Efficient and mild Ytterbium(III)-catalyzed tosylation of alcohols

Article abstract of DOI:10.1055/s-2004-815998

Ytterbium(III) trifluoromethanesulfonate efficiently catalyzes the reaction of primary and secondary alcohols with toluenesulfonic acid anhydride to yield the alkyl tosylates in high yields. The reactions were carried out under neutral and mild conditions and product purification was easily achieved by means of short column chromatography.

Full text of DOI:10.1055/s-2004-815998

PAPER
885
Efficient and Mild Ytterbium(III)-Catalyzed Tosylation of Alcohols
Y
tterbium(III)
l
-Cataly
o
z
ed Tosylati
b
on of
A
lcoho
o
ls dan Comagic, Ralf Schirrmacher*
Institute of Nuclear Chemistry, University of Mainz , Fritz Strassmann-Weg 2, 55128 Mainz, Germany
E-mail: schirrmacher@mail.kernchemie.uni-mainz.de
Received 27 December 2003; revised 2 February 2004
investigated (Table 1). This water-tolerant reusable Lewis
acid catalyst has been applied in a wide variety of reac-
tions.11 The synthetic use of lanthanide(III) catalysts for a
ring opening in the aminolysis of epoxides and oxetanes
Abstract: Ytterbium(III) trifluoromethanesulfonate efficiently cat-
alyzes the reaction of primary and secondary alcohols with toluene-
sulfonic acid anhydride to yield the alkyl tosylates in high yields.
The reactions were carried out under neutral and mild conditions
and product purification was easily achieved by means of short col- has been reported.12,13 These applications led us to use the
umn chromatography.
oxophilicity of Yb(III) to polarize and weaken the oxy-
gen–sulfur bond making nucleophilic attacks of alcohols
easier.
Key words: ytterbium(III) trifluoromethanesulfonate, alcohols, ca-
talysis, tosylation, Lewis acids
To prove the general feasibility of this catalysis, primary
as well as sterically more challenging secondary alcohols
were reacted at room temperature with toluenesulfonic
acid anhydride in the presence of a catalytic amount of
Yb(OTf)3 (Scheme 1). In nearly every case, the corre-
sponding tosylates were obtained in an average yield of
80% after workup (Table 1). Although the reaction time
can be considered to be relatively long (between 5 and 24
h), in one case (entry 2) the reaction was complete after 10
minutes. An interesting observation was made in the reac-
tion of diphenylmethanol. The reaction was complete af-
ter 10 min and only one new spot could be detected on
TLC which was identified to be the bis(diphenylmethyl)
ether exclusively. We presume that the nucleophilic char-
acter of the hydroxy moiety and the highly reactive elec-
trophilic tosylate might be responsible for the exclusive
formation of the ether compound. As an intermediate
which could however not be detected, the tosylate must
have been formed previously to allow further reaction. It
is also possible that the tosylate dissociated immediately
to form a highly reactive carbocation, which reacted with
the alcohol present. Another explanation would be that yt-
terbium(III) facilitates the formation of ethers and alkenes
when alcohols were used as reactants, which has been re-
ported for bismuth(III) halides.14 Thus, the reaction was
carried out without adding toluene sulfonic acid anhy-
The development of mild and efficient methods for the to-
sylation of alcohols is constantly receiving attention due
to the fact that tosylates are among the most common
leaving groups in organic synthesis. Most methods use tri-
ethylamine or pyridine as a base in the reaction of appro-
priate alcohols with tosylating agents.1 Other methods
involve aqueous sodium hydroxide,2 ring opening of dibu-
tylstannylene acetal,3 tetramethylalkyldiamine4 as a base,
silver(I) oxide,5 DMAP,6 zinc tosylate in a Mitsunobu
type reaction,7 1-(p-toluenesulfonyl)-3-methylimidazoli-
um triflate8 and DABCO.9 Most recently, cobalt(II)-cata-
lyzed tosylation of alcohols with p-toluenesulfonic acid
has been reported which displayed chemoselective tosyla-
tion of secondary alcohols in the presence of primary hy-
droxy groups.10 Special problems arise when tosyl
chloride/pyridine is used which is present in excess (10
equiv) and can facilitate side reactions in more complex
compounds. This problem can be solved by using DAB-
CO and tosyl chloride without adding an additional base
such as pyridine. The amount of DABCO in the tosylation
of alcohols can be lowered to 1.0–2.0 equivalents without
significant loss in yield although the amount of tosyl
chloride is reduced to 1.0–1.5 equivalents.9
The most important drawback, however, is the concomi-
tant loss of the tosylates into their chlorides, often ob-
served during the tosylation due to formation of
pyridine·HCl as a source of nucleophilic chloride. We ob-
served this unwanted side reaction in the synthesis of a to-
sylated D2-receptor ligand 2 where the chlorination
became the predominant reaction pathway and the yield of
the tosylated product 2 was relatively low.
Ts2O/
Yb(OTf)3
R-OH
R-OTs
CH2Cl2, rt
R-OH = primary, secondary alcohol
O
O
O
O
Ts2O/
In search for milder conditions, the catalytic effect of yt-
terbium(III) trifluoromethanesulfonate [Yb(OTf)3] as a
catalyst for the tosylation of a variety of primary and sec-
ondary alcohols with toluene sulfonic acid anhydride was
Yb(III)(OTf)3
N
H
N
H
N
CH2Cl2, rt
N
SYNTHESIS 2004, No. 6, pp 0885–0888
Advanced online publication: 04.03.2004
x
x
.
x
x
.2
0
0
4
TsO
85 %
2
1
HO
DOI: 10.1055/s-2004-815998; Art ID: T12803SS.pdf
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

