A novel approach to the indoloquinoline alkaloids cryptotackieine and cryptosanguinolentine by application of cyclization of o-vinylsubstituted arylheterocumulenes

Article abstract of DOI:10.1016/S0040-4020(01)00597-X

1-Methyl-3-(o-azidophenyl)quinoline-2-one prepared by cyclization of the corresponding o-vinylsubstituted isocyanate under microwave irradiation is directly converted into cryptotackieine 1 by an intramolecular aza-Wittig reaction with trimethylphosphine; alternatively heating followed by reduction of the resulting indoloquinoline derivative provided cryptosanguinolentine 2.

Full text of DOI:10.1016/S0040-4020(01)00597-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6197±6202
A novel approach to the indoloquinoline alkaloids
cryptotackieine and cryptosanguinolentine by application of
cyclization of o-vinylsubstituted arylheterocumulenes
Pilar M. Fresneda,p Pedro Molinap and Santiago Delgado
  Â
Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo, E-30071 Murcia, Spain
Received 5 April 2001; revised 16 May 2001; accepted 30 May 2001
AbstractÐ1-Methyl-3-(o-azidophenyl)quinoline-2-one prepared by cyclization of the corresponding o-vinylsubstituted isocyanate under
microwave irradiation is directly converted into cryptotackieine 1 by an intramolecular aza-Wittig reaction with trimethylphosphine;
alternatively heating followed by reduction of the resulting indoloquinoline derivative provided cryptosanguinolentine 2. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
azahexatriene systems,7 we have reported that arylhetero-
cumulenes containing an appropriate either ethylenic or
acetylenic side chain at the ortho-position undergo thermal
cyclization to afford either quinoline derivatives or
indolo[2,3-b]quinolines.8 This protocol was used by us9
for our ®rst synthesis of the cryptotackieine at the same
time of Timari's work. In our synthesis the reaction of
iminophosphorane derived from o-aminophenylacetylene
with phenyl isocyanate led to the indolo[2,3-b]quinoline
albeit in low yield (14%), the 2-phenylaminoquinoline
(electrocyclic ring closure product) being the major product
(40%). Recently, this methodology has successfully been
applied by the Wang10 and Schmittel11 groups for the synth-
esis of several kinds of fused-indole compounds.
In recent years combined research efforts have led to the
isolation of a diverse assortment of indoloquinoline alka-
loids from Cryptolepis sanguinolenta1 a shrub indigenous to
tropical West Africa, which has long been used in folk
medicine in the treatment of infectious diseases, amoebiasis,
fever and as an antimalarial agent.2 In 1996 two independent
groups3 reported the isolation of two new structurally and
biosynthetically related alkaloids: cryptotackieine 1 (also
named neocryptolepine) and cryptosanguinolentine 2 (also
named isocryptolepine). Cryptotackieine 1, which displays
a strong antiplasmodial activity against P. falciparum chlor-
oquine-resistant strains,4 was found to be a N-methyl deri-
vative of the linear indolo[2,3-b]quinoline ring system,
whereas the cryptosanguinolentine 2 which differs in the
fusion of the indole and quinoline ring, possesses an angular
indolo[3,2-c]quinoline ring system. It has been reported that
these compounds and some methyl derivatives display
various biological properties such as antimuscarinic, anti-
bacterial, antiviral, antimicotic, antihyperglycemic and
cytotoxic activities as well as signi®cant antitumor proper-
ties in vitro.5
2. Results
We have devised and improved a reliable divergent
approach for the preparation of the target alkaloids 1 and
2, which is based on the formation of the key common 1-
methyl-(o-azidophenyl)quinoline-2-one intermediate 10
and its suitable use for the preparation of cryptotackieine
1 and cryptosanguinolentine 2 by a selective indolization
process (Scheme 1).
In 1997 Timari et al.6 reported the synthesis of cryptotack-
ieine 1 and cryptosanguinolentine 2 by a palladium cross-
coupling reaction of 3-bromoquinoline derivative with N-
pivaloylaminophenyl boronic acid and further indolization.
