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DOI: 10.1055/a-1811-7948
Assembly of the Hydroxycinnoline Core via Hydrazide-Assisted Rh(III)-Catalyzed C–H Functionalization and Annulation
This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (nos. 2019R1A4A2001451, 2020R1A2C3005357, and 2020R1I1A1A01052800).
Abstract
The structural modification of phthalazinones and indazolones has emerged as a pivotal topic in catalytic C–H functionalization events. Herein we report the hydrazide-assisted rhodium(III)-catalyzed cross-coupling reactions of N-arylphthalazinones and N-arylindazolones with vinylene carbonate. This method provides direct access to tetracyclic hydroxycinnolines. Complete site-selectivity and functional group compatibility were observed.
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Key words
C–H functionalization - cinnolines - indazolones - phthalazinones - rhodium - vinylene carbonateBiographical Sketches
Suho Kim received his B.S. degree from the Department of Chemistry, Yonsei University in 2021. Then, he moved to join the M.S. course in the School of Pharmacy, Sungkyunkwan University under the supervision of Prof. In Su Kim. His research goal is the development of catalytic C–H functionalization and its application to the synthesis of pharmaceutical molecules.
Heon Kyu Park received his B.S. (2006) and M.S. (2008) degrees from the Department of Chemistry, Chungbuk National University. Then, he has worked in JW C&C Research Laboratories from 2009 to 2021. Along with a company job, he joined the part-time Ph.D. course in the School of Pharmacy, Sungkyunkwan University under the supervision of Prof. In Su Kim. He has focused on the development of novel catalytic C–H functionalization chemistry.
Ju Young Kang completed his B.S. from the Department of Chemistry, Kangwon National University in 2020. Then, he joined the M.S. course in the School of Pharmacy, Sungkyunkwan University under the supervision of Prof. In Su Kim. His research focuses on the transition-metal-catalyzed C–H functionalization and annulation strategy for the formation of biologically relevant N-heterocycles.
Neeraj Kumar Mishra completed his B.Sc. and M.Sc. from KNIPSS Sultanpur, UP, India, and his Ph.D. from the Department of Chemistry, University of Delhi. He worked as a postdoctoral fellow (2013–2016) under the guidance of Prof. In Su Kim. Presently, Dr. Mishra is working as a Research Professor (since 2016) at the School of Pharmacy, Sungkyunkwan University. His research interests include synthetic organic chemistry with special reference to transition-metal-catalyzed reactions.
In Su Kim received B.S. (2001), M.S. (2003), and Ph.D. (2006) degrees from the School of Pharmacy, Sungkyunkwan University under the supervision of Prof. Young Hoon Jung. Then, he moved to join the group of Prof. Michael J. Krische at the University of Texas at Austin as a postdoctoral research associate. In 2009, he started his independent career as an Assistant Professor at the Department of Chemistry, University of Ulsan. In 2012, he joined the College of Pharmacy, Sungkyunkwan University as an Associate Professor, and was promoted to Full Professor in 2018. His research interest includes the development of new methodology based on transition-metal-catalyzed C–H functionalization and application to the total synthesis of bioactive molecules.
Cinnolines are important motifs in medicinal chemistry and drug discovery as they display suitable pharmacological properties including anti-inflammatory, anticancer, GABA modulatory, and antibacterial.[1] In addition, cinnoline molecules have been exploited for their application in materials science such as cell imaging[2] and semiconductors.[3] The developed methods for the cinnoline core include the intramolecular annulation reaction of azo substrates[4] and nitriles[5] as well as intermolecular cycloaddition with aryl ketenimines.[6] Alternatively, azo- and hydrazine-assisted C–H functionalization and cyclization under various transition-metal catalysis have been also investigated.[7] Recently, N-arylphthalazinones containing a hydrazide directing group have been utilized for the construction of tetracyclic cinnoline frameworks. For example, Gandhi and co-workers described the Ru(II)-catalyzed C–H functionalization and annulative cyclization of N-arylphthalazinones with propargylic alcohols, a highlight of which is the traceless directing nature of the hydroxyl group (Scheme [1]).[8] In addition, Perumal and co-workers investigated the reaction mode of diarylalkynes into N-arylphthalazinones under Rh(III) catalysis in the presence of a Cu(II) additive, which provided a series of phthalazino[2,3-a]cinnolines.[9] Recently, Sakhuja and co-workers also demonstrated the synthesis of [6,6,6,6]-tetracyclic cinnolines through Rh(III)-catalyzed C–H annulation by using α-diazo compounds and nitroalkenes.[10] Moreover, [6,6,5,6]-tetracyclic phthalazinone derivatives were also derived from N-arylphthalazinones with coupling partners under Rh(III) catalysis.[11] Vinylene carbonate has emerged as a valuable C2 surrogate in carbon–carbon bond formation.[12] In particular, vinylene carbonate has been recently employed in the C–H functionalization and annulation strategy, affording a range of N-heterocycles.[13] Various annulative routes such as [4+2], [4+1], and [5+1] have been examined with Rh(III), Ru(II), and Co(III) catalysts.
With a rational design based on the unique reactivity of vinylene carbonate, we herein disclose the direct access to [6,6,6,6]-tetracyclic hydroxycinnolines via a hydrazide-assisted Rh(III)-catalyzed C–H functionalization and annulation of N-arylphthalazinones and N-arylindazolones with vinylene carbonate as an acetaldehyde equivalent. Notably, in the presence of a silver additive, hydroxycinnolines bearing a hemiaminal moiety were exclusively formed without undergoing elimination of the hydroxyl group.
The optimization of reaction conditions was commenced with the reaction between N-phenylphthalazinone 1a and vinylene carbonate (2a) under rhodium(III) catalysis (Table [1]). A cationic rhodium complex, generated from [RhCp*Cl2]2 and AgSbF6, afforded no formation of hydroxycinnoline 3a, and 60% of olefinated adduct 3aa was obtained (entry 1). The chemical structure of hydroxycinnoline 3a was elucidated by X-ray crystallographic analysis (Figure [1]; see the Supporting Information for details).[14]
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (5 mol%), additives (quantity noted), solvent (1 mL), at the indicated temperature, 20 h, under air in pressure tubes.
b Isolated yield by flash column chromatography.
c [Ru(p-cymene)Cl2]2 was used instead of [RhCp*Cl2]2 as catalyst.
Control experiments revealed that a neutral Rh(III) catalyst in the absence of AgSbF6 provided the desired product 3a in 51% yield along with the formation of 3aa in 16% yield (entry 4). Based on these results, olefinated compound 3aa can be derived from 3a by a dehydration reaction, which might be facilitated by a cationic Rh(III) catalyst as a Lewis acid. Switching NaOAc to AgOAc displayed the improved formation of 3a in 62% yield (entry 5). Notably, a high yield (89%) of 3a was obtained by using a AgOAc additive at reduced temperature (60 °C), as shown in entry 6. The increased formation of hydroxycinnoline 3a over olefinated adduct 3aa might be realized by tight coordination of the carbonyl and hydroxyl groups on 3a to the AgOAc additive under lower temperature, which might inhibit the further elimination process of the hydroxyl group. This result was also supported by using 100 mol% of AgOAc under otherwise identical conditions (entry 7). However, this reaction was found to be less effective when decreasing the AgOAc amount (20 mol%) or reducing the reaction temperature (40 °C), as shown in entries 8 and 9. After further screening of solvents and catalysts (entries 10–12), we selected entry 6 as the optimal reaction conditions.
With the optimal reaction conditions in hand, a variety of N-arylphthalazinones were screened for coupling with 2a (Scheme [2]). para-Substituted phthalazinones 1b–1e smoothly participated in the C–H functionalization and annulation to afford hydroxycinnoline adducts 3b–3e in good to high yields. However, para-CF3-substituted substrate 1f exhibited a decreased reactivity for the formation of the corresponding product 3f (25%) under the current reaction conditions. Recovered starting material 1f was obtained in 45% yield, and about 5% yield of olefinated adduct was also formed. This transformation was also compatible with meta- and ortho-substituted substrates 1g–1k to produce the corresponding products 3g–3k in 32–93% yield. Complete site-selectivity was detected at the less hindered C–H bond in all cases. It is noted that the highly electron-deficient NO2 group on 1i, which is often problematic in catalytic C–H bond activation, was tolerated in this coupling reaction. Moreover, substituents on the phthalazinone ring (1l and 1m) were also tolerated in this coupling reaction. With the importance of functionalized pyridazinones in medicinal chemistry and drug discovery, we have performed the reaction of N-arylpyridazinone 1n with 2a to generate pyridazinohydroxycinnoline 3n in 67% yield.
The indazolone motif is a privileged core of biological applications such as anticancer, anti-inflammatory, analgesic, antipsychotic, antiviral, and antihyperlipidemic agents.[15] Therefore, the development of efficient methods for indazolone derivatives is important in the field of medicinal chemistry and drug discovery. With advances in C–H functionalizations,[16] a hydrazide functional group on N-arylindazolones has been employed to provide a rapid assembly of N-arylindazolone derivatives.[17] After establishing the robust method for the C–H annulation reaction using N-arylphthalazinones and vinylene carbonate, the optimized reaction conditions were firstly tested with N-phenylindazolone 4a and 2a. The desired indazolohydroxycinnoline 5a was formed in a moderate yield (45%). After a screening of reaction conditions, a monomeric Rh(III) catalyst, [RhCp*(OAc)2], in the presence of 20 mol% of AgOAc was found to accelerate the coupling reaction to produce 5a in a high yield (81%), as shown in Scheme [3]. Thus, the modified conditions were subsequently employed for a range of N-arylindazolones 4b–4k. Regardless of the electronic properties, para-substituted substrates 4b–4f were found to be suitable in this transformation to give the corresponding products 5b–5f in moderate to high yields. However, in the case of meta-substituted compounds, the important role of electronic and steric properties was observed. For example, compound 4h bearing an electron-deficient CF3 group reacted with 2a to afford 5h in a relatively low yield (28%). In addition, a separable mixture of 5ia (47%) and 5ib (28%) was obtained in the reaction of meta-F-substituted N-arylindazolone 4i. Next, the effect of the aryl ring on the indazolone framework was examined. C5-Methyl-substituted substrate 4j smoothly coupled with 2a to furnish 5j in 65% yield, but pyrazolopyridin-3-one 4k was unreactive.
To highlight the robustness and practicality of the developed method, gram-scale experiments were performed, with the reaction of N-phenylphthalazinone 1a (1 g, 4.2 mmol) with 2a providing 1.0 g of 3a in 85% yield (Scheme [4]). In addition, this transformation was compatible with a scale-up experiment with N-phenylindazolone 4a (1 g, 4.8 mmol) to provide 5a (0.91 g) in 75% yield.
A plausible reaction pathway is outlined in Scheme [5]. In the presence of AgOAc, a neutral Rh(III) complex, [Rh(III)Cp*(OAc)2], can be generated in situ by ligand exchange, which might undergo hydrazide-directed C–H activation at the ortho-position of 1a to afford the five-membered cyclorhodated complex A. Coordination of vinylene carbonate (2a) followed by migratory insertion can furnish the seven-membered N–Rh(III)–C species B. Subsequently, 1,2-Rh–C bond migration occurs along with the release of CO2 to deliver the ring-contracted rhodacycle C.[18] Then, protonation takes place for the formation of acetaldehyde intermediate D, which rapidly undergoes the annulation reaction to provide hydroxycinnoline 3a. Depending on the reaction conditions (see Table [1]), olefinated adduct 3aa can be formed by a dehydration reaction of 3a.
To further examine the role of catalyst and additive for the formation of 3a, control experiments were performed (Scheme [6]). In the presence of a cationic Rh(III) catalyst, the hydroxyl group on 3a was readily eliminated to provide 3aa in 72% yield. In addition, 30 mol% of AgSbF6 additive as a cationic silver salt also provided the eliminated adduct 3aa in 65% yield along with recovered starting material 3a (31%). However, treatment with AgOAc showed the recovery of most of 3a, and 5% of 3aa was formed. These results reveal that the elimination process of the hydroxyl group might be inhibited by tight coordination of the carbonyl and hydroxyl groups on 3a to a neutral silver salt such as AgOAc.
In conclusion, we have described the hydrazide-assisted rhodium(III)-catalyzed C–H functionalization and annulation reaction of N-arylphthalazinones and N-arylindazolones with vinylene carbonate. Notably, the use of AgOAc as additive is crucial for the formation of tetracyclic hydroxycinnolines by inhibiting elimination of the hydroxyl group on the products. Complete chemoselectivity and broad functional group tolerance were observed.
Commercially available reagents were used without additional purification, unless otherwise stated. Vinylene carbonate (2a) was purchased from TCI. N-Arylphthalazinones 1a–1n and N-arylindazolones 4a–4k were prepared according to the reported literature.[8] [9] [11b] [17a] All reactions were performed in an oil bath by using an IKA universal hot plate magnetic stirrer. Sealed tubes (13 × 100 mm2) were purchased from Fisher Scientific, and oven-dried overnight and cooled at room temperature prior to use. TLC was carried out using plates coated with Kieselgel 60F254 (Merck). For flash column chromatography, Merck Kieselgel 60 (230–400 mesh) was used. NMR spectra (1H, 13C, and 19F NMR) were recorded on Bruker Unity 400, 500, and 700 MHz spectrometers in acetone-d 6, CDCl3, CD3OD, and DMSO-d 6 solution and chemical shifts are reported as parts per million (ppm). Resonance patterns are reported with the notations s (singlet), br (broad), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and m (multiplet). Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Varian 2000 infrared spectrophotometer and are reported as cm–1. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-600 spectrometer.
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6-Hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3a); Typical Procedure for the Formation of Hydroxycinnolines 3a–3n
To an oven-dried sealed tube charged with 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) (47.7 mg, 0.2 mmol, 100 mol%), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol, 5 mol%), and AgOAc (16.7 mg, 0.1 mmol, 50 mol%) were added vinylene carbonate (2a) (34.4 mg, 0.4 mmol, 200 mol%) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 20 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc, 12:1 to 10:1) to afford 3aa (1.6 mg) in 3% yield as a yellow solid; mp 165.7–166.8 °C and 3a (49.8 mg) in 89% yield as a light yellow solid; mp 182.4–185.3 °C by flash column chromatography (n-hexanes/acetone, 4:1 to 3:1).
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6-Hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3a)
IR: 3394, 3068, 3045, 1635, 1604, 1490, 1465, 1338, 1290, 1222, 1093, 1060, 1025, 912 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.41 (dd, J = 6.8, 2.0 Hz, 1 H), 8.30 (dd, J = 7.2, 2.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.89–7.82 (m, 2 H), 7.39–7.34 (m, 2 H), 7.29 (d, J = 7.6 Hz, 1 H), 6.54 (q, J = 3.6 Hz, 1 H), 4.29 (brs, 1 H), 3.18 (d, J = 3.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 157.9, 156.7, 135.2, 134.2, 133.9, 129.9, 129.2, 128.6, 128.5, 127.6, 127.4, 126.4, 123.1, 78.7, 33.3.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H12N2O3: 280.0848; found: 280.0847.
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Phthalazino[2,3-a]cinnoline-8,13-dione (3aa)
IR: 2925, 1656, 1600, 1492, 1459, 1388, 1328, 1292, 1263, 1184 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.47–8.45 (m, 1 H), 8.39–8.36 (m, 1 H), 8.09 (dt, J = 8.4, 1.2 Hz, 1 H), 7.92–7.85 (m, 2 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.25 (td, J = 8.0, 1.6 Hz, 1 H), 7.19 (td, J = 7.6, 1.2 Hz, 1 H), 7.11 (dd, J = 7.6, 2.0 Hz, 1 H), 6.17 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 156.7, 154.2, 134.2, 134.0, 133.8, 129.2, 128.4, 128.0, 127.9, 127.6, 127.2, 125.6, 125.5, 125.1, 121.4, 110.2.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H10N2O2: 262.0742; found: 262.0741.
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6-Hydroxy-3-methoxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3b)
The reaction of 1b (53.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3b (42.2 mg) in 68% yield as a light yellow solid; mp 230.4–233.2 °C.
IR: 3440, 3002, 1710, 1635, 1604, 1496, 1414, 1353, 1267, 1218, 1174, 1060, 914 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.28–8.23 (m, 2 H), 7.98–7.92 (m, 2 H), 7.84 (d, J = 9.2 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.87 (dd, J = 9.2, 2.8 Hz, 1 H), 6.73 (d, J = 4.0 Hz, 1 H), 6.52 (q, J = 2.8 Hz, 1 H), 3.79 (s, 3 H), 3.17 (dd, J = 14.8, 3.2 Hz, 1 H), 2.98 (dd, J = 15.2, 2.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 157.3, 155.7, 155.3, 133.9, 133.7, 129.5, 129.4, 128.4, 127.5, 127.4, 127.1, 124.5, 113.9, 111.8, 75.7, 55.3, 33.9.
HRMS (quadrupole, EI): m/z [M]+ calcd for C17H14N2O4: 310.0954; found: 310.0956.
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6-Hydroxy-3-methyl-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3c)
The reaction of 1c (50.5 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3c (32.9 mg) in 56% yield as a light yellow solid; mp 211.5–214.4 °C.
IR: 3394, 2965, 1710, 1635, 1494, 1398, 1288, 1218, 1178, 1095, 1056, 1027, 916 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.29–8.22 (m, 2 H), 7.98–7.92 (m, 2 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.15 (s, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.75 (d, J = 4.0 Hz, 1 H), 6.54 (q, J = 3.2 Hz, 1 H), 3.14 (dd, J = 14.4, 3.2 Hz, 1 H), 2.93 (dd, J = 15.2, 2.8 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.8, 155.6, 135.7, 133.9, 133.8, 131.9, 129.6, 129.5, 128.5, 127.6, 127.4, 127.2, 126.7, 123.0, 75.7, 33.7, 20.6.
HRMS (quadrupole, EI): m/z [M]+ calcd for C17H14N2O3: 294.1004; found: 294.1001.
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3-Chloro-6-hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3d)
The reaction of 1d (54.5 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3d (45.4 mg) in 72% yield as a light yellow solid; mp 228.2–231.1 °C.
IR: 3394, 2923, 1710, 1641, 1602, 1469, 1340, 1276, 1228, 1096, 1008, 912 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.31–8.21 (m, 2 H), 7.98–7.94 (m, 3 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J = 8.8, 2.4 Hz, 1 H), 6.84 (d, J = 4.4 Hz, 1 H), 6.56 (q, J = 3.2 Hz, 1 H), 3.20 (dd, J = 14.4, 2.8 Hz, 1 H), 3.03 (dd, J = 15.2, 2.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.9, 155.7, 133.9, 133.2, 130.1, 130.0, 129.2, 128.8, 128.5, 127.7, 127.2, 126.0, 124.9, 75.3, 33.6.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H11ClN2O3: 314.0458; found: 314.0454.
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3-Fluoro-6-hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3e)
The reaction of 1e (51.3 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3e (42.3 mg) in 71% yield as a light yellow solid; mp 211.7–213.5 °C.
IR: 3390, 2921, 1710, 1637, 1600, 1492, 1340, 1274, 1203, 1058, 1027, 863 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.29–8.23 (m, 2 H), 7.98–7.95 (m, 3 H), 7.48 (s, 1 H), 7.39–7.36 (m, 1 H), 6.85 (d, J = 4.4 Hz, 1 H), 6.57 (s, 1 H), 3.22–3.17 (m, 1 H), 3.07–3.02 (m, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 159.7 (d, J C-F = 242.6 Hz), 155.8, 155.7, 133.8 (d, J C-F = 5.9 Hz), 130.7 (d, J C-F = 6.3 Hz), 130.6, 129.3, 128.5, 127.4 (d, J C-F = 43.0 Hz), 125.3 (d, J C-F = 8.7 Hz), 115.8, 115.6, 113.1, 112.9, 75.6, 33.8.
19F NMR (376 MHz, DMSO-d 6): δ = –115.6.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H11FN2O3: 298.0754; found: 298.0749.
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6-Hydroxy-3-(trifluoromethyl)-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3f)
The reaction of 1f (61.3 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3f (17.4 mg) in 25% yield as a light yellow solid; mp 195.8–198.4 °C.
IR: 3415, 2985, 1712, 1644, 1604, 1508, 1467, 1421, 1326, 1274, 1222, 1126, 1054, 958 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.33–8.24 (m, 2 H), 8.18 (d, J = 8.4 Hz, 1 H), 8.00–7.96 (m, 2 H), 7.79 (s, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 4.0 Hz, 1 H), 6.61 (q, J = 3.6 Hz, 1 H), 3.26 (dd, J = 15.2, 3.6 Hz, 1 H), 3.17 (dd, J = 15.6, 2.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.4, 155.7, 137.7, 137.6, 134.2, 134.1, 129.2, 128.6, 127.8, 127.3, 126.3 (q, J C-F = 3.0 Hz), 126.1 (q, J C-F = 31.8 Hz), 124.1 (q, J C-F = 270.3 Hz), 123.8, 123.2 (q, J C-F = 3.2 Hz), 75.1, 33.6.
19F NMR (376 MHz, DMSO-d 6): δ = –60.7.
HRMS (quadrupole, EI): m/z [M]+ calcd for C17H11F3N2O3: 348.0722; found: 348.0720.
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6-Hydroxy-2-methyl-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3g)
The reaction of 1g (50.5 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3g (44.8 mg) in 76% yield as a light yellow solid; mp 204.5–207.4 °C.
IR: 3394, 2923, 1710, 1633, 1604, 1581, 1509, 1467, 1409, 1340, 1284, 1220, 1130, 1060, 1027, 898 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.29–8.23 (m, 2 H), 7.98–7.93 (m, 2 H), 7.74 (s, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.06 (dd, J = 8.0, 2.0 Hz, 1 H), 6.73 (d, J = 4.0 Hz, 1 H), 6.52 (q, J = 3.2 Hz, 1 H), 3.16–3.12 (m, 1 H), 2.94 (dd, J = 14.8, 2.4 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.9, 155.8, 135.3, 134.3, 133.9, 133.8, 129.5, 129.1, 128.5, 127.6, 127.2, 127.1, 124.6, 123.5, 75.8, 33.4, 20.9.
HRMS (quadrupole, EI): m/z [M]+ calcd for C17H14N2O3: 294.1004; found: 294.1000.
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2-Chloro-6-hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3h)
The reaction of 1h (54.5 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3h (58.7 mg) in 93% yield as a light yellow solid; mp 209.2–212.1 °C.
IR: 3299, 2925, 1710, 1623, 1577, 1484, 1407, 1321, 1265, 1220, 1062, 1031 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.31–8.22 (m, 2 H), 8.05 (s, 1 H), 8.00–7.95 (m, 2 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.32 (dd, J = 8.4, 1.6 Hz, 1 H), 6.86 (d, J = 4.4 Hz, 1 H), 6.57 (q, J = 3.2 Hz, 1 H), 3.17 (d, J = 14.4 Hz, 1 H), 3.03 (d, J = 14.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.2, 155.7, 135.2, 134.1, 134.0, 130.8, 130.2, 129.2, 128.6, 127.8, 127.3, 126.4, 126.1, 122.9, 75.2, 33.3.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H11ClN2O3: 314.0458; found: 314.0457.
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6-Hydroxy-2-nitro-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3i)
The reaction of 1i (56.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3i (20.8 mg) in 32% yield as a light yellow solid; mp 222.4–225.1 °C.
IR: 3369, 3058, 1712, 1643, 1567, 1523, 1490, 1419, 1359, 1268, 1222, 1139 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.94 (s, 1 H), 8.35–8.31 (m, 1 H), 8.28–8.24 (m, 1 H), 8.12 (dd, J = 8.4, 1.6 Hz, 1 H), 8.02–7.97 (m, 2 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 4.0 Hz, 1 H), 6.66 (dd, J = 6.8, 3.2 Hz, 1 H), 3.34–3.30 (m, 1 H), 3.22 (dd, J = 7.6, 2.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.5, 155.6, 145.7, 135.1, 134.6, 134.3, 134.1, 130.6, 129.0, 128.6, 127.8, 127.3, 120.6, 118.1, 74.8, 34.0.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H11N3O5: 325.0699; found: 325.0696.
#
6-Hydroxy-2,3-dimethyl-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3j)
The reaction of 1j (53.3 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3j (48.7 mg) in 79% yield as a light yellow solid; mp 223.3–225.2 °C.
IR: 3392, 2969, 1710, 1633, 1604, 1504, 1467, 1336, 1272, 1222, 1168, 1089, 1027, 910 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.29–8.21 (m, 2 H), 7.98–7.92 (m, 2 H), 7.71 (s, 1 H), 7.10 (s, 1 H), 6.70 (dd, J = 4.0, 1.2 Hz, 1 H), 6.52 (q, J = 2.8 Hz, 1 H), 3.12 (dd, J = 15.2, 4.4 Hz, 1 H), 2.90 (dd, J = 14.8, 2.4 Hz, 1 H), 2.23 (s, 3 H), 2.22 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.8, 155.6, 134.5, 133.9, 133.8, 132.1, 130.0, 129.5, 128.5, 127.6, 127.2, 124.6, 123.8, 75.7, 33.3, 19.4, 18.9.
HRMS (quadrupole, EI): m/z [M]+ calcd for C18H16N2O3: 308.1161; found: 308.1158.
#
6-Hydroxy-1-methyl-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3k)
The reaction of 1k (50.5 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3k (33.6 mg) in 57% yield as a light yellow solid; mp 220.6–223.0 °C.
IR: 3426, 2983, 1710, 1639, 1494, 1469, 1338, 1270, 1218, 1132, 1056, 914 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.29–8.23 (m, 2 H), 7.98–7.93 (m, 2 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.15 (s, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.75 (q, J = 4.0 Hz, 1 H), 6.53 (q, J = 2.8 Hz, 1 H), 3.16 (dd, J = 15.2, 2.8 Hz, 1 H), 2.95 (dd, J = 14.8, 2.4 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.8, 155.6, 135.7, 133.9, 133.8, 131.9, 129.6, 129.5, 128.5, 127.6, 127.4, 127.2, 126.7, 122.9, 75.7, 33.7, 20.6.
HRMS (quadrupole, EI): m/z [M]+ calcd for C17H14N2O3: 294.1004; found: 294.1003.
#
10,11-Dichloro-6-hydroxy-5,6-dihydrophthalazino[2,3-a]cinnoline-8,13-dione (3l)
The reaction of 1l (61.4 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3l (35.7 mg) in 51% yield as a light yellow solid; mp 240.0–242.9 °C.
IR: 3438, 2983, 1710, 1643, 1594, 1567, 1540, 1455, 1359, 1267, 1222, 1137, 914 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.39 (s, 1 H), 8.35 (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.37–7.25 (m, 3 H), 6.90 (d, J = 4.4 Hz, 1 H), 6.51 (q, J = 2.8 Hz, 1 H), 3.18 (dd, J = 14.8, 2.8 Hz, 1 H), 2.99 (dd, J = 15.2, 2.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 154.2, 154.1, 137.1, 137.0, 134.1, 129.5, 129.3, 129.0, 128.6, 127.8, 126.7, 126.6, 126.2, 123.3, 76.2, 33.7.
HRMS (quadrupole, EI): m/z [M]+ calcd for C16H10Cl2N2O3: 348.0068; found: 348.0064.
#
6-Hydroxy-5,6-dihydrobenzo[6,7]phthalazino[2,3-a]cinnoline-8,15-dione (3m)
The reaction of 1m (57.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3m (50.9 mg) in 77% yield as a light yellow solid; mp 239.3–241.9 °C.
IR: 3405, 3056, 1710, 1644, 1619, 1457, 1419, 1348, 1286, 1236, 1197, 1120, 1006 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.93 (d, J = 18.8 Hz, 2 H), 8.36–8.33 (m, 2 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.81–7.79 (m, 2 H), 7.37–7.31 (m, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 6.80 (d, J = 4.4 Hz, 1 H), 6.58 (q, J = 2.8 Hz, 1 H), 3.22 (dd, J = 14.4, 3.2 Hz, 1 H), 3.02 (dd, J = 15.2, 2.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.7, 156.6, 134.7, 134.5, 134.4, 129.6, 129.5, 129.4, 129.3, 128.8, 127.6, 126.1, 125.3, 124.6, 123.2, 75.9, 33.9.
HRMS (quadrupole, EI): m/z [M]+ calcd for C20H14N2O3: 330.1004; found: 330.1003.
#
6-Hydroxy-2,3-dimethyl-6,7-dihydropyridazino[1,2-a]cinnoline-1,4-dione (3n)
The reaction of 1n (43.3 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 3n (34.6 mg) in 67% yield as a light yellow solid; mp 140.6–143.2 °C.
IR: 3392, 2985, 1710, 1631, 1540, 1511, 1490, 1459, 1421, 1336, 1276, 1220, 1122, 1068, 902 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 7.92 (d, J = 8.0 Hz, 1 H), 7.32–7.30 (m, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.6 Hz, 1 H), 6.71 (d, J = 4.4 Hz, 1 H), 6.45 (q, J = 3.2 Hz, 1 H), 3.07 (dd, J = 15.2, 3.2 Hz, 1 H), 2.94 (dd, J = 15.2, 2.8 Hz, 1 H), 2.12 (s, 3 H), 2.10 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.8, 155.6, 139.4, 138.2, 134.2, 129.3, 127.1, 126.2, 126.1, 122.6, 74.9, 33.7, 13.8, 13.6.
HRMS (quadrupole, EI): m/z [M]+ calcd for C14H14N2O3: 258.1004; found: 258.1003.
#
6-Hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5a); Typical Procedure for the Formation of Indazolohydroxycinnolines 5a–5k
To an oven-dried sealed tube charged with 1-phenyl-1,2-dihydro-3H-indazol-3-one (4a) (42.1 mg, 0.2 mmol, 100 mol%), [RhCp*(OAc)2] (3.6 mg, 0.01 mmol, 5 mol%), and AgOAc (6.7 mg, 0.04 mmol, 20 mol%) were added vinylene carbonate (2a) (34.4 mg, 0.4 mmol, 200 mol%) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 18 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc, 9:1 to 1:9) to afford 5a (40.9 mg) in 81% yield as a brown solid; mp 197.5–199.8 °C.
IR: 3237, 2962, 1644, 1619, 1494, 1461, 1355, 1318, 1220, 1150, 1106, 1072, 1020, 901 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 7.8 Hz, 1 H), 7.58–7.47 (m, 3 H), 7.40–7.36 (m, 2 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 6.54 (t, J = 3.3 Hz, 1 H), 3.27 (dd, J = 15.3, 2.7 Hz, 1 H), 3.14 (dd, J = 15.3, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3/CD3OD, 10:1): δ = 158.1, 139.1, 135.2, 132.9, 130.5, 127.9, 124.5, 124.4, 122.5, 121.5, 116.2, 114.2, 110.8, 71.8, 34.3.
HRMS (Orbitrap, ESI): m/z [M]+ calcd for C15H12N2O2: 252.0899; found: 252.0903.
#
6-Hydroxy-3-methoxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5b)
The reaction of 4b (48.1 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5b (42.9 mg) in 76% yield as a white solid; mp 202.4–205.2 °C.
IR: 3249, 2923, 1638, 1619, 1504, 1459, 1433, 1359, 1316, 1230, 1191, 1148, 1071, 1035 cm–1.
1H NMR (700 MHz, acetone-d 6/CD3OD, 10:1): δ = 7.83 (dt, J = 8.4, 0.7 Hz, 1 H), 7.79 (dq, J = 7.7, 0.7 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.64 (ddd, J = 9.8, 7.0, 1.4 Hz, 1 H), 7.16 (ddd, J = 8.4, 7.0, 0.7 Hz, 1 H), 7.02 (d, J = 2.8 Hz, 1 H), 6.96 (dd, J = 9.1, 3.5 Hz, 1 H), 6.39 (t, J = 2.8 Hz, 1 H), 3.83 (s, 3 H), 3.22–3.21 (m, 2 H).
13C NMR (175 MHz, acetone-d 6/CD3OD, 10:1): δ = 158.2, 157.1, 140.4, 133.5, 130.1, 125.6, 124.7, 121.5, 116.9, 116.7, 116.3, 113.6, 111.4, 71.9, 55.9, 35.6.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C16H14N2O3Na: 305.0902; found: 305.0900.
#
6-Hydroxy-3-methyl-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5c)
The reaction of 4c (44.9 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5c (44.2 mg) in 83% yield as a sticky brown solid.
IR: 3142, 2921, 1667, 1651, 1617, 1492, 1458, 1366, 1348, 1314, 1275, 1225, 1044 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.51–7.48 (m, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.18–7.16 (m, 2 H), 7.04 (ddd, J = 9.0, 7.0, 1.0 Hz, 1 H), 6.54 (t, J = 3.0 Hz, 1 H), 3.23 (dd, J = 15.5, 2.5 Hz, 1 H), 3.12 (dd, J = 15.0, 3.0 Hz, 1 H), 2.37 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.5, 138.9, 134.0, 132.8, 132.7, 131.3, 128.4, 124.4, 122.1, 121.1, 115.6, 114.1, 110.5, 71.9, 34.3, 21.0.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C16H14N2O2Na: 289.0953; found: 289.0951.
#
3-Chloro-6-hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5d)
The reaction of 4d (48.9 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5d (35.1 mg) in 61% yield as a sticky yellow solid.
IR: 3210, 2923, 1634, 1602, 1582, 1495, 1461, 1446, 1361, 1328, 1315, 1233, 1216, 1189, 1090, 1065, 862 cm–1.
1H NMR (400 MHz, acetone-d 6): δ = 7.92 (d, J = 8.8 Hz, 1 H), 7.83–7.79 (m, 2 H), 7.69 (ddd, J = 10.0, 7.2, 1.6 Hz, 1 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.41 (dd, J = 8.4, 2.4 Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1 H), 6.43 (t, J = 3.2 Hz, 1 H), 3.26 (d, J = 2.8 Hz, 1 H), 2.82 (d, J = 13.2 Hz, 1 H).
13C NMR (100 MHz, acetone-d 6): δ = 158.0, 140.6, 135.4, 133.7, 131.0, 128.3, 128.2, 125.8, 124.8, 122.2, 117.8, 116.4, 111.8, 71.4, 35.2.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C15H11ClN2O2Na: 309.0407; found: 309.0399.
#
3-Fluoro-6-hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5e)
The reaction of 4e (45.6 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5e (31.4 mg) in 58% yield as a sticky yellow solid.
IR: 3167, 2917, 1632, 1503, 1459, 1441, 1363, 1317, 1272, 1216, 1145, 1101, 1066, 1020, 899 cm–1.
1H NMR (700 MHz, acetone-d 6/CD3OD, 70:1): δ = 7.91 (dt, J = 8.4, 0.7 Hz, 1 H), 7.85 (dq, J = 7.7, 0.7 Hz, 1 H), 7.80 (dd, J = 9.1, 4.9 Hz, 1 H), 7.70 (ddd, J = 9.8, 7.0, 0.7 Hz, 1 H), 7.26–7.24 (m, 1 H), 7.23 (ddd, J = 9.1, 7.7, 0.7 Hz, 1 H), 7.19–7.16 (m, 1 H), 6.41 (t, J = 2.8 Hz, 1 H), 3.27–3.26 (m, 2 H).
13C NMR (175 MHz, acetone-d 6/CD3OD, 70:1): δ = 159.7 (d, J C-F = 239.9 Hz), 158.4, 140.6, 133.8, 133.1, 126.5 (d, J C-F = 8.1 Hz), 124.8, 122.2, 118.0 (d, J C-F = 23.3 Hz), 117.4, 116.6 (d, J C-F = 8.2 Hz), 114.9 (d, J C-F = 22.9 Hz), 111.7, 71.8, 35.4.
19F NMR (470 MHz, acetone-d 6/CD3OD, 70:1): δ = –120.7 (td, J = 8.5, 4.2 Hz).
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C15H11FN2O2Na: 293.0702; found: 293.0697.
#
6-Hydroxy-3-(trifluoromethyl)-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5f)
The reaction of 4f (55.6 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5f (51.3 mg) in 80% yield as a light yellow solid; mp 244.7–247.2 °C.
IR: 3168, 2922, 1649, 1616, 1509, 1464, 1440, 1357, 1348, 1316, 1278, 1226, 1175, 1155, 1108, 1081, 1070, 1029, 872 cm–1.
1H NMR (400 MHz, CD3OD/CDCl3, 1:1): δ = 7.92 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.63–7.60 (m, 2 H), 7.25 (t, J = 7.6 Hz, 1 H), 6.44 (t, J = 3.2 Hz, 1 H), 3.28 (dd, J = 16.0, 2.4 Hz, 1 H), 3.18 (dd, J = 15.2, 3.6 Hz, 1 H).
13C NMR (100 MHz, acetone-d 6): δ = 158.1, 140.6, 139.3, 133.9, 128.4 (q, J C-F = 33.1 Hz), 128.3 (q, J C-F = 3.7 Hz), 125.9 (q, J C-F = 268.9 Hz), 124.9, 124.6, 124.0, 122.8, 118.3, 114.9, 112.2, 71.3, 35.3.
19F NMR (376 MHz, CD3OD/CDCl3, 1:1): δ = –62.4.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C16H11F3N2O2Na: 343.0670; found: 343.0667.
#
2-Chloro-6-hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5g)
The reaction of 4g (48.9 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5g (37.3 mg) in 65% yield as a sticky brown solid.
IR: 3236, 2923, 1679, 1654, 1618, 1598, 1539, 1492, 1461, 1426, 1351, 1289, 1220, 1152, 1107, 1088, 1027, 998 cm–1.
1H NMR (400 MHz, CDCl3/CD3OD, 5:1): δ = 7.86 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.55 (s, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.32 (t, J = 2.8 Hz, 1 H), 3.17–3.13 (m, 1 H), 3.02 (dd, J = 15.2, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3/CD3OD, 5:1): δ = 157.9, 138.9, 135.7, 133.5, 133.4, 131.4, 124.3, 124.1, 122.2, 120.7, 116.1, 114.4, 110.8, 71.2, 33.9.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C15H11ClN2O2Na: 309.0407; found: 309.0402.
#
6-Hydroxy-2-(trifluoromethyl)-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5h)
The reaction of 4h (55.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5h (17.9 mg) in 28% yield as a light yellow solid; mp 228.6–230.9 °C.
IR: 3166, 2922, 1657, 1608, 1585, 1512, 1458, 1437, 1357, 1323, 1287, 1147, 1112, 1072, 1024, 979 cm–1.
1H NMR (700 MHz, acetone-d 6/CD3OD, 70:1): δ = 7.97 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.88 (dt, J = 7.7, 1.4 Hz, 1 H), 7.76 (ddd, J = 9.8, 7.0, 1.4 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.29 (ddd, J = 8.4, 7.0, 0.7 Hz, 1 H), 6.47 (t, J = 2.8 Hz, 1 H), 3.35–3.34 (m, 2 H).
13C NMR (175 MHz, acetone-d 6/CD3OD, 70:1): δ = 158.3, 140.5, 137.0, 134.2, 132.3, 130.5, 130.1, 128.3, 124.9, 124.4 (q, J C-F = 280.8 Hz), 122.9, 120.6 (q, J C-F = 3.7 Hz), 111.9, 111.3 (q, J C-F = 3.7 Hz), 71.7, 35.4.
19F NMR (470 MHz, acetone-d 6/CD3OD, 70:1): δ = –62.9.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C16H11F3N2O2Na: 343.0670; found: 343.0665.
#
2-Fluoro-6-hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5ia)
The reaction of 4i (45.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5ia (25.5 mg) in 47% yield as a light yellow solid; mp 205.0–207.9 °C.
IR: 3270, 2920, 1611, 1501, 1460, 1353, 1302, 1239, 1156, 1092, 1051, 1029, 935 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.04 (d, J = 8.8 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.71 (ddd, J = 10.0, 7.2, 1.2 Hz, 1 H), 7.62 (dd, J = 10.8, 2.8 Hz, 1 H), 7.41–7.38 (m, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 6.96 (td, J = 8.4, 2.4 Hz, 1 H), 6.85 (d, J = 4.4 Hz, 1 H), 6.28 (q, J = 2.8 Hz, 1 H), 3.11 (s, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 161.4 (d, J C-F = 240.1 Hz), 156.6, 138.9, 135.6 (d, J C-F = 10.8 Hz), 133.2, 131.7 (d, J C-F = 9.5 Hz), 123.8, 121.7, 118.2 (d, J C-F = 2.8 Hz), 116.3, 111.4, 109.5 (d, J C-F = 21.2 Hz), 101.7 (d, J C-F = 27.3 Hz), 69.9, 33.9.
19F NMR (376 MHz, DMSO-d 6): δ = –113.3.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C15H11FN2O2Na: 293.0702; found: 293.0699.
#
4-Fluoro-6-hydroxy-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5ib)
The reaction of 4i (45.7 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5ib (15.2 mg) in 28% yield as a light yellow solid; mp 209.7–212.4 °C.
IR: 3151, 2922, 1611, 1590, 1494, 1471, 1461, 1354, 1242, 1195, 1152, 1074, 1026, 904 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 8.03 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.70–7.67 (m, 1 H), 7.41 (q, J = 7.6 Hz, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.01 (t, J = 8.4 Hz, 1 H), 6.93 (d, J = 4.0 Hz, 1 H), 6.35–6.33 (m, 1 H), 3.25–3.21 (m, 1 H), 3.01 (dd, J = 15.6, 4.0 Hz, 1 H).
13C NMR (100 MHz, CD3OD/CDCl3, 3:1): δ = 161.7 (d, J C-F = 244.1 Hz), 158.4, 139.7, 136.5 (d, J C-F = 7.3 Hz), 133.7, 129.0 (d, J C-F = 9.5 Hz), 124.5, 122.3, 116.3, 111.3, 110.9 (d, J C-F = 22.1 Hz), 110.2 (d, J C-F = 3.3 Hz), 109.9 (d, J C-F = 21.9 Hz), 70.8, 27.4 (d, J C-F = 3.8 Hz).
19F NMR (376 MHz, CD3OD/CDCl3, 3:1): δ = –117.1.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C15H11FN2O2Na: 293.0702; found: 293.0695.
#
6-Hydroxy-10-methyl-5,6-dihydro-8H-indazolo[1,2-a]cinnolin-8-one (5j)
The reaction of 4j (44.9 mg, 0.2 mmol) with 2a (34.4 mg, 0.4 mmol, 200 mol%) afforded 5j (34.6 mg) in 65% yield as a white solid; mp 221.4–224.3 °C.
IR: 3179, 2917, 1628, 1504, 1462, 1423, 1359, 1326, 1207, 1155, 1099, 1072, 960 cm–1.
1H NMR (400 MHz, CD3OD): δ = 7.83 (d, J = 8.8 Hz, 1 H), 7.71–7.69 (m, 2 H), 7.56 (dd, J = 8.8, 2.0 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.14 (t, J = 7.6 Hz, 1 H), 6.07 (q, J = 2.0 Hz, 1 H), 3.28 (dd, J = 15.6, 2.0 Hz, 1 H), 3.16 (dd, J = 15.6, 3.2 Hz, 1 H), 2.45 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 160.1, 139.3, 136.3, 136.2, 132.8, 131.2, 128.9, 124.9, 124.2, 123.5, 116.4, 115.9, 111.6, 79.8, 34.2, 20.9.
HRMS (Orbitrap, ESI): m/z [M + Na]+ calcd for C16H14N2O2Na: 289.0953; found: 289.0943.
#
Gram-Scale Preparation of 3a
To an oven-dried sealed tube charged with 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) (1.0 g, 4.2 mmol, 100 mol%), [RhCp*Cl2]2 (129.8 mg, 0.21 mmol, 5 mol%), and AgOAc (350.5 mg, 2.1 mmol, 50 mol%) were added vinylene carbonate (2a) (722.8 mg, 8.4 mmol, 200 mol%) and DCE (24 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 20 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/acetone, 4:1 to 3:1) to afford 3a (1.0 g) in 85% yield.
#
Gram-Scale Preparation of 5a
To an oven-dried sealed tube charged with 1-phenyl-1,2-dihydro-3H-indazol-3-one (4a) (1.0 g, 4.8 mmol, 100 mol%), [RhCp*(OAc)2]2 (85.5 mg, 0.24 mmol, 5 mol%), and AgOAc (160.2 mg, 0.96 mmol, 20 mol%) were added vinylene carbonate (2a) (826.1 mg, 9.6 mmol, 200 mol%) and DCE (24 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 18 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc, 9:1 to 1:9) to afford 5a (0.91 g) in 75% yield.
#
Control Experiments for Elimination of the Hydroxyl Group from 3a to 3aa
(i) To an oven-dried sealed tube charged with 3a (56.1 mg, 0.2 mmol, 100 mol%) and [RhCp*(MeCN)3(SbF6)2] (8.3 mg, 0.01 mmol, 5 mol%) was added DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 2 h at 100 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/acetone, 9:1 to 1:1) to provide 3a (3.9 mg) in 7% yield and 3aa (37.8 mg) in 72% yield.
(ii) To an oven-dried sealed tube charged with 3a (56.1 mg, 0.2 mmol, 100 mol%) and AgSbF6 (20.6 mg, 0.06 mmol, 30 mol%) was added DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 20 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/acetone, 9:1 to 1:1) to provide 3a (17.4 mg) in 31% yield and 3aa (34.1 mg) in 65% yield.
(iii) To an oven-dried sealed tube charged with 3a (56.1 mg, 0.2 mmol, 100 mol%) and AgOAc (10.0 mg, 0.06 mmol, 30 mol%) was added DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir in an oil bath for 20 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/acetone, 9:1 to 1:1) to provide 3a (51.6 mg) in 92% yield and 3aa (2.6 mg) in 5% yield.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1811-7948.
- Supporting Information
-
References
- 1a Han YT, Jung J.-W, Kim N.-J. Curr. Org. Chem. 2017; 21: 1265
- 1b Szumilak M, Stanczak A. Molecules 2019; 24: 2271
- 2 Shen Y, Shang Z, Yang Y, Zhu S, Qian X, Shi P, Zheng J, Yang Y. J. Org. Chem. 2015; 80: 5906
- 3a Tsuji H, Yokoi Y, Sato Y, Tanaka H, Nakamura E. Chem. Asian J. 2011; 6: 2005
- 3b Chen J.-C, Wu H.-C, Chiang C.-J, Chen T, Xing L. J. Mater. Chem. C 2014; 2: 4835
- 4a Al-Awadi NA, Elnagdi MH, Ibrahim Y, Kaul K, Kumar A. Tetrahedron 2001; 57: 1609
- 4b Gomaa MA.-M. Tetrahedron Lett. 2003; 44: 3493
- 4c Jurberg ID, Gagosz F. J. Organomet. Chem. 2011; 696: 37
- 5 Alhambra C, Becker C, Blake T, Chang A, Damewood JR. Jr, Daniels T, Dembofsky BT, Gurley DA, Hall JE, Herzog KJ, Horchler CL, Ohnmacht CJ, Schmiesing RJ, Dudley A, Ribadeneira MD, Knappenberger KS, Maciag C, Stein MM, Chopra M, Liu XF, Christian EP, Arriza JL, Chapdelaine M. Bioorg. Med. Chem. 2011; 19: 2927
- 6 Alajarin M, Bonillo B, Marin-Luna M, Vidal A, Orenes R.-A. J. Org. Chem. 2009; 74: 3558
- 7a Satoh T, Miura M. Chem. Eur. J. 2010; 16: 11212
- 7b Gandeepan P, Cheng C.-H. Chem. Asian J. 2016; 11: 448
- 7c Li S.-S, Qin L, Dong L. Org. Biomol. Chem. 2016; 14: 4554
- 7d Mishra NK, Park J, Oh H, Han SH, Kim IS. Tetrahedron 2018; 74: 6769
- 7e Sharma S, Han SH, Han S, Ji W, Oh J, Lee S.-Y, Oh JS, Jung YH, Kim IS. Org. Lett. 2015; 17: 2852
- 8 Rajkumar S, Savarimuthu SA, Kumaran RS, Nagaraja C, Gandhi T. Chem. Commun. 2016; 52: 2509
- 9 Mayakrishnan S, Arun Y, Balachandran C, Emi N, Muralidharan D, Perumal PT. Org. Biomol. Chem. 2016; 14: 1958
- 10a Karishma P, Mahesha CK, Agarwal DS, Mandal SK, Sakhuja R. J. Org. Chem. 2018; 83: 11661
- 10b Karishma P, Mahesha CK, Mandal SK, Sakhuja R. J. Org. Chem. 2021; 86: 2734
- 11a Wu X, Ji H. J. Org. Chem. 2018; 83: 4650
- 11b Kim K, Han SH, Jeoung D, Ghosh P, Kim S, Kim SJ, Ku J.-M, Mishra NK, Kim IS. J. Org. Chem. 2020; 85: 2520
- 12a Hara H, Hirano M, Tanaka K. Org. Lett. 2009; 11: 1337
- 12b Wang Z, Xue F, Hayashi T. Angew. Chem. Int. Ed. 2019; 58: 11054
- 13a Nishii Y, Miura M. ACS Catal. 2020; 10: 9747
- 13b Kato M, Ghosh K, Nishii Y, Miura M. Chem. Commun. 2021; 57: 8280
- 13c Li X, Huang T, Song Y, Qi Y, Li L, Li Y, Xiao Q, Zhang Y. Org. Lett. 2020; 22: 5925
- 13d Park MS, Moon K, Oh H, Lee JY, Ghosh P, Kang JY, Park JS, Mishra NK, Kim IS. Org. Lett. 2021; 23: 5518
- 13e Kim S, Choi SB, Kang JY, An W, Lee SH, Oh H, Ghosh P, Mishra NK, Kim IS. Asian J. Org. Chem. 2021; 10: 3005
- 13f Wang C, Fan X, Chen F, Qian P.-C, Cheng J. Chem. Commun. 2021; 57: 3929
- 13g Nan J, Ma Q, Yin J, Liang C, Tian L, Ma Y. Org. Chem. Front. 2021; 8: 1764
- 14 CCDC 2154376 (3a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
- 15a Fletcher SR, McIver E, Lewis S, Burkamp F, Leech C, Mason G, Boyce S, Morrison D, Richards G, Sutton K, Jones AB. Bioorg. Med. Chem. Lett. 2006; 16: 2872
- 15b Yu W, Guo Z, Orth P, Madison V, Chen L, Dai C, Feltz RJ, Girijavallabhan VM, Kim SH, Kozlowski JA, Lavey BJ, Li D, Lundell D, Niu X, Piwinski JJ, Popovici-Muller J, Rizvi R, Rosner KE, Shankar BB, Shih NY, Siddiqui MA, Sun J, Tong L, Umland S, Wong MK, Yang DY, Zhou G. Bioorg. Med. Chem. Lett. 2010; 20: 1877
- 16a Lee H, Kang D, Han SH, Chun R, Pandey AK, Mishra NK, Hong S, Kim IS. Angew. Chem. Int. Ed. 2019; 58: 9470
- 16b Zhang Z, Zhou X.-Y, Wu J.-G, Song L, Yu D.-G. Green Chem. 2020; 22: 28
- 16c Rajamanickam S, Saraswat M, Venkataramani S, Patel BK. Chem. Sci. 2021; 12: 15318
- 16d Xu H.-B, Chen Y.-J, Chai X.-Y, Yang J.-H, Xu Y.-J, Dong L. Org. Lett. 2021; 23: 2052
- 16e Tian S, Luo T, Zhu Y, Wan J.-P. Chin. Chem. Lett. 2020; 31: 3073
- 16f Zhang X, Wang P, Zhu L, Chen B. Chin. Chem. Lett. 2021; 32: 695
- 17a Gogoi K, Bora BR, Borah G, Sarma B, Gogoi S. Chem. Commun. 2021; 57: 1388
- 17b Kang JY, An W, Kim S, Kwon NY, Jeong T, Ghosh P, Kim HS, Mishra NK, Kim IS. Chem. Commun. 2021; 57: 10947
- 18 Shen B, Liu S, Zhu L, Zhong K, Liu F, Chen H, Bai R, Lan Y. Organometallics 2020; 39: 2813
For selected reviews on the biological activities of cinnolines, see:
For selected examples, see:
For recent selected examples, see:
Corresponding Authors
Publication History
Received: 24 February 2022
Accepted after revision: 30 March 2022
Accepted Manuscript online:
30 March 2022
Article published online:
28 April 2022
© 2022. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1a Han YT, Jung J.-W, Kim N.-J. Curr. Org. Chem. 2017; 21: 1265
- 1b Szumilak M, Stanczak A. Molecules 2019; 24: 2271
- 2 Shen Y, Shang Z, Yang Y, Zhu S, Qian X, Shi P, Zheng J, Yang Y. J. Org. Chem. 2015; 80: 5906
- 3a Tsuji H, Yokoi Y, Sato Y, Tanaka H, Nakamura E. Chem. Asian J. 2011; 6: 2005
- 3b Chen J.-C, Wu H.-C, Chiang C.-J, Chen T, Xing L. J. Mater. Chem. C 2014; 2: 4835
- 4a Al-Awadi NA, Elnagdi MH, Ibrahim Y, Kaul K, Kumar A. Tetrahedron 2001; 57: 1609
- 4b Gomaa MA.-M. Tetrahedron Lett. 2003; 44: 3493
- 4c Jurberg ID, Gagosz F. J. Organomet. Chem. 2011; 696: 37
- 5 Alhambra C, Becker C, Blake T, Chang A, Damewood JR. Jr, Daniels T, Dembofsky BT, Gurley DA, Hall JE, Herzog KJ, Horchler CL, Ohnmacht CJ, Schmiesing RJ, Dudley A, Ribadeneira MD, Knappenberger KS, Maciag C, Stein MM, Chopra M, Liu XF, Christian EP, Arriza JL, Chapdelaine M. Bioorg. Med. Chem. 2011; 19: 2927
- 6 Alajarin M, Bonillo B, Marin-Luna M, Vidal A, Orenes R.-A. J. Org. Chem. 2009; 74: 3558
- 7a Satoh T, Miura M. Chem. Eur. J. 2010; 16: 11212
- 7b Gandeepan P, Cheng C.-H. Chem. Asian J. 2016; 11: 448
- 7c Li S.-S, Qin L, Dong L. Org. Biomol. Chem. 2016; 14: 4554
- 7d Mishra NK, Park J, Oh H, Han SH, Kim IS. Tetrahedron 2018; 74: 6769
- 7e Sharma S, Han SH, Han S, Ji W, Oh J, Lee S.-Y, Oh JS, Jung YH, Kim IS. Org. Lett. 2015; 17: 2852
- 8 Rajkumar S, Savarimuthu SA, Kumaran RS, Nagaraja C, Gandhi T. Chem. Commun. 2016; 52: 2509
- 9 Mayakrishnan S, Arun Y, Balachandran C, Emi N, Muralidharan D, Perumal PT. Org. Biomol. Chem. 2016; 14: 1958
- 10a Karishma P, Mahesha CK, Agarwal DS, Mandal SK, Sakhuja R. J. Org. Chem. 2018; 83: 11661
- 10b Karishma P, Mahesha CK, Mandal SK, Sakhuja R. J. Org. Chem. 2021; 86: 2734
- 11a Wu X, Ji H. J. Org. Chem. 2018; 83: 4650
- 11b Kim K, Han SH, Jeoung D, Ghosh P, Kim S, Kim SJ, Ku J.-M, Mishra NK, Kim IS. J. Org. Chem. 2020; 85: 2520
- 12a Hara H, Hirano M, Tanaka K. Org. Lett. 2009; 11: 1337
- 12b Wang Z, Xue F, Hayashi T. Angew. Chem. Int. Ed. 2019; 58: 11054
- 13a Nishii Y, Miura M. ACS Catal. 2020; 10: 9747
- 13b Kato M, Ghosh K, Nishii Y, Miura M. Chem. Commun. 2021; 57: 8280
- 13c Li X, Huang T, Song Y, Qi Y, Li L, Li Y, Xiao Q, Zhang Y. Org. Lett. 2020; 22: 5925
- 13d Park MS, Moon K, Oh H, Lee JY, Ghosh P, Kang JY, Park JS, Mishra NK, Kim IS. Org. Lett. 2021; 23: 5518
- 13e Kim S, Choi SB, Kang JY, An W, Lee SH, Oh H, Ghosh P, Mishra NK, Kim IS. Asian J. Org. Chem. 2021; 10: 3005
- 13f Wang C, Fan X, Chen F, Qian P.-C, Cheng J. Chem. Commun. 2021; 57: 3929
- 13g Nan J, Ma Q, Yin J, Liang C, Tian L, Ma Y. Org. Chem. Front. 2021; 8: 1764
- 14 CCDC 2154376 (3a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
- 15a Fletcher SR, McIver E, Lewis S, Burkamp F, Leech C, Mason G, Boyce S, Morrison D, Richards G, Sutton K, Jones AB. Bioorg. Med. Chem. Lett. 2006; 16: 2872
- 15b Yu W, Guo Z, Orth P, Madison V, Chen L, Dai C, Feltz RJ, Girijavallabhan VM, Kim SH, Kozlowski JA, Lavey BJ, Li D, Lundell D, Niu X, Piwinski JJ, Popovici-Muller J, Rizvi R, Rosner KE, Shankar BB, Shih NY, Siddiqui MA, Sun J, Tong L, Umland S, Wong MK, Yang DY, Zhou G. Bioorg. Med. Chem. Lett. 2010; 20: 1877
- 16a Lee H, Kang D, Han SH, Chun R, Pandey AK, Mishra NK, Hong S, Kim IS. Angew. Chem. Int. Ed. 2019; 58: 9470
- 16b Zhang Z, Zhou X.-Y, Wu J.-G, Song L, Yu D.-G. Green Chem. 2020; 22: 28
- 16c Rajamanickam S, Saraswat M, Venkataramani S, Patel BK. Chem. Sci. 2021; 12: 15318
- 16d Xu H.-B, Chen Y.-J, Chai X.-Y, Yang J.-H, Xu Y.-J, Dong L. Org. Lett. 2021; 23: 2052
- 16e Tian S, Luo T, Zhu Y, Wan J.-P. Chin. Chem. Lett. 2020; 31: 3073
- 16f Zhang X, Wang P, Zhu L, Chen B. Chin. Chem. Lett. 2021; 32: 695
- 17a Gogoi K, Bora BR, Borah G, Sarma B, Gogoi S. Chem. Commun. 2021; 57: 1388
- 17b Kang JY, An W, Kim S, Kwon NY, Jeong T, Ghosh P, Kim HS, Mishra NK, Kim IS. Chem. Commun. 2021; 57: 10947
- 18 Shen B, Liu S, Zhu L, Zhong K, Liu F, Chen H, Bai R, Lan Y. Organometallics 2020; 39: 2813
For selected reviews on the biological activities of cinnolines, see:
For selected examples, see:
For recent selected examples, see:
