




In this short review definition, mechanism, and recent developments of the Stetter reaction, in the period last ten years from 2011 to 2021 are presented. This reaction comprises N-heterocyclic carbene (NHC)-catalyzed umpolung of aldehydes followed by their capturing with activated carbon-carbon double bonds (Michael acceptors). This work includes also progresses in the inter-molecular and intra-molecular versions and enantioselective transformations. Underscoring the recent advances in the applications of Stetter reaction in the synthesis of various heterocyclic systems and total synthesis of natural products have been also introduced.

- Barman, D., Ghosh, T., Show, K., Debnath, S., Ghosh, T., & Maiti, D. K. (2021). NHC-Mediated Stetter-Aldol and Imino-Stetter-Aldol Domino Cyclization to Naphthalen-1 (2 H)-ones and Isoquinolines. Organic Letters, 23(6), 2178-2182. https://doi.org/10.1021/acs.orglett.1c00337
- Biju, A. T., Kuhl, N., & Glorius, F. (2011). Extending NHC-catalysis: coupling aldehydes with unconventional reaction partners. Accounts of chemical research, 44(11), 1182-1195. https://doi.org/10.1021/ar2000716
- Breslow, R. (1958). On the mechanism of thiamine action. IV. 1 Evidence from studies on model systems. Journal of the American Chemical Society, 80(14), 3719-3726. https://doi.org/10.1021/ja01547a064
- Bugaut, X., & Glorius, F. (2012). Organocatalytic umpolung: N-heterocyclic carbenes and beyond. Chemical Society Reviews, 41(9), 3511-3522. https://doi.org/10.1039/C2CS15333E
- Büttner, H., Steinbauer, J., & Werner, T. (2015). Synthesis of cyclic carbonates from epoxides and carbon dioxide by using bifunctional one‐component phosphorus‐based organocatalysts. ChemSusChem, 8(16), 2655-2669. https://doi.org/10.1002/cssc.201500612
- Chen, X. Y., Gao, Z. H., & Ye, S. (2020). Bifunctional N-heterocyclic carbenes derived from L-pyroglutamic acid and their applications in enantioselective organocatalysis. Accounts of chemical research, 53(3), 690-702. https://doi.org/10.1021/acs.accounts.9b00635
- DiRocco, D. A., Noey, E. L., Houk, K. N., & Rovis, T. (2012). Catalytic asymmetric intermolecular stetter reactions of enolizable aldehydes with nitrostyrenes: Computational study provides insight into the success of the catalyst. Angewandte Chemie, 124(10), 2441-2444. https://doi.org/10.1002/ange.201107597
- Draskovits, M., Kalaus, H., Stanetty, C., & Mihovilovic, M. D. (2019). Intercepted dehomologation of aldoses by N-heterocyclic carbene catalysis–a novel transformation in carbohydrate chemistry. Chemical Communications, 55(81), 12144-12147. https://doi.org/10.1039/C9CC05906G
- Draskovits, M., Stanetty, C., Baxendale, I. R., & Mihovilovic, M. D. (2018). Indium-and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses – Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal. The journal of organic chemistry, 83(5), 2647-2659. https://doi.org/10.1021/acs.joc.7b03063
- Dvorak, C. A., & Rawal, V. H. (1998). Catalysis of benzoin condensation by conformationally-restricted chiral bicyclic thiazolium salts. Tetrahedron letters, 39(19), 2925-2928. https://doi.org/10.1016/S0040-4039(98)00439-0
- Ema, T., Nanjo, Y., Shiratori, S., Terao, Y., & Kimura, R. (2016). Solvent-free benzoin and Stetter reactions with a small amount of NHC catalyst in the liquid or semisolid state. Organic letters, 18(21), 5764-5767. https://doi.org/10.1021/acs.orglett.6b03115
- Enders, D., & Balensiefer, T. (2004). Nucleophilic carbenes in asymmetric organocatalysis. Accounts of chemical research, 37(8), 534-541. https://doi.org/10.1021/ar030050j
- Enders, D., & Kallfass, U. (2002). An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angewandte Chemie International Edition, 41(10), 1743-1745. https://doi.org/10.1002/1521-3773(20020517)41:10%3C1743::AID-ANIE1743%3E3.0.CO;2-Q
- Enders, D., Breuer, K., Runsink, J., & Teles, J. H. (1996). The first asymmetric intramolecular Stetter reaction. Preliminary communication. Helvetica chimica acta, 79(7), 1899-1902. https://doi.org/10.1002/hlca.19960790712
