Foun- with Stephen Lippard, he selective catalysts for the dation Young Investigator began an appointment at regio- and enantioselective Award in 1994, and both Yale University in 1992, amination of allylic carbon- Dupont and Dreyfus Foun- where he is now the Irénée ates. With each system, his dation New Faculty Awards P. duPont Professor of group has conducted exten- in 1992. He was the 1998 Chemistry. He and his wife sive mechanistic investiga- R.C. Fusan lecturer at the Anne Baranger have recent- tions. He has revealed University of Illinois, the ly accepted positions at the several new classes of re- first AstraZeneca lecturer in University of Illinois, where ductive eliminations, has Stockholm, and the 2001 they will move during 2006 isolated discrete compounds Carl Ziegler lecturer at Mül- with their two daughters that functionalize alkanes, heim. Most recently, he was Pauline and Amelia. and has reported unusual named the 2006 recipient of Professor Hartwig’s re- three-coordinate arylpalla- the ACS Award in Organo- search focuses on the dis- dium complexes that are metallic Chemistry. covery and understanding of intermediates in cross-cou- new reactions catalyzed by pling. Synlett 2006, No. 9, 1283–1294 © Thieme Stuttgart · New York ACCOUNT Transition-Metal-Catalyzed Aromatic Substitution Reactions 1285 Several other nitrogen nucleophiles that participate in the X O O Pd/L Y Y + R'' coupling process are listed at the bottom of Equation 2. R base R The scope of the coupling of these nucleophiles tends to X = Br, Cl R' R' R'' be narrower, the amount of catalyst required for good L = bidentate or hindered monodentate ligands yields tends to be higher, and the temperatures required BINAP, DTPF, Xantphos i-Pr i-Pr P(t-Bu)3, PAr(t-Bu)2, NN for full conversion tend to be higher than those of reac- 1-Ad2P(t-Bu)2 tions of amines.
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