Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Blom, Jakob; Reyes‐Rodríguez, Gabriel J.; Tobiesen, Henriette N.; Lamhauge, Johannes N.; Iversen, Marc V.; Barløse, Casper L.; Hammer, Niels; Rusbjerg, Matilde; Jørgensen, Karl Anker

doi:10.1002/anie.201911793

Cited by 40 publications

(41 citation statements)

References 40 publications

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“…The primary amine 2 b containing a morpholine functionality has been demonstrated to be efficient in inducing high enantioselectivity in organocatalyzed α-functionalisation reactions of α-branched aldehydes. [8] In the chlorination presented herein, this catalyst proved to significantly accelerate the reaction, affording 3 a in 96 % yield after only 2 h with 24 % ee (entry 3). For practical purposes, the enantiomeric excess was determined by transforming 3 a via an S N 2 reaction with thiophenol into the corresponding thioether 4 a (see Supporting Information).…”

Section: Experimental Studiesmentioning

confidence: 78%

“…Given that the predominantly strong acids employed generate anions with a weak basicity, a deprotonation event by such species seems unlikely; 3) a somewhat curious phenomenon has to be considered when catalyst 2 b is applied: Recent work by our group provided evidence, that the morpholine nitrogen is prone to protonation, which changes the steric and electronic properties of the catalyst and thereby its role in the catalytic reaction. [8,14] The possibility of a protonated nitrogen at the morpholine moiety and the potential consequences will be further disclosed in the computational section of this paper. However, a comparison of the pK a -values (0.52 for TFA, 7.38 for N-methylmorpholine in H 2 O) renders the protonation of the catalyst by a strong acid feasible.…”

Section: Experimental Studiesmentioning

confidence: 99%

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Investigation of the Organocatalytic Chlorination of 2‐Phenylpropanal

Mohr

McCulley

Blom

et al. 2021

Chemistry A European J

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Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)-and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.

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Section: Experimental Studiesmentioning

confidence: 78%

Section: Experimental Studiesmentioning

confidence: 99%

Investigation of the Organocatalytic Chlorination of 2‐Phenylpropanal

Mohr

McCulley

Blom

et al. 2021

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Very recently, Jørgensen and co‐workers disclosed the first organocatalytic oxidative α‐thiolation of aldehydes. Instead of an enamine‐electrophile coupling, the authors describe a novel umpolung strategy that allows the activation of aldehydes which can be then paired with different types of nucleophiles, including thiols [20r] . To achieve that, the generated enamine is activated through organocatalysis and quinone‐promoted oxidation to access O‐bound quinol‐intermediates 43 that undergo nucleophilic substitution reactions (Scheme 14).…”

Section: Methods For the Synthesis Of α‐Sulfenylated Carbonyl Compoundsmentioning

confidence: 99%

Assessing Methodologies to Synthesize α‐Sulfenylated Carbonyl Compounds by Green Chemistry Metrics

Margalef

Samec

2020

ChemSusChem

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α‐Sulfenylated carbonyl compounds are important both as active pharmaceutical ingredients and as intermediates in organic synthesis. Owing to their relevance in synthetic organic chemistry, this Minireview focuses on assessing the most relevant synthetic procedures based on green chemistry metrics. The Minireview starts with the traditional routes and then focuses on more recently developed methodologies. These routes include sulfenylating reagents using organocatalysis, cross‐dehydrogenative couplings using in situ halogenations to prevent reactive intermediates in high concentrations, oxidative couplings using terminal oxidants such as DDQ or TEMPO, and redox‐neutral couplings using transition metal catalysis. These methodologies have been evaluated on the basis of atom economy, E factor, and the safety and toxicity of the transformations and the solvents used. Besides using green metrics to evaluate these novel methodologies, the synthetic utility is also assessed with regard to the availability of starting materials and the generality of the reactions. This Minireview aims to inspire researchers to apply green assessments to other methodologies and also for them to take measures to increase the greenness of their developed transformations.

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“…Presently, organocatalysis continues to be a rapidly developing research area, as shown by the large number of publications that have appeared since 2000 [36]. Some recent examples are highlighted in references [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56].…”

Section: Catalyzed Reactions Under Solvent-free Ball-milling Conditionsmentioning

confidence: 99%

Novel Methodologies for Chemical Activation in Organic Synthesis under Solvent-Free Reaction Conditions

Avila‐Ortiz

Juaristi

2020

Molecules

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One central challenge for XXI century chemists is the development of sustainable processes that do not represent a risk either to humanity or to the environment. In this regard, the search for more efficient and clean alternatives to achieve the chemical activation of molecules involved in chemical transformations has played a prominent role in recent years. The use of microwave or UV-Vis light irradiation, and mechanochemical activation is already widespread in many laboratories. Nevertheless, an additional condition to achieve “green” processes comes from the point of view of so-called atom economy. The removal of solvents from chemical reactions generally leads to cleaner, more efficient and more economical processes. This review presents several illustrative applications of the use of sustainable protocols in the synthesis of organic compounds under solvent-free reaction conditions.

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Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Cited by 40 publications

References 40 publications

Investigation of the Organocatalytic Chlorination of 2‐Phenylpropanal

Investigation of the Organocatalytic Chlorination of 2‐Phenylpropanal

Assessing Methodologies to Synthesize α‐Sulfenylated Carbonyl Compounds by Green Chemistry Metrics

Novel Methodologies for Chemical Activation in Organic Synthesis under Solvent-Free Reaction Conditions

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