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 the Knoevenagel 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 the Stetter 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 enantioselective Stetter Reaction is shown below: :||
model explaining the facial selectivity
Enantioselective Michael Addition using phase transfer catalysis:
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 general picture of recent developments: V. D. B. Bonifacio, Proline Derivatives in Organic Synthesis, Org. Chem. Highlights 2007, March 25.
Books on Organocatalysis
Albrecht Berkessel, Harald Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
A visible-light photocatalytic aerobic oxidative lactonization of arene C(sp2)-H bonds provides benzocoumarin derivatives in good yields in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and tert-butyl nitrite. This atom economic method offers mild reaction conditions, use of a green oxidant and metal-free catalysis.
Y. Wang, S. Wang, B. Chen, M. Li, X. Hu, B. Hu, L. Jin, N. Sun, Z. Shen, Synlett, 2020, 31, 261-266.
The energetic limitations of visible light can be circumvented by electrochemically priming a photocatalyst prior to excitation. This method enables the use of aryl chlorides with reduction potentials hundreds of millivolts beyond the potential of Na0 in carbon-carbon and carbon-heteroatom bond-forming reactions.
N. G. W. Cowper, C. P. Chernowsky, O. P. Williams, Z. K. Wickens, J. Am. Chem. Soc., 2020, 142, 2093-2099.
A general, metal-free visible light-induced photocatalytic borylation platform enables borylation of electron-rich derivatives of phenols and anilines, chloroarenes, as well as other haloarenes in the presence of phenothiazine as photocatalyst. The reaction exhibits excellent functional group tolerance.
S. Jin, H. T. Dang, G. C. Haug, R. He, V. D. Nguyen, V. T. Nguyen, H. D. Arman, K. S. Schanze, O. V. Larionov, J. Am. Chem. Soc., 2020, 142, 1603-1613.
A carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent provides β-trifluoromethyl-α-substituted ketones with a broad scope and good yields.
B. Zhang, Q. Peng, D. Guo, J. Wang, Org. Lett., 2020, 22, 443-447.
An organic photoredox catalyst promotes a metal-, base-, and additive-free amide bond formation reaction in high yields. This green approach offers a broad substrate scope, good compatibility with water and air, and tolerates functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles.
W. Song, K. Dong, M. Li, Org. Lett., 2020, 22, 371-375.
Acyclic guanidinium salts catalyze the formation of five-membered cyclic carbonates in good yields through cycloaddition of CO2 to epoxides at nearly ambient temperatures and pressures. To achieve good catalytic activity of the guanidinium salt, it is essential to have active hydrogens on the cation moiety as well as an iodide ion as the anion moiety.
N. Aoyagi, Y. Furusho, T. Endo, Synthesis, 2020, 52, 150-158.
The Petasis condensation of vinylic or aromatic boronic acids, salicylaldehydes, and amines is assisted by the hydroxy group adjacent to the aldehyde moiety. A subsequent cyclization with ejection of amine upon heating provides 2H-chromenes. A catalytic method using a resin-bound amine enables a convenient preparation of 2H-chromenes.
Q. Wang, M. G. Finn, Org. Lett., 2000, 2, 4063-4065.
An organic acridinium salt catalyzes an anti-Markovnikov hydroazidation of activated olefins under irradiation from blue LEDs. This method is applicable to a variety of substituted styrenes and several vinyl ethers, yielding synthetically versatile hydroazidation products in excellent yield, whereas terminal styrenes provide hydroazidation products in moderate yields.
N. P. R. Onuska, M. E. Schutzbach-Horton, J. L. R. Collazo, D. A. Nicewicz, Synlett, 2020, 31, 55-59.
A chiral phosphoric acid catalyst catalyzes an intramolecular reaction of a range of benzylic alcohols bearing an internal oxetane to form chiral 1,4-benzodioxepines with high enantioselectivity. This oxetane desymmetrization process enables a direct synthesis of seven-membered heterocycles with good stereocontrol.
