Color-tunable fluorescent dyes based on benzo[c]coumarin

FULL PAPER

DOI: 10.1002/ejoc.201300374

Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

Maciej Krzeszewski,^[a,b]Olena Vakuliuk,^[a]and Daniel T. Gryko*^[a,b]

Keywords: Synthetic methods / Heterocycles / Dyes/Pigments / Fluorescent probes / Fluorescence

Hurtley condensation was shown to be a perfect tool with

which to assemble a diversified library of derivatives of

benzo[c]coumarin. Not only do simple resorcinols and ortho-

bromobenzoic acids undergo this reaction, but also di-

hydroxynaphthalenes and 3-bromothiophene-2-carboxylic

acid, affording the desired compounds in moderate yields.

In the case of naphthalenediols, intriguing regioselectivity is

observed, which holds promise for its utilization in the syn-

thesis of previously inaccessible molecules. Further transfor-

mation made it possible to obtain benzo[c]coumarin bearing

amino and nitro groups at various positions, which served as

entry points to prepare complex hybrids of 1,4-benzoxazin-

2-ones and benzo[c]coumarins. The hydroxyl group proved

to be the synthetic handle, enabling the synthesis of strongly

solvatochromic, soluble analogues. The effect of structural

variation on photophysical properties was studied in detail

for almost 30 compounds. The relationship between the

structure and photophysical properties was thoroughly eluci-

dated by comparison with simple analogues (coumarins,

benzoxazinones). All of the obtained compounds exhibit

moderate to large Stokes shifts (3300–12500 cm^–1). The type

of π-expansion of the chromophore strongly influences the

overall optical phenomena. Compounds possessing alkyl

substituents on the benzo[c]coumarin core have much higher

fluorescence quantum yields than their analogues bearing

amino, fluorine, and other complex substituents. Interest-

ingly, the product possessing a fused coumarin–thiophene

skeleton exhibits over twofold higher fluorescence quantum

yield than any of its coumarin–benzene analogues.

together with [4+2]-cyclization of 4-cyanocoumarins and 1-

silyloxydienes.^[10]Notably, the condensation of coumarin-

derived electron-poor dienes with a range of corresponding

electron-rich dienophiles (mostly enamines) to afford the

corresponding benzo[c]coumarin through inverse electron-

demand Diels–Alder reaction has been developed by

Bodwell and co-workers.^[11]Minuti et al. recently described

a novel approach through Diels–Alder reaction under high-

pressure.^[11d]

Overshadowed by their presence in nature and their wide

spectrum of biological activities is the fact that many

benzo[c]coumarins emit light in the visible region.^[12]Be-

cause their stability is generally higher than that of couma-

rins, benzo[c]coumarins could be a suitable fluorescent plat-

form for bioimaging. Indeed, the design of new coumarin-

based functional dyes must address the problem of the in-

stability of simple coumarins, which is partially related to

the presence of a reactive carbon–carbon double bond that

can undergo [2+2] cycloaddition.^[13]Within the last decade,

the fusion of coumarins with pyrroles and furans has led to

the creation of compounds with very advantageous lumi-

nescent properties.^[14]

Introduction

Coumarins fused with another aromatic ring at positions

3 and 4 have been known for some time. The most typical

example is the benzo[c]coumarin (6H-dibenzo[b,d]pyran-6-

one) skeleton, which is prevalent in many synthetic and nat-

urally occurring medicinal substances.^[1]They display a

wide spectrum of biological^[2]and pharmacological activi-

ties, among which we can distinguish anticoagulant, spas-

molytic, diuretic and anticancer properties.^[3]Furthermore,

this class of molecules can be used as valuable intermediates

in the synthesis of more complex molecules such as canna-

binoids, which are the active agents in pain relievers and

drugs with antiemetic action.^[4]Recently, new methods have

been added to the growing arsenal of tools used to con-

struct benzo[c]coumarin such as lactonization of hydroxy

esters^[5]and 2Ј-halobiphenylo-2-carboxylic acids,^[6]oxi-

dation of the corresponding benzo[c]pyrans^[7]and phenan-

threnes,^[8][3+3]-cyclization of the 1,3-bis(silyl enol) ethers

with 1-(2-methoxyphenyl)-1-(trimethylsilyloxy)alk-1-en-3-

ones followed by subsequent BBr₃-mediated lactonization^[9]

[a] Warsaw University of Technology, Faculty of Chemistry,

Noakowskiego 3, 00-664 Warsaw, Poland

Whereas the influence of substitution patterns on the

fluorescence of coumarins has been comprehensively

studied, little is known about the relationship between

structural and optical properties of benzo[c]coumarins.

Herein, we present the synthesis of benzo[c]coumarin deriv-

atives and analogues with both electron-donating and

[b] Institute of Organic Chemistry, Polish Academy of Sciences,

Kasprzaka 44/52, 01-224 Warsaw, Poland

Fax: +48-22-632-66-81

E-mail: dtgryko@icho.edu.pl

Homepage: ww2.icho.edu.pl/DTG_group/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300374.

Eur. J. Org. Chem. 2013, 5631–5644

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M. Krzeszewski, O. Vakuliuk, D. T. Gryko

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-withdrawing substituents in different positions through

We directed our initial attempts at the synthesis of com-

Hurtley condensation, combined with comprehensive op- pounds possessing electron-withdrawing or reactive groups

tical investigations.

at suitable positions around the scaffold. For this purpose,

we chose 4-fluoro, 4,5-difluoro and 6-fluoro derivatives of

2-bromobenzoic acid 2b–d, as well as 2-bromo-5-nitroben-

Synthesis

To perform a broad optical study, we sought the means zoic acid (2e), 2-bromo-5-(trifluoromethyl)benzoic acid (2f),

to place substituents capable of modifying electron density and 2-bromo-5-iodobenzoic acid (2g). Needless to say, the

at different positions around the molecule. In principle, the presence of fluorine atom(s) added no significant steric hin-

synthesis of derivatives and analogues of the benzo[c]cou- drance around the carboxyl group/halogen. The yields of

marin skeleton can be achieved in two ways. First, the de- expected products 3b–d were lower in comparison to model

sired core may be assembled in one operation, involving 3a. Product 3d was obtained in lower yield than its re-

such reactions as lactonization,^[5,6]cyclization^[7–11]or Hur- gioisomer 3b. We expected the electronic influence of a

tley condensation between phenols and 2-bromobenzoic given substituent located in either the ortho- or para-posi-

acid.^[15]Alternatively, the desired compounds may be real- tion to the carboxylic group would be similar. However,

ized by postfunctionalization of the parent benzo[c]couma- Taylor and co-workers proposed that a substituent in the 6-

rin or its easily available 3-hydroxy derivative.^[16]Both stra- position might prevent the formation of a planar copper

tegies may potentially be efficient pathways to the desired chelate and would have a negative impact on the yield of

products. We followed both approaches with a heavy focus the desired product.^[18]Benzo[c]coumarins 3e, 3j, and 3k

on the former. This choice was governed by our strong bearing electron-withdrawing groups (NO₂, CF₃) in the 8-

interest in the study of the correlation between the chemical position were isolated in similar yields (35–40%). The use

structure of the starting material and the Hurtley condensa- of phenol-substituted compounds with electron-donating

tion output.

groups as one of the substrates is known to promote suc-

Almost a century ago, Hurtley reacted resorcinol and 2- cessful Hurtley condensation reactions.^[17]Bearing this idea

bromobenzoic acid under relatively mild conditions,^[15]ob- in mind, we tested the reactivity of substituted resorcinols

taining 3-hydroxy-6H-dibenzo[b,d]pyran-6-one in moderate 1b–d. The reaction with 2-bromobenzoic acid proceeded

yield. Surprisingly, this methodology has been little ex- smoothly when alkyl-substituted resorcinols were used.

plored since that time because its application seemed to be Benzo[c]coumarins 3f and 3i were formed in yields of 43

limited.^[17]We envisioned that this convergent and conve- and 51%, respectively (Table 1). In the case of product 3i,

nient protocol could be a perfect tool for the generation the solubility increased appreciably in typical solvents.

of benzo[c]coumarins possessing substituents with different

Reaction with analogues of resorcinol possessing an ad-

electronic characteristics. We conducted a range of experi- ditional hydroxyl group depended on the position of the

ments under classical conditions and present the results in second hydroxyl moiety. Condensation of phloroglucinol

Table 1.

(1d) proceeded efficiently with both 2-bromobenzoic acid

Table 1. Synthesis of benzo[c]coumarin derivatives through Hurtley condensation.^[a]

[a] Reaction conditions: 1 (20 mmol, 2 equiv.), 2 (10 mmol, 1 equiv.), aq. NaOH (20 mmol, 2 equiv. in 50 mL H₂O), 60 °C, 15 min; then

10% aq. CuSO₄, 95 °C, 3 h; then room temp. overnight. [b] Isolated yield.

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Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

(2a) and 2-bromo-5-nitrobenzoic acid (2e), leading to deriv- (ABCD) systems. This observation eliminates the possibility

atives 3h and 3j in 59 and 35% yield, respectively. Pyrogallol of formation of 5B (see the Supporting Information). Ad-

(1c), on the other hand, was not reactive under these condi- ditionally, according to the NOESY data, the correlation

tions, as described earlier by Leederer and Polonsky.^[17b]between the hydroxyl proton and two neighboring protons

Mass spectrometry analysis of the crude reaction mixtures (belonging to one AMX spin system, multiplet, 7.21–

revealed the presence of both unreacted 2-bromobenzoic 7.23 ppm, 2 H) was observed. This fact let us exclude 5C

acid and salicylic acid.^[17a]Consequently, competitive reac- as a possible structure and to assign these protons to H¹

tion with hydroxide anion and limited conversion ac- and H³. Moreover, closer inspection of the AMX system in

counted for the mediocre yields of the Hurtley condensa- the COSY spectrum revealed an exclusive cross peak of H³

tion.

with only one proton (doublet, δ = 8.82 ppm, 1 H), as-

Both π-expansion and replacement of benzene with a signed to H⁴, confirming the structure 5A. The above find-

heterocyclic unit alter the physicochemical properties of ings were additionally confirmed by the presence of an iso-

aromatic fluorophores. Therefore, a series of regioisomeric lated AB system that does not have a response with the

dihydroxynaphthalenes and exemplary heterocyclic ana- –OH proton on the NOESY spectrum. The ¹H NMR spec-

logues of o-bromobenzoic acid were investigated in the trum measured for compound 6 indicated the presence of

Hurtley condensation. We questioned how these types of two ABCD spin systems and two signals of isolated ¹H

phenols would behave in this reaction. Three naphthalene- atoms (singlets). One signal (broad singlet, δ = 11.24 ppm,

diols, possessing various arrangements of hydroxyl groups, 1 H) was assigned to the –OH group and possessed two

were selected (Scheme 1).

correlation signals in NOESY: an isolated proton and a

proton coming from an ABCD spin system. Only two struc-

tures, 6A and 6C, were expected to exhibit such cross peaks.

1

Moreover, isolated H atoms did not show NOESY corre-

lation with any peak belonging to ABCD systems,

satisfying only the 6C structure. Thus, according to the

spectroscopic data, we can claim the formation of re-

gioisomerically pure 5 and 6. Compound 5 possessed the

skeleton that is present in the structure of many naturally

occurring compounds in Streptomyces such as ravidomycin

and chrysomycins.^[19]

3-Bromothiophene-2-carboxylic acid (7) also underwent

the Hurtley condensation (Scheme 2). Product 8, which rep-

resents one of the first thieno[c]coumarins known, was ob-

tained in 40% yield.^[14f]

Scheme 1. Synthesis of π-extended coumarins through Hurtley con-

densation.

Scheme 2. Synthesis of derivative of 4H-thieno[2,3-c]chromen-4-

one (8) through application of the Hurtley protocol.

We were pleased to obtain the expected products in the

case of 1,6-dihydroxynaphthalene (4a) and 1,3-dihydroxy-

Both 7-methoxy-4-methylcoumarin^[20]and 8-methoxy-4-

naphthalene (4c) in 15 and 48% yields, respectively. Accord- methylbenzo[g]coumarin^[21]displayed significantly stronger

ing to the experimental results, conversion of starting mate- fluorescence in polar media than in nonpolar media. Ester

rial was observed in all entries; however, unwanted side re- 9 was synthesized by the Williamson method (Scheme 3) to

action leading to the formation of a black tar material investigate whether it also possessed such unusual optical

(probably polycondensation products) took place in each properties. The ether, containing the tert-butyl ester func-

reaction to a greater or lesser extent. Reaction of 1,7-di- tionality rather than a simple methyl ether, was chosen due

hydroxynaphthalene (4b) did not afford the expected to its prospective solubility in nonpolar solvents.

product.

Aiming to significantly influence the photophysical pa-

It is worth noting that formation of regioisomeric prod- rameters, we designed amine-substituted benzo[c]couma-

ucts can occur (see Figure S1 in the Supporting Infor- rins. Subjecting the previously obtained fluorobenzo[c]cou-

mation). Structural identification and signal assignments marins 3b–d to the typical nucleophilic aromatic substitu-

were performed by the use of 2D NMR techniques. Inspec- tion conditions afforded the expected products 10a–c in

tion of the COSY spectra obtained for 5 revealed AMX good yields (Scheme 4). Most of the previously prepared

and AB spin systems together with one showing a corre- benzo[c]coumarins possess limited solubility in the majority

lation that is characteristic of ortho-disubstituted benzene of organic solvents, complicating their analysis and limiting

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M. Krzeszewski, O. Vakuliuk, D. T. Gryko

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attractive synthetic pathways leading to 1,4-benzoxazine-2-

ones involves transformation of the corresponding nitro de-

rivatives. However, nitration of unsubstituted 3-hydroxy-

benzocoumarin is known to lead to mixtures of two re-

gioisomeric mono-nitro compounds and the bis-nitro deriv-

ative.^[22]Consequently, we turned to a different approach

involving utilization of substrates having one of the elec-

tron-rich positions blocked by alkyl substituents. This

change minimizes the possibility of side reactions while

simultaneously improving the solubility of the final

product. Nitration of previously prepared 3f and 3i led

cleanly to compounds 11a and 11b, regioselectively, in 91–

93% yields (Scheme 5). The reduction of these products to

the corresponding amines 12a and 12b, respectively, pro-

Scheme 3. Synthesis of O-alkylated derivative of 3a.

further applications. Consequently, morpholine, rather than

dimethylamine, was chosen as a nucleophilic partner in all

of these reactions. In the case of benzo[c]coumarin 3c, the

process was fully regioselective and, according to experi-

mental data, only fluorine located in the para position with

respect to the C=O group was replaced with morpholine.

Scheme 4. Synthesis of morpholine-substituted benzo[c]coumarins.

The benzo[c]coumarin skeleton has, in principle, various

positions that can serve as entry points to further extend

the π-conjugated system. In this context, we designed four

different hybrids of coumarins and 1,4-benzoxazin-2-ones

13–16 with linear and angular junctions of the rings. Such

molecules possess a π-expanded chromophore that may re-

sult in bathochromic shifts of absorption. One of the most Scheme 5. Synthesis of benzoazacoumarins 13–16.

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Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

ceeded smoothly.^[23]The final condensation with reactive α-

keto esters, such as diethyl mesoxalate and ethyl pyruvate,

were performed under typical conditions (Scheme 5).^[24]

Biaryls are typical structural motifs in functional dyes

because this arrangement of aromatic rings often leads to

significant Stokes shifts, as a result of the difference in

geometry between ground and excited states. Phenols are

known to undergo oxidative aromatic coupling,^[25a]leading

to such architectures. In this context, we advanced the hy-

pothesis that electron-rich benzo[c]coumarins will undergo

Figure 1. Position numbering.

The photophysical properties of compounds 3a–l, 5, 6,

dehydrogenation at positions adjacent to OH groups. In- 8, 10a–c, 11a–b, 12a–b, and 13–18 were studied in N,N-di-

deed, a derivative of 3-hydroxybenzo[c]coumarin 3i treated methylformamide (DMF), which was chosen because of its

with cobalt trifluoride^[25b]in trifluoroacetic acid underwent ability to dissolve all compounds and thus allow direct

oxidative coupling, and product 17 was obtained in 25% comparison and assessment of the effect of the architecture

yield (Scheme 6).

on the photophysical properties of the chromophore

(Tables 2 and 3, Figures 2, 3, and 4). Optical properties of

Schiff base 20 were measured in dichloromethane. In anal-

ogy to many coumarins, benzo[c]coumarins 3a–l, 5, 6, 8 and

10a–c absorbed UV radiation while emitting violet-blue

light. The broad absorption band was located between 260

and 400 nm. Coumarins with amino and/or hydroxyl

groups in position 7, or at both positions 7 and 6, are highly

fluorescent and are known to display large Stokes

shifts.^[28,29]In comparison to the photophysical behavior of

7-hydroxycoumarin (umbelliferone) in DMF^[30](Table 2), 3-

hydroxybenzo[c]coumarin (3a) exhibited bathochromic

shifts in both absorption and emission spectra, which re-

sulted in slightly larger Stokes shift. Because Stokes shifts

in these two compounds are almost identical, one can con-

clude that their large values are caused by a factor that is

common in both, i.e., a change in the electronic structure

of the luminophore upon excitation. Umbelliferone and

compound 3a are planar, structurally rigid luminophores,

the planar structure of which does not change substantially

upon electronic excitation. Consequently, the large values

of the Stokes shift cannot be realized in these compounds

as a result of conformational processes. Notably, 3a does

possess a Φ_flthat is 2.5 times higher than that of umbelli-

ferone. The fluorescence quantum yield of coumarins is

strongly influenced by substituents in the 7-position, which

control the relative energy ordering of the two lowest ex-

cited states; a nonemissive (n,π*) state that originates from

the carbonyl-oxygen lone pair and an emissive locally ex-

cited state with (π,π*) character.^[31]In addition, 7-hy-

droxycoumarin and its derivatives are known to undergo

excited-state proton transfer (ESPT).^[32]This is due to the

presence of two photoactive centers (weakly acidic hydroxyl

group and weakly basic carbonyl group). 7-Hydroxycouma-

rins undergo dramatic decreases in pK_aupon electronic ex-

citation. As a consequence, three emitting states have been

observed for these types of molecules (normal, anion, and

tautomer).^[33]To confirm that an analogous situation oc-

curs for hydroxy-benzo[c]coumarins, fluorometric pH ti-

tration was performed for compound 3i so that emission

bands could be unambiguously assigned (see Figure S3 in

the Supporting Information). It was found that the acidic

form displays emission at 405 nm, whereas fluorescence of

the anion appears at 450 nm. The fact that fluorescence of

Scheme 6. Oxidative aromatic coupling of compound 3i.

Finally, transformation of 3i using the optimized Duff

protocol^[26]led to aldehyde 18, which, upon reaction with

aromatic primary amine 19, gave the corresponding imine

20,^[27]which possessed reasonable solubility in organic sol-

vents (Scheme 7 and Figure 1).

Scheme 7. Synthesis of Schiff base 20.

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M. Krzeszewski, O. Vakuliuk, D. T. Gryko

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the acidic form is not observed at pH values greater than sorption hypsochromically, although a redshift is observed

pH 2 confirms that benzocoumarin 3i is a very strong acid in the case of derivative 10c, which possesses a morpholine

in the excited state. It appears that the presence of the ring in direct proximity to the carbonyl group (Figure 2,

weakly electron-withdrawing fluorine atoms (in ring C) al- Table 2). The hypsochromic shift is most probably caused

ters the order of energetically close (nπ*) and (ππ*) states, by a decreased accepting ability of the ring C imparted by

resulting in a decrease in Φ_fl. Varying these substituents in an amino group, which leads to a weaker intramolecular

ring C does not result in large shifts for these compounds charge transfer (ICT). The presence of an additional amino

and does not seem to follow a predictable pattern. On the group at position 6 or 8 in coumarin directly triggers a non-

other hand, the effect of simple alkyl substituents is rather emissive state. In analogy, dyes 12a and 12b, bearing NH₂

negligible in these cases. The presence of an additional hy- in positions 2 or 4 (ring A), do not display any measurable

droxy group at position 1 of compound 3h does not alter fluorescence, whereas compounds bearing a tertiary amino

this delicate balance either, resulting in a moderate quan- groups at positions 7 or 9 (10a–c, ring C) have Φ_flca. 5–

tum yield of fluorescence (16%). Bisbenzo[c]coumarin 17 9%. Nevertheless, their λ_em(ca. 410–450 nm) is far from the

displays a larger Stokes shift than its parent compound 3i, value reported for analogous 7-hydroxybenzo[c]coumarins

although the fluorescence quantum yields dropped signifi- by Langer and co-workers^[12](ca. 480 nm), which implies

cantly. Again, this outcome is attributed to reversal of the excited-state intramolecular proton transfer (ESIPT) in the

order of (nπ*) and (ππ*) states rather than to the presence latter case as the most probable explanation.

of an additional C–C bond allowing internal conversion fol-

lowed by vibrational relaxation. Both aldehyde 18 and im-

ine 20 possess low fluorescence in solution but strong, red

fluorescence in the solid state.

Table 2. Optical properties of benzo[c]coumarins.

Compound

λ_abs

[nm]

λ_em

[nm]

Φ_fl

Stokes shift

[cm^–1]

[%]^[a]

3a

334

325

370

339

351

368

338

341

332

375

339

375

350

357

399

341

304

321

376

473

418

351

330

341

323

311

321

329

401

467

427

400

422

443

423

557

427

438

434

452

454

–

451

450

460

425

408

426

453

–

457

522

508

422

444

542

566

21

8

6500

5800^[b]

3300

6900

4900

9200

6200

6500

7100

4400

7500

–

6400

5800^[d]

3300

5800

8400

7700

4500

–

Umbelliferone

3b

3c

3d

3e

3f

3h

3i

3j

3

16

0.3

13

16

18

0.1

5

–

8

–

4

36

5

9

–

3

Figure 2. Absorption and emission of 3a (solid line), 10a (dotted

line) and 10c (dashed line) in DMF (excitation at 310 nm).

The presence of a nitro group, according to expectations,

had a strong influence on both the absorption and emission

properties of the studied molecules. Regardless of the loca-

tion of the nitro group, its presence shifted the absorption

maximum to ca. 370–480 nm in dyes 3e, 3j, 11a and 11b.

The nitro group is known to quench fluorescence.^[34]Never-

theless, in contrast to nonfluorescent dyes 11a and 11b (pos-

sessing a nitro group attached to ring A), compounds 3e

and 3j possess low but measurable fluorescence (Table 2).

These benzo[c]coumarins have a push-pull arrangement of

substituents and, in this respect, bear analogy to fluorescent

π-expanded coumarins possessing a 4-nitrophenylvinyl

group at position 3, as reported previously.^[35]

3k

3l

5

5Ј^[c]

6

8

10a

10b

10c

11a

11b

12a

12b

13

14

15

16

17

18

20

–

7400

11800

12500

7500

7900

6500

3800

A variable bathochromic shift of absorption is seen when

the benzo[c]coumarin chromophore is fused with an ad-

ditional benzene ring (Scheme 1, compounds 5 and 6). Vari-

ous types of benzocoumarin have been synthesized and

studied in the last decades.^[36]Among them, linear benzo[g]-

coumarins have recently attracted the widest attention due

to their superb fluorescence properties.^[36c–36f]Direct com-

parison of compound 5 and structurally related 8-hydroxy-

benzo[h]coumarin^[36a](5Ј, Table 2) enabled us to conclude

2

0.8

0.1

0.2

5

1^[e]

[a] Determined in DMF using quinine sulfate as standard. [b] Data

in DMF.^[30][c] 8-Hydroxybenzo[h]coumarin. [d] Data in DMF.^[34a]

[e] Determined in CH₂Cl₂using Rhodamine 6G as standard.

For amino-substituted benzo[c]coumarins, there is also a that the addition of a benzene ring does not shift either

strong dependence of the optical properties on the position absorption or fluorescence. Among the possible expansions

of the amino group. When compared with 3a, the presence of coumarin through fusion with the benzene ring, attach-

of a tertiary amino group at ring C typically shifts the ab- ment of benzo[c]coumarins had a relatively small effect. Al-

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Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

though dyes 5 and 6 are regioisomers, they differed signifi- = 3% (toluene), 8% (EtOAc), 10% (CH₂Cl₂), 17%

cantly in emission properties (Φ_flare 8 and 4%, respec- (CH₃CN), 18% (DMF), 4% (MeOH)]. Such a dramatic

tively). Vibronic coupling remains the most likely channel change can presumably be attributed to the fact that the

for nonradiative deactivation of their electronically excited hydrogen bond enhances excited-state proton transfer

states. However, intersystem crossing as a dominant process (ESPT)^{[31a,32,37b,37c]}and intersystem crossing.^[37d]In anal-

has also been observed for some coumarin derivatives.^[37a]ogy to compound 9, no solvent-dependent solvatochromism

The highest fluorescence quantum yield (36%) was mea- of absorption was observed.

sured for 7,9-dihydroxy-4H-thieno[2,3-c]coumarin (8),

which otherwise possessed analogous optical properties to

benzo-analogue 3h.

Ether 9, according to expectations based on the weaker

electron-donating properties of OCH₂CO₂tBu group versus

OH, displayed hypsochromically shifted absorption and

emission. In analogy to 7-methoxycoumarin, benzocouma-

rin 9 exhibited low fluorescence in aprotic solvents (Φ_fl

=

4% in toluene), whereas it strongly fluoresced in protic sol-

vents (Φ_fl= 25% in methanol) (Figure 3, Table 3). In con-

trast to 8-methoxybenzo[g]coumarin,^[21]the bathochromic

shift of emission (27 nm) was not accompanied by any shift

of absorption (Table 3).

Figure 4. Absorption (dotted line) and emission spectra (excitation

at 310 nm) of 3i in toluene (double solid line), ethyl acetate (dashed

line), dichloromethane (dotted/solid line), acetonitrile (dotted line),

methanol (solid line).

Simple 1,4-benzoxazin-2-ones possess λ_absca. 280 nm

and λ_emca. 420 nm whereas the presence of a push-pull

system shifts these values to 360 and 440 nm, respec-

tively.^[38]Fluorescence quantum yields are typically not

high, and these compounds were studied as photogenera-

tors of singlet oxygen.^[38]Derivatives of 1,4-benzoxazin-2-

one, bearing a dimethylamino group at position 7, have

been utilized as a fluorescent chemodosimeter for cyste-

ine.^[39]For substituted 1,4-benzoxazin-2-one, a large in-

Figure 3. Absorption (dotted line) and emission spectra (excitation

at 310 nm) of 9 in toluene (double dashed line), ethyl acetate

(dashed line), dichloromethane (dotted/solid line), acetonitrile (dot- crease in the dipole moment of the molecule can be ex-

ted line) and methanol (solid line).

pected during the excitation S₀ǞS₁, which will result in a

large rearrangement of the surrounding solvent molecules

around the excited state. Thus, the energy level of this ex-

cited state will be markedly lowered before the emission

Table 3. Optical properties of dye 9 depending on the solvent.

Solvent

λ_abs

[nm]

ε

λ_em

[nm]

Φ_fl

Stokes shift

takes place, with respect to the energy level of its Franck–

Condon excited state.^[40]Hybrids of 1,4-benzoxazin-2-ones

and benzo[c]coumarins 13–16 possess rather low Φ_flbut

high Stokes shifts. In analogy to simpler 1,4-benzoxazin-

ones,^[38–41]the presence of an ester group causes a further

decrease in Φ_fl(Figure 5, Table 2). Needless to say, large

Stokes shifts always indicate significant changes in the elec-

tronic structure between the ground and the first excited

[m^–1cm^–1]

[%]^[a][cm^–1]

Toluene 327

6300

6600

6900

6500

389

393

398

402

416

4

6

11

12

25

4800

5100

5500

5700

6500

EtOAc

CH₂Cl₂

MeCN

MeOH

327

[a] Determined by using quinine sulfate as standard.

The optical characteristics are different for benzo[c]cou- state. Because compounds 13–16 have rather limited pos-

marin 3i (possessing an OH group), which can be consid- sibilities of appreciable geometry reorganization in the ex-

ered as a direct analogue of umbelliferone (Figure 4). An cited state, ICT is the only explanation.

appreciable bathochromic shift (ca. 30 nm) of emission was

Collecting the photophysical parameters of this large

observed upon moving from nonpolar solvents towards po- number of fluorophores enabled us to demonstrate that the

lar aprotic solvents, which can be related to the fact that, introduction of many types of substituents (such as alkyls,

following excitation, the solvent cage undergoes relaxation, F, tertiary amines at ring C) does not substantially decrease

i.e., a reorganization, leading to a relaxed state of minimum the fluorescence quantum yield of 3-hydroxybenzo[c]cou-

free energy (the higher polarity of the solvent, the larger marins. On the other hand, π-expansion of that chromo-

the redshift of the emission spectrum). On the other hand, phore either by fusion with an additional benzene ring or

in contrast to what was observed for compound 9, the fluo- by transformation into 1,4-benzoxazinones, activates vari-

rescence quantum yield drastically decreased in MeOH [Φ_flous radiationless deactivation channels. It seems that the

Eur. J. Org. Chem. 2013, 5631–5644

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5637

M. Krzeszewski, O. Vakuliuk, D. T. Gryko

FULL PAPER

7-hydroxycoumarins) and to undergo both various electro-

philic aromatic substitutions and oxidative aromatic cou-

pling.

The replacement of the C–C double bond in 7-hy-

droxycoumarin with the benzene unit bathochromically

shifts both absorption and emission only ca. 10–25 nm. At

the same time, Φ_flincreases from 8 to 21% and the Stokes

shifts remain almost the same. Systematic optical studies

of substituted benzo[c]coumarins proved that most of these

compounds are characterized by large Stokes shifts. Re-

placement of the OH group with OCH₂CO₂tBu makes it

possible to obtain more soluble compounds displaying an

attractive phenomenon Ϫ a strong dependence of fluores-

cence on solvent polarity. The most promising compound,

7,9-dihydroxy-thieno[2,3-c]coumarin (8), possesses a high

fluorescence quantum yield (36%) while its calculated

Stokes shift remained relatively large (5800 cm^–1).

The addition of the 1,4-benzoxazin-2-one ring in either

linear or angular fashion to the benzo[c]coumarin chromo-

phore does not shift absorption but red-shifts emission con-

siderably. The other notable findings are as follows: (1) In

most cases, π-expansion of the benzo[c]coumarin chromo-

phore leads to compounds with bathochromically shifted

absorption and lower Φ_flwhen compared with the parent

molecule; and (2) the presence of an auxochromic amino

group shifts the absorption bathochromically or hypso-

chromically depending on the exact location of the amino

group. These results are not only of theoretical significance

in that they provide the first comprehensive study of the

optical properties of derivatives and analogues of benzo[c]-

coumarin, but they may also open the door to practical

applications.

Figure 5. Absorption of compounds 12a (solid/dotted line) and 12b

(dotted line), as well as absorption and emission of compounds 13

(solid line) and 15 (dashed line) in DMF (excitation at 310 nm).

combination of replacement of the benzene unit with vari-

ous five-membered heterocycles as well as transformation

of the OH into elaborated ethers is the most promising di-

rection for further studies.

Interestingly, for complex 1,4-benzoxazinone 13, only

moderate solvatochromism was observed (Figure 6). Again,

the fluorescence quantum yield decreased sharply in protic

solvent [Φ_fl= 1.7% (toluene), 1.5% (EtOAc), 2.1%

(CH₂Cl₂), 1.1% (CH₃CN), 3.0% (DMF), 0.3% (MeOH)].

Experimental Section

General: All reagents and solvents were purchased from commer-

cial sources and were used as received unless otherwise noted. Rea-

gent-grade solvents (Et₂O, CH₂Cl₂, hexanes) were distilled prior to

use. DMF was dried with magnesium sulfate, then distilled and

stored under argon. Transformations with moisture- and oxygen-

sensitive compounds were performed under a stream of argon. The

reaction progress was monitored by means of thin-layer chromatog-

raphy (TLC), which was performed on aluminum foil plates, cov-

ered with Silica gel 60 F₂₅₄(Merck) or Aluminum oxide 60 F₂₅₄

(neutral, Merck). Product purification was achieved by means of

column chromatography with Kieselgel 60 (Merck) or Aluminum

oxide (Fluka). Occasionally, dry column vacuum chromatography

Figure 6. Absorption (dotted line) and emission spectra (excitation

at 310 nm) of 13 in toluene (dashed line), ethyl acetate (double solid

line), dichloromethane (dotted/solid line), acetonitrile (dotted line),

methanol (solid line).

Conclusions

We have demonstrated that by arranging various substit-

uents and/or additional extension of the chromophore it is (DCVC) for purification of products obtained by palladium-cata-

lyzed protocol was performed by using Silica gel Type D 5F. The

identity and purity of prepared compounds were established by ¹H

and ¹³C NMR spectrometry as well as by MS-spectrometry (EI-

MS or ESI-MS). NMR spectra were measured with Bruker AM

500 MHz, Bruker AM 600 MHz, Varian 600 MHz, Varian

400 MHz or Varian 200 MHz instruments with TMS as internal

standard. All chemical shifts are given in ppm. All melting points

for crystalline products were measured with automated melting

point apparatus EZ-MELT and are given without correction. 2-

Bromo-5-nitrobenzoic acid was synthesized according to a pre-

possible to easily manipulate the emission characteristics of

benzo[c]coumarin, with λ_maxranging from 420 to 560 nm.

These functional dyes are easily accessible either through

Hurtley condensation or by efficient transformation of its

products. 3-Bromothiophene-2-carboxylic acid was also ef-

fective in this reaction.

The fusion of coumarin to a benzene ring at positions 3

and 4 leads to compounds lacking the reactive α,β-unsatu-

rated ester moiety. Consequently, 3-hydroxybenzo[c]couma-

rins were shown to have more predictable reactivity (than viously published procedure.^[42]

5638

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Eur. J. Org. Chem. 2013, 5631–5644

Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

General Procedure for the Synthesis of Benzo[c]coumarins 3, 5, 6,

8:^[15]A 100 mL two-necked round-bottomed flask was equipped

with reflux condenser and flushed with argon. Phenol 1 (20 mmol,

2.0 equiv.), acid 2 (10 mmol, 1.0 equiv.) and an aqueous solution

of sodium hydroxide (0.80 g, 20 mmol, 2.0 equiv. in 50 μL of water)

were added. The resulting solution was stirred at 60 °C for 15 min.

Aq. CuSO₄(10%, 0.5 mL) was added dropwise to the hot reaction

mixture under a positive pressure of argon. Heating was continued

at 95 °C for an additional 3 h, followed by stirring overnight at

room temperature. The precipitate was filtered off, washed with a

significant amount of water, and dried under high vacuum. Crude

products were recrystallized from acetic acid unless otherwise

noted.

3-Hydroxy-8-nitro-6H-dibenzo[b,d]pyran-6-one (3e): According to

the general procedure, 2-bromo-5-nitrobenzoic acid (2.46 g) and

resorcinol (2.20 g) were reacted, affording 3e (1.03 g, 40%) as yel-

low crystals. R_f= 0.36 (CHCl₃/acetone, 98:2); m.p. 218–220 °C

1

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 10.73 (br. s, 1 H,

3

OH), 8.77 (d, J = 2.4 Hz, 1 H, C7-H), 8.56 (dd, J₁= 9.0, J₂=

3

2.5 Hz, 1 H, C9-H), 8.44 (d, J = 9.0 Hz, 1 H, C10-H), 8.22 (d, J

= 8.9 Hz, 1 H, C1-H), 6.87 (dd, J₁= 8.8,³J₂= 2.4 Hz, 1 H, C2-

3

H), 6.76 (d, J = 2.4 Hz, 1 H, C4-H) ppm. ¹³C NMR (125 MHz,

3

[D₆]DMSO): δ = 162.3 (C6), 159.8 (C3), 153.7 (C4a), 146.2 (C8),

140.9 (C10a), 129.4 (C7), 126.8 (C1), 125.5 (C9), 124.0 (C10), 120.0

(C6a), 114.2 (C2), 108.8 (C10b), 103.5 (C4) ppm. HRMS (EI,

70 eV): calcd. for C₁₃H₇NO₅[M⁺] 257.0324; found 257.0313.

3-Hydroxy-4-methyl-6H-dibenzo[b,d]pyran-6-one (3f): According to

the general procedure, 2-bromobenzoic acid (2.01 g) and 2-methyl-

resorcinol (2.48 g) were reacted, affording 3f (0.97 g, 43%) as beige

3-Hydroxy-6H-dibenzo[b,d]pyran-6-one (3a): According to the gene-

ral procedure, o-bromobenzoic acid (2.01 g) and resorcinol (2.20 g)

were reacted, affording 3a (1.48 g, 70%) as white crystals. R_f= 0.46

(CH₂Cl₂/acetone, 98:2); m.p. 236.5–237.5 °C (AcOH) (ref.^[3c]235–

236 °C); spectral and physical properties concurred with published

data.^[3c]C₁₃H₈O₃(212.20): calcd. C 73.58, H 3.80; found C 73.28,

H 4.13.

crystals. R_f

=

0.38 (CH₂Cl₂/acetone, 98:2); m.p. 250–252 °C

1

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 10.24 (br. s, 1 H,

3

OH), 8.23 (d, J = 8.1 Hz, 1 H, C7-H), 8.18 (dd, J₁= 8.0, J₂=

2.5 Hz, 1 H, C10-H), 8.00 (d, ³J = 8.8 Hz, 1 H, C1-H), 7.86 (dt,

³J₁= 7.6, ³J₂= 1.4 Hz, 1 H, C9-H), 7.54 (dt, ³J₁= 7.6, ³J₂

=

1.0 Hz, 1 H, C8-H), 6.90 (d, ³J = 8.6 Hz, 1 H, C2-H), 2.20 (s, 3 H,

CH₃) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 161.1 (C6),

158.1 (C3), 150.6 (C4a), 136.0 (C9), 135.7 (C7), 130.1 (C1), 128.0

(C6a), 122.2 (C10), 121.7 (C8), 119.1 (C10a), 112.5 (C2), 111.8

(C10b), 109.8 (C4), 8.6 (CH₃) ppm. HRMS (EI, 70 eV): calcd. for

C₁₄H₁₀O₃[M⁺] 226.0630; found 226.0620. C₁₄H₁₀O₃(226.23):

calcd. C 74.33, H 4.46; found C 74.03, H 4.57.

9-Fluoro-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (3b): According to

the general procedure, 2-bromo-4-fluorobenzoic acid (2.19 g) and

resorcinol (2.20 g) were reacted, affording 3b (1.01 g, 44%) as white

crystals. R_f= 0.29 (CHCl₃/acetone, 98:2); m.p. 305.5–306.5 °C

1

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 10.47 (br. s, 1 H,

3

OH), 8.23 (dd, J₁= 8.8, J₂= 6.0 Hz, 1 H, C7-H), 8.16 (d, J =

3

8.8 Hz, 1 H, C10-H), 8.11 (dd, J₁= 10.5, J₂= 2.4 Hz, 1 H, C8-

3

H), 7.38 (dt, J = 8.6, 2.4 Hz, 1 H, C2-H), 6.83 (dd, J₁= 8.6, J₂

1,3-Dihydroxy-6H-dibenzo[b,d]pyran-6-one (3h): According to the

general procedure, 2-bromobenzoic acid (2.01 g) and phlorogluc-

inol (2.52 g) were reacted, affording 3h (1.35 g, 59%) as yellowish

crystals. R_f= 0.43 (CH₂Cl₂/acetone, 9:1); m.p. 300–302 °C (AcOH).

¹H NMR (500 MHz, [D₆]DMSO): δ = 10.88 (br. s, 1 H, C3-OH),

= 2.4 Hz, 1 H, C1-H), 6.74 (d, J = 2.4 Hz, 1 H, C4-H) ppm. ¹³C

3

NMR (125 MHz, [D₆]DMSO): δ = 166.0 (C9), 161.0 (C6), 160.3

(C3), 153.0 (C4a), 138.8 (C10a), 133.8 (C7), 126.0 (C1), 116.0

(C6a), 113.7 (C10), 109.4 (C10b), 108.6 (C2), 108.4 (C8), 103.3

(C4) ppm. HRMS (EI, 70 eV): calcd for C₁₃H₇O₃F [M⁺] 230.0379;

found 230.0373.

3

10.12 (br. s, 1 H, C1-OH), 8.94 (d, J = 8.0 Hz, 1 H, C7-H), 8.17

(d, ³J = 7.4 Hz, 1 H, C10-H), 7.81 (t, ³J = 7.1 Hz, 1 H, C9-H),

3

7.47 (t, J = 7.1 Hz, 1 H, C8-H), 6.39 (s, 1 H, C4-H), 6.25 (s, 1 H,

8,9-Difluoro-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (3c): According

to the general procedure, 2-bromo-4,5-difluorobenzoic acid (2.37 g)

and resorcinol (2.20 g) were reacted, affording 3c (1.04 g, 42%) as

white crystals. R_f= 0.46 (CHCl₃/acetone, 98:2); m.p. 261–262 °C

C2-H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 160.7 (C4a),

159.2 (C6), 157.7 (C3), 153.3 (C1), 135.4 (C10a), 135.0 (C9), 129.4

(C7), 126.4 (C8), 125.8 (C10), 118.4 (C6a), 99.8 (C2), 98.6 (C10b),

95.1 (C4) ppm. Spectral and physical properties concurred with

published data.^[31]

1

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 10.47 (br. s, 1 H,

3

OH), 8.37 (dd, J₁= 7.4, J₂= 4.6 Hz, 1 H, C7-H), 8.11 (d, J =

8.9 Hz, 1 H, C1-H), 8.08 (dd, ³J₁= 8.2, ³J₂= 2.4 Hz, 1 H, C10-

H), 6.82 (dd, ³J₁= 8.6, ³J₂= 2.4 Hz, 1 H, C2-H), 6.72 (d, ³J =

2.4 Hz, 1 H, C4-H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

160.9 (C6), 159.5 (C3), 156.1 (C9), 154.0 (C8), 152.6 (C4a), 134.6

(C10a), 125.8 (C1), 118.7 (C6a), 116.7 (C10), 113.8 (C2), 111.5

(C7), 108.8 (C10b), 103.4 (C4) ppm. HRMS (EI, 70 eV): calcd. for

C₁₃H₆O₃F₂[M⁺] 248.0285; found 248.0289. C₁₃H₆O₃F₂(238.03):

C 62.91, H 2.44, F 15.31; found C 62.71, H 2.40, F 15.37.

