Intramolecular Dehydrative Cyclization Research Articles

Regio‐ and Chemoselectivity of Tandem N‐Ketoalkylation/Cyclization of 2‐Thioxoimidazoline‐4‐One

AbstractThe reaction of 2‐thioxoimidazolidin‐4‐one (thiohydantoin) with aliphatic, aromatic and heteroaromatic α‐iodomethylketones has been investigated in the absence of bases or catalysts. The reaction proceeds as N‐alkylation with subsequent intramolecular dehydrative cyclization. A series of new mono‐ and fused bicyclic iodide and triiodide salts was obtained based on the 5‐oxo‐2‐thioxoimidazolidin‐1‐ium and imidazo[2,1‐b]thiazolium cations. The observed regioselectivity has been rationalized and the mechanism was proposed.

In-situ formed aryl acid-triggered intramolecular dehydrative cyclization whilst supported Pd-catalyzed carbonylative synthesis of 2-aryl benzimidazoles

Herein, polystyrene supported palladium (Pd@PS) nanoparticles (NPs) catalyzed carbonylative synthesis of 2-aryl benzimidazoles from aryl iodides and aromatic diamines has been introduced. In-situ formed aryl carboxylic acid was revealed as a catalyst for dehydrative cyclization of secondary (2°) and tertiary (3°) amides formed via aminocarbonylation between aryl iodides and aromatic diamines. Herein, oxalic acid acts as carbon monoxide (CO) and carbon dioxide (CO2) gases source plausibly leading to aminocarbonylation via CO gas as major pathway and carboxylation of aryl iodides via CO2 as minor pathway. The Pd@PS catalyst was found to be easily separable, air/moisture stable and recyclable under the targeted reaction conditions. In addition, the present protocol requires only catalytic amount of inorganic base (K2CO3) to achieve the highest yields of desired products.

2-Amino-1,3-benzothiazole: Endo N-Alkylation with α-Iodo Methyl Ketones Followed by Cyclization.

Reactions of 2-amino-1,3-benzothiazole with aliphatic, aromatic and heteroaromatic α-iodoketones in the absence of bases or catalysts have been studied. The reaction proceeds by N-alkylation of the endocyclic nitrogen atom followed by intramolecular dehydrative cyclization. The regioselectivity is explained and the mechanism of the reaction is proposed. A number of new linear and cyclic iodide and triiodide benzothiazolium salts have been obtained and their structure proved by NMR and UV spectroscopy.

Chemoselective Ring Closure of 4-(3-Methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal Leading to Pandalizine A.

Starting from methylmaleic anhydride, a facile total synthesis of pandalizine A alkaloid is described via the regioselective reduction of methylmaleimide and acid-catalyzed enolization of 4-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal followed by chemoselective intramolecular dehydrative cyclization as the key steps. It is noteworthy that the analogous model system with an additional β-methyl group followed an alternative chemoselective intermolecular aldol condensation pathway.

One‐Pot Sequential Synthesis of Fused Isoquinolines via Intramolecular Cyclization/Annulation and their Photophysical Investigation

AbstractOne of the cyano group of γ‐keto malononitrile gets hydrolyzed selectively to an amide in the presence of copper(II) acetate monohydrate. The in situ generated amide undergo an intramolecular dehydrative cyclization to a 1,2‐dihydropyridone intermediate. Further annulation of the 1,2‐dihydropyridone with an internal alkyne in the same pot produce a fused isoquinolone, 4‐oxo‐2,6,7‐triaryl‐4H‐pyrido[2,1‐a]isoquinoline‐3‐carbonitrile. This one‐pot process is associated with the formation of one C−C, two C−N, two C=C and a C=O bonds. The final synthesis is a four‐step process consisting of selective hydrolysis of a cyano group to an amide, dehydrative cyclization of the amide to a cyclic amide, aromatization of the cyclic amide (2‐oxo‐1,2,3,4‐tetrahydropyridine moiety) to a 2‐oxo‐1,2‐dihydropyridine and finally, the C−H/N−H annulation with an alkyne. Density functional theory calculation reveals that the highest occupied molecular orbital (HOMO) is localized at the central core extending to the nitrile group and a negligible contribution from the two phenyl rings of the diphenylacetylene. On the other hand, the lowest unoccupied molecular orbital (LUMO) is also localized at the identical central core and extended up to the other phenyl ring. The calculated ΔE(LUMO‐HOMO) is in the range of 2.88 to 3.45 eV and the compounds display emission in the green region (502–560) nm and absorption (λmax) in the range of (454–490) nm. Therefore, these molecules may find application in bio‐imaging, theranostics and various applications in material science.magnified image

