Synthesis of 2-substituted 3-nitro-1,2-dihydropyridines by heterocyclic annulation reactions of a sec-nitrodienamine with aldehyde compounds

The reaction of a sec-nitrodienamine 3 with aldehyde compounds afforded 2-substituted 3-nitro-1,2-dihydropyridines 5, providing a heterocyclic annulation reaction.     

A new synthesis of N-alkyl 4-methyl-1,4-dihydropyridines utilizing sec-aminodienyl esters with crotonaldehyde

The reactions of sec-aminodienyl esters 3 with crotonaldehyde (4) afforded N-alkyl 3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-dihydropyridines 5, providing a new azaelectrocyclization reaction.     

Regioselective synthesis of 1,2-dihydropyridines by rhodium-catalyzed hydroboration of pyridines

Pyridine undergoes addition of pinacolborane at 50 °C in the presence of a rhodium catalyst, giving N-boryl-1,2-dihydropyridine in a high yield. The selective 1,2-hydroboration also takes place in the reactions of substituted pyridines. In the reaction of 3-substituted pyridines, 3-substituted N-boryl-1,2-dihydropyridines are formed regioselectively.     

A new three-component domino synthesis of 1,4-dihydropyridines

Cerium ammonium nitrate (CAN) catalyzed the three-component domino reaction between aromatic amines, α,β-unsaturated aldehydes, and ethyl acetoacetate, providing an efficient new entry into 1,4-dihydropyridines. This new reaction requires very mild reaction conditions, has water as the only side product and is complementary to the classical Hantzsch synthesis in that it is well suited to the preparation of N-aryl-5,6-unsubstituted dihydropyridines. Experiments in the presence of a radical trap suggest that a one-electron oxidative mechanism can be excluded and that CAN acts as a Lewis acid.     

A new method for regioselective synthesis of 2-substituted 1-(methoxycarbonyl)-1,2-dihydropyridines

2-Substituted 1,2-dihydropyridines including an optically active one were regioselectively prepared from 2-substituted piperidines through three intermediates, that is, (a) 1,2,3,4-tetrahydropyridines, (b) 5-bromo-6-methoxypiperidines, and (c) 1,2,3,6-tetrahydro- 6-methoxypyridines.     

A new synthesis of N-alkyl 3-acetyl-4-methoxycarbonylmethyl-2-methyl-1,4-dihydropyridines utilizing sec-aminodienyl esters with acetylacetone

The reactions of sec-aminodienyl esters 3 with acetylacetone (4) afforded N-alkyl 3-acetyl-4-methoxycarbonylmethyl-2-methyl-1,4-dihydropyridines 5 and enamines 6, providing a new azaelectrocyclization reaction.     

Solid-phase synthesis of pyrroloisoquinolines via the intramolecular N-acyliminium Pictet-Spengler reaction

In the present investigation, solid-phase routes toward 1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-ones via the intramolecular N-acyliminium Pictet-Spengler reaction are established. Peptide aldehydes generated from their parent N-Boc 1,3-oxazines by acidic reaction conditions undergo intramolecular condensation reactions with the amide N of a solid-supported peptide backbone, thus forming a 1:1 epimeric mixture of a cyclic 5-hydroxylactam, which in turn is in equilibrium with the corresponding intermediate N-acyliminium ion. Provided appropriate acidic reaction conditions, a second ring may be appended via Pictet-Spengler cyclization from the aromatic ring of a neighboring phenylalanine derivative in the peptide sequence. The aromatic substitution pattern of the nucleophilic benzene ring of the phenylalanine derivative and the nature of the acidic reaction media are critically important for the course of the reaction, and both Lewis and Br?nsted acids may be employed to effect the cyclization process. This intramolecular reaction is under strict control of stereoselectivity, and only a single stereoisomer is detected in the crude products. A range of mono-, di-, and trisubstituted phenylalanines with diverse sets of electron-donating and electron-withdrawing substituents, pyrene, and naphthalenes have successfully been brought within the scope of the reaction, thus providing a unique scaffold for combinatorial library synthesis.     

Solid-phase and solution-phase parallel synthesis of tetrahydro-isoquinolines via Pictet-Spengler reaction

An efficient parallel synthesis of 6,7-dimethoxytetrahydroisoquinolines is reported. The key reaction step is 3,4-dimethoxyphenethylimines reacting with acid chlorides to form an N-acyliminium ion intermediate, which undergoes Pictet-Spengler condensation to give the desired products in >80% yield. Both solution-phase and solid-phase synthesis of 6,7-dimethoxytetrahydroisoquinolines are described.     

Synthesis and structure of new substituted 2-dicyanomethylene-1,2-dihydropyridines

The synthesis of substituted 2-dicyanomethylene-1,2-dihydropyridines 3b-c and 2-dicyanomethylene-2,3,4,5-tetrahydropyridine 4 is accomplished from malononitrile dimer and propenenitriles 2 . All structures were determined by nmr techniques; however to put our structural assignment for 6-amino-3-cyano-5-ethoxycarbonyl-2-dicyanomethylene-1,2-dihydropyridine 3d on a firm and unequivocal basis we decided to perform X-ray diffraction analysis of this compound.     

Organocatalyzed regioselective and enantioselective synthesis of 1,4- and 1,2-dihydropyridines

Abstract

Herein, we introduce one of the first examples of asymmetric organocatalyzed synthesis of 1,2-dihydropyridines, affording enantioselective access to and partially solving regioselectivity challenges in the synthesis of dihydropyridines. We demonstrate that through modification of organocatalysts both 1,2- and 1,4-dihydropyridines (1,2- and 1,4-DHPs) can be obtained with high regioselectivity (ratio of 1,2-DHP/1,4-DHP from 95/5 to 0/100) and enantioselectivity (33% ee for 1,2-DHPs and up to 98% ee for 1,4-DHPs) in good yields (up to 87%).     

