Short communication
The Synthesis of 7-Substituted-2,3-dihydropyrido [4,3-d]pyridazine-1,4-diones and 1,4-Dioxo-7-substituted-1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-Oxides
from Methyl Ketones
Benjamin Prek and Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, P. O. Box 537, 1000 Ljubljana, Slovenia
* Corresponding author: E-mail: branko.stanovnik@fkkt.uni-lj.si
Received: 12-07-2017
Dedicated to Professor Emeritus Miha Tisler, University of Ljubljana, on the occasion of his 90th birthday.
Abstract
A general four-step transformation of alkyl, cycloalkyl, aryl, and heteroaryl methyl ketones via 3-(dimethylamino)-1-sub-stituted-prop-2-en-1-ones, followed by microwave [2+2] cycloaddition of dimethyl acetylenedicarboxylate, cyclization of (2E,3E)-2-[(dimethylamino)methylene]-3-(2-substituted)succinates with ammonia or hydroxylamine hydrochloride into 2-substituted-pyridine-4,5-dicarboxylates and their N-oxides and final cyclization with hydrazine hydrate into of 7-substituted-2,3-dihydropyrido[3,4-d]pyridazine- 1,4-diones and 1,4-dioxo-7-substituted- 1,2,3,4-tetrahydropyri-do[4,3-d]pyridazine 6-oxides is shown.
Keywords: methyl ketones, 7-substituted-2,3-dihydropyrido[4,3-d]pyridazine- 1,4-diones, 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyrido [4,3-d]pyridazine 6-oxides
1. Introduction
There are several methods for the preparation of 2,3-dihydro[4,3-d]pyridazine-1,4- dione derivatives. They have been prepared by treatment of diethyl or dimethyl pyridine-3.4-dicarboxylate with hydrate of hydrazine in refluxing ethanol, and 6-aryl- and 6-aryl-2-methyl derivatives with hydrate of hydrazine in refluxing ethanol, which allow the formation of the corresponding 7-substituted and 5,7-disubstituted-2,3-dihydropyridazine[3,4-d]pyri-dazine-1,4-diones.1-4 Cyclization of ethyl 3-cyanoisonico-tinate with hydrazine proceeds at room temperature to give 4-aminopyrido[3,4-d]pyridazine-1(2H)-one,5,6 while pyridine-3,4-dicarbonitriles give the corresponding pyr-ido[3,4-d]pyridazine-1,4-diones.7 Other methods include cycloamination of 4-carbofunctional-5-vinylpyridazi-nes,A9 condensation of 4,5-dicarbofunctional pyridazines with amines,9,10 condensation of 4-(iminomethyl)pyri-dazines with enolates,10 intramolecular cyclization of pyri-dinecarbohydrazides,1,11 intramolecular cyclization of
4-vinylpyridazine-5-carbonitriles,12,13 by ring enlargement of furo[3,4-c]pyridine-1,3-diones,2,3,5,14,15 1H-pyrrolo[3,4-c] pyridine-1,3(2H) -diones with hydrazine,1,4,16,17 by reaction of 5H-pyrano[3,4-d]pyridazines with amines,8 intramolecular [4+2]cycloaddition of 1,2,4,5-tetrazines,18 ring contraction of 2H-1,2,4-triazepines.14 For a review see.19
Enaminones are well known starting compounds in the synthesis of heterocyclic systems. Their reactivity enables various transformations and functionalizations. Their synthetic value and broad applicability has also been demonstrated in the preparation of natural products and their analogues, such as aplysinopsins,20 meridi-anines,21 and dipodazines.22 Besides the evident reactions with nucleophiles, they also exhibit reactivity with elec-trophiles as well, which only adds to their importance as building blocks in organic synthesis.23 Reactions with electrophiles have been demonstrated in the synthesis of polysubstituted butadienes by microwave-assisted formal [2 + 2] cycloadditions of enaminones to electron-poor acetylenes.24
The functionalized buta-1,3-dienes as the basis of the synthetic route presented in this paper are prepared from simple and commercially available compounds such as al-kyl, aryl, and heteroaryl methyl ketones. These are transformed by treatment with N,N-dimethylformamide dimethyl acetal (DMFDMA) or tert-butoxybis(dimethyl-amino)methane (Bredereck's reagent) into the corre-
sp onding 3 - ( dimethylamino) -1 -substituted-prop- 2- en-ones, which are further transformed in a regiospecific microwave assisted [2 + 2] cycloaddition with dimethyl acetylenedicarboxylate (DMAD)25 to the before mentioned 1,3-butadienes. These highly functionalized buta-1,3-dienes proved to be useful and versatile reagents in the formation of highly substituted pyridine, pyridine N-oxides,
Scheme 1. Preparation of 7-substituted-2,3-dihydropyrido[3,4-^]pyridazine-1,4-diones 6a-c,f and 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyri-do[4,3-^]pyridazine 6-oxides 7a,b,d,e,g from methyl ketones 1a-g.
