Synthesis of the first tris(crown formazan)

Article abstract of DOI:10.1016/j.tetlet.2005.12.078

A synthesis of tris(crown formazan) 2 from the corresponding hexakis(acetamidophenoxymethyl)benzene 11 by hydrolysis with an ethanolic solution containing hydrochloric acid followed by diazotization and subsequent coupling with cyanoacetic acid in pyridin

Full text of DOI:10.1016/j.tetlet.2005.12.078

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1303–1306
Synthesis of the first tris(crown formazan)
Ahmed H. M. Elwahy* and Ashraf A. Abbas
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Received 22 September 2005; revised 2 December 2005; accepted 14 December 2005
Available online 9 January 2006
Abstract—A synthesis of tris(crown formazan) 2 from the corresponding hexakis(acetamidophenoxymethyl)benzene 11 by hydrol-
ysis with an ethanolic solution containing hydrochloric acid followed by diazotization and subsequent coupling with cyanoacetic
acid in pyridine containing CuSO4 is described.
Ó 2005 Elsevier Ltd. All rights reserved.
The chemistry and diverse applications of acyclic
formazans as well as monocyclic crown-formazans have
received much attention and are the subject of a large
number of reviews.1 Many macrocyclic formazans have
been synthesized and their applications in selective metal
extraction2 and determination3 were studied. Such
applications depend mainly on the cavity size of the
macrocyclic crown formazans as well as on the substitu-
ents in the macrocycle. In this respect we recently
reported the synthesis of macrocyclic formazans 1 and
studied their behavior in spectrophotometric determina-
tion of lithium as well as carriers in cesium ion selective
electrodes.4
two or more guest metal cations. In continuation of
these studies we report here the first synthesis of the
tris(crown formazan) 2, which is expected to be useful
analytically on account of its ability to bind more than
one metal ion.
Two strategies have been investigated for the synthesis
of the target compound 2. In the first strategy (Scheme
1) we studied the synthesis of crown formazan 3, which
should undergo cyclotrimerization upon heating with a
catalytic amount of CpCo(CO)2 to give the target com-
pound 2.6
For this purpose the bis(acetamido) derivative 6 was
prepared in 70% yield as outlined in Scheme 2, by react-
ing the K-salt 5 (obtained upon treatment of acetamido-
phenol 4 with KOH) with 1,4-dibromo-2-butyne in
boiling DMF. Compound 6 underwent acid hydrolysis
upon treatment with an ethanolic solution containing
hydrochloric acid to give an 85% yield of the corre-
sponding bis(amine hydrochloride) 7. Unfortunately,
diazotization of 7 with NaNO2 in hydrochloric acid
followed by coupling with cyanoacetic acid in pyridine
containing CuSO4 did not yield the corresponding
macrocyclic formazan 3. The reaction instead gave a
mixture of products that were difficult to separate and
were not characterized.
Moreover, interest has recently been directed towards
the synthesis of multi-site crown compounds.5 These
multi-site molecular receptors are capable of binding
X
O
O
H
N
N
N
N
R
It is also noteworthy that the macrocyclic formazan 9
could not be obtained by coupling of the corresponding
bis(diazonium salt) 87,8 with cyanoacetic acid (Scheme
3).
1
X, = (CH2)3, (CH2)4, CH2C(=CH2)CH2, CH2CH(OH)CH2,
(CH2)2-O-(CH2)2,
R = H, Ph, CN, ArSO2
In search of an expedient pathway to prepare 2 our
attention focused on compound 12 as a precursor, which
should undergo diazotization and subsequent coupling
Keywords: Alkylation; Diazotization; Coupling; Macrocyclic formazan.
*
Corresponding author. E-mail: aelwahy@hotmail.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.078

1304
A. H. M. Elwahy, A. A. Abbas / Tetrahedron Letters 47 (2006) 1303–1306
with cyanoacetic acid to furnish the target molecule 2
(Scheme 4). Thus, six-fold substitution of hexakis(bromo-
methyl)benzene 109 with 6 equiv of the potassium
salt 5 in refluxing DMF gave an 82% yield of the corre-
sponding hexakis(acetamidophenoxymethyl)benzene 11
as colourless crystals. Treatment of the latter with an
ethanolic solution containing hydrochloric acid gave
the corresponding hexakis(amine hydrochloride) 12 in
78% yield. Diazotization with NaNO2 in hydrochloric
acid followed by coupling with cyanoacetic acid in pyr-
idine containing CuSO4 and subsequent purification
gave the corresponding tris(crown formazan) 2 as deep
red crystals in 10% yield.10
CN
N
N
N
H
NC
N
H
N
O
O
N
N
N
O
O
O
O
H
N
N
N
N
CN
The structure of 2 was confirmed by IR, NMR and MS
as well as elemental analysis. The symmetry of com-
pound 2 is manifested by a singlet characteristic of the
2
1
six equivalent OCH2 groups in the H NMR spectrum.
O
O
CpCo(CO)2
The structure of compound 2 was further confirmed
by comparison with those of the related crown forma-
zans 13 and 14.
2
H
N
N
N
N
Compound 13 was synthesized as described4c by cou-
pling of the corresponding bis(diazonium salt) with
cyanoacetic acid in pyridine containing CuSO4. Com-
pound 14 was prepared as outlined in Scheme 5. Thus,
reaction of the K-salt 5 with 1,3-bis(bromomethyl)benz-
ene 15 in boiling DMF yielded 75% of the correspond-
CN
3
Scheme 1.
O
O
OH
OK
KOH / EtOH
Br
Br
HN
COCH3
NHCOCH3
NHCOCH3
NH
boiling DMF
COCH3
4
5
6
HCl EtOH
reflux
1)
2)
NaNO2 / HCl
O
O
CNCH COOH/ pyridine
2
3
H2N
HCl
NH2
HCl
7
Scheme 2.
O
O
O
O
CNCH2COOH/ pyridine
H
N
N
N
N
N2Cl
ClN2
CN
8
9
Scheme 3.

A. H. M. Elwahy, A. A. Abbas / Tetrahedron Letters 47 (2006) 1303–1306
1305
tons in the downfield region at d = 15.70 and 16.0 ppm,
respectively, which confirm the existence of an intra-
molecular hydrogen bond.12
O
O
O
O
On the other hand the NH proton signal of the macro-
cyclic formazan 14 is at d = 11.94. This upfield shift of
the NH proton indicates weakening of the intramole-
cular hydrogen bond, which can be attributed to the in-
crease in size of the macrocycle 14 compared with that
of 13.
H
H
N
N
N
N
N
N
N
N
CN
CN
In conclusion, we have developed a simple method for
the preparation of the tris(crown formazan) 2. Full char-
acterization of this compound is reported. Comparison
of the structure of the latter with those of related crown
formazans 13 and 14 is reported. Our current studies are
directed towards extending the scope of this method to
cover additional multi-site crown compounds with
potential diverse applications in supramolecular chemis-
try. Studies on the cation binding properties of this new
macrocycle are in progress.
13
14
ing bis(acetamido) derivative 16. The latter underwent
acid hydrolysis upon treatment with an ethanolic solu-
tion containing hydrochloric acid to give the corre-
sponding bis(amine hydrochloride) 17 in quantitative
yield. Diazotization of 17 and subsequent coupling with
cyanoacetic acid in pyridine afforded, after purifica-
tion,11 the macrocyclic formazan 14 as deep red crystals
in 18% yield.
Physical data for compounds 2, 6, 11, 14 and 16:13 Com-
pound 2: mp >250 °C, MS (ESI): m/z (%) 1016
1
[(M+Na)+, 32%], 413 (100); IR: 2230 (CN) cmÀ1; H
Comparison of the positions of the NH proton signals in
1
the H NMR spectra of the target compound 2 with
NMR (300 MHz, CDCl3) d 5.50 (s, 12H, OCH2),
6.98–7.75 (m, 24H, ArH), 15.70 (s, 3H, NH) ppm.
(Calcd for C54H39N15O6 (994.01): C, 65.25; H, 3.96;
N, 21.14%. Found: C, 65.20; H, 4.20; N, 20.90%).
those of crown formazans 134c and 14 confirmed the
structure of 2. Thus, compounds 2 and 13 were charac-
terized by the presence of sharp signals for the NH pro-
R
R
Br
Br
O
O
OK
R
R
NHCOCH3
DMF
Br
O
O
+
Br
Br
Br
O
O
R
R
5
10
11: R = NHCOCH3
12: R = NH2.HCl
EtOH/HCl
reflux
1) NaNO2/HCl, 0 oC
2
CNCH COOH/
2)
2
pyridine, 0 oC
Scheme 4.
5
O
O
EtOH/HCl
reflux
O
O
1) NaNO2/HCl, 0 oC
14
DMF, reflux
5 min
NH
HN
COCH3
NH2
HCl
H2N
HCl
CNCH COOH/
2)
2
Br
Br
COCH3
pyridine, 0 oC
15
17
16
Scheme 5.

1306
A. H. M. Elwahy, A. A. Abbas / Tetrahedron Letters 47 (2006) 1303–1306
Lett. 1996, 37, 3133–3136; (e) Zeng, W.; Mao, Z. H.; Wei,
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6. For relevant papers and reviews on cyclooligomeriza-
tion of alkynes catalyzed by transition metal complexes
see: (a) Grotjahn, D. B. In Comprehensive Organometallic
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Compound 6: colourless crystals (ethanol) mp 142–
144 °C; IR: 3304 (NH) cmÀ1, 1663 (CO); 1H NMR
(300 MHz, CDCl3) d 2.19 (s, 6H, NHCOCH3), 4.80 (s,
4H, OCH2), 6.88–8.38 (m, 10H, ArH, NH) ppm. Com-
pound 11: colourless crystals (ethanol) mp 246–248 °C;
1
IR: 3305 (NH) cmÀ1, 1673 (CO); H NMR (300 MHz,
DMSO) d 1.91 (s, 18H, NHCOCH3), 5.28 (br s, 12H,
OCH2), 6.94–7.79 (m, 24H, ArH), 8.94 (s, 6H, NH)
ppm. Compound 14: mp >280 °C, MS (EI): m/z (%)
383 [M+, 60%], 373 (73), 282 (100). IR: 3295 (NH)
cmÀ1, 2226 (CN). (Calcd for C22H17N5O2 (383.41): C,
68.92; H, 4.47; N, 18.27%. Found: C, 68.90; H, 4.60;
N, 18.40%). 1H NMR (300 MHz, DMSO) d 5.20 (s,
4H, OCH2), 6.85–7.90 (m, 12H, ArH), 11.94 (br s, 1H,
NH) ppm. Compound 16: colourless crystals (ethanol)
Chem. Rev. 1996, 96, 49–92; (c) Fruhauf, H.-W. Chem.
¨
Rev. 1997, 97, 523–596; (d) Stara, I. G.; Stary, I.;
Kollarovic, A.; Teply, F.; Vyskocil, S.; Saman, D.
Tetrahedron Lett. 1999, 40, 1993–1996; (e) Sato, Y.;
Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231–
5234.
1
mp 176–178 °C; IR: 3300 (NH) cmÀ1, 1660 (CO); H
7. Compound 8 was obtained by first reacting 5 with 1,4-
dibromo-2-butene in boiling DMF to give the correspond-
ing bis(acetamido) derivative. The latter then underwent
acid hydrolysis upon treatment with an ethanolic solution
containing hydrochloric acid followed by diazotization
with NaNO2.
NMR (300 MHz, CDCl3) d 2.14 (s, 6H, NHCOCH3),
5.16 (s, 4H, OCH2), 6.87–8.38 (m, 14H, ArH, NH) ppm.
References and notes
8. Compound 9 could only be obtained by ring closure
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exhaustive bromomethylation of commercially available
1,3,5-trimethylbenzene followed by bromination following
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10. Typical experimental procedure for the synthesis of 2: A
solution of the hexakis(amine hydrochloride) 12 (1 mmol)
in water (5 ml) and concd HCl (3 ml) was diazotized at
À5 °C with a solution of sodium nitrite (0.23 g in 5 ml
water) for 0.5 h. Stirring was continued for 1 h at À5 °C
and then the reaction mixture was added dropwise with
stirring to a solution containing cyanoacetic acid (3 mmol)
in pyridine (150 ml), CuSO4Æ5H2O (0.5 g) and 20 ml water
over a period of 1 h. The reaction mixture was then stored
in a freezer overnight. A solid precipitated upon addition
of concentrated hydrochloric acid, which was filtered and
purified.11
11. Compounds 2 and 14 were purified on preparative TLC
using silica gel (60 F254) with CH2Cl2 as eluent (Rf = 0.33)
for compound 2 and with a mixture of CH2Cl2:CH3OH
(40:1) as eluent (Rf = 0.69) for compound 14.
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13. All new compounds described here gave correct elemental
analyses.