Synthesis of 2-Alkenyl-2H-indazoles from 2-(2-Carbonylmethyl)-2H-indazoles

A procedure has been developed for synthesis of 2-alkenyl-2H-indazoles starting from 2-(2-carbonylmethyl)-2H-indazoles, which are prepared by gallium/aluminium- and aluminium-mediated, direct, regioselective alkylation of indazoles with α-bromocarbonyl compounds. The structure of 3-(2H-indazol-2-yl)-2H-chromen-2-one was proven by X-ray crystallography. The styrene- and coumarin-2H-indazoles produced by using the new method were found to have interesting fluorescence properties.


Introduction
Owing to their unique binding affinities to key enzymes and proteins involved metabolic processes, nitrogen-containing heterocyclic compounds have drawn intensive attention in the area of drug discovery [1][2][3][4]. Among these substances, indazoles display a broad range of interesting biological properties that have been used advantageously in the design of new drugs. Consequently, methods for the synthesis of indazole derivatives are in high demand. Special interest has been given to the development of procedures for regioselective introduction of functionality on the two nitrogen atoms of indazoles [5][6][7][8]. This task is simplified somewhat by the fact that the reactivities of the two nitrogen atoms in indazoles are dramatically different. In general, N-1 substituted indazoles are thermodynamically favored products of these processes. However, finding new methods for regioselective synthesis of 2H-indazoles remains a significant challenge in the field of nitrogen heterocycles. While reasonable progress has been made in devising techniques to prepare 2-alkyl-and 2-aryl-2H-indazoles [9][10][11][12][13][14][15][16], fewer advances have been made in developing methods for the preparation of 2-alkenyl-2H-indazoles. Thus, a need exists to design operationally simple methods to access the privileged 2-alkenyl-2H-indazole pharmacophore.
Of the methods described thus far, copper-catalyzed vinylation reactions appear to hold the most promise as a new 2-alkenyl-2H-indazole synthesis approach. Unfortunately, our initial studies of this process demonstrated that reaction of indazole (1) with β-bromostyrene is very inefficient, producing 2 in only 9% yield (path (a) in Scheme 1) [17]. An alternative strategy that begins with conventional cyclization reactions of 2-nitrobenzaldehyde and 2-azidobenzaldehyde are not applicable to construction of 2-alkenyl-2H-indazoles owing to the substrate limitations associated with N-alkenyl primary amine, (path (b), Scheme 1) [9,10]. A potentially more productive approach to 2-alkenyl-2H-indazole targets begins with alkylation of indazole with α-bromocarbonyl compounds (path (c), Scheme 1). The major difficulty associated with this process is that N-1 alkylation products predominate in reactions run under most basic conditions [18]. Fortunately, the results of recent studies in this area show that 2H-indazoles are generated through gallium/aluminiumand aluminium-mediated direct regioselective alkylation reactions of an indazole with α-bromocarbonyl compounds [19]. Below, we describe observations made in an investigation in which this new alkylation procedure was applied to the synthesis of a variety of 2-alkenyl-2H-indazoles.

Results and Discussion
One approach to the synthesis of 2-alkenyl-2H-indazoles 2 from ketones 3a-j, produced by regioselective alkylation reactions of indazoles with α-bromocarbonyl compounds, is based on a reduction-elimination strategy. Specifically, treatment of 3a-j with sodium borohydride generates alcohols, which are then transformed to either chloride or mesylate derivatives to facilitate elimination to form alkenes. The results in which this sequence is applied to selected indazole-ketones are displayed in Table 1. Conversion of the intermediate alcohols to the corresponding chlorides was accomplished by using phosphoryl chloride. Under these conditions, minor amounts of elimination products were formed along with the chloride intermediates. Treatment of these mixtures with DBU led to clean formation of the target 2-alkenyl-2H-indazoles 2. However, elimination product 2e was formed directly when the corresponding alcohol was treated with phosphoryl chloride. A decomposition process occurred in the chlorination reaction with alcohol intermediate indazole bearing nitro substituent (Table 1, entry 9). The alcohols to alkene transformations can also be accomplished by first forming the mesylate derivatives followed by DBU promoted elimination. Overall, the route B predominated in terms of functional group compatibility and yield. The elimination reactions were observed to generate either E-regioisomers exclusively (Table 1, entries 1, 3-6, 8 and 10) or mixtures of E and Z-isomers (Table 1, entries 2, 7 and 9). The E double bond geometry of 2a was unambiguously assigned by using X-ray crystallography (Figure 1) [20]. The detailed X-ray crystallographic data for 2a are provided in the Supplementary Materials. Scheme 1. Strategies for the synthesis of 2-alkenyl-2H-indazoles.

Scheme 3. Formation of the indene-linked 2H-indazole.
Recently, 2-aryl-2H-indazoles have been identified as a new class of fluorescent compounds [15]. In addition, coumarin derivatives have been widely studied and utilized as fluorescent probes in living cells [23][24][25][26]. We envisioned that coumarin-substituted 2H-indazoles 6 (Scheme 4, Equation (2)) possessing a planar, rigid π-conjugated system might display interesting luminescent behavior. In studies pursuing this proposal we observed that coumarin-indazole 6 can be generated by condensation reaction of the indazole-ester 3k with salicylaldehyde (Equation (2)). It should be noted that the synthesis of coumarin-indazole 6 was carried out previously through a route that begins with reaction of 3-aminocoumarin with o-nitrobenzaldehyde (Scheme 4, Equation (3)) [27]. In addition, coumarin derived N1-indazole 7 was synthesized previously by palladium catalyzed coupling of 3-bromo-coumarin with indazole (Scheme 4, Equation (4)) [28]. Interestingly, the NMR spectroscopic data of our synthetic 6 are totally different from those of the It should be noted that the synthesis of coumarin-indazole 6 was carried out previously through a route that begins with reaction of 3-aminocoumarin with o-nitrobenzaldehyde (Scheme 4, Equation (3)) [27]. In addition, coumarin derived N1-indazole 7 was synthesized previously by palladium catalyzed coupling of 3-bromo-coumarin with indazole (Scheme 4, Equation (4)) [28]. Interestingly, the NMR spectroscopic data of our synthetic 6 are totally different from those of the substance prepared earlier as well as those of 7. To gain support for the structural assignment we have made to 6, X-ray crystallographic analysis was performed (Figure 2) [29]. The conflicting observations uncovered in this effort lend credence to our earlier statement in the Introduction section that "conventional cyclization reactions to prepare members of the 2H-indazole family from 2-nitrobenzaldehyde and 2-azidobenzaldehyde are not applicable to the construction of 2-alkenyl-2H-indazoles". Finally, we determined the fluorescence properties of the new compounds prepared in this effort ( Table 2). As can be seen in Table 2, the planar, rigid π-conjugated system 2H-indazoles 2a and 5 display strong fluorescence and 6 possesses a large red stark shift. substance prepared earlier as well as those of 7. To gain support for the structural assignment we have made to 6, X-ray crystallographic analysis was performed ( Figure 2) [29]. The conflicting observations uncovered in this effort lend credence to our earlier statement in the Introduction section that "conventional cyclization reactions to prepare members of the 2H-indazole family from 2-nitrobenzaldehyde and 2-azidobenzaldehyde are not applicable to the construction of 2-alkenyl-2H-indazoles". Finally, we determined the fluorescence properties of the new compounds prepared in this effort ( Table 2). As can be seen in Table 2, the planar, rigid π-conjugated system 2H-indazoles 2a and 5 display strong fluorescence and 6 possesses a large red stark shift.

General Information
All commercially available chemicals were used without further purification. TLC analyses were run on glass TLC plates (Silica gel 60 F254) and were visualized using UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was performed using silica gel (70-230 mesh). 1 H-NMR spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13 C-NMR spectra were recorded at 75 MHz with complete proton decoupling spectrometer. Chemical shifts are reported relative to CHCl3 [δH 7.24, δC (central line) 77.0]. Mass spectra were recorded under electron impact ionization (EI) conditions, and high-resolution mass spectra were recorded by electron impact ionization with magnetic sector.

General Procedure for the Synthesis of 2-Alkenyl-2H-indazoles 2 (Route A)
To a cold solution (ice bath 0-5 °C) of ketone 3 (0.5 mmol) in MeOH/CH2Cl2 (1/1, 10 mL) NaBH4 (0.5 mmol, 1.0 equiv.) was added slowly. The resulting mixture was warmed to ambient temperature (ice bath removal). Reaction was monitored by TLC until no starting material was observed and normally the reaction was stirred at ambient temperature for 2 h. The reaction was then cooled to 0-5 °C and quenched with 2 N HCl (10 mL). CH2Cl2 (10 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was dissolved in POCl3 (0.5 mL) and the mixture was heated to reflux (110 °C) under N2 overnight. The resulting mixture was cooled to 0-5 °C and sat. NaHCO3 was added slowly until no

General Information
All commercially available chemicals were used without further purification. TLC analyses were run on glass TLC plates (Silica gel 60 F254) and were visualized using UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was performed using silica gel (70-230 mesh). 1 H-NMR spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13 C-NMR spectra were recorded at 75 MHz with complete proton decoupling spectrometer. Chemical shifts are reported relative to CHCl 3 [δ H 7.24, δ C (central line) 77.0]. Mass spectra were recorded under electron impact ionization (EI) conditions, and high-resolution mass spectra were recorded by electron impact ionization with magnetic sector.

General Procedure for the Synthesis of 2-Alkenyl-2H-indazoles 2 (Route A)
To a cold solution (ice bath 0-5˝C) of ketone 3 (0.5 mmol) in MeOH/CH 2 Cl 2 (1/1, 10 mL) NaBH 4 (0.5 mmol, 1.0 equiv.) was added slowly. The resulting mixture was warmed to ambient temperature (ice bath removal). Reaction was monitored by TLC until no starting material was observed and normally the reaction was stirred at ambient temperature for 2 h. The reaction was then cooled to 0-5˝C and quenched with 2 N HCl (10 mL). CH 2 Cl 2 (10 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated on a rotary evaporator. The residue was dissolved in POCl 3 (0.5 mL) and the mixture was heated to reflux (110˝C) under N 2 overnight. The resulting mixture was cooled to 0-5˝C and sat. NaHCO 3 was added slowly until no bubble was observed. EtOAc (10 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with EtOAc (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered through a silica-gel pad (dˆl, 3 cmˆ3 cm) and concentrated in a rotary evaporator. The residue was dissolved in DBU (1 mL) and the mixture was heated to 90˝C under N 2 overnight. The mixture was cooled to ambient temperature. EtOAc (10 mL) and H 2 O (10 mL) were added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with EtOAc (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc/hexanes (1/9) as eluent to give the product 2.

General Procedure for the Synthesis of 2-Alkenyl-2H-indazoles 2 (Route B)
To a cold solution (ice bath 0-5˝C) of ketone 3 (0.5 mmol) in MeOH/CH 2 Cl 2 (1/1, 10 mL) was added NaBH 4 (0.5 mmol, 1.0 equiv.) slowly. The resulting mixture was warmed to ambient temperature (ice bath removal). Reaction was monitored by TLC until no starting material was observed and normally the reaction was stirred at ambient temperature for 2 h. The reaction was then cooled to 0-5˝C and quenched with 2 N HCl (10 mL). CH 2 Cl 2 (10 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in a rotary evaporator. The residue was dissolved in CH 2 Cl 2 (5 mL) and the mixture was cooled 0-5˝C (ice bath) under N 2 . Et 3 N (0.25 mL, 1.8 mmol) was added followed by MsCl (0.07 mL, 0.9 mmol). The resulting mixture was warmed to ambient temperature (ice bath removal). Reaction was monitored by TLC until no starting material was observed and normally the reaction was stirred at ambient temperature for 2 h. The resulting mixture was cooled to 0-5˝C and sat. NaHCO 3 (5 mL) was added slowly. The mixture was transferred to a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in a rotary evaporator. The residue was dissolved in DBU (0.6 mL) and the mixture was heated to 90˝C under N 2 overnight. The mixture was cooled to ambient temperature. EtOAc (10 mL) and H 2 O (10 mL) were added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with EtOAc (10 mLˆ2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc/hexanes (1/9) as eluent to give the product 2. A mixture of ketone 3g (1.0 mmol), aldehyde (1.5 mmol), and conc. HCl (3 drops) in CH 3 CN (1 mL) was heated to reflux under nitrogen. Reaction was monitored by TLC until no starting material was observed and normally the reaction was stirred under reflux for 4 h. The reaction was then cooled to ambient temperature and quenched with sat. NaHCO 3 until pH was 7. CH 2 Cl 2 (10 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (10 mLˆ2). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc/hexanes (1/10) as eluent to give the product 4.

Conclusions
In conclusion, the studies described above have led to the development of a method for the synthesis of 2-alkenyl-2H-indazoles from α-(2H-indazol-2-yl)ketones. The 2-alkenyl-2H-indazole products may be potentially useful as fluorescent probes or as anticancer drugs.