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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.

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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A photochemical activation of formate salts using a thiyl radical initiator without an exogenous chromophore enables a hydrocarboxylation of unactivated alkenes. This redox-neutral method is technically simple to execute and effective across a broad range of alkene substrates.
S. N. Alektiar, H. Han, Y. Dang, C. Z. Rubel, Z. W. Wickens, J. Am. Chem. Soc., 2023, 145, 10991-10997.

An efficient and convenient NHC (N-heterocyclic carbene)-catalyzed radical coupling reaction between aldehydes and azobis(isobutyronitrile) (AIBN) provides β-ketonitriles containing a quaternary carbon center in very good yields. This protocol offers broad substrate scope and good functional group tolerance under metal-free and mild reaction conditions.
J.-M. Wang, T. Chen, C.-S. Yao, K. Zhang, Org. Lett., 2023, 25, 3325-3329.

The charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor.
M. A. Horwitz, A. B. Dürr, K. Afratis, Z. Chen, J. Soika, K. E. Christensen, M. Fushimi, R. S. Paton, V. Gouverneur, J. Am. Chem. Soc., 2023, 145, 9708-9717.

A convenient reductive photocleavage of sulfonamides using thioureas as organophotocatalysts tolerates a variety of substrates and occurs under mild reaction conditions in the presence of tetrabutylammonium borohydride as a reducing agent.
J. Brom, A. Maruani, L. Micouin, E. Benedetti, J. Org. Chem., 2023, 88, 5923-5935.

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt to provide valuable α,α-difluoro substituted aliphatic carboxylate esters.
C. Liu, N. Shen, R. Shang, Synthesis, 2023, 55, 1401-1409.

A photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst provides chiral α-chlorinated carboxylic acid esters. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.
D. Weinzierl, M. Piringer, P. Zebrowski, L. Stockhammer, M. Waser, Org. Lett., 2023, 25, 3126-3130.

CBZ6, a redox-neutral non-donor-acceptor-type organo-photocatalyst, has a strong reductive potential and mediates both single-electron transfer and triplet energy transfer processes. The intramolecular hydroarylation of acrylamides provides both oxindoles as 5-exo-trig and dihydroquinolinones as 6-endo-trig cyclization products regiospecfically under mild conditions depending on the solvent used.
X.-P. Cai, B.-H. Han, F.-T. Cen, J.-P. Qu, Y.-B. Kang, Org. Lett., 2023, 25, 2863-2867.

An N-heterocyclic carbene catalyzes a radical-mediated sulfonyl methylation of readily available aldehydes to provide α-sulfonyl ketones. This protocol involves a single-electron transfer reduction of α-iodosulfones by NHC-bound Breslow intermediates, followed by a radical-radical coupling to afford the target compounds.
C. Liu, Z. Liang, A. Jialingbieke, J. Gao, D. Du, Org. Lett., 2023, 25, 2657-2662.

1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) catalyzes an efficient photosynthesis of various arylated 2-aryl-2H-indazoles in good yields. This mild protocol features wide substrate scope, good functional group tolerance, and operational simplicity. In addition, the strategy was successfully applied to the late-stage modification of drug molecules.
A. Shi, P. Xiang, Y. Wu, C. Ge, Y. Liu, K. Sun, B. Yu, Synlett, 2023, 34, 457-464.

A phenalenyl-based molecule catalyzes a transition-metal-free C-alkylation via a borrowing hydrogen pathway for α-alkylations of ketones, synthesis of substituted quinolines, and 9-monoalkylations of fluorene. A preliminary investigation of the reaction mechanism has been carried out, suggesting a radical-mediated borrowing hydrogen pathway.
A. Banik, P. Datta, S. K. Mandal, Org. Lett., 2023, 25, 1305-1309.

An organic photocatalyst mediates a deconstructive alkynylation of an unstrained ketone under blue light irradiation. This alkynylation method offers a broad substrate scope and excellent functional group tolerance. A trifluoromethylation reagent for the trifluoromethylation reaction of various alkynyl bromides is also described.
H. Wu, S. Chen, D. Xiao, F. Li, K. Zhou, X. Yin, C. Liu, X. He, Y. Shang, Org. Lett., 2023, 25, 1166-1171.

A N-heterocyclic carbene catalyzes a formal [3 + 3] annulation of alkynyl esters with enolizable ketones to provide functionalized 2H-pyran-2-ones in a highly regioselective manner. This simple protocol offers a broad substrate scope and mild metal-free conditions.
Z. Liang, J. Li, L. Wang, Z. Wei, J. Huang, X. Wang, D. Du, J. Org. Chem., 2023, 88, 1836-1843.

Under irradiation of 407 nm LEDs using sodium formate as reductant and thiol as hydrogen atom transfer agent, a variety of (hetero)aryl chlorides, bromides, and iodides can be reduced to the corresponding (hetero)arenes. The key intermediates, aryl radicals, can be trapped by either hydrogen, phosphite, or borates. The same conditions can be used for the deprotection of sulfonamides.
S.-D. Wang, B. Yang, H. Zhang, J.-P. Qu, Y.-B. Kang, Org. Lett., 2023, 25, 816-820.

A (diiodo(trimethylsilyl)methyl)boronic ester was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. The use of this carbene precursor in an organocatalyzed and visible light mediated borosilylcyclopropanation of styrene provides 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes in excellent yields and diastereoselectivity.
L. Thai-Savard, M. Sayes, J. Perreault-Dufour, G. Hong, L. A. Wells, M. C. Kozlowski, A. B. Charette, J. Org. Chem., 2023, 88, 1515-1521.

Chiral BINOL derivatives catalyze an enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane to provide enantioenriched N-unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for asymmetric crotylboration reactions, as well as for the enantioselective synthesis of homopropargylic alcohols.
J. Braire, A. Macé, R. Zaier, M. Cordier, J. Vidal, C. Lalli, A. Martel, F. Carreaux, J. Org. Chem., 2023, 88, 1457-1468.

2-(Bromomethyl)naphthalene promotes an organocatalytic and base-free Cloke-Wilson rearrangement of chain doubly activated cyclopropanes for the construction of 2,3-dihydrofurans via a carbocation-initiated tandem intramolecular ring-opening/recyclization process. The strategy is especially suitable for the construction of furan units in complex molecules.
G. Zhang, L. Chen, Z. Hu, Z. Zhang, J. Bi, M. Li, X. Zhang, J. Org. Chem., 2023, 88, 1003-1017.

Activation of the C-Br bond of CBrX3 (X = Cl, Br) using 9-mesityl-10-methylacridinium perchlorate as a visible-light photocatalyst enables the synthesis of gem-dihaloenones from terminal alkynes via a SET mechanism.
T. K. Dinda, P. Mal, J. Org. Chem., 2023, 88, 573-584.

SPINOL-derived borophosphates catalyze an asymmetric reductive amination of ketones with pinacolborane to provide a series of chiral amine derivatives bearing multiple functional groups in very good yields and enantioselectivities under mild reaction conditions.
Z. Wu, H. He, M. Chen, L. Zhu, W. Zheng, Y. Cao, J. C. Antilla, Org. Lett., 2022, 24, 9436-9441.

Development of Carbazole-Cored Organo-Photocatalyst for Visible Light-Driven Reductive Pinacol/Imino-Pinacol Coupling
S. Kundu, L. Roy, M. S. Maji, Org. Lett., 2022, 24, 9001-9006.

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.

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