Isolable analogues of the Breslow intermediate derived from chiral triazolylidene carbenes

Article abstract of DOI:10.1021/ja302031v

Since Breslow's initial report on the thiamine mode of action, the study of catalytic acyl carbanion processes has been an area of immense interest. With the advent of azolylidene catalysis, a plethora of reactivtiy has been harnessed, but the crucial nucleophilic intermediate proposed by Breslow had never been isolated or fully characterized. Herein, we report the isolation and full characterization of nitrogen analogues of the Breslow intermediate. Both stable and catalytically relevant, these species provide a model system for the study of acyl carbanion and homoenolate processes catalyzed by triazolylidene carbenes.

Full text of DOI:10.1021/ja302031v

Communication
pubs.acs.org/JACS
Isolable Analogues of the Breslow Intermediate Derived from Chiral
Triazolylidene Carbenes
Daniel A. DiRocco, Kevin M. Oberg, and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
Scheme 1. Breslow’s Proposed Thiamine Mode of Action
ABSTRACT: Since Breslow’s initial report on the
thiamine mode of action, the study of catalytic acyl
carbanion processes has been an area of immense interest.
With the advent of azolylidene catalysis, a plethora of
reactivtiy has been harnessed, but the crucial nucleophilic
intermediate proposed by Breslow had never been isolated
or fully characterized. Herein, we report the isolation and
full characterization of nitrogen analogues of the Breslow
intermediate. Both stable and catalytically relevant, these
species provide a model system for the study of acyl
carbanion and homoenolate processes catalyzed by
triazolylidene carbenes.
carbenes can be alkylated with alkyl bromides, leading to the
formation of ene-diamines.7 While these reports have provided
ature has long been a source of inspiration for the
N
development of chemical synthesis. The understanding of
enormous insight, they have neither confirmed nor debunked
the existence of the species in question due to their lack of
catalytic relevance in acyl-carbanion processes. Importantly,
these intermediates are formed irreversibly and do not lead to
catalyst release, and thus, one questions their relevance to
catalysis in either a biological or a chemical setting.
biological processes has, in many cases, led to the direct
realization of modern chemical reactions. One captivating
example pertains to the mode of action of thiamine
pyrophosphate, a coenzyme in a variety of biological processes
responsible for vital functions in life.1 Thiamine is thus an
essential vitamin in humans and deficiency is associated with
diseases such as beriberi and Wernicke-Korsakoff syndrome.2
The common thread in these processes is the formation of an
acyl-carbanion equivalent, which is responsible for thiamine’s
unique mode of action. In 1958, Breslow disclosed his work
pertaining to the thiamine mode of action, in which he showed
the thiazolium moiety to be responsible for its unique activity,
not the amino group which had been proposed previously.3 On
the basis of his mechanistic studies, Breslow described that the
thiazolium moiety could be deprotonated under relatively mild
conditions, forming an ylide or carbene. Reaction of this active
species with a pyruvic acid unit in biological systems, or an
aldehyde, would then lead to a nucleophilic enaminol as the
relevant carbanion equivalent, similar to Lapworth’s originally
proposed mechanism of the cyanide catalyzed benzoin reaction
(Scheme 1).4 Unfortunately, Breslow was not able to isolate
this proposed intermediate.
With a renaissance in azolylidene catalysis of organic
reactions in recent years, much effort has been expended
searching for this intermediate, and until recently, no structural
information had been disclosed.5 Berkessel, Teles, and co-
workers have reported an investigation of the Breslow
intermediate derived from a triazolylidene carbene,6 but after
extensive investigation, only the keto-form could be identified
spectroscopically. Most recently, Jacobi von Wangelin and co-
workers have shown that more nucleophilic imidazolylidene
Triazolylidene carbenes have proven to be workhorses for
asymmetric N-heterocyclic carbene (NHC) catalyzed trans-
formations, potentially due to their similarities to thiazolylidene
carbenes.8 We were interested in identifying isolable
intermediates derived from our family of chiral triazolylidene
carbenes to more closely study both their formation and
fundamental reactivity. Because of the proven difficulty in
isolating aldehyde-derived Breslow intermediates, we hypothe-
sized that the enol moiety may be responsible for the inherent
transient nature of this species. We envisioned that if the enol
were replaced with a more chemically inert but electronically
similar group,9 a relevant longer-lived intermediate may result.
To that end, we identified iminium ion electrophiles, which
