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.     

One-pot synthesis of N-acyl-substituted sulfamides from chlorosulfonyl isocyanate via the Burgess-type intermediates

The title N-alkoxycarbonyl- or N-aryloxycarbonyl-substituted sulfamides were synthesised in one-pot in efficient yields from chlorosulfonyl isocyanate (CSI), alcohols and aqueous (or dry) amines via the corresponding water-resistant intermediates, carboxysulfamoylammonium salts (Burgess-type reagents), which were generated in situ by the deactivation of the corresponding water-sensitive N-(chlorosulfonyl)carbamates with tertiary amines.     

A new approach towards 2-amino-1-aryloxy-3-methoxypropanes from 1-arylmethyl-2-(bromomethyl)aziridines

1-Arylmethyl-2-(bromomethyl)azirdines were converted into the corresponding 2-(aryloxymethyl)aziridines upon treatment with the appropriate potassium phenoxides in DMF/acetone in excellent yields, followed by regioselective ring opening towards N,N-di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines using benzyl bromide in acetonitrile. Treatment of the latter β-bromoamines with sodium methoxide afforded the desired 2-amino-1-aryloxy-3-methoxypropanes as the major compounds (49-58%) besides the isomeric 3-amino-1-aryloxy-2-methoxypropanes in minor quantities (9-15%).     

Synthesis and crystal structures of the first C2-symmetric bis-aldimine NCN-pincer complexes of platinum and palladium

(S,S)-2,6-bis[(N-α-methylbenzyl)imino]phenylpalladium bromide was synthesised by oxidative addition of palladium(0) to (S,S)-1-bromo-2,6-bis[(N-α-methylbenzyl)imino]benzene. In contrast, (S,S)-2,6-bis[(N-α-methylbenzyl)imino]phenylplatinum chloride was synthesised by direct C-H activation from the reaction of potassium tetrachloroplatinate with (S,S)-1,3-bis[(N-α-methylbenzyl)imino]benzene. The X-ray crystal structures of both pincer complexes were obtained. Treatment of both complexes with silver hexafluoroanimonate gave effective but not stereoselective catalysts for a Michael reaction between methyl vinyl ketone and methyl 2-cyanopropanoate.     

Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction

trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of α,β-unsaturated ketones utilising in situ generated N–N ylides (aminimines). A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity relationships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed with several enones to ascertain the effect of substrate structure on product ee, while the intermediate hydrazinium salt was characterised by X-ray crystallography.     

Epoxy-based polymer bearing activated azo dye (methyl orange) units: novel colorimetric indicator for amines

Novel epoxy-based polymer 2-bearing activated azo dye, 4-(4-sulphophenylazo)-N,N-dimethylaniline (methyl orange), moieties were synthesised by post-azo-coupling reaction of poly(hydroxy ether amine) 1 and investigated sensory responses towards amines. The reversible protonation–deprotonation chemistry of activated azobenzene moiety makes it of potential use as a colorimetric indicator for amines.     

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.     

Iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for synthesis of α-tertiary amines

A protocol for the synthesis of α-tertiary amines was developed by iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides. Nucleophilic 1,2-addition of organolithium reagents to carboxamides forms anionic tetrahedral carbinolamine (hemiaminal) intermediates, which are subsequently treated with bromotrimethylsilane (Me₃SiBr) followed by organomagnesium (Grignard) reagents, organolithium reagents or tetrabutylammonium cyanide, affording α-tertiary amines. Employment of (trimethylsilyl)methylmagnesium bromide as the 2^nd nucleophile allowed for aza-Peterson olefination of the resulting α-tertiary (trimethylsilyl)methylamines with acidic work-up, resulting in the formation of 1,1-diarylethylenes.

We herein report a concise protocol for iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for the synthesis of α-tertiary amines.     

Peptoid dendrimers—microwave-assisted solid-phase synthesis and transfection agent evaluation

Three generations of peptoid-based dendrimers were synthesised by solid-phase methods, using N-Fmoc-N-(6-N′-Fmoc-aminohexyl)-glycine as both the initiator core and the monomer unit, which offer an unusual dendrimeric periphery composed of both secondary and primary amines. The third generation compound proved to be an efficient mediator of transfection while displaying minimal cytotoxicity.     

