Transition-metal-free synthesis of aryl-substituted tert-butyl ynol ethers through addition/elimination substitution at an sp centre

Article abstract of DOI:10.1002/chem.201203015

Nucleophilic attack of an alkoxide on an alkynyl sulfonamide leads to displacement of the sulfonamide at the sp centre and isolation of the ynol ether in good yield in a single operation (see scheme). The mechanistic pathway has been probed by the use of coordinating additives, ¹³C-labelling experiments and ab initio calculations, which indicated that an addition/elimination mechanism is in operation. Copyright

Full text of DOI:10.1002/chem.201203015

DOI: 10.1002/chem.201203015
Transition-Metal-Free Synthesis of Aryl-Substituted tert-Butyl Ynol Ethers
through Addition/Elimination Substitution at an sp Centre
Vincent J. Gray, Ben Slater, and Jonathan D. Wilden*[a]
Dedicated to Professor William B. Motherwell on his retirement
Ynol ethers are one of the most interesting functional
groups for the preparation of more complex molecules and
the development of new synthetic methodology.[1] In particu-
lar, tert-butyl ynol ethers are particularly desirable as precur-
sors to ketenes by the liberation of isobutene on warming.[2]
Although a number of ynol ethers have been prepared
(mainly by halogenation and subsequent elimination of enol
ethers, because the reaction of alkoxide nucleophiles with
haloalkenes is rarely synthetically useful),[3] access to more
complex systems has been limited by their arduous and
costly synthetic routes that typically employ starting materi-
als, complexity of which exceed that of the product ynol
ether. Although transition-metal-mediated processes have
been used to give ynamides and related compounds[4] from
haloalkynes with oxygen nucleophiles, the X-philic reaction
tends to dominate, giving only the parent alkyne
(Scheme 1).[5]
in addition to the b-product 3 was unexpected. Therefore,
we compared the total-energy differences of molecules 2
and 3 in DMF by using DFT approaches and found that 2 is
0.8 kcalmolÀ1 more stable than 3. The a-product is surpris-
ingly stable due in part to the formation of a weak intramo-
lecular hydrogen bond between a H in the R group and
SO2NEt2, which causes the conjugated carbon framework to
remain planar. In contrast, there is no intramolecular hydro-
gen bond in the b-product, and it adopts a non-planar struc-
ture.
These experimental results immediately suggested to us
the possibility that the addition of alkoxide anions to these
species might be a reversible process, which generates two
transient vinyl anions (2a and 3a) with four possible fates as
outlined in Figure 1. These fates are following: 1) protona-
Scheme 1. X-philic behaviour of acetylinic halides.
During the course of on-going research in our laboratory,
it was found that exposure of the sulfonamide 1a to potassi-
um tert-butoxide in standard grade DMF gave a small
amount of ynol ether 4a as well as the two addition prod-
ucts 2 and 3 (Scheme 2). The observation of the a-product 2
Figure 1. Proposed mechanistic pathway for the formation of products 2,
3 and 4a.
tion of the anion adjacent to the phenyl group giving 2;
2) protonation of the anion adjacent to the sulfonamide
giving 3; 3) elimination of SO2 to form the ynol ether 4a;
and 4) elimination of alkoxide to regenerate 1 and KOtBu.
We reasoned that rigorous exclusion of water or any
proton source from the reaction mixture would therefore
demonstrate our hypothesis and improve the yield of 4a. To
our delight, employing dried DMF as the solvent gave ynol
ether 4a as the sole product in good yield (Scheme 3). Sub-
stitutions of this type at sp centres with carbon nucleophiles
are known,[6] however, examples of heteroatomic nucleo-
philes are scarce.
Scheme 2. Addition of KOtBu to aryl acetylinic sulfonamides.
[a] V. J. Gray, Dr. B. Slater, Dr. J. D. Wilden
Department of Chemistry
University College London
20 Gordon Street
London, WC1H 0AJ (UK)
E-mail: j.wilden@ucl.ac.uk
Because sulfonyl groups can behave as radical-leaving
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203015.
groups in certain circumstances,[7] we were keen to demon-
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Chem. Eur. J. 2012, 18, 15582 – 15585

COMMUNICATION
At this juncture, we were keen to see if the methodology
to the synthesis of a range of new tert-butyl ynol ethers can
be applied and to demonstrate their reactivity in liberating
ketenes at elevated temperatures. A range of alkynyl sulfo-
namides (1a–j) were prepared by standard techniques (see
the Supporting Information) and exposed to potassium tert-
butoxide in dry DMF.[10] The results are outlined in Table 1
Scheme 3. Reactivity of acetylinic sulfonamides.
strate whether a radical mechanism was in operation. Addi-
tion of a radical inhibitor ((2,2,6,6-tetramethylpiperidin-1-
yl)oxyl, TEMPO) to the reaction mixture had no effect on
the reaction, so we concluded that a radical process was un-
likely to be operating in this case.
Table 1. Synthesis of ynol ethers from alkynyl sulfonamides.
Entry
1
Sulfonamide 1a–k
Ynol ether 4a–j
Yield [%][a]
70
One of the intriguing features of this process is the unique
role of the potassium counterion in facilitating the reaction.
Employing lithium, sodium, aluminium, magnesium and
barium tert-butoxides resulted in no reaction, although the
reaction can be initiated by employing a soluble potassium
salt with any of the above-mentioned metal tert-butoxide
(Scheme 3). Aware of many recent reports of reactions spe-
cific to KOtBu and the current debate regarding whether
trace metals actually catalyse the reactions,[8] we employed
both standard reagent grade KOtBu and the freshly sub-
limed reagent in our reaction. No improvement or deterio-
ration in reaction rate, yield or efficiency was observed by
using either reagent. We concluded from this that the potas-
sium ion must be playing a critical role, possibly coordinat-
ing to the sulfonamide, alkyne or aromatic ring (or even all
or a combination of the three components) and activating
the molecule towards nucleophilic attack by the alkoxide
anion.[9] To demonstrate the significance of the counterion,
an experiment, in which the crown ether [18]crown-6 was in-
cluded in the reaction mixture, was performed. No reaction
was observed in this case (Scheme 3). A second experiment
conclusively demonstrated the necessity of potassium ions in
the reaction. Thus, addition of lithium tert-butoxide to 1 in
dry DMF resulted in no reaction even after several hours.
However, addition of KPF6 to the reaction mixture almost
immediately caused a reaction to occur and the ynol ether
was isolated in moderate yield.
To probe the role of the potassium, we turned once more
to DFT modelling and found that potassium provides a
facile source of nucleophilic tert-butoxide in comparison to
lithium and sodium. Calculations showed short bond lengths
(1.70–2.05 ꢁ), and that there is significant covalent charac-
ter between the alkal metal and oxygen in LiOtBu and
NaOtBu. However, in the case of KOtBu/KOR, the potassi-
um–oxygen bond length is 2.46 ꢁ indicating a relatively
weak binding, and analysis of the charge distribution
showed much greater charge transfer from the potassium
(i.e., the formation of an ion pair) than in the lithium and
sodium compounds. In fact, we see that KOtBu spontane-
ously dissociates in the presence of 1, resulting in the bar-
rierless attack of tBuOÀ to form the anion intermediate or
2/3. For LiOtBu and NaOtBu, the stronger metal–oxygen
bond gives rise to a barrier that hinders heterolytic dissocia-
tion and presumably explains their inertness.
2
3
4
5
6
68
76
70
69
69
7
8
9
61
59
60
93
10
11
[b]
–
0
[a] Isolated yields. [b] Recovered starting material.
(ynol ethers 4a–j). The versatility of this new reaction
regime is signalled by the good yield of ynol ethers with
electron-rich and electron-deficient aromatics, although so
far, aliphatic examples have not been successful (entry 11).
By following preparation, the ynol ethers can undergo dime-
rization to give cyclobutenones in excellent yield. Structures
with this molecular architecture are very desirable synthetic
intermediates due to their ability to undergo facile rear-
rangements to form a variety of highly functionalised mole-
cules with numerous synthetic applications (Scheme 4).[11]
Although there are other methods of preparing these mole-
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J. D. Wilden et al.
the scope of the reaction and synthetic utility of the prod-
ucts will be broadened (Scheme 7).
In conclusion, a new synthesis of tert-butyl ynol ethers
from acetylinic sulfonamides that proceeds through a one-
Scheme 4. Thermal decomposition and [2+2] dimerization of tert-butyl
ynol ethers giving cyclobutenones 5a–d.
Scheme 7. Synthesis of a neopentyl ynol ether.
cules,[12] this method offers a complementary approach to
these reactive compounds.
Although the addition/elimination mechanism outlined in
Scheme 2 seemed to be most likely (particularly, given the
elegant mechanistic work by Poisson and co-workers),[13] we
could not rule out the possibility of a carbene intermediate
resulting in a Fritsch–Buttenberg–Wiechell (FBW) rear-
rangement[14] involving the sulfonyl group acting as a leaving
group (Scheme 5).[15]
pot nucleophilic addition/elimination pathway at the sp
centre was described. The reaction mechanism was estab-
lished by isotopic-labelling studies supported by insights
from DFT modelling. A unique dependence on the potassi-
um counterion has also been demonstrated. With a clear un-
derstanding of the reaction mechanism and the critical role
of the potassium counterion, research into extending the
scope and applicability of the reaction to the synthesis of
other more challenging ynol ethers is now underway in our
laboratory.
Scheme 5. The Fritsch–Buttenberg–Wiechell rearrangement.
Acknowledgements
The authors would like to thank UCL for support by the new doctoral
training programme in Organic Chemistry: Drug Discovery. The authors
also gratefully acknowledge the assistance of Dr. Abil Aliev and Lisa
Haigh for spectroscopic support.
To understand fully, which mechanism was in operation, a
simple 13C-labelling experiment outlined in Scheme 6 was
carried out. Treatment of 2-13C-labelled 1a with potassium
Keywords: alkynes
·
elimination
·
sp substitution
·
sulfonamides · synthetic methods
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Scheme 6. 13C-labelling experiment.
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(easily observed in the 13C NMR spectrum by the enhanced
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Transition-Metal-Free Synthesis of Ynol Ethers
COMMUNICATION
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Received: August 24, 2012
Published online: October 19, 2012
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