Synthetic Pathways to Pyrido[3,4- c ]pyridazines and Their Polycyclic Derivatives

: Pyrido[3,4- c ]pyridazines are nitrogen-containing scaffolds that have been described as being promising in medicinal chemistry, but they are rather rare chemicals. In this review article, the literature on synthetic pathways towards pyrido[3,4- c ]pyridazines is listed exhaustively, ﬁrst with the bicyclic systems themselves that are obtained starting either from pyridines, pyridazines or other heterocycles. Then, the reports on the related tricyclic derivatives are discussed, again according to the source heterocycle, and ﬁnally we mention some examples on polycyclic


Introduction
Nitrogen-containing heterocycles play an important role in nature [1] and are also part of the structure of many small molecule drugs. A 2014 study estimated that 59% of the FDA-approved drugs had a nitrogen-containing ring in their structure [2]. However, among those drugs there are clearly much more of the "common" monoheterocycles such as the six-membered pyridine, piperidine and piperazine, or five-membered thiazole, pyrrolidine and imidazoles. Bicyclic structures are somewhat less popular, and in those cephem, penam, indoles and benzimidazoles constitute the majority. Clearly, medicinal chemists have in the past mainly relied on only a few well-known heterocyclic building blocks. W. R. Pitt et al., in "heteroaromatic molecules of the future", referred to a virtual list of unexplored chemicals selected on synthetic tractability [3]. These 22 bicyclic molecules all had at least one nitrogen in their structure. Among those molecules, one was a derivative of the pyrido [3,4-c]pyridazine 1, the 6-oxo-derivative 2. The synthesis of differently fused pyridopyridazine isomers 1, 3-8 ( Figure 1) has been previously reviewed [4], but specific derivatives of 1 or 2 were only briefly mentioned in these texts. In a 2019 follow-up article on the "heteroaromatic molecules of the future", the literature of 2009-2019 was reviewed [5] and indeed synthetic chemists had risen to the challenge, with reports appearing on 15 of the 22 aforementioned heteroaromatic molecules, but notably the pyridopyrazidinone 2 was not among these, although there had been two theoretical studies on this scaffold [6,7] concerning enhanced inhibition of cytochrome P450s and hydrogen bonding accepting properties, respectively.
With this short review we hope to increase the interest in the heterocycle 1 and its derivatives by exhaustively summarizing synthetic efforts so far. Earlier reviews on "pyridopyridazines" [5,8,9] focus on the other isomers and have mentioned almost nothing on the title subject. As far as we know, this is the first dedicated effort of bringing together all literature on the synthesis of pyrido [3,4-c]pyridazine 1. At the same time, we will also have a detailed look at the related tricyclic and polycyclic analogs of this bicyclic system. Where appropriate, we will also mention any biological properties of the different compounds synthetized. One of the earliest procedures towards pyrido [3,4-c]pyridazines led to the synthesis of 10, named 1,2,7-triazanaphthalenes [10], which was based on the Widman-Stoermer cinnoline synthesis, involving a one-pot diazotisation/cyclization sequence of 4-propenyl-3-aminopyridines 9. Unfortunately, only a low yield of 10 (14-17%) was obtained after chromatography. In a later effort [11], the same strategy was applied to obtain the corresponding pyrido [3,4-c]pyridazine-4-one 12b from 4-acetyl-3-aminopyridine 11. This Borsche reaction probably involves the electron rich enol form of the acetyl substituent, to afford (38% yield) a tautomeric equilibrium mixture of 12a,b. This molecule was referred to as a 7-azacinnolin-4(1H)-one. The tautomerism of compound 12 was studied in detail with 1 H, 13 C and 15 N NMR spectroscopy, concluding that the main isomer is indeed 12b in polar solvents such as deuterated DMSO, methanol and water (Scheme 1). Further examples of pyridopyridazinone analogs of 12 prepared by Borsche cyclization of acyl substituted pyridines have been described in the patent literature [12]. The Japp-Klingemann approach was also used to synthesize 3,8-disubstituted pyridopyridazinone from the reaction with 2-chloro-3-aminopyridine 13. The corresponding diazonium salt of 9 is combined with Ethyl-2-methyl-acetoacetate to afford the hydrazone 14, which was then cyclized in polyphosphoric acid to give a low yield of the 8-chloro-3methyl-pyridopyridazine-4-one 15, which was described as the 4-hydroxy tautomer [13], although probably based on the later study [10] on the analog 12, the structure should be reassigned as the keto tautomer 15 (Scheme 2). Scheme 2. Synthesis of pyridopyrazin-8-one by acid-catalyzed cyclization of hydrazone.
A Hetero-Diels-Alder cycloaddition reaction of 2-vinylpyridines and electron poor azo derivatives was studied by Gurnos et al. [14,15] as an entry into different pyridopyrimidine isomers, including the pyrido [3,4-c]pyrimidine. 2-Vinylpyridine 16 and azodicarboxylates 17 (R = Et, t-Bu) to afford the tetrahydropyridopyrimidines 18 (16% yield for R = t-Bu), that are subsequently deprotected (R = t-Bu) with trifluoroacetic acid (TFA) and oxidized with red mercuric oxide, with a 52% yield for the two final steps leading to the parent compound 1. The cycloaddition reaction is incomplete and possibly polymerization of 16 occurs, explaining the low yield in the first step (Scheme 3). Starting from N-protected 3-pyridone-4-acetate derivative 19 [16,17] after condensation with hydrazine and oxidation with bromine in acetic acid, the tetrahydropyridopyridazinone 20 is obtained. The latter can then be chlorinated with phosphoryl chloride to the chloro derivative 21, which is used as a convenient building block for further derivatization at the piperidine nitrogen (after deprotection) and/or after reaction of the reactive chlorine, e.g., amine substitutions, and Suzuki arylation (Scheme 4). We do not describe these reactions in detail as they are no longer ring forming reactions but rather standard derivatizations. These derivatives constitute the largest and most studied library of pyridopyridazine analogs in the literature. Different biological properties of these compounds were investigated, including inhibitors of the dipeptidyl peptidase-IV enzyme useful in the treatment of type 2 diabetes [18], histamine H3 receptor binders with CNS activity [16], kinase inhibitors [19], gamma-aminobutyric acid A receptor subunit alpha 5 (GABA A α5) positive allosteric modulators [20] or sphingosine-1phosphate (S1P) inhibitor activity [21]. The 4-methyl-3-cyano-pyridine-2,6-diones 22 are easily available from the condensation reaction of acetoacetate esters and N-arylcyanoacetamide. Azo coupling with phenyldiazonium salt then gave the hydrazone 23. The latter underwent a one-pot conversion with dimethyl formamide dimethylacetal (DMFDMA) to an enamine 24, followed by cyclocondensation with evolution of dimethylamine, affording the 6,8-dione derivative 25. The reaction takes place either in xylene at reflux (77% yield) or solventless after microwave irradiation (no yield given, Scheme 5) [22].  [23,24]. A similar entry to analogs of 28 (6-C(CN)2 instead of 6-oxo) by Knoevenagel condensation of 4-methyl-6-dicyanomethylpyridones with aromatic aldehydes was reported [25]. Several variants on this condensation/cyclization strategy starting from pyridazinones have been reported [27][28][29], leading to different pyridopyridazinedione derivatives 32-34 ( Figure 2). Compounds 32a,b were obtained in poor yield (around 10%) from the condensation of 2-(arylhydrazono) -3-oxobutyrates with two equivalents of ethyl cyanoacetate. Pyridazinones analogous to 29a,b (Ar = 3,4-dimethylphenyl or 3-chloro-4-methylphenyl) were the main isolated products (70% yield), but also the intermediates towards 32a,b, via an aldol-type of condensation of 29 to a second equivalent of the hydrazine and cyclization were obtained. The structure of 32a,b was confirmed by an extensive NMR study [27]. Condensation of 29 (Ar = 4-methylphenyl) with triethyl orthoformate and 4-methylaniline in the presence of piperidine gave further analogs of 31, while condensation of enamine 30 (piperidine instead of dimethylamino) with hydrazine gave the 7-amino derivative 33 [28]. The hydrazones derived from aromatic aldehydes and the carbohydrazide derivative of 29 (Ar = 4-MeOC 6 H 5 ) were involved in a Knoevenagel condensation/cyclization, affording hydrazones 34 with different combinations of the two aryl groups Ar' and Ar" [1997PSS]. Further examples of analogues of 31-34 prepared similarly from derivatives of 29 have been reported in the literature [30][31][32].

Benzo Fused Tricyclic Derivatives Starting from Quinolines
4-Acetyl-3-amino-2-phenylquinoline 44 (R = H) was diazotized with nitrous acid and ring closed in alkaline medium, forming the pyridazino[3,4-c]quinoline named 4-hydroxy-10-phenyl-1,2,9-triazaphenanthrene by the authors (more probable the oxo tautomer 45 shown). The Borsche reaction product 45 was obtained in 80% yield on a 10 g scale by precipitation from the reaction mixture. Chlorination of 45 with phosphorous pentachloride gave the chloro derivative 46, which could then be converted to a number of derivatives 47 by nucleophilic substitution [35,36]. Some of the above reactions were also carried out on the 4-propionyl derivative 44 (R = Me). Methylation of the compound 45 occurred regioselectively on one of the pyrazine nitrogens, affording a zwitterionic pyridazinoquinoline 48. Widman-Stoermer reaction starting from 4-alkenyl-3-aminoquinoline substrates as shown before for the synthesis of bicyclic pyridopyridazines 10 analogously gave the tricyclic derivatives 49, in low to good yields [10] (Scheme 10).

Scheme 10. Borsche and Widman-Stoermer reactions leading to pyridazinoquinoline derivatives.
Starting from the 3-aminobenzazepine-2,5-dione derivative 50, nitrosation was accompanied by a ring contraction, leading to diazo compound 51, which in acidic medium underwent a Borsche-like cyclization to form tricyclic pyrazinoquinolinedione derivative 52 in almost quantitative yield. However, there seems to be only this one example in the literature of this interesting transformation [37] (Scheme 11). Scheme 11. Pyridazinoquinolines via diazotation, ring contraction and cyclization.

Benzo Fused Tricyclic Derivatives Starting from Pyridines
Diazotation of 4-aryl-3-aminopyridine derivatives 53 resulted in intramolecular electrophilic substitution of the very electron rich 3,4,5-trimethoxyphenyl substituent to afford the tricyclic pyrido [3,4-c]cinnolines 54 in 64-84% yield, similar to the Widman-Stoermer approach whereas for other less electron rich aryl groups the diazonium salt can be used without such cyclization to prepared azides, that then were thermolysed in xylene to carboline derivatives 55 (Scheme 12) [38]. Both isomers were subjected to vacuum pyrolysis at 800 • C, giving the respective azabiphenylenes 59 (58%) and 60 (34%) after dinitrogen extrusion [39]. In a later study, the hydrochloride salt of the diamino analog of 56 (R = NH 2 ) was irradiated with a 400 W medium pressure mercury vapor lamp in a dilute methanol solution, affording 35% of the product 57 (R = NH 2 ), together with small amounts of several products resulting from N-N cleavage [40] (Scheme 13).  In an early study, formazan 65 was oxidized to a tetrazolium salt 66, which upon irradiation with an ultraviolet high pressure immersion lamp PL 313 at 25 • cyclized to the fused tetrazolium salt 67. The reduction in the latter gave the parent pyridocinnoline 57 (R = H) [42] (Scheme 15). Scheme 15. Synthesis of pyridocinnoline by reduction in tetrazolium salt.

Heterocycle Fused Tricyclic Derivatives
Reduction of 2,2 -dinitro-4,4 -bipyridyl 76 with sodium sulfide initially led to a 3: 1 mixture of bispyridopyridazine 77 (59% yield) and its N-oxide 78. The latter could be deoxygenated with iron at 250 • C. [48] The reduction with sodium sulfide could be optimized later to give 89% of only 77. Reduction of 76 with arsenious oxide gave the N, N'-oxide 79, whereas the Pd/C catalyzed hydrogenation gave the diamine 80 [49]. The bispyridopyridazine 77 was used in these and many subsequent studies for the synthesis of 2,7-diazabiphenylene 81 in a 57% yield [50] by extrusion of nitrogen under different vacuum pyrolysis conditions. The bispyridopyridazine 77 can also be prepared from diamine 80 by diazotation in a 38% yield [51]. The reaction sequence in Scheme 19 was also used to prepared unsymmetrically fused bispyridopyridazine 82 by reductive cyclization of the corresponding ortho, ortho'-dinitro-2,4 -bipyridine [52].
A special case of a pyridine fused pyridopyridazine salt 98, called the 8a-azonia-3,4diazaphenanthrene cation by the authors, was available in a 36% yield as the only product obtained after hetero-Diels-Alder cycloaddition of 3,6-(2-pyridyl)-1,2,4,5-tetrazine 96 with cis-3,4-dichlorocyclobutene. The expected product 97 was not isolated, but under the reaction circumstances it is probable that ring opening of cyclobutyl/ring closure involving pyridine nitrogen occurs, finally affording 98. The structure of the salt 98 was proven unambiguously by single crystal X-ray crystallographic analysis [57] (Scheme 23).

Polycyclic Derivatives
Pentacyclic analogs 99 or their N-oxide analogs could be prepared from bis(nitroquinolines) similarly to the chemistry in Scheme 19 [48]. Thermolysis of 99 led to the condensed derivative 100 [49]. In a series of publications, thebaine or other morphinanediene derivatives were combined in a room temperature Diels-Alder reaction with diazodicarboxylate, triazole dione or other cyclic diazo dienophiles, to afford diverse complex polycyclic derivatives 101 that strictly speaking contain a reduced pyridopyridazine but are somewhat out of the scope of this review. A β-face attack of the dienophile occurs in the case of the natural products containing a furan ring, whereas the derivatives with opened furan favor α-attack [58][59][60][61]. No biological properties seem to have been reported for these compounds (Figure 4).

Conclusions
The pyrido [3,4-c]pyridazines and their fused derivatives remain rare chemicals and the reports that have appeared so far are widely scattered, with often only a few examples given in low or only fair yield without any follow-up studies to widen the scope. Therefore, applications of this scaffold as biologically active compounds have been limited. To make further advances and to realize the recognized potential of this moiety in medical chemistry, more attention should be given in the future to apply new advances in organic synthesis, including transition metal catalyzed reactions, as well as organocatalytic, photocatalytic and electrocatalytic processes. We hope to meet this challenge in following reports of our laboratories; it was also our aim to have stimulated further research by our colleagues in the field of heterocyclic and medicinal chemistry.