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 visible light mediated sulfurization of alkenes and
alkynes with aromatic and heteroaromatic thiols enables a benign and metal-free
functionalization using Eosin Y as photocatalyst and eco-friendly air (O2)
as the sole oxidant. This selective approach shows good substrate generality to
afford sulfoxides, β-hydroxysulfoxides, and β-keto sulfides in high yield.
R. Rahaman, M. T. Hoque, D. K. Maiti, Org. Lett.,
2022, 24, 6885-6890.
The combination of flavin and iodine catalyzes a facile and atom-economical
oxidative cross-dehydrogenative coupling between amidines and chalcones to
provide tetra-substituted imidazoles in good yields. The riboflavin-iodine
catalytic system played multiple roles in substrate- and O2-activation
generating benign H2O as the only byproduct.
A. Takeda, H. Okai, K. Watabe, H. Iida, J. Org. Chem., 2022, 87,
10372-10376.
The regioselectivity of the intramolecular cyclization of bifunctional
α-phenyl alkenes can be controlled simply by the choice of the organic
chromophore as the photocatalyst. Whereas N,N-(4-diisobutylaminophenyl)phenothiazine
catalyzes exo-trig cyclizations,
1,7-dicyanoperylene-3,4,9,10-tetracarboxylic acid bisimides catalyze endo-trig
additions.
. Weick, D. Steuernagel, A. Belov, H.-A. Wagenknecht, Synlett, 2022,
33,
1199-1203.
Host-guest assemblies of a designed 1,4-bis(diarylamino)naphthalene and
V-shaped aromatic amphiphiles are highly reducing photoredox catalysis systems
for an efficient demethoxylative hydrogen transfer of Weinreb amides in water.
Y. Hyodo, K. Takahashi, Y. Chitose, M. Abe, M. Yoshizawa, T. Koike, M. Akita, Synlett, 2022,
33,
1184-1188.
The use of an ortho-naphthoquinone catalyst enables a biomimetic
alcohol dehydrogenase (ADH)-like oxidation protocol as green alternative to
existing stoichiometric and metal-catalyzed alcohol oxidation reactions. The
developed organocatalytic aerobic oxidation protocol proceeds through an
intramolecular 1,5-hydrogen atom transfer of naphthalene alkoxide intermediates.
J. Baek, T. Si, H. Y. Kim, K. Oh, Org. Lett.,
2022, 24, 4982-4986.
Mandelic acid catalyzes a highly regioselective aromatic bromination with
N-bromosuccinimide (NBS) under aqueous conditions at room temperature.
Computational results demonstrate that Lewis basic additives interact with NBS
to increase the electropositive character of bromine prior to electrophilic
transfer.
S. I. Baker, M. Yaghoubi, S. L. Bidwell, S. L. Pierce, H. P. Hratchian, R. D.
Baxter, J. Org. Chem., 2022, 87,
8492-8502.
Catalysts comprised of Pd(OAc)2 and either PCy3 or
sterically hindered N-heterocyclic carbene ligands provide fast rates for a
mild, palladium-catalyzed synthesis of oxindoles in high yields by amide
α-arylation.
S. Lee, J. F. Hartwig, J. Org. Chem., 2001,
66, 3402-3415.
2,4-dinitrophenol (2,4-DNP) mediates an efficient photoannulation of
α-azidochalcones into 2,5-diaryloxazoles under visible-light irradiation. The
scope of the reaction was studied by synthesizing a series of 2,5-diaryloxazoles
including two naturally occurring oxazoles (Texamine and Balsoxin) in excellent
yields.
U. D. Newar, S. Borra, R. A. Maura, Org. Lett.,
2022, 24, 4454-4458.
Individual β-hydroxy thiocyanates can be synthesized in high yield and with
more than 90% regioselectivity in the presence of phenol-containing macrocyclic
diamides under mild reaction conditions. The method offers high regioselectivity,
simple regeneration/reuse of catalyst through several cycles without a decrease
in activity, and ease of workup of the reaction.
H. Sharghi, M. A. Nasseri, K. Niknam, J. Org. Chem., 2001,
66, 7287-7293.
A mild, rapid, straightforward visible-light-mediated sulfonamide ethylation of
easily available redox active esters or alkyl iodides with vinylsulfonamides
provides a diverse array of compounds with C(sp3)-sulfonamide
skeletons. This method offers a broad substrate scope and has and
potential utility for late-stage functionalization of natural products and
synthetic medicines.
M. Zhang, M. Yu, Z. Wang, Y. Liu, Q. Wang, Org. Lett.,
2022, 24, 3932-3937.
Sodium benzene sulfinate catalyzed a visible-light-driven aerobic oxidative
cleavage of olefins to provide the corresponding aldehydes and ketones under
transition-metal-free conditions. Notably, α-halo-substituted styrenes proceeded
with photoinduced oxidation to finally afford α-halo-acetophenones with halogen
migration.
Y.-X. Chen, J.-T. He, M.-C. Wu, Z.-L. Liu, K. Tang, P.-J. Xia, K. Chen, H.-Y.
Xiang, X.-Q. Chen, H. Yang, Org. Lett.,
2022, 24, 3920-3925.
