Rh(iii)-catalyzed, hydrazine-directed C-H functionalization with 1-alkynylcyclobutanols: A new strategy for 1: H -indazoles

Article abstract of DOI:10.1039/c9cc08884a

Rh(iii)-catalyzed coupling of phenylhydrazines with 1-alkynylcyclobutanols was realized through a hydrazine-directed C-H functionalization pathway. This [4+1] annulation, based on the cleavage of a Csp-Csp triple bond in alkynylcyclobutanol, provides a new pathway to prepare diverse 1H-indazoles under mild reaction conditions. This journal is

Full text of DOI:10.1039/c9cc08884a

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DOI: 10.1039/C9CC08884A
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Rh(III)-Catalyzed, Hydrazine-directed C−H Functionalization with
1-Alkynylcyclobutanols: A New Strategy for 1H-Indazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Lei Zhanga, Junyu Chena, Xiahe Chen b, Xiangyun Zhenga, Jian Zhoua, Tianshuo Zhonga, Zhiwei Chena,
Yun-Fang Yang b, Xinpeng Jiang*a, Yuan-Bin She *b, and Chuanming Yu*a
DOI: 10.1039/x0xx00000x
Previous work
Rh(III)-catalyzed coupling of phenylhydrazines with 1-
alkynylcyclobutanols was realized through a hydrazine-directed
C−H functionalization pathway. This [4+1] annulation, based on
the cleavage of Csp-Csp triple bond in alkynylcyclobutanol,
provides a new pathway to prepare diverse 1H-indazoles under
mild reaction conditions.
H
N
N
HO
[Rh]
(a)
(b)
O
N
+
Ph
N
[3+2]
Ph
O
Ac
HO
O
[Rh]
O
N
Ph
+
H
[3+2]
Ph
This work
Indazole scaffolds are ubiquitous and present in natural
products,1 bioactive molecules2 and many drugs.3 As shown in
Figure 1, nigellidine,4 isolated from the Nigella glandulifera,
has the potential to regulate glucose consumption, EP1
receptor antagonist is used for the treatment of overactive
bladder (OAB),5 trypanothione synthetase (TryS)6 inhibitor
displays anti-HAT activity, whereas tyrosine threonine kinase
(TTK) inhibitor possesses good anti-cancer activity.7 Thus,
development of a practical and efficient synthetic method for
1H-indazoles has great significance.
In the past few decades, functionalization of C−H bond using
transition-metal-catalyst provided a straightforward approach
to complicated molecules through synchronous C−C and C−N
bond formation.8 Various types of alkynes9 and alkynyl
alcohols10 were employed for different transformations. In
2017, Zeng and co-workers11 reported Rh(III)-catalyzed
carboamination of alkynyl cycloalkanols with arylamines,
which involved Csp2−H/Csp3−Csp3 activation relay and
provided a concise approach to 1,2,3-trisubstituted indoles
R
N
R
N
R
N
N
O
[Rh]
[Rh]
X
HO
(c)
NH2
+
Ph
[4+1]
Ph
Ph
not observed
[3+2]
product
Scheme 1. Transition-metal-catalyzed C−H functionalization
with alkynyl cycloalkyl alcohols.
(Scheme 1a). Very recently, Pan and co-workers12 reported Rh-
(III)-catalyzed redox-neutral C−H/C−C activation using internal
oxidative O−NHAc and −OH as the two directing groups
(Scheme 1b). In both cases, butyryl groups were present in the
final products as residual alkynylcyclobutanols after the
cascade [3+2] annulation and ring opening reactions. To the
best of our knowledge, [4+1] annulation based on the cleavage
of Csp-Csp triple bond in alkynylcyclobutanol has never been
reported. As part of our ongoing research in transition-metal
catalyzed C−H activation reactions13 and construction of
heterocycles,14 herein, we describe a novel Rh(III) catalyzed
synthesis of 1H-indazoles via hydrazine-directed C−H
functionalization of phenylhydrazines and coupling with 1-
alkynylcyclobutanols (Scheme 1c). This is different from the
conventional hydrazine-directed transformations, in which the
fragile N-N bond was not cleaved by the rhodium catalyst to
OH
F
SO2NH2
O
N
N
H
N
N
N
N
O
N
N
N
O
S
N
N
form
1-(1-methyl-3-phenyl-1H-indol-2-yl)butan-1-one.15
H
COOH
TryS inhibitor
EP1 receptor antagonists
anti-overactive bladder activity
TTK inhibitor
anti-cancer activity
Instead, the Csp-Csp triple bond in alkynylcyclobutanol is
cleaved in this transformation (Scheme 1c). To the best of our
knowledge, this is first report on the construction of 1H-
indazoles through cascading C-H functionalization and Csp-Csp
triple bond cleavage reactions.16
We embarked on our study with the optimization of reaction
conditions using 1-methyl-1-phenylhydrazine 1a and 1-
(phenylethynyl) cyclobutan-1-ol 2a as the model substrates
Nigellidine
anti-HAT activity
Figure 1. Representative biologically active 1H-indazole scaffolds.
