Design, synthesis and cytotoxicity of novel chalcone analogs derived from 1-cyclohexylpyrrolidin-2-one and 2,3-dihydrobenzo[f]chromen-1-one

Article abstract of DOI:10.1002/ardp.201100265

Two divergent series of novel chalcone analogs, one derived from 1-cyclohexylpyrrolidin-2-one and the other derived from 1-benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1-benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC ₅₀ values between the range of 5 and 6μM. With an IC₅₀ value of 3.4μM, compound 4g was also active against human MDA-MB-435 melanoma cells. X-ray structures of the β-hydroxy ketone product (4a) and the α,β-unsaturated ketone (4h) were collected, and confirm the syn-configuration between the carbonyl moiety and the β-vinylic proton in 4h. X-ray structures of two 1-cyclohexylpyrrolidin-2-one derivatives were also obtained, and both showed an E-configuration for the double bond. Twenty-four chalcone analogs and one aldol product derived from 1-benzo[f]chromanone and N-cyclohexylpyrrolidinone were synthesized and tested for cytotoxicity against murine cancer cells B16 and L1210. One 1-benzo[f]chromanone derivative (4g), containing a 3,4,5-trimethoxy benzylidene moiety, was quite active also against human MDA-MB-435 melanoma cells. The structure and conformation of the target compounds were ascertained by single crystal X-ray analysis of four compounds. Copyright

Full text of DOI:10.1002/ardp.201100265

Arch. Pharm. Chem. Life Sci. 2011, 000, 1–8
1
Full Paper
Design, Synthesis and Cytotoxicity of Novel Chalcone
Analogs Derived from 1-Cyclohexylpyrrolidin-2-one and
2,3-Dihydrobenzo[f]chromen-1-one
Kimberly A. Brien1, Ravi Kumar Bandi2, Ajaya Kumar Behera2, Bijay Kumar Mishra2,
Poulomi Majumdar2, Vijay Satam1, Mia Savagian1, Samuel Tzou1, Megan Lee1, Matthias Zeller3,
Andrew J. Robles4, Susan Mooberry4,5, Hari Pati2, and Moses Lee1
1 Division of Natural Sciences and Department of Chemistry, Hope College, Holland, MI, USA
2 Department of Chemistry, Sambalpur University, Jyoti Vihar, Sambalpur, Orissa, India
3 Department of Chemistry, Youngstown State University, Youngstown, OH, USA
4 Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio,
TX, USA
5 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio,
TX, USA
Two divergent series of novel chalcone analogs, one derived from 1-cyclohexylpyrrolidin-2-one and
the other derived from 1-benzo[f]chromanone, were designed, synthesized and evaluated for
cytotoxicity against two murine cancer cell lines. Two 1-benzo[f]chromanone analogs, 4g and 4j
yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with
IC50 values between the range of 5 and 6 mM. With an IC50 value of 3.4 mM, compound 4g was
also active against human MDA-MB-435 melanoma cells. X-ray structures of the b-hydroxy ketone
product (4a) and the a,b-unsaturated ketone (4h) were collected, and confirm the syn-configuration
between the carbonyl moiety and the b-vinylic proton in 4h. X-ray structures of two 1-
cyclohexylpyrrolidin-2-one derivatives were also obtained, and both showed an E-configuration for
the double bond.
Keywords: Benzochromanone / Chalcones / Cytotoxicity / Tubulin / X-ray
Received: July 24, 2011; Revised: October 8, 2011; Accepted: October 14, 2011
DOI 10.1002/ardp.201100265
Introduction
designed, synthesized and investigated for their ability to
initiate cytotoxicity in multiple cancer cell lines [7].
