Chemistry Letters Vol.34, No.9 (2005)
1267
Table 2. N-Alkylation of sulfonamides using alkyl diphenyl-
phoshinitesa
OR
OR
1
XN
R SO NH
3
2
2
XN PPh
Ph POR
2
XN PPh
2
2
Me SiCH N
2 3
(1.5 equiv.)
3
2
3
1
1
X= Me3SiCH2
R SO NH
R SO NHR
2
+
Ph POR
2
2
2
1,2-dichloropropane
(1.0 equiv.)
(1.5 equiv.)
R
o
80 C, 6 h
O
O
1
XHN PPh
1
Entry
1
Ph POR
Yield/%
2
R SO NH
+
2
R SO NHR XHN PPh
2
2
2
2
1
R SO NH
Ph
2
5
p-NsNH
70
2
OPPh
2
4
2
3
o-NsNH
78
85
TBSO
AcO
OPPh
2
2
Scheme 2.
6
p-NsNH
OPPh
2
2
6
methylsilylmethyl)diphenylphosphinamide 5.
Typical experimental procedure is as follows: to a mixture
of sulfonamides (0.3 mmol) and alkyl diphenylphosphinites
(0.45 mmol) was added a solution of trimethylsilylmethyl azide
(0.45 mmol) in 1,2-dichloropropane (0.6 mL) at 0 ꢁC under
argon atmosphere. The reaction mixture was stirred for 6.0 h at
80 ꢁC. After completion of the reaction (detected by TLC), the
crude product was purified by preparative TLC to afford the
corresponding sulfonamides.
Thus, it is noted that trimethylsilylmethyl azide is the suita-
ble oxidant in preparing monoalkylated sulfonamides by way of
oxidation–reduction condensation using alkyl diphenylphos-
phinites and unsubstituted sulfonamides and various mono-
alkylated sulfonamides were obtained in good yields under
neutral conditions. Further study on this type of condensation
reaction is now in progress.
4
5
o-NsNH
p-NsNH
82
89
2
2
2
OPPh
2
6
TsNH
37
76
2
Ph
b,c
d,e
7
p-NsNH
o-NsNH
OPPh
2
8
9
84
12
OPPh
2
2
f
p-NsNH
2
2
OPPh
2
p-NsNH
10
5
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
Ph PO
2
Ph
aReactions were carried out on a 0.3 mmol scale. bThe phosphin-
ite was prepared from the (R)-(ꢂ)-4-phenyl-2-butanol (99% ee).
cDAICEL CHIRALCEL OD column was used for HPLC analy-
References and Notes
sis. dThe desired product was obtained in 96% ee. DAICEL
e
1
a) T. Shintou, K. Fukumoto, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 77, 1569 (2004). b) T. Shintou, W. Kikuchi, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 76, 1645 (2003). c) T.
Mukaiyama, T. Shintou, and K. Fukumoto, J. Am. Chem. Soc.,
125, 10538 (2003).
f
CHIRALCEL AD column was used for HPLC analysis. The
corresponding compound was obtained with perfect inversion.
tyl or tert-butyldimethylsilyl group survived under the reaction
conditions (Entries 2 and 3). On the other hand, the reaction with
secondary alkyl diphenylphosphinites including acyclic/cyclic
ones smoothly proceeded to give the corresponding alkyl sulfo-
namides in good yields without forming dialkylated compounds
(Entries 4–8). The reactions with bulky L-menthyl diphenylphos-
phinite and tert-alkyl diphenylphosphinite gave the desired
products in low yields (Entries 9 and 10). When the reactions
with (R)-4-phenyl-2-butyl diphenylphosphinite and L-menthyl
diphenylphosphinite were tried, the inverted products were ob-
tained (Entries 7 and 9). This suggests that the reaction proceed-
ed basically via SN2 mechanism. In order to compare the reactiv-
ities of sulfonamides, sec-butylations of o-NsNH2, p-NsNH2 and
TsNH2 were examined and the reactivities of o-NsNH2 and p-
NsNH2 were found to be almost the same, which was higher than
that of TsNH2 having a higher pKa value (Entries 4–6).
A proposed reaction mechanism is shown in Scheme 2:
Alkyl diphenylphosphinites reacted initially with trimethylsilyl-
methyl azide to form the phosphinimidate 2 or 3,13 which is in
turn transformed to the phosphonium salt 4 by the interaction
with sulfonamides. An attack of the sulfonamide anion to the
carbon atom adjacent to an oxygen atom of the alkoxy group af-
forded the corresponding alkyl sulfonamides along with N-(tri-
2
3
T. Shintou and T. Mukaiyama, J. Am. Chem. Soc., 126, 7359 (2004).
T. Mukaiyama, K. Masutani, and Y. Hagiwara, Chem. Lett., 33,
1192 (2004).
a) T. Mukaiyama and K. Ikegai, Chem. Lett., 33, 1522 (2004). b) K.
Ikegai, W. Pluempanupat, and T. Mukaiyama, Chem. Lett., 34, 638
(2005).
T. Mukaiyama and H. Aoki, Chem. Lett., 34, 142 (2005).
S. Bittner, Y. Assaf, P. Krief, M. Pomerantz, B. T. Ziemnicka, and
C. G. Smith, J. Org. Chem., 50, 1712 (1985).
T. Tsunoda, H. Yamamoto, K. Goda, and S. Ito, Tetrahedron Lett.,
37, 2457 (1996).
4
5
6
7
8
For examples: a) T. Kan and T. Fukuyama, Chem. Commun., 2004,
353. b) S. Sumi, K. Matsumoto, H. Tokuyama, and T. Fukuyama,
Tetrahedron, 59, 8571 (2003).
9
O. Mitsunobu, Synthesis, 1981, 1.
10 T. Tsunoda, J. Otsuka, Y. Yamamiya, and S. Ito, Chem. Lett., 1994,
539.
11 Torii et al. reported a method for O-alkylation of carboxylic acid
and phenol derivatives by use of trialkylphosphite and benzyl azide
mixtures: S. Torii, H. Okumoto, M. Fujikawa, and M. A. Rashid,
Chem. Express, 7, 937 (1992).
12 Preparation of various alkyl diphenylphosphinites: See Ref. 1a or
4b.
13 Y. G. Gololobov, I. N. Zhmurova, and L. F. Kasukhin, Tetrahedron,
37, 437 (1981).
Published on the web (Advance View) August 13, 2005; DOI 10.1246/cl.2005.1266