The Journal of Organic Chemistry
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CDCl3) δ 7.35 (d, J = 8.7 Hz, 2H), 7.38−7.42 (m, 3H), 7.46−7.50 (m,
3H), 7.53−7.58 (m, 2H), 7.67−7.71 (m, 3H), 8.24 (d, J1 = 8.3 Hz, J2 =
1.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 123.9, 127.9, 128.7,
128.8, 129.0, 130.1, 130.2, 130.8, 133.2, 133.5, 134.0, 152.0, 164.6; IR
(KBr) ν 1725 (CO), 1262, 1202 (C−O) cm−1. Anal. Calcd for
C21H15ClN2O3: C, 66.58; H, 3.99; N, 7.40. Found: C, 66.47; H, 4.03;
N, 7.33.
Tetrahydro-1,2,4,5-tetrazin-3(2H)-ones 5a−5e. General Pro-
cedure. To a solution of carbamoyl chloride 4 (1.0 mmol) in EtOH
(15 mL), arylhydrazine hydrochloride 2·HCl or 4-hydrazinobenzoic
acid (2e, 1.2 mmol) followed by Et3N (2.4 mmol) were added. The
resulting mixture was heated at 50 °C for 2−4 h and cooled to rt. For
tetrazines 5a−5c, colorless precipitate was separated and washed with
cold EtOH. For tetrazines 5d and 5e, the cooled reaction mixture was
poured into ice, and the resulting precipitation was filtered. For
tetrazines 5f and 5g, the cooled reaction mixture was poured into 2%
HCl and ice, and the product was filtered.
143.0, 147.7, 155.2, 156.5. Anal. Calcd for C27H23N5O4: C, 67.35; H,
4.81; N, 14.54. Found: C, 67.49; H, 4.84; N, 14.26.
2-(4-Iodophenyl)-6-(4-nitrophenyl)-4-phenyltetrahydro-1,2,4,5-
tetrazin-3(2H)-one (5e). Obtained in 90% yield as yellow solid using
carbamoyl chloride 4a, 4-iodophenylhydrazine free base (2d) and 1
equiv of Et3N. Crude product was washed with warm EtOAc and
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recrystallized from EtOH: mp 197−200 °C; H NMR (400 MHz,
acetone-d6) δ 5.59 (t, J = 9.0 Hz, 1H), 6.09 (d, J = 9.1 Hz, 1H), 6.13
(d, J = 8.8 Hz, 1H), 7.22−7.32 (m, 3H), 7.47 (d, J = 8.9 Hz, 2H),
7.50−7.56 (m, 2H), 7.60 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 9.4 Hz, 2H),
8.12 (d, J = 9.4 Hz, 2H); 13C NMR (400 MHz, acetone-d6) δ 74.2,
118.9, 122.7, 123.9, 126.8, 128.4, 128.5, 137.0, 137.6, 142.3, 142.4,
148.5. Anal. Calcd for C20H16IN5O3: C, 47.92; H, 3.22; N, 13.97.
Found: C, 47.75; H, 3.24; N, 13.70.
2-(4-Carboxyphenyl)-6-(4-nitrophenyl)-4-phenyltetrahydro-
1,2,4,5-tetrazin-3(2H)-one (5f). Obtained in 30% yield. Crude
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tetrazine was purified by washing with hot EtOAc: H NMR (500
MHz, DMSO-d6) δ 5.47 (t, J = 8.9 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H),
6.69 (d, J = 8.8 Hz, 1H), 7.30−7.40 (m, 3H), 7.49 (d, J = 6.5 Hz, 2H),
7.76 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 9.4 Hz, 2H), 7.92 (d, J = 8.9 Hz,
2H), 8.24 (d, J = 9.4 Hz, 2H). Anal. Calcd for C21H17N5O5: C, 60.14;
H, 4.09; N, 16.70. Found: C, 59.88; H, 4.18; N, 16.74.
2,6-bis(4-Benzyloxyphenyl)-4-phenyltetrahydro-1,2,4,5-tetrazin-
3(2H)-one (5a). Crude tetrazine obtained in 77% yield was partially
purified by flash chromatography (SiO2 washed with 1% Et3N in
hexanes, hexanes/CH2Cl2 20:1) and used in the next step. Analytical
sample of 5a was obtained by recrystallization from EtOAc at −5 °C:
mp 208−211 °C; 1H NMR (600 MHz, CDCl3) δ 4.74 (d, J = 10.6 Hz,
2H), 5.06 (s, 4H), 5.47 (t, J = 10.6 Hz, 1H), 6.96 (d, J = 9.0 Hz, 4H),
7.32 (t, J = 7.3 Hz, 2H), 7.36−7.44 (m, 11H), 7.54 (d, J = 9.0 Hz, 4H),
7.58 (br d, J = 6.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 70.4,
72.3, 114.8, 124.1, 126.4, 127.4, 127.9, 128.5, 128.6, 128.8, 129.0,
130.1, 135.8, 137.1, 156.1; IR (KBr) ν 3238 (N−H), 1629 (CO),
1504, 1237 (C−O) cm−1; EI-HRMS, calcd. for C34H30N4O3 [M]+ m/z
542.2318, found m/z 542.2314. Anal. Calcd for C34H30N4O3: C, 75.26;
H, 5.57; N, 10.33. Found: C, 75.29; H, 5.64; N, 10.15.
2-(4-Benzyloxyphenyl)-6-(4-carboxyphenyl)-4-phenyltetrahydro-
1,2,4,5-tetrazin-3(2H)-one (5g). Obtained in 33% yield as a colorless
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solid after washing with hot toluene: mp 248−249 °C (EtOAc); H
NMR (600 MHz, DMSO-d6) δ 5.11 (s, 2H), 5.39 (t, J = 9.0 Hz, 1H),
6.41 (d, J = 9.1 Hz, 1H), 6.43 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.1 Hz,
2H), 7.32−7.37 (m, 4H), 7.38−7.41 (m, 2H), 7.45−7.48 (m, 4H),
7.53 (d, J = 7.1 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.9 Hz,
2H), 12.6 (br s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 69.4, 72.7,
114.3, 119.2, 123.6, 124.4, 126.9, 127.6, 127.7, 128.1, 128.3, 128.4,
129.5, 135.8, 137.2, 137.5, 146.8, 155.0, 156.6, 167.0; IR (KBr) ν 3241
(N−H), 1684, 1632 (CO), 1506, 1293, 1247 (C−O) cm−1; EI-
HRMS, calcd. for C28H24N4O4 [M]+ m/z 480.1798, found m/z
480.1796. Anal. Calcd for C28H24N4O4: C, 69.99; H, 5.03; N, 11.66.
Found: C, 69.87; H, 5.23; N, 11.68.
2,6-bis(4-Benzoyloxyphenyl)-4-phenyltetrahydro-1,2,4,5-tetrazin-
3(2H)-one (5b). The crude tetrazine was obtained in 81% yield as
colorless solid. An analytically pure sample was prepared by
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recrystallization from EtOH: mp 219−220 °C; H NMR (600 MHz,
CDCl3) δ 4.87 (d, J = 10.1 Hz, 2H), 5.45 (t, J = 10.1 Hz, 1H), 7.20 (d,
J = 9.0 Hz, 4H), 7.37−7.43 (m, 3H), 7.49−7.52 (m, 4H), 7.59 (d, J =
7.2 Hz, 2H), 7.63 (t, J = 7.4 Hz, 2H), 7.74 (d, J = 9.0 Hz, 4H), 8.19 (d,
J = 7.2 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 72.7 (CH2), 121.5
(CH), 122.8 (CH), 126.5 (CH), 128.5 (CH), 128.9 (CH), 129.1,
129.6 (CH), 130.2 (CH), 133.5 (CH), 135.5, 139.7, 147.4, 155.3
(CO), 165.3 (CO); IR (KBr) ν 3240 (N−H), 1737, 1625 (C
O), 1500, 1268, and 1200 (C−O) cm−1; EI-HRMS, calcd. for
C34H26N4O5 [M]+ m/z 570.1903, found m/z 570.1896. Anal. Calcd
for C34H26N4O5: C, 71.57; H, 4.59; N, 9.82. Found: C, 71.39; H, 4.62;
N, 9.87.
2-(4-Benzyloxyphenyl)-6-(4-(3,5-dimethylphenyloxycarbonyl)-
phenyl)-4-phenyltetrahydro-1,2,4,5-tetrazin-3(2H)-one (5t). The
mixture of tetrazine 5g (250 mg, 0.52 mmol) and 3,5-dimethylphenol
(254 mg, 2.08 mmol) in dry DMF (2.5 mL) was added at 0 °C DCC
(118 mg, 0.57 mmol) followed by DMAP (13 mg, 20% mol with
respect to tetrazine). After 30 min the cooling bath was removed, and
the mixture was stirred at rt for 3 days. Then H2O (30 mL) was added,
and the mixture was extracted with EtOAc (3 × 25 mL). Combined
organics were dried (MgSO4), and solvents were removed to dryness.
Resulting violet oil was filtered through a silica gel pad (CH2Cl2, SiO2
washed with 1% Et3N in CH2Cl2 before usage) to give the fraction
(386 mg) containing desired material contaminated with unconsumed
phenol (ca. 1:3.5 mixture, respectively). Additional flash chromatog-
raphy (SiO2 washed with 1% Et3N in CH2Cl2; CH2Cl2/EtOAc, 20:1)
furnished analytically pure ester 5t (171 mg, 56% yield) as colorless
solid: mp 210−212 °C (MeCN); 1H NMR (600 MHz, CDCl3) δ 2.33
(s, 6H), 4.75 (d, J = 9.9 Hz, 1H), 4.82 (d, J = 10.3 Hz, 1H), 5.05 (s,
2H), 5.45 (t, J = 10.1 Hz, 1H), 6.82 (s, 2H), 6.89 (s, 1H), 6.97 (d, J =
9.0 Hz, 2H), 7.31−7.34 (m, 1H), 7.37−7.44 (m, 7H), 7.51 (d, J = 9.0
Hz, 2H), 7.54−7.56 (m, 2H), 7.87 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.9
Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 21.2, 70.3, 72.9, 114.9,
119.3, 119.9, 124.0, 124.5, 126.4, 127.4, 127.5, 128.0, 128.6, 128.9,
129.1, 130.7, 134.9, 135.5, 136.9, 139.3, 146.8, 150.9, 155.5, 156.4,
165.0; IR (KBr) ν 3235 (N−H), 1737 (CO), 1629 (CO), 1258
(C−O) cm−1; EI-HRMS, calcd. for C36H32N4O4 [M]+ m/z 584.2424,
found m/z 584.2431. Anal. Calcd for C36H32N4O4: C, 73.95; H, 5.52;
N, 9.58. Found: C, 73.67; H, 5.76; N, 9.42.
2-(4-Benzoyloxyphenyl)-6-(4-benzyloxyphenyl)-4-phenyltetrahy-
dro-1,2,4,5-tetrazin-3(2H)-one (5c). Crude tetrazine was obtained
from chloride 4b in 75% yield as a white solid (mp 211−213 °C).
Analytical sample of 5c was obtained by recrystallization from EtOAc:
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mp 213-214 °C; H NMR (200 MHz, CDCl3) 4.77 (d, J = 10.4 Hz,
1H), 4.83 (d, J = 10.4 Hz, 1H), 5.07 (s, 2H), 5.49 (t, J = 10.4 Hz, 1H),
6.96−7.00 (m, 2H), 7.18−7.23 (m, 2H), 7.34−7.64 (m, 15H), 7.77
(m, 2H), 8.21 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 70.4, 72.5,
114.9, 121.4, 122.7, 124.2, 126.4, 127.4, 127.9, 128.5, 128.6, 128.9,
129.1, 129.7, 130.1, 130.2, 133.5, 135.5, 137.1, 139.9, 147.3, 155.1,
156.2, 165.2; IR (KBr) ν 3213 (N−H), 1736 (CO), 1625 (CO),
1505, 1265, 1246 (C−O), 1203 (C−O) cm−1; EI-HRMS calcd for
C34H28N4O4 [M]+ 556.2111, found 556.2108.
2-(4-Benzyloxyphenyl)-6-(4-nitrophenyl)-4-phenyltetrahydro-
1,2,4,5-tetrazin-3(2H)-one (5d). Crude tetrazine was obtained in 72%
yield and was partially purified by flash chromatography (SiO2 washed
with 1% Et3N in hexanes, hexanes/CH2Cl2 1:1) and used in the next
step. Analytical sample of 5d was obtained by recrystallization from
EtOH: mp 78−80 °C; 1H NMR (400 MHz, CDCl3) δ 4.79 (d, J = 9.9
Hz, 1H), 4.87 (d, J = 10.2 Hz, 1H), 5.08 (s, 2H), 5.54 (t, J = 9.9 Hz,
1H), 7.00 (d, J = 9.1 Hz, 2H), 7.30−7.46 (m, 8H), 7.51 (d, J = 9.1 Hz,
2H), 7.52−7.59 (m, 2H), 7.95 (d, J = 9.4 Hz, 2H), 8.20 (d, J = 9.4 Hz,
2H); 13C NMR (400 MHz, CDCl3) δ 70.2, 72.8, 114.9, 119.7, 124.1,
124.3, 126.3, 127.4, 128.0, 128.6, 129.0, 129.3, 134.4, 135.0, 136.7,
4-Benzoyloxyaniline (7b).25 4-Nitrophenyl benzoate25,39 (6b, 37.4
g, 0.153 mol) was dissolved in i-propanol (400 mL) at 60 °C, followed
by addition of SnCl2·2H2O (178 g, 0.740 mol). The resulting mixture
was heated at this temperature for 4 h and then stirred overnight at rt
and quenched with excess saturated aqueous Na2CO3 solution. After
the evolution of CO2 was stopped, the resulting precipitate was
filtered, and the filtrate was extracted with three portions of EtOAc.
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dx.doi.org/10.1021/jo400843y | J. Org. Chem. XXXX, XXX, XXX−XXX