T. Legigan, E. Migianu-Griffoni, M.A. Redouane et al.
European Journal of Medicinal Chemistry 214 (2021) 113241
4.5. Synthesis of TMS-substituted triazole 21
Compound 18a. White solid (81 mg, 84% yield). 1H NMR
(
400 MHz, MeOD, 298 K):
d
ppm ¼ 7.54 (s, 1H), 5.21 (s, 2H), 2.67 (t,
3
CuSO
269 mg, 1.36 mmol,16 mol%) were successively added to a solution
of TMS-acetylene 19 (999 mg, 10.17 mmol, 1.2 eq.) and azide 10
976 mg, 8.48 mmol, 1.0 eq.) in t-BuOH/H O 1/2 (60 mL). The
4
$5H
2
O (85 mg, 0.34 mmol, 4 mol%) and sodium ascorbate
2H, J ¼ 7.7 Hz), 1.73e1.62 (m, 2H), 1.49e1.37 (m, 2H), 0.97 (t, 3H,
3
13
(
J ¼ 7.4 Hz). C NMR (100 MHz, MeOD, 298 K):
d
ppm ¼ 169.8,
140.7, 132.6, 49.5 (partially masked by MeOD signal), 30.9, 23.4,
-
ꢃ
2
: 182.1; found:
(
2
23.3, 14.0. MS (ESI): [M ꢃ H] calcd for C
8
H
12
N
3
O
mixture was stirred at room temperature for 12 h and was diluted
with water (50 mL). The resulting aqueous layer was extracted with
AcOEt (3 ꢄ 50 mL). The combined organic layers were dried over
182.1.
Compound 18b. White solid (64 mg, 79% yield). 1H NMR
(400 MHz, MeOD, 298 K):
d
ppm ¼ 7.54 (s, 1H), 5.21 (s, 2H), 2.66 (t,
3
MgSO
4
and evaporated. Triazole 20 (1.480 g, 82% yield, white solid)
2H, J ¼ 7.7 Hz), 1.73e1.64 (m, 2H), 1.47e1.31 (m, 6H), 0.92 (t, 3H,
3
13
was obtained after purification by chromatography over silica gel
J ¼ 7.0 Hz). C NMR (100 MHz, MeOD, 298 K):
d
ppm ¼ 169.8,
1
(
(
(
EP/AcOEt 50/50). Rf: 0.61 (petroleum ether/AcOEt 50/50). H NMR
400 MHz, CDCl , 298 K):
s, 3H), 0.33 (s, 9H).
140.7, 132.6, 49.5 (partially masked by MeOD signal), 32.6, 29.9,
-
ꢃ
2
3
d
ppm ¼ 7.66 (br s, 1H), 5.20 (s, 2H), 3.80
28.8, 23.7, 23.6, 14.4. [M ꢃ H] calcd for C10
16 3
H N O : 210.1; found:
1
3
C
NMR (100 MHz, CDCl
3
,
298 K):
210.0.
þ
Compound 18c. White solid (142 mg, 100% yield). 1H NMR
d
ppm ¼ 167.1, 147.3, 130.4, 53.1, 50.2, ꢃ1.1 (3C). MS (ESI): [MþH]
þ
calcd for C
5
H
16
N
3
O
2
Si : 214.1; found: 214.0.
(400 MHz, MeOD, 298 K):
d
ppm ¼ 7.54 (s, 1H), 5.21 (s, 2H), 2.66 (t,
3
2
H, J ¼ 7.8 Hz), 1.72e1.65 (m, 2H), 1.44e1.26 (m, 10H), 0.90 (t, 3H,
3
13
4.6. Synthesis of monosubstituted triazole 22
J ¼ 6.8 Hz). C NMR (100 MHz, MeOD, 298 K):
d
ppm ¼ 169.8,
1
40.7, 132.6, 49.5 (partially masked by MeOD signal), 33.0, 30.3
-
Acetic acid (230
mL, 4.00 mmol, 1.4 eq.) and TBAF (1 M in THF,
(2C), 30.2, 28.8, 23.7 (2C), 14.4. MS (ESI): [M ꢃ H] calcd for
ꢃ
4
mL, 4.00 mmol, 1.4 eq.) were successively added to a cooled so-
C
12
20
H N
3
O
2
: 238.2; found: 238.1.
lution of TMS-substituted triazole 20 (610 mg, 2.86 mmol,1.0 eq.) in
dry THF (14.7 mL). The mixture was stirred at room temperature for
Compound 18d. White solid (129 mg, 100% yield). 1H NMR
(400 MHz, MeOD, 298 K):
ppm ¼ 7.82 (s, 1H), 7.53e7.47 (m, 5H),
5.23 (s, 2H). C NMR (100 MHz, MeOD, 298 K):
ppm ¼ 169.9,
d
13
3
6 h and THF was removed in-vacuo. The crude was purified by
chromatography over silica gel (petroleum ether/AcOEt 20/80) to
afford triazole 21 (339 mg, 84% yield) as a white solid. R : 0.30
, 298 K):
d
140.7, 133.5, 130.9, 130.3 (2C) 129.8 (2C), 127.7, 50.3. MS (ESI):
-
ꢃ
f
[M ꢃ H] calcd for C10
8 3
H N O : 202.1; found: 202.1.
2
1
Compound 23. White solid (500 mg, 87% yield). 1H NMR
(
d
petroleum ether/AcOEt 50/50). H NMR (400 MHz, CDCl
3
13
3
ppm ¼ 7.76 (s, 1H), 7.73 (s, 1H), 5.22 (s, 2H), 3.80 (s, 3H). C NMR
(400 MHz, DMSO‑d
6
, 298 K):
d
13
ppm ¼ 8.11 (d, 1H, J ¼ 1 Hz), 7.74 (d,
3
(
(
100 MHz, CDCl
ESI): [MþH] calcd for C
3
, 298 K):
d
ppm ¼ 167.0, 134.3, 125.1, 53.1, 50.6. MS
1H, J ¼ 1 Hz), 5.29 (s, 2H). C NMR (100 MHz, DMSO‑d
6
, 298 K):
þ
þ
-
5
H
8
N
3
O
2
: 142.1; found: 142.0.
d
ppm ¼ 168.7, 133.2, 126.3, 50.3. MS (ESI): [M ꢃ H] calcd for
ꢃ
4 4 3 2
H N O : 126.0; found: 126.0.
C
4.7. Synthesis of carboxylic acids 13a-d, 18a-d and 23
4.8. Synthesis of HMBP 8a-d, 9a-d and 19
Aqueous solution of NaOH (1 M, 6 equiv.) was added to a solu-
tion of methyl ester 12a-d, 17a-d or 22 in MeOH (0.05 M). The
mixture was refluxed for 30 min and MeOH was removed under
reduced pressure. Aqueous solution of HCl (1 M) was added until
pH reached 1. The aqueous layer was extracted with AcOEt
(COCl)
2
(1.8 eq.) was added to a solution of carboxylic acid 13a-d,
ꢀ
17a-d or 22 in dry DCM (0.44 M) at 0 C under argon atmosphere.
The mixture was stirred for 15 min and the solvent was evaporated
under reduced pressure at 0 C. The residue was dried under high
ꢀ
(
3 ꢄ 50 mL). The combined organic layers were dried over MgSO
4
vacuum to afford the corresponding acyl chloride which was
immediately engaged in the next step without further purification.
P(OSiMe ) (3.0 eq.) was slowly added to a cooled solution of acyl
3 3
and evaporated to afford carboxylic acid 13a-d, 17a-d or 22 which
was used in the next step without further purification.
1
Compound 13a. White solid (862 mg, 93% yield, white solid). H
chloride in dry THF (0.24 M). The mixture was stirred for 20 min at
ꢀ
NMR (400 MHz, MeOD, 298 K):
2
3
d
ppm ¼ 7.76 (s, 1H), 5.23 (s, 2H),
0 C and for 30 min at room temperature. The solvent was removed
3
.71 (t, 2H, J ¼ 7.7 Hz),1.70e1.63 (m, 2H),1.44e1.35 (m, 2H), 0.95 (t,
under reduced pressure to afford the crude phosphonosilaester
which was solubilized in dry MeOH (0.14 M). The mixture was
stirred for 16 h at room temperature and evaporated. Crude com-
pound was dissolved in a minimum amount of MeOH and this
solution was added dropwise to a large volume of dry acetone
under stirring. The white precipitate was collected and washed
with acetone to afford the pure HMBP. Freshly prepared 0.2 M
aqueous solution of NaOH (2.0 eq.) was added to a solution of the
corresponding HMBP in water (0.07 M). The pH of the resulting
solution is z 4.5. The mixture was freeze-dried to yield HMBP 8a-d,
9a-d or 18 as a disodium salt.
3
13
H, J ¼ 7.4 Hz). C NMR (100 MHz, MeOD, 298 K): ppm ¼ 169.9,
d
-
1
49.3, 124.7, 51.5, 32.7, 25.9, 23.2, 14.1. MS (ESI): [M ꢃ H] calcd for
ꢃ
C
8
H
12
N
3
O
2
: 182.1; found: 182.1.
Compound 13b. White solid (1.50 g, 87% yield). 1H NMR
400 MHz, MeOD, 298 K):
ppm ¼ 7.75 (s, 1H), 5.22 (s, 2H), 2.71 (t,
H, J ¼ 7.6 Hz), 1.74e1.62 (m, 2H), 1.42e1.28 (m, 6H), 0.90 (t, 3H,
(
d
3
2
3
13
J ¼ 7.0 Hz). C NMR (100 MHz, MeOD, 298 K):
d
ppm ¼ 169.9,
-
1
49.3, 124.7, 51.6, 32.7, 30.5, 29.9, 26.2, 23.6, 14.4. MS (ESI): [M ꢃ H]
ꢃ
16 3 2
H N O : 210.1; found: 210.1.
calcd for C10
Compound 13c. White solid (1.95 g, 89% yield). 1H NMR
400 MHz, MeOD, 298 K):
ppm ¼ 7.75 (s, 1H), 5.22 (s, 2H), 2.71 (t,
H, J ¼ 7.6 Hz), 1.74e1.62 (m, 2H), 1.43e1.23 (m, 10H), 0.95 (t, 3H,
1
(
d
Compound 8a. White solid (371 mg, 46% yield, purity ꢁ 98%). H
3
2
NMR (400 MHz, D
2
O, 298 K):
d
ppm ¼ 7.81 (s, 1H), 4.83 (t, 2H,
3
13
3
3
J ¼ 6.9 Hz). C NMR (100 MHz, MeOD, 298 K):
d
ppm ¼ 169.9,
J ¼ 9.7 Hz, partially masked by H
2
O signal), 2.65 (t, 2H, J ¼ 7.5 Hz),
3 31
1
49.3, 124.7, 51.6, 33.0, 30.5, 30.4, 30.3, 30.2, 26.2, 23.7, 14.4. MS
1.62e1.54 (m, 2H), 1.32e1.23 (m, 2H), 0.85 (t, 3H J ¼ 7.4 Hz).
P
-
ꢃ
13
(
ESI): [M ꢃ H] calcd for C12
H
20
N
3
O
2
: 238.2; found: 238.1.
NMR (162 MHz, D
2
O, 298 K):
d
ppm ¼ 14.2 (br s). C NMR
1
Compound 13d. White solid (922 mg, 99% yield). 1H NMR
400 MHz, MeOD, 298 K):
ppm ¼ 8.34 (s, 1H), 7.84e7.81 (m, 2H),
.46e7.41 (m, 2H), 7.37e7.33 (m, 1H), 5.33 (s, 2H). C NMR
100 MHz, MeOD, 298 K):
ppm ¼ 169.8, 148.9, 131.6, 130.0 (2C),
(100 MHz, D O, 298 K):
d
ppm ¼ 147.8, 125.1, 73.2 (t, J ¼ 133 Hz),
2
-
(
7
(
1
d
53.2, 30.7, 24.1, 21.3, 13.0. HRMS (ESI): [M-2Na þ H] calculated for
13
ꢃ
C
8
16
H N
3
O
7
P
2
: 328.0469; found 328.0465.
1
d
Compound 8b. White solid (89 mg, 47%, yield, purity ꢁ 98%). H
NMR (400 MHz, D O, 298 K):
ppm ¼ 7.87 (s, 1H), 4.90e4.85 (m,
2H), 2.69 (t, 2H, J ¼ 7.5 Hz), 1.68e1.60 (m, 2H), 1.34e1.23 (m, 6H),
29.4, 126.7 (2C), 123.7, 51.7. Spectral data are in agreement with
2
d
2
2
3
those previously reported in the literature.
6