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
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.
L-proline as a catalyst enables a simple and efficient route for the synthesis
of a series of 5-substituted 1H-tetrazoles from a broad range of
substrates, including aliphatic and aryl nitriles, organic thiocyanates, and
cyanamides. This environmentally benign, cost effective, and high-yielding
L-proline-catalyzed protocol offers simple experimental procedure, short
reaction time, simple workup, and excellent yields.
S. B. Bhagat, V. N. Telvekar,
Synlett, 2018, 29, 874-879.
Iminium catalysis of the challenging Morita-Baylis-Hillman reaction of
cyclopenten-2-one provides allylic alcohols in excellent yields. Experimental
evidence shows that secondary amines act as co-catalysts activating the enone
moiety towards the nucleophilic attack at the β-position by DABCO as the Lewis
base catalyst.
R. Innocenti, G. Menchi, A. Trabocchi,
Synlett, 2018, 29, 820-824.
Trialkylphosphines catalyze a regioselective anti-hydroboration of
internal alkynes with pinacolborane reagents to provide (E)-disubstituted
alkenylboronate compounds. The alkenylboronates can be used for derivatizations,
such as protodeborylations, Suzuki-Miyaura couplings, conjugate reductions, and
Diels-Alder reactions.
K. Nagao, A. Yamazaki, H. Ohmiya, M. Sawamura, Org. Lett.,
2018, 20, 1861-1865.
Asymmetric Michael addition-lactonization reactions of β,γ-unsaturated α-keto
esters with thioesters catalyzed by a proline-derived urea provide
3,4-dihydropyranones and spiro-3,4-dihydrocoumarin-fused 3′,4′-dihydropyranones
in high yield with excellent stereoselectivities via bioinspired S-to-O
acyl-transfer reactions.
H. Jin, J. Lee, H. Shi, J. Y. Lee, E. J. Yoo, C. E. Song, D. H. Ryu, Org. Lett.,
2018, 20, 1584-15888.
Photocatalysis enables the construction of 3-acyl-4-arylcoumarins in good yields
from simple aldehydes and ynoates in the presence of inexpensive 2-tBu-anthraquinone
as catalyst. The reaction proceeds through generation of an acyl radical
intermediate, that reacts with ynoate, and then cyclization.
K. Kawaai, T. Yamaguchi, E. Yamaguchi, S. Endo, N. Tada, A. Ikari, A. Itoh, J. Org. Chem., 2018, 83,
1988-1996.
An N-heterocyclic carbene-catalyzed oxidative LUMO activation of the β-cabons of
saturated carboxylic esters enables an efficient asymmetric access to lactams
and lactones. The method introduces functional groups at the typically inert
β-sp3 carbons of saturated esters. The use of HOBt as an additive
improves both yields and enantioselectivities of the reactions.
B. Liu, W. Wang, R. Huang, J. Yan, J. Wu, W. Xue, S. Yang, Z. Jin, Y. R. Chi, Org. Lett.,
2018, 20, 260-263.
An isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of
various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols
proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium
intermediates, followed by an enantioselective formation of a seven-membered
ring. This method enables a facile and divergent synthesis of optically active
2- and 3-substituted 1,5-benzothiazepines.
Y. Fukata, K. Yao, R. Miyaiji, K. Asano, S. Matsubara, J. Org. Chem.,
2017, 82, 12655-12668.
Tetraarylphosphonium salts (TAPS) catalyze the [3 + 2] coupling reaction of
isocyanates and epoxides to provide a range of oxazolidinones, including
enantioenriched N-aryl-substituted oxazolidinones. These Brønsted acid/halide
ion bifunctional catalysts accelerate epoxide ring opening with high
regioselectivity.
Y. Toda, S. Gomyou, S. Tanaka, Y. Komiyama, A. Kikuchi, H. Suga, Org. Lett.,
2017, 19, 5786-5789.
Bioinspired ortho-quinone catalysts have been applied to oxidative
synthesis of benzimidazoles, quinoxalines and benzoxazoles from primary amines
in high yields under mild conditions with oxygen as the terminal oxidant.
R. Zhang, Y. Qin, L. Zhang, S. Luo, Org. Lett.,
2017, 19, 5629-5632.
1,2,4,3-triazaphospholenes halides catalyze the 1,2 hydroboration of imines and
α,β unsaturated aldehydes with pinacolborane, including examples that did not
undergo hydroboration by previously reported diazaphospholene systems. DFT
calculations support a mechanism where a triazaphospholene cation interacts with
the substrate.
C.-H. Tien, M. R. Adams, M. J. Ferguson, E. R. Johnson, A. W. H. Speed, Org. Lett.,
2017, 19, 5565-5568.
Please cite and link this page as follows:
Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )
