2-acylbenzoic Acids Research Articles

A H4SiW12O40-catalyzed three-component tandem reaction for the synthesis of 3,3-disubstituted isoindolinones

A H4SiW12O40-catalyzed three-component tandem reaction of 2-acylbenzoic acids, primary amines and phosphine oxides to form 3,3-disubstituted isoindolinones was developed. By employing H4SiW12O40 as the catalyst and dimethyl carbonate (DMC) as the solvent, a diverse range of 2-acylbenzoic acid derivatives and primary amines worked well to give the C3-phosphinoyl-functionalized 3,3-disubstituted isoindolinones with the yield range of 61%-87%. Advantages of this transformation include green catalyst and solvent, available starting materials, broad substrate scope, high efficiency and operational simplicity with water as the sole by-product. The strategy achieved an efficient and green molecular fragment assembly to access isoindolinones, which would provide opportunities for the synthesis of potential biologically active molecules in a green manner.

One-pot synthesis of diverse isoindolobenzoxazinone and isoindoloquinazolinone derivatives through a transition metal-free cascade cyclization

We herein report a practical and efficient transition metal-free cascade cyclization reaction of 2-acylbenzoic acids with various anthranilic acids and anthranilamides to furnish isoindolobenzoxazinones and isoindoloquinazolinones, respectively, in good overall yields. This one-pot synthetic protocol features simple operation, broad substrate scope and good tolerance of functional groups. Furthermore, the synthetic utility of this reaction was extended for various chemical transformations and could be performed in gram-scale.

Acid/Base-Steered Cascade Cyclization: An Efficient One-Pot Access to Diverse Isobenzofuranone and Isoindolobenzoxazinone Derivatives.

We herein report the acid/base-steered two distinct reaction pathways of 2-acylbenzoic acids with isatoic anhydrides. In the presence of Na2CO3, the cascade process consists of the cyclization of 2-acetylbenzoic acid and nucleophilic ring-opening reaction of isatoic anhydride to furnish isobenzofuranone derivatives with high efficiency. However, p-toluenesulfonic acid can promote the product isobenzofuranones to undergo sequential intramolecular rearrangment, nucleophilic addition and cyclization reaction to produce diverse isoindolobenzoxazinones in good yields. The synthetic utility of this method was further demonstrated by the gram-scale preparation of the desired products and the facile transformations of the resulting products.

Catalyst-free one-pot cascade cyclization: An efficient synthesis of isoindolobenzoxazinones and isoindoloquinazolinones derivatives

A practical and efficient catalyst-free cascade cyclization reaction of 2-acylbenzoic acids with various amino alcohols or diamines was developed. This protocol provides a powerful and straightforward method for the one-pot synthesis of diverse isoindolobenzoxazinones, isoindoloquinazolinones and their derivatives. The synthetic strategy evades the use of catalyst, shows a broad substrate scope and could be performed in gram-scale.

Diverse privileged N-polycyclic skeletons accessed from a metal-free cascade cyclization reaction.

An exquisite metal-free cascade cyclization reaction of 2-acylbenzoic acids with amines was developed, which provided a powerful method for the one-pot synthesis of diverse isoindoloisoquinoline and benzoindolizinoindole derivatives. This protocol avoided the use of metal catalysts, proceeded with high efficiency and had broad substrate scope. These resulting products could be transformed into tertiary amines under the reduction of LiAlH4/AlCl3, followed by the Hofmann elimination offering lots of nitrogen-containing nine-membered ring compounds in excellent yields. All synthesized products containing fused N-polycyclic skeletons were difficult to be constructed using traditional methods and they have a wide range of applications in the pharmaceutical area.

Stereoselective synthesis of (Z)-3-ylidenephthalides via AlCl3-mediated cyclization with 2-acylbenzoic acids

An efficient method for the synthesis of (Z)-3-ylidenephthalides is reported in moderate to high yield with AlCl3 as catalyst. Different substrates of the 2-acylbenzoic acids are well performed in the Z/E selectivity. This method is highlighted by the gram-scale synthesis of the natural product (Z)-3-butylidene-5-hydroxyphthalide with anti-inflammatory activity.

Solid-state 17O NMR study of 2-acylbenzoic acids and warfarin

We report synthesis and solid-state 17O NMR characterization of four site-specifically 17O-labeled 2-acylbenzoic acids (2-RC(O)C6H4COOH) where R=H and CH3): 2-[3-17O]formylbenzoic acid, 2-[1,2-17O2]formylbenzoic acid, 2-[3-17O]acetylbenzoic acid, and 2-[1,2,3-17O3]acetylbenzoic acid. In the solid state, both 2-formyl- and 2-acetyl-benzoic acids exist as the cyclic phthalide form each containing a five-membered lactone ring and a cyclic hemiacetal/hemiketal group. Static and magic-angle-spinning 17O NMR spectra were recorded at 14.1 and 21.1T for these compounds, from which the 17O chemical shift and nuclear quadrupolar coupling tensors were determined for each oxygen site. These results represent the first time that 17O NMR tensors are fully characterized for lactone, cyclic hemiacetal, and cyclic hemiketal functional groups. We also report solid-state 17O NMR data for the cyclic hemiketal group an anticoagulant drug, warfarin. Experimental 17O NMR tensors in these compounds were compared with computational results obtained with a periodic DFT code BAND.

