HETEROCYCLES

Review | Regular issue | Vol. 89, No. 7, 2014, pp. 1557-1584
Received, 9th February, 2014, Accepted, 14th April, 2014, Published online, 21st April, 2014.
DOI: 10.3987/REV-14-793

■ The Reactivity of 8-Hydroxyquinoline and Its Derivatives Toward α-Cyanocinnamonitriles and Ethyl α-Cyanocinnamates: Synthesis, Reactions, and Applications of 4H-Pyrano[3,2-h]quinoline Derivatives

Ahmed M. El-Agrody* and Tarek H. Afifi

Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11884, Egypt

Abstract

The main purpose of this review is to present a literature survey on the reactivity of 8-hydroxyquinoline and its derivatives toward α-cyanocinnamonitrile or ethyl α-cyanocinnamate derivatives, which leads to the formation of a variety of 4H-pyrano[3,2-h]quinoline derivatives. The reactions of the synthesized β-enaminonitriles and β-enaminoesters with different electrophilic followed by nucleophilic reagents were also explored. Some of these reactions provided successful routes to produce biologically important privileged structures.

CONTENTS
1. Introduction
2. Synthesis of 2-amino-4H-pyrano[3,2-h]quinoline derivatives
2-1. From 8-hydroxyquinoline and 8-hydroxy-2-substitutedquinoline
2-2. From 5-chloro-8-hydroxyquinoline
2-3. From 8-hydroxyquinoline-5-sulfonamide
2-4. From (E)-2-(4-halostyryl)-8-hydroxyquinoline
3. Reactions of 2-amino-4H-pyrano[3,2-h]quinoline derivatives with electrophilic reagents
3-1. Reactions with carboxylic acid derivatives
3-1-1. Reactions with formic acid
3-1-2. Reactions with formamide
3-1-3. Reactions with acetic anhydride
3-1-4. Reactions with triethyl orthoformate
3-1-5. Reactions with dimethylformamide dipentyl acetal (DMF-DPA)
3-1-6. Reactions with ethyl cyanoacetate
3-1-7. Reactions with sodium nitrite
3-2. Reactions with carbon disulfide
3-3. Reactions with ethylenediamine
3-4. Reactions with 2,5-dimethoxytetrahydrofuran
4. Reactions of 4H-pyrano[3,2-h]quinoline derivatives with nucleophilic reagents
4-1. Reactions with ammonia and its derivatives
4-1-1. Reactions with ammonia
4-1-2. Reactions with methylamine and aniline
4-1-3. Reactions with dimethylamine
4-1-4. Reactions with hydrazine hydrate
5. Reactions of 4-hydrazino-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives with electrophilic reagents
5-1. Reactions with sodium nitrite
5-2. Reactions with formic acid
5-3. Reactions with carbon disulfide
6. Reactions of 4H-pyrano[3,2-h]quinoline-3-carbohydrazide derivatives with electrophilic reagents
6-1. Reactions with sodium nitrite
7. Reactions of 7H-dihydropyrrolyl[1'',2'': 1',2']pyrazino[5,6: 5',6']pyrano[3,2-h]quinoline derivatives
8. Reactions of dihydro-1H-imidazol-2-yl-4H-pyrano[3,2-h]quinoline derivatives with electrophilic reagents
8-1. Reactions with triethyl orthoformate
8-2. Reactions with carbonyl compounds
9. Reactions of 2,9-diamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile with electrophilic reagents
9-1. Reactions with ethyl isocyanate and ethyl thioisocyanate
9-2. Reactions with iodomethane
9-3. Reactions with acetic anhydride
10. Conclusion

1. INTRODUCTION
A variety of 4H-pyrans and condensed 4H-pyrans were prepared recently by utilizing nitriles as starting materials.1-7 The α-cyanocinnamonitrile or ethyl α-cyanocinnamate derivatives reacted with different aromatic and heterocyclic compounds containing hydroxyl group to produce condensed 4H-pyrans derivatives.8-14 Due to the wide spectrum of activities shown by 4H-pyran moiety, various substituted 4H-pyrano[3,2-h]quinoline and their condensed analogues have been synthesized. In sequel, the main purpose of this review is to present a survey on the chemistry of 8-hydroxyquinoline and its derivatives toward α-cyanocinnamonitrile or ethyl α-cyanocinnamate derivatives in the last fifteen years, as well as to explore the reactions of the synthesized β-enaminonitriles and β-enaminoesters with different electrophilic followed by nucleophilic reagents. The chemistry of quinoline and fused quinoline derivatives has attracted many researchers due to their biological activities and their potential applications as pharmacological agents. Many compounds that synthesized from 8-hydroxyquinoline and its derivatives possess diverse therapeutic activities such as antifungal,15 antibacterial,16-18 antiprotozoic drugs as well as antineoplastics19 and antiproliferative20,21 activities. In addition styrylquinoline derivatives have been explored as potential HIV integrase inhibitors22-28 and also for their extensive biological activities.29-33 Furthermore, 4H-pyrano[3,2-h]quinoline and fused 4H-pyrano[3,2-h]quinoline derivatives display in-vitro antimicrobial12,34-36 and/or antitumor37-39 activities. A more extensive study for these compounds is crucial to determine additional antitumor parameters to give a deeper insight to their structure activity relationship. This series of molecules can be used in large scale in development of antitumor therapeutics.

2. SYNTHESIS OF 2-AMINO-4H-PYRANO[3,2-h]QUINOLINE DERIVATIVES
2-1. From 8-hydroxyquinoline and 2-substituted 8-hydroxyquinoline
Treatment of 8-hydroxyquinoline and 8-hydroxy-2-methylquinoline (1a,b) with α-cyanocinnamonitriles (2) (Ar = 4-Cl/BrC6H5) in ethanolic piperidine under reflux for 1-5 h gave 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile8 (R = H, Me) (3), while reaction of 8-hydroxyquinoline (1a) with α-cyano-cinnamonitriles and ethyl α-cyanocinnamates (2) (Ar = C6H5, 4-MeOC6H5) afforded 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile and ethyl 2-amino-4-aryl-4H-pyrano-[3,2-h]quinoline-3-carboxylate derivatives40 (R = H) (3) in 62-83% yield, respectively (Scheme 1). Attempts to react 8-hydroxyquinoline and 8-hydroxy-2-methylquinoline (1a,b) with ethyl α-cyano-p-chloro/bromo-cinnamates (2) was unsuccessful, the ester derivatives 3 were not formed.8 Furthermore, the three components reaction of 8-hydroxyquinoline, 8-hydroxy-2-methylquinoline, 2-amino-8-hydroxyquinoline and 2,8-quinolinediol (1a-d), malononitrile and 3-bromo-4,5-dimethoxy-benzaldehyde in ethanol at room temperature, charged with 1,4-diazabicyclo[2.2.2]octane (DABCO) and then stirred at 80 °C under LC-MS control for 3-18 days afforded 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile39 (3) (R = H, Me, NH2, OH) in 4-61.6% yield, respectively (Scheme 1).

The formation of 3 indicates that the phenolate anion (C-7) of 1 attacks at the electrophilic β-carbon of 2 to yield an acyclic Michael adduct, which underwent cyclization to afforded 3 as shown in Figure 1.

2-2. From 5-chloro-8-hydroxyquinoline
The reaction of 5-chloro-8-hydroxyquinoline (4) with α-cyanocinnamonitriles and ethyl α-cyano-cinnamates (2) in ethanolic piperidine under reflux for 6 h afforded 2-amino-4-aryl-6-chloro-4H-pyrano-[3,2-h]quinoline-3-carbonitrile12,36 and ethyl 2-amino-4-aryl-6-chloro-4H-pyrano[3,2-h]quinoline-3-carboxylate derivatives35 (5) in 65-83% yield, respectively (Scheme 2). Furthermore, the three components reaction of 5-chloro-8-hydroxyquinoline (4), malononitrile and 3-bromo-4,5-dimethoxy-benzaldehyde in ethanol at room temperature, charged with 1,4-diazabicyclo[2.2.2]octane (DABCO) and then stirred at 80 °C under LC-MS control for 18 h afforded 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-6-chloro-4H-pyrano[3,2-h]quinoline-3-carbonitrile39 (5) in 60% yield (Scheme 2).

2-3. From 8-hydroxyquinoline-5-sulfonamide
Treatment of 8-hydroxyquinoline-5-sulfonamide (6) with α-cyanocinnamonitriles and ethyl α-cyano-cinnamates (2) in ethanolic piperidine under reflux for 8 h afforded 2-amino-4-aryl-3-cyano-4H-pyrano-[3,2-h]quinoline-6-sulfonamide14 and ethyl 2-amino-4-aryl-6-sulfamoyl-4H-pyrano[3,2-h]quinoline-3-carboxylate derivatives14 (7) in 65-83% yield, respectively (Scheme 3).

2.4. From (E)-2-(4-halostyryl)-8-hydroxyquinoline
Treatment of (E)-2-(4-halostyryl)-8-hydroxyquinoline (8) with α-cyanocinnamonitriles and ethyl α-cyanocinnamates (2) in ethanolic piperidine under reflux for 30-45 min gave (E)-2-amino-4-aryl-9-(4-halostyryl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile8,37 in 81-90% yield and ethyl (E)-2-amino-4-aryl-9-(4-halostyryl)-4H-pyrano[3,2-h]quinoline-3-carboxylate derivatives8,37 (9) in 79-82% yield, respectively (Scheme 4). The relative E configuration of compounds 9 were established from the coupling constant values8, 37 (J = 16-16.5 Hz).

The tendency of the 8-hydroxyquinoline, 8-hydroxy-2-methylquinoline (1a,b) and (E)-2-(4-halostyryl)-8-hydroxyquinoline (8) towards the electrophilic β-carbon of α-cyano-p-chloro/bromocinnamonitriles and ethyl α-cyano-p-chloro/bromocinnamates (2) follows the sequence 8-hydroxy-2-styrylquinoline (8) > 8-hydroxyquinoline (1a) > 8-hydroxy-2-methylquinoline (1b) as shown in Figure 2.

Thus, the reactivity was enhanced with the presence of the styryl group (conjugation effect) in the 2-position, while the presence of methyl group in the 2-position suppress the reactivity via (+I effect), in addition to the expected hydrogen bond formation as shown in Figure 3.

Also, this observation was supported by the easy attacks of phenolate anion (C-7) of 8 at the electrophilic β-carbon of ethyl α-cyano-p-chloro/bromocinnamates (2) rather than 1a,b to yield an acyclic Michael adduct, which underwent cyclization to give the ester 9 (X = CO2Et) as illustrate in Figure 1.
In case of 2-amino-8-hydroxyquinoline and 2,8-quinolinediol (1c,d) the tendency of 1c,d towards the electrophilic β-carbon of α-cyanocinnamonitriles (2) follows the sequence 2-amino-8-hydroxyquinoline (1c) > 2,8-quinolinediol (1d) as shown in Figure 4.

Thus, the reactivity was enhanced with the presence of the amino group in the 2-position rather than the hydroxyl group and this was explained through the resonance effect which activated the quinoline ring towards the electrophilic β-carbon of α-cyanocinnamonitrile derivatives (2) and also, the amino group accommodate the positive charge rather than hydroxyl group as shown in Figure 5.

In addition, the tendency of the 5-chloro-8-hydroxyquinoline (4) and 8-hydroxyquinoline-5-sulfonamide (6) towards the electrophilic β-carbon of α-cyanocinnamonitrile and ethyl α-cyanocinnamate derivatives (2) follows the sequence 5-chloro-8-hydroxyquinoline (4) > 8-hydroxyquinoline-5-sulfonamide (6) as shown in Figure 6.

Thus, the reactivity was enhanced with the presence of the chloro atom in the 5-position rather than the sulfonamide group because the chloro atom act as weakly deactivating the quinoline ring through (-I effect) as shown in Figure 7, while the sulfonamide group act as strongly deactivating the quinoline ring through (-I effect) as shown in Figure 8.

3. REACTIONS OF 2-AMINO-4H-PYRANO[3,2-h]QUINOLINE DERIVATIVES WITH ELECTROPHILIC REAGENTS

3-1. Reactions with carboxylic acid derivatives
3-1-1. Reactions with formic acid
Condensation of the β-enaminonitriles 3, 5 and 7 with formic acid or formic acid/formamide under reflux for 2-3 h proceeded via the addition of the formic acid on the amino group of β-enaminonitriles followed by cyclization and Dimroth rearrangement via nucleophilic attack of the oxygen atom of the hydroxyl group on the cyano group to gave 7-aryl-7H,9H-pyrimido[4',5':6,5]pyrano[3,2-h]quinolin-8-one derivatives12,14,34,40 (10) in 63-74% yield (Scheme 5). In a similar manner, reaction of the β-enaminonitrile 3 (Ar = 4-BrC6H4) with formic acid under reflux for 2 h afforded the 2-amino-4-(4-bromophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carboxylic acid34 (11) in 68% yield via acid hydrolysis of the cyano group of 3 to carboxylic group (Scheme 5).

3-1-2. Reactions with formamide
The reaction of the β-enaminonitriles 3, 5 and 7 with formamide under reflux for 2-3 h proceeded via condensation of the amino group of β-enaminonitriles with formamide followed by cyclization via nucleophilic attack of the nitrogen atom of the amino group on the cyano group to provided 8-amino-7-aryl-7H-pyrimido[4',5':6,5]pyrano[3,2-h]quinoline derivatives12,14,40,41 (12) in 50-78% yield (Scheme 6).

3-1-3. Reactions with acetic anhydride
Treatment of the β-enaminonitriles 3, 5 and 7 with acetic anhydride under reflux for 0.5 or 3 h give 2-acetylamino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives12,14,40,41 (13) in 80-83% yield, via nucleophilic attack of the nitrogen atom of the amino group on the carbonyl group of acetic anhydride, while boiling of 3, 5 and 7 with acetic anhydride or acetic anhydride/pyridine for 5-8 h afforded the corresponding 7-aryl-10-methyl-7H,9H-pyrimido[4',5':6,5]pyrano[3,2-h]quinolin-8-one derivatives12,14,40,41 (14) in 71-88% yield, respectively (Scheme 7) via acylation of the amino group followed by cyclization and Dimroth rearrangement by nucleophilic attack of the oxygen atom of the hydroxyl group on the cyano group.

3-1-4. Reactions with triethyl orthoformate
Treatment of the β-enaminonitriles 3, 5, 7 and 9 with triethyl orthoformate in acetic anhydride under reflux for 2 h gave the corresponding 4-aryl-2-ethoxymethyleneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives12,14,40-42 in 71-88% yield and (E)-4-(4-chlorophenyl)-9-(4-chlorostyryl)-2-ethoxymethyleneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile38 (15) (R2 = 4-Cl-styryl) in 81% yield, respectively (Scheme 8) through loss of 2 EtOH molecules. The relative E configuration of compounds 15 was established from the coupling constant values38 (J = 16 Hz).

3-1-5. Reactions with dimethylformamide dipentyl acetal (DMF-DPA)
Condensation of the β-enaminonitriles 3 and 9 with DMF-DPA in benzene under reflux for 3 h gave the 4-(4-chlorophenyl)-2-dimethylaminomethyleneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile41 in 83% yield, 4-(4-chlorophenyl)-2-dimethylaminomethyleneamino-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile41 in 81% yield and (E)-4-(4-chlorophenyl)-9-(4-chlorostyryl)-2-dimethylaminomethyleneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile38 (16) (R = 4-Cl-styryl) in 85% yield, respectively (Scheme 9). The relative E configuration of compounds 16 was established from the coupling constant values38 (J = 16.5 Hz). The formation of 16 was explained according to the explanation described for compound 12.

3-1-6. Reactions with ethyl cyanoacetate
Treatment of the β-enaminonitriles 5 and 7 with ethyl cyanoacetate under fusion for 3 h gave 8-amino-7-aryl-5-chloro/sulfamoyl-9-cyano-10-oxo-pyrido[2',3':6,5]pyrano[3,2-h]quinoline derivatives12,42 (17) in 60-72% yield (Scheme 10). This can be explained through the nucleophilic addition of nitrogen atom of the amino group of β-enaminonitriles to the carbocation of the carbonyl group of ethyl cyanoacetate with elimination of EtOH followed by cyclization to give 17.

3-1-7. Reactions with sodium nitrite
Diazotization of the β-enaminonitriles 5 in acetic acid with an aqueous solution of sodium nitrite and hydrochloric acid in ice cold solution under stirring for 3 h lead to the formation of the intermediate diazonium salt, which underwent cyclization to gave 5-aryl-4,7-dichloro-5H-[1,2,3]triazino[4',5':6,5]-pyrano[3,2-h]quinoline derivatives36 (18) in 55-69% yield (Scheme 11).

3-2. Reactions with carbon disulfide
The mixture of 2-amino-4-phenyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3) with carbon disulfide in pyridine was heated in water bath for 8 h to give 7-phenyl-7H-pyrimido[4',5':6,5]pyrano[3,2-h]quinoline-8,10-dithiol40 (19) in 68% yield. The reaction proceeded by the intermediate formation of 4-iminothiazine which rearranged rapidly and irreversibly by a base-catalyzed (pyridine) ring-opening, ring-closure sequence to give the observed product 19. Methylation of 19 with methyl iodide in ethanol containing anhydrous sodium acetate under reflux for 2 h afforded the bis(methylthio) derivative40 (20) in 84% yield (Scheme 12).

3-3. Reactions with ethylenediamine
Treatment of the β-enaminonitriles 5 or 7 with ethylenediamine in toluene in the presence of p-toluene- sulfonic acid under reflux for 12 h yielded the 2-amino-4-aryl-6-chloro/sulfamoyl-3-(4,5-dihydro-1H-imidazol-2-yl)-4H-pyrano[3,2-h]quinoline derivatives36,42,43 (21) in 62-78% yield. These reactions were carried out via the nucleophilic addition of the amino group to the protonated ethylenediamine followed by cyclization to give the imidazolyl derivatives (21) (Scheme 13).

