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Organocatalysis

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:

Steglich Esterification

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: :


D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899-1902.


model explaining the facial selectivity

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 Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH


Recent Literature

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The combination of organophotoredox catalysis with hydrogen atom transfer enables a mild C-H alkylation of quinoxalin-2(1H)-ones with feedstock aldehydes, amides, alcohols, ethers, or cycloalkanes. This reaction occurred under environmentally benign and external oxidant-free reaction conditions with good functional group compatibility.
L. Wang, Z. Chen, G. Fan, X. Liu, P. Liu, J. Org. Chem., 2022, 87, 14580-14587.


Visible light mediates a metal-free oxygenation of quinoxalin-2(1H)-one to quinoxaline-2,3-diones in very good yields by employing Mes-Acr-MeClO4 as a photocatalyst without using any additive or cocatalyst. O2 serves as the eco-friendly and green oxidant source for this conversion. In addition, this sustainable approach tolerates a broad range of functional groups.
S. Sau, P. Mal, J. Org. Chem., 2022, 87, 14565-14579.


A bis(imidazoline)-phosphoric acid catalyzes an enantioselective hydrophosphonylation of ketimines with phosphine oxides to provide chiral α-quaternary aminophosphorous compounds having a primary amino group in excellent yields and enantioselectivities. Based on experimental results and DFT calculation, transition states were proposed to explain the stereoselectivity of the reaction.
K. Ogura, I. Isozumi, T. Takehara, T. Suzuki, S. Nakamura, Org. Lett., 2022, 24, 8088-8092.


A metal-free quinoid catalyst, namely 1-hexylKuQuinone (KuQ), promotes a chemoselective, light-induced thioether to sulfoxide oxidation in HFIP, using O2 as the oxidant, at room temperature. Remarkably, the system can be recharged and recycled without loss of activity and selectivity.
M. Forchetta, F. Sabuzi, L. Stella, V. Conte, P. Galloni, J. Org. Chem., 2022, 87, 14016-14025.


Benzoic acid catalyzes an efficient multicomponent reaction of readily available vinyl azides, aromatic aldehydes, and aromatic amines to provide 1,2,5-trisubstituted imidazoles under metal-free conditions without generating any toxic waste. This convenient approach offers high functional group compatibility.
J. Li, X. Jia, J. Qiu, M. Wang, J. Chen, M. Jing, Y. Xu, X. Zheng, H. Dai, J. Org. Chem., 2022, 87, 13945-13954.


The combination of crown ether based host-guest chemistry with chiral phosphoric acid mediated asymmetric catalysis enables a supramolecular regulation of catalytic asymmetric two-component tandem acetalization reactions. After addition of the alkali metal guest, an improvement in yield and an increased enantioselectivity demonstrated the great advantages of this supramolecular regulation strategy.
J. Tang, C. Chen, T. Hong, Z. Zhang, C. Xie, S. Li, Org. Lett., 2022, 24, 7955-7960.


A visible-light-induced perfluoroalkylation reactions of aryl acrylic acids uses perfluoroalkyl iodides as radical precursors and inexpensive eosin Y as a photocatalyst. The easy accessibility of perfluoroalkyl iodides and the broad substrate scope, mild conditions, and metal-free catalyst make this decarboxylative protocol applicable for the transformation of inexpensive raw materials to high-value chemicals.
M. Yu, K. Niu, Z. Wang, Y. Liu, Q. Wang, Org. Lett., 2022, 24, 7622-7626.


Structurally well-defined C2-symmetric chiral quaternary ammonium bromides catalyze a highly enantioselective solid-liquid phase transfer catalytic alkylation of aldimine Schiff bases of amino acid
tert-butyl esters to provide a wide variety of α,α-dialkyl-α-amino acids.
T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem. Soc., 2000, 122, 5228-5229.


An operationally simple organocatalytic method generates a chiral tertiary/quaternary stereocenter at the C3 position of pyrroles. The process proceeds through an amine-catalyzed direct aldol reaction of succinaldehyde with various acceptor carbonyls, followed by a Paal-Knorr reaction with a primary amine in the same pot.
A. P. Pawar, J. Yadav, A. J. Dolas, Y. K. Nagare, E.  Iype, K. Rangan, I. Kumar, Org. Lett., 2022, 24, 7549-7554.


A visible light mediated sulfurization of alkenes and alkynes with aromatic and heteroaromatic thiols enables a benign and metal-free functionalization using Eosin Y as photocatalyst and eco-friendly air (O2) as the sole oxidant. This selective approach shows good substrate generality to afford sulfoxides, β-hydroxysulfoxides, and β-keto sulfides in high yield.
R. Rahaman, M. T. Hoque, D. K. Maiti, Org. Lett., 2022, 24, 6885-6890.


The combination of flavin and iodine catalyzes a facile and atom-economical oxidative cross-dehydrogenative coupling between amidines and chalcones to provide tetra-substituted imidazoles in good yields. The riboflavin-iodine catalytic system played multiple roles in substrate- and O2-activation generating benign H2O as the only byproduct.
A. Takeda, H. Okai, K. Watabe, H. Iida, J. Org. Chem., 2022, 87, 10372-10376.