a. College of pharmaceutical sciences, Zhejiang University of Technology, Hangzhou
310014, P. R. of China. E-mail: xjiang@zjut.edu.cn; ycm@zjut.edu.cn.
b. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou,
Zhejiang 310014, P. R. of China. E-mail: sheyb@zjut.edu.cn
Electronic
supplementary
information
(ESI)
available.
See
DOI:
10.1039/x0xx00000x
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(Table S1, see ESI in detail). The reaction was found to produce the
desired product 3a most efficiently in 2a (0.4 mmol), 1a (1.2 equiv),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), and Zn(OAc)2 (1.2 equiv)
in toluene (3.0 mL) at 50 °C for 24 h under Ar atmosphere (entry 14,
Table S1). Based on previous work,17 we reasoned that the
cooperation of Cp*Rh(III) and Zn(OAc)2 would improve the
electrophilicity of the carbonyl group and facilitate the nucleophilic
addition process.
R2
N
R2
View Article Online
[Cp*RhCl2]2 (5 mol %)
AgSbF6 (20 mol %)
Zn(OAc)2 (1.2 equiv)
HO
N
DOI: 10.1039/C9CC08884A
NH2
R1
R1
N
+ Ph
Toluene, 50 oC, 24 h, Ar
1
2a
Ph
4
Ph
N
N
Bn
N
N
N
N
N
N
F
Ph
59%
Ph
4c
, 0%
Ph
4d, 56%
Ph
, 41%
4a,
4b
N
N
N
N
With the optimized reaction conditions in hand, the scope
N
N
N
N
and limitations of 1-arylethynyl cyclobutanols
2 were
Cl
Br
O
Ph
Ph
Ph
Ph
examined, as shown in Scheme 2. Substrate 1-arylethynyl
cyclobutanols with both electron-withdrawing and electron-
donating groups at the para and meta positions of the
benzene ring, reacted smoothly to afford 3a−3h in 51−73%
yields. Ortho-substituted substrate 2i, however, did not provide
the desired products under standard conditions. When AgNO3
was used instead of AgSbF6, 3j and 3l could be obtained in
higher yields (63% and 45% respectively).25 Moreover, phenyl
substituted also afforded 3k in 74% yield. To demonstrate the
synthetic utility of this protocol, a gram-scale reaction of 1-methyl-
1-phenylhydrazine 1a and 2a was carried out under the optimized
conditions, giving corresponding product 3a in 68% yield.
A variety of arylhydrazines coupling partners were further
examined (Scheme 3). A range of substituents on aryl-linked
nitrogen was then explored, wherein 1-ethyl and 1-Bn
phenylhydrazines produced 4a and 4b in 59% and 41% yields,
respectively. N-phenyl substituted substrate, however, failed to
afford 4c, probably due to the stereo hindrance effect.
Arylhydrazines with electron-deficient halides (F, Cl, and Br) and
electron-donating groups (Me and OMe) at the para-position of
benzene ring also furnished the corresponding 1H-indazoles 4d-4h
in moderate to good yields under standard conditions. When
AgOAc was used instead of AgSbF6, 4e could be obtained
c
4e
, 40% (45% )
4g
4f
, 61%
4h
, 50%
, 58%
Cl
N
N
Br
N
N
N
N
N
N
Ph
Ph
Ph
Ph
4i
4j
, 48%
, 35%
4k
, 77%
4l
, 41%
Scheme 3 Scope of substrate 1-alkyl-1-phenylhydrazinesa,b
aReaction conditions:
(0.48 mmol), 2a (0.4 mmol),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %) and Zn(OAc)2 (1.2
equiv) in toluene (3.0 mL) at 50 oC for 24 h under Ar
atmosphere. Isolated yield calculated based on 2a. AgOAc
instead of AgSbF6.
.
1
b
c
in higher yield (45%). In addition, electron-donating group (Me)
substituted substrate 2k was more reactive than the electron-
deficient groups (Cl and Br) substituted substrates 2i and 2j, giving
the target products 4i-4k in 35-77% yields. Moreover, ortho-methyl
substituted substrates 2l gave 4l in 41% yield.
To gain a better understanding of the reaction mechanism,
several experiments were conducted. First, the C−H activation
process was investigated by conducting the H/D exchange
experiment for 1a under standard conditions in the presence of
D2O. 1H NMR analysis showed approximately 62% deuteration at
the ortho-positions, suggesting that the C−H activation step
was reversible (Scheme 4a). Subsequently,
a deuterium
competition experiment between substrates 1a and [D3]-1a
illustrated a kinetic isotope effect (KIE) of 2.8 (Scheme 4b).
Meanwhile, two parallel independent reactions of 1a and [D3]-1a
were performed, and a KIE of 2.8 was observed (Scheme 4c). Both
[Cp*RhCl2]2 (5 mol %)
AgSbF6 (20 mol %)
Zn(OAc)2 (1.2 equiv)
N
N
HO
NH2
N
+
R
Toluene, 50 oC, 24 h, Ar
R
1a
2
3
results suggested that the C-H bond cleavage might be involved in
3a
, R = H (65%)
18
N
the rate-determining step
.
Then, a competitive experiment
N
(68% in gram-scale)
N
N
3f
3g
3h
, R = Cl (73%)
, R = Br (61%)
, R = CH3 (61%)
between two phenylhydrazines differing in electronic effects
was carried out. The ratio of two corresponding products
(4g/4f = 1.7 and 4k/4j = 1.2) suggested that the electron-
deficient arylhydrazine exhibited slightly higher reactivity
(Scheme 4d and 4e). In the absence of arylhydrazine, 2a failed
to convert to benzaldehyde 5 or 2-oxo-2-phenylacetic acid 6,
which suggested that neither of them was a reaction
intermediate (Scheme 4f). Furthermore, the replacement of 2a
with benzaldehyde failed to afford coupling product 3a, indicating
that 2a is critical in this novel annulation. On the other hand,
replacement of 2a by methyl or ethyl propiolate resulted in ~40%
yield of 3a and slightly higher amount of methyl or ethyl N-methyl-
2-phenylindole-3-carboxylate.25 (see table S2 ESI in detail).
Meanwhile, in the presence of arylhydrazine 2a, the formation
of 8 could be determined by GC−MS under standard
3b
3c
3d
3e
, R = Cl (68%)
, R = Br (51%)
, R = CF3 (71%)
, R = CH3 (60%)
R
R
N
N
N
N
N
N
N
N
Cl
S
F
F
c
c
3l
, 41% (45% )
3k
, 74%
3i
3j,
, N.R.
N.R. (63% )
Scheme
2 .
Scope of substrate 1-arylethynyl cyclobutanolsa,b
aReaction conditions: 1a (0.48 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5
mol %), AgSbF6 (20 mol %) and Zn(OAc)2 (1.2 equiv.) in toluene (3.0
mL) at 50 oC for 24 h under Ar atmosphere. Isolated yield
b
calculated based on 2. c AgNO3 instead of AgSbF6.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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H/D
[Cp*RhCl2]2 (5 mol %)
shown in Figure 2 (see ESI for details). From the complex E, the
DOI: 10.1039/C9CC08884A
acetic acid assisted Michael addition step via transition state TS1
View Article Online
N
N
65% recovered
~62% D
NH2
NH2
a)
AgSbF6 (20 mol %)
Zn(OAc)2 (1.2 equiv)
D2O: 10 equiv
H/D
had a barrier of 26.7 kcal mol-1. Subsequently, the intermediate F
underwent a proton transfer process assisted by acetic acid to give
intermediate G.19 Then the intermediate G went through enol-to-
keto tautomerization to afford the intermediate H.20 Finally, the
elimination step had a barrier of 22.8 kcal mol-1 (TS2) and led to the
product 1H-indazoles 3a.
1a
(0.48 mmol)
Toluene, 50 oC, Ar
D
D
N
2a
N
(0.4 mmol)
standard conditions
N
N
NH2
NH2
N
+
N
+
b)
D
1h
KIE = 2.8
D
D
Ph
Ph
1a
1a
[D3]- (0.24 mmol)
(0.24 mmol)
3a
3a
-d2
N
N
NH2
2a
(0.2 mmol)
N
standard conditions
Based on the previous reports,21 a plausible mechanism was
proposed, as shown in Scheme 5. First step involved the
formation of an active rhodium(III) catalyst Cp*RhX2 (X = SbF6
or OAc) due to anion exchange between [Cp*RhCl2]2 and
AgSbF6/Zn(OAc)2. This active rhodium complex formed a co-
ordinate bond with the hydrazine group of 1a. This was
followed by C(aryl)−H activation, generating the five-
Ph
1h
1a
(0.24 mmol)
D
3a
c)
KIE = 2.8
D
2a
(0.2 mmol)
standard conditions
N
NH2
N
N
D
D
1h
D
1a
[D3]- (0.24 mmol)
Ph
3a
-d2
N
N
2a
standard conditions
4g/4f
N
N
N
NH2
NH2
N
+
Br
d)
e)
+
Br
Ph
Ph
= 1.7:1
membered
rhodacycle
B
via
a
concerted
regioselective
4g
1g
(0. 24 mmol)
N
4f
1f
(0.24 mmol)
determined by HPLC
metalation/deprotonation.15b
Subsequent
Br
N
2a
Br
N
N
NH2
migratory insertion of the alkynyl alcohol 2a into Rh(III)
complex B resulted in the formation of the seven-membered
intermediate C. This further afforded another six-membered
rhodacycle intermediate D by β-carbon elimination. Next, an
intramolecular nucleophilic attack of phenyl hydrazine
nitrogen on rhodium(III) ion produced intermediate E.11-12,22
Subsequently, complex E underwent intramolecular Michael
addition reaction to yield intermediate F. Then, F underwent
proton transfer to form intermediate H, which was
transformed to 1H-indazoles 3a by releasing rhodium-carbene
I.23 Finally, protonolysis of I afforded pentan-2-one 7 along
with generation of Rh(III) catalyst.24
NH2
N
+
N
standard conditions
4k/4j
determined by HPLC
+
= 1.2:1
Ph
Ph
1j
4k
4j
(0.24 mmol)
HO
1k
(0. 24 mmol)
O
O
standard conditions
No Reaction
OH
+
f)
H
or
Ph
O
2a
(0.4 mmol)
N
6
5
N
N
N
HO
standard conditions
N
g)
NH2
+
Ph
Ph
Ph
, 65%
8
1a
2a
(0.48 mmol)
(0.4 mmol)
3a
detected by GC-MS
Scheme 4 Investigation of experimental mechanism.
conditions. We speculated that the formation of 8 was due to the
reaction of the byproduct pentan-2-one 7 and excess starting
material 1a (Scheme 4g).
The density functional theory (DFT) calculations were performed
to investigate the Michael addition/elimination steps. The free
energy profile of the most favourable pathway for Michael
addition/elimination steps with the acetic acid coordination was
In summary, an unprecedented Rh(III)-catalyzed [4+1]
annulation of phenylhydrazines and 1-alkynylcyclobutanols
was achieved through
a
hydrazine-directed C−H
functionalization pathway. The main feature was the Csp-Csp
triple bond cleavage of 1-alkynylcyclobutanols. This cascading
transformation provided a new pathway to prepare diverse
range of 1H-indazoles under mild reaction conditions. Further
studies on the synthetic applications of this method are
underway in our laboratory.
O
O
H
O
O
*Cp
H
O
Cp*
Rh
Rh
O
H
2.14
N
N
C3H7
C3H7
H
Ph
N
N
2.21
Ph
1.98
O
[Cp*RhCl2
]
2
1a
TS1
AgSbF6
Zn(OAc)2
TS2
N
N
N
NH2
7
Ph
26.7
1a
GToluene
kcal/mol
Cp*RhX2
X = SbF6 or OAc
8
O
TS1
*Cp
N
Rh
NH
Rh
3a
I
+ HOAc
9.7
9.3
HOAc
A
9.6
TS2
X
Cp*
elimination
G
F
HX
0.0
HOAc
E
N
O
H
O
NH2
Rh
*Cp
Rh
O
Cp*
-12.3
B
-13.2
3a + I
HO
N
H
C3H7
H
N
migratory
insertion
Ph
Ph
Michael Addition
2a
Proton Transfer
Elimination
H
AcO
H
O
O
H
O
H
*Cp
NH
*Cp
O
N
Cp*
N
O
H
Cp*
Rh
O
OH
Rh
O
N
proton transfer
3a
Rh
Rh Cp*
Rh
HN
N
C3H7
Ph
N
C3H7
N
N
N
O
H
Cp*
C3H7
C3H7
Ph
H
Ph
N
N
Ph
HO
Ph
Ph
O
C
O
O
H
N
Rh
Rh
β-carbon
elimination
*Cp
C3H7
I
N
E
F
G
H
N
Ph
NH2
Rh
intramolecular
*Cp
F
/michael addition
Figure 2. Free energy profiles for the Michael addition, proton
transfer, and elimination steps. The distances are shown in Å.
Calculations were done at the M06/6-311+G(d,p)-SDD (SMDToluene
//B3LYP/6-31G(d)-LANL2DZ level of theory.
NH
Rh Cp*
N
Ph
O
D
HOAc
nucleophilic attack
/metal protonation
Ph
O
)
E
Scheme 5. Proposed mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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There are no conflicts to declare.
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for suggesting this experiment.
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