Highly Chemoselective NH- and O-Transfer to Thiols Using Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.8b00788

Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.

Full text of DOI:10.1021/acs.orglett.8b00788

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Chemoselective NH- and O‑Transfer to Thiols Using
Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and
Sulfonamides
Arianna Tota,‡,§ Sahra St John-Campbell,†,§ Edward L. Briggs,† Gala Ogalla Estevez,† Michelle Afonso,†
́
Leonardo Degennaro,‡ Renzo Luisi,*,‡ and James A. Bull*,†
†Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
‡Department of Pharmacy-Drug Sciences, University of Bari, “A. Moro” Via E, Orabona 4, Bari 70125, Italy
S
* Supporting Information
ABSTRACT: Aryl thiols can be selectively converted to
sulfonimidates or sulfonamides with three new S−X connections
being made selectively in one pot. Using hypervalent iodine
reagents in the presence of ammonium carbamate, NH- and O-
groups are transferred under mild and practical conditions.
Reducing the loading of ammonium carbamate changed the
product distribution, converting the sulfonimidate to the
sulfonamide. Studies into the possible intermediate species are
presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species
forming the same products.
unctional groups that contain S−O and S−N linkages
Fcomprise some of the most useful motifs used in medicinal
chemistry.1 Sulfonamides are the most common and are widely
found in marketed drug compounds. Recently, sulfoximines
have emerged as valuable groups for medicinal chemistry as
chiral alternatives to sulfones2 and have progressed into clinical
trials in several compounds.3 These have seen considerable
synthetic advances in recent years,4 with developments in
sulfoxide imination5 and sulfide imination, followed by
oxidation.6 Sulfonimidamides, aza-analogues of sulfonamides,
have also become recently appreciated for potential in
medicinal chemistry and agrochemistry.7 Related sulfonimi-
dates are less studied8 and are more reactive at S through
displacement of the alkoxide. This has led to application as
sulfoximine precursors on reaction with organometallics,9 and
in materials science as monomers for polymerization.10 They
are also reactive by SN2 at the alkoxy carbon with the sulfur
group as an effective leaving group affording a sulfonamide.11,12
Here, we report the selective formation of sulfonimidates
through a highly chemoselective NH, O, and OR transfer to
aryl thiols using hypervalent iodine reagents. A modified set of
Figure 1. NH and O transfer to S-groups to form sulfoximines,
sulfondimidamides, and, in this work, sulfonimidates/sulfonamides.
conditions affords sulfonamides, proceeding through the
sulfonimidate as an intermediate. Preliminary studies into the
order of atom transfer are presented, suggesting multiple
pathways could afford the same products.
We recently reported facile conditions for the transfer of NH
groups to sulfoxides to form NH-sulfoximines, using
bisacetoxyiodobenzene and ammonium carbamate (Figure
1).13 These conditions provided a mild and functional group
tolerant approach to the unprotected sulfoximine group. An
intermediate iminoiodinane species was invoked as the reactive
N-species. We then demonstrated that using sulfides, under
essentially the same conditions, a chemoselective NH and O
transfer occurred to generate sulfoximines directly.14,15
Applying the reaction conditions to diphenyl sulfilimine gave
Received: March 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00788
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
the conversion to the sulfoximine with or without the nitrogen
source. Reboul reported related mechanistic and synthetic work
at a similar time, which indicated that the O atom derived from
methanol or acetate.13 Adopting these ammonium carbamate
Scheme 2. Reaction Scope Forming Sulfonimidates with Aryl
Thiols
and bisacetoxyiodobenzene conditions, Stockman and Lucking
̈
reported NH transfer to sulfinamides to form sulfonimidamides
with chemoselective NH transfer.16 Previously, the oxidation of
sulfinamides to methyl sulfonimidates was demonstrated by
Malacria using iodosobenzene in methanol to promote
oxidation.17
Given the value of these compound classes, we were
intrigued by the potential for chemoselective transfer of N
and/or O atoms to S-functional groups starting at much lower
oxidation levels. We intended to explore direct S−N and S−O
bond formations from thiols targeting multiple bond
formations in a single process to give valuable S-derivatives,
and extend the N-transfer chemistry of hypervalent iodine
reagents.18,19
Initially, we examined 4-tert-butylbenzenethiol 1a using a
modification of our previously reported conditions (Scheme 1).
We were delighted to find that a major product was formed
corresponding to methyl sulfonimidate 2a. Primary sulfona-
mide 3a was also formed as a minor product.
