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
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.
An organocatalyzed oxidative C-N bond formation of
phenylpropanamide derivatives provides
3,3-disubstituted oxindole derivatives in very good yields. This highly efficient intramolecular reaction
offers transition metal-free mild conditions and
the ability to perform the reaction on a gram scale.
Y. Wang, M. Yang, Y.-Y. Sun, Z.-G. Wu, H. Dai, S. Li, Org. Lett., 2021, 23,
8750-8754.
Lewis bases catalyze vicinal dioxygenation of olefins with hypervalent iodine
reagents under mild conditions. The reaction tolerates various functional groups.
L. Pan, Z. Ke, Y.-Y. Yeung, Org. Lett., 2021, 23,
8174-8178.
A chlorinative cyclization of aryl alkynoates in the presence of N-chlorosuccinimide
(NCS) and Mes-Acr-MeClO4 as photocatalyst provides 3-chlorocoumarins
under visible-light irradiation. The radical initiated reaction proceeds via Cl-
addition, 5-exo-trig spirocyclization and subsequent 1,2-ester migration.
M. Pramanik, A. Mathuri, S. Sau, M. Das, P. Mal, Org. Lett., 2021, 23,
8088-8092.
A dianionic
phase-transfer catalyst enables an asymmetric fluorofunctionalization of γ,γ-disubstituted allylamine
derivatives. Depending on the substituents on the alkene moiety, the
reaction afforded chiral allylic fluorides and fluorinated dihydrooxazines in a
highly enantioselective manner.
T. Niwa, K. Nishibashi, H. Sato, K. Ujiie, K. Yamashita, H. Egami, Y.
Hamashima, J. Am. Chem. Soc.,
2021, 143, 16599-16609.
Triphenylphosphine oxide catalyzes amidation and esterification for an
efficient synthesis of dipeptides, amides, and esters in good yields in less
than 10 m without racemization. This reaction is applicable to challenging
couplings of hindered carboxylic acids with weak nucleophiles amines or
alcohols.
J.-W. Ren, M.-N. Tong, Y.-F. Zhao, F. Ni, Org. Lett., 2021, 23,
7497-7502.
Organophotoredox catalysis enables an intermolecular hydroaminoalkylation (HAA)
of styrenes with unprotected primary alkylamines to provide pharmacologically
relevant γ-arylamines. A broad range of functionalities are tolerated, and the
reactions can be run on multigram scale in continuous flow.
H. E. Askey, J. D. Grayson, J. D. Tibbetts, J. C. Turner-Dore, J. M. Holmes,
G. Kociok-Kohn, G. L. Wirgley, A. J. Cresswell, J. Am. Chem. Soc.,
2021, 143, 15936-15945.
A small ring phosphacycle (phosphetane) catalyzes the synthesis of unsymmetrical
hydrazines by cross-selective intermolecular NN reductive coupling of
nitroarenes and anilines in the presence of a hydrosilane as the terminal
reductant. The reaction offers good chemoselectivity and functional group
tolerance.
G. Li, S. P. Miller, A. T. Radosevich, J. Am. Chem. Soc.,
2021, 143, 14464-14469.
A chiral primary amino acid organocatalyst mediates an enantioselective
α-allylation and -propargylation of α-branched aldehydes with alkyl halides in a
good yield and high enantioselectivity to furnish α-allylated or -propargylated
aldehydes with chiral quaternary carbon stereocenters. The reaction proceeded
smoothly in a mildly basic aqueous solution of potassium hydrogen carbonate.
M. Yoshida, J. Org. Chem., 2021, 86,
10921-10927.
A photochemical process for the preparation of carboxylic acids from formate
salts and alkenes proceeds in high yields across diverse functionalized alkene
substrates with excellent regioselectivity. This operationally simple and
redox-neutral hydrocarboxylation can be readily scaled in batch at low
photocatalyst loading (0.01% photocatalyst).
S. N. Alektiar, Z. K. Wickens, J. Am. Chem. Soc.,
2021, 143, 13022-13028.
A visible-light-mediated oxidative cyclization of 2-aminobenzyl alcohols with
secondary alcohols provides quinolines in good yields at room temperature. This
photocatalytic method employes anthraquinone as an organic small-molecule
catalyst and DMSO as an oxidant.
J.-x. Xu, N.-l. Pan, J.-x. Chen, J.-w. Zhao, J. Org. Chem., 2021, 86,
10747-10754.
An efficient visible-light-induced decarboxylative coupling reaction of
N-protected α-amino acids with heterocycles provides aminoalkylated heterocycles
in good yields. Attractive features of
this process include the generation of aminomethyl radical by an inexpensive
organic photocatalyst under transition-metal-free conditions.
Y. Li, C. Dai, S. Xie, P. Liu, P. Sun, Org. Lett., 2021, 23,
5906-5910.
Under blue-light irradiation with
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene as photocatalyst, silyl enol
ethers reacted with alkenes in the presence of a small amount of water to afford
α-alkylated products in very good yields. A thiol cocatalyst was found to expand
the substrate scope of the reaction.
T. Hirata, Y. Ogasawara, Y. Yamashita, S. Kobayashi, Org. Lett., 2021, 23,
5693-5697.
The combination of a riboflavin-derived organocatalyst and molecular iodine
successfully promoted the aerobic oxidation of thiols to disulfides under
metal-free mild conditions at room temperature. The the biomimetic flavin
catalyst enables the transfer of electrons from the iodine forming the basis for
a green oxidative synthesis of disulfides from thiols.
M. Oka, R. Kozako, H. Iida, Synlett, 2021,
32,
1227-1230.
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