Facile diastereoselective synthesis of functionally enriched hydantoins via base-promoted intramolecular amidolysis of C-3 functionalized azetidin-2-ones

Synthesis of functionally enriched hydantoins has been developed and validated via base-assisted intramolecular amidolysis of C-3 functionalized β-lactams.     

Stereoselective synthesis of 3-alkylidene/alkylazetidin-2-ones from azetidin-2,3-diones

Azetidin-2,3-diones have been used as synthons for the synthesis of C-3 alkylidene/alkylazetidin-2-ones. Some of the 3-alkylazetidin-2-ones are well known for their cholesterol absorption inhibitor activity. A regio and stereoselective Grignard reaction on a keto group followed by dehydration using PPh₃/CCl₄ reagent is a key step in this synthesis. Hydrogenation of the 3-alkylideneazetidin-2-ones provided stereoselectively cis-3-alkylazetidin-2-ones in very good yields.     

An efficient formal synthesis of (S)-dapoxetine from enantiopure 3-hydroxy azetidin-2-one

An efficient formal synthesis of S-(+) dapoxetine starting from 3-hydroxy azetidin-2-one is described. The intermediate (S)-3-(dimethyl amino)-3-phenylpropan-1-ol was synthesized in enantiopure form starting with 3-hydroxy azetidin-2-one in seven steps.     

Enantioselective total synthesis of (2S,3R,4R)-d-xylo-phytosphingosine from substituted azetidin-2-one

Enantiomerically pure (2S,3R,4R)-d-xylo phytosphingosine is synthesized in 36% overall yield in seven steps from known β-lactam (8) derived from d-mannitol triacetonide.     

A new entry to functionalized cycloalkylamines: diastereoselective intramolecular amidoalkylation of N,O-acetal TMS ether possessing allylsilane

Highly diastereoselective cyclization (>20:1) as a new entry to functionalized cycloalkylamines has been conducted with acyclic N,O-acetal TMS ethers possessing an allylsilane moiety.     

InBr3-catalyzed intramolecular cyclization of 2-alkynylanilines leading to polysubstituted indole and its application to one-pot synthesis of an amino acid precursor

We describe InBr₃-catalyzed cyclization of 2-alkynylaniline derivatives having a variety of functional groups producing polysubstituted indoles. This methodology could be applied to the one-pot synthesis of an amino acid precursor by the addition of a catalytic amount of the indium salt, an imine, and TMSCl.     

An efficient approach to isoindolo[2,1-b][2]benzazepines via intramolecular [4+2] cycloaddition of maleic anhydride to 4-α-furyl-4-N-benzylaminobut-1-enes

Acylation of 4-α-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid via amide formation followed by intramolecular Diels-Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25 °C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates.     

A novel reaction of the ‘Huisgen zwitterion’ with benzofuran-2,3-diones: an efficient strategy for the synthesis of spirocyclic benzofuran-2-one derivatives

The nitrogen-based nucleophile generated from azodicarboxylate and triphenylphosphine displayed good reactivity toward benzofuran-2,3-diones to generate a variety of spirocyclic benzofuran-2-one derivatives. The reactions accommodate a number of benzofuran-2,3-diones and different dialkylazodicarboxylates to give the enriched functionalized 3-spirooxadiazole benzofuran-2-ones with moderate to good yields (up to 93%).     

Ring opening [3+2] cyclization of azaoxyallyl cations with benzo[d]isoxazoles: Efficient access to 2-hydroxyaryloxazolines

A selective ring-opening [3+2] cyclization reaction of benzo[d]isoxazoles with 2-bromo-propanamides has been developed.The azaoxyallyl cation intermediates are employed as C^O 3-atom synthon to build oxa-heterocycles via the selectivity of suitable cyclization partners.This transformation provides rapid access to highly functionalized 2-hydroxyaryl-oxazolines under mild conditions and excellent regioselectivity.     

Reaction between isocyanides and chalcones: an efficient solvent-free synthesis of 5-hydroxy-3,5-diaryl-1,5-dihydro-2H-pyrrol-2-ones

A simple and efficient synthesis of 5-hydroxy-3,5-diaryl-1,5-dihydro-2H-pyrrol-2-ones is described. Heating a mixture of an isocyanide and a 1,3-diaryl-2-propen-1-one under solvent-free conditions produces the title compounds in good to excellent yields.     

Photoreaction of 2′-chloro-4-R-benzanilide: synthesis of 2-(4-R-phenyl)-1,3-benzoxazole and 9-R-phenanthridin-6(5H)-one (R=H, CH3, CH3O)

The UV photolysis of 2′-chloro-4-R-benzanilides in acetonitrile solution under nitrogen atmosphere leads to the formation of intramolecular photocyclization products (9-R-phenanthridin-6(5)-one, 20–30%), along with the minor photoreduction, photo-Fries, and intramolecular photosubstitution products. The photoreaction of 2′-chloro-4-R-benzanilide in acetonitrile solution containing 10% of water or aqueous sodium hydroxide however gives 2-(4-R-phenyl)-1,3-benzoxazole as a major product (30%) along with the photoreduction, photo-Fries and intramolecular photocyclization products.     

