Synthesis of C5-allylindoles through an iridium-catalyzed asymmetric allylic substitution/oxidation reaction sequence of N-alkyl indolines

Article abstract of DOI:10.1021/acs.orglett.1c00810

Iridium/Br?nsted acid cooperative catalyzed asymmetric allylic substitution reactions at the C5 position of indolines have been reported for the first time. The highly efficient protocol allows rapid access to various C5-allylated products in good to high

Full text of DOI:10.1021/acs.orglett.1c00810

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Letter
Synthesis of C5-Allylindoles through an Iridium-Catalyzed
Asymmetric Allylic Substitution/Oxidation Reaction Sequence of
N‑Alkyl Indolines
Jiamin Lu,† Ruigang Xu,† Haixia Zeng, Guofu Zhong,* Meifang Wang, Zhigang Ni, and Xiaofei Zeng*
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ABSTRACT: Iridium/Brønsted acid cooperative catalyzed asymmetric allylic substitution reactions at the C5 position of indolines
have been reported for the first time. The highly efficient protocol allows rapid access to various C5-allylated products in good to
high yields (48−97%) and enantioselectivities (82% to >99% ee) with wide functional group tolerance. The transformations allow
not only the formation of C5-allylindoline derivatives but also the synthesis of C5-allylindole analogues in good yields and excellent
stereoselectivities via an allylation/oxidation reaction sequence.
Scheme 1. Previous Studies and Approaches for
Constructing Chiral C5-Allylindoles
ptically active indole fragments are ubiquitous features of
numerous bioactive natural products and bioactive
O
pharmaceuticals.1 Thus, the enantioselective functionalization
of the indole structure has attracted a great deal of attention,2
and the transition metal-catalyzed asymmetric allylic sub-
stitution (AAS) reaction is particularly useful.3 There are six
C−H bonds and one N−H bond in the indole structure that
could be functionalized. It has been proven that the C3
position has priority in the intermolecular AAS reactions, and
the first AAS reaction of indoles with allylic acetate was
4a
́
reported by Kocovsky and co-workers in 1999. Since then,
several successful examples have been reported by different
research groups.4 In addition, the branched selective N1-
allylation reaction of indoles has also been described by
Hartwig,5 You,6 Krische,7 and others.8 Furthermore, asym-
metric C2-allylation has also been investigated. To overcome
the regioselectivity issues, intramolecular asymmetric indole
C2-allylation procedures were disclosed, which allowed the
synthesis of annulated chiral C2-allylated indoles stereo-
selectively.9 As an exception, Tambar and co-workers
developed a chiral phosphoric acid-catalyzed intramolecular
asymmetric aza-Claisen rearrangement approach to form chiral
C2-allylated 3-amino indoles.10 Very recently, Zheng, Taylor,
Unsworth, and You reported an unprecedented enantioselec-
tive intermolecular C2-allylation of 3-substituted indoles,
generating the C2-allylated products in excellent enantiose-
lectivities with excellent regiocontrol.11 However, the methods
for the synthesis of 5-allylindoles are still a challenge due to the
innate reactivity of the indole skeleton (Scheme 1a).
Received: March 15, 2021
Published: April 13, 2021
https://doi.org/10.1021/acs.orglett.1c00810
Org. Lett. 2021, 23, 3426−3431
© 2021 American Chemical Society
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Chiral C5-substituted indoles are key building blocks in
many biologically active compounds, including the antitumor
alkaloid drug vinblastine,12 the haplophytine alkaloid,13
murrafoline D,14 the raputindole family,15 etc., and have
attracted a great deal of attention from synthetic chemists.
Most indole C5-functionalization reactions involve C−H
activation,2e,16 coupling,17 and semireduction18 strategies.
However, the dependency on directing groups and the
formation of achiral products are obvious drawbacks. Aniline,
which is always used as a nucleophile to react with
electrophiles due to its high electron density at the para
position,19 was successfully applied in the AAS reaction by Fu’s
research group (Scheme 1b).20 As a continuation of our
research interest in AAS reactions,21 herein we report the
highly stereoselective synthesis of C5-allylindoles through an
iridium-catalyzed AAS reaction of N-alkyl indolines with allylic
alcohols followed by an oxidation reaction in a one-pot
reaction (Scheme 1c). This method tolerates a broad range of
indolines and 1,2,3,4-tetrahydroquinoline analogues with
various functional groups. The transformation could be easily
scaled up to gram scale, and the formed products could be
applied in the synthesis of bioactive chiral C5-functionalized
indoles.
acid additives, it was found that the desired product could be
afforded in 71% yield and 99% ee in the presence of
(PhO)2POOH [entries 9 and 10 (for more details, see Table
S3)]. Further investigation of the equivalents of 2a, acid
additive, catalytic loading, and reaction concentration shows
that 3a could be achieved in 93% yield and >99% ee e by using
2 mol % [Ir(COD)Cl]2, 8 mol % (R)-L2, and 30 mol %
(PhO)2POOH in CH3CN (0.25 M) at room temperature for
12 h.
Notably, the methyl- and benzyl-protected indolines were
also successful in the reaction, giving the corresponding
products in excellent enantioselectivities; however, the yields
are lower (entries 12 and 13). Unfortunately, the indolines
with electron-withdrawing protecting group, such as acetyl,
Boc, alloc, and Ts groups, could not be promoted in the
reaction, probably due to the lower nucleophilicity of these
substrates (entry 14). Furthermore, the synthesis of C5-allylic
indole was tested, and 5 equiv of MnO2 was added after the
completion of the AAS process. Fortunately, desired C5-allylic
indole 4a was obtained in 72% yield without a loss of
enantiomeric purity (Scheme 2).
Scheme 2. One-Pot Synthesis of C5-Allylindole
We initially selected the AAS reaction of N-benzylindoline
(1a) with 1-(3-methoxyphenyl)prop-2-en-1-ol (2a) as the
model substrate (Table 1). The combination of commercially
a
Table 1. Optimization of Reaction Conditions
To assess the generality of the C5-allylation of indolines, the
thus obtained optimal reaction conditions were first applied to
diverse substrates. Beyond the parent allylic alcohol, electroni-
cally diverse allylic alcohols substituted at the ortho, meta, or
para position of the aromatic ring each proceeded smoothly in
the AAS reaction, delivering the respective C5-regioselective
allylated products with good yields and stereoselectivities
(Figure 1). It was found that allylic alcohols bearing electron-
donating groups on the phenyl ring (3a−3e, 3g, and 3r−3u)
gave rise to the products in moderate to good yields (59−98%)
with excellent enantioselectivities (92% to >99% ee) in less
time than with electron-withdrawing substituents (3h−3q,
48−87% yields and 97% to >99% ee). In addition, the
synthetically important ester group and nitro group were
compatible in the reaction, providing the corresponding
products in excellent enantioselectivities (97% to >99% ee);
however, the yields were relatively lower. Furthermore,
heteroaromatic ring-substituted allylic alcohols were also well
tolerated, providing the desired products (3v and 3w) with
good results. When the naphthyl-substituted allylic alcohol was
used, the desired 3x was afforded in 94% yield and 99% ee.
Next, a broad range of N-Bn indolines were examined in the
AAS reaction followed by oxidation using MnO2 as the oxidant
(Figure 2). Indolines bearing electron-neutral and electron-
donating substituents, including methyl (4b−4e), phenyl (4f),
and methoxy (4g) groups at positions C2−C6, underwent
facile transformations and afforded the corresponding C5-
indole allylation products in excellent yields and enantiose-
lectivities. C2 and C3 disubstituted indoles (1g and 1h) also
delivered allylation/oxidation products 4g and 4h, respectively,
with good results.
b
c
entry
R
acid
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Bn
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
(PhO)2POOH
Sc(OTf)3
(PhO)2POOH
(PhO)2POOH
La(OTf)3
THF
DCM
Et2O
67
74
57
60
62
71
48
93
64
82
−
96
81
95
96
98
99
84
>99
>99
>99
−
Bn
Bn
Bn
Bn
Bn
Bn
Bn
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
d
e
f
g
9
Me
PMB
Ac
10
11
g
La(OTf)3
a
Reaction conditions: 2 mol % [Ir(COD)Cl]2, 8 mol % ligand, 20
mol % (PhO)2POOH, 0.2 mmol of 1a, and 0.4 mmol of 2a in solvent
at room temperature for 12 h. Isolated yields of 3a. Determined by
HPLC analysis on a chiral stationary phase. With 2.5 equiv of 2a.
With 30 mol % (PhO)2POOH. Reaction concentration of 0.25 M.
b
c
d
e
f
g
For 24 h.
available chiral phosphoramidite ligands [e.g., (R)-L2, (R)-L3,
and (R)-L4] with an iridium catalyst did not promote the
reaction (entries 2−4). In contract, a mixture of [Ir(COD)-
Cl]2/(R)-L1 and BF3·Et2O afforded the corresponding AAS
product 3a in 67% yield and 96% ee (entry 1). The reaction
could not proceed without acid. The solvent plays an
important role in the reaction, and CH3CN was found to be
the best, which gave rise to an ee value of 98% [entries 5−8
(for more details, see Table S2)]. Upon investigation of other
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Then, the AAS reaction was explored with a series of 1-
benzyl-1,2,3,4-tetrahydroquinoline and its analogues (Figure
3). Conveniently, the conditions demonstrated to be optimal
Figure 3. Substrate scope of 1,2,3,4-tetrahydroquinoline analogues.
for N-benzyl indoline extended well to these other
nucleophiles, which led to a diverse series of allylation
products. For example, when 1-benzyl-1,2,3,4-tetrahydroquino-
line, 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 1,4-di-
benzyl-1,2,3,4-tetrahydroquinoxaline, and 1-benzyl-1,2,3,4-
tetrahydrobenzo[h]quinoline were used, products 5a−5d,
respectively, were isolated in moderate to good yields.
To further prove the reliability and practicability of our
approach, a scaled-up reaction was carried out by using 8.0
mmol of 1a as the starting material, affording 2.12 g of 4a in
82% yield and >99% ee (Scheme 3a). The product thus
Scheme 3. (a) Large-Scale Reaction and (b) Versatile
a
Transformations of C5-Allylindole
Figure 1. Synthesis of enantioenriched N-allylated indolines with
various allylic alcohols.
a
t
Conditions: (i) H2, Pd/C, MeOH, reflux; (ii) CH2CHCO2 Bu,
Hoveyda-Grubbs II catalyst, DCM, reflux; (iii) POCl3, DMF, 0 °C to
rt.
obtained could be easily elaborated in different ways. The vinyl
group of 4a could be reduced by Pd/C under a hydrogen
atmosphere to give corresponding product 6 in 63% yield, with
the enantiomeric excess of the product remaining. Compound
4a could also undergo an olefin metathesis reaction to form 7
in 56% yield with excellent stereoselectivities. Further
transformation of 4a was also successful through a
Vilsmeier−Haack formylation, and the respective aldehyde 8
was afforded in 77% yield without erosion of the optical purity
(Scheme 3b). Then, the stereodivergent syntheses of
Figure 2. One-pot synthesis of various C5-allylindoles.
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Letter
Author Contributions
diallylated products were carried out by using 4a and ent-4a as
the starting materials; all four stereoisomers (9a−9d) were
afforded in 83−85% yields in >20:1 dr, and the ee values were
all >99% (see Scheme S5). Finally, the AAS/oxidation strategy
could be applied in the enantioselective synthesis of dopamine
transporter (DAT) inhibitor 5-indolyl aryl propylamine
intermediate through a three-step process, and key inter-
mediate 11 could be obtained in 91% yield and 99% ee (see
Scheme S6).
In conclusion, we have developed a highly enantioselective
protocol for the synthesis of chiral C5-allylindolines by an
iridium-catalyzed AAS reaction of allylic alcohols with various
N-protected indolines and their analogues. More importantly,
various enantioenriched 5-allylindoles could be achieved
through a one-pot strategy involving the Ir-catalyzed
asymmetric allylic alkylation and subsequent oxidation of N-
alkyl indolines. This strategy features mild reaction conditions,
readily available starting materials, a wide substrate scope, and
excellent stereoselectivities and is easily scaled up. Further-
more, the C5-allylindole products can be used as effective
linchpins for the streamlined preparation of various syntheti-
cally useful building blocks, which makes this protocol
potentially useful in organic synthesis.
†J.L. and R.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the Natural Science
Foundation of China (21672048), the Natural Science
Foundation of Zhejiang Province (LY18B020015), and
Hangzhou Normal University for financial support. X.Z.
acknowledges a Xihu Scholar award from Hangzhou City,
and G.Z. acknowledges a Qianjiang Scholar from Zhejiang
Province in China.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00810.
■
sı
Experimental details, analytical data of products, NMR
and HPLC spectra, and plausible transition state
structure (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xiaofei Zeng − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; orcid.org/0000-0003-4222-1365;
Email: chemzxf@hznu.edu.cn
Guofu Zhong − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; orcid.org/0000-0001-9497-9069;
Email: zgf@hznu.edu.cn
Authors
Jiamin Lu − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Ruigang Xu − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Haixia Zeng − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
(4) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
Meifang Wang − College of Materials, Chemistry and
Chemical Engineering, Hangzhou Normal University,
Hangzhou 311121, China
Zhigang Ni − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; orcid.org/0000-0002-0109-3275
̌
́
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Complete contact information is available at:
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