Synthesis of a new family of receptors having dibenz[c,h]acridine as spacers and their binding affinity with urea

Article abstract of DOI:10.1016/S0040-4020(99)01080-7

New molecular receptors with a dibenz[c,h]acridine as spacer and having functionality complementary to urea have been developed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01080-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 909–912
Synthesis of a New Family of Receptors having
Dibenz[c,h]acridine as Spacers and their Binding Affinity
with Urea
*
Jayanta K. Ray, Manas K. Haldar, Susmita Gupta and Gandhi K. Kar
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, West Bengal, India
Received 11 May 1999; revised 22 November 1999; accepted 9 December 1999
Abstract—New molecular receptors with a dibenz[c,h]acridine as spacer and having functionality complementary to urea have been
developed. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Scheme 1. Reagents and conditions: (i) POCl
3
, DMF, trichloroethylene, 60–65ЊC, 6 h; (ii) 7-bromo-1-naphthylamine, benzene, reflux, 20 h; (iii) 250–270ЊC,
Cl, reflux, 20 h; (v) n-BuLi, TMEDA, THF, Ϫ78ЊC, 35–40 min, then DMF at Ϫ78ЊC, 2 h; (vi) diethylenetriamine, benzene, reflux,
, EtOH, rt, 12 h.
2
5 min; (iv) DDQ, C
6 5
H
1
5 h; (vii) NaBH
4
Keywords: dibenz[c,h]acridine; spacers; urea.
*
Corresponding author. E-mail: JKray@hijli.iitkgp.ernet.in
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01080-7

9
10
J. K. Ray et al. / Tetrahedron 56 (2000) 909–912
Molecular recognition of dibenz[c,h]acridine derivatives as
spacers carrying different functional groups are interesting
due to their potential to mimic enzyme-like catalysts and
As urea is insoluble in chloroform, quantitative binding
studies were carried out with 8 at 300 K in CDCl . Binding
3
was evaluated by NMR titration in CDCl at 300 K by
3
1
suitability for binding guests by hydrogen bonds. In recent
adding increasing amounts of the guest. The addition of
years, many such receptors have been designed and their
binding capabilities with dicarboxylic acid derivatives
have been studied. The incorporation of substituents by
functionalising the parent nucleus with three more ligands
should have a profound influence on the capabilities of
dibenz[c,h]acridine derivatives to act as good receptors
and chelating agents.
powdered urea to CDCl solution of receptor 8 leads to its
dissolution and a downfield shift of the receptor NH protons.
3
2
–4
The binding constant of urea and receptor 8 was found to be
2
Ϫ1
1:5×10 M as determined by the gravimetric method of
7
Horman. The effect of addition of urea to receptor 7 led to
Ϫ1
an association constant Ͻ10 M .
The binding capability of 7 and 8 with urea was not that
strong compared with some reported receptors; however, 7
1
Here, we report the synthesis and complexation properties
of two novel receptors with a defined geometry suitable for
association with urea. Synthesis of the receptors was
achieved from 7-bromo-1-tetralone (1) (Scheme 1), which
was converted to the b-chlorovinylaldehyde derivative (2)
and 8 are not as rigid or complementary to urea. The 3D
structure of the compound 8 is absolutely symmetric (Fig.
1), so the formation of a complex with urea with a greater8
binding constant might be expected. However, DTMM
(Desktop Molecular Modeller) energy minimization for
the complex clearly showed that the linker portion is tilted
to one side (Fig. 2).
with POCl /DMF in 94% yield. The chlorovinylimine (3)
3
was obtained from the chloroaldehyde (2) on refluxing with
7-bromo-1-naphthylamine in 92% yield. The thermal cycli-
zation (250–270ЊC) of the chlorovinylimine produced the
dihydrodibenz[c,h]acridine derivative (4) in 85% yield as
the only isolable regioisomer in agreement with our earlier
Thus, when urea approaches 8 for complexation, it can only
do so from the bottom side because of some steric crowding;
we presume the reduction of the association constant is a
consequence of this.
5
,6
findings. The dehydrogenation of 4 with DDQ generated
2,12-dibromodibenz[c,h]acridine (5) in 94% yield. The
dibromo derivative was converted to dialdehyde (6) by
n-BuLi/DMF in 84% yield. This was condensed with
diethylenetriamine to generate the macrocyclic compound
In summary, we have achieved the first synthesis of new
18-membered macrocyclic ligands based on dibenz[c,h]-
acridine framework incorporating four nitrogen atoms in
(
7) in 93% yield. Compound 7 on reduction with NaBH in
4
ethanol afforded 8 in 95% yield, which has the correct func-
tionalities to bind the urea molecule.
Figure 1.
Figure 2.

J. K. Ray et al. / Tetrahedron 56 (2000) 909–912
911
the macrocyclic cavity, the binding studies show its affinity
for urea.
2,12-Dibromo-5,6-dihydrodibenz[c,h]acridine (4). Chloro-
vinylimine (510 mg, 1.07 mmol) was taken in a 25 ml single
neck round bottom flask, fitted with an air condenser and a
guard tube. It was then heated at 250–260ЊC. First the solid
melted to an orange oil and at 240–250ЊC a vigorous
exothermic reaction began with liberation of white subli-
mate. The reaction almost subsided within 5 min. It was
kept at 250–260ЊC for another 15 min, cooled to room
temperature, extracted with hot benzene, washed with
Experimental
1
13
H and C NMR spectra were recorded in CDCl solution
3
on a 200 MHz Bruker machine. Chemical shifts are
expressed in ppm using TMS as internal standard. Coupling
constant (J) values are given in Hz. IR spectra were
recorded on a Perkin–Elmer 800 machine. Melting points
water, dried (Na
brownish yellow solid thus obtained was purified by column
[Al , pet. ether/benzene 1:4] to afford a light yellow solid,
(400 mg, 85%); mp 211–212ЊC; d (CDCl ): 2.92–2.96 (m,
2H, CH ), 3.07–3.14 (m, 2H, CH
SO ) and the solvent evaporated off. The
2
4
(
uncorrected) were taken in one-side open glass capillaries
O
2 3
using a sulphuric acid bath. Elemental analyses have been
performed by CDRI, Lucknow (India). Yields of the
products are referred to spectroscopically homogeneous
substances.
H
3
), 7.11(d, 1H, Jˆ8.0 Hz,
2
2
4
3
H ), 7.45 (dd, 1H, Jˆ2.1 and 8.0 Hz, H ), 7.56 (d, 1H,
9
8
Jˆ8.8 Hz, H ), 7.66 (d, 1H, Jˆ8.8 Hz, H ), 7.66–7.80 (m,
10
11
7
1
2
H, H , H ), 7.85 (s, 1H, H ), 8.71(d, 1H, Jˆ2.1 Hz, H ),
13
7
-Bromo-1-chloro-3,4-dihydronaphthalene-2-aldehyde
9.44 (d, 1H, Jˆ1.2 Hz, H ). [Found: C, 57.31; H, 2.79; N,
(2). To an ice cooled solution of DMF (3–4 ml) in trichloro-
3.07. C21 requires C, 57.40; H, 2.96; N, 3.19%].
H13NBr
2
ethylene (10 ml), POCl (3.5 ml) was added dropwise and
3
stirred at 0–5ЊC for an additional 10 min. To this solution, a
solution of 7-bromo-1-tetralone (6.07 g, 27 mmol) in
trichloroethylene (65 ml) was added dropwise, maintaining
the temperature at 0–5ЊC. The mixture was allowed to warm
to room temperature gradually over 1 h and then stirred at
2,12-Dibromodibenz[c, h]acridine (5). To a solution of
dihydrodibromo compound 4 (540 mg, 1.23 mmol) in chloro-
benzene (70 ml), DDQ (307 mg, 1.35 mmol) was added and
refluxed for 20 h. After the usual work up, treatment with
charcoal and passing through small column (neutral Al
CHCl ) led to a light cream coloured solid. Yield 99%; mp
257–258ЊC; d
7.83 (dd, 2H, Jˆ1.8 and 8.6 Hz, H , H ), 8.56 (s, 1H,
O /
2
3
60–70ЊC for 6 h. During this time the colour of the solution
3
4
–6
8–10
changed to deep brown. It was then cooled to room tempera-
ture, poured into 100 ml ice cooled 25% NaOAc solution
and extracted with dichloromethane. The organic layer was
(CDCl ) 7.70–7.85 (m, 6H, H , H ),
H 3
3 11
7
1
13
H ), 9.68 (d, 2H, Jˆ1.8 Hz, H , H ). [Found: C, 57.59; H,
washed successively with brine solution, 5% NaHCO solu-
2.41; N, 3.09. C21
3.20%].
