A new short synthesis of 3-substituted 5-Amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indoles (Amino-CBIs)

Article abstract of DOI:10.1021/jo0263115

A new short synthesis of 3-substituted 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indoles from Martius Yellow is disclosed. The key steps of the synthesis were three efficient regioselective reactions (iodination, 5-exo-trig aryl radical-alkene cyclization and carboxylation).

Full text of DOI:10.1021/jo0263115

A New Sh or t Syn th esis of 3-Su bstitu ted
5-Am in o-1-(ch lor om eth yl)-1,2-d ih yd r o-3H-ben zo[e]in d oles
(Am in o-CBIs)
Shangjin Yang and William A. Denny*
Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of
Auckland, Private Bag 92019, Auckland 1000, New Zealand
b.denny@auckland.ac.nz
Received August 12, 2002
A new short synthesis of 3-substituted 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indoles
from Martius Yellow is disclosed. The key steps of the synthesis were three efficient regioselective
reactions (iodination, 5-exo-trig aryl radical-alkene cyclization and carboxylation).
In tr od u ction
forms that are cleaved by rapid and nonspecific enzy-
matic hydrolysis.
The cyclopropylindole antitumor antibiotics, exempli-
fied by the natural products (+)-CC-1065 (1) and (+)-
duocarmycin SA (2), are extremely cytotoxic DNA-
alkylating agents with subnanomolar potencies in cell
culture.1 This class of compounds has been extensively
investigated to understand the mechanism of the alkyl-
ation step, the basis for their DNA sequence selectivity,
and their potent cytotoxcity.2 The simplified and more
synthetically accessible benzo[e]indoles such as CBI-TMI3
and the corresponding open-chain 5-hydroxy-1,2-dihydro-
3H-benzo[e]indole (5-hydroxyCBI-TMI; 3)4 retain the
potency and biological properties characteristic of the
more complex natural products, binding in the minor
groove of DNA and alkylating at the N3 of adenine in a
highly regio- and sequence-selective manner.5,6 There are
now efficient syntheses of these hydroxy-CBIs, where the
key indoline ring is constructed via radical cyclization of
an aryl radical onto a tethered alkene.4 Analogues in
which the 5-hydroxy group is protected as a carbamate,
including carzelesin (5)7 and KW-2189 (6),8 are less toxic
To obtain more stable prodrugs in this class, we have
developed the corresponding 5-amino-1,2-dihydro-3H-
benzo[e]indoles (amino-CBI-TMI, e.g., 4) (Scheme 1).9
These show similar biological properties to the 5-hydroxy
compounds, but form more stable carbamate prodrugs
(e.g., 7)10 that have been of interest to us as prodrugs for
gene-directed enzyme-prodrug therapy (GDEPT) in con-
junction with the minor aerobic nitroreductase (NTR)
from E. coli.11
(1) Boger, D. L.; J ohnson, D. S. Angew. Chem., Int. Ed. Engl. 1996,
35, 1438 and references therein.
(2) For recent contributions, see: (a) Boger, D. L.; Schmitt, H. W.;
Fink, B. E.; Hedrick, M. P. J Org. Chem. 2001, 66, 6654. (b) Boger, D.
L.; Hughes, T. V.; Hedrick, M. P. J . Org. Chem. 2001, 66, 2207. (c)
Boger, D. L.; Santillan, A., J r.; Searcey, M.; Brunette, S. R.; Wolken-
berg, S. E.; Hedrick, M. P.; J in, Q. J Org. Chem. 2000, 65, 4101. (d)
Boger, D. L.; Boyce, C. W. J . Org. Chem. 2000, 65, 4088. (e) Boger, D.