Scheme 1. Initial Results Forming Sulfonimidate and
Sulfonamide
reaction of the benzylic alcohol in preference to the methanol
solvent.21 Alternatively, running the reaction in EtOH afforded
the corresponding ethyl sulfonimidates 2aa−ac. This protocol
provides much more facile access to alkyl aryl-NH-sulfonimi-
dates than has previously been available and avoids the
preparation of sulfinamides.
We subsequently optimized this process, varying the reaction
conditions and equivalents of reagents. It was clear through
these studies that running the reaction with fewer equivalents of
ammonium carbamate gave increasing amounts of the
sulfonamide. The best conditions to form sulfonimidate 2a
used 4 equiv of ammonium carbamate and 4 equiv bisacetoxy-
iodobenzene. Unfortunately, despite considerable efforts to
prevent formation of the sulfonamide product, it was always
formed in small amounts and was inseparable by silica
chromatography; hence, the sulfonimidate was not isolated
cleanly. To improve separation and due to concern about the
stability of the acid sensitive sulfonimidate on silica, we
examined various stationary phases.20 Pleasingly, the use of
neutral alumina was effective at removing the sulfonamide and
afforded the pure sulfonimidate. Under these conditions the
scope of the reaction was assessed, varying the arylthiol
component (Scheme 2).
At the same time, we optimized conditions for the direct
formation of sulfonamides from the thiols (Scheme 3).22
Scheme 3. Reaction Scope Forming Sulfonamides with Aryl
Thiols
Using 4-tert-butylbenzene thiol, sulfonimidate 2a was isolated
in 65% yield. Various para-substituted examples were also
successful (2b−g), with generally higher yields with more
electron-rich substrates. ortho-Substitution gave a somewhat
reduced yield for the corresponding sulfonimidates 2h−k
(Scheme 2). Better yields were obtained for meta-substituted
aromatic sulfonimidates 2l−n. More substituted aromatic thiols
were found to be suitable for this transformation affording
sulfonimidates 2o−q. Electron-rich heterosubstituted thiols
such as thiophene-2-thiol furnished the corresponding
sulfonimidate 2r in good yield.
Running the reaction with only 1 equiv of ammonium
carbamate and extending the reaction time to 24 h, at 25 °C,
gave full conversion from the thiol to the sulfonamide, via the
sulfonimidate.23 For this reaction, the yields were higher than
those for the sulfonimidates and were again found to be
dependent on the electronics of the aryl group. Sulfonamides
3a−n were obtained in good to excellent yields from the
corresponding aromatic thiols (Scheme 3). The protocol was
successfully applied to thiols bearing polysubstituted aromatics
Cyclohexanethiol was also suitable, furnishing sulfonimidate
2s in 40% yield. Interestingly, the use of 2-mercaptobenzyl-
alcohol gave the cyclic sulfonimidate 2t through intramolecular
B
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(3o,p) as well as electron-rich heterocycle (3r) and alkyl
moieties (3s).
Malacria method,15 applying our conditions to a primary
sulfinamide 9 also formed sulfonimidate 2c with small
quantities of the sulfonamide (Scheme 5d). As recently
Cyclic sulfonimidate 2t did not significantly convert to the
sulfonamide under the longer reaction conditions, perhaps
representing the stability of the cyclic system. Instead, and to
provide insight into the mechanism, sulfonimidate 2t was
treated with other nucleophiles (Scheme 4).
reported by Lucking and Stockman,14 we also observed NH
̈
transfer in the presence of N,N-disubstituted sulfinamides
(Scheme 5e). This is in contrast to the oxidation observed for
the NH2 species.
In terms of the source of the O-atom in the sulfonimidates, it
is likely to be the MeOH solvent or acetate. This is consistent
with Reboul’s proposal for sulfide oxidation to form
sulfoximines,15a which can also be compared with the
conversion of sulfonimidate to sulfonamide by nucleophilic
substitution.
