Yigang Zhao

A Practical in situ Generation of the Schwartz Reagent. Reduction of Tertiary Amides to Aldehydes and Hydrozirconation

A new, highly efficient in situ protocol (Cp2ZrCl2/LiAlH(OBu-t)3) is described for the generation of the Schwartz reagent which provides a convenient method for the amide to aldehyde reduction and the regioselective hydrozirconation-iodination of alkynes and alkenes. Highlighted are chemoselective reductions of benzamides derived by directed ortho metalation (DoM) chemistry, allowing the synthesis of valuable 1,2,3-substituted benzaldehydes. The single-step, three-component process proceeds in a very short reaction time, shows excellent functional group compatibility, and uses inexpensive and long-storage stable reducing reagents.

Beyond directed ortho metalation: Ru-catalyzed CAr-O activation/cross-coupling reaction by amide chelation.

Disclosed is a new, catalytic, and general methodology for the chemical synthesis of biaryl, heterobiaryl, and polyaryl molecules by the cross-coupling of o-methoxybenzamides with aryl boroneopentylates. The reaction is based on the activation of the unreactive C-OMe bond by the proximate amide directing group using catalytic RuH2(CO)(PPh3)3 conditions. A one-step, base-free coupling process is thereby established that has the potential to supersede the useful two-step directed ortho metalation/cross-coupling reaction involving cryogenic temperature and strong base conditions. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, minimum waste, and convenient scale-up make these reactions suitable for industrial applications.

Beyond Directed Ortho Metalation: Ruthenium-Catalyzed Amide-Directed CAr–N Activation/C–C Coupling Reaction of Anthranilamides with Organoboronates

A new, catalytic, and general methodology for the synthesis of biaryls and heterobiaryls by the cross coupling of anthranilamide derivatives (o-NMe2 benzamides) with aryl boroneopentylates is described. The reaction proceeds under catalytic RuH2(CO)(PPh3)3 conditions driven by the activation of the unreactive C-N bond by amide directing group (DG)-Ru catalyst chelation. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, and convenient scale-up are features of these reactions which may lend themselves to industrial applications.

Beyond Directed ortho Metalation: Ruthenium-Catalyzed Amide-Directed CAr-OMe Activation/Cross-Coupling Reaction of Naphthamides with Aryl Boronates.

A new and general synthetic methodology for the construction of biaryl, heterobiaryl, and polyaryl molecules by the ruthenium-catalyzed cross-coupling of ortho-methoxy naphthamides with aryl boroneopentylates is described. The isomeric 1-MeO-2-naphthamides and 2-MeO-1-naphthamides furnish an expansive series of arylated naphthamides in excellent yields. Competition experiments showed the higher reactivity of 1-MeO-2-naphthamide over 2-MeO-benzamide. Orthogonality between the C-O activation/cross-coupling and the Suzuki-Miyaura reactions was established. The method provides naphthalenes which are difficult to prepare by directed ortho metalation.

Reductive Cleavage of Aryl O-Carbamates to Phenols by the Schwartz Reagent. Expedient Link to the Directed Ortho Metalation Strategy‡

A general, mild, and efficient method for the reductive cleavage of aryl O-carbamates to phenols, 1 → 2 using the Schwartz reagent is reported. The method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and, notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1 ) allowing new entries into difficult to prepare contiguously substituted aromatics and heteroaromatics.

Amide-Directed Ru-Catalyzed Hydrodemethoxylation of ortho-Methoxy-Benzamides and -Naphthamides: A DoM Reaction Counterpart

A new ruthenium-catalyzed hydrodemethoxylation of ortho-methoxy-benzamides and -naphthamides involving amide-directed C-OMe bond activation and hydride reduction is disclosed. The reaction is general, proceeding under RuH2(CO)(PPh3)3 catalysis using either triethylsilane (Et3SiH) or diisobutylaluminum hydride (DIBAL-H) as the reductant. The corresponding C-N hydrodeamination reaction is also briefly reported.

Three-Component Route for the Regioselective Construction of N-Arylbenzimidazoles

Significance: Reported is a regiocontrolled synthesis of N-arylbenzimidazoles 3 and 4 via a threecomponent reaction using a palladium catalyst. In this reaction, the 2-chloroarenes 1 and 2 show different reactivities in combining with anilines and amides in sequential intermolecular amination and amidation reactions and cyclizations to regioselectively afford two types of N-arylbenzimidazoles, 3 and 4, in moderate to good yields. The reaction scope and limitations for the 2-chloroarenes 2 were not well investigated. Comment: Benzimidazoles are often found in nature and in drugs displaying broad spectrum pharmaceutical activities (see Review below). Poor regiocontrolled benzimidazole arylations to give mixtures of isomeric products have been previously reported (e.g., D. Yang et al. J. Org. Chem. 2008, 73, 7841). The present method not only assembles the substituted benzimidazoles in a straightforward way from readily available starting materials, but also offers a high regiocontrol in the construction of single isomer products.