A concise formal synthesis of alkaloid cryptotackiene and substituted 6H-indolo[2,3-b]quimolines

Article abstract of DOI:10.1021/jo049227t

A five-step formal synthesis of alkaloid cryptotackiene and its 2-formyl, 11-methyyphenyl derivatives involving conjugate addition of enolate anion from cyclohexanone (or 4-methylcyclohexanone) to bis[(methylsulfanyl)-methylene] -2-oxindole followed by heterocyclization in the presence of ammonium acetate as the key step has been developed. The 11-methylsulfanyl group in the initial precursor can be either desulfurized (Raney Ni) or replaced by methyl/phenyl groups via nickel-catalyzed cross-coupling reaction with appropriate Grignard reagents.

Full text of DOI:10.1021/jo049227t

CHART 1
A Con cise F or m a l Syn th esis of Alk a loid
Cr yp tota ck ien e a n d Su bstitu ted
6H-In d olo[2,3-b]qu in olin es
G. S. M. Sundaram† C. Venkatesh† U. K. Syam Kumar†
H. Ila*,† H. J unjappa‡
Department of Chemistry, Indian Institute of Technology,
Kanpur-208016, India, and Bio Organics and Applied
Materials Pvt. Ltd., No. B-64/ 1, Peenya Industrial Area,
Peenya, Bangalore-560058, India
indolo[2,3-b]quinolines7-9 (precursor to cryptotackiene)
and 6H-indolo[2,3-b][1,6]naphthyridines.10 A few synthe-
ses of cryptotackiene have been recently reported.6a,11,12
Thus, Molina and co-workers have described two syn-
theses of cryptotackiene involving eight steps, based on
sequential construction of both pyridine and indole rings
via aza-Wittig electrocyclic process as the key step for
the formation of the appropriate 3-arylquinoline precur-
sors.11 Timari and co-workers have developed an alterna-
tive synthesis of cryptotackiene in which the key 3-(2-
aminophenyl)-N-methyl-2-quinolone intermediate is ob-
tained by a palladium-catalyzed cross-coupling reaction
of the 3-bromo-2-quinolone derivative with (2-N-pivaloyl-
aminophenyl)boronic acid.12 Recently, Wang et al. have
reported biradical-mediated thermolysis of N-[2-(1-alky-
nyl)phenyl]-N′-phenylcarbodiimides leading to the cor-
responding 6H-indolo[2,3-b]quinoline8 and its 11-alkyl/
aryl derivatives which on methylation with dimethyl
sulfate are known to yield cryptotackiene and its 11-
methyl derivative.
During the course of our studies directed toward
synthesis of novel polycyclic aromatic and heteroaromatic
compounds based on R-oxoketene dithioacetals mediated
aromatic and heteroaromatic annulation,13,14 we have
recently reported an efficient two-step method for the
synthesis of a wide range of substituted and annulated
pyrido[2,3-b]indoles (R-carbolines).15 The overall trans-
formation involves base-induced conjugate displacement
on R-oxoketene dithioacetals by 1-substituted-2-oxindole
hila@iitk.ac.in
Received May 7, 2004
Abstr a ct: A five-step formal synthesis of alkaloid crypto-
tackiene and its 2-formyl, 11-methyl/phenyl derivatives
involving conjugate addition of enolate anion from cyclohex-
anone (or 4-methylcyclohexanone) to bis[(methylsulfanyl)-
methylene]-2-oxindole followed by heterocyclization in the
presence of ammonium acetate as the key step has been
developed. The 11-methylsulfanyl group in the initial pre-
cursor can be either desulfurized (Raney Ni) or replaced by
methyl/phenyl groups via nickel-catalyzed cross-coupling
reaction with appropriate Grignard reagents.
The discovery of antitumor activity1 of ellipticine 1 and
9-methoxyellipticine 2 (Chart 1), two naturally occurring
6H-pyrido[4,3-b]carbazole alkaloids,2 has led to an explo-
sion of activities toward synthesis and biological evalu-
ation of these polyheteroaromatic alkaloids and their
derivatives.3 More recently, cryptotackiene 3a , a linear
5-N-methyl-5H-indolo[2,3-b]quinoline alkaloid isolated
from the West African shrub Cryptolepis sanguinolenta,4
has been reported to exhibit strong antiplasmodial activ-
ity.5 Also, a few of the methyl-substituted derivatives of
cryptotackiene such as 3b are found to display strong
antimicrobial and cytotoxic activities in vitro and sig-
nificant antitumor properties in vivo.6 The interesting
biological activities of ellipticine and indoloquinolines has
stimulated a surge of interest in developing new synthetic
pathways to polyheteroaromatic ring systems such as 6H-
(7) (a) Molina, P.; Alajarin, M.; Vidal, A. J . Chem. Soc., Chem.
Commun. 1990, 1277. (b) Molina, P.; Alajarin, M.; Vidal, A.; Sanchez-
Andrada, P. J . Org. Chem. 1992, 57, 929.
(8) Shi, C.; Zhang, Q.; Wang, K. K. J . Org. Chem. 1999, 64, 925.
(9) (a) Saito, T.; Ohmori, H.; Furuno, E.; Motoki, S. J . Chem. Soc.,
Chem. Commun. 1992, 22. (b) Saito, T.; Ohmori, H.; Ohkubo, T.;
Motoki, S. J . Chem. Soc., Chem. Commun. 1993, 1802.
* To whom correspondence should be addressed. Fax: 91-0512-
2590007, 91-0512-2590260.
† Indian Institute of Technology.
(10) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K. K. J . Org. Chem.
2000, 65, 7977.
‡ Bio Organics and Applied Materials Pvt. Ltd.
(1) Dalton, L. K.; Demerac, S.; Elmes, B. C.; Loder, J . W.; Swan, J .
M.; Teiter, T. Aust. J . Chem. 1967, 20, 2715.
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81, 1903.
(11) (a) Molina, P.; Fresneda, P. M.; Delgado, S. Synthesis 1999, 326.
(b) Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron Lett. 1999,
40, 7275. (c) Alajarin, M.; Molina, P.; Vidal, A. J . Nat. Prod. 1997, 60,
747.
(3) (a) Gribble, G. W. In Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1990; Vol. 39, p 239. (b) Kansal, V. K.; Potier, P. Tetrahedron
1986, 42, 2389. (c) Ishikura, M.; Hino, A.; Yaginuma, T.; Agata, I.;
Katagiri, N. Tetrahedron 2000, 56, 193. (d) Diaz, M. T.; Cobas, A.;
Guitian, E.; Castedo, L. Synlett 1998, 157. (e) Ergun, Y.; Patir, S.;
Okay, G. J . Heterocycl. Chem. 1998, 35, 1445.
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Nantka-Namirski, P.; Peczynska-Czoch, W.; Mordarski, M. Arch.
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(13) Reviews: (a) Ila, H.; J unjappa, H.; Mohanta, P. K. Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Perga-
mon: New York, 2001; Vol. 13, Chapter 1, p 1. (b) J unjappa, H.; Ila,
H.; Patro, B.; Rao, Ch. S. J . Ind. Chem. Soc. 1994, 71, 501. (c) Ila, H.;
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H. J . Org. Chem. 2003, 68, 3498 (b) Barun, O.; Nandi, S.; Panda, K.;
Ila, H.; J unjappa, H. J . Org. Chem. 2002, 67, 5398. (c) Mahata, P. K.;
Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; J unjappa, H. J . Org. Chem.
2003, 68, 3966. (d) Mahata, P. K.; Syam Kumar, U. K.; Sriram, V.;
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Syam Kumar, U. K.; Ila, H.; J unjappa, H. Tetrahedron 2001, 57, 781.
