Abstract
We demonstrated that the loading amounts and concentrations of reactant 1,3-cyclohexanedione affect reaction rates and outcomes. In certain cases, reactions with higher concentrations of 1,3-cyclohexanedione were slower than those with lower concentrations. By minimizing the use of the cyclic 1,3-dione derivatives and by tuning the reaction concentration, the acid catalyst was reduced to 0.1 mol % to afford the desired products in high yields, and the reaction scope was expanded.
Understanding the factors that affect catalyst loading is necessary for the development of catalysts and catalyzed chemical transformations and for minimization of the amount of catalyst used. Cyclic 1,3-diketone derivatives, such as 1,3-cyclohexanedione, are versatile reactants, and various transformations of these molecules have been developed for the synthesis of a range of molecules.1−4 We recently observed that cyclic 1,3-diketone derivatives that have a reactive α-methylene group on their β-diketone moiety serve as more than just reactants.5 Those cyclic 1,3-diketone derivatives function as buffering molecules in non-aqueous solutions.5 Here we report that the loading and concentration of reactant 1,3-cyclohexanedione affect the reaction rate and the amount of catalyst required (Scheme 1). By minimizing the use of the cyclic 1,3-dione derivatives and by tuning the concentrations of the reactants and the catalyst, the catalyst amount was cut by 450-fold compared to that used under previously reported conditions, and the desired products were obtained in higher yields with higher diastereoselectivities in shorter reaction times as described below. In addition, with the use of less catalyst, the scope of the reaction was expanded.
Scheme 1. Previously Reported Reactions That Required an Acid Catalyst Loading of 0.45 equiv and This Work That Results in the Required Catalyst Loading of 0.001 equiv.
We recently reported acid-catalyzed formal (4+1) cycloaddition reactions that led to the formation of spiro[4,5]decanes (Scheme 1a).6 Enone derivatives 1 were used as the C4 reactants, and 1,3-cyclohexanedione or related cyclic 1,3-diketone derivatives were used as the C1 reactants. The conditions required 0.45 equiv of acid catalyst CF3SO3H when the reactions of 1 (1.0 equiv) with cyclic 1,3-dione derivative 2 (3.0 equiv) were performed to afford products 3.6 Depending on the conditions and substituents on 1, products 4 (the diastereomers of 3) were also formed; isomerization of 3 to 4 often occurred during the reaction.6 Whereas both 3 and 4 are useful compounds, which have been used for the synthesis of functionalized polycyclic derivatives by further transformations,6,7 selective formation of 3 is required for the synthesis of molecules that are derived from 3.
We sought to understand why relatively high loading of the acid catalyst (0.45 equiv) was required. We hypothesized that the acid was neutralized by 2 on the basis of the buffering functions of 2 in non-aqueous solutions5 (Scheme 1, proposed mechanisms) and that minimizing the loading of 2 would reduce the amounts of the acid catalyst necessary for the formation of 3. The rapid dynamics of the tautomerization equilibrium of 2 would allow 2 to interact with and neutralize the acid or base that is added as the catalyst. A high loading of 2 and/or a high concentration of 2 should shift the equilibrium of the binding of 2 with the acid or base toward the bound form, inhibiting the interactions between the acid or base and the reactants and/or the intermediates that are necessary for the catalysis. Thus, we investigated how the loading and concentration of 2 influence the reactions of 2 catalyzed by an acid or a base.
To test the hypothesis, the reactions of 1a and 2a in CDCl3 were performed with various loadings of 2a and the acid catalyst CF3SO3H, and the formation of 3a and 4a was monitored (Table 1). When the loading of 2a was 3.0 equiv relative to 1a, the use of lower loadings of the acid catalyst decreased the yield of 3a at 60 min (Table 1, entries 1 and 4–7). The formation of 3a in the reaction using 1.0 equiv of 2a relative to 1a in the presence of 0.01 equiv (1.0 mol %) of the acid catalyst was faster than that in the reaction using 3.0 equiv of 2a in the presence of the same amount of the acid (Table 1, entry 8 vs entry 7). The addition of 2b (2.0 equiv) in the reaction using 2a (1.0 equiv) in the presence of the acid (0.01 equiv) resulted in a decrease in the rate of formation of 3a and 4a (Table 1, entry 9 vs entry 8). In addition, when the amount of the acid catalyst was 0.001 equiv (0.1 mol %) relative to 1a, the reactions with lower concentrations of 2a gave product 3a in higher yields at the same reaction times (at 30 or 100 min) (Table 1, entries 10–13). With the use of only 1.1 equiv of 2a relative to 1a, the amount of the acid catalyst was able to be reduced to only 0.1 mol % without decreasing the rate of formation of 3a compared to the reactions using 3.0 equiv of 2a (Table 1, entry 13 vs entry 1). The amount of the acid catalyst was able to be reduced 450-fold when 1.1 equiv of 2a was used relative to 1a. The reaction with 1.1 equiv of 2a in the presence of the acid catalyst (0.001 equiv) (Table 1, entry 13) was cleaner than the reactions with exactly 1.0 equiv of 2a relative to 1a in the presence of the acid (0.01 equiv) (Table 1, entry 8); the use of a small excess of 2a suppressed side reactions.
