Bismuth-Mediated α-Arylation of Acidic Diketones with ortho-Substituted Boronic Acids.

The α-arylation of cyclic and fluoroalkyl 1,3-diketones is made challenging by the highly stabilized nature of the corresponding enolates, and is especially difficult for sterically demanding aryl partners. As a general solution to this problem, we report the Bi-mediated oxidative coupling of acidic diones and ortho-substituted arylboronic acids. Starting from a bench-stable bismacycle precursor, a sequence of B-to-Bi transmetallation, oxidation and C-C bond formation furnishes the arylated diones. Development of methodology that tolerates both sensitive functionality and steric demand is supported by interrogation of key reactive intermediates. Application of our strategy to cyclic diones enables the concise synthesis of important agrochemical intermediates which were previously prepared using toxic Pb reagents. This methodology also enables the first ever arylation of fluoroalkyl diones which, upon condensation with hydrazine, provides direct access to valuable fluoroalkyl pyrazoles.

Umpolung Synthesis of Pyridyl Ethers by BiV -Mediated O-Arylation of Pyridones.

We report that O-selective arylation of 2- and 4-pyridones with arylboronic acids is affected by a modular, bismacycle-based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on SN Ar or cross-coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5-membered transition state. The kinetically-controlled regioselectivity for O-arylation-which is reversed relative to previous BiV -mediated pyridone arylations-is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.

Dissecting Solvent Effects on Hydrogen Bonding.

The experimental isolation of H-bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H-bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H-bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas-phase computed energies exhibited wild solvent-dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/ß solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H-bonds.

Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions.

Interactions between carbonyl groups are prevalent in protein structures. Earlier investigations identified dominant electrostatic dipolar interactions, while others implicated lone pair n→π* orbital delocalisation. Here these observations are reconciled. A combined experimental and computational approach confirmed the dominance of electrostatic interactions in a new series of synthetic molecular balances, while also highlighting the distance-dependent observation of inductive polarisation manifested by n→π* orbital delocalisation. Computational fiSAPT energy decomposition and natural bonding orbital analyses correlated with experimental data to reveal the contexts in which short-range inductive polarisation augment electrostatic dipolar interactions. Thus, we provide a framework for reconciling the context dependency of the dominance of electrostatic interactions and the occurrence of n→π* orbital delocalisation in C=O⋅⋅⋅C=O interactions.

The Importance of 1,5-Oxygen⋠⋠⋠Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis.

The importance of 1,5-O⋅⋅⋅chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch=O, S, Se) is investigated. Conformational analyses of N-acyl isochalcogenouronium species and comparison with kinetic data demonstrate the significance of 1,5-O⋅⋅⋅Ch interactions in enantioselective catalysis. Importantly, the selenium analogue demonstrates enhanced rate and selectivity profiles across a range of reaction processes including nitronate conjugate addition and formal [4+2] cycloadditions. A gram-scale synthesis of the most active selenium analogue was developed using a previously unreported seleno-Hugerschoff reaction, allowing the challenging kinetic resolutions of tertiary alcohols to be performed at 500 ppm catalyst loading. Density functional theory (DFT) and natural bond orbital (NBO) calculations support the role of orbital delocalization (occurring by intramolecular chalcogen bonding) in determining the conformation, equilibrium population, and reactivity of N-acylated intermediates.

The Origin of Chalcogen-Bonding Interactions.

Favorable molecular interactions between group 16 elements have been implicated in catalysis, biological processes, and materials and medicinal chemistry. Such interactions have since become known as chalcogen bonds by analogy to hydrogen and halogen bonds. Although the prevalence and applications of chalcogen-bonding interactions continues to develop, debate still surrounds the energetic significance and physicochemical origins of this class of σ-hole interaction. Here, synthetic molecular balances were used to perform a quantitative experimental investigation of chalcogen-bonding interactions. Over 160 experimental conformational free energies were measured in 13 different solvents to examine the energetics of O···S, O···Se, S···S, O···HC, and S···HC contacts and the associated substituent and solvent effects. The strongest chalcogen-bonding interactions were found to be at least as strong as conventional H-bonds, but unlike H-bonds, surprisingly independent of the solvent. The independence of the conformational free energies on solvent polarity, polarizability, and H-bonding characteristics showed that electrostatic, solvophobic, and van der Waals dispersion forces did not account for the observed experimental trends. Instead, a quantitative relationship between the experimental conformational free energies and computed molecular orbital energies was consistent with the chalcogen-bonding interactions being dominated by n → σ* orbital delocalization between a lone pair (n) of a (thio)amide donor and the antibonding σ* orbital of an acceptor thiophene or selenophene. Interestingly, stabilization was manifested through the same acceptor molecular orbital irrespective of whether a direct chalcogen···chalcogen or chalcogen···H-C contact was made. Our results underline the importance of often-overlooked orbital delocalization effects in conformational control and molecular recognition phenomena.

