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Sulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective "SO" donor to enable the one‐pot, three‐component synthesis of sulfoxides and sulfinamides. [ABSTRACT FROM AUTHOR]

Since its introduction in 2004, Knochel's so called Turbo‐Grignard reagents revolutionized the usage of Grignard reagents. Through the simple addition of LiCl to a magnesium alkyl an outstanding increase in reactivity can be achieved. Though the exact composition of the reactive species remained mysterious, the reactive mixture itself is readily used not only in synthesis but also found its way into more distant fields like material science. To unravel this mystery, we combined single‐crystal X‐ray diffraction with in‐solution NMR‐spectroscopy and closed our investigations with quantum chemical calculations. Using such a variety of methods, we have gained insight into and an explanation for the extraordinary reactivity of this extremely convenient reagent by determining the structure of the first bimetallic reactive species [t‐Bu2Mg ⋅ LiCl ⋅ 4 thf] with two tert‐butyl anions at the magnesium center and incorporated lithium chloride. [ABSTRACT FROM AUTHOR]

Sulfoxides and sulfinamides represent versatile sulfur functional groups found in ligands, chiral auxiliaries, and bioactive molecules. Canonical two‐component syntheses, however, rely on substrates with a preinstalled C−S bond and impede efficient and modular access to these sulfur motifs. Herein is presented the application of an easily prepared, bench‐stable sulfoxide reagent for one‐pot, three‐component syntheses of sulfoxides and sulfinamides. The sulfoxide reagent donates the SO unit upon the reaction with a Grignard reagent (RMgX) as a sulfenate anion (RSO−). While subsequent trapping reactions of this key intermediate with carbon electrophiles provide sulfoxides, a range of tertiary, secondary, and primary sulfinamides can be prepared by substitution reactions with electrophilic amines. The syntheses of sulfinamide analogs of amide‐ and sulfonamide‐containing drugs illustrate the utility of the method for the rapid preparation of medicinally relevant molecules. [ABSTRACT FROM AUTHOR]

A one‐pot, three‐step protocol for the preparation of Grignard reagents from organobromides in a ball mill and their subsequent reactions with gaseous carbon dioxide (CO2) or sodium methyl carbonate providing aryl and alkyl carboxylic acids in up to 82 % yield is reported. Noteworthy are the short reaction times and the significantly reduced solvent amounts [2.0 equiv. for liquid assisted grinding (LAG) conditions]. Unexpectedly, aryl bromides with methoxy substituents lead to symmetric ketones as major products. [ABSTRACT FROM AUTHOR]

A big problem with the chemistry literature is that it is not standardized with respect to precise operational parameters, and real time corrections are hard to make without expert knowledge. This lack of context means difficult reproducibility because many steps are ambiguous, and hence depend on tacit knowledge. Here we present the integration of online NMR into an automated chemical synthesis machine (CSM aka. "Chemputer" which is capable of small‐molecule synthesis using a universal programming language) to allow automated analysis and adjustment of reactions on the fly. The system was validated and benchmarked by using Grignard reactions which were chosen due to their importance in synthesis. The system was monitored in real time using online‐NMR, and spectra were measured continuously during the reactions. This shows that the synthesis being done in the Chemputer can be dynamically controlled in response to feedback optimizing the reaction conditions according to the user requirements. [ABSTRACT FROM AUTHOR]

Abstract: The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high‐yielding, mass‐efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2, this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures. [ABSTRACT FROM AUTHOR]

A tetracyclic dinitrile was synthesized in twelve steps from cyclohex-2-en-1-one by using a chelation-triggered conjugate addition to a g-hydroxy-substituted a,β-unsaturated nitrile and an oxidative dearomatization/Diels-Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirineC (in 19 steps) was accomplished by a hydrogenatom-transfer reaction of the tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization, and subsequent functional group manipulation. [ABSTRACT FROM AUTHOR]

Abstract: Despite the manifold use of heterocyclic fluorophores, only a fraction of the desired dye diversity can be accessed by contemporary synthetic approaches. Herein, we describe a modular method that converts various carboxylic acid esters directly into a broad spectrum of heteroanthrylium fluorophores. The double addition of heteroatom‐bridged 1,5‐bifunctional organomagnesium reagents to esters leads to the formation of acridinium, xanthylium, and SiR fluorophores after dehydrative acidic work‐up. This one‐step synthetic method provides access to organophotoredox catalysts for dual catalysis with nickel and dyes amenable to fluorescence enhancement. [ABSTRACT FROM AUTHOR]

A direct functionalization of unsubstituted isoxazole ( 1) was achieved by generation of 4-isoxazolyl anion species ( 3). An efficient 4-iodination of isoxazole and halogen-metal exchange reaction using a turbo Grignard reagent ( iPrMgCl⋅ LiCl) were essential for the generation of 3, which reacted with various electrophiles to give 4-functionalized isoxazoles in good to high yields. Isoxazolyl boronate, boronic acid, and stannane were also synthesized as useful building blocks from 1. The current methods enabled us to synthesize multi-functionalized isoxazoles by introducing each substituent into the desired positions. Furthermore, total synthesis of triumferol, which was isolated from Triumfetta rhomboidea, was achieved from 1 in only three steps. [ABSTRACT FROM AUTHOR]

Stable CO linkages are generally unreactive in cross-coupling reactions which mostly employ more electrophilic halides or activated esters (triflates, tosylates). Acetates are cheap and easily accessible electrophiles but have not been used in cross-couplings because the strong CO bond and high propensity to engage in unwanted acetylation and deprotonation. Reported herein is a selective iron-catalyzed cross-coupling of diverse alkenyl acetates, and it operates under mild reaction conditions (0 °C, 2 h) with a ligand-free catalyst (1-2 mol %). [ABSTRACT FROM AUTHOR]

Arynes participate in three-component coupling reactions with N, S, P, and Se functionalities to yield 1,2-heteroatom-difunctionalized arenes. Using 2-iodophenyl arylsulfonates as benzyne precursors, we could effectively add magnesiated S-, Se-, and N-nucleophilic components to the strained triple bond. In the same pot, addition of electrophilic N, S, or P reagents and a copper(I) catalyst trapped the intermediate aryl Grignard to produce a variety of 1,2-difunctionalized arenes. [ABSTRACT FROM AUTHOR]

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one-pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper-catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods. [ABSTRACT FROM AUTHOR]

AAA: The asymmetric allylic alkylation (AAA) of trisubstituted cyclic allyl bromides with Grignard reagents is catalytic (2 mol % of ligand) and regioselective (SN2'/SN2=91:9→100:0). The quaternary carbon centers are formed with good to high enantioselectivity (e.r.=81.5:19.5→96:4). [ABSTRACT FROM AUTHOR]

Cover Picture: Standardization and Control of Grignard Reactions in a Universal Chemical Synthesis Machine using online NMR (Angew. Keywords: Grignard reaction; NMR spectroscopy; process analytical technology; process control EN Grignard reaction NMR spectroscopy process analytical technology process control 23029 23029 1 10/13/21 20211018 NES 211018 B The digitization of chemistry b requires that synthesis procedures can be written and optimized in a chemical programming language to perform reliable "chemputation" for the synthesis on the "chemputer" robot, a universal synthesis machine. The cover image shows how a universal chemical synthesis engine equipped with an NMR sensor can be used to optimize reactions producing the automated synthesis procedure as an optimized process code ensuring that the chemputation can be improved and is reliable. [Extracted from the article]