Synthesis of Alkynylthiopyridinium Salts and Their Use as Thioketene Equivalents

Article abstract of DOI:10.1002/chem.201901895

A synthetic method has been developed for the preparation of dihalo(pyridinium)sulfuranes and their transformation into alkynylthiopyridinium salts, starting from inexpensive thiopyridones. The reactivity of these salts towards different nucleophiles is evaluated. Most thiols and amines are converted into dithioesters and thioamides, respectively; whereas sterically demanding thiols delivered alkynylthioethers. These results, together with preliminary mechanistic studies reveal that alkynylthiopyridinium salts can be considered synthetic equivalents of unstable thioketenes.

Full text of DOI:10.1002/chem.201901895

A Journal of
Accepted Article
Title: Synthesis of Alkynylthiopyridinium Salts and Their Use as
Thioketene Equivalents
Authors: Manuel Alcarazo, Kai F. G. Averesch, Henner Pesch Pesch,
and Cristopher Golz
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
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To be cited as: Chem. Eur. J. 10.1002/chem.201901895
Link to VoR: http://dx.doi.org/10.1002/chem.201901895
Supported by

Chemistry - A European Journal
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Synthesis of Alkynylthiopyridinium Salts and Their Use as
Thioketene Equivalents
[a]
Kai F. G. Averesch, Henner Pesch, Christopher Golz and Manuel Alcarazo*
Abstract:
A
synthetic method has been developed for the
same level of success for the development of electrophilic
alkynylation reagents. While the umpolung and transfer of
alkynes decorated with electron withdrawing substituents such
as 4 proceded satisfactorily; alkyl-, aryl- or silyl-substituted
alkynylthioimidazolium salts 5 did not get involved in reaction
with typical soft nucleophiles. Only strongly nucleophilic
Grignard reagents are able to react with 5, but in this case the
attack takes place at the S-atom, providing the corresponding
preparation of dihalo(pyridinium) sulfuranes and their transformation
into alkynylthiopyridinium salts, starting from inexpensive
thiopyridones. The reactivity of these salts toward different
nucleophiles is evaluated. Most thiols and amines are converted into
dithioesters and thioamides, respectively; while sterically demanding
thiols delivered alkynylthioethers. These results, together with
preliminary mechanistic studies reveal that alkynylthiopyridinium
salts can be considered synthetic equivalents of unstable
thioketenes.
[
11]
alkynyl thioethers (Scheme 1c).
a) From Iodine to Sulfur
b) Bonding situation
isolobal
X
I
Y
B
X
S
Y
Introduction
Me
Me
N
N
The unique ability of hypervalent I(III) compounds to invert the
polarity of the groups coordinated to iodine and provide
electrophilic synthons starting from classical nucleophiles;
combined with the weakness of their three center-four electron
X-I-Y bond, which allows the mild transfer of either X or Y to
advanced organic intermediates, make I(III)-derived reagents
A
c) Our previous work
S
Br
S
Br
iPr
iPr Br
iPr
iPr
N
N
2
N
N
[
1
]
Me
Me
Me
Me
2
b)
extremely versatile tools for the synthetic practitioner.
1
a)
c)
Transformations which benefit from the use of I(III) platforms are,
[
2
]
among
alkynylations,
fluorinations
others,
electrophilic
(hetero)arylations,
and cyanations.
trifluoromethylations,
[
3
]
[
4
]
[
5
]
Br
iPr
S
CN
iPr
S
C
C
CO Et
S
5
C
C
Alkyl/
Aryl
aminations,
Unfortunately, several
2
[
6
]
[ 7 ]
iPr
iPr
iPr
iPr
N
N
N
N
N
N
hypervalent iodine reagents suffer from thermal instability, which
reduces their range of practical application. In addition, Lewis
acids, bases or even transition metal catalysts may promote
their undesired decomposition. This problem has been in part
alleviated by the employment of cyclic hypervalent iodine
SbF6
SbF
6
Me
Me
Me
Me
Me
Me
3
4
R-H
R-H
R-MgBr
thiols, amines
enamines,
ketoesters,
thiols,
ketoesters
[
8]
reagents, in particular benziodoxolones.
