Heterocyclyl linked anilines and benzaldehydes as precursors for biologically significant new chemical entities

Article abstract of DOI:10.1007/s12039-012-0298-1

Benzylidene and benzyl thiazolidinediones, oxazolidinediones, isoxazolidinediones and their acyclic analogs like alpha alkylthio/alkoxy phenylpropanoic acids, beta-keto esters and tyrosine-based compounds possess broad therapeutic potential in general and as Peroxisome Proliferator Activated Receptors (PPARs) agonists in particular in the management of hyperglycemia and hyperlipidaemia for the treatment of Type 2 Diabetes (T2D). We have synthesised and characterized some novel and suitably substituted heterocyclyl linked benzaldehydes and anilines, which can be easily and very readily derivatized to all the above mentioned classes to generate new chemical entities of broader biological significance. Synthesis of their benzylidene thiazolidinedione and diethyl malonate and also benzyl diethyl malonate and alpha-bromoesters derivatives is reported in some of the cases in the present work. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0298-1

c
J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1063–1069. ꢀ Indian Academy of Sciences.
Heterocyclyl linked anilines and benzaldehydes as precursors
for biologically significant new chemical entities
RAMAN K VERMAa,∗, VIJAY KUMARa, PRITHWISH GHOSHa and LALIT K WADHWAb
aSynthetic Organic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University,
Patiala 147 002, India
bInd-Swift Laboratories Limited (Research and Development Centre), Plot No. E-5, Industrial Area, Phase-2,
SAS Nagar, Mohali 160 055, India
e-mail: raman_verma58@yahoo.com
MS received 28 November 2011; revised 25 February 2012; accepted 8 March 2012
Abstract. Benzylidene and benzyl thiazolidinediones, oxazolidinediones, isoxazolidinediones and their
acyclic analogs like alpha alkylthio/alkoxy phenylpropanoic acids, beta-keto esters and tyrosine-based com-
pounds possess broad therapeutic potential in general and as Peroxisome Proliferator Activated Receptors
(PPARs) agonists in particular in the management of hyperglycemia and hyperlipidaemia for the treatment of
Type 2 Diabetes (T2D). We have synthesised and characterized some novel and suitably substituted hetero-
cyclyl linked benzaldehydes and anilines, which can be easily and very readily derivatized to all the above
mentioned classes to generate new chemical entities of broader biological significance. Synthesis of their
benzylidene thiazolidinedione and diethyl malonate and also benzyl diethyl malonate and alpha-bromoesters
derivatives is reported in some of the cases in the present work.
Keywords. Benzimidazole; indole; acridone; benzaldehyde; aniline.
1. Introduction
in drug discovery research. The compounds containing
acridone structural unit may act potentially as antiher-
pesvirus agents,12 antitumour agents,13 NS3 helicase
inhibitor (that inhibits hepatitis C virus replication),14
antimalarial agents.15
It is well-documented in the literature that benzim-
idazole, indole and acridone scaffolds are important
structural core in medicinal chemistry because their
derivatives exhibit illustrious biological and pharma-
cological activities. The synthesis of benzimidazole
derivatives has gained importance during recent years
because of their broad spectrum of activities as antivi-
ral,1 antitumour,2 antioxidant,3 anticoagulant,4 antihy-
pertensive5 and antiparasitic agents.6
Indole nucleus is another heterocyclic pharma-
cophoric component of immense medicinal signifi-
cance. Suitably substituted or fused indole ring
containing compounds demonstrate antiproliferative
activity in many types of human cancer cells,7 agonism
to cannabinoid receptors,8 antitumour activity,9 free
radical scavenging activity,10,11 anti-inflammatory acti-
vity.11 Similarly, acridone nucleus is also indispensible
Aldehyde and amino, the two important func-
tional groups, are of versatile utility in the field of
organic synthesis. A medicinally significant library of
numerous compounds, which may prove to be potent
pharmacological agents, can be prepared starting
from substituted benzaldehydes and aminobenzenes.
