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
Visible-light-excited 9,10-phenanthrenequinone (PQ*) catalyzes a mild and efficient electrocyclization of 2-vinylarylimines for the synthesis of 2,4-disubstituted quinolines in very good yields.
J. Talvitie, I. Alanko, E. Bulatov, J. Koivula, T. Pöllänen, J. Helaja, Org. Lett., 2022, 24, 274-278.
A chiral diarylketone catalyzes a photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones. Mechanistic evidence suggests the reaction to occur by selective hydrogen atom transfer (HAT). The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.
J. Großkopf, M. Plaza, A. Seitz, S. Breitenlechner, G. Storch, T. Bach, J. Am. Chem. Soc., 2021, 143, 21241-21245.
Zwitterionic catalysts promote the formation of halogenated γ-butenolides from cyclopropene carboxylic acids in the presence of N-haloamides as the halogen sources. The catalytic protocol could also be applied to the synthesis of halogenated pyrrolones by using cyclopropene amides as the starting materials.
R.-B. Hu, S. Qiang, Y.-Y. Chan, J. Huang, T. Xu, Y.-Y. Yeung, Org. Lett., 2021, 23, 9533-9537.
A chiral phosphoric acid (CPA) catalyzes a versatile transition metal/oxidant free synthesis of chiral 2H-1,4-benzoxazines through enantioselective desymmetrization of prochiral oxetanes (30 examples) in very good yield and high enantioselectivity under mild reaction conditions.
V. A. Bhosale, M. Nigríni, M. Dračínský, I. Císařová, J. Veselý, Org. Lett., 2021, 23, 9376-9381.
Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) enables a highly enantioselective Prins cyclization of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts withstand the strongly acidic reaction conditions and induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone.
D. A. Kutateladze, E. N. Jacobsen, J. Am. Chem. Soc., 2021, 143, 20077-20083.
An enantioselective intermolecular Prins reaction of styrenes and paraformaldehyde provides 1,3-dioxanes, using confined imino-imidodiphosphate (iIDP) Brønsted acid catalysts via a concerted, highly asynchronous addition of an acid-activated formaldehyde oligomer to the olefin. The enantioenriched 1,3-dioxanes can be transformed into the corresponding optically active 1,3-diols.
C. D. Díaz-Oviedo, R. Maji, B. List, J. Am. Chem. Soc., 2021, 143, 20598-20604.
Dibrominated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is an organic photocatalyst with similar optoelectronic, electrochemical, and performance properties to those of Ru(bpy)3Cl2, commonly used in radical-ionic transformation, such as the formation of 1,4-dicarbonyl compounds. BODIPY also catalyzes syntheses of γ-alkoxylactones, monoprotected 1,4-ketoaldehydes, and dihydrofurans.
W. H. García-Santos, J. Ordóñez-Hernández, M. Farfán-Paredes, H. M. Castro-Cruz, N. A. Macías-Ruvalcaba, N. Farfán, A. Cordero-Vargas, J. Org. Chem., 2021, 86, 16315-16326.
The use of an organic redox catalyst enables an efficient electrocatalytic synthesis of 3-substituted and 2,3-disubstituted indoles through dehydrogenative cyclization of 2-vinylanilides. The reactions do not require any external chemical oxidant.
Y.-T. Zheng, J. Song, H.-C. Xu, J. Org. Chem., 2021, 86, 16001-16007.
A selective electrochemical aminoxyl-mediated Shono-type oxidation of pyrrolidines provides pyrrolidinones with high selectivity and functional group compatibility.
N. R. Deprez, D. J. Clausen, J.-X. Yan, F. Peng, S. Zhang, J. Kong, Y. Bai, Org. Lett., 2021, 23, 8834-8837.
An organocatalyzed oxidative C-N bond formation of phenylpropanamide derivatives provides 3,3-disubstituted oxindole derivatives in very good yields. This highly efficient intramolecular reaction offers transition metal-free mild conditions and the ability to perform the reaction on a gram scale.
Y. Wang, M. Yang, Y.-Y. Sun, Z.-G. Wu, H. Dai, S. Li, Org. Lett., 2021, 23, 8750-8754.
Lewis bases catalyze vicinal dioxygenation of olefins with hypervalent iodine reagents under mild conditions. The reaction tolerates various functional groups.
L. Pan, Z. Ke, Y.-Y. Yeung, Org. Lett., 2021, 23, 8174-8178.
A chlorinative cyclization of aryl alkynoates in the presence of N-chlorosuccinimide (NCS) and Mes-Acr-MeClO4 as photocatalyst provides 3-chlorocoumarins under visible-light irradiation. The radical initiated reaction proceeds via Cl- addition, 5-exo-trig spirocyclization and subsequent 1,2-ester migration.
