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
The use of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as catalyst
enables a Machetti-De Sarlo reaction of nitroalkenes with alkynes/alkenes under
sustainable conditions to afford a library of isoxazole/isoxaline products.
M. Vadivelu, S. Sampath, K. Muthu, K. Karthikeyan, C. Praveen, J. Org. Chem., 2019, 84,
13636-13645.
A streamlined and general enantioselective Mannich reaction of enamides with
C-alkynyl N-Boc N,O-acetals, which serve as readily available
C-alkynyl imine precursors, provides a range of chiral β-keto N-Boc-propargylamines
in high yields and in high enantioselectivities.
F.-F. Feng, S. Li, C. W. Cheung, J.-A. Ma,
Org. Lett., 2019, 21, 8419-8423.
Tri(9-anthryl)borane catalyzes a visible-light-induced trifluoromethylation
of unactivated alkenes with CF3I. The mild reaction conditions
tolerate various functional groups, and the reaction could be extended to
perfluoroalkylations with C3F7I and C4F9I.
J. Moon, Y. K. Moon, D. D. Park, S. Choi, Y. You, E. J. Cho, J. Org. Chem., 2019, 84,
12925-12932.
A N-heterocyclic carbene-catalyzed radical relay enables the vicinal
alkylacylation of styrenes, acrylates and acrylonitrile with complete
regioselectivity using aldehydes and tertiary alkyl carboxylic acid-derived
redox-active esters to produce functionalized ketone derivatives.
T. Ishii, K. Ota, K. Nagao, H. Ohmiya, J. Am. Chem. Soc.,
2019, 141, 14073-14077.
A visible-light-promoted regioselective coupling of aryl-2H-azirines
and (diacetoxy)iodobenzene provides C(sp3)-H acyloxylated azirines in
the presence of Rose Bengal as an organophotoredox catalyst. The reaction
proceeds under aerobic condition at room temperature via a radical pathway.
A. De, S. Santra, A. Hajra, G. V. Zyrayanov, A. Majee, J. Org. Chem., 2019,
84, 11735-11740.
A chiral bisphosphine dioxide catalyzes an asymmetric conjugate reduction of
acyclic β,β-disubstituted α,β-unsaturated ketones with trichlorosilane to
provide saturated ketones with high enantioselectivities. Due to concomitant
E/Z-isomerizations of enone substrates, reduction products with the
same absolute configurations are obtained from either (E)- or (Z)-enones.
M. Sugiura, Y. Ashikari, Y. Takahashi, K. Yamaguchi, S. Kotani, M. Nakajima, J. Org. Chem., 2019,
84, 11458-11473.
Morpholine efficiently catalyzes Galat reactions between aldehydes and
substituted malonic acids half oxyester in refluxing toluene to provide diverse
α,β-disubstituted acrylates in to good yields. This method constitutes an
attractive alternative to existing methods in terms of scope and
eco-compatibility.
T. Xavier, S. Condon, C. Pichon, E. Le Gall, M. Presset,
Org. Lett., 2019, 21, 6135-6139.
A multifunctional modular organocatalysis enables a simple and efficient
approach to enantioenriched α,β-disubstituted γ-butyrolactones via a one-pot
sequential Michael-hemiacetalization-oxidation reaction. The catalytic process
offers good substrate compatibility, and the products can be transformed to
synthetically useful molecules.
P. Mahto, N. K. Rana, K. Shukla, B. G. Das, H. Joshi, V. K. Singh,
Org. Lett., 2019, 21, 5962-5966.
A broadly applicable method for amide C-N and ester C-O bond formation is
based on formylpyrrolidine (FPyr) as a Lewis base catalyst and trichlorotriazine
(TCT) as a cost-efficient reagent for OH-group activation. The new approach is
distinguished by excellent cost-efficiency, waste-balance, scalability, and high
levels of functional group compatibility.
P. H. Huy, C. Mbouhom, J. Org. Chem., 2019, 84,
7399-7406.
The organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides
as radical precursors enable an intramolecular arene alkylation reaction. This
reaction provides a diverse set of fused, partially saturated cores which are of
high interest in synthetic and medicinal chemistry.
