Scholarly article on N-(2-Bromobenzylidene)cyclohexylamine 128651-80-9 from RSC Advances p. 14178

RSC Advances

View Article Online

View Journal | View Issue

PAPER

Oxidative cross-dehydrogenative coupling (CDC)

2

via C_{(sp )}–H bond functionalization: tert-butyl

Cite this: RSC Adv., 2021, 11, 14178

peroxybenzoate (TBPB)-promoted regioselective

direct C-3 acylation/benzoylation of 2H-indazoles

with aldehydes/benzyl alcohols/styrenes†

*

Richa Sharma, Lalit Yadav, Ravi Kant Yadav and Sandeep Chaudhary

2

An eﬃcient, cost-eﬀective, transition-metal-free, oxidative

C_{(sp )}–H/C_{(sp )}–H cross-dehydrogenative

2

coupling via a C_{(sp )}–H bond functionalization protocol for the regioselective direct C-3 acylation/

benzoylation of substituted 2H-Indazoles 1a–m with substituted aldehydes 2a–q/benzyl alcohols 5a–e/

styrenes 6a–e is reported. The operationally simple protocol proceeds in the presence of tert-butyl

peroxybenzoate (TBPB) as an oxidant in chlorobenzene (PhCl) as a solvent at 110 ^ꢀC for 24 h under an

inert atmosphere, which furnished a diverse variety of substituted 3-(acyl/benzoyl)-2H-indazoles 3a–q/

4a–l in up to 87% yields. The reaction involves a free-radical mechanism and proceeds via the addition

of an in situ generated acyl radical (from aldehydes/benzyl alcohols/styrenes) on 2H-indazoles. The

functional group tolerance, broad substrate scope, control/competitive experiments and gram-scale

synthesis and its application to the synthesis of anti-inﬂammatory agent 11 and novel indazole-fused

diazepine 13 further signify the versatile nature of the developed methodology.

Received 20th March 2021

Accepted 26th March 2021

DOI: 10.1039/d1ra02225c

rsc.li/rsc-advances

structural motifs for various medications.⁴Therefore, the

development of a new synthetic pathway to introduce various

Introduction

functional groups on 2H-indazoles leading to an increase in the

molecular abundance and the formation of new bioactive

molecules, will always be of the utmost importance to medicinal

chemistry and drug discovery.

In particular, acylated 2H-indazoles have received tremen-

dous attention as a pharmaceutically important class of struc-

During the last two decades, oxidative cross-dehydrogenative

coupling, oen abbreviated to “oxidative CDC reaction”,

between two C–H bonds has been recognized as a greener

fundamental synthetic approach in C–C bond forming reac-

tions due to its association with several advantages such as

being metal-free, high yields, cost eﬀectiveness, operational

simplicity, high selectivity, step-/atom-economy, product selec-

tivity, no pre-functionalization of starting materials, reduced

waste, energy and resource competence, etc.¹Indazoles are

renowned bioactive heterocyclic scaﬀolds which are found

abundantly in several pharmaceutically privileged bioactive

natural products/therapeutics/drugs molecules²and are

bestowed with a wide array of biological activities such as

antimicrobial, anticancer, antitumor, HIV-protease inhibition,

antiplatelet, anti-depressant, and anti-inammatory actions.³

Indazole functionalization has achieved emerging demand

in the elds of organic and medicinal chemistry as the func-

tionalization of indazoles can be rendered into advantageous

tural motifs in

a large number of bioactive skeletons/

therapeutic molecules. Noticeably, C3-acylated-(2H)-indazoles

I–V are endowed with several biological activities, such as

antiemetic and anti-inammatory properties (Fig. 1).⁵There-

fore, the development of a direct synthetic strategy via an

oxidative cross-dehydrogenative coupling pathway for the C-3

acylation of 2H-indazoles is a highly desirable and chal-

lenging area of investigation. It becomes more appealing if it

proceeds through a transition-metal-free approach. A few

transition-metal-catalyzed (Ag, Ni) synthetic approaches via

2

C

_{(sp )}–H bond activation/functionalization have been reported

for the direct, regioselective, C-3 acylation of (2H)-indazoles

with either Ag-catalyzed decarboxylative cross-coupling of a-

keto acids⁶or with an Ni-catalyzed reaction on substituted

aldehydes⁷and with an Ag-catalyzed reaction with substituted

Hantzsch esters as acyl radical sources⁸(Scheme 1). However,

these strategies are associated with several drawbacks such as

the use of costly metals, the use of additives/ligands, and

limited substrate scope. In addition, the separate synthesis of

Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry,

Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur-302017,

India.

E-mail:

schaudhary.chy@mnit.ac.in;

Fax:

+911412529029;

Tel:

+911412713319

† Electronic supplementary information (ESI) available: Characterization data, ¹H

NMR and ¹³C NMR spectra. See DOI: 10.1039/d1ra02225c

14178 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

Results and discussion

We initiated our optimization study by investigating direct

2

C

_{(sp )}–C_{(sp )}coupling by taking 2-(4-methoxyphenyl)-2H-indazole

1a and 4-methylbenzaldehyde 2a as the starting substrate

(Table 1).

It has been noted that TBHP, either alone or in combination,

has been utilized in several oxidative cross-dehydrogenative

coupling reactions;⁹we had chosen tert-butyl hydroperoxide

(TBHP) as an oxidant and N-chlorosuccinimide (NCS) as

a catalyst for the beginning of our study. Therefore, using the

procedure in the literature,^9fwe carried out a reaction of 1a with

2a in the presence of TBHP (0.53 mmol, 4 equiv.) and NCS

(30 mol%) in dichloroethane (DCE) at 110 ^ꢀC for 24 h under an

inert atmosphere. However, the desired product 3a was not

found at all and several spots appeared on TLC (Table 1, entry

1). Then, keeping all other reaction parameters the same, we

carried out the same reaction as shown in entry no. 1 with

reduced equivalents of both TBHP and NCS catalyst. Intrigu-

ingly, 3a was obtained, albeit in low (30%) yield (Table 1, entry

2). Subsequently, we examined the screening of some other well-

known reagents which had previously been utilized extensively

in CDC reactions (Table 1, entries 3–7). While the reaction

performed in TFA furnished 3a in 40% yield, iodine-based

catalysts were found ineﬀective in improving the yield of the

reaction. Furthermore, keeping all the reaction conditions the

same, the reaction was performed without a catalyst, which

furnished 3a in 65% yield (Table 1, entry 8). This observation

instructed us to stop further use of any additives as a catalyst.

However, the reaction performed with less equivalents of 2a (1

equiv.) drastically reduced the yield of 3a (Table 1, entry 9). It

has been reported in the literature that chlorobenzene has been

utilized as an eﬀective solvent for cross-dehydrogenative

coupling reactions.¹⁰Therefore, we conducted the same reac-

tion in chlorobenzene instead of DCE and 3a was obtained in

68% yield (Table 1, entry 10).

Then, we carried out the screening of several organic as well

as inorganic oxidants, such as di-tert-butyl peroxide (DTBP),

tert-butyl peroxybenzoate (TBPB), dicumyl peroxide (DCP),

lauroyl peroxide, H₂O₂, cumene hydroperoxide, K₂S₂O₈, oxone,

(NH₄)₂S₂O₈, (diacetoxyiodo)benzene (PIDA), and oxygen gas,

while keeping all the other reaction parameters the same (Table

1, entries 11–21). It was found that while DTBP, TBPB and DCP

furnished 3a in 70%, 82% and 51% yields, respectively; the

reaction performed using lauroyl peroxide gave 3a in only 18%

yield (Table 1, entries 11–14). The rest of the oxidants either did

not furnish 3a at all or aﬀorded 3a in only trace amounts (Table

1, entries 15–21).

Sequentially, the screening of several polar/non-polar

solvents was also carried out (Table 1, entries 22–30). It

should be noted that none of the solvents were found to be

eﬀective except for chlorobenzene. Aerwards, keeping all

reaction parameters the same, the eﬀect of variation in

temperature and time was studied. It was observed that

increasing or decreasing the temperature and time did not have

a benecial eﬀect on the yield of the reaction (Table 1, entries

Fig. 1 Representative examples of various bioactive molecules/drugs/

therapeutics with a 2H-indazole moiety.

Scheme

1 Previous methodologies and present work: TBPB-

promoted approach to regioselective direct C-3 acylation/benzoyla-

tion of 2-aryl-2H-indazoles with substituted aldehydes/benzyl alco-

hols/styrenes.

an acylation/benzoylation source further amplies its limita-

tions and increases the tediousness of these methodologies.

However, there has been no report of the direct C-3 acylation of

2-aryl-2H-indazoles with metal-free and ligand-/additive-free

catalysis.

Herein, we report a cost-eﬀective, highly eﬃcient, tert-butyl

peroxybenzoate (TBPB)-promoted, regioselective, direct C-3

acylation/benzoylation of 2-aryl-2H-indazoles 1a–m with

diﬀerent aldehydes 2a–q/benzyl alcohols 5a–e/styrenes 6a–e via

2

C

_{(sp )}–H/C_{(sp )}–H cross-dehydrogenative coupling at 110 ^ꢀC for

24 h under N₂atmosphere which furnished 3-(acylated/ben-

zoylated)-2-aryl-2H–indazoles 3a–q/4a–l in excellent (87%)

yields, with a broad range of functional group tolerances and

varied substrate compatibilities [Scheme 1]. Succinctly, this is

2

the rst detailed investigation of an oxidant-promoted C_{(sp )}–H/

2

C

_{(sp )}–H cross-dehydrogenative coupling method for the regio-

selective direct C-3 acylation/benzoylation of 2-aryl-2H-

indazoles.

RSC Adv., 2021, 11, 14178–14192 | 14179

View Article Online

RSC Advances

Paper

Table 1 Optimization study^a

S. no.

Oxidant (2.5 equiv.)

Catalyst (20 mol%)

Solvent

Temp. (^ꢀC)

Yield (%)

1

2

3

4

5

6

7

8

TBHP^b

TBHP

DTBP

TBPB

DCP

Lauroyl peroxide

H₂O₂

Cumene hydroperoxide

K₂S₂O₈

Oxone

(NH₄)₂S₂O₈

PIDA

O₂

TBPB

TBHP

TBPB

NCS

TFA

TBAI

NaI

KI

I₂

—

DCE

—

110

80

NR^c

30

40^d

NR

65

DCE

PhCl

ACN

Toluene

DMSO

Dioxane

DMF

THF

9

10^e

68

70

82

51

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

18

NR

Trace

NR

Trace

NR

71

70

18

15

Trace

NR

72

H₂O

AcOH

TFA

PhCl

140

110

68

TBPB

71^f

a

Reaction conditions: 2-(4-methoxyphenyl)-2H-indazole 1a (0.13 mmol), 4-methyl benzaldehyde 2a (0.27 mmol), oxidant (0.33 mmol), catalyst

b

c

d

e

(20 mol%), N₂atm, 110 ^ꢀC, 24 h. For details, see ref. 9f. TBHP (0.53 mmol) and NCS (30 mol%) were used. TFA (0.6 equiv.) was used. 2a

(1 equiv.) was used. ^fReaction was allowed to run for 16 h.

31–33). Thus, overall, 2 equivalents of substituted aldehydes, 2.5 be well-tolerated and aﬀorded the corresponding C-3 benzoy-

equivalents of tert-butyl peroxybenzoate (TBPB) dissolved in chlo- lated-2H-indazoles 3a and 3c in 82% and 86% yields, respec-

robenzene as solvent at 110 ^ꢀC for 24 h under N₂atmosphere were tively. However, aromatic aldehyde 2d with two EDG (i.e., OCH₃)

found to be the best optimization reaction conditions for the groups was subjected to reaction with 1a under the optimized

direct C-3 acylation/benzoylation of 2-aryl-2H-indazoles via conditions; 3d was aﬀorded in slightly lower (78%) yield

2

a

C

_{(sp )}–H/C_{(sp )}–H

cross-dehydrogenative

coupling compared to 3a and 3c. This could be due to the steric

hindrance created by the OCH₃group at the o-position to the

methodology.

Taking 2-(4-methoxyphenyl)-2H-indazole 1a as a starting aldehydic functionality. In the case of aromatic aldehydes

substrate, several substituted aromatic/aliphatic/hetero- containing a halo (X ¼ F, Cl, Br) group at the para-position, the

aromatic aldehydes 2a–q were reacted under the optimized reaction of 1a with 2e–g under optimized conditions furnished

reaction conditions, which furnished substituted 3-(acylated/ 3e–g in 81–84% yield. However, keeping all the reaction

benzoylated)-2-(4-methoxyphenyl)-2H-indazoles 3a–q in 57– conditions the same, a decrease in the reactivity of aromatic

86% yield (Scheme 2). Like 3a, 1a was reacted with benzalde- aldehydes containing halo groups at the meta-/ortho-positions,

hyde 2b under the optimized reaction conditions and furnished was observed and 3h and 3i were obtained in 67% and 58%

3b in 80% yield. It has been noted that aromatic aldehydes with yields, respectively. In addition, the aromatic aldehyde con-

electron-donating groups (EDGs) at the p-position were found to taining an electron-withdrawing group (EWG) 2p was found to

14180 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

Scheme 2 Substrate scope: reaction of 2-(4-methoxyphenyl)-2H-indazole 1a with various aldehydes 2a–q for the synthesis of substituted 3-

acylated 2-(4-methoxyphenyl)-2H-indazoles 3a–q^{a,b a}Reaction conditions: 2-(4-methoxyphenyl)-2H-indazole 1a (0.5 mmol), substituted

.

aldehydes 2a–q (1.0 mmol), oxidant (1.25 mmol), PhCl, N₂atm, 110 ^ꢀC, 24 h. ^bIsolated yield.

be totally reluctant to undergo the optimized reaction condi- of unprecedented 3l from 2l in 60% yield. Furthermore, the

tions. Similarly, phenyl acetaldehyde 2q was also found to be instability of the acyl radical formed from 2m on treatment with

unreactive. Furthermore, in order to check the versatility of the TBPB can be understood by the formation of a more stable

methodology, a few aliphatic aldehydes 2j–k were reacted with secondary free-radical of isobutyraldehyde (generated aer

1a under the optimized reaction conditions and aﬀorded 3j and decarbonylation of n-isobutyraldehyde).^6,7Later on, the gener-

3k in 68% and 61% yields, respectively. Comparing aromatic ated alkyl free-radical attacks at the C-3 position of 2-aryl-2H-

aldehydes with aliphatic aldehydes, the latter were found to be indazole, subsequently leading to the formation of C-3-alky-

less reactive than the former. A diﬀerent observation was lated-2-aryl-2H-indazoles.^6,7Our protocol was also found to be

noticed in the current protocol when the number of carbon feasible with hetero-aromatic aldehydes. Signicantly, good

atoms increased to four (unbranched and/or branched) in the yields were observed when pyrrole-2-carboxaldehyde 2n, furan-

aldehydes.⁷Compounds 2l–m on reaction with 1a under the 2-carboxaldehyde 2o, 5-methyl-furan-2-carboxaldehyde 2p and

optimized reaction conditions did not furnish C-3 acylated 2H- 5-bromothiophene-2-carboxaldehyde 2q were reacted under the

indazoles but incorporated the corresponding alkyl group of the optimized reaction conditions to furnish 3n–q.

2l and 2m via decarbonylation and furnished 3l and 3m in 60%

Overall, the reactivity order for diﬀerent types of aldehydes

and 71% yields, respectively. We could speculate on the stability has been depicted as:

of the corresponding generated free-radicals on treatment with

Aromatic > aliphatic > hetero-aromatic

TBPB based on the greater +I eﬀect of the propyl group

(generated aer decarbonylation of n-butyraldehyde) compared

to the +I eﬀect of the ethyl group (generated aer decarbon-

ylation of n-propionaldehyde). This could lead to the formation

On the other hand, electron-donating groups (EDGs) con-

taining aldehydes were found to be more favorable to the

RSC Adv., 2021, 11, 14178–14192 | 14181

View Article Online

RSC Advances

Paper

Scheme 3 Substrate scope: reaction of diﬀerent substituted 2H-indazoles 1b–m with benzaldehyde 2a–b for the synthesis of 4a–l^a,b. ^aReaction

conditions: substituted 2H-indazoles 1b–m (0.5 mmol), substituted aldehydes 2a–b (1.0 mmol), oxidant (1.25 mmol), PhCl, N₂atm, 110 ^ꢀC, 24 h.

^bIsolated yield.

optimized reaction conditions compared to electron- optimized reaction conditions aﬀorded 4b and 4e in 71% and

withdrawing groups (EWGs) containing aldehydes. The 78% yields, respectively. 2H-Indazoles 1g–i (R₂¼ p-OCH₃, CH₃,

synthetic utility was also demonstrated by performing a gram- Cl) and 1m (R₂¼ H) on coupling with benzaldehyde 2a and 2b

scale synthesis of 3a by the reaction of 1a with 2a under our aﬀorded C-3 benzoylated product 4f–h in 58–85% yields and 4l

optimized reaction conditions, which furnished 3a in 65% in 80% yield, respectively. Similarly, heteroaryl 2H-indazoles 1j–

isolated yield (Scheme 2).

l were reacted with 4-methylbenzaldehyde 2a, which furnished

Sequentially, a diverse variety of substituted 2H-indazoles 3-benzyolated-(heteroaryl)-2H-indazoles 4i–k in 72%, 71% and

1b–m were reacted with substituted benzaldehyde 2a–b under 82% yields, respectively. The substrates, 2-cyclohexyl-2H-inda-

the optimized reaction conditions, which furnished the 3-ben- zole 1n and 1H-indazole 1o were found to be unreactive under

zyolated-2H-indazoles 4a–l in 54–80% yield (Scheme 3). 2H- the optimized reaction conditions. This clearly illustrates that

Indazoles with EDGs, i.e., 1b (R₁¼ –OCH₂O–), 1d (R₁¼ –OCH₃), the 2-aryl substitution in 2H-indazole plays a dynamic role in

1e (R₁¼ CH₃) and 1g (R₁¼ –OCH₂O–), were reacted with 2a stabilizing the intermediate for the coupling of aldehydes. This

under the optimized reaction conditions, which furnished 4a, transition-metal-free, regioselective, direct C-3 benzoylation of

2

4c, 4d and 4f in 55%, 65%, 68% and 58% moderate yields, 2-aryl-2H-indazoles

via

a

C

_{(sp )}–H/C_{(sp )}–H

cross-

respectively. However, 2H-indazoles with a halo group (R₁¼ F, dehydrogenative coupling also works eﬀectively with several

Cl) 1c and 1f, when subjected to CDC reaction with 2a under the substituted benzyl alcohols 5a–e and styrenes 6a–e on reaction

14182 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

Scheme 4 Reaction of oxidative coupling of diﬀerent substituted benzyl alcohol 5a–e with 2H-indazole 1a^a,b

.

^aReaction conditions: 2-(4-

methoxyphenyl)-2H-indazole 1a (0.5 mmol), substituted benzyl alcohols 5a–e (1.0 mmol), TBPB (1.25 mmol), PhCl, N₂atm, 110 ^ꢀC, 24 h.

^bIsolated yield.

Scheme 5 Benzoylation reaction of diﬀerent substituted styrenes 6a–e with 2H-indazole 1a^a,b. ^aReaction conditions: 2-(4-methoxyphenyl)-2H-

indazole 1a (0.5 mmol), substituted styrenes 6a–e (1.0 mmol), TBPB (1.25 mmol), PhCl, N₂atm, 110 ^ꢀC, 24 h. ^bIsolated yield.

with 1a, which furnished C-3-benzoylated-2-aryl-2H-indazole 6, eqn (i)]. However, 3a was not formed and the reaction was

products 3a–c and 3e–f in good yields (Schemes 4 and 5).

completely aborted when TEMPO (2.5 equiv.) was added under

In order to understand the mechanism of this unique the standard reaction conditions. We were successful in

protocol, control experiments were conducted [Scheme 6, eqn isolating the TEMPO-trapped acyl adduct 7 in 71% yield

(i)–(iv)]. It has already been exemplied in the literature that [Scheme 6, eqn (ii)]. The isolation of adduct 7 conrmed that

tert-butyl peroxybenzoate (TBPB) acts as a radical initiator.¹¹the synthetic pathway towards the regioselective synthesis of 3-

Keeping all the reaction conditions the same, 1a was reacted (acyl/benzoyl)-2-aryl-2H-indazoles proceed via the free-radical

with 2a under the optimized reaction conditions in the presence pathway. This underlines the importance of the oxidant in

of TEMPO (1 equiv.), which furnished 3a in 51% yield [Scheme this free-radical-catalyzed reaction. In order to interpret the

Scheme 6 Control experiments.

RSC Adv., 2021, 11, 14178–14192 | 14183

View Article Online

RSC Advances

Paper

Fig. 2 Plausible mechanism.

reactivity order among EDGs and EWGs while keeping all the order of this CDC reaction between aliphatic and aromatic

reaction conditions the same, a competitive experiment was aldehydes. Thus, substrate 1a was reacted with an equimolar

executed in which substrate 1a was reacted with an equimolar amount of 2a and 2j under optimized reaction conditions,

amount of 2c and 2e, which aﬀorded the C-3 benzoylated which furnished 3-(4-methylbenzyolated)-2-aryl-2H-indazole 3a

products 3c and 3e in 56% and 30% yields, respectively [Scheme and 3-(acetyl)-2-aryl-2H-indazole 3j in 55% and 29% yields,

6, eqn (iii)]. Therefore, it has been concluded that 2c with an respectively [Scheme 6, eqn (iv)]. This reaction demonstrated

EDG showed higher reactivity than 2e with an EWG. Another that the aromatic aldehydes were found to be more reactive

competitive experiment was carried out to analyse the reactivity than aliphatic aldehydes.

Scheme 7 Practical synthetic applications.

14184 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

A plausible free-radical mechanism for this regioselective

RSC Advances

Experimental

General

benzoylation method has been depicted in Fig. 2. Initially,

t

thermal cleavage of TBPB generates a BuO free-radical and

t

a carboxyl (PhCOO) free-radical. Then, the BuO free-radical

Oven-dried laboratory glassware was used for carrying out all

the synthetic procedures. Melting points were taken in open

capillaries on Sisco melting point apparatus and are presented

through hydrogen radical abstraction (HRA) from 4-methyl-

benzaldehyde 2a generates a benzoyl (acyl) free-radical 8 [note:

the radical species 8 was trapped with TEMPO to give adduct 7].

The free-radical 8 can also be derived from benzyl alcohol 5a as

well as styrene 6a.^10a,bThis benzoyl free-radical species 8 was

regioselectively added to the C-3 position of 1a. Subsequently,

the carboxyl free-radical abstracted the hydrogen radical from

the intermediate radical species 9 to aﬀord the desired

product 3a.

To illustrate the synthetic application of the developed CDC

methodology, using our optimized reaction conditions, we

synthesized the indazole-based anti-inammatory agent 11

(Scheme 7). The substrate 1p on reaction with m-acetox-

ybenzaldehyde 2r under the optimized reaction conditions fur-

nished 10, which on deacetylation furnished anti-inammatory

agent 11 in 51% yield. It has been noted that compound 11 was

earlier synthesized in 7 steps;¹²in contrast, we were successful in

synthesizing 11 in 51% in two steps. Progressively, the (2-bro-

mophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)methanone 12

was synthesized by the reaction of 1a with o-bromobenzaldehyde

using our optimized reaction conditions which on further

subjection to Pd-catalyzed biaryl coupling leads to the formation

of a novel class of heterocycles, i.e., 3-methoxy-9H-dibenzo

[4,5:6,7]azepino[1,2-b]indazol-9-one 13 in 75% yield, which can

be utilized for medicinal chemistry applications.¹³In addition,

the synthesized benzoylated product 3a on subjection to NaBH₄

reduction in methanol furnished the reduced hydroxylated

product, i.e., (2-(4-methoxyphenyl)-2H-indazol-3-yl)(p-tolyl)meth-

anol 14, in 90% yield, which can be utilized further for

uncorrected. H NMR and ¹³C NMR spectra were recorded on

1

a JEOL ECS-400 spectrometer (2-channel console with a exible

broadband RF performance), which was operating at 400 MHz

for ¹H and 100 MHz for ¹³C NMR and utilized CDCl₃and DMSO-

d6 as solvents for sample preparation. Tetramethylsilane (d 0.00

ppm) and CDCl₃both served as internal standards in ¹H NMR (d

7.246 ppm) and ¹³C (d 77.0 ppm) NMR. Patterns of chemical

shis are reported in parts per million. Peak splitting patterns

are described as singlet (s), broad singlet (brs), doublet (d),

double doublet (dd), triplet (t), and multiplet (m). Coupling

constants (J) are reported in Hertz (Hz). High-Resolution Elec-

tron Impact Mass Spectra (HR-EIMS) were obtained on Xevo G2-

S Q-Tof (Waters, USA) compatible with ACQUITY UPLC® and

nano ACQUITY UPLC® systems. Column chromatography was

performed over normal (particle size: 60–120 mesh, 100–200

mesh) and ash (particle size: 230–400 mesh) silica gel, which

was procured from Qualigens™ (India), Rankem (India), and

Spectrochem (India). TLC plates coated with silica gel (Kiesel

60-F₂₅₄, Merck (India)) were used for monitoring the progress of

the reactions. The visualizing agents used for TLC was UV light.

A BUCHI Rotavapor R-210 was used for all drying and concen-

tration procedures. All the analytical grade supplied solvents

such as MeOH, EtOH were used without further purication. All

the AR grade chemicals and reagents obtained from Sigma

Aldrich (USA), Merck (India), TCI (India) and/or Spectrochem

(India) etc. were used without further purication.

derivatization/functionalization

transformations.

and

other

organic

Synthesis of starting material 2H-indazoles 1a–o (Scheme 8)¹⁴

A

solution of 2-bromobenzaldehyde or substituted-2-

Conclusions

bromobenzaldehyde (1.5 mmol) and aromatic/hetero-

aromatic/aliphatic/cyclic amine (2.4 mmol) in methanol (20

mL) was reuxed for 6–7 h at 80 ^ꢀC. Aer the completion of the

reaction, the solvent was evaporated under reduced pressure to

get the corresponding imine product, which was further used in

the next step without prior purication.

The imine product was dissolved in anhydrous DMSO (10.0

mL) and CuI (38 mg, 0.20 mmol), NaN₃(261 mg, 4.0 mmol) and

TMEDA (22 mg, 0.20 mmol) were added. The reaction mixture

was heated at 120 ^ꢀC for 12 h. Aer cooling the reaction mixture,

In summary, we have developed an eﬃcient, cost-eﬀective,

transition-metal-free, regioselective, TBPB-promoted, oxidative

2

C

_{(sp )}–H/C_{(sp )}–H cross-dehydrogenative coupling protocol for

the direct C-3 acylation/benzoylation of 2-substituted-2H-inda-

zoles 3a–q/4a–l via the reaction of various 2-substituted-2H-

indazoles 1a–m with diﬀerent substituted aldehydes 2a–q/

benzyl alcohols 5a–e/styrenes 6a–e in up to 87% yields. The

operationally simple, oxidant-promoted protocol exhibits

a variety of functional group tolerances and wide substrate

compatibilities. The reaction involves a free-radical mechanism

and proceeds via the addition of an in situ generated acyl radical

(from aldehydes/benzyl alcohols/styrenes) on 2H-indazoles. The

gram-scale synthesis, and facile synthesis of anti-inammatory

agent 11, 3-methoxy-9H-dibenzo[4,5:6,7]azepino[1,2-b]indazol-

9-one 13 and hydroxylated product 14 further highlights the

versatile nature of the developed methodology. We believe that

our acylation/benzoylation regioselective CDC protocol will

accomplish several kinds of utilization in constructing a ubiq-

uitous class of bioactive azaheterocycles.

Scheme 8 General procedure for the synthesis of 2H-indazole 1a–o.

RSC Adv., 2021, 11, 14178–14192 | 14185

View Article Online

RSC Advances

Paper

it was poured into chloroform (70.0 mL) and sequentially

washed with water (3 ꢁ 30 mL) and brine (3 ꢁ 30 mL), then

dried over anhyd. Na₂SO₄. Then, aer evaporation of the solvent

under reduced pressure, the crude product was further puried

by column chromatography (hexane : EtOAc ¼ 99 : 1 to 90 : 10)

to produce the corresponding 2H-indazole 1a–m.

(2-(4-Methoxyphenyl)-2H-indazol-3-yl)(phenyl)-methanone

(3b). Product 3b was obtained by utilizing the general procedure

(Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

0.5 mmol) and benzaldehyde 2b (102 mL, 1 mmol) and isolated

by column chromatography (hexane : EtOAc ¼ 95 : 05) as

a yellow solid in 80% yield (131 mg, 0.39 mmol); mp: 93–95 ^ꢀC;

1

R_f(hexane : EtOAc ¼ 85 : 15): 0.45; H NMR (400 MHz, chloro-

Synthetic procedure for the C-3 benzoylation of 2H-indazoles

3a–q/4a–l (Schemes 2 and 3)

form-d) d 7.88–7.84 (m, 3H), 7.59 (t, J ¼ 7.2 Hz, 1H), 7.47–7.43

(m, 4H), 7.38–7.32 (m, 2H), 7.17–7.13 (m, 1H), 6.91 (d, J ¼

8.8 Hz, 2H), 3.81 (s, 3H); ¹³C NMR (100 MHz, chloroform-d)

d 186.15, 159.99, 148.46, 137.99, 133.74, 133.63, 132.20, 130.01,

128.73, 126.95, 126.78, 124.95, 124.05, 120.63, 118.51, 114.33,

55.63; HRMS (ESI/QTOF) m/z: calcd for C₂₁H₁₆N₂O₂, 329.1285

[M + H]⁺; found, 329.1282.

For the C-3 benzoylation of 2H-indazoles 3a–q/4a–l, a mixture of

2H-indazole 1a–m (0.5 mmol), aromatic/hetero-aromatic/

aliphatic aldehydes 2a–q (1 mmol) and TBPB (1.25 mmol) dis-

solved in PhCl were taken in a sealed reaction tube under

nitrogen atmosphere. Then the reaction mixture was stirred at

(4-Methoxyphenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

methanone (3c). Product 3c was obtained by utilizing the

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-

indazole 1a (112 mg, 0.5 mmol) and 4-methoxybenzaldehyde 2c

(121 mL, 1 mmol) and isolated by column chromatography

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 86% yield

(154 mg, 0.43 mmol); mp: 123–125 ^ꢀC; R_f(hexane : EtOAc ¼

85 : 15): 0.38; ¹H NMR (400 MHz, chloroform-d) d 7.89–7.83 (m,

3H), 7.47–7.44 (m, 2H), 7.39–7.33 (m, 2H), 7.16–7.12 (m, 1H),

6.94–6.91 (m, 4H), 3.87 (s, 3H), 3.81 (s, 3H); ¹³C NMR (100 MHz,

chloroform-d) d 184.89, 164.25, 159.91, 148.39, 133.73, 132.63,

132.51, 130.67, 126.90, 126.63, 124.56, 123.71, 120.65, 118.40,

114.35, 114.07, 55.70, 55.64; HRMS (ESI/QTOF) m/z: calcd for

ꢀ

110 C for 24 h. Aer completion of the reaction, the reaction

mixture was cooled and the work-up was done with a saturated

solution of NaHCO₃(10 mL) and ethyl acetate (3 ꢁ 20 mL). The

combined organic layers were dried over anhydrous Na₂SO₄,

ltered, and concentrated under reduced pressure to get the

crude residue which was further puried through column

chromatography on silica gel (100–200 mesh) using hex-

ane : ethyl acetate (95 : 5 ratio) as an eluent to aﬀord the cor-

responding desired product.

General procedure for the gram-scale synthesis of compound

3a

A mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (1.0 g, 4.46

mmol), 4-methyl benzaldehyde 2a (1.05 mL, 8.92 mmol) and

TBPB (2.12 mL, 11.15 mmol) was taken in a 50 mL round-

bottom ask under nitrogen atmosphere. Then, the reaction

C

₂₂H₁₈N₂O₃, 359.1390 [M + H]⁺; found, 359.1392.

(2,5-Dimethoxyphenyl)(2-(4-methoxyphenyl)-2H-indazol-3-

yl)methanone (3d). Product 3d was obtained by utilizing the

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-

indazole 1a (112 mg, 0.5 mmol) and 2,5-dimethox-

ybenzaldehyde 2d (166 mg, 1 mmol) and isolated by column

chromatography (hexane : EtOAc ¼ 95 : 05) as a brown oil in

78% yield (152 mg, 0.39 mmol); R_f(hexane : EtOAc ¼ 85 : 15):

0.30; ¹H NMR (400 MHz, chloroform-d) d 7.84 (d, J ¼ 8.8 Hz, 1H),

7.44 (d, J ¼ 9.2 Hz, 2H), 7.35–7.33 (m, 2H), 7.17–7.14 (m, 1H),

7.04 (d, J ¼ 3.2 Hz, 1H), 6.99–6.96 (m, 1H), 6.88 (d, J ¼ 9.2 Hz,

2H), 6.74 (d, J ¼ 9.2 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.48 (s,

3H); ¹³C NMR (100 MHz, chloroform-d) d 184.23, 159.38, 153.19,

151.66, 147.87, 133.21, 133.15, 128.89, 126.53, 126.34, 124.61,

123.37, 120.08, 118.91, 117.86, 113.95, 113.37, 112.36, 55.70,

55.49, 55.13. HRMS (ESI/QTOF) m/z: calcd for C₂₃H₂₀N₂O₄,

389.1496 [M + H]⁺; found, 389.1498.

ꢀ

mixture was stirred at 110 C for 24 h. Aer completion of the

reaction, the reaction mixture was cooled and the work-up was

done with a saturated solution of NaHCO₃(10 mL) and ethyl

acetate (3 ꢁ 20 mL). The combined organic layers were dried

over anhydrous Na₂SO₄, ltered, and concentrated under

reduced pressure to get the crude residue which was further

puried through column chromatography on silica gel (100–200

mesh) using hexane : ethyl acetate (95 : 5 ratio) as an eluent to

aﬀord compound 3a as a yellow solid in 65% yield (0.97 g).

Characterization of C-3 acylated/benzoylated 2H-indazoles

2-(4-Methoxyphenyl)-2H-indazol-3-yl)(p-tolyl)methanone

(3a). Product 3a was obtained by utilizing the general procedure

(Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

0.5 mmol) and 4-methyl benzaldehyde 2a (118 mL, 1 mmol) and

isolated by column chromatography (hexane : EtOAc ¼ 95 : 05)

as a yellow solid in 82% yield (140 mg, 0.40 mmol); mp: 153–

(4-Fluorophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

methanone (3e). Product 3e was obtained by utilizing the

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-

indazole 1a (112 mg, 0.5 mmol) and 4-urobenzaldehyde 2e

(106 mL, 1 mmol) and isolated by column chromatography

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 83% yield

(143 mg, 0.41 mmol); mp: 135–137 ^ꢀC; R_f(hexane : EtOAc ¼

85 : 15): 0.42; ¹H NMR (400 MHz, chloroform-d) d 7.92–7.87 (m,

3H), 7.46–7.44 (m, 2H), 7.40–7.36 (m, 2H), 7.22–7.18 (m, 1H),

1

ꢀ

155 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.48; H NMR (400 MHz,

chloroform-d) d 7.86 (d, J ¼ 8.4 Hz, 1H), 7.79 (d, J ¼ 8.0 Hz, 2H),

7.49–7.44 (m, 2H), 7.38–7.33 (m, 2H), 7.27 (d, J ¼ 8.4 Hz, 2H),

7.17–7.13 (m, 1H), 6.93 (d, J ¼ 8.8 Hz, 2H), 3.82 (s, 3H), 2.44 (s,

3H); ¹³C NMR (100 MHz, chloroform-d) d 185.87, 159.94, 148.41,

144.80, 135.37, 133.75, 132.41, 130.29, 129.47, 126.89, 126.70,

124.69, 123.86, 120.68, 118.44, 114.33, 55.63, 21.89; HRMS (ESI/

QTOF) m/z: calcd for C₂₂H₁₈N₂O₂, 343.1441 [M + H]⁺; found,

343.1446.

7.14 (t, J ¼ 8.8 Hz, 2H), 6.94 (d, J ¼ 9.2 Hz, 2H), 3.83 (s, 3H); ¹³

C

NMR (100 MHz, chloroform-d) d 184.52, 165.94 (J_C-F¼ 254.7

Hz), 159.96, 148.37, 134.18 (J_C-F¼ 2.9 Hz), 133.52, 132.60 (J_C-F

¼

14186 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

9.4 Hz), 131.81, 126.95, 126.65, 125.03, 123.90, 120.30, 118.52, 1H), 7.06–7.04 (m, 1H), 6.84 (d, J ¼ 8.8 Hz, 2H), 3.75 (s, 3H); ¹³

C

115.91 (J_C-F¼ 22.0 Hz), 114.28, 55.57; HRMS (ESI/QTOF) m/z: NMR (100 MHz, chloroform-d) d 183.82, 160.11, 148.53, 138.80,

calcd for C₂₁H₁₅FN₂O₂, 347.1191 [M + H]⁺; found, 347.1194.

133.59, 132.21, 132.16, 131.94, 130.37, 129.90, 127.20, 127.09,

126.08, 124.52, 120.20, 118.77, 114.09, 55.68; HRMS (ESI/QTOF)

(4-Chlorophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

methanone (3f). Product 3f was obtained by utilizing the m/z: calcd for C₂₁H₁₅ClN₂O₂, 363.0895 [M + H]⁺; found,

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H- 363.0898.

indazole 1a (112 mg, 0.5 mmol) and 4-chlorobenzaldehyde 2f

1-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)ethan-1-one

(3j).

(141 mg, 1 mmol) and isolated by column chromatography Product 3j was obtained by utilizing the general procedure

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 81% yield (Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

(147 mg, 0.41 mmol); mp: 142–144 ^ꢀC; R_f(hexane : EtOAc ¼ 0.5 mmol) and acetaldehyde 2j (57 mL, 1 mmol) and isolated by

1

85 : 15): 0.45; H NMR (400 MHz, chloroform-d) d 7.86 (d, J ¼ column chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow

8.8 Hz, 1H), 7.78 (d, J ¼ 8.8 Hz, 2H), 7.44–7.40 (m, 4H), 7.37–7.33 oil in 68% yield (90 mg, 0.34 mmol); R_f(hexane : EtOAc ¼

(m, 2H), 7.19–7.16 (m, 1H), 6.91 (d, J ¼ 8.8 Hz, 2H), 3.81 (s, 3H); 85 : 15): 0.36; ¹H NMR (400 MHz, chloroform-d) d 7.70–7.68 (m,

¹³C NMR (100 MHz, chloroform-d) d 184.77, 160.07, 148.45, 1H), 7.60 (d, J ¼ 8.4 Hz, 1H), 7.45 (d, J ¼ 8.8 Hz, 2H), 7.32–7.28

140.09, 136.28, 133.57, 131.75, 131.36, 129.09, 127.05, 126.76, (m, 1H), 7.06–7.00 (m, 3H), 3.87 (s, 3H), 2.60 (s, 3H); ¹³C NMR

125.23, 124.01, 120.38, 118.63, 114.37, 55.65; HRMS (ESI/QTOF) (100 MHz, chloroform-d) d 188.07, 159.75, 148.49, 133.02,

m/z: calcd for C₂₁H₁₅ClN₂O₂, 363.0895 [M + H]⁺; found, 132.07, 127.53, 127.06, 126.70, 120.86, 120.02, 117.52, 114.37,

363.0897.

(4-Bromophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

methanone (3g). Product 3g was obtained by utilizing the

55.69, 11.12; HRMS (ESI/QTOF) m/z: calcd for C₁₆H₁₄N₂O₂,

267.1128 [M + H]⁺; found, 267.1131.

1-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)propan-1-one (3k).

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H- Product 3k was obtained by utilizing the general procedure

indazole 1a (112 mg, 0.5 mmol) and 4-bromobenzaldehyde 2g (Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

(165 mg, 1 mmol) and isolated by column chromatography 0.5 mmol) and propionaldehyde 2k (73 mL, 1 mmol) and iso-

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 84% yield lated by column chromatography (hexane : EtOAc ¼ 95 : 05) as

(170 mg, 0.42 mmol); mp: 141–143 ^ꢀC; R_f(hexane : EtOAc ¼ a yellow oil in 61% yield (86 mg, 0.31 mmol); R_f(hexane : EtOAc

1

85 : 15): 0.48; ¹H NMR (400 MHz, chloroform-d) d 7.89–7.87 (m, ¼ 85 : 15): 0.31; H NMR (400 MHz, chloroform-d) d 7.86–7.59

1H), 7.73 (d, J ¼ 8.4 Hz, 2H), 7.61 (d, J ¼ 8.4 Hz, 2H), 7.44 (d, J ¼ (m, 2H), 7.47–7.40 (m, 2H), 7.31–7.28 (m, 1H), 7.07–7.00 (m,

9.2 Hz, 2H), 7.45–7.35 (m, 2H), 7.22–7.18 (m, 1H), 6.94 (d, J ¼ 3H), 3.87 (s, 3H), 3.02 (q, J ¼ 7.6 Hz, 1H), 2.60 (s, 1H), 1.27–1.23

8.8 Hz, 2H), 3.84 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) (m, 3H); ¹³C NMR (100 MHz, chloroform-d) d 188.08, 159.92,

d 184.93, 160.08, 148.46, 136.71, 133.56, 132.07, 131.70, 131.43, 159.76, 148.55, 138.10, 133.09, 127.36, 127.06, 126.59, 120.86,

128.83, 127.05, 126.76, 125.26, 124.00, 120.38, 118.64, 114.38, 120.84, 120.15, 117.61, 114.36, 55.68, 18.91, 14.15; HRMS (ESI/

55.66; HRMS (ESI/QTOF) m/z: calcd for C₂₁H₁₅BrN₂O₂, 407.0390 QTOF) m/z: calcd for C₁₇H₁₆N₂O₂, 281.1285 [M + H]⁺; found,

[M + H]⁺; found, 407.0392.

281.1287.

1-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)butan-1-one

(3-Chlorophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

(3l).

methanone (3h). Product 3h was obtained by utilizing the Product 3l was obtained by utilizing the general procedure

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H- (Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

indazole 1a (112 mg, 0.5 mmol) and 3-chlorobenzaldehyde 2h 0.5 mmol) and butyraldehyde 2l (90 mL, 1 mmol) and isolated by

(141 mg, 1 mmol) and isolated by column chromatography column chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 67% yield oil in 60% yield (88 mg, 0.30 mmol); R_f(hexane : EtOAc ¼

(122 mg, 0.34 mmol); mp: 155–157 ^ꢀC; R_f(hexane : EtOAc ¼ 85 : 15): 0.32; ¹H NMR (400 MHz, chloroform-d) d 7.70–7.64 (m,

1

85 : 15): 0.44; H NMR (400 MHz, chloroform-d) d 7.88 (d, J ¼ 2H), 7.45–7.40 (m, 2H), 7.31–7.27 (m, 1H), 7.06–7.00 (m, 3H),

8.8 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J ¼ 7.6 Hz, 1H), 7.54 (d, J ¼ 3.87 (s, 3H), 2.96 (t, J ¼ 7.6 Hz, 2H), 1.66 (q, J ¼ 7.6 Hz, 2H), 0.88

8.0 Hz, 1H), 7.43–7.37 (m, 5H), 7.23–7.19 (m, 1H), 6.92 (d, J ¼ (t, J ¼ 7.2 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d) d 159.89,

8.8 Hz, 2H), 3.81 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) 148.49, 136.89, 133.16, 127.49, 127.06, 126.56, 120.84, 120.29,

d 184.63, 160.07, 148.51, 139.52, 134.98, 133.57, 133.37, 131.66, 117.58, 114.37, 114.32, 55.68, 27.36, 22.87, 14.08; HRMS (ESI/

130.01, 129.76, 128.03, 127.11, 126.81, 125.45, 124.20, 120.37, QTOF) m/z: calcd for C₁₇H₁₈N₂O, 267.1492 [M + H]⁺; found,

118.66, 114.37, 55.66; HRMS (ESI/QTOF) m/z: calcd for 267.1495.

C

₂₁H₁₅ClN₂O₂, 363.0895 [M + H]⁺; found, 363.0892.

(2-Chlorophenyl)(2-(4-methoxyphenyl)-2H-indazol-3-yl)

1-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)-2-methylpropan-1-

one (3m). Product 3m was obtained by utilizing the general

methanone (3i). Product 3i was obtained by utilizing the general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole

procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and isobutyraldehyde 2m (91 mL, 1

1a (112 mg, 0.4459 mmol) and 2-chlorobenzaldehyde 2i mmol) and isolated by column chromatography (hex-

(141 mg, 1 mmol) and isolated by column chromatography ane : EtOAc ¼ 95 : 05) as a yellow solid in 71% yield (104 mg,

(hexane : EtOAc ¼ 95 : 05) as a yellow solid in 58% yield 0.35 mmol); mp: 98–100 ^ꢀC; R_f(hexane : EtOAc ¼ 85 : 15): 0.34;

(105 mg, 0.29 mmol); mp: 90–92 ^ꢀC; R_f(hexane : EtOAc ¼ ¹H NMR (400 MHz, chloroform-d) d 7.81 (dd, J ¼ 8.4 Hz, 0.8 Hz,

1

85 : 15): 0.44; H NMR (400 MHz, chloroform-d) d 7.8–7.78 (m, 1H), 7.69 (d, J ¼ 8.8 Hz, 1H), 7.39–7.37 (m, 2H), 7.30–7.26 (m,

1H), 7.39 (d, J ¼ 8.8 Hz, 2H), 7.36–7.24 (m, 5H), 7.14–7.09 (m, 1H), 7.03–7.00 (m, 3H), 3.87 (s, 3H), 3.36–3.29 (m, 1H), 1.46 (d, J

RSC Adv., 2021, 11, 14178–14192 | 14187

View Article Online

RSC Advances

Paper

¼ 7.2 Hz, 6H); ¹³C NMR (100 MHz, chloroform-d) d 160.01, d 7.78 (d, J ¼ 8.8 Hz, 1H), 7.56 (d, J ¼ 8.8 Hz, 1H), 7.39 (d, J ¼

148.77, 142.10, 133.18, 127.70, 126.28, 120.97, 120.56, 119.06, 9.2 Hz, 2H), 7.33–7.29 (m, 2H), 7.17–7.13 (m, 1H), 7.02–7.03 (m,

117.86, 114.29, 55.69, 27.20, 22.51; HRMS (ESI/QTOF) m/z: calcd 1H), 6.88 (d, J ¼ 8.8 Hz, 2H), 3.76 (s, 3H); ¹³C NMR (101 MHz,

for C₁₇H₁₈N₂O, 267.1492 [M + H]⁺; found, 267.1498.

chloroform-d) d 176.80, 160.09, 148.49, 145.70, 135.74, 133.39,

(2-(4-Methoxyphenyl)-2H-indazol-3-yl)(1H-pyrrol-2-yl)

131.53, 131.17, 127.12, 126.59, 125.03, 124.85, 123.46, 120.22,

methanone (3n). Product 3n was obtained by utilizing the 118.55, 114.45, 55.67; HRMS (ESI/QTOF) m/z: calcd for C₁₉H₁₃

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H- BrN₂O₂S, 412.9954 [M + H]⁺; found, 412.9957.

-

indazole 1a (112 mg, 0.5 mmol) and 1H-pyrrole-2-carbaldehyde

(2-Phenyl-2H-[1,3]dioxolo[4,5-f]indazol-3-yl)(p-tolyl)meth-

2n (95 mg, 1 mmol) and isolated by column chromatography anone (4a). Product 4a was obtained by utilizing the general

(hexane : EtOAc ¼ 95 : 05) as a brown solid in 58% yield (92 mg, procedure (Scheme 3) using 2-phenyl-2H-[1,3]dioxolo[4,5-f]

0.29 mmol); mp: 134–136 ^ꢀC; R_f(hexane : EtOAc ¼ 85 : 15): 0.29; indazole 1b (119 mg, 0.5 mmol) and 4-methylbenzaldehyde 2b

¹H NMR (400 MHz, chloroform-d) d 10.35 (b, 1H), 7.84 (d, J ¼ (118 mL, 1 mmol) and isolated by column chromatography

8.8 Hz, 1H), 7.74 (dd, J ¼ 8.4 Hz, 0.8 Hz, 1H), 7.51–7.49 (m, 2H), (hexane : EtOAc ¼ 95 : 05) as a yellow oil in 55% yield (91 mg,

1

7.38–7.34 (m, 1H), 7.21–7.17 (m, 1H), 7.03 (s, 1H), 6.96–6.94 (m, 0.26 mmol); R_f(hexane : EtOAc ¼ 85 : 15): 0.40; H NMR (400

3H), 6.33–6.31 (m, 1H), 3.83 (s, 3H); ¹³C NMR (100 MHz, chlo- MHz, chloroform-d) d 7.75 (d, J ¼ 8.4 Hz, 2H), 7.47–7.45 (m, 2H),

roform-d) d 174.34, 159.87, 148.50, 133.85, 132.45, 132.25, 7.39–7.35 (m, 4H), 7.23 (s, 1H), 7.08 (s, 1H), 6.58 (s, 1H), 5.98 (s,

127.24, 126.95, 126.66, 124.31, 123.14, 121.36, 120.80, 118.21, 2H), 2.41 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) d 185.80,

114.29, 111.60, 55.65; HRMS (ESI/QTOF) m/z: calcd for 149.62, 147.86, 146.11, 144.59, 140.49, 135.13, 132.16, 130.03,

C

₁₉H₁₅N₃O₂, 318.1237 [M + H]⁺; found, 318.1233.

129.39, 129.00, 128.34, 125.08, 120.78, 101.40, 95.69, 94.54,

Furan-2-yl(2-(4-methoxyphenyl)-2H-indazol-3-yl)methanone

21.79; HRMS (ESI/QTOF) m/z: calcd for C₂₂H₁₆N₂O₃, 357.1234

(3o). Product 3o was obtained by utilizing the general procedure [M + H]⁺; found, 357.1239.

(Scheme 2) using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

(5-Fluoro-2-phenyl-2H-indazol-3-yl)(p-tolyl)methanone (4b).

0.5 mmol) and furan-2-aldehyde 2o (83 mL, 1 mmol) and isolated Product 4b was obtained by utilizing the general procedure

by column chromatography (hexane : EtOAc ¼ 95 : 05) as (Scheme 3) using 5-uoro-2-phenyl-2H-indazole 1c (106 mg, 0.5

a brown solid in 57% yield (91 mg, 0.28 mmol); mp: 70–72 ^ꢀC; R_fmmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and

(hexane : EtOAc ¼ 85 : 15): 0.29; ¹H NMR (400 MHz, chloro- isolated by column chromatography (hexane : EtOAc ¼ 95 : 05)

form-d) d 7.85 (d, J ¼ 9.6 Hz, 1H), 7.68 (d, J ¼ 8.4 Hz, 1H), 7.60 (b, as an oﬀ-white solid in 71% yield (101 mg, 0.31 mmol); mp: 65–

1

ꢀ

1H), 7.46 (d, J ¼ 8.8 Hz, 2H), 7.40–7.36 (m, 1H), 7.24–7.20 (m, 67 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.51; H NMR (400 MHz,

2H), 6.93 (d, J ¼ 8.8 Hz, 2H), 6.56–6.54 (m, 1H), 3.81 (s, 3H); ¹³

C

chloroform-d) d 7.88–7.84 (m, 1H), 7.78 (d, J ¼ 8.4 Hz, 2H), 7.54–

NMR (100 MHz, chloroform-d) d 178.93, 172.80, 159.93, 152.39, 7.51 (m, 2H), 7.44–7.42 (m, 3H), 7.28 (d, J ¼ 7.6 Hz, 2H), 7.18 (td,

148.49, 147.78, 133.70, 127.06, 126.55, 124.94, 123.70, 121.20, J ¼ 9.2, 2.4 Hz, 1H), 6.97–6.94 (m, 1H), 2.45 (s, 3H); ¹³C NMR

120.42, 118.45, 114.35, 112.79, 55.64; HRMS (ESI/QTOF) m/z: (100 MHz, chloroform-d) d 185.31, 160.09 (J_C-F¼ 243.3 Hz),

calcd for C₁₉H₁₄N₂O₃, 319.1077 [M + H]⁺; found, 319.1073.

145.89, 144.94, 140.39, 134.92, 130.05, 129.51, 129.14, 129.02,

(2-(4-Methoxyphenyl)-2H-indazol-3-yl)(5-methylfuran-2-yl)

125.35, 123.78 (J_C-F¼ 11.9 Hz), 120.77 (J_C-F¼ 9.9 Hz), 118.67 (J_C-F

methanone (3p). Product 3p was obtained by utilizing the ¼ 29.0 Hz), 103.63 (J_C-F¼ 25.5 Hz), 97.22, 21.83.3; HRMS (ESI/

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H- QTOF) m/z: calcd for C₂₁H₁₅FN₂O, 331.1241 [M + H]⁺; found,

indazole 1a (112 mg, 0.5 mmol) and 5-methylfuran-2- 331.1244.

carboxaldehyde 2p (99 mL, 1 mmol) and isolated by column

(5-Methoxy-2-phenyl-2H-indazol-3-yl)(p-tolyl)methanone

chromatography (hexane : EtOAc ¼ 95 : 05) as a brown solid in (4c). Product 4c was obtained by utilizing the general procedure

61% yield (101 mg, 0.30 mmol); mp: 76–78 ^ꢀC; R_f(hex- (Scheme 3) using 5-methoxy-2-phenyl-2H-indazole 1d (112 mg,

1

ane : EtOAc ¼ 85 : 15): 0.24; H NMR (400 MHz, chloroform-d) 0.5 mmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and

d 7.83 (d, J ¼ 9.2 Hz, 1H), 7.72 (d, J ¼ 8.8 Hz, 1H), 7.48 (d, J ¼ isolated by column chromatography (hexane : EtOAc ¼ 95 : 05)

8.8 Hz, 2H), 7.39–7.35 (m, 1H), 7.24–7.19 (m, 1H), 7.12 (dd, J ¼ as a brown solid in 65% yield (111 mg, 0.32 mmol); mp: 140–

1

ꢀ

3.6, 0.7 Hz, 1H), 6.93 (d, J ¼ 8.8 Hz, 2H), 6.17–6.16 (m, 1H), 3.82 142 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.48; H NMR (400 MHz,

(s, 3H), 2.33 (s, 3H); ¹³C NMR (101 MHz, chloroform-d) d 172.24, chloroform-d) d 7.75–7.72 (m, 3H), 7.48–7.46 (m, 2H), 7.36–7.32

159.88, 159.60, 151.18, 148.50, 133.84, 131.85, 127.02, 126.44, (m, 3H), 7.20 (d, J ¼ 7.2 Hz, 2H), 7.07–7.04 (m, 1H), 6.67 (s, 1H),

124.64, 123.63, 120.52, 118.32, 114.31, 109.71, 55.66, 14.18; 3.68 (s, 3H), 2.39 (s, 3H); ¹³C NMR (100 MHz, chloroform-d)

HRMS (ESI/QTOF) m/z: calcd for C₂₀H₁₆N₂O₃, 333.1234 [M + H]⁺; d 185.93, 157.54, 145.56, 144.41, 140.72, 135.32, 131.84, 130.07,

found, 333.1235.

129.29, 129.08, 128.61, 125.39, 125.01, 122.14, 119.92, 97.13,

(5-Bromothiophen-2-yl)(2-(4-methoxyphenyl)-2H-indazol-3-

55.44, 21.84; HRMS (ESI/QTOF) m/z: calcd for C₂₂H₁₈N₂O₂,

yl)methanone (3q). Product 3q was obtained by utilizing the 343.1441 [M + H]⁺; found, 343.1445.

general procedure (Scheme 2) using 2-(4-methoxyphenyl)-2H-

(6-Methyl-2-phenyl-2H-indazol-3-yl)(p-tolyl)methanone (4d).

indazole 1a (112 mg, 0.5 mmol) and 5-bromothiophene-2- Product 4d was obtained by utilizing the general procedure

carboxaldehyde 2q (119 mL, 1 mmol) and isolated by column (Scheme 3) using 6-methyl-2-phenyl-2H-indazole 1e (104 mg, 0.5

chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow solid in mmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and

59% yield (122 mg, 0.29 mmol); mp: 70–72 ^ꢀC; R_f(hex- isolated by column chromatography (hexane : EtOAc ¼ 95 : 05)

1

ane : EtOAc ¼ 85 : 15): 0.34; H NMR (400 MHz, chloroform-d) as a yellow solid in 68% yield (111 mg, 0.34 mmol); mp: 102–

14188 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

1

ꢀ

104 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.44; H NMR (400 MHz, as a yellow semi-solid in 85% yield (142 mg, 0.41 mmol); R_f

chloroform-d) d 7.80 (d, J ¼ 8.4 Hz, 2H), 7.61 (s, 1H), 7.53–7.38 (hexane : EtOAc ¼ 85 : 15): 0.48; ¹H NMR (400 MHz, chloro-

(m, 6H), 7.27–7.25 (m, 2H), 7.00 (d, J ¼ 8.8 Hz, 1H), 2.47 (s, 3H), form-d) d 7.86 (dd, J ¼ 8.8 Hz, 0.8 Hz, 1H), 7.81 (d, J ¼ 8.0 Hz,

2.44 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) d 185.70, 149.13, 2H), 7.52–7.48 (m, 2H), 7.41 (d, J ¼ 8.8 Hz, 2H), 7.38–7.33 (m,

144.67, 140.56, 136.99, 135.24, 132.28, 130.18, 129.35, 129.04, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.19–7.15 (m, 1H), 2.46 (s, 3H); ¹³

C

128.71, 127.75, 125.43, 122.38, 120.14, 116.69, 22.08, 21.80; NMR (100 MHz, chloroform-d) d 185.59, 148.70, 145.14, 139.10,

HRMS (ESI/QTOF) m/z: calcd for C₂₂H₁₈N₂O, 327.1492 [M + H]⁺; 135.13, 134.90, 132.54, 130.30, 129.58, 129.35, 127.29, 126.74,

found, 327.1494.

(5-Chloro-2-phenyl-2H-indazol-3-yl)(p-tolyl)methanone (4e). calcd for C₂₁H₁₅ClN₂O, 347.0946 [M + H]⁺; found, 347.0942.

Product 4e was obtained by utilizing the general procedure (2-(5-Methylpyridin-2-yl)-2H-indazol-3-yl)(p-tolyl)methanone

125.12, 123.97, 120.72, 118.55, 21.93; HRMS (ESI/QTOF) m/z:

(Scheme 3) using 5-chloro-2-phenyl-2H-indazole 1f (114 mg, 0.5 (4i). Product 4i was obtained by utilizing the general procedure

mmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and (Scheme 3) using 2-(5-methylpyridin-2-yl)-2H-indazole 1j

isolated by column chromatography (hexane : EtOAc ¼ 95 : 05) (105 mg, 0.5 mmol) and 4-methylbenzaldehyde 2b (118 mL, 1

as a yellow solid in 78% yield (134 mg, 0.39 mmol); mp: 158– mmol) and isolated by column chromatography (hex-

1

ꢀ

160 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.50; H NMR (400 MHz, ane : EtOAc ¼ 95 : 05) as a yellow solid in 72% yield (118 mg,

chloroform-d) d 7.81 (dd, J ¼ 9.2 Hz, 0.8 Hz, 1H), 7.76 (d, J ¼ 0.36 mmol); mp: 130–132 ^ꢀC; R_f(hexane : EtOAc ¼ 85 : 15): 0.34;

8.4 Hz, 2H), 7.52–7.50 (m, 2H), 7.42–7.37 (m, 4H), 7.32–7.26 (m, ¹H NMR (400 MHz, chloroform-d) d 8.08 (s, 1H), 7.91 (d, J ¼

3H), 2.26 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) d 185.29, 8.0 Hz, 1H), 7.83 (d, J ¼ 8.8 Hz, 1H), 7.79 (d, J ¼ 8.0 Hz, 2H),

146.83, 145.14, 140.22, 134.78, 132.19, 130.71, 130.11, 129.55, 7.69–7.66 (m, 1H), 7.43 (d, J ¼ 8.8 Hz, 1H), 7.38–7.34 (m, 1H),

129.16, 129.09, 128.54, 125.33, 124.19, 120.00, 119.36, 21.85; 7.24 (d, J ¼ 7.6 Hz, 2H), 7.15–7.11 (m, 1H), 2.42 (s, 3H), 2.32 (s,

HRMS (ESI/QTOF) m/z: calcd for C₂₁H₁₅ClN₂O, 347.0946 [M + 3H); ¹³C NMR (100 MHz, chloroform-d) d 186.88, 149.95, 148.92,

H]⁺; found, 347.0947.

148.30, 144.37, 139.19, 135.40, 133.35, 132.60, 129.95, 129.39,

127.60, 124.43, 123.49, 120.67, 118.40, 116.99, 21.86, 18.10;

(2-(4-Methoxyphenyl)-2H-[1,3]dioxolo[4,5-f]indazol-3-yl)(p-

tolyl)methanone (4f). Product 4f was obtained by utilizing the HRMS (ESI/QTOF) m/z: calcd for C₂₁H₁₇N₃O, 328.1445 [M + H]⁺;

general procedure (Scheme 3) using 2-(4-methoxyphenyl)-2H- found, 328.1449.

[1,3]dioxolo[4,5-f]indazole 1g (134 mg, 0.5 mmol) and 4-meth-

(2-(5-Chloropyridin-2-yl)-2H-indazol-3-yl)(p-tolyl)methanone

ylbenzaldehyde 2b (118 mL, 1 mmol) and isolated by column (4j). Product 4j was obtained by utilizing the general procedure

chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow oil in (Scheme 3) using 2-(5-chloropyridin-2-yl)-2H-indazole 1k

58% yield (112 mg, 0.29 mmol); R_f(hexane : EtOAc ¼ 85 : 15): (115 mg, 0.5 mmol) and 4-methylbenzaldehyde 2b (118 mL, 1

0.40; ¹H NMR (400 MHz, chloroform-d) d 7.75 (d, J ¼ 8.4 Hz, 2H), mmol) and isolated by column chromatography (hex-

7.39 (dd, J ¼ 6.8 Hz, 2.0 Hz, 2H), 7.26 (s, 2H), 7.09 (s, 1H), 6.90 ane : EtOAc ¼ 95 : 05) as a white solid in 71% yield (124 mg,

(dd, J ¼ 6.8 Hz, 2.0 Hz, 2H), 6.56 (s, 1H), 5.99 (s, 2H), 3.81 (s, 3H), 0.35 mmol); mp: 104–106 ^ꢀC; R_f(hexane : EtOAc ¼ 85 : 15): 0.38;

2.44 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) d 185.62, 159.25, ¹H NMR (400 MHz, chloroform-d) d 8.18–8.17 (m, 1H), 8.03–8.00

149.25, 147.49, 145.60, 144.32, 135.00, 133.54, 131.87, 129.82, (m, 1H), 7.85–7.75 (m, 4H), 7.42–7.34 (m, 2H), 7.24 (d, J ¼

129.17, 126.08, 120.30, 113.95, 101.14, 95.52, 94.31, 55.31, 8.8 Hz, 2H), 7.14–7.10 (m, 1H), 2.41 (s, 3H); ¹³C NMR (100 MHz,

21.58; HRMS (ESI/QTOF) m/z: calcd for C₂₃H₁₈N₂O₄, 387.1340 chloroform-d) d 186.65, 150.10, 149.12, 146.77, 144.62, 138.41,

[M + H]⁺; found, 387.1346.

135.09, 132.81, 131.34, 129.85, 129.42, 127.98, 124.70, 123.56,

p-Tolyl(2-(p-tolyl)-2H-indazol-3-yl)methanone (4g). Product 120.59, 118.33, 118.07, 21.80; HRMS (ESI/QTOF) m/z: calcd for

4g was obtained by utilizing the general procedure (Scheme 3)

using 2-(p-tolyl)-2H-indazole 1h (104 mg, 0.5 mmol) and 4-

C

₂₀H₁₄ClN₃O, 348.0898 [M + H]⁺; found, 348.0895.

(2-(Pyridin-2-yl)-2H-indazol-3-yl)(p-tolyl)methanone

(4k).

methylbenzaldehyde 2b (118 mL, 1 mmol) and isolated by Product 4k was obtained by utilizing the general procedure

column chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow (Scheme 3) using 2-(pyridin-2-yl)-2H-indazole 1l (98 mg, 0.5

solid in 79% yield (129 mg, 0.40 mmol); mp: 167–169 ^ꢀC; R_fmmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and

(hexane : EtOAc ¼ 85 : 15): 0.48; ¹H NMR (400 MHz, chloro- isolated by column chromatography (hexane : EtOAc ¼ 95 : 05)

form-d) d 7.87 (dd, J ¼ 8.4 Hz, 0.8 Hz, 1H), 7.81 (d, J ¼ 8.0 Hz, as a yellow solid in 82% yield (131 mg, 0.42 mmol); mp: 98–

1

ꢀ

2H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.35 (t, J ¼ 8.4 Hz, 2H), 7.27 (d, J ¼ 100 C; R_f(hexane : EtOAc ¼ 85 : 15): 0.33; H NMR (400 MHz,

8.0 Hz, 2H), 7.22 (d, J ¼ 8.4 Hz, 2H), 7.16–7.13 (m, 1H), 2.44 (s, chloroform-d) d 8.25–8.23 (m, 1H), 8.06–8.04 (m, 1H), 7.89–7.82

3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) d 185.71, (m, 2H), 7.77 (d, J ¼ 8.4 Hz, 2H), 7.46 (d, J ¼ 8.8 Hz, 1H), 7.40–

148.38, 144.72, 138.94, 138.08, 135.22, 132.33, 130.21, 129.67, 7.35 (m, 1H), 7.23–7.21 (m 3H), 7.16–7.12 (m, 1H), 2.40 (s, 3H);

129.37, 126.81, 125.17, 124.62, 123.79, 120.59, 118.41, 21.80, ¹³C NMR (100 MHz, chloroform-d) d 186.81, 151.87, 149.01,

21.19; HRMS (ESI/QTOF) m/z: calcd for C₂₂H₁₈N₂O, 327.1492 [M 148.04, 144.29, 138.64, 135.30, 132.73, 129.78, 129.30, 127.74,

+ H]⁺; found, 327.1495.

124.47, 123.50, 123.28, 120.62, 118.35, 117.33, 21.76; HRMS

(2-(4-Chlorophenyl)-2H-indazol-3-yl)(p-tolyl)methanone

(ESI/QTOF) m/z: calcd for C₂₀H₁₅N₃O, 31.1288 [M + H]⁺; found,

(4h). Product 4h was obtained by utilizing the general procedure 314.1286.

(Scheme 3) using 2-(4-chlorophenyl)-2H-indazole 1i (114 mg, 0.5

Phenyl(2-phenyl-2H-indazol-3-yl)methanone (4l). Product 4l

mmol) and 4-methylbenzaldehyde 2b (118 mL, 1 mmol) and was obtained by utilizing the general procedure (Scheme 3)

isolated by column chromatography (hexane : EtOAc ¼ 95 : 05) using 2-phenyl-2H-indazole 1m (97 mg, 0.5 mmol) and

RSC Adv., 2021, 11, 14178–14192 | 14189

View Article Online

RSC Advances

Paper

benzaldehyde 2a (118 mL, 1 mmol) and isolated by column J ¼ 2.8 Hz, 1H), 7.09 (dd, J ¼ 9.2, 2.8 Hz, 1H), 3.89 (s, 3H); ¹³C

chromatography (hexane : EtOAc ¼ 95 : 05) as a yellow solid in NMR (100 MHz, chloroform-d) d 183.27, 159.12, 148.62, 139.52,

80% yield (119 mg, 0.40 mmol); mp: 125–127 ^ꢀC; R_f(hex- 138.11, 134.80, 132.75, 131.61, 130.70, 130.17, 129.16, 128.72,

1

ane : EtOAc ¼ 85 : 15): 0.42; H NMR (400 MHz, chloroform-d) 127.93, 127.60, 125.89, 123.69, 121.09, 118.05, 116.36, 115.47,

d 7.89–7.85 (m, 3H), 7.62–7.57 (m, 1H), 7.55–7.52 (m, 2H), 7.47– 55.84; HRMS (ESI/QTOF) m/z: calcd for C₂₁H₁₄N₂O₂, 327.1128

7.35 (m, 7H), 7.19–7.15 (m, 1H); ¹³C NMR (100 MHz, chloro- [M + H]⁺; found, 327.1126.

form-d) d 186.07, 148.66, 140.58, 137.90, 133.67, 132.35, 130.00,

129.18, 129.03, 128.74, 127.12, 125.63, 125.12, 124.16, 120.68,

118.63; HRMS (ESI/QTOF) m/z: calcd for C₂₀H₁₄N₂O, 299.1179

[M + H]⁺; found, 299.1176.

General procedure for the synthesis of 14

To a solution of 3a (0.29 mmol; 1.0 equiv.) in methanol (10–15

mL) was added NaBH₄(0.58 mmol; 2.0 equiv.) portionwise at

room temperature and the reaction was stirred at the same

temperature for 1 h. Aer completion of the reaction monitored

General procedure for the synthesis of 11

The starting substrate 1p was synthesized using the reported by TLC, the solvent was evaporated under reduced pressure and

procedure¹⁵and was reacted with m-acetoxybenzaldehyde 2r the crude solid product was extracted with ethyl acetate (3 ꢁ 20

under the optimized reaction conditions to aﬀord 10. In the mL) and water (10 mL). The combined organic layers were dried

reaction vessel, 2-(3-methoxyphenyl)-2H-indazole (1p, 112 mg, 0.5 over anhydrous Na₂SO₄, ltered, and concentrated under

mmol) was charged with m-acetoxybenzaldehyde (2r, 164 mg, 1 reduced pressure to get the crude residue which was further

mmol) and TBPB (238 mL, 1.25 mmol) dissolved in chloroben- puried through column chromatography on silica gel (100–200

zene. The reaction mixture was then stirred under N₂atmosphere mesh) using hexane : ethyl acetate (80 : 20 ratio) as an eluent to

at 110 ^ꢀC for 24 h. Aer completion of the reaction, the reaction aﬀord the corresponding product 14 as a white solid in 90%

mixture was cooled and the work-up was done with a saturated yield.

solution of NaHCO₃(10 mL) and ethyl acetate (3 ꢁ 20 mL). The

(2-(4-Methoxyphenyl)-2H-indazol-3-yl)(p-tolyl)methanol (14).

combined organic layers were dried over anhydrous Na₂SO₄, Product 14 was obtained by utilizing the general procedure and

ltered, and concentrated under reduced pressure to get the isolated by column chromatography (hexane : EtOH ¼ 80 : 20)

crude residue which was further puried through column chro- as a white solid in 90% yield (90 mg, 0.26 mmol); mp: 106–

1

matography on silica gel (100–200 mesh) using hexane : ethyl 108 ^ꢀC; R_f(hexane : EtOH ¼ 70 : 30): 0.3; H NMR (400 MHz,

acetate (95 : 5 ratio) as an eluent to aﬀord the corresponding chloroform-d) d 7.51 (d, J ¼ 9.2 Hz, 1H), 7.39 (d, J ¼ 9.2 Hz, 1H),

product 10 which upon deprotection under basic conditions 7.15–7.09 (m, 3H), 7.04 (d, J ¼ 8.4 Hz, 2H), 6.98 (d, J ¼ 8.0 Hz,

furnished the desire product 11 (anti-inammatory agent).

(3-Hydroxyphenyl)(2-(3-methoxyphenyl)-2H-indazol-3-yl)

2H), 6.87–6.83 (m, 1H), 6.69 (d, J ¼ 8.8 Hz, 2H), 5.93 (s, 1H), 3.69

(s, 3H), 2.22 (s, 3H); ¹³C NMR (101 MHz, chloroform-d) d 159.98,

methanone (11). Product 11 was obtained by utilizing the 148.56, 138.37, 137.65, 137.54, 132.49, 129.26, 127.48, 126.69,

general procedure and isolated by column chromatography 126.47, 121.84, 121.40, 120.39, 117.40, 114.16, 68.75, 55.62,

(hexane : EtOAc ¼ 95 : 05) as a white solid in 51% yield (87 mg, 21.25; HRMS (ESI/QTOF) m/z: calcd for C₂₂H₂₀N₂O₂, 345.1598

1

0.25 mmol); R_f(hexane : EtOAc ¼ 85 : 15): 0.20; H NMR (400 [M + H]⁺; found, 345.1596.

MHz, DMSO-d₆) d 9.84 (s, 1H), 7.84 (d, J ¼ 8.8 Hz, 1H), 7.40–7.17

(m, 6H), 7.13 (t, J ¼ 2.4 Hz, 1H), 7.11–7.09 (m, 1H), 7.04–6.96 (m,

General procedure for the competition reaction

3H), 3.72 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) d 186.09,

A mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5

160.00, 158.10, 148.30, 141.66, 139.09, 132.77, 130.49, 127.70,

mmol), 4-methoxybenzaldehyde 2c (61 mL, 0.5 mmol) and 4-

125.58, 123.85, 121.48, 121.08, 120.75, 118.74, 118.22, 116.01,

uorobenzaldehyde 2e (53 mL, 0.5 mmol) and TBPB (238 mL,

115.27, 111.66, 56.02; HRMS (ESI/QTOF) m/z: calcd for

1.25 mmol) was taken in a sealed reaction tube under nitrogen

C

₂₁H₁₆N₂O₃, 345.1234 [M + H]⁺; found, 345.1236.

atmosphere. Then, the reaction mixture was stirred at 110 ^ꢀC for

24 h. Aer completion of the reaction, the reaction mixture was

cooled and the work-up was done with a saturated solution of

General procedure for the synthesis of 13

The starting material 12 was synthesized by utilizing our NaHCO₃(10 mL) and ethyl acetate (3 ꢁ 20 mL). The combined

general procedure which on subjection to Pd-catalyzed direct organic layers were dried over anhydrous Na₂SO₄, ltered, and

biaryl coupling using the reported procedure¹⁶aﬀorded a new concentrated under reduced pressure to get the crude residue

class of bio-azaheterocycles, i.e., 3-methoxy-9H-dibenzo[4,5:6,7] which was further puried through column chromatography on

azepino[1,2-b]indazol-9-one (indazole-fused diazepine).

3-Methoxy-9H-dibenzo[4,5:6,7]azepino[1,2-b]indazol-9-one

silica gel (100–200 mesh) using hexane : ethyl acetate (95 : 5

ratio) as an eluent to aﬀord the corresponding product 3c in

(13). Product 13 was obtained by utilizing the general procedure 56% (101 mg, 0.28 mmol as a yellow solid) and 3e in 30%

and isolated by column chromatography (hexane : DCM ¼ (52 mg, 0.15 mmol as a yellow solid) yields, respectively. Simi-

90 : 10) as a yellow solid in 75% yield (123 mg, 0.37 mmol); mp: larly, a mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg,

108–110 ^ꢀC; R_f(hexane : DCM ¼ 50 : 50): 0.5; ¹H NMR (400 0.5 mmol), 4-methylbenzaldehyde 2a (59 mL, 0.5 mmol) and

MHz, chloroform-d) d 8.14–8.09 (m, 2H), 8.05–8.03 (m, 1H), 7.82 acetaldehyde 2j (28 mL, 0.5 mmol) and TBPB (238 mL, 1.25

(d, J ¼ 8.8 Hz, 1H), 7.77 (d, J ¼ 7.6 Hz, 1H), 7.66–7.62 (m, 1H), mmol) was taken in a sealed reaction tube under nitrogen

7.55–7.51 (m, 1H), 7.41–7.37 (m, 1H), 7.31–7.27 (m, 1H), 7.19 (d, atmosphere. Then the reaction mixture was stirred at 110 ^ꢀC for

14190 | RSC Adv., 2021, 11, 14178–14192

View Article Online

Paper

RSC Advances

24 h. Aer work-up, the crude residue was further puried

through column chromatography on silica gel (100–200 mesh)

using hexane : ethyl acetate (95 : 5 ratio) as an eluent to aﬀord

the corresponding product 3a in 55% (94 mg, 0.27 mmol as

a yellow solid) and 3j in 29% (39 mg, 0.14 mmol as a yellow

solid) yields, respectively.

2 (a) C. N. Sternberg, I. D. Davis, J. Mardiak, C. Szczylik, E. Lee,

J. Wagstaﬀ, C. H. Barrios, P. Salman, O. A. Gladkov,

´

A. Kavina, J. J. Zarba, M. Chen, L. McCann, L. Pandite,

D. F. Roychowdhury and R. E. Hawkins, J. Clin. Oncol.,

2010, 28, 1061–1068; (b) P. Jones, S. Altamura, J. Boueres,

F. Ferrigno, M. Fonsi, C. Giomini, S. Lamartina,

E. Monteagudo, J. M. Ontoria, M. V. Orsale, M. C. Palumbi,

S. Pesci, G. Roscilli, R. Scarpelli, C. Schultz- Fademrecht,

C. Toniatti and M. Rowley, J. Med. Chem., 2009, 52, 7170–

7185; (c) A. Floridi, M. G. Paggi, M. L. Marcante,

B. Silvestrini, A. Caputo and C. D. Martino, J. Natl. Cancer

Inst., 1981, 66, 497; (d) H. Shen, S. Gou, J. Shen, Y. Zhu,

Y. Zhang and X. Chen, Bioorg. Med. Chem. Lett., 2010, 20,

2115; (e) L. A. Clutterbuck, C. G. Posada, C. Visintin,

D. R. Riddal, B. Lancaster, P. J. Gane, J. Garthwaite and

D. L. Selwood, J. Med. Chem., 2009, 52, 2694; (f) D. Szymon,

B. Marta, P. Arkadiusz, P. Michał, F. Michał, W. Maria,

D. Anna, S. Sebastian, T. Adam and K. Marcin, Int. J.

Synthetic procedure for performing the control experiment

A mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5

mmol), 4-methylbenzaldehyde 2a (118 mL, 1 mmol) and TBPB

(238 mL, 1.25 mmol) and TEMPO (195 mg, 1.25 mmol) was taken

in a sealed reaction tube under nitrogen atmosphere. Then, the

reaction mixture was stirred at 110 ^ꢀC for 24 h. Aer completion

of the reaction, the reaction mixture was cooled and the work-

up was done with a saturated solution of NaHCO₃(10 mL)

and ethyl acetate (3 ꢁ 20 mL). The combined organic layers

were dried over anhydrous Na₂SO₄, ltered, and concentrated

under reduced pressure to get the crude residue which was

further puried through column chromatography on silica gel

(100–200 mesh) using hexane : ethyl acetate (95 : 5 ratio) as an

eluent to aﬀord the TEMPO trapped acyl adduct (7) as a viscous

liquid. TLC observation showed that there was no formation of

3a in the TEMPO-assisted reaction. The intermediate, i.e.

benzoyl free radical, was trapped with TEMPO to aﬀord the

TEMPO-acyl adduct 7.

´

Cardiol., 2018, 269, 283; (g) M. C. Vega, M. Rolon,

A. Montero-Torres, C. Fonseca-Berzal, J. A. Escario,

´

A. Gomez-Barrio, J. Galvez, Y. Marrero-Ponce and

´

V. J. Aran, Eur. J. Med. Chem., 2012, 58, 214; (h)

A. Tanitame, Y. Oyamada, K. Ofuji, Y. Kyoya, K. Suzuki,

H. Ito, M. Kawasaki, K. Nagai, M. Wachi and J. Yamagishi,

Bioorg. Med. Chem. Lett., 2004, 14, 2857; (i) W. Han,

J. C. Pelletier and C. N. Hodge, Bioorg. Med. Chem. Lett.,

1998, 8, 3615.

2,2,6,6-Tetramethylpiperidin-1-yl

4-methylbenzo-ate

7.

Product 7 was obtained in 71% yield as a viscous liquid; R_f

3 (a) A. Thangadurai, M. Minu, S. Wakode, S. Agrawal and

B. Narasimhan, Med. Chem. Res., 2012, 21, 1509; (b)

I. Denya, S. F. Malan and J. Joubert, Expert Opin. Ther. Pat.,

2018, 28, 441; (c) H. Cerecetto, A. Gerpe, M. Gonzalez,

V. Aran and C. de Ocariz, Mini-Rev. Med. Chem., 2005, 5,

869; (d) J. Dong, Q. Zhang, Z. Wang, G. Huang and S. Li,

ChemMedChem, 2018, 13, 1490; (e) F.-Y. Lee, J.-C. Lien,

L.-J. Huang, T.-M. Huang, S.-C. Tsai, C.-M. Teng, C.-C. Wu,

F.-C. Cheng and S.-C. Kuo, J. Med. Chem., 2001, 44, 3746;

(f) Y. Ikeda, N. Takano, H. Matsushita, Y. Shiraki, T. Koide,

R. Nagashima, Y. Fujimura, M. Shindo, S. Suzuki and

T. Iwasaki, Arzneim. Forsch., 1979, 29, 511; (g) S.-G. Zhang,

C.-G. Liang and W.-H. Zhang, Molecules, 2018, 23, 2783.

4 (a) L. Yadav and S. Chaudhary, Org. Biomol. Chem., 2020, 18,

5927–5936; (b) S. Ghosh, S. Mondal and A. Hajra, Adv. Synth.

Catal., 2020, 362, 3768–3794.

1

(hexane : ethyl acetate ¼ 85 : 15) 0.5; H NMR (400 MHz, chlo-

roform-d) d 7.93 (d, J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 8.0 Hz, 2H), 2.37

(s, 3H), 1.77–1.63 (m, 3H), 1.55–1.52 (m, 2H), 1.43–1.40 (m, 1H),

1.23 (s, 6H), 1.08 (s, 6H); ¹³C NMR (100 MHz, chloroform-d)

d 166.50, 143.56, 129.66, 129.22, 128.52, 126.98, 60.40, 39.11,

32.03, 25.43, 21.72, 20.91, 17.08; HRMS (ESI/QTOF) m/z: calcd

for C₁₇H₂₅NO₂, 276.1958 [M + H]⁺; found, 276.1955.

Conﬂicts of interest

The author declares no competing nancial interest.

Acknowledgements

S. C. acknowledges DST-NRF Indo-South Africa Joint research

project [DST/INT/South Africa/P-19/2016]. R. S. acknowledges

MNIT Jaipur for providing an institute fellowship. L. Y. and R. K.

Y. thanks DST, New Delhi and UGC, New Delhi for providing

nancial assistance in the form of a senior research fellowship.

Materials Research Centre (MRC), MNIT Jaipur is gratefully

acknowledged for providing analytical facilities.

5 H. Oh, S. Han, A. K. Pandey, S. H. Han, N. K. Mishra, S. Kim,

R. Chun, H. S. Kim, J. Park and I. S. Kim, J. Org. Chem., 2018,

83, 4070–4077.

6 G. Bogonda, H. Y. Kim and K. Oh, Org. Lett., 2018, 9, 2711–

2715.

7 Y.-L. Liu, Y.-L. Pan, G.-J. Li, H.-F. Xu and J.-Z. Chen, Org.

Biomol. Chem., 2019, 17, 8749–8755.

8 L. Liu, P. Jiang, Y. Liu, H. Du and J. Tan, Org. Chem. Front.,

2020, 7, 2278–2283.

Notes and references

9 (a) R. Chen, J. Chen, J. Zhang and X. Wan, Chem. Rec., 2018,

18, 1292; (b) S. Rajamanickam, G. Majji, S. K. Santra and

B. K. Patel, Org. Lett., 2015, 17, 5586; (c) G. Majji,

S. Rajamanickam, N. Khatun, S. K. Santra and B. K. Patel,

J. Org. Chem., 2015, 80, 3440; (d) A. Gogoi, A. Modi,

1 (a) C.-Y. Huang, H. Kang, J. Li and C.-J. Li, J. Org. Chem.,

2019, 84, 12705–12721; (b) S. Girard, T. Knauber and

C. -J. Li, Angew. Chem., Int. Ed., 2014, 53, 74–100; (c)

C.-J. Li, Acc. Chem. Res., 2009, 42, 335–344.

RSC Adv., 2021, 11, 14178–14192 | 14191

View Article Online

RSC Advances

Paper

S. Guin, S. K. Rout, D. Das and B. K. Patel, Chem. Commun.,

2014, 50, 10445; (e) X.-F. Wu, J.-L. Gonga and X. Qia, Org.

H. Zhang, Z. Gu, P. Xu, H. Hu, Y. Chenga and C. Zhu,

Chem. Commun., 2016, 52, 477–480.

Biomol. Chem., 2014, 12, 5807; (f) Y. Siddaraju and 12 R. J. Steﬀan, E. M. Matelan, [(1H-Indazol-3-ly)Methyl]

K. R. Prabhu, Tetrahedron, 2016, 72, 959–967.

Phenols

and

(Hydroxyphenyl),

(1H-Indazol-3-yl)

10 (a) N. Khatun, A. Banerjee, S. K. Santra, A. Behera and

Methanones, WO Pat., 2006050006, 2006.

B. K. Patel, RSC Adv., 2014, 4, 54532; (b) S. K. Rout, 13 A. H. Shinde, S. Vidyacharan and D. S. Sharada, Org. Biomol.

S. Guin, A. Gogoi, G. Majji and B. K. Patel, Org. Lett., 2014,

16, 1614.

11 (a) J.-J. Cao, T.-H. Zhu, S.-Y. Wang, Z.-Y. Gu, X. Wang and

Chem., 2016, 14, 3207–3211.

14 M. R. Kumar, A. Park, N. Park and S. Lee, Org. Lett., 2011, 13,

3542–3545.

S.-J. Ji, Chem. Commun., 2014, 50, 6439–6442; (b) 15 N. E. Genung, L. Wei and G. E. Aspnes, Org. Lett., 2014, 16,

S.-L. Zhou, L.-N. Guo, H. Wang and X.-H. Duan, Chem.– 3114–3117.

Eur. J., 2013, 19, 12970–12973; (c) T. He, H. Li, P. Li and 16 A. P. Kozikowski and D. Ma, Tetrahedron Lett., 1991, 32,

L. Wang, Chem. Commun., 2011, 47, 8946–8948; (d)

3317–3320.

14192 | RSC Adv., 2021, 11, 14178–14192

Article Doi

Oxidative cross-dehydrogenative coupling (CDC)viaC(sp2)-H bond functionalization:tert-butyl peroxybenzoate (TBPB)-promoted regioselective direct C-3 acylation/benzoylation of 2H-indazoles with aldehydes/benzyl alcohols/styrenes

DOI: 10.1039/d1ra02225c

Source and publish data:

Authors:

Article abstract of DOI:10.1039/d1ra02225c

Full text of DOI:10.1039/d1ra02225c

Products guided by the article

R&D Labs maybe for 128651-80-9

Relevant to this article

Synthesis of new [(2S)-N-(p-Tolylsulfonyl)-2-Pyrrolidinyl]Propyl 2,3,4-Tri-O-Acetyl- and 2,3,4-Tri-O-Benzyl-β-L-Fucopyranosides

SYNTHESIS OF (+)-8a,9-SECOARTEMISININ AND RELATED ANALOGS

Total syntheses of penicillanic acid s,s-dioxide and 6-aminopenicillanic acid using(benzyloxy)nitromethane

First asymmetric total synthesis of (R,E)-1-[4-(3-hydroxyprop-1-enyl) phenoxyl]-3-methylbutane-2,3-diol

Oxidative burst inhibitory and cytotoxic amides and lignans from the stem bark of Fagara heitzii (Rutaceae)

Electrophile-driven regioselective synthesis of functionalized quinolines