Elsevier

Tetrahedron Letters

Volume 52, Issue 38, 21 September 2011, Pages 4906-4910
Tetrahedron Letters

Regioselective addition of thiophenol to α,β-unsaturated N-acylbenzotriazoles

https://doi.org/10.1016/j.tetlet.2011.07.057Get rights and content

Abstract

Regioselective addition of thiophenol to α,β-unsaturated N-acylbenzotriazoles has been achieved by controlling the conditions. Thus, three types of products, namely α,β-unsaturated thioesters, β-thiophenoxy substituted N-acylbenzotriazoles, and β-thiophenoxy substituted thioesters were selectively obtained in good to excellent yields.

Introduction

Sulfur-containing compounds are important in bioorganic chemistry and in medicinal areas for their antibiotic, antimicrobial, anti-inflammatory, antitumor, and anti-HIV activities.1 Among them, α,β-unsaturated thioesters show their attractive pharmacological properties such as antiatherogenic,2 antitubercular,3 and antitumor4 activities; they are also employed for the assembly of bioactive complex molecules.5 β-Thiophenoxy substituted amides are medicinally useful.6 As a class of β-thiophenoxy substituted amides, β-thiophenoxy substituted N-acylbenzotriazoles may possess potent biological activities. β-Thiophenoxy substituted thioesters were reported as key intermediates for the synthesis of valuable thioesters,7 and β-thiophenoxy substituted acids.8

α,β-Unsaturated N-acylbenzotriazole (α,β-acylBt) is a class of useful unsaturated amides which contain both electron-withdrawing carbon–carbon double bond moiety (for Michael addition) and active amide moiety (for acylation).9 Therefore, it may act as a Michael addition acceptor and/or an acylating reagent.10 The acylation of various N-,11 S-,12 and C-nucleophiles13 with α,β-acylBt has been realized with high efficiency. Besides, α,β-acylBt successfully reacted with indoles,14a amines,14b and azlactones14c to afford the corresponding 1,4-adducts. Bis-addition of binucleophile to α,β-acylBt was also known. Although α,β-acylBt could smoothly acylate hydrazine to form the corresponding α,β-unsaturated hydrazides,11a the reaction with arylhydrazines afforded unexpectedly the 2-aryl-substituted pyrazolidin-3-ones in good yields with the aryl-substituted NH being acylated (1,2-addition) while the unsubstituted NH attacked in a 1,4-mode at the same time.15 In most cases, the 1,2-and 1,4-selectivity was substrate-dependent. Tuning the regioselectivity for the addition reaction of α,β-acylBt remains a challenge.

Herein, we wish to report that thiophenol could undergo regioselective 1,2-addition (acylation), 1,4-addition (Michael addition) and bis-addition (both the 1,2- and 1,4-addition) to α,β-acylBt under controlled conditions (Scheme 1).

In light of the fact that thiophenol could be acylated smoothly by N-acylbenzotrizoles in the presence of triethylamine (TEA),16 the acylation of thiophenol with N-cinnamoyl benzotriazole was carried out under the same conditions. In this case, a mixture of α,β-unsaturated thioester 1a and β-thiophenoxy substituted thioester 1c was obtained (they were inseparable by column chromatography) with a molar ratio of 2:3 (based on 1H NMR, see Supplementary data) (Scheme 2).

Nevertheless, we fortunately found that ZnCl2/TEA could efficiently promote the acylation with complete selectivity and 1a could be obtained as the sole product.17 It was reasonable to propose that ZnCl2 chelated with the N-acylbenzotriazole moiety, and meanwhile TEA deprotonated the thiophenol to form the more nucleophilic thiolate (Scheme 3). The combination of these factors possibly favored the 1,2-addition and led to the selective formation of α,β-unsaturated thioesters. The presence of TEA is necessary for the good yields of 1a since a controlled experiment without TEA resulted in poor conversion of the two substrates in 20 h regardless of the presence of ZnCl2.

The generality of the reaction was subsequently investigated. As summarized in Table 1, the α,β-acylBt with an electron-donating or weak electron-withdrawing group on the aromatic ring afforded good to excellent yields of the α,β-unsaturated thioesters (entries 2–5 and 7), while the substrate with a strong electron-withdrawing group (p-NO2) only gave moderate yield (entry 6). It was worth mentioning that the acylation proceeded with high 1,2-addition selectivity for all the aromatic α,β-acylBts examined. Interestingly, crotonoyl benzotriazole under the same conditions afforded the bis-addition product in 48 h (Scheme 4). The expected α,β-unsaturated thioester was neither isolated nor detected. In contrast, the 1,4-adduct and bis-addition product were detected in the process. In addition, the 1,4-adduct finally disappeared and transformed into the bis-addition product completely. We postulated that crotonoyl benzotriazole, with less hindrance at the β-position (R1: methyl vs aryl in Scheme 3), preferably underwent the 1,4-addition and subsequent acylation of thiolate occurred resulting in the bis-addition product.

