Synthesis and in vitro antimalarial activity of tetraoxane-amine/amide conjugates

Article abstract of DOI:10.1016/j.ejmech.2011.04.002

A series of tetraoxanes, tetraoxane-amine and tetraoxane-amide conjugates have been synthesized and screened for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Most of the conjugate

Full text of DOI:10.1016/j.ejmech.2011.04.002

European Journal of Medicinal Chemistry 46 (2011) 2816e2827
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro antimalarial activity of tetraoxane-amine/amide conjugates
,
,
Nitin Kumar a, Shabana I. Khan b c, Himanshu Atheaya a, Ritu Mamgain a, Diwan S. Rawat a
*
a Department of Chemistry, University of Delhi, Delhi 110007, India
b National Centre for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA
c Department of Pharmacognosy, School of Pharmacy, University of Mississippi, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of tetraoxanes, tetraoxane-amine and tetraoxane-amide conjugates have been synthesized and
screened for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant strains
of Plasmodium falciparum. Most of the conjugates showed slightly better antimalarial activity than the
parent tetraoxanes. Three of the conjugate compounds were potentially active with IC50 values in the
Received 15 November 2010
Received in revised form
1 April 2011
Accepted 1 April 2011
Available online 15 April 2011
range of 0.38e0.80
cancer (SK-MEL, KB, BT-549, SK-OV-3) and two non-cancer (Vero and LLC-PK11) cell lines up to
a concentration of 25 M and none of the compounds was found toxic to any of the cells.
Ó 2011 Elsevier Masson SAS. All rights reserved.
mM. Cytotoxicity of four selected compounds was also evaluated in a panel of four
m
Keywords:
Plasmodium falciparum
Artemisinin
Tetraoxane
Amine conjugates
1. Introduction
to interact with heme or ferrous ions in the acidic food vacuole of
the parasite which results in the generation of radical species
[13e16]. In order to improve antimalarial activity of peroxide based
antimalarials, several possibilities were explored and in one of the
approach polar groups that can undergo protonation in the acidic
food vacuole of the parasite were attached covalently to the
endoperoxides [16e20]. It was hypothesized that this kind of
chemical modification would enhance the cellular accumulation of
the drug within the acidic food vacuole of the parasite by ion
trapping and hence improve the antimalarial activity [21]. In
continuation of our work on the development of novel antimalar-
ials [22e26], we herein report the synthesis and antimalarial
activity evaluation of tetraoxane and tetraoxane-imine, tetraoxane-
amine or amide conjugates.
Malaria is the third most deadly disease after tuberculosis and
AIDS. It affects more than 225 million people with 781,000 deaths
every year [1,2]. Amongst the four species of Plasmodium causing
malaria in humans, Plasmodium falciparum is the most fatal and
responsible for most of the malaria related deaths [3,4]. The
problem has been complicated since P. falciparum has developed
resistance against commonly used antimalarials and no new drug
has been launched in last 30 years. Artemisinin and its semi-
synthetic derivatives such as dihydroartemisinin, artemether,
artether and artesunate are the only alternatives for the treatment
of P. falciparum related infections [5e7]. However, clinical applica-
tions of these compounds have been limited due to their poor
bioavailability, poor pharmacokinetic properties, and high cost [8].
Recent report of emergence of P. falciparum resistance to artemi-
sinin further complicates the problem [9]. So there is an urgent
need for the development of new drugs which can solve the
problem of drug resistance and have higher efficacy for the treat-
ment of malaria especially in the developing countries. In recent
years, another class of cyclic peroxides namely 1,2,4,5-tetraoxanes
has received considerable interest due to their artemisinin like
antimalarial activity [10e12]. Some of these compounds have
shown very promising activity and entered in the clinical trials [12].
These compounds exhibit antimalarial activity due to their ability
2. Chemistry
In order to incorporate polar functional groups in the tetraoxane
pharmacophore, we explored the possibility of introducing a free
CHO group in tetraoxanes, so that a library of compounds can
be generated by chemical modification of CHO functionality.
Keeping this in mind, we decided to synthesize tetraoxanes which
have a free CHO group. Literature survey revealed that there are
very few methods available for the synthesis of tetraoxanes. Among
these, the acid-catalyzed cyclocondensation of hydrogen peroxides
(30%, 50% and 70e90%) with ketones and aldehydes [27e30],
ozonolysis of olefins [31], enol-ethers [32], O-ether oxime [33],
and trimethyl silyltrifluoromethanesulphonate (TMSOTf) [34,35]
* Corresponding author. Tel.: þ91 11 27667465; fax: þ91 11 27667501.
E-mail address: dsrawat@chemistry.du.ac.in (D.S. Rawat).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.04.002

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2817
O O
O O
CHO
R1
3a-f
O
O
O
O
O
H
a
CHO
CHO
R1
R1
R1
1
2
4a-f
a, R1 = H; b, R1 = p-Me; c, R1 = m-Me; d,
R1 = o-Me; e, R1 = Et; f, R1 = i-Pr
O O
OHC
CHO
O O
5a-f
Scheme 1. Reagents and conditions: a) (i) MTO (0.001 equiv), TFE, H2O2 (2.0 equiv), 2 h, RT; (ii) 2 (2.0 equiv), HBF4$Et2O (1.0 equiv), 1 h, RT, 1 h, 32e45%.
catalyzed cyclocondensation of bis (trimethylsilyl) peroxides
with carbonyl compounds are the most common methods.
The non-symmetrical tetraoxanes have been synthesized by
cyclocondensation of the carbonyl compounds with steroids gem-
hydroperoxides (H2SO4, catalyst) [36], gem-bis(trimethylsillyldioxy)
alkanes (TMSOTf catalyst [37]), alicyclic and aliphatic gem-
hydroperoxide (MeReO3eHBF4 catalyst) [38] and cyclocondenstion
of carbonyl compounds in the presence of I2 as a catalyst [22].
Recently Dussault et al. have also reported Re2O7 calatyzed
synthesis of tetraoxanes [39].
mesylate derivatives (9a, 9b). The nucleophilic substitution of
mesylates (9a, 9b) with substituted amines leads the desired
products (10aew) in quantitative yield.
Next, we explored the possibility of conversion of tetraoxanes to
their amide counterparts. Jones oxidation of compounds 3b and 3e
afforded the acid derivatives (11a, 11b) in good yield (Scheme 4).
The resulting acids were coupled with selected amines via a mixed
anhydride method to give corresponding amides in good yield
(Scheme 4).
Over all 74 tetraoxanes, tetraoxane-amine and tetraoxane-
amide conjugates have been synthesized by literature methods
and synthetic route is shown in Schemes 1e4. The starting tet-
raoxanes (3aef) were prepared by the acid-catalyzed peroxidation
of substituted benzaldehydes by 30% H2O2 in fluorinated alcohol in
the presence of MTO as a catalyst (Scheme 1). During the prepa-
ration of compounds 3aef, we noticed the formation of symmet-
rical tetraoxanes 4aef and 5aef. Compounds 3aef was isolated in
32e45% yield and compounds 4aef in 27e32% yield. Formation of
compounds 5aef was noticed in LCeMS and all the efforts to isolate
compounds 5aef were unsuccessful. The formation of symmetrical
tetraoxanes during the preparation of non-symmetrical tetraox-
anes has been reported earlier in low yield [25]. High yield of the
symmetrical tetraoxanes (4aef) may be due to the low reactivity of
terephthalaldehyde under the given reaction conditions. Variations
in the reaction conditions did not improve the yield of desired
tetraoxanes (3aef). The non-symmetrical tetraoxane (3b) was
converted to corresponding imines as shown in Scheme 2 and
amine counterpart of compound 3b was prepared in moderate
yield by the reductive amination as shown in Scheme 2 [40]. In both
the cases yield of the desired product was moderate. So we decided
to explore an alternative route for the synthesis of tetraoxane-
amine conjugates and the synthesis is depicted in Scheme 3. Tet-
raoxanes (3aef) which have a free CHO group were reduced to
corresponding alcohols (8aef) using NaBH4 as a reducing agent and
subsequently compounds 8b and 8e were converted to the
3. Results and discussion
3.1. Biological evaluations
All the synthesized compounds were screened for antimalarial
activity against D6 (chloroquine-sensitive) and W2 (chloroquine-
resistant) strains of P. falciparum and for cytotoxicity towards
mammalian kidney cells (Vero cells) up to a highest concentration of
12.5 mM in an in vitro assay as described earlier [22,25]. Chloroquine
and artemisinin were used as standard drugs for antimalarial activity
and doxorubicin was used as standard drug for cytotoxicity. The
in vitro antimalarial activity was determined on the basis of plas-
modial LDH activity as an index of plasmodial growth [41] and
expressed as IC50 values. Selectivity index (S.I.) of antimalarial activity
was calculated based on the cytotoxicity to mammalian cells
(S.I. ¼ ratio of IC50 of cytotoxicity and IC50 of antimalarial activity).
Antimalarial activity of all the tetraoxanes (3aef, 8aef, 9a, 9b, 11a
and 11b), tetraoxane-imines (6ael), amine and amide conjugates
(6ael, 7aef, 10aew, 12aeq) is shown in Tables 1 and 2. Compounds
3aef, 11a and 11b which contain electron withdrawing groups such
as CHO and COOH at the para position of the phenyl ring of the tet-
raoxanewere devoid of anyactivity with the exception of compounds
3a, 3e, 3f and 11a, which showed poor activity. This is in good
agreement with our earlier observation that electron withdrawing
CF3 leads to devoid of antimalarial activity [25]. Interestingly, alcohol
counterparts (8aef) of compounds 3aef exhibited good antimalarial
O
O
O
O
R1
CHO
3b
a
b
O
O
O
O
O
O
O
O
R1
R1
HN R2
N
R2
6a-l
7a-f
Scheme 2. Reagents and conditions: a) R2NH2 (1.0 equiv), THF, RT, 18 h, 25e55%; b) R2NH2 (1.0 equiv), NaBH(OAc)3 (1.5 equiv), THF, RT, 12 h, 20e52%.

2818
N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
O O
O O
a
R1
CHO
R1
CH2OH
O O
3a-f
O O
8a-f
b
O O
O O
c
R1
CH2NH R2
R1
CH2OMs
O O
O O
9a, R1 = CH3
9b, R1 = C2H5
10a-w
Scheme 3. Reagents and conditions: a) NaBH4 (4.0 equiv), THF, RT, 4 h, 48e75%; b) MsCl (1.0 equiv), Et3N (3.0 equiv), THF, 6 h, RT, 86e93%; c) R2NH2 (1.0 equiv), THF, RT, 18 h,
20e62%.
activity against both the strains of P. falciparum (Table 1) with IC50
values ranging from 1.28 to 3.09 M against D6 clone and 1.09 to
2.42 M against W2 clone. But activity dropped when alcohols were
was the least, while in the amine derivative of the same compound
(10a, R2 ¼ Ph) was the most active compound. The activity profile in
case of imine was in the order of R2 ¼ CH2CH2Ph > CH2Ph > Ph, while
in the case of amine derivatives the activity order was reversed
(R2 ¼ CH2CH2Ph < CH2Ph < Ph). The imine of tetraoxane-
aminoquinoline conjugate (6k) was more active than its reduced
counterpart (7f). Two other compounds (6h, 7d) were found to be
very active against both the strains of P. falciparum. Among the
tetraoxane-amine conjugates, compounds having fluoro or chloro
group (10kep) with phenyl ring attached with nitrogen have shown
good activity compared to bromo derivative (10r). All the compounds
in which OH, OMe, and NH2 groups are at the para position of the
phenyl ring were less active (10sew). Other compounds in which
methyl, ethyl and iso-propyl groups are at the para position of the
phenyl ring showed varied activity pattern (10hej). Among the
amide series, the tetraoxane-aminoquinolines (12kem) showed
better antimalarial activity than other compounds of the series.
Interestingly amide counterpart (12a) was found to be totally inac-
tive, which could be due to less basicity of the amide.
m
m
converted to mesylates (9a, 9b). The amine analogues (10aew)
of compound 8a exhibits almost similar kind of antimalarial activity
pattern against both D6 and W2 strains of P. falciparum except
compounds 10b, 10d, 10f, and 10o which were found to be totally
inactive. Further derivatization of these alcohols is under progress
and results will be published in due course of time. When compound
3b was reacted with substituted amines, the resulting imines
(6ael) gained antimalarial activity against both the strains of
P. falciparum. Compound 6a (R2 ¼ cyclohexyl) showed better activity
[IC50 ¼ 1.90
IC50 ¼ 7.74
m
M
(D6), 1.85
m
M
(W2)] than 6b [R2 ¼ phenyl,
mM (D6), 5.53 mM (W2)]. There is a clear trend of improved
activity in series of compounds 6bed when R2 is Ph, CH2Ph,
CH2CH2Ph with IC50 values ranging between 7.74 M (D6), 5.53
(W2); 4.80 M (D6), 6.40 M (W2) and 1.54 M (D6), 1.49 M (W2)
respectively. The phenyl group with chloro at para position (6e)
showed better antimalarial activity with IC50 values 1.46 M against
both D6 and W2 clones than its bromo counterpart (6f) with IC50
values 7.95 M against D6 and 4.09 M against W2 clone. Two
compounds, 6h and 6k, were found to be the most active against both
strains of P. falciparum with IC50 ranging from 0.47 to 0.75 M (D6)
and 0.57 to 0.80 M (W2). The amine counterpart (7d, 7f) of
compounds 6h, and 6k showed IC50 values 0.38e2.64 M (D6) and
0.57e1.62 M (W2) clones respectively. In order to understand the
m
mM
m
m
m
m
m
Cytotoxicity of three potentially active compounds 6h, 6k, and
7d along with compound 7f (reduced counterpart of compound 6k)
was also evaluated in a panel of four cancer (SK-MEL, KB, BT-549,
SK-OV-3) and two non-cancer (Vero and LLC-PK11) cell lines up to
a concentration of 25 mM and none of the compounds was found
toxic to any of the cell lines (data not included).
m
m
m
m
m
m
role of basicity in the observed antimalarial activity of these
compounds (6h, 6k, 7d and 7f) we calculated pKa values of
compounds 6h, 6k, 7d and 7f and found no direct correlation of
observed antimalarial activity with their basicity. Moving from
imines (6bed) to tetraoxane-amine conjugates (10a, 7a, 7b) trend of
antimalarial activity was reversed. In case of imine compound 6d
(R2 ¼ CH2CH2Ph) was the most active compound while compound 6b
4. Conclusion
We have successfully synthesized new series of substituted
tetraoxanes using substituted benzaldehydes as a starting material
and these compounds have been converted to imines, amines and
amide derivatives. Electron withdrawing groups at para position of
the phenyl ring have negative effect on the antimalarial activity.
O
O
O
O
O
O
O
O
a
R1
CHO
R1
COOH
3b, R1 = p-CH3
3e, R1 = p-CH2CH3
11a, R1 = p-CH3
11b, R1 = p-CH2CH3
b
O
O
O
O
R1
CONH R2
12a-q
Scheme 4. Reagents and conditions: a) CrO3/H2SO4/H2O (1 g/1 mL/10 mL), acetone, RT, 4 h, 67e82%; b) Et3N (3.0 equiv), ClCO2Et (1.0 equiv), R2NH2 (2.0 equiv), THF, RT, 2 h, 38e73%.

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2819
Table 1
In vitro antimalarial activity and cytotoxicity of tetraoxane-imine derivatives and tetraoxane-amine conjugates.
Entries
R1
R2
P. falciparum (D6) IC50
(
m
M)
S.I
P. falciparum (W2) IC50
(m
M)
S.I
Cytotoxicity (vero cells)
3a
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
9a
9b
H
13.22
NA
NA
>1.3
>17.48
NA
NA
>1.0
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
e
p-CH3
m-CH3
o-CH3
p-Et
NA
NA
10.9
6.99
1.90
7.74
4.80
1.54
1.46
7.95
6.86
0.75
2.82
4.76
0.47
2.59
3.44
7.67
2.19
0.38
6.64
2.64
3.09
1.83
1.28
2.15
1.58
2.02
7.64
4.99
1.84
NA
>1.4
>2.2
>6.8
>1.7
>2.6
>7.9
>8.2
>1.4
>1.8
>17.6
>5.1
>2.4
>20.7
>9.0
>3.7
>1.6
>5.5
>34.0
>1.7
>3.7
>5.6
>9.0
>12.9
>7.7
9.9
5.99
3.11
1.85
5.53
6.4
>2.6
>4.9
>7.0
>2.4
>2.0
>8.2
>8.2
>2.6
>2.4
>16.4
>6.1
>2.2
>17.0
>9.0
>3.7
>1.9
>7.6
>22.7
>2.4
>6.0
>9.5
>6.8
>11.9
>8.7
14.4
p-iso-Pr
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
H
C6H11
C6H5
CH2C6H5
CH2CH2C6H5
4-ClC6H4
4-BrC6H4
2-SHC6H4
3-Pyridine
CH2CH2OH
Adamantane
CH2CH2NHCQ
NH2
1.49
1.46
4.09
5.08
0.80
2.37
5.24
0.57
1.26
3.44
6.39
1.59
0.57
4.74
1.62
1.82
2.42
1.38
1.90
1.09
1.89
8.18
3.94
1.59
NA
CH2C6H5
CH2CH2C6H5
2-SHC6H4
3-Pyridine
Adamantane
CH2CH2NHCQ
p-CH3
m-CH3
o-CH3
p-Et
p-iso-Pr
p-CH3
p-Et
>7.4
>1.7
>2.5
>7.1
>7.9
>1.6
>3.2
>8.2
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
Chloroquine
Artemisinin
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
p-CH3
C6H5
C10H7
NCH3C6H4
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
2,6-CH3C6H3
4-EtC6H4
4-iso-Pr-C6H4
4-n-Pr-C6H4
4-FC6H4
3-FC6H4
2-FC6H4
4-ClC6H4
3-ClC6H4
1.51
NA
2.64
NA
>8.4
>4.8
2.11
NA
2.38
NA
>6.0
>5.3
1.48
3.32
2.39
5.67
2.09
2.46
1.88
1.79
NA
2.51
8.57
7.69
8.13
6.37
6.32
3.42
5.28
0.042
0.03
>8.2
>3.7
>4.9
>2.3
>6.0
>5.1
>6.6
>6.8
1.45
2.35
3.20
4.19
2.35
1.83
1.83
1.70
NA
2.76
6.42
4.97
10.16
9.20
7.11
3.95
7.39
0.42
0.025
>8.4
>5.2
>3.7
>2.8
>5.3
>6.8
>6.8
>7.0
2-ClC6H4
>4.8
>1.2
>1.4
>1.5
>1.8
>1.8
>3.7
>2.4
>300
>500
>4.3
>1.6
>2.2
>1.2
>1.2
>1.8
>3.2
>1.7
>30
2,4,5-ClC6H2
4-BrC6H4
4-OCH3C6H4
3,5-OCH3C6H3
4-OHC6H4
3-OHC6H4
4-NH2C6H4
>670
e
Introduction of imine, amine, and amide functionalities in these
inactive tetraoxanes leads to slightly better antimalarial activity of
the resulting compounds. Some of the compounds have shown
low micro molar in vitro antimalarial activity without showing any
cytotoxicity. This study shows that basicity is not the main factor
for the observed antimalarial activity of these compounds. This
opens up the possibility of developing these new compounds (6h,
6k, 7d and 7f) as potent, water soluble tetraoxane derivatives for
malaria treatment. Further derivatization of the most active
analogues is under progress and results will be published in due
course.
5. Experimental section
All of the chemicals used in the syntheses were purchased from
SigmaeAldrich and were used as such. Thin layer chromatography
was used to monitor the progress of the reaction. The compounds
were purified by silica gel column. Melting points were determined
on a melting point apparatus and are uncorrected. IR (KBr, film)
spectra were recorded using PerkineElmer FT-IR spectrophotom-
eter and the values are expressed as nmax cmꢀ1. Mass spectral data
were recorded in waters micro mass LCT Mass Spectrometer/Data
system. The 1H NMR spectra were recorded on Bruker 320

2820
N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
Table 2
In vitro antimalarial activity and cytotoxicity of the tetraoxane-amide conjugates.
Entries
R1
R2
P. falciparum (D6) IC50
(
m
M)
S.I
P. falciparum (W2) IC50
(
mM)
S.I
Cytotoxicity (vero cells)
11a
11b
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
C2H5
C2H5
CH3
CH3
C2H5
CH3
CH3
CH3
CH3
10.58
NA
NA
6.67
NA
4.82
NA
3.36
8.73
NA
6.73
NA
1.10
1.19
1.08
2.71
4.03
4.43
5.13
0.042
0.03
>1.5
9.26
NA
NA
7.51
NA
4.82
NA
4.81
13.86
NA
6.99
NA
>1.7
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
CH2CH2OH
CH2CH2OH
CH2(CH2)2OH
CH2(CH2)2OH
CH2(CH2)5OH
CH2(CH2)5OH
(CH2)2CH3
(CH2)3CH3
(CH2)3CH3
(CH2)4CH3
(CH2)2NHCQ
(CH2)3NHCQ
(CH2)3NHCQ
(CH2)2Ph
Ph piperazine
Cyclohexyl
(CH2)7NH2
>2.0
>2.6
>1.8
>2.6
>3.4
>3.4
>2.4
>1.0
>1.9
>1.8
>8.5
>7.7
>8.2
>4.3
>2.6
>2.8
>2.2
>300
>500
1.5
>6.3
>4.3
>3.7
>5.6
>1.5
>4.3
>2.4
>30
2.11
2.43
2.09
7.16
2.86
4.66
0.42
0.025
12p
12q
Chloroquine
Artemisinin
>670
Spectrospin spectrometer at 300 MHz and Jeol ECX spectospin at
400 MHz and 13C NMR spectra recorded at 75.5 MHz and 100 MHz
respectively, using TMS as an internal standard. The chemical shift
5.3. 4-(6-m-Tolyl[1,2,4,5]tetroxan-3-yl)benzaldehyde (3c)
Yield: 36%; mp 185 ꢂC; IR(KBr, cmꢀ1): 2922, 2850, 1708, 1610,
1354, 1203, 1018, 1007, 834, 786, 698; 1H NMR (300 MHz, CDCl3):
values are recorded on the d scale and the coupling constants (J) are
in hertz. Elemental analyses were performed on a Carlo Erba Model
EA-1108 elemental analyzer and the data of C, H and N are within
ꢁ0.4% of calculated values.
d (ppm) 2.39 (s, 3H), 6.90 (s, 1H), 6.99 (s, 1H), 7.26e7.32 (m, 3H),
7.59 (s, 1H), 7.69 (m, 2H), 7.96 (m, 2H), 10.07 (s, 1H); ESI-HRMS
calcd. for C16H14O5 286.0841; found: 287.0842 (Mþ þ H).
5.4. 4-(6-o-Tolyl[1,2,4,5]tetroxan-3-yl)benzaldehyde (3d)
5.1. 4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzaldehyde (3b)
Yield: 41%; mp 155 ꢂC; IR (KBr, cmꢀ1): 2922, 2852, 1704, 1462,
A mixture of 4-methyl-benzaldehyde (5 g, 41.66 mmol), 30%
H2O2 (9.43 mL, 83.33 mmol), and MTO (10 mg, 0.042 mmol) in
50 mL of 2,2,2-trifluoroethanol (TFE) was stirred for 2 h at room
temperature and terephthalaldehyde (2) (11.15 g, 83.33 mmol) was
added to the reaction mixture, followed by the addition of 54%
ethereal solution of HBF4 (5.68 mL, 41.66 mmol). The reaction
mixture was stirred for an additional hour at room temperature.
After the completion of reaction as evident by thin layer chroma-
tography (TLC), chloroform was added to the reaction mixture and
organic layer was washed with saturated NaHSO3 solution followed
by saturated solution of NaCl. Chloroform layer was then dried over
Na2SO4 and solvent was evaporated under reduced pressure. The
crude product was then purified over SiO2 column chromatography
using CHCl3/hexane as an eluent to yield 3b (4.76 g, 40%) as a white
solid; mp 195 ꢂC; IR (film, cmꢀ1): 2924, 2845,1707,1610,1358,1202,
1360, 1205,1000, 913, 830, 753; 1H NMR (300 MHz, CDCl3):
d (ppm)
2.54 (s, 3H), 6.97 (s, 1H), 7.01 (s, 1H), 7.12 (s, 1H), 7.36e7.48 (m, 2H),
7.76e7.77 (m, 3H), 7.96e8.06 (m, 2H), 10.07 (s, 1H); ESI-HRMS
calcd. for C16H14O5 286.0841; found: 287.0842 (Mþ þ H).
5.5. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]benzaldehyde (3e)
Yield: 45%; mp 199 ꢂC; IR (KBr, cmꢀ1): 2866, 1692, 1498, 1385,
1368, 1301, 1199, 1014, 910, 815, 772; 1H NMR (300 MHz, CDCl3):
d
(ppm) 1.57 (t, 3H, J ¼ 5.3 Hz), 2.65e2.72 (q, 2H), 6.91 (s, 1H), 6.94
(s, 1H), 7.26e7.29 (m, 2H), 7.42 (d, 2H, J ¼ 9.0 Hz), 7.68 (m, 2H),
7.94e7.96 (d, 2H, J ¼ 6.5 Hz), 9.98 (s, 1H); ESI-MS: 301.1 (Mþ þ H).
Anal. calcd. for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.43; H, 5.30.
5.6. 4-[6-(4-Isopropyl-phenyl)[1,2,4,5]tetroxan-3-yl]benzaldehyde
(3f)
1018, 1007, 911, 835, 797; 1H NMR (300 MHz, CDCl3):
d (ppm) 2.39
(s, 3H), 6.90 (s, 1H), 6.98 (s, 1H), 7.25 (d, 2H, J ¼ 7.8 Hz), 7.40 (d, 2H,
J ¼ 7.8 Hz), 7.69 (d, 2H, J ¼ 7.8 Hz), 7.95 (d, 2H, J ¼ 8.1 Hz), 10.06 (s,
1H); 13C NMR (75.5 MHz, CDCl3): 21.52, 107.09, 108.53, 127.06,
127.80,129.53, 129.90, 136.40, 138.13, 141.94,191.47; ESI-MS: 287.30
(Mþ þ H). Anal. calcd. for C16H14O5: C, 67.13; H, 4.93. Found:
C, 66.33;H, 4.90.
Yield: 40%; mp 170 ꢂC; IR (KBr, cmꢀ1): 2963, 1706, 1639, 1423,
1364, 1298, 1066, 1017, 911, 841, 806; 1H NMR (300 MHz, CDCl3):
d
(ppm) 1.24e1.26 (d, 6H, J ¼ 6.2 Hz), 2.89e2.96 (m,1H), 6.91 (s,1H),
6.99 (s, 1H), 7.25e7.31 (m, 2H), 7.42e7.45 (m, 2H), 7.68e7.70 (m,
2H), 7.94e7.96 (m, 2H), 10.06 (s, 1H); 13C NMR (75.5 MHz, CDCl3):
23.76, 34.18, 107.11, 108.55, 126.99, 127.91, 128.00, 128.40, 129.91,
136.46, 138.16, 152.76, 191.46; ESI-MS: 315.1 (Mþ þ H). Anal. calcd.
for C18H18O5: C, 68.78; H, 5.77. Found: C, 68.88; H, 5.94.
5.2. 4-(6-Phenyl[1,2,4,5]tetroxan-3-yl)benzaldehyde (3a)
Yield: 32%; mp 220 ꢂC; IR (KBr, cmꢀ1): 2921, 2851, 1706, 1456,
1365, 1298, 1204, 1103, 1056, 1018, 1002, 914, 837, 806, 755, 696; 1H
5.7. Benzyl[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzylidene]amine
NMR (300 MHz, CDCl3):
d
(ppm) 6.90 (s, 1H), 6.99 (s, 1H), 7.41e7.46
(6c)
(m, 3H), 7.68e7.72 (m 3H), 7.79e8.22 (m, 3H),10.08 (s, 1H); ESI-MS:
273.18 (Mþ þ H). Anal. calcd. for C15H12O5: C, 66.17; H, 4.44. Found:
C, 66.12; H, 4.49.
Compound 3b (100 mg, 0.35 mmol) was dissolved in dry THF
(25 mL), benzylamine (37 mg, 0.35 mmol) was added to the above

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2821
solution and reaction mixture was stirred at room temperature for
5.13. 2(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzylideneamino)
benzenethiol (6g)
18 h. After completion of reaction, the product was extracted with
CHCl3 and the solvent was removed under vaccum. The crude
product was purified over silica gel column using EtOAc/hexane to
yield 6c (52 mg, 40%) as a white solid; mp 140 ꢂC; IR (film, cmꢀ1):
2919, 2845, 1620, 1501, 1414, 1352, 1249, 1109, 938, 838, 797; 1H
Yield: 37%; mp 185 ꢂC; IR (KBr, cmꢀ1): 2922, 2853, 1610, 1454,
1360, 1309, 1198, 1110, 1010, 911, 834, 798, 755; 1H NMR (300 MHz,
CDCl3): d (ppm) 2.39 (s, 3H), 4.35 (br s, 1H), 6.92 (s, 1H), 6.98 (s, 1H),
NMR (300 MHz, CDCl3):
d
(ppm) 2.39 (s, 3H), 4.85 (s, 2H), 6.89 (s,
7.25e7.40 (m, 6H), 7.64e8.02 (m, 6H), 8.49 (s, 1H); ESI-HRMS calcd.
1H), 6.94 (s, 1H), 7.23e7.26 (m, 3H), 7.34e7.41 (m, 6H), 7.56 (d, 2H,
J ¼ 7.8 Hz), 7.85 (d, 2H, J ¼ 8.1 Hz), 8.41 (s, 1H); 13C NMR (75.5 MHz,
CDCl3): 21.48, 65.02, 107.61, 108.50, 127.08, 127.76, 128.03, 128.51,
129.46, 132.88, 138.67, 141.73, 160.85; ESI-MS calcd. for C23H21NO4:
375.1; found: 376.1 (Mþ þ H).
for C22H19NO4S: 393.1035; found: 394.1032 (Mþ þ H).
5.14. N-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzylidene)pyridin-
3-amine (6h)
Yield: 36%; mp 188 ꢂC; IR (KBr, cmꢀ1): 2921, 2852, 1608, 1454,
1357, 1295, 1198, 1013, 908, 829, 792; 1H NMR (300 MHz, CDCl3):
5.8. Phenethyl[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzylidene]
amine (6d)
d
(ppm) 2.39 (s, 3H), 6.87 (m, 2H), 6.90 (s, 1H), 6.98 (s, 1H),
7.22e7.25 (m, 4H), 7.38e7.41 (m, 4H), 7.63e7.67 (m, 1H), 7.94 (s,
1H), 7.96 (s, 1H); ESI-MS: 363.2 (Mþ þ H). Anal. calcd. for
C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found: C, 69.48; H, 5.23;
N, 7.80.
Yield: 48%; mp 188 ꢂC; IR (film, cmꢀ1): 2921, 2845, 1358, 1259,
1201, 1019, 911, 832, 795; 1H NMR (300 MHz, CDCl3):
d (ppm) 2.34
(s, 3H), 2.90 (t, 2H, J ¼ 6.2 Hz), 3.56 (t, 2H, J ¼ 6.3 Hz), 6.81 (s, 1H),
6.84 (s, 1H), 7.16e7.19 (m, 2H), 7.32e7.38 (m, 6H), 7.43e7.45 (m,
3H), 7.80e7.98 (m, 2H), 8.41 (s, 1H); ESI-MS calcd. for C24H23NO4
389.1; found: 390.2 (Mþ þ H).
5.15. 2-{[4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzylidene]amino}
ethanol (6i)
5.9. N-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzylidene)
cyclohexanamine (6a)
Yield: 32%; mp 143 ꢂC; IR (KBr, cmꢀ1): 3310, 2920, 1645, 1611,
1360, 1307, 1260, 1199, 1055, 1022, 911, 873, 835, 796; 1H NMR
(300 MHz, CDCl3): d (ppm) 1.93 (br s, 1H), 2.58 (s, 3H), 3.98 (m, 2H),
4.11 (m, 2H), 7.09 (s, 1H), 7.13 (s, 1H), 7.43e7.45 (m, 2H), 7.58e7.61
(m, 2H), 7.74e7.77 (m, 2H), 7.98e8.01 (m, 2H), 8.56 (s, 1H); ESI-MS:
330.14 (Mþ þ H). Anal. calcd. for C18H19NO5: C, 65.64; H, 5.81;
N, 4.25. Found: C, 65.81; H, 5.61; N, 4.23.
Yield: 48%; mp 121 ꢂC; IR (film, cmꢀ1): 2924, 2853, 1638, 1610,
1450, 1360, 1176, 1108, 911, 831, 795; 1H NMR (300 MHz, CDCl3):
d
(ppm) 1.25e1.60 (m, 5H), 1.65e1.86 (m, 4H), 2.38 (s, 3H), 3.22 (m,
2H), 6.87 (s, 1H), 6.88 (s, 1H), 7.15e7.22 (m, 2H), 7.38e7.41 (m, 2H),
7.53 (d, 2H, J ¼ 8.1 Hz), 7.78 (d, 2H, J ¼ 8.1 Hz), 8.32 (s, 1H); ESI-MS:
368.2 (Mþ þ H). Anal. calcd. for C22H25NO4: C, 71.91; H, 6.86;
N, 3.81. Found: C, 71.63; H, 6.66; N, 3.83.
5.16. Adamantan-1-yl[4-(6-p-tolyl[1,2,4,5]tetraoxan-3-yl)
benzylidene]amine (6j)
5.10. N-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzylidene)aniline
Yield: 35%; mp 161 ꢂC; IR (KBr, cmꢀ1): 2915, 2851, 1629, 1529,
(6b)
1381, 1007, 838, 801, 756; 1H NMR (300 MHz, CDCl3):
d (ppm)
Yield: 42%; mp 166 ꢂC; IR (KBr, cmꢀ1): 2919, 2845, 1620, 1501,
1414, 1352, 1249, 1109, 938, 838, 797; 1H NMR (300 MHz, CDCl3):
1.74e2.17 (m, 15H), 2.38 (s, 3H), 6.89 (s, 1H), 6.92 (s, 1H), 7.25 (m,
2H), 7.39e7.41 (m, 2H), 7.55 (m, 2H), 7.82e7.96 (m, 2H), 8.27 (s, 1H);
ESI-HRMS calcd. for C26H29NO4: 419.2097; found: 420.2099
(Mþ þ H).
d
(ppm) 2.32 (s, 3H), 6.84 (s,1H), 6.89 (s,1H), 7.18e7.33 (m, 9H), 7.56
(m, 2H), 7.89 (m, 2H), 8.41 (s, 1H); ESI-MS: 362.18 (Mþ þ H). Anal.
calcd. for C22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found: C, 73.43;
H, 5.01; N, 3.86.
5.17. N-(7-Chloro-quinolin-4-yl)-N0-[4-(6-p-tolyl[1,2,4,5]tetroxan-
3-yl)benzylidene]ethane-1,2-diamine (6k)
5.11. (4-Chloro-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)
benzylidene]amine (6e)
Yield: 40%; mp 120 ꢂC; IR (KBr, cmꢀ1): 3402, 3065, 2923, 2851,
1610, 1579, 1363, 1297, 1212, 1141, 1025, 1006, 912, 836, 800, 700; 1H
Yield: 45%; mp 160 ꢂC; IR (KBr, cmꢀ1): 2925, 2861, 1622, 1310,
NMR (300 MHz, CDCl3):
d
(ppm) 2.32 (s, 3H), 3.60 (t, 2H, J ¼ 5.3 Hz),
1183, 1091, 1011, 911, 842, 795; 1H NMR (300 MHz, CDCl3):
d (ppm)
3.92 (t, 2H, J ¼ 5.2 Hz), 5.61 (br s, 1H), 6.43 (d, 1H, J ¼ 5.1 Hz), 6.82 (s,
1H), 6.87 (s, 1H), 7.17e7.21 (m, 2H), 7.29e7.34 (m, 3H), 7.49e7.52
(m, 2H), 7.64 (d, 1H, J ¼ 9.0 Hz), 7.73(d, 2H, J ¼ 7.8 Hz), 7.89 (s, 1H),
8.29 (s, 1H), 8.49 (d, 1H, J ¼ 5.2 Hz); ESI-MS: 490.1 (Mþ þ H). Anal.
calcd. for C27H24ClN3O4: C, 66.19; H, 4.94; N, 8.58. Found: C, 66.39;
H, 5.09; N, 8.78.
2.34 (s, 3H), 6.99 (s, 1H), 7.06 (s, 1H), 7.15e7.20 (m, 2H), 7.31e7.34
(m, 3H), 7.44e7.49 (m, 3H), 7.71e7.74 (m, 2H), 8.03e8.05 (m, 2H),
8.69 (s, 1H); ESI-MS: 396.1 (Mþ þ H). Anal. calcd. for C22H18ClNO4:
C, 66.75; H, 4.85; N, 3.54. Found: C, 66.80; H, 4.61; N, 3.60.
5.12. (4-Bromo-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)
benzylidene]-amine (6f)
5.18. [4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzylidene]hydrazine (6l)
Yield: 55%; mp 170 ꢂC; IR (KBr, cmꢀ1): 2917, 2854, 1621, 1476,
1354, 1008, 913, 843, 828, 798; 1H NMR (300 MHz, CDCl3):
d
(ppm)
Yield: 25%; mp 218 ꢂC; IR (KBr, cmꢀ1): 3369, 2920, 2850, 1609,
1357, 1178, 1004, 910, 829, 792, 692; 1H NMR (300 MHz, CDCl3):
2.41 (s, 3H), 7.14 (s, 1H), 7.16 (s, 1H), 7.30e7.35 (m, 2H), 7.44e7.46
(m, 2H), 7.64e7.66 (m, 2H), 7.83e7.89 (m, 2H), 8.04e8.20 (m, 4H),
8.88 (s, 1H); ESI-MS: 440.1 (Mþ þ H). Anal. calcd. for C22H18BrNO4:
C, 60.01; H, 4.12; N, 3.18. Found: C, 59.80; H, 4.21; N, 3.28.
d
(ppm) 2.38 (s, 3H), 4.74 (s, 2H), 6.88e6.95 (m, 2H), 7.23e7.60 (m,
8H), 7.73e7.75 (m, 1H); ESI-HRMS calcd. for C16H16N2O4: 300.1110;
found: 301.1114 (Mþ þ H).

2822
N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
5.19. Phenethyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine
5.24. N-(7-Chloro-quinolin-4-yl)-N0-[4-(6-p-tolyl[1,2,4,5]tetroxan-
(7b)
3-yl)benzyl]ethane-1,2-diamine (7f)
Equimolar quantity of 3b (150 mg, 0.52 mmol) and phenyleth-
ylamine (63 mg, 0.52 mmol) were stirred in THF (20 mL) and
sodiumtriacetoxyborohydride (167 mg, 0.79 mmol) was added to
the reaction mixture. The reaction mixture was stirred at room
temperature for 12 h and progress of reaction was monitored by
TLC. The solvent was evaporated under vaccum and product was
extracted with chloroform. Organic layer was dried over anhydrous
Na2SO4 and solvent was removed under vacuum. The crude product
was purified over silica gel using EtOAc/hexane as eluent to give
product 7b (106 mg, 52%) as a white solid; mp 155 ꢂC; IR (KBr,
cmꢀ1): 3407, 3028, 2962, 2923, 2850, 1608, 1538, 1454, 1378, 1261,
Yield: 40%; mp 138 ꢂC; IR (KBr, cmꢀ1): 3401, 3266, 2957, 2921,
2851, 1609, 1542, 1457, 1375, 1261, 1091, 1018, 897, 875, 805, 772; 1H
NMR (300 MHz, CDCl3): d (ppm) 2.32 (s, 3H), 2.98e2.99 (m, 2H), 3.28
(s, 2H), 3.82 (br s, 1H), 3.92 (s, 2H), 5.75 (br s, 1H), 6.31 (d, 1H,
J ¼ 5.1 Hz), 6.81 (s, 1H), 6.83 (s, 1H), 7.16e7.19 (m, 3H), 7.32e7.34 (m,
4H), 7.41e7.44 (m, 2H), 7.61 (d,1H, J ¼ 9.0 Hz), 7.89 (s,1H), 8.50 (d,1H,
J ¼ 5.1 Hz); ESI-MS: 492.2 (Mþ þ H). Anal. calcd. for C27H26ClN3O4:
C, 65.92; H, 5.33; N, 8.54. Found: C, 65.63; H, 5.60; N, 8.54.
5.25. [4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)phenyl]methanol (8b)
1094, 1018, 912, 797, 773; 1H NMR (300 MHz, CDCl3):
d (ppm) 1.77
The sodium borohrdride (106 mg, 2.80 mmol) was added to
a solution of compound 3b (200 mg, 0.70 mmol) in THF (20 mL)
and the reaction mixture was stirred at room temperature for 4 h.
The progress of reaction was monitored by TLC. After completion of
reaction, the reaction mixture was extracted with CHCl3 and water.
The organic layer was dried over anhydrous Na2SO4 and solvent
was removed under vacuum. The crude product thus obtained was
purified over silica gel column using EtOAc/hexane as eluent to
yield 8b (167 mg, 83%); mp: 165 ꢂC; IR (film, cmꢀ1): 3325, 2922,
1613, 1420, 1361, 1211, 1110, 1004, 912, 832, 792; 1H NMR (300 MHz,
(br s, 1H), 2.31 (s, 3H), 2.77 (t, 2H, J ¼ 6.6 Hz), 2.81 (t, 2H, J ¼ 6.6 Hz),
3.76 (s, 2H), 6.80 (s, 1H), 6.82 (s, 1H), 7.11e7.15 (m, 5H), 7.18e7.22
(m, 3H), 7.26e731 (m, 2H), 7.34e7.37 (m, 3H); ESI-MS calcd. for
C24H25NO4: 391.1; found: 392.1 (Mþ þ H), Anal. calcd. for
C24H25NO4: C, 73.64; H, 6.44, N, 3.58. Found: C, 73.81; H, 4.64,
N, 3.88.
5.20. Benzyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine (7a)
Yield: 43%; mp 158 ꢂC; IR (KBr, cmꢀ1): 3390, 2918, 2850, 1613,
1379, 1261, 1111, 1019, 827, 792, 697; 1H NMR (300 MHz, CDCl3):
CDCl3): d (ppm) 1.54 (br s, 1H), 2.31 (s, 3H), 4.67 (s, 2H), 6.81 (s, 1H),
6.84 (s, 1H), 7.16e7.19 (m, 2H), 7.32e7.38 (m, 4H), 7.43e7.45 (m,
2H); ESI-MS: 289.1 (Mþ þ H). Anal. calcd. for C16H16O5: C, 73.19;
H, 6.14; N, 3.71. Found: C, 73.32; H, 6.09; N, 3.58.
d
(ppm) 1.87 (br s, 1H), 2.38 (s, 3H), 3.80 (s, 2H), 3.84 (s, 2H), 6.87 (s,
1H), 6.88 (s, 1H), 7.23 (s, 2H), 7.33e7.39 (m, 4H), 7.41e7.46 (m, 5H),
7.47e7.59 (m, 2H); 13C NMR (75.5 MHz, CDCl3): 21.47, 52.37, 52.79,
108.10, 108.17, 126.95, 127.14, 127.75, 127.92, 128.21, 128.45, 128.53,
129.11, 139.50, 141.58, 141.63, 143.55; ESI-MS: 378.23 (Mþ þ H).
Anal. calcd. for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found:
C, 73.32; H, 6.09; N, 3.58.
5.26. [4-(6-Phenyl[1,2,4,5]tetroxan-3-yl)phenyl]methanol (8a)
Yield: 55%; mp 158 ꢂC; IR (KBr, cmꢀ1): 3338, 2924, 2868, 1456,
1423, 1367, 1023, 999, 913, 842, 791, 753, 695; 1H NMR (300 MHz,
CDCl3):
d (ppm) 3.76 (br s, 1H), 4.70 (s, 2H), 6.92 (s, 2H), 7.32e7.52
5.21. 2-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzylamino)
benzenethiol (7c)
(m, 9H); ESI-MS: 275.1 (Mþ þ H). Anal. calcd. for C15H14O5: C, 65.69;
H, 5.15. Found: C, 65.58; H, 5.20.
Yield: 46%; mp 198 ꢂC; IR (KBr, cmꢀ1): 3394, 2919, 1592, 1494,
1458, 1417, 1311, 1008, 966, 913, 837, 801, 748; 1H NMR (300 MHz,
5.27. [4-(6-m-Tolyl[1,2,4,5]tetroxan-3-yl)phenyl]methanol (8c)
CDCl3):
d (ppm) 1.17 (br s, 1H), 2.38 (s, 3H), 4.74 (s, 2H), 6.41e6.43
Yield: 75%; mp 145 ꢂC; IR (KBr, cmꢀ1): 3354, 2921, 2847, 1612,
1422, 1356, 1199, 1008, 935, 905, 825, 783, 698; 1H NMR (300 MHz,
CDCl3): d (ppm) 1.61 (br s, 1H), 2.38 (s, 3H), 4.74 (s, 2H), 6.89 (s, 1H),
6.92 (s,1H), 7.26e7.37 (m, 4H), 7.42e7.45 (m, 2H), 7.50e7.53 (m, 2H);
13C NMR (75.5 MHz, CDCl3): 20.29, 63.64, 106.95, 107.29, 123.92,
125.97, 127.03, 127.33, 127.67, 129.02, 129.67, 131.12, 137.67, 143.24;
ESI-HRMS calcd. for C16H16O5: 288.0997; found: 289.0994 (Mþ þ H).
(m, 2H), 6.88 (s, 1H), 6.91 (s, 1H), 7.34e7.60 (m, 4H), 7.70e7.78 (m,
4H), 8.03e8.09 (m, 2H), 8.75 (br s, 1H); ESI-MS 396.2 (Mþ þ H).
Anal. calcd. for C22H21NO4S C, 66.82; H, 5.35; N, 3.54. Found:
C, 66.51; H, 5.23; N, 3.71.
5.22. N-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzyl)pyridin-3-
amine (7d)
Yield: 42%; mp 194 ꢂC; IR (KBr, cmꢀ1): 3407, 3387, 1597, 1519,
1495, 1458, 1417, 1308, 1243, 1148, 1009, 876, 793, 744; 1H NMR
(300 MHz, CDCl3): d (ppm) 2.71 (br s, 1H), 2.36 (s, 3H), 4.68 (s, 2H),
6.81 (s, 1H), 6.84 (s, 1H), 7.16e7.19 (m, 5H), 7.34e7.48 (m, 6H),
7.90e7.93 (m, 1H); ESI-MS: 365.2 (Mþ þ H). Anal. calcd. for
C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 68.96; H, 5.80;
N, 7.53.
5.28. [4-(6-o-Tolyl[1,2,4,5]tetroxan-3-yl)phenyl]methanol (8d)
Yield: 55%; mp 136 ꢂC; IR (KBr, cmꢀ1): 3428, 2921, 2851, 1613,
1454, 1423, 1357, 1017, 890, 827, 785, 699; 1H NMR (300 MHz,
CDCl3):
d (ppm) 1.76 (br, 1H), 2.38 (s, 3H), 4.75 (s, 2H), 6.94 (s, 1H),
7.10 (s, 1H), 7.22e7.36 (m, 3H), 7.43e7.54 (m, 5H); 13C NMR
(75.5 MHz, CDCl3): 19.23, 64.77, 106.25, 108.03, 126.23, 127.02,
127.67, 128.02, 129.28, 130.06, 130.90, 131.07, 137.42, 144.25; ESI-
HRMS calcd. for C16H16O5: 288.0997; found: 289.0992 (Mþ þ H).
5.23. Adamantan-1-yl[4-(6-p-tolyl-[1,2,4,5]tetraoxan-3-yl)benzyl]
amine (7e)
5.29. {4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]phenyl}
methanol (8e)
Yield: 20%; mp 178 ꢂC; IR (KBr, cmꢀ1): 3395, 2908, 1593, 1494,
1416, 1310, 1174, 1085, 1006, 910, 834, 747; 1H NMR (300 MHz,
CDCl3):
d
(ppm) 0.81e2.21 (m, 15H), 2.34 (s, 3H), 3.5 (br s, 1H), 4.67
Yield: 55%; mp 138 ꢂC; IR (KBr, cmꢀ1): 3393, 2932, 1638, 1422,
(s, 2H), 6.81 (s, 1H), 6.84 (s, 1H), 7.19 (m, 4H), 7.32e7.45 (m, 3H),
7.87e7.98 (m, 1H); ESI-HRMS calcd. for C26H31NO4: 421.2253;
found: 422.2258 (Mþ þ H).
1363,1203,1003, 948, 838, 794; 1H NMR (300 MHz, CDCl3):
d (ppm)
1.21 (t, 3H, J ¼ 9 Hz), 1.80 (br s, 1H), 2.64e2.71 (m, 2H), 4.69 (s, 2H),
6.89 (s, 1H), 6.91 (s, 1H), 7.25e7.27 (m, 2H), 7.36e7.44 (m, 4H),

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2823
7.49e7.52 (m, 2H); ESI-MS: 303.3 (Mþ þ H). Anal. calcd. for
5.34. Naphthalen-1-yl[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10b)
C17H18O5: C, 67.54; H, 6.00. Found: C, 67.58; H, 6.01.
Yield: 48%; mp 129 ꢂC; IR (film, cmꢀ1): 3453, 2923, 1581, 1462,
1260, 1018, 913, 745; 1H NMR (300 MHz, CDCl3):
(ppm) 2.32 (s, 3H),
4.55 (s, 2H), 6.52 (m, 1H), 6.81e6.84 (d, 2H, J ¼ 9.3 Hz), 7.13 (m, 6H),
7.32e7.52 (m, 9H); ESI-MS: 414.2 (Mþ þ H). Anal. calcd. for
C26H23NO4:C, 75.53;H, 5.61; N, 3.39. Found:C, 75.63;H, 5.58;N, 3.39.
5.30. {4-[6-(4-Isopropyl-phenyl)[1,2,4,5]tetroxan-3-yl]phenyl}
methanol (8f)
d
Yield: 48%; mp 131 ꢂC; IR (KBr, cmꢀ1): 3306, 2961, 2863, 1613,
1424, 1363, 1261, 1203, 1005, 913, 839, 802; 1H NMR (300 MHz,
CDCl3):
d (ppm) 1.24 (d, 6H), 1.72 (br s, 1H), 2.89e2.98 (m, 1H),
5.35. Methyl-phenyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
4.74 (s, 2H), 6.89 (s, 1H), 6.91 (s, 1H), 7.26e7.31 (m, 2H), 7.42e7.45
(m, 4H), 7.50e7.53 (m, 2H); 13C NMR (75.5 MHz, CDCl3): 23.77,
23.99, 34.14, 64.70, 107.89, 108.22, 126.63, 126.92, 126.98, 127.19,
127.89, 128.04, 128.25, 130.11, 144.21, 152.52; ESI-MS: 317.1
(Mþ þ H). Anal. calcd. for C18H20O5: C, 68.34; H, 6.37. Found:
C, 68.58; H, 6.31.
amine (10c)
Yield: 38%; mp 137 ꢂC; IR (film, cmꢀ1): 2924, 1599, 1426, 1506,
1360, 1278, 1212, 1120, 1022, 1003, 934, 909; 1H NMR (300 MHz,
CDCl3): d (ppm) 2.38 (s, 3H), 3.01 (s, 3H), 4.50 (s, 2H), 6.71e6.73 (m,
2H), 6.87e6.88 (m, 2H), 7.22e7.31 (m, 3H), 7.38e7.46 (m, 8H); ESI-
HRMS calcd. for C23H23NO4: 377.1627; found: 378.1625 (Mþ þ H).
5.31. Methanesulfonic acid 4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)
benzyl ester (9a)
5.36. p-Tolyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine (10d)
Yield: 62%; mp 162 ꢂC; IR (film, cmꢀ1): 3389, 2954, 2924, 1613,
To a stirred solution of compound 8b (245 mg, 0.85 mmol) in
THF 20 mL, triethylamine (258 mg, 2.55 mmol) was added followed
by the drop wise addition of methanesulfonyl chloride (97 mg,
0.85 mmol). The reaction mixture was stirred for 4 h at room
temperature. The progress of reaction was monitored by TLC. After
the completion of reaction, the reaction mixture was extracted with
CHCl3 and the organic layer was dried over anhydrous MgSO4. The
excess of solvent was removed under vacuum. The crude product
was purified over silica gel column using EtOAc/hexane as eluent to
give 9a (290 mg, 93%) as white solid; mp 122 ꢂC; IR (KBr, cmꢀ1):
2925, 2852, 1354, 1175, 1020, 953, 829, 796, 747, 695; 1H NMR
1520, 1460, 1363, 1020, 911, 792, 772; 1H NMR (300 MHz, CDCl3):
d
(ppm) 2.23 (s, 3H), 2.38 (s, 3H), 4.36 (s, 2H), 6.51e6.54 (d, 2H,
J ¼ 8.4 Hz), 6.88e6.90 (d, 2H, J ¼ 6.0 Hz), 6.96e6.99 (d, 2H,
J ¼ 8.1 Hz), 7.23e7.26 (m, 3H), 7.39e7.49 (m, 6H); ESI-MS: 378.2
(Mþ þ H). Anal. calcd. for C23H23NO4: C, 73.19; H, 6.14; N, 3.71.
Found: C, 73.52; H, 6.18; N, 3.69.
5.37. m-Tolyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine (10e)
Yield: 53%; mp 144 ꢂC; IR (film, cmꢀ1): 3451, 3038, 2924, 2852,
1607, 1492, 1362, 1326, 1010, 908, 830, 793, 763, 611; 1H NMR
(300 MHz, CDCl3):
d (ppm) 2.32 (s, 3H), 2.88 (s, 3H), 5.19 (s, 2H),
(300 MHz, CDCl3):
d (ppm) 2.26 (s, 3H), 2.38 (s, 3H), 4.36 (s, 2H),
6.81 (s, 1H), 6.86 (s, 1H), 7.16e7.19 (d, 2H, J ¼ 7.5 Hz), 7.31e7.34 (d,
2H, J ¼ 7.8 Hz), 7.40e7.43 (d, 2H, J ¼ 7.8 Hz), 7.48e7.50 (d, 2H,
J ¼ 7.8 Hz); 13C NMR (75.5 MHz, CDCl3): 21.57, 38.47, 46.09, 70.25,
107.32, 108.32, 127.76, 128.31, 128.82, 129.48, 131.67, 136.58, 141.84;
ESI-MS: 367.1 (Mþ þ H). Anal. calcd. for C17H18O7S: C, 55.73; H, 4.95.
Found: C, 55.33; H, 5.04.
6.39e6.56 (m, 3H), 6.87e6.90 (d, 2H, J ¼ 6.6 Hz), 7.02e7.07 (m, 2H),
7.22e7.25 (d, 2H, J ¼ 8.4 Hz), 7.38e7.49 (m, 6H); ESI-MS 378.1
(Mþ þ H), Anal. calcd. for C23H23NO4: C, 73.19; H, 6.14; N, 3.71.
Found: C, 73.41; H, 6.11; N, 3.71.
5.38. o-Tolyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine (10f)
Yield: 41%; mp 126 ꢂC; IR (film, cmꢀ1): 3453, 3012, 2950, 2925,
5.32. Methanesulfonic acid 4-[6-(4-ethyl-phenyl)[1,2,4,5]tetroxan-
3-yl]benzyl ester (9b)
2852, 1723, 1606, 1586, 1512, 1454, 1364, 1324, 1263, 1215, 1181,
1019, 1007, 911, 793, 764; 1H NMR (300 MHz, CDCl3):
d (ppm) 2.18
Yield: 86%; mp 139 ꢂC; IR (film, cmꢀ1): 3033, 2962, 2919, 2868,
(s, 3H), 2.39 (s, 3H), 4.40 (s, 2H), 6.52e6.58 (m, 1H), 6.74 (m, 2H),
6.8e6.9 (m, 2H), 7.07 (m, 2H), 7.26e7.59 (m, 8H); ESI-HRMS calcd.
for C23H23NO4: 377.1627; found: 378.1690 (Mþ þ H).
1424, 1346, 1253, 1173, 1005, 958, 919, 836, 801; 1H NMR (300 MHz,
CDCl3):
d
(ppm) 1.21e1.26 (t, 3H, J ¼ 7.5 Hz), 2.64e2.72 (q, 2H), 2.96
(s, 3H), 5.26 (s, 2H), 6.89 (s, 1H), 6.93 (s, 1H), 7.26e7.28 (d, 2H,
J ¼ 7.2 Hz), 7.41e7.44 (d, 2H, J ¼ 8.1 Hz), 7.47e7.50 (d, 2H, J ¼ 8.1 Hz),
7.55e7.58 (d, 2H, J ¼ 8.1 Hz); ESI-HRMS calcd. for C18H20O7S:
380.0929; found: 381.0926 (Mþ þ H).
5.39. (2,6-Dimethyl-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)
benzyl]amine (10g)
Yield: 55%; mp 148 ꢂC; IR (film, cmꢀ1): 3392, 2950, 2923, 2853,
1733, 1612, 1362, 1216, 1003, 909, 793, 764; 1H NMR (300 MHz,
5.33. Phenyl[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]amine (10a)
CDCl3): d (ppm) 2.25 (s, 6H), 2.38 (s, 3H), 4.18 (s, 2H), 6.88e6.95 (m,
3H), 6.99e7.02 (m, 2H), 7.22e7.25 (d, 2H, J ¼ 7.5 Hz), 7.39e7.50 (m,
7H); 13C NMR (75.5 MHz, CDCl3): 18.53, 21.61, 52.49, 52.64, 108.03,
108.33, 127.88, 128.18, 128.35, 129.02, 129.39, 141.80, 143.92, 145.51,
162.32; ESI-HRMS calcd. for C24H25NO4: 391.1783; found: 392.1784
(Mþ þ H).
Compound 9a (150 mg, 0.41 mmol) was stirred with aniline
(38 mg, 0.41 mmol) for 18 h at room temperature in THF. The
progress of the reaction was monitored by TLC. After usual workup
the crude product was purified over SiO2 column and the product
was eluted in EtOAc/hexane to yield compound 10a (77 mg, 52%) as
a white solid; mp 128 ꢂC; IR (film, cmꢀ1): 3392, 2924, 2845, 1733,
1600, 1506, 1460, 1362, 1311, 1253, 1181, 1019, 829, 793, 752; 1H
5.40. (4-Ethyl-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10h)
NMR (300 MHz, CDCl3): d (ppm) 2.39 (s, 3H), 4.38 (s, 2H), 6.60e6.76
(m, 3H), 6.88e6.90 (d, 2H, J ¼ 6.0 Hz), 7.14e7.23 (m, 3H), 7.39e7.50
(m, 8H); ESI-MS: 364.1 (Mþ þ H). Anal. calcd. for C22H21NO4: C,
72.71; H, 5.82; N, 3.85. Found: C, 72.94; H, 5.80; N, 3.78.
Yield: 52%; mp 140 ꢂC; IR (film, cmꢀ1): 3401, 3033, 2956, 2924,
2854, 1614, 1518, 1459, 1362, 1311, 1016, 911, 827, 792, 696; 1H NMR
(300 MHz, CDCl3):
d
(ppm) 1.15e1.20 (t, 3H, J ¼ 7.8 Hz), 2.38 (s, 3H),

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N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2.49e2.57 (q, 2H), 4.35 (s, 2H), 6.53e6.56 (d, 2H, J ¼ 8.4 Hz),
6.87e6.89 (d, 2H, J ¼ 6.0 Hz), 6.98e7.01 (d, 2H, J ¼ 8.4 Hz), 7.22e7.25
(d, 2H, J ¼ 8.1 Hz), 7.38e7.49 (m, 7H); 13C NMR (75.5 MHz, CDCl3):
15.74, 16.03, 21.61, 28.02, 28.55, 48.39, 108.05, 108.32, 111.19, 121.06,
127.75, 127.89, 128.21, 128.71, 129.58, 141.79, 141.89, 143.46, 145.77,
158.37; ESI-MS: 392.2 (Mþ þ H). Anal. calcd. for C24H25NO4: C, 73.64;
H, 6.44; N, 3.58. Found: C, 73.38; H, 6.48; N, 3.41.
136.09, 136.20, 141.70, 142.80; ESI-MS 382.2 (Mþ þ H). Anal. calcd.
for C22H20FNO4: C, 69.28; H, 5.29; N, 3.67. Found: C, 69.69; H, 5.29;
N, 3.63.
5.46. (4-Chloro-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10n)
Yield: 53%; mp 162 ꢂC; IR (film, cmꢀ1): 3386, 3235, 2950, 2922,
2851, 1736, 1498, 1460, 1357, 1176, 1084, 1010, 824, 793; 1H NMR
5.41. (4-Isopropyl-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)
benzyl]amine (10i)
(300 MHz, CDCl3):
d (ppm) 2.38 (s, 3H), 4.35 (s, 2H), 6.50e6.52 (d,
2H, J ¼ 8.7 Hz,), 6.87e6.90 (d, 2H, J ¼ 7.2 Hz), 7.08e7.11 (d, 2H,
J ¼ 9.0 Hz), 7.15e7.25 (m, 2H), 7.35e7.50 (m, 7H); ESI-MS: 398.1
(Mþ þ H). Anal. calcd. for C22H20ClNO4: C, 66.42; H, 5.07; N, 3.52.
Found: C, 66.01; H, 5.11; N, 3.57.
Yield: 42%; mp 142 ꢂC; IR (film, cmꢀ1): 3393, 2956, 2922, 2852,
1615, 1518, 1662, 1362, 1008, 911, 827, 796, 695; 1H NMR (300 MHz,
CDCl3):
d
(ppm) 1.18e1.28 (d, 6H, J ¼ 6.9 Hz), 2.38 (s, 3H), 2.77e2.82
(m, 1H), 4.35 (s, 2H), 6.54e6.57 (d, 2H, J ¼ 8.4 Hz), 6.87e6.90 (d, 2H,
J ¼ 6.6 Hz), 7.02e7.05 (d, 2H, J ¼ 8.4 Hz), 7.17e728 (m, 2H), 7.38e7.49
(m, 7H); ESI-MS: 406.1 (Mþ þ H). Anal. calcd. for C25H27NO4: C,
74.05; H, 6.71; N, 3.45. Found: C, 74.22; H, 6.81; N, 3.51.
5.47. (3-Chloro-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10o)
Yield: 46%; mp 132 ꢂC; IR (film, cmꢀ1): 3449, 2953, 2925, 2854,
1735, 1597, 1499, 1482, 1377, 1363, 1325, 1007, 909, 830; 1H NMR
5.42. (4-Propyl-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10j)
(300 MHz, CDCl3):
d (ppm) 2.38 (s, 3H), 4.36 (s, 2H), 6.44e6.70 (m,
3H), 6.8e6.90 (m, 2H), 7.03e7.08 (m, 2H), 7.23e7.50 (m, 8H); ESI-
MS: 398.2 (Mþ þ H). Anal. calcd. for C22H20ClNO4: C, 66.42;
H, 5.07; N, 3.52. Found: C, 66.74; H, 5.01; N, 3.63.
Yield: 37%; mp 140 ꢂC; IR (film, cmꢀ1): 3391, 3286, 2950, 2923,
2853, 1652, 1615, 1518, 1462, 1362, 1249, 1007, 911, 828, 796; 1H
NMR (300 MHz, CDCl3):
d (ppm) 0.89e0.98 (m, 3H), 1.53e1.70 (m,
2H), 2.38 (s, 3H), 2.44e2.49 (t, 2H, J ¼ 7.2 Hz), 4.35 (s, 2H),
6.52e6.55 (d, 2H, J ¼ 8.4 Hz), 6.87e6.89 (d, 2H, J ¼ 6.3 Hz),
6.96e6.99 (d, 2H, J ¼ 8.4 Hz), 7.15e7.25 (m, 2H), 7.38e7.62 (m, 7H);
13C NMR (75.5 MHz, CDCl3): 13.82, 21.49, 24.83, 37.12, 48.22, 107.92,
108.18, 112.87, 120.83, 127.61, 127.77, 127.93, 128.09, 128.16, 128.90,
129.19,129.45,129.64,132.10,141.68, 143.39,145.71; ESI-MS: 406.18
(M þ Hþ). Anal. calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45.
Found: C, 73.83; H, 6.79; N, 3.44.
5.48. (2-Chloro-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10p)
Yield: 33%; mp 188 ꢂC; IR (film, cmꢀ1): 3443, 2921, 2852, 1597,
1509, 1459, 1423, 1365, 1325, 1288, 1007, 910, 835, 740; 1H NMR
(300 MHz, CDCl3):
d (ppm) 2.38 (s,3H), 4.44e4.46 (d, 2H,
J ¼ 5.7 Hz), 6.52e6.54 (d, 2H, J ¼ 8.1 Hz), 6.62e6.67 (m, 1H),
6.87e6.90 (d, 2H, J ¼ 7.8 Hz), 7.04e7.09 (m, 1H), 7.22e7.28 (m, 2H),
7.38e7.50 (m, 7H); ESI-HRMS calcd. for C22H20ClNO4: 397.1080;
found: 398.1082 (Mþ þ H).
5.43. (4-Fluoro-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10k)
Yield: 51%; mp 136 ꢂC; IR (film, cmꢀ1): 3376, 2923, 2852, 1612,
5.49. [4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzyl](2,4,5-trichloro-
phenyl)amine (10q)
1511, 1462, 1421, 1361, 1223, 1106, 1010, 911, 820, 792, 695; 1H NMR
(300 MHz, CDCl3):
d (ppm) 2.38 (s, 3H), 4.33 (s, 2H), 6.50e6.55 (m,
Yield: 31%; mp 180 ꢂC; IR (film, cmꢀ1): 3384, 3235, 2955, 2921,
4H), 6.84e6.90 (m, 2H), 7.20e7.30 (m, 2H), 7.38e7.49 (m, 7H); 13C
NMR (75.5 MHz, CDCl3): 21.48, 48.47, 107.84, 108.20, 113.63, 113.69,
115.57, 115.79, 127.58, 127.76, 128.14, 129.45, 141.72, 142.89; ESI-
HRMS calcd. for C22H20FNO4: 381.1376; found: 382.1374 (Mþ þ H).
2851, 1755, 1498, 1460, 1357, 1176, 1084, 1001, 824, 791; 1H NMR
(400 MHz, CDCl3):
d (ppm) 2.32 (s, 3H), 4.33e4.34 (d, 2H,
J ¼ 5.5 Hz), 6.54 (s, 1H), 6.81 (s, 1H), 6.85 (s, 1H), 7.16e7.19 (m, 2H),
7.28 (s, 2H), 7.32e7.34 (d, 4H, J ¼ 8.2 Hz), 7.44e7.46 (d, 2H,
J ¼ 8.2 Hz); ESI-HRMS calcd. for C22H18Cl3NO4: 465.0301; found:
466.0304 (Mþ þ H).
5.44. (3-Fluoro-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10l)
Yield: 49%; mp 148 ꢂC; IR (film, cmꢀ1): 3451, 3054, 2940, 2914,
5.50. (4-Bromo-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10r)
2752, 1613, 1609, 1415, 1401, 1343, 1311, 1001, 843, 798, 730; 1H
NMR (300 MHz, CDCl3): d (ppm) 2.39 (s, 3H), 4.43 (s, 2H), 6.67e6.69
Yield: 34%; mp 149 ꢂC; IR (film, cmꢀ1): 3411, 2997, 2950, 2927,
(m, 2H), 6.90e6.92 (d, 2H, J ¼ 6.0 Hz), 6.95e7.04 (m, 2H), 7.24e7.27
(d, 2H, J ¼ 8.1 Hz), 7.40e7.53 (m, 7H); ESI-HRMS calcd. for
C22H20FNO4: 381.1376; found: 382.1378 (Mþ þ H).
2850, 1613, 1512, 1460, 1362, 1174, 1204, 1152, 1010, 808, 757; 1H
NMR (300 MHz, CDCl3): d (ppm) 2.38 (s, 3H), 4.33 (s, 2H), 6.48e6.59
(m, 4H), 6.89e6.98 (m, 2H), 7.14e8.02 (m, 9H); ESI-MS: 442.1
(Mþ þ H). Anal. calcd. for C22H20BrNO4: C, 59.74; H, 4.56; N, 3.17.
Found: C, 59.24; H, 4.55; N, 3.19.
5.45. (2-Fluoro-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzyl]
amine (10m)
Yield:47%; mp 160 ꢂC; IR (film, cmꢀ1): 3453, 3064, 2950, 2924,
5.51. (4-Methoxy-phenyl)[4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)
benzyl]amine (10s)
2852, 1653, 1619, 1515, 1451, 1363, 1335, 1010, 833, 795, 740; 1H
NMR (300 MHz, CDCl3): d (ppm) 2.38 (s, 3H), 4.41 (s, 2H), 6.65e6.67
(m, 2H), 6.88e6.90 (d, 2H, J ¼ 7.8 Hz), 6.93e7.02 (m, 2H), 7.22e7.25
(d, 2H, J ¼ 8.7 Hz), 7.38e7.51 (m, 7H); 13C NMR (75.5 MHz, CDCl3):
21.48, 47.39, 107.84, 108.19, 112.25, 112.28, 114.32, 114.51, 117.03,
117.10, 124.54, 124.58, 127.44, 127.76, 127.89, 128.18, 128.38, 129.45,
Yield: 39%; mp 146 ꢂC; IR (film, cmꢀ1): 3390, 2925, 2852, 1702,
1611, 1513, 1460, 1363, 1247, 1112, 1008, 828, 794, 756; 1H NMR
(300 MHz, CDCl3):
d (ppm) 2.39 (s, 3H), 3.79 (s, 3H), 4.38 (s, 2H),
6.62e6.79 (m, 4H), 6.87e6.93 (m, 2H), 7.23e7.46 (m, 9H); ESI-MS:

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2825
394.2 (Mþ þ H). Anal. calcd. for C23H23NO5: C, 70.21; H, 5.89; N,
7.13 (s, 1H), 7.23 (s, 1H), 7.38e7.41 (d, 2H, J ¼ 7.2 Hz), 7.55e7.57 (d,
2H, J ¼ 7.2 Hz), 7.76e7.78 (d, 2H, J ¼ 7.5 Hz), 8.09e8.12 (d, 2H,
J ¼ 7.2 Hz), 13.33 (br s, 1H); ESI-MS: 317.1 (Mþ þ H). Anal. calcd. for
C17H16O6: C, 64.55 H, 5.10. Found: C, 64.94; H, 5.07.
3.56. Found: C, 66.93; H, 5.51; N, 3.53.
5.52. (3,5-Dimethoxy-phenyl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)
benzyl]amine (10t)
5.58. General procedure for the synthesis of amides
Yield: 48%; mp 125 ꢂC; IR (film, cmꢀ1): 3447, 3374, 2924, 2852,
1610, 1460, 1421, 1361, 1204, 1152, 1008, 803, 677; 1H NMR
The acid 11a or 11b was dissolved in THF and triethylamine was
added to the solution. After 15 min ethylchloroformate was added
to the reaction mixture. The reaction mixture was stirred for 30 min
and amine was added to the reaction mixture. Reaction mixture
was stirred for 2 h and progress of the reaction was monitored by
TLC. The reaction mixture was extracted with CHCl3 and organic
layer was dried over anhydrous Na2SO4. Excess of the solvent was
removed under vacuum. The crude product was purified over silica
gel column using EtOAc/hexane as eluent.
(300 MHz, CDCl3):
d (ppm) 2.38 (s, 3H), 3.72 (s, 6H), 4.34 (s, 2H),
5.79e5.89 (m, 3H), 6.87e6.89 (d, 2H), 7.22e7.30 (m, 2H), 7.38e7.48
(m, 7H); ESI-MS 424.2 (Mþ þ H). Anal. calcd. for C24H25NO6:
C, 68.07; H, 5.95; N, 3.31. Found: C, 68.51; H, 5.85; N, 3.33.
5.53. 4-[4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzylamino]phenol
(10u)
Yield: 45%; mp 117 ꢂC; IR (film, cmꢀ1): 3449, 2950, 2922, 2847,
1701, 1363, 1207, 1007, 911, 829, 793; 1H NMR (300 MHz, CDCl3):
5.58.1. N-(2-Hydroxy-ethyl)-4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)
benzamide (12a)
d
(ppm) 2.39 (m, 3H), 4.32 (s, 2H), 4.75 (br s, 1H), 6.50e6.53 (d, 2H,
J ¼ 8.1 Hz), 6.68e6.70 (d, 2H, J ¼ 8.7 Hz), 6.88e6.91 (m, 2H),
7.23e7.53 (m, 9H); ESI-HRMS: 380.1438 (Mþ þ H). Anal. calcd. for
C22H21NO5: C, 69.64; H, 5.58; N, 3.69. Found: C, 69.42; H, 5.57; N, 3.61.
Yield: 53%; mp 190 ꢂC; IR (Nujol, cmꢀ1): 3286, 2924, 2854, 1638,
1551, 1458, 1377, 1120, 852, 804; 1H NMR (300 MHz, DMSO-d6):
d
(ppm) 2.26 (s, 3H), 3.39e3.43 (t, 2H, J ¼ 5.7 Hz), 4.63e4.67 (t, 2H,
J ¼ 5.7 Hz), 6.97 (s, 1H), 7.05 (s, 1H), 7.21e7.24 (d, 2H, J ¼ 7.8 Hz),
7.37e7.40 (d, 2H, J ¼ 8.1 Hz), 7.57e7.59 (d, 2H, J ¼ 8.1 Hz), 7.84e7.87
(d, 2H, J ¼ 8.1 Hz), 8.49 (br s, 2H); 13C NMR (100 MHz, DMSO-d6):
21.07, 42.27, 59.63, 106.72, 107.50, 127.77, 127.91, 127.98, 129.51,
133.03, 137.38, 141.67, 165.58; ESI-MS: 346.12 (Mþ þ H). Anal. calcd.
for C18H19NO6: C, 62.60; H, 5.55; N, 4.06. Found: C, 62.91; H, 5.47;
N, 4.16.
5.54. 3-[4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzylamino]phenol
(10v)
Yield: 43%; mp 150 ꢂC; IR (film, cmꢀ1): 3425, 2955, 2925, 1615,
1458, 1363, 1208, 1008, 793, 760; 1H NMR (300 MHz, CDCl3):
d
(ppm) 2.38 (s, 3H), 4.36 (s, 2H), 4.74 (br s, 1H), 6.28 (m, 2H),
6.88e6.91 (m, 2H), 7.23e7.30 (m, 2H), 7.38e7.52 (m, 9H); ESI-HRMS
calcd. for C22H21NO5: 379.1419; found: 380.1413 (Mþ þ H).
5.58.2. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]-N-(2-hydroxy-
ethyl)benzamide (12b)
5.55. N1-(4-(6-p-Tolyl-1,2,4,5-tetraoxan-3-yl)benzyl)benzene-1,4-
diamine (10w)
Yield: 68%; mp 197 ꢂC; IR (film, cmꢀ1): 3286, 2918, 2850, 1718,
1638, 1621, 1543, 1461, 1418, 1286, 1178, 1062, 1021, 996, 914, 852;
1H NMR (300 MHz, DMSO-d6):
d
(ppm) 1.16e1.21 (t, 3H, J ¼ 7.2 Hz),
Yield: 20%; mp 138 ꢂC; IR (film, cmꢀ1): 3386, 2924, 2854, 1597,
2.62e2.66 (q, 2H), 3.38e3.52 (m, 4H), 4.56 (br s, 1H), 7.07 (s, 1H),
7.14 (s, 1H), 7.34e7.36 (d, 2H, J ¼ 7.5 Hz), 7.49e7.52 (d, 2H,
J ¼ 7.2 Hz), 7.66e7.69 (d, 2H, J ¼ 7.5 Hz), 7.94e7.96 (d, 2H,
J ¼ 7.5 Hz), 8.57 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): 15.34,
28.10, 41.08, 59.62, 106.71, 107.50, 127.75, 127.89, 128.05, 128.19,
128.34, 133.01, 137.37, 147.78, 165.54; ESI-MS: 360.1 (Mþ þ H). Anal.
calcd. for C19H21NO6: C, 63.50; H, 5.89; N, 3.90. Found: C, 63.11;
H, 5.79; N, 3.89.
1509, 1363, 1009, 912, 827, 794, 739; 1H NMR (300 MHz, CDCl3):
d
(ppm) 0.78e0.80 (br s, 2H), 2.31 (s, 3H), 4.27 (s, 2H), 5.86e6.03
(m, 4H), 6.80e6.90 (m, 2H), 7.15e7.18 (m, 2H), 7.31e7.42 (m, 7H);
ESI-HRMS calcd. for C22H22N2O4: 378.1579; found: 379.1576
(Mþ þ H).
5.56. 4-(6-p-Tolyl[1,2,4,5]tetroxan-3-yl)benzoic acid (11a)
Compound 3b (400 mg, 1.40 mmol) was dissolved in acetone
(80 mL), and a solution of CrO3/H2SO4/H2O (1 g/1 mL/10 mL) was
added drop wise to the above solution at the interval of 2 h. The
progress of the reaction was monitored by TLC. After usual workup
the crude product was purified over silica gel column using EtOAc/
hexane as eluent to obtain compound 11a (346 mg, 82%) as a white
solid; mp 247 ꢂC; IR (Nujol, cmꢀ1): 2924, 2854, 1720, 1695, 1460,
1377, 1292, 1034, 1003, 915,765; 1H NMR (300 MHz, DMSO-d6):
5.58.3. N-(3-Hydroxy-propyl)-4-(6-p-tolyl-[1,2,4,5]tetroxan-3-yl)
benzamide (12c)
Yield: 72%; mp 170 ꢂC; IR (film, cmꢀ1): 3390, 3297, 2950, 2852,
2918, 1637, 1540, 1018, 997, 852, 803; 1H NMR (300 MHz, DMSO-
d6): d (ppm) 1.66e1.72 (m, 2H), 2.35 (s, 3H), 3.45e3.47 (m, 2H), 4.48
(m, 3H), 7.06 (s, 1H), 7.14 (s, 1H), 7.30e7.33 (d, 2H, J ¼ 7.8 Hz),
7.47e7.49 (d, 2H, J ¼ 7.8 Hz), 7.66e7.68 (d, 2H, J ¼ 8.1 Hz), 7.91e7.94
(d, 2H, J ¼ 7.8 Hz), 8.57e8.59 (br s, 1H); 13C NMR (75.5 MHz, DMSO-
d6): 21.02, 32.30, 36.67, 58.55, 56.25, 106.69, 107.46, 127.64, 127.87,
127.92, 129.45, 136.95, 137.45, 141.60, 165.43; ESI-MS: 360.1
(Mþ þ H). Anal. calcd. for C19H21NO6: C, 63.50; H, 5.89; N, 3.90.
Found: C, 63.59; H, 5.47; N, 3.84.
d
(ppm) 2.26 (s, 3H), 6.98 (s, 1H), 7.09 (s, 1H), 7.22e7.24 (d, 2H,
J ¼ 7.5 Hz), 7.38e7.41 (d, 2H, J ¼ 7.5 Hz), 7.61e7.64 (d, 2H, J ¼ 7.8 Hz),
7.95e7.98 (d, 2H, J ¼ 7.8 Hz), 13.17 (br s, 1H); 13C NMR (75.5 MHz,
DMSO-d6): 21.04, 106.53, 107.53, 127.77, 127.96, 128.16, 129.47,
129.76,133.50, 134.62, 141.65,166.56; ESI-MS: 303.1 (Mþ þ H). Anal.
calcd. for C16H14O6: C, 63.57; H, 4.67. Found: C, 63.65; H, 4.63.
5.58.4. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]-N-(3-hydroxy-
propyl)benzamide (12d)
5.57. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]benzoic acid
(11b)
Yield: 73%; mp 162 ꢂC; IR (film, cmꢀ1): 3297, 2919, 2850, 1695,
1635, 1538, 1259, 1017, 993, 851, 810, 766; 1H NMR (300 MHz,
DMSO-d6):
d
(ppm) 1.16e1.21 (t, 3H, J ¼ 7.5 Hz), 1.64e1.73 (m, 2H),
Yield: 67%; mp 248e250 ꢂC; IR (Nujol, cmꢀ1): 2924, 2854, 2669,
2.62e2.71 (q, 2H), 3.30e3.49 (m, 5H), 7.07 (s, 1H), 7.14 (s, 1H),
7.34e7.36 (d, 2H, J ¼ 7.8 Hz), 7.49e7.52 (d, 2H, J ¼ 7.8 Hz), 7.66e7.69
(d, 2H, J ¼ 8.1 Hz), 7.92e7.95 (d, 2H, J ¼ 7.8 Hz), 8.57e8.58 (br s, 1H);
1695, 1612, 1463, 1316, 1285, 1031, 1001, 914, 767; 1H NMR
(300 MHz, DMSO-d6): d (ppm) 1.21e1.26 (t, 3H), 2.69e2.71 (m, 2H),

2826
N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
13C NMR (100 MHz, DMSO-d6): 15.35, 28.87, 32.08, 46.23, 58.55,
106.72, 107.51, 127.69, 127.93, 128.06, 128.35, 132.99, 137.46, 147.79,
165.46; ESI-MS: 374.2 (Mþ þ H). Anal. calcd. for C20H23NO6:
C, 64.33; H, 6.21; N, 3.75. Found: C, 64.42; H, 6.30; N, 3.69.
HRMS: 372.1740 (Mþ þ H). Anal. calcd. for C21H25NO5: C, 67.91;
H, 6.78; N, 3.77. Found: C, 68.11; H, 6.68; N, 3.77.
5.58.10. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]-N-pentyl-
benzamide (12j)
5.58.5. N-(6-Hydroxy-hexyl)-4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)
benzamide (12e)
Yield: 65%; mp 190 ꢂC; IR (film, cmꢀ1): 3300, 2950, 2924, 2853,
1696,1636,1539,1256,1020, 999, 853, 803, 769; 1H NMR (300 MHz,
Yield: 69%; mp 175 ꢂC; IR (film, cmꢀ1): 3298, 2927, 2857, 1804,
1701, 1637, 1534, 1458, 1255, 1198, 1148, 1121, 1078, 1007, 873, 760;
DMSO-d6): d (ppm) 0.83e0.87 (m, 3H), 1.06e1.53 (m, 9H),
2.91e2.98 (m, 2H), 3.18e3.34 (m, 2H), 7.07 (s, 1H), 7.17 (s, 1H),
7.30e7.33 (d, 2H, J ¼ 7.8 Hz), 7.47e7.50 (d, 2H, J ¼ 7.8 Hz), 7.66e7.69
(d, 2H, J ¼ 8.1 Hz), 7.93e7.95 (d, 2H, J ¼ 7.8 Hz), 8.57 (br s, 1H); 13C
NMR (100 MHz, DMSO-d6): 13.92, 14.70, 21.04, 21.84, 28.45, 28.71,
29.13, 59.36, 106.72, 107.49, 127.67, 127.89, 127.96, 128.17, 129.77,
132.95, 141.62, 156.23, 165.29; ESI-MS: 386.2 (Mþ þ H). Anal. calcd.
for C22H27NO5: C, 68.55; H, 7.06; N, 3.63. Found: C, 68.92; H, 7.12;
N, 3.69.
1H NMR (300 MHz, DMSO-d6):
d (ppm) 1.03e1.52 (m, 6H), 2.35 (s,
3H), 3.25e3.45 (m, 4H), 3.92e3.99 (m, 3H), 7.03e7.18 (m, 2H),
7.30e7.33 (d, 2H, J ¼ 7.5 Hz), 7.47e7.57 (m, 2H), 7.66e7.83 (m, 2H),
7.89e8.16 (m, 2H), 8.57 (br s, 1H); 13C NMR (100 MHz, DMSO-d6):
21.06, 25.25, 26.20, 29.52, 32.51, 56.04, 59.45, 60.67, 106.57, 107.62,
127.99, 128.20, 129.50, 132.92, 133.52, 135.98, 137.52, 141.66, 143.02,
156.30, 166.60; ESI-MS 402.2 (Mþ þ H). Anal. calcd. for C22H27NO6:
C, 65.82; H, 6.78; N, 3.49. Found C, 65.49; H, 6.69; N, 3.51.
5.58.11. N-[2-(7-Chloro-quinolin-4-ylamino)ethyl]-4-(6-p-tolyl
[1,2,4,5]tetroxan-3-yl)benzamide (12k)
5.58.6. 4-[6-(4-Ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]-N-(6-hydroxy-
hexyl)benzamide (12f)
Yield: 45%; mp 128 ꢂC; IR (film, cmꢀ1): 3278, 2931, 1701, 1611,
1582, 1543, 1369, 1264, 1140, 1036, 805; 1H NMR (300 MHz, DMSO-
Yield: 64%; mp 202 ꢂC; IR (film, cmꢀ1): 3308, 2929, 2859, 1696,
1638, 1537, 1506, 1362, 1016, 1003, 843; 1H NMR (300 MHz, DMSO-
d6):
d (ppm) 2.36 (s, 3H), 3.24e3.66 (m, 4H), 6.57e6.68 (m, 2H),
d6):
d
(ppm) 1.06e1.53 (m, 11H), 2.64e2.67 (m, 2H), 3.28e3.39 (m,
7.28e7.30 (m, 2H), 7.40e7.55 (m, 2H), 7.70e7.84 (m, 2H), 7.92e8.12
(m, 3H), 8.24e8.32 (m, 3H), 8.37e8.50 (m, 2H), 8.89e8.95 (br s,1H);
ESI-MS: 506.2 (Mþ þ H). Anal. calcd. for C27H24ClN3O5: C, 64.10;
H, 4.78; N, 8.31. Found: C, 64.52; H, 4.91; N, 8.29.
5H), 7.05 (s, 1H), 7.12e7.14 (m, 1H), 7.33e7.35 (d, 2H, J ¼ 7.2 Hz),
7.49e7.51 (d, 2H, J ¼ 7.5 Hz), 7.65e7.72 (m, 2H), 7.92e7.94 (d, 2H,
J ¼ 6 Hz), 8.48 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): 14.70,
15.32, 25.28, 26.42, 28.14, 29.08, 32.52, 60.65, 106.70, 107.51, 127.68,
127.91, 128.06, 128.35, 129.43, 132.96, 137.52, 147.80, 165.31; ESI-
HRMS calcd. for C23H29NO6: 415.1994; found: 416.1998 (Mþ þ H).
5.58.12. N-[3-(7-Chloro-quinolin-4-ylamino)propyl]-4-(6-p-tolyl
[1,2,4,5]tetroxan-3-yl)benzamide (12l)
Yield: 38%; mp 118 ꢂC; IR (film, cmꢀ1): 3210, 2923, 2852, 1702,
5.58.7. N-Propyl-4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzamide
(12g)
1610, 1463, 1377, 722; 1H NMR (300 MHz, DMSO-d6):
d (ppm)
1.74e1.96 (m, 2H), 2.36 (s, 3H), 3.07e3.13 (m, 2H), 3.28e3.42 (m,
2H), 6.51e6.56 (m, 2H), 7.06 (s,1H), 7.14e7.18 (m,1H), 7.28e7.69 (m,
6H), 7.80e8.04 (m, 4H), 8.27e8.42 (m, 2H), 8.71e8.73 (br s, 1H);
ESI-MS: 520.1 (Mþ þ H). Anal. calcd. for C28H26ClN3O5: C, 64.68;
H, 5.04; N, 8.08. Found: C, 64.89; H, 5.17; N, 8.11.
Yield: 48%; mp 209 ꢂC; IR (film, cmꢀ1): 3293, 2922, 1806, 1698,
1638, 1540, 1421, 1364, 1288, 1200, 1018, 914, 852, 709; 1H NMR
(300 MHz, DMSO-d6): d (ppm) 0.87e0.92 (t, 3H), 1.51e1.58 (m, 2H),
2.36 (s, 3H), 3.20e3.26 (m, 2H), 7.07 (s, 1H), 7.16 (s, 1H), 7.31e7.33
(d, 2H, J ¼ 7.5 Hz), 7.47e7.50 (d, 2H, J ¼ 7.8 Hz), 7.66e7.69 (d, 2H,
J ¼ 8.1 Hz), 7.92e7.95 (d, 2H, J ¼ 7.8 Hz), 8.58 (br s, 1H,); 13C NMR
(100 MHz, DMSO-d6): 11.46, 15.33, 22.31, 39.50, 41.05, 106.72,
107.49, 127.68, 127.90, 128.05, 128.34, 165.37; ESI-MS: 344.2
(Mþ þ H). Anal. calcd. for C19H21NO5: C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.77; H, 6.05; N, 4.04.
5.58.13. N-[3-(7-Chloro-quinolin-4-ylamino)propyl]-4-[6-(4-ethyl-
phenyl)[1,2,4,5]tetroxan-3-yl]benzamide (12m)
Yield: 42%; mp 138 ꢂC; IR (film, cmꢀ1): 3390, 2929, 2857, 1702,
1582, 1541, 1370, 1273, 1043, 804; 1H NMR (300 MHz, DMSO-d6):
d
(ppm) 1.11e1.22 (m, 3H), 1.76e1.83 (m, 2H), 2.65e2.71 (m, 2H),
3.06e3.13 (m, 2H), 3.25e3.45 (m, 2H), 6.47e6.51 (m, 2H), 7.17 (m,
2H), 7.31e7.47 (m, 4H), 7.78e8.11 (m, 4H), 8.24e8.40 (m, 4H), 8.75
(br s, 1H); ESI-HRMS calcd. for C29H28ClN3O5: 533.1717; found:
534.1758 (Mþ þ H).
5.58.8. N-Butyl-4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzamide (12h)
Yield: 53%; mp 180 ꢂC; IR (film, cmꢀ1): 3305, 2924, 2854, 1637,
1539, 1463, 1377; 1H NMR (300 MHz, DMSO-d6):
d (ppm) 0.87e0.92
(t, 3H),1.29e1.36 (m, 2H),1.48e1.53 (m, 2H), 2.35 (s, 3H), 3.25e3.34
(m, 2H), 7.06 (s, 1H), 7.14 (s, 1H), 7.31e7.33 (d, 2H, J ¼ 7.5 Hz),
7.47e7.49 (d, 2H, J ¼ 7.8 Hz), 7.65e7.68 (d, 2H, J ¼ 7.8 Hz), 7.91e7.94
(d, 2H, J ¼ 7.8 Hz), 8.57 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6):
13.70, 19.64, 20.13, 31.13, 106, 107, 127.66, 127.86, 127.93, 129.46,
129.58, 129.72; ESI-MS: 358.2 (Mþ þ H). Anal. calcd. for C20H23NO5:
C, 67.21; H, 6.49; N, 3.92. Found: C, 67.42; H, 6.43; N, 3.91.
5.58.14. N-Phenethyl-4-(6-p-tolyl[1,2,4,5]tetroxan-3-yl)benzamide
(12n)
Yield: 39%; mp 146 ꢂC; IR (film, cmꢀ1): 3312, 2921, 2852, 1695,
1634, 1534, 1255, 1181, 1004, 909, 849, 798, 744, 696; 1H NMR
(300 MHz, DMSO-d6):
d (ppm) 2.33 (s, 3H), 2.81e2.86 (t, 2H,
J ¼ 7.2 Hz), 3.47e3.51 (t, 2H, J ¼ 6.3 Hz), 6.99 (s, 1H), 7.12e7.31 (m,
8H), 7.45e7.48 (d, 2H, J ¼ 7.8 Hz), 7.64e7.67 (d, 2H, J ¼ 7.8 Hz),
7.88e7.91 (d, 2H, J ¼ 8.1 Hz), 8.69 (br s, 1H); 13C NMR (100 MHz,
DMSO-d6): 14.62, 21.05, 35.06,106.61,107.49,126.00,127.97,128.36,
128.67, 129.48, 139.42, 165.37; ESI-HRMS calcd. for C24H23NO5:
405.1576; found: 406.1573 (Mþ þ H).
5.58.9. N-Butyl-4-[6-(4-ethyl-phenyl)[1,2,4,5]tetroxan-3-yl]
benzamide (12i)
Yield: 58%; mp 198 ꢂC; IR (film, cmꢀ1): 3302, 2950, 2921, 2850,
1635, 1542, 1458, 1364, 1292, 1017, 994, 852; 1H NMR (300 MHz,
DMSO-d6):
d
(ppm) 0.88e0.92 (t, 3H, J ¼ 7.2 Hz), 1.16e1.21 (t, 3H,
J ¼ 7.5 Hz), 1.27e1.39 (m, 2H), 1.46e1.56 (m, 2H), 2.61e2.69 (q, 2H),
3.23e3.33 (m, 2H), 7.07 (s, 1H), 7.16 (s, 1H), 7.33e7.36 (d, 2H,
J ¼ 7.8 Hz),7.49e7.52 (d, 2H, J ¼ 7.8 Hz), 7.65e7.69 (m, 2H),
7.89e7.94 (m, 2H), 8.53e8.58 (br s, 1H); 13C NMR (100 MHz, DMSO-
d6): 14.30, 15.90, 20.19, 28.69, 31.74, 107.30, 108.06, 127.62, 128.24,
128.47, 128.62, 128.91, 133.52, 137.44, 138.10, 148.33, 165.90; ESI-
5.58.15. (4-Phenyl-piperazin-1-yl)[4-(6-p-tolyl[1,2,4,5]tetroxan-3-
yl)phenyl]methanone (12o)
Yield: 42%; mp 204 ꢂC; IR (film, cmꢀ1): 3018, 2925, 1635, 1540,
1311, 1018, 945, 914, 852, 834, 812, 767, 668; 1H NMR (300 MHz,
DMSO-d6):
d (ppm) 2.38 (s, 3H), 3.34e3.60 (m, 8H), 6.26 (m, 1H),
6.85 (m, 2H), 7.03e7.19 (m, 2H), 7.28e7.53 (m, 4H), 7.63e7.81 (m,

N. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 2816e2827
2827
2H), 7.98e8.13 (m, 4H); ESI-MS: 447.2 (Mþ þ H). Anal. calcd. for
C26H26N2O5: C, 69.94; H, 5.87; N, 6.27. Found: C, 69.64; H, 5.77; N,
6.31.
[9] P. Lim, C. Wongsrichanalai, P. Chim, N. Khim, S. Kim, S. Chy, R. Sem, S. Nhem,
P. Yi, S. Duong, D.M. Bouth, B. Genton, H.-P. Beck, J.G. Gobert, W.O. Rogers, J.-
Y. Coppee, T. Fandeur, O. Mercereau-Puijalon, P. Ringwald, J. Le Bras, F. Ariey,
Antimicrob. Agents Chemother. 54 (2010) 2135e2142.
[10] J.L. Vennerstrom, H.-N. Fu, W.Y. Ellis, A.L. Ager, J.K. Wood, S.L. Andersen,
L. Gerena, W.K. Milhous, J. Med. Chem. 35 (1992) 3023e3027.
[11] R.K. Haynes, K.-W. Cheu, M.M.-K. Tang, M.-J. Chen, Z.-F. Guo, Z.-H. Guo,
P. Coghi, D. Monti, ChemMedChem. 6 (2011) 279e291.
[12] P.M. O’Neill, R.K. Amewu, G.L. Nixon, E.F. Bousejra, M. Mungthin, J. Chadwick,
A.E. Shone, L. Vivas, H. Lander, V. Barton, S. Muangnoicharoen, P.G. Bray,
J. Davies, B.K. Park, S. Wittlin, R. Brun, M. Preschel, K. Zhang, S.A. Ward,
Angew. Chem., Int. Ed. Engl. 49 (2010) 1e6.
5.58.16. N-Cyclohexyl-4-(6-p-tolyl-1,2,4,5-tetraoxan-3-yl)
benzamide (12p)
Yield: 43%; mp 220 ꢂC; IR (film, cmꢀ1): 3440, 3307, 2928, 2854,
1805, 1705, 1630, 1537, 1450, 1368, 1253, 1215, 1172, 1058, 1005, 804,
759; 1H NMR (300 MHz, DMSO-d6):
d (ppm) 1.14e1.82 (m, 10H),
2.36 (s, 3H), 3.77 (m, 1H,), 7.06 (s, 1H), 7.13 (s, 1H), 7.31e7.33 (d, 2H,
J ¼ 6.9 Hz), 7.46e7.49 (d, 2H, J ¼ 7.2 Hz), 7.64e7.67 (d, 2H,
J ¼ 7.8 Hz), 7.91e7.94 (d, 2H, J ¼ 7.5 Hz), 8.31 (br s, 1H); 13C NMR
(100 MHz, DMSO-d6): 20.98, 24.88, 25.24, 32.33, 48.46, 106.38,
107.40, 127.76, 127.81, 127.94, 128.05, 129.43, 132.86, 137.66, 141.69,
164.62; ESI-MS: 384.1 (Mþ þ H). Anal. calcd. for C22H25NO5: C,
68.91; H, 6.57; N, 3.65. Found: C, 69.42;, 6.36; N, 3.61.
[13] J. Golenser, J.H. Waknine, M. Krugliak, N.H. Hunt, G.E. Grau, Int. J. Parasitol. 36
(2006) 1427.
[14] S.R. Meshnick, Int. J. Parasitol. 32 (2002) 1655e1660.
[15] R.K. Haynes, S. Krishna, Microbes Infect. 6 (2004) 1339e1346.
[16] A.E. Mercer, J.L. Maggs, X.-M. Sun, G.M. Cohen, J. Chadwick, P.M. O’Neill,
B.K. Park, J. Biol. Chem. 282 (2007) 9372e9382.
[17] P.M. O’Neill, L.P. Bishop, N.L. Searle, J.L. Maggs, R.C. Storr, S.A. Ward, B.K. Park,
F. Mabbs, J. Org. Chem. 65 (2000) 1578e1582.
[18] A.R. Butler, B.C. Gilbert, P. Hulme, L.R. Irvine, L. Renton, A.C. Whitwood, Free
Radical Res. 28 (1998) 471e476.
[19] P.M. O’Neill, N.L. Searle, J.L. Maggs, K.J. Yaynes, S.A. Ward, R.C. Storr, B.K. Park,
G.H. Posner, Tetrahedron Lett. 39 (1998) 6065e6068.
[20] G.H. Posner, D. Wang, J.N. Cumming, C.H. Oh, A.N. French, A.L. Bodley,
T.A. Shapiro, J. Med. Chem. 38 (1995) 2273e2275.
[21] S. Hindley, S.A. Ward, R.C. Storr, N.L. Searle, P.G. Bray, B.K. Park, J. Davies,
P.M. O’Neill, J. Med. Chem. 45 (2002) 1052e1063.
[22] N. Kumar, S.I. Khan, M. Sharma, H. Atheaya, D.S. Rawat, Bioorg. Med. Chem.
Lett. 19 (2009) 1675.
[23] N. Kumar, S.I. Khan, Beena, G. Rajalakshmi, P. Kumaradhas, D.S. Rawat, Bioorg.
Med. Chem. 17 (2009) 5632e5638.
[24] D.S. Rawat, N. Kumar, M. Sharma, Indian Patent Application No: 2103/DEL/
2008.
[25] H. Atheaya, S.I. Khan, R. Mamgain, D.S. Rawat, Bioorg. Med. Chem. Lett. 18
(2008) 1446e1449.
[26] N. Kumar, R. Singh, D.S. Rawat, Med. Res. Rev. doi:10.1002/med.20223.
[27] H.-S. Kim, Y. Nagai, K. Ono, K. Begum, Y. Watayo, Y. Hamada, K. Tsuchiya,
A. Masuyama, M. Nojima, K. McCullongh, J. Med. Chem. 44 (2001) 2357e2361.
[28] B.A. Solaja, N. Terzic, G. Pocsfalvi, L. Genena, B. Tinant, J.P. Declerca, D.E. Kule,
W.K. Milhous, J. Med. Chem. 45 (2002) 3331e3336.
[29] N.A. Milas, S.A. Harris, P.C. Panagiotakos, J. Am. Chem. Soc. 61 (1939)
2430e2432.
[30] W. Adam, G. Asensio, R. Curci, J.A. Marco, M.E. Gonzaleznunnez, R. Melio,
Tetrahedron Lett. 33 (1992) 5833e5836.
[31] H. Keul, Chem. Berg. 108 (1975) 1198e1206.
[32] B.J. Wojciechowski, W.H. Pearson, R.L. Kuczkowski, J. Org. Chem. 54 (1989)
115e121.
[33] Y. Ito, H. Yokaya, Y. Umehara, T. Matsuura, Bull. Chem. Soc. Jpn. 53 (1980)
2407e2408.
5.58.17. N-(7-Aminoheptyl)-4-(6-p-tolyl-1,2,4,5-tetraoxan-3-yl)
benzamide (12q)
Yield: 50%; mp 178 ꢂC; IR (film, cmꢀ1): 3310, 2927, 2852, 1804,
1688, 1636, 1540, 1463, 1367, 1264, 1200, 1006, 853, 804, 759; 1H
NMR (300 MHz, DMSO-d6): d (ppm) 1.03e1.52 (m, 8H), 2.35 (s, 3H),
2.92e2.94 (m, 2H), 3.25e3.44 (m, 4H), 3.88e3.96 (m, 2H),
7.07e7.21 (m, 2H), 7.31e7.33 (d, 2H, J ¼ 6 Hz), 7.47e7.49 (d, 2H,
J ¼ 6 Hz), 7.65e7.73 (m, 2H), 7.79e7.94 (m, 2H), 8.56 (br s, 1H); ESI-
HRMS calcd. for C23H30N2O5: 414.2154; found: 415.2152 (Mþ þ H).
Acknowledgments
D.S.R. thanks Department of Science and Technology (SR/S1/OC-
08/2008), New Delhi, India, for financial support and USIC-CIF,
University of Delhi for NMR data. N.K. and H.A. are thankful to
CSIR, New Delhi, for the award of senior research fellowships.
United States Department of Agriculture (USDA), Agricultural
Research Service Specific Cooperative Agreement No. 58-6408-2-
0009 is also acknowledged for partial support of this work. Mr. John
Trott is acknowledged for his excellent technical assistance in the
screening of biological activity at NCNPR.
[34] C.W. Jefford, A. Jaber, J. Boukouvalas, Synthesis (1988) 391e393.
[35] D. Opsenica, G. Poesfalvi, Z. Juranic, B. Tinant, J.P. Declerca, D.E. Kule,
W.K. Milhous, B.A. Solaja, J. Med. Chem. 43 (2000) 3274e3282.
[36] N.M. Todorovic, M. Stefanovic, B. Tinant, J.-P. Declercq, M.T. Makler,
B.A. Solaja, Steroids 61 (1996) 688e696.
References
[1] WHO Report on Malaria, 2009.
[37] H.-S. Kim, K. Tsuchiya, Y. Shibata, Y. Wataya, Y. Ushigoe, A. Masuyama,
A. Nojima, K. McCullongh, J. Chem. Soc., Perkin Trans. I (1999) 1867e1870.
[38] J. Iskra, D. Bonnet-Delpon, J.-P. Begue, Tetrahedron Lett. 44 (2003) 6309e6312.
[39] P. Ghorai, P.H. Dussault, Org. Lett. 11 (2009) 213e216.
[40] R. Amewu, A.V. Stachulski, S.A. Ward, N.G. Berry, P.G. Bray, J. Davies, G. Labat,
L. Vivas, P.M. O’Neill, Org. Biomol. Chem. 4 (2006) 4431e4436.
[41] M.T. Makler, J.M. Ries, J.A. Williams, J.E. Bancroft, R.C. Piper, B.L. Gibbins,
D.J. Hinriches, Am. J. Trop. Med. Hyg. 48 (1993) 739e741.
[2] M. Wahlgren, M.T. Bejarano, Nature 400 (1999) 506e507.
[3] M. Balter, E. Marshall, G. Vogel, G. Taubes, E. Pennisi, M.A. Enserink, Science
290 (2000) 428e441.
[4] P. Newton, N. White, Annu. Rev. Med. 50 (1999) 179e192.
[5] D.L. Klayman, ACS Symp. Ser. 534 (1993) pp. 242e255.
[6] P.M. O’Neill, G.H. Posner, J. Med. Chem. 47 (2004) 2945e2964.
[7] R.K. Haynes, Curr. Top. Med. Chem. 6 (2006) 509e537.
[8] G.H. Posner, P.M. O’Neill, Acc. Chem. Res. 37 (2004) 397e404.