Synthesis of N-protected staurosporinones

Article abstract of DOI:10.1021/jo062184r

We report a method for the synthesis of N-protected staurosporinones, which are useful for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids and related compounds. An interaction of gramine methiodide (2) with 3-(N-benzyl)indolylacetonitrile

Full text of DOI:10.1021/jo062184r

Synthesis of N-Protected Staurosporinones
Yasuhiro Wada, Hideo Nagasaki, Masao Tokuda, and Kazuhiko Orito*
Laboratory of Organic Synthesis, DiVision of Molecular Chemistry, Graduate School of Engineering,
Hokkaido UniVersity, Sapporo 060-8628, Japan
orito@org-mc.eng.hokudai.ac.jp
ReceiVed October 20, 2006
We report a method for the synthesis of N-protected staurosporinones, which are useful for the synthesis
of indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids and related compounds. An interaction of gramine
methiodide (2) with 3-(N-benzyl)indolylacetonitrile (3) in the presence of t-BuLi, followed by a
CF3COOH-catalyzed intramolecular indole-indole coupling and dehydrogenation with DDQ, produced
5-cyanoindolo[2,3-a]carbazole 6 almost quantitatively. Reduction of its cyano group followed by
N-benzylation produced N-benzylaminomethylindolo[2,3-a]carbazole 8b, which was subjected to Pd-
(OAc)2-catalyzed direct aromatic carbonylation to give N-protected staurosporinone 9b. Treatment with
AlCl3 in anisole removed N-benzyl groups to afford staurosporinone quantitatively.
Introduction
synthetic precursors of indolo[2,3-a]pyrrolo[3,4-c]carbazole
alkaloids and staurosporinone (1) involving a Pd(OAc)2-
catalyzed direct aromatic carbonylation that was recently
developed by us for preparation of five- or six-membered
benzolactams.20
Indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids have been
isolated from soil organisms, blue-green algae, and slime
molds.1,2 Because of their unique diindole structure and remark-
able biological activities,3 such as potent protein kinase C
inhibitory activity,1c,3c,4 potent antitumor activities with topo-
isomerase inhibitory activities,2c,5 platelet aggregation inhibitory
activity,4d,6 antimicrobial and hypotensive activities,7 anti-HIV
activitiy,8 and immunosuppressive activity,4i many groups have
made efforts toward achieving the synthesis of the alkaloids9-17
and related compounds.18-19 We report a new access to possible
Results and Discussion
We first examined a synthetic route starting from a reaction
of gramine methiodide (2) with 3-(N-benzylindolyl)acetonitrile
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10.1021/jo062184r CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/20/2007
2008
J. Org. Chem. 2007, 72, 2008-2014

Synthesis of N-Protected Staurosporinones
(3) via 3-methyleneindolenine (2′)21,22 (Scheme 1). This coupling
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in 96% yield, 0.82 equiv of 3 being recovered. When the amount
of acetonitrile 3 was less than 2 equiv, the reaction did not give
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J. Org. Chem, Vol. 72, No. 6, 2007 2009

Wada et al.
SCHEME 1. Preparation of 6-Cyanoindolo[2,3-a]carbazole
SCHEME 2. Formation of Byproduct C
6
TABLE 1. Preparation of Diindole 4 from Methiodide 2 and
Acetonitrile 3a
entry
2/3 (equiv)
t-BuLi
ratio (3:4:C)b
yields of 4 and C
1
2
3
4
1/1
1/1
1/1.5
1/2
1.1
2.2
2.2
2.2
1:0.1:0
1:1:1
1:1.3:1
1:1:0
33%, 23%
96%, 0%
a To a mixture of 3 and t-BuLi in THF at -78 °C was added a solution
of 2 in DMF, and the mixture was stirred at rt for 4 h. b Determined by 1H
NMR analysis.
very successful and afforded indolo[2,3-a]carbazole 6 in only
26% yield. On the basis of Hill’s Pd(OAc)2-induced oxidative
(19) For other synthetic approaches to 5,7-dioxoindolo[2,3-a]pyrrolo-
[3,4-c]carbazoles, see: (a) Weinreb, S. M.; Garigipati, R. S.; Gainer, J. A.
Heterocycles 1984, 21, 309-324. (b) Bergmann, J.; Pelcman, B. Tetrahe-
dron Lett. 1987, 28, 4441-4444. (c) Somei, M.; Kodama, A. Heterocycles
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Morishima, H. Tetrahedron 1997, 53, 5937-5950. (f) Wood, J. L.; Petsch,
D. T.; Stoltz, B. M.; Hawkins, E. M.; Elbaum, D.; Stover, D. R. Synthesis
1999, 1529-1533. (g) Riley, D. A.; Simpkins, N. S.; Moffat, D. Tetrahedron
1999, 40, 3929-3932. (h) Wang, J.; Rosingama, M.; Watson, D. J.; Dowdy,
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42, 8935-8937. (i) Akao, A.; Hiraga, S.; Iida, T.; Kamatani, A.; Kawasaki,
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Rossen, K.; Petrillo, D.; Reamer, R. A.; Volante, R. P. Tetrahedron 2001,
57, 8917-8923. (j) Sanchez-Martinez, C.; Shih, C.; Zhu, G.; Li, T.; Brooks,
H. B.; Patel, B. K. R.; Schltz, R. M.; DeHahn, T. B.; Spencer, C. D.;
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pyrrolo[3,4-c]carbazoles, see: (l) Faul, M. M.; Engler, T. A.; Sullivan, K.
A.; Grutsch, J. L.; Clayton, M. T.; Martinelli, M. J.; Pawlak, J. M.;
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2975.
good results because of a competitive side reaction between 3
and pivalaldehyde or its equivalent A that was presumably
formed by an interaction of t-BuLi with DMF, leading to an
adduct C, as shown in Scheme 2 and Table 1. In fact, an
interaction of nitrile 3 with pivalaldehyde itself in the presence
of NaH gave C. The cis-â-alkylacrylonitrile structure of C was
determined by 1H NMR analysis using the nuclear Overhouser
effect (NOE),23 the values of which are shown in Scheme 2.
Oxidation of 4 with chloranil (2 equiv) in boiling xylene for
2 h24 gave a single diindole 7 (60%), the trans structure of which
was also determined by NOE analysis, as shown in Scheme 1.
The application of stilbene photocyclization10e,g,25,26 to 7 involv-
ing trans-cis isomerization in the presence of iodine was not
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K.; Suda, H. J. Antibiot. 1992, 45, 1797-1798. (b) Zembower, D. E.; Zhang,
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2795-2797. (b) Weinreb, S. M.; Garigipati, R. S.; Gainor, J. A. Heterocycles
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Stoltz, B. M.; Hawkins, E. M.; Elbaum, D.; Stover, D. R. Synthesis 1999,
1529-1533. (f) Eils, S.; Winterfeldt, E. Synthesis 1999, 275-281. (g)
Tamaki, K.; Shotewell, J. B.; White, R. D.; Drutu, I.; Petsch, D. T.; Nheu,
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1689-1692. (h) Nomak, R.; Snyder, J. K. Tetrahedron Lett. 2001, 42,
7929-7933. (i) Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. M. Org.
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Prabhakar, S.; Maeques, M. M. B. Tetrahedron Lett. 2004, 45, 2347-2349.
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Yuguchi, M; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342-14343. (b) Orito, K.; Miyazawa, M.; Nakamura, N.; Horibata, A.;
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Tokuda, M. J. Org. Chem. 2006, 71, 5951-5958.
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Tetrahedron 1997, 53, 51-58.
(23) Noggle, J. H.; Schirmer, R. E. The Nuclear OVerhauser Effect:
Chemical Applications; Academic Press: New York, 1971.
(24) The use of DDQ instead of Chloranil resulted in the lower yield
(<50%) of 8.
(25) Mallory, F. B.; Mallory, C. W. In Organic Reactions; Dauben, W.
G., Ed.; John Wiley & Sons: New York, 1984; Vol. 30, pp 1-456.
2010 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of N-Protected Staurosporinones
TABLE 2. Preparation of Indolo[2,3-a]carbazole 6 by Oxidative
TABLE 4. Preparation of N-Benzylamine 8b from 6
Coupling of 4a
entry
1
reagent
solvent
temp. time yield of 8b
entry PdX2 (mol %)
solvent atmosphere ratio (4:6)b yield of 6
MS4Å
NaBH4
THF
MeOH
reflux
2 h
1 h
1
2
3
4
5
Pd(OAc)2 (100) AcOH
air
air
Ar
N2
air
0:1
c
1:0.4
1:1
1:0.5
40%
rt
rt
rt
rt
93%
a
Pd(OAc)2 (200) AcOH
Pd(OAc)2 (100) dioxane
Pd(OAc)2 (100) AcOH
2
3
4
5
pyridine-BH3, MS4 Å34 DMF
17 h
8 h
NaBH4CN-MS3 Å35
NaB(OAc)3H-AcOH36 THF
NaB(OAc)3H36
DMSO
a
6 h
31%
40%
PdCl2 (100)
DMF
1,2-DCE rt
8 h
a A stirred mixture of 4 and PdX2 (100 or 200 mol %) in AcOH, dioxane,
or DMF was heated at 130 °C for 24 h. b Determined by 1H NMR analysis.
c A complex mixture was obtained.
a A complex mixture was obtained.
SCHEME 3. Synthesis of N-Protected Staurosporinones,
9a,b and 10, and Staurosporinone (1)
TABLE 3. Preparation of Indolo[2,3-a]carbazole 6 by Pd-catalyzed
Oxidative Coupling of 4a
entry catalyst (mol %) additive (mol %) atm ratio of 4:6b yield of 6
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
CuCl2 (100)
O2
1:0.1
1:2.5
1:0.1
1:0.1
0:1
1:0
1:3.3
1:0.1
Cu(OAc)2 (50) Air
Cu(OAc)2 (50) O2
K2S2O8 (900)
t-BuOOH (250) Ar
Sn(OAc)2 (10) O2
31%
47%
Pd(OOCCF3)2 (5) Sn(OAc)2 (10) O2
Pd(OOCCF3)2 (5) Sn(OAc)2 (50) O2
a A stirred mixture of 4 and PdX2 (5 mol %) in AcOH was heated at
1
130 °C for 24 h. b Determined by H NMR analysis.
coupling of diindolylmaleimide,10d direct conversion of 4 to 6
was examined. As shown in Table 2, treatment of 4 with a
stoichiometric amount of Pd(OAc)2 afforded 6 in 40% yield
after purification of a tarry reaction mixture (entry 1), although
the addition of air (oxygen) accelerated the reaction (entry 1 vs
entry 4). PdCl2 was not suitable for this coupling (entry 5). As
shown in Table 3, an alternative one-pot method based on
Wang’s catalytic procedure,19h using Pd(OAc)2 (5 mol %) as a
catalyst and CuCl2,27 Cu(OAc)2 or K2S2O8 as an oxidant,
resulted in low yields of 6. The use of t-BuOOH29 led to the
complete consumption of 4 after 2 h, but 6 was obtained in
27
28
30
only 31% yield. The use of Pd(OAc)2 (5 mol %)-Sn(OAc)2
(10 mol %) in boiling AcOH under oxygen was not effective,
but the use of Pd(OCOCF3)2 (5 mol %)-Sn(OAc)2 gave a better
result (47% yield) (entry 7).