L.; Searcey, M.; Tse, W. C.; J in, Q. Bioorg. Med. Chem. Lett. 2000, 10,
495. (f) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.; Boyce,
C. W.; Boger, D. L. Bioorg. Med. Chem. Lett. 1999, 9, 3087. (g) Boger,
D. L.; Stauffer, F.; Hedrick, M. P. Bioorg. Med. Chem. Lett. 2001, 11,
2021. (h) Boger, D. L.; Yun, W. J . Am. Chem. Soc. 1994, 116, 7996. (i)
Boger, D. L.; Munk, S. A. J . Am. Chem. Soc. 1994, 116, 7996.
The radical cyclization method4 used previously for the
hydroxy analogues could not be used in our previous
(7) Li, L. H.; DeKoning, T. F.; Kelly, R. C.; Krueger, W. C.;
McGovren, J . P.; Padbury, G. E.; Petzold, G. L.; Wallace, T. L.; Ouding,
R. J .; Prairie, M. D.; Gebhard, I. Cancer Res. 1992, 52, 4904.
(8) Kobayashi, E.; Okamoto, A.; Asada, M.; Okabe, M.; Nagamura,
S.; Asai, A.; Saito, H.; Gomi, K.; Hirata, T. Cancer Res. 1994, 54, 2404.
(9) Atwell, G. J .; Tercel, M.; Boyd, M.; Wilson, W. R.; Denny, W. A.
J . Org. Chem. 1998, 63, 9414.
(3) For
a review of synthetic approaches to CC-1065 and the
duocarmycins and their analogues, see: Boger, D. L.; Boyce, C. W.;
Garbaccio, R. M.; Goldberg, J . A. Chem. Rev. 1997, 97, 787.
(4) (a) Boger, D. L.; McKie, J . A. J . Org. Chem. 1995, 60, 1271. (b)
Boger, D. L.; Brunette, S. R.; Garbaccio, R. M. J . Org. Chem. 2001,
66, 5163 and references therein.
(5) Boger, S. L.; Munk, S. A.; Zarrinmayeh, H.; Ishizaki, T.; Haught,
J .; Bina, M. Tetrahedron, 1991, 47, 2661.
(6) Gieseg, M. A.; Matejovic, J .; Denny, W. A. Anti-Cancer Drug Des.
1999, 14, 77.
(10) Hay, M. P.; Sykes, B. M.; Denny, W. A.; Wilson, W. R. Bioorg.
Med. Chem. Lett. 1999, 9, 2237.
(11) Parkinson, G. N.; Skelly, J . V.; Neidle, S. J . Med. Chem. 2000,
43, 3624
10.1021/jo0263115 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/09/2002
8958
J . Org. Chem. 2002, 67, 8958-8961

New Short Synthesis of 3-Substituted Amino-CBIs
SCHEME 1
SCHEME 3. Regioselective 5-Exo-tr ig
F r ee-Ra d ica l Cycliza tion a
SCHEME 2. Syn th esis of Iod id e 10a
a
Reagents and conditions: (a) 3.0 equiv of NaH, then 10.0 equiv
of CH2dCHCH2Cl; (b) 7.0 equiv of TEMPO/5.0 equiv of Bu3SnH
added portionswise, benzene, 60 °C, 130 min; (c) 16 equiv of Zn
powder, THF-HOAc-H2O, 70 °C, 10 h; (d) 3.0 equiv of Ph3P/10.0
equiv of CCl4, CH2Cl2, rt, 2 h.
a
Reagents and conditions: (a) 1.3 equiv of Tf2O/2.6 equiv of
Et3N, CH2Cl2, 0 °C then rt, 2 h; (b) 34 equiv of NaI, EtOAc, reflux,
2 h; (c) 15 equiv of SnCl2, EtOAc, reflux, 30 min, basic workup
then 4.7 equiv of BOC2O, THF, reflux, 5 h; (d) 1.37 equiv of NIS/
2.0 equiv of TsOH, 1:1 THF-MeOH, -78 °C then rt over 4 h.
