Isoprene: A Promising Coupling Partner in C-H Functionalizations

Article abstract of DOI:10.1055/s-0040-1707172

Five-carbon dimethylallyl units, such as prenyl and reverse-prenyl, are widely distributed in natural indole alkaloids and terpenoids. In conventional methodologies, these valuable motifs are often derived from substrates bearing leaving groups, but these

Full text of DOI:10.1055/s-0040-1707172

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© Georg Thieme Verlag Stuttgart · New York
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Isoprene: A Promising Coupling Partner in C–H Functionalizations
Wei-Song Zhanga,b
Yan-Cheng Hua
Qing-An Chen*a
a Dalian Institute of Chemical Physics, Chinese Academy
of Science, Dalian 116023, P. R. of China
b University of Chinese Academy of Sciences, Beijing
100049, P. R. of China
qachen@dicp.ac.cn
Received: 12.05.2020
Accepted after revision: 30.05.2020
Published online: 02.07.2020
DOI: 10.1055/s-0040-1707172; Art ID: st-2020-p0285-sp
Abstract Five-carbon dimethylallyl units, such as prenyl and reverse-
prenyl, are widely distributed in natural indole alkaloids and terpenoids.
In conventional methodologies, these valuable motifs are often derived
from substrates bearing leaving groups, but these processes are accom-
panied by the generation of stoichiometric amounts of by-products.
From an economical and environmental point of view, the basic indus-
trial feedstock isoprene is an ideal alternative precursor. However, given
that electronically unbiased isoprene might undergo six possible addi-
Qing-An Chen was born in 1984 in Fujian Province, China. He received
tion modes in the coupling reactions, it is difficult to control the selec-
a B.S. degree from the University of Science and Technology of China in
tivity. This article summarizes the strategies we have developed to
2007 and earned his Ph.D. from the Dalian Institute of Chemical Physics
achieve regioselective C–H functionalizations of isoprene under transi-
in 2012. He worked with Prof. Vy M. Dong at the University of California
Irvine as a postdoctoral fellow from 2012 to 2015. Then he joined Prof.
tion-metal and acid catalysis.
1
2
3
4
5
6
Introduction
Martin Oestreich’s group at Technische Universitat Berlin as an Alexander
von Humboldt Fellow. In 2017 he began his independent research ca-
reer at the Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, where currently he is Professor of Chemistry. His research
interests include the development of catalytic asymmetric reactions,
mechanistic elucidation, and asymmetric synthesis. He has authored
over 35 publications and received the 2020 Thieme Chemistry Journal
Award.
Catalytic Coupling of Indoles with Isoprene
Catalytic Coupling of Formaldehyde, Arenes and Isoprene
Catalytic Coupling of 4-Hydroxycoumarins with Isoprene
Catalytic Coupling of Cyclic 1,3-Diketones with Isoprene
Conclusion and Outlook
Key words isoprene, prenylation, C–H functionalization, regioselec-
tivity, catalysis
Yan-Cheng Hu was born in Jiangsu Province, China, in 1989. He ob-
tained his B.S. degree from Nanjing Normal University in 2010 and PhD
degree from the Dalian Institute of Chemical Physics in 2015, under the
supervision of Prof. Boshun Wan. He did his postdoctoral research with
Prof. Tao Zhang at the same institute from 2015 to 2018. Later, he
worked in the group of Prof. Qing-An Chen, where he is currently an as-
sociate professor. His research focuses on transition-metal and acid-cat-
alyzed transformations of isoprene, as well as their applications in the
total synthesis of natural products.
Wei-Song Zhang was born in Chongqing Municipality, China, received
a B.S. degree from Dalian University of Technology in 2018. Currently,
he works in the group of Prof. Qing-An Chen at Dalian Institute of
Chemical Physics as a graduate student. His research focuses on transi-
tion-metal-catalyzed hydrofunctionalizations of terpenes.
1 Introduction
Five-carbon (C5) dimethylallyl units, such as 3-methyl-
2-butenyl (prenyl) and 2-methyl-3-butenyl (reverse-pre-
nyl), are ubiquitous in nature (Figure 1).1 Because the pres-
ence of these unique groups can enhance the lipophilicity
of molecules and facilitate permeation across cellular mem-
brane, these natural products usually exhibit intriguing bio-
logical properties. For example, Annonidine B,2 isolated
from West African medicinal tree Annonidium mannii, pos-
sesses two prenyl groups at the 3- and 7-positions of the in-
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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W.-S. Zhang et al.
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dole ring. Caulindole C,3 a C3 reverse-prenylated indole al-
kaloid, shows antifungal and antimalarial activities. Flustra-
mine B,4 a cyclized N- and C3-prenylated tryptamine
derivative, exhibits smooth-muscle relaxant activity. Bear-
ing 2-reverse prenyl and 7-prenyl groups on indole core,
Notoamide S5 is a common precursor for the biosynthesis of
diverse bioactive metabolites in the genus Aspergillus. As
polycyclic polyprenylated acylphloroglucines (PPAPs) de-
rived from the plants of Hypericum family, Hyperforin6 and
Papuaforin A7 display potent antibiotic, antitumor and anti-
depressant properties. Therefore, the selective incorpora-
tion of prenyl and reverse-prenyl motifs into important
frameworks has been an active research field in catalysis
and synthesis.8
ingly, it would be ideal if isoprene can serve as a building
block to install prenyl (4,1-adduct) and reverse-prenyl
groups (2,1-adduct) (Scheme 1b). Nevertheless, electroni-
cally unbiased isoprene can lead to six possible regioiso-
mers, thus often making it challenging to modulate the
product distributions. This account introduces the strate-
gies we have developed to address this issue, by which the
selectivity for the isoprene couplings can be manipulated
by varying the catalyst.
a) Previous works:
LG
catalyst
H
or
+
LG
prenylated
products
reverse-prenylated
products
LG = OCO2R, OCOR
Bpin, ZnBr, Cl, OH
NH
b) Our works:
N
N
H
N
4
1
1
Br
H
4
3
transition metals
or acids
N
H
N
H
+
2
H
2
1
Annonidine B
O
Caulindole C
O
Flustramine B
isoprene
800000 t/y
4,1-adduct
Challenges:
Unactivated diene (four reactive sites)
Difficulty in controlling the selectivity
2,1-adduct
N
Advantages:
Cheap isoprene as C5 source
High step- and atom-economy
O
HN
O
OH
O
N
HO
Other possible regioisomers (excluding alkene isomerization):
H
4
1
1
4
O
2
iPr
4
O
O
iPr
3
O
3
Notoamide S
Hyperforin
Papuaforin A
1,4-adduct
1,2-adduct
3,4-adduct
4,3-adduct
Figure 1 Selected prenylated and reverse-prenylated natural products
Scheme 1 Catalytic installation of prenyl and reverse-prenyl groups
Transition-metal-catalyzed allylic substitution and di-
rected C–H activation are two representative strategies for
C–H functionalizations with dimethylallylic compounds.9
The organic chemistry community has developed some ef-
fective C5 coupling partners such as dimethylallylic alco-
hols10 and their derivatives including halides,11 acetates,12
carbonates13 and organometals14 (Scheme 1a). Leaving
groups play a critical role in the process, since they can dif-
ferentiate the electronic properties of the precursors and
facilitate the selective formation of key -allylmetal inter-
mediates.15 However, the pre-installation of leaving groups
and the consequent generation of stoichiometric by-prod-
ucts diminish both the step and atom economy. In this con-
text, from the viewpoint of green chemistry, the direct use
of unactivated C5 alkenes or dienes as prenyl or reverse-pre-
nyl sources would be highly demanded yet remains seldom
explored.
2 Catalytic Coupling of Indoles with Isoprene
Metal-hydride catalysis has emerged as a powerful tool
to promote the hydrofunctionalization of linear 1,3-
dienes.18 In the process, the active metal-hydride species is
often generated in situ via oxidative addition of low-valent
transition metals such as Pd(0), Ru(0), Rh(I), and Ni(0), with
Brønsted acids or alcohols.19 Compared with the tremen-
dous advances achieved in this area, the metal-hydride cat-
alyzed hydrofunctionalization of isoprene has been rather
limited, presumably because of the difficulty in controlling
the regioselectivity. We recently developed a regiodivergent
coupling of simple indoles with isoprene under metal-hy-
dride catalysis (Scheme 2).20 Reverse-prenylated indoles 3
were furnished with high selectivity when using
[Rh(cod)Cl]2 as a pre-catalyst, DTBM-Segphos as a ligand,
and 10-camphorsulfonic acid (CSA) as an additive. In com-
parison, a combination of Pd(PPh3)4, DTBM-Segphos and
BEt3 altered the coupling products to 3-prenylated indoles
4. 5-Prenyl indole was also compatible with both transfor-
mations, albeit with slightly decreased yields (3b, 4b). The
Isoprene is an important C5 conjugated diene in indus-
try, with a production capacity of approximately 800,000
metric tons per year.16 Furthermore, isoprene can also be
biosynthesized on a large scale via a modified Escherichia
coli fermentation process.17 In this respect, isoprene can be
regarded as an economic feedstock to some extent. Accord-
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electron-withdrawing (3c, 4c) and electron-donating sub-
stituents (3d, 4d) on phenyl ring, regardless of their posi-
tions, were all well tolerated.
teract with the nitrogen atom of indole, leading to the for-
mation of the adduct D′. The -allyl-Pd intermediate B′,
formed by isoprene insertion into A, undergoes nucleophil-
ic addition with D′ to produce complex C′ with the libera-
tion of BEt3 and HBEt2. Finally, prenylated indole 4a is af-
forded via an aromatization step. It is noteworthy that the
released HBEt2 serves as the hydride source to regenerate
Et2B–Pd(II)–H complex A in the next cycle.
[Rh(cod)Cl]2 (2.5 mol%)
DTBM-Segphos (5 mol%)
O
CSA (15 mol%)
tBuOH, 70 °C, 24 h
N
H
N
O
O
R
PAr2
PAr2
R
H
1
3
+
O
3 Catalytic Coupling of Formaldehyde,
Arenes and Isoprene
Ar = 3,5-(tBu)2-4-OMeC6H2
DTBM-Segphos
Pd(PPh3)4 (5 mol%)
DTBM-Segphos (5 mol%)
2a
N
BEt3 (30 mol%)
DCE, 70 °C, 24 h
H
R
4
Catalytic multicomponent coupling, featuring one-step
formation of multiple new bonds, has become one of the
most efficient strategies for the rapid assembly of structural
diversity and complexity in organic synthesis.21 In recent
years, three-component couplings of arenes, dienes and
carbonyls via C–H activation processes have attracted par-
ticular attention, since they can provide atom-economical
access to homoallylic alcohols.22 However, in these studies,
the coupling of isoprene often gives low yields and selectiv-
ities. In this context, we set out to exploit a catalytic system
to achieve regioselective coupling of isoprene, formalde-
hyde and 2-arylpyridines.23 It was found that homoallylic
alcohols 7 were afforded with exclusive regioselectivities
when Cp*Co(CO)I2 was employed as a catalyst with HOAc
and AgSbF6 as additives (Scheme 4). The electronic and ste-
ric factors of the substituents on the phenyl ring had no sig-
F
N
H
N
H
N
H
N
H
MeO
3b+4b, 49%
(3b/4b = 8/1)
3a, 70%
3c, 74%
3d, 76%
F
N
H
N
H
N
H
N
H
MeO
4a, 76%
4b, 43%
4c, 70%
4d, 81%
Scheme 2 Catalytic couplings of indoles with isoprene
A plausible mechanism for the divergent process is de-
picted in Scheme 3. For Rh catalysis, an initial oxidative ad-
dition of Rh(I) pre-catalyst with CSA delivers Rh(III)–H spe-
cies A. A subsequent isoprene insertion into A gives -allyl-
Rh intermediate B, followed by a nucleophilic attack of in-
dole to furnish complex C with release of CSA. An ultimate
aromatization results in reverse-prenylated indole 3a and
regenerates Rh(I) catalyst. For Pd catalysis, a small amount
of BEt3 is sacrificed for the generation of Et2B–Pd(II)–H spe-
cies A, involving oxidative addition of BEt3 with Pd(0) and
subsequent -hydride elimination. BEt3 is also likely to in-
Three-component coupling:
OH
DG
Cp*Co(CO)I2 (5 mol%)
AgSbF6 (10 mol%)
+
R
+
(CH2O)n
R
AcOH (40 mol%)
dioxane, 50 °C
DG
5
2a
6
7
OH
OH
OH
OH
Py
Py
Py
Py
7a, 86%
F
MeO
O
7b, 86%
7c, 52%
7d, 82%
Rh catalysis
X = RSO3
Pd catalysis
X = BEt2
OH
OH
HO
N
H
HX
N
Pd0-Ln
BEt3
RhI-Ln
Py
H
from 2b: myrcene
Py
3a
4a
7f, 76%
7e, 64%
OH
1a
RhI
Pd0
X
M
Ln
Py
N
H
C'
from 2c: farnesene
7g, 63%
BEt3
C
H
N
A
N
D'
OH
OH
OH
OH
HX
X
X
PdII
RhIII
N
HX
1a
Py
from 2d: myrcenol
B
B'
7h, 79%
7i, >99%
2a
Scheme 3 Proposed mechanism for divergent selectivity
Scheme 4 Catalytic couplings of formaldehyde, arenes and isoprene
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

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W.-S. Zhang et al.
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nificant impact on the reaction (7a–d), and even free hy-
droxyl was tolerated (7e). Notably, other complex terpene
derivatives including myrcene, farnesene, and myrcenol
were also suitable coupling partners (7f–h). Benzoquino-
line could also participate in the three-component cou-
pling, giving the target product 7i in nearly quantitative
yield.
a) Mechanistic studies
Py
Py
Py
OH
(CH2O)n
+/or
D5
Co cat.
standard conditions
H4 or D4 (8)
D5-5a
5a
Competitive reaction: KIE = 2.0 (36% yield)
Parallel reaction: KIE = 2.8 (27% yield)
The kinetic isotope effect (KIE) experiments reveal that
C–H bond cleavage is likely to be a rate-determining step
(Scheme 5a). Subjecting isoprene and 2-phenylpyridine to
the standard conditions afforded an oxidative coupling
product 9 (Scheme 5a). Additionally, in the absence of iso-
prene, a two-component coupling of formaldehyde and 2-
phenylpyridine could take place to deliver arylmethanol 10
in 15% yield (Scheme 5a). However, neither product was de-
tected under three-component coupling reactions. These
results demonstrate that the chemoselectivity stems from
coordination ability difference between isoprene and form-
aldehyde with the five-membered cobaltacycle intermedi-
ate generated in situ.
Py
Py
Py
(CH2O)n
OH
Co cat.
standard conditions
Co cat.
standard conditions
9, 5% yield
b) Proposed mechanism
Cp*Co(CO)I2
5a
10, 15% yield
Py
Py
OH
5a
AgSbF6
N
4
3
CoIII
7a
cationic CoIII
2
1
E
H+
isoprene insertion into E
Based on these preliminary results, a plausible mecha-
nism is tentatively outlined in Scheme 5b. In the presence
of AgSbF6, the pre-catalyst Cp*Co(CO)I2 is first converted
into an active cationic Co(III) species, which reacts with 2-
phenylpyridine to yield five-membered cyclocobalt com-
plex E via a C–H activation step. The subsequent isoprene
insertion into E has four possible pathways. Owing to the
steric hindrance, the generation of adducts F1 and F2 can
be disfavored. The adduct F3 is reluctant to undergo -hy-
dride elimination, thus ruling out this possibility as well. In
comparison, a -hydride elimination of 4,3-adduct F4 yields
Co(III)–H species G, followed by 1,4-insertion with the iso-
prene motif to produce prenyl-Co(III) complex H. Eventual-
ly, a directed addition of H with formaldehyde via a six-
membered chair-like transition state I furnishes the desired
product 7a with the regeneration of cationic Co(III) catalyst.
H
N
CoIII
CoIII
N
CoIII
CoIII
N
N
N
CoIII
H
O
2
4
1
3
4
3
2
1
I
1,2-adduct
2,1-adduct
3,4-adduct
4,3-adduct
F4, favored
F1, disfavored F2, disfavored F3, disfavored
(CH2O)n
β-H
elimination
H
N
N
CoIII
CoIII
1,4-insertion
H
G
Scheme 5 Mechanistic studies and proposed mechanism
tron-rich (12c, 13c) 4-hydroxycoumarins were applicable
to both catalytic systems. Remarkably, 4-hydroxyquinoli-
none was a suitable substrate as well, and the resulting
products 12d and 13d could be used to synthesize natural
alkaloids flindersine and khaplofoline.
To gain a deeper insight into the competitive formation
of pyranocoumarin 12a and pyranochromone 13a, the ex-
periments were monitored at decreased temperatures
within 12 h (Scheme 7, top). With an increment of the tem-
perature (40→90 °C), the yield of 12a increased significant-
ly, while initial improvement and further decrease of the
yield of 13a were observed. Pyranochromone 13a could be
converted into pyranocoumarin 12a under the standard
conditions (Scheme 7, bottom). These results imply that
pyranocoumarin 12a is the thermodynamically favored
product, whereas the formation of pyranochromone 13a is
kinetically favored and reversible.
4 Catalytic Coupling of 4-Hydroxycouma-
rins with Isoprene
Dimethylpyrans, containing a cyclized prenyl, are also
widely present in natural products (e.g., papuaforin A in
Figure 1),24 which prompted us to construct these import-
ant frameworks with isoprene. On the other hand, besides
transition-metals, acid catalyst can also activate isoprene to
facilitate its coupling reactions.25 In this context, an acid-
catalyzed regiodivergent annulation of 4-hydroxycoumarin
with isoprene was developed by our group, which provides
an atom-economical protocol for the assembly of dimeth-
ylpyran skeletons (Scheme 6).26 The utilization of strong
Brønsted acid 2,4-(NO2)2C6H3SO3H as catalyst exclusively
delivered pyranocoumarins 12, whereas pyranochromones
13 turned out to be predominant in the presence of Lewis
acid Sm(OTf)3. Both electron-deficient (12b, 13b) and elec-
Based on these experimental results, a plausible mecha-
nism for the generation of pyranocoumarin and pyrano-
chromone is illustrated in Scheme 8. An initial protonation
of isoprene results in active isopentenyl cation J, which can
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
W.-S. Zhang et al.
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be attacked by the enolate of 11a to produce prenylated
diketone K. Finally, an acid-catalyzed intramolecular cy-
clization of K furnishes pyranocoumarin 12a or pyrano-
chromone 13a via carbocation intermediate L. It is note-
worthy that 13a is produced reversibly, whereas the path-
way to 12a is irreversible, which can account for the
conversion of 13a into 12a in the presence of acid at high
temperature.
OH
O
O
Acid
+
+
O
O
O
O
O
O
O
2,4-(NO2)2C6H3SO3H
(10 mol%)
2a
11a
12a
13a
R
–H+
dioxane, 90 °C, 24 h
OH
–H+
H+
H+
X
O
12
O
O
O
O
+
H
H
O
X
11
O
11a
R
2a
–H+
H+
X = O, NMe
O
R
O
Sm(OTf)3 (10 mol%)
DCE, 90 °C, 24 h
J
K
L
X
13
O
Scheme 8 Proposed mechanism for acid-catalyzed divergent annulation
O
O
O
O
O
O
F
5 Catalytic Coupling of Cyclic 1,3-Diketones
with Isoprene
N
O
O
O
O
MeO
O
O
12d, 43% (150 °C)
N-Methyldihydroflindersine
12a, 81%
12b, 72%
12c, 77%
Compared with homogeneous catalysis, the advantages
of heterogeneous catalysis include facile separation and re-
cycling of the catalyst, minimal catalyst contamination of
the product, low cost, and low environmental impact. With
this concept in mind, we further attempted to use solid ac-
ids to catalyze the coupling of isoprene.27 It was found that,
in the presence of Nafion resin, simple cyclic 1,3-diketones
and isoprene could undergo formal [3+3] annulations to af-
ford dimethylpyrans 15 (Scheme 9). A variety of 5-substi-
tuted 1,3-cyclohexanediones all worked well (15a–d). Sub-
mitting sterically hindered syncarpic acid to the standard
conditions gave the desired product 15e in 32% yield; its
structure was confirmed by X-ray crystallographic analysis.
This protocol could be further extended to other cyclic 1,3-
dicarbonyls such as 1,3-cyclopentanedione and 4-hydroxy-
2H-pyranone (15f, 15g).
O
O
O
O
F
O
N
O
O
O
MeO
O
O
13d, 28% (150 °C)
13d/12d = 1/2
N-Methylkhaplofoline
13a, 60%
13a/12a = 5/1
13b, 58%
13b/12b = 6/1
13c, 53% (110 °C)
13c/12c = 3/1
Scheme 6 Catalytic couplings of 4-hydroxycoumarins with isoprene
O
O
OH
O
2,4-(NO2)2C6H3SO3H
(10 mol%)
+
+
dioxane, T °C, 12 h
O
O
O
O
O
11a
2a
12a
13a
O
O
Nafion (10 wt%)
DCE, 110 °C
X
X
+
R
R
n
O
n
O
14
2a
15
X = CH2, O; n = 0 or 1
O
O
O
O
Ph
O
O
O
O
O
15a, 82%
15b, 74%
15c, 81%
15d, 84%
O
O
O
O
O
O
O
no acid
dioxane, 90 °C, 24 h
2,4-(NO2)2C6H3SO3H
dioxane, 90 °C, 24 h
O
N.R.
O
O
O
O
O
15f, 46%
(150 °C)
15e, 32%
X-ray of 15e
15g, 47%
13a
12a, 64%
Scheme 7 Mechanistic studies for acid-catalyzed divergent annulation
Scheme 9 Catalytic couplings of cyclic 1,3-diketones with isoprene
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The reusability of solid acid Nafion for the annulation of
5-phenyl-1,3-cyclohexanedione and isoprene was tested
(Scheme 10). The catalytic activity of Nafion slightly de-
creased with increasing number of recycling, which is pre-
sumably ascribed to coke formation on the catalyst surface
via isoprene polymerization. Even so, the yield of 15a was
still acceptable after three cycles.
and reverse-prenylation of indoles is of great significance in
the total synthesis of natural indole alkaloids. Therefore,
the development of efficient catalytic systems, non-noble
metals in particular, to realize such reactions with isoprene
is highly desirable. The regiodivergent formation of C–B, C–
N, and C–Si bonds will be another important research area.
We anticipate that the studies of isoprene chemistry will
also open a new avenue for the total synthesis of ter-
penoids.
O
O
Nafion (10 wt%)
+
DCE, 110 °C
Ph
O
Ph
O
Funding Information
14a
2a
15a
We are grateful for financial support from the Dalian Institute of
Chemical Physics, Dalian Outstanding Young Scientific Talent, and the
National Natural Science Foundation of China (21702204, 21801239).
N
ati
o
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References
(1) (a) Kuzuyama, T. Biosci., Biotechnol., Biochem. 2002, 66, 1619.
(b) Heide, L. Curr. Opin. Chem. Biol. 2009, 13, 171. (c) Li, S. M.
Nat. Prod. Rep. 2010, 27, 57.
(2) Achenbach, H. Pure Appl. Chem. 1986, 58, 653.
(3) Makangara, J. J.; Henry, L.; Jonker, S. A.; Nkunya, M. H. H. Phyto-
chemistry 2004, 65, 227.
(4) Cordero-Rivera, R. E.; Meléndez-Rodríguez, M.; Suárez-Castillo,
O. R.; Bautista-Hernández, C. I.; Trejo-Carbajal, N.; Cruz-Bor-
bolla, J.; Castelán-Durte, L. E.; Morales-Ríos, R. S.; Joseph-
Nathan, P. Tetrahedron: Asymmetry 2015, 26, 710.
Scheme 10 Recycling test with Nafion catalyst
6 Conclusion and Outlook
(5) McAfoos, T. J.; Li, S.; Tsukamoto, S.; Sherman, D. H.; Willams, R.
M. Heterocycles 2010, 82, 461.
From an economical and environmental point of view,
bulk chemical isoprene is an ideal five-carbon source for
the installation of valuable prenyl and reverse-prenyl mo-
tifs. However, electronically unbiased isoprene might un-
dergo six possible addition modes in the coupling reactions,
thus often making it cumbersome to obtain a single isomer.
This account summarizes the strategies we have developed
to achieve regioselective couplings of isoprene through C–H
functionalizations. By varying the metal-hydride catalysts,
both prenyl and reverse-prenyl groups could be selectively
incorporated into the C3 position of indoles with isoprene.
A Co(III)-catalyzed three-component coupling of isoprene,
formaldehyde and 2-arylpyridines was developed in which
the exclusive regioselectivity derives from the favored 4,3-
insertion of isoprene into the Co–C bond. A regiodivergent
annulation of 4-hydroxycoumarin with isoprene was
achieved with acid catalysis. Furthermore, solid acid Nafion
was identified as a promising catalyst for the annulation of
cyclic 1,3-diketones with isoprene.
(6) Ruchti, J.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 16756.
(7) Bellavance, G.; Barriault, L. Angew. Chem. Int. Ed. 2014, 53, 6701.
(8) Lindel, T.; Marsch, N.; Adla, S. K. Top. Curr. Chem. 2012, 309, 67.
(9) (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 276. (b) Trost, B.
M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (c) Lu, Z.; Ma, S.
Angew. Chem. Int. Ed. 2008, 47, 258. (d) Jensen, T.; Fristrup, P.
Chem. Eur. J. 2009, 15, 9632. (e) Butt, N. A.; Zhang, W. Chem. Soc.
Rev. 2015, 44, 7929. (f) Haydl, A. M.; Breit, B.; Liang, T.; Krische,
M. J. Angew. Chem. Int. Ed. 2017, 56, 11312.
(10) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592. (b) Bower, J. F.; Skucas, E.; Patman, R. L.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 15134. (c) Shibahara,
F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6338.
(d) Usui, L.; Schmidt, S.; Keller, M.; Breit, B. Org. Lett. 2008, 10,
1207. (e) Gruber, S.; Zaitsev, A. B.; Worle, M.; Pregosin, P. S.;
Veiros, L. F. Organometallics 2009, 28, 3437. (f) Yang, H. W.;
Fang, L.; Zhang, M.; Zhu, C. J. Eur. J. Org. Chem. 2009, 666.
(g) Sundararaju, B.; Achard, M.; Demerseman, B.; Toupet, L.;
Sharma, G. V. M.; Bruneau, C. Angew. Chem. Int. Ed. 2010, 49,
2782. (h) Zhang, X.; Yang, Z.-P.; Liu, C.; You, S.-L. Chem. Sci.
2013, 4, 3239. (i) Zhang, X.; Han, L.; You, S.-L. Chem. Sci. 2014, 5,
1059.
Despite these advances, there is still plenty of room for
further exploration. For example, additional theoretical
studies will be needed to elucidate the catalyst-controlled
divergence, which will presumably provide guidance for the
discovery of new couplings. The asymmetric prenylation
(11) (a) Gerbino, D. C.; Mandolesi, S. D.; Schmalz, H.-G.; Podestá, J. C.
Eur. J. Org. Chem. 2009, 3964. (b) Ren, H.; Zhang, Z.; Xu, L.; Chen,
Z.; Liu, Z.; Miao, M.; Song, J. Synlett 2015, 26, 2784. (c) Bose, S.
K.; Brand, S.; Omoregie, H. O.; Haehnel, M.; Maier, J.;
Bringmann, G.; Marder, T. B. ACS Catal. 2016, 6, 8332.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
W.-S. Zhang et al.
Synpacts
Synlett
(12) (a) Durandetti, M.; Meignein, C.; Perichon, J. J. Org. Chem. 2003,
68, 3121. (b) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am.
Chem. Soc. 2007, 129, 14172. (c) Vece, V.; Ricci, J.; Poulain-Mar-
tini, S.; Nava, P.; Carissan, Y.; Humbel, S.; Duñach, E. Eur. J. Org.
Chem. 2010, 6239.
Zhou, Y.; Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2019, 141,
2251. For selected examples for coupling dienes with nucleo-
philes, see: (h) Johns, A. M.; Liu, Z. J.; Hartwig, J. F. Angew. Chem.
Int. Ed. 2007, 46, 7259. (i) Banerjee, D.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2014, 53, 1630. (j) Roberts, C. C.; Matias, D.
M.; Goldfogel, M. J.; Meek, S. J. J. Am. Chem. Soc. 2015, 137, 6488.
(k) Marcum, J. S.; Roberts, C. C.; Manan, R. S.; Cervarich, T. N.;
Meek, S. J. J. Am. Chem. Soc. 2017, 139, 15580. (l) Yang, X. H.; Lu,
A.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 14049. (m) Shen, H.
C.; Wu, Y. F.; Zhang, Y.; Fan, L. F.; Han, Z. Y.; Gong, L. Z. Angew.
Chem. Int. Ed. 2018, 57, 2372.
(13) (a) Muraoka, T.; Itoh, K.; Matsuda, I. Tetrahedron Lett. 2000, 41,
8807. (b) Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Org. Lett. 2004,
6, 1321. (c) Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.;
Martin, S. F. J. Org. Chem. 2007, 72, 9018. (d) Wilt, J. C.; Faller, J.
W. Org. Lett. 2004, 7, 633; Organometallics; 2005, 24: 5076.
(e) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem. Int. Ed. 2007,
46, 7259. (f) Holzwarth, M.; Dieskau, A.; Tabassam, M.; Plietker,
B. Angew. Chem. Int. Ed. 2009, 48, 7251. (g) Trost, B. M.;
Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328.
(h) Holzwarth, M. S.; Frey, W.; Plietker, B. Chem. Commun. 2011,
47, 11113. (i) Klein, J. E. M. N.; Holzwarth, M. S.; Hohloch, S.;
Sarkar, B.; Plietker, B. Eur. J. Org. Chem. 2013, 6310. (j) Hethcox,
J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem. Int. Ed. 2018, 57,
8664. (k) Tu, H. F.; Zhang, X.; Zheng, C.; Zhu, M.; You, S.-L. Nat.
Catal. 2018, 1, 601. (l) Schlatzer, T.; Schröder, H.; Trobe, M.;
Fadum, C. L.; Stangl, S.; Schlögl, C.; Weber, H.; Breinbauer, R.
Adv. Synth. Catal. 2019, 362, 331.
(20) Hu, Y.-C.; Ji, D.-W.; Zhao, C.-Y.; Zheng, H.; Chen, Q.-A. Angew.
Chem. Int. Ed. 2019, 58, 5438.
(21) (a) Kimura, M.; Matsuo, S.; Shibata, K.; Tamaru, Y. Angew. Chem.
Int. Ed. 1999, 38, 3386. (b) Kimura, M.; Shibata, K.; Koudahashi,
Y.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 6789. (c) Morgan, J. B.;
Morken, J. P. Org. Lett. 2003, 5, 2573. (d) Kimura, M.; Ezoe, A.;
Mori, M.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 201. (e) Cho, H.
Y.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 16140. (f) Ohira, Y.;
Hayashi, M.; Mori, T.; Onodera, G.; Kimura, M. New J. Chem.
2014, 38, 330. (g) Xiong, Y.; Zhang, G. J. Am. Chem. Soc. 2018,
140, 2735.
(14) (a) Yang, Y.; Mustard, T. J. L.; Cheong, P. H.-Y.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2013, 52, 14098. (b) Yang, Y.; Buchwald, S.
L. J. Am. Chem. Soc. 2013, 135, 10642.
(15) (a) Baker, R. Chem. Rev. 1973, 73, 487. (b) Kurosawa, H.
J. Organomet. Chem. 1987, 334, 243. (c) Consiglio, G.;
Waymouth, R. M. Chem. Rev. 1989, 89, 257. (d) Yamamoto, Y.;
Asao, N. Chem. Rev. 1993, 93, 2207. (e) Lichtenberg, C.; Okuda, J.
Angew. Chem. Int. Ed. 2013, 52, 5228.
(16) (a) Kuzuyama, T.; Seto, H. Nat. Prod. Rep. 2003, 20, 171.
(b) Chaves, J. E.; Melis, A. FEBS Lett. 2018, 592, 2059. (c) Zhou, Y.
J.; Kerkhoven, E. J.; Nielsen, J. Nat. Energy 2018, 3, 925.
(17) Lin, Y.-H.; Shen, X.-L.; Yuan, Q.-P.; Yan, Y.-J. Nat. Commun. 2013,
4, 2603.
(22) (a) Boerth, J. A.; Hummel, J. R.; Ellman, J. A. Angew. Chem. Int. Ed.
2016, 55, 12650. (b) Boerth, J. A.; Ellman, J. A. Angew. Chem. Int.
Ed. 2017, 56, 9976. (c) Boerth, J. A.; Maity, S.; Williams, S. K.;
Mercado, B. Q.; Ellman, J. A. Nat. Catal. 2018, 1, 673. (d) Li, R.; Ju,
C.-W.; Zhao, D. Chem. Commun. 2019, 55, 695.
(23) Yang, J.; Ji, D.-W.; Hu, Y.-C.; Min, X.-T.; Zhou, X.-G.; Chen, Q.-A.
Chem. Sci. 2019, 10, 9560.
(24) (a) Poumale, H. M. P.; Hamm, R.; Zang, Y.; Shiono, Y.; Kuete, V.
Coumarins and Related Compounds from the Medicinal Plants of
Africa, In Medicinal Plant Research in Africa; Kuete, V., Ed.; Else-
vier: Oxford, 2013, 261. (b) Sarker, S. D.; Nahar, L. Progress in the
Chemistry of Naturally Occurring Coumarins, In Progress in the
Chemistry of Organic Natural Products; Kinghorn, A. D.; Falk, H.;
Gibbons, S.; Kobayashi, J. I., Ed.; Springer International Publish-
ing: Cham, 2017, 241.
(18) Holmes, M.; Schwartz, L. A.; Krische, M. J. Chem. Rev. 2018, 118,
6026.
(19) For selected examples for coupling dienes with electrophiles,
see: (a) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y.
J. Am. Chem. Soc. 2006, 128, 8559. (b) Omura, S.; Fukuyama, T.;
Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130,
14094. (c) Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Krische, M.
J. Science 2012, 336, 324. (d) Chen, Q. A.; Kim, D. K.; Dong, V. M.
J. Am. Chem. Soc. 2014, 136, 3772. (e) Nguyen, K. D.;
Herkommer, D.; Krische, M. J. J. Am. Chem. Soc. 2016, 138,
14210. (f) Li, C.; Liu, R. Y.; Jesikiewicz, L. T.; Yang, Y.; Liu, P.;
Buchwald, S. L. J. Am. Chem. Soc. 2019, 141, 5062. (g) Liu, R. Y.;
(25) (a) Yang, R. Y.; Kizer, D.; Wu, H.; Volckova, E.; Miao, X. S.; Ali, S.
M.; Tandon, M.; Savage, R. E.; Chan, T. C.; Ashwell, M. A. Bioorg.
Med. Chem. 2008, 16, 5635. (b) Jung, E. J.; Park, B. H.; Lee, Y. R.
Green Chem. 2010, 12, 2003. (c) Appendino, G.; Cravotto, G.;
Giovenzana, G. B.; Palmisano, G. J. Nat. Prod. 1999, 62, 1627.
(26) Li, Y.; Hu, Y.-C.; Zheng, H.; Ji, D.-W.; Cong, Y.-F.; Chen, Q.-A. Eur.
J. Org. Chem. 2019, 6510.
(27) Li, Y.; Hu, Y.-C.; Zhang, W.-S.; He, G.-C.; Cong, Y.-F.; Chen, Q.-A.
Chin. J. Catal. 2020, 41, 1401.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G