Stereoselective synthesis of cis and trans-fused 3a-aryloctahydroindoles using cyclization of N-vinylic α-(methylthio)acetamides: synthesis of (−)-mesembrane

Treatment of N-(2-arylcyclohex-1-en-1-yl)-α-(methylthio)acetamides with N-chlorosuccinimide (NCS) gave 3a-aryl-2,3,3a,4,5,6-hexahydro-3-(methylthio)indol-2-ones. Desulfurization of the cyclization products followed by a catalytic hydrogenation of the resulting hexahydroindol-2-ones gave predominantly or exclusively trans-fused octahydroindol-2-ones. On the other hand, reduction of the desulfurization products with Et₃SiH in CF₃CO₂H exclusively provided cis-fused octahydroindol-2-ones. A chiral induction of N-[2-(3,4-dimethoxy)phenylcyclohex-1-en-1-yl]-α-(methylthio)acetamide having an (R)-1-(1-naphthyl)ethyl group on the nitrogen atom led to the synthesis of (−)-mesembrane and (−)-trans-mesembrane.     

4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides

4-Methyl- and 4-benzyl-5-aminoisoquinolin-1-ones are close analogues of the water-soluble PARP-1 inhibitor 5-AIQ. Their synthesis was approached through Pd-catalysed cyclisations of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave a mixture of 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydroisoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide similarly gave 2-benzhydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. The isomeric products are not interconvertible. A deuterium-labelling study indicated that the isomers were formed by different pathways: a π-allyl-Pd route and the classical Heck route. The corresponding secondary amides N-allyl-2-iodo-3-nitrobenzamide and N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCl, 150 °C, rapid heating). Hydrogenation of the nitro groups gave 4-methyl- and 4-benzyl-5-aminoisoquinolin-1-ones, which were potent inhibitors of PARP-1 activity.     

Diastereoselective synthesis of 6-functionalized 4-aryl-1,3-oxazinan-2-ones and their application in the synthesis of 3-aryl-1,3-aminoalcohols and 6-arylpiperidine-2,4-diones

Halocyclocarbamation of benzyl N-(1-phenyl-3-butenyl)carbamates afforded 6-functionalized 4-aryl-1,3-oxazinan-2-ones with moderate to excellent diastereoselectivity depending on the N-substituent. Importantly, in contrast to reported cyclocarbamations of homoallylic carbamates, which are generally trans-diastereoselective, cyclization of N-unsubstituted Cbz-protected homoallylamines led to cis-1,3-oxazinan-2-ones, predominantly. The use of N-benzylated and in situ prepared N-silylated derivatives resulted however in trans-selectivity. Transition states are proposed to explain the stereochemical influence of the N-substituent on the cyclocarbamations. The functionalized 1,3-oxazinan-2-ones could be further elaborated towards biologically or synthetically important 6-arylpiperidine-2,4-diones and 3-aryl-1,3-aminoalcohols.     

Formation of meta-arylsulfanyl- and meta-(alkylsulfanyl)phenols from cyclohexane-1,3-diones

Reaction of cyclohexane-1,3-diones with TsCl/Et₃N and treatment of the resulting 3-(tosyloxy)cyclohex-2-en-1-ones with aryl- or alkyl thiols and K₂CO₃ in MeCN gives 3-(arylsulfanyl)cyclohex-2-en-1-ones or 3-(alkylsulfanyl)cyclohex-2-en-1-ones, respectively. These compounds are easily brominated at C-2 by using NBS in MeCN; exposure to DBU in MeCN at room temperature then causes aromatization to afford meta-arylsulfanyl- and meta-(alkylsulfanyl)phenols.     

Palladium-Catalyzed Cross-Coupling Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides

Potassium N-methyltrifluoroborate isoindolin-1-one was synthesized and used in Suzuki–Miyaura palladium-catalyzed cross-coupling reactions with aryl and heteroaryl chlorides to prepare 29 examples of substituted N-benzyl isoindolin-1-ones. The new approach benefits from mild reaction conditions that tolerate a variety of functional groups. In addition, because of the large number of commercially available aryl and heteroaryl chlorides that can serve as coupling partners, the approach readily provides access to libraries of substituted N-benzyl isoindolin-1-ones.     

Synthesis of a new compound family, 1-aryl-3H-pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-ones

Representatives of a new family, 1-aryl-3H-pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-ones have been synthesized at our laboratory as bioisosters of biologically active 1-aryl-2,3-benzodiazepine-4-ones. The efficient synthetic route described applies the synthesis of 2-(2-aroylpyrrol-1-yl)acyl hydrazides followed by ring closure under acidic conditions. The N(3)-unsubstituted title compounds thus obtained can optionally be N-alkylated rendering the preparation of variously substituted derivatives possible. Scope and limitations of the new protocol and some interesting side reactions are also discussed in detail.     

Ring opening of 2-(cyanomethyl)aziridines by acid chlorides: synthesis of novel 4-amino-2-butenenitrile derivatives through intermediate aziridinium salts

1-Arylmethyl-2-(cyanomethyl)aziridines were transformed into novel N-arylmethyl-N-(2-chloro-3-cyanopropyl)amides as the major reaction products upon treatment with acid chlorides in CH₂Cl₂ through the ring opening of intermediate aziridinium salts. Subsequently, N-arylmethyl-N-(2-chloro-3-cyanopropyl)amides were converted into stable N-arylmethyl-N-(3-cyano-2-propenyl)amides for the first time by means of a dehydrochlorination mediated by Et₃N in CH₂Cl₂.     

Electrochemical regioselective synthesis of N-substituted/unsubstituted 4-selanylisoquinolin-1(2H)-ones

A novel and efficient electro-chemical initiated radical strategy was developed for the preparation of both N-substituted and N-unsubstituted 4-selanylisoquinolin-1(2H)-ones through selenylation of isoquinolin-1(2H)-ones with organodiselenides under chemical oxidant-, additive-free and ambient conditions.     

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.     

Synthesis and evaluation of some variants of the Nefkens’ reagent

A series of N-substituted phthalimides have been prepared in an effort to explore synthetic variants of the Nefkens’ reagent. Three N-acylphthalimides [R = –CH₃, –CH₂CH₃, and –C(CH₃)₃] were prepared and employed for the protection of a series of representative amines. In addition, an N-methanesulfonylphthalimide and N-(diethylphosphoryl)phthalimide were also prepared. It was determined that among the phthalimides that were prepared N-propanoylphthalimide was the most effective reagent for the protection reaction.     

Synthesis and photochromism of a series of new 2-unsubstituted 3-(2-benzylbenzoyl)quinolin-4(1H)-ones

Synthesis and characterization of a series of new 2-unsubstituted 3-(2-benzylbenzoyl)quinolin-4(1H)-ones is described. In addition to their potential biological activity, these compounds exhibit photoreversible photochromic properties in anaerobic conditions. Using the 1 and 2D NMR techniques we demonstrated that the coloration occurred owing to the formation of fluorescent 5a,6-dihydrobenzo[b]acridin-(5H)-ones. The photoreaction is stereoselective and the S,R-isomers are the major products (83%) whereas the S,S-isomers are the minor (6%). In addition, the irreversible formation of two oxidation products, 3-(2-benzoylbenzoyl)quinolin-4(1H)-ones, and acridin-12(5H)-one derivatives was observed in the presence of air.     

Photoinduced electron transfer cyclizations of aryl-linked phthalimides

The photochemistry of arene-linked phthalimides incorporating the carboxylate or thioether donor group was investigated. Simple N-phthalimidophenyl alkanoates exclusively gave photoreduction (CO₂H/H-exchange) products. In contrast, ω-phthalimido-meta-phenoxy carboxylates underwent photodecarboxylative cyclizations in yields of 6-48%. Likewise, catechol-linked derivatives furnished analogue cyclization products in 18-38% yield. Using the photodecarboxylation protocol, macrocyclic target compounds with ring sizes up to 17 could thus be realized. Two model phthalimides containing a thioether branch at the ortho-position of the arene-linker gave the analogue seven-membered cyclization products in yields of 28% and 35%, respectively.     

Novel route of the reaction of trifluoromethyl-containing N-methyl(4-ethoxyphenyl)imidazolidin-2-ones with urea

The reactions of perfluorobiacetyl with N-(4-ethoxyphenyl)- and N-methylurea afforded cis- and trans-isomers of 1-methyl-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one and 1-(4-ethoxyphenyl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one in a yield of ～60—75%. N-Alkyl(aryl)bis(trifluoromethyl)imidazooxazoles were obtained as unexpected products in the reaction of 1-alkyl(aryl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-ones with urea in dimethylacetamide. The reaction is accompanied by the rearrangement of imidazolidin-2-ones to N-alkyl(aryl)-5,5-bis(trifluoromethyl)hydantoins with CF₃ group migration from position 5 to position 4 of the starting heterocycle. A similar rearrangement is observed on boiling of the studied imidazolidin-2-ones in dimethylacetamide. The molecular structures of 3-(4-ethoxyphenyl)-5,5-bis(trifluoromethyl)imidazolidine-2,4-dione and 6-(4-ethoxyphenyl)-3a,6a-bis(trifluoromethyl)tetrahydroimidazo[4,5-d]oxazole-2,5-dione were studied by X-ray diffraction analysis.     

Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR,X-ray and Photophysical Analysis §

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K₂CO₃ in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (¹H, ¹³C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.     

An Oxidation Study of Phthalimide-Derived Hydroxylactams

A systematic study of the oxidation of 3-hydroxy-2-substituted isoindolin-1-ones (hydroxylactams) and their conversion to the corresponding phthalimides was undertaken using three oxidants. Of special interest was the introduction of nickel peroxide (NiO₂) as an oxidation system for hydroxylactams and comparison of its performance with the commonly used pyridinium chlorochromate (PCC) and iodoxybenzoic acid (IBX) reagents. Using a range of hydroxylactams, optimal conversions of these substrates to the corresponding imides was achieved with 50 equivalents of freshly prepared NiO₂ in refluxing toluene over 5–32 h reaction times. By comparison, oxidations of the same substrates using PCC/silica gel (three equivalents) and IBX (three equivalents) required oxidation times of 1–3 h for full conversion but required lengthier purification. While nominal amounts (~25 mg) of substrate hydroxylactams were used to ascertain conversion, scale-up procedures using all three methods gave good to excellent isolated yields of imides.     

Regioselective synthesis of 5-aminopyrazoles from reactions of amidrazones with activated nitriles: NMR investigation and X-ray structural analysis

N-Arylbenzamidrazones and ethyl 2-cyano-3-ethoxybut-2-enoate reacted together in ethanol and catalyzed by triethylamine (Et₃N) to give 5-amino-3-methyl-1-(aryl(phenylimino)methyl)-1H-pyrazole derivatives. Reaction of the target amidrazones with bis-(methylthio)methylidene)malononitrile in EtOH/Et₃N/DMF mixture proceeded to give the corresponding 5-aminopyrazoles. The structure of the obtained products was proved by IR, mass, and NMR spectra and elemental analyses. Two-dimensional NMR spectroscopy and X-ray structural analyses were used to differentiate the assigned structures from other possible ring systems and regioisomers. The reaction mechanism is discussed.     

Intramolecular cyclization of lithium 4,4-dimethoxy-1-(perfluoroalkyl)pentane-1,3-dionates on treatment with boron trifluoride diethyl etherate

Lithium 4,4-dimethoxy-1-(perfluoroalkyl)pentane-1,3-dionates react with BF₃?Et₂O to give 2-methoxy-2-methyl-5-(perfluoroalkyl)furan-3(2H)-ones in high yields.     

The use of anhydrous CeCl3 as a catalyst for the synthesis of 3-sulfenyl indoles

Anhydrous CeCl₃ was successfully used as a catalyst for the synthesis of several 3-sulfenyl indoles in good to excellent yields through the reaction of indole with N-(alkylthio) and N-(arylthio)phthalimides in DMF.     

Carbon-carbon bond formation via a tandem cationic 2-aza-Cope rearrangement-Lewis acid promoted Petasis reaction

Potassium alkynyltrifluoroborates and potassium (2-phenyl)vinyltrifluoroborates react with N-3-butenyl-(2,2-dichloro-1-propylidene)amine in the presence of BF₃·Et₂O as a Lewis acid to synthesize rearranged Mannich products. The reaction starts with a cationic 2-aza-Cope rearrangement of the imine, followed by the Lewis acid promoted borono-Mannich-type reaction on the rearranged imine to result in a new class of functionalized N-homoallylamines.     

Diaminomethylidene derivatives of β-oxo sulfones as potential reagents in heterocyclic synthesis and chelating ligands

Active methylene β-oxo sulfones add to the C≡N bond of benzoylcyanamide in the presence of catalytic amounts of Ni(acac)₂. Debenzoylation of the reaction products under the action of MeONa in MeOH gives N,N′-unsubstituted diaminomethylidene derivatives of β-oxo sulfones (acyl(R-sulfonyl)ketene aminals), which can be used as reagents for heterocyclic synthesis and as chelating ligands. The syntheses of 2-amino-3-arylsulfonylpyridin-4(1H)-ones and 5-sulfonylcytosine derivatives are presented as examples.