Grob Fragmentation of 2-Azabicyclo[2.2.2]oct-7-ene: Tool for the Stereoselective Synthesis of Polysubstituted Piperidines

The Grob fragmentation of azabicyclo[2.2.2]­octene leads to a dihydropyridinium intermediate. This highly reactive species reacts with a variety of organocuprates and other soft nucleophiles in a regioselective manner, allowing for the rapid and stereoselective synthesis of 2,3,4-trisubstituted 1,2,3,4-tetrahydropyridines. The resulting products were either reduced in situ to the corresponding piperidine or used to achieve the stereoselective construction of various nitrogen heterocycles

Diastereoselective Fluorocyclopropanation of Chiral Allylic Alcohols Using an α‑Fluoroiodo­methylzinc Carbenoid

Chiral fluorocyclopropyl carbinols were synthesized in high diastereoselectivities via a zinc mediated cyclopropanation reaction, using <i>sec</i>-allylic alcohols as simple building blocks. An enantioselective version of this transformation was achieved through <i>in situ</i> formation of chiral allylic zinc <i>sec</i>-alkoxides from the requisite aldehydes using Walsh’s protocol

Diastereoselective Borocyclopropanation of Allylic Ethers Using a Boromethylzinc Carbenoid

A borocyclopropanation of (<i>E</i>)- and (<i>Z</i>)-allylic ethers and styrene derivatives via the Simmons–Smith reaction using a novel boromethylzinc carbenoid is described. The carbenoid precursor is prepared via a 3-step sequence from inexpensive and commercially available starting materials. This methodology allows for the preparation of 1,2,3-substituted borocyclopropanes in high yields and diastereoselectivities. Several postfunctionalization reactions were also performed to illustrate the versatility of these building blocks

Diastereoselective Fluorocyclopropanation of Chiral Allylic Alcohols Using an α‑Fluoroiodo­methylzinc Carbenoid

Chiral fluorocyclopropyl carbinols were synthesized in high diastereoselectivities via a zinc mediated cyclopropanation reaction, using <i>sec</i>-allylic alcohols as simple building blocks. An enantioselective version of this transformation was achieved through <i>in situ</i> formation of chiral allylic zinc <i>sec</i>-alkoxides from the requisite aldehydes using Walsh’s protocol

Triflic Anhydride Mediated Synthesis of Imidazo[1,5‑<i>a</i>]azines

Imidazo[1,5-<i>a</i>]azines are synthesized in moderate to excellent yields using a mild cyclodehydration/aromatization reaction triggered by the use of triflic anhydride (Tf₂O) and 2-methoxypyridine (2-MeOPyr). Various substitution patterns and functional groups were found to be compatible under the optimized conditions. In addition, a 5-bromo-3-aryl derivative was also shown to be active in a Sonogashira cross-coupling and direct arylation reactions. A tertiary amide was compatible as a substrate leading to the synthesis of an imidazo[1,5-<i>a</i>]pyridinium triflate

C–H Functionalization of Cyclopropanes: A Practical Approach Employing a Picolinamide Auxiliary

A Pd-catalyzed, picolinamide-enabled, and efficient C–H arylation of cyclopropanes is described. The reaction can be promoted by either a silver additive or catalytic pivalic acid in the presence of a carbonate base. Various aryl iodides can be employed as coupling partners, providing exclusively <i>cis</i>-substituted cyclopropylpicolinamides

Access to Cyclopropyl-Fused Azacycles via a Palladium-Catalyzed Direct Alkenylation Strategy

Palladium-catalyzed direct alkenylation of cyclopropyl C–H bonds proceeds in high efficiency. This transformation provides access to novel cyclopropyl-fused azacycles. Ligand studies suggest that bisphosphine monoxide analogues of dppf and <i>rac</i>-BINAP are the active ligand species. Preliminary results support that both BozPhos and IPrMonophos ligands can achieve high enantioinduction for this novel direct alkenylation reaction. To date, this represents the first example of enantioselective C–H functionalization employing a bisphosphine monoxide ligand

Design and Synthesis of Chiral Heteroleptic Rhodium(II) Carboxylate Catalysts: Experimental Investigation of Halogen Bond Rigidification Effects in Asymmetric Cyclopropanation

A general method for the synthesis of chiral heteroleptic rhodium­(II) tetracarboxylate catalysts is reported. The chlorinated TCPT unit was found to be an efficient polarity-control group, allowing the isolation of each complex from a mixture of six possible products. This approach contributes to enlarging the scope of accessible chiral Rh­(II) catalysts and allowed further study of the halogen bond rigidification effect observed in chlorinated complexes

Design and Synthesis of Chiral Heteroleptic Rhodium(II) Carboxylate Catalysts: Experimental Investigation of Halogen Bond Rigidification Effects in Asymmetric Cyclopropanation

A general method for the synthesis of chiral heteroleptic rhodium­(II) tetracarboxylate catalysts is reported. The chlorinated TCPT unit was found to be an efficient polarity-control group, allowing the isolation of each complex from a mixture of six possible products. This approach contributes to enlarging the scope of accessible chiral Rh­(II) catalysts and allowed further study of the halogen bond rigidification effect observed in chlorinated complexes

Difluorocarbene Addition to Alkenes and Alkynes in Continuous Flow

The first <i>in-flow</i> difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF₃ and a catalytic quantity of NaI. The <i>in situ</i> generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes, allowing the synthesis of the corresponding difluorocyclo­propanes and difluorocyclo­propenes. The reaction is complete within a 10 min residence time at high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this process in a green, atom-economic, and safe manner