The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

Asymmetric enamine catalysis.

4.2.8. Reductive Coupling 3109 5. Reaction of Aromatic Compounds 3110 5.1. Electrophilic Substitutions 3110 5.2. Radical Substitution 3111 5.3. Oxidative Coupling 3111 5.4. Photochemical Reactions 3111 6. Reaction of Carbonyl Compounds 3111 6.1. Nucleophilic Additions 3111 6.1.1. Allylation 3111 6.1.2. Propargylation 3120 6.1.3. Benzylation 3121 6.1.4. Arylation/Vinylation 3121 6.1.5. Alkynylation 3121 6.1.6. Alkylation 3121 6.1.7. Reformatsky-Type Reaction 3122 6.1.8. Direct Aldol Reaction 3122 6.1.9. Mukaiyama Aldol Reaction 3124 6.1.10. Hydrogen Cyanide Addition 3125 6.2. Pinacol Coupling 3126 6.3. Wittig Reactions 3126 7. Reaction of R,â-Unsaturated Carbonyl Compounds 3127

Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations: A Decade Update

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.

Asymmetric multicomponent reactions (amcrs): the new frontier

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Organocatalytic Asymmetric Domino Knoevenagel/Diels–Alder Reactions: A Bioorganic Approach to the Diastereospecific and Enantioselective Construction of Highly Substituted Spiro[5,5]undecane‐1,5,9‐triones

Here we report on our studies on combinations of amino acids and copper(I) for catalyzing multicomponent reactions (MCRs). We aimed to prepare both diene and dienophiles simultaneously, under very mild and environmentally friendly conditions, thus giving the constituents for a stereocontrolled Diels–Alder reaction, which in turn yields compounds 4 to 8. A diversity-oriented synthesis of polysubstituted spirotriones 4 to 6 were assembled from simple substrates like 1-(triphenylphosphanylidene)-propan-2-one, two aldehydes, and cyclic-1,3-diketones through Wittig/Knoevenagel/Diels–Alder and aldol/Knoevenagel/Diels–Alder reaction sequences in one pot under stereospecific organocatalysis. Chemical diversity libraries of polysubstituted spirotrione-1,2,3-traizoles 8 were assembled from simple substrates by means of Wittig/Knoevenagel/Diels–Alder/Huisgen cycloaddition reaction sequences in one pot under stereospecific organo/CuI catalysis. Functionalized dispirolactones such as 6 are biologically active antioxidants and radical scavengers, and spirotrione-1,2,3-traizoles 8 have found wide applications in chemistry, biology, and materials science. Experimentally simple and environmentally friendly, organocatalytic, asymmetric four-component Diels–Alder (AFCDA) reactions of 1-(triphenylphosphanylidene)- propan-2-one, two different aldehydes, and cyclic-1,3-diketones produced diastereospecific and highly enantioselective substituted spirotriones 4 by means of a Wittig/Knoevenagel/Diels–Alder reaction sequence in one pot. Additionally we have developed an organocatalytic, asymmetric three-component Michael (ATCM) reaction of 1-(triphenylphosphanylidene)-propan-2-one, aldehyde, and cyclic-1,3-diketones that produced Michael adducts 15, 16 through a Wittig/Michael reaction sequence in a highly enantioselective one-pot process.

Towards organo-click chemistry: Development of organocatalytic multicomponent reactions through combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions

Creating sequential one-pot combinations of multi-component reactions (MCRs) and multi-catalysis cascade (MCC) reactions is a challenging task that has already emerged as a new technology in synthetic organic chemistry. Through one-pot sequential combination of MCRs/MCC reactions, the chemical products (fine chemicals, agrochemicals and pharmaceuticals) that add value to our lives can be produced with less waste and greater economic benefits. Within this Emerging Area, we describe our recent developments and designs for sequential one-pot MCRs/MCC reactions to facilitate their realization as biomimetics in organic chemistry.

Sequential one-pot combination of multi-component and multi-catalysis cascade reactions: an emerging technology in organic synthesis

Dienamine Catalysis: An Emerging Technology in Organic Synthesis

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.

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

Dhevalapally B. Ramachary

Papers

Organocatalytic Asymmetric Domino Knoevenagel/Diels–Alder Reactions: A Bioorganic Approach to the Diastereospecific and Enantioselective Construction of Highly Substituted Spiro[5,5]undecane‐1,5,9‐triones

Towards organo-click chemistry: Development of organocatalytic multicomponent reactions through combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions

Sequential one-pot combination of multi-component and multi-catalysis cascade reactions: an emerging technology in organic synthesis

Dienamine Catalysis: An Emerging Technology in Organic Synthesis

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