Copper Catalyzed One-Pot Three-Component Imination-Alkynylation-aza-Michael Sequence: Enantio- And Diastereoselective Syntheses of 1,3-Disubstituted Isoindolines and Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b01507

An enantio- and diastereoselective syntheses of 1, 3-disubstituted isoindolines and tetrahydroisoquinolines via Cu^I-Pybox-diPh catalyzed one-pot imination-alkynylation-aza-Michael sequence has been reported. The three-component reaction produces one C-C and two C-N bonds sequentially with high yield (up to 92%), enantioselectivity (up to 99%), and diastereoselectivity (up to 9:1) in a single operation. Furthermore, the synthetic utility of the product has been demonstrated by LiAlH₄ reduction of ester and hydrogenation of alkyne functionality without losing the stereoselectivity.

Full text of DOI:10.1021/acs.orglett.9b01507

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper Catalyzed One-Pot Three-Component Imination−
Alkynylation−aza-Michael Sequence: Enantio- and
Diastereoselective Syntheses of 1,3-Disubstituted Isoindolines and
Tetrahydroisoquinolines
Braja Gopal Das,† Sadhna Shah,† and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, Uttar Pradesh, India
S
* Supporting Information
ABSTRACT: An enantio- and diastereoselective syntheses of 1, 3-disubstituted
isoindolines and tetrahydroisoquinolines via CuI-Pybox-diPh catalyzed one-pot
imination−alkynylation−aza-Michael sequence has been reported. The three-
component reaction produces one C−C and two C−N bonds sequentially with
high yield (up to 92%), enantioselectivity (up to 99%), and diastereoselectivity
(up to 9:1) in a single operation. Furthermore, the synthetic utility of the
product has been demonstrated by LiAlH4 reduction of ester and hydrogenation
of alkyne functionality without losing the stereoselectivity.
Scheme 1. Structure of Related Bioactive Molecules (a);
Synthetic Routes of 1,3-Substituted Isoindolines (b, c, d)
n asymmetric multicomponent reaction sequence is a
Avery attractive method because of its ability to construct
complex chiral molecules in a single operation from readily
available substrates in two or more steps under mild, one-pot
reaction conditions. These reactions can eliminate the tedious
process of isolation/purification of the synthetic intermediates
as well as save time and chemicals by reducing steps. During
the past decades, asymmetric multicomponent reaction
sequences have emerged as a powerful tool for the
construction of heterocycles.1
Enantioenriched substituted isoindolines and tetrahydroiso-
quinolines (THIQ) are an essential class of synthetically useful
heterocyclic compounds (Scheme 1a) with impressive
applications in pharmaceuticals, natural products, and bio-
logically active molecules.2 Their biological potential manifests
from observed anxiolytic,3 antidiabatic,4 and dopaminergic5
activity. Some of these compounds show as a potent
endothelin-A6 selective receptor antagonist. On the other
hand, biologically important disubstituted tetrahydroisoquino-
lines display β-adrenergic receptor7 antagonist, antitumor,8,9
and antimicrobial10 activities.
Because of these important factors, several approaches were
made for the synthesis of unsubstituted11 and monosubstituted
isoindolines,12 but only a few methods have been reported for
the catalytic asymmetric synthesis of 1,3-disubstituted isoindo-
lines in an enantio- and diastereoselective manner. Other than
chiral pool synthesis,13 two types of catalytic approaches have
been made. First one, was the nucleophilic addition to the
presynthesized imine (Scheme 1b) followed by cyclization,
reported by the Enders14 and Sasai15 groups. Pre-synthesized
imine as starting material restricts the versatility of the method.
Both reports use an organocatalyst, and in some cases, reaction
required 10 days to obtain a reasonable outcome. The other
approach was a [3 + 2] cycloaddition (Scheme 1c) of the
azomethine ylide (D) with quinone (C) in the presence of
chiral catalysts, reported by Gong16 and Wang17 et al. Major
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01507
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Organic Letters
Letter
a
disadvantages of this process include the instability of the
starting materials and requirement of multiple steps in the
synthesis. Also, the product contains a p-hydroxy phenol
derivative, which can make it more difficult for further
functionalization.
Table 1. Optimization of Reaction Conditions
On the other hand, there are some elegant methods reported
for the asymmetric synthesis of 1,3-disubstituted tetrahydroi-
soquinolines in a stereoselective manner. Studies have been
reported by Enders,18 Liu,19 Yamamoto,20 Ferraccioli,21 and
Zhou22 with different organometallic catalysts.
Other than these few approaches toward individual synthesis
of disubstituted isoindolines and tetrahydroisoquinolines, no
such straightforward synthetic methodology has been reported
which includes both 1,3-disubstituted isoindoline and
tetrahydroisoquinoline synthesis via the same operation from
simple, stable, and readily available starting materials. In this
context, here, we report a CuI-Pybox-diPh catalyzed one-pot
imination−alkynylation−aza-Michael sequence for the syn-
thesis of enantio- and diastereoselective 1,3-disubstituted
isoindolines and tetrahydroisoquinolines. A multicomponent
reaction occurs sequentially via copper-catalyzed imine
formation (Scheme 1d) from the aldehyde functionality of 2-
formylphenyl acrylate 2 or 2-formylphenyl crotonate 6 and
aniline 3, followed by asymmetric alkynylation with phenyl-
acetylene 4 producing the intermediate 2′ or 6′. The
intermediate undergoes base-promoted aza-Michael cyclization
in the same reaction vessel and leads to the desired product 5
or 7 with an exceptionally high level of yield as well as enantio-
and diastereoselectivity. Three elementary steps proceed in
one pot by generating one C−C and two C−N bonds,
simultaneously.
Several potential catalysts were screened for the synthesis of
1,3-disubstituted isoindoline 5a via a three-component
imination−alkynylation−aza-Michael sequence in the presence
of pybox ligand La with 2-formylphenyl acrylate 2a, aniline 3a,
and phenyl acetylene 4a (Table 1, entries 1−5) as model
substrates. Only CuI-triflate and CuII-triflate produced the
desired product with yields of 41% and 35% and
enantioselectivities of 68% and 65%, respectively. Other
catalysts such as Sc(OTf)2, Zn(OTf)2, etc. failed to catalyze
the reaction. Therefore, further study was carried out in the
presence of CuI-triflate (10 mol %) with different oxazoline
ligands in chloroform at room temperature under an inert
atmosphere. CuI-complexes of Ligand Lb-e either did not
initiate the reaction or furnished 5a in very low yield (<20%).
However, the CuI-complexes of ligand Lf-g, CuI-Pybox-diPh,
afforded 5a in up to 82% yield with 90% ee and 8:1 dr (Table
1, entries 8−9). Here, the noticeable improvement in yield and
selectivity was found by using the modified Pybox ligands Lf-g.
This modification was first made by our group to improve the
steric and electronic nature of the ligand by introducing diaryl
substitution on the 5-position of oxazoline which gave the best
result in the CuI-catalyzed propargylation reaction.23 Extensive
temperature and solvent study indicated that the imination−
alkynylation occurs best at room temperature in toluene, but
the final product was obtained in optimal yield on exposure of
the reaction mixture to an equimolar solution of lithium
hexamethyldisilyl amide (LHMDS)24 in THF at 0 °C. Thus,
the isoindoline 5a was isolated in 85% yield and 91% ee with a
diastereomeric ratio of 9:1 (Table 1, entry 12) (see Supporting
Information for complete screening). Lowering the catalyst
loading to 5 mol % led to a slower reaction rate.
b
c
b
entry
catalyst
Sc(OTf)2
Zn(OTf)2
Cu(CH3CN)4PF6
Cu(OTf)2
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
L
yield (%)
ee (%)
dr
1
2
3
4
5
6
7
8
9
La
La
La
La
La
Lb
Lc
Lf
Lg
Lg
Lg
Lg
<20
<20
<20
35
−
−
−
65
68
−
−
−
−
4:1
4:1
−
41
<20
<20
75
82
55
−
−
62
90
85
−
4:1
8:1
7:1
−
d
10
11
12
e
0
f
g
87(85)
91
9:1
a
Reaction conditions: 2a (0.2 mmol, 1 equiv), 3a (0.22 mmol, 1.1
equiv), 4a (0.3 mmol, 1.5 equiv), metal (10 mol %), ligand (11 mol
b
%), base (0.2 mmol, 1 equiv), solvent (2 mL). Yield and dr were
determined from 1H NMR of the crude reaction mixture with
c
acenaphthene as an internal standard. Ee was determined by HPLC
analysis using chiral column. CH2Cl2 was used as solvent. CH3CN
was used as solvent. Toluene was used as solvent. Isolated yield in
parentheses.
d
e
f
g
Scope and limitations of the reaction under the optimized
conditions with various amines (Scheme 2) revealed that
aromatic amines containing an electron-donating group
improve the yield and enantioselectivity of the reaction. 4-
a
Scheme 2. Substrate Scope of Anilines
a
Reaction conditions were same as those for Table 1, unless otherwise
noted. The reaction was carried out also in 2 mmol scale. Reaction
b
c
was carried out at 50 °C.
B
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Letter
a
Methoxy and 4-methyl aniline afforded isoindolines 5b−c in
more than 90% yields with 96% and 92% ee’s, respectively.
Different halide substituted anilines resulted in excellent yields
and enantioselectivities. For 3-fluoro aniline, the reaction was
quite slow (78% yield of 5g), but the enantioselectivity was
excellent (99% ee). All the substituted anilines gave very high
enantioselectivities and up to 9:1 diastereoselectivities, except
4-nitroaniline, which required a higher temperature (50 °C)
for imination and alkynation reactions. A few electron-deficient
amines, e.g., TsNH2, CbzNH2, etc., have also been
investigated, but these were unable to form imine in the
given reaction conditions. It might be due to their electron-
deficient nature. We have carried this imination−alkynylation−
aza-Michael sequence with alkyl amines such as n-pentyl amine
and phenylethyl amine. Unfortunately, the desired products
5k−l were not formed and we have ended up with a complex
mixture of products. To demonstrate practical usefulness, the
reaction was scaled up to 2 mmol scale, and the product 5b
was obtained with the same level of yield and enantioselec-
tivity.
Scheme 4. Substrate Scope of Aldehydes
a
Reaction conditions were same as those for Table 1, unless otherwise
noted.
Since 4-methoxyaniline gave a higher yield and enantiose-
lectivity, the three-component imination−alkynylation−aza-
Michael sequence was further extended to a variety of terminal
alkynes (Scheme 3) with this amine. There were no significant
provided isoindoline 5w in comparatively lower yield (66%)
with 88% ee. A quaternary carbon center was generated in
isoindoline 5x without affecting the stereoselectivity of the
reaction. When different substitution in the aromatic ring of 2-
formylphenyl acrylate 2 was introduced, no significant change
was observed in yields (up to 92%) as well as enantio- (up to
95%) and diastereoselectivities (up to 9:1) of isoindolines 5y−
ae (Scheme 4).
a
Scheme 3. Substrate Scope of Alkynes
The absolute configuration of the product was assigned as
(S, S) based on the X-ray crystal structure analysis of 5y
(CCDC 1893283; see Supporting Information).
After successful synthesis of isoindolines, we then turned our
focus toward 1,3-disubstituted tetrahydroisoquinolines
(THIQ), starting from 2-formylphenyl crotonate 6 (Scheme
5). Different amines, such as aniline, 4-methyl, and 4-fluoro
aniline, produced the corresponding tetrahydroisoquinolines
7a−c with yields up to 80%, enantioselectivities up to 99%, and
dr’s up to 8:1. Various alkynes were also examined and
afforded tetrahydroisoquinolines 7d−e with yields up to 82%
and enantioselectivities up to 91% via the CuI-Pybox-diPh
a
a
Scheme 5. Synthesis of 1,3-Disubstituted Isoquinolines
Reaction conditions were same as those for Table 1, unless otherwise
noted.
changes in yields and selectivities by changing the electronic
nature of the substitution on the aromatic ring of alkyne. The
corresponding isoindolines 5m−r were obtained in high yields,
up to 86%, and ee’s up to 96% with good diastereoselectivities.
A differently substituted alkyne, such as trimethylsilyl
acetylene, was unable to produce 5s. Only the imine formation
was observed in the reaction mixture. The reaction was also
smooth for aliphatic terminal alkynes, generating the
corresponding isoindolines 5t−u with high yields (84% and
86%, respectively) and enantioselectivities (93% and 87%,
respectively).
Next, we explored the scope of the reaction by installing a
variety of functional groups in aldehyde 2 (Scheme 4).
Different ester functionalities, e.g., ethyl ester, gave the
corresponding isoindoline 5v in very good yield (85%) and
enantioselectivity (94%). Sterically bulky tert-butyl ester
a
Reaction conditions were same as those for Table 1, unless otherwise
noted.
C
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Letter
complex catalyzed three-component imination−alkynylation−
aza-Michael sequence.
research fellowship. B.G.D. thanks DST for the INSPIRE
Faculty award (DST/INSPIRE/04/2016/000702). We also
thank Dr. Monoj Gangwar from IIT Kanpur for solving the
crystal structure.
To demonstrate the synthetic utility of the protocol,
isoindoline 5b was transformed into the corresponding alcohol
8b with a 68% yield and 96% ee by LiAlH4 reduction. Alkyne
functionality was easily hydrogenated by molecular hydrogen
in the presence of 10% Pd/C to furnish 8a in 92% yield and
94% ee (Scheme 6).
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In conclusion, we developed a multicomponent reaction
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tetrahydroisoquinolines with an unprecedented level of yield as
well as enantio- and diastereoselectivity. Three elementary
steps, imination−alkylation−aza-Michael, occur in one pot to
furnish the product. Substituted aldehydes were synthesized in
one step from the commercially available starting material. The
reaction was scaled up to demonstrate the practical usefulness.
Transformation of the ester and alkyne functionalities shows
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01507.
Experimental procedures, and characterization data and
spectra of new compounds (PDF)
Accession Codes
CCDC 1893283 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
ORCID
Vinod K. Singh: 0000-0003-0928-5543
Author Contributions
†B.G.D. and S.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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V.K.S. acknowledges DST/SERB, India for a J. C. Bose
fellowship (SR/S2/JCB-17/2008) and SERB (CRG/2018/
000552) for the financial support. S.S. thanks IIT Kanpur for a
D
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E
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