Organocatalyzed synthesis and biological activity evaluation of hybrid compounds 4H-pyrano[2,3-b]pyridine derivatives

Article abstract of DOI:10.1080/00397911.2020.1757717

1,4-Dihydropyridines and 4H-pyran derivatives are common and important structures in various pharmaceutical compounds. Dihydropyridines are well-known moieties in compounds that have analgesic, fungicidal, and antibacterial activities and 4H-pyran structu

Full text of DOI:10.1080/00397911.2020.1757717

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Organocatalyzed synthesis and biological
activity evaluation of hybrid compounds 4H-
pyrano[2,3-b]pyridine derivatives
Hoai-Thu Pham, James P. Martin & Truong-Giang Le
To cite this article: Hoai-Thu Pham, James P. Martin & Truong-Giang Le (2020): Organocatalyzed
synthesis and biological activity evaluation of hybrid compounds 4H-pyrano[2,3-b]pyridine
derivatives, Synthetic Communications, DOI: 10.1080/00397911.2020.1757717
To link to this article: https://doi.org/10.1080/00397911.2020.1757717
View supplementary material
Published online: 18 May 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1757717
Organocatalyzed synthesis and biological activity
evaluation of hybrid compounds 4H-pyrano[2,3-b]pyridine
derivatives
Hoai-Thu Phama,b, James P. Martina,b, and Truong-Giang Lea
aInstitute of Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam;
bGraduate University of Science and Technology, VAST, Hanoi, Vietnam
ABSTRACT
ARTICLE HISTORY
Received 12 March 2020
1,4-Dihydropyridines and 4H-pyran derivatives are common and
important structures in various pharmaceutical compounds.
Dihydropyridines are well-known moieties in compounds that have
analgesic, fungicidal, and antibacterial activities and 4H-pyran struc-
tures are populous in compounds with antibacterial and anti-cancer
potential; exploiting the biological activities of both 1,4-dihydropyri-
dines and 4H-pyran moieties through the exploration of hybrid com-
pounds featuring combinations of these two heterocyclic
functionalities is an interesting avenue of research. In this research,
we developed novel 1,4-dihydropyridines and 4H-pyran hybrid com-
pounds generated under organocatalytic conditions and evaluated
their cytotoxic activity toward KB and HepG2 cancer cell lines.
KEYWORDS
Dihydropyridine derivatives;
hybrid compounds; 4H-
pyran; 4H-pyrano[2,3-
b]pyridine derivatives;
organocatalysis
GRAPHICAL ABSTRACT
Introduction
The synthesis of novel hybrid compounds containing two or more active sites is an
interesting avenue of research that may lead to a synergistic increase of bioactivity
accompanied by a decrease of disadvantages when compared to the lone components.
1,4-Dihydropyridines and 4H-pyran derivatives are attractive moieties to investigate due
to their structure, functionality, and biological activities. 1,4-Dihyropyridines can act as
selective calcium channel blockers,[1] seeing use in the treatment of cardiovascular dis-
orders, and present vasodilating activity[2]; 4H-pyran derivatives are recognized as a
CONTACT Hoai-Thu Pham
phamht145@gmail.com
Institute of Chemistry, Vietnam Academy of Science and
Technology (VAST), Hanoi, Vietnam.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
H.-T. PHAM ET AL.
Figure 1. Structures of selected bioactive dihydropyridine and pyran derivatives.
pharmacophoric moiety associated with analgesic, fungicidal, and antibacterial activ-
ities[3,4]; pyranopyridines have been previously investigated for anti-cancer and cytotoxic
activity.[5,6]
1,4-Dihydropyridines are NADH mimics[7,8] and can be used as hydride donors in a
broad range of asymmetric transformations.[9,10] Due to the importance of these classes
of heterocyclic compounds, many efforts have been devoted to the preparation of 1,4-
dihydropyridine derivatives using Hantzsch[11,12] and Biginelli reactions[13] with many
published reports on the synthesis of dihydropyridine analogues[14–20] and dihydropyri-
dine bicycloadducts[21–23] and their pharmaceutical activities.[16] Similarly, the develop-
ment of 4H-pyran structures has attracted the investigative attention of many
laboratories[20,23–25] over the years. During the course of our interest in developing
dihydropyridine structures, we found that 1,4-dihydropyridines act as electron-rich
alkenes in reactions with iminium ions, leading to the generation of novel and pharma-
ceutically promising hybrid 4H-pyrano[2,3-b]pyridine derivatives. Herein, we first report
the synthesis of hybrid 4H-pyrano[2,3-b]pyridine derivatives which have been formed
by the reactions between 1,4-dihydropyridines and acrolein in the presence of (5S)-
(ꢀ)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone monohydrochloride as an organocatalyst
(Figure 1).
Results and discussion
The preparation of 1,4-dihydropyridines was achieved by the reaction between an enam-
inoester, a modest library of which were prepared according to modified procedures
reported by Nitin,[26] and an unsaturated aldehyde under Lewis acid activation. The
cycloaddition was first investigated in the presence of aqueous HCl (catalyst A), (2S,4S)-
4-methyl-2,5,5-triphenyloxazolidine hydrochloride (catalyst B) and (S)-5-benzyl-2,2,3-

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 1. The synthesis of enaminoesters, 1,4-dihydrpopyridine, and 4H-pyrano[2,3-b]pyridine bicly-
coadducts in the presence of organocatalyst.
trimethylimidazolidin-4-one hydrochloride (catalyst C) in aqueous acetonitrile at room
temperature (Scheme 1).
The low yield of cycloadduct produced by catalyst B could be explained by the
increased substitution around secondary amine hindering the optimal approach of the
acrolein to form the iminium ion; therefore, catalyst C was chosen as the most promis-
ing catalyst and was taken forward for optimization. The screening of different condi-
tions such as solvent, temperature and reaction time was studied (Table 1). We found
that polar solvents, such as CH3CN/H2O (19:1), seemed to be the best solvent system
for the reaction with nonpolar solvents providing low yields. Raising temperature helped
improve the yields from 33% up to 54%, all reaction substrates had been consumed
after 16 h of reaction time; however, better yields were observed in cases where the reac-
tion was stopped between 2 and 4 h. Under the conditions screened no enatioenrich-
ment of the isolated cycloadduct was observed when investigated by measuring the
rotation of plane-polarized light. The substrate scope of the synthesis was then investi-
gated employing a variety of unsaturated aldehydes and 1,4-dihydropyridine derivatives.
The reaction was wide in scope and robust regarding the identity of the 1,4-dihydropyr-
idine producing the desired bicyclic adducts in yields of 43–68% (entries 14–18,

4
H.-T. PHAM ET AL.
1
Table 1. The H NMR, 13C NMR, HSQC, HMBC, COSY, and NOESY of compound 8.
No.
Product
Cat.
Solvent
Temp., ꢁC
Time, h
Yield, %
1
2
3
4
5
6
7
8
–
–
–
A
B
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN
MeOH
CH2Cl2
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
RT
RT
RT
RT
RT
RT
RT
ꢀ20
0
50
50
50
50
50
50
50
50
50
2
2
2
2
2
2
2
2
2
2
4
8
16
4
4
4
4
4
–
–
5
36
22
13
11
–
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
9
7
10
11
12
13
14
15
16
17
18
54
48
39
37
67
43
59
61
68
Figure 2. 1H NMR and 13C NMR of compound 8a and 9.
Table 1); however, various side-products generated by the reactions of acrolein with
itself were found during the reaction. The scope of unsaturated aldehydes was found to
be more narrow, with substituted unsaturated aldehydes returning the unreacted 1,4-
dihydropyridine and products resulting from the reactions of the unsaturated aldehyde
with itself.
While catalyst A did not provide any products, two cycloadducts, 8 and 9, were gen-
erated under activation with catalyst B and catalyst C in low and moderate yields,
respectively. The mass spectrum showed that one molecule of acrolein was incorporated
into the 1,4-dihydropyridine derivative. 13C NMR, HMBC, HSQC, COSY, and DEPT
spectra were recorded to determine the structure of the cycloadduct 8 (Figure 2 (8a, 8b)
and Table 2).
HSQC spectra reveals a correlation of proton H7 (Table 2, singlet, 7.61 ppm) with C7
(Table 2, 144.4 ppm). HMBC spectra shows the proton H7 exhibits correlation with the
carbonyl group (Table 2, 13C NMR located at 168.1 ppm), C9 (54.7 ppm), C6 (41.8 ppm),
and C1 (78.4 ppm). Protons on the aromatic ring show their correlation with carbons of
aromatic rings on HSQC and HMBC. Protons H2 and H3 show their correspondence
on HSQC, COSY, and NOSY with J coupling constant J ¼ 6.0 Hz, consistent with
cis isomerism.

R
SYNTHETIC COMMUNICATIONSV
5
1
Table 2. The H NMR, 13C NMR, HSQC, HMBC, COSY, and NOESY of compound 8a.
Interaction
1H NMR
13C NMR
HSQC
COSY
HMBC
NOESY
H7, s, 7.61
144.4 (CH ¼ C)
H7–C7
H7–C ¼ O (168.1),
H7–C9 (54.7),
H7–C6 (41.8),
H7–C1 (78.4)
HAr
10HAr, m, 7.08–7.40
127.6–128.2 (Ar)
H
Ar–CAr
Interactions among
aromatic protons
(7.08–7.37)–CAr
(125.9–144.3)
0
H2, d, J ¼ 6.0 Hz, 6.1
H3, d,
139.3 (CH)
101.2 (CH)
H2–C2
H3–C3
H2–H3, 0H4,4
H2–H3, H4
H3–H2
H3–H4,4 , H5
J ¼ 6.0 Hz, 4.75
0
H1, d,
78.7 (CH)
41.8 (CH)
54.7 (CH2)
H1–C1
H6–C6
H1–H5, H4, H4’, H9,9
H1–H5
J ¼ 3.0 Hz, 4.61
H6, m, 3.61
H6–H5, H1
H9–H9’, H1
H6–CAr (127.8),
H6–H4, H5, H1
H9–H9’
H6–C7 (144.4)
0
0
H9, JAB
14.7 Hz, 4.40
¼
H9,9 –C9
H9,9 –CAr(128,6,
136.3, 144.6)
0
H9’, JAB
14.7 Hz, 4.30
¼
H9’–H1, H9, H7
H9/9 –C7 (144.4)
3H, s, 3.52
50.8 (CH3)
37.0 (CH)
22.5 (CH2)
OCH3
3H–C ¼ O (168.2)
0
H5, m, 2.15
H4, m, 2.05
H4’, m, 1.95
H5–C5
H5–H3, H1, H4,4
H5–H1
0
H4, 4 –C4
H4–H3, H5, H4’
H4’–H5, H4
H4’–H2, H5
HSQC and HMBC show the correlation of the three methyl protons (singlet,
3.52 ppm on proton NMR) and the adjacent carbonyl group (found at 168.2 ppm on
13C NMR). The protons H9 and H9 show correspondence with carbons on the aromatic
ring (located at 128.6, 163.3, and 144.6 ppm on 13C NMR) and the carbon C7 (located
at 144.4 ppm). NOESY and 1H NMR show the correlation of H9 and H9’ with
JAB¼14.7 Hz. HMBC has shown the correlation among H6 and the carbons of aromatic
ring and H7, COSY, and NOESY NMR have shown the correlation of H6, H5, and H1
to be consistent with the cis,cis-diastereomer in which these three protons are on one
side of the structure. The NOESY spectrum showed a correlation between H5 and H6
on the one side and between H5 and H1 on the other side. These interactions would be
consistent with cis–cis diastereoselectivity of the cycloadduct.
Based on structures of two cycloadducts, a mechanism is proposed for this transform-
ation (Scheme 2). The reaction likely starts by the formation of an iminium ion from
the catalyst and acrolein, increasing the electrophilicity of the terminal carbon atom of
acrolein. A Michael addition of the vinylogous enamine moiety of the 1,4-dihydropyri-
dine 6 on the iminium intermediate 10 then leads to the formation of the cationic
adduct 11. After hydrolysis of the enamine and probable formation of the hydrate, cyc-
lization leads to the bicyclic compound 9 that furnishes 8 upon dehydration.

6
H.-T. PHAM ET AL.
Scheme 2. Mechanism of the synthesis of 4H-pyrano[2,3-b]pyridine derivatives.
Table 3. Cytotoxic activity of 8a–f against KB and HepG2 cancer cell lines.
Cytotoxicity (mM)
No.
Product
KB
HepG2
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
2.0
8.0
0.75
32.0
16.0
32.0
4.0
8.0
2.0
16.0
64.0
32.0
With acceptably optimized catalytic conditions and a modest library of 4H-pyrano-
[2,3-b]pyridines in hand an in vitro cytotoxic activity screening against two cancer cell
lines, KB and HepG2, chosen as readily available in vitro models, was embarked upon
(Table 3) to evaluate the potential of these hybrid compounds as anti-cancer agents.
These results show that most of the derivatives possess a moderate cytotoxic activity,
with 8d–f portraying an IC50 of between 16.0 and 64.0 mM to both cell lines. 8f exhib-
ited an IC50 of 32.0 mM against both KB and HepG2 cells and 8d exhibited greater
potency against HepG2 cells than KB cells (IC50 of 16.0 mM and 32.0 mM, respectively).
A starker contrast was observed with 8e, which exhibited an IC50 of 64.0 mM against
HepG2 cells but had a comparatively potent IC50 of 16.0 mM against KB cells. 4H-pyr-
ano[2,3-b]pyridines 8a, 8b, and 8c show promising biological activity with IC50 <10 mM
to both cancer cell lines. 8b had an IC50 of 8.0 mM for both cell lines and 8a provided
an IC50 of 4.0 mM and 2.0 mM to HepG2 and KB cells, respectively. Of particular prom-
ise is 8c, which presented an IC50 of 2.0 mM for HepG2 cells and 0.75 mM for the KB
cell line. The increased cytotoxicity of 8c in comparison to 8a,b,d–f may be a result of
cytotoxic interactions involving the N-phenyl substituent.

R
SYNTHETIC COMMUNICATIONSV
7
Conclusion
In conclusion, hybrid compounds of 4H-pyrano[2,3-b]pyridine derivatives were first
synthesized in the reaction between 1,4-dihydropyridines and acrolein under organoca-
talyst activation in moderate yields (43–68%) and high diastereoselectivity. New com-
pounds were determined by using model spectroscopies such as IR, MS, and NMR. The
biological activity and cytotoxic evaluation of six novel 4H-pyrano[2,3-b]pyridine hybrid
compounds was investigated with KB and HepG2 cancer cell lines and gave very prom-
ising results (all compounds have at least moderate IC50, three compounds with
IC50 < 10 mM and one compound with IC50<1 mM).
Experimental part
Supporting information: Full experimental detail and compound characterization
1
including H and 13C NMR spectra and HRMS may be found via the “Supplementary
Content” section on this article’s webpage.
General information
All chemicals are reagent grade and purchased from Sigma-Aldrich (St. Louis, MO,
USA) and were used without further purification. All reactions were carried out under
an argon atmosphere with dried, freshly distilled solvents under anhydrous conditions,
unless otherwise noted. Merck silica gel (60, particle size 0.040–0.063 mm) was used for
flash chromatography. Preparative thin-layer chromatography (PTLC) separations were
carried out on self-made 0.2 mm. Merck silica gel plates (60F-254). IR spectra were
recorded on Perkin Elmer 16 PC FT-IR. Mass spectra were provided by HRMS which
was carried out by Orbitrap Q Exactive Focus Thermo Fisher at Institute of Chemistry,
Vietnam Academy of Science and Technology.
General procedure for the preparation of hybrid compounds 4H-pyrano[2,3-
b]pyridine derivatives
To a solution of the requisite DHP (6a–f, 1.0 equivalent) and catalyst (catalyst A–C, 0.10
equivalent) in a mixture of solvent CH3CN/H2O (19:1 ratio, 1 mL/0.1 mmol), acrolein (2
equivalents) was added dropwise over 20 min at 0ꢁC. The reaction mixture was stirred at
0 ꢁC for 1 h, then the temperature was increased to 50ꢁC for 3 h. Solvent was removed and
the residue was purified by chromatography on silica (eluent pentane: EtOAc ¼ 9:1 for the
first compound (8a–f), eluent pentane: EtOAc ¼ 1:1 to 1:3 for the second compound (9a–f)).
Biological assay
Epidermoid carcinoma cell line ((KB)-ATCC CCL-17TM) and hepatoma carcinoma cell
R
V
R
V
line ((HepG2)-ATCC HB-8065TM) were used to determine IC50 of the six new com-
pounds 8a–f. KB and HepG2 cancer cell lines were grown separately in RPMI 1640
medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 mg/
mL streptomycin at 37 ꢁC in a humidified atmosphere (95% air and 5% CO2). The

8
H.-T. PHAM ET AL.
exponentially growing cells were used throughout the experiments. The inhibitory
effects of the compounds on the growth of the human cancer cell lines were determined
by measuring the metabolic activity using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte-
trazolium bromide (MTT) assay. Briefly, human cancer cell lines (1 ꢂ 105 cells/mL)
were treated for 3 d with a series of concentrations of the compounds (in DMSO):
0.125, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, 64.0, and 128.0 mg/mL. After incubation,
0.1 mg MTT solution (50 mL of a 2 mg/mL solution) was added to each well, and the
cells were then incubated at 37 ꢁC for 4 h. The plates were centrifuged at 1000 rpm for
10 min at room temperature, and the media were then carefully aspirated.
Dimethylsulfoxide (150 mL) was added to each well to dissolve the formazan crystals.
The plates were read immediately at 540 nm on a microplate reader. All the experiments
were performed three times, and the mean absorbance values were calculated. The
results are expressed as the percentage of inhibition that produced a reduction in the
absorbance by the treatment of the compounds compared to the untreated controls. A
dose–response curve was generated, and the inhibitory concentration of 50% (IC50) was
determined for each compound as well as each cell line.
Funding
This research is funded by Graduate University of Science and Technology under Grant no.
-
GUST.STS.DT2017-HH10.
References
[1] Vanden Eynde, J. J.; Mayence, A. Synthesis and Aromatization of Hantzsch 1,4-
Dihydropyridines under Microwave Irradiation. An Overview. Mol. J. Synth. Chem. Nat.
Prod. Chem. 2003, 8(4), 381–391. DOI: 10.3390/80400381.
ꢀ
[2] Suarez, M.; Verdecia, Y.; Illescas, B.; Martıꢀnez-Alvarez, R.; Alvarez, A.; Ochoa, E.; Seoane,
C.; Kayali, N.; Martıꢀn, N. Synthesis and Study of Novel Fulleropyrrolidines Bearing
Biologically Active 1,4-Dihydropyridines. Tetrahedron. 2003, 59, 9179–9186. DOI: 10.
1016/j.tet.2003.09.047.
[3] Shehab, W. S.; Ghoneim, A. A. Synthesis and Biological Activities of Some Fused Pyran
Derivatives. Arabian J. Chem. 2016, 9, S966–S970. DOI: 10.1016/j.arabjc.2011.10.008.
[4] Nazari, P.; Bazi, A.; Ayatollahi, S. A.; Dolati, H.; Mahdavi, S. M.; Rafighdoost, L.;
Amirmostofian, M. Synthesis and Evaluation of the Antimicrobial Activity of Spiro-4H-
Pyran Derivatives on Some Gram Positive and Gram Negative Bacteria. Iran. J. Pharm.
Res. 2017, 16, 943–952.
[5] Bykhovskaya, O. V.; Aladzheva, I. M.; Makarov, M. V.; Rybalkina, E. Y.; Klemenkova,
Z. S.; Brel, V. K. Synthesis and Study of Antitumor Activity of 4H-Pyrano[3,2-c]Pyridines
Based on N-(2-Azidoethyl)- and N-Propargyl-3,5-Bis(Arylidene)Piperidin-4-Ones. Russ.
Chem. Bull. 2017, 66, 104–110. DOI: 10.1007/s11172-017-1707-x.
[6] El-Subbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Al-Obaid, A. M.
Synthesis and Biological Evaluation of Certain a,b-Unsaturated Ketones and Their
Corresponding Fused Pyridines as Antiviral and Cytotoxic Agents. J. Med. Chem. 2000,
43, 2915–2921. DOI: 10.1021/jm000038m.
€
[7] Gaillard, S.; Papamicael, C.; Marsais, F.; Dupas, G.; Levacher, V. Preparation of 1,4-
Dihydroquinolines Bearing a Chiral Sulfoxide Group: New Highly Enantioselective
Recyclable NADH Mimics. Synlett. 2005, 16, 441–444. DOI: 10.1055/s-2005-862350.

R
SYNTHETIC COMMUNICATIONSV
9
[8] Xie, K.; Liu, Y.-C.; Cui, Y.; Wang, J.-G.; Fu, Y.; Mak, T. N-Methyl-(R)-3-(tert-Butyl)-
Sulfinyl-1,4-Dihydropyridine: A Novel NADH Model Compound. Molecules. 2007, 12,
415–422. DOI: 10.3390/12030415.
[9] Lavilla, R. Recent Developments in the Chemistry of Dihydropyridines. J. Chem. Soc,
Perkin Trans. 2002, 1, 1141–1156. DOI: 10.1039/b101371h.
[10] Stout, D. M.; Meyers, A. I. Recent Advances in the Chemistry of Dihydropyridines. Chem.
Rev. 1982, 82, 223–243. DOI: 10.1021/cr00048a004.
[11] Saini, A. K. S.; Sandhu, J. S. Hantzsch Reaction: Recent Advances in Hantzsch 1,4-
Dihydropyridines. J. Sci. Ind. Res. 2008, 67, 95–111.
[12] Mao, Y.-Z.; Jin, M.-Z.; Liu, Z.-L.; Wu, L.-M. Oxidative Reactivity of S-Nitrosoglutathione
with Hantzsch 1,4-Dihydropyridine. Org. Lett. 2000, 2, 741–742. DOI: 10.1021/ol990367c.
[13] Suresh, S.; Sandhu, J. S. Past, Present and Future of the Biginelli Reaction: A Critical
Perspective. ARKIVOC. 2012, 2012, 66–133.
[14] Goswami, P. One Pot Synthesis of Unsymmetrical Dihydropyridines by Green, Catalyst
Free and Environmentally Benign Protocol. Green Chem. Lett. Rev. 2008, 1, 173–177.
DOI: 10.1080/17518250802403774.
[15] Geirsson, J. K. F.; Johannesdottir, J. F. Convenient Synthesis of N-Benzyl-1,4-
Dihydropyridines, Cyclohexenones, and Bicyclo[3.3.1]Nonan-3-One Derivatives from 1-
Aza-1,3-Butadienes. J. Org. Chem. 1996, 61, 7320–7325. DOI: 10.1021/jo960942f.
[16] Kumar, S.; Idhayadhulla, A.; Nasser, A.; Selvin, J. Synthesis and Antimicrobial Activity of
a New Series 1,4-Dihydropyridine Derivatives. J. Serb. Chem. Soc. 2011, 76, 1–11. DOI:
10.2298/JSC091127003K.
[17] Yan, X.; Ling, F.; Zhang, Y.; Ma, C. Three-Component Functionalized Dihydropyridine
Synthesis via a Formal Inverse Electron-Demand Hetero-Diels–Alder Reaction. Org. Lett.
2015, 17, 3536–3539. DOI: 10.1021/acs.orglett.5b01622.
[18] Kaithal, A.; Chatterjee, B.; Gunanathan, C. Ruthenium-Catalyzed Regioselective 1,4-
Hydroboration of Pyridines. Org. Lett. 2016, 18, 3402–3405. DOI: 10.1021/acs.orglett.
6b01564.
[19] Dong, W.; Yuan, Y.; Hu, B.; Gao, X.; Gao, H.; Xie, X.; Zhang, Z. Combining Visible-
Light-Photoredox and Lewis Acid Catalysis for the Synthesis of Indolizino[1,2-b]Quinolin-
9(11H)-Ones and Irinotecan Precursor. Org. Lett. 2018, 20, 80–83. DOI: 10.1021/acs.
orglett.7b03395.
[20] Pourian, E.; Javanshir, S.; Dolatkhah, Z.; Molaei, S.; Maleki, A. Ultrasonic-Assisted
Preparation, Characterization, and Use of Novel Biocompatible Core/Shell
Fe3O4@GA@Isinglass in the Synthesis of 1,4-Dihydropyridine and 4H-Pyran Derivatives.
ACS Omega. 2018, 3, 5012–5020. DOI: 10.1021/acsomega.8b00379.
[21] Hirama, M.; Kato, Y.; Seki, C.; Nakano, H.; Takeshita, M.; Oshikiri, N.; Iyoda, M.;
Matsuyama, H. An Efficient Synthesis of Chiral Isoquinuclidines by Diels–Alder Reaction
Using Lewis Acid Catalyst. Tetrahedron. 2010, 66, 7618–7624. DOI: 10.1016/j.tet.2010.07.026.
[22] Chung, J. Y. L.; Ho, G.-J. An Improved Preparation of 2-Azabicyclo[2.2.2]Octane. Synth.
Commun. 2002, 32, 1985–1995. DOI: 10.1081/SCC-120004848.
[23] Zhou, W.; Ni, C.; Chen, J.; Wang, D.; Tong, X. Enantioselective Synthesis of 4H-Pyran via
Amine-Catalyzed Formal (3 þ 3) Annulation of Delta-Acetoxy Allenoate. Org. Lett. 2017,
19, 1890–1893. DOI: 10.1021/acs.orglett.7b00658.
[24] Ni, C.; Tong, X. Amine-Catalyzed Asymmetric (3 þ 3) Annulations of b0-Acetoxy
Allenoates: Enantioselective Synthesis of 4H-Pyrans. J. Am. Chem. Soc. 2016, 138,
7872–7875. DOI: 10.1021/jacs.6b04935.
[25] Zhang, S.; Luo, Y.-C.; Hu, X.-Q.; Wang, Z.-Y.; Liang, Y.-M.; Xu, P.-F. Enantioselective
Amine-Catalyzed [4 þ 2] Annulations of Allene Ketones and 2,3-Dioxopyrrolidine
Derivatives: Synthesis of 4H-Pyran Derivatives. J. Org. Chem. 2015, 80, 7288–7294. DOI:
10.1021/acs.joc.5b00961.
[26] Randive, N. A.; Kumar, V.; Nair, V. A. A Facile Approach to Substituted Acrylates by
Regioselective and Stereoselective Addition of Thiols and Amines to an Alkynyl Ester in
Water. Monatsh. Chem. 2010, 141, 1329–1332. DOI: 10.1007/s00706-010-0399-9.