T. C. Sherwood, H.-Y. Xiao, R. G. Bhaskar, E. M. Simmons, S. Zaretsky, M. P.
Rauch, R. R. Knowles, T. G. M. Dhar, J. Org. Chem., 2019, 84,
8360-8379.
Phthaloyl chloride as reagent and N-formylpyrrolidine as Lewis base
catalyst enable a transformation of aldehydes into geminal dichlorides. This
simple reaction offers mild reaction conditions, high levels of functional group
compatibility, and scalability.
P. H. Huy, Synthesis, 2019, 51,
2474-2483.
In a catalytic system for the chlorination of alcohols under Appel conditions,
benzotrichloride is used as a cheap and readily available chlorinating agent in
combination with trioctylphosphane as the catalyst and phenylsilane as the
terminal reductant under solvent-free conditions. In total, 27 different primary,
secondary, and tertiary alkyl chlorides were synthesized in good yields.
L. Longwitz, S. Jopp, T. Werner, J. Org. Chem., 2019, 84,
7863-7870.
The combination of Brønsted acid catalysis with visible-light induction
enables a highly enantioselective synthesis of 2-substituted
tetrahydroquinolines from 2-aminoenones
through a relay visible-light-induced cyclization/chiral phosphoric
acid-catalyzed transfer hydrogenation reaction.
W. Xiong, S. Li, B. Fu, J. Wang, Q.-A. Wang, W. Yang,
Org. Lett., 2019, 21, 4173-4176.
In a triphenylphosphine oxide-catalyzed reduction of conjugated
polyunsaturated ketones using trichlorosilane as reducing reagent, the α,β-C=C
double bond was selectively reduced while all other reducible functional groups
remained unchanged. Additionally, a tandem one-pot Wittig/conjugate-reduction
reaction sequence provides γ,δ-unsaturated ketones from simple building blocks.
X. Xia, Z. Lao, P. H. Toy, Synlett, 2019,
30, 1100-1104.
In a disulfide-catalyzed electrophilic iodination of electron-rich aromatic
compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH), the disulfide activates
DIH as a Lewis base to promote the iodination reaction in acetonitrile under
mild conditions. This system is applicable to a wide range of substrates,
including anisoles, acetanilides, imidazoles, and pyrazoles.
K. Iida, S. Ishida, T. Watanabe, T. Arai, J. Org. Chem., 2019, 84,
7411-7417.
A diboron/methoxide/pyridine reaction system enables a photoactivation of an
in situ generated super electron donor for an efficient, transition-metal-free
borylation of unactivated aryl chlorides.
L. Zhang, L. Jiao, J. Am. Chem. Soc.,
2019,
141, 9124-9128.
An efficient catalytic Staudinger reduction at room temperature provides
structurally diverse amines from azides in excellent yields in the presence of
catalytic amounts of triphenylphosphine and diphenyldisiloxane as terminal
reducing agent. The reaction exhibits high chemoselectivity and tolerates
nitriles, alkenes, alkynes, esters, and ketones.
D. C. Lenstra, J. J. Wolf, J. Mecinović, J. Org. Chem., 2019, 84,
6536-6545.
The use of N-oxides in butanol as solvent enables a site-selective
oxidation of vicinal bis(boronates) with good efficiency and selectivity across
a range of substrates to provide 2-hydro-1-boronic esters, which are shown to be
versatile intermediates in the synthesis of chiral building blocks.
L. Yan, J. P. Morken,
Org. Lett., 2019, 21, 3760-3763.
The Doebner-Knoevenagel condensation enables a selective synthesis of
acrylamides under mild conditions at ambient temperatures. The scalable reaction
tolerates a wide range of functional groups, and affords the E-isomer
with high selectivity. An organocatalytic mechanism has been proposed.
M. J. Zacuto, J. Org. Chem., 2019, 84,
6465-6474.
Phosphazene P4-tBu effectively catalyzes a nucleophilic substitution
reaction of gem-difluoroalkenes with ketene silyl acetals under mild
conditions to provide monofluoroalkenes possessing an alkoxycarbonylmethyl group
in high yields with high Z selectivities.
A. Kondoh, K. Koda, M. Terada,
Org. Lett., 2019, 21, 2277-2280.
Please cite and link this page as follows:
Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )
