Highly efficient p-toluenesulfonic acid-catalyzed alcohol addition or hydration of unsymmetrical arylalkynes

Article abstract of DOI:10.1055/s-2004-831310

Under a catalytic amount of PTSA in aqueous or alcoholic media, activated unsymmetrical arylalkynes 1 undergo regioselective water or alcohol addition to afford successfully carbonyl compounds 2 in good to excellent yields. This new environmentally metal-free procedure, which afforded only Markovnikov adducts, is characterized by the mildness of acidic conditions and the excellent regio- and chemoselectivity.

Full text of DOI:10.1055/s-2004-831310

LETTER
2175
Highly Efficient p-Toluenesulfonic Acid-Catalyzed Alcohol Addition or
Hydration of Unsymmetrical Arylalkynes
p
-Toluenesulfonic
a
A
cid-Catal
t
yzed A
h
lcohol
A
ddit
a
ion naël Olivi, Emmanuel Thomas, Jean-François Peyrat, Mouâd Alami,* Jean-Daniel Brion
Laboratoire de Chimie Thérapeutique, BioCIS – CNRS (UMR 8076), Université Paris Sud XI, Faculté de Pharmacie, rue J. B. Clément
92296 Châtenay-Malabry Cedex, France
Fax +33(1)46835828; E-mail: mouad.alami@cep.u-psud.fr
Received 4 May 2004
activated unsymmetrical aryl-alkynes 1 in aqueous or al-
Abstract: Under a catalytic amount of PTSA in aqueous or alcohol-
coholic media. This new environmentally friendly proce-
dure, which allows the formation of the corresponding
ketones in good to excellent yields, is characterized by the
ic media, activated unsymmetrical arylalkynes 1 undergo regiose-
lective water or alcohol addition to afford successfully carbonyl
compounds 2 in good to excellent yields. This new environmentally
metal-free procedure, which afforded only Markovnikov adducts, is mildness of reaction conditions, inexpensive reactants and
characterized by the mildness of acidic conditions and the excellent
the excellent functional group tolerance.
regio- and chemoselectivity.
At first, we studied the p-toluenesulfonic acid-catalyzed
Key words: unsymmetrical arylalkyne, hydration, PTSA, ketone,
hydration of 3-(4-methoxyphenyl)prop-2-yn-1-ol (1a) as
alcohol addition, water
a model system. The required arylalkynes 1 were readily
prepared by Pd-catalyzed Sonogashira–Linstrumelle (SL)
coupling reaction.6 Substrate 1a, bearing a free hydroxyl
The direct addition of O-H bonds to alkynes, known as
group was chosen so as to illustrate the advantages of the
hydration, is one of the most simple and powerful tools to
use of PTSA in terms of yield, catalytic efficiency and
convert alkynes into carbonyl compounds.1 Toward this
chemoselectivity of the procedure in comparison with
end, a large number of metal-catalyzed methods has been
other literature conditions.4,5 Table 1 summarizes the re-
developed. The older catalyst was mercury(II) salt2 which
sults of these studies (Equation 1).
allows hydration of alkynes in very good yields. However,
the necessity of a stoichiometric amount of toxic mercu-
O
OR
O
OH
ry(II) and/or the strongly acidic conditions do not meet the
contemporary requirement against hazardous reagents. In
recent years, considerable effort has been expended to ex-
tend the hydration reaction to applications in fine chemi-
cals, and to use new metal-transition catalysts, including
Ru, Rh, Pd, Pt and Au.3 All these catalysts have been used
for the hydration of alkynes in moderate to good yields,
however, the use of expensive metal-transition catalysts
limits the exploitation of these methods. Therefore, a met-
al-free hydration of alkynes has been developed under
acidic conditions4 including concentrated sulfuric acid,
formic acid and catalytic Brønsted acid such as trifluo-
romethanesulfonic acid or trifluoromethanesulfonimide.5
While these reactions are suitable methods in the case of
robust substrates, many of them either require harsh con-
ditions (large excess of strong acid, long reaction times) or
are particularly limited to terminal alkynes and/or display
low selectivity when sensitive functional groups are
present on the alkynes. To perform selective hydration of
alkyne compounds on functionalized fragile substrates,
the discovery and development of environmentally
friendly procedures remain as intriguing challenges.
MeO
MeO
a: R = H
MeO
2
3
1a
b: R = Et
c: R = CHO
Equation 1
Table 1 Effect of Acid Mediated Hydration of Arylalkyne 1a
Entry Reactants
Yield Product
(%)a
1
2
3
4
5
6
PTSA (20 mol%), H2O,b 100 °C, 12 h
75
2a
2b
2b
PTSA (20 mol%), EtOH,c 78 °C, 5 h
CH3SO3H (20 mol%), EtOH,c 78 °C, 18 h
CF3COOH (30 mol%), EtOH,c 78 °C
HCOOH, 100 °C, 5 h
94
85
d
0
–
50e
60e
2c
3
CF3SO3H (20 mol%), H2Ob–dioxane,
100 °C, 4 h
e
7
H2SO4 (65%), 20 °C, 2 h
0
–
We report herein a metal-free procedure for the synthesis
of carbonyl compounds which involves an efficient p-tol- a Yield of isolated product.
b Deionized water was used.
uenesulfonic acid-catalyzed water or alcohol addition to
c Commercially absolute EtOH was used.
d Exclusively starting material was recovered.
e No starting material was recovered.
SYNLETT 2004, No. 12, pp 2175–2179
0
1
.1
0
.2
0
0
4
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831310; Art ID: G16604ST
© Georg Thieme Verlag Stuttgart · New York

2176
N. Olivi et al.
LETTER
The use of PTSA monohydrate (20 mol%) in water allows 1c bearing longer alkynol chains (entries 1 and 2). The lat-
hydration of 1a in a 75% isolated yield; the reaction was ter reacts more slowly as 36 hours are required to achieve
completed within twelve hours at 100 °C (Table 1, entry complete conversion of the substrate. More importantly,
1). Since the water adds to the triple bond in accordance etherification of the free hydroxyl group is not observed in
with Markovnikov’s rule, 4-hydroxy-1-(4-methoxyphe- this case. Another arylalkyne, 1d, bearing para electron-
nyl)-1-propan-1-one (2a) was obtained as the only prod- donating groups such as amine, leads to similar results
uct in this reaction. Performing the reaction of 1a in (entry 3). The reaction was also successful from unsym-
ethanolic media assisted both etherification of free hy- metrical arylalkyne 1e, which contains a hexynyl side
droxyl group and carbonyl formation producing carbonyl chain (entry 4); the yield of the corresponding ketone 2g
ether compound 2b in an excellent isolated yield (94%, remains high, although a longer reaction time was needed.
entry 2). Changing the catalyst from PTSA to methane- Reaction from arylalkyne 1f having a secondary propar-
sulfonic acid resulted in a similar yield but in longer reac- gylic alcohol provided the expected carbonyl ether 2h in
tion times (entry 3), whereas no reaction occurred in the an excellent isolated yield (91%, entry 5). Under these
presence of trifluoroacetic acid (entry 4). It should be not- conditions, tertiary propargyl alcohol 1g leads in 73%
ed that the presence of PTSA catalyst is essential in aque- yield to the corresponding conjugated ketone 2i, well
ous or ethanolic media. In its absence no reaction has been known as the Rupe’s rearrangement8 adduct (entry 6).
observed. With formic acid as a solvent according to the
As shown in Table 2, the reaction rate proved to be depen-
dent significantly on the steric and electronic nature of the
substrate. Thus, arylalkynes 1h and 1i bearing in the ortho
position of the aromatic ring an electron-donating substit-
conditions described by Shvo,4c,d alkyne 1a undergoes af-
ter hydrolysis both hydration and formylation of the alco-
hol function and produced the corresponding ketone 2c in
only 50% yield (entry 5). The use of trifluoromethane-
uent such as a methoxy group reacted as well and pro-
sulfonic acid (20 mol%) under the recent report of
duced the corresponding ketones in good yields (entries 7
Shirakawa’s conditions5 resulted in hydration of 1a fol-
and 8). Owing to their bulkiness, they require, however,
longer reaction times and in the case of 1i, 1.2 equivalents
lowed by elimination of water to give exclusively unsat-
urated ketone 3 in 60% yield (entry 6). Finally, when
of PTSA are needed to achieve complete conversion of 1i.
performing the hydration of 1a in the presence of sulfuric
However, no reaction was observed from arylalkynes 1j
and 1k as well as from terminal alkyne 1l where the phe-
acid4a no carbonyl compounds could be detected in the re-
sulting crude polymers mixture (entry 7). Thus, the results
nyl ring is not activated by an electron-donating group in
of Table 1 unambiguously demonstrate that the use of
the ortho or para position (entries 9–11). Finally, unsym-
metrical diarylalkynes such as 1m leads regioselectively
to the formation of ketone 2o in which the carbonyl func-
tion was proximal to the electron-rich phenyl ring (entry
PTSA in the hydration of arylalkynol compounds com-
pares favorably with the previous acid mediated hydration
reaction.
