Catalysis for Organic Syntheses

Our research group is interested in the development of environmentally benign and economically sound processes of importance to organic synthesis. This combines techniques of organic synthesis and organometallic chemistry for the development of more efficient catalytic transformations. Thus far, our program is focused on four main research areas: (A) catalytic functionalizations of unactivated C–H bonds. This work includes the use of inter alias ruthenium, titanium, zirconium, palladium, nickel, and copper catalysts on a day to day basis; (B) development of air-stable secondary phosphine oxides as preligands for catalytic cross-couplings; (C) hydroaminations of alkynes, allenes, and alkenes; and (D) efficient syntheses of biologically relevant compounds.

C–H Bond-Functionalizations

Our research group is interested in the development of environmentally benign and economically sound processes of importance to organic synthesis. This combines techniques of organic synthesis and organometallic chemistry for the development of more efficient catalytic transformations. Thus far, our program is focused on four main research areas: (A) catalytic functionalizations of unactivated C–H bonds. This work includes the use of inter alias ruthenium, titanium, zirconium, palladium, nickel, and copper catalysts on a day to day basis; (B) development of air-stable secondary phosphine oxides as preligands for catalytic cross-couplings; (C) hydroaminations of alkynes, allenes, and alkenes; and (D) efficient syntheses of biologically relevant compounds.

C–H Bond-Functionalizations

Direct arylation reactions via C–H bond functionalizations represent economically attractive alternatives to traditional cross-coupling reactions with organometallic reagents (Scheme 1).^[1]

Scheme 1: Catalytic direct arylations: C–H bond functionalizations.

We reported on generally applicable ruthenium-catalyzed direct arylations with chlorides or tosylates as electrophiles. The application of ruthenium-catalyzed direct arylations to alkenes set the stage for an efficient sequential catalysis (Scheme 2).^[2]

Scheme 2: Ruthenium-catalyzed C–H bond functionalizations.

Subsequently, we employed phenols as proelectrophiles in operationally simple ruthenium-catalyzed formal dehydrative direct arylations, proceeding through regioselective functionalizations of C–H and C–OH bonds (Scheme 3).^[2a]

Scheme 3: Dehydrative direct arylations.

Additionally, we reported on a palladium-catalyzed domino reaction, consisting of an intermolecular amination and an intramolecular direct arylation with chlorides as the sole leaving groups (Scheme 4),^[3b] as well as of direct arylations with tosylates or mesylates as electrophile.^[3a]

Scheme 4: Palladium-catalyzed direct arylations.

With respect to regioselectivity, ruthenium-catalyzed direct arylations proved to be complementary to palladium-based methodologies, when applied to 1,2,3-triazoles.^[2] On the contrary, inexpensive copper catalysts enabled modular one-pot multicomponent syntheses of fully decorated triazoles through a sustainable "click" reaction/direct arylation sequence (Scheme 5).^[3c]

Scheme 5: Copper-Catalyzed “Click” Reaction/Direct Arylation Sequence.

 

Air-Stable Preligands for Cross Coupling Chemistry

We developed three different types of preligands for transition metal-catalyzed cross-coupling^[1] reactions of challenging substrates (Scheme 6).^[4] First, diaminooxo-phosphine (daop) 1 allowed for efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reactions as well as arylation reactions of amines and α-C–H acidic ketones. Second, diaminochlorophosphine 2 proved to generate a highly active palladium catalyst for amination reactions of demanding substrates. Third, we reported on air-stable, modular heteroatom-substituted secondary phosphine oxides (HASPO) as preligands for transition metal-catalyzed cross-coupling reactions. These preligands can be prepared in a highly flexible fashion from inexpensive and readily available starting materials. Notably, they proved to be generally applicable, allowing among others Kumada-Corriu, Stille, Hiyama and Suzuki-Miyaura cross-coupling reactions of aryl and alkenyl bromides, chlorides, or fluorides.

Scheme 6: Preligands for metal-catalyzed cross couplings.

Particularly, commercially available air-stable PinP(O)H (4) gave rise to a catalyst for highly efficient and generally applicable Kumada-Corriu cross-couplings of (hetero)aryl tosylates (Scheme 7).^[1b,4d]

Scheme 7: Catalytic cross-couplings of (hetero)aryl tosylates.

 

Hydroamination Reactions

Metal-catalyzed transformations allow for environmentally benign and economically attractive organic syntheses.^[1] The hydroamination reaction of carbon-carbon multiple bonds provides a highly atom-economical access to substituted imines and amines. In this context, we reported on widely applicable protocols for user-friendly catalysts for addition reactions of amines onto alkynes and alkenes (Scheme 8).^[5]

Scheme 8: Catalytic hydroamination reactions.

 

Syntheses of Biologically Relevant Compounds

We employed catalytic hydroamination reactions for novel syntheses of diversely-substituted heterocycles, for example of the following structures illustrated in Figure 1.^[1b]

Figure 1: Heterocycles synthesized by hydroaminations.

Due to the prevalence of indoles in natural products and biologically active compounds, a continued strong demand for the development of general, flexible, and especially regioselective synthetic methods of this structural moiety exists. We established novel protocols for highly efficient syntheses of the indole backbone employing inexpensive and readily available aryl chlorides as starting materials (Scheme 9).^[1b] First, we developed a hydroamination–Heck reaction sequence for regioselective indole syntheses with 2-chloroanilines. Second, regioselective indole syntheses were developed that are based on amination reactions of 2-alkynyl haloarenes. These transformations proceed through intermolecular palladium- or copper-catalyzed amination reactions, and subsequent intramolecular hydroaminations. Third, a multicatalytic one-pot indole synthesis starting from ortho-chloroiodobenzenes is viable using a single catalytic system consisting of an N-heterocyclic carbene palladium complex and copper cocatalyst.

Scheme 9: Efficient indole syntheses.