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.     

Synthesis of 2-naphthylacrylamides and 2-naphthylacrylates via homogeneous catalytic carbonylation of 1-iodo-1-naphthylethene derivatives

Two highly reactive iodoalkenes (1-iodo-1-(2-naphthyl)ethene and 1-iodo-1-(1-naphthyl)ethene) were prepared from the corresponding acetonaphthone isomers via their hydrazones and used as substrates in palladium-catalysed carbonylations. Both iodoalkenyl substrates proved to be highly reactive in the presence of various N-nucleophiles and the corresponding N-substituted naphthylacrylamides were formed chemoselectively in nearly quantitative yields. High isolated yields (up to 93%) were achieved with all types of amines under mild reaction conditions. The alkoxycarbonylation of the above iodoalkenes resulted in esters of unexpectedly good isolated yields (up to 77%).     

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 8-hydroxy- and 8-benzyloxy-5,7-diiodoquinoline under aminocarbonylation conditions

Various 5-carboxamido-7-iodo-8-benzyloxyquinolines were synthesised via selective aminocarbonylation of 5,7-diiodo-8-benzyloxyquinoline in the presence of ‘in situ’ generated palladium(0) catalysts. Under similar conditions (50 °C, 80 bar CO), 5,7-bis(N-tert-butyl-glyoxylamido)-8-hydroxyquinoline was obtained using tert-butylamine as N-nucleophile. The unprotected 5,7-diiodo-8-hydroxyquinoline underwent dehydroiodination resulting in 8-hydroxyquinoline as the major product.     

Synthesis of tetrahydrophthalazine and phthalamide (phthalimide) derivatives via palladium-catalysed carbonylation of iodoarenes

1,2,3,4-Tetrahydrophthalazin-1-one and 1,2,3,4-tetrahydrophthalazin-1,4-dione derivatives were synthesised in high (up to 85%) and low yields using 2-iodobenzyl bromide and 1,2-diiodobenzene as bifunctional substrates, respectively. Iodoarenes, carbon monoxide and various hydrazine derivatives as N-nucleophiles were used in a three-component palladium-catalysed cascade hydrazinocarbonylation. A similar palladium-catalysed reaction, the aminocarbonylation of 1,2-diiodobenzene, resulted mainly in the formation of two types of major products depending on the amine N-nucleophiles: the use of primary amines yielded N-substituted phthalimides in double carbonylation, while secondary amines react with one of the iodoarene functionalities affording the corresponding 2-iodobenzamides. Due to double carbon monoxide insertion at one or both iodoarene functionalities, ketocarboxamide-carboxamide or bis-ketocarboxamide derivatives could be isolated by the modification of the reaction conditions. Some mechanistic details of the ring-closure reactions and the conditions leading to side-products are also discussed.     

Palladium-catalysed aminocarbonylation of iodoarenes and iodoalkenes with aminophosphonate as N-nucleophile

The high-yielding synthesis of novel N-acyl phosphonates with unprecedented structure was carried out by a homogeneous carbonylation reaction under mild reaction conditions. The palladium-catalysed aminocarbonylation of iodoalkenes (1-iodo-cyclohexene, 1-iodo-4-tert-butyl-cyclohexene, 1-iodo-2-methyl-cyclohexene and α-iodostyrene) with diethyl α-aminobenzyl-phosphonate as N-nucleophile resulted in the exclusive formation of carboxamides. The same reaction with iodoaromatics (iodobenzene, 2-iodothiophene) provided the corresponding carboxamide in high yields and some 2-keto-carboxamides as side products due to single and double carbon monoxide insertion, respectively.     

