Azaxanthones and azathioxanthones are effective sensitisers for europium and terbium luminescence

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Azaxanthones and azathioxanthones are effective sensitisers for europium and

terbium luminescence

Paul Atkinson, Karen S. Findlay, Filip Kielar, Robert Pal, David Parker,* Robert A. Poole, Horst Puschmann,

Siobhan L. Richardson, Philip A. Stenson, Amber L. Thompson and Junhau Yu

Received 27th January 2006, Accepted 6th March 2006

First published as an Advance Article on the web 23rd March 2006

DOI: 10.1039/b601357k

Several azaxanthone and azathioxanthone sensitising chromophores have been incorporated into

macrocyclic ligands and form well-deﬁned Eu and Tb complexes in polar media. Excitation of the

heterocyclic chromophore in the range 330 to 382 nm leads to modest amounts of aromatic

ﬂuorescence and relatively efﬁcient metal-based luminescence, with absolute metal-based quantum

yields of up to 24% in aqueous media.

Over the past twenty years, there has been much interest in the de-

velopment of highly emissive lanthanide complexes incorporating

an aromatic sensitising group to enhance efﬁcient light absorption

and promote energy transfer to the proximate Ln(III) ion. The

stimulus for this work has been the utility of such complexes as

optical probes or sensors in a wide variety of applications. The

ﬁrst uses were in heterogeneous bio-assays¹and were followed by

the introduction of single-component systems, based on europium

cryptates.²Complexes of Eu(III) and Tb(III) are now used to

good effect in a variety of high throughput assays and screening

protocols, and several use time-resolved spectroscopy to enhance

the signal to noise ratio in luminescence detection.³

Several recent reviews serve to highlight the key issues which

have been addressed in optimising the design features of such

systems.^4–10The essential features of a ligand suitable for such

applications may be summarised as follows: a small singlet–triplet

energy separation minimising ligand ﬂuorescence and allowing

efﬁcient inter-system crossing to populate the triplet state of

the sensitiser; a high extinction coefﬁcient for the sensitiser

absorption band in the range 337–420 nm, facilitating single-

photon excitation of biological samples; a fast energy transfer step

leading to population of the lanthanide excited state, by selecting

the triplet energy level of the sensitiser to lie at least 2,000 cm⁻¹

above the emissive lanthanide excited state; a 7 to 9-coordinating

ligand, preferably with at least one donor incorporated into

the sensitising moiety to minimise the sensitiser–Ln³⁺distance,

that not only effectively shields the lanthanide(III) excited state

from radiationless deactivation, involving vibrational and/or

electronic energy transfer, but also inhibits quenching by electron

transfer.

for improvement. Particular targets include maximising the

product of φ_emand e as well as minimising lanthanide ex-

cited state deactivation by electron transfer from electron rich

donors.¹²

It is well known that aryl ketones are effective triplet sensitisers

in organic photochemistry. Indeed, substituted acetophenones,¹⁵

benzophenones¹⁶and acridones¹⁷have been incorporated into lig-

and structures to promote lanthanide sensitisation. In the case of

the acridone systems studied, sensitisation of europium emission

but not terbium was possible. Acridone ﬂuorescence accounted

for at least 80% of the emitted luminescence. Recent photophysical

studies on 1-azaxanthone 1a¹⁸and various thioxanthones 2a¹⁹have

been reported, suggesting that such aromatic ketones may be well

suited to sensitise lanthanide luminescence. For example, 1a has a

triplet energy of 25,400 cm⁻¹and absorbs light around 335 nm in

polar media, with an efﬁcient intersystem crossing step (φ^f_H

=

O

2

0.01, φ^isc

= 0.82). The parent thioxanthone analogue absorbs

H

O

2

around 375 nm with a slightly greater tendency to ﬂuoresce. By

replacing one phenyl group with a pyridine, possessing an a-

methyl substituent, e.g. 1b, 2b, it was envisaged that binding to

the lanthanide ion by the pyridyl N would be facilitated, with the

alpha substituent allowing linkage to a suitable ligand framework.

For example, the a-Me group may be easily converted into an a-

CH₂Br derivative with N-bromosuccinimide prior to introduction

into a suitable ligand.

The similarity in energy of azaxanthone np* and pp* excited

states¹⁸leads to a marked sensitivity of their photochemical prop-

erties to variation of solvent and substituent. A small library of

substituted 1-azaxanthones and 1-azathioxanthones was therefore

prepared, in order to analyse the effect of varying the nature and

position of substituents in the benzenoid ring on both their singlet

and triplet energies and their ability to ﬂuoresce. Such a process

informs the selection of the chromophore to be incorporated

into the ﬁnal octadentate ligand for lanthanide ion complexation.

Herein, we report the outcome of the ﬁrst phase of these studies

and report on the photochemical behaviour of selected europium

and terbium complexes of ligands incorporating some of these

heterocyclic chromophores. A preliminary account of a related

europium complex, bearing an azathioxanthone sensitiser has

been communicated recently.²⁰

A very small number of single-component systems have

been devised that meet these stringent design criteria for

applications in biological media. Encouraging behaviour has

been reported for terbium complexes of acyclic podands with

phenolic amide donors,¹¹for Eu and Tb complexes incorpo-

rating tetraazatriphenylene sensitisers^10,12,13and for certain ter-

pyridyl derivatives.¹⁴However, there remains considerable scope

Department of Chemistry, University of Durham, South Road, Durham, UK

DH1 3LE. E-mail: david.parker@dur.ac.uk

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Scheme 1

1-Azaxanthone and 1-azathioxanthone synthesis and spectroscopic

properties

extent. The low-temperature phosphorescence spectrum of 1b

(EPA glass, 77 K) possesses a highest energy band at 24,800 cm⁻¹

(quoted in Table 1 as the ’zero–zero’ transition, with the value

corresponding to the maximum intensity of this band). Fine

structure was observed, with three less intense bands separated by

∼1650 cm⁻¹, typical of carbonyl vibration ﬁne structure, (Fig. 1).

Such behaviour is also consistent with the dominant np* character

The synthesis of 1-azaxanthones is most expeditiously addressed

by a two-step process involving reaction of a substituted phenol (or

thiophenol) with a 2-chloronicotinic acid derivative, followed by

electrophilic cyclisation under acidic conditions,^21,22(Scheme 1).

Ortho and para-substituted phenols give rise to a single product

whereas a meta-substituted phenol leads to formation of 6- and

8-substituted constitutional isomers. These may be separated

by chromatography. The synthesis of compounds 1 to 16 was

undertaken in this manner, using standard procedures.

The photophysical properties of 2-methyl-1-azaxanthone (1b),

do not deviate signiﬁcantly from those reported for 1-azaxanthone,

1a.¹⁸The absorption spectrum of 1b exhibited a small red shift

in the longest wavelength band upon increasing solvent polarity,

shifting from 329 nm (EPA) to 330 and 334 nm in MeOH and

H₂O. Such behaviour is consistent with an increasing contribution

from low-lying pp* states, to the lowest energy transition which has

predominantly np* character, as deduced for 1a.¹⁸The extinction

coefﬁcient of the 330 nm band for 1b in MeOH was measured

in the presence of increasing amounts of water. It fell from

6,900 M⁻¹cm⁻¹to approach a limiting value of 4,500 M⁻¹cm⁻¹

in 33% water–methanol. The reduction in the oscillator strength

of the transition had been noted previously for 1a to a similar

Fig. 1 Phosphorescence emission spectra for compounds 1b and 10 (77 K,

EPA glass), illustrating the vibrational ﬁne structure for 1b and the longer

wavelength, less structured emission for 10, associated with the enhanced

‘pp* character’ of its triplet state.

Table 1 Photophysical properties of 2-methyl-1-azaxanthone derivatives

a

b

c

2-Me-azaxanthone derivative

k_max/nm (e; M⁻¹cm⁻¹

)

k_em/nm (I^r_e^e_m^l

)

E_T/cm⁻¹

1b^g

330 (6,900)

[350 (9,000)]

328 (5,720)

336 (9,380)

355 (4,845)

341 (5555)

421 (8,800)

404 (8,000)

334 (11,140)

369 (20,176)

356 (18,000)

329 (9,780)

405 (1)

24,800

[23,250]

24,900

24,600

21,500

[490 (10)]

392 (1.3)

409 (0.4)

453 (320)

474 (40)

555^f(1.6)

3a

4

5a

5b

6

21,900

d

7

545^f(1.2)

d

8

9

472 (505)

458 (515)

392 (1.3)

21,200

21,600

24,900

10

11

^aMeOH, 295 K; triplet energies are quoted here as the observed zero–zero transition i.e. an intensity maximum and are subject to an error of 400 cm⁻¹

.

^bRelative ﬂuorescence emission intensity in MeOH is given, referenced to the very weakly ﬂuorescent derivative 1b^e. ^c77 K in an Et₂O–isopentane–ethanol

(EPA) frozen glass with typically a 100 l delay. ^dNo signiﬁcant emission was detected. ^eUnder these conditions, acridone (k_abs412 nm, E_T= 21,050 cm⁻¹

)

has a relative ﬂuorescence emission intensity of 470. ^fThis emission band was observed at room temperature in solution, but not at low temperature in

the glass. At 77 K, ﬂuorescence emission at 413 nm was observed (k_exc352 nm). ^gValues in square brackets refer to the N-oxide for which a very broad

emission band was noted.

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of this triplet state. This behaviour may be contrasted with that

observed for the 8-amino-derivative, 10. The lowest energy absorp-

tion band was observed at 356 nm and was more intense than the

band at 330 nm (shoulder: Fig. 2). The triplet energy lowered to

21,600 cm⁻¹with no distinct vibrational ﬁne structure and there

was a 500-fold increase in room temperature relative ﬂuorescence

emission intensity. Taken together, such behaviour is consistent

with conjugation of the exocyclic N lone pair, lowering the energy

of the LUMO of 10 compared to 1b, accompanied by a switch

to predominant pp* character in the singlet and triplet excited

states. The bands at 330 and 356 nm presumably correspond

to transitions with dominant np* and p–p* character. Similar

observations have been reported when comparing the behaviour of

benzophenone with 4,4-dimethylaminobenzophenone (Michler’s

ketone) in polar media.^24,25

Fig. 2 Absorption spectra for compounds 1b (lower) and 10 (295 K,

MeOH).

was noted for the methoxy-derivatives 5a and 5b (very similar

band widths and parallel diminution in emission intensity as

concentration was reduced). A broad emission band was reported

for 2-aminoxanthone in polar media, and was interpreted in terms

of the formation of solvent-mediated formation of dimers or

trimers—termed loosely as ‘excimer-like aggregates of dynamic

type’,²⁶this phenomenon having been previously postulated for

various anthraquinone dyes.²⁷Here, the variation in concentration

was similar to that observed by these authors, but there seems no

compelling reason to invoke molecular aggregation or clustering,

mediated by the polar solvent, to explain the observed emission

proﬁle. The methoxy-substituted compounds 5a and 5b exhibited

a long-lived phosphorescence at 77 K. Lifetimes of 1.0 and

0.85 seconds were measured and may be compared to a value of

2 ms for the parent 1a, for which considerable np* character in the

lowest energy triplet was deduced. The measured triplet energies

of 21,500 and 21,900 cm⁻¹respectively are rather low triplet energy

values and similar to those found for the amino derivatives 9 and

10. They are too low to allow efﬁcient Tb sensitisation at ambient

temperature.

The absence of low-T phosphorescence and the very weak room-

temperature ﬂuorescence emission for 6–8 may be attributed to

deactivation of the singlet and triplet excited states, via vibronic

coupling involving an intramolecular hydrogen bond.¹⁹For com-

pound 6, direct support for this premise was found following

analysis of the molecular structure by X-ray crystallography at

120 K (Fig. 3). The C(10)–N(2)–H(2) bond angle was found to

be 117.8^◦, and observed torsion angles around the substituent

were consistent with a planar N atom, allowing optimal overlap

The constitutionally isomeric methoxy derivatives 5a and 5b

broadened and slightly shifted the lowest energy absorption band

to the red, the effect being most distinct for the 7-substituted

isomer, 5a. This compound was also about 8 times more ﬂu-

orescent than the 9-substituted isomer, 5b, which was, in turn,

40 times more ﬂuorescent than the parent 1b. The 7-tert-butyl,

4, and 7-carboxymethyl, 3b, derivatives perturbed the singlet and

triplet energies of the chromophore very little compared to 1b.

The tert-butyl derivative, 4, was the least ﬂuorescent of all the

derivatives examined, consistent with its enhanced tendency to

undergo radiationless deactivation of the singlet excited state,

via internal conversion associated with the increased number of

vibrational/rotational modes of the tert-butyl group.

The ortho-substituted series 6–8 presented quite different be-

haviour. The 6-substituted compounds exhibit no measurable low

temperature phosphorescence. In their absorption spectra quite

intense bands above 400 nm were observed for the amines 6 and 7

(k_max421 and 404 nm respectively), whereas for the amide 8 (lacking

the ability to engage in signiﬁcant N lone pair conjugation with

the aryl moiety), the absorption band was not shifted compared

to 1b. At 77 K, a distinct ﬂuorescent emission was deﬁned at

489 nm for 6. The room temperature emission spectra of 6 and

7 (but not 8) revealed very broad and weak bands at 565 and

545 nm respectively. The relative intensity of this band decreased

proportionately as the concentration of the solution was varied

over the range 1 → 50 lM. A similar pattern of behaviour

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those for 2b (k_absc371 nm; k_em= 425 nm; E_T= 23,700 cm⁻¹).

Alkyl substitution in the 7, 8 or 9-position did not perturb the

observed singlet and triplet energies signiﬁcantly, nor did it affect

the observed band intensities. The solvent dependence of the weak

ﬂuorescence emission of 2b was studied to help probe the character

of the singlet excited state. The broad and weak ﬂuorescence

emission band observed at room temperature shifted to the blue

and became even less intense in solvents of lower polarity (Fig. 4).

Indeed a structureless emission band was not observed in CH₂Cl₂,

EtOAc, THF and toluene. Such behaviour is consistent with a

slight enhancement of the pp* character in the singlet excited

state in more polar media. Low temperature phosphorescence

emission was strong, and in every case examined, the vibrational

ﬁne structure observed was indicative of a signiﬁcant np* character

in the T₁state.

Fig. 3 Crystal and molecular structure of 6 (120 K), illustrating the

˚

intramolecular hydrogen bond (N2 · · · O1 distance is 2.676(3) A), and

showing the crystallographic numbering scheme.

of the N lone pair with the p-system. No evidence for any

other hydrogen bonding interactions in the solid-state structure

was found, involving either solvent (absent in the lattice) or an

intermolecular interaction. The amide, 8, also gave rise to no

signiﬁcant ﬂuorescence at room temperature nor was any low-T

phosphorescence observed. In this case, a weak intramolecular C–

H · · · O interaction may be invoked to rationalise this behaviour.

Such C–H · · · O interactions have been postulated previously

to account for related cases of non-radiative deactivation, for

example, those observed in the excited state chemistry of 6-

methylthioxanthone.¹⁹

Given the behaviour observed with the 1-azaxanthone, a

slightly different series of compounds was screened with the 1-

azathioxanthones. It had previously been noted that introduction

of a nitrogen atom into a xanthone^18,28skeleton reduces the inten-

sity of ﬂuorescence and relatively weak ﬂuorescence was therefore

expected. The photophysical behaviour of the parent-2-methyl, 2b,

6-carboxy-2-methyl 12 and four isomeric monomethyl derivatives

13–16 was studied, (Table 2). Much more subtle variations in

singlet and triplet energies were noted. Alkyl-substitution in the

6-position (i.e. 4) produced the most signiﬁcant red shift in the

absorption spectrum, with a parallel increase in the ﬂuorescence

emission wavelength (very weak at 440 nm) and a decrease in the

triplet energy to 22,800 cm⁻¹. These values may be compared to

Implications for Eu³⁺/Tb³⁺sensitisation

Fluorescence emission for the 1-azaxanthones examined was

weak unless donor N or O lone-pairs were introduced into the

chromophore in the 7, 8 or 9 position. Such a substitution pattern

also led to a signiﬁcant lowering of the triplet energy, obviating

their use for Tb sensitisation. Substitution in the 6-position tended

to lead to fast radiationless deactivation of both singlet and triplet

excited states, precluding the use of such systems for sensitised

luminescence. Introduction of alkyl or carboxy groups perturbed

the triplet energy much less and also did not enhance the tendency

of the chromophore to ﬂuoresce.

Table 2 Photophysical properties of 2-methyl-1-azathioxanthone derivatives

a

b

1-Axathioxanthone derivative

k_max/m(e, M⁻¹cm⁻¹

)

k_em/nm(I^rel

)

E_T/cm^−1c

em

2b

12a

13

14

15b

16

371 (6,770)

369 (5,360)

372 (5,790)

381 (5,350)

375 (5,450)

374 (5,760)

425 (3.3)

423 (0.7)

428 (3.6)

440^d

437 (1.0)

437 (5.1)

23,700

23,800

23,500

22,800

23,500

23,600

^aMeOH, 295 K. ^bRelative ﬂuorescence emission intensity, compared to compound 1b. ^c77 K in a 1 : 1 MeOH/EtCH glass (of 20,400 cm⁻¹for ⁵D₄Tb

excited state and 17,200 cm⁻¹for ⁵D₀Eu excited state). In each case, vibrational ﬁne structure was evident, although the emission bands were rather broad

consistent with mainly ‘np* character’ in the triplet excited state. ^dVery weak.

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the intermediacy of the appropriate 2-bromomethyl derivative,

prepared by radical bromination of the 2-methyl precursor with N-

bromosuccinimide. Complexes of Eu and Tb were prepared using

standard methods and were puriﬁed either by chromatography on

alumina or by reverse-phase HPLC.

Measurements of the radiative rate constant for decay of lan-

thanide emission were made in H₂O and D₂O for each lanthanide

complex, allowing an estimation of the complex hydration state

by application of the well-known relationship between the number

of bound water molecules and the difference in excited state

quenching rates in the two media.²⁹In every case, a hydration

state close to one was found, consistent with the behaviour of

related complexes.⁶These include a close analogue of 17, where

a 4-morpholino-substitued pyridine replaces the azaxanthone

moiety.³⁰Such behaviour is in accord with a complex structure

in which the pyridyl N is bound to the lanthanide ion, generating

a nine coordinate complex in which one water binds to cap a

square anti-prismatic coordination geometry.⁶Further support for

formation of the mono-aqua species came from the measurement

of the relaxivities of selected Gd complexes. For example, with

[Gd.17], a relaxivity of 2.94 mM⁻¹s⁻¹was measured (310 K,

60 MHz). At this ﬁeld and frequency, such a value is in the range

expected for Gd complexes of this molecular weight.⁶

Quantum yield measurements for the complexes were made

using published procedures. For the complexes with azathiox-

anthone chromophores (Table 3), rather low values were found

with the terbium complexes in aerated solution, consistent with

the low measured radiative lifetimes. Much longer lifetimes were

measured in degassed solution, consistent with competitive back

energy transfer from the lanthanide excited state to the aryl triplet,

enhancing its susceptibility to quenching by molecular oxygen.

Many examples of this phenomenon have been reported,⁶where

the gap between the aryl triplet and the Tb excited state is less than

about 2,500 cm⁻¹. For the corresponding europium complexes,

Fig. 4 Variation of the ﬂuorescence emission band with the solvent

polarity parameter, E³_T⁰(295 K) for 2-methyl-1-azathioxanthone, 15a, and

for the derived europium complex, [Eu.20]³⁺

.

For the 1-azathioxanthones, the singlet–triplet energy gap was

smaller than that observed with azaxanthones, and typically

were of the order of 3,500 cm⁻¹; triplet energies examined were

typically close to 23,500 cm⁻¹( 500 cm⁻¹). This energy is well

suited to Eu³⁺sensitisation, but is at the practicable limit for

5

Tb³⁺(Tb: D₄lies at 20,400 cm⁻¹), at least for room temperature

applications. In order to assess the utility of these chromophores in

sensitised emission, selected octadentate ligands were constructed

incorporating the xanthone chromophores and the luminescence

behaviour of their Eu³⁺and Tb³⁺complexes deﬁned. Ligands 17, 18

and 19 were prepared, and compared to the heptadentate ligand 20

which had been prepared earlier for anion-binding studies.²⁰The

synthesis of 17–19 followed established methodology¹²involving

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Table 3 Photophysical properties of Eu³⁺and Tb³⁺complexes of ligands

17–20 (H₂O, 295 K)

ﬂuorescence was observed in less polar media. Comparing the

behaviour of [Tb.20]³⁺and [Eu.20]³⁺in water and methanol, for

example, the ligand based ﬂuorescence was 10 times less in the

latter case. The ﬂuorescence emission band also shifted to the blue

as the solvent polarity diminished (Fig. 4); this effect correlated

well with that observed for the parent chromophore 15a. Evidently,

the presence of the proximate lanthanide ion appears neither to

perturb the facility of inter-system crossing in the xanthone entity

signiﬁcantly, nor to change the sensitivity of the energy of the np*

and pp* excited states to local solvation effects.

Less ligand ﬂuorescence was evident in the emission spectra

of the terbium complexes in water with integral azaxanthone

sensitisers, e.g. [Tb.17] and [Tb.18] (Fig. 6)]. Such behaviour

accords with the lower intrinsic ﬂuorescence of the azaxanthone

chromophores, 1b and 3 (Table 1). The measured absolute

quantum yield for [Tb.17] was 24%, which is quite a high value for

a complex with one coordinated water molecule. Moreover, this

high emission intensity and long emission lifetime was conserved

in aqueous solutions containing added salts. For example, the

terbium emission lifetime in [Tb.17] was 1.98 ms in 1 M aqueous

sodium acetate solution buffered to pH4, and was invariant ( 5%)

over a period of 48 h.

Complex

s_{H O}/ms

s_{D O}/ms

q

φ^em

(%)

O

H₂

2

[Eu. 17]^a,b

[Tb. 17]

[Eu. 18]^a

[Tb. 18]

[Eu. 19]^c

[Tb. 19]

[Eu. 20]^d

[Tb. 20]

0.57

1.82

0.60

1.89

0.51

0.49

0.32

0.059

(0.66)

2.02

2.73

2.08

2.88

1.62

0.60

0.49

0.060

(0.84)

1.2

0.6

1.1

0.64

1.3

1.25

1.1

n/a

(1.25)

6.9

24

8.0

12^e

2.2

2.1

8.9

not measured

(12)

^aIn each case, k_abs= 336 nm; q values are subject to an estimated error

of 25% and quantum yields are given as the mean of 3 observations

(

20%). ^bFor the corresponding complex [Gd.17], E_T= 24,950 cm⁻¹

(77 K, 1 : 1 EtOH–MeOH glass). ^ck_exc= 375 nm. ^dk_exc= 382 nm; emission

quantum yields (φ_f, %) for thioxanthone ﬂuorescence were as follows: 20:

4.4 (MeOH), 25 (H₂O); [Eu. 20]: 44 (H₂O); [Tb. 20]: 50 (H₂O); for the

Tb complex, values in parentheses refer to a degassed sample. The lower

lifetime of this Eu complex is due to quenching by the ring NH oscillator.

^eThe lower quantum yield here compared to [Tb.17] may be related to less

efﬁcient inter-system crossing and/or enhanced vibrational deactivation

of the azaxanthone singlet excited state.

[Eu.19] and [Eu.20]³⁺quantum yields were higher, but there

was still a fairly signiﬁcant ﬂuorescence from the thioxanthone

chromophore, as noted in the chromophore spectral studies

discussed above (Fig. 5). Indeed, the quantum yield for ligand

ﬂuorescence was measured to be 44 and 50% in water for [Eu.20]³⁺

and [Tb.20]³⁺respectively. Considerably less azathioxanthone

Fig. 6 Total emission spectra (aerated water, 295 K, k_exc334 nm) for

[Tb.17] compared to [Tb.18]⁻(upper) showing the very low azaxanthone

ﬂuorescence, and the typical terbium emission pattern in each case.

Conclusions

Fig. 5 Total emission spectra (aerated water, 295 K, k_exc375 nm) for

[Ln.19] (Ln = Eu {upper}; Ln = Tb {lower}) showing the ligand

ﬂuorescence around 440 nm and the lanthanide emission bands to lower

energy.

Azaxanthone and thioxanthone chromophores are superior to

acridone chromophores as sensitising moieties for Eu and Tb

emission. In such systems, the most obvious synthetic strategy

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allows the incorporation of a range of different substituents in the

benzenoid ring. Alkoxy and amino-substituents tend to favour

molecular ﬂuorescence or lower the triplet energy to such an

extent that Tb-sensitised emission becomes impracticable. Simple

alkyl, acylamino or carboxy substituents do not perturb the

chromophore triplet energy very much, allowing the identiﬁcation

of appropriate derivatives for conjugation to vectors for assays or

for other molecular probe applications.

of 5a, 6 and 15a) and full-matrix least squares on F using

CRYSTALS³⁵(for 5b). Reﬂection intensities were corrected by

numerical integration using SHELXTL software, based on crystal

measurements and indexing of the faces³⁴or by the multi-scan

method, based on multiple scans of identical and Laue equivalent

reﬂections (using the SADABS software).³⁶Non-hydrogen atoms

were reﬁned with anisotropic displacement parameters and the

hydrogen atoms were positioned geometrically and reﬁned using a

riding model. Crystallographic data (excluding structure factors)

for the structures included herein have been deposited with

the Cambridge Crystallographic Data Centre† CCDC reference

numbers 296391–296394..

Experimental

General Procedures

Excited state measurements

All commercially available reagents were used as received, from

their respective suppliers. Solvents were dried using an appropriate

drying agent when required. Reactions requiring anhydrous con-

ditions were carried out using Schlenk-line techniques under an

atmosphere of dry argon. Water and H₂O refer to high purity water

with conductivity ≤0.04 lS cm⁻¹obtained from the ‘Purite_STILL

plus’ puriﬁcation system.

Thin-layer chromatography was carried out on neutral alumina

plates (Merck Art 5550) or silica plates (Merck 5554) and visu-

alised under UV (254 nm) or by staining with iodine. Preparative

column chromatography was carried out using neutral alumina

(Merck Aluminium Oxide 90, activity II-III, 70–230 mesh), pre-

soaked in ethyl acetate, or silica (Merck Silica Gel 60, 230–

400 mesh).

The lifetimes of the Tb and Eu complexes were measured by

exciting the sample using a short pulse of light (336 nm) followed

by the monitoring of the integrated intensity of light (546 nm for

terbium, 613 nm for europium) emitted during a ﬁxed gate time,

t_g, after a delay time, t_d. At least 20 delay times were used covering

3 or more lifetimes. A gate time of 0.1 ms was employed, and the

excitation and emission slits set to a bandpass of 10 nm and 2.5 nm

respectively. The obtained exponential decay curves were ﬁtted to

the equation below, using Microsoft Excel,

I = A₀+ A₁exp( − kt)

where:

¹H and ¹³C NMR spectra were recorded on a Varian Mercury

200 (¹H at 199.98 MHz, ¹³C at 50.29 MHz), Varian Unity 300

(¹H at 299.91 MHz, ¹³C at 75.41 MHz), Varian VXR 400 (¹H

at 399.97 MHz, ¹³C at 100.57 MHz), or a Bruker AMX 500 spec-

trometer. Spectra were referenced internally to the residual protio-

solvent resonances. Electrospray mass spectra were recorded on

a VG Platform II (Fisons instrument), operating in positive or

negative ion mode as stated, with methanol as the carrier solvent.

Accurate mass spectra were recorded using a Thermo Finnigan

LTQ FT mass spectrometer. Melting points were recorded using a

Ko¨ﬂer block and are uncorrected. UV/Vis absorbance spectra

were recorded on a Perkin Elmer Lambda 900 UV/Vis/NIR

spectrometer. Emission Spectra and Lifetimes were measured on a

Fluorolog-3 and a Perkin Elmer LS55 luminescence spectrometer

using FL Winlab software. All samples were contained in quartz

cuvettes with a path length of 1 cm and measurements obtained

relative to a reference of pure solvent contained in a matched cell.

I = intensity at time t after the ﬂash

A₀= intensity after the decay has ﬁnished

A₁= pre-exponential factor

k = rate constant for decay of the excited state.

Quantum yield measurements were made relative to

a

standard,¹²LnPh₃dpqC(CF₃SO₃)₃, for each of the Tb³⁺and Eu³⁺

complexes. For the standard and each of the unknowns, ﬁve

solutions with absorbances between 0.02 and 0.1 were used. For

each of these solutions the absorbance at the excitation wavelength

and the total integrated emission was determined. A plot of total

integrated emission against absorbance gave a straight line with

slope Em./Abs. The unknown quantum yield was calculated using

the equation below:

ꢀ

ꢁ

2

slope_x

slope_r

n_x

n_r

U_x= U_r·

·

Single crystal X-ray diffraction

Since values for both the sample and reference compounds were

recorded in water the refractive index term cancels out. Errors in

quantum yield determinations can arise due to the inner ﬁlter

effect or errors in the amount of absorbed light. These effects were

minimised by only using samples with absorbances below 0.2.

Errors in assessing the amount of light absorbed by each sample

were minimised by choosing the excitation wavelength to be on a

relatively ﬂat area of the absorption curve and by using a small

band-pass for excitation.

Crystal structures were determined for 5a, 5b, 6 and 15a. Data

were collected using graphite monochromated Mo Ka radiation

˚

(k = 0.71073 A) on a Bruker area detector diffractometer (Bruker

SMART CCD 1 K or Bruker ProteumM with Bede Microsource),

equipped with Cryostream N₂open-ﬂow cooling device.³¹In

each case, series of narrow x-scans (0.3^◦) at several φ-settings

were carried out to cover approximately a sphere of data to a

˚

maximum resolution between 0.70 and 0.77 A. Cell parameters

were determined and reﬁned using the SMART software,³²and

raw frame data were integrated using the SAINT program.³³

Structures were solved by direct methods and reﬁned by full-matrix

least squares on F²using SHELXTL software³⁴(for structures

† CCDC reference numbers 296391–296394. For crystallographic data in

CIF or other electronic format see DOI: 10.1039/b601357k

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Low temperature phosphorescence spectra of heterocyclic lig-

ands and gadolinium(III) complexes were recorded to enable the

triplet energy of the bound chromophore to be determined. An

Oxford Instruments optical cryostat operating at 77 K was used

with the samples dissolved in EPA (diethyl ether–isopentane–

ethanol, 5 : 5 : 2) or EtOH–MeOH mixtures and contained in

10 mm cuvettes. The triplet energy was considered as the highest

energy (shortest wavelength) observed phosphorescence band,

corresponding to the 0–0 transition, using time-gated detection.

The longitudinal water proton relaxation rate was measured

at 60 MHz using a Bruker Minispec mq spectrometer operating

at 310 K, by means of a standard inversion-recovery technique.

The data obtained was accurate to a reproducibility of 1%. A

correction was made for the diamagnetic contribution to allow

the estimation of the paramagnetic relaxivity. The gadolinium

concentration of the solution was measured in triplicate using

a Perkin Elmer ICPOES (Inductively Coupled Plasma Optical

Emission) spectrometer.

J 8, 1.5, H⁶), 8.60 (1H, d, J 7.8, H⁴); d_C(CDCl₃) 25.2 (CH₃),

114.3 (C^4ꢀ), 118.6 (C⁹), 121.3 (C³), 121.8 (C^6ꢀ), 124.7 (C⁷), 126.7

(C⁶), 135.5 (C⁸), 137.4 (C⁴), 155.8 (C^9ꢀ), 160.0 (C^1ꢀ), 165.2 (C²),

177.7 (C⁵); m/z (ESMS⁺) 233.7 ([M + Na], 100%); HRMS (ES⁺),

found: 212.0707 [M + H], C₁₃H₁₀NO₂requires 212.0706; UV-vis

(H₂O) k_max(e/mol⁻¹dm³cm⁻¹) 289 (16,180) and 334 nm (8790).

2-Methyl-1-azaxanthone-N-oxide. 2-Methyl-1-azaxanthone

(45 mg, 213 lmol) was dissolved in triﬂuoroacetic acid (TFA)

(400 lL) and H₂O₂(100 lL, 37%) and the resulting solution

boiled under reﬂux for 4 hours. A further two additions of

TFA (400 lL) and H₂O₂(100 lL, 37%) were made at 4 hour

intervals and then the reaction was evaporated to dryness under

reduced pressure. The residue was taken up in aqueous NaHCO₃

(10 cm³) and extracted with CH₂Cl₂(2 × 10 cm³). The combined

organics were washed with aqueous NaCl solution (10 cm³), dried

(Na₂SO₄), ﬁltered and evaporated under reduced pressure to give

the crude compound as a yellow solid. Subsequent puriﬁcation

via column chromatography (silica, CH₂Cl₂to 2% EtOH) yielded

the title compound (24 mg, 106 lmol, 50%) as a pale yellow solid,

R_f0.33 (silica, 3% EtOH:CH₂Cl₂), m.p. 191–2 ^◦C. Found: C, 66.2;

H, 4.15; N, 5.83%; C₁₃H₉NO₃.H₂O requires C, 66.1; H, 4.27; N,

5.93%.

Synthesis

6-Methyl-2-phenoxynicotinic acid. Sodium (1.44 g, 62.6 mmol)

was dissolved in dry MeOH (27 cm³), followed by the addition of

6-methyl-2-chloronicotinic acid (5.09 g, 29.6 mmol) and phenol

(13.27 g, 0.14 mol) under argon, forming a yellow solution. The

MeOH was removed under reduced pressure, and the brown melt

heated for 1 hour at 180 ^◦C under argon with stirring. Upon

cooling, the melt was treated with water (200 cm³) forming a

pale yellow suspension, which was washed with diethyl ether (3 ×

200 cm³). The aqueous layer was acidiﬁed with acetic acid to pH 4,

yielding a ﬁne white precipitate upon cooling which was collected

via ﬁltration, and after thorough drying yielded the title compound

d_H(CDCl₃). 8.32 (d, 1H, J 7.9 Hz, H⁶), 8.09 (d, 1H, J 8.2 Hz,

H⁴), 7.88–7.80 (m, 2H, H^8,9), 7.51 (t, 1H, H⁷), 7.34 (d, 1H, J 8.2 Hz,

H³), 2.74 (s, 3H, CH₃).

d_C(CDCl₃). 176.2 (C⁵), 155.2 (C²), 155.1 (C^1ꢀ), 154.9 (C^9ꢀ),

136.3 (C⁸), 126.9 (C⁶), 126.0 (C⁷), 122.7 (C⁴), 121.3 (C^6ꢀ), 120.7

(C³), 119.1 (C⁹), 117.5 (C^4ꢀ), 18.9 (CH₃).

(m/z) ESMS⁺228 ([M + H]⁺, 5%), 250 ([M + Na]⁺, 100%), 477

([2M + Na]⁺, 20%).

◦

as a pale yellow solid (3.01 g, 44%), m.p. 134–136 C (lit.²³155–

Found: (ES⁺) 250.0473; C₁₃H₉NO₃Na requires 250.0475, [M +

Na]⁺.

156 ^◦C). Found: C, 67.79; H, 4.74; N, 6.11%. C₁₃H₁₁NO₃requires

C, 68.11; H, 4.84; N, 6.11%. d_H(CDCl₃) 2.40 (3H, s, CH₃), 7.03

(1H, d, J 7.8, H⁵⁾, 7.18 (2H, d, J 7.6, H^2ꢀ), 7.29 (1H, t, J 7.6,

H^4ꢀ), 7.44 (2H, t, J 7.6, H^3ꢀ), 8.41 (1H, d, J 7.8, H⁴)10.6 (1H, br s

OH); d_C(CDCl₃, 125 MHz) 24.4 (CH₃), 110.0 (C³), 119.4 (C⁵),

121.8 (C^2ꢀ), 125.8 (C^4ꢀ), 129.6 (C^3ꢀ), 143.6 (C⁴), 152.0 (C^1ꢀ), 160.2

(C²), 163.2 (C⁶), 164.7 (COOH); m/z (ESMS⁻) 184 (M − COOH,

95%), 228 (M − H, 100%). HRMS (ES⁺), found: 230.0809 [M +

H]; C₁₃H₁₂NO₃requires 230.0812.

2-Bromomethyl-1-azaxanthone, 1c. 2-Methyl-1-azaxanthone

(0.200 g, 0.947 mmol) was dissolved in CCl₄(10 cm³) and the

reaction heated to 80 ^◦C under argon. N-Bromosuccinimide

(NBS) (85 mg, 0.475 mmol, 0.5 eq.) was added along with benzoyl

peroxide (3 mg) with stirring and the reaction mixture was stirred

at room temperature under argon, using a tungsten lamp for

activation. The reaction was monitored using TLC (SiO₂, toluene–

CH₂Cl₂–MeOH, 48.5 : 48.5 : 3) and ¹H NMR. After 8 hours and

the addition of 2 equivalents of NBS and benzoyl peroxide, the

crude reaction mixture was allowed to cool to room temperature

and then ﬁltered. The solvent was removed under reduced pressure

and the residue puriﬁed by column chromatography on silica gel

(toluene–DCM, 80 : 20) to yield the title compound as a white

crystalline solid (0.102 g, 0.35 mmol, 37%), m.p. 169–171 ^◦C;

R_f(SiO₂, toluene–dichloromethane–MeOH, 48.5 :48.5 : 3): 0.67.

Found C, 53.9; H, 2.74; N, 4.85%. C₁₃H₈NO₂Br requires: C, 53.8;

H, 2.78; N, 4.83%. d_H(CDCl₃) 4.61 (2H, s, CH₂Br), 7.45 (1H, ddd,

J 8,7.2, 1.0, H⁷), 7.58 (1H, d, J 8, H³), 7.62 (1H, d, J 8, H⁹), 7.80

(1H, ddd, J 8,7.2,1.6, H⁸), 8.31 (1H, d, J 8, H⁶), 8.72 (1H, d, J

8, H⁴); d_C(CDCl₃) 32.3 (CH₂Br), 116.1 (C^4ꢀ), 118.6 (C⁹), 120.9

(C³), 121.7 (C^6ꢀ), 125.0 (C⁷), 126.8 (C⁶), 135.9 (C⁸), 138.8 (C⁴),

155.8 (C^9ꢀ), 158.8 (C^1ꢀ), 162.1 (C²), 177.2 (C⁵); m/z (ESMS⁺) 290.1

([M + H], 100%), 312.1 ([M + Na], 20%). HRMS (ES⁺) found:

289.9817 [M + H], C₁₃H₉BrNO₂requires 289.9811.

2-Methyl-1-azaxanthone, 1b. Polyphosphoric acid (80 g) was

added to 2-phenoxy-6-methylnicotinic acid (1.535 g, 6.7 mmol)

and the reaction mixture heated at 120 ^◦C for 20 hours under

argon with stirring. The resulting light-brown liquid was cooled

to room temperature and then slowly and carefully poured onto

ice (200 g) with stirring until a homogeneous solution formed.

The pH of the solution was then carefully adjusted to 12 by

the addition of 50% aqueous KOH solution and the yellow

crystals that formed upon cooling were removed via ﬁltration.

The product was recrystallised from toluene–petroleum ether (40–

60 ^◦C). The crystals that formed upon standing were ﬁltered and

dried thoroughly to yield the title compound as a pale yellow

crystalline solid (1.23 g, 87%), m.p. 131–132 ^◦C (lit.²³136–8 ^◦C);

R_f(SiO₂, DCM): 0.30. Found C, 73.9; H, 4.27; N, 6.73. C₁₃H₉NO₂

requires C, 73.9; H, 4.29; N, 6.63%. d_H(CDCl₃) 2.71 (3H, s, CH₃),

7.30 (1H, d, J 7.8, H³), 7.43 (1H, ddd, J 8,7, 0.9 H⁷), 7.61 (1H,

dd, J 8.4, 0.9, H⁹), 7.77 (1H, ddd, J 8, 7, 1.5 H⁸), 8.32 (1H, dd,

1714 | Org. Biomol. Chem., 2006, 4, 1707–1722

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2-(4-Methoxycarbonylphenoxy)-6-methylnicotinic acid. Sodium

methoxide (660 mg, 12.2 mmol) was dissolved in dry MeOH

(5 cm³) with stirring, followed by methyl-4-hydroxybenzoate

(4.26 g, 28 mmol) and 6-methyl-2-chloronicotinic acid (1.0 g,

5.9 mmol). The methanol was removed under reduced pressure

and the reaction heated for 24 hours at 180 ^◦C with stirring. The

reaction mixture was left to cool to ∼120 ^◦C and poured onto

ice (∼40 g) to give a white suspension, which was treated with

diethyl ether (3 × 50 cm³). The separated aqueous solution was

acidiﬁed with acetic acid yielding a pale yellow precipitate, which

was ﬁltered, washed with water and dried thoroughly to yield the

title compound as a white crystalline solid (1.005 g, 60%), m.p. 118–

120 ^◦C. Found C, 59.2; H, 4.52; N, 4.49. C₁₅H₁₃NO₅.H₂O requires

title compound as a white crystalline solid (0.140 g, 0.40 mmol,

50%), m.p. 156–158 C; R_f(SiO₂, EtOAc–hexane, 50 : 50): 0.65.

Found C, 49.4; H, 3.34; N, 4.07%. C₁₅H₁₀NO₄Br.H₂O requires C,

49.2; H, 3.30; N, 3.83%.

d_H(CDCl₃) 3.98 (3H, s, OCH₃), 4.62 (2H, s, CH₂Br), 7.62 (1H,

d, J 8, H³), 7.68 (1H, d, J 8.5, H⁹), 8.44 (1H, dd, J 8.5, H⁸), 8.74

(1H, d, J 8, H⁴), 9.00 (1H, d, J 2,H⁶); d_C(CDCl₃) 32.3 (CH₂Br),

52.8 (OCH₃), 116.2 (C^4ꢀ), 119.2 (C⁹), 121.5 (C^6ꢀ), 121.6 (C³), 127.3

(C⁷), 129.4 (C⁶), 136.6 (C⁸), 139.0 (C⁴), 158.4 (C^9ꢀ), 159.8 (C^1ꢀ),

162.7 (C²), 165.8 (CO₂Me), 176.7 (C⁵); m/z (ESMS⁺) 348.1 ([M +

H], 100%), 370.1 ([M + Na], 30%).

