Synthesis of Anthradan analogues by regioselective Friedel-Crafts reactions on N,N-dihexylanthracen-2-amine

Article abstract of DOI:10.1016/j.tetlet.2013.02.085

An efficient synthetic route using a Friedel-Crafts acylation approach was developed to obtain fluorophores such as 1-(6-(dihexylamino)anthracen-1-yl) propan-1-one (1b) and 1-(7-(dihexylamino)anthracen-1-yl)propan-1-one (1c) with a push-pull electronic conjugation starting from 2-aminoanthracene-9,10-dione (4). These compounds are analogues of 1-(6-(dihexylamino)anthracen-2-yl)propan- 1-one (Anthradan) and they exhibit the same additional redshift emission and absorption spectra. Furthermore, we have synthesized other derivatives of Anthradan via the Friedel-Crafts approach in good yields.

Full text of DOI:10.1016/j.tetlet.2013.02.085

Tetrahedron Letters 54 (2013) 2587–2590
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of Anthradan analogues by regioselective Friedel–Crafts reactions
on N,N-dihexylanthracen-2-amine
Maicon G. de Miranda, Matheus F. G. de Oliveira, Rosangela S. C. Lopes, Antonio J. R. da Silva,
⇑
André L. M. Albert, Claudio C. Lopes
Universidade Federal do Rio de Janeiro, Instituto de Química, Departamento de Química Analítica, CT, Bloco A, s. 508, Rio de Janeiro, RJ CEP 21949-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route using a Friedel–Crafts acylation approach was developed to obtain fluoro-
phores such as 1-(6-(dihexylamino)anthracen-1-yl)propan-1-one (1b) and 1-(7-(dihexylamino)anthra-
cen-1-yl)propan-1-one (1c) with a push–pull electronic conjugation starting from 2-aminoanthracene-
9,10-dione (4). These compounds are analogues of 1-(6-(dihexylamino)anthracen-2-yl)propan-1-one
(Anthradan) and they exhibit the same additional redshift emission and absorption spectra. Furthermore,
we have synthesized other derivatives of Anthradan via the Friedel–Crafts approach in good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 31 January 2013
Revised 21 February 2013
Accepted 26 February 2013
Available online 13 March 2013
Keywords:
Solvent effects
Regioselectivity
Electrophilic aromatic substitution
Reduction
Alkylation
Fluorescent probes are compounds widely used as tools for
diagnosis and monitoring of various diseases.1 Lu et al. introduced
the fluorophore 1-(6-(dihexylamino)anthracen-2-yl)propan-1-one
(Anthradan).2 This compound is a push–pull charge-transfer chro-
mophore with an electron-donating dihexylamino group and an
electron-withdrawing propionyl group located at the 2,6-positions
of the anthracene ring (Fig. 1). Other related compounds generally
employed as fluorescent probes include 2-propionyl-6-dimethyla-
minonaphthalene (PRODAN),3 6-acryloyl-2-dimethylaminonaph-
thalene (ACRYLODAN),4 6-lauroyl-2-dimethylaminonaphthalene
(LAURDAN),5 2-(N,N-dimethylamino)-6-naphthoyl-4-trans-cyclo-
hexanoic acid (DANCA),6 7-aryl-3-hydroxychromones,7 and
3-methoxychromones.8
The most common fluorophores used in this type of procedure
are anthracene derivatives, because they exhibit good emission
properties with moderate to high quantum yields.1a These com-
pounds have all the desired spectroscopic requirements for biolog-
ical applications as well as absorption in the visible region
(>400 nm), high absorption coefficient (>30,000 MÀ1 cmÀ1), high
fluorescence quantum yield (>50%) and photostability, with a
strong solvatochromism.9 This intrinsic alteration of the absorp-
tion and/or emission properties of a chromo(fluoro)phore is due
to the influence of its molecular environment and the supporting
solvent. Anthradan showed a significantly redshifted absorption
and emission (around 460 nm) with a low absorption coefficient
(12,000 MÀ1 cmÀ1). However, the preparation of Anthradan in-
volves a multistep synthesis with low overall yield and high cost
of reactants, which are major drawbacks limiting its use in large
scale applications such as forensics.2,10,11
The interest in fluorescent dyes for single-molecule fluores-
cence spectroscopy in biologically relevant systems led us to ex-
plore the synthesis of anthracene analogues of Anthradan. The
push–pull structures of 1,6-substituted and 1,7-substituted
anthracene derivatives would retain the useful properties found
in Anthradan such as polarity-induced shift of emission and sensi-
tivity to local nanoenvironments, and thus shifting the absorption
further to the red which will improve results in cellular imaging. In
Anthradan, the dihexylamine group was attached in order to en-
hance the solubility in ordinary organic solvents without signifi-
cantly influencing the absorption and emissions spectra. The
same properties were observed with the dimethylamino group in
the PRODAN structure.
O
9
8
1
7
6
2
3
(Hex)2N
10
5
4
(Anthracene)
(Anthradan)
⇑
Corresponding author. Tel./fax: +55 21 25627853
E-mail address: claudiosabbatini@uol.com.br (C.C. Lopes).
Figure 1. Anthracene and 1-(6-(dihexylamino)anthracen-2-yl)-propan-1-one
(Anthradan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.085

2588
M. G. de Miranda et al. / Tetrahedron Letters 54 (2013) 2587–2590
O
1
1
R =
;R2=R3=H;
R =
;R2=R3=H
O
(1a):
(1b):
(1f):
O
CF3
1
3
2
1
3
2
(1g):
(1h):
R =R =H;R =
;
R =R =H;R =
O
O
R3
R1
N(Hex)2
O
1
2
3
1
2
3
(1c):
(1d):
(1e):
R =R =H;R =
;
R =R =H;R =
O
O
1
2
3
1
R =R =H;R =
;
R =
; R2=R3=H
R2=R3=H
O
R2
(1i):
(1j):
(1a-j)
H
1
1
R =
O
;R2=R3=H;
F
R =
F
F
F
F
Figure 2. Donor–acceptor-substituted anthracene derivatives (1a–j).
R3
R2
R1
R1
R2
N(Hex)2
N(Hex)2
O
O
a
R1=CH3
(1b)
(1g)
(2)
(3)
R1=
H
(1a-j)
R2=CH3 (1c)
O
O
R2=
H
(1h)
NH2
NH2
(2)
N(Hex)2
N(Hex)2
N(Hex)2
Scheme 4. Reagents and conditions: (a) Acetyl chloride or propionyl chloride, AlCl3,
1,2-dichloroethane, 40 °C, 92% (1b:1c, 46%:46%) and 90% (1g:1h, 45%:45%).
(4)
Scheme 1. Retrosynthetic analysis of asymmetric push–pull anthracene derivatives
(1a–j).
R= CF3 (1f)
R= pentafluorphenyl (1e)
NH2
a or b or c
NH2
R= phenyl (1j)
N(Hex)2
O
O
a
b
R
(4)
(3)
(2)
N(Hex)2
N(Hex)2
(2)
O
Scheme 5. Reagents and conditions: (a) TFAA, 0–40 °C, (90%); (b) penta-
fluorbenzoyl chloride, AlCl3, 1,2-dichloroethane, 0–40 °C, (80%); (c) benzoyl chlo-
ride, AlCl3, 1,2-dichloroethane, 0 °C, (80%).
Scheme 2. Reagents and conditions: (a) Zn, NaOH, reflux 24 h (85%);
(b) 1-Iodohexane, K2CO3, ethanol, reflux 24 h (90%).
R
R=CH3 (1a)
R=H (1i)
O
N(Hex)2
O
a
H
a
N(C6H13 2
)
(2)
Scheme 3. Reagents and conditions: (a) Acetyl chloride or propionyl chloride, AlCl3,
1,2-dichloroethane, 0 °C, 85% (1a) and 83% (1i).
(2)
N(Hex)2
(1e)
N(Hex)2
Scheme 6. Reagents and conditions: (a) POCl3, DMF, 150 °C, 70%.
As we searched for an efficient fluorescent probe whose emis-
sion properties may be modulated by their environment, we pre-
pared 10 analogues of Anthradan (Fig. 2) as part of a forensic
program of research with the main objective to introduce new
compounds for the formulations of invisible inks used in marking
currency notes.12
Herein we report the straightforward synthesis and some
physical properties of these new anthracene derivatives (1a–j)
including the first examples of 1,2-acceptor–donor, 1,6-acceptor–
donor, and 1,7-acceptor–donor Anthradan analogues. Our

M. G. de Miranda et al. / Tetrahedron Letters 54 (2013) 2587–2590
2589
Figure 3. Absorption spectra of 1d in hexanes, THF, chloroform, methanol, ethanol, isopropanol, acetonitrile, toluene, DMF, DMSO, and ethylene glycol.
Table 1
Absorption/emission of Anthradan, 2 and 1a–f in different solventsa
Fluorophore solvent
1a
1b
1c
1d
1e
1f
2
Antradanb
n-Hexane
Toluene
380/435
456
431/575
459
446/595
455
446/510
458
381/507
390
423/510
428
423/510
390
439/483
447
Chloroform
THF
455/519
381
450/561
449
458/586
446
457/514
421
394/493
434
434/499
429
431/490
429
458/536
450
Acetonitrile
DMF
449/501
458
449/568
451
448/601
450
451/512
459
392/510
410
430/513
433
390/508
390
455/557
458
DMSO
463
463
462
463
429
436
390
460
1-Propanol
Ethanol
Methanol
Ethyleneglycol
451
451/479
449
448
445/506
456
449
451/523
448
453
451/—
450
419
426/463
419
425
424/479
425
390
390/463
390
456
452/601
456
361
453
468
426
448
432
430
464
a
The concentration for absorption measurement was 10À5 M. The concentration for emission measurement was 10À7 M, and the excitation wavelength was at the
absorption kmax
.
b
Data for Anthradan are from Ref. 2
retrosynthetic analysis for the preparation of asymmetric anthra-
cenes (1a–j) (Scheme 1) is based on regioselective acylation of
the commercially available 2-aminoanthracene-9,10-dione (4).
DFT calculations at the B3LYP 6-31G⁄ level on N,N-dihexylanthra-
cen-2-amine (2) indicated that the carbon atoms at C-1, 5, and 8
are susceptible to eletrophilic attack. We believed the regioselec-
tivity could be switched between these positions by carrying on
the reactions under thermodynamic or kinetic control.
It should be pointed out that the susceptibility of positions 1, 5,
and 8 to electrophilic attack can be explained in terms of stable
resonance structures. Electrophilic attack at position 1 involves
breaking the aromaticity at one ring and gives rise to the kinetic
product. On the other hand, reactivity at positions 5 and 8 leads
to very stable canonical forms and is the result of thermodynamic
control at higher temperatures.
We began our synthetic work by reducing the 9,10 dicarbonyls
in 2-aminoanthracene-9,10-dione (4). Vigorous stirring with zinc
dust in aqueous sodium hydroxide13 solution afforded the desired
anthracen-2-amine (3) in 85% yield. In the second step, N,N-
dihexylanthracen-2-amine (2) was obtained in good yield (90%)
by refluxing anthracen-2-amine (3) in a suspension of 1-iodohex-
ane and potassium carbonate in ethanol (Scheme 2).14
Figure 4. Normalized fluorescence spectra of 1c (10À7 M) and 2 (10À7 M) in hexane.
Amine (2) was subjected to the traditional conditions of
Friedel–Crafts acylation15 with propionyl or acetyl chloride using
aluminum chloride as Lewis acid at 0 °C in 1,2-dichloroethane.
We obtained 1-(2-(dihexylamino)anthracen-1-yl)propan-1-one

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M. G. de Miranda et al. / Tetrahedron Letters 54 (2013) 2587–2590
(1a) and 1-1-(2-(dihexylamino)anthracen-1-yl)ethanone (1i) in
85% and 83% yields, respectively (Scheme 3).
When the Friedel–Crafts acylation was repeated at a higher
temperature of 40 °C, a separable mixture of two equal isomers
of 1-(6-(dihexylamino)anthracen-1-yl)propan-1-one (1b) and
compounds with 1,2-dipolar, 1,6-dipolar, and 1,7-dipolar anthra-
cene fluorophores by a simple and straightforward synthesis.
These compounds have a bathochromic shifted absorption and
emission when compared to anthracene. The new fluorophores re-
tain the same absorption and emission properties observed with
Anthradan.
1-(7-(dihexylamino)anthracen-1-yl)propan-1-one
(1c),
were
obtained in 46% yield. We also obtained 45% each of 1-(6-
(dihexylamino)anthracen-1-yl)ethanone (1g) and 1-(7-(dihexyla-
mino)anthracen-1-yl)ethanone (1h), (Scheme 4).
To demonstrate their potential, the isomeric mixtures of
1-(6-(dihexylamino)anthracen-1-yl)propan-1-one (1b):1-(7-
(dihexylamino)anthracen-1-yl)propan-1-one (1c), and 1-(6-
However, when N,N-dihexylanthracen-2-amine (2) was treated
with more reactive electrophiles such as trifluoroacetic anhydride
or pentafluorbenzoyl chloride and aluminum chloride at 0–40 °C,
(dihexylamino)anthracen-1-yl)ethanone
no)anthracen-1-yl)ethanone (1h) were used in a formulation of
two invisible inks to mark currency notes and paper.
(1g):1-(7-(dihexylami-
we obtained only
a single regioselective acylation of 1-(2-
(dihexylamino)anthracen-1-yl)-2,2,2-trifluoroethanone (1f) and
(2-(dihexylamino)anthracen-1-yl)(perfluorophenyl)-methanone
(1e) in 80% and 90% yields, respectively. Another Friedel–Crafts
reaction on N,N-dihexylanthracen-2-amine (2) was performed
with benzoyl chloride and aluminum chloride as Lewis acid at
0 °C in 1,2-dichloroethane. We obtained (2-(dihexylamino)anthra-
cen-1-yl)(phenyl)methanone (1j) with 80% yield. However, the
same reaction when conducted at 40 °C produces a complex mix-
ture of products together with a small amount of starting material.
All the three procedures above led to the kinetic products (1e, f,
and j), which were formed by the attack of the electrophilic species
at position 1 of N,N-dihexylanthracen-2-amine (2), and no thermo-
dynamic products arising from attack at position 5 or 8 were ob-
served (Scheme 5).
Finally, the anthracene derivative 7-(dihexylamino)anthracene-
1-carbaldehyde (1d) was obtained by the Vilsmeier–Haack reac-
tion16 of N,N-dihexylanthracen-2-amine (2) with POCl3 and DMF
at 150 °C (Scheme 6). All new compounds were characterized by
1H and 13C NMR, IR, and high-resolution mass spectroscopy.
The absorption spectrum of compound 1d (Fig. 3) is characteris-
tic of substituted anthracene derivatives with a donor–acceptor sys-
tem that is dependent on the solvent properties unlike anthracene
structures without the push–pull conjugation. The broad band
around 390–540 nm is assigned as an intramolecular charge-trans-
fer band.2 The maximum charge-transfer molar extinction coeffi-
cients of 1a–f in THF are 5.53 Â 103; 3.53 Â 103; 9.55 Â 103;
9.16 Â 103; 5.54 Â 103; 1.13 Â 104 L cmÀ1 molÀ1, respectively.
The maximum absorption of compounds 1a–f (Fig. 3) in a vari-
ety of solvents spanning a wide range of polarity including nonpo-
lar, polar and polar aprotic solvents are listed in Table 1.
Acknowledgments
The authors would like to thank CAPES and CNPq for the
scholarships granted and FAPERJ for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.085.
References and notes
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15. Name Reactions; Li, J. J., Ed; Springer Dordrecht Heidelberg London New York,
2009; p 145.
The influence of selected solvents on the absorption of 1d is
shown in Figure 3. In contrast to the absorption, solvent polarity
has a dramatic effect on the emission wavelength. Thus, an in-
crease in solvent polarity causes a redshift of the emission band.
This effect is especially pronounced for 1c (Fig. 4) and leads to
the conclusion that the dipole moment of the excited state is larger
than the ground state (Table 1).17
In summary, we have prepared novel environment-sensitive
16. Name Reactions; Li, J. J., Ed; Springer Dordrecht Heidelberg London New York,
2009, 419–420.
fluorophores
1-(2-(dihexylamino)anthracen-1-yl)propan-1-one
(1a), 1-(6-(dihexylamino)anthracen-1-yl)propan-1-one (1b), and
1-(7-(dihexylamino)anthracen-1-yl)propan-1-one (1c) and other
17. Ihmels, H.; Meiswinkel, A.; Mohrschladt, C. J.; Otto, D.; Waidelich, M.; Towler,
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