Two-pot synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from aryl(2-isothiocyanatophenyl)methanones and secondary amines

A convenient synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from aryl(2-isothiocyanatophenyl)methanones using a two-pot procedure has been developed. Thus, treatment of these isothiocyanato ketones with secondary amines gave the corresponding keto thioureas, which were allowed to react with sodium borohydride or methylmagnesium bromide to afford 1,1-dialkyl-3-{2-[aryl(hydroxy)methyl]phenyl}thioureas or 1,1-dialkyl-3-[2-(1-aryl-1-hydroxyethyl)phenyl]thioureas, respectively, in one pot. Hydrobromic acid-mediated cyclization of these hydroxy thiourea precursors provided the desired 4H-3,1-benzothiazin-2-amines.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

Synthesis of dendrimeric N-glyoxylamide peptide mimics

A range of peptidomimetic dendrimers based on 1,3,5-benzenetricarbonyl trichloride and tris(2-aminoethyl)amine central cores has been synthesised through the facile ring-opening of N-acylisatins with amino acids, alcohols and other amines.     

Amphiphilic poly(N,N-dimethylamino-2-ethyl methacrylate)-g-poly(ε-caprolactone) graft copolymers: synthesis and characterisation

Amphiphilic poly(N,N-dimethylamino-2-ethyl methacrylate)-g-poly(ε-caprolactone) graft copolymers (PDMAEMA-g-PCL) with various compositions and molecular weights were synthesised via a fully controlled three-step strategy. First, poly(ε-caprolactone) macromonomers (PCLMA) were prepared by ring-opening polymerization (ROP) of ε-caprolactone (CL) initiated by aluminum triisopropoxide (Al(OⁱPr)₃), followed in a second step by quantitative esterification of PCL hydroxy end-groups with a methacrylic acid derivative. Finally, the controlled copolymerization of PCLMA and N,N-dimethylamino-2-ethyl methacrylate (DMAEMA) was carried out by atom transfer radical polymerisation (ATRP) in THF at 60 °C using CuBr ligated with 1,1,4,7,10,10, hexamethyl triethylenetetramine and ethyl 2-bromoisobutyrate as catalyst and initiator, respectively. Furthermore, PDMAEMA-g-PCL graft copolymers were reacted with methyl iodide to convert the pendant tertiary amines into quaternary ammonium iodides increasing accordingly their water solubility. Some preliminary experiments was further carried out by tensiometry and dynamic light scattering in order to shed so light on the tensioactive behaviour of these amphiphilic graft copolymers (with protonated amines or quaternary ammonium cations).     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

Palladium-catalysed carbonylation of 4-substituted 2-iodoaniline derivatives: carbonylative cyclisation and aminocarbonylation

2-Iodoaniline derivatives were used as bifunctional substrates in palladium-catalysed carbonylation. Depending on the substituents, two types of compounds were synthesised: having methyl or hydrogen in 4-position 2-aryl-benzo[d][1,3]oxazin-4-one derivatives have been formed, chloro, bromo, cyano or nitro groups in the same position resulted in the formation of dibenzo[b,f][1,5]-diazocine-6,12-dione derivatives. In the presence of various primary and secondary amines (tert-butylamine, amino acid methyl esters) as N-nucleophiles 2-ketocarboxamides were obtained as major products in aminocarbonylation reaction with double carbon monoxide insertion.     

