Kinetic and Structure-Activity Studies of the Triazolium Ion- Catalyzed Intramolecular Stetter Reaction

Article abstract of DOI:10.1002/ejoc.202100384

Mechanistic studies of the triazolium ion-catalyzed intramolecular Stetter reaction using initial rates analysis in NEt₃/NEt₃ ? HCl buffered methanol showed the reaction to be first-order in catalyst and zero-order in aldehyde over a broad range of aldehyde concentrations. The observed reaction rate is higher for catalysts bearing N-aryl substituents with electron-withdrawing groups. A concurrent, NHC-independent substrate isomerization was also observed and found to demonstrate a first-order dependence on aldehyde concentration. The reported data are consistent with deprotonation to form the Breslow intermediate being turnover-limiting in this process.

Full text of DOI:10.1002/ejoc.202100384

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Kinetic and Structure-Activity Studies of the Triazolium Ion-
catalyzed Intramolecular Stetter Reaction
Authors: Christopher J. Collett, Claire. M. Young, Richard. S. Massey,
AnnMarie C. O’Donoghue, and Andrew David Smith
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100384
Link to VoR: https://doi.org/10.1002/ejoc.202100384
01/2020

10.1002/ejoc.202100384
European Journal of Organic Chemistry
COMMUNICATION
Kinetic and Structure–Activity Studies of the Triazolium Ion–
catalyzed Intramolecular Stetter Reaction
Christopher J. Collett,[a] Claire M. Young,[a] Richard S. Massey,[b] AnnMarie C. O’Donoghue,*[b] Andrew
D. Smith*[a]
[a]
Dr. Christopher J. Collett, Dr. Claire M. Young, Prof. Dr. Andrew D. Smith, EaStCHEM, School of Chemistry, University of St. Andrews,
North Haugh, St. Andrews KY16 9ST, UK
E-mail: ads10@st-andrews.ac.uk; https://ads-group.squarespace.com/
[b]
Dr. Richard S. Massey, Dr. AnnMarie C. O’Donoghue; Department of Chemistry, Durham University,
South Road, Durham DH1 3LE, UK
E-mail: annmarie.odonoghue@durham.ac.uk; https://odonoghueresearchgroupdotcom.wordpress.com/about/
Supporting information for this article is given via a link at the end of the document.
Abstract: Mechanistic studies of the triazolium ion-catalyzed
intramolecular Stetter reaction using initial rates analysis in
NEt3/NEt3HCl buffered methanol showed the reaction to be first-
order in catalyst and zero-order in aldehyde over a broad range
of aldehyde concentrations. The observed reaction rate is higher
for catalysts bearing N-aryl substituents with electron-
withdrawing groups. A concurrent, NHC-independent substrate
isomerization was also observed and found to demonstrate a
first-order dependence on aldehyde concentration. The reported
data are consistent with deprotonation to form the Breslow
intermediate being turnover-limiting in this process.
demonstrated
a
close to first-order dependence on
[benzaldehyde].[8] In contrast, an initial rates analysis of the
triazolium ion-catalyzed benzoin reaction of benzaldehyde in a
buffered MeOH solution (NEt3:NEt3HCl 2:1) by our groups
indicated that reaction order was dependent upon
concentration.[9]
Introduction
First reported in 1973, the Stetter reaction is considered closely
related mechanistically to the more commonly employed
benzoin reaction.[1] For both of these processes, the reaction is
widely accepted to proceed via umpolung activation of an
aldehyde 3 using catalysts such as nucleophilic heterocyclic
carbenes (NHCs). For example, triazolium salts such as 1 can
be deprotonated in situ to give the corresponding reactive NHC
2. Addition of the NHC to the aldehyde 3 leads initially to an
isolable tetrahedral species 4 before the formation of an
enaminol 5 that acts as an acyl anion equivalent that is
commonly known as the Breslow intermediate (Figure 1A).[2]
While this key intermediate reacts with another equivalent of
aldehyde 3 in the benzoin reaction, in the Stetter reaction
nucleophilic addition to a Michael acceptor 8 occurs, followed by
protonation and catalyst release (Figure 1B). Building upon this
mechanistic model, the Stetter reaction has found widespread
synthetic use, including the development of effective enantio-
and diastereoselective transformations.[3]
Due to their mechanistic similarity, it is often considered
that insight into the mechanism of the Stetter reaction can be
intimated from studies of the benzoin reaction. The validity of
this general mechanism for the benzoin reaction has been
substantiated by computational predictions;[4] identification and
characterization of intermediates;[5] the use of intermediates or
their analogues in control reactions,[6] and further validated
through dynamic covalent binding using boronic esters.[7]
Despite this combined knowledge, a variety of detailed kinetic
analyses of the benzoin reaction of benzaldehyde have given
different and often ambiguous results. As an example, specific
mechanistic investigations by Leeper into the thiazolium ion-
catalyzed benzoin reaction of benzaldehyde in buffered MeOH
(NEt3:NEt3HCl 2:1) employed an initial rate method and
Figure 1: Proposed mechanistic pathway for A: the benzoin reaction and B:
the Stetter reaction, via a common Breslow intermediate 5.
1
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10.1002/ejoc.202100384
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COMMUNICATION
At low concentration (< ~0.5 M) in aldehyde, a first-order
aldehyde dependence was observed, but at increased
concentration (> ~0.5 M) a change to zero-order dependence
was observed. At higher benzaldehyde concentrations, the rate
is limited by deprotonation to form the Breslow intermediate, but
at reduced benzaldehyde concentrations, catalyst addition to
form the initial adduct and product-forming steps are considered
rate-limiting. The observed variation of reaction mechanism
depending on choice of catalyst, or even with change in
substrate concentration, highlights the mechanistic complexity of
these reactions.
To fully develop the NHC-catalyzed Stetter reaction as a
synthetic process, specific studies regarding its reaction
mechanism are needed. The Stetter transformation employing
compound 11 as starting material is among the most commonly
used benchmarks for reactivity and selectivity when reporting
new NHC catalysts, particularly for (chiral) triazolium ion-
catalyzed processes (Figure 1A).[10] Importantly, this substrate
has also been used for mechanistic investigations of the Stetter
reaction. For example, in 2011, reports from the Rovis group
demonstrated that deprotonation to form the Breslow
intermediate is turnover-limiting under two mechanistically
different scenarios.[11,12] In the first,[11] in the presence of
catechol as an additive and in MeOH as solvent, a primary
kinetic isotope effect (kH/kD = 2.7) was observed (Figure 2A).
Further studies using chiral NHC 14 in toluene showed that the
reaction process was first-order in both NHC catalyst and
aldehyde substrate, with kH/kD = 2.6.[12] Building upon these
results and previous reports from our groups,[13,14] in this
manuscript kinetic studies upon the intramolecular Stetter
reaction using substrate 11 are reported. The buffered
conditions (MeOH, NEt3:NEt3HCl 2:1) initially reported by
Leeper for investigation of the thiazolium-catalyzed benzoin
reaction,[8] and since used in many analyses of NHC-catalyzed
umpolung processes, were chosen for kinetic analysis to enable
direct comparison with reported benzoin reaction (Figure 2B).
Results and Discussion
Model studies and identification of a NHC-independent
isomerization process
Initially, reaction orders were sought. As described by Leeper,[8]
potential issues associated with changes in reaction order as
substrate concentration changes, combined with catalyst
degradation and failure of the assumption of irreversibility at all
stages of the reaction, may hamper elucidation of reaction
orders in NHC-catalyzed reactions. As a result, an initial rate
method at low (< 10%) product formation was employed. To
reliably assess the reaction progress at low concentrations of
product, timepoint analysis was performed using high-
performance liquid chromatography (HPLC).
Figure 3: A: Observed isomerization side-reaction under the triazolium 15-
catalyzed Stetter reaction conditions. B: Kinetic analysis of isomerization in
buffered methanol (NEt3:NEt3HCl (2:1, 160 mM total)) at 35 °C under argon: i)
11 (0.64 M), 15 (40 mM (teal) or 0 mM (purple)); ii) 11 (0.08–0.64 M), 15 (40
mM).
Figure 2: A: Previous mechanistic studies of the NHC-catalyzed Stetter
reaction. B: This work: initial rates analysis in buffered MeOH solution
(NEt3:NEt3HCl 2:1)
2
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10.1002/ejoc.202100384
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COMMUNICATION
In an initial experiment, aldehyde 11 and triazolium salt 15 were
dissolved in methanol at 35 °C under argon and a buffer solution
of NEt3 and NEt3HCl (2:1 in methanol) was added, initiating the
reaction (Figure 3A). Aliquots were removed from the reaction
every hour and, after quenching, analyzed by HPLC (Figure 1B).
Starting material 11 and a 50:50 mixture of both enantiomers of
racemic Stetter product 12 were identified by HPLC analysis on
a chiral stationary phase.[15] Interestingly, two by-products were
also observed that were identified upon isolation as (Z)-16 and
(E)-17, the products of isomerization of 11, in an 80:20 ratio.
Similar isomerizations have been reported in the literature, both
in NHC-catalysis,[16] and in the absence of NHCs.[17] Further
control studies were performed to determine if this isomerization
was NHC-catalyzed and therefore potentially interfering with the
Stetter reaction. Simply stirring aldehyde 11 in buffered MeOH
solution (NEt3:NEt3HCl 2:1) for 72 hours led to the formation of
(Z)-16 and (E)-17 in an identical 80:20 ratio, and isolation in 32%
yield, suggesting this process occurs independently of the NHC.
Performing the reaction both with and without triazolium 15, and
monitoring the rate of formation of the isomerization products,
led to essentially identical reaction profiles (Figure 3B).[15] The
initial rate for the isomerization process showed a first-order
dependence on aldehyde concentration with a first-order rate
constant, kisom = 2.14 × 10-6 s-1 (Figure 3B). Exposing 16 to the
reaction conditions (with NHC precursor 15 and buffer) resulted
in no further reaction after 12 hours, suggesting that on this
timescale this isomerization reaction is irreversible and that the
product does not significantly interfere with the NHC-promoted
Stetter transformation. Over the range of aldehyde
concentrations tested (0.08 M to 0.64 M) the isomerization
process is therefore an independent parallel reaction, allowing
simultaneous monitoring of the NHC-catalyzed Stetter reaction.
benzaldehyde (as present in 11) resulted in a significant
increase in the rate and equilibrium constants for adduct
Initial rate studies of the NHC-catalyzed Stetter reaction
The NHC-catalyzed Stetter reaction was then investigated, and
reaction orders with respect to NHC 15 and aldehyde 11 were
identified. Initial rate analyses of the reaction were performed at
aldehyde 11 concentrations of 0.08 M, 0.16 M, 0.32 M and 0.64 M,
and triazolium 15 concentrations of 0.01 M, 0.02 M and 0.04 M.
Despite the wide range of aldehyde concentrations probed, the
reaction rate was independent of aldehyde concentration (zero-
order in aldehyde) across all those tested (Figure 4). A plot of
initial rates against initial triazolium salt concentration (0.01 M,
0.02 M and 0.04 M) shows a clear first-order dependence on
catalyst concentration[18] with an estimated first-order rate
constant of kobs = 2.21 × 10-5 s-1 (Figure 4).
The zero-order dependence on aldehyde concentration is
distinct from the first-order dependence observed in toluene
carried out by Rovis, indicating the kinetic importance of the
different solvents and reaction conditions employed in these
investigations. Applying the steady-state approximation to the
concentration of the Breslow intermediate,[15] the absence of the
aldehyde from the rate equation can be rationalized assuming
that the initial equilibrium (Figure 5A) between aldehyde 11 and
triazolium 1 significantly favors 3-(hydroxybenzyl)azolium salt 19.
In previous work from our groups using N-aryl triazolium salt
precatalysts, we have shown that NHC addition to a range of
substituted benzaldehydes to give isolable tetrahedral hydroxy
adducts (c.f. 4, Figure 1) is rapid and reversible, and favors
adduct formation (e.g. for Ar = Ph, Kexp = 27 in CH2Cl2, Figure
5A).[14] Significantly, ortho-alkoxy substitution on the
Figure 4: Initial rates analysis of 15-catalyzed Stetter reaction in buffered
methanol (NEt3:NEt3HCl (2:1 0.16 M total)) at 35 °C under argon: i) initial rates
at [11] = 0.08 M, 0.16 M, 0.32 M and 0.64 M; and [15] = 0.04 M (green),0.02 M
(purple) and 0.01 M (teal); ii) ν0 for each [15]0 taken from the respective y-
intercept in i).
formation. As aldehyde concentration is significantly higher than
triazolium precatalyst concentration in the present study ([11] >
[15]), this equilibrium is expected to substantially favor the
tetrahedral hydroxy adduct. In addition, the observed zero-order
dependence on [11] in the context of the current catalytic
conditions is consistent with adduct-formation from triazolium 1
not being turnover-limiting (Figure 5B). Experiments at lower
initial aldehyde concentrations (to test whether aldehyde
dependence could be observed) did not give reliable data due to
difficulty in measuring small concentration changes accurately
under the initial rates regime (< 10% product formation). It was
proposed that kBI (deprotonation to form the Breslow
intermediate 19) and kintra (intramolecular Michael addition of the
acyl anion equivalent to give 20) could be differentiated based
on the electronic requirements of each step (Figure 5B).[19]
3
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10.1002/ejoc.202100384
European Journal of Organic Chemistry
COMMUNICATION
Both steps, if turnover limiting, would be expected to result in a
zero-order dependence on aldehyde concentration. Previous
reports have shown that deprotonation to form the Breslow
intermediate is affected by through-bond electronic effects, with
an increase in the rate of C(α)-H/D exchange of methylated
adducts observed for compounds containing electron-
withdrawing N-aryl substituents (Figure 5A).[13] If deprotonation
is turnover-limiting in this reaction, a similar trend in overall
reaction rate would be predicted. Conversely, the Michael
addition would be expected to be accelerated by electron-
donating N-aryl substituents due to an increase in the
nucleophilicity of the acyl anion equivalent (Figure 5B).
Comparable reactions with catalysts 21 and 22 were therefore
performed and their first-order rate constants compared with that
for 15 (Figure 5C).[20] The rates of product formation for the
reactions catalyzed by 15, 21 and 22 indicate enhanced rates
when the NHC N-Ar substituent incorporates an electron-
withdrawing group (EWG): 21 (N-(p-F-Ph)) > 15 (N-Ph) > 22 (N-
Mes) (Figure 5C).[19] Significantly, the reaction catalyzed by N-
Mes 22 required a higher catalyst concentration (20–80 mM)
than either N-(p-F-Ph) 21 or N-Ph 15 (10–40 mM) due to the
slow rate of Stetter product formation compared with
isomerization in this case. This trend, along with the reaction
orders and observed rate constant, is consistent with
deprotonation to form the Breslow intermediate (k2) being
turnover-limiting rather than the Michael addition step.
The first-order rate constant measured herein, kobs = 2.21 ×
10-5 s-1, based on the observed Stetter initial rate dependence
on triazolium 15 concentration at 35 °C, can be compared to the
analogous value for the benzoin reaction of benzaldehyde 3 (R =
Ph) using the same catalyst 15, buffer and solvent (albeit at the
higher reaction temperature of 50 °C). In the case of the benzoin
reaction, a clear change in dependence of initial rate on
benzaldehyde concentration from first- to zero-order was
observed at higher aldehyde concentrations according to
Equation 1. At high [PhCHO]0 when kp[PhCHO] >> k-BI, values
for νmax approach kBI[4] (c.f. kBI [18] in Figure 5B).
kpνmax[PhCHO]
[ ]
kpkBI 4 [PhCHO]
ν =
=
(1)
k-BI + kp[PhCHO] k-BI + kp[PhCHO]
As the nucleophilic addition of the acyl anion equivalent to
benzaldehyde is intermolecular in the benzoin process, only a
turnover-limiting Breslow intermediate-forming step could
explain the zero-order dependence on aldehyde in this case.