3-4. Reactions with 2,5-dimethoxytetrahydrofuran
Treatment of the β-enaminoester 5 with 2,5-dimethoxytetrahydrofuran in acetic acid solution under reflux for 2 h afforded ethyl 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline derivatives35 (22) in 62-71% yield. This methodology has been achieved through the nucleophilic addition of the amino group to the protonated 2,5-dimethoxytetrahydrofuran followed by cyclization to give the pyrrolyl ester derivatives (22) (Scheme 14).

4. REACTIONS OF 4H-PYRANO[3,2-h]QUINOLINE DERIVATIVES WITH NUCLEOPHILIC REAGENTS
4-1. Reactions with ammonia and its derivatives
4-1-1. Reactions with ammonia
Treatment of the imidate 15 (R = H, CH3) with NH3 gas bubbled in methanol at room temperature for 1 h yielded the 8-amino-7-aryl-7H-pyrimido[4',5':6,5]pyrano[3,2-h]quinoline derivatives41 (12) in 39-44% yield, together with the open chain product, 2-aminomethyleneamino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives41 (23) in 38-40% yield (Scheme 15). The open chain product can be separated from the filtrate of the reaction mixture. These reactions were carried out via the nucleophilic addition of the NH3 gas to the carbocation of the ethoxymethyleneamino group followed by elimination of EtOH to give the open chain product 23, or nucleophilic addition of the amino group on the cyano group of 23 followed by cyclization to give the cyclic product 12 respectively.
In a similar manner, reaction of the imidate 15 (R = 4-Cl-styryl) with NH3 gas yielded only the open chain product (E)-2-aminomethyleneamino-4-(4-chlorophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile38 (24) in 83% yield (Scheme 15).
The relative E configuration of compound 24 was established from the coupling constant values38 (J = 16 Hz). The tetracyclic structure 12 was supported by its independent synthesis from the β-enaminonitriles 3 and formamide44,45 as described before Scheme 6 and also by cyclization of 23 in ethanolic piperdine solution under reflux46 (mp and mixed mp and identical IR and MS spectra) (Scheme 15).

4-1-2. Reactions with methylamine and aniline
When the imidate 15 (R1 = H, R2 = H, Me) was treated with methylamine in ethanol at room temperature under stirring for 1 h, the open chain product 4-aryl-2-methylaminomethyleneamino-4H-pyrano[3,2-h]-quinoline-3-carbonitrile derivatives40,41 (25) (R2 = H, Me) was formed in 74-81% yield, rather than the expected cycloaddition compound, imino derivative 27 (Scheme 16), while treatment the imidate 15 (R1 = Cl, R2 = H) with aniline and the imidate 15 (R1 = H, R2 = 4-Cl-styryl) with methylamine in ethanol at room temperature under stirring for 1 h, afforded the expected cycloaddition compound,7-aryl-5-chloro-8-imino-8,9-dihydro-9-phenyl-7H-pyrimido[4',5':6,5]pyrano[3,2-h]quinoline derivatives12 (26) in 58-71% yield and (E)-9-methyl-7-(4-chlorophenyl)-2-(4-chlorostyryl)-8-imino-8,9-dihydro-7H-pyrimido-[4',5':6,5]pyrano[3,2-h]quinoline38 (27) in 84% yield, respectively (Scheme 16). The formation of compounds 25-27 was explained according to the explanation described for compounds 12 and 23.

The relative E configuration of compound 27 was established from the coupling constant values38 (J = 16 Hz). When the imidate 15 (R1 = H, R2 = Me) was treated with methylamine under the same conditions, the addition product 28 was formed and loss ethyl N-methylformimidate to give β-enaminonitrile46,47 (3) (R1 = H, R2 = Me) instead of the imino derivative 29 (R1 = H, R2 = Me) (Scheme 16).

4-1-3. Reactions with dimethylamine
Reaction of the imidate 15 with dimethylamine in ethanol at room temperature under stirring for 1 h afforded the amidine derivative38,41 (16) in 81-85% yield (Scheme 17), which can be obtained as described before from the reaction of the β-enaminonitriles 3 and 9 with dimethylformaide dipentyl acetal (DMF-DPA) (mp and mixed mp and identical IR and MS spectra) (Scheme 9). The formation of compound 16 can be explained according to the explanation described for compound 23.

4-1-4. Reactions with hydrazine hydrate
Hydrazinolysis of the imidate 15 (R1 = SO2NMe2, SO2piperidin-2-yl, R2 = H) in ethanol at room temperature under stirring for 1 h afforded the open chain product 4-aryl-2-hydrazinomethyleneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives14,41 (30) (R1 = SO2NMe2, SO2piperidin-2-yl) in 80-81% yield instead of the cycloaddition product, aminoimino derivative 31 (Scheme 18), while hydrazinolysis of the imidate 15 (R1 = H, SO2NMe2, R2 = H, 4-Cl-styryl) under the same conditions yielded the cycloaddition compound, 9-amino-7-aryl-8-imino-8,9-dihydro-7H-pyrimido[4',5':6,5]pyrano-[3,2-h]quinoline-5-sulfonamide derivatives38 (31) (R1 = SO2NMe2, R2 = H) in 80-88% yield and (E)-9-amino-7-(4-chlorophenyl)-2-(4-chlorostyryl)-8-imino-8,9-dihydro-7H-pyrimido[4',5':6,5]pyrano[3,2-h]-quinoline38 (31) (R1 =H, R2 = 4-Cl-styryl) in 88% yield (Scheme 18). These reactions were carried out via the nucleophilic addition of the amino group of hydrazine hydrate to the carbocation of the ethoxymethyleneamino group followed by elimination of EtOH to give the open chain product 30, or nucleophilic addition of the imino group on the cyano group of 30 followed by cyclization to give the cyclic product 31 respectively. The relative E configuration of compound 31 (R1 =H, R2 = 4-Cl-styryl) was established from the coupling constant values38 (J = 16.5 Hz).
When the imidate 15 (R = H, Me) was treated with hydrazine hydrate in ethanol at room temperature under stirring for 1 h, the addition product 32 was formed and loss ethyl formohydrazonate to give the β-enaminonitrile46,47 3 (R = Me) instead of the aminoimino derivative 31 (Scheme 18).

Hydrazinolysis of the amidine 16 (R = H, Me) in ethanol at room temperature under stirring for 1 h or in toluene/p-toluenesulfonic acid under reflux for 7 h was unsuccessful, the aminoimino derivative48 31 (R = H, Me) was not formed (Scheme 19).

Hydrazinolysis of 5-aryl-4,7-dichloro-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives (18) at reflux for 6 h gave 5-aryl-7-chloro-4-hydrazino-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives36 (33) in 66-80% yield (Scheme 20), while hydrazinolysis of the ethyl 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline derivatives (22) under the same conditions, yielded 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline-3-carbohydrazide35 (34) in 65-78% yield, respectively (Scheme 20). The formation of compound 33 proceeded via the nucleophilic substitution reaction, while compound 34 proceeded via the nucleophilic addition reaction respectively.

5. REACTIONS OF 4-HYDRAZINO-5H-[1,2,3]TRIAZINO[4',5':6,5]PYRANO[3,2-h]-QUINOLINE DERIVATIVES WITH ELECTROPHILIC REAGENTS
5-1. Reactions with sodium nitrite
Diazotization of the 5-aryl-7-chloro-4-hydrazino-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives (33) in acetic acid with an aqueous solution of sodium nitrite and hydrochloric acid in ice cold solution under stirring for 1 h led to the formation of the intermediate diazonium salt, which lost HCl to gave 5-aryl-4-azido-7-chloro-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives36 (35) in 55-63% yield instead of the tetrazol structure36 (36), which ruling out on the basis of spectral data (Scheme 21).

5-2. Reactions with formic acid
Condensation of 5-aryl-7-chloro-4-hydrazino-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives (33) with formic acid under reflux for 8 h gave the corresponding 14-aryl-12-chloro-14H-[1,2,4]triazolo[3,4-f][1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives36 (37) in 59-74% yield (Scheme 22). The formation of compound 37 proceeded via the nucleophilic addition of the amino group of hydrazino group to the carbocation of the formic acid followed by rearrangement and cyclization with elimination of H2O to give compound 37.

5-3. Reactions with carbon disulfide
Treatment of 5-aryl-7-chloro-4-hydrazino-5H-[1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives (33) with carbon disulfide/KOH in ethanol under reflux for 6 h gave the corresponding 14-aryl-12-chloro-3-thioxo-14H-[1,2,4]triazolo[3,4-f][1,2,3]triazino[4',5':6,5]pyrano[3,2-h]quinoline derivatives36 (38) in 59-74% yield (Scheme 23). The reaction proceeded by nucleophilic addition of the amino group of hydrazino group to the carbocation of the carbon disulfide followed by rearrangement and cyclization with elimination of H2S to give compound 38.

6. REACTIONS OF 4H-PYRANO[3,2-h]QUINOLINE-3-CARBOHYDRAZIDE DERIVATIVES WITH ELECTROPHILIC REAGENTS
6-1. Reactions with sodium nitrite
Diazotization of the 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline-3-carbohydrazide (34) in acetic acid with an aqueous solution of sodium nitrite and hydrochloric acid in ice cold solution under stirring for 0.5 h gave 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline-3-oylazide35 (39) in 61-78% yield (Scheme 24). The formation of compound 39 can be explained according to the explanation described for compound 35.

When the acid azide 39 was heated in a high-boiling point inert solvent such as xylene led to Curtius rearrangement with concomitant ring closure of the isocyanate intermediate 40 giving 7-aryl-5-chloro-9-oxo-7H-8,9-dihydropyrrolyl[1'',2'':1',2']pyrazino[5,6:5',6']pyrano[3,2-h]quinoline derivatives35 (41) in 61-69% yield, while heating the acid azide 39 in excess ethanol for 2 h afforded the ethyl 4-aryl-6-chloro-2-(1-pyrrolyl)-4H-pyrano[3,2-h]quinoline-3-carbamate derivatives35 (42) in 70-82% yield (Scheme 24).
Hydrazinolysis of the acid azide 39 in ethanol under reflux for 1 h afforded N-(4-aryl-6-chloro-2-(1H-pyrrol-1-yl)-4H-pyrano[3,2-h]quinolin-3-yl)hydrazinecarboxamide35 (43) in 69-82% yield (Scheme 24).

7. REACTIONS OF 7H-DIHYDROPYRROLYL[1'',2'': 1',2']PYRAZINO-[5,6: 5',6']PYRANO[3,2-h]QUINOLINE DERIVATIVES
Chlorination of the 7-aryl-5-chloro-9-oxo-7H-8,9-dihydropyrrolyl[1'',2'': 1',2']pyrazino[5,6: 5',6']pyrano-[3,2-h]quinoline derivatives (41) with phosphorus oxytrichloride under reflux for 4 h gave 7-aryl-5,9-dichloro-7H-pyrrolo[1'',2'':1',2']pyrazino[5,6:5',6']pyrano[3,2-h]quinoline derivatives35 (44) in 68-77% yield (Scheme 25). Hydrazinolysis of 44 with hydrazine hydrate in ethanol under reflux for 5 h gave 7-aryl-5-chloro-9-hydrazino-7H-pyrrolo[1'',2'':1',2']pyrazino[5,6:5',6']pyrano[3,2-h]quinoline derivatives35 (45) in 62-71% yield (Scheme 25). Treatment of 45 with acetic acid under reflux for 6 h gave 7-aryl-5-chloro-9-methyl-7H-[1,2,4]triazolo[3'',4'':3',4']pyrrolo[1'',2'':1',2']pyrazino[5,6:5',6']pyrano[3,2-h]quinolinederivatives35 (46) in 54-63% yield, while reaction of 45 with carbon disulfide / KOH in ethanol under reflux for 6 h gave 7-aryl-5-chloro-9-thioxo-9,10-dihydro-7H-[1,2,4]triazolo[3'',4'':3',4']pyrrolo-[1'',2'':1',2']pyrazino[5,6: 5',6']pyrano[3,2-h]quinoline derivatives35 (47) in 58-67% yield (Scheme 25).
The formation of compound 45 proceeded via the nucleophilic substitution reaction, while compounds 46 and 47 were formed via nucleophilic addition of the amino group of hydrazino group to the AcOH or CS2 followed by elimination of H2O or H2S to give 46 and 47 respectively.

8. REACTIONS OF DIHYDRO-1H-IMIDAZOL-2-YL-4H-PYRANO[3,2-h]QUINOLINE DERIVATIVES WITH ELECTROPHILIC REAGENTS
8-1. Reactions with triethyl orthoformate
Interaction of 2-amino-4-aryl-6-chloro/sulfamoyl-3-(4,5-dihydro-1H-imidazol-2-yl)-4H-pyrano[3,2-h]-quinoline derivatives (21) with triethyl orthoformate in formic acid under reflux for 7 h gave the 14-aryl-12-chloro/sulfamoyl-2,3-dihydroimidazo[1,2-c]pyrimido[4',5':6,5]-14H-pyrano[3,2-h]quinoline derivatives36,49 (48) in 62-78% yield (Scheme 26) through the loss of 2 EtOH molecules to give the intermediate ethoxymethyleneamino derivative which cyclized with imino group of 1H-imidazoly ring to afforded the compound 48.

8-2. Reactions with carbonyl compounds
Condensation of 2-amino-4-aryl-6-chloro/sulfamoyl-3-(4,5-dihydro-1H-imidazol-2-yl)-4H-pyrano-[3,2-h]quinoline derivatives (21) with carbonyl compounds, namely, acetaldehyde, acetone, cyclopentanone and cyclohexanone in absolute ethanol under stirring and reflux at 80-100 оC for 12 h afforded 14-aryl-12-chloro/sulfamoyl-2,3,6-trihydroimidazo[1,2-c]pyrimido[4',5':6,5]-14H-pyrano[3,2-h]quinoline derivatives16,29 (49-52) in 30-63% yield, respectively (Scheme 27). These reactions were carried out via the nucleophilic addition of the amino group to the carbocation of the carbonyl compounds with elimination of H2O followed by cyclization of imino group of 1H-imidazoly ring with benzylideneamino group (-N=CHR) to afforded the compounds 49-52.

9. Reactions of 2,9-diamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile with electrophilic reagents
9-1. Reactions with ethyl isocyanate or ethyl thioisocyanate
2,9-Diamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3) and ethyl isocyanate or ethyl thioisocyanate were taken in 2 mL dry acetonitrile and stirred at 60 °C monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high performance liquid chromatography) (21 mm x 250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 mL/min) to afforded 1-(2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4H-pyrano[3,2-h]quinolin-9-yl)-3-methylurea39 (53) and 1-(2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4H-pyrano[3,2-h]quinolin-9-yl)-3-methylthiourea39 (54) in 59-73% yield, respectively (Scheme 28). The reaction proceeded by nucleophilic addition of the amino group to the carbocation of ethyl isocyanate or ethyl thioisocyanate followed by rearrangement to gave compounds 53 and 54.

9-2. Reactions with iodomethane
2,9-Diamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3) and potassium carbonate were taken in 5 mL dry acetonitrile, charged with iodomethane and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (21 mm x 250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 mL/min) to afforded 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-9-(methylamino)-4H-pyrano[3,2-h]quinoline-3-carbonitrile39 (55) in 87.8% yield (Scheme 29). The formation of compound 55 was explained via the nucleophilic addition of the amino group to the carbocation of the iodomethane to give compound 55.

9-3. Reactions with acetic anhydride
2,9-Diamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3) was taken in 2 mL pyridine at 0 °C, charged with acetic anhydride by dropwise addition and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (21 mm x 250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 mL/min) to get the title compound, N-(2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4H-pyrano[3,2-h]quinolin-9-yl)acetamide39 (56) in 71.4% yield (Scheme 30). Acylation of compound 56 can be explained according to the explanation described for compound 13.

10. CONCLUSION
The present review outlined the synthesis of 4H-pyrano[3,2-h]quinoline derivatives by reaction of 8-hydroxyquinoline and its derivatives with α-cyanocinnamonitriles and ethyl α-cyanocinnamates, fused 4H-pyrano[3,2-h]quinoline derivatives by treatment of 4H-pyrano[3,2-h]quinoline derivatives with different electrophilic followed by nucleophilic reagents and heterocyclic ring transformations. The tendency of the 8-hydroxyquinoline, 2-substituted 8-hydroxyquinoline (1a-d) and 8-hydroxy-2-styryl-quinoline (8) towards the electrophilic β-carbon of α-cyanocinnamonitriles and ethyl α-cyanocinnamates illustrated that the order of reactivity of 8-hydroxyquinoline and its derivatives follows the following sequence:
8-hydroxy-2-styrylquinoline (8) > 2-amino-8-hydroxyquinoline (1c) 2,8-quinolinediol (1d) > 8-hydroxyquinoline (1a) > 8-hydroxy-2-methylquinoline (1b)
In addition, the tendency of the 5-chloro-8-hydroxyquinoline (4) and 8-hydroxyquinoline-5-sulfonamide (6) towards the electrophilic β-carbon of α-cyanocinnamonitriles illustrated that the order of reactivity of 5-substituted 8-hydroxyquinolines follow the following sequence:
5-chloro-8-hydroxyquinoline (4) > 8-hydroxyquinoline-5-sulfonamide (6)
This can be explained through the mesomeric effect between the quinoline-N and the hydroxyl group in the 8-position, the conjugation effect, resonance effect and inductive effect between different substituent groups at 2-postion and 5-postion and the quinoline ring.
The investigation of antimicrobial and antitumor screening data for the synthesis compounds revealed that some of the tested compounds have demonstrated congruent activities against the most tested microorganisms and human tumor cell lines as compared with the standard drugs.

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