Alexander V. Lygin

Ruthenium-Catalyzed Oxidative Annulation by Cleavage of CH/NH Bonds†

Oxidative transition-metal-catalyzed C H bond functionalizations have attracted significant recent interest, because these methods avoid the multi-step preparation of preactivated starting materials, and hence allow for an overall streamlining of organic synthesis. Pioneering reports by the research groups of Miura and Satoh, Fagnou, and Jones revealed that particularly rhodium catalysts enabled effective dehydrogenative annulation reactions of alkynes through chelation assistance, which have set the stage for very recently developed rhodium-catalyzed isoquinolone syntheses. On the contrary, the use of less-expensive ruthenium catalysts for oxidative annulations through cleavage of C H bonds has thus far not been reported. During studies on oxidative ruthenium-catalyzed homodehydrogenative arylations, we observed unprecedented ruthenium-catalyzed direct annulations of alkynes through the chemoand site-selective functionalization of both C H and N H bonds, and we wish to disclose our results herein. At the outset of our studies, we explored the effect of different reaction parameters on the oxidative annulation of alkyne 2a by amide 1a, which included the use of representative ruthenium precursors, solvents, oxidants, and additives (Table 1, and Table S1 in the Supporting Information). Among a variety of ruthenium complexes, optimal yields of product 3a were obtained with [{RuCl2(p-cymene)}2], along with Cu(OAc)2·H2O as the terminal oxidant, and tAmOH (tAm= tert-amyl) as the solvent. On the contrary, the use of silver(I) salts as stoichiometric oxidants resulted in decreased catalytic efficacy. As to the reaction mechanism (see below), the formation of compound 4a in apolar solvents is noteworthy. With an optimized catalytic system in hand, we explored its scope in C H bond functionalizations by employing differently substituted benzamides 1 (Scheme 1). Owing to its remarkable chemoselectivity the ruthenium catalyst proved tolerant of valuable electrophilic functional groups, such as fluoro, chloro, or ester substituents. Furthermore, amides 1 bearing different groups on the nitrogen atom, such as N-alkyl, N-benzyl, or N-aryl derivatives, were efficiently reacted, with the latter being chemoselectively converted into isoquinolones 3k and 3 l, without the formation of any indole by-products. Likewise, the successful use of a heteroaromatic benzamide turned out to be viable. The catalytic system was not restricted to the use of tolane (2a), but also allowed for efficient oxidative annulations of aryl-, alkenylor alkyl-substituted alkynes 2 (Scheme 2). Importantly, the annulation process occurred with high regioselectivity even when using unsymetrically substituted aryl/alkyl or alkenyl/alkyl alkynes 2. Given the remarkable activity of the novel catalytic system, we became interested in understanding its mode of action. Thus, intramolecular competition experiments with meta-substituted substrates were largely controlled by steric interactions, thus delivering isoquinolones 3m and 3n as the sole products (Scheme 1). In contrast, the use of substrates 1b and 1c, which have electronegative heteroatoms in metaposition, gave significant amounts of products 3w and 3y, respectively, through C H bond functionalizations at the 2[*] Prof. Dr. L. Ackermann, Dr. A. V. Lygin, Dipl.-Chem. N. Hofmann Institut f r Organische und Biomolekulare Chemie Georg-August-Universit t Tammannstrasse 2, 37077 G ttingen (Germany) Fax: (+49)551-39-6777 E-mail: lutz.ackermann@chemie.uni-goettingen.de Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/

Isocyanides in the Synthesis of Nitrogen Heterocycles

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition-metal-catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.

Cationic Ruthenium(II) Catalysts for Oxidative C–H/N–H Bond Functionalizations of Anilines with Removable Directing Group: Synthesis of Indoles in Water

Cationic ruthenium(II) complexes enabled oxidative C-H bond functionalizations with anilines bearing removable directing groups. The C-H/N-H bond cleavages occurred most efficiently in water as a sustainable solvent and provided general access to various bioactive indoles. Mechanistic studies provided strong support for a novel reaction manifold.

Ruthenium-Catalyzed Direct C–H Bond Arylations of Heteroarenes

Ruthenium-catalyzed C-H bond arylations of indoles, thiophenes, and pyrroles were accomplished in a highly chemo- and site-selective manner through the use of removable directing groups.

Ruthenium-Catalyzed Oxidative C–H Alkenylations of Anilides and Benzamides in Water

A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to double C-H bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of benzamides.

Ruthenium-Catalyzed Oxidative Synthesis of 2-Pyridones through C–H/N–H Bond Functionalizations

An inexpensive ruthenium catalyst enabled oxidative annulations of alkynes by acrylamides with ample scope, which allowed for the preparation of 2-pyridones employing various electron-rich and electron-deficient acrylamides as well as (di)aryl- and (di)alkyl-substituted alkynes.

Ruthenium-catalyzed aerobic oxidative coupling of alkynes with 2-aryl-substituted pyrroles

Ruthenium-catalyzed aerobic oxidative annulations of alkynes were accomplished with co-catalytic amounts of Cu(OAc)2·H2O under ambient air. The C–H/N–H bond functionalization occurred with unparalleled selectivities and ample scope to deliver structural analogs of bioactive marine alkaloids.

Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and Acetylenes

The formal cycloaddition of alpha-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 25-97% yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu(I)-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5-88% yield).

ortho-Lithiophenyl Isocyanide: A Versatile Precursor for 3H-Quinazolin-4-ones and 3H-Quinazolin-4-thiones

ortho-Lithiophenyl isocyanide has been generated from ortho-bromophenyl isocyanide and successfully employed toward the synthesis of 2-substituted phenyl isocyanides as well as 2,3-disubstituted 3H-quinazoline-4-ones and 3H-quinazolin-4-thiones.

Reactions of ortho-lithiophenyl (-hetaryl) isocyanides with carbonyl compounds: rearrangements of 2-metalated 4H-3,1-benzoxazines.

ortho-Lithiophenyl (-hetaryl) isocyanides react with aldehydes and ketones providing isocyanoalcohols 8 (36-89%, nine examples), 4H-3,1-benzoxazines 9 (45-78%, six examples) or, after two types of rearrangements, isobenzofuran-1(3H)-imines (iminophthalanes) 18 (52-75%, four examples), or indolin-2-ones 19 (42-79%, two examples), depending on the reaction conditions and substitution patterns. Isocyanoalcohols 8, in turn, were converted to 9 or 18 under Cu(I) catalysis (66-86%, eight examples). 4H-3,1-Benzoxazin-4-ones 39-Nu and isatoic anhydride 40 were obtained by the reaction of 2 with carbon dioxide followed by trapping of the lithiated intermediate with iodine and subsequent reactions with nucleophiles (45-60%, three examples).