Triflic acid promoted fries rearrangement of C-3 vinyl/isopropenyl-azetidin-2-ones: Single-pot synthesis of C-3 functionalized-2-aryl-2,3-dihydro-quinoline-4(1H)-ones

Article abstract of DOI:10.1039/c4ra07452a

The β-lactam-synthon-interceded synthesis of C-3 functionalized 2-aryl-2,3-dihydro-quinoline-4(1H)-ones has been described via the Fries rearrangement of C-3 vinyl/isopropenyl substituted β-lactams. The reaction at 0 °C resulted in the isolation of a tautomeric mixture, and the preferential formation of the conjugated product was observed at higher temperatures. Density functional theory (DFT) calculations and molecular dynamics (MD) simulations were additionally performed to explain the preferential formation of product 2 over 3. The proposed mechanism was further validated via the base-induced isomerisation of the mixture of 2a and 3a. This journal is

Full text of DOI:10.1039/c4ra07452a

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Triflic acid promoted fries rearrangement of C-3
vinyl/isopropenyl-azetidin-2-ones: single-pot
synthesis of C-3 functionalized-2-aryl-2,3-dihydro-
quinoline-4(1H)-ones†
Cite this: RSC Adv., 2014, 4, 41793
a
b
c
a
*
Vishu Mehra, Parvesh Singh, Krishna Bisetty and Vipan Kumar
The b-lactam-synthon-interceded synthesis of C-3 functionalized 2-aryl-2,3-dihydro-quinoline-4(1H)-
ones has been described via the Fries rearrangement of C-3 vinyl/isopropenyl substituted b-lactams. The
reaction at 0 ꢀC resulted in the isolation of a tautomeric mixture, and the preferential formation of the
conjugated product was observed at higher temperatures. Density functional theory (DFT) calculations
and molecular dynamics (MD) simulations were additionally performed to explain the preferential
formation of product 2 over 3. The proposed mechanism was further validated via the base-induced
isomerisation of the mixture of 2a and 3a.
Received 22nd July 2014
Accepted 22nd August 2014
DOI: 10.1039/c4ra07452a
www.rsc.org/advances
montmorillonite,9c InCl3,9d silica gel supported TaBr5,9e silica
gel supported NaHSO4,9f ZnCl2,9g Silica-supported Yb(OTf)3,9h
PEG-400 (ref. 9i) or alumina supported-CeCl3$7H2O–NaI.9j The
strategies viz. the Pd-catalyzed allylic amination-thiazolium salt
reaction,10a
catalyzed Stetter multicomponent cyclo-
Introduction
Quinoline-4-ones represent an important class of heterocyclic
scaffolds that have attracted signicant interest due to their
various biological and pharmacological activities.1 This
heterocyclic unit also constitutes an integral component in
drugs used for the treatment of neurodegenerative diseases,
sleep disorders and in antibiotics viz. noroxacin and cipro-
oxacin.2 The synthetic accessibility and possibility of func-
tionalization at varied positions in quinoline-4-ones exemplies
an elegant platform for the designing of combinatorial
libraries3 of functionally enriched scaffolds with a range of
pharmacological proles.4 They are also considered to be
attractive precursors for the synthesis of medicinally imperative
molecules such as non-steroidal androgen receptor antago-
nists,5 antimalarial drug Chloroquine6 and martinellines with
antibacterial activity.7 2-Aryl-2,3-dihydroquinolin-4(1H)-ones
are present in many natural and non-natural compounds and
are considered to be the aza-analogs of avanones.8
carbonylation of o-iodoanilines with allenes and CO using
palladium complex in ionic liquids10b and Lewis acid-promoted
one-pot multistep transformation of 2-alkynylanilines or -ben-
zamides with aldehydes11 have recently appeared in the litera-
ture for accessing 3-substituted 2,3-dihydroquinolin-4(1H)-
ones. However, most of the reported synthetic protocols are
invariably associated with signicant drawbacks, including the
use of highly corrosive reagents, long reaction times, tedious
work up procedures, the need for large amounts of catalyst and
specialized solvents which limit their synthetic applicability.
The b-lactam class of antibiotics is generally recognized to be
a cornerstone of human health care due to the unparalleled
clinical efficacy and safety of this type of antibacterial
compound.12 In addition to their biological relevance as
potential antibiotics, b-lactams have also acquired a prominent
place in organic chemistry as synthons and provide highly
efficient routes to a variety of non-protein amino acids, such as
oligopeptides, peptidomimetics, nitrogen-heterocycles, as well
as biologically active natural and unnatural products of
medicinal interest such as indolizidine alkaloids, paclitaxel,
docetaxel, taxoids, cyptophycins, lankacidins, etc.13
Numerous synthetic protocols have been reported for the
synthesis of 2,3-dihydroquinolin-4(1H)-ones, of which the most
widely used pathway is the isomerization of substituted 20-
aminochalcones in the presence of NaOEt,9a H3PO4,9b
aDepartment of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab,
India. E-mail: vipan_org@yahoo.com; Fax: +91-183-2258819-20; Tel: +91-183-
2258802 ext. 3320
A straight forward route toward the synthesis of quinoline-4-
ones via the triic acid assisted Fries rearrangement of N-aryl-b-
lactams has been reported by Tepe and co-workers.14 The ring
expansion observed in this case was solely attributed to the
inherent ring strain in b-lactam ring because g-lactam failed to
undergo rearrangement under reaction conditions. The
bSchool of Chemistry and Physics, University of Kwa-Zulu Natal, Chiltern Hill, Durban
4000, South Africa
cDepartment of Chemistry, Durban University of Technology, Durban 4000, South
Africa
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra07452a
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abovementioned protocol has been recently extended by our
The plausible mechanism for the abovementioned trans-
group for the synthesis of benzo[b]-azocinon-6-ones via a formations is believed to involve the initial protonation of 3-
tandem Michael addition–Fries rearrangement of sorbyl ani- vinyl/isopropenyl-b-lactam 1 generating the carbenium ion
lides15 as well as for the single-pot synthesis of 2-aryl-quinolin- intermediate 5. The intermediate 5 readily undergoes Fries
4(3H)-ones16e through the Fries rearrangement of 3-dienyl-b- rearrangement via an ortho attack of the aromatic substituent
lactams. In continuation with our synthetic endeavours with the on the nitrogen atom, resulting in a ring expanded intermediate
b-lactam ring16 and in view of the lack of convenient approaches 6. Its aromatization accompanied by proton abstraction gener-
for the synthesis of C-3 functionalized quinolin-4(1H)-ones, the ates the intermediate 7, which undergoes [1,5] sigmatropic
present work describes the single-pot synthesis of C-3 func- shi/tautomerization to yield a mixture of 3-ethylidene/iso-
tionalized quinolin-4(1H)-ones via the triic acid promoted propylidene-2-aryl-2,3-dihydro-1H-quinolin-4-ones 2a–h and3-
Fries rearrangement of C-3 vinyl/isopropenyl substituted b-lac- vinyl/isopropenyl-2-aryl-2,3-dihydro-1H-quinolin-4-ones 3a–h,
tams. In addition, DFT calculations and MD simulations were as shown in Scheme 2.
performed to investigate the stability proles of synthetic
compounds (2a and 3a).
Interestingly, similar reactions carried out under reux in
dry chloroform led to the exclusive formation of 2a–h in excel-
lent yields without the formation of 3, even in trace amounts, as
conrmed by the 1HNMR spectrum of the crude reaction
mixture (Scheme 3).
To unequivocally conrm the preferential formation of 2
over 3, the representative compounds 2a and 3a were geomet-
rically optimized in the gas phase and in the self-consistent
reaction-model (SCRF) chloroform model using the B3LYP/6-
31+G(d) basis set at the DFT level (details in the method
section). A Gaussian computer program19 was used for these
optimizations. The electronic energies (DE) and free energies
(DG) of 3a and intermediate (7a) computed relative to 2a are
depicted in the Table 1.
Compound 2a was clearly found to be more energetically
favorable than 3a both in the gas phase (9 kcal molꢁ1) and in
chloroform (9.6 kcal molꢁ1), as depicted in Table 1. The
computed free energies (DG) also further favoured the forma-
tion of 2a over 3a, as depicted in Table 1. In addition, the
associated energy barriers for the conversion of intermediate 7a
(Scheme 2) to products (2a and 3a) at experimental tempera-
tures (273 K and 320 K) were calculated at the same level of
theory in the gas phase. These results show that the energy
Results and discussion
The precursors viz. 3-vinyl/isopropenyl-1,4-diaryl-azetidin-2-
ones 1a–h were prepared via. the Staudinger reaction of cor-
responding imines with vinyl/isopropenyl ketene generated in
situ from crotonic/3-methylcrotonic acid chloride in the pres-
ence of triethylamine. The trans-stereochemistry of compound
1 was assigned on the basis of the coupling constant J ¼ 2.1 Hz
between H-3 and H-4.17 The treatment of C-3vinyl/isopropenyl
b-lactams 1a–h (3.0 eq.) with 1.0 eq. of tri-
oromethanesulphonic acid (triic acid) in dry chloroform at
ꢀ
0 C for 6 h resulted in the formation of a mixture of 3-ethyl-
idene/isopropylidene-2-aryl-2,3-dihydro-1H-quinolin-4-ones 2a–h
and3-vinyl/isopropenyl-2-aryl-2,3-dihydro-1H-quinolin-4-ones
3a–h, which was separated by column chromatography using a
mixture of (hexane : ethylacetate 90 : 10) for compound 2 and
(hexane : ethylacetate 75 : 25) for compound 3 (Scheme 1). The
trans-stereochemistry assigned to product 3 was based on the
coupling constant J ¼ 6.0 Hz between H-2 and H-3.18
Scheme 1 Synthesis of 2-aryl-2,3-dihydro-1H-quinolin-4-ones 2 and 3.