(
hetero)arenes
Considering the tremendous synthetic utility of I(III)-based
reagents, but also their limitations, our group recently started a
research program focused on the identification of other
structurally related scaffolds, yet not based in iodine, which
could deliver similar reactivity. In this regard, we recently
demonstrated that imidazolium sulfuranes A, which are isolobal
to I(III) species and also depict the key three-center four-electron
bond motive might be considered alternative platforms for this
CO Et
Alkyl/Aryl
2
CN
R
R
R
S
Cyanation
Alkynylation
Thioalkynylation
d) This work: From imidazolium to pyridinium
S
C C R
S
C
C
R
Modification of reactivity
via heterocycle
R'
exchange
iPr
iPr
N
N
N
purpose (Scheme 1a-b). Specifically,
a
new electrophilic
SbF6
SbF6
R
cyanation reagent 3 was developed, which was able to carry out
Me
Me
the metal-free direct C-H cyanation of electron rich hetero- and
R = Alkyl/Aryl/SiR3
R = Alkyl/Aryl/SiR
3
[
9, 10]
polyaromatics in good to excellent yields.
Unfortunately, the
use of the imidazolium sulfurane platform A did not match the
Scheme 1. Synthesis and reactivity of imidazolium thiocyanates and
imidazolium thioalkynes. Reagents and conditions: a) TMSCN, CH Cl , r.t.,
9%; b) AgC≡C-COOEt, CH Cl , r.t., and then AgSbF , CH Cl , r.t., 93%, two
steps; c) RC≡C-ZnBr, THF, -78°C→r.t., and then NaSbF , 81-98%, two steps.
2
2
8
2
2
6
2
2
[a]
M. Sc. K. F. G Averesch, H. Pesch, Dr. C. Golz, Prof. Dr. M.
Alcarazo
6
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstr 2, 37077 Göttingen
E-mail: malcara@gwdg.de
Homepage: www.uni-goettingen.de/en/569043.html
Once the significant influence on the reactivity of the
terminal group at the alkyne was recognized, we wondered if the
exchange of the imidazolium moiety by another cationic group
might also be a method to efficiently modulate the reactivity of
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
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FULL PAPER
the resulting species. Specifically, pyridinium rests might be
interesting alternatives because in these moieties the positive
charge is less efficiently stabilized than in imidazolium ones. For
this reason the pyridinium units are expected to deplete more
electron density from the central S-atom and, as consequence,
the corresponding cationic thioalkynes should depict enhanced
if compared with those present in the parent thiolactam (C1; δ =
180-176 ppm.). This chemical shift is consistent with the
disappearance of the C=S double bond from the original
thiolactones 9a-c, and the subsequent increase of the aromatic
character at the pyridinium ring in 10a-c.
To our satisfaction, monocrystals of 10c could be obtained
and X -ray analysis confirmed its sulfurane structure. In the solid
state 10c adopts a slightly distorted T-shape with a nearly linear
(177.50°(3)) Br1-S1-Br2 distribution. However, in sharp contrast
with the situation observed in imidazolium sulfurane 2, where
both S-Br distances are identical (2.505(3)Å), the three center-
four electron bond interaction in 10c is not symmetrical. The
Br1-S1 bond length is slightly elongated (2.5917(7)Å) from the
average distance, while the Br2-S1 bond gets shortened in a
similar magnitude (2.3947(7)Å) (Scheme 2). A closer inspection
at the unit cell of this compound explains this asymmetry. Two
secondary Br-S bonding interactions hold two molecules of 10c
together forming a face-to-face dimer. The two bromine atoms
involved in these short contacts have shorten Br-S bonds, while
the other two slightly elongate their S-Br distances.
[
12]
reactivity towards nucleophiles (Scheme 1d).
In an attempt to
bring this initial hypothesis into practice, we report herein the
synthesis of dihalo(pyridinium) sulfuranes, their derivatization to
the desired alkynylthiopyridinium salts and the reactivity of these
towards typical S-, N-, and C-based nucleophiles. Interestingly,
the alkyne transfer reaction was found not to be operative for
most of the substrates. Instead, the prevalent reaction pathway
found consists on the attack of the chosen nucleophile at the C1
atom of the pyridinium moiety following a nucleophilic aromatic
substitution mechanism. This releases an aldothioketene, which
further reacts with a second equivalent of the nucleophile to
afford dithioesters or thioamides, when thiols and amines are
used as nucleophiles, respectively. The scope of this
transformation is presented together with insights supporting the
proposed mechanism. Considering that the synthetic
applications of aldothioketenes are often limited to their
availability, due to their high tendency to oligo- or polymerize;
the use of alkynylthiopyrydinium salts as easy-to-handle
aldothioketene surrogates might actually broaden the range of
Cl
Me
Et
N
N
BF4
8
6
Me
c)
a)
[
13]
S
Cl
Br
R1
S Br
applications of these compounds.
