Al(OTf)3: An efficient recyclable catalyst for direct nucleophilic substitution of the hydroxy group of propargylic alcohols with carbon- and heteroatom-centered nucleophiles to construct C-C, C-O, C-N and C-S bonds

Article abstract of DOI:10.1016/j.tetlet.2011.12.060

A general and highly efficient Al(OTf)₃-catalyzed methodology has been developed for the direct nucleophilic substitution of the hydroxy group in propargylic alcohols with a variety of carbon- and heteroatom-centered nucleophiles such as alcohols, aromatic compounds, amides, and thiols, leading to the construction of C-C, C-O, C-N and C-S bonds.

Full text of DOI:10.1016/j.tetlet.2011.12.060

Tetrahedron Letters 53 (2012) 1048–1050
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Al(OTf)3: an efficient recyclable catalyst for direct nucleophilic substitution
of the hydroxy group of propargylic alcohols with carbon- and
heteroatom-centered nucleophiles to construct C–C, C–O, C–N and C–S bonds
⇑
Mukut Gohain, Charlene Marais, Barend C.B. Bezuidenhoudt
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and highly efficient Al(OTf)3-catalyzed methodology has been developed for the direct nucle-
ophilic substitution of the hydroxy group in propargylic alcohols with a variety of carbon- and hetero-
atom-centered nucleophiles such as alcohols, aromatic compounds, amides, and thiols, leading to the
construction of C–C, C–O, C–N and C–S bonds.
Received 14 September 2011
Revised 6 December 2011
Accepted 16 December 2011
Available online 23 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aluminum triflate
Propargylic alcohols
Nucleophiles
Regioselectivity
The substitution of the hydroxy group of an alcohol by a nucle-
ophile is an important process in organic chemistry for the con-
struction of C–C or carbon–heteroatom bonds.1 Substitution of
the hydroxy group of propargylic alcohols by nucleophiles, in par-
ticular, gives access to functionalized alkynes which can be readily
converted into a variety of other functional groups.2 As a result of
the wide synthetic applicability associated with the alkyne func-
tional group, the propargylic alcohol substitution reaction has
played a major role in organic synthesis. In this regard, the most
useful methodologies are based on transition metal,3 Lewis4 and
Brønsted acid5 catalyzed/mediated substitution reactions. Many
of these and other methods6 are, however, hampered by the cost
and availability of the catalysts, excessive catalyst loading and/or
limited nucleophile applicability. While a few catalyst systems
(FeCl3 in CH3CN, MoCl5 in CH2Cl2, and phosphomolybdic acid on
silica) have been reported for propargylic alcohol substitution
reactions in good yields,7 none of these methods allow for C–C
bond formation. In view of the synthetic importance of these prop-
argylic synthons, the development of a general and convenient
method for their synthesis is desired.
heteroatom-centered nucleophiles with propargylic alcohols were
reported by Huang et al.,10 whereas Noji et al.11 disclosed novel lan-
thanoid, scandium, and hafnium triflate catalyzed direct substitu-
tions of benzyl alcohols with nucleophiles. All of these, however,
contain expensive metal ions. On the other hand, aluminum triflate
[Al(OTf)3], which has been utilized in various organic transforma-
tions,12 not only contains a readily available cheap metal ion, but
is also reusable and therefore represents a desirable catalyst from
an environmental point of view. To the best of our knowledge,
Al(OTf)3-catalyzed direct nucleophilic substitution of propargylic
hydroxy groups by nucleophiles has not been reported to date. In
this Letter, we disclose our results on the Al(OTf)3-catalyzed direct
substitution of propargylic hydroxy groups with various aromatic
and heteroatomic nucleophiles to afford the corresponding products
in excellent yields (Table 1). Furthermore, water is the only side
product from the reaction.
At first we investigated the Al(OTf)3-catalyzed coupling reaction
of diphenylpropargyl alcohol (1a) with benzyl alcohol (2a) as the
nucleophile (Table 1, entry 1). We were pleased to find that
0.5 mol % of Al(OTf)3 in acetonitrile at 60 °C produced the corre-
sponding propargylic ether 3aa in excellent yield.13 Increased
amounts of catalyst failed to improve the yield, while decreasing
the amount of catalyst had a negative impact on the yield, so a cat-
alyst concentration of 0.5 mol % was optimal. Extending the reac-
tion to alcohols such as methanol (2b) and ethanol (2c) also led
to excellent yields of ethers 3ab and 3ac (Table 1, entries 2 and
3). In all the cases, the reaction proceeded smoothly without taking
any precautions to exclude moisture or air from the reaction
mixture.
Metal triflates have received wide attention for their role as Lewis
acids in a number of reactions.8 Examples such as Bi(OTf)3, Sc(OTf)3
and Yb(OTf)3 in ionic liquids have been used successfully for the
propargylation of arenes and the synthesis of propargylic ethers.9
Ytterbium triflate catalyzed propargylations of carbon- and
⇑
Corresponding author. Tel.: +27 51 4019021; fax: +27 51 4446384.
E-mail address: bezuidbc@ufs.ac.za (B.C.B. Bezuidenhoudt).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.060

M. Gohain et al. / Tetrahedron Letters 53 (2012) 1048–1050
1049
Table 1
Substitution of the hydroxy group in propargylic alcohols with various nucleophilesa
Nu
OH
Al(OTf)3
CH3CN
R1
+
Nu-H
R1
3
+
H2O
R2
R2
2
1
1a R1 = R2 = Ph
1b R1 = Ph,
2a PhCH2OH 2h PhCONH2
2b MeOH
2c EtOH
2i PhSO2NH2
R2 = nC4H9
2j p-MeC6H4SO2NH2
2k p-NO2C6H4NH2
2l PhSH
1c R1 = p-MeOC6H4,
R2 = Ph
2d PhOH
2e PhOMe
2f thiophene
2g pyrrole
1d R1 = p-ClC6H4,
R2 = Ph
2m PhCH2SH
Entry
Alcohol
NuH
Time (min)
Productb
Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2a
2j
2e
2j
60
60
80
120
120
40
3aa4a
3ab4a
3ac4a
3ad9
3ae4c
3af3i
3ag9
92
92c
90c
92
92
90d
92d
85
89
95
85e
90
93
90
89
93
94
90
94
30
100
390
180
180
150
60
260
220
30
3ah4c
3ai5a
3aj3n
3ak9
3al3d
3am6b
3ba6a
3bj3k
3ce6c
3cj6d
3de3n
3dj
9
10
11
12
13
14
15
16
17
18
19
120
150
240
2e
2j
a
b
c
Substrates in equimolar amounts, Al(OTf)3 (0.5 mol %), CH3CN, 60 °C unless specified differently.
References to full analytical data for known compounds.
2.5 equiv of alcohol was required to achieve maximum conversion.
Substrates in equimolar amounts, Al(OTf)3 (0.5 mol %), CH3CN, room temperature.
Substrates in equimolar amounts, Al(OTf)3 (2.5 mol %), CH3CN, 80 °C.
d
e
When phenol (2d), anisole (2e), thiophene (2f), and pyrrole (2g)
were used as nucleophiles, the corresponding C-substituted prod-
ucts were obtained in excellent yields (Table 1, entries 4–7). While
a reaction temperature of 60 °C was required for acceptable rates
in the case of anisole (2e) and phenol (2d), reactions with the more
nucleophilic reagents, thiophene (2f) and pyrrole (2g), could be run
at room temperature. For all these nucleophiles (2d–2g), substitu-
tion involved regioselective attack by the aromatic carbon with the
highest electron density, that is, C-4 for phenol and anisole and C-2
for thiophene and pyrrole.
Subsequent extension of the reaction to include amides such as
benzamide (2h), benzenesulfonamide (2i) and p-tolyl-sulfonamide
(2j) led to the formation of C–N bonds with the corresponding prod-
ucts being obtained in excellent yields using the optimized reaction
conditions (Table 1, entries 8–10). Surprisingly, the reaction of ani-
line with alkynol (1a) was unsuccessful. However, aromatic amines
having electron-withdrawing substituents, such as 4-nitroaniline
(2k), could be reacted with the alkynol in the presence of a slight
excess of the catalyst (2.5 mol %) to give the secondary propargylic
amine (3ak) in high yield (Table 1, entry 11). Finally, the reactions
of thiophenol (2l) and benzyl mercaptan (2m) with propargylic
alcohol (1a) gave the corresponding thioethers 3al and 3am in
excellent yields through the application of the previously optimized
reaction conditions (Table 1, entries 12 and 13).
(Table 1, entries 16 and 17 vs 5 and 10, respectively), while elec-
tron-withdrawing substituents in the same position slowed down
the substitution process (Table 1, entries 18 and 19 vs 5 and 10,
respectively). When the terminal aromatic ring of the alkyne was
replaced by an aliphatic group as in 1b, excellent product yields
could still be obtained at acceptable rates (Table 1, entries 14
and 15).
Since the reusability of catalysts is an important factor from
both an economical and environmental point of view, this topic
has attracted wide attention in recent years. To check this aspect
of the Al(OTf)3 catalyst, it was recovered after completion of some
of the reactions (TLC) by adding a mixture of ethyl acetate and
water (1:1, v/v; 10 mL) to the reaction mixture and stirring for five
minutes. The water layer was subsequently concentrated in vacuo
at an elevated temperature14 and the catalyst reused. The recov-
ered catalyst could be successfully recycled 3 times in this way
with only minimal loss of efficiency (Table 2).
In summary, Al(OTf)3 was found to be an effective and recycla-
ble Lewis acid catalyst in an improved, general and efficient meth-
od for the direct substitution of the hydroxy group of propargylic
Table 2
Reusability of the Al(OTf)3 catalyst
Entry
Product
1st Cycle
2nd Cycle
3rd Cycle
Electron-donating substituents at the para position of an aro-
matic ring located at the propargylic position were found to en-
hance the reactivity, thus increasing the rate of the reaction
1
2
3ae
3ak
92
85
92
85
90
84

1050
M. Gohain et al. / Tetrahedron Letters 53 (2012) 1048–1050
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:
{[(1-Phenyl-2-heptyn-1-yl)oxy]methyl}-benzene 3ba6a 1H NMR (600 MHz,
CDCl3) 7.59–7.49 (m, 2H), 7.47–7.29 (m, 8H), 5.24 (s, 1H), 4.72 (d,
d
J = 11.6 Hz, 1H), 4.67 (d, J = 11.6 Hz, 1H), 2.37–2.31 (m, 2H), 1.61–1.55 (m,
2H), 1.50–1.45 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) d
139.4, 138.1, 128.5, 128.4, 128.3, 128.2, 127.8, 127.6, 88.9, 77.8, 70.8, 69.8,
30.8, 22.1, 18.7, 13.7.
N-[1-(4-Chlorophenyl)-3-phenyl-2-propyn-1-yl]-4-methylbenzene-sulfonamide
3dj: White solid; mp 199–200 °C; 1H NMR (600 MHz, CDCl3)
d 7.81 (d,
J = 8.1 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.5 Hz, 3H), 7.29–7.23 (m,
4H), 7.13(d, J = 7.3 Hz, 2H), 5.53 (d, J = 9.2 Hz, 1H), 5.06 (d, J = 9.2 Hz, 1H), 2.34
(s, 3H); 13C NMR (150 MHz, CDCl3) d 143.78, 137.13, 135.95, 134.43, 131.57,
129.64, 128.84, 128.78, 128.19, 127.52, 121.68, 87.02, 84.88, 49.22, 21.45;
HRMS (ES+) m/z calcd for C22H18NO2NaSCl [M+23]+ 418.0644, found 418.0641.
14. Williams, D. B. G.; Lawton, M. Tetrahedron Lett. 2006, 47, 6557–6560.
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