Dhevalapally B. Ramachary

Amino Acid‐Catalyzed Cascade [3+2]‐Cycloaddition/Hydrolysis Reactions Based on the Push–Pull Dienamine Platform: Synthesis of Highly Functionalized NH‐1,2,3‐Triazoles

1,2,3-Triazoles are an important class of heterocycles, which display very large spectrum of biological activities and are widely used as pharmaceuticals and agrochemicals. Compounds containing 1,2,3-triazoles have also found industrial applications as corrosion inhibitors, lubricants, dyes, and photostabilizers. As such, the development of new and more general methods for their preparation is of significant interest. The conventional method to triazoles is the Huisgen 1,3-dipolar cycloaddition of alkynes with azides. Recent discovery of the novel technology of Cu-catalyzed [3+2]cycloaddition reactions of terminal alkynes with organic azides provided a general route to a variety of 1,4-disubstituted 1,2,3-triazoles in good yields, and it has become a paradigm of a “click chemistry” reaction. The advent of click reaction technology triggered a burst of activity in the synthesis of a huge variety of differently substituted 1,2,3-triazoles as in vitro and in vivo conditions. Recently, the copper-catalyzed azide–alkyne click reaction has proven extremely valuable for attaching small molecular probes to various biomolecules in a test tube or on immobilized cells. However, its use in the labeling of biomolecule in living cells or organisms is not feasible because the reaction conditions require a cytotoxic copper catalyst. As part of our program to engineer direct organocatalytic cascade reactions, herein we have report the discovery of a copper-free, novel and green technology for the synthesis of highly substituted a-diazo compounds and NH-1,2,3-triazoles using organocatalytic cascade enamine amination/elimination (EA/E) and [3+2]-cycloaddition/hydrolysis ([3+2]CA/H) reactions from commercially available activated enones, azides and amines/amino acid [Eq. (1)]. In this communication, we report to the best of knowledge for the first time an organocatalytic approach for the synthesis of NH1,2,3-triazole products. Over the last few years, we have been interested in amine-mediated in situ generation and application of novel push–pull dienamines/push–pull dienols [A and B, see Eq. (2)] in cascade reactions from Hagemann3s esters with nitrogen-containing species for the formation of C N bonds. During our search for new coupling species for such processes, we decided to explore the potential ability of organic azides to participate in an amine/amino acid-catalyzed coupling reaction. We expected that the coupling of an organic azide with in situ generated push–pull dienamines would lead to protected 1,2,3-triazoles. However, protected 1,2,3-triazoles were not detected, but instead NH1,2,3-triazoles were obtained under the standard reaction conditions. This unexpected result of the cascade reaction represents a novel methodology for the preparation of NH1,2,3-triazoles and a new reactivity for amino acid catalysts. Herein, we report our findings regarding these new amino acid-catalyzed cascade reactions. We initiated our preliminary studies of the cascade EA/E or [3+2]-CA/H reactions by screening a number of both [a] Prof. Dr. D. B. Ramachary, K. Ramakumar, V. V. Narayana School of Chemistry University of Hyderabad Hyderabad-500046 (India) Fax: (+91)40-23012460 E-mail : ramsc@uohyd.ernet.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200801325.

Proline-catalyzed asymmetric assembly reactions: enzyme-like assembly of carbohydrates and polyketides from three aldehyde substrates☆

Abstract Directed asymmetric assembly of simple achiral building blocks into stereochemically complex molecules like triketides has been described for the first time using l -proline catalyzed asymmetric double aldol reactions. The product pyranoses contain four asymmetric centers constructed under proline catalysis in a highly diastereoselective and modestly enantioselective fashion from three aldehyde molecules. These results suggest that the construction of complex products from simple starting materials is within the realm of organocatalysis involving the simple naturally occurring amino acid l -proline. Our successful assembly of pyranoses from simple aldehydes under proline catalysis suggests that this approach may warrant consideration as a prebiotic route to sugars and polyketides.