should react analogously to aldehydes producing a Breslow
intermediate with similar reactivity but lacking the acidic X−H
bond (Scheme 2).10 As a further design element, we realized
that the crystallinity of these intermediates would be crucial and
structures that could limit degrees of freedom may increase the
chance for isolation.
With this in mind, we reacted highly crystalline NHC
precatalyst 1 with iminium salt 2 in the presence of Hunig’s
̈
base (Figure 1). After resting undisturbed for 12 h, a yellow
material crystallized from the reaction mixture. Analysis by X-
Received: March 7, 2012
Published: March 28, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
Scheme 2. Intermediates in NHC Catalysis
Scheme 3. Catalytic Activity of Aza-Breslow Intermediate 3
result confirms the relevance of this type of structure as a
precatalyst for NHC catalyzed reactions.12
While Breslow analogue 3 is a good model system for acyl
anion reactivity, we were also interested in probing the
homoenolate reactivity commonly displayed with chiral
triazolylidene carbenes.13,14 Subjection of triazolium salt 1 to
cinnamaldehyde derived iminium salt 6 leads to the generation
of another yellow crystalline solid. X-ray analysis confirmed the
identity of this species to be homoenolate equivalent 7 (Figure
2). To demonstrate the extended nucleophilicity of this
intermediate, it was subjected to a weak D+ source (AcOD).
1
By H NMR, complete deuterium incorporation is observed at
the γ-position.15
Figure 1. Synthesis and X-ray structure of an aza-Breslow
intermediate. Ellipsoids are shown at the 50% probability level.
ray crystallography identified the species to be a nitrogen
analogue of the Breslow intermediate. We were excited that 3
was isolable, but we questioned whether this compound was
catalytically relevant. It seemed reasonable that protonation of
the nucleophilic olefin would allow for regeneration of active
catalyst while reforming the iminium salt (Scheme 3). Addition
of excess HBF4 to intermediate 3 leads to complete conversion
1
to triazolium salt 1 and iminium salt 2 by H NMR. With the
assumption that this could be a reversible process with weak
acid, we subjected the Breslow intermediate to the well-studied
intramolecular Stetter reaction in the presence of a catalytic
amount of AcOH. After 48 h, complete conversion to ketone 5
was achieved, in excellent enantioselectivity (Scheme 3).11 This
Figure 2. Synthesis and X-ray structure of a homoenolate equivalent.
Ellipsoids are shown at the 50% probability level.
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Journal of the American Chemical Society
Communication
DFT studies have suggested the E-olefin geometry to be
favored in aldehyde-derived systems.16,17 Solid-state analysis of
both isolated aza-Breslow intermediates indicates a preferred Z-
olefin geometry as seen in the X-ray structures. This
contradiction may arise from stabilizing interactions exhibited
by the electron rich/electron deficient aryl substituents present
in these analogues. Since the geometry of this nucleophilic
olefin likely plays a significant role in determining the
stereochemical outcome of NHC catalyzed processes, we
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, crystallographic data, and character-
ization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
■
1
were interested in probing these intermediates in solution. H
Notes
NMR analysis of 3 reveals at least four distinct species present,
which we attribute to both the C1−C19 olefin isomers as well
as rotamers around the C19−N4 bond. At room temperature, a
∼1:1 ratio of two major isomers is present which does not
change significantly at elevated temperatures. EXSY NMR
experiments at room temperature do not show appreciable
exchange on the NMR time scale, but at 100 °C
interconversion is observed. In the absence of a catalyst,
interconversion provides evidence of rotation around the
formal C1−C19 double bond, speaking to its nucleophilicity
and partial single bond character.18 NMR studies of
homoenolate equivalent 7 show similar characteristics.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIGMS (GM 72586) for generous support of this
research. T.R. thanks Amgen and Roche for unrestricted
support. D.A.D.. thanks Chris Rithner (CSU-CIF) for
assistance with NMR studies, C. Michael Elliot and Daniel
Bates (CSU) for cyclic voltammetry experiments and Matthew
P. Shores and Stephanie Fiedler (CSU) for UV−vis studies. We
thank Donald Gauthier (Merck) for a generous gift of
aminoindanol.
To gain further insight into the nature of these intermediates,
oxidation potentials were measured by cyclic voltammetry.
Intermediate 3 undergoes a highly reversible oxidation at +0.17
eV (vs SSCE in CH2Cl2), while 7 is oxidized irreversibly at
+0.49 eV (vs SSCE in CH2Cl2) (Figure 3). The irreversible
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