- Enders, D., Han, J., & Henseler, A. (2008). Asymmetric intermolecular Stetter reactions catalyzed by a novel triazolium derived N-heterocyclic carbene. Chemical communications, (34), 3989-3991. https://doi.org/10.1039/B809913H
- Fang, X., Chen, X., Lv, H., & Chi, Y. R. (2011). Enantioselective Stetter Reactions of Enals and Modified Chalcones Catalyzed by N‐Heterocyclic Carbenes. Angewandte Chemie, 123(49), 11986-11989. https://doi.org/10.1002/ange.201105812
- Fleige, M., & Glorius, F. (2017). α‐Unsubstituted Pyrroles by NHC‐Catalyzed Three‐Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative. Chemistry–A European Journal, 23(45), 10773-10776. https://doi.org/10.1002/chem.201703008
- Garapati, V. K. R., & Gravel, M. (2018). Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes. Organic letters, 20(20), 6372-6375. https://doi.org/10.1021/acs.orglett.8b02636
- Ghosh, A., Patra, A., Mukherjee, S., & Biju, A. T. (2018). Synthesis of 2-aryl naphthoquinones by the cross-dehydrogenative coupling involving an NHC-catalyzed endo-stetter reaction. The Journal of Organic Chemistry, 84(2), 1103-1110. https://doi.org/10.1021/acs.joc.8b02931
- Ghosh, A., Patra, A., Mukherjee, S., & Biju, A. T. (2018). Synthesis of 2-aryl naphthoquinones by the cross-dehydrogenative coupling involving an NHC-catalyzed endo-stetter reaction. The Journal of Organic Chemistry, 84(2), 1103-1110. https://doi.org/10.1021/acs.joc.8b02931
- Harnying, W., Sudkaow, P., Biswas, A., & Berkessel, A. (2021). N‐Heterocyclic Carbene/Carboxylic Acid Co‐Catalysis Enables Oxidative Esterification of Demanding Aldehydes/Enals, at Low Catalyst Loading. Angewandte Chemie International Edition, 60(36), 19631-19636. https://doi.org/10.1002/anie.202104712
- Hinkamp, L., & Schäfer, H. J. (2015). Allylic oxidation of methyl 10‐undecenoate and nucleophilic additions to methyl 9‐oxo‐10‐undecenoate. European Journal of Lipid Science and Technology, 117(2), 255-265. https://doi.org/10.1002/ejlt.201400238
- Jousseaume, T., Wurz, N. E., & Glorius, F. (2011). Highly enantioselective synthesis of α‐amino acid derivatives by an NHC‐catalyzed intermolecular Stetter reaction. Angewandte Chemie International Edition, 50(6), 1410-1414. https://doi.org/10.1002/anie.201006548
- Kerr, M. S., & Rovis, T. (2004). Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. Journal of the American Chemical Society, 126(29), 8876-8877. https://doi.org/10.1021/ja047644h
- Li, Y., Geng, L., Song, Z., & Zhang, Z. (2022). A DFT study of NHC-catalyzed reactions between 2-bromo-2-enals and acylhydrazones: mechanisms, and chemo-and stereoselectivities. New Journal of Chemistry, 46 (19), 9146-9154. https://doi.org/10.1039/D2NJ01078J
- Liu, F., Bugaut, X., Schedler, M., Fröhlich, R., & Glorius, F. (2011). Designing N‐Heterocyclic Carbenes: Simultaneous Enhancement of Reactivity and Enantioselectivity in the Asymmetric Hydroacylation of Cyclopropenes. Angewandte Chemie International Edition, 50(52), 12626-12630. https://doi.org/10.1002/anie.201106155
- MináKim, S., YuáJin, M., JináKim, M., SugáKim, Y., EuiáSong, C., HyunáRyu, D., & WoonáYang, J. (2011). N-Heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde. Organic & Biomolecular Chemistry, 9(7), 2069-2071. https://doi.org/10.1039/C0OB01178A
- Mitra, R. N., Show, K., Barman, D., Sarkar, S., & Maiti, D. K. (2018). NHC-catalyzed dual Stetter reaction: a mild cascade annulation for the syntheses of naphthoquinones, isoflavanones, and sugar-based chiral analogues. The Journal of Organic Chemistry, 84(1), 42-52. https://doi.org/10.1021/acs.joc.8b01503
- Moore, J. L., Silvestri, A. P., de Alaniz, J. R., DiRocco, D. A., & Rovis, T. (2011). Mechanistic investigation of the enantioselective intramolecular Stetter reaction: Proton transfer is the first irreversible step. Organic letters, 13(7), 1742-1745. https://doi.org/10.1021/ol200256a
- Moore, J. L., Silvestri, A. P., de Alaniz, J. R., DiRocco, D. A., & Rovis, T. (2011). Mechanistic investigation of the enantioselective intramolecular Stetter reaction: Proton transfer is the first irreversible step. Organic letters, 13(7), 1742-1745.
