Aerobic, Diselenide-Catalyzed Redox Dehydration: Amides and

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Aerobic, Diselenide-Catalyzed Redox Dehydration: Amides and Peptides Srirama Murthy Akondi, Pavankumar Gangireddy,† Thomas C. Pickel, and Lanny S. Liebeskind* Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States S Supporting Information *

ABSTRACT: At 2.5 mol % loadings using reaction temperatures between 30−55 °C, orthofunctionalized diaryl diselenides are highly effective organocatalytic oxidants for aerobic redox dehydrative amidic and peptidic bond formation using triethyl phosphite as a simple terminal reductant. This simple-to-perform organocatalytic reaction relies on the ability of selenols to react directly with dioxygen in air without recourse to metal catalysts. It represents an important step toward the development of a general, economical, and benign catalytic redox dehydration protocol.

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disclosed,26 and Taniguchi described a carefully studied, ironcatalyzed aerobic generation of acyloxyphosphonium intermediates that participate in esterification with alcohols.27 We recently described a new aerobic, catalytic acylative oxidation−reduction condensation system for efficient amide and peptide bond formations that relies on benzoisothiazolones 1, as organocatalytic oxidants that are linked via Cu-catalysis to O2 in air as the terminal oxidant (Scheme 1, Z = S).28,29 This mild redox dehydration system uses inexpensive triethyl phosphite as a stoichiometric terminal reducing agent and possesses good substrate generality.

ehydrative bond-forming reactions represent one of the most foundational of all chemical process, broadly spanning carbon-centered alkylative and acylative protocols as well as their heavier atom congeners. Traditionally, these bond-forming methods rely on a wasteful and inefficient process, the stoichiometric activation of the hydroxyl moiety to polarize the C−O bond prior to elimination of the functional equivalent of H2O. Modern chemical synthesis focuses on the development of new catalytic dehydrative methods that avoid expensive and wasteful stoichiometric activators,1−10 thus mitigating negative environmental and economic impacts. Various catalytic methods for alkylative2,6−9 and acylative3−5,10−12 dehydrative bond constructions have been explored; however, these processes can suffer from modest scope requiring fine-tuning to each new substrate and/or harsh reaction conditions. A particularly gentle and general dehydrative bond formation involves the removal of the elements of H2O from two reaction partners through the combined use of an organic oxidant to accept [2H] and an organic reductant to accept [O].13−17 These mild, pH-neutral “oxidation−reduction condensation” reactions were developed using stoichiometric quantities of both an organic oxidant and reductant, allowing the preparation of acylated derivatives from carboxylic acids13,18,19 and alkylated derivatives from alcohols.14−16 The transition from a stoichiometric mode redox dehydration, where full equivalents of organoreductants and organooxidants are used, to the catalytic domain involves the incorporation of redox regeneration steps. For all currently known protocols, the regeneration cycles for the organocatalytic oxidant and reductant are independent20 and in the best case scenarios linked to earthabundant terminal oxidants and reductants. None of the currently known protocols for redox dehydration is yet fully catalytic in both the organic reductant and oxidant.21 Alkylative redox dehydration processes (Mitsunobu reaction) that are catalytic in the organic oxidant have been disclosed,21−25 and a phosphinebased catalytic cycle using PhSiH3 as the terminal reductant was also described.25 For catalytic acylative redox dehydrations, less is known. An example catalytic in R3P using (EtO)2MeSiH as terminal reductant and CCl4 as stoichiometric oxidant was © XXXX American Chemical Society

Scheme 1. Organochalcogen Intermediates in Aerobic Redox Dehydrationa

a

See Figure 1 for a listing of substituents. Ortho 3° amide aryl dichalcogenides are restricted to the lower pathway of the mechanism.

The slow step in this catalytic redox dehydration reaction is the aerobic regeneration of the benzoisothiazolone 1 from the 2mercaptobenzamide 2, a process that requires a Cu cocatalyst and proceeds via the disulfide 3.30 Competitive side reactions29 and the slow rate of aerobic regeneration of the benzoisothiazolone from the 2-mercaptobenzamide compromise the viability of the organocatalyst. Thus, high loadings (20 mol %) are needed at 50 Received: November 21, 2017

