Facile and practical methods for the sulfonylation of alcohols using Ts(Ms)Ci and Me2N(CH2)(n)NMe2 as a key base

Article abstract of DOI:10.1055/s-1999-3561

Several alcohols were smoothly and practically tosylated by two Methods A and B. Method A uses the TsCl/Me₂N(CH₂)(n)NMe₂ (n = 3 or 6) reagent and Method B uses TsCl/Et₃N/catalytic Me₂N(CH₂)

Full text of DOI:10.1055/s-1999-3561

PAPER
1633
Facile and Practical Methods for the Sulfonylation of Alcohols Using Ts(Ms)Cl
and Me2N(CH2)nNMe2 as a Key Base
Yoshihiro Yoshida, Koji Shimonishi, Yoshiko Sakakura, Shin Okada, Naoya Aso, Yoo Tanabe*
School of Science, Kwansei Gakuin University, 1-1-155 Uegahara, Nishinomiya, Hyogo 662–8501, Japan
Received 8 February 1999; revised 1 March 1999
action frequently takes place when excess amounts of Py
Abstract: Several alcohols were smoothly and practically tosylated
solvent are used and/or when the reaction temperature is
elevated. (c) The reaction time for unreactive alcohols
generally requires a relatively long time (over 10 hours).
by two Methods
A and B. Method A uses the TsCl/
Me2N(CH2)nNMe2 (n = 3 or 6) reagent and Method B uses TsCl/
Et3N/catalytic Me2N(CH2)nNMe2 (n = 3 or 6) reagent. Compared
with the traditional Py-solvent method, Method A has the advantag-
es of its much higher reaction rate, operational simplicity, and cir-
cumvention of the undesirable side reaction from ROTs to RCl.
Method B has the advantage of economy in the use of the amine.
Related methanesulfonylations in toluene solvent also proceeded
successfully.
Taking this information into consideration, we now report
a couple of facile and practical Methods (A and B) for the
tosylation
of
various
alcohols
employing
Me2N(CH2)nNMe2 (n = 3 or 6) as the key base. Related
methanesulfonylations using Me2N(CH2)nNMe2 are also
described.
Key words: tosylation, mesylation, alcohols, diamine, catalytic re-
action
We chose water-soluble and readily available diamines
such as TMEDA (N,N,N’,N’-tetramethylethylenedi-
amine), which has the advantage of being conveniently re-
Among a number of methods for p-toluenesulfonylation moved from the organic phase containing the desired
(tosylation) of alcohols,1 TsCl/Py (Ts = para-toluene- tosylate after the workup. Actually, TsCl/ TMEDA (1.5
sulfonyl, Py = pyridine) reagent has been traditionally and equiv) reagent was found to be a good promoter for the to-
routinely employed. This tosylation is established as a sylation of octan-3-ol (yield 80~90%), however, a serious
fundamental unit reaction in various fields of organic syn- side reaction took place: TsCl slowly reacted with TME-
theses, however, there still remain some problems. (a) Ex- DA to produce N,N-dimethyl p-toluenesulfonamide by
cess amounts (ca. 10 equiv) of Py are generally required the Hofmann degradation. About 20% of N,N-dimethyl p-
for the completion of the tosylation. Therefore, this meth- toluenesulfonamide was produced during the tosylation of
od suffers from a tedious procedure to remove pyridine. 3,3-dimethylbutanol using the reagent at 0–5 °C for 1
(b) Undesirable and concomitant loss of the tosylates to hour. Thus, we planned the tosylation using an inexpen-
their chlorides is liable to occur during the tosylation; the sive and available Me2N(CH2)nNMe2 (n = 3 or 6) (1.5
Py.HCl byproduct acts as the Cl-nucleophile. This side re- equiv) as the amine reagent (Method A).
Table 1 Tosylation of Alcohols Using TsCl / Me2N(CH2)nNMe2 Reagent (Method A)
TsCl
ROTs
ROH
Me2N(CH2)nNMe2
0-5 °C, 1 h
Alcohol
Aminea (Eq)
Eq (TsCl)
Solvent
Tosylate
Yield (%)
Me(CH2)6CH2OH
A (1.5)
A (1.5)
B (1.5)
B (1.5)
A (1.5)
A (1.5)
B (1.5)
Py (1.5)b
Py (11)c
B (1.5)
B (2.0)
B (3.0)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
3.0
toluene
MeCN
MeCN
toluene
MeCN
MeCN
MeCN
MeCN
–
1
87
94
95
95
94
92
94
trace
40
CH2=CH(CH2)7CH2OH
EtO2C(CH2)4CH2OH
Me(CH2)4CH(OH)Et
2
3
4
l-menthol
t-BuCH(OH)Me
EtCH(OH)CH2OH
MeCN
MeCN
MeCN
5
6
7
92
91d
91
a A: Me2N(CH2)3NMe2. B: Me2N(CH2)6NMe2.
b Pyridine was used as the amine.
c Conventional pyridine solvent method.
d 0–5°C, 1 h and room temp. 3 h.
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1634
Y. Yoshida et al.
PAPER
TsCl / Me2N(CH2)6NMe2
OH
and
OTs
Cl
30 °C, 2 h
1
Method A
91%
51%
trace
43%
Py-method
Scheme 1
Me2N(CH2)nNMe2 . HCl
Me2N(CH2)nN+TsMe2 . Cl-
Et3N
ROTs
ROH
Et3N.HCl
Me2N(CH2)6NMe2
TsCl
(Method B)
Scheme 2
Table 1 lists these results. The salient features are as fol- ment; octan-1-ol was safely tosylated under identical con-
lows. (a) Several primary and secondary alcohols were ditions at 30–35 °C for 2 hours (Scheme 1). This result
smoothly tosylated in toluene or CH3CN at 0–5 °C for 1 h. indicates
much
lower
nucleophilicity
of
.
(b) 1.5 equiv of the diamine base was sufficient for the to- Me2N(CH2)6NMe2 HCl salt compared with the Py.HCl
sylation. (c) In the case of octan-3-ol replacement of the salt.
diamine base for Py and the conventional Py-solvent
Method B involves the tosylation using TsCl/Et3N (1.5
method resulted in lower yields under identical condi-
equiv)/cat. Me2N(CH2)nNMe2 (0.1 equiv) reagent. From
tions. (d) Even unreactive 3,3-dimethylbutan-2-ol under-
the standpoint of the economy of amine base, it is desir-
went tosylation at room temperature. Me2N(CH2)4NMe2
able to use 1.5 equiv of very cheap Et3N as the main base
was also effective (In the case of octan-1-ol, 91% under
combined with a catalytic amount of Me2N(CH2)nNMe2.
identical conditions). Therefore, compared with conven-
Table 2 lists these results. Although the reaction velocity
tional Py-solvent method, Method A showed significantly
was a little inferior to Method A, several primary and sec-
ondary alcohols were practically tosylated in CH3CN at
higher reaction velocity.2
It is also worth noting that Method A significantly circum- 0–5 °C for 1 h and room temperature for 3 h. For the
vented the side undesirable chlorination (from ROTs to tosylation of secondary alcohols, Me2N(CH2)6NMe2 was
RCl) exemplified by the following comparable experi- somewhat superior to Me2N(CH2)3NMe2.
A plausible mechanism of Method B is illustrated in
Table 2 Tosylation of Alcohols Using TsCl / Et3N / cat.
Scheme 2. Our earlier report described that alk-2-enyl and
Me2N(CH2)nNMe2 Reagent (Method B)
alk-2-ynyl alcohols were safely tosylated using K2CO3
and a catalytic, sterically unhindered amine.1g,h Based on
TsCl
ROTs
ROH
the results, Me2N(CH2)nNMe2 would preferentially form
the reactive sulfonylammonium salt with TsCl in situ. Af-
ter the tosylation of an alcohol, Et3N would drive the cat-
Et3N (1.5 eq.) -
cat. Me2N(CH2)nNMe2 (0.1 eq.)
.
0-5 ºC, 1 h
alytic cycle by neutralizing Me2N(CH2)nNMe2 HCl to
reform Me2N(CH2)nNMe2.
Alcohol
Aminea Solvent Tosy-
late
Yield
(%)
Consequently, Method A will adequately replace the Py-
method with respect to (1) its higher reaction rate; (2)
safety for preparing tosylates; (3) operational simplicity.
Method B has a merit of economy in the use of the amine.
Additionally, from the standpoint on decreasing amounts
of the amine base, both methods give advantage over the
Py-method.
Me(CH2)6CH2OH
B
B
B
B
A
B
B
B
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1
87
94
93
94
CH2=CH(CH2)7CH2OH
EtO2C(CH2)4CH2OH
Me(CH2)4CH(OH)Et
2
3
4
86b
95b
94b
92b
l-menthol
EtCH(OH)CH2OH
5
7
Finally, the related methanesulfonylation (mesylation)
was examined. Mesylations are carried out conventionally
in halogenated solvents (e.g. CH2Cl2) or ether solvents
(e.g. Et2O, THF), because of their high reaction velocity.
a A: Me2N(CH2)3NMe2. B: Me2N(CH2)6NMe2.
b 0–5°C, 1 h and r. t. 3 h.
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Facile and Practical Methods for the Sulfonylation of Alcohols
1635
similar workup and purification to Method A gave the desired tosy-
late.
Table 3 Mesylation of Alcohols in Toluene Using MsCl / (cat.)
Me2N(CH2)nNMe2 / (Et3N) Reagent
MsCl
Mesylation of Alcohols Using (a) MsCl/Me2N(CH2)nNMe2 or (b)
MsCl/Et3N and cat. Me2N(CH2)nNMe2 (n = 2, 3 or 6)
ROMs
ROH
Me2N(CH2)nNMe2 or
(a) MsCl (172 mg, 1.5 mmol) in toluene (0.5 ml) was added to a
stirred solution of an alcohol (1.0 mmol) and Me2N(CH2)nNMe2
(1.5 mmol) in toluene (1.0 ml) at 0–5 °C, and the mixture was stirred
for 1 h. A similar workup and purification of Method B followed by
silica gel column chromatography (hexane/EtOAc = 5:1) gave the
desired mesylate. (b) MsCl (172 mg, 1.5 mmol) in toluene (0.5 ml)
was added to a stirred solution of an alcohol (1.0 mmol), Et3N (152
mg, 1.5 mmol), and Me2N(CH2)nNMe2 (0.1 mmol) in toluene (1.0
mL) at 0–5 °C, and the mixture was stirred for 1 h. A similar workup
and purification in the case of (a) gave the desired mesylate.
Et3N - cat. Me2N(CH2)nNMe2
/ toluene
0-5 ºC, 1 h
Alcohol
Aminea Eq
(equiv) (Et3N) late
Mesy-
Yield
(%)
Me(CH2)4CH(OH)Et
A (1.5)
B (1.5)
–
–
8
93
94
94
B (0.1) 1.5
1.5
C (0.1) 1.5
B (1.5)
B (0.1) 1.5
–
<10
94
N,N-Dimethyl 4-Toluenesulfonamide
Colorless crystals: mp 83.0–83.5 °C.
IR (KBr): n = 2906, 1597, 1471, 1454, 1336, 1163, 957, 646 cm–1.
1H NMR (CDCl3): d = 2.40 (3H, s), 2.70 (6H, s), 7.30 (2H, d,
J = 10.0 Hz), 7.65 (2H, d, J = 10.0 Hz).
t-BuCH(OH)Me
–
9
94b
95b
a A: Me2N(CH2)3NMe2. B: Me2N(CH2)6NMe2. C: TMEDA
[Me2N(CH2)2NMe2].
b 0–5°C, 1 h and r. t. 5 h.
These spectral data accorded with those of the authentic sample pre-
pared by TsCl and dimethylamine.
1-Octyl 4-Toluenesulfonate (1)3
Colorless oil.
Taking a recent experimental requirement into account,
especially, for industrial productions, the reaction in tolu-
ene as solvent should be desirable. Actually, Et3N (1.5
equiv) and Me2N(CH2)nNMe2 (0.1 equiv) were found to
be effective reagents for the mesylation in toluene as
shown in Table 3. In the case of octan-3-ol, independent
use of Et3N was markedly ineffective. It should be noted
that TMEDA also worked as an efficient promoter. Unfor-
tunately, dihydrolinalool, a tertiary alcohol, was not tosy-
lated and mesylated by these present methods.
IR (film): n = 2928, 2857, 1599, 1466, 1362, 1177, 1098, 949, 910
cm–1.
1H NMR (90 MHz, CDCl3): d = 0.87 (3H, t, J = 7.2 Hz), 1.08–1.82
(12H, m), 2.44 (3H, s), 4.03 (2H, t, J = 6.9 Hz), 7.24–7.49 (2H, m),
7.72–7.91 (2H, m).
Dec-9-enyl 4-Toluenesulfonate (2)4
Colorless oil.
IR (film): n = 2928, 1639, 1599, 1362, 1177, 937 cm–1.
1H NMR (90 MHz, CDCl3): d = 0.78–2.18 (14H, m), 2.44 (3H, s),
4.02 (2H, t, J = 7.7 Hz), 4.81–5.12 (2H, m), 5.58–6.04 (1H, m),
7.22–7.44 (2H, m), 7.72–7.91 (2H, m).
Ethyl 6-(4-Toluenesulfonyloxy)hexanoate (3)5
Colorless oil.
Mps were determined on a hot stage microscope apparatus
(Yanagimoto) and were uncorrected. 1H NMR spectra were record-
ed on a JEOL EX-90 (90 MHz) and/or JEOL a (400 MHz) spec-
trometer in CDCl3 using a TMS internal standard. IR spectra were
recorded on a JASCO FT/IR-8000 spectrophotometer. Silica gel
column chromatography was performed on a Merck Art. 7734 and/
or 9385. Commercial TsCl was recrystallized from EtOAc prior to
use. The solvents were purified by standard methods.
IR (film): n = 2942, 1734, 1458, 1360, 1177, 1030, 951 cm–1.
1H NMR (90 MHz, CDCl3): d = 1.24 (3H, t, J = 7.7 Hz), 1.34–1.83
(6H, m), 2.25 (2H, t, J = 7.7 Hz), 2.45 (3H, s), 3.91–4.28 (4H, m),
7.23–7.44 (2H, m), 7.70–7.92 (2H, m).
3-Octyl 4-Toluenesulfonate (4)6
Colorless oil.
Method A; General Procedure
TsCl (1.5 mmol) in solvent (toluene or CH3CN; 1.0 mL) was added
to a stirred solution of an alcohol (1.0 mmol) and Me2N(CH2)nNMe2
(n = 3 or 6) (1.5 mmol) in solvent (toluene or CH3CN; 1.0 mL) at
0–5 °C, and the mixture was stirred for 1 h. To decompose an excess
TsCl, N,N-dimethylethylenediamine (ca. 130 mg) was added to the
mixture, which was stirred for 10 min. (This procedure is not always
necessary, when TsCl is easily separated off by column chromatog-
raphy). H2O was added to the mixture, which was extracted with
EtOAc. The organic phase was washed with H2O and brine, dried
(Na2SO4) and concentrated. The obtained crude product was puri-
fied by silica gel column chromatography (hexane/Et2O = 30~10:1)
to give the desired tosylate.
IR (film): n = 2957, 2934, 2864, 1597, 1460, 1364, 1188, 1177,
1098, 910 cm–1.
1H NMR (90 MHz, CDCl3): d = 0.80 (3H, t, J = 7.7 Hz), 1.01–1.82
(13H, m), 2.42 (3H, s), 4.38–4.62 (1H, m), 7.22–7.48 (2H, m),
7.71–7.89 (2H, m).
l-Menthyl 4-Toluenesulfonate (5)7
Colorless crystals: mp 92.5–93.5 °C.
IR (KBr): n = 2963, 2936, 1599, 1454, 1358, 1179, 1098, 943, 910
cm–1.
1H NMR (90 MHz, CDCl3): d = 0.52 (3H, d, J = 6.4 Hz), 0.70–2.27
(15H, m), 2.42 (3H, s), 4.23–4.56 (1H, m), 7.23–7.43 (2H, m),
7.71–7.91 (2H, m).
3,3-Dimethylbutan-2-yl 4-Toluenesulfonate (6)8
Colorless oil.
Method B; General Procedure
TsCl (1.5 mmol) in solvent (toluene or CH3CN; 1.0 ml) was added
to a stirred solution of an alcohol (1.0 mmol), Et3N (1.5 mmol) and
Me2N(CH2)nNMe2 (n = 3 or 6) (0.1 mmol) in solvent (toluene or
CH3CN; 1.0 ml) at 0–5 °C, and the mixture was stirred for 1–3 h. A
IR (film): n = 2971, 1599, 1480, 1362, 1177, 1074, 901 cm–1.
Synthesis 1999, No. 9, 1633–1636 ISSN 0039-7881 © Thieme Stuttgart · New York

1636
Y. Yoshida et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 0.84 (9H, s), 1.21 (3H, d, J = 6.8
Hz), 2.44 (3H, s), 4.39 (1H, q, J = 6.4 Hz), 7.31–7.33 (2H, m), 7.78–
7.80 (2H, m).
References and Notes
(1) (a) Sekera, V. C.; Marvel, C. S. J. Am. Chem. Soc. 1933, 55,
345.
1,2-Bis(4-toluenesulfonyloxy)butane (7)
Colorless crystals: mp 57.5–58.5 °C.
