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 N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction
enables a transition-metal-free and mild cross-dehydrogenative coupling of
2-cinnamoyl benzaldehydes to provide 2-aryl naphthoquinones. The intramolecular
Stetter reaction is followed by an aerobic oxidation to reinstall the C-C double
bond.
A. Ghosh, A. Patra, S. Mukherjee, A. T. Biju, J. Org. Chem., 2019, 84,
1103-1110.
A mild, late-stage conversion of primary sulfonamides to several other other
functional groups occurs via initial reductive deamination of sulfonamides to
sulfinates via an NHC-catalyzed reaction of transiently formed N-sulfonylimines.
This method tolerates common functional groups, as exemplified by the late-stage
derivatization of several complex pharmaceutical compounds.
P. S. Fier, K. M. Maloney, J. Am. Chem. Soc.,
2019,
141, 1441-1445.
C2-symmetric
chiral-substituted 1,16-dihedroxytetraphenylenes (DHTP) were used as organocatalysts in asymmetric allylboration
of ketones under very mild conditions. Several tertiary alcohols
were isolated in good yields with high ees.
G.-L. Chai, B. Zhu, J. Chang, J. Org. Chem., 2019, 84,
120-127.
A N-heterocycle carbene (NHC)-catalyzed dual Stetter cascade reaction
enables a coupling of β-nitrostyrene with phthalaldehyde under mild conditions
to furnish valuable aryl-naphthoquinones, whereas the reaction of
salicylaldehydes with β-nitrostyrene provides functionalized
dihydroisoflavanones.
R. N. Mitra, K. Show, D. Barman, S. Sarkar, D. K. Maiti, J. Org. Chem., 2019, 84,
42-52.
A N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of
aldimines generated from 2-amino phenols and aromatic aldehydes provides
2-arylbenzoxazoles in good yields under mild conditions. The reaction tolerates
a broad range of functional groups.
A. Patra, A. James, T. K. Das, A. T. Biju, J. Org. Chem., 2018, 83,
14820-14826.
An N-heterocyclic carbene (NHC) organocatalytic aerobic oxidation of aldehydes
provides the corresponding carboxylic acids under mild reaction conditions.
Remarkably, this method enables an efficient conversion of different classes of
aldehydes including highly challenging electron-rich aryl aldehydes, ortho-substituted
aryl aldehydes, various heteroaromatic aldehydes and α,β-unsaturated aldehydes.
A. K. Khatana, V. Singh, M. K. Gupta, B. Tiwari, Synthesis, 2018, 50,
4290-4294.
Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes
V. K. R. Garapati, M. Gravel, Org. Lett.,
2018, 20, 6372-6375.
A chiral phosphoric acid as the sole catalyst enables an enantioselective synthesis
of
tetrahydroquinolines from 2-aminochalcones via chiral phosphoric acid-catalyzed
dehydrative cyclization, followed by chiral phosphoric acid-catalyzed asymmetric
reduction with Hantzsch ester. Various 2-aminochalcones could be applicable to
this protocol, and the desired tetrahydroquinolines were obtained in excellent
yields and with excellent enantioselectivities.
D. Y. Park, S. Y. Lee, J. Jeon, C.-H. Cheon, J. Org. Chem., 2018, 83,
12486-12495.
Chiral task-specific ionic liquids bearing chiral
anions as the catalysts enable an enantioselective multicomponent Biginelli
reaction. A combined role of asymmetric
counteranion-directed catalysis (ACDC) and ionic liquid effect (ILE) for the
chiral induction in the Biginelli multicomponent reaction is demonstrated.
H. G. O. Alvim D. L. J. Pinheiro, V. H. Carvalho-Silva, M. Fioramonte, F. C.
Gozzo, W. A. da Silva, G. W. Amarante, B. A. D. Neto, J. Org. Chem., 2018, 83,
12143-12153.
A reaction of diphenyl carbonate and various diols provides highly valuable cyclic carbonates
in the presence of
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as organocatalyst. This practical, safe, and highly efficient carbonylation system
successfully
replaced highly toxic and unstable phosgene or its derivatives while maintaining
the desired high reactivity. Moreover, this new system can be used to synthesize
sterically demanding cyclic carbonates.
E. R. Baral, J. H. Lee, J. G. Kim, J. Org. Chem., 2018, 83,
11768-11776.
The use of a cation-binding oligoEG catalyst and KF as the base enables a highly
enantioselective cycloetherification for the straightforward synthesis of
enantioenriched tetrahydrofurans, tetrahydropyrans, and oxepanes from ε-, ζ-,
and η-hydroxy-α,β-unsaturated ketones.
A. P. Jadhav, J.-A Oh, I.-S. Hwang, H. Yan, C. E. Song, Org. Lett.,
2018, 20, 5319-5322.
A series of charge-containing thiourea salts catalyze cycloadditions of
epoxides with CO2 under mild conditions to provide cyclic
five-membered ring organic carbonates of broad interest from a synthetic,
environmental, and green chemistry perspective.
Y. Fang, M. Tiffner, J. Schörgenhumer, R. Robiette, M. Waser, S. R. Kass, J. Org. Chem., 2018, 83,
9991-10000.
(Bis(dimethylamino)carbazole) was used as photocatalyst in the reduction of
unactivated aryl chlorides and alkyl chlorides in the presence of CHD as
hydrogen atom donor at room temperature. The catalytic system can also be
applied to the coupling of aryl chlorides with electron-rich arene and
heteroarenes to affect C-C bond-forming reactions.
R. Matsubara, T. Yabuta, U. M. Idros, M. Hayashi, F. Ema, Y. Kobori, K. Sakata, J. Org. Chem., 2018, 83,
9381-9390.
An anthraquinone-catalyzed photooxidative keto-trifluoromethylation of
styrenes with the readily available Langlois reagent (CF3SO2Na)
under an oxygen atmosphere proceeds smoothly to give α-trifluoromethyl ketones
in good yield with good selectivity.
E. Yamaguchi, Y. Kamito, K. Matsuo, J. Ishihara, A. Itoh, Synthesis, 2018, 50,
3161-3168.
A mild and metal-free multi-component reaction enables the synthesis of
4,5-disubstituted 1H-1,2,3-triazoles from phosphonium salts, aldehydes,
and sodium azide. An organocatalyzed coupling of the formyl group with the
phosphonium group provides an olefinic phosphonium salt as key intermediate,
that undergoes [3+2] cycloaddition with the azide.
G.-L. Wu, Q.-P. Wu, Synthesis, 2018, 50,
2768-2774.
A N-heterocyclic carbene (NHC)-catalyzed trifluoromethylation of α-chloro
aldehydes provides valuable α-trifluoromethyl ester derivatives in good yields.
The unique combination of an electrophilic trifluoromethylation reagent with NHC
catalysis was the key for the functionalization of a broad range of substrate.
An enantioselective version of this reaction afforded products in moderate
yields with good ee values.
F. Gelat, A. Patra, X. Pannecoucke, A. T. Biju, T. Poisson, T. Besset, Org. Lett.,
2018, 20, 3897-3901.
A three-component reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2
as sulfur dioxide surrogate, and alkenes under photocatalysis provides diverse
sulfones in very good yields at room temperature. This reaction works
efficiently under mild conditions via generation of alkyl and alkylsulfonyl
radicals as key intermediates, and a reductive single-electron transfer.
T. Liu, Y. Li, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett.,
2018, 20, 3605-3608.
A practical nucleophilic substitution of alcohols furnishes alkyl chlorides,
bromides, and iodides under stereochemical inversion in the presence of
diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride
as a reagent. Moreover, acetyl chloride has been used as a stoichiometric
promotor in an invertive SN-type transformation for the first time.
T. Stach, J. Dräger, P. H. Huy, Org. Lett.,
2018, 20, 2980-2983.
An enantioselective decarboxylative alkylation of β-keto acids, followed by
sequential cyclization and dehydration, enables an efficient asymmetric
synthesis of useful 2,4-diaryl-1-benzopyrans in good yields and high
enantioselectivities . This one-pot, two-step sequence offers a facile way to
prepare chiral 2,4-diaryl-1-benzopyran derivatives and tolerates a wide range of
functional groups.
H. J. Jeong, D. Y. Kim, Org. Lett.,
2018, 20, 2944-2947.
Scope and Mechanism of a True Organocatalytic Beckmann Rearrangement with a
Boronic Acid/Perfluoropinacol System under Ambient Conditions
X. Mo, T. D. R. Morgan, H. T. Ang, D. G. Hall, J. Am. Chem. Soc.,
2018,
140, 5264-5271.
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