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

Correction to "Safety Considerations and Proposed Workflow for Laboratory Scale Chemical Synthesis by Ball Milling".

[This corrects the article DOI: 10.1021/acs.oprd.2c00226.].

Synthesis and Reactivity of N-Allenyl Cyanamides.

N-Allenyl cyanamides have been accessed via a one-pot deoxycyanamidation-isomerization approach using propargyl alcohol and N-cyano- N-phenyl- p-methylbenzenesulfonamide. The utility of this novel class of allenamide was explored through derivatization, with hydroarylation, hydroamination, and cycloaddition protocols employed to access an array of cyanamide products that would be challenging to access using existing methods.

Scalable total synthesis and comprehensive structure-activity relationship studies of the phytotoxin coronatine.

Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

Diastereoselective Simmons-Smith cyclopropanations of allylic amines and carbamates.

Cyclopropanation of 3-(N,N-dibenzylamino)cyclohexene with either Zn(CH(2)I)(2)(Wittig-Furukawa reagent) or CF(3)CO(2)ZnCH(2)I (Shi's reagent) gives the corresponding syn-cyclopropane as a single diastereoisomer, whilst cyclopropanation of 3-(N-tert-butoxycarbonylamino)cyclohexene with CF(3)CO(2)ZnCH(2)I gives the corresponding anti-cyclopropane exclusively; facile N-deprotection gives access to either diastereoisomer of the trifluoroacetic acid salt of 2-aminobicyclo[4.1.0]heptane.

Deoxycyanamidation of Alcohols with N-Cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS).

The first one-pot deoxycyanamidation of alcohols has been developed using N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as both a sulfonyl transfer reagent and a cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields. This approach exploits the underdeveloped desulfonylative (N-S bond cleavage) reactivity pathway of NCTS, which is more commonly employed for electrophilic C- and N-cyanation processes.

N-Cyanation of Secondary Amines Using Trichloroacetonitrile.

A one-pot N-cyanation of secondary amines has been developed using trichloroacetonitrile as an inexpensive cyano source. A diverse range of cyclic and acyclic secondary amines can be readily transformed into the corresponding cyanamides in good isolated yields, with the method successfully utilized in the final synthetic step of a biologically active rolipram-derived cyanamide. This approach exhibits distinct selectivity when compared to the use of highly toxic cyanogen bromide.

Direct ortho-Arylation of Pyridinecarboxylic Acids: Overcoming the Deactivating Effect of sp2-Nitrogen.

Direct arylations of pyridines are challenging transformations due to the high Lewis basicity of the sp2-nitrogen. The use of carboxylates as directing groups is reported, facilitating the Pd-catalyzed C-H arylation of this difficult class of substrates. This methodology allows regioselective C3/C4 arylation, without the need to use solvent quantities of the pyridine, and using low-cost chloro- and bromoarenes as coupling partners. Furthermore, carboxylates could be employed as traceless directing groups through a one-pot C-H arylation/Cu(I)-mediated decarboxylation sequence, thereby accessing directing-group-free pyridine biaryls.

α-Aroyloxyaldehydes: scope and limitations as alternatives to α-haloaldehydes for NHC-catalysed redox transformations.

α-Aroyloxyaldehydes are readily prepared bench stable synthetic intermediates. Their ability to act as α-haloaldehyde surrogates for NHC-promoted redox esterifications and in [4+2] cycloadditions is described.

Syntheses of trans-SCH-A and cis-SCH-A via a stereodivergent cyclopropanation protocol.

A highly diastereoselective cyclopropanation protocol has been employed in the syntheses of trans-SCH-A and cis-SCH-A. This strategy encompasses a stereodivergent procedure for the preparation of syn- and anti-cyclopropane diastereoisomers in high dr from a common allylic carbamate precursor.

Asymmetric synthesis of beta2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives.

Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium beta-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2'-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of beta-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of beta-amino-beta'-hydroxy N-acyl oxazolidinones.

Asymmetric synthesis of beta-amino-gamma-substituted-gamma-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters.

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.