Synthesis of the indole alkaloids meridianins from the tunicate Aplidium meridianum

Article abstract of DOI:10.1016/S0040-4020(01)00102-8

The marine natural products meridianins A and C-E have been synthesized for the first time starting from the appropriate N-tosyl-3-acetylindole. A facile two-step conversion of N-tosyl-3-acetylindoles to the corresponding meridianins by treatment with dimethylformamide dimethylacetal and further cyclization of the resulting enaminone with aminoguanidine is described. This method has also been applied for the preparation of the 3-[(2-amino)pyrimidin-4-yl]-7-azaindole.

Full text of DOI:10.1016/S0040-4020(01)00102-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2355±2363
Synthesis of the indole alkaloids meridianins from the tunicate
Aplidium meridianum
Pilar M. Fresneda,p Pedro Molinap and Juan A. Bleda
  Â
Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo, E-30071 Murcia, Spain
Received 27 November 2000; revised 16 January 2001; accepted 19 January 2001
AbstractÐThe marine natural products meridianins A and C±E have been synthesized for the ®rst time starting from the appropriate
N-tosyl-3-acetylindole. A facile two-step conversion of N-tosyl-3-acetylindoles to the corresponding meridianins by treatment with
dimethylformamide dimethylacetal and further cyclization of the resulting enaminone with aminoguanidine is described. This method
has also been applied for the preparation of the 3-[(2-amino)pyrimidin-4-yl]-7-azaindole. q 2001 Elsevier Science Ltd. All rights reserved.
A variety of biologically active metabolites containing the
indole ring have been identi®ed from marine organisms.1
Among these, 3-substituted indoles represent an emerging
structural class of marine alkaloids based upon their high
degree of biological activity. The substituent at 3-position of
the indole ring is often an additional heterocyclic ring:
imidazole (nortopsentins2 and topsentins3); dihydroimida-
zole (discodermindole4); maleimide (didemidines5);
oxazole (martefragin,6 amazol7); oxadiazine (alboinon8);
and piperazine (dragmacidon9). Recently, ®ve new indole
alkaloids, meridianins10 A±E have been isolated from the
tunicate Aplidium meridianum. These alkaloids, which
show cytotoxicity towards murine tumor cell lines, have a
brominated and/or hydroxylated indole nucleus with a
pyrimidine ring as substituent at 3-position. Meridianins
can also be considered as guanidine-based alkaloids in
which the guanidine moiety is found in the guise of a
2-aminopyrimidine ring.
In connection with our effort on the synthesis of non-
traditional guanidine-based alkaloids from marine origin,11
we became interested in the synthesis of the family of
meridianins because of its pharmacological potential as
well as its structural similarity with the alkaloids variolins12
isolated from the Antarctic sponge Kirkpratickia varialosa
which display antitumor and antiviral activity.
In general, previous syntheses of 3-heteroarylindoles
involve coupling of an appropriately functionalized
3-substituted indole with a preformed heterocyclic ring. In
this context, 3-iodoindoles13 or 3-indolyltri¯ates14 and 3-in-
dole boronic acids,15 3-indolylzinc derivatives16 and 3-tri-
butylstannylindoles17 have been employed as indole
components in the palladium (0)-catalyzed Stille and Suzuki
reactions.
Here we report our effort resulting in a convenient total
synthesis of meridianins. In our approach the acetyl side
chain at the indole 3-position has been used a C2 moiety
for the construction of the 2-aminopyrimidine ring.
1. Results
The starting material required for the synthesis of the hydro-
xylated meridianins A and E was the previously unreported
4-benzyloxy-7-bromoindole 1a. This compound was
prepared from the commercially available 5-bromo-2-
hydroxybenzaldehyde by the following ®ve-step sequence:
(a) O-benzyl protection with benzyl bromide in the presence
Keywords: marine metabolites; indoles; pyrimidines; acylation; cyclization.
Corresponding authors. Tel.: 134-968-36-74-96; fax: 134-968-36-41-
49; e-mail: fresnada@fcu.um.es; Tel.: 134-968-36-74-96; fax: 134-
968-36-41-49; e-mail: pmolina@um.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00102-8

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P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
Scheme 1. Reagents and conditions: (a) (i) NaH, DMF, 08C, (ii) Ph-CH2Br (100%); (b) N3CH2COOEt, EtONa, EtOH, 2158C (75%); (c) toluene, re¯ux
(92%); (d) LiOH; THF/H2O (99%); (e) quinoline, copper, 2358C (72%).
of NaH (100%); (b) condensation with ethyl azidoacetate in
the presence of NaOEt at 2158C (75%); (c) indolization of
the resulting ethyl a-azido-b-aryl propenoate by heating in
toluene at re¯ux temperature (92%); (d) hydrolysis of the
ester group of the 2-ethoxycarbonyl indole derivative with
LiOH/THF/H2O (99%) and (e) decarboxylation by heating
at 2308C in quinoline in the presence of copper (72%).
(Scheme 1)
indole in very poor yield. Things got even worse when the
subsequent acylation also proceeded in poor yield, and the
desired substrate 3a was never obtained. However, all was
not lost, simply by changing the reaction sequence
compound 3a was obtained in fair yield. Indole 1a reacted
with acetyl chloride in the presence of tin (IV) tetrachloride
in benzene at re¯ux temperature to give the 3-acetylindole
2a in 89% yield. N-protection with p-toluenesulfonyl
chloride proceeded without incident to give the required
N-tosyl-3-acetylindole 3a in 55% yield.
The N-tosyl-3-acylindole 3a was used for the construction
of 2-aminopyrimidine ring. The ®rst attempt, however, to
prepare 3a was very disappointing. The reaction of indole
1a with p-toluenesulfonyl chloride provided the N-tosyl-
The Bredereck protocol18 was used for the formation of the
2-aminopyrimidine ring. When compound 3a was submitted
Scheme 2. Reagents and conditions: (a) CH3COCl, SnCl4, C6H6; (b) p-toluenesulfonyl chloride, NaH, DMF; (c) DMF-DMA, DMF, 1108C;
(d) H2N(vNH)NH2.HCl, K2CO3, 2-methoxyethanol, re¯ux (e) H2, 10% Pd/C, EtOAc; (f) CF3±COOH, thioanisole, rt.

P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
2357
Scheme 3. Reagents and conditions: (a) p-toluenesulfonyl chloride, NaH, DMF; (b) Ac2O, AlCl3, CH2Cl2; (c) CH3±COCl, SnCl4, C6H6; (d) DMF-DMA,
DMF, 1108C; (e) H2N(vNH)NH2.HCl, K2CO3, 2-methoxyethanol, re¯ux.
to react with dimethylformamide dimethylacetal in DMF at
1108C the enaminone 4a was obtained in 45% yield.
Pyrimido annelation and the unexpectly N-tosyl deprotec-
tion to give 5 took place in 82% yield by treatment of 4a
with guanidine hydrochloride in 2-methoxyethanol in the
presence of anhydrous potassium carbonate.
and 2c in 46±65% yield and N-protection to give 3b and
3c, respectively, was achieved in 90±87% yield.
When compounds 3b and 3c were treated with dimethyl-
formamide dimethylacetal in DMF at 1108C the correspond-
ing enaminones 4b and 4c were obtained in yields ranging
from 82 to 83%. Direct conversion of 4b and 4c into
meridianin C and meridianin D, which involves formation
of the 2-aminopyrimidine ring and N-tosyl deprotection,
was achieved in 72±78% by treatment with guanidine
hydrochloride in the presence of anhydrous potassium
carbonate (Scheme 3).
The hydroxylated meridianin A was obtained in 83% yield
from compound 5 by hydrogenation in ethyl acetate at room
temperature under normal pressure using 10% palladium on
charcoal as catalyst. The transformation of 5 to meridianin E
required the selective deprotection of the O-benzyl group in
the presence of the bromo substituent at the indole ring. This
was achieved in a yield of 65% by treatment with tri¯uoro-
acetic acid in the presence of an excess of thioanisole19 at
room temperature (Scheme 2).
