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Extending Mechanistic Routes in Heterazolium CatalysisЦPromising Concepts for Versatile Synthetic Methods.

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DOI: 10.1002/anie.200502617
Extending Mechanistic Routes in Heterazolium
Catalysis–Promising Concepts for Versatile Synthetic
Kirsten Zeitler*
aldehydes · carbenes · nitrogen heterocycles ·
stereoselective catalysis · umpolung
the development of sustainable
chemical transformations, the discovery
of new, efficient synthetic methods,
especially for carbon–carbon bond formation, remains a great challenge. Organocatalytic processes mediated by
small nucleophilic molecules have
gained in importance enormously over
the last few years.[1] Their benefits
include not only atom economy and
operational simplicity, but also the possibility of nontraditional retrosynthetic
bond disconnections. A powerful example for such a strategy is the inversion of
reactivity of functional groups (umpolung).[2] The catalytic version of this
concept was first discovered in the
context of benzoin reactions[3] and has
ble functional groups have been employed successfully so far to generate
subsequent electrophilic character at the
previously umpoled carbonyl carbon.
The covalent activation of aldehydes
and a-keto acids[6] as acyl anion equivalents through addition of nucleophilic,
heterazolium-derived carbene 2 leads to
the so-called Breslow intermediate 5
Scheme 1. Comparison of classical versus extended heterazolium catalysis.
[*] Dr. K. Zeitler
Institut f*r Organische Chemie
Universit,t Regensburg
Universit,tsstrasse 31
93053 Regensburg (Germany)
Fax: (+ 49) 941-943-4121
[**] The author is indebted to the Fonds der
Chemischen Industrie for a Liebig fellowship.
led together with the extention to the
Stetter reaction to highly valuable asymmetric methods, even for the construction of quaternary stereocenters.[4, 5]
The use of functionalized aldehydes
as donor substrates in N-heterocyclic
carbene (NHC)-catalyzed umpolung reactions opens new mechanistic pathways
and gives rise to new synthetic strategies
(Scheme 1). Alkenes and other reduci-
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
(Scheme 2).[3b, 7] Depending on the kind
of electrophile applied, benzoins or 1,4dicarbonyls 15 (Stetter reaction) are
formed (cycle A).[8]
Based on mechanistic considerations
starting from the nucleophilic alkene 5,
the scope and utility of this umpolung
can be extended by the use of further
functionalized donor substrates that allow the subsequent formation of an acyl
Angew. Chem. Int. Ed. 2005, 44, 7506 – 7510
Scheme 2. Mechanistic considerations for extended reaction pathways.
azolium species, i.e. activated carboxylates 7 and 10. This key intermediate can
be formed by means of an internal redox
reaction (cycle B) from a-heteroatomic
aldehydes, such as a-halo aldehydes[11]
and a,b-epoxy aldehydes[12] 5-B by elimination of the leaving group Y through
enol 6 followed by isomerization to give
the corresponding acyl azolium tautomer 7. Alternatively, the acyl azolium
species arises from a,b-unsaturated aldehydes via a conjugated (“vinylogous”)
acyl anion equivalent 5-C (cycle C).[11]
This homoenolate 5-C can undergo
electrophilic trapping with subsequent
tautomerization to form the pivotal
catalyst-bound activated ester 10. Reaction with appropriate nucleophiles (inter- or intramolecular) yields carboxylic
acid derivatives 8 or 11, and regenerates
the catalyst 2.
Bode et al. recently developed a
direct stereoselective, catalytic method
Angew. Chem. Int. Ed. 2005, 44, 7506 – 7510
for the generation of anti-b-hydroxy
esters from epoxy aldehydes using thiazolium precatalysts.[12] Aromatic and
aliphatic epoxy aldehydes 16 react with
alcohols to provide the desired esters 18
in good yield and stereoselectivity under
mild conditions (Scheme 3). If one considers reaction pathway B (Scheme 2),
the activated carboxylate 7 is formed by
an epoxide-opening step from intermediate 5-B. The synthesis of N-tosylb-amino esters from a,b-aziridinyl-
aldehydes under similar conditions
greatly extends the scope of this esterification approach.
Concurrently, Rovis et al. found that
secondary and tertiary a-halo aldehydes
provide access to dehalogenated acyl
azolium species 7 (Scheme 2, pathway
B) catalyzed by thiazolium- or triazolium-derived nucleophilic carbenes.[11]
The possible nucleophiles for the interception of these acylation agents range
from primary and secondary alcohols
Scheme 3. Stereoselective synthesis of b-hydroxy esters from epoxy aldehydes. Bn = benzyl.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 4. Desymmetrization of meso diols.
(with tolerance of epimerizable stereocenters) to phenols
and anilines. The use of chiral
triazolium catalyst 21 allows
the desymmetrization of meso
diols 20 (Scheme 4). Interestingly, although they used reacScheme 5. Organocatalyzed conjugate umpolung for the
tion conditions similar to those synthesis of g-butyrolactones. Reaction conditions:
for benzoin reactions, neither a) R1 = Ph; R2 = H; R3 = Br, CO2Me; 8 mol % IMes·HCl,
Bode nor Rovis could observe 7 mol % DBU, THF/tBuOH 10:1, > 79 %, d.r. > 4:1.
the formation of significant b) R1 = Ph; R2 = CF3 ; R3 = H. 5 mol % IMes·HCl, 10 mol %
amounts of the corresponding KOtBu, THF, 84 %, d.r. 2:1. Mes = 2,4,6-trimethylphenyl,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
benzoin or acyloin products.
