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:
D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta,
1996, 79, 1899-1902.
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
PIII/PV=O redox cycling enables a one-step dehydroxylative
thioetherification of alcohols with
various hypervalent organosulfur compounds. This method offers excellent functional group tolerance, broad substrate scope,
and scalability.
G. Sun, S.-P. Zhang, Y.-F. Zhao, Y. Du, M.-Y. Shi, J. Li, H. Yuan, X. Wen, H.
Sun, Q.-L. Xu, J. Org. Chem., 2024, 89,
1083-1090.
An organocatalyst delivers nitroalkanes from β,β-disubstituted nitroalkenes
with a generality otherwise achievable only by a combination of several organo-
and organometallic catalysts. The catalyst improves yield and/or
enantioselection of the reduction of some major classes of nitroalkenes.
Z. Deng, M. A. Padalino, J. E. L. Jan, S. Park, M. W. Danneman, J. N.
Johnston, J. Am. Chem. Soc.,
2024, 146, 1269-1275.
A N-heterocyclic carbene (NHC)-catalyzed synthesis of N-substituted
isoindolinone acetates proceeds through a tandem imine umpolung-intramolecular
aza-Michael addition followed by oxidation with molecular oxygen in air as the
sole oxidant. This method offers atom efficiency, operational simplicity,
large-scale syntheses, and mild reaction conditions.
J. Ramarao, P. C. Behera, M. S. Reddy, S. Suresh, J. Org. Chem., 2024, 89,
414-424.
A simple 2,2'-biphenol-derived phosphoric acid catalyst promotes a
dehydrative esterification from an equimolar mixture of carboxylic acids and
primary or secondary alcohols in toluene at 100 °C without the necessity to
remove water. This reaction was also successfully conducted at the gram scale.
M. Hatano, C. Nishioka, A. Mimura, R. Kimura, Y. Okuda, T. Yamada, K. Sakata, Synlett, 2023,
34,
2508-2514.
A catalytic Appel reaction using a P(III)/P(V) redox cycling at very low
catalyst loadings, hexachloroacetone as the halogen source and phenylsilane as
the terminal reductant converted alcohols and epoxides containing a wide variety
of functional groups to the respective chlorides and dichlorides in very good
yields and with high enantiospecificities for inversion.
J. Tönjes, L. Kell, T. Werner, Org. Lett., 2023, 25,
9114-9118.
Silyl carbamates undergo allylation using allylic fluorides in the presence
of common Lewis base catalysts. The reactions are rendered enantioselective in
the presence of chiral Lewis base catalysts and produce suitably protected
derivatives of enantioenriched chiral β-amino acids.
M. Lange, F. L. Meyer, O. Nosovska, I. Vilotijevic, Org. Lett., 2023, 25,
9097-9102.
An NHC-catalyzed Michael addition reaction enables a quick and efficient
synthesis of dihydropyranone molecules. Substituents with various electronic and
steric effects are well tolerated, with the target products afforded in good to
excellent yields.
C. Mou, Y. Lv, J. Jin, H. Chai, T. Li, Y. R. Chi, Z. Jin, Org. Lett., 2023, 25,
8706-8710.
Quinazolinedione derivatives were obtained from 2-aminobenzoic acids and
bench-stable α-chloroaldoxime O-methanesulfonates under mild reaction
conditions via a DMAP-catalyzed domino reaction consisting of nucleophilic
substitution, Tiemann rearrangement, and cyclic urea formation.
W. Kaewman, J. Kaeobamrung, Synlett, 2023,
34,
2052-2058.
Non-activated water can be applied directly as a hydrogen donor to achieve a
carbanion-mediated alkene reduction with 9-HTXTF serving as an
organophotocatalyst. Syntheses of high-value-added drugs and bioactive molecules
showcase the usefulness of the protocol in chemical synthesis.
W.-J. Kang, Y. Pan, A. Ding, H. Guo, Org. Lett., 2023, 25,
7633-7638.
N-Heterocyclic carbenes (NHCs) catalyze a highly enantioselective
synthesis of fluoroalkylated benzopyranones and 3-coumaranones with all-carbon
quaternary stereocenters via annulation reactions between in situ generated acyl
anion intermediates and highly substituted trifluoromethyl-β,β-disubstituted
Michael acceptors. The method can also be extended to perfluoroalkyl homologues.
I. Barańska, K. Rafińska, Z. Rafiński, J. Org. Chem., 2023, 88,
14339-14344.
Readily available and structurally diverse alkyl carboxylic acids can serve as
the starting materials for sulfinamides, sulfonamides, and sulfonimidamides
syntheses. The methods harness alkyl radical generation from carboxylic acids
using acridine photocatalysts and 400 nm light with subsequent radical addition
to sulfinylamine reagents, delivering sulfinamide products.
J. A. Andrews, J. Kalepu, C. F. Palmer, D. L. Poole, K. E. Christensen, M. C.
Willis, J. Am. Chem. Soc.,
2023, 145, 21623-21629.
A N-triflyl phosphoramide catalyzes an enantioselective transformation of bicyclo[1.1.0]butanes
into cyclobutenes with good regio- and enantiocontrol. This isomerization proceeds under mild conditions with low
catalyst loading as well as good functional group compatibility.
S.-L. Lin, Y.-H. Chen, H.-H. Liu, S.-H. Xiang, B. Tan, J. Am. Chem. Soc.,
2023, 145, 21152-21158.
