Transition metal-free, chemoselective arylation of thioamides yielding aryl thioimidates or N-aryl thioamides

Article abstract of DOI:10.1039/c8cc04795b

Reactions of secondary thioamides with diaryliodonium salts under basic, transition metal-free conditions resulted in chemoselective S-arylation to provide aryl thioimidates in good to excellent yields. Equimolar amounts of thioamide, base and diaryliodonium salt were sufficient to obtain a diverse selection of products within short reaction times. Reactions with thiolactams delivered N-arylated thioamides in good yield at room temperature.

Full text of DOI:10.1039/c8cc04795b

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DOI: 10.1039/C8CC04795B
Chemical Communications
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Transition Metal-Free, Chemoselective Arylation of Thioamides
Yielding Aryl Thioimidates or N-Aryl Thioamides
Piret Villo, a,b Gabriella Kervefors, a and Berit Olofsson *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reactions of secondary thioamides with diaryliodonium salts only report obtaining acyclic aryl thioimidates by direct S-
under basic, transition metal-free conditions resulted in arylation of thioamides.
Diaryliodonium salts (diaryl-
3-iodanes) are easily prepared
chemoselective S-arylation to provide aryl thioimidates in good to
excellent yields. Equimolar amounts of thioamide, base and
diaryliodonium salt were sufficient to obtain a diverse selection of
products within short reaction times. Reactions with thiolactams
delivered N-arylated thioamides in good yield at room
temperature.
λ
hypervalent iodine reagents with low toxicity.12 They have
frequently been employed to arylate heteroatom- or carbon
nucleophiles,12-13 including the S-arylation of thioureas or
closely related scaffolds under both metal-free,14 and copper-
catalyzed conditions.15 While thioamides have never been
arylated with diaryliodonium salts, iodine(III) reagents have
been used to transfer alkenyl, alkynyl, trifluoromethyl, and
nitrile functionalities to thioamides or similar compounds.16
Additionally, thioamides can be converted into benzothiazoles
via oxidative arylation with bis(trifluoroacetoxyiodo)benzene.17
In our research line on hypervalent iodine chemistry, we have
Thioamides and their aryl thioimidate derivatives are
important units in bioactive molecules, and in intermediates
towards such compounds.1 The thioimidate moiety can also be
found in heterocycles such as thiazoles and benzothiazoles,2
and in early stage solar absorbers.3 The aryl thioimidate
scaffold has also been shown to regioselectively react with
reported efficient, metal-free arylations of
a range of
alkynes
to
give
aryl
thio
azadienes.4
heteroatom and carbon nucleophiles.18 Mechanistic aspects
have been explored to expand the utility of these reagents in
organic synthesis, also with focus on chemoselectivity using
unsymmetric diaryliodonium salts.19 Reactions of nucleophiles
with two possible arylation sites, e.g. enolates, amides, nitrite,
oximes and quinolones, have proven highly selective towards
C- and N-arylation, respectively.18b, 18c, 19a, 20 Continuing on this
track, we explored the arylation of thioamides, and herein
describe the highly selective S-arylation of secondary
thioamides with diaryliodonium salts under basic, transition
metal-free conditions (Scheme 1).
While alkylation of thioamides to access alkyl thioimidates is
straightforward, the corresponding methodology to reach aryl
thioimidates is much less developed.5 Conventional routes to
access aryl thioimidates include reacting imidoyl chlorides,
ketenimines or nitriles with thiophenols that already have an
6
established S-aryl bond (Pinner synthesis).5c,
A one-pot
reaction between aryl thiol, hexamethyldisilazane and
nitromethane gives related methaneimidothioate scaffolds.7
Formation of an aryl-sulfur bond in the synthesis of
benzothiazoles can be achieved either via palladium-catalyzed
S-arylation of thioacetamide with o-iodoanilines, followed by a
cyclization;8 metal-free condensation of thioamides with 2-
aminothiophenols,9 or an intramolecular cyclization of o-
iodothiobenzanilide.10 Radical arylation of thioamides gave
high yields of S-arylated products but could not be applied to
thiolactams.11 To the best of our knowledge, the latter is the
Scheme 1 Arylation of thioamides with diaryliodonium salts.
Initial screenings revealed that the reaction of thioamide 1a
a.Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Sweden.
with diphenyliodonium triflate
thioimidate 3a in 30-40% yield with a selection of organic and
inorganic bases in toluene at room temperature
and side-products from either hydrolysis22 of 3a into the
(
2a
)
delivered phenyl
b.Institute of Technology, University of Tartu, 50 411 Tartu, Estonia.