IR (KBr): n = 2976, 1597, 1460, 1362, 1194, 1179, 909 cm–1.
1H NMR (90 MHz, CDCl3): d = 0.82 (3H, t, J = 7.7 Hz), 1.48–1.81
(2H, m), 2.47 (6H, s), 4.02 (2H, d, J = 6.8 Hz), 4.40–4.71 (1H, m),
7.19–7.48 (4H, m), 7.59–7.91 (4H, m).
(b) Roos, A. T.; Gilman, H.; Beaber, N. J. In Organic
Synthesis, 2nd ed.; Gilman, H., Ed.; Wiley: New York, 1941;
Col. Vol. 1, pp 145–147.
(c) Sekera, V. C.; Marvel, C. S. Organic Synthesis; Wiley:
New York, 1955; Col. Vol. 3, pp 366–367.
(d) Fieser, L. F.; Fieser, M. Reagent for Organic Synthesis;
Wiley: New York, 1967; Vol 1., pp 1179–1184.
(e) March, J. Advanced Organic Chemistry; 4th ed.; Wiley:
New York, 1992, pp 352–354.
Anal. Calcd for C16H22O6S2: C, 54.25; H, 5.56. Found: C, 54.0; H,
5.4.
Other representative references are cited in the following
reports.
Reaction of Octan-1-ol in the Py Solvent Method at 30 °C for 2
h (Scheme 1).
(f) Kabalka, G. W.; Varma, M.; Varma, R. S.; Srivastava, P.
C.; Knapp, F. F. Jr. J. Org. Chem. 1986, 51, 2386.
(g) Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.;
Utsumi, N. Bull. Chem. Soc. Jpn. 1995, 68, 297.
(h) Yoshida, Y.; Sakakura, Y.; Aso, N.; Tanabe, Y.; Okada, S.;
Tanabe, Y. Tetrahedron 1999, 55, 2183.
TsCl (286 mg, 1.5 mmol) was added to a stirred solution of octan-
1-ol (130 mg, 1.0 mmol) in pyridine (0.87 ml) at 0–5 °C, and the
mixture was stirred at 30 °C for 2 h. Usual workup of this method
gave a crude product (275 mg), which contained 1-octyl tosylate
(51%) and 1-chlorooctane (43%) by the estimation of 1H NMR (400
MHz).
3-Octyl Methanesulfonate (8)6
Colorless oil.
IR (film): n = 2938, 2872, 1350, 1175, 918 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (3H, t, J = 7.2 Hz), 0.99 (3H,
t, J = 7.2 Hz), 1.22–1.81 (10H, m), 3.03 (3H, s), 4.64–4.72 (1H, m).
3,3-Dimethylbutan-2-yl Methanesulfonate (9)8
Colorless oil.
IR (film): n = 2969, 2878, 1350, 1175, 905 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.99 (9H, s), 1.40 (3H, d, J = 7.2
Hz), 3.01 (3H, s), 4.51 (1H, q, J = 7.2 Hz).
(2) A phase transfer method was reported: Szeja, W. Synthesis
1979, 822. However, when octan-1-ol was examined in this
method, some trials in our hands failed to obtain the desired
tosylate 1 in practical yields (<10%).
(3) Drahowzal, F.; Klamann, D. Monatsh. Chem. 1951, 82, 452.
(4) Quackenbush, F. W.; Grogan, W. M. Jr.; Midland, S. L.; Bell,
F. P.; MacNintch, J. E.; Hutsell, T. C.; Cruzan, G.; Klauda, H.
C. Artery 1977, 3, 553.
(5) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K. J. Org. Chem.
1989, 54, 4732.
(6) Pritzkow, W.; Schoeppler, K. H. Chem. Ber. 1962, 95, 834.
(7) Rule, H. G.; Miles, J. B.; Smith, G.; Barnett, M. M. J. Chem.
Soc. 1931, 1478.
(8) Fainberg, A. H.; Robinson, G. C.; Winstein, S. J. Am. Chem.
Soc. 1956, 78, 2777.
Acknowledgement
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Cul-
ture (Japan). One of the authors (Y. Y) acknowledges Sasakawa
Scientific Research Grant from the Japan Science Society.
Article Identifier:
1437-210X,E;1999,0,09,1633,1636,ftx,en;F11399SS.pdf
Synthesis 1999, No. 9, 1633–1636 ISSN 0039-7881 © Thieme Stuttgart · New York