accessible by external reagents. However, as the present
deprotection is initiated at the remote position from the amine
moiety (see Scheme 3), followed by the cascade steps ending
with the intramolecular scission of an S-N bond, sterically
hindered sulfonamides such as 12-15 were readily depro-
tected as illustrated in entries 13-19. As for the equivalents
of BuLi, 3 equiv of this base generally gave better results
(cf. entries 5 and 6, or 14 and 15), and most experiments
were performed accordingly. A couple of modifications
making this method more flexible are also shown in Table 1
and should be emphasized. First, the use of LDA in place
of BuLi resulted in a similar outcome as shown in entries 4,
7, and 19.11 Second, a more practical alternative to oxygen
gas is dry air, which did not lower the yield of the amines
(entries 3 and 16).
presence of another sulfonyl group such as a benzene- or
trifluoromethanesulfonyl group lacking an R-sulfonyl hy-
drogen. Thus, when doubly protected diamines 16-20 were
subjected to the above deprotection (eqs 1 and 2), mono-
protected diamines 21-25 were obtained in comparable
yields to those of Table 1. Compatibility with the tert-
butyloxycarbonyl (Boc) group, a typical N-protecting group
of a different type, is also shown. In these reactions, a less
nucleophilic LDA, rather than BuLi, proved to be more
suitable.12 To the best of our knowledge, the differentiation
between sulfonyl groups on the basis of the presence or
absence of their R-hydrogen(s) has not been established.
A more important aspect of this reaction is its application
to selective deprotection of a methanesulfonyl group in the
(9) Typical procedures for the demesylation of N,N-dioctylmethane-
sulfonamide (1) to dioctylamine (3): With BuLi (2 equiv) and O2 (entry
1, Table 1): To a stirred solution of N,N-dioctylmethanesulfonamide (1)
(63.9 mg, 0.200 mmol) in THF (3 mL) was added BuLi (1.58 M in hexane,
0.253 mL, 0.400 mmol) at 0 °C under argon. After being stirred for 15 min
at that temperature, the argon inlet tube was replaced by a balloon filled
with oxygen gas. After being stirred for 1 h at room temperature under an
O2 atmosphere, the reaction was terminated by the addition of water (0.15
mL). The resulting heterogeneous mixture was filtered through Celite with
the aid of CH2Cl2. The organic phase was dried over Na2SO4 and
concentrated in vacuo to give a crude product, which was chromatographed
on Chromatorex “NH” (DM1020, 100-200 mesh, Fuji Silysia Chemical
Ltd., Japan) with ca. 0.5% t-BuNH2 in hexane to afford the title compound
(34.3 mg, 71%) as an oil. With BuLi (3 equiv) and O2 (entry 2):
Sulfonamide 1 (63.9 mg, 0.200 mmol) and BuLi (1.57 M in hexane, 0.382
mL, 0.600 mmol) under the same operations as above afforded the title
compound (33.6 mg, 70%) as an oil. With BuLi (3 equiv) and air (entry
3): To a stirred solution of 1 (32.0 mg, 0.100 mmol) in THF (2 mL) was
added BuLi (1.63 M in hexane, 0.184 mL, 0.300 mmol) at 0 °C under
argon. After being stirred for 15 min at that temperature, the argon inlet
tube was replaced by a balloon filled with air dried through drying agent,
Sicapent (Merck). After being stirred for 1 h at room temperature under
dry air, the reaction was terminated by the addition of water (0.15 mL).
The same workup and purification as above afforded the title compound
(17.4 mg, 72%) as an oil. With LDA (3 equiv) and O2 (entry 4): To a
stirred solution of 1 (32.0 mg, 0.100 mmol) in THF (1 mL) was added
LDA (prepared from BuLi (1.63 M in hexane, 0.184 mL, 0.300 mmol) and
diisopropylamine (30.4 mg, 0.300 mmol) in THF (1 mL)) at 0 °C under
argon. After being stirred for 15 min at that temperature, the argon inlet
tube was replaced by a balloon filled with oxygen gas. After being stirred
for 1 h at room temperature under an O2 atmosphere, the reaction was
terminated by the addition of water (0.15 mL). The same workup and
purification as above afforded the title compound (17.2 mg, 71%) as an
In conclusion, we reported here an efficient deprotection
of methanesulfonamides to their parent amines even when
they are sterically hindered. Its reaction mechanism enables
the deprotection of methanesulfonamide in the presence of
other sulfonamides lacking R hydrogens, which provides a
new criterion of selection.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Area (No.16073208)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
1
oil. H NMR δ 0.86 (t, J ) 6.9 Hz, 6H), 0.88 (br s, 1H, NH), 1.16-1.40
(m, 20H), 1.46 (quintet, J ) 6.9 Hz, 4H), 2.56 (t, J ) 7.2 Hz, 4H). 13C
NMR δ 14.07, 22.64, 27.41, 29.25, 29.53, 30.19, 31.81, 50.16. IR (neat)
3276 (NH), 2925, 2854, 2809, 1467, 1378, 1131, 722 cm-1. These spectral
properties and TLC mobility were in agreement with those of a commercially
available authentic sample. Caution: Although hydroperoxides were not
detected in our hands, care must be taken particularly in a large-scale
deprotection. For safe operation, see the Supporting Information of ref.7a
Attempted deprotection of methanesulfonamides derived from primary
amines was unsuccessful, due probably to oxygenation of the nitrogen atom
of the resulting C,N-dilithiated amide.
Supporting Information Available: Physical properties
of products. This material is available free of charge via the
OL100086J
(10) Escoubet, S.; Gastaldi, S.; Timokhin, V. I.; Bertrand, M. P.; Siri,
D. J. Am. Chem. Soc. 2004, 126, 12343–12352.
(12) It is known that triflamides are susceptible to the attack of BuLi.
For example, see: Bozec-Ogor, S.; Salou-Guiziou, V.; Yaouanc, J. J.;
Handel, H. Tetrahedron Lett. 1995, 36, 6063–6066.
(11) Excess LDA proved necessary to perform the deprotection in good
yields. It would play the same role as the excess BuLi does.
1230
Org. Lett., Vol. 12, No. 6, 2010