Hydrogen-bonding catalysis of sulfonium salts

Abstract

Although quaternary ammonium and phosphonium salts are known as important catalysts in phase-transfer catalysis, the catalytic ability of tertiary sulfonium salts has not yet been well demonstrated. Herein, we demonstrate the catalytic ability of trialkylsulfonium salts as hydrogen-bonding catalysts on the basis of the characteristic properties of the acidic α hydrogen atoms on alkylsulfonium salts.

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The importance of onium salt compounds has been established in the field of organic chemistry.¹ Alkyl-ammonium, phosphonium, and sulfonium salts are some of the most important and reliable onium salt reagents in organic synthesis (Fig. 1). These compounds are often utilized as very useful reagents in the construction of organic building blocks, and the reactions using these reagents appear in textbooks of organic chemistry as important, named reactions.^2,3 Furthermore, quaternary ammonium and phosphonium salts are also known as reliable catalysts, which are used to promote a wide variety of organic transformations as phase-transfer and/or base catalysts.⁴ Despite the wide synthetic utility of onium salt compounds as reagents and catalysts, the catalytic ability of tertiary sulfonium salts has not yet been demonstrated well in organic synthesis.⁵ The limitation of sulfonium salt catalysts has been attributed mainly to the high reactivity and instability of the compounds with acidic α hydrogen atoms. To create new possibilities for sulfonium salts as catalysts, we focused on the hydrogen-bonding abilities of α hydrogen atoms on alkylsulfonium salts when we reported the use of type 1 tetraalkylammonium salts as hydrogen-bonding catalysts on the basis of the characteristic properties of the α hydrogen atoms (Fig. 2).^6,7 Herein, we demonstrate the catalytic ability of trialkylsulfonium salts in hydrogen-bonding catalysis.⁸

Fig. 1 Onium salts in organic synthesis.

Fig. 2 Comparison between ammonium iodide 1a and sulfonium iodide 2a.

Based on the design of type 1 tetraalkylammonium salts as effective hydrogen-bonding catalysts,⁶ we focused on simple type 2 trialkylsulfonium salts (Fig. 2). The structures of the α hydrogen atoms that bound to the iodide anion compared favorably to the X-ray crystal structures of ammonium iodide 1a and sulfonium iodide 2a.^9,10 Furthermore, we expected the acidity of the α hydrogen atoms of 2a to approximate the acidity of 1a, based on the reported pK_a values.¹¹

With the important structural information of the sulfonium salts of type 2 in hand, the catalytic ability of 2 as a hydrogen-bonding catalyst was investigated in a Mannich-type reaction of N-acylisoquinoline 5a, which was generated in situ from 2,2,2-trichloroethyl chloroformate (TrocCl) and isoquinoline, as a benchmark reaction (Table 1).¹² As previously reported,^6a the reaction of 5a with ketene silyl acetal 6a proceeded slowly in the absence of a catalyst at −78 °C for 3 h (7% yield; entry 1). The reaction with ammonium iodide catalyst 1a was promoted to a moderate extent (38% yield; entry 2). Sulfonium iodide 2a was then examined as a catalyst, and a moderate acceleration of the reaction was also observed (30% yield; entry 3). It should be noted that simple ammonium iodide catalyst 3a showed almost no acceleration of the reaction (9% yield; entry 4). These results clearly demonstrated the importance of the acidity of α hydrogen atoms on a sulfonium salt 2a to promote the reaction. The exchange of the counteranion in 2a to tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF⁻) as a non-coordinating counteranion (2b) improved the results (47% yield, entry 5). The reaction with benzylsulfonium barfate 4 further improved the results, and catalyst 4 exhibited a somewhat higher reactivity than that of ammonium barfate 1b (67 and 61% yields, respectively; entry 6 vs. 7).

