Facile synthesis of enol ethers via Zn(OTf)2-mediated formal alkyne hydration-Smiles rearrangement

Article abstract of DOI:10.1039/c4ra00159a

An efficient protocol involving commercially available zinc trifluoromethanesulfonate was able to transform a terminal alkyne to an enol ether via a formal tandem Markovnikov hydration-Smiles type rearrangement. The chemoselective reaction was able to work with a range of heteroaromatic tethers such as diazine, pyridine, benzimidazole and benzothiazole.

Full text of DOI:10.1039/c4ra00159a

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Facile synthesis of enol ethers via Zn(OTf)2-
mediated formal alkyne hydration-Smiles
Cite this: RSC Adv., 2014, 4, 16765
rearrangement†
a
b
a
Received 8th January 2014
Accepted 25th March 2014
*
Xinying Chew, Yuhan Lin and Yee Hwee Lim
DOI: 10.1039/c4ra00159a
www.rsc.org/advances
An efficient protocol involving commercially available zinc tri- Markovnikov hydration using silica gel-supported zinc borohy-
fluoromethanesulfonate was able to transform a terminal alkyne to an dride to afford terminal alcohols rather than the aldehyde was
enol ether via a formal tandem Markovnikov hydration-Smiles type disclosed.14
rearrangement. The chemoselective reaction was able to work with a
During the course of our investigations on diazines, we
range of heteroaromatic tethers such as diazine, pyridine, benzimid- discovered an extremely facile protocol to convert the terminal
azole and benzothiazole.
alkynes to enol ethers using cheap and commercially available
reagent, zinc triate (Scheme 2). We believed that the terminal
alkyne 1a was rst hydrated in a Markovnikov manner to give an
intermediate A that underwent an intramolecular Smiles-type
rearrangement15 to yield the diazine-protected enol ether 2a. No
ketone was ever observed or isolated.
An initial experiment was performed using 1a with Zn(OTf)2
in MeCN at ambient temperature. To our pleasant surprise, the
reaction proceeded cleanly to give new product in nearly
quantitative yield (95%) aer 16 h. Aer extensive NMR, mass
and IR spectroscopic analyses, the product was characterized to
be 2a.16 As Zn(OTf)2 is not known to mediate alkyne hydration
nor Smiles rearrangement to the best of our knowledge, we
decided to further investigate this serendipitous observation.
A range of metal salts and acids commonly known to effect
alkyne hydrations were rst screened to determine if the
Alkyne hydration or the addition of water to an alkyne is an
atom-economical1 method to generate useful carbonyl
compounds and therefore is a subject of much interest. Since
the discovery of mercury(II) salts that hydrate alkynes with
Markovnikov selectivity to give ketones,2 most of the research
has focused on the development of less toxic, more selective and
efficient metal and acid catalysts or biocatalysts for this
process.3 Non-metal based catalysts such as formic acid,4 triic
acid5 or triuoroacetic acid6 can be used to hydrolyze terminal
alkynes to the Markovnikov ketone product at elevated
temperatures in water. Numerous metal salts and complexes
have also been identied to convert terminal alkynes to ketones
(Markovnikov product) or aldehydes (anti-Markovnikov
product), (Scheme 1) with the most prominent being palladiu-
m(II),7 gold(I),7e,8 gold(III),9 platinum(II)10 and ruthenium11 cata-
lysts. Catalytic anti-Markovnikov alkyne hydration is a relatively
new and exciting area where ruthenium12 has emerged to be a
highly efficient catalyst.
Being in the same group as mercury, studies using zinc for
alkyne hydrations was reported as early as 1909 by Kutscheroff2c
but was found to require very harsh conditions.13 There were
few reported research using zinc thereaer. In 1994, an anti-
Scheme 1 General scheme of terminal alkyne hydration.
aOrganic Chemistry, Institute of Chemical and Engineering Sciences (ICES), Agency for
Science, Technology and Research (A*STAR), 11 Biopolis Way, #03-08 Helios Block,
Singapore 138667, Singapore. E-mail: lim_yee_hwee@ices.a-star.edu.sg
bSingapore Bioimaging Consortium (SBIC), Agency for Science, Technology and
Research (A*STAR), 11 Biopolis Way, #01-02 Helios Block, Singapore 138667,
Singapore
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra00159a
Scheme
rangement of diazine 1a.
2 Zinc-mediated formal alkyne hydration-Smiles rear-
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Table
1 Initial screening for the alkyne hydration-Smiles
and 9–11). A control experiment with triic acid was carried out
to determine whether the reaction was mediated by Brønsted
acid and only a small amount (7%) of the desired product could
be obtained with catalytic amount of TfOH (Table 1, entry 8).
Zn(OTf)2 was by far superior in terms of efficiency and yield
(Table 1, entries 1 and 12). At elevated temperature (80 ꢀC), the
reaction could be completed within 2 h to give 2a in 95% NMR
yield (Table 1, entry 12). Stoichiometric amount of Zn(OTf)2 was
necessary to effect the reaction as the conversion and yield
dropped drastically with sub-stoichiometric amount of Zn(OTf)2
(Table 1, entry 13).
rearrangementa
Entry
Metal salt/acid
Temp. (ꢀC)
Conv.b (%)
Yieldb (%)
1
2
3
4
5
6
Zn(OTf)2
AgOTf
CuOTf
FeCl3
PdCl2
CuF2
25
25
25
25
25
25
25
80
80
80
80
80
80
60
15
45
0
100
10
100
16
80
50
10
25
0
0
0
Table 3 Hydration-rearrangement of diazines 1a
7
RuCl3
TfOH
0
7
8c
9
AgNTf2
AgOTf
CuOTf
Zn(OTf)2
Zn(OTf)2
40
45
40
95
45
Entry
1
Substrate
Product
Tb (h)
Yieldc (%)
10
11
12
13d
50
100
100
48
2
97
a
Conditions: 1a (1 equiv.), metal salt/acid (1 equiv.), MeCN (0.1 M), 2 h;
then H2O, 80 ꢀC, 1 h. b Determined by 1H NMR with 2,4,6-collidine as an
internal standard. 5 mol% of TfOH was used instead. 50 mol% of
Zn(OTf)2 was used instead.
c
d
2
3
4
2
2
3
95
95
88
observed reactivity behavior was exclusive (Table 1).17 It was
found that a variety of other metal salts such as AgNTf2, AgOTf18
and CuOTf could yield the same product 2a (Table 1, entries 2, 3
Table
2 Solvent optimization for the alkyne hydration-Smiles
rearrangementa
5
6
3
86
85
Entry
Solvent
Conv.b (%)
Yieldb (%)
1
2
3
MeCN
MeOH
DMSO
100
15
0
95
10
0
3.5
4
5
6
7
8
9
10
11
12
Acetone
1,4-Dioxane
EtOAc
100
100
100
10
100
90
75
0
25
20
40
5
75
70
55
0
H2O
7
3
87
MeCN–H2O (9 : 1)
MeCN–H2O (4 : 1)
MeCN–H2O (1 : 1)
MeCN–H2O (1 : 4)
MeCN–H2O (1 : 9)
a
Conditions: substrate 1 (1 equiv.), Zn(OTf)2 (1 equiv.), MeCN (0.1 M),
0
0
80 ꢀC, for specied time; then H2O (1 mL mmolꢁ1), 80 ꢀC for 1 h.
a
b
Conditions: 1a (1 equiv.), Zn(OTf)2 (1 equiv.), solvent (0.1 M), 80 ꢀC, 2
h; then H2O, 80 ꢀC, 1 h. b Determined by 1H NMR with 2,4,6-collidine as
an internal standard.
Reaction was monitored by TLC until all starting material was
c
d
consumed. Isolated yields. The dehydrated product 2g was isolated
instead of the expected tertiary alcohol.
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Different polar solvents were screened to determine the optimized conditions of using stoichiometric amount of
ꢀ
effect of solvents on the reaction (Table 2). Whilst solvents like Zn(OTf)2 in MeCN at 80 C, the scope of the reaction was then
MeOH, acetone, 1,4-dioxane and EtOAc were found to give some examined.20
conversion (Table 2, entries 2, 4, 5 and 6), MeCN was found to be
A range of diazines 1 were explored (Table 3). In general, the
the best solvent. It is interesting to note that the reaction pro- reactions proceeded smoothly with excellent yields (85–97%) to
ceeded even in pure water, albeit with very low conversion afford the corresponding enol ethers. The reaction was found to be
(Table 2, entry 7). We then studied the water tolerance level of tolerant of ether (Table 3, entry 4) as well as alkene functional
this reaction (Table 2, entries 8–12). For reactions in a mixture groups (Table 3, entry 7). As expected, the stereochemistry of 1d was
of MeCN and water, the efficiency of the reaction decreases as retained in the hydration-rearrangement process (Table 3, entry
the water content increases. At 1 : 1 MeCN–H2O mixture, the 4).21 Excellent chemoselectivity was observed as demonstrated by
conversion dropped to 75% whilst the yield was only 55% (Table substrate 1f where the integrity of the second alkyne remained
2, entry 10).
intact under the reaction conditions (Table 3, entry 6). The expected
In order to conrm that an external molecule of water was tertiary alcohol product for substrate 1g was not obtained; instead
added during the hydration-rearrangement, 1c was treated with the dehydrated triene 2g was isolated (Table 3, entry 7).
ꢀ
Zn(OTf)2 in MeCN at 80 C for 2 h followed by a few drops of
The presence of the diazine was vital for the success of the
enriched 18O[H2O]. Indeed, mass spectroscopic analysis of the hydration-rearrangement reaction. Apart from diazine as the
product 18O-2c found incorporation of heavy water, affording a tether for the hydration-rearrangement, we decided to explore if
product of m/z 225.0278 for [M + Na]+.19 Based on the above other similar aromatic groups could be used. Numerous func-
tionalities were attempted, Table 4 detailed some of the results.
The pyridinyl 3a proceeded smoothly to afford the corre-
Table 4 Other successful hydration-rearrangementsa
sponding enol ether 4a in excellent yields (89%) (Table 4, entry 1).
Benzoxazole ether 3b did not react while the corresponding ben-
zoxazole thioether 3c gave the expected product 4c in 45% yield
together with another by-product 4c0 in 25% (Table 4, entries 2
and 3). 4c0 was presumed to be formed through a transfer of the
benzoxazole group from another starting molecule 3c. A similar
reaction involving benzothiazole thioether 3d afforded the
expected enol ether 4d in 92% yield in 6 h (Table 4, entry 4).
Similarly, the benzimidazole thioether 3e proceeded smoothly to
give 4e in 81% yield (Table 4, entry 5). No side products were
observed in both cases. This difference in reactivity remains
unclear at this point and is subject to further investigation.
Entry
1
Substrate
Product
T
b (h)
Yieldc (%)
24
24
89
2
3
4
0
3
6
45d
Conclusions
In summary, a mild and efficient protocol to transform terminal
alkynes to enol ethers via a formal tandem Markonikov hydra-
tion-Smiles rearrangement using cheap and commercially
available zinc triate has been developed. The reaction is highly
chemoselective and works in a range of heteroaromatic such as
diazine, pyridine, benzimidazole, benzoxazole and benzothia-
zole. The present study also highlights Zn(OTf)2 as an eco-
friendly reagent where the transformation is 100% atom-
economical. Further investigations into the mechanism as well
as other applications in synthesis are currently in progress.
92
5
6
81
Acknowledgements
a
Conditions: substrate 3 (1 equiv.), Zn(OTf)2 (1 equiv.), MeCN (0.1 M),
80 ꢀC, for specied time; then H2O (1 mL mmolꢁ1), 80 ꢀC for 1 h.
b
We thank Ms Doris Tan (ICES) for high resolution mass spec-
trometric (HRMS) assistance. Financial support for this work
Reaction was monitored by TLC until all starting material was
consumed. Isolated yields. d 25% of side product 4c0 was obtained.
c
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fully acknowledged for helping to obtain a sample of enriched
18O[H2O] from Singapore Radiopharmaceuticals Ltd for our
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16 For more details on the structural assignment of 2a, please
see ESI.†
17 For detailed screening results, please see ESI.†
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19 2c: C8H9N2O2ClNa has [M + Na]+ calcd: 223.0245, found:
223.0249. 18O-2c: C8H9N2O18OClNa has [M + Na]+ calcd:
225.0293, found: 225.0278.
20 Representative procedure: To a solution of 1a (182 mg,
1 mmol) in MeCN (10 ml) was added Zn(OTf)2 (365 mg,
1 mmol) and the reaction mixture was stirred at 80 ꢀC
until consumption of 1a. Water (1 mL) was then added
and the reaction was stirred for another 1 h. Solvent was
removed and the crude was diluted with EtOAc and
washed with saturated NaHCO3. The crude was puried by
column chromatography to afford the desired product 2a
as a colorless oil (95%).
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21 See ESI† for more details on determination of absolute
conguration.
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