α,β-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: Observation and mechanistic investigation

Article abstract of DOI:10.1002/anie.201005352

Caught in the act: Acyl azoliums have long been thought to be key reactive intermediates in N-heterocyclic carbene catalysis, but they have never been observed under catalytic conditions. Now, this has been successfully achieved by the characterization of α,β-unsaturated acyl azoliums (see scheme) using different spectroscopic techniques. Kinetic studies revealed the origin of their unexpected chemoselectivity in acylation and annulation reactions.

Full text of DOI:10.1002/anie.201005352

DOI: 10.1002/anie.201005352
N-Heterocyclic Carbenes
a,b-Unsaturated Acyl Azoliums from N-Heterocyclic Carbene
Catalyzed Reactions: Observation and Mechanistic Investigation**
Jessada Mahatthananchai, Pinguan Zheng, and Jeffrey W. Bode*
Catalytically generated acyl azoliums I and their a,b-unsatu-
rated counterparts II are thought to be key reactive inter-
mediates in a rapidly growing number of transformations
promoted by N-heterocyclic carbene (NHC) catalysts.[1] Acyl
azoliums are invoked in the postulated catalytic cycles of
nearly all of the new NHC-catalyzed reactions of a-function-
alized aldehydes reported since 2004, in which they are
generally assumed to possess the reactivity of an activated
carboxylic acid, that is, analogous to an activated ester.[2] In
NHC-catalyzed processes, they are most often obtained
through internal redox reactions of functionalized aldehydes
but have also been prepared by oxidations of the Breslow
intermediates[3] or additions to ketenes.[4] Acyl azoliums I are
important intermediates in thiamine pyrophosphate (ThPP)
dependent enzymatic reactions.[5] Townsend et al. have
recently proposed that unsaturated acyl azolium III is the
key intermediate in clavulanic acid biosynthesis;[6] despite
Scheme 1. Various acyl azoliums and the hemiacetals.
careful efforts, III or its analogues II have never been
characterized or independently synthesized. Here, we docu-
ment the observation and characterization of a,b-unsaturated
acyl azoliums 1 and 2 (Scheme 1) and demonstrate that their
corresponding hemiacetals (1’ and 2’) are the kinetically
important intermediates in both their acylation and annula-
tion reactions.
Simple acyl azoliums prepared under stoichiometric
conditions were extensively studied in a seminal work by
Breslow[7] and continued by Daigo,[8] White and Ingraham,[9]
Bruice,[10] Lienhard,[11] and Owen.[12] These investigations
revealed the unique and rich chemistry of acyl azoliums,
including their remarkable reluctance to acylate amines[12,13]
and high preference for reactions with water or alcohols.
Despite the more than 120 publications since 2004 that
feature acyl azoliums, including the rediscovery of their
unusual chemoselectivity, there have been no reports of the
isolation, detection, or properties of novel acyl azoliums
thought to be generated under catalytic conditions.[14]
Even at high catalyst loadings, most NHC-catalyzed
reactions do not give any detectable intermediates that can
be observed with conventional techniques such as UV, IR,
NMR spectroscopy,[15] or MS methods.[16] For example, no
intermediates could be observed during the redox esterifica-
tion of cinnamaldehyde, even when the reaction was run with
high catalyst loadings or in the absence of base to ensure slow
reaction. This is consistent with NMR studies of the redox
esterification of ynals by Zeitler, in which the postulated a,b-
unsaturated acyl azolium II was not observed.[17]
Our recent studies of reactions of ynals catalyzed by
azolium salts revealed that the rate-limiting step of the
catalytic cycle occurs after the formation of the acyl
azolium.[18] These findings strongly suggested that generation
of substantial amounts of the a,b-unsaturated acyl azolium
intermediate should be possible in the absence of a nucleo-
phile. Careful preparation of a mixture of triazolium 3 and
para-chlorophenyl ynal 4 in anhydrous CDCl3 gives a clear
solution (Figure 1). Upon addition of NaOAc, the solution
rapidly becomes yellow, and turns deep red within 20 minutes.
The color change was monitored by UV/Vis spectroscopy, and
we observed a maximum absorption at 355 nm, with a
significantly smaller absorption at 520 nm, for the solution
containing acyl azolium 1 (Figure 2). Townsend et al. have
speculated that the related protein-bound species III
(Scheme 1) has a characteristic UV/Vis absorption at 310–
320 nm.[6a] Our mixture was further investigated by electro-
spray ionization–high resolution mass spectrometry (ESI-
HRMS), which verified the molecular formula of 1 (Figure 2).
