Reactivity of the Acridine Ring: One-Pot Regioselective Single and Double Bromomethylation of Acridine and Some Derivatives

Article abstract of DOI:10.1055/s-2003-42104

We report here a new efficient regioselective synthetic route to 4-bromomethylacridine and to 4,5-bis-(bromomethyl)acridine, two interesting starting materials for various 4-methyleneacridine and 4,5-bis-(methylene) acridine derivatives, in one step by di

Full text of DOI:10.1055/s-2003-42104

LETTER
2349
Reactivity of the Acridine Ring: One-Pot Regioselective Single and Double
Bromomethylation of Acridine and Some Derivatives
R
J
eactivity
u
of the
A
crid
l
ine Rin
i
g
en Chiron,* Jean-Pierre Galy
Laboratoire de Valorisation de la Chimie Fine, case 552, UMR 6009, Faculté des Sciences de Saint Jérôme,
av. Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Fax +33(4)91288323; E-mail: julien.chiron@univ.u-3mrs.fr
Received 11 September 2003
Abstract: We report here a new efficient regioselective synthetic
route to 4-bromomethylacridine and to 4,5-bis-(bromomethyl)acri-
dine, two interesting starting materials for various 4-methyleneacri-
dine and 4,5-bis-(methylene)acridine derivatives, in one step by
direct bromomethylation of acridine with bromomethylmethylether
(
BMME). We also describe some biologically interesting diesters
derivatives from the corresponding 4,5-bis(hydroxymethyl)acridine
precursor.
Key words: acridines, bromomethylation, electrophilic aromatic
substitution, regioselectivity, reactivity
Scheme 1 Chloromethylation of acridine.
Regioselective functionalization of position 4 of the acri-
dine ring has been poorly described in the literature. The
first example reported by Hess in 1971 is about the syn- acidic conditions, 5 reacts with acridine by electrophilic
thesis of 4-phthalimidoacridines from acridine, involving substitution regioselectively at position 4. Compound 6
1
6
a Tscherniac–Einhorn reaction. This regioselective reac- was obtained in one step and under mild conditions with
tivity seems to be possible because of the protonation of a yield of 31%. In the previously reported synthetic
3b
the acridine ring nitrogen. We did recently optimize this route, 6 was obtained in 4 steps and with only 27% over-
method to synthesize various 4-amino- and 4-hydroxy- all yield. However, unlike the results described in the
methylacridine derivatives. Halomethylacridines are also
synthetic precursors of choice that were widely described
in the literature and extensively used in our laboratory, but
their synthesis generally involves many steps. In search
for an efficient method to get halomethylacridines, we de-
cided to exploit the particular reactivity of the lateral phe-
2
Hess article, in which mono- or di-alkylation was depend-
ing only on the quantity of electrophile, in the case of
BMME reaction, monoalkylation was difficult to carry
out in higher yield. It seems that the intermediate 4-bro-
momethylacridinium has a higher reactivity towards N-
protonated 6 than acridinium, leading to 4,5-bis(bromom-
7
3
nylenes of protonated acridine. Many assays were carried ethyl)acridine as by-product. We decided to exploit this
out in order to functionalize directly the acridine ring, but particular reactivity to get 4,5-bis(bromomethyl)acridine.
4
,5
classical chloromethylation methods, involving formal- Increasing BMME/acridine ratio at a controlled tempera-
dehyde, paraformaldehyde or trioxane with HCl/ZnCl or ture was critical to get the bisfunctional product in good
2
H SO , under heating, microwave irradiation or sonica- yield. This method afforded 4,5-bis(bromomethyl)acri-
2
4
tion, were completely inefficient. Neither chloromethyl- dine 7 with a suitable yield of 64%.8
acridines nor hydroxymethylacridines were obtained and
the starting acridine was totally recovered every time.
4
,5-Bis(bromomethyl)acridine was easily converted into
the corresponding 4,5-bis(hydroxymethyl)acridine (8) us-
9
Use of chloromethylethylether (CMEE, 2) under strong ing the classical CaCO hydrolyzing method. Yield after
3
acidic conditions gave some traces (less than 5% conver- column chromatography (CH Cl /EtOAc, 5/5 v:v) was
2
2
sion) of product 3 and 4 that were isolated by column 92%.
chromatography (Scheme 1). Because of these encourag-
Several diester derivatives 9a–h (Scheme 3) were pre-
pared using classical esterification methods with various
ing results, we decided to follow the halomethylether way.
Bromomethylmethylether (BMME, 5) was the reagent of acyl chlorides and DMAP as activator.10 These com-
choice for this reaction. It has already been described by pounds were synthesized because of their structural simi-
Taylor as an efficient bromomethylating agent of aro-
larities with various anticancer and antileishmanian
5
11
matic compounds. As shown in Scheme 2, under strong
drugs.
In conclusion, we have described for the first time the
one-pot regioselective synthesis of 4-bromomethyl-
acridine and 4,5-bis(bromomethyl)acridine by taking
SYNLETT 2003, No. 15, pp 2349–2350
Advanced online publication: 22.10.2003
DOI: 10.1055/s-2003-42104; Art ID: G23603ST
0
1
.1
2
.2
0
0
3
©
Georg Thieme Verlag Stuttgart · New York

2
350
J. Chiron, J.-P. Galy
LETTER
(
3) (a) Chiron, J.; Galy, J. P. Z. Kristallogr. NCS 2002, 217,
87. (b) Sourdon, V.; Mazoyer, S.; Pique, V.; Galy, J. P.
Molecules 2001, 6, 673. (c) Filloux, N.; Galy, J.-P. Synlett
001, 1137.
2
2
(
(
(
4) Charmantray, F.; Duflos, A.; Lhomme, J.; Demeunynck, M.
J. Chem. Soc., Perkin Trans. 1 2001, 2962.
5) Taylor, R. C. In Electrophilic Aromatic Substitution; John
Wiley and Sons: Chichester, 1990, 219.
6) 4-Bromomethylacridine 6: Acridine 1 (1 g, 5.58 mmol)
was dissolved in H SO (20 mL) at 20 °C under N and
2
4
2
BMME 5 (1.05 g, 7,71 mmol) was added in one portion. The
mixture was maintained at 20 °C for 17 h then it was poured
into ice and stirred for 1 h. The precipitated was filtered off
and dissolved in CHCl . The organic layer was then dried
3
with MgSO , the solvent was removed under vacuo and the
4
resulting yellow solid was chromatographed (silica gel,
CHCl /cyclohexane, 7/3, v:v) to give 6 as a bright yellow
3
3
b
powder (466 mg, 31%). Mp 166 °C, lit. 165 °C.
7) Hess, F. K.; Stewart, P. B. J. Med. Chem. 1975, 18, 320.
8) 4,5-Bis(bromomethyl)acridine 7: Acridine 1 (2 g, 11.16
mmol) was heated in H SO (25 mL) to 50 °C under N and
Scheme 2 Bromomethylation of acridine.
(
(
2
4
2
BMME 5 (6.08 g, 44.64 mmol) was added in one portion.
The mixture was maintained at 50 °C for 12 h then it was
poured into ice and stirred for 1 h. The precipitated was
filtered off and dissolved in CHCl . The organic layer was
3
then dried with MgSO , the solvent was removed under
4
vacuo and the resulting yellow solid was recrystallized from
Scheme 3 a) CaCO , H O/Dioxane, reflux; b) RCOCl, DMAP,
3
2
dry Et O to give 7 as a bright yellow powder (2.49 g, 64%).
2
Et N, CH Cl .
3
2
2
1
Mp 156 °C. H NMR (300 MHz, CDCl ): d = 5.19 (s, 4 H),
3
7
.95 (dd, 1 H, J = 8 Hz), 8.37 (d, 1 H, J = 8 Hz), 8.50 (d, 1
1
3
H, J = 8 Hz), 9.91 (s, 1 H). C NMR (75 MHz, CDCl ): d =
27.01, 126.94, 127.59, 128.81, 131.55, 137.83, 139.45,
3
Table 1 Yields and Melting Points of Diester Derivatives
1
51.22. Anal. Calcd for C H Br N: C, 49.35; H, 3.04; N,
15 11 2
Moiety
R
Yield (%)
Mp (°C)
160
3.84. Found: C, 49.49; H, 3,03; N, 3.83.
(
9) (a) Georghiou, P. E.; Ashram, M.; Li, Z.; Chaulk, S. G. J.
Org. Chem. 1995, 60, 7284. (b) Smith, J. G.; Dibble, P. W.;
Sandborn, R. E. J. Org. Chem. 1986, 51, 3762. (c)Grissom,
J. W.; Klingberg, D.; Meyenburg, S.; Stallman, B. J. Org.
Chem. 1994, 59, 7876.
10) (5-{[(4-Chlorobenzoyl)oxy]methyl}-4-acridinyl)methyl
4-Chlorobenzoate 9b: A solution of 4-chlorobenzoyl
chloride (471 mg, 2.75 mmol) in CH Cl (10 mL) was added
a
b
c
d
e
f
Ph
79
79
82
81
67
32
65
42
4-Cl-C H
170
6
4
4-F-C H4
186
6
(
4-MeO-C H
199
6
4
2
2
4-Me N-C H
263
2
6
4
dropwise under N to a stirred solution of 7 (300 mg, 1.25
mmol), Et N (0.44 mL, 3.17 mmol) and DMAP (383 mg,
2
3
CH =CH
104
2
3.14 mmol) in CH Cl (20 mL) at 0 °C. After complete
2 2
–a
addition, the mixture was allowed to stand at r.t. for 6 h. The
organic layer was then washed with NaOH 1 N (2 × 35 mL),
dried with MgSO and the solvent was removed under
g
4-Cl-Prop
h
4-(Ph-N=N)-C H
218
6
4
4
vacuo. The resulting solid was purified by column
a
Compound 9g is an oil.
chromatography (silica gel, CH Cl /EtOAc, 99:1, v:v) to
2
2
1
give 9b as a yellow powder (515 mg, 81%). Mp 170 °C. H
NMR (300 MHz, CDCl , 25 °C): d = 6,21 (s, 4 H), 7.35 (m,
3
4
H), 7.53 (dd, J = 8.5, 6.9 Hz, 2 H), 7.84 (dd, J = 6.9, 0.8
advantage of the particular reactivity of position 4, respec-
tively 5, of acridine enhanced by protonation of the central
ring nitrogen. We also reported for the first time the 4,5-
bis(hydroxymethyl)acridine, which undergoes esterifica-
tion to give new 4,5-bisfunctional acridinic esters 9a–h
that are potential anticancer and antileishmanian drugs
Hz, 2 H), 7.97 (dd, J = 8.5, 0.8 Hz, 2 H), 8.02 (m, 4 H), 8.77
13
(
s, 1 H). C NMR (75 MHz, CDCl , 25 °C): d = 63.67,
3
125.50, 126.33, 128.26, 128.67, 128.73, 128.85, 131.10,
134.46, 136.18, 139.31, 146.13, 165.61. Anal. Calcd for
C H Cl NO : C, 67.58; H, 3.71; N, 2.71. Found: C, 67.45;
29 19
2
4
H, 3.70; N, 2.70.
(
11) (a) Read, M.; Harrison, R. J.; Romagnoli, B.; Tanious, F. A.;
Gowan, S. H.; Reszka, A. P.; Wilson, W. D.; Kelland, L. R.;
Neidle, S. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 4844.
(
Table 1).
(
b) Di Giorgio, C.; Delmas, F.; Filloux, N.; Robin, M.;
References
Seferian, L.; Azas, N.; Gasquet, M.; Costa, M.; Timon-
David, P.; Galy, J. P. Antimicrob. Agents Chemother. 2003,
47, 174.
(
(
1) Hess, F. K.; Cullen, E.; Grozinger, K. Tetrahedron Lett.
971, 28, 2591.
2) Chiron, J.; Galy, J. P. Heterocycles 2003, 60, 1653.
1
Synlett 2003, No. 15, 2349–2350 © Thieme Stuttgart · New York