Electronic Supplementary Information (ESI) available: Experimental details,
21
.
Recovered 1a
analytical
data
and
NMR
spectra
of
novel
compounds.
See
DOI: 10.1039/x0xx00000x
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corresponding amide and thiol, or desulfurization,17,
Journal Name
23
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DOI: 10.1039/C8CC04795B
constituted the remaining mass. Remarkably, no N-arylated
thioamide product was observed. Product 3a was isolated as
an inseparable Z:E isomeric mixture in 93:7 ratio, based on
24
NMR analysis and literature data on similar compounds.7,
This is in accordance with alkylations of thioamides, which
have been reported to proceed with S-functionalization.25
Based on these initial promising results, an extensive
optimization was performed.21 A solvent screening with LiOtBu
as base revealed that EtOAc, iPrOAc and CH2Cl2 gave
comparable yields to reactions in toluene. The reaction
temperature had a great impact on the reaction outcome, and
reactions at 80 °C allowed the reaction time to be decreased
from overnight to one hour (Table 1, entries 1-4). While
running the reaction under argon atmosphere only influenced
the outcome marginally (entry 5), degassing the solvent
enhanced the yield considerably (entry 6). A counterion effect
for the iodonium salt was also observed, where
diphenyliodonium salts with OTf, OTs and Br outperformed
iodonium salts with BF4, TFA and PF6.21
Table 1 Selected optimization data.
Entry
Solvent quality
Temp
(°C)
Time
(h)
Yield
(%)a
1
2
3
4
5
6
anhydrous
anhydrous
anhydrous
anhydrous
rt
16
16
16
1
1
1
42
61
71
75
79
91
40
80
80
80
80
anhydrous under Ar
degassed, anhydrous under Ar
a Isolated yields, major isomer of 3a shown.
With the optimized conditions in hand, we looked into the
scope of diaryliodonium salts with thioamide 1a (Scheme 2A).
Symmetric and unsymmetric diaryliodonium salts were
synthesized using efficient one-pot methodology,26 with
phenyl, anisyl and trimethoxyphenyl (TMP) as “dummy”
groups. The use of unsymmetric iodonium salts is often more
atom efficient and cost effective, e.g. when highly
functionalized or precious aryl groups are transferred.21 High
chemoselectivity is crucial for this approach, i.e. selective
transfer of only one of the aryl groups,19b, 19d and the arylation
results with unsymmetric diaryliodonium salts proved superior
to the corresponding symmetric salts in several S-arylations
Scheme 2 Arylation scope with major isomer (Z) shown. Z:E ratios 91:9
to 96:4, except 3d (89:11), 3f (88:12), 3h (86:14), 3i (90:10), 3o (86:14),
a
and 3q (87:13). Only one isomer obtained of 3v-4b
.
In non-degassed
toluene. b NMR yield. c Combined yield. d At rt for 16 h, 1.5 equiv base.
shown
below.21
Further so, aryls with p-OCF3 (3d) and p-CF3 (3e) were
Electron deficient diaryliodonium salts generally behave well in
heteroatom arylations, and the synthesis of p-CN product 3b
indeed proceeded in excellent yield. Likewise, the p-NO2
product 3c was easily obtained, and surprisingly performed
better in a non-degassed solvent.27
delivered in good yields as well. Electron-withdrawing
substituents in the meta- and ortho-positions were also
tolerated, providing m-CF3 substituted 3f, with slightly lower
Z:E ratio than previously observed; and o-F and o-COOMe
decorated 3g-3h. Importantly, the introduction of aryl groups
with a straightforward handle for further derivatization proved
feasible, as exemplified by a p-N3 aryl moiety in 3i and halide-
2 | J. Name., 2012, 00, 1-3
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substituted products 3j
COMMUNICATION
,
3k, for which unsymmetric iodonium
View Article Online
DOI: 10.1039/C8CC04795B
salts proved more efficient than the corresponding symmetric
salts.21
Arylations with electron donating diaryliodonium salts can be
demanding, as competing reaction pathways tend to give
product mixtures.19c Pleasingly, this S-arylation proved
compatible with such iodonium salts, and alkyl-substituted
products 3l-3o were obtained in good yields, including the
Scheme 3 Competition experiments.
sterically congested 3n-3o. Furthermore, an anisyl group could
easily be transferred (3p), and the synthesis of pyridyl product
3q was viable. Complete chemoselectivity was generally
observed in the arylations, with minor amounts of dummy
Preliminary mechanistic investigations revealed that addition
of aryne or radical scavengers (piperidine and 1,1-
diphenylethylene, respectively) had negligible effect on the
reaction outcome.21 Hence both an aryne pathway and a
radical mechanism can be excluded. Based on previous
group transfer only in the synthesis of 3j 21
The reaction was
.
demonstrated to have a considerable ortho-effect,28 with high
yields and complete chemoselectivity in the synthesis of 3k
and
experimental and mechanistic studies of enolates, amides and
3o 21
.
