Diastereoselective Synthesis of Tetracyclic Tetrahydroquinoline Derivative Enabled by Multicomponent Reaction of Isocyanide, Allenoate, and 2-Aminochalcone

Article abstract of DOI:10.1021/acs.orglett.1c00912

We report here a multicomponent protocol to assemble several polycyclic dihydropyran-fused tetrahydroquinoline structures with excellent diastereoselectivity. This procedure employs simple feedstocks to accomplish a series of diverse structures, which is

Full text of DOI:10.1021/acs.orglett.1c00912

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Letter
Diastereoselective Synthesis of Tetracyclic Tetrahydroquinoline
Derivative Enabled by Multicomponent Reaction of Isocyanide,
Allenoate, and 2‑Aminochalcone
Zhishuang Wang, Youwen Fei, Chongrong Tang, Lei Cui,* Jie Shen, Kun Yin,* Shanya Lu, and Jian Li*
Cite This: Org. Lett. 2021, 23, 4094−4098
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ABSTRACT: We report here a multicomponent protocol to assemble several polycyclic dihydropyran-fused tetrahydroquinoline
structures with excellent diastereoselectivity. This procedure employs simple feedstocks to accomplish a series of diverse structures,
which is difficult to attain by traditional sequences.
droquinolines have attracted considerable interest from
chemists and pharmacologists.3,4 As such, reactions including
aza-Diels−Alder reactions, hydrogenation, and sequential
cycloaddition, as well as metal-catalyzed arylation processes,
have been well-documented.5−7 A careful literature screening
reveals that 2-aminochalcone and its derivatives are useful
synthons to create many types of tetrahydroquinolines and
other related N-containing heteroycles.8 Thus, the Hui group
has developed a NHC-catalyzed synthesis from readily
available 2-aminochalcones and 2-bromoenals. This method
enables the generation of three consecutive stereogenic centers
through double Michael addition and lactonization processes.9a
The Zhu group has demonstrated that the combination of
ortho-amino cinnamate, aldehyde, and α-isocyano acetamide
provided a successful example to approach structurally unusual
bridged tetrahydroquinoline (Scheme 2, eq 1).9b On the other
hand, phosphine-catalyzed annulation involving electron-
deficient allenoate has also been widely investigated.10,11 In
such cases, Guo and co-workers have reported that 2-
tosylaminochalcones could react with allenoates to synthesize
disubstituted indolines (Scheme 2, eq 2).12a Interestingly, a
modification by Kwon with 2-amidobenzaldehydes as substrate
etrahydroquinolines belong to a privileged class of
Tnitrogen-containing scaffolds usually found in natural
products, and they possess many biological activities.1 For
example, haplophytin-A (I), which is a tricyclic hemiterpenoid
alkaloid, is isolated from a methanol extract of Haplophyllum
acutifolium (Scheme 1).2a Furanoquinoline II exhibits impres-
sive antitubercular activity.2b Tetrahydroquinoline derivatives
III and IV also shows in vitro cytotoxicity and antibacterial
activity, respectively.2c,d In addition, cyclopropane-fused
tetrahydroquinolines are found to behave as potent HIV-1
inhibitors with the aid of cyclopropane and ester moiety.2e As a
consequence, new methods to access functionalized tetrahy-
Scheme 1. Examples of Biologically Active
Tetrahydroquinoline Scaffolds
Received: March 16, 2021
Published: May 13, 2021
https://doi.org/10.1021/acs.orglett.1c00912
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4094−4098
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a
Scheme 2. Previous Reports and Our Design
Table 1. Reaction Optimization
bc
,
entry
solvent
temperature (°C)
ratio (1:2:3)
yield (%)
1
2
3
4
5
6
7
toluene
dioxane
THF
80
80
80
80
80
80
80
80
60
70
90
100
120
90
90
90
90
90
90
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:2:1
1:1:2
2:1:1
2:2:1
3:2:1
2.5:2:1
13
16
trace
trace
20
25
33
15
trace
15
37
31
17
39
36
41
66
73
DMSO
DMF
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
d
8
9
10
11
12
13
14
15
16
17
18
19
has been utilized to produce 1,2-dihydroquinoline.12b
Although many successful approaches toward tetrahydroquino-
lines synthesis exist, stereoselective synthesis of such species
with structural diversity remains underexploited.
Isocyanides as fundamental building blocks offer a
straightforward pathway for the occurrence of a wide range
of reactions.13 In particular, multicomponent reactions
incorporating isocyanides are believed to maximize synthetic
efficiency and increase structural complexity, which substan-
tially expands their application prospect in organic synthesis, as
well as drug discovery endeavor.14,15 Regardingly, our group is
engrossed in introducing the isocyanide reactivity to engage
new transformations.16 As a continuation, we expected that a
multicomponent strategy incorporating isocyanide, 2-amino-
chalcone, and allenoate (Scheme 2, eq 3) might furnish
complementary access aiming to the diastereoselective
construction of polycyclic tetrahydroquinoline.
At the outset of our investigation, tert-butyl isocyanide (1a)
was used as the model substrate to react with partners allene
(2a) and 2-aminochalcone (3a). Upon treating this mixture in
toluene at 80 °C, we observed an annulation adduct 4a (13%
yield) (Table 1, entry 1). Then, we screened the influence of
solvent, temperature, and substrate ratio to improve the
reaction performance. Among the solvents tested, dioxane,
dimethylformamide (DMF), and acetane (MeCN) could
enhance 4a, while tetrahydrofuran (THF) and dimethylsulf-
oxide (DMSO) only produced poor results (Table 1, entries
2−6). An elevated yield of 4a (33% yield) was isolated when
DCE was used as the solvent (Table 1, entry 7). Next, we
found that the reaction temperature had a strong impact on
present conversion. For instance, slightly increased temper-
ature seemed to be favorable (Table 1, entry 11). In sharp
contrast, heating the mixture at other temperatures, such as 60,
70, 100, and 120 °C, simply resulted in negative outcomes
(Table 1, entries 9−13), respectively. In addition, attempts to
improve the reaction performance also relied on the
appropriate ratio between substrates. Pleasingly, the employ-
ment of excess amount of substrates 1a and 2a dramatically
increased adduct 4a (Table 1, entries 14−17) and the ratio
3:2:1 brought the highest yield.
69
a
Unless specified otherwise, all reactions were performed with tert-
butyl isocyanide 1a (0.1 mmol), ethyl 2-benzylbuta-2,3-dienoate 2a
(0.1 mmol), and 2-aminochalcone 3a (0.1 mmol) in 3 mL of solvent
in a sealed tube, 12 h. Yields after silica gel chromatography. In all
b
c
d
cases, d.r. > 20:1. Reaction time is 8 h.
including both n-butyl isocyanide and benzyl isocyanide were
found to be particularly good reaction components (4b and
4c). Reaction with ethyl 2-isocyanoacetate also worked well for
the developed annulation (4d). In particular, sterically
hindered isocyanides such as 1,1,3,3-tetramethylbutyl, cyclo-
hexyl, and admantyl isocyanides also served as efficient
reaction couplers (4e−4g). We also defined the configuration
of compound 4a using the single crystal analysis (CCDC
2054200). Then, aromatic isocyanides were evaluated under
standard conditions. Accordingly, the dihydropyran-fused
tetrahydroquinoline derivatives 4h−4l were prepared smoothly
when isocyanides having para- and meta-position substitution
were utilized. Unfortunately, the experiments also suggested
that aromatic isocyanides bearing substituents at the ortho-
position were unable to give the corresponding product.
We also employed various substituted allenoates 2 to
undergo this conversion and these substrates were effectively
converted to the desired products 5a−5i (Scheme 4).
Similarly, α-methyl substituted allenoate underwent the
present transformation to deliver product 5j. Nevertheless,
the scope of this method could not be extended to
unsubstituted allenoate, which remained intact when subjected
to standard conditions. Absolute configuration of compound
5k was also defined (CCDC 2054194).
The feasibility of a variety of 2-aminochalcones 3 under the
standard conditions were subsequently examined. In this
regard, these reactions were insensitive to differently
substituted TsNH-tethered chalcones 3 with substituent R2
at C5, C4, or C3 on the aniline moiety. As shown in Scheme 5,
After the optimal reaction conditions were identified, we
then surveyed the substrate scope of different isocyanides 1
(Scheme 3). Aliphatic isocyanides 1 having linear chain
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Scheme 3. Scope of the Reaction, with Respect to the
Isocyanide 1
Scheme 4. Scope of the Reaction with Respect to the
a c
a
−c
−
Allenoate 2
a
b
Reaction condition A. Yields of product after silica gel
c
chromatography. d.r. > 20:1.
Scheme 5. Scope of the Reaction, with Respect to the 2-
Aminochalcone 3.
a
Reaction condition A: 0.3 mmol of isocyanide 1, 0.2 mmol ethyl 2-
benzylbuta-2,3-dienoate 2a, and 0.1 mmol 2-aminochalcone 3a in
a−c
b
DCE (3 mL) in sealed tube, 90 °C, 12 h. Yields of product after
silica gel chromatography. d.r. > 20:1.
c
many substituents including chloro, methyl, bromo, and
methoxyl groups on the aromatic ring were compatible (6a−
6g). Next, varying the substituent R3 on another aromatic ring
of 2-aminochalcone 3 was conducted. In such cases,
compound 6h was isolated in excellent yield (93%) when
substrate 3 having para-methyl substitution on the R3 group
was used. Notably, the above-mentioned experimental results
also showed that electronic properties and substitution on the
aromatic ring had no influence on the diastereoselectivities,
which was exemplified by the high diasteromeric ratio (dr)
value (>20:1) in all cases.
To probe more insight into this multicomponent protocol,
several control experiments were subsequently performed (see
the Supporting Information for details). In this light, 2-
aminocinnamaldehyde 7a having an aldehyde group experi-
enced the standard conditions to produce corresponding
product 8a. Unfortunately, no reaction occurred when 2-
aminocinnamate 9a was used. These results suggested that this
annulation might necessitate the presence of a strongly
electron-deficient group bearing the alkenyl group. In addition,
a scale-up reaction was also conducted.
Following previous reports and the obtained experimental
data, an explanation of present conversion is detailed (Scheme
6). The first step involves a previously described generation of
active zwitterionic intermediate A ↔ B10,11,16b through
interaction of isocyanide 1 and allenoate 2. This resonance
a
b
Reaction conditionA. Yields of product after silica gel chromatog-
c
d
raphy. d.r. > 20:1. d.r.= 2.5:1.
stabilized intermediate experiences proton transfer with 3a to
afford compound C and D. Subsequent Michael addition
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Jian Li − Department of Chemistry, College of Sciences &
Scheme 6. Proposed Mechanism
Institute for Sustainable Energy, Shanghai University,
Shanghai 200444, People’s Republic of China; School of
Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, People’s Republic of
China; orcid.org/0000-0002-3136-5112; Email: lijian@
shu.edu.cn
Authors
Zhishuang Wang − Department of Chemistry, College of
Sciences & Institute for Sustainable Energy, Shanghai
University, Shanghai 200444, People’s Republic of China
Youwen Fei − Department of Chemistry, College of Sciences &
Institute for Sustainable Energy, Shanghai University,
Shanghai 200444, People’s Republic of China
Chongrong Tang − Department of Chemistry, College of
Sciences & Institute for Sustainable Energy, Shanghai
University, Shanghai 200444, People’s Republic of China
Jie Shen − Department of Chemistry, College of Sciences &
Institute for Sustainable Energy, Shanghai University,
Shanghai 200444, People’s Republic of China
Shanya Lu − Department of Chemistry, College of Sciences &
Institute for Sustainable Energy, Shanghai University,
Shanghai 200444, People’s Republic of China
generates key intermediate E. Next, sequential annulation
essentially produces intermediate H.16b,17 After that, the
elimination and nucleophilic addition occurs to yield the
final product.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00912
In summary, an arduous diastereoselective synthesis of
polycyclic tetrahydroquinoline derivative has been achieved
through multicomponent methods using readily available
starting materials. Mechanistically, the formation of resultant
[6.6.5]-fused rings involves sequential Michael addition, triple
intramolecular cyclization, proton transfer, and elimination
processes. This method is also distinguished by operational
simplicity, increased molecular complexity, and structural
diversity.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Key Research and
Development Program of China (No. 2017YFB0102900) and
Natural Science Foundation of Shanghai (No. 18ZR1413900)
for financial support. The project was supported by School of
Chemistry and Chemical Engineering, Henan Normal
University. This work was also sponsored by Talent Project
of Fuyang Normal University (No. 2018kyqd0035).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00912.
REFERENCES
■
1
Experimental procedures, characterization data, and H
(1) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Advances in
the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011, 111, 7157.
(2) (a) Michael, J. P. Quinoline, quinazoline and acridone alkaloids.
Nat. Prod. Rep. 2003, 20, 476. (b) Kumar, A.; Srivastava, S.; Gupta,
G.; Chaturvedi, V.; Sinha, S.; Srivastava, R. Natural Product Inspired
Diversity Oriented Synthesis of Tetrahydroquinoline Scaffolds as
Antitubercular Agent. ACS Comb. Sci. 2011, 13, 65. (c) Nagaiah, K.;
Venkatesham, A.; Srinivasa Rao, R.; Saddanapu, V.; Yadav, J.S.; Basha,
S.J.; Sarma, A.V.S.; Sridhar, B.; Addlagatta, A. Synthesis of new cis-
fused tetrahydrochromeno[4,3-b]quinolines and their antiproliferative
activity studies against MDA-MB-231 and MCF-7 breast cancer cell
lines. Bioorg. Med. Chem. Lett. 2010, 20, 3259. (d) Ramesh, E.;
Manian, R. D. R. S.; Raghunathan, R.; Sainath, S.; Raghunathan, M.
Synthesis and antibacterial property of quinolines with potent DNA
gyrase activity. Bioorg. Med. Chem. 2009, 17, 660. (e) Ellis, D.; Kuhen,
K. L.; Anaclerio, B.; Wu, B.; Wolff, K.; Yin, H.; Bursulaya, B.;
Caldwell, J.; Karanewsky, D.; He, Y. Design, Synthesis, and biological
evaluations of novel quinolones as HIV-1 non-nucleoside reverse
transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 4246.
(3) For reviews, see: (a) Muthukrishnan, I.; Sridharan, V.;
Menéndez, J. C. Progress in the Chemistry of Tetrahydroquinolines.
Chem. Rev. 2019, 119, 5057. (b) Wang, D.-S.; Chen, Q.-A.; Lu, S. M.;
Zhou, Y.-G. Asymmetric Hydrogenation of Heteroarenes and Arenes.
Chem. Rev. 2012, 112, 2557.
NMR and 13C NMR spectra for new compounds (PDF)
Accession Codes
CCDC 2054200 and 2054194 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge viawww.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, U.K.; fax: + 44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Lei Cui − Department of Chemistry, College of Sciences &
Institute for Sustainable Energy, Shanghai University,
Shanghai 200444, People’s Republic of China;
Email: cuilei@shu.edu.cn
Kun Yin − Anhui Province Key Laboratory for Degradation
and Monitoring of Pollution of the Environment, School of
Chemistry & Materials Engineering, Fuyang Normal
University, Fuyang, Anhui 236037, People’s Republic of
China; Email: yk0309403@163.com
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pubs.acs.org/OrgLett
Letter
(4) (a) Xuan, Q.; Song, Q. Diboron-Assisted Palladium-Catalyzed
Transfer Hydrogenation of N-Heteroaromatics with Water as
Hydrogen Donor and Solvent. Org. Lett. 2016, 18, 4250. (b) Zhou,
X.; Xia, J.; Zheng, G.; Kong, L.; Li, X. Divergent Coupling of Anilines
and Enones by Integration of C−H Activation and Transfer
Hydrogenation. Angew. Chem., Int. Ed. 2018, 57, 6681.
(17) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Cyclizations of N-Acyliminium Ions. Chem. Rev.
2004, 104, 1431.
(5) Wang, Z.-H.; Shen, L.-W.; Xie, K.-X.; You, Y.; Zhao, J.-Q.; Yuan,
W.-C. Diastereoselective Construction of Cyclopropane-Fused
Tetrahydroquinolines via a Sequential [4 + 2]/[2 + 1] Annulation
Reaction. Org. Lett. 2020, 22, 3114.
(6) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.;
Zhou, Y.-G. Dihydrophenanthridine: A New and Easily Regenerable
NAD(P)H Model for Biomimetic Asymmetric Hydrogenation. J. Am.
Chem. Soc. 2012, 134, 2442.
(7) Han, Y.-Q.; Zhang, Q.; Yang, X.; Jiang, M.-X.; Ding, Y.; Shi, B.-F.
Pd(II)-Catalyzed Enantioselective Intramolecular Arylation of Un-
biased C(sp3)−H Bonds to Construct Chiral Benzo-ring Compounds.
Org. Lett. 2021, 23, 97.
(8) (a) Zhou, X.-J.; Zhao, J.-Q.; Chen, X.-M.; Zhuo, J.-R.; Zhang, Y.-
P.; Chen, Y.-Z.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Organo-
catalyzed Asymmetric Dearomative Aza-Michael/Michael Addition
Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-
Aminochalcones. J. Org. Chem. 2019, 84, 4381. (b) Li, J.-H.; Du, D.-
M. Organocatalyzed Cascade Aza-Michael/Michael Addition for the
Asymmetric Construction of Highly Functionalized Spiropyrazolone
Tetrahydroquinolines. Chem. - Asian J. 2014, 9, 3278.
(9) (a) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-
P. N-Heterocyclic Carbene-Catalyzed Stereoselective Cascade Re-
action: Synthesis of Functionalized Tetrahydroquinolines. Org. Lett.
2013, 15, 4750. (b) González-Zamora, E.; Fayol, A.; Bois-Choussy,
M.; Chiaroni, A.; Zhu, J. Three component synthesis of oxa-bridged
tetracyclic tetrahydroquinolines. Chem. Commun. 2001, 1684.
(10) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Phosphine
Organocatalysis. Chem. Rev. 2018, 118, 10049.
(11) (a) Zhu, X.-F.; Lan, J.; Kwon, O. An Expedient Phosphine-
Catalyzed [4 + 2] Annulation: Synthesis of Highly Functionalized
Tetrahydropyridines. J. Am. Chem. Soc. 2003, 125, 4716. (b) Tian, J.;
He, Z. Phosphine-catalyzed [3 + 2] annulation of α-substituted
allenoates with ester-activated α,β-unsaturated imines: a novel
variation of the Lu [3 + 2] cycloaddition reaction. Chem. Commun.
2013, 49, 2058.
(12) (a) Gao, Z.; Wang, C.; Yuan, C.; Zhou, L.; Xiao, Y.; Guo, H.
Phosphine-catalyzed [4 + 1] annulation of 2-tosylaminochalcones
with allenoates: synthesis of trans-2,3-disubstitued indolines. Chem.
Commun. 2015, 51, 12653. (b) Zhang, K.; Cai, L.; Yang, Z.; Houk, K.
N.; Kwon, O. Bridged [2.2.1] bicyclic phosphine oxide facilitates
catalytic γ-umpolung addition−Wittig olefination. Chem. Sci. 2018, 9,
1867.
(13) (a) Zheng, S.-C.; Wang, Q.; Zhu, J. Catalytic Atropenantio-
selective Heteroannulation between Isocyanoacetates and Alkynyl
Ketones: Synthesis of Enantioenriched Axially Chiral 3-Arylpyrroles.
Angew. Chem., Int. Ed. 2019, 58, 1494. (b) Hu, Z.; Dong, J.; Men, Y.;
Lin, Z.; Cai, J.; Xu, X. Silver-Catalyzed Chemoselective [4 + 2]
Annulation of Two Isocyanides: A General Route to Pyridone-Fused
Carbo- and Heterocycles. Angew. Chem., Int. Ed. 2017, 56, 1805.
(14) Zhu, J.; Wang, Q.; Wang, M.-X., Eds. Multicomponent Reactions
in Organic Synthesis; Wiley−VCH: Weinheim, Germany, 2015.
(15) Santra, S.; Andreana, P. R. Bioinspired Ugi/Michael/Aza-
Michael Cascade Reaction in Aqueous Media: Natural-Product-like
Molecular Diversity. Angew. Chem., Int. Ed. 2011, 50, 9418.
(16) (a) Huang, J.; Li, F.; Cui, L.; Su, S.; Jia, X.; Li, J. Palladium-
catalyzed cascade reactions of enynones and isocyanides: access
towards functionalized ketenimine and its application. Chem.
Commun. 2020, 56, 4555. (b) Su, S. K.; Li, C. J.; Jia, X. S.; Li, J.
Isocyanide-Based Multicomponent Reactions: Concise Synthesis of
Spirocyclic Oxindoles with Molecular Complexity by Using a [1,5]-
Hydrogen Shift as the Key Step. Chem. - Eur. J. 2014, 20, 5905.
4098
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