SCHEME 4. Regioselective Dep r otection a n d
Cou p lin ga
synthesis of the aminoCBIs,9 where instead the 5-amino
group was protected throughout the synthesis as a nitro
group and an alternative method via formation of the
corresponding lactam was employed. By this route, 4 was
synthesized from 1-hydroxynaphthalene-2-carboxylic acid
in 15 steps, in an overall yield of 3%. We now describe a
new and more convenient synthesis of racemic 4 and
analogues, based on the regioselective 5-exo-trig aryl
radical-alkene cyclization, using allylamine as the amine
equivalent.
Resu lts a n d Discu ssion
As envisaged in the retrosynthesis in Scheme 1, the
indoline was formed via radical cyclization of the naph-
thalenyl radical onto the neighboring allyl group, while
the second allyl was a protecting group for the incipient
5-amino moiety. As an inexpensive starting material we
chose the commercially available 2,4-dinitro-1-hydroxy-
naphthalene Martius Yellow (8), which was converted to
iodide 10 through trifluoromethanesulfonate 9 (Scheme
2). Attempts to reduce the two nitro groups in the
presence of the iodine using many of the standard
reagents (Fe, Ni2B, SnCl2, H2)12 resulted in extensive
deiodination. The desired iodide 12 was thus prepared
in two steps from 10 in 71% overall yield, by reduction/
deiodination with SnCl2 and protection of the amines
with BOC anhydride to give 11, followed by electrophilic
iodination of this with NIS.4 Reduction/deiodination using
hydrogenation (H2/Pd-C, EtOAc) gave the same product
but with lower yield (69% compared to 88%).
a
Reagents and conditions: (a) TFA, 0 °C, 2 h, removed the TFA,
workup then 5,6,7-trimethoxyindole-2-carboxylic acid/EDCI; (b)
TFA, 0 °C, 2 h, removed the TFA, workup then 4-methoxycinnamic
acid/EDCI; (c) 10 mol % Cl2(PCy3)2RudCHPh added portionswise,
toluene, 8 h, reflux.
cyclization4 with in situ TEMPO to give 14 (Scheme 3).
This was subsequently reduced (Zn/AcOH) to alcohol 15,
in 94% yield over the three steps. The alcohol was
converted to chloride 16 with Ph3P/CCl4. The next task
was to achieve an appropriate order of deprotection and
reaction of the amine groups of 16. The BOC groups were
removed by acid-catalyzed deprotection (TFA), and cou-
pling with 5,6,7-trimethoxyindole-2-carboxylic acid using
EDCI proved to be highly regioselective, affording only
the desired regioisomer 17 (Scheme 4). Deblocking of the
allyl group proved to be difficult but was eventually
effected using Grubb’s carbene according to newly pub-
lished work from Alcaide et al,13 to give the desired
amino-CBI-TMI (4) in 10 steps from 8, with an overall
yield of 22%.
Allylation of 12 (NaH/allyl bromide) gave 13, which
underwent a Bu3SnH-promoted 5-exo-trig free-radical
(12) (a) Tercel, M.; Gieseg, M. A.; Denny, W. A.; Wilson, W. R. J .
Org. Chem. 1999, 64, 5946. (b) Seltzman, H. H.; Berrang, B. D.;
Tetrahedron Lett. 1993, 34, 3083. (c) Bellamy, F. D.; Ou, K. Tetrahedron
Lett. 1984, 25, 839.
(13) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F. Org. Lett.
2001, 3, 3781.
J . Org. Chem, Vol. 67, No. 25, 2002 8959

Yang and Denny
Na2S2O3 and stirred at room temperature for 15 min. The
reaction mixture was extracted with EtOAc (3 × 100 mL),
dried, and concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel.
Elution with CH2Cl2 and crystallization from EtOAc/petroleum
ether afforded 12 (9.46 g, 81%) as a brown solid: mp 154-
A similar synthesis gave cinnamate analogue 19 in 9%
overall yield (the lower yield being largely due to a lower
yield in the deallylation reaction. However, the original14
preparation of this compound was also of lower yield, due
to a longer route.
In summary, the above synthesis of 3-substituted
5-amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]in-
doles from Martius Yellow, involving three efficient
regioselective reactions (iodination, 5-exo-trig aryl radi-
cal-alkene cyclization, and carboxylation), is a consider-
able improvement (shorter and higher-yielding) over the
original method.9
1
156 °C (dec); H NMR (CDCl3) δ 8.65 (s, 1 H), 8.12 (m, 1 H),
7.76 (m, 1 H), 7.52 (m, 1 H), 7.45 (m, 1 H), 7.19 (s, 1 H), 6.83
(s, 1 H), 1.57 (s, 9 H), 1.55 (s, 9 H); 13C NMR δ 153.1, 152.6,
138.2, 134.8, 134.6, 132.6, 128.2, 125.3, 124.8, 121.3, 113.5,
81.3, 81.0, 28.3. Anal. Calcd for C20H25IN2O4: C, 49.6; H, 5.2;
N, 5.8. Found: C, 49.8; H, 5.2; N, 5.8.
N,N′-Bis[a llyl(ter t-bu tyloxyca r bon yl)]-1-iod o-2,4-n a p h -
th a len ed ia m in e (13). A solution of 12 (4.86 g, 10.0 mmol) in
anhydrous DMF (150 mL) under nitrogen was treated with
NaH (1.2 g, 30 mmol, 60% oil dispersion), and the reaction
mixture was stirred for 30 min at 0 °C. Allyl bromide (12.1 g,
100 mmol) was added dropwise over 5 min, and the solution
was allowed to warm to room temperature and stirred for 2
h. Saturated aqueous NaHCO3 (100 mL) was added, and the
aqueous phase was extracted with EtOAc (3 × 100 mL), dried,
and concentrated under reduced pressure; the residue was
purified by column chromatography on silica gel. Elution with
EtOAc/petroleum ether (from 1:10 to 1:5) and crystallization
from EtOAc/petroleum ether afforded 13 (5.64 g, 100%) as a
Exp er im en ta l Section
2,4-Din itr o-1-n a p h th yl Tr iflu or om eth a n esu lfon a te (9).
A solution of Martius Yellow (8) (5.0 g, 21.4 mmol) in CH2Cl2
(100 mL) was treated with Et3N (8 mL, 57 mmol), and the
resulting solution was cooled in an ice-salt bath and treated
dropwise with trifluoromethanesulfonic anhydride (5 mL, 28
mmol). After the mixture was stirred at room temperature for
2 h, 0.5 N HCl (100 mL) was added in one portion, and the
mixture was stirred for 30 min. The aqueous phase was
separated and extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were washed with saturated NaHCO3
and brine, dried, and concentrated under reduced pressure,
and the residue was purified by column chromatography on
silica gel. Elution with CH2Cl2, gave 9 (7.0 g, 89%) as yellow
needles: mp (EtOAc/CH2Cl2) 105-107 °C; 1H NMR [(CD3)2-
SO] δ 8.90 (s, 1 H), 8.59 (m, 1 H), 8.55 (m, 1 H), 7.98 (m, 1 H),
7.78 (m, 1 H); 13C NMR δ 158.2, 135.1, 133.2, 127.9, 127.9,
127.7, 127.3, 125.5, 123.3, 122.4. Anal. Calcd for C11H5F3N2O7S:
C, 36.1; H, 1.4; N, 7.7. Found: C, 36.0; H, 1.3; N, 7.6.
1-Iod o-2,4-d in itr on a p h th a len e (10). A solution of 9 (5.0
g, 13.7 mmol) and NaI (7.0 g) in EtOAc (200 mL) was heated
under reflux for 2 h. After cooling to room temperature, the
reaction mixture was washed with saturated Na2S2O3, dried,
and concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel. Elution with
CH2Cl2 gave 10 (4.3 g, 91%) as yellow needles: mp (EtOAc/
CH2Cl2) 194-195 °C; 1H NMR [(CD3)2SO] δ 8.76 (s, 1 H, H-3),
8.54 (m, 1 H), 8.33 (m, 1 H), 8.00 (m, 2 H); 13C NMR δ 151.8,
147.1, 135.0, 132.2, 131.2, 123.9, 123.3, 117.5, 102.7. Anal.
Calcd for C10H5IN2O4: C, 34.9; H, 1.5; N, 8.1. Found: C, 34.8;
H, 1.2; N, 7.9.
1
white solid: mp 150-152 °C; H NMR (CDCl3) δ 8.23 (m, 1
H), 7.77 (m, 1 H), 7.58 (m, 2 H), 7.10 (m, 1 H), 5.93 (m, 2 H),
5.07 (m, 4 H), 4.62 (m, 2 H), 3.87 (m, 2 H), 1.33 (m, 10 H),
1.25 (m, 8 H); 13C NMR δ 154.7, 153.7, 133.6, 133.5, 131.6,
128.1, 127.3, 127.3, 123.4, 123.3, 120.5, 118.3, 80.4, 52.8, 28.1.
Anal. Calcd for C26H33IN2O4: C, 55.3; H, 5.9; N, 5.0. Found:
C, 55.6; H, 5.9; N, 5.1.
5-[Allyl(ter t-b u t yloxyca r b on yl)a m in o]-3-(ter t-b u t yl-
oxyca r bon yl)-1-{[(2′,2′,6′,6′-tetr a m eth ylp ip er id in o)oxy]-
m eth yl}-1,2-d ih yd r o-3H-ben zo[e]in d ole (14). A solution of
13 (2.82 g, 5.0 mmol) in benzene (200 mL) was treated
sequentially with TEMPO (3.0 equiv) and Bu3SnH (1.0 equiv),
and the reaction mixture was warmed to 60 °C and kept there
for an additional 135 min. Additional Bu3SnH (1 equiv) was
added after 30, 60, and 90 min, and additional TEMPO (2
equiv) was added after 60 and 90 min. The solvent was then
removed by evaporation, and the residue was purified by
column chromatography on silica gel. Elution with EtOAc/
petroleum ether (from 1:20 to 1:5) afforded 12 (2.97 g, 100%),
which was sufficiently pure for the next step reaction as a pale
1
N,N′-Bis(ter t-b u t yloxyca r b on yl)-1,3-n a p h t h a len ed i-
a m in e (11). A suspension of 10 (1.0 g, 2.9 mmol) and SnCl2‚
2H2O (9.8 g, 43.6 mmol) in EtOAc (100 mL) was heated under
reflux for 30 min. The white suspension was poured onto ice
(ca. 100 g), and NaHCO3 was added until the aqueous layer
was basic to litmus. The mixture was extracted with EtOAc;
the organic layer was washed with water and dried, and the
solvent was removed under reduced pressure to give crude 1,3-
naphthalenediamine. This was dissolved in THF (30 mL) and
treated with (BOC)2O (3.0 g), and then the mixture was heated
under reflux for 5 h. The solvent was removed, and the residue
was purified by column chromatography on silica gel. Elution
with CH2Cl2 gave 11 (0.916 g, 88%) as a brown solid: mp
yellow gum: H NMR (CDCl3) δ 8.09 (vbr, 1H), 7.76 (m, 2 H),
7.43 (m, 1 H), 7.32 (m, 1 H), 5.95 (m, 1 H), 5.07 (m, 2 H), 4.40-
4.23 (m, 3 H), 4.09 (m, 2 H), 3.86 (m, 2 H), 1.59-1.0 (m, 36
H); 13C NMR δ 152.5, 134.0, 133.8, 129.9, 128.9, 126.4, 126.0,
123.8, 123.4, 117.5, 80.0, 59.9, 52.4, 39.7, 33.1, 28.5, 28.2, 20.1,
17.1; HRMS m/z required for C35H51N2O8 593.3828, found
593.3819.
