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
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.
A modified binaphthol catalyzes an asymmetric conjugate alkynylation of
β-enaminones with potassium alkynyltrifluoroborates via in situ generated
organodifluoroboranes. Mechanistic studies revealed the impact of molecular
sieves on efficiency and stereocontrol. Additional functionalization provides a
diverse set of valuable β-alkynyl-β-amino carbonyl scaffolds.
J.-F. Wang, X. Meng, C.-H. Zhang, C.-M. Yu, B. Mao,
Org. Lett., 2020, 22, 7424-7426.
Stable zwitterionic compounds catalyze a synthesis of α,α-dihalo-N-arylacetamides
from β-oxo amides and N-halosuccinimides as the halogen sources. The
corresponding α,α-dihalo-N-arylacetamides were obtained in very good
yields under mild conditions without strong base or acid.
Z. Ke, Y.-P. Lam, K.-S. Chan, Y.-Y. Yeung,
Org. Lett., 2020, 22, 7353-73572.
An organophosphorus-catalyzed reductive C-N coupling of nitromethane with
arylboronic acid derivatives provides N-methylanilines. The small ring organophosphorus-based catalyst (1,2,2,3,4,4-hexamethylphosphetane
P-oxide) together with phenylsilane as mild terminal reductant mediate the
selective installation of the methylamino group.
G. Li, Z. Qin, A. T. Radosevich, J. Am. Chem. Soc.,
2020, 142, 16205-16210.
By utilizing N-heterocyclic carbenes as stabilizer through electrostatic
interaction rather than electron donation, a visible-light-triggered radical-radical cross-coupling of
N-alkenoxypyridinium salts and NaI provides a variety of α-iodo ketones.
H. Sheng, Q. Liu, X.-D. Su, Y. Lu, Z.-X. Wang, X.-Y. Chen,
Org. Lett., 2020, 22, 7187-7192.
Azetidinium triflates are suitable substrates for enantioselective ring
opening with CsF and a chiral bis-urea catalyst. The ability of hydrogen bonding
phase-transfer catalysts to couple two ionic reactants, affords enantioenriched
γ-fluoroamines in high yields.
G. Roagna, D. M. H. Ascough, F. Ibba, A. C. Vicini, A. Fontana, K. E.
Christensen, A. Peschiulli, D. Oehrich, A. Misale, A. A. Tranco, R. S. Paton, G.
Pupo, V. Gouverneur, J. Am. Chem. Soc.,
2020, 142, 14045-14051.
A chiral phosphoric acid catalyzes an asymmetric transfer hydrogenation of
trans-chalcones in the presence of pinacolborane as hydride source. This
methodology provides chiral dihydrochalcone derivatives in high yields and with
high enantioselectivities under mild conditions.
F. Na, S. S. Lopez, A. Beauseigneur, L. W. Hernandez, Z. Sun, J. C. Antilla,
Org. Lett., 2020, 22, 5953-5957.
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