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
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.
An organophotoredox-catalyzed oxidative coupling enables a general and practical C-H amination of 2H-indazoles with a series of amines including aliphatic primary amines, secondary amines,
azoles, and sulfoximines at room temperature under ambient air conditions.
S. Neogi, A. K. Ghosh, K. Majhi, S. Samanta, G. Kibriya, A. Hajra,
Org. Lett., 2020, 22, 5605-5609.
A zwitterion-catalyzed intermolecular bromoesterification of alkenes works
with acid and olefin in an equimolar ratio. Mechanistic study revealed that the
charge pair in the zwitterion works synergistically in activating both NBS and
carboxylic acid.
W.-H. Ng, R.-B. Hu, Y.-P. Lam, Y.-Y. Yeung,
Org. Lett., 2020, 22, 5567-5571.
An oxidative deprotection of p-methoxy benzyl (PMB) ethers was
achieved using a nitroxyl radical catalyst with electron-withdrawing ester
groups adjacent to the nitroxyl group in the presence of 1 equiv of PIFA as
co-oxidant. The corresponding carbonyl compounds were obtained in the presence
of an excess of PIFA.
S. Hamada, K. Sugimoto, E. E. Elboray, T. Kawabata, T. Furuta,
Org. Lett., 2020, 22, 5486-5490.
β-Turn tetrapeptides catalyze asymmetric aldol reactions of α-branched
aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to
provide acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high
yield and excellent enantioselectivity under mild conditions.
Z.-H. Du, B.-X. Tao, M. Yuan, W.-J. Qin, Y.-L. Xu, P. Wang, C.-S. Da,
Org. Lett., 2020, 22, 4444-4450.
DBU catalyzes a sequence of 1,4-conjugate addition of water to alkynyl o-quinone
methide (o-AQM), followed by an alkyne-allene isomerization and
subsequent intramolecular oxa-Michael addition to provide a broad range
of flavanones in very good yields with good functional-group tolerance.
X. He, M. Xie, R. Li, P. Y. Choy, Q. Tang, Y. Shang, F. Y. Kwong,
Org. Lett., 2020, 22, 4306-4310.
A nucleophilic activation of elemental sulfur by thiols enables a mild and
chemoselective thioacylation of amines with α-keto acids and elemental sulfur.
The reaction tolerates a broad range of functional groups, including unprotected
hydroxyl, carboxyl, amide, sulfide, and tertiary amine moieties.
M. Saito, S. Murakami, T. Nanjo, Y. Kobayashi, Y. Takemoto, J. Am. Chem. Soc.,
2020, 142, 8130-8135.
A (thio)urea cocatalyst accelerates O-monoacyltartaric acid (MAT)-catalyzed
enantioselective conjugate additions of boronic acid to unsaturated ketone.
T. Yoshimitsu, Y. Kuboyama, S. Nishiguchi, M. Nakajima, M. Sugiura,
Org. Lett., 2020, 22, 3780-3784.
A structurally simple and easily accessible l-proline derived aminocatalyst
provides 2-alkyl/aryl-3-nitro-2H-chromenes in excellent
enantioselectivity within a short reaction time via an asymmetric tandem
oxa-Michael-Henry reaction of salicylaldehyde with conjugated nitroalkene.
R. Mohanta, G. Bez, J. Org. Chem., 2020, 85,
4627-4636.
Iodobenzene catalyzes an oxidative cyclization of Michael adducts of activated
methylene compounds with nitroolefins or chalcones in the presence of mCPBA as
terminal oxidant together with Bu4NI to provide a range of highly
functionalized cyclopropanes with high diastereoselectivities.
Y. Li, H. Guo, R. Fan, Synthesis, 2020, 52,
928-932.
Peri-xanthenoxanthene mediates a reaction of an iododifluoromethylphosphonium
salt with unactivated alkenes under blue-light irradiation. This
iododifluoromethylation proceeds via activation of the carbon-iodine bond to
generate a (phosphonio)difluoromethyl radical cation, which attacks the double
bond with subsequent quenching by the iodine.
A. L. Trifonov, L. I. Panferova, V. V. Levin, V. A. Kokorekin, A. D. Dilman,
Org. Lett., 2020, 22, 2409-2413.
Diarylprolinol silyl ether catalyzes an asymmetric enantioselective domino
oxa-Michael-Mannich-[1,3]-amino rearrangement reaction of N-tosylsalicylimines
with a wide range of α,β-unsaturated aldehydes to produce the corresponding
chair N-tosylimines-chromenes with excellent enantioselectivity and yield. The
reaction tolerates a range of functional groups.
S. Hu, J. Wang, G. Huang, K. Zhu, F. Chen, J. Org. Chem., 2020, 85,
4011-4018.
A diaminomethylenemalononitrile catalyzes an asymmetric 1,4-addition of
phosphonates to trans-crotonophenone and chalcone derivatives to provide
chiral γ-ketophosphonates in high yields with excellent enantioselectivities.
R. Arai, S.-i. Hirashima, T. Nakano, M. Kawada, H. Akutsu, K. Nakashima, T.
Miura, J. Org. Chem., 2020, 85, 3872-3878.
Eosin Y catalyzes a visible-light-promoted C2 selective arylation of quinoline and
pyridine N-oxides with diaryliodonium tetrafluoroborate as an arylation reagent under mild conditions. This methodology
offers high regioselectivity, simple operation and good functional group tolerance.
D. Li, C. Liang, Z. Jiang, J. Zhang, W.-T. Zhuo, F.-Y. Zou, W.-P. Wang, G.-L.
Gao, J. Song, J. Org. Chem., 2020, 85,
2733-2742.
A visible-light photocatalytic aerobic oxidative lactonization of arene C(sp2)-H
bonds provides benzocoumarin derivatives in good yields in the presence of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone and tert-butyl nitrite. This
atom economic method offers mild reaction conditions, use of a green oxidant and
metal-free catalysis.
Y. Wang, S. Wang, B. Chen, M. Li, X. Hu, B. Hu, L. Jin, N. Sun, Z. Shen, Synlett, 2020,
31,
261-266.
The energetic limitations of visible light can be circumvented by
electrochemically priming a photocatalyst prior to excitation. This method
enables the use of aryl chlorides with reduction potentials hundreds of
millivolts beyond the potential of Na0 in carbon-carbon and
carbon-heteroatom bond-forming reactions.
N. G. W. Cowper, C. P. Chernowsky, O. P. Williams, Z. K. Wickens, J. Am. Chem. Soc.,
2020, 142, 2093-2099.
A general, metal-free visible light-induced photocatalytic borylation
platform enables borylation of electron-rich derivatives of phenols and
anilines, chloroarenes, as well as other haloarenes in the presence of
phenothiazine as photocatalyst. The reaction exhibits excellent functional group
tolerance.
S. Jin, H. T. Dang, G. C. Haug, R. He, V. D. Nguyen, V. T. Nguyen, H. D. Arman, K. S. Schanze, O. V. Larionov, J. Am. Chem. Soc.,
2020, 142, 1603-1613.
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