A reaction or concept becomes so vital when it has a wide applicability, such concepts will be respected with a Nobel prize every year. This year, the prestigious Nobel prize in chemistry was awarded to Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless for their enormous contribution in the ‘development of click reactions and bioorthogonal chemistry’.
In early 2000’s, Sharpless at The Scripps Research Institute (San Diego, USA) and Meldal at Carlsberg Research Laboratory (Copenhagen, Denmark) independently discovered a new copper catalysed [3+2]-cycloaddition of terminal alkynes with different azides for the synthesis of highly regioselective 1,4-disubstituted 1,2,3-triazoles. During the development of this reaction, Sharpless coined these copper catalysed [3+2]-cycloadditions as click reactions and proposed a few principles which a reaction must satisfy to get categorised under click reaction. Even though the [3+2]-cycloadditions of alkyne and azide were known from 1893s which were proposed by Michael, Huisgen; these reactions were thermally induced and also resulted in mixture of regioisomers namely 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles which were difficult to separate. Due to this reason, this protocol failed in grabbing the attention of scientific community because of its least selectivity and slow reaction rates. But, soon after the rediscovery of regioselective copper-catalysed [3+2]-cycloaddition of terminal alkyne with azides by Sharpless and Meldal, it opened a new window for the scientists of all disciplines to investigate the applications of the 1,2,3-triazoles in the drug discovery to materials chemistry (see Figure 1).
Even though this concept has a wide utility, it did not escape from the drawbacks. This copper-catalysed [3+2]-cycloaddition works only for the terminal alkynes, but not for the internal alkynes. In order to solve this problem, many scientists came up with different metal catalysis including ruthenium, rhodium, gold, silver etc. for reacting the internal alkynes with azides, but none of them were as efficient as copper catalysed click reactions.
Bertozzi (Stanford University, USA) discovered the strain-promoted click reaction, where she has chosen highly strained alkyne such as cyclooctyne and azide. Kudos for her intelligence, she started utilizing this reaction as a bioorthogonal reaction in vivo. She explored different varieties of substituted cyclooctynes for the better reaction rates and yields. This reaction performs excellently at the ambient temperature without disturbing the cell environment, thus making them bioorthogonal. But this methodology is limited to bioorthogonal reactions since it doesn’t have many applications in medicinal chemistry due to the poor regioselectivity (see Figure 1).
Meanwhile, at the University of Hyderabad, School of Chemistry, the vision of Prof. D. B. Ramachary’s laboratory went beyond the metal-catalysed click reactions. Since copper catalysed click reactions work only for the terminal alkynes and the strain promoted click reactions are limited to bioorthogonal systems and also lack regioselectivity, Ramachary’s laboratory thought to develop a common metal-free green click reaction for the synthesis of 1,4-disubstitued, 1,5-disubstituted, and 1,4,5-trisubstituted 1,2,3-triazoles in a more sustainable pathway. They have chosen alpha-methylene carbonyl compounds (because of its wide availability and stability) as a dipolarophile source to react with aryl/alkyl-azides in [3+2]-cycloaddition fashion, using the amine/amino acid catalysis (see Figure 2).
In 2008, under the proline catalysis, his laboratory discovered the click reaction between cyclohexenones and tosyl azide in DMSO at room temperature and succeeded in achieving the NH-1,2,3-triazoles with excellent yield. In a one-pot, they achieved both the [3+2]-cycloaddition and the tosyl deprotection reactions in a stepwise manner. It was the first green organocatalytic click reaction for synthesizing 1,2,3-triazoles. This led a new green pathway for the scientific community. With this motivation, in 2011, Wang from Singapore and Bressy from France demonstrated the [3+2]-cycloaddition of less activated alpha-methylene carbonyl species such as cyclohexanone and activated alkyl carbonyls such as beta-keto esters with various azides to synthesize the corresponding 1,2,3-triazoles in excellent yields (see Figure 2).
In 2013, once again Ramachary’s research group came up with an in situ approach for the synthesis of benzotriazoles, using organocatalytic [3+2]-cycloaddition followed by oxidative aromatization, which are drug-like molecules. He also developed a new enolate-mediated amine-catalysed [3+2]-cycloaddition where different azides were reacted with acetaldehydes in DMSO at room temperature to access 1,4-disubstituted 1,2,3-triazoles, within 30 minutes in excellent yields. Further he applied the same methodology on various ketones to make 1,4,5-trisubstituted 1,2,3-triazoles with excellent yield and regioselectivities.
In 2014, these two reactions opened the door for the high yielding, green, metal-free organocatalytic click reaction for the synthesis of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles in excellent yields. He further demonstrated the efficiency of the reaction by choosing various functionalized ketones as dipolarophile source and reacting with different azides to make a variety of 1,2,3-triazoles which are medicinally important. Soon after this discovery, many research groups started utilising this green concept in various disciplines such as medicinal chemistry, material chemistry etc. and thus it became a ground-breaking discovery for the synthesis of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles through organocatalysis. Especially in the drug synthesis, attaining 1,2,3-triazoles using this organocatalytic metal-free [3+2]-cycloaddition of carbonyls with azides will be much more preferable than the copper-mediated [3+2]-cycloaddition of terminal alkynes with azides. Exchange of the terminal alkynes with acetaldehydes, which are low-cost, stable and abundant in nature makes this protocol very appealing. When comes to pharmaceutical chemistry, getting rid of metal impurities such as rhodium, ruthenium etc. will be a challenging task, whereas amino acids are bio friendly molecules. With these postulates, Prof. Ramachary suggests the scientific community to utilise this concept in various fields of science to reveal the secrets of nature. He strongly believes that the organocatalytic metal-free click reaction becomes an important tool for the drug synthesis in the coming future.
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