Metal oxide in aqueous organic solution promoted chemoselective N-sulfonylation of hydrophilic amino alcohols

Article abstract of DOI:10.1016/S0040-4039(03)01666-6

The reaction of hydrophilic amino alcohols with sulfonyl chlorides in the presence of metal oxide (MgO, CuO, Ag₂O) in aqueous organic solution cleanly provided alkanolsulfonamide. Advantages of this method were mild, neutral reaction conditions

Full text of DOI:10.1016/S0040-4039(03)01666-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7225–7227
Metal oxide in aqueous organic solution promoted chemoselective
N-sulfonylation of hydrophilic amino alcohols
Hak Hee Kang,a Ho Sik Rho,b,* Duck Hee Kimb and Seong-Geun Oha
aDepartment of Chemical Engineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea
bR&D Center, AmorePacific Corporation, 314-1, Bora-ri, Kiheung-eup, Kyounggi-do 449-900, Republic of Korea
Received 26 May 2003; revised 4 July 2003; accepted 4 July 2003
Abstract—The reaction of hydrophilic amino alcohols with sulfonyl chlorides in the presence of metal oxide (MgO, CuO, Ag2O)
in aqueous organic solution cleanly provided alkanolsulfonamide. Advantages of this method were mild, neutral reaction
conditions, chemoselectivity and easy isolation of the final product.
© 2003 Published by Elsevier Ltd.
Organic sulfonamides are very important protected
intermediates of amines,1,2 which are also found in a
variety of biologically active compounds.3,4 They are
usually prepared by treating the corresponding amine
with sulfonyl chloride and various base in organic
solvent.5 Although the use of this method was success-
ful for the simple sulfonylation of amines or alcohols,
the lack of chemoselectivity was presented in case of
amino alcohols. Although the use of dibutylstannylene
acetal intermediate has been reported in a few cases,6,7
simple and efficient method for the selective N-sulfonyl-
ation of amino alcohols has not been established.
Recently, we have found an efficient method for the
chemoselective N-acylation of amino alcohols pro-
moted by MgO in aqueous organic solution.8
with MgO (5.0 equiv.) in THF/H2O (v/v=4:1) solution
with vigorously stirring at 25°C followed by addition of
benzenesulfonyl chloride gave the desired disulfon-
amide (2) in 80% yield.9 Of the metal oxide tested, the
best choice was 5 equiv. of magnesium oxide. Using
copper oxide and silver(I) oxide, compound 2 was also
obtained in high yield (entries 8 and 9). We could not
discriminate the critical difference of metal oxide
(MgO, CuO and Ag2O) in this reaction. As solvent,
THF/H2O (4:1) was preferred even if dioxane/H2O (4:1)
was also effective. The reaction temperature is impor-
tant factor for the chemoselective N-sulfonylation. The
Table 1. Conditions for chemoselective disulfonamide (2)
formation
Entry
Solvent
Basea
Time (h)
Yield (%)b
In the context of this ongoing research, we tried to
apply the chemoselective N-acylation method to sulfo-
nyl chloride and other metal oxide (CuO and Ag2O). A
series of experiments were performed on the 1,3-bis[(hy-
droxymethyl)amino]propan-2-ol (BHAP, 1) with ben-
zenesulfonyl chloride (2.2 equiv.) under various
reaction conditions (entries 1–5 in Table 1). However,
only a slight amount of desired sulfonamide was
obtained in these attempted conditions. Next, we tested
MgO (5.0 equiv.) suspended in aqueous organic solu-
tion, which has been used for the chemoselective N-
acylation of amino alcohols. Treatment of BHAP 1
1
2
CH2Cl2
CH2Cl2
TEA (2.2)
Pyridine
(2.2)
TEA (2.2)
Pyridine
(2.2)
3.5
3.5
0
0
3
4
DMF
DMF
3
3
10
12
5
6
H2O
THF/H2O
(4:1)
Dioxane/H2O MgO (5.0)
(4:1)
THF/H2O
(4:1)
THF/H2O
(4:1)
NaOH (2.2) 2.5
MgO (5.0)
20
80
2.5
2.5
3
7
8
9
78
75
74
CuO (5.0)
Ag2O (5.0)
4
Keywords: amino alcohols; sulfonamide; sulfonyl chloride; metal
oxide; aqueous organic solution.
* Corresponding author. Fax: +82-31-281-8397; e-mail: thiocarbon@
freechal.com
a The molar equivalents are given in parentheses.
b Isolated yields.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01666-6

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H. H. Kang et al. / Tetrahedron Letters 44 (2003) 7225–7227
Scheme 1.
Table 2. Conditions for chemoselective sulfonamide formationa
best temperature was around 25°C. When the tempera-
ture was elevated to above 25°C, O-sulfonyl disulfon-
amide has been observed as a side product. The
formation of the O-chemoselective sulfonate has not
been detected in any case examined (Scheme 1).
sulfonyl chloride activates the leaving ability of chlo-
ride.11 More nucleophilic amino groups may only react
with activated sulfonyl chloride.12 The activating ability
of CuO and Ag2O for sulfonyl chloride was similar to
that of MgO. The reaction also worked well for the
other hydrophilic amine such as ethanolamine,
Metal oxide10 mediated reaction showed several advan-
tages over the organic base used methods. For instance,
the reaction occurs in neutral condition and necessitates
simple isolation process. The sulfonamide is often iso-
lated pure after a simple filtration, evaporation, and
precipitation or short column chromatography. We
extended this optimized reaction condition to other
sulfonyl chlorides and hydrophilic substrates. The
results are summarized in Table 2.
propanolamine,
diethanolamine.
DL-serine
methyl
ester
and
In summary, we have developed an efficient and
chemoselective N-sulfonylation reaction by the treat-
ment of amino alcohols with various sulfonyl chlorides
in the presence of metal oxide in aqueous organic
solution. The use of metal oxide afforded several
advantages such as neutral reaction condition, short
reaction time, easy handling and simple isolation of
product.
In case of NsCl, p-methoxy benzenesulfonyl chloride
and TsCl, the desired disulfonamide products were
obtained in high yield (entries 1–3 in Table 2).
Although the reason for N-sulfonylation induced by
metal oxide has not been clarified, the reaction mecha-
nism was similar to that of selective N-acylation.8 The
coordination of metal ion to the double bond of SꢀO of
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H. H. Kang et al. / Tetrahedron Letters 44 (2003) 7225–7227
7227
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