1
3
.
Method A
shown by H NMR. This material was of good enough quality
to use in the step. Analytically pure samples could be obtained
Cyclen (4, 2.52 g, 14.7 mmol) and 5Cl (2.87 g, 9.78 mmol) were
by column chromatography [silica, EtOAc–CH
ESI-MS (C15
2
Cl
2
(1 : 9)]: HR-
dissolved in dry DMF (30 mL). K CO (3 g, 22 mmol) and NaI
3 g, 20 mmol) were added to the solution. The reaction mixture
2
3
+
H
16NO
3
Br) calcd 338.0386 [M + H] , obsd 338.0389
(
+
1
[
M + H] ; H NMR d 1.10 (t, J = 7.0 Hz, 3H), 2.27 (s, 3H),
◦
was stirred at 80 C under an Ar atmosphere for 24 h. The DMF
was removed at reduced pressure. The residue was dissolved in
a mixture of water and CH
the aqueous phase was extracted with 2 × 30 mL CH
combined organic phases were washed with 30 mL water, dried
over MgSO , filtered, and evaporated to dryness. The dark yellow
oily residue was dissolved in a minimum amount of methanol and
triturated with ether. The crystals were filtered and washed with
small portions of cold diethyl ether. The product was isolated as
pale yellow crystals in 87% yield (3.65 g). For characterisation see
Method B.
2
6
1
1
1
.40 (s, 3H), 3.13–3.23 (m, 1H), 3.61 (s, 2H), 4.08–4.18 (m, 1H),
13
.28 (s, 1H), 7.09 (s, 1H), 7.49 (s, 1H); C NMR 12.49, 17.38,
8.64, 41.54, 43.99, 116.04, 117.58, 120.38, 127.24, 131.97, 142.17,
51.29, 152.02, 159.96, 165.45; mp: 171 C; IR (mmax/(cm ), KBr):
723, 1676, 1626, 1614, 1558, 1502, 1444.
2
Cl
2
. The phases were separated and
2
2
Cl . The
◦
−1
4
+
1
(5) . (Limited characterisation) ESI-MS: 513 [M + H] ; H
2
NMR d 1.11 (t, J = 7.1 Hz, 6H), 2.23 (s, 6H), 2.39 (s, 6H), 3.20–
3.31 (m, 2H), 3.45 (d, J = 15.8 Hz, 2H), 3.74 (d, J = 15.8 Hz,
2H), 4.07–4.19 (m, 2H), 6.28 (s, 2H), 7.03 (s, 2H), 7.53 (s, 2H);
C NMR 12.76, 17.12, 18.65, 30.29, 43.67, 60.66, 116.18, 117.58,
20.56, 132.01, 140.39, 151.24, 152.20, 159.79, 171.14; mp: 133–
1
3
1
1
1
◦
−1
34 C; IR (mmax/(cm ), KBr): 3450, 3066, 2983, 2930, 1728, 1662,
611, 1557, 1499, 1448.
Method B
Cyclen (4, 2.52 g, 14.7 mmol) and 5Cl (2.87 g, 9.78 mmol)
were dissolved in 100% EtOH (25 mL), in the presence of TEA
6
Boc. A sample of 3 (3.10 g, 7.23 mmol) was dissolved in
CHCl (100 mL) and TEA (10.20 mL, 7.40 g, 72.3 mmol) was
added to the solution. The solution was flushed with Ar for
0 min. N-Boc-Bromoethylamine (1.77 g, 7.95 mmol), dissolved in
CHCl (20 mL) was added dropwise (1 h). Stirring was continued
for 24 h. Water was added. The phases were separated and
the aqueous phase was extracted with CH Cl . The combined
organic phases were washed with water and dried (MgSO ). The
solution was concentrated. The sample was subjected to column
3
(
2
4.12 mL, 29.34 mmol, 3 eq). The solution was heated at reflux for
4 h under an inert atmosphere. The solvents were evaporated.
Chromatography on basic alumina [pH 9.5, CH Cl –MeOH
0 → 10%)] yielded a pale yellow foam (1.89 g, 45%): HR-ESI-MS
): calcd 430.2813 obsd 430.2814 [M + H] ; H NMR
1
2
2
3
(
(
+
1
C
23
H
35
N
5
O
3
2
2
d 1.11–1.16 (t, J = 6.8 Hz, 3H), 2.27 (s, 3H), 2.40 (s, 3H), 2.66–3.32
4
(
m, 17H), 3.41 (q, J = 6.8 Hz, 2H), 3.99–4.11 (m, 1H), 6.26 (s,
13
1
4
1
H), 7.04 (s, 1H), 7.50 (s, 1H); C NMR 12.80, 15.22, 17.53, 18.69,
3.36, 45.33, 46.40, 47.65, 51.87, 65.79, 115.81, 117.27, 120.21,
27.48, 131.95, 142.23, 151.58, 152.07, 160.10, 169.88.
i
chromatography [silica, CH
pale yellow solid (1.21 g, 29%): HR-ESI-MS (C30
2
Cl
2
– PrNH
2
(0 → 20%)] to afford a
H
48
N
6
O
5
): calcd
+
1
5
3
4
1
5
1
5
1
73.3759 [M + H] , obsd 573.3765; H NMR d 1.06 (t, J = 7.1 Hz,
H), 1.22 (s, 9H), 2.24 (s, 3H), 2.39 (s, 3H), 2.38–3.23 (m, 24H),
5
Cl. Coumarin 2 (11, 210 mg, 1.00 mmol) was dissolved in
CH Cl (10 mL). Chloroacetic acid (0.13 g, 1.30 mmol) and EDCI
0.19 g, 1.00 mmol) were added and the solution was stirred at
room temperature for three days. The solution was diluted with
CH Cl and water, the phases were separated, the aqueous phase
was extracted with CH Cl . The combined organic phases were
washed with dilute NaOH and water. The organic layer was dried
MgSO ), filtered and concentrated. Chromatography [silica, ethyl
acetate–hexane (1 : 1)] yielded recovered coumarin 2 (70 mg,
3%) and a white, crystalline solid (200 mg, 67%): HR-ESI-MS
1
3
.02 (m, 1H), 6.26 (s, 1H), 7.00 (s, 1H), 7.48 (s, 1H); C NMR
2.72, 17.22, 18.55, 28.19, 38.79, 43.09, 45.96, 47.41, 47.63, 51.49,
1.75, 51.98, 53.16, 53.35, 77.98, 115.67, 117.07, 120.02, 127.25,
31.65, 142.70, 151.44, 152.05, 156.07, 159.96, 169.56, 172.73; mp:
2
2
(
2
2
◦
−1
5 C; IR (mmax/(cm ), KBr): 3368, 2975, 2933, 2824, 1703, 1664,
2
2
626, 1614, 1559, 1502.
(
4
1
5Boc. A sample of 6Boc (1.09 g, 1.91 mmol) was dissolved
in CH CN (6 mL). K CO (4.25 g, 30.6 mmol), NaI (4.58 g,
0.6 mmol) and ethyl bromoacetate (2.12 mL, 3.19 g, 19.1 mmol)
3
2
3
3
3
+
+
(
C
15
H
16NO
3
Cl): calcd 294.0891 [M + H] , obsd 294.0891 [M + H] ;
were added to the solution. The mixture was refluxed under Ar
for 24 h. The sample was concentrated. The residue was dissolved
in a mixture of water and CH
the aqueous phase was extracted with CH
organic phases were washed with water and dried (MgSO
The solution was concentrated. Column chromatography [silica,
CH
0%): ESI-MS: 743 [M + H] , 765 [M + Na] ; H NMR d 1.12
m, 3H), 1.25 (m, 6H), 1.38 (s, 9H), 2.32 (s, 3H), 2.45 (s, 3H),
.00–3.21 (m, 33H), 4.15 (m, 1H), 6.29 (s, 1H), 6.95 (s, 1H), 7.62
1
H NMR d 1.11 (t, J = 7.0 Hz, 3H), 2.27 (s, 3H), 2.39 (s, 3H), 3.14–
3
1
1
1
1
.26 (m, 1H), 3.67 (s, 2H), 4.04–4.18 (m, 1H), 6.28 (s, 1H), 7.08 (s,
H), 7.48 (s, 1H); C NMR 13.04, 17.94, 19.17, 42.05, 44.54,
16.62, 118.16, 120.88, 127.75, 132.51, 142.55, 151.96, 152.78,
60.55, 165.86; mp: 172 C; IR (mmax/(cm ), KBr): 1722, 1678,
626, 1615, 1558, 1502, 1444, 1402.
2
Cl
2
. The phases were separated and
Cl . The combined
).
1
3
2
2
4
◦
−1
i
2
Cl
2
– PrNH
2
(0 → 5%)] yielded an off-white solid (0.99 g,
+ + 1
7
(
5
Br. Coumarin 2 (11, 4.06 g, 18.70 mmol) and bromoacetic
acid (10.40 g, 74.80 mmol, 4 eq) were dissolved in CH Cl
2
2
.
2
(
EDCI (14.36 g, 74.80 mmol, 4 eq) was added in small portions
to the vigorously stirred solution. The reaction was allowed to
proceed for 24 h at room temperature. The reaction mixture was
1
3
s, 1H); C NMR 12.58, 14.06, 14.12, 17.53, 18.87, 28.38, 43.48,
4
1
1
3.71, 50.52, 53.40, 55.10, 55.73, 56.27, 61.23, 61.36, 67.74, 79.98,
05.01, 115.84, 116.78, 117.10, 120.49, 127.99, 141.48, 141.55,
51.86, 160.06, 170.64, 173.24.
diluted with water and CH
the aqueous layer was extracted with CH
organic phases were washed with water and NaOH (2 M), dried
MgSO ), and filtered. The sample was concentrated to dryness
2
Cl
2
. The phases were separated and
2
2
Cl . The combined
15. A solution of 15Boc (0.99 g, 1.33 mmol) in CH
was treated with TFA (5 mL). The reaction mixture was stirred
at room temperature for 30 min. The volatile components were
2
2
Cl (10 mL)
(
4
to yield a white solid (5.28 g, 84%), which was ∼87% pure, as
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2274–2282 | 2281