Photochemical Dual-Catalytic Synthesis of Alkynyl Sulfides

Article abstract of DOI:10.1002/anie.201705903

A photochemical dual-catalytic cross-coupling to form alkynyl sulfides via C(sp)?S bond formation is described. The cross-coupling of thiols and bromoalkynes is promoted by a soluble organic carbazole-based photocatalyst using continuous flow techniques. Synthesis of alkynyl sulfides bearing a wide range of electronically and sterically diverse aromatic alkynes and thiols can be achieved in good to excellent yields (50–96 %). The simple continuous flow setup also allows for short reaction times (30 min) and high reproducibility on gram scale. In addition, we report the first application of photoredox/nickel dual catalysis towards macrocyclization, as well as the first example of the incorporation of an alkynyl sulfide functional group into a macrocyclic scaffold.

Full text of DOI:10.1002/anie.201705903

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Accepted Article
Title: Photochemical Dual-Catalytic Synthesis of Alkynyl Sulfides
Authors: Shawn Collins, Jeffrey Santandrea, Clémentine Minozzi, and
Corentin Cruché
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705903
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10.1002/anie.201705903
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Photochemical Dual-Catalytic Synthesis of Alkynyl Sulfides
Jeffrey Santandrea, Clémentine Minozzi, Corentin Cruché and Shawn K. Collins*[a]
Dedication ((optional))
Abstract: A photochemical dual-catalytic cross-coupling to form
alkynyl sulfides via C(sp)-S bond formation is described. The cross-
coupling of thiols and bromoalkynes is promoted by a soluble
organic carbazole-based photocatalyst using continuous flow
techniques. Synthesis of alkynyl sulfides bearing a wide range of
electronically and sterically diverse aromatic alkynes and thiols can
be achieved in good to excellent yields (50-96%). The simple
continuous flow setup also allows for short reaction times (30 min)
and high reproducibility on gram scale. In addition, we report the first
alkynyl sulfides, but aryl alkynes were found to be generally
incompatible. Thiols and alkynes can also be employed as
reaction partners in the photochemical thiol-yne click reaction to
form C(sp2)-S bonds,[9] while C(sp3)-S bonds can also be formed
photochemically from thiols and alkenes via thiol-ene coupling
(Figure 1C).[ 10 ] Surprisingly, photochemical methods for the
synthesis of alkynyl sulfides (forming C(sp)-S bonds) are absent
from the toolbox of synthetic chemists.[11] Herein, we describe a
complementary photochemical continuous flow alkynylation of
thiols employing dual photocatalysis to generate structurally
diverse and complex alkynyl sulfides (Figure 1D).
application
of
photoredox/nickel
dual
catalysis
towards
macrocyclization, as well as the first example of the incorporation of
an alkynyl sulfide functional group into a macrocyclic scaffold.
Carbon-sulfur bonds have an important role in the chemical
sciences.[1] The functionalization of thiols has long served as a
key tool in medicinal chemistry and chemical biology, but is now
playing a prominent role in modern materials science.[2] As such,
there is an increasing demand to expand the set of thiol-based
coupling reactions that are chemoselective, tolerant of complex
functionality and provide facile access to new functional group
architectures. Interest in heteroatom-substituted alkynes has
focused mainly on nitrogen-substituted alkynes (ynamides) or
alkynyl ethers.[ 3 ] However, the prominence of carbon-sulfur
bonds in molecules of interest in both medicine and material
science has recently led to the development of thio-alkynylation
methodologies.[4] The direct substitution of an alkyne by a sulfur
provides a fascinating arrangement of functional groups, as the
electron-rich sulfur atom permits conjugation with its lone pair(s)
to afford enhanced reactivity to the triple bond as well as a
handle for modulation of physical properties and desired
applications. Alkynyl sulfides can be obtained in chemoselective
fashion through the use of Umpolung-type strategies: the C-S
bond can be formed through manipulation of a leaving group on
sulfur, typically employing a copper- or a rhodium-catalyzed
coupling with disulfides[5] or by nucleophilic displacement of a
sulfur-halogen functionality or Bunte salts (Figure 1A).[6] Direct
oxidative coupling of thiols and terminal alkynes is also possible
via copper catalysis, but competing homocoupling of both the
alkyne and the thiol can be problematic.[7] Consequently, novel
routes to the alkynylation of thiols continue to be reported, such
as a recent disclosure of a transition-metal-free protocol using
ethynyl benziodoxolone (EBX) reagents to promote the C-S
bond formation (Figure 1B).[8] The base-mediated strategy is
highly efficient for accessing alkyl-[8b] and silyl-substituted[8c]
Figure 1. Selected examples of carbon-sulfur bond forming reactions between
thiols and alkynes.
Investigation into a photochemical synthesis of alkynyl sulfides
focused on exploiting dual catalysis involving a Ni-catalyzed
cross-coupling and photocatalysis (Table 1). In addition, the
present work placed an emphasis on the use of continuous flow
conditions to provide optimal photon flux and more practical
scale-up potential.[12] Important targets also included exploiting
inexpensive, readily accessible photocatalysts with good
solubility profiles. As such, method development began using
4CzIPN, an organic carbazole-based sensitizer reported by
[
13 ]
Zhang.
The model cross-coupling employed the 4-
chlorobenzylthiol 1a and bromoalkyne 2a using the 4CzIPN
photocatalyst under blue LED irradiation. A solvent mixture of
MeCN:DMF (23:1) (50 mM), was found to be optimal and
afforded the desired alkynyl sulfide 3a in 96 % yield in a
residence time of 30 minutes within the flow apparatus (Table 1).
In addition, only traces of 3a were found in the absence of light,
4CzIPN or pyridine. No additional bipyridine-based ligand was
found to be necessary, in contrast to other photoredox/nickel
dual catalyzed transformations.[14] Organic photocatalyst eosin Y,
and transition-metal-based complexes of Ir, Ru and Cu only
provided the desired product in low yields.[15] Finally, irradiation
[a]
Jeffrey Santandrea, Clémentine Minozzi, Corentin Cruché and Prof.
Dr. Shawn K. Collins
Department of Chemistry and Centre for Green Chemistry and
Catalysis
Université de Montréal
CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7
E-mail: shawn.collins@umontreal.ca
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705903
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using a 23 W energy saving light bulb also provided a good yield
alkynyl sulfides 3v and 3w in 96 and 78% yield respectively. As
well, two complex heterocyclic thiols afforded the cross-coupling
products in good to excellent yields (3x and 3y,[16] 52 and 95%).
Note that all of the substrate scope was explored in continuous
flow at short residence times (30 min), but reactions can be run
in batch with longer reaction times (4 h) although yields diminish
upon scale-up.[15]
of alkynyl sulfide 3a (82 %).[15]
Table 1. Control Reactions for Photoredox/Ni Dual-Catalyzed C-S Coupling.
entry
variation from standard conditions
yield (%)[a]
1
2
3
4
5
none
96
<5
<5
28
<5
no light (dark)
no 4CzIPN
.
no NiCl2 dme
no pyridine
[a] Yield determined by 1H NMR spectroscopy using anisole as an internal
standard. PMP = p-methoxyphenyl.
With optimized conditions, the scope of the coupling was first
explored with respect to the alkyne (Scheme 1). With regards to
electronic effects, the dual-catalyzed photocatalytic cross-
coupling was tolerant of electron-donating or neutral substituents
(OMe 3a, Me 3b, H 3c) on the aromatic alkyne, affording high
yields of alkynyl sulfide products (88-96%). Electron-withdrawing
substituents (Br 3d, F 3e, CO2Me 3f) on the aromatic alkyne
cross-coupling partners also reacted smoothly (71-95% yields).
Di-substituted aromatic alkynes were also competent partners,
providing good yields of thioalkynes 3g and 3h, even with
groups in the ortho-positions of the aromatic (74 and 80 %
respectively). Gratifyingly, a number of more complex alkynes
underwent coupling to form the desired C-S bonds in high yields.
For example, alkynes bearing a substituted naphthyl (3i, 65%),
pyridine (3j, 83%), indole (3k, 94%) and thiophene (3l, 95%) all
provided the products in good to excellent yields. To our delight,
phenylalanine-substituted thioalkyne 3m was synthesized in
excellent yield (94%), thus illustrating the feasibility of
incorporating alkynyl sulfides in a peptidic scaffold. The scope of
the dual-catalyzed photocatalytic cross-coupling to form
thioalkynes was next explored with regards to the thiol coupling
partner (Scheme 1). Electron-rich benzylic thiols reacted
smoothly under optimized conditions to generate 3n and 3o (80
and 91 % respectively). A primary alkyl thiol bearing a halogen
underwent productive coupling (3p, 61%). Boc-protected
cysteine also underwent coupling to provide the thioalkyne
amino acid 3q in 75 % yield. Secondary alkyl thiols were also
competent reaction partners, as the cyclohexyl substituted
alkynyl sulfide 3r was isolated in 66% yield. An enantiomerically
pure secondary thiol was employed under photochemical
conditions to generate 3s in 70% yield without loss of the optical
activity. Functionalization of captopril afforded the corresponding
alkynyl sulfide derivative 3t in 62% yield. Furthermore, a
thioglucose derivative was also successfully coupled to furnish
3u in 50% yield. Aromatic thiols provided the corresponding
Scheme 1. Substrate scope. Yields after chromatography.
To demonstrate the versatility of alkynyl sulfides as synthons, a
series of functionalizing transformations were performed
(Scheme 2). First, the model thioalkyne 3a was prepared on
gram scale using the photocatalytic dual-catalyzed cross-
coupling. Even upon scale-up, the method was highly
reproducible, affording thioalkyne 3a in 90 % yield.[15] Next,
diversification using the alkyne unit was pursued. The thioalkyne
3a could undergo hydration upon treatment with pTsOH/SiO2 to
afford the corresponding thioester 4 (62%).[17] Reduction using
LiAlH4 affords the (E)-thiovinyl ether 5 (75% yield). It is to be
noted that (Z)-thiovinyl ethers can be obtained using a weaker
hydride source in the presence of CuBr.[18] The sulfur atom of
the alkynyl sulfide can also undergo oxidation to the
corresponding sulfoxide (6) and sulfone (7), and such activated
alkynes have already been demonstrated as valuable building
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10.1002/anie.201705903
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blocks able to undergo conjugate additions.[19] Cycloadditions
could also be used to install additional structural complexity: a
Ru-catalyzed [2+2] cycloaddition provided the norbornene-
catalyst system, albeit at a reduced concentration (2 mM).
Gratifyingly, the desired 19-membered ring 11 was isolated in
28 % yield (2 h residence time) and an improvement was
observed over a batch process (17 %, 20 h). X-ray quality
crystals of 11 were obtained and subsequent analysis[ 25 ]
confirmed the macrocyclic structure (Scheme 3).
20
]
adduct
8
in 82% yield.[
A Ru-catalyzed azide-alkyne
cycloaddition afforded the corresponding triazole 9 in 77%
yield;[21] alkynyl sulfides are representative of a small class of
internal alkynes known to undergo selective azide-alkyne
cycloaddition.[22]
Scheme 2. Diversification/functionalization of alkynyl sulfides.[15]
Figure 2. Mechanistic proposals for the synthesis of alkynyl sulfides.
Recently, other dual catalytic systems have been reported for C-
S bond formation,[11] but do not report the synthesis of alkynyl
sulfides. The mechanism proposed involves generation of the
thiyl radical being trapped by a nickel species (A, Figure 2, top).
