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
A class of axially chiral pyridoxamines bearing a lateral amine arm exhibited high catalytic activity and excellent enantioselectivity in asymmetric transamination of α-keto acids, to give various α-amino acids in very good yields and with high ee's. The lateral amine arm likely participates in cooperative catalysis as the Lys residue does in biological transamination and enhances both the activity and the enantioselectivity.
Y. E. Liu, Z. Lu, B. Li, J. Tian, F. Liu, J. Zhao, C. Hou, Y. Li, L. Niu, B. Zhao, J. Am. Chem. Soc., 2016, 138, 10730-10733.
Catalytic amounts of phosphine and triethylamine enable an efficient protocol for the synthesis of highly functionalized furans via intramolecular Wittig reaction. Silyl chloride as the initial promoter activates the phosphine oxide for reduction, while decomposition of Et3N·HCl resulted in regeneration of base, which mediated formation of phosphorus ylide.
C.-J. Lee, T.-H. Chang, J. K. Yu, G. M. Reddy, M.-Y. Hsiao, W. Lin, Org. Lett., 2016, 18, 3758-3761.
Helical peptide foldamers catalyze Michael addition reactions of nitroalkanes or dialkyl malonates to α,β-unsaturated ketones to give Michael adducts with high enantioselectivities. The amide protons at the N terminus in the α-helical peptide catalyst are crucial for activating Michael donors, while the N-terminal primary amine activates Michael acceptors through the formation of iminium ion intermediates.
A. Ueda, T. Umeno, M. Doi, K. Akagawa, K. Kudo, M. Tanaka, J. Org. Chem., 2016, 81, 6343-6356.
Amidine-based catalysts, particularly homobenzotetramisole and its analogues, achieve high enantioselectivities and yields in a reagent-free catalytic transformation of α,β-unsaturated thioesters into 2-substituted thiochromenes with carbon dioxide as the only byproduct.
N. A. Ahlemeyer, V. B. Birman, Org. Lett., 2016, 18, 3454-3457.
In systematic investigations to develop an efficient enantioselective synthetic method for α-alkyl-alanine by catalytic phase-transfer alkylation, the alkylation of 2-naphthyl aldimine tert-butyl ester in the presence of RbOH and O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide as catalyst at -35°C showed the highest enantioselectivities.
S.-s. Jew, B.-S. Jeong, J.-H. Lee, M.-S. Yoo, Y.-J. Lee, B.-s. Park, M. G. Kim, H.-g. Park, J. Org. Chem., 2003, 68, 4514-4516.
A carbene-catalyzed reaction enables a dynamic kinetic resolution of α,α-disubstituted carboxylic esters with up to 99:1 er and 99% yield.
X. Chen, J. Z. M. Fong, J. Xu, C. Mou, Y. Lu, S. Yang, B.-A. Song, Y. R. Chi, J. Am. Chem. Soc., 2016, 138, 7212-7215.
DABCO is a suitable catalyst for the isomerization of γ-hydroxy enones in an organocatalytic redox isomerization strategy for the synthesis of 1,4-ketoaldehydes in high yields.
K. Mondal, B. Mondal, S. C. Pan, J. Org. Chem., 2016, 81, 4835-4840.
Catalytic amounts of alkylidene derivatives of N-heterocyclic carbenes promote transesterification reactions. Because of their strong Brønsted/Lewis basicity, these organocatalysts can enhance the nucleophilicity of alcohols for acylation reactions with carboxylic esters.
M. Blümel, J.-M. Noy, D. Enders, M. H. Stenzel, T. V. Nguyen, Org. Lett., 2016, 18, 2208-2211.
A catalytic, vicinal difluorination of olefins displays broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are reported.
I. G. Molnár, R. Gilmour, J. Am. Chem. Soc., 2016, 138, 5004-5007.
Upon exposure of enamides to aldehydes in the presence of a chiral NHC catalyst, C-C bond formation provides N-protected amines, bearing a quaternary carbon center, in good yields and with high enantioselectivities.
J. Wu, C. Zhao, J. Wang, J. Am. Chem. Soc., 2016, 138, 4706-4709.
With a suitable combination of N-heterocyclic carbene precatalyst, base, and fluorine reagent, a fluorination of alkynals proceeded smoothly to yield a wide range of α-fluoroallenoates with excellent chemoselectivity. α-Fluorinated allenoates are versatile synthetic intermediates toward other useful fluorine-containing building blocks.
