Synthesis of 6H-isoindolo[2,1-a]indol-6-ones via Pd-catalyzed cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO

An efficient method for preparation of substituted 6H-isoindolo[2,1-a]indol-6-ones (2) that are important structural components of a vast array of naturally occurring and pharmacologically active compounds, has been developed by the palladium-catalyzed intramolecular cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO. Significantly, the intermolecular aminocarbonylation products 2-(1H-indol-2-yl)benzamides are formed when an excess of amine is used in this reaction system. Alternatively, 2-(1H-indol-2-yl)benzamides can also be synthesized by the in situ aminolysis of 2. Furthermore, treatment of 2 with hydrosilane in the presence of KOH gave the unprecedented reducing products 2-(-1H-indol-2-yl)benzyl alcohols in 75–86% yields. These results demonstrate that 6H-isoindolo[2,1-a]indol-6-ones are versatile substrates for further synthetic elaboration.     

Homogeneous catalytic aminocarbonylation of 1-iodo-1-dodecene. The facile synthesis of odd-number carboxamides via palladium-catalysed aminocarbonylation

Various amine nucleophiles including glycine methyl ester were used in the palladium-catalysed aminocarbonylation of (E)- and (Z)-1-iodo-1-dodecene. The substrates were synthesised from 1-dodecanal via the corresponding hydrazone, which was treated with iodine in the presence of tetramethylguanidine. The homogeneous catalytic aminocarbonylation resulted in the corresponding odd-number carboxamides in moderate to good yields. The reaction was accompanied by the formation of some carboxamides with triple bonds in the 2-position. The latter products were formed in relatively high yields with secondary amines such as piperidine and morpholine and were isolated as pure compounds.     

Palladium-catalysed reactions of 6-halogeno-1,1′-binaphthyl derivatives. A detailed investigation of structure/reactivity and structure/selectivity relationships

Five 6-halogeno-binaphthyl derivatives of different structure were synthesised starting from 2,2′-dihydroxy-1,1′-binaphthyl 1. Several new 6-substituted binaphthyl compounds were obtained via the palladium-catalysed reactions of these derivatives. The reactivity of 6-iodo derivatives was much greater in most cases. In cross-coupling reactions the 6-bromo compounds were converted into the products using longer reaction times and/or higher temperatures. The reactivity difference between the two types of substrates was especially marked in aminocarbonylation and Heck reactions.     

Synthesis of N-picolylcarboxamides via palladium-catalysed aminocarbonylation of iodobenzene and iodoalkenes

A systematic investigation of the palladium-catalysed aminocarbonylation of iodobenzene, 1-iodocyclohexene and 1′-iodostyrene in the presence of N-nucleophiles containing pyridyl moieties (2-, 3- and 4-picolylamine, N-ethyl-4-picolylamine, di-(2-picolyl)amine) was carried out. The two types of iodo substrates differ substantially regarding the selectivity towards carbonylation: while the aminocarbonylation of iodobenzene resulted in the formation of carboxamide and ketocarboxamide mixtures under various conditions, with the predominant formation of ketocarboxamide even at low carbon monoxide pressure, the aminocarbonylation of iodoalkenes under same conditions gave the corresponding unsaturated carboxamide exclusively. Most of the carboxamides and phenylglyoxylamides, obtained via single and double carbon monoxide insertion, respectively, were isolated in yields of synthetic interest (up to 86%). Low reaction rates and unexpected chemoselectivity towards carboxamide formation have been observed with di-(2-picolyl)amine as N-nucleophile in the aminocarbonylation of iodobenzene.     

Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino‐Isocyanates

The ubiquity of nitrogen heterocycles in biologically active molecules challenges synthetic chemists to develop a variety of tools for their construction. While developing metal‐free hydroamination reactions of hydrazine derivatives, it was discovered that carbazates and semicarbazides can also lead to alkene aminocarbonylation products if nitrogen‐substituted isocyanates (N‐isocyanates) are formed in situ as reactive intermediates. At first this reaction required high temperatures (150–200 °C), and issues included competing hydroamination and N‐isocyanate dimerization pathways. Herein, improved conditions for concerted intramolecular alkene aminocarbonylation with N‐isocyanates are reported. The use of βN‐benzyl carbazate precursors allows the effective minimization of N‐isocyanate dimerization. Diminished dimerization leads to higher yields of alkene aminocarbonylation products, to reactivity at lower temperatures, and to an improved scope for a reaction sequence involving alkene aminocarbonylation followed by 1,2‐migration of the benzyl group. Furthermore, fine‐tuning of the blocking (masking) group on the N‐isocyanate precursor, and reaction conditions relying on base catalysis for N‐isocyanate formation from simpler precursors resulted in room temperature reactivity, consequently minimizing the competing hydroamination pathway. Collectively, this work highlights that controlled reactivity of aminoisocyanates is possible, and provides a broadly applicable alkene aminocarbonylation approach to heterocycles possessing the β‐aminocarbonyl motif.     

Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors under controlled microwave heating

A novel and highly selective silver-promoted monobenzylation method was developed to promote synthesis of nonsymmetrical sulfamide-based HIV-1 inhibitors. Microwave-accelerated palladium-catalyzed N-amide arylation- and aminocarbonylation reactions were employed for rapid and reliable compound generation. With this class of inhibitory agents, six active inhibitors were identified, the most potent inhibitor possessing a K_i-value of 20 nM.     

Palladium-catalysed selective aminocarbonylation of 1′,4-diiodostyrene

1′,4-Diiodostyrene possessing both iodo-aryl and iodo-alkenyl functionalities was prepared and used as substrate in palladium-catalysed aminocarbonylation. The corresponding dicarboxamides were obtained as major products in high yields by using several amine nucleophiles including amino acid methyl esters. Due to the highly different reactivity of the two iodo-functionalities, the selective aminocarbonylation of the iodo-vinyl moiety was carried out at atmospheric carbon monoxide pressure resulting in the formation of 4-iodo-phenyl-acrylamides. The latter amides were used as substrates in high pressure aminocarbonylation resulting in amide-ketocarboxamide type products. The latter functionality was formed via double carbon monoxide insertion into the iodo-aryl bond.     

Regioselective functionalization of quinolin-4(1H)-ones via sequential palladium-catalyzed reactions

A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alkyl-6-bromo-3-iodoquinolin-4(1H)-one is described, based on regioselective sequential palladium-catalyzed cross-coupling reactions, namely Suzuki-Miyaura, Sonogashira and aminocarbonylation reactions, under microwave irradiation. Good substrate generality, ease of execution and practicability make this method exploitable for the generation of libraries of chemically diverse 4-quinolones.     

The first enantioselective intramolecular aminocarbonylation of alkenes promoted by Pd(II)-spiro bis(isoxazoline) catalyst

The highly ligand acceleration effect of spiro bis(isoxazoline) ligand (SPRIX) on the Pd(II)-catalyzed intramolecular aminocarbonylation of alkenyl amine derivatives was realized. Furthermore, the chiral Pd(II)-SPRIX catalyst accomplished the first enantioselective intramolecular aminocarbonylation. The reaction of N-(2,2-dimethyl-pent-4-enyl)-p-toluenesulfonamide in the presence of Pd(II)-SPRIX catalyst and p-benzoquinone in methanol under a carbon monoxide atmosphere afforded [4,4-dimethyl-1-(p-toluene-sulfonyl)-pyrrolidin-2-yl]-acetic acid methyl ester in good yield with moderate enantioselectivity.     

High-yielding synthesis of Weinreb amides via homogeneous catalytic carbonylation of iodoalkenes and iodoarenes

Iodoarenes (iodobenzene and 2-iodothiophene) and iodoalkenes (1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, 1-iodo-2-methylcyclohexene and 1-iodo-1-(1-naphthyl)ethene) were used as substrates in palladium-catalysed aminocarbonylation with N,O-dimethylhydroxylamine. The corresponding Weinreb amides were prepared in high isolated yields (up to 87%) when forcing conditions (40-60 bar of CO, 50 °C) were used. The aminocarbonylation provides the Weinreb amides as pure products in a chemoselective reaction. No formation of ketocarboxamides, due to double CO insertion, except for 2-iodothiophene, was observed even at 60 bar of CO pressure.     

Homogeneous catalytic aminocarbonylation of iodoalkenes and iodobenzene with amino acid esters under conventional conditions and in ionic liquids

Amino acid methyl esters were used as amine nucleophiles in palladium catalysed aminocarbonylation of iodobenzene and iodoalkenes (1-iodo-cyclohexene and 17-iodo-androst-16-ene). 2-Oxo-carboxamide type derivatives can be isolated as a result of double CO insertion by using iodobenzene as a substrate at elevated carbon monoxide pressure. On the contrary, carboxamides of expected structure were obtained exclusively in excellent yields in the whole pressure range by using iodoalkenes. The aminocarbonylation of 17-iodo-androst-16-ene in [bmim][PF₆] or [bmim][BF₄] (where bmim=1-butyl-3-methyl-imidazolium cation) ionic liquids was also carried out and the ionic liquid-catalyst mixtures have been reused several times with only a small loss of activity.     

High-yielding synthesis of 1-isoindolinone derivatives via palladium-catalysed cycloaminocarbonylation

1-Isoindolinone derivatives were synthesised in high yields (up to 89%) by using 2-iodobenzyl bromide and 2-iodobenzylamine as bifunctional substrates in palladium-catalysed carbonylation. Depending on the N-nucleophiles, two types of compounds were synthesised with 2-iodobenzyl bromide: the use of primary amines, including amino acid methylesters, resulted in the formation of N-substituted 1-isoindolinones, while secondary amines react both with the benzyl bromide and iodoarene moieties resulting in the corresponding ortho-(N-piperidino/morpholinomethyl)-benzamides. The parent 1-isoindolinone was obtained in a facile, highly chemoselective intramolecular aminocarbonylation of 2-iodobenzylamine. The mechanistic details of the ring-closure reaction and the conditions leading to side-products are discussed as well.     