On the other hand, by a modification of Gribble’s and
Vranken’s methods,31,32 cyclization of 4 by acid treatment with
CF3COOH in CH2Cl2 at rt for 2 h followed by DDQ oxidation
of the resulting crude cyclization products 5a and/or 5b was
successfully carried out to produce 6 in 93% yield.
to afford N-(2,6-dimethyl)benzylamine 8a in 91% yield in two
steps. N-(2,4,6-Trimethoxy)benzylamine 8b was also obtained
in 93% yield (entry 1 in Table 4). However, the use of a one-
pot procedure, so-called “reductive amination” using a pyri-
dine-borane-MS4 Å complex,34 NaBH3CN-MS3 Å,35 or
NaB(OAc)3H,36 did not give satisfactory results (entries 2-5
in Table 4).
The cyano group of 6 was reduced with NaBH4-CoCl2 in
MeOH-THF33 at rt for 1 h to afford a primary amine 8 (74%),
which was condensed with 2,6-dimethylbenzaldehyde in the
presence of 4-Å molecular sieves (MS4 Å) in boiling THF for
24 h. The resultant imino bond was then treated with NaBH4
Benzylamine 8a was subjected to carbonylation with
Pd(OAc)2 (5 mol %) and Cu(OAc)2 (50 mol %)20 in gently
boiling toluene in an atmosphere of CO gas containing air corre-
sponding to 0.5 molar equiv of O2 delivered from a toy balloon
for 2 h to give a lactam 9a in 15% yield, although carbonylation
of the model compounds 11a,b to benzolactams 12a,b gave
better results (Scheme 4). Under the same conditions trimeth-
oxybenzylamine 8b was converted in 38% yield to benzolactam
9b. The use of DMSO (110 °C) instead of gently boiling toluene
enhanced the yield of benzolactam 9b to 50%. Three nitrogen
atoms of 9a,b have different substituents. This should be useful
for synthesis of staurosporine or related sugar-binding chiral
(26) (a) Liu, L. Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem.
1991, 56, 3769-3775. (b) Lee, M. L.; Kudo, H.; Tedjamulia, M. L.; Castle,
R. N. J. Heterocycl. Chem. 1984, 21, 185-192.
(27) Hosokawa, T.; Murahashi, S. Acc. Chem. Res. 1990, 23, 49-52.
(28) Fujiwara, Y.; Takaki, K.; Taniguchi, Y. Synlett 1996, 591-599.
(29) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097-
2100.
(30) (a) Bryant, D. R.: Mckeon, J. E.; Ream, B. C. J. Org. Chem. 1968,
28, 4123-4127. (b) Hagelin, H.; Oslob, J. D.; Akermark, B. Chem.-Eur.
J. 1999, 5, 2413-2416.
(34) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60,
5995-5996.
(31) Gribble, G. W.; Pelcman, B. J. Org. Chem. 1992, 57, 3636-3642.
(32) Gilbert, E. J.; Van, Vranken, D. L. J. Am. Chem. Soc. 1996, 118,
5500-5501.
(35) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897-2904.
(33) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron
Lett. 1969, 4555-4558.
(36) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
J. Org. Chem, Vol. 72, No. 6, 2007 2011

Wada et al.
SCHEME 4. Carbonylation of Benzylamines 11a,b
water (5 × 20 mL), dried (Na2SO4), and concentrated in vacuo to
give a residue, which was purified by column chromatography on
silica gel (starting with 1:1 hexane-CH2Cl2 and ending with
CH2Cl2) to afford the unchanged nitrile 3 (0.65 g, 82%) as an oil
and then 4 (1.20 g, 96%) as a white solid, mp 127-129 °C.
Recrystallization from Et2O-hexane afforded an analytical sample
of 4, mp 128.5-129 °C: IR (Nujol) 3354, 2248 cm-1; 1H NMR δ
3.39-3.55 (m, 2H), 4.39-4.45 (m, 1H), 5.24 (s, 2H), 7.02-7.46
(m, 14H), 7.71-7.74 (m, 1H), 8.02 (br. s, 1H); EI-MS m/z (relative
intensity) 375 (M+, 4.8), 130 (100), 91 (21.6). Anal. Calcd for
C26H21N3: C, 83.17; H, 5.64; N, 11.19. Found: C, 83.12; H, 5.58;
N, 11.07.
alkaloids and optimization of their biological activity by modifi-
cation of the aglycone portion, as described in some reports.18d,f,h,i,k
Deprotection of two benzyl groups of benzolactams 9a,b was
examined. Debenzylation of 6 via generation of a benzyl anion
Condensation of 2 with 3 in a 1:1 Ratio. Formation of (Z)-
3-tert-Butyl-2-(N-benzyl-3-indolyl)acrylonitrile (C) (Entry 2 in
Table 1). To a stirred solution of 3 (75 mg, 0.3 mmol) in dry THF
(2 mL) was added t-BuLi (1.62 M in pentane, 0.4 mL, 0.65 mmol)
at-78 °C under argon. After being stirred at-78 °C for 1 h, a solution
of 2 (95 mg, 0.3 mmol) in dry DMF (1 mL) was added dropwise.
The mixture was stirred at rt for 4 h, quenched with water (5 mL),
and extracted with CH2Cl2 (3 × 10 mL). The CH2Cl2 layers were
washed with water (5 × 10 mL), dried (Na2SO4), and concentrated
in vacuo. The residue (134 mg) was purified by preparative TLC
(30% hexane-CH2Cl2). A fraction with Rf ) 0.7-0.8 gave C as
yellow crystals (22 mg, 23%). Recrystallization from MeOH
afforded an analytical sample of C, mp 79-80 °C: IR (Nujol) 2220
37
with t-BuOK in DMSO followed by treatment with O2 did
not work at all, probably due to the generation of a potassium
salt on the indole NH. In contrast, the use of Murakami’s
procedure with a combination of AlCl3 and anisole38 at 110 °C
for 1 h gave 6a in 96% yield. Although Raphael reported that
benzyl groups at the 6 position of staurosporinone derivatives
could not be removed,10b a trimethoxybenzyl group of 9b was
also removed quantitatively under the latter conditions to give
staurosporinone (1) in 99% yield [31% overall yield from
gramine (f4f6f8bf9bf1)]. A similar debenzylation at 110
°C of 9a proceeded more slowly to give 1 in 71% yield. Under
milder conditions at 80 °C for 30 min, 9a was successfully
converted to 6-(2,6-dimethylbenzyl)staurosporinone 10 (99%).
In summary, t-BuLi-induced cross-coupling of grammine
methiodide with N-benzyl-3-indolylacetonitrile produced N-ben-
zyl-1,2-di-(3-indolyl)propionitrile, whose CF3COOH-catalyzed
cyclization followed by dehydrogenation produced 5-cyanoin-
dolo[2,3-a]carbazole. Reduction of its CN group and benzylation
of the resultant amine, followed by Pd(OAc)2-catalyzed direct
aromatic carbonylation, provided indolo[2,3-a]pyrrolo[3,4-c]-
carbazole with two different benzyl groups at the 6 and 12
positions. Treatment with AlCl3 and anisole resulted in efficient
debenzylation to give staurosporinone quantitatively.
1
cm-1; H NMR δ 1.38 (s, 9H), 5.31 (s, 2H), 6.80 (s, 1H), 7.12-
7.31 (m, 8H), 7.39 (s, 1H), 7.82-7.85 (m, 1H); EI-MS m/z (relative
intensity) 314 (M+, 30.5), 299 (30.3), 223 (5.4), 91 (100). Anal.
Calcd for C22H22N2: C, 84.04; H, 7.05; N, 8.91. Found: C, 84.17;
H, 7.04; N, 8.83. A less mobile fraction with Rf ) 0.2-0.4 afforded
4 as colorless crystals (39 mg, 0.1 mmol, 33%), mp 127-129 °C
(MeOH).
Preparation of Acetonitrile C by Condensation of 3 with
Pivalaldehyde. A mixture of 3 (244 mg, 1.0 mmol), pivalaldehyde
(103 mg, 1.2 mmol) and NaH (36 mg, 1.5 mmol) in dry THF (4
mL) was refluxed under nitrogen overnight. After being cooled to
rt and quenched with water (10 mL), the mixture was extracted
with CH2Cl2 (3 × 10 mL). The CH2Cl2 layers were washed with
water (3 × 10 mL), dried (Na2SO4), and concentrated in vacuo.
The residue (293.2 mg) was purified by column chromatography
on silica gel (30% hexane-CH2Cl2) to afford C (136 mg, 0.43 mmol,
44%), mp 79-80 °C (MeOH), as a yellow solid.
Experimental Section
All melting points were uncorrected. Mass spectrometric data
Preparation of 12-Benzyl-5-cyano-11,12-dihydroindolo[2,3-
a]-carbazole (6) via an Acid-Catalyzed Cyclization of 4. A
solution of 4 (111 mg, 0.3 mmol) in CF3COOH (1 mL) was stirred
at rt for 30 min and concentrated in vacuo. The residue was
dissolved in CH2Cl2 (20 mL) and washed with saturated aq NaHCO3
(10 mL) and water (2 × 10 mL) and dried over Na2SO4. The solvent
was evaporated, and the residue (124.9 mg) was stirred with DDQ
(173 mg, 0.76 mmol) in dry 1,4-dioxane (2 mL) at rt for 1.5 h.
The reaction mixture was diluted with CH2Cl2 (100 mL), washed
with saturated aq NaHCO3 (3 × 50 mL) and water (2 × 50 mL),
and dried over Na2SO4. The solvent was evaporated, and the residue
(123 mg) was purified by preparative TLC (CH2Cl2). A crystalline
solid (112 mg) with Rf ) 0.3-0.5 was recrystallized from benzene-
CH2Cl2 to afford 6 as pale-yellow crystals (102.4 mg, 93%), mp
1
were obtained by electron ionization at 70 eV. H NMR spectra
were obtained in CDCl3 at 270 MHz using TMS as an internal
reference, unless otherwise noted. Preparative thin-layer chroma-
tography (TLC) was carried out on silica gel.
2-[3-(1-Benzyl)indolyl]-3-(3-indolyl)propionitrile (4) (Entry 4
in Table 1). To a stirred solution of 1-benzyl-3-indolylacetonitrile
[3, almost quantitatively prepared using THF and benzyl bromide
instead of benzene and benzyl chloride according to MacLean’s
procedure,39 mp 94.5-95.5 °C (EtOH-CH2Cl2) (ref 39, mp 95-
96 °C), 1.60 g, 6.5 mmol] in dry THF (25 mL) was added t-BuLi
(1.62 M in pentane, 4.4 mL, 7.15 mmol) at -78 °C under argon.
After being stirred at -78 °C for 1 h, a solution of gramine
methiodide [2 (1.06 g, 3.35 mmol), freshly and quantitatively
prepared by Weir’s procedure,21a mp 168-169 °C (ref 40, mp
167.5-170.5 °C; refs 41 and 42, mp 168-169 °C; ref 21a, 168-
170 °C) in dry DMF (8 mL) was added dropwise. The mixture
was stirred at rt for 4 h, quenched with water (20 mL), and extracted
with CH2Cl2 (3 × 20 mL). The CH2Cl2 layers were washed with
1
294-295 °C: IR (Nujol) 3392, 2204 cm-1; H NMR (DMSO-
D6) δ 6.19 (s, 2H), 7.12-7.40 (m, 7H), 7.48 (d, J ) 7.9 Hz, 1H),
7.54 (d, J ) 8.2 Hz, 1H), 7.68 (d, J ) 8.2 Hz, 1H), 7.75 (d, J )
8.2, 1H), 8.33 (d, J ) 7.6 Hz, 1H), 8.56 (d, J ) 7.9 Hz, 1H), 8.68
(s, 1H), 12.01 (br. s, 1H); EI-MS m/z (relative intensity) 371 (M+,
83.3), 280 (100), 91 (68.7). Anal. Calcd for C26H17N3: C, 84.07;
H, 4.61; N, 11.31. Found: C, 84.07; H, 4.83; N, 11.18.
(37) Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. Tetra-
hedron Lett. 2002, 43, 399-402.
(Z)-2-(N-Benzyl-3-indolyl)-3-(3-indolyl)acrylonitrile (7). A
mixture of propionitrile 4 (372 mg, 1.0 mmol) and Chloranil (491
(38) Watanabe, T.; Kobayashi, A.; Nishimura, M.; Takahashi, H.; Usui,
T.; Kamiyama, I.; Mochizuki, N.; Noritake, Y.; Yokoyama, Y.; Murakami,
Y. Chem. Pharm. Bull. 1991, 39, 1152-1156.
(39) Jahangtr; Brook, M, A.; MacLean, D, B.; Holland, H. L. Tetrahedron
1987, 43, 5761-5768.
(41) Geissman, T. A.; Armen, A. J. Am. Chem. Soc. 1952, 74, 3916-
3919.
(42) Torralba, A. F.; Meyers, T. C. J. Org. Chem. 1957, 22, 972-975.
(40) Melhado, L. L. J. Org. Chem. 1981, 46, 1920-1923.
2012 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of N-Protected Staurosporinones
mg, 2 mmol) in o-xylene (10 mL) was refluxed under nitrogen for
4 h. The mixure was cooled to rt, diluted with CH2Cl2 (30 mL),
washed with a 2 N NaOH solution (20 mL), water (2 × 20 mL),
and brine (20 mL), and dried over Na2SO4. Evaparation of the
solvent and purification by column chromatography on silica gel
(30 g) (CH2Cl2) afforded 7 as a solid (285 mg, 76%). Recrystal-
lization from benzene afforded 7 as yellow crystals (223 mg, 60%),
MeOH-CH2Cl2). A fraction with Rf ) 0.5-0.8 give a crystalline
solid (532 mg), which was recrystallized from CH2Cl2-EtOH to
give 8a (448 mg, 91%), mp 189-190 °C (CH2Cl2-EtOH), as a
pale-yellow solid: IR (CHCl3) 3456, 3434 cm-1; 1H NMR δ 2.39
(s, 6H), 4.06 (s, 2H), 4.63 (s, 2H), 5.87 (s, 2H), 6.99-7.09 (m,
3H), 7.21-7.50 (m, 11H), 7.89 (br. s, 1H), 7.93 (s, 1H), 8.11(d, J
) 7.9 Hz, 1H), 8.20 (d, J ) 7.9 Hz, 1H); EI-MS m/z (relative
intensity) 493 (M+, 27.8), 374 (4.1), 360 (100), 282 (9.7), 269
(76.8), 255 (12.1), 132 (5.8), 118 (90.7), 91 (33.3). Anal. Calcd
for C26H17N3: C, 85.16; H, 6.33; N, 8.51. Found: C, 85.08; H,
6.56; N, 8.35.
1
mp 201-202 °C: IR (Nujol) 3322, 2212 cm-1; H NMR δ 5.36
(s, 2H), 7.16-7.47 (m, 12H), 7.78-7.82 (m, 1H), 7.89 (s, 1H),
8.07-8.10 (m, 1H), 8.36 (d, J ) 2.6 Hz, 1H), 8.56 (br. s, 1H);
EI-MS m/z (relative intensity) 373 (M+, 91.0), 282 (100), 91 (19.2).
Anal. Calcd for C26H19N3: C, 83.62; H, 5.13; N, 11.25. Found: C,
83.46; H, 5.19; N, 11.21.
A solution of 7 (238 mg, 0.64 mmol) in CH3CN (35 mL)
containing a catalytic amount of I2 in a Pyrex tube without a stopper
was irradiated with a 500-W high-pressure Hg arc lamp for 8 h. A
5% Na2S2O3 solution (20 mL) was added to the mixture and was
extracted with CH2Cl2 (3 × 20 mL). The organic layer was washed
with water (20 mL), dried over Na2SO4, and concentrated. The
residue was purified by preparative TLC (CH2Cl2). A band with Rf
) 0.57-0.82 afforded 7 (62 mg, 0.17 mmol, 26%) as brown
crystals, mp 292-294 °C (benzene-CH2Cl2).