[*] J. Mahatthananchai, Prof. Dr. J. W. Bode
Laboratory for Organic Chemistry, Department of Chemistry and
Applied Biosciences, Swiss Federal Institute of Technology (ETH)
Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)
Fax: (+41)44-633-1235
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bodegroup.org
Dr. P. Zheng
Department of Chemistry, University of Pennsylvania
231 South 34th Street, Philadelphia, PA 19104 (USA)
[**] We are grateful to NIGMS (National Institutes of Health, GM-
079339), the National Science Foundation (CHE-0449587), Bristol
Myers Squibb, and ETH Zurich for support of this research. We
thank Darko Santrac for a preliminary study, and NMR and MS
services (ETHZ) for spectroscopic data.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005352.
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d = 7.6 ppm (1J = 18.0 Hz), which is consistent with the
expected acyl azolium 1, was detected and grew in intensity
over time, reaching a maximum of 30% conversion after
about 40 minutes. This new product immediately disappeared
upon the addition of MeOH (Figure 1c), cleanly forming the
corresponding unsaturated ester 5 and regenerating the
protonated triazolium 3 (C-2 proton peak at d = 12.1 ppm).[19]
Although this solution could be filtered away from
undissolved NaOAc or stored for several hours in the NMR
tube, acyl azolium 1 was exceedingly prone to hydrolysis to
give para-chlorocinnamic acid; all attempts to isolate 1 in
pure form were unsuccessful. However, this intermediate was
successfully characterized by COSY, HSQC, and
HMBC NMR experiments that were performed on the
mixture (see the Supporting Information for spectra and
details). Correlation spectroscopy (Figure 3) clearly showed
Figure 1. 1H NMR investigation of a,b-unsaturated acyl azolium 1
generated from 3 and 4, and its methanolysis to 5 (the labeled H
Figure 3. Key NMR correlation assignments of acyl azolium 1.
atoms correlate to the indicated signals in the spectra).
the bond between the acyl group containing an a,b-unsatu-
rated moiety and the triazolium, and ruled out a triazole
adduct, which we had previously observed in prior attempts at
detecting catalytically generated acyl azoliums with non-
anhydrous conditions.[20] 1H NMR experiments were also
repeated with para-methoxyphenyl ynal, which led to the
formation of acyl azolium 2 with higher conversion (about
50%) relative to that of the aldehyde, but was much more
susceptible to hydrolysis (see the Supporting Information).
The reactivity of 1, generated in this pseudo-stoichiomet-
ric fashion, paralleled the chemistry observed under catalytic
conditions (Scheme 2). It reacts instantaneously with water or
MeOH to give acid 6 or ester 5, but only a complex,
unidentifiable mixture was obtained when 1 was treated with
piperidine, an observation consistent with the known chemis-
Figure 2. UV/Vis and ESI-HRMS characterizations of 1. Black: precata-
lyst + aldehyde; gray: acyl azolium.
To confirm the formation of 1, the reaction was monitored
by 1H NMR spectroscopy. Figure 1 shows the 1H NMR
spectra of the region from d = 1.0–13.0 ppm before (Fig-
ure 1a) and after (Figure 1b) treatment of the mixture of
azolium 3 and aldehyde 4 with NaOAc. A new product,
characterized by doublets at d = 8.7 ppm (1J = 18.0 Hz) and at
Scheme 2. Reactions of a catalytically generated acyl azolium with
various nucleophiles.
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try of saturated acyl azoliums and the reluctance of NHC-
catalyzed acylations to deliver amide products in the absence
of a suitable co-catalyst.[8,12,13] The addition of the kojic acid
derivative 7 gives annulation product 8 through a mechanism
that we believed to be a Coates–Claisen rearrangement from
a hemiacetal intermediate (Scheme 3). Very recent related
works by Lupton,[21] Xiao,[22] and Studer,[23] however, invoked
a direct 1,4-addition of a nucleophile to the a,b-unsaturated
acyl azolium.
rates with electron-deficient ynals were observed (Scheme 3).
With the role of a,b-unsaturated acyl azolium in the
catalytic cycle involving 3 and ynals established, we postu-
lated that the mode of reactivity of NHC-catalyzed reactions
of ynals and nucleophilic partner is governed by the pathways
available to the corresponding hemiacetal (1’ or 2’) derived
from the a,b-unsaturated acyl azolium (1 or 2). To investigate
this hypothesis, we undertook the measurement of the
difference in the activation parameters (DDH° and
DDS°)[28] between the Claisen and the redox reactions from
the reaction of an ynal with sesamol—a reactant that could
undergo both reactions (Scheme 4). We measured a DDH° of
7.61 kcalmolÀ1 and a DDS° of 26.62 calKÀ1 molÀ1 from an
Eyring analysis of the product ratio (krel = %10/%9) at five
temperatures (see the Supporting Information). These values
parallel the data obtained from the rate measurements of the
independent processes (Scheme 3) and substantiates our
postulate for the role of the kinetically important hemiacetal
in the catalytic cycle of both the annulation and esterification
reactions. The activation parameters of the competing
processes arising for the same hemiacetal intermediate
determine the reaction outcome.
Scheme 3. Activation parameters, rate constants, and rate laws com-
parison between NHC-catalyzed redox and Claisen reactions.
Confirmation of the involvement of hemiacetal V as the
final intermediate in the catalytic cycle of the esterification
reaction was obtained by linear free-energy relationship
analysis.[29] The Hammett plot revealed that electron-rich
ynals underwent esterification faster than their more electro-
philic counterparts (Figure 4), an observation consistent with
a mechanism featuring the breakdown of hemiacetal V as the
rate-limiting step in the catalytic cycle (Scheme 5). This
With the role of the acyl azolium 1 in both the annulation
and acylation chemistry established, we sought to further
clarify the mechanistic pathways and chemical properties of
a,b-unsaturated acyl azoliums by kinetic investigations. In
NHC-catalyzed reactions, kinetic studies are often compli-
cated by the complex reaction mechanism and catalyst
inhibition events.[15c] Our recent finding that ynals are
sufficiently reactive under NHC-catalyzed reac-
tions in the absence of added base[24] simplified the
reaction systems and allowed determination of the
rate laws and activation parameters for both the
esterification and annulation pathways.
This observed rate equation of the redox
esterifications reaction is first order in aldehyde,
partial order in the triazolium precatalyst, and
partial negative order in MeOH (Scheme 3). The
negative order in the nucleophile is initially
surprising as we had expected that turnover of
the acyl azolium to the ester and the NHC would
be the rate-determining step. The negative order
could be attributed to catalyst inhibition events.
The inhibitory effects of the nucleophile were also
observed even in the presence of base; the exact
nature of this inhibition is not entirely clear.[25]
Nonetheless, we were able to rationalize this
observed partial rate orders with the derived
rate law (see the Supporting Information). From
the experimental rate law, we performed an
Eyring analysis, which revealed an activation
enthalpy (DH°) of + 23.60 kcalmolÀ1 and an
activation entropy (DS°) of À2.93 calKÀ1 molÀ1
for the redox esterification reaction.[26] These
activation parameters can be contrasted to those
of our recent studies on Coates–Claisen reac-
tions[27] of ynals and enols, in which a large
Scheme 4. a) Differential activation parameters measurement from a competition
negative DS°, a lower DH°, and higher reaction experiment and b) the mechanistic rationale.
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the reactions of simpler acyl azoliums generated under
stoichiometric conditions and found the hemiacetal to be
kinetically relevant. Our work demonstrates that the unusual
reactivities and kinetics observed under catalytic conditions
are governed by the unique properties of the catalytically
generated a,b-unsaturated acyl azoliums rather than by any of
[30]
À
the prior C C bond formations or protonation steps
involved in its formation.
In summary, we have successfully generated and charac-
terized the acyl azolium intermediates key to the reactions of
N-heterocyclic carbenes and a-functionalized aldehydes. The
confirmation that this intermediate is involved in both NHC-
catalyzed acylation and annulation reactions has allowed us to
demonstrate that a common intermediate, hemiacetal V, is the
kinetically important species in both of these processes. These
studies reveal the origin of the unique reactivities and
selectivities observed in NHC-catalyzed reactions and con-
firm that NHC-catalyzed annulation reactions of a,b-unsatu-
rated acyl azoliums proceed through a Coates–Claisen
reaction rather than a direct Michael addition. Our kinetics
investigations provide a rate law (see the Supporting Infor-
mation) that rationalizes the observed kinetics of both the
esterifications and annulation pathways and considers the
catalyst generation and inhibition processes that are the
origin of the unexpected rate orders in the nucleophiles.
These observations will serve as a guideline for future
mechanistic investigations and identification of new reactions
proceeding through catalytically generated acyl azoliums.
Figure 4. Linear free-energy relationship (Hammett study) for NHC-
catalyzed redox reaction with para-substituted ynals: 1=À0.69
(Z=CF3, Cl, H, Me, or OMe as indicated in the plot).
y=À0.6901x+0.0326, R2 =0.903.
Received: August 26, 2010
Revised: October 14, 2010
Published online: January 5, 2011
Keywords: acyl azolium · N-heterocyclic carbenes ·
.
organocatalysis · reaction mechanisms · redox reactions
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