Rh(III)-catalyzed oxidative coupling of 1,2-disubstituted arylhydrazines and olefins: A new strategy for 2,3-dihydro-1H-indazoles

Article abstract of DOI:10.1021/ol500865j

A rhodium(III)-catalyzed oxidative olefination of 1,2-disubstituted arylhydrazines with alkenes via sp² C-H bond activation followed by an intramolecular aza-Michael reaction is described. This strategy allows the direct and efficient construct

Full text of DOI:10.1021/ol500865j

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Oxidative Coupling of 1,2-Disubstituted
Arylhydrazines and Olefins: A New Strategy for
2,3‑Dihydro‑1H‑Indazoles
Sangil Han, Youngmi Shin, Satyasheel Sharma, Neeraj Kumar Mishra, Jihye Park, Mirim Kim,
Minyoung Kim, Jinbong Jang, and In Su Kim*
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed oxidative olefination
of 1,2-disubstituted arylhydrazines with alkenes via sp2 C−H
bond activation followed by an intramolecular aza-Michael
reaction is described. This strategy allows the direct and
efficient construction of highly substituted 2,3-dihydro-1H-
indazole scaffolds.
Scheme 1. Indazole Synthesis via C−H Functionalization
he indazole nucleus is a ubiquitous structural motif found
Tin heterocyclic compounds with a broad spectrum of
biological and medicinal applications.1 In fact, compounds
containing the indazole motif are known to exhibit a variety of
biological activities, such as high binding affinity for estrogen
receptors,2 inhibition of protein kinases,3 serotonin 5-HT2
receptor agonists,4 HIV protease inhibition,5 and antitumor
activity.6 The prevalence of indazoles in bioactive molecules has
led to the development of many useful methods for their
preparation.7 Surprisingly, however, the 2,3-dihydro-1H-inda-
zole scaffold remains virtually unknown and untested, despite
its obvious structural resemblance to the indazole ring system.8
Thus, the 2,3-dihydro-1H-indazole class can be a new candidate
for the next generation of pharmaceutical molecules.
Transition-metal-catalyzed C−H bond functionalization has
attracted much attention owing to its remarkable potential for
atom economy and environmental sustainability.9 In particular,
a great deal of effort has been devoted to the formation of
various heterocycles via transition-metal-catalyzed C−H
functionalization events.10 In this context, there has been
recent progress in the area of indazole synthesis via oxidative
annulation protocols (Scheme 1).11 For example, Inamoto and
Hiroya reported the Pd-catalyzed C−H activation of tosylhy-
drazones followed by intramolecular amination to afford 3-aryl
or 3-alkyl indazoles.11a Bao11b and Jiang,11c respectively,
demonstrated the Fe- and Cu-catalyzed aerobic C−N bond
formation of hydrazones for the formation of indazoles. Glorius
described the tandem Rh-catalyzed C−N bond formation and
Cu-catalyzed N−N bond formation between arylimidates and
organo azides to provide 1H-indazoles.11d Recently, Lavis and
Ellman disclosed an efficient method for the preparation of N-
aryl-2H-indazoles via Rh(III)-catalyzed C−H bond addition of
azobenzenes to aldehydes without external oxidants.12 The past
years have witnessed considerable progress in the field of
rhodium-catalyzed C−H functionalization reactions.13 Notably,
Rh(III)-catalyzed C−H activation followed by an annulation
reaction with carbon−carbon π-bonds has been frequently used
as a powerful tool to construct various heterocycles.14
Recently, we described tandem rhodium-catalyzed oxidative
C−C bond formation followed by intramolecular cyclization of
acetanilides15 and N-benzyltriflamides16 with olefins to afford
the corresponding indole and isoindoline heterocylces. Our
continued efforts in catalytic C−H bond functionalization17
prompted us to explore the direct coupling reaction of
arylhydrazines and olefins. Herein, we present the tandem
Rh(III)-catalyzed oxidative olefination and intramolecular aza-
Michael reaction of 1,2-disubstituted arylhydrazines with
alkenes via sp2 C−H bond activation to give highly substituted
2,3-dihydro-1H-indazoles. To the best of our knowledge, this is
Received: March 23, 2014
Published: April 22, 2014
© 2014 American Chemical Society
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Letter
a first report of the direct and catalytic formation of 2,3-
dihydro-1H-indazoles.
Our investigation was commenced by examining the
conversion of N′-methyl-N′-phenylacetohydrazide (1a) to
2,3-dihydro-1H-indazole 3a using a combination of a rhodium
catalyst and copper salt as an oxidant (Table 1). To our delight,
play a role as a terminal oxidant in the reaction catalyzed by
Cu(II).
Next we examined the influence of N,N′-protection groups
under optimal reaction conditions, and the selected results are
outlined in Table 2. 1-Methyl-1-phenylhydrazine (1b) did not
a
Table 2. Screening of N,N′-Protection Groups
a
Table 1. Selected Optimization for Reaction Conditions
b
entry
R1
R2
product
yield (%)
yield
1
2
3
4
5
6
Me
Me
Me
Me
Et
Ac
H
3a
3b
3c
3d
3e
3f
75
b
entry
catalyst
oxidant (equiv)
solvent
(%)
N.R.
N.R.
N.R.
66
1
2
3
[RhCp*Cl2]2
Cu(OAc)2·H2O (2) t-AmOH
55
pivaloyl
Bz
[Ru(p-cymene)Cl2]2 Cu(OAc)2·H2O (2) t-AmOH
Pd(OAc)2
N.R.
N.R.
39
Cu(OAc)2·H2O (2) t-AmOH
Cu(OAc)2·H2O (2) t-AmOH
Cu(OAc)2·H2O (2) DMF
Cu(OAc)2·H2O (2) DCE
Cu(OAc)2·H2O (2) THF
Cu(OAc)2·H2O (2) MeCN
Cu(OAc)2 (2)
Cu(OAc)2 (1)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.25)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Ac
c
4
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Bn
Ph
Ac
27
5
12
c
7
Ac
3g
23
6
47
a
Reaction conditions: 1a−1g (0.3 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (50 mol %), MeCN (1 mL)
7
65
8
68
b
under air at 100 °C for 20 h in pressure tubes. Isolated yield by flash
c
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
73
column chromatography. C2-Olefinated compound 3gg on a phenyl
moiety at R1 position was also obtained in 18% yield (see Supporting
Information for details).
10
11
12
80
75
57
d
13
70
yield the desired product 3b (Table 2, entry 2). N′-Methyl-N′-
phenylhydrazides 1c and 1d with a pivaloyl or benzoyl group at
the R2 position were found to be unreactive (Table 2, entries 3
and 4). 2-Ethyl-substituted 2-phenylacetohydrazide 1e was
compatible with the reaction conditions (Table 2, entry 5),
whereas benzyl- or phenyl-substituted hydrazides 1f and 1g
were far more ineffective in this coupling reaction (Table 2,
entries 6 and 7).
e
14
43
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (2.5 mol
%), oxidant (quantity noted), solvent (1 mL) under air at 100 °C for
20 h in pressure tubes. Isolated yield by flash column chromatog-
b
c
d
raphy. AgSbF6 (10 mol %) was added as an additive. O2 gas (1 atm)
e
was used. N2 gas (1 atm) was used.
the coupling reaction of 1a and 2a in the presence of 2.5 mol %
of [RhCp*Cl2]2 and 2 equiv of Cu(OAc)2·H2O in tert-amyl
alcohol (t-AmOH) at 100 °C for 20 h provided the desired
product 3a in 55% yield (Table 1, entry 1). However, other
catalysts such as [Ru(p-cymene)Cl2]2 and Pd(OAc)2 were
found to be ineffective in this coupling reaction (Table 1,
entries 2 and 3). In addition, the cationic rhodium complex,
derived from [Cp*RhCl2]2 and AgSbF6, was found to be less
effective in the current reaction system (Table 1, entry 4).
After a screening of solvents under otherwise identical
conditions, MeCN and THF were found to be highly effective
solvents in this coupling reaction, whereas other solvents such
as DMF and DCE failed to facilitate high levels of conversion
(Table 1, entries 5−8). Further study showed that the
Cu(OAc)2 oxidant displayed increased catalytic activity to
afford 3a in 73% yield (Table 1, entry 9). Interestingly, the use
of a decreased amount (100 mol %) of Cu(OAc)2 afforded the
increased formation of our desired product 3a in high yield
(80%), as shown in entry 10. A further decrease in the amount
of oxidant to 50 mol % also provided a comparable yield (75%)
(Table 1, entry 11), but a considerable lowering in the
formation of product was observed when a catalytic amount
(25 mol %) of oxidant was used (Table 1, entry 12). The
reaction was then performed under an oxygen and nitrogen
atmosphere affording 3a in 70% and 43% yields, respectively
(Table 1, entries 13 and 14), while no formation of 3a was
observed under an air or oxygen atmosphere without
Cu(OAc)2. These results indicate that oxygen in the air may
With the optimized reaction conditions in hand, the scope
and limitation of N′-methyl-N′-arylacetohydrazides were
examined, as shown in Scheme 2. The coupling of ethyl
acrylate (2a) and N′-methyl-N′-arylacetohydrazides 1h−1l with
electron-donating and -withdrawing groups at the para-position
on the aromatic ring was found to be favored in the oxidative
olefination and subsequent intramolecular cyclization to afford
the corresponding products 3h−3l in moderate to good yields.
Particularly noteworthy were the monoselectivity of olefination
at two ortho-C−H bonds and the tolerance of the reaction
conditions to the bromo and chloro moieties, which provides a
versatile synthetic handle for further functionalization of the
products. This reaction was also compatible with meta-
substituted arylacetohydrazides 1m−1o, and all reactions
preferentially occurred at the less hindered position furnishing
the corresponding products 3m−3o as a single regioisomer. In
addition, ortho-substituted compounds also participated in the
oxidative coupling to furnish 3p and 3q with slightly decreased
reactivity.
To further explore the substrate scope and limitation of this
process, a broad range of olefins 2b−2k were screened to
couple with 1a, as shown in Scheme 3. To our pleasure,
acrylates 2b−2f and acrylamide 2g proved to be good
substrates for this transformation affording the corresponding
products 4b−4g in high yields. In contrast, acrylonitrile (2h)
and but-3-en-2-one (2i) were coupled with 1a with significantly
decreased reactivity under the optimal reaction conditions.
After further optimization, we found that an increased loading
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Organic Letters
Letter
a
a
Scheme 2. Scope of Hydrazides
Scheme 4. Oxidative Coupling of Diacrylate
a
Condition A: 1a (0.75 mmol), 2l (0.3 mmol), [RhCp*Cl2]2 (2.5 mol
%), Cu(OAc)2 (50 mol %), MeCN (1 mL) under air at 100 °C for 20
h in pressure tubes. Condition B: 1a (0.75 mmol), 2l (0.3 mmol),
[RhCp*Cl2]2 (5 mol %), Cu(OAc)2 (100 mol %), MeCN (1 mL)
under air at 100 °C for 20 h in pressure tubes. Condition C: 1a (0.9
mmol), 2l (0.3 mmol), [RhCp*Cl2]2 (5 mol %), Cu(OAc)2 (300 mol
%), MeCN (1.5 mL) under air at 100 °C for 40 h in pressure tubes.
a
compound 4la and bis-functionalized compound 4lb in 45%
and 22% yields, respectively, under the standard reaction
conditions. In addition, upon use of increased amounts of 1a,
rhodium catalyst, and copper salt, the bis-functionalized 2,3-
dihydro-1H-indazole 4lb was obtained in 63% yield.
To highlight the robustness and practicality of the
preparation of 2,3-dihydro-1H-indazole, we successfully scaled
the reaction to 3.65 mmol and obtained 0.71 g of 4c after 32 h
in 67% isolated yield (Scheme 5). In addition, we performed an
Reaction conditions: 1a and 1h−1q (0.3 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (50 mol %), MeCN (1 mL)
under air at 100 °C for 20 h in pressure tubes. b Isolated yield by flash
c
column chromatography. THF was used as a solvent.
a
Scheme 3. Scope of Olefins
Scheme 5. Scale-up Experiment
intermolecular competition reaction between acrylate 2a and
acrylamide 2g to afford the corresponding products with a 1.5:1
ratio in 64% combined yield (see Supporting Information for
details).
Finally, we were pleased to find that an acetyl protecting
group was efficiently removed. Thus, acid-mediated hydrolysis
was successfully applied to compounds 3a and 4g, providing
access to 1H-indazoles 5a and 5b in high yields (Scheme 6).
Scheme 6. Removal of N-Protection Group
a
Reaction conditions: 1a (0.3 mmol), 2b−2k (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (50 mol %), MeCN (1 mL)
under air at 100 °C for 20 h in pressure tubes. b Isolated yield by flash
c
column chromatography. Olefin (0.9 mmol), Cu(OAc)2 (100 mol
%), THF (1 mL).
of Cu(OAc)2 in THF solvent provided our desired products
4h−4j in good to high yields. Finally, this protocol offers the
possibility of late-stage functionalization of biologically active
compounds that contain the olefin functional groups. For
example, acrylate 2k with an estrogen scaffold was smoothly
converted to 4k in 74% yield.
To further evaluate the scope of this process, the coupling of
diacrylate 2l with 1a was examined, as shown in Scheme 4. As
expected, diacrylate 2l was converted to monofunctionalized
In conclusion, we have disclosed a highly efficient method for
the preparation of 2,3-dihydro-1H-indazoles via the rhodium-
catalyzed oxidative alkenylation of 1,2-disubstituted arylhydra-
zines with olefins and subsequent intramolecular cyclization.
These transformations have been applied to a wide range of
substrates and typically proceed with excellent levels of
chemoselectivity as well as with high functional group
tolerance. Furthermore, this protocol allows the generation of
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
■
S
C
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. J. Am. Chem.
Soc. 2013, 135, 7122.
(13) For selected reviews on Rh-catalyzed C−H functionalization,
see: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41,
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Acta 2012, 45, 31.
(14) For recent examples of Rh(III)-catalyzed nitrogen-containing
heterocycle synthesis via coupling with carbon−carbon π-bonds, see:
(a) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66. (b) Zhen,
W.; Wang, F.; Zhao, M.; Du, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 51,
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: insukim@skku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
11819. (c) Hyster, T. K.; Knorr, L.; Ward, T. R.; Rovis, T. Science
̈
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (No. 2013R1A2A2A01005249).
2012, 338, 500. (d) Ye, B.; Cramer, N. Science 2012, 338, 504.
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