2-Hexyl-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (3i): According to

the general procedure, 2-bromobenzoic acid (2.01 g) and 4-hexyl-

resorcinol (3.88 g) were reacted, affording 3i (1.51 g, 51%) as yel-

lowish crystals. R_f= 0.34 (CH₂Cl₂/acetone, 98:2); m.p. 182–184 °C

1

3

(AcOH). H NMR (500 MHz, CDCl₃): δ = 8.39 (dd, J₁= 7.9, J₂

3

= 1.6 Hz, 1 H, C7-H), 8.06 (d, J = 8.2 Hz, 1 H, C10-H), 7.82 (m,

1 H, C9-H), 7.80 (s, 1 H, C1-H), 7.52 (dt, J₁= 7.6, J₂= 1.2 Hz,

1 H, C8-H), 6.98 (s, 1 H, C4-H), 5.66 (br. s, 1 H, OH), 2.73 (t, J

3

= 7.5 Hz, 2 H, ArCH₂), 1.70 (quint, ³J = 7.5 Hz, 2 H, ArCH₂CH₂),

1.44 [m, 2 H, CH₃(CH₂)₂CH₂], 1.36 (quint, 4 H, CH₃CH₂CH₂),

0.92 (t, ³J = 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 162.0 (C6), 155.8 (C3), 150.5 (C4a), 135.5 (C10a), 134.9 (C1),

130.6 (C9), 127.6 (C7), 126.6 (C6a), 123.8 (C8), 121.1 (C10), 120.0

(C2), 111.0 (C10b), 103.8 (C4), 31.7 (CH₃CH₂CH₂), 29.9

(ArCH₂CH₂), 29.8 (ArCH₂), 29.2 (ArCH₂CH₂CH₂), 22.6

(CH₃CH₂), 14.1 (CH₃CH₂) ppm. HRMS (EI, 70 eV): calcd. for

C₁₉H₂₀O₃[M⁺] 296.1412; found 296.1411. C₁₉H₂₀O₃(296.37):

calcd. C 77.00, H 6.74; found C 76.95, H 6.74.

7-Fluoro-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (3d): According to

the general procedure, 2-bromo-6-fluorobenzoic acid (2.19 g) and

resorcinol (2.20 g) were reacted, affording 3d (0.41 g, 18%) as white

crystals. R_f= 0.38 (CHCl₃/MeOH, 99:1); m.p. 261–262 °C (AcOH).

¹H NMR (500 MHz, [D₆]DMSO): δ = 10.46 (br. s, 1 H, OH), 8.14

(d, ³J = 8.8 Hz, 1 H, C10-H), 8.07 (d, ³J = 8.1 Hz, 1 H, C8-H),

7.88 (m, 1 H, C9-H), 7.33 (dd, J₁= 12.0, J₂= 8.2 Hz, 1 H, C2-

H), 6.83 (dd, ³J₁= 8.6, ³J₂= 1.7 Hz, 1 H, C1-H), 6.71 (d, ³J =

1.7 Hz, 1 H, C4-H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

162.0 (C7), 160.9 (C6), 156.6 (C3), 152.9 (C4a), 138.2 (C10a), 137.3

(C9), 125.9 (C1), 118.1 (C10b), 115.2 (C10), 113.7 (C6a), 109.1

3

1,3-Dihydroxy-8-nitro-6H-dibenzo[b,d]pyran-6-one (3j): According

(C8), 108.4 (C2), 103.2 (C4) ppm. HRMS (EI, 70 eV): calcd. for to the general procedure, 2-bromo-5-nitrobenzoic acid (2.46 g) and

C₁₃H₇O₃F [M⁺] 230.0379; found 230.0386.

phloroglucinol (2.52 g) were reacted, affording 3j (0.96 g, 35%) as

Eur. J. Org. Chem. 2013, 5631–5644

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5639

M. Krzeszewski, O. Vakuliuk, D. T. Gryko

FULL PAPER

orange crystals. R_f= 0.31 (CH₂Cl₂/acetone, 1:1); m.p. 230–232 °C

¹H NMR (600 MHz, [D₆]DMSO): δ = 11.25 (br. s, 1 H), 8.69 (d,

1

3

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 11.33 (br. s, 1 H,

³J = 8.7 Hz, 1 H), 8.53 (d, J = 8.2 Hz, 1 H), 8.26 (m, 2 H), 7.91

3

C3-OH), 10.55 (br. s, 1 H, C1-OH), 9.08 (d, J = 9.1 Hz, 1 H, C7-

(dt, J₁= 7.1, J₂= 1.4 Hz, 1 H), 7.69 (dt, J₁= 7.1, J₂= 1.2 Hz,

1 H), 7.57 (t, ³J = 7.6 Hz, 1 H), 7.53 (t, ³J = 7.6 Hz, 2 H) ppm.

¹³C NMR (150 MHz, [D₆]DMSO): δ = 161.0, 156.7, 151.6, 135.7,

3

H), 8.78 (d, ³J = 2.4 Hz, 1 H, C10-H), 8.55 (dd, J₁= 8.9, ³J₂=

3

2.7 Hz, 1 H, C9-H), 6.42 (d, J = 2.4 Hz, 1 H, C2-H), 6.29 (d, J

= 2.4 Hz, 1 H, C4-H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ 135.5, 130.5, 129.7, 129.0, 127.4, 125.7, 125.1, 124.9, 124.0, 123.5,

= 162.2 (C4a), 160.3 (C3), 159.3 (C6), 155.7 (C1), 146.0 (C8), 141.7

(C10a), 129.2 (C9), 128.4 (C7), 125.6 (C10), 120.7 (C6a), 100.9

(C2), 99.7 (C10b), 97.0 (C4) ppm. HRMS (ESI): calcd. for

C₁₃H₇NO₆Na [M + Na]⁺296.0166; found 296.0158.

120.5, 104.3, 99.2 ppm. HRMS (EI, 70 eV): calcd. for C₁₇H₁₀O₃

[M⁺] 262.0630; found 262.0624.

7,9-Dihydroxy-4H-thieno[2,3-c]chromen-4-one (8): According to the

general procedure, 3-bromothiophen-2-carboxylic acid (2.07 g) and

phloroglucinol (2.52 g) were reacted, affording the crude product,

which was purified by means of column chromatography (CH₂Cl₂/

2-Hexyl-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (3k): According to

the general procedure, 2-bromo-5-(trifluoromethyl)benzoic acid

(2.69 g) and 4-hexylresorcinol (3.88 g) were reacted, affording the EtOAc, 7:3) leading to 8 (0.94 g, 40%) as yellowish crystals. R_f=

1

crude product, which was purified by means of column chromatog-

0.36 (CH₂Cl₂/EtOAc, 7:3); m.p. 265 °C (dec) (CH₂Cl₂/EtOAc). H

raphy (CH₂Cl₂/MeOH, 98:2) leading to 3k (1.31 g, 36%) as yellow-

NMR (400 MHz, [D₆]DMSO): δ = 10.80 (s, 1 H, C7-OH), 10.16

3

ish crystals. R_f= 0.37 (CH₂Cl₂/MeOH, 98:2); m.p. 177–178 °C

(s, 1 H, C9-OH), 8.24 (d, J = 5.2 Hz, 1 H, C1-H), 8.02 (d, ³J =

1

(CH₂Cl₂/MeOH). H NMR (500 MHz, CDCl₃): δ = 8.62 (s, 1 H, 5.2 Hz, 1 H, C2-H), 6.37 (s, 1 H, C6-H), 6.31 (s, 1 H, C8-H) ppm.

3

C7-H), 8.12 (d, J = 8.4 Hz, 1 H, C10-H), 7.98 (d, J = 8.2 Hz, 1

H, C9-H), 7.78 (s, 1 H, C1-H), 7.07 (s, 1 H, C4-H), 6.19 (br. s, 1 156.2 (C9), 155.4 (C4), 144.9 (C9b), 138.3 (C2), 127.1 (C3a), 119.7

¹³C NMR (100 MHz, [D₆]DMSO): δ = 160.4 (C7), 157.6 (C5a),

H, OH), 2.72 (t, ³J = 7.7 Hz, 2 H, ArCH₂), 1.68 (quint, ³J = 7.7 Hz,

(C1), 100.2 (C9a), 98.6 (C8), 95.3 (C6) ppm. HRMS (EI, 70 eV):

2 H, ArCH₂CH₂), 1.42 [m, 2 H, CH₃(CH₂)₂CH₂], 1.34 (quint, 4 H, calcd. for C₁₁H₆O₄S [M⁺] 233.9987; found 233.9979.

CH₃CH₂CH₂), 0.90 (t, ³J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

tert-Butyl 2-[(6-Oxo-6H-benzo[c]chromen-3-yl)oxy]acetate (9):

(125 MHz, CDCl₃): δ = 161.2 (C6), 157.2 (C3), 151.0 (C4a), 138.4

A

mixture of benzo[c]coumarin 3a (0.53 g, 2.5 mmol, 1.0 equiv.), tert-

butyl bromoacetate (0.50 mL, 3.4 mmol, 1.4 equiv.), potassium car-

bonate (0.47 g, 3.4 mmol, 1.4 equiv.), and potassium iodide (0.16 g,

1.0 mmol, 0.4 equiv.) in anhydrous DMF (5 mL) was heated at

130 °C for 20 h in a pressure tube (Aldrich, 38 mL) under an inert

atmosphere. The reaction was cooled and poured into water and

extracted with CH₂Cl₂(3ϫ 30 mL), and the combined organic

phases were dried with anhydrous Na₂SO₄and evaporated under

reduced pressure. The crude product was recrystallized from ethyl

acetate, affording the expected product 9 (0.69 g, 85%) as white

(C10a), 131.1 (C9), 129.4 (q, CF₃), 128.0 (C7), 127.5 (C2), 124.3

(C1), 122.4 (C6a), 122.0 (C10), 119.8 (C8), 109.7 (C10b), 103.9

(C4), 31.9 (CH₃CH₂CH₂), 29.9 (ArCH₂CH₂), 29.7 (ArCH₂), 29.2

(ArCH₂CH₂CH₂), 22.6 (CH₃CH₂), 14.1 (CH₃CH₂) ppm. HRMS

(EI, 70 eV): calcd. for C₂₀H₂₀O₃F₃[M + H⁺] 365.1365; found

365.1360.

3-Hydroxy-8-iodo-6H-dibenzo[b,d]pyran-6-one (3l): According to

the general procedure, 2-bromo-5-iodobenzoic acid (3.26 g) and

resorcinol (2.20 g) were reacted, affording 3l (1.31 g, 39%) as yel-

lowish crystals. R_f= 0.48 (CHCl₃/acetone, 98:2); m.p. 266–268 °C

1

crystals. R_f= 0.33 (CH₂Cl₂); m.p. 145–147 °C (EtOAc). H NMR

1

3

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 11.00 (br. s, 1 H,

(500 MHz, CDCl₃): δ = 8.36 (dd, J₁= 8.0, J₂= 1.0 Hz, 1 H, C7-

3

OH), 8.38 (d, J = 1.8 Hz, 1 H, C7-H), 8.13 (dd, J₁= 8.5, J₂= H), 8.01 (d, J = 8.1 Hz, 1 H, C10-H), 7.97 (d, J = 8.8 Hz, 1 H,

3

1.8 Hz, 1 H, C10-H), 8.08 (d, J = 8.8 Hz, 1 H, C9-H), 7.99 (d, J

C1-H), 7.79 (dt, J₁= 7.7, J₂= 1.5 Hz, 1 H, C9-H), 7.52 (dt, J₁

3

= 8.5 Hz, 1 H, C1-H), 6.79 (d, J = 8.6 Hz, 1 H, C2-H), 6.68 (s, 1 = 7.6, J₂= 1.0 Hz, 1 H, C8-H), 6.96 (dd, J₁= 8.8, J₂= 2.6 Hz,

H, C4-H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 162.4 (C6), 1 H, C2-H), 6.82 (d, ³J = 2.5 Hz, 1 H, C4-H), 4.59 (s, 2 H, OCH₂),

159.9 (C3), 152.9 (C4a), 143.7 (C9), 137.9 (C7), 135.1 (C10a), 125.2 1.51 (s, 9 H, 3ϫ CH₃) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ

(C1), 124.2 (C10), 121.0 (C6a), 114.3 (C10b), 108.4 (C2), 103.6

(C4), 92.5 (C8) ppm. HRMS (EI, 70 eV): calcd. for C₁₃H₇O₃I [M⁺]

337.9440; found 337.9435.

= 167.2 (CO₂tBu), 161.3 (C6), 159.7 (C3), 152.4 (C4a), 135.0 (C9),

134.9 (C7), 130.5 (C1), 128.0 (C6a), 123.9 (C10), 121.1 (C8), 120.1

(C10a), 112.8 (C2), 111.9 (C10b), 102.4 (C4), 82.9 [C(CH₃)₃], 65.7

(OCH₂), 28.0 [C(CH₃)₃] ppm. HRMS (ESI): calcd. for C₁₉H₁₉O₅

[M + H]⁺327.1232; found 327.1227. C₁₉H₁₈O₅(326.35): calcd. C

69.93, H 5.56; found C 69.68, H 5.68.

2-Hydroxy-6H-benzo[d]naphtho[1,2-b]pyran-6-one (5): According to

the general procedure, 2-bromobenzoic acid (2.01 g) and 1,6-dihy-

droxynaphthalene (3.20 g) were reacted, affording the crude prod-

uct, which was purified by means of column chromatography

(CH₂Cl₂/acetone, 98:2) leading to the desired product 5 (0.39 g,

15%) as beige crystals. R_f= 0.56 (CH₂Cl₂/acetone, 96:4); m.p. 290–

General Procedure for the Synthesis of Compounds 10a–c:^[43]A mix-

ture of parent benzo[c]coumarin 3 (0.30 mmol, 1.0 equiv.), morph-

oline (160 μL, 1.8 mmol, 6.0 equiv.) and potassium carbonate

292 °C. ¹H NMR (600 MHz, [D₆]DMSO): δ = 10.22 (br. s, 1 H), (50 mg, 0.36 mmol, 1.2 equiv.) in anhydrous DMF (2 mL) was

3

8.40 (d, J = 8.1 Hz, 1 H), 8.26 (dd, J₁= 7.8, J₂= 1.1 Hz, 1 H), heated at 120 °C for 20 h in a pressure tube (Aldrich, 38 mL) under

3

8.22 (m, 2 H), 7.92 (dt, J₁= 7.3, J₂= 1.4 Hz, 1 H), 7.66 (d, J = an inert atmosphere. The reaction was cooled and poured into

8.8 Hz, 1 H), 7.62 (dt, ³J₁= 7.5, ³J₂= 1.0 Hz, 1 H), 7.22 (m, 2 water and extracted with ethyl acetate (3ϫ 10 mL). The combined

H) ppm. ¹³C NMR (150 MHz, [D₆]DMSO): δ = 160.8, 157.7,

147.3, 136.5, 135.9, 135.7, 130.2, 128.9, 123.7, 123.4, 123.0, 120.9,

120.3, 119.9, 117.5, 110.7, 109.9 ppm. HRMS (EI, 70 eV): calcd.

for C₁₇H₁₀O₃[M⁺] 262.0630; found 262.0620.

organic phases were dried with anhydrous sodium sulfate and evap-

orated under reduced pressure. The crude product was purified by

column chromatography (silica; pentane/EtOAc, 1:9) to afford the

expected product 10a–c.

8-Hydroxy-5H-dibenzo[c,f]chromen-5-one (6): According to the ge-

neral procedure, 2-bromobenzoic acid (2.01 g) and 1,3-dihydroxy-

naphthalene (3.20 g) were reacted, affording the crude product,

which was purified by means of column chromatography (CH₂Cl₂/

acetone, 98:2) leading to the desired product 6 (1.26 g, 48%) as

3-Hydroxy-9-(morpholin-4-yl)-6H-dibenzo[b,d]pyran-6-one (10a):

According to the general procedure, benzo[c]coumarin 3b (69 mg)

and morpholine (160 mg, 160 μL) were reacted, affording 10a

(45 mg, 50%) as white crystals. R_f= 0.33 (CH₂Cl₂/acetone, 96:4);

m.p. 266–268 °C (DMA/hexanes). ¹H NMR (500 MHz, [D₆]-

beige crystals. R_f= 0.32 (CH₂Cl₂/acetone, 98:2); m.p. 290–292 °C. DMSO): δ = 10.33 (br. s, 1 H, OH), 8.21 (dd, ³J₁= 9.0, ³J₂

=

5640 Eur. J. Org. Chem. 2013, 5631–5644

www.eurjoc.org

Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

3.2 Hz, 1 H, C7-H), 8.00 (dd, ³J₁= 22.5, ³J₂= 9.2 Hz, 1 H, C1- (C1), 115.7 (C10b), 110.5 (C4), 8.5 (CH₃) ppm. HRMS (EI, 70 eV):

H), 7.21 (m, 2 H, C8-H and C10-H), 6.79 (dt, ³J₁= 8.6, ³J₂

=

calcd for C₁₄H₉O₅N [M⁺] 271.0481; found 271.0472.

2.6 Hz, 1 H, C2-H), 6.72 (dd, ³J₁= 25.0, ³J₂= 2.5 Hz, 1 H, C4-

H), 3.78 (m, 4 H, OCH₂), 3.49 (m, 4 H, NCH₂) ppm. ¹³C NMR

(125 MHz, [D₆]DMSO): δ = 159.5 (C6), 155.2 (C3), 154.4 (C4a),

152.5 (C9), 136.4 (C10a), 131.3 (C7), 125.0 (C1), 114.0 (C10), 112.6

(C6a), 109.8 (C2), 108.6 (C8), 106.3 (C10b), 103.4 (C4), 65.8 (2)

(OCH₂), 46.6 (2) (NCH₂) ppm. HRMS (EI, 70 eV): calcd. for

C₁₇H₁₅NO₄[M⁺] 297.1001; found 297.1010. C₁₇H₁₅NO₄(297.31):

calcd. C 68.68, H 5.09, N 4.71; found C 68.40, N 5.07, N 4.95.

2-Hexyl-3-hydroxy-4-nitro-6H-dibenzo[b,d]pyran-6-one (11b): Ac-

cording to the general procedure, benzo[c]coumarin 3i (1.18 g) and

nitric acid (0.40 mL) were reacted, affording 11b (1.24 g, 91%) as

1

orange crystals. R_f= 0.28 (CH₂Cl₂); m.p. 147–149 °C (AcOH). H

3

NMR (500 MHz, CDCl₃): δ = 10.59 (br. s, 1 H, OH), 8.39 (dd, J

= 8.0 Hz, 1 H, C7-H), 8.05 (m, 2 H, C10-H and C1-H), 7.88 (dt,

³J₁= 7.5, ³J₂= 1.4 Hz, 1 H, C9-H), 7.62 (dt, ³J₁= 7.5, ³J₂= 1.0 Hz,

1 H, C8-H), 2.80 (t, ³J = 7.8 Hz, 2 H, Ar-CH₂-), 1.70 (quint, ³J

8-Fluoro-3-hydroxy-9-(morpholin-4-yl)-6H-dibenzo[b,d]pyran-6- = 7.6 Hz, 2 H, ArCH₂CH₂), 1.44 [m, 2 H, CH₃(CH₂)₂CH₂], 1.37

3

one (10b): According to the general procedure, benzo[c]coumarin

3c (74 mg) and morpholine (160 mg, 160 μL) were reacted, afford-

ing 10b (61 mg, 65%) as white crystals. R_f= 0.34 (CH₂Cl₂/acetone,

96:4); m.p. 274–276 °C (DMA/heaxanes). ¹H NMR (500 MHz,

(m, 4 H, CH₃CH₂CH₂), 0.92 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 159.1 (C6), 154.2 (C3), 144.1 (C4a),

135.4 (C1), 133.8 (C6a), 130.7 (C9), 129.1 (C2), 128.9 (C4), 128.7

(C7), 125.4 (C10a), 121.4 (C8), 119.6 (C10), 110.5 (C10b), 31.6

(CH₃CH₂CH₂), 30.2 (ArCH₂CH₂), 29.3 (ArCH₂), 29.1

(ArCH₂CH₂CH₂), 22.6 (CH₃CH₂), 14.1 (CH₃CH₂) ppm. HRMS

3

[D₆]DMSO): δ = 10.30 (br. s, 1 H, OH), 8.20 (d, J = 8.5 Hz, 1 H,

3

C7-H), 7.77 (d, J = 13.6 Hz, 1 H, C1-H), 7.61 (d, J = 8.2 Hz, 1

H, C10-H), 6.82 (dd, J₁= 8.8, J₂= 2.4 Hz, 1 H, C2-H), 6.73 (d, (ESI): calcd. for C₁₉H₁₉NO₅Na [M + Na]⁺364.1155; found

3

³J = 2.4 Hz, 1 H, C4-H), 3.79 (t, ³J = 4.6 Hz, 4 H, OCH₂), 3.32 (t,

364.1151. C₁₉H₁₉NO₅(341.36): calcd. C 66.85, H 5.61, N 4.10;

³J = 4.6 Hz, 4 H, NCH₂) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): found C 66.61, H 5.41, N 3.98.

δ = 160.2 (C8), 154.7 (C6), 152.8 (C4a), 152.6 (C3), 146.5 (C9),

General Procedure for the Reduction of Nitro-Derivatives of Benzo[-

133.7 (C10a), 125.6 (C1), 116.4 (C7), 113.4 (C10), 112.1 (C6a),

110.6 (C10b), 109.5 (C2), 103.3 (C4), 66.4 (2ϫ OCH₂), 50.3 (2ϫ

NCH₂) ppm. HRMS (EI, 70 eV): calcd. for C₁₇H₁₄NO₄F [M⁺]

315.0907; found 315.0912.

c]coumarin:^[23]Pd/C (65 mg, 0.060 mmol, 2 mol-%) and 2-propanol

(40 mL) were placed in a 100 mL round-bottom ace pressure flask

(Aldrich). An aqueous solution of ammonium formate (1.80 g,

30 mmol, 10 equiv. in 4 mL water) and the corresponding nitro

compound (3 mmol, 1 equiv.) were added and the resulting mixture

was heated at 85 °C for 72 h under an inert atmosphere. When the

reaction was complete (monitored by TLC), Pd/C was filtered off

through a pad of Celite using hot 2-propanol as eluent. The solvent

was removed under reduced pressure and reaction mixture was di-

3-Hydroxy-7-(morpholin-4-yl)-6H-dibenzo[b,d]pyran-6-one (10c):

According to the general procedure, benzo[c]coumarin 3d (69 mg)

and morpholine (160 mg, 160 μL) were reacted, affording 10c

(35 mg, 39%) as yellow crystals. R_f= 0.53 (CH₂Cl₂/acetone, 9:1);

m.p. 238–241 °C (DMA/hexanes). ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 10.26 (br. s, 1 H, OH), 8.06 (d, ³J = 8.8 Hz, 1 H, C10- luted with dichloromethane, washed twice with brine, and dried

H), 7.77 (dd, ³J₁= 8.1, ³J₂= 1.1 Hz, 1 H, C1-H), 7.71 (t, ³J₁

with anhydrous sodium sulfate. The crude product was purified by

8.0 Hz, 1 H, C9-H), 7.08 (dd, J₁= 8.1, J₂= 1.1 Hz, 1 H, C8-H), column chromatography (silica; CH₂Cl₂/acetone, 98:2).

=

3

6.79 (dd, ³J₁= 8.8, J₂= 2.4 Hz, 1 H, C2-H), 6.66 (d, J = 2.4 Hz,

1 H, C4-H), 3.79 (m, 4 H, OCH₂), 3.07 (m, 4 H, NCH₂) ppm. ¹³C

NMR (125 MHz, [D₆]DMSO): δ = 160.2 (C6), 157.9 (C3), 155.6

(C4a), 152.6 (C7), 138.4 (C10a), 135.9 (C9), 125.7 (C1), 117.3

(C6a), 114.6 (C8), 113.3 (C10), 110.2 (C2), 110.1 (C10b), 102.5

(C4), 66.7 (2 ϫ OCH₂), 53.0 (2 ϫ N-CH₂) ppm. HRMS (ESI):

calcd. for C₁₇H₁₅NO₄Na [M + Na]⁺320.0893; found 320.0900.

C₁₇H₁₅NO₄(297.31): calcd. C 68.68, H 5.09, N 4.71; found C

68.52, N 5.02, N 4.56.

2-Amino-3-hydroxy-4-methyl-6H-dibenzo[b,d]pyran-6-one (12a): Ac-

cording to the general procedure, nitrobenzo[c]coumarin 11a

(0.81 g) and ammonium formate (1.80 g) were reacted, affording

12a (0.30 g, 42%) as pale-yellow crystals. R_f= 0.32 (CH₂Cl₂/acet-

one, 96:4); m.p. 239–241 °C (CH₂Cl₂/acetone). ¹H NMR

3

(500 MHz, [D₆]DMSO): δ = 9.95 (br. s, 1 H, OH), 8.19 (dd, J₁=

7.9, J₂= 1.3 Hz, 1 H, C7-H), 8.02 (d, J = 7.9 Hz, 1 H, C10-H),

3

7.87 (dt, J₁= 7.9, J₂= 1.5 Hz, 1 H, C9-H), 7.54 (dt, J₁= 7.6,

³J₂= 0.9 Hz, 1 H, C8-H), 7.32 (s, 1 H, C1-H), 2.24 (s, 3 H,

CH₃) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 161.5 (C6),

145.3 (C4a), 142.4 (C3), 136.0 (C10a), 135.5 (C2), 130.2 (C9), 127.7

(C7), 124.6 (C6a), 121.9 (C8), 119.6 (C10), 112.6 (C10b), 109.9

(C4), 104.2 (C1), 9.6 (CH₃) ppm. HRMS (EI, 70 eV): calcd. for

C₁₄H₁₁NO₃[M⁺] 241.0739; found 241.0735.

General Procedure for Nitration of Parent Benzo[c]coumarin Deriva-

tive:^[22]Concentrated HNO₃(0.40 mL, 6.0 mmol, 1.5 equiv.) was

added to a stirred suspension of benzo[c]coumarin derivative

(4.0 mmol, 1.0 equiv.) in glacial acetic acid (10 mL) and the re-

sulting mixture was stirred at room temperature for 3 h. Water

(10 mL) was poured into the reaction mixture, and stirring was

continued for an additional 15 min. The crude product was filtered

off, washed with water, dried under high vacuum and recrystallized

from acetic acid if not otherwise noted.

4-Amino-2-hexyl-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (12b): Ac-

cording to the general procedure, nitrobenzo[c]coumarin 11b

(1.02 g) and ammonium formate (1.80 g) were reacted, affording

12b (0.70 g, 75%) as pale-yellow crystals. R_f= 0.34 (CH₂Cl₂/acet-

one, 96:4); m.p. 148–152 °C (CH₂Cl₂/acetone). ¹H NMR

(500 MHz, [D₆]DMSO): δ = 8.25 (d, ³J = 8.1 Hz, 1 H, C7-H), 8.20

3-Hydroxy-4-methyl-2-nitro-6H-dibenzo[b,d]pyran-6-one (11a): Ac-

cording to the general procedure, benzo[c]coumarin 3f (0.91 g) and

3

nitric acid (0.40 mL) were reacted, affording 11a (1.01 g, 93%) as (dd, J₁= 8.0, J₂= 1.1 Hz, 2 H, C10-H), 7.85 (dt, J₁= 7.8, J₂

3

yellow crystals. R_f= 0.62 (CH₂Cl₂/acetone, 98:2); m.p. 277–279 °C

= 1.4 Hz, 1 H, C9-H), 7.54 (dt, J₁= 7.5, J₂= 1.0 Hz, 1 H, C8-

1

(AcOH). H NMR (500 MHz, [D₆]DMSO): δ = 10.24 (br. s, 1 H,

H), 7.33 (s, 1 H, C4-H), 4.82 (br. s, 2 H, NH₂), 2.64 (t, ³J = 7.6 Hz,

OH), 8.81 (s, 1 H, C1-H), 8.45 (d, J = 8.0 Hz, 1 H, C7-H), 8.23 2 H, Ar-CH₂-), 1.58 (quint, ³J = 7.2 Hz, 2 H, ArCH₂CH₂), 1.31

3

(dd, J₁= 8.0, J₂= 1.2 Hz, 1 H, C10-H), 7.93 (dt, J₁= 7.6, J₂[m, 6 H, CH₃(CH₂)₃], 0.86 (t, ³J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C

3

= 1.4 Hz, 1 H, C9-H), 7.66 (dt, J₁= 7.6, J₂= 1.0 Hz, 1 H, C8- NMR (125 MHz, [D₆]DMSO): δ = 160.1 (C6), 143.8 (C3), 138.1

H), 2.30 (s, 3 H, CH₃) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ

= 159.2 (C6), 153.0 (C4a), 151.9 (C3), 135.4 (C9), 133.4 (C2), 133.1

(C10a), 129.5 (C7), 128.9 (C8), 122.5 (C10), 119.4 (C6a), 117.7

(C4a), 136.3 (C10a), 135.5 (C9), 130.1 (C7), 127.9 (C8), 127.0

(C6a), 125.2 (C1), 122.6 (C2), 119.5 (C10), 111.1 (C4), 110.3

(C10b), 31.7 (CH₃CH₂CH₂), 30.4 (ArCH₂CH₂), 30.1 (ArCH₂),

Eur. J. Org. Chem. 2013, 5631–5644

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5641

M. Krzeszewski, O. Vakuliuk, D. T. Gryko

FULL PAPER

29.1 (ArCH₂CH₂CH₂), 22.6 (CH₃CH₂), 14.5 (CH₃CH₂) ppm. (C8), 120.7 (C6a), 120.6 (C10a), 114.6 (C10), 31.4 (CH₃CH₂CH₂),

HRMS (EI): calcd. for C₁₉H₂₁NO₃[M⁺] 311.1521; found 311.1518.

C₁₉H₂₁NO₃(311.38): calcd. C 73.29, H 6.80, N 4.50; found C

73.12, H 6.75, N 4.42.

29.6 (ArCH₂CH₂), 28.8 (ArCH₂), 28.6 (ArCH₂CH₂CH₂), 22.3

(CH₃CH₂), 21.7 (ArCH₃), 14.1 (CH₃CH₂) ppm. HRMS (EI,

70 eV): calcd. for C₂₂H₂₁NO₄[M⁺] 363.1471; found 363.1467.

General Procedure for the Synthesis of Benzoazacoumarins:^[24]The

corresponding α-keto ester (0.90 mmol, 1.1 equiv.) was added to a

stirred suspension of the parent aminobenzo[c]coumarin

(0.80 mmol, 1.0 equiv.) in anhydrous toluene (4 mL). The reaction

mixture was stirred in a sealed ace pressure tube (Aldrich) at 115 °C

for 7 h under an inert atmosphere. Subsequently, solvent was evap-

orated to dryness under reduced pressure and the crude product

was purified by column chromatography.

Ethyl 12-Hexyl-2,6-dioxo-2,6-dihydrobenzo[3,4]chromeno[7,8-

b][1,4]oxazine-3-carboxylate (16): According to the general pro-

cedure, 12b (250 mg) and diethyl mesoxalate (157 mg, 140 μL) were

reacted, affording 16 (212 mg, 63%) as yellow crystals. The product

was purified by column chromatography (CH₂Cl₂/acetone, 98:2);

R_f= 0.63 (CH₂Cl₂/acetone, 95:5); m.p. 166–170 °C (CH₂Cl₂/acet-

1

one). H NMR (500 MHz, [D₆]DMSO): δ = 8.54 (s, 1 H, C11-H),

3

8.49 (d, ³J = 8.2 Hz, 1 H, C7-H), 8.27 (dd, ³J₁= 8.0, J₂= 1.2 Hz,

1 H, C10-H), 7.99 (dt, ³J₁= 7.7, ³J₂= 1.4 Hz, 1 H, C9-H), 7.72

7,10-Dimethylbenzo[3,4]chromeno[7,6-b][1,4]oxazine-5,9-dione (13):

According to the general procedure, 12a (190 mg) and ethyl puryv-

ate (128 mg, 120 μL) were reacted, affording the crude product,

which was purified by column chromatography (CH₂Cl₂/acetone,

98:2) leading to the desired product 13 (91 mg, 39%) as yellow

crystals. R_f= 0.70 (CH₂Cl₂/acetone, 95:5); m.p. 275–277 °C

3

(dt, J₁= 7.6, J₂= 1.1 Hz, 1 H, C8-H), 4.46 (q, J = 7.2 Hz, 2 H,

3

CH₃CH₂O), 2.79 (t, J = 8.0 Hz, 2 H, ArCH₂), 1.67 (quint, J =

7.8 Hz, 2 H, ArCH₂CH₂), 1.34 [m, 6 H, CH₃(CH₂)₃], 1.30 (t, J =

3

7.2 Hz, 3 H, OCH₂CH₃), 0.88 (t, ³J = 7.0 Hz, 3 H, CH₃CH₂) ppm.

¹³C NMR (125 MHz, [D₆]DMSO): δ = 161.9 (CO₂Et), 160.1 (C6),

149.6 (C2), 147.0 (C3), 145.4 (C4b), 144.9 (C12a), 136.1 (C9), 134.0

(C4a), 130.4 (C11), 130.0 (C7), 128.4 (C10b), 126.3 (C12), 123.3

(C8), 120.4 (C6a), 119.9 (C10a), 114.7 (C10), 62.6 (OCH₂CH₃),

31.5 (CH₃CH₂CH₂), 29.7 (ArCH₂CH₂), 28.9 (ArCH₂), 28.7

(ArCH₂CH₂CH₂), 22.5 (CH₃CH₂), 14.5 (OCH₂CH₃), 14.4

(CH₃CH₂) ppm. HRMS (EI, 70 eV): calcd. for C₂₄H₂₃NO₆[M⁺]

421.1525; found 421.1521. C₂₄H₂₃NO₆(421.45): calcd. C 68.40, H

5.50, N 3.32; found C 68.39, H 5.68, N 3.41.

1

(CH₂Cl₂/acetone). H NMR (500 MHz, [D₆]DMSO): δ = 8.47 (m,

2 H, C12-H and C4-H), 8.29 (ddd, ³J₁= 8.1, ³J₂= 1.4, ³J₃= 0.6 Hz,

1 H, C1-H), 7.97 (dt, ³J₁= 7.8, ³J₂= 1.4 Hz, 1 H, C2-H), 7.71 (dt,

3

³J₁= 7.5, J₂= 1.2 Hz, 1 H, C3-H), 2.50 (s, 3 H, ArCH₃), 2.44 (s,

3 H, N=CCH₃) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 160.0

(C5), 154.9 (C9), 152.6 (C10), 150.0 (C6a), 146.4 (C11a), 135.9

(C2), 134.4 (C7a), 130.2 (C4), 129.8 (C7), 128.4 (C12a), 123.5 (C3),

120.7 (C1), 120.5 (C12b), 115.5 (C4a), 113.7 (C12), 21.0 (N=C-

CH₃), 8.1 (ArCH₃) ppm. HRMS (EI, 70 eV): calcd. for C₁₇H₁₁NO₄

[M⁺] 293.0688; found 293.0694. C₁₇H₁₁NO₄(293.28): calcd. C

69.62, H 3.78, N 4.51; found C 69.56, H 4.02, N 4.51.

2,2Ј-Dihexyl-3,3Ј-dihydroxy-6H,6ЈH-[4,4Ј-dibenzo[c]chromene]-

6,6Ј-dione (17): A mixture of benzo[c]coumarin 3i (0.30 g,

1.0 mmol) and cobalt trifluoride (0.12 g, 1.0 mmol) in trifluoro-

acetic acid (10 mL) was heated to reflux for 24 h. The reaction mix-

ture was poured into water and extracted with chloroform (4ϫ

15 mL). The organic layers were collected, combined, and dried

with magnesium sulfate. The crude product was purified by column

chromatography (CH₂Cl₂, 100 %), affording 17 (0.15 g, 25%) as

yellowish crystals. R_f= 0.30 (CH₂Cl₂); m.p. 101–102 °C (CH₂Cl₂).

Ethyl 7-Methyl-5,9-dioxo-5,9-dihydrobenzo[3,4]chromeno[7,6-

b][1,4]oxazine-10-carboxylate (14): According to the general pro-

cedure, 12a (190 mg) and diethyl mesoxalate (157 mg, 140 μL) were

reacted, affording the crude product, which was purified by column

chromatography (CH₂Cl₂/acetone, 98:2) leading to the desired

product 14 (101 mg, 36%) as orange crystals. R_f= 0.56 (CH₂Cl₂/

acetone, 98:2); m.p. 244–246 °C (CH₂Cl₂/acetone). ¹H NMR

(500 MHz, [D₆]DMSO): δ = 8.71 (s, 1 H, C12-H), 8.52 (d, ³J =

3

¹H NMR (500 MHz, CDCl₃): δ = 8.23 (d, J₁= 8.0, J₂= 0.8 Hz,

2 H, C7-H and C7Ј-H), 8.01 (d, ³J = 8.0 Hz, 2 H, C10-H and C10Ј-

H), 7.88 (s, 2 H, C1-H and C1Ј-H), 7.77 (dt, ³J₁= 8.0, ³J₂= 1.4 Hz,

3

7.9 Hz, 1 H, C4-H), 8.20 (dd, J₁= 7.9, J₂= 1.2 Hz, 1 H, C1-H),

3

2 H, C9-H and C9Ј-H), 7.48 (t, J = 7.6 Hz, 2 H, C8-H and C8Ј-

7.93 (dt, J₁= 7.8, J₂= 1.4 Hz, 1 H, C2-H), 7.68 (dt, J₁= 7.5,

³J₂= 1.1 Hz, 1 H, C3-H), 4.42 (q, ³J = 7.1 Hz, 2 H, CH₂CH₃),

H), 5.62 (br. s, 2 H, 2ϫ OH), 2.73 (m, 4 H, 2ϫ ArCH₂), 1.70 (m,

4 H, 2ϫ ArCH₂CH₂), 1.43 [m, 4 H, 2ϫ CH₃(CH₂)₂CH₂], 1.34 (m,

8 H, 2 ϫ CH₃CH₂CH₂), 0.90 (m, 6 H, 2 ϫ CH₃CH₂) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 161.1 (C6 and C6Ј), 153.9 (C3 and

C3Ј), 148.5 (C4a and C4aЈ), 135.2 (C10a and C10aЈ), 134.8 (C1

and C1Ј), 130.5 (C9 and C9Ј), 127.7 (C7 and C7Ј), 127.3 (C6a and

C6aЈ), 124.8 (C8 and C8Ј), 121.1 (C10 and C10Ј), 119.9 (C2 and

C2Ј), 111.4 (C10b and C10bЈ), 105.2 (C4 and C4Ј), 31.7 (2 ϫ

CH₃CH₂CH₂), 30.4 (2ϫ ArCH₂CH₂), 29.8 (2ϫ ArCH₂), 29.3 (2ϫ

ArCH₂CH₂CH₂), 22.6 (2ϫ CH₃CH₂), 14.1 (2 ϫ CH₃CH₂) ppm.

HRMS (EI, 70 eV): calcd. for C₃₈H₃₈O₆[M⁺] 590.2668; found

590.2664. C₃₈H₃₈O₆(590.71): calcd. C 77.26, H 6.48; found C

77.08, H 6.51.

2.33 (s, 3 H, ArCH₃), 1.38 (t, ³J = 7.1 Hz, 3 H, CH₂CH₃) ppm. ¹³

C

NMR (125 MHz, [D₆]DMSO): δ = 161.8 (CO₂Et), 159.8 (C5),

151.9 (C9), 149.5 (C6a), 146.8 (C10), 144.2 (C11a), 136.1 (C2),

133.9 (C7a), 130.1 (C4), 130.0 (C7), 127.4 (C12a), 123.8 (C3), 122.9

(C1), 120.2 (C12b), 116.0 (C4a), 113.8 (C12), 62.6 (OCH₂CH₃),

14.5 (OCH₂CH₃), 8.2 (ArCH₃) ppm. HRMS (EI, 70 eV): calcd. for

C₁₉H₁₃NO₆[M⁺] 351.0743; found 351.0749.

12-Hexyl-3-methylbenzo[3,4]chromeno[7,8-b][1,4]oxazine-2,6-

dione (15): According to the general procedure, 12b (250 mg) and

ethyl pyruvate (128 mg, 120 μL) were reacted, affording 15 (162 mg,

55 %) as yellow crystals. The product was purified by column

chromatography (CH₂Cl₂/acetone, 98:2); R_f= 0.69 (CH₂Cl₂/acet-

one, 98:2); m.p. 208–210 °C (CH₂Cl₂/acetone). ¹H NMR

(E)-4-({[4-(tert-Butyl)phenyl]imino}methyl)-2-hexyl-3-hydroxy-

6H-benzo[c]chromen-6-one (20): A mixture of aldehyde 18 (0.32 g,

1.0 mmol) and 4-tert-butylaniline (19; 0.15 g, 1.0 mmol) in ethanol

3

(500 MHz, [D₆]DMSO): δ = 8.44 (dd, J₁= 8.0, ³J₂= 0.8 Hz, 1 H,

3

C7-H), 8.31 (m, 2 H, C11-H and C10-H), 7.98 (dt, ³J₁= 7.5, J₂

3

= 1.5 Hz, 1 H, C9-H), 7.71 (dt, J₁= 7.5, J₂= 1.3 Hz, 1 H, C8- (5 mL) was stirred at reflux under argon atmosphere in the pres-

H), 2.86 (t, ³J = 7.8 Hz, 2 H, ArCH₂), 2.53 (s, 3 H, N=C-CH₃),

ence of molecular sieves for 1 h. Upon completion of the reaction,

the solvent was evaporated and the crude product was recrys-

1.75 (quint, ³J = 7.2 Hz, 2 H, ArCH₂CH₂), 1.43 [m, 2 H, CH₃-

3

(CH₂)₂CH₂], 1.37 (m, 4 H, CH₃CH₂CH₂), 0.9 (t, J = 7.0 Hz, 3 H, tallized from hexanes, affording 20 (0.45 g, 99%) as orange crystals.

CH₃CH₂) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 160.2 (C6), R_f= 0.8 (CH₂Cl₂); m.p. 117–118 °C (hexane). ¹H NMR (500 MHz,

3

155.5 (C2), 152.5 (C3), 146.3 (C4b), 144.8 (C12a), 135.8 (C9), 134.6 CDCl₃): δ = 9.39 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 7.99 (d, J =

(C4a), 130.2 (C11), 129.6 (C7), 126.4 (C10b), 124.9 (C12), 123.1

3

7.6 Hz, 1 H), 7.84 (s, 1 H), 7.79 (t, J₁= 7.6 Hz, 1 H), 7.48 (m, 3

5642

www.eurjoc.org

Eur. J. Org. Chem. 2013, 5631–5644

Color-Tunable Fluorescent Dyes Based on Benzo[c]coumarin

H), 7.36 (d, ³J = 8.5 Hz, 2 H), 2.75 (t, ³J = 7.8 Hz, 2 H), 1.71

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3

(quint, J = 7.6 Hz, 2 H), 1.44 (m, 2 H), 1.36 (m, 13 H), 0.92 (t, ³J

= 7.2 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 164.4,

160.8, 155.9, 150.9, 149.7, 143.7, 135.4, 135.0, 130.6, 128.9, 127.3,

126.7, 126.4, 120.9, 120.8, 119.4, 107.4, 106.7, 34.7, 31.8, 31.3, 29.9,

29.5, 29.3, 22.7, 14.1 ppm. HRMS (EI, 70 eV): calcd. for

C₃₀H₃₃NO₃[M⁺] 455.2460; found 455.2468.

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Optical Measurements: A Perkin–Elmer Lambda 25 UV/Vis spec-

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ric grade solvents were used without further purification. Fluores-

cence quantum yields were determined in DMF by using quinine

sulfate in 0.05 m H₂SO₄as standard, and in CH₂Cl₂by using rho-

damine in ethanol as standard.

[10]

[11]

Supporting Information (see footnote on the first page of this arti-

1

cle): Absorption and emission spectra as well as copies of the H

and ¹³C NMR spectra of all new compounds.

Acknowledgments

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Financial support of our work from the Foundation for Polish Sci-

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The research leading to these results has received partial funding

from the European Community’s Seventh Framework Programme

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Published Online: July 16, 2013

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Color-tunable fluorescent dyes based on benzo[c]coumarin

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