Pyrrolo [ 1 , 2-b ] pyridazines . A revisit

Although a relatively simple system, pyrrolo[1,2-b]pyridazines have been subject to numerous studies and synthetic attempts. The present review represents an update to the 1976 review of Kuhla and Lombardino.


Table of Contents
Although the synthesis and properties of the pyrrolo [1,2-b]pyridazines were reviewed in 1977 by Kuhla and Lombardino, 1 the high interest in the synthetic pathways leading to such derivatives and their properties has remained constant to this date.Thus, new papers were published concerning the synthesis and optical and biological properties of pyrrolo [1,2b]pyridazine derivatives.
Herein we present the approaches for the obtaining of the pyrrolo[1,2-b]pyridazine system and its uses reported after Kuhla and Lombardino's review. 1 The same classification of the synthetic methods was used as in the first review, considering the starting compounds: syntheses starting from pyridazine and its derivatives, syntheses starting from the pyrrole ring and syntheses starting from acyclic compounds.

Scheme 4
The mechanism of formation of the pyrrolopyridazine derivatives presented in Scheme 1, implies in the first step the nucleophilic addition of the ring nitrogen atom to the triple bond with the formation of a zwitterionic intermediate, which fixes the proton provided by methanol, afterwards the methoxide ion generates a new dipolar species.One of the resonance structures, a 1,5-dipole, attacks intramolecularly the α carbon in regard to the ring nitrogen, leading to the closing of a pyrrolidinic ring, which is subsequently aromatized by elimination reactions of certain molecular fragments.
The Chichibabin reaction was first applied for the series of pyrrolopyridazines by Letsinger and Lasco in 1956, as a means of confirming the structure of the compounds obtained from the reaction between DMAD and pyridazines. 2Thus, 3,6-dimethylpyridazine was quaternized with ethyl bromopyruvate, and the treatment of the cycloimmonium bromide formed with sodium bicarbonate lead to the ethylic ester of the pyrrolo [1,2-b]pyridazine-6-carboxylic acid 6 (Scheme 6).Fraser synthesized a series of pyrrolopyridazines 7, substituted in the 6 and 7 positions by alkyl and/or aryl groups, starting from 2-halogenoketones and 3,6-dimethylpyridazine (Scheme 7). 24

9
Scheme 8 1.1.3.From pyridazines and cyclopropenones.Lown and Matsumoto studied the reaction between diphenyl-cyclopropenone and various N-heterocyclic aromatic compounds. 27,28Thus, starting from pyridazine and diphenyl-cyclopropenone, 5,6-diphenyl-7-hydroxy-pyrrolo[1,2b]pyridazine 10 is obtained in about 70% yield (Scheme 9).The structure of the cycloadduct 10 was ascertained mainly by the NMR data for hydroxy-indolizine and its chemical transformation products.0][31] Starting from inconsistencies between various physical properties (melting point, NMR data) of the obtained compounds and those reported by Lown and Matsumoto, it was postulated that the initially assumed structures were incorrect.Thus, NOE experiments performed on the hydroxy-indolizine acetates showed that the hydroxy group is in the 5 position.The same observation was made for the hydroxypyrrolopyridazine acetate 12. Also, when 3-methylpyridazine reacts with diphenylcyclopropenone, the pyrrolopyridazine derivative 11b is obtained in good yields (Scheme 11).For the product formed in the reaction between cyclohepten-cyclopropenone and pyridazine, structure 10c was assigned (Scheme 10).