Table 1. Evaluations of Conditions for the Reaction of 1a and 2a to Afford 3aa.
| entry | 2a (equiv) | CF3SO3H (equiv) | time (min) | yield of 3a (%)b | yield of 4a (%)b |
|---|---|---|---|---|---|
| 1 | 3.0 | 0.45 | 60 | 70 | 0 |
| 150 | 94 | 6 | |||
| 2c | 3.0 | 0.45 | 60 | 60 | 0 |
| 150 | 94 | 6 | |||
| 3c | 3.0 | 0.45 | 82 | 40 | 1 |
| 147 | 69 | 3 | |||
| 4 | 3.0 | 0.20 | 60 | 46 | 0 |
| 5 | 3.0 | 0.10 | 60 | 39 | 0 |
| 6 | 3.0 | 0.05 | 60 | 32 | 0 |
| 7 | 3.0 | 0.01 | 60 | 31 | 0 |
| 120 | 60 | 0 | |||
| 240 | 94 | 6 | |||
| 8 | 1.0 | 0.01 | 48 | 45 | 2 |
| 75 | 78 | 5 | |||
| 9d | 1.0 | 0.01 | 48 | 14 | 0 |
| 75 | 24 | 1 | |||
| 10e | 3.0 | 0.001 | 30 | 18 | 0 |
| 100 | 38 | 0 | |||
| 11e | 2.0 | 0.001 | 30 | 23 | 0 |
| 100 | 58 | 1 | |||
| 12e | 1.5 | 0.001 | 30 | 29 | 2 |
| 100 | 88 | 2 | |||
| 13e | 1.1 | 0.001 | 30 | 30 | 0 |
| 100 | 90 | 2 |
For the reactions, to a solution of 2a (indicated equivalents relative to 1a) and CF3SO3H (indicated equivalents relative to 1a) in CDCl3 (1.0 mL), 1a (0.029 mmol, 1.0 equiv) was added, and the mixture was heated at 60 °C. See the Supporting Information for details.
Determined by 1H NMR analysis.
To a solution of 1a (0.029 mmol, 1.0 equiv) and 2a (indicated equivalents) in CDCl3 (1.0 mL) (entry 2) or in C6D5CD3 (1.0 mL) (entry 3), CF3SO3H (indicated equivalents) was added, and the mixture was heated at 60 °C.
2b (2.0 equiv) was added.
A 0.11 mmol scale reaction.
Next, the effects of the concentrations of the reaction on the formation of 3a were evaluated (Table 2). The experiment shown in entry 13 of Table 1 had the same concentrations as the experiment shown in entry 2 of Table 2. The yields of 3a at 30 min were determined to compare the rates of formation of 3a. The reaction performed under 2-fold more concentrated conditions was approximately 1.6-fold faster on the basis of the formation of 3a at 30 min (Table 2, entry 4 vs entry 2). However, the reaction with 4-fold more concentrated conditions resulted in a reaction rate similar to that of the initial conditions (Table 2, entry 2 vs entry 5). These results suggest that the concentration of 2a affects the acidic environment of the reaction on the basis of the buffering function of 2a. The reaction in the presence of 0.1 mol % of the acid catalyst under the conditions shown in entry 4 of Table 2 was identified to be the fastest reaction among those evaluated. The use of optimized reaction conditions (Table 2, entry 4) resulted in the formation of 3a in a high yield before the formation of 4a from 3a by isomerization became significant.
Table 2. Effects of Concentrations in the Reaction on the Formation of 3aa.
| entry | CDCl3 (mL) | 2a (mM) | CF3SO3H (mM) | time (min) | yield of 3a (%)b | yield of 4a (%)b |
|---|---|---|---|---|---|---|
| 1 | 8.0 | 16 | 0.014 | 30 | 29 | 0 |
| 2 | 4.0 | 31 | 0.028 | 30 | 31 | 0 |
| 3 | 3.0 | 42 | 0.038 | 30 | 42 | 0 |
| 4 | 2.0 | 63 | 0.057 | 30 | 51 | 0 |
| 60 | 97 | 1 | ||||
| 5 | 1.0 | 126 | 0.11 | 30 | 33 | 1 |
For the reactions, to a solution of 2a (0.13 mmol, 1.1 equiv) and CF3SO3H (0.00011 mmol, 0.001 equiv) in CDCl3 (indicated volume), 1a (0.11 mmol, 1.0 equiv) was added, and the mixture was heated at 60 °C. See the Supporting Information for details.