R1
R2
R2
R2
b)
N
N
d)
N
BF4
= Me
2
1
1
Results and Discussion
7a; R
7
R
R
= H; R
2
=
=
=
H; R2
H; R2
Me; R2 = Et
2
9a; R1
= Me
= Et
10a; R
10b
10c
1
= Me
= Et
b; R = Et
= H; R2
= Me; R2 = Et
b; R1
c; R1
; R1
; R1
9
9
Synthesis of dibromo(pyridinium)sulfurane precursors:
While it is well established that both cyclic and acyclic thioureas
react with elemental chlorine or bromine to form 1:1 adducts of
sulfurane structure, little is known about the generality of this
[
14]
reaction. In fact, we are not aware of any report describing the
involvement of other structurally or electronically related species,
[
15 ]
such as for example thiolactams, in this transformation.
Considering the effectiveness of the syntheses of
alkynylthioimidazolium salts by reaction of dihalo(imidazolium)
sulfuranes with organozinc species, we were encouraged
already at the earliest phase of this research project to evaluate
whether dihalo(pyridinium) sulfuranes could be efficiently
prepared. Hence, we first synthesized thiopyridones 9a-c either
from 2-chloropyridine 6 or from pyridinium salt 8 following
Scheme 2. Synthesis of dibromo(pyridinium)sulfuranes. Reagents and
conditions: a) Me OBF or Et OBF , CH Cl , r.t., 7a, 98%; 7b, 98%; b) NaSH,
MeOH/H O, 45 °C, 9a, 92%; 9b, 85%; c) LiHMDS (1 equiv.), THF, -100 °C,
3
4
3
4
2
2
[
4a]
reported procedures.
The ethyl group in 9b-c was used to
2
and then S
8 2 2 2
(excess); 9c, 68%; d) Br , CH Cl , 0°C→r.t., 10a, 98%; 10b, 97%;
improve the solubility of the corresponding derivatives, while the
two additional methyl rests in 9c where introduced to sterically
protect the pyridine ring from the undesired attack of
nucleophiles (Scheme 2).
10c, 98%. Molecular structure of compound 10c. Anisotropic displacement
parameter shown at 50% probability level, hydrogen atoms omitted for clarity.
Selected bond lengths [Å] and angles [deg]: S1-Br1, 2.5917(7); S1-Br2,
2.3947(7); S1-C1, 1.778(3); Br1-S1-Br2, 177.50(3).
[
16]
Addition of one equivalent of bromine to solutions of 9a-c
in dichloromethane immediately caused the precipitation of
intense orange powders, which were isolated in excellent yields
after filtration. This reaction has been scaled up to multigram
quantities with reproducible yields. Diagnostic spectroscopic
Synthesis of alkynylthiopyridinium salts: Reaction of 10a-c
with alkynylzinc bromides, obtained by transmetallation of the
corresponding organolithium species with ZnBr2, cleanly
provided the desired alkynylthiopyridinum salts as the
corresponding tetrabromozincates 11a-d in moderate to
excellent yields. These conditions were applicable to both, aryl-
1
3
features indicating the formation of sulfuranes 10a-c are the C-
NMR signals for the carbon atoms directly attached to sulfur
(
C1; δ = 165-160 ppm.), which are significantly high field shifted
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Chemistry - A European Journal
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FULL PAPER
and silyl-substituted alkyne rests. All four compounds 11a-d
were isolated as crystalline materials and can be handled in air;
for long time storage, the use of inert atmosphere is
recommended. Subsequent treatment of 11d with a saturated
6
necessary for the complete consumption of 11d(SbF ) and its
quantitative transformation into a 1:1 mixture of the already
mentioned products.
aqueous solution of NaSbF
tetrabromozincate anion by
hexafluoroantimonate in 11d(SbF
6
allowed the exchange of the original
a
more chemical inert
6
). Contrarily, phenyl
substituted salts 11a-c decompose slowly in contact with water
Scheme 3). The preparation of 11d(SbF ) was scaled up to 16
grams (30 mmols) without compromising the yield of the product.
