Tetrazole-Substituted Pyroaminoadipic and Pipecolic Acid Derivatives
FULL PAPER
1
(m) cmϪ1. H NMR (CDCl3, SiMe4): δ ϭ 1.4 (m, 2 H), 2.4 (m, 2 158.6, 166.0, 170.8, 170.9, 171.6 ppm. HRMS calcd. for
H), 3.6 (s, 6 H), 3.8 (m, 1 H), 4.15 (s, 2 H), 5.4 (m, 1 H), 7.2 (m,
5 H) ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 27.4, 27.9, 32.2, 53.3,
53.8, 61.3, 64.9, 127.3, 129.1, 129.2, 136.8, 166.3, 167.7, 170.4 ppm.
HRMS calcd. for C16H20N7O4: 374.1577; found 374.1571.
C12H14N5O4: 292.1046; found 292.1053.
4e: The general procedure was applied with 3e (3480 mg, 10 mmol)
to afford 2380 mg (82% yield) of the title compound as a yellowish
solid. IR (neat): ν˜ ϭ 3455 (s), 3443 (s), 3261 (s), 2940 (m), 1743 (s),
1
1225 (m), 1000 (s) cmϪ1. H NMR (CDCl3, SiMe4): δ ϭ 2.4 (m, 4
Dimethyl 2-Azido-5-[5-(thiophen-2-ylmethyl)tetrazol-2-yl]hexanedio-
ate (3g): The general procedure was applied with 2g (832 mg, 2
mmol) to afford 3050 mg (84% yield) of the title compound as a
greenish oil. IR (neat): ν˜ ϭ 3027 (s), 3003 (s), 2955 (m), 2109 (s),
H), 3.5 (s, 3 H), 4 (m, 1 H), 4.7 (br. s, 1 H), 5.5 (m, 1 H), 6 (m, 1
H), 6.6 (m, 1 H) ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 23.6, 29.2,
52.8, 54.3, 64.8, 109.4, 110.3, 119.1, 121.5, 160.8, 168.2, 172.5 ppm.
HRMS calcd. for C12H15N6O3: 291.1206; found 291.1236.
1754 (s), 1237 (m), 1207 (m), 788 (s) cmϪ1 1H NMR (CDCl3,
.
SiMe4): δ ϭ 1.3 (m, 2 H), 2.3 (m, 2 H), 3.5 (s, 6 H), 3.75 (m, 1 H),
4.2 (s, 2 H), 5.35 (m, 1 H), 6.65 (d, J ϭ 3.5 Hz, 2 H), 7 (s, 1 H)
ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 27.3, 27.8, 26.6, 53.0, 53.5,
61.3, 64.8, 125.2, 126.6, 127.4, 138.6, 165.6, 167.7, 170.5 ppm.
HRMS calcd. for C14H18N7O4S: 364.1210; found 364.1202.
4f: The general procedure was applied with 3f (3740 mg, 10 mmol)
to afford 2520 mg (80% yield) of the title compound as a white
solid. IR (neat): ν˜ ϭ 3366 (s), 3150 (s), 2155 (s), 1747 (s), 1671 (m),
1
1228 (m), 730 (s) cmϪ1. H NMR (CDCl3, SiMe4): δ ϭ 2.1 (m, 4
H), 3.6 (s, 3 H), 4.2 (m, 3 H), 5.7 (m, 1 H), 7.3 (m, 6 H), 8.6 (br.
s, 1 H) ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 24, 26, 32.5, 53.0,
54.4, 61.9, 127.2, 129.0, 129.0, 129.1, 129.2, 136.9, 166.4, 169.7,
171.8 ppm. HRMS calcd. for C15H18N5O3: 316.1410; found
316.1407.
Synthesis of Methyl 6-Oxo-5-(5-substituted tetrazol-2-yl)piperidine-
2-carboxylates 4: 5% Pd/C or Pd(OH)2/C (500 mg) was added to
the appropriate dimethyl 2-azido-5-(5-substituted tetrazol-2-yl)hex-
anedioate 3 (10 mmol) in 30 mL of anhydrous MeOH[18] and the
reaction mixture was stirred at room temperature under hydrogen
(1 atm) for 24 h. The catalyst was then filtered off through Celite,
and the filtrate was concentrated under reduced pressure and the
product precipitated by addition of Et2O. The product was recrys-
tallized from ethyl acetate. The NMR spectroscopic data are given
for the major isomer.
4g: The general procedure was applied with 3g (3690 mg, 10 mmol)
to afford 2640 mg (82% yield) of the title compound as a white
solid. IR (neat): ν˜ ϭ 3450 (s), 3102 (s), 3130 (m), 2940 (m), 1756
1
(s), 1672 (m), 1210 (m), 1000 (s) cmϪ1. H NMR (CDCl3, SiMe4):
δ ϭ 2.1 (m, 2 H), 2.4 (m, 2 H), 3.8 (s, 3 H), 4.3 (m, 1 H), 4.5 (s, 2
H), 5.7 (m, 1 H), 6.9 (m, 2 H), 7.2 (s, 1 H), 8.7 (br. s, 1 H) ppm.
13C NMR (CDCl3, SiMe4): δ ϭ 23.6, 26.6, 33.3, 53.0, 61.9, 65.5,
125.1, 126.7, 127.4, 138.7, 166.1, 171.6, 173.4 ppm. HRMS calcd.
for C13H16N5O3S: 322.0974; found 322.0962.
4a: The general procedure was applied with 3a (3600 mg, 10 mmol)
to afford 2400 mg (80% yield) of the title compound as a colorless
solid. M.p. 144Ϫ146 °C. IR (neat): ν˜ ϭ 3441 (m), 3166 (s), 3007
1
(s), 2936 (s), 1743 (s), 1670 (m) 1272 (m), 808 (s) cmϪ1. H NMR
Synthesis of 5-(5-Substituted tetrazol-2-yl)piperidine-2-carboxylic
Acids 5: A solution of borane (10 mmol, 1 m in THF) in 4 mL of
THF was added at Ϫ10 °C to a solution of the appropriate methyl
6-oxo-5-(5-substituted tetrazol-2-yl)piperidine-2-carboxylate 4 (1
mmol).[27] The reaction mixture was maintained at Ϫ10 °C during
the addition, then stirred at Ϫ5 °C for 24 h and concentrated under
reduced pressure. The mixture was hydrolyzed by addition of 6 n
HCl at 60 °C during 12 h and then propylene oxide was added.
The aqueous layer was extracted with CH2Cl2. The organic layers
were dried with Na2SO4, filtered, and concentrated to yield the
title compound. The NMR spectroscopic data are given for the
major isomer.
(CDCl3, SiMe4): δ ϭ 2.2 (m, 2 H), 2.5 (m, 2 H), 3.7 (s, 3 H), 4.2
(m, 1 H), 5.5 (m, 1 H), 6.8 (br. s, 1 H), 7.4 (m, 3 H), 8 (m, 2 H)
ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 23.5, 26.3, 53.5, 54.7, 61.9,
127.4, 127.61, 127.64, 129.2, 130.79, 130.82, 165.0, 170.7, 171.1
ppm. HRMS calcd. for C14H16N5O3: 302.1259; found 302.1253.
4b: The general procedure was applied with 3b (3930 mg, 10 mmol)
to afford 2680 mg (80% yield) of the title compound as a white
solid. IR (neat): ν˜ ϭ 3367 (s), 2956 (s), 2253 (s), 1750 (s), 1671 (m)
1
1232 (m), 732 (s) cmϪ1. H NMR (CDCl3, SiMe4): δ ϭ 2.2 (m, 4
H), 3.75 (s, 3 H), 4.3 (m, 1 H), 5.7 (m, 1 H), 7.4 (m, 3 H), 8.1 (m,
1 H), 8.7 (br. s, 1 H) ppm. 13C NMR (CDCl3, SiMe4): δ ϭ 21.6,
31.3, 52.1, 54.6, 65.2, 126.5, 127.5, 129.3, 130.9, 131.2, 163.7, 166.4,
171.6, 173.4 ppm. HRMS calcd. for C14H14ClN5O3: 335.0785;
found 335.0798.
5a: The general procedure was applied with 4a (301 mg, 1 mmol)
to afford 220 mg (80% yield) of the title compound as a white solid.
M.p. 147Ϫ149 °C. IR (neat): ν˜ ϭ 3346 (s), 3232 (s), 3120 (s), 2954
1
(m), 1738 (s), 1208 (m), 917 (s) cmϪ1. H NMR (CDCl3, SiMe4):
4c: The general procedure was applied with 3c (3490 mg, 10 mmol)
to afford 2460 mg (80% yield) of the title compound as a greenish
solid. M.p. 155Ϫ158 °C. IR (neat): ν˜ ϭ 3368 (s), 3154 (s), 2156 (s),
δ ϭ 1.2 (m, 2 H), 2 (br. s, 1 H), 2.5 (m, 2 H), 3.5 (m, 2 H), 3.8 (m,
1 H), 4.75 (m, 1 H), 7.4 (m, 3 H), 8.1 (m, 2 H), 11 (s, 1 H) ppm.
13C NMR (CDCl3, SiMe4): δ ϭ 23.0, 27.9, 48.1, 52.6, 63.1, 127.2,
127.4, 127.7, 129.3, 130.8, 165.1, 173.6 ppm. HRMS calcd. for
C13H15N5O2: 273.1227; found 273.1229.
1748 (s), 1675 (m), 1227 (m), 727 (s) cmϪ1 1H NMR (CDCl3,
.
SiMe4): δ ϭ 2.3 (m, 4 H), 3.8 (s, 6 H), 4.2 (m, 1 H), 5.55 (m, 1 H),
6.9 (br. s, 1 H), 7.2 (m, 1 H), 7.5 (dd, J1 ϭ 1.3, J2 ϭ 3.8 Hz, 1 H),
7.83 (dd, J1 ϭ 1, J2 ϭ 2.6 Hz, 1 H) ppm. 13C NMR (CDCl3,
SiMe4): δ ϭ 23.6, 26.2, 53.5, 54.7, 62.0, 128.3, 128.4, 128.5, 129.3,
161.7, 165.4, 171.2 ppm. HRMS calcd. for C12H14N5O3S:
308.0817; found 308.0805.
5b: The general procedure was applied with 4b (335 mg, 1 mmol)
to afford 240 mg (80% yield) of the title compound as a white solid.
IR (neat): ν˜ ϭ 3355 (m), 3236 (m), 2926 (s), 1736 (s), 1090 (s), 919
1
(s) cmϪ1. H NMR (CDCl3, SiMe4): δ ϭ 1.5 (m, 2 H), 2 (m, 2 H),
2.5 (br. s, 1 H), 3.25 (m, 2 H), 4.25 (m, 1 H), 5.12 (m, 1 H), 7.25
(m, 3 H), 8.25 (m, 1 H), 11 (s, 1 H) ppm. 13C NMR (CDCl3,
SiMe4): δ ϭ 22.4, 32.3, 58.6, 59.5, 66.9, 127.6, 129.3, 130.9, 131.7,
133.5, 164.1, 165.3, 170.4 ppm. HRMS calcd. for C13H15ClN5O2:
308.091; found 308.182.
4d: The general procedure was applied with 3d (3500 mg, 10 mmol)
to afford 2330 mg (80% yield) of the title compound as a reddish
solid. IR (neat): ν˜ ϭ 3453 (s), 3107 (s), 2945 (m), 1755 (s), 1673
(m), 1213 (m), 1002 (s) cmϪ1. 1H NMR (CDCl3, SiMe4): δ ϭ 2 (m,
2 H), 2.4 (m, 2 H), 3.6 (s, 3 H), 4.3 (m, 1 H), 5.6 (m, 1 H), 6.5 (s,
1 H), 7.1 (s, 1 H), 7.6 (s, 1 H), 8.6 (br. s, 1 H) ppm. 13C NMR
(CDCl3, SiMe4): δ ϭ 23.6, 26.9, 53.4, 54.9, 62.2, 112.0, 112.1, 142.9,
5c: The general procedure was applied with 4c (307 mg, 1 mmol)
to afford 220 mg (80% yield) of the title compound as a greenish
Eur. J. Org. Chem. 2005, 326Ϫ333
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
331