Mössbauer studies on ferrocene complexes: XVI. Structure of triorganostannyl derivatives of dimethylaminomethylferrocene and N,N-dimethylbenzylamine

A series of new stannylated derivatives of dimethylaminomethylferrocene (DMAMF) and N,N-dimethylbenzylamine have been synthesised and their structures investigated by ¹H, ¹³C and ¹¹⁹Sn NMR together with ⁵⁷Fe and ¹¹⁹Sn Mössbauer spectroscopy. Polystannylated derivatives were synthesised from DMAMF and BuLi in the presence of TMED. The methylene protons of the CH₂NMe₂ group were diastereotopic for all the DMAMF derivatives synthesised. The chemical shift differences of these protons is discussed in terms of conformational changes. ¹³C and 119Sn shifts were used to establish the substitution patterns in the polystannylated derivatives. ¹³C shifts for the 2-substituted derivatives of both DMBA and DMAMF were reasonably additive, for both the free amines and the quaternary ammonium salts. The Mössbauer data show no evidence of pentacoordination in any of the derivatives.     

Synthesis of sugar-derived isoselenocyanates, selenoureas, and selenazoles

Aryl, alkyl, and sugar-derived isoselenocyanates were prepared by a one-pot procedure starting from the corresponding formamides, using triphosgene as a dehydrating agent, triethylamine, and black selenium powder. The preparation of sugar selenoureas by coupling of O-protected sugar-derived isoselenocyanates with different amines, and by coupling of unprotected glycopyranosyl amines with phenyl isoselenocyanate was also accomplished. The synthesis of a glucopyranos-2-yl-selenazole starting from O-protected 2-amino-2-deoxy-d-glucose by coupling with benzoyl isoselenocyanate, Se-alkylation with phenacyl bromide, and acid-catalyzed dehydration is also reported. Unprotected N-(β-d-glucopyranosyl)-N′-phenylselenourea was transformed into a 1,2-trans-fused bicyclic isourea upon treatment with aqueous hydrogen peroxide; the same isourea was prepared by a one-pot three-step procedure from β-d-glycopyranosylamine by thiophosgenation, coupling with aniline, and HgO-mediated desulfurization.     

“One pot” synthesis of tertiary amines: Ru(II) catalyzed direct reductive N-benzylation of imines with benzyl bromide derivatives

The direct reductive N-benzylation of imines by reaction with benzyl bromide derivatives, in the presence of [RuCl₂(p-cymene)]₂ catalyst and PhSiH₃, is performed under mild conditions without additional base. This reaction proceeds by a tandem imine hydrosilylation/nucleophilic substitution with benzyl bromide derivatives to result the tertiary amines.     

N-(Benzoyloxy)amines: an investigation of their thermal stability, synthesis, and incorporation into novel peptide constructs

A series of N-benzoyloxyamines were pyrolyzed and their decomposition temperatures correlated well with the amine architecture's ability to stabilize a N-centered radical. A variety of amine substrates were treated with a biphasic mixture of benzoyl peroxide (BPO), CH₂Cl₂ and an aqueous carbonate buffer (at pH 10.5). Primary and secondary amines were successfully N-benzoyloxylated in good yield. Tertiary amines and BPO gave low yields of the corresponding N-oxide and complex product mixtures, presumably via radical decomposition. Electron deficient amines (such as fluorinated aliphatic amines, α-aminoacids, α-aminoesters, and α-aminoamides) were not N-benzoyloxylated under these conditions. Instead, N-benzoylation was observed with the fluorinated amines and the reaction was sensitive to temperature and the pH of the aqueous medium. A one-pot-two-step synthesis of N^α-FMOC-l-Leu-N^β-(benzoyloxy)-β-alanine ethyl ester, a peptide containing both an α- and a novel β-amino acid framework, was also developed.     

The synthesis of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones from 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide precursors

Sulfinylation of o-nitrobenzamide and subsequent hetero Diels-Alder reaction gave a series of 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides. The 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides undergo a ring opening reaction with phenyl magnesium bromide to give allylic sulfoxides, which, after [2,3]-sigmatropic rearrangement and desulfurisation, furnish unsaturated vicinal N-(o-nitrobenzoyl)-1,2-amino alcohols. Oxidation of the alcohol and reductive ring closure gave a series of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones, a subset of the ‘privileged’ 1,4-benzodiazepine structure. A 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide was synthesised by the same route starting from o-nitrobenzenesulfonamide.