Scheme 4. Reaction of Sulfonimidates 2t and 2b with
Nucleophiles
To identify intermediate species, reactions using various
sulfides were sampled and analyzed directly by GC and GCMS
analysis. The reaction in all cases was fast, and intermediate
species were not detected with the exception of the
corresponding disulfide and sulfinate ester species. Only
when investigating cyclohexanethiol as the substrate was
another intermediate detected in the MS trace, which was
putatively assigned as cHexS(NH)OMe. Based on these results
and our prior studies, the sequence reported in Scheme 6 is
Treating the isolated sulfonimidate 2t with pyrrolidine in
MeOH or with acetic acid resulted in ring opening to the
sulfonamide products 4 and 5, incorporating the nucleophile at
the benzylic position. By contrast, treating the electron-rich 4-
methoxyphenyl sulfonimidate 2b with morpholine gave
sulfonimidamide 6 in high yield with displacement at the
sulfur center (Scheme 4b).
Scheme 6. Plausible Reaction Sequence
To provide insight into the reaction mechanism and order of
events, we next examined other sulfur functional groups under
related reaction conditions. Treating PhSH with oxidant alone
quantitatively formed diphenyl disulfide 7.24 The disulfide was
converted to the methyl sulfinate ester 8 with an excess of
oxidant (Scheme 5a). A mixture of 7 and 8 was obtained on
Scheme 5. Control Reactions
proposed. It is likely that multiple pathways may be followed,
but that these are selectively converted to the same product.
However, the exact sequence of events remains unclear.
In conclusion, sulfonimidates are selectively formed from
thiols using ammonium carbamate and bisacetoxyiodobenzene
in methanol. Conversion to sulfonamides occurs in the
presence of lower ammonia concentrations and extended
reaction times through substitution of the alkoxy group.
Disulfides, sulfinates, and sulfinamides are all suitable
precursors to sulfonimidates under these reaction conditions.
Further studies are underway in our laboratories to elucidate
mechanistic pathways and exploit these simple reagents for
selective transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00788.
treating the thiol with 3.5 equiv of oxidant in MeOH (Scheme
5b). Using methyl benzenesulfinate 8 as the substrate,
sulfonimidate 2d was formed, using acetonitrile as the solvent
(Scheme 5c). Importantly for the selectivity, the use of the
reagents in the absence of the N-source did not lead to
oxidation of the sulfinate ester to the corresponding sulfonate
ester. This provides a potentially valuable alternative route to
sulfonimidates from sulfinate esters. In comparison to the
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: j.bull@imperial.ac.uk.
*E-mail: renzo.luisi@uniba.it.
C
DOI: 10.1021/acs.orglett.8b00788
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
B.; Zhou, S.; Zhou, S.; Wei, W.; Liu, J.; Zhan, Y.; Cheng, D.; Chen, M.;
Li, Y.; Wang, B.; Xue, X.; Li, Z. ChemistrySelect 2017, 2, 1620.
(16) Izzo, F.; Schafer, M.; Stockman, R.; Lucking, U. Chem. - Eur. J.
Leonardo Degennaro: 0000-0002-2187-9419
Renzo Luisi: 0000-0002-9882-7908
James A. Bull: 0000-0003-3993-5818
̈
̈
2017, 23, 15189.
(17) (a) Leca, D.; Fensterbank, L.; Laco
̂
te, E.; Malacria, M. Org. Lett.
2002, 4, 4093. (b) Felim, A.; Toussaint, A.; Phillips, C. R.; Leca, D.;
Vagstad, A.; Fensterbank, L.; Lacote, E.; Malacria, M. Org. Lett. 2006,
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Author Contributions
§A.T. and S.S.J.-C. contributed equally
̂
̂
Notes
(18) (a) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
(b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571.
(19) For selected developments in hypervalent iodine reagents with
N-ligands, see: (a) Sandtorv, A. H.; Stuart, D. R. Angew. Chem., Int. Ed.
2016, 55, 15812. (b) Krasnova, L. B.; Hili, R. M.; Chernoloz, O. V.;
Yudin, A. K. ARKIVOC 2005, iv, 26. (c) Souto, J. A.; Martínez, C.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Royal Society for a University
Research Fellowship (to J.A.B.) and EPSRC [CAF to J.A.B.
(EP/J001538/1), Impact Acceleration Account (EP/K503733/
1), DTA Studentship (to S.S.J.-C. and E.L.B.)]. This research
was supported by the project Laboratorio Sistema Code
PONa300369 financed by MIUR, the University of Bari.
Velilla, I.; Muniz, K. Angew. Chem., Int. Ed. 2013, 52, 1324.
(d) Lucchetti, N.; Scalone, M.; Fantasia, S.; Muniz, K. Angew. Chem.,
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DOI: 10.1021/acs.orglett.8b00788
Org. Lett. XXXX, XXX, XXX−XXX