One of the principal research interests of our laboratory is the
study of a,b-unsaturated ketones that are analogs of chalcone
[1]. The interest is due to a number of factors including ease of
synthesizing chalcones from substituted benzaldehydes and
acetophenones and the observation that chalcones display a
wide range of biological activities including anti-inflamma-
tory [2], anti-malarial [3], and anti-bacterial actions [4]. It is
well known that chalcones are also active against cancer cells
[5, 6]. As a result, a variety of chalcone analogs have been
Chalcone is a generic term given to compounds bearing the
1,3-diphenylprop-2-en-1-one template (1, Figure 1). There are
several reports in the literature which describe structural
modifications of the chalcone template such as introduction
of different substituents on the phenyl moieties [8], replace-
ment of the phenyl rings with heterocyclic and polyaromatic
groups [9], introduction of a substituted enone linking the
two rings [10], and cyclization of the chalcone to give con-
formationally restricted analogs [11].
A series of chalcone analogs derived from 1-tetralone (2,
Fig. 1) were reported to exhibit promising cytotoxic activities
against human Molt 4/C8 leukemia, CEM lymphoma, and
murine L1210 lymphoma cells [12]. In vivo toxicity studies of
these 2-benzylidene-1-tetralones (2) demonstrated that a
Correspondence: Moses Lee, Division of Natural Sciences and
Department of Chemistry, Hope College, Holland, MI 49423, USA.
E-mail: lee@hope.edu
Fax: þ1 616 395 7923
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K. A. Brien et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–8
exhibit potent cytotoxic activities against malignant cells.
Hence, ten novel chalcone analogs derived from 1-benzo[f]-
chromanone were designed and synthesized. In addition,
fifteen related chalcone analogs (5a–e, 5g–o) derived from
N-cyclohexylpyrrolidinone were also prepared by conden-
sation reactions. All analogs were evaluated for their cyto-
toxic activity against murine B16 and L1210 cancer cells. Four
analogs were subjected to single crystal X-ray crystallo-
graphic analysis in order to ascertain the geometry of the
alkene bond as well as the overall structure and confor-
mation of the compounds.
Figure 1. Chalcone and chromanone derivatives.
number of analogs in the series were well tolerated in mice
and did not produce mortalities at doses of up to 300 mg/kg.
Another series in which the 4-methylene group of the 2-
benzylidene-1-tetralones was replaced by an oxygen atom Results and discussion
to give 3-benzylidene-4-chromanones (3, Fig. 1) was synthes-
ized and assessed for cytotoxic activity [13]. The study
revealed that a number of 3-benzylidene-4-chromanones (3)
displayed greater cytotoxicity and were better tolerated in
mice than the related 2-benzylidene-1-tetralones (2).
Synthesis of novel chalcone analogs
The ten novel benzochromanone-based chalcone analogs
(4b, 4d–l) were synthesized in good yields by using a classical
aldol cross-condensation reaction as outlined in Scheme 1.
The suitably substituted benzaldehydes were condensed with
1-benzo[f]chromanone in ethanol at ambient temperature
using 10% aqueous sodium hydroxide. In all cases except
4a, spontaneous dehydration occurred to give the a,b-
unsaturated ketones as evidenced by the 1H NMR signals
for the vinylic protons at >7 ppm.
Encouraged by these results, we sought to prepare and
evaluate two more classes of chalcone analogs (Fig. 2) that
contain an exocyclic benzylidene functionality. It was envis-
aged that condensation of 1-benzo[f]chromanone with suit-
ably substituted aromatic aldehydes would result in a novel
series of prototypic molecules (4a,b, 4d–l, Fig. 2) that might
Figure 2. General structures of chalcone ana-
logs derived from benzochromanone (4b, 4d–l)
and N-cyclohexylpyrrolidinone (5a–e, 5g–o).
Scheme 1. Synthesis of aldol product 4a and
the chalcone analogs 4b, 4d-l.
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Arch. Pharm. Chem. Life Sci. 2011, 000, 1–8
Cyclohexylpyrrolidinone, Dihydrobenzo[f]chromenone compounds
3
Scheme 2. Synthetic pathway towards the chalcone analogs
5a–e, 5g–o.
showed the alkene to exist in the E-configuration. Both struc-
tures reveal that the a-anisylidenyl-N-cyclohexylpyrrolidi-
none units are essentially planar. They are rotated against
the chair-shaped cyclohexyl moiety at about an angle of 73.98
in 5b and of 45.4 and 64.38 angles in the two crystallograph-
ically independent molecules in the structure of 5c. The
vinylic protons are syn to the carbonyl in both structures.
Cytotoxicity
All twenty-five compounds were initially screened against the
murine L1210 (lymphoma) cell line at 10 mM concentration.
Cytotoxicity was measured using the MTT assay after 72 h
Figure 3. X-ray structures of compounds 4a and 4h.
The 1H NMR spectrum of compound 4a provided initial
evidence for the lack of a vinylic proton, and its identity was
confirmed by a phenylcarbinol proton signal at 5.72 ppm.
Crystals of 4a and 4h were obtained from methanol and X-ray
structures were determined (Fig. 3). Consistent with the
1H NMR data, 4a was isolated as the b-hydroxy ketone prod-
uct. The benzochromanone structure of 4h was unambigu-
ously ascertained by the X-ray analysis. The core
benzochromanone portion of the molecule is virtually planar
with the exception of the methylene carbon atoms of the
dihydropyrone moiety, which deviate from the benzochro-
˚
manone plane by 0.530 and 0.643 A in the two crystallo-
graphically independent molecules in the structure. The 4-
methylbenzylidene groups are twisted by approximately 60.7
and 54.48 about the plane of the benzochromanone moiety,
and the b-vinylic proton is held syn to the carbonyl group,
thus confirming the E-configuration.
Compounds 5a–e, 5g–o were synthesized by quantitative
formation of the amide enolate followed by condensation
with selected benzaldehydes (Scheme 2) to give the b-hydroxy
amides in 80–85% yield. These intermediates were sub-
sequently dehydrated using POCl3 to give the a,b-unsatu-
rated amides in 40–45% yield.
Compounds 5b and 5c were crystallized from methanol.
The X-ray structures of these two compounds given in Fig. 4
Figure 4. X-ray structures of compounds 5b and 5c.
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K. A. Brien et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–8
Encouraged by the results obtained with compounds 4g
and 4h, further tests using the SRB assay were undertaken to
look at their anti-proliferative effects against human mela-
noma MDA-MB-435 cells. The IC50 values for 4g and 4h are
3.4 ꢀ 0.2 and 23 ꢀ 1 mM, respectively, which are compar-
able to the activities observed in murine cancer cells. It is,
however, interesting to note that compound 4g is more
cytotoxic than 4h and it contains the trimethoxyphenyl
moiety. This moiety is a common structural feature present
in the combretastatins, which is a class of tubulin inhibitor
anticancer agents [15]. It is also worthy to indicate that
compound 4j has comparable activity to 4g in the B16 and
L1210 studies. Structurally, one common feature in these two
compounds is the sizable meta substituent (Br or OMe group)
in the benzylidene unit. This bulky substituent may affect
their ability to interact with biological targets. Due to the
similarity of compounds 4g and 4h to the combretastatins,
they were tested for the ability to cause microtubule depo-
lymerization in A-10 cells [1, 14, 16]. At 30 mM, a concen-
tration above their cytotoxic IC50 values, neither compound
had any effect on the microtubules suggesting that unlike
the combretastatins inhibition of tubulin polymerization is
not a likely biological mechanism of how these compounds
inhibit cancer cell growth.
Conclusion
Figure 5. Average values from the initial screen of compounds
4a,b,d–l and 5a–e, 5g–o at 10 mM concentration for activity against
murine L1210 cells. The difference in mean cell viability (x-axis) is
defined as A–B, in which A ¼ (absorbance at 570 nm for an indivi-
dual compound – absorbance at 570 nm for the negative vehicle
control)ꢁ1. B ¼ average of A for all compounds within each series.
Bars to the right of the average indicate compounds that are more
active than the average for each series of molecules.
