Redox-Neutral Synthesis of Selenoesters by Oxyarylation of

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Redox-Neutral Synthesis of Selenoesters by Oxyarylation of Selenoalkynes under Mild Conditions Lucas L. Baldassari,†,§ Anderson C. Mantovani,†,§ Samuel Senoner,‡,§ Boris Maryasin,‡ Nuno Maulide,*,‡ and Diogo S. Lüdtke*,† †

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Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av Bento Gonçalves 9500, 91501-970 Porto Alegre, RS, Brazil ‡ Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria S Supporting Information *

ABSTRACT: An approach for the mild synthesis of selenoesters starting from selenoalkynes through an acid-catalyzed, redoxneutral oxyarylation reaction is reported. Brønsted acid activation of a selenoalkyne leads to a selenium-stabilized vinyl cation, which is captured by an aryl sulfoxide and undergoes sigmatropic rearrangement to deliver the final α-arylated selenoester product. Computational studies have been carried out to elucidate the nature of the Se-stabilized carbocation. Table 1. Optimization of the Reaction Conditionsa

S

elenoesters are versatile functional groups in synthetic organic chemistry. They have been used as mild acyltransfer agents,1 as acyl-radical precursors,2 for heterocycle Scheme 1. Key Precedents and This Work

entry

TfOH (equiv)

solvent

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9

1.0 0.5 0.1 0.1 0.1 0.1 0.1 0.1 0.1

CH2Cl2 CH2Cl2 CH2Cl2 DCE PhCl toluene hexane THF

1 1 1 1 1 1 1 1 1

60 80 86 40 32 35 18 17 75

a The reaction was performed in the presence of 1a (0.25 mmol) and 2 (0.50 mmol). bYield determined by NMR spectroscopy using mesitylene as the internal standard.

synthesis,3 in asymmetric aldol reactions,4 and as key intermediates for the incorporation of the amino acid selenocysteine (and other selenoamino acids) in peptides through the native chemical ligation method.5 In addition, selenoesters have found applications in pharmaceutical6 and material sciences.7 The vast majority of the methods available for the synthesis of selenoesters typically employ acyl chlorides and a nucleophilic selenium source (Scheme 1A).8 Other Received: August 8, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b02544 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of the Selenoalkyne

the amount of TfOH to 0.5 and 0.1 equiv, and gratifyingly, the arylated selenoester was obtained in 86% yield using only 10 mol % of triflic acid (entry 3). A solvent screening was also carried out, revealing that dichloromethane outperforms all other solvents investigated (entries 3−8). It should be noted that an efficient reaction was observed without solvent, albeit at slightly decreased yield (entry 9). On the basis of these studies, the two best conditions shown in entries 3 (conditions A) and 9 (conditions B) have been selected for further screening of the substrate scope using a broader range of selenoalkynes (Scheme 2). A number of selenoalkynes with different substitution patterns have been studied. Variations at the R2 group attached to the selenium atom have shown that alkyl (3a−d) and benzylic (3e) groups were well tolerated under the reaction conditions. Noteworthy is the tolerance to the presence of a primary alkyl chloride, with the corresponding product 3d being formed in 86% isolated yield. Arylselenoalkynes were also examined, and the corresponding selenoesters 3f−k were obtained in good yields. The presence of chlorine, methoxy, phenyl, and trifluoromethyl groups was well tolerated as well as the presence of an ortho substituent. Variations at the R1 position have also been performed, and selenoalkynes bearing longer linear alkyl chains resulted in the desired selenoester product in good yields. Additionally, a cyclohexenyl substituent at the selenoalkyne also resulted in the corresponding product 3u, albeit in low

approaches include oxidative coupling of aldehydes and diphenyl diselenide,9 addition of organocopper reagents to carbonyl selenide (SeCO),10 a reaction of carboxylic acids with aryl selenocyanates11 and Pd-catalyzed coupling of PhSeSnBu3 with acyl chlorides.12 The hydrolysis of alkynyl selenides has also been reported.13 Despite the wealth of available methods, selenoesters are not easy to synthesize, and the reported routes can be cumbersome, with substrate scope frequently limited to simple (usually aromatic) substrates. Herein, we present an original approach starting from selenoalkynes through an acid-catalyzed, redox-neutral oxyarylation reaction. The concept can be traced back to our previous studies on acid-mediated activations of ynamides in which a nitrogen-stabilized vinyl cation intermediate was generated (Scheme 1B).14,15 We reasoned that this concept could be extended to selenoalkynes, and thus, a seleniumstabilized vinyl cation would result from the reaction with TfOH.16 This intermediate might then be intercepted by an aryl sulfoxide, which in turn would be poised to undergo a Claisentype [3,3]-sigmatropic rearrangement, ultimately delivering an α-arylated selenoester product (Scheme 1C). At the outset, we selected selenoalkyne 1a and diphenyl sulfoxide as model substrates for the optimization of the oxyarylation conditions. Selected results are summarized in Table 1.17 In initial experiments employing a full equivalent (1.0 equiv) of TfOH, the product 3a was obtained in 60% yield (entry 1). Aiming to render the reaction catalytic, we lowered B


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Organic Letters Scheme 3. Scope of the Sulfoxide

Figure 2. (Left) Relative Gibbs free energies of selenoalkynes and sulfur−alkynes (the alkynes are taken as references) and corresponding seleno and sulfur vinyl cations calculated at the B3LYP-D3-SMD/ def2-TZVP level of theory. (Right) Stabilizing donor−acceptor interactions.

yield. Finally, using an unsubstituted selenoalkyne delivered the selenoester 3v in 79% yield. We next turned our attention to the scope of the aryl sulfoxide reaction partner (Scheme 3). Both electron-donating

Figure 1. Computed reaction profiles (B3LYP-D3-SMD/6-31+G(d,p), ΔG298,DCM) for the conversion of sulfur−alkyne (red) vs selenoalkynes (green) into the final product F. The energy of the reactant complex A is taken as a reference (0.0 kcal mol−1). C


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Organic Letters

donor−acceptor interaction is stronger for the seleniumsubstituted vinyl cation than for its sulfur counterpart and vice versa for the alkyne case; i.e., the thioalkyne is more strongly stabilized than its selenium counterpart. Put in intuitive terms, the larger polarizability of selenium20 appears to play the more important role in vinyl cation stabilization (compared with “size”-dependent orbital overlap efficiency, which could be expected to be larger for sulfur and is predominant in stabilization of the allene). This computationally documented superior ability of selenium to stabilize the vinyl cation intermediate should be of considerable significance in the development of further chemistry of selenoalkynes. In summary, we have reported herein the redox-neutral oxyarylation of selenoalkynes as a mild and efficient approach for the synthesis of selenoesters. The reaction involved the activation of the triple bond to generate a selenium-stabilized vinyl cation which was trapped with an aryl sulfoxide and subsequently underwent a Claisen-type rearrangement to afford the α-arylated sulfoxide product. The reported method is a mild and complementary alternative to the previously reported methods. Computational studies using DFT and NBO analysis reveal that selenium is superior to sulfur in stabilizing the vinyl cation intermediate, an observation likely to have fundamental and practical implications for future work.

and electron-withdrawing groups were successfully used (4a− f). Importantly, alkylaryl sulfoxides are also competent nucleophiles for oxyarylation, and smooth aryl transfer was observed (4g−j). Using symmetric 4-tolyl(phenyl) sulfoxide led to selective transfer of the phenyl group leading to product 4j. In our hands, the oxyarylation products appear to decompose upon prolonged exposure to light, presumably due to facile cleavage of the labile carbonyl−Se bond. While such a cleavage is likely to be of homolytic nature when induced by light, it should be noted that selenoester 4d underwent hydrolysis during silica gel chromatographic purification. That compound was thus ultimately isolated as the corresponding carboxylic acid. In contrast to seleniumstabilized alkyl carbocations, long known in the literature,18 vinyl carbocations have been largely overlooked and rarely explored or proposed as intermediates in organic synthesis.19 Therefore, in order to further elucidate the mechanism of the reaction, a computational study was carried out (Figure 1). In this study, thio- and selenoalkyne substrates were analyzed comparatively. Figure 1 compares the computed reaction profiles for the conversion of thio- (red) and selenoalkynes (green) into the final product. The two considered substrates show similar energetic behavior. The overall reaction is exergonic for both systems, and the barriers are relatively low, in agreement with the mild reaction conditions. The most significant distinction between the computed sulfur and seleno pathways is the stability of intermediates B ternary complexes of vinyl cations, sulfoxides, and triflate anions. While this energy difference might be the result of intermolecular interactions within the complexes B, it appears reasonable to assume the nature of the vinyl cations selenium- vs sulfur-stabilized vinyl cationscan cause this effect. To validate this assumption, we have reoptimized the structures of the alkyne (part of the complex A) and vinyl cation (part of the complex B) for both cases, separately from sulfoxide, TfOH, and TfO−. For these simplified systems, we have improved the computational approach applying the larger basis set def2-TZVP. Figure 2 (left) shows that for both seleno and thio systems the alkynes are, unsurprisingly, more stabilized than the vinyl cations (in agreement with the results shown in Figure 1) and the energy gap is ∼1 kcal mol−1 smaller in the case of selenium. The latter is also in accordance with the computed reaction profiles (Figure 1). Thus, the electronic structures of the alkynes and the vinyl cations, rather than the intermolecular interactions within reaction intermediates, predetermine the computed energy gap. To elucidate the factors responsible for stabilization, we have performed a Natural Bond Orbital (NBO) analysis of the alkynes and the vinyl cations for both cases. Figure 2 (right) depicts the most important donor−acceptor interactions for these systems. The interacting orbitals and the second-order perturbation energies E(2) of these interactions are also shown. The vinyl cations are stabilized via an interaction between the lone pair on sulfur/selenium atom and the σ*(antibonding) C1−C2 orbital. Analogously, there are interactions between the lone pairs and the π*(antibonding) C1− C2 orbitals for the corresponding alkynes. The fact that the stabilization interactions are stronger for the alkynes than for the vinyl cations is in agreement with the fact that vinyl cation formation is an endergonic process (Figures 1 and 2). However, as can be seen from Figure 2, the stabilizing

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02544. Experimental procedures, analytical data, copies of NMR spectra, and computational details ((PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Nuno Maulide: 0000-0003-3643-0718 Diogo S. Lüdtke: 0000-0002-9135-4298 Author Contributions §

L.L.B., A.C.M., and S.S. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Brazilian Agencies CNPq, CAPES, and INCTCatálise for financial support. Calculations were partially performed at the Vienna Scientific Cluster (VSC). We thank Prof. Leticia González (University of Vienna) for fruitful discussions and computational resources. Support of this research by the European Research Council (CoG 682002 VINCAT) and the University of Vienna is gratefully acknowledged.

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REFERENCES

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Redox-Neutral Synthesis of Selenoesters by Oxyarylation of

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