Synthesis of latonduine derivatives via intramolecular Heck?reaction

Article abstract of DOI:10.1016/j.tet.2006.11.042

The synthesis of indole ring-fused benzazepinone series as latonduine derivatives has been developed via an intramolecular Heck reaction. The scope has been enlarged not only to indole moiety but also to pyrrolo and benzo[b]thiophene nuclei. Several derivatives prepared have been evaluated in vitro for their antiproliferative activities on breast cancer cell lines. Some of them showed promising cytotoxic activities.

Full text of DOI:10.1016/j.tet.2006.11.042

Tetrahedron 63 (2007) 867–879
Synthesis of latonduine derivatives via intramolecular
Heck reaction
a
Aurelien Putey, Lionel Joucla, Laurent Picot, Thierry Besson and Benoıt Joseph
a
b
b
a,
*
ˆ
ꢀ
a
´
Laboratoire de Chimie Organique 1, UMR-CNRS 5181, Universite Claude Bernard—Lyon 1,
CPE—Ba^timent 308, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
bLaboratoire de Biotechnologies et Chimie Bio-organique, FRE-CNRS 2766, UFR Sciences Fondamentales et Sciences pour
´
l’Ingenieur, Batiment Marie Curie, Universite de la Rochelle F-17042, La Rochelle Cedex 1, France
^
´
Received 18 September 2006; revised 13 November 2006; accepted 16 November 2006
Abstract—The synthesis of indole ring-fused benzazepinone series as latonduine derivatives has been developed via an intramolecular Heck
reaction. The scope has been enlarged not only to indole moiety but also to pyrrolo and benzo[b]thiophene nuclei. Several derivatives prepared
have been evaluated in vitro for their antiproliferative activities on breast cancer cell lines. Some of them showed promising cytotoxic
activities.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Latonduines A and B have been isolated from the Indonesian
sponge Stylissa carteri (Fig. 1).1 These natural products ap-
pear to be related to the well-known pyrrolo[2,3-c]azepin-8-
one family (aldisine, hymenialdisine, stevensine, hymenin,
and spongiacidins).2 Latonduine A and latonduine B ethyl
ester were found inactive in cytotoxicity assays against
a panel of human cancer lines and for enzyme inhibition
against a panel of protein kinases. Latonduine A has been
synthesized in five steps from 4,5-dibromo-N-[2-(1,3-dioxo-
lan-2-yl)ethyl]pyrrole-2-carboxamide.1
Compounds 3a–d were prepared in two steps from the
commercially available ethyl-1H-indole-2-carboxylate 1a,
methyl 4-methoxy-1H-indole-2-carboxylate 1b, ethyl 5-
methoxy-1H-indole-2-carboxylate 1c, and methyl 6-methoxy-
1H-indole-2-carboxylate 1d (Scheme 1). N-Alkylation of
1a–d was performed in the presence of sodium hydride and
ethoxymethyl chloride (EOMCl) to afford 2 in good yield.
Saponification of 2 gave the desired 1-(ethoxymethyl)-
1H-indole-2-carboxylic acids 3 in near-quantitative yield.
The5,8-dihydroindolo[2,3-d][2]benzazepin-7(6H)-one deri-
vatives 9a–d were prepared from 3a–d in four or five steps
(Scheme 2). The amidification of 3 was achieved using
DMAP, EDCI, and freshly prepared 2-iodobenzylamine 4.7
The compounds 5 were obtained in 85–95% yield. Attempts
of Heck reaction on 5a or N-methyl derivatives of 5a and 5b
led to low yield of cyclized compounds (15–17% yield).
Boc protection of the amide nitrogen of 5 was carried out
under classical conditions (Boc2O and DMAP) to afford 6
In our laboratory, we focused on the synthesis of latonduine
derivatives I (Fig. 1) where the pyrrole and the pyrimidine
nuclei were replaced, respectively, by heterocycle and ben-
zene moieties. In a previous communication,3 we have re-
ported the general sequence using an intramolecular Heck
coupling4 as key reaction to reach the N-protected deriva-
tives. According to the same approach, Beccalli et al. have
recently disclosed the synthesis of N-methyl six-membered
latonduine and paullone derivatives.5,6 In this paper, we de-
tail the strategy for obtaining the non-protected or N-methyl
derivatives I. Amongst the products prepared, some of them
were evaluated for their in vitro cytotoxicity against human
breast cancer cell lines.
NH2
N
N
R
Br
Het
N
NH
R
Br
N
H
O
O
I R = H, Me
latonduine A R = H
latonduine B R = CO2H
Keywords: Indole; Heck; Intramolecular cyclization; Cytotoxic agent.
* Corresponding author. Tel.: +33 472 448 135; fax: +33 472 431 214;
e-mail: benoit.joseph@univ-lyon1.fr
Figure 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.042

868
A. Putey et al. / Tetrahedron 63 (2007) 867–879
R1
R1
R1
R2
R3
R2
R3
R2
R3
i
ii
CO2R
EOM
CO2H
EOM
CO2R
N
N
H
N
1a R = Et, R1 = R2 = R3 = H
2a-d
3a-d
1b R = Me, R1 = OMe R2 = R3 = H
1c R = Et, R1 = R3 = H, R2 = OMe
1d R = Me, R1 = R2 = H, R3 = OMe
Scheme 1. (i) NaH, DMF, EOMCl, 0 ꢀC to rt, 15 h, 2a¼97%, 2b¼96%, 2c¼95%, 2d¼87%; (ii) LiOH$H2O, EtOH or MeOH, reflux, 2 h, 3a¼98%, 3b¼99%,
3c¼96%, 3d¼97%.
Table 1. Heck reaction on compounds 6a–d
N-Methyl derivatives 11a and 11b were prepared in two
steps (Scheme 3). N-Alkylation of 8a and 8b afforded 10a
and 10b in 99% yield. EOM deprotection of 10 gave 11a
and 11b, respectively, in 92 and 36% yield.
6
R1
R2
R3
7
Yield (%)
6a
6b
6c
6d
H
OMe
H
H
H
OMe
H
H
H
H
OMe
7a
7b
7c
7d
96
90
93
96
H
R1
10a R1 = H
R = EOM
10b R1 = OMe R = EOM
11a R1 = H
R = H
11b R1 = OMe R = H
N
in near-quantitative yield. The intramolecular ring closure of
6 was performed in the presence of Pd(OAc)2 (0.05 equiv),
PPh3 (0.1 equiv), and silver carbonate (2 equiv) in DMF at
100 ꢀC for 1 h to give 7 in excellent yield (Table 1). The dif-
ference of reactivity between 5, N-methyl 5 and 6 can be ex-
plained by the presence of the bulky group on amide, which
favors a more reactive conformation.8,9 Removal of protect-
ing groups on 7 could be carried out in one or two-step
procedures according to the final derivatives envisaged. Se-
quential deprotection of 7 was achieved by removal of the
N-Boc group (1 N NaOH and 1,4-dioxane) and then the
N-EOM group (1 N HCl and 1,4-dioxane) to afford, respec-
tively, 8 and 9 in good yield. Compounds 9 could also be
obtained from 7 in fair yield by a one pot treatment in acidic
conditions (1 N HCl and 1,4-dioxane). It should be noted that
the 1H NMR spectrum of 9b in DMSO-d6 at room tempera-
ture showed a mixture of rotamers, while on raising the
temperature to 120 ꢀC the coalescence of the signals was
observed.
i
Me
8a, 8b
ii
N
O
R
Scheme 3. (i) NaH, ICH3, THF, 0 ꢀC to rt, 4 h, 10a,b¼99%; (ii) 1 N HCl,
1,4-dioxane, 80 ꢀC, 2 h, 11a¼92%, 11b¼36%.
In the case of the preparation of benzo[b]thiophene deriva-
tive (Scheme 4), the amides 12 and 13 were prepared from
commercially available benzo[b]thiophene-2-carboxylic acid
and 2-iodobenzylamine 4 according to the procedure de-
scribed for indole derivatives 5 and 6. Heck cyclization
procedure was applied on 13 to afford 14 in 82% yield (in
this reaction, final derivative 15 was also isolated in 8%
yield). Removal of the Boc group of 14 was effective by
treatment with a solution of trifluoroacetic acid in dichloro-
methane at room temperature to give 15 in 88% yield. The
same assay in basic medium (1 N NaOH and 1,4-dioxane)
led to the degradation of 14.
I
I
R1
R1
R1
I
R2
R3
R2
R3
R2
R3
N
NH
O
Boc
i
ii
+
CO2H
EOM
N
N
N
O
NH2
EOM
6a-d
EOM
5a-d
4
3a R1 = R2 = R3 = H
iii
3b R1 = OMe R2 = R3 = H
3c R1 = R3 = H, R2 = OMe
3d R1 = R2 = H, R3 = OMe
R1
R1
R1
R2
R3
R2
R3
R2
R3
NH
N
v
iv
NH
Boc
N
N
O
O
N
H
O
EOM
8a-d
vi
EOM
7a-d
9a-d
Scheme 2. (i) EDCI, DMAP, CH2Cl2, 0 ꢀC to rt, 24 h, 5a¼95%, 5b¼91%, 5c¼90%, 5d¼85%; (ii) Boc2O, DMAP, CH3CN, rt, overnight, 6a–d¼99%; (iii)
Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Ag2CO3, DMF, 100 ꢀC, 1 h, see Table 1; (iv) 1 N NaOH, 1,4-dioxane, 80 ꢀC, 1 h, 8a¼80%, 8b¼93%, 8c¼65%,
8d¼73%; (v) 1 N HCl, 1,4-dioxane, 80 ꢀC, 2 h, 9a¼94%, 9b¼42%, 9c¼97%, 9d¼81%; (vi) 1 N HCl, 1,4-dioxane, 80 ꢀC, 5 h, 9a¼79%, 9b¼42%,
9c¼65%, 9d¼63%.

A. Putey et al. / Tetrahedron 63 (2007) 867–879
869
I
N
N
NH
R
Boc
iv
i
iii
CO2H
S
S
S
S
O
O
O
15
14
12 R = H
ii
13 R = Boc
Scheme 4. (i) Compound 4, EDCI, DMAP, CH2Cl2, 0 ꢀC to rt, 24 h, 77%; (ii) Boc2O, DMAP, CH3CN, rt, overnight, 99%; (iii) Pd(OAc)2 (5 mol %), PPh3
(10 mol %), Ag2CO3, DMF, 100 ꢀC, 1 h, 82%; (iv) TFA, CH2Cl2, rt, 1 h, 88%.
I
N
ii
iii
v
vi
R
N
N
NH
CO2H
CO2Et
Boc
Boc
N
N
R
N
O
N
N
H
N
O
BOM
17
BOM
O
O
18 R = H
R = H
BOM
20
21
EOM
22
iv
i
19 R = Boc
16 R = BOM
Scheme 5. (i) NaH, DMF, BOMCl, 0 ꢀC to rt, 15 h, 99%; (ii) LiOH$H2O, EtOH, reflux, 2 h, quantitative; (iii) 4, EDCI, DMAP, CH2Cl2, 0 ꢀC to rt, 24 h, 95%;
(iv) Boc2O, DMAP, CH3CN, rt, overnight, 99%; (v) Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Ag2CO3, DMF, 140 ꢀC, 1 h, 85%; (vi) Pd(OH)2, H2 (1 atm), EtOH/
THF, 4:1, rt, 2 h, then 1 N NaOH, 1,4-dioxane, 80 ꢀC, 1 h, 88%.
Pyrrole derivative 21, close latonduine scaffold, was
prepared in fair yield from commercially available ethyl-
1H-pyrrole-2-carboxylate (Scheme 5). N-Alkylation of this
latter compound was performed in the presence of sodium
hydride and benzyloxymethyl chloride (BOMCl) to afford
16 in near-quantitative yield. Saponification of 16 gave the
desired 1-(benzyloxymethyl)-1H-pyrrole-2-carboxylic acid
17 in quantitative yield. Amides 18 and 19 were obtained in
good yield. The intramolecular cyclization of protected amide
19 required the modification of experimental parameters as
reported in Table 2. Thus, the ring closure reaction was im-
proved (20, 85% yield) when 0.1 equiv of Pd(OAc)2 was
used and the cyclization was performed at 140 ꢀC.
Moreover, we used the N-BOM derivative 20 instead of
N-EOM derivative 22 (previously prepared in our labora-
tory)3 to access the desired pyrrole 21. Removal of the
N-Boc group of 22 in basic medium was highly effective
(1 N NaOH and 1,4-dioxane, quantitative yield). Unfortu-
nately, EOM deprotection in 1 N HCl led to complete degra-
dation of the starting material. Similarly, the cleavage of the
N-BOM group of 20 by hydrogenolysis followed by removal
of the N-Boc group afforded 21 in 88% yield.
Table 2. Heck reaction on compound 19
Catalyst (equiv) Temp (ꢀC) Time (h) 20, yield (%) 19, recovered
yield (%)
Using the same synthetic sequence, 5,12-dihydroindolo[3,2-
d][2]benzazepin-7(6H)-one derivatives 27, close analogue
of paullones,10 were obtained from 1H-indole-3-carboxylic
acids 23a9 and 23b (Scheme 6). Compound 23b was
0.05
0.1
0.1
100
100
140
2.5
2.5
1
62
76
85
36
20
—
O
O
N
N
H
CO2H
I
I
R1
R1
R1
Boc
i
ii
N
N
N
SO2Ph
SO2Ph
24a-b
SO2Ph
25a-b
23a R1 = H
iii
23b R1 = OMe
Boc
N
H
N
O
O
R1
R1
iv,v
N
N
H
SO2Ph
26a-b
27a-b
Scheme 6. (i) Compound 4, EDCI, DMAP, CH2Cl2, 0 ꢀC to rt, 24 h, 24a¼82%, 24b¼76%; (ii) Boc2O, DMAP, CH3CN, rt, overnight, 25a,b¼99%; (iii)
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Ag2CO3, DMF, 100 ꢀC, 2 h, 26a¼92%, 26b¼96%; (iv) TFA, CH2Cl2, rt, 2 h; (v) 1 M TBAF, THF, 70 ꢀC, 30 min,
27a¼40%, 27b¼43% (two-step yield).

870
A. Putey et al. / Tetrahedron 63 (2007) 867–879
Table 3. Percentage growth-inhibition of MCF-7 cells treated with com-
pounds 9a, 9c, 9d, 15, 21, and 27 at 1 mM for 72 h
SCIEX API spectrometer and Thermo Finnigan Mat 95
XL. Elemental analyses were performed on a Thermoquest
Flash 1112 series EA analyzer. TLC was conducted on pre-
coated silica gel plates (Merck 60F254) and the spots were vi-
sualized under UV light. Flash chromatography was carried
out on column using flash silica gel 60 Merck (40–63 mm)
with the indicated solvents (petroleum ether (PE): bp 40–
60 ꢀC). All reactions requiring anhydrous conditions were
conducted in flame-dried apparatus.
Compounds
9a
9c 9d 15 21
27a 27b
4.8
Growth-inhibitiona (%) 70.2 27 64 17 4.5 5.8
a
Inhibition of MCF-7 cell proliferation was measured by the MTT assay.
prepared by oxidation of 5-methoxy-1-(phenylsulfonyl)-
indole-3-carboxaldehyde11 in 81% yield. In this case, the
cyclization reaction of 25 was performed in the presence
of 0.1 equiv of palladium catalyst at 100 ꢀC for 2 h to afford
26 in 92–96% yield.3 A two-step deprotection sequence was
developed to reach compounds 27. Removal of the N-Boc
group was first carried out by treatment of 26 with trifluoro-
acetic acid in dichloromethane at room temperature fol-
lowed by the second deprotection in the presence of TBAF
in refluxing THF. The derivatives 27a and 27b were obtained
in 40–43% yield (two-step yield).
4.2. General procedure for EOM protection
At 0 ꢀC, sodium hydride (636 mg, 15.9 mmol, 60% dis-
persed in oil) was added to a solution of 1 (10.6 mmol) in
anhydrous DMF (21 mL). The reaction mixture was stirred
for 1 h at room temperature and ethoxymethyl chloride
(1.97 mL, 21.2 mmol) was added dropwise. The final solu-
tion was stirred for 15 h at room temperature. The solvent
was evaporated in vacuo. The residue was taken up in H2O
(10 mL) and extracted with CH2Cl2 (5ꢁ10 mL). The com-
bined organic phases were dried over Na2SO4 and concen-
trated in vacuo. The crude residue was purified by flash
chromatography to give 2.
The MCF-7 breast adenocarcinoma cell line was used to as-
sess the cytotoxic potential of compounds 9a, 9c, 9d, 15, 21,
27a and 27b. The best antiproliferative activity was found
for 5,8-dihydroindolo[2,3-d][2]benzazepin-7(6H)-one de-
rivatives 9a and 9d (Table 3). From this preliminary screen-
ing, growth-inhibitory activity (IC50) of lead compounds 9a
and 9b was determined on MCF-7 and MDA-MB231 cancer
cell lines (Table 4). These compounds showed significant
cytotoxic activity. Structure–activity relationship studies are
in progress to improve the potency of this new indole series.
4.2.1. Ethyl 1-(ethoxymethyl)-1H-indole-2-carboxylate
(2a). According to the general procedure, compound 2a
was prepared from 1a. Chromatography eluent: PE/EtOAc
95:5; yield: 97%; oil; IR (film) n 3070, 2978, 1709, 1522,
1
1314, 1249, 1210, 1094, 748 cmꢂ1; H NMR (CDCl3) d
1.13 (t, 3H, J¼7.2 Hz, CH3), 1.41 (t, 3H, J¼7.2 Hz, CH3),
3.50 (q, 2H, J¼7.2 Hz, CH2), 4.39 (q, 2H, J¼7.2 Hz, CH2),
6.04 (s, 2H, CH2), 7.19 (t, 1H, J¼8.2 Hz, H5), 7.35–7.40 (m,
2H, H3+H6), 7.58 (d, 1H, J¼8.5 Hz, H7), 7.68 (d, 1H,
J¼7.9 Hz, H4); 13C NMR (CDCl3) d 14.4 (CH3), 15.1 (CH3),
60.8 (CH2), 63.9 (CH2), 73.4 (CH2), 111.4 (CH), 112.2
(CH), 121.4 (CH), 122.6 (CH), 125.6 (CH), 126.4 (C), 127.9
(C), 139.9 (C), 162.1 (CO); MS (IS) m/z 248 (M+H)+. Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.33; H, 7.13; N, 5.77.
Table 4. Growth-inhibitory activity of compounds 9a and 9d
Compounds
Cell lines IC50 (mM)a,b
MCF-7 MDA-MB231
9a
9d
1.2
0.6
3
4
a
MTT assay.
Values obtained for mean of three different experiments.
b
4.2.2. Methyl 1-(ethoxymethyl)-4-methoxy-1H-indole-2-
carboxylate (2b). According to the general procedure, com-
pound 2b was prepared from 1b. Chromatography eluent:
PE/EtOAc 85:15; yield: 96%; white solid; mp 71–72 ꢀC
(EtOAc/PE); IR (KBr) n 3000, 2956, 1724, 1615, 1438,
3. Conclusion
In conclusion, we have developed an efficient and straightfor-
ward synthesis for new heterocyclic ring-fused benzazepi-
none scaffolds via intramolecular Heck coupling reaction.
The 5,8-dihydroindolo[2,3-d][2]benzazepin-7(6H)-one se-
ries shows significant and encouraging cytotoxic activity.
This synthetic approach will be applied for the preparation
of marine natural product latonduines.
1
1232, 1186, 1092, 754 cmꢂ1; H NMR (CDCl3) d 1.12 (t,
3H, J¼7.2 Hz, CH3), 3.49 (q, 2H, J¼7.2 Hz, CH2), 3.90
(s, 3H, CH3), 3.95 (s, 3H, CH3), 6.00 (s, 2H, CH2), 6.55
(d, 1H, J¼7.7 Hz, H5), 7.16 (d, 1H, J¼8.5 Hz, H7), 7.29 (t,
1H, J¼8.1 Hz, H6), 7.47 (s, 1H, H3); 13C NMR (CDCl3)
d 15.1 (CH3), 51.8 (CH3), 55.5 (CH3), 63.9 (CH2), 73.7
(CH2), 100.6 (CH), 104.4 (CH), 110.1 (CH), 117.8 (C),
126.3 (C), 126.8 (CH), 141.4 (C), 154.7 (C), 162.4 (CO);
MS (IS) m/z 264 (M+H)+. Anal. Calcd for C14H17NO4: C,
63.87; H, 6.51; N, 5.32. Found: C, 63.80; H, 6.40; N, 5.19.
4. Experimental
4.1. General experimental procedures
€
4.2.3. Ethyl 1-(ethoxymethyl)-5-methoxy-1H-indole-2-
carboxylate (2c). According to the general procedure, com-
pound 2c was prepared from 1c. Chromatography eluent:
PE/EtOAc 9:1; yield: 95%; white solid; mp 63–64 ꢀC
(EtOAc/PE); IR (KBr) n 3000, 2978, 1709, 1517, 1464,
Melting points were measured with a Buchi Tottoli SMP-20
heating unit and are uncorrected. IR spectra were recorded
with a Perkin–Elmer spectrum one spectrophotometer.
NMR spectra were recorded with an AVANCE 300 Bruker
spectrometer at 300 MHz for 1H and 75 MHz for 13C. Chem-
ical shifts are expressed in parts per million (ppm) relative to
TMS. Mass spectra were recorded with a Perkin–Elmer
1
1382, 1212, 1082 cmꢂ1; H NMR (CDCl3) d 1.12 (t, 3H,
J¼7.2 Hz, CH3), 1.41 (t, 3H, J¼7.2 Hz, CH3), 3.48 (q, 2H,

A. Putey et al. / Tetrahedron 63 (2007) 867–879
871
J¼7.2 Hz, CH2), 3.85 (s, 3H, CH3), 4.37 (q, 2H, J¼7.2 Hz,
CH2), 5.99 (s, 2H, CH2), 7.02–7.06 (m, 2H, H4+H6), 7.26 (s,
1H, H3), 7.47 (d, 1H, J¼8.7 Hz, H7); 13C NMR (CDCl3)
d 14.5 (CH3), 15.2 (CH3), 55.8 (CH3), 60.8 (CH2), 63.8
(CH2), 73.6 (CH2), 102.8 (CH), 111.7 (CH), 112.4 (CH),
116.9 (CH), 126.7 (C), 128.2 (C), 135.3 (C), 155.2 (C),
162.0 (CO); MS (IS) m/z 278 (M+H)+. Anal. Calcd for
C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 65.12;
H, 6.99; N, 4.98.
(CDCl3) d 15.1 (CH3), 55.5 (CH3), 64.0 (CH2), 73.8
(CH2), 100.7 (CH), 104.4 (CH), 112.4 (CH), 117.9 (C),
125.5 (C), 127.6 (CH), 142.0 (C), 154.9 (C), 166.9 (CO);
MS (IS) m/z 248 (MꢂH)+. Anal. Calcd for C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.55; H, 5.98; N, 5.65.
4.3.3. 1-(Ethoxymethyl)-5-methoxy-1H-indole-2-carb-
oxylic acid (3c). According to the general procedure, com-
pound 3c was prepared from 2c. Yield: 96%; white solid;
mp 146–147 ꢀC (EtOAc/PE); IR (KBr) n 3100–2500,
1
4.2.4. Methyl 1-(ethoxymethyl)-6-methoxy-1H-indole-2-
carboxylate (2d). According to the general procedure, com-
pound 2d was prepared from 1d. Chromatography eluent:
PE/EtOAc 85:15; yield: 87%; white solid; mp 57–58 ꢀC
(EtOAc/PE); IR (KBr) n 3014, 2964, 1705, 1620, 1464,
2973, 1674, 1524, 1431, 1226, 1093, 827 cmꢂ1; H NMR
(CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 3.50 (q, 2H,
J¼7.2 Hz, CH2), 3.86 (s, 3H, CH3), 6.00 (s, 2H, CH2),
7.07–7.09 (m, 2H, H4+H6), 7.42 (s, 1H, H3), 7.49 (d, 1H,
J¼9.8 Hz, H7); 13C NMR (CDCl3) d 15.1 (CH3), 55.8
(CH3), 63.9 (CH2), 73.6 (CH2), 102.7 (CH), 112.5 (CH),
114.1 (CH), 118.0 (CH), 126.6 (C), 127.0 (C), 135.9 (C),
155.3 (C), 167.0 (CO); MS (IS) m/z 248 (MꢂH)+. Anal.
Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found:
C, 62.88; H, 6.21; N, 5.73.
1
1212 cmꢂ1; H NMR (CDCl3) d 1.14 (t, 3H, J¼7.2 Hz,
CH3), 3.51 (q, 2H, J¼7.2 Hz, CH2), 3.89 (s, 6H, 2CH3),
6.00 (s, 2H, CH2), 6.86 (dd, 1H, J¼2.2, 8.8 Hz, H5), 6.98
(d, 1H, J¼2.2 Hz, H7), 7.28 (s, 1H, H3), 7.54 (d, 1H,
J¼8.8 Hz, H4); 13C NMR (CDCl3) d 14.8 (CH3), 51.2
(CH3), 55.1 (CH3), 63.3 (CH2), 73.0 (CH2), 93.1 (CH),
112.3 (CH), 112.5 (CH), 120.2 (C), 123.1 (CH), 126.1 (C),
140.7 (C), 158.8 (C), 161.9 (CO); MS (IS) m/z 264
(M+H)+. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51;
N, 5.32; O, 24.31. Found: C, 63.63; H, 6.35; N, 5.15.
4.3.4. 1-(Ethoxymethyl)-6-methoxy-1H-indole-2-carb-
oxylic acid (3d). According to the general procedure, com-
pound 3d was prepared from 2d. Yield: 97%; white solid;
mp 149–151 ꢀC (EtOAc); IR (KBr) n 3100–2500, 2939,
1673, 1620, 1498, 1441, 1225, 1126 cmꢂ1 1H NMR
;
4.3. General procedure for the saponification
(CDCl3) d 1.16 (t, 3H, J¼7.2 Hz, CH3), 3.53 (q, 2H,
J¼7.2 Hz, CH2), 3.90 (s, 3H, CH3), 6.01 (s, 2H, CH2),
6.88 (dd, 1H, J¼2.2, 8.8 Hz, H5), 6.98 (d, 1H, J¼2.2 Hz,
H7), 7.46 (s, 1H, H3), 7.57 (d, 1H, J¼8.8 Hz, H4); 13C
NMR (CDCl3) d 15.1 (CH3), 55.7 (CH3), 63.8 (CH2), 73.5
(CH2), 93.4 (CH), 113.3 (CH), 115.1 (CH), 120.6 (C),
123.8 (CH), 125.7 (C), 141.8 (C), 159.7 (C), 166.9 (CO);
MS (IS) m/z 248 (MꢂH)+. Anal. Calcd for C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.66; H, 5.98; N, 5.71.
Lithium hydroxide monohydrate (507 mg, 12.1 mmol) and
H2O (2 mL) were added to a solution of 2 (10.1 mmol) in
ethanol or methanol (28 mL). The reaction mixture was
stirred at reflux for 2 h and the solvent was evaporated.
The residue was taken up in H2O (5 mL), acidified with
1 N HCl, and extracted with EtOAc (3ꢁ10 mL). The com-
bined organic phases were dried over Na2SO4 and concen-
trated in vacuo. The solid was then recrystallized from
EtOAc or EtOAc/PE to afford 3.
4.4. General procedure for peptidic coupling
4.3.1. 1-(Ethoxymethyl)-1H-indole-2-carboxylic acid
(3a). According to the general procedure, compound 3a
was prepared from 2a. Yield: 98%; white solid; mp 139–
141 ꢀC (EtOAc/PE); IR (KBr) 3100–2500, 3042, 2984,
Under argon atmosphere, indole 3 (4.29 mmol), DMAP
(0.52 g, 4.29 mmol), and EDCI (0.91 g, 4.72 mmol) were
added to a solution of 2-iodobenzylamine 4 (1.10 g,
4.72 mmol) in CH2Cl2 (45 mL) at 0 ꢀC. The mixture was
stirred for 4 h at 0 ꢀC and then for 20 h at room temperature.
H2O (10 mL) was added, the mixture was acidified with 6 N
HCl solution (pH 1–2), and extracted with CH2Cl2
(3ꢁ10 mL). The combined organic phases were dried over
Na2SO4, then filtered and concentrated in vacuo to give
a crude solid, which was washed with Et2O to afford 5.
1677, 1519, 1432, 1391, 1259, 1235, 1087, 746 cmꢂ1
;
1H NMR (CDCl3) d 1.15 (t, 3H, J¼7.2 Hz, CH3), 3.52 (q,
2H, J¼7.2 Hz, CH2), 6.04 (s, 2H, CH2), 7.22 (t, 1H,
J¼8.2 Hz, H5), 7.41 (t, 1H, J¼8.2 Hz, H6), 7.52 (s, 1H,
H3), 7.60 (d, 1H, J¼8.5 Hz, H7), 7.72 (d, 1H, J¼7.9 Hz,
H4); 13C NMR (CDCl3) d 15.1 (CH3), 64.0 (CH2), 73.5
(CH2), 111.5 (CH), 114.8 (CH), 121.7 (CH), 123.0 (CH),
126.3 (C), 126.4 (CH), 126.8 (C), 140.5 (C), 167.2 (CO);
MS (IS) m/z 218 (MꢂH)+. Anal. Calcd for C12H13NO3:
C, 65.74; H, 5.98; N, 6.39. Found: C, 66.06; H, 6.07;
N, 6.45.
4.4.1. 1-(Ethoxymethyl)-N-(2-iodobenzyl)-1H-indole-2-
carboxamide (5a). According to the general procedure,
compound 5a was prepared from 3a. Yield: 95%; white
solid; mp 141–142 ꢀC (washing Et2O); IR (KBr) n 3292,
2978, 1630, 1538, 1343, 1265, 1091, 1067, 1013,
4.3.2. 1-(Ethoxymethyl)-4-methoxy-1H-indole-2-carb-
oxylic acid (3b). According to the general procedure, com-
pound 3b was prepared from 2b. Yield: 99%; white solid; mp
154–155 ꢀC (EtOAc); IR (KBr) n 3100–2500, 2958, 1674,
739 cmꢂ1
;
1H NMR (CDCl3) d 1.09 (t, 3H, J¼7.2 Hz,
CH3), 3.51 (q, 2H, J¼7.2 Hz, CH2), 4.67 (d, 2H,
J¼5.9 Hz, CH2), 5.91 (s, 2H, CH2), 7.01 (t, 1H, J¼7.7 Hz,
Har), 7.03 (s, 1H, Har), 7.08 (br t, 1H, J¼5.9 Hz, NH), 7.18
(t, 1H, J¼7.5 Hz, Har), 7.31–7.37 (m, 2H, Har), 7.47 (d,
1H, J¼7.5 Hz, Har), 7.53 (d, 1H, J¼8.3 Hz, Har), 7.64 (d,
1H, J¼7.7 Hz, Har), 7.87 (d, 1H, J¼7.9 Hz, Har); 13C
NMR (DMSO-d6) d 14.9 (CH3), 47.6 (CH2), 63.1 (CH2),
72.5 (CH2), 98.4 (C), 106.6 (CH), 111.2 (CH), 120.9 (CH),
1
1517, 1498, 1264, 1243, 1186, 1079, 740 cmꢂ1; H NMR
(CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 3.51 (q, 2H,
J¼7.2 Hz, CH2), 3.97 (s, 3H, CH3), 6.02 (s, 2H, CH2),
6.56 (d, 1H, J¼7.7 Hz, H5), 7.15 (d, 1H, J¼8.5 Hz, H7),
7.33 (t, 1H, J¼8.1 Hz, H6), 7.65 (s, 1H, H3); 13C NMR

