Antimycobacterial activity of novel 1,2,4-oxadiazole-pyranopyridine/ chromene hybrids generated by chemoselective 1,3-dipolar cycloadditions of nitrile oxides

Article abstract of DOI:10.1016/j.bmc.2011.04.033

The 1,3-dipolar cycloaddition of nitrile oxides generated in situ from benzohydroximinoyl chloride and triethylamine to 2-aminopyranopyridine-3- carbonitriles and 2-aminochromene-3-carbonitriles occurred chemoselectively furnishing novel 1,2,4-oxadiazole-

Full text of DOI:10.1016/j.bmc.2011.04.033

Bioorganic & Medicinal Chemistry 19 (2011) 3444–3450
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Antimycobacterial activity of novel 1,2,4-oxadiazole-pyranopyridine/chromene
hybrids generated by chemoselective 1,3-dipolar cycloadditions of nitrile oxides
Raju Ranjith Kumar a, Subbu Perumal a, , J. Carlos Menéndez b, , Perumal Yogeeswari c,
⇑
⇑
Dharmarajan Sriram c
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
b Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
c Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 January 2011
Revised 4 April 2011
Accepted 13 April 2011
Available online 22 April 2011
The 1,3-dipolar cycloaddition of nitrile oxides generated in situ from benzohydroximinoyl chloride and
triethylamine to 2-aminopyranopyridine-3-carbonitriles and 2-aminochromene-3-carbonitriles occurred
chemoselectively furnishing novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrid heterocycles in
moderate yields. In vitro screening of these compounds against Mycobacterium tuberculosis H37Rv
(MTB) disclosed that the 1,2,4-oxadiazole-pyranopyridine hybrids display enhanced activity relative to
the 1,2,4-oxadiazole-chromene hybrids. Among the compounds screened, 3-[3-(4-chlorophenyl)-1,2,4-
oxadiazol-5-yl]-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)-methylidene]-6-methyl-5,6,7,8-tet-
Keywords:
Antimycobacterial activity
Mycobacterium tuberculosis
Pyranopyridines
Pyranochromenes
1,2,4-Oxadiazoles
rahydro-4H-pyrano[3,2-c]pyridin-2-amine (MIC: 0.31
standard antitubercular drugs, viz. isoniazid, ciprofloxacin and ethambutol, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
lM) is 1.2, 15.2 and 24.6 times more active than
1. Introduction
ing, which brought to light various antitubercular leads.5,6 In
particular, one of our studies7 disclosed that tetrahydro-4H-pyr-
Tuberculosis (TB) is a chronic bacterial infection and most peo-
ple infected with Mycobacterium tuberculosis (MTB) harbor the bac-
terium without displaying symptoms (latent TB), but some develop
into active TB disease. The World Health Organization (WHO) esti-
mates that more than 2 billion people are infected with MTB and 1
in 10 people infected with TB will become sick with active TB in
their lifetime. In 2008, 9.4 million new TB cases were reported,
out of which 1.8 million people died.1 Directly observed treatment
short-course (DOTS) is presently the mainstay of TB control glob-
ally,2a,b which employs agents like isoniazid, rifampicin, and the
aminoglycoside antibiotic streptomycin.2c Correctly applied treat-
ment with DOTS has a success rate of 95% and also prevents the
emergence of further multi-drug resistant tuberculosis (MDR-TB).
With the increasing TB incidence3 and the emergence of MDR-
TB4 the development of new TB therapeutics can be considered
of great importance.
ano[3,2-c]pyridine derivatives 3 inhibited MTB and MDR-TB
in vitro (Scheme 1). This provided the impetus to synthesize com-
pounds 4, designed by bioisosteric replacement of the N-Me group
of 3 by a CH2 and further transformation via 1,3-dipolar cycloaddi-
tion with nitrile oxides, which have led to novel heterocyclic hy-
brids combining the structure of 3 and 4 with 1,2,4-oxadiazole
pharmacophores. 1,2,4-Oxadiazoles constitute a versatile class of
organic compounds with biological activities such as analgesic,8
antirhinoviral,9 antipicornaviral (Pleconaril drug),10 antioxidant11
and antiinflammatory.11 These compounds are also used as angio-
tensin II receptor antagonists,12 besides finding utility in plant pro-
tection, as liquid crystalline mesophases,13 and as dipeptide
mimics.14 These observations lead to the conclusion that 1,2,4-oxa-
diazoles satisfy the definition of privileged scaffolds, that is, molec-
ular frameworks that are able to bind to a diverse array of
receptors.15
We have recently embarked on a program on the synthesis of
structurally diverse novel heterocycles employing domino, cyclo-
addition and other reactions, followed by their biological screen-
Interestingly, the 1,3-dipolar cycloaddition of nitrile oxides gen-
erated in situ from the dehydrohalogenation of N-hydroxyarylcar-
boximidoyl chloride and triethylamine to compounds 3 and 4
proceeded in a chemoselective manner affording the novel 1,2,4-
oxadiazole-pyranopyridine/chromene hybrids 5 and 6, respec-
tively, in moderate yields (Scheme 1). These compounds displayed
significantly enhanced in vitro activities against MTB compared to
⇑
Corresponding authors.
E-mail address: josecm@farm.ucm.es (J.C. Menéndez).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.04.033

R. Ranjith Kumar et al. / Bioorg. Med. Chem. 19 (2011) 3444–3450
3445
N-hydroxyarylcarboximidoyl chloride in presence of triethylamine
in benzene (Scheme 1).
After completion of the reaction (TLC), the solvent was evapo-
rated in vacuo and the residue, upon column chromatographic
purification, afforded 1,2,4-oxadiazole-pyranopyridine/chromene
hybrids 5 and 6, respectively, in 40–65% yields (Table 2). It is per-
tinent to note that the product of nitrile oxide cycloaddition to the
exocyclic alkene moiety of either 3 or 4 was not obtained, even
when an excess of nitrile oxide and prolonged reaction times were
employed, leading to the conclusion that this cycloaddition occurs
chemoselectively on the nitrile function.
The structure of all the products was elucidated with the help of
one- and two-dimensional (H,H-COSY, C,H-COSY and HMBC) NMR
spectroscopic data and single crystal X-ray crystallographic stud-
ies. The 1H and 13C NMR chemical shifts of 1,2,4-oxadiazole-pyr-
anopyridine/chromene hybrid heterocycles
5 and 6 and the
corresponding 2-aminopyranopyridine- and 2-aminochromene-3-
carbonitriles 3 and 4 were found to be almost similar, apart from
the presence of new signals arising from the 1,2,4-oxadiazole ring
and the lack of signal of the nitrile function. The 1H NMR spectrum
of 5g has singlets for the N-CH3, NH2 and benzylidene hydrogen
(H-9), respectively, at 2.31, 6.56 and 6.94 ppm and a multiplet
for the aromatic hydrogens in the range of 6.87–7.97 ppm. The
C,H-COSY correlation of H-9 assigns C-9 to 121.6 ppm. The HMBCs
of H-9 (Fig. 1) with the carbon at 55.3 ppm and C-8a at 139.6 ppm
assign the former signal at 55.3 ppm to C-7. The C,H-COSY spec-
trum assigns the 7-CH2 hydrogens to the doublets at 3.39 and
3.57 ppm (J = 14.8 Hz). The 5-CH2 hydrogens appear as doublets
at 2.85 and 3.12 ppm (J = 15.9 Hz) and show: (i) C,H-COSY correla-
tion with the carbon at 54.5 ppm due to C-5 and (ii) HMBC with C-
8a at 139.6 ppm and the carbon at 40.6 ppm due to C-4. From C,H-
COSY spectrum, the singlet at 4.42 ppm is readily assigned to H-4.
From the HMBCs, the carbon signals at 73.6, 113.9, 156.7 and
175.8 ppm were assigned to C-3, C-4a, C-2 and the C-5 of the
1,2,4-oxadiazole ring, respectively. The carbon signal at 166.0 can
be readily assigned to C-3 of 1,2,4-oxadiazole ring.
Scheme 1. Synthesis of hybrid compounds 5 and 6.
their precursors 3 and 4 and these results are presented in this
manuscript.
2. Chemistry
In the present paper, the synthesis of compounds 4 in almost
quantitative yields (97–99%, Table 1) was achieved in an eco-com-
patible manner by the reaction of 2,6-bis-arylidenecyclohexanones
2 with malononitrile in the presence of solid sodium ethoxide
employing solvent-free conditions as described earlier for series
3,7 by simply grinding the reaction mixture at ambient tempera-
ture (Scheme 1). Previously Jin et al.16 have reported the synthesis
of 2-aminochromene-3-carbonitriles 4a, 4b, 4c and 4f in 80–93%
yields from the reaction of 2 and malononitrile in water for 8 h
at 110 °C in the presence of hexadecyltrimethyl ammonium bro-
mide as a phase-transfer catalyst. The latter reaction was reported
by Wang et al.17a in the presence of KF/Al2O3 and by Zhou17b under
microwave irradiation in the presence of piperidine in ethanol in
71–92% yield. The present expedient synthetic protocol is clearly
far more advantageous than the foregoing literature methods with
reference to yield, eco-friendliness and cost.
The proton and carbon signals of 6 have also been assigned sim-
ilarly. As a representative example, the 1H and 13C NMR chemical
shifts of 6b are shown in Figure 2. The H-4, NH2 and benzylidene
hydrogens appear as singlets at 4.31, 6.84 and 6.91 ppm, respec-
The compounds of series 3 and 4 were subjected to 1,3-dipolar
cycloaddition reactions with nitrile oxides generated in situ from
Table 2
Yield and antimycobacterial activity of 5 and 6 and their respective precursors 3a and
4 against MTBb
Compd
Ar
Yield (%)
MIC (lM)
Table 1
5/6
3/4
Yields of 2-aminochromene-3-carbonitriles 4
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
C6H5
p-ClC6H4
56
61
59
50
47
45
65
40
50
40
52
51
47
41
55
12.28
0.35
3.28
21.97
11.64
5.50
0.73
0.31
5.26
23.67
24.08
12.63
>25.00
24.08
12.63
0.12
0.36
4.71
7.64
3a
35.21
0.92
16.32
30.12
16.32
15.06
0.99
25.36
0.43
>25
>25
>25
>25
>25
>25
—
Compd
Ar
Yielda (%)
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
—
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
C6H5
p-ClC6H4
p-MeC6H4
p-MeOC6H4
p-FC6H4
99 (93)b (92)c
p-MeC6H4
p-MeOC6H4
o-MeC6H4
o-MeOC6H4
m-FC6H4
o,p-Cl2C6H4
p-Me2NC6H4
p-ClC6H4
p-MeOC6H4
p-FC6H4
o-MeC6H4
o-MeOC6H4
m-FC6H4
98 (87)b (91)c
98 (82)b
99
99
o-ClC6H4
99 (80)b
98
o-MeC6H4
o-MeOC6H4
m-O2NC6H4
m-FC6H4
2-Thienyl
2-Furyl
o,p-Cl2C6H3
p-Me2NC6H4
Ph-CH@CH
1-Naphthyl
98
98 (71)c
97
98
98
99
98
99
99
Rifampicin
Isoniazid
Ciprofloxacin
Ethambutol
—
—
—
—
—
—
a
b
c
Yields are quantitative, except the loss during workup.
From Ref. 18.
From Ref. 19.
