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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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 phosphetane-based catalyst operating within P^III/P^V=O redox cycling is able to capture HNO, generated in situ by Nef decomposition of 2-nitropropane, to selectively furnish versatile primary arylamines from arylboronic acid substrates with the preservation of otherwise reactive functional groups.
S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc., 2022, 144, 8902-8907.

An NHC-catalyzed [2 + 4] cyclization of alkynyl ester with α,β-unsaturated ketone provides highly substituted 4H-pyran derivatives in gooy yields. This strategy offers cheap and easily available starting materials, mild reaction conditions, and high atom economy.
F. Lu, Y. Chen, X. Song, C. Yu, T. Li, K. Zhang, C. Yao, J. Org. Chem., 2022, 87, 6902-6909.

A simple, efficient, and environmentally beneficient disulfide-catalyzed photocatalytic regioselective oxidative cleavage of 1-arylbutadienes to cinnamaldehydes offers mild reaction conditions, excellent regioselectivity, and compatibility with a wide range of functional groups.
R. A. Fernandes, P. Kumar, A. Bhowmik, D. A. Gorve, Org. Lett., 2022, 24, 3436-3439.

An organophosphorus-catalyzed C-N bond-forming reductive coupling of nitroalkanes with arylboronic acids and esters shows excellent chemoselectivity for the nitro/boronic acid substrate pair, allowing the synthesis of N-(hetero)arylamines rich in functionalization.
G. Li, Y. Kanda, S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc., 2022, 144, 8242-8248.

A mechanochemical route enables a selective synthesis of 4-nitro-1,2,3-triazoles via organocatalyzed oxidative [3 + 2] cycloaddition between β-nitrostyrenes and organic azides. The reaction features a nontoxic catalyst, catalyst recyclability, no rigorous solvent-extraction, no toxic byproducts, atmospheric oxygen as oxidant, and scalability to gram-scale.
M. Vadivelu, A. A. Raheem, J. P. Raj, J. Elangovan, K. Karthikeyan, C. Praveen, J. Sun, Org. Lett., 2022, 24, 2798-2803.

Dibenziodolium triflate displays high catalytic activity for the Groebke-Blackburn-Bienaymé Reaction that leads to a series of imidazopyridines. This salt can play the role of a hybrid hydrogen- and halogen-bond-donating organocatalyst, which electrophilically activates the carbonyl and imine groups.
M. V. Il'in, A. A. Sysoeva, A. S. Novikov, D. S. Bolotin, J. Org. Chem., 2022, 87, 4569-4579.

Oxetane desymmetrization enables an asymmetric synthesis of chiral pyrrolidines bearing an all-carbon quaternary stereocenter in the 3-position either using a readily available tert-butylsulfinamide chiral auxiliary or a catalytic system with a chiral phosphoric acid as the source of chirality.
R. Zhang, M. Sun, Q. Yan, X. Lin, X. Li, X. Fang, H. H. Y. Sung, J. D. Williams, J. Sun, Org. Lett., 2022, 24, 2359-2364.

Low loadings of a 1,3,5,2,4,6-triazatriphosphorine (TAP)-derived organocatalyst promote a metal-free, biomimetic cyclization of N-(2-hydroxyethyl)amides to the corresponding 2-oxazolines in very good yields. This dehydrative cyclization exhibits a broad substrate scope and high functional-group tolerance can can be conducted on a gram scale.
F. S. Movahed, S. W. Foo, S. Mori, S. Ogawa, S. Saito, J. Org. Chem., 2022, 87, 243-257.

An isothiourea-catalyzed fluorination of alkynyl-substituted acetic acids provides a broad range of optically active tertiary α-alkyl fluorides in high enantioselectivity (up to 97% ee). Furthermore, this methodology can be scaled up to a Gram scale without loss of enantioselectivity.
S. Yuan, W.-H. Zheng, J. Org. Chem., 2022, 87, 713-720.

An organic photoredox-catalyzed gem-difluoroallylation of α-trifluoromethyl alkenes with alkyl iodides provides gem-difluoroalkene derivatives via C-F bond cleavage. This transition-metal-free transformation utilizes a readily available organic dye (4CzIPN) as the sole photocatalyst and N,N,N',N'-tetramethylethylenediamine as the radical activator.
S. Yan, W. Yu, J. Zhang, H. Fan, Z. Lu, Z. Zhang, T. Wang, J. Org. Chem., 2022, 87, 1574-1584.

A β,β-diaryl serine catalyzes an enantioselective fluorination of α-substituted β-diketones to afford the corresponding fluorinated products in very good yields with excellent enantioselectivity. The CO₂H group of the primary amine organocatalyst plays an important role in inducing the high enantioselectivity. Products could be converted into diols, aldols, and allylic fluorides without racemization.
S. Poorsadeghi, K. Endo, S. Arimitsu, Org. Lett., 2022, 24, 420-424.

A metal- and additive-free photoredox cyclization of N-arylacrylamides provides dihydroquinolinones in good yields in the presence of the organic light-emitting molecule 4CzIPN as photocatalyst.
Z. Liu, S. Zhong, X. Ji, G.-J. Deng, H. Huang, Org. Lett., 2022, 24, 349-353.

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.

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