Synthesis of C5-tetrazole derivatives of 2-amino-adipic acid
919
1 mmol) and potassium phthalimide (555 mg, 3 mmol) to
afford 288 mg (77%) of the title compound as a greenish
oil. 1H NMR (CDCl3, SiMe4): d 2 (m, 1H), 2.2 (m, 3H), 3.5
(s, 3H), 3.6 (s, 3H), 4.7 (m, 1H), 5.4 (m, 1H), 6.1 (m, 1H),
6.7 (d, 1H, J = 2 Hz), 6.8 (d, 1H, J = 9.2 Hz), 7.5 (m,
2H), 7.65 (m, 2H), 10.1 (s, 1H) ppm. 13C NMR (CDCl3,
SiMe4): d 25.77, 28.09, 51.88, 53.38, 53.79, 65.11, 110.59,
110.76, 119.63, 121.40, 124.13, 132.00, 134.84, 134.87,
160.44, 167.91, 168.10, 169.35, 169.37 ppm. HRMS cal-
culated for C21 H21 O6 N6 453.1523; found 453.1648.
124.00, 124.12, 127.40, 127.48, 127.51, 129.26, 130.89,
132.06, 134.79, 134.83, 165.75, 167.85, 168.00, 169.29
ppm. HRMS calculated for C23 H22 O6 N5 464.1570; found
464.1598.
General procedure for the synthesis of 2-amino-5-
(5-(substituted-2-yl)-2H-tetrazol-2-yl)hexanedioic acid
hydrochloride (L)
A mixture of phthalimido derivative 2 (400 mg) and 6 N
HCl (30 ml) and acetic acid (3 ml) was refluxed during
10 h. The reaction mixture was cooled to room temperature
and concentrated. The residue was dissolved in water and
extracted with AcOEt. Treatment of reaction in acidic
conditions followed by addition of a large excess of pro-
pylene oxide in methanol afforded L1–L5.
Dimethyl 2-(1,3-dioxoisoindolin-2-yl)-5-(5-(furan-2-yl)-
2H-tetrazol-2-yl)hexanedioate (2c)
The general procedure was applied to dimethyl 2-bromo-5-
[5-(furan-2-yl)tetrazol-2-yl] hexanedioate (386 mg, 1 mmol)
and potassium phthalimide (555 mg, 3 mmol) to afford
1
289 mg (75%) of the title compound as a greenish oil. H
2-Amino-5-(5-(thiophen-2-yl)-2H-tetrazol-2-
yl)hexanedioic acid hydrochloride (L1)
NMR (CDCl3, SiMe4): d 2.2 (m, 1H), 2.5 (m, 3H), 3.6 (s,
3H), 3.7 (s, 3H), 4.9 (m, 1H), 5.7 (m, 1H), 6.5 (m, 1H), 7.15
(m, 1H), 7.75 (m, 4H) ppm. 13C NMR (CDCl3, SiMe4):
d 25.87, 28.13, 51.76, 53.07, 53.32, 65.77, 112.37, 112.23,
124.07, 131.94, 131.99, 134.78, 134.83, 142.99, 144.92,
158.84, 167.60, 167.88, 169.26 ppm. HRMS calculated for
C21 H20 O7 N5 454.1363; found 454.1396.
The general procedure was applied to dimethyl 2-(1,3-
dioxoisoindolin-2-yl)-5-(5-(5-methylthiophen-2-yl)-2H-
tetrazol-2-yl) hexanedioate (400 mg, 0.85 mmol) to afford
318 mg (70%) of the title compound as a greenish oil.
1H NMR (D2O, SiMe4): d 1.5 (m, 1H), 185 (m, 1H), 2.27
(m, 2H), 38 (m, 1H), 5.48 (m, 1H), 6.8 (t, 1H, J1 =
3.74 Hz, J2 = 1.29 Hz), 7.25 (d, 1H, J1 = 1.09 Hz,
J2 = 3.94 Hz), 7.4 (d, 1H, J1 = 1.06 Hz, J2 = 2.63 Hz)
ppm. 13C NMR (D2O, SiMe4): d 25.33, 26.58, 52.52,
66.02, 127.28, 128.71, 129.22, 129.73, 161.33, 170.80,
Dimethyl 2-(5-benzyl-2H-tetrazol-2-yl)-5-(1,3-
dioxoisoindolin-2-yl)hexanedioate (2d)
The general procedure was applied to dimethyl 2-(5-ben-
zyltetrazol-2-yl)-5 bromohexanedioate (411 mg, 1 mmol)
and potassium phthalimide (555 mg, 3 mmol) to afford
171.67 ppm. HRMS calculated for C11 H14 O4 N5
312.0767; found 312.0762.
S
1
287 mg (70%) of the title compound as a greenish oil. H
NMR (CDCl3, SiMe4): d 2.1 (m, 4H), 3.7 (s, 3H), 3.8 (s,
3H), 4.3 (s, 2H), 4.8 (m, 1H), 5.7 (m, 1H), 7.3 (m, 5H), 7.7
(m, 2H), 7.9 (m, 2H) ppm. 13C NMR (CDCl3, SiMe4): d
25.23, 28.11, 35.8, 50.91, 53.40, 69.62, 124.10, 124.12,
129.21, 128.41, 125.52, 127.41, 132.00, 132.30, 137.71,
134.79, 134.83, 164.21, 167.92, 168.01, 172.02 ppm.
HRMS calculated for C24 H24 O6 N5 478.1727; found
478.1716.
2-(5-(1H-pyrrol-2-yl)-2H-tetrazol-2-yl)-5-
aminohexanedioic acid hydrochloride (L2)
The general procedure was applied to dimethyl 2-(5-(1H-
pyrrol-2-yl)-2H-tetrazol-2-yl)-5-(1,3-dioxoisoindolin-2-yl)
hexanedioate (400 mg, 0.87 mmol) to afford 307 mg
1
(70%) of the title compound as a greenish oil. H NMR
(D2O, SiMe4): d 1.5 (m, 1H), 1.8 (m, 1H), 2.3 (m, 2H), 3.75
(m, 1H), 5.43 (m, 1H), 5.95 (m, 1H), 6.5 (d, 1H,
J = 2.2 Hz), 6.7 (s, 1H) ppm. 13C NMR (D2O, SiMe4):
d 26.41, 26.50, 52.48, 65.61, 110.01, 110.65, 118.37,
122.70, 160.07, 170.99, 171.63 ppm. HRMS calculated for
C11 H15 O4 N6 295.1155; found 295.1171.
Dimethyl 2-(1,3-dioxoisoindolin-2-yl)-5-(5-phenyl-2H-
tetrazol-2-yl)hexanedioate (2e)
The general procedure was applied to dimethyl 2-bromo-5-
(5-phenyltetrazol-2-yl) hexanedioate (397 mg, 1 mmol)
and potassium phthalimide (555 mg, 3 mmol) to afford
2-Amino-5-(5-(furan-2-yl)-2H-tetrazol-2-yl)hexanedioic
acid hydrochloride (L3)
1
356 mg (77%) of the title compound as a greenish oil. H
NMR (CDCl3, SiMe4): d 2.1 (m, 1H), 2.25 (m, 3H), 3.6 (s,
3H), 3.65 (s, 3H), 4.8 (m, 1H), 5.5 (m, 1H), 7.37 (m, 3H),
7.65 (m, 2H), 7.77 (m, 2H), 8.08 (m, 2H) ppm. 13C NMR
(CDCl3, SiMe4): d 25.92, 28.25, 51.87, 53.33, 53.77, 65.50,
The general procedure was applied to dimethyl 2-(1,3-di-
oxoisoindolin-2-yl)-5-(5-(furan-2-yl)-2H-tetrazol-2-yl)hex-
anedioate (400 mg, 0.88 mmol) to afford 316 mg (70%) of
123