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
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.
A chiral bisphosphine dioxide catalyzes an asymmetric conjugate reduction of acyclic β,β-disubstituted α,β-unsaturated ketones with trichlorosilane to provide saturated ketones with high enantioselectivities. Due to concomitant E/Z-isomerizations of enone substrates, reduction products with the same absolute configurations are obtained from either (E)- or (Z)-enones.
M. Sugiura, Y. Ashikari, Y. Takahashi, K. Yamaguchi, S. Kotani, M. Nakajima, J. Org. Chem., 2019, 84, 11458-11473.
Morpholine efficiently catalyzes Galat reactions between aldehydes and substituted malonic acids half oxyester in refluxing toluene to provide diverse α,β-disubstituted acrylates in to good yields. This method constitutes an attractive alternative to existing methods in terms of scope and eco-compatibility.
T. Xavier, S. Condon, C. Pichon, E. Le Gall, M. Presset, Org. Lett., 2019, 21, 6135-6139.
A multifunctional modular organocatalysis enables a simple and efficient approach to enantioenriched α,β-disubstituted γ-butyrolactones via a one-pot sequential Michael-hemiacetalization-oxidation reaction. The catalytic process offers good substrate compatibility, and the products can be transformed to synthetically useful molecules.
P. Mahto, N. K. Rana, K. Shukla, B. G. Das, H. Joshi, V. K. Singh, Org. Lett., 2019, 21, 5962-5966.
A broadly applicable method for amide C-N and ester C-O bond formation is based on formylpyrrolidine (FPyr) as a Lewis base catalyst and trichlorotriazine (TCT) as a cost-efficient reagent for OH-group activation. The new approach is distinguished by excellent cost-efficiency, waste-balance, scalability, and high levels of functional group compatibility.
P. H. Huy, C. Mbouhom, J. Org. Chem., 2019, 84, 7399-7406.
The organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors enable an intramolecular arene alkylation reaction. This reaction provides a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.
T. C. Sherwood, H.-Y. Xiao, R. G. Bhaskar, E. M. Simmons, S. Zaretsky, M. P. Rauch, R. R. Knowles, T. G. M. Dhar, J. Org. Chem., 2019, 84, 8360-8379.
Phthaloyl chloride as reagent and N-formylpyrrolidine as Lewis base catalyst enable a transformation of aldehydes into geminal dichlorides. This simple reaction offers mild reaction conditions, high levels of functional group compatibility, and scalability.
P. H. Huy, Synthesis, 2019, 51, 2474-2483.
Please cite and link this page as follows:
Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )