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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.

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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Visible light promotes a practical and precise deoxygenative deuteration of common aliphatic alcohols using D2O as the deuterium source. Upon intermediacy of xanthate anions, a variety of primary, secondary, and tertiary alcohols can be facilely transformed into deuterioalkanes with excellent D-incorporation. The sequence is catalyzed by in situ formed deuterated 2-mercaptopyridine.
B.-Q. He, X. Wu, Org. Lett., 2023, 25, 6571-6576.


A visible-light-promoted and transition-metal-free photoredox-catalysis strategy provides thioxanthone derivatives (TXs) via hydrogen atom transfer, C-C formation, and oxidative dehydrogenation with high regioselectivity and reactivity. Significantly, this method can be used to produce commercial photoinitiators and drugs at the gram level.
W. Liao, J. Hou, H. Tang, X. Guo, G. Sheng, M. Jin, Org. Lett., 2023, 25, 6352-6356.


A general and convenient thiazolium-catalyzed cross-coupling of various aldehydes with acylimines derived from sulfonylamides provides ready access to structurally diverse α-amido ketones.
J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski, P. J. Reider, J. Am. Chem. Soc., 2001, 123, 9696-9697.


3-Fluoro-2-iodo-1-methylpyridinium triflate catalyzes a one-pot cascade reaction for 2,3-dihydropyridinone synthesis. The desired [4+2] cycloaddition products, bearing aryl, heteroaryl, alkyl, and alicyclic substituents, were successfully furnished in good yields. A strong halogen-bonding interaction between the iodopyridinium catalyst and imine intermediate was essential.
Y. Li, Y. Ge, R. Sun, X. Yang, S. Huang, H. Dong, Y. Liu, H. Xue, X. Ma, F. Fu, Z. Chen, J. Org. Chem., 2023, 88, 11069-11082.


An unprecedented visible-light-mediated metal-free oxidation of alcohols provides carbonyls with hydrogen evolution. By synergistic combination of organophotocatalyst 4CzIPN and a thiol hydrogen atom transfer catalyst, a broad range of alcohols, including primary and secondary benzylic alcohols as well as aliphatic alcohols, were readily oxidized to carbonyls in good yields.
X. Yang, Y. Guo, H. Tong, H. Guo, R. Liu, R. Zhou, Org. Lett., 2023, 25, 5486-5491.


Enantioselective α-fluorination of both cyclic and acyclic β-dicarbonyl compounds with β,β-diaryl serines as primary amine organocatalysts was conducted with only 1.1 equiv of Selectfluor by adding alkali carbonates, such as Na2CO3 or Li2CO3. The reaction afforded α-fluorinated β-dicarbonyl compounds in good yield with excellent enantioselectivity.
K. Endo, D. Tomon, S. Arimitsu, J. Org. Chem., 2023, 88, 9037-9045.


A catalytic protio-semipinacol ring-expansion reaction for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. In a stepwise mechanism, protonation of the alkene is followed by C-C bond migration.
M. A. S. Blackburn, C. C. Wagen, M. R. Bodrogean, P. M. Tadross, A. J. Bendelsmith, D. A. Kutateladze, E. N. Jacobsen, J. Am. Chem. Soc., 2023, 145, 15036-15042.


An organophosphorus-catalyzed umpolung reaction achieves the deoxygenation of sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven by PIII/PV=O redox cycling. This operationally simple approach uses a stable phosphine oxide as a precatalyst and shows broad functional group tolerance.
G. Sun, J. Li, X. Liu, Y. Liu, X. Wen, H. Sun, Q.-L. Xu, J. Org. Chem., 2023, 88, 8628-8635.


A chiral pyridoxamine catalyzes an asymmetric biomimetic transamination of trifluoromethyl ketones with 2,2-diphenylglycine as the amine source to produce optically active α-trifluoromethyl amines in very good yields with excellent ee's under mild conditions.
W. Cai, D. Cai, H. Liang, X. Ren, B. Zhao, J. Org. Chem., 2023, 88, 7849-7857.


An inexpensive aminoguanidine efficiently catalyzes a reductive cyclization of o-phenylenediamines with CO2 in the presence of triethoxysilane. Various functionalized benzimidazoles, benzoxazole, and benzothiazole were synthesized in high yields. Mechanistic studies indicate that formic acid acts as a cocatalyst.
Y. Sun, K. Gao, J. Org. Chem., 2023, 88, 7463-7468.


A photocatalytic decarboxylative coupling of imine and 2,2-diethoxyacetic acid in the presence of a nonstoichiometric amount of a radical initiator provides α-aminoacetals. This atom-economical C-C coupling tolerates various functional groups. The diversely functionalized α-aminoacetals serve as a promising platform for further research.
S. Kim, B. Park, G. S. Lee, S. H. Hong, J. Org. Chem., 2023, 88, 6532-6537.


A visible-light photoredox-catalyzed decarboxylation of α-oxo carboxylic acids in the presence of D2O enables a metal-free synthesis of C1-deuterated aldehydes in very good yields under mild conditions. The reaction tolerates various functional groups and can also be applied to the synthesis of various aldehydes.
C.-H. Hu, Y. Li, J. Org. Chem., 2023, 88, 6401-6406.


An organic pyrimidopteridine photoredox catalyst mediates hydro- and deuterodecarboxylation of carboxylic acids. Under optimized reaction conditions, the conversion of commercially available nonsteroidal anti-inflammatory drugs (NSAIDs) was realized. In addition, a deuterium incorporation of up to 95% by using D2O as inexpensive deuterium source was achieved.
T. S. Mayer, T. Taeufer, S. Brandt, J. Rabeah, J. Pospech, J. Org. Chem., 2023, 88, 6347-6353.


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.


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