Palladium-Catalyzed Aminocarbonylation of Aryl Halides with N,N-Dialkylformamide Acetals

We developed a protocol for the palladium-catalyzed aminocarbonylation of aryl halides using less-toxic formamide acetals as bench-stable aminocarbonyl sources under neutral conditions. Various aryl (including heteroaryl) halides reacted with N,N-dialkylformamide acetals in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and xantphos to give the corresponding aromatic carboxamides at 90–140 °C without any activating agents or bases in up to quantitative chemical yield. This protocol was applied to aryl bromides, aryl iodides, and trifluoromethanesulfonic acid, as well as to relatively less-reactive aryl chlorides. A wide range of functionalities on the aromatic ring of the substrates were tolerated under the aminocarbonylation conditions. The catalytic aminocarbonylation was used to prepare the insect repellent N,N-diethyl-3-methylbenzamide as well as a synthetic intermediate of the dihydrofolate reductase inhibitor triazinate.     

Selective Synthesis of N-Acylnortropane Derivatives in Palladium-Catalysed Aminocarbonylation

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)₂/2 PPh₃ catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.     

Cycloadditions of 3,4-dimethyl-1-thio-1-phenyl phosphole

Phosphole sulfide 1 undergoes cycloaddition to give a new 15-phosphasteroid. The ¹³C-NMR and ²J_PC-coupling constants of several compounds prepared similarly are discussed, permitting structure assignment to one of the 7-phosphabicyclo[2.2.1]heptane adduct 5. Thiophosgene reacts with the PS moiety of 1, giving 12 after hydrolysis, through a PS to PO transformation coupled in case of 1 with a proton migration.     

Etude des petits cycles—XXX : Extension de cycle generale de cyclopropanols: Halomethyl-1, hydroxymethyl-1, vinyl-1, acyl-1, cyclopropanols,et des oxaspiropentanes en cyclobutanones

Cyclopropanols 5, 6 and 2 with substituent groups (-CH₂OH, -CH₂OTs, -CH₂Br) in the 1-position, and oxaspiropentane 8, have been prepared from methylenecyclopropane. Cyclopropanols with vinyl groups in the 1-position (1-vinyl 12, 1-cyclopentenyl 13 and 1-cyclohexenyl 14) and 1-cyclopropylcyclopropanol 20 have been prepared from 1, 3-dichloroacetone.Each of the compounds readily undergoes ring expansion to the corresponding cyclobutanones. The reaction provides a simple route to cyclobutanones, the parent ketone itself being easily obtained from oxaspiropentane 8.     

A convenient synthesis of 1α- and 1β-hydroxycholesterol

An efficient procedure for the preparation of 1α-hydroxycholesterol 3-acetate 4 is described, which starts from cholesterol and involves as key steps transannular cyclization of the ten-membered ring ontaining (E)-3β-acetoxy-5,10-seco-1(10)-cholesten-5-one 1 to the oxetane derivative 1α,5-epoxy-5α-cholestan-3β-ol acetate 3, and opening of the four-membered ether ring in the latter compound. 1β-Hydroxycholesterol diacetate 9 was obtained by oxidation of 4 to the 1-oxo derivative 8, followed by metal hydride reduction and acetylation.     

Transition metal complexes of N-1-tosylcytosine and N-1-mesylcytosine

The syntheses as well as chemical and X-ray structural characterization of dichlorobis[1-(p-toluenesulfonyl)cytosine]copper(II) (2), its solvated pseudopolymorph containing two methanol molecules (3), dichlorobis[1-(p-toluenesulfonyl)cytosine]cadmium(II) (4), 1-methanesulfonylcytosine (6) and its copper complex dichlorobis(1-methanesulfonylcytosine)copper(II) (7) are described. In addition, spectroscopic studies of dichlorobis[1-(p-toluenesulfonyl)cytosine]cobalt(II) (5), as well as of dichlorobis(1-mesylcytosine)cadmium(II) (8) are presented. Pseudopolymorphs 2 and 3, as well as their 1-mesylcytosine analog 7, reveal square-planar coordination spheres, almost ideal in the case of 2, but considerably distorted in the case of 3 and 7. In all cases, the Cu(II) ion is coordinated by two endocyclic N3 atoms from two ligand molecules and by two chlorine atoms. The analogous coordination sphere was found in complex 4, where Cd(II) lies in the center of a slightly distorted tetrahedron formed by two endocyclic N3 atoms and by two chlorine atoms.     

Palladium-catalysed aminocarbonylation of 17-iodo-5α-androst-16-ene with L-amino acid esters in ionic liquids

Ionic liquids were effectively used as solvents in palladium catalysed aminocarbonylation of 17-iodo-5α-androst-16-ene (1) with L-amino acid esters. The Pd(OAc)₂ + phosphine catalysts could be recirculated with small loss of activity.     

Synthesis and characterization of 1-methyl-1-silaindane and 1-methyl-1-germaindane

New synthetic routes to 1-methyl-1-silaindane (1b) and 1-methyl-1-germaindane (1b) were developed and the desired products were obtained in good isolated yield. Compounds 1a and 1b were fully characterized by mass spectroscopy, ¹H and ¹³C{¹H} NMR, and infrared spectroscopy.