Access to paullone analogues by intramolecular Heck reaction

Article abstract of DOI:10.1002/hlca.200790076

The syntheses of paullone (1a) and three paullone derivatives, including a sulfur analogue (2a), a tricyclic derivative (2b), and a ring-enlarged variant (2c), are described, Pd-catalyzed intramolecular Heck reaction being the key step. The kinase-inhibitory properties of the novel paullone analogues were investigated.

Full text of DOI:10.1002/hlca.200790076

Helvetica Chimica Acta – Vol. 90 (2007)
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Access to Paullone Analogues by Intramolecular Heck Reaction
by Lionel Jouclaa), Florence Popowycza), Olivier Lozachb), Laurent Meijerb), and Benoît Joseph*a)
a
´
) Laboratoire de Chimie Organique 1, UMR – CNRS 5181, Universite Claude Bernard – Lyon 1,
ˆ
CPE – Batiment 308, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne Cedex
b) Station Biologique – CNRS, Place G. Teissier, BP 74, F-29682 Roscoff Cedex
The syntheses of paullone (1a) and three paullone derivatives, including a sulfur analogue (2a), a
tricyclic derivative (2b), and a ring-enlarged variant (2c), are described, Pd-catalyzed intramolecular
Heck reaction being the key step. The kinase-inhibitory properties of the novel paullone analogues were
investigated.
Introduction. – Paullone (1a), alsterpaullone (1b), and kenpaullone (1c), a series of
indolo[3,2-d][1]benzazepines, have been described as potent cyclin-dependent kinase
and glycogen-synthase kinase inhibitors [1a – d]. Thus, the synthesis of paullone and
analogues thereof has raised huge interest over the last decade [2a – c]. Several
synthetic strategies have been already reported to access the paullone system. The first
synthetic pathway involved a construction of the fused 1H-indole moiety by a Fischer
indolization of benzazepinone [3]. Thiophene analogues of kenpaullone (1c) were
synthesized according to a similar approach [4]. Strategies starting from an indole
precursor and using Pd-catalyzed coupling were reported by Baudoin and co-workers
(Suzuki – Miyaura reaction) [5], by Bremner and Sengpracha (Heck reaction) [6], and
´
by Merour and co-workers (Stille reaction) [7].
Recently, we have reported a straightforward and easy synthesis of the same
skeleton based on an intramolecular Heck reaction [8]. Since our preliminary results,

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two research teams have used the same approach to prepare paullones and its
derivatives [9][10]. In the present paper, we wish to apply our methodology to the
synthesis of paullone (1a) and some derivatives thereof, including the sulfur analogue
2a, the tricyclic variant 2b, and the ring-enlarged compound 2c.
Results and Discussion. – 1. Synthesis. First, we have envisaged a synthetic strategy
allowing the access to fully deprotected analogues (Scheme 1). Thus, commercially
available 1H-indole-3-acetic acid was first esterified, and the so-formed ester 3 [11] was
protected under classical conditions with an easily removable, electron-donating
ethoxymethyl (EOM) group, providing compound 4 in 69% yield over two steps. This
moderate yield could be due to the acidity of the benzylic CH2 moiety, leading to the
formation of undesired by-products. Compound 4 was then condensed with a large
excess of 2-iodoaniline in the presence of Me3Al (EDCI coupling failed in our hands)
to afford the amide 5 in 98% yield. Protection of the amide N-atom with another EOM
group was effected by exposure to NaH and EtOCH2Cl, which afforded the fully
protected derivative 6 in 69% yield to be used as precursor for the intramolecular Heck
reaction. As reported in our first paper [8], this cyclization is highly effective in the
presence of [Pd(OAc)2] (10 mol-%), Ph3P (20 mol-%), and Ag2CO3 (2 equiv.) in
anhydrous DMF at a substrate concentration of ca. 50 mm. When this method was
applied, compound 6 was converted within only 30 min at 1008 to the doubly EOM-
protected paullone 7 in an excellent yield of 92%. Finally, deprotection of 7 was carried
Scheme 1
a) 1. NaH, THF; 2. EtOCH2Cl, 08 ! r.t., 18 h; 69%. b) 2-Iodoaniline, Me3Al, CH2Cl2, À 158 ! r.t., 18 h;
98%. c) 1. NaH, THF; 2. EtOCH2Cl, 08 ! r.t., 2 h; 69%. d) [Pd(OAc)2] (10 mol-%), Ph3P (20 mol-%),
Ag2CO3, DMF, 1008, 30 min; 92%. e) 1n aq. HCl, 1,4-dioxane, 808, 1 h; 37%.

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out under acidic conditions, which furnished paullone proper (1a) in 37% yield. (Note
that the use of BCl3 in CH2Cl2 at À 788 [12] leads to the degradation of 7).
These results prompted us to investigate the synthesis of paullone bioisosteres by
substituting the indole nucleus by a benzo[b]thiophene or by a simple pyrrole ring.
Following the same pathway as described above, commercially available benzo[b]-
thiophene-3-acetic acid was converted into the Me ester 8 in near-quantitative yield
(Scheme 2). Amide coupling and subsequent EOM protection of the amide N-atom
afforded, via 9, the amide 10 in 62% overall yield. The following cyclization proved to
be incomplete when 10% of [Pd(OAc)2] was used at 1008 (65% conversion, based on
1H-NMR analysis). However, the use of 5% of catalyst at 1408 gave rise to the desired
cyclized product 11 in a fair 70% yield (with 16% of starting material being recovered).
The yield could be further improved to 87%, when 10% of the Pd catalyst was used.
Finally, deprotection of the EOM group in an acidic medium afforded the target sulfur
analogue 2a in 57% yield.
Scheme 2
a) 2-Iodoaniline, Me3Al, CH2Cl2, À 158 ! r.t., 18 h; 82%. b) 1. NaH, THF; 2. EtOCH2Cl, 08 ! r.t., 2 h;
75%. c) [Pd(OAc)2] (10 mol-%), Ph3P (20 mol-%), Ag2CO3, DMF, 1408, 30 min; 87%. d) 1n aq. HCl,
1,4-dioxane, 808, 1 h; 57%.
Application of the previously described methodology to ethyl {1-[(4-methylphe-
nyl)sulfonyl]-1H-pyrrol-3-yl}acetate (12), prepared according to a procedure reported
by Lemaire and co-workers [13], provided an easy access to the precursor of the pyrrole
analogue (Scheme 3). Recent studies suggested the strong influence of the electron
density of the olefine during the Pd-catalyzed arylation of nitrogen heterocycles [14].
Indeed, the intramolecular Heck coupling failed when the indole nitrogen was
protected with a tosyl (Ts) group. Thus, the pyrrole system, characterized by a higher
electron density at C(2), should provide the expected cyclized product despite the
presence of an electron-withdrawing group at N(1). Thus, condensation between 2-
iodoaniline and 12 afforded the amide 13 in 98% yield, which was further reacted to
afford either the EOM-protected derivative 14a or the (benzyloxy)methyl (BOM)-

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protected analogue 14b in yields of 98 and 86%, respectively1). Both compounds were
individually submitted to the intramolecular Heck cyclization, providing 15a and 15b in
excellent yields (86 and 87%, resp.). The reaction ran to completion in less than 30 min,
1
and no trace of a C(4)-arylated product was detected. In the H-NMR spectra of 15a
and 15b, two characteristic doublets (J ¼ 3.4 Hz) were observed for HÀC(4) and
HÀC(5) of the pyrrole moiety, which confirmed the regioselectivity of the reaction,
pointing out the pivotal role of electron-rich heterocycles. Finally, removal of the EOM
group of 15a under mild acidic conditions afforded the mono-deprotected paullone
analogue 16 in only 42% yield. Fortunately, the BOM group of 15b could be
successfully cleaved by exposure to Pearlmanꢀs catalyst under classical hydrogenolysis
conditions, and the remaining Ts group was removed in basic medium to afford the fully
deprotected pyrrole analogue 2b in 72% yield over both steps.
Scheme 3
a) 2-Iodoaniline, Me3Al, CH2Cl2, À 158 ! r.t., 18 h; 98%. b) 1. NaH, THF; 2. EtOCH2Cl or BnOCH2Cl,
08 ! r.t., 2 h; 98% (14a), 86% (14b). c) [Pd(OAc)2] (10 mol-%), Ph3P (20 mol-%), Ag2CO3, DMF, 1008,
30 min; 86% (15a), 87% (15b). d) 1n aq. HCl, 1,4-dioxane, 808, 1 h; 42%. e) [Pd(OH)2], H2 (1 atm),
EtOH/THF, r.t., 2 h. f) 1n aq. NaOH, 1,4-dioxane, 808, 1 h; 72% (two steps).
The synthesis of the ring-enlarged compound 2c started from 1H-indole-3-
carbaldehyde (17)2), as shown in Scheme 4. Compound 17 was converted into the
ester 18 via a three-step reaction sequence: a) protection of the indole N-atom, b)
Wittig olefination with the appropriate phosphorane, and c) hydrogenation of the
resulting a,b-unsaturated ester. Condensation of 18 with 2-iodoaniline afforded 19,
1
)
)
The higher yields obtained with the pyrrole nucleus might be explained by a lower stabilization of
the carbanion leading to undesired C-alkylated by-products.
Protection of methyl 1H-indole-3-propanoate proved to be tedious.
2

