Rhodium(III)-catalyzed regioselective C7-allylation of indazoles

Article abstract of DOI:10.1055/s-0039-1691488

An efficient rhodium-catalyzed regioselective C-H allylation of N, N-diisopropylcarbamoyl indazoles with allylic carbonates as allylating agents has been developed. This methodology provides facile access to C7-allylated indazoles with high regioselectivi

Full text of DOI:10.1055/s-0039-1691488

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
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J. Huo et al.
Letter
Synlett
Rhodium(III)-Catalyzed Regioselective C7-Allylation of Indazoles
Jiyou Huo
[RhCp*Cl2]2 (5 mol%)
Hongshun Yuan
Lanting Xu*1
AgNTf2 (20 mol%)
R1
R1
N
N
0
0
0
0-0
0
0
1-8
4
6
7-3
6
4
8
.
O
O
Cu(OAC)2 H2O (50 mol%)
N
N
R
+
R
Xianhua Pan*
R2
O
N
H
N
4Å (100 mg), TCP (1.0 mL), N2
65 °C, 24 h
O
O
R
R
School of Perfume and Aroma Technology, Shanghai
Institute of Technology, 100 Haiquan Road, Shanghai,
201418, P. R. of China
R2
wide subtrate scope 38 examples,
up to 82% yield
xulanting@shnu.edu.cn
mild conditions
regioselective allylation
Received: 05.10.2019
Accepted after revision: 31.10.2019
Published online: 19.11.2019
ization of indazole at the benzene core (C4-C7 positions),
especially when lacking any substituent at the 3-position,
remains challenging.7c To override this intrinsic selectivity,
the introduction of directing groups on the N-1 atom of in-
dazole has proven to be an efficient strategy to ensure high
regioselectivity of these inactive positions.13 Very recently,
our group has reported the first example of direct C7-olefi-
nation of indazoles by using [Cp*RhCl2]2 as a catalyst and
N,N-diisopropylcarbamoyl as a directing group.14 Without
any protection or blocking group at the C3-position, this
method displayed excellent C7-regioselectivity, which pro-
vides a powerful way to introduce a wide variety of side
chains at the C7-position of indazole derivatives.
Allylation has been considered as one of the most im-
portant and fundamental transformations in organic syn-
thesis because the allyl moieties can be easily handled and
they allow access to various and versatile functional groups
by classical oxidation, olefin metathesis and coupling reac-
tions.15 Furthermore, the installation of an allyl group on
bioactive heteroarenes may cause a dramatic change in its
biological and physical properties.16 For example, widely
distributed in the genera Penicillium and Aspergillus of as-
comycota, C7-allylated indole natural products often carry
distinct biological and pharmacological activities compared
with their non-allylated precursors. We can envision that
the introduction of an allyl group into the C7-position of
the indazole would provide a platform not only for the
preparation of structurally complex and diverse molecules
through manipulation of the allyl groups, but also for the
introduction of a variety of indazole molecules with dis-
tinct biological and pharmacological activities.17 Consider-
ing the high importance of both allyl groups and indazole
moiety, and our continuous efforts in regioselective C–H
activation of bioactive heteroarenes, herein, we disclose the
first regioselective C–H allylation of indazoles at the C7
position.14,18
DOI: 10.1055/s-0039-1691488; Art ID: st-2019-r0533-l
Abstract An efficient rhodium-catalyzed regioselective C–H allylation
of N,N-diisopropylcarbamoyl indazoles with allylic carbonates as allylat-
ing agents has been developed. This methodology provides facile access
to C7-allylated indazoles with high regioselectivity, ample substrate
scope and broad functional group tolerance.
Key words indazoles, C–H activation, regioselectivity, allylation, rho-
dium catalysis
Indazole derivatives, which are bioisosteres of indole,
have attracted enormous attention due to their wide bio-
logical activities and irreplaceable role in pharmaceuticals
as anti-inflammatory, antiarrhythmic, antitumor, antifun-
gal, antibacterial, and anti-HIV agents.2 There is hence a
continuing high demand for efficient synthetic methodolo-
gy enabling the construction of indazole derivatives.3 Direct
functionalization of indazoles, which could significantly
simplify synthetic routes to this important class of het-
eroarene, provides probably one of the most efficient and
straightforward approaches to access structurally diverse
indazole derivatives.4
In the last decade, great progress has been made in tran-
sition-metal-catalyzed C–H activation, which has already
become a useful tool for late-stage functionalization of
complex organic molecules.5 Owing to its high step-effi-
ciency and atom-economy, direct C–H bond-functionaliza-
tion processes have clear advantages in structural diversity
oriented synthesis and in the modification of bio-organic
molecules.6 On account of the higher electron density of the
azole ring, extensive research has been done on the direct
C3 functionalization of indazole, such as arylation,7 alke-
nylation,8 phosphonylation,9 trifluoromethylation,10 thiocy-
anation,11 and oxyalkylation.12 However, the inherently
poor reactivity means that direct regioselective functional-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Huo et al.
Letter
Synlett
According to our previous study, we initially examined a
set of potential N-amide direction groups in the reaction of
indazole derivatives with allylic carbonate 2a (Table S-1 in
the Supporting Information).14 It was found that in the
presence of [Cp*RhCl2]2, AgNTf2, and Cu(OAc)2·H2O in DCE
at 65 °C, N,N-diisopropylcarbamoyl indazole 1a gave a bet-
ter performance, producing the C7-allyation product 3aa in
64% yield (Table S-1, entry 5). It is noteworthy that the large
size of the directing group and the N-disubstituted direct-
ing group both play important roles in facilitating this
transformation.
Encouraged by the initial result, we selected N,N-diiso-
propylcarbamoyl indazole 1a and allylic carbonate 2a as
model substrates to optimize the reaction conditions (Table
1). An investigation of alternative counterion additives
showed that AgNTf2 was most suitable for this reaction; the
reaction could not occur when AgOTf or AgOTs were used
(entries 1–4).
Replacing Cu(OAc)2·H2O with Cu(OAc)2 or AgOAc as ad-
ditives gave slightly lower yields (Table 1, entries 5 and 6),
while Cu(OTf)2 was found to be almost entirely ineffective,
with only 6% yield being isolated (entry 7). Further screen-
ing of a series of representative solvents revealed that this
transformation is highly solvent-dependent. Solvents in-
cluding dichloromethane, dimethyl sulfoxide, methanol,
acetonitrile, and tetrahydrofuran gave poor results of the
desired product (entries 8–12). To our delight, 1,2,3-trichlo-
ropropane showed a great promoting effect on the transfor-
mation, affording the 3aa in 78% yield (entry 13). The best
conditions were obtained when 4Å molecular sieves were
added while shortening the reaction time to 24 h.19 We
speculated that molecular sieves could remove the generat-
ed MeOH from the reaction system, thus improving the
Table 1 Optimization of Reaction Conditionsa
N
N
catalyst system
additive, solvent
N
N
N
N
OCO2Me
+
+
N
N
N
O
O
O
OCO2Me
1a
2a
3aa
4aa
Entry
Catalyst System
Additive
Solvent
Yield (%)b
1
2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgOTs
[RhCp*Cl2]2/AgOTf
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/–
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
DMSO
MeOH
MeCN
THF
64
41
3
n.d.
n.d.
62
4
5
6
AgOAc
50
7
Cu(OTf)2
6
8
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
–
37
9
n.d.
<5
10
11
12
13
14
15
16
17
18
19
n.d.
50
TCP
78
TCP
82c,d
78e
74f
n.d.c
n.d.c
<5c
TCP
TCP
TCP
–/AgNTf2
TCP
[RhCp*Cl2]2/AgNTf2
TCP
a Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), catalyst (5 mol%), counterion (20 mol%), additive (50 mol%), solvent (1.0 mL), 65 °C, 48 h. TCP = 1,2,3-
trichloropropane, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl.
b Yield of 3aa (n.d. = not detected).
c 4Å MS (100 mg/mL) was added, 65 °C, 24 h.
d 4aa was obtained in 11% yield.
e 4Å MS (100 mg/mL) was added, 50 °C, 24 h.
f 4Å MS (100 mg/mL) was added, 80 °C, 24 h.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

C
J. Huo et al.
Letter
Synlett
yield (entry 14). Interestingly, under optimized reaction
conditions, branched product 4aa, which was accessed
through 1,2-migratory insertion and subsequent -elimina-
tion, was also inevitably isolated in 11% yield. The reaction
proceeded most efficiently at 65 °C; either lowering or in-
creasing the temperature resulted in reduced yield (entries
15 and 16). Finally, control reactions established that
[Cp*RhCl2] as catalyst, AgNTf2 as counterion and
Cu(OAc)2·H2O as additive were all essential to this reaction
(entries 17–19). The structure of 3aa was unambiguously
confirmed by single-crystal X-ray diffraction analysis.
With the optimized reaction conditions in hand (Table
1, entry 14), we subsequently investigated the limitations
and functional group tolerance of this transformation
[RhCp*Cl2]2, AgNTf2,
Cu(OAc)2.H2O, 4A MS
N
N
R
R'''
R'
N
N
OCO2Me
R''
+
N
R'''
R'
TCP
N
O
O
R''
1
2a, R' = H, R'' = H
2b, R' = Me, R'' = H
2c, R' = Et, R'' = H
2d, R' = Me, R'' = Me
3
2e, R' = R'' = H, R''' = Me
R
R
R
N
N
N
N
N
N
O
N
N
N
O
O
3aa: R = H, 82%
3ha: R = Me, 76%
3na: R = Me, 75%
3ba: R = Me, 78%
3ia: R = COOMe, 70%
3ja: R = COOiPr, 55%b
3ka: R = F, 71%
3la: R = Cl, 75%
3ma: R = Br, 77%
3oa: R = OMe, 81%
3pa: R = OEt, 75%a
3qa: R = COOMe, 71%
3ra: R = F, 69%
3sa: R = Cl, 77%
3ta: R = Br, 72%
3ca: R = COOMe, 68%
3da: R = COOEt, 60%a
3ea: R = COOiPr, 61%a
3fa: R = Cl, 74%
3ga: R = NPhth, 70%
3ua: R = I, 75%
3va: R = NO2, 30%c
R
N
N
N
N
N
N
R
N
O
N
O
N
O
3ab: R = H, 55%b (E/Z = 6:1)
3bb: R = Me, 50%b (E/Z = 7:1)
3cb: R = COOMe, 30%d (E/Z = 7:1)
3hb, 41%b (E/Z = 7:1)
3wa: R = F, 80%
3xa: R = Cl, 11%
3ya: R = Br, 0%
3za: R = Me, 0%
R
R
N
N
N
N
N
N
F
N
O
N
O
N
O
3nb: R = Me, 35%b (E/Z = 6:1)
3ub: R = I, 30%b (E/Z = 5:1)
3wb: 35%b (E/Z = 5:1)
3ac: R = H, 21%b (E/Z = 4:1)
3bc: R = Me, 29%e (E/Z = 5:1)
N
N
N
N
N
N
N
N
N
O
N
O
N
N
O
O
3hc: 30%e (E/Z = 5:1)
3nc: 30%e (E/Z = 5:1)
3ad: 0%
3ae: 0%
Scheme 1 Substrate scope of regioselective C7-allylation of indazoles. Reagents and conditions: a 1 (0.2 mmol), 2 (1.0 mmol), [Cp*RhCl2]2 (5 mol%),
AgNTf2 (20 mol%), Cu(OAc)2·H2O (50 mol%), TCP (1.0 mL), 4A MS (100 mg), 65 °C, 24 h. b 65 °C, 48 h. c 65 °C, 72 h. d 80 °C, 48 h. e AgNTf2 (30 mol%).
f 65 °C, 96 h.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

D
J. Huo et al.
Letter
Synlett
(Scheme 1). Generally, our methodology was applied to var-
ious substituted indazoles with excellent C7-regioselectivi-
ty, producing the corresponding C7-allylation products in
moderate to good yield in most cases. It was found that in-
dazoles with an electron-donating substituent at the C3, C4
or C5 position afforded the desired products in higher yields
relative to those with an electron-withdrawing group (3ba–
ea, 3ia, 3ja, and 3na–qa). However, the indazole ring bear-
ing a strong electron-withdrawing group such as C5-NO2
was found to be less reactive; the conversion was moderate
even at 80 °C for 48 h and the allylated product 3va was ob-
tained in only 30% yield. The 3-amino-substituted indazole
was not compatible with the catalyst system. We suspect
that the ineffective results were presumably due to the
competitive chelation of 3-amino to the metal center. When
phthalic anhydride protected substrate was used, the reac-
tion proceeded smoothly (3ga). To our delight, indazoles
with various halogen groups substituted at the C3, C4 and
C5 positions were well tolerated, which offers ample oppor-
tunity for further derivatization (3fa, 3ka–ma and 3ra–ua).
Notably, this regioselective C7-allylation reaction is sen-
sitive to steric hindrance. When C6-methyl or C6-bromide
substituted indazoles were used, the desired 3ya and 3za
were not detected. With smaller fluoride groups, higher
conversion was observed, delivering 3wa in 80% yield.
Next, the scope of the C7-allylation reaction was ex-
tended to substituted allylic carbonates. When but-3-en-2-
yl acetate 2b was selected as the coupling partner with N,N-
dimethylcarbamoyl-indazole under the standard condi-
tions, no branched product of type 4 was observed and only
3ab was obtained with low conversion (20%). To improve
the conversion rate, we further optimized the reaction tem-
perature and reaction time. It was found that higher tem-
perature such as 80 °C and 100 °C were not beneficial to
this process. However, when the reaction time was pro-
longed to 72 h, 3ab could be obtained in moderate yield
(55%), indicating this transformation is sensitive to steric
hindrance again. Under the same conditions, -methyl and
ethyl substituted allylic carbonates (2b and 2c) reacted
smoothly with various substituted indazoles 1 to furnish
the desired products in acceptable yields in 4:1 to 7:1 E/Z
stereoisomeric rations. Unfortunately, methyl (2-methyl-
but-3-en-2-yl) carbonate (2d) and methyl (2-methylallyl)
carbonate (2e) were found to be unreactive and the inda-
zole substrate could be completely recovered.
served the olefin migrated product 5aa and subsequent
deprotected C7-alkenylated indazole 6aa in 80% and 70%
yield, respectively, which highlights the synthetic potential
of this transformation (Scheme 2b).
(a) Gram Scale Experiment
[RhCp*Cl2]2, AgNTf2
N
R
N
Cu(OAc)2.H2O
4A MS, TCP
R
N
N
OCO2Me
+
N
N
65 °C, 24 h
O
O
1
2a
12
3aa: R = H, 74%a
1a: R = H, (4.1 mmol)
3ca: R = COOMe, 63%b
3ma: R = 4-Br, 57%b
3oa: R = 5-OMe, 65%b
1c: R = 3-COOMe (4.1 mmol)
1m: R = 4-Br (4.1 mmol)
1o: R = 5-OMe (4.1 mmol)
(b) Deprotection of the C7-Allylation Products
N
N
N
50% NaOH aqueous : EtOH (1:4)
100 °C, 2 h
N
N
N
O
O
3aa
5aa, 80%c (E/Z = 10:1)
N
N
50% NaOH aqueous : EtOH (1:4)
100 °C, 20 h
N
N
H
N
O
3aa
6aa, 70%d (E/Z = 10:1)
Scheme 2 Synthetic utility of C7-allylated indazoles. a Reagents and con-
ditions: 1 (4.1 mmol), 2a (20.5 mmol), [RhCp*Cl2]2 (2 mol%), AgNTf2 (8
mol%), Cu(OAc)2·H2O (50 mol%), 4A MS (1 g), TCP (5.0 mL), 65 °C, 24 h.
b 48 h. c 3aa (0.4 mmol), solvent: 50% NaOH aq/EtOH (1:4), 100 °C, 2 h.
d 3aa (0.4 mmol), solvent: 50% NaOH aq/EtOH (1:4), 100 °C, 20 h.
Based on previous reports, a plausible catalytic cycle for
the present rhodium-catalyzed C–H allylation reaction
mechanism is proposed (Scheme 3). First, a catalytically ac-
tive rhodium species I is formed from the dimeric precursor
[RhCp*Cl2]2 with AgSbF6 and Cu(OAc)2·H2O. Coordination of
RhIII species I to the N-amide group of 1a and subsequent
C–H activation affords a six-membered rhodium metallacy-
cle II. Coordination of allylic carbonate 2a then gives the
complex III, which may undergo olefin insertion to afford
an eight-membered metallacycle IV followed by -oxygen
elimination to give the major allylated product 3aa. The
RhIII intermediate III may also undergo a 1,2-migratory in-
sertion and further furnish the minor alkenylation product
4aa by -H elimination.
To further demonstrate the synthetic utility of this pro-
tocol, we first evaluated the scalability of the current pro-
cess (Scheme 2a). The reaction of 1a with 2a was conducted
on 4.1 mmol scale. We were pleased to find that the catalyst
loading could be reduced to 2 mol% and the desired product
3aa could still be obtained in 74% yield. Under the same
conditions, other substrates, including C3-CO2Me (1c), C4-
Br (1m) and C5-OMe (1o) were also successfully applied on
a gram scale, albeit with slightly diminished yield. Mean-
while, under our previous deprotection method, we ob-
In summary, we have developed the first example of
rhodium-catalyzed N,N-diisopropylcarbamoyl directed re-
gioselective C7-allylation reaction with indazoles. The reac-
tion tolerates a wide range of indazoles with electron-do-
nating and electron-withdrawing substituents and gives
the product in moderate to good yields. Considering the
simple operation, large-scale preparation and high value of
C7-allylated indazole scaffolds, this synthetic strategy
should have potential synthetic utility for the construction
of structurally diverse indazole derivatives.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

E
J. Huo et al.
Letter
Synlett
Major Product
1/2 [Cp*RhCl2]2
AgNTf2, Cu(OAc)2.H2O
N
N
MeOH, CO2
+
2AgCl
N
O
3aa
1a
[Cp*Rh(OAc)]+ [NTf2]- (Rh = Cp*Rh)
I
Minor Product
N
HOAc
N
N
O
β-H elimination
β-oxygen elimination
OCO2Me
4aa
HOAC
N
N
N
N
N
N
N
H
H
O
O
N
Rh
N
Rh
O
*Cp
O
O
O
Rh
O
O
O
V
IV
II
OH
O
1,2-migratory insertion
OCO2Me
Olefin Insertion
2a
N
N
HOAc
N
Rh
*Cp
O
O
O
III
O
Scheme 3 Proposed mechanism
References and Notes
(1) New address: College of Chemistry and Materials Science,
Shanghai Normal University, No. 100 Guilin Rd., Shanghai
200234, P. R. of China.
Funding Information
This work was supported by the Shanghai Sailing Program
(17YF1418900).()
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691488.
S
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p
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orti
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gInformati
o
n
S
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p
p
orit
n
gInformati
o
n
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(19) Preparation of 3aa; Typical Procedure: To a 10 mL dry Schlenk
tube with a stirring bar, indazole substrate 1a (0.2 mmol),
[RhCp*Cl2]2 (6.2 mg, 5 mol%), Cu(OAc)2·H2O (20 mg, 50 mol%),
AgNTf2 (15.5 mg, 20 mol%), and 4Å MS (100 mg) were added.
The tube was evacuated and backfilled with nitrogen before
allyl methyl carbonate 2a (116 L, 1.0 mmol) and 1,2,3-trichlo-
ropropane (1.0 mL) were added. The reaction mixture was
stirred at 65 °C for 24 h. After cooling to room temperature, the
reaction mixture was purified by chromatography on silica with
a gradient eluent of petroleum ether and ethyl acetate to give
the corresponding product.
7-Allyl-N,N-diisopropyl-1H-indazole-1-carboxamide (3aa):
Yield: 82% (46.7 mg); white solid. 1H NMR (500 MHz, CDCl3):  =
8.07 (s, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 7.1 Hz, 1 H),
7.19 (t, J = 7.5 Hz, 1 H), 6.06–6.00 (m, 1 H), 5.07 (d, J = 10.1 Hz,
1 H), 4.96 (d, J = 17.2 Hz, 1 H), 4.12 (brs, 1 H), 3.77 (d, J = 4.7 Hz,
2 H), 3.61 (brs, 1 H), 1.56 (brs, 6 H), 1.26 (brs, 6 H). 13C NMR
(125 MHz, CDCl3):  = 151.62, 139.15, 136.55, 136.18, 128.91,
125.84, 124.68, 122.73, 119.02, 116.28, 51.36, 46.29, 36.71,
20.59, 20.08. HRMS (ESI): m/z [M + H]+ calcd for C17H24N3O+:
286.19139; found: 286.19119.
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2017, 7, 2821. (b) Thoke, M. B.; Kang, Q. Synthesis 2019, 51,
2585.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F