Synthesis of Chromone-Related Pyrazole Compounds

Chromones, six-membered oxygen heterocycles, and pyrazoles, five-membered two-adjacent-nitrogen-containing heterocycles, represent two important classes of biologically active compounds. Certain derivatives of these scaffolds play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis. In this context, we will discuss the most relevant advances on the chemistry that involves both chromone and pyrazole rings. The methods reviewed include the synthesis of chromone-pyrazole dyads, synthesis of chromone-pyrazole-fused compounds, and chromones as starting materials in the synthesis of 3(5)-(2-hydroxyaryl)pyrazoles, among others. This review will cover the literature on the chromone and pyrazole dual chemistry and their outcomes in the 21st century.


Introduction
4H-Benzopyran-4-ones, 4H-chromen-4-ones or simply chromones 1 (Figure 1) are six-membered oxygen-containing heterocyclic compounds widespread in Nature. The structural diversity regarding type, number and position of substituents attached to the main core are especially important to the physical, chemical and biological properties of both natural and synthetic derivatives [1][2][3]. Moreover, the chromone moiety is nowadays an active pharmacophore used in varied therapeutic fields in drugs such as cromolyn, nedocromil, diosmin, flavoxate, among others [2,4]. Chromone and its reduced form chromanone (4H-chroman-4-one, 2, Figure 1) are also valuable intermediates in the synthesis of novel bioactive compounds and of new heterocyclic systems [1,5].
Pyrazoles (1H-pyrazoles, 3, Figure 1) are constituted by an aromatic five-membered ring with three carbons and two nitrogen atoms, located at the 1-and 2-positions and are one of the most studied groups of compounds among the azole family [6]. These studies have involved a huge variety of natural and synthetic analogues which have been applied, over the years, in areas such as technology, medicine and agriculture. In fact, drugs such as celecobix, rimonabant and sildenafil are currently used as therapeutic agents [6,7]. N-Unsubstituted pyrazoles may present three identical and non-separable tautomers, due to rapid interconversion in solution, and it is usually impossible to unequivocally assign the proton resonances of the pyrazole core in the proton-nuclear magnetic resonance ( 1 H-NMR) spectra of these compounds. Three partially reduced forms may also exist: 1-pyrazolines 4, 2-pyrazolines 5 and 3-pyrazolines 6 ( Figure 1) [6,7].
Inspired by this knowledge, research devoted to the synthesis and transformation of both chromone and pyrazole units remain an interesting and challenging topic for organic chemists. In this context, the present review will present and discuss the most relevant developments in the chemistry that involves these two classes of heterocyclic compounds from the year 2000 till the present. The transformations reviewed include: (i) synthesis of chromone-pyrazole dyads using a pyrazole moiety as substituent (via cyclodehydration and oxidative cyclization reactions) and involving pyrazole
The synthesis of 3-benzylidenoflavanones 37 via condensation of flavanone 35 (2-phenylchromanone) with aromatic aldehydes 36, in the presence of a catalytic amount of piperidine and their further reaction with diazomethane led to the formation of a pyrazoline ring condensed at carbon C-3 of the pyrone ring (Scheme 9) [32]. These spiropyrazolines 38 were the only product confirmed by high performance liquid chromatography (HPLC) obtained in good yields from the reaction of 37 with diazomethane [32]. The cytotoxic effect of the nine spiropyrazolines 38 was determined on two human leukaemia cell lines (HL-60 and NALM-6) and melanoma (WM-115) cells, as well as on normal human umbilical vein endothelial cells (HUVEC). The highest cytotoxicity was observed for the para-methoxy-derivative, with an half maximal inhibitory concentration (IC 50 ) < 10 mM for all three cancer cell lines, with five to twelve-fold lower sensitivity against normal cells (HUVEC) [32].
