Regioselective C3-Formylation of 2H-Indazoles Using Selectfluor under Microwave-Assisted Conditions

Abstract

An efficient microwave-assisted Selectfluor-mediated regioselective C3-formylation of 2H-indazoles bearing a variety of alkyl and aryl substituents using DMSO as the formylating agent has been developed. This methodology provides access to 3-formyl 2H-indazoles with moderate to excellent yields. These functionalized indazoles are potentially useful as templates for drug discovery. Control experimental results suggest that this formylation probably proceeds through a radical pathway.

Key words

2H-indazoles - Selectfluor - C3-formylation - microwave - radical pathways

Indazoles are important heterocyclic scaffolds in the pharmaceutical field owing to their various biological properties such as anti-inflammatory, antibacterial, anti-HIV, antiarrhythmic, antifungal, and antitumor activities.[1] In particular, 2H-indazoles have received a great deal of attention as they are important moieties in fragment-based drug discovery (FBDD) and in scaffold hopping exercises for protein kinase inhibitors.[2] 2H-Indazole derivatives are an essential pharmacophore that display diverse pharmacological activity; compounds containing this group include the antitumor drug Pazopanib, Nirapirab (a PARP inhibitor), an estrogen receptor agonist, Bazitinib (c-Met/HGFR inhibitor), a dual anti-inflammatory and antimicrobial agent, and a selective Famesold X-receptor agonist (Figure [1]).[3] [4]

Figure 1 Representative examples of biologically active APIs encompassing 2H-indazoles

Table 1Optimization of Reaction Conditions^a

Entry	Oxidant (equiv)	Solvent (2 mL)	Temp (°C)	Time (h)	Conv. (%)b
1	Selectfluor (2.5)	DMSO	80c	1	20
2	Selectfluor (2.5)	DMSO	100c	1	26
3	Selectfluor (2.5)	DMSO	120c	1	31
4	Selectfluor (2.5)	DMSO	125 (MW)	1	55
5	Selectfluor (1)	DMSO	125 (MW)	1	trace
6	Selectfluor (2)	DMSO	125 (MW)	1	trace
7	Selectfluor (3)	DMSO	125 (MW)	1	80
8	Selectfluor (3)	DMSO/H2O	125 (MW)	1	nr
9	Selectfluor (3)	HFIP	80 (MW)	1	nr
10	Selectfluor (3)	DMF	125 (MW)	1	nr
11	Selectfluor (3)	DMA	125 (MW)	1	nr
12	Oxone (3)	DMSO	125 (MW)	1	nr
13	diacetoxyiodobenzene (3)	DMSO	125 (MW)	1	nr
14	hydroquinone (3)	DMSO	125 (MW)	1	nr
15	sodium persulfate (3)	DMSO	125 (MW)	1	7
16	tert-butylhydroperoxide (3)	DMSO	125 (MW)	1	nr
17	Cu(OAc)2 (3)	DMSO	125 (MW)	1	nr
18	Selectfluor-II (3)	DMSO	125 (MW)	1	28
19	(Ir[dF(CF3)ppy]2(dtbpy))PF6/Selectfluor (0)	DMSO	100 W blue LED r.t.	12	nr
20	(Ir[dF(CF3)ppy]2(dtbpy))PF6/Selectfluor (3)	DMSO	100 W blue LED r.t.	12	nr
21	Selectfluor (3)	DMSO	100 W blue LED r.t.	12	nr
22	Vilsmeier–Haack	DMF/POCl3	125c	1	trace
23	–	DMSO	125 (MW)	1	trace
24	hexamethylenetetramine/acetic acid	–	110c	3	trace

^a Reaction conditions: All reactions were carried out with 1a (0.2 mmol) and oxidant in DMSO (2 mL) for 1 h.

^b Determined by LCMS.

^c Reaction under conventional heating.

Considering the significant importance of indazole and its derivatives in drug discovery research, the past decade was witness to tremendous research on the synthesis and functionalization of indazoles. Therefore, direct C3-functionalization on 2H-indazoles is worth pursuing as it would provide an efficient route for the synthesis of various 2H-indazole derivatives. Very recently, some remarkable breakthroughs related to C3-functionalization of 2H-indazoles through acylation, arylation, alkylation, alkenylation, trifluoromethylation, selenylation, and phosphorylation using different approaches including visible-light-mediated reactions were reported.[3b] [5] In our quest to synthesize fluoro derivatives of 2H-indazoles, the use of Selectfluor was explored. Selectfluor is a widely used electrophilic fluorinating reagent in organic synthesis and has been employed not only as an electrophilic fluorinating reagent but also as an oxidant in many chemical transformations.[6] Our recent efforts include the late-stage functionalization of APIs with fluorination, trifluoromethylation and other CH-functionalization.[7] In a continuation of our interest, we began our investigation of fluorination on 2H-indazoles using Selectfluor in DMSO solvent; contrary to our expectation, the formylated product was observed instead of fluorination. In an extension of the literature precedence of such formylation on 2H-indazole by Hajra et al. [8] using potassium persulfate oxidant, herein we report the scope and limitations of Selectfluor-mediated microwave-assisted C3-formlyation of 2H-indazoles.

As part of our drug discovery program, we were interested in late-stage functionalization of fluoro/trifluoromethyl group on indazoles. Hence, the fluorination of indazoles by using Selectfluor was proposed, which can act as both fluorinating reagent as well as an oxidant. When the reaction was performed using 2.5 equivalent of Selectfluor in DMSO at 80 °C for one hour, to our surprise, 3-formylated indazole was formed as a major product (20%) rather than the expected 3-fluorinated indazole, as shown in Scheme [1a]. The formylated compound was characterized thoroughly and the structure of compound 2a was confirmed by single-crystal X-ray crystallography as presented in Scheme [1b].[9]

Scheme 1 (a) C3-functionalization of 2H-indazoles. (b) Single-crystal X-ray structure of compound 2a (CCDC 2315017, see the Supporting Information for full single-crystal X-ray details).[9]

Scheme 2 Substrate scope of Selectfluor-mediated formylation. Reagents and conditions: 1 (0.2 mmol) and Selectfluor (3.0 equiv) in DMSO (2 mL) for 1 h under microwave irradiation at 125 °C. Isolated yields given.

As the aldehyde functional group can be utilized for the formation of a wide variety of C–C and C–hetero bonds, we believed that the 3-formylated 2H-indazoles can serve as a key precursor for indazole-based drug discovery. With this, an investigation was initiated to optimize the reaction conditions (Table [1]). Increasing the temperature from 80 to 120 °C furnished only a marginal improvement in the yield (entries 2 and 3). To optimize the reaction further, microwave conditions were studied and, to our delight, the yield was improved to 55% (entry 4). Attention then turned towards the number of equivalents of oxidant, and the experiments suggested that the reaction requires three equivalents for better yields (entries 5–7). The negative results shown in entries 8–11 suggested that DMSO was the only suitable solvent for the present transformation. Further screening with different oxidants such as oxone, diacetoxyiodobenzene, hydroquinone, sodium persulphate, TBHP, and copper acetate (entries 12–17) did not show the formation of the product, except in the case of sodium persulfate, with which 7% product formation was observed along with multiple impurities. The reaction with Selectfluor II yielded 28% of the product under standard conditions (entry 18). Attempts to conduct a photochemical condition using Ir photoredox catalyst such as Ir[dF(CF₃)ppy]₂(dtbpy))PF₆ under blue LED conditions (entries 19–21) were not successful. Formylation performed under classical Vilsmeier–Haack reaction conditions using POCl₃ and DMF, unfortunately, gave no product (entry 22). Similarly, only a trace amount of product was observed when Duff’s formylation conditions were used with hexamethylene tetramine / AcOH under heating (entry 24).

Scheme 3 Control experiments

Scheme 4 Plausible reaction mechanism

After extensive screening of the reaction with different parameters, the optimal reaction conditions were established as microwave irradiation of a solution of Selectfluor (3 equiv) in DMSO as a solvent at 125 °C, which produced 80% conversion into the desired product (Table [1], entry 7). The substrate scope was explored with 2H-indazoles bearing a variety of aryl/alkyl/heteroaryl substituents on the indazole part. The 2H-indazoles were then subjected to formylation under the optimized conditions. The yields of the formylated 2H-indazoles 2a–ac are summarized in Scheme [2]. Aryl substituents with electron-donating and -withdrawing groups afforded the desired formylated product 2a–ac with moderate to good yields of 40–80%. Halogen-substituted indazoles 2b, 2c, 2f, 2g, 2l–o, 2q, 2aa, and 2ab also afforded moderate yields of 41–69%. Fortunately, N-alkyl (2s, 2t) and N-cycloalkyl (2v–y) derivatives also gave moderate yield of 40–60%. Such derivatives were not successfully synthesized with the recently reported K₂S₂O₈-mediated formylation of 2H-indazoles.[8] One more advantage of the current method compared to the reported approach is the duration of reaction, with the present method requiring only 1 h compared to 24 h. Unfortunately, heteroaryl and hindered 2H-indazoles 2ad–ag failed to produce the desired 3-formylated products.

To probe the mechanistic pathway of the reaction, several control experiments using 1d as a model substrate were carried out. First, the reaction was performed with DMSO-d ₆ instead of DMSO under standard conditions, which resulted in the product with –CDO mass and not a –CHO mass in LCMS. This clearly indicated that the source of aldehydic hydrogen was the solvent DMSO. A further control experiment was performed to confirm the source of aldehydic proton; the reaction was conducted under standard conditions with DMSO and quenched with D₂O (Scheme [3], equation ii). Under these conditions the deuterated aldehyde mass was not observed in LCMS or NMR analyses. This result again suggests that the aldehydic proton comes from DMSO. Such type of formylation using DMSO as a C1-source has been reported previously.[8] To understand the reaction pathway, a reaction was performed in the presence of TEMPO, which acts as a radical scavenger (Scheme [3], equation iii). Under these conditions, no product formation was observed, thereby supporting a free-radical pathway for the reaction. The product mass was clearly observed by LCMS even without quenching the reaction mass with external water (Scheme [3], equation iv). Two parallel reactions were performed under inert conditions by using nitrogen and argon. In both cases the solvent and the reaction mixtures were thoroughly purged with nitrogen and argon prior to starting the reaction under microwave conditions (Scheme [3], equation v). In neither case was the desired product mass observed in LCMS, indicating that dissolved O₂ plays an important role in generating the aldehyde.

Based on these control experiments and on previous reports,[10] a possible mechanism was proposed as shown in Scheme [4]. DMSO reacts with Selectfluor and is activated to generate methyl radical (A) and methylsulfone radical species (B) via single electron transfer (SET). 2H-Indazole 1d, upon oxidation with Selectfluor, forms radical intermediate C through SET. Radical coupling of C with the methyl radical leads to the formation of intermediate D. Intermediate D undergoes SET and is trapped by O₂ to form peroxy species E, which is converted into the desired aldehyde 2d.

In summary, an efficient methodology for regioselective C3-formylation of 2H-indazoles bearing a variety of alkyl and aryl groups has been demonstrated. The advantages of this methodology include the greener microwave process, shorter time, extensive substrate scope including N-alkylated derivatives, and the use of DMSO as both solvent and formylating source. The deuterated labeling experiments indicate that this reaction may proceed through a radical pathway. This method thus provides rapid access to a variety of C3-formylated 2H-indazoles and related derivatives, which will generate a library of compounds on an important scaffold for drug discovery research in the pharmaceutical industry.

All starting materials, reagents, and solvents were purchased from commercial suppliers and used without further purification. The starting materials were synthesized according to the reported procedures. Reactions were monitored by thin-layer chromatography (TLC) using Merck silica gel 60 F₂₅₄ pre-coated plates and visualized with a UV lamp for reaction monitoring. All ¹H NMR (400 MHz), ¹³C NMR (100 MHz), and ¹⁹F NMR spectra were recorded with a Bruker 300 or 400 MHz spectrometer, and chemical shifts are reported in ppm using TMS or the residual solvent peak as the reference. High-resolution mass spectra (HRMS) were recorded with LTQ XL Orbitrap Discovery-X caliber and Agilent-Q-TOF-Mass hunter instruments. LC-MS analyses were recorded with an Agilent 6140 quadrupole LCMS instrument using C18 columns (see the Supporting Information for more details on the respective spectra). A discover SP system microwave synthesizer (CEM Corporation) was used for the reaction. All 2H-indazole substrates were synthesized using reported procedures.[11]

General Procedure

To a stirred solution of 2H-indazole (0.2 mmol) in DMSO (2 mL; 1 M) in a 10-mL microwave vial, Selectfluor (0.6 mmol) was added at room temperature, then the mixture was stirred for 1 h at 125 °C under microwave irradiation. The reaction mixture was diluted with water and extracted with EtOAc (2 × 20 mL), washed with water, dried over sodium sulfate, and concentrated under vacuum to afford the crude compound. The crude product was purified by ISCO (Red Sep, SiO₂) using 15 to 20% EtOAc/hexane as eluant to give 2H-indazole-3-carbaldehyde derivatives 2a–ab.

The analytical data for the reported aldehydes 2a,[8] [12] 2c–g,[8] 2j,[8] 2k,[8] 2m–n,[8] 2r,[8] 2u,[13] 2aa–ab [8] matched the respective data.

2-(4-(Trifluoromethyl)phenyl)-2H-indazole-3-carbaldehyde (2b)

Yield: 49%; yellow solid; mp 136–139 °C.

¹H (400 MHz, DMSO-d ₆): δ = 10.06 (s, 1 H), 8.25 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.88–7.93 (m, 2 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.46–7.57 (m, 2 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 180.3, 147.9, 141.9, 131.87, 129.9 (q, J = 32.7 Hz, 1C), 128.0, 127.3, 127.0, 126.6 (q, J = 3.3 Hz, 1C), 123.2, 123.8 (q, J = 272.5 Hz, 1C), 120.5, 118.5.

¹⁹F NMR (282 MHz, DMSO-d ₆): δ = 61.08 (s, 3F).

HRMS: m/z [M + H]⁺ calcd for C₁₅H₉F₃N₂O: 291.0747; found: 291.0740.

2-(4-Hydroxyphenyl)-2H-indazole-3-carbaldehyde (2h)

Yield: 39%; brown liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.14 (s, 1 H), 9.99 (s, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.65 (d, J = 8.51 Hz, 2 H), 7.43–7.56 (m, 2 H), 7.00 (d, J = 8.5 Hz, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.6, 158.7, 147.3, 131.5, 130.0, 127.7, 127.3, 126.5, 120.4, 118.3, 115.7.

HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₀N₂O₂: 239.0822; found: 239.0820.

2-([1,1′-Biphenyl]-4-yl)-2H-indazole-3-carbaldehyde (2i)

Yield: 52%; yellow gummy solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.12 (s, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 7.94–8.00 (m, 5 H), 7.82 (d, J = 7.5 Hz, 2 H), 7.43–7.58 (m, 5 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.3, 147.9, 141.8, 131.7, 127.9, 127.3, 127.0, 126.5, 123.1, 120.50, 18.5, 79.1.

HRMS: m/z [M + H]⁺ calcd for C₂₀H₁₄N₂O: 299.1186; found: 299.1182.

2-(3-(Trifluoromethyl)phenyl)-2H-indazole-3-carbaldehyde (2l)

Yield: 41%; yellow solid; mp 120–123 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.04 (s, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.61–7.70 (m, 2 H), 7.43–7.58 (m, 4 H).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 180.1, 147.8, 139.4, 131.8, 130.7, 130.6, 130.1 (q, J = 32.7 Hz, 1C), 127.9, 126.9, 126.5 (q, J = 3.6 Hz, 1C), 123.3 (q, J = 4.4 Hz, 1C), 123.1, 123.5 (q, J = 273.2 Hz, 1C), 120.4, 118.5, 114.5, 15.1.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = 61.0 (s, 3F).

HRMS: m/z [M + H]⁺ calcd for C₁₅H₉F₃N₂O: 291.0747; found: 291.0743.

2-(3-Fluorophenyl)-2H-indazole-3-carbaldehyde (2o)

Yield: 61%; yellow solid; mp 91–93 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.08 (s, 1 H), 8.25 (d, J = 8.5 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.91–7.82 (m, 1 H), 7.78–7.68 (m, 2 H), 7.59–7.48 (m, 3 H), 3.40 (br d, J = 18.6 Hz, 1 H), 2.68 (s, 1 H), 2.59 (br d, J = 13.6 Hz, 1 H).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 180.9, 162.4 (d, J = 245.8 Hz, 1C), 148.2, 140.4 (d, J = 11.0 Hz, 1C), 132.3, 131.7 (br d, J = 8.8 Hz, 1C), 128.4, 127.4, 123.3, 121.0, 119.0, 117.4 (br d, J = 20.5 Hz, 1C), 114.6 (br d, J = 25.7 Hz, 1C).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = 111.2 (s, 1F).

HRMS: m/z [M + H]⁺ calcd for C₁₄H₉FN₂O: 241.0778; found: 241.0770.

2-(2-Methoxyphenyl)-2H-indazole-3-carbaldehyde (2p)

Yield: 81%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.82–9.80 (m, 1 H), 8.22–8.16 (m, 1 H), 7.94–7.90 (m, 1 H), 7.69–7.63 (m, 2 H), 7.54–7.45 (m, 2 H), 7.38–7.34 (m, 1 H), 7.26–7.20 (m, 1 H), 3.79 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.5, 153.2, 147.8, 132.2, 131.8, 128.4, 127.3, 127.1, 126.5, 121.8, 120.9, 120.2, 118.4, 112.7, 56.0.

HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂N₂O₂: 253.0978; found: 253.0968.

2-(2-Fluorophenyl)-2H-indazole-3-carbaldehyde (2q)

Yield: 51%; yellow solid; mp 92–95 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.05 (d, J = 2.0 Hz, 1 H), 8.23–8.27 (m, 1 H), 7.94–7.98 (m, 1 H), 7.87 (dt, J = 1.7, 7.6 Hz, 1 H), 7.70–7.77 (m, 1 H), 7.48–7.63 (m, 4 H).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 179.8 (d, J = 2.2 Hz, 1C), 155.9 (d, J = 250.9 Hz, 1C), 148.2, 132.4 (d, J = 8.1 Hz, 1C), 132.2, 129.2, 127.9, 127.0, 125.3 (d, J = 3.7 Hz, 1C), 122.7, 120.1, 118.5, 116.7 (d, J = 19.1 Hz, 1C).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = 124.1 (s, 1F).

HRMS: m/z [M + H]⁺ calcd for C₁₄H₉FN₂O: 241.0778; found: 241.0777.

2-Butyl-2H-indazole-3-carbaldehyde (2s)

Yield: 52%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.38 (s, 1 H), 8.13–8.18 (m, 1 H), 7.83–7.88 (m, 1 H), 7.37–7.46 (m, 2 H), 4.81–4.87 (m, 2 H), 1.87–1.96 (m, 2 H), 1.25–1.35 (m, 2 H), 0.90 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 179.8, 146.7, 130.4, 126.4, 125.8, 123.5, 119.5, 118.1, 51.8, 32.3, 19.1, 13.3.

LCMS: m/z [M + H]⁺ calcd for C₁₂H₁₄N₂O: 203.1186; found: 203.1120.

2-Propyl-2H-indazole-3-carbaldehyde (2t)

Yield: 54%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.38 (s, 1 H), 8.13–8.18 (m, 1 H), 7.83–7.88 (m, 1 H), 7.37–7.46 (m, 2 H), 4.81–4.87 (m, 2 H), 1.87–1.96 (m, 2 H), 1.25–1.35 (m, 2 H), 0.90 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 179.7, 146.6, 29.8, 126.3, 125.7, 123.6, 119.6, 118.3, 53.1, 22.7.

HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₄N₂O: 189.1029; found: 189.1025.

2-Cyclopropyl-2H-indazole-3-carbaldehyde (2v)

Yield: 61%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.52 (s, 1 H), 8.08–8.14 (m, 1 H), 7.79–7.84 (m, 1 H), 7.37–7.45 (m, 2 H), 4.72 (td, J = 3.6, 7.4 Hz, 1 H), 1.43–1.48 (m, 2 H), 1.23–1.30 (m, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.3, 147.9, 141.8, 131.7, 127.9, 127.3, 127.0, 126.5, 123.1, 120.5, 118.5, 79.1.

HRMS: m/z [M + H]⁺ calcd for C₁₁H₁₀N₂O: 187.0873; found: 187.0865.

2-Cyclobutyl-2H-indazole-3-carbaldehyde (2w)

Yield: 52%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.35 (s, 1 H), 8.13 (td, J = 1.13, 8.3 Hz, 1 H), 7.88–7.92 (m, 1 H), 7.37–7.47 (m, 2 H), 5.88 (t, J = 8.3 Hz, 1 H), 2.69–2.82 (m, 2 H), 2.57 (ddt, J = 1.25, 3.13, 6.07 Hz, 2 H), 1.89–1.99 (m, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.3, 147.9, 141.8, 131.7, 127.9, 127.3, 127.0, 126.5, 123.1, 120.5, 118.5, 79.1.

HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₂N₂O: 201.1029; found: 201.1026.

2-Cyclopentyl-2H-indazole-3-carbaldehyde (2x)

Yield: 40%; yellow gummy solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.42 (s, 1 H), 8.14 (d, J = 7.0 Hz, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.35–7.45 (m, 2 H), 5.79–5.88 (m, 1 H), 2.25 (td, J = 6.3, 12.9 Hz, 2 H), 2.10–2.20 (m, 2 H), 1.93 (br dd, J = 5.8, 9.3 Hz, 2 H), 1.67–1.80 (m, 2 H), 1.22–1.29 (m, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 179.9, 126.4, 125.8, 123.6, 119.6, 118.3, 61.929, 33.3, 24.4.

HRMS: m/z [M + H]⁺ calcd for C₁₃H₁₄N₂O: 215.1186; found: 215.1179.

2-Cyclohexyl-2H-indazole-3-carbaldehyde (2y)

Yield: 34%; yellow liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.42 (s, 1 H), 8.13–8.17 (m, 1 H), 7.84–7.89 (m, 1 H), 7.37–7.45 (m, 2 H), 5.26–5.35 (m, 1 H), 1.84–2.15 (m, 6 H), 1.74 (br d, J = 13.1 Hz, 1 H), 1.51 (td, J = 3.33, 12.9 Hz, 2 H), 1.29 (br d, J = 12.6 Hz, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.3, 147.9, 141.8, 131.7, 127.9, 127.3, 127.0, 126.5, 123.1, 120.5, 118.5, 79.1.

HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₆N₂O: 229.1343; found: 229.1335.

5-Bromo-2-(4-chlorophenyl)-2H-indazole-3-carbaldehyde (2z)

Yield: 62%; pale-yellow solid; mp 144–146 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.03 (s, 1 H), 8.44 (d, J = 2.0 Hz, 1 H), 7.97–7.93 (m, 1 H), 7.91–7.87 (m, 2 H), 7.76–7.71 (m, 1 H), 7.75 (s, 2 H), 7.67–7.63 (m, 1 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.3, 146.1, 137.3, 134.7, 131.2, 131.0, 129.4, 128.1, 124.0, 122.5, 120.7, 119.9.

HRMS: m/z [M + H]⁺ calcd for C₁₄H₈BrClN₂O: 334.9588; found: 334.9547.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr Li Jianqing and Dr James Kempson for their helpful suggestions and proofreading. The analytical support from the Discovery Analytical Department, Biocon Bristol Myers Squibb Research Centre (BBRC), Bangalore (India) is gratefully acknowledged.

• References

• 1 Qin J, Cheng W, Duan Y.-T, Yang H, Yao Y. Anti-Cancer Agents Med. Chem. 2021; 21: 839
• 2 Zhang SG, Liang CG, Zhang WH. Molecules 2018; 23: 2783
• 3a Mal S, Malik U, Mahapatra M, Mishra A, Pal D, Paidesetty SK. Drug Dev. Res. 2022; 83: 1469
• 3b Ghosh S, Mondal S, Hajra A. Adv. Synth. Catal. 2020; 362: 3768
• 3c Schoene J, Gazzi T, Lindemann P, Christian M, Volkamer A, Nazaré M. ChemMedChem 2019; 14: 1514
• 4a Benson GM, Bleicher K, Feng S, Grether U, Kuhn K, Martin RE, Plancher JM, Richter H, Rudolph M, Taylor S. US 2010/0076026A1, 2010
• 4b Villanueva JP, Mulia LY, Sánchez IG, Espinosa JF. P, Arteche OS, Sainz-Espuñes TR, Cerbón MA, Villar KR, Vicente AK. R, Gines MC, Galván ZC, Estrada-Castro DB. Molecules 2017; 22: 1864
• 4c Villar KR, Campos AH, Mulia LY, Sainz-Espuñes TR, Arteche OS, Espinosa JF. P, Benitez FC, Lugo ML, Petrissans BV, Quintana-Salazar EA, Villanueva JP. Pharmaceuticals 2021; 14: 176
• 5a Vidyacharan S, Murugan A, Sharada DS. J. Org. Chem. 2016; 81: 2837
• 5b Yang Z, Yu JT, Pan C. Org. Biomol. Chem. 2022; 20: 7746
• 6 Nyffeler PT, Duron SG, Burkart MD, Vincent SP, Wong CH. Angew. Chem. Int. Ed. 2005; 44: 192
• 7a Kempson J, Zhang H, Wong MK. Y, Li J, Li P, Wu DR, Rampulla R, Galella MA, Dabros M, Traeger SC, Muthalagu V, Gupta A, Arunachalam PN, Mathur A. Org. Process Res. Dev. 2018; 22: 846
• 7b Panja C, Puttaramu JC, Chandran TK, Nimje RY, Kumar H, Gupta A, Arunachalam PN, Corte JR, Mathur A. J. Fluorine Chem. 2020; 236: 109516
• 7c Pitchai, M.; Premsai, R.; Mathur, A.; Gupta, A. unpublished results.
• 8a Bhattacharjee S, Laru S, Ghosh P, Hajra A. J. Org. Chem. 2021; 86: 10866
• 8b Xiang S, Chen H, Liu Q. Tetrahedron Lett. 2016; 57: 3870
• 9 CCDC 2315017 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 10a Tashrifi Z, Khanaposhtani MM, Larijani B, Mahdavi M. Adv. Synth. Catal. 2020; 362: 65
• 10b Cao H, Lei S, Li N, Chen L, Liu J, Cai H, Qiu S, Tan J. Chem. Commun. 2015; 51: 1823
• 10c Ma X, Du W, Liu W, Liu Y, Tiebo XT, Jiang Y. J. Chem. Sci. 2019; 131: 55
• 11 Kumar MR, Park A, Park N, Lee S. Org. Lett. 2011; 13: 3542
• 12 Shortcliff LD, Weakley TJ. R, Haley MM, Kohler F, Herges R. J. Org. Chem. 2004; 69: 6979
• 13 Williams SJ, Jarrott B. WO 2016/149765 A1, 2016

Publication History

Received: 18 August 2023

Accepted after revision: 09 February 2024

Accepted Manuscript online:
12 February 2024

Article published online:
04 March 2024