A perfluorophenyl substituted 1,1′-bi-2-naphthol (BINOL) is an effective photoacid catalyst for promoting the acetalization of enol ethers
with alcohols under irradiation with visible light. The reactions proceed
efficiently with a wide range of substrates under mild and near neutral conditions.
H. Liu, Y. Chen, D. An, X. Zhang, S. Liao, Synlett, 2022,
33,
800-804.
A metal-free photoredox catalyzed amidyl N-centered radical addition to the
C-C triple bond of o-alkynylated benzamides provides isoquinoline-1,3,4(2H)-triones,
3-hydroxyisoindolin-1-ones, and phthalimides via a proton-coupled electron
transfer (PCET) process under mild reaction conditions.
M. B. Reddy, K. Prasanth, R. Anandhan, Org. Lett.,
2022, 24, 3674-3679.
A metal-free photoredox catalyzed amidyl N-centered radical addition to the
C-C triple bond of o-alkynylated benzamides provides isoquinoline-1,3,4(2H)-triones,
3-hydroxyisoindolin-1-ones, and phthalimides via a proton-coupled electron
transfer (PCET) process under mild reaction conditions.
M. B. Reddy, K. Prasanth, R. Anandhan, Org. Lett.,
2022, 24, 3674-3679.
A phosphetane-based catalyst operating within PIII/PV=O
redox cycling is able to capture HNO, generated in situ by Nef decomposition of
2-nitropropane, to selectively furnish versatile primary arylamines from
arylboronic acid substrates with the preservation of otherwise reactive
functional groups.
S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc.,
2022, 144, 8902-8907.
An NHC-catalyzed [2 + 4] cyclization of alkynyl ester with α,β-unsaturated
ketone provides highly substituted 4H-pyran derivatives in gooy yields.
This strategy offers cheap and easily
available starting materials, mild reaction conditions, and high atom economy.
F. Lu, Y. Chen, X. Song, C. Yu, T. Li, K. Zhang, C. Yao, J. Org. Chem., 2022, 87,
6902-6909.
A simple, efficient, and environmentally beneficient disulfide-catalyzed
photocatalytic regioselective oxidative cleavage of 1-arylbutadienes to
cinnamaldehydes offers mild reaction conditions, excellent regioselectivity, and
compatibility with a wide range of functional groups.
R. A. Fernandes, P. Kumar, A. Bhowmik, D. A. Gorve, Org. Lett.,
2022, 24, 3436-3439.
An organophosphorus-catalyzed C-N bond-forming reductive coupling of
nitroalkanes with arylboronic acids and esters shows excellent chemoselectivity
for the nitro/boronic acid substrate pair, allowing the synthesis of
N-(hetero)arylamines rich in functionalization.
G. Li, Y. Kanda, S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc.,
2022, 144, 8242-8248.
A mechanochemical route enables a selective synthesis of 4-nitro-1,2,3-triazoles via
organocatalyzed oxidative [3 + 2] cycloaddition between β-nitrostyrenes and
organic azides. The reaction features a nontoxic catalyst, catalyst
recyclability, no rigorous solvent-extraction, no toxic byproducts, atmospheric
oxygen as oxidant, and scalability to gram-scale.
M. Vadivelu, A. A. Raheem, J. P. Raj, J. Elangovan, K. Karthikeyan, C. Praveen, J. Sun, Org. Lett.,
2022, 24, 2798-2803.
Dibenziodolium triflate displays high catalytic activity
for the Groebke-Blackburn-Bienaymé Reaction that leads to a series of imidazopyridines.
This salt can play the role of a hybrid hydrogen- and halogen-bond-donating organocatalyst, which electrophilically activates the carbonyl and imine groups.
M. V. Il'in, A. A. Sysoeva, A. S. Novikov, D. S. Bolotin, J. Org. Chem., 2022, 87,
4569-4579.
Oxetane desymmetrization enables an asymmetric synthesis of chiral
pyrrolidines bearing an all-carbon quaternary stereocenter in the 3-position
either using a readily available tert-butylsulfinamide chiral auxiliary
or a catalytic system with a chiral phosphoric acid as the source of chirality.
R. Zhang, M. Sun, Q. Yan, X. Lin, X. Li, X. Fang, H. H. Y. Sung, J. D. Williams,
J. Sun, Org. Lett.,
2022, 24, 2359-2364.
Low loadings of a 1,3,5,2,4,6-triazatriphosphorine (TAP)-derived
organocatalyst promote a metal-free, biomimetic cyclization of N-(2-hydroxyethyl)amides
to the corresponding 2-oxazolines in very good yields. This dehydrative
cyclization exhibits a broad substrate scope and high functional-group tolerance
can can be conducted on a gram scale.
F. S. Movahed, S. W. Foo, S. Mori, S. Ogawa, S. Saito, J. Org. Chem., 2022, 87,
243-257.
An isothiourea-catalyzed fluorination of alkynyl-substituted acetic acids
provides a broad range of optically active tertiary α-alkyl fluorides in high
enantioselectivity (up to 97% ee). Furthermore, this methodology can be scaled
up to a Gram scale without loss of enantioselectivity.
S. Yuan, W.-H. Zheng, J. Org. Chem., 2022, 87,
713-720.
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