Application of thiopyrylium trifluoromethanesulfonates as Lewis acids in organocatalytic reactions

Abstract

The successful application of thiopyrylium trifluoromethanesulfonate (triflate) as organic Lewis-acidic catalysts in electro-philic aromatic bromination, acetalization, cascade, and three-component reactions is disclosed. All these transformations provided the desired products in good yield. In particular, a catalytic amount of thiopyrylium triflate was used to activate N-bromosuccinimide for the bromination of various aromatic compounds under ambient and dark conditions.

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Catalyst-mediated organic synthesis is a widely used and versatile tool in the field of organic chemistry. In particular, the use of transition metals as Lewis-acidic catalysts has attracted considerable attention.¹ By definition, a Lewis acid has a low-lying lowest unoccupied molecular orbital (LUMO) that can accept lone-pair electrons.² Compared with transition-metal catalysis, synthetic chemistry using metal-free Lewis-acidic organocatalysts is less explored, despite the inherent interest of synthesizing high purity molecules without metals in the fields of materials science and pharmaceutical research.

Recently, cationic organic salts, i.e., cationic organic molecules that bear counter anions, have been sporadically used for promoting specific target transformations such as electrophilic aromatic substitutions and aza-Diels–Alder reactions,³ paving the way for the design of cationic organic Lewis-acidic catalysts. For instance, Mukaiyama and coworkers have used carbocations as Lewis acids for the first time and employed triphenylcarbenium salts as catalysts for aldol, allylations, and Michael reactions.⁴ Cyclopropenium,⁵ tropylium,⁶ pyridinium,⁷ bromonium,⁸ and iodonium salts⁹ have also been applied as catalysts in several organic reactions as electron-pair acceptors. In addition, organocatalysis using chalcogen(IV) species such as sulfonium,¹⁰ selenonium,¹¹ and telluronium salts¹² has recently received much attention; however, reports on catalytic reactions using tertiary chalcogenium compounds remain limited.

Among the aforementioned compounds, thiopyrylium salts are of interest owing to their unique electronic structure and as new building blocks for sulfur-containing aromatic molecules.¹³ In 2020, we reported the synthesis of a new series of thiopyrylium salts via the Lewis- or Brønsted-acid-promoted intramolecular cyclization of diarylthioethers.¹⁴ The resulting thiopyrylium compounds bear a cationic organic framework, as revealed by their spectroscopic characterization, and can be handled under atmospheric conditions. Owing to the presence of a cationic sulfur atom whose charge is delocalized over a conjugated π-electron system, we envisioned that the thiopyrylium salt could serve as a Lewis acid in solution. Here, we demonstrate for the first time that thiopyrylium trifluoromethanesulfonates (triflates) can be used as a Lewis acid in bromination, acetalization, cascade, and multi-component reactions. In particular, we describe the application of thiopyrylium triflates as a Lewis acid to activate N-bromosuccinimide (NBS) for bromination reactions. This reaction is especially important because traditional electrophilic brominations using molecular bromine to obtain brominated aromatic hydrocarbons, which are relevant compounds in metal-catalyzed cross-coupling reactions, pharmaceuticals, and naturally occurring products,¹ often suffer from complications associated with toxicity and operational complexity. Therefore, intense efforts have been devoted to enhancing the inherently low reactivity of NBS as an alternative bromination reagent using catalytic activators.¹⁵

We initially synthesized new thiopyrylium triflates 1a–c using our previously developed intramolecular cyclization (Scheme 1).¹⁴ Coupling reactions of 5-(tert-butyl)-2-sunfanylbenzaldehyde with naphthalen-2-ylboronic acid (2a), phenanthren-9-ylboronic acid (2b), and pyren-2-ylboronic acid pinacol ester (2c) afforded diarylthioethers 3a–c, respectively, in moderate yields (see SI for details). Then, treatment of thioethers 3a–c with trifluoromethanesulfonic acid (TfOH) at room temperature afforded thiopyrylium triflates 1a–c in good yields via intramolecular cyclization. Thiopyrylium triflates 1a–c are thermally stable under atmospheric conditions and do not exhibit any signs of decomposition or hygroscopicity.

Scheme 1 Synthesis of new thiopyrylium triflates 1a–c by a TfOH-promoted cyclization.

We first investigated the Lewis acidity of thiopyrylium triflates 1a–c using the Gutmann–Beckett method,¹⁶ which is based on the use of trioctylphosphine oxide (n-Oc₃P=O) as a probe to detect the chemical-shift changes (Δδ_P) in the ³¹P NMR spectra of the evaluated systems upon addition of n-Oc₃P=O. Adding one equivalent of n-Oc₃P=O to a solution of 1a–c in CD₃CN resulted in downfield shifts of Δδ_P = 12.0, 16.3, and 19.5 ppm, respectively, compared to the chemical shift of free n-Oc₃P=O.¹⁷ These results suggest that thiopyrylium triflates 1a–c inherently behave as Lewis acids in solution, whereby 1b and 1c exhibiting higher Lewis acidity than 1a. Thus, intermolecular interaction between these salts and trioctylphosphine oxide would be affected by their molecular structures of 1a–c.

Then, the intermolecular interaction of thiopyrylium triflate 1b with NBS was investigated via NMR spectroscopy using a 1 : 1 stoichiometric mixture of thiopyrylium salt 1b and NBS. The ¹H and ¹³C NMR spectra of the mixture in CDCl₃ showed slightly shifted signals compared with those of free 1b and NBS, indicating that no covalent bond was formed between 1b and NBS. Therefore, thiopyrylium triflate 1b behaves as a soft Lewis acid toward NBS in solution. Moreover, theoretical investigations on the interactions between thiopyrylium cations 1a′–c′ and NBS were conducted using the Gaussian 16 programs suite. In all cases, the interactions were exothermic. In particular, thiopyrylium cation 1b′ and NBS showed the most effective interaction with an exothermic energy of 1.98 kcal mol⁻¹, which is consistent with the experimentally observed affinity of 1b for NBS. Regarding the optimized structure, interaction between HOMO of 1b′ and LUMO of NBS might be caused by a planar stacked conformation of the 1b′/NBS complex.

Having examined the Lewis acidity of 1a–c in solution, we tested their catalytic activity in the electrophilic aromatic bromination of anisole by reacting anisole with NBS in the presence of 5.0 mol% of 1a–c under dark conditions. The results are summarized in Table 1.

Table 1 Bromination of anisole with NBS in the presence of 4 mol% thiopyrylium triflates 1a–c in CH₂Cl₂ at room temperature

Entry	Thiopyrylium triflate	Additive	Yield of 4 (%)
1	—	—	1
2	—	TfOH (5.0 mol%)	63
3	—	TfOH (5.0 mol%) + 2,4,6-trimethylpyridine (5.0 mol%)	0
4	1a	—	48
5	1b	—	58
6	1c	—	33
7	1b	2,4,6-Trimethylpyridine (5.0 mol%)	52

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First, we confirmed that the bromination did not proceed without thiopyrylium triflate or any additive (entry 1). Using TfOH as a Brønsted acid enhanced the bromination, resulting in the formation of 4-bromoanisole in 63% yield (entry 2); however, the addition of both TfOH and 2,4,6-trimethylpyridine did not afford the desired product (entry 3). The bromination proceeded smoothly in the presence of 5.0 mol% of thiopyrylium triflate 1b under dark conditions to furnish 4-bromoaniole in 58% yield (entry 5), whereas thiopyrylium triflates 1a and 1c afforded 4-bromoaniole in lower yield, i.e., 48% and 33%, respectively (entries 4 and 6). The observed lower activity for 1c might be caused by its low solubility toward CH₂Cl₂. No significant change in the yield was observed when using 1b in the presence of 2,4,6-trimethylpyridine (entry 7). These results confirmed that thiopyrylium triflate 1b effectively catalyzes this electrophilic aromatic bromination as a Lewis acid and that the 1b-catalyzed bromination was not affected by the presence of a Lewis base.

With the optimized reaction conditions in hand, we next explored the substrate scope of the electrophilic bromination by NBS (Chart 1). In the presence of 5.0 mol% of 1b, 1,3-benzodioxole, mesitylene, acetanilide and thioanisole reacted with NBS to afford monobrominated compounds 5, 6, 7, and 8 in 54%, 94%, quantitative, and 45% yield, respectively. Although naphthalene did not undergo the desired bromination, 2-methylnaphthalene readily furnished 1-bromo-2-methylnaphthalene (9) in 77% yield. When using pyrene, the reaction proceeded regioselectively to produce 1-bromopyrene (10) in 84% yield. In the cases of anisole, anthracene, and dibenzo[b,d]thiophene, two-fold bromination occurred preferentially to afford 2,4-dibromoanisole (11), 9,10-dibromoanthracene (12), and 2,8-dibromodibenzo[b,d]thiophene (13) in 73%, 68%, and 64% yield, respectively. We confirmed that the thiopyrylium-catalyzed bromination can also be applied to agricultural chemicals and alkaloid molecules. Specifically, boscalid and strychnine reacted under the applied bromination conditions to furnish brominated derivatives 14 and 15 in 61% and 92% yield, respectively. Dibromoaniline derivative 16, an important compound in the field of pharmaceutical chemistry, was also obtained via two-fold bromination. Conversely, 2-methylquinoline, 9H-thioxanthen-9-one, 2,5-dimethylthiophene, phenanthrene, neopentylbenzene, and 1-bromo-3-chlorobenzene were not converted to the corresponding brominated products under the applied reaction conditions. The monobromination of anisole was also performed using N-bromophthalimide instead of NBS under the otherwise optimized conditions, to afford 4 in 74% isolated yield. Moreover, chlorination and iodination reactions using N-chloro- and N-iodosuccinimide, respectively, were successfully conducted, which furnished 1-chloropyrene (17), 1-iodopyrene (18), 4-iodoanisole (19), and iodomesitylene (20) in 53%, 89%, 11%, and 33% isolated yield, respectively (Chart 1). Thus, the thiopyrylium-triflate-promoted bromination, chlorination, and iodination is suitable for a variety of aromatic hydrocarbons, sulfur-containing heterocycles, agricultural chemicals, and alkaloids.

Chart 1 Substrate scope of the electrophilic bromination catalyzed by thiopyrylium triflate 1b.

The robustness of the developed organic catalytic system was tested by recovering the catalyst after the reaction and using the reused catalyst for new reaction cycles. Upon completion of the bromination of pyrene in the presence of 1b, the reaction mixture was separated by centrifugation at 0 °C, affording an orange solid. The obtained solid was then treated repeatedly with another portion of pyrene and NBS in CH₂Cl₂. The catalytic system could be reused at least five times with complete conversion and virtually no activity loss. Specifically, the product yield from the first to the fifth experiments was 91%, 100%, 86%, 86%, and 82%. These results demonstrate the robustness of catalyst 1b in these electrophilic bromination reactions.

Having confirmed the activity and stability of thiopyrylium triflate 1b in electrophilic bromination reactions, we examined its ability to catalyze other organic reactions. Thiopyrylium triflate 1b was thus applied in the acetalization reaction of benzaldehyde derivatives using a diol. First, the acetalization reaction of p-tolualdehyde and 2,2-dimethylpropane-1,3-diol proceeded using 5.0 mol% of 1b at room temperature (Scheme 2). The ¹H NMR spectrum of the reaction mixture revealed the complete conversion of the substrate within 24 h. After chromatographic purification, acetal 21 was isolated in 79% yield. Then, we evaluated the effect of different substituents on the benzene ring of the benzaldehyde precursors. Installing an electron-withdrawing group on the aromatic ring did not significantly alter the cyclization outcome (cf. compounds 22 and 23 in Chart 2). When using 1-naphthaldehyde, the acetalization smoothly proceeded to provide acetal 24 in quantitative isolated yield. π-Expanded 1-pyrenecarboxaldehyde successfully reacted with the diol in the presence of 1b (5.0 mol%) to afford the corresponding acetal (25) in 95% isolated yield. Terephthalaldehyde also proved to be a suitable substrate, which provided bisacetal derivative 26 in good yield. These results clearly demonstrate the versatility of 1b, whose sufficient Lewis acidity renders it suitable for a variety of catalytic reactions.

Scheme 2 Reaction of p-tolualdehyde with 2,2-dimethylpropane-1,3-diol in the presence of 1b.

Chart 2 Substrate scope of acetalization reactions catalyzed by thiopyrylium triflate 1b.

Next, we turned our attention to expand the reaction of propargylic alcohols with naphthalen-2-ol in the presence of thiopyrylium triflate 1b as a Lewis acid (Scheme 3). First, we confirmed the complete recovery of the substrates in the absence of 1b. When using 5.0 mol% of 1b, this cascade reaction smoothly proceeded at 80 °C within 3 h according to ¹H NMR spectroscopy monitoring. 3H-Benzochromene derivative 27 was obtained in 95% isolated yield after chromatographic separation. In addition, this direct construction of the 3H-benzochromene framework provided 28 and 29 in excellent yield under the applied conditions (Chart 3). Thus, propargylic alcohols could be activated by thiopyrylium triflate 1b to undergo the Friedel–Crafts reaction with naphthalen-2-ol to give 3H-benzochromene derivatives.

Scheme 3 Reactions of naphthalen-2-ol with 2-methyl-4-phenyl-3-butyn-2-ol in the presence of 1b.

Chart 3 Substrate scope of cascade reactions catalyzed by thiopyrylium triflate 1b.

Finally, we examined Mannich reactions catalyzed by thiopyrylium triflate 1b as a model three-component reaction (Scheme 4). In the absence of 1b at room temperature, the control reaction did not lead to the desired three-component product. Meanwhile, in the presence of 5.0 mol% of 1b, the reaction of 4-chlorobenzaldehyde, aniline, and acetophenone furnished Mannich product 30 in 58% isolated yield. 4-Bromobenzaldehyde, p-tolualdehyde, and 1-naphthaldehyde were also tolerated as substrates instead of 4-chlorobenzaldehyde, providing three-component products 31, 32, and 33 in 62%, 59%, and 67% yield, respectively. In the case of substituted acetophenone and aniline derivatives, the reactions smoothly produced 34 and 35 in 57% and 58% yield, respectively. These results confirm that thiopyrylium triflate 1b also works as a Lewis-acidic organocatalyst in Mannich-type condensations to afford the three-component products in moderate yield.

Scheme 4 Three-component reactions in the presence of 1b.

In summary, we have for the first time, successfully used thiopyrylium triflate 1b as a Lewis-acidic organocatalyst in electrophilic bromination reactions of aromatic compounds, acetalization reactions of benzaldehydes, cascade reactions, and Mannich reactions. The corresponding products were obtained in good yield. DFT calculations suggested the formation of noncovalent interactions between the thiopyrylium cation fragment and the imide/carbonyl group of NBS or the benzaldehydes. Further studies on the application of thiopyrylium salts to catalyze other organic reactions are currently in progress in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental details, characterization data, and supporting figures and tables. See DOI: https://doi.org/10.1039/d5ob01353d.

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17. We also observed that adding one equivalent of n-Oc₃P=O to a solution of tropylium tetrafluoroborate/triphenylcarbenium tetrafluoroborates in CD₃CN resulted in downfield shifts of Δδ_P = 5.01/24.4 ppm, respectively, compared to the chemical shift of free n-Oc₃P=O.

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