(
6
S
Ph
S
Si(iPr)3
R1
R2
R1
R2
a)
b)
N
N
10a-c
-
4
2
-2
R1
1/2 [ZnBr]
R1
1
/2
[ZnBr]
4
=
=
H; R2
H; R2
Me; R2 = Et
= H; R2
1
1
1
1a; R1
1b; R1
1c; R1
= Me
= Et
11d; R1
= Me
c)
11d (SbF6)
=
6
Figure 1. Molecular structures of compounds 11b (left) and 11d(SbF ) (right).
Scheme 3. Synthesis of alkynylthiopyridinium salts. Reagents and conditions:
a) Phenylacetylene (1 equiv.), BuLi (1 equiv.), THF, -78°C→r.t., and then
ZnBr , 11a, 95%; 11b, 87%; 11c, 95%; b) TIPS-C≡CH (1 equiv.), BuLi (1
2
Anisotropic displacement parameter shown at 50% probability level, anions
and hydrogen atoms omitted for clarity. Selected bond lengths [Å] and angles
[deg] in 11b, S1-C1, 1.769(3); S1-C7, 1.675(3); C1-S1-C7, 101.59(15); in
[
16]
2 6 6
equiv.), THF, -78°C→r.t., then ZnBr , and finally aq. NaSbF , 11d(SbF ), 65%,
6
11a(SbF ), S1-C1, 1.759(3); S1-C7, 1.693(4); C1-S1-C7, 101.17(17).
two steps.
We also suspected from the differentiated retention factor
on thin liquid chromatography that one of these products was a
6
Crystals suitable for X-ray analysis of 11b and 11d(SbF )
were grown by slow diffusion of diethylether into saturated
dichloromethane solution of the corresponding salts; their
connectivity was thus unambiguously established (Figure 1).
Similarly to imidazolium derivatives 4 and 5, both 11b and
salt. Extraction of the reaction mixture with CH
separation of both components and their complete
characterization. The material insoluble in CH Cl was found to
be pyridinium salt 13, the product of thiol attack at C1 of the
pyridinium ring following typical nucleophilic aromatic
substitution pathway. The component soluble in CH Cl was
2 2
Cl allowed the
2
2
1
1
6
1d(SbF ) adopt an angular geometry, with C1-S1-C7 angles of
a
01.2(2)° and 101.9(2)°, respectively; however, some
2
2
differences are also evident when comparing the unit cells of the
identified as dithioester 14, which we assume results from the
nucleophilic attack of the second equivalent of thiol 12 to the
thioketene liberated as byproduct at the initial nucleophilic
aromatic substitution (Scheme 4).
[
11]
imidazolium and the pyridinium derivatives.
While short
contacts are present in 4 and 5 between the anions and S1,
these weak interactions are not observed neither in 11b nor in
1
1d(SbF
the counteranions and the pyridinium rings in 11b and
1d(SbF (not shown in Figure 1; See the Supporting
6
). On the other hand, short contacts appear between
Me
N
S
(iPr)
3
Si
(
2 equiv.)
1
6
)
12
S
H
11d (SbF6
)
Information), which are not detectable in the imidazolium
analogues. These interactions are probably a manifestation of
the high electrophilicity at the pyridinium moiety and have, as it
will be described in the next sections, a decisive influence on the
reactivity of alkynylthiopyridinium salts.
DCM, rt
not observed
SbF6
12
MeO
13
(95%)
S
S
MeO
TIPS
Reactivity towards nucleophiles and mechanistic insights:
Once alkynylthioimidazolium salts 11 were completely
characterized, we set up to preliminary explore their reactivity
towards nucleophiles of different nature. For the initial studies
1
4
(94%)
Scheme 4. Reactivity of alkynylthiopyridinium salts towards thiols.
the reaction of 11d(SbF
methoxyphenyl) methanethiol 12 was monitored. Interestingly,
while the thiol substrate was found to be completely consumed
after only five minutes, half equivalent of 11d(SbF ) was still
present in the reaction mixture, together with similar amounts of
two unidentified products. Careful optimization of the reaction
conditions revealed that two equivalents of the thiol were
6
)
with one equivalent of 4-
(
The reaction just described seems to be general for both,
aliphatic and aromatic thiols, and can be used for preparative
purposes provided that the starting thiol is available in sufficient
quantities; note however, that two equivalents are to be
consumed to produce only one of the dithioester 14-21 (Scheme
6
[
17]
5).
The transformation has been be extended to primary and
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secondary amines and phenols to afford the corresponding
thiolactams and thioesters 22-26, respectively. Aminothiols can
be used as substrates as well; in that case both basic
functionalities react to afford product 27. 2-Naphtol is
Non-expected reactivities were found in particular cases as
well. For example, when the nucleophilicity of the thiol is
severely reduced by conjugation, as in the case of thiobenzoic
acid, or the thiol unit is embedded in a sterically very demanding
environment such as in tritylthiol, then the already described
nucleophilic aromatic substitution at the pyridine moiety gets
disfavored. These nucleophiles preferentially attack 11a-d at the
much more accessible and softer α-position of the alkyne moiety,
allowing the isolation of the products of electrophilic alkynylation
[
18 ]
transformed into the corresponding thioester 28 as well.
From the results compiled in Scheme 5 it can be concluded that
alkynylthiopyridinium salts efficiently behave as synthetic
equivalents of aldothioketenes, which are notoriously unstable
[
19]
members of the heterocumulene family.
2
9 and 30, which are formed after elimination of the thiopyridone
R-XH
2 equiv.)
11d (SbF
)
S
6
fragment (Scheme 6a-b). Very similar reactivity, although
applicable to a much larger scope of substrates, has been
recently
(
TIPS
DIPEA, DCM, rt
5 min. for thiols
R-X
X = S, N
3h. for amines
described
for
the
reaction
of
5-(alkynyl)
dibenzothiophenium triflates with S-, N-, and even C-based
nucleophiles.
S
S
S
[
20]
TIPS
TIPS
Me
NHBoc
S
O
S
MeO
TIPS
TIPS
a)
alkynyl transfer
TIPS
O
S
S
O
O
R is bulky or electron
withdrawing
MeO
TIPS
R-SH
14
15
S
16
S
(94%)
(51%)
(41%)
α
29
(98%)
β
S
S
S
S
Si(iPr)3
favored
pathway
S
1
TIPS
O
TIPS
Me
S
N
S
TIPS
MeO
S
SbF6
19
7
18
S
(62%)
(26%)
(98%)
11d (SbF6
)
OH
S
30
(84%)
S
TIPS
S
Et
TIPS
N
b)
TIPS
S
H
O N
2
20
21 (67%)
22 (85%)
(97%)
S
3
S
S
Et
TIPS
TIPS
TIPS
N
N
N
Et
2
O
H
25
(54%)
(
78%)
24
(91%)
c)
O
TIPS
tBu
S
TIPS
S
OtBu
O
O O
N
TIPS
Et
S
NH
Et
O
O
H
31
S
+
O
S
11b
N
TIPS
N
DIPEA, DCM, rt
H
O
S
[ZnBr4]2-
Ph
½
26
27
(41%)
28 (59%)
(81%)
32
(74%)
d)
S
S
S
S
TBAF
11b
DCM, rt
3
4
33
(68%)
not observed
6
Scheme 6. Reactivity of 11d(SbF ) and 11b towards selected nucleophiles.
Molecular structure of compound 30. Anisotropic displacement parameters
shown at 50% probability level and hydrogen atoms omitted for clarity.
Selected bond lengths [Å] and angles [deg]: S1-C1, 1.8949(8); S1-C2,
Scheme 5. Reactivity of 11d(SbF
scope. Molecular structures of compounds 16 and 17. Anisotropic
displacement parameters shown at 50% probability level and hydrogen atoms
omitted for clarity. Selected bond lengths [Å] and angles [deg] for 16: S2-C2,
6
) with thiols, amines and phenols: Substrate
[
16]
1.6804(9); C2-C3, 1.2130(13); Si1-C3, 1.8398(10); C1-S1-C2, 103.35(4).
1.644(3); C2-S1, 1.7434(19); S1-C3, 1.799(2); C1-C2-S1, 125.06(13); C1-C2-
S2, 111.32(14), C2-S2-C3, 103.21(10); for 17: S1-C2, 1.644(3); C2-S2,
1
.758(3); S2-C3, 1.820(3); C1-C2-S1, 123.9(3); C1-C2-S2, 111.2(2), C2-S2-
[16]
Also interesting is the isolation of compound 32 after
C3, 104.17(16).
reaction of cyclic ketoester 31 with 11b under basic conditions.