Access to Fluorazones by Intramolecular Dehydrative Cyclization of Aromatic Tertiary Amides: A Synthetic and Mechanistic Study.

An efficient synthesis has been developed for the preparation of 9H-pyrrolo[1,2-a]indol-9-ones (fluorazones) from readily available anthranilic acid derivatives via a one-pot amide- and pyrrole-formation step, followed by an intramolecular cyclodehydration. The cyclodehydration process is mediated by the activation of aromatic tertiary amides by triflic anhydride (Tf2O). Comparison of various benzo-substituents is shown to demonstrate the high functional group tolerance of this transformation. In addition, study of the reaction mechanism is also presented to unfold the exact role of the applied base additive. Herein, as a first example, we report our findings that Tf2O-mediated amide activation is obstructed by the easy protonation of amides by the formed triflic acid during the activation step. Additionally, it has been also proven that the base additive is not involved in the transformation of O-triflyliminium triflates into reactive species (e.g., nitrilium triflates) and is only responsible to neutralize the superacid to avoid the protonation of both the secondary or tertiary amides.

Carbazole Annulation via Cascade Nucleophilic Addition-Cyclization Involving 2-(Silyloxy)pentadienyl Cation.

We report a new strategy toward the synthesis of highly functionalized carbazoles via 2-(silyloxy)pentadienyl cation intermediates, which were generated upon ionization of vinyl-substituted α-hydroxy silyl enol ethers under Brønsted acid catalysis. These electrophilic species were found to readily undergo cascade reactions with substituted indoles to generate carbazole molecular scaffolds in good yields via a sequence of regioselective nucleophilic addition, followed by intramolecular dehydrative cyclization.

ChemInform Abstract: Copper‐Catalyzed Tandem Ullmann Type C—N Coupling and Dehydrative Cyclization: Synthesis of Imidazo[1,2‐c]quinazolines.

AbstractAn efficient one‐pot procedure is elaborated for the preparation of imidazo[1,2‐c]quinazolines (III) by an Ullmann‐type C—N coupling of bromides (I) with formamide followed by intramolecular dehydrative cyclization.

Stereoselective Total Synthesis of the Marine Macrolide Sanctolide A

AbstractThe stereoselective total synthesis of sanctolide A, a 14‐membered polyketide‐nonribosomal peptide (PK‐NRP) hybrid macrolide, was accomplished. Sanctolide A contains a rare N‐methyl enamide and 2‐hydroxyisovaleric acid functionality embedded into the macrocycle. The synthesis relied on Yamaguchi esterification and intramolecular dehydrative cyclization reactions to construct the core skeleton of the macrolide. The two key chiral centers were generated by Maruoka's allylation and Noyori's asymmetric ketone reduction reactions. Commercially available, inexpensive 2‐hydroxyisovaleric acid and hexanaldehyde were utilized as the raw materials for the total synthesis.

Total Synthesis of Laingolide A Diastereomers

The first total syntheses of two (±)-laingolide A diastereomers were achieved in 11 and 12 steps, respectively. The key steps include a tandem cross-dimerization/oxonia-Cope reaction and an intramolecular dehydrative cyclization for the formation of either the trans- or cis-enamide moieties.

PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives

New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 μM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.

