N-Alkynylthio Phthalimide: A Shelf-Stable Alkynylthio Transfer Reagent for the Synthesis of Alkynyl Thioethers

Article abstract of DOI:10.1021/acs.orglett.9b02174

A new kind of electrophilic alkynylthiolating reagent, called N-alkynylthio phthalimide, is designed and synthesized herein. This electrophilic sulfenylating reagent can be easily prepared in three steps from commercially available phthalimide and corresp

Full text of DOI:10.1021/acs.orglett.9b02174

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Alkynylthio Phthalimide: A Shelf-Stable Alkynylthio Transfer
Reagent for the Synthesis of Alkynyl Thioethers
Wen-Chao Gao,*,†,§ Yu-Zhu Shang,† Hong-Hong Chang,† Xing Li,† Wen-Long Wei,†
Xin-Zhang Yu,‡ and Rong Zhou*,†
†Taiyuan University of Technology, Taiyuan 030024, P.R. China
‡Taiyuan Institute of Technology, Taiyuan 030008, P.R. China
§Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai 200062, P.R.
China
S
* Supporting Information
ABSTRACT: A new kind of electrophilic alkynylthiolating reagent, called N-alkynylthio phthalimide, is designed and
synthesized herein. This electrophilic sulfenylating reagent can be easily prepared in three steps from commercially available
phthalimide and corresponding silver acetylide. Furthermore, the N-alkynylthio phthalimides are demonstrated to be efficient
alkynylthio transfer reagents that can react with various C-nucleophiles, including β-ketoesters, aryl boronic acids, and Grignard
reagents to afford a diverse range of alkynyl thioethers under mild conditions.
Scheme 1. Methods for the Synthesis of Alkynyl Thioethers
evelopment of efficient methods for introducing valuable
DS-containing structural units has received considerable
attention because of the unique properties of sulfur in biology,
medicine, and material science.1,2 Alkynyl thioethers bearing a
sulfur atom directly attached to the C−C triple bond serve as a
versatile platform for many transformations at both sulfur and
alkyne moieties.3 Furthermore, the electron-rich sulfur atom
allows conjugation with its lone electron pair(s) to enhance the
reactivity of the C−C triple bond, thereby giving chances for new
chemical transformations and the modulation of their physical
properties.4 The most commonly used strategy for the alkyne
thioether synthesis is thioalkynylation, which requires both thio
and alkyne partners for C−S formation.5−7 This thioalkynylation
process could be realized through direct transition-metal-
catalyzed C−S coupling5 or employing the umpolung-type
strategy: one synthetic route involves the umpolung of thio
groupsthroughthereactionofterminalalkyneswithpreactivated
thiols, such as sulfenyl chloride, disulfides, and Bunte salts
(Scheme 1a);6 until recently, the umpolung of alkynes based on
the thiol alkynylation using active alkynylating reagents has
attracted more attention, and alkynes have been modified to
ethynyl benziodoxolone reagents,7a , b (alkynyl)-
dibenzothiophenium triflates,7c and haloalkynes7d,e (Scheme
1b). All of these strategies focus on the Csp−S bond formation,
which required both S-containing compounds and alkynyl
equivalents. Nevertheless, access to alkynyl thioethers from
molecules without the thiol or alkynyl group remains a great
challenge but is still highly desirable.
In the past few years, the reaction of S-electrophiles (N-
thiosucccinimides, N-thiophthalimides, N-thiochlorides, etc.)
Received: June 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02174
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Letter
with unactivated arene, alkene, and alkyne derivatives has been
well-established and has become a powerful tool for the synthesis
of various sulfides.8 With this strategy, our group has also
developed several synthetic methods for the construction of
heterocyclic sulfides.9 However, due to the π-electrophilic nature
of thio cations, the compatibility of S-electrophiles with
unsaturated C−C bonds still limits the development and utility
of unsaturated S-electrophiles. In 2017, Alcarazo et al. prepared
one kind of alkynylthioimidazolium salt, which was employed as
an alkynylthio electrophile to react with a range of Grignard
reagents for thioalkynylation (Scheme 1c).10 However, the
sensitive synthetic procedure and the low solubility of
imidazolium salts as well as the narrow reaction scope (only
with Grignard reagents) undermined their application to access
valuable alkynyl thioethers in synthetic chemistry. We disclose
herein a new kind of readily available and bench-stable
alkynylthio electrophiles, N-alkynylthio phthalimides, which
can serve as versatile alkynylthio transfer reagents to access a
diverse range of alkynyl thioethers through the alkynylthiolation
of different C-nucleophiles, such as β-keto esters, aryl boronic
acids, and Grignard reagents, in which neither a thiol nor an
alkynyl group is contained.