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Scheme 2 Plausible mechanism for the formation of 2-aryl-2,3-dihydro-1H-quinolin-4-ones 2 and 3.
barrier for the formation of product 2a was signicantly lower gas phase nature. To investigate the effect of solvent, the tran-
(38 kcal molꢁ1, Fig. 1) at 320 K, and supports the preferential sition energy barriers were computed at the same level of theory
formation of product 2a over 3a, in accordance with the exper- using a PCM model of chloroform. A small decrease in the TS
imental observations. The DFT calculations performed at 273 K energy barrier (dotted lines, Fig. 1) was observed for both the
did not produce any change in the transition state energies, and products in the presence of the solvent model, suggesting the
could not explain the experimental formation of the minor role of solvent in their stabilities. However, the results were still
product (3a) at low temperatures, which is probably due to its inadequate to explain the experimental formation of 3a in lower
Scheme 3 Synthesis of 3-ethylidene/isopropylidene-2-aryl-2,3-dihydro-1H-quinolin-4-ones 2 under reflux in chloroform.
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Table 1 Corrected relative electronic energies (in kcal molꢁ1) and free
energies of 2a, 3a, TS2a and TS3a with respect to intermediate 7a,
computed at the DFT level
Gas phase
CHCl3 (PCM)
Compound
DE
DG
DE
DG
7a
0
0
0
0
2a
ꢁ13.5
ꢁ4.5
10.9
ꢁ15.7
ꢁ4.6
11.1
ꢁ15.4
ꢁ5.8
10.4
ꢁ16.2
ꢁ4.7
12.0
3a
Fig. 2 Total energy profile for the compound MD2a (in green) and
TS2a
TS3a
MD3a (in blue).
49.0
48.2
47.8
48.4
Fig. 2), temperature (T) and density, as a function of simulation
time. The average uctuation of T around 273 K (Fig. A, ESI†)
and of density around 1.46 g mLꢁ1 (Fig. B, ESI†) suggested the
stability and accuracy of the simulations performed. Moreover,
the average uctuation of TE for 2a (in green) was comparatively
lower than 3a (in blue) throughout the progress of MD simu-
lation, which suggests the better stability of the former than the
later.
The lowest energy structures (solvent stripped off) of both
compounds (2a and 3a) were further extracted from their
respective trajectories (MD2a and MD3a) using the PTRAJ
module in the AMBER program, and are pictorially represented
in Fig. 3. The inter-atomic distance between the carbonyl oxygen
(O16) and the olenic hydrogen (H18) in 2a was also compar-
˚
˚
atively smaller (2.35 A, Fig. 3a) than those present in 3a (2.54 A,
Fig. 3b), clearly suggesting stronger H-bond interactions
between the two atoms. The additional interaction between O16
and the tautomeric proton (H34) in 3a was also relatively weaker
˚
(2.885 A, Fig. 4b). The presence of these unusual hydrogen bond
Fig. 1 Potential energy diagram for the conversion of intermediate
(7a) to products 2a and 3a, both in the gas phase (solid lines, in red) and
in chloroform (dotted lines, in blue). All the energies are in kcal molꢁ1
.
ꢀ
percentages at 0 C. Similar calculations under explicit solvent
conditions could have provided deeper insights into their
stability proles; however, the non-feasibility of such calcula-
tions at the quantum mechanical level in the Gaussian program
limited our further study.
Because the three dimension (3D) structural orientation and
stability of organic molecules are severely affected by the
physical presence of solvent molecules, it was considered to be
worthwhile to investigate the dynamics of both the compounds
(2a and 3a) in the presence of explicit solvent molecules.
Considering the inability of DFT calculations to represent
explicit solvent effects, molecular dynamics (MD) simulations
were used because of their extensive applications in peptide
chemistry coupled with their recent successful utilization in our
research group.20 Accordingly, both compounds (2a and 3a)
were soaked in boxes of chloroform molecules (see method
section) to mimic the experimental solvent conditions. MD2a
and MD3a simulations for compounds 2a and 3a, respectively,
were subsequently performed using the AMBER program.21 The
quality of the MD simulations was rst assessed by plotting
Fig. 3 Lowest energy structure of compound 2a (a) and 3a (b)
different thermodynamic properties, such as total energy (TE, extracted from the simulations MD2a and MD3a, respectively.
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The results were further substantiated by studying the
evolution of the dihedral angle, C11–C12–C17–C19 (highlighted
in red, Fig. 3) for the sampled conformations of both trajecto-
ries (MD2a and MD3a), and is diagrammatically depicted in
Fig. 6. As is evident, the dihedral angle was xed in the case of
compound 2a (in black, Fig. 6), exhibiting average uctuations
at 175ꢀ and ꢁ175ꢀ. Although similar average angle uctuations
(175, ꢁ175) were attained by the conformations of compound
3a, the extent of oscillation was comparatively higher (in red,
Fig. 6) than those observed in 3a due to fast C–C bond rotations.
Finally, a comparison of the MD studies was performed with
the DFT results. For this purpose, the DFT optimized structures
of 2a and 3a were overlaid on the LE structures of the MD using
the Discovery Studio program,23 and are depicted in Fig. 7a and
b. The calculated root mean square deviations (RMSDs) of the
MD structures (in blue, Fig. 7a and b) of 2a and 3a relative to
their gas phase structures (in green, Fig. 7a and b) were found to
Fig. 4 Evolution of distance (O16–H18) in the trajectories MD2a (in
black) and MD3a (in red). Both red and black dots represent the
computed distances in the simulations.
interactions (CO/HC–) has already been established in the
literature.22
Fig. 4 represents the progress of inter-atomic distance (O16–
H18) during the sampling process in the trajectories MD2a (in
black) and MD3a (in red). Clearly, a strong hydrogen bond
˚
˚
be around 0.56 A and 0.80 A, respectively, clearly indicating
structural resemblance between them. Although the MD struc-
tures and the DFT optimized structures t well on each other
˚
(RMSD <1 A), the plane of the quinoline ring in the MD struc-
˚
interaction uctuating around 2.5 A (in black, Fig. 5) was
tures (in blue, Fig. 7a and b) was slightly folded to bring the
carbonyl and olenic hydrogen (H18) in closer vicinity for
potential hydrogen bond interaction. The presence of chloro-
form molecules probably stabilized the folded geometries of 2a
and 3a. The gas phase (in green, Fig. 7a and b) and implicit
chloroform structures (in red, Fig. 7a and b) of 2a and 3a,
overlapped perfectly on each other showing their RMSDs
observed immediately aer the start of the simulation (MD2a),
and was sustained throughout the progress of the trajectory.
˚
Although similar bond distances (ꢂ2.5 A) in equilibrium with
˚
larger ones (ꢂ4.0 A), as depicted in Fig. 4 (in red), were present
in the conformations of 3a sampled during the rst 5 ns
segment of the trajectory MD3a, the oscillations increased
˚
rapidly (3.0–4.3 A) during the last 5 ns part of the trajectory. The
˚
˚
around 0.14 A and 0.07 A, respectively.
faster C12–C17 bond rotations attributed to its low conforma-
tional energy barrier could be the reason for the larger uctu-
ations in 3a and probably decreases its stability compared to its
structural analogue 2a.
Similar hydrogen bonding (O16–H18) was further moni-
tored at higher temperatures by performing two additional
MD simulations for both the compounds at 320 K under
explicit solvent conditions, and is depicted in Fig. 5. Clearly,
the distance (O16–H18), in the case of 3a, was unstable and
Based on the DFT results, it is believed that the requirement
of high activation energy is one of the major factors responsible
for the formation of the product 2a as the major or exclusive
product in the reaction. In addition, the MD results suggest that
the hydrogen bond interaction between the carbonyl oxygen
(CO) and the hydrogen atom at position 17 (C17), and the
double bond (–C12¼C17–) could be another factor that deter-
mines the stability of synthetic compounds. In chloroform, the
presence of both these factors in the folded geometry of
compound 2a is probably responsible for its formation as the
major product under experimental conditions. Similarly, the
presence of hydrogen bonding (O16/H18) led to the formation
˚
uctuates between 2.8–4.3 A in all the sampled conformations
(in red, Fig. 5). The average uctuation in the case of
compound 2a, on the other hand, was stable and oscillates
˚
around 2.85 A (in black, Fig. 5) throughout the progress of the
MD trajectory.
Fig. 5 Progress of distance (O16–H18) in the trajectories MD2a (in Fig. 6 Progress of the dihedral angle C11–C12–C17–C19 in the
black) and MD3a (in red) performed at 320 K.
trajectories MD2a (in black) and MD3a (in red).
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formation of the conjugated product. Compound 2a was found
to be energetically more favourable than 3a on the basis of DFT
calculations. Furthermore, the MD studies suggested the
folding nature of these structures leading to a potential
hydrogen bond interaction between O16–H18 and the stability
of 2a and 3a at 0 ꢀC, with a greater percentage of the former due
to an additional conjugation. At higher temperatures, the faster
C–C rotation probably destabilizes 3a leading to the exclusive
formation of 2a. The proposed mechanism was further vali-
dated via the base-induced isomerisation of the mixture of 2a
and 3a.
Experimental section
General
Melting points were determined by open capillary method using
a Veego Precision Digital Melting Point apparatus (MP-D) and
are uncorrected. IR spectra were recorded on a Shimadzu D-
8001 spectrophotometer. 1H NMR spectra were recorded in
deuterochloroform with Jeol 300 (300 MHz) spectrometers
using TMS as the internal standard. Chemical shi values are
expressed as parts per million downeld from TMS, and J values
are in hertz. Splitting patterns are indicated as s: singlet, d:
doublet, t: triplet, m: multiplet, dd: double doublet, ddd:
doublet of a doublet of a doublet, and br: broad peak. 13C NMR
spectra were recorded on a Jeol 300 (75 MHz) spectrometer in
deuterochloroform using TMS as the internal standard. Mass
spectra were recorded on a Brucker-micrOTOF-Q II mass spec-
trometer. Elemental analyses were performed on a Heraus CHN-
O-Rapid Elemental Analyzer. Column chromatography was
performed using silica gel (60–120 mesh).
Fig. 7 (a) Overlay of the optimized structures of 2a and 3a obtained in
gas phase (in green) and in the implicit chloroform model (in red) at
DFT level, and in explicit chloroform from MD simulations (in blue).
Scheme 4 Exclusive formation of 2a in the presence of triethylamine.
of 3a in lower percentages, which is attributed to the slower C–C
Computational method
ꢀ
The full optimization of all the molecules in the gas phase and
in the SCRF chloroform model was performed using the B3LYP/
6-31+G (d,p) basis set with the Gaussian 09 program.19 Vibra-
tional frequency calculations were also carried out to verify the
nature of all the stationary points obtained and to calculate the
zero-point vibrational energies (ZPVE). Transition states
obtained were conrmed by the occurrence of only one imagi-
nary frequency on the potential energy surface.
For MD simulations, the restrained electrostatic potential
(RESP) atomic charges consistent with the Amber program were
computed for both the compounds (2a and 3a) using the
general amber force eld (GAFF) in AMBER. Molecular
dynamics (MD) simulations were performed using the Amber
9.0 program.21 Prior to MD, both the compounds were soaked in
boxes of chloroform molecules and minimized using 500 steps
of steepest descent, followed by 100 steps of conjugate gradient.
The equilibration (500 picoseconds) of both the systems was
subsequently performed at temperatures of 273 K and 320 K to
bond (C12–C17) rotation at 0 C.
To unequivocally validate the proposed mechanism and
conrm isomerization as the principle route governing the
formation of a mixture of products, it was considered worth-
while to stir the reaction mixture in the presence of the base,
such as triethylamine, which would promote the formation of
the thermodynamically stable conjugate 3-ethylidene-6-methyl-
2-phenyl-2,3-dihydro-1H-quinolin-4-one 2a. Thus, the treatment
of a mixture of 2a and 3a obtained via the triic acid promoted
Fries rearrangement of 1a with triethylamine at room temper-
ature for 12 h resulted in the exclusive formation of 2a, as
conrmed by its superimposable 1H NMR and undepressed
mixed melting point with a sample of 2a obtained earlier
(Scheme 4).
Conclusion
The present manuscript describes the triic acid promoted create a uniform density solvent around both the compounds
synthesis of C-3 functionalized quinolin-4(1H)-ones via the using the periodic boundary conditions (PBC). Finally, the MD
Fries rearrangement of C-3 vinyl-/isopropenyl substituted aze- simulations for 10 nanoseconds were performed at constant
tidin-2-ones. The reaction at 0 ꢀC invariably resulted in the temperature (273 K and 320 K) and pressure. A total of 10 000
tautomeric mixture of products with a preference for the conformations were obtained by sampling each conformation
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at an interval of 1 picosecond from each trajectory. The PTRAJ
module of AMBER 9.0 was used for the analysis of both the MD
trajectories.
3-Ethylidene-2-phenyl-2,3-dihydro-1H-quinolin-4-one (2b).
White solid; m.p.119–120 ꢀC;1H NMR (300 MHz, CDCl3): d: 1.49
(d, J ¼ 7.5 Hz, 3H, –CH3), 1.62 (s, 1H, H2), 3.91 (q, J ¼ 7.2 Hz, 1H,
H4), 7.10–7.60 (m, 9H, ArH), 7.70 (s, 1H, NH, exchangeable with
D2O);13C NMR (75 MHz, CDCl3):d: 16.1, 44.8, 119.8, 122.9, 123.2,
124.3, 127.0, 127.3, 129.0, 134.2, 137.9, 140.9, 146.9, 150.3,
163.0; ESI-MS [M + H]+ m/z 250; anal. calcd forC17H15NO: C,
81.90; H, 6.06; N, 5.62. Found: C, 81.98; H, 6.19, N, 5.54.
2-Phenyl-3-vinyl-2,3-dihydro-1H-quinolin-4-one (3b). Yellow
liquid; 1H NMR (300 MHz, CDCl3): d: 3.53 (t, J ¼ 6.0 Hz, 1H, H3),
4.17 (d, J ¼ 5.7 Hz, 1H, H2), 5.10–5.21 (m, 2H, H5), 5.72–5.84 (m,
1H, H4), 6.80 (m, 1H, ArH), 7.00 (d, J ¼ 7.2 Hz, 2H, ArH), 7.12 (d,
J ¼ 7.2 Hz, 2H, ArH), 7.20–7.37 (m, 4H, ArH), 8.23 (s, 1H, NH,
exchangeable with D2O);13C NMR (75 MHz, CDCl3):d:48.2, 52.8,
115.6, 118.3, 123.5, 125.1, 127.1, 127.7, 128.2, 128.8, 129.3,
133.7, 136.4, 141.1, 170.8; ESI-MS [M + H]+ m/z 250; anal. calcd
forC17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C, 81.84, H, 6.16,
N, 5.71.
6-Chloro-3-ethylidene-2-phenyl-2,3-dihydro-1H-quinolin-4-
one (2c). White solid; m.p.121–122 ꢀC;1H NMR (300 MHz,
CDCl3): d:1.47 (d, J ¼ 7.2 Hz, 3H, –CH3), 1.64 (s, 1H, H2), 3.93 (q,
J ¼ 7.5 Hz, 1H, H4), 6.90–7.52 (m, 8H, ArH), 7.72 (s, 1H, NH,
exchangeable with D2O);13C NMR (75 MHz, CDCl3):d:16.2, 44.3,
119.6, 122.7, 123.1, 124.4, 127.0, 127.5, 129.2, 134.4, 137.8,
140.7, 146.5, 150.2, 163.1; ESI-MS [M + H]+ m/z 284, [M + H]2+ m/
z 285; anal. calcd for C17H14ClNO: C, 71.96; H, 4.97; N, 4.94.
Found: C, 71.78, H, 4.82, N, 4.80.
Typical procedure for the synthesis of 2-aryl-2,3-dihydro-1H-
quinolin-4-ones 2 and 3. The synthesis of quinolin-4(1H)-one
was realized by the slow addition of triic acid (10 mmol) to an
ice cold solution of trans-3-vinyl/isopropenyl-b-lactam 1 (30
mmol) in dry chloroform (20 mL). Aer completion of the
reaction, (monitored through TLC) the reaction mixture was
quenched with ice cold water and extracted into chloroform (2
ꢃ 50 mL). The combined organic layers were dried over anhy-
drous Na2SO4, concentrated under reduced pressure to yield the
crude product, which was then puried by column chroma-
tography using a mixture of ethyl acetate and hexane as the
eluent (10 : 90 for product 2 and 25 : 75 for product 3).
Typical procedure for the synthesis of 3-ethylidene/iso-
propylidene-2-aryl-2,3-dihydro-1H-quinolin-4-ones 2a–h. To a
well stirred solution of trans-3-vinyl/isopropenyl-b-lactam 1 (30
mmol) in dry chloroform (20 mL) a solution of triic acid (10
mmol) was added and the reaction mixture was reuxed for 3 h.
Aer the completion of the reaction, (as evident via TLC) the
reaction mixture was quenched with ice cold water and extrac-
ted into chloroform (2 ꢃ 50 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated under vacuo
and puried by column chromatography using a mixture
(10 : 90) of ethyl acetate and hexane as the eluent to yield the
desired product 2.
Typical procedure for the synthesis of 3-ethylidene-6-methyl-
2-phenyl-2,3-dihydro-1H-quinolin-4-one 2a in the presence of
base. To a well stirred mixture of 2a and 3a in dry chloroform
triethylamine was added and the reaction was stirred for 12 h at
room temperature. Aer the completion of the reaction (as
evidenced via TLC), the reaction mixture was extracted into
chloroform (2 ꢃ 50 mL). The combined organic layers were
dried over anhydrous Na2SO4, concentrated under vacuo to
yield the product 2a, which was puried via column chroma-
tography using a mixture of ethyl acetate and hexane (10 : 90) as
the eluent.
3-Ethylidene-6-methyl-2-phenyl-2,3-dihydro-1H-quinolin-
4-one(2a). White solid; m.p.118–119 ꢀC;1H NMR (300 MHz,
CDCl3): d:1.47 (d, J ¼ 7.5 Hz, 3H, –CH3), 1.66 (s, 1H, H2), 2.31 (s,
3H, –CH3), 3.89 (q, J ¼ 7.5 Hz, 1H, H4), 7.10–7.52 (m, 8H, ArH),
7.69 (s, 1H, NH, exchangeable with D2O);13C NMR (75 MHz,
CDCl3):d:16.1, 20.8, 44.8, 120.0, 122.9, 123.1, 127.0, 127.3, 129.5,
133.9, 134.0, 135.3, 141.0, 147.1, 150.3, 162.8; ESI-MS [M + H]+
m/z 264; anal. calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32.
Found: C, 82.19, H, 6.64, N, 5.25.
6-Chloro-2-phenyl-3-vinyl-2,3-dihydro-1H-quinolin-4-one (3c).
Yellow liquid;1H NMR (300 MHz, CDCl3): d: 3.55 (t, J ¼ 5.7 Hz, 1H,
H3), 4.19 (d, J ¼ 6.0 Hz, 1H, H2), 5.12–5.24 (m, 2H, H5), 5.70–5.82
(m, 1H, H4), 6.83 (m, 1H, ArH), 7.05 (d, J ¼ 7.5 Hz, 2H, ArH), 7.10
(d, J ¼ 7.2 Hz, 2H, ArH), 7.22–7.40 (m, 3H, ArH), 8.21 (s, 1H, NH,
exchangeable with D2O);13C NMR (75 MHz, CDCl3):d:48.4, 52.7,
115.5, 118.6, 123.4, 125.2, 127.4, 127.7, 128.3, 128.9, 129.2, 133.6,
136.3, 141.2, 170.7 ppm.ESI-MS [M + H]+ m/z 284, [M + H]2+ m/z
285; anal. calcd forC17H14ClNO: C, 71.96; H, 4.97; N, 4.94. Found:
C, 71.82, H, 4.85, N, 4.83.
3-Ethylidene-6-methyl-2-p-tolyl-2,3-dihydro-1H-quinolin-4-one
1
ꢀ
(2d). White solid; m.p.123–124 C; H NMR (300 MHz, CDCl3):
d:1.48 (d, J ¼ 7.2 Hz, 3H, –CH3), 1.68 (s, 1H, H2), 2.32 (s, 3H,
–CH3), 2.34 (s, 3H, –CH3), 3.94 (q, J ¼ 7.2 Hz, 1H, H4), 7.08 (d, J ¼
7.2 Hz, 2H, ArH), 7.15 (d, J ¼ 7.2 Hz, 2H, ArH), 7.22–7.47 (m, 3H,
ArH), 7.76 (s, 1H, NH, exchangeable with D2O);13C NMR (75 MHz,
CDCl3):d ¼ 16.4, 20.4, 20.6, 44.5, 119.6, 122.5, 123.7, 124.1, 127.5,
127.6, 129.3, 134.4, 137.5, 140.7, 146.4, 150.8, 163.2 ppm.ESI-MS
[M + H]+ m/z 278; anal. calcd forC19H19NO: C, 82.28; H, 6.90; N,
5.05. Found: C, 82.12, H, 6.74, N, 5.25.
6-Methyl-2-phenyl-3-vinyl-2,3-dihydro-1H-quinolin-4-one(3a).
Yellow liquid; 1H NMR (300 MHz, CDCl3): d: 2.23 (s, 3H, –CH3),
3.50 (t, J ¼ 6.2 Hz, 1H, H3), 4.12 (d, J ¼ 6.0 Hz, 1H, H2), 5.12–5.21
(m, 2H, H5), 5.73–5.82 (m, 1H, H4), 6.72–7.22 (m, 8H, ArH), 8.28
(s, 1H, NH, exchangeable with D2O);13C NMR (75 MHz, CDCl3):d:
20.8, 48.1, 52.8, 115.3, 118.6, 124.8, 127.0, 127.7, 128.6, 128.8,
129.9, 133.1, 133.8, 133.9, 141.3, 170.4; ESI-MS [M + H]+ m/z 264;
anal. calcd forC18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
82.21, H, 6.42, N, 5.43.
6-Methyl-2-p-tolyl-3-vinyl-2,3-dihydro-1H-quinolin-4-one (3d).
Yellow liquid; H NMR (300 MHz, CDCl3): d:2.31 (s, 3H, –CH3),
1
2.34 (s, 3H, –CH3), 3.53 (t, J ¼ 6.0 Hz, 1H, H3), 4.19 (d, J ¼ 6.0 Hz,
1H, H2), 5.17–5.27 (m, 2H, H5), 5.70–5.82 (m, 1H, H4), 7.11 (d, J ¼
7.2 Hz, 2H, ArH), 7.17 (d, J ¼ 7.2 Hz, 2H, ArH), 7.24–7.49 (m, 3H,
ArH), 8.24 (s, 1H, NH, exchangeable with D2O);13C NMR (75 MHz,
CDCl3):d: 20.3, 20.7, 48.1, 52.7, 115.6, 118.1, 123.7, 125.2, 127.6,
127.9, 128.1, 128.5, 129.2, 133.6, 136.8, 141.4, 170.6; ESI-MS [M +
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H]+ m/z 278; anal. calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05.
Found: C, 82.37, H, 6.72, N, 5.17.
3-Isopropylidene-6-methyl-2-p-tolyl-2,3-dihydro-1H-quino-
lin-4-one (2h). White solid; m.p.114–115 ꢀC; 1H NMR (300 MHz,
CDCl3): d: 1.41 (s, 1H, H2), 2.00 (s, 3H, –CH3), 2.14 (s, 3H, –CH3),
2.31 (s, 3H, –CH3), 2.36 (s, 3H, –CH3), 7.00–7.42 (m, 7H, ArH),
7.82 (s, 1H, NH, exchangeable with D2O); 13C NMR (75 MHz,
CDCl3):d: 19.4, 19.7, 22.3, 23.6, 46.4, 114.7, 117.2, 122.5, 124.3,
125.8, 126.5, 127.8, 128.9, 129.4, 136.2, 141.4, 147.8, 165.9; ESI-
MS [M + H]+ m/z 292; anal. calcd forC20H21NO: C, 82.44; H, 7.26;
N, 4.81. Found: C, 82.31, H, 7.37, N, 4.65.
3-Isopropenyl-6-methyl-2-p-tolyl-2,3-dihydro-1H-quinolin-4-
one (3h). Yellow liquid;1H NMR (300 MHz, CDCl3): d:2.04 (s, 3H,
–CH3), 2.27 (s, 3H, –CH3), 2.33 (s, 3H, –CH3), 5.60 (s, 1H, H4a),
5.72 (s, 1H, H4b), 6.65 (d, J ¼ 6.6 Hz, 1H, H3), 6.72 (t, J ¼ 3.0, 6.6
Hz, 1H, H2), 7.00–7.52 (m, 7H, ArH), 7.89 (d, J ¼ 3.0 Hz, NH,
exchangeable with D2O);13C NMR (75 MHz, CDCl3):d: 19.8, 20.2,
20.3, 50.6, 57.8, 114.6, 117.9, 120.1, 125.8, 127.3, 128.1, 128.7,
129.5, 134.6, 141.9, 147.4, 148.5, 185.6 ppm.ESI-MS [M + H]+ m/z
292; anal. calcd forC20H21NO: C, 82.44; H, 7.26; N, 4.81. Found:
C, 82.56, H, 7.16, N, 4.95.
3-Isopropylidene-2-phenyl-2,3-dihydro-1H-quinolin-4-one (2e).
White solid; m.p.115–116 ꢀC;1H NMR (300 MHz, CDCl3): d ¼ 1.36
(s, 1H, H2), 2.06 (s, 3H, –CH3), 2.27 (s, 3H, –CH3), 6.74–7.29 (m,
9H, ArH), 7.73 (s, 1H, NH, exchangeable with D2O);13C NMR (75
MHz, CDCl3):d ¼ 22.5, 23.5, 46.2, 114.9, 117.1, 122.7, 124.7, 125.9,
126.7, 127.7, 128.9, 129.2, 136.3, 141.5, 147.2, 165.9; ESI-MS [M +
H]+ m/z 264; anal. calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32.
Found: C, 82.23, H, 6.39, N, 5.52.
3-Isopropenyl-2-phenyl-2,3-dihydro-1H-quinolin-4-one (3e).
1
Yellow liquid; H NMR (300 MHz, CDCl3): d:2.05 (s,3H, –CH3),
5.64 (s, 1H, H4a), 5.74 (s, 1H, H4b), 6.66 (d, J ¼ 6.0Hz, 1H, H3),
6.71 (t, J ¼ 3.0, 6.0 Hz, 1H, H2), 7.11–7.55 (m, 9H, ArH), 7.86 (d, J
¼ 3.0 Hz, NH, exchangeable with D2O); 13C NMR (75 MHz,
CDCl3):d: 19.8, 50.0, 57.9, 114.8, 117.4, 120.4, 125.6, 127.4,
128.0, 128.6, 129.6, 134.6, 141.8, 147.4, 148.7, 185.8; ESI-MS [M
+ H]+ m/z 264; anal. calcd for C18H17NO: C, 82.10; H, 6.51; N,
5.32. Found: C, 82.21, H, 6.65, N, 5.24.
6-Chloro-3-isopropylidene-2-phenyl-2,3-dihydro-1H-quino-
lin-4-one (2f). White solid; m.p.124–125 ꢀC;1H NMR (300 MHz,
CDCl3): d:1.69 (s, 6H, –CH3), 2.64 (t, J ¼ 2.4Hz, 1H, H2), 3.71 (d, J
¼ 2.2 Hz, NH, exchangeable with D2O), 7.17–7.56 (m, 8H,
ArH);13C NMR (75 MHz, CDCl3):d ¼ 16.2, 16.4, 44.3, 119.2,
122.4, 123.1, 124.6, 127.2, 127.5, 129.4, 134.2, 137.5, 140.6,
146.2, 150.4, 163.6; ESI-MS [M + H]+ m/z 298; [M + H]2+ m/z 299.
anal. calcd for C18H16ClNO: C, 72.60; H, 5.42; N, 4.70. Found: C,
72.45, H, 5.54, N, 4.58.
Acknowledgements
Mr VM gratefully acknowledge the Senior Research Fellowship
granted under CSIR open Scheme09/254(0244)/2012-EMR-I. PS
express his acknowledgement to the centre for high perfor-
mance computing (CHPC), an initiative supported by the
Department of Science and Technology, South Africa.
6-Chloro-3-isopropenyl-2-phenyl-2,3-dihydro-1H-quinolin-4-
one (3f). Yellow liquid;1H NMR (300 MHz, CDCl3): d:2.02 (s,3H,
–CH3), 5.61 (s, 1H, H4a), 5.73 (s, 1H, H4b), 6.62 (d, J ¼ 6.0Hz, 1H,
H3), 6.70 (t, J ¼ 3.3, 6.0 Hz, 1H, H2), 7.05–7.45 (m, 8H, ArH), 7.81
(d, J ¼ 3.3 Hz, NH, exchangeable with D2O); 13C NMR (75 MHz,
CDCl3):d: 20.1, 50.3, 57.6, 114.9, 117.2, 120.6, 125.8, 127.3,
128.0, 128.7, 129.5, 134.8, 141.9, 147.5, 148.8, 185.1; ESI-MS [M
+ H]+ m/z 298, [M + H]2+ m/z 299; anal. calcd for C18H16ClNO: C,
72.60; H, 5.42; N, 4.70. Found: C, 72.71, H, 5.56, N, 4.82.
3-Isopropylidene-6-methyl-2-phenyl-2,3-dihydro-1H-quino-
lin-4-one (2g). White solid; m.p.127–128 ꢀC; 1H NMR (300 MHz,
CDCl3): d:1.48 (s, 1H, H2), 2.02 (s, 3H, –CH3), 2.16 (s, 3H, –CH3),
2.30 (s, 3H, –CH3), 7.08–7.42 (m, 8H, ArH), 7.79 (s, 1H, NH,
exchangeable with D2O);13C NMR (75 MHz, CDCl3):d: 19.2, 22.1,
23.5, 46.2, 114.5, 117.1, 122.6, 124.6, 125.9, 126.7, 127.6, 128.7,
129.3, 136.1, 141.6, 147.5, 165.8; ESI-MS [M + H]+ m/z 278; anal.
calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.12,
H, 6.74, N, 5.21.
Notes and references
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–CH3), 2.31 (s, 3H, –CH3), 5.62 (s, 1H, H4a), 5.70 (s, 1H, H4b), 6.68
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19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.41, H, 6.77, N,
5.18.
41800 | RSC Adv., 2014, 4, 41793–41801
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