HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 647-658
Received, 25th September, 2008, Accepted, 28th November, 2008, Published online, 28th November, 2008.
DOI: 10.3987/COM-08-S(D)31

■ Ruthenium Tetroxide Oxidation of N,N’-DiBoc-Hexahydropyridazines

Mamoru Kaname, Shigeyuki Yoshifuji, and Haruki Sashida*

Faculty of Pharmaceutical Sciences, Hokuriku University, 3-Ho, Kanagawa machi, Kanazawa 920-1181, Japan

Abstract

The ruthenium tetroxide (RuO4) oxidation of the 3-substituted N,N’-diBochexahydropyridazines gave the 6-oxohexahydropyridazines in good to high yields, whereas the oxidation of the unsubstituted ones also gave the 3,6-dioxo derivatives. The 3,6-cis-disubstituted pyridazines were essentially oxidized to give the 3-hydroxypyridazines; no oxidation of the trans-derivative occurred.

INTRODUCTION
RuO4 is an effective multipurpose oxidant1 and has been widely used for the oxidation of various amines, alcohols, olefins and aromatic compounds in recent years. In the RuO4 oxidation of the N-acyl amines, only the methylene moiety adjacent to the nitrogen atom is generally oxidized to afford the imides; the second and higher stages of oxidation never occur (eq. 1). There are many reports concerning both the

transformation of cyclic and acyclic N-acyl amines into the corresponding lactams2,3 and imides4 including natural products5 using a catalytic amount of RuO2 hydrate and an appropriate co-oxidant by us6 and other workers7 in this field. However, to the best of our knowledge, only a few papers8,9 have described the RuO4 oxidation of the heterocycles containing two nitrogen atoms; the RuO4 oxidation of N,N’-diacethylhexahydropyrazine (4)8 gives the pyrazi-2,3-dione 5, not pyrazi-2,5-dione 6 (eq. 2). We now report the result of the RuO4 oxidation of the N-acylhexahydropyridazines, six-membered heterocycles containing two nitrogen atoms.

RESULTS AND DISCUSSION
In order to obtain the hexahydropyridazines, which are the substrates for the RuO4 oxidation, the Diels-Alder (DA) reaction using the 1,3-dienes and azodicarboxylate was carried out. The hetero DA reaction between the 1,3-dienes 7a-h and di-tert-butyl azodicarboxylate (8)3 produced the corresponding adducts, the 6-unsubstituted 1,2-di-tert-butyl 1,2,3,6-tetrahydropyrydazine-1,2-carboxylates (9) in good to excellent yields except for the 1-methoxycarbonyl-1,3-diene (7d) having an electron withdrawing group (Scheme 2). Similarly, the reaction of 2,4-hexadiene (7i) and methyl hexa-2,4-dienate (7j) with 8 gave the 3,6-disubstituted cis-tetrahydropyrydazines 9i, j in almost quantitative yields. The olefin moiety in 9 was hydrogenated by Pd-C in EtOH to give the hexahyropyridazine derivatives 10 in high yields as shown in Schemes 2 and 3.

The methyl cis-ester 10j was epimerized into the trans-ester 10k by treatment with NaOMe in refluxing MeOH in 94% yield.

Next, the RuO4 oxidation of the hexahyropyridazines 10a-h was carried out at room temperature according to our standard method3 using a catalytic amount of RuO2 hydrate and excess of 10% NaIO4 in a double layer system of ethyl acetate-water. When the 3-substituted 6-unsubstituted pyridazines 10b-d, g, h were oxidazed, the reaction smoothly proceeded to give the desired pyridazinones 11b-d, g, h in good to excellent yields as the sole product. The oxidation of the pyridazines 10a, e, f having no substituted at the C-3 and -6 positions in spite of the existence or absence of the functional groups at the C-4 and -5 positions, gave both the pyridazin-3-ones 11a, e, f and 3,6-dioxo derivatives 12a, e, f as shown in Scheme 4.

