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DOI: 10.1055/a-2048-8030
Palladium-Catalyzed Regioselective C-Arylation and C,N-Diarylation of N-Aryl-2,3-dihydrophthalazine-1,4-diones Using Diaryliodonium Salts
S.N. is thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi for providing a Junior Research Fellowship. N.K.D. and C.K.M. are thankful to the Birla Institute of Technology and Science, Pilani, for providing Junior and Senior Research Fellowships, respectively. The authors acknowledge the Science and Engineering Research Board (SERB), New Delhi, for providing a research grant (CRG/2021/000131).
Abstract
Regioselective C-arylation and C,N-diarylation in 2-aryl-2,3-dihydrophthalazine-1,4-diones has been successfully accomplished with diaryliodonium salts under base-mediated slightly modified Pd-catalyzed conditions. These ligand-driven transformations provided a variety of diversely decorated bi(hetero)aryls in good-to-excellent yields, while N-arylated product could be obtained under similar Pd-catalyzed conditions in the absence of a ligand.
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Diazaheterocyclic scaffolds are found embedded within the molecular structures of several marketed drugs,[1] and functional materials.[2] In particular, the naturally occurring and synthetic analogues of the phthalazine nucleus are known to exhibit varied biological activities, such as antitumor,[3] [4] [5] anticonvulsant,[6,7] antihypertensive,[8] anti-inflammatory,[9] cardiotonic,[10] antimicrobial[11] [12] etc. (Figure [1]).
Consequently, a significant interest by eminent research groups has been noticed in the past few years in the construction of functionalized or fused-phthalazines via transition-metal-catalyzed C–H activation. Under this domain, ortho-Csp2-functionalization at N-aryl-2,3-dihydrophthalazine-1,4-diones has been accomplished by using sulfoxonium ylides,[13] arylsulfonyl chlorides,[14] N-halosuccinimides,[14] maleimides,[15] isocyanates,[16] dioxazolones,[17] and activated carbonyl compounds[18] by exploring the chelation-assisted inbuilt cyclic amide directing group aided C–H activation approach under Ru(II), Rh(III), and Pd(0) catalysis (Scheme [1], top right).
In striking contrast, hypervalent iodine reagents (e.g., diaryliodonium salts) have been exemplified as ideal aryl transferring agents because of their high stability, lower air/moisture sensitivity, mild and nontoxic behavior, and their ease of accessibility from commercially available reagents.[19] [20] [21] [22] In lieu of the valuable applications of biaryls in material/medicinal chemistry,[23–26] noteworthy advancements have been made towards the synthesis of bi(hetero)aryls by using diaryliodonium salts as efficient coupling partners either by directing group assisted or non-directed functionalization in the presence of a variety of palladium catalysts. Particularly, the pioneering work by Sanford and co-workers towards direct C2-arylation of indoles, involving the generation of aryl–palladium(IV) species via oxidation of palladium(II) catalyst with diaryliodonium salts is worth appraising (Scheme [1a]).[27] Following this work, several transition-metal-catalyzed C–H/N–H arylation strategies with diaryliodonium salts have been disclosed by leading scientists, including Fairlamb,[28] Li,[29] Kumar,[30] Vaccaro,[31] Glorius,[32] McGlacken,[33] Zhang,[34] Hong,[35] Gaunt,[36] Sharma,[37] Shi,[38] Wang,[39] and others to furnish highly valuable bi(hetero)aryl scaffolds (Scheme [1b–f]). Interestingly, the functionalization of N-aryl-2,3-dihydrophthalazine-1,4-diones with iodonium salts remains unexplored. In the backdrop of the above discussion, and our continuous efforts on executing C–H functionalization, we herein disclose regioselective strategies for the C-arylation, and C,N-diarylation in 2-aryl-2,3-dihydrophthalazine-1,4-diones with diaryliodonium salts under slightly modified palladium-catalyzed conditions.
Our initial studies focused on optimizing the reaction conditions for the envisioned Csp2–H arylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) with diphenyliodonium triflate ([Ph2I]OTf, 2a) under Pd-catalyzed condition as a model reaction (Table [1]). A combination of Pd(OAc)2 (2.5 mol%) and KOAc (0.5 equiv) in DMF failed to facilitate the reaction between the model substrates 1a and 2a at room temperature under oxygen atmosphere (Table [1], entry 1), while traces of new spots were visible on TLC along with the major amounts of starting materials when the temperature of the reaction was methodically raised from 80 °C to 130 °C (Table [1], entry 2) To our delight, the use of external ligands led to a substantial product formation along with the consumption of reasonable amount of starting materials. For example, a mixture of Pd(OAc)2, KOAc, and 2,2′-bipyridyl ligand (10 mol%) in DMF at 130 °C promoted the arylation of 1a with 2a, furnishing 3aa in 34% yield (Table [1], entry 3). The structure of 3aa was unambiguously confirmed by its detailed spectroscopic analysis, such as 1H NMR, 13C NMR, and HRMS. Replacement of 2,2′-bipyridyl with tricyclohexylphosphine (10 mol%) and triphenylphosphine ligands (10 mol%) improved the products yield to 44% and 48%, respectively (Table [1], entries 4 and 5). Gratifyingly, the product yield was enhanced to 67% by the employment of XPhos ligand (10 mol%), which was further elevated to 80% and 91% by sequentially increasing the base concentration to 1 equivalent and 2 equivalents, respectively (Table [1], entries 6–8). Notable, no considerable change in the yield of 3aa was observed by increasing the catalyst concentration to 3 mol%, while a detrimental effect on reducing the amount of the ligand to 5 mol% was noticed on the product yield (Table [1], entries 9 and 10). Surprisingly, the use of CsOAc with the model reaction using the Pd(OAc)2/XPhos catalytic system was unsuccessful, while the application of NaOAc produced only 30% of 3aa (Table [1], entries 11 and 12). In contrast, the usage of K2CO3 (2 equiv) afforded a mixture of C-arylated and C/N-diarylated products 3aa and 4aa in 15% and 32%, respectively (Table [1], entry 13). Solvent screening studies suggested toluene to be an inferior solvent for the model reaction, while acetonitrile, ethanol, tert-butanol, and 1,2-dichloroethane did not initiate any substantial product formation (Table [1], entries 14–18). Notably, the model reaction was unsuccessful under a nitrogen atmosphere, while only 38% of 3aa was obtained by performing the model reaction under an air atmosphere (Table [1], entries 19 and 20).
a Reaction conditions: 1a (0.21 mmol), 2a (0.23 mmol), catalyst/base/ligand (as indicated in the table), solvent (3 mL), temp (°C), 3 h, under O2 atmosphere.
b Isolated yields after column chromatography.
c 32% of C,N-diarylated product (4aa) isolated.
d Under N2 atmosphere.
e Under air atmosphere.
With the optimized reaction conditions in hand, the substrate scope of various N-aryl-2,3-dihydrophthalazine-1,4-diones 1 with [Ph–I–Ph]OTf (2a) was examined (Scheme [2]). It was found that electron-releasing as well as moderately electron-withdrawing substituents on the aryl ring (substrates: 1b–n) were viable under the optimized conditions. For example, para-substituted N-aryl-2,3-dihydrophthalazine-1,4-diones possessing electron-donating substituents [substrates: 1b (R2 = 4-Me), 1c (R2 = 4- i Pr), and 1d (R2 = 4-OMe)] reacted extremely well with 2a to produce the corresponding ortho-phenyl-substituted products, 3ba, 3ca, and 3da in 93%, 94%, and 95% yields respectively. Also, moderate electron-withdrawing halogen-containing substrates [1e (R2 = 4-F), 1f (R2 = 4-Cl), and 1g (R2 = 4-Br)] reacted reasonably well with 2a to produce the corresponding ortho-phenyl-substituted products 3ea–3ga in good yields (79–84%), whereas meta-halogen-substituted substrates [1h (R2 = 3-F) and 1i (R2 = 3-Cl)] reacted with 2a in comparatively lower reactivity, providing the desired products 3ha and 3ia in 69–72% yields. The arylation proceeded with great ease for N-aryl-2,3-dihydrophthalazine-1,4-diones bearing disubstitution on the aryl ring [substrate: 1j (R2 = 3,4-Me2)], delivering an inseparable isomeric mixture of C-arylated products 3ja in 92% yield. Furthermore, inseparable regioisomeric forms of N-aryl-2,3-dihydrophthalazine-1,4-diones decorated with electron-releasing and electron-withdrawing substituents on the phthalazinedione moiety [substrates: 1k (R1 = 5/8-F), 1l (R1 = 6/7-Me), 1m (R1 = 6/7-OMe), 1n (R1 = 6/7- t Bu), 1o (R1 = 6/7-Br)] pleasingly reacted with 2a to furnished their corresponding C-arylated products 3ka–3oa as regioisomeric mixtures of varying ratios in good-to-excellent yields (64–85%). Unfortunately, the presence of strong deactivating substituents on the substrates [1p (R2 = 4-NO2), 1q (R2 = 4-CN), 1r (R2 = 4-CF3), 1t (R2 = 3-NO2), and 1u (R1 = 6-NO2)] disfavor any C-arylation with 2a under the described conditions (Scheme [2]). Also iodo-substituted N-phenyl-2,3-dihydrophthalazine-1,4-dione substrate 1s was unreactive under the optimized conditions.
Next, the generality of the reaction was explored by performing the reaction of 1a with various unsymmetrical diaryliodonium salts 2b–j under the optimized Pd conditions to access corresponding C-arylated products 3. Interestingly, unsymmetrical diaryliodonium salts, such as [Ph–I–(p-Me-C6H4)]OTf (2b), [Ph–I–(p- t Bu-C6H4)]OTf (2c), [Ph–I–(p-Cl-C6H4)]OTf (2d), [Ph–I–(m-Me-C6H4)]OTf (2e), and [Ph–I–(3,5-Me2-C6H3)]OTf (2f) reacted comfortably with 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) under the standard conditions to furnish C-arylated products 3ab–3af in good yields (64–72%). On the other hand, halo-substituted unsymmetrical diaryliodonium salts, [Ph–I–(p-Br-C6H4)]OTf (2g) and [Ph–I–(m-Br-C6H4)]OTf (2h) reacted with 1a with moderate reactivity to produce C-arylated products 3ag and 3ah in 67% and 62% yields, respectively. In most cases, excellent chemoselectivity is achieved by the transfer of electron-rich aryl ring (R3 = Me, t Bu, Me2), enabling the elimination of iodobenzene [with the exception of moderately electron-withdrawing chloro-substituted unsymmetrical iodonium salt (2d)]. In contrast, with bromo-substituted unsymmetrical diaryliodonium salts 2g and 2h, the corresponding products 3ag and 3ah were obtained as regioisomeric inseparable mixtures possessing major amounts of C-(p or m-bromo)phenyl-substituted isomers and minor amounts of C-phenyl-substituted isomer. Unfortunately, diaryliodonium salts, such as [Ph–I–(p-F-C6H4)]OTf (2i) and [Ph–I–(p-NO2-C6H4)]OTf (2j), failed to react with 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) under the described conditions (Scheme [3]).
During one of the optimization studies, the formation of C,N-diarylated product 4aa was observed in low yields under K2CO3-mediated Pd-catalyzed conditions in DMF at 130 °C within 3 h (Table [1], entry 13). Further optimization studies suggested that the use of 3.0 equivalents of iodonium salt under standard conditions could directly produce the C,N-diarylated product within 3 h in appreciable yield from the starting material. Under this domain, successful C,N-diarylation (products: 4aa, 4ba, and 4ga) in a variety of N-aryl-2,3-dihydrophthalazine-1,4-diones [substrates: 1a (R2 = H), 1b (R2 = 4-Me), and 1g (R2 = 4-Br)] were accomplished with [Ph–I–Ph]OTf (2a) (3.0 equiv) under the standard conditions in 86–92% yields (Scheme [4]).
To gain insight into the reaction mechanism, a few control experiments were carried out (Scheme [5]). The ortho Csp2–H arylation reaction between 1a and 2a did not proceed without the use of Pd catalyst in presence of base and ligand (Scheme [5] I). The possibility of a radical pathway was unambiguously eliminated as the reaction efficiency between 1a and 2a under standard conditions remains unaffected in the presence of radical scavengers, such as TEMPO or BHT (Scheme [5] II). Intermolecular competitive experiments conducted between 2a and N-aryl-2,3-dihydrophthalazine-1,4-diones containing electron-rich and moderately electron-deficient groups on the aryl ring (substrates: 1b (R2 = Me) and 1f (R2 = Cl) resulted in the formation of a mixture of their corresponding C–H arylation products 3ba and 3fa in 2:1 ratio, respectively (Scheme [5] III). The conversion of C-arylated product 3aa into C,N-diarylated product 4aa in 91% yield was observed by using 1.1 equivalents of diaryliodonium salt 2a under Pd-catalyzed conditions in absence of XPhos (Scheme [5] IV). While the N-arylated product 3′ea was obtained by the reaction of diphenyliodonium triflate (2a) with 1e using a catalytic amount of Pd(OAc)2 in the absence of XPhos and O2 atmosphere. Also, 3′ea was not transformed into the corresponding C,N-diarylated product 4ea under Pd-catalyzed conditions in presence of XPhos, even with heating the reaction mixture for up to 12 h (Scheme [5v]). These observations suggested the C-arylated product (albeit not N-arylated product) to be an intermediate for the formation of C,N-diarylated product, and the critical requirement of XPhos ligand for C-arylation, but not for N-arylation. Further, in situ intermediate monitoring the reaction between 1a and 2a under standard conditions in DMF at 80 °C after 1 h by mass spectrometry indicated the formation of a C-palladated species A and a five-membered palladacyclic intermediate B (Scheme [5] VI).
Based on our investigations and literature reports,[40] [41] the Csp2–H arylation of N-aryl-2,3-dihydrophthalazine-1,4-diones 1 with diaryliodonium salts 2 is believed to proceed via a PdII/IV catalytic cycle with the aid of KOAc for which the presence of oxygen is crucial. Initially, coordination of 1a to PdII species followed by ortho Csp2–H activation forms a five-membered cyclopalladation species B via A (Scheme [6]). Next, oxidative addition of diaryliodonium salt 2a generates a PdIV species C along with the elimination of iodoarene. Finally, the ortho-arylated product 3a is formed by the reductive elimination of PdII(OAc)OTf species from C, which subsequently is transformed to Pd(OAc)2 in the presence of KOAc for the next catalytic cycle. In the presence of excess of diaryliodonium salt 2a, the second PdII/PdIV catalytic sub-step (in presence of O2) transforms the C-arylated product 3aa into C,N-diarylated product 4aa via species D and E.
In summary, we have developed straightforward palladium-catalyzed strategies for the direct Csp2–H arylation, and C,N-diarylation of 2-aryl-2,3-dihydrophthalazine-1,4-diones with diaryliodonium salts using the Pd(OAc)2/XPhos catalytic system via directing group-assisted C–H activation. While direct N-arylation in one of the derivatives, 2-(4-fluorophenyl)-2,3-dihydrophthalazine-1,4-dione was achieved under slightly modified KOAc-mediated Pd-catalyzed conditions without using an external ligand. These mild strategies furnished variedly decorated bi(hetero)aryls in good-to-excellent yields. A series of preliminary experiments were conducted to probe the reaction mechanism.
Commercially available reagents were used without purification. Commercially available solvents were dried by standard procedures prior to use. NMR spectra were recorded on a 400 MHz spectrometer, and the chemical shifts are reported relative to residual CHCl3 (δ = 7.26) or DMSO (δ = 2.5) in the deuterated solvent. 13C NMR spectra are reported relative to CDCl3 (δ = 77.0) or DMSO-d 6 (δ = 39.5). Melting points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorrected. HRMS were recorded on Agilent Technologies 6545 Q-TOF LC/MS by using electrospray mode. Column chromatography was performed on silica gel (100–200) mesh using varying ratio of EtOAc/hexanes as eluent. Compounds 1a–u and 2a–j were prepared according to the literature procedure and identified by comparison of melting point/1H NMR data with the literature melting point/1H NMR data.[42] [43]
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C-Arylation of N-Aryl-2,3-dihydrophthalazine-1,4-diones; General Procedure
To an oven-dried 10-mL round-bottom flask containing 2-aryl-2,3-dihydrophthalazine-1,4-dione 1 (50 mg, 1 equiv) in DMF (2 mL), diaryliodonium salt 2 (1.1 equiv), Pd(OAc)2 (0.025 equiv), XPhos (0.1 equiv), and KOAc (2 equiv) were added under an O2 atmosphere. The mixture was stirred and heated in an oil bath at 130 °C for 3 h (monitored by TLC). After completion of the reaction, the mixture was cooled to r.t., concentrated, diluted with water, and extracted with EtOAc (20 mL × 2). The organic layers were separated and concentrated under reduced pressure to afford a residue that was purified by column chromatography (SiO2, 100–200 mesh, hexanes/EtOAc 8:2) to afford the desired product 3.
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2-([1,1′-Biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3aa)
White solid; yield: 60 mg (91%); mp 251–253 °C.
1H NMR (400 MHz, CDCl3): δ = 8.38 (d, J = 5.2 Hz, 1 H), 7.89–7.83 (m, 1 H), 7.82–7.75 (m, 2 H), 7.61–7.46 (m, 3 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.33–7.26 (m, 2 H), 7.22–7.14 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 152.1, 140.4, 138.5, 137.8, 133.2, 132.9, 131.0, 129.6, 129.5, 128.7, 128.5, 128.4, 128.2, 127.7, 127.4, 125.1, 125.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H15N2O2: 315.1133; found: 315.1129.
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2-(5-Methyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ba)
White solid; yield: 61 mg (93%); mp 297–299 °C.
1H NMR (400 MHz, CDCl3): δ = 8.39–8.33 (m, 1 H), 7.93–7.87 (m, 1 H), 7.82–7.75 (m, 2 H), 7.33–7.32 (m, 1 H), 7.31–7.28 (m, 4 H), 7.20–7.15 (m, 3 H), 2.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 152.4, 140.1, 139.5, 138.6, 135.1, 133.1, 132.9, 131.7, 129.6, 129.2, 128.4, 128.4, 128.2, 127.7, 127.3, 125.3, 125.1, 21.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O2: 329.1290; found: 329.1285.
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2-(5-Isopropyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ca)
White solid; yield: 60 mg (94%); mp 178–180 °C.
1H NMR (400 MHz, CDCl3): δ = 8.43–8.35 (m, 1 H), 7.92–7.84 (m, 1 H), 7.82–7.75 (m, 2 H), 7.39–7.37 (m, 1 H), 7.36–7.29 (m, 4 H), 7.21–7.16 (m, 3 H), 3.06 (sept, J = 6.8 Hz, 1 H), 1.36 (d, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.1, 152.2, 150.3, 140.1, 138.8, 135.3, 133.1, 132.8, 129.7, 129.2, 128.4, 128.4, 128.2, 127.8, 127.3, 126.7, 125.3, 125.0, 34.1, 24.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H21N2O2: 357.1603; found: 357.1596.
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2-(5-Methoxy-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3da)
White solid; yield: 61 mg (95%); mp 181–183 °C.
1H NMR (400 MHz, CDCl3): δ = 8.40–8.34 (m, 1 H), 7.95–7.90 (m, 1 H), 7.82–7.77 (m, 2 H), 7.36–7.29 (m, 3 H), 7.22–7.16 (m, 3 H), 7.04–6.98 (m, 2 H), 3.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 158.2, 152.5, 141.8, 138.4, 133.1, 132.9, 130.4, 129.8, 129.6, 128.3, 128.3, 127.8, 127.5, 125.5, 125.2, 116.1, 113.9, 55.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O3: 345.1239; found: 345.1232.
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2-(5-Fluoro-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ea)
White solid; yield: 51 mg (79%); mp 162–164 °C.
1H NMR (400 MHz, CDCl3): δ = 8.37 (dd, J = 6.4, 2.2 Hz, 1 H), 7.92–7.87 (m, 1 H), 7.86–7.77 (m, 2 H), 7.43–7.37 (m, 1 H), 7.28–7.24 (m, 2 H), 7.23–7.14 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 162.6 (1 J C-F = 248 Hz), 158.4, 151.9, 142.7 (3 J C-F = 8 Hz), 137.5, 133.9 (4 J C-F = 3 Hz), 133.4, 133.0, 130.6, 130.5, 129.5, 128.4, 128.2, 127.9, 127.7, 124.8 (3 J C-F = 8 Hz), 117.7 (2 J C-F = 22.8 Hz), 115.3 (2 J C-F = 22.7 Hz).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14FN2O2: 333.1039; found: 333.1032.
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2-(5-Chloro-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3fa)
White solid; yield: 51 mg (80%); mp 226–228 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.84 (br s, 1 H), 8.14–8.05 (m, 1 H), 7.94–7.78 (m, 3 H), 7.62–7.49 (m, 3 H), 7.33–7.15 (m, 5 H).
13C NMR (100 MHz, DMSO-d 6): δ = 158.1, 150.6, 141.8, 138.9, 137.6, 134.1, 133.7, 133.0, 131.6, 130.4, 129.2, 128.8, 128.7, 128.5, 128.3, 127.1, 125.2, 124.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14ClN2O2: 349.0743; found: 349.0739.
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2-(5-Bromo-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ga)
White solid; yield: 52 mg (84%); mp 252–254 °C.
1H NMR (400 MHz, CDCl3): δ = 8.47–8.40 (m, 2 H), 7.94–7.88 (m, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.34–7.31 (m, 3 H), 7.26–7.20 (m, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 158.1, 150.7, 142.1, 139.3, 137.5, 134.1, 133.2, 133.0, 131.8, 131.7, 129.1, 128.8, 128.5, 128.3, 127.1, 125.2, 124.8, 122.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14BrN2O2: 393.0238; found: 393.0228.
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2-(6-Fluoro-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ha)
White solid; yield: 45 mg (69%); mp 193–195 °C.
1H NMR (400 MHz, CDCl3): δ = 8.36 (dd, J = 6.8, 2.0 Hz, 1 H), 7.87–7.83 (m, 1 H), 7.82–7.74 (m, 2 H), 7.50–7.41 (m, 1 H), 7.35–7.31 (m, 1 H), 7.30–7.23 (m, 3 H), 7.22–7.16 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.1 (1 J C-F = 246 Hz), 158.3, 151.9, 139.8 (3 J C-F = 4.8 Hz), 133.1 (2 J C-F = 39.5 Hz), 131.4, 129.5, 129.4, 129.2 (3 J C-F = 9.4 Hz), 129.1, 128.9, 128.0, 127.9, 127.6, 124.9, 124.7, 124.4 (4 J C-F = 3.4 Hz), 116.7 (2 J C-F = 22.9 Hz).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14FN2O2: 333.1039; found: 333.1028.
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2-(6-Chloro-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ia)
White solid; yield: 46 mg (72%); mp 241–243 °C.
1H NMR (400 MHz, CDCl3): δ = 8.40–8.33 (m, 1 H), 7.97–7.90 (m, 1 H), 7.88–7.77 (m, 2 H), 7.54 (dd, J = 8.4, 1.8 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.28–7.24 (m, 2 H), 7.23–7.17 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 151.7, 138.9, 138.8, 137.5, 133.7, 133.5, 133.0, 132.0, 129.7, 129.4, 129.0, 128.4, 128.2, 127.7, 127.7, 124.9, 124.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14ClN2O2: 349.0743; found: 349.0738.
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2-(4,5-Dimethyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione + 2-(5,6-Dimethyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (0.65:1 or 1:0.65) (3ja)
White solid; yield: 59 mg (92%); mp 229–231 °C.
1H NMR (400 MHz, CDCl3): δ = 8.47–8.42 (m, 1.65 H), 8.40–8.36 (m, 0.65 H), 7.99–7.75 (m, 5.20 H), 7.32–7.28 (m, 2.80 H), 7.25–7.14 (m, 5.20 H), 7.06 (s, 1 H), 7.00 (s, 1.65 H), 2.38 (s, 3 H), 2.32 (s, 3 H), 2.16 (s, 3.9 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 158.4, 158.2, 152.4, 138.5, 138.2, 137.6, 137.5, 137.3, 137.2, 137.1, 135.1, 135.0, 133.9, 133.8, 133.0, 132.8, 132.1, 129.9, 129.7, 129.6, 129.4, 128.7, 128.6, 128.4, 128.3, 128.2, 128.2, 127.7, 127.1, 126.1, 125.5, 125.1, 19.69, 19.65, 19.50.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19N2O2: 343.1446; found: 343.1438.
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2-([1,1′-Biphenyl]-2-yl)-5-fluoro-2,3-dihydrophthalazine-1,4-dione + 2-([1,1′-Biphenyl]-2-yl)-8-fluoro-2,3-dihydrophthalazine-1,4-dione (0.60:1 or 1:0.60) (3ka)
White solid; yield: 42 mg (64%); mp 235–237 °C.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.75 (m, 1.6 H), 7.74–7.71 (m, 1.6 H), 7.60–7.51 (m, 4.2 H), 7.50–7.49 (m, 1.6 H), 7.48–7.43 (m, 2.6 H), 7.37–7.31 (m, 3.4 H), 7.27–7.22 (m, 4.2 H).
13C NMR (100 MHz, CDCl3): δ = 161.8 (1 J C-F = 286 Hz), 155.7, 155.6, 149.9, 149.9, 146.6, 140.4, 138.5, 137.9, 134.7 (3 J C-F = 9 Hz), 131.1, 129.5, 128.7, 128.5, 128.4, 128.4, 127.4, 127.0, 120.9, 120.9, 120.5, 120.3.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14FN2O2: 333.1039; found: 333.1048.
#
2-([1,1′-Biphenyl]-2-yl)-6-methyl-2,3-dihydrophthalazine-1,4-dione + 2-([1,1′-Biphenyl]-2-yl)-7-methyl-2,3-dihydrophthalazine-1,4-dione (1:1.1 or 1.1:1) (3la)
White solid; yield: 54 mg (82%); mp 282–284 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1.1 H), 7.74 (d, J = 8.0 Hz, 1.1 H), 7.62 (s, 1 H), 7.61–7.44 (m, 8.4 H), 7.42–7.37 (m, 2.1 H), 7.32–7.26 (m, 4.2 H), 7.23–7.12 (m, 6.3 H), 2.53 (s, 6.3 H).
13C NMR (100 MHz, CDCl3): δ = 158.3, 158.2, 152.5, 152.2, 144.1, 144.0, 140.5, 140.5, 138.6, 137.8, 134.4, 134.2, 131.0, 129.5, 129.4, 129.4, 128.7, 128.7, 128.5, 128.4, 128.4, 128.2, 127.7, 127.5, 127.3, 125.1, 125.0, 124.7, 122.8, 22.0, 21.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O2: 329.1290; found: 329.1285.
#
2-([1,1′-Biphenyl]-2-yl)-6-methoxy-2,3-dihydrophthalazine-1,4-dione + 2-([1,1′-Biphenyl]-2-yl)-7-methoxy-2,3-dihydrophthalazine-1,4-dione (1.1:1 or 1:1.1) (3ma)
White solid; yield: 51 mg (79%); mp 202–204 °C.
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 1.1 H), 7.73 (s, 1.1 H), 7.59–7.49 (m, 6.3 H), 7.48–7.44 (m, 2.1 H), 7.37–7.30 (m, 7.3 H), 7.25–7.13 (m, 6.3 H), 3.95 (s, 6.3 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 158.1, 157.9, 152.4, 151.8, 140.4, 138.5, 138.5, 137.8, 137.7, 131.8, 131.0, 131.0, 129.9, 129.5, 129.5, 128.8, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3, 128.2, 127.4, 127.4, 127.3, 127.0, 123.1, 122.8, 121.6, 118.5, 108.3, 106.4, 56.0, 55.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O3: 345.1239; found: 345.1236.
#
2-([1,1′-Biphenyl]-2-yl)-6-tert-butyl-2,3-dihydrophthalazine-1,4-dione + 2-([1,1′-Biphenyl]-2-yl)-7-tert-butyl-2,3-dihydrophthalazine-1,4-dione (1.1:1 or 1:1.1) (3na)
White solid; yield: 53 mg (85%); mp 238–240 °C.
1H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 H), 8.30 (d, J = 8.3 Hz, 1.1 H), 7.89–7.82 (m, 4.1 H), 7.58–7.48 (m, 6.4 H), 7.41 (d, J = 7.5 Hz, 2.2 H), 7.34–7.30 (m, 4.3 H), 7.23–7.18 (m, 6.1 H), 1.41 (s, 18.9 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 157.2, 157.1, 152.8, 152.6, 140.5, 138.5, 137.8, 131.1, 131.0, 129.4, 128.8, 128.5, 128.4, 128.3, 127.6, 127.3, 125.0, 123.9, 122.8, 121.3, 35.6, 35.5, 31.1, 31.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23N2O2: 371.1759; found: 371.1755.
#
2-([1,1′-Biphenyl]-2-yl)-6-bromo-2,3-dihydrophthalazine-1,4-dione + 2-([1,1′-Biphenyl]-2-yl)-7-bromo-2,3-dihydrophthalazine-1,4-dione (0.40:1 or 1:0.40) (3oa)
White solid; yield: 47 mg (76%); mp 297–299 °C.
1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 1.4 Hz, 0.4 H), 8.22 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 1.3 Hz, 1 H), 7.93–7.83 (m, 1.4 H), 7.74 (d, J = 8.4 Hz, 0.4 H), 7.62–7.46 (m, 4.2 H), 7.41 (d, J = 7.7 Hz, 1.4 H), 7.28–7.25 (m, 2.8 H), 7.24–7.17 (m, 4.2 H).
13C NMR (100 MHz, CDCl3): δ = 157.7, 150.1, 140.3, 138.4, 137.7, 136.2, 131.2, 131.1, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.7, 127.6, 127.5, 126.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14BrN2O2: 393.0238; found: 393.0226.
#
2-(4′-Methyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ab)
White solid; yield: 49 mg (71%); mp 189–191 °C.
1H NMR (400 MHz, CDCl3): δ = 8.43–8.37 (m, 1 H), 7.98–7.91 (m, 1 H), 7.86–7.79 (m, 2 H), 7.59–7.41 (m, 4 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.02 (d, J = 7.7 Hz, 2 H), 2.27 (s 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.1, 152.0, 140.3, 137.7, 137.2, 135.5, 133.2, 132.9, 131.2, 129.7, 129.6, 129.1, 128.7, 128.3, 128.2, 127.8, 125.3, 125.1, 21.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O2: 329.1290; found: 329.1287.
#
2-(4′-tert-Butyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ac)
White solid; yield: 56 mg (72%); mp 195–197 °C.
1H NMR (400 MHz, CDCl3): δ = 8.39–8.33 (m, 1 H), 7.92–7.86 (m, 1 H), 7.82–7.75 (m, 2 H), 7.57–7.50 (m, 2 H), 7.49–7.43 (m, 1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.4 Hz, 2 H), 1.21 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 152.3, 150.2, 140.4, 137.8, 135.5, 133.1, 132.8, 131.1, 129.7, 129.5, 128.7, 128.3, 128.0, 127.7, 125.3, 125.2, 125.0, 34.4, 31.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23N2O2: 371.1759; found: 371.1757.
#
2-(4′-Chloro-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ad)
White solid; yield: 47 mg (64%); mp 171–173 °C.
1H NMR (400 MHz, CDCl3): δ = 8.42–8.35 (m, 1 H), 7.92–7.78 (m, 3 H), 7.60–7.47 (m, 3 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3 + DMSO-d 6): δ = 163.2, 155.9, 144.4, 143.5, 142.2, 137.9, 137.8, 136.9, 135.2, 134.5, 133.9, 133.8, 133.7, 133.4, 133.1, 131.8, 131.7, 130.1, 129.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14ClN2O2: 349.0743; found: 349.0741.
#
2-(3′-Methyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3ae)
White solid; yield: 48 mg (69%); mp 214–216 °C.
1H NMR (400 MHz, CDCl3): δ = 8.44–8.35 (m, 1 H), 7.93–7.86 (m, 1 H), 7.84–7.75 (m, 2 H), 7.59–7.45 (m, 3 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 7.09–7.01 (m, 2 H), 6.98 (d, J = 6.8 Hz, 1 H), 2.11 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 152.2, 140.5, 138.3, 137.8, 137.7, 133.2, 132.9, 131.0, 129.6, 129.5, 129.1, 128.7, 128.4, 128.1, 128.1, 127.7, 125.4, 125.2, 125.0, 21.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H17N2O2: 329.1290; found: 329.1285.
#
2-(3′,5′-Dimethyl-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (3af)
White solid; yield: 50 mg (70%); mp 235–237 °C.
1H NMR (400 MHz, CDCl3): δ = 8.44–8.37 (m, 1 H), 7.96–7.89 (m, 1 H), 7.85–7.78 (m, 2 H), 7.57–7.50 (m, 2 H), 7.50–7.44 (m, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 6.89 (s, 2 H), 6.80 (s, 1 H), 2.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 152.3, 140.5, 138.1, 137.6, 137.5, 133.1, 132.9, 131.0, 129.7, 129.5, 129.1, 128.8, 128.3, 127.7, 126.1, 125.1, 21.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19N2O2: 343.1446; found: 343.1441.
#
2-([1,1′-Biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione + 2-(4′-Bromo-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (0.30:1) (3ag)
White solid; yield: 55 mg (67%); mp 173–175 °C.
1H NMR (400 MHz, CDCl3): δ = 8.47–8.43 (m, 0.3 H), 8.41–8.35 (m, 1 H), 7.93–7.87 (m, 1.3 H), 7.87–7.76 (m, 2.3 H), 7.61–7.41 (m, 4.8 H), 7.37–7.29 (m, 3.3 H), 7.24–7.17 (m, 2.6 H), 7.05 (d, J = 8.1 Hz, 0.3 H).
13C NMR (100 MHz, CDCl3): δ = 158.3, 151.8, 139.0, 138.8, 137.6, 133.7, 133.5, 133.1, 132.0, 129.7, 129.4, 129.0, 128.5, 128.3, 127.8, 127.7, 125.0, 124.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14BrN2O2: 393.0238; found: 393.0236.
#
2-([1,1′-Biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione + 2-(3′-Bromo-[1,1′-biphenyl]-2-yl)-2,3-dihydrophthalazine-1,4-dione (0.70:1) (3ah)
White solid; yield: 51 mg (62%); mp 210–212 °C.
1H NMR (400 MHz, CDCl3): δ = 8.41–8.36 (m, 1.7 H), 7.96–7.92 (m, 1.7 H), 7.85–7.80 (m, 3.4 H), 7.58–7.48 (m, 6.9 H), 7.36–7.31 (m, 2.7 H), 7.25–7.19 (m, 3.7 H), 7.06 (t, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 151.5, 141.6, 139.6, 138.9, 137.8, 137.5, 132.4, 132.4, 131.04, 131.0, 130.8, 129.9, 129.86, 129.8, 129.7, 129.6, 129.5, 129.0, 128.8, 127.9, 127.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14BrN2O2: 393.0238; found: 393.0249.
#
N-Arylation of N-Aryl-2,3-dihydrophthalazine-1,4-diones; General Procedure
To an oven-dried, 10-mL round-bottom flask containing 2-aryl-2,3-dihydrophthalazine-1,4-dione 1 (50 mg, 1 equiv) in DMF (2 mL), diaryliodonium salt 2 (1.1 equiv), Pd(OAc)2 (0.025 equiv), and KOAc (2 equiv) were added under an air atmosphere. The mixture was stirred and heated in an oil bath at 130 °C for 1 h (monitored by TLC). After completion of the reaction, the mixture was cooled to r.t., concentrated, diluted with water, and extracted with EtOAc (20 mL × 2). The organic layers were separated and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (SiO2, 100–200 mesh, hexanes) to afford the desired product 3′.
#
2-(4-Fluorophenyl)-3-phenyl-2,3-dihydrophthalazine-1,4-dione (3′ea)
Yellow solid; yield: 46 mg (71%); mp 315–317 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.40–8.35 (m, 1 H), 8.19–8.15 (m, 1 H), 8.09–7.98 (m, 2 H), 7.59–7.52 (m, 2 H), 7.46–7.40 (m, 2 H), 7.39–7.35 (m, 2 H), 7.29–7.20 (m, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 161.1 (1 J C-F = 243 Hz), 158.3, 153.9, 149.8, 138.2 (4 J C-F = 2.9 Hz), 134.7, 133.7, 130.2, 129.6, 128.1 (3 J C-F = 8 Hz), 127.7, 125.5, 124.8, 124.2, 121.1, 115.7 (2 J C-F = 23 Hz).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H14FN2O2: 333.1039; found: 333.1041.
#
C,N-Diarylation of N-Aryl-2,3-dihydrophthalazine-1,4-diones; General Procedure
To an oven-dried, 10-mL round-bottom flask containing 2-aryl-2,3-dihydrophthalazine-1,4-dione 1 (50 mg, 1 equiv) in DMF (2 mL), diaryliodonium salt 2 (3 equiv), Pd(OAc)2 (0.025 equiv), XPhos (0.1 equiv), and KOAc (2 equiv) were added under an O2 atmosphere. The mixture was stirred and heated in an oil bath at 130 °C for 3 h (monitored by TLC). After completion of the reaction, the mixture was cooled to r.t., concentrated, diluted with water, and extracted with EtOAc (20 mL × 2). The organic layers were separated and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (SiO2, 100–200 mesh, hexanes/EtOAc 9:1) to afford the desired product 4.
#
2-([1,1′-Biphenyl]-2-yl)-3-phenyl-2,3-dihydrophthalazine-1,4-dione (4aa)
White solid; yield: 74 mg (90%); mp 231–233 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.33–8.29 (m, 1 H), 8.09–7.95 (m, 3 H), 7.55–7.45 (m, 4 H), 7.37–7.27 (m, 5 H), 7.18–7.12 (m, 3 H), 6.79–6.74 (m, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 159.4, 153.5, 149.0, 139.6, 139.2, 139.1, 133.4, 132.4, 131.1, 129.44, 129.38, 128.9, 128.6, 128.5, 128.3, 128.1, 127.8, 127.1, 125.1, 124.5, 123.8, 119.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H19N2O2: 391.1446; found: 391.1439.
#
2-(5-Methyl-[1,1′-biphenyl]-2-yl)-3-phenyl-2,3-dihydrophthalazine-1,4-dione (4ba)
White solid; yield: 74 mg (92%); mp 211–213 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52–8.48 (m, 1 H), 8.07–8.02 (m, 1 H), 7.89–7.82 (m, 2 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.31–7.27 (m, 6 H), 7.24 (d, J = 7.8 Hz, 3 H), 7.11 (t, J = 7.4 Hz, 1 H), 6.69 (d, J = 7.7 Hz, 2 H), 2.43 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.5, 153.6, 148.9, 139.3, 139.2, 138.8, 136.7, 133.3, 132.3, 131.7, 129.5, 129.4, 128.7, 128.6, 128.2, 127.8, 127.0, 125.1, 124.4, 123.7, 120.1, 21.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H21N2O2: 405.1603; found: 405.1598.
#
2-(5-Bromo-[1,1′-biphenyl]-2-yl)-3-phenyl-2,3-dihydrophthalazine-1,4-dione (4ga)
White solid; yield: 64 mg (86%); mp 198–200 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52–8.44 (m, 1 H), 8.10–8.04 (m, 1 H), 7.91–7.83 (m, 2 H), 7.62 (d, J = 2.2 Hz, 1 H), 7.55 (dd, J = 8.4, 2.3 Hz, 1 H), 7.35–7.27 (m, 5 H), 7.27–7.21 (m, 3 H), 7.15 (t, J = 7.4 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 159.3, 153.2, 149.4, 141.6, 138.2, 137.8, 133.9, 133.6, 132.5, 131.0, 130.2, 129.4, 129.3, 128.4, 127.8, 127.7, 125.0, 124.7, 123.9, 122.5, 120.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H18BrN2O2: 469.0551; found: 469.0556.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
The authors acknowledge the support of DST-FIST for HRMS facility at BITS Pilani.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2048-8030.
- Supporting Information
-
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Corresponding Author
Publikationsverlauf
Eingereicht: 29. Januar 2023
Angenommen nach Revision: 07. März 2023
Accepted Manuscript online:
07. März 2023
Artikel online veröffentlicht:
13. April 2023
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-
References
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