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 Gr÷ger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH
4-Mesityl-2,6-diphenylpyrylium tetrafluoroborate (MDPT) and 4-mesityl-2,6-di-p-tolylpyrylium tetrafluoroborate (MD(p-tolyl)PT) are highly robust photoredox catalysts, and exhibit some of the highest oxidation potentials reported. Their utility was demonstrated in the mild and efficient generation of carbonyl ylides from benzylic epoxides.
E. Alfonzo, F. S. Alfonso, A. B. Beeler, Org. Lett., 2017, 19, 2989-2992.
A water-soluble photocatalyst promotes an aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions.
H.-Y. Xie, L.-S. Han, S. Huang, X. Lei, Y. Cheng, W. Zhao, H. Sun, X. Wen, Q.-L. Xu, J. Org. Chem., 2017, 82, 5236-5241.
1,2,2,3,4,4-hexamethylphosphetane catalyzes a deoxygenative N-N bond-forming Cadogan heterocyclization of o-nitrobenzaldimines and o-nitroazobenzenes with good functional group compatibility in the presence of phenylsilane as terminal reductant.
T. V. Nykaza, T. S. Harrison, A. Ghosh, R. A. Putnik, A. T. Radosevich, J. Am. Chem. Soc., 2017, 139, 6839-6842.
A highly enantioselective cascade sulfa-Michael/Julia-Kocienski olefination reaction between 2-mercaptobenzaldehydes and β-substituted vinyl PT-sulfones provies a wide range of 3,4-unsubstituted 2H-thiochromenes with excellent enantioselectivities. This reaction is catalyzed by diphenylprolinol TMS ether and proceeds through an aromatic iminium intermediate.
A. K. Simlandy, S. Mukherjee, J. Org. Chem., 2017, 82, 4851-4858.
A metal-free catalytic strategy for the facile synthesis of biologically relevant indolizines and imidazopyridines scaffolds is promoted by amine and N-heterocyclic carbene (NHC) relay catalysis via Michael addition-[3 + 2] fusion of simple azaarenes and α,β-unsaturated aldehydes.
H. Li, X. Li, Y. Yu, J. Li, Y. Liu, H. Li, W. Wang, Org. Lett., 2017, 19, 2010-2013.
N-Heterocyclic olefins (NHOs) are promising organocatalysts with strong nucleophilicity and Br°nsted basicity. NHOs are efficient promoters for a direct dehydrogenative silylation of alcohols or hydrosilylation of carbonyl compounds. Preliminary results of an asymmetric dehydrogenative silylation are also discussed.
U. Kaya, U. P. N. Tran, D. Enders, J. Ho, T. V. Nguyen, Org. Lett., 2017, 19, 1398-1401.
A bifunctional organocatalyst enables a 1,3-addition of silyl-dienol ethers to nitroalkenes to provide Rauhut-Currier type products with tri- and tetrasubstituted double bonds. The process takes place under smooth, nonanionic conditions, and with high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments.
M. Frias, R. Mas-BallestÚ, S. Arias, C. Alvarado, J. Alemßn, J. Am. Chem. Soc., 2017, 139, 672-679.
A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes enables a green and efficient synthesis of isoxazolines utilizing H2O2 as the oxidant. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in good yields.
I. Triandafillidi, C. G. Kokotos, Org. Lett., 2017, 19, 106-109.
A N-heterocyclic carbene-catalyzed [2 + 4] annulation of α-bromoenals and α-cyano-β-methylenones enables a direct and efficient approach to 1,3,5-trisubstituted benzenes. The reaction worked well for both aryl- and alkylenones.
C.-L. Zhang, S. Ye, Org. Lett., 2016, 18, 6408-6411.
A highly stereoselective one-pot intramolecular Mannich reaction using 2-oxopropyl-2-formylbenzoates and anilines as substrates, catalyzed by a secondary amine, provides 4-aminoisochromanones bearing two adjacent stereocentres in good yields with excellent cis-stereoselectivities and ee values.
