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

Mechanistic studies of the triazolium ion-catalyzed intramolecular Stetter reaction using initial rates analysis in NEt 3 /NEt 3 ·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-with-drawing groups. A concurrent, NHC-independent substrate isomerization was also observed and found to demonstrate a first-order dependence on aldehyde concentration. The re-ported data are consistent with deprotonation to form the Breslow intermediate being turnover-limiting in this process.


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]hile 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]e 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]espite 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 ioncatalyzed benzoin reaction of benzaldehyde in buffered MeOH (NEt 3 : NEt 3 • HCl 2 : 1) employed an initial rate method and 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 (NEt 3 : NEt 3 • HCl 2 : 1) by our groups indicated that reaction order was dependent upon concentration. [9]t 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 ioncatalyzed 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 (k H /k D = 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 k H /k D = 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, NEt 3 : NEt 3 • 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).

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).
In an initial experiment, aldehyde 11 and triazolium salt 15 were dissolved in methanol at 35 °C under argon and a buffer solution of NEt 3 and NEt 3 • 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 (NEt 3 : NEt 3 • 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, k isom = 2.14 × 10 À 6 s À 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.

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 k obs = 2.21 × 10 À 5 s À 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, K exp = 27 in CH 2 Cl 2 , Figure 5A). [14]Significantly, orthoalkoxy substitution on the benzaldehyde (as present in 11) resulted in a significant increase in the rate and equilibrium constants for adduct 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 turnoverlimiting (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 k BI (deprotonation to form the Breslow  5B). [19]oth 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 electronwithdrawing 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 (k 2 ) being turnover-limiting rather than the Michael addition step.
The first-order rate constant measured herein, k obs = 2.21 × 10 À 5 s À 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 k p [PhCHO] @ k -BI , values for ν max approach k BI [4] (c.f.k BI [18] in Figure 5B).
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 ν max plateau values observed for electron-withdrawing N-aryl substituents.The dependence of ν max on triazolium concentration for the benzoin reaction catalyzed by 15 yielded k obs = 7.48 × 10 À 5 s À 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 k obs for a more electron-donating orthoalkoxy substituent and turnover-limiting Breslow intermediate formation.

Conclusion
In conclusion, an initial rates analysis of the NHC-catalyzed intramolecular Stetter reaction in NEt 3 /NEt 3 • HCl buffered methanol has been investigated.A concurrent, NHC-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]OMMUNICATIONS Mechanistic studies of the triazolium ion-catalyzed intramolecular Stetter reaction using initial rates analysis in NEt 3 /NEt 3 • 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.

Figure 1 .
Figure 1.Proposed mechanistic pathway for A: the benzoin reaction and B: the Stetter reaction, via a common Breslow intermediate 5.