Determined by 1H NMR analysis.
Next, using the optimized conditions, various oxindole-derived spiro[4,5]decanes 3 were synthesized by the formal (4+1) cycloaddition reactions of 1 and 2a in the presence of acid catalyst CF3SO3H (0.1 mol %) (Scheme 2). The reaction time to afford 3 was shorter under these conditions than under previously reported conditions6 with 3.0 equiv of 2a and 0.45 equiv of CF3SO3H. Products 3, including those bearing functional groups, such as olefin, chloro, furyl, thienyl, and imido (3d, 3e, 3h, 3i, and 3l, respectively), were obtained in high yields as single diastereomers. In addition, no additional acid other than CF3SO3H (0.1 mol %) was required to afford products bearing pyridyl or dimethylaminophenyl substitution (3j or 3k, respectively). With an acid catalyst loading of 0.1 mol %, the reactions of functionalized substrates to form 3 were enabled.
Scheme 2. Scope of the Formation of 3 from 1 and 2 in the Presence of a Catalyst Loading of 0.001 equiv.
In addition, the loading amounts and the concentration of 2a also affected reactions of 2a catalyzed by a base. We previously reported DBU-catalyzed addition of 2a to enone derivative 5 to afford 6(1j) (Table 3). During the optimization of the conditions, lower concentrations and less loading of 2a resulted in a faster reaction rate and a higher yield of the desired product within the same reaction time or a shorter reaction time (Table 3, entry 3 vs entries 1 and 2). These results indicate that 2a also interacts with the base catalyst and that the loading amounts and concentrations of reactant 2a affect the outcomes of the base-catalyzed reactions.
Table 3. Effects of Concentrations for the Reaction of 5 and 2a to Afford 6a.
| entry | toluene (mL) | 2a (equiv; mM) | DBU (equiv; mM) | time (h) | yield of 6 (%)b |
|---|---|---|---|---|---|
| 1c | 0.5 | 1.5; 135 | 0.1; 9.0 | 2 | 76 |
| 2c | 1.0 | 1.5; 67 | 0.1; 4.5 | 3 | 94 |
| 3c | 1.0 | 1.05; 47 | 0.1; 4.5 | 2 | 96 |
For the reactions, to a solution of 5 (0.045 mmol, 1.0 equiv) and 2a (0.067 mmol, 1.5 equiv or 0.047 mmol, 1.05 equiv) in toluene (indicated volume), DBU (0.0045 mmol, 0.1 equiv) was added, and the mixture was heated at 60 °C.
Determined by 1H NMR analysis.
Results reported in ref (1j) are interpreted (concentrations are calculated for this study).
In summary, we have demonstrated that the loading amount and the concentration of reactant 1,3-cyclohexanedione affect reaction rates and outcomes and that, for certain cases, the reactions with higher concentrations of 1,3-cyclohexanedione are slower than those with lower concentrations. Our results indicate that when cyclic 1,3-diketone derivatives are used as reactants in non-aqueous solutions, they have buffering functions. Limiting the loading of 1,3-cyclohexanedione allowed reduction of the acid catalyst loading to 0.1 mol % and, in combination with tuning of the concentration of the reaction, resulted in the formation of the desired products in high yields as single diastereomers in short reaction times. In addition, the limited loading of 1,3-cyclohexanedione and the use of a less loading of the acid catalyst enabled the expansion of the scope of the reaction. In addition, limiting the loading of 1,3-cyclohexanedione also allowed the use of less loading of the base catalyst. Thus, for either acid- or base-catalyzed reactions that use 1,3-cyclohexanedione as the reactant, the loading amounts and concentrations of 1,3-cyclohexanedione influence the catalyst loading required, the reaction rates, and the reaction outcomes. For the development of the reactions of 1,3-cyclohexanedione derivatives that have a reactive α-methylene group on their β-diketone moiety, the buffering functions of the 1,3-cyclohexanedione derivatives must be considered.
Acknowledgments
The authors thank Dr. Michael Chandro Roy (Research Support Division, Okinawa Institute of Science and Technology Graduate University) for mass analyses. This study was supported by the Okinawa Institute of Science and Technology Graduate University.
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00838.
Experimental procedures, characterization data of compounds, and NMR spectra (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.