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 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.
Tropylium salts promote the hydroboration reaction of alkynes to provide a
broad range of vinylboronates. Similar metal-free hydroboration reactions of
alkenes and epoxides can also be efficiently catalyzed by the same tropylium
catalysts. Experimental studies and DFT calculations suggested that the reaction
is triggered by the hydride abstraction of pinacolborane with tropylium ion.
N. N. H. Ton, B. K. Mai, T. V. Nguyen, J. Org. Chem., 2021, 86,
9117-9133.
A chiral triazole-substituted iodoarene catalyzes an enantioselective
oxidative cyclization of N-allyl carboxamides to provide highly
enantioenriched oxazolines and oxazines. Quaternary stereocenters can be
constructed and, besides N-allyl amides, the corresponding thioamides and
imideamides are well tolerated as substrates.
A. H. Abazid, T.-N. Hollwedel, B. J. Nachtsheim, Org. Lett., 2021, 23,
5076-5080.
N,O-Acetals derived from α,β-unsaturated β-aryl substituted aldehydes
and (1-aminocyclohexyl)methanol undergo a catalytic enantioselective [2 + 2]
cycloaddition to a variety of olefins under visible light irradiation (λ = 459
nm). The photocycloaddition is catalyzed by a chiral phosphoric acid with
thioxanthone moieties for a facile triplet energy transfer.
F. Pecho, Y. Sempere, J. Gramüller, F. M. Hörmann, R. M. Gschwind, T. Bach, J. Am. Chem. Soc.,
2021, 143, 9350-9354.
Planar chiral [2.2]paracyclophane-based isothiourea catalysts catalyze a
highly efficient enantioselective fluorination of carboxylic acids to provide a
broad range of optically active α-fluoroesters in high yield and excellent
enantioselectivity.
S. Yuan, C. Liao, W.-H. Zheng, Org. Lett., 2021, 23,
4142-4146.
Depending on the Lewis base catalyst, a Michael addition of
α-aminonitriles to simple activated alkenes provides functionalized γ-amino acid
esters or γ-lactams. The scope,
versatility, and efficiency of the methods were demonstrated.
Z.-Y. He, H.-C. Jang, L.-S. Teng, Z.-L. Wei, W.-W. Liao, Synthesis, 2021, 53,
1833-1841.
Using a cinchona squaramide-based organocatalyst, an enantioselective
intramolecular oxa-Michael reaction of enones as well as α,β-unsaturated esters
containing benzylic alcohols provided their corresponding
1,3-dihydroisobenzofuranyl-1-methylene ketones and
1,3-dihydroisobenzofuranyl-1-methylene esters in excellent yields with high
enantioselectivities.
E. C. Son, S. Y. Kim, S.-G. Kim, J. Org. Chem., 2021, 86,
6826-6839.
4-Dimethylaminopyridine (DMAP) catalyzes a single-step preparation of
nitrones from benzyl halides and nitrosoarenes under mild reaction conditions.
The reaction provides both keto- and aldonitrones in good yields. As an
application of the reaction, methyl 2-bromo-2-phenylacetate was used to prepare
the corresponding isoxazolidine by a sequential one-pot synthesis.
Y. Jung, J. E. Hong, J.-H. Kwak, Y. Park, J. Org. Chem., 2021, 86,
6343-6350.
A metal-free C(sp3)-H aroylation of amines via visible-light
photoredox catalysis provides useful α-amino aryl ketones. A series of
experiments indicate that this transformation undergoes a photoredox catalytic
radical-radical cross-coupling pathway.
G.-Q. Xu, T.-F. Xiao, G.-X. Feng, C.-Liu, B. Zhang, P.-F. Xu, Org. Lett., 2021, 23,
2846-2852.
[DCPP]n aggregates can act as a versatile visible-light
photocatalyst in decarboxylative C-C cross-coupling, amidation, and
esterification reactions. In these reactions, [DCPP]n aggregates were formed in
situ through physical π-π stacking of DCPP monomers in organic solvents.
M. He, X. Yu, Y. Wang, F. Li, M. Bao, J. Org. Chem., 2021, 86,
5016-5025.
Direct α-C-H acylation of various alkenes with aroyl fluorides using NHC,
sulfinate, and photoredox cooperative triple catalysis provides α-substituted
vinyl ketones in good yields with excellent functional group tolerance.
K. Liu, A. Studer, J. Am. Chem. Soc.,
2021, 143, 4903-4909.
Trifluoroacetone catalyzes a mild and operationally simple epoxidation of
various alkens in good yields using hydrogen peroxide as primary oxidant at high
pH. The use of H2O2 as oxidant significantly reduces the
amount of solvent and salts introduced.
L. Shu, Y. Shi, J. Org. Chem., 2000,
65, 8807-8810.
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.
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