Scheme 12
The study of the biological activity of compounds 11, 12, as well as of those obtained starting from pyridines and diphenylcyclopropenone, showed a strong inhibition of the peroxidation of lipids in vitro for some of the studied derivatives.[34] 1.1.4.From pyridazines and alkylidene-cyclopropane. 35 The synthesis of 5-azaindolines starting from 1,2-diazines and alkylidenecyclopropane has been considered, as in the case of the reaction between azines and diphenylcyclopropenone, a formal cycloaddition [3+2]. 35Thus, in the reaction between pyridazine and akylidenecyclopropane (R 1 , R 2 = alkyl) without solvent and in the presence of a Pd catalyst, 5-alkyl substituted pyrrolopyridazines 13 are obtained in moderate yields (39-49%) (Scheme 13).1.1.6.From 3-chloropyridazines using the Sonogashira reaction. 37,387-Dialkylaminopyrrolo[1,2-b]pyridazines 22a-e were synthesized by the "one-pot" reaction of 3chloropyridazines 20a-c with propargyl alchohol, followed by cyclization with dialkyl amines, in the presence of Pd(PPh 3 )Cl 2 -CuI as catalyst.The yields for the pyrrolopyridazine derivatives were found to be in the range of 13-49%.It is very likely that the reaction mechanism for the formation of compounds 22 is the same as in the case of using pyridine derivatives as starting materials.This mechanism implies in the first stage the alkynylation of the C-3 atom via a Sonogashira coupling.1][42][43][44][45][46][47] Popp et al. 39 obtained the Reissert compound of 3-methylpyridazine using as reagents trimethylsilyl cyanide and freshly distilled benzoyl chloride.The reaction of pyridazine and 3methylpyridazine with undistilled benzoyl chloride lead to the Reissert compound salts 24a,b.

Scheme 21
Good yields for pyrrolopyridazine derivatives are obtained when symmetrical esters of acetylene dicarboxylic acid or esters of acetylene monocarboxylic acid are used as dipolarophiles and when the N-ylide is monosubtituted at the carbanion with an alkoxycarbonyl, aroyl or heteroaroyl moiety (Scheme 21).Most probably these groups stabilize the ylidic dipole sufficiently for it to react with the acetylenic dipolarophile.When the acetylenic dipolarophile is insufficiently active in order to react with N-ylides of type 38, low yields are obtained, as the Nylide decomposition and dimerization rates are higher than that of the [3+2] cycloaddition.
The mechanism of formation of pyrrolo [1,2]pyridazines from N-ylides and acetylenic esters (Scheme 22) implies in the first step the formation of the primary cycloadduct 40, which isomerizes to 4a,5-dihydro-pyrrolo [1,2]pyridazine 41 in the reaction conditions.Although the formation of 4a,7-dihydroderivatives of type 40 has been mentioned in many papers, no data was presented for the presence of these compound, as opposed to the case of phtalazinium Nylides. 104Finally, the dihydroderivative is aromatized in the reaction conditions, but in some cases mixtures of dihydropyrrolopyridazine 41 and aromatic compound 42 were obtained.The addition of an oxidizing agent after the completion of the cycloaddition, such as chloranil, results in an increase of the yield. 69Microwave assisted cycloaddition between pyridazinium N-ylides and methyl propiolate 102 does not significantly improved the yield, as similar results were obtained in the absence of microwaves. 79

Scheme 22
97][98][99] It must be mentioned that pyridazinium dicyanomethylides 39 are very stable N-ylides, which translates into the ability to react with low reactivity acetylenic dipolarophiles, such as bis(trimethylsilyl) acetylene.The preparation of dicyanomethylides 39a-f was performed using the method described by Linn et al. 105 from pyridazines and tetracyanoethylene oxide(Scheme 23).
The cycloaddition between ylides 39a-f and DMAD leads to 7-cyano-pyrrolopyridazines 44, which result from the intermediate cycloadducts 43 through the elimination of a cyano group from the 7 position together with the R 3 group.In the case of reacting ylids 39a, 39b and 39d with cyanoacetylene, 5,7-dicyano-pyrrollopyridazines substituted in the 5 position with a hydrogen, methoxy and ethoxy group, respectively (Scheme 24). 71At the same time, another group of researchers 70

Scheme 24
The dicyanomethylide 39a reacts with bis(trimethylsilyl)acetylene under reflux in toluene, leading to the formation of 1,2-bistrimethylsilyl-3-cyano-pyrrolopyridazine 45 with 92% yield. 72- 97In similar reaction conditions, the use of phenylsulfenyl-ethene as dipolarophile leads to 7cyano-pyrrolo[1,2-b]pyridazine 46 in 42% yield (Scheme 25).The reaction mechanism includes the dipole-dipolarophile interaction from the pyrrolidinic ring and the elimination of the cyano and phenylsulfenyl groups from the intermediary cycloadduct.Butler et al. studied the influence of water on the kinetics and yields of the cycloadditions between pyridazinium-dicyanomethylide 39a and a series of olefinic and acetylenic dipolarophiles. 98,99On the basis of numerous experiments, the authors classified the dipolarophiles in two types: "water-normal" and "water-super" and evidenced the principal factors affecting the reaction rate: hydrophobic effects which aggregate the organic compounds, the effects of hydrogen bonding on the transition state and the increase in polarity of the transition state in water.It was established that esters, ethers, sulfones and nitriles, as well as aryl cycles linked to a double bond are "water-normal" dipolarophiles, while compounds with a ketone group linked to a double or triple bond are "water-super" dipolarophiles.It should be mentioned that the authors isolated and characterized several primary cycloadducts 43 resulting from the dipole-dipolarophile reaction.
Ylides of type 38 readily react with acyclic activated olefins (acrylonitrile, acrylic, fumaric and maleic acid esters) or cyclic activated olefins (maleic anhydride, N-substituted maileimides) leading to the tetrahydro-pyrrolopyridazine derivatives 47-51 (Scheme 26).  Literure data indicates that tetrahydro-pyrrolopyridazines are relatively unstable in solution, but stable in solid state.When the cycloaddition reaction is microwave assisted, the primary cycloadduct is partially dehydrogenated or aromatized. 102The stereochemistry of these cycloadducts was established using NMR spectroscopy and in a single case X-ray diffraction. 89The cycloaddition reaction between pyridazinium N-ylides and non-symmetrical olefinic dipolarophiles is completely regioselective in the case of ylides substituted at the carbanion by a COAr radical.However, it was observed that when the COAr radical is replaced by R 2 =CO 2 Me radical, both regiomers 50 and 51 are formed. 89

Scheme 26
The aromatization of tetrahydro-pyrrolopyridazines of type 47, 48 to pyrrolopyridazines 52 was performed using tetrakispyridino-cobalt(II) dichromate (TPCD), [Co(Py) 4 ](HCrO 4 ) 2 , as oxidizing agent. 106,107][110][111][112][113][114][115]  Zhang and Huang 90 have used for the synthesis of pyrrolopyridazine derivatives 53 2,2dihydroperfluoroalkanoates and phenacyl pyridazinium bromide.The formation of compounds 53 implies the [3+2] cycloaddition between the pyridazinium N-ylide and the alkene, both generated in situ in the presence of a base, followed by the aromatization of the intermediary cycloadduct (Scheme 28).Khlebnikov et al. 91,92 proposed a general method for the synthesis of pyrrole-substituted pyrroloazines, which is based on the reaction between dichlorocarbene and an azine in the presence of dimethyl maleate.The reaction mechanism, shown for pyridazine, implies the in situ generation of dichlorocarbene, which forms with pyridazine the corresponding dichloromethanide.The 1,3-dipolar cycloaddition between the pyridazinium N-ylide 54 and dimethyl maleate leads to the tetrahydropyrrolopyridazine derivative 55, which undergoes dehydrogenation in the reaction conditions with the formation of 5,6-dicarbomethoxy-7-chloro-pyrrolo[1,2-b]pyridazine 56 (Scheme 30).The 7-chloro group was replaced by a 7-amino group (compound 59) through a series of reactions: the substitution of the chlorine atom with a benzylamino group with the formation of the aminoderivative 57, followed by the oxidation to the Schiff base 58 and the subsequent treatment of this with a hydrochloric acid solution in methanol.

Syntheses starting from pyrrole and its derivatives
A general method of synthesis for pyrrolo[1,2-b]pyridazine derivatives starts from 1aminopyrrole 64 and its derivatives.This original method was reported by Flitsch and Kramer 135- 137 who obtained a series of pyrrole unsubstituted pyrrolopyridazines 65 starting from 1-aminopyrrole and β-dicarbonylic compounds (Scheme 34).Benzoylacetone, by condensation with 64, leads to only one isomer, 2-methyl-4-phenyl-pyrrolopyridazine, while benzoylacetaldehyde forms a mixture of 2-phenyl and 4-phenylpyrrolopyridazine 65f and 65e, respectivly.When starting from phenyl-malondialdehyde and 1-aminopyrrole, 3-phenyl-pyrrolopyridazine 65g is obtained. 138Around the same period Zupan et al. 139 synthesized pyrrolopyridazines 65e and 65f in order to study their chemical properties, using the method described by Flitsch and Kramer.
When diketone or acetonylacetate are used as condensation agents, 1(2H)-pyrrolopyridazine 66 is obtained.Unsubstituted pyrrolopyridazine 1 was synthesized in 21% yield from 1aminopyrrole and 3-ethoxyacroleine diethylacetate (Scheme 34).Ruxter et al. 140 synthesized a series of quinolone analogues in order to investigate their antibacterial activity.Among the analogues obtained by the authors is pyrrolopyridazine 68 which was synthesized starting from compound 67, which in turn was obtained starting from the condensation reaction between diethyl 1-aminopyrrole ethoxymethylenemalonate (Scheme 35).By functional group transformations of compound 68, five new pyrrolopyridazine derivatives were obtained.

Scheme 35
Recently, using as raw materials 1-aminopyrrole derivative 69 and 3,3dimethoxypropionitrile, the pyrrolopyridazine derivative 71 was obtained (Scheme 36). 141A large number of compounds 72 were synthesized from the chloroderivative 71 and were tested as MEK inhibitors.o this date, there is only one literature example of such synthesis.By treating 2,3-dihydrodiazepinone 73 with acid chlorides, the bicyclic compounds 74 are obtained instead of the expected products.By reacting with DMAD with compounds 74a-c on heating, the cycloadducts 76 are obtained, most likely via a [3+2] cycloaddition between the dipoles 75 and the triple bond (Scheme 37). 142The cycloadducts 76a-c rearrange in various conditions to pyrrolopyridazines 77a-c, with the structure of compound 77c confirmed by X-ray analysis.studied the ability of conjugated azoalkenes to give intramolecular [3+2] cycloaddition reactions, 145,146 which are rarely encountered for this type of compounds. 147,148Treating unsaturated hydrozones 82 with anhydrous sodium bicarbonate in methylene chloride proved to be an interesting method for the synthesis of hexadropyrrolo

Scheme 40
Tetrahydro-pyrrolopyridaznies 84 were reduced stereoselectively using an Adams catalyst to the corresponding hexahydropyrrolopyridazines 85. 146 The acetylation of the nitrogen atom with acetic anhydride of compounds 85, followed by the reacton with sodium in liquid ammonia, leads to the cleavage of the N-N bond and the formation of pyrolidinones 86 (Scheme 41). 146

Scheme 45
Fraser 25 performed the formylation of pyrrolopyridazines using the Vilsmeier reaction (POCl 3 + DMF) and obtained 5-formyl pyrrolopyrdazines, as the 7 position was occupied by a phenyl moiety.By the reduction of the 5-formyl-pyrrolopyridazine derivatives with lithium aluminohydride in ethyl ether and in the presence of aluminium chloride, two new 5-methylpyrrolopyridazines were synthesized (Scheme 46).

Scheme 46
Strong electrophiles as in the case of bromination and nitration reactions lead to polysubstituted derivatives (Scheme 47).Thus, the bromination reaction of 2,4-dimethyl-and 2methyl-4-phenyl-pyrrolopyridazine leads to the following results: the use of N-bromosuccimide leads to 5,7-dibromoderivatives 95a,b; molecular bromine in various solvents (acetic acid, chloroform, carbon tetrachloride) leads to the formation of the tribromo derivatives 96a,b; the tetrabromo derivative 97a was obtained by the bromination of dibromo derivative 95a with bromine in carbon tetrachloride.Flitsch and Kramer 137 proposed the structure of 5,6,7-tribromopyrrolopyridazine for the bromination of 2,4-dimethylpyrrolopyridazine 65b, but a more rigorous inspection of the NMR spectra indicated a structure corresponding to 96a. 139By treating 65b with sulfonitric mixture, 5,7-dinitro derivative 98a is obtained.Under the same conditions, the use of pyrrolopyridazine 65c leads to the introduction of a third nitro group in the para position of the benzene ring.

Scheme 47
Charge density calculations on the pyrropyridazine ring indicate that electrophilic substitution is strongly favoured for the positions 5 and 7. A good correlation between theoretical computations and the experimental results was observed. 139lectrophilic addition to a double or triple activated bond occurs in the 7 position, and if this position is occupied, the reaction occurs at atom C-5.Thus, by the reaction between pyrrolopyridazines and tetracyanoethylene in acetone media in the presence of pyridine, pyrrolopyridazine derivatives 100 are formed (Scheme 48). 139The isolation of intermediary 99 and the fact that it eliminates hydrogen cyanide, forming compound 100, represents proof for the mechanism.

Scheme 48
Pyrrolopyridazines unsubstituted at the pyrrole ring form with DMAD compounds 101, by the Michael addition to the triple acetylenic bond (Scheme 49).From the NMR data it was concluded that only the trans isomers were formed in 6 to 69% yields, with the fumaryl residue found in the 7 position.Together with pyrrolopyridazines 101, compounds 102 are obtained as a result of the intramolecular cyclization of the Michael adducts.This hypothesis is backed up by the fact that by heating in the presence of hydrochloric acid, the transformation 101→102 is possible. 135,137Starting from the Michael adduct 101b, Zupan et al. 139 obtained the tetracyclic compound 104 (Scheme 49) by a sequence of reactions which includes the alkaline hydrolysis followed by acidification with the formation of anhydride 103, followed by the treating of this with hydrazine hydrate.

Scheme 49
Fraser et al. 26 investigated the reaction between 2,6,7-trimethyl-pyrrolo[1,2-b]pyridazine and DMAD in toluene at room temperature.Because the 7 position in compound 7b is occupied by a methyl group, the addition takes place in position 5 (Scheme 50).Both trans(E)-105 and cis(Z)-105 are obtained, in a 2.5/1 ratio, with a total yield of 53%.The two geometric isomers were separated by thin layer chromatography (TLC) and their configuration established on the basis of H-NMR data. 61-67,154,

Scheme 50
The action of 40%-formaldehyde on 2,6,7-trimethyl-pyrrolo [1,2-b]pyridazine leads to the formation of methylene-bis(5,5'-pyrrolopyridazine) 106 in 98% yield (Scheme 51). 25 Protonation with trifluoroacetic acid leads to a mixture containing a species protonated at carbon atoms C-7 and C-7' (32%, 106a) and one at C-2 and C-7' (32%, 106b).Scheme 52 6-Aryl-pyrrolopyridazines were heteroarylated with yields in the range of 4-93% in the 7 position using as arylation agent 3,6-dichloropyridazines in dichloromethane as medium and in the presence of aluminium chloride (Scheme 53). 157Heteroarylation with 3-chloro-6methoxypyridazine occurs only in the case of one pyrrolopyridazine derivative with 20% yield.The reaction represents a new synthetic method for the obtaining of 6,7-disubstituted pyrrolopyridazines with 110 structure.Aiming at obtaining new pyrrolopyridazine derivatives with possible biological applications, the compound with the aryl group 4-ethylphenyl was hydrolized to pyridazinone 111.This was subsequently transformed into ester 112, which in turn was hydrolized to acid 113 (Scheme 53).The synthesis of the intermediate pyrrolopyridazines 109 was performed using the Chichibabin reaction.2.2.Protonation and deuteration 24,25,137 Usually the protonation of a N-aromatic heterocycle occurs at the nitrogen atom, but protonation at a ring carbon atom is also possible.From the studies performed on indolizine and its derivatives, it was shown that protonation occurs at position 3 or 1.As can be observed (Scheme 54), protonation of the carbon atom leads to a preservation of aromaticity in the pyridine ring and the loss of the weaker aromaticity of the pyrrole ring.It was concluded that the protonation of the nitrogen atom requires more energy than protonation of the carbon atom.Scheme 56 H-NMR data show that protonation of 6-phenyl-5-methyl-pyrrolopyridazine, in the same conditions, leads to a mixture of two species, one protonated at C-7 (80%) and one at C-5 (20%).The different protonation of compounds 7d (protonation at C-5 and C-7) and 7b (protonation at C-5) can be explained by the steric and electronic effects of the methyl and phenyl groups.In the case when the three hydrogen atoms from the pyrrole ring are substituted by methyl and phenyl (position 6) groups, protonation by trifluoroacetic acid takes place at atom C-7.By using a strongly acidic medium (perchloric acid in ethyl acetate), the reaction is kinetically controlled and nitrogen atom N-1 is protonated.Flitsch and Kramer 138 established independently from Fraser that pyrrole-unsubstituted pyrrolopyridazine protonation takes place with trifluoroacetic acid at C-7 in 10%.Deuterium substitution (CF 3 COOD) implies the atoms H-5 and H-7.As a result of the deuteration studies on pyrrolopyridazines the following conclusions can be drawn: protonation usually occurs at C-7, and when this position is occupied, at C-5; the process is kinetically or thermodynamically controlled, this being determined by the strength of the protonation agent; the results are not in agreement with theoretical computations, which indicate the highest electron density at atom N-1. 51he hydrogenation of pyrrolopyridazines was recently reported in the literature. 51By treating with zinc in acetic acid at reflux, pyrrolopyridazines 32a and 35b,c are hydrogenated selectively in positions 3 and 4 (Scheme 57).The structure of 3,4-dihydropyrrolopyridazines 114a-c was established on the basis of NMR data and X-ray analysis for compound 114b.The hydrogenation of dihydro-pyrrolopyridazines to tetrahydro-pyrrolopyridazines and of hexahydropyrrolopyridazines 84 to octahydro-pyrrolopyridazines 85 was mentioned above. 146

Scheme 58
A good example is the synthesis of 7-aroyl-pyrrolopyridazines 117 by the hydrolysis of cycloadducts 115 to acids 116, followed by their decarboxylation by simple heating above their melting point (Scheme 58). 79ther examples of chemical transformations of the functional groups grafted on the pyrrolopyridazine scaffold such as transesterification, 4 cyano group hydrolysis to ester, 4 or the acylation of an amino group 36

Physico-chemical and Biological Properties
,135 Although the high fluorescence of pyrrolopyridazines was known since the 1970's, 24,135 the first quantitative study of their fluorescent properties and how substituents alter them was performed by Wudl et al. 3 in 1999.After this, numerous articles treated the optical properties and especially the fluorescence of such compounds in detail. 4,5,102,159,160For example, Wudl et al. 159 synthesized and polymerized a series of monomers containing grafted pyrrolopyridazinic residues (Scheme 60).Fluorescence studies of these polymers showed a long quench time, strong solid state luminiscence and a high quantum yield.The resulting polymers can be made into films or fibers, which makes them suitable for use in optoelectronic devices.
Mass spectrometry has been used only for determining the molecular mass, as no studies on the fragmentation mechanisms of pyrrolopyridazine derivatives have been performed to this date. 27,71,161IR and NMR spectroscopies were used for structural assignment.NMR data is readily available in papers treating the synthesis and chemical transformations of pyrrolo [1,2b]pyridazines.