Synthesis of 5-methylfuro[3,2-c]quinolin-4(5H)-one via palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide

A new synthesis of the furo[3,2-c]quinolin-4(5H)-one heterocycle has been developed using a palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide. By varying the catalyst, base and solvent, the yield of the cyclisation was optimised. It was found that the use of palladium oxide with potassium acetate in N,N-dimethylacetamide (DMA) with a small amount of tetrabutylammonium chloride gave the highest yield of 5-methylfuro[3,2-c]quinolin-4(5H)-one (9).     

Effective synthetic routes to activated pyrrolo[3,2,1-hi]indoles

Pyrrolo[3,2,1-hi]indoles have been formed by the aldol cyclisation of 7-formyl-N-indolylacetates. The synthetic sequence incorporates three steps from suitably activated indoles: these are alkylation at nitrogen with a bromoacetic ester, formylation at C7 and an aldol condensation between these two substituents. An X-ray crystal structure of pyrrolo[3,2,1-hi]indole 24 is described.     

A versatile and efficient synthesis of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone

A versatile and efficient method for the preparation of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone from l-(−)-phenylalanine 2 utilising the aromatic system as a masked β-keto aldehyde was developed. The key step in the sequence is an intramolecular cyclisation of 6 to give 2,3-dihydropyridin-4-ones.     

An expedient, regioselective synthesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]indoles

1-Benzenesulfonyl-5-aminoindole 5, prepared from 5-nitroindole 3, was condensed with alkyl isothiocyanates and separately with carbon disulfide and alkyl bromides/iodides to furnish efficiently the corresponding N-alkyl-thioureidoindoles 6a-c and the alkyl N-(indol-5′-yl)dithiocarbamates 9a-e, respectively. Their cyclisation using N-bromosuccinimide (NBS) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in the cold, followed by indolic N-deprotection, furnished regioselectively the 2-alkylamino- and the 2-alkylthiothiazolo[5,4-e]indoles 8a-c and 11a-e, respectively, in good overall yields.     

Aryl pyrrolidinones via radical 1,4-aryl migration and 5-endo-trig cyclisation of N-(2-bromoallyl)arylcarboxamides

Radical reaction of a series of N-(2-bromoallyl)arylcarboxamides led to the production of 4-arylpyrrolidin-2-ones and directly reduced materials in comparable yields. A cascade process, involving sequential 5-exo-trig spirocyclisation, β-scission, and 5-endo-trig cyclisation of the resulting acyl radical, is proposed to explain the pyrrolidinone products.     

Amino-zinc-ene-enolate cyclisation: a short access to (2S,3R)- and (2S,3S)-3-benzylprolines (3-benzylpyrrolidine-2-carboxylic acids)

The synthesis of 3-benzylprolines can be easily achieved in a diastereoselective and enantioselective way via amino-zinc-ene-enolate cyclisation. Transmetalation of the cyclic zinc intermediate with Pd₂(dba)₃/P(o-Tolyl)₃ allowed functionalisation with an aromatic ring. One-pot hydrogenolysis and Boc-protection led to the cis-isomer readily usable for peptide synthesis. The trans-isomer was obtained by epimerisation of the α-centre in a sealed tube at 200 °C.     

Thermal cyclization of N-[2-(2-propenyl)-1-naphthyl] ketenimines: intramolecular Diels-Alder reaction versus [1,5] hydrogen migration. Synthesis of dibenz[b,h]acridines and benzo[h]quinolines

The thermal treatment of N-(2-propenyl)-1-naphthylamines provided the expected aza-Claisen rearranged products, 2-(2-propenyl)-1-naphthylamines and benz[g]indoles, these last derived from an intramolecular hydroamination reaction on those primary products. The 2-(2-propenyl)-1-naphthylamines were converted into their triphenylphosphazene derivatives, which by aza-Wittig reaction with disubstituted ketenes yielded N-[2-(2-propenyl)-1-naphthyl] ketenimines. The heating of these ketenimines in boiling toluene induced their cyclization either via an intramolecular Diels-Alder reaction, to afford dibenz[b,h]acridines, or via [1,5] hydrogen migration from the sp³ carbon atom of the propenyl substituent to the central carbon atom of the ketenimine fragment, followed by a 6π electrocyclic ring closure, to give benzo[h]quinolines.     