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10.1021/jo049227t CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004
5760
J . Org. Chem. 2004, 69, 5760-5762

SCHEME 1
SCHEME 3
SCHEME 4
SCHEME 2
8a in improved yield. However, treatment of 11 with
ammonium acetate under previously described conditions
afforded the tetrahydroindolo[2,3-b]quinolone 8a in only
a comparable yield of 54% (Scheme 2). Dehydrogenation
of tetrahydroindoloquinoline 8a with DDQ in refluxing
1,4-dioxane afforded the desired 6H-indolo[2,3-b]quino-
line 9a in 88% yield (Scheme 1). N-Methylation of
indoloquinoline 9a with dimethyl sulfate has been re-
ported to give cryptotackiene 3 in good yields.6a,11a
The methodology was also extended for the synthesis
of 2-methyl-6H-indolo[2,3-b]quinoline 9b following a
similar sequence by subjecting 4-methylcyclohexanone 5b
to conjugate addition-elimination with 4 and subsequent
cyclization of the adduct 6b under identical conditions
to give 2-methyl-6H-11-(methylsulfanyl)tetrahydroindolo-
[2,3-b]quinoline 7b in 53% yield (Scheme 1). Dethio-
methylation of 7b with Raney Ni afforded the corre-
sponding 11-unsubstituted compound 8b in high yield.
However, subsequent dehydrogenation of 8b with DDQ
yielded the corresponding 2-formyl-6H-indolo[2,3-b]-
quinoline 12 instead of 9b by concomitant oxidation of
the 2-methyl group (Scheme 3).
The synthesis of the corresponding 11-methyl-6H-
indolo[2,3-b]quinoline 15a was next investigated via
nickel-catalyzed displacement of the 11-methylsulfanyl
group in 7a by a methyl Grignard reagent (Scheme 4).16
It should be noted that the corresponding 11-methyl
derivative 3b of cryptotackiene has been reported to
induce significant topoisomerase II-DNA mediated cleav-
able complexes in in vitro studies, thus making this
compound a potential antitumor agent.6a Thus, treatment
of 11-(methylsulfanyl)tetrahydroindoloquinoline 7a with
enolate anion and subsequent heterocyclization of the
conjugate adduct in the presence of ammonium acetate.
In conjunction with these studies, we have now elabo-
rated this strategy for the construction of the 6H-indolo-
[2,3-b]quinoline ring system which constitutes a short
concise approach to cryptotackiene and its 11-methyl
derivative.
The 3-bis[(methylsulfanyl)methylene]-2-oxindole 414e
was subjected to conjugate addition with cyclohexanone
5a in the presence of sodium hydride to give the requisite
adduct 6a in 81% yield. However, heterocyclization of the
adduct 6a with ammonium acetate in refluxing acetic
acid yielded the tetrahydro-6H-indolo[2,3-b]quinoline 7a
in poor yield (15%). Optimization of the reaction condi-
tions by heating the adduct 6a with ammonium acetate
in dry DMSO in the presence of 4 Å molecular sieves
under nitrogen atmosphere yielded the indoloquinoline
7a in a maximum yield of 52% (Scheme 1). Subsequent
dethiomethylation of 7a with Raney Ni in refluxing
ethanol proceeded smoothly to give tetrahydro-6H-indolo-
[2,3-b]quinoline 8a in 90% yield. Alternatively, the
synthesis of indoloquinoline 8a was achieved by hetero-
cyclization of the adduct 11 obtained by base induced
conjugate addition of cyclohexanone with 3-[methylsul-
fanyl(methylene)]-2-oxindole 10 (Scheme 2). It was con-
sidered that the absence of the bulkier methylsulfanyl
group in the adduct 11 may facilitate its cyclization to
(15) Barun, O.; Patra, P. K.; Ila, H.; J unjappa, H. Tetrahedron Lett.
1999, 40, 3797.
(16) Wenkert, E.; Hanna, J . M., J r.; Leftin, M. H.; Michelotti, E. L.;
Potts, K. T., Usifer, D. J . Org. Chem. 1985, 50, 1125.
J . Org. Chem, Vol. 69, No. 17, 2004 5761

mL) and dried over anhydrous sodium sulfate and the solvent
evaporated under reduced pressure to give the 1,4-addition-
elimination adducts (6a , 6b, or 11). The adducts 6a and 6b were
purified by column chromatography over silica gel using hexane/
EtOAC (10:1) as eluent for spectral and analytical data, whereas
the adduct 11 was used as such for heterocyclization.
