Anthranilic Esters Research Articles

Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas.

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N'-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.

Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety

A series of 2,4,6-trisubstituted pyrimidines with antharanilic acid ester moiety have been designed and synthesized by employing a one-pot multicomponent approach from methyl 5-(ethynyl)anthranilate, aroyl or cinnamoyl chlorides and various amidines. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, U-937, MDA-MB-231, BT-474, DU-145) using conventional MTT assays. Structure-activity relationship analysis revealed that 4,6-diarylpyrimidines 13–17, substituted with a pyridine or a pyrimidine ring in the 2 position displayed an increasing of activity compared to 2-methyl or 2-phenyl substituted pyrimidines. The 2-amino substututed compound 9 showed selectivity on the human monocyte-like cells U-937. Trisubstituted pyrimidines 18–21, containing a (E)-styryl substituent in the 6 position of the pyrimidine core, demonstrated an increasing of activity against the breast cancer cell lines MDA-MB-231, BT-474, and also against the human prostate cell lines DU-145. Compounds 18 and 20 shown the best potency towards the cancer cell lines MDA-MB-231; theirs activity was comparable with the activity of Doxorubicin on this cell lines. These compounds were confirmed to be cyclin-dependent kinase 9 (CDK9) inhibitors through in silico molecular modeling studies for the mode of action. The newly synthesized compounds may serve as lead molecules for the future research regarding the identification of new anticancer agents in the pyrimidine series.

Efficient Microwave-Assisted Synthesis of Methyl 4- or 5-Nitro­anthranilate

A novel method for the synthesis of anthranilate esters is described. The esterification reaction of nitro-substituted anthranilic acids was carried out under microwave irradiation. A range of solvents and other reaction parameters were investigated to provide the most environmentally friendly reaction conditions. The feasibility of scale-up was demonstrated, allowing a simple and inexpensive production of anthranilate esters.

ChemInform Abstract: Beyond Conventional Routes, an Unprecedented Metal‐Free Chemoselective Synthesis of Anthranilate Esters via a Multicomponent Reaction (MCR) Strategy.

A hitherto unreported route for the synthesis of anthranilate esters is demonstrated using 2-nitrobenzaldehyde, malonitrile and an alcohol or amine via a metal and oxidant free multicomponent reaction (MCR) strategy. This process simultaneously installs an ester and urea or urethane functionality via CO and CN bond formations via concurrent oxidation of the aldehyde group and reduction of the nitro group involving an intramolecular redox process.

Beyond conventional routes, an unprecedented metal-free chemoselective synthesis of anthranilate esters via a multicomponent reaction (MCR) strategy.

A hitherto unreported route for the synthesis of anthranilate esters is demonstrated using 2-nitrobenzaldehyde, malonitrile and an alcohol or amine via a metal and oxidant free multicomponent reaction (MCR) strategy. This process simultaneously installs an ester and urea or urethane functionality via CO and CN bond formations via concurrent oxidation of the aldehyde group and reduction of the nitro group involving an intramolecular redox process.

Synthesis and Characterization of Carboxyl-Substituted Polyanilines Doped with Halogenated Acids: Combining Conductivity with Solubility

Copolymers of aniline with anthranilic acid and two esters, ethyl and methyl anthranilate, were prepared through chemical synthesis using a variety of acids as the dopant. All polymers and copolymers were characterized by UV-Vis, Fourier transform infrared (FTIR) and Raman spectroscopies, as well as scanning electron microscopy. The data support the formation of variable amounts of phenazine-like structures due to ortho-coupling polymerization that competes with the para-coupling mode for the construction of the polymer backbone. The electrical conductivity and the solubility in a diversity of solvents were determined and correlated with the spectral data. The copolymers of aniline with anthranilic esters are more soluble than the corresponding polyanilines. In addition, the conductivity of the copolymer with methyl anthranilate doped with trifluoroacetic acid is of the same order of magnitude as that observed for the regular polyanilines. Overall, higher conductivities were obtained for all polymers and copolymers doped with hydrochloric acid and trifluoroacetic acid.

A Simple, Mild, and Practical Method for the Esterification and Thioesterification of Anthranilic Acid Utilizing N-(2-Aminobenzoyl)benzotriazole

A convenient and efficient method for the preparation of anthranilic esters and anthranilic thioesters has been developed by the treatment of N -(2-aminobenzoyl)benzotriazoles with alcohols and thiols in the presence of 4-(dimethylamino)pyridine (DMAP).