Preparation of 6 from 4 Using 100 mol % of Pd(OAc)2 (Entry
1 in Table 2). A mixture of 4 (35.4 mg, 0.09 mmol) and Pd(OAc)2
(21.9 mg, 0.1 mmol) in AcOH (2 mL) was refluxed for 24 h. AcOH
was evaporated. The residue was dissolved in dioxane (10 mL),
and precipitates were removed by suction filtration through a thin
pad of powdered MgSO4. Dioxane was evaporated to afford an
oily residue (35 mg), which was subjected to preparative TLC noted
above to afford 6 (14 mg, 40%), mp 294-295 °C (benzene-
CH2Cl2), as pale yellow crystals.
Preparation of 6 from 4 Using Pd(OCOCF3)2-Sn(OAc)2
(Entry 7 in Table 3). A mixture of 4 (37.2 mg, 0.1 mmol),
Pd(OCOCF3)2 (1.7 mg, 0.005 mmol), and Sn(OAc)2 (2.4 mg, 0.01
mmol) in AcOH (2 mL) was refluxed under oxygen delivered from
a toy balloon for 24 h. Preparative TLC of the crude product (37.8
mg) afforded 6 (17.3 mg, 47%), mp 294-295 °C (benzene-
CH2Cl2), as pale-yellow crystals.
12-Benzyl-5-(aminomethyl)-11,12-dihydroindolo[2,3-a]carba-
zole (8). To a stirred mixture of carbazole 6 (1.86 g, 5 mmol) and
CoCl2‚6H2O (2.75 mg, 10 mmol) in MeOH (200 mL) and THF
(80 mL) was added NaBH4 (1.92 mg, 51 mmol). After 1 h, a 2 N
HCl solution (100 mL) was added, and the mixture was stirred
until black precipitates disappeared. The resultant solution was
concentrated, and a 2 N NH4OH solution was added. The basic
solution was extracted with CH2Cl2 (2 L, 2 × 500 mL). The extracts
were washed with water (3 × 300 mL) and dried (Na2SO4). The
solvent was evaporated to give crude amine 8 (1.694 g, 90%).
Recrystallization from THF-EtOH afforded an analytical sample
of 8 (1.37 g, 3.7 mmol, 74%), mp 245-247 °C, as pale-yellow
crystals: IR (Nujol) 3350 cm-1; 1H NMR δ 1.64 (br. s, 2H), 4.65
(s, 2H), 5.89 (s, 2H), 7.33-7.54 (m, 11H), 7.89 (s, 1H), 7.90 (br.
s, 1H), 8.11 (d, J ) 7.9 Hz, 1H), 8.31 (d, J ) 7.9 Hz, 1H); EI-MS
m/z (relative intensity) 375 (M+, 100), 360 (57.3), 284 (35.6), 269
(93.8), 257 (49.5), 91 (31.6). Anal. Calcd for C26H17N3: C, 83.17;
H, 5.64; N, 11.19. Found: C, 82.96; H, 5.71; N, 11.09.
12-Benzyl-5-[N-(2,6-dimethylbenzyl)aminomethyl]-11,12-di-
hydroindolo[2,3 -a]carbazole (8a). A stirred suspension of 2,6-
dimethylbenzaldehyde (134 mg, 1.0 mmol), amine 8 (455 mg, 1.2
mmol), and MS4 Å (4 g) in THF (36 mL) was refluxed for 24 h,
then cooled, and filtered. The filtrate was concentrated to give an
imine, which was dissolved in a mixture of CH2Cl2 (18 mL) and
MeOH (18 mL). NaBH4 (48 mg, 1.3 mmol) was added in portions,
and the mixture was stirred at rt for 2 h, and the solvents were
evaporated. The residue was dissolved in water (15 mL) and
CH2Cl2 (15 mL). The water layer was separated and extracted with
CH2Cl2 (3 × 15 mL). The combined CH2Cl2 layers were washed
with water (3 × 15 mL), dried over Na2SO4, and concentrated.
The residue (574 mg) was purified by preparative TLC (3%
12-Benzyl-6-(2,6-dimethylbenzyl)staurosporinone (9a). A stirred
mixture of 8a (49.5 mg, 0.1 mmol), Pd(OAc)2 (1.2 mg, 0.005
mmol), and Cu(OAc)2 (9.2 mg, 0.05 mmol) in toluene (2 mL) was
gently refluxed in an oil bath in an atmosphere of CO gas (1 L)
containing air (6 mL, 0.5 molar equiv of O2) delivered from a toy
balloon for 12 h. The reaction mixture was cooled to rt and filtered
through a thin pad of powdered MgSO4. Toluene was removed on
a rotary evaporator. The residue (51.8 mg) was purified by
preparative TLC, being developed 3 times with CH2Cl2. A fraction
with Rf ) 0.5-0.6 afforded 9a as pale-yellow crystals (7.6 mg,
0.015 mmol, 15%) from benzene, mp >258 °C (dec): IR (Nujol)
1
3252, 1647 cm-1; H NMR δ 2.48 (s, 6H), 4.29 (s, 2H), 4.97 (s,
2H), 5.76 (s, 2H), 7.09-7.51 (m, 14H), 7.71 (d, J ) 7.6 Hz, 1H),
7.79 (br, 1H), 9.59 (d, J ) 7.6 Hz, 1H); EI-MS m/z (relative
intensity) 519 (M+, 100), 400 (43.9), 310 (17.7), 119 (23.0), 91
(14.0). Anal. Calcd. for C37H31 N3O4: C, 83.21; H, 5.63; N, 8.09.
