Secondary amines and unexpected 1-aza-anthraquinones from 2-methoxylapachol

Article abstract of DOI:10.1016/S0040-4020(01)00973-5

A series of 1-aza-anthraquinones were characterized, besides the expected N-alkylamino derivatives, from the substitution reactions of 2-methoxylapachol with primary amines. An investigation of the reaction conditions allowed reasonable selectivity in the products distribution.

Full text of DOI:10.1016/S0040-4020(01)00973-5

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 9569±9574
Secondary amines and unexpected 1-aza-anthraquinones
from 2-methoxylapachol
Celso A. Camara,a Angelo C. Pinto,a Maria A. Rosab and Maria D. Vargasb,p
a
Â
Instituto de Quõmica, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, Ilha do FundaÄo,
21945-970 Rio de Janeiro, RJ, Brazil
Instituto de Quõmica, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas, SP, Brazil
b
Â
Received 19 July 2001;accepted 11 October 2001
AbstractÐA series of 1-aza-anthraquinones were characterized, besides the expected N-alkylamino derivatives, from the substitution
reactions of 2-methoxylapachol with primary amines. An investigation of the reaction conditions allowed reasonable selectivity in the
products distribution. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
droxy-1,4-naphthoquinone,10 extracted, along with its cyclic
isomer b-lapachone and other naphthoquinones, from the
bark of various species of the genus Tabebuia sp. A number
of biological activities have been reported for these natural
naphthoquinones and their derivatives11 including micro-
bicidal, cytostatic, anti-in¯ammatory, bactericidal, fungi-
cidal, virucidal, anti-Plasmodium falciparum 4the agent
of malaria), anti-Schistosoma mansoni 4agent of schisto-
somiasis) and anti-Trypanosoma cruzi 4agent of Chagas
disease).12
The presence of a nitrogen atom in e.g. simple alkylamino
derivatives1 or in a fused heterocycle2 is related with a wide
range of biological properties in quinone compounds.3
Potent antitumor4 and antimalarial5 activities have been
described in both cases. In addition, the aminonaphtho-
quinone moiety is a component of the molecular framework
of several natural products 4e.g. rifamycins, kinamycins,
etc.)6 and is also present as a key synthetic intermediate
for the construction of biologically important compounds.7
We found that in the presence of primary amines the prenyl
side-chain in 2 undergoes further cyclization,13 to result in
novel compounds identi®ed as 1-aza-1,2-dihydro-5,10-
anthraquinones or 1,2,5,10-tetrahydro-benzo[g]quinoline-
5,10-diones 4.14 The 1-aza-anthraquinone nucleus is
frequently encountered in various natural products, e.g.
markanyn,15 cleistopholyn16 and grif®azanone B.17 Litera-
ture methods for the synthesis of 1-aza-anthraquinones are
dominated by the hetero Diels±Alder cycloaddition. This
method allows the construction of the structural backbone
of the added heterocycle moiety.18
In the work described herein we were interested in using a
derivative of lapachol 1, 2-methoxylapachol 2, to synthesize
a series of 2-alkylamino derivatives 3 4Scheme 1). Nucleo-
philic displacement of methoxynaphthoquinone derivatives
with primary amines has been investigated previously.8 No
reports on the analogous reactions of 2 were found in the
literature, although the reactions of the parent compound 1
with various amines have been described.9
Compound 1 is a naturally occurring 3-prenylated 2-hy-
Scheme 1. Reagents and conditions: 4a) K2CO3, acetone, 4CH3)2SO4, 2 h, 88%;4b) R 1NH2 4excess).
Keywords: 1-aza-anthraquinone;lapachol;1,4-naphthoquinone.
Corresponding author;e-mail: mdvargas@iqm.unicamp.br
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00973-5

9570
C. A. Camara et al. / Tetrahedron 57 72001) 9569±9574
Table 1. Products, methods and chemical yields of derivatives 3 and 4
Entry
Amine
3 4%)
4 4%)
Time/method 4see text)
Conversion 4%)
1
2
3
4
5
6
7
8
4a) CH2vCHCH2NH2
4b) PhCH2NH2
54
75
59
61
,1
20
,1
5
24/A
12/B
24/A
24/B
4/B
0.5/B 41008C)
4/B
24/A
24/A
3/Ad
92
90
89
90a
82
100
80
63
85
80
62
64
60
52
26
49
32
4±)b
48
4c) 4H3CO)2CHCH2NH2
70
76
4±)c
4±)c
57
9
4d) HOCH2CH2NH2
4e) PhNH2
10
11
12
13
4±)b
4±)
4±)
4±)
22
18
22
10 min/B 41208C)
10 min/B 41208C)
10 min/B 41208C)
4f) 4 4H3CO)C6H4NH2
4g) 4 4H3C)C6H4NH2
a
Inert atmosphere 4N2).
Trace.
Not visible under tlc inspection.
Ethanol/re¯ux.
b
c
d
2. Results and discussion
result of an ipso aromatic nucleophilic substitution in the
methoxyl.20 Similar results were obtained from the reactions
of 2 with aniline 4entry 11) and p-toluidine 4g) 4entry 13)
under the same conditions.
The reactions of 2-methoxylapachol 2 with allylamine 4a),
benzylamine 4b), aminoethyl-2,2-dimethoxyacetal 4c) and
ethanolamine 4d), in ethanol 4or methanol),19 at room
temperature, for 24 h 4method A) provided the correspond-
ing substitution products 3a±d in 54, 59, 70 and 76% yields,
respectively 4entries 1, 3, 7 and 9 of Table 1), obtained as
red crystals after puri®cation. Tlc inspection of the reaction
mixtures containing 3a and b before puri®cation showed the
presence of a purple-colored side-product, identi®ed latter
as the corresponding cyclic products 4a and b 4see Scheme
1). Interestingly, the reaction of 2 with aniline 4e) proceeded
in re¯uxing EtOH to give, after 3 h, only the cyclic product
4e in 57% yield, with 80% conversion 4entry 10). Aniline
being less nucleophilic than the investigated alkylamines it
only reacts under forcing conditions and, in this case, we
believe that isomerization is thermally induced 4entry 10 of
Table 1). We have also investigated the reaction of 2 with
the more nucleophilic p-methoxyaniline 4f) 4entry 12, Table
1), in the expectation that an even higher yield of the corre-
sponding cyclized product 4f would be formed. The reaction
only gave 4f, although in 18% yield, after 10 min at 1208C
464% conversion based on recovered 2) and, after 30 min,
only a black tar was obtained. This low yield is probably the
The results of this work suggest therefore that the products
distribution depends upon the nucleophilic character of the
amine. In an attempt at improving the yields of the cyclic
products, the reactions were reinvestigated: solvent-free
mixtures of the appropriate primary amine and 2 were
mixed together at room temperature 4method B). The
reaction with allylamine resulted in 90% conversion, after
4 h, and led to an approximate product distribution of 4:1,
favoring the amino derivative 3a over the cyclic product 4a
4entry 2). In the case of the reaction with aminoethyl-2,2-
dimethoxyacetal, under the same conditions, an 80%
conversion factor was observed, with a 3c/4c product distri-
bution of 3:2 4entry 7);when this reaction was carried out at
80±1008C, however, an intractable tar was obtained from
which no products were identi®ed by tlc analysis. A slightly
different ratio 42:1) was encountered in the case of the room
temperature solvent free reaction of 2 with benzylamine,
which proceeded with an 82% conversion factor and also
favored substitution product 3b over cyclic product 4b
4entry 5). Although an improved conversion factor 489%)
Scheme 2.

Table 2. 1H NMR shift values for derivatives 3 and 4 4200 MHz, CDCl3)
dH 4na, mult., J)
3a
4a
3b
4b
3c
4c
3d
4e
4f
4g
1
2
3
4
5.33 4d, 1H, 9.5)
6.80 4d, 1H, 9.5)
5.39 4d, 1H, 9.4)
6.88 4d, 1H, 9.4)
5.37 4d, 1H, 9.4)
6.77 4d, 1H, 9.4)
5.49 4d, 1H, 9.4)
6.91 4d, 1H, 9.4)
5.38 4d, 1H, 9.5)
6.81 4d, 1H, 9.5)
5.37 4d, 1H, 9.3)
6.82 4d, 1H, 9.3)
4a
5
8.08 4dd, 1H, 7.7)
8.00 4d, 1H, 7.4)
8.07 4d, 1H, 7.4)
8.05 4d, 1H, 7.6)
5a
6
7
7.69 4m, 1H)
7.57 4m, 1H)
7.99 4d, 1H, 7.7)
8.05 4d, 1H, 7.5)
7.62 4m, 1H)
7.62 4m, 1H)
7.54 4m, 1H)
7.54 4m, 1H)
7.91 4d, 1H, 7.4)
8.05 4d, 1H, 7.6)
7.62 4m, 1H)
7.62 4m, 1H)
7.62 4m, 1H)
7.62 4m, 1H)
7.97 4d, 1H, 7.4)
8.05 4d, 1H, 7.6)
7.58 4m, 1H)
7.58 4m, 1H)
7.57 4m, 1H)
7.57 4m, 1H)
7.93 4d, 1H, 7.6)
8.07 4d, 1H, 7.8)
7.59 4m, 1H)
7.59 4m, 1H)
8.0 4d, 1H, 7)
7.55 4m, 1H)
7.45 4m, 1H)
8.0 4d, 1H, 7.5)
7.59 4m, 1H)
7.47 4m, 1H)
8
8a
9
7.90 4d, 1H, 7.4)
7.80 41, 1H, 7.4)
7.93 4d, 1H, 7.8)
7.76 4d, 1H, 7.6)
7.76 4d, 1H, 7.6)
7.71 4d, 1H, 7.5)
9a
10
10a
10
20
30
400
500
100
2
300
400
500
NH
1.69 4s, 3H)
1.40 4s, 3H)
1.40 4s, 3H)
1.54 4s, 3H)
1.35 4s, 3H)
1.35 4s, 3H)
1.70 4s, 3H)
1.24 4s, 3H)
1.24 4s, 3H)
1.68 4s, 3H)
1.32 4s, 6H)
1.21 4s, 6H)
1.21 4s, 6H)
5.09 4t, 1H, 6.2)
3.36 4d, 2H, 6.2)
1, 73 4s, 3H)
4.13 4m, 2H)
5.93 4m, 1H)
5.24 4m, 2H)
5.02 4m)
5.08 4t, 1H, 5.9)
3.36 42H)
1.76 4s, 3H)
3.68 4t, 1H, 5.2)
4.49 4t, 1H, 5.2)
3.41 4s, 6H)
5.07 4t, 1H, 5.9)
3.37 4d, 2H, 5.9)
1.74 4s, 3H)
3.71 4m, 2H)
3.85 4m, 2H)
2.3 4l, 1H)
3.26 4d, 2H, 5.7)
1.62 4s, 3H)
4.63 4s, 2H)
4.46 4d, 2H, 5.0)
6.06 4m, 1H)
5.18 4m, 2H)
5.18 4s, 2H)
4.06 4d, 2H, 5.1)
4.39 4t, 1H, 5.1)
3.33 4s, 6H)
7.37 4m, 2H)
7.20 4m, 2H)
7.37 4m, 1H)
6.80 4d, 2H, 4.5)
7.02 4d, 2H, 4.5)
6.99 4d, 2H, 6)
7.09 4d, 2H, 6)
7.24 4m)
7.24 4m)
7.24 4m)
5.85 4l, 1H)
7.25 4m)
7.25 4m)
7.25 4m)
3.78 4s, 3H)
2.32 4s, 3H)
5.85 4l, 1H)
5.78 4l, 1H)
6.01 4l, 1H)
a
n, number of protons.

9572
C. A. Camara et al. / Tetrahedron 57 72001) 9569±9574
Table 3. 13C NMR shift values for derivatives 3 and 4 450 MHz, CDCl3)
3a
4a
3b
4b
3c
4c
3d
4e
4f
4g
1
2
3
4
4a
5
5a
6
7
8
183.1
145.5
116.8
182.9
132.4
126.3
183.2
145.8
116.2
183.0
132.7
126.4
183.1
146.2
116.6
183.0
132.9
126.3
183.2
146.2
116.2
183.1
132.8
126.3
59.3
128.1
117.1
118.6
176.9
59.6
128.0
117.7
118.9
180.0
133.4
125.6
132.3
133.7
58.6
128.5
118.4
118.9
180.1
133.4
126.9
132.3
133.5
59.3
127.5
118.5
119.2
180.9
132.4
125.8
132.5
133.7
59.3
129.3
118.5
118.9
180.5
135.9
125.7
132.4
133.7
59.2
129.1
118.5
125.7
180.8
137.3
126.4
132.5
133.6
131.8
134.3
126.0
133.3
125.6
132.5
133.7
132.0
134.5
126.1
133.5
132.0
134.3
126.1
133.4
132.0
134.5
126.1
133.4
8a
9
126.3
132.3
183.3
145.4
28.0
126.9
133.1
183.0
145.5
27.9
126.3
n.v.
183.5
145.9
27.9
126.4
132.7
181.6
143.4
28.8
126.5
130.3
181.7
143.3
28.6
129.3
132.7
181.6
143.4
28.7
9a
10
10a
10
20
30
400
500
1
200
300
400
500
18.1
130.4
123.2
23.6
25.6
47.1
18.2
130.6
123.1
23.8
25.8
49.3
138.8
127.9
129.1
127.3
18.2
130.7
122.7
23.8
25.8
46.4
18.2
130.6
122.7
23.8
25.8
47.2
28.0
27.9
27.9
28.8
28.6
28.7
49.6
137.8
116.1
50.5
140.5
126.4
128.7
126.2
48.0
106.0
55.5
143.1
129.6
128.7
129.5
143.8
126.1
113.7
158.7
55.5
134.8
129.9
129.4
140.4
21.4
134.7
115.2
102.9
54.3
62.1
Multiplicities were determined by DEPT or PENDANT.
was observed when the reaction was carried out with an
excess benzylamine at 1008C, only the cyclic purple product
4b was obtained, in 49%, after 0.5 h 4entry 6). Table 1
summarizes the products and chemical yields obtained
from the above procedures.
of the hydroquinone intermediate by any quinone present in
the reaction mixture, as quinones are known oxidants.
Tables 2 and 3 summarize the NMR data for the derivatives
3 and 4, assigned on the basis of one and two-dimensional
NMR techniques 4HMBC and HMQC).
Formation of the cyclic products 4 was initially rationalized
in terms of a tautomerization7e of the amino derivatives 3,
followed by Michael addition, and then air oxidation, to
form the quinone product.13 To test this hypothesis,
compound 3b was left to react with one equivalent of
benzylamine under solvent-free conditions for several
hours;it was also heated under re¯ux in EtOH, but no cyclic
product 4b could be visualized by tlc inspection in either
case.
3. Conclusion
New 1-aza-anthraquinones were obtained from the reactions
of primary amines and methoxylapachol, which revealed an
entirely novel aspect of the chemistry of an abundant
naturally occurring naphthoquinone. Preliminary studies
involving solvent and temperature conditions led to reason-
able product selectivity. These reactions provide an entry
to novel compounds with structural features which are
attractive from the biological viewpoint.
Formation of 4 seems therefore to proceed by nucleophilic
attack of the amine at an extended Michael acceptor, formed
from the tautomerization of 2 that would result in 5 4Scheme
2). This compound, after air-oxidation, would undergo an
intramolecular cyclization, to result in the ®nal compound 4.
If the air-oxidation step is blocked, amines 3 would be
formed instead 4Scheme 2). This is in agreement with the
result of the reaction of 2 with benzylamine, quoted in entry
4 4Table 1), which was carried out under N2 and resulted
only in minute amounts of 4b. The formation of a small
amount of 4b in the absence of O2 can be due to oxidation
4. Experimental
4.1. General
Melting points are uncorrected and were determined on a
Thomas±Hoover capillary apparatus. Column chroma-
tography was performed on silica gel G60 470±230 mesh,

C. A. Camara et al. / Tetrahedron 57 72001) 9569±9574
9573
ASTM, Merck). Thin-layer chromatography was performed
on 0.2 mm plates 4Merck) and visualized with short-wave-
length UV light. 1H and 13C NMR spectra were recorded on
a Bruker ACF-200 or Bruker AMX-300 spectrometer.
Values reported for coupling constants are ®rst order.
High-resolution mass spectra were obtained by electron
impact 470 eV) on a VG Autospec spectrometer. Natural
241 430), 226 4100), 91 415), 77 414);Anal. found: C,
80.48;H, 6.19;N, 4.22;Calcd for C 22H21NO2: C, 79.76;
H, 6.34;N, 4.23.
4.2.4. 1-Benzyl-2,2-dimethyl-1,2,5,10-tetrahydrobenzo-
[g]quinoline-5,10-dione ,4b). Obtained as purple crystals,
mp 125±1278C;IR 4KBr) 4 n max., cm21) 1660, 1616, 1589,
1530;M/S 4rel int) m/z 329 4M1, 14), 314 4M215, 62), 225
458), 91 4100). HRMS found: 329.14158. Calcd for
C22H19NO2: 329.14157.
Lapachol
1
[2-hydroxy-3-43-methyl-2-butenyl)-1,4-di-
hydro-1,4-naphthalenedione] was extracted from the bark
of species of Tabebuia sp., by submitting wooden chips to
an aqueous sodium carbonate extraction 410% w/v),
followed by dilute hydrocloridric acid precipitation and
then, diethyl ether crystallization of 1, mp 137±98C 4lit.
1408C),21 in 1±2% yield from the bark and pure enough
for the next methylation step.
4.2.5. 2-,2,2-Dimethoxyethylamino)-3-,3-methyl-2-bu-
tenyl)-1,4-dihydro-1,4-naphthalenedione ,3c). Obtained
as red oil. IR 4KBr) 4n max., cm21) 3343, 1699, 1625,
1604, 1571;MS 4rel int) m/z 329 4M1, 2), 297 45), 282
420), 75 4100). HRMS found 329.16271. Calcd for
C19H23NO4 329.16270.
4.1.1. 2-Methoxylapachol ,2). Lapachol 1 4484 mg,
2 mmol) was added to a stirred mixture of potassium car-
bonate 41.38 g, 10 mmol) in acetone 450 ml) at room
temperature. Dimethyl sulfate 40.28 ml, 2.5 mmol) was
slowly added to the purple mixture with stirring. After
2 h, tlc inspection showed no 1 left in the reaction media.
The solvents were removed under vacuum, and solids were
extracted with ethyl acetate, washed with brine and then
with water and dried over anhydrous sodium sulfate. After
removal of solvents under vacuum the product 2 was
puri®ed by ¯ash chromatography with 99% hexanes/1%
ethyl acetate 485±89%) and crystallized from hexane/
CH2Cl2, as bright yellow needles 4450 mg, 88%): mp
438C 4lit. 548C);20 IR 4nujol) 1670, 1654.
4.2.6. 1-,2,2-Dimethoxyethyl)-2,2-dimethyl-1,2,5,10-tetra-
hydrobenzo[g]quinoline-5,10-dione ,4c). Obtained as a
purple oil. IR 4KBr) 4n max., cm21) 1668, 1626,
1593,1529;MS 4rel int) m/z 327 4M1, 3), 312 428), 75
4100). HRMS found: 327.14706. Calcd for C19H21NO4:
327.14705.
4.2.7. 2-,2-Hydroxyethylamino)-3-,3-methyl-2-butenyl)-
1,4-dihydro-1,4-naphthalenedione ,3d). Obtained as red
crystals, mp 80±818C;IR 4KBr) 4 n max., cm21) 3391,
3321, 1678, 1599, 1555, 1513;MS 4rel int) m/z 285 4M1,
57), 270 4100), 198 470). HRMS found: 285.13649. Calcd
for C17H19NO3: 285.13649.
4.2. Procedures for the reactions with amines
4.2.8. 2,2-Dimethyl-1-phenyl-1,2,5,10-tetrahydro-benzo-
[g]quinoline-5,10-dione ,4e). Obtained as purple crystals,
mp 145±68C;IR 4KBr) 4 n max., cm21) 1672, 1627, 1591,
1536;M/S 4rel int) m/z 315 4M1, 3), 300 4100), 77 47).
HRMS found: 315.12593. Calcd for C21H17NO2: 315.12592.
Method A. 1 mmol of 2-methoxylapachol 2 and 1.5 mmol of
the appropriate amine were mixed in a beaker with a pestle.
The reaction was followed by tlc and, after completion, the
mixture was submitted to ¯ash column chromatography on
silica gel and ethyl acetate/hexane 415:85 for a, b and e;1:9
for c;3:7 for d).
4.2.9. 2,2-Dimethyl-1-,4-methoxy)-phenyl-1,2,5,10-tetra-
hydro-benzo[g]quinoline-5,10-dione ,4f). Obtained as
purple crystals, mp 145±68C;IR 4KBr) 4 n max., cm21
)
Method B. 1 mmol of 2 in MeOH or EtOH 410 ml) was
slowly added to 1.5 mmol of the appropriate amine in the
same solvent 440 ml) with stirring. After reaction com-
pletion, the solvent was removed under vacuum and the
residue submitted to ¯ash chromatography on silica gel
and ethyl acetate/hexane 4as stated before).
1667, 1621, 1587, 1530;M/S 4rel int) m/z 4M1, 3), 330
4100). HRMS found: 345.1364. Calcd for C22H19NO3:
345.1365.
4.2.10. 2,2-Dimethyl-1-,4-methyl)-phenyl-1,2,5,10-tetra-
hydro-benzo[g]quinoline-5,10-dione ,4g). Obtained as a
purple oil. IR 4KBr) 4n max., cm21) 1670, 1626, 1598,
1540;M/S 4rel int) m/z 4M1, 5), 314 4100),. HRMS found:
329.14158. Calcd for C22H19NO2: 329.14157.
4.2.1. 2-Allylamino-3-,3-methyl-2-butenyl)-1,4-dihydro-
1,4-naphthalene-dione ,3a). Obtained as red crystals, mp
558C, IR 4nujol) 4n max., cm21) 3346, 1669;Anal. found: C,
77.04;H, 6.79;N, 4,74. Calcd for C 18H19NO2: C, 76.87;H,
6.76;N, 4.98.
4.3. Attempts to obtain 4b from 3b
Compound 3b 40.2 mmol) and excess benzylamine 41 ml) or
triethylamine 41 ml) were stirred at ambient temperature for
three days without any change, by inspection by tlc. The
mixture with excess benzylamine was also re¯uxed in
absolute ethanol for up to 24 h, and no trace of 4b could
be visualized by tlc inspection. In order to investigate the
proposal made by Weider and cols 4see Ref. 13), we
submitted the mixture of compound 3b 40.2 mmol) and
chloranil 4146.15 mg, 0.6 mmol) in toluene under N2 to a
36 h re¯ux period, and, among the various decomposition
4.2.2. 2,2-Dimethyl-1-,2-propenyl)-1,2,5,10-tetrahydro-
benzo[g]quinoline-5,10-dione ,4a). Purple crystals, mp
88±898C, IR 4KBr) 4n max., cm21) 1666, 1624, 1593;MS
4rel int) m/z 279 4M1, 10), 264 4100), 246 48), 224 424);
HRMS found: 279.12593. Calcd for C18H17NO2: 279.12592.
4.2.3.
2-Benzylamino-3-,3-methyl-2-butenyl)-1,4-di-
hydro-1,4-naphthalenedione ,3b). Orange crystals, mp
93±958C;IR 4KBr) 4 n max., cm21) 3296, 1677, 1618,
1568;MS 4rel int) m/z 331 4M1, 10), 275 46), 256 420),

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C. A. Camara et al. / Tetrahedron 57 72001) 9569±9574
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Acknowledgements
Â
cycles 1997, 45, 2431. 4b) Chaves, J. P.;Pinto, M. C. F. R.;
The authors thank FAPERJ, FAPESP, CNPq and FUJB for
®nancial support and Professor M. G. Carvalho 4ICE-
UFRRJ) for the use of facilities 4CAC).
Pinto, A. V. J. Braz. Chem. Soc. 1990, 1, 22.
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