Br?nsted Acid-Mediated Hydrative Arylation of Unactivated Alkynes

Article abstract of DOI:10.1002/chem.201600432

The Br?nsted acid-mediated reaction of unactivated alkynes with aryl sulfoxides leads to simultaneous hydration and intermolecular C-C bond formation. This solvent- A nd metal-free transformation directly delivers α-arylated carbonyl compounds as the prod

Full text of DOI:10.1002/chem.201600432

DOI: 10.1002/chem.201600432
Communication
&
Synthetic Methods
Brønsted Acid-Mediated Hydrative Arylation of Unactivated
Alkynes
Daniel Kaiser,[a] Luís F. Veiros,[b] and Nuno Maulide*[a]
This manuscript is dedicated with respect and admiration to Prof. Istvµn E. Markó on the occasion of his 60th birthday
these species with aryl sulfoxides, such as 2a, would then con-
ceivably lead to the formation of an intermediate II, poised to
undergo charge-accelerated [3,3]-sigmatropic rearrangement
to yield a-arylated ketones 3a–l.
However, from the outset we were well aware of the poten-
tial drawbacks in this proposal (Scheme 1). For one, the poor
basicity of unactivated alkynes for the formation of vinyl cat-
ions through protonation poses a challenge. Additionally, the
low nucleophilicity of the sulfoxide oxygen implies that com-
petitive addition of the counterion XÀ (leading to a covalent
collapse of the ion pair and possibly a “dead-end” addition
Abstract: The Brønsted acid-mediated reaction of unacti-
vated alkynes with aryl sulfoxides leads to simultaneous
hydration and intermolecular CÀC bond formation. This
solvent- and metal-free transformation directly delivers a-
arylated carbonyl compounds as the products of a formal
hydrative arylation in an atom-economical manner. The
products bear useful synthetic handles for further func-
tionalization.
The addition of water to an alkyne, affording
a ketone, is a textbook organic transformation first
discovered by Kucherov in 1881.[1] Numerous reports
on the hydration of alkynes have appeared since that
time,[2] and continuous developments employing
water or Brønsted acids,[3,4] as well as mercury,[1,5]
iron,[6] copper,[7] platinum,[8] iridium,[9] palladium,[10]
and gold catalysts,[11] leading to the formation of the
Markovnikov product, have been reported. Converse-
ly, tungsten[12] and ruthenium catalyze the anti-Mar-
kovnikov hydration of alkynes,[13] whereas titanium is
able to selectively yield both products.[14] This reac-
tion forms a critical link between alkyne and carbonyl
chemistries.[15] Formation of ketones by the hydration
of alkynes with concomitant carbon–carbon bond
formation at their a-position has been previously ex-
plored.[16,17] Examples include the gold- and mercury-
catalyzed addition of sulfoxides or N-oxides to al- Scheme 1. Proposed hydrative a-arylation of unactivated alkynes and possible complica-
kynes as well as iridium catalysis.[18,19]
tions.
Herein we describe the synthesis of a-arylated ke-
tones by an atom-economical, Brønsted acid-cata-
lyzed hydrative arylation of alkynes using sulfoxides. Inspired
by our prior work on ynamides,[20a] we speculated that the pro-
tonation of unactivated alkynes 1a–l could transiently furnish
highly reactive vinyl cations I (Scheme 1).[21] The interception of
product) or cationic oligomerization (or polymerization) of the
alkyne partner could become serious issues.
Accordingly, initial experiments employing phenylacetylene
(1a) with varying amounts of Brønsted acids in the presence
of diphenyl sulfoxide (2a) led only to the formation of traces
of 3a (Scheme 2a).[22] Suspecting an important concentration
effect with respect to the sulfoxide (given the multitude of
competing processes possible; cf. Scheme 1), we turned to
running the reaction under solvent-free conditions in the pres-
ence of an excess of 2a at 808C. Pleasingly, these changes ena-
bled the formation of a-arylated ketone 3a (Scheme 2b) in
a high yield with either triflic acid or bis(trifluoromethane)sul-
fonamide (not shown). The target compound was isolated in
[a] D. Kaiser, Prof. Dr. N. Maulide
Faculty of Chemistry, Institute of Organic Chemistry
University of Vienna Währinger Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[b] Prof. L. F. Veiros
Centro de Química Estrutural, Instituto Superior TØcnico
Universidade de Lisboa Av. Rovisco Pais 1, 1049-001 Lisboa (Portugal)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201600432.
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ketone 3m in good yield without any trace of the
other regioisomer.
Subsequently, the scope of aryl sulfoxides in this
reaction was investigated (Scheme 4). Products 4ab–
ad were easily prepared from 1a and diaryl sulfox-
ides 2b–d. Additionally, alkyl aryl sulfoxides could be
employed to provide 4ae–cl, containing an alkyl sul-
fide moiety as a handle for further functionalization
(vide infra), in moderate to excellent yields. Impor-
tantly, all sulfoxides employed in Scheme 4 were
either commercially available or readily prepared in
a single step.[22]
Scheme 2. Screening of conditions for successful metal-free arylative coupling of phenyl-
acetylene (1a) and diphenyl sulfoxide (2a).
96% yield, alongside a virtually complete recovery (99%) of
the excess unreacted 2a.
With suitable reaction conditions in hand, we explored the
applicability of this transformation to various alkynes 1a–
l (Scheme 3). Both electron-rich and -poor substrates afforded
Control experiments were conducted in order to
gain more insight into the reaction (Scheme 5). The
reaction of 1a with equimolar amounts of 2b and 2c
led to the formation of a 70:30 mixture of 4ab and
4ac, showing a clear bias towards the sulfoxide bear-
ing the more electron-rich aryl moieties (Scheme 5a).
Furthermore, addition of 2a to equimolar amounts of
alkynes 1c and 1e gave rise to the formation of 3c
and 3e in a ratio of 79:21 (Scheme 5b). This result
confirms the expected preferential protonation of the
more electron-rich alkyne.
The simple solvent-free conditions, under which
the atom-economical reaction takes place, enable
a straightforward scaling up. Thus, treating 1a (2 g,
19.7 mmol) with triflic acid and 2a afforded 5.74 g of
the corresponding a-arylated ketone 3a [Eq (2)]. A
rapid filtration over silica allows easy isolation of the
product and near quantitative recovery of the un-
reacted sulfoxide.
DFT calculations were used to investigate a mecha-
nism of the reaction, using phenylacetylene (1a) and
either diphenyl sulfoxide (2a) or methyl phenyl sulf-
oxide (2e) as reactants.[23] The free energy profile ob-
tained for the reaction with 2a is represented in
Scheme 6 (For the reaction with 2e, see the Support-
ing Information). The first step, A!B, corresponds to
Scheme 3. Hydrative arylation of alkynes with 2a. [a] 1.0 Equiv of TfOH was used. All re-
actions were carried out with 4 equiv of 2a and 0.5 equiv of TfOH. See the Supporting
Information for details.
high yields, generating 3a–g. Esters and nitriles were also well-
tolerated to afford 3h and 3i, respectively, in good yields. Im-
portantly, 3j, derived from an internal alkyne, was isolated in
very good yield. Aliphatic substitution in the alkyne (to form
3k) is also possible. Additionally, heteroaryl ketone 3l was
smoothly furnished in excellent yield.
the protonation of the acetylene by triflic acid. This step has
a barrier of 10.1 kcalmolÀ1 and is endergonic (DG=5.6 kcal
molÀ1), reflecting the instability of the vinyl cation intermedi-
ate. The reaction proceeds with O-nucleophilic attack of the
sulfoxide on the carbocation, B!D, producing an intermediate
The connectivity of the final a-arylketone product depends
on the selective formation of a vinyl cation. Nevertheless, cer-
tain dialkyl-substituted alkynes enable very high levels of re-
gioselectivity [Eq. (1)]. As depicted, the use of cyclopropyl
pentyl acetylene (1m) enables the preparation of cyclopropyl-
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with the [3,3] shift has a value of DG° =13.7 kcal
molÀ1, suggesting a facile step, under the reaction
conditions (see Scheme 2 and 3). The two final steps
are both exergonic, as is the entire reaction with an
overall free energy balance of DG=À65.0 kcalmolÀ1
,
indicating a thermodynamically favorable process.
The profile for the reaction of 1a with methyl
phenyl sulfoxide (2e) was also calculated (see Fig-
ure S2 in the Supporting Information). The reaction
path is similar to the one obtained for 2a, with barri-
ers within less than 2 kcalmolÀ1 difference for both
sulfoxide O-nucleophilic attack and the final acid–
base step. However, the [3,3]-sigmatropic shift has
a barrier 4.4 kcalmolÀ1 higher than the one calculated
for the reaction with 2a. This difference indicates an
easier reaction in the case of diphenyl sulfoxide (2a)
and is in agreement with the experimental results
discussed above (see Scheme 2 and 3).[24]
Moreover, results obtained by the calculations are
also in agreement with the results of the control ex-
periments. It is shown in Scheme 5a that sulfoxide
2b, being more electron-rich, outcompetes 2c for
nucleophilic attack (as reflected in the relative prod-
uct ratios). Calculations for diphenyl sulfoxide (2a)
Scheme 4. Hydrative arylation of alkynes with various aryl sulfoxides. All reactions were
carried out with 4 equiv of sulfoxide and 0.5 equiv of TfOH. See the Supporting Informa-
tion for details.
with the OÀC bond fully established and a formally positive S-
atom. This is a fairly easy step, with a barrier of only 2.0 kcal
molÀ1, being also clearly exergonic (DG=À27.8 kcalmolÀ1).
The reaction is completed with a [3,3]-sigmatropic shift, fol-
lowed by facile rearomatization (D!E!F) with triflate acting
as base, and regenerating triflic acid. The barrier associated
and methyl phenyl sulfoxide (2e) show that the energy barrier
for the nucleophilic attack of 2a, the less-electron rich sulfox-
ide of the pair 2a/2e, lies 1.6 kcalmolÀ1 higher than the corre-
sponding barrier for 2e, thus reflecting the experimental re-
sults. In addition, the stability of the vinyl cation is crucial for
the entire process. A more electron-rich alkyne will produce
Scheme 5. Control experiments.
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Scheme 6. Schematic profile calculated for the reaction of 1a with 2a (distances in Š). Free energy values (kcalmolÀ1) relative to the separated reactants. See
the Supporting Information for details and for a larger version of this Scheme.
a more stable cation and therefore lead to a faster reaction, as
shown by the control experiments described in Scheme 5b.
Electrospray ionization mass spectrometry is an emerging
technique for monitoring of short-lived intermediates in reac-
tions proceeding through cationic mechanisms. The applica-
tion of this technique to our reaction afforded further insight
into the mechanism by allowing the identification of key inter-
mediates and expected fragments thereof (see the Supporting
Information for MS spectra and further details), corroborating
and consubstantiating the results obtained by DFT analysis.
Bearing a carbonyl and thioether functionality, the products
of the hydrative arylation procedure lend themselves to further
structural elaborations. While reduction of the aryl sulfanyl
moiety has been previously reported for similar substrates,[20a]
a palladium-catalyzed cross coupling of alkyl aryl sulfides with
arylzinc reagents offers a possibility of increasing structural
complexity in a facile manner.[25] The reaction of 4ce/ae/cf
with an arylzinc reagent and Pd-PEPPSI-SIPr afforded 5a–d in
very good yields, showing complete chemoselectivity and no
competing addition of the organometallic species to the car-
bonyl moiety (Scheme 7a).
conveniently, aerobic oxidation of 3a can also be conducted in
situ in the presence of o-phenylenediamine to deliver the dis-
ubstituted quinoxaline 9 in excellent yield.[29] The overall atom
economy of these sequences towards various heterocycles is
testified by the fact that 9 is prepared in only two steps from
phenylacetylene, diphenyl sulfoxide, o-phenylenediamine, air,
and two simple non-metallic promoters (TfOH and DABCO).
Quinoxaline cores related to 9 have been described in DNA-
cleaving agents or electroluminescent materials.[30]
The activation of alkynes is not limited to the proton, the
simplest electrophile. In an unoptimized experiment, combin-
ing 1a with N-bromosuccinimide (NBS) and diphenyl sulfoxide
(2a) led to the formation of a-bromo ketone 10, in what is ef-
fectively a three-component coupling [Eq (3)].
Additionally, rapid conversion of the products to drug-like
aromatic heterocycles can be achieved by a simple oxidation
to the corresponding 1,2-diketone (Scheme 7b). Diketone 6 is
furnished in excellent yield from 3a by a copper-catalyzed oxi-
dation,[26] and can be smoothly converted to imidazole 7 and
diaryl-thioxoimidazolidinone 8 in high yields.[27,28] Even more
In summary, we have developed an atom-economical, opera-
tionally simple, and metal-free hydrative arylation of alkynes.
This solvent-free reaction tolerates a range of functional
groups and yields valuable a-arylated ketones in good to ex-
cellent yields. The promising possibility to use electrophiles
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Scheme 7. a) Palladium-catalyzed cross coupling of 4ce/ae/cf with an arylzinc reagent. b) Facile oxidation and subsequent condensation of the products,
leading to heterocycles. [a] Yield based on recovered starting material.
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Generous support of this research by the University of Vienna
is acknowledged. D.K. is a recipient of a DOC Fellowship of the
Austrian Academy of Sciences. L.F.V. acknowledges Fundażo
para a CiÞncia e Tecnologia, UID/QUI/00100/2013. N.M. ac-
knowledges the Deutsche Forschungsgemeinschaft (Grant MA
4861/4-1 and 4-2). We are indebted to Dr. I. D. Jurberg and
Prof. M. Eberlin of the University of Campinas, Brazil (UNICAMP)
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Keywords: alkynes
rearrangement · sulfoxides
·
arylation
·
organic chemistry
·
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Received: January 29, 2016
Published online on February 25, 2016
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