With these results in hand, the 7-azaindole was employed
for the preparation of the 3-[(2-amino)pyrimidin-4-yl]-7-
azaindole 10 present in the backbone of the marine alkaloids
variolins. At ®rst, acylation of the 7-azaindole ring proved
to be troublesome. Acylation of the 7-azaindole with acetyl
chloride in the presence of tin(IV) tetrachloride in benzene
at room temperature afforded a white precipitated solid,
which we are not able to isolate in pure form and probably
arises from the N-acylation on the more nucleophilic
pyridinic nitrogen atom. This salts by heating in THF either
alone or in the presence of additional acetyl chloride
remained unchanged. However, when a solution of this
salt in THF was treated with additional acetyl chloride
and tin (IV) tetrachloride, the 3-acetyl-7-azaindole 7 was
In a similar way, the synthesis of meridianins C and D
was achieved starting from the corresponding brominated
indole. The best results for the preparation of the N-tosyl-3-
acylindoles 3b and 3c were obtained when the commercially
available 5-bromo and the previously reported 6-bromo-
indole20 were N-protected by the tosyl group (90±93%)
and then acylated with acetyl chloride in the presence of
aluminum chloride (80±84%). Overall yields somewhat
lower were obtained when the reaction sequence was
changed. Thus, the acylation of 1b and 1c provided 2b

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P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
Scheme 4. Reagents and conditions: (a) (i) CH3±COCl, SnCl4, C6H6; (ii) CH3±COCl, SnCl4, THF; (b) p-toluenesulfonyl chloride, NaH, DMF; (c) DMF-DMF,
1108C; (d) H2N(vNH)NH2.HcL, K2CO3, 2-methoxyethanol, re¯ux.
obtained in 45% yield along with small amount of 7-azain-
dole.
3.1.1. 2-Benzyloxy-5-bromobenzaldehyde. To a cooled at
08C suspension of sodium hydride (0.44 g, 11 mmol) in dry
DMF (15 mL) a solution of 5-bromosalicylaldehyde (2 g,
10 mmol) in the same solvent (5 mL) as added dropwise
under N2. The mixture was stirred at 08C for 30 min and
then a solution of benzyl bromide (1.88 g, 11 mmol) in dry
DMF (2 mL) was added. The reaction mixture was allowed
to warm to room temperature and then stirred for 4 h. The
resultant solution was poured into water (100 mL) and the
precipitated solid was collected by ®ltration and then chro-
matographed on a silica gel column using CH2Cl2/hexane
(6:4) as eluent to give 2-benzyloxy-5-bromobenzaldehyde
(2.9 g, 100%) mp 67.5±69.58C (colorless prisms). 1H NMR
(300 MHz, CDCl3) d 5.17 (s, 2H, CH2), 6.94 (d, 1H,
Jˆ8.9 Hz, H-3), 7.37±7.41 (m, 5H, Ph), 7.59 (dd, 1H,
Jˆ8.9, 2.6 Hz, H-4), 7.93 (d, 1H, Jˆ2.6 Hz, H-6), 10.45
(s, 1H, CHO). 13C NMR (75 MHz, CDCl3) d: 70.9 (CH2),
113.8 (C-5), 115.1 (C-3), 126.5 (C-1), 127.3 (Co), 128.5
(Cp), 128.8 (Cm), 131.0 (C-6), 135.5 (Ci) 138.2 (C-4),
159.9 (C-2), 188.2 (CHO). IR (CH2Cl2) n: 1679 (s), 1589
(s), 1481 (s), 1272 (s) cm21. MS: m/z (%) (EI positive) 292
(M12, 40), 290 (M1, 40), 263 (12), 261 (12), 201 (23), 299
(23), 181 (43), 91 (100). Anal. Calcd for C14H11BrO2: C,
57.76; H, 3.81. Found; C, 57.54; H, 3.93.
Conversion of compound 7 into the desired 3-[(2-amino)-
pyrimidin-4-yl]-7-azaindole 10 was successfully achieved
following the above described protocol employed for the
synthesis of meridianins. N-Protection of 7 with the tosyl
group provided the N-tosyl-3-acetyl-7-azaindole 8 in 87%
yield. Formation of the enaminone 9 (60%) followed by
cyclization with guanidine hydrochloride with concomitant
N-deprotection afforded 10 in 70% yield (Scheme 4).
2. Conclusions
We have developed an useful method for the preparation of
3-pyrimidyl substituted indoles and 7-azaindole. In this
approach an acetyl group at the heteroaromatic 3-position
is used as a precursor to create the appropriately substituted
pyrimidine ring. The method appears to be general and its
utility is demonstrated in the ®rst synthesis of the marine
alkaloids meridianins A an E in ®ve steps with overall yields
of 12±15%, and meridianins C and D in four steps with
overall yields of 46%. Although explicit here, this process
should have additional application to the synthesis of the
marine alkaloids variolins.
3.1.2. Ethyl 2-azido-3-(2-benzyloxy-5-bromophenyl)pro-
penoate. To a well stirred solution containing sodium
(1.9 g) in anhydrous ethanol (50 mL), a solution of ethyl
azidoacetate (10.64 g, 32.5 mmol) and 2-benzyloxy-5-
bromosalicylaldehyde (3 g, 10.31 mmol) in the same
solvent (50 mL) was added dropwise at 2158C under N2.
The reaction mixture was stirred at that temperature for 3
days. After this time it was poured into aqueous saturated
ammonium chloride (150 mL). The precipitated solid was
separated by ®ltration and chromatographed on a silica gel
column using CH2Cl2/hexane (4:6) as eluent to give ethyl 2-
azido-3-(2-benzyloxy-5-bromophenyl)propenoate (3.11 g,
75%) mp 105±1078C (d) (colorless prisms). 1H NMR
(300 MHz, CDCl3) d: 1.36 (t, 3H, CH3, Jˆ7.2 Hz), 4.33
(q, 2H, CH3CH2, Jˆ7.2 Hz), 5.09 (s, 2H, OCH2), 6.79 (d,
1H, Jˆ8.7 Hz, H-3), 7.32±7.42 (m, 6H, H-7 and Ph), 7.35
3. Experimental
3.1. General methods
All melting points were determined on a Ko¯er hot-plate
melting point aparatus and are uncorrected. IR spectra were
obtained as Nujol emulsion or ®lms on a Nicolet Impact 400
spectrophotometer. NMR spectra were recorded on a Bruker
AC200 (200 MHz) or a varian Unity 300 (300 MHz). Mass
spectra were recorded on a Hewlett±Packard 5993C spec-
trometer or a Fisson AUTOSPEC5000 VG. Microanalyses
were performed on a Perkin±Elmer 240C instrument.

P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
2359
(dd, 1H, Jˆ8.7, 2.7 Hz, H-4), 8.35 (d, 1H, Jˆ2.7 Hz, H-6).
13C NMR (75 MHz, CDCl3) d: 14.1 (CH2CH32), 62.3
(CH2CH3), 70.8 (OCH2), 113.3 (C-5), 113.9 (C-3), 1173
(C-7), 124.7 (Ca), 126.4 (C-1), 126.9 (Co), 128.1 (Cp),
128.6 (Cm), 133.0 (C-4 and C-6), 136.3 (Ci), 155.7 (C-2),
163.4 (CO). IR (CH2Cl2) n: 2119 (s), 1697 (s), 1381 (s),
1290 (s), 1191 (m) cm21. MS: m/z (%) (EI positive) 375
(M122N2, 10), 373 (M12N2, 9), 284 (8), 282 (7), 238
(10), 91 (100). Anal. Calcd for C18H16N3BrO3: C, 53.75;
H, 4.01; N, 10.45. Found; C, 53.50; H, 4.88; N, 10.69.
was washed with 0.1N hydrochloric acid (3£50 mL) and the
extracted with ethyl acetate (3£20 mL). The combined
organic layers were dried (MgSO4) and concentrated to
dryness to afford the crude product which was chromato-
graphed on a silica gel column using CH2Cl2/hexane (6:4) as
eluent to give 1a (0.32 g, 72%), mp 103±1058C (colorless
prisms). 1H NMR (200 MHz, CDCl3) d: 5.18 (s, 2H, OCH2),
6.47 (d, 1H, Jˆ8.3 Hz, H-3), 6.77 (m, 1H, H-5), 7.12 (m,
1H, H-6), 7.19 (d, 1H, Jˆ8.3 Hz, H-2), 7.31±7.49 (m, 5H,
Ph), 8.27 (brs, 1H, NH). 13C (50 MHz, CDCl3) d: 70.2
(OCH2), 96.4 (C-7), 101.5 (C-3), 102.8 (C-5), 119.9
(C-3a), 123.1 (C-2), 124.5 C-6), 127.3 (Co), 127.8 (Cp),
128.5 (Cm), 135.5 (C-7a) 137.2 (Ci), 152.0 (C-4). IR
(CH2Cl2) n: 3414 (m), 1614 (m), 1496 (s), 1348 (m), 1336
(s), 1280 (s), 1084 (s) cm21. MS: m/z (%) (EI positive) 303
(M12, 31), 301 (M1, 30), 222 (18), 212 (22), 210 (33), 91
(100). Anal. Calcd for C15H12NOBr: C, 59.62; H, 4.00; N,
4.64. Found; C, 59.77; H, 4.18; N, 4.86.
3.1.3. Ethyl 4-benzyloxy-7-bromoindole-2-carboxylate.
A
solution of ethyl 2-azido-3-(2-benzyloxy-5-bromo-
phenyl)propenoate (1 g, 2.49 mmol) in dry toluene
(12 mL) was heated at re¯ux temperature for 12 h under
N2. After cooling, the solvent was removed under reduced
pressure and the remaining residue was slurried with diethyl
ether (2 mL). The separated solid was collected by ®ltration
and then chromatographed on a silica gel column using
CH2Cl2/hexane (6:4) as eluent to give ethyl 4-benzyloxy-
7-bromoindole-2-carboxylate (0.85 g, 92%), mp 135.5±
3.1.6. 2-Acetyl-4-benzyloxy-7-bromoindole 2a. To at 08C
cooled mixture of 4-benzyloxy-7-bromoindole 1a (0.4 g,
1.34 mmol), acetyl chloride (0.212 g, 2.7 mmol) and dry
benzene (10 mL) a solution of SnCl4 (0.704 g, 2.7 mmol)
in the same solvent (4 mL) was added dropwise under N2.
The resultant solution was stirred at that temperature for 2 h.
Afterwards H2O (15 mL) was added and the resulting
mixture was extracted with EtOAc (3£20 mL). The
combined organic layers were dried (MgSO4) and concen-
trated to dryness. The resultant residue was slurried with
diethyl eyther (4 mL) and the separated solid was ®ltered
and chromatographed on a silica gel column using EtOAc/
hexane as eluent (6:4) to give 2a (0.405 g, 89%), mp 161±
1
136.58C (colorless prisms). H NMR (300 MHz, CDCl3)
d: 1.40 (t, 3H, Jˆ7.2 Hz, CH2CH3), 4.4 (q, 2H, Jˆ7.2 Hz,
CH2CH3), 5.17 (s, 2H, OCH2), 6.47 (d, 1H, Jˆ8.1 Hz, H-5),
7.30±7.48 (m, 7H, H-6, H-3, Ph), 8.95 (brs, 1H, NH). 13C
NMR (75 MHz, CDCl3) d: 14.3 (CH2CH3), 61.1 (CH2CH3),
70.1 (OCH2), 96.3 (C-7), 102.7 (C-3), 107.4 (C-5), 120.0
(C-2), 126.8 (C-3a), 127.3 (Co), 128.0 (Cp and C-6), 136.5
(C-7a), 136.7 (Ci), 153.2 (C-4), 161.4 (CO). IR (CH2Cl2) n:
3320 (m), 1705 (s), 1256 (s), 1191 (m) cm21. MS: m/z (%)
(EI positive) 375 (M12, 46), 373 (M1, 46), 294 (16), 284
(30), 282 (30), 238 (30), 236 (30), 91 (100). Anal. Calcd for
C18H16NBrO3: C, 57.77; H, 4.31; N, 3.74. Found; C, 57.54;
H, 4.55; N, 3.80.
1
1628C (colorless prisms). H NMR (300 MHz, DMSO-d6)
d: 2.48 (s, 3H, COCH3), 5.21 (s, 2H, OCH2), 6.47 (d, 1H,
Jˆ8.6 Hz, H-5), 7.31±7.61 (m, 6H, H-6, Ph), 8.05 (d,1H,
Jˆ2 Hz, H-2), 12.02 (brs,1H, NH). 13C NMR (75 MHz,
DMSO-d6) d: 30.0 (COCH3), 69.9 (OCH2), 96.3 (C-7),
105.3 (C-5), 116.0 (C-3), 119.7 (C-3a), 125.7 (C-6), 127.5
(Co), 127.6 (Cp), 128.2 (Cm), 132.6 (C-2), 136.5 (C-7a)
137.0 (Ci), 152.1 (C-4), 192.6 (CO). IR (nujol) n: 3377
(m), 1639 (s), 1506 (s), 1472 (s) cm21. MS: m/z (%) (EI
positive) 345 (M12, 35), 343 (M1, 39), 302 (42), 300 (56),
254 (29), 252 (29), 211 (47), 209 (56), 91 (100). Anal. Calcd
for C17H14NO2Br: C, 59.32; H, 4.10; N, 4.07. Found; C,
59.47; H, 4.25; N, 4.22.
3.1.4. 4-Benzyloxy-7-bromoindole-2-carboxylic acid. To
a mixture of ethyl 4-benzyloxy-7-bromoindole-2-carboxyl-
ate (2.3 g, 6.15 mmol), THF (170 ml) and H2O (67 ml),
LiOH (0.92 g, 21.5 mmol) was added. The resultant mixture
was stirred at room temperature for 2 days. The solution was
concentrated to the half of volume and 0.1N hydrochloric
acid was added until a precipitated solid appeared. The solid
was collected by ®ltration, washed with H2O and air dried.
Recrystallization from CH2Cl2 afforded 4-benzyloxy-7-
bromoindole-2-carboxylic acid (2.10 g, 99%). Mp 257±
1
2608C (colorless prisms). H NMR (300 MHz, DMSO-d6)
d: 3.59 (brs, 1H, COOH), 5.23 (s, 2H, OCH2), 6.61 (d, 1H,
Jˆ8.1 Hz, H-5), 7.22 (s, 1H, H-3), 7.33±7.51 (m, 6H, H-6,
Ph), 11.73 (brs, 1H, NH). 13C NMR (75 MHz, DMSO-d6) d:
69.4 (OCH2), 96.0 (C-7), 102.8 (C-3), 106.2 (C-5), 119.7
(C-2), 127.4 (Co), 127.8 (Cp), 128.5 (Cm), 128.9 (C-6), 136.7
(C-7a), 136.9 (Ci) 152.2 (C-4), 162.1 (CO). IR (nujol) n:
3454 (m), 1684 (s), 1537 (m), 1376 (m), 1270 (m), 1135 (m)
cm21. MS: m/z (%) (EI positive) 347 (M12, 18), 373 (M1,
19), 238 (9), 236 (9), 91 (100). Anal. Calcd for
C16H12NO3Br: C, 55.51; H, 3.49; N, 4.01. Found; C,
55.73; H, 3.61; N, 4.23.
3.1.7. N-Tosyl-3-Acetyl-4-benzyloxy-7-bromoindole 3a.
To a suspension of sodium hydride (0.0195 g, 0.81 mmol)
in dry DMF (10 mL), a solution of 3-acetyl-4-benzyloxy-7-
bromoindole 2a (0.23 g, 0.67 mmol) in the same solvent
(3 mL) was added dropwise under N2. The mixture was
stirred for 1 h at room temperature and then cooled at 08C.
A
solution of p-toluenesulfonyl chloride (0.15 g,
0.81 mmol) in dry DMF (3 mL) was added and the mixture
was stirred at that temperature for 2 h. The solution was
poured into H2O (100 mL) and extracted with EtOAc
(3£20 mL). The combined organic layers were dried
(MgSO4) and concentrated to dryness. The remaining
solid was chromatographed on a silica gel column using
EtOAc/hexane (6:4) as eluent to give 3a (0.184 g, 55%),
mp 157±1598C (colorless prisms). 1H NMR (200 MHz,
CDCl3) d: 2.41 (s, 3H, COCH3), 2.51 (s, 3H, CH3), 5.16
(s, 2H, OCH2), 6.67 (d, 1H, Jˆ8.7 Hz, H-5), 7.26±7.72 (m,
3.1.5. 4-Benzyloxy-7-bromoindole 1a. A mixture of
4-benzyloxy-7-bromoindole-2-carboxylic
acid (0.5 g,
1.45 mmol), copper powder (0.1 g) and freshly distilled
quinoline (20 mL) was heated in a molten salts bath at
2358C for 2 h under N2. After cooling the reaction mixture

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P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
10H, H-6, Ho, Hm, Ph), 8.19 (s,1H, H-2). 13C NMR
(50 MHz, CDCl3) d: 21.6 (COCH3), 31.2 (CH3), 70.9
(OCH2), 97.1 (C-7), 107.8 (C-5), 122.9 (C-3), 127.2 (Co),
127.6 (C-20), 128.2 (C-40), 128.6 (C-30), 129.5 (C-3a), 129.8
(Cm), 131.6 (C-6), 132.2 (C-2), 134.8 (Ci), 135.7 (C-7a),
136.8 (C-10), 145.1 (Cp), 151.9 (C-4), 196.1 (CO). IR
(CH2Cl2) n: 1687 (s), 1489 (s), 1374 (s), 1174 (s), 1090
(s) cm21. MS: m/z (%) (EI positive) 499 (M12, 28), 497
(M1, 31), 456 (32), 454 (34), 344 (40), 342 (44), 302 (44),
300 (51), 209 (12), 207 (18), 91 (100). Anal. Calcd for
C24H20NO4SBr: C, 57.84; H, 4.04; N, 2.81. Found; C,
57.61; H, 4.16; N, 2.95.
3145 (m), 1657 (m), 1571 (s), 1503 (s), 1301 (s), 1231 (s),
1079 (s) cm21. MS: m/z (%) (EI positive) 396 (M12, 20),
394 (M1, 20), 305 (16), 303 (16), 224 (17), 149 (13), 91
(100). Anal. Calcd for C19H15N4OBr: C, 57.74; H, 3.83; N,
14.17. Found; C, 57.90; H, 3.61; N, 14.28.
3.1.10. Meridianin A. A solution of indole 5 (0.04 g,
0.101 mmol) in anhydrous EtOH (20 mL) was hydro-
genated in the presence of 10% palladium on charcoal
(0.01 g) at room temperature under atmospheric pressure.
After 2 h, the mixture was ®ltered on celite and the solvent
was evaporated to leave meridianin A as a yellow solid
(0.019 g, 83%). recrystallization from EtOH/hexane gave
analitically pure material, mp 164±1688C (yellow prisms).
1H NMR (300 MHz, DMSO-d6) d: 7.13 (dd, 1H, Jˆ7.8,
0.9 Hz, H-5), 7.48 (brs, 2H, NH2), 7.57 (dd, 1H, Jˆ8.1,
0.9 Hz), 7.74 (dd, 1H, Jˆ7.8 Hz, H-6), 7.88 (d, 1H,
Jˆ5.7 Hz, H-50), 8.88 (d, 1H, Jˆ5.7 Hz, H-60), 9.0 (s, 1H,
H-2), 11.8 (s, 1H, NH), 13.9 (s, 1H, OH). 13C NMR
(75 MHz, DMSO-d6) d 102.3 (C-7), 104.4 (C-50), 105.4
(C-5), 113.7 (C-3), 114.4 (C-3a), 124.4 (C-6), 128.4
(C-2), 139.2 (C-7a), 152.0 (C-4), 158.4 (C-60), 160.5
(C-40), 161.7 (C-20). IR (nujol) n: 3456 (m), 3416 (m),
3340 (m), 3181 (m), 1627 (m), 1586 (s), 1532 (s), 1270
(s), 1124 (s), 1072 (s) cm21. MS: m/z (%) (EI positive)
226 (M1, 100), 185 (26), 167 (16), 149 (59). Anal. Calcd
for C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found; C,
63.57; H, 4.31; N, 24.93.
3.1.8. Enaminone 4a. To a solution of N-tosyl-3-acetyl-4-
benzyloxy-7-bromoindole 3a (0.160 g, 0.32 mmol) in dry
DMF (5 mL) was added a solution of dimethylformamide
dimethylacetal (0.06 g, 0.50 mmol) in the same solvent
(2 mL). The resultant solution was heated at 1108C for 4 h
under N2. After cooling, the solution was poured into H2O
(100 mL) and then extracted with EtOAc (2£10 mL). The
combined organic layers were dried (MgSO4) and concen-
trated to dryness under reduced pressure. The residue was
chromatographed on a silica gel column using EtOAc as
eluent to give 4a (0.08 g, 45%), mp 70±728C (yellow
1
prisms). H NMR (300 MHz, CDCl3) d: 2.40 (s,3H, CH3),
2.67 (brs, 3H, NCH3), 2.99 (brs, 3H, NCH3), 5.13 (s, 2H,
OCH2), 5.42 (d, 1H, Jˆ12.9 Hz, H-a), 6.60 (d, 1H,
Jˆ8.7 Hz, H-5), 7.25±7.45 (m, 9H, Hm, H-b, H-6, Ph),
7.70 (d, 2H, Jˆ8.4 Hz, Ho), 7.98 (s, 1H, H-2). 13C NMR
(75 MHz, CDCl3) d: 21.5 (CH3), 37.0 (NCH3), 44.8
(NCH3), 70.4 (OCH2), 96.9 (C-7), 99.3 (C-a), 107.5
(C-5), 122.6 (C-3), 127.1 (Co, C-20, C-6), 127.5 (C-40),
128.2 (C-30), 129.6 (Cm), 131.6 (C-2), 134.4 (Ci), 136.5
(C-7a), 137.2 (C-10), 144.7 (Cp), 152.0 (C-4), 154.5 (C-0),
186.5 (CO). IR (CH2Cl2) n: 1730 (s), 1647 (s), 1553 (s),
1262 (s), 1094 (s) cm21. MS: m/z (%) (EI positive) 554
(M12, 21), 552 (M1, 21), 399 (31), 397 (37), 371 (25),
369 (27), 280 (23), 273 (25), 91 (100). Anal. Calcd for
C27H24N2O4SBr: C, 58.70; H, 4.38; N, 5.07. Found; C,
58.55; H, 4.22; N, 5.17.
3.1.11. Meridianin E. To a solution of indole 5 (0.062 g,
0.157 mmol) in tri¯uoro acetic acid (5 mL), thioanisole
(0.975 g, 7.85 mmol) was added dropwise under N2. The
resultant solution was stirred at room temperature for 2 h.
