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Late-stage ortho-C–H alkenylation of 2-

Cite this: RSC Adv., 2022, 12, 19412
arylindazoles in aqueous medium by Manganese(I)-
catalysis†
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Krishna Kanta Das, Asim Kumar Ghosh and Alakananda Hajra *

Earth-abundant and water-tolerant manganese(I) catalyzed alkenylation of 2-arylindazole with alkyl and aryl
alkynes through C–H bond activation is described with a unique level of E-selectivity. The reaction
Received 8th June 2022
Accepted 27th June 2022
proceeds through the control of C3 nucleophilicity of 2-aryl indazoles. This method is applied to the
late-stage functionalization of complex molecules including ethinylestradiol, norethisterone, and N-
DOI: 10.1039/d2ra03547b
protected amino acid derivatives. The kinetic isotope studies suggest that the C–H bond activation step
rsc.li/rsc-advances may not be the rate-determining step.

inhibitor, votrient), etc.9 Therefore, various methodologies have

Introduction been developed for the synthesis and functionalization of
Direct functionalization of inert C–H bonds is still one of the indazoles because of their extensive biological applications.10
most attractive strategies due to the formation of the versatile Recently few methodologies of ortho C–H activation in 2-
fundamental linkage in organic compounds.1 In this context, arylindazole moiety have been developed.11 However, C–H
noble metals such as iridium,2a,b ruthenium,2c–e rhodium,2f,g and activation of 2-aryl indazoles using water-tolerant metal-catalyst
palladium2h–k have been extensively employed for C–C and C– has not been explored yet. We concentrated our focus on Mn-
hetero atom bond formation reactions in the past two decades catalyzed selective ortho-C–H functionalization of 2-aryl inda-
because of their high catalytic performance. However, these zoles through the control of C3 nucleophilicity.12 Herein, we
noble metal catalysts usually suffer from toxicity, low natural have described manganese-catalyzed ortho-C–H alkenylation of
abundance, and high cost. In recent years, remarkable progress 2-arylindazole with alkyl and aryl alkynes in water (Scheme 1).
in 3d-transition metals such as Mn,3a Fe,3b,c Co,3d,e Ni,3f and Cu3g
based C–H activations have been observed due to the metals'
low price, high earth abundance, low toxicity, and potential to
Results and discussion
develop unique reactivity. In this topic, Mn-complexes typically The study was initiated by investigating the reaction of 2-
exhibit low toxicity, thus the utilization in C–H functionaliza- phenyl-2H-indazole (1a) and prop-2-yn-1-yl 4-methylbenzoate
tion is highly desirable.4 The Wang group rst reported the (2a) in the presence of Mn-catalyst. The reaction was performed
alkenyation of hetero-arene with alkynes via C–H bond activa- using 10 mol% MnBr(CO)5 as a catalyst and 20 mol% NaOAc as
tion using Mn(CO)5Br as a catalyst.5 Aerward, various research an additive in 1,4-dioxane at 100
C under N2 atmosphere.
groups such as Ackermann,6a Glorius,6b Kuninobu6c and oth-
ers6d–j independently developed Mn-catalyzed C–H functionali-
zation. Even though C–H bond activation in an aqueous
medium is sought aer, only a few examples of such reactions
are known that occur in water.7
Indazole, a nitrogen-containing heterocycle is widely used in
pharmaceutical and material science. In particular, antitumor,
antiplatelet, anticancer, anti-inammatory, HIV-protease inhi-
bition, etc., are shown by indazole.8 Various marketed drugs
contain indazole moiety, such as pazopanib, gamendazole,
anticancer agent (MK-4827), bendazac (tyrosine kinase

Department of Chemistry, Visva-Bharati (A Central University), Santiniketan, 731235,

West Bengal, India. E-mail: [email protected]
† Electronic supplementary information (ESI) available. See
https://doi.org/10.1039/d2ra03547b Scheme 1 Indazole-Directed C–H Alkenylation.

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Table 1 Optimization of the reaction conditionsa

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Entry Catalyst (10 mol%) Additives (20 mol%) Solvent (2.0 mL) Yield (%)

1 MnBr(CO)5 NaOAc 1,4-Dioxane 85

2 Mn2(CO)10 NaOAc 1,4-Dioxane 65
3 MnCl2 NaOAc 1,4-Dioxane nr
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4 Mn(OAc)2 NaOAc 1,4-Dioxane nr

5 MnBr(CO)5 NaOAc 1,2-DCE 61
6 MnBr(CO)5 NaOAc THF 46
7 MnBr(CO)5 NaOAc Toluene 52
8 MnBr(CO)5 NaOAc DMF 21
9 MnBr(CO)5 NaOAc CH3CN 10
10 MnBr(CO)5 NaOAc H2O 91
11 MnBr(CO)5 KOAc H2O 78
12 MnBr(CO)5 K2CO3 H2O 62
13 MnBr(CO)5 K3PO4 H2O 57
14 MnBr(CO)5 Et3N H2O 45
15 — NaOAc H2O nr
16 MnBr(CO)5 — H2O 36
17 MnBr(CO)5 NaOAc H2O 67b, 62c
18 MnBr(CO)5 NaOAc H2O 69d, 72e
a
Reaction conditions: All reactions were carried out with 0.25 mmol of 1a, 0.3 mmol of 2a, 10 mol% of MnBr(CO)5, 20 mol% NaOAc in 2.0 mL
solvent for 8 h at 100
C under N2. b Stirred at 120
C. c Stirred at 80
C. d Under air. e 2.0 equiv. of 2a was used. nr ¼ no reaction.

Gratifyingly, the coupling product (E)-3-(2-(2H-indazol-2-yl) yield. It is noteworthy that aliphatic acids like pivalic acid,
phenyl)allyl 4-methylbenzoate (3aa) was obtained in 85% yield cyclohexanecarboxylic acid, and adamantane-1-carboxylic acid
aer 8 h (Table 1, entry 1). Next, we screened the effect of derived alkynes were successfully employed, leading to the
various Mn-catalyst like Mn2(CO)10, MnCl2, and Mn(OAc)2. But desired products 3ae–3ag in good to excellent yields of 89–96%.
in all the cases, unsatisfactory results were observed (Table 1, Pent-4-yn-1-yl benzoate (2h) was treated with 2-phenyl-2H-
entries 2–4). Further optimization was carried out using various indazole (1a), and the expected alkenylation reaction occurred
solvents such as 1,2-DCE, THF, Toluene, DMF, CH3CN, and H2O with moderate yield. Remarkably, phenol, aniline, and thio-
(Table 1, entries 5–10). It was found that polar protic solvent phenol derivatives alkynes were efficiently converted to the
H2O afforded the desired product in 91% yield (Table 1, entry desired products 3ai–3ak with complete E-selectivity. Speci-
10). No signicant improvement of the yield was observed on cally, N-Boc-protected amino acid derivatives 2l and 2m were
further screening of additives like KOAc, K2CO3, K3PO4, and well tolerated, which will be precious for further post-synthetic
Et3N (Table 1, entries 11–14). However, no product was formed application. Furthermore, N-Boc-protected indoline-2-
in the absence of catalyst (Table 1, entry 15). Next, we checked carboxylic acid derived alkyne (2n) was converted to the
the reaction without additives (Table 1, entry 16). In addition, desired product in 72% yield. Inspired by the incredible versa-
varying the reaction temperature did not improve the yield of tility of Mn(I)-catalyzed alkenyation, we became interested in
the product (Table 1, entry 17). The reaction yield did not performing this alkenylation reaction with more challenging
enhance under air atmosphere, and no difunctionalized steroid structures. In this regard, ethinylestradiol and nor-
product was obtained in the presence of 2.0 equiv. of 2a (Table ethisterone took part effectively in the reaction to deliver 3ao
1, entry 18). From these results, the optimum reaction condi- and 3ap in 68% and 60% yields, respectively. Again, 1-octyne
tions was determined to be those in entry 10. was smoothly reacted, giving the desired product 3aq in 57%
Aer getting the optimized reaction conditions for the yield with excellent E-selectivity. Moreover, 3-hexyne was reac-
manganese-catalyzed C–H alkenylation in hand, we next ted with 2-phenyl-2H-indazole (1a) under the standard reaction
investigated its versatility (Table 2). The electron-donating conditions, but unfortunately obtained an inseparable mixture.
(–Me), halogen (–Cl), and electron-withdrawing (–CN) A number of electron-neutral and -donating (–Me, –OMe)
substituted benzoic acid derived alkynes smoothly underwent and electron-decient (–F) phenylacetylenes (2) were taken part
with indazole (1a) through C–H activation, effectively providing in the reaction with 2-arylindazole (1a) to afford the desired
the expected products (3aa–3ac) with excellent yields even on products (3ar–3au) up to 87% yields. 2-Ethynyl-6-
a gram scale of 3aa. Nicotinic acid derived alkyne was examined, methoxynaphthalene (2v) was also amenable to this method.
furnishing the corresponding alkenylated product 3ad in 78% Moreover, internal alkyne (2w and 2x) also provided ortho-

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Table 2 Substrate Scope of Alkynesa

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Scheme 2 Control experiments.

Motivated by the versatility of the Mn(I)-catalysis, a variety of

indazoles were examined. Electron-donating group (–Me) at the
phenyl ring of 2-arylindazole gave the corresponding alkeny-
lated product 3br in excellent yields. Halogen (–F, –Cl, and –Br)
containing substrates produced the desired products (3cr–3er)
in moderate to good yields. An electron-withdrawing (–COOEt)
group containing 2H-indazole was well tolerated in this method
and gave the expected products in moderate yields (3fr). meta-
Substituted 2-arylindazoles (1g and 1h) were also reacted under
the optimal reaction conditions (3gr and 3hr) with good yields.
a
Reaction conditions: 0.25 mmol of 1, 0.3 mmol of 2 in presence of
2H-indazoles, bearing halogens (–F and –Cl) on the C-5 position
10 mol% of MnBr(CO)5, 20 mol% NaOAc in 2.0 mL of H2O at 100
C of arene, successfully reacted to produce the desired products
for 8 h under N2. b 5 mmol scale. (3ir and 3kr). Furthermore, disubstituted indazoles (1j, 1l, and
1m) were explored and gave the corresponding products
without any difficulties (3jr, 3lr, and 3mr). On the other side,
alkenyated product 3aw–3bx in moderated yields (55–82%).
due to the difficulty in the formation of a ve-membered
Interestingly, heteroaryl substituted alkyne such as 3-ethynyl
mangancyclic intermediate, indazole substituted at the ortho-
thiophene (2y) was successfully converted into the corre-
position did not produce the desired product. Interestingly,
sponding alkenylated product 3ay in decent yields. The regio-
similar N-containing heterocycles such as 2-phenylpyridine (1n)
selectivity of unsymmetrical alkynes (direction of alkynes) have
been determined from the 1H-NMR data and coupling constant
(J) values.

Table 3 Substrate Scope of Hetrocyclesa

a
Reaction conditions: 0.25 mmol of 1, 0.3 mmol of 2 in presence of
10 mol% of MnBr(CO)5, 20 mol% NaOAc in 2.0 mL of H2O at 100
C
for 8 h under N2. Scheme 3 Plausible mechanistic pathway.

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