Visible-Light-Induced Organophotoredox Catalyzed Phosphonylation

Article Cite This: J. Org. Chem. 2018, 83, 12694−12701

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Visible-Light-Induced Organophotoredox-Catalyzed Phosphonylation of 2H‑Indazoles with Diphenylphosphine Oxide Mukta Singsardar,† Amrita Dey,† Rajib Sarkar, and Alakananda Hajra* Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India

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S Supporting Information *

ABSTRACT: A metal-free visible-light-induced phosphonylation of 2H-indazoles with diphenylphosphine oxide has been developed using rose bengal as an organophotoredox catalyst under ambient air at room temperature. A library of diphenyl(2phenyl-2H-indazol-3-yl)phosphine oxide with broad functionalities has been synthesized in high yields. The experimental result suggests the radical pathway of the reaction.

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INTRODUCTION Indazoles are an essential group of N-heterocycles which have gained a great importance in the field of medicinal and organic chemistry, as they exhibit numerous pharmaceutical and biological activities.1 Effective bioactivities such as antitumor, antimicrobial, antidepressant, anti-inflammatory, anti-HIV, antiplatelet, etc., of 2H-indazole make it very useful for pharmacological purposes.2 Besides being an efficient bioisostere of indoles and benzimidazoles, it is an interesting core moiety in various marketed drugs such as MK-4827 (anticancer agent),3a bendazac,3b pazopanib (votrient, tyrosine kinase inhibitor),3c and gamendazole3d (Figure 1). Recently, it was also applied to

compounds containing the carbon−phosphorus bond, especially the N−C−P bond, acquire a huge capacity to influence physiological and pathological processes with broad applications in the medicinal field.8 In these circumstances, transition-metal-catalyzed strategies of C−P bond formation involving terminal alkynes or substituted alkenes with P−H species have been well established.9 However, a limited number of methodologies for direct phosphonylation of different heterocyclic moieties have been developed.10 Most of these methodologies require the use of expensive transition metals, selective ligands, external oxidants, and high temperature. Therefore, we became interested to develop an efficient and environmentally benign method for the direct construction of the C(sp2)−P bond under metal-free conditions. Organic dyes, being less toxic, less expensive, and easy to handle, are useful as good transition-metal complexes in photoredox-catalyzed reactions.11 In recent years, photoredox-based P-radical reactions have been developed to synthesize a range of organophosphorus compounds.12 Wu and his group have developed a photocatalysis cross-coupling C(sp2)− H phosphorylation of thiazole derivatives using white LED (Scheme 1a).13 Remarkably, Xie and co-workers have also developed a strategy to produce substituted alkenylphosphine oxides from alcohols employing rhodamine B and Bronsted acid as a co-operative catalytic system under white LED (Scheme 1b).14 However, there is no report for the phosphonylation of indazole derivatives. On the basis of our experiences on functionalization of heterocyclic moieties,15,16 we envisaged that the phosphonylation of indazoles could be carried out with diphenylphosphine oxide under visible-light-mediated photoredox catalysis. Herein we report a direct and environmentally friendly method for the C(sp2)−H phosphonylation

Figure 1. Biologically active molecules having the 2H-indazole scaffold.

selective estrogen receptors4a and bacterial gyrase B inhibitors.4b Though there are a few strategies for the preparation of the indazole core moiety,5 the methods for the functionalization of indazoles are very limited.6 Likewise, phosphine-containing aromatic compounds are found to be widely applicable in organic synthesis, materials science, and inorganic chemistry, as the presence of phosphorus controls the physical, chemical, and biological properties of the adjacent arenes.7 A number of biologically active © 2018 American Chemical Society

Received: August 4, 2018 Published: September 24, 2018 12694

DOI: 10.1021/acs.joc.8b02019 J. Org. Chem. 2018, 83, 12694−12701

Article

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Photoredox Catalysis toward C−P Bond Formation

entry

photocatalyst (mol %)

base (equiv)

1 2 3 4 5

rose rose rose rose rose

bengal bengal bengal bengal bengal

DBU DBU DBU DBU DBU

6

rose bengal

DBU

7

eosin Y

DBU

8

eosin B

DBU

of indazoles using rose bengal as an organophotoredox catalyst irradiated with blue LED under ambient air at room temperature (Scheme 1c).

9

rose bengal

DABCO

10

rose bengal

Et3N

RESULTS AND DISCUSSION In the initial study, we have chosen 2-phenyl-2H-indazole (1a) (0.2 mmol) and diphenylphosphine oxide (2a) (0.3 mmol) as model substrates employing DBU (2.0 equiv) as base with 3 mol % rose bengal as a photocatalyst in CH3CN irradiated with 34 W blue LED under ambient air at room temperature. Delightfully, diphenyl(2-phenyl-2H-indazol-3-yl)phosphine oxide (3a) was obtained in 48% yield after 16 h (Table 1, entry 1). Then the effect of other solvents such as 1,2-DCE, DMSO, and DMF was checked, but CH3CN was found to be more competent among these (Table 1, entries 2−4). Interestingly, the yield of the desired product was increased to 75% when a binary solvent CH3CN/H2O (1.0/0.14 mL) mixture was used as reaction medium (Table 1, entry 5). It was observed that the organophotocatalyst rose bengal worked effectively in water and acetonitrile medium due to its solubility and kinetic effects.17 Further screening of the proportion of the solvents revealed that 1.0/0.18 mL CH3CN/H2O mixture was the best option, affording the product 3a in excellent yield (Table 1, entry 6). Then other photocatalysts including eosin Y and eosin B were also tested (Table 1, entries 7 and 8), but lower yields were obtained with these photocatalysts. The catalytic effect of Ru(bpy)3Cl2·6H2O and Ir(ppy)3 photoredox catalysts were checked for this transformation. In the presence of Ru(bpy)3Cl2·6H2O, a trace amount of product was obtained whereas Ir(ppy)3 provided 60% yield of the product (see SI, Table S1, entries 18 and 19). Subsequently the reaction was also performed with bases such as DABCO and Et3N. It was observed that these were not as effective as DBU for the formation of 3a (Table 1, entries 9 and 10). The reaction did not proceed without base (Table 1, entry 11). Decreasing or increasing the loading of rose bengal (see SI, Table S1, entries 24 and 25) or changing the proportion of the two substrates was not helpful (see SI, Table S1, entries 26 and 27). Decreasing the loading of base also decreased the yield of the product (see SI, Table S1, entry 28). Then the reaction was carried out in the absence of photoredox catalyst and also in the dark, and in both the cases phosphonylation product 3a was not generated (Table 1, entries 12 and 13). Moreover, the formation of the product was diminished under inert

11

rose bengal

−

12

−

DBU

13c

rose bengal

DBU

d

rose bengal

DBU

■

14

solvent (1 mL) CH3CN 1,2- DCE DMSO DMF CH3CN/H2O (1.0/0.14 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL) CH3CN/H2O (1.0/0.18 mL)

yield (%)b 48 38 trace trace 75 88 32 20 45 42 NR NR NR trace

a Reaction conditions: All reactions were carried out with 1a (0.2 mmol), 2a (0.3 mmol), photocatalyst (3 mol %), base (2.0 equiv), and solvent (1.0 mL) irradiated with 34 W blue LED for 16 h under air at room temperature. bYields. NR = no reaction. cIn the dark. d Under argon atmosphere.

atmosphere (Table 1, entry 14). These results indicated that the photoredox process is a fundamental route in this reaction and that aerial oxygen is necessary for the oxidation. The phosphonylation was tried with a lower-power white LED (10 W). However, formation of the desired product was not observed. No significant temperature change was observed during the reaction. Finally, the maximum yield (88%) of the desired product was obtained in this optimized reaction condition by using 3 mol % rose bengal with 2.0 equiv of DBU in CH3CN/ H2O (1.0/0.18 mL) irradiated with 34 W blue LED for 16 h under ambient air at room temperature (Table 1, entry 6). After establishing the optimized reaction conditions, we examined the scope of this protocol with different functionalities in the 2H-indazole system. We first checked the electronic effect of N-2 substituent of 2H-indazoles, and the results are summarized in Scheme 2. 2-Phenyl-2H-indazole bearing an electron donating group such as 4-Me and 4-OMe at the phenyl ring efficiently reacted to provide good yield of the desired products 3b and 3c. 2-(m-Tolyl)-2H-indazole reacted smoothly as well, giving 90% yield of 3d. 2H-Indazoles containing halogens such as 4-F, 4-Cl, 3-Cl, and 4-Br in the phenyl ring successfully reacted under the present reaction conditions to give the desired products 3f−h in excellent yields. 2H-Indazole with a dihalogenated phenyl ring also gave 84% yield of the product 3i. Similarly, methylenedioxy group substitution on the phenyl ring resulted in a good yield (3j, 89%). Notably, a pyridine-substituted derivative afforded good result 12695


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The Journal of Organic Chemistry

in good to excellent yields. The 5,6-dimethoxy-substituted derivative also gave 70% yield of the product (3p). Similarly, halo-substitution of 2H-indazole at the C-5 position (5-F and 5-Cl) reacted well to produce the desired products (3q−t) in moderate to high yields. However, the current methodology is not applicable for the indole moiety. Furthermore, the scope of substrates with a variation in phosphine oxide was considered (Scheme 4). Bis(4-methoxyphenyl)-

Scheme 2. Substrate Scopes with Variation of N-2 Substituents on 2H-Indazolea,b

Scheme 4. Substrate Scopes with a Variation of Phosphine Oxidea,b

a

Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), rose bengal (3 mol %), DBU (2.0 equiv), and CH3CN/H2O (1.0 mL) irradiated with 34 W blue LED for 16 h under ambient air at room temperature. b Yields. cFive mmol scale. a

under this standardized reaction condition (3k, 90%). 2-(4Methoxybenzyl)-2H-indazole as well as 2-(tert-butyl)-2Hindazole also worked well in this reaction protocol to give good yields of the desired products (3l and 3m). 2H-Indazole having an electron-withdrawing group such as NO2 in the phenyl ring did not react in this reaction. 2H-Indazole also did not react with diethyl phosphite, diphenyl phosphite, and ethyl phenylphosphinate under the present conditions. To verify the practical applicability of the current methodology, the gramscale reaction was also performed in the usual laboratory setup using 2-phenyl-2H-indazole (1a). Diphenyl(2-phenyl-2H-indazol-3-yl)phosphine oxide (3a) was obtained without significant decrease in yield. Next, the scope of substrates with various substitutions in the arene part of 2H-indazoles was studied (Scheme 3).

Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), rose bengal (3 mol %), DBU (2.0 equiv), and CH3CN/H2O (1.0 mL) irradiated with 34 W blue LED for 16 h under air at room temperature. bYields.

phosphine oxide reacted well with 2-(p-tolyl)-2H-indazole and 2-(4-chlorophenyl)-2H-indazole, providing the desired products 5a and 5b in good yields. Di-p-tolylphosphine oxide also performed well with 2-(4-fluorophenyl)-2H-indazole and 2-(4bromophenyl)-2H-indazole to give the corresponding products 5c and 5d in good yields. Di(thiophen-2-yl)phosphine oxide also reacted with 2-(p-tolyl)-2H-indazole to give 83% yield of the product 5e. Phosphine oxides with electron-donating groups (OMe and Me) at ortho and meta positions in the phenyl ring reacted smoothly with 2-(p-tolyl)-2H-indazole, providing the desired products 5f−h in excellent yields. Phosphine oxide-bearing electron-withdrawing group (F) at the para position also afforded the product in 88% yield (5i). To acquire the mechanistic insights into the reaction pathway, a few control experiments were carried out (Scheme 5).

Scheme 3. Substrate Scopes with Variation of Arene Substituents on 2H-Indazolea,b

Scheme 5. Control Experiments

It was found that 2-phenyl-2H-indazole (1a) failed to give the corresponding phosphonylation product 3a in the presence of radical scavengers including 2,2,6,6-tetramethylpiperidine-1oxyl (TEMPO), 2,6-di-tert-butyl-4-methyl phenol (BHT), and p-benzoquinone (BQ). These observations imply that the reaction proceeds through a radical pathway. Based on the control experiments (Scheme 5) and literature reports,11d,12a,b,16a a plausible mechanism for the formation of phosphonylation product is depicted here in Scheme 6. First, RB is converted to its excited state RB* upon absorption of photons. Then RB* oxidizes the indazole 1a to indazole radical cation A along with formation of photocatalyst radical anion

a

Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), rose bengal (3 mol %), DBU (2.0 equiv), and CH3CN/H2O (1.0 mL) irradiated with 34 W blue LED for 16 h under air at room temperature. bYields.

5-OMe-substituted 2H-indazoles having either 4-Me or 4-OMe in the N-phenyl ring provided the desired products 3n and 3o 12696


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General Experimental Procedure for the Synthesis of 3. Indazoles (0.2 mmol), diphenylphosphine oxide (0.3 mmol, 61 mg), rose bengal (3 mol %, 6 mg), and DBU (2.0 equiv, 61 mg) were placed in an oven-dried reaction vessel equipped with a magnetic stir bar. Then 1 mL of the CH3CN/H2O (1.0/0.18 mL) solvent was added, and the reaction mixture was irradiated using a 34 W blue LED at room temperature under open atmosphere for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10 mL of water/ethyl acetate (1:3). Then the reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous Na2SO4. After evaporation of the solvent under reduced pressure, the crude residue was obtained. Finally, it was purified by column chromatography on silica gel (60− 120 mesh) using petroleum ether/ethyl acetate as an eluent to afford the pure products. Diphenyl(2-phenyl-2H-indazol-3-yl)phosphine Oxide (3a). Gummy solid (69 mg, 88%), Rf 0.5 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.86−7.84 (m, 1H), 7.68−7.63 (m, 4H), 7.52−7.47 (m, 4H), 7.40−7.36 (m, 4H), 7.32−7.28 (m, 1H), 7.26− 7.20 (m, 3H), 6.94−6.91 (m, 1H), 6.31 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 148.9 (d, JC−P = 12.0 Hz), 140.7, 132.5, 132.3, 131.9 (d, JC−P = 10.0 Hz), 131.4, 129.3, 128.7 (d, JC−P = 13.0 Hz), 128.5, 127.9 (d, JC−P = 14.0 Hz), 127.0, 126.6, 124.3, 120.5, 118.6; 31P NMR (CDCl3, 162 MHz): δ 12.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H20N2OP 395.1308; found: 395.1306. Diphenyl(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (3b). Gummy solid (66 mg, 81%), Rf 0.5 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.86−7.83 (m, 1H), 7.67−7.62 (m, 4H), 7.52−7.48 (m, 2H), 7.41−7.34 (m, 6H), 7.31−7.27 (m, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.94−6.90 (m, 1H), 6.33 (d, J = 9.2 Hz, 1H), 2.28 (s, 3H) ; 13C{1H} NMR (CDCl3, 100 MHz): δ 148.8 (d, JC−P = 12.0 Hz), 139.3, 138.3, 132.6, 132.3, 131.9 (d, JC−P = 10.0 Hz), 131.5, 129.1, 128.7 (d, JC−P = 12 0.0 Hz), 127.8 (d, JC−P = 15.0 Hz), 127.1, 126.7, 126.4, 124.2, 120.5, 118.6, 21.2; 31P NMR (CDCl3, 162 MHz): δ 12.9. Anal. Calcd for C26H21N2OP: C, 76.46; H, 5.18; N, 6.86; found: C, 76.64; H, 5.09; N, 6.66%. (2-(4-Methoxyphenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3c). Gummy solid (69 mg, 82%), Rf 0.45 (PET:EtOAc = 3:2); 1 H NMR (CDCl3, 400 MHz): δ 7.85−7.82 (m, 1H), 7.68−7.63 (m, 4H), 7.52−7.48 (m, 2H), 7.41−7.37 (m, 6H), 7.30−7.26 (m, 1H), 6.93−6.89 (m, 1H), 6.71−6.69 (m, 2H), 6.29 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H) ; 13C{1H} NMR (CDCl3, 100 MHz): δ 160.1, 148.8 (d, JC−P = 12.0 Hz), 133.8, 132.6, 132.3 (d, JC−P = 3.0 Hz), 131.9 (d, JC−P = 10.0 Hz), 131.4, 128.8, 128.6, 128.2, 127.8, 126.4, 124.2, 120.4, 118.5, 113.6, 55.6; 31P NMR (CDCl3, 162 MHz): δ 12.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H22N2O2P 425.1413; found: 425.1415. Diphenyl(2-(m-tolyl)-2H-indazol-3-yl)phosphine Oxide (3d). Gummy solid (73 mg, 90%), Rf 0.55 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.99−7.96 (m, 1H), 7.82−7.77 (m, 4H), 7.64−7.60 (m, 2H), 7.53−7.49 (m, 4H), 7.46−7.39 (m, 2H), 7.36 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.07−7.04 (m, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 148.8, 140.6, 138.5, 132.6, 132.2 (d, JC−P = 3.0 Hz), 131.8 (d, JC−P = 10.0 Hz), 131.5, 130.0, 128.6 (d, JC−P = 13.0 Hz), 128.4, 127.9, 127.8, 127.5, 126.5, 124.2, 124.0, 120.5, 118.5, 21.1; 31P NMR (CDCl3, 162 MHz): δ 12.6. Anal. Calcd for C26H21N2OP: C, 76.46; H, 5.18; N, 6.86; found: C, 76.30; H, 5.22; N, 6.62%. (2-(4-Fluorophenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3e). Gummy solid (73 mg, 89%), Rf 0.55 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.85−7.82 (m, 1H), 7.69−7.63 (m, 4H), 7.55−7.47 (m, 4H), 7.43−7.39 (m, 4H), 7.32−7.28 (m, 1H), 6.94− 6.87 (m, 3H), 6.25 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 162.8 (d, JC−F = 248.0 Hz), 148.9, 136.8 (d, JC−P = 2.0 Hz), 132.5 (d, JC−P = 2.0 Hz), 132.3, 131.9 (d, JC−P = 10.0 Hz), 131.2, 129.0, 128.9 (d, JC−F = 3.0 Hz), 128.7, 127.6, 126.7, 124.4, 120.4, 118.6, 115.4 (d, JC−F = 23.0 Hz); 31P NMR (CDCl3, 162 MHz): δ 12.6. Anal. Calcd for C25H18FN2OP: C, 72.81; H, 4.40; N, 6.79; found: C, 73.00; H, 4.35; N, 6.68%.

Scheme 6. Plausible Mechanistic Pathway

RB•− through a single electron transfer (SET) process. After that, the photocatalyst radical anion RB•− is oxidized to RB by reducing O2 to superoxide radical anion (O2•−). Thereafter, the intermediate P-centered diphenylphosphinoyl radical B is generated through HAT (hydrogen atom transfer) between highly active superoxide radical anion (O2•−) and diphenylphosphine oxide (2a) in the presence of DBU and then undergoes intermolecular addition with indazole radical cation A to form cation intermediate C. Phosphonylation does not occur in DBU. This suggests that DBU cannot act as a competitor of indazoles and it acts only as a base. Finally, deprotonation by HO2− from intermediate C affords the phosphonylation product 3a along with H2O2. The presence of H2O2 is detected by the starch−iodine test.11h Formation of the desired product is completely stopped in the presence of p-benzoquinone, which acts as a superoxide radical anion scavenger.11i

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CONCLUSION In summary, we have developed a metal-free visible-lightinduced organophotoredox-catalyzed radical phosphonylation of indazoles using rose bengal as a photocatalyst under aerobic reaction conditions. A variety of phosphonylated indazoles have been synthesized in high to excellent yields. To the best of our knowledge, this is the first report of visible-lightpromoted functionalization of indazoles. The further development of related photoinduced oxidative C-heteroatom bondforming reactions is ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification. 1H NMR spectra were determined on a 400 MHz spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (δ), and the signals are reported as s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublet), and coupling constants (J) given in hertz (Hz). 13C{1H} and 31P NMR spectra were recorded at 100 and 162 MHz in CDCl3 solution. Chemical shifts are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as internal standard. TLC was performed on silica gel-coated glass slides. All solvents were dried and distilled before use. Commercially available solvents were freshly distilled before reaction. All reactions involving moisture-sensitive reactants were executed using oven-dried glassware. All 2-substituted indazoles were prepared by the reported method.5c,6a 12697


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NMR (CDCl3, 400 MHz): δ 9.22 (d, J = 8.4 Hz, 1H), 8.32−8.30 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.94−7.89 (m, 5H), 7.58−7.54 (m, 4H), 7.51−7.46 (m, 5H), 6.96−6.94 (m, 2H), 3.87 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 151.9, 134.6, 132.3 (d, JC−P = 9.0 Hz), 132.3 (d, JC−P = 3.0 Hz), 131.3, 130.2, 129.2, 128.6, 128.4, 127.6, 127.3, 125.3, 114.1, 55.5, 21.8; 31P NMR (CDCl3, 162 MHz): δ 27.9. Anal. Calcd for C27H23N2O2P: C, 73.96; H, 5.29; N, 6.39; found: C, 74.07; H, 5.34; N, 6.30%. (2-(tert-Butyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3m). Gummy solid (47 mg, 63%), Rf 0.4 (PET:EtOAc = 2:3); 1H NMR (CDCl3, 400 MHz): δ 8.34 (d, J = 2.0 Hz, 1H), 7.93−7.88 (m, 3H), 7.71−7.66 (m, 3H), 7.49−7.45 (m, 4H), 7.40−7.35 (m, 3H), 1.47 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 133.1, 132.5, 132.4, 132.3, 132.2, 132.1 (d, JC−P = 3.0 Hz), 131.4 (d, JC−P = 2.0 Hz), 128.7 (d, JC−P = 13.0 Hz), 128.4, 128.3, 127.9 (d, JC−P = 12.0 Hz), 124.4, 124.3, 122.2 (d, JC−P = 3.0 Hz), 121.3, 119.3, 30.2, 30.0; 31P NMR (CDCl3, 162 MHz): δ 29.8. Anal. Calcd for C23H23N2OP: C, 73.78; H, 6.19; N, 7.48; found: C, 73.57; H, 6.29; N, 7.55%. (5-Methoxy-2-(p-tolyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3n). Gummy solid (62 mg, 71%), Rf 0.5 (PET:EtOAc = 3:2); 1 H NMR (CDCl3, 400 MHz): δ 7.70−7.64 (m, 5H), 7.49−7.47 (m, 2H), 7.42−7.35 (m, 6H), 6.99−6.94 (m, 3H), 5.48 (d, J = 2.4 Hz, 1H), 3.33 (s, 3H), 2.26 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 156.5, 145.5, 139.1, 138.4, 132.9, 132.18 (d, JC−P = 3.0 Hz), 132.11, 132.0, 131.8, 129.0, 128.7, 128.6, 128.5, 126.6, 125.4, 121.6, 119.7, 96.8, 55.0, 21.2; 31P NMR (CDCl3, 162 MHz): δ 12.6; HRMS (ESITOF) m/z: [M + H]+ Calcd for C27H24N2O2P 439.1570; found: 439.1573. (5-Methoxy-2-(4-methoxyphenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3o). Gummy solid (81 mg, 89%), Rf 0.45 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.71−7.65 (m, 5H), 7.49−7.47 (m, 2H), 7.43−7.39 (m, 6H), 6.97−6.94 (m, 1H), 6.70−6.67 (m, 2H), 5.46 (d, J = 2.0 Hz, 1H), 3.75 (s, 3H), 3.33 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 159.9, 156.5, 145.5, 133.9, 132.8, 132.2 (d, JC−P = 2.0 Hz), 132.1 (d, JC−P = 9.0 Hz), 131.7, 128.7 (d, JC−P = 13.0 Hz), 128.4, 128.1, 121.5, 119.7, 113.6, 96.8, 55.6, 55.0; 31P NMR (CDCl3, 162 MHz): δ 12.5. Anal. Calcd for C27H23N2O3P: C, 71.36; H, 5.10; N, 6.16; found: C, 71.20; H, 5.04; N, 6.27%. (5,6-Dimethoxy-2-phenyl-2H-indazol-3-yl)diphenylphosphine Oxide (3p). Gummy solid (63 mg, 70%), Rf 0.45 (PET:EtOAc = 3:2); 1 H NMR (CDCl3, 400 MHz): δ 7.71−7.66 (m, 4H), 7.54−7.52 (m, 2H), 7.49−7.45 (m, 2H), 7.41−7.37 (m, 4H), 7.20−7.18 (m, 3H), 7.07 (d, J = 1.6 Hz, 1H), 5.47 (s, 1H), 3.92 (s, 3H), 3.38 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.5, 149.2, 145.7 (d, JC−P = 12.0 Hz), 140.8, 132.8, 132.2, 132.0 (d, JC−P = 10.0 Hz), 131.6, 128.8, 128.6 (d, JC−P = 12.0 Hz), 126.7, 123.5, 97.6, 96.1, 56.0, 55.6; 31P NMR (CDCl3, 162 MHz): δ 12.4. Anal. Calcd for C27H23N2O3P: C, 71.36; H, 5.10; N, 6.16; found: C, 71.54; H, 5.07; N, 6.07%. (5-Fluoro-2-(p-tolyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3q). Gummy solid (71 mg, 83%), Rf 0.5 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.82−7.80 (m, 2H), 7.66−7.61 (m, 4H), 7.54−7.50 (m, 2H), 7.42−7.40 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.12−7.06 (m, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.83 (dd, J = 2.4, 10.4 Hz, 1H), 2.28 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 159.4 (d, JC−F = 241.0 Hz), 146.1 (d, JC−P = 12.0 Hz), 139.5, 138.2, 132.4 (d, JC−F = 3.0 Hz), 132.3, 131.8 (d, JC−P = 10.0 Hz), 131.7, 131.1, 130.2, 129.1, 128.8 (d, JC−P = 13.0 Hz), 128.6, 126.6, 123.4, 121.0, 120.6 (d, JC−F = 10.0 Hz), 118.1 (d, JC−P = 28.0 Hz), 103.5 (d, JC−F = 27.0 Hz), 21.2; 31P NMR (CDCl3, 162 MHz): δ 12.8;Anal. Calcd for C26H20FN2OP: C, 73.23; H, 4.73; N, 6.57; found: C, 73.59; H, 4.87; N, 6.40%. (5-Fluoro-2-(4-methoxyphenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3r). Gummy solid (74 mg, 84%), Rf 0.4 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.83−7.77 (m, 2H), 7.67−7.62 (m, 4H), 7.55−7.51 (m, 2H), 7.44−7.37 (m, 5H), 7.11−7.06 (m, 1H), 6.71−6.69 (m, 2H), 5.81−5.78 (m, 1H), 3.76 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 133.7, 132.5 (d, JC−F = 2.0 Hz), 132.3, 132.2, 131.8 (d, JC−P = 10.0 Hz),

(2-(4-Chlorophenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3f). Gummy solid (74 mg, 86%), Rf 0.6 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.84−7.82 (m, 1H), 7.68−7.63 (m, 4H), 7.55−7.50 (m, 2H), 7.47−7.45 (m, 2H), 7.43−7.38 (m, 4H), 7.31− 7.27 (m, 1H), 7.20−7.17 (m, 2H), 6.94−6.90 (m, 1H), 6.26 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.0 (d, JC−P = 11.0 Hz), 139.2, 135.3, 132.5 (d, JC−P = 3.0 Hz), 132.2, 131.9 (d, JC−P = 10.0 Hz), 131.1, 128.9, 128.7 (d, JC−P = 13.0 Hz), 128.2, 127.8 (d, JC−P = 14.0 Hz), 127.5, 126.8, 124.5, 120.3, 118.5; 31P NMR (CDCl3, 162 MHz): δ 12.8. Anal. Calcd for C25H18ClN2OP: C, 70.02; H, 4.23; N, 6.53; found: C, 70.25; H, 4.13; N, 6.42%. (2-(3-Chlorophenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3g). Gummy solid (66 mg, 77%), Rf 0.65 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.85−7.82 (m, 1H), 7.71−7.66 (m, 4H), 7.56−7.51 (m, 3H), 7.44−7.40 (m, 5H), 7.33−7.29 (m, 1H), 7.24− 7.16 (m, 2H), 6.95−6.92 (m, 1H), 6.29 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 134.2, 132.6, 132.2, 131.9 (d, JC−P = 10.0 Hz), 129.5 (d, JC−P = 7.0 Hz), 128.9, 128.8, 127.2, 126.9, 125.3, 124.6, 120.5, 118.6; 31P NMR (CDCl3, 162 MHz): δ 12.5. Anal. Calcd for C25H18ClN2OP: C, 70.02; H, 4.23; N, 6.53; found: C, 70.18; H, 4.30; N, 6.64%. (2-(4-Bromophenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3h). Gummy solid (82 mg, 87%), Rf 0.6 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.85−7.82 (m, 1H), 7.68−7.63 (m, 4H), 7.56−7.52 (m, 2H), 7.44−7.39 (m, 6H), 7.36−7.25 (m, 3H), 6.94− 6.91 (m, 1H), 6.30−6.26 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.1 (d, JC−P = 11.0 Hz), 139.8, 137.6, 132.5, 132.3, 131.9 (d, JC−P = 10.0 Hz), 131.6, 131.2, 128.9 (d, JC−P = 13.0 Hz), 128.6, 128.5, 126.8, 124.5, 123.5, 120.4, 118.6; 31P NMR (CDCl3, 162 MHz): δ 12.7. Anal. Calcd for C25H18BrN2OP: C, 63.44; H, 3.83; N, 5.92; found: C, 63.61; H, 3.76; N, 5.84%. (2-(3-Chloro-4-fluorophenyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3i). Gummy solid (75 mg, 84%), Rf 0.55 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.83−7.81 (m, 1H), 7.71−7.65 (m, 4H), 7.58−7.48 (m, 4H), 7.46−7.41 (m, 4H), 7.33−7.29 (m, 1H), 7.03−6.99 (m, 1H), 6.95−6.91 (m, 1H), 6.25 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 158.3 (d, JC−F = 251.0 Hz), 149.0 (d, JC−P = 12.0 Hz), 137.1 (d, JC−P = 3.0 Hz), 132.7 (d, JC−P = 3.0 Hz), 132.0, 131.9 (d, JC−P = 10.0 Hz), 130.9, 129.5, 129.0, 128.9 (d, JC−P = 13.0 Hz), 127.9, 127.7 (d, JC−P = 14.0 Hz), 127.1 (d, JC−F = 9.0 Hz), 127.0, 124.7, 121.0 (d, JC−P = 19.0 Hz), 120.3, 118.6, 116.2 (d, JC−F = 22.0 Hz); 31P NMR (CDCl3, 162 MHz): δ 12.6. Anal. Calcd for C25H17ClFN2OP: C, 67.20; H, 3.83; N, 6.27; found: C, 67.05; H, 3.74; N, 6.38%. (2-(Benzo[d][1,3]dioxol-5-yl)-2H-indazol-3-yl)diphenylphosphine Oxide (3j). Gummy solid (78 mg, 89%), Rf 0.45 (PET:EtOAc = 3:2); 1 H NMR (CDCl3, 400 MHz): δ 7.84−7.81 (m, 1H), 7.70−7.65 (m, 4H), 7.55−7.51 (m, 2H), 7.44−7.39 (m, 4H), 7.31−7.27 (m, 1H), 7.03−7.01 (m, 1H), 6.94−6.90 (m, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.92 (s, 2H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 148.6 (d, JC−P = 47.0 Hz), 147.3, 134.7, 132.5, 132.4 (d, JC−P = 3.0 Hz), 132.2, 131.9 (d, JC−P = 10.0 Hz), 131.4, 128.8 (d, JC−P = 13.0 Hz), 126.6, 124.3, 122.6, 121.3, 120.5, 118.5, 107.8 (d, JC−P = 63.0 Hz), 101.9; 31P NMR (CDCl3, 162 MHz): δ 12.7. Anal. Calcd for C26H19N2O3P: C, 71.23; H, 4.37; N, 6.39; found: C, 71.39; H, 4.22; N, 6.44%. Diphenyl(2-(pyridin-2-yl)-2H-indazol-3-yl)phosphine Oxide (3k). Gummy solid (71 mg, 90%), Rf 0.45 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 8.01−7.99 (m, 2H), 7.85−7.83 (m, 1H), 7.76−7.70 (m, 5H), 7.50−7.46 (m, 2H), 7.42−7.37 (m, 4H), 7.32− 7.28 (m, 1H), 7.13−7.10 (m, 1H), 6.96−6.92 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H) ; 13C{1H} NMR (CDCl3, 100 MHz): δ 147.1, 138.4, 133.3, 132.4, 132.2, 132.1, 131.8 (d, JC−P = 2.0 Hz), 131.6 (d, JC−P = 10.0 Hz), 128.7, 128.5 (d, JC−P = 13.0 Hz), 128.2, 127.2, 124.7, 123.6, 121.5, 118.8, 117.9; 31P NMR (CDCl3, 162 MHz): δ 17.6. Anal. Calcd for C24H18N3OP: C, 72.90; H, 4.59; N, 10.63; found: C, 72.77; H, 4.61; N, 10.66%. (2-(4-Methoxybenzyl)-2H-indazol-3-yl)diphenylphosphine Oxide (3l). Gummy solid (58 mg, 67%), Rf 0.45 (PET:EtOAc = 1:1); 1H 12698


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Di(thiophen-2-yl)(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5e). Gummy solid (70 mg, 83%), Rf 0.5 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.86−7.83 (m, 1H), 7.74−7.71 (m, 2H), 7.49−7.46 (m, 2H), 7.37−7.30 (m, 3H), 7.14−7.12 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.05−7.01 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 139.5, 138.3, 137.1 (d, JC−P = 12.0 Hz), 134.6 (d, JC−P = 6.0 Hz), 129.1, 128.5, 128.4, 126.8, 126.6, 124.6, 120.2, 118.6, 105.1, 21.3; 31P NMR (CDCl3, 162 MHz): δ −0.8. Anal. Calcd for C22H17N2OPS2: C, 62.84; H, 4.08; N, 6.66; found: C, 62.69; H, 4.10; N, 6.57%. Bis(3-methoxyphenyl)(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5f). Gummy solid (80 mg, 86%), Rf 0.5 (PET:EtOAc = 7:3); 1 H NMR (CDCl3, 400 MHz): δ 7.85−7.82 (m, 1H), 7.35−7.33 (m, 2H), 7.31−7.25 (m, 4H), 7.23−7.22 (m, 1H), 7.16−7.11 (m, 2H), 7.03−7.00 (m, 4H), 6.97−6.93 (m, 1H), 6.43 (d, J = 9.2 Hz, 1H), 3.75 (s, 6H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 159.7 (d, JC−P = 16.0 Hz), 148.8, 139.3, 138.3, 133.8, 132.7, 129.9, 129.8, 129.0, 127.7 (d, JC−P = 15.0 Hz), 126.8, 126.5, 124.2, 124.0 (d, JC−P = 10.0 Hz), 120.5, 118.7 (d, JC−P = 3.0 Hz), 118.5, 116.6 (d, JC−P = 11.0 Hz), 55.5, 21.2; 31P NMR (CDCl3, 162 MHz): δ 13.0. Anal. Calcd for C28H25N2O3P: C, 71.79; H, 5.38; N, 5.98; found: C, 71.60; H, 5.42; N, 5.85%. Di-o-tolyl(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5g). Gummy solid (70 mg, 80%), Rf 0.55 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 8.59 (s, 1H), 8.00−7.97 (m, 1H), 7.74− 7.72 (m, 2H), 7.46−7.42 (m, 2H), 7.34−7.25 (m, 4H), 7.15−7.09 (m, 3H), 7.09−6.97 (m, 3H), 2.56 (s, 6H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.3 (d, JC−P = 9.0 Hz), 143.7 (d, JC−P = 7.0 Hz), 138.3, 138.0, 133.0 (d, JC−P = 13.0 Hz), 132.2, 132.1, 131.2, 130.1, 128.9, 128.8, 125.7 (d, JC−P = 13.0 Hz), 125.6 (d, JC−P = 13.0 Hz), 125.3, 124.3, 123.0, 122.4, 122.2, 121.0, 21.99, 21.95, 21.1; 31 P NMR (CDCl3, 162 MHz): δ 34.9. Anal. Calcd for C28H25N2OP: C, 77.05; H, 5.77; N, 6.42; found: C, 76.89; H, 5.86; N, 6.31%. Di-m-tolyl(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5h). Gummy solid (76 mg, 87%), Rf 0.45 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.85−7.83 (m, 1H), 7.50 (d, J = 13.2 Hz, 2H), 7.40−7.34 (m, 3H), 7.31−7.27 (m, 5H), 7.25−7.22 (m, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.95−6.91 (m, 1H), 6.41 (d, J = 8.8 Hz, 1H), 2.30 (s, 6H), 2.28 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 148.8 (d, JC−P = 12.0 Hz), 139.2, 138.6, 138.5, 138.3, 133.0 (d, JC−P = 2.0 Hz), 132.49, 132.43, 132.3, 131.3, 128.9, 128.8, 128.6, 128.4, 127.7 (d, JC−P = 15.0 Hz), 126.7, 126.4, 124.0, 120.7, 118.4, 21.4, 21.2; 31P NMR (CDCl3, 162 MHz): δ 13.4. Anal. Calcd for C28H25N2OP: C, 77.05; H, 5.77; N, 6.42; found: C, 77.21; H, 5.68; N, 6.37%. Bis(4-fluorophenyl)(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5i). Gummy solid (78 mg, 88%), Rf 0.5 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.86−7.84 (m, 1H), 7.66−7.59 (m, 4H), 7.35−7.29 (m, 3H), 7.10−7.02 (m, 6H), 7.00−6.96 (m, 1H), 6.40 (d, J = 8.8 Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 165.3 (d, JC−F = 257.0 Hz), 148.8 (d, JC−P = 13.0 Hz), 139.6, 138.1, 134.36, 134.35 (d, JC−F = 21.0 Hz), 129.1, 128.4, 127.8 (d, JC−P = 16.0 Hz), 127.3, 126.6 (d, JC−F = 3.0 Hz), 124.6, 120.1, 118.7, 116.3 (d, JC−F = 13.0 Hz), 116.1, 116.0, 21.2; 31P NMR (CDCl3, 162 MHz): δ 11.2. Anal. Calcd for C26H19F2N2OP: C, 70.27; H, 4.31; N, 6.30; found: C, 70.43; H, 4.39; N, 6.16%.

131.7, 131.1, 128.9 (d, JC−P = 12.0 Hz), 128.7, 128.6, 128.1, 122.5, 120.7 (d, JC−P = 10.0 Hz), 118.1 (d, JC−P = 29.0 Hz), 114.7, 113.7, 103.4 (d, JC−F = 27.0 Hz), 55.6; 31P NMR (CDCl3, 162 MHz): δ 12.6. Anal. Calcd for C26H20FN2O2P: C, 70.58; H, 4.56; N, 6.33; found: C, 70.60; H, 4.62; N, 6.29%. (5-Chloro-2-phenyl-2H-indazol-3-yl)diphenylphosphine Oxide (3s). Gummy solid (64 mg, 75%), Rf 0.6 (PET:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 9.2 Hz, 1H), 7.67−7.62 (m, 4H), 7.55−7.48 (m, 4H), 7.43−7.39 (m, 4H), 7.25−7.22 (m, 4H), 6.19 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 140.5, 132.6 (d, JC−P = 3.0 Hz), 132.3, 131.9 (d, JC−P = 10.0 Hz), 130.9, 129.5, 128.9, 128.8, 128.6, 128.5, 128.1, 126.9, 119.8 (d, JC−P = 52.0 Hz); 31 P NMR (CDCl 3 , 162 MHz): δ 12.7. Anal. Calcd for C25H18ClN2OP: C, 70.02; H, 4.23; N, 6.53; found: C, 69.89; H, 4.09; N, 6.46%. (2-(Benzo[d][1,3]dioxol-5-yl)-5-chloro-2H-indazol-3-yl)diphenylphosphine Oxide (3t). Gummy solid (62 mg, 66%), Rf 0.45 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.77−7.74 (m, 1H), 7.69−7.63 (m, 4H), 7.57−7.54 (m, 2H), 7.47−42 (m, 4H), 7.24−7.22 (m, 1H), 7.01−6.99 (m, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 5.93 (s, 2H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 134.4, 132.6 (d, JC−P = 2.0 Hz), 132.0 (d, JC−P = 10.0 Hz), 130.2, 128.9 (d, JC−P = 12.0 Hz), 128.6, 128.1, 121.2, 119.7 (d, JC−P = 51.0 Hz), 107.7 (d, JC−P = 47.0 Hz), 102.0; 31P NMR (CDCl3, 162 MHz): δ 12.7. Anal. Calcd for C26H18ClN2O3P: C, 66.04; H, 3.84; N, 5.92; found: C, 65.84; H, 3.92; N, 5.81%. Bis(4-methoxyphenyl)(2-(p-tolyl)-2H-indazol-3-yl)phosphine Oxide (5a). Gummy solid (77 mg, 82%), Rf 0.5 (PET:EtOAc = 3:2); 1 H NMR (CDCl3, 400 MHz): δ 7.83 (d, J = 8.8 Hz, 1H), 7.55−7.50 (m, 4H), 7.33−7.26 (m, 3H), 7.02 (d, J = 8.0 Hz, 2H), 6.97−6.93 (m, 1H), 6.89−6.86 (m, 4H), 6.50 (d, J = 8.8 Hz, 1H), 3.82 (s, 6H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 162.7 (d, JC−P = 2.0 Hz), 148.6, 139.2, 138.5, 133.7 (d, JC−P = 11.0 Hz), 129.0, 127.8, 127.6, 126.7, 126.4, 124.3, 124.0, 123.1, 120.7, 118.4, 114.2 (d, JC−P = 13.0 Hz), 55.5, 21.2; 31P NMR (CDCl3, 162 MHz): δ 13.6. Anal. Calcd for C28H25N2O3P: C, 71.79; H, 5.38; N, 5.98; found: C, 71.61; H, 5.49; N, 5.88%. (2-(4-Chlorophenyl)-2H-indazol-3-yl)bis(4-methoxyphenyl)phosphine Oxide (5b). Gummy solid (77 mg, 79%), Rf 0.55 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.83−7.80 (m, 1H), 7.56−7.51 (m, 4H), 7.45−7.43 (m, 2H), 7.32−7.28 (m, 1H), 7.22−7.20 (m, 2H), 6.98−6.94 (m, 1H), 6.92−6.89 (m, 4H), 6.44 (d, J = 8.8 Hz, 1H), 3.84 (s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 162.9, 148.9 (d, JC−P = 12.0 Hz), 139.4, 135.2, 133.7 (d, JC−P = 11.0 Hz), 128.6, 128.3, 127.9, 127.8, 127.7, 126.7, 124.3, 123.8, 122.7, 120.7, 118.5, 114.4 (d, JC−P = 14.0 Hz), 55.5; 31P NMR (CDCl3, 162 MHz): δ 13.2. Anal. Calcd for C27H22ClN2O3P: C, 66.33; H, 4.54; N, 5.73; found: C, 66.52; H, 4.49; N, 5.81%. (2-(4-Fluorophenyl)-2H-indazol-3-yl)di-p-tolylphosphine Oxide (5c). Gummy solid (70 mg, 80%), Rf 0.5 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.83−7.81 (m, 1H), 7.54−7.46 (m, 6H), 7.31−7.27 (m, 1H), 7.21−7.19 (m, 4H), 6.95−6.89 (m, 3H), 6.35 (d, J = 8.8 Hz, 1H), 2.38 (s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 162.7 (d, JC−F = 248.0 Hz), 148.8 (d, JC−P = 12.0 Hz), 143.0 (d, JC−P = 3.0 Hz), 136.9 (d, JC−F = 3.0 Hz), 131.8 (d, JC−P = 10.0 Hz), 129.5 (d, JC−P = 13.0 Hz), 129.3, 129.2, 128.9 (d, JC−F = 8.0 Hz), 128.1, 127.7, 127.5, 126.6, 124.2, 120.6, 118.4, 115.3 (d, JC−F = 24.0 Hz), 21.7; 31 P NMR (CDCl3, 162 MHz): δ 13.4. Anal. Calcd for C27H22FN2OP: C, 73.63; H, 5.03; N, 6.36; found: C, 73.81; H, 5.00; N, 6.25%. (2-(4-Bromophenyl)-2H-indazol-3-yl)di-p-tolylphosphine Oxide (5d). Gummy solid (81 mg, 81%), Rf 0.6 (PET:EtOAc = 3:2); 1H NMR (CDCl3, 400 MHz): δ 7.83−7.81 (m, 1H), 7.53−7.48 (m, 4H), 7.39−7.33 (m, 4H), 7.32−7.28 (m, 1H), 7.22−7.19 (m, 4H), 6.96− 6.92 (m, 1H), 6.40 (d, J = 8.8 Hz, 1H), 2.39 (s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 148.9, 143.1 (d, JC−P = 3.0 Hz), 139.8, 131.8 (d, JC−P = 10.0 Hz), 131.5, 129.5 (d, JC−P = 13.0 Hz), 129.3, 129.1, 128.5, 128.1, 127.9, 127.7, 126.8, 124.3, 123.4, 120.7, 118.5, 21.7; 31P NMR (CDCl3, 162 MHz): δ 13.7. Anal. Calcd for C27H22BrN2OP: C, 64.68; H, 4.42; N, 5.59; found: C, 64.84; H, 4.36; N, 5.71%.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02019.

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Scanned copies of 1H, 13C{1H}, and 31P NMR spectra of the synthesized compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 12699


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Indazole. Org. Lett. 2011, 13, 3542−3545. (d) Shi, D.-Q.; Dou, G.-L.; Ni, S.-N.; Shi, J.-W.; Li, X.-Y.; Wang, X.-S.; Wu, H.; Ji, S.-J. A Novel and Efficient Synthesis of 2-Aryl-2H-indazoles via SnCl2-Mediated Cyclization of 2-Nitrobenzylamines. Synlett 2007, 16, 2509−2512. (e) Vidyacharan, S.; Sagar, A.; Chaitra, N. C.; Sharada, D. S. A Facile Synthesis of 2H-Indazoles under Neat Conditions and Further Transformation into Aza-γ-Carboline Alkaloid Analogues in a Tandem One-Pot Fashion. RSC Adv. 2014, 4, 34232−34236. (f) Zhang, C.; Chang, S.; Dong, S.; Qiu, L.; Xu, X. Acid-Promoted Bicyclization of Diaryl Alkynes: Synthesis of 2H-Indazoles with in Situ Generated Diazonium Salt as Nitrogen Source. J. Org. Chem. 2018, 83, 9125−9136. (g) Shinde, A. H.; Vidyacharan, S.; Sharada, D. S. BF3·OEt2 Mediated Metal-Free One-Pot Sequential Multiple Annulation Cascade (SMAC) Synthesis of Complex and Diverse Tetrahydroisoquinoline Fused Hybrid Molecules. Org. Biomol. Chem. 2016, 14, 3207−3211. (6) (a) Bogonda, G.; Kim, H. Y.; Oh, K. Direct Acyl Radical Addition to 2H-Indazoles Using Ag-Catalyzed Decarboxylative CrossCoupling of α-Keto Acids. Org. Lett. 2018, 20, 2711−2715. (b) Vidyacharan, S.; Murugan, A.; Sharada, D. S. Functionalization of 2H-Indazoles at C3-Position via Palladium(II)-Catalyzed Isocyanide Insertion Strategy Leading to Diverse Heterocycles. J. Org. Chem. 2016, 81, 2837−2848. (c) Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Direct Arylations of 2H-Indazoles On Water. Org. Lett. 2010, 12, 224−226. (7) (a) Zhao, D.; Wang, R. Recent Developments in Metal Catalyzed Asymmetric Addition of Phosphorus Nucleophiles. Chem. Soc. Rev. 2012, 41, 2095−2108. (b) Fernández-Pérez, H.; Etayo, P.; Panossian, A.; Vidal-Ferran, A. Phosphine-Phosphinite and Phosphine-Phosphite Ligands: Preparation and Applications in Asymmetric Catalysis. Chem. Rev. 2011, 111, 2119−2176. (c) George, A.; Veis, A. Phosphorylated Proteins and Control over Apatite Nucleation, Crystal Growth, and Inhibition. Chem. Rev. 2008, 108, 4670−4693. (8) (a) Vassiliou, S.; Węglarz-Tomczak, E.; Berlicki, Ł.; Pawełczak, M.; Nocek, B.; Mulligan, R.; Joachimiak, A.; Mucha, A. StructureGuided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases. J. Med. Chem. 2014, 57, 8140−8151. (b) Mucha, A.; Kafarski, P.; Berlicki, Ł. Remarkable Potential of the αAminophosphonate/Phosphinate Structural Motif in Medicinal Chemistry. J. Med. Chem. 2011, 54, 5955−5980. (c) Xie, J.; Li, H.; Xue, Q.; Cheng, Y.; Zhu, C. A Scalable, Efficient Gold-Catalyzed Oxidative Phosphonation of sp3 C-H Bonds using Air as Sustainable Oxidant. Adv. Synth. Catal. 2012, 354, 1646−1650. (9) (a) Hu, G.; Gao, Y.; Zhao, Y. Copper-Catalyzed Decarboxylative C−P Cross-Coupling of Alkynyl Acids with H-Phosphine Oxides: A Facile and Selective Synthesis of (E)-1-Alkenylphosphine Oxides. Org. Lett. 2014, 16, 4464−4467. (b) Islas, R. E.; García, J. J. Hydrophosphonylation of Alkynes with Trialkyl Phosphites Catalyzed by Nickel. ChemCatChem 2017, 9, 4125−4131. (c) Wu, Y.; Liu, L.; Yan, K.; Xu, P.; Gao, Y.; Zhao, Y. Nickel-Catalyzed Decarboxylative C−P Cross-Coupling of Alkenyl Acids with P(O)H Compounds. J. Org. Chem. 2014, 79, 8118−8127. (d) Li, X.; Yang, F.; Wu, Y.; Wu, Y. Copper-Mediated Oxidative Decarboxylative Coupling of Arylpropiolic Acids with Dialkyl H-Phosphonates in Water. Org. Lett. 2014, 16, 992−995. (10) (a) Sun, W.-B.; Xue, J.-F.; Zhang, G.-Y.; Zeng, R.-S.; An, L.-T.; Zhang, P.-Z.; Zou, J.-P. Silver-Catalyzed Direct Csp2-H Phosphorylation of Indoles Leading to Phosphoindoles. Adv. Synth. Catal. 2016, 358, 1753−1758. (b) Zhang, H.-J.; Lin, W.; Wu, Z.; Ruan, W.; Wen, T.-B. Silver-Mediated Direct Phosphorylation of Benzothiazoles and Thiazoles with Diarylphosphine Oxides. Chem. Commun. 2015, 51, 3450−3453. (11) (a) Hari, D. P.; König, B. Synthetic Applications of Eosin Y in Photoredox Catalysis. Chem. Commun. 2014, 50, 6688−6699. (b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166. (c) Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Dehydrogenative Coupling Reactions Catalysed by

Alakananda Hajra: 0000-0001-6141-0343 Author Contributions †

Both the author contributed equally in this work

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.H. acknowledges the financial support from CSIR, New Delhi (grant no. 02(0307)/17/EMR-II). M.S. thanks UGCNew Delhi for NFHE, A.D. thanks CSIR for her fellowship, and R.S. thanks SERB-DST for NPDF.

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REFERENCES

(1) (a) Haddadin, M. J.; Conrad, W. E.; Kurth, M. J. The DavisBeirut Reaction: A Novel Entry into 2H-Indazoles and Indazolones. Recent Biological Activity of Indazoles. Mini-Rev. Med. Chem. 2012, 12, 1293−1300. (b) Vidyacharan, S.; Adhikari, C.; Krishna, V. S.; Reshma, R. S.; Sriram, D.; Sharada, D. S. A Robust Synthesis of Functionalized 2H-Indazoles via Solid State Melt Reaction (SSMR) and Their Anti-Tubercular Activity. Bioorg. Med. Chem. Lett. 2017, 27, 1593−1597. (2) (a) Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.; Levin, J.; Sprankle, K. G.; Tedder, M. E.; Almassy, R.; Appelt, K.; Yager, K. M. Structure-Based Design, Synthesis, and Antimicrobial Activity of Indazole-Derived SAH/MTA Nucleosidase Inhibitors. J. Med. Chem. 2003, 46, 5663−5673. (b) Ikeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide, T.; Nagashima, R.; Fujimura, Y.; Shindo, M.; Suzuki, S.; Iwasaki, T. Pharmacological Studies on a New Thymoleptic Antidepressant, 1-[3(Dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32). Arzneim.-Forsch. 1979, 29, 511−520. (c) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A. Efficient Synthesis of 5(Bromomethyl)- and 5-(Aminomethyl)-1-THP-Indazole. J. Org. Chem. 1997, 62, 5627−5629. (3) (a) De Lena, M.; Lorusso, V.; Latorre, A.; Fanizza, G.; Gargano, G.; Caporusso, L.; Guida, M.; Catino, A.; Crucitta, E.; Sambiasi, D.; Mazzei, A. Paclitaxel, Cisplatin and Lonidamine in Advanced Ovarian Cancer. A phase II Study. Eur. J. Cancer 2001, 37, 364−368. (b) Shen, H.; Gou, S.; Shen, J.; Zhu, Y.; Zhang, Y.; Chen, X. Synthesis and Biological Evaluations of Novel Bendazac Lysine Analogues as Potent Anticataract Agents. Bioorg. Med. Chem. Lett. 2010, 20, 2115−2118. (c) Keisner, S.; Shah, S. Pazopanib: The Newest Tyrosine Kinase Inhibitor for the Treatment of Advanced or Metastatic Renal Cell Carcinoma. Drugs 2011, 71, 443−454. (d) Veerareddy, A.; Surendrareddy, G.; Dubey, P. K. Total Syntheses of AF-2785 and Gamendazole-Experimental Male Oral Contraceptives. Synth. Commun. 2013, 43, 2236−2241. (4) (a) De Angelis, M.; Stossi, F.; Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Indazole Estrogens: Highly Selective Ligands for the Estrogen Receptor Beta. J. Med. Chem. 2005, 48, 1132−1144. (b) Cross, J. B.; Zhang, J.; Yang, Q.; Mesleh, M. F.; Romero, J. A. C.; Wang, B.; Bevan, D.; Poutsiaka, K. M.; Epie, F.; Moy, T.; Daniel, A.; Shotwell, J.; Chamberlain, B.; Carter, N.; Andersen, O.; Barker, J.; Ryan, M. D.; Metcalf, C. A.; Silverman, J.; Nguyen, K.; Lippa, B.; Dolle, R. E. Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design. ACS Med. Chem. Lett. 2016, 7, 374−378. (5) (a) Hu, J.; Cheng, Y.; Yang, Y.; Rao, Y. A General and Efficient Approach to 2H-Indazoles and 1H-Pyrazoles Through CopperCatalyzed Intramolecular N−N Bond Formation under Mild Conditions. Chem. Commun. 2011, 47, 10133−10135. (b) Khatun, N.; Gogoi, A.; Basu, P.; Das, P.; Patel, B. K. CuO Nanoparticle Catalysed Synthesis of 2H-Indazoles under Ligand Free Conditions. RSC Adv. 2014, 4, 4080−4084. (c) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Consecutive Condensation, C-N and N-N Bond Formations: A Copper-Catalyzed One-Pot Three-Component Synthesis of 2H12700


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The Journal of Organic Chemistry Rose Bengal Using Visible Light Irradiation. Green Chem. 2011, 13, 2682−2685. (d) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (e) Xiao, W.-J.; Zhou, Q.-Q.; Zou, Y.-Q.; Lu, L.-Q. Visible-LightInduced Organic Photochemical Reactions via Energy Transfer Pathways. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/ anie.201803102. (f) Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J. Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization. J. Am. Chem. Soc. 2010, 132, 1464−1465. (g) Kundu, D.; Ahammed, S.; Ranu, B. C. Visible Light Photocatalyzed Direct Conversion of Aryl-/Heteroarylamines to Selenides at Room Temperature. Org. Lett. 2014, 16, 1814−1817. (h) Fabry, D. C.; Rueping, M. Merging Visible Light Photoredox Catalysis with Metal Catalyzed C-H Activations: On the Role of Oxygen and Superoxide Ions as Oxidants. Acc. Chem. Res. 2016, 49, 1969−1979. (i) Li, W.; Xu, W.; Xie, J.; Yu, S.; Zhu, C. Distal Radical Migration Strategy: an Emerging Synthetic Means. Chem. Soc. Rev. 2018, 47, 654−667. (j) Xie, J.; Jin, H.; Hashmi, A. S. K. The Recent Achievements of Redox-Neutral Radical C-C Cross-Coupling Enabled by Visible-Light. Chem. Soc. Rev. 2017, 46, 5193−5203. (k) Hopkinson, M. N.; Tlahuext-Aca, A.; Glorius, F. Merging Visible Light Photoredox and Gold Catalysis. Acc. Chem. Res. 2016, 49, 2261− 2272. (l) Arora, A.; Weaver, J. D. Visible Light Photocatalysis for the Generation and Use of Reactive Azolyl and Polyfluoroaryl Intermediates. Acc. Chem. Res. 2016, 49, 2273−2283. (m) Ghosh, I.; Marzo, L.; Das, A.; Shaikh, R.; König, B. Visible Light Mediated Photoredox Catalytic Arylation Reactions. Acc. Chem. Res. 2016, 49, 1566−1577. (12) (a) Li, C.-X.; Tu, D.-S.; Yao, R.; Yan, H.; Lu, C.-S. VisibleLight-Induced Cascade Reaction of Isocyanides and N-Arylacrylamides with Diphenylphosphine Oxide via Radical C−P and C−C Bond Formation. Org. Lett. 2016, 18, 4928−4931. (b) Wang, C.-H.; Li, Y.-H.; Yang, S.-D. Autoxidation Photoredox Catalysis for the Synthesis of 2-Phosphinoylindoles. Org. Lett. 2018, 20, 2382−2385. (c) Zhao, Z.; Min, Z.; Dong, W.; Peng, Z.; An, D. Photoredox Catalyst-Mediated Direct Regioselective Phosphonylation of Indoles. Synth. Commun. 2016, 46, 128−133. (d) Peng, P.; Lu, Q.; Peng, L.; Liu, C.; Wang, G.; Lei, A. Dioxygen-Induced Oxidative Activation of a P−H Bond: Radical Oxyphosphorylation of Alkenes and Alkynes toward β-Oxy Phosphonates. Chem. Commun. 2016, 52, 12338− 12341. (13) Luo, K.; Chen, Y.-Z.; Yang, W.-C.; Zhu, J.; Wu, L. CrossCoupling Hydrogen Evolution by Visible Light Photocatalysis toward C(sp2)−P Formation: Metal-Free C−H Functionalization of Thiazole Derivatives with Diarylphosphine Oxides. Org. Lett. 2016, 18, 452− 455. (14) Xie, P.; Fan, J.; Liu, Y.; Wo, X.; Fu, W.; Loh, T.-P. Bronsted Acid/Organic Photoredox Cooperative Catalysis: Easy Access to Triand Tetrasubstituted Alkenylphosphorus Compounds from Alcohols and P−H Species. Org. Lett. 2018, 20, 3341−3344. (15) (a) Bagdi, A. K.; Hajra, A. Design, Synthesis, and Functionalization of Imidazoheterocycles. Chem. Rec. 2016, 16, 1868−1885. (b) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Synthesis of Imidazo[1,2-a]pyridines: A Decade Update. Chem. Commun. 2015, 51, 1555−1575. (c) Mondal, S.; Samanta, S.; Singsardar, M.; Hajra, A. Aminomethylation of Imidazoheterocycles with Morpholine. Org. Lett. 2017, 19, 3751−3754. (d) Jana, S.; Dey, A.; Singsardar, M.; Bagdi, A. K.; Hajra, A. Zn(OTf)2-Catalyzed Synthesis of Imidazole-Substituted Allenes. J. Org. Chem. 2016, 81, 9489−9493. (e) Samanta, S.; Mondal, S.; Santra, S.; Kibriya, G.; Hajra, A. FeCl3-Catalyzed Cross-Dehydrogenative Coupling between Imidazoheterocycles and Oxoaldehydes. J. Org. Chem. 2016, 81, 10088−10093. (16) (a) Kibriya, G.; Samanta, S.; Jana, S.; Mondal, S.; Hajra, A. Visible Light Organic Photoredox-Catalyzed C−H Alkoxylation of Imidazopyridine with Alcohol. J. Org. Chem. 2017, 82, 13722−13727. (b) Mitra, S.; Ghosh, M.; Mishra, S.; Hajra, A. Metal-Free

Thiocyanation of Imidazoheterocycles through Visible Light Photoredox Catalysis. J. Org. Chem. 2015, 80, 8275−8281. (17) Ludvíková, L.; Friš, P.; Heger, D.; Š ebej, P.; Wirz, J.; Klán, P. Photochemistry of Rose Bengal in Water and Acetonitrile: A Comprehensive Kinetic Analysis. Phys. Chem. Chem. Phys. 2016, 18, 16266−16273.

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Visible-Light-Induced Organophotoredox Catalyzed Phosphonylation

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