In the course of our studies directed towards the synthesis of
azaheterocycles based on heterocyclization reactions of
Condensation of (2-nitrobenzyl)triphenylphosphonium
bromide with o-azidobenzaldehyde12 in the presence of
anhydrous potassium carbonate and catalytic amounts of
dibenzo-18-crown-6 yielded the stilbene derivative 3 in
85% yield as a 4:1 mixture of Z/E isomers. Staudinger reaction
between triphenylphosphine and the azide 3 in dry dichloro-
methane provided the iminophosphorane 4a in 92% yield as a
4:1 mixture of Z/E isomers. Thiophenol/AIBN-catalyzed
isomerization afforded the E-iminophosphorane isomer 4a
Keywords: alkaloids; aza-Wittig reaction; microwave heating; insertion
reaction; nitrogen heterocycles.
Corresponding authors. Tel.: 134-968-36-74-96; fax: 134-968-36-41-
49; e-mail: fresneda@um.es; pmolina@um.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00597-X

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P. M. Fresneda et al. / Tetrahedron 57 (2001) 6197±6202
Scheme 1. Reagents and conditions: (a) K2CO3/dibenzo-18-crown-6/CH2Cl2, rt, 85%; (b) i: Ph3P, CH2Cl2, rt, ii: PhSH/AIBN/benzene, re¯ux, E-4a 70%; (c) i:
from 4b, THF/H2O, rt, 84%; ii: PhSH/AIBN/benzene, re¯ux, 92%; (d) triphosgene, CH2Cl2, 08C!rt; (e) MW, nitrobenzene, 80%; (f) CH3I, DMF, 608C, 82%;
(g) H2, Pd/C, EtOH, rt, 91%; (h) NaNO2/H2SO4, H2O-NaN3, 85%; (i) MW, Me3P, nitrobenzene, 1808C, 40%; (j) o-xylene, 1508C, 82%; (k) Red-Al, toluene,
re¯ux, 90%.
in 70% yield. Aza-Wittig reaction of the E-isomer 4a with
carbon dioxide in toluene at re¯ux temperature led to a
mixture of the isocyanate 6 (minor product) and the corre-
sponding diaryl carbodiimide (major product), presumably
formed by intermolecular aza-Wittig reaction of the imino-
phosphorane 4a with the isocyanate 6. When the reaction was
carried out at 2788C the isocyanate 6 was found to be the
major product, being now the carbodiimide the minor
product. However, all attempts for the isolation of 6 in pure
state failed.
microwave-promoted cyclization of the resulting isocyanate
6. Conversely, isocyanate derived from the Z-5 isomer did
not undergo cyclization to the quinoline-2-one neither by
classical heating nor under microwave irradiation.
Conversion of the quinoline-2-one 7 into 10 was achieved
by the three-step sequence: (a) methylation to give 8 (82%);
(b) catalytic hydrogenation in the presence of palladium on
charcoal to afford 9 (91%) and (c) diazotization followed by
the reaction with sodium azide provided 10 (85%).
After these frustrating results, we turned our attention to the
`phosgene route' for the preparation of 6. Surprisingly,
iminophosphorane 4a was recovered unaltered after treat-
ment with hydrochloric acid in THF solution at room
temperature for seven days. However, reaction of 3 with
tri-n-butylphosphine followed by hydrolysis of the resulting
iminophosphorane 4b gave the stilbene derivative 5 in 84%
yield as a 7:1 mixture of Z/E isomers, which were separated
by column chromatography; Z!E isomerization led the (E)-
2-amino-20-nitrostilbene 5 in 92% yield. One-¯ask conver-
sion of compound E-5 into the quinoline-2-one derivative 7
was achieved in 80% yield by sequential treatment with
bis(trichloromethyl)carbonate (triphosgene) and further
Initial attempts to promote cyclization of the intermediate
10 into cryptotackieine 1 by treatment with triphenyl-
phosphine and then thermal cyclization of the resulting
iminophosphorane were unsuccessful even after an
extended reaction time and high temperature (2008C).
