Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-Catalyzed Regiodivergent Couplings between Indazoles and Isoprene

Article abstract of DOI:10.1002/anie.202100137

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N¹- or N²-position of indazoles is governed by the acid co-catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N-functionalization of indazoles.

Full text of DOI:10.1002/anie.202100137

Angewandte
Research Articles
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 8321–8328
International Edition: doi.org/10.1002/anie.202100137
German Edition: doi.org/10.1002/ange.202100137
Palladium Catalysis
Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-
Catalyzed Regiodivergent Couplings between Indazoles and Isoprene
+
+
Wen-Shuang Jiang , Ding-Wei Ji , Wei-Song Zhang, Gong Zhang, Xiang-Ting Min, Yan-
Cheng Hu, Xu-Liang Jiang,* and Qing-An Chen*
Abstract: Depending on the reactant property and reaction
mechanism, one major regioisomer can be favored in a reaction
that involves multiple active sites. Herein, an orthogonal
regulation of nucleophilic and electrophilic sites in the
regiodivergent hydroamination of isoprene with indazoles is
demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-
insertion pathway with respect to the electrophilic sites on
isoprene could be controlled by the choice of ligands. In terms
of the nucleophilic sites on indazoles, the reaction occurs at
as an attractive precursor in the chemical synthesis of
[5]
dimethylallyl-derived molecules. As a result, tremendous
[6]
effort has been devoted to the functionalization of isoprene.
Among them, the catalytic hydrofunctionalization process
[7]
represents the most atom-economic protocol. However,
most of the established methods focus on the regioselective
synthesis of one major isomer, despite multiple isomeric
1
2
either the N - or N -position of indazoles is governed by the
acid co-catalysts. Preliminary experimental studies have been
performed to rationalize the mechanism and regioselectivity.
This study not only contributes a practical tool for selective
functionalization of isoprene, but also provides a guide to
manipulate the regioselectivity for the N-functionalization of
indazoles.
Introduction
Dimethylallyl-related units are ubiquitous five-carbon
[1]
(
C5) skeletons in natural and bioactive compounds. The
existence of these groups usually plays a significant role in
enhancing the lipophilicity of molecules and facilitating
[2]
permeation across the cellular membrane. Therefore, the
installation of such motifs into important frameworks has
become an active research area in organic chemistry and drug
[
3]
discovery. In nature, prenylated and reverse-prenylated
moieties are usually assembled by employing dimethylallyl
pyrophosphate (DMAPP) as starting materials through
[
4]
enzyme catalyzed biosynthesis, whereas their isomeric
variants are less commonly encountered (Figure 1A). Owing
to its low cost and large-scale production, isoprene can serve
[
+]
[
*] W. S. Jiang, Prof. Dr. X. L. Jiang
Department of Medicinal Chemistry, Shenyang Pharmaceutical
University
1
03 Wenhua Road, Shenyang 110016 (China)
E-mail: xuliangjiang@syphu.edu.cn
[
+]
[+]
W. S. Jiang, D. W. Ji, W. S. Zhang, G. Zhang, X. T. Min, Dr. Y. C. Hu,
Prof. Dr. Q. A. Chen
Dalian Institute of Chemical Physics, University of Chinese Academy
of Sciences
4
57 Zhongshan Road, Dalian 116023 (China)
E-mail: qachen@dicp.ac.cn
Homepage: http://www.lbcs.dicp.ac.cn
+
[
] These authors contributed equally to this work.
Figure 1. A) Biosynthesis pathway for dimethylallyl units (B) Bioactive
molecules containing the indazole skeleton (C) Catalytic allylation of
indazoles with allenes (D) Pd-catalytic regiodivergent dimethylallylation
of indazole with isoprene.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100137.
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328
ꢀ 2021 Wiley-VCH GmbH
8321

Angewandte
Research Articles
Chemie
[a]
outcomes possible. The development of regiodivergent meth-
odologies, which is of great importance to synthetic efficiency
and molecular diversity, still remains in its infancy.
Table 1: Acid and ligand effects.
[
8,9]
Indazoles are pharmacologically important scaffolds that
usually serve as indole bioisosteres in medicinal research
[
10]
(
Figure 1B). The direct allylation of indazoles is one of the
[11,12]
most efficient methods to derivatize these molecules.
Nevertheless, the presence of tautomeric forms inevitably
introduces site-selectivity challenges. Normally, the direct N-
allylation of indazoles under basic conditions delivers a mix-
1
2
[13]
ture of N and N -allylic products. The successful discovery
of efficient catalysis for the selective N-allylation of indazoles
[
14,15]
is very limited.
In 2015, Lin and co-workers reported
2
a metal-mediated regioselective N -allylation of indazoles
with allyl bromides in the presence of stoichiometric gallium
or aluminum metal. With the aid of excess amount of titanium
tetraisopropoxide, a Pd-catalyzed protocol was also disclosed
1
by Wu et al. for the N -selective allylation of the unsubstituted
indazole with allylic alcohols. Very recently, Breitꢀs group
reported an impressive achievement in metal catalyzed
[16]
couplings of indazole with allenes (Figure 1C).
In our
continued interest towards regiodivergent transformations of
[
6k,9h,j]
isoprene,
it is noteworthy that the exploitation of
naturally and industrially abundant isoprene in coupling with
indazoles is largely absent in the literature. This is speculated
to be attributed to obstacles towards regiocontrol: 1) the
1
2
competitive nucleophilic sites between the N and N
positions of indazole; 2) the four electrophilic sites derived
from the electronically unbiased alkenyl carbon atoms of
isoprene. Herein, we report a ligand and acid-regulated
strategy for the Pd-catalyzed regiodivergent coupling reac-
tions between indazoles and isoprene (Figure 1D). The
present protocol features an orthogonal control of nucleo-
philic and electrophilic sites in catalytic hydrofunctionaliza-
tion.
Results and Discussion
product 4a via 4,3-addition. By replacing Pd(PPh ) with
3 4
t
n
Pd(P Bu ) and increasing the amount of ( BuO) PO H to
3
2
2
2
We began our study with indazole 1a and isoprene 2 as the
model substrates (Table 1). Previous works have shown that
an acid co-catalyst can play a crucial role in the generation of
the metal-hydride for catalytic hydrofunctionalization of
50 mol%, 82% yield of 4a could be obtained (Table 1B).
Next, we turned our attention to the N -selectivity (Ta-
1
ble 1C). With the aid of BEt , all the ligands employed here
3
primarily delivered 4,3-adduct 5a or 4,1-adduct 6a as
mixtures, and the ligand L7 exhibiting the best performance
in terms of regioselectivity. Using the combination of 5 mol%
[
17,18]
dienes.
Thereby, various acids were first examined using
Pd(PPh ) and L5 as the catalyst combo (Table 1A). Delight-
3
4
t
fully, Brønsted acids, such as carboxylic acid, sulfonic acid and
phosphoric acid, all promoted the formation of 1,2 or 4,3-
Pd(P Bu ) and 75 mol% BEt , 82% yield of 5a was produced
3
2
3
1
in good regioselectivity. Notably, no 1,2-adduct at the N -site
was observed in all cases.
2
addition products (3a and 4a) in excellent N -selectivity. In
1
contrast, the selectivity towards the N -allylic product (5a and
Having established the optimal conditions, the generality
2
6
a) was achieved by switching to the Lewis acid BEt3.
of substrates towards 1,2-adducts at the N -site was first
Encouraged by these promising results, the evaluation of
ligands was subsequently carried out to enhance the reactivity
explored with the assistance of ligand L5 and (PhO) PO H.
2
2
As depicted in Table 2, subjecting unsubstituted indazole 1a
to the standard conditions successfully delivered the reverse-
prenylated indazole 3a in 65% isolated yield. Reverse-
prenylation of the 5-Me substituted indazole proceeded
n
and selectivity (Table 1B). In the presence of ( BuO) PO H
2
2
(
20 mol%), Cy-DPEphos (L5) was found to facilitate the
2
formation of N -products 3a and 4a in good yield (67% and
%, respectively). The yield of 3a could be further increased
to 69% with excellent regioselectivity when (PhO) PO H was
2
7
smoothly to provide 3b in 68% yield with good N -selectivity.
The indazole derivative bearing a methoxy group at the 5-
position also reacted well with isoprene and produced 3c in
good yield and excellent regioselectivity. Substrates possess-
2
2
n
used instead of ( BuO) PO H. Interestingly, the bulky ligand
L7 remarkably diverted the regioselectivity to N -allyl
2
2
2
8
322
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328

Angewandte
Research Articles
Chemie
2
Table 2: Substrate scope towards 1,2-adducts and 4,3-adducts at N -site.
ing electron-withdrawing substituents, such as CF , halides,
under current reaction conditions (4i–4n), albeit product 4n
3
CO Me at the 4, 5 or 6-positions of the indazole core all
was obtained in comparably lower yield. Similar to the 1,2-
adducts, substrates with a sensitive group, such as -Br and
-B(pin), were accommodated in all case (4g, 4j, 4l and 4n–
4p). 7-Methyl substituted indazole could also be effectively
transformed (4o). Notably, all these 4,3-addition products 4
could be obtained in pure form after flash chromatography
without the contamination of other minor isomers. However,
no desired products were observed when substrate having
a nitro, cyano or alkynyl group at the 5 or 6-position. Due to
the steric hindrance, 3-substituted indazoles were also not
suitable under the current protocol.
2
efficiently afforded products 3d–3n in 41–79% yields with
regioselectivities consistently maintained at high levels. To
our delight, the bromo group, regardless of their positions,
was all tolerated under current protocol (3g, 3j, 3l, 3n and
3
o). Besides, Indazole possessing a B(pin) group is also
compatible in our system (3p). These products may be good
handles for further functionalization. The regioselectivity for
this hydroamination was further confirmed by X-ray analysis
of 3i (see the Supporting Information for detail).
2
The substrate tolerance towards the 4,3-adducts at the N -
position was then examined (Table 2, right). By choosing L7
as the ligand, simple indazole 1a could be efficiently
converted into the 4,3-addition product 4a in 70% isolated
yield with 10:1 selectivity (N vs. N ). Substrates bearing
either electron-withdrawing or electron-donating substituents
at the 5-position of indazoles all proceeded smoothly to
produce the corresponding products with moderate to good
yields and acceptable regioselectivities (4b–4h). Substituents
at the 4 and/or 6-position of indazoles were also compatible
Subsequently, the generality of current regiodivergent
strategy was further examined by important and challenging
pyrazole substrates (Table 3). In the presence of L5 and
(PhO) PO H, we were pleased to found that the reactions
with various unsymmetrical pyrazoles could exclusively gave
the 1,2-adducts in good yields and excellent regioselectivities
(7a–7e). With the assistance of L7, the allylic reactions in 4,3-
addition also proceeded smoothly to deliver products 8a–8e
in 41–86% yields and good to excellent regioselectivities.
2
1
2
2
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
8323

Angewandte
Research Articles
Chemie
1
Table 3: Substrate scope of substituted pyrazoles.
Table 4: Substrate scope towards 4,3-adducts at N -site.
Remarkably, pyrazoles with formyl group were all feasible in
these cases. The regioselectivity for these hydroamination
were further confirmed by X-ray analysis of 7b and 8c (see
the Supporting Information for detail).
Next we probed the scope of the reaction with respect to
N -allylation of indazoles (Table 4). The model substrate 1a
1
could be efficiently converted to product 5a in 82% yield and
1
4
4:1 regioselectivity. Moreover, a range of indazoles bearing
-, 5 or 6-substituents, including -Me, -OMe, -F, -Cl, -CF and
3
-
CO Me, all worked well in this protocol to give products 5b–
2
5
j in good yields (71–90%) and high regioselectivities. 6-
Boron substituted indazole was successfully employed as well
to afford the desired product 5k in 61% yield and excellent
regioselectivity. It is noteworthy that the transformation could
be further extended to azaindazoles and the corresponding
products 5l and 5m were generated in 83% and 77% yields,
respectively. In addition, indazoles with a methyl or ester
group at 3-position were well applied in this case (5n and 5o).
Regrettably, the bromo, nitro, cyano or alkynyl group could
not be tolerated.
groups appear to have no obvious effects on both reactivity
and selectivity under the condition C, which highlights the
broad applicability of this regiodivergent protocol. The
structure of 12 was further confirmed by X-ray analysis (see
the Supporting Information for detail).
To gain insight into the mechanism of our regiodivergent
catalysis, deuterium-labeled experiments were conducted
i
(Figure 3A). When excess PrOD-d was employed in the
8
standard condition A, the corresponding allylic product 3a
was obtained only with 5% of deuterium at the methyl group.
The low rate of deuterium incorporation may be attributed to
To further demonstrate the practical utility of this
protocol, late-stage diversification of several indazole-con-
taining bioactive molecules were examined (Figure 2). Picti-
lisib (9) is an orally available small-molecule inhibitor of the
class I phosphatidylinositol-3-kinases (PI3K) and has shown
II
the reversible migratory insertion of isoprene into Pd -
hydride. As expected, deuterated isoprene was indeed
observed by GC-MS (see the Supporting Information for
detail). Furthermore, no obvious deuterium scrambling
suggests that the 1,2-addition of Pd-hydride to isoprene is
preferred over other inserted orientation in this transforma-
tion. In comparison, under condition B and C, deuterium
labeling in product 4a or 5a was detected at both the two
methyl groups and terminal position of alkenes, which
indicates that both 1,2-addition and 4,3-addition of the Pd-
hydride to isoprene are occurred reversibly.
[10e]
clinically significant antitumor activity.
Pleasingly, this
compound reacts favorably under our divergent Pd-hydride
catalysis, leading to the N2-allylic product 10a or 10b in 49%
1
and 32% yields, respectively. For solubility issue, N -selective
product 10c was only obtained in 16% yield under the
[
10d]
condition C. Compound 11 is a Syk-selective inhibitor
compound 13 is a ROCK1 inhibitor,
and
[10a]
both of which possess
multiple reactive NH groups. Remarkably, these extra NH
8
324
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328

Angewandte
Research Articles
Chemie
Figure 2. Late-stage modification of bioactive molecules.
Figure 3. Mechanistic insights.
A general strategy for regiodivergent control in organic
reaction stems from interchangeable isomerization between
kinetic and thermodynamic products. For better interpre-
tation of the regio-selective alteration principle, product 3a
was isolated and subjected to the three standard conditions
(Figure 3B). Under the condition A (with L5 as ligand and
[19]
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
8325

Angewandte
Research Articles
Chemie
(
PhO) PO H as acid), substrate 1a was achieved in 45%
2 2
yield, no product 4a or 5a was produced under this reaction.
This result supports the reversibility for the formation of 3a
under condition A. Besides, it is also consistent with the good
regioselectivity observed for 3a. Interestingly, 35% yield of
4
a and 13% yield of 5a were both obtained in the case of
condition B, which indicates that the isomerization from 3a to
n
4
a and 5a indeed occurred with ligand L7 and ( BuO) PO H
2 2
(
condition B). In contrast, only 5a rather than 4a was
detected when BEt was employed (condition C), which also
3
agrees with the excellent selectivity of 5a observed in other
reactions.
The kinetic experiments were also conducted (Figure 3C).
An approximately linear relationship between yield and
reaction time was noticed for product 3a under the condition
A at the early stage of the reaction. Similar observations were
also obtained under condition C where product 5a predom-
inates over the time. However, under condition B, an
interesting inverted V-shaped formation of 3a was observed
over the time. Meanwhile, an approximately linear increase in
yield of product 4a was found. These results support the
conclusion that formation of 3a from 1a is reversible.
On the basis of experimental observations and previous
reports, we proposed the following mechanism for the ligand-
regulated hydroindazoylation of isoprene (Figure 4). First,
0
oxidative addition of acid HX to a Pd precursor leads to
II
1
Figure 5. Bifunctional roles of BEt in N -hydroamination.
coordinatively unsaturated (16 electron) Pd -hydride species
3
[
20]
II
A. The last one unoccupied orbital at Pd center is spared
to facilitate the coordination of isoprene 2. Then, migratory
II
2
insertion of isoprene into Pd -hydride delivers the p-allyl-Pd
formation of 1H-indazole complex by coordinating with N
atom (Int 1). Theoretically, four possible tautomers (Int 1–4)
could be formed during the complexation of indazole 1a with
BEt (Figure 5A) In terms of thermodynamics, tautomer Int
1 is preferred over Int 4 based on density functional theory
(DFT) calculations of relative energy difference (5.9 kcal
mol , Figure 5A, see the Supporting Information for detail).
The calculations also suggest tautomer Int 2 and 3 are too
unstable to form. The coordinated site of Int 1 could be
further confirmed as N -position by NOESY spectra analysis
(see the Supporting Information for detail). A comparison of
intermediate B or B’. Based on the analysis of coordination
geometry and kinetic studies (Figure 3C), 1,2-insertion is
kinetically favored in the presence of the less bulky ligand L5,
while 4,3-insertion becomes the alternative pathway with the
aid of the bulky ligand L7. A final nucleophilic substitution of
indazole 1a to B or B’ affords the product 3a or 4a,
3
.
À1
0
respectively and regenerates the Pd species. The good
regioselectivity for product 4a resulting from that bulky
ligand L7 could facilitate the transformation of kinetic
product 3a to thermodynamic product 4a under palladium
catalysis.
2
1
H NMR spectra between 1a and 1a + BEt3 also clearly
1
With regard to nucleophilic site regulation towards N -
indicated the formation of one single complex with a clear
downfield shift (Figure 5B). This is a result of decreasing
electron density at the aromatic carbons of indazole through
the formation of complex Int 1. No obvious changes was
found in the case of 1a + (RO) PO H (see the Supporting
hydroamination products, we speculated BEt plays bifunc-
3
tional roles (Figure 5). First, the BEt3 can facilitate the
2
2
Information for detail). Therefore, the regioselective switch
between condition B and C probably results from the
2
deactivation of N atom by BEt in terms of nucleophilicity.
3
On the other hand, a small amount of BEt was expected to
3
0
undergo oxidative addition with Pd and the subsequent b-
II
[9h]
hydride elimination to deliver the Et B-Pd -H species.
2
II
Subsequent migratory insertion of isoprene into Pd -hydride
and nucleophilic substitution will deliver 5a (Figure 5B).
2
Figure 4. Proposed mechanism towards N -hydroamination.
8
326
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328

Angewandte
Research Articles
Chemie
Conclusion
Org. Chem. 2018, 83, 7276; o) H.-F. Tu, X. Zhang, C. Zheng, M.
Zhu, S.-L. You, Nat. Catal. 2018, 1, 601; p) X. Wang, X. Zeng, Q.
Lin, M. Li, P. J. Walsh, J. J. Chruma, Adv. Synth. Catal. 2019, 361,
In conclusion, we have developed an orthogonal regu-
3
751.
lation of nucleophilic and electrophilic sites in regiodivergent
couplings between indazoles and isoprene. Under Pd-hydride
catalysis, the 1,2- or 4,3-insertion pathways with regard to
electrophilic sites is controlled by the choice of ligands. In
terms of nucleophilic sites, the reaction occurs at either the
[
4] a) T. Kuzuyama, Biosci. Biotechnol. Biochem. 2002, 66, 1619;
b) T. Kuzuyama, H. Seto, Nat. Prod. Rep. 2003, 20, 171; c) L.
Heide, Curr. Opin. Chem. Biol. 2009, 13, 171; d) T. Kuzuyama, J.
Antibiot. 2017, 70, 811; e) Q. Wang, S. Quan, H. Xiao, Bioresour.
Bioprocess. 2019, 6, 6.
1
2
N - or N -position of indazoles and is governed by the acid co-
catalysts. Furthermore, regio-divergent late-stage modifica-
tion of bioactive molecules has been performed to demon-
strate the potentially broad applicability of this protocol. This
regiodivergent method not only features high atom economy,
but also contributes to emerging metal-catalyzed regiodiver-
gent methodologies
[5] A. R. C. Morais, S. Dworakowska, A. Reis, L. Gouveia, C. T.
Matos, D. Bogdal, R. Bogel-Lukasik, Catal. Today 2015, 239, 38.
[
6] For selected examples, see: a) L. M. Geary, B. W. Glasspoole,
M. M. Kim, M. J. Krische, J. Am. Chem. Soc. 2013, 135, 3796;
b) T. Nishimura, Y. Ebe, T. Hayashi, J. Am. Chem. Soc. 2013, 135,
2
092; c) T. Nishimura, M. Nagamoto, Y. Ebe, T. Hayashi, Chem.
Sci. 2013, 4, 4499; d) B. Y. Park, T. P. Montgomery, V. J. Garza,
M. J. Krische, J. Am. Chem. Soc. 2013, 135, 16320; e) J. Y.
Hamilton, D. Sarlah, E. M. Carreira, J. Am. Chem. Soc. 2014,
1
2
2
36, 3006; f) Y. Ebe, M. Hatano, T. Nishimura, Adv. Synth. Catal.
015, 357, 1425; g) M. S. McCammant, M. S. Sigman, Chem. Sci.
015, 6, 1355; h) L. Jiang, P. Cao, M. Wang, B. Chen, B. Wang, J.
Acknowledgements
Liao, Angew. Chem. Int. Ed. 2016, 55, 13854; Angew. Chem.
016, 128, 14058; i) K. B. Smith, Y. Huang, M. K. Brown, Angew.
We thank Prof. Yong-Gui Zhou (DICP), Prof. Kevin G. M.
Kou (UCR) and Prof. Zhi-Shi Ye (DUT) for helpful
discussions and manuscript revisions. Financial support from
Dalian Outstanding Young Scientific Talent, the National
Natural Science Foundation of China (22071239, 21801239)
2
Chem. Int. Ed. 2018, 57, 6146; Angew. Chem. 2018, 130, 6254;
j) J.-J. Feng, Y. Xu, M. Oestreich, Chem. Sci. 2019, 10, 9679; k) Y.
Li, Y. C. Hu, H. Zheng, D. W. Ji, Y. F. Cong, Q. A. Chen, Eur. J.
Org. Chem. 2019, 6510; l) J. Yang, D. W. Ji, Y. C. Hu, X. T. Min,
X. G. Zhou, Q. A. Chen, Chem. Sci. 2019, 10, 9560.
and
Liaoning
Revitalization
Talents
Program
[
7] For selected examples, see: a) O. Lçber, M. Kawatsura, J. F.
Hartwig, J. Am. Chem. Soc. 2001, 123, 4366; b) M. Kimura, A.
Ezoe, M. Mori, K. Iwata, Y. Tamaru, J. Am. Chem. Soc. 2006,
(
XLYC1807181) is acknowledged.
1
28, 8559; c) H. Qin, N. Yamagiwa, S. Matsunaga, M. Shibasaki,
Conflict of interest
J. Am. Chem. Soc. 2006, 128, 1611; d) D. Banerjee, K. Junge, M.
Beller, Angew. Chem. Int. Ed. 2014, 53, 1630; Angew. Chem.
2
014, 126, 1656; e) D. Banerjee, K. Junge, M. Beller, Org. Chem.
The authors declare no conflict of interest.
Front. 2014, 1, 368; f) X. Fang, H. Li, R. Jackstell, M. Beller, J.
Am. Chem. Soc. 2014, 136, 16039; g) X.-H. Yang, A. Lu, V. M.
Dong, J. Am. Chem. Soc. 2017, 139, 14049; h) B. Fu, X. Yuan, Y.
Li, Y. Wang, Q. Zhang, T. Xiong, Q. Zhang, Org. Lett. 2019, 21,
Keywords: hydroamination · indazole · isoprene · palladium ·
regiodivergent
3
576; i) C. Li, R. Y. Liu, L. T. Jesikiewicz, Y. Yang, P. Liu, S. L.
Buchwald, J. Am. Chem. Soc. 2019, 141, 5062; j) Y.-L. Li, W.-D.
Li, Z.-Y. Gu, J. Chen, J.-B. Xia, ACS Catal. 2020, 10, 1528.
8] a) A. M. Haydl, B. Breit, T. Liang, M. J. Krische, Angew. Chem.
Int. Ed. 2017, 56, 11312; Angew. Chem. 2017, 129, 11466; b) C.
Nµjera, I. P. Beletskaya, M. Yus, Chem. Soc. Rev. 2019, 48, 4515.
9] a) T. Smejkal, H. Han, B. Breit, M. J. Krische, J. Am. Chem. Soc.
[
[
[
1] a) E. Breitmaier, Terpenes: Flavors, Fragrances, Pharmaca,
Pheromones, Wiley-VCH, Weinheim, 2006; b) S. M. Li, Nat.
Prod. Rep. 2010, 27, 57.
2] T. Koyama, K. Ogura in Comprehensive Natural Products
Chemistry (Eds.: S. D. Barton, K. Nakanishi, O. Meth-Cohn),
Pergamon, Oxford, 1999, p. 69.
3] For related examples, see: a) Y. J. Zhang, E. Skucas, M. J.
Krische, Org. Lett. 2009, 11, 4248; b) B. M. Trost, S. Malhotra,
W. H. Chan, J. Am. Chem. Soc. 2011, 133, 7328; c) J. L. Farmer,
H. N. Hunter, M. G. Organ, J. Am. Chem. Soc. 2012, 134, 17470;
d) Y. Yang, S. L. Buchwald, J. Am. Chem. Soc. 2013, 135, 10642;
e) Y. Yang, T. J. L. Mustard, P. H.-Y. Cheong, S. L. Buchwald,
Angew. Chem. Int. Ed. 2013, 52, 14098; Angew. Chem. 2013, 125,
[
[
2
009, 131, 10366; b) A. Kçpfer, B. Sam, B. Breit, M. J. Krische,
Chem. Sci. 2013, 4, 1876; c) K. Xu, N. Thieme, B. Breit, Angew.
Chem. Int. Ed. 2014, 53, 2162; Angew. Chem. 2014, 126, 2194;
d) K. Xu, N. Thieme, B. Breit, Angew. Chem. Int. Ed. 2014, 53,
7
268; Angew. Chem. 2014, 126, 7396; e) K. B. Smith, M. K.
Brown, J. Am. Chem. Soc. 2017, 139, 7721; f) N. Thieme, B. Breit,
Angew. Chem. Int. Ed. 2017, 56, 1520; Angew. Chem. 2017, 129,
1542; g) T. Jia, Q. He, R. E. Ruscoe, A. P. Pulis, D. J. Procter,
Angew. Chem. Int. Ed. 2018, 57, 11305; Angew. Chem. 2018, 130,
11475; h) Y. C. Hu, D. W. Ji, C. Y. Zhao, H. Zheng, Q. A. Chen,
Angew. Chem. Int. Ed. 2019, 58, 5438; Angew. Chem. 2019, 131,
5492; i) X.-H. Yang, R. T. Davison, S.-Z. Nie, F. A. Cruz, T. M.
McGinnis, V. M. Dong, J. Am. Chem. Soc. 2019, 141, 3006; j) C.-
S. Kuai, D.-W. Ji, C.-Y. Zhao, H. Liu, Y.-C. Hu, Q.-A. Chen,
Angew. Chem. Int. Ed. 2020, 59, 19115; Angew. Chem. 2020, 132,
19277; k) Z.-Q. Li, Y. Fu, R. Deng, V. T. Tran, Y. Gao, P. Liu,
K. M. Engle, Angew. Chem. Int. Ed. 2020, 59, 23306; Angew.
Chem. 2020, 132, 23506; l) W. Shao, C. Besnard, L. Guenee, C.
Mazet, J. Am. Chem. Soc. 2020, 142, 16486.
1
1
1
2
4348; f) M. J. Ardolino, J. P. Morken, J. Am. Chem. Soc. 2014,
36, 7092; g) J. Ruchti, E. M. Carreira, J. Am. Chem. Soc. 2014,
36, 16756; h) M. Ellwart, P. Knochel, Angew. Chem. Int. Ed.
015, 54, 10662; Angew. Chem. 2015, 127, 10808; i) R. Alam, C.
Diner, S. Jonker, L. Eriksson, K. J. Szabo, Angew. Chem. Int. Ed.
016, 55, 14417; Angew. Chem. 2016, 128, 14629; j) M. Ellwart,
2
I. S. Makarov, F. Achrainer, H. Zipse, P. Knochel, Angew. Chem.
Int. Ed. 2016, 55, 10502; Angew. Chem. 2016, 128, 10658; k) S.
Tanaka, S. Shiomi, H. Ishikawa, J. Nat. Prod. 2017, 80, 2371;
l) J. C. Hethcox, S. E. Shockley, B. M. Stoltz, Angew. Chem. Int.
Ed. 2018, 57, 8664; Angew. Chem. 2018, 130, 8800; m) S. Priya,
J. D. Weaver III, J. Am. Chem. Soc. 2018, 140, 16020; n) M.
Shiozawa, K. Iida, M. Odagi, M. Yamanaka, K. Nagasawa, J.
[10] a) K. B. Goodman, H. Cui, S. E. Dowdell, D. E. Gaitanopoulos,
R. L. Ivy, et al., J. Med. Chem. 2007, 50, 6; b) N. Brown,
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
8327

Angewandte
Research Articles
Chemie
Bioisosterism in Medicinal Chemistry, Wiley-VCH, Weinheim,
012; c) S. K. Knutson, T. J. Wigle, N. M. Warholic, C. J. Sneer-
e) X. Wu, L. Z. Gong, Synthesis 2019, 51, 122; f) G. Li, X. Huo,
X. Jiang, W. Zhang, Chem. Soc. Rev. 2020, 49, 2060; g) G. J. P.
Perry, T. Jia, D. J. Procter, ACS Catal. 2020, 10, 1485.
2
inger, C. J. Allain, et al., Nat. Chem. Biol. 2012, 8, 890; d) K. S.
Currie, J. E. Kropf, T. Lee, P. Blomgren, J. Xu, et al., J. Med.
Chem. 2014, 57, 3856; e) D. Sarker, J. E. Ang, R. Baird, R.
Kristeleit, K. Shah, et al., Clin. Cancer Res. 2015, 21, 77; f) I. E.
Krop, I. A. Mayer, V. Ganju, M. Dickler, S. Johnston, et al.,
Lancet Oncol. 2016, 17, 811.
[18] For related examples, see: a) M. J. Goldfogel, S. J. Meek, Chem.
Sci. 2016, 7, 4079; b) N. J. Adamson, E. Hull, S. J. Malcolmson, J.
Am. Chem. Soc. 2017, 139, 7180; c) Y. Y. Gui, N. Hu, X. W.
Chen, L. L. Liao, T. Ju, J. H. Ye, Z. Zhang, J. Li, D. G. Yu, J. Am.
Chem. Soc. 2017, 139, 17011; d) J. S. Marcum, C. C. Roberts,
R. S. Manan, T. N. Cervarich, S. J. Meek, J. Am. Chem. Soc. 2017,
139, 15580; e) X. H. Yang, V. M. Dong, J. Am. Chem. Soc. 2017,
139, 1774; f) N. J. Adamson, K. C. E. Wilbur, S. J. Malcolmson, J.
Am. Chem. Soc. 2018, 140, 2761; g) L. Cheng, M. M. Li, L. J.
Xiao, J. H. Xie, Q. L. Zhou, J. Am. Chem. Soc. 2018, 140, 11627;
h) S. Z. Nie, R. T. Davison, V. M. Dong, J. Am. Chem. Soc. 2018,
140, 16450; i) L. J. Xiao, L. Cheng, W. M. Feng, M. L. Li, J. H.
Xie, Q. L. Zhou, Angew. Chem. Int. Ed. 2018, 57, 461; Angew.
Chem. 2018, 130, 470; j) X. H. Yang, R. T. Davison, V. M. Dong,
J. Am. Chem. Soc. 2018, 140, 10443; k) X. W. Chen, L. Zhu, Y. Y.
Gui, K. Jing, Y. X. Jiang, Z. Y. Bo, Y. Lan, J. Li, D. G. Yu, J. Am.
Chem. Soc. 2019, 141, 18825; l) Y. G. Chen, B. Shuai, X. T. Xu,
Y. Q. Li, Q. L. Yang, H. Qiu, K. Zhang, P. Fang, T. S. Mei, J. Am.
Chem. Soc. 2019, 141, 3395; m) J. Long, P. Wang, W. Wang, Y. Li,
G. Yin, iScience 2019, 22, 369; n) L. Lv, D. Zhu, Z. Qiu, J. Li, C.-J.
Li, ACS Catal. 2019, 9, 9199; o) X.-Y. Lv, C. Fan, L.-J. Xiao, J.-H.
Xie, Q.-L. Zhou, CCS Chem. 2019, 1, 328; p) G. Tran, W. Shao, C.
Mazet, J. Am. Chem. Soc. 2019, 141, 14814; q) L. Lv, L. Yu, Z.
Qiu, C.-J. Li, Angew. Chem. Int. Ed. 2020, 59, 6466; Angew.
Chem. 2020, 132, 6528; r) H. Yang, D. Xing, Chem. Commun.
2020, 56, 3721.
[
[
11] For selected reviews on indazole, see: a) H. Cerecetto, A. Gerpe,
M. Gonzalez, V. J. Aran, C. O. de Ocariz, Mini-Rev. Med. Chem.
2
005, 5, 869; b) A. Schmidt, A. Beutler, B. Snovvdovych, Eur. J.
Org. Chem. 2008, 4073; c) D. D. Gaikwad, A. D. Chapolikar,
C. G. Devkate, K. D. Warad, A. P. Tayade, R. P. Pawar, A. J.
Domb, Eur. J. Med. Chem. 2015, 90, 707; d) S. G. Zhang, C. G.
Liang, W. H. Zhang, Molecules 2018, 23, 41.
12] For selected reviews on allylic substitutions, see: a) J. Tsuji, I.
Minami, Acc. Chem. Res. 1987, 20, 140; b) B. M. Trost, D. L.
VanVranken, Chem. Rev. 1996, 96, 395; c) M. Johannsen, K. A.
Jorgensen, Chem. Rev. 1998, 98, 1689; d) B. M. Trost, M. L.
Crawley, Chem. Rev. 2003, 103, 2921; e) G. Helmchen, A. Dahnz,
P. Dubon, M. Schelwies, R. Weihofen, Chem. Commun. 2007,
6
75; f) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem. 2008, 3765;
g) Z. Lu, S. Ma, Angew. Chem. Int. Ed. 2008, 47, 258; Angew.
Chem. 2008, 120, 264; h) J. F. Hartwig, L. M. Stanley, Acc. Chem.
Res. 2010, 43, 1461; i) G. Poli, G. Prestat, F. Liron, C. Kammerer-
Pentier, Top. Organomet. Chem. 2012, 38, 1; j) L. Milhau, P. J.
Guiry, Top. Organomet. Chem. 2012, 38, 95; k) W. B. Liu, J. B.
Xia, S. L. You, Top. Organomet. Chem. 2012, 38, 155; l) J. M.
Begouin, J. Klein, D. Weickmann, B. Plietker, Top. Organomet.
Chem. 2012, 38, 269; m) Q. Cheng, H. F. Tu, C. Zheng, J. P. Qu,
G. Helmchen, S. L. You, Chem. Rev. 2019, 119, 1855.
[19] a) I. D. G. Watson, A. K. Yudin, J. Am. Chem. Soc. 2005, 127,
17516; b) I. Dubovyk, I. D. G. Watson, A. K. Yudin, J. Org.
Chem. 2013, 78, 1559; c) Q.-A. Chen, Z. Chen, V. M. Dong, J.
Am. Chem. Soc. 2015, 137, 8392; d) W.-F. Zheng, Q.-J. Xu, Q.
Kang, Organometallics 2017, 36, 2323; e) J. Zheng, B. Breit,
Angew. Chem. Int. Ed. 2019, 58, 3392; Angew. Chem. 2019, 131,
3430.
[
[
13] a) A. Albini, G. Bettinetti, G. Minoli, Heterocycles 1988, 27,
1
207; b) K. W. Hunt, D. A. Moreno, N. Suiter, C. T. Clark, G.
Kim, Org. Lett. 2009, 11, 5054.
14] a) Y. Wu, F. Y. Kwong, P. Li, A. S. C. Chan, Synlett 2013, 24,
2
009; b) M.-H. Lin, H.-J. Liu, W.-C. Lin, C.-K. Kuo, T.-H.
Chuang, Org. Biomol. Chem. 2015, 13, 11376; c) H. Wang, C.
Guo, Angew. Chem. Int. Ed. 2019, 58, 2854; Angew. Chem. 2019,
[20] a) R. W. Armbruster, M. M. Morgan, J. L. Schmidt, C. M. Lau,
R. M. Riley, D. L. Zabrowski, H. A. Dieck, Organometallics
1986, 5, 234; b) I. Kadota, A. Shibuya, Y. S. Gyoung, Y.
Yamamoto, J. Am. Chem. Soc. 1998, 120, 10262; c) B. M. Trost,
C. Jakel, B. Plietker, J. Am. Chem. Soc. 2003, 125, 4438; d) S.
Park, N. J. Adamson, S. J. Malcolmson, Chem. Sci. 2019, 10,
5176; e) Z. Yang, X. Gu, L.-B. Han, J. Wang, Chem. Sci. 2020, 11,
7451; f) M.-M. Li, L. Cheng, L.-J. Xiao, J.-H. Xie, Q.-L. Zhou,
Angew. Chem. Int. Ed. 2021, 60, 2948 – 2951; Angew. Chem. 2021,
133, 2984 – 2987.
1
31, 2880; d) C.-Yu. Chang, Y.-H. Lin, Y.-K. Wu, Chem.
Commun. 2019, 55, 1116.
[
15] Y. Ye, I. Kevlishvili, S. Feng, P. Liu, S. L. Buchwald, J. Am. Chem.
Soc. 2020, 142, 10550.
16] a) A. M. Haydl, K. Xu, B. Breit, Angew. Chem. Int. Ed. 2015, 54,
[
7
149; Angew. Chem. 2015, 127, 7255; b) L. J. Hilpert, S. V.
Sieger, A. M. Haydl, B. Breit, Angew. Chem. Int. Ed. 2019, 58,
378; Angew. Chem. 2019, 131, 3416.
3
[
17] For related reviews, see: a) N. Herrmann, D. Vogelsang, A. Behr,
T. Seidensticker, ChemCatChem 2018, 10, 5342; b) M. Holmes,
L. A. Schwartz, M. J. Krische, Chem. Rev. 2018, 118, 6026; c) Y.
Xiong, Y. W. Sun, G. Z. Zhang, Tetrahedron Lett. 2018, 59, 347;
d) N. J. Adamson, S. J. Malcolmson, ACS Catal. 2019, 9, 1060;
Manuscript received: January 5, 2021
Accepted manuscript online: January 18, 2021
Version of record online: March 5, 2021
8
328
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 8321 – 8328