I am eternally grateful to her all the time for her valuable guidance and encouragement during my research in the laboratory. Ponnusamy (Madurai Kamaraj University-Madurai) who helped me for my higher studies and difficult times and also expressed my gratitude to Dr. Ravikumar (Senior) for their moral support, encouragement and really always guiding me on the right path during my M. Sc and higher studies.
Sonali biswal for their help and support and for tolerating my mood during my Ph. Jayalakshmi (Anni) who helped my initial days in IITH and also my special thanks to Dr.
Introduction
Regioselective C3-H trifluoromethylation of 2H-indazole under transition metal- free photoredox catalysis
In this chapter, we have described introduction about heterocycles, photoredox catalysis, sustainable chemistry and hypervalent compounds. In this chapter, we have described the C3-H nitration of 2H-indazole via radical mechanistic pathway in a regioselective manner. Recently, direct CH functionalization via the radical pathway has been a rapidly growing area of research and has emerged as a promising and sustainable approach to molecular engineering, often complementing traditional methods.
Despite these developments, selective C–H functionalization via the radical route is still in its infancy, and control over the reactivity, chemo/regioselectivity of radical species for selective C–H functionalization requires efforts to find milder and more appropriate methods, which present many opportunities and challenges to address. Among them, C-H functionalization of heteroarenes via the radical route is one of the most attractive and simple strategies.
Radical C-H nitration of Heteroarene
- H Functionalization of Heterocycles
Here, we are pleased to report for the first time, a C-H radical functionalization of 2H-indazole via Fe(NO3) 3.9H2O promoted C3-H nitration. Having benzyl group instead of aryl in the second position of 2H-indazole 2w & x did not show any improvement in yield. In this chapter, we have discussed the synthesis of trifluoromethylated 2H-indazole via transition metal-free photoredox catalysis.
Considering the extreme importance of 2H-indazole derivatives, much effort has been devoted to the synthesis and functionalization of 2H-indazole. Similarly, the amine partner of 2H-indazoles bearing electron-donating groups (-Me, -OMe) gave rise to products in excellent yields (6k-n & 6p), which may be due to the increased electron density at the C3-position of 2H-indazole.
Sustainable approach
Due to the awareness of environmental concerns, some chemists have paid much attention to the development of sustainable strategies around the globe.4. Iodine compounds in higher oxidation states are called hypervalent iodine compounds.5 Among them, organic iodine reagents, especially iodide(III) reagents have emerged as versatile and environmentally friendly reagents in organic synthesis. The structure and reactivity of organic iodine reagents are generally similar to that of transition metal catalysts. In particular, reactions of organic iodine reagents are usually accounted for by ligand exchange, oxidative addition, reductive elimination, and ligand coupling.
Generally, hypervalent iodine reagents are used in various chemical transformations such as catalysis, promoter, oxidant, atom insertion and group transfer reagent. Due to the importance of hypervalent iodine reagents, many researchers are investigating the application of hypervalent iodine reagents (figure 4).6.
Hypervalent iodine
Hypervalent iodine chemistry: preparation, structure and synthetic application of polyvalent iodine compounds; John Wiley & Sons Ltd.: New York, 2014.
Iron-Promoted C3-H Nitration of 2H-Indazole
Direct access to 3-Nitro-2H-Indazoles
- BACKGROUND
- C-H functionalization methods for 2H-indazoles
- Radical C-H Nitration Methods
- Chelation assisted radical C-H Nitration Methods
- This method proceeds through a single electron transfer mechanism and uses inexpensive tert-butyl nitrite (TBN) as nitro source (Scheme 15). 38
- Control Experiments and Mechanistic studies
- Plausible Mechanism
However, the first report of the synthesis of 2H-indazole was in 1880.19 Indeed, publications in the early years of the 20th century and many recent publications have described improvements in methods for the synthesis of indazole. Although few promising strategies have been established for the selective synthesis of 2H-indazole, most synthetic reports favored the formation of a thermodynamically stable compound, i.e. Aiming at this, we envisioned developing a new and innovative method for the synthesis of 2H-indazoles and their further functionalization leading to annulated indazoles.
Based on control experiments, literature reports41,42 and quantum chemical calculations, we proposed a plausible reaction mechanism for the synthesis of 3-nitro-2-phenyl-2H-indazole as depicted in Scheme 20. The synthetic utility of nitroindazole was demonstrated by synthesis of bio-relevant benzimidazoindazoles.
Single crystal X-ray data
Mass data for Intermediate
Quantum Chemical Calculations
General procedure (GP-II) for the synthesis of 3-nitro-2-phenyl-2H-indazole
General procedure (GP-II) for the synthesis of Indazolo[2,3-a]quinazoline
Characterization Data of the Products
On the deceptive nature of o-formylazobenzenes: Exploiting the nucleophilicity of the Azo group for cyclization to indazole derivatives. Synthesis of 3-aryl-1-[(4-phenyl-1-piperazinyl)butyl]indazole derivatives and their affinity for 5-HT1A serotonin and dopamine D1 receptors. Process development of C-N cross-coupling and enantioselective biocatalytic reactions for the asymmetric synthesis of Niraparib.
Intramolecular trapping of a phosphazide by an imine: Formation of 2,3-diamino-2H-indazole derivatives from o-azidobenzaldimines and tertiary phosphines. A robust protocol for Pd(II)-catalyzed C-3 arylation of (1H)-indazoles and pyrazoles: total synthesis of nigellidine hydrobromide. A robust protocol for Pd(II)-catalyzed C-3 arylation of (1H)-indazoles and pyrazoles: total synthesis of nigellidine hydrobromide.
Palladium(II)-catalyzed, heteroatom-directed, regioselective C–H nitration of aniline using pyrimidine as a removable guiding group. Vinayak B.; Chandrasekharam, M.; Copper-Catalyzed Direct Nitration of Aryl C−H Bonds by Simultaneous Azidation-Oxidation with TMS Azide and TBHP under Aerobic Conditions. Copper-catalyzed rapid CH-nitration of 8-aminoquinolines using sodium nitrite as nitro source under mild conditions.
Liu, Y.; Palladium-catalyzed aromatic C-H bond nitration using removable directing groups: regiospecific synthesis of substituted o-nitrophenols from related phenols. A novel route for the synthesis of highly substituted 4-aminoquinoline drug-like molecules via aza hetero-Diels-Alder reaction Org. A facile synthesis of 2H-indazoles under neat conditions and further transformation into aza-γ-carboline alkaloid analogues in a tandem one-pot manner RSC Adv.
Regioselective C3-H trifluoromethylation of 2H-indazole under transition-metal-free
BACKGROUND
- Various Trifluoromethylating Reagents
- Trifluoromethylation using Langlois’ reagent
- Photoredox catalysis
- C3-H functionalization of 2H-indazole
Here they used CF3SO2Cl as a trifluoromethylation source, simultaneously losing sulfur dioxide. Jin-Quan Yu and co-workers developed a copper(II)-promoted synthesis of trifluoromethyl-substituted arenes 8 via direct ortho C-H trifluoromethylation of arenes and heteroarenes 7. In this method, they used Togni reagent 10 as a CF3 radical source and is commercially available and easy to handle (Diagram 5).8.
Sangit Kumar and co-workers reported a copper-catalyzed trifluoromethylation of alkenes 12 for the construction of trifluoromethylated benzoxazines 14 with a simple base and ligand-free mode. In this method, they have used t-butyl hydroperoxide as an oxidant and catalytic amount of copper controlling the monotrifluoromethylation, whereas mono- and bis-trifluoromethylated product were observed almost the same as in the absence of copper(II) (Scheme 8).11. Despite these developments, the approach to radical trifluoromethylation of arenes and heteroarenes has been achieved in recent years.
Langlois and co-workers developed the trifluoromethylation of alkene bromide 22 for the synthesis of the corresponding trifluoromethyl-substituted alkene 23 using sodium trifluoromethanesulfinate with t-butyl hydroperoxide as an oxidant (Scheme 10).13. This method provides an oxidant and metal-free reaction condition for the synthesis of acylated C3-aryl/benzofurans, CF3-containing benzothiophenes and indoles (Scheme 13).16. Here, they have used the cheap and easily stored Langlois reagent 34 (sodium trifluoromethanesulfinate) as the trifluoromethyl source and iodobenzene diacetate [PhI(OAc)2] as the oxidant (Scheme 15).18.
Nitrogen-containing heterocyclic compounds have gained great importance in natural products and they exhibit a wide range of biological activities.21 Among them, indazoles are widely known for their bioactivities22 such as antitumor,23 antimicrobial,24 anti-inflammatory,25 anti-HIV , 26 anti-platelet27 and anti-contraceptive.28 Considering the extraordinary importance of 2H-indazole derivatives, many efforts have been devoted to the synthesis and functionalization of 2H-indazole.29. Recently, Hajra and co-workers described a new approach for the direct metal-free C3-trifluoromethylation of 2H-indazole 36 with access to peroxide-mediated trifluoromethyl-functionalized 2H-indazole 44. Transition metal catalyst, peroxides and high temperatures are somewhat disadvantages for the C3-H functionalization of 2H-indazoles.
Results and Discussion
In the initial experiments, we chose 2-phenyl-2H-indazole as the model substrate, Langlois's reagent as CF3 radical source and phenyliodium(III) diacetate (PIDA) as an oxidant with 2 mol% rose bengal as a photocatalyst in MeCN and irradiated with 60 W Compact Fluorescent Bulb (CFL) at room temperature for 24 h. To improve the reaction efficiency in terms of yield, we tested the different photocatalysts. Among others, methylene blue (Table 1, entry 12) was found to be effective photocatalyst and provided the desired product 44a in 75% yield.
Among the solvents examined (Table 1, entries 15-23), dichloromethane was found to be the most efficient solvent for this strategy. To improve the yield, various sources of CF3 were screened without much success (Table 1, entries 24–26). A halogen substituent at the para position of the amine partner of the 2H-indazoles (44e-h) gave 45% to 68% yield.
However, the electron donating groups (-Me, -OMe) at the ortho position (44i, 44j) gave moderate yields; this is due to the steric hindrance of the ortho substitution. We observed poor yield while substituting the electron withdrawing group on 2H-indazole (44o), because the electron density at the C3 position on 2H-indazole could be reduced. Due to the presence of the 2H-indazole skeleton in several biologically relevant compounds, we also evaluated the scalability of our protocol.
Thus, when we performed the reaction at 1g scale, it produced the C3 trifluoromethylation of 2H-indazole 44a by 69%.
Gram-scale synthesis of 2-phenyl-3-(trifluoromethyl)-2H-indazole (44a)
Control Experiments
Then, the photocatalyst oxidizes the radical anion (PC∙−) to PC by reducing acetate radical to acetate anion.
Plausible reaction mechanism
- Conclusions
- Experimental Section General Considerations
Furthermore, the developed protocol for regioselective trifluoromethylation of 2H-indazole would be of great importance in pharmaceutical chemistry and materials sciences. 1H NMR spectra were recorded on 400 MHz spectrometers at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported by default with respect to internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometers at room temperature in CDCl3; chemical shifts (δ ppm) are reported relative to CHCl3 [δC = 77.00 ppm (central line of the triplet)].
Reactions were monitored by TLC on silica gel using a combination of petroleum ether and ethyl acetate as eluents. Acmes silica gel (60-120 mesh) was used for column chromatography (approximately 20 g per gram of raw material). After completion of the starting material, the mixture was cooled to room temperature and was purified on silica gel column chromatography (hexane/ethyl acetate 90:10) to give the respective products 41a-s.
General procedure (GP-II) for the synthesis of 2-phenyl-3-(trifluoromethyl)-2H-indazole In an oven-dried reaction vessel equipped with a magnetic stir bar. Purification of the residue on silica gel column chromatography using petroleum ether/ethyl acetate as (petroleum ether/ethyl acetate 97:3 to 95:5) eluent gave the product trifluoromethylated indazoles 44a-s.
