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
Chiral triazolium salts based on the camphor scaffold are highly efficient
catalysts for the asymmetric intramolecular Stetter reaction. With a catalyst
loading of 10 mol%, the desired products were obtained in excellent yields with
up to 97% ee.
Z.-Q. Rong, Y. Li, G.-Q. Yang, S.-L. You, Synlett, 2011,
1033-1037.
An asymmetric direct Michael addition of α,β-unsaturated aldehydes with
acetophenone catalyzed by a Jørgensen-Hayashi catalyst in methanol gave δ-keto
aldehydes in up to 82% yield and 98% ee.
W. Li, W. Wu, J. Yang, X. Liang, J. Ye, Synthesis, 2011,
1085-1091.
Rasta resin-PPh3BnCl, a heterogeneous polystyrene-based phosphonium
salt, catalyzes cyanosilylation reactions of aldehydes and ketones efficiently.
In these reactions, rasta resin-PPh3BnCl was separated from the
desired reaction product simply by filtration, and it could be reused without
significant loss of catalytic activity numerous times.
Y. Teng, P. H. Toy, Synlett, 2011,
551-554.
Iodobenzene can be used as a recyclable catalyst in combination with m-chloroperbenzoic
acid as the terminal oxidant for an efficient and regioselective monobromination
of electron-rich aromatic compounds. The bromination of electron-rich aromatic
compounds with lithium bromide was fast in tetrahydrofuran at room temperature,
providing regioselective monobrominated products in good yields.
Z. Zhou, X. He, Synthesis, 2011,
207-209.
A combined amino- and N-heterocyclic carbene (NHC)-catalyzed one-pot
reaction sequence using commercially available catalysts at low catalyst
loadings gives β-hydroxy and β-amino esters in high yield and excellent
enantiopurity. The generation of quaternary stereocenters and application in
gram-scale synthesis were also realized, with no requirements of inert or
anhydrous reaction conditions.
H. Jiang, B. Gschwend, Ł. Albrecht, K. A. Jørgensen, Org. Lett., 2010,
12, 5052-5055.
A highly enantioselective Michael addition of malonates to α,β-unsaturated
ketones in water is catalyzed by a primary-secondary diamine catalyst containing
a long alkyl chain. This asymmetric Michael addition process allows the
conversion of various α,β-unsaturated ketones.
Z. Mao, Y. Jia, W. Li, R. Wang, J. Org. Chem., 2010,
75, 7428-7430.
A Brønsted acid catalyzed transfer hydrogenation of indole derivatives with
Hantzsch dihydropyridine as the hydrogen source enables an efficient synthesis
of various optically active indolines with high enantioselectivities.
M. Rueping, C. Brinkmann, A. P. Antonchick, I. Atoresei, Org. Lett., 2010,
12, 4604-4607.
An organocatalytic, direct synthesis of α-hydroxy phosphonates via reaction of
aldehydes and ketones with trimethylphosphite in the presence of catalytic
amounts of pyridine 2,6-dicarboxylic acid in water is simple, cost-effective and
environmentally benign.
F. Jahani, B. Zamenian, S. Khaksar, M. Taibakhsh, Synthesis, 2010,
3315-3318.
Chiral diaminodioxaphosphonium salts can be used in catalytic amounts in a
highly enantioselective protonation of α-amino acid-derived ketene disilyl
acetals in the presence of 2,6-dimethylphenol as stoichiometric proton source.
D. Uraguchi, N. Kinoshita, T. Ooi, J. Am. Chem. Soc., 2010,
132, 12240-12242.
An Organocatalytic Asymmetric Nazarov Cyclization
A. K. Basak, N. Shimada, W. F. Bow, D. A. Vicic, M. A. Tius, J. Am. Chem. Soc., 2010,
132, 8266-8267.
An efficient one-pot procedure allows the synthesis of various functionalized
2-aminothiophene scaffolds catalyzed by L-proline in high yields under mild
conditions. Low catalyst loading, simple procedure, and high yields are the
important attributes of this methodology.