872
A. Putey et al. / Tetrahedron 63 (2007) 867–879
121.7 (CH), 124.2 (CH), 126.0 (C), 127.7 (CH), 128.3 (CH),
129.0 (CH), 131.9 (C), 138.5 (C), 138.9 (CH), 140.5 (C),
161.9 (CO); MS (IS) m/z 435 (M+H)+. Anal. Calcd for
C19H19IN2O2: C, 52.55; H, 4.41; N, 6.45. Found: C, 52.43;
H, 4.50; N, 6.40.
Calcd for C20H21IN2O3: C, 51.74; H, 4.56; N, 6.03. Found:
C, 51.66; H, 4.44; N, 5.95.
4.5. General procedure for Boc protection
A solution of amide 5 (4.24 mmol), Boc2O (1.48 g,
6.78 mmol), and a catalytic amount of DMAP in acetonitrile
(65 mL) was stirred overnight at room temperature. After
evaporation of the solvent, the residue was partitioned be-
tween EtOAc (30 mL) and H2O (20 mL). The two phases
were separated and the aqueous phase was extracted with
EtOAc (2ꢁ30 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The crude
residue was purified by flash chromatography to give 6.
4.4.2. 1-(Ethoxymethyl)-N-(2-iodobenzyl)-4-methoxy-
1H-indole-2-carboxamide (5b). According to the general
procedure, compound 5b was prepared from 3b. Yield:
91%; white solid; mp 158–159 ꢀC (washing Et2O); IR
(KBr) n 3266, 2970, 1623, 1531, 1373, 1257, 1098, 1016,
740 cmꢂ1
;
1H NMR (CDCl3) d 1.09 (t, 3H, J¼7.2 Hz,
CH3), 3.50 (q, 2H, J¼7.2 Hz, CH2), 3.95 (s, 3H, CH3),
4.66 (d, 2H, J¼6.0 Hz, CH2), 5.92 (s, 2H, CH2), 6.56 (d,
1H, J¼7.5 Hz, Har), 6.92 (t, 1H, J¼6.0 Hz, NH), 7.00 (t,
1H, J¼7.7 Hz, Har), 7.12 (s, 1H, Har), 7.13 (d, 1H, J¼
7.5 Hz, Har), 7.26 (t, 1H, J¼7.7 Hz, Har), 7.34 (t, 1H,
J¼7.5 Hz, Har), 7.46 (d, 1H, J¼7.5 Hz, Har), 7.86 (d, 1H,
J¼7.9 Hz, Har); 13C NMR (DMSO-d6) d 14.9 (CH3), 47.6
(CH2), 55.2 (CH3), 63.0 (CH2), 72.7 (CH2), 98.4 (C),
100.7 (CH), 104.2 (CH), 104.3 (CH), 116.7 (C), 125.4
(CH), 127.8 (CH), 128.3 (CH), 129.0 (CH), 130.3 (C),
138.9 (CH), 140.0 (C), 140.6 (C), 153.5 (C), 161.7
(CO); MS (IS) m/z 465 (M+H)+. Anal. Calcd for
C20H21IN2O3: C, 51.74; H, 4.56; N, 6.03. Found: C, 52.01;
H, 4.68; N, 6.14.
4.5.1. tert-Butyl {[1-(ethoxymethyl)-1H-indol-2-yl]car-
bonyl}(2-iodobenzyl)carbamate (6a). According to the
general procedure, compound 6a was prepared from 5a.
Chromatography eluent: PE/EtOAc 85:15; yield: 99%;
white solid; mp 108–109 ꢀC (EtOAc/PE); IR (KBr) n
2975, 1734, 1659, 1460, 1338, 1318, 1212, 1144, 1094,
983, 742 cmꢂ1; 1H NMR (CDCl3) d 1.16 (t, 3H, J¼7.2 Hz,
CH3), 1.19 (s, 9H, 3CH3), 3.55 (q, 2H, J¼7.2 Hz, CH2),
4.99 (s, 2H, CH2), 5.82 (s, 2H, CH2), 6.95 (s, 1H, Har),
6.95–6.99 (m, 1H, Har), 7.19 (t, 1H, J¼7.1 Hz, Har), 7.28–
7.38 (m, 3H, Har), 7.58 (d, 1H, J¼8.5 Hz, Har), 7.66 (d,
1H, J¼7.9 Hz, Har), 7.85 (d, 1H, J¼7.9 Hz, Har); 13C
NMR (CDCl3) d 15.0 (CH3), 27.6 (3CH3), 54.3 (CH2),
64.0 (CH2), 73.6 (CH2), 83.6 (C), 97.7 (C), 109.1 (CH),
111.1 (CH), 121.4 (CH), 122.3 (CH), 125.2 (CH), 126.3
(C), 126.9 (CH), 128.5 (CH), 128.9 (CH), 133.0 (C), 139.0
(C), 139.5 (CH+C), 153.5 (CO), 165.8 (CO); MS (IS) m/z
535 (M+H)+. Anal. Calcd for C24H27IN2O4: C, 53.94; H,
5.09; N, 5.24. Found: C, 54.23; H, 4.99; N, 5.33.
4.4.3. 1-(Ethoxymethyl)-N-(2-iodobenzyl)-5-methoxy-
1H-indole-2-carboxamide (5c). According to the general
procedure, compound 5c was prepared from 3c. Yield:
90%; white solid; mp 161–162 ꢀC (washing Et2O); IR
(KBr) n 3265, 2964, 1630, 1546, 1471, 1382, 1235, 1091,
740 cmꢂ1
;
1H NMR (CDCl3) d 1.08 (t, 3H, J¼7.2 Hz,
CH3), 3.49 (q, 2H, J¼7.2 Hz, CH2), 3.84 (s, 3H, CH3),
4.66 (d, 2H, J¼6.0 Hz, CH2), 5.86 (s, 2H, CH2), 6.95 (s,
1H, Har), 7.00 (dd, 1H, J¼2.3, 9.1 Hz, Har), 7.01–7.05 (m,
3H, Har+NH), 7.35 (t, 1H, J¼7.5 Hz, Har), 7.42 (d, 1H,
J¼9.1 Hz, Har), 7.47 (d, 1H, J¼7.5 Hz, Har), 7.86 (d, 1H,
J¼7.9 Hz, Har); 13C NMR (CDCl3) d 15.1 (CH3), 48.6
(CH2), 55.8 (CH3), 64.0 (CH2), 73.7 (CH2), 99.2 (C),
102.7 (CH), 106.9 (CH), 111.8 (CH), 115.8 (CH), 126.9
(C), 128.7 (CH), 129.6 (CH), 130.0 (CH), 132.8 (C), 134.4
(C), 139.7 (CH), 140.4 (C), 155.2 (C), 162.0 (CO); MS
(IS) m/z 465 (M+H)+. Anal. Calcd for C20H21IN2O3: C,
51.74; H, 4.56; N, 6.03. Found: C, 51.98; H, 4.69; N, 6.23.
4.5.2. tert-Butyl {[1-(ethoxymethyl)-4-methoxy-1H-indol-
2-yl]carbonyl}(2-iodobenzyl)carbamate (6b). According
to the general procedure, compound 6b was prepared from
5b. Chromatography eluent: PE/EtOAc 9:1; yield: 99%;
oil; IR (film) n 2976, 1735, 1666, 1518, 1497, 1438, 1368,
1
1258, 1147, 741 cmꢂ1; H NMR (CDCl3) d 1.15 (t, 3H,
J¼7.2 Hz, CH3), 1.21 (s, 9H, 3CH3), 3.53 (q, 2H,
J¼7.2 Hz, CH2), 3.95 (s, 3H, CH3), 4.97 (s, 2H, CH2), 5.81
(s, 2H, CH2), 6.55 (dd, 1H, J¼7.7 Hz, Har), 6.92–6.98 (m,
1H, Har), 7.10 (s, 1H, Har), 7.15 (d, 1H, J¼8.3 Hz, Har),
7.24–7.37 (m, 3H, Har), 7.84 (d, 1H, J¼7.5 Hz, Har); 13C
NMR (CDCl3) d 15.0 (CH3), 27.7 (3CH3), 54.4 (CH2), 55.4
(CH3), 63.9 (CH2), 73.8 (CH2), 83.6 (C), 97.7 (C), 100.6
(CH), 104.1 (CH), 107.5 (CH), 117.5 (C), 126.4 (CH), 126.9
(CH), 128.5 (CH), 128.8 (CH), 131.5 (C), 139.5 (CH), 139.7
(C), 140.6 (C), 153.7 (CO), 154.6 (C), 165.6 (CO); MS (IS)
m/z 565 (M+H)+. Anal. Calcd for C25H29IN2O5: C, 53.20; H,
5.18; N, 4.96. Found: C, 53.24; H, 5.08; N, 5.06.
4.4.4. 1-(Ethoxymethyl)-N-(2-iodobenzyl)-6-methoxy-
1H-indole-2-carboxamide (5d). According to the general
procedure, compound 5d was prepared from 3d. Yield:
85%; white solid; mp 164–165 ꢀC (washing Et2O); IR
(KBr) n 3278, 2903, 2840, 1620, 1536, 1236, 1212, 1090,
1014, 736 cmꢂ1
;
1H NMR (CDCl3) d 1.11 (t, 3H,
J¼7.2 Hz, CH3), 3.52 (q, 2H, J¼7.2 Hz, CH2), 3.88 (s,
3H, CH3), 4.65 (d, 2H, J¼6.0 Hz, CH2), 5.90 (s, 2H, CH2),
6.84 (dd, 1H, J¼2.2, 8.8 Hz, Har), 6.91 (br t, 1H, J¼
6.0 Hz, NH), 6.95–7.03 (m, 3H, Har), 7.34 (t, 1H,
J¼7.5 Hz, Har), 7.46 (d, 1H, J¼7.7 Hz, Har), 7.50 (d, 1H,
J¼8.8 Hz, Har), 7.86 (d, 1H, J¼7.8 Hz, Har); 13C NMR
(DMSO-d6) d 14.9 (CH3), 47.5 (CH2), 55.4 (CH3), 63.0
(CH2), 72.4 (CH2), 93.9 (CH), 98.3 (C), 107.0 (CH), 111.6
(CH), 120.0 (C), 122.5 (CH), 127.6 (CH), 128.3 (CH),
129.0 (CH), 130.7 (C), 138.9 (CH), 139.8 (C), 140.6 (C),
157.6 (C), 161.9 (CO); MS (IS) m/z 465 (M+H)+. Anal.
4.5.3. tert-Butyl {[1-(ethoxymethyl)-5-methoxy-1H-indol-
2-yl]carbonyl}(2-iodobenzyl)carbamate (6c). According
to the general procedure, compound 6c was prepared from
5c. Chromatography eluent: PE/EtOAc 95:5; yield: 99%;
foam; IR (film) n 2981, 1734, 1664, 1523, 1369, 1265,
1
1211, 1147, 739 cmꢂ1; H NMR (CDCl3) d 1.15 (t, 3H,
J¼7.2 Hz, CH3), 1.20 (s, 9H, 3CH3), 3.53 (q, 2H,
J¼7.2 Hz, CH2), 3.86 (s, 3H, CH3), 4.98 (s, 2H, CH2),
5.77 (s, 2H, CH2), 6.87 (s, 1H, Har), 6.93–7.06 (m, 3H,

