Regioselectivity in the Nucleophile Trapping of Arynes: The Electronic and Steric Effects of Nucleophiles and Substituents

Karmakar, Rajdip; Yun, Sang Young; Wang, Kung Pern; Lee, Daesung

doi:10.1021/ol403237z

Cited by 67 publications

(32 citation statements)

References 46 publications

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“…The expected alcohol nucleophilic addition to aryne (Scheme 1, right) was found to be second-order with respect to the alcohol (Figure 1), and consequently is favored only at high concentration of the latter. This computational result is consistent with early success where alcohols were used as solvents, and is also consistent with Hoye's and Lee's earlier results where large excess of alcohols was typically used [11][12]. Interestingly, this mechanistic rationale is in good agreement with a half-century-old finding from Bunnett that alcohol addition to arynes comes with accumulation of negative charge on aryne[4].…”

supporting

confidence: 90%

“…Meanwhile, it also sparked another curiosity standing equally elusive, that is, whether the lack of reactivity of aliphatic carboxylic acids and primary carboxyamides with arynes [7] could be explained by the same model. In fact, if one compares Hoye's and Lee's results [11,12] where acetic acid underwent nucleophilic addition to arynes with Larock's conditions [7] where no synthetically meaningful yield was obtained, it follows that the former success can be, at least partially, attributed to the excess and higher concentration of AcOH [15] which in turn might suggest higher-order kinetics with respect to the acid. It remains questionable as to why phenols behave differently from aliphatic alcohols in the nucleophilic addition with arynes, and why aromatic carboxylic acids behave differently from aliphatic ones [7].…”

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confidence: 99%

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Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

Dubrovskiy¹

2017

MOJBOC

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CommentaryMOJ Biorg Org Chem 2017, 1(1): 00004 manner [7]. As an illustrative example, when carbodiimide, a not well recognized nucleophile, and methanol are both present, aryne would selectively react with the former [8]. This seemingly counterintuitive "inertness" of benzyne toward aliphatic alcohols, along with some others highlighted in our recent review [9], constitutes a long-standing curiosity for aryne chemists, both synthetically and mechanistically.

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confidence: 90%

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confidence: 99%

Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

Dubrovskiy¹

2017

MOJBOC

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“…The derived benzyne 56 often undergoes nucleophilic capture competitively at both benzyne carbon atoms, 19 consistent with the relatively small difference between its two internal bond angles (DFT) 37 . When 55 (1.2 g, 5 mmol) was heated in toluene with 54 (1.5 equiv), indeed, a (separable) mixture of adducts 57a and 57b was cleanly formed (67% combined, Fig.…”

Section: Trapping With Quinidine and Quinine (Fig 6)mentioning

confidence: 53%

“…The tetrayne 6 undergoes HDDA cyclization highly regioselectively 19 to produce only the benzyne 8 (Fig. 2b).…”

Section: Trapping With Phenolics (Fig 2)mentioning

confidence: 99%

Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

Ross

Hoye

2017

Nature Chem

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The studies reported here were motivated by the desire to probe the extent to which benzynes, one of the classical reactive intermediates in organic chemistry, would react in discriminating fashion with benzyne trapping reagents that contain multiple functional groups and, accordingly, possible modes and sites of reactivity. We deemed that natural products comprise a palette of potential multifunctional compounds with which to address this question. We show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a high preference for one among several potential pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products, some in as few as three steps, that enable subsequent and rapid access to structurally diverse, polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity—a trait perhaps not broadly appreciated.

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“…4 h at 80 °C in C 6 D 6 ). We have trapped the resulting benzyne 19 with methanol 19,20 or acetic acid 5,19 to produce 20a or 20b , respectively (Fig. 2a).…”

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confidence: 99%

The pentadehydro-Diels–Alder reaction

Wang

Naredla

Thompson

et al. 2016

Nature

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In the classic Diels–Alder (DA) [4+2] cycloaddition reaction1, the overall degree of unsaturation of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic DA reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the hydrogen atom count in the reactant pair and in the resulting product is reduced by2, for example, four in the tetradehydro-DA (TDDA) and by six in the hexadehydro-DA (HDDA3,4,5,6,7) reactions. Any oxidation state higher than tetradehydro leads to the production of a reactive intermediate that is more highly oxidized than benzene. This significantly increases the power of the overall process because trapping of the benzyne intermediate8,9 can be used to increase the structural complexity of the final product in a controllable and versatile manner. In this manuscript, we report an unprecedented net 4π+2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is at the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization reaction a pentadehydro-Diels–Alder (PDDA) reaction—a nomenclature chosen for chemical taxonomic rather than mechanistic reasons. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π-component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.

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Regioselectivity in the Nucleophile Trapping of Arynes: The Electronic and Steric Effects of Nucleophiles and Substituents

Cited by 67 publications

References 46 publications

Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

The pentadehydro-Diels–Alder reaction

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