Checked by Richard Hutchings and Albert I. Meyers.
1. Procedure
2. Notes
1. The submitters employed, without purification,
ethyl diazoacetate obtained from Aldrich Chemical Company, Inc.
2. A time lag (10–15 min) is observed before the exothermic reaction begins. Addition of
ethyl diazoacetate is then maintained at such a rate that the reaction temperature does not rise above 80°C. The checkers had to heat the mixture to 60°C.
3. Drying of the free acid should be rapid with a large surface area since traces of
hydrochloric acid promote hydrolysis of the product to hydrazine salts. Slight warming (≤ 60°C) during drying accelerates the drying process. The IR spectrum is as follows: IR (KBr) γ
max cm
−1: 3700–3100, 3320, 3000–1850, 1710, 1630. The checkers found that this step does not work as well on a smaller scale (0.14 mol).
5. The submitters employed, without purification,
thionyl chloride obtained from Fisher Scientific Company. The procedure should be performed in a
well-ventilated hood since
thionyl chloride is a lachrymator. The yield of dimethyl ester was found to be lower in instances when the thionyl chloride-methanol solution was not allowed to stir (30 min, −30°C) prior to the addition of
dihydro-1,2,4,5-tetrazine-3,6-dicarboxylic acid.
6. The temperature is maintained at −30°C during the additions.
7. The submitters employed
ether distilled from
sodium benzophenone ketyl.
8. The spectral properties of the product are as follows:
1H NMR (CDCl
3) δ: 3.92 (s, 6 H, CO
2CH
3), 7.42 (br s, 2 H, NH); IR (KBr) ν
max cm
−1: 3160, 3050, 1740, 1720.
9. The submitters employed
methylene chloride from Fisher Scientific Company, which was distilled before use.
10. Nitrous gases are generated in a separate vessel by the disproportionation of
nitrous acid (HONO):
200 mL of 6 N NaNO2 (1.2 mol) is added dropwise to
125 mL of concentrated hydrochloric acid (1.5 mol) in a
500-mL, three-necked, round-bottomed flask fitted with a nitrogen inlet, a 500-mL addition funnel, and an outlet tube leading to the reaction flask. The brown gases evolved are bubbled directly into the reaction mixture through a
5-mm (inside diameter) glass tube (smaller inlet tubes occasionally became plugged) using a
nitrogen stream.
CAUTION: all operations involving nitrous gases should be conducted in a well-ventilated hood because of the toxicity of these gases.
11. The checkers observed some starting material in the product which depressed the mp. It could be removed by crystallization from
ethyl acetate to give pure
3, mp
176–177°C, but with significant loss of product. The spectral properties of the product are as follows:
1H NMR (CDCl
3) δ: 4.22 (s, 6 H, CO
2CH
3); IR (KBr) η
max cm
−1: 2970, 1752, 1445, 1385, 1219, 1175, 1082, 960, 912; UV (dioxane) λ
max(log ε) 520 nm (2.754).
12. The submitters employed
1,4-dioxane obtained from Fisher Scientific Company and distilled before use.
14. The elemental analysis and the spectral analysis of the product are as follows: Anal. Calcd for C
14H
12N
2O
4: C, 61.76; H, 4.44; N, 10.29. Found: C, 62.01; H, 4.50; N, 10.19;
1H NMR (CDCl
3) δ: 3.89 (s, 3 H, CO
2CH
3), 4.12 (s, 3 H, CO
2CH
3), 7.40–7.60 (m, 5 H, Ph), 8.27 (s, 1 H, C5-H); IR (KBr) ν
max cm
−1: 2955, 1742, 1584, 1447, 1399, 1287, 1244, 1142, 766; EI-MS (70 eV): m/e (relative intensity) 272 (M
+, 9), 242 (7), 241 (6), 214 (34), 182 (10), 155 (base), lit
3 mp
94–95.5°C.
15. The submitters employed, without purification,
glacial acetic acid obtained from Fisher Scientific Company.
16.
Zinc dust obtained from Fisher Scientific Company was activated prior to use following an established procedure.