Twenty-four chalcone analogs (4b,d–l and 5a–e,g–o) and one
aldol product (4a) derived from 1-benzo[f]chromanone and
N-cyclohexylpyrrolidinone were synthesized, characterized
and tested for cytotoxicity against murine cancer cells B16
and L1210. Compounds 4g and 4h were also tested against
the growth of human MDA-MB-435 cells. Two 1-benzo[f]chro-
manone derivatives (4a and 4h) produced high quality crys-
tals from which X-ray structures were determined. The
results provided unequivocal evidence to support the aldol
or b-hydroxy ketone structure for product 4a and the E-
configured, a,b-unsaturated ketone for compound 4h.
Two structures of N-cyclohexylpyrrolidinone derivatives also
gave X-ray structures both showing an E-configuration about
the double bond. Two compounds 4g and 4j yielded moderate
toxicity against both B16 and L1210 cell lines with IC50 values
between 5 and 6 mM.
incubation [1, 14]. Based on the screening data, compounds
that showed greater activity than the average (i.e. bars
to the right in Fig. 5) were selected for detailed studies
where the IC50 values (concentration causing 50% cytotoxicity)
were measured. Accordingly, eight compounds, 4d, 4h, 4j, 5k,
5l, 5m, 5n, 5o were selected for further testing in inhibition
of the growth of murine B16 (melanoma) and L1210 cell lines
using a 72 h continuous exposure MTT assay technique. The
average IC50 (mM) for each compound was determined from
duplicate experiments and the results are presented in
Table 1.
Experimental
Analogs in the 1-benzo[f]chromanone series were active
against B16 and L1210 cancer cells, with analogs 4g and 4j
being the most potent with IC50 values in the single-digit mM
range. None of the N-cyclohexylpyrrolidinone compounds
tested were active at inhibiting the growth of L1210 and
B16 cell lines, even at a concentration of 100 mM.
General method for preparation of 4a,b,d–l
Benzochromanone (0.3 g, 1.5 mmol, 1.0 eq.) and the appropriate
arylaldehyde (1.0 eq.) were dissolved in ethanol (5 mL) at room
temperature. Aqueous sodium hydroxide (10 mL, 10% solution)
was added dropwise and the reaction stirred for 10–12 h while
being monitored by TLC for completion. The solution was filtered
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Cyclohexylpyrrolidinone, Dihydrobenzo[f]chromenone compounds
5
Table 1. IC50 values of selected compounds based on initial screening
Cmpd
4g
Structure
B16 IC50
(mM)
L1210 IC50
(mM)
Cmpd
5l
Structure
B16 IC50
(mM)
L1210 IC50
(mM)
6.4 ꢀ 1.3
5.0 ꢀ 0.2
>100
>100
4h
>100
56 ꢀ 19
5m
>100
>100
4j
6.3 ꢀ 0.8
5.6 ꢀ 0.4
5n
>100
>100
5k
>100
>100
5o
>100
>100
and the solid product was washed with chilled ethanol (5 mL).
The crude compounds were purified by silica gel (60–120 mesh)
column chromatography and eluted with hexane/EtOAc (10–
20%) mobile phase to obtain the pure product (yield: 35–40%).
General method for preparation of 5a–e,g–o
A freshly prepared LDA solution (1.0 eq.) was added to a solution
of N-cyclohexylpyrrolidinone (0.5 g, 3.3 mmol) in anhydrous THF
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K. A. Brien et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–8
(5 mL) at ꢁ70 to ꢁ758C under nitrogen atmosphere. The reaction
mixture was stirred at ꢁ70 to ꢁ758C for 30 min. A solution of the
appropriate arylaldehyde in dry THF (5 mL) was added at ꢁ70
to ꢁ758C. The solution was allowed to reach 20–258C and
maintained at room temperature for 8–10 h. Completion of
the reaction was monitored by TLC (hexane/EtOAc, 80:20). At
that time, a saturated ammonium chloride solution was added
and the solution was extracted with ethyl acetate (3 ꢂ 75 mL).
