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 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 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.

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