An Organocatalytic Azide–Aldehyde [3+2] Cycloaddition: High-Yielding Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles†

An organocatalytic azide-aldehyde [3+2] cycloaddition (organo-click) reaction of a variety of enolizable aldehydes is reported. The organo-click reaction is characterized by a high rate and regioselectivity, mild reaction conditions, easily available substrates with simple operation, and excellent yields with a broad spectrum of substrates. It constitutes an alternative to the previously known CuAAC, RuAAC, and IrAAC click reactions.

Amine-catalyzed direct self Diels–Alder reactions of α,β-unsaturated ketones in water: synthesis of pro-chiral cyclohexanones

Abstract Amine-catalyzed direct self Diels–Alder reactions of α,β-unsaturated ketones have been developed. ( S )-1-(2-Pyrrolidinyl-methyl)pyrrolidine, l -proline and pyrrolidine catalyzed the reaction of α,β-unsaturated ketones to provide cyclohexanone derivatives with good yield (up to 80%) in a single step via in situ-generation of 2-amino-1,3-butadienes and iminium ion-activated enones. Pro-chiral cyclohexanones were selectively prepared with pyrrolidine catalysis in water.

Organocatalytic Triazole Formation, Followed by Oxidative Aromatization: Regioselective Metal-Free Synthesis of Benzotriazoles

Herein we report on our studies on the sequential one-pot combinations of amine-catalyzed multicomponent reactions (MCRs). We have developed the copper-free synthesis of functionalized bicyclic N-aryl-1,2,3-triazole and N-arylbenzotriazole products 4 and 5 from the simple unmodified starting materials through [3+2]-cycloaddition ([3+2]-CA) and oxidative aromatization reactions in one pot under amine catalysis. The sequential one-pot reaction proceeds in good yields with high selectivity by using pyrrolidine as the catalyst from the simple unmodified substrates of enones, aryl azides, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Furthermore, we have demonstrated the medicinal applications of products 4 and 5 through simple organic reactions.

Asymmetric Synthesis of Druglike Six-Membered Spirooxindoles through an Amino Enyne Catalysis

An effective reflexive-Michael (r-M) reaction has been disclosed to access drug-like six-membered spirooxindoles in good yields and excellent enantioselectivities by using an aminoenyne-catalysis.

Direct Catalytic Asymmetric Synthesis of Highly Functionalized 2‐Methylchroman‐2,4‐diols via Barbas–List Aldol Reaction

A practical and sustainable chemical process for the synthesis of highly substituted aldol<-->lactol products was achieved for the first time through the asymmetric Barbas-List aldol (BLA) reaction of 2-hydroxybenzaldehydes with acetone in the presence of a catalytic amount of trans-4-OH-L-proline (see scheme).

Development of drug intermediates by using direct organocatalytic multi-component reactions

Novel, economic and environmentally friendly one-pot three-component Knoevenagel/hydrogenation (K/H) and four-component Knoevenagel/hydrogenation/alkylation (K/H/A) reactions of ketones, CH-acids, dihydropyridines and alkyl halides using proline and proline/metal carbonate catalysis, respectively, have been developed. Many of the products of these K/H and K/H/A reactions have direct applications in pharmaceutical chemistry.

Towards organo-click reactions: development of pharmaceutical ingredients by using direct organocatalytic bio-mimetic reductions

Economic and environmentally friendly bio-mimetic one-pot three and four-component Knoevenagel-hydrogenation (K-H), five-component Knoevenagel-hydrogenation-alkylation (K-H-A) and six-component Knoevenagel-hydrogenation-alkylation-Huisgen cycloaddition (K-H-A-HC) reactions of aldehydes, CH-acids, o-phenylenediamine, alkyl halides and azides using proline, proline-metal carbonate and proline-metal carbonate-Cu(I)-catalysis, respectively have been developed. Many of K-H and K-H-A compounds have direct application in pharmaceutical chemistry.

Stereoselective Synthesis of Five-Membered Spirooxindoles through Tomita Zipper Cyclization

Functionalized five-membered spirooxindoles were furnished in good yields and excellent stereoselectivities by using an effective Tomita zipper cyclization (TZC) reaction through organophosphine catalysis.