Synthesis of new molecules containing head, spacer, and label moieties

Article abstract of DOI:10.1021/jo025691r

We describe the synthesis and characterization of novel molecules containing head with precise shape, spacer, and label moieties. The protocol is based on a Pd(0)-catalyzed cross-coupling reaction between ethynylphenyl/bromide to obtain a rigid head followed by the attachment of a flexible spacer possessing two reactive functional groups on the termini. The final step consists of forming a covalent bond between spacer and label. In addition, monosubstituted soluble labels were synthesized in good yields.

Full text of DOI:10.1021/jo025691r

Syn th esis of New Molecu les Con ta in in g Hea d , Sp a cer , a n d La bel
Moieties
Abderrahim Khatyr, Huub Maas, and Gion Calzaferri*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3,
CH-3012, Bern, Switzerland
gion.calzaferri@iac.unibe.ch
Received March 7, 2002
We describe the synthesis and characterization of novel molecules containing head with precise
shape, spacer, and label moieties. The protocol is based on a Pd(0)-catalyzed cross-coupling reaction
between ethynylphenyl/bromide to obtain a rigid head followed by the attachment of a flexible
spacer possessing two reactive functional groups on the termini. The final step consists of forming
a covalent bond between spacer and label. In addition, monosubstituted soluble labels were
synthesized in good yields.
In tr od u ction
In natural photosynthesis, arrays of antennae collect
solar energy and convert it into the chemical potential
energy that drives the chemistry of the photosynthetic
machinery. The processes involved are very fast and
highly efficient.1,2 Good examples of the scientific progress
in light-harvesting systems are the artificial photonic
antenna systems, where highly effective energy transport
has been reported.3-7 In these systems, zeolite L crystals
are used as a host to organize dye molecules inside
monodirectional channels as shown in Figure 1A. Light
shining on the cylindrical crystals is first absorbed by
donor molecules (D) and then transported to the acceptor
molecules (A). These antenna systems work so well that
it is a major challenge to modify them to utilize the
collected energy. For a number of technological applica-
tions, e.g. on a semiconductor surface, it is favorable to
trap the excitation energy at the external surface of the
crystals. This enables coupling of the antenna function
with the environment of the crystals and simultaneously
stabilizes the dye-loaded zeolite material.
F IGURE 1. (A) Simplified view of a bidirectional photonic
antenna. (B) Schematic representation of the typical shape of
a stopcock molecule located at the end of a zeolite channel.
inserted. The head and the label are connected by an
inert flexible spacer, which also improves the solubility
of the whole molecule. Various types of molecules with a
stopcock shape have been explored, including substrates
with an affinity for the cytochrome P450cam heme pocket,9
biomaterials,10,11 modified amino acids with defined bind-
ing sites for transition-metal complexes,12-14 and selective
molecular chemosensors.15,16 Here, we report the synthe-
sis of products with a combination of structural and
functional moieties, which pave the way for their ap-
plication as dyes or closures for the channels of zeolite
L.
Our approach involves adding “stopcock” molecules
with polar groups at the end of the channels 6,8 as shown
schematically in Figure 1B. The stopcock molecule has
a part that is too big to penetrate into the channels of
zeolite L (head), whereas the label is small enough to be
Resu lts a n d Discu ssion
A synthetic strategy was developed for the preparation
of varying stopcock molecules. The adopted procedure
* Address correspondence to this author. Phone: 0041-031-6314236.
Fax: 0041-031-6313994.
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Schaafsma, T. J . Mater. Chem. 2002, 12, 1.
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10.1021/jo025691r CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
J . Org. Chem. 2002, 67, 6705-6710
6705

Khatyr et al.
SCHEME 1a
SCHEME 2a
a
Conditions: (i) 4-bromobutyryl chloride (n)1) or 6-bromohex-
anoyl chloride (n)3) (1 equiv), (Et)3N (3 equiv), DMAP (10% mol),
CH2Cl2, rt, 2d. (ii) 7-amino-4-methycoumarin (1.2 equiv), CF3-
CH3OH, 100 °C, 2 d.
a new low spot Rf (0.27, CH2Cl2/hexane, 8/2) due to the
unwanted cyclic succinimid product. The 13C NMR spec-
trum data of 2 show the carbon of acid chloride and amide
functions as singlets at 170.6 and 174.2 ppm, respec-
tively.21 Nonetheless, two singlets at 82.4 and 97.3 ppm
being typical for acetylenic signals clearly point to the
number of triple bonds in agreement with the expected
structure.22 The absorption spectra of 1 and 2 carried in
dichloromethane at room temperature show several
bands below 370 nm. Upon excitation of 2 at 300 nm, an
emission at 400 nm was observed. The shift with respect
to the emission of 1 is ascribed to a perturbation of the
conjugated system due to the attached chain.
The preparation of the stopcock molecules 3 and 4 was
accomplished by the stoichiometric esterification23,24 of
the acid chloride function from 2, with 7-hydroxy-4-
methylcoumarin and N-hydroxysuccinimid in moderate
yields of 22 and 34%, respectively. The UV-vis absorp-
tion spectra of labeled compounds 3 and 4 measured in
dichloromethane exhibited three maxima between 250
and 360 nm. After excitation at 300 nm, an emission
maximum was observed around 375 nm with a broad
band around 413 nm for 3 and 380 nm for 4. Because of
the low solubility of stopcocks 3 and 4, other spacers were
used, first to improve the solubility and second to vary
the distance between head and label.
a
Conditions: (i) Pd(PPh3)4 (6% mol), (Et)3N (excess), benzene,
70 °C, 22 h. (ii) succinyl chloride (1 equiv), (Et)3N (1 equiv), CH2Cl2,
rt, 16 h. (iii) 7-hydroxy-4-methycoumarin (1 equiv), (Et)3N (1
equiv), CH2Cl2, rt, 30 h. (iv) N-hydroxysuccinimid (1 equiv), K2CO3
(excess), CH3CN, 50 °C, 16 h.
utilizes key intermediates 1, 2, and 6. Precursor 1
(Scheme 1) is synthesized by a cross-coupling reaction
between 2,6-dibromo-4-nitroaniline and 4-ethynyltoluene
in good yield (92%). The use of the catalytic system Pd-
(PPh3)2Cl2/CuI
17,18
in THF overnight at room tempera-
ture showed only the monocoupled product. However, this
reaction was carried out in the presence of catalytic
amounts of [Pd(PPh3)4], and an excess of triethylamine
in nitrogen-degassed benzene at 70 °C. It is worth
knowing that the Sonogashira coupling reaction tolerates
the presence of nitro and arylamine functions without
significantly perturbing the course of the palladium-
promoted catalytic reaction. The emission spectrum of 1
shows a band at 470 nm, after excitation at 300 nm in
dichloromethane.
The reaction of the intermediate 1 with succinyl
chloride proceeded under nitrogen in dry dichloromethane
at room temperature in the presence of 1 equiv of
triethylamine.19,20 After recrystallization from an ap-
propriate solvent, 2 was recovered in 42% yield as a
yellow solid. Upon exposure to the atmosphere, after a
few days, compound 2 was decomposed and gave a brown
solid. Repeating the reaction with an increasing quantity
of triethylamine gave a dark mixture. TLC analysis
during the course of the reaction showed an increase of
Further reaction of intermediate 1 with 4-bromobutyryl
chloride (Scheme 2) in the presence of 3 equiv of triethyl-
amine and 4-(dimethylamino)pyridine (DMAP) in dry
dichloromethane at room temperature25 afforded inter-
mediate 5. After purification by flash chromatography
(17) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 50, 4467.
(18) Takahashi, S. N.; Kuroyama, Y.; Sonogashira, K.; Hagihara,
N. Synthesis 1980, 8, 627.
(19) Shalem, H.; Shatzmiller, S.; Feit, B.-A. J . Chem. Soc., Perkin
Trans. 1 2000, 16, 2831.
(20) Marson, C. M.; Schwarz, I. Tetrahedron Lett. 2000, 41, 8999.
(21) Karlstro¨m, A.; Unde´n, A. Tetrahedron Lett. 1996, 37, 4243.
(22) Khatyr, A.; Ziessel, R. J . Org. Chem., 2000, 65, 3126.
(23) Wang, X.; Parlow, J . J .; Porco, J . A., J r. Org. Lett. 2000, 2, 3509.
(24) Tietze, L. F.; Schirok, H.; Wo¨hrmann, M.; Schrader, K. Eur. J .
Org. Chem. 2000, 13, 2433.
(25) Nguyen-Ba, N.; Lee, N.; Chan, L.; Zacharie, B. Bioorg. Med.
Chem. Lett. 2000, 10, 2223.
6706 J . Org. Chem., Vol. 67, No. 19, 2002

New Molecules with Head, Spacer, and Label Moieties
SCHEME 3a
a
Conditions: (i) NaOH, CH3OH/H2O, rt, 1 h. (ii) Benzaldehyde (1 equiv), NaOH, CH3OH/H2O, rt, 5 h. (iii) Br2 (2 equiv), CHCl3, rt, 0.5
h. (iv) (a) NH2OH‚HCl (2 equiv), EtOH, 80 °C, 2 h; (b) KOH (6 equiv), EtOH, 80 °C, 1.5 h.
The FT-IR spectra recorded for 1 to 7 all show a band
between 2208 and 2214 cm-1, associated with the acety-
lene stretching vibration.
In the second part of this work, we present the
synthesis of monofunctionalized dyes with good solubility
and linear structural properties. Monocondensation of
1,4-diacetylbenzene with 1 equiv of anisaldehyde (Scheme
3) in methanolic sodium hydroxide solution afforded a
mixture of cis- and trans-1-(3-{4-methoxyaryl}-2-prope-
noyl)-4-acetylbenzene isomers,27 where the product re-
sulting from the biscondensation was observed. The
monocondensation is profoundly influenced by the con-
centration, the solvent, and the amount of base. Purifica-
tion on alumina followed by recrystallization in dichlo-
romethane/hexane gave the trans isomer 8 in 63% yield.
F IGURE 2. Absorption (solid) and luminescence (dotted)
spectra recorded for 7. The luminescence spectrum has been
scaled to the absorption maximum.
Condensation under similar conditions of 8 with one
molar proportion of benzaldehyde gave isomers 9 in 67%
yield. Reaction of bromine in chloroform with 9 at room
temperature gave compound 10. Cyclization has been
realized by refluxing 10 with 2 equiv of hydroxylammo-
nium chloride in an ethanolic potassium hydroxide
solution for about 2 h, affording 11 in 32% yield. The
absorption spectrum of 8 shows two bands, one at 265
nm and the other at 349 nm. After reaction with
benzaldehyde, 9 was obtained and the absorption maxima
shifted to 273 and 341 nm, respectively. Bromation of
the double bonds led to compound 10, which showed only
one weak absorption band at 273 nm. The band at 341
nm has disappeared. It can therefore be attributed to the
olefins groups. Product 11 has an intense absorption at
280 nm with a long wavelength shoulder.
on alumina and recrystallization in dichloromethane/
hexane, 5 was recovered in 68% yield. Under similar
conditions, reaction of 1 with 6-bromohexanoyl chloride
gave 6. This compound was obtained by similar workup
in 74% yield. The pure intermediates 5 and 6 are soluble
in most chlorinated solvents and are isolated as deep-
yellow powders.
Stopcock molecule 7 was prepared by N-alkylation26
between compound 6 and 1 equiv of 7-amino-4-methyl-
coumarin under nitrogen in 2,2,2-trifluoroethanol at 100
°C. After purification, 7 was recovered in 48% yield. The
UV-vis absorption spectrum of 7 (Figure 2) measured
in dichloromethane at room temperature exhibited a
maximum at 300 nm with a shoulder at 275 nm and an
additional band at 370 nm. After excitation at 300 nm,
the fluorescence maximum was observed at 400 nm
together with a long wavelength shoulder. These fluo-
rescence bands can be attributed to the head and label,
respectively. This is also confirmed by excitation spectra.
Esterification of the hydroxy group of 7-hydroxy-4-
methylcoumarin (Scheme 4) was carried out by reacting
it with 6-bromohexanoyl chloride or 0.5 equiv of succinyl
chloride in dichloromethane as a solvent and triethyl-
amine as a base at room temperature to give, after
(27) Devi, Y. U.; Ashok, K.; Rao, K. M. Indian J . Chem. Sect. B 1990,
29, 898.
(26) Chan, C. M. Synth. Commun. 1989, 19, 1981.
J . Org. Chem, Vol. 67, No. 19, 2002 6707

Khatyr et al.
F IGURE 3. (A) Fluorescence microscope image showing a 2000 nm length zeolite L crystal modified with a molecule of 7 on each
side of the channels. The sample was excited at 330-385 nm and observed through a cutoff filter at 420 nm. The rectangle
indicates a single zeolite L crystal. (B) Schematic picture of 7 plugging a zeolite L channel in a stopcock manner.
SCHEME 4a
rescence microscope with 100× magnification with use
of immersion oil with a refractive index close to that of
zeolite L to exclude refraction effects. Figure 3A shows a
zeolite L crystal modified with a molecule of 7 on each
side of the channels. The image clearly shows that the
emission stems from the bases of the cylindrical crystals,
which appear as two bright lines. Since the free open
diameter of the zeolite L channel is 7.1 Å and 7 is
approximately 18 Å wide, the molecules cannot enter the
channels, but the label can penetrate into the channel
ends and plug them as shown in Figure 3B. This explains
why the base surfaces of the crystals strongly emit.
a
Conditinos: (i) 6-bromohexanoyl chloride (1 equiv), (Et)3N (1
equiv), CH2Cl2, rt, 6 h (ii) succinyl chloride (0.5 equiv), (Et)3N (1
equiv), CH2Cl2, rt, 2 h.
Exp er im en ta l Section
Gen er a l Meth od s. The 300-MHz 1H and 75-MHz 13C NMR
spectra were recorded at room temperature, unless specified,
using perdeuterated solvent as an internal standard: δ (H)
in ppm relative to residual protiated solvent in CDCl3 (7.26);
δ (C) in ppm relative to the solvent in CDCl3 (77.0); all carbon
signals were detected as singlets. Melting points were obtained
on an open-ended Bu¨chi (type Dr. Tottoli) capillary melting
point apparatus and are uncorrected. FT-IR spectra were
measured in KBr pellets. UV-vis spectra were measured with
a Perkin-Elmer Lambda 900 spectrophotometer in CH2Cl2 at
room temperature. Fluorescence spectra were recorded on a
Perkin-Elmer LS-50B luminescence spectrometer with suitable
cutoff filters. El-MS data were provided by analytical research
services of the University of Bern. Elemental analyses (C, H,
N) were performed with an elemental analyzer. Optical
microscopy images of fluorescent samples were recorded under
an Olympus BX 60 microscope combined with a Kappa CF 20
DCX Air K2 CCD camera with 100× magnification and an
immersion oil.
Ma ter ia ls. 2,6-Dibromo-4-nitroaniline, 4-bromobutyryl chlo-
ride, 6-bromohexanoyl chloride, 1,4-diacetylbenzene, 7-amino-
4-methylcoumarin and 7-hydroxy-4-methylcoumarin were pur-
chased from Aldrich. [Pd(PPh3)4], triethylamine, succinyl
chloride, anisaldehyde, and benzaldehyde were purchased from
Fluka. 4-Ethynyltoluene was prepared according to a similar
procedure in the literature.17,18 All reactions were carried out
under dry nitrogen by using Schlenk-tube techniques.
2,6-Bis(4-eth yn yltolu en e)-4-n itr oa n ilin e (1). A Schlenk
flask equipped with a septum, a Teflon-coated magnetic
stirring bar, and an nitrogen inlet was charged with 25 mL of
nitrogen-degassed benzene, and then 0.500 g (1.689 mmol) of
2,6-dibromo-4-nitroaniline, 0.428 mL (3.378 mmol) of 4-eth-
ynyltoluene, and 0.117 g (0.101 mmol) of [Pd(PPh3)4] were
added, followed by 3 mL of nitrogen-degassed triethylamine.
After heating at 70 °C for 22 h, the solvent was removed under
purification, products 12 and 13 in quantitative yields
(84 and 95%). Both absorption spectra of 12 and 13
measured in dichloromethane exhibited two distinct
maxima at 272 and 312 nm and they are of almost
identical shape. The molar extinction coefficients of 12
and 13 at the 312 nm band are 9800 and 14100 M-1 cm-1
,
respectively. This reflects the number of coumarin units
but also the fact that the chain has some influence on
the oscillator strength.
Con clu sion
We have provided a practical method for the synthesis
of new stopcock molecules and soluble dyes with potential
value for artificial antenna systems. The ready avail-
ability of the reagents, the overall simplicity of the
procedure, the use of mild reaction conditions, and the
reasonable yields obtained suggest that this methodology
is a useful entry for the preparation of hybrid molecules
bearing other luminescent fragments.
With product 7 some preliminary experiments with
zeolite L crystals were done according to a similar
procedure as described earlier.8 Zeolite L crystals of about
2000 nm length were suspended in dichloromethane and
the appropriate amount of 7 for a modification of 2
molecules per crystal channel was added. The suspension
was first put in an ultrasonic bath for half an hour and
then stirred for 2 h. Some drops were given on a
microscope slide and the dichloromethane was evapo-
rated. Then, the crystals were examined under a fluo-
6708 J . Org. Chem., Vol. 67, No. 19, 2002

New Molecules with Head, Spacer, and Label Moieties
vacuum, and the purification was performed by flash chroma-
tography on alumina with hexane/CH2Cl2 (50 to 80%) as eluant
to afford 0.569 g of 1 (92%). Mp 217-8 °C; 1H NMR (CDCl3) δ
2.40 (s, CH3, 6H), 5.57 (bs, NH2, 2H), 7.20 (d, J ) 7.7 Hz, Ph,
4H), 7.44 (d, J ) 8.1 Hz, Ph, 4H), 8.24 (s, Ph, 2H); 13C NMR
(CDCl3) δ 21.6, 82.5 (CtC), 96.8 (CtC), 119.0, 124.9, 129.4,
131.6, 139.5, 153.1; FT-IR (KBr, cm-1) 3486 (m), 3376 (s), 2208
(w, υCtC), 1606 (s), 1513 (s), 1497 (m), 1341 (s), 1324 (s), 1300
(s), 1287 (s), 895 (m), 812 (s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1
cm-1) 269 (48 200), 299 (44 500), 368 (34 500); El-MS, m/z 367
([M + H]+, 47), 366 ([M]+, 100), 320 ([M - NO2]+, 45), 305 ([M
- NO2 - NH2 + H]+, 20). Anal. Calcd for C24H18N2O2: C, 78.69;
H, 4.92; N, 7.65. Found: C, 78.21; H, 5.03; N, 7.46.
dissolved in dry CH2Cl2 (20 mL) and 0.095 mL (0.683 mmol)
of triethylamine and 0.008 g (0.068 mmol) of DMAP were
added followed by 0.079 mL (0683 mmol) of 4-bromobutyryl
chloride. The solution was stirred at room temperature for 2
days. After evaporation, the residue was purified by flash
chromatography on alumina with CH2Cl2 as eluant to afford
0.239 g of 5 (68%). Mp 230-1 °C; 1H NMR (CDCl3) δ 2.33 (td,
J ) 13.1 Hz, J ) 6.4 Hz, CH2, 2H), 2.39 (s, CH3, 6H), 2.72 (t,
J ) 6.8 Hz, CH2, 2H), 3.52 (t, J ) 6.3 Hz, CH2, 2H), 7.20 (d, J
) 7.7 Hz, Ph, 4H), 7.43 (d, J ) 7.7 Hz, Ph, 4H), 7.59 (bs, NH,
1H), 8.35 (s, Ph, 2H); 13C NMR (CDCl3) δ 21.6, 28.0, 33.2, 34.4,
83.4 (CtC), 97.9 (CtC), 118.7, 126.8, 129.4, 131.8, 139.9,
143.5, 172.2; FT-IR (KBr, cm-1) 3235 (m), 3184 (m), 2214 (m,
υ
CtC), 1675 (s), 1533 (s), 1511 (s), 1441 (m), 1355 (s), 1333 (s),
2,6-Bis(4-eth yn yltolu en e)-4-n itr o-N-(bu tyr yl-4-ch lor ide)-
a n ilin e (2). A 0.200 g (0.546 mmol) sample of 1 was dissolved
under nitrogen in dry CH2Cl2 (20 mL) and 0.061 mL (0.546
mmol) of succinyl chloride was added followed by 0.076 mL
(0.546 mmol) of triethylamine. The solution was stirred at
room temperature for 16 h and 20 mL of EtOAc was added.
After filtration the solid was washed with ether and recrystal-
lized in CH2Cl2/hexane to afford 0.111 g of 2 (42%). Mp 205-6
1247 (m), 1163 (m), 896 (m), 812 (s); UV-vis (CH2Cl2) λ, nm
(ꢀ, M-1 cm-1) 282 (33 800), 298 (48 100); El-MS, m/z 516 ([M
+ H]+, 12), 434 ([M - Br + H]+, 100), 366 ([M - CO(CH2)3Br
+ H]+, 29). Anal. Calcd for C28H23BrN2O3: C, 65.24; H, 4.47;
N, 5.44. Found: C, 65.11; H, 4.27; N, 5.12.
2,6-Bis(4-eth yn yltolu en e)-4-n itr o-N-(6-br om oh exa n oyl-
a m id e)a n ilin e (6). Compound 1 (0.300 g, 0.820 mmol) was
dissolved in 25 mL of dry CH2Cl2 and 0.114 mL (0.820 mmol)
of triethylamine and 0.010 g (0.082 mmol) of DMAP were
added followed by 0.126 mL (0820 mmol) of 6-bromohexanoyl
chloride. The solution was stirred at room temperature for 2
days. After evaporation, the residue was purified by flash
chromatography on alumina with CH2Cl2 as eluant to afford
0.239 g of 6 (74%). Mp 205-6 °C; 1H NMR (CDCl3) δ 1.50 (quin,
J ) 7.4 Hz, CH2, 2H), 1.77 (td, J ) 14.7 Hz, J ) 7.4 Hz, CH2,
4H), 2.40 (s, CH3, 6H), 2.50 (t, J ) 7.4 Hz, CH2, 2H), 3.22 (t,
J ) 6.8 Hz, CH2, 2H), 7.19 (d, J ) 8.1 Hz, Ph, 4H), 7.40 (d, J
) 8.1 Hz, Ph, 4H), 7.60 (bs, NHCO, 1H), 8.31 (s, Ph, 2H); 13C
NMR (CDCl3) δ 21.6, 28.0, 33.2, 34.4, 83.4 (CtC), 97.9 (Ct
C), 118.7, 126.8, 129.4, 131.8, 139.9, 143.5, 172.2; FT-IR (KBr,
cm-1) 3263 (s), 3186 (m), 2923 (s), 2214 (m, υCtC), 1673 (s),
1533 (s), 1505 (s), 1439 (m), 1355 (s), 1335 (s), 1252 (m), 1178
1
°C dec; H NMR (CDCl3) δ 2.39 (s, CH3, 6H), 2.99 (bs, CH2,
4H), 7.18 (d, J ) 8.1 Hz, Ph, 4H), 7.35 (d, J ) 8.1 Hz, Ph, 4H),
8.40 (s, Ph, 2H); 13C NMR (CDCl3) δ 21.6, 28.3, 29.1, 82.4 (Ct
C), 97.3 (CtC), 118.3, 125.6, 126.4, 129.4, 131.7, 140.1, 147.9,
170.6, 174.2; FT-IR (KBr, cm-1) 3082 (w), 2212 (m, υCtC), 1726
(s), 1533 (s), 1456 (m), 1427 (m), 1341 (s), 1363 (s), 1175 (s),
895 (m), 816 (s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 254
(30 000), 298 (39 500), 355 (4 700); El-MS, m/z 448 ([M - Cl]+,
100), 418 ([M - Cl - O2 + H]+, 29), 366 ([M - CO(CH2)2COCl
+ H]+, 20). Anal. Calcd for C28H21ClN2O4: C, 69.42; H, 4.34;
N, 5.79. Found: C, 69.29; H, 4.32; N, 5.58.
2,6-Bis(4-yleth yn yltolu en e)-4-n itr o-N-(bu tyr yl-4-{7-oxy-
4-m eth ylcou m a r in ester })a n ilin e (3). A 0.100 g (0.207
mmol) sample of 2 was dissolved under nitrogen in dry CH2-
Cl2 (15 mL) and 0.036 g (0.207 mmol) of 7-hydroxy-4-methyl-
coumarin was added followed by 0.029 mL (0.207 mmol) of
triethylamine. The solution was stirred at room temperature
for 30 h, 20 mL of water was added, and the product was
extracted with CH2Cl2. The solvent was evaporated and the
residue was washed with ether. The pure compound was
obtained by recrystallization from CH2Cl2/hexane affording
(m), 893 (m), 815 (s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1
)
276 (49 500), 300 (62 000); El-MS,: m/z 544 ([M + H]+, 11),
462 ([M - Br]+, 40), 366 ([M - CO(CH2)5Br + H]+, 31). Anal.
Calcd for C30H27BrN2O3: C, 66.30; H, 4.97; N, 5.16. Found:
C, 66.73; H, 5.34; N, 4.77.
2,6-Bis(4-et h yn ylt olu en e)-4-n it r o-N-(6-N-{7-a m in o-4-
m eth ylcou m a r in }h exa n oyla m id e)a n ilin e (7). A Schlenk
flask was charged under nitrogen with 0.115 g (0.212 mmol)
of 6, 0.045 g (0.254 mmol) of 7-amino-4-methylcoumarin, and
25 mL of 2,2,2-trifluoroethanol. The solution was stirred at
100 °C for 2 days. The solvent was evaporated and the residue
was purified by flash chromatography on alumina with CH2-
Cl2/CH3OH (0 to 15%) as eluant to afford 0.065 g of 7 (48%).