X. Wang, Z. Wu, J. Wang, Org. Lett., 2016, 18, 576-579.
Catalytic enantioselective diboration of alkenes is accomplished with readily available carbohydrate-derived catalysts via the intermediacy of 1,2-bonded diboronates.
L. Fang, L. Yan, F. Haeffner, J. P. Morken, J. Am. Chem. Soc., 2016, 138, 2508-2511.
A highly para-selective halogenation of arenes bearing electron-donating coordinating groups in the presence of a dimidazolium salt rpovides p-haloarenes in good yields. A plausible mechanism for the catalytic reaction is proposed.
J. Chen, X. Xiong, Z. Chen, J. Huang, Synlett, 2015, 26, 2831-2834.
The reactivity of iodoarene amide catalysts in the α-oxytosylation of propiophenone is influenced by steric and electronic properties. A very reactive meta-substituted benzamide catalyst was employed in the α-oxytosylation of a series of substituted propiophenones to provide α-tosyloxy ketones in excellent isolated yield.
T. R. Lex, M. I. Swasy, D. C. Whitehead, J. Org. Chem., 2015, 80, 12234-12243.
An easily prepared recyclable TEMPO derived sulfonic salt catalyst, and mineral acids (NaNO2 and HCl) enable a selective aerobic oxidation of structurally diverse benzylic sp3 C-H bonds of ethers and alkylarenes to provide synthetically and biologically valued isochromanones and xanthones in good yields.
Z. Zhang, Y. Gao, Y. Liu, J. Li, H. Xie, H. Li, W. Wang, Org. Lett., 2015, 17, 5492-5495.
An N-heterocyclic carbene catalyzes a highly enantioselective [3 + 3] annulation reaction of N-hydroxyphthalimide (NHPI) 3,3-disubstituted acrylates and N-Ts ketimines, providing the desired chiral dihydropyridinone products bearing an all carbon quaternary stereogenic center in good yields with excellent enantioselectivities. The reaction demonstrates that NHPI acrylates are excellent substrates in NHC-catalysis.
Z. Zhang, X. Zeng, D. Xie, D. Chen, L. Ding, A. Wang, L. Yang, G. Zhong, Org. Lett., 2015, 17, 5052-5055.
Using a confined imidodiphosphate catalyst, a highly enantioselective intramolecular carbonyl-ene reaction of olefinic aldehydes delivers diverse trans-3,4-disubstituted carbo- and heterocyclic five-membered rings in high yields and with good to excellent diastereo- and enantioselectivities.
L. Liu, M. Leutzsch, Y. Zheng, M. W. Alachraf, W. Thiel, B. List, J. Am. Chem. Soc., 2015, 137, 13268-13271.
Coupling of benzaldehydes and benzyl chloride derivatives under basic conditions with an organocatalyst gives good yields of alkynes. The catalyst, a highly reactive sulfenate anion, is readily generated in situ from air-stable precursors. This method represents an attractive organocatalytic alternative to well-established stoichiometric approaches to alkynes and to transition-metal-based alkyne functionalization methods.
M. Zhang, T. Jia, C. Y. Wang, P. J. Walsh, J. Am. Chem. Soc., 2015, 137, 10346-10350.
Brønsted acid catalysis enables highly efficient, regioselective, and enantioselective transfer hydrogenation of α-keto ketimines and reductive amination of diketones. A series of chiral α-amino ketones is prepared in high yields, excellent regioselectivities, and enantioselectivities.
W. Wen, Y. Zeng, L.-Y. Peng, L.-N. Fu, Q.-X. Guo, Org. Lett., 2015, 17, 3922-3925.
A chiral primary amine-thiourea catalyst based on dehydroabietic amine enables a highly enantioselective Michael addition of nitroalkanes to α,β-unsaturated ketones to yield γ-nitro ketones with excellent enantioselectivities (up to 99% ee) and in up to 96% yield. This protocol was successfully applied in asymmetric syntheses of (R)-baclofen and (R)-phenibut.
X.-T. Guo, J. Shen, F. Sha, X.-Y. Wu, Synthesis, 2015, 47, 2063-2072.
Please cite and link this page as follows:
Organocatalysis ( URL: http://www.organic-chemistry.org/topics/organocatalysis.shtm )