Pharmacologically active 2,4-thiazolidinediones,16
oxazolidinediones,17 isoxazolidine-3,5-dione,18 1,3-di-
carbonyls,18 (1,3-diacids, 1,3-diesters, 1,3-diamides),18
and α-alkoxy carboxylic acids19,20 (figure 1) have
been prepared from variously heterocyclyl linked
benzaldehydes. Similarly, there are reports of phar-
macologically active 2,4-thiazolidinediones21,22 and
thiazolidinone derivatives23 prepared from heterocycle
linked aminobenzenes. The α-bromopropanoic acid
ester derivative prepared from substituted aminoben-
zene leads to α-alkylthiocarboxylic acids19 and Tyro-
sine derivatives24 are of immense importance for the
treatment of T2D. Reviewing the synthetic application
of the discussed, our work is projected upon three
heterocycles and the two functional groups mentioned.
∗For correspondence
1063

1064
Raman K Verma et al.
O
O
O
NH
O
NH
N
N
S
NH
N
S
N
O
O
S
O
N
O
O
O
BRL 48482
Pioglitazone
Rosiglitazone BRL 49653
O
O
O
N
NH
NH
O
S
N
O
O
O
O
Reglitazar JTT 501
DRF 2189
O
O
O
O
O
N
O
OH
O
OH
N
N
O
O
O
O
O
O
Novo Nordisk Compound
JTT Compound
Ragaglitazar DRF 2725
O
O
H
O
O
O
N
H
O
N
HN
O
HN
O
O
O
GW 409544
Farglitazar
Figure 1. PPAR activating molecules.
2. Experimental
catalyst was filtered through diatomaceous earth/celite
and the filtrate was evaporated under reduced pressure
to give a residue which upon trituration with hexane
or upon column chromatography (hexane/EtOAc, 1:5)
gave the desired compound as a solid.
2.1 Materials and methods
All the chemicals used in the present work were pur-
chased from SD Fine Chemical and Aldrich Chemi-
cal Company. The melting/boiling points reported here
were recorded using an open conc. sulphuric acid bath
2.2a 4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]-
aniline (compound 3, scheme 1): Yield: 75%,
mp: 138–140◦C; FTIR (KBr): 3447, 3317, 2942,
2840, 1512, 1480, 1446, 1364, 1246, 1035, 831,
1
and are uncorrected. The Infrared and H NMR spec-
tra of these compounds were recorded on Perkin-Elmer
Spectrum RX FTIR Spectrophotometer and AC400F,
400 MHz Bruker spectrometer at RSIC, Panjab Uni-
versity, Chandigarh. LCMS of these compounds were
recorded on LCMS LCQ Finnigan Matt (APCI +ve
mode) at Central Instrumentation Lab, NIPER, SAS
Nagar, Mohali, Punjab. GCMS and Elemental analy-
sis of these compounds were carried out on Shimadzu
GCMS-QP2010 Plus and VarioMICRO VI Elemen-
tal Analyzer respectively at Instrumental Laboratory,
Department of Chemistry, Punjabi University, Patiala.
1
747. cm−1; H NMR (CDCl3) δ: 7.76 (d, 2H), 7.36–
7.27 (m, 3H), 6.89 (d, J = 6.56 Hz, 1H), 6.63 (d, J =
6.64 Hz, 2H), 5.30 (s, 2H), 3.88 (s,3H), 2.78 (br.s, 2H);
LCMS m/z (254) [M+1]+; Anal. Calcd for C15H15N3O:
C, 71.13; H, 5.97; N, 16.59. Found: C, 71.75; H, 5.68;
N, 16.82.
