A Combination System of p -Toluenesulfonic Acid and Acetic Acid for the Hydration of Alkynes

Article abstract of DOI:10.1055/s-0035-1562779

A simple combination system of p-toluenesulfonic acid/acetic acid has been developed for efficient hydration of alkynes. The corresponding ketones can be obtained in good to excellent yields under mild conditions. The mechanism of the reaction was disclosed unambiguously which was a stepwise process (addition and then hydrolysis). Furthermore, this system was proved to be powerful that has the potential to be used to synthesize vinyl 4-methylbenzenesulfonates.

Full text of DOI:10.1055/s-0035-1562779

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
H. Liu et al.
Letter
Synlett
A Combination System of p-Toluenesulfonic Acid and Acetic Acid
for the Hydration of Alkynes
Haixuan Liu
Yunyang Wei
Chun Cai*
Powerful p-Toluenesulfonic Acid/Acetic Acid System!
O
TsOH•H2O, AcOH
CH2Cl2 or DCE, r.t. to 110 °C, 2.5–20 h
R2
R2
R1
R1
School of Chemical Engineering, Nanjing University
of Science and Technology, Xiaolingwei 200, Nanjing
210094, P. R. of China
17 examples
75–97% isolated yields
OTs
c.cai@njust.edu.cn
R2
R1
via
Received: 16.04.2016
Accepted after revision: 15.06.2016
Published online: 15.07.2016
tion-metal catalysts, Brønsted acids have advantages such
as economical, environmentally friendly (no metal contam-
ination), and easy handling (no need of inert atmosphere).
However, there are still deficiencies concerning the existing
protocols, such as long reaction time, high temperature, and
limited substrate scope.
DOI: 10.1055/s-0035-1562779; Art ID: st-2016-w0263-l
Abstract A simple combination system of p-toluenesulfonic acid/ace-
tic acid has been developed for efficient hydration of alkynes. The cor-
responding ketones can be obtained in good to excellent yields under
mild conditions. The mechanism of the reaction was disclosed unam-
biguously which was a stepwise process (addition and then hydrolysis).
Furthermore, this system was proved to be powerful that has the po-
tential to be used to synthesize vinyl 4-methylbenzenesulfonates.
Based on the concept of combined acid catalysis,11 that
the acidity of weak Brønsted acid can be greatly enhanced
by combining with another Brønsted acid or Lewis acid,
Hammond, Xu, and coworkers12 developed a highly efficient
Ga(OTf)3/AcOH system for hydration of alkynes. Also in-
spired by the concept, and in order to find a practical, low
cost, and efficient metal-free system, herein we disclosed a
simple and cheap p-toluenesulfonic acid (PTSA)/acetic acid
protocol for alkyne hydration.13 This system can also be
used for the synthesis of vinyl 4-methylbenzenesulfonates.
Initially, phenylacetylene (1a) was chosen as the model
substrate to evaluate the reaction conditions for alkyne hy-
dration. At the beginning, using PTSA·H2O alone, acetophe-
none (2a) was obtained in 62% yield after 24 hours (Table 1,
entry 1). In order to accelerate the reaction and increase the
yield of 2a, combination system was examined. Acetic acid
was found to be able to significantly increase the reaction
rate and yield (Table 1, entries 2 and 3). One equivalent of
PTSA·H2O and 50 °C were needed to make the hydration re-
action occur smoothly (Table 1, entries 4 and 5).
Key words hydration, alkynes, ketones, hydrolysis, vinyl sulfonates
Hydration of alkynes, one of the most useful methods to
provide ketone substrates, has found wide applications in
laboratories and industries.1 For more than a century, this
transformation has aroused chemists’ interests due to its
convenience and atom economical features. Significant pio-
neering work by Berthelot2 reported in 1862 opened up this
area. However, the use of highly toxic mercury(II) salt ham-
pered its practical use and therefore suggests the discovery
of environmentally acceptable catalysts. Over the past sev-
eral decades, numerous transition-metal catalysts have
been developed, including gold,3 silver,4 copper,5 iron,6 plat-
inum,7 ruthenium,8 and others.9 At the same time, much ef-
forts have been made in terms of catalyst recycling, lower
catalyst loading, and broader substrate scope. For example,
using [(IPr)AuCl]/AgSbF6 as a catalyst, the effective catalyst
loading can be lowered to 0.001 mol% in hydration of 3-
hexanone.3g The AuSH/SO3H-PMO(Et) nanostructure, which
exhibits high catalytic activity in alkynes hydration, can be
easily recycled and used repetitively ten times without sig-
nificant loss of catalytic efficiency.3j
During our investigation, water was found to be able to
mediate the formation of 1-phenylvinyl 4-methylbenzene-
sulfonate (3a). Further exploration showed that 3a can be
formed in 51% yield in the absence of dichloromethane (Ta-
ble 1, entries 6–8). The reaction process was monitored at
one hour, and the results reveal that 2a and 3a can reach
equilibrium in the reaction mixture, which explain why 3a
was obtained in moderate yield (Table 1, entries 9 and 10).
