Transition-Metal-Free Thioamination of Arynes Using Sulfenamides

Article abstract of DOI:10.1021/acs.orglett.8b03966

The insertion of arynes into the S-N σ-bond of sulfenamides allowing the synthesis of o-sulfanylaniline derivatives with reasonable functional group compatibility is presented. The aryne generated from 2-(trimethylsilyl)aryl triflates using CsF in DME was the key for the success of this transition-metal-free thioamination reaction, which involves new C-N and C-S bond formations in a single step under mild conditions. Moreover, the synthetic potential of this method was demonstrated by the synthesis of the antidepressant drug vortioxetine.

Full text of DOI:10.1021/acs.orglett.8b03966

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Thioamination of Arynes Using Sulfenamides
Rahul N. Gaykar, Subrata Bhattacharjee, and Akkattu T. Biju*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: The insertion of arynes into the S−N σ-bond
of sulfenamides allowing the synthesis of o-sulfanylaniline
derivatives with reasonable functional group compatibility is
presented. The aryne generated from 2-(trimethylsilyl)aryl
triflates using CsF in DME was the key for the success of this
transition-metal-free thioamination reaction, which involves
new C−N and C−S bond formations in a single step under
mild conditions. Moreover, the synthetic potential of this
method was demonstrated by the synthesis of the antidepressant drug vortioxetine.
o-Sulfanylanilines are aromatic compounds bearing nitrogen
and sulfur atoms on adjacent carbons and are important
molecules having broad range of applications in medicinal
chemistry and materials science.1 Some of important
pharmaceuticals and drug molecules such as benzothiazepines,
benzothiazoles, and phenothiazines have o-sulfanylanilines as
the core structure.2 For example, the phenothiazine-containing
drug chlorpromazine is used to treat psychotic disorders
including schizophrenia (Figure 1).3 Moreover, the FDA-
trifluoromethanesulfenamides (Scheme 1, eq 1).11,12 Notably,
the presence of a CF3 group on sulfinamide was necessary for
Scheme 1. Synthesis of o-Sulfanylaniline Derivatives
Figure 1. Selected medicinally important o-sulfanylaniline containing
scaffolds.
approved antidepressant drug vortioxetine (sold as Trintellix)
contains o-sulfanylaniline moiety,4 and the benzothiazole-
derived drug riluzole (marketed as Rilutek and Teglutik) is
used in the treatment of amyotrophic lateral sclerosis.5 In
addition, the benzothiazepine-containing drug diltiazem
(calcium channel blocker) is used in the treatment of
hypertension and angina.6 Given the significance of function-
alized o-sulfanylanilines in medicine, development of new
synthetic routes to these molecules is highly important.7
In view of our interest in the transition-metal-free aryne
reactions,8,9 we envisioned that the cleavage of the S−N σ-
bonds in sulfenamides and stitching the two fragments at the
C−C triple bond of arynes could result in straightforward
access to o-sulfanylanilines.10 The synthesis of o-sulfanylaniline
using aryne as the aryl source was demonstrated by Larock in
2005 via the insertion of arynes into the S−N bond of
the reaction, which increases the N−H acidity and also the
electrophilicity of the sulfinyl moiety. Later in 2015, Greaney
and co-workers uncovered the aryne three-component
coupling triggered by thiols and O-benzoyl N,N-dialkylhydrox-
ylamines as the third component for the construction of o-
sulfanylanilines (eq 2).13 Moreover, employing sulfilimines,
Received: December 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03966
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Letter
a
Hosoya and co-workers reported the thioamination of arynes
for o-sulfanylaniline synthesis resulting in C−N and C−S bond
formation as well as a migratory N-arylation (eq 3).14 Herein,
we demonstrate a mild and simple insertion of arynes into the
S−N σ-bond of sulfenamides for the synthesis of diverse o-
sulfanylaniline derivatives (eq 4).15,16
Scheme 3. Substrate Scope of the Reaction
The present studies were initiated by the treatment of the
unsubstituted aryne generated in situ from 2-(trimethylsilyl)
aryl triflate 1a17 (using excess CsF) with the sulfenamide 2a in
DME as solvent. Interestingly, a facile insertion reaction
occurred under these conditions, leading to formation of the o-
sulfanylaniline derivative 3a in 83% yield (Scheme 2).18 The
Scheme 2. Thioamination of Aryne Using Sulfenamides
other fluoride sources such as KF (along with 18-crown-6
additive) and TBAF provided a reduced yield of 3a and DME
was found to be the best solvent for this transformation. The
reaction proceeds via the nucleophilic addition of sulfenamide
nitrogen to the in situ generated aryne from 1a, leading to the
formation of the aryl anion intermediate A, which is
subsequently added to the sulfur resulting in the formation
of 3a.19
Having these reaction conditions in hand, we then examined
the substrate scope of this thioamination reaction (Scheme 3).
Sulfenamides synthesized from N-methylaniline derivatives
bearing electron-releasing, -neutral, and -withdrawing sub-
stituents at the 4-position and the 3-position of the ring
underwent the S−N insertion reaction to aryne leading to the
formation of the o-sulfanylaniline derivatives in moderate to
good yields (3a−j). In the case of the cyano-substituted
substrate, the yield of the desired product 3f was only 13%.
Moreover, the morpholine- and piperidine-derived sulfena-