A novel one-pot, three-component reaction: formation of tricyclic 1,2-dihydropyridines via mesomeric betaines

A one-pot, three-component reaction of pyridine, thiophthalimide and acyl chloride gives novel tricyclic 1,2-dihydropyridines regio- and stereoselectively, in which a mesomeric betaine would be a key intermediate for [4+2]-cycloaddition reaction with thiocarbonyl compounds.     

Total synthesis of (+)-yohimbine via an enantioselective organocatalytic Pictet-Spengler reaction

The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2-(phenylseleno)pentanoate leads to the tetrahydro-β-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.     

Application of modified Pictet-Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines

Two new thiazole and pyrazole-based arylamine substrate have been used for the Pictet-Spengler reaction. This is in contrast to the traditionally used indole/imidazole-based aliphatic amine substrates that has remained in use for the last ∼100 years. The condensation of both the substrates with a variety of aldehydes in the presence of 2% TFA-DCM at 0° for 30 min or pTsOH in toluene at reflux led to the synthesis of thiazoloquinolines and pyrazoloquinolines, respectively. Unlike aliphatic amine substrates, our substrates readily underwent Pictet-Spengler cyclization even with aldehydes having electron donating group. The studies are based on a new concept proposed by us that arylamines linked to an activated heterocyclic ring can lead to a variety of second-generation substrates for the Pictet-Spengler cyclization. Our studies open up new avenues for the application of Pictet-Spengler reaction beyond syntheses of the tetrahydroisoquinolines and tetrahydro-β-carbolines.     

A new synthesis, including asymmetric synthesis, of alkylidenecyclopropanes by 1,2-CC insertion of cyclobutylmagnesium carbenoides as the key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters gave adducts in high yields. The adducts were converted to 1-chlorocyclobutyl p-tolyl sulfoxides in four steps in high overall yields. Treatment of the 1-chlorocyclobutyl p-tolyl sulfoxides with cyclopentylmagnesium chloride in THF at −40 °C resulted in the formation of cyclobutylmagnesium carbenoids. The magnesium carbenoid 1,2-CC insertion reaction took place smoothly from the cyclobutylmagnesium carbenoids to afford alkylidenecyclopropanes in good to high yields. An asymmetric synthesis of optically active alkylidenecyclopropane was successfully achieved starting from optically active 1-chlorovinyl p-tolyl sulfoxide.     

A new synthesis of 5-phenylmorphans1,2

A new procedure for the synthesis of 2-azabicyclo- [3.3.1]nonanes by intramolecular cyclization of 4-acetonyl-2- piperidinecarbonitriles under acidic conditions is described. The procedure allows the preparation of the pharmacologically interesting 5-phenylmorphans and involves the initial formation of 4-acetonylidenepiperidine 4, conjugate addition of a diarylcuprate, and cyclization of the resulting 4-acetonylpiperidine by way of the corresponding 2-cyano derivative.     

A modified strategy for Pictet-Spengler reaction leading to the synthesis of imidazoquinoxalines on solid phase

An alternative strategy for Pictet-Spengler reaction involving an N-1 linked aromatic amine of imidazole and aldehydes is described. This is in contrast to a typical Pictet-Spengler reaction, which involves an aliphatic amine attached to the carbon of an activated aromatic nucleus and an aldehyde. Our strategy commences with the nucleophilic replacement of fluorine in resin-bound o-fluoro-nitrobenzoic acid with mono- or disubstituted imidazole, followed by reduction of the nitro group to give an N1 linked aromatic amine of the resin-bound imidazole. This was subsequently treated with an aldehyde in toluene at 80 degrees C and then oxidized in the presence of DDQ to give resin-bound imidazoquinoxalines. Finally, acidolytic cleavage furnished the desired compounds in high yields and purities.     

A carbon-carbon bond formation using endoperoxides of 1,2-dihydropyridines

A novel type of a nucleophilic substitution on the piperidine ring was achieved by a stannous chloride-effected reaction of endoperoxides of N-alkoxycarbonyl-1,2-dihydropyridines with various kinds of carbon nucleophiles.     

A clean procedure for the synthesis of 1,4-dihydropyridines via Hantzsch reaction in water

A clean and efficient procedure was established to synthesize 1,4-dihydropyridines via one-pot Hantzsch reactions in aqueous medium without the use of a catalyst and/or organic solvent. The reaction with stoichiometric molar ration could be carried out in a sealed vessel with a water steam, air, or nitrogen atmosphere to afford Hantzsch esters in good to excellent yields and purities. After the simple filtration, the 1,4-dihydropyridines were isolated, and the filtrate could be recycled and reused without significantly decreasing the yields and purities. The novel and clean methodology offers the advantages including short reaction time, good yields, operational simplicity, less leaks, and environmentally benign.     

A new synthesis of benzo[b]thiophenes utilizing an interrupted Pummerer reaction

A convenient synthesis of 3-arylbenzo[b]thiophenes utilizing an interrupted Pummerer reaction of 2-(1-arylvinyl)phenyl ethyl sulfoxides is described. Thus, treatment of these sulfoxides, which were readily prepared from 2-sulfanylphenyl ketones or 2-fluoro-5-methoxybenzaldehyde, with acetic anhydride at 100 °C afforded 3-arylbenzo[b]thiophenes in reasonable yields.