Enantiopure Indolizinoindolones with in vitro Activity against Blood- and Liver-Stage Malaria Parasites.

Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.

ChemInform Abstract: Synthesis of 4‐Substituted Phthalazin‐1(2H)‐ones from 2‐Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate Through PAT‐Guided Process Development.

A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.

Synthesis of 4-Substituted Phthalazin-1(2H)-ones from 2-Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate through PAT-Guided Process Development

A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.

Rapid synthesis of novel isoindolo[1,2-a]quinazoline on ionic liquid support under microwave irradiation

An efficient ionic liquid-supported (ILs) strategy is applied for the synthesis of substituted isoindolo[1,2-a]quinazoline under microwave irradiation. The ILs enhances the coupling capability of microwave flash heating in green organic synthesis. The acid-catalyzed heterocyclization of ionic liquid bounded 3-amino-4-[(alkylamino)methyl]benzoate was carried out with α-ketobenzoic acids or γ-ketoaliphatic acid to synthesize five and six member fused N-heterocycles. The one-pot heterocyclization proceeded via amidation between primary amines and 2-acylbenzoic acids or γ-ketoaliphatic acid, followed by the intramolecular dehydrocyclization with the keto group under microwave heating. The significant advantages in green synthesis by using ILs synthesis under controlled microwave dielectric heating are the dramatic reduction in reaction time, improved energy utilization, simple purification, and increasing the productivity of desired compounds.

Benzo[4,5]imidazo[2,1-a]phthalazines: I. substituted o-nitrophenylhydrazines in the synthesis of phthalazin-1(2H)-ones

Efficient cyclization procedure was developed for 2-nitro-, 2,4-dinitro-, 2-nitro-5-chloro-, and 4,5-dichloro-2-nitrophenylhydrazines with 2-acylbenzoic acids by heating the reagents in a mixture of of concentrated sulfuric acid and ethanol. A series of new phthalazin-1-ones was obtained with a substituted 2-nitrophenyl group in the position 2 and various substituents in the position 4.

Design and synthesis of tricyclic derivatives as high density lipoprotein cholesterol enhancers

A pharmacophore for increasing HDLC was proposed based on common structural features of non-thio-containing compounds with HDLC enhancing properties. A search of the compound database identified various series of these non-thio-containing compounds, including a novel tricyclic imidazoisoquinolone. Preparation of l-aryl-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamides using a novel and widely applicable one-step process from 2-acyl benzoic acids is reported. Reaction of diamines with 1-aryl-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamides and related aza-analogues proceeded with regio-control to furnish imidazoisoquinolones, pyrimidoisoquinolones, and imidazonaphthyridines. NMR studies and X-ray crystallography confirmed the regiochemistry of the products. Compounds of these series increased concentrations of HDLC in test animals following oral administration.

A Neighboring Group Effect of Carbonyl as Shown in the Mass Fragmentation Patterns of 4-Oxochroman-5-acetic Acids and of Some Related Compounds

Two examples of a neighbouring group effect of carbonyl first observed with 4-oxochroman-5-acetic acids are shown to occur quite generally during electron impact mass spectrometry of 2-acylbenzeneacetic acids, 2-acylbenzoic acids and their methyl esters. The free acids readily give the [parent - CO2] ion. 2-Acylbenzeneacetic acids and their methyl esters after loss of water or methanol, respectively, as a first step, lead to very stable isobenzofuran radical cations which form the base peaks in the mass spectra of the esters.

The structure of 2-keto and 2-aldehydobenzoic acids (spectroscopic studies)

1H NMR (with particular reference to the acidic protons) and 13C NMR examination of the reaction products from phthalic anhydride and dialkylcadmiums, formally represented as 2-acylbenzoic acids (open chain structure), show that they are 3-hydroxy-3-alkylphthalides (the ring structure) in the solid state and in solution. Similarly, so-called phthalaldehydic acid has been confirmed to be 3-hydroxy phthalide. Only in aqueous alkaline solution do the preceeding compounds exist as 2-acylbenzoates and a 2-formylbenzoate respectively. By contrast, 2-benzoylbenzoic acid has the open chain structure in the solid state and in solution. Mass, i.r. and u.v. absorption spectra support the results found by NMR investigation. In appropriately nuclear-substituted acetobenzoic acids, namely 2-aceto-3-hydroxy and 2-aceto-3-amino benzoic acids the existence of intramolecular hydrogen bonding may well be the reason for the absence of the 3-hydroxy-3-methylphthalide structure.

322. Reactions of organic azides. Part VI. The interaction of 2-acylbenzoic acids and alkylidenephthalides with hydrazoic and sulphuric acids

322. Reactions of organic azides. Part VI. The interaction of 2-acylbenzoic acids and alkylidenephthalides with hydrazoic and sulphuric acids