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:
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:
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
A chiral phosphine-catalyzed enantioselective [1 + 4] annulation of
Morita-Baylis-Hillman carbonates with β,γ-unsaturated α-keto esters and
α,β-unsaturated ketones provides a wide range of optically active
2,3-dihydrofurans in high yields with excellent asymmetric induction via a
Michael alkylation process.
Y. Cheng, Y. Han, P. Li, Org. Lett.,
2017, 19, 4774-4777.
A synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis
enables direct aldehyde C-H functionalization. This mild, operationally simple
protocol provides a broad range of ketones in excellent yield from commercially
available aldehydes, along with aryl or alkyl bromides.
X. Zhang, D. W. C. MacMillan, J. Am. Chem. Soc., 2017,
139, 11353-11356.
A readily accessible thiourea organocatalyst catalyzes reductive condensations
of alcohols with aldehydes/ketones to provide ethers without homocoupling of the
carbonyl component in the presence of HCl and 1,1,3,3-tetramethyldisiloxane as a
convenient reducing reagent. This strategy is applicable to challenging
substrate combinations and exhibits functional group tolerance.
C. Zhao, C. A. Sojdak, W. Myint, D. Seidel, J. Am. Chem. Soc., 2017,
139, 10224-10227.
The use of tert-butyl nitrite as the co-catalyst in a 2-azaadamantane-N-oxyl
(AZADO)- and 9-azanoradamantane-N-oxyl (nor-AZADO)-catalyzed efficient
aerobic oxidation of primary alcohols in MeCN instead of the previously reported
AcOH provides the corresponding aldehydes selectively. The addition of saturated
aqueous NaHCO3 after the completion of the reaction suppresses the
overoxidation of the product during the workup.
M. Shibuya, K. Furukawa, Y. Yamamoto,
Synlett, 2017, 28, 1554-1557.
A N-heterocyclic carbene (NHC) catalyzed transformylation of 1°, 2°, and 3°
alcohols in the presence of methyl formate as the formyl transfer reagent
provides a broad range of formates in good yields. The reaction employs low
catalyst loadings, is insensitive to common nitrogen and oxygen protecting
groups and can be achieved in the presence of a number of heterocycles.
J. E. M. Fernando, A. Levens, D. Moock, D. W. Lupton, Synthesis, 2017,
49, 3505-3510.
A N-heterocyclic carbene catalyzed formal [3 + 2] annulation of enals
with 2-aminoacrylates provides various γ-lactam derivatives in good yields with
excellent diastereo- and enantioselectivities. In this process, two consecutive
stereocenters and a quaternary carbon center are constructed.
X.-S. Li, L.-L. Zhao, X.-K. Wang, L.-L. Cao, X.-Q. Shi, R. Zhang, J. Qi, Org.
Lett.,
2017, 19, 3943-3946.
The direct oxidative N-acylation reaction of primary amides with aryl/α,β-unsaturated
aldehydes was achieved in the presence of an azolium salt and an inorganic base
using 3,3′,5,5′-tetra-tert-butyldiphenoquinone as the oxidant. The
reaction provides an efficient approach for the synthesis of N-sulfonylcarboxamides,
N-sulfinylcarboxamides, and dicarboxyimides in good yield.
C. Zheng, Y. Liu, C. Ma, J. Org. Chem.,
2017, 82, 6940-6945.
Peroxy trichloroacetimidic acid, in situ generated from aqueous hydrogen
peroxide and trichloroacetonitrile, acts as a competent electrophilic
oxygenating agent for a direct enantioselective α-hydroxylation of oxindoles in
the presence of a chiral 1,2,3-triazolium salt as a phase-transfer catalyst.
K. Ohmatsu, Y. Ando, T. Ooi,
Synlett, 2017, 28, 1291-1294.
A pyrene-substituted imidazolium-based ionic liquid (PIL) serves as organic
catalyst for the SN2 fluorination using CsF. In this system, the PIL
significantly enhanced the reactivity of the metal fluoride due to the
phase-transfer catalytic effect of the imidazolium moiety as well as the metal
cation-π (pyrene) interactions. Furthermore, PIL can easily be separated from
the reaction mixture using reduced graphene oxide by π-π stacking.
A. Taher, K. C. Lee, H. J. Han, D. W. Kim, Org. Lett.,
2017, 19, 3342-3345.
