Synthesis of cryptolepine and cryptoteckieine from a common intermediate

Article abstract of DOI:10.1002/1522-2675(200211)85:11<3823::AID-HLCA3823>3.0.CO;2-S

Both cryptolepine 1 and cryptotackieine 3 have been synthesized from 1,3-bis(2-nitrophenyl)propan-2-one. The approach to 1 involved reduction of the NO₂ groups, oxidative cyclization with PhI(OAc)₂, and N-methylation, whereas 3 was obtained via bromination, Favorskii rearrangement, reduction (in situ cyclization), and N-methylation.

Full text of DOI:10.1002/1522-2675(200211)85:11<3823::AID-HLCA3823>3.0.CO;2-S

Helvetica Chimica Acta Vol. 85 (2002)
3823
Synthesis of Cryptolepine and Cryptoteckieine from a Common
Intermediate
by Tse-Lok Ho* and Der-Guey Jou
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan, Republic of China
(e-mail: tlho@cc.nctu.edu.tw)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
Both cryptolepine 1 and cryptotackieine 3 have been synthesized from 1,3-bis(2-nitrophenyl)propan-2-one.
The approach to 1 involved reduction of the NO2 groups, oxidative cyclization with PhI(OAc)2, and N-
methylation, whereas 3 was obtained via bromination, Favorskii rearrangement, reduction (in situ cyclization),
and N-methylation.
Introduction. Over the past several years, we have been interested in exploiting
apparent or hidden symmetry aspects of molecules for their synthesis [1]. This activity
extends to a synthetic study in the series of the cryptolepine 1 [2] and related alkaloids.
Here, we describe an approach to two representative structural types from 1,3-bis(2-
nitrophenyl)propan-2-one.
Shrubs of the Cryptolepis genus, indigenous to tropical Africa, yield an extremely
bitter sap, which turns red on exposure to air. They are used in the dyeing of leather and
textiles, as well as in traditional medicine of West and Central Africa, including the
treatment of malaria, infections of the respiratory, urogenital and urinary tracts, colic,
and rheumatism. The roots of C. sanguinolenta (Lindl.) Schlechter (Periplocaceae)
contain several alkaloids with indoloquinoline skeletons: quindoline 2 [3], cryptoteck-
ieine 3 [4] (in [5] named neocryptolepine), cryptosanguinolentine 5 [4], and the
dimeric cryptospirolepine 6 [6], cryptolepicarboline 7 [7], and cryptomisrine 8 [8].
Concerning synthesis of these substances, it is of interest to note that Fichter and
Boehringer reported [9] the preparation of quindoline 72 years before its isolation from
natural sources.
In view of both the intrinsic heterocyclic arrays and the diverse therapeutic value of
these alkaloids, many chemists have engaged in their synthesis. Thus, quindoline was
obtained from 3-aminoquinoline by way of N-phenylation and a Pd-catalyzed
cyclization [10], from 2-iodo-3-fluoroquinoline by Suzuki coupling, followed by an
intramolecular N-arylation [11]. For access to cryptoteckieine, the decomposition of 2-
(1-benzotriazolyl)quinoline in polyphosphoric acid [12], intramolecular N-arylation of
either 2-chloro-3-(2-aminophenyl)quinoline [13] or 3-(2-bromophenyl)-2-(tosylami-
no)quinoline [14] are quite useful. A more novel approach involving thermolysis of N-
phenyl-N'-(2-ethynylphenyl)carbodiimide [15] unfortunately gave norcryptoteckieine
only as a minor product in 16% yield. There is also a synthesis of cryptolepine starting
from condensation of 3-acetoxy-1H-indole and isatin [16].

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Helvetica Chimica Acta Vol. 85 (2002)
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Results and Discussion. The route we chose for the elaboration of both the
indolo[3,2-b]quinoline (quindoline) system and the isomeric indolo[2,3-b]quinoline
framework was based on consideration of their accessibility from a common sym-
metrical intermediate, 1,3-bis(2-nitrophenyl)propan-2-one (9a).
The preparation of 9a from (2-nitrophenyl)acetic acid is readily achieved by
reaction with dicyclohexylcarbodiimide (DCC) [17]. Reduction of 9a with sodium
dithionite in aqueous MeOH led to the diamino ketone, which underwent spontaneous
cyclization. Accordingly, the isolated product was 2-(2-aminobenzyl)-1H-indole (10).
While the transformation of 10 into quidoline 2 by reaction with N-chlorosuccinimide
and Et3N was very unsatisfactory, it was subsequently achieved with iodosobenzene
diacetate as the reagent. This oxidizing agent is known to promote condensation of 2-
substituted indoles with arylamines to form the 3-arylimino-3H-indoles [18], but, in our
case, the initial product suffered isomerization to afford quindoline directly. Sub-
sequently, a regioselective N-methylation of quindoline to furnish cryptolepine (1) was
accomplished according to established procedure [10].
Our initial plan for the synthesis of cryptoteckieine called for the oxidation of 9a to
a trione with SeO2. However, the desired transformation was unsuccessful, and only
o,o'-dinitrobenzil was produced in low yield. The loss of a C unit may be due to the
instability of the trione or an abnormal oxidative degradation of the highly reactive 1,2-
dione intermediate.
In a revised approach, ketone 9a was brominated, and the ensuing bromo ketone 9b
was exposed to MeONa to induce a Favorskii rearrangement. The resulting methyl
ester 11a was then reduced with sodium dithionite to the bis(2-aminophenyl) ester 11b,
which may be converted to a 3-substituted oxindole 12a. On the other hand, by
reduction with Fe powder in hot AcOH, norcryptoteckieine (4) could be obtained
directly. Finally, N-methylation of 4 completed the synthesis of cryptoteckieine (3).
The alternative pathway to norcryptoteckieine (4) is via Favorskii rearrangement of
the dibromo ketone 9c. Owing to the generation of an (E)-ester, which, on reduction,
led to (E)-3-(2-aminobenzylidene)oxindole (12b), this route became an impasse.
In summary, we demonstrated once again the economy and effectiveness of using a
common intermediate for the synthesis of two different molecular skeletons by proper
manipulation. It is a continuation along the line of our previous work concerning the
access to occidol and tavacpallescensin, and cuparene and herbertene [1].
We thank the National Science Council of ROC for financial support.
Experimental Part
General. Column chromatography (CC) was performed on Merck silica gel. M.p.: uncorrected. IR Spectra:
.
BIO-RAD FTS 165, nÄ in cmÀ1 1H-and 13C-NMR spectra: Varian Unity-300 and Bruker DRX-300, CDCl3 as
solvent unless otherwise indicated, d in ppm, J in Hz. EI-MS: TRIO-2000 and JEOL SX-102A, ionization
potential 70 eV.
1,3-Bis(2-nitrophenyl)propan-2-one (9a). A soln. of (2-nitrophenyl)acetic acid (5.0 g, 27.6 mmol) in anh.
THF (50 ml) was added slowly to dicyclohexylcarbodiimide (DCC; 6.0 g, 29 mmol) and 4-(dimethylamino)-
pyridine (DMAP; 1.0 g, 8.18 mmol) in anh. THF (50 ml) at r.t. The mixture was then heated to reflux for 3 h,
cooled, filtered, and evaporated under reduced pressure. The solid residue was recrystallized from AcOEt to
afford 9a (14.2 g, 86%). M.p. 138 1398. IR: 1723, 1547, 1519, 1408, 1347. H-NMR: 4.28 (s, 4 H); 7.35 (d, J ˆ 7.8,
2 H); 7.46 (t, J ˆ 7.8, 2 H); 7.58 (t, J ˆ 7.8, 2 H); 8.10 (d, J ˆ 7.8, 2 H). 13C-NMR: 47.8 (t); 125.2 (d); 128.5 (d);
‡
130.1 (s); 133.8 (d); 134.0 (d); 148.3 (s); 201.1 (s). EI-MS: 300 (0.08, M ), 251 (0.18), 224 (52), 164 (18), 142

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Helvetica Chimica Acta Vol. 85 (2002)
‡
(34), 136 (30), 98 (75), 56 (100). HR-MS: 300.0746 (C15H12N2O5 ; calc. 300.0747). Anal. calc.: C 60.00, H 4.03, N
9.33; found: C 60.05, H 4.39, N 9.37.
2-(2-Aminobenzyl)-1H-indole (10). A mixture of 9a (3.0 g, 10 mmol), Fe powder (4.6 g, 82.38 mmol),
glacial AcOH (54 ml), and EtOH (54 ml) was stirred and refluxed under N2 for 3.5 h. On cooling, the liquid was
poured into H2O (200 ml), neutralized with Na2CO3, and EtOH was removed in vacuo. Extraction of the aq.
suspension with AcOEt (3 Â 50 ml), followed by evaporation and CC (hexane/AcOEt 3 :1), gave the crystalline
10 (2.1 g, 94.6%). M.p. 110 1128. IR: 3398, 3053, 3028, 1619, 1495, 1456, 1414, 1285. 1H-NMR: 3.46 (s, 2 H); 3.85
(s, 2 H); 6.25 (s, 1 H); 6.56 (d, J ˆ 7.8, 1 H); 6.74 (t, J ˆ 7.5, 1 H); 7.07 (m, 5 H); 7.48 (m, 1 H); 7.93 (s, 1 H).
13C-NMR: 31.1 (t); 100.4 (d); 110.5 (d); 116.2 (d); 118.9 (d); 119.6 (d); 119.7 (d); 121.2 (d); 123.0 (s); 128.1 (d);
‡
128.3 (s); 130.4 d); 136.1 (s); 136.5 (s); 144.8 (s). EI-MS : 222 (70, M ), 221 (100), 219 (19), 204 (34), 130 (44),
‡
117 (28), 111 (28), 102 (30). HR-MS: 222.1163 (C15H14N2 ; calc. 222.1158).
Quindoline (ˆ 7H-Indolo[3,2-b]quinoline; 2). To a stirred soln. of 10 (3.0 g, 13.5 mmol) in anh. THF
(50 ml) at r.t. was added phenyliodine diacetate (9.0 g, 28 mmol) in portions. After 3 h, the mixture was treated
with 10% NaHCO3 (50 ml) and evaporated. The residue was extracted with AcOEt (3 Â 50 ml), dried
(Na2SO4), evaporated, and chromatographed. Elution with hexane/AcOEt 3 :1 provided 2 (1.2 g, 40.7%). M.p.
252 2538 ([11]: 254 2568). IR: 3416, 1639, 1563, 1481, 1460, 1397, 1337. 1H-NMR ((D6)DMSO): 7.28 (t, J ˆ 7.5,
1 H); 7.64 (m, 4 H); 8.07 (d, J ˆ 8.4, 1 H); 8.18 (d, J ˆ 8.4, 1 H); 8.28 (s, 1 H); 8.38 (d, J ˆ 7.5, 1 H); 11.45
(s, 1 H). 13C-NMR ((D6)DMSO): 111.5 (d); 113.0 (d); 119.3 (d); 121.0 (s); 121.4 (d); 124.9 (d); 126.0 (d); 126.7
‡
(s); 127.5 (d); 128.7 (d); 129.7 (d); 132.4 (s); 143.4 (s); 144.0 (s); 145.7 (s). EI-MS: 218 (100, M ), 190 (11), 109
‡
(14). HR-MS: 218.0844 (C15H10N2 ; calc. 218.0845).
Cryptolepine (ˆ1-Methyl-1H-indolo[3,2-b]quinoline 1). MeI (5 ml) was added to a soln. of 2 (0.25 g,
1.15 mmol) in anh. THF (20 ml), and the mixture was heated under reflux for 18 h. After cooling to r.t., the
precipitate (0.34 g) was collected and recrystallized from H2O to afford the bright yellow 1 ¥ HI (0.30 g, 72.3%).
M.p. 273-2748 ([10]: 271 2738). IR: 3416, 1639, 1563, 1481, 1460, 1397, 1337. 1H-NMR ((D6)DMSO): 4.83
(s, 3 H); 7.37 (t, J ˆ 7.8, 1 H); 7.59 (d, J ˆ 8.1, 1 H); 7.77 (m, 2 H); 8.04 (t, J ˆ 7.8, 1 H); 8.34 (d, J ˆ 7.8, 1 H); 8.53
(t, J ˆ 9.0, 2 H); 9.00 (s, 1 H); 12.66 (s, 1 H). 13C-NMR ((D6)DMSO): 40.4 (q); 113.3 (d); 113.8 (s); 117.8 (d);
121.9 (d); 125.0 (d); 126.2 (d); 126.3 (s); 127.5 (d); 130.1 (d); 133.0 (d); 133.3 (s); 134.3 (d); 135.5 (s); 137.9 (s);
‡
‡
145.8 (s). EI-MS: 233 (31), 232 (100, [M À HI] ), 218 (29), 217 (30), 190 (21). HR-MS: 233.1074 (C15H10N2 ;
calc. 233.1080).
Cryptolepine (1) was liberated from its hydroiodide by treatment with 5% Na2CO3 and extraction with
CHCl3. Chromatography over neutral alumina (CH2Cl2/MeOH 99 :1) afforded 1 in 54.6% yield. M.p. 173 1758
([16]: 178 1808). IR: 1692, 1631, 1584, 1551, 1513, 1484, 1356. 1H-NMR: 4.49 (s, 3 H); 6.86 (t, J ˆ 7.5, 1 H); 7.40
(t, J ˆ 7.5, 1 H); 7.50 (t, J ˆ 7.8, 1 H); 7.72 (m, 2 H); 7.91 (t, J ˆ 7.8, 1 H); 8.00 (d, J ˆ 7.8, 1 H); 8.57 (s, 1 H).
13C-NMR: 37.9 (q); 113.3 (s); 114.8 (d); 117.1 (d); 119.7 (d); 123.6 (d); 124.4 (s); 126.4 (d); 128.7 (d); 129.7 (d);
‡
130.7 (d); 132.6 (s); 138.9 (s); 144.7 (s); 160.6 (s). EI-MS : 232 (100, M ), 218 (14), 216 (25), 190 (15). HR-MS:
‡
232.0998 (C16H12N2 ; calc. 232.1002).
1-Bromo-1,3-bis(2-nitrophenyl)propan-2-one (9b). Br2 (1 ml) was diluted with CHCl3 (10 ml) and slowly
added to a stirred soln. of 9a (6.0 g, 20 mmol) at r.t. The resulting mixture was refluxed for 1.5 h, cooled, and concen-
trated in vacuo to give a rather unstable oil (7.43 g, 98%), which was used directly without further purification.
1H-NMR: 4.65 (dd, J ˆ 17.8, 8.2, 2 H); 6.28 (s, 1 H); 7.37 (d, 1 H); 7.55 (m, 3 H); 7.68 (t, J ˆ 8.2, 1 H); 7.86 (d,
J ˆ 8.2, 1 H); 8.03 (t, J ˆ 8.2, 1 H); 8.09 (d, J ˆ 8.2, 1 H). 13C-NMR: 45.2 (t); 49.2 (q); 124.9 (d); 125.1 (d); 128.7
(d); 128.9 (s); 129.9 (d); 130.1 (s); 133.5 (d); 133.6 (d); 133.8 (d); 133.9 (d); 147.2 (s); 148.6 (s); 196.1 (s).
Methyl 2,3-Bis(2-nitrophenyl)propanoate (11a). To an ice-cooled and stirred soln. of 9b (7.43 g, 20 mmol)
in dry CHCl3 (30 ml) under N2 was slowly added MeONa (3.3 g, 60 mmol) in MeOH (30 ml). After 20 min, the
ice bath was removed, the mixture was kept overnight, and then poured into 5% HCl (50 ml). The product was
isolated by extraction with CH2Cl2 (3 Â 30 ml), concentration, and chromatography (hexane/AcOEt 3 :1) to
afford 11a (3.76 g, 57%). M.p. 92 938. IR: 1732, 1610, 1547, 1524, 1434, 1347, 1206, 1168. 1H-NMR: 3.37 (dd, J ˆ
13.8, 7.7, 1 H); 3.62 (s, 3 H); 3.90 (dd, J ˆ 13.8, 7.7, 1 H); 4.67 (t, J ˆ 7.5, 1 H); 7.12 (d, J ˆ 7.5, 1 H); 7.38 (m, 4 H);
7.52 (t, J ˆ 7.5, 1 H); 7.88 (t, J ˆ 8.0, 2 H). 13C-NMR: 35.5 (t); 47.6 (d); 52.4 (q); 124.8 (d); 124.9 (d); 127.9 (d);
128.5 (d); 129.4 (s); 130.8 (d); 131.7 (s); 132.5 (d); 133.2 (d); 133.5 (d); 148.9 (s); 149.4 (s); 171.8 (s). Anal. calc.
for C16H14N2O6: C 58.18, H 4.27, N 8.48; found: C 58.22, H 4.26, N 8.75.
3-(2-Aminobenzyl)-2,3-dihydro-1H-indol-2-one (12a). A mixture of 11a (1.0 g, 3.03 mmol) and Na2S2O6 ¥
2H2O (11.5 g, 66 mmol) in MeOH (40 ml) and H2O (20 ml) was refluxed for 18 h. Evaporation of MeOH was
followed by extraction with AcOEt (3 Â 50 ml). The dried extracts were concentrated, and the residue was
chromatographed (hexane/AcOEt 9 :1) to give 12a (0.23 g, 32%). M.p. 148 1508 (dec). IR: 3238, 2921, 2853,
1666, 1593, 1493, 1330. 1H-NMR: 3.37 (d, J ˆ 5.7, 2 H); 4.00 (t, J ˆ 6.3, 1 H); 4.41 (s, 2 H); 6.62 (t, J ˆ 7.8, 1 H);

Helvetica Chimica Acta Vol. 85 (2002)
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6.70 (m, 2 H); 7.01(m, 3 H); 7.17 (t, J ˆ 7.2, 1 H); 7.25 (d, J ˆ 7.5, 1 H); 7.89 (s, 1 H). 13C-NMR: 30.7 (t); 40.9 (d);
115.1 (d); 117.0 (d); 118.9 (d); 123.4 (s); 123.7 (d); 124.1 (s); 127.1 (d); 127.5 (d); 128.0 (d); 128.3 (d); 136.3 (s);
‡
‡
145.8 (s); 171.2 (s). EI-MS : 238 (9, M ), 237 (4), 218 (8), 106 (100), 93 (46). HR-MS: 238.1116 (C15H14N2O ;
calc. 238.1107).
Norcryptotackieine (ˆ 7H-Indolo[2,3-b]quinoline; 4). A stirred mixture of 11a (5.0 g, 15.2 mmol) and Fe
powder (7.7 g, 137.9 mmol) in AcOH/EtOH 1:1 (180 ml) was refluxed under N2 for 3 h. After cooling, it was
diluted with H2O (250 ml), made basic with Na2CO3, and concentrated. The product was extracted with AcOEt
and chromatographed to afford 4 (2.38 g, 72%). M.p. 336 3388 ([14]: 338 3408). IR: 3141, 3118, 3029, 1580, 1548,
1477, 1494. 1H-NMR ((D6)DMSO): 7.26 (t, J ˆ 7.2, 1 H); 7.49 (m, 3 H); 7.71 (t, J ˆ 7.2, 1 H); 7.96 (d, J ˆ 8.4, 1 H);
8.10 (d, J ˆ 8.4, 1 H); 8.25 (d, J ˆ 8.4, 1 H); 9.00 (s, 1 H); 11.70 (s, 1 H). 13C-NMR ((D6)DMSO): 110.9 (d); 117.9
(s); 119.6 (d); 120.3 (s); 121.8 (d); 122.7 (d); 123.7 (s); 127.0 (d); 127.5 (d); 128.2 (d); 128.7 (d); 141.4 (s); 146.3
‡
‡
(s); 152.9 (s). EI-MS : 218 (100, M ), 190 (12), 163 (4), 108 (16). HR-MS: 218.0840 (C15H10N2 ; calc. 218.0845).
Cryptotackieine (ˆ6-Methyl-6H-indolo[2,3-b]quinoline; 3). MeI (2 ml) was added to a soln. of 4 (1.0 g,
4.59 mmol) in THF (20 ml). After heating at reflux overnight, the solvent was removed from the mixture and
the residue was chromatographed to provide 3 (1.02 g, 96%). M.p. 104 1058 ([14]: 107 1098). IR: 1566, 1519,
1459, 1422, 1312, 1296, 1234, 1203. H-NMR ((D6)DMSO): 4.30 (s, 3 H); 7.19 (dd, J ˆ 7.5, 7.2, 1 H); 7.49 (m, 2 H);
7.57 (dd, J ˆ 8.1, 1, 1 H); 7.83 (t, J ˆ 7.2, 1 H); 7.97 (d, J ˆ 8.1, 1 H); 8.13 (d, J ˆ 7.5, 2 H); 8.94 (s, 1 H). 13C-NMR
((D6)DMSO): 32.7 (q); 114.9 (d); 117.0 (d); 119.2 (d); 120.2 (s); 121.3 (d); 121.8 (d); 123.7 (s); 126.8 (s); 128.7
‡
(d); 129.9 d); 130.6 (d); 130.7 (d); 136.5 (s); 155.5 (s); 156.1 (s). EI-MS : 232 (0.56, M ), 218 (100), 190 (15), 109
‡
(18). HR-MS: 232.0997 (C16H12N2 ; calc. 232.1002).
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Received June 19, 2002