ChemInform Abstract: Heterocycles as Nonclassical Bioisosteres of α‐Amino Acids

AbstractReview: 58 refs.

Heterocycles as Nonclassical Bioisosteres of α‐Amino Acids

Bioisosterism of α-amino acids is often accomplished by replacing the α-carboxylate with one of the many known carboxylic acid bioisosteres. However, bioisosterism of the whole α-amino acid moiety is accomplished with heterocyclic bioisosteres that often display an acidic function. In this Minireview, we summarized the reported heterocycles as nonclassical bioisosteres of α-amino acids, which include quinoxaline-2,4(1H)-dione, quinoxaline-2,3(1H)-dione and quinolin-2(1H)-one, azagrevellin and azepine-derived structures. The binding mode of the crystalized bioisosteres were compared with those of the crystalized α-amino acids that bind in the same domain, and where no data on the crystal structure were available, the displacement studies of known orthosteric ligands were used. The reported bioisosteres share the following essential structural features for mimicking α-amino acids: an aromatic ring system joined to a lactam ring system with an acidic feature next to the lactam carbonyl, where this acidic feature together with the lactam carbonyl can mimic the α-carboxylate, and the lactam nitrogen together with the aromatic ring system can mimic the α-ammonium. The majority of these heterocycles can be prepared from three common corresponding starting materials: the corresponding anilines, isatins or anthranilic esters. The data collected here show the potential of this class of bioisosteres in the design of glutamate receptor ligands and beyond.

ChemInform Abstract: Efficient Synthesis of Anthranilic Esters via Pd‐Catalyzed Dehydrogenative/Decarbonylative Coupling of Anilides and Glyoxylates.

A novel way of synthesizing anthranilic esters was developed via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates.

Efficient synthesis of anthranilic esters via Pd-catalyzed dehydrogenative/decarbonylative coupling of anilides and glyoxylates

A novel way of synthesizing anthranilic esters was developed via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates.

Identifying the Binding Site of Novel Methyllycaconitine (MLA) Analogs at α4β2 Nicotinic Acetylcholine Receptors

Neuronal nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels that mediate fast synaptic transmission. Methyllycaconitine (MLA) is a selective and potent antagonist of the α7 nAChR, and its anthranilate ester side-chain is important for its activity. Here we report the influence of structure on nAChR inhibition for a series of novel MLA analogs, incorporating either an alcohol or anthranilate ester side-chain to an azabicyclic or azatricyclic core against rat α7, α4β2, and α3β4 nAChRs expressed in Xenopus oocytes. The analogs inhibited ACh (EC(50)) within an IC(50) range of 2.3-26.6 μM. Most displayed noncompetitive antagonism, but the anthranilate ester analogs exerted competitive behavior at the α7 nAChR. At α4β2 nAChRs, inhibition by the azabicyclic alcohol was voltage-dependent suggesting channel block. The channel-lining residues of α4 subunits were mutated to cysteine and the effect of azabicyclic alcohol was evaluated by competition with methanethiosulfonate ethylammonium (MTSEA) and a thiol-reactive probe in the open, closed, and desensitized states of α4β2 nAChRs. The azabicyclic alcohol was found to compete with MTSEA between residues 6' and 13' in a state-dependent manner, but the reactive probe only bonded with 13' in the open state. The data suggest that the 13' position is the dominant binding site. Ligand docking of the azabicyclic alcohol into a (α4)(3)(β2)(2) homology model of the closed channel showed that the ligand can be accommodated at this location. Thus our data reveal distinct pharmacological differences between different nAChR subtypes and also identify a specific binding site for a noncompetitive channel blocker.

Synthesis of 3-aryl-4(3H)-quinazolinones from anthranilic acid, ortho esters, and anilines using Ce(CH3SO3)3·2H2O as catalyst

3-Aryl-4(3H)-quinazolinones were synthesized efficiently by the three component one-pot cyclocondensation of anthranilic acid, ortho esters, and anilines in the presence of Ce(CH3SO3)3·2H2O at room temperature under solvent-free conditions. This method offers several advantages, such as a simple procedure, mild reaction conditions, short reaction time, and reusability of the catalyst.