5
17. The elemental analysis and the spectral analysis of the product are as follows: Anal. Calcd for C
14H
13NO
4: C, 64.86; H, 5.05; N, 5.40. Found: C, 65.10; H, 4.99; N, 5.48;
1H NMR (CDCl
3) δ: 3.82 (s, 3 H, OCH
3), 3.91 (s, 3 H, OCH
3), 6.94 (d, 1 H, J = 3, C4-H), 7.30–7.60 (m, 5 H, Ph), 9.80 (br, s, 1 H, NH); IR (KBr) ν
max cm
−1: 3314, 2958, 1726, 1564, 1464, 1436, 1270, 1096, 1008, 940, 846, 762, 696. The additional formation of
methyl 3-phenyl-5-carboxamidopyrrole-2-carboxylate in
32% yield is observed. The spectral properties of the product are as follows:
1H NMR (CDCl
3) δ: 1.75 (br s, 2 H), 3.92 (s, 3 H), 7.14 (s, 1 H), 7.40–7.60 (m, 5 H); IR (KBr) ν
maxcm
−1: 3442, 3346, 2950, 1708, 1642, 1580, 1528, 1476, 1366, 1280, 1132, 1022, 936, 808, 728, 618; CI-MS (70 eV): m/e (relative intensity) 245 (M
+ + H, base).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The procedure describes the preparation and use of a reactive, electron-deficient heterocyclic azadiene suitable for Diels-Alder reactions with electron-rich, unactivated, and electron-deficient dienophiles.
6 7 8 9 10 11 Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, because of its electron-deficient character, is ideally suited for use in inverse electron demand (LUMO
diene-controlled)
12 Diels-Alder reactions. Table I and Table II detail representative examples of the reaction of
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with electron-rich
carbon dienophiles
13 and heterodienophiles,
6,7,8 respectively. Complete surveys of the reported Diels-Alder reactions of
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate have been compiled.
6,7,8,9,10,11 Reductive ring contraction of the substituted
dimethyl 1,2-diazine-3,6-dicarboxylate [4 + 2] cycloadducts effected by
zinc in
acetic acid provides the corresponding substituted dimethyl pyrrole-2,5-dicarboxylates.
13,14 Table III details representative examples of this general reductive ring contraction reaction.
14,15
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
sodium benzophenone ketyl
1,2-DIAZINE (DIMETHYL 4-PHENYL-1,2-DIAZINE-3,6-DICARBOXYLATE)
PYRROLE (DIMETHYL 3-PHENYLPYRROLE-2,5-DICARBOXYLATE)
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
sodium hydroxide (1310-73-2)
thionyl chloride (7719-09-7)
sodium bicarbonate (144-55-8)
magnesium (7439-95-4)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
nitrous acid (7782-77-6)
carbon (7782-42-5)
zinc (7440-66-6)
methylene chloride (75-09-2)
Pyrrole (109-97-7)
magnesium sulfate (7487-88-9)
ethyl diazoacetate (623-73-4)
Dihydro-1,2,4,5-tetrazine-3,6-dicarboxylic acid (3787-09-5)
hexane (110-54-3)
1,4-dioxane (123-91-1)
1,2-DIAZINE (289-80-5)
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate,
1,2,4,5-Tetrazine-3,6-dicarboxylic acid, dimethyl ester (2166-14-5)
Dimethyl 4-phenyl-1,2-diazine-3,6-dicarboxylate,
3,6-Pyridazinedicarboxylic acid, 4-phenyl-, dimethyl ester (2166-27-0)
Dimethyl 3-phenylpyrrole-2,5-dicarboxylate,
1H-Pyrrole-2,5-dicarboxylic acid, 3-phenyl-, dimethyl ester (92144-12-2)
Disodium dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate (96898-32-7)
Dimethyl dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate (3787-10-8)
1-Phenyl-1-(trimethylsiloxy)ethylene (13735-81-4)
methyl 3-phenyl-5-carboxamidopyrrole-2-carboxylate
dimethyl 1,2-diazine-3,6-dicarboxylate
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