18c, 19a
nitrite,18b,
we propose that the reaction proceeds by
The scope of thioamide scaffolds was explored next (Scheme
2B). Both electron donating and withdrawing groups on the
benzothioamide were well tolerated, delivering 3r and 3s in
good yields. Contrary to the aryl thioamides, the arylation of
alkylated thioamides resulted in S-arylated products 3t, 3u in
deprotonation and ligand exchange to provide T-shaped
intermediate
intermediate
A
A
and/or
B
(Scheme 4). Ligand coupling in I-N
would
to form the S-arylated thioimidate
3
proceed via a [2,3] rearrangement, whereas I-S intermediate
would undergo a [1,2] rearrangement to yield . Alternatively,
intermediates and could yield N-aryl thioamide through
[1,2] and [2,3] rearrangement, respectively.
B
3
moderate yield, along with a minor amount of N-arylation. The
A
B
4
N-benzyl group could be replaced by a hexyl group to deliver
3w. More importantly, an easily removable Boc group was also
tolerated, delivering S-arylated products 3w and 3x in high
yields. Interestingly, reactions with this substrate in the
presence of the weaker base potassium carbonate only gave
recovered starting material, despite the more acidic NH
proton.21 Furthermore, the heteroaromatic substrate pyridine-
2-thiol proved suitable for this transformation, providing 3y in
78%
yield.
Cyclic thioamides, on the other hand, acted differently under
Scheme 4 Proposed mechanism for S- and N-arylation.
the optimized conditions. Pyrrolidine-2-thione gave a mixture
The S-arylation selectivity observed for all acyclic thioamides,
as well as the aromatic thioamide, can be rationalized by
efficient conjugation of the nitrogen lone pair in the thioamide
moiety, making the sulfur lone pairs most nucleophilic. The
observed N-selectivity in arylation of thiolactams could be
caused by less efficient conjugation due to cyclic constraints,
making nitrogen a better nucleophile. While early literature
proposed a rearrangement from S-arylated to N-arylated
products,31 we observed constant N/S-arylation ratios
throughout the reactions, making this mechanism unlikely.21
To conclude, we have developed a transition metal-free
arylation of thioamides with diaryliodonium salts under basic
conditions. Complete selectivity in favor of S-arylated products
was observed with acyclic and aromatic thioamides, whereas
thiolactams preferably were N-arylated. A wide scope of
functional groups are tolerated in both thioamides and
diaryliodonium salts. Furthermore, sterically congested aryl
groups were transferred in high yield, and a considerable
ortho-effect was observed. Efficient use of unsymmetric
diaryliodonium salts have been demonstrated, with excellent
chemoselectivity and improved yields compared to the
corresponding symmetric reagents.
of N- and S-arylated products
(4a,
N:S ratio 1.5:1).21
Interestingly, the synthesis of 4b proceeded in excellent yield
and complete N-selectivity at room temperature. This product
class could give access to N-arylated amides after a one-step
desulfurization.23b,
Competition experiments were performed to evaluate the S-
arylation in the presence of O- and N-nucleophiles that have
29
been reported to undergo arylation with diaryliodonium salts
under metal-free conditions.18c,
30
Hence, reactions of
thioamide 1a and Ph2IOTf were performed in the presence of
amide or , benzoic acid ( ), or alcohol 8, and 2 equiv of
5
6
7
base, to allow deprotonation of both nucleophiles (Scheme 3).
The reactions proved to be completely chemoselective, with
arylation of only thioamide 1a in all of the cases. S-Arylated
thioimidate 3a was isolated in yields of 40-80%, with complete
recovery of the competing nucleophile in all reactions.
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15. H. Zhu, X. Liu, Y. Cheng, H.-Y. Peng, Y.-S. Li and Z.-B. Dong,
The Estonian Research Council (MOBTP59, PUTJD114) and
the Swedish Research Council (2015-04404) are kindly
acknowledged for financial support.
Conflicts of interest
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Synthesis, 2018, 50, 2247-2254.
DOI: 10.1039/C8CC04795B
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There are no conflicts to declare.
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