Homogeneous catalytic aminocarbonylation of nitrogen-containing iodo-heteroaromatics. Synthesis of N-substituted nicotinamide related compounds

Various primary and secondary amines, including amino acid methyl esters, were used as nucleophiles in palladium-catalysed aminocarbonylation of 2-iodopyridine, 3-iodopyridine and iodopyrazine. N-Substituted nicotinamides and 3-pyridyl-glyoxylamides (2-oxo-carboxamide type derivatives) of potential biological importance can be obtained from 3-iodopyridine as a result of simple and double carbon monoxide insertions, respectively. The latter examples can be obtained in synthetically acceptable yields by using elevated carbon monoxide pressure. On the contrary, N-alkyl/aryl-carboxamides were obtained exclusively in the whole pressure range by using 2-iodopyridine and iodopyrazine.     

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.     

Palladium-catalysed aminocarbonylation of diiodopyridines

The aminocarbonylation of 2,5- and 2,3-diiodopyridine, as well as 2-chloro-3,4-diiodopyridine with carbon monoxide and various primary and secondary amines was carried out using palladium-catalysed aminocarbonylation. The formation of the products containing carboxamide and ketocarboxamide functionalities was accompanied by the formation of imides when ortho-diiodo compounds were used as substrates. In spite of several possible reaction pathways, most of the products were synthesised as major product in yields of synthetic interest by the appropriate modification of the reaction conditions.     

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.     

Efficient synthesis of alkynyl amides via aminocarbonylation of iodoalkynes

Iodoethynylbenzene as iodoalkyne model compound was aminocarbonylated with tert-butylamine under carbon monoxide atmosphere in the presence of in situ palladium(0) catalysts. The formation of the unsaturated carboxamide (alkynyl amide) is always accompanied by that of the Glaser coupling product, diphenylbutadiyne. The yield of the amide-forming reaction was optimised by the systematic variation of the phosphine ligand, carbon monoxide pressure and temperature. The scope of the reaction was investigated by using various primary and secondary amines including amino acid methyl esters as N-nucleophiles.17α-(Iodoethynyl)-testosterone was also functionalised by using this methodology providing the corresponding 17α-(carboxamidoethynyl)-testosterone derivatives in up to 96% yields. The reaction was extended to 1-(iodoethynyl)cyclohex-1-ene and 1-iodohex-1-yne. Ethyl iodopropiolate gave the enamine type product by the addition of amine to the alkyne functionality which was formed from the iodoalkyne via deiodination under standard aminocarbonylation conditions. The bromo analogue, bromoethynylbenzene has shown lower reactivity than the corresponding iodo derivative.     

Synthesis of benzamide-benzothiazole conjugates via palladium-catalysed aminocarbonylation (hydrazinocarbonylation)

The palladium-catalysed aminocarbonylation of iodoarenes was investigated using 2-amino- and 2-hydrazinobenzothiazole as N-nucleophile. The reaction proved to be highly chemoselective in all cases: carboxamides and the corresponding carbohydrazides, obtained by the acylation at the nitrogen adjacent to the C-2 of the benzothiazole moiety, were obtained exclusively and isolated in moderate to high yields. Systematic investigation of the reaction conditions revealed that the reaction requires relatively high temperature (higher than 70?°C). The effect of the carbon monoxide pressure is different in the synthesis of the two types of products: while the carboxamide formation is favoured, the carbohydrazide formation is lowered by the increasing CO pressure.     

Facile synthesis of 1,8-naphthalimides in palladium-catalysed aminocarbonylation of 1,8-diiodo-naphthalene

1,8-Diiodo-naphthalene was aminocarbonylated with various primary and secondary amines in the presence of palladium(0) complexes formed in situ from palladium(II) acetate and triphenylphosphine. In the case of primary amines, depending on the amine to substrate ratio, two types of products have been obtained in highly chemoselective reaction: dicarboxamides and N-substituted imides have been formed at high and low amine to substrate ratio, respectively. The reaction tolerates the ester functionality, so that amino acid esters could serve as N-nucleophiles and in this way, naphthalimides possessing stereogenic centre in the N-substituent could be synthesised.     

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.     

