A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides

Demkiw, Krystyna M.; Araki, Hirofumi; Elliott, Eric L.; Franklin, Christopher L.; Fukuzumi, Yoonjoo; Hicks, Frederick A.; Hosoi, Kazushi; Hukui, Tadashi; Ishimaru, Yoichiro; O’Brien, Erin M.; Omori, Yoshiaki; Mineno, Masahiro; Mizufune, Hideya; Sawada, Naotaka; Sawai, Yasuhiro; Zhu, Lei

doi:10.1021/acs.joc.6b00194

Cited by 17 publications

(8 citation statements)

References 37 publications

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“…In agreement with the general notion in the literature, ,,,,, our exploratory studies (Table ) revealed that no addition of phenylmagnesium bromide ( 8a ) occurs to the sodium carboxylate ( Na-6a ; entry 1), and a similar result is obtained in the presence of PrNHLi ( 9b ; entry 2), probably due to the THF in the commercial Grignard solution . In stark contrast, i -Pr 2 NMgCl·LiCl ( 9a ) has a dramatic effect in enhancing the conversion and selectivity of the reaction, yielding ketone 1a as the major product (entry 3).…”

supporting

confidence: 89%

“…The addition of aromatic Grignard reagents to benzoates would give rise to important benzophenone compounds, but it is particularly problematic due to the lower reactivity of aromatic carboxylates and aryl Grignard reagents. To the best of our knowledge, this reaction has only been studied using chelate-assisted heteroaryl substrates or lithium propylamide as an additive (Scheme B) . However, the application of these processes in organic synthesis is severely limited by the narrow scope, and the inhibition in the presence of tetrahydrofuran, which is the most common solvent for synthesizing, storing, and distributing Grignard reagents. , Overcoming the challenges associated with the direct addition of Grignard nucleophiles ( 8 ) to carboxylate anions ( 6 ) is key to enabling an extended modular synthesis of ketones from CO 2 ( 3 ) .…”

mentioning

confidence: 99%

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i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Colas

Mendoza

2019

Org. Lett.

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The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions. This strategy enables the modular synthesis of ketones from CO2 and the preparation of isotopically-labelled pharmaceutical building blocks in a single operation. Ketones (1) are one of the cornerstones of organic chemistry, being a fundamental class of products and essential synthetic intermediates. Aromatic ketones are particularly relevant drugs and fragrances, and they are key to the synthesis of heterocyclic cores in valuable products. 1 As a result, extensive research has been dedicated to obtain ketones from raw carboxylic acids (2) and CO2 (3). However, the addition of localized carbon nucleophiles to carboxylic acids is a key transformation that remains challenging after decades of research (Scheme 1A). Most approaches elaborate carboxylic acids 2 into more electrophilic derivatives 4, such as acyl chlorides, 2 anhydrides, 3 thioesters, 2f,4 cyanides, 5 ketimines, 6 imides, 7 amides 8 and Weinreb amides. 9 Special carbon nucleophiles 5 with lower reactivity like cuprates, 10 organozincs, 4,11 and boronates, 2g,3b,7,12 are often used to avoid the rapid over-addition to the resulting ketone products 1. Alternatively, the direct coupling of carbon nucleophiles with unactivated carboxylic acids requires unstable organolithium reagents, often in excess. 13,14 These addition reactions to lithium carboxylate anions Li-6 benefit from the stability of the addition complex Li-7, but are limited by competing metalation reactions, carbonyl reduction, and the narrow functional scope of the lithium organometallics. 14 Grignard reagents (8) are preferred nucleophiles for their enhanced stability and functionalgroup tolerance, particularly in large-scale processes. 15,16 Unlike organolithiums, Grignard reagents (8) are poorly reactive towards carboxylate anions (6), and the resulting addition intermediates are unstable, giving rise to tertiary alcohol over-addition by-products. 13d,14

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supporting

confidence: 89%

mentioning

confidence: 99%

i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Colas

Mendoza

2019

Org. Lett.

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“…The polymer structures and synthetic routesa re depicted in Scheme1.T hree brominated benzoylpyridine derivatives 2benzoyl-5-bromopyridine (1), 2-(4-bromobenzoyl)pyridine (2), and 3-(4-bromobenzoyl)pyridine (3)a sa cceptor building blocks were obtained by the optimizeds ynthetic method. [64][65][66] The corresponding precursors 9,9-dihexal-10-(6-benzoylpyridin-3-yl)-9,10-dihydroacridine( A3PyB), 9,9-dihexal-10-(4-((pyridin-2yl)carbonyl)phenyl)-9,10-dihydroacridine (AB2Py), and 9,9-dihexal-10-(4-((pyridin-3-yl)carbonyl)phenyl)-9,10-dihydroacridine (AB3Py) were preparedf rom the Pd-catalyzed CÀNcoupling reaction of brominated benzoylpyridine and 9,9-dihexal-9,10-dihydroacridine with tBuONa as the base in excellent yield. Further bromination in the dark smoothly afforded almostq uantitative bromoacridine monomers M A3PyB ,M AB2Py ,a nd M AB3Py ,o f which the fluorescencew as dramatically weakenedr elative to their precursors.…”

Section: Resultsmentioning

confidence: 99%

Effect of a Pendant Acceptor on Thermally Activated Delayed Fluorescence Properties of Conjugated Polymers with Backbone‐Donor/Pendant‐Acceptor Architecture

