Table 3 Chemoselective acylation.a
M. Kawase and H. Tamiya, Tetrahedron Lett., 1990, 31, 243; (j)
T. Keumi, M. Shimada, T. Morita and H. Kitajima, Bull. Chem. Soc.
Jpn., 1990, 63, 2252; (k) N. Akikusa, K. Mitsui, T. Sakamoto and
Y. Kikugawa, Synthesis, 1992, 1058; (l) A. R. Katritzky and H. X.
Chang, Synthesis, 1995, 62, 503; (m) M. C. O’Sullivan and D. M.
Dalrymple, Tetrahedron Lett., 1995, 36, 3451; (n) D. Xu, K. Prasad,
O. Repic and T. J. Blacklock, Tetrahedron Lett., 1995, 36, 7357; (o)
R. S. Atkinson, E. Barker and M. J. Sutcliffe, Chem. Commun., 1996,
1051; (p) A. R. Katritzky, B. Yang and D. Semenzin, J. Org. Chem.,
1997, 62, 726; (q) I. S. Blagbrough and A. Geall, Tetrahedron Lett.,
1998, 39, 439.
Entry Reagent Diamine
Products and yields (%)
2 (a) Y. Murakami, K. Kondo, K. Miki, Y. Akiyama, T. Watanabe and
Y. Yokoyama, Tetrahedron Lett., 1997, 38, 3751; (b) K. Kondo and
Y. Murakami, Chem. Pharm. Bull., 1998, 46, 1217; (c) enantio-
selective N-acetylation: K. Kondo, T. Kurosaki and Y. Murakami,
Synlett, 1998, 725.
3 Preparation of diacylanilines 2 with BuLi–R2COCl (R2 = BnO,
cyclohexyl, t-butyl) was also unsuccessful.
4 N-Acetyl and benzoyl-N-trifluoromethanesulfonylanilines have been
shown to behave as acylating reagents: J. B. Hendrickson and
R. Bergeron, Tetrahedron Lett., 1973, 4607. However, preparation
of N-benzyloxycarbonyl-N-trifluoromethanesulfonylaniline was un-
successful.
a All reactions were carried out with 4b or 8b (1.05 equiv) in THF at
0 ЊC for 24 h and were then left stirring at rt for 12 h.
5 The selectivity in the acylation of a 1:1 mixture of a less hindered
amine and a hindered amine was also investigated with 4b and 8b,
respectively. The observed selectivity in the acylation with 4b and 8b
was superior to the currently used reagents, as shown in Table 4
below.
The substantial difference in reaction rates between less
hindered and hindered amines prompted us to examine the
chemoselective acylation of diamines. The acylation was per-
formed with diamines containing structurally diverse amino
groups as shown in Table 3, and products acylated at the less
hindered nitrogen were obtained in good yields.5
Table 4 Competition acylation.
Our new reagents6 4b–8b have several advantages as follows;
(1) they are easily prepared from a common substrate 3b under
mild conditions, especially for benzyloxycarbonyl groups, (2)
stable in air and easy to handle, (3) good selectivity: in a mole-
cule with both less hindered and hindered amino groups, acyl
transfer occurred only at the less hindered amino group.
In summary, 2-fluoro-N-acyl-N-mesylanilines 4b–8b pre-
pared easily from 2-fluoro-N-mesylaniline 3b, are convenient
chemoselective N-acylation reagents in view of their facile
preparation, easy handling and stability.
Yield (%) Selectivitya
Entry Reagent
Conditions
13ϩ 14
(13:14)
1
2
3
4
5
6
4b
THF, rt, 18 h
90
92
89
92
97
88
8:1
3:1
10:1
5:1
5:1
3:1
BnOCOCl
8b
Et3N, THF, 0 ЊC, 1 h
THF, 0 ЊC, 48 h
THF, 0 ЊC, 1 h
CH2Cl2, 0 ЊC, 12 h
THF, 0 ЊC, 12 h
Bz2O
BzCN
Bz2NOMe
Acknowledgements
This study was financially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science
and Culture, Japan, and a Sasakawa Scientific Research Grant
from The Japan Science Society.
a Determined by 1H NMR analysis.
6 Preparation of 4b: to a stirred solution of 3b (1.89 g, 10.0 mmol) in
pyridine (25.0 mL) was gradually added ZCl (5.71 mL, 40.0 mmol) at
0 ЊC. The mixture was stirred for 1 h at rt. After usual work-up,
purification by silica gel column chromatography (10% EtOAc in
benzene) and subsequent recrystallization (benzene–hexane) afforded
4b (2.91 g, 90%) as colorless needles, mp 97–100 ЊC; νmax(Nujol)/cmϪ1
1737, 1497, 1346 and 1155; δH(CDCl3) 3.42 (s, 3 H), 5.21 (s, 2 H),
7.12–7.42 (m, 9 H); m/z (EI-MS) 323 (Mϩ), 244, 91 (bp). A satisfac-
tory CHN analysis 0.3% was obtained. Other compounds 5b–8b
were prepared in an analogous fashion.
Notes and references
1 Chemoselective N-acylation reagents: (a) H. A. Staab and
G. Walther, Angew. Chem., 1960, 72, 35; (b) T. Kunieda, T. Higuchi,
Y. Abe and M. Hirobe, Tetrahedron Lett., 1982, 23, 1159; (c) A. Hus-
son, R. Besselievre and H.-P. Husson, Tetrahedron Lett., 1983, 24,
1031; (d) T. Kunieda, T. Higuchi, Y. Abe and M. Hirobe, Chem.
Pharm. Bull., 1984, 32, 2174; (e) A. V. Joshua and J. R. Scott, Tetra-
hedron Lett., 1984, 25, 5725; ( f ) Y. Nagao, K. Seno, K. Kawabata,
T. Miyasaka, S. Takao and E. Fujita, Chem. Pharm. Bull., 1984, 32,
2687; (g) S.-I. Murahashi, T. Naota and E. Saito, J. Am. Chem. Soc.,
1986, 108, 7846; (h) S.-I. Murahashi, T. Naota and N. Nakajima,
Chem. Lett., 1987, 879; (i) Y. Kikugawa, K. Mitsui, T. Sakamoto,
Communication 8/06186F
2974
J. Chem. Soc., Perkin Trans. 1, 1998, 2973–2974