Enantioselective Three-Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates

Article abstract of DOI:10.1002/anie.202014781

Asymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron-rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3-Disubstituted tetrahydrofurans and pyrrolidines are produced in trans conf

Full text of DOI:10.1002/anie.202014781

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantioselective Three-Component Coupling of Heteroarenes,
Cycloalkenes and Propargylic Acetates
Authors: Shenghan Teng, Yonggui Robin Chi, and Jianrong Steve
Zhou
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014781
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10.1002/anie.202014781
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Three-Component Coupling of Heteroarenes,
Cycloalkenes and Propargylic Acetates
Shenghan Teng, Yonggui Robin Chi and Jianrong Steve Zhou*
Abstract: Asymmetric coupling proceeds efficiently between
propargylic acetates, cycloalkenes and electron-rich heteroarenes
including indoles, pyrroles, activated furans and thiophens. 2,3-
Disubstituted tetrahydrofurans and pyrrolidines are produced in trans
configuration and excellent enantiomeric ratios. The reaction
proceeds via Wacker-type attack of heteroarenes on alkenes
activated by electron-deficient Pd(II) species.
needed to in situ produce active low-valent metal catalysts.[9] In
iridium-catalyzed enantioselective alkylation of indoles and other
heteroarenes, insertion was limited to reactive bicyclic
norbornenes and alike (Fig 1c), as disclosed by Hartwig et al.[10]
Recently, Sigman et al. reported that in oxidative Heck reaction,
in situ generated indolyl Pd species underwent b-insertion of
acyclic alkenols in good enantiomeric ratios (Fig 1d).[11]
Additionally, Zhu et al. reported that oxadiazole and other
heteroarenes containing acidified CH bonds were in situ
deprotonated by bases and intercepted alkyl palladium species,
which were produced from asymmetric Heck-type cyclization.[12]
Asymmetric
Friedel-Crafts
alkylation
allows
direct
incorporation of heteroarenes, such as indoles, pyrroles and
some other electron-rich (hetero)arenes, into useful chiral building
blocks. In these reactions, diverse types of alkylating reagents
with innate polar bonds can be used, including carbonyl
compounds, imines, epoxides and aziridines, allylic electrophiles
and Michael acceptors.[1] Some of these catalytic methods have
been applied in total syntheses of bioactive natural products.[2]
Previously, we reported Pd-catalyzed enantioselective
Wacker-type coupling of propargylic acetates, cycloalkenes and
weak O- and N-nucleophiles, such as alcohols, water and
(hetero)arylamines.[13] Herein, we extend the Wacker reactivity to
nucleophilic heteroarenes including indoles, pyrroles and some
activated furans and thiophenes, as well as some anilines. The
three-component coupling produces trans-adducts in excellent
enantiomeric ratios, without the aid of a directing group (Fig 1e).
Unactivated alkenes are an alternative and attractive class of
alkylating reagents. Alkenes can survive under many reaction
conditions in a multi-step synthesis, and can be activated to react
with heteroarenes once properly activated. For example, alkenes
can be readily activated by electrophilic metal complexes (Pt, Pd
and Au) towards nucleophilic attack by pendant indoles and
pyrroles to form 5- or 6-membered rings (for example, see Fig
1a).[3] The intermolecular version is more challenging. Chen et al.
recently disclosed stereoselective g-selective addition of indoles
to alkenes activated by palladacycles in situ derived from N-8-
quinolinyl-amides (Fig 1b).[4] Asymmetric heteroarylation of
alkenes is deemed to be difficult without aid of a directing group
or covalent linkage to metal centers, because of inherent difficulty
in controlling conformations of alkenes during bond-forming
processes.
Substituted pyrrolidines and tetrahydrofurans are among the
most frequently used heterocycles in pharmaceutical cores.[14] In
recent years, incorporation of saturated azacycles, in place of
unsaturated heteroarenes, has become a common strategy to
increase chance of clinical success of drugs.[15] But catalytic
methods to access 2,3-disubstituted pyrrolidines and
tetrahydrofurans are still limited.[16] The allene functionality in the
products are useful intermediates in stereoselective synthesis.[17]
Many catalytic methods are now available for stereo- and
regioselective transformation of allenes.[18]
Me
N
Me
N
Ar2
P
(Ar-MeO-biphep)PtCl2
10 mol%
Cl
Cl
MeO
MeO
a)
Pt
CO2Me
CO2Me
CO2Me
CO2Me
P
Ar2
AgOTf, MeOH
In another type of reaction pathways, low-valent late metals
(Ni,[5] Rh[6] and Ir[7]) can cleave heteroaryl C-H bonds and then
promote asymmetric insertion to pendant alkenes.[8] The
intermolecular insertion of this type, however, is more challenging
and examples are limited. In Fe- or Co- catalyzed directed
alkylation of indoles, insertion into styrene occurred in good ee
values, but stoichiometric amounts of Grignard reagents were
Widenhoefer et al. (2006)
Me
90% ee
Ar-MeObiphep
Ar = 4-OMe-3,5-t-Bu-C6H2
Ar
O
Pd(OAc)2 10 mol%
MOXin 20 mol%
O
N
Me
O
NHAQ
Me
b)
Me
N
H
N
o-PhC6H4CO2H, MeOH
N
MOXin
Ar = 3,5-(CF3
N
Me
Chen et al. (2018)
86% ee
)
2C6H3
N
Me
[Ir(coe)2Cl]2 1.5 mol%
(S)-DTBM-Segphos 3 mol%
c)
THF, 100 o
C
N
H
N
H
Hartwig et al. (2013)
96% ee
[*]
Prof. Dr. J. S. Zhou
Et
Et
n-Bu
State Key Laboratory of Chemical Oncogenomics, Key Laboratory
of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School,
Room F-312, 2199 Lishui Road, Nanshan District, Shenzhen
518055 (China)
Pd(MeCN)2(OTs)2 10 mol%
PyrOx 20 mol%
n-Bu
O
OH
F3
C
O
2-Naph
d)
N
N
CuSO4, DMF, O2
N
PyrOx
Me
92% ee
Sigman et al. (2015)
N
Me
OAc
R
E-mail: jrzhou@pku.edu.cn
Dr. S. Teng, Prof. Dr. Y. R. Chi
[(R)-furyl-MeO-biphep]PdCl2
L
L
Me
Me
Pd
R
1-2 mol%
Me
Me
e)
R
X
HCO2Na, MeCN or
ethylene carbonate
X
X
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, 21 Nanyang Link, 637371
(Singapore)
Supporting information for this article is given via a link at the end of
the document.
(Het)Ar
(Het)Ar-H
Me
Me
(Het)Ar-H
most >90% ee
(this work)
X = O, NBoc
(Het)Ar-H = indole, pyrrole, furan
thiophen, arenes
Figure 1. Asymmetric heteroarylation of alkenes based on Wacker-type
nucleophilic attack (a,b,e) and b-insertion of heteroaryl metal species (c,d).
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10.1002/anie.202014781
Angewandte Chemie International Edition
COMMUNICATION
Pd(cod)Cl2 5 mol%
(R)-Ar-MeO-biphep 6 mol%
O
Me
Me
Me
Me
Me
(L1)PdCl2 1 mol%
(a)
Me
O
Me
O
N
Me
Ph
OAc
HCO2Na 1.2 equiv
MeCN, 30 oC, 48 h
Me
R
Me
N
R
OAc
HCO2Na 1.2 equiv
MeCN, 30 oC, 48 h
N
Me
1a
2a
Me
3a
1a
2a
3a
4a R = Ph
70% yield, 90% ee
O
Me
Me
O
Me
Me
other examples
i-Pr
AcO
Ph
Ph
Me
Ph
4a'
N
Me
R =
4a''
4a
O
O
Me
MeO
4b 65% yield, 90% ee
4c 69% yield, 89% ee
4d 65% yield, 91% ee 4e 66% yield, 89% ee
result (4a)
Ar
PAr2
MeO
MeO
72% yield, 90% ee
13% yield, 50% ee
0% yield
2-furyl
phenyl
3,5-xyl
PAr2
S
MeO2C
X
4j 60% yield, 93% ee
4i 66% yield, 87% ee
4f 63% yield, 92% ee
4g X = F 73% yield, 93% ee
4h X = Br 65% yield, 92% ee
with 2% Pd
[(R)-Ar-MeO-biphep]PdCl2
1 mol%
Me
Scheme 2. Examples of propargylic acetates in 3-component coupling
with 2,3-dihydrofuran.
Me
(b)
4a
O
Me
HCO2Na 1.2 equiv
MeCN, 30 oC, 48 h
N
Me
Ph
OAc
2a
1 mol% palladium complex of L1 was successfully applied to
reactions of 2,3-dihydrofuran with different propargylic acetates,
carrying both electron-donating methoxy and electron-
withdrawing ester groups on aryl rings (4c,4f) (Scheme 2). The
reaction also tolerated aryl fluoride and bromide (4g-h).
Furthermore, the C3-substituents can be thienyl and cycloalkenyl
rings (4i-j). However, omission of two methyl groups on the
propargyl fragment failed to deliver the desired adduct.
1a
3a
ligand
Ar
result (4a)
73% yield, 90% ee
L1
L2
L3
2-furyl
2-benzofuryl 20% yield, 92% ee
2-thienyl
46% yield, 72% ee
Scheme 1. Effect of MeO-biphep ligands on model reaction of 2,3-
dihydrofuran and 1,2-dimethylindole using a mixture of Pd(cod)Cl2 and
diphosphines (a) and isolated Pd complexes (b).
We used a model reaction of propargylic acetate 2a, 2,3-
dihydrofuran (2 equiv) and 1,2-dimethylindole 3a (3 equiv). In our
initial study, common diphosphines including Segphos,
Difluorphos and P-Phos didn't produce active Pd catalysts. To our
gratification, a Pd catalyst of electron-deficient MeO-biphep L1
carrying P-furyl substituents[19] led to desired adduct 4a in good
yield and 90% ee (Scheme 1a). Minor side products included a
ternary adduct with acetic acid 4a' and, to a lesser extent, another
ternary adduct with formic acid. In comparison, a Pd catalyst of
parent MeO-biphep[20] having P-phenyl groups led to formation
4a in 13% yield, with reduction of propargylic acetate to 4a'' (56%
yield) as main side reaction.
The model reaction of 1,2-dimethylindole provided good yield
of adduct 4a in acetonitrile. In exploration of substrate scope, we
found that most of other indoles gave better yields in ethylene
carbonate instead (Scheme 3a). Ethylene carbonate has an
exceptional high dielectric constant of 95 and melting point of 35
oC; it quickly melted in the reaction mixture upon heating.
Furthermore, for most indoles without C2-substituents, PdCl2
complex of ligand L2 carrying P-benzofuryl rings led to higher
conversions. Thus, indoles carrying both electron-donating and
electron-withdrawing groups reacted smoothly to give adducts in
reasonably good yields (5g-i). Adduct 5b was crystalline and X-
ray diffraction helped to set its absolute configuration and others
by analogy.[21] Notably, 1,3-dimethylindole led to formation of
ternary adducts (30% yield) at the C2-position of indole.
Stirring of Pd(cod)Cl2 and L1 generated complex (L1)PdCl2
as yellow precipitate in acetonitrile. The isolated complex
provided similar results in the model reaction and also improved
reproducibility (Scheme 1b). Thus, 1 mol% Pd complex of L1 was
sufficient to promote full conversion and gave adduct 4a in 73%
yield and 90% ee. Complexes of modified MeO-biphep's carrying
P-benzofuryl and P-thienyl groups L2 and L3 were less reactive,
in comparison. Sodium formate was found to be optimal to reduce
(L1)PdCl2 to generate the active Pd0 catalyst in situ, but It also led
to 10% of side product 4a''. Potassium formate led to 61% of 4a
in the model reaction, whereas neither K3PO4 nor NEt3 produce
an active catalyst at all.
Substituted pyrroles can also participate in the three-
component reactions to furnish adducts 5j-m in acetonitrile or
ethylene carbonate (Scheme 3b). the reaction of N-methylpyrrole
resulted in two isomers 5l and 5l' in 2:1 ratio, both in over 90% ee.
2,5-Diphenylpyrrole, unfortunately, was too hindered to react, due
to shielding of reacting sites by two phenyl rings.
Furthermore, the new method was successfully applied to an
activated furan, thiophen and several anilines to give 5n-q
(Scheme 3c). Without strongly electron-donating alkoxy or
alkylamino groups on these substrates, no reaction was detected.
Interestingly, very hindered 1,3,5-trimethoxybenezene also
coupled to give adduct 5r, although in moderate yield (42%). In
some examples above, Pd complex of L2 was used instead of L1
to give better yields of desired products. Addition of 20 mol%
calcium hydroxide also helped to improve yields of some
examples by neutralizing acetic acid produced from the reaction,
but it didn't help when used in stoichiometric amounts.
Intuitively, the choice of polar solvents was crucial to
stabilizing a cationic allenyl palladium complex, a key species in
the catalytic cycle. 4a was formed in 73% and 63% yields in the
model reaction in acetonitrile and ethylene carbonate,
respectively. The yields were much lower in some polar solvents,
23% in EtOH, 31% in i-PrOH and 43% in CH2Cl2, whereas no
desired product was formed in DMF, DMSO or dioxane.
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10.1002/anie.202014781
Angewandte Chemie International Edition
COMMUNICATION
Boc
N
Me
Me
In the aforementioned reactions in Scheme 3 that gave poor
or moderate yields, ternary adduct of 2,3-dihydrofuran and acetic
acid 4a' was the main side product. When isolated and added
separately into another living catalytic reaction, 4a' was not
consumed indicating that it was not a competent intermediate for
the generation of 4a under catalytic conditions.
(L1)PdCl2 2 mol%
Me
Me
(a)
Boc
N
Me
HCO2Na 1.2 equiv
MeCN, 30 oC, 48 h
N
H
Ph
OAc
Ph
Me
N
H
1b
2a
3b
6a 88% yield, 96% ee
examples of indoles and pyrroles with C2-substituents
Boc
N
Boc
N
Me
Me
CbzN
Me
Me
O
Me
Me
Ph
Me
Ph
Me
Ph
Me
Me
(L1)PdCl2 1 mol%
Me
O
N
Me
N
Me
N
H
Me
HCO2Na 1.2 equiv
ethylene carbonate
30 oC, 48 h
Ph
OAc
N
H
Ph
Me
N
H
6b 67% yield, 91% ee
6c 68% yield, 92% ee
6d 71% yield, 89% ee
45 o
1a
2a
3b
C
5a 75% yield, 90% ee
Boc
N
N
Me
Me
Boc
N
Me
Me
(a) examples of indoles
H
Me
H
H
H
Ph
Me
Ph
Me
Me
Me
N
H
Me
Ph
N
H
N
N
i-Pr
N
Me
Me
6f 70% yield, 92% ee
6e 72% yield, 93% ee
5d 74% yield, 88% ee
5b 61% yield, 87% ee 5c 84% yield, 87% ee
[X-ray structure]
5e 65% yield, 91% ee
with 2% (L2)PdCl2
with (L2)PdCl2, 45 o
C
H
BocN
Me
Me
Me
(L1)PdCl2 2 mol%
Me
OAc
F
(b)
MeO
BocN
H
H
H
H
N
Me
Ph
HCO2Na 1.2 equiv
ethylene carbonate
30 oC, 48 h
Ph
MeO
N
Me
N
N
H
N
H
N
H
1b
examples of a pyrrole and indoles
2a
3c
Me
6h 81% yield, 92% ee
5f 65% yield, 85% ee 5g 82% yield, 90% ee
5h 64% yield, 86% ee
with (L2)PdCl2
5i 53% yield, 86% ee
with (L2)PdCl2, 45 o
C
with (L2)PdCl2
with (L2)PdCl2, 45 o
C
H
H
H
(b) examples of pyrroles
H
H
Ph
N
H
N
H
H
Ph
N
H
N
H
i-Pr
Ph
H
N
6g 66% yield, 92% ee
[X-ray structure]
Me
Me
6k 81% yield, 95% ee
H
N
H
6i 77% yield, 92% ee
6j 78% yield, 94% ee
Me
Me
N
N
H
Me
Me
X
MeO
H
Me
72% yield, C2/C3 2:1
5m 28% yield, 92% ee
5l 90% ee (major), 5l' 92% ee 4% (L2)PdCl2 in MeCN
Me
H
5j 79% yield, 91% ee
H
5k 72% yield, 92% ee
H
in MeCN
in MeCN
with (L2)PdCl2
N
N
Me
N
Me
(c) examples of other (hetero)arenes
N
H
Me
H
H
O
O
6o X = F 76% yield, 91% ee
6p X = Cl 63% yield, 90% ee
6m 80% yield, 93% ee
6l 74% yield, 91% ee
6n 83% yield, 92% ee
NEt2
OMe
H
O
40 o
C
MeO
H
examples of other (hetero)arenes
S
Et2N
Me2N
H
5n 74% yield, 91% ee
with (L2)PdCl2
H
5p 77% yield, 93% ee
with (L2)PdCl2
5o 62% yield, 83% ee
(L2)PdCl2, 20% Ca(OH)2
5q 74% yield, 94% ee
O
O
NMe2
OMe
H
MeO
O
H
OMe
H
S
Me2N
Me2N
6t 82% yield, 92% ee
6q 71% yield, 93% ee 6r 55% yield, 91% ee
(L2)PdCl2, 20% Ca(OH)2
6s 71% yield, 92% ee
MeO
OMe
H
5r 42% yield, 85% ee
4% (L2)PdCl2, 20% Ca(OH)2
Me2N
Scheme 3. Examples of 3-component coupling of 2,3-dihydrofuran with
indoles, pyrroles and other (hetero)arenes.
6u 30% yield, 86% ee
with (L2)PdCl2
Scheme 4. 3-component coupling of N-Boc-2,3-dihydropyrrole with
indoles and pyrroles and other (hetero)arenes in MeCN (a) and ethylene
carbonate (b) (Boc = t-butoxycarbonyl).
The complex of L1 was applicable to asymmetric
heteroarylation of N-Boc-2,3-dihydropyrrole. Herein, no ternary
adduct with acetic acid analogous to 4a' was detected as side
product. Instead, a racemic Friedel-Crafts-type adduct of N-Boc-
2,3-dihydropyrrole and indole was the main side product, which
was catalyzed by in situ produced acetic acid. In acetonitrile,
indoles and pyrroles carrying C2-substituents reacted efficiently
to give adducts 6a-f (Scheme 4a). 2-Phenylpyrrole coupled
cleanly at C5-position (as confirmed by X-ray structure)[21] and its
yield was higher in ethylene carbonate than acetonitrile. For most
indoles without C2-substituents, higher yields were also obtained
in ethylene carbonate (Scheme 4b). The reaction tolerated well
substituents including a methoxy group, aryl fluoride and chloride
on indoles (6l-p). An activated furan, thiophene and some
anilines were also suitable substrates, giving adducts 6q-t in
reasonably good yields. Notably, N,N-dimethylaniline was
moderately reactive to afford product 6u in 30% yield when
(L2)PdCl2 was used as the catalyst.
O
HO
H
Pd/C x mol%
H2 (balloon)
i-Pr
H
O
Me
Me
Me
or
Ph
Me
MeOH, RT
Me
Ph
Me
Ph
Me
N
N
Me
x = 25
7b 77% yield, dr 3.3:1
Me
x = 2.5
7a 72% yield, dr 10:1
N
Me
4a 90% ee
O
O
O3, pyridine
CH2Cl2
Pd/C, PMHS
4-chloroanisole
Ph
O
Ph
O
MeOH, 50 o
C
NAc
Me
7c 71% yield
NAc
Me
7d 71% yield
Scheme 5. Transformations of heteroarylative adducts.
The allenes in the adducts can be readily converted to other
functional groups (Scheme 5). For example, Pd/C-catalyzed
selective monohydrogenation of 4a afforded 7a with 10:1 dr at 2.5
mol% Pd loading. But at higher 25 mol% Pd loading, not only the
allene group was fully hydrogenated, but also the tetrahydrofuran
ring was selectively cleaved at the benzylic site to provide 7b.
Thus, the hydrogenation process did not halt halfway after double
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10.1002/anie.202014781
Angewandte Chemie International Edition
COMMUNICATION
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heterocyclic ring of indole were cleaved by ozone to give diketone
7c.[22] Both aromatic ketone groups were then deoxygenated to
give
7d
via
Pd/C-catalyzed
reduction
using
polymethylhydrosiloxane (PMHS).[23]
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In summary, we report herein
a
three-component
difunctionalization of cycloalkenes using propargylic electrophiles
and heteroarene such as indoles, pyrroles and some activated
furans and thiophenes. Asymmetric Wacker-type attack of
nucleophilic (hetero)arenes on cycloolefins without the aid of a
directing group proceeds in excellent stereo-control. 2,3-
Disubstitututed tetrahydrofurans and pyrrolidines are generated
in trans configuration and excellent ee values. Mechanistically,
the electron-deficient s-allenyl palladium center rendered by
weakly donating MeO-biphep proved instrumental to activating
cycloalkenes for external attack by heteroarenes.
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Acknowledgements
We acknowledge financial support from Peking University
Shenzhen Graduate School, Shenzhen Bay Laboratory Institute
of Chemical biology, Nanyang Technological University, GSK-
EDB Trust Fund (2017 GSK-EDB Green and Sustainable
Manufacturing Award) and A*STAR Science and Engineering
Research Council (AME IRG A1783c0010). We thank Dr Li
Yongxin for X-ray diffraction.
Keywords: palladium catalysis • heteroarylation • allene •
Wacker reaction • alkene difunctionalization
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10.1002/anie.202014781
Angewandte Chemie International Edition
COMMUNICATION
Palladium Catalysis
Ar'
1-2 mol%
OAc
(diphosphine)PdCl2
R
R
(Het)Ar-H
Shenghan Teng, Yonggui Robin Chi and
Jianrong Steve Zhou
R
X
X
R
Ar'
(Het)Ar
X = O, NBoc
indole, pyrrole
furan, thiophen
anilines
PAr2
MeO
most >90% ee
MeO
PAr2
Page – Page
(R)-Ar-MeO-biphep
Enantioselective Three-Component
Coupling of Heteroarenes,
Ar = 2-furyl, 2-benzofuryl
Cycloalkenes and Propargylic Acetates
Wacker-type coupling of cyclic alkenes, propargylic acetates and nucleophilic
heteroarenes and arenes, including indoles, pyrroles, activated thiophenes, furans and
anilines, proceeds to give trans-isomers of 2,3-disubstituted pyrrolidines and
tetrahydrofurans.
This article is protected by copyright. All rights reserved.