Found: C, 83.25; H, 5.71; N, 8.06.
The carbonylation under compressed CO gas (20 atm) in an
autoclave at 110 °C for 5 h resulted in recovery of 8a.
12-Benzyl-6-(2,4,6-trimethoxybenzyl)indolo[2,3-a]pyrrolo[3,4-
c]carbazole (9b). In a similar manner to the above, 2,4,6-
trimethoxybenzylamine 8b (55.6 mg, 0.1 mmol) was treated with
Pd(OAc)2 (1.2 mg, 0.005 mmol) and Cu(OAc)2 (9.1 mg, 0.05 mmol)
in DMSO (2 mL) in an atmosphere of CO gas (1 L) containing air
(6 mL) at 110 °C for 12 h. A crude product (67.2 mg) was purified
by preparative TLC (twice with 2% EtOAc-CH2Cl2). A fraction
with Rf ) 0.2 afforded 9b (29.0 mg, 50%) from EtOAc, mp >207
°C (dec), as pale yellow crystals: IR (Nujol) 3218, 1653 cm-1; 1H
NMR δ 3.86 (s, 3H), 3.88 (s, 6H), 4.45 (s, 2H), 4.97 (s, 2H), 5.75
(s, 2H), 6.21 (s, 2H) 7.16-7.46 (m, 11H), 7.72 (d, J ) 7.9 Hz,
1H), 7.80 (br. s, 1H), 9.62 (d, J ) 7.3 Hz, 1H); EI-MS m/z (relative
intensity) 581 (M+, 76.5), 413 (77.7), 401 (47.3), 310 (37.7), 181
(100), 151 (17.9), 121 (21.0), 91 (30.0). Anal. Calcd. for C37H31
N3O4: C, 76.40; H, 5.37; N, 7.22. Found: C, 76.28; H, 5.53; N,
7.08.
Carbonylation of 8b (55.6 mg) in boiling toluene afforded 9b
(22 mg, 38%).
5-Cyano-11,12-dihydroindolo[2,3-a]carbazole (6a). To a stirred
suspension of AlCl3 (80 mg, 0.6 mmol) in anisole (1 mL) in an ice
bath was added a solution of carbazole 6 (36 mg, 0.096 mmol) in
anisole (1 mL). The mixture was stirred at 110 °C for 50 min and
worked up similarly to the above. The residue was purified by
preparative TLC (5% EtOAc-CH2Cl2). A band with Rf ) 0
.51-0.58 afforded 6a (26 mg, 0.092 mmol, 96%), mp >300 °C
(CH2Cl2-benzene), as pale-yellow crystals: IR (Nujol) 3368, 2220;
1H NMR (DMSO-d6) δ 7.28-7.38 (m, 2H), 7.46-7.56 (m, 2H),
7.78 (d, J ) 7.9 Hz, 1H), 7.82 (d, J ) 8.2 Hz, 1H), 8.29 (d, J )
7.9 Hz, 1H), 8.46 (d, J ) 7.9 Hz, 1H), 8.57 (s, 1H), 11.57 (s, 1H),
11.61 (s, 1H); EI-MS m/z (relative intensity) 281 (M+, 100). Anal.
Calcd for C19H11N3: C, 81.12; H, 3.94; N, 14.94. Found: C, 81.09;
H, 4.08; N, 14.97.
Staurosporinone (1). To a stirred suspension of AlCl3 (41 mg,
0.3 mmol) in anisole (1 mL) in an ice bath was added a solution of
9b (30 mg, 0.05 mmol) in anisole (1 mL). The mixture was stirred
at 110 °C for 1 h. The reaction mixture was poured into water and
extracted with AcOEt (3 × 10 mL). The organic layer was washed
with 5% NaHCO3 (10 mL), water (10 mL), and brine (10 mL) and
dried over Na2SO4. The solvent was evaporated, and the residue
J. Org. Chem, Vol. 72, No. 6, 2007 2013

Wada et al.
was purified by preparative TLC (2:1 AcOEt/hexane). A band with
Rf ) 0.43-0.60 afforded 1 as pale-yellow crystals (16 mg, 0.05
mmol, quantitative), mp > 300 °C (acetone-benzene). Recrystal-
lization from the same solvents afforded an analytical sample, mp
> 300 °C (ref 10c, mp > 310 °C; refs 2e and 10b,g,h, mp >310
°C; ref 10a, mp 323-326 °C; ref 10j, mp > 350 °C): IR (Nujol)
3438, 3294, 1648 cm-1; 1H NMR (DMSO-d6) δ 4.96 (s, 2H), 7.23,
7.31, 7.43, 7.48 (each t, J ) 7.3 Hz, each 1H), 7.72 (d, J ) 8.3
Hz, 1H), 7.79 (d, J ) 8.3 Hz, 1H), 8.04 (d, J ) 7.6 Hz, 1H), 8.49
(s, 1H), 9.22 (d, J ) 7.9 Hz, 1H), 11.32 (s, 1H), 11.49 (s, 1H);
EI-MS m/z (relative intensity) 311 (M+, 100), 282 (59.4), 255 (20.5),
156 (12.4), 128 (10.2). Anal. Calcd for C20H13N3O: C, 77.16; H,
4.21; N, 13.50. Found: C, 76.88; H, 4.16; N, 13.44. The NMR
data were essentially identical with those obtained previously using
the same solvent.10b,g,h,j Acetone-D6 has also been used as solvent.10c
A similar debenzylation of 9a (26 mg, 0.05 mmol) afforded 1
(11 mg, 71%).
