Synthesis of alkyl-ynol-ethers by anti-Michael addition of metal alkoxides to β-substituted alkynylsulfones

Article abstract of DOI:10.1002/ejoc.201300395

The reaction of metal alkoxides with β-substituted 2-(p-tolylsulfonyl)acetylenes, involving an anti-Michael addition reaction followed by the in situ elimination of the sulfonyl moiety, provides a direct method for the synthesis of alkyl alkynyl ethers bearing aryl or TIPS groups joined to the triple bond. Arylalkynyl ethers derived from primary alkoxides are in situ hydrolyzed into arylacetic esters. Copyright

Full text of DOI:10.1002/ejoc.201300395

FULL PAPER
DOI: 10.1002/ejoc.201300395
Synthesis of Alkyl-Ynol-Ethers by “Anti-Michael Addition” of Metal
Alkoxides to β-Substituted Alkynylsulfones
Leyre Marzo,[a] Alejandro Parra,[a] María Frías,[a] José Alemán,*[a] and
José Luis García Ruano*[a]
Keywords: Synthetic methods / Michael addition / Hydrolysis / Alkynes / Metal alkoxides
The reaction of metal alkoxides with β-substituted 2-(p-tolyl-
sulfonyl)acetylenes, involving an anti-Michael addition reac-
tion followed by the in situ elimination of the sulfonyl moiety,
provides a direct method for the synthesis of alkyl alkynyl
ethers bearing aryl or TIPS groups joined to the triple bond.
Arylalkynyl ethers derived from primary alkoxides are in situ
hydrolyzed into arylacetic esters.
metals but is restricted to aryloxy alkynes.[8] Therefore, it
would be highly desirable to find new direct and efficient
method for the synthesis of ynol ethers.
Introduction
Ynol ethers are well-known structures in organic synthe-
sis[1] that have seen increased interest in recent years with
the publication of interesting new synthetic applications,
such as the synthesis of amides in supercritical carbon diox-
ide,[2] Nazarov reactions with carbonyl compounds,[3] the
synthesis of aromatic (1E)-α-chloroenol ethers,[4] and cyclo-
addition reactions,[5] among others.[6] The large synthetic
potential of the enolethers could be similar for ynol ethers,
therefore it is surprising that ynol ethers are not used exten-
sively in organic synthesis, which can be explained by the
limitations of the methods used in their preparation.
There are three classic methods for synthesizing ynol
ethers.[7] Two of them have limited scope because they in-
volve the preparation of lithiated terminal tert-butoxy[7a]
and ethoxy-acetylenes[7b] (other alkoxides cannot be pre-
pared), which are only able to react efficiently with primary
halides. The third and most recent method is based on the
reaction of diazoketones with alcohols to form alkoxy
ketones, which are converted into enol triflates (or phos-
phates) and subsequently transformed into ynol ethers by
treatment with base.[7c] This is the most general method so
far reported and allows the preparation of any alkyl- or
aryl-substituted acetylene with primary, secondary and ter-
tiary alkoxide groups. However, this methodology requires
several steps and the manipulation of potentially explosive
diazo compounds. In 2012, Evano et al. described a new
method based on coupling reactions mediated by transition
Our group recently reported[9] the unexpected electro-
philic behavior of arylsulfonylacetylenes (1) that undergo
reactions with nucleophiles such as organolithiums (alkyl,
aryl, heteroaryl and alkenyl) through an unusual α-attack
(anti-Michael addition) followed by elimination of the
–
ArSO2 moiety to allow the alkynylation of lithiated sp2
and sp3 carbon atoms (Scheme 1, top). Because the scope
of the reaction is quite general and allows the preparation
of any dialkyl, alkyl-aryl or diaryl-substituted alkyne, we
wondered if less nucleophilic species, such as alkoxides,
would also be successful in these reactions. If so, the reac-
tion would create C(sp)–O bonds, thus providing a direct
method for the synthesis of ynol ethers (Scheme 1, bottom).
In this paper, we describe the scope and limitations of the
reaction of β-substituted (alkyl-, aryl-, and silyl-) sulfonyl-
acetylenes with primary, secondary and tertiary metal alk-
oxides as a general method for the synthesis ynol ethers. A
mechanistic proposal to rationalize the results will also be
discussed.
[a] Department of Organic Chemistry (Módulo-1), Universidad
Autónoma de Madrid,
Scheme 1. Alkynylation of organolithiums[9] and synthetic proposal
for preparing ynol ethers in this paper.
Cantoblanco, 28049 Madrid, Spain
Fax: +34-91497466
E-mail: jose.aleman@uam.es
joseluis.garcia.ruano@uam.es
During the preparation of this manuscript, Wilden et
al.[10] described a similar protocol starting from alkynyl sulf-
onamides instead of the more available sulfones based on
Homepage: www.uam.es/JLGR
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300395
Eur. J. Org. Chem. 2013, 4405–4409
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4405

L. Marzo, A. Parra, M. Frías, J. Alemán, J. L. Garcia Ruano
FULL PAPER
our results from ref.[9] The main differences between both Table 1. Optimization screening of the reaction of 1a with different
metal alkoxides derived from tert-butanol.[a]
procedures are related to the scope and the mechanistic pro-
posals of the study, which in ref.[10] only concern tertiary
alkoxides.
Results and Discussion
Our initial trial (Table 1, Entry 1), involved the reaction
Entry
M
T [°C]
Time
Conversion [%] 3Aa/4Aa/5Aa
of 2-phenyl sulfonylacetylene (1a) with LiOtBu (2A) at
–78 °C under similar conditions to those reported for alk-
ynylating sp2 and sp3 carbon atoms.[9a–9b] Three products
were detected and characterized. Expected ynol ether 3Aa
(resulting from the anti-Michael addition/elimination pro-
cess) and sulfones 4Aa and 5Aa, obtained by anti-Michael
and Michael addition reactions of the LiOtBu, respectively.
The (Z) configuration of 4Aa, and therefore of its precursor
anion, hinders elimination of the sulfonyl group (presum-
ably requiring an antiperiplanar arrangement[11]), thus justi-
fying its stability. The regioselectivity for the addition step
(anti-Michel versus Michael products), measured as the
(3Aa + 4Aa)/5Aa ratio, was only moderate at –78 °C
(Table 1, Entry 1) but was improved at higher temperatures
(Table 1, Entries 2 and 3), with the best result obtained at
room temperature (Table 1, Entry 3). Under these condi-
tions 3Aa was obtained in 65% isolated yield. Changes in
the metal produced significant alterations. The reaction did
not work with NaOtBu (Table 1, Entry 4), whereas faster
conversions were obtained with KOtBu (Table 1, Entries 5
and 6). Moreover, the regioselectivity was also better with
KOtBu than with LiOtBu, with only traces of the Michael
addition olefin observed under optimal conditions. With re-
spect to the alkyne/alkene (3Aa/4Aa) ratio, the results were
not so clear because they were dependent on several factors
such as temperature and, mainly, the reaction times. Longer
reaction times increased the proportion of alkyne 3Aa
(Table 1, Entries 5 and 6). After studying many conditions,
we found that the optimal ones were those indicated in En-
1
2
3
4
5
6
7
8
Li
Li
Li
Na
K
K
K
K
K
K
K
–78 to r.t. 18 h
100
61
51:19:30
45:37:18
73:16:11
–
57:35:8
63: 37:0
77:23:0
84:16:0
87:13:0
100:0:0
–
–10
24 h
r.t.
3 h
100
n.r.[b]
100
100
100
100
100
100
n.r.[b]
–10
48 h
–78
–78
15 min
3 h
–43
10 min
10 min
–43[d]
–43[e]
–43 to r.t.
–43[f]
9
10
11
10 min
–[c]
10 min
[a] Performed in THF (1.0 mL) by using 2A (0.4 mmol) and 1a
(0.2 mmol). [b] No reaction. [c] 10 min at –43 °C and 2 h at r.t.
[d] 2A (0.8 mmol). [e] 2A (2.0 mmol). [f] Performed in the presence
of 18-crown-6 ether (0.4 mmol).
Figure 1. Mechanistic proposal for the reaction of sulfonylacetyl-
enes with KOR.
We then tested the scope of the reaction of tBuOK (2A)
try 10 (10 min at –43 °C and then 2 h at room temp.) that with different sulfonylacetylenes (1a–1j) under optimized
gave 3Aa as a single product. Other interesting effects con- conditions (Table 2). Starting from 1a (Table 2, Entry 1),
cerned the increase of the 3Aa/4Aa ratio when the concen- 3Aa was obtained in 84% yield. When this reaction was
tration of the base increased (Table 1, Entries 7, 8 and 9). scaled up to 4.0 mmol, the yield was not significantly affec-
Finally, it was notable that the presence of 18-crown-6 ether ted (Table 2, Entries 1 and 2). These reactions were simi-
completely inhibited the reaction, despite the presumably larly efficient for aryl derivatives containing electron-with-
increased reactivity of the alkoxide (Table 1, Entry 11), sug- drawing and electron-donating groups (Table 2, Entries 3–
gesting an essential role of the counterion in the reaction.
8). Although all of the reactions proceeded to completion
Presumably, α-attack of the alkoxides to sulfonylacetyl- (nearly quantitative yield as calculated by NMR), the iso-
enes is favored by prior association of the metal to the sulf- lated yields of ynol ethers were clearly lower (likely owing
onyl oxygen (as was established in reactions with organo- to their volatility).
lithiums[9b] by theoretical calculations), which would ex-
A different behavior was observed for alkyl-substituted
plain the detrimental effect of crown ethers (Table 1, En- acetylenes and the reaction with 1h (n-butyl derivative;
try 11). This addition would afford both the (Z) and (E) Table 2, Entry 9) did not work. Initially, we attributed this
vinyl carbanions (Figure 1), with the former easily evolving absence of reactivity (which had also been observed in reac-
into ynol ether 3. The (E) vinyl carbanion, stabilized by the tions with organolithiums[9]) to the acidity of the proparg-
chelating potassium, would favor formation of 4 by proton- ylic protons, but the lower basicity of KOtBu suggested that
ation or regenerate 1 by elimination of the anti-OR group, other factors could also contribute to this behavior. A sim-
thus opening a route to be equilibrated with the (Z)-carban- ilar lack of reactivity observed for tert-butyl derivative 1i
ion. The influence of the reaction time on the 3/4 ratio sup- (Table 2, Entry 10), lacking propargylic protons, which had
ports the existence of this equilibrium.
undergone the reaction with organolithiums,[9b] suggested
4406
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4405–4409

Synthesis of Alkyl-Ynol-Ethers
Table 2. Scope of the reaction: structure of the sulfonylacetylenes.[a] ucts (Scheme 3). The major product was olefin 4Ca, iso-
lated in 66% yield. However, the minor product was iden-
tified as n-butyl phenyl acetate 5Ca. It was formed as the
only product after 2 h at room temp. by using 10 equiv. of
KOnBu (30% isolated yield).[12] Finally, we studied the be-
havior of primary alkoxide 2D, derived from benzyl alcohol
because of the interest of benzyl as a protecting group. The
reaction was very clean yielding only ester 5 Da in 51%
yield (Scheme 3).
Entry
R1
Yield [%]
1
2
3
4
5
6
7
8
Ph-1a
Ph-1a
84–3Aa
88–3Aa[b]
51–3Ab
70–3Ac
67–3Ad
84–3Ae
45–3Af
61–3Ag
n.r.[c]
p-MeOC6H4-1b
p-MeC6H4-1c
2,4,5-(Me)3C6H2-1d
o-ClC6H4-1e
p-FC6H4-1f
3,5-(CF3)2C6H3-1g
nBu-1h
9
10
11
tBu-1i
TIPS-1j
n.r.[c]
65–3Aj
[a] Performed under conditions of Table 1, Entry 10. [b] Reaction
carried out on a 4.0 mmol scale. [c] No reaction.
Scheme 3. Reactions of 1a with primary alkoxydes 2C and 2D.
A mechanistic proposal for the formation of esters 5
from ynol ethers 3 is outlined in Scheme 4. Tertiary alkoxy
acetylenes are less prone to hydrolysis than primary ones
because of the lower stability of intermediate I, destabilized
by the +I effect of the R group (tertiary Ͼ primary).[13]
that the stabilization of the vinyl anion resulting from the
α-attack is required and is provided by aryl but not for alkyl
groups. The good result obtained with triisopropylsilyl
(TIPS) derivative 1j (Table 2, Entry 11) supports this expla-
nation as the silyl atom d orbitals are also capable of pro-
viding electron delocalization to the anionic electron pair.
Next, we focused our attention on the preparation of alk-
oxy acetylenes derived from primary and secondary
alcohols with this methodology. Unexpectedly, under the
optimal conditions found for KOtBu, the reaction of 1a
with secondary alkoxide 2B [derived from (–)-menthol]
yielded a 28:72 mixture of compound 3Ba (18% isolated
yield) and undesired olefin 4Ba. All attempts to improve
these results by performing the reaction at different tem-
peratures and reaction times were unsuccessful. The lower
yield of desired enol-ether 3Ba can be explained by destabi-
lizing steric interactions of the (E)-carbanion (precursor of
4) with respect to the (Z)-one (Figure 1), which is more im-
portant for species resulting in the attack of tertiary alk-
oxide 2A than secondary alkoxide 2B. Fortunately, the use
of a large excess of nucleophile (10 equiv.) allowed us to
obtain a 85:15 mixture of 3Ba and 4Ba (calculated from
the NMR spectra of the crude reaction mixture; Scheme 2).
Under these conditions, 3Ba was isolated in 45% yield. The
excess of alkoxide could favor the transformation of 4 into
1 (E2 process), thus increasing the equilibration between
the (Z) and (E) anions.
Scheme 4. Mechanistic proposal for the hydrolysis of ynol ethers.
According to this proposal, an increase in the size of RЈ
would hinder the attack of water to Cβ thus increasing the
stability of the ynol ethers to hydrolysis. Similar conse-
quences could provoke substituents with large electron-do-
nating character, which would decrease the efficiency of the
+M effect of the OR. Because the TIPS group has both
features, reactions of 1j with primary alkoxides would pro-
vide ynol ethers stable to hydrolysis. Supporting this as-
sumption, reaction of 1j with KOnBu (2C) only gave ynol
ether 3Cj with 72% yield (Scheme 5).
Scheme 5. Reactions of 1j with primary alkoxide 2C.
Scheme 2. Reactions of 1a with secondary alkoxides 2B.
Conclusions
Finally, we studied the behavior of alkoxides derived
In conclusion, we have found that the addition of KOR
from primary alcohols. Despite many attempts, alkoxy- to substituted 2-(p-tolylsulfonyl)acetylenes provides a direct
acetylene 3Ca was not obtained by using KOnBu. After 2 h, method for the synthesis of alkyl alkynyl ethers bearing aryl
we observed the formation of a 25:75 mixture of two prod- or TIPS groups joined to the triple bond. Arylalkynyl ethers
Eur. J. Org. Chem. 2013, 4405–4409
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4407

L. Marzo, A. Parra, M. Frías, J. Alemán, J. L. Garcia Ruano
FULL PAPER
1-(tert-Butoxyethynyl)-4-fluorobenzene (3Af): The product was ob-
tained, by following the standard procedure with sulfone 1f, as col-
orless oil (45% yield). H NMR (CDCl3): δ = 7.25–7.19 (m, 2 H),
derived from primary alkoxide are in situ hydrolyzed into
arylacetic esters.
1
6.86 (t, J = 7.5 Hz, 2 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3): δ
= 161.4 (d, J = 244.5 Hz, 1 C), 132.9 (d, JC,F = 8.2 Hz, 2 C), 120.7
(d, JC,F = 3.0 Hz, 1 C), 115.2 (d, JC,F = 21.8 Hz, 2 C), 94.9, 86.8,
41.7, 27.2 ppm. HRMS: calcd. for C12H3OF [M]+ 192.0950; found
192.0942.
Experimental Section
General Methods: NMR spectroscopic data were acquired with a
Bruker 300 spectrometer operating at 300 and 75 MHz for H and
1
13C nuclei, respectively. Chemical shifts (δ) are reported relative to
residual solvent signals (CHCl3 7.26 ppm for 1H NMR, and
CDCl3, 77.0 ppm for 13C NMR). 13C NMR spectra were acquired
by using a broadband decoupled mode. Analytical TLC was per-
formed by using pre-coated aluminium-backed plates (Merck Kie-
selgel 60 F254) and visualized with ultraviolet irradiation or
KMnO4 dip. Purification of reaction products was carried out by
using flash chromatography with silica gel Merck-60 or fluorisil®
100–200 mesh. Commercially available alcohols, and solvents were
used without further purification. Alkynylsulfones 1a–1g,[14] 1h–
i[15] and 1j[16] were synthesized following reported procedures.
1-(tert-Butoxyethynyl)-3,5-bis(trifluoromethyl)benzene (3Ag): The
product was obtained, by following the standard procedure with
sulfone 1g, as colorless oil (61% yield). 1H NMR (CDCl3): δ = 7.72
(s, 2 H), 7.72 (s, 1 H), 1.51 (s, 9 H) ppm. 13C NMR (CDCl3): δ =
138.5, 132.4 (JC,F = 34.0 Hz), 131.2, 121.3 (JC,F = 271.0 Hz), 120.4,
110.6, 88.8, 68.9, 27.3 ppm. HRMS: calcd. for C14H12F6O [M]+
310.0792; found 310.0691.
(tert-Butoxyethynyl)triisopropylsilane (3Aj): The product was ob-
tained, by following the standard procedure with sulfone 1j, as col-
orless oil (65% yield). The data for this compound are in agreement
with those described in the literature.[17] 1H NMR (CDCl3): δ =
1.46 (s, 9 H), 1.05 (s, 21 H) ppm. HRMS: calcd. for C15H30OSi
[M]+ 254.2066; found 254.1999.
General Procedure for the Synthesis of Compounds 3Aa–3Aj, 4Aa
and 5Aa: To a cooled (–43 °C) solution of potassium tert-butoxide
(2A, 0.40 mmol) in dry THF (0.5 mL), a solution of sulfone (1a–j)
(0.2 mmol) in THF (0.5 mL) was added. Once the alkynylsulfone
has disappeared (followed by TLC), the reaction mixture was
warmed to room temperature over 1–2 h. The crude mixture was
purified by flash chromatography through a short pad of fluorisil®
by using n-pentane as solvent. Owing to the volatility of the prod-
ucts any reduced pressures must remain over 300 Torr.
(E)-1-{[1-(tert-Butoxy)-2-phenylvinyl]sulfonyl}-4-methylbenzene
(4Aa): The product was obtained, by following the standard pro-
cedure with sulfone 1a, as colorless oil. The E geometry was deter-
mined by means of NOESY experiments (see Supporting Infor-
1
mation, page S16). H NMR (CDCl3): δ = 7.81 (d, J = 9.0 Hz, 2
H), 7.58 (dd, J = 9.0, 3.0 Hz, 2 H), 7.41 (s, 1 H), 7.36–7.21 (m, 5
H), 2.44 (s, 3 H), 1.39 (s, 9 H) ppm. 13C NMR (CDCl3): δ = 151.1,
144.1, 136.6, 132.8, 129.8, 129.6, 129.0, 128.5, 128.4, 125.5, 87.9,
29.2, 21.6 ppm. HRMS: calcd. for C19H22O3SNa [M + Na]+
353.1181; found 353.1184.
(tert-Butoxyethynyl)benzene (3Aa): The product was obtained, by
following the standard procedure with sulfone 1a, as colorless oil
(84% yield). 1H NMR (CDCl3): δ = 7.26 (d, J = 9.0 Hz, 2 H),
7.20–7.11 (m, 3 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3): δ =
131.4, 128.1, 126.2, 124.8, 95.6, 86.7, 42.8, 27.2 ppm. HRMS:
calcd. for C12H14O [M]+ 174.1045; found 174.1039.
(Z)-1-{[2-(tert-Butoxy)-2-phenylvinyl]sulfonyl}-4-methylbenzene
(5Aa): The product was obtained, by following the standard pro-
cedure with sulfone 1a, as colorless oil. The Z geometry was deter-
mined by means of NOESY experiments (see Supporting Infor-
1-(tert-Butoxyethynyl)-4-methoxybenzene (3Ab): The product was
obtained, by following the standard procedure with sulfone 1b, as
colorless oil (51% yield). 1H NMR (CDCl3): δ = 7.27 (d, J =
9.0 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H), 3.79 (s, 3 H), 1.46 (s, 9
H) ppm. 13C NMR (CDCl3): δ = 158.2, 132.7, 116.8, 113.8, 94.1,
86.4, 55.3, 41.2, 27.2 ppm. HRMS: calcd. for C13H16O2 [M]+
204.1150; found 204.1160.
1
mation, page S18). H NMR (CDCl3): δ = 7.89 (d, J = 6.0 Hz, 2
H), 7.40–7.26 (m, 7 H), 6.03 (s, 1 H), 2.43 (s, 3 H), 1.33 (s, 9
H) ppm. 13C NMR (CDCl3): δ = 165.8, 143.4, 136.9, 132.7, 130.3,
129.3, 128.4, 128.1, 127.4, 118.2, 84.8, 29.3, 21.5 ppm. HRMS:
calcd. for C19H22O3SNa [M + Na]+ 353.1205; found 353.1195.
General Procedure for the Synthesis of Compounds 3Ba, 4Ba, 5Ca,
4Ca and 3Cj: A solution of corresponding alcohol (0.4 mmol) in
THF (0.5 mL) is added to a solution of potassium hydride
(0.4 mmol) in THF (0.5 mL) at room temperature. After 10 min the
reaction is cooled to –43 °C and the solution of corresponding sulf-
one (0.2 mmol) in THF (0.5 mL) is added. Once the alkynylsulfone
had reacted (followed by TLC), the reaction mixture was warmed
to room temperature over 1–2 h. The crude reaction was purified
by flash chromatography through a short pad of fluorisil® by using
n-pentane as solvent. Owing to the volatility of the products any
reduced pressures must remain over 300 Torr.
1-(tert-Butoxyethynyl)-4-methylbenzene (3Ac): The product was ob-
tained, by following the standard procedure with sulfone 1c, as
colorless oil (70% yield). 1H NMR (CDCl3): δ = 7.16 (d, J =
9.0 Hz, 2 H), 6.98 (d, J = 6.0 Hz, 2 H), 2.24 (s, 3 H), 1.39 (s, 9
H) ppm. 13C NMR (CDCl3): δ = 136.0, 131.2, 128.8, 94.8, 86.5,
42.6, 27.1, 21.2 ppm. HRMS: calcd. for C13H16O [M]+ 188.1201,
found 188.1204.
1-(tert-Butoxyethynyl)-2,4,5-trimethylbenzene (3Ad): The product
was obtained following the standard procedure with sulfone 1d, as
colorless oil (67% yield). 1H NMR (CDCl3): δ = 7.11 (s, 1 H), 6.93
(s, 1 H), 2.33 (s, 3 H), 2.20 (s, 3 H), 2.18 (s, 3 H), 1.48 (s, 9 H) ppm.
13C NMR (CDCl3): δ = 136.7, 134.7, 133.4, 132.7, 130.6, 121.5,
98.4, 86.3, 41.6, 27.2, 20.4, 19.4, 19.0 ppm. HRMS: calcd. for
C15H20O [M]+ 216.1514; found 216.1311.
({[(1R,2S,4S)-2-Isopropyl-4-methylcyclohexyl]oxy}ethynyl)benzene
(3Ba): The product was obtained, by following the standard pro-
cedure with sulfone 1a, as colorless oil (18% yield when 2 equiv. of
alkoxide was used and 45% yield when 10 equiv. were used). 1H
NMR (CDCl3): δ = 7.36–7.32 (m, 2 H), 7.28–7.24 (m, 2 H), 7.24–
7.22 (m, 1 H), 3.95 (dt, J = 6.0, 4.0 Hz, 1 H), 2.38–2.18 (m, 2 H),
1-(tert-Butoxyethynyl)-2-chlorobenzene (3Ae): The product was ob-
tained, by following the standard procedure with sulfone 1e, as col-
1
orless oil (84% yield). H NMR (CDCl3): δ = 7.30–7.25 (m, 2 H), 1.73–1.68 (m, 3 H), 1.67–1.64 (m, 2 H), 1.43–1.26 (m, 1 H), 1.22–
7.20–7.14 (m, 1 H), 7.06–7.02 (m, 1 H), 1.44 (s, 9 H) ppm. 13C
NMR (CDCl3): δ = 135.3, 132.6, 128.9, 127.0, 126.2, 124.7, 100.8,
88.0, 40.7, 27.2 ppm. HRMS: calcd. for C12H3OCl [M]+ 208.0655;
found 208.0645.
1.20 (m, 1 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.94 (d, J = 5.3 Hz, 3 H),
0.87 (d, J = 5.3 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 131.4, 128.1,
126.3, 124.5, 97.7, 88.7, 68.0, 47.0, 40.8, 39.8, 34.1, 31.7, 26.0, 22.1,
20.6, 16.4 ppm.
4408
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4405–4409

Synthesis of Alkyl-Ynol-Ethers
Triple-Bonded Functional Groups (Ed.: S. Patai), John Wiley &
Sons, New York, 1994, chapter 19.
[2] X. Y. Mak, R. P. Ciccolini, J. M. Robinson, J. W. Tester, R. L.
Danheiser, J. Org. Chem. 2009, 74, 9381.
1-[((E)-1-{[(1R,2S,4S)-2-Isopropyl-4-methylcyclohexyl]oxy}-2-phen-
ylvinyl)sulfonyl]-4-methylbenzene (4Ba): The product was obtained,
by following the standard procedure with sulfone 1a, as colorless
oil (67% yield when 3 equiv. of alkoxide was used). 1H NMR
(CDCl3): δ = 7.81 (d, J = 9.0 Hz, 2 H), 7.68 (d, J = 9.0 Hz, 2 H),
7.37–7.30 (m, 5 H), 7.25 (s, 1 H), 4.51 (td, J = 10.8, 4.2 Hz, 1 H),
2.43 (s, 3 H), 2.12–2.08 (m, 2 H), 1.67–1.57 (m, 2 H), 1.49–1.42 (m,
1 H), 1.28–1.22 (m, 2 H), 1.10–0.98 (m, 1 H), 0.87 (d, J = 7.0 Hz,
3 H), 0.79 (d, J = 5.3 Hz, 3 H), 0.75 (d, J = 5.3 Hz, 3 H) ppm. 13C
NMR (CDCl3): δ = 150.1, 144.3, 131.4 (2 C), 129.2, 128.1 (2 C),
126.4, 124.5, 83.2, 48.8, 39.1, 34.1, 23.3, 26.0, 25.0, 23.4, 22.1, 20.6,
16.4 ppm. HRMS: calcd. for C25H32O3SNa [M + Na]+ 435.1964;
found 435.1977.
[3] C. J. Rieder, K. J. Winberg, F. G. West, J. Am. Chem. Soc. 2009,
131, 7504.
[4] H. Cai, Z. Yuan, W. Zhu, G. Zhu, Chem. Commun. 2011, 47,
8682.
[5] a) Y. E. Türkmen, T. J. Montavon, S. A. Kozmin, V. H. Rawal,
J. Am. Chem. Soc. 2012, 134, 9062; b) W. Zhao, Z. Wang, J.
Sun, Angew. Chem. 2012, 124, 6313; Angew. Chem. Int. Ed.
2012, 51, 6209.
[6] For examples of recent papers, see: a) C. Verrier, S. Carret, J. F.
Poisson, Org. Lett. 2012, 14, 5122; b) V. Tran, T. G. Minehan,
Org. Lett. 2011, 13, 6588; c) T. Mejuch, M. Botoshansky, I.
Marek, Org. Lett. 2011, 13, 3604; d) P. W. Davies, A. Cre-
monesi, N. Martin, Chem. Commun. 2011, 47, 379; e) R.
Hanna, B. Daoust, Tetrahedron 2011, 67, 92; f) A. Levin, A.
Basheer, I. Marek, Synlett 2010, 2, 329; g) F. Longpre, N. Rusu,
M. Larouche, R. Hanna, B. Daoust, Can. J. Chem. 2008, 86,
970; h) B. Darses, A. Milet, C. Philouze, A. E. Greene, J.-P.
Poisson, Org. Lett. 2008, 10, 4445.
[7] a) A. Moyano, F. Charbonnier, A. E. Greene, J. Org. Chem.
1987, 52, 2919; b) S. Raucher, B. L. Bray, J. Org. Chem. 1987,
52, 2332; c) J. R. Sosa, A. A. Tudjarian, A. Minehan, Org. Lett.
2008, 10, 5091.
[8] a) K. Jovin, A. Bayle, F. Legrand, G. Evano, Org. Lett. 2012,
14, 1652; b) K. Jouvin, A. Coste, A. Bayle, F. Legrand, G.
Karthikeyan, K. Tadiparthi, G. Evano, Organometallics 2012,
DOI: 10.1021/om3005614.
[9] a) J. L. García Ruano, J. Alemán, L. Marzo, C. Alvarado, M.
Tortosa, S. Díaz-Tendero, S. Fraile, Angew. Chem. 2012, 124,
2766; Angew. Chem. Int. Ed. 2012, 51, 2712; b) J. L. García Ru-
ano, J. Alemán, L. Marzo, C. Alvarado, M. Tortosa, S. Díaz-
Tendero, S. Fraile, Chem. Eur. J. 2012, 18, 8414; c) J. L.
García Ruano, L. Marzo, C. Alvarado, V. Marcos, J. Alemán,
Chem. Eur. J. 2012, 18, 9975.
(E)-1-[(1-Butoxy-2-phenylvinyl)sulfonyl]-4-methylbenzene (4Ca):[4]
The product was obtained, by following the standard procedure
1
with sulfone 1a, as colorless oil (66% yield). H NMR (CDCl3): δ
= 7.54 (d, J = 9.0 Hz, 2 H), 7.35–7.30 (m, 2 H), 7.06–6.99 (m, 5
H), 6.90 (s, 1 H), 3.77 (t, J = 9.0 Hz, 2 H), 2.28 (s, 3 H), 1.42–1.25
(m, 2 H), 1.12–1.00 (m, 2 H), 0.61 (t, J = 6.1 Hz, 3 H) ppm. 13C
NMR (CDCl3): δ = 152.8, 144.5, 136.1, 131.8, 129.7, 129.2, 128.7,
128.5, 126.7, 121.9, 74.4, 41.4, 21.6, 18.9, 13.7 ppm. HRMS: calcd.
for C19H23O3S [M + H]+ 331.1362; found 331.1389.
Butyl 2-Phenylacetate (5Ca):[5] The product was obtained, by fol-
lowing the standard procedure with sulfone 1a, as yellow oil (64%
yield). Data for 5Ca are in agreement with those described in the
literature.[18] 1H NMR (CDCl3): δ = 7.37–7.26 (m, 5 H), 4.11 (t, J
= 6.0 Hz, 2 H), 3.64 (s, 2 H), 1.62–1.59 (m, 2 H), 1.41–1.30 (m, 2
H), 0.93 (t, J = 6.0 Hz, 3 H) ppm.
Benzyl 2-Phenylacetate (5Da): The product was obtained, by fol-
lowing the standard procedure with sulfone 1a, as yellow oil (51%
yield). Data for 5Da are in agreement with those described in the
literature.[19] 1H NMR (CDCl3): δ = 7.41–7.28 (m, 10 H), 5.15 (s,
2 H), 3.69 (s, 2 H) ppm.
[10] V. J. Gray, B. Slater, J. D. Wilden, Chem. Eur. J. 2012, 18,
15582.
(Butoxyethynyl)triisopropylsilane (3Cj): The product was obtained,
by following the standard procedure with sulfone 1j, as colorless
[11] For the anti-β-elimination of bromoalkenes to alkynes, see: M.
Okutani, Y. Moria, J. Org. Chem. 2009, 74, 442, and references
cited therein.
1
oil (72% yield). H NMR (CDCl3): δ = 3.61 (t, J = 9.2 Hz, 2 H),
1.35–1.32 (m, 2 H), 1.23–1.25 (m, 1 H), 1.16–1.11 (m, 2 H), 0.98
(d, J = 3.3 Hz, 18 H), 0.85 (t, J = 9.1 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 104.5, 63.2, 35.1, 25.2, 19.2, 18.2, 17.7, 13.9,
12.6 ppm.
[12] We followed the reaction in [D8]THF by NMR spectroscopy
and observed the formation of corresponding benzyl-ynol-
ethers 3Da, indicating that the aqueous media used in the
workup procedure is responsible of the hydrolysis to ether 5Da.
[13] Taking into account that the approach of the nucleophile
(H2O) must take place as indicated in Scheme 4 (the opposite
face is occupied by the lone electron pair at oxygen interacting
with the enriched π bond at the triple bond), the steric hin-
drance of the R group (tertiary Ͼ secondary Ͼ primary) could
also explain the higher stability of the tertiary ynol ethers.
[14] V. Nair, A. Augustine, T. D. Suja, Synthesis 2002, 2259–2265.
[15] H. Shimada, S. Kikuchi, S. Okuda, K. Haraguchi, H. Tanaka,
Tetrahedron 2009, 65, 6008–6016.
[16] a) C. J. Helal, P. A. Magriotis, E. J. Corey, J. Am. Chem. Soc.
1996, 118, 10938–10939; b) T. Kitamura, M. Kotani, Y. Fuji-
wara, Synthesis 1998, 1416–1418; c) R. K. Tykwinski, B. L.
Williamson, D. R. Fischer, P. J. Stang, A. M. Arif, J. Org.
Chem. 1993, 58, 5235–5237.
[17] F. Denonne, P. Seiler, F. Diederich, Helv. Chim. Acta 2003, 86,
3096.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data for compounds 3Aa–3Aj, 4Aa, 4Ca, 4Da,
5Aa, 5Ca, 5Da.
Acknowledgments
Financial support from the Spanish Government (grant number
CTQ-2012-12168) and the Madrid Local Government (CAM)
(grant number CS2009/PPQ-1634) is gratefully acknowledged. J. A.
thanks the Ministerio de Ciencia e Innovación (MICINN) for a
“Ramon y Cajal” contract. L. M. thanks Spanish Ministerio de
Educación y Ciencia (MEC) for a FPU fellowship.
[1] For the use of acetylene-ethoxide, see: a) J. F. Arens, Advances
in Organic Chemistry, Interscience Publishers, New York, 1960;
vol. 2, p. 117; b) M. Shindo, Tetrahedron 2007, 63, 10; c) L.
Brandsma, H. J. Bos, J. F. Arens, in: The Chemistry of Acetyl-
enes (Ed.: H. G. Viehe), Marcel Dekker, New York, 1969, p.
751; d) P J. Stang, P. J. V. V. Zhdankin, in: The Chemistry of
[18] P. Xie, Y. Xie, B. Quian, H. Zhou, C. Xia, H. Huang, J. Am.
Chem. Soc. 2012, 134, 9902.
[19] M. Meurillon, L. Chaloin, C. Périgaud, S. Peyrottes, Eur. J.
Org. Chem. 2011, 3794.
Received: March 15, 2013
Published Online: May 21, 2013
Eur. J. Org. Chem. 2013, 4405–4409
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4409