M. Pramanik, A. Mathuri, S. Sau, M. Das, P. Mal, Org. Lett., 2021, 23, 8088-8092.
A dianionic phase-transfer catalyst enables an asymmetric fluorofunctionalization of γ,γ-disubstituted allylamine derivatives. Depending on the substituents on the alkene moiety, the reaction afforded chiral allylic fluorides and fluorinated dihydrooxazines in a highly enantioselective manner.
T. Niwa, K. Nishibashi, H. Sato, K. Ujiie, K. Yamashita, H. Egami, Y. Hamashima, J. Am. Chem. Soc., 2021, 143, 16599-16609.
Triphenylphosphine oxide catalyzes amidation and esterification for an efficient synthesis of dipeptides, amides, and esters in good yields in less than 10 m without racemization. This reaction is applicable to challenging couplings of hindered carboxylic acids with weak nucleophiles amines or alcohols.
J.-W. Ren, M.-N. Tong, Y.-F. Zhao, F. Ni, Org. Lett., 2021, 23, 7497-7502.
Organophotoredox catalysis enables an intermolecular hydroaminoalkylation (HAA) of styrenes with unprotected primary alkylamines to provide pharmacologically relevant γ-arylamines. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow.
H. E. Askey, J. D. Grayson, J. D. Tibbetts, J. C. Turner-Dore, J. M. Holmes, G. Kociok-Kohn, G. L. Wirgley, A. J. Cresswell, J. Am. Chem. Soc., 2021, 143, 15936-15945.
A small ring phosphacycle (phosphetane) catalyzes the synthesis of unsymmetrical hydrazines by cross-selective intermolecular NN reductive coupling of nitroarenes and anilines in the presence of a hydrosilane as the terminal reductant. The reaction offers good chemoselectivity and functional group tolerance.
G. Li, S. P. Miller, A. T. Radosevich, J. Am. Chem. Soc., 2021, 143, 14464-14469.
A chiral primary amino acid organocatalyst mediates an enantioselective α-allylation and -propargylation of α-branched aldehydes with alkyl halides in a good yield and high enantioselectivity to furnish α-allylated or -propargylated aldehydes with chiral quaternary carbon stereocenters. The reaction proceeded smoothly in a mildly basic aqueous solution of potassium hydrogen carbonate.
M. Yoshida, J. Org. Chem., 2021, 86, 10921-10927.
A photochemical process for the preparation of carboxylic acids from formate salts and alkenes proceeds in high yields across diverse functionalized alkene substrates with excellent regioselectivity. This operationally simple and redox-neutral hydrocarboxylation can be readily scaled in batch at low photocatalyst loading (0.01% photocatalyst).
S. N. Alektiar, Z. K. Wickens, J. Am. Chem. Soc., 2021, 143, 13022-13028.
A visible-light-mediated oxidative cyclization of 2-aminobenzyl alcohols with secondary alcohols provides quinolines in good yields at room temperature. This photocatalytic method employes anthraquinone as an organic small-molecule catalyst and DMSO as an oxidant.
J.-x. Xu, N.-l. Pan, J.-x. Chen, J.-w. Zhao, J. Org. Chem., 2021, 86, 10747-10754.
An efficient visible-light-induced decarboxylative coupling reaction of N-protected α-amino acids with heterocycles provides aminoalkylated heterocycles in good yields. Attractive features of this process include the generation of aminomethyl radical by an inexpensive organic photocatalyst under transition-metal-free conditions.
Y. Li, C. Dai, S. Xie, P. Liu, P. Sun, Org. Lett., 2021, 23, 5906-5910.
Under blue-light irradiation with 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene as photocatalyst, silyl enol ethers reacted with alkenes in the presence of a small amount of water to afford α-alkylated products in very good yields. A thiol cocatalyst was found to expand the substrate scope of the reaction.
T. Hirata, Y. Ogasawara, Y. Yamashita, S. Kobayashi, Org. Lett., 2021, 23, 5693-5697.
The combination of a riboflavin-derived organocatalyst and molecular iodine successfully promoted the aerobic oxidation of thiols to disulfides under metal-free mild conditions at room temperature. The the biomimetic flavin catalyst enables the transfer of electrons from the iodine forming the basis for a green oxidative synthesis of disulfides from thiols.
M. Oka, R. Kozako, H. Iida, Synlett, 2021, 32, 1227-1230.
Please cite and link this page as follows:
Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )