362 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 362–363†
Synthesis of 2-Aminotropone Oximes and 2-Alkoxytropone
Imines†
Tetsuo Nozoe,1‡ Lung Ching Lin,*ab Chih-Hsien Hsu,a Shwu-Chen Tsay,b
Gholam H. Hakimelahib and Jih Ru Hwu*b,c
aDepartment of Chemistry, National Taiwan University, Taipei, Taiwan 10671, Republic of
China
bInstitute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, Republic of China
cDepartment of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, Republic of
China
A synthetic route was developed for preparation of 2-aminotropone oximes 10–14, a new class of compounds, from
tropolone 2; 2-methoxytropone imines 7–9 and tropylium salts 17 were generated as the key intermediates.
cis-Diamminedichloroplatinum analogues 1 are used as
drugs for clinical cancer chemotherapy.2,3 In order for 1 to
exhibit significant biological activity, the two amino groups
must be in a cis configuration in 1.4,5 Here we report the
preparation of 2-aminotropone oximes (e.g., 10–14), in which
the two adjacent nitrogen atoms are attached to a planar
nucleus and could coordinate to Pt to form cis-platinum
complexes.
more, our attempts to oximate 2-(p-tolylsulfonyl)tropone
and 2-aminotropone were also unsuccessful. Herein we
report an indirect way to convert tropolone 2 to the desired
2-aminotropone oximes 10–14. To the best of our know-
ledge, this provides the only available up-to-date route for
the preparation of 2-aminotropone oximes, an unprece-
dented class of compounds.
After tosylation of 2,10 the resultant toluene-p-sulfonate 3
was treated with various amines,11 including p-toluidine,
benzylamine and cyclohexylamine, in BuOH under reflux to
give the corresponding 2-aminotropones 4–6 in 65–76%
yields (Scheme 1). Methylation11 of 4–6 with dimethyl sulfate
in toluene under reflux followed by treatment with NaHCO3
afforded the 2-methoxytropone imines 7–9 in 60–65% over-
Cl
Cl
NH2R
NH2R
Pt
1 R = alkyl, aryl
.
Reaction of tropone with NH2OH HCl and pyridine in
methanol generates tropone oxime and 2-aminotropone.6
Under the same conditions, 2-alkyltropones can also be con-
verted to 2-alkyltropone oximes and 2-alkyl-7-aminotro-
pones,7 yet tropolone 2 remains intact.8 By replacement of
pyridine with various bases, including NaOH, NaOMe,
NaOAc, Na2CO3 and Et3N, we were also unable to convert
tropolone to the corresponding oximes by using
.
all yields. Upon reaction with NH2OR HCl (R = H or Me)
and NaOMe in MeOH, 7–9 were converted to the desired
oximes 10–14 in 24–54% yields. The spectroscopic data are
summarized in Table 1. In these reactions, an unexpected
by-product (i.e., 2-methoxytropone oxime 15 or 16) was
generated and its structure was determined with the aid of
single-crystal X-ray diffraction analysis.§ Formation of
oximes 10–14 came from a nucleophilic attack of 7–9 by
NH2OR (R = H or Me) at the C-2 position and formation of
oximes 15 and 16 came from an attack at the C-1 position.
Furthermore, we found that reactions of 2-aminotropones
4–6 with methyl fluorosulfonate gave the corresponding isol-
able tropylium salts 17 (Scheme 2).12 The desired oximes
.
NH2OH HCl. The unusual resonance phenomenon associ-
ated with tropolone and an inherent intramolecular hydro-
gen bonding between the OH and the CtO groups9 may
decrease its reactivity towards oxime formation. Further-
O
O
OMe
H
2
O
N
1
N
R1
R2
R2
i,ii
iii
.
10–14 can be obtained by treatment of 17 with NH2OH HCl
.
or NH2OMe HCl. Moreover, we were able to synthesize
2 R1 = H
3 R1 = SO2C6H4-p-Me
4 R2 = C6H4-p-Me
5 R2 = CH2Ph
6 R2 = c-C6H11
7 R2 = C6H4-p-Me
8 R2 = CH2Ph
9 R2 = c-C6H11
2-aminotropone imines 18–20 in high yields (ꢀ80%) by
treating tropylium salts 17 with primary amines, including
p-toluidine and benzylamine.13 These 2-aminotropone imines
were also obtained in excellent yields (91–98%) by the reac-
tions of 2-methoxytropone imines 7 and 8 with amines
(Scheme 2 and Table 1).11
iv
R3O
OMe
N
H
In conclusion, 2-methoxytropone imines 7–9 and tropy-
lium salts 17 were prepared readily from tropolone 2 via
toluene-p-sulfonate 3 and 2-aminotropones 4–6. These key
intermediates (i.e., 7–9 and 17) were successfully converted
to the 2-aminotropone oximes (10 and 11) and oxime methyl
N
N
OR3
R2
+
15 R3 = H
16 R3 = Me
10 R2 = C6H4-p-Me, R3 = H
11 R2 = CH2Ph, R3 = H
.
ethers (12–14) upon treatment with NH2OR HCl (R = H or
Me), and to 2-aminotropone imines 18–20 with primary
amines. Use of the resultant new nitrogen-containing planar
compounds to form cis-diamminedichloroplatinum ana-
logues and to test their biological activity are under investiga-
tion in our laboratory.
12 R2 = C6H4-p-Me, R3 = Me
13 R2 = CH2Ph, R3 = Me
14 R2 = c-C6H11, R3 = Me
Scheme 1 Reagents and conditions: i, for 2h3:
p-MeC6H4SO2Cl, pyridine, 0 °C (96%); ii, for 3h4: p-MeC6H4NH2,
BuOH, reflux (72%); for 3h5: PhCH2NH2, BuOH, reflux (76%);
for 3h6: cyclohexylamine, BuOH, reflux (65%); iii, for
4–6h7–9: Me2SO4, toluene, reflux, NaHCO3 (aq) (60–65%); iv,
Experimental
General Procedure for the Conversion of 2-Methoxytropone Imines
(7–9) to 2-Aminotropone Oximes 10–14.sTo a clear solution of
.
for 7h10ǹ15 and 8h11ǹ15: NH2OH HCl, NaOMe, MeOH; for
.
.
NH2OH HCl or NH2OMe HCl (2.30 mmol) and NaOMe (2.30
mmol) in MeOH (20 mL) was added a 2-methoxytropone imine
(7–9, 2.22 mmol). The reaction mixture was stirred at room tem-
perature for 4.0 h. After the solvent was removed under reduced
.
7–9h12–14ǹ16: NH2OMe HCl, NaOMe, MeOH
*To receive any correspondence.
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
‡Deceased April 4, 1996.
§Details of the X-ray crystal-structure determination will be
reported elsewhere.
Nozoe, Tetsuo