Yang

Wang

et al. 2019

Chemistry An Asian Journal

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Three sets of conjugated polymers with backbone‐donor/pendant‐acceptor architectures, named PCzA3PyB, PCzAB2Py, and PCzAB3Py, are designed and synthesized. The three isomeric benzoylpyridine‐based pendant acceptor groups are 6‐benzoylpyridin‐3‐yl (3PyB), 4‐((pyridin‐2‐yl)carbonyl)phenyl (B2Py) and 4‐((pyridin‐3‐yl)carbonyl)phenyl (B3Py), whereas the identical backbone consists of 3,6‐carbazolyl and 2,7‐acridinyl rings. One acridine ring and each acceptor group constitute a definite thermally activated delayed fluorescence (TADF) unit, incorporated into the main chain of the polymers through the 2,7‐position of the acridine ring with the varied content. All of the polymers display legible TADF features with a short microsecond‐scale delayed lifetime (0.56–1.62 μs) and a small singlet/triplet energy gap (0.10–0.19 eV). Progressively redshifted emissions are observed in the order PCzAB3Py, PCzA3PyB, and PCzAB2Py owing to the different substitution patterns of the pyridyl group. Photoluminescence quantum yields can be improved by regulating the molar content of the TADF unit in the range 0.5–50 %. The non‐doped organic light‐emitting devices (OLEDs) fabricated by solution‐processing technology emit yellow‐green to orange light. The polymers with 5 mol % of the TADF unit exhibit excellent comprehensive electroluminescence performance, in which PCzAB2Py5 achieves a maximum external quantum efficiency (EQE) of 11.9 %, low turn‐on voltage of 3.0 V, yellow emission with a wavelength of 573 nm and slow roll‐off with EQE of 11.6 % at a luminance of 1000 cd m−2 and driving voltage of 5.5 V.

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“…Acids underwent deprotonation to give intermediate 20.1 , which led to coupling products 20.2 . The Zhu group developed the construction of 2‐pyridyl benzyl ketone 20.3 via a one‐pot reaction of i PrMgBr, i PrMgCl⋅LiCl and 2‐iodopyridine (Eq. 20‐2).…”

Section: Deprotonationmentioning

confidence: 99%

Arylacetic Acids in Organic Synthesis

et al. 2019

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Arylacetic acids are widely used in organic reactions and their recent advances are summarized in six categories according to their triggered pathways: (1) the acid as directing group in ortho-or meta-CÀ H activation; (2) decarboxylation; (3) deprotonation; (4) nucleophilic methylenes; (5) nucleophilic acids; (6) electrophilic acids. Reactions with alkenes, alkynes, aldehydes, amines, water, Grignard reagents, silanes and so forth are discussed. We hope this Minireview will promote future research in this area. Recently, the Zeng group [3g] reported a weakly coordinationassisted alkynylation of arylacetic acids with iridium catalysis under air atmosphere (Eq. 2-2). It was supported the sixmembered ring cycloiridiated 2.5 acted as the key intermediate. The alkynylation of indole, thiophene, pyrrole, and benzo[b] thiophene afforded better yields than phenylacetic acids. The acid moiety could also participated in the intramolecular ortho-CÀ H activation, which was developed by the Shi group to obtain lactonization 2.6 (Eq. 2-3) (Scheme 2). Meta-CÀ H ArylationThe study of Yu group [3e] in 2017 revealed a successful control of meta selectivity 3.1 of arylation from aryl iodides (Eq. 3-1). The use of mono-protected 3-amino-2-hydroxypyridine (as ligand) and 2-carbomethoxynorbornene (NBE-CO 2 Me) were crucial. In the absence of NBE-CO 2 Me, only ortho-arylated product was obtained. This method was still efficient in a gramsale (Scheme 3). Decarboxylation Decarboxylative CouplingAs shown in Scheme 4, the decarboxylation could generate benzyl radicals 4.1. Then, direct couplings of 4.1 with diverse [ + ] These authors contributed equally. Scheme 1. Six categories based on triggered mechanism. 2 3 4 5 6 7 8 . Passerini Three-Component ReactionThe Passerini reaction was the oldest multicomponent reaction (MCR) [37d] in which isocyanides, carboxylic acids and aldehydes were used. It was powerful for the rapid construction of complex molecules. The tactic to expand the scope of Passerini reaction was to use surrogates of the carbonyl partners. As described in Scheme 51, syn-chlorooximes, [37b] diazoketones, [37c] alcohols, [37d,e] azirines [37f] and isatins [37g] could be employed instead of aryl or alkyl aldehydes [37a] (Scheme 51). Besides, in 2018, Zhang and co-workers [37] have firstly reported asymmetric phosphoric acid-catalyzed four-component Ugi reaction, which Scheme 45. BTM-catalyzed cycloaddition. Scheme 46. HBTM-catalyzed cycloaddition. Scheme 47. TFA-catalyzed reaction. Scheme 48. Friedel-Crafts triggered tandem reactions. Scheme 49. C-acylation of 1,3-diones. Scheme 50. C-acylation of 1,3-indandiones.

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A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides

Cited by 17 publications

References 37 publications

i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Effect of a Pendant Acceptor on Thermally Activated Delayed Fluorescence Properties of Conjugated Polymers with Backbone‐Donor/Pendant‐Acceptor Architecture

Arylacetic Acids in Organic Synthesis

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A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides

Cited by 17 publications

References 37 publications

i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Effect of a Pendant Acceptor on Thermally Activated Delayed Fluorescence Properties of Conjugated Polymers with Backbone‐Donor/Pendant‐Acceptor Architecture

Arylacetic Acids in Organic Synthesis

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Product

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i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions