Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism

Article abstract of DOI:10.1021/ja5083014

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.

Full text of DOI:10.1021/ja5083014

Article
pubs.acs.org/JACS
Fast and Highly Chemoselective Alkynylation of Thiols with
Hypervalent Iodine Reagents Enabled through a Low Energy Barrier
Concerted Mechanism
Reto Frei,† Matthew D. Wodrich, Durga Prasad Hari, Pierre-Antoine Borin, Clement Chauvier,
́
and Jerome Waser*
́
̂
́ ́
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015
Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: Among all functional groups, alkynes occupy a
privileged position in synthetic and medicinal chemistry,
chemical biology, and materials science. Thioalkynes, in
particular, are highly useful, as they combine the enhanced
reactivity of the triple bond with a sulfur atom frequently
encountered in bioactive compounds and materials. Never-
theless, general methods to access these compounds are
lacking. In this article, we describe the mechanism and full
scope of the alkynylation of thiols using ethynyl benziodox-
olone (EBX) hypervalent iodine reagents. Computations led to
the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction
rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes
containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen
sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of
thioalkynes.
impact neighboring research areas. When considering the
importance of alkynes for progress in numerous fields of
molecular sciences, the development of new methods to access
them efficiently under user-friendly conditions is highly
desirable.
INTRODUCTION
■
One of the most important tasks of organic chemistry is
discovering practical and general methods for introducing
functional groups into molecules to modify their properties and
to serve as a platform for further modifications. At a time when
research in neighboring fields such as medicine, biology, or
materials science is becoming increasingly molecular, easy-to-
perform transformative reactions that do not require highly
specialized synthetic skills have a particularly broad impact.
Among all functional groups in organic chemistry, alkynes
occupy a privileged position in this respect.1 Despite being one
of the simplest functional groups with only two carbon atoms,
the reactivity of the triple bond makes alkynes exceptionally
useful in organic chemistry. They have found applications in
bulk chemical synthesis based on acetylene gas2 as well as in
fine chemistry for the stereoselective construction of the carbon
backbone of complex natural products3 and in a myriad of
complexity-enhancing metal-catalyzed cyclization reactions to
access carbo- and heterocycles.4 Most importantly, the utility of
alkynes has now crossed the boundaries of organic chemistry:
their electronic properties have led to widespread applications
in organic materials and dyes5 and the [3 + 2] cycloaddition
with azides is now recognized as one of the best biorthogonal
conjugation method to modify biomolecules and polymers.6
The latter transformation is particularly representative of how
discoveries in fundamental organic reactivity can strongly
Among the different classes of alkynes, those directly
substituted by a heteroatom are especially interesting for two
reasons:7 (1) the electron-rich heteroatom makes the triple
bond more reactive, allowing new chemical transformations and
(2) they constitute value-added building blocks, as heteroatoms
are essential for the physical and biological properties of small
molecules. In short, they bring together the new properties
conferred by heteroatoms with the exceptionally rich chemistry
of alkynes (Scheme 1). Nevertheless, the synthetic potential of
heteroatom-substituted alkynes has long remained under-
developed due to the absence of convenient methods to access
these often sensitive compounds. The coupling of heteroatoms
with acetylides is indeed not favorable, as both fragments are
inherently nucleophilic and an Umpolung of the reactivity is
required.
In the specific case of nitrogen-substituted alkynes (ynamines
and ynamides), however, the situation has changed dramatically
in the last two decades, when new synthetic methods for the
Received: August 13, 2014
© XXXX American Chemical Society
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alcohols, carboxylic acids, electron-rich aromatic groups or free
amines. Nevertheless, two aspects of the developed method-
ology were not fully satisfying: (1) The mechanistic basis of the
extreme efficiency of the reaction could not be rationalized. An
in-depth understanding of the alkynylation would be highly
useful for further development. (2) The reaction was limited to
the transfer of silyl acetylenes on thiols as nucleophiles.
Although we demonstrated that the obtained products could
easily be deprotected and functionalized, this made our
approach less convergent and attractive if the introduction of
functionalized alkyne groups is desired. Furthermore, the
alkynylation of other sulfur nucleophiles such as thioacetals,
thioacids or sulfides salts would also be important in extending
the range of accessible thioalkynes.
In this article, we address both issues. On the basis of the
isolated side products and computational studies, we propose a
mechanism for the reaction. In particular, computations showed
that a concerted transition state between the deprotonated thiol
and the iodine reagent was possible, leading to an exceptionally
low (10.8 kcal/mol) activation energy for the alkynylation using
silylated EBX reagents. This type of mechanism has never been
proposed for the alkynylation of nucleophiles using hypervalent
iodine reagents and is expected to change the way many
researchers think about these transformations. We then report
an extension of the alkynylation reaction to the use of aryl and
functionalized alkyl acetylenes and further extend the scope of
thiols to thioglycosides, thioacids and sufide salts, resulting in
the most general and practical thiol alkynylation method
reported to date.
Scheme 1. Heteroatoms-Substituted Alkynes: The Best of
Two Worlds, but How To Access Them?
alkynylation of nitrogen with either hypervalent iodine reagents
or terminal and halogeno alkynes in the presence of copper
catalysts were developed.8 Ynamides in particular are now
intensively used in modern synthetic chemistry.7c,d In contrast,
the chemistry of thioalkynes is still underdeveloped. This is
surprising considering the importance of sulfur in drugs,
materials and biomolecules.9 In fact, the high nucleophilicity of
thiols has led to the development of very efficient methods for
the formation of S−S (oxidative disulfide formation), S−C(sp3)
(alkylation, thiol−ene) and S−C(sp2) (thiol−yne) bonds.10 All
of these reactions are routinely used for important trans-
formations in chemical biology and materials science. Until very
recently, the direct synthesis of thioalkynes from thiols, on the
other hand, has been limited to addition−elimination reactions
on alkynyl or alkenyl halides under strongly basic conditions
(Scheme 2).11 The most commonly used methods permitting
Scheme 2. Method To Access Thioalkynes Based on
Umpolung of Sulfur or Alkyne
RESULTS AND DISCUSSION
■
Mechanism and Computational Studies. Investigating
the reaction mechanism of the alkynylation with TIPS-EBX
(1a) is particularly challenging because of the fast rate: even 10
s after addition of the reagent, full conversion of thiol 2 was
already observed when using 1,1,3,3-tetramethyl guanidine
(TMG) as a base (eq 1). Furthermore, low-temperature
access have been based on the reaction of terminal alkynes with
activated sulfur derivatives bearing a leaving group, such as
chloride, tosyl or cyano, or disulfides.12 This lack of efficient
synthetic methods under mild conditions has clearly limited the
applications of potentially very useful thioalkynes in synthetic
and medicinal chemistry.
In 2013, the first efficient metal-catalyzed examples of
alkynylation of thiols appeared using copper, palladium or
nickel catalysts.13 Nevertheless, these transformations still
required the use of a transition metal catalyst, and the scope
of thiols described in these works remained limited to very
simple thiophenols and aliphatic thiols13a or to thioglycosi-
des,13b,c respectively. The same year, our group reported the
first method for the alkynylation of thiols using 1-
[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-
EBX, 1a, R = SiiPr3).14 In contrast to previously published
methods, the reaction was efficient and user-friendly, leading to
the complete alkynylation of aromatic and aliphatic thiols in
less than 1 min at room temperature in an open flask.
Furthermore, selective alkynylation of thiols was possible in the
presence of numerous functional groups such as halogens,
experiments are difficult because of low solubility of the
hypervalent iodine reagent below 0 °C. Nevertheless, control
experiments showed that no or very little alkynylation was
observed in the absence of a base. In this case, oxidative
dimerization to form disulfide 4 was the major process. In
addition, no reaction or interaction was observed by NMR
between reagent 1a and TMG. These results permit the
reasonable assumption that deprotonation of thiol 2 to form
thiolate 2′ is required for the reaction to occur (Scheme 3).
From this point forward, a first possible mechanism would be
substitution on iodine to give intermediate a1, followed by
reductive elimination (pathway a, blue in Scheme 3). This
mechanism is well-established in hypervalent iodine chemistry,
especially with aryliodonium salts.15
Alternatively, a single electron transfer mechanism (SET) has
also been proposed.16 Nevertheless, in the case of the
alkynylation reaction, no radical intermediate could be trapped
when using TEMPO as a reagent and the reaction occurred
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Scheme 3. Initial Speculative Mechanism for the
Alkynylation Reaction
strong support for the conjugate-addition/α-elimination/1,2-
shift mechanism. Furthermore, the relatively good yield of
isolated alkynylation product was in accordance with a shift of
the sulfur atom, as the migration of the methyl group was
expected to be too slow to be productive.
Nevertheless, no intermediate could be observed in the case
of TIPS-EBX (1a). To gain a more comprehensive under-
standing of the mechanistic details leading to thioalkyne
formation, density functional theory (DFT) computations were
undertaken using benzyl thiol (2) as a substrate. As described
above, in the most likely scenario, a deprotonated thiol directly
attacks TIPS-EBX (1a). This occurs either by direct attack onto
the hypervalent iodine atom (pathway a in Scheme 3) or
through a conjugate addition (pathway b in Scheme 3).
Computations (at the PBE0-dDsC/TZ2P//M06-2X/def2-SVP
theoretical level, see Computational Details for additional
information) designed to probe the potential energy surface
revealed two low-energy van der Waals complexes that roughly
correspond to the entry points into the two mechanistic
pathways a and b. The first, a0 in Figure 1, is a lower energy
with the same yield and reaction time. Although this
experiment is naturally not sufficient to exclude a SET pathway,
it is also important to note that most reactions of hypervalent
iodine reagents occurring via a SET pathway require activation
of the reagent by a Lewis or Brønsted acid to accelerate
electron transfer,16 and the alkynylation reaction occurs only
under basic conditions.
Nevertheless, alkynyliodonium salts constitute a unique class
of hypervalent iodine reagents, as the β-carbon of the alkyne
has very strong electrophilic character.17 In this case, an
alternative mechanism is possible: conjugate addition of the
thiolate 2′ on EBX 1 to give a vinyl benziodoxolone
intermediate b1 (pathway b, red in Scheme 3). From b1, α-
elimination of iodobenzoate 5 followed by a 1,2-shift of either
the sulfur or silicium substituent gave thioalkyne 3. In fact, this
type of mechanism was proposed by Ochiai and co-workers in
the case of carbon nucleophiles based on the isolation of C−H
insertion products originating from carbene intermediate b2.18
Importantly, such insertion products could be observed only
when carbon-substituted alkynyliodonium salts were used in
the reaction, as the 1,2-shift of silyl groups was faster than
insertion reactions.
To establish if Ochiai’s mechanism was also correct in the
case of sulfur nucleophiles, we decided to investigate Me-EBX
(1b) as a reagent, as the methyl group was expected to have a
very low migrating aptitude. This reagent was easily synthesized
using the one-step protocol recently developed by Olofsson
and co-workers.19 Surprisingly, the desired alkynylation product
3b could still be isolated in 70% yield, although the reaction
was less clean than usual (eq 2). In particular, a polar side
product with NMR signals in accordance with vinyl
benziodoxolone 6 could be observed, although the small
quantities of 6 formed did not allow us to isolate this product in
pure form at this stage. Compound 6 most likely originated
from protonation of intermediate b1. Consequently, we
hypothesized that its formation could be favored if only a
catalytic amount of base was used. Indeed, this was the case and
we were pleased to see that 6 precipitated directly from the
reaction mixture in 20% yield as a single Z isomer when only 10
mol % of TMG was used (eq 3). The isolation of 6 constituted
Figure 1. Computed geometries (M06-2X/def2-SVP level) of the van
der Waals complexes a0 and b0 for TIPS-EBX (1c) and thiolate 2′.
Free energies computed at the PBE0-dDsC/TZ2P//M06-2X/def2-
SVP level and include solvation correction in THF determined using
COSMO-RS.
conformation in which the sulfur atom and the iodine atom are
in close proximity (2.913 Å). However, the sulfur atom is not
exactly opposite to the aryl ring as generally expected for
interaction of nucleophiles with hypervalent iodine reagents,
but instead lies in a position roughly equidistant between the
iodine (2.913 Å) and α-carbon (3.128 Å) atoms of the
acetylene. A second complex (b0 in Figure 1), lying ∼15.8 kcal/
mol higher in energy, was found to correspond to the
aforementioned conjugate addition pathway b. Here, the sulfur
atom of the deprotonated thiol can clearly participate in a direct
attack on the β-carbon of the acetylene unit.
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Figure 2. Reaction free energy profile [PBE0-dDsC/TZ2P//M06-2X/def2-SVP level in implicit THF solvent (COSMO-RS)] for the two possible
mechanistic pathways a (blue) and b (red) for the reaction of TIPS-EBX (1a) with thiolate 2′. *Positive deltaE at the M06-2X/def2-SVP level.
Our initial assumption was that complex a0 (depicted in
blue) is the reactant species leading to formation of a S−I bond,
as represented by intermediate a1. To our surprise, no minima
containing a formal S−I bond could be located on the potential
energy surface (Figure 2, blue pathway). Instead, the quasi-
triangular atomic arrangement between the sulfur, iodine, and
α-carbon atoms results in a direct addition of the sulfur onto
the α-carbon atom of the acetylene unit with simultaneous
breaking of the C−I bond.20 This process is associated with a
quite modest aTS1 barrier height of only 10.8 kcal/mol.21 Upon
formation of the new S−C bond (Figure 3, aTS1 in blue), the
thioalkyne-iodobenzoic acid complex a3•5 is spontaneously
formed in a highly exergonic process. Importantly, we find no
computational evidence predicting formation of a stable
intermediate, which is in agreement with of our failure to
isolate any side products with TIPS-EBX (1a) as reagent.
The conjugate addition pathway b (Figure 2, red pathway),
begins from the higher energy (+15.8 kcal/mol, red) van der
Waals complex b0. Here, the reaction proceeds as originally
proposed by Ochiai.18 Formation of the new S−C bond occurs
in a facile process, requiring only ∼7.2 kcal/mol of energy
(bTS1). In contrast to the previously discussed pathway, the β-
carbon conjugate addition route b does lead to the formation of
the expected intermediate species b1. However, the TS barrier
associated with cleavage of the I−C bond (bTS2, Figure 3) is
Figure 3. Computed geometries (M06-2X/def2-SVP level) of the
negligible (ΔG = −0.7 kcal/mol at the PBE0-dDsC/TZ2P//
relevant structures.
M06-2X/def2-SVP level, ΔE = +0.3 kcal/mol at the M06-2X/
def2-TZVP//M06-2X/def2-SVP level), meaning the species is
likely short-lived, making experimental characterization, ob-
servation or even protonation highly unlikely. As in pathway a,
formation of the final product complex is highly exergonic,
proceeding via a 1,2-shift of the silicium atom. No minima
corresponding to a free carbene b2 could be located on the
potential energy surface.
From the reaction free energy profile in Figure 2, it is clear
that both the a (blue) and b pathway (red) mechanisms are
easily accessible at room temperature. While the β-conjugate
addition pathway b involves a slightly lower TS barrier bTS1
corresponding to S−C bond formation, the lower relative
energy of the α-addition van der Waals complex a0 (blue,
Figure 1) results in pathway a being the overall energetically
preferred reaction mechanism by 12.2 kcal/mol. This is highly
interesting, considering that a mechanism involving addition to
the α-carbon atom concerted with elimination of the iodine has
never seriously been considered for alkynyl hypervalent iodine
reagents.
To ensure that other mechanisms that include either direct
attack by a protonated thiol or explicit involvement of the base
(TMG) are not more energetically favorable, we computed a
number of additional pathways (see SI for details). However,
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Figure 4. Reaction free energy profile [PBE0-dDsC/TZ2P//M06-2X/def2-SVP level in implicit THF solvent (COSMO-RS)] for the two possible
mechanistic pathways a (blue) and b (red) for the reaction of Me-EBX (1b) with thiolate 2′.
none were found to be energetically competitive with the direct
attack of thiolate mechanism described above. As an example,
direct attack by the protonated thiol species involves a TS
barrier of 32.6 kcal/mol for S−C bond formation. This
compares quite unfavorably to the 10.8 kcal/mol barrier seen
when the deprotonated thiol is involved in a direct attack type
mechanism.22
looking closely at the unsymmetrical structure of transition
state aTS1. Indeed, the sulfur atom is already in close proximity
to the α carbon atom of the alkyne, and the geometry around
the β carbon is strongly distorted from sp to sp2. This would
lead to the formation of a partial charge on the β carbon.
Indeed, calculations indicated an iterative Hirshfeld charge of
−0.82 at this position in the case of TIPS-EBX (1a) (Figure 2).
In contrast, no strong charge transfer was observed in the case
of Me-EBX (1b) (charges of −0.27 and −0.12 at the α and β
positions, respectively, Figure 4). Silicium is well-known to
stabilize negative charges on adjacent carbons (α-silicium
effect).24 Consequently, a lower activation barrier could be
expected in this case through transition state stabilization.
The computational results obtained for the reaction of TIPS-
EBX (1a) are highly interesting. Nevertheless, they seemed to
be in contradiction with the isolation of side product 6 when
Me-EBX (1b) was used (eq 3), as 6 would be generated from
very short-lived intermediate b1 via the least favored pathway b.
To see if this result could be rationalized by computation, we
also examined the reaction free energy profile for Me-EBX (1b)
(Figure 4). Like for TIPS-EBX (1a) (Figure 2), a mechanism
featuring attack on the α-carbon is favored based on enhanced
stability of the prereaction van der Waals complex a0 and b0. In
contrast, however, the TS barrier associated with formation of
the S−C bond (aTS1 and bTS1, Figure 4) lie relatively close to
each other (within 5 kcal/mol at the PBE0-dDsC/TZ2P level
and within 2 kcal/mol at the M06-2X/def2-TZVP level).23
Since this first transition state represents the highest point
along the reaction pathway for both mechanisms, it can be
envisaged that a small percentage of reactions proceed via the
red pathway a, as opposed to the more energetically favorable
blue pathway b. Furthermore, a significant bTS2 barrier height
(+5.7 kcal/mol) is obtained, in contrast to the reaction with
silylated reagent 1c. This enhanced barrier, probably due to the
less favorable shift of the sulfur group in this case, likely equates
to a longer-lived intermediate that can be protonated and
observed as 6 (eq 3).
SCOPE EXTENSION
■
The previous method developed in our group was very efficient
using TIPS-EBX (1a) as a reagent. However, to introduce a
fluorophore or other functional groups on the alkyne, two
further steps were required (silyl deprotection and cyclo-
addition), making the approach less convergent.14a Further-
more, sensitive substrates could potentially not resist in the
desilylation step using basic TBAF. Consequently, it would be
highly desirable to install the desired functionality on the alkyne
on the cyclic hypervalent iodine reagent before carrying out the
thioalkynylation reaction. On the basis of the side reactions
observed by Ochiai and co-workers with alkyl-substituted
alkynyliodonium salts and carbon nucleophiles,18 a general-
ization of the scope appeared highly challenging to us when we
started this project. However, the surprisingly good results
obtained with Me-EBX (1b) during our mechanistic inves-
tigations and the very low activation energies obtained by
computation indicated that sulfur nucleophiles should behave
differently and have a much broader scope in the alkynylation
reaction. To test this hypothesis, benziodoxolone hypervalent
iodine reagents were first synthesized via Olofsson’s one-step
method starting from alkynyl boronic esters (eq 4).19 This
When comparing the lowest energy pathway a for the
reaction of TIPS-EBX (1a) and Me-EBX (1b), a strong
accelerating effect of the silicium atom (about 5 kcal/mol) is
apparent. Although understanding fully this effect will require
more in-depth studies, some insights can already be gained by
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a
Table 1. Scope of EBX Reagents with o-Bromo Thiophenol
protocol turned out to be very efficient and easily scalable
giving the EBX reagents in 71−95% yield in up to 9 g scale in
the case of Me-EBX (1b). Nevertheless, in case of more
functionalized alkynes, it was not possible to access the very
sensitive alkynyl boronic esters. In this case, the use of more
stable silylated alkynes gave the desired products in 27−47%
yield. Importantly, EBX reagents bearing functional groups
such as alkenes, alkynes, halogens, azides or alcohols were
synthesized for the first time. Although the yield was moderate,
the procedure was easily scalable to the multigram scale and the
enhanced stability of benziodoxolone compared to alkynylio-
donium salts allowed easy purification by column chromatog-
raphy to obtain pure reagents 1. A significant amount of silyl
acetylenes could also be recovered.25
Due to the significance of aromatic thiols as important
structural motifs in the synthesis of pharmaceutical, natural, and
medicinal compounds and the excellent results obtained in our
previous work, we decided to start our investigation with this
class of substrates. o-Bromo thiophenol 8 was chosen as a
substrate for studying the different EBX reagents, as the bromo
group constitutes an ideal handle for further functionalization.
In the case of aliphatic EBX reagents, we found that TBD
(1,5,7-triazabicyclo[4.4.0]dec-5-ene) was superior to TMG as a
base and THF was still the optimal solvent. When EBX reagent
1b was added to the mixture consisting of o-bromo thiophenol
(8), TBD, and THF at room temperature and stirred for 5 min
in an open flask, the corresponding thioalkynylated product 9a
was obtained in 93% yield (Table 1, entry 1). Noteworthy, the
reaction was not affected by the water which was added to
increase the solubility of the formed thiolate salts in certain
cases. The alkynylation with longer alkyl chains (entries 2 and
3) or a tert-butyl group (entry 4) proceeded in quantitative
yields. At this point, the use of functionalized alkyl-EBX
reagents was investigated for the first time (entries 5−9).
We were pleased to see that the alkynylation with reagents
bearing an alkene, an alkyne, a chloride, an azide or a free
alcohol proceeded in 87−98% yield. The fact that functional
groups are tolerated both on the thiol and alkyne reagent makes
the method more attractive for the synthesis of thioalkynes.
Finally, the alkynylation was not limited to the transfer of
aliphatic alkynes: mesityl-substituted product 9j was also
obtained in quantitative yield (entry 10).
a
O-Bromo thiophenol (8, 0.30−0.80 mmol), alkyne transfer reagent
(1, 0.33−0.88 mmol), base (0.30−0.80 mmol), THF (3.75−10.0 mL),
Inspired by the efficiency of the thioalkynylation reaction
(Table 1), we further studied the use of EBX reagents for the
multiple alkynylation of benzene-1,3,5-trithiol (10) (eq 5). In
b
23 °C, 5 min, open flask. Isolated yield after purification by column
chromatography.
this context, TIPS-EBX (1a) and EBX reagents 1g and 1k were
examined. We were able to isolate the corresponding triple-
alkynylated products 11a−c in 96%, 87% and 88% yield,
respectively. Due to the efficiency of the reaction and the
versatility of the introduced functional groups, the method is
highly useful for the synthesis of dendrimers with potential
applications in materials science or drug delivery.
To further demonstrate the utility of the synthesized
thioalkyne products, we investigated their transformation into
other useful building blocks. We first examined the trans-
formation of thioalkyne 9b into the corresponding benzothio-
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phene 12 using a protocol developed by Knochel and co-
that avoids the use of expensive or toxic metal catalysts, ligands,
base and higher temperature. Furthermore, only the synthesis
of aromatic alkynes had been reported to date. Using our
method, protected thioglycoside 15a was alkynylated with
TIPS-EBX (1b) and reagents 1j and 1k in a few minutes at
room temperature to afford the corresponding products 18a−c
in 45−84% yield. Protection of the hydroxy groups of the
carbohydrate was not required: products 18d and 18e bearing
four free hydroxy groups were also obtained in 81% and 60%
yields, respectively.
workers (eq 6).26 The addition of PrMgCl·LiCl in THF to 9b
i
After demonstrating that the reaction protocol worked well
with simple aliphatic thiols and thioglycosides, we studied the
alkynylation of a cysteine containing dipeptide 16a (TrpCys).
In fact, cysteine is one of the natural amino acids and plays a
key role in the activity and structure of proteins. It is also an
ideal entry for bioconjugation reactions.9,30 As shown in
Scheme 4C, the reaction worked efficiently for a variety of EBX
reagents. Substituents containing an alkyl chain without
(product 19a) or with additional functional groups (products
19b−e) were tolerated including a chloro, an ether,31 an azido
and a hydroxy group. Finally, a mesityl-substituted alkyne group
could also be introduced in 80% yield (product 19f). The
selective alkynylation of dipeptide 16a with different function-
alized alkynes is an important preliminary result in view of the
modification of more complex molecules, such as peptides and
proteins. In addition, the alkynylation of N-unprotected
followed by CuCN·2LiCl afforded the 3-alkyl benzothiophene
12 in 83% yield after 24 h. Thiolakyne 9k, easily obtained from
the alkynylation of thiophenol with reagent 1d, was subjected
to acid hydrolysis to furnish the corresponding thioester 13 in
93% yield (eq 7).27
After having successfully extended the scope of the
alkynylation to alkyl- and aryl-substituted EBX reagents in the
case of thiophenols, we turned to aliphatic thiols (Scheme 4).
(4-Methoxyphenyl)methanethiol (14) was alkynylated success-
fully, furnishing alkynylation products 17a−d in 59−84% yield
(Scheme 4A).28 Again, long and short alkyl chains, as well as a
chloride and an alcohol, were well tolerated on the reagent,
although the yields were lower than in the case of thiophenols.
As a second important class of aliphatic thiols, we decided to
turn to thioglycosides (Scheme 4B). These compounds are key
building blocks in carbohydrate synthesis and exhibit important
biological activities.29 Recently, Messaoudi and co-workers
reported the alkynylation of protected and unprotected
thioglycosides using transition metal catalysts.13b,c Our metal
free thioalkynylation method provides a valuable alternative
t
cysteine ester 16b with Bu-EBX (1f) gave exclusively thiol
alkynylation in 94% yield.
As a last example of more complex aliphatic thiol,
angiotensin-converting enzyme (ACE) inhibitor Captopril
(20), which is used as a drug to treat hypertension,32 was
a
Scheme 4. Scope of the Alkynylation for Benzylic Thiol 14 (A), Thioglycosides 15 (B), and Amino Acid Derivative 16 (C)
a
See Supporting Information for experimental details (solvents, base).
G
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Article
successfully alkynylated with 1e to give the corresponding
thioalkyne 21 in 94% yield (eq 8). This result demonstrated
that free carboxylic acid groups were tolerated in the
alkynylation reaction.
to access this class of compounds. The double alkynylation
worked for all three classes of alkynes: silyl (product 25a), alkyl
(product 25b) and aryl (product 25c). The lower yield of the
latter is probably due to the low solubility of the reagent Ph-
EBX (1o). The reaction also worked for the introduction of a
propargylic ether (product 25d) or an alcohol (product 25e).34
We then examined if the alkynylation method could be
extended to selenium nucleophiles. In fact, alkynyl selenium
compound 28 was obtained in 45% yield from phenylselenol
(27) without further optimization of the reaction conditions.
This preliminary result is promising for the development of a
more general method for the alkynylation of selenols.
To further demonstrate the generality of the alkynylation
reaction, we studied two classes of sulfur nucleophiles which
were not included in our previous studies: thiocarboxylic acids
and sodium hydrogen sulfide, the simplest of all sulfur
nucleophiles (Scheme 5). Thiocarboxylates are less nucleophilic
Scheme 5. Alkynylation of Thioacids 22 (A) and Sodium
Hydrogen Sulfide (23) (B)
CONCLUSION
■
In summary, in this manuscript we described the first
computational studies of the alkynylation of thiols using
ethynyl benziodoxolone (EBX) reagents. An unprecedented
concerted mechanism involving the sulfur, iodine and α-carbon
atoms of the alkyne was discovered by computation, leading
directly to the alkynylation products with a low activation
barrier. In case of silyl-substituted EBX reagents, the activation
energy was exceptionally low (10.8 kcal/mol), which made this
pathway the most favorable according to the computations and
may explain the high rate observed for the reaction. For the
case of alkyl-substituted reagents, a second mechanism
involving conjugate addition, followed by simultaneous α
elimination of iodobenzoic acid and sulfur 1,2-shift was also
found to be competitive. This latter result rationalizes the
isolation of small amounts of vinyl benziodoxolone inter-
mediate 6 resulting from conjugate addition of benzylthiol (2)
on Me-EBX (1b) followed by protonation.
The unique properties of thiolates in reaction with EBX
reagents led us to anticipate that the transformation may have a
broader scope than reactions involving carbon nucleophiles.
This was indeed the case, and we could use, for the first time,
functionalized alkyl- and aryl-substituted EBX reagents for the
alkynylation of both aromatic and aliphatic thiols. Functional
groups such as alkenes, alkynes, ethers, chlorides, azides and
alcohols were tolerated on the alkynes. In addition to simple
thiophenols and benzylic thiols, the alkynylation of cysteine in a
dipeptide, thioglycosides, thiobenzoic acid derivatives and
sodium hydrogen sulfide was also successful. The practical
and user-friendly character of the method (5 min reaction time,
open-flask, water tolerance, room temperature) and a deeper
understanding of the reaction mechanism have set the stage for
a broader application in the functionalization of materials and
biomolecules in the future.
than thiolates. Nevertheless, TIPS-EBX (1a) was again an
excellent reagent for the alkynylation of thiobenzoic acid (22a)
giving the desired product 24a in 94% yield. Electron-donating
and -withdrawing groups were well tolerated on the benzene
ring (products 24b−d). On the other hand, thioesters derived
from aliphatic alkynes were unstable under the reaction
conditions, and ketone product 26, probably resulting from
the hydration of the triple bond, was instead isolated in 45%
yield. Only very low yields were obtained in the case of aliphatic
thioacids (results not shown). Unlike other thiols, the
alkynylation of thioacids did not require the use of base,
probably due to the higher acidity of these substrates.
COMPUTATIONAL DETAILS
■
All geometries were optimized using Truhlar’s M06-2X35 density
functional with the def2-SVP basis set in Gaussian09.36 M06-2X
computations employed the “Ultrafine” grid to remove known
problems with the size of the integration grid for this functional
family.37 To obtain refined energy estimations that explicitly account
for nonbonded interactions, a density dependent dispersion
correction38 was used appended to the PBE039 functional (PBE0-
dDsC). PBE0-dDsC single point computations made use of the slater-
Due to the significant properties of diethynyl sulfides in
material and interstellar chemistry,33 we then attempted their
synthesis through the alkynylation of sodium hydrogen sulfide.
The resulting one-step protocol would be unprecedentedly fast
H
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Article
type orbital 3-ζ basis set, TZ2P, as implemented in ADF.40 To confirm
the accuracy of the PBE0-dDsC computations, a second set of single
point energies was obtained at the M06-2X/def2-TZVP level. All
reported free energies include the effects of solvation (in THF) using
the implicit continuum model for realistic solvents41 (COSMO-RS),
also as implemented in ADF, as well as free energy correction derived
from M06-2X/def2-SVP computations. Iterative Hirshfeld charges42
were computed using Q-Chem43 at the M06-2X/def2-SVP level.
48, 6974. (g) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev.
2013, 113, 4905.
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Yeom, H. S.; Fang, L. C.; He, S. H.; Ma, Z. X.; Kedrowski, B. L.;
Hsung, R. P. Acc. Chem. Res. 2014, 47, 560.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data for all new
compounds. Additional computational, data including Cartesian
coordinates of relevant compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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2003, 125, 2368. (d) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011. (e) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833. (f) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17.
(g) Evano, G.; Gaumont, A. C.; Alayrac, C.; Wrona, I. E.; Giguere, J.
R.; Delacroix, O.; Bayle, A.; Jouvin, K.; Theunissen, C.; Gatignol, J.;
Silvanus, A. C. Tetrahedron 2014, 70, 1529.
■
S
AUTHOR INFORMATION
Corresponding Author
jerome.waser@epfl.ch.
■
(9) (a) Zambrowicz, B. P.; Sands, A. T. Nat. Rev. Drug Discovery
2003, 2, 38. (b) Paquette, L. A. Sulfur-Containing Reagents; Wiley:
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Human Health and Disease; Wiley: Hoboken, 2009. (d) Hoyle, C. E.;
Lowe, A. B.; Bowman, C. N. Chem. Soc. Rev. 2010, 39, 1355.
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49, 1540. (b) Hoogenboom, R. Angew. Chem., Int. Ed. 2010, 49, 3415.
(c) Lowe, A. B.; Hoyle, C. E.; Bowman, C. N. J. Mater. Chem. 2010,
20, 4745. (d) Stephanopoulos, N.; Francis, M. B. Nat. Chem. Biol.
2011, 7, 876. (e) Stenzel, M. H. ACS Macro Lett. 2012, 2, 14.
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E.; Kikkawa, S.; Miller, S. I. J. Am. Chem. Soc. 1963, 85, 1648.
(b) Marchueta, I.; Montenegro, E.; Panov, D.; Poch, M.; Verdaguer,
X.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 2001, 66, 6400.
(c) Ni, Z.; Wang, S.; Mao, H.; Pan, Y. Tetrahedron Lett. 2012, 53,
3907. In addition, an interesting example of the reaction of thioethers
with alkynyliodonium salts to give thioalkynes has been reported by
Ochiai and co-workers: (d) Ochiai, M.; Nagaoka, T.; Sueda, T.; Yan, J.;
Chen, D. W.; Miyamoto, K. Org. Biomol. Chem. 2003, 1, 1517.
(12) Selected examples: (a) Braga, A. L.; Reckziegel, A.; Menezes, P.
H.; Stefani, H. A. Tetrahedron Lett. 1993, 34, 393. (b) Bieber, L. W.; da
Silva, M. F.; Menezes, P. H. Tetrahedron Lett. 2004, 45, 2735.
(c) Arisawa, M.; Fujimoto, K.; Morinaka, S.; Yamaguchi, M. J. Am.
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(e) Chandanshive, J. Z.; Bonini, B. F.; Gentili, D.; Fochi, M.; Bernardi,
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Present Address
†Bern University of Applied Sciences, Solothurnstrasse 102,
CH-2504 Biel, Switzerland.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPFL and F. Hoffmann-La Roche Ltd for financial
support. The work of R.F. was further supported by a Marie
Curie International Incoming Fellowship (Grant Number
331631) of the 7th Framework Program of the European
Union and the work of M.D.W. by ERC (European Research
Council, Starting Grant iTools4MC, number 334840). M.D.W.
thanks Prof. Clemence Corminboeuf (EPFL) for helpful
́
suggestions and comments. The Laboratory for Computational
Molecular Design at EPFL is acknowledged for providing
computational resources. Dr. Gergely Tolnai from Eotvos
Lorand University in Hungary is acknowledged for the
́
synthesis of reagent 1n during his stay in our laboratory.
̈
̈
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