Iminophoshorane-mediated synthesis of the alkaloid cryptotackieine

Article abstract of DOI:10.1055/s-1999-3386

A new synthesis of the alkaloid cryptotackieine based on the stepwise formation of the pyridine and indole ring is described. The key step, formation of the appropriate 3-arylquinoline, involves a Staudinger/aza- Wittig/electrocyclic ring-closure process.

Full text of DOI:10.1055/s-1999-3386

326
PAPER
Iminophosphorane-Mediated Synthesis of the Alkaloid Cryptotackieine
P. Molina,* P. M. Fresneda,* S. Delgado
Departamento de Qu’mica Org‡nica, Facultad de Qu’mica, Universidad de Murcia, Campus de Espinardo, E-30071 Murcia, Spain
Fax +34(968)364149; E-mail: pmolina@fcu.um.es
Received 15 July 1998
pyridine and indole rings starting from an appropriate
Abstract: A new synthesis of the alkaloid cryptotackieine based on
2,2'-disubstituted stilbene derivative (Scheme).
the stepwise formation of the pyridine and indole ring is described.
The key step, formation of the appropriate 3-arylquinoline, involves
a Staudinger/aza-Wittig/electrocyclic ring-closure process.
Condensation of the (2-nitrobenzyl)triphenylphosphoni-
um bromide with o-bromobenzaldehyde in the presence
of anhydrous K2CO3 and catalytic amounts of dibenzo-18-
crown-6 afforded the stilbene derivative 2 in 95% yield as
a 4:1 mixture of Z/E isomers. Thiophenol/AIBN-cata-
lyzed isomerization to the E-isomer 3 (89% yield) fol-
lowed by reduction with an iron/acetic acid system
provided the (E)-2-amino-2'-bromostilbene (4) in 85%
yield. The key intermediate iminophosphorane 5 was pre-
pared in 87% yield by reacting the aminostilbene deriva-
tive 4 with triphenylphosphine dibromide in the presence of
triethylamine. An aza-Wittig type reaction of the imino-
phosphorane 5 with tosyl isocyanate in toluene at room
temperature led to the carbodiimide 6 (as evidenced by IR),
which was used in the next step without further purifica-
tion. When a toluene solution of the carbodiimide 6 was
heated at reflux temperature the 2-amino-3-arylquinoline
derivative 7 (electrocyclic ring-closure product) was isolat-
ed as the only reaction product in 72% yield. Treatment of
the quinoline derivative 7 with sodium hydride in the pres-
ence of cuprous iodide leads to the indolo[2,3-b]quinoline
8 in 85% yield, and thus completing the assemblage of the
carbon framework of the cryptotackieine (1) (Scheme).
Key words: Staudinger reaction, aza-Wittig reaction, electrocyclic
ring-closure, cryptotackieine, microwave-promoted methylation
Nine alkaloids, most of them with an indoloquinoline
framework, have so far been isolated from Cryptolepis
sanguinolenta1 a shrub indigenous to tropical West Afri-
ca, which has long been used in folk medicine as an anti-
malarial agent.2 In 1996 two independent groups reported
the isolation of a new indoloquinoline alkaloid from etha-
nolic extracts of C. sanguinolenta which was named as
cryptotackieine3 or neocryptolepine.4 This compound,
which displays a strong antiplasmodial activity,5 was
found to be 5-methyl-5H-indolo[2,3-b]quinoline. Quite
recently, Timar’ et al6 reported the synthesis of crypto-
tackieine by a palladium-catalyzed cross-coupling reac-
tion of 3-bromoquinoline derivative with N-
pivaloylaminophenylboronic acid and further indoliza-
tion.
In the course of our studies directed towards the synthesis
of nitrogen heterocyclic compounds based on heterocy-
clization reactions of azahexatriene systems, we have de-
veloped the so-called aza-Wittig/electrocyclic ring
closure for the synthesis of fused pyridines.7 In this con-
text, we have reported that iminophosphoranes derived
from anilines containing an unsaturated side-chain at the
ortho position, react with isocyanates to give carbodiim-
ides which under thermal conditions undergo either elec-
trocyclic ring-closure to afford quinoline derivatives or
intramolecular hetero DielsÐAlder cycloaddition to give
indolo[2,3-b]quinolines.8
This protocol was used by us9 for the formal total synthe-
sis of the cryptotackieine at the same time of Timar’Õs
work. In our synthesis the reaction of iminophosphorane
derived from o-aminophenylacetylene with phenyl iso-
cyanate led to the indolo[2,3-b]quinoline (intramole-
cular hetero DielsÐAlder cycloaddition product) albeit in
low yield (14%), the 2-phenylaminoquinoline (electro-
cyclic ring-closure product) being the major product
(40%).
Attempts at the direct conversion of compound 8 into the
target molecule 1 by treatment with trimethyloxonium tet-
rafluoroborate (ÒMeerwein saltÓ) followed by methanoly-
sis of the intermediate salt10 failed and only the unreacted
starting material was recovered. Conversion of the indo-
lo[2,3-b]quinoline derivative 8 into cryptotackieine (1)
was achieved in two steps: a) deprotection of the N-sulfo-
nyl group with tetrabutylammonium fluoride (TBAF)11
gave 9 in 90% yield and b) microwave-promoted methy-
lation with dimethyl sulfate in dimethylformamide at
140¡C followed by deprotonation provided the target mol-
ecule 1 in 75% yield.
In conclusion we have developed a new and efficient
eight-step synthesis of the alkaloid cryptotackieine (1) in
an overall yield of 25%. Due to the easy availability of
starting materials and high yields of the different steps,
this approach shows to be a useful alternative to those pre-
viously reported.
We have been interested in developing a reliable general
route to indolo[2,3-b]quinolines following the aza-Wittig/
electrocyclic ring-closure strategy. Herein, we want to re-
port a useful and efficient synthesis of cryptotackieine (1).
This approach is based on the stepwise formation of the
(E)-2-Bromo-2'-nitrostilbene (3)
To a mixture of (2-nitrobenzyl)triphenylphosphonium bromide12
(8 g, 16.73 mmol), anhyd CH2Cl2 (100 mL), anhyd K2CO3 (3.47 g,
25.09 mmol), and dibenzo-18-crown-6 (5.0 mg) was added o-bro-
mobenzaldehyde (2.67 g, 14.44 mmol) under N2. The resultant mix-
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PAPER
Iminophosphorane-Mediated Synthesis of Cryptotackieine
327
¥
Reagents and Conditions: a) K2CO3/dibenzo-18-crown-6/CH2Cl2, r.t.; b) PhSH/AIBN/benzene, reflux; c) Fe/AcOH/EtOH, reflux; d) Ph3P Br2/
Et3N/benzene, 0¡C → r.t.; e) TsNCO/toluene, 0¡C → r.t.; f) toluene, reflux; g) NaH/CuI/diglyme, r.t.; h) TBAF/THF, r.t.; i) MW, Me2SO4/DMF,
140¡C, 5 min
Scheme
ture was stirred at r.t. for 16 h. After filtration the mixture was
concentrated to dryness and the crude product was chromato-
graphed (silica gel column, CH2Cl2/hexane, 1:1) to give 2 in 95%
yield as a mixture of Z/E (4:1) isomers as revealed by the 1H NMR
spectrum.
(E)-2-Amino-2'-bromostilbene (4)
To a well stirred mixture of 3 (1 g, 3.29 mmol) and iron filings
(3.67 g) in EtOH (22 mL) was added glacial AcOH (22 mL). The
reaction mixture was heated at reflux temperature for 2 h. After
cooling, the mixture was poured into H2O (100 mL) and neutralized
with Na2CO3. The resultant mixture was extracted with Et2O (5 ×
30 mL) and the combined organic layers were washed with H2O
(30 mL) and dried (MgSO4). The solvent was removed under re-
duced pressure and the crude product was purified by column chro-
matography on silica gel using CH2Cl2/hexane (1:1) as eluent to
give 4 (0.77g); yield 85%; mp 185¡C.
To a solution of 2 (1g, 3.29 mmol) in anhyd benzene (25 mL) was
added thiophenol (0.187 g, 1.7 mmol) and the mixture was refluxed
for 15 min, then AIBN (0.7 g, 4.27 mmol) was added slowly over
5 h. The resultant solution was heated at reflux temperature over-
night. After cooling, the solvent was removed under reduced pres-
sure and the residue was taken up in EtOH (10 mL) and the resultant
yellow solid was separated by filtration and recrystallized from
CHCl3/hexane, to give 3 (0.88 g); yield 89%; mp 114Ð115¡C.
IR (Nujol): n = 1022, 1632, 3364, 3461 cmÐ1.
1H NMR (300 MHz, CDCl3/TMS): d = 3.7 (br s, 2 H), 6.68 (dd, 1
H, J = 8.0, 1.2 Hz, H-3), 6.80 (td, 1 H, J = 7.4, 1.0 Hz, H-5),7.06 (d,
1 H, J = 16.0 Hz, H-7 or H-8), 7.04Ð7.16 (m, 2 H, H-4 + H-4'), 7.27
(td, 1 H, J = 7.6, 0.8 Hz, H-5'), 7.32 (d, 1 H, J = 16.0 Hz, H-7 or H-
8), 7.42 (dd, 1 H, J = 7.6, 1.3 Hz, H-6), 7.56 (dd, 1 H, J = 8.0,
1.3 Hz, H-3'), 7.62 (dd, 1 H, J = 8.0, 1.6 Hz, H-6').
13C NMR (50 MHz, CDCl3/TMS): d = 116.4 (C-3),119.1 (C-5),
123.4 (C-2'), 124.0 (C-1), 126.7 (C-6'), 127.2 (C-7 or C-8), 127.5
(C-5'), 127.6 (C-6), 128.7 (C-4'), 128.9 (C-8 or C-7), 129.0 (C-4),
133.0 (C-3'), 137.5 (C-1'), 144.1 (C-2).
IR (Nujol): n = 1519, 1460, 1340 cmÐ1.
1H NMR (300 MHz, CDCl3/TMS): d = 7.16 (ddd, 1 H, J = 8.1, 7.4,
1.8, 1.6 Hz, H-4), 7.33 (ddd, 1 H, J = 7.4, 0.9, 0.5 Hz, H-5), 7.42 (td,
1 H, J = 7.1, 1.6, 1.3 Hz, H-4'), 7.42 (d, 1 H, J = 16.1 Hz, H-7), 7.53
(d, 1 H, J = 16.1 Hz, H-8), 7.58 (dd, 1 H, J = 7.9, 1.1 Hz, H-3), 7.62
(ddd, 1 H, J = 7.9, 1.3, 0.7 Hz, H-5'), 7.69 (dd, 1 H, J = 7.9, 1.6 Hz,
H-6), 7.79 (dd, 1 H, J = 7.9, 1.1 Hz, H-6'), 7.98 (dd, 1 H, J = 8.1,
1.01 Hz, H-3').
13C NMR (75 MHz, CDCl3/TMS): d = 124.3 (C-2), 124.7 (C-3'),
126.4 (C-7), 127.3 (C-6), 127.7 (C-5), 128.3 (C-4'), 128.6 (C-6'),
129.6 (C-4), 132.3 (C-8), 132.7 (C-1'), 133.0 (C-3), 133.2 (C-5'),
136.3 (C-1), 147.9 (C-2').
MS (EI, 70 eV); m/z (%) = 275 (M++2, 57), 273 (M+, 58), 194 (M+
Ð Br, 100).
Anal. Calcd for C14H12BrN: C, 61.33; H, 4.41; N, 5.11; Br, 29.14.
Found: C, 61.35; H, 4.45; N, 5.16; Br, 29.17.
MS (EI,70 eV); m/z (%) = 305 (M++2, 9), 303 (M+, 9).
Anal. Calcd for C14H10BrNO2: C, 55.29; H, 3.31; N, 4.61; Br, 26.27.
Found: C, 55.32; H, 3.34; N, 4.59; Br, 26.30.
