The first synthesis of the pentacyclic pyridoacridine marine alkaloids: Arnoamines A and B

Article abstract of DOI:10.1021/jo000011a

The synthesis of the marine pyridoacridine alkaloids arnoamines A and B has been accomplished in six and seven steps from 4-chloro-8-methoxy-5-nitroquinoline in 13% and 4% overall yield, respectively.

Full text of DOI:10.1021/jo000011a

5476
J . Org. Chem. 2000, 65, 5476-5479
Th e F ir st Syn th esis of th e P en ta cyclic P yr id oa cr id in e Ma r in e
Alk a loid s: Ar n oa m in es A a n d B
Evelyne Delfourne,* Celine Roubin, and J ean Bastide
Centre de Phytopharmacie, UMRCNRS 5054 Universite de Perpignan, 52 avenue de Villeneuve,
66860 Perpignan Cedex, France
delfourn@univ-perp.fr
Received J anuary 6, 2000
The synthesis of the marine pyridoacridine alkaloids arnoamines A and B has been accomplished
in six and seven steps from 4-chloro-8-methoxy-5-nitroquinoline in 13% and 4% overall yield,
respectively.
Sch em e 1
The search for new pharmaceuticals from marine
environment has resulted in the isolation of an ever-
increasing number of alkaloids.1 Among them, the largest
group to have been characterized so far is based on the
pyrido[2,3,4-kl] acridine skeleton.2 These structurally
related polycyclic aromatic alkaloids show a broad range
of biological properties including tumor toxicity and
fungal growth inhibition.3
In 1998, Plubrukarn and Davidson4 reported the isola-
tion and structure elucidation of two new cytotoxic
metabolites: arnoamines A (1) and B (2) isolated from
the brownish purple ascidian Cystodytes sp. collected
near Arno Atoll (Republic of the Marshall Islands). These
are the first members of a new family of pentacyclic
pyridoacridine alkaloids that possess a pyrrole ring fused
to the pyridoacridine ring system.
In continuation of our work in this area,5 we now report
the first synthesis of the compounds (1) and (2).
Sch em e 2a
The retrosynthetic analysis shown in Scheme 1 is
derived from that developed by Dunn and McKillop for
the synthesis of norsegoline.6
The heart of our plan was the coupling of the quinoline
halide 5 with 2-fluorobenzene boronic acid via the Suzuki
reaction.7 The indole moiety was introduced by the
a
Key: (a) Meldrum acid, HC(OEt)3; (b) PhOPh, N2, reflux 40
min; (c) POCl3, PCl5, 85 °C, 1 h; (d) Tf2O, DMAP, 2,6-lutidine, 0
°C, 2 h.
Fischer method,8 the last cycle being formed according
to the procedure previously described by Smith and
Sawyer for the N-arylation of indoles.9
As starting material, the chloroquinoline 5 was ob-
tained in a three-step procedure from 2-methoxy-5-
nitroaniline via the Meldrum derivative 3 and the
quinolinone 4 with 52% overall yield. This new pathway
to obtain 5 constitutes an improvement of the synthesis
of this compound reported in the literature.10 The triflate
(1) Kobayashi, J .; Ishibashi, M.; In Alkaloids: Chemistry and
Pharmacology; Brossi, A., Cordell, G. A., Eds.; Academic Press: San
Diego, 1992; Vol. 41, pp 41-124.
(2) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(3) Ding, Q.; Chichak, K.; Lown, J . W. Current Med. Chem. 1999,
6, 1.
(4) Plubrukarn, A.; Davidson, B. S. J . Org. Chem. 1998, 63, 1657.
(5) (a) Bontemps, N.; Bonnard, I.; Banaigs, B.; Combaut, G.;
Francisco, C. Tetrahedron Lett. 1994, 35, 7023. (b) Bonnard, I.;
Bontemps, N.; Lahmy, S.; Banaigs, B.; Combaut, G.; Francisco, C.;
Colson, P.; Houssier, C.; Bailly, C.; Waring, M. J . Anticancer Drug
Design 1995, 10, 333. (c) Bontemps, N.; Delfourne, E.; Bastide, J .;
Francisco, C.; Bracher, F. Tetrahedron 1997, 53, 1743.
(6) Dunn, S. H.; McKillop, A. J . Chem. Soc., Perkin Trans. 1 1993,
879.
(8) Robinson, B. The Fisher Indole Synthesis; Wiley: New York,
1982.
(9) Smith III, W. J .; Sawyer, J . S. Tetrahedron Lett. 1996, 37, 299.
(10) Bordin, A. Ann. Chim. (Roma) 1967, 57, 347.
(7) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
10.1021/jo000011a CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/15/2000

Synthesis of Arnoamines A and B
J . Org. Chem., Vol. 65, No. 18, 2000 5477
Sch em e 3a
Sch em e 4a
a
Key: (a) 10% Pd/C, cyclohexene, EtOH, reflux, 15 min; (b)
NaNO2, 36% HCl, 0 °C, 15 min; (c) Na2S2O4, H2O/Et2O 1:1; (d)
methyl pyruvate, EtOH, 130 °C, 1 h.
a
Key: (a) ethyl-2-methyl-3-oxobutyrate, KOH, EtOH, H2O, 0
°C, overnight; (b) polyphosphoric acid, 100 °C, 6 h; (c) 37% KF/
Al2O3, cat. 18-crown-6, DMSO, 120 °C, 2 h; (d) 2 M NaOH, H2O,
EtOH, 2 h; (e) copper chromite, quinoline, 200 °C, 1 h; (f) BBr3,
CH2Cl2.
6 was obtained from the quinolinone 4. The Suzuki
reaction, which is formally a palladium-catalyzed cross-
coupling of organoboranes with organic electrophiles in
the presence of base, was applied both on the triflate 6
and the chloride 5 to produce the expected adduct 7 with
47 and 78% yield, respectively. This nitro compound 7
was reduced by catalytic hydrogenation (the hydrogen
donor being cyclohexene) to afford the amino derivative
8, which was transformed into its diazonium salt 9. Since
the Fisher indole synthesis involved the formation of an
arylhydrazone, we tried to reduce compound 9 into its
hydrazine derivative. However, when 9 was treated with
sodium dithionite, the tetracyclic hydrazine 10, which
corresponds to the cyclization of the expected hydrazine,
was obtained. Unfortunately, attempts to form the five-
membered ring by reaction of methyl pyruvate with
compound 10 failed. In that case, the sole product isolated
was the deaminated product 11. An alternative was the
conversion in 86% yield of the amino compound 8, via
its diazonium salt, into the hydrazone 12 by J app-
Klingemann reaction.11 The cyclization of 12 to the indole
13 was accomplished in polyphosphoric acid. The forma-
tion of the last pyridine ring was performed in the
presence of 37% KF/Al2O3 and catalytic 18-crown-6 in
DMSO at 120 °C as previously described by Smith and
Sawyer in 57% yield.9 The ester 14 was hydrolyzed in 2
N sodium hydroxide at reflux. The sodium salt obtained
was then decarboxylated by copper chromite in quinoline
to give quantitatively arnoamine B. This alkaloid was
finally demethylated by boron tribromide to yield the
second natural product arnoamine A.
methyl-4,6-dioxo-1,3-dioxane (10.4 g, 72.2 mmol) in triethyl
orthoformate (91 mL) was refluxed for 2 h, and 2-methoxy-5-
nitroaniline (10 g, 59.5 mmol) was added. Filtration of the
reaction mixture afforded a yellow solid: mp 230 °C (17 g, 89%
yield); 1H NMR (CDCl3) 1.75 (6H, s), 4.09 (3H, s), 7.01 (1H, d,
J ) 8.8 Hz), 8.09 (1H, dd, J ) 8.8, 2.4 Hz), 8,19 (1H, d, J )
2.4 Hz), 8.66 (1H, d, J ) 14.4 Hz), 11.55 (1H, d, J ) 14.4 Hz),
13C NMR (CDCl3) 27.13, 57.05, 89.25, 105.42, 110.83, 111.07,
122.45, 127.82, 141.79, 150.88, 153.77, 163.15, 165.15, IR
(CHCl3) 3300, 1729, 1684 cm-1
.
8-Meth oxy-5-n itr oqu in olin -4-on e (4). The Meldrum de-
rivative 3 (10 g, 31.1 mmol) in diphenyl ether (500 mL) was
refluxed under nitrogen for 40 min. After the mixture was
cooled to room temperature, petroleum ether (700 mL) was
added. Filtration of the reaction mixture afforded the expected
quinolone as a green brown solid: mp 212 °C (5.9 g, 86% yield);
1H NMR (DMSO-d6) 4.06 (3H, s), 6.13 (1H, d, J ) 7.4 Hz),
7.29 (1H, d, J ) 8.4 Hz), 7.51 (1H, d, J ) 8.4 Hz), 7.84 (1H, d,
J ) 7.4 Hz); 13C NMR (DMSO-d6) 56.86, 109.66, 110.81, 116.95,
117.90, 131.28, 139.32, 141.29, 149.98, 173.57.
4-Ch lor o-8-m eth oxy-5-n itr oqu in olin e (5). To a solution
of phosphorus pentachloride (176 mg, 0.8 mmol) in phosphorus
oxychloride (32 mL) was added the quinolinone 4 (8 g, 36.4
mmol), and the resulting mixture was warmed at 85 °C for 1
h. After cooling to room temperature and evaporation under
reduced pressure to remove POCl3, a saturated sodium car-
bonate solution was added. The reaction mixture was extracted
with CH2Cl2. The organic extracts were dried over MgSO4 and
evaporated. Purification of the crude product on a silica gel
chromatography column (CH2Cl2) afforded 5 as a clear brown
1
solid: mp 191 °C (lit.10 mp 189-191 °C) (3.5 g, 68% yield); H
The spectroscopic data obtained in the same solvent
conditions for 1 and 2 were identical to the values
reported for the natural products arnoamines A and B.
NMR (DMSO-d6) 4.16 (3H, s), 7.05 (1H, d, J ) 8.8 Hz), 7.68
(1H, d, J ) 4.4 Hz), 7.87 (1H, d, J ) 8.8 Hz), 8.88 (1H, d, J )
4.4 Hz); 13C NMR (CDCl3) 57.26, 106.26, 120.16, 125.59,
126.05, 140.00, 140.26, 140.43, 150.04, 158.69; IR (KBr) 1531,
1500, 1360 cm-1
.
Exp er im en ta l Section
8-Meth oxy-5-n itr o-4-qu in olin yl Tr iflu or om eth a n esu l-
fon a te (6). To a solution of quinolone 4 (9.71 g, 44.1 mmol) in
CH2Cl2 (466 mL) were successively added, at 0 °C under
nitrogen atmosphere, 4-(dimethylamino)pyridine (0.81 g, 6.7
mmol), 2,6-lutidine (5.8 mL, 54.2 mmol) and trifluoromethane
sulfonic anhydride (8.2 mL, 46.1 mmol). After being stirred
for 2 h at 0 °C and then 1 h at room temperature, the reaction
mixture was washed with water, dried over MgSO4 and
concentrated under reduced pressure. Purification of the crude
product by flash chromatography (CH2Cl2) gave the expected
triflate as a brown oil (1.6 g, 50% yield): 1H NMR (CDCl3)
Gen er a l P r oced u r es. All commercial chemicals were used
without further purification. Flash chromatography was per-
formed on flash silica gel 60 (Merck 0.015-0.040 mm). Nuclear
magnetic resonance spectra were recorded at 400 MHz for 1H
and 100 MHz for 13C.
5-[(2′-Met h oxy-5′-n it r op h en yla m in o)m et h ylen e]-2,2-
d im et h yl-4,6-d ioxo-1,3-d ioxa n e (3). A solution of 2,2-di-
(11) Zhang, Z.; Tillekaratne, L. M. V.; Hudson, R. A. Synthesis 1996,
377.

5478 J . Org. Chem., Vol. 65, No. 18, 2000
Delfourne et al.
4.12 (3H, s), 7.12 (1H, d, J ) 8.8 Hz), 7.68 (1H, d, J ) 5.2 Hz),
8.03 (1H, d, J ) 8.8 Hz), 9.08 (1H, d, J ) 5.2 Hz); 13C NMR
(CDCl3) 57.10, 106.72, 114.60, 114.87, 118.29 (q, J ) 320 Hz),
126.54, 137.97, 141.92, 150.12, 150.85, 158.56; IR (KBr) 1601,
(1H, ddd, J ) 7, 7, 1.5 Hz), 7.42 (1H, d, J ) 5 Hz), 7.93 (1H,
d, J ) 7.4 Hz), 8.48 (1H, d, J ) 5. Hz); 13C NMR (DMSO-d6)
56.25, 101.87, 107.09, 112.67, 115.06, 115.42, 119.30, 120.04,
124.22, 132.06, 132.13, 140.13, 140.29, 140.44, 145.10, 150.42;
IR (KBr) 3336, 1628, 1591, 1457, 1358 cm-1; EIMS m/z
(relative intensity) 248 (81), 247 (100), 233 (38), 219 (33). Anal.
Calcd for C16H12N2O, 1 CH2Cl2: C, 61.26; H, 4.20; N, 8.41.
Found: C, 61.03; H, 4.20; N, 8.21.
1534, 1346 cm-1
.
8-Meth oxy-5-n itr o-4-(2′-flu or op h en yl)qu in olin e (7). To
a solution of 2 M K2CO3 (14 mL), EtOH (7 mL), and deoxy-
genated toluene (135 mL) were added chloride 5 (3.2 g, 13.4
mL) and 2-fluorobenzene boronic acid (1.9 g, 13.4 mmol). The
mixture was stirred under nitrogen pressure, at room tem-
perature, for 30 min, and tetrakis(triphenylphosphine)pal-
ladium (471 mg, 0.402 mmol) was added. The reaction mixture
was refluxed overnight. After cooling, the precipitate was
washed with toluene. The filtrate was dried over MgSO4 and
concentrated under reduced pressure. The crude product was
purified by flash chromatography (CH2Cl2) to give 7 as a
yellow-orange solid: mp 215 °C (3.1 g, 78% yield); 1H NMR
(CDCl3) 4.15 (3H, s), 7.04 (1H, d, J ) 8.8 Hz), 7.18 (3H, m),
7.40 (1H, m), 7.57 (1H, d, J ) 4.4 Hz), 7.99 (1H, d, J ) 8.8
Hz), 9.05 (1H, d, J ) 4.4 Hz); 13C NMR (CDCl3) 56.84, 105.07,
115.97 (d, J ) 21.4 Hz), 120.71, 124.34, 125.88, 126.21 (d, J )
16 Hz), 126.84, 129.50, 130.75, 140.29, 140.60, 141.05, 149.56,
Eth yl 2-[N-[8-Meth oxy-4-(2′-flu or op h en yl)qu in olin -5-
yl]h yd r a zon o]p r op ion a te (12). To a well-stirred suspension
of amino derivative 8 (0.5 g, 1.87 mmol) in 4 M HCl solution
(2.5 mL, 9.35 mmol) was slowly added a solution of NaNO2
(0.131 g, 1.87 mmol) in water (0.4 mL). After being stirred, at
0 °C, for 30 min, the resulting diazonium salt solution was
added into a vigorously stirred mixture of ethyl-2-methyl-3-
oxobutyrate (90%, 0.3 g, 1.87 mmol), EtOH (2.4 mL), KOH
(0.56 g, 10.1 mmol), NaOAc (0.56 g), and H2O (3.5 mL)
maintained at 0 °C. The mixture was stirred continuously at
0 °C for 1 h. The precipitate was collected by filtration and
washed with water to obtain 12 as a bright yellow solid: mp
64 °C (0.612 g, 86% yield); 1H NMR (CDCl3) 1.22 (3H, s), 1.34
(3H, t, J ) 7.3 Hz), 4.11 (3H, s), 4.26 (2H, q, J ) 7.3 Hz), 7.14
(1H, d, J ) 8.8 Hz), 7.22 (1H, d, J ) 4.4 Hz), 7.24 (1H, d, J )
7.4 Hz), 7.33 (1H, ddd, J ) 7.4, 7.4, 1.1 Hz), 7.43 (1H, ddd, J
) 7.4, 7.4, 1.8 Hz), 7.47 (1H, bs), 7.51 (2H, m), 7.71 (1H, d, J
) 8.8 Hz); 13C NMR (CDCl3) 9.21, 14.31, 56.21, 61.18, 108.66,
113.25, 116.55 (d, J ) 21 Hz), 117.80, 124.23, 124.98, 127,
130.64, 131.26, 132.55 (d, J ) 40 Hz), 138.85, 140.63, 147.87,
151.32, 159.19 (d, J ) 227 Hz), 165.38, 175.14; IR (CHCl3)
3370, 1700, 1613, 1559, 1490 cm-1; EIMS m/z (relative
158.53 (d, J ) 245 Hz),159.22; IR (KBr) 1614, 1517, 1342 cm-1
;
EIMS m/z (relative intensity) 298 (19), 297 (16), 252 (68), 251
(80), 222 (83), 221 (100). Anal. Calcd for C16H11FN2O3: C, 64.43;
H, 3.69; N, 9.40. Found: C, 64.19; H, 3.60; N, 9.36.
8-Met h oxy-5-a m in o-4-(2′-flu or op h en yl)q u in olin e (8).
To a suspension of the nitro derivative 7 (1.45 g, 4.87 mmol)
and 10% Pd/C (2.68 g) in absolute EtOH (67 mL) was added
cyclohexene (3 mL). The reaction mixture was refluxed for 45
min. After evaporation, the crude product was purified by flash
chromatography to yield the amino derivative as a yellow-
intensity) 381 (100), 247 (91), 218 (39). Anal. Calcd for C21H20
-
FN3O3: C, 66.14; H, 5.25; N, 11.02. Found: C, 66.10; H, 5.45;
N, 10.68.
1
brown solid: mp 191 °C (0.85 g, 65% yield); H NMR (CDCl3)
4.04 (3H, s), 6.66 (1H, d J ) 8.2 Hz), 6.95 (1H, d ) 8.2 Hz),
7.17 (1H, d, J ) 4.2 Hz), 7.20 (1H, dd, J ) 8.8 Hz; 0.7 Hz),
7.26 (1H, dd, J ) 7.4, 1.1 Hz), 7.38 (1H, dd, J ) 7.4 Hz; 1.8
Hz), 7.48 (1H, m), 8.9 (1H, d, J ) 4.2 Hz); 13C NMR (CDCl3)
56.20, 108.79, 111.52, 115.9 (d, J ) 21.4 Hz), 118.13, 123.30,
124.11, 128.40 (d, J ) 18 Hz), 130.36, 130.67, 136.32, 140.41,
141, 147.94, 148.94, 159.2 (d, J ) 240 Hz); IR (CHCl3) 3468,
3362, 1611, 1474, 1277 cm-1; EIMS m/z (relative intensity) 268
(100), 267 (91), 239 (26), 218 (38). Anal. Calcd for C16H13FN2O:
C,71.64; H,4.85; N,10.45. Found: C, 71.85; H, 5.09; N, 10.47.
7-Am in o-4-m et h oxy-7H -p yr id o[2,3,4-k l]a cr id in e (10).
To a solution of amino derivative 8 (100 mg, 0.4 mmol) in water
(1 mL) were added, at 0 °C, 36% HCl (51 µL) and a solution of
sodium nitrite (27 mg, 0.4 mmol) in water (70 µL). The reaction
mixture was stirred for 15 min and then was added to a
solution of Na2S2O4 in water/ether (2 mL/2 mL) before being
stirred for an additional 30 min. NaOH (1 N) was added until
basic pH and the etheral phase was decanted. The aqueous
phase was extracted with CH2Cl2, and the organic layers were
dried over MgSO4 and concentrated. Purification of the crude
product by flash chromatography gave compound 10 as an
orange solid: mp 244 °C (35 mg, 33% yield); 1H NMR (DMSO-
d6) 3.88 (3H, s), 5.74 (2H, s), 6.98 (1H, dd, J ) 7.8, 7.8 Hz),
7.04 (1H, d, J ) 8.4 Hz), 7.21 (1H, d, J ) 8.4 Hz), 7.45 (1H,
dd, J ) 7.8, 7.8 Hz), 7.56 (1H, d, J ) 5.2 Hz), 7.74 (1H, d, J )
Eth yl 9-(2′-Flu or oph en yl)-5-m eth oxypyr r olo[2,3-f]qu in -
olin e-2-ca r boxyla te (13). A mixture of ester derivative 12
(200 mg, 0.53 mmol) and polyphosphoric acid (1.3 g) in toluene
(2.5 mL) was warmed at 100 °C for 6 h. After cooling, water
was added until complete dissolution. The reaction mixture
was extracted with CH2Cl2, and the organic layers were dried
over MgSO4 and concentrated under reduced pressure. Puri-
fication of the crude product by flash chromatography (CH2-
Cl2) afforded the indolic compound 13 as a yellow solid: mp
105 °C (110 mg, 58% yield); 1H NMR (CDCl3) 1.31 (3H, t, J )
7.3 Hz), 4.13 (3H, s), 4.23 (2H, q, J ) 7.3 Hz), 7.16 (1H, d, J )
2.2 Hz), 7.25 (1H, s), 7.37 (1H, d, J ) 8.4 Hz), 7.41 (1H, d, J
) 4.4 Hz), 7.45 (1H, m), 7.47 (1H, ddd, J ) 7.7, 7, 2.2 Hz),
7.67 (1H, m), 8.15 (1H, bs), 9.02 (1H, d, J ) 4.4 Hz); 13C NMR
(CDCl3) 14.19, 56.06, 60.65, 101.71, 108.46, 116.72 (d, J ) 15
Hz), 117.02, 122.85, 124.25, 125.20 (d, J ) 3.8 Hz), 125.63,
126.41, 126.58, 130.51, 132.16, 138.24, 141.28, 147.12, 150.80,
159.27 (d, J ) 300 Hz), 160.25; IR (CHCl3) 3449, 1700, 1613,
1330 cm-1; EIMS m/z (relative intensity) 364 (100), 363 (95),
317 (62), 316 (61), 288 (25). Anal. Calcd for C21H17FN2O3: C,
69.23; H, 4.67; N, 7.69. Found: C, 69.13; H, 4.71; N, 7.77.
Eth yl 4-Meth oxyp yr id o[4,3,2-m n ]p yr r olo[3,2,1-d e]a cr i-
d in e-1-ca r boxyla te (14). The indole derivative 13 (50 mg,
0.137 mmol) in DMSO (0.5 mL) was heated at 120 °C for 2 h,
in the presence of 18-crown-6 (4 mg, 0.0137 mmol) and 37%
potassium fluoride absorbed onto basic alumina (1 weight
equivalent based on the indole, 50 mg). The reaction mixture
was filtered and partitioned between water and CH2Cl2. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2) to give the pentacyclic derivative as
a yellow solid: mp 179 °C (141 mg, 57% yield); 1H NMR (CDCl3)
1.50 (3H, t, J ) 7.3 Hz), 4.19 (3H, s), 4.52 (2H, q, J ) 7.3 Hz),
7.43 (1H, s), 7.56 (1H, dd, J ) 8.8, 7 Hz), 7.75 (1H, dd, J ) 7,
8.1 Hz), 7.91 (1H, s), 8.13 (1H, d, J ) 5.1 Hz), 8.54 (1H, d, J
) 8.1 Hz), 9.03 (1H, d, J ) 8.8 Hz), 9.17 (1H, d, J ) 5.1 Hz);
13C NMR (CDCl3) 14.41, 56.04, 61.26, 101.01, 110.92, 114.02,
115.15, 118.02, 120.21, 120.81, 124.61, 124.84, 125.10, 126.14,
130.49, 133.28, 135.40, 140.49, 148.17, 150.96, 162.11; IR
(CHCl3) 1700, 1507, 1428 cm-1; EIMS m/z (relative intensity)
344 (56), 343 (100), 342 (72), 315 (14), 314 (17), 242 (10), 241
7.8 Hz), 8.04 (1H, d, J ) 7.8 Hz), 8.55 (1H, d, J ) 5.2 Hz); 13
C
NMR (DMSO-d6) 56.05, 101.15, 107.60, 111.39, 114.26, 115.88,
119.30, 119.97, 123.82, 131.80, 134.91, 138.36, 140.70, 143.14,
146.30, 150.25; IR (KBr) 3418, 3299, 3138, 1534, 1359 cm-1
;
EIMS m/z (relative intensity) 263 (71), 247 (100), 218 (61).
Anal. Calcd for C16H13N3O: C, 73.00; H, 4.94; N, 15.97.
Found: C, 72.92; H, 4.87; N, 15.92.
4-Meth oxy-7H-p yr id o[2,3,4-kl]a cr id in e (11). Hydrazine
derivative 10 (263 mg, 1 mmol) was dissolved in ethanol (5
mL). Methyl pyruvate (110 mg, 1.07 mmol) was added, and
the resulting solution was stirred for 1 h. The solution was
concentrated under reduced pressure. The crude product was
heated at 130 °C under reduced pressure (20 mmHg) for 1 h.
Purification by flash chromatography (CH2Cl2/MeOH 95:5)
gave 11: mp > 260 °C (65 mg, 26%); 1H NMR (DMSO-d6) 3.84
(s, 3H), 6.58 (1H, d, J ) 8.4 Hz), 6.91 (1H, dd, J ) 7.8, 7.8
Hz), 6.94 (1H, d, J ) 8.4 Hz), 7.10 (1H, d, J ) 8.8 Hz), 7.33

Synthesis of Arnoamines A and B
J . Org. Chem., Vol. 65, No. 18, 2000 5479
(15). Anal. Calcd for C21H16N2O3: C, 73.26; H, 4.65; N, 8.14.
Found: C, 73.01; H, 4.29; N, 7.98.
(1H, d, J ) 8.4 Hz), 8.51 (1H, d, J ) 6 Hz), 8.57 (1H, d, J )
3.3 Hz), 8.78 (1H, d, J ) 8.1 Hz), 9.05 (bd, 1H); 13C NMR
(CDCl3) 56.34, 102.52, 107.33, 110.79, 114.16, 115.24, 116.79,
117.11, 120.31, 121.75, 124.06, 125.75, 131.09, 132.85, 134.85,
138.96, 147.43, 150.53; IR (film) 1610, 1471, 1359 cm-1; EIMS
m/z (relative intensity) 272 (55), 271 (100), 270 (34), 242 (77),
229 (38). Anal. Calcd for C18H12N2O (1.25 CH2Cl2): C, 61.07;
H, 3.83; N, 7.40. Found: C, 61.33; H, 3.70; N, 7.74.
4-Met h oxyp yr id o[4,3,2-m n ]p yr r olo[3,2,1-d e]a cr id in e-
1-ca r boxyla te, Sod iu m Sa lt (15). A suspension of ester 14
(17 mg, 0.049 mmol) in 2 M NaOH (0.12 mL), and MeOH (2
mL) was refluxed for 2 h. CH2Cl2 (20 mL) was added, and the
mixture was filtered to yield the expected salt as a yellow solid:
mp > 260 °C (14 mg, 91% yield); 1H NMR (DMSO-d6) 3.31
(3H, s), 7.19 (1H, s), 7.53 (1H, dd, J ) 7, 8.1 Hz), 7.65 (1H, s),
7.73 (1H, dd, J ) 7, 8.8 Hz), 8.34 (1H, d, J ) 5.1 Hz), 8.72
(1H, d, J ) 8.1 Hz), 8.98 (1H, d, J ) 5.1 Hz), 9.41 (1H, d, J )
8.8 Hz); 13C NMR (DMSO-d6) 56.09, 103.55, 108.42, 110.51,
113.99, 115.66, 120.45, 120.95, 121.44, 123.73, 125.20, 130.33,
132.36, 135.84, 138.06, 139.45, 146.27, 149.62, 164.79; IR (KBr)
1582, 1502, 1435 cm-1. Anal. Calcd for C19H11N2O3Na, (0.75
CH2Cl2), C, 58.99; H, 3.11; N, 6.97. Found: C, 59.02; H, 3.48;
N, 7.24.
4-Hydr oxypyr ido[4,3,2-mn ]pyr r olo[3,2,1-de]acr idin e: Ar -
n oa m in e A (1). To arnoamine B (2) (10 mg, 0.037 mmol) was
added a solution of BBr3 (1 M/CH2Cl2, 2 mL) under a dry
nitrogen atmosphere. After 24 h, aqueous solution of NaHCO3
(1 M, 5 mL) was added and extracted with CH2Cl2 (3 × 10
mL), dried (MgSO4), and concentrated. Purification of the
crude product by flash chromatography gave 1 as a yellow
1
solid: mp 176 °C (3 mg, 0.012 mmol, 30%); H NMR (CDCl3)
7.21 (1H, d, J ) 3 Hz), 7.52 (1H, ddd, J ) 8.4, 7.0, 1.5 Hz),
7.72 (1H, s), 7.78 (1H, ddd, J ) 8.4, 7.0, 1.5 Hz), 8.06 (1H, d,
J ) 5.1 Hz), 8.08 (1H, dd, J ) 8.4, 1.5 Hz), 8.19 (1H, d, J )
4-Met h oxyp yr id o[4,3,2-m n ]p yr r olo[3,2,1-d e]a cr id in e:
Ar n oa m in e B (2). A suspension of sodium salt 15 (5 mg, 0.015
mmol) and copper chromite (5 mg) in quinoline (0.5 mL) was
heated at 200 °C for 1 h. Water (3 mL) was added, and the
mixture was extracted with CH2Cl2. The organic layers were
dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by flash chromatography (CH2-
Cl2/MeOH 99:1) to give quantitatively the expected alkaloid 2
1
3.0 Hz), 8.54 (1H, dd, J ) 8.4, 1.5 Hz), 9.01 (1H, d, 5 Hz); H
NMR (CDCl3 + TFA) 7.59 (1H, d, J ) 3.3 Hz), 7.83 (1H, dd, J
) 8.1, 7.0 Hz), 8.15 (1H, dd, J ) 8.4, 7.0 Hz), 8.31 (1H, s), 8.36
(1H, d, J ) 8.4 Hz), 8.42 (1H, d, J ) 6.6 Hz), 8.57 (1H, d, J )
3.3 Hz), 8.75 (1H, d, J ) 8.1 Hz), 8.93 (1H, d, J ) 6.6 Hz); 13
C
NMR (CDCl3) 103.98, 108.01, 110.77, 113.04, 115.25, 115.65,
117.32, 119.12, 121.12, 123.93, 126.06, 126.1, 126.7, 130.86,
131.37, 146.44, 148.44; IR (CHCl3) 1611, 1509, 1472, 1446,
1263 cm-1; EIMS m/z (relative intensity) 258 (94), 229 (30),
202 (3). Anal. Calcd for C17H10N2O (0.5 CH2Cl2): C, 69.90; H,
3.66; N, 9.31. Found: C, 69.77; H, 3.84; N, 9.13.
1
as a yellow solid: mp 180 °C; H NMR (CDCl3) 4.20 (3H, s),
7.16 (1H, d, J ) 2.9 Hz), 7.49 (1H, dd, J ) 7.0, 7.3 Hz), 7.55
(s, 1H), 7.74 (1H, dd, J ) 7.3, 8.0 Hz), 8.00 (1H, d, J ) 8.0
Hz), 8.04 (1H, d, J ) 4.8 Hz), 8.12 (1H, d, J ) 2.9 Hz), 8.48
(1H, d, J ) 7.0 Hz), 9.13 (1H, d, J ) 4.8 Hz); 1H NMR (CDCl3
+ TFA) 4.27 (3H, s), 7.59 (1H, d, J ) 3.3 Hz), 7.83 (1H, dd, J
) 8.1, 7.3 Hz), 8.14 (1H, dd, J ) 7.3, 8.4 Hz), 8.16 (1H, s), 8.35
J O000011A