5-[Allyl(ter t-b u t yloxyca r b on yl)a m in o]-3-(ter t-b u t yl-
oxyca r bon yl)-1-(h yd r oxym eth yl)-1,2-d ih yd r o-3H-ben zo-
[e]in d ole (15). A solution of 14 (2.97 g, 5.0 mmol) in THF/
AcOH/H2O (3:1:1, 200 mL) was treated with Zn powder (30 g,
80 equiv), and the mixture was warmed at 70 °C for 10 h. The
Zn powder was removed by filtration through Celite, and the
mixture was concentrated under reduced pressure. The residue
was extracted with CH2Cl2 (3 × 100 mL), dried, and concen-
trated under reduced pressure, and the crude product was
purified by column chromatography on silica gel. Elution with
EtOAc/petroleum ether (from 1:4 to 1:1), and crystallization
from EtOAc/petroleum ether afforded 15 (2.13 g, 94%): mp
125-128 °C; 1H NMR (CDCl3) δ 8.14 (vbr, 1 H), 7.75 (m, 1 H),
7.43 (m, 1 H), 7.34 (m, 1 H), 5.98 (m, 1 H), 5.11 (m, 2 H), 4.20
(m, 2 H), 4.11 (m, 2 H), 3.90 (m, 2 H), 3.70 (m, 2H), 1.59 (m,
12 H), 1.26 (m, 6 H); 13C NMR δ 153.0, 152.5, 133.9, 128.9,
126.8, 126.0, 124.4, 123.9, 117.6, 64.7, 60.4, 52.1, 28.5, 28.2,
21.0. Anal. Calcd for C26H34N2O5: C, 68.7; H, 7.5; N, 6.2.
1
(petroleum ether) 129-131 °C; H NMR (CDCl3) δ 7.94 (s, 1
H), 7.78 (s, 1 H), 7.74 (m, 2 H), 7.41 (m, 2 H), 6.94 (s, 1 H),
6.69 (s, 1 H), 1.55 (s, 9 H), 1.54 (s, 9 H); 13C NMR δ 153.1,
152.8, 135.8, 134.8, 133.7, 128.5, 126.5, 124.4, 122.3, 119.7,
110.6, 110.5, 80.9, 80.6, 28.3. Anal. Calcd for C20H26N2O4: C,
67.0; H, 7.3; N, 7.8. Found: C, 67.0; H, 7.3; N, 7.8.
N,N′-Bis(ter t-b u t yloxyca r b on yl)-1-iod o-2,4-n a p h t h a -
len ed ia m in e (12). A solution of 11 (8.63 g, 24.1 mmol) in
THF/CH3OH (200 mL, 1:1) at -78 °C was treated with
N-iodosuccinimide (NIS, 8.5 g, 33.7 mmol) in THF (10 mL)
followed by TsOH‚H2O (9.5 g, 50.2 mmol) in CH3OH (10 mL).
The reaction mixture was allowed to slowly warm to room
temperature over 4 h and then diluted with 5% aqueous
8960 J . Org. Chem., Vol. 67, No. 25, 2002

New Short Synthesis of 3-Substituted Amino-CBIs
Found: C, 69.0; H, 7.6; N, 6.3. HRMS m/z required for
5-Am in o-1-(ch lor om eth yl)-3-(5,6,7-tr im eth oxyin d ol-2-
ca r bon yl)-1,2-d ih yd r o-3H-ben zo[e]in d ole (4). To a solution
of 17 (70 mg) in anhydrous toluene (5 mL) protected from light
and heated at reflux was added Cl2(Cy3P)2RudCHPh in small
portions under N2 every 20 min (overall total ) 0.02 mmol).13
After 8 h, the resulting mixture was concentrated under
reduced pressure. Chromatography of the residue eluting with
EtOAc/CH2Cl2 recovered 17 mg of starting material, followed
by 4 (27 mg, 55% based on consumption of starting material).
The product was crystallized from CH2Cl2/diisopropyl ether
and spectroscopically identical to an authentic sample.9
5-Allyla m in o-1-(ch lor om et h yl)-3-[(2E)-3-(4-m et h oxy-
ph en yl)-2-pr open oyl]-1,2-dih ydr o-3H-ben zo[e]in dole (18).
Similar treatment of 16 (2.74 g, 5.81 mmol) with 4-methoxy-
cinnamic acid (1.14 g, 6.4 mmol) and EDCl‚HCl (2.77 g),
followed by column chromatography of the product on silica
gel, eluting with EtOAc/CH2Cl2 (1:5) and crystallization from
CH2Cl2/diisopropyl ether, afforded 18 (980 mg, 39%) as a
C
26H34N2O5 454.2468, found 454.2473.
5-[Allyl(ter t-b u t yloxyca r b on yl)a m in o]-3-(ter t-b u t yl-
oxyca r bon yl)-1-(ch lor om eth yl)-1,2-d ih yd r o-3H-ben zo[e]-
in d ole (16). A solution of 15 (4.55 g, 10.0 mmol) in CH2Cl2
(100 mL) under N2 was treated sequentially with Ph3P (7.9 g,
30.0 mmol, 3 equiv) and CCl4 (14.0 g, 90 mmol, 9 equiv) and
then stirred at room temperature for 2 h. The solvent was
evaporated under reduced pressure, and the crude product was
purified by column chromatography on silica gel. Elution with
EtOAc/petroleum ether (from 1:4 to 1:1) afforded 16 (4.46 g,
90%) as a pale yellow oil: 1H NMR (CDCl3) δ 8.10 (vbr, 1 H),
7.78 (d, J ) 8.2 Hz, 1 H), 7.71 (t, J ) 7.2 Hz, 1 H), 7.50 (t, J
) 7.2 Hz, 1 H), 7.38 (t, J ) 7.7 Hz, 1 H), 5.98 (m, 1 H), 5.10
(m, 2 H), 4.43 (br, 1 H), 4.28 (m, 1 H), 4.13 (m, 2 H), 4.05 (m,
1 H), 3.95 (m, 1 H), 3.47 (m, 1 H), 1.60 (m, 12 H), 1.20 (m, 6
H); 13C NMR δ 154.9, 152.4, 133.9, 132.0, 128.4, 127.2, 124.4,
123.9, 122.5, 117.7, 60.4, 52.7, 46.3, 28.5, 28.2, 21.0; HRMS
m/z required for C26H33ClN2O4 472.2129, found 472.2129.
5-Allylam in o-1-(ch lor om eth yl)-3-(5,6,7-tr im eth oxyin dol-
2-ca r bon yl)-1,2-d ih yd r o-3H-ben zo[e]in d ole (17). A solu-
tion of 16 (406 mg, 0.858 mmol) in 50 mL of trifluoroacetic
acid (TFA) was kept at 0 °C for 2 h under nitrogen to cleave
the t-BOC protecting group. The reaction mixture was then
concentrated under reduced pressure, and the residue was
diluted with benzene (30 mL) and concentrated once more, to
remove any remaining TFA. The resulting residue was treated
with saturated aqueous NaHCO3, extracted with CH2Cl2 (3 ×
50 mL), dried, and concentrated under reduced pressure. To
the residue was added 5,6,7-trimethoxyindole-2-carboxylic acid
(220 mg) and EDCI‚HCl (411 mg), followed by 10 mL of DMA,
and the reaction mixture was stirred at room temperature
overnight, diluted with saturated aqueous NaHCO3, extracted
with EtOAc (3 × 50 mL), dried, and concentrated under
reduced pressure. The product was purified by column chro-
