Synthesis of some new substituted photochromic N,N′-bis(spiro[1- benzopyran-2,2′-indolyl])diazacrown systems with substituent control over ion chelation

Article abstract of DOI:10.1002/ejoc.200500681

The reversible photochemical ion chelation of the newly synthesised substituted N,N′-bis(spiro[1-benzopyran-2,2′-indolyl])diazacrown systems 15a-c and the subsequent molecular electronic control of this process using appropriately placed substituent groups on the spiro-benzopyran skeleton is reported. The principle of molecular electronic control of ion chelation is demonstrated by comparing the behaviour of the newly synthesised nitro-substituted and pyrido-annulated spiro-benzopyran system 9b with that of the unsubstituted compound 9a. Electronic substituent control over ion chelation is then exemplified for the new N,N′-bis(5′-nitrospiro[1- benzopyran-2,2′-indolyl])diazacrown system 15c and further exemplified for the corresponding 5′-trifluoromethyl derivative 15b, which contains the photochemically more robust trifluoromethyl group. The crown system 15a, unsubstituted in the spiro-indole moiety, is also reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500681

FULL PAPER
DOI: 10.1002/ejoc.200500681
Synthesis of Some New Substituted Photochromic N,NЈ-Bis(spiro[1-
benzopyran-2,2Ј-indolyl])diazacrown Systems with Substituent Control over Ion
Chelation
Craig J. Roxburgh*[a][‡] and Peter G. Sammes[a]
Keywords: Photochromism / Ion chelation / Diazacrown systems / UV/Vis spectroscopy / Spiro compounds
The reversible photochemical ion chelation of the newly syn-
thesised substituted N,NЈ-bis(spiro[1-benzopyran-2,2Ј-indol-
yl])diazacrown systems 15a–c and the subsequent molecular
electronic control of this process using appropriately placed
substituent groups on the spiro-benzopyran skeleton is re-
ported. The principle of molecular electronic control of ion
chelation is demonstrated by comparing the behaviour of the
newly synthesised nitro-substituted and pyrido-annulated
spiro-benzopyran system 9b with that of the unsubstituted
compound 9a. Electronic substituent control over ion chela-
tion is then exemplified for the new N,NЈ-bis(5Ј-nitrospiro[1-
benzopyran-2,2Ј-indolyl])diazacrown system 15c and further
exemplified for the corresponding 5Ј-trifluoromethyl deriva-
tive 15b, which contains the photochemically more robust tri-
fluoromethyl group. The crown system 15a, unsubstituted in
the spiro-indole moiety, is also reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
benzopyran-2,2Ј-indole] system 1 and its analogues since
these have well-documented photochemical properties.[3]
Photoirradiation with UV light at 380 nm leads to the ring-
opened zwitterionic (merocyanine) form 2, which can be
converted back to the ring-closed form either by photoirra-
diation with visible light or thermally. This process may be
repeated many times and has formed the basis of light-in-
duced ionic switches. The reversible chelation of specific
metal ions has been reported in other systems.[4–7]
Introduction
There is ongoing interest in the development of reversible
metal-chelating agents in which chelation can be switched
on and off by exposure to light of different wavelengths.[1]
Several groups have made contributions to this area.[2]
A
popular substrate for such studies is the 6-nitrospiro[1-
Results and Discussion
In order to test our hypothesis that the specific place-
ment of substituents on the spiro-benzopyran moiety could
be used to indirectly exert control over metal-ion chelation
we firstly synthesised the unsubstituted, pyrido-annulated
spiro-benzopyran system[8] 9a and subsequently the new 5Ј-
nitro-substituted system 9b in order to undertake compara-
tive studies (see Scheme 1).
In a solution containing metal ions such as cupric, ferric
and also Li+ and Zn2+, 9a was found to convert rapidly and
totally to the chelated open merocyanine form 9c at room
temperature. When metal ions were not present, 9a/9c ex-
isted in an equilibrium state of both the open and closed
forms. We thus believe the presence of metal ions results in
the chelation of the open form, driving the equilibrium
towards the right, 9c. However, when the temperature was
reduced to –78 °C no coloration was noted for several min-
utes, indicating that energetically the ring-opening reaction
was not so strong as to preclude possible thermodynamic
influence/control by selective substituent placement. In the
[a] Department of Chemistry, University College, University of
London,
London, WC1H OAJ, UK
[‡] Current address: The Institute of Naval Medicine,
Alverstoke, Gosport, Hants, PO12 2DL, UK
1050
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Diazacrown Systems with Substituent Control over Ion-Chelation
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Scheme 1. Synthesis of 5-substituted indolenines.
former case the thermodynamics of the chelation to metal relatively long reflux times (24 h). Treatment of the 5-nitro
ions far outweighed the energies available from visible light, system 9b with Li+ (perchlorate) at room temperature
required to photochemically convert this system back to the caused a high degree of ring-opening to the merocyanine
closed form, as it was not possible to bias this equilibrium form 9d with only a small portion of the spiro system 9b
by photoirradiation. We hypothesised that we could pro- remaining, as evidenced by UV spectroscopy. Irradiation of
mote destabilisation of the iminium ion in 9d, and hence the the mixture with visible light caused an observable increase
open zwitterionic form, by the introduction of a 5Ј-para- in the concentration of the closed form 9b, and conversely
substituted electron-withdrawing substituent (R1) in the photoirradiation with UV light promoted an increase in the
spiro-benzopyran skeleton, which would further encourage/ concentration of the open form. These effects demonstrate
promote ring-closure to the spirocyclic structure 9b. This the principle that thermodynamic control can be exerted
would thus lead to some control over the thermodynamics over the photoreversible chelation of metal ions by suitably
of the system, thus allowing a degree of electronic/photo- placed substituents on the spiro-benzopyran skeleton, and
chemical control over metal-ion chelation. Substituent ef- in particular, at room temperature.
fects in the quinoline portion of quinoline-spiro-pyranindo-
We subsequently turned our attention to the synthesis of
lines have been reported.[9] Ultimately, we could make fur- the bis(spiro-benzopyran) diazacrown systems 15a–c
ther use of this control when trying to influence photore- (Scheme 2; R1 = H, CF3, NO2). The synthesis of 1,3,3-tri-
versibly induced metal-ion chelation.
methyl-2-methylene-5-(trifluoromethyl)indolenine (8c) was
Synthesis of the pyrido-annulated 5Ј-nitrospiro[1-benzo- achieved through BF3·OEt2-catalysed Fischer indole syn-
pyran-2,2Ј-indole] system 9b was achieved by refluxing thesis and subsequent steps,[10–12] as shown in Scheme 1.
1,3,3-trimethyl-2-methylene-5-nitroindolenine (8b) and 8- Attempts to prepare the 5-nitro-substituted indolenine 6 by
hydroxyquinoline-7-carbaldehyde in ethanol. The electron- direct nitration[13] of commercially available 2,3,3-trimethyl-
withdrawing nature of the para-substituted 5-nitro group indolenine resulted in a 1:1 mixture of the 5- and 6-nitrated
was clearly demonstrated by the poor reactivity of the ene- indolenines (total yield 81%), which were almost insepa-
amine group, which resulted in a mediocre yield (22%) and rable by flash chromatography. The two isomers ran, by
Eur. J. Org. Chem. 2006, 1050–1056
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C. J. Roxburgh and P. G. Sammes
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TLC, as a figure-of-eight, however, by taking the leading
We initially tried to synthesise the mono-N-substituted
and trailing fractions it was possible to obtain small, but crown system 14 by the reaction of one equivalent of 3-
pure fractions of both isomers. This is contrary to reports (chloromethyl)-2-hydroxy-5-nitrobenzaldehyde[17] (12) with
of the reaction yielding solely 5-nitroindolenine in 88% one equivalent of the diazacrown in dry THF. The reaction
yield.[13] Since it was envisaged that a relatively large quan- yielded a complex mixture from which the di-N-substituted
tity of the 5-nitrated indolenine would be required to com- derivative 13 was obtained as a crystalline solid (28% yield)
plete the synthesis of 15c an alternative method was em- together with a considerable amount of oil, chromatog-
ployed. We therefore prepared the 5-nitro-substituted in- raphy of which gave the mono-N-substituted-azacrown sys-
dolenine[14–16] 6 (R1 = NO2) in good overall yield by the tem 14 in 19% yield. Synthesis of the N,NЈ-bis(spiro-benzo-
unambiguous but slightly longer Fisher indole synthesis, as pyran)-substituted crowns 15a–c was achieved by treatment
shown in Scheme 1 (see Expt. Sect.).
of the di-N-substituted crown 13 with the appropriate 5-
Scheme 2. Synthesis of the compounds 15a–c and 17.
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Diazacrown Systems with Substituent Control over Ion-Chelation
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substituted indolenines 8a–c (R1 = H, CF3, NO2) in boiling the amount of the open form of the above systems was ob-
ethanol. For 15a the reaction went to completion within served in the presence of lithium or other group I metals,
eight hours, giving the required product in a reasonable as evidenced by UV spectroscopy. This is perhaps not unex-
48% yield. However, when the 5-para-trifluoromethyl sub- pected since 4,13-diaza-1,7,10,16-tetraoxacyclooctadecane
stituent was introduced into the indolenine structure signifi- is known to exhibit selectivity for the larger group II metal
cant deactivation of the tertiary-eneamine was noted, neces- ions. However, significant effects were noted in the presence
sitating reaction times of 72 h for the reaction to go to com- of the larger group II metal ions Ba2+, Mg2+ and Ca2+
pletion, and resulted in a lower yield of 38%. Further, intro-
.
The unsubstituted spiro-benzopyran system 15a (R1
=
duction of the strongly deactivating 5-nitro group into the H) showed a strong affinity for Ca2+, as has previously been
indolenine resulted in a further decrease in reactivity of the found.[18] Additionally, we found that 15a has a particularly
tertiary eneamine, with reaction times of 96 h required to strong affinity for Ba2+, and in its presence converted en-
drive the reaction to completion. Consequently the yield for tirely to its open zwitterionic form. It was not possible to
this reaction was only 8% and a considerable amount of bias this equilibrium with visible light indicating strong
polymeric material was also produced.
thermodynamic chelation. However, when the same system
The mono-substituted crown system 16 was similarly was investigated in the presence of Mg2+, photoreversibility
synthesised, as shown in Scheme 2, by refluxing 14 with the was noted. Photoirradiation with UV light in the presence
unsubstituted indolenine in ethanol for 6 h. N-Methyl of Mg2+ (2000-fold molar excess) resulted in large increases
acetylation of the crown system 16 was achieved by treat- in the amount of the open form. This effect was reversible,
ment with methyl bromoacetate in the presence of a proton photoirradiation with visible light causing ring-closure to a
sponge to yield 17.
degree of approximately 14% below that of the dark equi-
All the bis-crowned spiro-benzopyrans 15a–c (R1 = H, librium position.
CF3, NO2) are photochromic, as evidenced by UV spec-
The 5Ј-trifluoromethyl-substituted system 15b proved to
troscopy, photoirradiation with UV light (see Expt. Sect.) be largely photoreversible in the presence of Ba2+, however,
generating the open zwitterionic forms 16a–c, irradiation only small degrees of photoreversibility, as evidenced by
with visible light causing ring-closure to the starting spi- UV spectroscopy, were noted with Mg2+ and Ca2+, these
rocyclic structures.
ions causing almost complete isomerisation to the open
The reactions of 15a–c in the presence of selected group zwitterionic form, it not being possible to bias this equilib-
I and II metal ions were studied. When equilibrated in a rium using either UV or visible light. [The transformation
“dark” solution of dried acetonitrile, no further increase in of this system, in the presence of Mg2+, to the open merocy-
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C. J. Roxburgh and P. G. Sammes
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1
anine form was followed and confirmed by H NMR spec- the following: 1) the type and nature of the substituent at
troscopy. Compound 15b was dissolved in deuterioaceton- the 5-position, 2) the crown, 3) the size of the metal ion, 4)
itrile in an NMR tube and Mg(ClO4)2 was added (2000-fold the charge density of the metal ion, 5) the distribution of
molar excess). The 1H NMR spectrum showed the complete charge throughout the zwitterionic structure (in particular
disappearance of the cis-vicinal protons associated with the that on the phenoxide ion), 6) solvent interactions and 7)
closed spirocyclic structure and the appearance of the trans- the conformation of the overall system in solution. How-
vicinal protons associated with the open merocyanine form ever, despite the complexity of these systems some conclu-
16b.] In the case of Ba2+ this effect supports our hypothesis sions and trends can be ascertained. It is clear that the 5-
that the electron-withdrawing group of 16b destabilises and nitro substituent of 9b does energetically disfavour the open
disfavours the open zwitterionic form compared with the form 9d, as described earlier. This system, therefore, has a
unsubstituted 16a since far less of the merocyanine form is clear advantage over the unsubstituted 9a when considering
formed. However, our theory is not supported in the case their potential use as a possible photoactivated ion-chela-
of 16b in the presence of Mg2+ since, similarly, far less of tion system since the unsubstituted system irreversibly con-
the merocyanine would be expected compared with the un- verts to the open form 9c under identical external physical
substituted 16a. We postulate (see below) that this is the conditions.
result of a complex interplay of interactions involving not
The dinitro crown system 15c similarly allowed photoac-
only the electron-withdrawing effects of the CF3 group, but tivated control over ring-opening to the merocyanine 16c,
also the size, charge density and overall “fit” of the metal and thus switchable ion chelation, with Ba2+, Ca2+ and
ions into the zwitterionic metal-ion chelated complex of Mg2+ ions. Incorporation of a 5-CF3 group into the system
16b. Thus, in this particular case, these other factors, in 16b does exert an influence over the open/closed equilib-
part, negate the electron-withdrawing effect of the CF3 rium position, however, the results are far less pronounced
group, dominating the overall effect. A clearer trend is than those of the 5-nitro-containing compound. The 5-CF3
noted for the very powerfully electron-withdrawing 5-nitro- group exerts its effects purely through an inductive electron-
substituted compound 15c/16c (see below).
withdrawing effect, as opposed to the 5-NO2 group, which
The 5-nitro-substituted system 15c, when subjected to is powerfully electron-withdrawing as a result of both in-
the same molar excess of Ba2+ as the unsubstituted system ductive and resonance effects. As such the 5-CF3 group is
15a, yielded some of the open zwitterionic structure, but not as effective as a 5-NO2 group in exerting control over
considerably less than the unsubstituted system, and less the equilibrium position, allowing the other factors, men-
than the CF3-substituted system 15b, confirming our hy- tioned above, to dominate.
pothesis of the additional thermodynamic destabilisation
Finally, it is often necessary to determine intracellular
conferred on the open zwitterionic structure by the 5-nitro Ca2+ levels when considering certain diseases as ionic cal-
group. It was possible to bias the position of this equilib- cium plays a role in mediating the actions of many bio-
rium by photoirradiation with either UV or visible light. logical structures such as proteins, catecholamines and hor-
Similarly, when comparing this system with that of the 5- mones, which are responsible for the functioning of normal
trifluoromethyl system 15b, both Ca2+ and Mg2+ ions physiological process. Thus, these systems may ultimately
caused a partial conversion to the open merocyanine form, be of potential use as intracellular pharmacological probes,
however, to a smaller degree (note, this was slightly less for in particular for Ca2+. Further, these systems may have
Ca2+). It was possible to bias the resulting equilibrium by some use in measuring the potency of potential new drug
photoirradiation with either visible or ultraviolet light.
structures that derive their activity from the moderation
Finally, we attempted to assess the photochromic behav- and hence transportation of ions through cellular ion chan-
iour of the crowned spiro-benzopyran system 15c in an nels.
aqueous-based medium for the reasons given below. Per-
haps not surprisingly the systems were not entirely water
soluble, however, they were solublised in 50% aqueous ace-
Experimental Section
tonitrile. The structure 15c exhibited photoreversible behav-
iour in a solution containing either Ca2+ or Mg2+ ions,
General: 1,3,3-Trimethyl-2-methyleneindoline was purchased from
Aldrich. 3-Chloromethyl-2-hydroxy-5-nitrobenzaldehyde (12) was
prepared from 5-nitrosalicylaldehyde and chloromethyl methyl
ether in 71% yield. 8-Hydroxyquinoline-7-carbaldehyde was pre-
however, it was not possible to shift the equilibrium be-
tween the closed spirocyclic and open merocyanine forms
to the same extent as that in the equivalent anhydrous sys-
pared in 39% yield using the method of Fiedler.[19]
tem (it is felt that competing hydration of the metal ions,
Photoirradiation Studies: The photochromic properties of these
and probably the open merocyanine form, together with
compounds
were
explored
by
making-up
solutions
significant quenching, are the most likely reasons for the
greatly reduced ability to bias the equilibrium position of
this system).