6-Methyl-2-(4^ꢀ-tert-butylphenoxy)nicotinic acid. To a solution

of sodium (1.03 g, 44.6 mmol) dissolved in dry MeOH (25 ml) was

added 2-chloro-6-methylnicotinic acid (3.62 g, 21.1 mmol) and 4-

tert-butylphenol (15.17 g, 101.0 mmol) and the mixture stirred

for 10 min. MeOH was removed in vacuo to afford a viscous

orange oil which was heated for 2 h at 180 ^◦C with stirring.

After cooling, the cream coloured gum was treated with H₂O

(200 cm³) and washed successively with Et₂O (3 × 200 cm³).

The aqueous solution was acidiﬁed to pH 5 with acetic acid

and the off white precipitate that formed collected by ﬁltration

and washed with H₂O. The crude product was recrystallised from

CH₂Cl₂–hexane and dried (MgSO₄) to afford 6-methyl-2-4^ꢀ-tert-

butylphenoxynicotinic acid as a white powder (4.60 g, 16.1 mmol,

76%), m.p. 179–181 ^◦C. Found: C, 71.28; H, 6.76; N, 4.96%.

C₁₇H₁₉NO₃requires: C, 71.56; H, 6.71; N, 4.91%. d_H(300 MHz,

CDCl₃), 1.38 (9H, s, C(CH₃)₃), 2.45 (3H, s, CH₃), 7.05 (1H, d, J

7.8, H³), 7.14 (2H, d, J 8.8, H^2ꢀ), 7.46 (2H, d, J 8.8, H^3ꢀ), 8.43

(1H, d, J 7.8, H⁴); d_C(CDCl₃), 24.68 (CH₃), 31.68 (C(CH₃)₃),

34.79 (C(CH₃)₃), 110.25 (C⁵), 119.64 (C³), 121.20 (C^2ꢀ), 126.76

(C^3ꢀ), 143.79 (C⁴), 148.92 (C^4ꢀ), 149.81 (C^1ꢀ), 160.46 (C²), 163.46

(C⁶), 164.84 (COOH); m/z (ESMS⁺) 286 ([M + H], 25%), 308

([M + Na], 100%); HRMS (ES⁺), found: 308.1256 [M + Na];

C₁₇H₁₉NO₃Na requires 308.1257.

◦

1

C, 59.0; H, 4.95; N, 4.59%. d_H(CDCl₃) 2.41 (3H, s, CH₃), 3.91

(3H, s, OCH₃), 7.02 (1H, d, J 8, H⁵), 7.18 (2H, d, J 9, H^2ꢀ), 8.07

(2H, d, J 9, H^3ꢀ), 8.32 (1H, d, J 8, H⁴); d_C(CDCl₃) 24.4 (CH₃), 52.3

(OCH₃), 111.3 (C³), 119.3 (C⁵), 121.0 (C^2ꢀ), 126.6 (C^4ꢀ), 131.4 (C^3ꢀ),

143.4 (C⁴), 157.6 (C^1ꢀ), 160.6 (C²), 163.2 (C⁶), 166.7 (COOCH₃),

168.2 (COOH); m/z (ESMS⁻) 242 ([M − COOH], 75%), 286 ([M −

H], 100%); HRMS (ES⁺) found: 288.0869 [M + H], C₁₅H₁₃NO₅

requires 288.0866.

7-Methoxycarbonyl-2-methyl-1-azaxanthone, 3a. Polyphos-

phoric acid (70 g) was added to 2-(4-methoxycarbonylphenoxy)-

6-methylnicotinic acid (0.90 g, 3.1 mmol) and the reaction mixture

heated at 120 ^◦C for 18 hours under argon with stirring. The

resulting brown liquid was cooled to room temperature and

then slowly and carefully poured into a beaker containing cold

MeOH (100 cm³) with stirring until a homogeneous solution

formed. The solution was carefully adjusted to an apparent pH of

approximately 7 by the addition of 10% aqueous KOH solution.

The resulting white suspension was extracted with chloroform

(3 × 50 cm³) and the solvent removed from the combined organic

washings to yield the title compound as a pale yellow crystalline

solid (0.428 g, 1.6 mmol, 51%), m.p. 194–196 ^◦C; R_f(SiO₂,

toluene–dichloromethane–MeOH, 48.5 : 48.5 : 3): 0.30. Found C,

66.5; H, 4.14; N, 5.13%. C₁₅H₁₁NO₄requires C, 66.9; H, 4.12; N,

5.20%.

d_H(CDCl₃) 2.73 (3H, s, CH₃), 3.98 (3H, s, OCH₃), 7.24 (1H,

d, J 9, H³), 7.65 (1H, d, J 9, H⁹), 8.41 (1H, d, J 9, H⁸), 8.61

(1H, d, J 9, H⁴), 9.0 (1H, s, H⁶); d_C(CDCl₃) 25.2 (CH₃), 52.6

(OCH₃), 114.4 (C^4ꢀ), 118.9 (C⁹), 121.4 (C^6ꢀ), 121.8 (C³), 126.8

(C⁷), 129.2 (C⁶), 136.0 (C⁸), 137.6 (C⁴), 158.3 (C^9ꢀ), 160.0 (C^1ꢀ),

165.72 (CO₂Me), 165.75 (CN), 176.9 (keto); m/z (ESMS⁺) 291.8

([M + Na], 100%), 269.7 ([M + H], 25%); HRMS (ES⁺), found:

270.0760 [M + H], C₁₅H₁₂NO₄requires 270.0761; UV-vis (H₂O)

k_max(e/mol⁻¹dm³cm⁻¹) 288 (12,860) and 334 nm (5720).

2-Methyl-1-aza-7-tert-butylxanthone, 4. Polyphosphoric acid

(80 g) was added to 6-methyl-2-4^ꢀ-tert-butylphenoxynicotinic acid

(1.91 g, 6.96 mmol) and the reaction heated at 120 ^◦C for 20 h. The

light brown mixture was poured whilst still hot onto crushed ice

(300 g) and carefully basiﬁed to pH 12 by addition of KOH. The

yellow precipitate was collected by ﬁltration and the crude product

recrystallised from CH₂Cl₂and dried (MgSO₄). Removal of all

solvents in vacuo afforded yellow crystals of the title product

◦

(1.57 g, 5.88 mmol, 88%), m.p. 117–119 C. Found: C, 76.3; H,

6.38; N, 5.23%. C₁₇H₁₇NO₂requires: C, 76.4; H, 6.41; N, 5.24%.

d_H(300 MHz, CDCl₃), 1.39 (9H, s, C(CH₃)₃), 2.70 (3H, s, CH₃),

7.28 (1H, d, J 7.9, H³), 7.54 (1H, d, J 8.7, H^6ꢀ), 7.82 (1H, dd,

J 8.7, H^5ꢀ), 8.28 (1H, d, J 2.4, H^3ꢀ), 8.59 (1H, d, J 7.9, H⁴); d_C

(CDCl₃), 25.34 (CH₃), 31.57 (C(CH₃)₃), 35.06 (C(CH₃)₃), 114.47

(C⁵), 118.34 (C³), 121.23 (C^2ꢀ), 122.63 (C^6ꢀ), 133.62 (C^3ꢀ), 137.64

(C^5ꢀ), 148.10 (C⁴), 154.03 (C^4ꢀ), 160.22 (C^1ꢀ), 165.15 (C²), 165.15

(C⁶), 178.00 (CO); m/z (ESMS⁺) 290 ([M + Na], 35%), 557 ([2M +

Na], 100%); HRMS (ES⁺) 290.1152 [M + Na]; C₁₇H₁₇NO₂Na

requires: 290.1152.

7-Methoxycarbonyl-2-bromomethyl-1-azaxanthone, 3b. 7-

Methoxycarbonyl-2-methyl-1-azaxanthone (0.215 g, 0.798 mmol)

was dissolved in a mixture of CCl₄and MeCN (2 : 1 ratio,

10 cm³) and the reaction heated to 80 ^◦C under argon. NBS

(71 mg, 0.399 mmol, 0.5 eq.) was added along with AIBN

(∼2 mg) with stirring and the reaction monitored using TLC

1

(SiO₂, EtOAc–hexane, 50 : 50) and H NMR. After 4 days and

the addition of 7 equivalents of NBS and AIBN the reaction

was halted and the crude reaction mixture allowed to cool to

room temperature before being ﬁltered. The solvent was removed

under reduced pressure and the residue puriﬁed by column

chromatography on silica gel (hexane–EtOAc, 50 : 50) to yield the

2-(4-Methoxyphenoxy)-6-methylnicotinic acid. Sodium (1.44 g,

62.6 mmol) was dissolved in dry MeOH (27 cm³), followed by the

addition of 6-methyl-2-chloronicotinic acid (5.09 g, 29.6 mmol)

and 4-methoxyphenol (17.50 g, 0.14 mol) under argon, forming a

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yellow solution. The solvent was removed under reduced pressure,

and the brown melt heated for 22 hours at 190 ^◦C under argon with

stirring. The melt was treated with water (200 cm³) producing a

pale yellow suspension, which was washed with diethyl ether (3 ×

200 cm³). The aqueous layer was acidiﬁed with acetic acid to pH 4,

yielding a ﬁne white precipitate upon cooling. This was collected

by ﬁltration, and dried thoroughly to yield the title compound as a

pale yellow solid (3.51 g, 46%), m.p. 138–139 ^◦C. Found: C, 64.8;

H, 5.05; N, 5.48%. C₁₄H₁₃NO₄requires C, 64.8; H, 5.06; N, 5.40%.

d_H(CDCl₃) 2.40 (3H, s, CH₃), 3.85 (3H, s, OCH₃), 6.95 (2H, dd, J

6.8, 2.2, H³^ꢀ⁾, 7.02 (1H, d, J 7.8, H⁵), 7.11 (2H, dd, J 6.8, 2.2, H^2ꢀ),

8.41 (1H, d, J 7.8, H⁴); d_C(CDCl₃, 125 MHz) 24.4 (CH₃), 55.6

(OCH₃), 109.7 (C³), 114.6 (C^3ꢀ), 119.3 (C⁵), 122.8 (C^2ꢀ), 143.6 (C⁴),

145.1 (C^1ꢀ), 157.3 (C^4ꢀ), 160.4 (C²), 163.2 (C⁶), 164.3 (COOH); m/z

(ESMS⁺) 282.1 ([M + Na], 100%). HRMS (ES⁺), found: 282.0734

[M + Na]; C₁₄H₁₃NO₄Na requires 282.0737.

removed under reduced pressure yielding an orange solid. The

crude product was puriﬁed by column chromatography (silica,

DCM → DCM–EtOH 97 : 3) yielding the title compound as a

◦

pale orange crystalline solid (40 mg, 68%), m.p. 220–222 C. d_H

(CDCl₃) 2.72 (3H, s, CH₃), 3.91 (3H, s, OCH₃), 7.33 (1H, d, J 8.2,

H³), 7.41 (1H, dd, J 9.2, 3.2, H⁸), 7.74 (1H, d, J 3.2, H⁹), 7.74 (1H,

d, J 9.2, H⁶), 8.12 (1H, d, J 8.2, H⁴); m/z (ESMS⁺) 258 (M + H,

100%), 280 (M + Na, 65%). HRMS (ES⁺), found: 258.0761 [M +

H]; C₁₄H₁₂NO₄requires 258.0761.

2-(2-Methoxyphenyl)-6-methylnicotinic acid. Sodium (1.44 g,

62.6 mmol) was dissolved in dry MeOH (27 cm³), followed by the

addition of 6-methyl-2-chloronicotinic acid (5.09 g, 29.6 mmol)

and 2-methoxyphenol (15.50 cm³, 0.14 mol) under argon, forming

a dark green solution. The MeOH was removed under reduced

◦

pressure, and the dark green melt heated for 40 hours at 155 C

7-Methoxy-2-methyl-1-azaxanthone, 5a. 2-(4-Methoxy-

phenoxy)-6-methylnicotinic acid (2.00 g, 7.71 mmol) was

dissolved in polyphosphoric acid (60 g) forming a yellow thick

solution that was heated for 20 hours at 120 ^◦C under argon

resulting in a brown melt. After cooling, the melt was dissolved

in cold concentrated sodium hydroxide solution (200 cm³). The

pH of the yellow solution was adjusted to 8 by further addition of

concentrated NaOH solution, forming a ﬁne yellow precipitate.

The product was extracted into diethyl ether (3 × 100 cm³),

and the solvent removed under reduced pressure. The product

was recrystallised using ethanol, and the solid that formed on

standing was collected and dried to yield the title compound as

under argon with stirring. The melt was treated with water

(200 cm³) producing a pale yellow suspension, which was washed

with diethyl ether (3 × 200 cm³). The aqueous layer was then

acidiﬁed with acetic acid to pH 4, yielding a ﬁne white precipitate

upon cooling. The product was extracted using ethyl acetate

(3 × 200 cm³) and the solvent removed under reduced pressure,

through drying yielded the title compound as a pale yellow solid

(4.52 g, 60%), m.p. 160–161 ^◦C. Found: C, 64.7; H, 5.05; N, 5.36%.

C₁₄H₁₃NO₄requires C, 64.8; H, 5.06; N, 5.40%. d_H(CDCl₃) 2.42

(3H, s, CH₃), 3.80 (3H, s, OCH₃), 7.03 (1H, dd, J 8.0, 1.5, H^3ꢀ),

7.04 (1H, d, J 7.5, H⁵), 7.06 (1H, td, J 8.0, 1.5, H^5ꢀ), 7.29 (1H, td,

J 8.0, 1.5, H^4ꢀ), 7.45 (1H, dd, J 8.0, 1.5, H^6ꢀ), 8.41 (1H, d, J 7.5,

H⁴); d_C(CDCl₃, 125 MHz) 24.7 (CH₃), 56.1 (OCH₃), 110.3 (C³),

112.6 (C^3ꢀ), 119.8 (C⁵), 121.0 (C^5ꢀ), 124.4 (C^6ꢀ), 127.1 (C^4ꢀ), 141.3

(C^1ꢀ), 143.8 (C⁴), 151.4 (C^2ꢀ), 160.3 (C²), 163.1 (C⁶), 164.9 (COOH);

m/z (ESMS⁻) 214 ([M − COOH], 60%), 258 ([M − H], 100%).

HRMS (ES⁻), found: 258.0768 [M − H]; C₁₄H₁₂NO₄requires

258.0772.

◦

pale yellow crystals (548 mg, 30%), m.p. 170–171 C. Found: C,

69.5; H, 4.61; N, 5.85%. C₁₄H₁₁NO₃requires C, 69.7; H, 4.60; N,

5.80%. d_H(CDCl₃) 2.71 (3H, s, CH₃), 3.93 (3H, s, OCH₃), 7.30

(1H, d, J 8.0, H³), 7.37 (1H, dd, J 9.2, 3.0, H⁸), 7.55 (1H, d, J 9.2,

H⁹), 7.67 (1H, d, J 3.0, H⁶), 8.60 (1H, d, J 8.0, H⁴); d_C(CDCl₃,

125 MHz) 25.1 (CH₃), 56.0 (OCH₃), 105.9 (C⁶), 119.6 (C^4ꢀ), 119.9

(C⁹), 121.0 (C³), 122.0 (C^6ꢀ), 125.3 (C⁸), 137.3 (C⁴), 150.4 (C^9ꢀ),

156.5 (C⁷), 159.8 (C^1ꢀ), 165.0 (C²), 177.4 (C⁵); m/z (ESMS⁺) 242.1

([M + H], 30%), 264.1 ([M + Na], 40%), 505.2 ([2M + Na],

100%), 746.1 ([3M + Na], 50%). HRMS (ES⁺), found: 264.0632

[M + Na]; C₁₄H₁₁NO₃Na requires 264.0631. The structure was

conﬁrmed by single crystal X-ray diffraction.‡

9-Methoxy-2-methyl-1-azaxanthone, 5b. 2-(2-Methoxyphenol)-

6-methylnicotinic acid (2.50 g, 9.6 mmol) was dissolved in

polyphosphoric acid (60 g) _◦forming a yellow thick solution, and

heated for 20 hours at 120 C under argon resulting in a brown

melt. Upon cooling, the melt was dissolved in cold concentrated

sodium hydroxide solution (200 cm³). The pH of the yellow

solution was adjusted to 8 by the further addition of concentrated

aqueous NaOH solution, forming a ﬁne yellow precipitate. The

product was extracted into diethyl ether (3 × 100 cm³), dried

(K₂CO₃), and the solvent removed under reduced pressure. The

product was recrystallised using ethanol, and the solid that formed

upon standing was collected and dried to yield the title compound

7-Methoxy-2-methyl-1-azaxanthone-N-oxide. 7-Methoxy-2-

methyl-1-azaxanthone (55 mg, 0.23 mmol) was dissolved in TFA

(0.4 ml) and H₂O₂(0.1 ml, 30%) forming an orange solution which

was reﬂuxed at 125 ^◦C under argon. Two further additions of

TFA (0.4 ml) and H₂O₂(0.1 ml, 30%) were made at two hour

intervals, and the reaction mixture reﬂuxed for 16 hours. After

cooling the orange brown solution, the solvents were removed

under reduced pressure yielding an orange brown solid. The crude

product was dissolved in aqueous NaHCO₃solution (10 cm³), and

washed with dichloromethane (2 × 10 cm³), and the combined

organics were then washed with aqueous NaCl (10 cm³) and dried

(Na₂SO₄). The resulting solution was ﬁltered and the solvent

◦

as pale yellow crystals (480 mg, 21%), m.p. 183–185 C. Found:

C, 68.5; H, 4.59; N, 5.67. C₁₄H₁₁NO₃.0.25H₂O requires C, 68.4;

H, 4.73; N, 5.70%. d_H(CDCl₃) 2.73 (3H, s, CH₃), 4.05 (3H, s,

OCH₃), 7.29 (1H, dd, J 8.0, 1.5, H⁸), 7.31 (1H, d, J 8.0, H³), 7.35

(1H, t, J 8.0, H⁷), 7.87 (1H, dd, J 8.0, 1.5, H⁶), 8.60 (1H, d, J

8.0, H⁴); d_C(CDCl₃, 125 MHz) 25.4 (CH₃), 56.6 (OCH₃), 114.3

(C^4ꢀ), 116.3 (C⁷), 117.5 (C⁶), 121.6 (C³), 122.9 (C^9ꢀ), 124.5 (C⁸),

137.5 (C⁴), 146.4 (C^6ꢀ), 149.3 (C⁹), 160.1 (C^1ꢀ), 165.6 (C²), 178.0

(C⁵); m/z (ESMS⁺) 242 ([M + H], 70%), 264 ([M + Na], 75%),

505 ([2M + Na], 100%), 746 ([3M + Na], 10%). HRMS (ES⁺),

˚

D

‡ C₁₄H₁₁N O₃, M_r= 241.24, Monoclinic_◦(P2₁/n), a = 12.191(2) A, b =

−1

˚

3.8876(8) A, c = 22.922(4) A, b = 90.223(6) , Z = 4, l = 0.105 mm

=

calc

1.475 Mg m⁻³, T = 120(2) K, 2132 independent reﬂections [R(int) =

0.1274], R₁= 0.0620, wR₂= 0.1416 [I > 2sigma(I)]. CCDC 296392.

For crystallographic data in CIF or other electronic format see DOI:

10.1039/b601357k

1716 | Org. Biomol. Chem., 2006, 4, 1707–1722

This journal is

The Royal Society of Chemistry 2006

©

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found: 242.0812 [M + H]; C₁₄H₁₂NO₃requires 242.0812. The

structure was conﬁrmed by single crystal X-ray diffraction.§

Found: C, 66.1; H, 5.77; N, 10.0%; C₁₅H₁₄N₂O₂·H₂O requires

C, 66.2; H, 5.92; N, 10.3%. The structure was conﬁrmed by single

crystal X-ray diffraction.¶

8-N-Ethylamino-2-methyl-1-azaxanthone, 9. (410 mg, 1.6 mmol,

25%) recrystallised from toluene, m.p. 177–178 ^◦C.

d_H8.54 (d, 1H, J 7.9 Hz, H⁴), 8.06 (d, 1H, J 8.8 Hz, H⁶), 7.23

(d, 1H, J 7.9 Hz, H³), 6.59 (dd, 1H, J 8.8, 2.1 Hz, H⁷), 6.54 (d,

1H, J 2.1 Hz, H⁹), 3.28 (q, 2H, J 7.2 Hz, CH₂), 2.67 (s, 3H, CH₃),

1.33 (t, 3H, J 7.2 Hz, CH₂CH₃).

2-[(3-(N-Acetyl-N-ethylamino)phenoxy]-6-methylnicotinic acid.

2-Chloro-6-methylnicotinic acid (2.88 g, 16.7 mmol) was added

to a stirred solution of 3-(N-acetyl-N-ethylamino)phenol (3.0 g,

16.7 mmol) in NaOMe solution (2 M, 16.8 cm³) and stirred for

5 minutes at room temperature under an argon atmosphere. The

solvents were removed under reduced pressure and the residue

dissolved in DMF (15 cm³). K₂CO₃(1.16 g, 8.4 mmol) and CuI

(0.1 g, 0.5 mmol) were added to the mixture and the resulting

suspension heated at 140 ^◦C for 12 hours, monitoring the reaction

using tlc. Upon completion, the reaction was cooled to room

temperature and the solvents removed under reduced pressure.

The residue was taken up in water (150 cm³) and ﬁltered. The

aqueous solution was acidiﬁed with aqueous HCl (1 M) and the

resulting precipitate collected via ﬁltration and dried thoroughly.

Recrystallisation from MeOH yielded the title compound as a

colourless solid, (3.5 g, 64%), m.p. 159–60 ^◦C.

d_C176.0 (C⁵), 163.5 (C²), 160.1 (C^1ꢀ), 158.4 (C^9ꢀ), 154.4 (C⁸),

137.1 (C⁴), 128.1 (C⁶), 120.7 (C³), 114.7 (C^4ꢀ), 112.2 (C^6ꢀ), 112.0

(C⁷), 96.9 (C⁹), 38.1 (CH₂), 25.0 (CH₃), 14.5 (CH₂CH₃). ESMS⁺

(m/z) 255 ([M + H]⁺, 15%), 277 ([M + Na]⁺, 40%), 532 ([2M +

Na]⁺, 100%). HRMS (ES⁺) 277.0946; C₁₅H₁₄N₂O₂Na requires

277.0945, [M + Na]⁺. Found: C, 69.9; H, 5.80; N, 10.8%;

C₁₅H₁₄N₂O₂·0.25H₂O requires C, 69.6; H, 5.65; N, 10.8%.

8-(N -Acetyl-N -ethylamino)-2-methyl-1-azaxanthone,

11.

(490 mg, 1.7 mmol, 26%) recrystallised from EtOH, m.p.

d_H8.32 (d, 1H, J 7.8 Hz, H⁴), 7.43 (t, 1H, H^5ꢀ), 7.16 (d, 1H, J

7.8 Hz, H^6ꢀ), 7.01 (d, 1H, J 8.1 Hz, H^4ꢀ), 7.00 (s, 1H, H^2ꢀ), 6.99 (d,

1H, J 7.8 Hz, H⁵), 3.76 (q, 2H, J 7.1 Hz, CH₂), 2.37 (s, 3H, CH₃),

1.92 (s, 3H, COCH₃), 1.12 (t, 3H, J 7.1 Hz, CH₂CH₃).

180–182 ^◦C.

d_C8.60 (d, 1H, J 7.9 Hz, H⁴), 8.36 (d, 1H, J 8.4 Hz, H⁶), 7.41

(d, 1H, J 2.0 Hz, H⁹), 7.34 (d, 1H, J 7.9 Hz, H³), 6.25 (dd, 1H, J

8.4, 2.0 Hz, H⁷), 3.85 (q, 2H, J 7.1 Hz, CH₂), 2.73 (s, 3H, CH₃),

1.98 (s, 3H, COCH₃), 1.17 (t, 3H, J 7.1 Hz, CH₂CH₃).

d_C170.7 (C O_(acid)), 167.4 (C O_(amide)), 162.5 (C⁶), 160.7 (C²),

154.2 (C^1ꢀ), 143.3 (C⁴), 130.5 (C^5ꢀ), 124.4 (C^4ꢀ), 122.3 (C^2ꢀ),

121.0 (C^6ꢀ), 118.9 (C⁵), 111.4 (C³), 44.0 (CH₂), 24.4 (CH₃), 22.8

(COCH₃), 13.1 (CH₂CH₃). ESMS⁻(m/z) 313 ([M − H]⁻, 100%).

HRMS (ES⁺) 337.1151; C₁₇H₁₈N₂O₄Na requires 337.1159, [M +

Na]⁺). Found: C, 64.8; H, 5.76; N, 8.78%; C₁₇H₁₈N₂O₄requires C,

64.9; H, 5.77; N, 8.91%.

=

5

2

1ꢀ

9ꢀ

=

d_C176.6 (C ), 169.4 (NC O), 165.5 (C ), 160.0 (C ), 156.1 (C ),

149.2 (C⁸), 137.4 (C⁴), 128.3 (C⁶), 124.5 (C⁷), 121.7 (C³), 120.8 (C^6ꢀ),

117.6 (C⁹), 114.3 (C^4ꢀ), 44.4 (CH₂), 25.2 (CH₃), 23.0 (COCH₃), 13.4

(CH₂CH₃). ESMS⁺(m/z) 297 ([M + H]⁺, 30%), 319 ([M + Na]⁺,

100%), 615 ([2M + Na]⁺,70%). Found: C, 68.5; H, 5.38; N, 9.41%;

C₁₇H₁₆N₂O₃requires C, 68.9; H, 5.44; N, 9.45%.

N-Substituted-1-azaxanthones. 2-[(3-(N-Acetyl-N-ethylamino)-

phenoxy]-6-methylnicotinic acid (2.0 g, 6.4 mmol) was added to

PPA (100 g) and heated at 120 ^◦C under an argon atmosphere

with stirring for 16 hours. The resulting viscous solution was

poured onto ice (300 g) and stirred until a homogeneous solution

formed. The solution was then basiﬁed to pH 12 using aqueous

KOH (50%) and the yellow precipitate that formed upon cooling

was isolated via ﬁltration. The resulting brown solid consisted of a

mixture of three major products which were separated by column

chromatography (silica, CHCl₃1 to 5% MeOH) and recrystallised

from the stated solvent.

6-(N-Acetyl-N-ethylamino)-2-methyl-1-azaxanthone, 8. Acetyl

chloride (13.5 lL, 190 lmol) was added dropwise to a stirred solu-

tion of 6-ethylamino-2-methyl-1-azaxanthone (48 mg, 190 lmol)

in ethyl acetate (10 cm³) under an argon atmosphere. Following

the addition, the reaction was stirred at room temperature for a

further 4 hours during which time a yellow precipitate formed.

The solvents were removed under reduced pressure to give a pale

yellow solid. The solid residue was suspended in CHCl₃(15 cm³)

and quickly washed with saturated NaHCO₃solution (5 cm³).

The organic solvents were dried (K₂CO₃), ﬁltered and evaporated

under reduced pressure to give the title compound (55 mg, 98%)

as a pale yellow solid, which was recrystallised from ethanol.

m.p. 171–173 ^◦C. Found: C, 68.7; H, 5.47; N, 9.44%; C₁₇H₁₆N₂O₃

requires C, 68.9; H, 5.44; N, 9.45%.

6-Ethylamino-2-methyl-1-azaxanthone, 6. (130 mg, 0.5 mmol,

8%) recrystallised from MeOH, m.p. 142–144 ^◦C.

d_H9.31 (br s, 1H, NH), 8.46 (d, 1H, J 7.9 Hz, H⁴), 7.47 (t, 1H,

H⁸), 7.22 (d, 1H, J 7.9 Hz, H³), 6.68 (d, 1H, J 8.8 Hz, H⁷), 6.47

(d, 1H, J 8.5 Hz, H⁹), 3.31 (q, 2H, J 7.2 Hz, CH₂), 2.67 (s, 3H,

d_H(CDCl₃) Major diastereoisomer (∼80%) 8.53 (d, 1H, J

7.9 Hz, H⁴), 7.80 (t, 1H, H⁸), 7.67 (d, 1H, J 8.5 Hz, H⁹), 7.31

(d, 1H, J 7.9 Hz, H³), 7.20 (d, 1H, J 7.6 Hz, H⁷), 4.31 (dq, 1H,

J 13.9, 7.3 Hz, CH₂), 3.22 (dq, 1H, J 13.9, 7.3 Hz, CH₂), 2.71 (s,

3H, CH₃), 1.76 (s, 3H, COCH₃), 1.10 (t, 3H, J 7.3 Hz, CH₂CH₃)

d_C(CDCl₃) Major diastereoisomer only 176.2 (C⁵), 169.5

CH₃), 1.38 (t, 3H, J 7.2 Hz, CH₂CH₃). d 180.1 (C⁵), 164.2 (C²),

C

159.5 (C^1ꢀ), 157.5 (C^9ꢀ), 151.9 (C⁶), 136.61 (C⁴), 136.57 (C⁸), 120.7

(C³), 114.6 (C^4ꢀ), 106.4 (C^6ꢀ), 104.5 (C⁷), 102.7 (C⁹), 37.8 (CH₂),

25.0 (CH₃), 14.4 (CH₂CH₃).

ESMS⁺(m/z) 255 ([M + H]⁺, 50%), 277 ([M + Na]⁺, 100%),

(C O_(amide)), 165.4 (C²), 159.0 (C^1ꢀ), 157.3 (C^9ꢀ), 142.3 (C⁶), 137.6

=

531 ([2M + Na]⁺, 70%).

(C⁴), 135.0 (C⁸), 127.0 (C⁷), 121.6 (C³), 119.4 (C⁹), 118.2 (C^6ꢀ), 114.8

˚

§ C₁₄H₁₁N O₃, M_r= 241.24, Monoclinic (P_◦2₁), a = 3.8200(6) A, b =

¶ C₁₅H₁₄N₂O₂, M_r= 254.28, Monoclinic (P2₁/c), a = 4.5840(3) A, b =

◦

−1

˚

9.5681(16) A, c = 14.756(2) A, b = 93.579(4) , Z = 2, l = 0.106 mm

D_calc= 1.488 Mg m⁻³, T = 120(2) K, 1380 independent reﬂections [R(int) =

0.027], R₁= 0.0276, wR₂= 0.0297 [I > 2sigma(I)] CCDC 296391.

For crystallographic data in CIF or other electronic format see DOI:

10.1039/b601357k

11.1889(7) A, c = 24.2034(15) A, b = 90.953(3) , Z = 4, l = 0.092 mm

D_calc= 1.361 Mg/m³, T = 120(2) K, 2722 independent reﬂections [R(int) =

0.1251], R₁= 0.0560, wR₂= 0.1174 [I > 2sigma(I)]. CCDC 296393.

For crystallographic data in CIF or other electronic format see DOI:

10.1039/b601357k

This journal is

The Royal Society of Chemistry 2006

Org. Biomol. Chem., 2006, 4, 1707–1722 | 1717

©

View Article Online

(C^4ꢀ), 43.8 (CH₂), 25.1 (CH₃), 22.7 (COCH₃), 12.9 (CH₂CH₃).

ESMS⁺(m/z) 297 ([M + H]⁺, 30%), 319 ([M + Na]⁺,100%),

615 ([2M + Na]⁺, 70%). HRMS (ES⁺) 319.1052; C₁₇H₁₆N₂O₃Na

requires 319.1053, [M + Na]⁺.

14 lmol, 20%), m.p. >250 ^◦C; d_H(D₂O, 500 MHz, 298 K) multiple

resonances from d − 440 to +400 ppm, indicating the presence

of 2 major paramagnetically shifted species, exchanging slowly on

1

the H NMR timescale; m/z (ESMS⁺) 734.2 (M + Na, 100%);

HRMS (ES⁺), found: 734.1248 (M + Na), C₂₇H₃₀N₅O₈TbNa

requires 734.1241; k_abs(H₂O): 336 nm; s_H₂_O: 1.82 ms; s_D₂_O: 2.73 ms;

φ_H₂_O: 0.24.

2-(1-Azaxanthonylmethyl)-1,4,7-tris(tert-butoxycarbonylmethyl)-

1,4,7,10-tetraazacyclododecane. 1,4,7-Tris(tert-butoxycarbonyl-

methyl)-1,4,7,10-tetraazacyclododecane (0.127 g, 0.246 mmol)

was combined with 2-bromomethyl-1-azaxanthone (70 mg,

0.243 mmol) and Cs₂CO₃(83 mg, 0.255 mmol) and dry

acetonitrile was added (5 cm³). The reaction mixture was heated

[Eu.17]. 2-(1-Azaxanthonylmethyl)-1,4,7-tris(carboxymethyl)-

1,4,7,10-tetraazacyclododecane (10 mg, 18 lmol) was added to

Eu(OAc)₃.3H₂O (5.9 mg, 18 lmol) and the solids dissolved in

a MeOH–H₂O mixture (1 : 1, 3 cm³). The solution was then

carefully adjusted to an apparent pH of approximately 5.5 by the

addition of 10% aqueous NaOH and the reaction heated at 55 ^◦C

under argon for 16 hours. The reaction was followed by TLC

(DCM–MeOH, 70 : 30) and upon completion the pale yellow

solution was adjusted to an apparent pH of approximately 10

by the addition of aqueous NaHCO₃solution and the resulting

white precipitate removed via a ﬁne syringe ﬁlter. The solvents

were removed from the clear colourless solution under reduced

pressure to yield the title compound as a pale yellow crystalline

solid (11 mg, 15.6 lmol, 87%), m.p. >250 ^◦C; d_H(D₂O, 500 MHz,

298 K) multiple resonances from d − 24 to +40 ppm, indicating

the presence of at least 2 diamagnetically shifted components,

◦

to reﬂux (85 C) under argon with stirring for 16 hours and the

reaction monitored by TLC to conﬁrm that all the brominated

starting material had been consumed. The solvent was removed

under reduced pressure and DCM (50 cm³) added and the solvent

again removed under reduced pressure. The resulting solid was

dissolved in a small volume of DCM (5 cm³) and the solution

ﬁltered to remove any solid CsBr. The crude mixture puriﬁed by

column chromatography on alumina (DCM–MeOH, 99.5 : 0.5) to

yield the title compound as a pale-yellow crystalline solid (0.152 g,

0.21 mmol, 86%), m.p. >250 ^◦C; R_f(SiO₂, DCM–MeOH, 95 : 5):

0.51; d_H(CDCl₃) 1.46 (27H, s, t-Bu), 3.15 (16H, m br, cyclen ring),

3.45 (2H, s, acetate CH₂), 3.59 (4H, s, 2 × acetate CH₂’s), 4.59

(2H, s, CH₂), 7.45 (1H, t, J 8, H⁷), 7.53 (1H, d, J 8, H³), 7.60 (1H,

d, J 8, H⁹), 7.77 (1H, t, J 8, H⁸), 8.31 (1H, d, J 8, H⁶), 8.67 (1H,

d, J 8, H⁴); m/z (ESMS⁺) 746.4 ([M + Na], 100%), 724.4 ([M +

H], 20%). HRMS (ES⁺), found: 724.4279 [M + H]; C₃₉H₅₈N₅O₈

requires 724.4280.

1

exchanging slowly with respect to the H NMR timescale; m/z

(ESMS⁺) 726.1 ([M + Na], 100%); HRMS (ES⁺), found: 726.1188

[M + Na], C₂₇H₃₀N₅O₈EuNa requires 726.1185; k_abs(H₂O):

336 nm; s_H₂_O: 0.57 ms; s_H₂_O: 2.02 ms; φ_H₂_O: 0.069.

2-(1-Azaxanthonylmethyl-1,4,7-tris(carboxymethyl)-1,4,7,10-

tetraazacyclododecane, 17. A mixture of triﬂuoroacetic acid

(1 cm³) in DCM (0.5 cm³) was added to 2-(1-azaxanthonylmethyl)-

1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclodo-

decane (0.107 g, 0.148 mmol) and the reaction mixture left under

argon for 48 hours at room temperature. The solvents were

removed under reduced pressure and a small volume of DCM (3 ×

5 cm³) was added and removed, again under reduced pressure to

yield the title compound as a pale-orange crystalline solid (69 mg,

0.124 mmol, 84%), m.p. >250 ^◦C; R_f(SiO₂, DCM–MeOH, 95 : 5):

0.50; d_H(CD₃CN) 2.75–3.27 (16H, m br, cyclen ring), 3.36 (2H, s,

acetate CH₂), 3.77 (4H, s, 2 × acetate CH₂’s), 4.51 (2H, s, CH₂),

7.48 (1H, t, J 8, H⁷), 7.51 (1H, d, J 8, H³), 7.73 (1H, d, J 8, H⁹),

7.87 (1H, t, J 8, H⁸), 8.20 (1H, d, J 8, H⁶), 8.58 (1H, d, J 8, H⁴). m/z

(ESMS⁺) 556.2 (M + H, 100%), 578.2 (M + Na, 15%). HRMS

(ES⁺), found: 556.2398 [M + H]; C₂₇H₃₄N₅O₈requires 556.2402.

[Gd.17]. The Gd complex was pre_◦pared in an analogous

manner to the Tb complex. m.p. >250 C; m/z (ESMS⁺) 733.0

(M + Na, 100%); HRMS (ES⁺), found: 733.1228 [M + Na],

C₂₇H₃₀N₅O₈GdNa requires 733.1228; r_1p(H₂O, 310 K, 60 MHz) =

2.94 mM⁻¹s⁻¹.

7-Methoxycarbonyl-2-(1-azaxanthonylmethyl)-1,4,7-tris(tert-

butoxycarbonylmethyl) - 1,4,7,10 - tetraazacyclododecane. 1,4,7-

Tris(tert-butoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane

(92 mg, 0.178 mmol) was combined with 7-methoxycarbonyl-2-

bromomethyl-1-azaxanthone (62 mg, 0.178 mmol) and K₂CO₃

(0.025 g, 0.181 mmol) and dry acetonitrile (5 cm³) was added.

The reaction mixture was heated to reﬂux (80 ^◦C) under argon

with stirring for 16 hours and the reaction monitored by TLC

to conﬁrm that all the brominated starting material had been

consumed. The solvent was removed under reduced pressure

and DCM (50 cm³) added and the solvent again removed under

reduced pressure. The resulting solid was dissolved in a small

volume of DCM (5 cm³) and the solution ﬁltered to remove any

solid KBr. The crude mixture puriﬁed by column chromatography

on silica gel (DCM–EtOH, 99 : 1) to yield the title compound as

a 50 : 50 mixture of two distinct stereoisomers in the form of a

[Tb.17]. 2-Methyl-1-azaxanthone-1,4,7-tris(carboxymethyl)-

1,4,7,10-tetraazacyclododecane (40 mg, 71 lmol) was added to

TbCl₃.6H₂O (27 mg, 72 lmol) and the solids dissolved in a

MeOH–H₂O mixture (1 : 1, 3 cm³). The solution was then

carefully adjusted to an apparent pH of approximately 5.5 by the

addition of 10% aqueous NaOH and the reaction heated at 55 ^◦C

under argon for 16 hours. The reaction was followed by TLC

(DCM–MeOH, 70 : 30) and upon completion the pale yellow

solution was adjusted to an apparent pH of approximately 10

by the addition of aqueous NaHCO₃solution and the resulting

white precipitate removed via a ﬁne syringe ﬁlter. The solvents

were removed under reduced pressure and the residue puriﬁed

by column chromatography on alumina (DCM–MeOH, 50 : 50)

to yield the title compound as a white crystalline solid (10 mg,

◦

pale-yellow foam (0.076 g, 0.097 mmol, 54%), m.p. >250 C; R_f

(Alumina, DCM–EtOH, 97 : 3): 0.40/0.60.

d_H(CDCl₃, 300 MHz) 1.44 (27H, s, t-Bu), 3.16 (16H, m br,

cyclen ring), 3.44 (2H, s, acetate CH₂), 3.58 (4H, s, 2 × acetate

CH₂’s), 3.97 (3H, s, OCH₃), 4.59 (2H, s, CH₂), 7.51 (1H, d, J 8,

H³), 7.68 (1H, d, J 8.5, H⁹), 8.40 (1H, dd, J 8.5, H⁸), 8.68 (1H, d,

J 8, H⁴), 8.98 (1H, s, H⁶); m/z (ESMS⁺) 804.8 ([M + Na], 100%),

782.2 ([M + H], 25%).

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7-Carboxy-2-(1-azaxanthonylmethyl)-1,4,7-tris(carboxymethyl)-

1,4,7,10-tetraazacyclododecane, 18. 7-Methoxycarbonyl-2-

further 16 h. The majority of the methanol was removed under

reduced pressure to give a sticky syrup, which was diluted by water

to give 1000 ml of solution. The pH of the solution was adjusted to

8 by the addition of NaOH pellets and was extracted with CHCl₃

(3 × 300 ml). The solvent was removed under reduced pressure

to yield the title compound as a pale greenish solid (3.25 g, 86%),

sublimes 190–194 ^◦C; (found C, 62.4; H, 3.71; N, 4.81. C₁₅H₁₁NO₃S

requires C, 63.4; H, 3.89; N, 4.91%); d_H(CDCl₃) 2.69 (3H, s, CH₃),

3.99 (3H, s, OCH₃), 7.32 (1H, d, J 8.0, H³), 7.70 (1H, d, J 8.5, H⁹),

8.25 (1H, dd, J 8.5, 2.0, H⁸), 8.58 (1H, d, J 8.0, H⁴), 8.88 (1H, d, J

2.0, H⁶); d_C(CDCl₃, 125 MHz) 25.2 (CH₃), 52.7 (OCH₃), 122.7

(C³), 124.4 (C^4ꢀ), 127.0 (C⁹), 128.8 (C^6ꢀ), 129.0 (C⁷), 131.7 (C⁶),

132.8 (C⁸), 138.1 (C⁴), 142.6 (C^9ꢀ), 157.8 (C^1ꢀ), 164.3 (C²), 166.2

(COOCH₃), 180.1 (C⁵); m/z (ESMS⁺) 286 ([M + H]⁺, 30%), 308

([M + Na]⁺, 100%), 593 ([2M + Na]⁺, 15%).

(1-azaxanthonylmethyl)-1,4,7-tris(tert-butoxycarbonylmethyl)-

1,4,7,10-tetraazacyclododecane (60 mg, 77 lmol) was suspended

in HCl (6 M, 4 cm³) and the reaction mixture heated to reﬂux

(100 ^◦C) under argon with stirring for 16 hours. The acid was

removed under reduced pressure to yield the title compound as a

pale-yellow solid (46 mg, 77 lmol, 100%), m.p. >250 ^◦C; d_H(D₂O,

200 MHz) 3.16 (16H, m br, cyclen ring), 3.44 (2H, s, acetate CH₂),

3.58 (4H, s, 2 × acetate CH₂’s), 4.59 (2H, s, CH₂), 7.49 (1H, d, J 8,

H³), 7.61 (1H, d, J 8.5, H⁹), 8.15 (1H, dd, J 8.5, H⁸), 8.36 (1H, s,

H⁶), 8.49 (1H, d, J 8, H⁴); m/z (ESMS⁺) 600.7 ([M + H], 100%).

[Tb.18]. 7-Carboxy-2-methyl-1-azaxanthone-1,4,7-tris(carboxy-

methyl)-1,4,7,10-tetraazacyclododecane (42 mg, 70 lmol) was

dissolved in H₂O (2 cm³) and a solution of TbCl₃.6H₂O (34 mg,

91 lmol) in H₂O (1 cm³) added. The solution was then carefully

adjusted to a pH of approximately 5.5 by the addition of

10% aqueous KOH solution and the reaction heated at 90 ^◦C

under argon for 16 hours. The reaction was followed by TLC

(DCM–MeOH, 70 : 30) and upon completion the pale yellow

solution was adjusted to a pH of approximately 10 by the addition

of aqueous NaHCO₃solution and the resulting white precipitate

removed via a ﬁne syringe ﬁlter. The solvents were removed from

the clear colourless solution under reduced pressure to yield the

title compound as a white crystalline solid (37 mg, 49 lmol, 70%),

m.p. >250 ^◦C; d_H(D₂O, 500 MHz, 298 K) multiple resonances

from d −440 to +400 ppm, indicating the presence of 2 major

2-Bromomethyl-7-methoxycarbonyl-1-azathioxanthone,

12b.

N-Bromosuccinimide (NBS) (175 mg, 0.98 mmol) and dibenzoyl

peroxide (10 mg, 0.04 mmol) were added to a solution of 7-

methoxycarbonyl-2-methylazathioxanthone (500 mg, 1.75 mmol)

in CCl₄(30 ml). The reaction mixture was heated under reﬂux for

2 h after which NBS (175 mg, 0.98 mmol) and dibenzoyl peroxide

(10 mg, 0.04 mmol) were added again. The reaction mixture

was heated under reﬂux for further 34 h. Further additions of

dibenzoyl peroxide were made at 4 h (10 mg, 0.04 mmol), 6.5 h

(10 mg, 0.04 mmol), 9.5 h (20 mg, 0.08 mmol), 24 h (10 mg,

0.04 mmol) and 29.5 h (10 mg, mmol) after the reaction start.

Further additions of NBS (90 mg, 0.51 mmol) were made at 24 h

and 29.5 h after the reaction start. The reaction mixture was

allowed to cool down, ﬁltered and the solvent was removed under

reduced pressure. The residue was puriﬁed by chromatography on

silica (gradient elution: CH₂Cl₂–toluene 1 : 1 to 2% CH₃OH–49%

CH₂Cl₂–49% toluene) to yield the title compound as a light yellow

solid (90 mg, 25%), R_f0.42 (silica, 2% MeOH: 49% toluene: 49%

1

paramagnetically shifted isomers, exchanging slowly on the H

NMR timescale; m/z (ESMS⁻) 754.1 ([M − H], 100%); k_abs

(H₂O): 336 nm; s_H₂_O: 1.89 ms; s_H₂_O: 2.88 ms; φ_H₂_O: 0.12.

2-(4^ꢀ-Methyloxycarbonylphenylthio)-6-methylnicotinic

acid.

To a stirred solution of methyl-4-thiobenzoate (5 g, 29.7 mmol)

and 2-chloro-6-methylnicotinic acid (4.25 g, 24.8 mmol) in DMF

(28 ml) was added copper(I) bromide (220 mg, 1.53 mmol) and

the resulting mixture was heated at 120 ^◦C for 10 minutes. K₂CO₃

(5.21 g, 37.7 mmol) was added, followed by DMF (20 ml).

The reaction mixture was heated to 150 ^◦C overnight and then

allowed to cool down. After being diluted by water (150 ml), the

resulting solution was washed with ether (4 × 150 ml). The pH

of the solution was adjusted to 4 by addition of acetic acid. The

precipitated product was collected by ﬁltration and dried under

reduced pressure to yield the title compound as a pale yellow solid

(4.8, 64%), m.p. 190–192 ^◦C; (found C, 59.23; H, 4.25; N, 4.47.

C₁₅H₁₃NO₄S requires C, 59.39; H, 4.32; N, 4.62%); d_H(DMSO,

500 MHz) 2.23 (3H, s, CH₃), 3.86 (3H, s, OCH₃), 7.11 (1H, d,

J 7.8, H⁵), 7.61 (2 H, d, J 8.1, H^2ꢀ, H^6ꢀ), 7.95 (2H, d, J 8.1, H^3ꢀ,

H^5ꢀ), 8.13 (1H, d, J 7.8, H⁴); d_C(DMSO, 125 MHz) 24.7 (CH₃),

52.9 (OCH₃), 120.3 (C⁵), 121.4 (C³), 129.9 (C^4ꢀ), 129.9 (C^3ꢀ, C^5ꢀ),

135.5 (C^2ꢀ, C^6ꢀ), 138.4 (C^1ꢀ), 140.1 (C⁴), 159.4 (C²), 162.1 (C⁶),

166.6 (COOCH₃), 167.7 (COOH); m/z (ESMS⁻) 302 ([M − H]⁻,

100%).

◦

CH₂Cl₂), sublimes 186–190 C; (found C, 49.2; H, 2.70; N, 3.84.

C₁₅H₁₀BrNO₃S requires C, 49.5; H, 2.77; N, 3.85%); d_H(CDCl₃,

500 MHz) 4.00 (3H, s, CH₃), 4.61 (2H, s, CH₂), 7.61 (1H, d, J 8.5,

H³), 7.71 (1H, d, J 8.5, H⁹), 8.28 (1H, dd, J 8.5, 1.5, H⁸), 8.82 (1H,

d, J 8.5, H⁴), 9.20 (1H, d, J 1.5, H⁶); d_C(CDCl₃, 125 MHz) 32.4

(CH₂), 52.8 (CH₃), 122.3 (C³), 125.8 (C^4ꢀ), 127.1 (C⁹), 128.9 (C^6ꢀ),

129.2 (C⁷), 131.8 (C⁶), 133.2 (C⁸), 139.3 (C⁴), 142.3 (C^9ꢀ), 157.8

(C^1ꢀ), 161.5 (C²), 166.1 (COOCH₃), 179.8 (C⁵); m/z (ESMS⁺) 364

([M + H]⁺, 20%), 386 ([M + Na]⁺, 100%), 749 ([2M + Na]⁺, 55%).

1-(7-Methoxycarbonyl-2-methyl-1-azathioxanthone)-4,7,10-

tris-tert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane.

A solution of 2-bromomethyl-7-methoxycarbonyl-1-azathioxan-

thone (90 mg, 0.25 mmol), 1,4,7-tris-tert-butoxycarbonylmethyl-

1,4,7,10-tetraazacyclododecane (130 mg, 0.25 mmol) and Cs₂CO₃

(84 mg, 0.26 mmol) in acetonitrile (5 ml) was heated under

reﬂux for 20 h. The solvent was removed under reduced pressure,

the residue was dissolved in CH₂Cl₂(20 ml), ﬁltered and the

solvent was removed under reduced pressure again. The residue

was dissolved in CH₂Cl₂(20 ml), the suspension was ﬁltered to

remove the salts and the solvent was removed under reduced

pressure. The residue was puriﬁed by chromatography on alumina

(gradient elution: CH₂Cl₂to 2% CH₃OH–CH₂Cl₂) to yield the

title compound as a brown glass (60 mg, 30%), R_f0.48 (alumina,

5% MeOH–CH₂Cl₂). d_H(CDCl₃, 500 MHz) 1.32 (18 H, s, CH₃),

1.59 (9H, s, CH₃), 2.05–3.90 (24H, br m, CH₂ring, CH₂CO, CH₂),

7-Methoxycarbonyl-2-methyl-1-azathioxanthone, 12a. A mix-

ture of 2-(4^ꢀ-methoxycarbonylphenlythio)-6-methylnicotinic acid

(4 g, 13.2 mmol) and polyphosphoric acid (120 ml) was heated to

120 ^◦C and vigorously stirred for 24 h. The reaction was allowed to

cool down to room temperature and was diluted by dry methanol

(300 ml). The reaction mixture was heated under reﬂux for a

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3.99 (3H, s, OCH₃), 7.44 (1H, d, J 8.5, H⁹), 7.52 (1H, d, J 8.2, H³),

8.26 (1H, dd, J 8.5, 1.5, H⁸), 8.81 (1H, d, J 8.2, H⁴), 9.21 (1H, d,

H⁶); d_C(CDCl₃, 125 MHz) 21.6 (CH₂), 28.3 (CH₃), 52.9 (OCH₃),

49.5–58.2 (CH₂ring, CH₂CO), 82.4 (C^tbutyl), 123.0 (C³), 125.4

(C^4ꢀ), 126.3 (C⁹), 128.8 (C^6ꢀ), 129.1 (C⁷), 131.8 (C⁶), 133.2 (C⁸),

138.9 (C⁴), 142.3 (C^9ꢀ), 158.4 (C^1ꢀ), 164.5 (C²), 166.0 (COOMe),

173.2 (COOtBu), 179.9 (C⁵); m/z (ESMS⁺) 798 ([M + H]⁺, 20%),

820 ([M + Na]⁺, 100%). Found: (ES⁺) 820.3926 (C₄₁H₅₉N₅O₉SNa

requires 820.3926, [M + Na]⁺).

80 cm³). The aqueous solution was acidiﬁed with acetic acid

yielding a very light yellow precipitate upon cooling, which was

ﬁltered, washed with water and dried thoroughly to yield the title

compound as a pale yellow, crystalline solid (5.90 g, 83%), m.p.

170–2 ^◦C. Found C, 63.7; H, 4.44; N, 5.60; S, 13.0% C₁₃H₁₁NO₂S

requires C, 63.7; H, 4.49; N, 5.73; S, 13.1%. d_H(CDCl₃) 13.40 (1H,

br s, –OH), 8.13 (1H, d, J 8 Hz, H⁴), 7.42–7.52 (5H, m, H^2ꢀ–^6ꢀ),

7.09 (1H, d, J 8 Hz, H⁵), 2.23 (3H, s, CH₃); d_c(CDCl₃) 24.8 (CH₃),

119.8 (C⁵), 121.4 (C⁴), 129.6 (C³), 130.1 (C³^ꢀ^,5ꢀ), 131.8 (C^1ꢀ), 136.1

(C²^ꢀ^,6ꢀ), 139.9 (C^4ꢀ), 160.4 (C²), 160.8 (C⁶), 167.4 (COOH); m/z

(ESMS⁺) 246 [M + H], 268 [M + Na].

[Tb.19].

A solution of 1-(7-methoxycarbonyl-2-methyl-1-

azathioxanthone)-4,7,10-tris-tert-butoxycarbonylmethyl-1,4,7,10-

tetraazacyclododecane (80 mg, 0.10 mmol) in TFA (3 ml) and

CH₂Cl₂(0.2 ml) was stirred at room temperature for 18 h. The

solvents were removed under reduced pressure. The residue was

repeatedly (3×) dissolved in CH₂Cl₂and the solvent removed

2-Methyl-1-azathioxanthone,

15a. Polyphosphoric

acid

(60 cm³) was added to 6-methyl-2-thiophenoxynicotinic acid

(5.50 g 22.4 mmol) and the mixture heated at 120 ^◦C for 4 hours

under argon with stirring. The resulting brown liquid was

cooled to room temperature and then slowly poured onto cold

concentrated aqueous sodium hydroxide solution (300 cm³) with

vigorous stirring. The light yellow precipitate that formed was

collected via ﬁltration. The product was recrystallised from warm

EtOH. The crystals that formed upon standing were ﬁltered and

dried thoroughly to yield the title compound as a yellow crystalline

solid (4.61 g, 90%) %), m.p. 145–7 ^◦C. Found C, 68.4; H, 3.95;

N, 6.17; S, 14.0%. C₁₃H₉NOS requires C, 68.7; H, 3.89; N, 6.10;

S, 14.0%. d_H(CDCl₃) 8.73 (1H, d, J 8.2 Hz, H⁴), 8.60 (1H, d, J

8 Hz, H⁶), 7.65 (2H, m, H^8,9), 7.48 (1H, m, H⁷), 7.31 (1H, d, J

8.2 Hz, H³), 2.70 (3H, s, CH₃); d_c(CDCl₃) 25.2 (CH₃), 121.7 (C³),

124.8 (C⁷), 127.3 (C⁹), 127.5 (C⁶), 129.6 (C^9ꢀ), 130.4 (C⁴), 133.5

(C⁸), 137.5 (C^6ꢀ), 138.5 (C^4ꢀ), 158.0 (C^1ꢀ), 162.1 (C²), 181.0 (C⁵);

m/z (ESMS⁺) 228 [M + H], 250 [M + Na], 477 [2M + Na]. The

structure was conﬁrmed by single crystal X-ray diffraction.*

1

under reduced pressure. The residue was analysed by H NMR

spectroscopy. The residue was dissolved in water (8 ml) and

MeOH (3 ml) and TbCl₃.6H₂O (45 mg, 0.12 mmol) was added.

The pH of the solution was adjusted to 5.5 by the addition of

1M KOH solution. The reaction mixture was stirred at 65 ^◦C

overnight. The pH dropped to 2.8 and was adjusted back to 5.5

and the mixture was stirred at 65 ^◦C for a further 10 h. Methanol

was removed under reduced pressure and the remaining solution

was diluted with water (10 ml). The reaction mixture was ﬁltered.

Water was removed by freeze-drying and the residue was puriﬁed

by HPLC to yield the title compound (15 mg, 13%). Found:

(ES⁻) 784.1078 (C₂₉H₃₁N₅O₉STb requires: 784.1091, [M − H]⁻).

k_abs(MeOH) 372 nm; e(MeOH) 5360 M⁻¹cm⁻¹, s_Tb(H₂O) 0.49 ms,

s_Tb(D₂O) 0.62ms; φ_Tb(H₂O) = 0.021.

[Eu.19].

A solution of 1-(7-methoxycarbonyl-2-methyl-1-

azathioxanthone)-4,7,10-tris-tert-butoxycabonylmethyl-1,4,7,10-

tetraazacyclododecane (60 mg, 0.076 mmol) in TFA (2 ml) and

CH₂Cl₂(0.1 ml) was stirred at room temperature for 18 h. The

solvents were removed under reduced pressure. The residue was

repeatedly (3×) dissolved in CH₂Cl₂and the solvent removed

1

2-(4^ꢀ-Methylthiophenoxy)nicotinic

acid. 2-Chloronicotinic

under reduced pressure. The residue was analysed by H NMR

spectroscopy. The residue was dissolved in water (5 ml) and MeOH

(2 ml) and EuCl₃.6H₂O (30 mg, 0.082 mmol) was added. The pH

of the solution was adjusted to 5.5 by the addition of 1M KOH

solution. The reaction mixture was stirred at 65 ^◦C overnight. The

pH dropped to 3.5 and was adjusted back to 5.5 and the mixture

was stirred at 65 ^◦C for further 10 h. Methanol was removed

under reduced pressure and the remaining solution was diluted

with water (10 ml). The reaction mixture was ﬁltered. Water was

removed by freeze drying and the residue was puriﬁed by HPLC

to yield the title compound (10 mg, 17%). Found: (ES⁻) 778.10605

(C₂₉H₃₁EuN₅O₉S requires 778.10604, [M − H]⁻). k_abs(MeOH)

372 nm; e(MeOH) 5360 M⁻¹cm⁻¹, s_Eu(H₂O) 0.51 ms, s_Eu(D₂O)

1.62ms; φ_Eu(H₂O) = 0.022.

acid (4.57 g, 29.2 mmol), 4-methylthiophenol (4.22 g, 34.5 mmol),

were dissolved in DMF (30 cm³) with stirring, followed by CuBr

(0.25 g, 17.5 mmol), and K₂CO₃(6.00 g, 43.5 mmol). The reaction

was heated for 15 minutes at 130 ^◦C followed by 18 hours at 150 ^◦C

to form a light yellow solution. The mixture was cooled and

treated with water (170 cm³) to give a yellow suspension, which

was washed with ether (3 × 80 cm³). The aqueous solution was

acidiﬁed with acetic acid yielding a very light yellow precipitate

upon cooling, which was ﬁltered, washed with water and dried

thoroughly to yield the title compound as a white crystalline solid

(6.14 g, 87%), m.p. 190–192 ^◦C. Found C, 63.5; H, 4.50; N, 5.64;

S, 13.1 C₁₃H₁₁NO₂S requires C, 63. 7; H, 4.49; N, 5.73; S, 13.1%.

d_H(CDCl₃) 13.60 (1H, br s, –OH), 8.41 (1H, d, J 7.5 Hz, H⁶), 8.20

ꢀ

(1H, d, J 7.5 Hz, H⁵), 7.38 (2H, m, H³^ꢀ^,5ꢀ), 7.20 (3H, m, H^{4,2 ,6ꢀ}),

6-Methyl-2-thiophenoxynicotinic

acid. 2-Chloro-6-methyl-

2.31 (3H, s, CH₃); d_c(CDCl₃) 20.2 (CH₃), 120.2 (C^4ꢀ), 123.2 (C⁵),

nicotinic acid (5.00 g, 29.2 mmol) and thiophenol (3.80 g,

34.5 mmol), were dissolved in DMF (30 cm³) with stirring,

followed by CuBr (0.25 g, 17.5 mmol), and K₂CO₃(6.00 g,

43.5 mmol). The reaction was heated for 15 minute at 130 ^◦C

followed by 18 hour at 150 ^◦C generating a light yellow solution.

The mixture was cooled down and treated with water (170 cm³)

to give a yellow suspension, which was washed with ether (3 ×

˚

* C₁₃H₉N O S, M_r= 227.27, Monoclinic (P2_◦₁), a = 3.8693(5) A, b =

−1

˚

12.3848(16) A, c = 10.4698(13) A, b = 95.015(2) , Z = 2, l = 0.296 mm

D_calc= 1.510 Mg m⁻³, T = 120(2) K, 2632 independent reﬂections [R(int) =

0.0551], R₁= 0.0634, wR₂= 0.1510 [I > 2sigma(I)]. CCDC 296394.

For crystallographic data in CIF or other electronic format see DOI:

10.1039/b601357k

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127.7 (C³), 130.5 (C³^ꢀ^,5ꢀ), 136.3 (C²^ꢀ^,6ꢀ), 139.6 (C^1ꢀ), 140.0 (C⁴),

152.9 (C⁶), 162.1 (C²), 167.4 (COOH); m/z (ESMS⁺) 246 [M +

H], 268 [M + Na].

mixture heated at 120 C for 4 hours under argon with stirring.

The resulting a brown liquid was cooled to room temperature

and then slowly poured onto cold concentrated aqueous sodium

hydroxide solution (300 cm³) with vigorous stirring and the light

grey precipitates that formed were removed via ﬁltration. The

product was washed with water and dried thoroughly to yield a

◦

7-Methyl-1-azathioxanthone, 13. Polyphosphoric acid (60 cm³)

was added to 2-4^ꢀ-methylthiophenoxy-nicotinic acid (5.50 g

22.4 mmol) and the mixture heated at 120 ^◦C for 4 hours

under argon with stirring. The resulting a brown liquid was

cooled to room temperature and then slowly poured onto cold

concentrated aqueous sodium hydroxide solution (300 cm³) with

vigorous stirring and the light green precipitate that formed was

removed via ﬁltration. The product was recrystallised from warm

EtOH. The crystals that formed upon standing were ﬁltered

and dried thoroughly to yield the title compound as a yellow

microcrystalline solid (4.32 g, 87%), m.p. 139–41 ^◦C. Found C,

68.6; H, 4.07; N, 5.89; S, 13.9%; C₁₃H₉NOS requires C, 68.7; H,

3.95; N, 6.17; S, 14.1%. d_H(CDCl₃) 8.85 (1H, d, J 7.9 Hz, H²),

8.72 (1H, d, J 7.9 Hz, H⁴), 8.50 (1H, s, H⁶), 7.78 (1H, d, J 8.2 Hz,

H⁹), 7.63 (2H, m, H^3,8), 3.29 (3H, s, CH₃); d_c(CDCl₃) 22.9 (CH₃),

123.1 (C³), 127.5 (C^9ꢀ), 128.2 (C⁷), 129.5 (C^6ꢀ), 129.6 (C⁹), 130.0

(C⁸), 136.3 (C⁶), 138.7 (C⁴), 139.4 (C^4ꢀ), 156.9 (C^1ꢀ), 159.7 (C²),

179.8 (C⁵); m/z (ESMS⁺) 228 [M + H], 250 [M + Na].

1

1 : 1 mixture (obtained from H-NMR) of the title compounds

as a light yellow powder. Products were separated by column

chromatography (silica, toluene–CH₂Cl₂–EtOAc 45 : 45 : 10), Pure

fractions were combined together and the solvents removed by

reduced pressure. Products were recrystallised from warm EtOH,

to yield the given compound as a light yellow crystalline solid.

6-Methyl-1-azathioxanthone, 14. Yield 0.41 g (8%) m.p. 184–

186 ^◦C. Found C, 69.1; H, 4.04; N, 6.02.; S, 13.8%; C₁₃H₉NOS

requires: C, 68.7; H, 3.95; N, 6.17; S, 14.1%. d_H(CDCl₃) 8.81 (1H,

dd, J 8 Hz, H²), 8.79 (1H, d, J 8 Hz, H⁴), 8.34 (1H, m, H⁹), 7.42

(2H, m, H^2,7), 7.31 (2H, m, H^3,8), 2.23 (3H, s, CH₃); d_c(CDCl₃)

22.3 (CH₃), 122.5 (C³), 126.2 (C⁸), 127.1 (C^4ꢀ), 128.7 (C⁷), 129.8

(C⁹), 138.8 (C^1ꢀ), 139.1 (C²), 142.3 (C^6ꢀ), 152.7 (C⁴), 159.2 (C^4ꢀ),

180.8 (C⁵); m/z (ESMS⁺) 228 [M + H], 250 [M + Na].

8-Methyl-1-azathioxanthone, 15b. Yield 0.56 g (11%) m.p.

126–128 ^◦C. Found C, 68.7; H, 3.99; N, 5.81.; S, 14.1%; C₁₃H₉NOS

requires C, 68.7; H, 3.95; N, 6.17; S, 14.1%. d_H(CDCl₃) 8.72 (1H,

d, J 8 Hz, H²), 8.66 (1H, d, J 8 Hz, H⁴), 7.52 (1H, s, H⁹), 7.50 (1H,

d, J 7.9 Hz, H⁶), 7.41 (1H, t, J 8 Hz, H³), 7.30 (1H, d, J 7.9 Hz, H⁷)

2.88 (3H, s, CH₃); d_c(CDCl₃) 24.5 (CH₃), 121.8 (C³), 125.5 (C⁶),

128.3 (C^1ꢀ), 130.7 (C⁷), 131.6 (C⁹), 131.8 (C^9ꢀ), 138.3 (C⁴), 138.8

(C^6ꢀ), 142.4 (C⁸), 153.3 (C²), 157.8 (C^4ꢀ) 182.1 (C⁵); m/z (ESMS⁺)

228 [M + H], 250 [M + Na].

2-(2^ꢀ-Methylthiophenoxy)nicotinic acid. This was prepared as

described above for the para isomer to yield the title compound as

a pale yellow, crystalline solid (6.02 g, 85%), m.p. 166–8 ^◦C. Found

C, 64.1; H, 4.29; N, 5.39; S,12.8%; C₁₃H₁₁NO₂S requires: C, 63.7;

H, 4.49; N, 5.73; S, 13.1%. d_H(CDCl₃) 13.55 (1H, br s, –OH), 8.36

(1H, d, J 7.2 Hz, H⁶), 8.22 (1H, d, J 7.2 Hz, H⁵), 7.45 (1H, d, J

7.6 Hz, H^6ꢀ), 7.34 (2H, m, H³^ꢀ^,5ꢀ), 7.20 (2H, m, H^4,4ꢀ) 2.20 (3H, s,

CH₃); d_c(CDCl₃) 21.5 (CH₃), 120.3 (C^2ꢀ), 127.2 (C⁵), 131.1 (C³),

131.6 (C⁴^ꢀ^,5ꢀ), 137.0 (C^6ꢀ), 137.2 (C^3ꢀ), 143.2 (C^1ꢀ), 143.7 (C⁴), 153.6

(C⁶), 162.0 (C²), 167.4 (COOH); m/z (ESMS⁺) 246 [M + H], 268

[M + Na].

Acknowledgements

9-Methyl-1-azathioxanthone, 16. This was prepared as de-

scribed for the isomer above yield the title compound as a light

yellow crystalline solid (4.73 g, 95%), m.p. 135–7 C. Found: C,

This paper is dedicated to Richard P. Wayne, who ﬁrst introduced

the author to the beneﬁts of excited state chemistry. We thank

Professor Judith Howard for access to crystallographic facilities.

Financial support from EPSRC, the Royal Society, ESF-COST

D18, the EC networks of excellence, EMIL and DiMI is gratefully

acknowledged.

◦

68.8; H, 3.97; N, 6.24; S, 13.9%; C₁₃H₉NOS requires: C, 68.7; H,

3.95; N, 6.17; S, 14.1%. d_H(CDCl₃) 8.92 (1H, dd, J 8, 1.8 Hz, H²),

8.74 (1H, dd, J 8, 1.8 Hz, H⁴), 8.34 (1H, dd, J 8, 2 Hz, H⁶), 7.76

(1H, dd, J 8, 2 Hz, H⁸), 7.67 (1H, t, J 8 Hz, H³), 7.54 (1H, t, J

8 Hz, H⁷), 2.52 (3H, s, CH₃); d_c(CDCl₃) 20.1 (CH₃), 123.8 (C³),

126.0 (C^4ꢀ), 127.3 (C⁷), 127.8 (C⁶), 129.1 (C^6ꢀ), 135.0 (C⁸), 135.2

(C⁹), 136.6 (C^9ꢀ), 138.1 (C⁴), 157.2 (C²), 158.9 (C^1ꢀ), 181.4 (C⁵);

m/z (ESMS⁺) 228 [M + H], 250 [M + Na].

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Azaxanthones and azathioxanthones are effective sensitisers for europium and terbium luminescence

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