Notes
N(2)-Cu m yl-5-(4′-m eth yl[1,1′-bip h en yl]-2-yl)tetr a zole (9).
J . Org. Chem., Vol. 64, No. 25, 1999 9305
p-tolyllithium to give a mixture of mono- and diaddition prod-
ucts. The mixture was separated to afford tetrazole 18 in 38%
yield as a crystalline solid: mp 138-139 °C; 1H NMR δ 7.46 (t,
J ) 7.8 Hz, 1H), 7.25-7.16 (m, 3H), 7.04-6.92 (m, 6H), 6.89-
6.84 (m, 2H), 3.79 (s, 3H), 2.31 (s, 3H), 2.07 (s, 6H); 13C NMR δ
161.0, 158.1, 144.2, 143.6, 136.8, 135.8, 130.3, 128.6, 128.0, 127.8,
126.9, 124.1, 121.7, 115.8, 109.1, 67.6, 55.4, 28.6, 20.6; EIMS
m/z (relative intensity) 384 (M+, 50),119 (100); EI-HRMS calcd
From compound 4, with 2.0 equiv of p-tolyllithium, tetrazole 9
was obtained in 47% yield as a crystalline solid: mp 99-100
°C; 1H NMR δ 7.84-7.81 (m, 1H), 7.50-7.47 (m, 3H), 7.25-7.22
(m, 3H), 7.03 (apparent s, 4H), 6.97-6.92 (m, 2H), 2.33 (s, 3H),
2.02 (s, 6H); 13C NMR δ 164.8, 143.8, 142.3, 138.1, 136.4, 130.6,
130.3, 129.8, 129.1, 128.5, 128.4, 127.6, 127.2, 126.7, 124.7, 124.6,
68.0, 29.0, 21.2. Anal. Calcd for C23H22N4: C, 77.94; H, 6.26; N,
15.81. Found: C, 77.87; H, 6.24; N, 15.75.
for
C24H24N4O 384.1950, found 384.1947. Anal. Calcd for
N(2)-Cu m yl-5-(n a p h th -1-yl)tetr a zole (10). The general
procedure using tetrazole 4 with 2.5 equiv of 1-lithionaphthalene
gave tetrazole 10 in 80% yield as a crystalline solid: mp 108-
109 °C; 1H NMR δ 8.19-8.15 (m, 1H), 7.81 (td, J ) 7.7, 1.4 Hz,
2H), 7.60-7.32 (m, 7H), 7.25-7.06 (m, 4 H), 6.60-6.55 (m, 2H),
1.67 (s, 3H), 1.63 (s, 3H); 13C NMR δ 163.6, 143.4, 140.1, 139.4,
133.3, 132.2, 131.6, 129.8, 129.3, 128.3, 128.0, 127.9, 127.8, 127.5,
127.4, 127.0, 125.9, 125.8, 125.4, 125.2, 124.5, 67.5, 28.8, 28.3.
Anal. Calcd for C26H22N4: C, 79.97; H, 5.68; N, 14.35. Found:
C, 79.72; H, 5.63; N, 14.26.
C24H24N4O (0.5 mol of H2O): C, 73.26; H, 6.40; N, 14.24.
Found: C, 73.54; H, 6.21; N, 14.21. Also isolated was tetrazole
19 in 24% yield as a crystalline solid: mp 168-169 °C; 1H NMR
(DMSO-d6) δ 7.68 (t, J ) 7.8 Hz, 1H), 7.47 (d, J ) 7.8 Hz, 2H),
7.32-7.20 (m, 3H), 7.06 (d, J ) 8.0 Hz, 4H), 6.94 (d, J ) 8.0 Hz,
4H), 6.80-6.72 (m, 2H), 2.28 (s, 6H), 1.87 (s, 6H); 13C NMR
(DMSO-d6) δ 163.0, 143.7, 142.8, 137.0, 136.2, 130.0, 128.7,
128.6, 128.4, 128.2, 125.2, 124.3, 67.4, 28.8, 20.6; EIMS m/z
(relative intensity) 444 (M+, 52), 269 (100); EI-HRMS calcd for
C
30H28N4 444.2314, found 444.2314. Anal. Calcd for C30H28N4:
N(2)-Cu m yl-5-(4′-(d im et h oxym et h yl)[1,1′-b ip h en yl]-2-
yl)-tetr a zole (11). The general procedure using compound 4
with 2.0 equiv of 4-(dimethoxymethyl)phenyllithium gave tet-
razole 11 in 90% yield as a colorless oil: 1H NMR δ 7.88 (dd, J
) 7.1, 1.3 Hz, 1H), 7.53-7.38 (m, 3H), 7.33 (d, J ) 8.0 Hz, 2H),
7.30-7.24 (m, 3H), 7.17 (d, J ) 8.0 Hz, 2H), 6.97-6.93 (m, 2H),
5.38 (s, 1H), 3.31 (s, 3H), 1.99 (s, 6H); 13C NMR δ 164.1, 143.8,
141.9, 141.2, 136.7, 130.7, 130.3, 129.8, 129.1, 128.5, 127.7, 127.5,
126.6, 126.2, 124.7, 103.0, 68.1, 52.6, 29.0; EIMS m/z (relative
intensity) 414 (M+, 24), 383 (17), 296 (28), 265 (34), 238 (19),
209 (30), 193 (65), 165 (56), 119 (100), 91 (75), 75 (100).
N(2)-Cu m yl-5-(2-n -bu tyl-3-m eth oxyph en yl)tetr azole (14).
The general procedure using compound 5 with 1.3 equiv of
n-BuLi afforded a 93% yield of tetrazole 14 as a colorless oil that
C, 81.05; H, 6.35; N, 12.60. Found: C, 80.68; H, 6.25; N, 12.75.
N(2)-Cu m yl-5-(2,6-d in a p h t h a len -1-yl-p h en yl)t et r a zole
(20). Tetrazole 6 reacted with 5.0 equiv of 1-naphthyllithium to
give tetrazole 20 as an apparent 45:55 mixture of slowly
interconverting meso and d,l forms in 60% yield: mp 173.5-
174.5 °C dec; 1H NMR (300 MHz, CDCl3, 23 °C) δ 7.80-7.25
(m, 17H), 7.12-7.05 (m, 1H), 7.01-6.92 (m, 2H), 6.20-6.10 (m,
2H), 1.38, 1.36, and 1.34 (singlets in ∼2:1:1 ratio, total integra-
tion 6H); 1H NMR (600 MHz, CDCl3, -78 °C) δ 7.9-7.0 (m, 20H),
6.16 (d, J ) 7.5 Hz, 2H, 45 mol % mixture), 6.05 (d, J ) 7.5 Hz,
2H, 55 mol % mixture), 1.42 (s, 6H, 45 mol % mixture), 1.35 (s,
3H, 55 mol % mixture), 1.17 (s, 3H, 55 mol % mixture); LSIMS
m/z (relative intensity) 517 (M + H+, 24), 399 (100). Anal. Calcd
for C36H28N4: C, 83.69; H, 5.46; N, 10.84. Found: C, 83.71; H,
5.44; N, 11.25.
1
crystallized on standing: mp 54-56 °C; H NMR δ 7.52 (dd, J
) 7.8, 1.1 Hz, 1H), 7.27-7.13 (m, 6H), 6.95 (dd, J ) 7.8, 1.1 Hz,
1H), 3.85 (s, 3H), 2.85 (m, 2H), 2.22 (s, 6H), 1.49-1.39 (m, 2H),
1.29-1.17 (m, 2H), 0.81 (t, J ) 7.2 Hz, 3H); 13C NMR δ 164.9,
158.0, 143.9, 131.6, 128.6, 127.8, 126.5, 124.7, 122.1, 111.8, 67.8,
55.7, 32.2, 29.1, 26.7, 23.1, 14.0; LSIMS-HRMS Calcd for
C21H27N4O (M + H+) 351.2185, found 351. 2187. Anal. calcd for
C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found: C, 71.68; H,
7.45; N, 16.06.
N(2)-Cu m yl-5-(6-m eth oxy-[1,1′-bip h en yl]-2-yl)tetr a zole
(15). With compound 5 and 2.0 equiv of PhLi the general
procedure gave tetrazole 15 in 92% yield as a colorless oil that
crystallized on standing: mp 66-68 C; 1H NMR δ 7.50 (dd, J )
7.8, 1.3 Hz, 1H), 7.43 (t, J ) 7.8 Hz, 1H), 7.30-7.20 (m, 6H),
7.15-7.10 (m, 2H), 7.08 (dd, J ) 7.8, 1.3 Hz, 1H), 6.90-6.84 (m,
2H), 3.76 (s, 3H), 1.94 (s, 6H); 13C NMR δ 164.3, 157.1, 143.7,
136.5, 131.2, 130.4, 128.7, 128.6, 128.4, 127.6, 124.7, 122.1, 112.4,
67.9, 56.0, 28.9; LSIMS-HRMS calcd for C23H23N4O (M + H+)
371.1872, found 371.1875. Anal. Calcd for C23H22N4O: C, 74.57;
H, 5.99; N, 15.12. Found: C, 74.14; H, 5.96; N, 14.98.
N(2)-Cu m yl-5-(2-n -bu tyl-6-m eth oxyph en yl)tetr azole (16).
Using 1.3 equiv of n-butyllithium with tetrazole 6, the general
procedure afforded crude tetrazole 16 contaminated with ∼10
mol % diaddition product. The mixture was separated to give
53% yield of pure 16 as a colorless oil: 1H NMR δ 7.35-7.25
(m, 4H), 7.14-7.08 (m, 2H), 6.88 (br d, J ) 8 Hz, 1H), 6.80 (br
d, J ) 8 Hz, 1H), 3.71 (s, 3H), 2.34 (m, 2H), 2.23 (s, 6H), 1.40-
1.30 (m, 2H), 1.12 (sextet, J ) 7.2 Hz, 2H), 0.75 (t, J ) 7.2 Hz,
3H); 13C NMR δ 162.0, 158.9, 145.2, 144.7, 131.1, 129.0, 128.1,
125.0, 122.0, 117.3, 108.9, 68.7, 56.2, 33.7, 29.5, 22.9, 14.2; EIMS
m/z (relative intensity) 350 (M+, 38), 119 (100); LSIMS-HRMS
calcd for C21H27N4O (M + H+) 350.2107, found 350.2109.
N(2)-Cu m yl-5-(2,6-d i-(n -bu tyl)p h en yl)tetr a zole (17). Us-
ing 3.0 equiv of n-butyllithium and tetrazole 6, the general
procedure gave tetrazole 17 in 84% yield as a colorless oil: 1H
NMR δ 7.35-7.25 (m, 4H), 7.16-7.12 (m, 2H), 7.10 (d, J ) 7.7
Hz, 2H), 2.32 (m, 2H), 2.23 (s, 6H), 1.40-1.28 (m, 2H), 1.14
(sextet, J ) 7.1 Hz, 2H), 0.76 (t, J ) 7.1 Hz, 3H); 13C NMR δ
163.8, 144.1, 143.1, 129.6, 128.7, 127.9, 126.9, 126.8, 124.6, 68.2,
33.7, 33.4, 29.1, 22.6, 13.8. Anal. Calcd for C24H32N4: C, 76.56;
H, 8.57; N, 14.88. Found: C, 76.54; H, 8.43; N, 14.71.
N(2)-Cu m yl-5-(2-h yd r oxyp h en yl)tetr a zole (12). Meth od
A. Compound 12 (0.0095 g, 2% yield) was isolated from the
reaction of 4 with n-butyllithium (vide supra).
Meth od B. Compound 12 was prepared independently as
follows: N(2)-Cumyl-5-phenyltetrazole (0.200 g, 0.8 mmol) was
dissolved in 1 mL of dry THF at -10 °C. A 1.6 M solution of
n-butyllithium in hexane (520 µL, 0.83 mmol) was added
dropwise to give a dark purple reaction mixture. After 45 min
at -10 °C, oxygen was bubbled into the reaction mixture through
a
dispersion tube to give a light yellow solution. Sodium
borohydride (0.03 g, 0.8 mmol) was added, and the reaction
mixture was stirred for 1 h, neutralized with dilute HCl, and
extracted with ethyl acetate to give a 1.5:1 mixture of starting
material and compound 12. Chromatographic separation of the
mixture afforded 55 mg of pure 12 as a crystalline solid: mp
70.5-71.0 °C; 1H NMR 9.76 (s, 1H), 8.06 (dd, J ) 7.8, 1.7 Hz,
1H), 7.39-7.25 (m, 4H), 7.17-7.12 (m, 2H), 7.07 (dd, J ) 8.4,
1.0 Hz, 1H), 6.97 (td, J ) 8.4, 1.0 Hz, 1H), 2.24 (s, 6H); 13C NMR
δ 163.8, 156.4, 143.1, 136.2, 132.1, 128.8, 128.1, 127.5, 124.7,
119.9, 117.5, 111.3, 69.0, 29.1; EIMS m/z (relative intensity) 280
(M+, 8), 119 (100). Anal. Calcd for C16H16N4O: C, 68.55; H, 5.75;
N, 19.99. Found: C, 69.03; H, 5.78; N, 19.70.
N(2)-Cu m yl-5-(2-n -bu tyl-6-h yd r oxyp h en yl)tetr a zole (13).
Meth od A. Compound 13 (0.0131 g, 2% yield) was isolated from
the reaction of 4 with n-butyllithium (vide supra).
Meth od B. Compound 13 was prepared independently as
follows: Tetrazole 16 (0.196 g, 0.56 mmol) and sodium thi-
omethoxide (0.235 g, 3.4 mmol) were added to 3 mL of dry DMF.
The solution was allowed to reflux for 1 h, cooled to room
temperature, diluted with water, and extracted with ether. The
crude extract was purified by column chromatography to give
32 mg (17% yield) of tetrazole 13 as a light yellow oil: 1H NMR
δ 7.40-7.15 (m, 6H), 6.93 (dd, J ) 8.3, 1.3 Hz, 1H), 6.80 (dd, J
) 7.6, 1.3 Hz, 1H), 3.01 (m, 2H), 2.24 (s, 6H), 1.50-1.47 (m, 2H),
1.26 (sextet, J ) 7.1 Hz, 2H), 0.80 (t, J ) 7.1 Hz, 3H); 13C NMR
δ 163.7, 157.9, 143.9, 143.3, 131.2, 128.7, 128.1, 124.7, 124.6,
122.3, 115.3, 110.2, 68.9, 35.5, 33.4, 29.0, 22.9, 14.0; LSIMS-
HRMS calcd for C20H25N4O (M + H+) 337.2028, found 337.2026.
Dep r otection of N(2)-Cu m yltetr a zoles. Meth od A. N(2)-
Cumyl-5-phenyltetrazole (0.2892 g, 1.1 mmol), potassium for-
mate (0.50 g, 6 mmol), and 20% Pd/C (0.1 g) were added to 5
mL of absolute ethanol, and the mixture was heated to reflux
for 4 h. The reaction mixture was cooled to room temperature,
N(2)-Cu m yl-5-(3-m eth oxy-4′-m eth yl-[1,1′-bip h en yl]-2-yl)-
tetr a zole (18) a n d N(2)-cu m yl-5-(4,4′′-[1,1′;3′,1′′]ter p h en yl-
2′-yl)tetr a zole (19). Tetrazole 6 reacted with 4.0 equiv of