A. Putey et al. / Tetrahedron 63 (2007) 867–879
873
Har), 7.27–7.37 (m, 2H, Har), 7.47 (d, 1H, J¼8.9 Hz, Har),
7.85 (d, 1H, J¼7.9 Hz, Har); 13C NMR (CDCl3) d 15.0
(CH3), 27.6 (3CH3), 54.2 (CH2), 55.6 (CH3), 63.8 (CH2),
73.6 (CH2), 83.4 (C), 97.6 (C), 102.6 (CH), 108.7 (CH),
112.0 (CH), 116.3 (CH), 126.6 (C), 126.8 (CH), 128.4
(CH), 128.8 (CH), 133.2 (C), 134.3 (C), 139.4 (CH), 139.5
(C), 153.4 (CO), 155.1 (C), 165.6 (CO); MS (IS) m/z 565
(M+H)+. Anal. Calcd for C25H29IN2O5: C, 53.20; H, 5.18;
N, 4.96. Found: C, 53.40; H, 5.05; N, 4.88.
compound 7b was prepared from 6b. Yield: 90%; white
solid; mp 145–146 ꢀC (EtOAc/PE); IR (KBr) n 2972,
1
1717, 1684, 1462, 1280, 1259, 1147, 1098, 763 cmꢂ1; H
NMR (CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 1.56 (s, 9H,
3CH3), 3.52–3.64 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.33
and 5.15 (d, 1H, J¼14.3 Hz, CH2), 5.88 and 6.11 (d, 1H,
J¼10.7 Hz, CH2), 6.65 (d, 1H, J¼7.5 Hz, Har), 7.26–7.45
(m, 5H, Har), 7.95 (d, 1H, J¼7.5 Hz, Har); 13C NMR
(CDCl3) d 15.2 (CH3), 28.2 (3CH3), 49.3 (CH2), 55.0
(CH3), 64.1 (CH2), 74.4 (CH2), 83.5 (C), 101.7 (CH),
104.6 (CH), 114.7 (C), 121.5 (C), 126.9 (CH), 127.0 (CH),
127.1 (2CH), 129.2 (C), 132.4 (C), 132.5 (CH), 135.5 (C),
141.4 (C), 150.8 (CO), 155.6 (C), 161.3 (CO); MS (IS)
m/z 437 (M+H)+. Anal. Calcd for C25H28N2O5: C, 68.79;
H, 6.47; N, 6.42. Found: C, 68.66; H, 6.50; N, 6.42.
4.5.4. tert-Butyl {[1-(ethoxymethyl)-6-methoxy-1H-indol-
2-yl]carbonyl}(2-iodobenzyl)carbamate (6d). According
to the general procedure, compound 6d was prepared from
5d. Chromatography eluent: PE/EtOAc 95:5; yield: 99%;
white solid; mp 121–122 ꢀC (EtOAc/PE); IR (KBr) 2975,
1711, 1665, 1619, 1493, 1313, 1143, 1101, 974, 747 cmꢂ1
;
1H NMR (CDCl3) d 1.16 (t, 3H, J¼7.2 Hz, CH3), 1.21 (s,
9H, 3CH3), 3.56 (q, 2H, J¼7.2 Hz, CH2), 3.89 (s, 3H,
CH3), 4.96 (s, 2H, CH2), 5.81 (s, 2H, CH2), 6.85 (dd, 1H,
J¼2.3, 8.8 Hz, Har), 6.91–6.99 (m, 3H, Har), 7.30–7.37 (m,
2H, Har), 7.52 (d, 1H, J¼8.8 Hz, Har), 7.84 (d, 1H,
J¼7.9 Hz, Har); 13C NMR (CDCl3) d 15.1 (CH3), 27.7
(3CH3), 54.5 (CH2), 55.7 (CH3), 63.9 (CH2), 73.7 (CH2),
83.4 (C), 93.5 (CH), 97.8 (C), 110.7 (CH), 112.8 (CH),
120.5 (C), 123.3 (CH), 127.1 (CH), 128.5 (CH), 128.9
(CH), 132.0 (C), 139.6 (CH), 139.7 (C), 140.6 (C), 153.8
(CO), 159.0 (C), 165.6 (CO); MS (IS) m/z 565 (M+H)+.
Anal. Calcd for C25H29IN2O5: C, 53.20; H, 5.18; N, 4.96.
Found: C, 53.33; H, 5.25; N, 4.88.
4.6.3. 8-(Ethoxymethyl)-11-methoxy-7-oxo-5,6,7,8-tetra-
hydroindolo[2,3-d][2]benzazepine-6-carboxylic acid
tert-butyl ester (7c). According to the general procedure,
compound 7c was prepared from 6c. Yield: 93%; white
solid; mp 157–158 ꢀC (EtOAc/PE); IR (KBr) n 2967,
1
1760, 1662, 1618, 1496, 1348, 1259, 1103, 767 cmꢂ1; H
NMR (CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 1.55 (s, 9H,
3CH3), 3.50–3.66 (m, 2H, CH2), 3.88 (s, 3H, CH3), 4.26
and 5.16 (d, 1H, J¼15.0 Hz, CH2), 5.90 and 6.14 (d, 1H,
J¼10.7 Hz, CH2), 7.14 (dd, 1H, J¼2.3, 9.0 Hz, Har), 7.39
(t, 1H, J¼7.5 Hz, Har), 7.45 (d, 1H, J¼2.3 Hz, Har), 7.52–
7.58 (m, 2H, Har), 7.61 (d, 1H, J¼9.0 Hz, Har), 8.01 (d,
1H, J¼7.5 Hz, Har); 13C NMR (CDCl3) d 15.1 (CH3), 28.1
(3CH3), 48.8 (CH2), 55.8 (CH3), 64.1 (CH2), 74.4 (CH2),
83.4 (C), 102.5 (CH), 112.8 (CH), 117.3 (CH), 120.6 (C),
124.8 (C), 127.1 (CH), 128.0 (CH), 128.3 (CH), 128.6
(CH), 129.7 (C), 133.1 (C), 135.0 (C), 136.0 (C), 150.8
(CO), 155.8 (C), 161.5 (CO); MS (IS) m/z 437 (M+H)+.
Anal. Calcd for C25H28N2O5: C, 68.79; H, 6.47; N, 6.42.
Found: C, 68.99; H, 6.56; N, 6.55.
4.6. General procedure for Heck coupling
A mixture of 6 (1.87 mmol), PPh3 (49 mg, 0.18 mmol),
Pd(OAc)2 (21 mg, 0.09 mmol), and silver carbonate
(1.03 g, 3.74 mmol) in anhydrous DMF (40 mL) was vigor-
ously stirred at 100 ꢀC for 1 h. After cooling, the solvent was
removed in vacuo. The residue was taken up in CH2Cl2, fil-
tered over CeliteÒ, and rinsed with CH2Cl2. The solvent was
evaporated in vacuo and the crude residue was purified by
flash chromatography (PE/EtOAc 85:15) to give 7.
4.6.4. 8-(Ethoxymethyl)-10-methoxy-7-oxo-5,6,7,8-tetra-
hydroindolo[2,3-d][2]benzazepine-6-carboxylic acid
tert-butyl ester (7d). According to the general procedure,
compound 7d was prepared from 6d. Yield: 96%; white
solid; mp 147–149 ꢀC (EtOAc/PE); IR (KBr) n 2974,
1712, 1664, 1615, 1455, 1325, 1281, 1206, 1148, 1104,
4.6.1. 8-(Ethoxymethyl)-7-oxo-5,6,7,8-tetrahydroindolo-
[2,3-d][2]benzazepine-6-carboxylic acid tert-butyl ester
(7a). According to the general procedure, compound 7a
was prepared from 6a. Yield: 96%; white solid; mp 104–
106 ꢀC (EtOAc/PE); IR (KBr) n 2978, 1708, 1677, 1462,
1076, 749 cmꢂ1
;
1H NMR (CDCl3) d 1.16 (t, 3H,
J¼7.2 Hz, CH3), 1.55 (s, 9H, 3CH3), 3.57–3.68 (m, 2H,
CH2), 3.93 (s, 3H, CH3), 4.25 and 5.15 (d, 1H, J¼14.5 Hz,
CH2), 5.92 and 6.12 (d, 1H, J¼10.7 Hz, CH2), 6.95 (dd,
1H, J¼2.3, 9.0 Hz, Har), 7.10 (d, 1H, J¼2.3 Hz, Har), 7.38
(t, 1H, J¼7.5 Hz, Har), 7.50–7.55 (m, 2H, Har), 7.91 (d,
1H, J¼9.0 Hz, Har), 7.99 (d, 1H, J¼7.7 Hz, Har); 13C
NMR (CDCl3) d 15.2 (CH3), 28.2 (3CH3), 48.9 (CH2),
55.7 (CH3), 64.1 (CH2), 74.4 (CH2), 83.4 (C), 93.9
(CH), 113.4 (CH), 118.8 (C), 122.0 (C), 123.0 (CH),
127.3 (CH), 128.3 (CH+C), 128.5 (CH), 128.6 (CH),
132.9 (C), 136.2 (C), 141.2 (C), 150.9 (CO), 159.5 (C),
161.6 (CO); MS (IS) m/z 437 (M+H)+. Anal. Calcd for
C25H28N2O5: C, 68.79; H, 6.47; N, 6.42. Found: C, 68.62;
H, 6.33; N, 6.47.
1
1368, 1325, 1282, 1146, 1100, 965, 738 cmꢂ1; H NMR
(CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 1.55 (s, 9H,
3CH3), 3.53–3.65 (m, 2H, CH2), 4.26 and 5.17 (d, 1H,
J¼14.7 Hz, CH2), 5.93 and 6.18 (d, 1H, J¼10.7 Hz, CH2),
7.27–7.57 (m, 5H, Har), 7.71 (d, 1H, J¼8.5 Hz, Har), 8.03–
8.08 (m, 2H, Har); 13C NMR (CDCl3) d 15.2 (CH3), 28.2
(3CH3), 48.9 (CH2), 64.2 (CH2), 74.3 (CH2), 83.6 (C),
111.9 (CH), 121.3 (C), 122.1 (2CH), 124.6 (C), 126.3
(CH), 127.4 (CH), 128.3 (CH), 128.6 (CH), 128.7 (CH),
129.4 (C), 132.9 (C), 136.2 (C), 139.8 (C), 150.8 (CO),
161.6 (CO); MS (IS) m/z 407 (M+H)+. Anal. Calcd for
C24H26N2O4: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.26;
H, 6.60; N, 6.97.
4.7. General procedure for Boc deprotection
4.6.2. 8-(Ethoxymethyl)-12-methoxy-7-oxo-5,6,7,8-tetra-
hydroindolo[2,3-d][2]benzazepine-6-carboxylic acid
tert-butyl ester (7b). According to the general procedure,
A solution of 7 (1.23 mmol) and 1 N NaOH (8 mL) in 1,4-di-
oxane (25 mL) was stirred at 80 ꢀC for 1 h. After cooling, the

874
A. Putey et al. / Tetrahedron 63 (2007) 867–879
solution was neutralized with 1 N HCl solution (pH 6–7) and
extracted with CH2Cl2 (3ꢁ20 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo.
The crude residue was purified by flash chromatography to
afford 8.
for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C,
71.63; H, 6.12; N, 8.44.
4.7.4. 8-(Ethoxymethyl)-10-methoxy-5,8-dihydroindolo-
[2,3-d][2]benzazepin-7(6H)-one (8d). According to the
general procedure, compound 8d was prepared from 7d.
Chromatography eluent: PE/EtOAc 3:7; yield: 73%; white
solid; mp 188–189 ꢀC (EtOAc/PE); IR (KBr) n 3280,
2968, 1620, 1439, 1337, 1300, 1220, 1170, 1077,
4.7.1. 8-(Ethoxymethyl)-5,8-dihydroindolo[2,3-d][2]-
benzazepin-7(6H)-one (8a). According to the general
procedure, compound 8a was prepared from 7a. Chromato-
graphy eluent: PE/EtOAc 1:1; yield: 80%; white solid; mp
180–181 ꢀC (EtOAc); IR (KBr) n 3364, 2975, 1640, 1455,
744 cmꢂ1
;
1H NMR (CDCl3) d 1.17 (t, 3H, J¼7.2 Hz,
CH3), 3.55–3.63 (m, 2H, CH2), 3.94 (s, 3H, CH3), 4.08
(dd, 1H, J¼7.0, 14.6 Hz, CH2), 4.25 (dd, 1H, J¼6.0,
14.6 Hz, CH2), 5.88 and 6.18 (d, 1H, J¼10.7 Hz, CH2),
6.23 (br s, 1H, NH), 6.95 (dd, 1H, J¼2.3, 9.0 Hz, Har),
7.11 (d, 1H, J¼2.3 Hz, Har), 7.32–7.39 (m, 2H, Har),
7.47–7.52 (m, 1H, Har), 7.91 (d, 1H, J¼9.0 Hz, Har), 7.95
(d, 1H, J¼7.9 Hz, Har); 13C NMR (DMSO-d6) d 15.0
(CH3), 44.3 (NCH2), 55.6 (OCH3), 63.3 (CH2), 72.9
(OCH2), 94.3 (CH), 112.2 (CH), 118.1 (C), 118.9 (C),
121.9 (CH), 127.1 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 129.1 (C), 132.5 (C), 138.2 (C), 139.7 (C), 158.2
(C), 162.7 (CO); MS (IS) m/z 337 (M+H)+. Anal. Calcd
for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C,
71.33; H, 5.88; N, 8.36.
1303, 1090, 1073, 931, 752 cmꢂ1 1H NMR (CDCl3)
;
d 1.15 (t, 3H, J¼7.2 Hz, CH3), 3.50–3.62 (m, 2H, CH2),
4.09 (dd, 1H, J¼6.9, 14.7 Hz, CH2), 4.26 (dd, 1H, J¼5.9,
14.7 Hz, CH2), 5.92 and 6.24 (d, 1H, J¼10.7 Hz, CH2),
6.39 (br s, 1H, NH), 7.27–7.53 (m, 5H, Har), 7.70 (d, 1H,
J¼8.5 Hz, Har), 8.00 (d, 1H, J¼7.5 Hz, Har), 8.05 (d, 1H,
J¼8.3 Hz, Har); 13C NMR (DMSO-d6) d 15.0 (CH3), 44.3
(CH2), 63.4 (CH2), 73.0 (CH2), 111.7 (CH), 118.4 (C),
121.0 (CH), 121.7 (CH), 124.1 (C), 125.1 (CH), 127.1
(CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 130.2 (C),
132.5 (C), 138.3 (C), 138.4 (C), 162.7 (CO); MS (IS) m/z
307 (M+H)+. Anal. Calcd for C19H18N2O2: C, 74.49; H,
5.92; N, 9.14. Found: C, 74.41; H, 6.01; N, 9.08.
4.7.2. 8-(Ethoxymethyl)-12-methoxy-5,8-dihydroindolo-
[2,3-d][2]benzazepin-7(6H)-one (8b). According to the
general procedure, compound 8b was prepared from 7b.
Chromatography eluent: PE/EtOAc 2:3; yield: 93%; white
solid; mp 168–169 ꢀC (EtOAc/PE); IR (KBr) n 3323,
4.8. General procedure for EOM deprotection
A solution of 8 (0.16 mmol) and 1 N HCl (1.6 mL) in 1,4-
dioxane (3.5 mL) was stirred at 80 ꢀC for 2 h. After cooling,
the solution was neutralized with a saturated aqueous
NaHCO3 solution and extracted with CH2Cl2 (2ꢁ10 mL).
The combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The crude residue was purified by
flash chromatography to afford 9.
2972, 1666, 1459, 1306, 1263, 1152, 1081, 852, 765 cmꢂ1
;
1H NMR (CDCl3) d 1.14 (t, 3H, J¼7.2 Hz, CH3), 3.47–
3.62 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.06 (dd, 1H,
J¼6.8, 14.4 Hz, CH2), 4.30 (dd, 1H, J¼6.2, 14.4 Hz,
CH2), 5.87 and 6.19 (d, 1H, J¼10.7 Hz, CH2), 6.33 (br s,
1H, NH), 6.67 (d, 1H, J¼7.7 Hz, Har), 7.27–7.43 (m, 5H,
Har), 7.86 (d, 1H, J¼8.1 Hz, Har); 13C NMR (CDCl3)
d 15.2 (CH3), 45.9 (CH2), 55.1 (CH3), 64.1 (CH2), 74.2
(CH2), 101.8 (CH), 104.5 (CH), 115.1 (C), 120.9 (C),
126.3 (CH), 126.4 (CH), 126.8 (CH), 127.0 (CH), 129.1
(C), 132.8 (C), 132.8 (CH), 137.1 (C), 140.7 (C), 155.4
(C), 164.1 (CO); MS (IS) m/z 337 (M+H)+. Anal. Calcd
for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C,
71.16; H, 6.20; N, 8.46.
4.8.1. 5,8-Dihydroindolo[2,3-d][2]benzazepin-7(6H)-one
(9a). According to the general procedure, compound 9a
was prepared from 8a. Chromatography eluent: CH2Cl2/
MeOH 98.5:1.5; yield: 94%; white solid; mp >210 ꢀC
(washing with cold MeOH); IR (KBr) n 3300–3100, 2980,
1651, 1615, 1524, 1471, 1331, 1048, 739 cmꢂ1; H NMR
1
(DMSO-d6) d 4.07 (d, 2H, J¼5.3 Hz, CH2), 7.20 (t, 1H,
J¼7.4 Hz, Har), 7.30–7.35 (m, 2H, Har), 7.46–7.55 (m, 3H,
Har), 7.94 (d, 1H, J¼7.7 Hz, Har), 8.00 (d, 1H, J¼8.1 Hz,
Har), 8.40 (t, 1H, J¼5.3 Hz, NH), 12.03 (s, 1H, NH); 13C
NMR (DMSO-d6) d 44.7 (CH2), 112.8 (CH), 116.1 (C),
120.7 (CH), 120.9 (CH), 124.4 (CH), 124.5 (C), 126.4
(CH), 127.3 (CH), 128.2 (CH), 128.3 (CH), 130.0 (C),
133.4 (C), 136.6 (C), 137.0 (C), 163.6 (CO); MS (IS) m/z
249 (M+H)+. Anal. Calcd for C16H12N2O: C, 77.40; H,
4.87; N, 11.28. Found: C, 77.35; H, 4.92; N, 11.37.
4.7.3. 8-(Ethoxymethyl)-11-methoxy-5,8-dihydroindolo-
[2,3-d][2]benzazepin-7(6H)-one (8c). According to the
general procedure, compound 8c was prepared from 7c.
Chromatography eluent: PE/EtOAc 35:65; yield: 65%;
foam; IR (film) n 3274, 2971, 1644, 1499, 1469, 1306,
1
1225, 1092, 1077, 795 cmꢂ1; H NMR (DMSO-d6, only
one rotamer) d 1.02 (t, 3H, J¼7.2 Hz, CH3), 3.32–3.48 (m,
2H, CH2), 3.83 (s, 3H, CH3), 3.97 (dd, 1H, J¼5.3,
14.3 Hz, CH2), 4.08 (dd, 1H, J¼6.6, 14.3 Hz, CH2), 5.84
and 6.10 (d, 1H, J¼10.7 Hz, CH2), 7.08 (dd, 1H, J¼2.3,
8.9 Hz, Har), 7.35–7.40 (m, 2H, Har), 7.46–7.55 (m, 2H,
Har), 7.68 (d, 1H, J¼8.9 Hz, Har), 7.96 (d, 1H, J¼7.2 Hz,
Har), 8.55 (t, 1H, J¼6.0 Hz, NH); 13C NMR (DMSO-d6)
d 14.9 (CH3), 44.3 (CH2), 55.4 (CH3), 63.2 (CH2), 73.0
(CH2), 101.8 (CH), 112.7 (CH), 115.5 (CH), 117.9 (C),
124.4 (C), 126.8 (CH), 127.7 (CH), 127.8 (CH), 128.2
(CH), 130.6 (C), 132.6 (C), 133.4 (C), 138.1 (C), 155.1
(C), 162.6 (CO); MS (IS) m/z 337 (M+H)+. Anal. Calcd
4.8.2. 12-Methoxy-5,8-dihydroindolo[2,3-d][2]benzaze-
pin-7(6H)-one (9b). According to the general procedure,
compound 9b was prepared from 8b. Chromatography elu-
ent: CH2Cl2/MeOH 98.5:1.5; yield: 42%; white solid; mp
>210 ꢀC (EtOAc/PE); IR (KBr) n 3349, 3221, 2940, 1638,
1582, 1500, 1465, 1443, 1353, 1260, 1101, 757, 742 cmꢂ1
;
1H NMR (DMSO-d6, 120 ꢀC, only one rotamer) d 3.83 (s,
3H, CH3), 4.08 (d, 2H, J¼5.5 Hz, CH2), 6.67 (d, 1H,
J¼7.7 Hz, Har), 7.15–7.39 (m, 5H, Har), 7.78 (d, 1H,
J¼7.9 Hz, Har), 8.08 (br s, 1H, NH), 11.70 (s, 1H, NH);
13C NMR (DMSO-d6) d 44.9 (CH2), 54.9 (CH3), 100.7

A. Putey et al. / Tetrahedron 63 (2007) 867–879
875
(CH), 105.6 (CH), 114.6 (C), 116.7 (C), 125.2 (CH), 125.9
(CH), 126.6 (CH), 126.9 (CH), 129.5 (C), 131.4 (CH),
133.2 (C), 136.5 (C), 138.2 (C), 154.6 (C), 163.1 (CO);
MS (IS) m/z 279 (M+H)+. Anal. Calcd for C17H14N2O2: C,
73.37; H, 5.07; N, 10.07. Found: C, 73.11; H, 6.91; N, 9.89.
J¼14.5 Hz, CH2), 5.91 and 6.19 (d, 1H, J¼10.7 Hz, CH2),
7.26–7.55 (m, 5H, Har), 7.69 (d, 1H, J¼8.3 Hz, Har), 8.01
(d, 1H, J¼7.9 Hz, Har), 8.03 (d, 1H, J¼8.3 Hz, Har); 13C
NMR (CDCl3) d 15.1 (CH3), 34.3 (CH3), 53.6 (CH2), 64.0
(CH2), 74.0 (CH2), 111.6 (CH), 119.3 (C), 121.2 (CH),
121.6 (CH), 124.6 (C), 125.2 (CH), 126.9 (CH), 127.5
(CH), 128.3 (CH), 128.5 (CH), 130.5 (C), 133.1 (C), 135.6
(C), 138.6 (C), 161.5 (CO); MS (IS) m/z 321 (M+H)+.
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74.
Found: C, 75.25; H, 6.36; N, 8.87.
4.8.3. 11-Methoxy-5,8-dihydroindolo[2,3-d][2]benzaze-
pin-7(6H)-one (9c). According to the general procedure,
compound 9c was prepared from 8c. Chromatography elu-
ent: CH2Cl2/MeOH 98.5:1.5; yield: 97%; white solid; mp
130 ꢀC dec (EtOAc/Et2O); IR (KBr) n 3340, 3234, 2969,
1629, 1521, 1502, 1469, 1221, 1151, 1027, 767, 731 cmꢂ1
;
4.9.2. 8-(Ethoxymethyl)-12-methoxy-6-methyl-5,8-di-
hydroindolo[2,3-d][2]benzazepin-7(6H)-one (10b). Ac-
cording to the procedure described for 10, compound 10b
was prepared from 8b. Yield: 99%; white solid; mp 145–
147 ꢀC (EtOAc/PE); IR (KBr) n 2980, 1642, 1567, 1499,
1H NMR (DMSO-d6) d 3.82 (s, 3H, CH3), 4.05 (d, 2H,
J¼5.1 Hz, CH2), 6.99 (dd, 1H, J¼2.3, 8.9 Hz, Har), 7.32 (t,
1H, J¼7.0 Hz, Har), 7.39–7.55 (m, 4H, Har), 7.96 (d, 1H,
J¼7.7 Hz, Har), 8.35 (t, 1H, J¼5.1 Hz, NH), 11.89 (s, 1H,
NH); 13C NMR (DMSO-d6) d 44.7 (CH2), 55.4 (CH3),
101.6 (CH), 113.6 (CH), 115.3 (CH), 115.7 (C), 124.6
(C), 126.2 (CH), 126.9 (CH), 128.2 (2CH), 130.4 (C),
131.8 (C), 133.6 (C), 136.8 (C), 154.5 (C), 163.6
(CO); MS (IS) m/z 279 (M+H)+. Anal. Calcd for
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.55; H, 5.01; N, 10.17.
1438, 1391, 1325, 1260, 1097, 752 cmꢂ1
;
1H NMR
(DMSO-d6) d 1.01 (t, 3H, J¼7.2 Hz, CH3), 3.08 (s, 3H,
CH3), 3.32–3.47 (m, 2H, CH2), 3.80 (s, 3H, CH3), 4.28
and 4.34 (d, 1H, J¼14.7 Hz, CH2), 5.82 and 6.03 (d, 1H,
J¼10.7 Hz, CH2), 6.73–6.76 (m, 1H, Har), 7.29–7.44 (m,
4H, Har), 7.51 (d, 1H, J¼7.4 Hz, Har), 7.80 (d, 1H,
J¼7.7 Hz, Har); 13C NMR (DMSO-d6) d 15.4 (CH3), 34.2
(CH3), 53.2 (CH2), 55.5 (CH3), 63.9 (CH2), 73.6 (CH2),
102.4 (CH), 104.7 (CH), 114.2 (C), 119.1 (C), 126.7 (CH),
127.3 (2CH), 127.5 (CH), 130.6 (C), 132.1 (CH), 132.5
(C), 136.0 (C), 140.3 (C), 155.1 (C), 161.0 (CO); MS (IS)
m/z 351 (M+H)+. Anal. Calcd for C21H22N2O3: C, 71.98;
H, 6.33; N, 7.99. Found: C, 71.72; H, 6.41; N, 8.14.
4.8.4. 10-Methoxy-5,8-dihydroindolo[2,3-d][2]benzaze-
pin-7(6H)-one (9d). According to the general procedure,
compound 9d was prepared from 8d. Chromatography elu-
ent: CH2Cl2/MeOH 98:2; yield: 81%; white solid; mp
>210 ꢀC (CHCl3); IR (KBr) n 3300–3129, 2950, 1633,
1
1528, 1460, 1294, 1241, 1166, 1028, 751 cmꢂ1; H NMR
(DMSO-d6) d 3.82 (s, 3H, CH3), 4.05 (d, 2H, J¼4.5 Hz,
CH2), 6.84 (br d, 1H, J¼8.9 Hz, Har), 6.97 (s, 1H, Har),
7.29–7.48 (m, 3H, Har), 7.86 (d, 1H, J¼8.9 Hz, Har), 7.89
(d, 1H, J¼7.9 Hz, Har), 8.26 (br t, 1H, J¼4.5 Hz, NH),
11.83 (s, 1H, NH); 13C NMR (DMSO-d6) d 44.7 (CH2),
55.2 (CH3), 94.5 (CH), 111.6 (CH), 116.5 (C), 118.7 (C),
121.8 (CH), 126.4 (CH), 127.2 (CH), 128.1 (CH), 128.2
(CH), 128.8 (C), 133.3 (C), 136.9 (C), 137.7 (C), 157.6
(C), 163.6 (CO); MS (IS) m/z 279 (M+H)+. Anal. Calcd
for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.67; H, 5.21; N, 10.22.
4.9.3. 6-Methyl-5,8-dihydroindolo[2,3-d][2]benzazepin-
7(6H)-one (11a). According to the procedure described for
9, compound 11a was prepared from 10a. Recrystallization
from EtOAc; yield: 92%; white solid; mp >210 ꢀC (EtOAc);
IR (KBr) n 3203, 2930, 1621, 1525, 1331, 1241, 1110,
1
746 cmꢂ1; H NMR (DMSO-d6) d 3.15 (s, 3H, CH3), 4.32
(s, 2H, CH2), 7.20 (t, 1H, J¼7.1 Hz, Har), 7.30–7.39 (m,
2H, Har), 7.50–7.62 (m, 3H, Har), 7.96 (d, 1H, J¼7.7 Hz,
Har), 8.00 (d, 1H, J¼7.9 Hz, Har), 12.03 (s, 1H, NH); 13C
NMR (DMSO-d6) d 34.5 (CH3), 52.7 (CH2), 112.7 (CH),
115.7 (C), 120.6 (CH), 120.7 (CH), 124.2 (C), 124.3 (CH),
126.3 (CH), 127.0 (CH), 128.4 (2CH), 130.4 (C), 133.2
(C), 135.2 (C), 136.5 (C), 161.7 (CO); MS (IS) m/z 263
(M+H)+. Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38;
N, 10.68. Found: C, 77.93; H, 5.27; N, 10.55.
4.9. General procedure for N-alkylation
At 0 ꢀC, sodium hydride (26 mg, 0.63 mmol, 60% dispersed
in oil) was added to a solution of 8 (0.42 mmol) in anhydrous
THF (1.5 mL). The reaction mixture was stirred for 10 min
at room temperature and iodomethane (32 mL, 0.51 mmol)
was added dropwise. The mixture was stirred for 4 h at
room temperature. The solvent was evaporated in vacuo.
The residue was taken up in H2O (5 mL) and extracted
with CH2Cl2 (2ꢁ5 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuo. The
crude residue was purified by flash chromatography (PE/
EtOAc 3:2) to give 10.
4.9.4. 12-Methoxy-6-methyl-5,8-dihydroindolo[2,3-d]-
[2]benzazepin-7(6H)-one (11b). According to the pro-
cedure for 9, compound 11b was prepared from 10b.
Chromatography eluent: CH2Cl2/MeOH 99:1; yield: 36%;
yellow solid; mp >210 ꢀC (EtOAc); IR (KBr) n 3215,
1
2930, 1617, 1507, 1445, 1354, 1260, 1109, 757 cmꢂ1; H
NMR (DMSO-d6) d 3.13 (s, 3H, CH3), 3.82 (s, 3H, CH3),
4.27 and 4.35 (d, 1H, J¼14.5 Hz, CH2), 6.65 (d, 1H,
J¼7.7 Hz, Har), 7.12 (d, 1H, J¼8.1 Hz, Har), 7.21–7.42 (m,
3H, Har), 7.50 (d, 1H, J¼7.3 Hz, Har), 7.78 (d, 1H,
J¼7.7 Hz, Har), 12.03 (s, 1H, NH); 13C NMR (DMSO-d6)
d 34.3 (CH3), 53.0 (CH2), 54.9 (CH3), 100.7 (CH), 105.5
(CH), 114.4 (C), 116.4 (C), 125.2 (CH), 125.6 (CH), 126.9
(CH), 127.1 (CH), 129.9 (C), 131.0 (CH), 133.0 (C),
134.6 (C), 138.1 (C), 154.6 (C), 161.2 (CO); MS (IS) m/z
293 (M+H)+. Anal. Calcd for C18H16N2O2: C, 73.96; H,
5.52; N, 9.58. Found: C, 74.18; H, 5.44; N, 9.73.
4.9.1. 8-(Ethoxymethyl)-6-methyl-5,8-dihydroindolo[2,3-
d][2]benzazepin-7(6H)-one (10a). According to the proce-
dure described for 10, compound 10a was prepared from 8a.
Yield: 99%; white solid; mp 143–144 ꢀC (EtOAc/PE); IR
(KBr) n 2972, 1627, 1519, 1387, 1328, 1080, 754 cmꢂ1
;
1H NMR (CDCl3) d 1.15 (t, 3H, J¼7.2 Hz, CH3), 3.22 (s,
3H, CH3), 3.52–3.62 (m, 2H, CH2), 4.06 and 4.48 (d, 1H,

876
A. Putey et al. / Tetrahedron 63 (2007) 867–879
4.9.5. N-(2-Iodobenzyl)benzo[b]thiophene-2-carbox-
amide (12). According to the procedure described for 5,
compound 12 was prepared from benzo[b]thiophene-2-
carboxylic acid and 4. Yield: 77%; white solid; mp 165–
166 ꢀC (washing Et2O); IR (KBr) n 3255, 3056, 1619,
and the resulting mixture was extracted with CH2Cl2
(2ꢁ5 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The solid was then re-
crystallized from EtOAc to afford 15 (46 mg, 88%). White
solid; mp >210 ꢀC (EtOAc); IR (KBr) n 3270, 2900, 1645,
1
1544, 1408, 1286, 1010, 875, 740 cmꢂ1
;
1H NMR
1521, 1464, 1407, 772 cmꢂ1; H NMR (DMSO-d6) d 4.11
(DMSO-d6) d 4.45 (d, 2H, J¼5.5 Hz, CH2), 7.05 (t,
1H, J¼7.5 Hz, Har), 7.32–7.50 (m, 4H, Har), 7.88 (d, 1H,
J¼7.7 Hz, Har), 7.95–7.97 (m, 1H, Har), 8.02–8.05 (m, 1H,
Har), 8.20 (s, 1H, Har), 9.32 (t, 1H, J¼5.5 Hz, NH);
13C NMR (DMSO-d6) d 48.0 (CH2), 98.6 (C), 122.8
(CH), 125.0 (CH), 125.2 (CH), 125.3 (CH), 126.3
(CH), 128.1 (CH), 128.4 (CH), 129.1 (CH), 139.0 (CH),
139.2 (C), 139.5 (C), 140.2 (C), 140.3 (C), 161.7 (CO);
MS (IS) m/z 394 (M+H)+. Anal. Calcd for C16H12INOS:
C, 48.87; H, 3.08; N, 3.56. Found: C, 49.13; H, 3.19; N, 3.39.
(d, 2H, J¼5.5 Hz, CH2), 7.49–7.59 (m, 5H, Har), 7.87 (d,
1H, J¼7.5 Hz, Har), 8.09–8.16 (m, 2H, Har), 8.73 (br t, 1H,
J¼5.5 Hz, NH); 13C NMR (DMSO-d6) d 44.4 (CH2),
123.3 (CH), 124.6 (CH), 125.4 (CH), 126.7 (CH), 128.1
(CH), 128.3 (CH), 128.6 (CH), 128.7 (CH), 132.3 (C),
135.2 (C), 136.6 (C), 137.2 (C), 139.2 (C), 139.4 (C),
164.1 (CO); MS (IS) m/z 266 (M+H)+. Anal. Calcd for
C16H11NOS: C, 72.43; H, 4.18; N, 5.28. Found: C, 72.43;
H, 4.09; N, 5.33.
4.9.9. Ethyl 1-(benzyloxymethyl)-1H-pyrrole-2-carb-
oxylate (16). At 0 ꢀC, sodium hydride (216 mg, 5.39 mmol,
60% dispersed in oil) was added to a solution of ethyl-
1H-pyrrole-2-carboxylate (500 mg, 3.59 mmol) in anhy-
drous DMF (17 mL). The reaction mixture was stirred for
1 h at room temperature and benzyloxymethyl chloride
(996 mL, 7.18 mmol) was added dropwise. The mixture
was stirred for 15 h at room temperature. The solvent was
evaporated in vacuo. The residue was taken up in H2O
(10 mL) and extracted with CH2Cl2 (5ꢁ20 mL). The com-
bined organic phases were dried over Na2SO4 and concen-
trated in vacuo. The crude residue was purified by flash
chromatography (PE/EtOAc 95:5) to afford 16 (930 mg,
99%) as an oil. IR (film) n 3035, 2980, 1704, 1537, 1418,
4.9.6. tert-Butyl (benzo[b]thiophen-2-ylcarbonyl)(2-iodo-
benzyl)carbamate (13). According to the procedure de-
scribed for 6, compound 13 was prepared from 12.
Chromatography eluent: PE/EtOAc 95:5; yield: 99%; oil;
IR (film) n 2977, 1735, 1670, 1518, 1458, 1365, 1342,
1
1226, 1147, 1013, 743 cmꢂ1; H NMR (CDCl3) d 1.24 (s,
9H, 3CH3), 4.98 (s, 2H, CH2), 6.96 (t, 1H, J¼7.5 Hz, Har),
7.26–7.47 (m, 4H, Har), 7.78 (s, 1H, Har), 7.84–7.86 (m,
3H, Har); 13C NMR (CDCl3) d 27.6 (3CH3), 54.8 (CH2),
83.9 (C), 97.7 (C), 122.7 (CH), 125.0 (CH), 125.4 (CH),
126.8 (CH), 127.1 (CH), 128.4 (CH), 128.5 (CH), 128.9
(CH), 138.3 (C), 138.7 (C), 139.4 (C), 139.5 (CH), 141.3
(C), 153.1 (CO), 167.2 (CO); MS (IS) m/z 494 (M+H)+.
Anal. Calcd for C21H20INO3S: C, 51.13; H, 4.09; N, 2.84.
Found: C, 50.88; H, 3.94; N, 2.77.
1
1317, 1236, 1113, 739 cmꢂ1; H NMR (CDCl3) d 1.36 (t,
3H, J¼7.2 Hz, CH3), 4.31 (q, 2H, J¼7.2 Hz, CH2), 4.51
(s, 2H, CH2), 5.78 (s, 2H, CH2), 6.21 (t, 1H, J¼3.2 Hz,
Hpyrrole), 7.01–7.04 (m, 2H, Hpyrrole), 7.28–7.37 (m, 5H,
Har); 13C NMR (CDCl3) d 14.0 (CH3), 59.5 (CH2), 69.7
(CH2), 76.0 (OCH2), 108.5 (CH), 118.6 (CH), 122.2 (C),
127.3 (3CH), 128.0 (2CH), 128.4 (CH), 137.1 (C), 160.5
(CO); MS (IS) m/z 260 (M+H)+. Anal. Calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.66;
H, 6.71; N, 5.43.
4.9.7. 7-Oxo-5,7-dihydro-6H-benzo[b]thieno[2,3-
d][2]benzazepine-6-carboxylic acid tert-butyl ester (14).
A mixture of 14 (105 mg, 0.21 mmol), PPh3 (5.6 mg,
0.02 mmol), Pd(OAc)2 (2.4 mg, 0.01 mmol), and silver car-
bonate (117 mg, 0.42 mmol) in anhydrous DMF (4 mL) was
vigorously stirred at 100 ꢀC for 1 h. After cooling, the sol-
vent was removed in vacuo. The residue was taken up in
CH2Cl2, filtered over CeliteÒ, and rinsed with CH2Cl2.
The solvent was evaporated in vacuo and the crude residue
was purified by flash chromatography (PE/EtOAc 95:5) to
afford 14 (64 mg, 82%) as a white solid, starting material
13 (10 mg, 10%) and 15 (4.8 mg, 8%). Mp 162–163 ꢀC
(EtOAc/PE); IR (KBr) n 2980, 1726, 1665, 1458, 1369,
4.9.10. 1-(Benzyloxymethyl)-1H-pyrrole-2-carboxylic
acid (17). According to the general procedure described
for 3, compound 17 was prepared from 16. Yield: quantita-
tive; white solid; mp 93–94 ꢀC (EtOAc/PE); IR (KBr)
n 3100–2500, 1681, 1537, 1443, 1314, 1254, 1129, 1072,
1
1
1289, 1152, 1092, 744 cmꢂ1; H NMR (CDCl3) d 1.55 (s,
905, 739 cmꢂ1; H NMR (CDCl3) d 4.52 (s, 2H, CH2),
9H, 3CH3), 4.30 and 5.28 (d, 1H, J¼14.7 Hz, CH2), 7.45–
7.60 (m, 5H, Har), 7.93 (d, 1H, J¼8.3 Hz, Har), 7.95 (d,
1H, J¼7.9 Hz, Har), 8.15 (d, 1H, J¼7.9 Hz, Har); 13C
NMR (CDCl3) d 28.1 (3CH3), 48.4 (CH2), 83.9 (C), 123.0
(CH), 125.2 (CH), 125.5 (CH), 127.2 (CH), 128.6
(CH), 128.9 (2CH), 129.0 (CH), 132.9 (C), 136.8 (C),
137.0 (C), 137.2 (C), 137.7 (C), 141.3 (C), 151.1 (CO),
163.3 (CO); MS (IS) m/z 366 (M+H)+. Anal. Calcd for
C21H19NO3S: C, 69.02; H, 5.24; N, 3.83. Found: C, 69.29;
H, 5.33; N, 3.96.
5.78 (s, 2H, CH2), 6.26 (dd, 1H, J¼2.5, 3.8 Hz, Hpyrrole),
7.08 (dd, 1H, J¼1.7, 2.5 Hz, Hpyrrole), 7.18 (dd, 1H, J¼1.7,
3.8 Hz, Hpyrrole), 7.29–7.38 (m, 5H, Har); 13C NMR
(CDCl3) d 70.4 (CH2), 76.6 (CH2), 109.6 (CH), 121.5
(CH), 121.8 (C), 128.0 (3CH), 128.5 (2CH), 130.2 (CH),
137.2 (C), 166.0 (CO); MS (IS) m/z 230 (MꢂH)+. Anal.
Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found:
C, 67.44; H, 6.78; N, 6.16.
4.9.11. 1-(Benzyloxymethyl)-N-(2-iodobenzyl)-1H-pyr-
role-2-carboxamide (18). According to the general proce-
dure described for 5, compound 18 was prepared from 17
and 4. Yield: 95%; white solid; mp 98–99 ꢀC (washing
Et2O); IR (KBr) n 3304, 2900, 1629, 1542, 1522, 1468,
4.9.8. 5,6-Dihydrobenzo[b]thieno[2,3-d][2]benzazepin-7-
one (15). At room temperature, trifluoroacetic acid
(600 mL, 8.08 mmol) was added to a solution of compound
14 (73 mg, 0.19 mmol) in anhydrous CH2Cl2 (3 mL). After
stirring for 1 h at room temperature, H2O (5 mL) was added
1
1311, 1253, 1075, 748 cmꢂ1; H NMR (300 MHz, CDCl3)
d 4.51 (s, 2H, CH2), 4.60 (d, 2H, J¼5.9 Hz, CH2), 5.76 (s,

