A general one-pot synthesis of pyridines 4a-t from the reaction of dialkyl acyclic/cyclic ketones 1a-i, methyl, aryl/heteroaryl ketones 1m-r, and aldehydes bearing alpha-hydrogens 1s,t with propargylamine 2 is described. Gold and copper salts are efficient catalysts for the reaction of ketones with 2. The formation of the pyridines 4 is suggested to proceed through the sequential amination of carbonyl compounds followed by regioselective 6-endo-dig cyclization of the N-propargylenamine (N-propargyldienamine) intermediate 3(5) and aromatization reaction. Whereas the preparation of linear polycyclic pyridine 4i can be carried out by reacting cholestan-3-one 1i with 2, the angular polycyclic pyridine 4j has been obtained starting from cholest-5-en-3-one 1j. Selectivity of the reaction of polycyclic dicarbonyls 1k,l with 2 has also been investigated.
A new approach to the Friedländer synthesis of quinolines is described. Polysubstituted quinolines are readily prepared under milder conditions than in other existing methods through a gold(III)-catalysed sequential condensation/annulation reaction of o-amino aromatic carbonyls and ketones containing active methylene groups.The presence of the quinoline scaffold in the framework of various pharmacologically active compounds with antiasthmatic, 1 antiinflamatory 2 and tyrosine kinase PDGF-RTK inhibiting properties 3 continues to spur synthetic efforts regarding their acquisition. 4Most of the classical synthetic protocols for quinolines suffer from harsh conditions, poor yields and the use of hazardous acid or basic catalysts. In particular, since 1882 the synthesis of the quinoline nucleus by the Friedländer procedure has been extensively explored. 5 Hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and polyphosphoric acid were widely employed as catalysts. In the cases in which acetic acid was used alone, it probably functioned as a convenient solvent and not as a catalyst. Uncatalysed Friedländer syntheses required more drastic reaction conditions, with temperatures in the range 150-220°C. The reaction path suggested for the Friedländer procedure may involve sequential formation of Ν-(o-acylphenyl)-β-enaminones/cyclodehydration reaction.During our studies towards the development of new environmentally friendly syntheses of heterocycles through transition metal catalysed domino reactions we observed the high efficiency of gold(III) catalysis 6 in sequential amination/annulation reaction of α-propargyl dicarbonyls with amine, aminoalcohols and α-aminoesters. 7 Moreover, we developed a simple and clean gold-catalysed synthesis of β-enaminones from 1,3-dicarbonyls and ammonia/amines that requires neither a corrosive acid catalyst nor azeotropic conditions using a large excess of aromatic solvents like benzene. 8 Consequently, since we were interested in the synthesis of functionalized quinolines, 9 we were driven to investigate the extension of the gold(III) catalysis to the development of a mild version of the Friedländer synthesis of quinolines. Indeed, by choosing as the model system the reaction of ethyl acetoacetate (1a) with 2-aminobenzophenone (2a) (Scheme 1), we failed to obtain the corresponding quinoline derivative 3a without adding any catalyst; the starting 2-aminobenzophenone (2a) was recovered (90%) after reacting at 40°C in ethanol for 6 hours. By contrast, in the presence of a catalytic amount of NaAuCl 4 ⋅2H 2 O (Aldrich) the quinoline 3a was isolated in 83% yield under the same reaction conditions. Furthermore, the reaction can be run very efficiently at room temperature (Table 1, entry 1).
Scheme 1A screening of the efficiency of other transition metal salts revealed that palladium(II)-, copper(I)-, and silver(I) salts were ineffective as catalysts; ZnCl 2 can lead to the formation of 3a (43% yield), even if its efficiency is lower 10 than that of gold(III). Recently, Kobayashi and co-wor...
2-Ethynyl-3-pyridinols and 3-ethynyl-2-pyridinols, readily available from halopyridinols, have been treated with aryl/ heteroaryl halides or vinyl triflates to give 2-substituted furo [3,2-b]pyridines and 2-substituted furo[2,3-b]pyridines through a coupling/cyclization process. Two catalyst systems have been used: PdCl 2 (PPh 3 ) 2 -CuI and Pd 2 (dba) 3 -P(t-Bu) 3 . Halopyridinols have been employed for an alternative approach to 2-substituted furo[2,3-b]pyridines and 2-substituted furo[2,3-c]pyridines via 2-(trimethylsilyl)furopyridines, 2-iodofuropyridines, palladiumcatalyzed reactions.Recently, considerable efforts have been focused on the development of HIV-1 specific non nucleoside reverse transcriptase inhibitors incorporating substituted furo[2,3-b]pyridine 1 and furo[2,3-c]pyridine 2 moieties. However, despite the emergence of the furopyridine nucleus as a useful pharmacophore also in other therapeutic areas (including the treatment of skin disease and relief of intraocular pressure), 3 synthetic methodologies for its construction remain limited, 4 one of the most efficient being our palladium-catalyzed reaction of iodopyridinols with terminal alkynes. 5 This protocol, which is based on the utilization of a specific acetylenic derivative for each furopyridine, has successfully been applied to the synthesis of 2-substituted furo[2,3-b]pyridines 1a and 2-substituted furo[2,3-c]pyridines. 2 As part of our ongoing interest in the utilization of palladium catalysis in the construction of benzo[b]furan 6 and furopyridine rings, 5 we decided to explore an alternative methodology in which 2-substituted furopyridines can be synthesized from a single alkynyl pyridinol and aryl and vinyl halides or triflates (Scheme 1). On the other hand, the growing importance of furopyridines as pharmacophores justifies efforts to develop more general and versatile synthetic methodologies, which accommodate considerable functionality and are broad in scope.
Scheme 1Here we report just such a process. 2-Ethynyl-3-pyridinols and 3-ethynyl-2-pyridinols 3, readily available through the sequence shown in Scheme 2 for the preparation of the former, 7 have been selected as suitable alkynes.
Scheme 2
The gold(III)-catalyzed sequential amination/annulation reaction of 2-propynyl-1,3-dicarbonyl compounds 1 with primary amines 2 produces 1,2,3,5-substituted pyrroles 4 in moderate to high yields.
The gold(III)‐catalyzed sequential amination/annulation reaction of 2‐propynyl‐1,3‐dicarbonyl compounds 1with primary amines 2produces 1,2,3,5‐substituted pyrroles 4 in moderate to high yields.
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