Bu4NI-catalyzed, oxidative C(sp2)-C(sp3)cross dehydrogenative coupling for the regioselective direct C-3 benzylation of 2: H -indazoles

Article abstract of DOI:10.1039/d0ob01282c

A Bu4NI-catalyzed, DTBP-promoted, regioselective C(sp2)-C(sp3) cross dehydrogenative coupling (CDC) protocol for the direct C-3 benzylation of 2H-indazoles is reported. The metal-free protocol is operationally simple and proceeds mechanistically via the g

Full text of DOI:10.1039/d0ob01282c

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DOI: 10.1039/D0OB01282C
ARTICLE
Bu4NI-catalyzed, Oxidative C(sp2)–C(sp ) Cross Dehydrogenative
Coupling for the Regioselective Direct C-3 Benzylation of 2H-
Indazoles
3
Received 00th January 20xx,
Accepted 00th January 20xx
Lalit Yadava and Sandeep Chaudharya*
DOI: 10.1039/x0xx00000x
3
A Bu4NI-Catalyzed, DTBP-promoted, regioselective C(sp2)–C(sp cross dehydrogenative coupling (CDC) protocol for the
)
direct C-3 benzylation of 2H-indazoles is reported. The metal-free protocol is operationally simple and proceeds
mechanistically via the generation of stable benzylic free-radical followed by regioselective addition at the C-3 position
of 2H-indazoles which afforded C–3 benzylated 2H-indazoles upto 87% yields. The methodology showed a varied array
of functional group tolerance and wide substrate compatibility. The gram-scale synthesis further highlights the
importance and versatile nature of this methodology.
Figure 1. Some representative examples of pharmaceutically
Introduction
important benzylated indazoles I-VIII.
Due to its pharmaceutical significance, the development of a
direct synthetic route for the introduction of the benzyl group
Indazole, an isostere of indole or purine, moiety is present in
several pharmaceutical privileged natural products, synthetic
therapeutic agents/drugs that are endowed with a wide range
of biological activities such as antitumor,1a antimicrobial,1b
anti-inflammatory,1c anticancer,1d HIV-protease inhibition,1e
anti-depressant,1f antiplatelet1g, etc. In particular, benzylated
into the 2H-indazole moiety is
a challenging area of
investigation. It becomes more significant if it proceeds
through a metal-free approach. Few transition metal-catalyzed
C(sp2)–H bond activation at regioselective C–3 position of 2H-
indazoles have been reported;3a-e However, there is no report
for the direct C–3 benzylation of 2H-indazoles either with
metal or metal-free catalysis. Contrary to the concept of direct
C–3 benzylation of 2H-indazoles, only one Pd-catalyzed report
is available in the literature for the synthesis of C–3 benzylated
2-substituted phenyl 2H-indazoles via the reaction of
phenylhydrazines with 2-halophenylacetylenes.4
indazoles
which have potential therapeutic applications for the
treatment of several ailments such as anticancer2a-c
pazopanib, MK-4827, lonidamine VI), neuroprotective sodium
channel modulator2e II), antichagasic2g III), antihypertensive2f
), non-steroid anti-
I-VIII are pharmaceutically important molecules
(I,
(
(
(riociguat IV), antibacterial2h
(V
inflammatory drug2d (bendazac VII), anti-HIV agent2i (VIII), etc.
Scheme 1. Our work: Bu4NI-catalyzed, DTBP-promoted
approach to regioselective C–3 benzylation of 2-aryl-2H-
indazoles.
Cross-dehydrogenative coupling (CDC) has been recognized as an
inimitable synthetic strategy to construct C–C bond formation in
natural and synthetic scaffolds due to its association with several
advantages such as step-/atom-economy, cost-effective, high yield,
less waste, product selectivity, energy, and resource competence,
operational ease, etc.5 Herein, we report the identification of
[a] L. Yadav, S. Chaudhary
a.Laboratory of Organic and Medicinal Chemistry (OMC lab), Department of
Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg,
Jaipur-302017, India;
tetra-n-butylammonium iodide (TBAI) as
a commercially
available homogeneous catalyst, which catalyzes DTBP-
promoted, regioselective direct C-3 benzylation of 2-aryl-2H-
indazoles via C(sp2)–H/C(sp3)–H cross dehydrogenative coupling
at 120 °C for 24 h which furnished 3-benzylated-2-aryl-2H–
indazoles in up to 89% yields, with a broad range of functional
b.Fax: 911412529029; Tel: 911412713319; https://orcid.org/0000-0002-1444-
3895;
c.
E-mail: schaudhary.chy@mnit.ac.in
d.Electronic Supplementary Information (ESI) available: Characterization data, 1
NMR and 13C NMR spectra.
H
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°C, 24 h, bTBAI 40 mol% used, cTBAI 10 mol % used, dDTBP (5.0 Equiv), eDTBP (3.0
group tolerance and wide substrate compatibility [Scheme 1].
To the best of our knowledge, this is the first account of a
Bu4NI-catalyzed, oxidant-promoted C(sp2)–H/C(sp3)–H cross
dehydrogenative coupling protocol for the regioselective direct
C-3 benzylation of 2-aryl-2H-indazoles.
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equiv), ftoluene (6.0 equiv.) and benzene (0.5 mL), gtoluene (6.0 equiv.) and
DOI: 10.1039/D0OB01282C
Dichloroethane (0.5 mL) used, hreaction was carried out without N2 atmosphere.
Since TBHP had already been established as a promising
oxidant in the cross-dehydrogenative coupling reactions;6 we
selected it as an oxidant either alone or in combination with
well-known radical accelerator TBAI as a catalyst in our initial
investigations. Therefore, we carried out a reaction with 1a
and 2a in the presence of TBHP (4 equiv.) at 120 °C for 24 h.
However, the desired product 3a was not obtained at all (Table
1, entry 1). Keeping all the reaction conditions same as taken
in entry no. 1, the addition of a catalytic amount of TBAI (20
mol %) as a catalyst also didn’t furnish 3a (Table 1, entry 2).
Subsequently, in combination with radical initiator TBAI (20
mol%), we screened several other organic oxidants such as
lauryl peroxide, tert-butyl-peroxybenzoate (DTPB), dicumyl
peroxide, cumene hydroperoxide, di-tert-butyl peroxide
(DTBP), and some inorganic oxidants such as oxone, K2S2O8,
(NH4)2S2O8, etc. or even oxygen (O2) balloon (Table 1, entries
3–11). Intriguingly, only dicumyl peroxide and DTBP
successfully furnished 3a in 68% and 86% yield, respectively,
keeping the same reaction conditions (Table 1, entry 5 and 7).
To further check the significance of the catalyst as a radical
accelerator; a control experiment was conducted in the
absence of TBAI which furnished 3a in 40% yield only (Table 1,
entry 12). Once DTBP was identified as an optimized oxidant
for our reaction, further screening of various organic ionic
liquids such as tetramethylammonium iodide (TMAI),
tetrabutylammonium bromide (TBAB), tetrabutylammonium
tribromide and 1,3-dimesitylimidazolium chloride were carried
out for the optimization of the efficient catalyst (Table 1, entry
Results and discussion
We commenced our optimization study by investigating the
3
direct C(sp2)–C(sp coupling via taking 2-(4-methoxyphenyl)-2H-
)
indazole 1a and toluene 2a as the starting substrate (Table 1).
Table 1: Optimization Study:a
Oxidant
Catalyst
(20 mol %)
Temp Time Yield
Entry
(4.0
equiv.)
TBHP
(℃
)
(h)
(%)
1.
2.
------
TBAI
120
120
24
24
0
0
TBHP
Lauryl
peroxide
DTPB
Dicumyl
peroxide
Cumene
hydropero
xide
3
TBAI
TBAI
TBAI
120
120
120
24
24
0
0
4.
