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 BINOL-derived boro-phosphate catalyzes an enantioselective reduction of
α-trifluoromethylated imines to provide chiral α-trifluoromethylated amines in
high yields and with excellent enantioselectivities in the presence of
catecholborane as hydride source under mild conditions.
H. He, X. Tang, Y. Cao, J. C. Antilla, J. Org. Chem., 2021, 86,
4336-4345.
A combination of pyrenedione (PD) and KOtBu achieves a facile alcohol
dehydrogenation under visible-light excitation in the presence of aerobic oxygen
as the terminal oxidant. The resulting carbonyl compounds can be easily
converted to vinyl nitriles in a single-pot reaction. This environmentally
benign, organocatalytic α-olefination of nitriles operates at low temperature.
A. K. Bains, Y. Ankit, D. Adhikari, Org. Lett., 2021, 23,
2019-2023.
In cycloadditions of carbon dioxide into epoxides to afford cyclic carbonates, a
strained ion pair tris(alkylamino)cyclopropenium halide catalyst, in which the
halide is repelled, is a very electrophilic H-bond donor, allowing it to
activate the oxygen of the epoxide, while the more nucleophilic halide is better
able to attack the methylene carbon of the epoxide.
J. Xu, A. Xian, Z. Li, J. Liu, Z. Zhang, R. Yan, L. Gao, B. Liu, L. Zhao, K. Guo, J. Org. Chem., 2021, 86,
3422-3432.
Organoiodine(I/III) chemistry enables a metal-free, catalytic enantioselective intermolecular oxyamination
of aryl- and alkyl-substituted alkenes with N-(fluorosulfonyl)carbamate as a bifunctional
N,O-nucleophile with high enantioselectivity and
electronically controlled regioselectivity. The oxyaminated products can be
easily deprotected in one step to reveal free amino alcohols in high yields.
C. Wata, T. Hashimoto, J. Am. Chem. Soc.,
2021, 143, 1745-1751.
The use of a bifunctional organocatalyst and Cs2CO3
enables a direct carboxylation of terminal alkynes with CO2 at atmospheric
pressure under mild temperatures to provide a range of propiolic acid
derivatives in high yields with broad substrate scope. This work has
demonstrated that this organocatalytic method offers a competitive alternative
to metal catalysis.
J.-B. Shi, Q. Bu, B.-Y. Liu, B. Dai, N. Liu, J. Org. Chem., 2021, 86,
1850-1860.
Zwitterionic organocatalysts with an amide anion/iminium cation charge pair
catalyze the isomerization of maleic acid diesters to give fumaric acid diesters.
Whereas the cooperative effect of the charges lower the activation barrier for a
Michael addition of the catalyst to the substrate, the key interaction results
from a nonclassical hydrogen bond.
Y.-P. Lam, Z. Lam, Y.-Y. Yeung, J. Org. Chem., 2021, 86,
1183-1190.
A cooperative primary amine and ketone dual catalytic approach enables the
asymmetric α-hydroxylation of β-ketocarbonyls with H2O2 in excellent yield and
enantioselectivity. Notably, late-stage hydroxylation for peptidyl amide or
chiral esters can also be achieved with high stereoselectivity.
M. Cai, K. Xu, Y. Li, Z. Nie, L. Zhang, S. Luo, J. Am. Chem. Soc.,
2021, 143, 1078-1087.
tert-Butyldimethylsilyl (TBDMS) ethers of primary, secondary, and
tertiary alcohols and phenolic TBDMS ethers are desilylated to their
corresponding alcohols and phenols, respectively, in DMSO, at 80°C, in very good
yield in the presence of P(MeNCH2CH2)3N as
catalyst. Desilylations of tert-butyldiphenylsilyl (TBDPS) ethers were
much less effective.
Z. Yu, J. G. Verkade, J. Org. Chem., 2000,
65, 2065-2068.
A photoredox-catalyzed decarboxylative cyclization reaction between commercially
available α-oxocarboxylic acids and a hypervalent iodine(III) reagent provides
2,5-disubstituted 1,3,4-oxadiazoles in very good yields.
J. Li, X.-C. Lu, Y. Xu, J.-X. Wen, G.-Q. Hou, L. Liu, Org. Lett., 2020, 22,
9621-9626.
An efficient reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium
azide provides 3,5-bis(het)arylisoxazoles in high yields at room temperature in
the presence of IBX as catalyst. The reaction is applicable to a broad range of
substrates. The reaction of β-ketodithioesters with sodium azide furnishes
β-ketonitriles in good yields.