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328
P. Molina et al.
PAPER
(E)-2-Bromo-2'-(triphenylphosphoranylidene)aminostilbene
(5)
and the resulting mixture was stirred for 30 h. The solution was
poured into 5% aq NH4OH (200 mL) and stirring continued for 1 h,
followed by extraction with CH2Cl2 (5 × 100 mL). The combined
organic layers were washed with H2O, brine and dried (MgSO4).
The MgSO4 was removed by filtration, the filtrate concentrated to
dryness and the resulting solid was washed with Et2O, air-dried and
recrystallized from acetone/Et2O to give 8 (0.14 g); 85% yield; mp
239Ð240¡C.
Br2 (0.874 g, 5.47 mml) in anhyd benzene (6 mL) was added drop-
wise to a stirred solution of Ph3P (1.43 g, 5.47 mmol) in the same
solvent (12 mL) at 0¡C under N2. The mixture was stirred for 1 h
and then allowed to warm to r.t. A solution of 4 (1.5 g, 5.47 mmol)
and Et3N (1.11 g, 11.1 mmol) in anhyd benzene (15 mL) was added;
after 5 h of heating under reflux, triethylammonium bromide was
deposited and separated by filtration. The filtrate was concentrated
to dryness, and the residual material was slurried with anhyd Et2O
(2 × 10 mL) and recrystallized from CHCl3/hexane to give 5
(2.54 g); 87% yield; mp 170¡C.
IR (Nujol): n = 1180, 1379, 1469 cmÐ1.
1H NMR (300 MHz, acetone-d6 /TMS): d = 2.30 (s, 3 H, CH3), 7.34
(dm, 2 H, J= 8.6 Hz, Hm), 7.50 (td, 1 H, J = 7.6, 1.0 Hz, H-8), 7.61
(ddd, 1 H, J = 8.0, 6.8, 1.2 Hz, H-2), 7.69 (ddd, 1 H, J = 8.5, 7.3,
1.5 Hz, H-9), 7.83 (ddd, 1 H, J = 8.5, 6.8, 1.5 Hz, H-3), 8.10 (dd,
1 H, J = 8.0, 1.2 Hz, H-1), 8.19 (d, 2 H, J = 8.6 Hz, Ho), 8.21 (dm,
1 H, J = 8.5 Hz, H-4), 8.26 (ddd, 1 H, J =7.8, 1.5, 0.7 Hz, H-7), 8.50
(dt, 1 H, J = 8.5, 0.7 Hz, H-10), 8.97 (s, 1 H, H-11).
13C NMR (50 MHz, DMSO-d6 /TMS): d = 20.5 (CH3), 114.1 (C-
10), 118.2 (C-10a), 121.5 (C-7), 122.1 (C-10b), 123.8 (C-8), 124.9
(C-2), 125.0 (C-11a), 127.0 (Co), 127.8 (C-1), 127.9 (C-11), 128.0
(C-4), 128.9 (C-9), 129.2 (Cm), 129.3 (C-3), 134.9 (Ci), 138.5 (Cp),
144.9 (C-6a), 145.3 (C-4a), 150.1 (C-5a).
IR (Nujol): n = 1108, 1334, 1444, 1588 cmÐ1.
1H NMR (300 MHz, CDCl3/TMS): d = 6.46 (dt, 1 H, J = 8.1 Hz, JP,H
= 1.4 Hz, H-3'), 6.69 (t, 1 H, J = 7.8 Hz, H-5'), 6.82 (td, 1 H, J = 7.8,
1.6 Hz, H-4'), 7.02 (td, 1 H, J = 7.8, 1.6 Hz, H-4), 7.26 (td, 1 H, J =
7.6, 0.6 Hz, H-5), 7.38Ð7.55 (m, 11 H, 6 Hm + 3 Hp + H-3 + H-7),
7.62 (dt, 1 H, J = 7.8 Hz, JP,H =1.9 Hz, H-6' ), 7.73Ð7.80 (m, 7 H,
6Ho + H-6), 8.16 (d, 1 H, J = 16.2 Hz, H-8 ).
13C NMR (75 MHz, CDCl3/TMS): d = 117.8 (C-5'), 122.3 (d, 3JP,C
= 9.8 Hz, C-3'), 123.8 (C-2), 124.2 (C-7), 126.1 (d, 4JP,C = 1.0 Hz, C-
6' ), 126.5 (C-6),127.3 (C-5), 127.6 (C-4), 128.2 (C-4'), 128.6 (d,
MS (EI, 70 eV); m/z (%) = 372 (M+,27), 308 (M+ Ð 64, 100), 217
1
3JP,C = 12.1 Hz, Cm), 131.0 (C-8), 131.3 (d, JP,C = 99.8 Hz, Ci),
(M+ Ð 155, 97).
3
4
131.3 (d, JP,C = 20.1 Hz), 131.7 (d, JP,C = 2.3 Hz, Cp), 132.5 (d,
2JP,C = 9.8 Hz, Co), 132.9 (C-3), 138.7 (C-1), 149.5 (C-2').
Anal. Calcd for C22H16N2SO2: C, 70.95; H, 4.33; N, 7.52; S, 8.61.
Found: C, 71.03; H, 4.38; N, 7.59; S, 8.65.
31P NMR (121 MHz, CDCl3/H3PO4 85%): d = 1.47.
MS (EI, 70 eV); m/z (%) = 535 (M++2, 40), 533 (M+, 40), 454 (M+
Ð Br, 10), 262 (100).
6H-Indolo[2,3-b]quinoline (9)
A solution of indolo[2,3-b]quinoline 8 (0.21 g, 0.56 mmol) in anhyd
THF (40 mL) was heated at reflux temperature for 10 min, then 1M
TBAF in THF (1.4 mL, 1.4 mmol) was added dropwise under N2.
The resultant mixture was stirred at reflux temperature for 6 h. After
cooling, the solvent was removed under reduced pressure and the
solid residue was dissolved in CH2Cl2 (30 mL). The solution was
washed with H2O (2 × 10 mL) and dried (MgSO4). After filtration
the solution was concentrated to 10 mL and the precipitated solid
was collected by filtration, washed with Et2O and air-dried to give
9 (0.11 g); 90% yield; mp > 300¡C (Lit.13 mp 346¡C).
Anal. Calcd for C32H25BrNP: C, 71.92; H, 4.72; N, 2.62; Br, 14.95;
P, 5.80. Found: C, 71.88; H, 4.65; N, 2.69; Br, 15.03; P, 5.75.
3-(2-Bromophenyl)-2-tosylaminoquinoline (7)
To a solution of iminophosphorane 5 (1 g, 1.87 mmol) in anhyd tol-
uene (25 mL) cooled at 0¡C was added dropwise a solution of to-
sylisocyanate (0.384 g, 1.87 mmol) in the same solvent (1 mL)
under N2. Then, the solution was allowed to warm to r.t. and stirring
was continued for 1 h (until the IR spectrum of the crude showed
the total disappearance of a strong band at 2230 cmÐ1 due to the iso-
cyanate and the appearance of a strong band at 2150 cmÐ1 due to the
carbodiimide 6). The mixture was heated at reflux temperature for
14 h. After cooling, the solvent was removed under reduced pres-
sure and the residual material was chromatographed on a silica gel
column using EtOAc/hexane (1:2) as eluent to give 7 (0.61 g); 72%
yield; mp 209Ð210¡C (CH2Cl2/hexane).
IR (Nujol): n = 1237, 1411, 1616, 3148 cmÐ1.
1H NMR (300 MHz, DMSO-d6 /TMS): d = 7.27 (tm, 1 H, H-9), 7.48
(td, 1 H, J = 7.3, 1.0 Hz, H-2), 7.50 (d, 1 H, J = 6.8 Hz, H-7), 7.53
(td, 1 H, J = 8.1, 1.0 Hz, H-8), 7.72 (ddd, 1 H, J = 8.5, 6.8, 1.0 Hz,
H-3), 7.98 (d, 1 H, J = 7.9 Hz, H-9), 8.11 (dd, 1 H, J = 8.1, 1.0 Hz,
H-1), 8.26 (d, 1 H, J = 7.7 Hz, H-10), 9.05 (s, 1 H, H-11), 11.70 (s,
1 H, NH).
13C NMR (50 MHz, DMSO-d6 /TMS): d = 111.1 (C-7), 118.1 (C-
10b), 119.9 (C-9), 120.5 (C-11a), 122.0 (C-10), 122.9 (C-2), 123.9
(C-10a), 127.1 (C-1), 127.7 (C-11), 128.4 (C-4), 128.8 (C-8 + C-3),
141.7 (C-6a), 146.5 (C-4a), 153.1 (C-5a).
IR (Nujol): n = 1080, 1547, 1610, 1635, 3212, 3244 cmÐ1.
1H NMR (300 MHz, DMSO-d6 /TMS): d = 2.32 (s, 3 H, CH3), 7.20Ð
7.52 (m, 6 H), 7.60Ð7.78 (m, 4 H), 7.85 (d, 1 H, J = 7.7 Hz, H-5),
8.02 (d, 1 H, J = 8.1 Hz, H-8), 8.16 (s, 1 H, H-4), 12.26 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3/TMS): d = 21.4 (CH3), 116.6 (C-8),
120.8 (C-3), 123.8 (C-2'), 124.7 (Co), 126.2 (C-6), 127.2 (C-5),
128.2 (C-5Õ), 129.0 (Cm), 129.8, 131.5, 132.6 133.2 (C-4a), 136.0
(C-8a), 136.7 ( C-1Õ), 139.9 (Ci), 140.7 (C-4), 142.4 (Cp), 152.7 (C-
2).
MS (EI, 70 eV); m/z (%) = 219 (M++1, 36), 218 (M+ +100), 190
(22).
Cryptotackieine (1)
6H-Indolo[2,3-b]quinoline (9; 50 mg, 0.23 mmol) and dimethyl
sulfate (0.45 g, 3.6 mmol) were dissolved in anhyd DMF (4 mL) in
a glass tube which was placed in a Synthewave 402 reactor and ir-
radiated for 5 min at 140¡C. After cooling, the reaction mixture was
poured into H2O (4 mL) and a solution of 2 N NaOH was added un-
til basic pH. The precipitated solid was collected by filtration,
washed with H2O, air-dried and recrystallized from hexane to give
1 (39.9 mg); 75% yield; mp 107Ð109¡C (Lit14 mp 108Ð110¡C).
MS (EI, 70 eV); m/z (%) = 454 (M++2, 3), 452 (M+, 3), 373 (M+ Ð
Br, 55), 218 (M+ Ð 234, 100).
Anal. Calcd for C22H17BrN2SO2: C, 58.29; H, 3.78; N, 6.18; Br,
17.60; S, 7.07. Found: C, 58.32; H, 3.85; N, 6.22; Br, 17.68; S, 7.13.
6-Tosyl-6H-indolo[2,3-b]quinoline (8)
To a solution of quinoline 7 (0.2 g , 0.44 mmol) in diglyme (20 mL)
was added CuI (0.4 g, 2.12 mmol) under N2. The mixture was
stirred at r.t. for 30 min. Then, NaH (0.061 g, 2.42 mmol) was added
Spectral data (IR, 1H and 13C NMR) were identical to those reported
for the natural product.3,4
Synthesis 1999, No. 2, 326–329 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Iminophosphorane-Mediated Synthesis of Cryptotackieine
329
(2) Boye, G. L.; Ampobo, O. Proceedings of the First Interna-
tional Symposium on Cryptolepine; University of Science and
Technology; Kumasi, Ghana, 1993.
(3) Sharaf, M. H. M.; Schiff Jr., P. L.; Tackie, A. N.; Phoebe Jr.,
C. H.; Martin, G. E. J. Heterocycl. Chem . 1996, 33, 239.
(4) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlie-
tinck, A. Tetrahedron Lett. 1996, 37, 1703.
Acknowledgement
We gratefully acknowledge the Þnancial support of the Direcci—n
General de Investigaci—n Cient’Þca y TŽcnica (project number
PB95-1019). S.D. thanks the ÓFoundation SenecaÓ for studentship.
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