An improved transition-metal-free synthesis of aryl alkynyl sulfides via substitution of a halide at an sp-centre

Article abstract of DOI:10.1039/c5ob00494b

A simple high-yielding preparation of aryl alkynyl sulfides is presented. The reaction of a chloroacetylene with a thiolate salt in the presence of an amine mediator (dimethylamine or N,N′-dimethylethylenediamine) yields the alkynyl sulfides in excellent yields. The alkynyl chloride is easily prepared from the parent alkyne.

Full text of DOI:10.1039/c5ob00494b

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB00494B
Communication
Cite this: DOI: 10.1039/x0xx00000x
An Improved Transition-Metal-Free Synthesis of Aryl
Alkynyl Sulfides via Substitution of a Halide at an sp-
Centre.
Received 00th January 2012,
Accepted 00th January 2012
Roomi Mohima Chowdhury† and Jonathan D. Wilden†*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple high-yielding preparation of aryl alkynyl sulfides
is presented. The reaction of a chloroacetylene with a
thiolate salt in the presence of an amine mediator
(dimethylamine or N,N’-dimethylethylenediamine) yields
the alkynyl sulfides in good yields. The alkynyl chloride is
easily prepared from the parent alkyne contrasting
sharply with the cumbersome synthesis of an alkynyl
sulfonamide previously required.
Nu
OR2
R1
Nu
Nu
Nu
R1
R1
OR2
SR2
SR2
R1
Scheme 1: Behaviour of acetylinic ethers and thioethers with
nucleophiles.
Introduction
Our previous work had established a synthesis of ynol ethers
and thioynol ethers based on the displacement of a sulfonamide
leaving group at the sp-centre of an aryl acetylene.4 Although
this reaction works well, both in terms of reaction scope, rate
and yield, the preparation of the alkynyl sulfonamide is non
trivial and requires the preparation of the intermediate alkynyl
sulfinamide followed by oxidation to the sulfonamide using
NaIO4 with RuCl3 as a catalyst.5 Furthermore, the sulfonamide
moiety as a leaving group represents poor atom economy and
conflicts with our aspirations to undertake sustainable
transformations (Scheme 2).
Acetylinic sulfides (‘thioynol ethers’) are valuable synthetic
intermediates with applications in a variety of processes.1 Their
balance between stability and reactivity; being stable enough to
purify and handle yet sufficiently reactive to undergo a wide
variety of synthetic manipulations makes them (and their
oxygen counterparts, ynol ethers) particularly versatile
intermediates.2 The high electron density and polarity in the
bond due to the resonance structures are outlined in figure 1:
R1
δ+
R1
XR2
R1
XR2
XR2
O
δ−
SO2NEt2
S
(i)
(ii)
NEt2
Ar
Ar
Ar
(iii)
Figure 1. Polarity exhibited by acetylinic ethers and thioethers.
Ar
XR
In particular, the high reactivity of the alkyne unit in
cycloaddition processes is particularly valuable since complex
molecules can be constructed in relatively few synthetic
operations. Their reactions with electrophiles are similar to
those of the related ynol ethers however the reactions of
nucleophiles with these two classes of compounds are quite
different. Ynol ethers tend to be attacked by nucleophiles at the
Scheme 2
:
Reagents and conditions: (i)
n
BuLi then ClSONEt2.
(ii) NaIO4, RuCl3. (iii) KXR, THF, 0oC, Me2NH.
Results and Discussion
α
-carbon atom (bearing the oxygen substituent) whereas
We recognized that a halide would be a more atom efficient
precursor and easier to prepare than the alkynyl sulfonamides since
these can be prepared in a single step from the parent alkyne. As
such we prepared chloro-, bromo- and iodophenylacetylene by
known literature procedures (Scheme 3).6
thioynol ethers are usually attacked at the
β
-carbon atom.3 This
property represents a potentially valuable ‘Umpolung’ strategy
which has not yet been fully exploited.
