Br?nsted- and Lewis acid-catalyzed cyclization giving rise to substituted anthracenes and acridines

Article abstract of DOI:10.1016/S0040-4039(02)01462-4

A versatile acid-catalyzed method for the preparation of symmetrically and unsymmetrically substituted 9,10-diphenylanthracenes is explored. Diveratrylmethanes are prepared and converted into 10-phenylanthracene-9-carbaldehydes by Lewis acid catalysis and into 9-phenylacridines by reduction.

Full text of DOI:10.1016/S0040-4039(02)01462-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6605–6608
Brønsted- and Lewis acid-catalyzed cyclization giving rise to
substituted anthracenes and acridines†
Raf Goossens, Mario Smet and Wim Dehaen*
Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Heverlee (Leuven), Belgium
Received 30 May 2002; accepted 12 July 2002
Abstract—A versatile acid-catalyzed method for the preparation of symmetrically and unsymmetrically substituted 9,10-diphenyl-
anthracenes is explored. Diveratrylmethanes are prepared and converted into 10-phenylanthracene-9-carbaldehydes by Lewis acid
catalysis and into 9-phenylacridines by reduction. © 2002 Elsevier Science Ltd. All rights reserved.
The acid-catalyzed condensation of veratrole (1,2-
dimethoxybenzene) and formaldehyde leads to
cyclotriveratrylene, an important building block in
supramolecular chemistry.1,2 On the other hand, with
different aldehydes and veratrole, only the 9,10-disub-
stituted anthracenes are obtained.3–5 Most of the work
described deals with aliphatic aldehydes, with only one
example referring to the synthesis of 9,10-diphenyl-
2,3,6,7-tetramethoxyanthracene from veratrole and
benzaldehyde.2 We wanted to explore this reaction, as a
general strategy towards 9,10-diarylanthracenes. A well
known strategy for the preparation of 9,10-diarylan-
thracenes is a two-step procedure from anthraquinones,
involving addition of a Grignard reagent or an aryl-
lithium and reduction of the resulting diols.6,7 The
scope of this protocol was recently widened by the
introduction of a new reducing agent by our group.6
Obviously, metal-catalyzed couplings between 9,10-
dihaloanthracenes and arylboronic acids are possible as
well.8 However, the direct condensation of an aromatic
aldehyde with veratrole presented in this paper, allows
the preparation of a number of these derivatives in one
single and highly convenient step.
sis of 3b–i from substituted benzaldehydes 2b–i. An
advantage of this synthesis is that all anthracenes are
substituted with four methoxy groups. This prevents
association of the anthracenes and enhances their solu-
bility. Anthracenes bearing aryl groups with 2%,6%-disub-
stitution at the 9- and 10-positions are less easily
prepared: the yield for the preparation of 3b is only
25%. However, we consider this compound to be of
interest as we propose that such a substitution will
protect the anthracene from oxidation or fluorescence
quenching.
Polycyclic aromatic aldehydes, including pyrene-1-car-
boxaldehyde, 1- and 2-naphthaldehyde did not yield
anthracenes and only starting material was recovered
from the reaction mixture. The same was observed
when heterocyclic aldehydes (thiophene-2-carboxalde-
hyde, 4-pyridinecarboxaldehyde, 4,6-dichloropyrim-
idine-5-carboxaldehyde) were used.
When the ratio of veratrole:benzaldehyde is changed
from 1:2 to 3:1, one obtains in high yield the [2+1]
adduct 4a. This protocol can again be applied to a
number of substituted benzaldehydes 2b–f,j, affording
the diveratrylmethanes 4b–f,j in 60–80% yield.9 Reac-
tion of heterocyclic or polyaromatic aldehydes under
these conditions again failed. It can be assumed that the
diveratrylmethanes of type 4 are intermediates in the
reactions with an excess of the aldehyde, leading to
anthracenes 3a–i. To test this, the adduct 4c was com-
bined with benzaldehyde (ratio 1:1.2). As we hoped, the
main product (40% yield) was the unsymmetrically
substituted anthracene 5c.10 On the other hand, a small
amount of the symmetrical anthracene 3c was also
formed. The same observation was made for the reac-
Firstly, we reinvestigated the reaction of veratrole 1 and
benzaldehyde 2a in a 1:2 ratio (Scheme 1). The
literature5 reaction conditions (84% sulfuric acid, 5°C)
appeared to be optimal and other reaction conditions
(lower or higher concentrations of sulfuric acid, glacial
acetic acid) did not improve the yield of 3a. This is
typically around 40% which is also true for the synthe-
* Corresponding author: Fax ++32 16 32 79 90; e-mail:
wim.dehaen@chem.kuleuven.ac.be
† Polycyclic aromatic compounds, Part IV. For Part III, see Ref. 6.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01462-4

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R. Goossens et al. / Tetrahedron Letters 43 (2002) 6605–6608
Z
X
X
Y
Y
Z
H2SO4 84%
2eq. aldehyde
H3CO
H3CO
OCH3
OCH3
OCH3
OCH3
+
X
Y
1
CHO
2a-j
3a-i
H2SO4 84%
3eq. veratrole
Z
Z
Z
X
Y
X
Y
H2SO4
84%
H3CO
OCH3
H3CO
OCH3
appropriate
aldehyde
H3CO
OCH3
H3CO
OCH3
4a-f,j
(1.2 eq.)
CHO
5b-d Z' = H
5e Z' = CHO
Z'
a X,Y,Z = H
H3CO
OCH3
b X,Y = Cl, Z = H
c X,Z = H, Y = Br
d X,Y = H, Z = Br
H3CO
OCH3
e X,Y = H, Z = N(CH3)2
f X,Y = H, Z = NO2
g X,Y= H, Z = COOMe
h X,Y = H, Z = CN
i X,Y = H, Z = CHO
j X,Z = H, Y = NO2
3i'
CHO
Scheme 1.
was recovered. The same result was obtained when we
used the Vilsmeier formylation. Ring closure did occur
with adducts 4a–f and dichloromethyl methyl ether in
the presence of TiCl4 in dry dichloromethane11 giving
rise to 10-arylanthracene-9-carboxaldehydes 6a–f in 30–
80% yield (Scheme 2).12 In the literature, these condi-
tions have been applied to obtain anthracenes from less
electron rich substrates. In our case, the yield could be
improved to a reliable 70–90% when the softer SnCl4
was used as the Lewis acid. Again, aldehyde 6e with
electron donating substituents is of potential use for the
synthesis of NLO materials. Furthermore, we applied
this synthetic method to prepare molecules with two
anthracene moieties. Tetrakis(veratryl) adduct 7 was
obtained from terephthaldehyde 2i and a tenfold excess
of 1. Upon treatment with SnCl4/CHCl2OCH3 this
compound yielded the poorly soluble dialdehyde 8.
tion of 4d with benzaldehyde. This proved that the
condensation of 1 with 2c and 2d to 4c and 4d, respec-
tively, is at least partially reversible under the reaction
conditions. Adducts 4b,e are less readily cleaved in
acidic medium, and no exchange products are formed.
This opens the possibility to obtain unsymmetrical
anthracenes, e.g. 5e, of potential use for non-linear
optical (NLO) applications by sequential combination
of veratrole with benzaldehydes having electron with-
drawing and electron donating groups. Direct mixed
condensation of equimolar amounts of 2e and 2i with
veratrole yielded only 3i and the proposed intermediate
dihydroderivative 3i%. Presumably, the presence of the
electron rich dimethylaminobenzaldehyde prevents the
expected oxidation of 3i% to a certain extent.
As an alternative to obtain unsymmetrical diarylan-
thracenes of type 5, we considered the Friedel–Crafts
acylation of diveratrylmethane 4a. With benzoyl chlo-
ride the intermediate benzophenone was expected to
undergo a Bradsher reaction to afford the correspond-
ing anthracene. Unfortunately, only starting material
Finally, we found that the diveratrylmethanes 4 were
useful for the synthesis of 9-phenyl acridines. Therefore,
diveratrylmethanes 4a and 4j were first nitrated using
an excess of concentrated nitric acid, yielding the dini-

R. Goossens et al. / Tetrahedron Letters 43 (2002) 6605–6608
6607
Z
Z
X
Y
X
Y
H3CO
H3CO
OCH3
OCH3
H3CO
H3CO
OCH3
OCH3
Cl2HCOCH3
TiCl4 or SnCl4
4a-f
CHO
6a-f
CHO
H3CO
H3CO
OCH3
OCH3
H3CO
H3CO
OCH3
OCH3
Cl2HCOCH3
SnCl4
H3CO
H3CO
OCH3
OCH3
H3CO
H3CO
OCH3
OCH3
CHO
7
8
Scheme 2.
X
X
X
excess
HNO3
Z
Z
Z
Z
Z
Sn, HCl
or
LiAlH4 for 4j
Z
Z
Z
Z
Z
Z
Z
N
O2N
NO2
4a X = H
j X = NO2
10a X = H
9a X = H
j X = NO2
Z = OCH3
j X = NH2
Scheme 3.
troderivatives 9a and 9j (70–90%) (Scheme 3). These
compounds could then be ring-closed by reduction with
tin in hydrochloric acid (36%) resulting in the forma-
tion of the acridines 10a and 10j (50–60%).13 Obviously,
in the case of substrate 9j, this treatment resulted in the
concomitant reduction of the 2%-nitro substituent. No
formation of an isomeric 9-(3,4-dimethoxyphenyl)-2,3-
dimethoxyacridine was observed. For derivative 9a,
LiAlH4 in dry THF, gave a slightly higher yield (65%)
of the desired 9-phenylacridine 10a.
References
1. Lindsey, A. J. Org. Chem. 1965, 30, 1685.
2. Collet, A. Tetrahedron 1987, 43, 5725.
3. Muller, A.; Raltschewa, M.; Papp, M. Chem. Ber. 1942,
6, 692.
4. Ostaszewski, R. Tetrahedron 1998, 54, 6897.
5. Aubry, J. M.; Schmitz, C.; Rigaudy, J.; Kim Cuong, N.
Tetrahedron 1983, 39, 623.
6. Smet, M.; Van Dijk, J.; Dehaen, W. Synlett 1999, 4, 495
and references cited therein.
7. Smet, M.; Van Dijk, J.; Dehaen, W. Tetrahedron 1999,
55, 7859 and references cited therein.
Acknowledgements
8. Kotha, S.; Ghosh, A. K. Synlett 2002, 7, 451.
9. General procedure for the preparation of compounds
4a–f,j. A solution of veratrole (30 mmol, 3 equiv.) and the
appropriate aldehyde (10 mmol, 1 equiv.) in dichloro-
methane (5 mL) was added dropwise to 84% sulfuric acid
(10 mL) while the temperature was kept between 0 and
The Katholieke Universiteit Leuven, the FWO-Vlaan-
deren and the Ministerie voor Wetenschapsbeleid are
thanked for their continuing financial support. M.S.
thanks the FWO Vlaanderen for
fellowship.
a postdoctoral

6608
R. Goossens et al. / Tetrahedron Letters 43 (2002) 6605–6608
5°C. After the addition, the suspension was stirred for 1
12. General procedure for the preparation of compounds
6a–f. To solution of 4a–f (1 equiv.) in dry
h at room temperature. The reaction was quenched with
water and neutralized by ammonia. After extraction with
dichloromethane, the solvent was stripped off in vacuo
and the product was purified chromatographically or by
crystallization. Compound 4d was obtained using the
standard procedure. The crude product was purified by
crystallization from methanol, affording 4d in 70% yield;
a
dichloromethane (25 mL) was added dichloromethyl
methyl ether (5 equiv.) and TiCl4 (4 equiv.) or SnCl4 (4
equiv.) at room temperature. After stirring overnight,
more dichloromethane was added (50 mL) and the solu-
tion was washed with water (3×100 mL). After evapora-
tion of the solvent, the crude product was purified
chromatographically. Compound 6d was prepared
according to the standard procedure. The crude product
was purified chromatographically eluting on silica gel
with dichloromethane, affording 6d in 83% yield (when
TiCl4 was used) or 93% yield (when SnCl4 was used); mp
1
mp 136°C; H NMR (400 MHz, CDCl3): lH 7.40 (2H, d,
J=8.4 Hz, 3,5-H phenyl), 6.98 (2H, d, J=8.4 Hz, 2,6-H
phenyl), 6.78 (2H, d, J=8.3 Hz, 4-H veratryl), 6.63 (2H,
s, 1-H veratryl), 6.53 (2H, dd, J=8.4 Hz, 5-H veratryl),
5.38 (1H, s, Ar3CH), 3.86 (6H, s, OCH3), 3.76 (6H, s,
OCH3); 13C NMR (100 MHz, CDCl3): lC 148.9, 147.7,
143.4, 136.0, 131.3, 131.0, 121.3, 120.1, 112.7, 111.0, 55.9,
55.8, 55.3; MS (EI) m/z 444 (M+).
1
230–232°C; H NMR (400 MHz, CDCl3): lH 11.42 (1H,
s, CHO), 8.43 (2H, s, 4,5-H anthracene), 7.76 (2H, d,
J=8.4 Hz, 3,5-H phenyl), 7.28 (2H, d, J=8.4 Hz, 2,6-H
phenyl), 6.60 (2H, s, 1,8-H anthracene), 4.11 (6H, s,
OCH3), 3.75 (6H, s, OCH3); 13C NMR (100 MHz,
CDCl3): lC 192.3, 151.9, 149.0, 140.1, 138.0, 132.1, 132.0,
128.9, 126.2, 104.4, 101.0, 56.0, 55.5; MS (E) m/z 482
(M+).
10. General procedure for the preparation of compounds
5b–e. A solution of 4b–e (10 mmol, 1 equiv.) and the
appropriate aldehyde (12 mmol, 1.2 equiv.) in
dichloromethane (5 mL) was added dropwise to 84%
sulfuric acid (10 mL) while the temperature was kept
between 0 and 5°C. After the addition, the suspension
was further stirred for 1 h at room temperature. The
reaction was quenched with water and neutralized by
ammonia. After extraction with dichloromethane, the
solvent was evaporated in vacuo and the product was
purified chromatographically or by crystallization. Com-
pound 5c was prepared using the standard procedure.
The crude reaction mixture was purified chromatographi-
cally eluting on silica gel with dichloromethane, affording
13. General procedure for the synthesis of acridines 10a,j.
The appropriate nitro compound (1 equiv., 0.02 mol) and
tin powder (4 equiv.) were suspended in hydrochloric acid
(10 mL, 36%). Ethanol (50 mL) was added and the
solution was refluxed for 24 h. After cooling and neutral-
izing with base (KOH), the solvent was removed under
reduced pressure and the residue was dissolved in
dichloromethane. After extraction with water (3×100
mL), the solvent was stripped off and the crude product
was purified chromatographically with the appropriate
solvent. Compound 10a was obtained according to the
standard procedure. The crude product was purified
chromatographically with a mixture of dichloromethane
(98.5%) and methanol (1.5%), to afford 10a in 55% yield;
1H NMR (400 MHz, CDCl3): lH 8.25 (2H, s, 4,5-H
acridine), 7.70–7.64 (m, 3H, 2,4,6-H phenyl), 7.48–7.44
(m, 2H, 3,5-H phenyl), 6.80 (s, 2H, 1,8-H acridine), 4.21
(6H, s, OCH3), 3.78 (6H, s, OCH3); 13C NMR (100 MHz,
CDCl3): lC 157.4, 150.6, 136.8, 134.6, 130.2, 129.7, 129.6,
103.4, 99.4, 57.8, 56.0; MS (CI) m/z 376 (MH+).
1
5c in 40% yield; mp 243°C; H NMR (400 MHz, CDCl3):
lH 7.88 (1H, d, J=7.7 Hz, 3-H phenyl), 7.50 (8H, m,
4-6-H phenyl, 2-6-H phenyl%), 6.84 (2H, s, 4,5-H anthra-
cene), 6.60 (2H, s, 1,8-H anthracene), 3.74 (6H, s, OCH3),
3.73 (6H, s, OCH3); 13C NMR (100 MHz, CDCl3): lC
149.7, 149.3, 140.9, 140.1, 134.1, 135.5, 133.4, 132.0,
131.4, 129.8, 129.1, 128.2, 127.9, 126.2, 126.2, 125.8,
104.6, 104.4, 103.7, 55.9; MS (E) m/z 530 (M+). Anal.
calcd: C, 68.06; H, 4.76. Found: C, 67.78; H, 4.94%.
11. Yamato, T.; Sakaue, N.; Shinoda, N.; Matsuo, K. J.
Chem. Soc., Perkin Trans. 1 1997, 8, 1193.