Synthesis, spectral characterization and photophysical studies of tetrahydroquinolines

Article abstract of DOI:10.1016/j.molstruc.2020.129365

A metal-free, ultrasound-assisted, fast synthesis of fluorescent N-Boc-protected 1,2,3,4–tetrahydroquinolines 9a-p is described through carbanion-induced ring transformation of 6-aryl-2H-pyran-2-ones 7 with tert?butyl 3-oxopiperidine-1-carboxylate 8 under

Full text of DOI:10.1016/j.molstruc.2020.129365

Journal of Molecular Structure 1226 (2021) 129365
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, spectral characterization and photophysical studies of
tetrahydroquinolines
C. Subashinia, L. John Kennedyb, Fateh V. Singha,∗
a Chemistry Division, School of Advanced Sciences, VIT-Chennai, Vandalur-Kelambakkam Road, Chennai-600127, Tamil Nadu, India
b Physics Division, School of Advanced Sciences, VIT-Chennai, Vandalur-Kelambakkam Road, Chennai-600127, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
metal-free, ultrasound-assisted, fast synthesis of fluorescent N-Boc-protected 1,2,3,4–
Received 28 July 2020
tetrahydroquinolines 9a-p is described through carbanion-induced ring transformation of 6-aryl-
2H-pyran-2-ones 7 with tert–butyl 3-oxopiperidine-1-carboxylate 8 under basic condition. The reaction
products 9a-p were isolated in high yields. Our synthetic approach is flexible for introducing electron-
withdrawing and electron-donating groups. All the synthesized 1,2,3,4–tetrahydroquinolines 9a-p showed
blue fluorescence in the range of 422–470 nm. Based on the optical behavior of compounds 9a–p,
we calculated stokes shift, quantum yield and optical band gap which are highly influenced by the
substituents in the ring.
Revised 28 September 2020
Accepted 28 September 2020
Available online 1 October 2020
Keywords:
Tetrahydroquinoline
2H-pyran-2-one
Ketone
© 2020 Elsevier B.V. All rights reserved.
Carbanion
Band gap
Fluorescence
1. Introduction
Tailor made fluorescent tetrahydroquinoline dyes acts as a
promising candidate as a metal free organic sensitizer for TiO2
based dye sensitized solar cell due to its suitable photo re-
sponse in the visible region [11]. Being good H-donor, tetrahy-
droquinoline compounds acts as a thermal stabilizer to improve
the thermal stability of fuels [12], fluorescent dyes [13], molecu-
lar glasses [14], hole transporting materials used for electropho-
tography [15] and OLED [16]. Since tetrahydroquinoline-based com-
pounds have broadened its mark in various fields of research, sev-
eral methods have been developed for their synthesis over the
years.
Nitrogen atom containing heterocyclic compounds repre-
sents
a core functioning unit in medicine, agrochemicals, bi-
ological and material chemistry [1–3]. Among them, 1,2,3,4-
tetrahydroquinolines constitutes an attractive and unique class
of heterocyclic compounds. They are isolated from variety of
natural sources [4,5]. 1,2,3,4-Tetrahydroquinolines-based com-
pounds are greatly targeted by several researchers due their
availability in most of the biologically active natural products
such as martinelline, martinellic acid, angustureine, cuspareine,
galipeine, galipinine, benzastatins (C and D) and 5-alkyl-1,2,3,4-
tetrahydroquinolines (Fig. 1) [6]. Whereas apart from the biolog-
ical activity, a great effort has been directed towards the total
synthesis of these privileged scaffolds [7]. Moreover, fluorescent
compounds play a major role in the detection of microorganisms
through imaging technique [8]. Additionally, natural and synthet-
ically derived 1,2,3,4–tetrahydroquinoline skeleton played promi-
nent role as chemotherapeutic agent such as anti-HIV agent, anti-
cancer activity, antimicrobial activity, antileishmanial activity, an-
tioxidant, antithrombotic, active antagonist against asthma, anti-
tubercular agent, anti-hyperlipidemic agent, anti-alzheimer agent,
anti-diabetic agent and anti-fertility agent [9,10].
Various metal-catalyzed intermolecular and intramolecular cy-
clization approaches have been successfully employed to con-
struct the functionalized 1,2,3,4-tetrahydroquinolines [17–20]. The
synthesis of 1,2,3,4-tetrahydroquinolines has been successfully
achieved by the partial hydrogenation of quinolines using differ-
ent transition metal catalysts such as ruthenium [21], iron [22],
cobalt [23], nickel [24], palladium [25] and gold catalyst [26] with
suitable hydrogen sources [26]. Besides this metal-catalyzed syn-
thesis, Povarov reactions triggered by various acid catalysts in-
volving [4 + 2] cycloaddition reaction have been used as alter-
nate route to access similar systems [27]. In 2017, Palacios and co-
workers illustrated an example of Povarov reaction for the synthe-
sis of phosphino- or phosphine sulfide-1,2,3,4-tetrahydroquinolines
involving multicomponent reaction of 2-phosphinoaniline or 2-
phosphine sulfide-aniline, styrenes and aldehydes [28]. Recently,
Reyes and co-authors employed helical dications (known as
∗
Corresponding author.
E-mail address: fatehveer.singh@vit.ac.in (F.V. Singh).
https://doi.org/10.1016/j.molstruc.2020.129365
0022-2860/© 2020 Elsevier B.V. All rights reserved.

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
medium thereby enhancing the reaction rates and product yields
of a chemical reaction. Sono-chemistry is associated with various
advantages such as shorter reaction time, non-toxic, low waste
generation, high efficiency and excellent selectivity in comparison
to existing traditional methods.
Since our on-going interest is in ultrasound and lactone
chemistry, herein we report an ultrasound-assisted synthesis
and photophysical behavior of 1,2,3,4-tetrahydroquinolines through
Fig. 1. Naturally occurring alkaloids 1 and 2 containing tetrahydroquinoline moiety.
ring transformation of 2H-pyran-2-ones
7 with tert–butyl 3-
oxopiperidine-1-carboxylate 8 under basic reaction condition.
helquats) as catalyst in the synthesis of diastereomeric 1,2,3,4-
tetrahydroquinolines by Povarov reaction of N-arylimine and 2,3-
dihydrofuran [29].
2. Experimental section
Stereoselective synthesis of 1,2,3,4-tetrahydroquinolines was
developed by Mori et al. via C–H bond functionalization of
benzylidene malonate using chiral phosphoric acid as catalyst
2.1. Materials and instrumental methods
1H NMR and 13C NMR spectra were studied on AV-400
Bruker using CDCl3 as the solvent and TMS as an internal stan-
dard, the operating frequency ranges 400 and 100 MHz, respec-
tively. Chemical composition was confirmed by Elementar Var-
ioMICRO Select 15,162,036 analyser. The molecular weights of
the compounds (m/z) were analysed using Shimadzu GC-mass
spectrometer-QP2020. Melting points were analysed on REMI
DDMS 2545 melting point apparatus in an open capillary tube. In-
frared spectra were recorded using Thermo Scientific Nicolet Nexus
470FT-IR spectrometer. The UV–Vis spectra of the compounds were
recorded on a Perkin Elmer Lambda 35. The emission spectra were
recorded on a Varian cary eclipse fluorescence. All the chemi-
cals and solvents were purchased from Avra Synthesis Pvt. Ltd.
Used without further purification. The reactions were monitored
by thin-layer chromatography (TLC) that was performed on Merck
KgaA pre-coated sheets of silica gel 60. Column chromatography
was carried out with neutral alumina (100–125 mesh) obtained
from Avra synthesis. Eluting solvents are indicated in the text.
[30]. Very recently, Chen and co-workers described
a three-
component cascade reaction to prepare similar systems in-
volving 2-alkenyl aniline, aldehydes and ethyl cyanoacetate in
the presence of 1,8-diazabicyclo[5.4.0]undec–7-ene (DBU) through
Knoevenagel condensation followed by aza-Michael–Michael ad-
dition [31]. Das and coworkers demonstrated the synthesis
of tetrahydroquinoline-embedded bridged benzothiaoxazepine-1,1-
dioxides by intramolecular Friedel-Crafts epoxide-arene (IFCEA) cy-
clization of N-aryl-2-fluorobenzenesulfonamides followed by NaH-
mediated cycloetherification reaction [32]. El-Badry et al. em-
ployed microwave-assisted base mediated preparation of tetrahy-
droquinoline derivatives in the presence of tetrabutylammonium
benzoate as a catalyst [33]. Gomez et al. found an eco-friendly
method for the synthesis of tetrahydroquinoline via aza Diels-
Alder reaction of substituted aldehydes, aromatic amines and
anise oil in chloride/zinc chloride (deep eutectic solvents) via Po-
varov reaction [34]. On the other hand, 3,3,4,4-tetrafluoro-1,2,3,4-
tetrahydroquinolines were prepared from N-(3-methyl–bromo–
2,2,3,3-tetrafluoropropyl)anilines by irradiating blue light emitting
diodes in the presence of [Ir(ppy)3] [35]. In 2017, the synthesis of
THQ from N,N-dimethylanilines and maleimides was also achieved
by using chlorophyll as a photosensitizer in a visible light medi-
ated redox reaction [36]. Pratap and coworkers reported the syn-
thesis of functionalized quinolines using 2H-pyran-2-ones as the
key precursor [37].
2.2. Synthesis
2.2.1. General procedure for the synthesis of ethyl
2-cyano-3,3-dimethylsulfanylacrylate 3 [42]
To an ice-cold solution of sodium methoxide, freshly prepared
in situ by dissolving sodium metal (3.44 g, 150.0 mmol) in ab-
solute MeOH (40 mL) at 0 °C, was added ethyl cyano acetate
(11.3 mL, 100.0 mmol) dropwise over a period of 15 min. The
white-coloured precipitate obtained was further stirred vigorously
for another 15 min followed by the drop-wise addition of carbon
disulfide (6.4 mL, 100.0 mmol) at 20 °C to give a yellow-colored
liquid. Next, dimethyl sulfate (23.6 mL, 248 mmol) was added
slowly over a period of 30 min. The yellow semi-solid material ob-
tained was stirred for another 15 min and excess MeOH was re-
moved under reduced pressure. Finally, the resulting reaction mix-
ture was poured into the beaker containing crushed ice with con-
stant stirring and the precipitate obtained was filtered, washed
with cold water, dried and recrystallized from EtOAc/hexane (1:4)
to give yellow crystalline compound 3 in 90% yield.
In spite of all the metal associated reactions shows consider-
able break through but having few disadvantages such as require
harsh reaction condition, associated with poor yield, involved mul-
tistep process, expensive reagents, require inert atmosphere and
difficulties in workup process. Thus, it is necessary to find an alter-
nate pathway towards the synthesis of 1,2,3,4-tetrahydroquinolines
functionalized with electron donor and acceptor functionalities.
2H-pyran-2-ones have emerged as versatile scaffolds owing
to their unique reactivity towards several nucleophiles generat-
ing diverse array of valuable molecules [38]. This methodology
marked considerable attention as it provides an alternate path-
way for the synthesis of functionalised benzenes [39–44] and het-
erocyclic compounds [45–47] which are associated with versa-
tile applications in medicinal and material chemistry. Recently, we
have already developed the synthesis of functionalized 2-tetralones
[48], diarylmethanes [49], tetrahydroisoquinolines [50], allylben-
zenes [51], meta- and para-terphenyls [52,53] under mild reaction
conditions.
2.2.2. General procedure for the synthesis of
6-Aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles 5 [57]
To the round bottom flask containing ethyl 2-cyano-3,3-
dimethylsulfanylacrylate 3 (2.17 g, 10.0 mmol, 1.0 equiv) in dry
DMSO, was added aryl ketones 4 (12 mmol, 1.2 equiv) and pow-
dered KOH (0.84 g, 15 mmol, 1.5 equiv) and the resulting mixture
was stirred at room temperature for 14–18 h. On completion of the
reaction, the reaction mixture was poured into the ice-cold water
with constant stirring. The residue obtained was then filtered and
purified by silica gel column chromatography using chloroform as
an eluent.
In recent years, use of ultrasound radiation in organic synthesis
is a powerful green technique, widely used in number of synthetic
transformation as an alternate source of energy [54]. In sono-
chemistry, the high intensity of ultrasound waves causes cavitation
effect which implies formation, expansion and collapse of bubbles
in a liquid medium subjected under ultra-sonication [55,56]. This
effect increases the pressure and temperature of the surrounding
2

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
2.2.3. General procedure for the synthesis of
3.29–3.59 (m, 1H, CH2), 3.84 (s, 4H, NCH2), 6.79 (s, 1H, ArH),
7.14–7.23 (m, 2H, ArH), 7.24–7.44 (m, 3H, ArH) ppm; 13C {1H}
NMR (101 MHz, CDCl3): δ = 23.9, 27.5, 28.5, 42.9, 52.2, 67.0,
80.7, 104.6, 116.8, 118.3, 127.8, 128.1, 128.5, 128.6, 128.8, 153.4,
154.2, 154.5 ppm; IR (KBr): 2208 cm−1 (CN), 1684 cm−1 (C=O),
1509 cm−1 (C=C), 1214 cm−1 (C–N), 1059 cm−1 (C–O),; MS (EI):
m/z = 421 [M + 1]+; Anal. for C25H29N3O3: C, 71.57; H, 6.97; N,
10.02; Found C, 71.23; H, 6.78; N, 9.91%
6-aryl-4-amino-2-oxo-2H-pyran-3-carbonitriles 7 [57]
A
mixture
of
6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-
carbonitrile
5
(1.0 mmol, 1.0 equiv) and secondary amine
4
(1.2 mmol, 1.2 equiv) was refluxed in MeOH for 6–8 h. Thin layer
chromatography was used to check the progress of the reaction.
Upon completion, the reaction mixture was cooled to room tem-
perature, filtered and the solid residue was rinsed with MeOH
(2 × 5 mL) to provide products 7.
2.2.4.4. Tert–butyl
8-(4-chlorophenyl)−5-cyano-6-(piperidin-1-
2.2.4. General procedure for the synthesis of
yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9d. Colourless solid;
yield: 89%; mp: 180–182 °C; 1H NMR (400 MHz, CDCl3): δ = 0.92
(m, 9H, 3 CH3), 1.47–1.55 (m, 2H, CH2), 1.61–1.90 (m, 5H, 2
CH2 + CH), 1.91–2.33 (m, 1H, CH2), 2.45–2.78 (m, 1H, CH2),
2.92–3.22 (m, 6H, 3 NCH2), 3.97–4.48 (m, 1H, CH2), 6.72 (s, 1H,
ArH), 7.21–7.38 (m, 4H, ArH) ppm; 13C {1H} NMR (101 MHz,
CDCl3): δ = 23.8, 24.1, 26.2, 27.6, 27.8, 43.1, 53.5, 80.7, 104.9, 116.9,
118.1, 128.4, 128.9, 129.2, 130.9, 133.9, 140.4, 153.4, 155.0 ppm;
IR (KBr): 2203 cm−1 (CN), 1692 cm−1 (C=O), 1522 cm−1 (C=C),
1214 cm−1 (C–N), 1061 cm−1 (C–O); MS (EI): m/z = 453 [M + 1]+,
455 [M + 3]+; Anal. for C26H30ClN3O2: C, 69.09; H, 6.69; Cl, 7.84;
N, 9.30. Found C, 69.19; H, 6.31; N, 9.06%.
N–tert–butyloxycarbonyl-protected tetrahydroquinolines 9a-p and 11
To the solution of 6-aryl-4-amino-2H-pyran-2-ones
7 or
2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromene-3-
carbonitrile 10 (1.0 mmol, 1.0 equiv) in DMF (3 mL) was added
N-Boc-3-piperidone (1.2 mmol, 1.2 equiv) and powdered KOH
(1.2 mmol). The reaction mixture was irradiated in an ultrasonic
bath maintaining the minimum frequency of 40 KHz at room
temperature for 40–70 min. The temperature of the ultrasonic
water bath was maintained at room temperature by replacing
the water at mild hot condition. Thin layer chromatography was
used to check the progress of the reaction. The reaction mixture
was poured into ice cold water and neutralised by adding dilute
HCl. The resultant organic layer was extracted with EtOAc. After
that, the organic layer collectively dried over anhydrous sodium
sulfate and concentrated under vacuum and the crude prod-
ucts were purified by column chromatography using the solvent
EtOAc:hexane (1:49) passed through neutral alumina. Finally,
the isolated products were characterized as 8-aryl-6-substituted-
1,2,3,4-tetrahydroquinoline-5-carbonitriles 9a-q and 11 by their
spectroscopic analysis.
2.2.4.5. Tert–butyl
8-(4-chlorophenyl)−5-cyano-6-morpholino-3,4-
dihydroquinoline-1(2H)-carboxylate 9e. Colourless solid; yield: 82%;
mp: 162–164 °C; 1H NMR (400 MHz, CDCl3): δ = 0.84–1.15 (m, 9H,
CH3), 1.16–1.24 (m, 1H, CH2), 1.51–1.92 (m, 2H, CH2), 2.02–2.39 (m,
1H, CH2), 2.55–2.86 (m, 1H, CH2), 2.92–3.30 (m, 4H, NCH2), 3.83
(t, J = 4.0 Hz, 4H, OCH2), 3.97–4.53(m, 1H, CH2), 6.74 (s, 1H, ArH),
7.22–7.43 (m, 4H, ArH) ppm; 13C {1H} NMR (101 MHz, CDCl3):
δ = 23.8, 26.1, 27.6, 29.3, 29.6, 43.2, 44.5, 52.1, 66.9, 80.9, 105.1,
116.6, 117.9, 118.2, 129.2, 131.9, 133.3, 137.3, 140.7, 153.4 ppm;
IR (KBr): 2214 cm−1 (CN), 1692 cm−1 (C=O), 1588 cm−1 (C=C),
1212 cm−1 (C–N), 1061 cm−1 (C–O); MS (EI): m/z = 455 [M + 1]+,
457 [M + 3]+; Anal. for C25H28ClN3O3: C, 66.14; H, 6.22; N, 9.26;
Found C, 65.87; H, 6.01; N, 9.53%.
2.2.4.1. Tert–butyl 5-cyano-8-phenyl-6-(4-phenylpiperazin-1-yl)−3,4-
dihydroquinoline-1(2H)- carboxylate 9a. Colourless solid; yield:
85%; mp: 150–152 °C; 1H NMR (400 MHz, CDCl3): δ = 0.53–1.16
(m, 9H, 3CH3), 1.32–1.66 (m, 1H, CH2), 1.68–1.93 (m, 1H, CH2),
1.99–2.39 (m, 1H, CH2), 2.45–2.77 (m, 1H, CH2), 2.86–3.13 (m, 1H,
CH2), 3.17–3.47 (m, 8H, 4NCH2), 3.98–4.56 (m, 1H, CH2), 6.76–6.82
(m, 1H, ArH), 6.84 (s, 1H, ArH), 6.91 (d, J = 8.0 Hz, 2H, ArH),
7.22 (t, J = 8.0 Hz, 3H, ArH), 7.25–7.47 (m, 4H, ArH) ppm; 13C
{1H} NMR (101 MHz, CDCl3): δ = 24.0, 26.1, 27.5, 43.0, 50.0, 51.9,
80.7, 104.7, 116.4, 116.8, 118.4, 120.1, 127.9, 128.1, 128.8, 129.2, 131.9,
139.3, 140.7, 142.8, 151.2, 153.4 ppm; IR (KBr): 2206 cm−1 (CN),
1693 cm−1 (C=O), 1547 cm−1 (C=C), 1214 cm−1 (C–N), 1061 cm−1
(C–O); MS (EI): m/z = 495 [M + 1]+; Anal. for C31H34N4O2: C,
75.28; H, 6.93; N, 11.33; Found C, 75.09; H, 6.82; N, 11.16%.
2.2.4.6. Tert–butyl 8-(4-chlorophenyl)−5-cyano-6-(4-phenylpiperazin-
1-yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9f. Colourless solid;
yield: 89%; mp: 180–182 °C; 1H NMR (400 MHz, CDCl3): δ = 0.93
(s, 9H, CH3), 1.60–1.95 (m, 2H, CH2), 1.99–2.40 (m, 1H, CH2),
2.45–2.79 (m, 1H, CH2), 2.92–3.14 (m, 1H, CH2), 3.17–3.44 (m,
8H, NCH2), 4.05–4.65 (m, 1H, CH2), 6.78 (s, 1H, ArH), 6.83(t, 1H,
J = 8.0 Hz, ArH), 6.91 (d, 2H, J = 8.0 Hz, ArH), 7.19–7.38 (m, 6H,
ArH) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 23.8, 26.1, 27.6,
43.2, 49.6, 51.8, 51.9, 80.8, 104.1, 108.2, 116.5, 116.6, 118.1, 120.2,
122.9, 129.2, 130.9, 131.7, 133.9, 140.5, 140.3, 151.2, 153.4 ppm;
IR (KBr): 2238 cm−1 (CN), 1733 cm−1 (C=O), 1542 cm−1 (C=C),
1216 cm−1 (C–N), 1049 cm−1 (C–O); MS (EI): m/z = 530 [M + 1]+,
532 [M + 3]+; Anal. for C31H33ClN4O2: C, 70.37; H, 6.29; Cl, 6.70;
N, 10.59. Found C, 70.02; H, 6.15; N, 10.26%.
2.2.4.2. Tert–butyl
5-cyano-8-phenyl-6-(piperidin-1-yl)−3,4-
dihydroquinoline-1(2H)-carboxylate 9b. Colourless solid; yield:
83%; mp: 152–154 °C; 1H NMR (400 MHz, CDCl3): δ = 0.87 (s,
9H, 3CH3), 1.45–1.57 (m, 2H, CH2), 1.62–1.80 (m, 5H, 2CH2 + CH),
2.00–2.35 (m, 1H, CH2), 2.49–2.80 (m, 1H, CH2), 2.88–3.24 (m,
6H, 3 NCH2), 3.90–4.43 (m, 1H, CH2), 6.78 (s, 1H, ArH), 7.21–7.40
(m, 5H, ArH) ppm; 13C {1H} NMR (101 MHz, CDCl3): δ = 23.9,
24.1, 26.0, 26.2, 27.5, 42.9, 53.5, 80.5, 104.4, 117.0, 118.5, 127.9,
128.7, 131.0, 139.5, 140.4, 142.6, 153.5, 154.9 ppm; IR (KBr):
2206 cm−1 (CN), 1688 cm−1 (C=O), 1569 cm−1 (C=C), 1059 cm−1
(C–O), 1222 cm−1 (C–N); MS (EI): m/z = 418 [M + 1]+; Anal. for
C26H31N3O2: C, 74.79; H, 7.48; N, 10.06. Found C, 74.38; H, 7.32;
N, 10.27%
2.2.4.7. Tert–butyl
8-(4-bromophenyl)−5-cyano-6-(piperidin-1-
g. Colourless solid;
yl)−3,4-dihydroquinoline-1(2H)-carboxylate
9
81%; mp: 143–145 °C; 1H NMR (400 MHz, CDCl3): δ = 0.83–1.18
(m, 9H, CH3), 1.45–1.60 (m, 2H, CH2), 1.62–1.89 (m, 5H, CH2),
2.02–2.34 (m, 1H, CH2), 2.46–2.84 (m, 1H, CH2), 2.85–3.24 (m,
6H, NCH2), 3.95–4.49 (m, 1H, CH2), 6.72 (s, 1H, ArH), 7.08–7.33
(m, 2H, ArH), 7.47 (s, 2H, ArH) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ = 23.8, 24.1, 26.0, 26.2, 27.6, 43.1, 53.5, 80.8, 104.9, 107.2,
115.7, 116.9, 118.0, 122.05, 129.4, 129.5, 131.8, 140.3, 155.0 ppm;
IR (KBr): 2214 cm−1 (CN), 1692 cm−1 (C=O); 1590 cm−1 (C=C),
1221 cm−1 (C–N), 1056 cm−1 (C–O); MS (EI): m/z = 497 [M + 1]+,
499 [M + 3]+; Anal.for C26H30BrN3O2: C, 62.90; H, 6.09; Br, 16.10;
N, 8.46. Found C, 62.72; H, 5.92; N, 8.15%.
2.2.4.3. Tert–butyl
5-cyano-6-morpholino-8-phenyl-3,4-
dihydroquinoline-1(2H)-carboxylate 9c. Colourless solid; yield:
78%; mp: 156–158 °C; 1H NMR (400 MHz, CDCl3): δ = 0.87 (s, 9H,
CH3), 1.70–1.92 (m, 1H, CH2), 1.96–2.42 (m, 1H, CH2), 2.46–2.721
(m, 2H, CH2), 2.74–2.94 (m, 1H, CH2), 2.96–3.27 (m, 4H, 2 OCH2),
3

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
2.2.4.8. Tert–butyl 8-(4-bromophenyl)-5-cyano-6-(4-phenylpiperazin-
1-yl)-3,4-dihydroquinoline-1(2H)-carboxylate 9h. Colourless solid;
yield: 84%; mp: 160–162 °C; 1H NMR (400 MHz, CDCl3): δ = 0.93–
1.11 (m, 9H, CH3), 1.43 (s, 2H, CH2), 1.69–1.95 (m, 1H, CH2),
1.99–2.29 (m, 1H, CH2), 2.43–2.75 (m, 1H, CH2), 3.11–3.46 (m,
8H, NCH2), 3.79–4.49 (m, 1H, CH2), 6.78 (s, 1H, ArH), 6.82 (t,
J = 8.0 Hz, 1H, ArH), 6.91 (d, J = 8.0 Hz, 2H, ArH), 7.22 (t,
J = 8.0 Hz, 4H, ArH), 7.41–7.59 (m, 2H, ArH) ppm;13C {1H} NMR
(101 MHz, CDCl3): δ = 23.8, 26.1, 27.6, 28.4, 43.05, 49.6, 51.9, 80.9,
116.5, 116.7, 118.2, 120.2, 123.5, 125.3, 129.2, 129.5, 130.3, 131.7,
131.9, 140.7, 151.1, 153.5 ppm IR (KBr): 2219 cm−1 (CN), 1694 cm−1
(C=O); 1507 cm−1 (C=C), 1222 cm−1 (C–N), 1049 cm−1 (C–O); MS
(EI): m/z = 575 [M + 1]+, 577 [M + 3]+; Anal. for C31H33BrN4O2:
C, 64.92; H, 5.80; N, 9.77. Found C, 64.66; H, 5.71; N, 9.51%.
128.2, 131.2, 132.7, 133.5, 137.2, 140.4, 142.6, 155.0 ppm; IR (KBr):
2213 cm−1 (CN), 1692 cm−1 (C=O), 1591 cm−1 (C=C), 1243 cm−1
(C–N), 1049 cm−1 (C–O); MS (EI): m/z = 468 [M + 1]+; Anal. for
C30H33N3O2: C, 77.06; H, 7.11; N, 8.99; Found C, 77.43; H, 6.99; N,
8.76%.
2.2.4.13. Tert–butyl
5-cyano-8-(naphthalen-1-yl)−6-(piperidin-1-
yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9m. Colourless solid;
yield: 76%; mp: 175–177 °C; 1H NMR (400 MHz, CDCl3): δ = 0.41–
1.11 (m, 9H, CH3), 1.40–1.59 (m, 2H, CH2), 1.61–1.94 (m, 5H,
CH2), 2.02–2.38 (m, 1H, CH2), 2.43–2.79 (m, 1H, CH2), 2.88–
3.29 (m, 6H, NCH2), 3.61–4.35 (m, 1H, CH2), 6.69–7.01 (m, 1H,
ArH), 7.21–7.67 (m, 5H, ArH), 7.68–7.97 (m, 2H, ArH) ppm; 13C
{1H} NMR (101 MHz, CDCl3): δ = 24.1, 26.2, 27.6, 43.7, 53.4,
79.2, 104.4, 107.4, 109.9, 114.7, 117.3, 119.3, 121.7, 125.0, 125.7,
126.4,127.3, 127.9, 128.5, 132.4, 139.9, 142.7, 155.3 ppm; IR (KBr):
2214 cm−1 (CN), 1690 cm−1 (C=O), 1589 cm−1 (C=C), 1233 cm−1
(C–N), 1048 cm−1 (C–O); MS (EI): m/z = 468 [M + 1]+; Anal. for
C30H33N3O2: C, 77.06; H, 7.11; N, 8.99; Found C, 77.27; H, 7.03; N,
8.75%.
2.2.4.9. Tert–butyl
5-cyano-8-(3,4-dichlorophenyl)-6-(4-
9i.
phenylpiperazin-1-yl)-3,4-dihydroquinoline-1(2H)-carboxylate
Colourless solid; yield: 81%; mp: 158–160 °C; 1H NMR (400 MHz,
CDCl3): δ = 1.11 (s, 9H, CH3), 1.61 (s, 1H, CH2), 1.69–2.18 (m, 2H,
CH2), 2.69–3.12 (m, 2H, CH2), 3.14–3.46 (m, 8H, NCH2), 3.73–4.45
(m, 1H, CH2), 6.64 (s, 1H, ArH), 6.82 (t, J = 8.0 Hz, 1H, ArH), 6.90
(d, J = 8.0 Hz, 2H, ArH), 7.11–7.47 (m, 5H, ArH) ppm;13C {1H}
NMR (101 MHz, CDCl3): δ = 23.7, 26.2, 27.8, 44.6, 49.6, 51.9, 80.7,
106.0, 107.9, 116.4, 116.5, 118.3, 120.2, 127.1, 128.2 129.2, 133.8,
136.9, 140.5, 143.7, 151.2, 153.5 ppm; IR (KBr): 2215 cm−1 (CN),
1691 cm−1 (C=O); 1586 cm−1 (C=C), 1232 cm−1 (C–N), 1049 cm−1
(C–O); MS (EI): m/z = 565 [M + 1]+; Anal. for C31H32Cl2N4O2: C,
66.07; H, 5.72; N, 9.94; Found C, 66.29; H, 5.35; N, 10.13%.
2.2.4.14. Tert–butyl
5-cyano-8-(naphthalen-2-yl)−6-(4-
9n.
phenylpiperazin-1-yl)−3,4-dihydroquinoline-1(2H)-carboxylate
Colourless solid; yield: 73%; mp: 134–136 °C; 1H NMR (400 MHz,
CDCl3): δ = 0.61–0.98 (m, 9H, CH3), 1.50 (s, 2H, CH2), 1.74–2.06
(m, 1H, CH2), 2.14–2.86 (m, 2H, CH2), 3.17–3.50 (m, 8H, NCH2),
3.97–4.62 (m, 1H, CH2), 6.82 (t, J = 8.0 Hz, 1H, ArH), 6.87–7.03
(m, 3H, ArH), 7.22 (t, J = 8.0 Hz, 2H, ArH), 7.36–7.52 (m, 3H,
ArH), 7.70–7.89 (m, 4H, ArH) ppm; 13C {1H} NMR (101 MHz,
CDCl3): δ = 23.9, 26.2, 27.4, 28.5, 49.6, 51.9, 80.7,104.7, 116.5,
116.8, 118.7, 120.1, 125.8, 126.5, 126.6, 127.7, 127.8, 128.1, 128.4,
129.2, 132.1, 132.8, 133.5, 142.8, 145.8, 151.2, 153.5 ppm; IR (KBr):
2206 cm−1 (CN), 1692 cm−1 (C=O), 1591 cm−1 (C=C), 1232 cm−1
(C–N), 1050 cm−1 (C–O); MS (EI): m/z = 545 [M + 1]+; Anal. for
C35H36N4O2 : C, 77.18; H, 6.66; N, 10.29;. Found C, 77.09; H, 6.29;
N, 10.04%
2.2.4.10. Tert–butyl
5-cyano-6-(piperidin-1-yl)−8-(p-tolyl)−3,4-
dihydroquinoline-1(2H)-carboxylate 9j. Colourless solid; yield:
69%; mp: 154–156 °C; 1H NMR (400 MHz, CDCl3): δ = 0.74–1.08
(m, 9H, CH3), 1.46–1.58 (m, 2H, CH2), 1.63–1.75 (m, 4H, NCH2),
1.76–1.86 (m, 2H, CH2), 2.06–2.17 (m, 1H, CH2), 2.29 (s, 3H, CH3),
2.52–2.66 (m, 1H, CH2), 2.94–3.17 (m, 4H, NCH2), 3.52–3.77 (m,
1H, CH2), 4.01–4.40 (m, 1H, CH2), 6.77 (s, 1H, ArH), 7.09–7.18 (m,
2H, ArH), 7.21–7.31 (m, 2H, ArH) ppm; 13C {1H} NMR (101 MHz,
CDCl3): δ = 21.1, 24.0, 24.1, 26.2, 27.5, 42.9, 53.5, 68.0, 80.5,
104.2, 117.1, 118.3, 127.7, 129.3, 131.0, 136.6, 137.8, 140.4, 142.6,
153.6, 154.9 ppm; IR (KBr): 2214 cm−1 (CN), 1691 cm−1 (C=O);
1586 cm−1 (C=C), 1232 cm−1 (C–N), 1049 cm−1 (C–O); MS (EI):
m/z = 433 [M + 1]+; Anal. for C27H33N3O2: C, 75.14; H, 7.71; N,
9.74; Found C, 74.85; H, 8.11; N, 9.53%.
ꢀ
2.2.4.15. Tert–butyl-8-([1,1 -biphenyl]−4-yl)−5-cyano-6-(piperidin-
1-yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9o. Colourless solid;
yield: 75%; mp: 212–214 °C; 1H NMR (400 MHz, CDCl3): δ = 0.79–
1.19 (m, 9H, CH3), 1.46–1.61 (m, 2H, CH2), 1.62–1.89 (m, 5H, CH2),
2.02–2.39(m, 1H, CH2), 2.49–2.78 (m, 1H, CH2), 2.90–3.24 (m,
6H, NCH2),4.26– 4.59(m, 1H, CH2), 6.83 (s, 1H, ArH), 7.26–7.33
(m, 1H, ArH), 7.33–7.47 (m, 4H, ArH), 7.48–7.65 (m, 4H, ArH)
ppm; 13C {1H} NMR (101 MHz, CDCl3): δ = 23.9, 24.1, 26.1, 26.2,
27.5, 43.1, 53.5, 80.7, 104.0, 117.0, 118.3, 127.0, 127.4, 127.5, 128.3,
128.9, 131.0, 131.1, 131.05, 140.9, 142.2, 153.6, 154.9 ppm; IR (KBr):
2209 cm−1 (CN), 1715 cm−1 (C=O), 1589 cm−1 (C=C), 1233 cm−1
(C–N), 1049 cm−1 (C–O); MS (EI): m/z = 494 [M + 1]+; Anal. for
C32H35N3O2: C, 77.86; H, 7.15; N, 8.51. Found C, 77.53; H, 7.01; N,
8.19%
2.2.4.11. Tert–butyl
5-cyano-7-methyl-8-phenyl-6-(piperidin-1-
yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9k. Colourless solid;
yield: 72%; mp: 177–179 °C; 1H NMR (400 MHz, CDCl3): δ = 1.10
(s, 9H, 3CH3), 1.45–1.84 (m, 2H, CH2), 1.91–2.19 (m, 6H, CH2), 2.96
(m, 3H, CH3), 3.14 (s, 2H, CH2), 3.56–3.92 (m, 6H, 3NCH2), 6.78 (s,
1H, ArH), 7.22–7.36 (m, 3H, ArH) ppm; 13C {1H} NMR (101 MHz,
CDCl3): δ = 16.6, 23.7, 25.5, 27.8, 31.6, 44.6, 50.6, 67.8, 80.6, 109.7,
117.0, 127.8, 129.2, 133.0, 133.4, 134.2, 135.5, 136.0, 136.5, 143.7,
150.6, 152.7 ppm; IR (KBr): 2214 cm−1 (CN), 1692 cm−1 (C=O);
1591 cm−1 (C=C), 1232 cm−1 (C–N), 1049 cm−1 (C–O); MS (EI):
m/z = 467 [M + 1]+; Anal. for C27H32ClN3O2: C, 69.59; H, 7.05; N,
9.02. Found C, 69.19; H, 6.88; N, 8.91%.
ꢀ
2.2.4.16. Tert–butyl 8-([1,1 -biphenyl]−4-yl)−5-cyano-6-morpholino-
3,4-dihydroquinoline-1(2H)-carboxylate 9p. Colourless solid; yield:
75%; mp: 192–194 °C; 1H NMR (400 MHz, CDCl3): δ = 0.74–1.15
(m, 9H, CH3), 1.15–1.52 (m, 1H, CH2), 1.63–1.95 (m, 1H, CH2),
2.06–2.36 (m, 1H, CH2), 2.38–2.90 (m, 1H, CH2), 2.91–3.35 (m, 5H,
NCH2), 3.83 (s, 4H, OCH2), 3.94–4.67 (m, 1H, CH2), 6.84 (s, 1H,
ArH), 7.25–7.33 (m, 1H, ArH), 7.34–7.47 (m, 4H, ArH), 7.48–7.67 (m,
4H, ArH) ppm; 13C {1H} NMR (101 MHz, CDCl3): δ = 23.9, 26.1,
27.5, 43.1, 52.2, 67.1, 80.2, 104.8, 116.8, 118.1, 127.0, 127.5, 128.2,
128.9, 132.0, 138.3, 140.5, 140.7, 141.0, 142.4, 153.4 ppm; IR (KBr):
2214 cm−1 (CN), 1692 cm−1 (C=O), 1602 cm−1 (C=C), 1262 cm−1
(C–N), 1061 cm−1 (C–O); MS (EI): m/z = 496 [M + 1]+; Anal. for
C31H33N3O3: C, 75.13; H, 6.71; N, 8.48; Found C, 74.97; H, 6.31; N,
8.21%.
2.2.4.12. Tert–butyl
5-cyano-8-(naphthalen-2-yl)−6-(piperidin-1-
yl)−3,4-dihydroquinoline-1(2H)-carboxylate 9l. Colourless solid;
yield: 68%; mp: 172–174 °C; 1H NMR (400 MHz, CDCl3): δ = 0.39–
1.00 (m, 9H, CH3), 1.47–1.59 (m, 2H, CH2), 1.64–1.93 (m, 5H,
CH2), 1.98–2.41 (m, 1H, CH2), 2.46–2.88 (m, 1H, CH2), 2.89–3.38
(m, 6H, NCH2), 3.91–4.66 (m, 1H, CH2), 6.90 (s, 1H, ArH), 7.42
(d, J = 8.0 Hz, 3H, ArH), 7.67–7.88 (m, 4H, ArH) ppm; 13C {1H}
NMR (101 MHz, CDCl3): δ = 23.9, 24.1, 26.1, 26.2, 27.4, 43.1, 53.5,
80.5, 104.6, 117.1, 118.7, 125.8, 126.4, 127.0, 127.6, 128.0, 128.1,
4

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Scheme 1. Synthesis of 6-aryl-4-amino-2H-pyran-2-ones 7 starting from ketene dithioacetal 3.
2.2.4.17. Tert–butyl-5-cyano-6-(piperidin-1-yl)-3,4,7,8-
tetrahydronaphtho[2,1-h]quinoline-1(2H)-carboxylate 11. Colourless
solid; yield: 76%; mp: 156–158 °C; 1H NMR (400 MHz, CDCl3):
δ = 0.83 (s, 9H, CH3), 1.17 (s, 1H, CH2), 1.54–1.70 (m, 4H, CH2),
1.71–1.87 (m, 2H, CH2), 2.08–2.31 (m, 2H, CH2), 2.44–2.64 (m, 2H,
CH2), 2.65–2.76 (m, 1H, CH2), 2.80–3.32 (m, 6H, CH2), 3.59 (s, 1H,
CH2), 4.16–4.49 (m, 1H, CH2), 7.05–7.16 (m, 2H, ArH), 7.20–7.25 (m,
1H, ArH), 7.47–7.58 (m, 1H, ArH) ppm; 13C {1H} NMR (101 MHz,
CDCl3): δ = 24.0, 24.2, 24.7, 25.8, 27.5, 29.5, 42.8, 52.1, 80.5, 106.5,
117.8, 125.1, 126.9, 127.6, 128.1, 132.3, 134.2, 135.7, 136.7, 137.9,
138.5, 150.9, 153.3 ppm; MS (EI): m/z = 444 [M + 1]+; IR (KBr):
2214 cm−1 (CN), 1691 cm−1 (C=O), 1565 cm−1 (C=C), 1218 cm−1
(C–N), 1061 cm−1 (C–O); Anal. for C28H33N3O2: C, 75.81; H, 7.50;
N, 9.47; Found C, 75.43; H, 7.15; N, 9.31%.
3. Results and discussions
3.1. Synthesis of compounds 9a-p and 11
With the comprehensive literature framework, we describe an
alternate approach for synthesizing functionalized N-Boc protected
tetrahyroquinoline derivatives 9 using 6-aryl-4-amino-2H-pyran-2-
ones 7 as starting material. The synthesis of parent precursors
7 was achieved in two chemical steps (Scheme 1) [57]. In first
step, ethyl 2-cyano-3,3-dimethylsulfanylacrylate 3 [42] was treated
with functionalized aryl ketones 4 in the presence of KOH in
DMSO to form 2-pyranones 5 in 57–73% yields [58]. In the sec-
ond step, the synthesized 2-pyranones 5 were reacted with cyclic
amines 6 in methanol at reflux temperature to form 6-aryl-4-
amino-2H-pyran-2-ones 7 in 71–85% [57, 58]. The synthon 3 was
ultimately prepared by reacting ethyl cyanoacetate with carbon
disulfide (CS2) followed by methylation in methanol under alkaline
condition in 84% yield [42]. Furthermore, the functionalized N-Boc
protected tetrahyroquinoline derivatives 9 was successfully synthe-
sized through ring transformation of 6-aryl-4-amino-2H-pyran-2-
ones 7 with commercially available tert–Butyl 3-oxopiperidine-1-
carboxylate 8 in an ultrasonic bath in the presence of KOH (1.2
equiv) and minimum amount of DMF. Overall, the ultrasound-
assisted method is a hands-on method and also an economical
pathway for the preparation of the desired product with high
yields and less time-consuming.
Fig. 2. UV–Vis spectra of compounds in chloroform (a) 9a-i; (b) 9j-p and 11.
In order to find the optimized reaction condition, various sol-
vents and bases were screened by taking 2-oxo-6-phenyl-4-(4-
phenylpiperazin-1-yl)-2H-pyran-3-carbonitrile 7a (1.0 equiv) and
tert–butyl 3-oxopiperidine-1-carboxylate (1.2 equiv) 8 as model
substrates and the results are shown in Table 1. At first, we
performed the reaction of 2-oxo-6-phenyl-4-(4-phenylpiperazin-1-
yl)-2H-pyran-3-carbonitrile 7a with tert–butyl 3-oxopiperidine-1-
carboxylate 8 in the presence of KOH as a base in DMF and the
desired product 9a was isolated in 74% yield (Table 1, entry 1).
With these preliminary results, we started monitoring the forma-
tion of required product 9a in the presence of NaOH which gave
64% yield (Table 1, entry 2). Reaction performed using K2CO3 as
base resulted in poor product 9a yield (Table 1, entry 3). The prod-
uct formation is observed in the presence of KOtBu and desired
product was isolated in 59% (Table 1, entry 4). However, the reac-
tion failed in the case of Et3N and the reactants were recovered
completely (Table 1, entry 5).
Moreover, the progress of the reaction was further monitored
using various solvents based on their polarity. We began the ring
transformation reaction of 7a and 8 in DMF using KOH and the de-
sired product 9a was obtained in 74% yield (Table 1, entry 1). Later,
the same reaction was performed in DMSO as a solvent and reac-
5

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Table 1
Screening of base and solvent for the ring transformation reaction of 2-oxo-6-phenyl-4-(4-
phenylpiperazin-1-yl)-2H-pyran-3-carbonitrile 7a with N-Boc 3-piperidone 8 to 9a.
Entry
Base
Solvent
Time
Yield (%)
1
KOH
DMF
10 h
10 h
10 h
10 h
10 h
10 h
10 h
10 h
10 h
10 h
45 min
74
64
10
59
–
2
NaOH
K2CO3
KOtBu
Et3N
KOH
DMF
3
DMF
4
DMF
5
DMF
6
DMSO
MeCN
Et2O
66
traces
–
7
KOH
8
KOH
9
KOH
MeOH
CHCl3
DMF
–
10
11a
KOH
–
KOH
85
a
Reaction was performed in an ultrasonic bath at room temperature.
tion product 9a was formed in 66% (Table 1, entry 6). However, the
course of reaction was found quite similar in both DMF and DMSO.
Furthermore, the course of the reaction was analysed in MeCN and
reaction could not proceed (Table 1, entry 7). Additionally, the ring
reaction was unsuccessful when Et2O, MeOH and CHCl3 were used
as solvents (Table 1, entries 8–10). After getting the optimized con-
dition, it was found that the KOH and DMF are the suitable base
and solvent for the ring transformation of lactone 7a (1.0 equiv)
with tert–butyl 3-oxopiperidine-1-carboxylate (1.2 equiv) 8 to de-
sired product 9a was found the best conventional reaction condi-
tion.
oxopiperidine-1-carboxylate (1.2 equiv) 8 in the presence of KOH
in DMF was subjected to ultrasound irradiation in an ultrasonic
bath at room temperature. As expected, the reaction time was re-
duced to 45 min and the anticipated product 9a was obtained in
85% yield (Table 1, entry 11).
With this optimum reaction condition (Table 1, entry 11),
we have synthesized N–tert–butyloxycarbonyl-protected tetrahy-
droquinoline derivatives 9a–q in good yield by treating 6-aryl-
2-oxo-4-(sec.amino)-2H-pyran-3-carbonitriles 7 with tert–butyl 3-
oxopiperidine-1-carboxylate (1.2 equiv) 8 in the presence of pow-
dered KOH (1.2 equiv) in DMF at room temperature under ul-
trasound irradiation condition for 40–70 min (Table 2, entries 1–
16). Interestingly, the precursor 6-aryl-4-amino-2H-pyran-2-ones 7
showed versatility towards the ring transformation reaction and
both electron-donating and withdrawing groups were successfully
tolerated under given reaction conditions. Initially, we performed
the ring transformation of simple 6-phenyl-2-oxo-4-(sec.amino)-
2H-pyran-3-carbonitriles 7a–7c containing different cyclic sec-
ondary amines such as N-phenylpiperazine, piperidine and mor-
pholine and the desired ring transformed products 9a-c were iso-
lated in 78–85% yields (Table 2, entry 1–3).
Based on the observed results, ring transformation of lactone
7 with tert–butyl–3-oxopiperidine-1-carboxylate (1.2 equiv) 8 in
the presence of KOH (1.2 equiv) in DMF at room temperature for
10 h shows good yield of desired product 9a. In this regard, the
only limitation was prolonged reaction timing. Therefore, we sub-
sequently concentrate on reducing the time of the reaction. Among
the other methods, sonication is an alternate technique to achieve
the chemical reactions. Sonication is advantageous over the con-
ventional reaction conditions due significant decrease in reaction
time by increasing in the reactivity. Moreover, it provides mini-
mum or no adverse impact on our environment and considered as
a green chemistry laboratory technique. It works by the principle
of cavitation involving the growth, oscillation and bubble collapse
by acoustic field. Chemical reactivity increases by ultrasound by
the formation and the collapse of the cavitation bubbles in a liquid
medium [59]. Cavitation is better attained at lower temperatures
when there is a constant ultrasonic power of the generator. When
the temperature increases, the vapor pressure of the solvent raises
and hence the cavitation bubbles are filled with more solvent va-
por that tends to collapse less violently. This ultimately leads to
less sonication effects. Dissolved gas bubbles can act as nuclei for
cavitation favoring the ultra-sonication process [60].
Later, the feasibility of the ring transformation was analyzed
with the 6-aryl-4-amino-2H-pyran-2-ones 7d–7i bearing electron-
withdrawing groups in the phenyl ring. The ring transformed
products 9d–9i were obtained in excellent yields (Table 2, en-
tries 4–9). Furthermore, we explored the feasibility of the de-
sired product in the presence of electron donating groups in
7j and 7k. It was observed that the yields of 9j and
9 K
slightly reduced when compared to the precursors bearing elec-
tron withdrawing groups (Table 2, entries 10 and 11). In the same
way, bulky 6-naphthyl-4-amino-2H-pyran-2-ones have been par-
ticipated in the ring transformation reaction and corresponding
ring transformed products 9l-n were obtained in moderate yields
(Table 2, entries 12–14). Similarly, the scope of the reaction was
expanded with 6-biphenyl-4-amino-2H-pyran-ones (Table 2, en-
tries 15 and16) and the reaction products were obtained in good
Thus, we thought to utilize this green technique in our ring
transformation reaction. Next, fresh reaction mixture of 6-aryl-
2-oxo-4-(sec.amino)-2H-pyran-3-carbonitrile 7a and tert–butyl–3-
6

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Table 2
Synthesis of N–tert–butyloxycarbonyl-protected tetrahydroquinoline 9 through ring transformation of 6-aryl-4-amino-
2H-pyran-2-ones 7 with tert–butyl 3-oxopiperidine-1-carboxylate 8.
Entry
9
Ar
R
amine
Time (min)
Yield (%)
1
9a
9b
9c
9d
9e
9f
C6H5
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
N-phenylpiperazin-1-yl
piperidin-1-yl
45
40
45
48
48
50
40
41
45
52
44
65
48
70
57
66
85
83
78
89
82
89
81
84
81
69
72
68
76
73
75
75
2
C6H5
3
C6H5
morpholin-1-yl
4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
piperidin-1-yl
5
morpholin-1-yl
6
N-phenylpiperazin-1-yl
piperidin-1-yl
7
9 g
9h
9i
8
N-phenylpiperazin-1-yl
N-phenylpiperazin-1-yl
piperidin-1-yl
–
9
3,4 ClC6H4
10
11
12
13
14
15
16
9j
4-MeC6H4
4-ClC6H5
9k
9l
piperidin-1-yl
1-Naphthyl
2-Naphthyl
2-Naphthyl
4-biphenyl
4-biphenyl
piperidin-1-yl
9m
9n
9o
9p
piperidin-1-yl
N-phenylpiperazin-1-yl
piperidin-1-yl
morpholin-1-yl
Scheme 2. The ring transformation of 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile 10 with N-Boc-3-piperidone 8 to corresponding ring trans-
formed product 11.
yields. Finally, our efforts were directed to explore the possibility
of the nucleophile 8 with 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile 10. The ring transformation reac-
tion was performed under same reaction and condition and cor-
responding ring transformed product 11 was isolated in 76% yield
(Scheme 2). All the synthesized compounds 9a-p and 11 were char-
acterized by their spectroscopic analysis.
3.2. Photophysical properties of compounds 9a-p and 11
Generally, quinolines and quinolones are excellent fluorescent
compounds, suitable for various applications such as the fluores-
cent probe for bio-imaging [8], solar cells [11] and OLED [16]. Inter-
estingly, the entire synthesized N–tert–butyloxycarbonyl-protected
tetrahydroquinolines 9 and 11 exhibit blue emission under UV
lamp in a solution state.
Based on the reported literature [48], the possible mechanistic
pathway for the ring transformation of 6-aryl-2H-pyran- 2-ones 8
to N–tert–butyloxycarbonyl protected tetrahydroquinolines 9 is il-
lustrated in Scheme 3. Initially, the presence of base could trigger
the anion generation of tert–Butyl 3-oxopiperidine-1-carboxylate
which attacks the C-6 position of 6-aryl-2H-pyran-2-ones through
the Michael addition and gives intermediate [A]. Immediately, the
bicyclic intermediate [B] was formed by the intramolecular cycliza-
tion of intermediate [A] involving the C-3 position of pyran ring
and the carbonyl functionality. Further, bicyclic intermediate pro-
vides intermediate [C] by decarboxylation and dehydration. Finally,
intermediate [C] undergoes aromatization to afford the N-Boc pro-
tected 1,2,3,4-tetrahydroquinolines.
In this regard, the optical properties of the synthesized com-
pounds 9a–p were studied by recording the absorption and emis-
sion spectra in the solution of concentration ~10−5 M in CHCl3. The
relative quantum yield of all the compounds were determined us-
ing quinine sulfate in 0.1 M H2SO4 (φ = 0.54) and the optical band
gap was also calculated using UV-DRS spectra using the formula
Eg = 1242/λmax [61]. Moreover, the stokes shift of all the synthe-
sized compounds were also calculated.
In UV–Vis absorption all the compounds 9a–p shows two major
peaks, the peak appears in the shorter wavelength region between
243 and 293 nm corresponds to π−π∗ electronic transition due to
the chromophores corresponding to aromatic π system (Fig. 3a and
7

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Scheme 3. Plausible mechanism for the synthesis of tetrahydroquinoline 9 via ring transformation reaction of 6-aryl-2H-pyran-2-ones 7 cyclic ketone 8 as carbanion source.
Fig. 3b). The longer wavelength absorption peak at 334–361 nm
appears due to the electronic transition corresponds probably due
to internal charge transfer from tertiary amino group and nitrogen
atom in the ring (Fig. 3a and Fig. 3b).
While comparing the emission spectra of the tetrahydroquino-
lines 9a–9p, the maximum emission wavelength appears between
435 and 470 nm (Fig. 3). In the simple phenyl substituted com-
pounds 9a–9c, emission wavelength was obtained in between 422
and 461 nm (Fig. 3a). Meanwhile, few blue fluorescing tetrahydro-
quinolines 9d–9i bearing electron withdrawing substituents in the
phenyl ring showed the emission wavelength in between 440 and
470 nm (Fig. 3a). Similarly, the tetrahydroquinolines 9d–9i bearing
electron donating moieties 9j and 9k exhibit the emission in the
range of 427–438 nm (Fig. 3b).
Notably, slight blue shift was observed when the simple phenyl
is replaced with naphthyl or biphenyl rings in the products 9l-p
(Fig. 3b).
Furthermore, our efforts were directed towards photophysical
studies by UV–Vis and fluorescence spectroscopy. The UV–Vis ab-
sorption spectrum of benzochromene based tetrahydroquinoline 11
shows strong absorption peak at 247 nm attributed to π-π∗ transi-
tion and weak absorption band appears around 349 nm due to the
n-π∗ transition. The fluorescence spectrum of compound 11 shows
emission maxima at 466 nm and exhibits large stokes shift due
to the presence of bulky group and intramolecular charge transfer
(ICT).
The optical band gap of compounds 9a-p and 11 were calcu-
lated using the formula Eg= 1242/λmax [61] longest wavelength
from UV-DRS measurements which explains the band structure
and nature of conducting material, modified by tuning the func-
tionalities in an organic compounds. The band gap of the com-
pounds 9a–p and 11 ranging between 3.01–3.29 eV are detail is
summarized in Table 4. It was observed that the compounds 9l
and 9j exhibit lower band gap of 3.01 eV and 3.04 eV. Based on
the results, it was observed that the optical band gap of the syn-
thesized compounds may be highly influenced by the amine func-
tionality at the C-6 position and the aryl substrates at C-8 posi-
tion of the 1,2,3,4-tetrahydroquinolines. Finally, the quantum yields
Fig. 3. Fluorescence spectra of compounds in chloroform (a) 9a-i; (b) 9j-p and 11.
8

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Scheme 4. Donor/acceptor based tetrahydroquinoline molecule.
of compounds 9a–p were calculated by using quinine sulfate in
0.1 M H2SO4 (φ = 0.54). All the synthesized compounds exhibit
the quantum yield in the range from 0.19 to 0.74. Interestingly,
compounds 9a, 9f, 9h, 9l, 9m and 9o exhibited better quantum
yield compare to quinine sulfate while compound 9f showed the
best quantum yield (φ = 0.74).
Likewise, the stokes shift values were also calculated for all the
compounds 9a-q and obtained in the range of 5387 to 7112 cm−1
due to internal charge transfer between the donor and acceptor
part of the molecule. Based on the results we found few molecules
such as 9a, 9h, 9j and 9o shows comparatively large stokes shift.
Among that, the molecule 9a bearing N-phenylpiperazine at C-
6 position showed slightly red shifted in the emission spectrum
due to the intramolecular charge transfer associated with ex-
tended π-electron conjugation in the N-phenylpiperazine. More-
over, 9h exhibits higher emission wavelength comparatively to all
the molecules due to the bulky bromo group substituted in the
phenyl ring when compared to 9i substituted with methyl group.
Interestingly, the molecule 9o possessing piperidine in C-6 posi-
tion and biphenyl group in C-8 position shows slight red shift
in the emission region which is attributed to the intramolecular
charge transfer between piperidine and cyano group, also exhibits
a greater influence in the rigidity in the molecule.
We carried out the solvatochromic response of compound 9a
with various solvents possessing different polarity index which
investigates the effect of solvent and solute interaction on ex-
cited state. Tetrahydroquinoline 9a shows good solvatochromic
shift based on the increasing polarity of the solvents for toluene
(λmax, UV = 332 nm and λmax, PL = 440 nm) to chloroform (λmax
,
UV = 348 nm and λmax, PL = 461 nm) to THF (λmax, UV = 349 nm
and λmax, PL = 470 nm) to acetonitrile (λmax, UV = 357 nm and
λ
max, PL = 489 nm). The maximum shift was observed for DMSO
(λmax, UV = 365 nm and λmax, PL = 493 nm) and DMF (λmax
,
UV = 385 nm and λmax, PL = 496 nm) as given in Fig. 4a and
b, Table 4.
These experimental results confirm the π-conjugated tetrahy-
droquinolines shows positive solvatochromic effect, as the polarity
of the solvent increases the peak is shifting to the red end of the
fluorescence spectrum due to the intramolecular charge transfer
process. This positive solvatochromic effect is favored only when
the excited-state of the molecule acquire greater dipole moment is
related to its ground state as from non-polar solvent to polar sol-
vent [62,64].
Fig. 4. (a) UV–Vis spectra of compound 9a in different solvents; (b) PL spectra of
compound 9a in different solvents.
A possible mechanism of fluorescence involves internal charge
transfer (ICT) in the compound 9a is given in Scheme 4. In tetrahy-
droquinoline molecules, the central core unit is attached to elec-
tron rich (amino group) in C-6 position and strong electron with-
drawing group (CN group) in C-5 position which makes them suit-
able for internal charge transfer (ICT). During the photo excitation,
the lone pair of electron of amine functionality is usually transfer
9

C. Subashini, L.J. Kennedy and F.V. Singh
Journal of Molecular Structure 1226 (2021) 129365
Table 3
Different photophysical parameters of compounds 9a–p and 11.
Entry
Compound
λmax (abs) (nm)
λmax (em) (nm)
Eop (eV)
ꢀ
ꢁῡ (cm−1
)
1
9a
9b
9c
9d
9e
9f
255, 348
255, 354
253, 338
258, 355
256, 349
257, 350
258, 355
258, 351
254, 349
277, 343
253, 334
256, 361
243, 356
263, 352
247, 349
282, 356
293, 348
461
444
422
442
440
466
449
470
460
438
427
456
446
435
466
451
443
3.11
3.25
3.28
3.11
3.21
3.08
3.29
3.18
3.25
3.04
3.25
3.01
3.16
3.18
3.18
3.09
3.18
0.58
0.48
0.45
0.19
0.46
0.74
0.47
0.69
0.51
0.47
0.52
0.57
0.66
0.22
0.58
0.40
0.34
7027
5726
5889
5387
5926
7112
5739
7213
6914
6324
6521
5819
5719
5420
7148
5917
6163
2
3
4
5
6
7
9 g
9h
9i
8
9
10
11
12
13
14
15
16
17
9j
9k
9l
9m
9n
9o
9p
9q
Table 4
L. John Kennedy: Supported in analysing of photophysical pa-
rameters of synthesizing compounds.
Absorbance and emission maxima of the compound 9a in
various solvents.
Fateh V. Singh: Supervision, proposal of work, arranging of
chemicals, reviewing and editing of the manuscript.
Entry
Solvents
λ
max, UV (nm)
λmax, PL (nm)
1
2
3
4
5
6
Toluene
Chloroform
THF
262,332
255, 348
269, 348
283, 357
279, 365
249, 385
440
461
470
489
493
496
Declaration of Competing Interest
Acetonitrile
DMSO
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
DMF
Acknowledgements
to the benzene ring of the molecule containing electron withdraw-
ing group in the excited state [62,63] (Scheme 4).
C. Subashini is thankful to VIT Chennai for providing financial
support. Fateh V Singh is thankful for DST-SERB New Delhi (Grant
No: SB/FT/CS-068/2014). C. Subashini and Fateh V Singh thank the
SAIF department, VIT Vellore for spectrometric analysis.
4. Conclusion
In conclusion, we have developed an ultrasound-assisted
rapid synthesis of N–tert–butyloxycarbonyl protected tetrahydro-
quinolines 9 via carbanion induced ring transformation reaction
Supplementary materials
of 6-aryl-2H-pyran-2-ones
7 with tert–butyl 3-oxopiperidine-1-
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129365.
carboxylate 8 under mild reaction conditions. Our methodology is
associated with notable advantages such as easy work-up proce-
dure, environmental friendly conditions, and shorter reaction time
and offers the flexibility of introducing electronic donating and
withdrawing groups in tetrahydroquinoline systems. Our synthetic
approach offers a possibly alternative to the conventional tran-
sition metal–catalyzed cross-coupling reactions. Additionally, the
photophysical behavior of the synthesized molecules was stud-
ied by using UV–Vis and fluorescence spectroscopy. All the syn-
thesized compounds 9 and 11 exhibit blue fluorescence in the
range 435–470 nm. The donor-acceptor based tetrahydroquinolines
substituted with bulky groups can be designated as tunable ICT
molecules possessing considerable changes in their photophysical
behavior. Moreover, the other photophysical parameters such as
optical band gap, quantum yield and stokes shift were calculated.
The fluorescent compounds 9 and 11 might be the strong candi-
dates in the future for developing new Organic Light Emitting De-
vices (OLED). Further investigations about this ring transformation
approach and its application in our research group are currently in
progress (Table 3 and Fig. 4).
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