In this case the sterically quite demanding enolate attacks again
at the α-position of the alkyne moiety, but instead of eliminating
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Chemistry - A European Journal
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FULL PAPER
the thiopyridone moiety, the intermediate has been trapped by
protonation (Scheme 6c). The formation of 32 still puzzle us
since for the analogue 5-(alkynyl)dibenzothiophenium salts of
similar substitution pattern, the attack takes place at the β-
up to room temperature by removing the cooling bath. Finally, an
aqueous solution of NaSbF (3 equiv., 36.2 g, 139.8 mmol) was added
6
under vigorous stirring, and successively, the two phases were
transferred to a separatory funnel. After drying the organic phase with
Na
beige solid (16.3 g, 30.0 mmol, 65%). H NMR: (300 MHz, CD
.64 – 8.56 (m, 1H), 8.44 (td, J = 8.0, 7.6, 1.5 Hz, 1H), 8.31 (dd, J = 8.5,
1.4 Hz, 1H), 7.78 (ddd, J = 7.6, 6.2, 1.5 Hz, 1H), 4.09 (s, 3H), 1.32 – 1.07
2
SO
4
the solvents were removed in vacuo affording 11d(SbF
6
) as a
[
21 ]
position.
Finally, we also decided to collect additional
1
3
CN) δ =
evidence for the proposed mechanistic picture trying to
demonstrate the formation of thioketenes under the reaction
conditions. Aldothioketenes are known to dimerize either to 2,4-
dimethylene-1,3-dithietanes 34 or to the corresponding 1,3-
8
1
3
(m, 21H) ppm. C NMR: (75 MHz, CD
3
CN) δ = 148.4, 146.0, 127.0,
-1
125.5, 113.6, 82.7, 46.9, 18.8, 11.9 ppm. IR: (ATR, cm ) 3516, 3140,
[
22, 23]
2
943, 2867, 2104, 1617, 1571, 1489, 1456, 1282, 1168, 1110, 993, 878,
dithiafulvenes 33 in the absence of a trapping nucleophile.
Thus, we treated 11b with (Bu) NF; the fluoride anion should be
+
851, 767, 656, 625, 595. HRMS(ESI) calcd. for [C17H28NSSi] : 306.1706 ;
4
found: 306.1707.
strong enough to promote the nucleophilic substitution at the
pyridinium ring, but unable to react with the nascent thioketene.
From this reaction dithiafulvene 33 was isolated in good yield as
a mixture of the cis- and trans-isomers, additionally supporting
Synthesis of 15: (4-methoxyphenyl)methanethiol (2 equiv, 83.6 µL, 0.6
mmol) and DIPEA (2 equiv, 104.5 µL, 0.6 mmol) were added to a
dichloromethane solution (4 mL) of 11d(SbF ) (1 equiv, 162.7 mg, 0.3
6
mmol). After completion of the reaction, the solvent was removed in
[
24]
the mechanistic picture proposed (Scheme 6).
vacuo and the products separated by column chromatography
1
(
Hexanes/Ethyl Acetate, 20:1). H NMR (300 MHz, CDCl
3
) δ = 7.25 –
7
.20 (m, 2H), 6.87 – 6.80 (m, 2H), 4.39 (s, 2H), 3.79 (s, 3H), 3.16 (s, 2H),
Conclusions
13
1
.32 – 1.17 (m, 3H), 1.16 – 1.05 (m, 18H) ppm. C NMR (126 MHz,
) δ = 236.1, 159.2, 130.5, 127.5, 114.2, 55.4, 42.5, 41.8, 18.7, 11.6
CDCl
ppm. IR (ATR, cm ): 2940, 2864, 1610, 1510, 1462, 1301, 1248, 1174,
3
We describe here for the first time a synthetic method for the
preparation of dihalo(pyridinium) sulfuranes starting from
inexpensive thiopyridones. Subsequently, alkynylthiopyrydinium
salts were also prepared by reaction of the corresponding
sulfuranes with organozinc species, and their reactivity was
-1
+
1102, 1036, 911, 880, 830, 658, 510. HRMS calcd. for [C19
2
H34OS Si] :
369.1737; found = 369.1736.
evaluated towards
a
series of thiols and amines.
Acknowledgments
Alkynylthiopyrydinium salts only transfer the alkynyl group to
sterically hindered nucleophiles; otherwise, they preferentially
react via aromatic substitution at the pyridinium ring with
concomitant elimination a thioketene, which can further trap a
second equivalent of the nucleophile. This makes
alkynylthiopyridinium salts synthetic equivalents of thioketenes
and useful precursors for the preparation of dithioesters or
thiolactams.