4-Mesityl-2,6-diphenylpyrylium tetrafluoroborate (MDPT) and 4-mesityl-2,6-di-p-tolylpyrylium
tetrafluoroborate (MD(p-tolyl)PT) are highly robust photoredox catalysts, and
exhibit some of the highest oxidation potentials reported. Their utility was
demonstrated in the mild and efficient generation of carbonyl ylides from
benzylic epoxides.
E. Alfonzo, F. S. Alfonso, A. B. Beeler, Org. Lett.,
2017, 19, 2989-2992.
A water-soluble photocatalyst promotes an aerobic oxidative hydroxylation of
arylboronic acids to furnish phenols in excellent yields. This transformation
uses visible-light irradiation under environmentally friendly conditions.
H.-Y. Xie, L.-S. Han, S. Huang, X. Lei, Y. Cheng, W. Zhao, H. Sun, X. Wen, Q.-L.
Xu, J. Org. Chem.,
2017, 82, 5236-5241.
1,2,2,3,4,4-hexamethylphosphetane catalyzes a deoxygenative N-N bond-forming
Cadogan heterocyclization of o-nitrobenzaldimines and o-nitroazobenzenes
with good functional group compatibility in the presence of phenylsilane as
terminal reductant.
T. V. Nykaza, T. S. Harrison, A. Ghosh, R. A. Putnik, A. T. Radosevich, J. Am. Chem. Soc., 2017,
139, 6839-6842.
A highly enantioselective cascade sulfa-Michael/Julia-Kocienski olefination
reaction between 2-mercaptobenzaldehydes and β-substituted vinyl PT-sulfones
provies a wide range of 3,4-unsubstituted 2H-thiochromenes with excellent
enantioselectivities. This reaction is catalyzed by diphenylprolinol TMS ether
and proceeds through an aromatic iminium intermediate.
A. K. Simlandy, S. Mukherjee, J. Org. Chem.,
2017, 82, 4851-4858.
A metal-free catalytic strategy for the facile synthesis of biologically
relevant indolizines and imidazopyridines scaffolds is promoted by amine and
N-heterocyclic carbene (NHC) relay catalysis via Michael addition-[3 + 2] fusion
of simple azaarenes and α,β-unsaturated aldehydes.
H. Li, X. Li, Y. Yu, J. Li, Y. Liu, H. Li, W. Wang, Org. Lett.,
2017, 19, 2010-2013.
N-Heterocyclic olefins (NHOs) are promising organocatalysts with strong
nucleophilicity and Brřnsted basicity. NHOs are efficient promoters for a direct
dehydrogenative silylation of alcohols or hydrosilylation of carbonyl compounds.
Preliminary results of an asymmetric dehydrogenative silylation are also
discussed.
U. Kaya, U. P. N. Tran, D. Enders, J. Ho, T. V. Nguyen, Org. Lett.,
2017, 19, 1398-1401.
Green Organocatalytic Oxidation of Sulfides to Sulfoxides and Sulfones
E. Voutyritsa, I. Triandafillidi, C. G. Kokotos, Synthesis, 2017,
49, 917-924.
A bifunctional organocatalyst enables a 1,3-addition of silyl-dienol ethers to
nitroalkenes to provide Rauhut-Currier type products with tri- and
tetrasubstituted double bonds. The process takes place under smooth, nonanionic
conditions, and with high enantiomeric excess. A rational mechanistic pathway is
presented based on DFT and mechanistic experiments.
M. Frias, R. Mas-Ballesté, S. Arias, C. Alvarado, J. Alemán, J. Am. Chem. Soc., 2017,
139, 672-679.
A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes enables a green
and efficient synthesis of isoxazolines utilizing H2O2 as
the oxidant. A variety of substitution patterns, both aromatic and aliphatic
moieties, are well tolerated, leading to isoxazolines in good yields.
I. Triandafillidi, C. G. Kokotos, Org. Lett.,
2017, 19, 106-109.
A N-heterocyclic carbene-catalyzed [2 + 4] annulation of α-bromoenals and
α-cyano-β-methylenones enables a direct and efficient approach to
1,3,5-trisubstituted benzenes. The reaction worked well for both aryl- and
alkylenones.
C.-L. Zhang, S. Ye, Org. Lett.,
2016, 18, 6408-6411.
A highly stereoselective one-pot intramolecular Mannich reaction using
2-oxopropyl-2-formylbenzoates and anilines as substrates, catalyzed by a
secondary amine, provides 4-aminoisochromanones bearing two adjacent
stereocentres in good yields with excellent cis-stereoselectivities and
ee values.
F. Vetica, J. Fronert, R. Puttreddy, K. Rissanen, D. Enders, Synthesis, 2016,
48, 4451-4458.
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