Despite these achievements in metal-based Lewis acid
catalysts, solely Brønsted acids without metal salts have
been investigated in few reports.10 Compared with transi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
H. Liu et al.
Letter
Synlett
Table 1 Development of Optimized Reaction Conditionsa
O
OTs
TsOH•H2O, AcOH
CH2Cl2, temp, time
+
1a
2a
3a
Entry
PTSA·H2O (equiv)
AcOH (mL)
H2O (mL)
Solvent
Temp (°C)
Time (h)
Yield (%)b
2a
3a
1
2
1.0
1.0
1.0
1.0
0.5
1.0
1.0
1.5
1.0
1.5
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
50
50
50
r.t.
50
50
50
50
50
50
24
3
62
0
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
–
75
0
3
–
3
97 (95c)
90
0
4
–
24
3
0
5
–
68
0
6
0.2
0.2
0.2
0.2
0.2
3
6
7
7
3
46
51 (49)c
52
8
–
3
46
9d
10e
–
1
15
15
–
1
35
29
a Reaction conditions: 1a (1.0 mmol), PTSA·H2O (1.0 mmol), solvent (1.0 mL).
b Yields were determined by 1H NMR spectroscopy using CH2I2 as internal standard.
c Isolated yields after column chromatography.
d 63% of 1a remained.
e 34% of 1a remained.
With the optimized conditions for alkyne hydration (Ta-
ble 1, entry 3), we started to explore substrate scopes using
various alkynes. Terminal alkynes that possess electron-
rich aromatic rings could be converted into the correspond-
ing ketones under mild conditions in good yields (Table 2,
entries 1–5, 11). Notably, the hydration of these alkynes
could proceed at room temperature, but longer reaction
times were needed. For example, 4-methoxyphenylacety-
lene (1e) was converted into 4-methoxyacetophenone (2e)
in 95% yield at room temperature after 15 hours (Table 2,
entry 5). Halogen-substituted phenylacetylenes all under-
went the hydration reaction smoothly, including 4-fluoro-
phenylacetylene and 2-fluorophenylacetylene as well (Ta-
ble 2, entries 6–9). The phenylacetylene bearing electron-
withdrawing substituent (CF3) on the 4′-position of the aro-
matic ring was investigated and gave 96% yield of the ke-
tone product (Table 2, entry 10). Gratefully, the hydration of
internal alkynes also worked well under the present combi-
nation system, albeit longer reaction times were needed
and decreased yields were obtained compared with termi-
nal alkynes (Table 2, entries 12 and 13). In consideration of
operation convenience, DCE which has a higher boiling
point was examined to replace CH2Cl2 at high reaction tem-
perature (>100 °C). We were delighted that the reactions
went well in DCE, and the corresponding ketones were
formed in good yields (Table 2, entries 10, 12). The hydra-
tion of asymmetrical internal alkyne 1-phenyl-1-butyne
(1m) shows great Markovnikov regioselectivity. (Bro-
moethynyl)benzene (1n) was also investigated, and 2-bro-
mo-1-phenylethanone (2n) was formed in 73% yield. Alkyl
alkyne (1o) went through the hydration to give the corre-
sponding aliphatic ketone 2o in 92% yield (Table 2, entry
14). In order to further demonstrate the utility of this pro-
tocol in the hydration of alkyl alkynes, 1p and 1q were test-
ed, and the corresponding methyl ketones were obtained in
81% and 88% yields, respectively.
Given the good results found by present PTSA/AcOH
combination system, we are curious to inspect the reaction
process in detail. In hope of detecting any possible interme-
diates, we performed the hydration in deuterated solvent
(CD2Cl2) and monitored in durations by 1H NMR spectrosco-
py. The results are summarized in Figure 1. After ten min-
utes of reaction, the peaks (δ = 2.59 ppm) corresponding to
acetophenone can be seen. At the same time, new peaks ap-
peared at δ = 5.41 ppm and δ = 5.11 ppm which probably
ascribe to the formation of intermediate. This thought was
confirmed as the monitoring goes: first, the accumulation
of acetophenone can be seen, at the same time the interme-
diate exist during the process; second, when the reaction
finished after three hours, the peaks of phenylacetylene
(δ = 3.14 ppm) disappear and the peaks of intermediate
cannot be observed either.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
H. Liu et al.
Letter
Synlett
Table 2 Substrate Scope of Alkyne Hydration Reactiona
R2
TsOH•H2O (1.0 equiv), AcOH (0.5 mL)
CH2Cl2, r.t. to 110 °C, 2.5–20 h
O
R2
R1
R1
2a–q
1a–q
Entry
1
Alkynes 1
Ketones 2
Temp (°C)
50
Time (h)
Yield of 2 (%)b
2a 95
O
3
1a
1b
2a
2b
2c
2d
O
O
2
3
4
5
50
2.5
2b 97
50
3
2c 75
1c
O
50
3
2d 95
1d
O
50/r.t.
2.5/15
2e 95/95
MeO
1e
MeO
2e
O
6
7
8
9
50
80
80
80
2.5
2f 96
2g 80
2h 95
2i 94
F
F
2f
1f
O
F
8
F
1g
2g
O
15
Cl
1h
Cl
2h
O
7
Br
1i
Br
2i
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
H. Liu et al.
Letter
Synlett
Table 2 (continued)
Entry
Alkynes 1
Ketones 2
Temp (°C)
Time (h)
Yield of 2 (%)b
O
110
110
15
10
2j 96
10
11
2j 97d
F3C
1j
F3C
2j
O
50
3.5
2k 88
S
S
1k
2k
O
110
110
20
12
2l 75/20c
2l 95d
12
13
2l
1l
O
O
80
20
2m 87
1m
2m
Br
Br
14d
15e
16d
110
80
20
15
18
2n 73
2o 92
2p 81
2n
2o
1n
1o
O
O
O
O
O
100
O
2p
2q
1p
1q
O
17d
110
15
2q 88
a Standard reaction conditions: alkyne (1.0 mmol), PTSA·H2O (1.0 mmol), AcOH (0.5 mL), CH2Cl2 (1.0 mL).
b Isolated yields after column chromatography.
c Isolated yield of corresponding vinyl 4-methylbenzenesulfonate (3l) after column chromatography.
d DCE was used as solvent for high temperature (100 °C and 110 °C).
e GC–MS yield.
1
Based on the above monitoring and judged by H NMR
peaks recognition, we consider 1-phenylvinyl 4-methylben-
zenesulfonate (3a) is the intermediate. The low concentra-
tion of 3a during the reaction process suggests that the for-
mation of 3a is the rate-determining step of the hydration.
Under the optimized conditions (Table 1, entries 6–8),
3a can be formed using water as solvent, but is in equilibri-
um with acetophenone. In order to further demonstrate
that 3a is the intermediate in hydration of phenylacetylene,
3a was synthesized and treated with the standard condi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
H. Liu et al.
Letter
Synlett
nation of PTSA and AcOH functions as the real catalyst. Vi-
nyl 4-methylbenzenesulfonate (3) is formed via the addi-
tion reaction of PTSA with alkynes. Then, 3 is hydrolyzed to
enol product. Last, the enol quickly tautomerizes to 2.
OAc
H
TsOH
TsO
R1
O
Ts
R1
H
HO
R1
R2
H2O
R2
R2
3
1
O
R2
R1
2
Scheme 3 Postulated mechanism for the PTSA/AcOH-mediated hydra-
tion reaction
Under the guiding concept of Brønsted acid assisted
Brønsted acid (BBA), we have developed a combination sys-
tem of PTSA/AcOH for hydration of alkynes.15 The hydration
reaction is clean, efficient, and successful with both termi-
nal alkynes and internal alkynes. The reaction shows great
regioselectivity and the corresponding ketones can be ob-
tained in high yields which is comparable to the metal-cat-
alyzed system. The mechanisms were investigated and pre-
sented in detail. By varying the reaction conditions, vinyl 4-
methylbenzenesulfonates can be formed in moderate yield.
In summary, combination system of PTSA/AcOH is simple,
cost-effective, also powerful, and promising for future re-
search.
Figure 1 Monitor hydration of 1a using 1H NMR spectroscopy
O
OTs
TsOH•H2O (1.0 equiv), AcOH (0.5 mL)
CH2Cl2 (1 mL), 50 °C, 3 h
3a
1.0 mmol
2a
97% yield
Scheme 1 Conversion of 3a into acetophenone
tions (Scheme 1). We were delighted that 3a could be fully
converted into the ketone and 2a was isolated in high yield.
When the hydration of 1l was investigated, the corre-
sponding vinyl 4-methylbenzenesulfonate (3l) can be iso-
lated. Its structure is determined by comparing its melting
Acknowledgment
We thank the Project Funded by the Priority Academic Program De-
velopment of Jiangsu Higher Education Institutions (PAPD).
1
point, H NMR and 13C NMR spectra data with the litera-
ture.14 It was worth to mention that the hydration reaction
displays high stereoselectivity and that 3l was the only iso-
mer that can be detected and which finally leads to 2l. The
exclusive produce of 3l suggests a syn addition of PTSA
(Scheme 2).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562779.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
A mechanism for this combined acid-catalyzed alkyne
hydration reaction was postulated (Scheme 3). The combi-
OTs
O
TsOH•H2O (1.0 equiv), AcOH (0.5 mL)
CH2Cl2 (1 mL), 110 °C, 20 h
+
2l
75%
1l
3l
20%
1.0 mmol
Scheme 2 Hydration of 1l
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
H. Liu et al.
Letter
Synlett
References and Notes
(9) (a) Blum, J.; Huminer, H.; Alper, H. J. Mol. Catal. 1992, 75, 153.
(b) Meier, I. K.; Marsella, J. A. J. Mol. Catal. 1993, 78, 31. (c) Hu,
N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Tetrahedron Lett. 1986, 27,
6099. (d) Jin, X. J.; Oishi, T.; Yamaguchi, K.; Mizuno, N. Chem.
Eur. J. 2011, 17, 1261. (e) Hirabayashi, T.; Okimoto, Y.; Saito, A.;
Morita, M.; Sakaguchi, S.; Ishii, Y. Tetrahedron 2006, 62, 2231.
(10) (a) Allen, A. D.; Chiang, Y.; Kresge, A. J.; Tidwell, T. T. J. Org.
Chem. 1982, 47, 775. (b) Menashe, N.; Shvo, Y. J. Org. Chem.
1993, 58, 7434. (c) Tsuchimoto, T.; Joya, T.; Shirakawa, E.;
Kawakami, Y. Synlett 2000, 1777. (d) Kamiguchi, S.; Takahashi,
I.; Kondo, K.; Nagashima, S.; Kurokawa, H.; Miura, H.; Chihara, T.
J. Cluster Sci. 2007, 18, 845.
(1) Hintermann, L.; Labonne, A. Synthesis 2007, 1121.
(2) Berthelot, M. C. R. Hebd. Seances Acad. Sci. 1862, 50, 805.
(3) (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729. (b) Teles,
J. H.; Brode, S.; Chabanas, M. Angew. Chem. Int. Ed. 1998, 37,
1415. (c) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew.
Chem. Int. Ed. 2002, 41, 4563. (d) Casado, R.; Contel, M.; Laguna,
M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003, 125, 11925.
(e) Roembke, P.; Schmidbaur, H.; Cronje, S.; Raubenheimer, H.
J. Mol. Catal. A: Chem. 2004, 212, 35. (f) Vasudevan, A.; Verzal,
M. K. Synlett 2004, 631. (g) Marion, N.; Ramón, R. S.; Nolan, S. P.
J. Am. Chem. Soc. 2009, 131, 448. (h) Almássy, A.; Nagy, C. E.;
Bényei, A. C.; Joó, F. Organometallics 2010, 29, 2484. (i) Nun, P.;
Ramón, R. S.; Gaillard, S.; Nolan, S. P. J. Organomet. Chem. 2011,
696, 7. (j) Zhu, F. X.; Wang, W.; Li, H. X. J. Am. Chem. Soc. 2011,
133, 11632. (k) Tachinami, T.; Nishimura, T.; Ushimaru, R.;
Noyori, R.; Naka, H. J. Am. Chem. Soc. 2013, 135, 50. (l) Li, F.;
Wang, N. N.; Lu, L.; Zhu, G. J. J. Org. Chem. 2015, 80, 3538.
(m) Liang, S. Z.; Jasinski, J.; Hammond, G. B.; Xu, B. Org. Lett.
2015, 17, 162.
(4) (a) Thuong, M. B. T.; Mann, A.; Wagner, A. Chem. Commun. 2012,
48, 434. (b) Das, R.; Chakraborty, D. Appl. Organomet. Chem.
2012, 26, 722. (c) Venkateswara Rao, K. T.; Sai Prasad, P. S.;
Lingaiah, N. Green Chem. 2012, 14, 1507. (d) Chen, Z. W.; Ye, D.
N.; Qian, Y. P.; Ye, M.; Liu, L. X. Tetrahedron 2013, 69, 6116.
(e) Saha, S.; Sarbajna, A.; Bera, J. K. Tetrahedron Lett. 2014, 55,
1444.
(5) (a) Jha, M.; Shelke, G. M.; Pericherla, K.; Kumar, A. Tetrahedron
Lett. 2014, 55, 4814. (b) Hassam, M.; Li, W. S. Tetrahedron 2015,
71, 2719.
(11) Yamamoto, H.; Futatsugi, K. Angew. Chem. Int. Ed. 2005, 44,
1924.
(12) Liang, S. Z.; Hammond, G. B.; Xu, B. Chem. Commun. 2015, 51,
903.
(13) (a) During our preparation of the manuscript, a similar work
was published13b in which CF3SO3H/CF3CH2OH system was used
for hydration of alkynes. The reaction occurs well under 25 °C
or 70 °C and mostly 45 h was needed. The hydration reaction
can also occur well at 25 °C using our system, we used higher
temperature just in order to accelerate the reaction rate. (b) Liu,
W. B.; Wang, H.; Li, C.-J. Org. Lett. 2016, 18, 2184.
(14) (a) Cui, D. M.; Meng, Q.; Zheng, J. Z.; Zhang, C. Chem. Commun.
2009, 12, 1577. (b) Klapars, A.; Campos, K. R.; Chen, C. Y.;
Volante, R. P. Org. Lett. 2005, 7, 1185.
(15) General Procedures for Alkyne Hydration
The corresponding alkyne (1 mmol) was added to a solution of
PTSA·H2O (1 mmol, 0.190 g), AcOH (0.5 mL) in CH2Cl2 (1.0 mL).
The reaction was then sealed and stirred at the indicated tem-
perature (°C) and for the indicated amount of times (h) in Table
2. After completion, sat. aq NaHCO3 (10 mL) was added to
quench the reaction and then extracted with CH2Cl2 (3 × 10 mL).
The organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography to
give the pure product.
(6) (a) Damiano, J. P.; Postel, M. J. Organomet. Chem. 1996, 522, 303.
(b) Wu, X. F.; Bezier, D.; Darcel, C. Adv. Synth. Catal. 2009, 351,
367. (c) Park, J.; Yeon, J.; Lee, P. H.; Lee, K. Tetrahedron Lett.
2013, 54, 4414. (d) Bassetti, M.; Ciceri, S.; Lancia, F.; Pasquini, C.
Tetrahedron Lett. 2014, 55, 1608.
(7) (a) Hiscox, W.; Jennings, P. W. Organometallics 1990, 9, 1997.
(b) Hartman, J. W.; Hiscox, W. C.; Jennings, P. W. J. Org. Chem.
1993, 58, 7613. (c) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem.
1997, 62, 669. (d) Lucey, D. W.; Atwood, J. D. Organometallics
2002, 21, 2481.
Acetophenone (2a)
Colorless liquid; yield: 114 mg (95%). 1H NMR (500 MHz,
CDCl3): δ = 7.95 (d, J = 7.5 Hz, 2 H), 7.56–7.54 (m, 1 H), 7.46–
7.43 (m, 2 H), 2.59 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ =
198.18, 137.16, 133.12, 128.59, 128.33, 26.62.
(8) (a) Halpern, J.; James, B. R.; Kemp, A. L. W. J. Am. Chem. Soc.
1961, 83, 4097. (b) Tokunaga, M.; Wakatsuki, Y. Angew. Chem.
Int. Ed. 1998, 37, 2867. (c) Grotjahn, D. B.; Lev, D. A. J. Am. Chem.
Soc. 2004, 126, 12232. (d) Ackermann, L.; Kaspar, L. T. J. Org.
Chem. 2007, 72, 6149.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F