Benzoin Condensation

The Benzoin Condensation is a coupling reaction between two aldehydes that allows the preparation
of -hydroxyketones. The first methods were only suitable for the conversion of aromatic aldehydes.

Mechanism of Benzoin Condensation
Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl
charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation: A
thiazolium salt may also be used as the catalyst in this reaction (see Stetter Reaction).

A strong base is now able to deprotonate at the former carbonyl C-atom:

A second equivalent of aldehyde reacts with this carbanion; elimination of the catalyst regenerates the
carbonyl compound at the end of the reaction:


Recent Literature

Lanthanum Tricyanide-Catalyzed Acyl Silane-Ketone Benzoin Additions
J. C. Tarr, J. S. Johnson, Org. Lett., 2009, 11, 3870-3873.

Kinetic Control in Direct -Silyloxy Ketone Synthesis: A New Regiospecific Catalyzed Cross Silyl
Benzoin Reaction
X. Linghu, J. S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534-2536.

Highly Enantioselective Benzoin Condensation Reactions Involving a Bifunctional Protic
Pentafluorophenyl-Substituted Triazolium Precatalyst
L. Baragwanath, C. A. Rose, K. Zeitler, S. J. Connon, J. Org. Chem., 2009, 74, 9214-9217.

An Efficient Nucleophilic Carbene Catalyst for the Asymmetric Benzoin Condensation
D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743-1745.

Highly Chemo- and Enantioselective Cross-Benzoin Reaction of Aliphatic Aldehydes and -
Ketoesters
K. Thai, S. M. Langdon, F. Bilodeau, M. Gravel, Org. Lett., 2013, 15, 2214-2217.

Asymmetric Intramolecular Crossed-Benzoin Reactions by N-Heterocyclic Carbene Catalysis
D. Enders, O. Niemeier, T. Balensiefer, Angew. Chem. Int. Ed., 2006, 45, 1463-1467.


Stetter Reaction

The Stetter Reaction is a 1,4-addition (conjugate addition) of an aldehyde to an a,-unsaturated
compound, catalyzed by cyanide or a thiazolium salt. This reaction competes with the corresponding
1,2-addition, which is the Benzoin Condensation. However, the Benzoin-Condensation is reversible,
and since the Stetter Reaction leads to more stable products, the main product will be derived from
1,4-addition.
Some of the possible products are: 1,4-diketones, 4-ketocarboxylic acids and the corresponding
nitriles.


Mechanism of the Stetter Reaction
The cyanide ion effects an umpolung of the normal carbonyl charge affinity, and the electrophilic
aldehyde carbon becomes nucleophilic after deprotonation:

This in situ generated nucleophile reacts with the unsaturated compound:

The thiazolium salts may be converted into ylides by deprotonation. These ylides are comparable to
the cyanide adducts in their ability to catalyze the Stetter Reaction effectively.

Recent Literature

Catalytic Activation of Carbohydrates as Formaldehyde Equivalents for Stetter Reaction with Enones
J. Zhang, C. Xing, B. Tiwari, Y. R. Chi, J. Am. Chem. Soc., 2013, 135, 8113-8116.

Dynamic Kinetic Resolution of -Keto Esters via Asymmetric Transfer Hydrogenation
K. M. Steward, E. C. Gentry, J. S. Johnson, J. Am. Chem. Soc., 2012, 134, 7329-7332.

Solvent-Free Synthesis of Alkylthiazolium-Based Ionic Liquids and their Use as Catalysts in the
Intramolecular Stetter Reaction
A. Aupoix, G. Vo-Thanh, Synlett, 2009, 1915-1920.

D-Camphor-Derived Triazolium Salts for Enantioselective Intramolecular Stetter Reactions
Z.-Q. Rong, Y. Li, G.-Q. Yang, S.-L. You, Synlett, 2011, 1033-1037.

The First Asymmetric Intramolecular Stetter Reaction
D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899-1902.

A Highly Enantio- and Diastereoselective Catalytic Intramolecular Stetter Reaction
J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289.

A Highly Enantio- and Diastereoselective Catalytic Intramolecular Stetter Reaction
J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289.
Acyloin Condensation

The bimolecular reductive coupling of carboxylic esters by reaction with metallic sodium in an inert
solvent under reflux gives an -hydroxyketone, which is known as an acyloin. This reaction is
favoured when R is an alkyl. With longer alkyl chains, higher boiling solvents can be used. The
intramolecular version of this reaction has been used extensively to close rings of different sizes, e.g.
paracyclophanes or catenanes.