Gen er a l P r oced u r e for Heter ocycliza tion of th e Ad -
d u cts 6a ,b a n d 11 w ith Am m on iu m Aceta te: Syn th esis of
Tetr a h yd r oin d olo[2,3-b]qu in olin es 7a ,b a n d 8a . To a solu-
tion of adducts 6a ,b or 11 (1.0 mmol) in dry DMSO (50 mL) were
added 4 Å molecular sieves (3.0 g), anhydrous ammonium
acetate (15 g), and a drop of acetic acid. The reaction mixture
was heated at 120 °C for 12 h. It was then cooled and poured
into ice-cold water (100 mL), and the molecular sieves were
removed by filtration through G-3 sintered funnel. The filtrate
was extracted with chloroform (3 × 100 mL), washed with water
(2 × 50 mL), dried (anhydrous Na2SO4), and evaporated under
reduced pressure to give crude tetrahydroindoloquinolines 7a ,b
and 8a which were purified by column chromatography over
silica gel using hexane/EtOAc (10:1) as eluent.
Gen er a l P r oced u r e for Ra n ey-Ni Deth iom eth yla tion of
Tetr a h yd r oin d oloqu in olin es 7a ,b. To a solution of tetrahy-
droindoloquinolines 7a ,b (1.0 mmol) in ethanol (10 mL) was
added Raney Ni (W2) (∼4 g), and the reaction mixture was
refluxed with stirring for 6-7 h. It was then filtered, washed
with hot ethanol, and concentrated under reduced pressure to
give crude products 8a ,b which were purified by column chro-
matography over silica gel using hexane/EtOAc (10:1) as eluent.
6H-1,2,3,4-Tetr a h yd r oin d olo[2,3-b]qu in olin e (8a ): yield
90% (0.20 g); colorless solid (hexanes-EtOAc); mp 220-221 °C
(spectral data as in the Supporting Information).
Gen er a l P r oced u r e for Deh yd r ogen a tion of Tetr a h y-
d r oin d oloqu in olin es 7a a n d 8a ,b w ith DDQ. To a solution
of tetrahydroindoloquinolines 7a , 8a , or 8b (1.0 mmol) in dry
1,4-dioxane (10 mL) was added DDQ (0.34 g, 1.5 mmol), and
the reaction mixture was refluxed with stirring under nitrogen
atmosphere for 6-8 h (monitored by TLC). It was then cooled,
filtered (G-3 sintered funnel), and extracted with chloroform (3
× 50 mL), washed with water (3 × 50 mL), and dried over
anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure to give crude products 14a , 9a ,20 or 12, which
were purified by column chromatography over silica gel using
hexane/EtOAc (1:20) as eluent.
Gen er a l P r oced u r e for Nick el-Ca ta lyzed Cr oss-Cou -
p lin g of 11-(Meth ylsu lfa n yl)in d olo[2,3-b]qu in olin es 7a a n d
14a w ith Meth yl/p h en yl Gr ign a r d Rea gen ts. A solution of
appropriate Grignard reagent [MeMgI or PhMgBr (0.10 mmol)]
in THF was added dropwise to a stirring suspension of (Ph3P)2-
NiCl2 (30 mol %, 0.19 g) in 25 mL of dry benzene under argon
atmosphere, and the reaction mixture was refluxed for 15 min.
It was then immediately added to the preformed suspension of
lithio salt of 7a or 14a [prepared by addition of n-BuLi (1.0 mmol,
0.62 mL, 1.6 M in hexane) to a solution of 7a or 14a (1.0 mmol)
in dry benzene (10 mL)] followed by further addition of Grignard
reagent [MeMgI or PhMgBr (1.90 mmol)]. The reaction mixture
was then refluxed for 5-6 h (monitored by TLC), cooled, and
poured into saturated NH4Cl solution (100 mL) followed by
extraction with CHCl3 (3 × 50 mL). The organic layer was dried
(anhydrous Na2SO4) and evaporated to give crude products 13a ,
15a , and 16, which were purified by column chromatography
over silica gel using hexane/EtOAc (5:1) as eluent.
methylmagnesium iodide in the presence of bis(triphen-
ylphosphino)nickel dichloride and n-butyllithium yielded
the corresponding 11-methyl-6H-tetrahydroindolo[2,3-b]-
quinoline 13a in 78% yield. However, attempted dehy-
drogenation of 13a to 15a in the presence of DDQ in
refluxing 1,4-dioxane yielded only complex product mix-
ture. On the other hand, the corresponding 11-(methyl-
sulfanyl)indoloquinoline 14a obtained by dehydrogena-
tion of 7a with DDQ underwent facile displacement of
the 11-methylsulfanyl group under the described condi-
tions yielding the desired 11-methyl-6H-indolo[2,3-b]-
quinoline 15a in 74% yield (Scheme 4). Similarly, the
corresponding 11-phenylindolo[2,3-b]quinoline 16 was
also obtained in good yield by displacement of the 11-
methylsulfanyl group in 14a by the phenylmagnesium
bromide in the presence of bis(triphenylphosphino)nickel
dichloride complex. The 5-N-methylation of 15a in the
presence of Me2SO4/NaOH is known to furnish the
corresponding 11-methylcryptotackiene 3b in 65% yield.6a
In conclusion, we have developed a new formal syn-
thesis of alkaloid cryptotackiene involving only five steps
from readily accessible starting materials in overall good
yield. Although the yield of the cyclization step (6 f 7)
is moderate, the overall sequence seems to provide an
efficient and short pathway for 6H-indolo[2,3-b]quino-
lines with a possibility of placing a number of substitu-
ents around the periphery of the heterocyclic ring system
by choice of appropriately substituted suitable precursors.
In addition, the 11-methylsulfanyl group can be either
dethiomethylated (Raney Ni) or displaced by an alkyl/
aryl groups through nickel chloride induced cross-
coupling with Grignard reagents.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded in CDCl3, DMSO-d6, and TMS was
used as an internal reference. Melting points are uncorrected.
Chromatographic purification was conducted by column chro-
matography using 60-120 mesh silica gel and neutral alumina
obtained from Acme Synthetic Chemicals. DMF and DMSO were
distilled over CaH2 and stored over 4 Å molecular sieves. THF
and 1,4-dioxane were distilled over sodium/benzophenone prior
to use. NaH (as 60% suspension in oil), cyclohexanone, 4-meth-
ylcyclohexanone, n-BuLi (1.6 M in hexane), DDQ, and anhydrous
NH4OAc (AR grade) were purchased from the standard firms
and used as such, whereas 2-oxindole17 and 2-bis[(methylsulfa-
nyl)methylene]oxindole18 were prepared according to the earlier
reported procedure. The 3-[(methylsulfanyl)methylene]-2-oxin-
dole19 was prepared by reduction of 4a with NaBH4 in AcOH
according to a previously reported procedure.
Gen er a l P r oced u r e for th e P r ep a r a tion of Con ju ga te
Ad d u cts 6a ,b a n d 11. A solution of cyclohexanone (or 4-meth-
ylcyclohexanone) (5.0 mmol) in benzene (30 mL) was added to a
suspension of sodium hydride (5.0 mmol, 0.12 g) in dry DMF
(10 mL) under nitrogen atmosphere at 0 °C over a period of 30
min. The reaction mixture was stirred for 45 min, and a solution
of 4 or 10 (5.0 mmol) in dry DMF (30 mL) was added at the
same temperature. The reaction mixture was further stirred at
room temperature for 12 h (monitored by TLC). The reaction
mixture was then poured into saturated ammonium chloride
solution (100 mL) and extracted with benzene (2 × 100 mL).
The combined benzene layer was washed with water (2 × 100
Ackn owledgm en t. G.S.M.S., C.V., and U.K.S. thank
CSIR for senior research fellowships. Financial as-
sistance under a DST project is also acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectral data for compounds 6a ,b, 7a ,b, 8a ,b, 9a , 10, 12, 13a ,
14a , 15a , and 16. This material is available free of charge via
the Internet at http://pubs.acs.org.
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