This was again supported by the rate dependence of different
triazoliums with higher νmax plateau values observed for electron-
withdrawing N-aryl substituents. The dependence of νmax on
triazolium concentration for the benzoin reaction catalyzed by 15
yielded kobs = 7.48 × 10-5 s-1, which is ~3-fold higher than for the
Stetter reaction with ortho-alkoxy aldehyde 11. Although some of
this difference can be attributed to the different temperatures
used, the remainder is also consistent with a decrease in kobs for
a more electron-donating ortho-alkoxy substituent and turnover-
limiting Breslow intermediate formation.
Figure 5: A: Reported effects of N-aryl substituents on NHC-mediated
processes. B: Predicted effects of N-aryl substituents on the NHC-catalyzed
Stetter reaction. C: Initial rate data for Stetter reactions with [11]0 = 0.32 M in
buffered methanol (NEt3 and NEt3HCl (2:1, 0.16 M total)) at 35 °C under argon
catalyzed by: 21 (green), 15 (purple) and 22 (teal) at 0.02 M catalyst loading.
Conclusion
In conclusion, an initial rates analysis of the NHC-catalyzed
intramolecular Stetter reaction in NEt3/NEt3HCl buffered
methanol has been investigated.
A
concurrent, NHC-
4
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10.1002/ejoc.202100384
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COMMUNICATION
[16] For representative examples, see: a) S. Wei, X.-G. Wei, X. Su, J. You,
Y. Ren, Chem. Eur. J. 2011, 17, 5965; b) M. M. Ahire, S. B. Mhaske,
ACS Omega, 2017, 2, 6598.
independent isomerization of 11 was observed and found to
have a first-order dependence on aldehyde concentration.
Mechanistic analysis of the Stetter process showed the reaction
to be first-order in catalyst and zero-order in aldehyde over a
broad range of aldehyde concentrations. Consistent with
previous reports, the reaction rate was higher for catalysts with
electron-withdrawing N-aryl substituents within the triazolium
skeleton. The data reported are consistent with deprotonation to
form the Breslow intermediate being turnover-limiting in this
reaction. [21]
[17] For representative examples, see: a) S. K. Guha, A. Shibayama, D.
Abe, M. Sakaguchi, Y. Ukaji, K. Inomata, Bull. Chem. Soc. Jpn. 2004,
77, 2147; b) K. Sunitha, K. K. Balasubramanian, Tetrahedron, 1987, 43,
3269; c) B. Harish, M. Subbireddy, O. Obulesu, S. Suresh, Org. Lett.
2019, 21, 1823.
[18] Data is shown for [11] = 0.032 M but the same trend was observed at
[11] = 0.008 M, 0.016 M, and 0.064 M.
[19] Catalyst release was ruled out as the turnover-limiting step based on
earlier findings that adduct [20] was not observed and so its decay is
likely rapid.
[20] Due to an extremely rapid reaction to give product, reliable initial rate
data could not be obtained for N-2,4,6-Cl3-C6H2 or N-C6F5-substituted
triazolium ion-precatalysts.
Acknowledgements
[21] The research data supporting this publication can be accessed
at https://doi.org/10.17630/7b18dcdd-72a3-4b26-909b-25ccd31cd58c.
We thank the EPSRC (CJC, RSM, EP/G0103268/1; CMY, ADS,
EP/S019359/1; A’OD EP/S020713/1) for funding.
Keywords: NHC • Breslow intermediate • triazolium • Stetter
reaction • initial rates analysis
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[15] See electronic supporting information for details.
5
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10.1002/ejoc.202100384
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Mechanistic studies of the triazolium ion-catalyzed intramolecular Stetter reaction using initial rates analysis in NEt3/NEt3HCl
buffered methanol showed the reaction to be first order in catalyst and zero order in aldehyde. The reported data are consistent with
deprotonation to form the Breslow intermediate being turnover-limiting in this process.
Institute and/or researcher Twitter usernames: @ADS_StAndrews; @StAChemistry
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