pyrrole, pyrido[3,4-c]pyridazine derivatives,25b 2-substi-tuted pyridine-3,4-dicarboxylates and their N-oxides,10g and triazafulvalene derivatives.254
Polysubstituted aminobutadienes, prepared by this procedure, are suitable for the preparation of polysubsti-tuted pyridine derivatives. They also represent a group of isomeric intermediates in regard to the aminobutadienes prepared via the Michael addition in the Bohlmann-Rahtz synthesis of pyridine derivatives.26 On this basis, a simple metal-free synthesis of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted pyridine-3,4-dicarboxylates and their N-oxides has also been reported.25g Recently, we reported on a simple one-pot metal-free synthesis of
2.4.5-trisubstituted	pyridine derivatives and their N-ox-ides by [2 + 2] cycloaddition of propyne iminium salts as electron-poor acetylenes to enaminones as well.27 We also reported a simple, metal-free synthesis of electron rich
2.4.6-trisubstituted	pyridine derivatives28 and the synthesis of polysubstituted benzene derivatives, where N,N-di-methylacetamide dimethyl acetal (DMADMA) served as the reagent and building block for generating aromatic final products.29,30 Our existing knowledge of the enaminones and 1,3-butadienes has been expanded to the synthesis of pyridines starting from Boc-protected amino acids, and the results of our research are presented in this paper.
2. Results and Discussion
In this communication we report a general and simple synthesis of 7-substituted-2,3-dihydropyrido[3,4-d] pyridazine-1,4-diones 6a-c,f and 1,4-dioxo-7-substitut-ed-1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-oxides 7a, b,d,e,g from methyl ketones 1a-g. We have reported earlier a simple metal-free synthesis of dimethyl 2-substitut-ed-pyridine-4,5-dicarboxylates 4a-c,f and their N-oxides 5a,b,d,e,g in the following manner: alkyl, aryl, and het-eroaryl ketones 1a-g have been converted by treatment with N,N-dimethylformamide dimethylacetal /DMFD-MA) or f-butoxybis(dimethylamino)methane (Brede-reck's reagent) into the corresponding 3-(dimethylami-no)-1-substituted-prop-2-en-ones 2a-g, followed by microwave assisted [2 + 2] cycloaddition to dimethyl acety-lenedicarboxylate to give dimethyl (2£,3£)-2-{(dimethyl-amino)methylene}-3-(2-substituted)succinates 3a-g. Compounds 3 gave by treatment with ammonium acetate or hydroxylamine hydrochloride the corresponding dimethyl 2-substituted-pyridine-4,5-dicarboxylates 4a-c,f and dimethyl 2-substituted-4,5-bis(methoxycarbonyl)pyr-idine N-oxides 5a,b,d,e,g.25e,f,g Treatment of compounds 4 and 5 with hydrazine hydrate afforded 7-substitut-ed-2,3-dihydropyrido[3,4-d]pyridazine-1,4-diones 6a-c,f and 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyrido [4,3-d]pyridazine 6-oxides 7a,b,d,e,g, respectively. (Scheme 1, Table 1).
3. Experimental
3. 1. General
Melting points were determined on a Stanford Research Systems MPA100 OptiMelt automated melting point system. The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C and on a Bruker Avance III UltraShield 500 plus at 500 MHz for 1H and 126 MHz for 13C, using acetone-d6, aceto-nitrile-d, CDCL, and DMSO-d with Me,Si as the internal
3	3'	6	4
standard, as solvents. Mass spectra were recorded on a Agilent 6224 Accurate Mass TOF LC/MS spectrometer, IR spectra on a Perkin Elmer Spectrum BX FTIR spectrophotometer. Column chromatography (CC) was performed on silica gel (Fluka, Silica gel 60, particle size 35-70 ^m).
The preparation of 2-substituted-pyridine-4,5-dicar-boxylates 4a-c,f and dimethyl 2-substituted-4,5-fc(me-thoxycarbonyl)pyridine N-oxides 5a,b,d,e,g from alkyl, cycloalkyl, aryl and heteroaryl methyl ketones has been previosly reported in our laboratory.25e,f,g
3. 2. General procedure for the preparation of 7-substituted-2,3-dihydropyrido [3,4-d]pyridazine-1,4-diones and 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-oxides
To a solution of 0.5 mmol of the starting compound (dimethyl 6-substituted pyridine-3,4-dicarboxylate or 2-substituted-4,5-bis(methoxycarbonyl)pyridine-N-ox-ide) in 2-3 mL of methanol, 1 mmol (2 equivalents) of hy-drazine monohydrate was added, followed by the addition of 2-3 drops of concentrated hydrochloric acid. The reaction mixture was stirred vigorously and heated to reflux temperature for 4-24 h.
3. 2. 1. 7-Ethyl-2,3-dihydropyrido[4,3-d] pyridazine-1,4-dione (6a)
N "O H
The product was prepareu irom dimethyl 6-eth-ylpyridine-3,4-dicarboxylate (4a,112 mg, 0.5 mmol), 90 °C, 8 h. The yellow product was collected by vacuum filtration and washed with Et2O. Yield: 57% (55 mg), yellow solid; mp = higher than 350 °C. 1H NMR (500 MHz, DMSO-d6): 5 1.30 (3H, t, J = 7.5 Hz, CH3); 2.97 (2H, q, J = 7.6 Hz, CH2); 7.74 (1H, s, 8-CH); 9.25 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-d6): 8 13.54, 30.77, 115.03, 148.30, 148.47, 164.77, 166.61, 166.74, 168.39. EI-HRMS: m/z = 192.0765 (MH+) found; C9H10N3O2 calculated: m/z
= 192.0768 (MH+); IR (ATR): v 3426, 3302, 3250, 2960, 1664, 1612, 1575, 1476, 1364, 1207, 1077, 899 cm-1.
3. 2. 2. 7-Phenyl-2,3-dihydropyrido[4,3-d] pyridazine-l,4-dione (6b)
The product was prepared from dimethyl 6-phen-ylpyridine-3,4-dicarboxylate (4b, 261 mg, 096 mmol), 90 °C, 12 h. The yellow product was collected by vacuum filtration and washed by Et2O. Yield: 74% (170 mg), yellow solid; mp = 335-339 °C. 1H NMR (500 MHz, DMSO-d6): 5 7.48-7.57 (3H, m, Ph); 8.19-8.23 (2H, m, Ph); 8.35 (1H, s, 8-CH); 9.36 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-dg): S 113.8, 121.9, 126.9, 128.9, 129.6, 135.4, 137.8, 149.1, 155.7, 156.2, 157.5. EI-HRMS: m/z = 240.0767 (MH+) found; C13H10N3O2 calculated: m/z = 240.0768 (mH+); IR (ATR): v 3289, 3178, 3034, 2978, 2920, 2798, 1898, 1648, 1559, 1454, 1112, 852 cm-1. LC-MS; 9.1 min; m/z: 240.1 (MH+).
3. 2. 3. 7-Cyclopentenyl-2,3-dihydropyrido[4,3-d] pyridazine-1,4-dione (6c)
The product was prepared from dimethyl 6-cyclo-pentenylpyridine-3,4-dicarboxylate (4c,150 mg, 0.56 mmol), 90 °C, 24 h. The solid product that was formed during the reaction was a mixture of the starting dicarbox-ylate and the product. The solid was collected by vacuum filtration, suspended in chloroform. The insoluble product was once more collected by vacuum filtration. Yield: 20% (26 mg), brown solid; mp = higher than 330 °C. 1H NMR (500 MHz, DMSO-d6): S 2.03 (2H, p, J = 7.5 Hz, 4-CH2); 2.54-2.60 (2H, m, 3-CH2); 2.76-2.82 (2H, m, 5-CH2); 6.8 7 (1H, s, 2-CH); 7.81 (1H, s, 8-CH); 9.23 (1H, s, CH). 13C NMR (125 MHz, DMSO-dg): S 22.8, 32.0, 33.2, 113.4, 121.0, 133.5, 134.5, 142.6, 148.6, 155.2, 155.8, 156.0. EI-HRMS: m/z = 230.0915 (MH+) found; C12H12N3O2 calculated: m/z = 230.0924 (MH+). IR (ATR): v 3162!, 3(016, 2947, 2892, 2839, 1649, 1598, 1553, 1434, 1368, 1325, 1291, 1232, 1101, 1036, 823 cm-1.
3. 2. 4. 7-(Thiazol-2-yl)-2,3-dihydropyrido[4,3-d] pyridazine-1,4-dione (6f)
The product was prepared from dimethyl 6-(thiazol-2-yl)pyridine-3,4-dicarboxylate (4f, 89 mg, 0.32 mmol), 90 °C, 15 h. The yellow product was collected by vacuum filtration and washed with Et2O. Yield: 44% (35 mg), yellow solid; mp = the product decomposes at 250 °C. 1H NMR (500 MHz, DMSO-d6): 5 7.97 (1H, d, J = 3.2 Hz, CH); 8.09 (1H, d, J = 3.2 Hz, CH); 8.54 (1H, d, J = 1.0 Hz, 8-CH); 9.29 (1H, d, J = 1.0 Hz, 5-CH). 13C NMR (125 MHz, DMSO-dfi): 8 113.3, 117.2, 123.6, 123.8, 144.9, 149.5, 151.8, 155.9, 165.8, 167.6. EI-HRMS: m/z = 245.015 (MH-) found; C10H5N4O2S calculated: m/z = 245.0139 (MH-); IR (ATR): v 3420, 3260, 1741,1721, 1661, 1654, 1602, 1569, 1465, 1438, 1298, 1242, 1134, 1085, 958 cm-1. LC-MS: 7.1 min; m/z: 247.3 (MH+).
3. 2. 5. 7-Ethyl-1,4-dioxo-1,2,3,4-tetrahydropyrido
[4,3-d]pyridazine 6-oxide (7a) Cr
N H
The product was prepared from 2-ethyl-4,5-bis(me-thoxycarbonyl)pyridine 1-oxide (5a, 156 mg, 0.65 mmol), 90 °C, 7 h. The yellow solid was collected by vacuum filtration and washed with Et2O. Yield: 23% (31 mg), yellow solid; mp = 270-276 °C. 1H NMR (500 MHz, DMSO-d6): S 1.26 (3H, t, J = 7.4 Hz, CH); 2.89 (2H, q, J = 7.4 Hz, CH2); 7.89 (1H, s, 8-CH); 8.61 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-dg): S 10.5, 23.3, 120.2, 123.5, 125.0, 134.8, 153.7, 154.3, 156.0. EI-HRMS: m/z = 208.0712 (MH+) found; C9H10N3O3 calculated: m/z = 208.0717 (MH+). IR (ATR): v 3203, 3047, 2974, 2810, 1626, 1549, 1454, 1432, 1366, 1317, 1268, 1043, 814 cm-1.
3. 2. 6. 1,4-Dioxo-7-phenyl-1,2,3,4-tetrahydropyrido
[4,3-d]pyridazine 6-oxide (7b)
The product was prepared from 4,5-bis(methoxycar-bonyl)-2-phenylpyridine 1-oxide (5b, 241 mg, 0.84 mmol), 90 °C, 12 h. The yellow solid was collected by vacuum filtration and washed with Et2O. Yield: 90% (190 mg), yellow
solid; mp = 275-285 °C. 'H NMR (500 MHz, DMSO-d6): 5 7.49-7.53 (3H, m, Ph); 7.82-7.85 (2H, m, Ph); 7.95 (1H, s, 8-CH); 8.65 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-dg): S 123.1, 124.3, 126.1, 127.9, 129.3, 129.6, 131.9, 135.9, 150.4, 153.9, 154.7. EI-HRMS: m/z = 256.0716 (MH+) found; C13H10N3O3 calculated: m/z = 256.0717 (MH+). IR (ATR): v 3338, 3066, 2861, 1807, 1657, 155, 1466, 1448, 1269, 1096, 813 cm-1. LC-MS: 7.4 min; m/z: 256.1 (MH+).
3. 2. 7. 7-(1-Methyl-m-pyrrol-2-yl)-1,4-dioxo-
1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-oxide (7d)
Cr
The product was prepared from 4,5-bis(methoxycar-bonyl)-2-(1-methyl-1H-pyrrol-2-yl)pyridine 1-oxide (5d, 173 mg, 0.6 mmol), 90 °C, 4 h. The yellow product was collected by vacuum filtration and washed with Et2O. Yield: 75% (115 mg), yellow solid; mp = 222-238 °C. 1H NMR (500 MHz, DMSO-d6): 5 3.58 (3H, s, CH3); 6.12 (1H, dd, J = 3.7 Hz, J2 = 2.6 Hz, 3-CH); 6.40 (1H, dd, J = 3.7 Hz, J2 = 1.8 Hz, 5-CH); 7.00 (1H, deg. dd, J = 2.2 H z, 4-CH); 7.85 (1H, s, 8-CH); 8.64 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-dg): 8 40.5, 112.9, 118.3, 129.6, 129.8, 130.1, 131.0, 131.7, 141.1, 149.9, 159.9, 160.6. EI-HRMS: m/z = 259.0822 (MH+) found; C12H11N4O3 calculated: m/z = 259.0826 (MH+); IR (ATR): v 3424,3301, 3078, 2953, 2929, 1664, 1651, 1558, 1485, 1471, 1308, 1255, 1103, 1072, 822 cm-1. LC-MS: 7.3 min; m/z: 259.2 (MH+).
3. 2. 8. 7-(1-Methyl-1H-pyrrol-3-yl)-1,4-dioxo-1,2,3,4-tet-rahydropyrido[4,3-d]pyridazine 6-oxide (7e)
(MH+) found; C12HuN4O3 calculated: m/z = 259.0826 (mH+); IR (ATR): v 3416, 3295, 3199, 2992, 1653, 1614, 1571, 1535, 1487, 1442, 1366, 1250, 1171, 1091, 831 cm-1. LC-MS: 6.6 min; m/z: 259.2 (MH+).
3. 2. 9. 1,4-Dioxo-7-(pyrazin-2-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-oxide (7g)
O" N'
The product was prepared from 4,5-bis(methoxycar-bonyl)-2-(pyrazin-2-yl)pyridine 1-oxide (5g,144 mg, 0.5 mmol), 90 °C, 24 h. The yellow product was collected by vacuum filtration and washed with Et2O. Yield: 95% (125 mg), yellow solid; mp = higher than 350 °C. 1H NMR (500 MHz, DMSO-d6): 8 8.56 (1H, s, CH); 8.72 (s, 1H, CH); 8.78 (1H, d, J = 2.5 Hz, CH); 8.87-8.91 (1H, m, CH); 9.87 (1H, d, J = 1.5 Hz, CH). 13C NMR (125 MHz, DMSO-dfi): 8 124.1, 136.5, 144.6, 144.9, 145.26, 145.29, 145.6, 146.9, 157.0, 158.1. EI-HRMS: m/z = 258.0624 (MH+) found; C11H8N5O3 calculated: m/z = 258.0622 (MH+); IR (aTR): v 3447, 3033, 2981, 1667, 1635, 1563, 1498, 1404, 1273, 1242, 1119, 827 cm-1. LC-MS: 5.9 min; m/z: 255.7 [(M-2H)-].
4. Conclusion
A general four-step metal-free synthesis of a series of 7-substituted-2,3-dihydropyrido[3,4-d]pyridazine-1,4-di-ones and 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyr-ido[4,3-d]pyridazine 6-oxides was designed starting from alkyl, cycloalkyl, aryl or heteroaryl methyl ketones in good to excellent yields.
The product was H	s(methoxycar-
bonyl)-2-(l-methyl-lH-pyrrol-3-yl)pyridine 1-oxide (5e, 340 mg, 1.17 mmol), 90 °C, 4 h. The yellow product was collected by vacuum filtration and washed with Et2O. Yield: 89% (269 mg), yellow solid; mp = decomposes at 292 °C. 1H NMR (500 MHz, DMSO-d6): 8 3.72 (3H, s, CH3); 6.84 (1H, deg. dd, J = 1.2, 4-CH); 6.91 (1H, deg. dd, J = 2.6 Hz, 5-CH); 8.18 (1H, s, 8-CH); 8.32 (1H, deg. dd, J = 2.0 Hz, 2 -CH); 8.62 (1H, s, 5-CH). 13C NMR (125 MHz, DMSO-dg): 8 36.1, 108.0, 113.8, 117.5, 122.0, 123.3, 123.9, 126.8, 13(5.2, 146.8, 153.9, 154.7. EI-HRMS: m/z = 259.0823
5. Acknowledgement
Financial support from the Slovenian Research Agency through grants P0-0502-0103, P1-0179 and J1-6689-0103-04 are gratefully acknowledged. We also thank the Krka d.d. (Novo mesto, Slovenia) for financial support.
6. Reference
1.	Y. Oka, K. Omura, A. Miyake, K. Itoh, M. Tomimoto, N. Tada, S. Yurugi, Chem. Pharm Bull. 1975, 23, 2239-2250.
2.	R. G. Jones, J. Am. Chem. Soc. 1956, 78, 159-163.
3.	D. B. Paul, Aust. J. Chem. 1984, 37, 87-93.
4.	T. J. Van Bergen, R. M. Kellogg, J. Amer. Chem. Soc. 1972, 94, 8451-8471.
5.	I. Matsuura, K. Okui, Chem. Pharm Bull. 1969, 17, 2266-2272.
6.	K. Yoshida, H. Otomasu, Yakugaku Zasshi 1976, 96, 33-36; Chem. Abstr. 1976, 84, 121754.
7.	F. Ishikawa, S. Miyazaki, K. Ueno, JP 46029876 (1971); Chem. Abst. 1971, 75, 140875.
8.	P. Y. Boamah, N. Haider, G. Heinisch, J. Moshuber, J. Hetero-cycl. Chem. 1988, 25, 879-883.
9.	P. Y. Boamah, N. Haider, G. Heinisch, J. Heterocycl. Chem. 1989, 26, 933-939.
10.	G. Heinisch, T. Langer, J. Tonnel, J. Heterocycl. Chem. 1996, 33, 1731-1735.
11.	J. Barluenga, M. J. Iglesias, V. Gotor, Synthesis 1987, 662-664.
12.	H. Al-Awadhi, F. Al-Omran, M. H. Elnagdi, L. Infantes, C. Foces-Foces, N. Jagorevic, J. Elguero, Tetrahedron 1995, 51, 12745-12762.
13.	F. M. Manhi, S. E. Zayed, F. A. Ali, M. H. Elnagdi, Collect. Czech. Chem. Commun.1992, 57, 1770-1774.
14.	A. Hasnaoui, M. El Messaoudi, J.-P. Lavergne, J. Heterocycl. Chem. 1985, 22, 25-27.
15.	K. J. Gould, N. P. Hacker, J. F. W. McOmie, D. H. Perry, J. Chem. Soc., Perkin Trans.1 1980, 1834-1840.
16.	J. Z. Brzezinski, H. B. Bzowski, J. Epsztajn, Tetrahedron 1996, 52, 3261-3272.
17.	H. Šladowska, J. Potoczek, M. Sokowska, G. Rajtar, M. Sieklucka-Dziuba, T. Kocki, Z. Kleinrok, Farmaco 1998, 53, 468-474; Chem. Abstr. 1999, 130, 110222.
18.	N. Heider, K. Mereiter, R. Wanko, Heterocycles 1994, 38, 1845-1858.
19.	M. Sako, Product Class18: Product Subclass 5: Pyridopyri-dazines. In: Houben-Weyl, Science of Synthesis, Georg Thime Verlag, Stuttgart, New York 2006, vol 16, pp. 1137-1153.
20.	(a) Selič, L.; Jakše, R.; Lampič, K.; Golič, L.; Golič-Grdadol-nik, S.; Stanovnik, B. Helv. Chim. Acta 2000, 83, 2802-2811; (b) Selič, L.; Stanovnik, B. Tetrahedron 2001, 57, 3159-3164.
21.	Jakše, R.; Svete, J.; Stanovnik, B.; Golobič, A. Tetrahedron 2004, 60, 4601-4608; (b) Časar, Z.; Bevk, D.; Svete, J.; Stanovnik, B. Tetrahedron 2005, 61, 7508-7519.
22.	(a) Wagger, J.; Bevk, D.; Meden, A.; Svete, J.; Stanovnik, B. Helv. Chim. Acta 2006, 89, 240-248; (b) Wagger, J.; Golič Gr-dadolnik, S.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik, B.
Tetrahedron: Asymmetry 2007, 18, 464-475; (c) Wagger, J.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron 2008, 64, 2801-2815.
23.	(a) Stanovnik, B. J. Heterocycl. Chem. 1999, 36, 1581-1593; (b) Stanovnik, B.; Svete, J. Synlett 2000 1077-1091; (c) Stanovnik, B; Svete, J. Targets in Heterocyclic Systems, Synthesis, Reactions and Properties, (Eds. O. A. Attanasi, D. Spinelli), Italian Society of Chemistry, Rome 2000, Vol. 4, p. 105-137; (d) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433-2480.
24.	(a) Bezenšek, J.; Koleša, T.; Grošelj, U.; Meden, A.; Stare, K.; Svete, J.; Stanovnik, B. Curr. Org. Chem. 2011, 15, 2530-2539; (b) Bezenšek, J.; Koleša, T.; Grošelj, U.; Wagger, J.; Stare, K.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron Lett. 2010, 51, 3392-3397.
25.	(a) Uršič, U.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron Lett. 2008, 49, 3775-3778; (b) Uršič, U., Svete, J.; Stanovnik, B. Tetrahedron 2008, 64, 9937-9946; (c) Uršič, U.; Grošelj, U.; Meden, A.; Svete, J., Stanovnik, B. Helv. Chim. Acta 2009, 92, 481-490; (d) Uršič, U.; Svete, J.; Stanovnik, B. Tetrahedron 2010, 66, 4346-4356; (e) Bezenšek, J.; Koleša, T.; Grošelj, U.; Meden, A.; Stare, K.; Svete, J.; Stanovnik, B. Curr. Org. Chem. 2011, 15, 2530-2539; (f) Bezenšek, J.; Koleša, T.; Grošelj, U.; Wagger, J.; Stare, K.; Meden, A.; Svete, J.; Stanovnik, B.-,Tetrahedron Lett.. 2010, 51, 3392-3397; (g) Bezenšek, J.; Prek, B.; Grošelj, U.; Kasunič, M.; Svete, J.; Stanovnik, B. Tetrahedron 2012, 68, 4719-4731.
26.	(a) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265-2272; (b) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 11491151.
27.	Bezenšek, J.; Prek, B.; Grošelj, U.; Golobič A.; Stare, K.; Svete, J.; Kantlehner, W.; Maas, G.; Stanovnik, B. Z. Naturforsch. 2014, 69b, 554-566.
28.	Prek, B.; Grošelj, U.; Kasunič, M.; Zupančič, S.; Svete, J.; Stanovnik, B. Aust. J. Chem. 2015, 68, 184-195.
29.	Prek, B.; Bezenšek, J.; Kasunič, M.; Grošelj, U.; Svete, J.; Stanovnik, B. Tetrahedron 2014, 70, 2359-2369. DOI:10.1016/j.tet.2014.02.039
30.	For a review see: Stanovnik, B. Org. Prep. Proc. Int. 2014, 46, 24-65.
Povzetek
V tem članku je opisana štiristopenjska pretvorba alkil, cikloalkil, aril in heteroaril metil ketonov, ki jih preko 3-(di-metilamino)-1-substituiranih-prop-2-en-1-onov z [2+2] cickloadicijo na dimetil acetilendikarboksilat pretvorimo v (2E,3E)-2-[(dimetilamino)metilen]-3-(2-substituirane)sukcinate in naprej z amoniakom ali hidroksilaminom v 2-sub-stituirane piridin-4,5-dikarboksilate in njihove N-okside. Iz teh nastanejo pri cilizaciji s hidrazinovim hidratom 7-sub-stituirani 2,3-dihidropirido[3,4-d]piridazin-1,4-dioni in 1,4-diokso-7-substituirani 1,2,3,4-tetrahidropirido[4,3-d]piri-dazin 6-oksidi.