5.
68
6.
TBAI
120
24
0
7.
8.
9.
10.
11.
12.
13.
14.
TBAI
TBAI
TBAI
TBAI
TBAI
------
TMAI
TBAB
DTBP
120
120
120
120
120
120
120
120
24
24
24
24
24
24
24
24
86
0
0
0
0
40
65
76
Oxone
K2S2O8
(NH4)2S2O8
O2
13-16).
Unfortunately, none were found beneficial in
improving the yield of 3a beyond 86% yield (Table 1, entry 13-
16). Nonetheless, other catalysts such as I2, KI, NaI, NaF, etc.
were not effective to improve the yield of 3a (Table 1, entry
17-20). Thus, we found that TBAI (20 mol%), DTBP (4 equiv.)
and toluene were found to be the best catalyst, oxidant, and
methylated arene partner for this CDC reaction, respectively;
at this juncture, variation in catalyst-loading, as well as
oxidant-loading, were investigated (Table 1, entry 21-22). It
has been observed that increasing or decreasing the amount
of TBAI or DTBP did not greatly influence the yield of the
reaction (Table 1, entry 21). Moreover, an increase in DTBP
loading up to 5.0 equivalents or a decrease in DTBP loading (3
equiv.) did not have a beneficial effect on the yield of the
reaction and furnished 3a in 72% and 83% yields, respectively
(Table 1, entry 22). In an attempt to decrease the amount of
2a, the use of benzene or DCM in combination with 2a leads to
a significant decrease in the yield of 3a (Table 1, entry 23). In
addition, keeping all the reaction parameters the same,
variation in the temperature or time was also found ineffective
in increasing the yield of 3a (Table 1, entry 24-26). As
compared to entry no. 7, 3a was obtained in lower yield when
the reaction was carried out in the air (Table 1, entry 27). In
general, 20 mol% TBAI, 4.0 equivalents of DTBP dissolved in
methylated arenes at 120 °C for 24 h was found to be the best-
optimized reaction conditions for the efficient synthesis of C–3
benzylated 2H-indazoles via CDC methodology.
DTBP
DTBP
DTBP
Tetrabutyla
mmonium
tribromide
1,3-
dimesitylim
idazolium
chloride
I2
15.
DTBP
DTBP
120
24
66
16.
120
24
75
17.
18.
19.
20.
DTBP
DTBP
DTBP
DTBP
120
120
120
120
24
24
24
24
60
40
50
KI
NaI
NaF
30
84b,
75c
72d,
83e
60f,
20g
50
21.
22.
23.
TBAI
TBAI
TBAI
DTBP
DTBP
DTBP
120
120
120
24
24
24
24.
25
26
27
TBAI
TBAI
TBAI
TBAI
DTBP
DTBP
DTBP
DTBP
80
24
24
16
24
140
120
120
75
70
80h
aReaction conditions: 2-(4-methoxyphenyl)-2H-indazole 1a (0.25 mmol), toluene
2a (1.0 mL), Tetrabutylammonium bromide (20 mol%), oxidant (1.0 mmol), 120
2 | J. Name., 2012, 00, 1-3
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We then explored the substrate scopes of the several occurrence of this reaction under our optimized conditions
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DOI: 10.1039/D0OB01282C
methylated arenes. 2-(4-methoxyphenyl)-2H-indazole 1a was with 4-acetyl ethylbenzene 2m clearly indicates that the
reacted with different methylated arenes 2a–l under the reaction is favoured exclusively with the terminal aromatic
optimized reaction conditions which furnished substituted 3- methyl group. Furthermore, 2-nitrotoluene 2n failed to
benzylated 2-(4-methoxyphenyl)-2H-indazoles 3a–l in 56-87% undergo C-3 benzylation under optimized reaction conditions
yield range (Scheme 2). It has been observed that methylated possibly due to the electron-withdrawing nature of -NO2
arenes having ortho- or meta-electron donating groups (EDGs) group. Unlike 2b, 4-acetyl-1,3,5-trimethylbenzene 2o also
are well tolerated and furnished the corresponding C-3 failed to undergo this reaction. In an event to investigate C-N
benzylated products 3b–c in 82% and 84% yields, respectively. bond coupling, aliphatic/aromatic amines 2p–q proved to be
Methylated heteroarenes i.e., 2,6-lutidine also underwent the forbidden substrate.
coupling with 1a smoothly which afforded 3d in 66% yield. Similarly, various substituted 2H-indazoles 1b–i were reacted
Thus, it has been interpreted that methylated arenes showed with different substituted methylated arenes 2a
relatively greater reactivity than methylated heteroarenes. On under the optimized reaction conditions, which furnished the
the other hand, electron-withdrawing groups (EWGs) such as – 3-benzylated-3-aryl-2H-indazoles 4a in 54-80% yield range
CN, –COCH3, etc., if present at the para-position of the (Scheme 3). 2H-indazoles 1b (R2 = p-Cl) on coupling with
–d/2h/2j
–q
methylated arenes showed lower reactivity and afforded 3e
–f
various methylated arenes 2a
–d afforded C-3 benzylated
in 66% and 61% yields, respectively.
coupled product 4a in 58-65% yield, respectively. A similar
–d
Scheme 2. Substrate scope: Reaction of 1a with various type of yield-pattern (54-70%) was also demonstrated by the
methylated arenes 2a-l compounds 4e when 1c (R2 = p-CH3) undergoes cross-
dehydrogenative coupling with methylated arenes 2a–d
.
–i
.
Subsequently, like the aryl 2H-indazoles, the heteroaryl 2H-
indazoles 1d–e does not behave differently and furnished C-3
benzylated 2H-indazoles 4j–m on coupling with methylated
arenes 2a 2b and 2d in 56-70% yield, respectively.
,
Scheme 3. Substrates scope: Reaction of various substituted
2H-indazoles 1b–I with different methylated arenes 2a–
d/2h/2j
.
aReaction conditions: 2-(4-methoxyphenyl)-2H-indazole 1a (0.50 mmol),
Tetrabutylammonium iodide (20 mol%), DTBP (2.0 mmol), methylated arene 2a-
q
(2 mL), 120 °C, 24 h under N2 atmosphere.
In the case of methylated arenes having halo (X = Br, Cl, I)
group at the para-position, it was observed that there is
reinstatement in the reaction efficiency and furnished 3g–i in
70-77% yield range probably due to their +I effect. However,
keeping all the reaction conditions the same, a decrease in the
reactivity of methylated arenes was observed when the halo
groups are present at ortho-/meta-positions as observed in the
case of compounds 3j and 3k which were obtained in 56% and
66% yields, respectively. A cumulative effect in the yield of the
reaction has been noticed when methylated arene 2l having
two EDG (i.e., I and CH3) groups was reacted with 1a under
optimized conditions which furnished 3l in excellent (87%)
yield. In addition, the optimized reaction condition doesn’t
work well with few methylated arenes 2m–q. The non-
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J. Name., 2013, 00, 1-3 | 3
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aReaction conditions: Substituted 2H-indazoles 1b–h (0.50 mmol),
Tetrabutylammonium Iodide (20 mol%), DTBP (2.0 mmol), substituted
In order to comprehend the mechanism of this unique
protocol, few control experiments were carried out (Scheme 4,
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DOI: 10.1039/D0OB01282C
methylated arene 2a–d
/
2h/
2j (2 mL), 120 °C, 24 h under N2 atmosphere.
equation (i)-(iv)). Keeping all the reaction conditions same, 1a
3
On the other hand, this Csp2–Csp CDC protocol showed less
reactivity with heteroaryl methylated arenes (2,6-lutidine) in
comparison to aryl methylated arenes (toluene, mesitylene).
Conversely, yield enhancement was noticed when the
substituted 2-phenyl-2H-indazole 1f–g having more electron-
donating groups (three OCH3 groups) showed improved
was reacted with 2a in the absence of TBAI which furnished 3
a
in 40% yield [eqn. (i)]. Further, while keeping all the reaction
conditions the same, the reaction did not occur if the reaction
was carried out in the absence of DTBP [eqn. (ii)]. However,
12% of 3a was observed when 100 mol% of TEMPO was added
in the standard reaction conditions [eqn. (iii)]. This underlines
the importance of the oxidant in this free-radical catalyzed
reaction. In order to interpret the reactivity order among EDG
and EWG while keeping all the reaction conditions same; a
competitive experiment was executed in which substrate 1a
was reacted with an equimolar amount of methylated arenes
2b and 2e [eqn. (iv)]. It was found that 2b having EDG showed
higher reactivity than 2e having EWG and afforded the
corresponding products, 3b and 3e in 57% and 30% yields,
respectively.
reactivity and furnished the C-3 benzylated 2H-indazoles 4n–o
in 78% and 80% yields, respectively. Also, unsubstituted 2H-
indazoles 1h showed good reactivity on coupling with 1a which
furnished 4p in 67% yield. It has been noted that ortho-bromo
methylated arenes 2j undergo CDC with 1c under optimized
conditions furnished 4q in relatively lower (53%) yield. The 2-
cyclohexyl-2H-indazole 1i didn’t furnish 4r clearly illustrates
that the 2-aryl substitution in 2H-indazole plays a vital role in
stabilizing the intermediate for the coupling of methylated
arenes. The synthetic utility was also demonstrated by
performing a gram-scale synthesis of 3a by the reaction of 1a
with 2a under our optimized reaction conditions which
furnished 3a in 84% isolated yield (Scheme 2).
A plausible single electron transfer (SET) mechanism for this
regioselective benzylation method has been depicted in Figure
t
2.7 Initially, TBAI cleaves the DTBP to generate a BuO anion
t
t
and BuO radical via a SET mechanism. Then, BuO radical
abstract a proton from toluene 2a to form a benzyl free-radical
Scheme 4. Control Experiments.
A
via C(sp3)-H activation [Note: the radical species
A
was
trapped with TEMPO to give adduct
species regioselectively added to the C-3 position of 1a
5]. This benzyl free-radical
A
.
Subsequently, the generated intermediate radical species
deprotonated by the BuO anion to afford the intermediate
B
is
t
radical-anion species
C which get further transformed to the
desired product 3a with the exclusion of a single electron. The
removed single electron again participates in the reaction to
sustain the radical chain.
Figure 2. Plausible Mechanism.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB01282C
ARTICLE
General procedure A for the preparation of 2H-indazoles 1a–l
8
:
The solution of 2-bromobenzaldehyde or substituted-2-
Conclusions
bromobenzaldehyde (1.5 mmol) and aromatic/aliphatic/cyclic
amine (2.4 mmol) in methanol (20 mL) was refluxed for 6h at
60 °C. After the completion of the reaction, the solvent was
evaporated under vacuum to get the corresponding imine
product, which was further used in the next step without prior
purification.
The imine product was dissolved in anhydrous DMSO (10.0 mL)
and added the CuI (38 mg, 0.20 mmol), NaN3 (261 mg, 4.0
mmol) and TMEDA (22 mg, 0.20 mmol). The reaction mixture
was heated at 120 oC for 12 h. After cooling, the reaction
mixture was poured into the chloroform (70.0 mL) and
sequentially washed with water (3 × 30 mL), brine (3 × 30 mL),
then dried over Na2SO4. After the evaporation of the solvent
under reduced pressure, the crude product was further
In summary, we have developed a regioselective, Bu4NI-
catalyzed, DTBP-promoted; direct C-3 benzylation of 2-
substituted 2H-indazoles 3a–l/4a–q via the reaction of various
2-substituted-2H-indazoles 1a–h with different methylated
arenes 2a–l up to 89% yields. The metal-free, operationally
simple, catalytic protocol demonstrates a variety of functional
group tolerance and wide substrate compatibility. The gram-
scale synthesis further highlights the importance and versatile
nature of this methodology. The probable reaction pathway
t
involves the BuO anion- tBuO free radical sequential approach
via single electron transfer (SET) mechanism for the synthesis
of structurally diverse 3-benzylated-2-aryl-2H-indazoles class
of heterocycles. We believe that our regioselective benzylation purified by column chromatography (Hexane/EtOAc = 99:1 to
90:10) to afford the corresponding 2H-indazole 1a-l
General procedure B for C-3 benzylation of 2H-indazoles 3a–
4a–q: A mixture of 2H-indazole 1a–h (0.5 mmol,) TBAI (37
.
CDC method will attain high utility in constructing the
biologically privileged molecules in both academia and
industry.
l
/
mg, 20 mol %) and DTBP (0.366 mL, 2.0 mmol) were taken in a
sealed reaction tube under nitrogen atmosphere. Then,
methylated arene 2a–l (2.0 mL) was added into it and stirred
at 120 °C for 24 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure to
get the crude residue which was further purified through
column chromatography on silica gel (100-200 mesh) using the
specified eluting solvent (hexane: ethyl acetate) to afford the
corresponding product.
General procedure for the gram-scale synthesis of compound
3a: A mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (1.2 g,
5.35 mmol,) TBAI (0.396 g, 20 mol %) and DTBP (3.92 mL, 21.4
mmol) were taken in a sealed reaction tube under nitrogen
atmosphere. Then, toluene 2a (21 mL) was added into it and
stirred at 120 °C for 24 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure to
get the crude residue which was further purified through
column chromatography on silica gel (100-200 mesh) using the
solvent Hexane:EtOAc = 95:5 to afford the compound 3a as a
brown solid in 84% yield (1.41g, 4.48 mmol).
General procedure for the competition reaction between 2a
and 2e: A mixture of 2-(4-methoxyphenyl)-2H-indazole 1a (112
mg, 0.5 mmol,) TBAI (37 mg, 20 mol %) and DTBP (0.366 mL,
2.0 mmol) was taken in a sealed reaction tube under nitrogen
atmosphere. Then, mesitylene 2a (1.0 mL) and 4-
methylbenzonitrile 2e (1.0 mL) were added into it and stirred
at 120 °C for 24 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure to
get the crude residue which was further purified through
column chromatography on silica gel (100-200 mesh) using the
solvent Hexane: EtOAc = 95:5 to afford the compound 3b in
Experimental
Reagent information: All the reactions were performed in a
screw cap reaction vial under a nitrogen atmosphere with
magnetic stirring. Di-tert-butyl peroxide (DTBP) was purchased
from TCI (India) and tetrabutylammonium iodide (TBAI) was
procured from Spectrochem (India) and were used without
prior purification. Methylated arenes (toluene, mesitylene, o-
xylene, 2,6-lutidine, etc.) were purchased from commercial
sources (Spectrochem and TCI) and were used without further
purification. Unless otherwise stated, all other reagents were
purchased from a commercial source and used as received. For
column chromatography silica gel (100-200 mesh) was used
which was supplied from Fischer Scientific. Thin-layer
chromatography was performed on EMD Chemicals Si 60 F254
TLC plates (silica gel 60F254) were supplied from MERCK.
.
Analytical information: The analytical techniques 1H-NMR, 13C-
NMR spectroscopy, and HRMS, were used to characterize all
the compounds. JEOL ECS-400 instrument (400 MHz) was used
for the record of the 1H-NMR spectra. Chemical shifts were
reported in parts per million (ppm) referenced to 0.0 ppm for
tetramethylsilane and 7.26 ppm for relative to residual CHCl3.
13C-NMR spectra were recorded on the JEOL ECS-400
instrument (100 MHz) and were fully decoupled by broadband
proton decoupling. Chemical shifts were reported in ppm
referenced to the centerline of a triplet at 77.16 ppm of CDCl3.
High-resolution mass spectra (HRMS) were recorded on a Xevo
G2-S Q-Tof (Waters, USA) mass spectrometer. The melting
point was recorded on a micro melting point Complab melting
point apparatus and are presented uncorrected. Column
chromatography was performed over silica gel (particle size:
100-200 Mesh) procured from Fischer Scientific (India).
57% (98 mg, 0.286 mmol as a yellow solid) and 3e 30% (51 mg,
0.150 mmol as a viscous liquid), respectively.
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General procedure for radical reaction pathway: A mixture of 21.35; HRMS (ESI-QTOF): calcd for C22H21N2O, 329.1649
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DOI: 10.1039/D0OB01282C
2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol), TBAI (M+H)+; found, 329.1652.
(37 mg, 20 mol %) DTBP (0.366 mL, 2.0 mmol) and TEMPO (0.5 2-(4-methoxyphenyl)-3-((6-methylpyridin-2-yl)methyl)-2H-
mmol) were taken in a sealed reaction tube under nitrogen indazole (3d): The product was obtained via the general
atmosphere. Then, toluene 2a (2.0 mL) was added into it and procedure B using 2-(4-methoxyphenyl)-2H-indazole 1a (112
stirred at 120 °C for 24 h. After completion of the reaction, the mg, 0.5 mmol) and 2,6-dimethylpyridine 2d (2 mL) and isolated
reaction mixture was cooled to RT. The TLC observation was by column chromatography (Hexane:EtOAc = 85:15) as a
found that the TEMPO-assisted reaction afforded the desired yellow solid in 66% yield (109 mg, 0.328 mmol); m.p.: 103-105
product in only 12% yield. The intermediate of methylated °C; Rf (Hexane/EtOAc = 5:5): 0.40; 1H NMR (400 MHz, CDCl3) δ
arene free radical was coupled to TEMPO to afford the 7.73 (d, J = 8.4, 1H), 7.48 (dt, J = 8.5, 0.9 Hz, 1H), 7.44 – 7.38
compound
5 and was successfully isolated through column (m, 3H), 7.32 – 7.28 (m, 1H), 7.04 – 7.02(m, 1H), 6.98 – 6.94
chromatography on silica gel (100-200 mesh) using the eluting (m, 3H), 6.69 (d, J = 7.6 Hz, 1H), 4.51 (s, 2H), 3.84 (s, 3H), 2.50
solvent hexane: ethyl acetate (95:5) in 45% (56 mg, 0.226 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 159.92, 158.31, 157.20,
1
mmol) as a viscous liquid. H NMR (400 MHz, CDCl3) δ 7.39 – 148.67, 137.08, 133.29, 132.80, 127.42, 126.71, 121.71,
7.27 (m, 5H), 4.84 (s, 2H), 156 – 1.34 (m, 6H), 1.27 (s, 6H), 1.17 121.45, 121.36, 120.28, 119.40, 117.72, 114.31, 55.67, 34.37,
(s, 6H).
Characterization data:
24.56; HRMS (ESI-QTOF): calcd for C21H20N3O, 330.1601
(M+H)+; found, 330.1604.
3-benzyl-2-(4-methoxyphenyl)-2H-indazole4 (3a): The product 4-((2-(4-methoxyphenyl)-2H-indazol-3-yl)methyl)benzonitrile
was obtained via the general procedure B using 2-(4- (3e): The product was obtained via the general procedure B
methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol)
toluene 2a (2 mL) and isolated by column chromatography and 4-methylbenzonitrile 2e (2 mL) and isolated by column
(Hexane:EtOAc = 95:5) as a brown solid in 86% yield (135 mg, chromatography (Hexane:EtOAc = 90:10) as a yellow viscous
1
0.429 mmol); m.p.: 88-90 °C; Rf (Hexane/EtOAc = 8:2): 0.31; H liquid in 66% yield (112 mg, 0.330 mmol); Rf (Hexane/EtOAc =
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 8:2): 0.28; 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.23 (m, 1H), 7.50
Hz, 1H), 7.34 – 7.29 (m, 3H), 7.25 – 7.12 (m, 3H), 7.06 – 7.03 (d, J = 8.4 Hz, 2H), 7.46 (dt, J = 8.5, 1.0 Hz, 1H), 7.35 – 7.31(m,
(m, 3H), 6.96 – 6.94 (m, 2H), 4.35 (s, 2H), 3.85 (s, 3H); 13C NMR 1H), 7.27 – 7.25 (m, 2H), 7.11 – 7.06 (m, 3H), 6.94 (d, J = 8.8 Hz,
(100 MHz, CDCl3) δ 159.95, 148.64, 138.03, 134.47, 132.85, 2H), 4.41 (s, 2H), 3.85 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ
128.76, 128.33, 127.40, 127.06, 126.73, 126.71, 121.49, 160.15, 148.65, 143.47, 132.70, 132.57, 132.47, 132.35,
120.23, 117.73, 114.28, 55.68, 31.40; 13C-NMR Dept 90 (100 129.06, 127.32, 126.93, 122.10, 121.63, 119.58, 118.75,
MHz, CDCl3) δ 128.77, 128.34, 127.40, 126.73, 121.50, 120.25, 118.00, 114.44, 110.78, 55.72, 31.41; HRMS (ESI-QTOF): calcd
117.73, 114.29; 13C-NMR Dept 135 (100 MHz, CDCl3) δ 128.77, for C22H18N3O, 340.1445 (M+H)+; found, 340.1448.
128.34, 127.40, 126.73, 121.50, 120.25, 117.73, 114.29, 55.69, 1-(4-((2-(4-methoxyphenyl)-2H-indazol-3-yl)methyl)phenyl)
31.40; HRMS (ESI-QTOF): calcd for C21H19N2O, 315.1492 ethan-1-one (3f): The product was obtained via the general
(M+H)+; found, 315.1495.
3-(3,5-dimethylbenzyl)-2-(4-methoxyphenyl)-2H-indazole
procedure B using 2-(4-methoxyphenyl)-2H-indazole 1a (112
mg, 0.5 mmol) and 1-(p-tolyl)ethan-1-one 2f (2 mL) and
(3b): The product was obtained via the general procedure B isolated by column chromatography (Hexane:EtOAc = 92:08) as
using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) a yellow solid in 61% yield (108 mg, 0.303 mmol); m.p.: 90-92
and mesitylene 2b (2 mL) and isolated by column °C; Rf (Hexane/EtOAc = 8:2): 0.22; 1H NMR (400 MHz, CDCl3) δ
chromatography (Hexane:EtOAc = 95:05) as a yellow solid in 7.83 – 7.81 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz,
84% yield (144 mg, 0.421 mmol); m.p.: 80-82 °C; Rf 1H), 7.34 – 7.27 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 7.08 – 7.04 (m,
1
(Hexane/EtOAc = 8:2): 0.28; H NMR (400 MHz, CDCl3) δ 7.73 1H), 6.96 – 6.93 (m, 2H), 4.40 (s, 2H), 3.84 (s, 3H), 2.55 (s, 3H);
(d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.34 – 7.28 (m, 3H), 13C-NMR (100 MHz, CDCl3) δ 197.75, 160.06, 148.65, 143.51,
7.06 – 7.03 (m, 1H), 6.96 – 6.94 (m, 2H), 6.83 (s, 1H), 6.63 (s, 135.76, 133.36, 132.62, 128.88, 128.52, 127.34, 126.84,
2H), 4.27 (s, 2H), 3.85 (s, 3H), 2.21 (s, 6H); 13C-NMR (100 MHz, 121.84, 121.67, 119.86, 117.88, 114.38, 55.70, 31.37, 26.70;
CDCl3) δ 159.93, 148.72, 136.15, 136.09, 133.95, 132.93, HRMS (ESI-QTOF): calcd for C23H21N2O2, 357.1598 (M+H)+;
130.40, 128.76, 127.12, 127.00, 126.68, 126.37, 121.82, found, 357.1563.
121.37, 120.31, 117.72, 114.37, 55.68, 29.68, 19.77; HRMS 3-(4-chlorobenzyl)-2-(4-methoxyphenyl)-2H-indazole
(3g):
(ESI-QTOF): calcd for C23H23N2O, 343.1805 (M+H)+; found, The product was obtained via the general procedure B using 2-
343.1807.
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and 1-
2-(4-methoxyphenyl)-3-(2-methylbenzyl)-2H-indazole
(3c): chloro-4-methylbenzene 2g (2 mL) and isolated by column
The product was obtained via the general procedure B using 2- chromatography (Hexane:EtOAc = 90:10) as a yellow solid in
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and o- 77% yield (134 mg, 0.384 mmol); m.p.: 116-118 °C; Rf
1
xylene 2c (2 mL) and isolated by column chromatography (Hexane/EtOAc = 7:3): 0.53; H NMR (400 MHz, CDCl3) δ 7.74 –
(Hexane:EtOAc = 95:05) as a brown solid in 82% yield (135 mg, 7.72 (m, 1H), 7.46 (dd, J = 8.4, 0.8 Hz, 1H), 7.31 – 7.28 (m, 2H),
0.411 mmol); m.p.: 85-87 °C; Rf (Hexane/EtOAc = 8:2): 0.33; 1H 7.19 (d, J = 8.4 Hz, 2H), 7.08 – 7.01 (m, 2H), 6.96 – 6.94 (m, 4H),
NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.8 Hz, 1H), 7.37 – 7.35 4.31 (s, 2H), 3.85 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 160.04,
(m, 2H), 7.32 – 7.28 (m, 1H), 7.26 – 7.23 (m, 1H), 7.16 (d, J = 148.64, 136.47, 133.82, 132.69, 132.57, 129.62, 128.88,
4.0 Hz, 2H), 7.08 – 7.04 (m, 2H), 6.99 – 6.94 (m, 2H), 6.91 (d, J = 127.35, 127.06, 126.79, 121.73, 121.60, 119.93, 117.84,
7.6 Hz, 1H), 4.28 (s, 2H), 3.84 (s, 3H), 2.15 (s, 3H); 13C-NMR 114.35, 55.70, 30.75; HRMS (ESI-QTOF): calcd for C21H18ClN2O,
(100 MHz, CDCl3) δ 159.92, 148.62, 138.25, 137.85, 134.75, 349.1102 (M+H)+; found, 349.1107.
132.91, 128.33, 128.15, 127.42, 126.71, 126.14, 125.46, 3-(4-bromobenzyl)-2-(4-methoxyphenyl)-2H-indazole
(3h):
121.71, 121.38, 120.38, 117.62, 114.22, 113.74, 55.68, 31.21, The product was obtained via the general procedure B using 2-
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and 1- 2H), 3.87 (s, 3H), 2.16 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ
bromo-4-methylbenzene 2h (2 mL) and isolated by column 160.07, 148.60, 140.57, 139.93, 136.48, 134V.3iew9,Arti1cl3e3O.n7lin8e,
DOI: 10.1039/D0OB01282C
chromatography (Hexane:EtOAc = 94:06) as a yellow solid in 132.67, 128.50, 127.45, 126.81, 121.74, 121.58, 119.96,
70% yield (138 mg, 0.350 mmol); m.p.: 126-128 °C; Rf 117.78, 114.34, 94.57, 55.72, 31.69, 30.73; HRMS (ESI-QTOF):
1
(Hexane/EtOAc = 8:2): 0.28; H NMR (400 MHz, CDCl3) δ 7.73 calcd for C22H20IN2O, 455.0615 (M+H)+; found, 455.0612.
(d, J = 8.8 Hz, 1H), 7.48 – 7.44 (m, 1H), 7.35 – 7.32 (m, 2H), 7.31 3-benzyl-2-(4-chlorophenyl)-2H-indazole (4a): The product
– 7.28 (m, 2H), 7.08 – 7.04 (m, 2H), 6.96 – 6.88 (m, 4H), 4.29 (s, was obtained via the general procedure B using 2-(4-
2H), 3.85 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 160.05, 148.64, chlorophenyl)-2H-indazole 1b (114 mg, 0.5 mmol) and toluene
137.00, 133.70, 132.68, 131.83, 129.99, 127.35, 126.79, 2a (2 mL) and isolated by column chromatography
121.75, 121.60, 120.62, 119.92, 117.85, 114.36, 55.70, 30.81; (Hexane:EtOAc = 94:06) as a yellow solid in 65% yield (104 mg,
HRMS (ESI-QTOF): calcd for C21H18BrN2O, 393.0597 (M+H)+; 0.326 mmol); m.p.: 89-91 °C; Rf (Hexane/EtOAc = 7:3): 0.80; 1H
found, 393.0602.
3-(4-iodobenzyl)-2-(4-methoxyphenyl)-2H-indazole (3i)
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.51 – 7.48
(m, 1H), 7.43 – 7.41 (m, 2H), 7.37 – 7.31 (m, 3H), 7.26 – 7.20
The product was obtained via the general procedure B using 2- (m, 3H), 7.08 – 7.02 (m, 3H), 4.37 (s, 2H); 13C-NMR (100 MHz,
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and 1- CDCl3) δ 148.96, 138.38, 137.70, 134.97, 134.42, 129.40,
iodo-4-methylbenzene 2i (2 mL) and isolated by column 128.88, 128.22, 127.33, 127.14, 126.91, 122.06, 121.91,
chromatography (Hexane:EtOAc = 94:06) as a light yellow solid 120.22, 117.81, 31.32; HRMS (ESI-QTOF): calcd for C20H16ClN2,
in 72% yield (158 mg, 0.359 mmol); m.p.: 138-140 °C; Rf 319.0997 (M+H)+; found, 319.0994.
1
(Hexane:EtOAc = 8:2) 0.26; H NMR (400 MHz, CDCl3): δ 7.73 2-(4-chlorophenyl)-3-(3,5-dimethylbenzyl)-2H-indazole (4b):
(d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.8 Hz, The product was obtained via the general procedure B using 2-
1H), 7.34 – 7.25 (m, 3H), 7.07 – 7.04 (m, 1H), 6.96 – 6.94 (m, (4-chlorophenyl)-2H-indazole 1b (114 mg, 0.5 mmol) and
2H), 6.77 (d, J = 8.0 Hz, 2H), 4.29 (s, 2H), 3.85 (s, 3H); 13C-NMR mesitylene 2b (2 mL) and isolated by column chromatography
(100 MHz, CDCl3) δ 160.04, 148.64, 137.80, 137.70, 133.62, (Hexane:EtOAc = 95:05) as an yellow solid in 63% yield (109
132.67, 130.28, 127.34, 126.79, 121.74, 121.60, 119.92, mg, 0.314 mmol); m.p.: 96-98 °C; Rf (Hexane/EtOAc = 8:2):
1
117.85, 114.36, 92.02, 55.70, 30.90; HRMS (ESI-QTOF): calcd 0.50; H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.51
for C21H18IN2O, 441.0459 (M+H)+; found, 441.0462.
3-(2-bromobenzyl)-2-(4-methoxyphenyl)-2H-indazole (3j)
(d, J = 8.4 Hz, 1H), 7.43 – 7.41 (m, 2H), 7.37 – 7.31 (m, 3H), 7.08
(dd, J = 8.4, 6.8 Hz, 1H), 6.83 (s, 1H), 6.61 (s, 2H), 4.29 (s, 2H),
The product was obtained via the general procedure B using 2- 2.20 (s, 6H); 13C-NMR (100 MHz, CDCl3) δ 148.94, 138.47,
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and 1- 138.44, 138.43, 138.41, 137.54, 134.88, 134.70, 129.33,
bromo-2-methylbenzene 2j (2 mL) and isolated by column 128.49, 127.36, 127.13, 126.02, 122.08, 121.79, 120.36,
chromatography (Hexane:EtOAc = 95:05) as an off-white solid 117.71, 31.13, 21.34; HRMS (ESI-QTOF): calcd for C22H20ClN2,
in 56% yield (110 mg, 0.280 mmol); m.p.: 105-107 °C; Rf 347.1310 (M+H)+; found, 347.1313.
(Hexane/EtOAc = 8:2): 0.28; 1H NMR (400 MHz, CDCl3) δ 7.75 – 2-(4-chlorophenyl)-3-(2-methylbenzyl)-2H-indazole (4c): The
7.73 (m, 1H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.36 – 7.28 (m, 4H), product was obtained via the general procedure B using 2-(4-
7.17 – 7.07 (m, 2H), 7.02 – 6.89 (m, 4H), 4.43 (s, 2H), 3.84 (s, chlorophenyl)-2H-indazole 1b (114 mg, 0.5 mmol) and o-xylene
3H); 13C-NMR (100 MHz, CDCl3) δ 159.95, 148.70, 137.27, 2c (2 mL) and isolated by column chromatography
133.00, 132.95, 132.75, 130.13, 128.56, 127.77, 127.05, (Hexane:EtOAc = 94:06) as an off-white solid in 60% yield (100
126.74, 124.34, 121.81, 121.61, 120.07, 117.82, 114.44, 55.69, mg, 0.300 mmol); m.p.: 90-92 °C; Rf (Hexane/EtOAc = 8:2):
32.28; HRMS (ESI-QTOF): calcd for C21H18BrN2O, 393.0597 0.32; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.43 –
(M+H)+; found, 393.0601.
3-(3-iodobenzyl)-2-(4-methoxyphenyl)-2H-indazole (3k):
7.37 (m, 4H), 7.33 – 7.27(m, 2H), 7.17 – 7.13 (m, 2H), 7.08 –
7.04 (m, 1H), 7.01 – 6.97 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.29
The product was obtained via the general procedure B using 2- (s, 2H), 2.16 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 149.02,
(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) and 1- 138.43, 136.04, 135.75, 134.91, 133.94, 130.50, 129.46,
iodo-3-methylbenzene 2k (2 mL) and isolated by column 128.56, 127.13, 127.11, 127.03, 126.46, 122.14, 121.77,
chromatography (Hexane:EtOAc = 94:06) as a yellow viscous 120.28, 117.78, 29.55, 19.74; HRMS (ESI-QTOF): calcd for
liquid in 66% yield (145 mg, 0.329 mmol); Rf (Hexane/EtOAc = C21H18ClN2, 333.1153 (M+H)+; found, 333.1155.
8:2): 0.28; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 2-(4-chlorophenyl)-3-((6-methylpyridin-2-yl)methyl)-2H-
7.52 – 7.48 (m, 2H), 7.33 – 7.27 (m, 4H), 7.09 – 7.07 (m, 1H), indazole (4d): The product was obtained via the general
6.97 – 6.93 (m, 4H), 4.28 (s, 2H), 3.86 (s, 3H); 13C-NMR (100 procedure B using 2-(4-chlorophenyl)-2H-indazole 1b (114 mg,
MHz, CDCl3) δ 160.09, 148.62, 140.26, 137.33, 135.86, 133.63, 0.5 mmol) and 2,6-dimethylpyridine 2d (2 mL) and isolated by
132.63, 130.45, 127.59, 127.44, 126.82, 121.81, 121.58, column chromatography (Hexane:EtOAc = 94:06) as an light
119.90, 117.84, 114.38, 94.67, 55.73, 30.83; HRMS (ESI-QTOF): brown solid in 58% yield (97 mg, 0.291 mmol); m.p.: 83-85 °C;
1
calcd for C21H18IN2O, 441.0459 (M+H)+; found, 441.0463.
3-(3-iodo-5-methylbenzyl)-2-(4-methoxyphenyl)-2H-indazole
Rf (Hexane/EtOAc = 5:5): 0.62; H NMR (400 MHz, CDCl3) δ
7.72 (d, J = 8.8 Hz, 1H), 7.54 – 7.49 (m, 3H), 7.44 – 7.40 (m, 3H),
(3l): The product was obtained via the general procedure B 7.33 – 7.29 (m, 1H), 7.06 – 7.03 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H),
using 2-(4-methoxyphenyl)-2H-indazole 1a (112 mg, 0.5 mmol) 6.74 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 2.49 (s, 3H); 13C-NMR (100
and 1-iodo-3,5-dimethylbenzene 2l (2 mL) and isolated by MHz, CDCl3) δ 158.49, 156.85, 148.97, 138.36, 137.15, 134.92,
column chromatography (Hexane:EtOAc = 94:06) as a viscous 133.37, 129.40, 127.45, 127.11, 121.99, 121.82, 121.50,
yellow liquid in 87% yield (198 mg, 0.436 mmol); Rf 120.24, 119.42, 117.80, 34.28, 24.53; HRMS (ESI-QTOF): calcd
(Hexane/EtOAc = 8:2): 0.28; 1H NMR (400 MHz, CDCl3) δ 7.73 for C20H17ClN3, 334.1106 (M+H)+; found, 334.1109.
(d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 – 7.26 (m, 4H), 3-(4-bromobenzyl)-2-(p-tolyl)-2H-indazole (4e): The product
7.11 – 7.06 (m, 2H), 6.99 – 6.92 (m, 2H), 6.74 (s, 1H), 4.24 (s, was obtained via the general procedure B using 2-(p-tolyl)-2H-
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Journal Name
indazole 1c (104 mg, 0.5 mmol) and 4-bromotoluene 2h (2 mL) 2.40 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 158.29, 157.23,
View Article Online
and isolated by column chromatography (Hexane:EtOAc = 148.76, 139.03, 137.32, 137.06, 133.17, 129.78, 126.72,
DOI: 10.1039/D0OB01282C
94:06) as an light yellow solid in 54% yield (102 mg, 0.270 125.96, 121.81, 121.46, 121.33, 120.31, 119.40, 117.78, 34.42,
mmol); m.p.: 128-130 °C; Rf (Hexane/EtOAc = 8:2): 0.23; 1H 24.54, 21.29; HRMS (ESI-QTOF): calcd for C21H20N3, 314.1652
NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 (M+H)+; found, 314.1654.
Hz, 1H), 7.35 – 7.28 (m, 3H), 7.27 – 7.23 (m, 4H), 7.07 – 7.03 3-benzyl-2-(pyridin-2-yl)-2H-indazole (4j): The product was
(m, 1H), 6.90 (d, J = 8.4 Hz, 2H), 4.31 (s, 2H), 2.42 (s, 3H); 13C- obtained via the general procedure B using 2-(pyridin-2-yl)-2H-
NMR (100 MHz, CDCl3) δ 148.72, 139.26, 137.22, 137.01, indazole 1d (98 mg, 0.5 mmol) and toluene 2a (2 mL) and
133.53, 131.83, 129.99, 129.84, 126.81, 125.87, 121.76, isolated by column chromatography (Hexane:EtOAc = 96:04) as
121.69, 120.62, 119.96, 117.90, 30.84, 21.32; HRMS (ESI- a yellow solid in 61% yield (87 mg, 0.305 mmol); m.p.: 96-98
1
QTOF): calcd for C21H18BrN2, 377.0648 (M+H)+; found, °C; Rf (Hexane/EtOAc = 8:2): 0.31; H NMR (400 MHz, CDCl3) δ
377.0651.
8.51 – 8.49 (m, 1H), 7.99 (dt, J = 8.2, 0.8 Hz, 1H), 7.85 – 7.81
3-benzyl-2-(p-tolyl)-2H-indazole (4f): The product was (m, 1H), 7.72 (dt, J = 8.9, 0.8 Hz, 1H), 7.50 (dt, J = 8.6, 1.0 Hz,
obtained via the general procedure B using 2-(p-tolyl)-2H- 1H), 7.33 – 7.25 (m, 3H), 7.20 – 7.13 (m, 4H), 7.04 – 7.00 (m,
indazole 1c (104 mg, 0.5 mmol) and toluene 2a (2 mL) and 1H), 4.92 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ 153.70, 149.01,
isolated by column chromatography (Hexane:EtOAc = 94:06) as 147.92, 138.74, 138.68, 135.85, 128.70, 128.45, 127.61,
an light yellow solid in 66% yield (98 mg, 0.328 mmol); m.p.: 126.37, 122.91, 121.87, 120.76, 118.73, 117.92, 32.13; HRMS
1
78-80 °C; Rf (Hexane/EtOAc = 8:2): 0.24; H NMR (400 MHz, (ESI-QTOF): calcd for C19H15N3, 286.1339 (M+H)+; found,
CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.32 – 286.1342.
7.29 (m, 3H), 7.26 – 7.19 (m, 5H), 7.06 – 7.02 (m, 3H), 4.37 (s, 3-benzyl-2-(5-methylpyridin-2-yl)-2H-indazole
(4k):
The
2H), 2.42 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 148.73, 139.08, product was obtained via the general procedure B using 2-(5-
138.05, 137.36, 134.32, 129.77, 128.76, 128.33, 126.73, methylpyridin-2-yl)-2H-indazole 1e (105 mg, 0.5 mmol) and
125.93, 121.80, 121.50, 120.28, 117.79, 31.44, 21.32. HRMS toluene 2a (2 mL) and isolated by column chromatography
(ESI-QTOF): calcd for C21H19N2, 299.1543 (M+H)+; found, (Hexane:EtOAc = 95:05) as viscous liquid in 66% yield (99 mg,
299.1547.
0.331 mmol); Rf (Hexane/EtOAc = 7:3): 0.64; 1H NMR (400
3-(3,5-dimethylbenzyl)-2-(p-tolyl)-2H-indazole
(4g):
The MHz, CDCl3) δ 8.32 – 8.31 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71
product was obtained via the general procedure B using 2-(p- – 7.68 (m, 1H), 7.64 (ddd, J = 8.3, 2.3, 0.6 Hz, 1H), 7.47 (dt, J =
tolyl)-2H-indazole 1c (104 mg, 0.5 mmol) and mesitylene 2b (2 8.6, 1.0 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.20 – 7.11 (m, 5H), 7.02 –
mL) and isolated by column chromatography (Hexane:EtOAc = 6.98 (m, 1H), 4.87 (s, 2H), 2.38 (s, 3H); 13C-NMR (100 MHz,
94:06) as an light yellow solid in 70% yield (114 mg, 0.349 CDCl3) δ 151.52, 148.84, 148.03, 139.22, 138.77, 135.53,
1
mmol); m.p.: 90-92 °C; Rf (Hexane/EtOAc = 8:2): 0.26; H NMR 132.77, 128.67, 128.43, 127.40, 126.33, 122.72, 121.69,
(400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 120.69, 118.29, 117.83, 32.02, 18.13; HRMS (ESI-QTOF): calcd
1H), 7.33 – 7.29 (m, 3H), 7.26 – 7.24(m, 2H), 7.06 – 7.02 (m, for C20H18N3, 300.1495 (M+H)+; found, 300.1499.
1H), 6.82 (s, 1H), 6.63 (s, 2H), 4.29 (s, 2H), 2.42 (s, 3H), 2.20 (s, 3-(3,5-dimethylbenzyl)-2-(5-methylpyridin-2-yl)-2H-indazole
6H); 13C-NMR (100 MHz, CDCl3) δ 148.71, 138.98, 138.24, (4l): The product was obtained via the general procedure B
137.85, 137.43, 134.59, 129.70, 128.31, 126.71, 126.14, using 2-(5-methylpyridin-2-yl)-2H-indazole 1e (105 mg, 0.5
125.96, 121.80, 121.38, 120.42, 117.68, 31.25, 21.34, 21.31; mmol) and mesitylene 2b (2 mL) and isolated by column
HRMS (ESI-QTOF): calcd for C23H23N2, 327.1856 (M+H)+; found, chromatography (Hexane:EtOAc = 94:06) as an yellow solid in
327.1859.
70% yield (115 mg, 0.351 mmol); m.p.: 92-94 °C; Rf
1
3-(2-methylbenzyl)-2-(p-tolyl)-2H-indazole (4h): The product (Hexane/EtOAc = 8:2): 0.32; H NMR (400 MHz, CDCl3) δ 8.34
was obtained via the general procedure B using 2-(p-tolyl)-2H- (dd, J = 1.6, 0.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8
indazole 1c (104 mg, 0.5 mmol) and o-xylene 2c (2 mL) and Hz, 1H), 7.67 – 7.63 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.32 –
isolated by column chromatography (Hexane:EtOAc = 94:06) as 7.28 (m, 1H), 7.03 – 6.97 (m, 1H), 6.77 (s, 1H), 6.72 (s, 2H),
a yellow solid in 65% yield (101 mg, 0.323 mmol); m.p.: 90-92 4.78 (s, 2H), 2.39 (s, 3H), 2.18 (s, 6H); 13C-NMR (100 MHz,
1
°C; Rf (Hexane/EtOAc = 8:2): 0.24; H NMR (400 MHz, CDCl3) δ CDCl3) δ 151.51, 148.86, 148.12, 139.16, 138.50, 137.88,
7.73 (d, J = 8.8 Hz, 1H), 7.34 – 7.20 (m, 6H), 7.15 (d, J = 4.0 Hz, 135.81, 132.82, 128.01, 127.38, 126.50, 124.92, 122.66,
2H), 7.09 – 7.06 (m, 1H), 6.98 – 6.91 (m, 2H), 4.29 (s, 2H), 2.41 121.58, 120.88, 118.51, 117.76, 31.80, 21.35, 18.13; HRMS
(s, 3H), 2.15 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 148.79, (ESI-QTOF): calcd for C22H22N3, 328.1808 (M+H)+; found,
139.02, 137.43, 136.14, 136.06, 133.80, 130.37, 129.82, 328.1811.
128.76, 126.97, 126.67, 126.35, 125.64, 121.88, 121.36, 2-(5-methylpyridin-2-yl)-3-((6-methylpyridin-2-yl)methyl)-2H-
120.32, 117.76, 29.74, 21.30, 19.73; HRMS (ESI-QTOF): calcd indazole (4m): The product was obtained via the general
for C22H21N2, 313.1699 (M+H)+; found, 313.1702.
procedure B using 2-(5-methylpyridin-2-yl)-2H-indazole 1e
3-((6-methylpyridin-2-yl)methyl)-2-(p-tolyl)-2H-indazole (4i): (105 mg, 0.5 mmol) and 2,6-dimethylpyridine 2d (2 mL) and
The product was obtained via the general procedure B using 2- isolated by column chromatography (Hexane:EtOAc = 80:20) as
(p-tolyl)-2H-indazole 1c (104 mg, 0.5 mmol) and 2,6- an light yellow solid in 56% yield (88 mg, 0.280 mmol); m.p.:
1
dimethylpyridine 2d (2 mL) and isolated by column 70-72 °C; Rf (Hexane/EtOAc = 5:5): 0.66; H NMR (400 MHz,
chromatography (Hexane:EtOAc = 80:20) as a light yellow solid CDCl3) δ 8.25 (dd, J = 1.6, 0.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H),
in 56% yield (88 mg, 0.281 mmol); m.p.: 103-105 °C; Rf 7.70 (d, J = 8.8Hz, 1H), 7.67 – 7.64 (m, 1H), 7.50 (d, J = 8.8 Hz,
(Hexane/EtOAc = 05:05): 0.53; 1H NMR (400 MHz, CDCl3) δ 1H), 7.34 – 7.27 (m, 2H), 7.01 – 6.97 (m, 1H), 6.92 (d, J = 7.6
7.73 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 – 7.38 (m, Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 2.51 (s, 3H), 2.35
3H), 7.32 – 7.24 (m, 3H), 7.02 (dd, J = 8.0, 7.2 Hz, 1H), 6.97 (d, J (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 158.15, 157.78, 151.47,
= 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 2.50 (s, 3H), 148.90, 148.12, 139.17, 136.80, 133.94, 132.69, 127.44,
8 | J. Name., 2012, 00, 1-3
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122.90, 121.69, 120.94, 120.78, 119.56, 118.12, 117.80, 35.11,
24.57, 18.09; HRMS (ESI-QTOF): calcd for C20H19N4, 315.1604
(M+H)+; found, 315.1602.
3-(3,5-dimethylbenzyl)-5,6-dimethoxy-2-(p-tolyl)-2H-indazole
(4n): The product was obtained via the general procedure B
using 5,6-dimethoxy-2-(p-tolyl)-2H-indazole 1f (142 mg, 0.5
mmol) and mesitylene 2b (2 mL) and isolated by column
chromatography (Hexane:EtOAc = 80:20) as a brown solid in
S. C. acknowledges CSIR, New Delhi for CSIR-EMR Grant [02
View Article Online
(0189)/14/EMR-II] and DST, New DelhDi OfIo: r10.D10S3T9-/RDF0BORB01In28d2oC-
Russian Joint Research Project (INT/RUS/RFBR/P-169) and DST-
NRF Indo-South Africa Joint research project [DST/INT/South
Africa/P-19/2016]. L.Y. thanks DST, New Delhi for providing
financial assistance in the form of senior research fellowship.
Materials Research Centre (MRC), MNIT Jaipur is gratefully
acknowledged for providing analytical facilities.
78% yield (151 mg, 0.391 mmol); m.p.: 105-107 °C; Rf
1
(Hexane/EtOAc = 8:2): 0.29; H NMR (400 MHz, CDCl3) δ (ppm) Notes and references
7.37 – 7.28 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.84
(s, 1H), 6.67 (s, 2H), 6.54 (s, 1H), 4.22 (s, 2H), 3.95 (s, 3H), 3.80
(s, 3H), 2.40 (s, 3H), 2.22 (s, 6H); 13C-NMR (100 MHz, CDCl3) δ
151.83, 147.55, 145.35, 138.38, 138.29, 137.94, 137.61,
133.11, 129.65, 128.26, 126.18, 125.63, 116.23, 97.22, 95.76,
55.95, 31.32, 21.36, 21.26; HRMS (ESI-QTOF): calcd for
C25H27N2O2, 387.2067 (M+H)+; found, 387.2070.
3-(3,5-dimethylbenzyl)-5,6-dimethoxy-2-(4-methoxyphenyl)-
2H-indazole (4o): The product was obtained via the general
procedure B using 5,6-dimethoxy-2-(4-methoxyphenyl)-2H-
indazole 1g (142 mg, 0.5 mmol) and mesitylene 2b (2 mL) and
isolated by column chromatography (Hexane:EtOAc = 80:20) as
a brown solid in 80% yield (161 mg, 0.40 mmol); m.p.: 123-125
°C; Rf (Hexane/EtOAc = 7:3): 0.18; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.31 – 7.29 (m, 2H), 7.00 (s, 1H), 6.94 – 6.92 (m, 2H),
6.84 (s, 1H), 6.66 (s, 2H), 6.56 (s, 1H), 4.20 (s, 2H), 3.95 (s, 3H),
3.84 (s, 3H), 3.81 (s, 3H), 2.22 (s, 6H); 13C-NMR (100 MHz,
CDCl3) δ 159.55, 151.81, 147.54, 145.24, 138.29, 137.94,
133.28, 133.15, 128.26, 127.15, 126.16, 116.07, 114.17, 97.20,
95.73, 55.96, 55.65, 31.25, 21.35; HRMS (ESI-QTOF): calcd for
C25H27N2O3, 403.2016 (M+H)+; found, 403.2018.
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3-benzyl-2-phenyl-2H-indazole4 (4p): The product was
obtained via the general procedure B using 2-phenyl-2H-
indazole 1h (97 mg, 0.5 mmol) and toluene 2a (2 mL) and
isolated by column chromatography (Hexane:EtOAc = 954:05)
as an light yellow liquid in 67% yield (95 mg, 0.334 mmol); Rf
1
(Hexane/EtOAc = 8:2): 0.27; H NMR (400 MHz, CDCl3) δ 7.77 –
7.74 (m, 1H), 7.49 – 7.44 (m, 5H), 7.35 – 7.19 (m, 5H), 7.07 –
7.04 (m, 3H), 4.39 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ 148.84,
139.87, 137.93, 134.39, 129.28, 129.23, 129.05, 128.79,
128.32, 126.88, 126.78, 126.19, 121.64, 120.30, 117.84, 31.43;
HRMS (ESI-QTOF): calcd for C20H17N2, 285.1386 (M+H)+; found,
285.1390.
3-(2-bromobenzyl)-2-(p-tolyl)-2H-indazole (4q): The product
was obtained via the general procedure B using 2-(p-tolyl)-2H-
indazole 1c (104 mg, 0.5 mmol) and 1-bromo-2-
methylbenzene 2j (2 mL) and isolated by column
chromatography (Hexane:EtOAc = 94:06) as an yellow solid in
53% yield (100 mg, 0.265 mmol); m.p.: 108-110 °C; Rf
1
(Hexane/EtOAc = 8:2): 0.24; H NMR (400 MHz, CDCl3) δ 7.76
(d, J = 8.4 Hz, 1H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.35 – 7.26 (m,
6H), 7.17– 7.07 (m, 2H), 7.01– 6.98 (m, 1H), 6.91 (dd, J = 7.6,
1.6 Hz, 1H), 4.45 (s, 2H), 2.41 (s, 3H); 13C-NMR (100 MHz,
CDCl3) δ 148.79, 139.10, 137.29, 132.99, 132.82, 130.14,
129.91, 129.82, 128.56, 127.77, 126.77, 125.58, 124.34,
121.91, 121.63, 120.10, 117.89, 32.34, 21.32; HRMS (ESI-
QTOF): calcd for C21H18BrN2, 377.0648 (M+H)+; found,
377.0651.
Conflicts of interest
The author declares no competing financial interest.
Acknowledgements
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Int. Ed. 2009, 48, 6879.
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Journal Name
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DOI: 10.1039/D0OB01282C
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DOI: 10.1039/D0OB01282C
Table of Content Entry
TBAI-Catalyzed Csp2-Csp3 Cross-Dehydrogenative coupling
Regioselective protocol
H
Ar
TBAI (20 mol%),
DTBP (4.0 equiv)
Ar-CH3
N
N
+
R1
Functional group tolerance
120 °C, 24h
R1
N
Wide substrate scope
R2
N
R2
29 examples
Yield: upto 87%
Gram-scale synthesis
1a-h
2a-l
3a-l/4a-q
First metal-free C-3 benzylation of 2 -indazoles
H