Support from the DFG (AL 1348/7-1 and INST 186/1237-1) is
gratefully acknowledged. We also thank Dr. R. Goddard from the
Max Planck Institute für Kohlenforschung (Muelheim an der
Ruhr) and Dr. Hendrik Tinnermann (University of Göttingen) for
their assistance in the resolution of structures 10c, 11a and 11b
and Dr. Michael John (University of Göttingen) for support with
NMR analyses.
Keywords: sulfuranes • pyridinium salts • thioketenes •dithioesters •
thioamides.
Experimental Section
Synthesis and characterization of representative products
[
1]
V. V. Zhdankin in Hypervalent Iodine Chemistry, John Wiley & Sons,
014.
Synthesis of 10a: Bromine (1 equiv, 365 µL, 7.1 mmol) was added
slowly to a solution of 9a (893 mg, 7.1 mmol) in dry CH Cl (20 mL) at 0
2 2
ºC, and the reaction mixture was stirred for 2 hours. After removal of all
2
[
2]
3]
J. Charpentier, N. Früh, A. Togni, Chem. Rev. 2015, 115, 650-682.
D. P. Hari, P. Caramenti, J. Waser, Acc. Chem. Res. 2018, 51, 3212-
[
volatiles in vacuo, 10a was obtained as a bright orange solid (2 g, 7.1
3225.
1
mmol, 99%). H NMR (500 MHz, C
2 2
D Cl
4
) δ= 8.39 (d, J = 7.9 Hz, 1H),
[4]
[5]
[6]
[7]
[8]
P. Caramenti, S. Nicolai, J. Waser, Chem. Eur. J. 2017, 23,
14702−14706.
8
1
1
2
.28 (d, J = 6.2 Hz, 1H), 8.17 (t, J = 7.8 Hz, 1H), 7.69 (ddd, J = 7.7, 6.2,
13
2 2 4
.6 Hz, 1H), 4.44 (s, 3H). C NMR (126 MHz, C D Cl ) δ = 163.5, 145.5,
J. A. Souto, C. Martínez, I. Velilla, K. Muñiz, Angew. Chem. Int. Ed.
+
44.6, 137.5, 125.8, 48.9 ppm. HRMS (ESI) calcd. for [C
6 7
H BrNS] :
2
013, 52, 1324-1328.
G. C. Geary, E. G. Hope, K. Singh, A. M. Stuart, Chem. Commun. 2013,
9, 9263-9265.
R. Frei, T. Courant, M. D. Wodrich, J. Waser, Chem. Eur. J. 2015, 21,
662 2668.
a) V. V. Zhdankin, Curr. Org. Synth. 2005, 2, 121
Wang, H. Geng, Y. Xie, Y.-D. Wu, X. Zhang, H. F. Schaefer III, Chem.
Commun. 2016, 52, 5371 5374.
03.9477; found: 203.9475.
4
Synthesis of 11d(SbF
was slowly added to a solution of tri(isopropyl)silylacetylene (1.1 equiv,
1.5 mL, 51.3 mmol) in THF (10 mL) at -78 ºC and the reaction mixture
thus obtained was allowed to warm up to room temperature over 2 hours.
After this, the flask was again cooled down to -78°C, and then ZnBr (1.1
6
): n-BuLi (1.1 equiv, 2.5 M, 20.5 mL, 51.3 mmol)
2
-
1
−145; b) T.-Y. Sun, X.
2
−
equiv., 11.5 g, 51.3 mmol) in THF (1 M) was added and stirred for an
additional hour. The solution thus obtained was then added drop wise to
a solution of 10a (1.0 equiv., 13.3 g, 46.6 mmol) in THF at -78 °C and 30
minutes after the addition was finished, the suspension was let to warm
[9]
For the synthesis of dihalo(imidazolium)sulfuranes see: A. J. Arduengo,
E. M. Burgess, J. Am. Chem. Soc. 1977, 99, 2376-2378.
[10] G. Talavera, J. Peña, M. Alcarazo, J. Am. Chem. Soc. 2015, 137, 8704-
707.
8
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Chemistry - A European Journal
10.1002/chem.201901895
FULL PAPER
[
11] J. Peña, G. Talavera, B. Waldecker, M. Alcarazo, Chem. Eur. J. 2017,
3, 75-78.