The regioselectivity of the intramolecular cyclization of bifunctional α-phenyl alkenes can be controlled simply by the choice of the organic chromophore as the photocatalyst. Whereas N,N-(4-diisobutylaminophenyl)phenothiazine catalyzes exo-trig cyclizations, 1,7-dicyanoperylene-3,4,9,10-tetracarboxylic acid bisimides catalyze endo-trig additions.
. Weick, D. Steuernagel, A. Belov, H.-A. Wagenknecht, Synlett, 2022, 33, 1199-1203.


Host-guest assemblies of a designed 1,4-bis(diarylamino)naphthalene and V-shaped aromatic amphiphiles are highly reducing photoredox catalysis systems for an efficient demethoxylative hydrogen transfer of Weinreb amides in water.
Y. Hyodo, K. Takahashi, Y. Chitose, M. Abe, M. Yoshizawa, T. Koike, M. Akita, Synlett, 2022, 33, 1184-1188.


The use of an ortho-naphthoquinone catalyst enables a biomimetic alcohol dehydrogenase (ADH)-like oxidation protocol as green alternative to existing stoichiometric and metal-catalyzed alcohol oxidation reactions. The developed organocatalytic aerobic oxidation protocol proceeds through an intramolecular 1,5-hydrogen atom transfer of naphthalene alkoxide intermediates.
J. Baek, T. Si, H. Y. Kim, K. Oh, Org. Lett., 2022, 24, 4982-4986.


Mandelic acid catalyzes a highly regioselective aromatic bromination with N-bromosuccinimide (NBS) under aqueous conditions at room temperature. Computational results demonstrate that Lewis basic additives interact with NBS to increase the electropositive character of bromine prior to electrophilic transfer.
S. I. Baker, M. Yaghoubi, S. L. Bidwell, S. L. Pierce, H. P. Hratchian, R. D. Baxter, J. Org. Chem., 2022, 87, 8492-8502.


Catalysts comprised of Pd(OAc)2 and either PCy3 or sterically hindered N-heterocyclic carbene ligands provide fast rates for a mild, palladium-catalyzed synthesis of oxindoles in high yields by amide α-arylation.
S. Lee, J. F. Hartwig, J. Org. Chem., 2001, 66, 3402-3415.


2,4-dinitrophenol (2,4-DNP) mediates an efficient photoannulation of α-azidochalcones into 2,5-diaryloxazoles under visible-light irradiation. The scope of the reaction was studied by synthesizing a series of 2,5-diaryloxazoles including two naturally occurring oxazoles (Texamine and Balsoxin) in excellent yields.
U. D. Newar, S. Borra, R. A. Maura, Org. Lett., 2022, 24, 4454-4458.


Individual β-hydroxy thiocyanates can be synthesized in high yield and with more than 90% regioselectivity in the presence of phenol-containing macrocyclic diamides under mild reaction conditions. The method offers high regioselectivity, simple regeneration/reuse of catalyst through several cycles without a decrease in activity, and ease of workup of the reaction.
H. Sharghi, M. A. Nasseri, K. Niknam, J. Org. Chem., 2001, 66, 7287-7293.


A mild, rapid, straightforward visible-light-mediated sulfonamide ethylation of easily available redox active esters or alkyl iodides with vinylsulfonamides provides a diverse array of compounds with C(sp3)-sulfonamide skeletons. This method offers a broad substrate scope and has  and potential utility for late-stage functionalization of natural products and synthetic medicines.
M. Zhang, M. Yu, Z. Wang, Y. Liu, Q. Wang, Org. Lett., 2022, 24, 3932-3937.


Sodium benzene sulfinate catalyzed a visible-light-driven aerobic oxidative cleavage of olefins to provide the corresponding aldehydes and ketones under transition-metal-free conditions. Notably, α-halo-substituted styrenes proceeded with photoinduced oxidation to finally afford α-halo-acetophenones with halogen migration.
Y.-X. Chen, J.-T. He, M.-C. Wu, Z.-L. Liu, K. Tang, P.-J. Xia, K. Chen, H.-Y. Xiang, X.-Q. Chen, H. Yang, Org. Lett., 2022, 24, 3920-3925.


A perfluorophenyl substituted 1,1′-bi-2-naphthol (BINOL) is an effective photoacid catalyst for promoting the acetalization of enol ethers with alcohols under irradiation with visible light. The reactions proceed efficiently with a wide range of substrates under mild and near neutral conditions.
H. Liu, Y. Chen, D. An, X. Zhang, S. Liao, Synlett, 2022, 33, 800-804.


A metal-free photoredox catalyzed amidyl N-centered radical addition to the C-C triple bond of o-alkynylated benzamides provides isoquinoline-1,3,4(2H)-triones, 3-hydroxyisoindolin-1-ones, and phthalimides via a proton-coupled electron transfer (PCET) process under mild reaction conditions.
M. B. Reddy, K. Prasanth, R. Anandhan, Org. Lett., 2022, 24, 3674-3679.


A metal-free photoredox catalyzed amidyl N-centered radical addition to the C-C triple bond of o-alkynylated benzamides provides isoquinoline-1,3,4(2H)-triones, 3-hydroxyisoindolin-1-ones, and phthalimides via a proton-coupled electron transfer (PCET) process under mild reaction conditions.
M. B. Reddy, K. Prasanth, R. Anandhan, Org. Lett., 2022, 24, 3674-3679.


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