2.2b 4-[(1-Methyl-1H-indol-2-yl)methoxy]aniline
(compound 7, scheme 2): Yield: 50%, mp: 141–
143◦C; FTIR (KBr): 3500–3200, 2923, 2840, 1656,
1593, 1511, 1468, 1380, 1232, 1010, 832, 751 cm−1;
1H NMR (CDCl3)δ: 7.59 (d, 1H), 7.33–7.31 (m, 1H),
7.25–7.21 (m, 1H), 7.11–7.07 (m, 1H), 6.84 (d, J =
8.8Hz, 2H), 6.66–6.63 (d„ J = 8.8Hz, 2H), 6.54 (s, 1H),
5.10 (s, 2H), 3.80 (s, 3H); LCMS m/z (253) [M+1]+;
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N,
11.10. Found: C, 76.45; H, 6.07; N, 11.44.
2.2 General procedure for the synthesis
of heterocyclyl linked anilines 3, 7 and 11
To (3.1 mmol) of the respective nitro compound
(2,6,10) placed in a Parr bottle with 10% Palladium
on charcoal (300 mg) and methanol/dioxane (150 ml),
and the mixture was hydrogenated at 20 psi for 2 h. The

Heterocyclyl linked anilines and benzaldehydes
1065
O
O
O
Br
N
N+
O
d
O
NH2
N
N
O
N
N
e
O-
N
3a
c
OH
N
N
2
3
O
f
O
H
NH
O
O
N
N
1a
h
S
N
Cl
N
N
O
g
N
4
4a
1b
a
i
b
O
O
NH2.HCl
N
O
O
O
N
NHCH3.HCl
d
4b
4c
1
O
O
N
O
O
O
N
Scheme 1. Synthesis of benzimidazolyl linked compounds. a: Glycolic acid, H2O,
Reflux; b: chloroacetic acid, H2O, reflux; c: 4-chloronitrobenzene, NaH, DMF, rt; d:
Pd/C-H2, methanol, rt; e: methanol, acetone,HBr, NaNO2, methyl acrylate,Cu2O; f: 4-
fluorobenzaldehyde, NaH, DMF, rt; g: 4-hydroxybenzaldehyde, NaH, DMF, rt; h: 2,4-
thiazolidinedione, piperidinium acetate, toluene, reflux; i: diethyl malonate, piperidinium
acetate, toluene, reflux.
O
O
N+
O
NH2
d
O-
N
c
N
OH
7
O
6
NH
N
O
H
e
S
O
O
f
O
5b
N
N
8a
8
b
g
O
O
N
O
5a
O
O
O
O
a
N
8b
O
O
N
H
5
Scheme 2. Synthesis of indolyl linked compounds. a: CH3I, NaH, DMF; b: LiAlH4-
THF; c: 4-chloro nitrobenzene, NaH, DMF, rt; d: Pd/C-H2, methanol; e: 4-fluoro-
benzaldehyde, NaH, DMF, rt; f: 2,4-thiazolidinedione, piperidinium acetate, toluene,
reflux; g: piperidinium acetate, toluene, reflux.
2.2c 10-[3-(4-Aminophenoxy)propyl]acridin-9(10H)- 100) [M+1]+; Anal. Calcd for C22H20N2O2: C, 76.72;
one (compound 11, scheme 3): Yield: 86%, mp: 151– H, 5.85; N, 8.13. Found: C, 76.59; H, 5.57; N, 8.29.
153◦C; FTIR (KBr): 3335, 3500–3200, 2924, 2840,
1629, 1595, 1509, 1491, 1459,1375, 820, 753 cm−1;
1H NMR (CDCl3)δ: 8.60–8.57 (m, 2H), 7.71–7.67
2.3 General procedure for the synthesis of
(m, 2H), 7.64–7.62 (d, 2H), 7.31–7.27 (m, 2H), 6.81
(d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.63
(t, J = 7.5 Hz, 2H), 4.08 (t, J = 5.3 Hz, 2H), 3.48 (br.s,
2H), 2.38 (quintet, J = 2.8 Hz, 2H); LCMS m/z (345,
heterocyclyl linked benzaldehydes 4 and 8
To a stirred suspension of sodium hydride (1.4 mmol,
60% w/w dispersion) in dry DMF (20 ml) was added

1066
Raman K Verma et al.
O
N+
O-
O
NH2
N+
HO
O-
c
N
O
N
O
a
O
O
+
O
11
N
-
O
10
Br
O
9a
O
N H
b
O
O
H
H
Br
O
9
N
O
9b
O
a
12
O
H
HO
Scheme 3. Synthesis of acridonyl linked compounds. a: 1,3-Dibromopropane, K2CO3,
acetone; b: KOH, DMF (MW); c: Pd/C-H2, methanol.
(1a/5b) (1.2 mmol) in dry DMF (5 ml) at 0◦C, and 2H), 7.62 (d, 1H), 7.35–7.33 (m, 1H), 7.28–7.24 (m,
the mixture was stirred for 30 min at room tempera- 1H), 7.13 (d, J = 8.76 Hz, 2H), 6.63 (s, 1H), 5.29
ture (rt) (ca. 30◦C). A solution of 4-fluorobenzaldehyde (s, 2H), 3.82 (s, 3H); LCMS m/z (266) [M+1]+; Anal.
(1.3 mmol) in dry DMF (5 ml) was added drop-wise Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28.
over 15 min at 0◦C, and stirred for 24 h at rt. The reac- Found: C, 76.58; H, 5.55; N, 5.60.
tion mixture was quenched with water and extracted
with EtOAc (3 × 30 ml). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4,
and concentrated. The residue was chromatographed
over silica gel using a mixture of methanol and
dichloromethane (1:10).
2.4 Synthesis of 4-[3-(9-oxoacridin-10(9H)-yl)pro-
poxy]benzaldehyde (compound 12, scheme 3)
To a mixture of acridone (9) (0.097 g, 0.5 mmol)
in DMF (15 ml) in a beaker, was added 4-(3-
bromopropoxy)benzaldehyde (9b) (0.146 g, 0.6 mmol)
and KOH (0.200 g, 3.6 mmol). The mixture was irra-
diated in a microwave oven for 5 min at 320 W, and
then the reaction mixture was poured into water (10 ml)
with stirring. After filtration of the insoluble materials,
the filtrate was neutralized (pH 7.0) with 2M- HCl, and
extracted with EtOAc (3 × 25 ml). The organic lay-
ers were combined, washed with brine and water, dried
over Na2SO4 and evaporated. The pure product (12)
was obtained as a yellow solid (0.030 g, 16.8%) by co-
lumn chromatography of the residue using methanol–
dichloromethane (1:99) mixture as eluent: mp 138–
140◦C; FTIR (KBr): 2954, 2880, 1685, 1600, 1496,
1462, 1314, 1258, 1160, 1057, 832, 761 cm−1; 1H NMR
(CDCl3)δ: 9.85 (s, 1H), 8.54–8.52 (m, 2H), 7.81 (d,
J = 8.76 Hz, 2H), 7.64–7.62 (m, 2H), 7.60–7.53 (m,
2H), 7.25–7.21 (m, 2H), 6.98 (d, J = 8.76, 2H), 4.61(t,
J = 7.6 Hz, 2H), 4.15(t, J = 4.8 Hz, 2H), 2.40 (quin-
tet, J = 6.4 Hz, 2H); LCMS m/z (358, 100) [M+1]+;
Anal. Calcd for C23H19NO3: C, 77.29; H, 5.36; N, 3.92.
Found: C, 77.61; H, 5.57; N, 28.19.
Compound 4 was also prepared by reacting 2-
(chloromethyl)-1-methyl-1H benzimidazole (1b) with
4-hydroxybenzaldehyde in the presence of sodium
hydride taken in DMF following similar procedure.
2.3a 4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]-
benzaldehyde (compound 4, scheme 1): Yield: 30 and
58.20%, mp: 120–122◦C; FTIR (KBr): 2926, 2823,
2733, 1697, 1601, 1577,1482, 1430, 1363, 1247,1005,
828, 749 cm−1; 1H NMR (CDCl3)δ: 9.88 (s, 1H),
7.86–7.81 (m, 3H), 7.42–735 (m, 3H), 7.25–7.23 (d,
J = 9.44 Hz, 2H), 5.52 (s, 2H), 3.91 (s, 3H); GCMS
m/z (%):266, 25) [M]+, 145 (100); Anal. Calcd for
C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C,
72.51; H, 5.57; N, 10.19.
2.3b 4-[(1-Methyl-1H-indol-2-yl)methoxy]benzal-
dehyde (compound 8, scheme 2): Yield: 30%, mp:
158–160◦C; FTIR (KBr): 2933, 2823, 2733, 1697,
1598, 1506, 1468, 1380, 1244, 1160, 828, 754 cm−1;
1H NMR (CDCl3) δ: 9.90 (s, 1H), 7.86 (d, J = 8.76 Hz

Heterocyclyl linked anilines and benzaldehydes
1067
2.5 Synthesis of methyl 2-bromo-3-{4-[(1-methyl-1H- 7.47–7.41 (m, 3H), 7.36–7.29 (m, 2H), 7.21–7.19;7.20
benzimidazol-2-yl)methoxy]phenyl} propanoate
(compound 3a, scheme 1)
(d, J = 8.80 Hz, 2H), 5.46 (s, 2H), 3.91 (s, 3H); LCMS
m/z (366) [M+1]+; Anal. Calcd for C19H15N3O3S: C,
62.45; H, 4.14; N, 11.50; S, 8.78. Found: C, 62.79; H,
4.135; N, 11.34; S.8.951.
To a slurry of (3) (1 g, 3.9 mmol) in methanol (10 ml)
and acetone (10 ml), cooled to −10◦C, was added 48%
aqueous HBr (0.83 ml, 15 mmol). The mixture was
stirred at 0◦C for 5 min, and a solution of sodium
nitrite (0.290 g, 4.2 mmol) in water (1 ml) was added
drop-wise so as to keep the reaction temperature below
5◦C. The mixture was stirred at 0–5◦C for 15 min,
and then methyl acrylate (2 ml, 23 mmol) was added
drop-wise. The mixture was warmed to 38◦C, pow-
dered cuprous oxide (120 mg, 0.84 mmol) was added,
and the mixture was stirred for 2 h at the same tem-
perature, then made basic with concentrated aqueous
ammonia, and extracted with EtOAc (3 × 20 ml). The
combined extracts were washed with water and brine,
dried over anhydrous Na2SO4, and concentrated. The
title compound (3a) was isolated by column chro-
matography MeOH/DCM (1:10) as a pale brown solid
(0.235 g, 15%): mp 83–85◦C; FTIR (KBr): 2926, 2855,
1734, 1600, 1486, 1406, 1364, 1239, 1016, 817, 750,
2.6b Synthesis of 5-{4-[(1-methyl-1H-indol-2-yl)-
methoxy]benzylidene}-1,3-thiazolidine-2,4-dione (8a,
scheme 2): Yield: 32.0%, mp: 173–175◦C; FTIR
(KBr): 3402, 2926, 2850, 2588, 1732, 1701, 1595,
1508, 1482, 1334, 1289, 1250, 1157, 1013, 820,
1
735 cm−1; H NMR (DMSO-d6)δ: 7.61 (d, 1H), 7.48
(d, J = 8.60 Hz, 2H), 7.35 (d, 1H), 7.22 (m, 1H), 7.11
(d, J = 8.60 Hz, 3H), 7.07 (d, 1H), 6.61 (s, 1H), 5.28
(s, 2H), 3.81 (s, 3H); LCMS m/z (365) [M+1]+; Anal.
Calcd for C20H16N2O3S: C, 65.92; H, 4.43; N, 7.69; S,
8.80. Found: C, 65.72; H, 4.78; N, 7.75; S, 8.63.
2.7 General procedure for the synthesis
of heterocyclyl linked diethyl benzylidene
propanedioates 4b and 8b
1
503 cm−1; H NMR (CDCl3)δ: 7.80–7.78 (m, 2H),
A solution of (4/8) (2.8 mmol) and diethyl malonate
(5.1 mmol) in toluene (30 ml) containing a catalytic
quantity of piperidinium acetate was refluxed for 7 h.
After cooling to rt, the solution was concentrated.
The residue was chromatographed using a mixture of
MeOH and DCM (1:99) or EtOAc and hexane (1:10) to
give (4b/8b) as white solid.
7.40–7.27 (m, 3H), 7.15–7.13 (d, J = 8.68 Hz, 2H),
7.04–7.01 (d, J = 8.68 Hz, 2H), 5.37 (s, 2H), 4.34 (dd,
J = 6.96 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.40(dd,
J = 6.9 Hz, 1H), 3.18 (dd, J = 6.9 Hz, 1H); GCMS
m/z (%): 402(3.8) [M]+, 404(4) [M+2]+ and 145 (100);
Anal. Calcd for C19H19BrN2O3: C, 56.69; H, 4.75; N,
6.95. Found: C, 56.85; H, 4.57; N, 6.73.
2.7a Diethyl {4-[(1-methyl-1H-benzimidazol-2-yl)-
methoxy]benzylidene} propanedioate (4b, scheme 1):
Yield: 45%, mp: 128–130◦C; FTIR (KBr): 2978, 2934,
2850, 1723, 1600, 1514,1471, 1399, 1260, 1212, 1175,
1064, 1013, 839, 744 cm−1; 1H NMR (CDCl3)δ: 7.79–
7.77 (m, 1H), 7.64 (s, 1H), 7.42–7.40 (d, J = 8.80 Hz,
2H), 7.37–7.27 (m, 3H), 5.42 (s, 2H), 7.09 (d, J =
8.8, 2H), 4.30 (two overlapping quartet, J = 7.2 Hz,
4H), 3.88 (s, 3H), 1.31 (t, J = 7.1Hz, 3H), 1.29 (t, J =
7.7 Hz, 3H); LCMS m/z (409) [M+1]+; Anal. Calcd
for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86. Found: C,
67.82; H, 6.21; N, 6.61.
2.6 General procedure for the synthesis
of heterocyclyl linked benzylidene-1,3-
thiazolidine-2,4-diones 4a and 8a
A mixture of (4/8) (0.25 mmol), thiazolidine-2,4-
dione (0.25 mmol) and catalytic quantity of piperi-
dinium acetate in toluene (50 ml) was refluxed for
7 h with continuous removal of water using a Dean–
Stark water separator. The reaction mixture was
cooled to rt and then stored inside a refrigerator
overnight. The yellow precipitate was collected by
filtration under suction, washed with hexane, and dried
to obtain (4a/8a) as pale yellow solid.
2.7b Diethyl {4-[(1-methyl-1H-indol-2-yl)methoxy]-
benzylidene} propanedioate (8b, scheme 2): Yield:
20.00%, mp: 108–110◦C; FTIR (KBr): 2979, 2920,
2850, 1720, 1602, 1511, 1464, 1381, 1340, 1263, 1207,
2.6a 5-{4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]-
benzylidene}-1,3-thiazolidine-2,4-dione(4a, scheme 1):
Yield: 40%, mp 271–273◦C; FTIR (KBr): 3410, 2948,
2850, 2532, 1730, 1704, 1580, 1509, 1482, 1450, 1408,
1334,1286, 1253, 1176, 1009, 831, 740 cm−1; 1H NMR
(DMSO-d6)δ: 7.75–7.73; 7.74 (d, 1H), 7.68 (s, 1H),
1
1178, 1007, 833, 751 cm−1; H NMR (CDCl3)δ: 7.67
(s, 1H), 7.61 (d,1H), 7.44 (d, J = 8.8 Hz, 2H), 7.34 (d,
1H), 7.25 (m, 1H), 7.12 (m, 1H), 7.01 (d, J = 8.8 Hz,
2H), 6.61 (s, 1H), 5.22 (s,2H), 4.35 (q, J = 7.1 Hz,

1068
Raman K Verma et al.
2H), 4.29 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.33 (t, amine (7) was similarly obtained by reduction of (6).
J = 4.3 Hz, 3H), 1.31 (t, J = 4.4 Hz, 3H); LCMS m/z The benzylidenes (8b) and (8a) were obtained from
(407) [M+1]+; Anal. Calcd for C24H25NO5: C, 70.46; (8) by condensation with diethyl malonate and 2,4-
H, 6.18; N, 3.44. Found: C, 70.13; H, 5.89; N, 3.27.
thiazolidinediones, respectively.
Acridonyl linked aldehyde and nitro compounds
were synthesized according to scheme 3. Acridone26
(9) brormopropoxybenzaldehyde20 (9b), and brormo-
propoxynitrobenzene20 (9a) were prepared by known
procedures. The aldehydes (12) and the nitro compound
(10) were prepared by microwave irradiation of (9)
and the corresponding bromo propoxy compounds27
(9b and 9a), (10a) was subsequently reduced to obtain
corresponding amine (11).
2.8 Synthesis of diethyl{4-[(1-methyl-1H-
benzimidazol-2-yl)methoxy]benzyl} propanedioate
(compound 4c, scheme 1)
A solution of 4b (400 mg, 0.98 mmol) in a mixture of
methanol and dioxane (125:50) was shaken in the pres-
ence of 10% Pd-C (100 mg) in a Parr Hydrogenator
under 20 psi H2 pressure at rt for 12 h. The mixture was
filtered through celite, and the filtrate was evaporated
under reduced pressure. The residue upon recrystalliza-
tion from methanol gave 4c (100 mg, 25%) as an off
white solid: mp 135–136◦C; FTIR (KBr): 2978, 2935,
2850, 1733,1610, 1511, 1475, 1372, 1235, 1147, 1037,
4. Conclusion
We report here the syntheses of benzaldehydes and
anilines linked at the para position, with an alkoxy
ether linkage to three crucial heterocycles namely,
benzimidazole, indole and acridone. Representative
procedure for the preparation of 1,3-diester, 2,4-
thiazolidinedione and α-bromopropanoic acid ester
derivatives in case of benzimidazole, and 1,3-diester
and 2,4-thiazolidinedione derivative in case of indole-
based precursors has been optimized, and the said
compounds have been successfully synthesised and
characterised.
1
1013, 825, 744 cm−1; H NMR (CDCl3)δ: 7.78–7.76
(m, 1H), 7.36–7.27 (m, 3H), 6.99–6.97 (m, 2H), 5.35
(s, 2H), 4.14 (two superimposed quartet, J = 2.7 Hz,
4H), 3.87 (s, 3H), 3.57 (t, J = 7.8 Hz, 1H), 3.14 (d,
J = 7.8 Hz, 2H), 1.18 (two superimposed triplet, J =
14.3 Hz, 6H); LCMS m/z (411) [M+1]+; Anal. Calcd
for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C,
67.47; H, 6.26; N, 6.59.
3. Results and discussion
Acknowledgements
Authors acknowledge the financial support from
IndSwift Labs. Ltd. (ISLL), SAS Nagar, Mohali for the
ISLL-Punjabi University Collaborative Research, and
providing the research fellowship to two of the authors
VK and PG.
The benzimidazolyl linked aldehyde and amino com-
pounds were prepared by the synthetic route as shown
in (scheme 1). N-methyl-1,2-phenylene diamine dihy-
drochloride (1) was cyclised drastically with glycolic
acid and chloroacetic acid to furnish the correspond-
ing hydroxyl-(1a) and chloro-(1b) compounds, respec-
tively in excellent yields. These were reacted with
4-fluorobenzaldehyde25 and 4-hydroxobenzaldehyde to
afford the aldehyde (4). The latter was condensed with
diethyl malonate18 and 2,4-thiazolidinedione16 to give
the benzylidenes (4b) and (4a), respectively. Catalytic
hydrogenation of (4b) with 10% palladium on car-
bon gave (4c). The amine (3) was prepared by treat-
ing (1a) with 4-chloronitrobenzene and subsequent
catalytic reduction of the resulting nitro compound (2).
The α-bromoester (3a) was prepared from (3) by a
known method.19
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