Copper-Catalyzed Hydrogen/Iodine Exchange in Terminal and 1‑Iodoalkynes

Detailed kinetic profiles of the copper-catalyzed exchange between the acetylenic proton and iodide of terminal and 1-iodophenylacetylenes are reported. The electronic nature of the alkynes does not influence the equilibrium of the exchange (<i>K</i>_eq = 1), only the rate of equilibration. Notably, the profiles are the same for electron-rich, methyl-substituted phenylacetylenes but are divergent for electron-deficient, trifluoromethyl-substituted variants. The heretofore unreported exchange process yields practical considerations regarding reactions involving iodo and terminal alkynes

A Revised Mechanism for the Kinugasa Reaction

Detailed kinetic analysis for the Cu­(I)-catalyzed Kinugasa reaction forming β-lactams has revealed an anomalous overall zero-order reaction profile, due to opposing positive and negative orders in nitrone and alkyne, respectively. Furthermore, the reaction displays a second-order dependence on the catalyst, confirming the critical involvement of a postulated bis-Cu complex. Finally, reaction progress analysis of multiple byproducts has allowed a new mechanism, involving a common ketene intermediate to be delineated. Our results demonstrate that β-lactam synthesis through the Kinugasa reaction proceeds via a cascade involving (3 + 2) cycloaddition, (3 + 2) cycloreversion, and finally (2 + 2) cycloaddition. Our new mechanistic understanding has resulted in optimized reaction conditions to dramatically improve the yield of the target β-lactams and provides the first consistent mechanistic model to account for the formation of all common byproducts of the Kinugasa reaction

Oxidative Esterification of Aldehydes Using Mesoionic 1,2,3-Triazolyl Carbene Organocatalysts

The synthesis and catalytic activity of a new class of 1,2,3-triazolyl N-heterocyclic carbene organocatalysts is described. These new catalysts chemoselectively facilitate the oxidative esterification of aldehydes. NMR acidity studies show an inverse correlation between triazolium acidity and reactivity. Kinetic studies show that the resting state of the catalyst involves a NHC–aldehyde adduct. A catalytically active intermediate was synthesized and characterized by X-ray diffraction as the initial carbene–aldehyde adduct

Reevaluating the Stability and Prevalence of Conglomerates: Implications for Preferential Crystallization

Chiral resolution by preferential crystallization from a racemic or scalemic solution occurs by selective crystallization of a single enantiomer as a homochiral solid phase, known as a conglomerate. However, there is a prevailing perception that stable homochiral crystals are quite rare and are estimated to form in only 5–10% of all chiral compounds. In this work, the prevalence rate of stable conglomerates is reexamined using dispersion-corrected density-functional theory calculations for a collection of homochiral and heterochiral crystal pairs. The homochiral crystal is found to be the thermodynamically stable phase for 19% of the examined compounds. This value represents a lower bound of the prevalence rate since our sample is necessarily biased because the comparison is limited to cases where a stable heterochiral phase exists and does not include molecules with no reported heterochiral phase. Even so, this lower bound is two to four times higher than the often-quoted conglomerate prevalence rate, a value that is also based on (experimental) thermodynamic quantities. In addition, our results are used to reexamine Wallach’s rule and the close-packing principle. It is concluded that the prevalence of stable conglomerates has been underestimated, and, provided thermodynamic equilibrium drives the crystallization process, preferential crystallization has a much wider scope of applicability than previously assumed

Synthesis of Esters by in Situ Formation and Trapping of Diazoalkanes

A general method has been developed for the in situ formation and trapping of diazoalkanes by carboxylic acids to form esters. The method is applicable to a large variety of carboxylic acids using diazo compounds that are formed from the hydrazones of benzaldehydes and aryl ketones. In situ reaction monitoring with IR spectroscopy (ReactIR) was used to demonstrate that slow addition of the hydrazone to a mixture of oxidant and carboxylic acid avoids the buildup of the diazo compound. This method enables the safe preparation of esters from simple precursors without isolation of diazo compounds

Measuring and Suppressing the Oxidative Damage to DNA During Cu(I)-Catalyzed Azide–Alkyne Cycloaddition

We have used the quantitative polymerase chain reaction (qPCR) to measure the extent of oxidative DNA damage under varying reaction conditions used for copper­(I)-catalyzed click chemistry. We systematically studied how the damage depends on a number of key reaction parameters, including the amounts of copper, ascorbate, and ligand used, and found that the damage is significant under nearly all conditions tested, including those commonly used for bioconjugation. Furthermore, we discovered that the addition of dimethyl sulfoxide, a known radical scavenger, into the aqueous mixture dramatically suppresses DNA damage during the reaction. We also measured the efficiency of cross-linking two short synthetic oligonucleotides via click chemistry, and found that the reaction could proceed reasonably efficiently even with DMSO present. This approach for screening both DNA damage and reactivity under a range of reaction conditions will be valuable for improving the biocompatibility of click chemistry, and should help to extend this powerful synthetic tool for both in vitro and in vivo applications

Efficient and Selective Iron-Complex-Catalyzed Hydroboration of Aldehydes

An imine-coupled [Fe–N₂S₂]₂ complex, prepared from a readily available benzothiazolidine ligand, catalyzes selectively the hydroboration of aliphatic and aromatic aldehydes at low catalyst loadings (0.1 mol %) using pinacolborane. Both mono- and disubstituted aromatic and aliphatic aldehydes are hydroborated selectively in the presence of ketones, nitriles, alkenes, amines, and halides. Reaction of the [Fe–N₂S₂]₂ complex with CO and preliminary reaction progress kinetic studies point to a complex mechanism

Synthesis of β‑Ketosulfonamides Derived from Amino Acids and Their Conversion to β‑Keto-α,α-difluorosulfonamides via Electrophilic Fluorination

β-Ketosulfonamides derived from Boc or Cbz-protected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating <i>N</i>-allyl, <i>N</i>-alkyl methanesulfonamides with <i>n</i>-BuLi, followed by reaction of the resulting carbanion with methyl esters of <i>N</i>-protected l-amino acids. The analogous reaction using the dianion derived from an <i>N</i>-alkyl methanesulfonamide proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15–60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be removed in good yield using cat. Pd­(PPh)₃)₄ and dimethyl barbituric acid. When the fluorination reaction was performed with Cs₂CO₃ as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while β-ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides

Efficient and Selective Iron-Complex-Catalyzed Hydroboration of Aldehydes

An imine-coupled [Fe–N₂S₂]₂ complex, prepared from a readily available benzothiazolidine ligand, catalyzes selectively the hydroboration of aliphatic and aromatic aldehydes at low catalyst loadings (0.1 mol %) using pinacolborane. Both mono- and disubstituted aromatic and aliphatic aldehydes are hydroborated selectively in the presence of ketones, nitriles, alkenes, amines, and halides. Reaction of the [Fe–N₂S₂]₂ complex with CO and preliminary reaction progress kinetic studies point to a complex mechanism