On the other hand, the behavior of the 3,6-disubstituted pyridazines 10i-k under the RuO4 oxidation was different. The hemiaminal 13 was produced by the RuO4 oxidation of cis-dimethylpyridazine 10i in 87% yield as the sole product. In contrast, the oxidation of the methyl cis-ester 10j under similar conditions resulted in the ring-opening reaction to give the hydrazine derivative 14 in 81% yield via the hemiaminal intermediate 15, which is essentially the same type of oxidation product as 13. However, the RuO4 oxidation of the methyl trans-ester 10k did not occur; the starting material was recovered. This distinction between the cis and trans carbon functionalities at the C-3 and C-6 positions of the chair-form conformation having two axial N-Boc groups with respect to the reactivity of the hexahyropyridazines 10i, j towards the RuO4 is explained in Scheme 5. During the RuO4 oxidation of the methyl cis-ester 10j, the reagent could slightly attack the nitrogen atom from the back side of the axial N-Boc group to oxidize the methyne carbon giving the hydroxypyridazine intermediate 15 as illustrated in 10j’. However, RuO4 could not approach the nitrogen atom of the methyl trans-ester 10k’ from any direction due to the steric hindrance of the two bulky Bocs, methyl and methoxycarbonyl groups, which are all axial. For that reason, no oxidized products were obtained.

CONCLUSION
In summary, we have developed the RuO4 oxidation of the N,N’-diacyl hexahydropyridazines. The results mentioned in this paper suggest that the RuO4 oxidation of the six-membered species containing two nitrogen atoms smoothly proceeded, and is synthetically very useful for the preparation of the hexahydropyridazin-ones and -diones. A distinction between the oxidation of the cis and trans 1,2,3,6-tetrasubstituted hexahydropyridazines was also examined.

EXPERIMENTAL
Melting points were measured on a Yanagimoto micro melting point hot stage apparatus and are uncorrected. IR spectra were determined with a Horiba FT-720 spectrometer. Mass spectra (MS) and HRMS were recorded on a JEOL JMS-DX300 instrument. NMR spectra were determined with a JEOL EX-90A (90 MHz) or a JEOL JNM-GSX 400 (400 MHz) spectrometer in CDCl3 using tetramethylsilane as internal standard and J values are given in Hz. Microanalyses were performed in the Microanalytical Laboratory in this Faculty.

