Regioselectivity in Hetero Diels–Alder Reactions

Grosso, Carla; Liber, Marta; Brigas, A. F.; Melo, Teresa M. V. D. Pinho e; Lemos, Américo

doi:10.1021/acs.jchemed.7b00933

Cited by 12 publications

(10 citation statements)

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“…A large number of new reviews [ 26 , 27 , 56 , 57 ] and original publications [ 31 , 58 , 59 , 60 , 61 , 62 ], which appeared in the last four years, demonstrates the growing interest in the chemistry of azoalkenes and their applications in hetero -Diels-Alder reactions. The presented study showed important mechanistic aspects and demonstrated that scarcely known 3,6-dihydro-2 H -1,3,4-thiadiazines can efficiently be prepared by regioselective hetero -Diels-Alder reactions of thioketones with in situ-generated azoalkenes, bearing an electron-withdrawing substituent at the terminal N-atom.…”

Section: Discussionmentioning

confidence: 99%

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies

et al. 2021

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The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27–2.58 Å) and longer N..C-distances (3.02–3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

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Section: Discussionmentioning

confidence: 99%

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies

et al. 2021

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“…Here, an unsymmetrical hetero‐dienes and unsymmetrical dienophiles provides cycloadduct regioisomers selectively as a paradigm of [4+2] cycloaddition [64] and their synthesis dictates by the orientation and approach of the transition state. In order to provide the view point of regioselectivity in hetero‐Diels‐Alder strategy, the group of Americo Lemos in 2019, scrutinized the hetero DA reaction of azoalkenes with electron rich alkenes towards accessing 1,4,5,6‐tetrahydropyridazine derivatives with high regio‐ and stereoselectivity (see Scheme 4a), as predicted by frontier molecular orbital (FMO) interactions and simple resonance theory [65] . Reaction commenced with the in situ generated diene 34 from 29 (tert‐butyl (Z)‐2‐(3‐bromo‐1‐ethoxy‐1‐oxopropan‐2‐ylidene)hydrazine‐1 carboxylate) and dienophile furan 30 and/or 2,3‐dihydrofuran 31 that afforded the cycloadduct 32 and/or 33 in <99% and 77% of yields respectively.…”

Section: Selectivity In Diels‐alder Cycloaddition Pathwaymentioning

confidence: 99%

“…In order to provide the view point of regioselectivity in hetero-Diels-Alder strategy, the group of Americo Lemos in 2019, scrutinized the hetero DA reaction of azoalkenes with electron rich alkenes towards accessing 1,4,5,6tetrahydropyridazine derivatives with high regio-and stereoselectivity (see Scheme 4a), as predicted by frontier molecular orbital (FMO) interactions and simple resonance theory. [65] Reaction commenced with the in situ generated diene 34 from 29 (tert-butyl (Z)-2-(3-bromo-1-ethoxy-1-oxopropan-2-ylidene)hydrazine-1 carboxylate) and dienophile furan 30 and/or 2,3dihydrofuran 31 that afforded the cycloadduct 32 and/or 33 in < 99% and 77% of yields respectively. Moreover, the resonance phenomena represented in Scheme 4b describing the regioselectivity issue in the inverse electron demand Diels-Alder reaction approach.…”

Section: Selectivity Influence By Molecular Arrangement Of Dienophilementioning

confidence: 99%

Regioselectivity Switch Towards the Development of Innovative Diels‐Alder Cycloaddition and Productive Applications in Organic Synthesis

2022

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The Diels‐Alder (DA) reaction is one of the fascinating synthetic strategies known for its pericyclic action and concerted mechanism that leads to various targets. Numerous synthetic pursuits have been rewarded with conceptually distinct and efficient ways. To date, extensive and spectacular accomplishments have been made in the field of Diels‐Alder chemistry to overcome the complexities of organic synthesis that inspired organic chemists to focus on expanding and establishing the postulates. In principle, DA reactions are governed by their straightforward reactivity pattern with a high degree of certainty, primarily attributed to the HOMO‐LUMO separation of reacting partners. Furthermore, general forecasts rely on account of background studies, conveniently hypothesizing the stereochemical outcomes and reaction dynamic pathways. DA has recently emerged as a technique for establishing a variety of products from the same reacting species under varying reaction conditions rather than a general reactivity profile. Such exceptional results are of significant interest in organic synthesis to pursue the challenges of unanticipated product establishment. Herein, we summarize the impressive finding of the remarkable switch in the regioselectivity and diastereoselectivity of DA reactions under a diverse set of reaction protocols in light of Diels‐Alder's unending importance in chemical science. This review aims to establish a beneficial account of Diels‐Alder towards the astonishing switches extended to study varying synthetic versions in organic synthesis protocols attributed to natural and biologically active scaffolds. This review also provides insight into distinct reaction dynamics in DA reactions that are subjected to access molecular frameworks ranging from simple to complicated ones to foster high levels of innovation in chemical sciences.

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“…Although there are several experiments reported in this Journal illustrating basic concepts of Diels–Alder reactions, undergraduate laboratory experiments on the application of the hetero-Diels–Alder reaction are more limited. − Moreover, this synthetic methodology features several aspects that make it suitable for an undergraduate laboratory experiment. The total synthesis involves four consecutive reactions carried out in one-pot, base-induced dehydrohalogenations, the hetero-Diels–Alder and Michael addition reactions, without the need of isolating or purifying any intermediate.…”

Section: Pedagogical Goals and Assessmentmentioning

confidence: 99%

“…The laboratory experiment described herein involves a regioselective one-pot synthetic approach to dipyrromethanes (e.g., 16 ) and bis(indolyl)methanes (e.g., 17 ) based on two consecutive reactions of nitrosoalkenes, generated in situ from 1,1-dichloro-2-propanone oxime ( 14 ), with pyrrole or indole, respectively (Scheme ). − …”

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confidence: 99%

One-Pot Synthetic Approach to Dipyrromethanes and Bis(indolyl)methanes via Nitrosoalkene Chemistry

et al. 2021

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A one-pot regio-and stereoselective synthesis of a dipyrromethane and a bis(indolyl)methane based on two consecutive reactions of nitrosoalkenes with pyrrole or indole, respectively, is described as an experiment to be carried out by upper-division undergraduate students in a laboratory classroom. Importantly, the ability of electrophilic conjugated nitrosoalkenes to react via Michael addition or hetero-Diels− Alder reactions with electron-rich heterocycles will provide an opportunity for students to acknowledge alternative reaction pathways underlying certain transformations. Reactions were performed under mild conditions using water as a solvent, followed by purification through column chromatography on silica gel, and characterization of the desired products by NMR and IR spectroscopy. This laboratory experiment combines organic synthesis, determination of the purity of compounds (TLC analysis and melting point measurements), as well as structural analysis (interpretation of 1D NMR spectra). Several important organic chemistry concepts, such as stereo-and regioselectivity, in situ generation and reactivity of conjugated nitrosoalkenes, conjugated 1,4-addition reactions, and cycloaddition reactions, are also discussed.

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Regioselectivity in Hetero Diels–Alder Reactions

Cited by 12 publications

References 12 publications

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies

Regioselectivity Switch Towards the Development of Innovative Diels‐Alder Cycloaddition and Productive Applications in Organic Synthesis

One-Pot Synthetic Approach to Dipyrromethanes and Bis(indolyl)methanes via Nitrosoalkene Chemistry

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