Subsequent oxidative addition forms B and reductive elimination
results in C-S bond formation. The failure of aliphatic alkynes to
react under the developed reaction conditions could be
explained by problematic oxidative addition of the alkynyl halide
(A→B, Figure 2, top). For example, the groups of Ranu[26] and
Li[27] demonstrated that a nickel-based catalyst system could not
undergo oxidative addition with an aliphatic alkynyl bromide. It is
important to note that the photochemical synthesis of alkynyl
sulfides proceeded in the absence of nickel to provide 28% of 3a
(Table 1, entry 4). A possible explanation would consist of
photochemical generation of the thiyl radical and addition to the
alkyne to form the stabilized radical C (Figure 2, bottom).[28]
Trapping of the radical with another thiol results in propagation
and formation of vinyl bromide D.[29] Subsequent base-mediated
elimination would form the desired alkynyl sulfide.
Scheme 3. Dual catalytic synthesis of a 19-membered macrocyclic alkynyl
sulfide.
Given the successful synthesis of the alkynyl sulfide cross-
coupling with cysteine, the possible application to the
preparation of macrocyclic peptide-like structures was
envisioned. To the best of our knowledge, dual-catalysis
employing photochemistry/Ni-catalysis has yet to be exploited in
the
context
of
macrocyclization.
Photochemical
macrocyclizations are rare; notable examples include the thiol-
ene reaction,[ 23 ] in which a cyclization occurred on solid
support[22b] (2 examples, 30% average yield) and a recent
decarboxylative photoredox macrocyclization (18 examples,
43% average yield).[ 24 ] Macrocyclizations in batch normally
require highly dilute reaction mixtures which make efficient light
penetration a significant challenge. As such, it was hoped that
the continuous flow protocol developed herein, would aid in the
development of a novel macrocyclization protocol. Macrocyclic
precursor 10 was prepared and submitted to the optimized
In summary, a novel photochemical dual-catalytic cross-coupling
to form alkynyl sulfides has been developed. The method
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10.1002/anie.201705903
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COMMUNICATION
provides the first photochemical route to C(sp)-S bond
architectures, and should complement existing photochemical
functionalizations as the thiol-ene (C(sp3)-S bond) and thiol-yne
(C(sp2)-S bond) reactions, which have been established as
important tools in the chemical sciences. The method exploits a
readily available and soluble organic photocatalyst that permits
exploiting continuous flow techniques. As such, facile and rapid
(30 min residence time) synthesis of thioalkynes on gram scale
is possible, and a wide range of electronically and sterically
diverse aromatic alkynes and thiols are viable coupling partners.
In addition, the first dual-catalytic macrocyclization was achieved
to prepare a 19-membered macrocycle, which represents, to the
best of our knowledge, the first incorporation of the thioalkyne
moiety into a macrocyclic scaffold. Considering the utility for new
chemoselective and functional group-tolerant thiol-based
coupling reactions, the method will provide access to new
thioalkyne architectures for application in medicinal chemistry,
chemical biology, and materials science.
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The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC), the NSERC CREATE
program in Continuous Flow Science, the Canadian Foundation
for Innovation for financial support for continuous flow
infrastructure and the Centre for Green Chemistry and Catalysis
(CGCC) for funding. Ms. Vanessa Kairouz is thanked for
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[16] Alkynyl sulfide 3y is unstable and decomposes neat and in solution at
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Keywords: photocatalysis • alkynyl sulfides • dual catalysis •
macrocycles • continuous flow
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Entry for the Table of Contents (Please choose one layout)
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Jeffrey Santandrea, Clémentine Minozzi,
Corentin Cruché and Shawn K. Collins*
((Insert TOC Graphic here))
Page No. – Page No.
Photochemical Dual-Catalytic
Synthesis of Alkynyl Sulfides
A photochemical dual-catalytic cross-coupling to form alkynyl sulfides via C(sp)-S
bond formation is promoted by a soluble organic carbazole-based photocatalyst
using continuous flow techniques in short reaction times (50-96%, 30 min). In
addition, incorporation of an alkynyl sulfide functional group into a macrocyclic
scaffold was demonstrated as the first application of photoredox/nickel dual
catalysis towards macrocyclization.
This article is protected by copyright. All rights reserved.