Visible light promotes a practical and precise deoxygenative deuteration of
common aliphatic alcohols using D2O as the deuterium source. Upon
intermediacy of xanthate anions, a variety of primary, secondary, and tertiary
alcohols can be facilely transformed into deuterioalkanes with excellent
D-incorporation. The sequence is catalyzed by in situ formed deuterated
2-mercaptopyridine.
B.-Q. He, X. Wu, Org. Lett., 2023, 25,
6571-6576.
A visible-light-promoted and transition-metal-free photoredox-catalysis
strategy provides thioxanthone derivatives (TXs) via hydrogen atom transfer, C-C
formation, and oxidative dehydrogenation with high regioselectivity and
reactivity. Significantly, this method can be used to produce commercial
photoinitiators and drugs at the gram level.
W. Liao, J. Hou, H. Tang, X. Guo, G. Sheng, M. Jin, Org. Lett., 2023, 25,
6352-6356.
A general and convenient thiazolium-catalyzed cross-coupling of various
aldehydes with acylimines derived from sulfonylamides provides ready access to
structurally diverse α-amido ketones.
J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski, P. J.
Reider, J. Am. Chem. Soc., 2001, 123, 9696-9697.
3-Fluoro-2-iodo-1-methylpyridinium triflate catalyzes a one-pot cascade
reaction for 2,3-dihydropyridinone synthesis. The desired [4+2] cycloaddition
products, bearing aryl, heteroaryl, alkyl, and alicyclic substituents, were
successfully furnished in good yields. A strong halogen-bonding interaction
between the iodopyridinium catalyst and imine intermediate was essential.
Y. Li, Y. Ge, R. Sun, X. Yang, S. Huang, H. Dong, Y. Liu, H. Xue, X. Ma, F.
Fu, Z. Chen, J. Org. Chem., 2023, 88,
11069-11082.
An unprecedented visible-light-mediated metal-free oxidation of alcohols
provides carbonyls with hydrogen evolution. By synergistic combination of
organophotocatalyst 4CzIPN and a thiol hydrogen atom transfer catalyst, a broad
range of alcohols, including primary and secondary benzylic alcohols as well as
aliphatic alcohols, were readily oxidized to carbonyls in good yields.
X. Yang, Y. Guo, H. Tong, H. Guo, R. Liu, R. Zhou, Org. Lett., 2023, 25,
5486-5491.
Enantioselective α-fluorination of both cyclic and acyclic β-dicarbonyl
compounds with β,β-diaryl serines as primary amine organocatalysts was conducted
with only 1.1 equiv of Selectfluor by adding alkali carbonates, such as Na2CO3
or Li2CO3. The reaction afforded α-fluorinated
β-dicarbonyl compounds in good yield with excellent enantioselectivity.
K. Endo, D. Tomon, S. Arimitsu, J. Org. Chem., 2023, 88,
9037-9045.
A catalytic protio-semipinacol ring-expansion reaction for the highly
enantioselective conversion of tertiary vinylic cyclopropyl alcohols into
cyclobutanone products bearing α-quaternary stereogenic centers relies on the
cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen
chloride. In a stepwise mechanism, protonation of the alkene is followed by C-C
bond migration.
M. A. S. Blackburn, C. C. Wagen, M. R. Bodrogean, P. M. Tadross, A. J.
Bendelsmith, D. A. Kutateladze, E. N. Jacobsen, J. Am. Chem. Soc.,
2023, 145, 15036-15042.
An organophosphorus-catalyzed umpolung reaction achieves the deoxygenation of
sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven
by PIII/PV=O redox cycling. This operationally simple
approach uses a stable phosphine oxide as a precatalyst and shows broad
functional group tolerance.
G. Sun, J. Li, X. Liu, Y. Liu, X. Wen, H. Sun, Q.-L. Xu, J. Org. Chem.,
2023, 88, 8628-8635.
A chiral pyridoxamine catalyzes an asymmetric biomimetic transamination of
trifluoromethyl ketones with 2,2-diphenylglycine as the amine source to produce
optically active α-trifluoromethyl amines in very good yields with excellent
ee's under mild conditions.
W. Cai, D. Cai, H. Liang, X. Ren, B. Zhao, J. Org. Chem., 2023, 88,
7849-7857.
An inexpensive aminoguanidine efficiently catalyzes a reductive cyclization
of o-phenylenediamines with CO2 in the presence of
triethoxysilane. Various functionalized benzimidazoles, benzoxazole, and
benzothiazole were synthesized in high yields. Mechanistic studies indicate that
formic acid acts as a cocatalyst.
Y. Sun, K. Gao, J. Org. Chem., 2023, 88,
7463-7468.
A photocatalytic decarboxylative coupling of imine and 2,2-diethoxyacetic
acid in the presence of a nonstoichiometric amount of a radical initiator provides
α-aminoacetals. This atom-economical C-C coupling tolerates various functional
groups. The diversely functionalized α-aminoacetals serve as a promising
platform for further research.
S. Kim, B. Park, G. S. Lee, S. H. Hong, J. Org. Chem., 2023, 88,
6532-6537.
A visible-light photoredox-catalyzed decarboxylation of α-oxo carboxylic
acids in the presence of D2O enables a metal-free synthesis of
C1-deuterated aldehydes in very good yields under mild conditions. The reaction
tolerates various functional groups and can also be applied to the synthesis of
various aldehydes.
C.-H. Hu, Y. Li, J. Org. Chem., 2023, 88,
6401-6406.
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