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DOI: 10.1021/acs.orglett.7b03620 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters °C to drive the redox dehydrations to completion. This analysis suggests that a low-loading, fast, ambient temperature organocatalytic reaction system should be feasible if the aerobic reoxidation step can be made faster and catalyst degradation avoided. Insight here is gleaned from Nature’s replacement of sulfur by selenium,31−33 particularly in glutathione oxidase and peroxidase, selenocysteine-containing enzymes that can react rapidly and directly with O2 and hydroperoxides without the intervention of metal catalysts.34,35 This suggests that replacement of S by Se as the catalytic oxidant of Scheme 1 (benzoisothiazolone, 1 → benzoisoselenazolones, 4) could lead to faster organocatalytic redox dehydration reactions, without the requirement for cocatalytic Cu to facilitate the aerobic regeneration of the catalytic organic oxidant.36 Two benzoisoselenazolones bearing substitution patterns relevant to the more active benzoisothiazolones from our earlier study28 (Scheme 1, 4, R′ = −CH2CH2NMe2 and −C(Me2)-2pyridyl) were studied initially. At 5% loadings in the absence of Cu they were paired with 1.5 equiv of triethyl phosphite as a stoichiometric reductant and O2 in dry air as the terminal oxidant (0.2 M in MeCN, 4 Å molecular sieves, 8 h at 30 °C). Under these conditions, toluic acid and benzylamine effectively transformed into N-benzyl-p-toluamide. However, under these Cu-free conditions, the benzoisoselenazolone was shown to be a precatalyst; it is the diselenide that carries the catalytic cycle.37 The first pass of the benzoisoselenazolone 4 through the catalytic cycle of Scheme 1 generates the 2° amidic diselenide 6. In the absence of a Cu cocatalyst, which is strictly required for the benzoisothiazolone system,28 the diselenide 6 does not regenerate the benzoisoselenazolone. For example, 6, R′ = −CH2CH2NMe2, in CD3CN under dry air showed no evidence of disproportionation to the corresponding benzoisoselenazolone over a 24 h period at room temperature (1H NMR) in the absence of Cu but does so in its presence.38 In support of this observation, diselenides 6a−h, which include those bearing both 2° and 3° ortho amidic functional groups, were prepared and studied as catalysts at 2.5 mol % loadings for the aerobic redox dehydration of p-toluic acid and benzylamine to ptoluoyl N-benzylamide at 30 °C in MeCN (Figure 1). Triethyl phosphite serves as an economical terminal reductant.

On the basis of these results, the 2° and 3° ortho amidic diselenides 6g and 6h were chosen as catalysts for further exploration (Table 1). Reactions were carried out at 2.5 mol % loadings of catalyst under dry air in the presence of 4 Å mol sieves (to minimize rapid hydrolysis of the triethyl phosphite39). The results shown in Table 1 reveal some specific attributes of the diselenide-catalyzed reaction system. While CH3CN was an effective solvent at 30 °C, some less soluble or less reactive substrates gave better results in DMF and sometimes at 55 °C. In the case of the biotin example in entry 3, its insolubility in CH3CN prompted a switch to DMF as solvent. However, the 2° amidic diselenide 6g was ineffective as a catalyst in DMF, degrading under the reaction conditions. Significantly, the very similar 3° amidic catalyst 6h proved to be robust and was a highly effective catalyst, even in polar solvents like DMF. Overall, 3° amidic catalyst 6h in CH3CN was preferred. If reactions are slow, a reaction temperature increase above 30 °C is of benefit. When reactant solubility is problematic, a switch to DMF is acceptable. Not just primary but secondary amines were effective reactants (i.e., see entries 12 and 14). Minor diacylation of a primary amine was noted in one case (entry 8, 8% of diacylated product was isolated). The reaction of entry 11 was problematic in CH3CN (gel formation at rt) and was accomplished by conducting the reaction at rt in DMF. Although organoselenium compounds are well-known oxidation catalysts in the presence of hydroperoxides,40−42 oxidation-sensitive moieties such as indoles, phenols, and thioethers readily survive the conditions of the aerobic redox dehydration reactions. In fact, reactions are faster in the presence of pure O2: exposure of p-toluic acid and benzylamine under O2 to 2.5% diselenide catalyst 6g in CH3CN at 30 °C generated p-toluic acid N-benzylamide in 92% yield after 4 h. Entries 1, 2, 6, 7, and 14 showed no evidence of racemization (i.e., formation of diastereomers). The very racemization sensitive Anteunis peptide (Z-Gly-L-Phe-L-ValOMe)43 was generated in 98:2 dr by coupling Z-Gly-L-PheOH and L-ValOMe·HCl, although addition of CuCl244 was required to minimize racemization in that case (entry 17). The diselenide-catalyzed redox dehydration bears a resemblance to our recently described benzoisothiazolone-catalyzed redox dehydrative amidation/peptidation chemistry,28,29 but it is mechanistically distinct. In the previous study (Scheme 1, Z = S, limited to organocatalysts bearing 2° ortho amidic substituents), the benzoisothiazolone 1 carried the catalytic cycle. The slow step is the aerobic regeneration of the benzoisothiazolone from the 2mercaptobenzamide 2, a process that proceeds via the disulf ide 3.30 Both the aerobic oxidation and disproportionation of the disulfide to the benzoisothiazolone require a Cu catalyst. In contrast, the diselenide-based system described herein relies on the ability of selenols/selenides (5, Scheme 1) to react directly with dioxygen to regenerate the diselenide 6 without the intervention of metal catalysts.34,35 Thus, the replacement of S by Se mitigates the need for cocatalytic Cu, which circumvents disproportionation of the diselenide 6 to a benzoisoselenazolone 4 (Scheme 1). The S to Se change also provides a robust increase in reaction rates at various steps.31−33 The overall rate enhancement here compared to that in ref 28 appears to result from increased rates of direct aerobic regeneration of the catalytic organoselenium oxidant relative to the very sluggish aerobic regeneration in the benzoisothiazolone system. For example, ortho 3° amidic diselenide 6h (λmax = 338 nm) at 0.04 mM in CH3CN under argon in a UV cuvette is stable to the presence of 1 equiv of P(OEt)3 but is rapidly transformed within 15 min into a new product with λmax = 458 nm when toluic

Figure 1. Diselenides as aerobic redox dehydration catalysts.