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757
which was EOM-protected to provide the Heck precursor 20 in an overall yield of 48%
(five steps). As observed for the sulfur analogue, it was necessary to work at a
temperature of 1408 to effect complete cyclization, which afforded the expected
product 21 in 82% yield. Unfortunately, deprotection of 21 failed under acidic
conditions. So, the desired product could only be observed by 1H-NMR analysis due to
the low quantity isolated.
Scheme 4
a) 1. NaH, THF; 2. EtOCH2Cl, 08 ! r.t., 2 h. b) Ph3P¼CHCO2Et, toluene, reflux, 18 h; 83% (two steps).
c) 10% Pd/C, H2 (20 atm), MeOH/THF, r.t., 3 h; 99%. d) 2-Iodoaniline, Me3Al, CH2Cl2, À 158 ! r.t.,
18 h; 92%. e) 1. NaH, THF; 2. EtOCH2Cl, 08 ! r.t., 2 h; 63%. f) [Pd(OAc)2] (10 mol-%), Ph3P
(20 mol-%), Ag2CO3, DMF, 1408, 30 min; 82%. g) 1n aq. HCl, 1,4-dioxane, 808, 1 h; traces only.
2. Kinase Activity. We tested the inhibitory properties of 2a and 2b towards CDK1/
cyclin B, CDK5/p25, and GSK-3 kinases. Both compounds showed no or only low
inhibition activities against these target kinases. The following IC50 values were
determined for CDK1, CDK5, and GSK-3, resp: 2a: IC50 > 100 mm (all three kinases);
2b: IC50 ¼ 25, 58, and 40 mm, resp. For comparison, the corresponding IC50 values for
paullone (1a) are 7, 0.62, and 10.1 mm, resp. [1b].
`
´
This work was supported by a grant from the Ministere de lꢀEnseignement Superieur et de la
Recherche (to L. J.).
Experimental Part
General. All commercially available reagents (Fluka, Aldrich) were used as received. Solvents were
dried by standard methods. Petroleum ether (PE) for chromatography had a b.p. range of 40 – 608. Thin-
layer chromatography (TLC): Merck 60F254 silica gel on Al plates; visualization under UV light. Column

