Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-Azolo Imines and Dioxazolones.

A wide range of azolo[1,3,5]triazines were obtained by Rh(III)-catalyzed annulation of N-azolo imines and dioxazolones. The reaction proceeds by the first catalytic C-H amidation of an imidoyl C-H bond followed by cyclodehydration. Good yields were obtained for N-azolo imines derived from aminoazoles and aromatic and heteroaromatic aldehydes. A range of dioxazolone amidating reagents were employed to introduce aryl, heteroaryl, and alkyl substituents. The reaction was also performed with a benchtop setup at 1 mmol scale using microwave heating.

Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines.

An efficient, three-component strategy for Rh(III)-catalyzed annulation of readily available 3-aminopyrazoles, aldehydes, and sulfoxonium ylides to give diverse pyrazolo[1,5- a]pyrimidines is disclosed. The reactions were performed under straightforward benchtop conditions using microwave heating with short reaction times. Good yields were obtained for many substituted aminopyrazoles and a very large variety of aromatic and heteroaromatic aldehydes, including those incorporating electron-withdrawing, electron-donating, basic nitrogen, halide and acidic functionality. Ester and methoxy functionalities could also be directly installed on the pyrimidine ring by employing ethyl glyoxylate and trimethyl orthoformate in place of the aldehyde, respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent competitive condensation of the formyl group with the aminopyrazole.

Rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles.

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.

Annulation of Hydrazones and Alkynes via Rhodium(III)-Catalyzed Dual C-H Activation: Synthesis of Pyrrolopyridazines and Azolopyridazines.

Hydrazones readily synthesized from N-aminopyrroles or N-aminoazoles and aldehydes undergo Rh(III)-catalyzed dual C-H activation and coupling with aryl- and alkyl-substituted alkynes to give pyrrolopyridazines or azolopyridazines, respectively. This transformation represents a rare example of hydrazoyl C-H activation and proceeds without heteroatom functionality to direct C-H activation. Hydrazones derived from aromatic, alkenyl, and aliphatic aldehydes were effective inputs, and tethering the alkyne to the hydrazone enabled annulations to more complex, tricyclic products.

Three-Component Coupling of Aldehydes, 2-Aminopyridines, and Diazo Esters via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrido[1,2- a]pyrimidin-4-ones.

Imines formed in situ from 2-aminopyridines and aldehydes undergo Rh(III)-catalyzed imidoyl C-H activation and coupling with diazo esters to give pyrido[1,2- a]pyrimidin-4-ones. Aromatic and enolizable aliphatic aldehydes were both effective substrates, and a broad range of functional groups were incorporated at different sites on the heterocyclic products. In addition, methoxy and dimethylamino functionalities could be directly installed on the pyrimidine ring by employing trimethyl orthoformate or N, N-dimethylformamide dimethyl acetal in place of the aldehyde, respectively.

Rhodium(III)-Catalyzed Imidoyl C-H Activation for Annulations to Azolopyrimidines.

Azolopyrimidines are efficiently prepared by direct imidoyl C-H bond activation. Annulations of N-azolo imines with sulfoxonium ylides and diazoketones under redox-neutral conditions and alkynes under oxidizing conditions provide products with various arrangements of nitrogen atoms and carbon substituents. We have also probed the mechanism of this first example of Rh(III)-catalyzed direct imidoyl C-H activation by structural characterization of a catalytically competent rhodacycle obtained after C-H activation and by kinetic isotope effects.

Enantioselective γ-borylation of unsaturated amides and stereoretentive Suzuki-Miyaura cross-coupling.

The rhodium-catalyzed, directed catalytic asymmetric hydroboration of γ,δ-unsaturated amides affords a direct route to chiral acyclic secondary γ-borylated carbonyl derivatives in high enantiomeric purity. In contrast to a similar ß-borylated amide derivative, the γ-borylated amide undergoes Suzuki-Miyaura cross-coupling with stereoretention. The utility of the boronic ester products is further illustrated by other stereospecific C-B bond transformations leading to γ-amino acid derivatives, 1,4-amino alcohols, and 5-substituted-γ-lactone and γ-lactam ring systems.

Enantioselective desymmetrization via carbonyl-directed catalytic asymmetric hydroboration and Suzuki-Miyaura cross-coupling.

The rhodium-catalyzed enantioselective desymmetrization of symmetric γ,δ-unsaturated amides via carbonyl-directed catalytic asymmetric hydroboration (directed CAHB) affords chiral secondary organoboronates with up to 98% ee. The chiral γ-borylated products undergo palladium-catalyzed Suzuki-Miyaura cross-coupling via the trifluoroborate salt with stereoretention.

Mechanistic Insights into Carbonyl-Directed Rhodium-Catalyzed Hydroboration: ab Initio Study of a Cyclic γ,δ-Unsaturated Amide.

A two-point binding mechanism for the cationic rhodium(I)-catalyzed carbonyl-directed catalytic asymmetric hydroboration of a cyclic γ,δ-unsaturated amide is investigated using density functional theory. Geometry optimizations and harmonic frequency calculations for the model reaction are carried out using the basis set 6-31+G** for C, O, P, B, N, and H and LANL2DZ for Rh atoms. The Gibbs free energy of each species in THF solvent is obtained based on the single-point energy computed using the PCM model at the ECP28MWB/6-311+G(d,p) level plus the thermal correction to Gibbs free energy by deducting translational entropy contribution. The Rh-catalyzed reaction cycle involves the following sequence of events: (1) chelation of the cyclic γ,δ-unsaturated amide via alkene and carbonyl complexation in a model active catalytic species, [Rh(L2)2S2]+, (2) oxidative addition of pinacol borane (pinBH), (3) migratory insertion of the alkene double bond into Rh-H (preferred pathway) or Rh-B bond, (4) isomerization of the resulting intermediate, and finally, (5) reductive elimination to form the B-C or H-C bond with regeneration of the catalyst. Free energy profiles for potential pathways leading to the major γ-borylated product are computed and discussed in detail. The potential pathways considered include (1) pathways proceeding via migratory insertion into the Rh-H bond (pathways I, I-1, and I-2), (2) a potential pathway proceeding via migratory insertion into the Rh-B bond (pathway II), and two potential competing routes to a ß-borylated byproduct (pathway III). The results find that the Rh-H migratory insertion pathway I-2, followed in sequence by an unanticipated isomerization via amide rotation and reductive elimination, is the most favorable reaction pathway. A secondary consequence of amide rotation is access to a competing ß-hydride elimination pathway. The pathways computed in this study are supported by and help explain related experimental results.

γ-Selective directed catalytic asymmetric hydroboration of 1,1-disubstituted alkenes.

Directed catalytic asymmetric hydroborations of 1,1-disubstituted alkenes afford γ-dioxaborato amides and esters in high enantiomeric purity (90-95% ee).