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
An N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction enables a transition-metal-free and mild cross-dehydrogenative coupling of 2-cinnamoyl benzaldehydes to provide 2-aryl naphthoquinones. The intramolecular Stetter reaction is followed by an aerobic oxidation to reinstall the C-C double bond.
A. Ghosh, A. Patra, S. Mukherjee, A. T. Biju, J. Org. Chem., 2019, 84, 1103-1110.
A mild, late-stage conversion of primary sulfonamides to several other other functional groups occurs via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed N-sulfonylimines. This method tolerates common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds.
P. S. Fier, K. M. Maloney, J. Am. Chem. Soc., 2019, 141, 1441-1445.
C2-symmetric chiral-substituted 1,16-dihedroxytetraphenylenes (DHTP) were used as organocatalysts in asymmetric allylboration of ketones under very mild conditions. Several tertiary alcohols were isolated in good yields with high ees.
G.-L. Chai, B. Zhu, J. Chang, J. Org. Chem., 2019, 84, 120-127.
A N-heterocycle carbene (NHC)-catalyzed dual Stetter cascade reaction enables a coupling of β-nitrostyrene with phthalaldehyde under mild conditions to furnish valuable aryl-naphthoquinones, whereas the reaction of salicylaldehydes with β-nitrostyrene provides functionalized dihydroisoflavanones.
R. N. Mitra, K. Show, D. Barman, S. Sarkar, D. K. Maiti, J. Org. Chem., 2019, 84, 42-52.
A N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and aromatic aldehydes provides 2-arylbenzoxazoles in good yields under mild conditions. The reaction tolerates a broad range of functional groups.
A. Patra, A. James, T. K. Das, A. T. Biju, J. Org. Chem., 2018, 83, 14820-14826.
An N-heterocyclic carbene (NHC) organocatalytic aerobic oxidation of aldehydes provides the corresponding carboxylic acids under mild reaction conditions. Remarkably, this method enables an efficient conversion of different classes of aldehydes including highly challenging electron-rich aryl aldehydes, ortho-substituted aryl aldehydes, various heteroaromatic aldehydes and α,β-unsaturated aldehydes.
A. K. Khatana, V. Singh, M. K. Gupta, B. Tiwari, Synthesis, 2018, 50, 4290-4294.
A chiral phosphoric acid as the sole catalyst enables an enantioselective synthesis of tetrahydroquinolines from 2-aminochalcones via chiral phosphoric acid-catalyzed dehydrative cyclization, followed by chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester. Various 2-aminochalcones could be applicable to this protocol, and the desired tetrahydroquinolines were obtained in excellent yields and with excellent enantioselectivities.
D. Y. Park, S. Y. Lee, J. Jeon, C.-H. Cheon, J. Org. Chem., 2018, 83, 12486-12495.
Chiral task-specific ionic liquids bearing chiral anions as the catalysts enable an enantioselective multicomponent Biginelli reaction. A combined role of asymmetric counteranion-directed catalysis (ACDC) and ionic liquid effect (ILE) for the chiral induction in the Biginelli multicomponent reaction is demonstrated.
H. G. O. Alvim D. L. J. Pinheiro, V. H. Carvalho-Silva, M. Fioramonte, F. C. Gozzo, W. A. da Silva, G. W. Amarante, B. A. D. Neto, J. Org. Chem., 2018, 83, 12143-12153.
A reaction of diphenyl carbonate and various diols provides highly valuable cyclic carbonates in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as organocatalyst. This practical, safe, and highly efficient carbonylation system successfully replaced highly toxic and unstable phosgene or its derivatives while maintaining the desired high reactivity. Moreover, this new system can be used to synthesize sterically demanding cyclic carbonates.
E. R. Baral, J. H. Lee, J. G. Kim, J. Org. Chem., 2018, 83, 11768-11776.
The use of a cation-binding oligoEG catalyst and KF as the base enables a highly enantioselective cycloetherification for the straightforward synthesis of enantioenriched tetrahydrofurans, tetrahydropyrans, and oxepanes from ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones.
A. P. Jadhav, J.-A Oh, I.-S. Hwang, H. Yan, C. E. Song, Org. Lett., 2018, 20, 5319-5322.
A series of charge-containing thiourea salts catalyze cycloadditions of epoxides with CO2 under mild conditions to provide cyclic five-membered ring organic carbonates of broad interest from a synthetic, environmental, and green chemistry perspective.
Y. Fang, M. Tiffner, J. Schörgenhumer, R. Robiette, M. Waser, S. R. Kass, J. Org. Chem., 2018, 83, 9991-10000.
(Bis(dimethylamino)carbazole) was used as photocatalyst in the reduction of unactivated aryl chlorides and alkyl chlorides in the presence of CHD as hydrogen atom donor at room temperature. The catalytic system can also be applied to the coupling of aryl chlorides with electron-rich arene and heteroarenes to affect C-C bond-forming reactions.
R. Matsubara, T. Yabuta, U. M. Idros, M. Hayashi, F. Ema, Y. Kobori, K. Sakata, J. Org. Chem., 2018, 83, 9381-9390.
An anthraquinone-catalyzed photooxidative keto-trifluoromethylation of styrenes with the readily available Langlois reagent (CF3SO2Na) under an oxygen atmosphere proceeds smoothly to give α-trifluoromethyl ketones in good yield with good selectivity.
E. Yamaguchi, Y. Kamito, K. Matsuo, J. Ishihara, A. Itoh, Synthesis, 2018, 50, 3161-3168.
A mild and metal-free multi-component reaction enables the synthesis of 4,5-disubstituted 1H-1,2,3-triazoles from phosphonium salts, aldehydes, and sodium azide. An organocatalyzed coupling of the formyl group with the phosphonium group provides an olefinic phosphonium salt as key intermediate, that undergoes [3+2] cycloaddition with the azide.
G.-L. Wu, Q.-P. Wu, Synthesis, 2018, 50, 2768-2774.
A N-heterocyclic carbene (NHC)-catalyzed trifluoromethylation of α-chloro aldehydes provides valuable α-trifluoromethyl ester derivatives in good yields. The unique combination of an electrophilic trifluoromethylation reagent with NHC catalysis was the key for the functionalization of a broad range of substrate. An enantioselective version of this reaction afforded products in moderate yields with good ee values.
F. Gelat, A. Patra, X. Pannecoucke, A. T. Biju, T. Poisson, T. Besset, Org. Lett., 2018, 20, 3897-3901.
A three-component reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2 as sulfur dioxide surrogate, and alkenes under photocatalysis provides diverse sulfones in very good yields at room temperature. This reaction works efficiently under mild conditions via generation of alkyl and alkylsulfonyl radicals as key intermediates, and a reductive single-electron transfer.
T. Liu, Y. Li, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett., 2018, 20, 3605-3608.
A practical nucleophilic substitution of alcohols furnishes alkyl chlorides, bromides, and iodides under stereochemical inversion in the presence of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent. Moreover, acetyl chloride has been used as a stoichiometric promotor in an invertive SN-type transformation for the first time.
T. Stach, J. Dräger, P. H. Huy, Org. Lett., 2018, 20, 2980-2983.
An enantioselective decarboxylative alkylation of β-keto acids, followed by sequential cyclization and dehydration, enables an efficient asymmetric synthesis of useful 2,4-diaryl-1-benzopyrans in good yields and high enantioselectivities . This one-pot, two-step sequence offers a facile way to prepare chiral 2,4-diaryl-1-benzopyran derivatives and tolerates a wide range of functional groups.
H. J. Jeong, D. Y. Kim, Org. Lett., 2018, 20, 2944-2947.
Scope and Mechanism of a True Organocatalytic Beckmann Rearrangement with a Boronic Acid/Perfluoropinacol System under Ambient Conditions
X. Mo, T. D. R. Morgan, H. T. Ang, D. G. Hall, J. Am. Chem. Soc., 2018, 140, 5264-5271.
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