F. Vetica, J. Fronert, R. Puttreddy, K. Rissanen, D. Enders, Synthesis, 2016, 48, 4451-4458.
In situ aerobic dual oxidation with asymmetric organocatalysis enables an enantioselective synthesis of α-hydrazino aldehydes from alcohols and N-Boc hydrazine instead of the conventional combination of aldehydes with azodicarboxylates. This reaction tolerates various substituents on the alcohol component and features excellent enantiocontrol, cheap starting materials, operational simplicity, and scalability.
Z. Cui, D.-M. Du, Org. Lett., 2016, 18, 5616-5619.
The use of diacyl disulfide as an acylation reagent enables an efficient ester formation under DMAP catalysis. A site-selective acylation of phenolic and primary aliphatic hydroxyl groups greatly expands the scope of protecting group chemistry. Diacyl disulfides offer excellent moisture tolerance, high efficiency, and potential in synthetic chemistry and biologically meaningful natural product modification.
H.-X. Liu, Y.-Q. Dang, Y.-F. Yuan, Z.-F. Xu, S.-X. Qiu, H.-B. Tan, Org. Lett., 2016, 18, 5584-5587.
A highly enantioselective Michael addition of malonates to enones is catalyzed by dipeptide-derived multifunctional phosphonium salts. This catalytic system offers wide substrate scope and gram scale-up synthesis of adducts with both excellent yield and enantioselectivity.
D. Cao, G. Fang, J. Zhang, H. Wang, C. Zheng, G. Zhao, J. Org. Chem., 2016, 81, 9973-9982.
A metal-free photoredox system, consisting of an acridinium photocatalyst, an organic base, and molecular sieve (MS) 4 ┼, promotes chemoselective photooxidation of aryl alkenes in the presence of oxygen. This oxo-acyloxylation of aryl alkenes provides a green, practical, and metal-free protocol for a wide range of α-acyloxy ketones.
Q.-B. Zhang, Y.-L. Ban, D.-G. Zhou, P.-P. Zhou, L.-Z. Wu, Q. Liu, Org. Lett., 2016, 18, 5256-5259.
A modular aerobic oxidation of amines to imines has been achieved using an ortho-naphthoquinone (o-NQ) catalyst. Whereas the cooperative catalyst system of o-NQ and Cu(OAc)2 provided homocoupled imines from benzylamines, the presence of TFA helped the formation of cross-coupled imines in excellent yields. The oxidation of secondary amines to imines or ketimines is facilitated with the help of Ag2CO3 as cocatalyst.
Y. Goriya, H. Y. Kim, K. Oh, Org. Lett., 2016, 18, 5174-5177.
Chiral phosphine-catalyzed coupling of two readily available partners, γ-aryl-substituted alkynoates and alcohols, under mild conditions enables the enantioselective synthesis of benzylic ethers via internal redox reaction of the alkynoate partner.
D. T. Ziegler, G. C. Fu, J. Am. Chem. Soc., 2016, 138, 12069-12072.
A chemoselective oxidation of α-hydroxy acids to α-keto acids is catalyzed by 2-azaadamantane N-oxyl (AZADO), a nitroxyl radical catalyst. The use of molecular oxygen as a cooxidant enables the desired chemoselective oxidation to α-keto acids, that are labile and can easily release CO2 under oxidation conditions.
K. Furukawa, H. Inada, M. Shibuya, Y. Yamamoto, Org. Lett., 2016, 18, 4230-4233.
A photocatalytic direct decarboxylative hydroxylation of carboxylic acids enables the conversion of various readily available carboxylic acids to alcohols in good yields under extremely mild reaction conditions using molecular oxygen as a green oxidant and visible light as a driving force.
H.-T. Song, W. Ding, Q.-Q. Zhou, J. Liu, L.-Q. Lu, W.-J. Xiao, J. Org. Chem., 2016, 81, 7250-7255.
Highly acidic confined imino-imidodiphosphate (iIDP) Br°nsted acids catalyze the asymmetric Prins cyclization of both aliphatic and aromatic aldehydes. Diverse functionalized 4-methylenetetrahydropyrans are obtained in very good yields and with high regio- and enantioselectivities.
L. Liu, P. S. J. Kaib, A. Tap, B. List, J. Am. Chem. Soc., 2016, 138, 10822-10825.
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