Synthesis of 4-arylamino-3-(trifluoromethyl)pyridazines and pyridazino[3,4-b]quinoxalines (as by-products) from 3-aroylmethyl-2-(trifluoromethyl)quinoxalines and hydrazine hydrate

Abstract

A number of 4-arylamino-3-(trifluoromethyl)pyridazines were obtained in good yields via the novel reaction of 3-aroylmethyl-2-(trifluoromethyl)quinoxalines with an excess of hydrazine hydrate in refluxing n-butanol with or without acetic acid. This reaction is accompanied by the formation of side-products with the pyridazino[3,4-b]quinoxaline skeleton. The possible reaction mechanism was discussed.

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Introduction

Pyridazines are an important class of heterocyclic compounds mainly because of their synthetic versatility, well-balanced physico-chemical properties, and the presence of possible binding sites for interactions with various receptors.¹ Trifluoromethyl-substituted pyridazines have also drawn considerable attention because they often show interesting biological activity, and usefulness for pharmaceutical (acetylcholinesterase inhibitors²) and agrochemical (herbicidal activity³) applications. These compounds are primarily prepared by the reactions of CF₃-containing 1,4-dicarbonyl compounds or their synthetic equivalents with hydrazines.⁴ These reactions involve the intermolecular condensation of hydrazines with one of the keto groups of the 1,4-dicarbonyl compound to produce an intermediate hydrazone, which undergoes intramolecular cyclization to afford the corresponding pyridazine derivatives. Thus, isomeric 4-(trifluoromethyl)pyridazin-3(2H)-ones⁵ and 3-(trifluoromethyl)pyridazin-4(1H)-ones⁶ were obtained by condensation of methyl trifluoropyruvate and methyl 2-methoxytetrafluoropropionate (protected methyl trifluoropyruvate) with ketones, followed by reaction of the 1,4-dicarbonyl adducts with hydrazine. Apart from this approach to trifluoromethylated pyridazines, a number of other methods for their preparation have been developed.⁷ However, the chemistry of the pyridazine nucleus is still ‘underexplored’ in comparison with the pyrimidine and pyrazine ring systems.¹ Only two examples of 3-amino-4-(trifluoromethyl)pyridazines were reported so far^2,8 and as far as we know, there are no relevant data concerning the synthesis of 4-amino-3-(trifluoromethyl)pyridazines. Our synthesis of these compounds is based on the reaction of hydrazine hydrate with 3-aroylmethyl-2-(trifluoromethyl)quinoxalines 1 existing in two tautomeric forms and prepared by us recently from 2-(trifluoroacetyl)chromones⁹ and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones¹⁰ (Scheme 1).

Scheme 1 Synthesis of quinoxalines 1.

It is known that some o-phenylenediamine derivatives such as 1,5-benzodiazepines 2 and 3, as well as quinoxalin-2-ones 4 and 5, may be regarded as latent 1,2- and 1,3-dicarbonyl compounds. Indeed, benzopyrano[1,5]benzodiazepine 2 as a synthetic equivalent of chromone-3-carboxylic acid reacts with hydrazines, amidines and guanidines to give benzopyrano[4,3-c]pyrazol-4-ones and benzopyrano[4,3-d]pyrimidin-5-ones;¹¹ 1,5-benzodiazepine part of the 1,5-benzodiazepinоquinoxaline system 3 represents a masked β-dicarbonyl moiety and is easily converted into 3-(pyrazolylmethyl)- and 3-(isoxazolylmethyl)quinoxalin-2-ones under the action of hydrazines and hydroxylamine.¹² Since 3-acylquinoxalin-2-ones 4 and 3-acylmethylquinoxalin-2-ones 5 react with benzene-1,2-diamine¹³ and hydrazines¹⁴ via rearrangement of intermediate spiroquinoxalin-2-one derivatives with a contraction of the pyrazine ring to the benzimidazole moiety (Mamedov rearrangement), these quinoxalinones behave as masked 1,2- and 1,3-diketones, respectively (Scheme 2).

Scheme 2 o-Phenylenediamine derivatives as synthetic equivalents of 1,2- and 1,3-dicarbonyl compounds.

Taking into account that 3-aroylmethyl-2-(trifluoromethyl)quinoxalines 1 possess several reactive sites and may be employed as synthons in routes to other heterocycles, we were interested to investigate their behaviour towards some nitrogen binucleophiles such as hydrazines and hydroxylamine, which would most likely undergo initial addition to the carbonyl group of the aroylmethyl substituent. We envisaged that compounds 1 can be considered as masked 1,2,4-triketones, the reaction of which with hydrazine via the formation of hydrazone 6 would produce either the corresponding pyrazoles 7 (if 1 will act as 1,3-dicarbonyl) or pyridazines 8 (if 1 will act as 1,4-dicarbonyl). The intermediate hydrazone 6 would possibly be able to recyclise under suitable experimental conditions through nucleophilic attack of the free NH₂ group at the 3- or 2-positions of the quinoxaline system with concomitant opening of the pyrazine ring at these positions, ultimately give rise to pyrazoles 7 or pyridazines 8, respectively (Scheme 3).

Scheme 3 Possible reaction routes of quinoxalines 1 with hydrazine.

In the present paper we wish to report that the reaction of hydrazine with quinoxalines 1 activated by the trifluoromethyl group provides a new and convenient synthesis of 6-aryl-4-arylamino-3-(trifluoromethyl)pyridazines 8, which are of interest from the view point of pharmacological activity because of their CF₃ functionality. In this reaction, quinoxalines 1 behave as a latent 1,4-diketone, having a masked o-phenylenediamine fragment, while their reaction with phenylhydrazine and hydroxylamine stopped at the phenylhydrazone or oxime stage. Moreover, we discuss here the structures of two side-products from the reaction with hydrazine hydrate and mechanism for their formation.

Results and discussion

Published data on the reactions of quinoxalines with hydrazines are scarce. Only three reports are known, which describe the reactions of 3-aroylmethylquinoxalin-2-ones 5 with hydrazines to give either 1,2-dihydropyridazino[3,4-b]quinoxalines^15,16 or 2-pyrazolylbenzimidazoles¹⁴ (Fig. 1).

Fig. 1 Products from the reactions of quinoxalinones 5 with hydrazines.

To demonstrate the ability of 3-aroylmethyl-2-(trifluoromethyl)quinoxalines 1 to undergo recyclization reactions, these compounds were reacted with dinucleophiles such as hydrazine, phenylhydrazine and hydroxylamine. The study of reactions of quinoxalines 1 with dinucleophiles was initiated with hydrazine hydrate in n-butanol medium. Several competing pathways for the reaction in both the initial step of nucleophilic attack and the subsequent heterocyclization would have been expected. However, we found that the principal direction of the reaction is the formation of 6-aryl-4-arylamino-3-(trifluoromethyl)pyridazines 8 and 9. When quinoxalines 1a–o, prepared from 2-(trifluoroacetyl)chromones and 1,2-diaminobenzene, 2,3-diaminopyridines and 2,3-diaminonaphthalene,⁹ were heated at reflux with hydrazine hydrate in n-BuOH for 16 h (method A), the reaction went smoothly providing pyridazines 8a–j and 9a–e as the main products in 41–81% yields with a small amount of by-products identified as pyridazino[3,4-b]quinoxalines 10a–e and 11a–e. Although they are not formed in appreciable amounts, we were able to investigate their structure (Scheme 4, structure assignments see below). These by-products could be avoided by reacting quinoxalines 1a,b,f with hydrazine hydrate in refluxing n-butanol in the presence of acetic acid (method B). Under these conditions, only pyridazines 8a,b,f were detected in the reaction mixture and a simple recrystallization from acetonitrile provides analytically pure products in 50–70% yields (Table 1). The use of pyridine as a solvent¹⁶ in this transformation gave a negative result.

Scheme 4 Synthesis of compounds 8–11 from quinoxalines 1a–o.

Table 1 Isolated yields of compounds 8–11, prepared from quinoxalines 1a–o

Quinoxaline	R	X	Product	Yield^a (%)	By-product	Yield^a (%)
a Method A.b Method B (in the presence of AcOH).
1a	H	CH	8a	57 (50)^b	10a	4
1b	Me	CH	8b	41 (51)^b	10b	4
1c	Cl	CH	8c	58	10c	2
1d	Br	CH	8d	65	10d	2
1e	MeO	CH	8e	52	10e	4
1f	H	N	8f	81 (70)^b	—	—
1g	Me	N	8g	79	—	—
1h	Cl	N	8h	77	—	—
1i	Br	N	8i	60	—	—
1j	MeO	N	8j	68	—	—
1k	H	CH, benzo	9a	54	11a	11
1l	Me	CH, benzo	9b	52	11b	13
1m	Cl	CH, benzo	9c	61	11c	8
1n	Br	CH, benzo	9d	75	11d	5
1o	MeO	CH, benzo	9e	53	11e	17

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It is noteworthy that, while conversion of quinoxalines 1a–e, prepared from 2-CF₃CO-chromones and 1,2-diaminobenzene, into pyridazines 8a–e is accompanied by the formation of hydrazones 10a–e in 2–4% yields, application of the same conditions to quinoxalines 1k–o, obtained on the basis of 2,3-diaminonaphthalene, gave pyridazines 9a–e (yields 52–75%) containing a small amount of 5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalines 11a–e (yields 5–17%). Because of the low solubility of by-products 10 and 11 in acetonitrile, their isolation in a pure state was possible. In the case of quinoxalines 1f–j, obtained from 2,3-diaminopyridine, formation of the corresponding by-products 10 was not observed. It should be noted that our attempt to prepare compound 10a from pyridazine 8a and hydrazine hydrate in refluxing n-butanol was fruitless and only starting material was recovered. This outcome shows that pyridazines 8 and 9 are the final products in this transformation and two reaction routes are realized, one of which leads to the formation of pyridazino[3,4-b]quinoxaline derivatives 10 and 11 as a result of substitution of the trifluoromethyl group (discussion of the reaction mechanism see below). Note that unlike a CCl₃ group,¹⁷ substitution of a CF₃ group under the action of nucleophilic reagents is a very rare case.¹⁸

The first pyridazino[3,4-b]quinoxalines were obtained by the reaction of tri- and tetrachloropyridazine with o-phenylenediamines.^15,19 Apart from this, only 3-chloro-4-[2-(o-chlorophenyl)hydrazine]pyridazino[3,4-b]quinoxaline²⁰ and 1,2-dihydropyridazino[3,4-b]quinoxalines have previously been reported.^15,16,21,22 On the other hand, numerous studies have been devoted to the chemistry of quinoxalino[2,3-c]cinnoline derivatives.²³

Unlike the reaction with quinoxalines 1a–o, which gave pyridazines 8a–j and 9a–e in good yields without AcOH (method A), we found that the yields of the reaction between hydrazine hydrate and quinoxalines 1p–w, prepared from 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones and 1,2-diaminobenzene and 2,3-diaminonaphthalene,¹⁰ were very low under the same conditions (3–36%), and the separation and purification of the desired pyridazines 8k–n and 9f–i were difficult. Interestingly, 5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalines 11f–i turned out to be the main products in this case (yields 36–44%) (Scheme 5). We think that it is attributed to the absence of the acidic phenolic proton in quinoxalines 1p–w, obtained on the basis of 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones. Thus, we employed the method B (with acetic acid) and the results showed that the yields of pyridazines 8k–n and 9f–i were improved dramatically, while compounds 10 and 11 were not afforded at all. Isolated yields of two synthetic procedures are summarized in Table 2. So the method B is more effective for the synthesis of pyridazine derivatives from quinoxalines 1p–w, while the presence or absence of AcOH does not exert any substantial influence in the case of quinoxalines 1a–j. It is pertinent to mention here, an important structural requirement for the synthesis of 5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalines 11 is the presence of the additional benzene ring. In other words, this polyaza heterocyclic system is always a minor (for 1k–o) or major product (for 1t–w) so long as the naphthalene moiety is present in the starting quinoxaline. Our findings clearly indicate that C-2 of quinoxalines 1, due to the electron-withdrawing effect of the CF₃ group, is very susceptible to nucleophilic attack, which makes them useful for constructing highly functionalized biologically and medicinally important products, as well as polyaza heterocycles.

Scheme 5 Synthesis of compounds 8–11 from quinoxalines 1p–y.

Table 2 Isolated yields of compounds 8–11, prepared from quinoxalines 1p–y

Quinoxaline	R	X	Product	Yield^a (%)	Yield^b (%)	By-product	Yield^a (%)
a Method A.b Method B (in the presence of AcOH).
1p	H	CH	8k	4	60	—	—
1q	Me	CH	8l	3	62	10l	9
1r	Cl	CH	8m	36	64	10m	8
1s	MeO	CH	8n	14	56	10n	12
1t	H	CH, benzo	9f	5	52	11f	41
1u	Me	CH, benzo	9g	15	55	11g	41
1v	Cl	CH, benzo	9h	12	50	11h	44
1w	MeO	CH, benzo	9i	27	57	11i	36
1x	H	N	—	—	—	—	—
1y	Cl	N	—	—	—	—	—

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It should be noted that when 2-(trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones were reacted with 2,3-diaminopyridine, having two amino groups with different nucleophilicity, 3-CF₃-quinoxalines 1f–j and 2-CF₃-quinoxalines 1x,y were obtained as the major products, respectively (Fig. 2).^9,10 Interestingly, while 3-CF₃-quinoxalines 1f–j reacted with hydrazine hydrate to give pyridazines 8f–j in 60–81% yields, their 2-CF₃-regioisomers 1x and 1y resulted in complex mixtures with low pyridazine content, indicative of a serious loss of regioselectivity due to the other position of the 5-N atom.

Fig. 2 Quinoxalines from the reactions of 2,3-diaminopyridine with 2-(trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones.

The structures of pyridazines 8 and 9 were unambiguously confirmed by X-ray diffraction analysis of crystals 8a and 8k as representative examples (Fig. 3 and 4). Pyridazines 8k,n were isolated in 56–60% yields as a 2 : 1 complex with N′-acetylacetohydrazide. The latter was formed from the reaction of hydrazine with acetic acid under the reaction conditions (method B). In addition, the structure of the products 8 and 9 was established by the usual spectral analyses. Thus, a characteristic feature of the ¹H NMR spectra of pyridazines 8a–j in a DMSO-d₆ solution is the appearance of three singlets at δ = 6.89–7.05, 8.38–8.49 and 11.10–12.34 ppm for the pyridazine 4′-H, NH and OH protons, respectively, indicating the involvement of the phenolic hydroxyl in the strong intramolecular O–H⋯N=C hydrogen bond.

Fig. 3 X-ray crystal structure of 8a (ORTEP drawing, 50% probability level).

Fig. 4 X-ray crystal structure of 8k as a 2 : 1 complex with (MeCONH)₂ (ORTEP drawing, 50% probability level).

The structures of the by-products 10 and 11 were established on the basis of their 1D and 2D NMR spectra and merit some comments. The hydrazone 10b and tetracycle 11d will be used for illustration. The 2D ¹H–¹³C HSQC spectrum unambiguously demonstrated the presence in compound 10b of seven protons directly bonded to sp² carbon atoms (δ = 6.70–7.76 ppm). Therefore, the other four protons in the molecule are bound to the heteroatoms N and O (δ = 8.99–11.98 ppm). In the HMBC spectrum, the most important are the following cross-peaks: NH^a/C-4, NH^b/C-4, OH/C-1′, OH/C-2′, OH/C-6′, H-3′/C-3, H-7/C-5a, H-9/C-5a, H-6/C-9a, H-8/C-9a, which agree well with the given structure.

In the 2D ¹H–¹⁵N HMQC spectrum, showing directly bound hydrogen and nitrogen atoms, two atoms ¹⁵N are revealed at δ = 150.7 and 154.4 ppm, of which the former has a direct constant with a pair of doublets at δ = 11.98 and 9.65 ppm, whereas the latter correlates with a singlet at δ = 11.46 ppm. The chemical shifts indicate that these atoms belong to the hydrazone primary (N-2′′) and secondary (N-1) amino nitrogens (Fig. 5). In the 2D ¹H–¹⁵N HMBC spectrum, valuable three- and two-bond correlations are obtained for the four nonprotonated nitrogens (H-9/N-10, H-6/N-5, H-1/N-2, H^a/N-1′′ and H^b/N-1′′) which provide a full ¹⁵N chemical shift assignment [247.2 (N-10), 294.8 (N-5), 297.0 (N-2), 362.1 (N-1′′)], confirming the suggested structure 10b. Furthermore, one-bond correlation H^a/N-5 was observed due to the spin–spin interaction through a hydrogen bond (coupling constants ^1hJ_N,H in N–H⋯N= systems have been measured²⁴) (Fig. 6).

Fig. 5 Fragment of ¹H–¹⁵N HMQC spectrum (500 MHz, DMSO-d₆) of compound 10b.

Fig. 6 Fragment of ¹H–¹⁵N HMBC spectrum (500 MHz, DMSO-d₆ of compound 10b.

It is noteworthy that hydrazones 10a–e,l–n gave rise to unique and very interesting ¹H NMR spectra in DMSO-d₆ solution. Despite the ¹⁴N quadrupole broadening of the resonance signals of the amino protons, the hydrazone NH₂ group appeared as two sharp doublets at δ = 11.94–12.16 and 9.65–9.73 ppm with the geminal coupling constant J_H–N–H = 15.3–15.4 Hz. The nonequivalence of the two N–H protons is not surprising since one of them is involved in an intramolecular hydrogen bond with the 5-N atom (the downfield signal remains unchanged upon dilution), however, an exceptionally large geminal coupling constant was unexpected. To our knowledge, there are only two related examples reported in the literature. Thus, the amino protons of heterocycles 12 and 13 have geminal couplings in the range of 4.0–4.5 Hz (fragments II and III), whereas in fragment IV the coupling was too small to observe.^25,26 It is presumed that two-bond H–N–H coupling is observed because of an increase in sp² character of the amino groups resulting from hydrogen bond formation.²⁵ Electronegative atoms change J_H–N–H couplings in a wide range of values as described in Fig. 7: when the β-C atom is substituted with a heteroatom like a nitrogen or an oxygen (fragments II and III), the coupling becomes larger in magnitude, ranging from 3.4 to 4.5 Hz; when the α-C atom is substituted with a nitrogen (fragment I), the coupling becomes large (J = 15.3 Hz, this is the first example of such a magnitude). Geminal H–N–H coupling is a reliable and important effect which can help with structure assignments in some specific cases.

Fig. 7 Changes in the structures which affect the magnitude of the J_H–N–H coupling.

In order to discriminate between the many tautomers of the dihydrogenated pyridazino[3,4-b]quinoxaline system, it must be remarked that in 5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline 11f the structure of the central benzene ring is similar to that of o-phenylenediamine, the protons of which lie between δ = 6.45 and 6.60 ppm. The complete ¹H and ¹³C NMR assignments of compound 11f were made by a combination of 2D ¹H–¹³C HSQC/HMBC, ¹H–¹⁵N HMQC/HMBC and ¹H–¹H NOESY experiments. In particular, the ¹H–¹³C HSQC spectrum demonstrated the presence of three upfield protons in the range δ = 6.48–6.68 ppm directly bonded to the aromatic carbon atoms C-4, C-6 and C-11. Thus, one can conclude that the only structure 11f is in agreement with this result (Fig. 8).

Fig. 8 Fragment of ¹H–¹³C HSQC spectrum (500 MHz, DMSO-d₆) of compound 11f.

For the formation of products 8–11 a plausible mechanism is depicted in Scheme 6. The first step of the reaction leading to a mixture of compounds 8 and 10 (or 9 and 11) apparently involves an attack of the hydrazine amino group at the carbonyl group of quinoxaline 1 with the formation of hydrazone 6. Subsequent intramolecular addition of the second NH₂ group at the C-2 atom bearing a trifluoromethyl group leads to the fused intermediate A, from which there are two possible directions. The first direction (path a) implies a rupture of the C–N bond with the formation of compound B, which undergoes a [1,3] H shift to give the major products 8 or 9. In the alternative direction (path b), elimination of fluoroform from intermediate A led straight to tetracyclic 4,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline C followed by a [1,3] H shift into the thermodynamically more stable 5,12-dihydro derivative 11. On the other hand, tricyclic tautomer 4,10-dihydropyridazino[3,4-b]quinoxaline C oxidizes in air into the keto derivative D (path c), which reacts with hydrazine to form by-product 10.

Scheme 6 Proposed reaction mechanism for the formation of compounds 8–11.

Finally, the reactions of quinoxalines 1 with phenylhydrazine and hydroxylamine hydrochloride were investigated. In contrast to hydrazine, reactions with these dinucleophiles stopped at the initial step and afforded the corresponding phenylhydrazones 14 and oximes 15. Indeed, we found that quinoxalines 1a,b reacted with phenylhydrazine in refluxing n-butanol for 2.5 h to give products 14a,b in ca. 90% yield. Hydrazone 14b was also obtained with phenylhydrazine hydrochloride but only for 8 h. When hydroxylamine hydrochloride was used under the same conditions (n-butanol, reflux, 6.5 h), the reaction proceeded smoothly to provide high yields of oximes 15a,b (Scheme 7). However, with MeNHNH₂·H₂SO₄ only starting material was isolated. The complete ¹H and ¹³C NMR assignments of hydrazone 14b were made on the basis of 2D ¹H–¹H COSY, ¹H–¹H NOESY and ¹H–¹³C HSQC/HMBC experiments. In the ¹⁹F NMR spectra of compounds 14 and 15 in DMSO-d₆, the CF₃ group appeared as a singlet at δ = 98.2–98.3 ppm.

