Table 2 Cyclization/recyclization of salicylamides 7
were silylated prior to the methylation, using TBSTrf and
Hünig’s base. Meerwein’s salt in dichloromethane was found
to be the reagent of choice for the methylation reaction. For
comparison reasons the obtained reaction mixtures were
subsequently desilylated in CF3COOH containing 1% of H2O.
A 1 : 1 N(2) : N(4) selectivity was found in all the investigated
cases, supporting the H-bridged theory by Ryabukhin.
In summary, we have developed a concise and efficient
synthetic methodology leading to a structurally diverse array
of oxadiazolium derivatives,11 starting from commercially
available halogenated phenols. The strategy also involves a
new and rapid access to all meta-halogenated salicylic acids,
compounds of high synthetic value.
Entry
R1
R2
R3
10 (%)a
3 (%)a
A
B
C
D
E
E
G
H
H
F
Cl
Br
H
F
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
91
68
63
51
87
74
60
65
95
72
76
71
59
54
56
58
Cl
Br
a Isolated yields.
Notes and references
1 K. S. Chester, Q. Rev. Biol., 1933, 8, 275–324.
2 J. P. Metraux, H. Signer, J. Ryals, E. W. Ward, M. Wyss-Benz,
J. Gaudin, K. Raschdorf, E. Schmidt, W. Blum and B. Invardi,
Science, 1990, 250, 1004–1006.
3 S. B. Bulgarevich, T. A. Yusman, O. Y. Ryabukhina, N. I. Doro-
khova, Y. I. Ryabukhin, G. N. Dorofeenko and O. A. Osipov, Zh.
Obshch. Khim., 1981, 51(6), 1418–22.
4 Y. I. Ryabukhin, A. Y. Eliseeva and K. Ph. Suzdalev, Chemistry of
Heterocyclic Compounds, 1992, 2, 236–237.
Scheme 2 Reagents and conditions: (i) Ac2O, HClO4, 72 h, rt; (ii)
NH2OHؒHCl, NaAc, AcOH, 2 h, rt.
5 Y. I. Ryabukhin, A. Y. Eliseeva, K. F. Suzdalev, S. B. Bulgarevich,
D. Y. Movshovich and A. P. Knyazev, Chem. Heterocycl. Compd.,
1992, 4, 454–463.
6 N. I. Vikrishchuk, K. F. Suzdalev, Y. I. Ryabukhin and A. Y.
Zhdanov, Russ. J. Org. Chem., 1998, 34(4), 564–569.
7 O. Piccolo, L. Filippini and L. Tinucci, Tetrahedron Lett., 1986,
42(3), 885–891.
8 M. Adachi and T. Sugasawa, Synth. Commun., 1990, 20(1),
71–84.
9 For alternative synthetic entries see: A. M. L. Micklatcher and
M. Cushman, Synthesis, 1999, 11, 1878–1880; B. S. Y. W. Lau and
B. A. Keay, Can. J. Chem., 2001, 79(11), 1541–1545; C. R. F. Pellon
Condom and M. L. Docampo Palacios, Synth. Commun., 2002,
32(13), 2055–2059.
10 Y. I. Ryabukhin, G. N. Dorofeenko and V. V. Mezheritskii, Khim.
Geterotsikl. Soedin., 1975, 2, 280.
11 All new compounds were completely characterized and gave
satisfactory spectral and analytical data. Selected data: Compound
10f (R1= F, R2 = R3 = Me): 1H-NMR (CD3CN) δ: 3.12(s, 3H);
3.80(s, 3H); 7.81(dt, 1H); 7.97(td, 1H); 8.08 (d, 1H); ES-MS m/z
411(Mϩ1); Mp: 202–205 ЊC (diethylether). Compound 11f (R1 = F,
1
Scheme 3 Reagents and conditions: (i) I. Me2SO4, 110 ЊC, 4 h; II.
HClO4, AcOH, rt; (ii) TBSTrf, Hünig’s base, CH2Cl2, rt, 8 h; (iii)
Meerwein’s salt, CH2Cl2, rt, 12 h; (iv) CF3COOH, 1% H2O, 80 ЊC, 4 h.
R2 = H, R3 = Me): H-NMR (CD3CN) δ: 2.58(s, 3H); 7.06(dt, 1H);
7.48(dd, 1H); 7.80(d, 1H); ES-MS m/z 196(Mϩ1); Mp: 120–122 ЊC
(H2O). Compound 3f (R1 = F, R2 = R3 = Me): 1H-NMR (CD3CN) δ:
2.52(s, 3H); 3.61(s, 3H); 6.98(dt, 1H); 7.35(dd, 1H); 7.61(d, 1H);
7.80(br s, 1H); ES-MS m/z 209(Mϩ1); Mp: 178–180ЊC (AcOH).
Compound 4f (R1 = F, R2 = R3 = Me): 1H-NMR (CD3CN) δ: 2.59(s,
3H); 4.11(s, 3H); 6.92(dt, 1H); 7.38(dd, 1H); 7.65(d, 1H); 7.80(br s,
1H); ES-MS m/z 209(Mϩ); Mp: 152–156ЊC (AcOH).
mixture of both regioisomers 3 and 4 (Scheme 3). Recrystalliz-
ation from AcOH–ether furnished pure oxazolium derivatives
4. To verify the H-bridge influence, compounds of the type 11
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 6 3 – 9 6 4
964