Access to 3-Acyl-(2H)-indazoles via Rh(III

Letter
pubs.acs.org/OrgLett
Access to 3‑Acyl-(2H)‑indazoles via Rh(III)-Catalyzed C−H Addition
and Cyclization of Azobenzenes with α‑Keto Aldehydes
Taejoo Jeong,†,§ Sang Hoon Han,†,§ Sangil Han,† Satyasheel Sharma,† Jihye Park,† Jong Suk Lee,‡
Jong Hwan Kwak,† Young Hoon Jung,† and In Su Kim*,†
†
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Biocenter, Gyeonggi Institute of Science & Technology Promotion, Suwon 443-270, Republic of Korea
‡
S Supporting Information
*
ABSTRACT: The rhodium(III)-catalyzed direct C−H functionalization of azobenzenes with ethyl glyoxalate and aryl
glyoxals is described. This protocol provides the facile and
efficient formation of various C3-acylated-(2H)-indazoles in
moderate to high yields.
T
Scheme 1. Indazole Synthesis via C−H Functionalization
he indazole heterocycle has been recognized as a crucial
structural core found in natural products and pharmaceuticals with a broad spectrum of medicinal applications.1 In
particular, the 3-acyl indazole motif is present in molecules that
possess anticancer, antiemetic, viral polymerase inhibition, and
anti-inflammatory activities (Figure 1).2 The classical routes to 3-
In addition, Glorius demonstrated the Rh- and Cu-catalyzed
tandem C−N and N−N bond formations between arylimidates
and sulfonyl azides providing 3-oxo-(1H)-indazoles.7 Recently,
our group reported a new strategy for the construction of 2,3dihydro-(1H)-indazoles from arylhydrazines with various olefins
under Rh(III) catalysis.8 Moreover, Wang reported the
recatalyzed annulation of azobenzenes and aldehydes affording
2,3-diaryl-(2H)-indazoles.9 In continuation of our recent studies
on the rhodium-catalyzed C−H functionalization and heterocycle synthesis,10 we herein present the Rh(III)-catalyzed direct
C−H addition followed by intramolecular cyclization of
azobenzenes with α-keto aldehydes, such as ethyl glyoxalate
and aryl glyoxals, affording 3-acyl-(2H)-indazoles.
The optimization of reaction conditions was initiated by
examining the coupling of azobenzene (1a) and ethyl glyoxalate
(2a) under rhodium catalysis (Table 1). To our delight, the
cationic rhodium complex, derived from [Cp*RhCl2]2 and
AgSbF6, was found to promote the coupling of 1a and 2a in DCE
at 60 °C to provide the monoalkylated compound 3aa in
Figure 1. Bioactive 3-acyl indazole compounds.
acyl indazoles involve (1) N-nitrosation of acetanilides followed
by intramolecular cyclization onto the ortho-methylene group,
(2) multistep synthesis from isatins via hydrolysis of the amide
unit, diazotization and reduction, and (3) direct lithiation at the
C3-position followed by the addition of electrophiles.3
Surprisingly, however, the catalytic preparation of 3-acyl indazole
scaffolds remains virtually unexplored.
With advances in transition-metal-catalyzed C−H bond
functionalization, great effort has been devoted to the formation
of various heterocycles.4 In this area, recent progress has been
focused on the preparation of indazoles via the oxidative
annulation process of hydrazones under palladium, copper, and
iron catalysis.5 Lavis and Ellman disclosed beautiful works on the
synthesis of 2,3-diaryl-2H-indazoles via the Rh(III)- or Co(III)catalyzed redox-neutral coupling of azobenzenes with aryl
aldehydes (Scheme 1).6
© 2016 American Chemical Society
Received: November 24, 2015
Published: January 7, 2016
232
DOI: 10.1021/acs.orglett.5b03368
Org. Lett. 2016, 18, 232−235
Letter
Organic Letters
Table 1. Selected Optimization for Reaction Conditionsa
entry
additive (mol %)
solvent
yield (%),b ratioc
1
2
3
4
5
6
7
8
9
10d
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10), NaOAc (30)
AgSbF6 (10), KOAc (30)
AgSbF6 (10), AgOAc (30)
AgSbF6 (10), Cu(OAc)2 (30)
AgSbF6 (10), NaOAc (30)
DCE
MeOH
t-AmOH
toluene
dioxane
DCE
DCE
DCE
DCE
DCE
30 (8:1:1)
N.R.
trace
trace
12 (1:0:1)
60 (5:1:4)
55 (6:1:3)
56 (5:1:4)
20 (1:2:1)
95 (0:1:48)
Scheme 2. Scope of Azobenzenesa
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [RhCp*Cl2]2
(2.5 mol %), additive (quantity noted), solvent (1 mL) at 60 °C for 20
h under air in reaction tubes. b Isolated yield by column
chromatography. cParentheses shows ratio of 3aa/3ab/3ac. dCompound 2a (0.6 mmol) was used.
concomitant with indazole compounds 3ab and 3ac (Table 1,
entry 1). Screening of solvents such as MeOH, t-AmOH, toluene,
and 1,4-dioxane did not provide the coupling products in a
satisfactory yield (Table 1, entries 2−5). However, the addition
of NaOAc as an additive showed an increment of the formation
of coupling products in 60% combined yield (Table 1, entry 6).
This reaction was found to be comparable with KOAc and
AgOAc additives, but Cu(OAc)2 was less effective in this
coupling reaction (Table 1, entries 7−9). In all cases, we could
not control the formation of alkylated azobenzene 3aa and
indazoles 3ab and 3ac. However, increasing the amount of ethyl
glyoxalate (2a) to 3 equiv, indazole 3ac was exclusively formed in
high yield (Table 1, entry 10).
To evaluate the scope of this process, the optimal reaction
conditions were subjected to a range of azobenzenes 1a−1n
(Scheme 2). In case of para-substituted azobenzenes 1b and 1c
with electron-rich groups, high yields of C7-alkylated indazole
compounds 3bc and 3cc were obtained. However, electrondeficient azobenzenes 1d−1f underwent the formation of
indazole products 3db−3fb and 3dc−3fc at elevated temperature (100 °C) in good to high yields, but lower ratio between
indazoles 3db−3fb and C7-alkylated indazoles 3dc−3fc was
detected. Thus, with the increased loading of 2a (5 equiv), a good
level of ratio and improved yields of indazole products were
obtained. Interestingly, meta-substituted azobenzenes 1g and 1h
with OMe and F groups, respectively, provided good to high
yields of C7-alkylated indazoles 3gc and 3hc. In contrast,
azobenzenes 1i and 1j containing halogen groups (Cl and Br) at
the meta-position, provided indazoles 3ib and 3jb along with C7alkylated indazoles 3ic and 3jc in high yields. However, sterically
congested meta-acetyl azobenzene 1k provided only C3-acylated
indazole 3kb. Additionally, ortho-substituted azobenzenes 1l−1n
proved to be good substrates for the formation of indazoles 3lb−
3nb.
a
Reaction conditions: 1a−1n (0.2 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), NaOAc (30 mol
%), DCE (1 mL) at 60 °C for 20 h under air in reaction tubes.
b
Isolated yield by flash column chromatography. cReactions were
performed at 100 °C for 20 h. dReactions were performed with 2a (1.0
mmol) at 100 °C for 20 h.
To further explore the scope and limitation of this transformation, various glyoxals 2b−2k were screened, as shown in
Scheme 3. Initially, ortho-substituted azobenzene 1m was
coupled with phenyl glyoxal (2b) under the optimized reaction
conditions to afford the desired indazole 4b in 46% yield.
However, the addition of AgOAc instead of NaOAc provided an
improved yield (56%) of 4b. Other reaction conditions were
found to be inferior for the coupling of 1m and 2b. The modified
conditions were applied to various aryl glyoxals 2c−2i to give the
corresponding products 4c−4i in moderate yields. To our
delight, heteroaryl glyoxal 2j and alkyl glyoxal 2k also
participated in the coupling reaction to furnish indazoles 4j
and 4k, respectively. In addition, in the case of para- and metasubstituted azobenzenes 1b and 1j, C3-acylated indazoles 4l and
4m were exclusively formed, and C7-alkylated indazoles were not
observed presumably due to fast intramolecular cyclization of
monoalkylated intermediates.
Further investigation of unsymmetrical azobenzenes 1o and
1p with 2a revealed that this transformation can predominantly
occur at the ortho-C−H bonds on the electron-rich aromatic ring
to provide the corresponding indazoles (5a and 6a′) as major
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DOI: 10.1021/acs.orglett.5b03368
Org. Lett. 2016, 18, 232−235
Letter
Organic Letters
Scheme 3. Scope of Glyoxalsa
Scheme 5. Reversibility and Competition Experiment
Thus, our reaction afforded C7-alkylated indazole 8a as a major
product in 56% yield, and no formation of 8b was detected,
which shows that intramolecular cyclization of α-hydroxy
ketones generated from aryl glyoxals is faster than α-hydroxy
esters generated from ethyl glyoxalate. The above results also
support the formation of indazoles 4l and 4m through
monoalkylation followed by fast intramolecular cyclization. In
sharp contrast, in the case of ethyl glyoxalate, the formation of
bis-alkylation took place faster than intramolecular cyclization to
give C7-alkylated indazole products.
Next, we envisioned the sequential C−H activation of our
products by assisting indazole and carbonyl directing groups.
Thus, the deuterium-labeling experiment of 4c was performed,
which resulted in H/D exchanges at all C−H bonds in the
proximity of indazole and carbonyl directing groups (Scheme 6).
However, the sequential C−H functionalization of 4c with
acrylate 9a took place preferentially on the 4-methoxyphenyl ring
to furnish mono-olefination product 10a in 32% yield.
a
Reaction conditions: 1b, 1j, and 1m (0.2 mmol), 2b−2k (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), AgOAc (30 mol %),
DCE (1 mL) at 100 °C for 20 h under air in reaction tubes. bIsolated
yield by flash column chromatography. cNaOAc (30 mol %) was used.
products (Scheme 4). In addition, when we performed the
reaction of azobenzene 1q containing sterically different
Scheme 4. Reactions of Unsymmetrical Azobenzenes
Scheme 6. Deuterium-Labelling Experiment and Sequential
C−H Functionalization of Indazole Product
aromatic rings, a single product 7a was obtained in 98% yield.
This result indicates that the steric environment of azobenzene is
also crucial to tune the site-selectivity of this transformation.
To gain mechanistic insight, we carried out an experiment of
3aa with aryl glyoxal 2c under the standard reaction conditions
(Scheme 5). A trace amount of 3ab and no crossover product 4p
was observed. This result indicates irreversible addition of α-keto
aldehydes to the rhodacycle intermediate, which is in contrast to
those of the Rh(III)- and Co(III)-catalyzed reversible insertion
of aldehydes, imines, and isocyanates.11 For an example on
irreversible insertion of aldehydes, Li demonstrated the Rh(III)catalyzed C−H addition of phenylpyridines to ethyl glyoxalate,12
which is thermodynamically favorable due to aldehyde
destabilization as opposed to additions to standard aldehydes.
Based on the precedent literatures on the C−H functionalization of azobenzenes with carbonyl compounds,6,9,10b,d a plausible
mechanistic pathway for the formation of ortho-alkylated
azobenzenes and indazoles is depicted in Scheme 7. First,
coordination of an azo group in azobenzene 1a to a cationic
Rh(III) catalyst and subsequent C−H cleavage generates a fivemembered rhodacycle species I.13 Then coordination of ethyl
glyoxalate 2a to I affords an intermediate II. An irreversible
insertion of α-keto aldehydes to a Rh−carbonyl bond of
intermediate II forms the seven-membered rhodacycle III,12
which undergoes protonation to give the alkylated product 3aa
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DOI: 10.1021/acs.orglett.5b03368
Org. Lett. 2016, 18, 232−235
Letter
Organic Letters
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Scheme 7. Plausible Reaction Pathway
and an active Rh(III) catalyst. Further alkylation of 3aa affords
bis-alkylated intermediate IV, which on cyclization and
subsequent aromatization delivers indazole 3ac.
In conclusion, we disclosed the rhodium(III)-catalyzed direct
insertion of ethyl glyoxalate and aryl glyoxals to azobenzenes C−
H bonds followed by intramolecular cyclization affording highly
substituted indazoles. This approach allows the generation of an
array of C3-carbonylated indazoles, which are known to be
crucial scaffolds of biologically active compounds. Further
mechanistic investigations revealed that the insertion step of αketo aldehydes to rhodacycle intermediate is irreversible, which is
in sharp contrast to those of other π-unsaturates under Rh- and
Co-catalysis.
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03368.
Experimental procedures, characterization data, and 1H
and 13C NMR spectra for all compounds (PDF)
X-ray crystallographic data (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected].
Author Contributions
§
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation
of Korea (NRF) funded by the Korea government (MSIP) (Nos.
2015R1A2A1A15053033 and 2015H1D3A1058932).
■
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DOI: 10.1021/acs.orglett.5b03368
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