Chemoselective α-sulfidation of amides using sulfoxide reagents

Article abstract of DOI:10.1021/acs.orglett.0c03160

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

Full text of DOI:10.1021/acs.orglett.0c03160

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Chemoselective α‑Sulfidation of Amides Using Sulfoxide Reagents
Mario Leypold,† Kyan A. D’Angelo,† and Mohammad Movassaghi*
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ABSTRACT: 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.
ew methods for the introduction of carbon−sulfur bonds
are of interest in the synthesis and diversification of
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
N
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
Scheme 1. Methods for the α-Sulfidation of Amides
Scheme 2. α-Sulfidation of Benzylic Amide 1a
amide activation for practical carbon−carbon and carbon−
nitrogen bond-forming reactions,5,6 we recognized an oppor-
tunity 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).
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
Received: September 19, 2020
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© XXXX American Chemical Society
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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.
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 trifluorome-
thanesulfonates 3aa and 3ba derived from morpholine and
pyrrolidine amides 1a and 1b could be isolated in 61 and 68%
yield, respectively.14
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 sub-
stituent 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
The application of this chemistry to the α-sulfidation of α-
aryl acetamides is illustrated in Scheme 3. Sulfide 4a could be
a
Scheme 3. α-Sulfidation of Benzylic Amides
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
a
Reagents and conditions: Method A (methyl sulfoxides): Tf2O (1.05
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 824 transfers the sulfonium moiety via a cyclic
transition state (Scheme 4).
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.
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),18 N-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
B
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a
Scheme 4. Proposed Intermolecular Sulfidation Pathway
Scheme 5. α-Sulfidation of Aliphatic Amides
Distinguishing intra- and intermolecular sulfidation path-
ways 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
a
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),
b
MeCN, 60 °C, 15 h. Sulfoxide 2f (2.50 equiv).
derivative 2f after regioselective dealkylation. For amide 1z,
single crystals suitable for X-ray diffraction were obtained of
intermediate 3za32 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
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 Mecha-
nistic 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
C
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57, 2832−2842. (c) Center for Drug Evaluation and Research. Orange
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03160.
■
sı
Experimental procedures, spectroscopic data, computed
free energy profiles, Cartesian coordinates, and copies of
1H, 13C, and 19F NMR spectra (PDF)
(3) For recent reviews on strategies for carbon−sulfur bond
formation, see: (a) Beletskaya, I. P.; Ananikov, V. P. Transition-
Metal-Catalyzed C−S, C−Se, and C−Te Bond Formation Cross-
Coupling and Atom-Economic Addition Reactions. Chem. Rev. 2011,
111, 1596−1636. (b) Eichman, C. C.; Stambuli, J. P. Transition Metal
Catalyzed Synthesis of Aryl Sulfides. Molecules 2011, 16, 590−608.
(c) Chauhan, P.; Mahajan, S.; Enders, D. Organocatalytic Carbon−
Sulfur Bond-Forming Reactions. Chem. Rev. 2014, 114, 8807−8864.
(d) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Recent
advances in C−S bond formation via C−H bond functionalization
and decarboxylation. Chem. Soc. Rev. 2015, 44, 291−314. (e) Wimmer,
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̈
A.; Konig, B. Photocatalytic formation of carbon−sulfur bonds.
AUTHOR INFORMATION
Corresponding Author
■
Beilstein J. Org. Chem. 2018, 14, 54−83.
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Peng, X.; Wang, Z. Direct access to α-sulfenylated amides/esters via
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Mohammad Movassaghi − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-0003-
3080-1063; Email: movassag@mit.edu
Authors
Mario Leypold − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States
Kyan A. D’Angelo − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0002-9688-5143
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03160
Author Contributions
(g) Gonca̧ lves, C. R.; Lemmerer, M.; Teskey, C. J.; Adler, P.;
†M.L. and K.A.D. contributed equally.
Funding
́
Kaiser, D.; Maryasin, B.; Gonzalez, L.; Maulide, N. Unified Approach
to the Chemoselective α-Functionalization of Amides with Heter-
oatom Nucleophiles. J. Am. Chem. Soc. 2019, 141, 18437−18443.
(h) Liu, C.; Li, Z.; Weng, Z.; Fang, X.; Zhao, F.; Tang, K.; Chen, J.;