6-(2,6-Dimethylbenzyl)staurosporinone (10). To a stirred sus-
pension of AlCl3 (40 mg, 0.3 mmol) in anisole (1 mL) in an ice
bath was added a solution of lactam 8a (27 mg, 0.05 mmol) in
anisole (1 mL). The mixture was stirred at 80 °C for 30 min. The
reaction mixture was poured into water (20 mL) and extracted with
AcOEt (3 × 10 mL). The extracts were washed with 5% NaHCO3
(10 mL), water (10 mL), and brine (10 mL) and dried over
Na2SO4. The solvent was evaporated, and the residue was purified
by preparative TLC (3% MeOH-CH2Cl2). A band with Rf ) 0.5
afforded 10 as colorless crystals (23 mg, 0.05 mmol, 99%), mp
>300 °C. Recrystallization from acetone-benzene afforded an
analytical sample, mp > 300 °C: IR (Nujol) 3290, 1638 cm-1; 1H
NMR (DMSO-d6) δ 2.46 (s, 6H), 4.69 (s, 2H), 4.97 (s, 2H), 7.09-
7.19 (m, 3H), 7.25 (t, J ) 7.3 Hz, 1H), 7.26 (t, J ) 7.3 Hz, 1H),
7.43 (d, J ) 7.3 Hz, 1H), 7.46 (d, J ) 7.3 Hz, 1H), 7.73 (d, J )
5.9 Hz, 1H), 7.75 (d, J ) 7.9 Hz, 1H), 7.82 (d, J ) 7.9 Hz, 1H),
9.30 (d, J ) 7.9 Hz, 1H), 11.37 (s, 1H), 11.52 (s, 1H); EI-MS m/z
(relative intensity) 429 (M+, 100), 323 (14.1), 310 (97.8), 282
(23.3), 119 (27.1). Anal. Calcd. for C29H23N3O: C, 81.09; H, 5.40;
N, 9.78. Found: C, 80.88; H, 5.67; N, 9.65.
(146 mg, 1.08 mmol) in CH2Cl2 (20 mL) at rt was added Na2SO4
(2 g). After 3 h, the solution was separated and concentrated. The
oily imine was dissolved in MeOH (2 mL) and treated with NaBH4
(76 mg, 2 mmol) for 2 h. MeOH was evaporated, and the residue
was dissolved in CH2Cl2 (20 mL), washed with H2O (4 × 20 mL),
dried over Na2SO4, and subjected to valve-to-valve distillation to
give 11b (211 mg, 87%), bp 150 °C/1.5 mmHg, as a colorless oil:
1
IR (neat) 3318 cm-1; H NMR δ 1.28 (br. s, 1H), 2.34 (s, 6H),
3.75 (s, 2H), 3.88 (s, 2H), 6.97-7.08 (m, 3H), 7.22-7.39 (m, 5H);
EI-MS (relative intensity) 225 (M+, 17.1), 118 (100), 106 (26.7),
91 (44.3). Anal. Calcd for C16H19N: C, 85.28; H, 8.50; N, 6.22.
Found: C, 85.09; H, 8.58; N, 6.17.
2-Benzylphthalimidine (12a). A stirred mixture of dibenzyl-
amine (11a) (19.7 mg, 0.1 mmol), Pd(OAc)2 (1.2 mg, 0.005 mmol),
and Cu(OAc)2 (9.1 mg, 0.05 mmol) in toluene (2 mL) was gently
refluxed under CO gas (1 atm) containing air (6 mL) delivered
from a toy balloon for 24 h. The reaction mixture was filtered
through a thin pad of powdered MgSO4. The crude product was
dissolved in CH2Cl2, washed with H2O, and dried over Na2SO4.
Evaporation of the solvent and crystallization of the residue (20
mg) from MeOH-Et2O afforded 12a (15.0 mg, 67%), mp 87-89
°C (MeOH-Et2O) (ref 43, mp 90-91 °C; ref 44, mp 90-91.5 °C)
as pale-yellow crystals. IR, 1H NMR, and EIMS spectra were
identical with the reported data.43
2-(2,6-Dimethylbenzyl)phthalimidine (12b). In a similar man-
ner, carbonylation of 11b (23 mg, 0.1 mmol) afforded 12b, mp
152-152.5 °C (Et2O-hexane) as pale-yellow crystals (8.5 mg,
1
33%); Rf ) 0.7 (1:1 EtOAc/hexane): IR (Nujol) 1688 cm-1; H
NMR δ 2.38 (s, 6H), 4.05 (s, 2H), 4.89 (s, 2H), 7.04-7.17 (m,
3H), 7.31-7.34 (m, 1H), 7.42-7.52 (m, 2H); EI-MS (relative
intensity) 251 (M+, 57.3), 145 (31.8), 118 (100), 91 (27.0). Anal.
Calcd for C16H19N: C, 85.28; H, 8.50; N, 6.22. Found: C, 85.09;
H, 8.58; N, 6.17.
JO062184R
(43) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684-1687.
(44) Rivett, D. E.; Wilshire, J. F. K. Org. Prep. Proc. 1969, 1, 263-
266.
N-Benzyl-2,6-dimethylbenzylamine (11b). To a stirred solution
of benzylamine (109 mg, 1.01 mmol) and 2,6-dimethylbenzaldehyde
2014 J. Org. Chem., Vol. 72, No. 6, 2007