1
room temperature. The mixture was heated at reflux for 90 h.
MeOH (200 cm ) was slowly added to the mixture at 0 ЊC and
the resulting solution stirred for 1 h at room temperature and
H NMR (CDCl ): δ 2.99 (6H, s), 3.22–3.44 (4H, dd), 3.66 (6H,
3
3
s), 4.92–4.94 (2H, ddd), 6.84 (2H, s), 7.41 (2H, s), 7.42 (2H, s)
and 8.97–9.00 (2H, d, J = 7.92 Hz).
neutralized with saturated aqueous NaHCO . After evapor-
3
ation of MeOH in vacuo, insoluble material was removed by
filtration and the filtrate extracted with ethyl acetate. The
extract was dried over Na SO , concentrated in vacuo and
the crystalline dimethyl 4-chloropyridine-2,6-dicarboxylate 5
deposited collected and washed with hexane. A suspension of
diester 5 in 1 M NaOH was stirred at 80 ЊC for 2 h. The solution
was cooled with ice and acidified with 1 M HCl to pH 4. The
white precipitate was collected to give compound 6 in 85% yield
based on 4.
Syntheses of the copper(II) complexes
II
[
Cu (HPH-Pep)]ؒ2H O 10ؒ2H O. To
a
solution of3
2
2
2
4
copper() acetate monohydrate (14.3 mg, 0.07 mmol) in 2 cm
of methanol was added dropwise a solution of 33.5 mg (0.07
3
mmol) of compound 1 in 5 cm of methanol under agitation.
The resulting blue solution was stirred at room temperature
for 18 h. The methanol was then removed under vacuum, and
3
the residue redissolved in 3 cm of 2:1 (v/v) methanol–
3
acetonitrile and filtered. Subsequent addition of 2 cm of
diethyl ether to the filtrate afforded light blue crystals which
were recrystallized from 70% aqueous methanol solution. Yield
Dimethyl 4-butylmethylaminopyridine-2,6-dicarboxylate (8).
A suspension of compound 6 (3 g, 14.8 mmol) in aqueous
1
8 mg (45%). Calc. for C H CuN O ؒ2H O: C, 44.51; H, 4.45;
3
21 21 7 6 2
N-butylmethylamine (25% solution, 35 cm ) was stirred at
N, 17.32. Found: C, 44.32; H, 4.40; N, 17.19%. Selected IR
1
50 ЊC for 2 h in a sealed tube. The resulting solution was con-
Ϫ1
bands (KBr): 1735 (νCO, vs, methyl ester) and 1581 cm (νCO
,
centrated in vacuo to give crude 7 that was used for the next step
vs, imido anion).
3
without further purification. Thionyl chloride (22.3 cm ) was
slowly added to an ice-cooled mixture of the above acid 7 in dry
MeOH (100 cm ). The solution was heated at reflux for 12 h and
concentrated in vacuo. The residue was partitioned between
II
[
Cu (MeBuN-HPH-Pep)] 11. To a stirred solution of
3
3
copper() acetate monohydrate (11.9 mg, 0.06 mmol) in 3 cm
of methanol was added dropwise a solution of 33.2 mg (0.06
mmol) of compound 2 in 3 cm of methanol under agitation.
The resulting blue solution was stirred at room temperature for
saturated aqueous NaHCO and ethyl acetate. The aqueous
3
3
layer was further extracted with ethyl acetate. The extract
was dried over Na SO and concentrated in vacuo. The residue
2
4
2
4 h. The methanol was then concentrated to one-third of its
was purified by chromatography on silica gel with CH Cl –
2
2
original volume. The blue solution was filtered and diethyl ether
MeOH (2:1) to give 8 as yellow-brown oil in 70% yield based
3
(
2
5 cm ) added to the filtrate. Light blue crystals formed within
4 h. They were collected by filtration, washed with diethyl
ether and dried in air. Yield 29 mg (71%). Calc. for C H -
on 6. IR (film): 3500, 2950, 1720, 1600, 1400, 1250, 1160, 1030,
Ϫ1
1
7
80 and 730 cm . MS(FAB): m/z 281. H NMR (CDCl ):
3
26
32
δ 0.94–1.00 (2H, t, J = 8.1), 1.36–1.58 (2H, m), 1.60–1.66 (2H,
m), 3.08 (3H, s), 3.42–3.47 (2H, t, J = 6.8 Hz), 3.98 (6H, s)
and 7.49 (2H, s). Calc. for C H N O ؒ0.5H O: C, 58.12; H,
CuN O ؒ2CH OH: C, 49.44; H, 5.94; N, 16.49. Found: C,
8
6
3
4
9.64; H, 5.45; N, 16.64%. Selected IR bands (KBr): 1733 (νCO,
Ϫ1
14
20
2
4
2
vs, methyl ester) and 1581 cm (νCO, imido anion).
7
.32; N, 9.68. Found: C, 58.17; H, 7.67; N, 9.52%.
II
[
Cu (Me N-HPH-Pep)]ؒ2CH OH 12ؒ2CH OH. To a stirred
2
3
3
4
-Butylmethylaminopyridine-2,6-dicarboxylic acid (7).
A
3
solution of copper() acetate monohydrate (8.6 mg, 0.02 mmol)
suspension of diester 8 (1 g, 4.0 mmol) in 1 M NaOH (5 cm )
was stirred at 80 ЊC for 1 h. The solution was acidified with 1 M
HCl to pH 4 and concentrated in vacuo to give compound 7 as a
white powder in quantitative yield. IR (KBr): 3450, 3320,
260, 3080, 2955, 2930, 2870, 1615, 1580, 1520, 1410, 1360,
280, 920, 895, 805 and 720 cm . MS (FAB): m/z 253. H
NMR (CDCl ): δ 0.98–1.04 (3H, t, J = 7.26), 1.38–1.51 (2H, m),
.65–1.73 (2H, m), 3.32 (3H, s), 3.66–3.72 (2H, t, J = 7.58 Hz)
and 7.51 (2H, s).
3
in 5 cm of methanol was added dropwise a solution of 22.0 mg
3
(
0.04 mmol) of compound 3 in 8 cm of methanol under
agitation. The resulting blue solution was stirred at room
temperature for 24 h. The methanol was then removed under
vacuum and the residue purified by chromatography on
3
1
Ϫ
1
1
silica gel eluted with MeOH to give complex 12ؒ2CH OH. The
3
3
3
eluate was concentrated and the residue redissolved in 2 cm of
1
methanol and filtered. Diethyl ether was allowed to diffuse
slowly into the filtrate. Light blue crystals formed within 48 h.
The crystals were collected by filtration, washed with diethyl
BuMeN-HPH-PepH (2). Diphenoxyphosphoryl azide (0.68
2
3
3
ether and dried in air. Yield 15 mg (55%). Calc. for C23H26-
cm , 3.17 mmol) and triethylamine (0.88 cm , 6.34 mmol) were
successively added to a solution of compound 7 (200 mg, 0.79
mmol) and histidine methyl ester dihydrochloride (348 mg, 1.58
CuN O ؒ2CH OH: C, 47.08; H, 5.38; N, 17.58. Found: C,
8
6
3
4
6.60; H, 5.29; N, 17.75%. Selected IR bands (KBr): 1733 (νCO,
Ϫ1
vs, methyl ester) and 1581 cm (νCO, vs, imido anion).
3
mmol) in DMF (10 cm ) at 0 ЊC. The solution was stirred at
0
ЊC for 2 h then at room temperature for 3 days and concen-
Crystallography
trated in vacuo. The residue was partitioned between saturated
aqueous NaHCO3 and chloroform. The aqueous layer was
further extracted with chloroform. The chloroform extract
was dried over Na SO and concentrated in vacuo. The residue
Diffraction data for complex 10ؒ2H O were collected with a
Rigaku AFC-5 diffractometer and graphite-monochromated
Cu-Kα radiation, those for 12ؒ2CH OH with a Rigaku AFC 7R
2
2
4
3
was purified by chromatography on silica gel with CH Cl –
diffractometer and graphite-monochromated MoKα radiation.
2
2
MeOH–Et N (20:1:1) as eluent to give 2 as a pale yellow
All the calculations were performed with the TEXSAN crystal-
3
8
powder in 40% yield. IR (KBr): 3300, 2960, 1740, 1660, 1610,
lographic software package on an Iris Indigo workstation. The
Ϫ1
9
1
525, 1435, 1215, 1175 and 740 cm . MS (FAB): m/z 555.
structures were solved by a direct method (SIR 88) and
1
10
H NMR(CDCl ): δ 0.89–0.94 (3H, t, J = 7.24), 1.37–1.52
expanded using Fourier techniques.
Scattering factors
3
(
4
2H, m), 1.65–1.72 (2H, m), 3.01 (3H, s), 3.16–3.29 (4H, dd),
.98–5.00 (2H, ddd), 3.36–3.39 (2H, t), 3.70 (6H, s), 6.84 (2H,
were taken from ref. 11. Non-hydrogen atoms except carbon
atoms C4 and C16 and oxygen atom O17 were refined aniso-
tropically, while C4, C16, and O17 were refined isotropically.
All the hydrogen atoms were included in the models at their
calculated positions but not refined. Crystal data are given in
Table 2.
s), 7.38 (2H, s), 7.46 (2H, s) and 8.86–8.89 (2H, d, J = 8.23 Hz).
Calc. for C H N O : C, 52.09; H, 5.97; N, 18.69. Found: C,
5
13
17
4
3
2.20; H, 5.79; N, 18.48%.
Me N-HPH-PepH (3). Compound 3 was prepared using 9
CCDC reference number 186/2296.
See http://www.rsc.org/suppdata/dt/b0/b006949n/ for crystal-
lographic files in .cif format.
2
2
as described above for 2. IR (KBr): 3300, 2960, 1740, 1660,
Ϫ1
1
610, 1525, 1435, 1220, 1175 and 775 cm . MS (FAB): m/z 513.
4
42 J. Chem. Soc., Dalton Trans., 2001, 441–447