M. A. P, G. L. Balaji, P. Iniyavan, H. Ila, J. Org. Chem., 2020, 85, 15422-15436.
An efficient carbene-catalyzed formal
[4 + 2] annulation of β-silyl enones with a HOBT ester followed by ring opening with nucleophiles
provides γ-keto-β-silyl esters and amides, most with extremely high
enantioselectivities. γ-Keto-β-silyl esters can be easily converted into
enantioenriched β,σ-dihydroxyl esters.
Y. Zhang, X. Huang, J. Guo, C. Wei, M. Gong, Z. Fu, Org. Lett., 2020, 22, 9545-9550.
L-proline catalyzes a reaction between α,β-unsaturated aldehydes and
maleimides to provide biologically and pharmaceutically important phthalimides.
The reaction involves an efficient benzannulation that proceeds via a formal [4
+ 2] cycloaddition of azadiene intermediates generated in situ from enals and
N-substituted maleimides.
M. S. Akhthar, Y. R. Lee, J. Org. Chem., 2020, 85,
15129-15138.
A catalytic amount of inexpensive salicylic acid promotes a straightforward
and scalable synthesis of diphenyl arylphosphonates from anilines and triphenyl
phosphite at 20°C within 1-2 h. The reaction proceeds via radical-radical
coupling and tolerates a wide range of functional groups.
M. Estruch-Blasco, D. Felipe-Blanco, I. Bosque, J. C. González-Gómez, J. Org. Chem., 2020, 85, 14473-14485.
Very low loadings of a N,N-diethylacetamide derived phosphorane
efficiently catalyze the cyanosilylation of a broad range of ketones. Aldehydes,
aldimines, and ketimines are also viable substrates.
W.-B. Wu, X.-P. Zang, J. Zhou, J. Org. Chem., 2020, 85, 14342-14350.
A series of 20 chiral epoxides were obtained with excellent yields and
enantioselectivities within short reaction times using hybrid amide-based
Cinchona alkaloids as catalysts at very low loading. Moreover, the catalyst
solution can be reused 10times, without further catalyst addition to the
reaction mixture.
M. Majdecki, A. Tyszka-Gumkowska, J. Jurczak,
Org. Lett., 2020, 22, 8687-8691.
Supramolecular nanoassemblies of an AIEE-ICT-active pyrazine derivative (TETPY)
with strong absorption in the visible region catalyze the synthesis of a variety
of a broad range of benzimidazoles, benzothiazoles and quinazolines in excellent
yields under "metal-free" conditions in a mixed aqueous media.
S. Dadwal, M. Kumar, V. Bhalla, J. Org. Chem., 2020, 85, 13906-13919.
Pyrimidopteridine N-oxides as organic photoredox-active catalysts
mediate a metal-free photoinduced decarboxylative Giese-type addition of
carboxylic acids to a variety of electron-deficient alkenes.
. El-Hage, C. Schöll, J. Pospech, J. Org. Chem., 2020, 85, 13853-13867.
A degradable 1,3,5-triazo-2,4,6-triphosphorine (TAP) motif enables a
dehydrative formation of amide bonds between diverse combinations of aromatic
carboxylic acids and amines. The underlying reaction mechanism was investigated,
and potential catalyst intermediates were characterized.
. S. Movahed, D. N. Sawant, D. B. Bagal, S. Saito, Synthesis, 2020, 52,
3253-3262.
The combination of flavin and iodine catalyzes an aerobic oxidative C-N
bond-forming process for the facile synthesis of imidazo[1,2-a]pyridines.
This dual catalytic system can also be applied to the one-pot, three-step
synthesis of 3-thioimidazo[1,2-a]pyridines from aminopyridines, ketones,
and thiols.
H. Okai, K. Tanimoto, R. Ohkado, H. Iida,
Org. Lett., 2020, 22, 8002-8006.
Chiral phosphoric acids catalyze an enantioselective addition of
bi(cyclopentyl)diol-derived boronates to aldehydes to provide homoallylic, propargylic,
and crotylic alcohols with high enantiomeric excess and diastereomeric ratios. A wide substrate scope was exhibited, and the novel boronates provided high
enantiocontrol.
J. Yuan, P. Jain, J. C. Antilla, J. Org. Chem., 2020, 85,
12988-13003.
DBU catalyzes a rearrangement of diarylated secondary propargylic alcohols to
give α,β-unsaturated carbonyl compounds in excellent yields. The typical
1,3-transposition of oxy functionality, characteristic of Meyer-Schuster
rearrangements, is not observed. This method offers a broad substrate scope,
functional-group tolerance, operational simplicity, and complete atom economy.
R. De, A. Savarimuthu, T. Ballav, P. Singh, J. Nanda, A. Hasija, D. Chopra, M.
K. Bera, Synlett, 2020,
31,
1587-1592.
Please cite and link this page as follows:
Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )
