Full Papers
and concentrated to give tert-butyl 4-[2-(6-aminohexyl)-2H-tetrazol-
-yl]benzoate. This intermediate (102 mg, 0.30 mmol) was dis-
Under
a
nitrogen atmosphere, this intermediate (95 mg,
5
0.39 mmol) was dissolved in dry CH Cl (10 mL) and Dess–Martin
2 2
solved in dry THF (7 mL) and then ethyl(diisopropyl)amine (57 mL)
and phenyl chloroformate (53 mg, 42 mL, 0.34 mmol) were added
dropwise. The resulting solution was stirred at RT for 5 h. Then, the
periodinane (245 mg, 0.58 mmol) was added. The mixture was
stirred at RT for 3 h. Then, a solution of Na S O (1 g) in a saturated
2
2
3
aqueous NaHCO3 solution (20 mL) was added. The mixture was
stirred for 5 min, diluted with H O, and extracted with CH Cl (2
mixture was poured into H O (20 mL) and extracted exhaustively
2
2
2
2
with CH Cl (330 mL). The organic layers were combined, dried
50 mL). The combined organic layer was dried (Na SO ), filtered,
2 4
2
2
(
Na SO ), filtered, and concentrated. The crude product was puri-
and concentrated. The residue was dissolved in a small amount of
2
4
fied by silica gel chromatography (hexane/EtOAc=8:2 to 7:3) to
yield 42 as a solid (116 mg, 83%); mp: 91–928C; H NMR (400 MHz,
toluene and chromatographed on silica gel (cyclohexane/EtOAc=
1
8:2) to yield 62 as an oil (51 mg, 54%). Data for 6-(5-phenyl-2H-tet-
1
[
D ]DMSO): d=1.26-1.40 (m, 4H), 1.40-1.51 (m, 2H), 1.57 (s, 9H),
6
razol-2-yl)hexan-1-ol: H NMR (400 MHz, CDCl ): d=1.36–1.50 (m,
3
1
.93-2.04 (m, 2H), 3.00-3.17 (m, 2H), 4.77 (t, J=7.0 Hz, 2H), 7.07 (d,
J=8.0 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 2H), 7.72
t, J=5.5 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 8.18 ppm (d, J=8.3 Hz,
4H), 1.52–1.64 (m, 2H), 2.08 (quint., J=7.1 Hz, 2H), 3.64 (t, J=
6.4 Hz, 2H), 4.66 (t, J=7.1 Hz, 2H), 7.45–7.52 (m, 3H), 8.11–
13
(
2
8.18 ppm (m, 2H); C NMR (101 MHz, CDCl ): d=25.2, 26.3, 29.5,
3
+
H); HRMS (APCI): m/z calcd for C H N O : 466.2449 [M+H ];
32.5, 53.2, 62.8, 126.9, 127.6, 129.1, 130.4, 165.2 ppm; HRMS (APCI):
2
5
31
5
4
+
found: 466.2526.
m/z calcd for C H N O: 247.1553 [M+H ]; found: 247.1551. Data
13
18
4
1
for 62: H NMR (400 MHz, CDCl ): d=1.34–1.46 (m, 2H), 1.63–1.77
3
4
-(2-{6-[(Phenoxycarbonyl)amino]hexyl}-2H-tetrazol-5-yl)benzoic
(
m, 2H), 2.00–2.14 (m, 2H), 2.46 (td, J=1.5, 7.2 Hz, 2H), 4.66 (t, J=
acid (43): TFA (1.0 mL, 13.1 mmol) was added dropwise to a solu-
tion of 42 (108 mg, 0.23 mmol) in dry CH Cl (20 mL) under an at-
7
1
5
.0 Hz, 2H), 7.43–7.53 (m, 3H), 8.09–8.17 (m, 2H), 9.76 ppm (t, J=
13
2
2
.5 Hz, 1H); C NMR (101 MHz, CDCl ): d=21.3, 25.9, 29.1, 43.5,
3
mosphere of nitrogen at 08C. The mixture was stirred at RT for
4 h. Then, the solvent was evaporated. To remove remaining TFA,
CH Cl was added and then distilled (2) to yield 43 as a solid
2.8, 126.8, 127.4, 128.9, 130.2, 165.1, 201.9 ppm. HRMS (ESI): m/z
2
+
calcd for C H N O: 245.1397 [M+H ]; found: 245.1464.
13
16
4
2
2
1
(
94 mg, 99%); mp: 189–1908C; H NMR (400 MHz, [D ]DMSO): d=
6
7-(5-Phenyl-2H-tetrazol-2-yl)heptan-1-amine (63): A solution of 5-
1
.27-1.40 (m, 4H), 1.41-1.52 (m, 2H), 1.92-2.05 (m, 2H), 2.96-3.17
phenyltetrazole (292 mg, 2.00 mmol) in propan-2-ol (6 mL) was
treated with powdered KOH (88%, 112 mg, 1.76 mmol) and heated
at reflux for 1 h. Then, a solution of 1,6-dibromoheptane (1.89 g,
(
m, 2H), 4.77 (t, J=7.0 Hz, 2H), 7.05-7.11 (m, 2H), 7.18 (t, J=7.4 Hz,
1
8
H), 7.32-7.39 (m, 2H), 7.72 (t, J=5.5 Hz, 1H), 8.09-8.13 (m, 2H),
1
3
.16-8.21 (m, 2H), 13.22 ppm (s, 1H);
C NMR (101 MHz,
1
.25 mL, 7.32 mmol) in propan-2-ol (6 mL) was added and heating
[
D ]DMSO): d=25.4, 25.5, 28.6, 28.9, 40.3, 52.9, 121.7, 124.8, 126.5,
6
was continued for 7 h. The solvent was distilled off, and the resi-
due was chromatographed on silica gel (cyclohexane/EtOAc=9:1)
to yield 1-bromo-7-(5-phenyl-2H-tetrazol-2-yl)heptane (330 mg,
1
29.2, 130.2, 130.8, 132.3, 151.1, 154.3, 163.3, 166.7 ppm; HRMS
+
(
ESI): m/z calcd for C H N O : 410.1823 [M+H ]; found: 410.1849.
21 23 5 4
5
1%). A mixture of this intermediate (310 mg, 0.96 mmol), potassi-
6
-(5-Phenyl-2H-tetrazol-2-yl)hexan-1-amine (61): A mixture of 5-
um phthalimide (178 mg, 0.96 mmol), K CO (1.4 g, 10 mmol), and
CH CN (10 mL) was heated at reflux for 14 h. After the addition of
H O (150 mL), the mixture was extracted with EtOAc (70 mL). The
organic layer was dried (Na SO ), filtered, and concentrated. The
2
3
phenyltetrazole (213 mg, 1.46 mmol), N-(6-bromohexyl)phthalimide
3
(
(
465 mg, 1.50 mmol), K CO (415 mg, 3.0 mmol), and dry CH CN
2 3 3
20 mL) was heated at reflux for 3 h. The mixture was diluted with
2
2
4
EtOAc (30 mL), filtered, and concentrated. The residue was dis-
solved in a small amount of toluene/CH Cl (3 mL) and chromato-
residue was chromatographed on silica gel (cyclohexane/EtOAc=
:1 to 8:2) to yield 2-[7-(5-phenyl-2H-tetrazol-2-yl)heptyl]isoindo-
2
2
9
graphed on silica gel (hexane/EtOAc=8:2) to yield 2-[6-(5-phenyl-
H-tetrazol-2-yl)hexyl]isoindoline-1,3-dione (393 mg, 72%). This in-
line-1,3-dione (74 mg, 20%). This intermediate (74 mg, 0.19 mmol)
was dissolved in EtOH (5 mL) and hydrazine hydrate (24% w/w,
1
solvent was evaporated, and the resulting residue was treated with
brine (30 mL). After adjusting the pH value of the mixture to ~10
with dilute NaOH, the solution was extracted exhaustively with
CH Cl2 (330 mL), dried (Na SO ), filtered, and concentrated to
yield 63 as a waxy substance (47 mg, 95%). Data for 1-bromo-7-(5-
phenyl-2H-tetrazol-2-yl)heptane: H NMR (300 MHz, CDCl3): d=
2
termediate (393 mg, 1.05 mmol) was dissolved in EtOH (25 mL), hy-
drazine hydrate (24% w/w, 1.8 mL) was added, and the mixture
was heated at reflux for 3 h. The solvent was evaporated, and the
resulting residue was treated with brine (30 mL). After adjusting
the pH value of the mixture to ~10 with dilute NaOH, the solution
was extracted exhaustively with CHCl (330 mL), dried (Na SO ),
.0 mL) was added. The mixture was heated at reflux for 3 h. The
2
2
4
3
2
4
filtered, and concentrated to yield 61 as a waxy compound
1
1
(
230 mg, 89%). H NMR (400 MHz, CDCl ): d=1.35–1.43 (m, 4H),
3
1
3
.33–1.51 (m, 6H), 1.85 (quint., J=6.9 Hz, 2H), 2.01–2.13 (m, 2H),
.40 (t, J=6.8 Hz, 2H), 4.65 (t, J=7.1 Hz, 2H), 7.43–7.53 (m, 3H),
1
6
8
4
.43–1.49 (m, 2H), 1.52–1.68 (m, 2H), 2.04–2.11 (m, 2H), 2.69 (t, J=
.6 Hz, 2H), 4.65 (t, J=7.1 Hz, 2H), 7.44–7.53 (m, 3H), 8.11–
.18 ppm (m, 2H); C NMR (101 MHz, CDCl ): d=26.3, 29.5, 33.4,
1
3
8.11–8.18 ppm (m, 2H); HRMS (ESI): m/z calcd for C H BrN :
14 19 4
3
(400 MHz, CDCl ): d=1.28–1.39 (m, 6H), 1.40–1.48 (m, 2H), 1.60–
1
7.1 Hz, 2H), 7.45–7.52 (m, 3H), 8.12–8.17 ppm (m, 2H); C NMR
(101 MHz, CDCl ): d=26.5, 26.8, 28.9, 29.5, 33.5, 42.1, 53.3, 126.9,
127.7, 129.0, 130.4, 165.2; HRMS (ESI): m/z calcd for C14
3
+
1
23.0866 [M+H ]; found: 323.0865. Data for 63: H NMR
2.1, 53.2, 126.9, 127.7, 129.0, 130.4, 165.2 ppm; HRMS (APCI): m/z
+
3
calcd for C H N : 246.1713 [M+H ]; found: 246.1734.
1
3
19
5
.77 (m, 2H), 2.03–2.10 (m, 2H), 2.66–2.72 (m, 2H), 4.64 (t, J=
1
3
6
-(5-Phenyl-2H-tetrazol-2-yl)hexanal (62): A solution of 5-phenyl-
tetrazole (292 mg, 2.00 mmol) in propan-2-ol (6 mL) was treated
with powdered KOH (88%, 112 mg, 1.76 mmol) and then heated at
reflux for 1 h.
3
H
21
N
:
5
+
A
solution of 6-bromohexan-1-ol (362 mg,
260.1870 [M+H ]; found: 260.1866.
2
.00 mmol) in propan-2-ol (6 mL) was then added and heating was
continued for 9 h. The solvent was distilled off and the residue was
7-(5-Phenyl-2H-tetrazol-2-yl)heptanal
(64):
5-Phenyltetrazole
treated with H O (150 mL). The resulting mixture was extracted
(292 mg, 2.00 mmol) was treated with 7-bromoheptan-1-ol
(390 mg, 2.00 mmol) by using the procedure described above for
the synthesis of 6-(5-phenyl-2H-tetrazol-2-yl)hexan-1-ol. The reac-
tion time was 15 h. An aliquot of the obtained intermediate, 7-(5-
phenyl-2H-tetrazol-2-yl)heptan-1-ol (148 mg, 0.57 mmol), was oxi-
2
with CH Cl (70 mL). The organic layer was dried (Na SO ), filtered,
2
2
2
4
and concentrated. The residue was dissolved in a small amount of
toluene and chromatographed on silica gel (cyclohexane/EtOAc=
7
:3) to yield 6-(5-phenyl-2H-tetrazol-2-yl)hexan-1-ol (197 mg, 40%).
ChemMedChem 2016, 11, 429 – 443
440
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim