Organocatalysis, Organocatalysts (original) (raw)
Organocatalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions. The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal catalysts.
In the example of theKnoevenagel Condensation, it is believed that piperidine forms a reactive iminium ion intermediate with the carbonyl compound:
Another organocatalyst is DMAP, which acts as an acyl transfer agent:
Thiazolium salts are versatile umpolung reagents (acyl anion equivalents), for example finding application in theStetter Reaction:
All of these organocatalysts are able to form temporary covalent bonds. Other catalysts can form H-bonds, or engage in pi-stacking and ion pair interactions (phase transfer catalysts). Catalysts may be specially designed for a specific task - for example, facilitating enantioselective conversions.
An early example of an enantioselectiveStetter Reaction is shown below:
D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta,1996, 79, 1899-1902.
Enantioselective Michael Addition using phase transfer catalysis:
T. Ooi, D. Ohara, K. Fukumoto, K. Maruoka, Org. Lett., 2005,7, 3195-3197.
The first enantioselective organocatalytic reactions had already been described at the beginning of the 20th century, and some astonishing, selective reactions such as the proline-catalyzed synthesis of optically active steroid partial structures by Hajos, Parrish, Eder, Sauer and Wiechert had been reported in 1971 (Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. 1971,10, 496,DOI). However, the transition metal-based catalysts developed more recently have drawn the lion’s share of attention.
Hajos-Parrish-Eder-Sauer-Wiechert reaction (example)
The first publications from the groups of MacMillan, List, Denmark, and Jacobson paved the way in the year 1990. These reports introduced highly enantioselective transformations that rivaled the metal-catalyzed reactions in both yields and selectivity. Once this foundation was laid, mounting interest in organocatalysis was reflected in a rapid increase in publications on this topic from a growing number of research groups.
Proline-derived compounds have proven themselves to be real workhorse organocatalysts. They have been used in a variety of carbonyl compound transformations, where the catalysis is believed to involve the iminium form. These catalysts are cheap and readily accessible:
A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol. Chem., 2005,3, 84-96.
Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed., 2006,45, 958-961.
Kumaragurubaran, K. Juhl, W. Zhuang, A. Gogevig, K. A. Jorgensen, J. Am. Chem. Soc., 2002, 124, 6254-6255.
A general picture of recent developments: V. D. B. Bonifacio,Proline Derivatives in Organic Synthesis, Org. Chem. Highlights 2007, March 25.
Books on Organocatalysis
Asymmetric Organocatalysis
Albrecht Berkessel, Harald Gr�ger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
Recent Literature
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V. Pathania, S. R. Roy, J. Org. Chem., 2024, 89, 4145-4155.
A carbene-catalyzed [4 + 2] annulation of activated esters and β-borate enones provides enantioenriched organoborones with two consecutive stereogenic centers. This organocatalytic protocol greatly enriches the structural diversity of chiral organoboron compounds.
Z. Li, J. Zhang, J. Wang, Org. Lett., 2024, 26, 1965-1969.
Acetophenone promotes a highly selective, efficient, and simple direct transamidation of thioamides with amines under metal-/solvent-free conditions. The reaction tolerates a wide range of functional groups and substrates, including single- or double-thioamides, benzylamines, or alkyl/cycloalkyl-substituted aliphatic amines.
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A chiral cyclopropenimine-based bifunctional catalysts featuring a thiourea moiety mediates an enantio- and diastereoselective conjugate addition of α-iminonitriles to a wide array of enones to provide α-chiral nitrile-containing 1-pyrroline derivatives bearing vicinal stereocenters following an in-situ cyclocondensation. Trans-to-cis isomerization enables the synthesis of all four stereoisomers.
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PIII/PV=O redox cycling enables a one-step dehydroxylative thioetherification of alcohols with various hypervalent organosulfur compounds. This method offers excellent functional group tolerance, broad substrate scope, and scalability.
G. Sun, S.-P. Zhang, Y.-F. Zhao, Y. Du, M.-Y. Shi, J. Li, H. Yuan, X. Wen, H. Sun, Q.-L. Xu, J. Org. Chem., 2024, 89, 1083-1090.
An organocatalyst delivers nitroalkanes from β,β-disubstituted nitroalkenes with a generality otherwise achievable only by a combination of several organo- and organometallic catalysts. The catalyst improves yield and/or enantioselection of the reduction of some major classes of nitroalkenes.
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A N-heterocyclic carbene (NHC)-catalyzed synthesis of _N_-substituted isoindolinone acetates proceeds through a tandem imine umpolung-intramolecular aza-Michael addition followed by oxidation with molecular oxygen in air as the sole oxidant. This method offers atom efficiency, operational simplicity, large-scale syntheses, and mild reaction conditions.
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A simple 2,2'-biphenol-derived phosphoric acid catalyst promotes a dehydrative esterification from an equimolar mixture of carboxylic acids and primary or secondary alcohols in toluene at 100 �C without the necessity to remove water. This reaction was also successfully conducted at the gram scale.
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J. T�njes, L. Kell, T. Werner, Org. Lett., 2023, 25, 9114-9118.
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C. Mou, Y. Lv, J. Jin, H. Chai, T. Li, Y. R. Chi, Z. Jin, Org. Lett., 2023, 25, 8706-8710.
Quinazolinedione derivatives were obtained from 2-aminobenzoic acids and bench-stable α-chloroaldoxime _O_-methanesulfonates under mild reaction conditions via a DMAP-catalyzed domino reaction consisting of nucleophilic substitution, Tiemann rearrangement, and cyclic urea formation.
W. Kaewman, J. Kaeobamrung, Synlett, 2023, 34, 2052-2058.
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W.-J. Kang, Y. Pan, A. Ding, H. Guo, Org. Lett., 2023, 25, 7633-7638.
_N_-Heterocyclic carbenes (NHCs) catalyze a highly enantioselective synthesis of fluoroalkylated benzopyranones and 3-coumaranones with all-carbon quaternary stereocenters via annulation reactions between in situ generated acyl anion intermediates and highly substituted trifluoromethyl-β,β-disubstituted Michael acceptors. The method can also be extended to perfluoroalkyl homologues.
I. Barańska, K. Rafińska, Z. Rafiński, J. Org. Chem., 2023, 88, 14339-14344.
Readily available and structurally diverse alkyl carboxylic acids can serve as the starting materials for sulfinamides, sulfonamides, and sulfonimidamides syntheses. The methods harness alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products.
J. A. Andrews, J. Kalepu, C. F. Palmer, D. L. Poole, K. E. Christensen, M. C. Willis, J. Am. Chem. Soc., 2023, 145, 21623-21629.
A _N_-triflyl phosphoramide catalyzes an enantioselective transformation of bicyclo[1.1.0]butanes into cyclobutenes with good regio- and enantiocontrol. This isomerization proceeds under mild conditions with low catalyst loading as well as good functional group compatibility.
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B.-Q. He, X. Wu, Org. Lett., 2023, 25, 6571-6576.
A visible-light-promoted and transition-metal-free photoredox-catalysis strategy provides thioxanthone derivatives (TXs) via hydrogen atom transfer, C-C formation, and oxidative dehydrogenation with high regioselectivity and reactivity. Significantly, this method can be used to produce commercial photoinitiators and drugs at the gram level.
W. Liao, J. Hou, H. Tang, X. Guo, G. Sheng, M. Jin, Org. Lett., 2023, 25, 6352-6356.
A general and convenient thiazolium-catalyzed cross-coupling of various aldehydes with acylimines derived from sulfonylamides provides ready access to structurally diverse α-amido ketones.
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