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acylation resulting in the formation of the desired 6,9-dichloro-2-
methoxy-4-nitroacridine precursor (8) in good yield (70%, step v).
Starting from precursor 8, two synthetic routes, see A and B in
Scheme 2, towards N4,N9-disubstituted diaminoacridines 2 were
developed, setting 2a (R1 = Me, R2 = R3 = R4 = H, R5 = R6 = Et,
m = n = 3 in 2) as the target compound. The major difference
between these routes was the order in which the N4 and the N9 ali-
phatic groups were introduced, i.e. in route A, introduction of the
N4-group preceded that of the N9-group, and this was reversed in
route B.
Fig. 1. Structure of mepacrine, also known as quinacrine (1).
As shown in Scheme 2, the initial step in Route A was the reduc-
tion of the nitro group in 8 to the respective aniline 9. The first two
attempts made, namely, standard catalytic hydrogenation using
H2(g) and Pd/C [29–31] (step i), and transfer hydrogenation accord-
ing to Mandal and co-workers [32], using triethylsilane (TES) as an
in situ hydrogen source and Pd/C as catalyst (step ii), resulted in
complex mixtures of products, from which it was possible to iden-
tify, by mass spectrometry (MS), the formation of a by-product of 9
corresponding to the loss of one chlorine atom (data not shown).
Considering the expectedly higher reactivity of the C-9 position
compared to the C-6 position in 9, the by-product was likely 4-
amino-6-chloro-2-methoxyacridine (9a in Scheme 2). Subsequent
reduction of 8 using SnCl2/HCl, according to a procedure by Scovill
and co-workers, produced 9 in high yield (72%, step iii) [34]. Ani-
line 9 was next alkylated with N-(4-bromobutyl)phthalimide
which, after optimization of the reaction conditions as summarized
in Table 1, afforded the expected product 10, using sodium acetate
and ethanol (EtOH) as the base and solvent, respectively, and
microwave heating at 120 °C for 2.5 h (Table 1, entry 7). However,
the yield was quite low (10%, step iv); this was mostly due to the
formation of multiple products, including 4-amino-6-chloro-2-
methoxyacridin-9(10H)-one, detected by MS analysis (data not
shown). In view of this, and considering that the high reactivity
of the chlorinated C-9 position in the acridine moiety was likely
to be the major factor underlying the complex behavior of the
tested steps in route A, this route was abandoned and route B
was pursued instead.
Route B started with the conversion of 8 into 4-nitromepacrine
11, via an SNAr reaction using N1,N1-diethylpentan-1,4-diamine as
the nucleophile (Scheme 2). After optimization of the reaction
parameters such as reaction time, solvent, base, and temperature,
11 was produced in moderate yield (50%) through an adaptation
of a procedure by Anderson and co-workers, based on the addition
of excess phenol for intermediate formation of an aryl ether at C-9,
which activates this position towards subsequent attack by the
amine, and the use of Cs2CO3 as a base (step v). The nitro group
in 11 was next reduced to aniline 12 in high yield (85%), using
the SnCl2/HCl method employed in Route A (step iii). Alkylation
Fig. 2. General structure of the targeted N4,N9-disubstituted 4,9-diaminoacridines,
2. Solid and dashed rectangles, respectively, delimit the structures of chloroquine
(R4 = Me, R5 = R6 = Et, m = 3) and primaquine (R1 = Me, R2 = R3 = H, n = 3)
antimalarials.
conversion into methyl ester 4; this was accomplished by the reac-
tion of 3 with excess iodomethane in the presence of Cs2CO3,
according to Parrish and co-workers [25] (step i). Ester 4 was next
reacted with trifluoroacetic (triflic) anhydride (Tf2O) for activation
of the phenol group via conversion into the corresponding triflate
5, which was achieved in high yield (67%) following a procedure
reported by Anderson and co-workers [20] (step ii). Triflate 5
was reacted with 4-methoxy-2-nitroaniline to afford intermediate
6 through a Buchwald-Hartwig amination, benefiting from the fact
that this palladium-catalyzed cross-coupling between aryl triflates
and substituted anilines is generally quite efficient [26]; to this
end, the conditions described by Åhman and co-workers [27] were
employed, and compound 6 was isolated in good (52%) yield (step
iii). Then, the ester group in 6 was hydrolyzed with barium hydrox-
ide octahydrate in methanol (MeOH), following a procedure by
Anderson and co-workers [28] for quantitative formation, after
acidification, of the corresponding carboxylic acid 7 (step iv).
Finally, this acid was reacted with phosphoryl chloride for in situ
generation of the acyl chloride intermediate that subsequently
underwent an intramolecular Friedel-Crafts intramolecular
Scheme 1. Synthesis of 6,9-dichloro-2-methoxy-4-nitroacridine 8, precursor to the target compound 2a. Reagents and conditions: (i) CH3I (5 equiv.), Cs2CO3 (0.5 equiv.),
DMF, rt, 90 min; (ii) Tf2O (1.5 equiv.), TEA (2 equiv.), CH2Cl2, N2 atmosphere, À25 °C, 30 min; (iii) 4-methoxy-2-nitroaniline (1.2 equiv.), Cs2CO3 (1.4 equiv.), Pd(OAc)2
(0.05 equiv.), rac-BINAP (1.8 equiv.), toluene, N2 atmosphere, 120 °C, 5 h; (iv) (1) Ba(OH)2∙8H2O (1.5 equiv.), MeOH, 90 °C, 2 h; (2) 1 M aq. HCl; (v) POCl3 (34 equiv.), 120 °C,
2.5 h.