Enantioselective dehydrative γ-arylation of α-indolyl propargylic alcohols with phenols: Access to chiral tetrasubstituted allenes and naphthopyrans

Article abstract of DOI:10.1021/acs.orglett.0c02386

Herein, we report an enantioselective dehydrative γ-arylation of α-indolyl propargylic alcohols with phenols via organocatalysis, which provides efficient access to chiral tetrasubstituted allenes and naphthopyrans in high yields with excellent regio- and

Full text of DOI:10.1021/acs.orglett.0c02386

pubs.acs.org/OrgLett
Letter
Enantioselective Dehydrative γ‑Arylation of α‑Indolyl Propargylic
Alcohols with Phenols: Access to Chiral Tetrasubstituted Allenes and
Naphthopyrans
Wen-Run Zhu, Qiong Su, Hong-Juan Diao, Er-Xuan Wang, Feng Wu, Yun-Long Zhao, Jiang Weng,*
and Gui Lu*
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ABSTRACT: Herein, we report an enantioselective dehydrative γ-arylation of α-indolyl propargylic alcohols with phenols via
organocatalysis, which provides efficient access to chiral tetrasubstituted allenes and naphthopyrans in high yields with excellent
regio- and enantioselectivities under mild conditions. This method features the use of cheaply available naphthols/phenols as the C−
H aryl source and liberating water as the sole byproduct. Control experiments suggest that the excellent enantioselectivity and
remote regioselectivity stem from dual hydrogen-bonding interaction with the chiral phosphoric acid catalyst.
xially chiral allenes are prevalent in many natural
Aproducts, functional materials, and bioactive molecules
and are used as chiral auxiliaries, ligands, and organocatalysts in
asymmetric synthesis.1 Moreover, allenes also serve as versatile
synthons in various chemical transformations in organic
synthesis.2 Consequently, optically active allenes have long
been recognized as attractive targets for synthetic chemists, and
various elegant strategies have been developed,3 which include
central-to-axial chirality transfer,4 kinetic resolution of racemic
allenes,5 and metal6 and organocatalytic7 asymmetric synthesis.
However, most of these methods are focused on the synthesis
of chiral 1,3-disubstituted or 1,1,3-trisubstituted allenes. In
contrast, the synthesis of chiral tetrasubstituted allenes,8
particularly (hetero)aryl-substituted allenes from readily
available starting materials, remains challenging and has less
been reported.
Propargylic alcohols and derivatives have been considered as
ideal precursors for the construction of chiral allenes, including
tetrasubstituted ones. The most classical approach to accessing
chiral tetrasubstituted allenes relies on stereospecific formal
SN2′ substitutions or sigmatropic rearrangements from
enantiopure propargylic precursors catalyzed by metal
catalysts.3 In contrast, catalytic asymmetric synthesis of
tetrasubstituted allenes from racemic propargylic precursors,
especially propargylic alcohol, is undoubtedly more attractive
but also more challenging. In 2017, the group of Sun has
reported the organocatalytic synthesis of chiral tetrasubstituted
allenes from racemic propargylic alcohols, which mechanisti-
cally involves asymmetric trapping of intermediate propargylic
cations with nucleophilic β-diketones or thioacetic acid.8g,h
More recently, Ma and co-workers have elegantly realized the
efficient catalytic asymmetric formation of tetrasubstituted 2,3-
allenoic acids from racemic propargylic alcohols via Pd-
catalyzed kinetic resolution.8c Despite these advances, it is still
desirable to develop new methods for synthesizing structurally
diverse chiral tetrasubstituted allenes.