The synthesis of 3-benzylidenoflavanones 37 via condensation of flavanone 35 (2-phenylchromanone) with aromatic aldehydes 36, in the presence of a catalytic amount of piperidine and their further reaction with diazomethane led to the formation of a pyrazoline ring condensed at carbon C-3 of the pyrone ring (Scheme 9) [32]. These spiropyrazolines 38 were the only product confirmed by high performance liquid chromatography (HPLC) obtained in good yields from the reaction of 37 with diazomethane [32]. The cytotoxic effect of the nine spiropyrazolines 38 was determined on two human leukaemia cell lines (HL-60 and NALM-6) and melanoma (WM-115) cells, as well as on normal human umbilical vein endothelial cells (HUVEC). The highest cytotoxicity was observed for the para-methoxy-derivative, with an half maximal inhibitory concentration (IC50) < 10 mM for all three cancer cell lines, with five to twelve-fold lower sensitivity against normal cells (HUVEC) [32].
Both methods gave the expected 3-(1,3-disubstituted-2-pyrazolin-5-yl)chromones 50 from reaction with hydrazine hydrate, hydrazinobenzothiazole and phenylhydrazine with similar results (yields were not presented in the original manuscript). However, the reaction of 49a with phenylhydrazine did not afford the expected 2-pyrazoline; instead a pyrazole-2-pyrazoline 50f was obtained due to the reaction of both α,β-unsaturated carbonyl systems, one of them involving also a pyrone ring opening (this mechanism will be discussed in Section 4) in conventional and thermal solvent-free conditions. The synthesized compounds 50, demonstrated moderate to good antimicrobial activity, which seemed to be dependent on the nature of the heterocyclic moieties. Moreover, although the tested compounds were more active against fungi than bacteria, none of them exceeded the activity of the commercial drugs ciprofloxacin and griseofulvin [37].  [35]. The evaluated compounds 46 were prepared in 45-61% yield from 3-(3-aryl-3-oxoprop-1-en-1-yl)-7-hydroxychromones 41 with phenylhydrazine hydrochloride in DMF [36].
Gill and coworkers reported the reaction of substituted 3-formylchromones with 3-methyl-1phenyl-1H-thieno[2,3-c]pyrazole-5-carbohydrazide using acetic acid as catalyst in methanol which gave the corresponding hydrazides in good yield (78-81%) [49]. Two of the four synthesized compounds showed promising antioxidant and anti-inflammatory activities [49]. were screened for their antifungal activity. Thus, compound 64 showed moderate activities against Alternaria alternata and Aspergillus flavipes and lower activity against Aspergillus niger while compound 62 showed moderate activities against these three fungi species [48].

Tandem Reactions of 3-Formylchromones with Pyrazole Derivatives
Structurally diverse chromone-fused pyrazoles can be prepared by tandem reactions of 3-formylchromones with several pyrazole [51] and pyrazolone derivatives [52], including the cycloaddition reaction of 3-formylchromones with pyrazole-o-quinodimethane derivatives [53]. The treatment of 3-formylchromone 69 with 5-amino-3-methyl-1H-pyrazole 70 in refluxing Suresh and coworkers reported a straightforward synthesis of chromone-fused pyrazoles 74 by a tandem O-arylation-oxidative coupling reaction between 2-pyrazolin-5-ones 72 and o-halo-arylaldehydes 73 under aerobic conditions [52]. The reaction was performed using a combination of CuI as catalyst, 1,10-phenantroline as a ligand and K 2 CO 3 as a base, in DMSO, which proved to be the best combination after a detailed screening of the reaction conditions (Scheme 21). For some derivatives the reaction was scaled-up to a gram scale while maintaining a high yield. The study of the reaction scope showed that 2-bromobenzaldehydes gave better yields of the desired product (74%) when compared to 2-chlorobenzaldehyde (25%) or 2-iodobenzaldehyde (52%). Furthermore, electron-donating groups on 2-bromobenzaldehydes afforded chromone-fused pyrazole derivatives in good yields (51-65%) while electron-withdrawing groups like fluorine gave the product in moderate yield (45%). 2-Bromobenzaldehyde bearing both electron-donating and electron-withdrawing substituents afforded the corresponding product in good yield (64%). A tetracyclic chromone fused pyrazole was obtained in good yield (66%) using 1-bromo-2-naphthaldehyde. Concerning to the substituents of the pyrazolone reagent, different electron-donating and electron-withdrawing substituents were well tolerated furnishing the diversely substituted chromone-fused pyrazole frameworks in moderate to good yields (35-68%). However, the reaction of N-Boc-pyrazolone and 2-bromobenzaldehyde did not give the desired product. Likewise the reaction with heteroaromatic aldehydes such as 2-chloronicotinaldehyde was not well succeeded. The synthetic utility of this method was demonstrated with the synthesis of a representative A2-subtype selective adenosine receptor antagonist (Scheme 21) [52].

Tandem Reactions of 3-Formylchromones with Pyrazole Derivatives
Structurally diverse chromone-fused pyrazoles can be prepared by tandem reactions of 3-formylchromones with several pyrazole [51] and pyrazolone derivatives [52], including the cycloaddition reaction of 3-formylchromones with pyrazole-o-quinodimethane derivatives [53]. The treatment of 3-formylchromone 69 with 5-amino-3-methyl-1H-pyrazole 70 in refluxing  [52]. The reaction was performed using a combination of CuI as catalyst, 1,10-phenantroline as a ligand and K2CO3 as a base, in DMSO, which proved to be the best combination after a detailed screening of the reaction conditions (Scheme 21). For some derivatives the reaction was scaled-up to a gram scale while maintaining a high yield. The study of the reaction scope showed that 2-bromobenzaldehydes gave better yields of the desired product (74%) when compared to 2-chlorobenzaldehyde (25%) or 2-iodobenzaldehyde (52%). Furthermore, electron-donating groups on 2-bromobenzaldehydes afforded chromone-fused pyrazole derivatives in good yields (51-65%) while electron-withdrawing groups like fluorine gave the product in moderate yield (45%). 2-Bromobenzaldehyde bearing both electron-donating and electron-withdrawing substituents afforded the corresponding product in good yield (64%). A tetracyclic chromone fused pyrazole was obtained in good yield (66%) using 1-bromo-2-naphthaldehyde. Concerning to the substituents of the pyrazolone reagent, different electron-donating and electron-withdrawing substituents were well tolerated furnishing the diversely substituted chromone-fused pyrazole frameworks in moderate to good yields (35-68%). However, the reaction of N-Boc-pyrazolone and 2-bromobenzaldehyde did not give the desired New fused tetrahydrochromeno[3,2-f ]indazoles were prepared by incorporating the chromone moiety into the pyrazole nucleus by cycloaddition reaction of chromone 75 with pyrazole-o-quinodimethane 77, generated in situ through reaction of sodium iodide with the appropriate dibromo-derivative 76. The cycloaddition reaction gave only cycloadducts 78 and 79 along with a small amount of the oxidation product 80, which, however, was the main reaction product in the case of 3-formylchromone 75a (Scheme 23) [53]. The reaction is highly regioselective and mixtures of only two diastereomers 78b-78e and 79b-79e, were isolated in moderate yields (20-51%) with the benzoyl group being always on the same side as the pyran oxygen. Although small amounts (less than 2%) of the other possible regioisomers 81 were formed as observed in the 1 H-NMR spectra of the crude reaction mixture, they were not isolated. In most cases the crude reaction mixture also presented small amounts (2-5% yield) of the corresponding oxidation products 80. An exception was the reaction with 75a that afforded the oxidation product 80a as the main reaction product (35% yield) together with 79a (20% yield). The authors have postulated that compound 79a may be formed by the dehydrogenation of the trans-bridgehead hydrogens (4a-H and 10a-H). All formed products were prone to deformylation under the reaction conditions. It is also remarkable that opening of the pyran ring was never observed. Yet, upon purification of 78 on preparative thin-layer chromatography (TLC) cleavage of the pyran ring occurred affording the hydroxy derivatives 82 (Scheme 23) [53]. main reaction product (35% yield) together with 79a (20% yield). The authors have postulated that compound 79a may be formed by the dehydrogenation of the trans-bridgehead hydrogens (4a-H and 10a-H). All formed products were prone to deformylation under the reaction conditions. It is also remarkable that opening of the pyran ring was never observed. Yet, upon purification of 78 on preparative thin-layer chromatography (TLC) cleavage of the pyran ring occurred affording the hydroxy derivatives 82 (Scheme 23) [53].

Other Transformations
Liu and coworkers reported a concise and mild route for the synthesis of chromeno[2,3-c]pyrazol-4(1H)-ones 84, in 43-78% yield, by using classical ionic liquids which contained a heterocyclic structure as the promoter, water as a solvent and tert-butyl hydroperoxide (TBHP) (70% aqueous solution) as the oxidant without any additives or catalysts, which proceeded

Other Transformations
Liu and coworkers reported a concise and mild route for the synthesis of chromeno [2,3-c] pyrazol-4(1H)-ones 84, in 43-78% yield, by using classical ionic liquids which contained a heterocyclic structure as the promoter, water as a solvent and tert-butyl hydroperoxide (TBHP) (70% aqueous solution) as the oxidant without any additives or catalysts, which proceeded through the intramolecular dehydrogenative coupling of the aldehyde C-H bonds and aromatic C-H bonds in 5-aryloxy-4-formyl-1H-pyrazoles 83 (Scheme 24) [54]. The ionic liquid was easily recycled and reused with the same efficacies for five cycles and the reaction tolerates diverse functional groups. Substrates bearing either electron-withdrawing or electron-donating groups led to the annulation products in good yields. Aryloxy parts with electron-withdrawing groups are generally more reactive than those with electron-donating groups giving relatively higher yields. Substituents at the o-position of the aryloxy group had little influence on the yield but when the substituent was at the m-position, the products were obtained as isomers in some cases. Reaction with pyrazoles having 1,3-dimethyl or 1,3-diphenyl groups also proceeded in mild conditions affording the desired products. The reaction was also applicable to the synthesis of a thiochromone which was obtained in good yield (63%). When performed at a gram-scale under the standard conditions the reaction afforded the expected product in 70% isolated yield, while in the model reaction it was obtained in 73% isolated yield. This method constitutes a straightforward and metal-free approach to prepare chromeno[2,3-c]pyrazol-4(1H)-ones overcoming the limitations found in other methods that require harsh conditions, have limited substrate scope, poor substituent tolerance and give the product in low yield. substituent tolerance and give the product in low yield.
Later Singh and coworkers reported a metal/additive-free, TBHP-promoted synthesis of fused chromeno [2,3-c]pyrazol-4(1H)-ones 84 from 5-aryloxy-4-formyl-3-methyl-1-phenyl-1H-pyrazoles 83 also via cross-dehydrogenative coupling of aldehydic C-H bond with arene C-H bond in very good yields (79-85%) (Scheme 24). Similarly, the reaction was found to proceed by a free radical mechanism [55]. According to the mechanism proposed by Liu and coworkers (Scheme 25), the reaction proceeds via generation of t-butoxyl radicals, promoted by the ionic liquid, which abstracts the aldehyde hydrogen atom to form an acyl radical A that adds to the aryloxy unit producing radical B. This radical leads to the formation of intermediate C via single-electron-transfer process. Then, the previously formed hydroxyl anion acts as the proton abstractor from C, providing the annulated product 84a. The authors proposed another possible mechanism where the acidic proton in B is trapped by the hydroxyl anion to give the radical anion intermediate. Formal liberation of an electron from this intermediate eventually leads to the formation of the product 84a [54]. . Similarly, the reaction was found to proceed by a free radical mechanism [55].
According to the mechanism proposed by Liu and coworkers (Scheme 25), the reaction proceeds via generation of t-butoxyl radicals, promoted by the ionic liquid, which abstracts the aldehyde hydrogen atom to form an acyl radical A that adds to the aryloxy unit producing radical B. This radical leads to the formation of intermediate C via single-electron-transfer process. Then, the previously formed hydroxyl anion acts as the proton abstractor from C, providing the annulated product 84a. The authors proposed another possible mechanism where the acidic proton in B is trapped by the hydroxyl anion to give the radical anion intermediate. Formal liberation of an electron from this intermediate eventually leads to the formation of the product 84a [54]. Novel ABCD-fused chromenopyrazolopyridines 88 were synthesized by a multicomponent reaction of chromone-3-benzoylhydrazones 85 with acetylenedicarboxylates 86 and isocyanides 87 in dichloromethane (Scheme 26). The reaction was diastereoselective affording the tetracyclic benzopyrone derivatives 88, containing three stereogenic centres, in moderate to good yields (52-65%) [56]. These compounds 88 are related to the alkaloid (+/−)-elaeocarpine having the same three fused-ring core and one derivative was identified as a promising lead compound for the design of novel tetracyclic chromenopyrazolopyridines combining antilipid peroxidation and Scheme 25. Plausible reaction mechanism for the formation of chromeno[2,3-c]pyrazol-4(1H)-ones 84 [54].
Novel ABCD-fused chromenopyrazolopyridines 88 were synthesized by a multicomponent reaction of chromone-3-benzoylhydrazones 85 with acetylenedicarboxylates 86 and isocyanides 87 in dichloromethane (Scheme 26). The reaction was diastereoselective affording the tetracyclic benzopyrone derivatives 88, containing three stereogenic centres, in moderate to good yields (52-65%) [56]. These compounds 88 are related to the alkaloid (+/−)-elaeocarpine having the same three fused-ring core and one derivative was identified as a promising lead compound for the design of novel tetracyclic chromenopyrazolopyridines combining antilipid peroxidation and lipoxygenase inhibitory activities [56]. [56]. In the next step, V undergoes an electrocyclic ring opening, supported by the adjacent enolate anion, to relieve the extra stretch, bend, torsion and Van der Waals energy and giving the isolated tetracyclic benzopyrone 88 (Scheme 27) [56].
The reaction of 2-amino-3-carbamoylchromone 89 with hydrazines afforded 3-aminochromeno [4,3-c]pyrazol-4-ones 90 and 91 (Scheme 28). The reaction with hydrazine afforded compound 90 in 55% yield, which in DMSO-d 6 was found to exist as a mixture of two tautomers in the ratio 77:23, being 2H-tautomer the major one. The reaction with methylhydrazine afforded compound 91 in 35% yield and the structure of the obtained regioisomer was confirmed based on two-dimensional nuclear Overhauser spectroscopy (2D NOESY) experiment, which exhibited a clear cross-peak between the protons of the Me and NH 2 groups [57]. Compounds 90 and 91, which are coumarins having a heterocyclic moiety like pyrazole at positions 3 and 4 are key substrates for the preparation of various medicinal drugs [57].
The reaction of 2-amino-3-carbamoylchromone 89 with hydrazines afforded 3-aminochromeno[4,3-c]pyrazol-4-ones 90 and 91 (Scheme 28). The reaction with hydrazine afforded compound 90 in 55% yield, which in DMSO-d6 was found to exist as a mixture of two tautomers in the ratio 77:23, being 2H-tautomer the major one. The reaction with methylhydrazine afforded compound 91 in 35% yield and the structure of the obtained regioisomer was confirmed based on two-dimensional nuclear Overhauser spectroscopy (2D NOESY) experiment, which exhibited a clear cross-peak between the protons of the Me and NH2 groups [57]. Compounds 90 and 91, which are coumarins having a heterocyclic moiety like pyrazole at positions 3 and 4 are key substrates for the preparation of various medicinal drugs [57].
Regioselective condensation reactions of compounds containing a pyrone and an exocyclic enone reactive system, with hydrazine hydrate in different reaction conditions were disclosed. reaction involves pyrazole ring closure by an intramolecular hydrazone formation (Scheme 35B).
The presence of two carbonyl groups in the 3-aroyl-2-aryl-5-benzyloxychromone structures 118 allowed the formation of two different types of pyrazoles when the reaction occurred in the presence of hydrazine, generated in situ by addition of potassium carbonate to hydrazinium sulfate or from the commercially available hydrate, in methanol at 80 • C (Scheme 40) [91]. Better overall yields were obtained with hydrazine hydrate, being in all cases the 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles 119 isolated as major products along with 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles 120 as minor compounds. These results pointed that the carbonyl group of 3-aroyl group is more reactive than the chromone carbonyl group [91]. The excess of hydrazine hydrate used in the reaction of 8-formyl-7-hydroxy-2-methyl-3-phenoxychromone 116 in refluxing ethanol led to the isolation of a unique structure 117 (Scheme 39) containing a hydrazone moiety, formed from the reaction of hydrazine with the 8-formyl group, but also the pyrazole ring, resulted from the reaction of hydrazine and recyclization of the γ-pyrone ring of the starting chromone [90]. Scheme 39. Reaction of 8-formyl-7-hydroxy-2-methyl-3-phenoxychromone 116 with an excess of hydrazine hydrate [90].
The presence of two carbonyl groups in the 3-aroyl-2-aryl-5-benzyloxychromone structures 118 allowed the formation of two different types of pyrazoles when the reaction occurred in the presence of hydrazine, generated in situ by addition of potassium carbonate to hydrazinium sulfate or from the commercially available hydrate, in methanol at 80 °C (Scheme 40) [91]. Better overall yields were obtained with hydrazine hydrate, being in all cases the 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles 119 isolated as major products along with 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles 120 as minor compounds. These results pointed that the carbonyl group of 3-aroyl group is more reactive than the chromone carbonyl group [91]. unique structure 117 (Scheme 39) containing a hydrazone moiety, formed from the reaction of hydrazine with the 8-formyl group, but also the pyrazole ring, resulted from the reaction of hydrazine and recyclization of the γ-pyrone ring of the starting chromone [90]. Scheme 39. Reaction of 8-formyl-7-hydroxy-2-methyl-3-phenoxychromone 116 with an excess of hydrazine hydrate [90].
The presence of two carbonyl groups in the 3-aroyl-2-aryl-5-benzyloxychromone structures 118 allowed the formation of two different types of pyrazoles when the reaction occurred in the presence of hydrazine, generated in situ by addition of potassium carbonate to hydrazinium sulfate or from the commercially available hydrate, in methanol at 80 °C (Scheme 40) [91]. Better overall yields were obtained with hydrazine hydrate, being in all cases the 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles 119 isolated as major products along with 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles 120 as minor compounds. These results pointed that the carbonyl group of 3-aroyl group is more reactive than the chromone carbonyl group [91]. The two carbonyl groups of 3-(polyfluoroacyl)chromones 121 were also reactive with different sources of hydrazine in different reaction conditions [92]. Thus, using hydrazine dihydrochloride in the presence of anhydrous sodium acetate in methanol at room temperature yielded different products according to the nature of the substituents in the chromone ring. The two carbonyl groups of 3-(polyfluoroacyl)chromones 121 were also reactive with different sources of hydrazine in different reaction conditions [92]. Thus, using hydrazine dihydrochloride in the presence of anhydrous sodium acetate in methanol at room temperature yielded different products according to the nature of the substituents in the chromone ring. On the other hand, the reaction of the 3-(polyfluoroacyl)chromones 121 with an aqueous solution of hydrazine hydrate in methanol at −10 • C afforded the same derivatives in the case of chromones substituted with chloro and nitro groups while for the unsubstituted chromone and substituted with a methyl group, starting chromones underwent detrifluoroacetylation and deformylation to afford the corresponding 2 -hydroxyacetophenones [92]. A couple of 3-(2-hydroxyphenyl)-5-(1-methylpyrrol-3-yl)-2-pyrazolines 125 were obtained from the reaction of (E)-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chromanones 124 with 3 equiv of hydrazine hydrate in refluxing ethanol (Scheme 42). The mechanism proposed involves deformylation of the starting chromanones to the corresponding chalcones followed by heterocyclization reactions [86]. hydrate in refluxing ethanol (Scheme 42). The mechanism proposed involves deformylation of the starting chromanones to the corresponding chalcones followed by heterocyclization reactions [86].
Interestingly, in 2004 Budzisz and coworkers reported the isolation of similar products of those described before, from the reaction of phosphonic chromone 135 and its C-3 methoxycarbonyl analogue 136 with an equimolar amount of methylhydrazine at room temperature, under solvent-free conditions. In this case, 3-(2-hydroxyphenyl)pyrazoles 138 were not isolated from the reaction mixture being 5-(2-hydroxyphenyl)-3-methyl-4-phosphonyl pyrazoles 137 obtained as major compounds along with tricyclic compounds 139 and 140, as minor products. The formation of compounds 139 and 140 result from the intramolecular transesterification of the formed pyrazoles 137 and 138, respectively (Scheme 46) [95]. The addition of a second equiv of methylhydrazine to the reaction mixture improved the yield of the tricyclic compounds [96].
According to the results, the reaction starts by the attack of phenylhydrazine to the exocyclic enone to deliver (3-chromonyl)-2-pyrazoline-type compounds 153 as primary reaction intermediates. Then, the reaction in acidic medium proceeds by only one pathway, involving the attack of the more nucleophilic amino group to the chromone C-2 carbon with consequent pyran ring opening and subsequent intramolecular reaction between the other amino group (NHPh) and the carbonyl unit leading to final pyrazolyl-2-pyrazoline derivatives 152 (pathway A, Scheme 52) [100].

Miscellaneous
The reactivity of 3-formylchromone derivatives with a series of hydrazines has been studied in detail over the most recent years (for recent reviews see [103,104]

Miscellaneous
The reactivity of 3-formylchromone derivatives with a series of hydrazines has been studied in detail over the most recent years (for recent reviews see [103,104]). Thus, treating 3-formyl-6-hydroxychromone with an equimolar amount of hydrazine hydrate and phenylhydrazine in refluxing ethanol provided the corresponding 4-(2,5-dihydroxybenzoyl)pyrazoles [46]. Other 4-(2-hydroxyaroyl)pyrazoles were synthesized through the reaction of 3-formylchromone with arylhydrazines in an alcoholic potassium hydroxide solution, under microwave irradiation at 120 • C [105]. A similar one-pot protocol was achieved with the reaction of the parent 3-formylchromone with cyanoacetic acid hydrazide in the presence of sodium ethoxide in refluxing ethanol to afford 4-(2-hydroxybenzoyl)pyrazole [106]. Rindhe and coworkers used a two-step strategy involving the reaction of 3-formylchromones with 2,4-difluorohydrazine using a catalytic amount of acetic acid in ethanol at 40 • C to give the corresponding hydrazones, which after treatment with potassium hydroxide at 50 • C provided the respective 4-(2,5-dihydroxybenzoyl)pyrazoles [107]. From eight of these pyrazoles, one presented a broad spectrum of antibacterial activity against the four tested strains (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis). Moreover, only one of the eight tested compounds showed antifungal activity against Candida albicans [107].
The condensation of 6-substituted 3-formylchromones 156 with equimolar amounts of aromatic primary hydrazines in refluxing THF occurs through 1,2-addition reaction at the formyl group to afford the respective hydrazones 157 (Scheme 54). On the other hand, using prolonged heating, the reaction evolved to the formation of 1-aryl-4-(2-hydroxybenzoyl)pyrazoles 158 (Scheme 54), via 1,4-addition reaction with pyrone ring-opening and subsequent recyclization and proton transfer mechanism [108,109]. Both compounds 157 and 158 were screened for their cytotoxic effect against brine shrimps (Artemia salina), presenting IC 50 values of 83-262 µM, considerably higher than the positive control podophyllotoxin (IC 50 = 5.8 µM). Moreover, the presence of the aromatic fluorine enhances the overall activity when compared with the similar non-fluorinated compounds [108]. In another study, the same compounds 157 and 158 were tested for their antiparasitic activity against promastigotes of Leishmania mexicana (Bel 21) and epimastigotes of Trypanosoma cruzi (DM28). The IC 50 values found were 6-53 µM for L. mexicana and 4-174 µM for T. cruzi, higher than the positive control miltefosine (IC 50 values of 4.7 µM for L. mexicana and 2.3 µM for T. cruzi). The most promising compound against both strains was derivative 157 (R 1 = H, R 2 = 2,4-(NO 2 ) 2 ), non-substituted on the chromone unit and bearing a 2,4-dinitrophenyl moiety linked to the hydrazone [109].
On the other hand, the reaction of 3-formyl-6-methylchromone 175 with an equimolar amount of 3(5)-amino-5(3)-(4-methylphenyl)-1H-pyrazole in the presence of a catalytic amount of p-toluenesulfonic acid in refluxing ethanol provided the regioisomer 6-(2-hydroxy-5-methylbenzoyl)-2-(4-methylphenyl)pyrazolo [1,5-a]pyrimidine 176 in 69% yield (Scheme 60) [114]. These type of pyrazoles 176 were also obtained from the reaction of 3-formylchromones with equimolar amounts of 3(5)-amino-5(3)-substituted pyrazoles in ethanol at reflux [117] or under microwave irradiation [118] (Scheme 60). The mechanism proposed for the formation of regioisomers 178 and 179 involves the condensation between the amino group at the pyrazole unit and the aldehyde group at the chromone ring to give intermediates I (Scheme 61). Then, intermediate I can follow an intramolecular ring opening of the chromone ring though nucleophilic displacement by attack of the nucleophilic nitrogen at the pyrazole ring to compound 178. The alternative is by attack of the C-4 at the pyrazole instead of the nitrogen to give regioisomer 179 [117]. To note that Zimmerman and coworkers also studied the two-step one-pot tandem reaction of 3-formylchromones 175 with equimolar amounts of 3(5)-amino-5(3)-substituted pyrazoles, via microwave-assisted protocol, to give the corresponding pyrazolo-pyrimidines, which underwent intermolecular radical addition in the presence of alkyliodides and triethylborane providing the substituted pyrazolopyrimidines 177 (Scheme 60) [118]. On the other hand, the reaction of 3-formyl-6-methylchromone 175 with an equimolar amount of 3(5)-amino-5(3)-(4-methylphenyl)-1H-pyrazole in the presence of a catalytic amount of p-toluenesulfonic acid in refluxing ethanol provided the regioisomer 6-(2-hydroxy-5-methylbenzoyl)-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine 176 in 69% yield (Scheme 60) [114]. These type of pyrazoles 176 were also obtained from the reaction of 3-formylchromones with equimolar amounts of 3(5)-amino-5(3)-substituted pyrazoles in ethanol at reflux [117] or under microwave irradiation [118] (Scheme 60). The mechanism proposed for the formation of regioisomers 178 and 179 involves the condensation between the amino group at the pyrazole unit and the aldehyde group at the chromone ring to give intermediates I (Scheme 61). Then, intermediate I can follow an intramolecular ring opening of the chromone ring though nucleophilic displacement by attack of the nucleophilic nitrogen at the pyrazole ring to compound 178. The alternative is by attack of the C-4 at the pyrazole instead of the nitrogen to give regioisomer 179 [117]. To note that Zimmerman and coworkers also studied the two-step one-pot tandem reaction of 3-formylchromones 175 with equimolar amounts of 3(5)-amino-5(3)-substituted pyrazoles, via microwave-assisted protocol, to give the corresponding pyrazolo-pyrimidines, which underwent intermolecular radical addition in the presence of alkyliodides and triethylborane providing the substituted pyrazolopyrimidines 177 (Scheme 60) [118].  [114,117,118].

Conclusions
In this review we have presented several strategies that have been developed, since the beginning of the 21st century, towards the synthesis of chromone related pyrazoles, namely chromone-pyrazole dyads, chromone-pyrazole-fused compounds and 3(5)-(2-hydroxyaryl)-pyrazoles, among other pyrazole derivatives. Thus, several chromone-pyrazole dyads have been synthesized, by cyclization of 1,3-dicarbonyl compounds, such as 1,3-diketones, and oxidative cyclization of 2 -hydroxychalcone-type compounds both bearing a pyrazole moiety. Other methods to prepare these dyads include cycloaddition reactions and Knoevenagel-type condensations. Only a few examples of chromone-pyrazole-fused compounds were found. The most straightforward methods to synthesize these compounds include, tandem O-arylation-oxidative coupling reactions, cycloaddition reactions and multicomponent reactions. The limited number of examples found suggests that the synthesis of this type of compounds deserves greater attention from synthetic chemists. A huge number of 3(5)-(2-hydroxyaryl)pyrazoles have been synthesized through the reaction of several chromone derivatives with hydrazines in varied experimental conditions. Also a wide variety of 3-formylchromones were found to react with aminopyrazoles giving pyrazole-pyridines and pyrazole-pyrimidines containing a 2-hydroxyaroyl moiety in their structures. The transformations presented in this review led to a huge variety of compounds possessing both nitrogen and oxygen heterocycles. The comprehensive details of these transformations and several mechanistic considerations were also presented.