matography on silica gel. Elution with EtOAc/CH2Cl2 (1:5) and
crystallization from CH2Cl2/diisopropyl ether afforded 17 (355
mg, 80%) as a yellow solid: mp 107-112 °C; 1H NMR (CDCl3)
δ 9.51 (s, 1 H), 7.81 (d, J ) 8.7 Hz, 1 H), 7.80 (s, 1 H), 7.67 (d,
J ) 8.3 Hz, 1 H), 7.51 (t, J ) 7.8 Hz, 1 H), 7.37 (t, J ) 7.8 Hz,
1 H), 6.98 (d, J ) 2.3 Hz, 1 H), 6.87 (s, 1 H), 6.05 (m, 1 H),
5.40 (dd, J ) 17.4, 1.4 Hz, 1 H), 5.24 (dd, J ) 10.3, 1.2 Hz, 1
H), 4.74 (dd, J ) 10.7, 1.4 Hz, 2 H), 4.66 (s, 1 H), 4.55 (t, J )
10.4 Hz, 1 H), 4.06 (s, 3 H), 4.03 (m, 1 H), 4.00 (m, 2 H), 3.94
(s, 3 H), 3.91 (m, 1 H), 3.90 (s, 3 H), 3.40 (t, J ) 10.9 Hz, 1 H);
13C NMR δ 160.4, 150.1, 144.9, 142.7, 140.4, 138.8, 134.5,
130.1, 130.0, 127.0, 125,4, 123.6, 123.3, 123.1, 121.2, 121.1,
116.9, 113.1, 106.4, 97.7, 96.8, 61.4, 61.1, 56.2, 55.1, 46.6, 46.1,
43.2; HRMS m/z required for C28H2835ClN3O4 505.1768, found
505.1765. Anal. Calcd for C28H28ClN3O4‚0.5H2O: C, 65.4; H,
5.5; N, 8.2. Found: C, 65.3; H, 5.4; N, 8.4.
1
yellow solid: mp 152-154 °C; H NMR (CDCl3) δ 7.95 (br, 1
H), 7.80 (s, 1 H), 7.79 (d, J ) 8.5 Hz, 1 H), 7.68 (d, J ) 8.2 Hz,
1 H), 7, 57 (s, 1 H), 7.55 (s, 1 H), 7.48 (m, 1 H), 7.33 (m, 1 H),
6.93 (s, 1 H), 6.91 (s, 1 H), 6.80 (br, 1 H), 6.09 (m, 1 H), 5.40
(m, 1 H), 5.26 (m, 1 H), 4.65 (br, 1 H), 4.49 (m, 1 H), 4.36 (m,
1 H), 4.00 (m, 4 H), 3.85 (s, 3 H), 3.41 (m, 1 H); 13C NMR δ
165.0, 161.2, 145.0, 143.5, 142.6, 134.6, 130.1, 129.8, 127.8,
127.0, 123.2, 123.0, 121.2, 121.0, 117.0, 116.3, 114.3, 96.9, 55.4,
53.4, 46.7, 46.3, 42.6; HRMS m/z required for C26H25ClN2O2
432.1605, found 432.1609. Anal. Calcd for C26H25ClN2O2‚
0.33H2O: C, 71.1; H, 5.7; N, 6.4. Found: C, 71.3; H, 5.8; N,
6.3.
5-Am in o-1-(ch lor om eth yl)-3-[(2E)-3-(4-m eth oxyph en yl)-
2-p r op en oyl]-1,2-d ih yd r o-3H-ben zo[e]in d ole (19). Depro-
tection of 18 (90 mg) with Cl2(Cy3P)2RudCHPh as described
above, followed by chromatography of the residue, eluting with
EtOAc/CH2Cl2, gave 19 (34 mg, 42%). Crystallization from
CH2Cl2/diisopropyl ether gave a product spectroscopically
identical to an authentic sample.14
Ack n ow led gm en t. This work was carried out with
financial assistance from the Marsden Fund (Contract
CSO701) and the Health Research Council of NZ (Grant
01/276).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 14 and 16-18. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0263115
(14) Atwell, G. J .; Milbank, J . J . B.; Wilson, W. R.; Hogg, A.; Denny,
W. A. J . Med. Chem. 1999, 42, 3400.
J . Org. Chem, Vol. 67, No. 25, 2002 8961