Improved synthesis of quinacridine derivatives

Article abstract of DOI:10.1055/s-2006-932465

An efficient synthetic pathway toward various substituted quinacridines 1 and 2 has been developed. Compared to the previous method, higher yields and easier workup were obtained. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932465

610
LETTER
Improved Synthesis of Quinacridine Derivatives
E
nhancedSynthe
é
sis of
Q
uin
m
acridines y Lartia, Hélène Bertrand, Marie-Paule Teulade-Fichou*
Laboratoire de Chimie des Interactions Moléculaires (CNRS, UPR285), Collège de France, 11 Place Marcelin Berthelot, 75005 Paris,
France
Fax +33(1)44271356; E-mail: mp.teulade-fichou@college-de-france.fr
Received 13 December 2005
oxidized derivatives of quinacridines, are well-known
Abstract: An efficient synthetic pathway toward various substi-
organic pigments and have been extensively studied for
tuted quinacridines 1 and 2 has been developed. Compared to the
their self-assembling,7 photoconductive, doping dye
previous method, higher yields and easier workup were obtained.
emitter8 and fluorescent9 properties in numerous devices
stemmed from materials chemistry.
Key words: heterocyclic synthesis, palladium coupling, aromatiza-
tion, selenium oxidation, quinacridine
For further developments and a broadened use in organic
chemistry, this class of compounds deserves an improved
synthetic access. Until now, angular quinacridines could
be obtained by three major approaches:10 Friedländer,11
Bernthsen4b and Ulmann–Goldberg methods5b (see
Scheme 1); each of which exhibit major drawbacks. The
Friedländer approach relies on a double condensation be-
tween cyclohexanedione and amino benzaldehyde, lead-
ing to dihydroquinacridine,12 followed by oxidation.
However, its use is limited by instability of starting mate-
rial, poor reproducibility of both reactions and lack of
access to asymmetric quinacridines. The microwave-
assisted Bernthsen reaction between N,N¢-diphenylphen-
ylenediamine and low-chain aliphatic carboxylic acid13
although representing an attractive one-pot process, is
limited to p-quinacridines bearing alkyl groups in posi-
tions 13 and 14.
Quinacridine is a pentacyclic diaza aromatic motif that
adopts a crescent shape when the junction between the
benzo and phenanthroline rings features a [b,j] type
(Figure 1). According to positions of the two endocyclic
nitrogen atoms, three isomeric series of quinacridines are
distinguished: ortho- meta- and para-quinacridine, two of
which are represented in Figure 1.
R2
R2
7
8
N
8
R1
6
5 N
R3
13
12
5
N
12
14
N
1
1
2
1
R1
R1
CHO
NH2
O
O
Figure 1 Structures and nomenclature of substituted o-quinacridine
(1) and p-quinacridine (2). R1, R2, R3 = H, CH3, CHO.
+
N
N
The numerous applications of quinacridines in material
science and bioorganic chemistry are directly related to
their electronic properties and their structural features
(substituents). For example, o-quinacridine, which is
structurally related to the 2,2¢-bipyridine bisimine ligand,
has been used to chelate Ru,1 Cu,2 and Pd.3 Also, sterically
crowded 13,14-disubstituted p-quinacridines display heli-
cal chirality,4 due to the strong distortion of the aromatic
core from the planarity. Interestingly, the size of the
quinacridine unit is particularly well-suited for overlap-
ping large aromatic areas of nucleobase associations, re-
sulting in strong and selective interactions of amino
quinacridines with triplex DNA5 and quadruplex DNA.5c,6
In addition, quinacridines have been shown to oxidize
guanines upon photoactivation, making them promising
candidates for studying photoinduced charge injection
into DNA.5b Finally, the linear quinacridones, i.e. the
Pd/C
O
i) Na
ii) FeCl3
O
N
H
N
NH
N
i) [Cu] or [Pd]
ii) H+
COOH
NH2
Br
+
Br
N
R
NHPh
NHPh
RCOOH, ZnCl2
MW
N
R
Scheme 1 Synthetic pathways towards quinacridine by the Fried-
länder method (upper part), Ullmann–Goldberg method (central part)
and Bernthsen-modified method (lower part).
SYNLETT 2006, No. 4, pp 0610–0614
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932465; Art ID: G38305ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enhanced Synthesis of Quinacridines
611
Finally, a third approach is based on copper- or palladium- Use of corresponding methyl ester 4 enabled us to carry
catalyzed coupling followed by cyclization leading to out palladium-catalyzed coupling with good yield and
quinacridone, which is then converted into quinacridine. made the purification steps easier.16 Hence, precursor 5
Since cross-coupling allows the use of a large variety of was obtained in 74% yield by use of the Pd(OAc)2–
commercially available starting materials, this pathway Cs2CO3–P(t-Bu)3 catalytic system (Scheme 2, b).17 Most
provides, in principle, an access to the three isomeric se- remarkably, these conditions led to a dramatic improve-
ries with a broad range of substitution pattern. However, ment of the double N-arylation of ortho bis-bromo deriv-
poor yields and extensive workup considerably diminish- atives. Thus, 6a and 6b were obtained in good yield (74–
es its synthetic usefulness especially in the ortho series. 76%) without carbazole formation (Scheme 2, c).
Here we describe several synthetic improvements that
significantly increase the overall efficiency of the initial
reactional scheme.
Ester 5 can be quantitatively saponified16 and converted
into dichloroquinacridines 7a with POCl3 (Scheme 3,
b),5b but this standard treatment failed in the ortho series.18
Initially, double coupling between dihalobenzene and an- Alternatively, the methyl esters 6a, 6b are directly cy-
thranilic acid was performed under either Ullmann–Gold- clized into quinacridones 8a,b by hot CH3SO3H
berg (Cu, CuI, K2CO3, n-pentanol) or Buchwald–Hartwig (Scheme 3, a).19
conditions [Pd(OAc)2, BINAP, Cs2CO3, dioxane]. These
reactions appeared highly substrate-sensitive, especially
O
in the ortho series where palladium catalysis led exclu-
sively to carbazole formation,14,15 and copper catalysis
revealed rather capricious (0–40% yields).14 For instance,
in our search of laterally monofunctionalized quinacridine
2a (R1 = CH3, R2 = R3 = H), intermediate 3 was obtained
in moderate yield (54%) under copper catalysis, whereas
further amination failed whatever the catalyst (Scheme 2).
a)
R1
R2
R2
R1
Na
H
O
reflux
N
H
N
H
47–80 %
(+ 1a,b)
9a,b
NH
NH
8a,b
[Ox]
CH3SO3H
92–98 %
R1
1a (R1 = CH3, R2 = H)
1b (R1 = H, R2 = CH3)
R1
6a,b
5-methylanthranilic
b)
5
2a
X anthranilic acid
Pd(OAc)2, BINAP,
Cs2CO3, dioxane ( X = I)
a)
acid
Cu, CuI, K2CO3
pentanol
i) NaOH / Acetone
ii) POCl3
X
R2
[Ox]
R2
96 %
HN
LiAlH4, THF
reflux
no
N
N
reaction
or
HOOC
54 %
Cu, CuI, K2CO3
n-pentanol
(X = I or Br)
R3
94 %
HN
I
N
R3
3
X = Br, I
H
Cl
Cl
7a (R1 = CH3, R2 = R3 =H)
CH3
H
9c (+ 2a)
CH3
R1
b)
R1
methyl anthranilate
Pd(OAc)2, P(t-Bu)3
Cs2CO3, toluene
24 h reflux
HN
I
CH3
Scheme 3
COOCH3
N
H
Quinacridones are classically reduced by sodium in
refluxing pentanol, whereas dichloroquinacridines are
reduced by LiAlH4 in refluxing THF (Scheme 3). Those
treatments, when applied to 8a,b and 7a, respectively, af-
forded complex mixtures of expected product (1a,b, 2a)
and over-reduced derivative (respectively 9a–c) in vari-
able amount. Thus, the mixture has to be fully reoxidized
to quinacridine, which is achieved by over-stoichiometric
FeCl3 treatment. However, this resulted in a dark and
thick suspension and, work up was notably tedious. Use of
a 5% amount of Fe(ClO4)3 in acetic acid20 led only to a
partial increase in expected product content.21 In contrast,
triphenylcarbenium tetrafluoroborate (TrBF4) was found
to be an efficient alternative reagent for reoxidation
(Scheme 4, a).22 Actually, o- (1a,b) and p-quinacridine
(2a,b: R2 = CH3, R1 = R3 = H) were obtained with 70–
97% yields from their corresponding over-reduced mix-
ture (respectively 9a–d) in milder and easier conditions as
described above.23
COOCH3
COOCH3
74 %
HN
R1
5
4
c)
Br
Pd(OAc)2, P(t-Bu)3
Cs2CO3, toluene
24 h reflux
COOCH3
R2
R1
Br
HN
+
COOCH3
HN
R2
74–76 %
COOCH3
NH2
R1
6a (R1 = CH3; R2 = H)
6b (R1 = H; R2 = CH3)
Scheme 2
Synlett 2006, No. 4, 610–614 © Thieme Stuttgart · New York

612
R. Lartia et al.
LETTER
Recently, it has been shown that selenium dioxide (SeO2) but NMR analysis revealed the presence of unidentified
is able to oxidize 1,4-dihydropyridine into pyridine.24 We by-products along with the desired compound 2c. After
quantitatively oxidized hydrogenated quinacridines 9d extensive purifications, 2c was obtained in a 36% yield.
into the quinacridine 2b (Scheme 4).25 Quinacridine-
HH
carboxaldehydes (such as 10b) are key precursors to
H
N
PdCl2, Et3SiH
THF
H
functionalized quinacridines and they are classically ob-
tained by oxidation of aromatic methyl groups by SeO2 in
refluxing naphthalene in 55–90% yield.5b Thus, it was
tempting to perform direct treatment of 9b in the aim to
combine the two oxidation steps (rearomatization and
methyl oxidation). After rapid optimization,26 a 92:8
mixture of 10b–2b was obtained from 9d as judged by
NMR analysis. Further purifications afforded 10b in a
40% yield.
a)
CH3
N
52 %
R
Cl
N
Cl
11
N
R
CH3
N
Cl
N
Cl
7c
SmI2, HMPA
THF
CH3
b)
CH3
N
36 %
2c
CH3
N
TrBF4, AcOH
a)
Scheme 5
2b
70–97 %
H
SeO2
naphtalene
55 %
CH3
N
Last, worth pointing out is the extremely low reactivity of
lateral methyl group independently of its position on the
external benzene ring. Its conversion into aldehydic
groups failed using DDQ in acetic acid,37 silver(II)
peroxodisulfate (AgS2O8)38 or IBX in DMSO–fluoro-
benzene.39 Similarly, oxidation into carboxylic acid deriv-
ative by warm potassium dichromate in sulfuric acid
failed, as did oxidation of methylated quinacridine 2a
using hot nitric acid.
N
CHO
H
H
N
9d
SeO2 / AcOH
SeO2/Naphtalene
N
b)
40 %
10b
In summary, significant improvement of each step com-
posing the synthetic pathway leading to quinacridines has
been carried out. Consequently, quinacridine derivatives
can now be obtained in four easy-to-perform steps from
commercially available materials. The overall chemical
yield ranging from 44–63%. Along with this gain in over-
all efficiency and practical convenience, the versatility of
the synthesis has been definitively broadened. Moreover,
quinacridines are structural related to acridines, thereby
both series should display similar chemical behavior and
the application of our study to acridine chemistry is
currently investigated.
Scheme 4
Since direct conversion of dichloroquinacridines to quina-
cridines is an attractive process, several reduction re-
agents have been tested in the hope to circumvent the
over-reduction observed with LiAlH4. Several assays
using Pd/C–N2H427 or PEG/KOH28 to reduce 7c revealed
unsuccessful. Finally, triethylsilane (Et3SiH) and palladi-
um chloride (PdCl2) that has been reported to be an effi-
cient reagent for dehydrogenation of chloroarenes29 was
assayed. Interestingly, instead of the expected compound
2c, we obtained exclusively the 6,7-dihydrogenated prod-
uct 1130 (52%, Scheme 5, a) which highlights the phenan-
throline-like reactivity of the quinacridine system. With
regards to the helical properties of 7c31 and 11, our results
reported herein could constitute a useful access towards
novel helicenes.
Acknowledgment
We would like to thank Dr. David Monchaud and Clémence
Jacquelin for valuable discussions.
Samarium diiodide (SmI2) was then subsequently at-
tempted in this step.32 It has been reported that such reac-
tions are greatly enhanced by presence of HMPA32,33 or
water34 as a co-solvent. However, since over-reduction of
4-chloropyridine into piperidine has been described in
water-containing medium,35 we focused on the HMPA/
SmI2 system (Scheme 5, b). In such conditions,36 com-
plete consumption of starting material 7c was observed
References and Notes
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Organometallics 1992, 11, 3954. (b) Sjögren, M. P. T.;
Hansson, S.; Åkermark, B. Organometallics 1994, 13, 1963.
Synlett 2006, No. 4, 610–614 © Thieme Stuttgart · New York

LETTER
Enhanced Synthesis of Quinacridines
613
(4) (a) Tanaka, Y.; Sekita, A.; Suzuki, H.; Yamashita, M.;
Oshikawa, O.; Yonemitsu, T.; Torii, A. J. Chem. Soc.,
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98, 3062. (d) Teulade-Fichou, M.-P.; Perrin, D.; Boutorine,
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H), 7.41 (s, 1 H), 7.26 (s, 4 H), 7.13–7.23 (m, 3 H), 6.75–6.80
(m, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.23 (s, 3 H). 13C NMR
(DMSO-d6): d = 168.6, 148.0, 145.2, 137.2, 135.8, 134.8,
131.8, 131.3, 126.7, 124.2, 123.1, 117.6, 115.0, 114.0,
112.3, 111.8, 52.4, 20.1. DCI-MS: m/z (%) = 391 (100), 392
(26), 393 (5).
Coumpound 6b: yellow solid; mp 97–98 °C; Rf = 0.37
(CH2Cl2–n-hexane, 1:1). 1H NMR (DMSO-d6): d = 9.26 (s,
1 H), 9.18 (s, 1 H), 7.95 (d, J = 1.5 Hz, 1 H), 7.92 (d, J = 1.5
Hz, 1 H), 7.25–7.36 (m, 4 H), 7.13 (dd, J = 8.4, 1.5 Hz, 1 H),
6.99 (m, 2 H), 6.74 (m, 2 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.39
(s, 3 H). 13C NMR (CDCl3): d = 168.7, 168.5, 150.8, 148.5,
135.3, 134.9, 134.1, 134.0, 133.9, 131.7, 131.5, 131.4,
125.1, 124.3, 117.2, 116.8, 114.6, 114.2, 112.7, 112.1, 51.7,
51.6, 21.1. DCI-MS: m/z (%) = 391 (100) [M+], 392 (26),
393 (4).
(6) (a) Teulade-Fichou, M.-P.; Carrasco, C.; Bailly, C.; Alberti,
P.; Mergny, J.-L.; David, A.; Lehn, J.-M.; Wilson, W. D. J.
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(18) In the ortho series, reaction with POCl3 leads to intractable
mixture. Nevertheless, dichloroquinacridines are preferred
over quinacridones since they are more soluble and less
hygroscopic.
(19) Cosimbescu, L.; Shi, J. US Pat. Appl. US 2004002605,
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(20) (a) Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Shoar,
R. H. Tetrahedron Lett. 2005, 46, 2775. (b) CAUTION:
metallic perchlorate salts were reported to be explosive.
(21) In our hands, a 29:71 molar ratio of quinacridine 2b
(R2 = CH3, R1 = R3 = H) and dihydroquinacridine(9b)
mixture was brought up only to 73:27 (2b:9b). Increasing
the catalytic load to 7% and the reaction time from 45 min to
16 h led to a similar result.
(22) (a) Bonthrone, W. J. Chem. Soc. 1959, 2773.
(b) Bonthrone, W. J. Chem. Ind. 1960, 1192. (c) In all
cases, quantitative aromatization was observed on the crude
mixture NMR analysis.
(9) Smith, J. A.; West, R. M.; Allen, M. J. Fluorescence 2004,
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(10) Others less straightforward routes towards quinacridines
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2002, 32, 729. (b) Seijas, J. A.; Vázquez-Tato, M.-P.;
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2002, 57, 1299.
(23) General Procedure.
The amount of hydrogenated quinacridines in the mixture
was estimated my NMR, based on the relative peak inten-
sities. Characteristic peaks of hydrogenated quinacridines
were located at d = 4.5 ppm (methylene group), whereas
those of quinacridine are the more downfield-shifted at d =
9.4 ppm (para) or d = 8.6 ppm (ortho). Lateral methyl groups
are also of relevant importance and are situated in the 2.3–
3.1 ppm zone, those borne by hydrogenated products being
shifted more upfield. Such a mixture (300 mmol in hydro-
genated compounds) was dissolved in AcOH (10 mL),
TrBF4 (330 mmol) was added and the mixture was heated to
reflux. Crude mixture was poured in cold H2O ca. 10 min
later. The pH value was adjusted to neutrality and the brown
suspension was filtered and dried. The mixture was purified
by column chromatography using a gradient of MeOH in
CH2Cl2 (1–3% v/v).
(14) Jacquelin, C.; Saettel, N.; Hounsou, C.; Teulade-Fichou, M.-
P. Tetrahedron Lett. 2005, 46, 2589.
(15) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.
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5737.
(17) General Procedure.
In freshly distilled and degassed toluene (20 mL) was placed
Pd(OAc)2 (5% molar) under an inert atmosphere. Then tri-
tert-butylphosphine was added (15%) and the solution was
allowed to stir 10 min. Dibromobenzene derivative (5
mmol), methyl anthranilate derivative (12 mmol) and
Cs2CO3 (15 mmol) were successively added. After overnight
reflux, crude mixture was allowed to cool and was then
quenched by 50 mL NH4Cl (1 M) solution. About 100 mL
CH2Cl2 were added and the biphasic mixture separated. The
aqueous phase was extracted twice by CH2Cl2. Organic
phases were dried on Na2SO4 and evaporated to dryness. The
resulting brown oil was purified by column chromatography,
using an CH2Cl2–n-hexane (1:1) mixture as eluant, affording
a yellow powder.
(24) Cai, X.-H.; Yang, H.-J.; Zhang, G.-L. Can. J. Chem. 2005,
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(25) After 80 min and at r.t., a 90% conversion is observed after
30 min as judged by NMR. Due to formation of red colloidal
selenium, use of TrBF4 seems to be of greater synthetic use
for conversion of dihydrogenated quinacridines into
quinacridines.
(26) Adding SeO2 twice in the same flask seems to be preferable
than an unique initial load. Selenium dioxide was firstly
reacted in a flask containing both substrate 9d and AcOH.
Then, 80 min later, AcOH was evaporated, naphthalene
added, SeO2 newly added and mixture heated to 230 °C.
When both loads of SeO2 were initially mixed with substrate
and acid, a 72:28 ratio was obtained.
Spectroscopic data for selected compounds.
Compound 5: yellow solid; mp 85–88 °C; Rf = 0.35
(CH2Cl2–n-hexane, 1:1). 1H NMR (DMSO-d6): d = 9.47 (s,
1 H), 9.33 (s, 1 H), 7.89 (dd, J = 1.8, 8.1 Hz, 1 H), 7.71 (s, 1
(27) Cellier, P. P.; Spindler, J.-F.; Taillefer, M.; Cristau, H.-J.
Tetrahedron Lett. 2003, 44, 7191.
Synlett 2006, No. 4, 610–614 © Thieme Stuttgart · New York

614
R. Lartia et al.
LETTER
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(30) Compound 11: white solid; mp 236–238 °C; Rf = 0.37
(CH2Cl2–MeOH, 9:1). 1H NMR (CDCl3): d = 8.18 (s, 2 H),
8.02 (d, 2 H, J = 8.4 Hz), 7.67 (dd, 2 H, J = 8.7. 1.8 Hz), 3.32
(m, 4 H), 2.66 (s, 6 H). 13C NMR (CDCl3): d = 160.6, 145.9,
141.1, 137.3, 133.0, 128.6, 126.1, 124.2, 124.0, 34.1, 21.9.
DCI-MS: m/z (%) = 379 (100) [M+], 380 (26), 381 (67), 382
(16), 383 (12).
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the molecule exhibits a dihedral angle of 35.9° (Cesario, M.;
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in a THF/HMPA mixture. Increasing the reaction time to 2 h
or 24 h, as well as using 6 equiv of SmI2, did not modify the
reaction course.
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