A. Putey et al. / Tetrahedron 63 (2007) 867–879
877
2H, CH2), 6.17 (dd, 1H, J¼2.8, 3.2 Hz, Hpyrrole), 6.70–6.72
(m, 2H, Hpyrrole+NH), 6.93 (br s, 1H, Hpyrrole), 6.98 (t, 1H,
J¼7.5 Hz, Har), 7.25–7.31 (m, 6H, Har), 7.42 (d, 1H,
J¼7.5 Hz, Har), 7.84 (d, 1H, J¼7.9 Hz, Har); 13C NMR
(CDCl3) d 48.2 (CH2), 70.4 (CH2), 76.7 (CH2), 99.1 (C),
108.6 (CH), 114.2 (CH), 126.4 (C), 127.3 (CH), 127.9
(2CH), 128.0 (CH), 128.6 (2CH), 128.7 (CH), 129.4
(CH), 129.9 (CH), 137.3 (C), 139.6 (CH), 140.7 (C), 161.5
(CO); MS (IS) m/z 447 (M+H)+. Anal. Calcd for
C20H19IN2O2: C, 53.83; H, 4.29; N, 6.28. Found: C, 54.13;
H, 4.42; N, 6.52.
next step without further purification. A solution of the crude
product and 1 N NaOH (1.25 mL) in 1,4-dioxane (4 mL)
was stirred at 80 ꢀC for 1 h. After cooling, the solution
was neutralized with 1 N HCl solution (pH 2–3) and ex-
tracted with EtOAc (3ꢁ10 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo.
The solid was finally recrystallized from EtOAc to afford
21 (44 mg, 88%) as a white solid. Mp 209–210 ꢀC (EtOAc);
IR (KBr) n 3350–3050, 2906, 1631, 1593, 1511, 1461, 1130,
1089, 754 cmꢂ1 1H NMR (DMSO-d6) d 4.01 (d, 2H,
;
J¼5.1 Hz, CH2), 6.58 (t, 1H, J¼2.6 Hz, Hpyrrole), 7.05 (t,
1H, J¼2.6 Hz, Hpyrrole), 7.24 (t, 1H, J¼7.3 Hz, Har), 7.32–
7.39 (m, 2H, Har), 7.62 (d, 1H, J¼7.7 Hz, Har), 7.88 (br t,
1H, J¼5.1 Hz, NH), 11.80 (br s, 1H, NH); 13C NMR
(DMSO-d6) d 45.0 (CH2), 106.8 (CH), 122.5 (CH), 124.1
(C), 125.3 (C), 126.3 (CH), 126.4 (CH), 127.8 (2CH),
134.1 (C), 135.5 (C), 163.4 (CO); MS (IS) m/z 199
(M+H)+. Anal. Calcd for C12H10N2O: C, 72.71; H, 5.08;
N, 14.13. Found: C, 72.88; H, 5.16; N, 14.23.
4.9.12. tert-Butyl {[1-(benzyloxymethyl)-1H-pyrrol-2-yl]-
carbonyl}(2-iodobenzyl)carbamate (19). According to the
general procedure described for 6, compound 19 was pre-
pared from 18. Chromatography eluent: PE/EtOAc 9:1;
yield: 99%; oil; IR (film) n 2971, 1732, 1655, 1532, 1425,
1331, 1213, 1143, 965, 748 cmꢂ1 1H NMR (CDCl3)
;
d 1.28 (s, 9H, 3CH3), 4.52 (s, 2H, CH2), 4.90 (s, 2H, CH2),
5.68 (s, 2H, CH2), 6.23 (dd, 1H, J¼2.6, 3.8 Hz, Hpyrrole),
6.75 (dd, 1H, J¼1.7, 3.8 Hz, Hpyrrole), 6.90–6.96 (m, 1H,
Har), 7.05 (dd, 1H, J¼1.7, 2.6 Hz, Hpyrrole), 7.27–7.35 (m,
7H, Har), 7.82 (d, 1H, J¼7.7 Hz, Har); 13C NMR (CDCl3)
d 27.8 (3CH3), 54.4 (CH2), 70.2 (CH2), 76.5 (CH2), 83.0
(C), 97.6 (C), 108.8 (CH), 118.5 (CH), 127.0 (CH), 127.3
(C), 127.9 (CH), 128.0 (2CH), 128.2 (CH), 128.4 (CH),
128.5 (2CH), 128.7 (CH), 137.3 (C), 139.4 (CH), 139.9
(C), 153.7 (CO), 164.6 (CO); MS (IS) m/z 547 (M+H)+.
Anal. Calcd for C25H27IN2O4: C, 54.95; H, 4.98; N, 5.13.
Found: C, 55.25; H, 5.16; N, 5.26.
4.9.15. 5-Methoxy-1-(phenylsulfonyl)-1H-indole-3-carb-
oxylic acid (23b). To a solution of 5-methoxy-1-(phenyl-
sulfonyl)-indole-3-carboxaldehyde (379 mg, 1.20 mmol) in
dioxane/H2O (14 mL, 4:1) was added NaClO2 (176 mg,
1.93 mmol) followed by sulfamic acid (664 mg, 6.85 mmol)
at room temperature. The reaction mixture was stirred for 2 h
at room temperature. A saturated NaHCO3 solution (15 mL)
was added with precaution to the solution and the final
mixture was stirred for 30 min. The solution was concen-
trated and the residue was dissolved in EtOAc. The organic
solution was washed with 3 N HCl and H2O. The organic
phase was dried over Na2SO4 and concentrated in vacuo.
The solid was recrystallized from EtOAc to give 23b
(323 mg, 81%) as a white solid. Mp >210 ꢀC (EtOAc); IR
(KBr) n 3135–2600, 1680, 1430, 1380, 1200, 970 cmꢂ1; 1H
NMR (DMSO-d6) d 3.77 (s, 3H, CH3), 7.02 (dd, 1H,
J¼2.5, 9.1 Hz, H6), 7.50 (d, 1H, J¼2.5 Hz, H4), 7.63 (t,
2H, J¼7.7 Hz, Har), 7.75 (t, 1H, J¼7.4 Hz, Har), 7.86 (d,
1H, J¼9.1 Hz, H7), 8.10 (d, 2H, J¼7.9 Hz, Har), 8.29 (s,
1H, H2), 12.81 (br s, 1H, OH); 13C NMR (DMSO-d6)
d 55.4 (CH3), 103.7 (CH), 114.0 (C), 114.1 (CH), 114.7
(CH), 127.1 (2CH), 128.7 (C), 128.8 (C), 130.1 (2CH),
132.4 (CH), 135.2 (CH), 136.5 (C), 156.8 (C), 164.4
(CO); MS (IS) m/z 332 (M+H)+. Anal. Calcd for
C16H13NO5S: C, 58.00; H, 3.95; N, 4.23. Found: C, 58.34;
H, 4.08; N, 4.36.
4.9.13. 8-(Benzyloxymethyl)-7-oxo-5,6,7,8-tetrahydro-
pyrrolo[2,3-d][2]benzazepine-6-carboxylic acid tert-butyl
ester (20). A mixture of 19 (492 mg, 0.90 mmol), PPh3
(47 mg, 0.18 mmol), Pd(OAc)2 (20 mg, 0.09 mmol), and
silver carbonate (496 mg, 1.80 mmol) in anhydrous DMF
(18 mL) was vigorously stirred at 140 ꢀC for 1 h. After cool-
ing, the solvent was removed in vacuo. The residue was
taken up in CH2Cl2, filtered over CeliteÒ, and rinsed with
CH2Cl2. The solvent was evaporated in vacuo and the crude
residue was purified by flash chromatography (PE/EtOAc
9:1) to give 20 (320 mg, 85%) as an oil. IR (film) n 2978,
1714, 1673, 1454, 1406, 1332, 1148, 1083, 941,
1
755 cmꢂ1; H NMR (CDCl3) d 1.51 (s, 9H, 3CH3), 4.19
and 5.10 (d, 1H, J¼14.7 Hz, CH2), 4.59 (s, 2H, CH2), 5.60
and 6.20 (d, 1H, J¼9.8 Hz, CH2), 6.56 (d, 1H, J¼2.8 Hz,
Hpyrrole), 7.21 (d, 1H, J¼2.8 Hz, Hpyrrole), 7.27–7.33 (m,
6H, Har), 7.40–7.45 (m, 2H, Har), 7.68 (d, 1H, J¼7.5 Hz,
Har); 13C NMR (CDCl3) d 28.0 (3CH3), 48.8 (CH2), 70.7
(CH2), 77.7 (CH2), 82.8 (C), 107.6 (CH), 123.4 (C), 126.9
(CH), 127.3 (CH), 127.7 (2CH), 127.8 (CH), 128.1
(CH), 128.4 (2CH), 128.5 (CH), 129.4 (CH), 130.8 (C),
133.5 (C), 134.9 (C), 137.3 (C), 151.1 (CO), 161.0
(CO); MS (IS) m/z 419 (M+H)+. Anal. Calcd for
C25H26N2O4: C, 71.75; H, 6.26; N, 6.69. Found: C, 71.52;
H, 6.10; N, 6.53.
4.9.16. N-(2-Iodobenzyl)-1-(phenylsulfonyl)-1H-indole-
3-carboxamide (24a). According to the procedure de-
scribed for 5, compound 24a was prepared from 23a9 and
4. A catalytic amount of DMAP was used. Yield: 82%; white
solid; mp 204–206 ꢀC (washing CH2Cl2); IR (KBr) n 3264,
1
3067, 2950, 1625, 1560, 1382, 1097, 744, 690 cmꢂ1; H
NMR (DMSO-d6) d 4.44 (d, 2H, J¼5.5 Hz, CH2), 7.03–
7.09 (m, 1H, Har), 7.30–7.41 (m, 4H, Har), 7.65 (t, 2H,
J¼7.7 Hz, Har), 7.75 (t, 1H, J¼7.4 Hz, Har), 7.89 (d, 1H, J¼
7.7 Hz, Har), 7.93 (d, 1H, J¼7.9 Hz, Har), 8.05 (d, 2H,
J¼8.0 Hz, Har), 8.16 (d, 1H, J¼8.1 Hz, Har), 8.67 (s, 1H,
Har), 8.97 (br t, 1H, J¼5.5 Hz, NH); 13C NMR (DMSO-d6)
d 47.5 (CH2), 98.8 (C), 112.9 (CH), 116.3 (C), 122.3 (CH),
124.2 (CH), 125.4 (CH), 126.9 (2CH), 128.4 (2CH+C),
128.5 (CH), 129.1 (CH), 130.1 (2CH), 133.9 (C), 135.1
(CH), 136.6 (C), 139.0 (CH), 140.6 (C), 162.7 (CO); MS
4.9.14. 5,8-Dihydropyrrolo[2,3-d][2]benzazepin-7(6H)-
one (21). A suspension of 20 (105 mg, 0.25 mmol) and
Pd(OH)2 (53 mg, 50% w/w) in ethanol/THF (10 mL, 4:1)
was stirred under H2 (1 bar) for 2 h at room temperature.
The catalyst was removed by filtration and the filtrate was
evaporated in vacuo. The residue obtained was used in the

878
A. Putey et al. / Tetrahedron 63 (2007) 867–879
(IS) m/z 517 (M+H)+. Anal. Calcd for C22H17IN2O3S: C,
51.17; H, 3.32; N, 5.43. Found: C, 50.97; H, 3.22; N, 5.35.
4.9.20. 12-(Phenylsulfonyl)-7-oxo-5,6,7,12-tetrahydro-
indolo[3,2-d][2]benzazepine-6-carboxylic acid tert-butyl
ester (26a). According to the procedure described for 7,
compound 26a was prepared from 25a. In this case,
Pd(OAc)2 (10 mol %) and PPh3 (20 mol %) were used. The
reaction mixture was stirred at 100 ꢀC for 2 h. Chromato-
graphy eluent: PE/EtOAc 9:1; yield: 92%; white solid;
mp 154 ꢀC dec (Et2O); IR (KBr) n 3078, 2978, 1759,
4.9.17. N-(2-Iodobenzyl)-5-methoxy-1-(phenylsulfonyl)-
1H-indole-3-carboxamide (24b). According to the pro-
cedure described for 5, compound 24b was prepared from
23b and 4. A catalytic amount of DMAP was used. Yield:
76%; white solid; mp >210 ꢀC (washing CH2Cl2); IR
(KBr) n 3308, 3070, 2936, 2822, 1630, 1552, 1378, 1093,
1
1693, 1446, 1387, 756 cmꢂ1; H NMR (CDCl3) d 1.51 (s,
1
752, 693 cmꢂ1; H NMR (DMSO-d6) d 3.75 (s, 3H, CH3),
9H, 3CH3), 3.66 and 5.09 (d, 1H, J¼14.5 Hz, CH2), 7.12
(br d, 2H, J¼8.5 Hz, Har), 7.20 (t, 2H, J¼8.5 Hz, Har),
7.37–7.58 (m, 6H, Har), 7.97–8.00 (m, 1H, Har), 8.16 (br d,
1H, J¼7.7 Hz, Har), 8.34 (d, 1H, J¼8.3 Hz, Har);
13C NMR (CDCl3) d 28.1 (3CH3), 47.8 (CH2), 83.8 (C),
117.6 (CH), 121.7 (C), 122.8 (CH), 126.0 (CH), 126.5
(2CH), 126.6 (CH), 127.5 (2CH), 128.7 (2CH+C),
129.7 (C), 130.3 (CH), 133.4 (CH), 134.2 (CH), 135.7 (C),
136.5 (C), 138.6 (C), 141.9 (C), 151.1 (CO), 162.7 (CO);
MS (IS) m/z 489 (M+H)+. Anal. Calcd for C27H24N2O5S:
C, 66.38; H, 4.95; N, 5.73. Found: C, 66.11; H, 4.82;
N, 5.70.
4.43 (d, 2H, J¼5.5 Hz, CH2), 6.99 (dd, 1H, J¼2.6, 9.0 Hz,
Har), 7.03–7.09 (m, 1H, Har), 7.36–7.44 (m, 2H, Har),
7.62–7.67 (m, 3H, Har), 7.75 (t, 1H, J¼7.4 Hz, Har), 7.82
(d, 1H, J¼9.0 Hz, Har), 7.89 (d, 1H, J¼7.5 Hz, Har), 8.01
(d, 2H, J¼8.0 Hz, Har), 8.64 (s, 1H, Har), 8.96 (br t, 1H,
J¼5.5 Hz, NH); 13C NMR (DMSO-d6) d 47.5 (CH2), 55.3
(CH3), 98.8 (C), 104.2 (CH), 113.8 (CH), 114.6 (CH), 116.1
(C), 126.8 (2CH), 128.4 (2CH), 128.5 (C), 129.0 (CH),
129.1 (CH), 129.6 (C), 130.1 (2CH), 135.0 (CH), 136.6
(C), 139.0 (CH), 140.6 (C), 156.5 (C), 162.8 (CO); MS (IS)
m/z 547 (M+H)+. Anal. Calcd for C23H19IN2O4S: C, 50.56;
H, 3.51; N, 5.13. Found: C, 50.79; H, 3.45; N, 5.26.
4.9.21. 9-Methoxy-12-(phenylsulfonyl)-7-oxo-5,6,7,12-
tetrahydroindolo[3,2-d][2]benzazepine-6-carboxylic
acid tert-butyl ester (26b). According to the procedure de-
scribed for 7, compound 26b was prepared from 25b. In this
case, Pd(OAc)2 (10 mol %) and PPh3 (20 mol %) were used.
The reaction mixture was stirred at 100 ꢀC for 2 h. Chroma-
tography eluent: PE/EtOAc 85:15; yield: 96%; white
solid; mp 146 ꢀC dec (EtOAc/PE); IR (KBr) n 3099, 2975,
4.9.18. tert-Butyl (2-iodobenzyl){[1-(phenylsulfonyl)-1H-
indol-3-yl]carbonyl}carbamate (25a). According to the
procedure described for 6, compound 25a was prepared
from 24a. Chromatography eluent: PE/EtOAc 95:5; yield:
99%; white solid; mp 85–87 ꢀC (Et2O/PE); IR (KBr) n
3065, 2977, 2872, 1723, 1677, 1447, 1383, 748, 694 cmꢂ1
;
1H NMR (CDCl3) d 1.06 (s, 9H, 3CH3), 5.00 (s, 2H, CH2),
6.96 (t, 1H, J¼7.5 Hz, Har), 7.24–7.39 (m, 4H, Har), 7.48
(t, 2H, J¼7.7 Hz, Har), 7.59 (t, 1H, J¼7.4 Hz, Har),
7.80 (d, 1H, J¼7.7 Hz, Har), 7.85 (d, 1H, J¼7.9 Hz,
Har), 7.95 (d, 2H, J¼8.0 Hz, Har), 8.00 (d, 1H, J¼8.1 Hz,
Har), 8.08 (s, 1H, Har); 13C NMR (CDCl3) d 27.5 (3CH3),
54.4 (CH2), 83.9 (C), 97.8 (C), 113.7 (CH), 119.4 (C),
121.5 (CH), 124.5 (CH), 125.6 (CH), 127.1 (CH), 127.3
(2CH), 128.0 (C), 128.5 (CH), 129.0 (CH), 129.7 (2CH),
130.2 (CH), 134.5 (C), 134.6 (CH), 137.9 (C), 139.6 (CH),
139.7 (C), 153.1 (CO), 167.1 (CO); MS (IS) m/z 617
(M+H)+. Anal. Calcd for C27H25IN2O5S: C, 52.61; H,
4.09; N, 4.54. Found: C, 52.66; H, 4.09; N, 4.50.
1
2843, 1749, 1652, 1446, 1389, 756, 699 cmꢂ1; H NMR
(DMSO-d6) d 1.45 (s, 9H, 3CH3), 3.79 (s, 3H, CH3), 3.88
and 5.10 (d, 1H, J¼14.8 Hz, CH2), 7.12 (dd, 1H, J¼2.6,
9.1 Hz, Har), 7.17 (d, 2H, J¼8.1 Hz, Har), 7.41 (t, 2H,
J¼7.9 Hz, Har), 7.48 (d, 1H, J¼2.6 Hz, Har), 7.54–7.64 (m,
4H, Har), 7.89–7.91 (m, 1H, Har), 8.11 (d, 1H, J¼9.1 Hz,
Har); 13C NMR (CDCl3) d 28.1 (3CH3), 47.8 (CH2), 55.8
(CH3), 83.8 (C), 104.3 (CH), 116.3 (CH), 118.6 (CH),
121.6 (C), 126.5 (2CH), 127.4 (CH), 127.5 (CH), 128.8
(2CH+C), 130.3 (CH), 131.0 (C), 132.8 (C), 133.5 (CH),
134.2 (CH), 135.6 (C), 136.4 (C), 142.6 (C), 150.9 (CO),
158.2 (C), 163.0 (CO); MS (IS) m/z 519 (M+H)+. Anal.
Calcd for C28H26N2O6S: C, 64.85; H, 5.05; N, 5.40. Found:
C, 65.00; H, 5.16; N, 5.53.
4.9.19. tert-Butyl (2-iodobenzyl){[5-methoxy-1-(phenyl-
sulfonyl)-1H-indol-3-yl]carbonyl}carbamate (25b). Ac-
cording to the procedure described for 6, compound 25b
was prepared from 24b. Chromatography eluent: PE/EtOAc
85:15; yield: 99%; white solid; mp 131–132 ꢀC (Et2O); IR
(KBr) n 3070, 2976, 2824, 1732, 1670, 1448, 1376, 1092,
4.10. General procedure for both deprotection
To a solution of 26 (0.20 mmol) in anhydrous CH2Cl2
(4 mL) at room temperature was added trifluoroacetic
acid (1 mL, 13.46 mmol). After stirring for 2 h, H2O
(20 mL) was added and the resulting mixture was extracted
with CH2Cl2 (2ꢁ20 mL). The combined organic phases
were dried over Na2SO4, filtered, and concentrated in vacuo
to afford a crude solid, which was engaged in the next step
without further purification. The crude product was dis-
solved in anhydrous THF (5 mL) and 1 M tetrabutyl-
ammonium fluoride (1.0 mL) was added. The resulting
solution was refluxed for 30 min, then solvent was evapo-
rated and the crude solid was recrystallized from methanol
to afford 27.
724, 693 cmꢂ1 1H NMR (DMSO-d6) d 0.93 (s, 9H,
;
3CH3), 3.74 (s, 3H, CH3), 4.85 (s, 2H, CH2), 7.03–7.08
(m, 2H, Har), 7.15 (d, 1H, J¼2.5 Hz, Har), 7.18 (d, 1H,
J¼7.4 Hz, Har), 7.43 (t, 1H, J¼7.0 Hz, Har), 7.64 (t, 2H,
J¼7.6 Hz, Har), 7.75 (t, 1H, J¼7.3 Hz, Har), 7.90 (d, 1H, J¼
7.6 Hz, Har), 7.93 (d, 1H, J¼9.1 Hz, Har), 8.13 (d, 2H, J¼
8.0 Hz, Har), 8.36 (s, 1H, Har); 13C NMR (CDCl3) d 27.6
(3CH3), 54.4 (CH2), 55.8 (CH3), 83.9 (C), 97.9 (C), 103.4
(CH), 114.5 (CH), 115.4 (CH), 119.0 (C), 127.2 (2CH),
127.4 (CH), 128.5 (CH), 129.0 (CH), 129.1 (2C), 129.7
(2CH), 130.8 (CH), 134.5 (CH), 137.8 (C), 139.6 (CH),
139.8 (C), 153.2 (CO), 157.4 (C), 167.3 (CO); MS (IS)
m/z 647 (M+H)+. Anal. Calcd for C28H27IN2O6S: C, 52.02;
H, 4.21; N, 4.33. Found: C, 51.78; H, 4.11; N, 4.45.
4.10.1. 5,12-Dihydroindolo[3,2-d][2]benzazepin-7(6H)-
one (27a). According to the general procedure described for

A. Putey et al. / Tetrahedron 63 (2007) 867–879
879
27, compound 27a was prepared from 26a. Yield: 40%;
white solid; mp >210 ꢀC (MeOH); IR (KBr) n 3320–3171,
Acknowledgements
This research work was supported by a grant from the
1
3049, 2978, 1623, 1573, 1489, 1448, 742 cmꢂ1; H NMR
ꢁ
ꢀ
(DMSO-d6) d 4.09 (d, 2H, J¼5.3 Hz, CH2), 7.14 (t, 1H,
J¼7.3 Hz, Har), 7.24 (t, 1H, J¼7.3 Hz, Har), 7.45–7.56 (m,
4H, 3Har+NH), 7.83–7.85 (d, 2H, J¼7.3 Hz, Har), 8.07 (d,
1H, J¼7.9 Hz, Har), 12.06 (s, 1H, NH); 13C NMR
(DMSO-d6) d 44.4 (CH2), 109.4 (C), 111.4 (CH), 120.5
(CH), 121.6 (CH), 123.0 (CH), 126.7 (CH), 127.9 (C),
128.0 (CH), 128.1 (CH), 128.9 (CH), 130.4 (C), 136.3 (C),
137.9 (C), 138.4 (C), 166.8 (CO); MS (IS) m/z 249
(M+H)+. Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87;
N, 11.28. Found: C, 77.53; H, 5.01; N, 11.41.
Ministere de l’Enseignement Superieur et de la Recherche
to A.P. and L.J.
References and notes
1. Linington, R. G.; Williams, D. E.; Tahir, A.; van Soest, R.;
Andersen, R. J. Org. Lett. 2003, 5, 2735–2738.
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J. Nat. Prod. 1998, 61, 693–695.
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8177–8179.
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4.10.2. 9-Methoxy-5,12-dihydroindolo[3,2-d][2]benzaze-
pin-7(6H)-one (27b). According to the general procedure
described for 27, compound 27b was prepared from 26b.
Yield: 43%; white solid; mp >210 ꢀC (CH2Cl2); IR (KBr)
n 3350–3180, 3000, 2957, 2843, 1622, 1490, 1466, 1033,
6. Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.;
Rossi, E. Synthesis 2006, 2404–2412.
1
741 cmꢂ1; H NMR (DMSO-d6) d 3.78 (s, 3H, CH3), 4.07
(d, 2H, J¼5.1 Hz, CH2), 6.88 (dd, 1H, J¼2.6, 8.9 Hz, Har),
7.39 (d, 1H, J¼8.9 Hz, Har), 7.43–7.55 (m, 3H, 2Har+NH),
7.58 (d, 1H, J¼2.6 Hz, Har), 7.80–7.82 (m, 2H, Har), 11.96
(s, 1H, NH); 13C NMR (DMSO-d6) d 44.5 (CH2), 55.3
(CH3), 102.9 (CH), 109.1 (C), 112.2 (CH), 113.4 (CH),
126.5 (CH), 128.0 (CH), 128.1 (CH), 128.5 (C), 128.8
(CH), 130.5 (C), 131.3 (C), 138.2 (2C), 154.3 (C), 167.0
(CO); MS (IS) m/z 279 (M+H)+. Anal. Calcd for
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.54; H, 4.98; N, 9.99.
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Tetrahedron 2001, 57, 9697–9710.
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ꢀ
9. Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y.
Synthesis 2000, 549–556.
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Sausville, E. A.; Meijer, L.; Kunick, C. J. Med. Chem. 1999, 42,
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ꢀ
ꢀ
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