Mechanistic elucidation of ketenimine–butynoate cycloaddition reaction: role of biradical intermediates in isotopomeric purity of benzyl (1,1a,6,6a- 13C 4)-6-methyl anthranilic ester

Thermal Diels–Alder reaction of vinyl ketenimines with 13C-labeled 2-butynoate, efficiently prepared from 13C 4-acetoacetate via the enol triflate, rendered at 160 °C the corresponding methylanthranilic ester isotopomerically pure. However, when the reaction was run at 100 °C, 7% of isotope exchange between C 6a and C 5 was observed. This result is explained through a base-like catalyzed isomerization of the alkyne to the corresponding allene. Combined DFT and coupled-cluster computations show the feasibility of this mechanistic proposal. Better agreement between DFT and coupled-cluster activation and reaction energies is observed for the meta-GGA MPWB1K functional as compared to previous B3LYP results.

Condensed isoquinolines. 21. Condensation of o-bromomethylphenylacetonitrile with substituted anthranilic acids

The reaction of substituted anthranilic acids and esters with o-bromomethylphenylacetonitrile give 2,3-R,R1-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one hydrobromides. It was found that 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones can exist in the two tautomeric imine and enamine forms. The tautomeric equilibrium position depends on the nature and position of the substituent in the quinazoline fragment. The borohydride reduction, oxidation, and reaction of 2,3-R,R1-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones with electrophilic reagents has been studied.

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

AbstractThe synthesis of several ABE tricyclic analogues 5, 31 and 32 of the alkaloid methyllycaconitine (1) is reported. The analogues contain two key pharmacophores: a tertiary N‐(3‐phenylpropyl) substituent attached to a 3‐azabicyclo[3.3.1]nonane ring system and a 2‐(3‐methyl‐2,5‐dioxopyrrolidin‐1‐yl)benzoate ester. Double Mannich reaction of the cyclic β‐keto esters 6 and 17 with the bis(aminol) ether 7 using methyltrichlorosilane as an activating agent provided an efficient method for the construction of the 3‐azabicyclo[3.3.1]nonanes 8 and 18. Ring‐closing metathesis of the derived dienes 11, 19, and 20 afforded the tricyclic ethers 12, 21, and 22, respectively, the C‐8 ester of which was reduced to a hydroxymethyl group to form the ABE tricyclic analogues 13, 23, and 24. Conversion of the alcohol 13 to the anthranilate ester 14 using N‐(trifluoroacetyl)anthranilic acid followed by fusion with methylsuccinic anhydride afforded the analogue 5 containing the key N‐(methylsuccinimido)anthranilate pharmacophore. In the case of the alcohols 23 and 24 the 2‐(3‐methyl‐2,5‐dioxopyrrolidin‐1‐yl)benzoate ester pharmacophore was appended by direct esterification with unsaturated acid 28 followed by hydrogenation to the ABE tricyclic compounds 33 and 34. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis of Simple Analogues of Methyllycaconitine — An Efficient Method for the Preparation of the N‐Substituted Anthranilate Pharmacophore.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of simple analogues of methyllycaconitine—an efficient method for the preparation of the N-substituted anthranilate pharmacophore

The synthesis of several A and AE ring analogues of the alkaloid methyllycaconitine is reported. The key 2-(2″-methylsuccinimido)benzoate ester pharmacophore is introduced using an efficient two step procedure. Esterification of the alcohol precursors with N-(trifluoroacetyl)anthranilic acid under Steglich conditions followed by sodium borohydride mediated cleavage of the trifluoroacetyl group affords the anthranilate esters. Subsequent fusion with methylsuccinic anhydride affords the N-substituted anthranilate derivatives containing the key pharmacophore present in a range of commonly occurring Delphinium and Aconitum alkaloids.

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment.

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.

Double Anion Capture Reactions of Anthranilic Esters with Oxaldiimidoyl Dichlorides − Efficient Synthesis of 2,2′-Biquinazoline-4,4′(3H,3′H)-diones

The reaction of anthranilic acids with oxaldiimidoyl dichlorides offers a new and convenient synthesis of quinazolin-4-ones. Condensation of anthranilic esters with diimidoyl dichlorides affords 2,2′-biquinazoline-4,4′(3H,3′H)-diones, which constitute a new class of dimeric heterocyclic compounds. In contrast, condensation of the dianion of N-methyl ortho-tolylamide with di(imidoyl) dichlorides affords seven- rather than six-membered ring products. Starting with 2-aminopyridine, 2,3-diimino-2,3-dihydroimidazo[1,2-a]pyridines could be efficiently prepared.