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Open AccessArticle

Domino Synthesis of 1,2,5-Trisubstituted 1H-Indole-3-carboxylic Esters Using a [3+2] Strategy

by Siddhartha Maji, Kwabena Fobi, Ebenezer Ametsetor and Richard A. Bunce

Molecules 2025, 30(3), 444; https://doi.org/10.3390/molecules30030444 - 21 Jan 2025

Cited by 1 | Viewed by 1921

A new approach to 1,2,5-trisubstituted 1H-indole-3-carboxylic esters has been developed and studied. The method begins with the preparation of imines from aldehyde and primary amine derivatives. Treatment of these imines with the K₂CO₃-derived anion from methyl 2-(2-fluoro-5-nitrophenyl)acetate [...] Read more.

A new approach to 1,2,5-trisubstituted 1H-indole-3-carboxylic esters has been developed and studied. The method begins with the preparation of imines from aldehyde and primary amine derivatives. Treatment of these imines with the K₂CO₃-derived anion from methyl 2-(2-fluoro-5-nitrophenyl)acetate or methyl 2-(5-cyano-2-fluorophenyl)acetate in DMF initiates a [3+2] cyclization by addition of the anion to the imine followed by ring closure of the adduct nitrogen to the activated aromatic moiety via an S_NAr process. Twenty-one examples are reported. Temperatures required for the conversion range from 90 to 95 °C for the nitro-activated substrates to 125 to 130 °C for the cyano-activated precursors. Though efficient and atom economical, limitations arise from steric hindrance in the reacting partners. The initial indoline formed is not observed but instead undergoes spontaneous air oxidation to the give the aromatic heterocycle. Imines from nonaromatic aldehydes and amines are also possible, but these give slightly lower yields of 1H-indoles and only react with the nitro-activated substrates. The results are presented with a discussion of the mechanism and the factors important to the success of the reaction. Full article

(This article belongs to the Section Organic Chemistry)

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20 pages, 976 KB

Open AccessArticle

Benzo[d]oxazoles from Anilides by N-Deprotonation–O-S_NAr Cyclization

by Nash E. Nevels, Luke Subera and Richard A. Bunce

Molecules 2024, 29(18), 4322; https://doi.org/10.3390/molecules29184322 - 12 Sep 2024

Cited by 2 | Viewed by 2169

Abstract

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-S_NAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward S_NAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation–cyclization using [...] Read more.

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-S_NAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward S_NAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation–cyclization using 2 equiv. of K₂CO₃ in anhydrous DMF. Following deprotonation at nitrogen, the delocalized anion cyclized from the amide oxygen to give high yields of benzo[d]oxazoles. The temperature required for the cyclization of benzanilides correlated with the potency of the C5 activating group on the S_NAr acceptor ring with nitro (most potent) reacting at 90 °C (1 h), cyano reacting at 115 °C (1 h), methoxycarbonyl reacting at 120 °C (2 h), and trifluoromethyl (least potent) reacting at 130 °C (3 h). Acetanilides were more difficult to cyclize but generally required 4–6 h at these same temperatures for completion. Product purification was accomplished by recrystallization or chromatography. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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17 pages, 6715 KB

Open AccessArticle

A [3+3] Aldol-S_NAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives

by Kwabena Fobi, Ebenezer Ametsetor and Richard A. Bunce

Molecules 2024, 29(14), 3406; https://doi.org/10.3390/molecules29143406 - 20 Jul 2024

Viewed by 2023

Abstract

A one-pot [3+3] aldol-S_NAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde S_NAr acceptors (dielectrophiles) in the presence of K₂CO₃ in [...] Read more.

A one-pot [3+3] aldol-S_NAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde S_NAr acceptors (dielectrophiles) in the presence of K₂CO₃ in DMF at 65–70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by S_NAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where S_NAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate esters as the products. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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4 pages, 399 KB

Open AccessCommunication

Methyl 12-Methyl-3,9-dinitro-5,6,7,12-tetrahydro-13-oxodibenzo[b.g]bicyclo[3.3.1]nonane-6-carboxylate and Related Compounds

by Dylan R. Nanney and Richard A. Bunce

Molbank 2022, 2022(4), M1526; https://doi.org/10.3390/M1526 - 12 Dec 2022

Viewed by 1596

Abstract

A synthesis of the title compound and related structures is reported. The procedure involves double alkylation of a β-ketoester followed by double S_NAr ring closure from the γ carbon to give a dibenzo[3.3.1]bicyclic unit. This paper appears to be the first [...] Read more.