Mp 222-3 °C; 1H NMR (CDCl3) δ 1.87 (m, CH2, 4H), 2.03 (m,
CH2, 2H), 2.39 (bs, CH3, 9H), 2.77 (t, J ) 4.8 Hz, CH2, 2H),
3.80 (t, J ) 4.6 Hz, CH2, 2H), 6.78-6.81 (m, Ph, 3H), 7.20 (d,
J ) 8.1 Hz, Ph, 4H), 7.37-7.47 (m, 5H), 8.35 (s, Ph, 2H); FT-
IR (KBr, cm-1) 2930 (m), 2213 (w, υCtC), 1679 (s), 1594 (s),
1527 (m), 1448 (m), 1388 (s), 1334 (m), 1240 (s), 1160 (m), 845
(s), 817 (m); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 300 (76 400);
El-MS, m/z 575 (24), 440 (40), 423 (32), 154 (92), 136(100).
Anal. Calcd for C40H35N3O5: C, 75.35; H, 5.49; N, 6.59.
Found: C, 75.26; H, 5.32; N, 6.68.
1-(3-{4-Meth oxyar yl}-2-pr open oyl)-4-acetylben zen e (8).
To a vigorously stirred solution of 0.300 g (1.850 mmol) of 1,4-
diacetylbenzene in methanol (40 mL) at room temperature was
added an aqueous solution of 0.222 g of NaOH (5.550 mmol)
and then 0.252 g (1.850 mmol) of anisaldehyde. After 2 h, the
precipitated product was filtered and washed with water/ether.
After purification by flash chromatography on alumina with
CH2Cl2 as eluant, the pure product was obtained by recrys-
tallization in CH2Cl2/hexane to afford 0.326 g of 8 (63%). Mp
127-8 °C; 1H NMR (CDCl3) δ 3.86 (s, OCH3, 3H), 6.95 (d, J )
8.8 Hz, Ph, 2H), 7.38 (d, J ) 15.8 Hz, CdC, 1H), 7.61 (d, J )
8.5 Hz, Ph, 2H), 7.80 (d, J ) 15.8 Hz, CdC, 1H), 8.06 (s, Ph,
4H);13C NMR (CDCl3) δ 26.9, 55.5, 114.1, 114.5, 119.5, 127.3,
1
0.028 g of 3 (22%). Mp 248-9 °C; H NMR (CDCl3) δ 2.39 (s,
CH3, 6H), 2.40 (s, CH3, 3H), 2.99 (bs, CH2, 4H), 6.14 (s, 1H),
6.80-6.85 (m, 2H), 7.18 (d, J ) 7.7 Hz, Ph, 4H), 7.35 (d, J )
8.1 Hz, Ph, 4H), 7.45-7.51 (m, 1H), 8.40 (s, Ph, 2H); FT-IR
(KBr, cm-1) 3120 (m), 2216 (m, υCtC), 1790 (w), 1726 (s), 1679
(s), 1597 (s), 1534 (s), 1455 (m), 1366 (s), 1158 (s), 1069 (m),
813 (s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 297 (93 800), 353
(11 200); El-MS, m/z 625 ([M + H]+, 20), 582 (58), 568 (100),
551 (65). Anal. Calcd for C38H28N2O7: C, 73.08; H, 4.49; N,
4.49. Found: C, 73.22; H, 4.62; N, 4.55.
2,6-Bis(4-eth yn yltolu en e)-4-n itr o-N-(bu tyr yl-4-{N-oxy-
su ccin im id ester })a n ilin e (4). To a suspension of 0.090 g
(0.196 mmol) of 2 in 12 mL of dry CH3CN was added 0.061
mL (0.546 mmol) of succinyl chloride followed by 0.076 mL
(0.546 mmol) of triethylamine. The solution was stirred at 50
°C for 16 h and then 20 mL of water was added. The product
was extracted with CH2Cl2. The solvent was evaporated and
the residue was washed with ether. The pure compound was
obtained by recrystallization from CH2Cl2/hexane affording
1
0.111 g of 4 (34%). Mp 235-6 °C; H NMR (CDCl3) δ 2.39 (s,
CH3, 6H), 2.74 (bs, CH2, 4H), 2.99 (bs, CH2, 4H), 7.18 (d, J )
8.1 Hz, Ph, 4H), 7.35 (d, J ) 7.7 Hz, Ph, 4H), 8.40 (s, Ph, 2H);
FT-IR (KBr, cm-1) 2212 (m, υCtC), 1782 (s), 1708 (s), 1655 (s),
1531 (s), 1427 (m), 1364 (m), 1219 (s), 1179 (m), 1080 (s), 814
(s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 298 (48 500), 356
(5 900); El-MS, m/z 563 ([M + H]+, 15), 471 ([M - C7H7]+, 72),
160 (100). Anal. Calcd for C32H24N3O7: C, 68.33; H, 4.27; N,
7.47. Found: C, 68.70; H, 4.44; N, 7.62.
2,6-Bis(4-eth yn yltolu en e)-4-n itr o-N-(4-br om obu tyr yl-
a m id e)a n ilin e (5). Compound 1 (0.250 g, 0.683 mmol) was
J . Org. Chem, Vol. 67, No. 19, 2002 6709

Khatyr et al.
128.3, 128.5, 128.6, 130.5, 139.7. 142.0, 145.8, 162.0, 190.1,
197.6; FT-IR (KBr, cm-1) 2839 (w), 1679 (s), 1655 (s), 1591
(s), 1507 (s), 1510 (s), 1401 (m), 1334 (m), 1306 (s), 1256 (s),
1216 (s), 1171 (m), 1032 (s), 1010 (m), 981 (m), 960 (m); UV-
vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 264 (33 500), 349 (23 900);
El-MS, m/z 280 ([M]+, 100), 265 ([M - CH3]+, 13), 249 ([M -
OCH3]+, 11), 237 ([M - COCH3]+, 65), 161 ([M - C6H4-
COCH3]+, 33). Anal. Calcd for C18H16O3: C, 77.14; H, 5.71.
Found: C, 76.91; H, 5.52.
1-(3-{4-Met h oxya r yl}-2-p r op en oyl)-4-(3-a r yl-2-p r op e-
n oyl)ben zen e (9). To a vigorously stirred solution of 0.250 g
(0.893 mmol) of 8 in methanol (40 mL) at room temperature
was added an aqueous solution of 0.107 g of NaOH (2.679
mmol) and then 0.114 g (1.071 mmol) of benzaldehyde. After
5 h, the precipitated product was filtered and washed with
water/ether and recrystallized in CH2Cl2/hexane to afford 0.220
g of 9 (67%). Mp 165-6 °C;1H NMR (CDCl3) δ 3.86 (s, OCH3,
3H), 6.95 (d, J ) 8.5 Hz, Ph, 2H), 7.38-7.65 (m, 9H), 7.78-
7.86 (m, 2H), 8.10 (s, Ph, 4H); 13C NMR (CDCl3) δ 55.4, 114.5,
119.4, 119.5, 121.8, 127.3, 128.5, 128.7, 129.0, 130.5, 130.9,
134.6, 141.1, 141.4, 141.6, 145.6, 145.7, 145.8, 161.9, 190.0,
190.1; UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 273 (33 400), 341
(34 600); FT-IR (KBr, cm-1) 2834 (w), 1683 (w), 1654 (s), 1590
(s), 1571 (s), 1511 (s), 1423 (m), 1333 (m), 1293 (s), 1255 (s),
1220 (s), 1173 (s), 1036 (s), 1009 (m), 991 (s), 824 (m); El-MS,
m/z 369 ([M + H]+, 40), 281 ([M - PhCH]+, 20), 155 (80), 119
(100). Anal. Calcd for C25H20O3: C, 81.52; H, 5.43. Found: C,
81.33; H, 5.24.
5.82 (d, J ) 11.0 Hz, 2H), 6.96 (d, J ) 8.5 Hz, Ph, 2H), 7.40-
7.55 (m, Ph, 7H), 8.25 (s, Ph, 4H); UV-vis (CH2Cl2) λ, nm (ꢀ,
M-1 cm-1) 280 (47 000); FT-IR (KBr, cm-1) 2840 (w), 1690 (s),
1606 (m), 1513 (m), 1406 (m), 1308 (m), 1272 (s), 1225 (s), 1179
(m), 1030 (m), 9761 (m), 834 (m); El-MS, m/z 394 ([M]+, 30),
135 ([M - C9H8O]+, 100), 105 ([M - C9H8O - OCH3]+, 65), 77
([M - C9H8O - Ph]+, 60). Anal. Calcd for C25H18N2O3: C,
75.76; H, 4.55; N, 7.07. Found: C, 75.69; H, 4.43; N, 6.92.
7-(6-Br om oh exa n oyl)-4-m eth ylcou m a r in Ester (12). To
a suspension of 0.100 g (0.568 mmol) of 7-hydroxy-4-methyl-
coumarin in 20 mL of CH2Cl2 was added 0.079 mL (0.568
mmol) of triethylamine. After dissolution 0.126 mL (0.568
mmol) of 6-bromohexanoyl chloride was added. The mixture
was stirred for 6 h at room temperature. After evaporation,
the residue was purified by flash chromatography on alumina
with CH2Cl2/CH3OH (0 to 15%) as eluant to afford 0.168 g of
12 (84%). Mp 75-6 °C; 1H NMR (CDCl3) δ 1.58 (quin, J ) 7.7
Hz, CH2, 2H), 1.79 (quin, J ) 7.7 Hz, CH2, 2H), 1.93 (quin, J
) 7.4 Hz, CH2, 2H), 2.43 (s, CH3, 3H), 2.62 (t, J ) 7.4 Hz,
COCH2, 2H), 3.44 (t, J ) 6.6 Hz, CH2Br, 2H), 6.26 (s, 1H),
7.05-7.10 (m, 2H), 7.60 (d, J ) 8.8 Hz, 1H); 13C NMR (CDCl3)
δ 18.7, 23.8, 27.4, 32.2, 33.4, 34.0, 110.3, 114.4, 117.7, 118.0,
125.4, 151.9, 153.0, 154.1, 160.4, 171.2; FT-IR (KBr, cm-1) 3087
(m), 2928 (m), 1757 (s), 1729 (s), 1613 (s), 1566 (m), 1412 (m),
1383 (s), 1327 (m), 1263 (s), 1229 (m), 1154 (s), 1132 (s), 1013
(m), 983 (m), 865 (s); UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1
)
272 (10 600), 312 (9 800); El-MS, m/z 354 ([M + H]+, 15), 176
([M - CO(CH2)5Br + H]+, 100), 148 ([M - CO(CH2)5Br - CO]+,
30). Anal. Calcd for C16H17BrO4: C, 54.39; H, 4.82. Found: C,
54.35; H, 4.94.
1-(3-{4-Meth oxya r yl}-2,3-d ibr om op r op en oyl)-4-(3-a r yl-
2,3-d ibr om op r op en oyl)ben zen e (10). To a solution of 0.150
g (0.407 mmol) of 9 in CHCl3 (10 mL) was added bromine
(0.036 mL, 0.815 mmol) in 2 mL of CHCl3 dropwise with
vigorous stirring for 15 min and the reaction mixture was
allowed to stand for 1 h. The precipitated product was filtered
and washed with ether and recrystallized in CH2Cl2/hexane
to afford 0.207 g of 10 (86%). Mp 178-9 °C;1H NMR (CDCl3)
δ 3.86 (s, OCH3, 3H), 5.65 (dd, J ) 11.0 Hz, J ) 11.4 Hz, 2H),
5.82 (d, J ) 11.0 Hz, 2H), 6.96 (d, J ) 8.5 Hz, Ph, 2H), 7.40-
7.55 (m, Ph, 7H), 8.25 (s, Ph, 4H); 13C NMR (CDCl3) δ 47.0,
47.3, 49.5, 50.1, 55.4, 114.3, 121.8, 128.4, 128.6, 128.9, 129.1,
129.4, 129.6, 131.0, 134.5, 137.3, 142.5, 146.2, 160.3, 189.9,
190.8; UV-vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 273 (400); FT-IR
(KBr, cm-1) 2840 (w), 1690 (s), 1606 (m), 1513 (m), 1406 (m),
1308 (m), 1272 (s), 1225 (s), 1179 (m), 1030 (m), 9761 (m), 834
(m); El-MS, m/z 608 ([M - Br]+, 3), 526 ([M - 2Br]+, 37), 448
([M - 3Br]+, 46), 367 ([M - 4Br + H]+, 100). Anal. Calcd for
Bis(7-oxy-4-m eth ylcou m a r in )su ccin yl Ester (13). To a
suspension of 0.250 g (1.419 mmol) of 7-hydroxy-4-methylcou-
marin in 25 mL of dry CH2Cl2 was added 0.198 mL (1.419
mmol) of triethylamine. After dissolution, 0.080 mL (0.710
mmol) of succinyl chloride was added. The mixture was stirred
at room temperature for 2 h and the precipitated product was
filtered and washed successively with water and ether afford-
ing 0.585 g of 13 (95%). Mp 238-9 °C; 1H NMR (CDCl3) δ 2.44
(s, CH3, 3H), 3.05 (m, CH2, 4H), 6.29 (s, 2H), 7.07-7.14 (m,
4H), 7.62 (d, J ) 8.5 Hz, 2H); 13C NMR (CDCl3) δ 18.8, 29.2,
111.8, 110.4, 114.6, 118.0, 125.5, 152.8, 162.2, 170.2; FT-IR
(KBr, cm-1) 3065 (w), 1732 (s), 1615 (s), 1573 (w), 1391 (m),
1316 (s), 1267 (s), 1154 (s), 1021 (m), 989 (m), 873 (m); UV-
vis (CH2Cl2) λ, nm (ꢀ, M-1 cm-1) 272 (15 200), 312 (14 100);
El-MS, m/z 434 ([M]+, 9), 259 ([M - C10H7O3]+, 50), 176 (92),
148 (100). Anal. Calcd for C24H18O3: C, 66.36; H, 4.15. Found:
C, 66.21; H, 4.16.
C
25H20Br4O3: C, 43.60; H, 2.91. Found: C, 43.66; H, 2.87.
1-(5-{4-Met h oxya r yl}-3-isoxa zolyl)-4-(5-a r yl-3-isoxa -
zolyl)ben zen e (11). To 20 mL of boiling ethanol were added
0.170 g (0.247 mmol) of 10 and 0.034 g (0.494 mmol) of
hydroxylamine hydrochloride and the mixture was refluxed
for 2 h. Then 0.083 g (1.482 mmol) of KOH in 4 mL of ethanol/
water (3/1) was added and the mixture was refluxed for 2 h.
The solution was allowed to stand for 1 h and the product thus
precipited was filtered and recrystallized in CH2Cl2/hexane to
afford 0.220 g of 11 (32%). Mp 178-9 °C;1H NMR (CDCl3) δ
3.88 (s, OCH3, 3H), 5.65 (dd, J ) 11.0 Hz, J ) 11.4 Hz, 2H),
Ack n ow led gm en t. This work was supported by the
Swiss National Science Foundation Project NFP 47
(4047-057481). We would like to thank Rene´ Bu¨hler,
Andre´ Devaux for the measurements of the FT-IR
spectra, and Dr. Antonio Currao for a critical reading
of the manuscript.
J O025691R
6710 J . Org. Chem., Vol. 67, No. 19, 2002