General synthesis of substituted 1,2-dihydropyridines

A general and practical metal-free protocol for the synthesis of 1,2-dihydropyridines with wide structural/functional diversity at the ring and featuring mono, double, or spiro substitution at the sp3 position is described. The protocol entails a microwave-assisted domino reaction of a propargyl vinyl ether (secondary or tertiary) and a primary amine (aliphatic or aromatic) in toluene or methanol. © 2014 American Chemical Society.This research was supported by the Spanish Ministerio de Economı́a y Competitividad (MICINN) and the European Regional Development Fund (CTQ2011-28417-C02-02). L.C. and G.M.-A. thank the Spanish MEC for FPI and FPU grants, respectively.Peer Reviewe

A convenient domino access to substituted alkyl 1,2-dihydropyridine- 3carboxylates from propargyl enol ethers and primary amines

A convenient domino access to substituted alkyl 1,2-dihydropyridine-3- carboxylates from propargyl enol ethers and primary amines was reported. A solution of propargyl sinyl ether 1a and p-anisidine in toluene was placed in a microwave-special closed vial and the solution was irradiated for 30 minutes in a single-mode microwave oven. The reaction mixture was dried over anhydrous sodium sulfate and filtrated using dichloromethane as solvent. After removing the solvent at reduced pressure the products were purified by flash column chromatography. Accordingly, the microwave irradiation of an ethanolic mixture of propargyl enol ether 1 a and MeONH2.HCl in the presence of NaOAc yielded the methyl 2-phenyl-4-pyridinecarboxylate in a convenient 54% yield. These results seem to point out to a new reaction pathway involving different thermally-driven rearrangements of the 2,4-dienal 3 intermediate.This research was supported by the Spanish Ministerio de Ciencia e Innovación, the European Regional Development Fund (CTQ2005-09074-C02-02 and CTQ2008-06806-C02-02) and the Spanish MSC ISCIII (RETICS, RD06/0020/1046, and RD06/0020/0041), CSIC (Proyecto Intramural Especial 200719), FUNCIS (REDESFAC PI01/06 and 35/06) and the Fundación Instituto Canario de Investigación del Cancer (FICI-G.I.N808/2007). G.M.-A. thanks Spanish MEC for a FPU grant.Peer Reviewe

Developing lithium chemistry of 1,2-dihydropyridines : from kinetic intermediates to isolable characterized compounds

Generally considered kinetic intermediates in addition reactions of alkyllithiums to pyridine, 1-lithio-2-alkyl-1,2-dihydropyridines have been rarely isolated or characterized. This study develops their "isolated" chemistry. By a unique stoichiometric (that is 1:1, alkyllithium:pyridine ratios) synthetic approach using tridentate donors we show it is possible to stabilize and hence crystallize monomeric complexes where alkyl is tert-butyl. Theoretical calculations probing the donor-free parent tert-butyl species reveal 12 energetically similar stereoisomers in two distinct cyclotrimeric (LiN)3 conformations. NMR studies (including DOSY spectra) and thermal volatility analysis compare new sec-butyl and iso-butyl isomers showing the former is a hexane soluble efficient hydrolithiation agent converting benzophenone to lithium diphenylmethoxide. Emphasizing the criticalness of stoichiometry, reaction of nBuLi/Me6TREN with two equivalents of pyridine results in non-alkylated 1-lithio-1,4-dihydropyridine·Me6TREN and 2-n-butylpyridine, implying mechanistically the kinetic 1,2-n-butyl intermediate hydrolithiates the second pyridine

Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis

During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4–O–C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB′ three-component reaction for PVEs; A2BB′ four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β,γ-unsaturated esters and acids, and fused polycycles. They can be transformed into more elaborated molecular skeletons by the use of chemical handles generated in their own domino reactions or by appending different functionalities to the pluripotent molecular platform (secondary reactivity principles).This research was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (CTQ2011-28417-C02-02).Peer reviewe

A copper-benzotriazole based coordination polymer catalyzes the efficient one-pot synthesis of (N'-substituted)-hydrazo-4-aryl-1,4-dihydropyridines from azines

A series of new (N’-substituted)-hydrazo-4-aryl-1,4 dihydropyridines were successfully synthesized via a facile one pot catalytic pathway utilizing azines and propiolate esters as starting materials and 1D Cu benzotriazoles based coordination polymer as catalyst. In the absence of catalyst, the corresponding 5-substituted 4,5-dihydro pyrazoles were formed in moderate to high yields. Fine-tuning the catalysts allowed us to gain more insights regarding the plausible reaction mechanism

Reactions of biologically inspired hydride sources with B(C6F5)3

The combination of 1-benzyl-1,4-dihydropyridines with the strong Lewis acid, B(C6F5)3, generates a stable pyridinium borohydride species in high yields (94%) in as little as 10 min. This use of biologically inspired hydride sources further builds on the recent work of new hydride donors in the formation of borohydrides. When functionalizing the dihydropyridine with an amide or carboxylic acid moiety, a disproportionation reaction composed of a series of protonation/reduction steps is observed upon the addition of B(C6F5)3. As a result, one equivalent of dihydropyridine undergoes net hydrogenation, whereas the other is dehydrogenated yielding the pyridinium counterpart in a transfer hydrogenation-type mechanism

Synthesis of Quinazoline and Quinazolinone Derivatives via Ligand-Promoted Ruthenium-Catalyzed Dehydrogenative and Deaminative Coupling Reaction of 2-Aminophenyl Ketones and 2-Aminobenzamides with Amines

The in situ formed ruthenium catalytic system ([Ru]/L) was found to be highly selective for the dehydrogenative coupling reaction of 2-aminophenyl ketones with amines to form quinazoline products. The deaminative coupling reaction of 2-aminobenzamides with amines led to the efficient formation of quinazolinone products. The catalytic coupling method provides an efficient synthesis of quinazoline and quinazolinone derivatives without using any reactive reagents or forming any toxic byproducts

Preparation of indole alkaloids via 1,4-dihydropyridine stage or cyano-masked iminium intermediates

Methods to synthesise substituted pyridine derivatives utilising 1,4-dihydropyridines were studied. Addition of nucleophiles to N-alkyl pyridinium salts and application of the products to alkaloid synthesis were investigated. Application of the Kröhnke procedure to the synthesis of indole alkaloids is described. The feasibility of applying the Kröhnke procedure to pyridine derivatives without an electron withdrawing β-substituent at the pyridinium ring was demonstrated by adding dimethyl malonate to the γ-position of Boc protected 1-[2-(3-indolyl)ethyl]pyridinium salts. The method permits access to the indoloquinolizidine skeleton present in several indole alkaloids. The total synthesis of (±)-tangutorine, a novel indole alkaloid, was achieved. The dithionite reduction leading to a 1,4-dihydropyridine derivative provided easy access to the tangutorine skeleton with good yields. In a second part of the work, dihydropyridines were stabilised through the introduction of cyanide ion to iminium intermediates. The Polonovski–Potier reaction and the cyano-trapping method were used in the preparation of dimethyl malonyl substituted indolo[2,3-α]quinolizidine derivative, a potential synthon of antirhine. A novel synthetic approach to the preparation of 2,6-dicyanopiperidine derivatives via 1,4-dihydropyridine intermediates was examined. The formation of 2,6-dicyanopiperidines in the Fry reaction was verified. The stereochemistry of 2,6-dicyanopiperidine derivatives is discussed.reviewe