A synthesis of the title compound and related structures is reported. The procedure involves double alkylation of a β-ketoester followed by double S_NAr ring closure from the γ carbon to give a dibenzo[3.3.1]bicyclic unit. This paper appears to be the first to generate a mid-sized bicyclic target by a double S_NAr process. The synthesis can be performed in one step, but yields are superior (52–62%) when a two-stage procedure is used. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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16 pages, 809 KB

Open AccessArticle

Domino Aza-Michael-S_NAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters

by Ebenezer Ametsetor, Spencer Farthing and Richard A. Bunce

Molecules 2022, 27(20), 6998; https://doi.org/10.3390/molecules27206998 - 18 Oct 2022

Cited by 5 | Viewed by 3685

Abstract

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards S_NAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. [...] Read more.

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards S_NAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23–90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of K₂CO₃ to give 61–92% of the indole products. The reaction involves an aza-Michael addition, followed by S_NAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed. Full article

(This article belongs to the Special Issue Recent Developments in the Synthesis and Functionalization of Nitrogen Heterocycles)

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44 pages, 20643 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

by Dianqing Sun

Molecules 2022, 27(3), 1012; https://doi.org/10.3390/molecules27031012 - 2 Feb 2022

Cited by 19 | Viewed by 8916

Abstract

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput [...] Read more.

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular S_NAr or S_N2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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22 pages, 10490 KB

Open AccessArticle

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

by Joel K. Annor-Gyamfi, Ebenezer Ametsetor, Kevin Meraz and Richard A. Bunce

Molecules 2021, 26(4), 890; https://doi.org/10.3390/molecules26040890 - 8 Feb 2021

Cited by 6 | Viewed by 3711

Abstract

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to [...] Read more.

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward S_NAr ring closure. A control experiment established that the initial reaction was an S_N2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the S_NAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O₂, the expected dihydroquinolines were formed, while in the presence of O₂, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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17 pages, 3584 KB

Open AccessArticle

Naphthalenes and Quinolines by Domino Reactions of Morita–Baylis–Hillman Acetates

by Joel K. Annor-Gyamfi, Ebenezer Ametsetor, Kevin Meraz and Richard A. Bunce

Molecules 2020, 25(21), 5168; https://doi.org/10.3390/molecules25215168 - 6 Nov 2020

Cited by 6 | Viewed by 3639

Abstract

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K₂CO₃ in dry N,N-dimethylformamide (DMF) at 23 °C. The [...] Read more.

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K₂CO₃ in dry N,N-dimethylformamide (DMF) at 23 °C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a S_NAr ring closure. A control experiment indicated that the initial reaction was an S_N2’-type displacement of a side chain acetoxy by the AMC anion to afford the alkene product bearing the added nucleophile trans to the S_NAr aromatic ring acceptor. Thus, equilibration of the alkene geometry of the initial product was required prior to cyclization. Products were isolated in good to excellent yields. Numerous cases (24) are reported, and several mechanistic possibilities are discussed. Full article

(This article belongs to the Special Issue Recent Advances in Cascade Reactions and Related One-Pot Processes)

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13 pages, 1481 KB

Open AccessFeature PaperArticle

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

by Joel K. Annor-Gyamfi, Krishna Kumar Gnanasekaran and Richard A. Bunce

Molecules 2018, 23(3), 674; https://doi.org/10.3390/molecules23030674 - 16 Mar 2018

Cited by 12 | Viewed by 8573

Abstract

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) [...] Read more.

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the S_NAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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29 pages, 725 KB

Open AccessReview

Recent Syntheses of 1,2,3,4-Tetrahydroquinolines, 2,3-Dihydro-4(1H)-quinolinones and 4(1H)-Quinolinones using Domino Reactions

by Baskar Nammalwar and Richard A. Bunce

Molecules 2014, 19(1), 204-232; https://doi.org/10.3390/molecules19010204 - 24 Dec 2013

Cited by 133 | Viewed by 16050

Abstract

A review of the recent literature is given focusing on synthetic approaches to 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones and 4(1H)-quinolinones using domino reactions. These syntheses involve: (1) reduction or oxidation followed by cyclization; (2) S_NAr-terminated sequences; (3) acid-catalyzed ring closures [...] Read more.

A review of the recent literature is given focusing on synthetic approaches to 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones and 4(1H)-quinolinones using domino reactions. These syntheses involve: (1) reduction or oxidation followed by cyclization; (2) S_NAr-terminated sequences; (3) acid-catalyzed ring closures or rearrangements; (4) high temperature cyclizations and (5) metal-promoted processes as well as several less thoroughly studied reactions. Each domino method is presented with a brief discussion of mechanism, scope, yields, simplicity and potential utility. Full article

(This article belongs to the Special Issue Domino Reactions)

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