MIC values taken from our previous work.7
MTB: Mycobacterium tuberculosis.
a
b

3446
R. Ranjith Kumar et al. / Bioorg. Med. Chem. 19 (2011) 3444–3450
Figure 1. HMBCs, 1H and 13C NMR chemical shifts of 5g.
the determination of MIC in triplicates. The MIC is defined as the
minimum concentration of compound required to inhibit 99% of
bacterial growth, and the MIC values of the synthesized com-
pounds along with the standard drugs for comparison are pre-
sented in Table 2. All compounds belonging to series 4 failed to
show significant antimycobacterial activity (MIC >25.00 lM), in
sharp contrast to series 3, wherein several compounds displayed
good activity,7 suggesting that N-CH3 in 3 is a key structural ele-
ment for antimycobacterial activity. It was also gratifying to note
that many compounds of the hybrid heterocycles 5 and 6, derived
from 3 and 4, respectively, showed enhanced activity against MTB
with MICs ranging from 0.31 to >25.00
and 5f–5i were more potent than the standard drug ethambutol
(MIC: 7.64 M), while four of them 5b, 5c, 5g, and 5h were more
active than ciprofloxacin (MIC: 4.71 M). Compound 5h, with a
MIC value of 0.31 M, was found to be the most potent in the li-
lM. Six compounds, 5b, 5c
Figure 2. 1H and 13C NMR chemical shifts of 6b.
l
l
l
brary, being 1.2, 15.2, and 24.6 times more active than isoniazid,
ciprofloxacin, and ethambutol, respectively. However, all the com-
pounds were less active than rifampicin (MIC: 0.12 lM).
From the structure-MTB activity viewpoint, these results dem-
onstrate that, in general, compounds 5 with three heterocyclic
rings are more active than those belonging to series 6 with one car-
bocyclic ring and two heterocyclic rings (Table 2). A comparison of
the activities of series 5 with their precursors 3 show that the anti-
mycobacterial activity is enhanced when the nitrile group in 3 is
transformed into the 1,2,4-oxadiazole ring. The data in Table 2 fur-
ther show that among the compounds screened, 5b, 5g, and 5h,
respectively, with p-Cl, m-F, and o,p-Cl2 phenyl rings and 3b, 3g
and 3i, respectively, with p-Cl, m-F, and p-Me2N phenyl rings dis-
play maximum potency, showing that the structural dependence
of activity of 3 and 5 display slightly different trends.
4. Conclusions
Figure 3. ORTEP diagram of 6b.
A facile chemoselective synthesis of novel 1,2,4-oxadiazole-pyr-
anopyridine/chromene hybrid heterocycles in moderate yields was
realized via the 1,3-dipolar cycloaddition of nitrile oxide to the ni-
trile function of 2-aminopyranopyridine- and 2-aminochromene-
3-carbonitriles, respectively. These compounds display good
in vitro antimycobacterial activity against MTB, among which
one compound was more potent than the standard first line drugs
isoniazid, ciprofloxacin, and ethambutol. The antimycobacterial
potency of these compounds renders them attractive leads for fur-
ther exploration.
tively. The 6-, 5- and 7-CH2 hydrogens appeared as multiplets at
1.53–1.74, 2.01–2.18 and 2.55–2.78 ppm, respectively, and their
C,H-COSY correlations assign the carbon signals at 22.4, 27.1 and
27.4 ppm to C-6, C-5 and C-7, respectively. The signals at 158.2
and 158.3 arise from the imine carbons of the 1,2,4-oxadiazole
ring. The structure of 6b elucidated from NMR spectroscopic data
was further confirmed by a single crystal X-ray crystallographic
study (Fig. 3).18
3. Pharmacology and structure–activity relationships
5. Experimental
The compounds were screened for their in vitro antimycobacte-
rial activity against MTB H37Rv by the agar dilution method19 for
Melting points were measured in open capillary tubes and are
uncorrected. The 1H, 13C and 2D-NMR spectra were recorded on a

R. Ranjith Kumar et al. / Bioorg. Med. Chem. 19 (2011) 3444–3450
3447
Bruker (Avance) 300 MHz NMR instrument using TMS as internal
5.1.5. 2-Amino-4-(3-fluorophenyl)-8-[(E)-(3-fluorophenyl)-
standard and CDCl3 as solvent. Standard Bruker software was used
throughout. Chemical shifts are given in parts per million (d-scale)
and the coupling constants are given in Hertz. Silica gel-G plates
(Merck) were used for TLC analysis with a mixture of petroleum
ether (60–80 °C) and ethyl acetate as eluent. Elemental analyses
were performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer.
methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4j)
White solid, yield 97%, mp 168–170 °C; [found C, 73.46; H, 4.74;
N, 7.37. C23H18F2N2O requires C, 73.39; H, 4.82; N, 7.44%]; dH
(300 MHz; CDCl3) 1.60–1.68 (2H, m, 6-CH2), 1.88–2.06 (2H, m,
5-CH2), 2.51–2.60 (1H, m, 7-CH2), 2.66–2.74 (1H, m, 7-CH2), 3.96
(1H, s, 4-CH), 4.66 (2H, s, NH2), 6.84 (1H, s, C@CH), 6.93–7.35 (8
H, m, ArH); dC (75 MHz, CDCl3) 22.0, 26.7, 27.3, 42.7, 59.6, 114.7,
119.7, 121.2, 130.2, 139.0, 159.0.
5.1. General procedure for the synthesis of 4H-pyrans 4
A mixture of 2,6-bis-arylidenecyclohexanones (2, 1 mmol), mal-
ononitrile (1 mmol), and sodium ethoxide (1 mmol) was ground
well in a mortar at ambient temperature for about 15–30 s. Then
water (50–70 mL) was added to the mixture and the product was
filtered, washed with water, and dried in vacuo.
5.1.6. 2-Amino-4-(2-thienyl)-8-[(E)-2-thienylmethylidene]-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4k)
White solid, yield 98%, mp 182–183 °C; [found C, 64.69; H, 4.51;
N, 7.88. C19H16N2OS2 requires C, 64.74; H, 4.58; N, 7.95%]; dH
(300 MHz; CDCl3) 1.60–1.68 (2H, m, 6-CH2), 1.92–2.06 (2H, m,
5-CH2), 2.49–2.57 (1H, m, 7-CH2), 2.63–2.70 (1H, m, 7-CH2), 4.17
(1H, s, 4-CH), 5.19 (2H, s, NH2), 6.80–7.20 (6 H, m, ArH), 7.26
(1H, s, C@CH); dC (75 MHz, CDCl3) 21.8, 27.1, 27.2, 38.6, 60.8,
114.9, 116.0, 125.1, 126.2, 126.8, 127.1, 128.5, 140.2, 141.3,
147.6, 158.8.
5.1.1. 2-Amino-4-(4-methoxyphenyl)-8-[(E)-(4-methoxy-phenyl)
methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4d)
White solid, yield 99%, mp 190–191 °C; [found C, 75.05; H, 6.12;
N, 6.92. C25H24N2O3 requires C, 74.98; H, 6.04; N, 7.00%]; dH
(300 MHz; CDCl3) 1.57–1.69 (2H, m, 6-CH2), 1.79–2.03 (2H, m,
5-CH2), 2.52–2.61 (1H, m, 7-CH2), 2.68–2.76 (1H, m, 7-CH2), 3.80
(Ar-OCH3), 3.83 (Ar-OCH3), 3.91 (1H, s, 4-CH), 4.54 (2H, s,
NH2), 6.82 (1H, s, C@CH), 6.85–7.27 (8 H, m, ArH); dC (75 MHz,
CDCl3) 22.2, 27.1, 27.4, 42.7, 55.2, 60.7, 113.6, 114.1, 114.7,
120.1, 122.0, 127.9, 128.9, 129.6, 130.5, 135.1, 141.4, 158.3,
158.7, 158.8.
5.1.7. 2-Amino-4-(2-furyl)-8-[(E)-2-furylmethylidene]-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4l)
White solid, yield 98%, mp 193–195 °C; [found C, 71.29; H, 4.98;
N, 8.80. C19H16N2O3 requires C, 71.24; H, 5.03; N, 8.74%]; dH
(300 MHz; CDCl3) 1.68–1.76 (2H, m, 6-CH2), 2.08–2.11 (2H, m,
5-CH2), 2.63–2.73 (1H, m, 7-CH2), 2.83–2.92 (1H, m, 7-CH2), 4.13
(1H, s, 4-CH), 4.59 (2H, s, NH2), 6.62 (1H, s, C@CH), 6.18–7.42 (6
H, m, ArH); dC (75 MHz, CDCl3) 21.6, 27.0, 27.2, 37.5, 57.2, 110.5,
111.0, 111.3, 119.8, 126.8, 141.8, 142.8, 143.4, 152.9, 154.5, 159.7.
5.1.2. 2-Amino-4-(4-fluorophenyl)-8-[(E)-(4-fluorophenyl)-
methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4e)
White solid, yield 99%, mp 187–188 °C; [found C, 73.32; H, 4.86;
N, 7.50. C23H18F2N2O requires C, 73.39; H, 4.82; N, 7.44%]; dH
(300 MHz; CDCl3) 1.60–1.66 (2H, m, 6-CH2), 1.89–2.05 (2H, m,
5-CH2), 2.51–2.58 (1H, m, 7-CH2), 2.66–2.73 (1H, m, 7-CH2), 3.98
(1H, s, 4-CH), 4.59 (2H, s, NH2), 6.85 (1H, s, C@CH), 7.02–7.30 (8
H, m, ArH); dC (75 MHz, CDCl3) 22.2, 27.0, 27.4, 42.9, 60.4, 114.3,
119.8, 121.7, 132.3, 141.4, 158.9.
5.1.8. 2-Amino-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichloro-
phenyl)methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4m)
White solid, yield 99%, mp 190–191 °C; [found C, 57.70; H, 3.29;
N, 5.95. C23H16Cl4N2O requires C, 57.77; H, 3.37; N, 5.86%]; dH
(300 MHz; CDCl3) 1.67–1.79 (2H, m, 6-CH2), 1.93–2.03 (1H, m,
5-CH2), 2.16–2.25 (1H, m, 5-CH2), 2.52–2.55 (1H, m, 7-CH2),
2.61–2.68 (1H, m, 7-CH2), 4.78 (1H, s, 4-CH), 4.83 (2H, s, NH2),
6.97 (1H, s, C@CH), 7.32–7.55 (6 H, m, ArH); dC (75 MHz, CDCl3)
22.0, 26.9, 27.0, 39.0, 58.5, 115.4, 119.2, 119.4, 126.6, 128.0,
129.3, 131.1, 131.2, 133.3, 133.5, 133.6, 134.1, 134.7, 138.7,
141.5, 159.4.
5.1.3. 2-Amino-4-(2-methylphenyl)-8-[(E)-(2-methylphenyl)-
methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4g)
White solid, yield 98%, mp 155–156 °C; [found C, 81.44; H, 6.50;
N, 7.56. C25H24N2O requires C, 81.49; H, 6.57; N, 7.60%]; dH
(300 MHz; CDCl3) 1.66–1.77 (2H, m, 6-CH2), 1.97–2.14 (2H, m,
5-CH2), 2.47 (3H, s, Ar-CH3), 2.50–2.54 (1H, m, 7-CH2), 2.59 (3H,
s, Ar-CH3), 2.63–2.70 (1H, m, 7-CH2), 4.49 (1H, s, 4-CH), 4.73 (2H,
s, NH2), 7.03 (1H, s, C@CH), 7.28–7.40 (8 H, m, ArH); dC (75 MHz,
CDCl3) 19.4, 20.0, 22.2, 27.0, 27.3, 39.2, 59.6, 115.0, 120.2, 121.4,
125.2, 126.6, 126.9, 128.7, 129.0, 129.4, 129.8, 130.1, 130.5,
135.7, 136.1, 136.6, 140.9, 141.5, 159.0.
5.1.9. 2-Amino-4-[4-(dimethylamino)phenyl]-8-(E)-[4-
(dimethylamino)phenyl]methylid-ene-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4n)
White solid, yield 98%, mp 196–197 °C; [found C, 76.12; H, 7.00;
N, 13.07. C27H30N4O requires C, 76.03; H, 7.09; N, 13.13%]; dH
(300 MHz; CDCl3) 1.60–1.67 (2H, m, 6-CH2), 1.90–2.03 (1H, m,
5-CH2), 2.20–2.27 (1H, m, 5-CH2), 2.59–2.67 (1H, m, 7-CH2),
2.70–2.77 (1H, m, 7-CH2), 2.89 (6 H, s, Ar-N(CH3)2), 2.94 (6 H, s,
Ar-N(CH3)2), 3.90 (1H, s, 4-CH), 4.60 (2H, br s, NH2), 6.69 (1H, s,
C@CH), 6.61–7.00 (8 H, m, ArH); dC (75 MHz, CDCl3) 21.0, 27.1,
27.9, 39.1, 41.0, 40.7, 62.1, 111.0, 112.9, 114.8, 120.9, 121.6,
121.9, 128.7, 130.9, 132.3, 136.3, 144.4, 147.9, 150.9, 157.1.
5.1.4. 2-Amino-4-(2-methoxyphenyl)-8-[(E)-(2-methoxy-
phenyl)methylidene]-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4h)
White solid, yield 98%, mp 93–95 °C; [found C, 74.91; H, 6.00; N,
7.06.
C
25H24N2O3 requires C, 74.98; H, 6.04; N, 7.00%]; dH
5.1.10. 2-Amino-4-[(E)-2-phenylethenyl]-8-[(E,2E)-3-phenyl-2-
propenylidene]-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4o)
White solid, yield 99%, mp 159–161 °C; [found C, 82.69; H, 6.25;
N, 7.05. C27H24N2O requires C, 82.62; H, 6.16; N, 7.14]; dH
(300 MHz; CDCl3) 1.70–1.76 (2H, m, 6-CH2), 2.03–2.10 (1H, m,
5-CH2), 2.22–2.26 (1H, m, 5-CH2), 2.65–2.70 (1H, m, 7-CH2),
2.75–2.80 (1H, m, 7-CH2), 3.58 (1H, d, J = 9.0 Hz, 4-CH), 4.61 (2H,
(300 MHz; CDCl3) 1.70–1.78 (2H, m, 6-CH2), 2.04–2.22 (2H, m,
5-CH2), 2.64–2.68 (1H, m, 7-CH2), 2.69–2.76 (1H, m, 7-CH2), 3.98
(3H, s, Ar-OCH3), 3.99 (3H, s, Ar-OCH3), 4.64 (2H, s, NH2), 4.74
(1H, s, 4-CH), 7.08 (1H, s, C@CH), 7.00–7.40 (8 H, m, ArH); dC
(75 MHz, CDCl3) 22.3, 27.2, 29.1, 34.7, 55.9, 56.2, 59.8, 110.5,
110.9, 115.4, 117.0, 117.3, 118.4, 120.3, 128.1, 125.8, 127.3,
128.1, 129.2, 129.6, 131.3, 141.9, 157.0, 157.1, 159.6.

3448
R. Ranjith Kumar et al. / Bioorg. Med. Chem. 19 (2011) 3444–3450
br s, NH2), 5.80–7.31 (15 H, m, ArH); dC (75 MHz, CDCl3) 21.8, 26.1,
27.1, 40.5, 60.2, 112.5, 120.9, 121.1, 123.6, 124.6, 125.5, 126.9,
127.9, 128.4, 128.6, 128.9, 129.9, 132.9, 136.7, 137.1, 138.4,
141.5, 159.8.
5.2.4. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-
methoxyphenyl)-8-[(E)-(4-methoxyphenyl)methylidene]-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine
(5d)
White solid, yield 50%, mp 190–192 °C; [found: C, 67.46; H,
5.10; N, 9.95. C32H29ClN4O4 requires C, 67.54; H, 5.14; N, 9.85];
dH (300 MHz, CDCl3) 2.31 (3H, s, N-CH3), 2.92 (1H, d, J 15.9 Hz,
5-CH2), 3.21 (1H, d, J 15.9 Hz, 5-CH2), 3.45 (1H, d, J 14.1 Hz,
7-CH2), 3.70 (1H, d, J 14.1 Hz, 7-CH2), 3.76 (3H, s, Ar-OCH3), 3.84
(3H, s, Ar-OCH3), 4.35 (1H, s, 4-CH), 6.53 (2H, br s, NH2), 6.97
(1H, s, C@CH), 6.81–7.97 (12H, m, Ar-H); dC (75 MHz, CDCl3)
39.8, 43.9, 54.0, 54.5, 55.2, 55.3, 113.8, 113.9, 122.9, 124.4, 125.9,
128.5, 128.6, 128.9, 129.0, 130.5, 135.9, 136.7, 139.4, 156.5,
158.6, 158.8, 176.1.
