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. 2020 Oct 13;22(22):8802–8807. doi: 10.1021/acs.orglett.0c03160

Chemoselective α-Sulfidation of Amides Using Sulfoxide Reagents

Mario Leypold 1, Kyan A D’Angelo 1, Mohammad Movassaghi 1,*
PMCID: PMC7680396  NIHMSID: NIHMS1641039  PMID: 33048547

Abstract

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The direct α-sulfidation of tertiary amides using sulfoxide reagents under electrophilic amide activation conditions is described. Employing convenient and readily available reagents, selective functionalization takes place to generate isolable sulfonium ions en route to α-sulfide amides. Mechanistic studies identified activated sulfoxides as promoters of the desired transformation and enabled the extension of the methodology from benzylic to aliphatic amide substrates.

New methods for the introduction of carbon–sulfur bonds are of interest in the synthesis and diversification of bioactive compounds given the existence of hundreds of sulfur-containing structures approved by the U.S. Food and Drug Administration for the treatment of human ailments.1−3 Existing methods for the α-sulfidation of amides rely on nucleophilic displacement, either through the use of basic conditions to activate the amide for nucleophilic attack or α-electrophiles in combination with nucleophilic thiols (Scheme 1A).4 As an outgrowth of our studies concerning electrophilic amide activation for practical carbon–carbon and carbon–nitrogen bond-forming reactions,5,6 we recognized an opportunity to develop an orthogonal approach compared with contemporary methods for the introduction of carbon–sulfur bonds. Herein we describe the direct, chemoselective α-sulfidation of amides using sulfoxide reagents (Scheme 1B).

Scheme 1. Methods for the α-Sulfidation of Amides.

Scheme 1

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We have previously demonstrated5,6 that the reagent combination of trifluoromethanesulfonic anhydride (Tf2O) and a substituted pyridine such as 2-chloropyridine (2-ClPy)7 is effective for electrophilic amide activation8 to enable the addition of various nucleophiles. Innovative reports continue to demonstrate the practical nature of this approach to amide derivatization.9,10 Inspired by observations on the addition of pyridine N-oxides to activated amides,11 as in our modified Abramovitch reaction that leads to carbon–nitrogen bond formation,5e and the use of sulfoxides in carbon–carbon bond formation,9j we envisioned the use of sulfoxide reagents for carbon–sulfur bond formation. Sulfoxides are readily available, easily derivatized, and bench stable in comparison with noxious thiols and can serve as both an oxidant and a sulfur source.12,13

We anticipated that the addition of dimethyl sulfoxide (DMSO, 2a) upon the electrophilic activation of amide 1a would lead to oxysulfonium ion 7aa en route to α-sulfonium amide 3aa, which could afford α-sulfide amide 4a after demethylation (Scheme 2). Under optimal conditions,14 the activation of amide 1a with Tf2O (1.05 equiv) and 2-ClPy (3.00 equiv) followed by the addition of DMSO (1.20 equiv) gave complete sulfoxide addition and conversion to α-sulfonium amide 3aa at −30 °C without the observation of any persistent intermediates by in situ IR.15 The exposure of sulfonium ion 3aa to excess triethylamine in acetonitrile at 60 °C subsequently led to quantitative demethylation16 and afforded α-sulfide amide 4a (67% yield, two steps). Furthermore, a single-step procedure was also developed wherein the use of tert-butyl methyl sulfoxide (TBMSO, 2b) as the sulfidation reagent enabled direct access to sulfide 4a in 54% yield via the spontaneous dealkylation of α-sulfonium amide 3ab.

Scheme 2. α-Sulfidation of Benzylic Amide 1a.

Scheme 2

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The application of this chemistry to the α-sulfidation of α-aryl acetamides is illustrated in Scheme 3. Sulfide 4a could be prepared on a 5.00 mmol scale without compromising the reaction efficiency via either the two-step procedure (Method A: 70% yield) or the single-step procedure (Method B: 56% yield). A variety of α-aryl acetamides including versatile morpholine-derived amides (4a and 4h–4o),17 in addition to N-methoxy- (4c),18N-phenyl- (4e and 4f), and N-benzyl-substituted (4d and 4g) amides, served as substrates for this transformation.19,20 Substituents that may compromise the stability of the α-sulfonium ion intermediate 3 led to low isolated yields of the desired product (4i and 4j). When demethylation was omitted, dimethylsulfonium trifluoromethanesulfonates 3aa and 3ba derived from morpholine and pyrrolidine amides 1a and 1b could be isolated in 61 and 68% yield, respectively.14

Scheme 3. α-Sulfidation of Benzylic Amides.