We next turned our attention to achieving the selective 1,4-addition between thiophenol and α,β-acylBt. Screening of the catalysts found that a number of Lewis acids18 such as AlCl3, FeCl3, Zn(OTf)2, and I2 were unsuitable for this selective thia-Michael addition (a mixture of products a, b, and c with different ratios was always obtained). When we employed silica gel,19 although the desired reaction in anhydrous THF almost failed to occur (Table 2, entries 1 and 2), it did proceed selectively in wet THF. The catalytic efficiency of silica gel was found to be highly dependent on the water content. And further studies revealed the yield increased remarkably when a suitable ratio of water was introduced as the co-solvent (entry 3). It was established that the optimal volume ratio of THF and H2O was 9:1 (entries 1–5). The presence of higher content of water suppressed the yield (entries 4 and 5). The molar ratio of the substrates was also optimized, and good yield was obtained by employing 1.4 equiv of thiophenol (entries 3 and 6–8). The selectivity and yield for 1b could be further improved by lowering the temperature (although longer reaction time was required) (entries 7, 9, and 10), and −20 °C was chosen as the most suitable temperature (entry 10).

With the optimized conditions, we then explored the 1,4-addition reactions of various α,β-acylBt. As shown in Table 3, the reaction was applicable to a variety of substrates and provided the desired Michael adducts in good to excellent yields. The α,β-acylBt with electron-withdrawing groups on the aromatic ring performed better than those with electron-donating groups (entries 3–7 and 10–11). The α,β-acylBt with an ortho-substituted aryl group also provided excellent yield (entry 5). Aliphatic α,β-acylBt was amenable to the addition reaction as well (entries 8 and 9). The 4-methoxyphenyl- and 2-furyl- substituted α,β-acylBt reacted much less efficiently and may even afford a mixture of several products (entries 12 and 13). The reason may be that the two electron-rich aryls weakened the electrophilicity of the β-position and make the 1,4-addition difficult.

Although the detailed mechanism of the reaction remains to be explored, water should play an important role in the regioselective 1,4-addition. Recently, water was found to be a good solvent for the thia-Michael addition of thiols to enones.20 Taking account of the action of silica gel21 and water, a plausible mechanism was proposed (Fig. 1). The water absorbed on the surface of the silica gel forms hydrogen bonds with the hydroxyls of the silica gel. Thus the hydroxyls could readily form a hydrogen bond between the carbonyl of α,β-acylBt and the –SH of the thiophenol. Two suitably located hydroxyls of the silica gel could activate the two substrates concurrently and make the 1,4-addition electronically and regionally favorable.

Finally, we attempted to extend this method to the one-pot synthesis of β-thiophenoxy substituted thioesters. Considering that N-acylbenzotriazoles are an efficient S-acylating reagent, we postulated that product b could further acylate thiophenol to achieve the bis-addition.

The reaction of 2.5 equiv of thiophenol with N-cinnamoyl benzotriazole showed that under the same conditions, the desired product 1c could be obtained in 63% yield accompanied with the side reaction of hydrolysis of the N-acylbenzotriazole moiety. Therefore, to minimize the hydrolysis, anhydrous conditions were applied in this case. To our delight, good to excellent yields of β-thiophenoxy substituted thioesters were obtained with silica gel as the catalyst in refluxing anhydrous THF (using 2.5 equiv of thiophenol), and the results are summarized in Table 4. Both electron-donating and electron-withdrawing groups on the aryl could be tolerated (entries 1–7). Aliphatic α,β-acylBt gave relatively lower yields (entries 8 and 9). 2-Furanyl substituted α,β-acylBt afforded an inseparable mixture (entry 10).

Although β-thiophenoxy substituted thioesters c could be formed via b by further acylation (Scheme 5, Path B). The possibility for the formation of c by an alternative way was also investigated (Scheme 5, Path A). Thus β-thiophenoxy substituted N-acylbenzotriazle 2b and α,β-unsaturated thioester 2a were mixed, respectively, with 1.2 equiv of thiophenol using silica gel as the promoter in refluxing THF. Interestingly, both of the reactions afforded product 2c successfully. Nevertheless, the conversion of 2a was much lower (about 68% of 2a was recovered after 30 h) while 2b could be consumed completely in 1.5 h to afford 2c in 89% yield. Based on the above experiments, we propose that the formation of c should proceed mainly via Path B (Scheme 5).

In summary, we have developed a facile and efficient protocol for the regioselective addition of thiophenol to α,β-unsaturated N-acylbenzotriazoles. Thus a variety of α,β-unsaturated thioesters, β-thiophenoxy substituted N-acylbenzotriazoles and β-thiophenoxy substituted thioesters could be prepared, respectively, in good to excellent yields under controlled conditions.22 The readily available catalysts, facile procedures, and potentially valuable products would make the methods practical and useful to synthetic chemists. Besides, the mechanism for the regioselectivity was discussed and it may provide an additional hint for the regioselective control of 1,2-, 1,4-, and bis-addition between other nucleophiles and electron-deficient alkenes. The application of the 1,4-adducts β-thiophenoxy substituted N-acylbenzotriazoles in the synthesis of structurally more versatile compounds is currently undergoing in our lab.

Section snippets

Acknowledgment

This work was financially supported by the National Natural Science Foundation of China (No. 20802070).

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