When 10 was treated with the more reactive tri-n-butylphos-
phine at room temperature, and further heating in o-xylene
at re¯ux temperature for 24 h of the resulting iminophos-
phorane, the alkaloid 1 was obtained albeit in a very disap-
pointing yield of 5%. However, treatment of 10 with
trimethylphosphine at room temperature until nitrogen
evolution was ceased followed by heating in nitrobenzene
at re¯ux temperature for 24 h of the resulting reactive

P. M. Fresneda et al. / Tetrahedron 57 (2001) 6197±6202
6199
iminophosphorane afforded 1 in low yield 24%. Switching
from classical heating to microwave irradiation produced
the best yield and shorter reaction time. Thus, when a solu-
tion of the iminophosphorane derived from 10 and
trimethylphosphine in nitrobenzene was heated under
microwave irradiation between 150 and 1808C for 30 min,
cryptotackieine 1 was obtained in 40% yield. Although
intramolecular aza-Wittig imination reactions involving
amide carbonyl groups have been reported,7 the conversion
10!1 represents the ®rst example of an intramolecular aza-
Wittig reaction involving a 2-pyridone carbonyl group, to
the best of our knowledge.
dibenzo-18-crown-6 (5.0 mg) a solution of o-azidobenzal-
dehyde (3.0 g, 20.1 mmol) in the same solvent was added
under N2. The resultant mixture was stirred at room
temperature for 16 h. After ®ltration the mixture was
concentrated to dryness and the crude product was chroma-
tographed on a silica gel column using CH2Cl2/hexane (1:1)
as eluent to give 3 in 85% yield as a mixture of Z/E (4:1)
1
isomers as revealed by the H NMR spectrum.
To a cooled at 08C solution of 3 (0.5 g, 1.88 mmol) in dry
CH2Cl2 (10 mL) a solution of triphenylphosphine (0.49 g,
1.88 mmol) in the same solvent (10 mL) was added drop-
wise under N2. After the addition was completed, the resul-
tant solution was allowed to warm at room temperature and
stirred for 5 h. The solvent was removed under reduced
pressure and the residual material was slurried with diethyl
ether (20 mL). The solid triphenylphosphine oxide was
separated by ®ltration and the ®ltrated was concentrated to
dryness to give the iminophosphorane 4a in 92% yield as a
Alternatively, when compound 10 was exposed to heat in o-
xylene at re¯ux temperature indolization took place by a
nitrene insertion process across the 4-position of the pyri-
done ring to give 11 in 82% yield, thus completing the
assembly of the framework of the cryptosanguinolentine.
The ®nal step was to effect the reduction of the carbonyl
group of the 2-pyridone ring. After several trials (DIBAL-H,
08C; LiAlH4/AlCl3 and Na(Hg)/EtOH), the best results were
obtained by using Red-Al as reducing agent. Thus, reaction
of 11 with Red-Al in toluene at re¯ux temperature and then
treatment of the crude product with anhydrous MgSO4
provided cryptosanguinolentine 2 in 90% yield.
1
mixture of Z/E (4:1) isomers as revealed by H NMR.
To a solution 4a E/Z mixture (2.0 g, 4.0 mmol) in dry tolu-
ene (50 mL), thiophenol (0.23 g, 2.07 mmol) was added.
