Synthesis of 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate and its application in the synthesis of 4-(aryl/heteroaryl/alkynyl)phthalazin-1(2H)-one

Abstract

The regioselective synthesis of 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate (3a) has been reported. The reaction of Tf₂O (2a) with phthalhydrazide (1a) provides a rapid access to 3a with an excellent yield and a high level of regioselectivity. The synthetic utility of this triflate is further enhanced by carrying out the successful Suzuki and Sonogashira coupling reactions for the first time on 3a, providing a simple access to a range of biologically significant 4-aryl/heteroaryl/alkynyl phthalazinones in good yields.

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Introduction

A realization of the intrinsic value of nitrogen heterocycles in medicinal and pharmaceutical chemistry enthralled researchers across the world. Nitrogen containing heterocycles are the cornerstone of many pharmaceutically active natural products. Furthermore, 59% of the drugs approved by US FDA contain nitrogen heterocycles, ranking them as the most privileged and haunted heterocycles by medicinal chemists.¹ Though nature has ascribed less importance to phthalazinone as a building block of natural products, it is often integrated in the synthesis of pharmaceuticals, as shown in Fig. 1.

Fig. 1 Biologically important compounds containing phthalazinones and phthalazines.

Phthalazinone and a class of compounds, which contain elements of this pharmacophore, are being developed preclinically for the treatment of cancer, diabetes, hepatitis, asthma, and arrhythmia.² These compounds are also used as the potent inhibitors of poly (ADP-ribose) polymerase-1 (PARP) and phosphodiesterase-4 (PDE-4).² The biological importance of 4-substituted phthalazinone (4SP) led to the continuous development of various meritorious synthetic methods in this field. The most undemanding and widely used method is the Friedel–Crafts acylation of phthalic anhydride followed by condensation with hydrazine,³ cycloaddition,⁴ multi component reaction for the synthesis of 4-aminophthalazin-1(2H)-ones,^5,6 heteroarylation of arenes⁷ and condensation reaction of 3-substituted 3-hydroxyisoindolin-1-ones with hydrazine.^8a However, all these methods generally suffer from significant drawbacks. Although 4SPs were effectively obtained by the Friedel–Crafts (FC) acylation of phthalic anhydride and 1,4-dichlorophthalazine, the reaction conditions were found to be amenable for only electron-rich aromatic and heteroaromatic rings as the Friedel–Crafts substrates, hence this allowed the synthesis of specific compounds, which indeed contributed to severely limiting structure activity relationship (SAR) studies of 4SPs and related heteroaromatics. Nguyen and coworkers⁸ have developed an alternative, efficient and general method to prepare 4-substituted aryl/heteroaryl/alkyl phthalazinones; however, their linear synthetic approach for 4SPs demands highly reactive pyrophoric reagents and tedious synthetic procedures. This methodology did not provide a suitable route to alkynyl substituted phthalazinones. Cross coupling reactions have not been employed in the synthesis of 4SPs except for the only report by Barreiro and coworkers,⁹ in which they used the tosylated phthalhydrazide for Suzuki reaction, which was limited only to phenylboronic acid. There is still a need for novel and more general methodologies to fulfil the increasing demands of modern drug discovery, such as combinatorial and parallel synthetic methods, which avoid harsh reaction conditions and allow for an efficient assembly of the phthalazinone core from the readily available starting materials. Herein, we report our investigation in this field.

Result and discussion

The study was initiated with the selective O-triflation of phthalhydrazide by investigating the reaction of phthalhydrazide (1a) and trifluoromethanesulphonic anhydride (2a) (Table 1). Initially, the reaction failed to give the triflate 3a after 36 h in dichloromethane and pyridine (1.1 eq.) at room temperature (Table 1, entry 1). When the same reaction was performed in acetonitrile and pyridine (1.1 eq.) at −50 °C, it provided 3a in less than 5% and when it was performed from 0 °C to room temperature, it provided 15–30% yield (Table 1, entry 2, 3). The biggest challenge for this reaction was the solubility of 1a, and thus we used pyridine as the solvent and this resulted in 80–90% yield of 3a in 2–3 h from −50 °C to room temperature (Table 1, entry 4). The best result was obtained when 20% pyridine was used in acetonitrile, which gave 3a in 90–95% yield (Table 1, entry 8). In the present protocol, triflation occurred selectively and exclusively at one of the carbonyl oxygen giving O-sulfonate rather than any of the amidic nitrogen of 2,3-dihydrophthalazine-1,4-dione/phthalhydrazide (1a).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Base	Base equivalent/proportion	Temp °C	Yield (%)
a Isolated yield.
1	Dichloromethane	Pyridine	1 : 1	rt	NR
2	Acetonitrile	Pyridine	1 : 1	−50	5
3	Acetonitrile	Pyridine	1 : 1	0 to rt	15–30
5	Pyridine			−50 to rt	80–90
6	Acetonitrile	Pyridine	1 : 1	0	80–90
7	Acetonitrile	Pyridine	2 : 1	0	80–90
8	Acetonitrile	Pyridine	4 : 1	0	90–95

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After a successful O-triflation, this triflate was subjected to a couple of cross coupling reactions, namely, Suzuki and Sonogashira coupling reactions which aimed to access the biologically relevant phthalazinone motif in a library fashion. Thus, for the Suzuki cross coupling reaction, triflate 3a (1.69 mmol), phenylboronic acid (1.78 mmol), Pd (0) catalyst (10 mol%) and K₂CO₃ (2.54 mmol) in acetonitrile was stirred at rt for 12 h under an nitrogen atmosphere, and the product 5a was obtained in less than 30% yield (Table 2, entry 1). The same reaction when refluxed in acetonitrile for 2–3 h resulted in 15% yield (Table 2, entry 2). Even a change of solvent from acetonitrile to 1,4-dioxane did not show considerable impact on the yield, either at room or reflux temperature (Table 2, entry 3,4). In these reactions, we observed that triflate 3a was consumed but phenylboronic acid was not. Therefore, we postulated that this may be due to the K₂CO₃ induced cleavage of triflate 3a, which depends on temperature. However, when we used a mild base such as K₃PO₄, we observed an improvement in the reaction profile in terms of the proportionate consumption of both the triflate and phenylboronic acid. Several other solvents were investigated but they did not show a considerable improvement in term of the yields and reaction profile (Table 2, entry 5–11). The screening of different Pd(II) catalysts demonstrated that PdCl₂(dppf) was best suitable for this reaction condition, and the product 5a was obtained in 74% yield (Table 2, entries 12–14). With the optimized reaction condition in hand, the scope and generality of the reaction was explored using various arylboronic acids 4a (Table 3). Arylboronic acids, such as –OMe, bearing electron-donating groups at para, meta and ortho positions were smoothly coupled with 3a to give the corresponding products 5b (77%), 5c (70%) and 5d (60%), respectively. Boronic acids with halogen substituents, such as chlorine on the benzene ring, were found to be compatible for this coupling reaction (5j, 75% and 5k, 73%). Boronic acids having electron-withdrawing functional groups, such as 2-CF₃– and 4-CHO–, were also tolerated to give the desired products 5h (59%) and 5e (72%), respectively. In addition, steric effect was observed because boronic acid with ortho-substituents led to relatively lower yields compared to para and meta substituted variants (Table 3, entries 4, 8); furthermore, boronic acid having 2-CHO– group failed to give the desired product. Heteroarylboronic acids, such as 3-pyridyl, 3-thienyl and benzo[b]thien-2-yl, were also coupled smoothly with 3a to give 5l (72%), 5m (71%) and 5n (69%), respectively. Using this methodology, we effectively incorporated 3-substituted (Table 3, entries 3, 6, 7, 9 and 11) and electron-deficient aromatic rings (Table 3, entries 5–8) in the Suzuki coupled products (5), which are not easily accessible through traditional methods (vide supra).

Table 2 Optimization of the reaction conditions^a

Entry	Catalyst^a	Solvent	Base^b	Time	Temp	Yield^c%
a Reaction conditions: unless otherwise noted, all reactions were carried out with 10 mmol% of catalyst in 5.0 mL of solvent under an nitrogen atmosphere.b 1.5 equiv. of base was used.c Isolated yield.d No reaction.
1	Pd(PPh3)4	Acetonitrile	K2CO3	12 h	rt	30
2	Pd(PPh3)4	Acetonitrile	K2CO3	2–3 h	Reflux	15
3	Pd(PPh3)4	1,4-Dioxane	K2CO3	12 h	rt	35
4	Pd(PPh3)4	1,4-Dioxane	K2CO3	2–3 h	Reflux	10
5	Pd(PPh3)4	Acetonitrile	K3PO4	12 h	rt	35
6	Pd(PPh3)4	Acetonitrile	K3PO4	2–3 h	Reflux	30
7	Pd(PPh3)4	1,4-Dioxane	K3PO4	12 h	rt	35
8	Pd(PPh3)4	1,4-Dioxane	K3PO4	2–3 h	Reflux	40
9	Pd(PPh3)4	Ethanol	K3PO4	2–3 h	Reflux	30
10	Pd(PPh3)4	Dimethylformamide	K3PO4	2–3 h	Reflux	NR^d
11	Pd(PPh3)4	Acetonitrile:ethanol	K3PO4	2–3 h	Reflux	15
12	Pd2(dba)3	1,4-Dioxane	K3PO4	2–3 h	Reflux	NR^d
13	PdCl2(PPh3)2	1,4-Dioxane	K3PO4	2–3 h	Reflux	NR^d
14	PdCl2(dppf)	1,4-Dioxane	K3PO4	2–3 h	Reflux	74

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Table 3 Synthesis of novel 4SPs from triflate (3a)

Entry	Ar/R	Compound	Yields (%)
1	Phenyl	5a	74
2	4-Methoxy phenyl	5b	77
3	3-Methoxy phenyl	5c	70
4	2-Methoxy phenyl	5d	60
5	4-Formyl phenyl	5e	72
6	3-Formyl phenyl	5f	62
7	3-Trifluoromethyl phenyl	5g	69
8	2-Trifluoromethyl phenyl	5h	59
9	3-Hydroxy phenyl	5i	74
10	4-Chloro phenyl	5j	75
11	3-Chloro phenyl	5k	73
12	3-Pyridyl	5l	72
13	3-Thienyl	5m	71
14	Benzo[b]thien-2-yl	5n	69
15	2-Naphthyl	5o	69
16	Phenyl	6a	85
17	3-Methyl phenyl	6b	80
18	3-Amino phenyl	6c	76
19	n-Pentyl	6d	70
20	n-Hexyl	6e	69

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To extend the scope further, in synthetic manipulations, we carried out the Sonogashira cross coupling reaction on 3a in a library fashion to get a completely new 4-alkynyl phthalazin-1(2H)-one (Table 3, entries 16–20). Phenyl acetylene, 3-methyl phenyl acetylene and 3-amino phenyl acetylene were coupled smoothly to give 6a (85%), 6b (80%) and 6c (76%), respectively.

Aliphatic alkynes, such as 1-heptyne and 1-octyne, were also effectively coupled to give the desired products 6d (70%) and 6e (69%), respectively. However, the yields of aromatic alkynes were relatively higher as compared to aliphatic alkynes.

Fig. 2, furthermore, elaborates the scope of 3a in combinatorial and diversity oriented synthesis to enrich the compound's bank with diversity around the phthalazin-1(2H)-one core. For this purpose, when 4-arylphthalazin-1(2H)-ones were treated with POCl₃, the corresponding chlorides were obtained;⁸ thus, we effectively chlorinated 5a and 5o to 7a (90%) and 7b (77%), respectively. These chlorinated intermediates (7a–b) would be effectively employed in the diversity oriented synthesis to get 4-aminophthalazin-1(2H)-one (8) by the nucleophilic displacement reactions with various 1°/2° aliphatic and alicyclic amines. Furthermore, symmetrically or non-symmetrically 1,4 substituted phthalazines (9) and 1-aryl,4-alkynyl phthalazines (10) are also accessible by Suzuki and Sonogashira cross coupling reactions. We have exemplified this diversity oriented synthesis by the reaction of 7a to obtain corresponding 1-morpholino-4-phenylphthalazine (8a) in 80% yield, 1-(3-methoxyphenyl)-4-phenylphthalazine (9a) in 68% yield and 1-phenyl-4-(2-m-tolylethynyl) phthalazine (10a) in 73% yield.

Fig. 2 Scope of 3a in combinatorial synthesis.

Conclusions

In conclusion, we have demonstrated that 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate (3a) can be synthesized exclusively from 1a with high efficacy, thereby providing a platform for further synthetic manipulations. The present protocol provides a direct access to the library oriented synthesis of 4-aryl/heteroaryl/alkynyl phthalazinones from 3a by metal catalyzed cross coupling reactions, such as Suzuki and Sonogashira reactions, in good yields. In addition, the refinement of existing protocols and development of completely new reaction parameters were carried out, which can afford non-obvious lead “hits”, viz., 4-(3-substituted-aryl) phthalazin-1(2H)-one, 4-alkynyl phthalazin-1(2H)-one and 1-aryl-4-alkynyl phthalazine, which might otherwise remain unexplored. This helps to fill gaps in the SAR of 4SPs and related heteroaromatics. The diversity oriented synthesis of 1-chloro-4-arylphthalazine can lead to an entire library of new chemical compounds such as 1-aryl,4-alkynyl phthalazines (10), symmetrically or non-symmetrically substituted 1,4 substituted phthalazines (9) and 4-aminophthalazin-1(2H)-one (8). The utility of the present protocol in the synthesis of biologically important phthalazinones containing heterocycles is currently underway in our laboratory.

Experimental section

General information

All the reactions were performed in oven dried glassware and under a N₂ atmosphere. Solvents were dried and degassed by standard methods before use. Thin-layer chromatography (TLC) was performed on silica gel 60F₂₅₄ (0.25 mm thickness) plates and were visualized under short (254 nm) and long (365 nm) UV light. Column chromatography was performed using a silica gel 200–400 mesh. Melting points (Mp) were determined in open capillary tubes using a paraffin oil bath and are uncorrected. ¹H and ¹³C NMR spectra were recorded on a 400 and 500 MHz NMR spectrometer using CDCl₃ and DMSO-d₆ as solvents. Chemical shifts δ are reported in ppm relative to Me₄Si, which was used as an internal standard. The multiplicity of signals is designated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). FTIR was recorded on an IR-Affinity1 Shimadzu DRS-8000A instrument. High-resolution mass spectra (HRMS) were obtained using a micromass-Q-TOF machine operating in the electrospray ionization (ESI) mode.

Synthesis of 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate (3a). Compound 1a (2.00 g, 12.33 mmol) was taken in 20 mL of acetonitrile and 5 mL of pyridine and after 10 min stirring at 0 °C, triflic anhydride (12.95 mmol) was added and stirred from 0 °C to rt. After the completion of the reaction (TLC check, 3–4 h), the reaction mixture was poured in ethyl acetate (100 mL) and water (50 mL) was added to it, and then stirred for 30 min to avoid the formation of an emulsion. The organic layer was washed with 5% HCl, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to get a crude compound, which was purified by column chromatography using ethyl acetate : n-hexane (25–30%) as the eluent to yield the pure product as a white solid (3.45 g, 95%).

Mp: 186–188 °C; IR (neat): [small nu, Greek, tilde] = 3174, 1681, 1602, 1423, 1321, 1056, 873, 744 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.82 (s, 1H, –NH), 8.31 (d, J = 7.6 Hz, 1H, Ar-H), 8.06–8.01 (m, 1H, Ar-H), 7.98–7.95 (m, 1H, Ar-H), 7.80 ppm (d, J = 7.6 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): 163.1, 159.1, 142.7, 135.7, 134.5, 133.4, 129.0, 129.0, 127.0, 124.39, 123.6, 122.6, 119.6, 116.4 ppm; HRMS (ESI) m/z: calcd for C₉H₆F₃N₂O₄S [M + H]⁺ 294.9995, found 294.9995.