The synthetic utility of
the conjugated umpolung
(Scheme 2, cycle C) as an alternative diastereomeric ratio of 3:1 (like/unlike)
pathway in heterazolium catalysis was with 12 % and 25 % ee.[13b]
illustrated by Bode et al.[13a] and Glorius
The scope of the nucleophile-cataet al.,[13b] who independently developed lyzed generation of homoenolates from
a direct, organocatalytic annulation of a,b-unsaturated aldehydes was only reenals 23 with aldehydes 24. Under cently extended by Bode et al.[14] In a
remarkably mild conditions the stereo- mechanistically similar process using
selective synthesis of g-butyrolactones imines as the electrophilic partner, the
25 was achieved in a flexible one-step direct annulation of enals 23 with N-4process via homoenolate intermediates methoxybenzenesulfonylimines 26 folgenerated by sterically demanding imi- lowed by cyclization led to disubstituted
dazolium ylides as catalysts (Scheme 5). g-lactams 27 in good yield and good
The conjugated acyl anion equivalent 5- to moderate diastereomeric ratios
C couples with an aldehyde to yield an (Scheme 6). It has to be noted that there
alkoxide intermediate, which is trapped is only a narrow range of suitable imine
intramolecularly by the catalyst-bound substrates (e.g. electron-rich N-sulfonyl
activated ester. A survey of different imines) as they compete to react with
catalysts showed the high preference for nucleophilic catalyst. This one-pot proimidazolium salts; thiazolium precur- cedure provides a fast access to the
sors proved to be inefficient. Whereas important class of g-butyrolactams, and
a wide range of enals can be used as the by nucleophilic ring-opening with alknucleophile, the electrophilic partner oxides g-amino acid derivatives are
has been limited to aromatic aldehydes readily available.
and trifluoromethylaryl ketones. The
configuration of the product is preferrably cis (d.r. up to 5:1), but the
stereochemical outcome is influenced
by substrate, reaction conditions, and
catalyst structure. The generation of
quaternary stereocenters from ketone
electrophiles was catalyzed by a tricyclic
imidazolium-derived NHC to give a
Scheidt et al. have shown that the
reactivity of these NHC-generated homoenolates is not restricted to the
coupling with aldehydes and imines as
electrophiles and the subsequent intramolecular nucleophilic attack of the
resulting heteroanions (alkoxides and
amides, respectively) on the acyl azolium species.[13c] The electrophilic and
nucleophilic partners could be decoupled by using phenol derivatives as the
proton source in combination with DBU
and imidazolium salts in the presence of
a second alcohol as nucleophile. In this
context, Bode et al. only very recently
reported on the product-determining
effect of the base for the subsequent
reactions of catalytically generated homoenolates 5-C.[13d] While strong bases
such as KOtBu predominately lead to
carbon–carbon bond formation, the use
of weaker bases acting as a catalytic
proton shuttle promotes in situ protonation of the homoenolate without an
additional proton source (Scheme 7).
amounts of the triazolium precatalyst
28, which is more readily deprotonated
than other NHC precursors, leads to the
catalytic, atom-economical redox esterification of a wide variety of enals 23
with alcohols R2OH as nucleophiles in
good to high yields (Scheme 7; optimized conditions).
Whereas the use of classical nitrogen-based nucleophiles (e.g. sulfonamides, azides, anilines) under ScheidtAs
conditions seems to be difficult in the
complex balance of acid and base in this
process, the use of chiral imidazolium
salts allows enantiodiscrimination. With
the participation of a chiral activated
ester as a possible intermediate, the
organocatalytic kinetic resolution of
racemic 1-phenylethanol (31) was achieved with cinnamaldehyde (32)
(Scheme 8).
In situ generated N-heterocyclic carbenes are also potent catalysts for trans-
Scheme 6. Organocatalytic direct annulation to give g-lactams. R1 = Ph, Ar; R2 = Ar, alkenyl.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7506 – 7510
Scheme 7. Product-determining role of the base in the catalytic redox esterification.
Scheme 8. Kinetic resolution of secondary alcohols by a discriminating homoenolate intermediate.
Scheme 9. Enantioselective acylation of secondary alcohols with N-heterocyclic carbenes.
esterifications[15] and ring-opening polymerization reactions. In these related
processes, similarily activated carboxylates, formed from NHCs and ester or
lactone precursors, are thought to be the
pivotal intermediates.[16] An application
of this concept to a nonenzymatic kinetic resolution has been published
recently.[17, 18] Chiral imidazolylidene
catalysts 36 mediate a highly enantioselective transesterification of racemic
secondary alcohols with vinyl esters
amounts of base (Scheme 9).[18]
Not only the synthetic utility of the
accessible products, but also the unique
reactivity of these catalytically generated nucleophilic precursors and their
should motivate chemists for further
novel developments on this versatile
mechanistic platform. Deeper insights
into the mechanism and the possible
Angew. Chem. Int. Ed. 2005, 44, 7506 – 7510
combinations of electrophiles and nucleophiles should smooth the way for
useful applications and further innovations in carbene-catalyzed reactions.
These versatile concepts and the ample
scope of possible substrates may lead to
the catalytic, enantioselective, and sustainable synthesis of highly valuable,
multifunctionalized molecules.
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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