5.1.11. 2-Amino-4-(1-naphthyl)-8-[(E)-1-naphthyl-methylidene]-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4p)
White solid, yield 99%, mp 201–202 °C; [found C, 84.55; H, 5.55;
N, 6.41. C31H24N2O requires C, 84.52; H, 5.49; N, 6.36]; dH
(300 MHz; CDCl3) 1.48–1.59 (2H, m, 6-CH2), 1.79–2.06 (2H, m,
5-CH2), 2.38–2.45 (1H, m, 7-CH2), 2.52–2.60 (1H, m, 7-CH2), 4.63
(2H, s, NH2), 4.90 (1H, br s, 4- CH), 7.39 (1H, s, C@CH), 7.37–8.30
(14 H, m, ArH); dC (75 MHz, CDCl3) 22.3, 27.3, 27.5, 28.8, 60.5,
116.1, 120.0, 122.9, 124.8, 124.9, 125.0, 125.7, 125.9, 126.0,
126.3, 126.5, 127.0, 127.5, 128.1, 128.9, 129.0, 131.0, 131.7,
132.0, 133.1, 133.6, 134.2, 135.4, 138.3, 141.6, 159.3.
5.2.5. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2-
methylphenyl)-8-[(E)-(2-methylphenyl)methylidene]-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine
(5e)
5.2. General procedure for the synthesis of 1,2,4-oxadiazoles 5
and 6
White solid, yield 47%, mp 193–194 °C; [found: C, 71.66; H,
The 4H-pyran (3 or 4, 1 mmol) and N-hydroxyaryl-carboximi-
doyl chloride (1 mmol) were dissolved in benzene (15 mL). A
solution of triethylamine (1 mmol) in benzene (2 mL) was added
drop-wise to the above mixture and refluxed for 5 h. Then the tri-
ethylamine hydrochloride was filtered off, the solvent removed in
vacuo and the residue purified by a column with silica gel using
petroleum ether/ethyl acetate (9:1 v/v) mixture to obtain pure
1,2,4-oxadiazoles 5 and 6.
5.38; N, 10.48. C32H29ClN4O2 requires C, 71.57; H, 5.44; N,
10.43]; dH (300 MHz, CDCl3) 2.24 (3H, s, Ar-CH3), 2.30 (3H, s,
Ar-CH3), 2.38 (3H, s, N-CH3), 2.75 (1H, d, J 15.9 Hz, 5-CH2), 3.11
(1H, d, J 15.9 Hz, 5-CH2), 3.40 (1H, d, J 14.5 Hz, 7-CH2), 3.61 (1H,
d, J 14.5 Hz, 7-CH2), 4.56 (1H, s, 4-CH), 6.60 (2H, br s, NH2), 6.98
(1H, s, C@CH), 7.10–8.00 (12H, m, Ar-H); dC (75 MHz, CDCl3)
20.9, 21.1, 40.1, 43.8, 53.9, 54.8, 73.9, 114.3, 122.6, 126.4, 127.0,
127.2, 127.7, 128.0, 128.8, 129.0, 129.2, 129.3, 130.0, 130.8,
133.0, 136.8, 137.6, 139.8, 141.0, 156.9, 160.0, 166.1, 175.8.
5.2.1 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-6-methyl-4-
phenyl-8-[(E)-phenylmethylidene]-5,6,7,8-tetrahydro-4H-
pyrano[3,2-c]pyridin-2-amine (5a)
White solid, yield 56%, mp 180–182 °C; [found: C, 70.73; H,
4.90; N, 11.07. C30H25ClN4O2 requires C, 70.79; H, 4.95; N, 11.01];
dH (300 MHz, CDCl3) 2.29 (3H, s, N-CH3), 2.85 (1H, d, J 15.9 Hz,
5-CH2), 3.13 (1H, d, J 15.9 Hz, 5-CH2), 3.41 (1H, d, J 14.5 Hz,
7-CH2), 3.61 (1H, d, J 14.8 Hz, 7-CH2), 4.41 (1H, s, 4-CH), 6.53
(2H, br s, NH2), 6.91 (1H, s, C@CH), 7.17–7.93 (14 H, m, Ar-H).
5.2.6. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2-
methoxyphenyl)-8-[(E)-(2-methoxyphenyl)methylidene]-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine
(5f)
White solid, yield 45%, mp 200–201 °C; [found: C, 67.64; H,
5.06; N, 9.74.
C32H29ClN4O4 requires C, 67.54; H, 5.14; N,
9.85]; dH (300 MHz, CDCl3) 2.25 (3H, s, N-CH3), 2.88 (1H, d, J
15.6 Hz, 5-CH2), 3.19–3.31 (2H, m, 5-CH2 and 7-CH2), 3.49 (1H, d,
J
14.1 Hz, 7-CH2), 3.86 (3H, s, Ar-OCH3), 3.93 (3H, s,
5.2.2. 4-(4-Chlorophenyl)-8-[(E)-(4-chlorophenyl)-
Ar-OCH3), 5.00 (1H, s, 4-CH), 6.56 (2H, br s, NH2), 6.89–7.96
(13H, m, Ar-H).
methylidene]-3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-ylamine
(5b)
5.2.7. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(3-
White solid, yield 61%, mp 197–199 °C; [found: C, 62.40; H,
4.08; N, 9.77. C30H23Cl3N4O2 requires C, 62.35; H, 4.01; N, 9.70];
dH (300 MHz, CDCl3) 2.34 (3H, s, N-CH3), 2.93 (1H, d, J 16.2Hz,
5-CH2), 3.25 (1H, d, J 16.2 Hz, 5-CH2), 3.51 (1H, d, J 14.1 Hz,
7-CH2), 3.67 (1H, d, J 14.1 Hz, 7-CH2), 4.39 (1H, s, 4-CH), 6.64
(2H, br s, NH2), 6.97 (1H, s, C@CH), 7.14–8.02 (12H, m, Ar-H); dC
(75 MHz, CDCl3) 40.1, 43.7, 53.6, 54.2, 73.6, 113.5, 122.6, 126.1,
126.7, 127.2, 128.1, 128.6, 128.8, 129.4, 129.7, 130.3, 130.8,
132.8, 133.2, 134.4, 139.5, 142.2, 156.4, 166.7, 175.6.
fluorophenyl)-8-[(E)-(3-fluorophenyl)methylidene]-6-methyl-
5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (5g)
White solid, yield 65%, mp 183–184 °C; [found: C, 66.05; H,
4.17; N, 10.20. C30H23ClF2N4O2 requires C, 66.12; H, 4.25; N,
10.28]; dH (300 MHz, CDCl3) 2.31 (3H, s, N-CH3), 2.85 (1H, d, J
15.9 Hz, 5-CH2), 3.12 (1H, d, J 15.9 Hz, 5-CH2), 3.39 (1H, d, J
14.8 Hz, 7-CH2), 3.57 (1H, d, J 14.8 Hz, 7-CH2), 4.42 (1H, s, 4-CH),
6.56 (2H, br s, NH2), 6.94 (1H, s, C@CH), 6.87–7.97 (12H, m,
Ar-H); dC (75 MHz, CDCl3) 40.6, 44.9, 54.5, 55.3, 73.6, 113.9,
115.0, 115.7, 121.6, 123.7, 124.9, 125.8, 128.1, 128.6, 129.0,
129.8, 130.0, 136.9, 139.6, 146.5, 156.7, 166.0, 175.9.
5.2.3. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-6-methyl-4-
(4-methylphenyl)-8-[(E)-(4-methylphenyl)methylidene]-
5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (5c)
Viscous liquid, yield 59%, [found: C, 71.47; H, 5.48; N, 10.49.
5.2.8. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2,4-
dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)methylidene]-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine
(5h)
White solid, yield 40%, mp 208–209 °C; [found: C, 55.77; H,
3.35; N, 8.60. C30H21Cl5N4O2 requires C, 55.71; H, 3.27; N, 8.66];
dH (300 MHz, CDCl3) 2.28 (3H, s, N-CH3), 2.81 (1H, d, J 12.3 Hz,
5-CH2), 3.18–3.25 (2H, m, 5-CH2 and 7-CH2), 3.37 (1H, d, J
16.2 Hz, 7-CH2), 5.06 (1H, s, 4-CH), 6.62 (2H, br s, NH2), 6.95 (1H,
s, C@CH), 7.08–7.96 (10H, m, Ar-H); dC (75 MHz, CDCl3) 37.5,
44.8, 54.4, 54.7, 73.6, 113.9, 119.0, 125.6, 126.7, 127.9, 128.5,
C32H29ClN4O2 requires C, 71.57; H, 5.44; N, 10.43]; dH (300 MHz,
CDCl3) 2.27 (3H, s, Ar-CH3), 2.28 (3H, s, Ar-CH3), 2.36 (3H, s,
N-CH3), 2.86 (1H, d, J 15.9 Hz, 5-CH2), 3.11 (1H, d, J 15.9 Hz,
5-CH2), 3.40 (1H, d, J 13.5 Hz, 7-CH2), 3.61 (1H, d, J 13.5 Hz,
7-CH2), 4.37 (1H, s, 4-CH), 6.53 (2H, br s, NH2), 6.95 (1H, s, C@CH),
7.07–8.01 (12H, m, Ar-H); dC (75 MHz, CDCl3) 21.0, 21.2, 40.3, 44.3,
54.4, 55.1, 74.4, 114.0, 122.8, 126.0, 127.3, 127.4, 127.9, 128.1,
128.6, 129.0, 129.1, 129.3, 129.8, 130.7, 133.4, 136.6, 137.1,
139.6, 140.9, 156.5, 159.7, 166.7, 176.0.

R. Ranjith Kumar et al. / Bioorg. Med. Chem. 19 (2011) 3444–3450
3449
128.8, 128.9, 129.2, 129.5, 131.0, 132.9, 133.2, 133.7, 133.9, 134.7,
136.8, 139.4, 157.0, 165.9, 175.6.
128.2, 128.3, 128.7, 128.9, 129.3, 129.9, 130.2, 130.6, 130.7,
136.4, 136.8, 140.7, 157.1, 166.7, 176.2.
5.2.9. 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[4-
(dimethylamino)phenyl]-8-(E)-[4-(dimethylamino)phenyl]-
methylidene-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-
c]pyridin-2-amine (5i)
5.2.14. 4-(2-Methoxyphenyl)-8-[(E)-(2-methoxyphenyl)-
methylidene]-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-chromen-2-ylamine (6e)
Viscous liquid, yield 41%, [found: C, 74.04; H, 5.52; N, 8.17.
Dark brown solid, yield 50%, mp 179–180 °C; [found: C, 68.69;
H, 5.84; N, 14.20. C34H35ClN6O2 requires C, 68.62; H, 5.93; N,
14.12]; dH (300 MHz, CDCl3) 2.31 (3H, s, N-CH3), 2.88 (6H, s, Ar-
N-(CH3)2), 2.95–3.00 (7H, m, Ar-N-(CH3)2 and 5-CH2), 3.18 (1H, d,
J 15.3 Hz, 5-CH2), 3.24 (1H, d, J 13.8 Hz, 7-CH2), 3.50 (1H, d, J
13.8 Hz, 7-CH2), 4.28 (1H, s, 4-CH), 6.50 (2H, br s, NH2), 6.92 (1H,
s, C@CH), 6.63–7.96 (12H, m, Ar-H); dC (75 MHz, CDCl3) 39.6,
40.2, 40.5, 44.1, 54.4, 54.8, 74.6, 111.8, 112.5, 122.8, 124.2, 126.0,
128.5, 128.6, 128.8, 130.4, 131.9, 136.5, 139.5, 149.4, 149.5,
156.6, 165.7, 176.3.
C32H29N3O4 requires C, 73.97; H, 5.63; N, 8.09]; dH (300 MHz,
CDCl3) 1.59–1.72 (2H, m, 6-CH2), 2.02–2.18 (2H, m, 5-CH2), 2.46–
2.57 (1H, m, 7-CH2), 2.69–2.79 (1H, m, 7-CH2), 3.89 (Ar-OCH3),
3.94 (Ar-OCH3), 5.01 (1H, s, 4-CH), 6.55 (2H, s, NH2), 7.02 (1H, s,
C@CH), 6.86–8.04 (13H, m, Ar-H); dC (75 MHz, CDCl3) 22.5, 26.9,
27.4, 34.5, 55.4, 56.1, 73.6, 110.2, 111.0, 116.9, 117.8, 119.9,
120.9, 126.1, 127.3, 127.6, 128.1, 128.6, 128.9, 129.4, 130.2,
130.3, 130.6, 133.5, 140.9, 157.2, 157.3, 157.6, 166.6, 176.2.
5.2.15. 4-(3-Fluorophenyl)-8-[(E)-(3-fluorophenyl)-
methylidene]-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-chromen-2-ylamine (6f)
5.2.10. 4-(4-Chlorophenyl)-8-[(E)-(4-chlorophenyl)-
methylidene]-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-chromen-2-ylamine (6a)
White solid, yield 55%, mp 166–168 °C; [found: C, 72.64; H,
4.60; N, 8.56. C30H23F2N3O2 requires C, 72.72; H, 4.68; N, 8.48];
dH (300 MHz, CDCl3) 1.61–1.73 (2H, m, 6-CH2), 2.02–2.22 (2H, m,
5-CH2), 2.54–2.63 (1H, m, 7-CH2), 2.68–2.77 (1H, m, 7-CH2), 4.39
(1H, s, 4-CH), 6.53 (2H, s, NH2), 6.93 (1H, s, C@CH), 6.85–8.04
(13H, m, Ar-H); dC (75 MHz, CDCl3) 22.3, 27.0, 27.5, 42.7, 73.9,
113.6, 114.1, 115.0, 116.0, 117.7, 121.4, 123.9, 125.0, 127.3,
128.7, 129.5, 129.8, 130.7, 129.3, 141.1, 147.1, 156.7, 164.7,
166.8, 175.8.
Viscous liquid, yield 40%, [found: C, 68.11; H, 4.30; N, 7.85.
C30H23Cl2N3O2 requires C, 68.19; H, 4.39; N, 7.95]; dH (300 MHz,
CDCl3) 1.58–1.75 (2H, m, 6-CH2), 1.98–2.26 (2H, m, 5-CH2),
2.55–2.59 (1H, m, 7-CH2), 2.66–2.71 (1H, m, 7-CH2), 4.35 (1H, s,
4-CH), 6.54 (2H, s, NH2), 6.91 (1H, s, C@CH), 7.23–8.04 (13H, m,
Ar-H); dC (75 MHz, CDCl3) 22.3, 27.0, 27.5, 42.3, 73.9, 117.5,
121.2, 127.3, 128.4, 128.6, 128.7, 128.9, 129.5, 130.2, 130.5,
130.8, 132.5, 132.6, 135.6, 141.2, 143.1, 156.7, 166.8, 175.8.
Acknowledgments
5.2.11. 4-(4-Methoxyphenyl)-8-[(E)-(4-methoxyphenyl)-
methylidene]-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-chromen-2-ylamine (6b)
S.P. and J.C.M. thank MICINN, Spain and the Department of Sci-
ence and Technology, New Delhi, for funding for an Indo-Spanish
collaborative major research project (Grants DST/INT/SPAIN/09
and ACI2009-0956). S.P. and J.C.M. also gratefully acknowledge
DST for funds under IRHPA program for the purchase of a high res-
olution NMR spectrometer and MICINN for grant CTQ2009-12320-
BQU, respectively. R.R.K. thanks DST, New Delhi for funds under
Fast Track Scheme (NO.SR/FT/CS-073/2009).
White solid, yield 52%, mp 145–147 °C; [found: C, 73.86; H,
5.71; N, 8.01. C32H29N3O4 requires C, 73.97; H, 5.63; N, 8.09]; dH
(300 MHz, CDCl3) 1.53–1.74 (2H, m, 6-CH2), 2.01–2.18 (2H, m,
5-CH2), 2.55–2.64 (1H, m, 7-CH2), 2.69–2.78 (1H, m, 7-CH2), 3.76
(Ar-OCH3), 3.84 (Ar-OCH3), 4.31 (1H, s, 4-CH), 6.48 (2H, s, NH2),
6.91 (1H, s, C@CH), 6.80–8.04 (13H, m, Ar-H); dC (75 MHz, CDCl3)
22.4, 27.1, 27.4, 41.8, 55.1, 55.2, 74.6, 113.5, 113.7, 117.1, 121.4,
127.2, 127.5, 128.3, 128.5, 129.1, 129.8, 130.5, 130.6, 136.8,
141.1, 156.6, 158.2, 158.3, 166.6.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.04.033.
5.2.12. 4-(4-Fluorophenyl)-8-[(E)-(4-fluorophenyl)-
methylidene]-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-chromen-2-ylamine (6c)
References and notes
White solid, yield 51%, mp 96–98 °C; [found: C, 72.80; H, 4.76;
N, 8.39. C30H23F2N3O2 requires C, 72.72; H, 4.68; N, 8.48]; dH
(300 MHz, CDCl3) 1.58–1.72 (2H, m, 6-CH2), 1.99–2.20 (2H, m,
5-CH2), 2.52–2.60 (1H, m, 7-CH2), 2.65–2.72 (1H, m, 7-CH2), 4.36
(1H, s, 4-CH), 6.51 (2H, s, NH2), 6.92 (1H, s, C@CH), 6.94–8.04
(13H, m, Ar-H); dC (75 MHz, CDCl3) 22.4, 27.0, 27.5, 42.1, 74.3,
115.1, 115.3, 117.5, 121.2, 127.3, 127.4, 128.7, 129.6, 129.7,
130.8, 130.9, 133.1, 133.2, 140.3, 141.1, 156.7, 166.8, 176.0.
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