The organic layers were combined, dried over sodium sulfate,
and the solvents evaporated under vacuum to obtain the inter-
mediate alcohol compound (yield: 80–85%). The residue was
dissolved in POCl3 (5 mL) and stirred at 20–258C for 10–15 h.
Upon completion of the reaction, the excess of POCl3 was
evaporated under vacuum to dryness. The residue obtained
was treated with ice water and the pH adjusted to 8–10 with
2 M NaOH. The aqueous layer was extracted with ethyl acetate
(3 ꢂ 75 mL). The organic layers were combined, washed with
brine solution, dried over sodium sulfate and the solvent
evaporated under vacuum to obtain the crude compound,
which was purified by using silica gel (60–120 mesh) column
chromatography using hexane/EtOAc (10–20%) as the mobile
phase (yield: 40–45%).
1595, 1580, 1505, 1463, 1455, 1434, 1416, 1368, 1332, 1273,
1259, 1236, 1208, 1188, 1125, 1096, 1000, 926, 823, 792, 756,
733, 700, 665, 627, 587, 547, 500, 455; MS: ESI (m/z) 377.5
(MþH)þ. Accurate mass for C23H20O5 calcd 376.1311, obsd
376.1307.
(E)-2-(4-Methylbenzylidene)-2,3-dihydrobenzo[f]chromen-
1-one 4h
Pale yellow solid; mp: 1518C; 1H NMR (DMSO-d6): d 9.32 (d, 1H,
J ¼ 9.0 Hz), 8.17 (d, 1H, J ¼ 9.0 Hz), 7.95 (d, 1H, J ¼ 8.0 Hz), 7.78
(s, 1H), 7.70 (t, 1H, J ¼ 8.0 Hz), 7.51 (t, 1H, J ¼ 8.0 Hz), 7.38 (d, 2H,
J ¼ 8.0 Hz), 7.33 (d, 2H, J ¼ 8.0 Hz), 7.24 (d, 1H, J ¼ 9.0 Hz), 5.50
(s, 2H), 2.39 (s, 3H); IR (ATR): 3024, 2918, 2851, 1655, 1614, 1593,
1566, 1508, 1468, 1444, 1431, 1403, 1370, 1340, 1274, 1244,
1225, 1206, 1192, 1180, 1142, 1112, 1083, 1048, 1026, 994,
950, 916, 848, 829, 803, 790, 776, 753, 724, 709, 700, 681,
653, 638, 623, 549, 532, 514, 486, 429, 416, 405; MS: ESI (m/z)
301.5 (MþH)þ. Accurate mass for C21H16O2 calcd 300.1150, obsd
300.1152.
(E)-2-(3-Bromobenzylidene)-2,3-dihydrobenzo[f]chromen-
Compounds 4a, 4h, 5b and 5c were recrystallized by dissolving
the respective samples in hot methanol. The clear solutions were
left at room temperature for two days. The crystals formed were
filtered, washed with cold methanol and dried in vacuum. All
diffraction data were collected on a Bruker AXS SMART APEX
CCD diffractometer at 100 K using monochromatic Mo Ka radi-
ation with the omega scan technique. Data were collected, their
unit cells determined, and the data integrated and corrected
for absorption and other systematic errors using the Apex2
suite of programs [17]. The structures were solved by direct
methods and refined by full matrix least squares against F2 with
all reflections using SHELXTL [18]. Compound 4h was found
to be pseudomerohedrally twinned, compound 5b to be non-
merohedrally twinned (see cif files deposited with the Cambridge
Crystallographic Database for details).
1-one 4j
Pale yellow solid; mp: 1338C; 1H NMR (CDCl3): d 9.43 (d, 1H,
J ¼ 9.0 Hz), 7.95 (d, 1H, J ¼ 9.0 Hz), 7.85 (s, 1H), 7.79 (d, 1H,
J ¼ 7.5 Hz), 7.68 (t, 1H, 7.5 Hz), 7.55 (d, 1H, J ¼ 9.0 Hz), 7.49–
7.47 (m, 3H), 7.34 (t, 1H, J ¼ 7.5 Hz), 7.11 (d, 1H, J ¼ 9.0 Hz), 5.36
(d, 2H, J ¼ 1.8); IR (ATR): 2925, 2849, 1662, 1607, 1592, 1569,
1509, 1464, 1431, 1398, 1368, 1342, 1272, 1241, 1222, 1204,
1190, 1157, 1136, 1072, 1050, 1025, 995, 964, 929, 908, 877,
857, 825, 811, 791, 779, 746, 731, 695, 664, 638, 557, 537, 498,
437, 406; MS: ESI (m/z) 367.4 (MþH)þ.
(E)-3-(3-Methoxybenzylidene)-1-cyclohexylpyrrolidin-2-
one 5b
Off white crystalline solid; mp: 1478C; H NMR (CDCl3): d 7.33–
7.23 (m, 2H), 7.07 (d, 1H, J ¼ 8.0 Hz), 7.00 (s, 1H), 6.86 (dd, 1H,
J ¼ 8.0, 2.3 Hz), 4.10–4.14 (m, 1H), 3.83 (s, 3H), 3.47 (t, 2H,
J ¼ 6.5 Hz), 3.04 (dt, 2H, J ¼ 6.5, 3.0 Hz), 1.83–1.69 (m, 6H),
1.50–1.41 (m, 4H); IR (ATR): 2925, 2851, 2833, 1670, 1642,
1601, 1509, 1461, 1438, 1421, 1301, 1285, 1247, 1216, 1192,
1175, 1117, 1030, 972, 949, 912, 892, 833, 810, 764, 709, 527;
MS: ESI (m/z) 285.35 (MþH)þ.
1
The analytical data for compounds selected for cytotoxicity
studies and X-ray crystallography analysis are given below.
(E)-2-Benzylidene-2,3-dihydrobenzo[f]chromen-1-one 4a
White solid; mp: 1378C; 1H NMR (CDCl3): d 9.42 (d, 1H,
J ¼ 8.8 Hz), 7.92 (d, 1H, J ¼ 8.8 Hz), 7.76 (d, 1H, J ¼ 8.8 Hz),
7.65 (ddd, J ¼ 8.8, 7.0, 1.3 Hz, 2H), 7.32–7.45 (ddd, J ¼ 8.0, 7.0,
1.3 Hz 6H), 7.38 (m, 1H), 7.39 (m, 3H), 7.05 (d, 1H, J ¼ 8.8 Hz), 5.72
(t, 1H, J ¼ 4.0, 2H), 4.68 (t, 1H, J ¼ 12.0 Hz), 4.44 (dd, 1H, J ¼ 12.0,
5.3 Hz), 3.23 (ddd, 1H, J ¼ (4.0, 5.3, 12.0 Hz), 2.87 (d, 1H, J ¼ 4.0);
IR (ATR): 3412, 3041, 2993, 2914, 1654, 1613, 1595, 1565, 1509,
1491, 1474, 1451, 1433, 1404, 1379, 1367, 1341, 1276, 1244,
1228, 1201, 1173, 1158, 1140, 1126, 1102, 1086, 1059, 1024, 991,
941, 896, 844, 822, 787, 767, 756, 746, 724, 700, 673, 650, 643,
577, 546, 526, 513, 486, 424, 408; MS: ESI (m/z) 305.3 (MþH)þ,
287.1 (MþH–H2O)þ.
(E)-3-(4-Methoxybenzylidene)-1-cyclohexylpyrrolidin-2-
one 5c
Off white crystalline solid; mp: 1378C; 1H NMR (CDCl3): d 7.43
(d, 2H, J ¼ 8.8 Hz), 7.29 (t, 1H, J ¼ 2.8 Hz), 6.92 (d, 2H, J ¼ 8.8 Hz),
4.10–4.11 (m, 1H), 3.84 (s, 3H), 3.47 (t, 2H, J ¼ 6.5 Hz), 3.01
(td, 2H, J ¼ 6.5, 2.8), 1.83–1.68 (m, 5H), 1.45–1.40 (m, 4H),
1.09–1.12 (m, 1H); IR (ATR): 2923, 2837, 1671, 1641, 1603,
1576, 1495, 1439, 1422, 1361, 1299, 1259, 1204, 1159, 1090,
1046, 928, 912, 888, 876, 768, 677, 631, 553, 466, 447; MS: ESI
(m/z) 285.35 (MþH)þ.
(E)-2-(3,4,5-Trimethoxybenzylidene)-2,3-
dihydrobenzo[f]chromen-1-one 4g
Pale yellow solid; mp: 127.68C; 1H NMR (CDCl3): d 9.43 (d, 1H,
J ¼ 8.5 Hz), 7.94 (d, 1H, J ¼ 8.5 Hz), 7.87 (s, 1H), 7.78 (d, 1H,
J ¼ 7.5 Hz), 7.67(t, 1H, J ¼ 7.5 Hz), 7.46 (t, 1H, J ¼ 7.5 Hz),
7.10 (d, 1H, J ¼ 8.5 Hz), 6.55 (s, 2H), 6.54 (d, 2H, J ¼ 1.8 Hz),
3.92 (s, 3H), 3.91 (s, 6H); IR (ATR): 2961, 2836, 1658, 1615,
(E)-3-(Benzo[d][1,3]dioxol-5-ylmethylene)-1-
cyclohexylpyrrolidin-2-one 5k
Light brown solid; mp: 1578C; 1H NMR (DMSO-d6): d 7.08–7.10
(m, 1H), 7.03–7.06 (m, 2H), 6.98 (d, 1H, J ¼ 8.0 Hz), 6.04 (s, 2H),
3.84–3.92 (m, 1H), 3.39–3.47 (m, 3H), 2.95–3.02 (m, 2 H), 1.82–1.73
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Cyclohexylpyrrolidinone, Dihydrobenzo[f]chromenone compounds
7
(m, 2H), 1.67–1.58 (m, 2H), 1.48 (qd, 1H, J ¼ 12.0, 3.0 Hz), 1.46
(qt, 1H, J ¼ 12.0, 3.0 Hz), 1.13 (qt, 1H, J ¼ 12.0, 3.0 Hz); IR (ATR):
2930, 2855, 1671, 1644, 1613, 1504, 1488, 1439, 1421, 1341,
1281, 1236, 1187, 1037, 936, 922, 806, 611; MS: ESI (m/z) 300.4
(MþH)þ.
The authors thank Conjura Pharmaceuticals, LLC for support. Support
from the Department of Chemistry, Sambalpur University for providing
facilities for research is also acknowledged. The X-ray diffractometer at
Youngstown State University was funded by NSF Grant 0087210, Ohio
Board of Regents Grant CAP-491, and by Youngstown State University.
Support from the President’s Council Excellence award is acknowledged
(SLM).
(E)-3-(5-Bromo-2-methylbenzylidene)-1-
cyclohexylpyrrolidin-2-one 5l
Off white solid; mp: 1328C; 1H NMR (CDCl3): d 7.48 (d, 1H,
J ¼ 2.5 Hz), 7.41 (t, 1H, J ¼ 2.5 Hz), 7.30 (dd, 1H, J ¼ 8.0,
2.5 Hz), 7.08 (d, 1H, J ¼ 8.0 Hz), 4.16–4.10 (m, 1H), 3.45 (t, 2H,
J ¼ 6.5 Hz), 2.96 (dt, 2H, J ¼ 6.5, 2.5 Hz), 2.34 (s, 3H), 1.85–1.66
(m, 5H), 1.50–1.38 (m, 4H), 1.16–1.11 (m, 1H); IR (ATR): 2927, 2853,
1667, 1642, 1487, 1479, 1437, 1420, 1358, 1288, 1255, 1221,
1197, 1185, 1014, 993, 908, 894, 879, 809, 772, 736, 703, 685,
562, 535, 468, 442; MS: ESI (m/z) 350.3 (MþH)þ.
The authors have declared no conflict of interest.
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