Developing highly active Cu(II)-triazolyl-pyridine complexes for C–H functionalization of 9H-fluorene and indole via a borrowing hydrogen strategy

Abstract

Herein, we present the distinct capability of air-stable Cu(II)-complexes with N-bound triazolyl-pyridine ligands for the C–H functionalization of 9H-fluorene and indole with alcohols, which can be used as more reliable and greener alkylating agents with the formation of environmentally benign water as the sole byproduct. Methodologies have been developed, utilizing a broad spectrum of alcohols, including primary benzyl alcohols, aliphatic alcohols, and, impressively, even secondary alcohols. Importantly, a few drug molecules, like benflumetol (an antimalarial drug), turbomycin B, and an orphan nuclear receptor, were also synthesized using the developed borrowing hydrogen strategy. The Cu(II)-complexes were characterized by EPR spectroscopy, IR spectroscopy, and UV-visible spectroscopy. Hirshfeld analysis and spin density calculations were also performed to shed light on the electrophilic propensity of the Cu-centre. The molecular structure of one of the Cu(II)-complexes was also determined via the single-crystal X-ray diffraction method. A number of post-functionalization reactions successfully demonstrated the practicality of the method. Additionally, this easily scalable procedure, which follows an ionic pathway by utilizing a hydrogen borrowing strategy, confirmed through various control experiments, operates smoothly under mild conditions with minimal catalyst loading.

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Transition metal catalysis is a key component in facilitating the development of novel, ecologically benign, and sustainable processes for the synthesis of a large number of vital organic molecules, medications, and fine chemicals.^1,2 Noble metals, including Ru, Rh, Pd, and Ir, have been widely used in catalysis during the past several decades because of their high catalytic activity and selectivity.³ However, their limited supply, high price, and growing demand make it necessary to look for more plentiful, less hazardous, and more reasonably priced substitutes.⁴ First-row transition metals, like Fe, Cu, Mn, Co, Ni, or Zn,^5–13 have shown promising results in recent research. These metals provide similar catalytic effectiveness at a fraction of the price. Academic and industrial researchers are drawn to them because of their greater accessibility and reduced toxicity compared to noble metals.¹⁴ The development of catalysis using first-row transition metals demonstrates their versatility and vital significance in the advancement of chemical science.¹⁵ Over the past several years, there has been a considerable interest in developing earth-abundant-metal-based complexes as catalysts for various C–X (X = C, N, O) bond-forming processes using acceptorless dehydrogenative coupling (ADC) or borrowing hydrogen (BH) methodologies, which were once dominated by precious metal catalysis.^16,17 In organic synthesis, it is important to develop catalytic procedures for C–C bond formation,^18–20 and one significant strategy is the direct functionalization of C–H bonds. The C–H alkylation or functionalization of a variety of substrates, including nitriles,⁹ carbonyls,⁵ and heterocycles,⁸ has been studied by several groups.¹¹ In this regard, the C–H alkylation of indole and 9H-fluorene provides a viable method for producing C-alkylated products, which are used in various components with potential applications in solar cells, optoelectronics, semiconductors, pharmaceuticals, therapeutics, natural products etc.^21–26 (Scheme 1). In 2020, Srimani et al. synthesized bis(indolyl)methanes (BIMs) using an Ru(II)-pincer complex.²⁷ Vu's group reported the C–H functionalization of indoles with alcohols using a magnetically regenerated CuFe₂O₄ catalyst.²⁸ Langer and coworkers reported a copper-catalyzed alkylation of indoles with alcohols for the synthesis of BIMs.²⁹ In 2021, Yadav and group presented the C–H functionalization of indole using a phosphine-free manganese(II)-catalyst.³⁰ Sofia Santos et al. explored a Thermomyces lanuginosus lipase (TLL)-PdNPs nanohybrid as a suitable catalyst for the C–H alkylation of indole.³¹ Paul et al. presented ruthenium-catalyzed selective synthesis of C3-alkylated indoles and BIMs.³²

Scheme 1 Examples of indole and 9H-fluorene based pharmaceutically active compounds.

In 2020, an Ru-catalyzed procedure for the C–H alkylation of fluorene was first described by the Gnanaprakasam group.³³ Srimani and coworkers used a cationic SNS-Ni(II) binuclear complex and an NNS-Mn(I) pincer complex for C-alkylated 9H-fluorene in two successive studies.^34,35 In 2022, Adhikari and group presented the C–H functionalization of 9H-fluorene.³⁶ Dey et al. reported nickel nanoparticles as a catalyst in the direct sp³ C–H alkylation of 9H-fluorene using alcohols as alkylating agents.³⁷ Samanta and team reported the C–H functionalization of 9H-fluorene, employing a non-innocent azo-aromatic cobalt(II) catalyst.³⁸ Recently, the Paul and Rit groups simultaneously discovered Zn-mediated transformation.^13,39 Very recently, Bagh and coworkers synthesized C-alkylated fluorene using NNS-Cu(I) and Fe(II)-phenanthroline catalysts.⁴⁰ To the best of our knowledge, there is only one piece of literature at present in which a copper catalyst is used in the C–H functionalization of 9H-fluorene.

Recent reports on the synthesis of transition metal complexes of N-bound triazolyl-pyridine ligands and their catalytic properties have shown an altered electronic effect on the metal ion in comparison to C-bound triazolyl-pyridine ligands.⁴¹ In our previous work, we utilized an N-bound triazolyl-pyridine-based cobalt(II) complex for the N-alkylation of amines with primary and sterically hindered secondary alcohols.¹² In the current study, we extend this approach by utilizing N-bound triazolyl-pyridine-based copper(II) complexes to achieve the C–H functionalization of 9H-fluorene and indole via the BH strategy.

Copper has gained significant interest in research and industrial applications because of its many benefits, including affordability and high reactivity, as well as minimal toxicity.^42,43 To the best of our knowledge, there have been only a few reports on the use of copper in alkylation reactions, making it the least employed base metal catalyst. To the best of our knowledge, no report is available where a Cu(II)-catalyst is used in the C–H functionalization of fluorene, except the one we previously mentioned [using Cu(I)].⁴⁰ Therefore, herein, we report the C–H functionalization of 9H-fluorene using Cu(II)-triazolyl-pyridine complexes with primary and secondary alcohols for the synthesis of C-alkylated products. Subsequently, utilizing the same Cu(II)-complexes, we also explored the C–H functionalization of indole with alcohols.

Recently, acceptorless dehydrogenation (AD) and the borrowing hydrogen (BH) technique have garnered significant attention in catalysis because they enable the use of renewable alcohols produced from lignocellulosic biomass.⁴⁴ Additionally, these procedures produce either water or H₂ as the only byproduct, making them greener and more sustainable in their entirety.

Following a procedure in the literature, we first successfully synthesized ligands 2-((4-((p-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl))pyridine (L1) and 2-(((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl) methyl) thio) benzo[d]thiazole (L2) with promising coordination characteristics, as established from their silver and cobalt metal complexes in our earlier study.^12,45 The silver complex was successfully employed in an A³ coupling reaction involving alkynes, aldehydes, and amines, demonstrating its catalytic efficiency.⁴⁴ Likewise, the cobalt complex facilitates the N-alkylation of amines using alcohols.¹² In this work, we expand the metal coordination chemistry of both ligands by presenting the synthesis of copper complexes.¹² The facile interaction of the ligands tmtp (L₁) and ptmtbt (L₂) with copper salt at room temperature resulted in the generation of Cu(II)-complexes (complex 1 and complex 2) (Scheme 2). The synthesized complexes were characterized using EPR spectroscopy, infrared spectroscopy, UV-visible spectroscopy, Hirshfeld analysis, and spin density calculations.

Scheme 2 Synthesis of complex 1 and complex 2.

Upon complexation of L1 and L2 with a Cu(II) ion, the υ_N=N stretching frequency changes from 3026.12 to 3085.07 cm⁻¹ and from 3057.01 to 3069.00 cm⁻¹, respectively, in the FT-IR spectra, signifying that one of the triazole nitrogen atoms has coordinated with the Cu(II) ion (Fig. S1 and S2, in SI). At the same time, the υ_C=N (pyridine) absorption frequency shifts from 1594.77 to 1615.67 and from 1597.33 to 1609.33 cm⁻¹, indicating additional coordination of the ligands to the Cu(II) ion via their pyridinie nitrogen. Furthermore, the appearance of a new band at 1300.74 cm⁻¹ implies that the isolated metal complex (complex 1) contains a coordinated nitrate (υ_N=O) ion. Electronic spectra (UV-visible) of the free ligands (L₁ and L₂) and their Cu(II) complexes (complex 1 and complex 2) were recorded at 10⁻⁵ M in acetonitrile and DMF solution, respectively, at room temperature. Ligands L₁ and L₂ exhibited two absorption bands at 225 nm and 273 nm (for L₁, ε = 30 800 mol L⁻¹ cm⁻¹) and at 276 nm and 299 nm (for L₂, ε = 51 200 mol L⁻¹ cm⁻¹) corresponding to the π–π* and n–π* transitions associated with the aromatic ring. On moving from the ligands to the Cu(II) complexes, the absorption peak positions [complex 1: 222 nm and 274 nm (ε = 88 400 mol L⁻¹ cm⁻¹) and complex 2: 277 nm and 301 nm (ε = 93 500 mol L⁻¹ cm⁻¹)] change only slightly; however, the peak intensities increase significantly (Fig. S3 and S4, in SI). The complexes were further characterized via mass spectrometry. For complex 1, the calculated mass value for [C₃₀H₂₈CuN₈O₂] was 595.1631 and was found to be 595.1743. For complex 2, the calculated mass for [C₃₀H₂₂CuN₁₀S₄] was 713.0208 and was observed at 713.0317 (Fig. S5 anf S6, in SI).

Green, needle-shaped single crystals suitable for X-ray diffraction were obtained by slow diffusion of acetonitrile into a solution of complex 1 in methanol. Single-crystal X-ray diffraction was used to determine the molecular structure. Complex 1 crystallizes in the monoclinic crystal system with P2₁/c space group. The molecular structure of complex 1 is depicted in Fig. 1, which confirms a 1 : 2 metal : ligand ratio in the synthesized complex. Both triazolyl-pyridine ligands coordinate to the central Cu(II) atom in a chelated fashion, where one N-atom of the pyridine ring and two N-atoms of the triazole ring are coordinated to the Cu-centre from equatorial positions. At the centre, both ligands form two separate five-membered CuCN₃ rings.

Fig. 1 Single-crystal molecular structure of complex 1 drawn at a 30% probability level. All the hydrogen atoms are omitted for clarity. Selected bond lengths [Å] and angles [°]: Cu1–N1 2.0215(13), Cu1–N3 2.0291(13), Cu1–O4 2.3002(13), N2–N3 1.3440(18), N3–N4 1.3040(18), N1–C1 1.341(2), N2–C1 1.4103(19), N1–Cu1–N3 79.61(5), N1–Cu1–O4 91.18(5), Cu1–N3–N4 139.28(11).

The EPR spectrum of complex 1 in DMF at low temperature (77 K) is presented in Fig. 3, with the experimental spectrum shown in black and the simulated spectrum in red. The spectrum exhibits distinct anisotropic features with slight rhombic distortion (see Fig. 4, left) in the g-factors, along with a well-defined hyperfine splitting pattern around the parallel component of the g tensor (g_∥ = 2.39758). This value aligns closely with the g_∥ value of 2.263 reported by Šimunková et al.⁴⁶ Similarly, the parallel component of hyperfine splitting (A_∥ = 393.577 MHz = 14.0438 mT) is comparable to the 17.94 mT reported in their study, indicating axial symmetry around the paramagnetic Cu(II) center in the complex. However, the resolution of the EPR spectrum does not allow for a definitive identification of the donor atoms coordinating to the Cu(II) ion. While nitrogen donor atoms could potentially contribute to additional hyperfine splitting due to their magnetic activity, no such interaction was observed in the recorded spectra, which may be due to line broadening near g_isor = 2.18877 of 1. The EPR spectrum of 2 is significantly different from that of 1, due to the presence of spin-active nuclei of two Cl-ions at the axial positions.

Unlike complex 1, the EPR spectrum of complex 2 exhibits broader, less resolved features and lacks clear hyperfine splitting patterns. This suggests significant spectral broadening or overlap of signals for 2. Although a similar set of parameters used to model complex 2 includes hyperfine couplings with ^63,65Cu, ^35,37Cl, and ¹⁴N nuclei, these features are not distinctly visible in the experimental spectrum. The g-values obtained from simulation, g_∥ = 2.38831 and g_⊥ = 2.06604, yield an isotropic g-value of g_iso = 2.1788, indicative of a predominantly axial geometry with a d_x²−y² ground state similar to that of complex 1. However, due to the limited resolution of the spectral features, the hyperfine coupling constants derived from simulation, particularly for the chloride and nitrogen donors, should be interpreted cautiously, as the well-resolved spectrum of complex 1 initially guided them. The lack of a discernible hyperfine structure in complex 2 highlights the limitations in directly probing donor atom contributions under these experimental conditions. The hyperfine coupling constant of ^35,37Cl was found to be 371.8 MHz. The computed Mulliken spin densities are nearly 14.6% on each Cl-atom of 2, rationalizing the high value of the hyperfine coupling constants of ^35,37Cl. In contrast, negligible Mulliken spin densities were collated in 1 (Fig. 2). A very similar EPR spectrum of a Cu-complex has recently been reported.⁴⁷ Hyperfine splitting due to the ¹⁴N_NO3 nucleus was not observed for 1, which may also be due to the replacement of weakly coordinating NO₃ by DMF molecules.

Fig. 2 [a] (A) The spin density plot and (B) % of α-spin density (blue color) of complex 1 calculated at B3LYP-D3(BJ)/def2-tzvp level of theory. [b] (A) The spin density plot and (B) % of α-spin density of complex 2 calculated at B3LYP-D3(BJ)/def2-tzvp level of theory.

Fig. 3 X-band EPR spectra (black) of complexes (a) complex 1 and (b) complex 2 at 77 K in DMF. Red and black lines represent the simulated and the experimental spectra using the EasySpin program.⁴⁷ For complex 1: [g_∥ (Cu²⁺ unpaired e⁻) = 2.39758, g_⊥ (Cu²⁺ unpaired e⁻) = 2.07651, LWPP (Gaussian broadening) = 3.43954 mT, LWPP (Lorentzian broadening) = 1.24184 mT, A_∥ (^63,65Cu) = 393.577 MHz, X-band experimental frequency = 9.095979 GHz]. For complex 2: [g_∥ (Cu²⁺ unpaired e⁻) = 2.38831, g⊥ (Cu²⁺ unpaired e⁻) = 2.06604, LWPP (Gaussian broadening) = 3.73405 mT, LWPP (Lorentzian broadening) = 1.33735 mT, A_∥ (^63,65Cu) = 97.0412 MHz, A_⊥ (^63,65Cu) = 111.914 MHz, A_∥ (^35,37Cl) = 371.871 MHz, A_⊥ (¹⁴N) = 187.32 MHz, X-band experimental frequency = 9.096374 GHz].

Fig. 4 Fingerprint plots (left) from the Hirshfeld surface generated for the Cu ion of complex 1. Hirshfeld surface (excluding nitrate anions) mapped for complex 1 with electrostatic potential (HF/STO-3G); −0.0667 to +0.2114 au, after removing two nitrate ions (right).

With the well-characterized Cu(II)-complexes in hand, we wanted to test their catalytic activity in various C–H functionalization reactions. C–H functionalization products of 9H-fluorene and indoles are biologically important and thus envisioned to do the same using our newly synthesized Cu(II) complexes. Initially, to start with the C–H functionalization of 9H-fluorene, 9H-fluorene 1a (1 mmol), benzyl alcohol 2a (2 mmol) were first treated for 18 h at 140 °C without any base, in the presence of complex 1 (3 mol%) in toluene; but no formation of the desired product was observed (Table 1, entry 1). When the same reaction was carried out in the presence of 0.1 mmol of KO^tBu, the desired product 3aa was produced in 88% yield (Table 1, entry 2). This observation indicates the important role the base plays in the dehydrogenation of alcohol as well as in the generation of a nucleophilic core at the 9-position of the fluorine ring. Following the first outcome, further reaction parameters were evaluated, including catalyst loading, solvent, and base. To optimize the catalyst loading, we performed the reaction using 3 mol%, 2 mol%, and 1 mol% of catalyst. The corresponding product yields were 88%, 85%, and 83%, respectively, indicating only a marginal decrease in efficiency with reduced catalyst concentration (Table 1, entries 2–4). These findings suggested that the ideal loading was 1 mol%, which provided a high yield with minimal use of the catalyst. Subsequently, an analogous study was carried out in the absence of a catalyst, which resulted in no formation of product 3a (Table 1, entry 7). This suggests that both the base and catalysts play an active role in the developed methodology. Under comparable reaction conditions, bases including K₂CO₃, Cs₂CO₃, and K₃PO₄, were unable to produce 9-benzyl-9H-fluorene 3a even in trace quantity (Table 1, entries 9–11). In contrast, KOH produced the desired product 3a but in a moderate yield (Table 1, entry 8). Relatively non-polar toluene outperformed other solvents, such as xylene, acetonitrile, 1,4-dioxane, or THF, during solvent screening. It is worth mentioning that both complex 1 and complex 2 show very similar catalytic activity for the C–H functionalization of 9H-fluorene under the standard conditions to generate benzylated 9H-fluorene. The reaction catalyzed by complex 1 was clean, producing only the desired product without any detectable by-products or impurities. In contrast, the reaction using complex 2 showed additional product spots, suggesting the formation of unwanted by-products. As the reaction using complex 1 is relatively clean, we report the substrate scope and corresponding yield obtained by applying this methodology using complex 1. Therefore, the most suitable reaction conditions are 9H-fluorene 1a (1 mmol), benzyl alcohol 2a (2 mmol), KO^tBu (0.1 mmol), and catalyst (1 mol%) at 140 °C for 18 h.

Table 1 Optimization of reaction conditions for C–H functionalization of 9H-fluorenes^a,b

Entry	Catalyst (mol%)	Solvent	Base	Yield
a Reaction conditions: alcohol 2 (2 mmol), 9H-fluorene 1 (1 mmol), catalyst (x mol%), base (0.1 mmol), 2 mL of solvent, at 140 °C for 18 h. b Yield of pure isolated product. n.r. = no reaction.
1.	Complex 1 (3 mol%)	Toluene	—	n.r.
2.	Complex 1 (3 mol%)	Toluene	KO^tBu	88%
3.	Complex 1 (2 mol%)	Toluene	KO^tBu	85%
4.	Complex 1 (1 mol%)	Toluene	KO^tBu	83%
5.	Complex 2 (1mol%)	Toluene	KO^tBu	80%
6.	Cu(NO3)2·3H2O (1 mol%)	Toluene	KO^tBu	38%
7.	—	Toluene	KO^tBu	Trace
8.	Complex 1 (1 mol%)	Toluene	KOH	65%
9.	Complex 1 (1 mol%)	Toluene	K2CO3	n.r.
10.	Complex 1 (1 mol%)	Toluene	Cs2CO3	n.r.
11.	Complex 1 (1 mol%)	Toluene	K3PO4	n.r.
12.	Complex 1 (1 mol%)	Xylene	KO^tBu	62%
13.	Complex 1 (1 mol%)	ACN	KO^tBu	Trace
14.	Complex 1 (1 mol%)	1,4-Dioxane	KO^tBu	68%
15.	Complex 1 (1 mol%)	THF	KO^tBu	30%

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We then assessed the applicability of the reaction process utilizing a range of primary and secondary alcohols (Scheme 3). Benzyl alcohols with different electron-donating substituents (2b–2d) at the ortho and para positions of the aromatic ring well tolerated the reaction, producing the desired products in excellent to good yields [Me (3b, 88%); OMe (3c, 79%); 2,4-OMe (3d, 70%)]. The reaction with halo-substituted benzyl alcohols (2e–2g) proceeded smoothly to generate the desired product in excellent to good yield [–F (3e, 87%); –Cl (3g, 85%); –Br (3f, 79%)]. A similar reaction with 2-chloro benzyl alcohol (2h) also produced the desired product in good yield following our developed methodology [2-Cl (3h, 75%)]. Indeed, an electron-withdrawing group on benzyl alcohol (–NO₂, –CN) was unable to yield the desired products under ideal reaction conditions. This suggests that the presence of –M or –I electronic effects on alcohol substituents hinders the process, possibly due to the lack of formation of intermediate aldehyde products. Reaction with inactivated primary and secondary aliphatic alcohols, like butanol (2k), cyclopentanol (2l), or cyclohexane methanol (2m), proceeded smoothly, and the expected products were formed in excellent yields [3k (90%), 3l (92%), 3m (89%)]. The reaction of di-bromo-substituted fluorene (1b) with benzyl alcohol (2a) also gave the desired product (3j, 90%) in excellent yield. The challenging secondary alcohol fluorenol (2i) gave the desired product (3i, 80%) in relatively good yield, but in the case of diphenylmethanol and 1-phenylethanol, we obtained the intermediate alkenylated products [3o (68%) and 3n (70%)] in slightly lower yields. Additionally, we obtained the alkenylated products (3p, 73%) with polyaromatic alcohol (2p), which may be due to the additional steric hindrance it provides. Moreover, 4-ethyl benzyl alcohol (3q, 80%) and substituted fluorene (3r, 79%) generate only the alkenylated product. Therefore, the products obtained via this methodology may vary between simple benzylated and alkenylated products, depending on the steric and electronic properties of both the benzyl alcohols and the substituents on fluorene.

Scheme 3 Substrate scope for the C–H functionalization of 9H-fluorene. Reaction conditions: alcohol 2 (2 mmol), 9H-fluorene 1 (1 mmol), catalyst (1 mol%), base (0.1 mmol), 2 mL of toluene, at 140 °C for 18 h. Yield of pure isolated product. n.d. = not detected.

Importantly, following this developed methodology, a prescribed antimalarial drug, benflumetol (also known as lumefantrine), was also synthesized in good yield (3s, 65%) to further establish the viability of this Cu(II)-catalyzed benzylation process (Scheme 4). Further, a couple of experiments were performed to check the possibility of post-functionalization of the synthesized molecules. First, to undertake hydroxy functionalization of the synthesized product, 9-(4-chlorobenzyl)-9H-fluorene was reacted with KO^tBu and DMSO, a well-known hydroxyl functionalization reagent, in air (Scheme 4). The target product 3g′ was obtained in good yield (95%). Then, we synthesized unsymmetrical 9,9′-dialkylated fluorene (3a′, 80%), a useful material for an optical sensor. The product 3a′ was synthesized by reacting 9-benzyl-9H-fluorene with 4-chloro nitrobenzene (Scheme 4).

Scheme 4 Synthesis of benflumetol and post-functionalization of monoalkylated fluorene derivatives.

The successful development of a versatile methodology for the C–H functionalization of 9H-fluorene motivated us to evaluate the efficacy of this catalyst in the C–H functionalization of indoles. As a preliminary step, we examined the reaction using indole 4 (1 mmol) and benzyl alcohol 2a (1 mmol) as prototype substances in the presence of complex 1 (1 mol%), and KO^tBu (0.1 mmol) in toluene, and the reaction was carried out in a closed apparatus at 110 °C for 12 h (Table 2). This reaction produced bis(3-indolyl) phenyl methane (BIM) selectively in excellent yield [5a (85%)] (Table 2, entry 1). Other than BIM, the above reaction also showed the possibilities of C3-alkylated and N-alkylated products. Therefore, the regio-selective formation of BIM in excellent yield is an excellent opportunity for study. To understand the roles of different reaction parameters, the catalyst and base, several optimization reactions were carried out. First, the above-mentioned indole functionalization reaction was carried out in the absence of a base, which did not produce any of the target product (Table 2, entry 4). Moreover, KOH produced BIM in good yield, though slightly lower than that obtained with KO^tBu under identical reaction conditions (Table 2, entry 6). Toluene was proven to be the most effective solvent among all the tested solvents (H₂O, m-xylene, 1,4-dioxane, and THF). Therefore, the ideal conditions are as follows: 1 mmol of alcohol, 1 mmol of indole, 0.5 mol% of Cu(II)-catalyst, and 0.1 mmol of KO^tBu at 110 °C for 12 hand toluene solvent.

Table 2 Optimization of reaction conditions for C–H functionalization of indoles^a,b

Entry	Catalyst (mol%)	Solvent	Base	Yield
a Reaction conditions: alcohol (1 mmol), indole (1 mmol), catalyst (0.5 mol%), base (0.1 mmol), 2 mL of toluene, at 110 °C for 12 h. b Absence of catalyst. c Yield of pure isolated product. n.r. = no reaction.
1.	Complex 1 (1 mol%)	Toluene	KO^tBu	85%
2.	Complex 1 (0.5 mol%)	Toluene	KO^tBu	80%
3.	Complex 2 (0.5 mol%)	Toluene	KO^tBu	75%
4.	Complex 1 (0.5 mol%)	Toluene	—	n.r.
5.	—	Toluene	KO^tBu	Trace
6.	Complex 1 (0.5 mol%)	Toluene	KOH	72%
7.	Complex 1 (0.5 mol%)	Toluene	K2CO3	Trace
8.	Complex 1 (0.5 mol%)	Toluene	Cs2CO3	Trace
9.	Complex 1 (0.5 mol%)	Toluene	NEt3	30%
10.	Complex 1 (0.5 mol%)	Xylene	KO^tBu	62%
11.	Complex 1 (0.5 mol%)	H2O	KO^tBu	n.r.
12.	Complex 1 (0.5 mol%)	1,4 dioxane	KO^tBu	68%
13.	Complex 1 (0.5 mol%)	THF	KO^tBu	n.r.

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To find a variety of BIMs, we next examined the range of alcohols with indoles under ideal reaction conditions (Scheme 5). First, unsubstituted indole 4 was reacted with benzyl alcohol 2, and the desired BIM, known as turbomycin B, a natural compound with antimicrobial properties, was produced in good yield [5a, (80%)]. Several other BIM derivatives [5b (85%), 5c (70%) and 5d (80%)] were also synthesized in good to excellent yield when reacted with various derivatives of benzyl alcohol with an electron-donating group on the phenyl ring [–Me 5b (70%), –OMe 5c (85%) and –Et 5d (80%)]. Product 5c is an orphan nuclear receptor with no known binding ligand. Interestingly, the presence of electron-withdrawing substituents on the phenyl ring of benzyl alcohols was well tolerated, and the desired BIMs were obtained in good to excellent yields [–Br 5e (80%), –Cl 5f (83%), –F 5g (75%) and −2, Br 5h (75%)]. 4-Nitrobenzyl alcohol unexpectedly did not provide the intended result. Furan-2-ylmethanol, a heteroaromatic alcohol, produced the desired product 5i with 82% yield under ideal reaction conditions when reacted with indole. A primary cyclic aliphatic alcohol, cyclohexyl methanol, also reacted to produce the desired product 5j in 79% yield, which was gratifying as this reagent is considered to be difficult to oxidize. Remarkably, (6-methoxynaphthalen-2-yl)methanol, a polyaromatic molecule, also interacted well with indole to produce 5k in 79% yield. Diphenylmethanol interacted with indole under standard reaction conditions and generated 5l in 60% yield. Interestingly, cyclohexanol, a secondary cyclic aliphatic alcohol, did not produce the desired BIM but selectively generated C3-alkylated product 5m in 55% yield. This may be because of the relatively higher steric hindrance by the cyclohexyl ring to closely accommodate the indole ring.

Scheme 5 Substrate scope for C–H functionalization of indole. Reaction conditions: alcohol (1 mmol), indole (1 mmol), complex 1 and complex 2 (0.5 mol%), base (0.1 mmol), 2 mL of toluene, at 110 °C for 12 h. Yield of pure isolated product. n.d. = not detected.

To gain more valuable insight into the C–H functionalization of 9H-fluorene and indole with alcohols catalyzed by the Cu(II)-complexes, several control experiments were conducted under optimal reaction conditions (Scheme 6). 4-Methylbenzaldehyde (2b′) was generated in 90% isolated yield when 4-methylbenzyl alcohol (2b) was treated under the ideal reaction conditions (Scheme 6Aa). This result implies that, under the optimized reaction conditions, the tested alcohols may be smoothly dehydrogenated to the corresponding aldehyde. Conversely, in the absence of either the base or the Cu(II)-complex, the reaction produces only trace quantities of benzaldehyde from benzyl alcohol. Furthermore, it was discovered that the condensation of indole 4 with 4-methylbenzaldehyde 2b′ under standard reaction conditions occurred quickly, and a comparable rate was noted when the reaction was carried out using only base (Scheme 6Ab). This suggests that the Cu(II)-complex is essential for activating the alcohol to produce the appropriate aldehydes or ketones, while KO^tBu catalyzes the condensation of two equivalents of indoles with one equivalent of aldehydes or ketones to produce BIM derivatives. Similarly, the condensation reaction between 4-methylbenzaldehyde (2b′) and 9H-fluorene (1a) requires only a base (KO^tBu) for the effective generation of intermediate 3b′ (Scheme 6A), as the inclusion or removal of complex 1 from the reaction did not increase the yield of BIM significantly. Furthermore, under optimal conditions, when 3b′ was treated with a second equivalent of 4-methyl benzyl alcohol (2b) the desired product 3b, along with the corresponding aldehyde (2b′), were produced in good yield (Scheme 6Ad). Further, two separate C–H functionalization reactions of 9H-fluorene and indoles were carried out under ideal conditions in the presence of 1 equivalent of TEMPO, a well-known radical scavenger (Scheme 6Ba and Bb). Conclusively, both reactions generated the desired products (3a and 5a) in comparable yields when carried out in the presence of TEMPO. This implies that neither of the C–H functionalization methodologies operates via a free radical pathway. Additionally, we carried out a reaction between 9H-fluorene (1a) and benzyl alcohol (2a) in the presence of a stoichiometric amount of trityl cation, a well-known hydride scavenger. The trityl cation suppresses the formation of products 3a, which indicates the involvement of a copper-hydride (Cu-H) species in the catalytic cycle (Scheme 6C). Furthermore, we performed another experiment between 9H-fluorene and 4-methylbenzyl alcohol (2b) in the presence of metallic mercury, and we observed no reduction in the yield of the desired product (3a). This result confirms the homogenous nature of the developed methodology (Scheme 6D).

Scheme 6 Control experiments to support the proposed mechanism.

A feasible mechanism for the C–H functionalization of 9H-fluorene and indole with alcohols catalyzed by an N-bound Cu(II)-triazolyl-pyridine complex has been proposed based on mechanistic investigations and prior findings in the literature.^30,40 Initially, we developed a plausible mechanism for the C–H functionalization of 9H-fluorene (Scheme 7). Initially, the Cu(II) complex converts into active catalyst I, which then generates Cu-H species II and dehydrogenates the alcohol to an aldehyde. After the aldehyde is released, it condenses with fluorene to produce 3b′ and water. Active species I is then renewed when the Cu-H species II hydrogenates the condensation product 3b′via the III species.

Scheme 7 Plausible mechanism for C–H functionalization of 9H-fluorenes.

A possible approach for the C–H functionalization of the indole was then proposed (Scheme 8). Complex 1 first produces intermediate I in the presence of alcohol and base, which then generates Cu–H species II via dehydrogenation of the alcohol to an aldehyde. After that, species II reacts with alcohol and releases an H₂ molecule to create active catalyst I, and the cycle continues. The in situ produced aldehyde or ketone reacts with indole via a base-catalyzed condensation reaction to produce an alkylideneindolenine intermediate, which leads to the creation of a BIM product that is followed by the Michael-type nucleophilic addition of another indole molecule. The above-mentioned reaction mechanism can be correlated with the electrostatic potential map onto the Hirshfeld surface of the Cu-complex (1) after removing two weakly coordinating nitrate ions, using CrystalExplorer,⁴⁸ excluding the nitrate anions (Fig. 4, right) using Hartree–Fock theory with the STO-3G basis set, within the range of −0.0667 to +0.2114 atomic units. The resulting electrostatic potential surface is visualized with red regions indicating areas of negative electrostatic potential and blue regions representing areas of positive electrostatic potential. Electrostatic potential mapping reveals a region of strong positive potential around the Cu(II) center, indicating a high degree of electrophilicity. This electropositive site provides a rational basis for the coordination of the primary alkoxide nucleophile, facilitating its axial binding to the metal center and initiating the subsequent transformation.

Scheme 8 Plausible mechanism for C–H functionalization of indoles.

In summary, alcohol proved to be a reliable coupling reagent in the development of an effective Cu(II)-catalyzed C–H functionalization procedure for 9H-fluorene and indole. This method used significantly lower amounts of base (0.1 vs. 0.2–2 equivalents) and catalyst (0.5 or 1 vs. 1–10 mol%) compared to earlier base metal-catalyzed processes. By employing the borrowing hydrogen technique, we are able to synthesize several significant compounds, such as the antimalarial medicine benflumetol, turbomycin B, and an orphan nuclear receptor. We were able to effectively test a wide range of benzyl alcohols, unactivated cyclic or acyclic aliphatic alcohols, even secondary alcohols, and substituted 9H-fluorenes. The synthetic utility of the current catalytic method was increased by demonstrating a few post-functionalization processes. Using a BH principle, we suggested a plausible mechanism based on control experiments. Copper catalysts are rarely used for the alkylation of substrates with alcohols. This contribution marks a significant advancement, being only the second report on the copper-catalyzed alkylation of 9H-fluorene using alcohols.

Conflicts of interest

All the authors declare there are no conflicts to declare.

Data availability

Supplementary information is available. See DOI: https://doi.org/10.1039/D5CY00610D.

CCDC 2445355 contains the supplementary crystallographic data for this paper.⁴⁹

The data supporting this article have been included as part of the SI.

Acknowledgements

B. J. gratefully acknowledges the Science and Engineering Research Board (SERB; CRG/2023/007224), New Delhi for financial support to carry out this work. B. S. and D. G. thank UGC-SRF for providing a research fellowship. P. S. G. thanks MNIT Jaipur for providing a research fellowship. All the authors acknowledge MRC, MNIT Jaipur for proving all the instrumentation facilities.

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