Aza Diels-Alder reaction of 1,3-butadiene (7) with azodicarboxylate (8)
1,3-Butadiene (7, 33 mmol) was added to a solution of di-tert-butyl azodicarboxylate (8, 30 mmol) in CH2Cl2 (30 mL). The mixture was stirred at room temperature for 18-48 h, and then evaporated in vacuo. The resulting residue was purified by silica gel chromatography to give 9. 9d and 9j were obtained by the reaction of 7d and 7j with 8 in refluxing benzene for 2-3 days.
Di-tert-butyl 1,2,3,6-Tetrahydropyridazine-1,2-dicarboxylate (9a)
Colorless prisms, mp 74-75 ˚C (from hexane) (lit.,10 mp 73-75 ˚C).
Di-tert-butyl 3-Methyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9b)
Colorless oil. MS m/z: 298 (M+). IR (neat) cm-1: 1703 (C=O). 1H-NMR δ: 1.22 (3H, d, J = 6.5 Hz, 3-Me), 1.44 (18H, s, t-Bu x 2), 3.29-3.85 (1H, m, 3-H), 3.95-4.83 (2H, m, 6-H2), 5.37-5.87 (2H, m, 4- and 5-H). EI-HR-MS m/z: 298.1889 (Calcd for C15H26N2O4: 298.1893).
Di-tert-butyl 3-Ethyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9c)
Colorless oil. MS m/z: 312 (M+). IR (neat) cm-1: 1705 (C=O). 1H-NMR δ: 0.73-1.37 (5H, m, 3-Et), 1.45 (18H, s, t-Bu x 2), 3.65 and 4.37 (each 1H, d, J = 16.5 Hz, 6-H2), 4.07-4.57 (1H, m, 3-H), 5.50-6.05 (2H, m, 4- and 5-H). EI-HR-MS m/z: 312.2051 (Calcd for C16H28N2O4: 312.2049).
Di-tert-butyl 3-Methyl 1,2,3,6-Tetrahydropyridazine-1,2,3-tricarboxylate (9d)
Colorless prisms, mp 100-103˚C (from hexane). MS m/z: 342 (M+). IR (KBr) cm-1: 1759, 1697 (C=O). 1H-NMR δ: 1.48 (18H, s, t-Bu x 2), 3.74 (3H, s, 3-COOMe), 3.56-3.92 and 4.24-4.52 (each 1H, br, 6-H2), 5.07-5.40 (1H, br, 3-H), 5.87-6.01 (2H, br, 4- and 5-H). 13C-NMR δ: 28.21 (q), 28.24 (q), 41.5 (t), 52.3 (q), 55.5 (d), 80.7 (s), 82.0(s), 122.3 (d), 125.5 (d), 153.9 (s), 154.4 (s), 169.1 (s). Anal. Calcd for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.12; H, 7.48; N, 8.26.
Di-tert-butyl 4-Methyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9e)
Colorless oil. MS m/z: 298 (M+). IR (neat) cm-1: 1709 (C=O). 1H-NMR δ: 1.45 (18H, s, t-Bu x 2), 1.68 (3H, br s, 4-Me), 3.38-4.48 (4H, m, 3- and 6-H2), 5.29-5.59 (1H, br, 5-H). EI-HR-MS m/z: 298.1890 (Calcd for C15H26N2O4: 298.1893).
Di-tert-butyl 4,5-Dimethyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9f)
Colorless prisms, mp 89-90 ˚C (from hexane). MS m/z: 312 (M+). IR (KBr) cm-1: 1720, 1709 (C=O). 1H-NMR δ: 1.45 (18H, s, t-Bu x 2), 1.60 (6H, br s, 4- and 5-Me), 3.48 and 4.10 (each 2H, d, J = 16.4 Hz, 3- and 6-H2). Anal. Calcd for C16H28N2O4: C, 61.51; H, 9.03; N, 8.97. Found: C, 61.54; H, 8.82; N, 8.98.
Di-tert-butyl 3,4-Dimethyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9g)
Colorless oil. MS m/z: 311 (M+-1). IR (neat) cm-1: 1703 (C=O). 1H-NMR δ: 1.24 (3H, d, J = 6.3 Hz, 3-Me), 1.45 (18H, s, t-Bu x 2), 1.66 (3H, d, J = 1.5 Hz, 4-Me), 3.33-3.88 (1H, m, 3-H), 3.97-4.63 (2H, m, 6-H2), 5.17-5.43 (1H, br, 5-H). EI-HR-MS m/z: 311.3961 (Calcd for C16H27N2O4: 311.3966).
Di-tert-butyl 3,5-Dimethyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9h)
Colorless oil. MS m/z: 312 (M+). IR (neat) cm-1: 1720, 1705 (C=O). 1H-NMR δ: 1.12 and 1.17 (total 3H, intensity ratio 3:7, each d, J = 6.5 and 6.8 Hz, 3-Me), 1.45 (18H, s, t-Bu x 2), 1.66 and 1.80 (total 3H, intensity ratio 7:3, each br s, 5-Me), 2.32-3.44 (1H, m, 3-H), 3.50-4.89 (2H, m, 6-H2), 5.24-5.95 (1H, m, 4-H). EI-HR-MS m/z: 312.2044 (Calcd for C16H28N2O4: 312.2049).
Di-tert-butyl cis-3,6-Dimethyl-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate (9i)
Colorless oil. MS m/z: 312 (M+). IR (neat) cm-1: 1726, 1711 (C=O). 1H-NMR δ: 1.25 (3H, d, J = 6.7 Hz, 3-Me), 1.44 (18H, s, t-Bu x 2), 1.51 (3H, d, J = 6.7 Hz, 6-Me), 3.86-4.87 (2H, m, 3- and 6-H), 5.23-5.92 (2H, m, 4- and 5-H). EI-HR-MS m/z: 312.2042 (Calcd for C16H28N2O4: 312.2049).
Di-tert-butyl 3-Methyl cis-6-Methyl-1,2,3,6-tetrahydropyridazine-1,2,3-tricarboxylate (9j)
Colorless prisms mp 87-88 ˚C (from hexane). MS m/z: 356 (M+). IR (KBr) cm-1: 1734, 1709 (C=O). 1H-NMR δ: 1.10-1.62 (21H, m, t-Bu x 2 and 6-Me), 3.71 (3H, s, 3-COOMe), 4.40-4.95 (2H, m, 3- and 6-H), 5.32-5.67 (1H, m, 5-H), 5.83-6.29 (1H, m, 4-H). Anal. Calcd for C17H28N2O6: C, 57.29; H, 7.92; N, 7.86. Found: C, 57.25; H, 7.71; N, 7.86.
Catalytic Hydrogenation of Tetrahydropyridazine (9): Hexahydropyridazine (10)
A mixture of 9 (5 mmol) and 10% Pd-C (175 mg) in MeOH (40 mL) was shaken in H2 gas (1-5 atm) at room temperature until disappearance of the starting material (about 12-60 h). The mixture was filtered off, the filtrate was evaporated in vacuo. The obtained residue was purified by silica gel chromatography (AcOEt-hexane, 1:1~2:1) to give 10.
Di-tert-butyl Hexahydropyridazine-1,2-dicarboxylate (10a)
Colorless prisms, mp 62-63 ˚C (from hexane). MS m/z: 286 (M+). IR (KBr) cm-1: 1697 (C=O). 1H-NMR δ: 1.12-1.72 (4H, m, 4- and 5-H2), 1.46 (18H, s, t-Bu x 2), 2.56-3.18 and 3.18-4.34 (each 2H, m, 3- and 6-H2). Anal. Calcd for C14H26N2O4: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.50; H, 8.98; N, 9.76.
Di-tert-butyl 3-Methylhexahydropyridazine-1,2-dicarboxylate (10b)
Colorless oil. MS m/z: 300 (M+). IR (neat) cm-1: 1701 (C=O). 1H-NMR δ: 1.16 (3H, d, J = 6.8 Hz, 3-Me), 1.28-2.01 (4H, m, 4- and 5-H2), 1.44 (18H, s, t-Bu x 2), 2.41-3.15 (1H, m, 3-H), 3.68-4.63 (2H, m, 6-H2). EI-HR-MS m/z: 300.2051 (Calcd for C15H28N2O4: 300.2049).
Di-tert-butyl 3-Ethylhexahydropyridazine-1,2-dicarboxylate (10c)
Colorless oil. MS m/z: 314 (M+). IR (neat) cm-1: 1701 (C=O). 1H-NMR δ: 0.99 (3H, t, J = 7.3 Hz, 3-CH2CH3), 1.46 and 1.47 (each 9H, s, t-Bu x 2), 1.25-1.52 and 1.59-1.85 (each 3H, m, 3-CH2CH3, 4-H and 4-H, 5-H2), 2.82-3.04 (1H, m, 3-H), 3.85-4.19 (2H, m, 6-H2). 13C-NMR δ: 11.4 (q), 19.3 (t), 23.6 (t), 26.9 (t), 28.3 (q x 2), 43.4 (t), 54.9 (d), 80.2 (s), 80.6 (s), 154.8 (s), 155.4 (s). EI-HR-MS m/z: 314.2201 (Calcd for C16H30N2O4:314.2206).
Di-tert-butyl 3-Methyl Hexahydropyridazine-1,2,3-tricarboxylate (10d)
Colorless oil. MS m/z: 344 (M+). IR (neat) cm-1: 1738, 1703 (C=O). 1H-NMR δ: 1.43 and 1.46 (each 9H, s, t-Bu x 2), 1.80-2.20 (4H, m, 4- and 5-H2), 2.47-3.17 and 3.87-4.27 (each 1H, m, 6-H2), 3.69 (3H, s, 3-COOMe), 4.75-5.07 (1H, m, 3-H). EI-HR-MS m/z: 344.1943 (Calcd for C16H28N2O6: 344.1947).
Di-tert-butyl 4-Methylhexahydropyridazine-1,2-dicarboxylate (10e)
Colorless oil. MS m/z: 300 (M+). IR (neat) cm-1: 1705 (C=O). 1H-NMR δ: 0.87 (3H, d, J = 5.8 Hz, 4-Me), 1.03-1.80 (3H, m, 4-H and 5-H2), 1.45 (18H, s, t-Bu x 2), 2.15-3.37 and 3.62-4.32 (each 2H, m, 3- and 6-H2). EI-HR-MS m/z: 300.2040 (Calcd for C15H28N2O4: 300.2049).
Di-tert-butyl cis-4,5-Dimethylhexahydropyridazine-1,2-dicarboxylate (10f)
Colorless oil. MS m/z: 314 (M+). IR (neat) cm-1: 1722, 1705 (C=O). 1H-NMR δ: 0.83 and 0.89 (each 3H, d, J = 5.9 and 6.3 Hz, 4- and 5-Me), 1.44 (18H, s, t-Bu x 2), 1.55-2.05 (2H, br, 4- and 5-H), 2.44-3.27 and 3.58-4.15 (each 2H, m, 3- and 6-H2). EI-HR-MS m/z: 314.2209 (Calcd for C16H30N2O4:314.2206).
Di-tert-butyl cis-3,4-Dimethylhexahydropyridazine-1,2-dicarboxylate (10g)
Colorless oil. MS m/z: 314 (M+). IR (neat) cm-1: 1699 (C=O). 1H-NMR δ: 1.02 (3H, d, J = 6.1 Hz, 4-Me), 1.19 (3H, d, J = 6.4 Hz, 3-Me), 1.35-2.23 (3H, m, 4-H and 5-H2), 1.45 (18H, s, t-Bu x 2), 2.79-3.46 (1H, m, 3-H), 3.58-4.46 (2H, m, 6-H2). EI-HR-MS m/z: 314.2205 (Calcd for C16H30N2O4:314.2206).
Di-tert-butyl cis-3,5-Dimethylhexahydropyridazine-1,2-dicarboxylate (10h)
Colorless oil. MS m/z: 314 (M+). IR (neat) cm-1: 1720, 1701 (C=O). 1H-NMR δ: 0.96 (3H, d, J = 6.0 Hz, 5-Me), 1.17 (3H, d, J = 6.5 Hz, 3-Me), 1.29-2.01 (3H, m, 4-H2 and 5-H), 1.45 (18H, s, t-Bu x 2), 3.03-3.56 and 3.89-4.47 (2H，m and 1H, m, 3-H and 6-H2). EI-HR-MS m/z: 314.2210 (Calcd for C16H30N2O4:314.2206).
Di-tert-butyl cis-3,6-Dimethylhexahydropyridazine-1,2-dicarboxylate (10i)
Colorless oil. MS m/z: 314 (M+). IR (neat) cm-1: 1720, 1705 (C=O). 1H-NMR δ: 1.21 (6H, d, J = 6.5 Hz, 3- and 6-Me), 1.48 (9H, s, t-Bu), 1.51 (9H, s, t-Bu), 1.41-1.77 (4H, m, 4- and 5-H2), 3.47-3.99 and 4.15-4.73 (each 1H, m, 3- and 6-H). EI-HR-MS m/z: 314.2205 (Calcd for C16H30N2O4:314.2206).
Di-tert-butyl 3-Methyl cis-6-Methylhexahydropyridazine-1,2,3-tricarboxylate (10j)
Colorless oil. MS m/z: 358 (M+). IR (neat) cm-1: 1753, 1739, 1707 (C=O). 1H-NMR δ: 1.28 and 1.31 (total 3H, intensity ratio 3:2, each d, J = 6.6 Hz, 6-Me), 1.33-1.52 (18H, m, t-Bu x 2), 1.52-1.69 and 1.69-1.88 (each 2H, m, 4- and 5-H2), 3.76 (3H, s, 3-COOMe), 4.15-4.50 (2H, m, 3- and 6-H). 13C-NMR δ: 19.4 and 19.9 (each q), 23.3 and 23.8 (each t), 24.4, 24.5 and 25.2 (each t), 28.0 and 28.1 (each q), 28.3 (q), 50.6 and 50.7 (each d), 51.9 and 52.1 (each d), 56.4, 56.8 and 58.2 (each q), 80.9 (s), 81.2 and 81.4 (each s), 153.4 (s), 154.8 and 155.8 (each s), 170.9 and 171.7 (each s). EI-HR-MS m/z: 358.2103 (Calcd for C17H30N2O6: 358.2104).
Di-tert-butyl 3-Methyl trans-6-Methylhexahydropyridazine-1,2,3-tricarboxylate (10k)
A mixture of 10j (209 mg) and Na metal (178 mg) in MeOH (3 mL) was refluxed for 2 h. After cooling, the mixture was neutralized with citric acid monohydrate (1.0 g), and evaporated. AcOEt (100 mL) and water (30 mL) was added to the residue. The organic layer was washed with water (30 mL x 2), dried over Na2SO4 and evaporated in vacou. The obtained residue was chromatographed on silica gel eluted with AcOEt-hexane to give 10k (197 mg, 94% yield).
Colorless oil. MS m/z: 358 (M+). IR (neat) cm-1: 1738, 1697 (C=O). 1H-NMR δ: 1.17 (3H, d, J = 6.6 Hz, 6-Me), 1.18-1.28, 1.70-1.86 and 1.94-2.07 (1H, m, 1H, m and 2H, m, 4- and 5-H2), 1.47 (9H, s, t-Bu), 1.48 (9H, s, t-Bu), 3.73 (3H, s, 3-COOMe), 4.11-4.24 and 4.27-4.44 (total 1H, intensity ratio 1:4, each m, 6-H), 4.55-4.64 and 4.86 (total 1H, intensity ratio 1:4, m and d, J = 6.2 Hz, 3-H). 13C-NMR δ: 17.6 and 18.2 (each q), 21.2 and 21.9 (each t), 26.0 and 26.5 (each t), 28.2 (q), 28.3 (q), 49.0 and 49.4 (each d), 51.9 and 52.0(each d), 54.7 and 57.4 (each q), 80.2 (s), 81.3 and 81.4 (each s), 154.0 (s), 155.1 (s), 170.8 (s). EI-HR-MS m/z: 358.2199 (Calcd for C17H30N2O6: 358.2104).

RuO4Oxidation under the Standard Conditions in a Double Layer System
A solution of a substrate (10, 12 mmol) to be oxidized in AcOEt (40 mL) was added to a mixture of RuO2·xH2O (120 mg) and 10% aqueous NaIO4 solution (120 mL). The mixture was vigorously stirred in a sealed flask at 20 ˚C until disappearance of the starting material.
Di-tert-butyl 3-Oxohexahydropyridazine-1,2-dicarboxylate (11a)
Colorless oil. MS (FAB) m/z: 301 (MH+). IR (neat) cm-1: 1711 (C=O). 1H-NMR δ: 1.47 (9H, s, t-Bu), 1.54 (9H, s, t-Bu), 1.81-2.53 (4H, m, 4- and 5-H2), 3.15-3.35 and 4.27-4.43 (each 1H, m, 6-H2). 13C-NMR δ: 20.4 (t), 28.0 (q), 28.1 (q), 32.5 (t), 41.8 (t), 82.3 (s), 83.9 (s), 148.9 (s), 154.2 (s), 171.3 (s). HR-MS (FAB) m/z: 301.1768 (Calcd for C14H25N2O5: 301.1763).
Di-tert-butyl 3,6-Dioxohexahydropyridazine-1,2-dicarboxylate (12a)
Colorless needles, mp 128-130 ˚C (from isopropyl ether). MS (FAB) m/z: 315 (MH+). IR (KBr) cm-1: 1736, 1716 (C=O). 1H-NMR δ: 1.54 (18H, s, t-Bu x 2), 2.78 (4H, s, 4- and 5-H2). 13C-NMR δ: 27.9 (q), 31.5 (t), 85.4 (s), 147.7 (s), 168.9 (s). Anal. Calcd for C14H22N2O6: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.38; H, 7.03; N, 8.90.
Di-tert-butyl 3-Methyl-6-oxohexahydropyridazine-1,2-dicarboxylate (11b)
Colorless oil. MS (FAB) m/z: 315 (MH+). IR (neat) cm-1: 1790, 1753, 1712 (C=O). 1H-NMR δ: 1.22 (3H, d, J = 7.0 Hz, 3-Me), 1.46 (9H, s, t-Bu), 1.53 (9H, s, t-Bu), 1.35-1.60 and 2.12-2.27 (each 1H, m, 4-H2), 2.33-2.44 (2H, m, 5-H2), 4.58-4.69 (1H, m, 3-H). 13C-NMR δ: 19.8 (q), 27.9 (q), 28.1 (q), 28.7 (t), 33.0 (t), 49.1 (d), 82.1 (s), 83.5 (s), 149.3 (s), 153.8 (s), 172.0 (s). HR-MS (FAB) m/z: 315.1917 (Calcd for C15H27N2O5: 315.1920.
Di-tert-butyl 3-Ethyl-6-oxohexahydropyridazine-1,2-dicarboxylate (11c)
Colorless oil. MS (FAB) m/z: 330 (MH2+). IR (neat) cm-1: 1790, 1752, 1716 (C=O). 1H-NMR δ: 1.03, (3H, t, J = 7.3 Hz, 3-CH2CH3), 1.47 (9H, s, t-Bu), 1.54 (9H, s, t-Bu), 1.32-1.61 and 2.10-2.29 (3H, m and 1H, m, 3-CH2CH3 and 4-H2), 2.29-2.44 (2H, m, 5-H2), 4.32-4.45 (1H, m, 3-H). 13C-NMR δ: 10.8 (q), 27.2 (t), 27.6 (t), 28.0 (q), 28.1 (q), 32.9 (t), 55.5 (d), 82.0(s), 83.5 (s), 149.2 (s), 154.6 (s), 172.2 (s). HR-MS (FAB) m/z: 330.2160 (Calcd for C16H30N2O5: 330.2155).
Di-tert-butyl 3-Methyl 6-Oxohexahydropyridazine-1,2,3-tricarboxylate (11d)
Colorless prisms, mp 107-108 ˚C (from hexane). MS m/z: 359 (MH+). IR (KBr) cm-1: 1790, 1743, 1712 (C=O). 1H-NMR δ: 1.48 (9H, s, t-Bu), 1.54 (9H, s, t-Bu), 2.09-2.33 (2H, m, 4-H2), 2.41-2.58 (2H, m, 5-H2), 3.76 (3H, s, 3-COOMe), 4.87-5.03 and 5.12-5.26 (total 1H, intensity ratio 4:1, each m, 3-H). 13C-NMR δ: 23.7 (t), 27.9 (q), 28.0 (q), 32.2 (t), 52.5 (q), 54.3 (d), 83.3 (s), 83.7 (s), 148.6 (s), 154.0 (s), 170.4 (s), 170.8 (s). Anal. Calcd for C16H26N2O7: C, 53.62; H, 7.31; N, 7.82. Found: C, 53.67; H, 7.21; N, 7.85.
Di-tert-butyl 5-Methyl-3-oxohexahydropyridazine-1,2-dicarboxylate (11e)
Colorless oil. MS m/z: 313 (M-1+). IR (neat) cm-1: 1712 (C=O). 1H-NMR δ: 0.86-1.29 (3H, br, 5-Me), 1.46 (9H, s, t-Bu), 1.52 (9H, s, t-Bu), 1.89-2.78 (3H, m, 4-H2 and 5-H), 3.11-4.51 (2H, br, 6-H2). EI-HR-MS m/z: 313.1760 (Calcd for C15H25N2O5: 313.1763).
Di-tert-butyl 4-Methyl-3,6-dioxohexahydropyridazine-1,2-dicarboxylate (12e)
Colorless oil. MS m/z: 327 (M-1+). IR (neat) cm-1: 1724 (C=O). 1H-NMR δ: 1.25 (3H, d, J = 6.3 Hz, 4-Me), 1.52 (18H, s, t-Bu x 2), 2.38-3.03 (3H, m, 4-H and 5-H2). EI-HR-MS m/z: 327.1551 (Calcd for C15H23N2O6: 327.1556).
Di-tert-butyl cis-4,5-Dimethyl-3-oxohexahydropyridazine-1,2-dicarboxylate (11f)
Colorless oil. MS (FAB) m/z: 329 (MH+). IR (neat) cm-1: 1790, 1751, 1709 (C=O). 1H-NMR δ: 0.89 (3H, d, J = 6.6 Hz, 5-Me), 1.06 and 1.13 (total 3H, intensity ratio 1:9, each d, J = 4.0 and 6.2 Hz, 4-Me), 1.46 (9H, s, t-Bu), 1.55 (9H, s, t-Bu), 2.47-2.61 (2H, m, 4- and 5-H), [2.80 and 2.89-2.98 (total 1H, intensity ratio 4:1, dd, J = 13.6, 3.7 Hz, m), 4.34-4.47 and 4.62 (total 1H, intensity ratio 1:4, m, dd, J = 13.6, 9.2 Hz), 6-H2]. 13C-NMR δ: 11.0 and 11.2 (each q), 16.1 and 16.4 (each q), 28.0 (q), 28.1 and 28.2 (each q), 33.2 and 33.8 (each d), 40.0 (d), 50.1 and 52.1 (each t), 82.2 (s), 83.8 and 83.9 (each s), 148.7 and 148.8 (each s), 153.0 and 153.6 (each s), 172.5 and 172.7 (each s). HR-MS (FAB) m/z: 329.2074 (Calcd for C16H29N2O5: 329.2076).
Di-tert-butyl cis-4,5-Dimethyl-3,6-dioxohexahydropyridazine-1,2-dicarboxylate (12f)
Colorless prisms, mp 100-101 ˚C (from isopropyl ether). MS (FAB) m/z: 343 (MH+). IR (KBr) cm-1: 1788, 1755 (C=O). 1H-NMR δ: 1.16 (6H, d, J = 7.3 Hz, 4- and 5-Me), 1.47 (9H, br s, t-Bu), 1.54 (9H, s, t-Bu), 2.85-3.03 (2H, m, 4-, 5-H). 13C-NMR δ: 10.5 (q), 27.9 (q), 41.2 (d), 85.3 (s), 147.9 (s), 171.3 (s). Anal. Calcd for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.15; H, 7.54; N, 8.19.
Di-tert-butyl cis-3,4-Dimethyl-6-oxohexahydropyridazine-1,2-dicarboxylate (11g)
Colorless prisms, mp 74-75 ˚C (from isopropyl ether). MS (FAB) m/z: 329 (MH+). IR (KBr) cm-1: 1786, 1716 (C=O). 1H-NMR δ: 1.11 (3H, d, J = 5.6 Hz, 4-Me), 1.21 (3H, d, J = 6.4 Hz, 3-Me), 1.46 (9H, s, t-Bu), 1.51 (9H, s, t-Bu), 1.65-2.93 (3H, m, 4-H and 5-H2), 3.80-4.27 (1H, m, 3-H). Anal. Calcd for C16H28N2O5: C, 58.52; H, 8.59; N, 8.53. Found: C, 58.61; H, 8.33; N, 8.55.
Di-tert-butyl cis-4,6-Dimethyl-3-oxohexahydropyridazine-1,2-dicarboxylate (11h)
Colorless prisms, mp 75-76 ˚C (from isopropyl ether). MS (FAB) m/z: 329 (MH+). IR (KBr) cm-1: 1786, 1707(C=O). 1H-NMR δ: 1.15 (3H, d, J = 6.5 Hz, 4-Me), 1.19 (3H, d, J = 6.5 Hz, 6-Me), 1.46 (9H, s, t-Bu), 1.53 (9H, s, t-Bu), 1.92-2.88 (3H, m, 4-H and 5-H2), 4.28-4.92 (1H, m, 6-H). Anal. Calcd for C16H28N2O5: C, 58.52; H, 8.59; N, 8.53. Found: C, 58.70; H, 8.45; N, 8.56.
Di-tert-butyl 3-Hydroxy-3,6-dimethylhexahydropyridazine-1,2-dicarboxylate (13)
Colorless prisms, mp 98-100 ˚C (from isopropyl ether). MS m/z: 330 (M+). IR (KBr) cm-1: 3475 (OH), 1741, 1689 (C=O). 1H-NMR δ: 1.01-1.10, 1.34-1.57, 1.69-1.77 and 1.90-2.07 (1H, m, 1H, m, 1H, m and 1H, m, 4- and 5-H2), 1.14 and 1.15 (total 3H, intensity ratio 3:2, each d, J = 6.6 and 6.2 Hz, 6-Me), 1.45, 1.47, 1.48 and 1.49 (total 18H, intensity ratio 1:2:3:2, each s, t-Bu x 2), 1.78 and 1.79 (total 3H, intensity ratio 3:2, 3-Me), 3.30-3.53 and 3.84 (total 1H, intensity ratio 3:2, br and s, OH), 4.07-4.19 and 4.34-4.46 (total 1H, intensity ratio 2:3, 6-H). 13C-NMR δ: 19.4 and 19.9 (each q), 25.5 and 25.7 (each q), 26.7 and 27.2 (each t), 28.2 and 28.25 (each q), 28.31 and 28.4 (each q), 35.7 and 36.8 (each t), 49.3 and 51.7 (each d), 80.7 (s), 81.1 (s), 88.0 and 88.2 (each s), 154.28 and 154.34 (each s), 155.4 (s). Anal. Calcd for C16H30N2O5: C, 58.16; H, 9.15; N, 8.48. Found: C, 58.37; H, 8.83; N, 8.58.
Methyl 2-(1,2-Di-tert-butoxycarbonyl)hydrozino-5-oxohexanate (14)
Colorless oil. MS m/z: 374 (M+). IR (neat) cm-1: 3321 (NH), 1743, 1712 (C=O). 1H-NMR δ: 1.46 (18H, s, t-Bu x 2), 1.83-2.02 and 2.18-2.34 (each 1H, m, 3-H2), 2.15 (3H, s, 5-Me), 2.65-2.95 (2H, m, 4-H2), 3.73 (3H, s, COOMe), 4.62-4.75 and 4.75-4.92 (total 1H, intensity ratio 3:7, each br, 2-H), 6.19-6.29 and 6.37-6.57 (total 1H, intensity ratio 3:7, each br, NH). 13C-NMR δ: 22.4, 22.8 (t), 28.1 (q), 28.2 (q), 30.0 (q), 39.7, 39.8 (t), 52.4 (q), 59.2, 61.2 (d), 81.0 (s), 82.1 (s), 115.2 (s), 115.7 (s), 171.9 (s), 208.3 (s). EI-HR-MS m/z: 374.2049 (Calcd for C17H30N2O7: 374.2053).

ACKNOWLEDGEMENT AND NOTES
This work was partially supported by The Specific Research Fund of Hokuriku University (2007).

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