Scheme 7 Synthesis of compounds 14a,b and 15a,b.

Conclusions

In conclusion, we have shown that 3-aroylmethyl-2-(trifluoromethyl)quinoxalines react with hydrazine hydrate in refluxing n-butanol with or without acetic acid to afford the corresponding 3-(trifluoromethyl)pyridazines in good yields. These products result from the double nucleophilic addition of hydrazine hydrate to the carbonyl group and C-2 atom of 3-aroylmethyl-2-(trifluoromethyl)quinoxalines and subsequent ring-opening of the diazine cycle. This is, to our knowledge, the first report of the preparation of pyridazines from the quinoxaline system. The structures of the by-products were established as pyridazino[3,4-b]quinoxaline derivatives and possible mechanism for their formation was discussed. In addition, for the first time, the geminal coupling constant J_H–N–H = 15.3 Hz was described.

Experimental

General information

¹H, ¹⁹F and ¹³C NMR spectra were recorded on Bruker DRX-400 (400, 376, 100 MHz) and AVANCE-500 (500, 470.5, 126 MHz) spectrometers in DMSO-d₆ with TMS and C₆F₆ as internal standards. IR spectra were recorded on a Nicolet 6700 instruments (FTIR mode). Mass spectra (ESI-MS) were measured with a Waters Xevo QTof instrument. Elemental analyses were performed at the Microanalysis Services of the Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences. All solvents used were dried and distilled by standard procedures. Known quinoxalines 1 were prepared by literature procedures.^9,10

General procedures for the synthesis of pyridazines 8a–n and 9a–i

Method A: a solution of the appropriate quinoxaline 1 (0.5 mmol) and hydrazine hydrate (5 mmol) in n-butanol (10 mL) was heated at reflux for 16 h and then concentrated under reduced pressure. The residue was treated with 5 mL of acetonitrile at reflux to precipitate insoluble by-products. After that, by-product 10 or 11 was subjected to hot filtration, while compound 8 or 9 was isolated from filtrate and recrystallized from acetonitrile.

Method B (with AcOH): a solution of the appropriate quinoxaline 1 (0.5 mmol) and hydrazine hydrate (5 mmol) in n-butanol (7 mL) in the presence of AcOH (1 mL) was heated at reflux for 16 h. After that, the mixture was concentrated under reduced pressure and the residue was recrystallized from acetonitrile.

2-[5-(2-Aminophenylamino)-6-(trifluoromethyl)pyridazin-3-yl]phenol (8a).

Yield 57% (A), 50% (B), beige crystals, mp 192–193 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.08 (s, 2H, NH₂), 6.64 (td, J = 7.5, 1.3 Hz, 1H, 5′′-H), 6.86 (dd, J = 8.1, 1.3 Hz, 1H, 3′′-H), 6.89 (s, 1H, 4′-H), 6.90–6.94 (m, 2H, 4-H, 6-H), 7.05 (dd, J = 7.8, 1.6 Hz, 1H, 6′′-H), 7.12 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H, 4′′-H), 7.32 (ddd, J = 8.3, 7.1, 1.6 Hz, 1H, 5-H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H, 3-H), 8.48 (s, 1H, NH), 12.34 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.4 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 106.2 (C-4′), 115.6 (C-3′′), 116.4 (C-5′′), 117.7 (C-4), 118.4 (C-2), 119.4 (C-6), 120.6 (C-1′′), 122.4 (q, ¹J_C,F = 273.6 Hz, CF₃), 127.8 (C-3), 128.6 (C-4′′, C-6′′), 132.1 (C-5), 135.5 (q, ²J_C,F = 32.9 Hz, C-6′), 142.7 (C-5′), 144.8 (C-2′′), 157.9 (C-1), 160.1 (C-3′); IR (ATR): ν = 3478, 3463, 3435, 3385, 3347, 3254, 3244, 3090, 1619, 1573, 1539, 1498, 1486 cm⁻¹. C₁₇H₁₃F₃N₄O (346.31): calcd C 58.96, H 3.78, N 16.18; found C 58.75, H 3.89, N 16.01.

Crystal data for 8a (C₁₇H₁₃F₃N₄O, 346.31). Triclinic, space group P1̄, a = 14.1362(7) Å, b = 14.3909(5) Å, c = 18.0057(8) Å, α = 66.933(4)°, β = 67.968(4)°, γ = 89.570(3)°, U = 3081.9(2) ų, Z = 8, T = 120.00(10) K, absorption coefficient 0.122 mm⁻¹, reflections collected 33 672, independent reflections 16 899 [R(int) = 0.0275], refinement by full-matrix least-squares on F², data/restraints/parameters 16 899/0/1001, goodness-of-fit on F² = 1.026, final R indices [I > 2σ(I)] R₁ = 0.0497, wR₂ = 0.1046, R indices (all data) R₁ = 0.0810, wR₂ = 0.1225, largest diff peak and hole 0.444 and −0.466 e Å⁻³.†

2-[5-(2-Aminophenylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-methylphenol (8b). Yield 41% (A), 51% (B), yellow crystals, mp 211–212 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.21 (s, 3H, Me), 5.08 (s, 2H, NH₂), 6.64 (td, J = 7.5, 1.3 Hz, 1H, 5′′-H), 6.82 (d, J = 8.3 Hz, 1H, H-6), 6.86 (dd, J = 8.1, 1.2 Hz, 1H, 3′′-H), 6.90 (s, 1H, 4′-H), 7.05 (dd, J = 7.8, 1.5 Hz, 1H, 6′′-H), 7.10–7.15 (m, 2H, 5-H, 4′′-H), 7.32 (d, J = 2.0 Hz, 1H, 3-H), 8.42 (s, 1H, NH), 11.87 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.4 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.2, 106.5, 115.6, 116.4, 117.5, 118.4, 120.7, 122.4 (q, ¹J_C,F = 273.9 Hz, CF₃), 127.7, 127.9, 128.6, 132.7, 135.4 (q, ²J_C,F = 32.4 Hz, C-6′), 142.6, 144.8, 155.6, 162.0 (one C is not observed); IR (ATR): ν = 3404, 3315, 3245, 3038, 2917, 2860, 1579, 1546, 1498, 1476 cm⁻¹. C₁₈H₁₅F₃N₄O (360.33): calcd C 60.00, H 4.20, N 15.55; found C 60.01, H 4.06, N 15.53.

2-[5-(2-Aminophenylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-chlorophenol (8c). Yield 58% (A), yellow crystals, mp 225–226 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.07 (s, 2H, NH₂), 6.64 (td, J = 7.5, 1.4 Hz, 1H, 5′′-H), 6.85 (dd, J = 8.2, 1.4 Hz, 1H, 3′′-H), 6.94 (d, J = 8.8 Hz, 1H, 6-H), 7.01 (s, 1H, 4′-H), 7.05 (dd, J = 7.8, 1.4 Hz, 1H, 6′′-H), 7.11 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H, 4′′-H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H, 5-H), 7.66 (d, J = 2.7 Hz, 1H, 3-H), 8.44 (s, 1H, NH), 11.73 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.4 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 107.9, 115.6, 116.4, 119.1, 120.8, 121.3, 122.4 (q, ¹J_C,F = 274.0 Hz, CF₃), 122.8, 123.5, 127.8, 128.5, 128.6, 131.2, 135.5 (q, ²J_C,F = 32.1 Hz C-6′), 142.6, 144.9, 156.0, 158.2; IR (ATR): ν = 3410, 3341, 1633, 1573, 1545, 1497, 1472 cm⁻¹. C₁₇H₁₂ClF₃N₄O (380.75): calcd C 53.63, H 3.18, N 14.97; found C 53.50, H 3.35, N 14.75.

2-[5-(2-Aminophenylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-bromophenol (8d). Yield 65% (A), white crystals, mp 229–230 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.06 (s, 2H, NH₂), 6.63 (t, J = 7.5 Hz, 1H, 5′′-H), 6.84 (d, J = 8.1 Hz, 1H, 3′′-H), 6.88 (d, J = 8.7 Hz, 1H, 6-H), 7.01 (s, 1H, 4′-H), 7.04 (d, J = 7.6 Hz, 1H, 6′′-H), 7.11 (t, J = 7.7 Hz, 1H, 4′′-H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H, 5-H), 7.79 (d, J = 2.4 Hz, 1H, 3-H), 8.42 (s, 1H, NH), 11.70 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.4 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 108.0, 110.3, 115.6, 116.4, 119.5, 120.8, 122.0, 122.5 (q, ¹J_C,F = 274.2 Hz, CF₃), 128.5, 128.6, 130.7, 134.0, 135.5 (q, ²J_C,F = 32.2 Hz, C-6′), 142.6, 144.9, 156.4, 158.1; IR (ATR): ν = 3409, 3311, 3251, 3222, 3077, 3038, 1580, 1543, 1497, 1472 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₂BrF₃N₄O [M + H]⁺ 425.0235, found 425.0225.

2-[5-(2-Aminophenylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-methoxyphenol (8e). Yield 52% (A), yellow crystals, mp 206–207 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.68 (s, 3H, MeO), 5.07 (s, 2H, NH₂), 6.64 (td, J = 7.7, 1.2 Hz, 1H, 5′′-H), 6.85 (dd, J = 8.1, 1.1 Hz, 1H, 3′′-H), 6.86 (d, J = 8.9 Hz, 1H, 6-H), 6.94 (s, 1H, 4′-H), 6.96 (dd, J = 8.9, 3.1 Hz, 1H, 6′′-H), 7.05 (dd, J = 7.8, 1.3 Hz, 1H, 4′′-H), 7.09–7.14 (m, 2H, 5-H, 3-H), 8.42 (s, 1H, NH), 11.25 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.5 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.4, 107.3, 112.6, 115.6, 116.4, 117.9, 118.2, 119.4, 120.8, 122.5 (q, ¹J_C,F = 273.9 Hz, CF₃), 128.5, 128.6, 135.4 (q, ²J_C,F = 32.4 Hz, C-6′), 142.5, 144.8, 151.3, 152.0, 159.5; IR (ATR): ν = 3482, 3469, 3401, 3369, 2935, 1622, 1576, 1543, 1496, 1449 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₅F₃N₄O₂ [M + H]⁺ 377.1225, found 377.1209.

2-[5-(2-Aminopyridin-3-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]phenol (8f). Yield 81% (A), 70% (B), beige crystals, mp 218–219 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.98 (s, 2H, NH₂), 6.65 (dd, J = 7.5, 4.9 Hz, 1H, 5′′-H), 6.89–6.95 (m, 2H, 4-H, 6-H), 6.91 (s, 1H, 4′-H), 7.32 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H, 5-H), 7.43 (dd, J = 7.6, 1.6 Hz, 1H, 4′′-H), 7.63 (dd, J = 8.0, 1.5 Hz, 1H, 3-H), 8.01 (dd, J = 4.9, 1.6 Hz, 1H, 6′′-H), 8.50 (br s, 1H, NH), 12.17 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.7 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 106.5, 112.4, 116.2, 117.6, 118.5, 119.4, 122.3 (q, ¹J_C,F = 274.1 Hz, CF₃), 128.1, 132.1, 135.8 (q, ²J_C,F = 32.4 Hz, C-6′), 136.6, 142.5, 147.5, 156.1, 157.8, 160.0; IR (ATR): ν = 3445, 3411, 3305, 3250, 3135, 2937, 2565, 1727, 1674, 1645, 1584, 1548, 1503, 1478 cm⁻¹. C₁₆H₁₂F₃N₅O (347.29): calcd C 55.33, H 3.48, N 20.17; found C 55.39, H 3.32, N 20.38.

2-[5-(2-Aminopyridin-3-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-methylphenol (8g). Yield 79% (A), beige crystals, mp 253–254 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.22 (s, 3H, Me), 5.97 (s, 2H, NH₂), 6.65 (dd, J = 7.5, 4.9 Hz, 1H, 5′′-H), 6.83 (d, J = 8.3 Hz, 1H, 6-H), 6.92 (s, 1H, 4′-H), 7.13 (dd, J = 8.3, 2.3 Hz, 1H, 5-H), 7.41–7.44 (m, 2H, 3-H, 4′′-H), 8.01 (dd, J = 4.9, 1.6 Hz, 1H, 6′′-H), 8.44 (s, 1H, NH), 11.76 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆) δ = 98.8 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.1, 106.8, 112.4, 116.4, 117.4, 118.5, 122.4 (q, ¹J_C,F = 273.9 Hz, CF₃), 127.8, 128.1, 132.7, 135.7 (q, ²J_C,F = 32.3 Hz, C-6′), 136.6, 142.5, 147.4, 155.5, 156.2, 160.0; IR (ATR): ν = 3429, 3330, 3289, 3183, 3093, 2957, 2923, 2866, 2781, 2685, 1633, 1585, 1574, 1555, 1507, 1485 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₄F₃N₅O [M + H]⁺ 362.1229, found 362.1216. C₁₇H₁₄F₃N₅O·0.25H₂O (365.83): calcd C 55.81, H 4.00, N 19.14; found C 55.96, H 3.88, N 19.29.

2-[5-(2-Aminopyridin-3-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-chlorophenol (8h). Yield 77% (A), beige crystals, mp 236–237 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.96 (s, 2H, NH₂), 6.65 (dd, J = 7.5, 4.9 Hz, 1H, 5′′-H), 6.94 (d, J = 8.8 Hz, 1H, 6-H), 7.05 (s, 1H, 4′-H), 7.35 (dd, J = 8.8, 2.7 Hz, 1H, 5-H), 7.42 (dd, J = 7.5, 1.7 Hz, 1H, 4′′-H), 7.78 (d, J = 2.7 Hz, 1H, 3-H), 8.00 (dd, J = 4.9, 1.7 Hz, 1H, 6′′-H), 8.46 (s, 1H, NH), 11.71 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.7 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 108.2, 112.4, 116.4, 119.1, 121.3, 122.4 (q, ¹J_C,F = 274.2 Hz, CF₃), 122.9, 128.0, 131.3, 135.9 (q, ²J_C,F = 32.2 Hz, C-6′), 136.6, 142.4, 147.4, 156.0, 156.2, 158.2; IR (ATR): ν = 3437, 3281, 3092, 1634, 1574, 1547, 1485 cm⁻¹. C₁₆H₁₁ClF₃N₅O (381.74): calcd C 50.34, H 2.90, N 18.35; found C 50.31, H 3.30, N 18.42.

2-[5-(2-Aminopyridin-3-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-bromophenol (8i). Yield 60% (A), beige crystals, mp 235–236 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.96 (s, 2H, NH₂), 6.64 (dd, J = 7.5, 4.9 Hz, 1H, 5′′-H), 6.89 (d, J = 8.8 Hz, 1H, 6-H), 7.05 (s, 1H, 4′-H), 7.42 (dd, J = 7.5, 1.6 Hz, 1H, 4′′-H), 7.46 (dd, J = 8.7, 2.6 Hz, 1H, 5-H), 7.90 (d, J = 2.6 Hz, 1H, 3-H), 8.00 (dd, J = 4.9, 1.6 Hz, 1H, 6′′-H), 8.44 (s, 1H, NH), 11.66 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.7 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 108.2, 110.4, 112.4, 116.4, 119.5, 122.0, 122.4 (q, ¹J_C,F = 274.2 Hz, CF₃), 130.9, 134.1, 135.9 (q, ²J_C,F = 32.5 Hz, C-6′), 136.6, 142.4, 147.4, 156.2, 156.4, 158.0; IR (ATR): ν = 3279, 3251, 3226, 3199, 3182, 3087, 1632, 1572, 1461 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₁BrF₃N₅O [M + H]⁺ 426.0177, found 426.0182.

2-[5-(2-Aminopyridin-3-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-methoxyphenol (8j). Yield 68% (A), yellow crystals, mp 246–247 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.69 (s, 3H, MeO), 5.96 (s, 2H, NH₂), 6.64 (dd, J = 7.5, 4.9 Hz, 1H, 5′′-H), 6.86 (d, J = 8.9 Hz, 1H, 6-H), 6.96 (dd, J = 8.9, 3.1 Hz, 1H, 5-H), 6.98 (s, 1H, 4′-H), 7.23 (d, J = 3.1 Hz, 1H, 3-H), 7.42 (dd, J = 7.5, 1.6 Hz, 1H, 4′′-H), 7.99 (dd, J = 4.9, 1.6 Hz, 1H, 6′′-H), 8.38 (s, 1H, NH), 11.10 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.8 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.4, 107.6, 112.4, 112.9, 116.5, 117.9, 118.1, 119.6, 122.4 (q, ¹J_C,F = 274.1 Hz, CF₃), 135.7 (q, ²J_C,F = 32.4 Hz, C-6′), 136.5, 142.4, 147.3, 151.2, 152.0, 156.2, 159.4; IR (ATR): ν = 3458, 3397, 3289, 3133, 3122, 3096, 3001, 2991, 1632, 1580, 1544, 1500, 1463 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₄F₃N₅O₂ [M + H]⁺ 378.1178, found 378.1166.

N-[6-Phenyl-3-(trifluoromethyl)pyridazin-4-yl]benzene-1,2-diamine (8k). Yield 4% (A), 60% (B, as complex with 0.5(MeCONH)₂), colourless crystals, mp 190–191 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.08 (br s, 2H, NH₂), 6.60 (s, 1H, 4′-H), 6.64 (td, J = 7.5, 1.5 Hz, 1H, 5′′-H), 6.86 (dd, J = 8.2, 1.4 Hz, 1H, 3′′-H), 7.06 (dd, J = 7.8, 1.5 Hz, 1H, 6′′-H), 7.12 (ddd, J = 8.2, 7.1, 1.5 Hz, 1H, 4′′-H), 7.48–7.53 (m, 3H, Ph), 7.77–7.82 (m, 2H, Ph), 8.39 (br s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.7 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.4 (Me), 106.1, 115.6, 116.5, 120.9, 122.8 (q, ¹J_C,F = 273.9 Hz, CF₃), 126.8, 128.5, 128.6, 129.0, 130.2, 135.93, 135.94 (q, ²J_C,F = 32.0 Hz, C-6′), 142.5, 144.8, 159.5, 167.9 (C=O); IR (ATR): ν = 3460, 3348, 3246, 3206, 3087, 2980, 2961, 2943, 2914, 2850, 2814, 2801, 1697, 1664, 1626, 1579, 1543, 1498, 1479 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₃F₃N₄ [M + H]⁺ 331.1171, found 331.1172. C₁₇H₁₃F₃N₄·0.5(MeCONH)₂ (388.37): calcd C 58.76, H 4.41, N 18.03; found C 58.47, H 4.30, N 18.04.

Crystal data for 8k (C₁₇H₁₃F₃N₄·0.5(MeCONH)₂, 388.38). Monoclinic, space group C2/c, a = 11.0546(15) Å, b = 19.664(3) Å, c = 17.9966(16) Å, β = 105.746(10)°, U = 3765.3(8) ų, Z = 8, T = 295(2) K, absorption coefficient 0.109 mm⁻¹, reflections collected 8604, independent reflections 4349 [R(int) = 0.0356], refinement by full-matrix least-squares on F², data/restraints/parameters 4349/0/273, goodness-of-fit on F² = 1.012, final R indices [I > 2σ(I)] R₁ = 0.0406, wR₂ = 0.0686, R indices (all data) R₁ = 0.1291, wR₂ = 0.0729, largest diff peak and hole 0.245 and −0.205 e Å⁻³.†

N-[6-(4-Methylphenyl)-3-(trifluoromethyl)pyridazin-4-yl]benzene-1,2-diamine (8l). Yield 3% (A), 62% (B), beige crystals, mp 151–152 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.34 (s, 3H, Me), 5.06 (br s, 2H, NH₂), 6.57 (s, 1H, 4′-H), 6.64 (td, J = 7.7, 1.3 Hz, 1H, 5′′-H), 6.86 (dd, J = 8.1, 1.1 Hz, 1H, 3′′-H), 7.05 (dd, J = 7.7, 1.3 Hz, 1H, 6′′-H), 7.12 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, 4′′-H), 7.31 (d, J = 8.0 Hz, 2H, 3-H, 5-H), 7.70 (d, J = 8.2 Hz, 2H, 2-H, 6-H), 8.33 (br s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.8 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.8, 105.6, 115.6, 116.5, 120.9, 122.7 (q, ¹J_C,F = 274.0 Hz, CF₃), 126.6, 128.4, 128.5, 129.5, 133.1, 135.8 (q, ²J_C,F = 32.1 Hz, C-6′), 139.9, 142.5, 144.8, 159.4; HRMS (ESI) calcd for C₁₈H₁₅F₃N₄ [M + H]⁺ 345.1327, found 345.1330.

N-[6-(4-Chlorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]benzene-1,2-diamine (8m). Yield 36% (A), 64% (B), beige crystals, mp 192–193 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.08 (s, 2H, NH₂), 6.61 (s, 1H, 4′-H), 6.64 (td, J = 7.5, 1.4 Hz, 1H, 5′′-H), 6.86 (dd, J = 8.1, 1.4 Hz, 1H, 3′′-H), 7.06 (dd, J = 7.8, 1.4 Hz, 1H, 6′′-H), 7.12 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H, 4′′-H), 7.58 (d, J = 8.6 Hz, 2H, 3-H, 5-H), 7.83 (d, J = 8.6 Hz, 2H, 2-H, 6-H), 8.42 (s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.7 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 106.0, 115.7, 116.5, 120.7, 122.7 (q, ¹J_C,F = 273.8 Hz, CF₃), 128.5, 129.1, 134.7, 135.1, 136.0 (q, ²J_C,F = 32.1 Hz, C-6′), 142.6, 144.8, 158.3; IR (ATR): ν = 3396, 3300, 3244, 3209, 3069, 3038, 1628, 1596, 1572, 1538, 1495, 1467 cm⁻¹. C₁₇H₁₂ClF₃N₄ (364.75): calcd C 55.98, H 3.32, N 15.36; found C 55.91, H 3.25, N 15.36.

N-[6-(4-Methoxyphenyl)-3-(trifluoromethyl)pyridazin-4-yl]benzene-1,2-diamine (8n). Yield 14% (A), 56% (B, as complex with 0.5(MeCONH)₂), beige crystals, mp 174–175 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.79 (s, 3H, MeO), 5.06 (br s, 2H, NH₂), 6.55 (s, 1H, 4′-H), 6.64 (td, J = 7.7, 1.4 Hz, 1H, 5′′-H), 6.86 (dd, J = 8.1, 1.2 Hz, 1H, 3′′-H), 7.05 (dd, J = 7.7, 1.4 Hz, 1H, 6′′-H), 7.06 (d, J = 8.9 Hz, 2H, 3-H, 5-H), 7.12 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H, 4′′-H), 7.77 (d, J = 8.9 Hz, 2H, 2-H, 6-H), 8.30 (br s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.8 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.4 (Me), 55.3, 105.0, 114.5, 115.6, 116.5, 121.0, 122.8 (q, ¹J_C,F = 273.8 Hz, CF₃), 128.1, 128.2, 128.4, 128.6, 135.6 (q, ²J_C,F = 31.9 Hz, C-6′), 142.4, 144.8, 159.0, 161.0, 167.9 (C=O); IR (ATR): ν = 3465, 3426, 3375, 3279, 3257, 3209, 3067, 3009, 1610, 1577, 1549, 1515, 1429 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₅F₃N₄O [M + H]⁺ 361.1276, found 361.1263.

2-[5-(3-Aminonaphthalen-2-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]phenol (9a).

Yield 54% (A), yellow crystals, mp 236–237 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.35 (br s, 2H, NH₂), 6.86 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H, 4-H), 6.89 (dd, J = 8.2, 1.1 Hz, 1H, 6-H), 7.03 (s, 1H, 4′-H), 7.14 (s, 1H, 4′′-H), 7.16 (ddd, J = 8.2, 7.0, 1.0 Hz, 1H, 7′′-H), 7.28 (ddd, J = 8.2, 7.1, 1.5 Hz, 1H, 5-H), 7.35 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H, 6′′-H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H, 3-H), 7.62 (d, J = 8.3 Hz, 1H, 5′′-H), 7.71 (d, J = 8.2 Hz, 1H, 8′′-H), 7.72 (s, 1H, 1′′-H), 8.69 (br s, 1H, NH), 12.04 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.5 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 106.9 (C-4′), 108.1 (C-4′′), 117.5 (C-6), 118.6 (C-2), 119.4 (C-4), 121.6 (C-7′′), 122.4 (q, ¹J_C,F = 274.1 Hz, CF₃), 124.7 (C-8′′a), 125.0 (C-5′′), 126.3 (C-6′′), 127.1 (C-1′′), 127.5 (C-8′′), 128.1 (C-3), 132.0 (C-5), 134.1 (C-4′′a), 135.5 (q, ²J_C,F = 32.3 Hz, C-6′), 142.9 (C-5′), 143.4 (C-3′′), 157.7 (C-1), 160.0; IR (ATR): ν = 3379, 3323, 3056, 1948, 1642, 1582, 1551, 1513, 1486 cm⁻¹. C₂₁H₁₅F₃N₄O (396.37): calcd C 63.63, H 3.81, N 14.14; found C 63.49, H 3.79, N 14.15.

2-[5-(3-Aminonaphthalen-2-ylamino)-6-(trifluoromethyl)pyridazin-3-yl]-4-methylphenol (9b). Yield 52% (A), yellow crystals, mp 236–237 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.17 (s, 3H, Me), 5.33 (s, 2H, NH₂), 6.77 (d, J = 8.3 Hz, 1H, 6-H), 7.06 (s, 1H, 4′-H), 7.08 (dd, J = 8.3, 2.0 Hz, 1H, 5-H), 7.13 (s, 1H, 4′′-H), 7.16 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H, 7′′-H), 7.34 (ddd, J = 8.2, 7.0, 0.9 Hz, 1H, 6′′-H), 7.40 (br d, J = 2.0 Hz, 1H, 3-H), 7.61 (d, J = 8.2 Hz, 1H, 5′′-H), 7.70 (s, 1H, 1′′-H), 7.71 (d, J = 7.7 Hz, 1H, 8′′-H), 8.62 (s, 1H, NH), 11.49 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.6 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.1, 107.3, 108.0, 117.3, 118.8, 121.6, 122.5 (q, ¹J_C,F = 274.0 Hz, CF₃), 125.0, 126.2, 126.4, 126.9, 127.5, 127.7, 128.2, 132.5, 134.0, 135.2, 135.5 (q, ²J_C,F = 29.4 Hz, C-6′), 142.9, 143.4, 155.3, 159.8; IR (ATR): ν = 3375, 3321, 3055, 2912, 1646, 1580, 1552, 1514, 1477 cm⁻¹. C₂₂H₁₇F₃N₄O (410.39): calcd C 64.39, H 4.18, N 13.65; found C 64.01, H 4.17, N 13.63.

2-[5-(3-Aminonaphthalen-2-yl)amino-6-(trifluoromethyl)pyridazin-3-yl]-4-chlorophenol (9c). Yield 61% (A), yellow crystals, mp 270–271 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.33 (s, 2H, NH₂), 6.88 (d, J = 8.8 Hz, 1H, 6-H), 7.12 (s, 1H, 4′-H), 7.16 (ddd, J = 8.1, 7.2, 0.9 Hz, 1H, 7′′-H), 7.17 (s, 1H, 4′′-H), 7.31 (dd, J = 8.8, 2.7 Hz, 1H, 5-H), 7.34 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H, 6′′-H), 7.61 (d, J = 8.2 Hz, 1H, 5′′-H), 7.70 (s, 1H, 1′′-H), 7.70 (d, 1H, J = 8.2 Hz, 8′′-H), 7.76 (d, J = 2.7 Hz, 1H, 3-H), 8.64 (s, 1H, NH), 11.44 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.6 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 108.1, 108.7, 118.9, 121.5, 121.6, 122.5 (q, ¹J_C,F = 274.1 Hz, CF₃), 122.9, 124.8, 125.0, 126.31, 126.32, 127.1, 127.5, 128.1, 131.2, 134.1, 135.6 (q, ²J_C,F = 32.2 Hz, C-6′), 142.8, 143.4, 155.8, 158.1; IR (ATR): ν = 3415, 3346, 3285, 3058, 1637, 1547, 1510, 1471 cm⁻¹. C₂₁H₁₄ClF₃N₄O (430.81): calcd C 58.55, H 3.28, N 13.00; found C 59.04, H 3.36, N 13.19.

2-[5-(3-Aminonaphthalen-2-yl)amino-6-(trifluoromethyl)pyridazin-3-yl]-4-bromophenol (9d). Yield 75% (A), light-green crystals, mp 259–260 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.32 (s, 2H, NH₂), 6.82 (d, J = 8.7 Hz, 1H, 6-H), 7.12 (s, 1H, 4′-H), 7.15 (t, J = 7.3 Hz, 1H, 7′′-H), 7.17 (s, 1H, 4′′-H), 7.34 (t, J = 7.3 Hz, 1H, 6′′-H), 7.42 (dd, J = 8.7, 2.5 Hz, 1H, 5-H), 7.61 (d, J = 8.3 Hz, 1H, 5′′-H), 7.70 (s, 1H, 1′′-H), 7.71 (d, 1H, J = 8.3 Hz, 8′′-H), 7.89 (d, J = 2.5 Hz, 1H, 3-H), 8.64 (s, 1H, NH), 11.38 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.6 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 108.0, 108.8, 110.4, 119.3, 121.6, 122.3, 122.5 (q, ¹J_C,F = 274.4 Hz, CF₃), 124.5, 124.8, 124.9, 126.3, 127.1, 127.5, 131.0, 134.0, 134.1, 135.5 (q, ²J_C,F = 32.2 Hz, C-6′), 142.7, 143.5, 156.1, 157.9; IR (ATR): ν = 3379, 3327, 3248, 3056, 1639, 1579, 1513, 1475 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₄BrF₃N₄O [M + H]⁺ 475.0381, found 475.0396.

2-[5-(3-Aminonaphthalen-2-yl)amino-6-(trifluoromethyl)pyridazin-3-yl]-4-methoxyphenol (9e). Yield 53% (A), yellow crystals, mp 224–225 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.66 (s, 3H, MeO), 5.33 (s, 2H, NH₂), 6.80 (d, J = 8.9 Hz, 1H, 6-H), 6.91 (dd, J = 8.9, 3.1 Hz, 1H, 5-H), 7.11 (s, 1H, 4′-H), 7.13 (s, 1H, 4′′-H), 7.16 (t, J = 7.5 Hz, 1H, 7′′-H), 7.20 (d, J = 3.1 Hz, 1H, 3-H), 7.34 (ddd, J = 8.0, 7.3, 0.7 Hz, 1H, 6′′-H), 7.61 (d, J = 8.3 Hz, 1H, 5′′-H), 7.70 (d, 1H, J = 8.3 Hz, 8′′-H), 7.71 (s, 1H, 1′′-H), 8.62 (s, 1H, NH), 10.85 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.6 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.4, 108.1, 108.2, 113.1, 117.8, 118.0, 119.8, 122.5 (q, ¹J_C,F = 273.8 Hz, CF₃), 121.7, 124.9, 125.0, 126.3, 126.4, 127.1, 127.5, 134.1, 135.4 (q, ²J_C,F = 32.4 Hz, C-6′), 142.7, 143.4, 151.0, 152.0, 159.3; IR (ATR): ν = 3413, 3408, 3379, 3321, 3278, 3252, 3135, 3059, 2996, 1640, 1582, 1550, 1510, 1479 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₇F₃N₄O₂ [M + H]⁺ 427.1382, found 427.1374.

N-[6-Phenyl-3-(trifluoromethyl)pyridazin-4-yl]naphthalene-2,3-diamine (9f). Yield 5% (A), 52% (B), beige crystals, mp 221–222 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.34 (br s, 2H, NH₂), 6.70 (s, 1H, 4′-H), 7.15 (s, 1H, 4′′-H), 7.16 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, 7′′-H), 7.35 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H, 6′′-H), 7.45–7.48 (m, 3H, Ph), 7.62 (d, J = 8.3 Hz, 1H, 5′′-H), 7.70 (d, J = 8.2 Hz, 1H, 8′′-H), 7.72 (s, 1H, 1′′-H), 7.79 (m, 2H, Ph), 8.64 (br s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.9 (s, CF₃); ¹³C (126 MHz, DMSO-d₆): δ = 106.4, 108.1, 121.7, 122.7 (q, ¹J_C,F = 274.1 Hz, CF₃), 124.8, 125.0, 126.3, 126.4, 126.9, 127.1, 127.5, 129.0, 130.2, 134.1, 135.8, 136.1 (q, ²J_C,F = 32.1 Hz, C-3), 142.8, 143.4, 159.6; IR (ATR): ν = 3378, 3286, 3054, 1631, 1608, 1581, 1551, 1497, 1475 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₅F₃N₄ [M + H]⁺ 381.1327, found 381.1320. C₂₁H₁₅F₃N₄ (380.37): calcd C 66.31, H 3.97, N 14.73; found C 65.84, H 3.89, N 14.65.

N-[6-(4-Methylphenyl)-3-(trifluoromethyl)pyridazin-4-yl]naphthalene-2,3-diamine (9g). Yield 15% (A), 55% (B), beige crystals, mp 207–208 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.31 (s, 3H, Me), 5.34 (s, 2H, NH₂), 6.67 (s, 1H, 4′-H), 7.14 (s, 1H, 4′′-H), 7.16 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H, 7′′-H), 7.35 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H, 6′′-H), 7.27 (d, J = 8.2 Hz, 2H, 3-H, 5-H), 7.62 (d, J = 8.3 Hz, 1H, 5′′-H), 7.68–7.72 (m, 1H, 8′′-H), 7.71 (s, 1H, 1′′-H), 7.69 (d, J = 8.2 Hz, 2H, 2-H, 6-H), 8.60 (s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.9 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.8, 105.9, 108.1, 121.6, 124.8, 124.9, 124.9 (q, ¹J_C,F = 274.0 Hz, CF₃), 126.2, 126.4, 126.7, 127.0, 127.4, 129.5, 132.9, 134.0, 135.9 (q, ²J_C,F = 32.1 Hz, C-6′), 139.9, 142.7, 143.3, 159.4; IR (ATR): ν = 3484, 3381, 3340, 3323, 3228, 3207, 3130, 3093, 3022, 2914, 1635, 1613, 1582, 1538, 1505, 1474 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₇F₃N₄ [M + H]⁺ 395.1484, found 395.1477.

N-[6-(4-Chlorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]naphthalene-2,3-diamine (9h). Yield 12% (A), 50% (B), beige crystals, mp 230–231 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 5.35 (s, 2H, NH₂), 6.71 (s, 1H, 4′-H), 7.14 (s, 1H, 4′′-H), 7.16 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H, 7′′-H), 7.35 (ddd, J = 8.3, 7.1, 1.0 Hz, 1H, 6′′-H), 7.53 (d, J = 8.6 Hz, 2H, 3-H, 5-H), 7.62 (d, J = 8.3 Hz, 1H, 5′′-H), 7.70 (d, J = 8.2 Hz, 1H, 8′′-H), 7.71 (s, 1H, 1′′-H), 7.83 (d, J = 8.7 Hz, 2H, 2-H, 6-H), 8.69 (s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.8 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 106.3, 108.2, 121.7, 122.7 (q, ¹J_C,F = 273.8 Hz, CF₃), 124.7, 125.0, 126.3, 126.4, 127.1, 127.5, 128.6, 129.1, 134.1, 134.5, 135.1, 136.2 (q, ²J_C,F = 32.2 Hz, C-6′), 142.8, 143.3, 158.4; IR (ATR): ν = 3382, 3349, 3310, 3231, 3191, 3052, 1633, 1613, 1579, 1542, 1510, 1495, 1473 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₄ClF₃N₄ [M + H]⁺ 415.0937, found 415.0931. C₂₁H₁₄ClF₃N₄·0.33H₂O (420.82): calcd C 59.94, H 3.51, N 13.31; found C 59.69, H 3.25, N 13.29.

N-[6-(4-Methoxyphenyl)-3-(trifluoromethyl)pyridazin-4-yl]naphthalene-2,3-diamine (9i). Yield 27% (A), 57% (B), light-brown crystals, mp 220–221 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.76 (s, 3H, Me), 5.33 (s, 2H, NH₂), 6.64 (s, 1H, 4′-H), 7.01 (d, J = 8.9 Hz, 2H, 3-H, 5-H), 7.15 (s, 1H, 4′′-H), 7.16 (t, J = 7.1 Hz, 1H, 7′′-H), 7.35 (ddd, J = 8.1, 7.1, 0.9 Hz, 1H, 6′′-H), 7.62 (d, J = 8.3 Hz, 1H, 5′′-H), 7.68–7.72 (m, 1H, 8′′-H), 7.71 (s, 1H, 1′′-H), 7.76 (d, J = 8.8 Hz, 2H, 2-H, 6-H), 8.56 (s, 1H, NH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 99.0 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.2, 105.4, 108.1, 114.5, 121.7, 122.8 (q, ¹J_C,F = 274.3 Hz, CF₃), 124.9, 125.0, 126.3, 126.4, 127.0, 127.5, 127.9, 128.3, 134.0, 135.7 (q, ²J_C,F = 31.7 Hz, C-6′), 142.7, 143.4, 159.1, 161.0; IR (ATR): ν = 3393, 3347, 3309, 3223, 3062, 3031, 2994, 2929, 2908, 2833, 1635, 1580, 1541, 1514, 1477 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₇F₃N₄O [M + H]⁺ 411.1433, found 411.1416.

(E)-2-(4-Hydrazono-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)phenol (10a). Yield 4% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.78–6.82 (m, 2H, 4′-H, 6′-H), 7.14–7.18 (m, 2H, 3′-H, 5′-H), 7.35 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H, 7-H), 7.44 (d, J = 8.4 Hz, 1H, 9-H), 7.51 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H, 8-H), 7.76 (d, J = 8.1 Hz, 1H, 6-H), 9.25 (s, 1H, OH), 9.66 (d, J = 15.3 Hz, 1H, NH^b), 11.47 (s, 1H, 1-NH), 11.98 (d, J = 15.3 Hz, 1H, NH^a); ¹³C NMR (126 MHz, DMSO-d₆): δ = 115.5, 118.3, 123.8, 125.2, 125.3, 125.7, 127.6, 129.0, 129.9, 130.2, 136.7, 139.4, 141.6, 148.5, 149.1, 155.3; IR (ATR): ν = 3345, 3316, 3281, 3227, 3126, 3090, 2901, 1651, 1618, 1574, 1542, 1523, 1484, 1459 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₂N₆O [M + H]⁺ 305.1151, found 305.1157. C₁₆H₁₂N₆O·0.67H₂O (316.32): calcd C 60.75, H 4.25, N 26.57; found C 61.18, H 3.80, N 26.15.

(E)-2-(4-Hydrazono-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)-4-methylphenol (10b).

Yield 4% (A), red crystals, mp > 300 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 2.21 (s, 3H, Me), 6.70 (d, J = 8.8 Hz, 1H, 6′-H), 6.95–6.98 (m, 2H, 3′-H, 5′-H), 7.35 (ddd, J = 8.2, 6.9, 1.0 Hz, 1H, 7-H), 7.44 (dd, J = 8.1, 1.0 Hz, 1H, 9-H), 7.52 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H, 8-H), 7.76 (dd, J = 8.1, 1.0 Hz, 1H, 6-H), 8.99 (s, 1H, OH), 9.65 (d, J = 15.3 Hz, 1H, NH^b), 11.46 (s, 1H, 1-NH), 11.98 (d, J = 15.3 Hz, 1H, NH^a); ¹³C (126 MHz, DMSO-d₆): δ = 20.0 (Me), 115.4 (C-6′), 123.5 (C-2′), 125.2 (C-9), 125.3 (C-7), 125.8 (C-4), 126.7 (C-4′), 127.7 (C-6), 129.4 (C-5′/C-3′), 130.0 (C-8), 130.5 (C-3′/C-5′), 136.7 (C-5a), 139.5 (C-4a), 141.6 (C-9a), 148.5 (C-10a), 149.2 (C-3), 153.0 (C-1′); ¹⁵N NMR (50.7 MHz, DMSO-d₆): δ = 150.7 (N-2′′), 154.4 (N-1), 247.2 (N-10), 294.8 (N-5), 297.0 (N-2), 362.1 (N-1′′); IR (ATR): ν = 3350, 3217, 3093, 2893, 2855, 1726, 1590, 1543, 1517, 1475 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₄N₆O [M + H]⁺ 319.1307, found 319.1297. C₁₇H₁₄N₆O·H₂O (336.36): calcd C 60.71, H 4.79, N 24.99; found C 60.90, H 3.95, N 24.34.

(E)-2-(4-Hydrazono-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)-4-chlorophenol (10c). Yield 2% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.84 (d, J = 8.5 Hz, 1H, 6′-H), 7.18–7.24 (m, 2H, 3′-H, 5′-H), 7.38 (t, J = 7.4 Hz, 1H, 7-H), 7.46 (d, J = 7.9 Hz, 1H, 9-H), 7.53 (t, J = 7.4 Hz, 1H, 8-H), 7.78 (d, J = 7.9 Hz, 1H, 6-H), 9.60 (s, 1H, OH), 9.69 (d, J = 15.4 Hz, 1H, NH^b), 11.54 (s, 1H, 1-NH), 11.95 (d, J = 15.4 Hz, 1H, NH^a); ¹³C NMR (126 MHz, DMSO-d₆): δ = 117.2, 121.8, 125.3, 125.4, 125.5, 125.6, 127.7, 128.6, 129.6, 130.0, 136.7, 139.4, 141.5, 147.7, 148.4, 154.4; HRMS (ESI) calcd for C₁₆H₁₁ClN₆O [M + H]⁺ 339.0761, found 339.0749.

(E)-2-(4-Hydrazono-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)-4-bromophenol (10d). Yield 2% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.79 (d, J = 8.6 Hz, 1H, 6′-H), 7.30 (d, J = 2.5 Hz, 1H, 3′-H), 7.33 (d, J = 8.6, 2.5 Hz, 1H, 3′-H), 7.37 (t, J = 7.6 Hz, 1H, 7-H), 7.45 (d, J = 7.6 Hz, 1H, 9-H), 7.52 (t, J = 7.6 Hz, 1H, 8-H), 7.78 (d, J = 7.8 Hz, 1H, 6-H), 9.62 (s, 1H, OH), 9.68 (d, J = 15.4 Hz, 1H, NH^b), 11.53 (s, 1H, 1-NH), 11.94 (d, J = 15.4 Hz, 1H, NH^a); HRMS (ESI) calcd for C₁₆H₁₁BrN₆O [M + H]⁺ 383.0256, found 383.0261.

(E)-2-(4-Hydrazono-1,4-dihydropyridazino[3,4-b]quinoxalin-3-yl)-4-methoxyphenol (10e). Yield 4% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.72 (d, J = 8.3 Hz, 1H, 6′-H), 6.90–6.98 (m, 2H, 3′-H, 5′-H), 7.36 (t, J = 7.6 Hz, 1H, 7-H), 7.45 (d, J = 8.0 Hz, 1H, 9-H), 7.52 (t, J = 7.4 Hz, 1H, 8-H), 7.76 (d, J = 8.0 Hz, 1H, 6-H), 8.80 (s, 1H, OH), 9.67 (d, J = 15.3 Hz, 1H, NH^b), 11.48 (s, 1H, 1-NH), 11.98 (d, J = 15.3 Hz, 1H, NH^a); HRMS (ESI) calcd for C₁₇H₁₄N₆O₂ [M + H]⁺ 335.1256, found 335.1263.

(E)-3-(4-Methylphenyl)-4-hydrazono-1,4-dihydropyridazino[3,4-b]quinoxaline (10l). Yield 9% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.33 (s, 3H, Me), 7.18 (d, J = 7.9 Hz, 2H, Ar), 7.36 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H, 7-H), 7.44 (d, J = 8.4 Hz, 1H, 9-H), 7.48 (d, J = 8.0 Hz, 2H, Ar), 7.52 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H, 8-H), 7.78 (d, J = 8.7 Hz, 1H, 6-H), 9.69 (d, J = 15.4 Hz, 1H, NH^b), 11.55 (s, 1H, 1-NH), 12.14 (d, J = 15.4 Hz, 1H, NH^a); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.8, 124.8, 125.2, 125.3, 127.7, 128.0, 128.6, 130.1, 133.1, 136.6, 137.5, 139.5, 141.6, 148.2, 149.0; HRMS (ESI) calcd for C₁₇H₁₄N₆ [M + H]⁺ 303.1358, found 303.1373.

(E)-3-(4-Chlorophenyl)-4-hydrazono-1,4-dihydropyridazino[3,4-b]quinoxaline (10m). Yield 8% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 7.38 (t, J = 7.4 Hz, 1H, 7-H), 7.42–7.48 (m, 1H, 9-H), 7.45 (d, J = 8.4 Hz, 2H, Ar), 7.53 (t, J = 7.6 Hz, 1H, 8-H), 7.63 (d, J = 8.4 Hz, 2H, Ar), 7.79 (d, J = 8.2 Hz, 1H, 6-H), 9.73 (d, J = 15.3 Hz, 1H, NH^b), 11.65 (s, 1H, 1-NH), 12.12 (d, J = 15.3 Hz, 1H, NH^a); IR (ATR): 3343, 3222, 3190, 3162, 3094, 2996, 2905, 2882, 1623, 1593, 1543, 1522, 1486 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₁ClN₆ [M + H]⁺ 323.0812, found 323.0821.

(E)-3-(4-Methoxyphenyl)-4-hydrazono-1,4-dihydropyridazino[3,4-b]quinoxaline (10n). Yield 12% (A), red crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.79 (s, 3H, MeO), 6.93 (d, J = 8.8 Hz, 2H, Ar), 7.36 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H, 7-H), 7.43 (dd, J = 8.1, 0.6 Hz, 1H, 9-H), 7.52 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H, 8-H), 7.56 (d, J = 8.8 Hz, 2H, Ar), 7.78 (dd, J = 8.2, 0.8 Hz, 1H, 6-H), 9.70 (d, J = 15.3 Hz, 1H, NH^b), 11.54 (s, 1H, 1-NH), 12.16 (d, J = 15.3 Hz, 1H, NH^a); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.1, 112.8, 124.8, 125.2, 125.3, 127.7, 128.3, 130.0, 130.1, 136.6, 139.5, 141.6, 148.2, 148.6, 159.3; HRMS (ESI) calcd for C₁₇H₁₄N₆O [M + H]⁺ 319.1307, found 319.1301.

2-(5,12-Dihydrobenzo[g]pyridazino[3,4-b]quinoxalin-3-yl)phenol (11a). Yield 11% (A), light green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.66 (s, 1H, 4-H), 6.69 (s, 1H, 6-H), 6.73 (s, 1H, 11-H), 6.85–6.91 (m, 2H, 4′-H, 6′-H), 7.08–7.14 (m, 2H, 8-H, 9-H), 7.25 (ddd, J = 8.0, 7.3, 1.0 Hz, 1H, 5′-H), 7.36–7.44 (m, 2H, 7-H, 10-H), 7.54 (d, J = 7.9 Hz, 1H, 3′-H), 9.65 (s, 1H, 5-NH), 9.89 (s, 1H, 12-NH), 14.21 (s, 1H, OH); ¹³C NMR (126 MHz, DMSO-d₆): δ = 99.1, 107.9, 108.1, 117.1, 117.5, 118.5, 124.1, 124.5, 125.4, 125.7, 125.9, 129.8, 130.2, 130.4, 130.7, 131.5, 134.7, 148.1, 156.1, 158.9; IR (ATR): ν = 3392, 3187, 3150, 2886, 2851, 1640, 1584, 1545, 1516, 1464 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₄N₄O [M + H]⁺ 327.1246, found 327.1238.

2-(5,12-Dihydrobenzo[g]pyridazino[3,4-b]quinoxalin-3-yl)-4-methylphenol (11b). Yield 13% (A), light green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.27 (s, 3H, Me), 6.67 (s, 1H, 4-H), 6.69 (s, 1H, 6-H), 6.72 (s, 1H, 11-H), 6.77 (d, J = 8.3 Hz, 1H, 6′-H), 7.06 (dd, J = 8.3, 1.6 Hz, 1H, 5′-H), 7.08–7.13 (m, 2H, 8-H, 9-H), 7.32 (d, J = 1.6 Hz, 1H, 3′-H), 7.35–7.44 (m, 2H, 7-H, 10-H), 9.59 (s, 1H, 5-NH), 9.87 (s, 1H, 12-NH), 13.83 (s, 1H, OH); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.2, 99.2, 107.9, 108.0, 116.8, 117.3, 124.1, 124.4, 125.5, 125.7, 125.9, 126.8, 129.8, 130.2, 130.7, 131.1, 131.5, 134.6, 148.0, 156.1, 156.5; IR (ATR): ν = 3406, 3196, 3176, 3123, 3049, 2970, 2879, 2870, 1638, 1589, 1544, 1519, 1489, 1473 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₆N₄O [M + H]⁺ 341.1402, found 341.1403.

4-Chloro-2-(5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalin-3-yl)phenol (11c). Yield 8% (A), light green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.67 (s, 1H, 4-H), 6.72 (s, 1H, 6-H), 6.73 (s, 1H, 11-H), 6.90 (d, J = 8.7 Hz, 1H, 6′-H), 7.07–7.15 (m, 2H, 8-H, 9-H), 7.28 (d, J = 8.7 Hz, 1H, 5′-H), 7.35–7.45 (m, 2H, 7-H, 10-H), 7.56 (d, J = 0.9 Hz, 1H, 3′-H), 9.61 (s, 1H, 5-NH), 9.95 (br s, 1H, 12-NH), 14.27 (br s, 1H, OH); IR (ATR): ν = 3390, 3345, 3325, 3276, 3255, 3219, 3191, 2954, 2902, 2883, 1641, 1594, 1580, 1548, 1519, 1477 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₃ClN₄O [M + H]⁺ 361.0856, found 361.0849.

4-Bromo-2-(5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalin-3-yl)phenol (11d). Yield 5% (A), light green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.67 (s, 1H, 4-H), 6.71 (s, 1H, 6-H), 6.73 (s, 1H, 11-H), 6.85 (d, J = 8.6 Hz, 1H, 6′-H), 7.08–7.15 (m, 2H, 8-H, 9-H), 7.34–7.46 (m, 3H, 7-H, 10-H, 5′-H), 7.67 (s, 1H, 3′-H), 9.57 (s, 1H, 5-NH), 9.94 (br s, 1H, 12-NH), 14.30 (br s, 1H, OH); HRMS (ESI) calcd for C₂₀H₁₃BrN₄O [M + H]⁺ 405.0351, found 405.0361.

4-Methoxy-2-(5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxalin-3-yl)phenol (11e). Yield 17% (A), dark green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.75 (s, 3H, MeO), 6.65 (s, 1H, 4-H), 6.68 (s, 1H, 6-H), 6.72 (s, 1H, 11-H), 6.81 (d, J = 8.8 Hz, 1H, 6′-H), 6.88 (dd, J = 8.9, 2.9 Hz, 1H, 5′-H), 7.03 (d, J = 2.9 Hz, 1H, 3′-H), 7.08–7.13 (m, 2H, 8-H, 9-H), 7.36–7.43 (m, 1H, 7-H, 10-H), 9.60 (s, 1H, 5-NH), 9.88 (br s, 1H, 12-NH), 13.47 (br s, 1H, OH); HRMS (ESI) calcd for C₂₁H₁₆N₄O₂ [M + H]⁺ 357.1352, found 357.1362.

3-Phenyl-5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline (11f).

Yield 41% (A), dark yellow crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.48 (s, 1H, 4-H), 6.61 (s, 1H, 6-H), 6.68 (s, 1H, 11-H), 7.05–7.10 (m, 2H, 8-H, 9-H), 7.32–7.42 (m, 3H, H_p, 7-H, 10-H), 7.45 (m, 2H, H_m), 7.81 (dd, J = 8.4, 1.2 Hz, 2H, H_o), 9.36 (s, 1H, 5-NH), 9.72 (br s, 1H, 12-NH); ¹³C NMR (126 MHz, DMSO-d₆): δ = 101.1 (br s, 4-C), 107.4 (6-C), 107.6 (br s, 11-C), 123.9 (8-C), 124.2 (9-C), 125.4 (C_o), 125.6 (10-C), 125.8 (7-C), 128.6 (C_m), 128.6 (C_p), 130.3 (6a-C), 130.5 (5a-C), 130.7 (10a-C), 132.3 (br s, 11a-C), 133.3 (br s, 4a-C), 137.0 (C_i), 149.5 (12a-C), 154.0 (br s, 3-C); IR (ATR): ν = 3369, 2727, 1633, 1595, 1548, 1516, 1487, 1472 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₄N₄ [M + H]⁺ 311.1297, found 311.1309. C₂₀H₁₄N₄·0.67H₂O (322.37): C 74.05, H 5.39, N 17.27; found C 74.23, H 4.67, N 17.20.

3-(4-Methylphenyl)-5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline (11g). Yield 41% (A), green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.34 (s, 3H, Me), 6.45 (s, 1H, 4-H), 6.60 (s, 1H, 6-H), 6.67 (s, 1H, 11-H), 7.04–7.10 (m, 2H, 8-H, 9-H), 7.26 (d, 2H, J = 8.0 Hz, H_m), 7.31–7.40 (m, 2H, 7-H, 10-H), 7.70 (d, 2H, J = 8.1 Hz, H_o), 9.31 (s, 1H, 5-NH), 9.67 (br s, 1H, 12-NH); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.7, 100.9, 107.3, 107.4, 123.8, 124.2, 125.3, 125.5, 125.7, 129.1, 130.2, 130.5, 130.7, 132.3, 133.2, 134.2, 138.0, 148.3, 153.9; IR (ATR): ν = 3374, 3238, 3220, 2744, 1633, 1595, 1548, 1504, 1486 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₆N₄ [M + H]⁺ 325.1453, found 325.1441.

3-(4-Chlorophenyl)-5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline (11h). Yield 44% (A), dark yellow crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 6.47 (s, 1H, 4-H), 6.61 (s, 1H, 6-H), 6.67 (s, 1H, 11-H), 7.05–7.10 (m, 2H, 8-H, 9-H), 7.31–7.40 (m, 2H, 7-H, 10-H), 7.50 (d, 2H, J = 8.6 Hz, H_m), 7.83 (d, 2H, J = 8.6 Hz, H_o), 9.37 (s, 1H, 5-NH), 9.7 (br s, 1H, 12-NH); IR (ATR): ν = 3367, 2751, 2720, 1632, 1593, 1549, 1516, 1486, 1472 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₃ClN₄ [M + H]⁺ 345.0907, found 345.0887. C₂₀H₁₃ClN₄·0.33H₂O (350.81): C 68.48, H 3.93, N 15.97; found C 68.49, H 3.93, N 15.94.

3-(4-Methoxyphenyl)-5,12-dihydrobenzo[g]pyridazino[3,4-b]quinoxaline (11i). Yield 36% (A), dark green crystals, mp > 300 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.80 (s, 3H, MeO), 6.43 (s, 1H, 4-H), 6.60 (s, 1H, 6-H), 6.67 (s, 1H, 11-H), 7.01 (d, 2H, J = 8.9 Hz, H_m), 7.04–7.10 (m, 2H, 8-H, 9-H), 7.31–7.39 (m, 2H, 7-H, 10-H), 7.75 (d, 2H, J = 8.8 Hz, H_o), 9.31 (s, 1H, 5-NH), 9.64 (br s, 1H, 12-NH); ¹³C NMR (126 MHz, DMSO-d₆): δ = 55.1, 100.6, 107.3, 107.4, 113.9, 123.8, 124.2, 125.5, 125.7, 126.7, 129.4, 130.2, 130.5, 130.7, 132.4, 133.2, 148.1, 153.7, 159.8; IR (ATR): ν = 3382, 3218, 3125, 2819, 1635, 1594, 1548, 1503, 1475 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₆N₄O [M + H]⁺ 341.1402, found 341.1412.

General procedure for the synthesis of hydrazones 14a,b

A solution of the appropriate quinoxaline 1 (0.5 mmol) and phenylhydrazine (270 mg, 2.5 mmol) in n-butanol (10 mL) was heated at reflux for 2.5 h and allowed to stand at room temperature overnight. The solid that formed was filtered and recrystallized from n-butanol.

(E)-2-(1-(2-Phenylhydrazono)-2-(3-(trifluoromethyl)quinoxalin-2-yl)ethyl)phenol (14a). Yield 90%, yellow crystals, mp 203–204 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 4.79 (s, 2H, 2′′-H), 6.74 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H, 4′-H), 6.85 (tt, J = 7.3, 1.1 Hz, 1H, H_p), 6.89 (dd, J = 8.2, 1.1 Hz, 1H, 6′-H), 7.04 (dd, J = 8.5, 1.1 Hz, 2H, H_o), 7.15 (ddd, J = 8.2, 7.1, 1.6 Hz, 1H, 5′-H), 7.25 (dd, J = 8.1, 1.6 Hz, 1H, 3′-H), 7.29 (dd, J = 8.5, 7.3 Hz, 2H, H_m), 7.92–7.98 (m, 3H, 6-H, 7-H, 8-H), 8.26 (m, 1H, 5-H), 9.70 (s, 1H, NH), 12.41 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.3 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 32.5 (q, ⁴J_C,F = 2.6 Hz, C-2′′), 112.6, 116.5, 118.9, 119.9, 120.8, 121.6 (q, ¹J_C,F = 275.9 Hz, CF₃), 127.3, 128.6, 129.2, 129.29, 129.31, 131.3, 133.1, 138.1, 140.5 (q, ²J_C,F = 34.0 Hz, C-3), 141.9, 144.7, 144.8, 149.5, 156.9; IR (ATR): ν = 3299, 3052, 2962, 1943, 1905, 1599, 1557, 1531, 1493, 1451 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₇F₃N₄O [M + H]⁺ 423.1433, found 423.1443. C₂₃H₁₇F₃N₄O·0.25H₂O (426.91): C 64.71, H 4.13, N 13.12; found C 64.76, H 4.02, N 12.93.

(E)-4-Methyl-2-(1-(2-phenylhydrazono)-2-(3-(trifluoromethyl)quinoxalin-2-yl)ethyl)phenol (14b).

Yield 89%, yellow crystals, mp 214–215 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.10 (s, 3H, Me), 4.77 (s, 2H, 2′′-H), 6.79 (d, J = 8.2 Hz, 1H, 6′-H), 6.85 (tt, J = 7.3, 1.1 Hz, 1H, H_p), 6.96 (dd, J = 8.2, 2.1 Hz, 1H, 5′-H), 7.04 (dd, J = 8.7, 1.1 Hz, 2H, H_o), 7.07 (d, J = 2.1 Hz, 1H, 3′-H), 7.28 (dd, J = 8.7, 7.3 Hz, 2H, H_m), 7.92–7.98 (m, 3H, 6-H, 7-H, 8-H), 8.26 (m, 1H, 5-H), 9.65 (s, 1H, NH), 12.16 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, [D₆]DMSO): δ = 98.3 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.2 (Me), 32.5 (q, ⁴J_C,F = 2.6 Hz, 2′′-C), 112.6 (C_o), 116.4 (6′-C), 119.9 (C_p), 120.5 (2′-C), 121.6 (q, ¹J_C,F = 275.8 Hz, CF₃), 127.2 (4′-C), 127.3 (3′-C), 128.6 (7-C), 129.29 (C_m), 129.31 (5-C), 129.8 (5′-C), 131.3 (8-C), 133.1 (6-C), 138.1 (4a-C), 140.5 (q, ²J_C,F = 34.1 Hz, 3-C), 142.0 (8a-C), 144.78 (1′′-C), 144.82 (C_i), 149.5 (2-C), 154.8 (1′-C); ¹⁵N NMR (50.7 MHz, DMSO-d₆): δ = 135 (NH), 303 (C=N), 318 (4-N), 330 (1-N); IR (ATR): ν = 3288, 3030, 2953, 2925, 2876, 2851, 1600, 1557, 1525, 1493, 1466 cm⁻¹; HRMS (ESI) calcd for C₂₄H₁₉F₃N₄O [M + H]⁺ 437.1589, found 437.1590. C₂₄H₁₉F₃N₄O·0.25H₂O (440.94): C 65.37, H 4.46, N 12.71; found C 65.42, H 4.68, N 12.73.

General procedure for the synthesis of oximes 15a,b

A solution of the appropriate quinoxaline 1 (0.5 mmol) and hydroxylamine hydrochloride (174 mg, 2.5 mmol) in n-butanol (10 mL) was heated at reflux for 6.5 h. After that, the mixture was concentrated under reduced pressure and the residue was washed with water and recrystallized from ethanol.

2-{(E)-N-Hydroxy-2-[3-(trifluoromethyl)quinoxalin-2-yl]ethanimidoyl}phenol (15a). Yield 83%, colourless crystals, mp 216–217 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 4.68 (s, 2H, 2′′-H), 6.82 (ddd, J = 7.8, 7.2, 1.3 Hz, 1H, 4′-H), 6.89 (dd, J = 8.3, 1.3 Hz, 1H, 6′-H), 7.22 (ddd, J = 8.3, 7.2, 1.5 Hz, 1H, 5′-H), 7.48 (dd, J = 7.8, 1.5 Hz, 1H, 3′-H), 7.92–7.96 (m, 3H, 6-H, 7-H, 8-H), 8.22 (m, 1H, 5-H), 11.11 (s, 1H, NOH), 11.60 (s, 1H, OH); ¹⁹F NMR (470.5 MHz, DMSO-d₆): δ = 98.1 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 31.0 (q, ⁴J_C,F = 3.1 Hz, C-2′′), 116.3, 119.0, 120.2, 121.6 (q, ¹J_C,F = 276.2 Hz, CF₃), 128.4, 128.9, 129.3, 130.0, 131.2, 133.1, 138.0, 140.2 (q, ²J_C,F = 34.2 Hz, C-3), 141.8, 150.3, 156.0, 156.6; IR (ATR): ν = 3415, 3391, 3342, 3321, 3297, 3181, 3054, 2932, 1614, 1578, 1556, 1487, 1468 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₂F₃N₃O₂ [M + H]⁺ 348.0960, found 348.0963. C₁₇H₁₂F₃N₃O₂ (347.30): C 58.79, H 3.48, N 12.10; found C 58.68, H 3.47, N 12.10.

2-{(E)-N-Hydroxy-2-[3-(trifluoromethyl)quinoxalin-2-yl]ethanimidoyl}-4-methylphenol (15b). Yield 88%, colourless crystals, mp 233–234 °C; ¹H NMR (500 MHz, DMSO-d₆): δ = 2.17 (s, 3H, Me), 4.66 (s, 2H, 2′′-H), 6.79 (d, J = 8.2 Hz, 1H, 6′-H), 7.03 (dd, J = 8.2, 2.0 Hz, 1H, 5′-H), 7.33 (d, J = 2.0 Hz, 1H, 3′-H), 7.92–7.98 (m, 3H, 6-H, 7-H, 8-H), 8.23 (m, 1H, 5-H), 10.93 (s, 1H, NOH), 11.56 (s, 1H, OH); ¹⁹F NMR (376 MHz, [D₆]DMSO): δ = 98.2 (s, CF₃); ¹³C NMR (126 MHz, DMSO-d₆): δ = 20.1, 31.1 (q, ⁴J_C,F = 2.9 Hz, C-2′′), 116.2, 119.7, 121.6 (q, ¹J_C,F = 275.9 Hz, CF₃), 127.4, 128.4, 128.9, 129.3, 130.6, 131.1, 133.1, 138.0, 140.2 (q, ²J_C,F = 34.1 Hz, C-3), 141.9, 150.5, 154.5, 156.1; IR (ATR): ν = 3317, 2927, 1625, 1586, 1556, 1491, 1466 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₄F₃N₃O₂ [M + H]⁺ 362.1116, found 362.1124. C₁₈H₁₄F₃N₃O₂ (361.32): C 59.83, H 3.91, N 11.63; found C 59.78, H 4.01, N 11.66.

Acknowledgements

This work was financially supported by the Act 211 Government of the Russian Federation, agreement No 02.A03.21.0006, and performed within the State Task from the Ministry of Education and Science of Russian Federation.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H, ¹⁹F, and ¹³C NMR spectra of compounds obtained. CCDC 1437995 and 1437996. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra27032d

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