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Ar = Ph
Cl, 80%
X = Br, 84%
I, 68%
The fact that alkynyl chlorides can be employed is significant
since other methods of functionalizing acetylenes, particularly
Ar
Ar
X
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those that use transition metals, often rely on oxidative insertion
DOI: 10.1039/C5OB00494B
into the weak C-X bond and almost invariably this renders
alkynyl chlorides unsuitable. For example earlier preparations of
thioynol ethers from thiols and alkynyl iodides and bromides
employs copper or palladium catalysis.10 The method outlined
here therefore represents an alternative and potentially orthogonal
method of preparing heteroatom substituted alkynes.
Scheme 3: Reagents and conditions: X = Cl: nBuLi then NCS. X =
Br: NBS, AgNO3, Me2CO. X = I: nBuLi then I2.
Exposure of each of these acetylinic halides to the potassium
salt of
t-butyl thiol under the conditions outlined in Scheme 2
gave the results shown in Scheme 4.
We then turned our attention to investigating the reaction scope.
Initially we prepared a range of alkynyl chlorides from
commercially available acetylenes by the method outlined in
scheme 3 (1a-g, Figure 2). In general this preparation is
(i)
Ph
Ph
X
Ph
StBu
+
StBu
77%
uneventful however,
p-bromophenylchloroacetylene, 1e, suffered
X = I
0%
a lower yield than the other examples, probably due to undesired
66%
0%
0%
77%
X = Br
X = Cl
metal-halogen exchange reactions when exposed to
nBuLi.
Cl
Cl
Cl
Cl
Scheme 4
:
Reagents and conditions: (i) KS
t
Bu, THF, RT,
1a
74 %
1b
54 %
1c
1d
58 %
DMEDA.
47 %
MeO
OMe
Pleasingly the chloroacetylenes yielded the thioynol ether in good
yield whereas both bromo and iodoacetylenes led to the thioenol
ethers as shown in scheme 4. It appears that the weaker C-I and C-Br
bonds allow a (well-documented) facile competing X-philic reaction
resulting in oxidation of the thiolate nucleophile.7 Protonation by
trace amounts of moisture then lead to the parent alkyne that can
then undergo addition reactions as we and others have previously
described (Scheme 5)8. The stronger C-Cl bond is apparently able to
resist the competing X-philic pathway with the soft thiolate
nucleophile and leads almost exclusively to the thioynol ether
product in good yield.
OMe
Cl
Cl
Cl
MeO
1e
1f
1g
Cl
F3C
1h
63 %
Br
22 %
72 %
44 %
Cl
Cl
Cl
Cl
Cl
1i
1l
1j
1k
Me2N
N
56 %
56%
51 %
68 %
Figure 2: Range of chloroacetylenes 1a-l prepared.
StBu
I
StBu
Ar
Ar
I
Exposure of these acetylinic chlorides to the potassium salt of t-butyl
thiol under the conditions shown in Figure 3 yielded the small
library of acetylinic sulfides in excellent yields.
H2O
(trace)
RSH
Ar
Ar
H
SR
Scheme 5: X-philic reaction of thiolates with iodoacetylenes.
We also noted that if the reaction was performed in the presence
of a small quantities of water (2-5%) then the formation of the
thioynol ether was greatly suppressed and the thioenol ether was
isolated instead, predominantly as the (Z)-geometrical isomer,
suggesting the involvement of a radical anion intermediate
(Scheme 6).9 When water was replaced by D2O, deuterium
incorporation was observed in both vinylic positions.
Presumably, when water is present, the hydroxide generated in
the reaction medium undergoes the X-philic reaction with the
acetylinic chloride to yield the parent alkyne (phenylacetylene)
which can then undergo addition of thiol as outlined in schemes 4
and 5.
KOH
Ph
Cl
Ph
H / D
KSR
H / D
THF, 5% H2O
or D2O
H / D
H / D
H2O or D2O
Ph
Ph
SR
RS
Scheme 6: Mechanistic pathway adopted when water is present.
2 | J. Name., 2012, 00, 1-3
Figure 3
Me2NH, 4h.
: Reagents and conditions: (i) KStBu, THF, -40 - RT,
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experimental detail, characterization data including 1H and 13C NMR
If the amine additive is removed from the reaction mixture the spectra are provided. See DOI: 10.1039/c000000x/
reaction still proceeds, however reaction times are significantly
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DOI: 10.1039/C5OB00494B
extended. The precise role of this additive and how it exerts its
beneficial effect on the reaction is somewhat ambiguous. Although
we and others have speculated as to possible mechanistic roles for
these additives, a decisive conclusion cannot yet be drawn.9 It
appears however that the additive may assist the initial electron
1
See for example (a) Hayashi, Y.; Narasaka, K. Chem. Lett.
1990, 1295-1298. (b) McConachie, L. K.; Schwan, A. L.
Tetrahedron Lett. 2000, 41, 5637-5641.
See for example (a) Hilt, G.; Luers, S.; Harms, K. J. Org.
Chem. 2004, 69, 624-630. (b) Spanka, C.; Schaumann, E.
Synlett, 2014, 25, 2415-2428.
2
12
transfer from the sulfur nucleophile to the alkyne.11,
3
4
5
6
7
Radchenko, A. I.; Petrov, A. A. Russ. Chem. Rev. 1989, 948-
966.
Gray, V. J.; Slater, B.; Wilden, J. D. Chem. Eur. J. 2012, 18,
15582-15585.
Gray, V. J.; Cuthbertson, J.; Wilden, J. D. J. Org. Chem. 2014,
79, 5869-5874.
Sud, D.; Wigglesworth, T. J.; Branda, N. R. Angew. Chem. Int.
Ed. 2007, 8017-8019.
Mechanistically therefore, we postulate that the reaction proceeds
through a similar pathway as for the displacement of the sulfonamide
group to which we have dedicated considerable effort.5 This work
has suggested that an addition-elimination mechanism is in operation
but that radical and radical anion intermediates are involved
(Scheme 7).
Zefirov, N. S.; Makhon’kov, D. I. Chem. Rev. 1982, 82, 615-
624.
Ph
Cl
Ph
SR
8
(a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999
,
40
,
,
KSR
6193-6195. (b) Bellucci, G.; Chiappe, C.; Lo Moro, G.; Synlett
1996, 880-882.
anhydrous
Cl
Cl
SR
Ph
Ph
RS
9
For a more detailed mechanistic study, see: Cuthbertson, J.;
Wilden, J. D. Tetrahedron, 2015, DOI: 10.1016/j.tet.2015.04.038
10 (a) Brachet, E.; Brion, J-D.; Alami, M.; Messaoudi, S. Adv.
Synth. Catal. 2013, 355, 2627-2636. (b) Braga, A. L.;
Reckziegel, A.; Menezes, P. H.; Stefani, H. A. Tetrahedron
Lett. 1993, 34, 393-394. (c) Yang, Y.; Dong, W.; Guo, Y.;
Rioux, R. M. Green Chem, 2013, 15, 3170-3175.
11 Cuthbertson, J.; Gray, V. J.; Wilden, J. D. Chem. Commun.
2014, 50, 2575-2578.
12 Zhou, S.; Doni, E.; Anderson, G. M.; Kane, R. G.;
MacDougall, S. W.; Ironmonger, V. M.; Tuttle, T.; Murphy, J.
A. J. Am. Chem. Soc. 2014, 136, 17818-17826.
Scheme 7: Postulated reaction mechanism.
Finally, we have demonstrated that other sulfur nucleophiles can be
employed. Substituting t-butyl thiolates with various analogues
furnishes the corresponding ynol ethers in good yields (Figure 4).
SEt
S(CH2)5CH3
2m
2n
69 %
64 %
S
Ph
S
2o
2p
65 %
97 %
Figure 4: Thioynol ethers 2m-2p bearing alternative R groups.
In conclusion a short and efficient approach to aryl thioynol
ethers from the acetylinic chlorides has been described. These
molecules have enormous synthetic potential and are difficult to
prepare by other methods. No transition metals or heavy metal
mediators are required and the use of chloride as the leaving
group is more atom efficient and sustainable than other
alternatives. Preliminary experiments suggest that a single
electron transfer mechanism is in operation, which is consistent
with our previous investigations in this field.
Acknowledgments
The authors gratefully acknowledge UCL for funding via the
doctoral training centre in Drug Discovery.
Notes and References
†
Department of Chemistry, University College London, 20 Gordon
Street, London, WC1H 0AJ, UK. Email j.wilden@ucl.ac.uk
Electronic Supplementary Information (ESI) available: Full
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