functional groups, including substituted phenyl rings (3a−d), 1-
naphthylring(3e),3-thienylring(3f), andcyclopropylring(3g),
werewell-toleratedinthisreaction, andthedesiredreagentswere
produced in moderate to good yields. Furthermore, not only the
chain alkynylthio phthalimides 3h and 3i but also the alkynylthio
reagents bearing a terminal siliyl, azide, or hydroxy group could
be successfully prepared in moderate to good yields (3j−l),
opening up more opportunities for further derivation. The single
crystal of N-phenylethynylthio phthalimide 3a was obtained in
the MeCN solvent, and the exact structure of N-alkynylthio
reagent 3 was unambiguously confirmed (Figure 1).
Figure 1. ORTEP drawing of 3a; ellipsoids shown at a 50% probability
level.
Considering the nonexistence of alkynylthiol (RCCSH),11
howtoobtainthealkynylthiosyntheticequivalentisthefirstissue
to address. Additionally, the alkynylthio transfer reagents are
inherent electrophiles, and their compatibility with C−C triple
bonds imposes another challenge in the preparation. In our
design, a convergent synthetic route from an alkynyl equivalent
and a thio cation precursor was alternatively employed for the
synthesis of N-alkynylthio phthalimides 3. Reagent 3 was
precisely prepared from the reaction of silver acetylide 2 and
N-(chlorosulfenyl)phthalimide 1 through an ion-exchange
strategy (Scheme 2) to avoid the interaction of the π-bond of
triple bonds with thio electrophiles. Both 1 and 2 could be
accessed from commercially available starting materials in one or
two steps.12 Notably, the reaction can be readily scaled up to 20
mmol to afford N-alkynylthio reagent 3a in 60% yield. A range of
With a series of N-alkynylthio phthalimides 3 in hand, we first
explored its reactivity with soft nucleophiles to accomplish the α-
alkynylthiolation of β-keto esters. Methyl 1-indanone-2-carbox-
ylate was selected as a model substrate to explore the reaction
conditions for the α-alkynylthiolation of the β-keto esters. The
reaction of 1-indanone-2-carboxylate with 1.5 equiv of 3a in the
presence of 0.2 equiv of DABCO could smoothly proceed at 45
°C to provide the desired product 4a in 95% yield (please see
Table S1 in the Supporting Information for details). A range of β-
keto esters and N-alkynylthio phthalimides were subsequently
examined for this transformation under the optimal conditions
(Scheme 3). Different esters, including methyl, ethyl, tert-butyl,
and 1-adamantyl, could be well-tolerated in this reaction.
Scheme 2. Preparation of N-Alkynylthio Phthalimides
Scheme 3. Substrate Scope for α-Alkynylthiolation of β-Keto
Esters
a
a
Reaction conditions: β-keto esters (0.1 mmol), 3 (0.15 mmol),
DABCO (0.02 mmol) in CH2Cl2 (1 mL) stirred at reflux for 2−4 h.
B
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Moreover, the corresponding α-alkynylthio products were
obtained in good to excellent yields (4a−d). Substrates with
electron-withdrawing or -donating functional groups on the
phenyl ring of the indanone moiety were also well-accom-
modated (4e−h), delivering the desired products in moderate to
excellent yields. Notably, the β-keto esters derived from α-
tetralone or cyclopentanone were also good substrates for this
transformation, affording their corresponding products 4i and 4j
in moderate yields. However, the reaction of 3a with the
noncyclic keto ester could not provide the desired product 4k
underthestandardconditions. Inaddition, variousN-alkynylthio
phthalimides 3 derived from either aliphatic or aromatic alkynes
wereinvestigated.Allofthereactionssmoothlyproceededtogive
the α-alkynylthiolation products in good to excellent yields (4l−
q).