X. Zou, G. Sun, H. Huang, J. Wang, W. Yang, J. Sun, Org. Lett., 2020, 22, 249-252.
Tertiary amines catalyze a β-azidation of α,β-unsaturated carbonyl compounds with a 1:1 mixture of TMSN3 and AcOH as azide source. Tertiary amines, either in solution or bound to a solid support, can be used.
D. J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett., 1999, 1, 1107-1109.
A recoverable chiral quaternary salt as catalyst enables phase transfer, ion-pair mediated reactions of racemic α-bromo ketones to chiral α-azido and α-amino ketones with high enantioselectivity in fluorobenzene-water. The process has been generalized to various other replacements of bromine.
R. da Silva Gomes, E. J. Corey, J. Am. Chem. Soc., 2019, 141, 20058-20061.
4,4′-Bipyridine worked as an organocatalyst for the reduction of nitroarenes by bis(neopentylglycolato)diboron (B2nep2), followed by hydrolysis to give the corresponding anilines with broad functional group tolerance.
H. Hosoya, L. C. M. Castro, I. Sultan, Y. Nakajima, T. Ohmura, K. Sato, H. Tsurugi, M. Suginome, K. Mashima, Org. Lett., 2019, 21, 9812-9817.
Coupling reactions of epoxides with carbon dioxide that proceed at atmospheric pressure at temperatures of less than 100°C are challenging. Tetraarylphosphonium salts (TAPS) catalyze the formation of five-membered cyclic carbonates by chemical fixation using 1 atm of carbon dioxide at 60°C. Electron-donating groups enhanced the reactivity of the used TAPS.
Y. Toda, Y. Komiyama, H. Esaki, K. Fukushima, H. Suga, J. Org. Chem., 2019, 84, 15578-15589.
Cyclopropenones undergo ring-opening reactions with catalytic amounts of phosphine, forming reactive ketene ylides. A subsequent cyclization with a pendant hydroxy group provides butenolide scaffolds. The reaction proceeds efficiently in diverse solvents and tolerates a broad range of functional groups.
S. S. Nguyen, A. J. Ferreira, Z. G. Long, T. K. Heiss, R. S. Dorn, R. D. Row, J. A. Prescher, Org. Lett., 2019, 21, 8673-8678.
The use of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as catalyst enables a Machetti-De Sarlo reaction of nitroalkenes with alkynes/alkenes under sustainable conditions to afford a library of isoxazole/isoxaline products.
M. Vadivelu, S. Sampath, K. Muthu, K. Karthikeyan, C. Praveen, J. Org. Chem., 2019, 84, 13636-13645.
A streamlined and general enantioselective Mannich reaction of enamides with C-alkynyl N-Boc N,O-acetals, which serve as readily available C-alkynyl imine precursors, provides a range of chiral β-keto N-Boc-propargylamines in high yields and in high enantioselectivities.
F.-F. Feng, S. Li, C. W. Cheung, J.-A. Ma, Org. Lett., 2019, 21, 8419-8423.
Tri(9-anthryl)borane catalyzes a visible-light-induced trifluoromethylation of unactivated alkenes with CF3I. The mild reaction conditions tolerate various functional groups, and the reaction could be extended to perfluoroalkylations with C3F7I and C4F9I.
J. Moon, Y. K. Moon, D. D. Park, S. Choi, Y. You, E. J. Cho, J. Org. Chem., 2019, 84, 12925-12932.
A N-heterocyclic carbene-catalyzed radical relay enables the vicinal alkylacylation of styrenes, acrylates and acrylonitrile with complete regioselectivity using aldehydes and tertiary alkyl carboxylic acid-derived redox-active esters to produce functionalized ketone derivatives.
T. Ishii, K. Ota, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2019, 141, 14073-14077.
A visible-light-promoted regioselective coupling of aryl-2H-azirines and (diacetoxy)iodobenzene provides C(sp3)-H acyloxylated azirines in the presence of Rose Bengal as an organophotoredox catalyst. The reaction proceeds under aerobic condition at room temperature via a radical pathway.
A. De, S. Santra, A. Hajra, G. V. Zyrayanov, A. Majee, J. Org. Chem., 2019, 84, 11735-11740.
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