Scheme 3

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Reagents and conditions: Method A (methyl sulfoxides): Tf2O (1.05 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; methyl sulfoxide (2a, 2f, 1.20 equiv), CH2Cl2, −78 → 22 °C, 45 min; Et3N (10 equiv), MeCN, 60 °C, 15 h. Method B (tert-butyl sulfoxides): Tf2O (1.05 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; tert-butyl sulfoxide (2b–2e, 1.20 equiv), CH2Cl2, −78 → 22 °C, 45 min. Yields are reported: Method A, Method B.

Employing our single-step sulfidation procedure, we also examined the use of other tert-butyl sulfoxides 2c–2e with amide 1a to give the corresponding α-sulfide amides 4p–4r.14 In each case, the primary alkyl substituent of the tert-butyl sulfoxide was preserved, owing to the relative stability of the cation derived from the tert-butyl substituent in the spontaneous dealkylation. Complimentarily, α-sulfide amide 4r was also obtained in 62% yield with methyl sulfoxide 2f after regioselective dealkylation, leaving the homobenzylic substituent intact. Whereas the two-step procedure generally affords higher yields, tert-butyl sulfoxides directly form the α-sulfide amides. Additionally, the use of tert-butyl sulfoxides enables the sulfidation of substrates where the α-sulfonium ion intermediate is subject to hydrolysis (e.g., sulfidation of α,α-diphenyl acetamide S1 to α-thiomethyl amide S4).14

graphic file with name ol0c03160_0006.jpg 1
graphic file with name ol0c03160_0007.jpg 2

In evaluating the scope of the transformation, we found that the conditions described in Scheme 3 were not compatible with amides other than α-aryl acetamides. We therefore pursued a series of mechanistic experiments to guide our efforts to expand the substrate scope of our amide sulfidation methodology. Whereas the use of DMSO-d6 (2a-d6) for the α-sulfidation of benzylic amide 1b led to α-sulfide amide 4b-d3 in 71% yield (eq 1), when DMSO-d6 (2a-d6) was used with aliphatic amide 1t, we only observed the recovery of tertiary amide 1t-d1 (85% yield) with 88 atom % D incorporation at the α-position (eq 2).14 We attributed these observations to a retro-ene reaction from intermediate 7ta-d6 that is preferred for aliphatic substrates.21,22

Toward our goal of the mechanism-guided expansion of the scope of our α-sulfidation chemistry, it was necessary to develop a detailed understanding of the underlying sulfidation pathway. We envisioned that oxysulfonium ion intermediate 7, derived from the addition of sulfoxide to keteniminium 6, undergoes rearrangement to give the α-sulfonium amide 3. Both intra- and intermolecular pathways for 1,3-sulfur shifts were identified by Kwart for neutral sulfides,23 and we have previously described an intramolecular pathway in our modified Abramovitch reaction.5e In contrast with these existing proposals, we identified a distinct intermolecular sulfidation pathway supported by density functional theory (DFT) calculations, wherein an electrophilically activated sulfoxide 8(24) transfers the sulfonium moiety via a cyclic transition state (Scheme 4).

Scheme 4. Proposed Intermolecular Sulfidation Pathway.

Scheme 4

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Distinguishing intra- and intermolecular sulfidation pathways was accomplished by means of a crossover experiment employing an equal mixture of DMSO (2a) and doubly labeled DMSO-18O-d6 (2a-18O-d6). When amide 1b was subjected to the standard reaction conditions using this sulfoxide mixture, we observed the substantial formation of crossover sulfonium ion products 3ba-18O/3ba-d6 and DMSO (2a-18O/2a-d6) by quadrupole time-of-flight (Q-TOF) mass spectrometry,14 consistent with our proposed intermolecular pathway.25,26 Notably, crossover in the recovered sulfoxide is inconsistent with a separate intermolecular pathway akin to Kwart’s,23 involving the combination of two oxysulfonium ions 7.27

In considering other intermolecular pathways, we sought to distinguish our mechanistic proposal from existing α-sulfidation methods that rely on nucleophilic displacement (Scheme 1A).4 Accordingly, when nucleophilic dimethyl sulfide-d6 (1.00 equiv) was added to the reaction mixture at −78 °C, we observed unsubstantial deuterium incorporation into sulfonium product 3aa.28 Furthermore, DFT calculations identified a relatively high barrier for sulfur–oxygen cleavage from oxysulfonium ion 7 to form the requisite nucleophile–electrophile pair.14

Our mechanistic insights suggested that the unproductive retro-ene pathway that initially precluded the α-sulfidation of aliphatic amide 1t may be outcompeted by increasing the concentration of electrophilically activated sulfoxide 8. Indeed, the α-sulfidation of amide 1t with DMSO proceeded in 79% yield by increasing the amount of sulfoxide used and adding supplemental Tf2O after amide activation, consistent with our mechanism-based hypothesis. Compared with other oxidants employed in amide activation protocols,4g our results collectively establish that sulfoxides serve additional roles as sulfur sources and promoters in this unique transformation.

The further evaluation of sulfoxide activators revealed that trifluoroacetic anhydride (TFAA) offered the sulfidated aliphatic amides in higher yield compared with Tf2O.14,29 This rationally modified protocol provided access to a variety of α-sulfidated aliphatic amides (Scheme 5, Method C).30,31 The α-sulfidated morpholine amide 4s could be prepared on a 5.00 mmol scale with similar reaction efficiency to saturated α-sulfide amides 4t and 4u. Terminal alkyne 1v, alkene 1w, and ester- and ketone-containing substrates 1x and 1y could be chemoselectively sulfidated adjacent to the amide group, even in the presence of other unprotected carbonyl groups. Aliphatic amide 1aa was sulfidated using methyl sulfoxide derivative 2f after regioselective dealkylation. For amide 1z, single crystals suitable for X-ray diffraction were obtained of intermediate 3za(32) en route to α-sulfide product 4z, revealing a noncovalent interaction33 between the sulfonium cation and the trifluoromethanesulfonate anion that underlies its high solubility in organic solvents and resistance toward elimination and hydrolysis.34

Scheme 5. α-Sulfidation of Aliphatic Amides.

Scheme 5

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Reagents and conditions, Method C: Tf2O (1.10 equiv), 2-ClPy (3.00 equiv), CH2Cl2, −78 → 0 °C, 15 min; DMSO (2a, 2.50 equiv), TFAA (1.00 equiv), CH2Cl2, −78 → 22 °C, 45 min; Et3N (10 equiv), MeCN, 60 °C, 15 h.

Sulfoxide 2f (2.50 equiv).

In conclusion, we have identified a direct procedure for the chemoselective α-sulfidation of amides. This transformation is applicable to a wide range of tertiary amides with high functional group tolerance. The use of convenient and easily accessible sulfoxides enhances the practicality of this strategy and enables the single-step functionalization of benzylic amides via spontaneous dealkylation. Our ability to sulfidate α-aryl acetamides and introduce small thioalkyl groups, otherwise derived from exceptionally noxious thiols, is unparalleled in comparison to existing amide activation protocols.4g Mechanistic studies supported the role of electrophilically activated sulfoxides as promoters for the sulfidation and enabled the extension of the methodology to aliphatic tertiary amide substrates. Overall, this approach offers a valuable alternative to existing solutions for the α-sulfidation of amides by introducing an orthogonal strategy under mild conditions and provides direct access to functionalized amides for fine chemical synthesis.1−3

Acknowledgments

We thank Dr. Peter Müller (Massachusetts Institute of Technology) for the assistance with the single-crystal X-ray diffraction of 3za. M.L. thanks the Graz University of Technology for access to the Zentraler Informatikdienst (ZID) computing facility and resources during manuscript refinement in the second phase of his Schrödinger Postdoctoral Fellowship in the laboratory of Prof. Dr. Rolf Breinbauer (Graz University of Technology).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.0c03160.

  • Experimental procedures, spectroscopic data, computed free energy profiles, Cartesian coordinates, and copies of 1H, 13C, and 19F NMR spectra (PDF)

Accession Codes

CCDC 1916405 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_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Contributions

† M.L. and K.A.D. contributed equally.

We acknowledge financial support from NIH-NIGMS (GM074825). M.L. was supported by a Schrödinger Postdoctoral Fellowship, financed by the Austrian Science Fund (FWF): J3930-N34. K.A.D. acknowledges the Natural Sciences and Engineering Research Council of Canada (NSERC) for a PGS-D3 scholarship.

The authors declare no competing financial interest.

Supplementary Material

ol0c03160_si_001.pdf (10.1MB, pdf)

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