High-yielding synthesis of 2-arylacrylamides via homogeneous catalytic aminocarbonylation of α-iodostyrene and α,α′-diiodo-1,4-divinylbenzene

Highly reactive iodoalkenes (α-iodostyrene and α,α′-diiodo-1,4-divinylbenzene) were prepared and used as substrates in palladium-catalysed aminocarbonylation reaction. Regardless of the type of amine nucleophile the corresponding N-substituted phenylacrylamides have been formed chemoselectively in nearly quantitative yields. High isolated yields (up to 83%) have been achieved both with unfunctionalised simple amines and amino acid methyl esters under mild reaction conditions.     

Novel synthesis of 3-carboxamidolactam derivatives via palladium-catalysed aminocarbonylation

Aminocarbonylation of alkenyl and (hetero)aryl iodides using medium-sized 3-aminolactams as N-nucleophiles was carried out in the presence of in situ palladium(0) catalysts. While the iodoalkenes were converted to the corresponding carboxamide under mild reaction condition (1?bar of CO, 50?°C) by using Pd(OAc)₂/PPh₃ catalysts, the iodobenzene shown decreased reactivity (39% conversion after 2 days) under the similar reaction conditions in the presence of 3-aminoazepan-2-one. The reactivity of iodobenzene and other iodo(hetero)aromatic substrates was increased with 3-aminoazepan-2-one under high (40?bar) carbon monoxide pressure, but the chemoselectivity was shifted towards the 2-ketocarboxamides formed via double carbon monoxide insertion (except 2-iodopyridine). Changing triphenylphosphine to Xantphos, the expected carboxamides were chemoselectively formed in all cases when iodo(hetero)aryl substrates were used in the presence of all of the three 3-aminolactams under mild reaction conditions. The products synthesized in the reactions mentioned above were isolated in moderate to high yields.     

Aminothiazoles and aminothiadiazoles as nucleophiles in aminocarbonylation of iodobenzene derivatives

Various 2-, 3- and 4-substituted iodobenzenes were aminocarbonylated using aminothiazole and aminothiadiazole derivatives in palladium-catalysed reaction. The reaction is chemospecific toward the corresponding carboxamides. Consequently, the application of the above N-nucleophiles provided the N-1,3-thiazol-2-yl- and N-1,3,4-thiadiazol-2-ylcarboxamides in moderate to high yields. Due to the facile work-up of the reaction mixture isolated yields of 90% or higher were obtained in most cases.     

Palladium-catalyzed carbonylative annulation of terminal alkynes: synthesis of coumarins and 2-quinolones

o-Iodophenols and o-iodoaniline derivatives react with terminal alkynes under 1 atm of CO in the presence of pyridine and catalytic amounts of Pd(OAc)₂ to generate coumarins and 2-quinolones, respectively, as the only products. Terminal alkynes bearing alkyl, aryl, silyl, hydroxyl, ester and cyano substituents are effective in these processes affording the desired products in moderate yields. The formation of coumarins and 2-quinolones in this process is in stark contrast with all previously described palladium-catalyzed reactions of o-iodophenols or o-iodoanilines with terminal alkynes and CO, which have afforded chromones and 4-quinolones. Moreover, under our reaction conditions terminal alkynes insert into the carbonpalladium bond instead of undergoing a Sonogashira-type coupling as confirmed by an isotope labeling experiment.     

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.     

Functionalisation of the uracil ring via palladium-catalysed aminocarbonylation

Iodouracil derivatives (5-iodouracil, 5-iodo-1,3-dimethyluracil) were aminocarbonylated using a set of primary and secondary amines in the presence of in situ palladium(0) catalysts. The formation of carboxamides via single CO insertion was favoured at atmospheric CO pressure. The chemoselectivity toward double CO insertion can be increased by using 40 bar of CO pressure, in this way up to 60% selectivity toward 2-ketocarboxamide was achieved. In the case of 5-iodouracil the corresponding 5-glyoxylamido-uracil derivatives were exclusively formed at 40 bar CO pressure. The only exception is the less basic aniline nucleophile which provided the corresponding carboxamide exclusively. A typical side-reaction took place when 5-iodouracil was used as substrate: this heterocycle, existing in lactam-lactim tautomeric forms, underwent deiodination providing the parent uracil as side-product.