We next investigated the scope and limitations of this new 12).
friendly reaction using various kinds of unsymmetrical
arylalkynes 1. As shown in Table 2, the PTSA-catalyzed
reaction is also effective in the case of arylalkynes 1b and
Table 2 PTSA-Catalyzed Synthesis of Various Carbonyl Compounds
Entry
Alkyne 1a
Solventb
Time
Product 2c
Yieldd
(%)
Temp
1
EtOH
24 h
78 °C
85
90
78
O
HO
OMe
EtO
1b
OMe
2d
2
3
EtOH
36 h
78 °C
O
O
HO
OMe
HO
4
1c
OMe
NH2
2e
EtOH
6 h
78 °C
HO
NH2
HO
4
1d
2f
Synlett 2004, No. 12, 2175–2179 © Thieme Stuttgart · New York

LETTER
p-Toluenesulfonic Acid-Catalyzed Alcohol Addition
2177
Table 2 PTSA-Catalyzed Synthesis of Various Carbonyl Compounds (continued)
Entry
4
Alkyne 1a
Solventb
Time
Temp
Product 2c
Yieldd
(%)
EtOH
60 h
81
O
C4H9
OMe
78 °C
1e
OMe
2g
5
6
7
8
EtOH
24 h
78 °C
91
73
73
80e
EtO
O
O
HO
OMe
OMe
1f
OMe
OMe
2h
EtOH
10 h
78 °C
HO
1g
2i
EtOH
144 h
78 °C
HO
O
EtO
2j
MeO
MeO
1h
EtOH
144 h
78 °C
O
C4H9
MeO
MeO
O
1i
2k
EtO
2l
9
10
11
12
EtOH
72 h
78 °C
0f
0f
HO
OMe
OMe
1j
EtOH
72 h
78 °C
HO
O
EtO
1k
1l
2m
O
EtOH
72 h
78 °C
0f
2n
EtOH
72 h
78 °C
80
O
O
O
OMe
1m
OMe
OMe
OMe
2o
13
14
15
MeOH
6 h
65 °C
98
66
33
HO
1a
OMe
OMe
OMe
MeO
2p
i-PrOH
7 h
82 °C
HO
1a
i-PrO
2q
HO
1a
HO
O
OH
HO
O
17 h
100 °C
OMe
2r
Synlett 2004, No. 12, 2175–2179 © Thieme Stuttgart · New York

2178
N. Olivi et al.
LETTER
Table 2 PTSA-Catalyzed Synthesis of Various Carbonyl Compounds (continued)
Entry
16
Alkyne 1a
Solventb
Time
Temp
Product 2c
Yieldd
(%)
EtOH
8 h
100 °C
90
79
73
O
MeO
OMe
EtO
2b
HO
2s
1n
OMe
17
18
H2Og
8 h
100 °C
HO
O
OH
1o
OH
H2Og
12 h
100 °C
HO
O
HO
2t
HO
HO
1p
a Prepared according to ref.6
b Commercially absolute EtOH was used as a solvent.
c All new compounds exhibited satisfactory spectral properties. For a general procedure, see ref.7
d Isolated yield.
e 1.2 equiv of PTSA were used.
f In the presence of a catalytic or a slight excess (1.2 equiv) of PTSA, exclusively starting material was recovered.
g Deionized water was used.
As the etherification process keeps an unexpected result in mediate formation, keeping free hydroxyl group
this new procedure, we managed to study the relation be- unchanged.
tween solvent and etherification reaction. In alcoholic me-
The ketone formation from substrates 1e, 1i and 1m
dia such as methanol or 2-propanol (entries 13 and 14) the
would also result from alcoholic media addition and sub-
ether derivatives 2p and 2q corresponding to the solvent
sequent enol ether species hydrolysis. To support this as-
sumption an experiment was carried out. When
performing the PTSA-catalyzed reaction from 1e in
methanolic or ethanolic media, attempts isolation of enol
used were formed in 98% and 66% yields, respectively,
whereas, in ethylene glycol mono-etherification occurs
smoothly and the ketone 2r was obtained in moderate
yield (33%, entry 15). Moreover, The PTSA-catalyzed re-
ether intermediate before hydrolysis were unsuccessful.
action from arylalkyne 1n bearing a methyl ether function
However, when 2-propanol was used as solvent the corre-
sponding enol ether adduct was isolated together with the
carbonyl derivative 2g.
resulted in a trans-etherification process furnishing the
ethyl ether derivative 2b in 90% yield (entry 16). Finally,
several attempts were made in water to avoid etherifica-
The requirement for an electron-donating substituent in
tion process. Under these conditions, hydration reactions
the aryl ring imparts additional chemoselectivity to this
occurred efficiently in good yields and free hydroxyl
new procedure and must especially underlined. Thus, ter-
group remained unchanged (entries 17 and 18).
minal alkynes as well as aliphatic and non-activated aryl-
According to these results (entries 1, 5, 7, 13–18), it seems
alkynes did not react under the reaction conditions used
that the PTSA-catalyzed reaction was clearly hetero atom-
before. Three examples of selective PTSA-catalyzed reac-
assisted. Substrates having a propargylic or homopropar-
tions of functionalized unsymmetrical arylalkynes 4 are
gylic function could provide a four or a five membered cy-
depicted below (Equation 2).
clic oxonium intermediate II which could result from an
intramolecular oxygen atom-addition (Scheme 1). Further
R1O
nucleophilic ring-opening by alcoholic or aqueous media
gives after hydrolysis the carbonyl compound. The forma-
tion of the intermediate II in this PTSA-catalyzed reaction
was either supported by ether formation (entries 1, 5, 7,
13–15) and trans-etherification process (entry 16). We
can notice that from substrates 1c and 1d having longer
alkynol chain (n = 4, entries 2, 3) direct alcoholic media
addition9 on I is preferred in comparison with thermody-
namically disfavored 7-membered cyclic oxonium inter-
OR1
H+
n
RO
RO
C
n
H
I
R1
O
R2OH
then
O
RO
RO
OR2
n
n
hydrolysis
II
n = 1, 2 R = H, Me
R1, R2 = H, Me, Et
Scheme 1 Proposed mechanism for the PTSA-catalyzed reaction
Synlett 2004, No. 12, 2175–2179 © Thieme Stuttgart · New York

LETTER
p-Toluenesulfonic Acid-Catalyzed Alcohol Addition
W. C.; Jennings, P. W. J. Org. Chem. 1993, 58, 7613.
2179
HO
R
PTSA 20 mol%
O
(h) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997,
62, 669. (i) Israelsohn, O.; Vollhardt, K. P. C.; Blum, J. J.
Mol. Catal. A: Chem. 2002, 184, 1. (j) Fukuda, Y.; Utimoto,
K. J. Org. Chem. 1991, 56, 3729. (k) Mizushima, E.; Sato,
K.; Hayashi, T.; Tanaka, M. Angew. Chem. Int. Ed. 2002,
41, 4563. (l) Vasudevan, A.; Verzal, M. K. Synlett 2004,
631. (m) Damiano, J. P.; Postel, M. J. Organomet. Chem.
1996, 522, 303.
EtOH, 78 °C, 12 h
O
4
EtO
O
5
R
a: R = H
b: R = C5H11
c: R = C6H5
82%
78%
76%
(4) (a) Smith, J. M. Jr.; Stewart, H. W.; Roth, B.; Northey, E. H.
J. Am. Chem. Soc. 1948, 70, 3997. (b) Allen, A. D.; Chiang,
Y.; Kresge, A. J.; Tidwell, T. T. J. Org. Chem. 1982, 47,
775. (c) Menashe, N.; Reshef, D.; Shvo, Y. J. Org. Chem.
1991, 56, 2912. (d) Menashe, N.; Shvo, Y. J. Org. Chem.
1993, 58, 7434.
(5) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y.
Synlett 2000, 1777.
(6) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403.
(7) Typical Procedure for the PTSA-Catalyzed Hydration of
Unsymmetrical Arylalkynes: To a stirred solution of 1a
(162 mg, 1 mmol) in 2 mL of absolute EtOH, was added
pTSA monohydrate (38 mg, 0.2 mmol). The mixture was
heated at reflux for 5 h, diluted with H2O and extracted with
EtOAc. The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. After removal of the
solvent under vacuo, the crude product was purified by
column chromatography on silica gel (CH2Cl2) to afford 196
mg (94%) of 2b as a yellow oil. 3-Ethoxy-1-(4-methoxy-
phenyl)propan-1-one (2b): 1H NMR (270 MHz, CDCl3):
d = 7.89 (2 H, d, J = 8.9 Hz), 6.87 (2 H, d, J = 8.9 Hz), 3.79
(2 H, t, J = 6.8 Hz), 3.78 (3 H, s), 3.47 (2 H, q, J = 7.0 Hz),
3.14 (2 H, t, J = 6.7 Hz), 1.14 (3 H, t, J = 7.0 Hz). 13C NMR
(67.5 MHz, CDCl3): d = 196.7, 163.3, 130.2, 130.0, 113.5,
66.3, 65.8, 55.2, 38.4, 14.9. 1-(4-Aminophenyl)-6-
hydroxyhexan-1-one (2f): 1H NMR (270 MHz, CD3OD):
d = 7.75 (2 H, d, J = 8.8 Hz), 6.63 (2 H, d, J = 8.8 Hz), 3.55
(2 H, t, J = 6.4 Hz), 2.87 (2 H, t, J = 7.6 Hz), 1.80–1.20 (6 H,
m). 13C NMR (67.5 MHz, CD3OD): d = 201.5, 153.6, 132.1,
126.8, 114.3, 62.3, 38.6, 33.5, 26.7, 26.1. 1-(2-
Equation 2
In conclusion, a novel and reliable procedure for the syn-
thesis of aromatic ketones was achieved via p-toluene-
sulfonic acid-catalyzed reaction of unsymmetrical
arylalkynes in alcoholic or aqueous media. This mild and
selective protocol allows the alcohol addition or the hy-
dration reaction to occur in the presence of free hydroxyl
group and non-activated carbon-carbon triple bond, which
is a valuable advantage over previously reported methods.
Further investigation of the scope and synthetic applica-
tion of this environmentally friendly procedure is under
way and will be reported in due course.
Acknowledgment
The CNRS is gratefully thanked for support of this research and for
a doctoral fellowship to N.O. We also thank ADIR (Servier Group)
for a doctoral fellowship to E.T.
References
(1) (a) Hudrlik, P. F.; Hudrlik, A. M. The Chemistry of Carbon-
Carbon Triple Bond, Part I; John Wiley and Sons: New
York, 1978. (b) Larock, L. C.; Leong, W. W. In
Comprehensive Organic Synthesis, Vol. 4; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 269.
(2) (a) Kagan, H. B.; Marquett, A.; Jacques, J. Bull. Soc. Chim.
Fr. 1960, 1979. (b) Budde, W. L.; Dessy, R. E. J. Am. Chem.
Soc. 1963, 85, 3964. (c) Olah, G. A.; Meidar, D. Synthesis
1978, 671. (d) Matsuo, K.; Urabe, K.; Izumi, Y. Chem. Lett.
1981, 1315. (e) Amiet, G.; Hügel, H. M.; Nurlawis, F.
Synlett 2002, 495. (f) Nishizawa, M.; Skwarczynski, M.;
Imagawa, H.; Sugihara, T. Chem. Lett. 2002, 12.
(3) (a) Tokunaga, M.; Wakatsuki, Y. Angew. Chem. Int. Ed.
1998, 37, 2867. (b) Alavarez, P.; Basetti, M.; Gimeno, J.;
Mancini, G. Tetrahedron Lett. 2001, 42, 8467. (c) Taqui
Khan, M. M.; Halligudi, S. B.; Shukla, S. J. Mol. Catal.
1990, 58, 299. (d) Setty-Fichman, M.; Sasson, Y.; Blum, J.
J. Mol. Catal. A: Chem. 1997, 126, 27. (e) Pal, M.;
Methoxyphenyl)hexan-1-one (2k): 1H NMR (270 MHz,
CDCl3): d = 7.61 (1 H, dd, J = 7.6 Hz, J = 1.8 Hz), 7.45–
7.30 (1 H, m), 7.00–6.85 (2 H, m), 3.84 (3 H, s), 2.92 (2 H,
t, J = 7.5 Hz), 1.75–1.55 (2 H, m), 1.35–1.25 (4 H, m), 0.87
(3 H, t, J = 6.9 Hz). 13C NMR (67.5 MHz, CDCl3):
d = 202.9, 158.1, 132.8, 129.9, 128.7, 120.4, 111.4, 55.2,
43.5, 31.4, 23.9, 22.3, 13.7.
(8) For a review see: Swaminathan, S.; Narayanan, K. V. Chem.
Rev. 1971, 71, 429.
(9) (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett.
1999, 40, 6193. (b) Hartman, J. W.; Sperry, L. Tetrahedron
Lett. 2004, 45, 3787. (c) For a review, see: Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett
2002, 1976. (f) Hiscox, W.; Jennings, P. W.
Organometallics 1990, 9, 1997. (g) Hartman, J. W.; Hiscox,
Synlett 2004, No. 12, 2175–2179 © Thieme Stuttgart · New York