Ma, W. Transition-Metal-Free Selective C(sp3)−H Thiolation of
Arylacetamides with Substituted Benzenethiols, Aryl Sulfenylchlorides
and Diaryl Disulfides. Asian J. Org. Chem. 2020, 9, 668−672.
(5) (a) Movassaghi, M.; Hill, M. D. Synthesis of Substituted
Pyridine Derivatives via the Ruthenium-Catalyzed Cycloisomerization
of 3-Azadienynes. J. Am. Chem. Soc. 2006, 128, 4592−4593.
(b) Movassaghi, M.; Hill, M. D. Single-Step Synthesis of Pyrimidine
Derivatives. J. Am. Chem. Soc. 2006, 128, 14254−14255. (c) Mo-
vassaghi, M.; Hill, M. D.; Ahmad, O. K. Direct Synthesis of Pyridine
Derivatives. J. Am. Chem. Soc. 2007, 129, 10096−10097. (d) Mo-
vassaghi, M.; Hill, M. D. A Versatile Cyclodehydration Reaction for
the Synthesis of Isoquinoline and β-Carboline Derivatives. Org. Lett.
2008, 10, 3485−3488. (e) Medley, J. W.; Movassaghi, M. Direct
Dehydrative N-Pyridinylation of Amides. J. Org. Chem. 2009, 74,
1341−1344. (f) Ahmad, O. K.; Hill, M. D.; Movassaghi, M. Synthesis
of Densely Substituted Pyrimidine Derivatives. J. Org. Chem. 2009, 74,
8460−8463. (g) Medley, J. W.; Movassaghi, M. Synthesis of
Spirocyclic Indolines by Interruption of the Bischler−Napieralski
Reaction. Org. Lett. 2013, 15, 3614−3617. (h) White, K. L.; Mewald,
M.; Movassaghi, M. Direct Observation of Intermediates Involved in
the Interruption of the Bischler−Napieralski Reaction. J. Org. Chem.
2015, 80, 7403−7411.
We acknowledge financial support from NIH-NIGMS
̈
(GM074825). M.L. was supported by a Schrodinger
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.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Peter Mu
̈
ller (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 Schrodinger Post-
doctoral Fellowship in the laboratory of Prof. Dr. Rolf
Breinbauer (Graz University of Technology).
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E
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
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supplemental DMSO and anhydride were not found to be beneficial.
(30) Replacing DMSO (2a) with TBMSO (2b) in Method C
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that TBMSO, upon electrophilic activation, is subject to spontaneous
dealkylation of the tert-butyl group to give a sulfenate; see:
(a) Yoshimura, T.; Tsukurimichi, E.; Yamazaki, S.; Soga, S.;
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sulfidation chemistry included γ-butyrolactams 1-methylindolin-2-one
and 1-methyl-3-phenylpyrrolidin-2-one; diketopiperazines (3R,8aS)-
2-methyl-3-phenylhexahydropyrrolo-[1,2-a]pyrazine-1,4-dione and
(3R,6S)-1,4-dimethyl-3,6-diphenylpiperazine-2,5-dione; and secon-
dary amides N-butyl-2-phenylacetamide and N-(4-methoxyphenyl)-
3-phenylpropanamide. These observations are consistent with the
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amides 1e−1g were also isolated; see the Supporting Information for
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(31) The starting aliphatic amides, derived from the competing
retro-ene pathway, were recovered (∼15%) in most cases.
(32) Sulfonium trifluoromethanesulfonate 3za can be stored at
22 °C for weeks. It can be demethylated by treatment with
triethylamine according to our standard conditions to give sulfide
4z in 92% yield.
(33) The noncovalent interaction is evidenced by the considerable
elongation of the Me2S+−C bond: 1.831 Å. Additionally, the oxygen
atom of the longest S−O bond in the trifluoromethanesulfonate anion
is engaged in this interaction (1.444 Å vs 1.428, 1.425 Å). For a
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methyl)sulfonium trifluoromethanesulfonate, 1.804 Å: (a) Hooper,
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(25) When a substoichiometric quantity of Tf2O was used in the
crossover experiment (0.50 equiv), the proportion of crossover
products 3ba-18O/3ba-d6 observed was diminished. This is consistent
with the predominance of an intramolecular pathway in the absence
of activated sulfoxide promoter 8 rather than an intermolecular
pathway.
(26) The use of enantiomerically enriched sulfoxide (−)-2b in the
sulfidation of amide 1a gave racemic product 4a.
(27) The complete transfer of the oxygen from the sulfoxide to the
sulfidated product was verified by the reaction of amide 1b with
DMSO-18O-d6 (2a-18O-d6). Thus the in situ formation of crossover
DMSO (2a-18O/2a-d6) via the 16O/18O exchange of the sulfoxide
with unlabeled Tf2O/TfO− does not occur prior to sulfidation.
(28) The distribution of sulfonium products 3ba and 3ba-d6 was 76
and 24%, respectively. The observation of the partial formation of
3ba-d6 is consistent with competitive reversible oxygen transfer from
electrophilically activated sulfoxides to sulfides; see: Tanikaga, R.;
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(29) Simple organic acids such as methanesulfonic acid (MsOH) or
trifluoroacetic acid (TFA) could also be added in place of additional
anhydride to activate DMSO, but this resulted in a lower yield of the
F
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Org. Lett. XXXX, XXX, XXX−XXX