Synthesis of 9-arylamino- and (Z)-9-arylimino-9H-pyrrolo[1,2-a]indoles by reactions of 2-(pyrrol-1-yl)benzaldehydes with aryl amines

Heating mixtures of 2-(pyrrol-1-yl)benzaldehydes and aryl amines under argon afforded 9-arylamino-9H-pyrrolo[1,2-a]indoles, via cyclization of the resulting 2-(pyrrol-1-yl)benzaldimine intermediates. Heating in the presence of oxygen afforded (Z)-9-arylimino-9H-pyrrolo[1,2-a]indoles, which were successfully hydrolyzed with hydrochloric acid to give pyrrolo[1,2-a]indol-9-ones.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

An enantiospecific synthesis of (+)-demethoxyerythratidinone from (S)-malic acid: key observations concerning the diastereocontrol in malic acid-derived N-acyliminium ion cyclisations

The stereochemical outcome of N-acyliminium ion mediated cyclisations of malic acid derived lactams depend upon the nature of the protecting group on the lactam secondary alcohol, and also on the nature of the substituent at the reacting electrophilic centre. The origins of an unusual syn-selective cyclisation of a TIPS protected lactam are discussed, and the cyclisation is employed as the key step in an asymmetric synthesis of 3-demethoxyerythratidinone (4).     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

N,N′-Dioxide-scandium(III) complex catalyzed highly enantioselective Friedel-Crafts alkylation of indole to alkylidene malonates

A highly efficient enantioselective Friedel-Crafts alkylation of indoles with alkylidene malonates has been developed using chiral N,N′-dioxide L4-scandium(III) complex as the catalyst, giving the corresponding products in high yields with excellent enantioselectivities (up to 99% yield and 95% ee). The product 3a was facilely converted into several interesting compounds, such as tryptamines, indolepropionic acids and β-carbolines. It is noteworthy that the seven-membered β-carboline-like compound has been synthesized for the first time. Based on the crystal structure of the chiral N,N′-dioxide L10-scandium(III) complex, the proposed transition state and possible catalytic cycle were presented to elucidate the reaction mechanism.     

Synthesis of substituted 4-(1H-indol-6-yl)-1H-indazoles as potential PDK1 inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki cross-coupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and S_NAr/reductive cyclisation sequences, respectively.     

Uncatalyzed addition of indoles and N-methylpyrrole to 3-formylchromones: synthesis of (chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones under solvent-free conditions

(Chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones have been obtained in good yields from 3-formylchromones on reaction with indoles and N-methylpyrrole under solvent-free conditions.     

(N,N-dimethylbenzylamine-2C,N)palladium(II) and -platinium(II) β-diketonates and thio-β-diketonates

(N,N-dimethylbenzylamine-2C,N)palladium(II) and -platinum(II) β-diketonates, DmbaML, have been synthesized by reaction of [DmbaMCl]₂ with the free ligand and KOH, or with the thallium(I) salt of the ligand. The various isomers formed have been investigated by ¹H and ¹⁹F NMR spectroscopy. Infrared and mass spectroscopic studies have also been made on the compounds.     

A clay-mediated, regioselective synthesis of 2-(aryl/alkyl)amino-thiazolo[4,5-c]carbazoles

The 3-aminocarbazoles 1a-e were condensed with phenyl and benzyl isothiocyanates on montmorillonite K10 clay or TLC-grade silica gel at room temperature to furnish efficiently the N-phenyl and N-benzylthioureidocarbazoles, 2a-e and 2f, respectively, within minutes. When adsorbed on montmorillonite K10 clay impregnated with para-toluene sulfonic acid (1:1, w/w) and heated at 60-70 °C, 2a-e and 2f furnished the 2-anilino and 2-benzylaminothiazolo[4,5-c]carbazoles, 3a-e and 3f, respectively, regioselectively in high yields. The cyclisation was also effective for the N-methylthioureidocarbazoles 2g-i.     

C-O and C-C bond formation in the cyclisation of gem-(dialkoxymethyl)-1,6-dienes catalysed by tin(IV) triflimidate at room temperature

We described herein a Sn(NTf₂)₄-catalysed cyclisation of gem-(dialkoxymethyl)-1,6-dienes and derivatives where cyclohexane or tetrahydrofuran rings are formed following either a 6-enexo-endo-trig process or a 5-exo-trig process, respectively, depending on substitution patterns. The latter process features an unusual dealkylative ether cyclisation, triggered by the strong Lewis acid character of the tin(IV) triflimidate catalyst.     

Indenols, indenones and (arylcyclohexadienyl)Mn(CO)3 π-complexes from the thermally promoted reactions of alkynes with ortho-Mn(CO)4 aryl ketone, amide, ester and aldehyde derivatives

Thermally promoted reactions of a range of alkynes with the orthomanganated acetophenone (η²-2-acetylphenyl)Mn(CO)₄ generally give 1H-inden-1-ols in good yield; effects of substituents and solvent on these reactions are reported, along with the crystal structure of 1-methyl-2,3-diphenyl-1H-inden-1-ol. The corresponding orthomanganated benzophenone similarly gives the indenol with diphenylacetylene but by exception, orthomanganated 3-acetylthiophene with phenylacetylene reacts via triple alkyne insertion and cyclisation, shown by crystal structure determination of the π-complex product [(1,2,3,4,5-η)-2-(3-acetylthien-2-yl)-1,3,5-triphenylcyclohexadienyl]tricarbonylmanganese. Corresponding orthomanganated derivatives of N,N-dimethylbenzamide, methyl 3,4,5-trimethoxybenzoate and 4-dimethylaminobenzaldehyde all give indenones with diphenylacetylene, but with (excess) acetylene only the aldehyde gives an indenone, the amide and ester giving instead [(1,2,3,4,5-η)-6-arylcyclohexadienyl]Mn(CO)₃ complexes. ¹H NMR analysis of these complexes shows H at C6 to be on the same face of the cyclohexadienyl ring as Mn(CO)₃ (endo-6-H; exo 6-aryl) as expected from three successive syn additions of alkyne at metallated carbon followed by intramolecular syn addition of alkene in the final cyclisation stage.     

(N,N) vs. (N,S) chelation of palladium in asymmetric allylic substitution using bis(thiazoline) ligands: A theoretical and experimental study

New thiazoline-containing ligands including non-symmetric bis(thiazolines) and oxazoline-thiazolines were synthesized and then compared to C₂-symmetric bis(thiazolines) in the palladium-catalyzed allylic substitution. The experimental results obtained in this study support the hypothesis of a competition between the (N,N) and the (N,S) palladium chelation, when sterically hindered bis(thiazolines) are used as ligands. A quantum chemical study performed on the Pd-complexes derived from three selected ligands, two C₂-symmetric bis(thiazolines) and one oxazoline-thiazoline, also supports this hypothesis.     

A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans

We investigated the Lewis acid-promoted Friedel-Crafts alkylation of indole and substituted indoles with dehydroalanine-containing dipeptides R-Xaa-Dha-OR¹. The reaction proceeded with modest to sufficient diastereoselectivity, and yields strongly varied depending on the Lewis acid selected. The substituent R¹ of the ester group revealed some impact on the preferential formation of (S)-Trp or (R)-Trp. We exploited the reaction to prepare different peptides containing substituted tryptophans. To test the efficacy of this method for preparing biologically relevant compounds, we synthesized two unprecedented analogues of endomorphin-1, the endogenous agonist of the μ-opioid receptor, having either (S)- or (R)-2-methyltryptophan in position 3.