H11NBr requires C, 57.67; H, 2.52; N,
2
3
tion and finally several times with water. The organic layer
was separated, dried (Na SO ) and the solvent removed to
2
4
afford a yellow coloured residue. It was purified by recrys-
2,12-bisformyldibenz[c, h]acridine (6). To a cooled solu-
tion (Ϫ78ЊC) of the fully aromatic dibromide 5 (100 mg,
0.23 mmol) in THF (7 ml) and TMEDA (120 l, 0.8 mmol)
under an argon atmosphere was added n-BuLi (600 l,
0.8 mmol) over a period of 5 min. The solution first became
light red and on continued addition of BuLi turned blood
red. The solution was stirred at this temperature for an
additional 30 min to ensure the completion of the formation
of the anion. Now, DMF (200 l) was added dropwise to the
reaction mixture maintaining the same temperature
(Ϫ78ЊC). No change in colour was observed. Stirring was
continued for 1 h and monitoring by TLC showed the
completion of the reaction. After additional stirring for 1 h
at this temperature, water (20 ml) was added to the reaction
flask. The aqueous layer was extracted with chloroform
(2×15 ml) and the combined organic extract was washed
tallization (ether) to afford 2 as a light yellow solid (6.9 g,
Ϫ1
9
4%); mp 93–94ЊC; nmax (KBr): 1665 cm ; d (CDCl3)
H
2
.59–2.68 (m, 2H, CH ), 2.77–2.85 (m, 2H, CH ), 7.09
2
2
5
(
d, 1H, Jˆ8.0 Hz, H ), 7.47 (dd, 1H, Jˆ1.5 and 8.0 Hz,
6
8
H ), 8.0 (brs, 1H, H ), 10.37 (s, 1H, CHO). [Found: C,
4
8.53; H, 2.79. C H BrClO requires C, 48.62; H, 2.94%].
11 8
0
0
7
3
-Bromo-1-chloro-2-(7 -bromo-1 -naphthyliminomethyl)-
,4-dihydronaphthalene (3). A mixture of bromochloro-
aldehyde 2 (800 mg, 2.94 mmol) and 7-bromo-1-naphthyl-
amine (640 mg, 2.88 mmol) was refluxed for 14 h on a
water bath in dry benzene (65 ml). The solvent was removed
by distillation and 50 ml of fresh dry benzene was added to
the reaction mass and refluxing was continued for an
additional 6 h. The solvent was evaporated to give a solid
mass which was purified by column chromatography
well with water, dried (Na SO ) and removal of solvent
2 4
(
Al O , pet. ether/benzene 4:1). Crystallization from ben-
afforded a sticky dirty yellow solid. This was purified by
preparative TLC (benzene/EtAc 4:1) to afford the title
2
3
zene, pet. ether afforded the pure compound as a bright
yellow solid 3 (1.12 gm, 92%), mp 106–107ЊC; n
(
compound 6 as an yellow solid (73 mg. 95%); mp 249–
max
Ϫ1
Ϫ1
KBr) 1580, 1637 cm ; d (CDCl ) 2.87–2.94 (m, 2H,
250ЊC; nmax (KBr) 1688, 2851 cm ; d
H
(CDCl6): 7.85 (d,
3
8
H
3
5
9
CH ), 3.05–3.12 (m, 2H, CH ), 7.08–7.14 (m, 2H,
2H, Jˆ9.0 Hz, H , H ), 7.97 (d, 2H, Jˆ9.0 Hz, H , H ), 8.02
2
2
5
13
6
4
10
H ,H ), 7.40–7.45 (dd, 1H, Jˆ1.9 and 7.4 Hz, H ), 7.49
(d, 2H, Jˆ8.8 Hz, H , H ), 8.26 (dd, 2H, Jˆ1.4 and 8.8 Hz,
1
2
15
14
15
3
11
7
1
13
(
d, 1H, Jˆ7.5 Hz, H or H ), 7.55–7.73 (m, 3H, H , H
H , H ), 8.66 (s, 1H, H ), 10.03 (d, 2H, Jˆ1.4 Hz, H , H ),
1
2
16
8
or H , H ), 7.93 (d, 1H, Jˆ1.9 Hz, H ), 8.50 (d, 1H,
10.44 (s, 2H, CHO). [Found: C, 82.32; H, 3.73; N, 4.01.
1
8
Jˆ1.6 Hz, H ), 8.96 (s, 1H, NyCH); d (CDCl ) 23.74,
C H O N requires C, 82.39; H, 3.88; N, 4.18%].
