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 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.
An organic photoredox-catalyzed gem-difluoroallylation of
α-trifluoromethyl alkenes with alkyl iodides provides gem-difluoroalkene
derivatives via C-F bond cleavage. This transition-metal-free transformation
utilizes a readily available organic dye (4CzIPN) as the sole photocatalyst and
N,N,N',N'-tetramethylethylenediamine as the radical activator.
S. Yan, W. Yu, J. Zhang, H. Fan, Z. Lu, Z. Zhang, T. Wang, J. Org. Chem., 2022, 87,
1574-1584.
A β,β-diaryl serine catalyzes an enantioselective fluorination of
α-substituted β-diketones to afford the corresponding fluorinated products in
very good yields with excellent enantioselectivity. The CO2H group of
the primary amine organocatalyst plays an important role in inducing the high
enantioselectivity. Products could be converted into diols, aldols, and allylic
fluorides without racemization.
S. Poorsadeghi, K. Endo, S. Arimitsu, Org. Lett., 2022, 24,
420-424.
A metal- and additive-free photoredox cyclization of N-arylacrylamides
provides dihydroquinolinones in good yields in the presence of the organic
light-emitting molecule 4CzIPN as photocatalyst.
Z. Liu, S. Zhong, X. Ji, G.-J. Deng, H. Huang, Org. Lett., 2022, 24,
349-353.
Visible-light-excited 9,10-phenanthrenequinone (PQ*) catalyzes a mild and
efficient electrocyclization of 2-vinylarylimines for the synthesis of 2,4-disubstituted
quinolines in very good yields.
J. Talvitie, I. Alanko, E. Bulatov, J. Koivula, T. Pöllänen, J. Helaja, Org. Lett., 2022, 24,
274-278.
A chiral diarylketone catalyzes a photochemical deracemization of
5-substituted 3-phenylimidazolidine-2,4-diones. Mechanistic evidence suggests
the reaction to occur by selective hydrogen atom transfer (HAT). The product
enantiomer is not processed by the catalyst and is thus enriched in the
photostationary state.
J. Großkopf, M. Plaza, A. Seitz, S. Breitenlechner, G. Storch, T. Bach, J. Am. Chem. Soc.,
2021, 143, 21241-21245.
Zwitterionic catalysts promote the formation of halogenated γ-butenolides
from cyclopropene carboxylic acids in the presence of N-haloamides as the
halogen sources. The catalytic protocol could also be applied to the synthesis
of halogenated pyrrolones by using cyclopropene amides as the starting
materials.
R.-B. Hu, S. Qiang, Y.-Y. Chan, J. Huang, T. Xu, Y.-Y. Yeung, Org. Lett., 2021, 23,
9533-9537.
A chiral phosphoric acid (CPA) catalyzes a versatile transition metal/oxidant
free synthesis of chiral 2H-1,4-benzoxazines through enantioselective
desymmetrization of prochiral oxetanes (30 examples) in very good yield and high
enantioselectivity under mild reaction conditions.
V. A. Bhosale, M. Nigríni, M. Dračínský, I. Císařová, J. Veselý, Org. Lett., 2021, 23,
9376-9381.
Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral
dual-hydrogen-bond donors (HBDs) enables a highly enantioselective Prins
cyclization of a wide variety of simple alkenyl aldehydes. The optimal chiral
catalysts withstand the strongly acidic reaction conditions and induce rate
accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone.
D. A. Kutateladze, E. N. Jacobsen, J. Am. Chem. Soc.,
2021, 143, 20077-20083.
An enantioselective intermolecular Prins reaction of styrenes and
paraformaldehyde provides 1,3-dioxanes, using confined imino-imidodiphosphate (iIDP)
Brønsted acid catalysts via a concerted, highly asynchronous addition of an
acid-activated formaldehyde oligomer to the olefin. The enantioenriched
1,3-dioxanes can be transformed into the corresponding optically active
1,3-diols.
C. D. Díaz-Oviedo, R. Maji, B. List, J. Am. Chem. Soc.,
2021, 143, 20598-20604.
Dibrominated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is an
organic photocatalyst with similar optoelectronic, electrochemical, and
performance properties to those of Ru(bpy)3Cl2, commonly
used in radical-ionic transformation, such as the formation of 1,4-dicarbonyl
compounds. BODIPY also catalyzes syntheses of γ-alkoxylactones, monoprotected
1,4-ketoaldehydes, and dihydrofurans.
W. H. García-Santos, J. Ordóñez-Hernández, M. Farfán-Paredes,
H. M. Castro-Cruz, N. A. Macías-Ruvalcaba, N. Farfán, A.
Cordero-Vargas, J. Org. Chem., 2021, 86,
16315-16326.
The use of an organic redox catalyst enables an efficient electrocatalytic
synthesis of 3-substituted and 2,3-disubstituted indoles through dehydrogenative
cyclization of 2-vinylanilides. The reactions do not require any external
chemical oxidant.
Y.-T. Zheng, J. Song, H.-C. Xu, J. Org. Chem., 2021, 86,
16001-16007.
A selective electrochemical aminoxyl-mediated Shono-type oxidation of
pyrrolidines provides pyrrolidinones with high selectivity and functional group
compatibility.
N. R. Deprez, D. J. Clausen, J.-X. Yan, F. Peng, S. Zhang, J. Kong, Y. Bai, Org. Lett., 2021, 23,
8834-8837.
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