The mixture was re¯uxed for 15 min, then AIBN (0.85 g,
5.2 mmol) was added slowly over 5 h. The resultant solution
was treated at re¯ux temperature overnight. After cooling,
the solvent was removed under reduced pressure. The resi-
due was extracted with dry benzene (3£15 mL) and the
combined extracts were concentrated to dryness. The
remaining solid was taken up in diethyl ether and the resul-
tant red solid was separated by ®ltration to give (E)-4a in
70% yield, mp 172±1748C (red prisms from dichloro-
methane/diethyl ether). 1H NMR (300 MHz, CDCl3)
d: 6.49 (d, 1H, Jˆ8.1 Hz, H-30), 6.68 (t, 1H, Jˆ7.2 Hz,
H-50), 6.84 (t, 1H, Jˆ7.2 Hz, H-40), 7.28 (t, 1H,
Jˆ7.5 Hz, H-4), 7.40±7.61 (m, 12H), 7.72±7.79 (m, 6H,
H-o), 7.87 (d, 2H, Jˆ8.1 Hz, H-31H-6), 8.24 (d, 1H,
Jˆ16.2 Hz, H-7 or H-8). 13C NMR (75 MHz, CDCl3)
3. Conclusions
In conclusion, we have developed a new and divergent
approach to the alkaloid cryptotackieine 1 (eight steps)
and cryptosanguinolentine 2 (nine steps). Preparation of
the key intermediate 3-arylquinoline-2-one 9 is based on
the electrocyclic ring closure of the appropriate o-vinylsub-
stituted isocyanate, selective indolization is achieved either
by intramolecular aza-Wittig reaction to give directly 1 or
by nitrene insertion process followed by reduction to give 2.
3
d: 117 (C-50), 119.7 (C-3), 122.2 (d, JC±Pˆ9.8 Hz, C-30),
124.6 (C-7 or C-8), 126.4 (C-60), 126.5 (C-6), 127.8 (C-4)
4. Experimental
4.1. General
3
128.6 (d, JC±Pˆ12.15 Hz, C-m), 128.8 (C-40), 130.7 (d,
1
3JC±Pˆ20.2 Hz, C-10), 131.1 (d, JC±Pˆ95.7 Hz, C-i),
4
2
131.7 (d, JC±Pˆ2.9 Hz, C-p), 132.5 (d, JC±Pˆ9.8 Hz,
C-o), 133.8 (C-5), 134.7 (C-1), 147.8 (C-2) 150.1 (C-20).
31P NMR (125 MHz, CDCl3) d: 2.57. IR (nujol) n: 1602 (s),
1510 (s), 1347 (s), 1116 (s), 1000 (m), 750 (s), 721 (s), 702
(s) cm21. MS: m/z (%) (EI positive) 501 (M11, 5), 500 (M,
14), 483 (100), 468 (47), 381 (51), 379 (36), 352 (87), 262
(69), 183 (81), 108 (39), 77 (17). Anal. Calcd for
C32H25NO2P: C, 76.79; H, 5.03; N, 5.60. Found: C, 76.72;
H, 4.97; N, 5.64.
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 Fisons AUTOSPEC5000 VG. Microanalyses
were performed on a Perkin Elmer 240C instrument. Reac-
tions under microwave irradiation were preformed in a
Synthewave 402 Prolabo microwave reactor (2.45 GH,
adjustable power within the range 0±300 W with a simple
mode focused system) ®tted with a rotational system and an
IR detector of temperature. The microwave oven is moni-
tored by a computer that allows the temperature of the reac-
tion mixture to be adjusted.
4.1.2. (E)-2-Amino-20-nitrostilbene 5. To a cooled at 08C
solution of the azide 3 (1:4 E/Z isomers mixture) (2.5 g,
9.4 mmol) in dry THF (100 mL), tri-n-butylphosphine
(2.0 g, 9.87 mmol) was added under N2. The solution was
stirred at room temperature for 1 h. Then, H2O (80 mL) and
hydrochloric acid (1 mL) were added and the mixture was
stirred at room temperature for 24 h. After addition of 5%
NaOH until basic pH, the combined organic layers were
dried on Na2CO3. The solvent was removed under reduced
pressure to give the crude product 5 as a mixture of Z/E
isomers. Chromatographic separation on a silica gel column
4.1.1. (E)-2-Nitro-20-(triphenylphosphoranylidene)amino-
stilbene 4a. To a mixture of (2-nitrobenzyl)triphenylphos-
phonium bromide13 (10.6 g, 22.16 mmol), dry CH2Cl2
(50 mL), anhydrous K2CO3 (4.17 g, 30.15 mmol), and

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P. M. Fresneda et al. / Tetrahedron 57 (2001) 6197±6202
using diethylether/hexane (4:1) as eluent afforded the Z
isomer in 86% yield and the E isomer in 14% yield. (Z)-5
mp 90±918C (dichloromethane/hexane). 1H NMR
(300 MHz, CDCl3) d: 3.77 (s, 2H, NH2), 6.54 (td, 1H,
Jˆ7.6, 1.3 Hz, H-5), 6.59 (d, 1H, Jˆ8.1 Hz, H-3), 6.7 (d,
1H, Jˆ8.1 Hz, H-7 or H-8), 6.84 (dd, 1H, Jˆ7.6, 0.8 Hz,
H-6), 6.90 (d, 1H, Jˆ11.8 Hz, H-7 or H-8), 6.99 (td, 1H,
Jˆ8.1, 1.6 Hz, H-4), 7.17±7.22 (m, 1H, H-50), 7.26±7.31
(m, 2H, H-40 and H-60), 7.95±7.98 (m,1H, H-30). 13C NMR
(75 MHz, CDCl3) d: 115.5 (C-3), 118.1 (C-5), 121.4 (C-1),
124.3 (C-30), 127.9 (C-40 or C-6), 128.0 (C-7), 128.6 (C-8),
128.7 (C-4), 129.9 (C-6), 131.7 (C-50), 132.7 (C-40 or C-600)
133.1 (C-10), 144.1 (C-2); 148.04 (C-20). IR (nujol) n: 3449
(m), 3365 (m), 1639 (s), 1518 (s) cm21. MS: m/z (%) (EI
positive): 240 (M, 47), 223 (M217, 36), 206 (18), 194 (24),
165 (40), 93 (100). Anal. Calcd for C14H12N2O2: C, 69.99;
H, 5.03; N, 11.66. Found: C, 69.91; H, 4.96; N, 11.70.
ing, the precipitated solid was separated by ®ltration,
washed with water (2£15 mL), diethyl ether (2£15 mL)
and air-dried, to give 7 (0.89 g, 80%); mp 3188C (yellow
prisms from tetrahydrofuran/diethyl ether). 1H NMR
(300 MHz, DMSO-d6) d 7.25 (t, 1H, Jˆ7.8 Hz, H-6), 7.36
(d,1H, Jˆ8.1 Hz, H-8), 7.56 (t, 1H, Jˆ8.1 Hz, H-7), 7.65 (d,
1H, Jˆ7.8 Hz, H-5), 7.67 (t, 1H, Jˆ7.8 Hz, H-40), 7.78 (d,
1H, Jˆ7.8 Hz, H-60), 7.83 (t, 1H, Jˆ7.8 Hz, H-50), 8.06 (d,
1H, Jˆ7.8 Hz, H-30), 8.17 (s, 1H, H-4), 12.00 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6) d 115.0 (C-8), 119.3 (C-4a),
122.1 (C-6), 123.9 (C-30), 128.2 (C-60), 129.4 (C-40), 130.6
(C-7), 130.9 and 131.0 (C-10 or C-3), 132.2 (C-5), 133.6
(C-50), 137.5 (C-4), 138.5 (C-8a), 148.9 (C-20), 160.0
(C-2). IR (nujol) n 1662 (s), 1531 (s), 1365 (m) cm21
.
MS: m/z (%) (EI positive) 267 (M11, 3), 266 (M, 18),
234 (14), 220 (100), 190 (13), 165 (20). Anal. Calcd for
C15H10N2O3: C, 67.67; H, 3.79; N, 10.52. Found: C,
67.61; H, 3.73; N, 10.60.
To a solution of (Z)-5 (91.7 g, 7.08 mmol) in dry benzene
(30 mL), thiophenol (0.47 g, 4.25 mmol) was added under
nitrogen. The mixture was heated at re¯ux tempertaure and
AIBN (1.47 g, 10.62 mmol) was added slowly over 2 h.
After cooling, the solvent was removed under reduced pres-
sure and the residue was taken up in diethyl ether 925 mL)
and recrystallized from CH2Cl2/hexane. To give the (E)-5 in
pure form in 92% yield. Mp 109±1118C (dichloromethane/
4.1.4. 1-Methyl-3-(o-nitrophenyl)-1H-quinoline-2-one 8.
To a mixture of 7 (1.0 g, 3.76 mmol) in dry DMF (40 mL),
and anhydrous K2CO3 (3.12 g, 22.56 mmol), methyliodide
(1.6 g, 11.28 mmol) was added dropwise under N2. The
resultant mixture was stirred at 608C for 2 h. After addition
of H2O (40 mL) the precipitated yellow solid was collected
by ®ltration, washed with diethyl ether (2£10 mL), air-dried
and recrystallized from CH2Cl2/diethyl ether (1:1) to give 8
1
diethyl ether). H NMR (300 MHz, CDCl3) d: 3.89 (s, 2H,
1
NH2), 6.70 (dd, 1H, Jˆ8.1, 1.0 Hz, H-3), 6.79 (t, 1H,
Jˆ7.5 Hz, H-5), 7.11 (d, 1H, Jˆ16.0 Hz, H-7 or H-8),
7.11 (td, 1H, Jˆ7.6, 1.0 Hz, H-4), 7.33±7.39 (m, 2H, H-40
and H-6), 7.43 (d, 1H, Jˆ16 Hz, H-7 or H-8), 7.56 (td, 1H,
Jˆ7.9, 0.8 Hz, H-50), 7.71 (dd, 1H, Jˆ7.9, 1.0 Hz, H-60),
7.93 (dd, 1H, Jˆ8.1, 1.3 Hz, H-30). 13C NMR (75 MHz,
CDCl3) d: 116.5 (C-3), 119.0 (C-5), 122.7 (C-1), 124.6
(C-30 and C-7 or C-8), 127.73 and 127.75 (C-40 or C-6),
128.2 (C-60), 129.6 and 129.9 (C-4 and C-7 or C-8), 133.1
(C-50), 133.3 (C-10), 144.4 (C-2); 147.7 (C-20). IR (nujol) n:
3441 (m), 3363 (m), 1637 (s), 1602 (s), 1516 (s), 1352
(s) cm21. MS: m/z (%) (EI positive): 240 (M, 100), 223
(M217, 96), 206 (47), 194 (67), 165 (87), 93 (96). Anal.
Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found:
C, 69.93; H, 4.95; N, 11.72.
in 82% yield. H NMR (300 MHz, CDCl3) d: 3.72 (s, 3H,
CH3), 7.27 (d, 1H, Jˆ7.5 Hz, H-6), 7.38 (d, 1H, Jˆ8.4 Hz,
H-8), 7.45 (dd, 1H, Jˆ7.6, 1.6 Hz, H-5), 7.52 (td, 1H,
Jˆ7.7, 1.3 Hz, H-40), 7.56±7.67 (m, 3H, H-7, H-50 and
H-60), 7.81 (s, 1H, H-4), 8.04 (dd, 1H, Jˆ8.1, 1.0 Hz,
H-30). 13C NMR (75 MHz, CDCl3) d: 29.9 (CH3), 114.2
(C-8), 120.4 (C-4a), 122.4 (C-6), 124.3 (C-30), 129.0
(C-60), 129.1 (C-40), 130.9 (C-7), 130.9 and 131.3 (C-30 or
C-10), 131.9 (C-5), 133.1 (C-50), 136.3 (C-4), 139.9 (C-8a),
149.4 (C-20), 160.5 (CO). IR (nujol) n 1642 (CO), 1529 (s),
1357 (s) cm21. MS: m/z (%) (EI positive) 280 (M, 96, 248
(17), 234 (82), 219 (100), 204 (44), 190 (63), 178 (22), 165
(44). Anal. Calcd for C16H12N2O3: C, 68.57; H, 4.32; N,
9.99. Found: C, 68.52; H, 4.27; N, 10.07.
4.1.5. 1-Methyl-3-(o-aminophenyl)-1H-quinoline-2-one 9.
To a suspension of 10% Pd/C (0.1 g) in EtOH (45 mL) was
added 8 (0.8 g, 2.86 mmol). The mixture was stirred at room
temperature for 5 h, while a stream of the H2 was bubbled
over the solution. The solid was separated by ®ltration and
washed with EtOH (3£10 mL). The combined ®ltrates were
concentrated to dryness and residue product was dissolved
in EtOAc (20 mL) and ®ltered over a celite pad. Concentra-
tion to dryness afforded a solid that was recrystallized from
4.1.3. 3-(o-Nitrophenyl)-1H-quinoline-2-one 7. To a solu-
tion of bis(trichloromethyl) carbonate (triphosgene) (0.45 g,
1.53 mmol) in dry dichloromethane (20 mL) was added
dropwise over a period of 15 min a mixture of 2-amino-
20-nitrostilbene 5 (1 g, 4.17 mmol), triethylamine (0.47 g,
4.59 mmol) and dry dichloromethane (25 mL) at 08C
under N2. Then, the resulting mixture was allowed to
warm to room temperature and stirred for 1 h. The solvent
1
1
was removed under reduced pressure to give 6. H NMR
EtOAc/diethyl ether to give 9 in 91% yield. H NMR.
(300 MHz, CDCl3) d: 7.17 (dd, 1H, Jˆ7.8, 1.8 Hz), 7.21±
7.32 (m, 2H), 7.33 (d, 1H, Jˆ15.9 Hz), 7.46 (td, 1H, Jˆ8.4,
1.5 Hz), 7.60 (d, 1H, Jˆ15.9 Hz), 7.66±7.69 (m, 2H), 7.80
(dd, 1H, Jˆ7.8, 1.2 Hz), 8.00 (dd, 1H, Jˆ8.1, 1.2 Hz). 13C
NMR (75 MHz, CDCl3) d: 118.7, 124.3, 125.7, 125.8,
126.2, 127.9, 128.1 (2C), 129.1, 130.7, 131.3, 132.3,
(300 MHz, CDCl3) d: 3.83 (s, 3H, CH3), 4.10 (br, 2H,
NH2), 6.81 (ddd, 1H, Jˆ7.6, 1.0, 0.8 Hz, H-30), 6.87 (td,
1H, Jˆ7.6, 1.3 Hz, H-50), 7.20 (d, 1H, Jˆ7.3 Hz, H-60),
7.22 (td, 1H, Jˆ7.3, 1.6 Hz, H-40), 7.28 (td, 1H, Jˆ7.6,
1.0 Hz, H-6), 7.42 (dd, 1H, Jˆ8.1, 0.8 Hz, H-8), 7.60 (td,
1H, Jˆ7.4, 1.6 Hz, H-7), 7.61 (d, 1H, Jˆ7.6 Hz, H-5), 7.82
(s, 1H, H-4). 13C NMR. (75 MHz, CDCl3) d: 29.9 (CH3),
114.0 (C-8), 117.1 (C-30), 118.9 (C-500), 120.6 (C-4a), 122.3
(C-6), 124.4 (C-3), 128.8 (C-5), 129.2 (C-40), 130.4 (C-7),
131.1 (C-60), 132.4 (C-10), 139.4 (C-4 and C-8a), 145.4
(C-20), 161.1 (CO). IR (nujol) n 3427 (m), 3330 (m),
133.1, 147.5. IR (nujol) n 2281 (s), 1532 (s), 1330 (s) cm21
.
The crude isocyanate 6 was dissolved in nitrobenzene
(15 mL), in a glass tube which was placed in a Synthewave
402 reactor and irradiated for 12 min at 1508C. After cool-

P. M. Fresneda et al. / Tetrahedron 57 (2001) 6197±6202
6201
1640 (CO) cm21.MS: m/z (%) (EI positive) 250 (M, 100),
233 (85), 219 (20). Anal. Calcd for C16H14N2O: C, 76.78; H,
5.64; N, 11.19. Found: C, 76.72; H, 5.58; N, 11.13.
loquinolone 11 (50 mg, 0.2 mmol) in dry toluene (15 mL),
sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al)
(0.42 mL of a 65% toluene solution) was added dropwise
under N2. The mixture was re¯uxed for 32 h. After cooling,
the solution was poured into 20% aqueous NaOH solution
(50 mL) and then stirred for 30 min. The mixture was
extracted with diethyl ether (3£50 mL) and dissolved in
dichloromethane (30 mL), anhydrous MgSO4 was added
and the mixture was stirred for 2 h. The solvent was
removed under reduced pressure and the solid was washed
with dichloromethane (3£20 mL). The remaining solid was
dissolved in H2O (75 mL) and the resultant solution was
extracted with dichloromethane (2£20 mL). The combined
organic layers were concentrated to dryness and the solid
residue was chromatographed on a silica gel column using
toluene/acetone/NH4OH 25:25:1 as eluent to give crypto-
sanguinolentine 2 90% yield.
4.1.6. 1-Methyl-3-(o-azidophenyl)-1H-quinoline-2-one 10.
To a cooled at 08C mixture of 9 (1.0 g, 4 mmol) H2O
(40 mL) and H2SO4 (0.9 mL) was added a cooled solution
of NaNO2 (0.4 g, 5.8 mmol) in H2O (3 mL). The suspension
was stirred at that temperature for 30 min. Then a solution
of NaN3 (0.54 g, 8.23 mmol) in H2O (6 mL) was added
dropwise. The resultant suspension was allowed to warm
at room temperature and stirred for 5 h. The solid was
®ltered, washed with 10% aqueous Na2CO3 solution
(2£20 mL) and H2O (2£10 mL) and air-dried. Recrystalli-
zation from CH2Cl2/hexane (1:1) yielded 10 in 85% yield;
mp 1678C (d) (brown prisms from dichloromethane/hex-
ane). 1H NMR. (300 MHz, DMSO-d6) d 3.68 (s, 3H,
CH3N), 7.25 (td, 1H, Jˆ7.7, 1.3 Hz) and 7.30 (td, 1H,
Jˆ7.6, 0.9 Hz) (H-50 or H-6), 7.34±7.38 (m, 2H,
H-301H-60), 7.49 (ddd, 1H, Jˆ9.0, 7.3, 1.7 Hz) and 7.65
(ddd, 1H, Jˆ8.6, 7.3, 1.7 Hz) (H-40 or H-7), 7.56 (d, 1H,
Jˆ9.0 Hz, H-8), 7.75 (dd, 1H, Jˆ7.7, 1.3 Hz, H-5), 7.91 (s,
1H, H-4). 13C NMR. (75 MHz, DMSO-d6) d 29.7 (CH3N),
114.6 (C-8), 119.0 (C-30), 119.7 (C-4a), 122.2 and 124.9
(C-50 or C-6), 129.9 (C-5), 129.2 and 129.5 (C-10 or C-3),
129.7 and 131.0 (C-40 or C-7), 131.6 (C-60), 138.0 (C-20),
138.6 (C-4), 139.6 (C-8a), 160.1 (C-2). IR (nujol) n 2123
(s), 2086 (s), 1652 (m) cm21. MS: m/z (%) (EI positive) 277
(M11, 5), 276 (M, 8), 248 (M2N2, 100), 234 (28), 219 (67).
Anal. Calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28.
Found: C, 69.48; H, 4.32; N, 20.33.
Acknowledgements
We gratefully acknowledge the ®nancial support of the
Â
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Direccion General de Investigacion Cientõ®ca y Tecnica
(PB95-1019). S. D. thanks the Fundacion Seneca (CARM)
for a studentship.
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in 82% yield. 1H NMR (300 MHz, MeOH-d4) d: 3.84 (s, 3H,
NCH3), 7.28 (td, 1H, Jˆ7.8,1.2 Hz), 7.34±7.41 (m, 2H),
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Jˆ7.5 Hz), 8.29 (d, 1H, Jˆ7.5 Hz). 13C NMR. (75 MHz,
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