Stereoselective synthesis of highly enantioenriched 3-methyl-2-cyclohexen-1-ones possessing an asymmetric quaternary carbon as C-4 or C-6: a sugar template approach

The 1,4-addition of the enolate generated from α-methylated acetoacetate incorporated at C-4 of methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside to methyl vinyl ketone, followed by aldol condensation of the resulting 1,4-addition product under two base-mediated conditions, provided 4-O-functionalized d-glucose derivatives with high diastereoselectivity. These products install a 3-methyl-2-cyclohexen-1-one-4- (or -6-) carboxylic acid as the O-4 ester, in which C-4 or C-6 is an asymmetric quaternary carbon. Removal of the sugar template from those aldol condensation products provided synthetically useful 3,6-dimethyl-2-cyclohexen-1-one-6-carboxylic acid and 3,4-dimethyl-2-cyclohexen-1-one-4-carboxylic acid derivatives both in high enantioenriched forms.     

[2+2] Cycloaddition of electron-poor acetylenes to (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones: synthesis of highly functionalized 1-heteroaroyl-1,3-butadienes

Microwave-assisted [2+2] cycloaddition of (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones to dimethyl acetylenedicarboxylates gives (2E,3E)-dimethyl-2-[(dimethylamino)methylene]-3-(substituted)succinates in 8-91% yield. In the case of a 4,5-dihydrothiazoline derivative, cycloaddition also took place at the endocyclic CN double bond.     

Superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids: synthesis of quinolin-2(1H)-one derivatives

The superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids by Bronsted superacids (CF₃SO₃H, HSO₃F) or strong Lewis acids AlX₃ (X=Cl, Br) results in the formation of 4-aryl quinolin-2(1H)-ones in quantitative yields. The vinyl triflates or vinyl chlorides may be formed as additional reaction products. The investigated amides in reactions with benzene give 4,4-diaryl 3,4-dihydroquinolin-2-(1H)-ones under the superelectrophilic activation. 4-Aryl quinolin-2(1H)-ones in POCl₃ are converted into 4-aryl 2-chloroquinolines. 4-Fluorophenyl-4-phenyl 3,4-dihydroquinolin-2-(1H)-one give N-formylation products in a yield of 79% under the Vilsmeier–Haack reaction conditions.     

Tandem C-3/C-2 annulation of indole,benzofuran, and benzothiophene with 2-alkynyl benzylalcohol: an efficient approach to the diverse tetracyclic heteroazulene ring systems

We demonstrate an efficient and flexible strategy toward the synthesis of a library of biologically and pharmaceutically important tetracyclic heteroazulene derivatives in the presence of inexpensive and less toxic molecular iodine. The present strategy involves a sequential alkylation and alkenylation of indole/benzofuran/benzothiophene with o-alkynyl benzyl alcohols derivatives to obtain tetracyclic heteroazulene derivatives in moderate to good yields. Compared to other methodologies, the present strategy is more general, versatile, and environmentally friendly.     

Molecular hybridization-guided annulation reactions of isatins with 4-methylpent-3-en-2-one: A direct access to spirooxindole tetrahydropyranones

An efficient molecular hybridization strategy has been utilized for the synthesis of pirooxindole tetrahydropyranones 3 through annulation reactions of isatins 1 with 4-methylpent-3-en-2-one 2. Products consist of a pirooxindole tetrahydropyranone scaffold and propan-2-ether unit were smoothly obtained in moderate yields (up to 56% yield). The one-pot, two-step reaction, avoiding the isolation and purification of intermediates C, has proved to be a practical protocol. This protocol leads to new knowledge in the fields of both molecular complexity and the lead compound discovery.     

Palladium mediated direct coupling of silylated arylalkynes with propargylic chlorides: an efficient access to functionalized conjugated allenynes

Pd/Cu-catalyzed one-pot reaction of 1-trimethylsilyl-2-arylalkynes with propargylic chlorides in the presence of TBAF is described. The present new procedure is applicable to a wide range of silylated arylalkynes with both electron-withdrawing and electron-donating substituents. Functionalized allenynes can thus be obtained in good yields without prior deprotection of the alkynes.     

Ruthenium-catalyzed formal sp3 C–H activation of allylsilanes/esters with olefins: efficient access to functionalized 1,3-dienes

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.

1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.^1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.¹⁵ Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.^16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.^25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,^28–31 acrylates/acrylamides,^32–36 enamides,³⁷ and enol esters/ethers.^38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,⁴⁰ and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.⁴¹ In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.⁴² The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.⁴³ A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp² C–H bond functionalization was described by Loh et al.⁴⁴ Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.⁴⁵ Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.⁴⁶ Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.⁴⁷ Innumerable methods are known for the preparation of both allyl and vinyl silanes^48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction⁵³ and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp³)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.^54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl₂(p-cymene)]₂ catalyst in the presence of AgSbF₆ as an additive and co-oxidant Cu(OAc)₂ in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.⁵⁶ Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.⁵⁷ The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization of reaction conditions^a

Thiophene-containing products of the Ugi reaction in an oxidation-triggered IMDA/aromatization cascade: a simple access to 3-oxoisoindolines

A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transformation and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps. The second step is thought to include S-oxidation/IMDA/S-oxidation/SO₂ extrusion/aromatization events.