886
S. Comagic, R. Schirrmacher
PAPER
dride to show whether the formation of the ether depends dride were used, only the ditosylated product was formed
on the intermediate formation of the tosylates. Even after (monitored by TLC). It should be mentioned that tosyla-
heating the reaction mixture at higher temperatures for 10 tion reactions of entries 2–7 and 9–13 however work fine
hours, no formation of the ether or additional products applying the combination of pyridine/tosyl chloride(for
could be observed (TLC control).
references cf. Table 1) and Yb(III) catalysis can be con-
sidered as an alternative under neutral conditions. In the
case of benzyl alcohol (entry 8) using pyridine/tosyl
chloridegave unsatisfactory yields of 38% only. Under
Co(II) catalysis the tosylate of benzyl alcohol was ob-
tained in 91% yield but the reaction requires reflux condi-
tions at 80 °C.10
Amino groups in the presence of alcohols have to be pro-
tected previously. Otherwise the amino group is tosylated
as well. 2-Aminoethanol (entry 7) for example was tosyl-
ated both at the amino and the hydroxy moiety when 2.4
equivalents of toluene sulfonic acid anhydride were used.
Even when 1.2 equivalents toluene sulfonic acid anhy-
Table 1 Reaction of Alcohols with Ts2O in the Presence of Yb(OTf)3
Entry Alcohols
Tosylated Products
Time
Ts2O
(equiv)
Yield
(%)
Literature Yield
(%)
1
2
1
2
12 h
1.2
1.2
85a
82
70a,16
7417
10 min
OH
OTs
3
24 h
24 h
20 h
1.2
1.2
1.2
84
75
76
8118
O
O
OH
OTs
4b
5
–
c,19
OH
OH
OTs
OTs
7920
6
7
12 h
12 h
1.2
2.4
83
85
52,21 9222
6823
OH
OTs
F
F
Ts
OH
OTs
H2N
N
H
8
20 h
1.2
80
38,24 80,25 9110
OH
OH
OTs
9
20 h
24 h
2.4
1.2
83
87
92,5 80,26 7727
66,28 9429
OTs
TsO
HO
10
OTs
OH
11
5 h
1.2
1.2
1.2
89
88
86
38,30 87,31 90,329832
86,33 8034
OTs
OH
12
20 h
24 h
OH
OTs
OTs
13b
9929
OH
14b
18 h
1.2
79
–
O
O
OTs
OH
O
O
N
N
OH
OH
a In our laboratory the yield did not exceed 50%.
b Racemates were used.
c The synthesis has been described in the literature but no yields were given.
Synthesis 2004, No. 6, 885–888 © Thieme Stuttgart · New York

PAPER
Ytterbium(III)-Catalyzed Tosylation of Alcohols
887
Apart from simple primary and secondary alcohols, the novel mild and efficient method. Every alcohol used pro-
Yb(III)-catalyzed tosylation of more complex molecules vided a single product only and even more complex mol-
was proved using an acid sensitive compound (entry 14) ecules such as acid sensitive compounds (entry 14) were
and the hydroxy form of a D2 receptor ligand 1 (entry 1). tosylated in satisfactory yields. Purification was easily
For example, tosylation of the tert-butyl ester imine (entry achieved by means of short column chromatography. Due
14) which bears two acid sensitive moieties, i.e. the tert- to its high hygroscopicity, Yb(OTf)3 must be stored under
butyl ester group and the extremely acid sensitive Schiff argon and even during the weighing process, it should be
base derived from the corresponding pinanone which is handled under argon. In the case of toluene sulfonic acid
cleavable with 15% citric acid,15 was achieved in high anhydride the same procedure for handling is warranted.
yields. Neither cleavage of the acid sensitive groups nor The use of other Lewis acids e.g. Li+, Ag+, BF3, AlCl3 and
tosylation of the sterically hindered 2-hydroxy moiety various transition metal ions as catalysts in tosylation re-
were observed. The spectral data of the tosylates prepared actions and polymer bound Yt(III) which would make the
are given in Table 2.
reaction even easier is currently under investigation.
In conclusion, the ytterbium(III)-catalyzed tosylation of
primary and secondary alcohols can be considered as a
Table 2 Spectral Data of the Tosylated Alcohols
Entry 1H NMR (DMSO-d6)d, J (Hz)
13C NMR (DMSO-d6) d
FD-MS
m/z (M+,
100%)
a
a
a
1
2
-
-
-
7.67 (d, 2 H, J = 8.46), 7.41 (d, 2 H, J = 7.72), 7.09–7.29 (m, 5 H), 4.21 (t, 144.9, 138.1, 136.8, 132.4, 130.2, 128.9, 128.5, 276.4
2 H, J = 6.44), 2.87 (t, 2 H, J = 6.44), 2.39 (s, 3 H) 127.6, 126.7, 125.6, 71.1, 64.5, 34.5, 21.2
3
4
7.77 (d, 2 H, J = 8.09), 7.47 (d, 2 H, J = 8.46), 6.97 (d, 2 H, J = 8.46), 6.77 160.2, 147.6, 135.1, 134.9, 132.9, 131.9, 130.7, 320.4
(d, 2 H, J = 8.82), 3.96 (t, 3 H, J = 6.25), 3.69 (s, 2 H), 2.47–2.50 (m, 2 H), 130.3, 128.2, 116.4, 72.7, 57.6, 32.8, 32.5, 23.8
2.41 (s, 3 H), 1.75–1.85 (m, 2 H)
7.77 (d, 2 H, J = 8.09), 7.45 (d, 2 H, J = 8.09), 4.37–4.42 (m, 1 H), 2.40 (s, 144.6, 134.2, 130.1, 128.1, 127.5, 125.6, 88.5, 270.4
3 H), 1.77–1.85 (m, 1 H), 1.41–1.48 (m, 2 H), 1.07–1.27 (m, 2 H), 0.72–
0.87 (m, 9 H)
32.2, 30.7, 27.6, 21.2, 17.7, 17.5, 17.3, 13.7
5
6
7
7.78 (d, 2 H, J = 8.46), 7.45 (d, 2 H, J = 8.09), 4.28–4.38 (m, 1 H), 2.40 (s, 144.7, 134.2, 130.2, 127.4, 82.1, 79.5, 32.2,
3 H), 0.76–1.76 (m, 12 H) 32.0, 30.6, 30.4, 29.7, 28.5, 21.9, 21.2
268.4
218.3
7.80 (d, 2 H, J = 8.46), 7.48 (d, 2 H, J = 8.09), 4.65 (t, 1 H, J = 3.68), 4.49 145.3, 132.2, 130.3, 127.8, 82.2, 80.0, 69.9,
(t, 1 H, J = 3.86), 4.31 (t, 1 H, J = 3.86), 4.21 (t, 1 H, J = 3.86), 2.41 (s, 3 H) 69.7, 21.2
7.85 (t, 1 H, J = 6.07), 7.74 (d, 2 H, J = 8.46), 7.61 (d, 2 H, J = 8.09), 7.47 145.1, 142.9, 137.4, 132.2, 130.3, 129.8, 127.7, 369.5
(d, 2 H, J = 8.46), 7.35 (d, 2 H, J = 8.46), 3.94 (t, 2 H, J = 5.52), 2.92–2.97 126.6, 69.2, 59.9, 41.5, 21.2, 21.0, 20.9, 14.2
(m, 2 H), 2.41 (s, 3 H), 2.36 (s, 3 H)
8
7.43–7.50 (m, 7 H), 7.11 (d, 2 H, J = 7.72), 5.31 (s, 2 H), 2.27 (s, 3 H)
145.8, 137.8, 134.1, 131.9, 130.5, 130.3, 129.8, 262.4
129.6, 129.5, 128.9, 128.2, 125.6, 76.9, 20.9
9
7.71 (d, 4 H, J = 8.46), 7.46 (d, 4 H, J = 8.09), 4.16 (s, 4 H), 2.41 (s, 6 H) 145.3, 131.9, 130.3, 127.7, 67.9, 21.2
370.5
10
7.78 (d, 2 H, J = 8.09), 7.46 (d, 2 H, J = 8.46), 4.59–4.68 (m, 1 H), 2.41 (s, 144.7, 133.5, 130.2, 128.1, 127.5, 125.6, 77.5, 214.4
3 H), 1.16 (d, 6 H, J = 6.25) 22.4, 21.2
11
12
13
7.77 (d, 2 H, J = 8.09), 7.47 (d, 2 H, J = 8.09), 3.98 (t, 2 H, J = 6.46), 2.41 144.9, 132.7, 130.2, 127.7, 71.0, 31.2, 29.6,
(s, 3 H), 1.48–1.56 (m, 2 H), 1.14–1.25 (m, 10 H), 0.83 (t, 3 H, J = 6.99) 28.3, 24.8, 22.1, 21.2, 14.0
284.6
7.77 (d, 2 H, J = 8.09), 7.47 (d, 2 H, J = 8.46), 3.99 (t, 2 H, J = 6.25), 2.40 144.9, 132.7, 130.2, 128.1, 127.6, 125.6, 70.7, 228.4
(s, 3 H), 1.47–1.56 (m, 2 H), 1.17–1.29 (m, 2 H), 0.75–0.80 (m, 3 H) 30.3, 21.2, 18.1, 13.3
7.77 (d, 2 H, J = 8.46), 7.46 (d, 2 H, J = 8.09), 4.44–4.54 (m, 1 H), 2.40 (s, 144.7, 133.5, 130.2, 128.1, 127.5, 125.6, 81.9, 228.5
3 H), 1.44-1.53 (m, 2 H), 1.14 (d, 3 H, J = 6.25), 0.70 (t, 3 H, J = 7.35)
28.8, 21.2, 20.1, 9.1
14b 7.72 (d, 2 H, J = 8.51), 7.28 (d, 2 H, J = 8.80), 4.17–4.26 (m, 1 H), 3.95–
179.4, 169.1, 144.7, 133.0, 129.7, 127.7, 81.0, 478.9
4.10 (m, 2 H), 2.50–2.54 (m, 3 H), 2.44 (s, 3 H), 2.23–2.30 (m, 2 H), 1.97– 76.3, 61.5, 53.3, 50.3, 38.4, 38.2, 34.8, 33.4,
2.02 (m, 1 H), 1.41–1.47 (m, 5 H), 1.37 (s, 9 H), 1.25 (s, 3 H), 0.84 (s, 3 H) 28.1, 28.0, 27.2, 22.7, 13.9
a Analytical data such as 1H, 13C NMR and MS were in accordance with an authentic sample synthesized as previously described.16,35
b Elemental analysis was carried out additionally for characterization. Anal. Calcd for C25H37NO6S: C, 62.60; H, 7.78; N, 2.92. Found: C, 62.92;
H, 7.62; N, 3.13
Synthesis 2004, No. 6, 885–888 © Thieme Stuttgart · New York

888
S. Comagic, R. Schirrmacher
PAPER
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Analytical TLC was performed using plates from Merck (silica gel
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formed with silica gel (Si-60, Merck). Solvents for column chroma-
tography were p.a. grade. Yb(OTf)3 (98%) and Ts2O (97%) were
purchased from Sigma-Aldrich Chemie GmbH (Germany). 1H and
13C NMR spectra were recorded using a DRX 400 spectrometer
(Bruker Analytic GmbH). Chemical shifts are quoted in d (ppm)
downfield from TMS as an internal standard. MS spectra were ob-
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Tosylation of Alcohols; General Procedure
To a solution of Ts2O (cf. Table 1 for equiv) in CH2Cl2 (2 mL) was
added Yb(OTf)3 (10 mg, 16 mmol) and the suspension was stirred
for 10 min until most of the solid had dissolved. The alcohol was
added in pure form to the solution under continuous stirring (cf.
Table 1). After the reaction was complete (TLC monitoring), the
mixture was poured into an aq sat. NaHCO3 solution, extracted with
CH2Cl2 (3 × 20 mL) and the combined organic phases were dried
(Na2SO4). The solvent was evaporated and purification was
achieved with short column chromatography on silica gel with
EtOAc–n-hexane. In most cases except for the tosylation displayed
in entry 14, n-hexane can be replaced by cyclohexane, which is less
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Synthesis 2004, No. 6, 885–888 © Thieme Stuttgart · New York