23 13 2
C
3
2
1
1
6.88, 113.67, 120.05, 120.50, 126.22, 126.27, 126.46,
28.39, 128.95, 129.33, 129.80, 130.15, 132.31, 132.44,
33.80, 134.57, 136.89, 136.92, 147.88, 158.15. [Found:
Macrocyclic bisimine derivative (7). The dialdehyde 6
(58 mg, 0.17 mmol) and diethylene triamine (18 mg,
0.17 mmol) were taken together in dry benzene (15 ml)
and refluxed for 15 h. The solvent was evaporated to give
C, 52.85; H, 2.77; N, 2.81. C H NClBr requires C,
5
2
1
14
2
2.99; H, 2.94; N, 2.94%].

9
12
J. K. Ray et al. / Tetrahedron 56 (2000) 909–912
compound 7 as a yellow solid (65 mg, 93%); mp Ͼ300ЊC;
[Found: C, 80.33; H, 5.66; N, 13.76. C H N requires C,
27 23 4
80.40; H, 5.70; N, 13.90%].
Ϫ1
nmax (KBr) 1610, 1632, 3411–3811 (br) cm ; d (CDCl )
H
3
2
4
H
.21–2.26 (brs, 1H, NH), 3.11 (t, 4H, Jˆ4.8 Hz, CH –NH),
2
4
–6
7
.02 (t, 4H, Jˆ4.8 Hz, CH –Ny), 7.72–7.83 (m, 6H, H
,
2
8
–10
3
11
Acknowledgements
), 7.90 (d, 2H, Jˆ8.0 Hz, H , H ), 8.52 (s, 1H, H ),
1
13
8
5
1
.63 (s, 2H, H , H ), 10.59 (s, 2H, CHyN); d (CDCl )
C 3
Thanks to DST & CSIR, New Delhi, for financial assistance.
0.30, 57.91, 78.34, 112.30, 124.85, 126.13, 126.65,
27.36, 129.27, 130.72, 133.82, 134.4, 144.88, 160.03.
[
8
Found: C, 80.66; H, 5.17; N, 13.88. C H N requires C,
0.79; H, 5.24; N, 13.97%].
27 21 4
References
1
1
. Bell, T. W.; Hou, Z. Angew. Chem., Int. Ed. Engl. 1997, 36,
536.
Macrocycle (8). To a stirred suspension of compound 7
76 mg, 0.2 mmol) in 10 ml of ethanol, NaBH (30 mg,
(
4
2. Hegde, V.; Hung, C. Y.; Madhukar, P.; Cunningham, R.;
Hopfner, T.; Thummel, R. P. J. Am. Chem. Soc. 1993, 115, 872.
0.8 mmol) was added portionwise. After the addition was
over the reaction was stirred at room temperature for 12 h.
Ethanol was removed under reduced pressure, the residue
was diluted with water and extracted with chloroform. The
organic layer was washed thoroughly with water, dried
3
. Roposo, C.; Sanz, M. J.; Mussons, M. L.; Crego, M.; Moran, J. R.
Ann. Quim. 1993, 89, 617.
. Mussons, M. L.; Raposo, C.; Crego, M.; Anaya, J.; Caballero,
4
M. C.; Moran, J. R. Tetrahedron Lett. 1994, 35, 7061.
5. Haldar, M. K.; Kar, G. K.; Ray, J. K. Synlett 1997, 1057.
(
Na SO ) and removal of solvent under reduced pressure
2 4
afforded the title compound 8 (73 mg, 95%); mp 181–
82ЊC; dH (CDCl ) 1.70–2.15 (br, 3H, NH), 2.93 (t, 4H,
6
. Kar, G. K.; Sami, I. M.; Ray, J. K. Chem. Lett. 1992, 1739.
1
3
7. Horman, I.; Dreux, B. Anal. Chem. 1983, 55, 1219.
8. Energy minimization was done using DTMM (version 1.0),
Crabbe, M. J. C.; Appleyard, J.; Oxford University Press: Oxford,
Jˆ5.2 Hz, CH ), 3.07 (t, 4H, Jˆ5.2 Hz, CH ), 4.22 (brs,
2
2
4
2
H, ArCH ), 7.55 (dd, 2H), 7.75–7.85 (m, 4H), 7.86 (d,
2
7 1 13
H, Jˆ8.1 Hz), 8.60 (s, 1H, H ), 9.99 (brs, 2H, H , H ).
1
989.