One the other hand, given the significance of chiral
tetrasubstituted allenes bearing aryl substituents, a great deal
of effort has been devoted to the asymmetric construction of
these skeletons based on the arylative transformation of various
propargylic precursors. In this context, the groups of
Aggarwal8a and Studer8b have developed metal-catalyzed
Received: July 20, 2020
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stereospecific synthesis of tetrasubstituted allenes via γ-
arylation of enantioenriched propargylic boronic esters and
carboxylic acids, respectively (Scheme 1a). However, this
of chiral fully substituted allenes through an organocatalytic
dehydrative C−H bond allenylation approach.12
To verify the feasibility of our hypothesis, α-indolyl-α-
trifluoromethyl propargylic alcohol 1a and 1-naphthol 2a were
chosen as the model substrates using chiral phosphoric acids as
the catalysts (Table 1). Propargylic alcohol 1a was chosen as
Scheme 1. Synthesis of (Chiral) Tetrasubstituted Allenes via
γ-Arylation of Propargylic Compounds
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
solvent
time (h)
yield (%)
er (%)
1
2
3
4
5
6
7
8
(S)-A1
(S)-A2
(R)-A3
(R)-A4
(R)-A5
(R)-A6
(R)-B1
(R)-B2
(R)-B3
(R)-B3
(R)-B3
(R)-B3
(R)-B3
(R)-B3
(R)-B3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
toluene
THF
DCM
DCM
96
12
48
72
36
48
40
32
32
72
72
32
NR
28
56
90
96
93
93
95
94
95
86
96
93
93
95
−
76:22
60:40
23:77
37:63
20:80
23:77
88:12
95:5
97:3
97:3
96:4
97:3
strategy suffers from the requirement of prefunctional starting
materials and pre-established central chirality, which limits its
application. Moreover, C−H functionalization reactions
provide a straightforward approach for the facile trans-
formation of readily available hydrocarbons.9 In this regard,
the groups of Ma,9a,d Glorius,9b and Sundararaju9c have
reported the metal-catalyzed C−H bond allenylation of
(hetero)arenes with propargylic precursors, affording tetrasub-
stituted allenes through a concerted metalation/deprotonation
(CMD) process (Scheme 1b). Despite significant advances,
these C−H allenylation reactions mainly furnish racemic
tetrasubstituted allenic compounds, and the catalytic enantio-
selective version of such a transformation remains less
explored. In addition, the covalent installation and removal
of special directing groups were generally required.
9
10
11
12
13
14
15
−
98:2
>99:1
d
96
96
d,e
a
Unless otherwise specified, all reactions were carried out with a
catalyst (10 mol %), 1a (0.10 mmol), and 2a (0.12 mmol) in the
b
indicated solvent (2.0 mL) at room temperature. Isolated yield of 3a.
c
d
Determined by chiral-phase HPLC analysis. With 50 mg of 4 Å
e
molecular sieves. Reaction carried out at 0 °C.
Inspired by these pioneering studies and the recent progress
on phenol-directed C−H functionalization reactions,10 we
envisioned that phenols might be directly used as the aryl
sources to react with propargylic alcohols, thereby providing
the possibility of developing a direct enantioselective
dehydrative arylation strategy for the construction of chiral
tetrasubstituted allenes (Scheme 1c). However, several
challenges need to be considered: (1) overcoming the C/O
chemoselectivity of the phenols, (2) obtaining high regiose-
lectivity between the ortho and para positions of phenols, (3)
achieving high regioselectivity at the C3 position versus the C1
position of propargylic alcohols, and (4) choosing an
appropriate chiral catalytic system to efficiently control the
chemo-, regio-, and enantioselectivities mentioned above. As a
continuation of our interest in asymmetric organocatalysis,11
we envisioned that synergistic hydrogen-bonding activation of
both the phenols and the propargylic alcohols could address
those challenges, thereby allowing the straightforward synthesis
the substrate due to their hydrogen-bonding interaction
property of the indole moiety with the phosphoric acid
catalyst.13 Meanwhile, to the best of our knowledge, the
formed chiral tetrasubstituted allenes bearing privileged indole
and CF3 moieties cannot be easily acquired by conventional
methods9b,14 and have not been accessed, which might open
up opportunities for further bioactivity studies.15 To our
delight, when (S)-A1 was employed as the catalyst, the
reactions proceeded smoothly and afforded allene 3a in 90%
yield with 76:22 er (Table 1, entry 1). Remarkably, the C−H
allenylation occurs at the para position rather than the ortho
position of 1-naphthol. To improve the stereoselectivity, a
series of chiral phosphoric acid catalysts were then examined
(Table 1, entries 2−9). Fortunately, we found the spirocyclic
phosphoric acid catalyst (R)-B3 gave the best yield (96%) and
enantioselectivity (97:3 er) (Table 1, entry 9). Next, the
solvent effect was investigated, and a significant solvent effect
B
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was observed (Table 1, entries 9−13). Compared with other
solvents, such as 1,2-dichloroethane, chloroform, and toluene,
DCM was the best choice for this reaction (Table 1, entry 9).
When using THF as the solvent, the reaction could not take
place (Table 1, entry 13). A higher enantioselectivity (98:2 er)
was observed when 50 mg of 4 Å molecular sieves was added
(Table 1, entry 14). When the reaction temperature was
decreased to 0 °C with a prolonged reaction time, excellent
enantioselectivity (>99:1 er) was achieved (Table 1, entry 15).
With optimal reaction conditions established (Table 1, entry
14), we next explored the scope of this reaction (Schemes 2
and 3). As illustrated in Scheme 2, we first investigated the
substrate scope with respect to α-indolyl propargylic alcohols.
Scheme 3. Substrate Scope for the Synthesis of
a
Naphthopyrans
Scheme 2. Substrate Scope for the Synthesis of Chiral
a
Tetrasubstituted Allenes
a
All reactions were carried out with (R)-A7 (20 mol %), 1 (0.05
mmol), and 4 (0.05 mmol) in DCM (0.5 mL) at −10 °C. The
isolated yield was determined after column chromatography. The er
value was determined by chiral-phase HPLC analysis.
The positions or electronic nature of the substituent on the
indole ring appeared to have limited effects on the
enantioselectivities, and the corresponding chiral tetrasubsti-
tuted allenes were afforded with 97:3−99:1 er (3a−3i).
However, lower yields were observed for substrates bearing
substituents at the C4 or C7 positions of the indole ring (3b
and 3i), probably due to the steric hindrance. Next, different
substituents, including methyl, methoxyl, and halogens, on the
phenyl ring of R2 were all compatible, giving 3j−3n in 82−98%
yields with excellent stereocontrol. In addition, the R2 group
could be alkyl groups such as trimethylsilyl, cyclopropyl, tert-
butyl, and n-butyl groups, delivering the corresponding
products without significant effects on the results (3o−3r,
82−95% yields, 96:4 − >99:1 er). Moreover, α-naphthols
bearing substituents could undergo effective transformations to
furnish allenes 3s−3u in high yields with excellent er.
Subsequently, the generality and limitations of this method
were further evaluated by changing from α-naphthols to less
nucleophilic phenols. Electron-neutral and electron-rich
phenols proved to be suitable aryl sources. Of note, 2,3-
disubstituted phenols gave the desired products with yields and
enantioselectivities that were better than those of 3,5-
disubstituted phenols (3v−3x, 82−90% yields, 95:5−99:1 er;
3y and 3z, 60−72% yields, 85:15−92:8 er). In addition, when
α-ester-substituted propargylic alcohol was subjected to the
reaction, corresponding allene 3aa was obtained in 86% yield
with 90:10 er. The absolute configurations of allenes 3 were
assigned by analogy to that of the literature,12 and that of 3z
was determined unambiguously by X-ray crystallographic
analysis.16
a
All reactions were carried out with (R)-B3 (10 mol %), 1 (0.10
During the investigation of the γ-arylation reaction of α-
indolyl propargylic alcohol 1 with 2-naphthol 4a as the
nucleophile, it was interesting to obtain an unexpected product
naphthopyran 5a (86% yield, 44:66 er, under the standard
mmol), 2 (0.12 mmol), and 4 Å molecular sieves (50 mg), in DCM
(2.0 mL) at room temperature. The isolated yield was determined
after column chromatography. The er value was determined by chiral-
phase HPLC analysis.
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conditions in Scheme 2), which was probably formed through
the intramolecular cyclization of allene intermediate 5′
(Scheme 3). It should be mentioned that the naphthopyran
skeleton bearing a tetrasubstituted stereogenic center at the C3
position is a privileged heterocyclic structure present in many
biologically active molecules and photochromic materials.17
Encouraged by this fascinating result, we next turned our
attention to improving the enantioselectivity of this reaction.
After optimization of the reaction conditions (see the
Supporting Information), naphthopyran 5a could be afforded
in 90% yield and 95:5 er when the reaction was performed at
−10 °C with chiral phosphoric acid (R)-A7 as the catalyst
(Schemes 3 and 5a). Next, the scope of α-indolyl propargylic
alcohols was explored with 2-naphthol 4a as the nucleophile.
As shown in Scheme 3, various α-indolyl propargylic alcohols 1
with electron-donating groups (-Me and -OMe) or electron-
withdrawing groups (-F, -Cl, and -Br) at the 5 position of the
indole ring produced the naphthopyrans in 82−92% yields
with 92:8−96:4 er. Moreover, chloro substituents on the 5 or 6
position of the indole ring also did not obviously affect the
reaction outcomes. In addition, various substituents, including
p-fluorophenyl, p-chlorophenyl, p-methylphenyl, and p-me-
thoxyphenyl, at R2 were quite compatible, giving 5h−5k in
85−96% yields with high enantioselectivities. R2 could also be
alkyl groups, such as the cyclopropyl group, efficiently
producing corresponding product 5l (96% yield, 90:10 er).
The absolute stereochemistry of naphthopyrans 5 was assigned
by analogy to that of 5d, which was determined by X-ray
crystallographic analysis16 and comparison of the electronic
circular dichroism (ECD) spectrum of 5d and its calculated
enantiomeric counterpart (for details, see the Supporting
Information).
substrate is switched to the p-hydroxyphenyl group, substrate
10 could react smoothly with 1-naphthol and 2-naphthol under
the standard conditions, delivering corresponding products 11
and 12 in racemic form, albeit with excellent yields. Although
propargylic alcohol 10 has been successfully employed as a
substrate by Sun and co-workers in the synthesis of chiral
tetrasubstituted allenes,8g it is not applicable to the current γ-
arylation transformation, suggesting that the α-indolyl moiety
of the propargylic alcohol is crucial for the stereocontrol of this
transformation.
Under standard reaction conditions, a scale-up experiment
(Scheme 5a) was carried out and 3a could be obtained without
Scheme 5. Scale-up Experiment and Synthetic
Transformations of Allene 3a
To explore the origins of the excellent stereocontrol and
regiocontrol in this catalytic system, several control experi-
ments were carried out (Scheme 4). When 1-methoxynaph-
Scheme 4. Control Experiments
obviously sacrificing the yield or enantioselectivity. Further-
more, to explore the utility of the products, we carried out the
derivatization of product 3a (Scheme 5). The hydroxy group
and the amino group of 3a could be selectively or
simultaneously transformed into triflate or p-toluenesulfonic
acid ester in good yield and without a loss of enantiomeric
purity, which provides possibilities for further functionaliza-
tion. The cyclization of 3a to 2-iodine-3,4-dihydrocyclopenta-
[b]-indole 15 was successfully realized in the presence of NIS.
In addition, a possible reaction mechanism was proposed for
this reaction as shown in the Supporting Information.
In conclusion, we have developed the enantioselective
dehydrative γ-arylation of propargylic alcohols with phenols/
naphthols catalyzed by chiral phosphoric acids. A wide range of
tetrasubstituted allenes and naphthopyrans were afforded in
high yields with excellent enantioselectivities (39 examples,
≤98% yield and >99:1 er) under mild reaction conditions. It is
noteworthy that the incorporation of an α-indolyl moiety into
thalene 6 was subjected to the standard conditions, desired
product 7 was not observed and 1a has only low conversion
(Scheme 4a). Similarly, N-methyl-protected substrate 8 led to
a trace amount of allene 9 (Scheme 4b). These results implied
that the free OH and NH groups might simultaneously interact
with the chiral phosphoric acid catalysts via dual hydrogen-
bonding interactions. Moreover, when the indole moiety of the
D
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Notes
propargylic alcohol substrates is the key to the success of this
protocol, which allows readily available phenols to be used as
the C−H aryl source, and enables dual remote functionaliza-
tion of two reaction components. Further synthetic applica-
tions of this strategy are ongoing in our laboratory and will be
reported in due course.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (81972824), the Guangdong
Basic and Applied Basic Research Foundation
(2020A1515011513 and 2020A1515010684), the Guangdong
Provincial Key Laboratory of Chiral Molecule and Drug
Discovery (2019B030301005), and the National Engineering
and Technology Research Center for New Drug Druggability
Evaluation (Seed Program of Guangdong Province,
2017B090903004). The authors are grateful to Dr. Shan-
Shui Meng (Sun Yat-sen University) for helpful discussion and
Prof. Ruibo Wu (Sun Yat-sen University) for ECD calculation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02386.
Full experimental procedures, spectroscopic character-
izations, and NMR and HPLC spectra (PDF)
Accession Codes
CCDC 2010785 and 2010790 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Jiang Weng − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China; orcid.org/0000-0002-4117-4686; Email: wengj2@
mail.sysu.edu.cn
Gui Lu − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China; orcid.org/0000-0003-0089-0907; Email: lugui@
mail.sysu.edu.cn
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Authors
Wen-Run Zhu − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
Qiong Su − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
Hong-Juan Diao − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
Er-Xuan Wang − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
Feng Wu − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
Yun-Long Zhao − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, P. R.
China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02386
E
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