The rate data provided in the SI show that ortho amidic substituted aryl diselenides possessing basic N-residues positioned three atoms removed from the amidic N (2° amidic 6f and 6g and 3° amidic 6h) are the most effective catalysts of those studied. The significant difference in reactivity between diselenides 6c (slow) and 6g (fast) that differ only in the distance of the pendant −NMe2 unit from the amidic N atom suggests an important role for intramolecular geometric factors in the catalysis. In fact, the three-carbon tethered catalyst 6c is similar in reactivity to 6b, which lacks a pendant NMe2 moiety. B

DOI: 10.1021/acs.orglett.7b03620 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Amidations and Peptidations Using Aerobic, Diselenide-Catalyzed Redox Dehydrationa

a

Reaction conditions: 1.0 equiv of carboxylic acid, 1.1−1.2 equiv of amine, 1.5 equiv of P(OEt)3, 2.5 mol % of catalyst 6g or 6h, solvent, dry air balloon and 4 Å mol sieves (1.0× wt % of acid). Solvent, temperature, and reaction time are given in the table entries. bDiisopropylethylamine (1.05−1.15 equiv) was added to neutralize the amine·HCl salt for entries 1, 2, 6, 7, 12, 14, 16, and 17. c8% of diacylated product was isolated. d1:1 mixture of diastereomers. eThe diastereomeric ratio (98:2) was determined using a chiral AS-RH column. Triethylphosphite and DIPEA were added at 0 °C; 1 equiv of CuCl2 was used to minimize racemization.44

deprotonated selenol 5h, derived from reduction of diselenide 6h, when an NMR tube solution of diselenide 6h, triethyl phosphite, and toluic acid in CD3CN was allowed to stand (see the SI for the X-ray crystallography). In conclusion, the experiments within demonstrate a role for specifically designed diselenides as highly effective, low-loading organocatalytic oxidants for the redox dehydrative formation of amides and peptides under simple aerobic, Cu-free conditions. Diaryl diselenides bearing a p-NO2 substituent in concert with an appropriately positioned pendant basic N atom on the substituent ortho to the selenium are especially effective. These nonvolatile organoselenium compounds possess no ill odor. This constitutes a useful step toward the development of a broadly general, economical, and benign catalytic acylation protocol.

acid is added (see the SI for UV/vis traces). Exposure of the resulting solution in the UV cuvette to dry air at room temp converts the system back to the original UV spectrum of diselenide 6h over a period of 15 h, the transformations in both directions taking place with the same clean isosbestic point. These observations are fully consistent with very rapid reduction of the diselenide by triethylphosphite in the presence of the carboxylic acid to generate the arylselenol/selenide 5h (selenide λmax = 458 nm) and a reasonable rate of oxidation back to the diselenide at room temperature. The boost in reaction rate when a basic moiety is positioned 3atoms removed from the amidic N on the ortho residue (6g and 6h but not 6c in Figure 1) suggests it is an intramolecular interaction of the −NMe2 that enhances reaction rates. Given the modest rate of the aerobic reoxidation step compared to the very fast cleavage of the diselenide by P(OEt)3/RCO2H, the substituent effect most likely occurs through enhanced rates of aerobic oxidation via intramolecular deprotonation of the intermediate selenol to the selenide (cf. Mugesh and co-workers for ortho-substituted, amine-based diaryldiselenides that function as glutathione peroxidase mimics45). Support for this suggestion comes from the formation of the stable, crystalline, internally

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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.7b03620. Full experimental details and characterization data (PDF) C

DOI: 10.1021/acs.orglett.7b03620 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Accession Codes

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CCDC 1577749 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lanny S. Liebeskind: 0000-0002-2223-6618 Present Address † (P.G.) Medicinal Chemistry Department, NIPER Hyderabad, Hyderabad, Telangana 500037, India.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE-1362281 and CHE-1531620 (NMR Facility)). We acknowledge the use of the Rigaku SYNERGY diffractometer, supported by the National Science Foundation (CHE-1626172). We thank Dr John Bacsa, Emory X-ray Crystallography Facility, for the X-ray structural analysis. We thank Dr. Nikolai V. Orlov (Moscow) for his early contributions to the project. Dr. Savita K. Sharma in Dr. Cora MacBeth’s Emory University laboratory provided assistance with the UV−vis studies.

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DEDICATION Dedicated to our colleague Professor Dr. Albert Padwa on the occasion of his 80th birthday. REFERENCES

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DOI: 10.1021/acs.orglett.7b03620 Org. Lett. XXXX, XXX, XXX−XXX