T. Wang, X.-G. Huang, J. Liu, B. Li, J.-J. Wu, K.-X. Chen, W.-L. Zhu, X.-Y. Xu,
B.-B. Zeng, Synlett, 2010,
1351-1354.
In a Michael addition of nitromethane to α,β-unsaturated aldehydes via iminium
activation, a MeOPEG-supported, recyclable Jørgensen-Hayashi catalyst provides
unchanged reactivity and selectivity as compared to the homogeneous catalyst.
The immobilization enables a simple, column-free isolation of pure, sensitive
aldehyde products and therefore may be useful for application in more
complicated syntheses.
I. Mager, K. Zeitler, Org. Lett., 2010,
12, 1480-1483.
The use of a chiral Brønsted acid catalyst for the activation of
trichloroacetimidate glycosyl donors influences the stereochemical outcome of
glycosylation processes in toluene, hinting that perhaps diastereocontrol may
become achievable through the judicious use of chiral organic catalysts.
D. J. Cox, M. D. Smith, A. J. Fairbanks, Org. Lett., 2010,
12, 1452-1455.
Asymmetric hydration of α,α-dichloro aldehydes and α-halo enals via a
NHC-catalyzed redox process gives enantioenriched α-chloro and α-fluoro
carboxylic acids. The reaction allows the installation of an α-deuterium to give
α-deutero α-halo acids using D2O as the deuteron source.
H. U. Vora, T. Rovis, J. Am. Chem. Soc., 2010,
132, 2860-2861.
A cinchona alkaloid-derived urea is an efficient organocatalyst for catalyzing
enantioselective conjugate addition between thiols and various α,β-unsaturated
ketones to provide optically active sulfides with high chemical yields and
enantiomeric excess. The reaction was performed with 0.1 mol % of catalyst in
toluene at room temperature.
N. K. Rana, S. Selvakumar, V. K. Singh, J. Org. Chem., 2010,
75, 2089-2091.
Use of water as reaction medium for O-TMS-diarylprolinol-catalyzed
cyclopropanation reactions of α,β-unsaturated aldehydes with diethyl
bromomalonate enables a base-free reaction system. A modified O-TMS-diarylprolinol
incorporating a hydrophobic alkyl side chain has been identified as a promising
catalyst for this reaction.
U. Uria, J. L. Vicario, D. Badía, L. Carrillo, E. Reyes, A. Pesquera, Synthesis, 2010,
701-713.
A fluorous (S)-pyrrolidine-thiourea bifunctional organocatalyst shows
good activity and enantioselectivity for direct α-chlorination of aldehydes
using N-chlorosuccinimide (NCS) as the chlorine source. The catalyst can
be recovered from the reaction mixture by fluorous solid-phase extraction with
excellent purity for direct reuse.
L. Wang, C. Cai, D. P. Curran, W. Zhang, Synlett, 2010, 433-436.
A N-heterocyclic carbene catalyzes the oxidative esterification of various
aldehydes in the presence of 3,3',5'5-tetra-tert-butyldiphenoquinone to
yield hexafluoroisopropylesters, which are useful active esters for in situ
amide bond formation. This transition metal-free organocatalytic system also
enabled a mild oxidative azidation of aldehydes.
S. De Sarkar, A. Studer, Org. Lett., 2010,
12, 1992-1995.
Cooperative carbene catalysis allows selective oxidative acylations of alcohols
with aldehydes even in the presence of amino groups by using a readily available
cheap organic oxidant. Quantum chemical calculations support the suggested
mechanism.
S. De Sarkar, S. Grimme, A. Studer, J. Am. Chem. Soc., 2010,
132, 1190-1191.
Various acetals or alcohols react with allyl(trimethyl)silane or
1-phenyl-2-(trimethylsilyl)acetylene in the presence of a catalytic amount of
the Brønsted acid o-benzenedisulfonimide under mild conditions to give
good yields of the allylated products. The catalyst can be easily recovered and
purified for use in further reactions.
M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera, C. Piccinini, Synthesis, 2010,
315-319.
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Organocatalysis ( URL: http://www.organic-chemistry.org/topics/organocatalysis.shtm )