Solid‐Phase Approach for the Synthesis of 2‐Amido‐1,3,4‐oxadiazoles

A new solid‐phase approach for the synthesis of 2‐amido‐1,3,4‐oxadiazoles has been developed. In this synthesis, hydroxypentyl JandaJel polymer support was treated with excess of oxalyl chloride to give resin‐bound 2‐chloro‐2‐oxoacetate, and this intermediate was then coupled with different hydrazides to give resin‐bound 2‐(N′‐acylhydrazinyl)‐2‐oxoacetate. Intramolecular dehydrative cyclization of resulting resin‐bound linear precursor followed by direct amidation using aluminum amide reagent provided 5‐substituted 1,3,4‐oxadiazoles as 2‐carboxamides. To explore the scope of this reaction sequence, we synthesized a small set of library using a combination of hydrazides and amines, and the desired products were obtained in good to high yields.

Total synthesis of palmyrolide A and its 5,7-epi isomers

Stereoselective total synthesis of palmyrolide A, a 15-membered neuroactive macrolide, was described by adopting a synthetic strategy developed for the proposed structures, and its 5,7-epi isomers. The strategy was designed in such a way that the set of stereoisomers, which were needed for establishing the absolute configuration of palmyrolide A, could be obtained from one time operation. The diastereoselective hydrogenation of exo-methylene-γ-butyrolactone to α-methyl-γ-butyrolactone, Yamaguchi esterfication, and intramolecular dehydrative cyclization to form trans-enamide were the key steps involved in the synthesis.

Synthesis and <i>in Vitro</i> Biological Activities of 4,5-Disubstituted 1,2,4-Triazole-3-Thiols

Purpose: The triazole nucleus is an important part of the therapeutically interesting drug candidate as antimicrobial, analgesic, anticancer, anticonvulsant and anti-inflammatory agents. Methods: Therefore, in this study, twelve 4,5-disubstituted-1,2,4-triazole-3-thiols were synthesized by the reaction of substituted isothiocyanates and hydrazides using the common method of base catalysed intramolecular dehydrative cyclization of substituted thiosemicarbazides 3(a-f) and 4(a-f). The structures of these compounds were characterized by means of FT-IR, 1H-NMR, and elemental analysis data. All these compounds were screened for antibacterial, antioxidant, antitumor and cytotoxic activities. Results: Among these compounds: 5c, 5f and 6f were found active against gram positive cocci, the compounds 5a, 5b, 5d, 6a and 6f showed 85% free radical scavenging effect at 3 ppm when tested for antioxidant activity, 75% tumors inhibition was recorded using 5c, 5d and 6a and brine shrimps lethality assay declared 5a, 5b and 6d was 129.62 μg/ml, 161.577 μg/ml and 81.56 μg/ml respectively. Conclusion: Compounds carrying significant bioactivity can be further studied using animal models to establish their safety profile prior to initiating clinical trials.

Hexamethyldisilazane‐iodine Induced Intramolecular Dehydrative Cyclization of Diamides: A General Access to Natural and Unnatural Quinazolinones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Hexamethyldisilazane-iodine induced intramolecular dehydrative cyclization of diamides: a general access to natural and unnatural quinazolinones

A simple and efficient general approach to various quinazolinone scaffolds, including peptidomimetic examples, has been demonstrated by employing HMDS/I 2 for the intramolecular dehydrative cyclization of diamides. The protecting groups –Boc, –Fmoc and –Cbz tolerated the present reaction conditions and we did not observe any racemization. The present protocol has also been used as a key step for the efficient four-step syntheses of the naturally occurring quinazolinones, sclerotigenin, (−)-circumdatin-F and (−)-fumiquinazoline-F.

HYPERVALENT IODINE IN SYNTHESIS. 75. A CONVENIENT SYNTHESIS OF OXADIAZOLES BY PALLADIUM-CATALYZED CARBONYLATION AND CYCLIZATION OF DIARYLIODONIUM SALTS AND AMIDOXIMES

ABSTRACT 3,5-Disubstituted-1,2,4-oxadiazoles were prepared in one-pot procedure in moderate yields via the palladium-catalyzed carbonylation of diaryliodonium salts with amidoximes under one atmosphere of carbon monoxide followed by intramolecular dehydrative cyclization.