Table 1 Effect of catalysts in the Mannich-type reaction of N-acylisoquinoline 5a^a

Entry	Catalyst	Yield^b (%)
a Reaction conditions: 5a (0.20 mmol), 6a (0.30 mmol), catalyst (0.020 mmol, 10 mol%), THF (4.0 mL), −78 °C, 3 h. b Yield of the isolated product 7a. c The reaction was performed without a catalyst.
1	None^c	7
2	1a	38
3	2a	30
4	3a	9
5	2b	47
6	4	67
7	1b	61

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To further investigate the hydrogen-bonding interaction between the α hydrogen atoms of sulfonium salts and the chloride substrates of type 5, we performed NMR titration studies of benzylsulfonium salt 4 with chlorodiphenylmethane 8 as a relatively stable chloride compound (Fig. 3). As a result of the titration of 8, the clear upfield chemical shifts (0.065–0.073 ppm after adding 20 equiv. of 8) of the α hydrogen atoms of 4 were observed in ¹H NMR measurements (0.010 M in CDCl₃). This result strongly supported the proposition that sulfonium salts could activate chloride substrates of type 5via hydrogen bonding to promote the Mannich-type reaction. A titration experiment with ammonium salt 1b was also performed with the same concentration (0.010 M in CDCl₃), and the degrees of chemical shifts (0.041–0.048 ppm after adding 20 equiv. of 8) were smaller than those for the titration with 4 (Fig. S2 in the ESI†).

Fig. 3 ¹H NMR titration study of 4.

Benzylsulfonium salt catalyst 4 could accelerate the reaction of N-acylisoquinoline 5a with ketone-derived silyl enol ether 6b to give the corresponding product 7b in a moderate yield (Scheme 1). The reaction of 3-methylisoquinoline derivative 5b with 6a was also accelerated by catalyst 4 to obtain product 7c in a moderate yield. We also examined sulfonium salt-catalyzed regioselective reactions with quinolines 9.¹³ The reaction of quinoline 9a was efficiently promoted by catalyst 4 to give product 10a in a good yield and regioselectivity (10a/11a 6 : 1). Furthermore, the reaction with 6-chloroquinoline 9b gave product 10b in a good yield with an almost perfect level of regioselectivity (10b/11b >30 : 1).

Scheme 1 Benzylsulfonium barfate-catalyzed Mannich-type reactions.

To expand the utility of sulfonium salt catalysts, we were next interested in the activation of imines 12. An aza Diels–Alder reaction of N-phenylbenzaldimine 12a with Danishefsky diene 13 was employed as a model reaction to evaluate the ability of sulfonium salt catalysts for the activation of imines (Scheme 2).^14,15 In this reaction, sulfonium iodide 2a showed higher reactivity than ammonium iodides 1a and 3a. Also, sulfonium barfate 2b was a more effective catalyst than ammonium barfates 1b and 3b, and the reaction with catalyst 2b gave the highest yield of product 14a (98% yield). It should be noted that the more sterically hindered benzylsulfonium barfate 4 showed reactivity that was inferior to that of 2b. These results completely agree with our previous observations that sterically less-hindered catalysts are more effective in activating imines 12.^6b

Scheme 2 Effect of catalysts in the aza Diels–Alder reaction of imine 12a.

The substrate generality for the aza Diels–Alder reaction of imines 12 was examined with catalyst 2b (Scheme 3). Not only substituted aromatics but also heteroaromatic and alkyl group-introduced imines could be employed for the reaction to obtain products 14b–14f in moderate to high yields (54–99% yields). It should be noted that the addition of catalyst 2b produced clear accelerations of each reaction.

Scheme 3 Scope of the aza Diels–Alder reaction.

Furthermore, sulfonium barfate 2b efficiently promoted the reduction of imines 12 with Hantzsch ester 15 (Scheme 4).¹⁶ The reactions with catalyst 2b gave secondary amine products 16a–16c in good yields (67–81% yields).¹⁷

Scheme 4 Reduction of imines 12 with Hantzsch ester 15.

In summary, we have successfully demonstrated that trialkylsulfonium salts can function as hydrogen-bonding catalysts. The structure and binding abilities of sulfonium salts were discussed in this study based on the X-ray crystal structures and ¹H NMR titration studies. The catalytic ability of trialkylsulfonium salts was superior to that of the related tetraalkylammonium salts in both the Mannich-type reaction and the aza Diels–Alder reaction. This report revealed a new dimension of sulfonium salt chemistry in organic synthesis on the basis of the characteristic properties of the acidic α hydrogen atoms on alkylsulfonium salts. Further applications of sulfonium salts as catalysts are currently underway in our laboratory.

This work was partially supported by a Grant-in-Aid for Scientific Research(C) from JSPS, the Cooperative Research Program of “Network Joint Research Center for Materials and Devices”, and The Naito Foundation.

Notes and references

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17. No catalyst decomposition was observed after the reaction.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization data for new compounds. See DOI: 10.1039/c6cc08411g

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