- Murry, J. A., Frantz, D. E., Soheili, A., Tillyer, R., Grabowski, E. J., & Reider, P. J. (2001). Synthesis of α-amido ketones via organic catalysis: thiazolium-catalyzed cross-coupling of aldehydes with acylimines. Journal of the American Chemical Society, 123(39), 9696-9697. https://doi.org/10.1021/ja0165943
- Patra, A., Bhunia, A., & Biju, A. T. (2014). Facile synthesis of γ-ketophosphonates by an intermolecular Stetter reaction onto vinylphosphonates. Organic letters, 16(18), 4798-4801. https://doi.org/10.1021/ol502262d
- Qi, J., Xie, X., He, J., Zhang, L., Ma, D., & She, X. (2011). N-Heterocyclic carbene-catalyzed cascade epoxide-opening and lactonization reaction for the synthesis of dihydropyrone derivatives. Organic & Biomolecular Chemistry, 9(17), 5948-5950. https://doi.org/10.1039/C1OB05854A
- Ranjbari, M. A., Tavakol, H., & Manoukian, M. (2021). Regioselective and solvent-free arylation of β-nitrostyrenes with mono-and dialkyl anilines. Research on Chemical Intermediates, 47(2), 709-721. https://doi.org/10.1007/s11164-020-04294-6
- Rezazadeh Khalkhali, M., Wilde, M. M., & Gravel, M. (2020). Enantioselective Stetter reactions catalyzed by bis (amino) cyclopropenylidenes: Important role for water as an additive. Organic Letters, 23(1), 155-159. https://doi.org/10.1021/acs.orglett.0c03879
- Rong, Z. Q., Li, Y., Yang, G. Q., & You, S. L. (2011). D-camphor-derived triazolium salts for enantioselective intramolecular Stetter reactions. Synlett, 2011(07), 1033-1037. https://doi.org/10.1055/s-0030-1259732
- Shen, G., Liu, H., Chen, J., He, Z., Zhou, Y., Wang, L., ... & Fan, B. (2021). Zinc salt-catalyzed reduction of α-aryl imino esters, diketones and phenylacetylenes with water as hydrogen source. Organic & Biomolecular Chemistry, 19(16), 3601-3610. https://doi.org/10.1039/D1OB00155H
- Stetter, H., & Schreckenberg, M. (1973). A new method for addition of aldehydes to activated double bonds. Angewandte Chemie International Edition in English, 12(1), 81-81. https://doi.org/10.1002/anie.197300811
- Steward, K. M., Gentry, E. C., & Johnson, J. S. (2012). Dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation. Journal of the American Chemical Society, 134(17), 7329-7332. https://doi.org/10.1021/ja3027136
- Trost, B. M., Shuey, C. D., & DiNinno Jr, F. (1979). A stereocontrolled total synthesis of (.+-.)-hirsutic acid C. Journal of the American Chemical Society, 101(5), 1284-1285. https://doi.org/10.1021/ja00499a043
- Um, J. M., DiRocco, D. A., Noey, E. L., Rovis, T., & Houk, K. N. (2011). Quantum mechanical investigation of the effect of catalyst fluorination in the intermolecular asymmetric stetter reaction. Journal of the American Chemical Society, 133(29), 11249-11254. https://doi.org/10.1021/ja202444g
- Wang, Y., Liu, Y., Gong, K., Zhang, H., Lan, Y., & Wei, D. (2021). Theoretical study of the NHC-catalyzed C–S bond cleavage and reconstruction reaction: mechanism, stereoselectivity, and role of catalysts. Organic Chemistry Frontiers, 8(19), 5352-5360. https://doi.org/10.1039/D1QO00706H
- Zarganes-Tzitzikas, T., Neochoritis, C. G., & Dömling, A. (2019). Atorvastatin (lipitor) by MCR. ACS Medicinal Chemistry Letters, 10(3), 389-392. https://doi.org/10.1021/acsmedchemlett.8b00579
- Zhang, J., Xing, C., Tiwari, B., & Chi, Y. R. (2013). Catalytic activation of carbohydrates as formaldehyde equivalents for Stetter reaction with enones. Journal of the American Chemical Society, 135(22), 8113-8116. https://doi.org/10.1021/ja401511r
- Zhou, Q., Bao, Y., & Yan, G. (2022). 2‐Bromo‐3, 3, 3‐Trifluoropropene: A Versatile Reagent for the Synthesis of Fluorinated Compounds. Advanced Synthesis and Catalysis, 364(8), 1371-1387. https://doi.org/10.1002/adsc.202200023
- Zhu, J., Moreno, I., Quinn, P., Yufit, D. S., Song, L., Young, C. M., ... & O’Donoghue, A. C. (2022). The Role of the Fused Ring in Bicyclic Triazolium Organocatalysts: Kinetic, X-ray, and DFT Insights. The Journal of organic chemistry, 87(6), 4241-4253. https://doi.org/10.1021/acs.joc.1c03073
- Zobel, M., & Schäfer, H. J. (2016). Synthesis of fatty acid conjugates with phenols, carbohydrates, amines, and CH‐acidic compounds by Pd (0)‐catalyzed allylic substitution. European Journal of Lipid Science and Technology, 118(1), 80-92. https://doi.org/10.1002/ejlt.201500195