In summary we believe the results described above are
mostly, but not entirely, simple to qualify and quantify. The
biasing of the equilibrium in these systems probably in-
(2×10–5 moldm–3 unless otherwise stated), in the dark, in freshly
dried and redistilled solvents (generally tetrahydrofuran and aceto-
nitrile). Perchlorate salts were dried with P2O5 for several days be-
fore use. Solutions were placed in a stoppered 1-cm cuvette at room
temperature (20–25 °C) and allowed to equilibrate for 1 h before
measurement of their UV/Vis absorption curves (dark curves). The
volves a complex set of interactions that are influenced by solutions were then irradiated for 1 min with UV light of λ =
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365 nm generated from a steady power source. The UV light source
was a 200-W mercury/xenon lamp, focussed in a LOT-Oriel air-
cooled lamp housing, with solution filters to eliminate light of
Ͻ320 nm and Ͼ400 nm (this allows photoirradiation with a λmax
The remaining filtrate was concentrated in volume and purified by
chromatography over silica gel using methanol as eluent to give 14
as a yellow oil which solidified on standing (0.39 g, 19%), m.p.
165.5–166.5 °C. IR (KBr): ν
= 3500, 3350, 1690, 1600, 1560,
˜
(max)
of around 380 nm, the absorption wavelength of the spiro-benzopy- 1510, 1320 cm–1; 1H NMR [(CDCl3)/(CD3)2SO]: δ = 9.8 (s, 1 H,
rans, and additionally avoids photoirradiation of the formed mero-
cyanine, which has a λmax of around 550 nm). The UV absorption
spectra were measured (UV curve) and then the cuvette was ex-
posed to a visible light source for 3 min using a 100-W tungsten
spotlight, and the UV absorption spectrum remeasured. The solu-
tions were used a second time to ensure reproducible results were
obtained.
CHO), 8.1–8.4 (m, 2 H, ArH), 8.1 (s, 1 H, OH), 4.5 (s, 2 H,
NCH2Ar), 3.65–4.0 (m, 16 H, OCH2), 3.3 (m, 8 H, NCH2) ppm;
m/z = 442 [MH]+, 464 [MNa]+. C20H31N3O8·2.5H2O (486.52):
calcd. C 49.4, H 7.4, N 8.6; found C 49.1, H 6.9, N 8.5.
Compound 15a: 1,3,3-Trimethyl-2-methyleneindoline (0.116 g,
0.644 mmol) and the diazadisalicylaldehyde 13 (0.2 g, 0.322 mmol)
were added to ethanol (20 mL) and the resulting mixture was re-
fluxed for 8 h. After this period the ethanol was removed under
reduced pressure to yield a red oil which was purified by
chromatography over silica gel using methanol as eluent to give 15a
as an off-white powder (143 mg, 48%), m. p. 142–3 °C. IR (KBr):
1H NMR studies were carried out with a JEOL FX200 spectrome-
ter using deuteriochloroform or [D6]dimethyl sulfoxide as the sol-
vent with tetramethylsilane as the internal reference. Elemental
analyses were carried out in house by Medac. The mass spectrome-
try service at Swansea University recorded the FAB mass spectra
of all the diazacrown systems 15a–c.
ν
(max) = 2800–3000, 1650, 1610, 1590, 1520, 1490, 1450, 1340 cm–1;
˜
1H NMR (CDCl3): δ = 6.4–8.2 (m, 12 H, ArH), 6.8 (d, Jvic
=
10.2 Hz, 2 H, CH=CH), 5.8 (d, Jvic = 10.2 Hz, 2 H, CH=CH), 3.4
(m, 16 H, OCH2), 3.45 (s, 4 H, ArCH2N), 2.5 (s, 6 H, NCH3), 2.4
(br. t, 8 H, NCH2), 3.4 (s, 6 H, ArCCH3), 1.2 (s, 6 H,
UV spectroscopy was carried out using Perkin–Elmer Lambda 5
and Lambda 9 spectrophotometers; both instruments are double-
beamed with thermostatically controlled cell blocks. The Lambda
9 is also fitted with an RS 232 port, which allows remote control
by PC. All UV measurements were taken at 25 °C using 3-cm3
quartz cells with a 1-cm path length and are referenced against air.
ArCCH3Ј) ppm;
m/z
=
931
[MH]+,
953
[MNa]+.
C52H62N6O10·2H2O (967.13): calcd. C 64.6, H 6.8, N 8.7; found C
64.2, H 6.5, N 8.65.
Compound 15b: 1,3,3-Trimethyl-5-trifluoromethyl-2-methylenein-
doline (0.15 g, 0.622 mmol) and the diazadisalicylaldehyde 13
(0.19 g, 0.31 mmol) were added to ethanol (9 mL) containing DMF
(1 mL) and the resulting mixture was refluxed for 72 h until the
disappearance, by TLC, of the starting materials. The hot solution
was filtered and left for 24 h at room temperature where upon a
light-tan-coloured powder was formed. This was filtered off and
washed with ethanol to yield 15b as a light-sand-coloured solid
Compound 9a: 1,3,3-Trimethyl-2-methyleneindoline (8a) (0.2 g,
0.867 mmol) and 8-hydroxyquinoline-7-carbaldehyde (0.15 g,
0.867 mmol) were added to ethanol (20 mL) and the resulting mix-
ture was refluxed for 16 h. After this period the solution was re-
duced in volume to approximately one half and allowed to stand
whereupon a purple-coloured solid was formed. Recrystallisation
from ethanol yielded 9a as a slightly purple-coloured solid (0.22 g,
58%), m.p. 188–189 °C.[7]
(0.13 g, 38%), m.p. 199–200 °C. IR (CDCl , film): ν
= 2750–
˜
3
(max)
2900, 1640, 1610, 1580, 1510, 1310 cm–1; 1H NMR (CDCl3): δ =
6.5–8.2 (m, 10 H, ArH), 6.9 (d, Jvic = 10.2 Hz, 2 H, CH=CH), 5.7
(d, Jvic = 10.2 Hz, 2 H, CH=CH), 3.4 (m, 16 H, OCH2), 3.2 (s, 4
H, ArCH2N), 2.7 (s, 6 H, NCH3), 2.6 (br. t, 8 H, NCH2), 1.3 (s, 6
H, ArCCH3), 1.2 (s, 6 H, ArCCH3Ј) ppm; m/z = 1067 [MH]+ (FAB
MH+: calcd. 1067.432263; found 1067.435337), 1089 [Mna]+.
C54H60F6N6O10·2H2O (1103.12): calcd. C 58.8, H 5.8, N 7.5; found
C 58.3, H 5.5, N 7.4.
Compound 9b: 1,3,3-Trimethyl-2-methylene-5-nitroindoline (8b)
(0.2 g, 0.917 mmol) and 8-hydroxyquinoline-7-carbaldehyde
(0.16 g, 0.917 mmol) were added to ethanol (10 mL) and the re-
sulting mixture was refluxed for 24 h. After this period the solution
was cooled to room temperature to yield a dark crystalline solid.
The solid was removed and recrystallised from ethanol to give 9b
as a greenish solid (72 mg, 22%), m.p. 230–231 °C. IR (CDCl3,
film): ν
= 2980, 1655, 1620, 1510, 1325 cm–1; 1H NMR
˜
(max)
(CDCl3): δ = 6.4–8.8 (m, 8 H, ArH), 6.95 (d, Jvic = 10.1 Hz, 1 H,
CH=CH), 5.7 (d, Jvic = 10.1 Hz, 1 H, CH=CH), 2.9 (s, 3 H,
NCH3), 1.3 (s, 3 H, ArCCH3), 1.2 (s, 3 H, ArCCH3Ј) ppm; m/z (%)
= 373 (26) [M]+, 358 (100). C22H19N3O3 (373.41): calcd. C 70.8, H
5.1, N 11.3; found C 70.5, H 5.2, N 11.1.
Compound 15c: 1,3,3-Trimethyl-5-nitro-2-methyleneindoline (0.1 g,
0.46 mmol) and the diazadisalicylaldehyde 13 (0.142 g,
0.229 mmol) were added to ethanol (8 mL) containing DMF
(1 mL) and the resulting mixture was refluxed for 96 h until the
disappearance, by TLC, of the starting materials. After this period
all the solvents were removed under high vacuum to give an oil
which was triturated with ethyl acetate. The resulting solid was
recrystallized from ethanol to yield compound (15c) as a light-tan-
Compounds 13 and 14: 3-Chloromethyl-2-hydroxy-5-nitrobenzalde-
hyde (12)[17] (1 g, 4.64 mmol) was added portionwise with stirring
to 4,13-diaza-1,7,10,16-tetraoxacyclooctadecane (1.2 g, 4.64 mmol)
in dried THF, containing a trace of TEA, over 20 min at ice tem-
perature. After 5 h at ice temperature the mixture was allowed to
warm to room temperature and stirring was continued for a further
16 h during which time a yellow solid was precipitated. The re-
sulting mixture was then refluxed for 5 h before being cooled and
concentrated to dryness. Methanol was added and the yellow solid
that formed was filtered off to give compound 13 as a yellow crys-
coloured powder (38 mg, 8%), m.p. 230–231 °C. IR (KBr): ν
˜
(max)
= 2800–3000, 1655, 1610, 1515, 1320 cm–1; H NMR (CDCl3): δ =
6.2–7.95 (m, 10 H, ArH), 6.6 (d, Jvic = 10.6 Hz, 2 H, CH=CH),
5.5 (d, Jvic = 10.6 Hz, 2 H, CH=CH), 3.15 (m, 16 H, OCH2), 3.1
(s, 4 H, ArCH2N), 2.5 (s, 6 H, NCH3), 2.4 (br. t, 8 H, NCH2), 1.05
(s, 6 H, ArCCH3), 0.9 (s, 6 H, ArCCH3Ј) ppm; m/z = 1021 [MH]
+, 1043 [MNa]+. C52H60N8O14·2H2O (1057.12): calcd. C 59.1, H
5.7, N 10.6; found C 58.7, H 5.6, N 10.5.
1
talline solid (0.8 g, 28%), m.p. 183–185 °C. IR (KBr): ν(max) = 3500,
˜
2900, 1670, 1610, 1580 cm–1; 1H NMR [(CD3)2SO]: δ = 9.8 (s, 1 H,
Compound 16: 1,3,3-Trimethyl-2-methyleneindoline (40 mg,
CHO), 8.1–8.4 (m, 2 H, ArH), 8.1 (s, 1 H, OH), 4.5 (s, 2 H, 0.226 mmol) was added to the monocrowned salicylaldehyde 14
NCH2Ar), 3.65–4.0 (m, 16 H, OCH2), 3.3 (m, 8 H, NCH2) ppm. (0.1 g, 0.226 mmol) in ethanol (10 mL) and the resulting mixture
C28H36N4O12·2H2O (640.64): calcd. C 51.2, H 6.1, N 8.5; found C was refluxed until the disappearance, by TLC, of the starting mate-
50.7, H 5.9, N 8.4.
rials (6 h). After this period the ethanol was reduced in volume to
Eur. J. Org. Chem. 2006, 1050–1056
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1055

C. J. Roxburgh and P. G. Sammes
FULL PAPER
O. A. Federova, S. S. Gromov, R. E. Hester, I. K. Lednev, J. N.
Moore, V. P. Oleshko, A. I. Vedernikov, J. Chem. Soc., Perkin
Trans. 2 1996, 1441; d) M. V. Alfimov, A. V. Churakov, Y. V.
Fedorova, S. P. Gromov, R. E. Hester, A. K. Howard, L. G.
Kuzimina, I. K. Lednev, J. N. Moore, J. Chem. Soc., Perkin
Trans. 2 1997, 2249; e) O. A. Federova, Y. P. Strokach, S. P.
Gromov, A. V. Koshkin, T. M. Valova, M. V. Alfimov, A. V.
Feonfanov, I. S. Alaverdian, V. A. Lokshin, A. Samat, R. Gug-
lielmetti, R. B. Girling, J. N. Moore, R. E. Hester, New J.
Chem. 2002, 26, 1137.
one third and the mixture left to stand to give compound (16) as
a golden-coloured crystalline solid (120 mg, 61%), m.p. 105–
106 °C. IR (CDCl , film): ν
= 3300, 2900, 1640, 1600, 1550,
˜
3
(max)
1510, 1330 cm–1; 1H NMR (CDCl3): δ = 6.3–8.2 (m, 6 H, ArH),
6.3–7.1 (d, J = 10.2 Hz, 1 H, CH=CH), 6.3–7.1 (d, J = 10.2 Hz, 1
H, CH=CH), 4.1 (s, 2 H, ArCH2N), 2.6–3.0 (m, 16 H, OCH2), 2.6–
3.0 (m, 8 H, NCH2), 2.8 (s, 3 H, NCH3), 1.6 (s, 3 H, ArCCH3), 1.3
(s,
3 H, ArCCH3Ј) ppm; m/z =
597 [MH]+, 619 [MNa]+.
C32H44N4O7·2H2O (632.75): calcd. C 60.75, H 7.6, N 8.9.; found
[3] a) R. C. Bertleson, “Photochromism”, in Techniques of Organic
Chemistry (Ed.: G. H. Brown), Wiley Interscience, New York,
1971, chapter 3, pp. 45–294; b) R. Guglielonetti in Photochro-
mism Molecules and Systems (Eds.: H. Dürr, H. Bouas-Laur-
ent), Elsevier, Amsterdam, 1990, chapter 8, pp. 314–466.
[4] a) K. Kimura, T. Yamashita, M. Yokoyama, J. Chem. Soc.,
Chem. Commun. 1991, 147; b) K. Kimura, T. Yamashita, M.
Yokoyama, J. Chem. Soc., Perkin. Trans. 2 1992, 613.
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Org. Chem. 1994, 59, 1251.
C 60.3, H 7.3, N 8.6.
Compound 17: Compound 16 (0.1 g, 0.226 mmol) was dissolved in
acetonitrile (5 mL) and cooled to ice temperature. After 15 min a
proton sponge (0.0534 g, 0.24 mmol) was added and after a further
5 min methyl bromoacetate (42 mg, 0.272 mmol) was also added.
The mixture was stirred at ice temperature for 1 h and then slowly
allowed to warm to room temperature. Stirring was continued for
a further 20 h at room temperature and then the mixture was re-
fluxed for 2 h. After this period the solvent was removed under
reduced pressure to give an oil. This oil was triturated with diethyl
ether, which resulted in the precipitation of a solid. The solid (pro-
tonated proton sponge) was filtered off and discarded. The residue
was reduced in volume and purified by chromatography over silica
gel using methanol as eluent. The product, compound (17), was
[7] M. Tanaka, K. Kamada, H. Ando, T. Kitagako, Y. Shibutani,
S. Yajima, H. Sakamoto, K. Kimura, Chem. Commun. 1999,
1453.
[8] J. P. Phillips, A. Mueller, F. Przystal, J. Am. Chem. Soc. 1965,
87, 4020.
[9] G. E. Collins, L. S. Choi, K. J. Ewing, V. Michelet, C. M.
Brown, J. P. Winkler, Chem. Commun. 1999, 321.
[10] E. J. Forbes, M. Stacey, J. C. Tatlow, R. T. Wragg, Tetrahedron
1960, 8, 67.
[11] V. I. Troitskaya, I. G. Oksengendler, Khim. Geterotsiki. Soedin.
1982, 1, 39 [Chem Abstr. 1982, 97, 57109Z].
[12] L. M. Yagupolskii, S. V. Pasenok, M. A. Gal’bershtam, G. K.
Bobyleva, V. I. Popov, N. V. Kondratenko, Dyes Pigm. 1981, 2,
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[14] D. S. Deorha, S. S. Joshi, J. Org. Chem. 1961, 26, 3527.
[15] V. I. Troitskaya, I. G. Oksengendler, S. V. Pazenok, M. S. Lyub-
ich, S. M. Larina, L. M. Yagulpol’skii, Khim. Geterotsiki. Soe-
din. 1982, 1, 39.
collected as a red semi-solid (80 mg, 29%). IR (CDCl , film): ν
˜
3
(max)
= 2800–3000, 1735, 1650, 1610, 1580, 1520, 1340 cm–1; 1H NMR
(CDCl3): δ = 6.4–8.1 (m, 6 H, ArH), 6.7 (d, Jvic = 10.5 Hz, 1 H,
CH=CH), 5.7 (d, Jvic = 10.5 Hz, 1 H, CH=CH), 3.6 (s, 2 H,
ArCH2N), 3.5 (s, 2 H, NCH2CO2Me), 3.4 (s, 3 H, OCH3), 3.35 (m,
8 H, NCH2CH2O), 2.85 (m, 8 H, NCH2), 2.7 (s, 8 H, OCH2CH2),
2.6 (s, 3 H, NCH3), 1.2 (s, 3 H, ArCCH3), 1.1 (s, 3 H, ArCCH3Ј);
m/z = 669 [MH]+, 691 [MNa]+. C35H48N4O9·2H2O (704.82): calcd.
C 59.65, H 7.4, N 7.95; found C 59.2, H 7.1, N 7.8.
Acknowledgments
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din. 1977, 8, 855.
C. J. R. thanks the S.E.R.C. for a postdoctoral fellowship.
[17] L. D. Taylor, R. B. Davis, J. Org. Chem. 1963, 28, 1713.
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ama, Supramol. Chem. 1996, 7, 11.
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Received: September 7, 2005
Published Online: December 5, 2005
1056
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1050–1056