Andreas Lindenschmidt

A General and Mild Palladium‐Catalyzed Domino Reaction for the Synthesis of 2H‐Indazoles

Indazoles play an increasingly important role in drug discovery. They act as an efficient isostere for privileged structures such as indoles and benzimidazoles. Furthermore, this important scaffold is able to interact with a variety of diverse targets, as highlighted by the growing number of reports of biologically active indazole derivatives. However, only a limited number of approaches for the regioselective synthesis of N-substituted indazoles are available today. Most approaches afford the thermodynamically favored 1H-indazole or mixtures of 1Hand 2H-indazoles, whereas the regioselective formation of 2H-indazoles remains a very challenging task. The lack of a direct, efficient, and regioselective synthetic procedure for the construction of 2Hindazoles prevents their broader application in, for example, medicinal chemistry. Thus, there is an unmet need for the development of a simple and general synthesis of 2Hindazoles from readily available precursors. Herein we report a straightforward domino reaction sequence consisting of a regioselective coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization of the exocyclic double bond to give the aromatic 2H-indazole (Scheme 1). The first challenge in this strategy was the development of a regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1 to afford the required N,N’-disubstituted hydrazines 4. Although a number of transition-metal-catalyzed coupling reactions of aryl halides with amides, amines, hydrazides, and hydrazones are known, only a few coupling reactions of hydrazines have been reported, and only one of the reported hydrazine couplings, for the formation of N,N-diaryl hydrazines, is regioselective. A second challenge in the development of our proposed strategy was the control of the hydroamination/ cyclization step to form the 1,2-dihydroindazole 5, as other possible cyclization pathways lead to other products, such as 1,2-dihydrocinnolines and N-azaindoles. The isomerization of the exocyclic double bond in dihydro-2H-indazole 5 to give the aromatic 2H-indazole 3 was expected to occur spontaneously under the reaction conditions and thus not to pose any problems. We initiated our investigation by screening for reaction conditions under which the coupling of 1-chloro-2-phenylethynylbenzene (1a) and phenylhydrazine (2a) would proceed efficiently to give the N,N’-diaryl hydrazine 4. Upon optimization of the reaction parameters (the transition metal, metal salt, ligand, base, solvent, and temperature), the desired coupling was found to proceed cleanly within just a few hours and with complete regioselectivity when the catalyst system [Pd2(dba)3]/PtBu3 (1:2) was used in toluene at 80 8C with NaOtBu as the base (dba = dibenzylideneacetone). This reaction is to our knowledge the first regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines to give N,N’-disubstituted hydrazine products. We further optimized the reaction parameters to identify conditions that would promote the complete domino reaction of 1 a with 2a as a one-pot reaction (Table 1). We found that the use of polar solvents, such as DMF, NMP, or DMA, in combination with Cs2CO3 led to the formation of the desired 2H-indazole 3a in good yield (Table 1, entries 2–4), whereas Scheme 1. Proposed synthesis of 2H-indazoles.

Small Macrocycles As Highly Active Integrin α2β1 Antagonists.

Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this. Subsequent docking into the metal-ion-dependent adhesion site (MIDAS) of a β1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.