Scheme 5. Substrate Scope for Cu-Catalyzed
Alkynylthiolation of Boronic Acids
a
Several known S-electrophiles have recently been used for the
catalytic enantioselective construction of sulfur-containing
carbon stereocenters.13 Inspired by this progress, we explored
the enantioselective α-alkynylthiolation of β-keto esters of four
commercially available cinchona alkaloids (i.e., cinchonine,
cinchonidine, quinine, and quinidine). Notably, with tert-butyl
1-indanone-2-carboxylate as the substrate, the asymmetric α-
alkynlthiolation could be achieved in 79% yield with 70%
enantioselectivityusingquinine asthe chiral catalyst(Scheme 4).
a
Reaction conditions: aryl boronic acid (0.1 mmol), 3 (0.15 mmol),
Cu(OTf)2 (20 mol %), 2,2′-bipyridine (20 mol %), and K2CO3 (0.2
mmol) in THF (1 mL) at 60 °C for 2−4 h.
Scheme 4. Enantioselective α-Alkynlthiolation of tert-Butyl 1-
Indanone-2-carboxylate
Scheme 6. Substrate Scope for Alkynylthiolation of Grignard
Reagents
a
As one kind of representative and commercially available C-
nucleophile, boronic acids have been widely used in C−S
coupling reactions. Reaction of 3 with boronic acids was then
explored herein to prepare the unsymmetrical aryl alkynyl
sulfides (Scheme 5). With the p-tolylboronic acid as the model
substrate,product5awasprovidedin96%yieldinthepresenceof
20 mol % of CuI, 20 mol % of bipyridine (bpy), and 2 equiv of
K2CO3 in THF at 60 °C (see Table S2 in the Supporting
Information for details). A series of aryl boronic acids with ortho-,
meta-, orpara-substituentswereabletoreactwith3a toaffordthe
corresponding aryl alkynyl sulfides in moderate to excellent
yields (5a−e). Additionally, 1-naphthyland 3-thienylringscould
also be well-tolerated in this system (5f and 5g). Other
alkynylthio electrophiles were also tested, and functional groups,
including thienyl, tert-butyl, and azide groups, could be very
compatible in this coupling reaction (5h−k), providing more
chances for further elaboration. The known Alcarazo reagents
were also used to transform an alkynylthio group to β-keto esters
and boronic acids, whereas alkynylation, instead of thioalkyny-
lation,occurredasthemainpathway(pleaseseeSchemeS1inthe
Supporting Information for details).
a
Reaction conditions: Grignard reagent (0.5 M in THF, 0.15 mmol),
b
3 (0.15 mmol) in THF (1 mL) at 0 °C for 1−2 h. 0.2 mmol of (p-
tolylethynyl)lithium is used instead.
advantage of the present transformation is remarkable because
the access to alkynyl−alkynyl thioethers and alkenyl−alkynyl
thioethers is a great challenge using other conventional
methods.14
The resulting alkynyl thioethers could accomplish a series of
functionalizing transformations. For example, alkynyl thioether
6b easily obtained from the reaction of 3a with 4-
methoxyphenylmagnesium bromide couldbe either transformed
to the corresponding thioester 7 under acid hydrolysis or reacted
with benzyl azide to furnish the fully substituted 5-thio-1,2,3-
triazole 8 through iridium-catalyzed azide−alkyne cycloaddition
reaction (Scheme 7).4b
Reaction of N-alkynylthio phthalimides with Grignard
reagents was subsequently investigated to further expand the
synthetic application of reagent 3. As shown in Scheme 6, various
Grignard reagents, including aryl (6a−d), alkynyl (6e−f),
alkenyl (6g−j), and alkyl (6k), could couple with the alkynylthio
reagents to give the corresponding alkynyl thioethers bearing
different functional groups in good to excellent yields. The
In summary, a new kind of electrophilic sulfenylating reagent,
called N-alkynylthio phthalimide, was developed herein for
direct alkynylthiolation. Reagent 3 was bench-stable, easily
activated, and readily prepared in three steps from commercially
C
DOI: 10.1021/acs.orglett.9b02174
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02174.
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CCDC 1916070 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 INFORMATION
Corresponding Authors
■
*E-mail: gaowenchao@tyut.edu.cn.
*E-mail: zhourong@tyut.edu.cn.
ORCID
́
(10) Pena, J.; Talavera, G.; Waldecker, B.; Alcarazo, M. Chem. - Eur. J.
2017, 23, 75.
Wen-Chao Gao: 0000-0002-1382-6210
Xing Li: 0000-0001-8096-4499
Rong Zhou: 0000-0002-0322-9199
Notes
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The authors declare no competing financial interest.
́
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Key Research
and Development Program of Shanxi Province (International
Cooperation) (No. 201803D421093) and China Postdoctoral
Science Foundation (No. 2019M651424).
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Org. Lett. XXXX, XXX, XXX−XXX