General procedure for synthesis of 4-aryl phthalazin-1(2H)-one (5a–o)

Compound 3a (0.5 g, 1.69 mmol), PdCl₂(dppf) (10 mol%), arylboronic acid 4a (1.78 mmol) and K₃PO₄ (2.54 mmol) were dissolved in 5 mL of 1,4-dioxane and refluxed for 2–3 h under an inert atmosphere. After the completion of the reaction (TLC check), the mixture was poured in (25 mL) water and extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get a crude compound, which was purified by column chromatography using ethyl acetate : n-hexane (40–60%) as the eluent to yield product as a white solid (59–77%).

4-Phenylphthalazin-1(2H)-one (5a). White solid; Mp: 224–226 °C; lit.¹⁰ IR (neat): [small nu, Greek, tilde] = 3057, 1678, 1489, 1336, 1153, 898, 750, 543 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ = 11.1 (s, 1H, –NH), 8.59–8.55 (m, 1H, Ar-H), 7.85–7.82 (m, 3H, Ar-H), 7.63–7.61 (m, 2H, Ar-H), 7.57–7.54 ppm (m, 3H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): δ = 160.5, 148.3, 135.0, 133.5, 131.6, 129.8, 129.4, 129.3, 128.7, 128.4, 127.1, 127.0 ppm; HRMS (ESI) m/z: calcd for C₁₄H₁₁N₂O [M + H]⁺ 223.0866, found 223.0861.

4-(4-Methoxyphenyl)phthalazin-1(2H)-one (5b). White solid; Mp: 238–240 °C; lit.³ IR (neat): [small nu, Greek, tilde] = 3099, 1668, 1608, 1516, 1255, 1028, 873, 682 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.78 (s, 1H, –NH), 8.36–8.34 (m, 1H, Ar-H), 7.87–7.84 (m, 2H, Ar-H), 7.74–7.71 (m, 1H, Ar-H), 7.53–7.50 (m, 2H, Ar-H), 7.10–7.07 (m, 2H, Ar-H), 3.86 ppm (s, 3H, –OCH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.6, 159.2, 146.1, 133.2, 131.2, 130.5, 129.2, 128.0, 127.3, 126.5, 126.0, 113.8, 55.1 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₃N₂O₂ [M + H]⁺ 253.0971, found 253.0968.

4-(3-Methoxyphenyl)phthalazin-1(2H)-one (5c). White solid; Mp: 182–184 °C; IR (neat): [small nu, Greek, tilde] = 3070, 1662, 1598, 1485, 1159, 860, 700 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.83 (s, 1H, –NH), 8.36–8.35 (m, 1H, Ar-H), 7.87–7.85 (m, 2H, Ar-H), 7.74–7.71 (m, 1H, Ar-H), 7.47–7.43 (m, 1H, Ar-H), 7.14–7.07 (m, 3H, Ar-H), 3.83 ppm (s, 3H, –OCH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.2, 159.2, 146.1, 136.3, 133.2, 131.3, 129.4, 129.0, 127.9, 126.4, 126.0, 121.4, 114.6, 114.4, 55.1 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₃N₂O₂ [M + H]⁺ 253.0971, found 253.0973.

4-(2-Methoxyphenyl)phthalazin-1(2H)-one (5d). White solid; Mp: 240–242 °C; IR (neat): [small nu, Greek, tilde] = 3022, 1658, 1606, 1153, 1024, 889, 752 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.78 (s, 1H, –NH), 8.33–8.31 (m, 1H, Ar-H), 7.81–7.77 (m, 2H, Ar-H), 7.53–7.49 (m, 1H, Ar-H), 7.33 (dd, J = 1.7, 7.4 Hz, 1H, Ar-H), 7.29–7.27 (m, 1H, Ar-H), 7.17 (d, J = 8.2 Hz, 1H, Ar-H), 7.12–7.08 (m, 1H, Ar-H), 3.70 ppm (s, 3H, –OCH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.5, 157.1, 144.9, 133.0, 131.1, 130.8, 130.6, 129.8, 127.4, 126.7, 125.5, 123.9, 120.5, 111.2, 55.2 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₃N₂O₂ [M + H]⁺ 253.0971, found 253.0974.

4-(4-Formylphenyl)phthalazin-1(2H)-one (5e). White solid; Mp: 280–282 °C; IR (neat): [small nu, Greek, tilde] = 3159, 2845, 1703, 1666, 1606, 1336, 1209, 833, 742 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.96 (s, 1H, –NH), 10.14 (s, 1H, –CHO), 8.39–8.37 (m, 1H, Ar-H), 8.09 (d, J = 8.2 Hz, 2H, Ar-H), 7.90–7.87 (m, 2H, Ar-H), 7.82 (d, J = 8.1 Hz, 2H, Ar-H), 7.72–7.69 ppm (m, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 192.3, 159.2, 145.2, 140.7, 136.1, 133.4, 131.5, 130.0, 129.5, 128.6, 127.9, 126.1, 126.1 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₁N₂O₂ [M + H]⁺ 251.0815, found 251.0815.

4-(3-Formylphenyl)phthalazin-1(2H)-one (5f). White solid; Mp: 256–258 °C; IR (neat): [small nu, Greek, tilde] = 3179, 2895, 1701, 1674 1338, 1184, 796, 684 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.92 (s, 1H, –NH), 10.12 (s, 1H, –CHO), 8.40–8.37 (m, 1H, Ar-H), 8.12 (s, 1H, Ar-H), 8.07 (d, J = 7.6 Hz, 1H, Ar-H), 7.94–7.86 (m, 3H, Ar-H), 7.79–7.75 (m, 1H, Ar-H), 7.72–7.69 ppm (m, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 192.4, 159.3, 145.2, 136.3, 136.0, 135.0, 133.4, 131.5, 130.3, 129.5, 129.3, 128.7, 128.0, 126.1, 126.1 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₁N₂O₂ [M + H]⁺ 251.0815, found 251.0814.

4-(3-(Trifluoromethyl)phenyl)phthalazin-1(2H)-one (5g). White solid; Mp: 272–274 °C; lit.^8a IR (neat): [small nu, Greek, tilde] = 3150, 1668, 1313, 1182, 1134, 688, 549 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.86 (s, 1H, –NH), 8.37–8.35 (m, 1H, Ar-H), 7.90 (d, J = 7.4 Hz, 1H, Ar-H), 7.85–7.74 (m, 4H, Ar-H), 7.56 (d, J = 7.3 Hz, 1H, Ar-H), 7.15 ppm (d, J = 7.4 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.3, 144.2, 133.1, 132.0, 131.7, 131.3, 130.0, 129.5, 128.8, 128.5, 127.5, 126.4, 126.4, 126.3, 126.0, 125.7, 125.0 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₀F₃N₂O [M + H]⁺ 291.0740, found 291.0741.

4-(2-(Trifluoromethyl)phenyl)phthalazin-1(2H)-one (5h). White solid; Mp: 278–280 °C; IR (neat): [small nu, Greek, tilde] = 3161, 1668, 1606, 1313, 1180, 781 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.89 (s, 1H, –NH), 8.36 (dd, J = 1.4, 7.8 Hz, 1H, Ar-H), 7.91 (d, 7.4 Hz, 1H, Ar-H), 7.87–7.75 (m, 4H, Ar-H), 7.58 (d, J = 7.4 Hz, 1H, Ar-H), 7.15 ppm (d, J = 7.5 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.3, 144.2, 133.2, 133.1, 133.1, 132.1, 131.8, 131.4, 130.0, 129.5, 128.7, 128.4, 127.5, 126.4, 126.4, 126.1, 125.8, 125.0, 122.3 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₀F₃N₂O [M + H]⁺ 291.0740, found 291.0740.

4-(3-Hydroxyphenyl)phthalazin-1(2H)-one (5i). White solid; Mp: 274–276 °C; IR (neat): [small nu, Greek, tilde] = 3213, 3053, 1651, 1589, 1471, 1354, 1201, 794, 704 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.75 (s, 1H, –NH), 9.57 (s, 1H, –OH), 8.38–8.35 (m, 1H, Ar-H), 7.88–7.83 (m, 2H, Ar-H), 7.79–7.75 (m, 1H, Ar-H), 7.78 (m, 1H, Ar-H), 6.98–6.97 (m, 2H, Ar-H), 6.94–6.91 ppm (m, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.3, 157.4, 146.4, 136.2, 133.0, 131.1, 129.2, 129.0, 128.0, 126.4, 125.9, 119.8, 116.1, 115.8 ppm; HRMS (ESI) m/z: calcd for C₁₄H₁₁N₂O₂ [M + H]⁺ 239.0815, found 239.0813.

4-(4-Chlorophenyl)phthalazin-1(2H)-one (5j). White solid; Mp: 256–258 °C; lit.^8a IR (neat): [small nu, Greek, tilde] = 3159, 1666, 1598, 1483, 1153, 877, 761, 686 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.8 (s, 1H, –NH), 8.37–8.34 (m, 1H, Ar-H), 7.89–7.84 (m, 2H, Ar-H), 7.70–7.67 (m, 1H, Ar-H), 7.62–7.56 ppm (m, 4H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.2, 145.2, 135.9, 133.8, 133.3, 131.4, 130.9, 128.7, 128.4, 127.9, 126.2, 126.0 ppm; HRMS (ESI) m/z: calcd for C₁₄H₁₀ClN₂O [M + H]+ 257.0476, found 257.0480.

4-(3-Chlorophenyl)phthalazin-1(2H)-one (5k). White solid; Mp: 216–218 °C; IR (neat): [small nu, Greek, tilde] = 3161, 1666, 1473, 1217, 887, 788, 688 cm⁻¹; ¹H NMR (500 MHz, CDCl₃ + D₂O): δ = 8.49–8.48 (m, 1H, Ar-H), 7.82–7.80 (m, 2H, Ar-H), 7.71–7.70 (m, 1H, Ar-H), 7.56 (s, 1H, Ar-H), 7.48–7.45 ppm (m, 3H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.2, 147.0, 136.6, 134.6, 134.5, 133.7, 131.9, 130.9, 129.9, 129.5, 129.4, 127.6, 126.9, 126.6, 123.4 ppm; HRMS (ESI) m/z: calcd for C₁₄H₁₀ClN₂O [M + H]⁺ 257.0476, found 257.0473.

4-(Pyridin-3-yl)phthalazin-1(2H)-one (5l). White solid; Mp: 242–244 °C; IR (neat): [small nu, Greek, tilde] = 3072, 1681, 1487, 1328, 1153, 821, 686, 632 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.96 (s, 1H, –NH), 8.80–8.79 (m, 1H, Ar-H), 8.74–8.72 (m, 1H, Ar-H), 8.39–8.36 (m, 1H, Ar-H), 8.03–8.02 (m, 1H, Ar-H), 7.91–7.88 (m, 2H, Ar-H), 7.69–7.67 (m, 1H, Ar-H), 7.59–7.56 ppm (m, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.2, 149.7, 149.5, 143.7, 136.5, 133.5, 131.6, 130.9, 128.8, 127.9, 126.1, 126.0, 123.3 ppm; HRMS (ESI) m/z: calcd for C₁₃H₁₀N₃O [M + H]⁺ 224.0818, found 224.0815.

4-(Thiophen-3-yl)phthalazin-1(2H)-one (5m). White solid; Mp: 230–232 °C; IR (neat): [small nu, Greek, tilde] = 3105, 1660, 1554, 1350, 1190, 792, 679 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.76 (s, 1H, –NH), 8.36–8.34 (m, 1H, Ar-H), 7.93–7.80 (m, 4H, Ar-H), 7.66–7.64 (m, 1H, Ar-H), 7.40–7.39 ppm (m, 1H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.2, 142.0, 135.8, 133.3, 131.2, 129.1, 128.3, 127.8, 126.2, 126.1, 126.0, 125.9 ppm; HRMS (ESI) m/z: calcd for C₁₂H₉N₂OS [M + H]⁺ 229.0430, found 229.0432.

4-(Benzo[b]thiophen-2-yl)phthalazin-1(2H)-one (5n). White solid; Mp: 228–230 °C; lit.^8a IR (neat): [small nu, Greek, tilde] = 3097, 1660, 1575, 1352, 1197, 914, 792, 746 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 13.00 (s, 1H, –NH), 8.39 (d, J = 7.8 Hz, 1H, Ar-H), 8.32 (d, J = 8.0 Hz, 1H, Ar-H), 8.03–7.88 (m, 5H, Ar-H), 7.45–7.41 ppm (m, 2H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 158.9, 140.1, 139.6, 138.9, 137.5, 135.8, 133.7, 131.6, 128.2, 127.8, 126.3, 125.9, 125.2, 125.0, 124.5, 124.2, 122.0 ppm; HRMS (ESI) m/z: calcd for C₁₆H₁₁N₂OS [M + H]⁺ 279.0587, found 279.0584.

4-(Naphthalen-3-yl)phthalazin-1(2H)-one (5o). White solid; Mp: 248–250 °C; IR (neat): [small nu, Greek, tilde] = 2899, 1666, 1494, 1348, 1153, 781 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.92 (s, 1H, –NH), 8.40–8.38 (m, 1H, Ar-H), 8.14 (s, 1H, Ar-H), 8.06 (d, J = 8.5 Hz, 1H, Ar-H), 8.02–7.99 (m, 2H, Ar-H), 7.89–7.85 (m, 2H, Ar-H), 7.79–7.77 (m, 1H, Ar-H), 7.71 (dd, J = 1.7, 8.4 Hz, 1H, Ar-H), 7.59 ppm (m, 2H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.3, 146.3, 133.3, 132.8, 132.6, 132.5, 131.3, 129.1, 128.6, 128.2, 128.0, 127.9, 127.5, 126.7, 126.7, 126.5, 126.5, 126.1 ppm; HRMS (ESI) m/z: calcd for C₁₈H₁₃N₂O [M + H]⁺ 273.1022, found 273.1027.

General procedure for synthesis of 4-alkynyl phthalazin-1(2H)-one (6a–e)

Compound 3a (0.5 g, 1.69 mmol), PdCl₂(dppf) (10 mol%), terminal alkynes 4b (1.71 mmol) and copper iodide (5 mol%) were dissolved in 5 mL of triethylamine and refluxed for 1–2 h under inert atmosphere. After the completion of the reaction (TLC check), the mixture was poured in water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using ethyl acetate : n-hexane (30–40%) as the eluent to yield pure product as white solid.

4-(2-Phenylethynyl)phthalazin-1(2H)-one (6a). White solid; Mp: 200–202 °C; IR (neat): [small nu, Greek, tilde] = 3151, 2225, 1660, 1496, 1338, 1022, 807, 756 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 13.00 (s, 1H, –NH), 8.30 (d, J = 7.7 Hz, 1H, Ar-H), 8.17 (d, J = 7.9 Hz, 1H, Ar-H), 8.03–7.99 (m, 1H, Ar-H), 7.91–7.88 (m, 1H, Ar-H), 7.73–7.70 (m, 2H, Ar-H), 7.50–7.47 ppm (m, 3H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆); δ = 159.0, 133.9, 131.9, 131.7, 131.1, 129.7, 129.5, 128.7, 127.1, 125.8, 125.8, 121.0, 92.9, 82.7 ppm; HRMS (ESI) m/z: calcd for C₁₆H₁₁N₂O [M + H]⁺ 247.0866, found 247.0863.

4-(2-m-Tolylethynyl)phthalazin-1(2H)-one (6b). White solid; Mp: 232–234 °C; IR (neat): [small nu, Greek, tilde] = 3101, 2220, 1662, 1577, 1494, 1332, 1155, 777, 682 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.99 (s, 1H, –NH), 8.29 (d, J = 7.7 Hz, 1H, Ar-H), 8.17 (d, J = 7.8 Hz, 1H, Ar-H), 8.03–7.99 (m, 1H, Ar-H), 7.91–7.87 (m, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.50 (d, J = 7.6 Hz, 1H, Ar-H), 7.37–7.33 (m, 1H, Ar-H), 7.29 ppm (d, J = 7.6 Hz, 1H, Ar-H), 2.38 (s, 3H, Ar-CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.0, 138.1, 133.9, 132.0, 131.9, 131.2, 130.3, 129.7, 128.8, 128.5, 127.1, 125.8, 125.8, 120.8, 93.2, 82.1 ppm; HRMS (ESI) m/z: calcd for C₁₇H₁₃N₂O [M + H]⁺ 261.1022, found 261.1020.

4-(2-(3-Aminophenyl)ethynyl)phthalazin-1(2H)-one (6c). White solid; Mp: 274–276 °C; IR (neat): [small nu, Greek, tilde] = 3414, 3161, 2218, 1668, 1598, 1348, 1159, 856, 773 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.96 (s, 1H, –NH), 8.30 (d, J = 7.7 Hz, 1H, Ar-H), 8.13 (d, J = 7.9 Hz, 1H, Ar-H), 8.03–8.0 (m, 1H, Ar-H), 7.91–7.87 (m, 1H, Ar-H), 7.14–7.10 (m, 1H, Ar-H), 6.91 (s, 1H, Ar-H), 6.86 (d, J = 7.5 Hz, 1H, Ar-H), 6.72 (d, J = 8.0 Hz, 1H, Ar-H), 5.27 ppm (s, 2H, –NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.0, 148.8, 133.9, 131.9, 131.3, 129.8, 129.2, 127.1, 125.8, 121.1, 119.2, 116.4, 115.5, 94.2, 81.4 ppm; HRMS (ESI) m/z: calcd for C₁₆H₁₂N₃O [M + H]⁺ 262.0975, found 262.0974.

4-(Hept-1-ynyl)phthalazin-1(2H)-one (6d). White solid; Mp: 138–140 °C; IR (neat): [small nu, Greek, tilde] = 3155, 2231, 1660, 1583, 1330, 1149, 906, 776 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.80 (s, 1H, –NH), 8.28–8.23 (m, 1H, Ar-H), 8.02 (d, J = 7.4 Hz, 1H, Ar-H), 7.98–7.93 (m, 1H, Ar-H), 7.88–7.84 (m, 1H, Ar-H), 2.58–2.54 (m, 2H, –CH₂), 1.70–1.63 (m, 2H, –CH₂), 1.51–1.45 (m, 2H, –CH₂), 1.43–1.33 (m, 2H, –CH₂), 0.94–0.91 ppm (t, 3H, –CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.0, 133.6, 131.7, 131.6, 129.9, 127.1, 125.8, 125.7, 95.2, 74.3, 30.6, 27.5, 21.6, 18.6, 13.8 ppm; HRMS (ESI) m/z: calcd for C₁₅H₁₇N₂O [M + H]⁺ 241.1335, found 241.1334.

4-(Oct-1-ynyl)phthalazin-1(2H)-one (6e). White solid; Mp: 118–120 °C; IR (neat): [small nu, Greek, tilde] = 3153, 2231, 1660, 1471, 1334, 1149, 904, 786 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.81 (s, 1H, –NH), 8.26 (d, J = 7.7 Hz, 1H, Ar-H), 8.02 (d, J = 7.4 Hz, 1H, Ar-H), 7.98–7.94 (m, 1H, Ar-H), 7.90–7.85 (m, 1H, Ar-H), 2.58–2.54 (m, 2H, –CH₂), 1.67–1.61 (m, 2H, –CH₂), 1.50–1.46 (m, 2H, –CH₂),1.35–1.31 (m, 4H, –CH₂), 0.91–0.89 ppm (m, 3H, –CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 158.9, 133.7, 131.8, 131.6, 129.9, 127.1, 125.8, 121.7, 95.3, 74.3, 30.7, 28.0, 27.8, 22.0, 18.6, 13.8 ppm; HRMS (ESI) m/z: calcd for C₁₆H₁₉N₂O [M + H]⁺ 255.1492, found 255.1491.

General procedure for synthesis of 1-chloro-4-arylphthalazine (7)

Compound 5 (3.0 g, 13.50 mmol) was taken in 20 mL of acetonitrile, and POCl₃ (12.63 mL, 135.09 mmol) was added to it at room temperature, and then refluxed for 5–6 h. After the completion of the reaction (TLC check), the reaction mixture was neutralized by aqueous saturated NaHCO₃ solution and then extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography using ethyl acetate : n-hexane (15–20%) as the eluent to get pure product as a white solid (2.8 g, 86%).

1-Chloro-4-phenylphthalazine (7a). White solid; Mp: 138–142 °C; lit.^8b IR (neat): [small nu, Greek, tilde] = 3041, 1527, 1446, 1292, 1174, 781, 760 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.38 (d, J = 8 Hz, 1H, Ar-H), 8.18–8.14 (m, 1H, Ar-H), 8.11–8.03 (m, 2H, Ar-H), 7.73–7.70 (m, 2H, Ar-H), 7.64–7.62 ppm (m, 3H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.9, 153.7, 134.9, 134.0, 133.8, 129.7, 129.5, 128.4, 126.6, 126.6, 125.5, 124.8 ppm; HRMS (ESI) m/z: calcd for C₁₄H₁₀ClN₂ [M + H]⁺ 241.0532, found 241.0537.

1-Chloro-4-(naphthalen-3-yl)phthalazine (7b). White solid; Mp: 178–180 °C; IR (neat): [small nu, Greek, tilde] = 3072, 1568, 1527, 1471, 746, 678, 634 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.40 (d, J = 8.2 Hz, 1H, Ar-H), 8.28 (s, 1H, Ar-H), 8.19–8.03 (m, 6H, Ar-H), 7.84–7.82 (m, 1H, Ar-H), 7.65–7.61 ppm (m, 2H, Ar-H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.9, 153.8, 134.1, 133.9, 133.1, 132.5, 132.4, 129.7, 128.4, 128.1, 127.6, 127.1, 126.9, 126.8, 126.7, 126.7, 125.5, 124.9 ppm; HRMS (ESI) m/z: calcd for C₁₈H₁₂ClN₂ [M + H]⁺ 291.0683, found 291.0685.

Synthesis of 1-morpholino-4-phenylphthalazine (8a). This compound was synthesized according to the reported method¹¹ in 81% yield.

White solid; Mp: 190–192 °C; lit.¹¹ IR (neat): [small nu, Greek, tilde] = 3047, 2852, 1529, 1444, 1408, 1111, 889, 706 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.20 (d, J = 8.1 Hz, 1H, Ar-H), 7.97–7.88 (m, 3H, Ar-H), 7.69–7.66 (m, 2H, Ar-H), 7.61–7.55 (m, 3H, Ar-H), 3.93 (t, J = 4.5 Hz, 4H, –OCH₂), 3.48 ppm (t, J = 4.5 Hz, 4H, –OCH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ = 158.8, 155.8, 136.3, 131.3, 131.9, 131.6, 129.6, 128.7, 128.3, 126.5, 126.2, 124.4, 120.8, 66.1, 51.3 ppm; HRMS (ESI) m/z: calcd for C₁₈H₁₈N₃O [M + H]⁺ 292.1444, found 292.1444.

Synthesis of 1-(3-methoxyphenyl)-4-phenylphthalazine (9a). Compound 7a (0.5 g, 2.07 mmol), PdCl₂(dppf) (10 mol%), 3-methoxyphenylboronic acid (2.09 mmol) and K₃PO₄ (3.11 mmol) were dissolved in 5 mL of 1,4-dioxane and refluxed for 2–3 h under an inert atmosphere. After completion of the reaction (TLC check), the reaction mixture was poured in 25 mL of water and extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude compound, which was purified by column chromatography using ethyl acetate : n-hexane (25–35%) as the eluent to yield product as a white solid (452 mg, 69%).

Mp: 168–170 °C; IR (neat): [small nu, Greek, tilde] = 3072, 1589, 1489, 1253, 1159, 1041, 790, 705 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.08–8.05 (m, 1H, Ar-H), 8.05–8.01 (m, 3H, Ar-H), 7.77 (dd, J = 2, 4.7 Hz, 2H, Ar-H), 7.67–7.61 (m, 3H, Ar-H), 7.61–7.54 (m, 1H, Ar-H), 7.33–7.32 (m, 2H, Ar-H), 7.20–7.18 (m, 1H, Ar-H), 3.86 ppm (s, 3H, –OCH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 159.2, 158.6, 158.4, 137.3, 136.0, 132.9, 129.8, 129.6, 129.3, 128.5, 126.1, 126.0, 124.9, 124.9, 122.1, 115.2, 115.0, 55.2 ppm; HRMS (ESI) m/z: calcd for C₂₁H₁₇N₂O [M + H]⁺ 313.1335, found 313.1336.

Synthesis of 1-phenyl-4-(2-m-tolylethynyl)phthalazine (10a). Compound 7a (0.5 g, 2.07 mmol), PdCl₂(dppf) (10 mol%), 1-ethynyl-3-methylbenzene (2.09 mmol) and copper iodide (5 mol%) were dissolved in 5 mL of triethylamine and refluxed for 1–2 h under an inert atmosphere. After completion of the reaction (TLC check), the reaction mixture was poured in 25 mL of water and extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude compound, which was purified by column chromatography using ethyl acetate : n-hexane (25–30%) as the eluent to yield pure product as a white solid (490 mg, 73%).

Mp: 164–166 °C; IR (neat): [small nu, Greek, tilde] = 3043, 2218, 1508, 1384, 1259, 1078, 788, 709 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.54 (d, J = 8.5 Hz, 1H, Ar-H), 8.19–8.15 (m, 1H, Ar-H), 8.10–8.04 (m, 2H, Ar-H), 7.78–7.76 (m, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 7.64–7.63 (m, 4H, Ar-H), 7.45–7.42 (m, 1H, Ar-H), 7.38 (d, J = 7.5 Hz, 1H, Ar-H), 2.39 ppm (s, 3H, Ar-CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 158.0, 144.9, 138.4, 135.6, 133.8, 133.6, 132.5, 131.0, 130.0, 129.5, 129.3, 128.9, 128.5, 126.9, 126.1, 125.5, 123.7, 120.5, 96.8, 83.8, 20.7 ppm; HRMS (ESI) m/z: calcd for C₂₃H₁₇N₂ [M + H]⁺ 321.1386, found 321.1387.

Acknowledgements

We would like to thank the Council of Scientific and Industrial Research (CSIR), (no. 02(0001)/11/EMR-II) New Delhi-110 001 and the Board of Colleges and University Development (BCUD), (no. OSD/BCUD/360/36) Savitribai Phule Pune University, Pune-411 007, MS, India for supporting this study. Ganesh Dhage thanks CSIR, New Delhi for a fellowship. We wish thank to Dr R. J. Barnabas (The Principal, Ahmednagar College, Ahmednagar) for helpful discussions and suggestions.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra03390j

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