If the reaction is carried out in the presence of a proton donor, such as alcohol, simple reduction of
the ester to the alcohol takes place (Bouveault-Blanc Reduction).
The Benzoin Condensation produces similar products, although with aromatic substituents and under
different conditions.
When the acyloin condensation is carried out in the presence of chlorotrimethylsilane, the enediolate
intermediate is trapped as the bis-silyl derivative. This can be isolated and subsequently is hydrolysed
under acidic condition to the acyloin, which gives a better overall yield.

Mechanism of Acyloin Condensation




Recent Literature

Switching Regioselectivity in Crossed Acyloin Condensations between Aromatic Aldehydes and
Acetaldehyde by Altering N-Heterocyclic Carbene Catalysts
M. Y. Jin, S. M. Kim, H. Han, D. H. Ryu, J. W. Yang, Org. Lett., 2011, 13, 880-883.

Synthesis of acyloins (-hydroxy carbonyl compounds)
Related:



Name Reactions

Acyloin Condensation

Benzoin Condensation

Corey-Seebach Umpolung

Recent Literature

Lanthanum tricyanide efficiently catalyzes a benzoin-type coupling between acyl silanes and ketones.
Good yields are obtained over a broad substrate scope encompassing aryl, alkyl, and sterically
hindered ketones.
J. C. Tarr, J. S. Johnson, Org. Lett., 2009, 11, 3870-3873.

Operationally simple cyanide-catalyzed silyl benzoin reactions afforded unsymmetrical aryl-,
heteroaryl-, and alkyl-substituted silyl ether protected benzoin adducts with complete regiocontrol.
X. Linghu, J. S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534-2536.

A hydrogen bond donating substituent to improve enantiocontrol together with an acidifying
pentafluorophenyl substituent to enhance catalyst efficiency results in a triazolium ion precatalyst that
promotes the asymmetric benzoin condensation with excellent efficiency and unprecedented
enantioselectivity.
L. Baragwanath, C. A. Rose, K. Zeitler, S. J. Connon, J. Org. Chem., 2009, 74, 9214-9217.

The development of a triazolium salt as an efficient precatalyst for the asymmetric benzoin
condensation is described. The high asymmetric inductions in benzoin condensations are a result of
the conformational rigidity of the bicyclic nucleophilic carbene catalyst and the shielding of the
Breslow intermediate by the sterically demanding tert-butyl group.
D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743-1745.

The appropriate choice of N-heterocyclic carbene catalysts enables an unprecedented high level of
regioselectivities in the intermolecular crossed acyloin condensations of various aromatic aldehydes
with acetaldehyde.
M. Y. Jin, S. M. Kim, H. Han, D. H. Ryu, J. W. Yang, Org. Lett., 2011, 13, 880-883.

A one-pot method allows the synthesis of -siloxy-Weinreb amides from aldehydes using N,O-
dimethylhydroxylamine and a masked acyl cyanide reagent bearing a tert-butyldimethylsilyl group.
The TBS group avoids the competitive reaction toward N-methoxy-N-methyl-2-amino-1-
siloxymalononitrile.
H. Nemoto, R. Ma, H. Moriguchi, T. Kawamura, M. Kamiya, M. Shibuya, J. Org. Chem., 2007, 72,
9850-9853.

-Silyloxy--keto esters are prepared through a cyanide-catalyzed benzoin-type reaction with silyl
glyoxylates and aldehydes. A subsequent dynamic kinetic resolution provides enantioenriched
orthogonally protected alcohols, that can be converted to the corresponding -silyloxy--amino esters.
K. M. Steward, J. S. Johnson, Org. Lett., 2010, 12, 2864-2867.

An enantioselective intramolecular crossed-benzoin reaction catalyzed by novel chiral N-heterocyclic
carbenes has been developed. A tetracyclic trazolium salt catalyzes the cyclization with generation of
a quartenary stereocenter in high yields and excellent enantomeric excess.
D. Enders, O. Niemeier, T. Balensiefer, Angew. Chem. Int. Ed., 2006, 45, 1463-1467.

While 3,4;5,6-di-O-isopropylidene-N-phthaloyl-D-glucosamine propane-1,3-diyl dithioacetal underwent
fast -elimination, the corresponding N-acetyl derivative was easily deprotonated with butyllithium to
form the dilithiated intermediate. Stoichiometry and temperature were crucial factors for selective C-C
coupling with various electrophiles.
Y.-L. Chen, R. Leguijt, H. Redlich, R. Frhlich, Synthesis, 2006, 4212-4218.