Metal-Free Synthesis of C-3-Alkoxycarbonylated 2H-Indazoles Using Alkyl Carbazates

This paper is dedicated to Professor Brindaban C. Ranu on the occasion of his 75^th birthday.

Abstract

A simple, efficient, and environmentally benign method for the direct C-3-alkoxycarbonylation of 2H-indazoles using alkyl carbazates has been developed under metal-free conditions at room temperature. This current protocol represents a facile access to C-3-carboxylic ester derived 2H-indazoles with wide functional group tolerance in good to excellent yields. The mechanistic studies suggest that the reaction proceeds through a radical pathway.

Carboxylic esters are an essential and ubiquitous component in manufacturing agrochemicals, plasticizers, pharmaceuticals, and cosmetics.[1] These are also important precursors for several synthetic organic transformations.[2] Because of their broad applicability, incorporating ester functional group in various organic moieties is a long-standing interest among the synthetic organic community.[3] Since the revolutionary works by Heck in 1974,[4] alkoxycarbonylation employing expensive Pd as the catalyst and toxic CO and alcohol as ester sources became the most common strategy.[5] [6b]

However, the essentiality of high-pressure equipment and the toxicity of the reagents remained a significant drawback for alkoxycarbonylation.[6] Henceforth, the design of environmentally friendly and cost-effective methodology for alkoxycarbonylation became highly demanding among the chemists. Pioneering works using carbazates as the alternative surrogate for ester sources have drawn the research community’s attention.[7] However, several metal-catalyzed C–H alkoxycarbonylations of heterocycles have been well developed by using readily available and operationally simple alkyl carbazates.[7] [8�] [b] Till to date, limited research has been accomplished involving metal-free methods for alkoxycarbonylation of various organic compounds by carbazates.[8c–e]

Indazoles, on the other hand, are a class of N-heterocycles having broad pharmaceutical importance for their versatile bioactivities such as antitumor, antimicrobial, HIV-protease inhibition, antiplatelet, antiprotozoal, etc.[9] Numerous marketed drugs also consist of indazole as the basic scaffold.[9] [10] Therefore, considering the importance of indazole in a wide spectrum, the direct C-3 functionalization of indazoles has gained momentous importance.[11] Over the past few years, our group has been searching for various methods of direct C-3 functionalization of 2H-indazoles under metal-free conditions.[12] Thus taking into consideration the importance of indazoles and the significance of alkoxycarbonylation, herein we report a metal-free C-3-alkoxycarbonylation of 2H-indazoles using alkyl carbazates at room temperature under mild reaction conditions (Scheme [1]).

Table 1 Optimization of the Reaction Conditions^a

Entry	Oxidant (equiv)	Solvent	Yield (%)
1	TBHP (4)	CH3CN	53
2	TBHP (4)	1,2-DCE	80, 45,b 55,c 12d
3	TBHP (4)	DCM	67
4	TBHP (4)	THF	27
5	TBHP (4)	1,4-dioxane	nre
6	TBHP (4)	toluene	35
7	TBHP (4)	EtOH	nre
8	TBHP (4)	1,2-DCB	16
9	TBHP (4)	DMSO	trace
10	TBHP (4)	H2O	nre
11	TBHP (4)	CH3COOH	trace
12	DTBP (4)	1,2-DCE	trace
13	TBPB (4)	1,2-DCE	51
14	K2S2O8 (4)	1,2-DCE	45
15	PIDA (4)	1,2-DCE	trace
16	TBHP (2)	1,2-DCE	66

^a Reaction conditions: all reactions were carried out with 1b (0.2 mmol), 2a (2.0 equiv), and oxidant (4.0 equiv) in solvent (2 mL) at room temperature for 8 h under N₂ atmosphere.

^b 1.0 equiv 2a was used.

^c At 60 °C.

^d Under aerobic conditions.

^e nr = no reaction.

We embarked on our inquisition into the most optimized reaction conditions upon selecting 2-(p-tolyl)-2H-indazole (1b) as the model substrate and methyl hydrazinecarboxylate (2a) as alkoxy carbonyl source using different oxidants and solvents (Table [1]). Initially, we executed our reaction by using 0.2 mmol 1b, 2 equiv of methyl hydrazinecarboxylate (2a) and 4 equiv TBHP as an oxidant in CH₃CN at room temperature under N₂ atmosphere. The C-3-alkoxycarbonylated product 3ba was formed in 53% yield after 8 h (Table [1], entry 1). Inspired by the initial progress, we probed into the effect of various solvents and oxidants to enhance the yield of the desired product. Initially, we screened the solvent effect for the reaction using other solvents like 1,2-DCE, DCM, THF, 1,4-dioxane, toluene, EtOH, 1,2-DCB, DMSO, H₂O, and CH₃COOH (Table [1], entries 2–11). We achieved the maximum yield of the desired product in 1,2-DCE (Table [1], entry 2). The productivity of the reaction was not improved by decreasing the loading of 2a in the reaction (Table [1], entry 2). When the reaction was carried out at a higher temperature, i.e., at 60 °C, the yield of the desired product was diminished (Table [1], entry 2). The reaction under aerobic conditions produced 3ba in 12% yield (Table [1], entry 2). After screening the solvent effect, we then monitored the impact of different oxidants in the reaction like di-tert-butyl peroxide (DTBP), tert-butyl peroxybenzoate (TBPB), K₂S₂O₈, and diacetoxyiodobenzene (PIDA, Table [1], entries 12–15). We have found that TBHP as an oxidant is the most recommendable among other oxidants. No further improvement in the yield of the desired product was found by lowering the amount of TBHP (Table [1], entry 16). Finally, we achieved the optimal reaction conditions by using of 2 equiv methyl hydrazinecarboxylate (2a) and 4 equiv of TBHP as an oxidant in 1,2-DCE under N₂ atmosphere at room temperature for 8 h (Table [1], entry 2).

After accomplishing the optimized reaction conditions, we focused on establishing the substrate scope for this protocol. We started our survey with the electronic effects of the N-phenyl ring of 2H-indazoles (Scheme [2]). Electronically neutral indazole 1a and electron-donating group (Me and OMe) substituted 2H-indazoles were reacted with methyl hydrazinecarboxylate (2a), affording their corresponding products 3aa–ca in 64–80% yield. Halogen (F, Cl, and Br) containing indazoles also produced C-3 alkoxycarbonylated products 3da–fa with up to 81% yields. Notably, high electron-dragging CO₂Et and CF₃-substituted 2H-indazoles were also capable enough to produce the desired products 3ga and 3ha in good yields. Various meta-substituted 2H-indazoles eminently furnished the desired products 3ia–ka in 66–84% yields. Delightfully, dihalogenated phenyl ring containing 2H-indazole smoothly reacted with 2a to afford 3la in 74% yield. Next, we turned our attention to extend our scope upon reacting various substituted 2H-indazoles with ethyl hydrazinecarboxylate (2b), affording the corresponding products 3ab, 3bb, 3eb, and 3mb up to 80% yields. N-Alkylated (tert-butyl and n-butyl) 2H-indazoles could not furnish the desired products under the current reaction conditions.

Next, to extend the scope of this current protocol, we screened the effect of different substituents at the fused arene part of 2H-indazoles (Scheme [3]). Substrates bearing an electron-donating OMe group at the C-5- and C-5,6-positions produced the C-3-methoxycarbonylated products 5aa and 5ba in 77% and 70% yields, respectively. Moreover, C-5 halogen (F and Cl) substituted indazoles were successfully reacted with 2a to furnish the anticipated products up to 88% yields (5ca–fa). Interestingly, the heterodihalo-substituted indazole 4g gave the estimated product 5ga in 78% yield. Pleasantly, 2-phenyl-2H-[1,3]dioxolo[4,5-f]indazole was well-tolerated with 2a to provide 5ha in 71% yield. Moreover, the ethyl-substituted alkyl carbazate 2b also efficiently reacted with indazole, having a substitution at the fused arene part to furnish the desired product 5cb in 69% yield.

To demonstrate the synthetic utility of our developed methodology, a scale-up synthesis of compound 3ba and further derivatizations of the synthesized C-3- alkoxycarbonylated derivative 3ba were carried out (Scheme [4]). We have found the anticipated product 3ba was formed in 72% yield in 5 mmol scale under the standard reaction conditions (Scheme [4]A). Next, alkaline hydrolysis of the ester group of 3ba was done and we obtained 2-(p-tolyl)-2H- indazole-3-carboxylic acid (7) in 70% yield (Scheme [4]B).[13a] The C-3-amidated indazole 8 was synthesized in 82% yield by conducting a reaction between 3ba and n-BuNH₂ at 100 °C (Scheme [4]C).[13b]

We performed a few control experiments to establish the mechanistic insight of this reaction (Scheme [5]). In the presence of radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methyl phenol (BHT), the outcome of the reaction was inhibited entirely (Scheme [5]A). A trace amount of product 3ba was found in the presence of p-benzoquinone (BQ) (Scheme [5]A). On the other hand, the presence of 1,1-diphenylethylene (DPE) in the reaction mixture also did not produce the desired product at all (Scheme [5]B). Interestingly we have observed the formation CO₂Me-radical-scavenged DPE adduct 6, which has been detected by GC–MS (Scheme [5]B and S7 in the Supporting Information). These observations highlight that the reaction possibly goes through a radical pathway.

A plausible mechanistic pathway of this reaction has been proposed based on the literature survey[14] and control experiments (Scheme [6]). Initially, the tert-butoxy radical is generated in situ via the O–O bond cleavage of TBHP.[14a] Then, the generated tert-butoxy radical reacts with methyl carbazate (2a) which forms CO₂Me radical intermediate I with the concomitant liberation of molecular N₂.[14b] In the next step, the generated alkoxycarbonyl radical I attacks regioselectively at C-3 position of 2-(p-tolyl)-2H-indazole (1b) to form the radical intermediate A. Finally, hydrogen abstraction of intermediate A by TBHP results in the formation of desired product 3ba.[14b]

In summary, we have established a simple and convenient strategy[15] for the direct C(sp²)–H alkoxycarbonylation of 2H- indazoles using carbazates at room temperature. This methodology offers safe, easy handling, and metal-free C-3 functionalization of 2H-indazoles using inexpensive and nontoxic alkyl carbazates as the ester source. A wide class of different substituted 2H-indazole-3-carboxylate derivatives has been synthesized in good to excellent yields. This present protocol will be helpful in the synthesis of alkoxycarbonylated derivatives in the fields of organic synthesis, medicinal chemistry, and material science.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 15 General Experimental Procedure for the Synthesis of C-3-Alkoxycarbonylated 2H-Indazoles 3 and 5 A mixture of 2-arylindazoles 1/4 (0.2 mmol), alkyl hydrazinecarboxylate 2 (2.0 equiv), and TBHP (4.0 equiv, 0.14 mL) was taken in an oven-dried reaction tube under N₂ atmosphere. Then 1,2-DCE (2 mL) was added to it using a syringe, and the reaction mixture was further stirred at room temperature for 8 h under N₂ atmosphere. After completion of the reaction (TLC), the reaction mixture was extracted with DCM (10 mL). The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (100–200 mesh) using a mixture of petroleum ether and ethyl acetate as an eluent to afford the corresponding products 3/5. Analytical Data for Compound 3ha White solid (67%, 42.9 mg); R_f = 0.50 (PE:EtOAc = 96:4); mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.46–7.42 (m, 1 H), 7.39–7.35 (m, 1 H), 3.94 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 160.0, 148.9, 143.6, 131.6, 131.3, 127.7, 127.0, 126.2, 125.9 (q, J _C–F = 4.0 Hz), 124.2, 123.8 (q, J _C–F = 271.0 Hz), 121.6, 118.8, 52.3. FTIR: ν = 3055, 1708, 1616, 1462, 1296, 1103 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for [C₁₆H₁₂F₃N₂O₂]⁺: 321.0845; found: 321.0841. Analytical Data for Compound 5aa White solid (77%, 45.6 mg); R_f = 0.5 (PE:EtOAc = 94 : 6); mp 134–135 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 9.2 Hz, 1 H), 7.39–7.37 (m, 2 H), 7.31–7.29 (m, 3 H), 7.10–7.07 (m, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 2.45 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 160.3, 158.1, 145.2, 139.3, 138.7, 129.3, 126.0, 125.0, 123.9, 122.0, 120.1, 97.9, 55.6, 51.9, 21.4. FTIR: ν = 3032, 1712, 1631, 1442, 1211, 1126 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for [C₁₇H₁₇N₂O₃]⁺: 297.1234; found: 297.1225.

Corresponding Author

Publication History

Received: 23 March 2024

Accepted after revision: 29 April 2024

Accepted Manuscript online:
29 April 2024

Article published online:
16 May 2024

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• References and Notes

• 1a Zhao Y, Li Y, Ou X, Zhang P, Huang Z, Bi F, Huang R, Wang Q. J. Agric. Food Chem. 2008; 56: 10176
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• 2a Levin JI, Turos E, Weinreb SM. Synth. Commun. 1982; 12: 989
  CrossrefSearch in Google Scholar
• 2b Zhang J, Leitus G, Ben-David Y, Milstein D. Angew. Chem. Int. Ed. 2006; 45: 1113
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  CrossrefPubMedSearch in Google Scholar
• 3 Pimparkar S, Dalvi AK, Koodan A, Maiti S, Al-Thabaiti SA, Mokhtar M, Dutta A, Lee YR, Maiti D. Green Chem. 2021; 23: 9283
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• 4 Schoenberg A, Bartoletti I, Heck RF. J. Org. Chem. 1974; 39: 3318
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• 15 General Experimental Procedure for the Synthesis of C-3-Alkoxycarbonylated 2H-Indazoles 3 and 5 A mixture of 2-arylindazoles 1/4 (0.2 mmol), alkyl hydrazinecarboxylate 2 (2.0 equiv), and TBHP (4.0 equiv, 0.14 mL) was taken in an oven-dried reaction tube under N₂ atmosphere. Then 1,2-DCE (2 mL) was added to it using a syringe, and the reaction mixture was further stirred at room temperature for 8 h under N₂ atmosphere. After completion of the reaction (TLC), the reaction mixture was extracted with DCM (10 mL). The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (100–200 mesh) using a mixture of petroleum ether and ethyl acetate as an eluent to afford the corresponding products 3/5. Analytical Data for Compound 3ha White solid (67%, 42.9 mg); R_f = 0.50 (PE:EtOAc = 96:4); mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.46–7.42 (m, 1 H), 7.39–7.35 (m, 1 H), 3.94 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 160.0, 148.9, 143.6, 131.6, 131.3, 127.7, 127.0, 126.2, 125.9 (q, J _C–F = 4.0 Hz), 124.2, 123.8 (q, J _C–F = 271.0 Hz), 121.6, 118.8, 52.3. FTIR: ν = 3055, 1708, 1616, 1462, 1296, 1103 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for [C₁₆H₁₂F₃N₂O₂]⁺: 321.0845; found: 321.0841. Analytical Data for Compound 5aa White solid (77%, 45.6 mg); R_f = 0.5 (PE:EtOAc = 94 : 6); mp 134–135 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 9.2 Hz, 1 H), 7.39–7.37 (m, 2 H), 7.31–7.29 (m, 3 H), 7.10–7.07 (m, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 2.45 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 160.3, 158.1, 145.2, 139.3, 138.7, 129.3, 126.0, 125.0, 123.9, 122.0, 120.1, 97.9, 55.6, 51.9, 21.4. FTIR: ν = 3032, 1712, 1631, 1442, 1211, 1126 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for [C₁₇H₁₇N₂O₃]⁺: 297.1234; found: 297.1225.

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