mides underwent smooth insertion to aryne to afford the
corresponding o-sulfanylaniline derivatives in moderate to
good yields (3k−m). Sulfenamides synthesized from sub-
stituted benzenethiols having substituents at various positions
of the benzene ring are tolerated well under the present
reaction conditions, and in each case the desired product was
formed in moderate to good yields (3n−u). Notably, the 2-
naphthalenethiol-derived sulfenamide resulted in smooth
conversion to the corresponding product 3q in 42% yield.
Disappointingly, sulfenamide substrates bearing −OH and
−CHO groups did not afford the expected insertion products
under the present conditions.
a
General reaction conditions; 1 (1.1 mmol), 2 (0.5 mmol), CsF (2.2
mmol), DME (2.0 mL), 25 °C and 24 h. Yields of isolated products
b
c
are given. Reaction performed on 0.25 mmol scale of 2. The
regioisomer ratio was determined by H NMR of crude mixture.
1
an inseparable mixture of regioisomers 3x and 3x′ in 75% yield
and 1:1 ratio.
To gain insight into the mode of addition of sulfenamides
(nucleophilic addition via nitrogen center or sulfur center) to
arynes, we have performed a few mechanistic experiments.
When the reaction was performed using the unsymmetrical 3-
methoxybenzyne generated from 1e and sulfenamide 2r under
the present conditions, the reaction afforded the single
regioisomer 3y in 53% yield (Scheme 4, eq 5). The structure
of 3y was further confirmed by single-crystal X-ray analysis.
Given the fact that nucleophilic addition on 3-methoxybenzyne
is more favored at the 1-position than the 2-position,20 the
selective formation of 3y with nitrogen at the 1-position is a
clear indication that the present insertion reaction proceeds via
the tertiary nitrogen center of sulfenamides.21 This was further
confirmed by the reaction of sulfenamide 2c with 3-methoxy
benzyne to furnish 3z in 74% yield. Moreover, when the
reaction of 2a was conducted using the domino aryne
precursor 1f22 under the present conditions, the insertion
product 3aa was formed in 45% yield with the second −OTf
The tolerance of the present reaction with differently
substituted arynes is also examined. The symmetrical 4,5-
dimethylaryne generated from the corresponding precursor
reacted with 2a, resulting in the formation of the o-
sulfanylaniline 3v in 74% yield. Interestingly, the unsym-
metrical naphthalyne furnished a single regioisomer 3w in 49%
yield. Furthermore, the insertion of the sulfenamide 2a onto
the unsymmetrical 4-methylaryne resulted in the formation of
B
DOI: 10.1021/acs.orglett.8b03966
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Organic Letters
Letter
Scheme 4. Studies on the Mechanism of the Reaction
Scheme 6. Aryne Insertion Route to Vortioxetine
sulfenamides resulting in the synthesis of o-sulfanylaniline
derivatives. This thioamination reaction of arynes involves
formation of new C−N and C−S bonds in a single-step
operation. Moreover, the utility of this methodology has been
demonstrated by the synthesis of the antidepressant drug
vortexetine. Further studies on related aryne insertion
reactions are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03966.
group intact (eq 6). This is an indication that the initially
formed aryl anion intermediate in this case prefers addition to
sulfur and, hence, S−N bond rupture leading to the formation
of 3aa, in preference to the generation of the second aryne
intermediate.
■
S
The present aryne insertion into the S−N σ-bond was not
only limited to sulfenamides but could be applicable to N-
(sulfanyl)phthalimide derivatives. Thus, treatment of aryne
generated from 1a using TBAT as the fluoride source with the
phthalimide derivative 4 resulted in the formation of the
insertion product 5a in 37% yield (Scheme 5). Toluene was
found to be the solvent of choice, and the reaction was
performed at 50 °C.
Details on experimental procedures, characterization,
and NMR spectra of sulfanylanilines derivatives (PDF)
Accession Codes
CCDC 1872526 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.
Scheme 5. Aryne Insertion into N-(Sulfanyl)phthalimides
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: atbiju@iisc.ac.in.
ORCID
Akkattu T. Biju: 0000-0002-0645-8261
Notes
The authors declare no competing financial interest.
Finally, we have demonstrated the application of the aryne
insertion into the S−N σ-bond strategy to the synthesis of the
FDA-approved antidepressant drug vortioxetine (sold as
Trintelli).23 The key sulfenamide derivative 7 was synthesized
in two steps starting from commercially available 2,4-
dimethylbenzenethiol 6 and protected piperazine derivative
(Scheme 6). Treatment of 7 with aryne generated from 1a
under the present reaction conditions resulted in the formation
of the o-sulfanylaniline 8 in 63% yield. Deprotection of the Boc
group using TFA afforded the vortioxetine 9. It may be
mentioned that the synthesis of the drug has been achieved
without the aid of transition metals.13
ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board-DST, Government of India (File No. EMR/
2016/007021), is gratefully acknowledged. R.N.G. thanks IISc
and S.B. thanks CSIR, respectively, for research fellowships.
We thank Mr. Shakil Ahmed and Dr. M. Venkateswarulu (both
IPC, IISc) for the X-ray data and Mr. Tony Roy (CSIR-NCL)
for helpful discussions.
REFERENCES
■
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DOI: 10.1021/acs.orglett.8b03966
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