Then, 5% NaOH solution was added until pH basic and the
mixture was extracted with EtOAc (2£10 mL). The
combined organic layers were dried (MgSO4) and concen-
trated to dryness under reduced pressure. The residue was
chromatographed on a silica gel column using CH2Cl2/
EtOH (9:1) as eluent to give meridianin E (0.031 g, 65%)
mp 173±1758C (yellow prisms). 1H NMR (300 MHz,
DMSO-d6) d: 6.37 (d, 1H, Jˆ8.4 Hz, H-5), 6.86 (brs, 2H,
NH2), 7.19 (d, 1H, Jˆ8.4 Hz, H-6), 7.24 (d, 1H, Jˆ5.1 Hz,
H-50), 8.18 (d, 1H, Jˆ5.1 Hz, H-60), 8.30 (s, 1H, H-2), 11.89
(s, 1H, NH), 13.92 (s, 1H, OH).). 13C NMR (75 MHz,
DMSO-d6) d: 92.5 (C-7), 104.6 (C-50), 107.1 (C-5), 115.0
(C-3a), 115.9 (C-3), 126.6 (C-6), 129.1 (C-2), 136.8 (C-7a),
151.9 (C-4), 158.9 (C-60), 160.0 (C-40), 161.6 (C-20). IR
(nujol) n: 3423 (m), 3288 (m), 3130 (m), 1629 (m), 1590
(s), 1532 (s), 1225 (m), 1164 (m) cm21. MS: m/z (%) (EI
positive) 306 (M12, 98), 304 (M1, 100), 225 (12), 197 (36).
Anal. Calcd for C12H9N4OBr: C, 47.24; H, 2.97; N, 18.36.
Found; C, 47.38; H, 2.74; N, 18.11.
3.1.9. 4-Benzyloxy-7-bromo-3-[(2-amino)pyrimidin-4-
yl]indole 5. A mixture of enaminone 4a (0.115 g,
0.208 mmol), guanidine hydrochloride (0.03 g, 0.314
mmol), anhydrous K2CO3 (0.06 g, 0.434 mmol) and
2-methoxyethanol (10 mL) was heated at re¯ux temperature
for 24 h under N2. After cooling, the solution was poured
into H2O (50 mL) and then extracted with EtOAc
(2£10 mL). The combined organic layers were dried
(MgSO4) and the concentrated to dryness under reduced
pressure. The remaining residue was chromatographed on
a deactivated (EtOH/NH3 9:1) silica gel column using
EtOAc/EtOH (9:1) as eluent to give 5 (0.065 g, 82%), mp
1
237±2408C (yellow prisms). H NMR (300 MHz, DMSO-
3.1.12. 3-Acetylindoles 2b and 2c. These compounds were
prepared from the corresponding indoles 1b an 1c by
reaction with acetyl chloride in the presence of tin(V) tetra-
chloride as described for the preparation of 2a.
d6) d: 5.19 (s, 2H, OCH2), 6.29 (s, 2H, NH2), 6.73 (d, 1H,
Jˆ8.1 Hz, H-5), 7.13 (d, 1H, Jˆ5.4 Hz, H-50), 7.30 (d, 1H,
Jˆ8.1 Hz, H-6), 7.33±7.46 (m, 5H, Ph), 7.81 (s, 1H, H-2),
7.82 (d, 1H, Jˆ5.4 Hz, H-60), 11.75 (brs, 1H, NH). 13C
NMR (75 MHz, DMSO-d6) d: 70.0 (OCH2), 96.4 (C-7),
103.9 (C-50), 110.3 (C-5), 116.2 (C-3a), 116.9 (C-3a),
124.8 (C-6), 127.8 (C-2), 128.0 (Co and Cp), 128.2 (Cm),
136.4 (C-7a and Ci), 152.0 (C-4), 156.9 (C-60), 161.0
(C-20), 163.1 (C-40). IR (nujol) n: 3398 (m), 3300 (m),
3.1.13. 3-Acetyl-5-bromoindole 2b. 65% mp 250±2528C
(colorless prisms). H NMR (200 MHz, DMSO-d6) d: 2.45
1
(s, 3H, CH3), 7.33 (dd, 1H, Jˆ8.7, 1.9 Hz, H-6), 7.45 (d, 1H,
H-7), 8.31 (d, 1H, H-4), 8.36 (brs, 1H, NH). 13C NMR
(50 MHz, DMSO-d6) d: 27.1 (CH3), 114.1 (C-7), 114.4

P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
2361
(C-3), 116.2 (C-5), 123.4 C-4), 125.3 (C-6), 127.0 (C-3a),
135.3 (C-7a), 135.5 (C-2), 192.7 (CO). IR (nujol) n: 3164
(m), 1629 (s), 1521 (m), 1226 (m), 1176 (m) cm21. MS: m/z
(%) (EI positive) 239 (M12, 49), 237 (M1, 56), 224 (97),
222 (100), 143 (47), 115 (36), 114 (25). Anal. Calcd for
C10H8NOBr: C, 50.45; H, 3.39; N, 5.88. Found; C, 50.61;
H, 3.52; N, 5.65.
CDCl3) d: 2.34 (s, 3H, CH3), 2.55 (s, 3H, COCH3), 7.29
(d, 2H, Jˆ8.4 Hz, Hm), 7.75 (dd, 1H, Jˆ8.7, 2.1 Hz, H-6).
7.79 (d, 1H, H-7), 7.80 (d, 2H, Ho), 8.18 (s, 1H, H-2), 8.49
(d, 1H, H-4). 13C NMR (75 MHz, CDCl3) d: 21.7 (CH3),
27.7 (COCH3), 114.4 (C-7), 118.7 (C-5), 120.8 (C-3), 125.9
(C-4), 127.9 (Cm), 128.8 (C-6), 129.1 (C-3a), 130.3 (Co),
132.8 (C-2), 133.6 (C-7a), 134.3 (Ci), 146.2 (Cp), 192.9
(CO). IR (CH2Cl2) n: 1668 (s), 1538 (s), 1437 (s), 1385
(s), 1163 (s), 1123 (s), 973 (s) cm21 MS: m/z (%) (EI posi-
tive) 393 (M12, 37), 391 (M1, 47), 351 (31), 349 (32), 239
(35), 237 (35), 224 (44), 222 (46), 115 (67), 91 (100). Anal.
Calcd for C17H14NO3SBr: C, 52.05; H, 3.60; N, 5.57. Found;
C, 52.20; H, 3.42; N, 5.79.
3.1.14. 3-Acetyl-6-bromoindole 2c. 46% mp 247±2498C
(colorless prisms). 1H NMR (300 MHz, DMSO-d6) d:
2.46 (s, 3H, CH3), 7.33 (dd, 1H, Jˆ8.5, 1.8 Hz, H-5), 7.67
(d, 1H, Jˆ1.8 Hz, H-7), 8.12 (d, 1H, Jˆ8.5 Hz, H-4), 8.33
(d, 1H, Jˆ2.5 Hz, H-2), 12.02 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6) d: 27.2 (CH3), 114.7 (C-7), 115.3
(C-3), 116.7 (C-6), 122.9 (C-4), 124.3 (C-3a), 124.5 (C-5).
135.51 (C-2), 137.5 (C-7a), 192.6 (CO). IR (nujol) n: 3154
(m), 1625 (s), 1520 (m), 1463 (s), 1377 (s), 1177 (m), 937 (s)
cm21. MS: m/z (%) (EI positive) 239 (M12, 60), 237 (M1,
66), 224 (76), 222 (100), 196 (71), 194 (75), 143 (81), 115
(77), 114 (73). Anal. Calcd for C10H8NOBr: C, 50.45; H,
3.39; N, 5.88. Found; C, 50.72; H, 3.55; N, 5.72.
3.1.20. N-Tosyl-3-acetyl-6-bromoindole 3c. 80% mp 167±
1698C (colorless prisms). H NMR (300 MHz, CDCl3) d:
1
2.37 (s, 3H, CH3), 2.55 (s, 3H, COCH3), 7.30 (d, 2H,
Jˆ8 Hz, Hm), 7.43 (dd, 1H, Jˆ8.6 Hz, 1.8 Hz, H-5), 7.82
(d, 2H, Jˆ8 Hz, Ho), 8.16 (s, 1H, H-2), 8.18 (d, 1H,
Jˆ8.6 Hz, H-4). 13C NMR (75 MHz, CDCl3) d: 21.6
(CH3), 27.6 (COCH3), 116.1 (C-7), 119.5 (C-6), 121.3
(C-3), 124.3 (C-4), 126.3 (C-3a), 127.1 (Co), 128.2 (C-5),
130.4 (Cm), 132.3 (C-2), 134.2 (C-7a) 135.5 (Ci), 146.2 (Cp),
193 (CO). IR (CH2Cl2) n: 1674 (s), 1535 (s), 1464 (s), 1381
(s), 1166 (s), 1090 (s), 977 (s) cm21. MS: m/z (%) (EI
positive) 393 (M12, 1), 391 (M1, 1), 354 (2), 352 (2),
239 (47), 237 (52), (224 (70), 222 (100), 196 (73), 194
(89), 143 (81). Anal. Calcd for C17H14NO3SBr: C, 52.05;
H, 3.60; N, 5.57. Found; C, 52.21; H, 3.40; N, 5.30.
3.1.15. N-Tosylindoles 6a and 6b. These compounds were
prepared from indoles 1b and 1c, respectively, using the
method described for the preparation of 3a.
3.1.16. N-Tosyl-5-bromoindole 6a. 93% mp 139±1408C
(colorless prisms). H NMR (300 MHz, CDCl3) d: 2.33 (s,
1
3H, CH3), 6.58 (dd, 1H, Jˆ3.6 Hz, H-3), 7.21 (d, 2H,
Jˆ8.3 Hz, Hm), 7.39 (dd, 1H, Jˆ8.3, 1.8 Hz, H-6), 7.55
(d, 1H, Jˆ3.6 Hz, H-2), 7.64 (d, 1H, Jˆ1.8 Hz, H-4), 7.73
(d, 2H, Jˆ8.3 Hz, Ho), 7.36 (d, 1H, Jˆ8.8 Hz, H-7). 13C
NMR (75 MHz, CDCl3) d: 21.5 (CH3), 108.2 (C-3), 114.9
(C-7), 116.7 (C-5), 124.0 (C-4), 126.7 (Co), 127.4 and 127.5
(C-2 or C-6), 129.5 (Cm), 132.4 (C-3a), 133.5 (C-7a), 135.0
(Ci), 145.2 (Cp). IR (CH2Cl2) n: 1638 (m), 1438 (s), 1372
(s), 1168 (s), 1131 (s) cm21. MS: m/z (%) (EI positive) 351
(M12, 22), 349 (M1, 41), 196 (31), 194 (37), 169 (13), 167
(17), 155 (47), 115 (100). Anal. Calcd for C15H12NO2SBr:
C, 51.44; H, 3.45; N, 4.00. Found; C, 51.70; H, 3.32; N,
4.25.
3.3. Enaminone 4b and 4c
These compounds were prepared from indoles 3b and 3c,
respectively, using the same procedure as described for the
preparation of enaminone 4a.
3.3.1. Enaminone 4b. 82% mp 175±1798C (yellow prisms).
1H NMR (200 MHz, DMSO-d6) d: 2.32 (s, 3H, CH3), 3.00
(brs, 3H, NCH3), 3.09 (brs, 3H, NCH3), 5.56 (d, 1H,
Jˆ12.2 Hz, H-a), 7.22 (d, 2H, Jˆ8.5 Hz, Hm), 7.40 (dd,
1H, Jˆ8.8, 1.9 Hz, H-6), 7.76 (d, 2H, Jˆ8.5 Hz, Ho), 7.76
(d, 1H, Jˆ12.2 Hz, H-b), 7.78 (d, 1H, Jˆ8.8 Hz, H-7), 8.08
(s, 1H, H-2), 8.53 (d, 1H, Jˆ1.9 Hz, H-4). 13C NMR
(50 MHz, DMSO-d6) d: 21.4 (CH3), 37.1 (NCH3), 44.9
(NCH3), 92.9 (C-a), 114.3 (C-7), 117.8 (C-5), 122.9
(C-3), 126.0 (C-4), 126.8 (Co), 127.9 (C-6), 129.0 (C-2),
130.0 (Cm), 130.5 (C-3a), 133.6 (C-7a), 134.4 (Ci), 145.7
(Cp), 153.2 (C-b), 183.2 (CO). IR (CH2Cl2) n: 1636 (s),
1533 (s), 1435 (s), 1374 (s), 1293 (s), 1153 (s), 1031 (s)
cm21. MS: m/z (%) (EI positive) 448 (M12, 54), 446 (M1,
59), 293 (71), 291 (85), 265 (48), 263 (62), 184 (65), 183
(37), 169 (81), 155 (72), 140 (64), 91 (100). Anal. Calcd for
C20H19N2O3SBr: C, 53.70; H, 4.28; N, 6.23. Found; C,
53.55; H, 4.426; N, 6.15.
3.1.17. N-Tosyl-6-bromolindole 6b. 90% mp 137±1388C
(colorless prisms). H NMR (300 MHz, CDCl3) d: 3.21 (s,
1
3H, CH3), 6.60 (dd, 1H, Jˆ3.67, 0.78 Hz, H-3), 7.22 (d, 2H,
Jˆ7.8 Hz, Hm), 7.36 (dd, 1H, Jˆ8.4, 1.58 Hz, H-5), 7.31 (d,
1H, Jˆ8.4 Hz, H-4), 7.52 (d, 1H, Jˆ3.67 Hz, H-2), 8.17
(dd, 1H, Jˆ1.58, 0.78 Hz, H-7). 13C NMR (75 MHz,
CDCl3) d: 21.6 (CH3), 108.7 (C-3), 116.5 (C-7), 118.1
(C-6), 122.4 (C-4), 126.6 (C-5), 126.8 (Co), 129.5 (C-3a),
130.0 (Cm), 135.0 (Ci), 135.4 (C-7a), 145.3 (Cp). IR
(CH2Cl2) : 1594 (s), 1437 (s), 1372 (s), 1169 (s), 1122
n
(s), 993 (s) cm21 MS: m/z (%) (EI positive) 351 (M12,
35), 349 (M1, 55), 196 (46), 194 (55), 155 (64), 115
(100), 89 (93). Anal. Calcd for C15H12NO2SBr: C, 51.44;
H, 3.45; N, 4.00. Found; C, 51.31; H, 3.30; N, 3.87.
3.3.2. Enaminone 4c. 83% mp 188±1908C (yellow prisms).
1H NMR (300 MHz, CDCl3) d: 2.36 (s, 3H, CH3), 2.95 (s,
3H, NCH3), 3.14 (NCH3), 5.55 (d, 1H, Jˆ12.6 Hz, H-a),
7.27 (d, 2H, Jˆ8.4 Hz, Hm), 7.41 (dd, 1H, Jˆ8.5, 1.58 Hz,
H-5), 7.77 (d, 1H, Jˆ12.6 Hz, H-b), 7.79 (d, 2H, Jˆ8.4 Hz,
Ho), 8.03 (s, 1H, H-2), 8.10 (d, 1H, Jˆ1.58 Hz, H-7), 8.22
(d, 1H, Jˆ8.57 Hz, H-4). 13C NMR (75 MHz, CDCl3) d:
21.5 (3H, CH3), 37.2 (NCH3), 44.8 (NCH3), 93.0 (C-a),
3.1.18. N-Tosyl-3-acetylindole 3b and 3c. These
compounds were prepared from 6a and 6b by acylation
with acetic anhydride in the presence of aluminum chloride.
3.1.19. N-Tosyl-3-acetyl-5-bromolindole 3b. 84% mp
155±1578C (colorless prisms). 1H NMR (300 MHz,

2362
P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
116.0 (C-7), 118.8 (C-6), 123.4 (C-3), 124.5 (C-4), 126.9
(Co), 127.5 (C-5), 127.5 (C-3a), 128.5 (c-2), 130.2 (Cm),
134.5 (C-7a), 135.6 (Ci), 145.7 (Cp), 153.2 (C-b), 183.4
(CO). IR (CH2Cl2) n: 1644 (s), 1529 (s), 1416 (s), 1376
(s), 1288 (s), 1163 (s), 1030 (s) cm21. MS: m/z (%) (EI
positive) 448 (M12, 10), 446 (M1, 13), 293 (57), 291
(57), 212 (58), 210 (24), 208 (24), 183 (33), 169 (30), 155
(17), 91 (100). Anal. Calcd for C20H19N2O3SBr: C, 53.70; H,
4.28; N, 6.23;. Found; C, 53.87; H, 4.15; N, 6.07.
(2£10 mL). To the aqueous layer 5% NaOH solution
(100 mL) was added and then extracted with EtOAc
(3£20 mL). The combined organic layers were dried
(MgSO4) and concentrated to dryness to give solid, which
was chromatographed on a silica gel column using EtOAc
as eluent to give 7 (0.03 g, 45%), mp 208±2108C (colorless
1
prisms). H NMR (300 MHz, DMSO-d6) d: 2.5 (s, 3H,
CH3), 7.28 (dd, 1H, Jˆ7.8, 4.5 Hz, H-5), 8.05 (s, 1H,
H-2), 8.41 (dd, 1H, Jˆ4.5, 1.2 Hz, H-4), 8.71 (dd, 1H,
Jˆ7.8, 1.2 Hz, H-6), 12.37 (brs, 1H, NH). 13C NMR
(75 MHz, DMSO-d6) d: 20.7 (CH3), 115.4 (C-3), 117.5
(C-3a), 117.9 (C-5), 129.5 (C-2), 134.5 (C-6), 144.1 (C-4),
149.0 (C-7a), 192.3 (CO). IR (nujol) n: 3144 (m), 1635 (s),
1463 (s), 1379 (s), 1113 (m) cm21. MS: m/z (%) (EI posi-
tive) 160 (M1, 31), 145 (100), 117 (43), 90 (35), 63 (34).
Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49.
Found; C, 67.52; H, 5.00; N, 17.40.
3.4. Meridianin C and D
These alkaloids were prepared from enaminones 4b and 4c,
respectively, using the same procedure described for the
preparation of 5 from 4a.
3.4.1. Meridianin C. 72% mp 103±1068C (yellow prisms).
1H NMR (300 MHz, DMSO-d6) d: 6.54 (s, 2H, NH2), 7.02
(d, 1H, Jˆ5.1 Hz, H-50), 7.31 (d, 1H, Jˆ8.5 Hz, H-6), 7.43
(d, 1H, Jˆ8.5 Hz, H-7), 8.13 (d, 1H, Jˆ5.1 Hz, H-60), 8.28
(d, 1H, H-60), 8.28 (s, 1H, H-2), 8.79 (s, 1H, H-4), 11.91
(brs, 1H, NH). 13C NMR (75 MHz, DMSO-d6) d: 105.2
(C-50), 113.2 (C-3), 113.7 (C-7), 124.5 (C-4), 124.6 (C-6),
127.0 (C-3a), 157.1 (C-60), 162.2 (C-40), 163.5 (C-20). IR
(nujol) n: 3509 (m), 3474 (m), 3387 (m), 3370 (m), 3194
(m), 1649 (s), 1571 (s), 1452 (s), 1375 (s), 1291 (s), 1120
(m), 893 (m) cm21. MS: m/z (%) (EI positive) 290 (M12,
21), 288 (M1, 100), 249 (38), 248 (24), 247 (55), 210 (25),
209 (33), 208 (46), 168 (65), 141 (32), 140 (33), 115 (26),
114 (31), 113 (34). Anal. Calcd for C12H9N4Br: C, 49.85; H,
3.14; N, 19.38. Found; C, 49.72; H, 3.07; N, 19.11.
3.4.4. N-Tosyl-3-acetyl-7-azaindole 8. This compound
was prepared in 87% yield from 3-acetyl-7-azaindole 7
and p-toluenesulfonyl chloride using the same procedure
as described for the preparation of 2a. Mp 187±1898C
1
(colorless prisms). H NMR (300 MHz, CDCl3) d: 2.39 (s,
3H, COCH3), 2.57 (s, 3H, CH3), 7.23 (dd, 1H, Jˆ7.9, 5 Hz,
H-5), 7.32 (d, 2H, Jˆ8.7 Hz, Hm), 8.15 (d, 2H, Jˆ8.7 Hz,
Ho), 8.35 (s, 1H, H-2), 8.46 (dd, 1H, Jˆ5, 1.6 Hz, H-4), 8.58
(dd, 1H, Jˆ1.6, 7.9 Hz, H-6). 13C NMR (75 MHz, CDCl3)
d: 21.7 (COCH3), 27.2 (CH3), 118.6 (C-3a), 120.2 (C-3),
120.4 (C-5), 128.5 (Co), 129.8 (Cm), 131.7 (C-2 and C-6),
134.4 (Ci), 146.9 (C-4), 147.0 (C-7a), 147.8 (Cp), 193.1
(CO). IR (CH2Cl2) : 1668 (s), 1529 (s), 1384 (s), 1175
n
(s), 1088 (s), 977 (s) cm21. MS: m/z (%) (EI positive) 314
(M1, 26), 299 (20), 250 (58), 235 (87), 155 (36), 91 (100).
Anal. Calcd for C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91.
Found; C, 61.28; H, 4.25; N, 8.67.
3.4.2. Meridianin D. 78% mp 217±2218C (yellow prisms).
1H NMR (300 MHz, DMSO-d6) d: 6.74 (brs, 2H, NH2), 7.00
(d, 1H, Jˆ5.3 Hz, H-50), 7.25 (dd, 1H, Jˆ8.7, 1.6 Hz, H-5),
7.65 (d, 1H, Jˆ1.6 Hz, H-7), 8.92 (d, 1H, Jˆ5.3 Hz, H-60),
8.23 (s, 1H, H-2), 8.57 (d, 1H, Jˆ8.7 Hz, H-4), 11.79 (brs,
3.4.5. Enaminone 9. This compound was prepared in 60%
yield from the N-tosyl-3-acetyl-7-azaindole 8 and dimethyl-
formamide dimethylacetal according to the procedure
described for the preparation of enaminones 4a±c. Mp
13
1H, NH). C NMR (75 MHz, DMSO-d6) d: 105 (C-50),
113.9 (C-6), 114.4 (C-7), 114.7 (C-3), 123.0 (C-5), 124.2
(C-4), 124.4 (C-3a), 129.1 (C-2), 137.9 (C-7a), 157.2 (C-60),
162.2 (C-40), 163.5 (C-20). IR (nujol) n: 1501 (m), 3477 (m),
3432 (m), 3377 (m), 3317 (m), 3169 (m), 1661 (s), 1567 (s),
1456 (s), 1373 (s), 1292 (s), 1126 (m), 886 (m), 817 (m)
cm21. MS: m/z (%) (EI positive) MS: m/z (%) (EI positive)
290 (M12, 35), 288 (M1, 100), 249 (34), 248 (13), 247 (43),
209 (21), 208 (34), 168 (34), 141 (23), 140 (32). Anal. Calcd
for C12H9N4Br: C, 49.85; H, 3.14; N, 19.38. Found; C,
49.63; H, 3.28; N, 19.20.
1
220±2238C (yellow prisms). H NMR (300 MHz, CDCl3)
d: 2.36 (s, 3H, CH3), 2.99 (s, 3H, NCH3), 3.10 (s, 3H,
NCH3), 5.0 (d, 1H, Jˆ12.6 Hz, H-a), 7.24 (dd, 1H, Jˆ7.9,
4.7 Hz, H-5), 7.27 (d, 2H, Jˆ8.9 Hz, Hm), 7.78 (d, 1H,
Jˆ12.6 Hz, H-b), 8.10 (d, 2H, Jˆ8.9 Hz, Ho), 8.22 (s, 1H,
H-2), 8.42 (dd, 1H, Jˆ4.7, 1.6 Hz, H-4), 8.63 (dd, 1H,
Jˆ7.9, 1.6 Hz, H-6). 13C NMR (75 MHz, CDCl3) d: 21.6
(CH3), 37.3 (NCH3), 45.0 (NCH3), 92.5 (C-a), 119.8 (C-5),
120.5 (C-3), 121.5 (C-3a), 127.9 (C-2), 128.2 (Co), 129.7
(Cm), 131.9 (C-6), 134.9 (Ci), 145.4 (C-4), 145.5 (Cp), 147.3
(C-7a), 153.1 (C-b), 183.4 (CO). IR (CH2Cl2) n: 1642 (s),
1559 (s), 1525 (s), 1390 (s), 1375 (s), 1172 (s) cm21. MS:
m/z (%) (EI positive) 370 (M1, 26), 369 (59), 215 (58), 214
(M2Ts, 100), 199 (32), 171 (49), 155 (23), 149 (66), (91
(62). Anal. Calcd for C19H19N3O3S: C, 61.77; H, 5.18; N,
11.37. Found; C, 61.55; H, 5.30; N, 11.51.
3.4.3. 3-Acetyl-7-azaindole 7. To cooled solution of 7-
azaindole (0.05 g, 0.42 mmol) in dry benzene 95 mL), a
solution of SnCl4 (0.91 g, 0.734 mmol) in the same solvent
(1 mL) was added under N2. The resultant solution was
stirred for 15 min at that temperature and then a solution
of acetyl chloride (0.06 g, 0.726 mmol) in the same solvent
(1 mL) was added. The mixture was stirred for 30 min at
08C. The solvent was removed under reduced pressure and
the remaining solid was dissolved in dry THF (10 mL). The
solution was cooled at 08C and subsequently SnCl4 (0.191 g,
0.734 mmol) and acetyl chloride (0.06 g, 0.726 mmol) were
added. The solution was allowed to warm to room tempera-
ture and stirred for 3 days. The solution was poured into 1N
hydrochloric acid (100 mL) and washed with hexane
3.4.6. 3-[(2-Amino)pyrimidin-4-yl]-7-azaindole 10. This
compound was prepared in 70% yield from enaminone 9
and guanidine hydrochloride by the procedure described for
1
the preparation of 5. Mp 286±2898C (yellow prisms). H
NMR (300 MHz, DMSO-d6) d: 6.47 (s, 2H, NH2), 7.05 (d,
1H, Jˆ5.13 Hz, H-50) 7.13 (dd, 1H, Jˆ8.12, 4.7 Hz, H-5),

P. M. Fresneda et al. / Tetrahedron 57 (2001) 2355±2363
2363
8.14 (d, 1H, Jˆ5.13 Hz, H-60), 8.28 (dd, 1H, Jˆ8.12,
1.28 Hz, H-6), 8.33 (s, 1H, H-2), 8.92 (dd, 1H, Jˆ4.7,
1.28 Hz, H-4) 12.17 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6) d: 105.0 C-50), 112.5 (C-3), 116.6 (C-5), 117.8
(C-3a), 128.3 (C-2), 130.6 (C-6), 143.4 (C-4), 143.4 (C-7a),
157.2 (C-60), 162.0 (C-40), 163.5 (C-20). IR (nujol) n: 3473
6. Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.; Fujita,
D.; Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527.
7. (a) N'Diaye, Y.; Guella, G.; Chiasera, G.; Mancini, Y.; Pietra,
F. Tetrahedron Lett. 1994, 50, 4147. (b) Guella, G.; Mancini,
Y.; N'Diaye, Y.; Pietra, F. Helv. Chim. Acta 1999, 77, 1994.
8. Bergmann, T.; Schories, D.; Steffan, B. Tetrahedron 1997, 53,
2055.
(m), 3294 (m), 3133 (m), 1670 (s), 1565 (s), 1223 (m) cm21
.
MS: m/z (%) (EI positive) 212 (M111, 35), 211 (M1, 100),
210 (68), 195 (11), 170 (48), 142 (31). C11H9N5: C, 62.55;
H, 4.29; N, 33.16 Found; C, 62.73; H, 4.45; N, 33.22.
9. Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L.;
Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116.
Â
10. Franco, L. H.; Joffe, E. B. K.; Puricelly, L.; Tatian, M.; Seldes,
A. M.; Palermo, J. A. J. Nat. Prod. 1998, 61, 1130.
11. Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999,
64, 2540.
Acknowledgements
12 (a) Perry, N. B.; Ettonati, L.; Litandon, M.; Blunt, J. W.;
Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994,
50, 3987. (b) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.;
Ettonati, L.; Litandon, M.; Blunt, J. W.; Munro, M. H. G.;
Jameson, G. B. Tetrahedron 1994, 50, 3993.
We gratefully acknowledge the ®nancial support of the
   Â
Direccion General de Investigacion Cientõ®ca y Tecnica
(PB95-1019).
13. (a) Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1995,
36, 2615. (b) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.;
Hibino, S. Synlett 1995, 147. (c) Choshi, T.; Yamada, S.;
Sugino, E.; Kuwada, T.; Hibino, S. J. Org. Chem. 1995, 60,
5899. (d) Choshi, T.; Yamada, S.; Nabuhiro, J.; Mihara, Y.;
Sugino, E.; Hibino, S. Heterocycles 1998, 48, 11.
14. Gribble, G. W.; Conway, S. C. Synth. Commun. 1992, 22,
2129.
References
1. Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155.
2. (a) Sakemi, S.; Sun, H. H. J. Org. Chem. 1991, 56, 4304.
(b) Kawasaki, Y.; Yamashita, M.; Otha, S. J. Chem. Soc.,
Chem. Commun. 1994, 2085. (c) Kawasaki, Y.; Yamashita,
M.; Otha, S. Chem. Pharm. Bull. 1996, 44, 1831.
15. (a) Zheng, Q.; Yang, Y.; Martin, A. R. Tetrahedron Lett. 1993,
34, 2235. (b) Takayama, H.; Watanabe, F.; Kitajima, K.;
Aimi, N. Tetrahedron Lett. 1997, 38, 5307.
3. (a) Bartik, K.; Braekman, J. C.; Daloze, D.; Stoller, C.;
Huysecom, J.; Vandevyver, G.; Ottinger, R. Can. J. Chem.
1987, 65, 2118. (b) Braekman, J. C.; Daloze, D.; Stoller, C.
Bull. Soc. Chim. Belg. 1987, 96, 809. (c) Tsuji, S.; Rinehart,
K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui, M. S.;
Pomponi, S. A.; Diaz, M. C. J. Org. Chem. 1988, 53, 5446.
(d) Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715.
(e) Kawasaki, Y.; Katsuma, H.; Nakayama, Y.; Yamashita,
M.; Otha, S. Heterocycles 1998, 48, 1887.
16. Sakamoto, T.; Kondo, Y.; Takazawa, N.; Yamanaka, M.
Tetrahedron Lett. 1993, 37, 5955.
17. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994,
35, 2405.
18. Bredereck, H.; Effenberger, F.; Botsch, H.; Rehn, H. Chem.
Ber. 1965, 98, 1081.
19. Kiso, Y.; Isawa, H.; Kitagawa, K.; Akita, T. Chem. Pharm.
Bull. 1978, 26, 2562.
4. Sun, H. H.; Sakemi, J. J. Org. Chem. 1991, 56, 4307.
5. Vervoort, H. C.; Richards-Gross, S. E.; Fenical, W.; Lee,
A. Y.; Clardy, J. J. Org. Chem. 1997, 62, 1486.
20. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986,
51, 5106.