Brandsma, Recl. des Trav. Chim. des Pays-Bas 1973, 92, 601-604;
f) H. Westmijze, H. Kleijn, J. Meijer, P. Vermeer, Synthesis 1979,
432-434; g) R. Hoffmann, K. Hartke, Chem. Ber. 1980, 113, 919-933; h)
A. C. Worth, C. E. Needham, D. B. Franklin, A. J. Lampkins, Synth.
Commun. 2012, 42, 2694-2706.
2
[12] The effect of pyridinium substituents on phosphines is reported in: a) H.
Tinnermann, C. Wille, M. Alcarazo, Angew. Chem. Int. Ed. 2014, 53,
8732-8736; b) H. Tinnermann, L. D. M. Nicholls, T. Johannsen, C. Wille,
C. Golz, R. Goddard, M. Alcarazo, ACS Catal. 2018, 8, 10457-10463;
c) L. D. M. Nicholls, M. Alcarazo, Chem. Lett. 2019, 48, 1-13.
13] E. Schaumann, Comp. Org. Chem., 1991, 6, 419-434.
14] H. W. Roesky, U. N. Hehete, S. Singh, H. G. Schmidt, Y. G.
Shermolovich, Main Group Chemistry, 2005, 4, 11-21.
[18] For the synthesis of thioamides see: a) K. A. Petrov, L. N. Andreev,
Russ. Chem. Rev. 1969, 38, 21-36; b) E. V. Brown, Synthesis, 1975,
358-375; c) A. B. Charette, M. Grenon, J. Org. Chem. 2003, 68, 5792-
5794.
[
[
[19] C. Spanka, E. Schaumann, Synlett, 2014, 25, 2415-2428.
[20] B. Waldecker, F. Kraft, C. Golz, M. Alcarazo, Angew. Chem. Int. Ed.
2018, 57, 12538-12542.
[
[
[
2
15] Lewis adducts formed by reaction of thiolactames and I are known,
see: M. Tretiakov, Y. G. Shermolovich, A. P. Singh, P. P. Samuel, H. W.
Roesky, B. Niepötter, A. Visscheraand, D. Stalke, Dalton Trans 2013,
[21] No switching of the selectivity towards alkynylation was observed with
compound 11c.
42, 12940-12946.
16] CCDC 1905834- 1905839, 1907719, 1907720 and 1907737 contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by The Cambridge Crystallographic Data
Centre.
[22] E. Schaumann, Tetrahedron, 1988, 44, 1827-1871.
[23] B. F. Bonini, M. C. Franchini, M. Fochi, S. Mangini, G. Mazzanti, A.
Ricci, Eur. J. Org. Chem. 2000, 2391-2399.
[24] An alternative mechanism may be simultaneously operative. The
incoming thiol may attack the α-position of the alkyne affording an
alkene such as 32. Attack of a second equivalent of thiol on the
pyridinium ring following a nucleophilic aromatic substitution should
liberate the corresponding dithioester. This mechanism however, does
not explain the formation of dimer 33 as byproduct.
17] For the synthesis of dithioesters see: a) J. Houben. Berichte der Dtsch.
Chem. Gesellschaft 1906, 39, 3219-3233; b) J. Houben; K. M. L.
Schultze, Berichte der Dtsch. Chem. Gesellschaft 1910, 43, 2481-
2
485; c) E. J. Hedgley, H. G. Fletcher, J. Org. Chem. 1965, 30, 1282-
283; d) P. J. W. Schuijl, L. Brandsma, J. F. Arens, Recl. des Trav.
1
Chim. des Pays-Bas 1966, 85, 889-894; e) J. Meijer, P. Vermeer, L.
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Chemistry - A European Journal
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FULL PAPER
FULL PAPER
Synthesis of Alkynylthiopyridinium
Salts and Their Use as Thioketene
Equivalents
S
R is bulky or electron
withdrawing
R-XH
TIPS
or
S
α
β
R
K. F. G. Averesch, H. Pesch, C. Golz, M.
Alcarazo*
S
Si(iPr)3
favored
pathway
S
Et
N
R'/H
TIPS
N
Page No. – Page No.
SbF6
X = S, N
R
1
6 examples
New reactivity was found when changing the imidazolium group in alkynylthioimidazolium salts by pyridinium ones. While the
formers react with Grignards to afford the corresponding thioethers, pyridinium-based salts behave as thioketene equivalents
and produce dithioesters and thioamides by reaction with thiols or amines respectively.
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