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chromatography (CC) and flash chromatography (FC): Merck silica gel 60 (40 – 63 mm). All reactions
requiring anh. conditions were conducted in a flame-dried apparatus. Melting points (m.p.) were
determined on a Büchi capillary apparatus, and are uncorrected. IR Spectra: Perkin-Elmer-681
spectrophotometer; in cmÀ1. 1H- and 13C-NMR Spectra: Bruker Avance-300 spectrometer; d in ppm, J in
Hz. Mass spectra: Perkin-Elmer SCIEX-API apparatus; in m/z. Elemental analyses: Thermoquest Flash-
1112 elemental analyzer.
Methyl [1-(Ethoxymethyl)-1H-indol-3-yl]acetate (4). At 08 and under N2 atmosphere, 4-(dimethyl-
amino)pyridine (DMAP; 403 mg, 3.3 mmol) was added to a soln. of 1H-indole-3-acetic acid (526 mg,
3.0 mmol) in anh. CH2Cl2 (30 ml). After stirring at 08 for 20 min, anh. MeOH (182 ml, 4.5 mmol) was
added dropwise, followed by portionwise addition of EDCI3) (634 mg, 3.3 mmol). The mixture was
warmed to r.t., and then stirred overnight. Hydrolysis was performed by addition of 1n aq. HCl (15 ml)
and H2O (15 ml). The layers were separated, and the aq. phase was extracted with CH2Cl2 (3 Â 30 ml).
The combined org. extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude residue
was purified by FC (SiO2; PE/AcOEt 8 :2) to afford methyl 1H-indol-3-ylacetate 3 (562 mg, 99%) as a
colorless oil.
To a soln. of 3 (3.0 mmol) in anh. THF (15 ml) was added, at 08 under N2 atmosphere, NaH (60%
dispersion in mineral oil; 154 mg, 3.86 mmol). After stirring at 08 for 30 min, EtOCH2Cl (555 ml,
5.94 mmol) was added dropwise. The soln. was warmed to r.t., and stirred overnight. The mixture was
hydrolyzed with 1n aq. HCl (5 ml) and H2O (10 ml), and extracted with CH2Cl2 (3 Â 20 ml). The
combined org. extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by FC (SiO2; PE/AcOEt 9 :1) to afford 4 (509 mg, 69%). Colorless oil. IR (NaCl): 2975, 2950,
2900, 1740, 1465, 1355, 1090, 745, 535. 1H-NMR (300 MHz, CDCl3): 1.15 (t, J ¼ 7.0, Me); 3.43 (q, J ¼ 7.0,
CH2); 3.71 (s, Me); 3.77 (s, CH2); 5.47 (s, CH2); 7.17 (t, J ¼ 7.5, HÀC(5)); 7.18 (s, HÀC(2)); 7.25 (t, J ¼ 7.5,
HÀC(6)); 7.48 (d, J ¼ 7.9, HÀC(7)); 7.60 (d, J ¼ 7.5, HÀC(4)). 13C-NMR (75 MHz, CDCl3): 14.8 (Me);
30.9 (CH2); 51.9 (Me); 63.8 (CH2); 75.8 (CH2); 108.2 (C); 110.0 (CH); 119.0 (CH); 120.0 (CH); 122.3
(CH); 126.8 (CH); 128.3 (C); 136.5 (C); 172.2 (C¼O). ESI-MS: 248 ([M þ H]þ). Anal. calc. for
C14H17NO3: C 68.00, H 6.93, N 5.66; found: C 68.27, H 7.11, N 5.80.
2-[1-(Ethoxymethyl)-1H-indol-3-yl]-N-(2-iodophenyl)acetamide (5). Under N2 atmosphere at
À 158, Me3Al (2m soln. in toluene; 7.5 ml, 15.0 mmol) was added to anh. CH2Cl2 (15 ml). A soln. of 2-
iodoaniline (2.63 g, 12.0 mmol) in anh. CH2Cl2 (10 ml) was added dropwise at À 158, and the mixture was
stirred for 1 h at this temp. The mixture was then slowly warmed to 08 over 1 h, and a soln. of 4 (0.74 g,
3.0 mmol) in anh. CH2Cl2 (10 ml) was added dropwise. The mixture was stirred overnight at r.t., and then
carefully quenched with 1n aq. HCl (10 ml) at 08. After addition of more 1n aq HCl (20 ml), the layers
were separated, and the aq. phase was extracted with CH2Cl2 (3 Â 30 ml). The combined org. extracts
were dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by FC (SiO2;
PE/AcOEt 85 :15) to give 5 (1.23 g, 98%). Solid. M.p. 81 – 838 (MeOH). IR (KBr): 3240, 2970, 1665,
1520, 1460, 1435, 1090, 740. 1H-NMR (300 MHz, CDCl3): 1.17 (t, J ¼ 7.0, Me); 3.49 (q, J ¼ 7.0, CH2); 3.93
(s, CH2); 5.53 (s, CH2); 6.75 (t, J ¼ 7.6, 1 arom. H); 7.20 (t, J ¼ 7.5, 1 arom. H); 7.28 – 7.33 (m, 3 arom. H);
7.52 (d, J ¼ 8.3, 1 arom. H); 7.59 – 7.64 (m, 2 arom. H); 7.81 (s, NH); 8.30 (dd, J ¼ 1.3, 8.3, 1 arom. H).
13C-NMR (75 MHz, (D6)DMSO): 14.8 (Me); 32.8 (CH2); 63.1(CH2); 75.0 (CH2); 94.7 (C); 108.8 (C);
110.2 (CH); 119.1 (CH); 119.5 (CH); 121.8 (CH); 125.9 (CH); 127.1 (CH); 128.0 (CH); 128.2 (C); 128.6
(CH); 136.3 (C); 138.9 (CH); 139.3 (C); 169.4 (C¼O). ESI-MS: 435 ([M þ H]þ). Anal. calc. for
C19H19IN2O2: C 52.55, H 4.41, N 6.45; found: C 52.05, H 4.13, N 6.48.
N-(Ethoxymethyl)-2-[1-(ethoxymethyl)-1H-indol-3-yl]-N-(2-iodophenyl)acetamide (6). At 08 and
under N2 atmosphere, NaH (60% dispersion in oil; 26 mg, 0.65 mmol) was added to a stirred soln. of 5
(217 mg, 0.5 mmol) in anh. THF (5 ml). The mixture was stirred for 30 min at 08, then EtOCH2Cl (70 ml,
0.75 mmol) was added dropwise. The mixture was warmed to r.t., and stirred for 2 h. After addition of 1n
aq. HCl (10 ml), the aq. layer was extracted with CH2Cl2 (3 Â 20 ml). The combined org. extracts were
dried (MgSO4), filtered, and evaporated in vacuo. The crude residue was purified by FC (SiO2; PE/
AcOEt 85 :15) to afford 6 (170 mg, 69%). Oil. IR (NaCl): 3055, 2975, 2925, 2880, 1670, 1470, 1375, 1090,
1015, 740. 1H-NMR (300 MHz, CDCl3): 1.13 (t, J ¼ 7.0, Me); 1.18 (t, J ¼ 7.0, Me); 3.40 (q, J ¼ 7.0, CH2);
3
)
1-Ethyl-3-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride.

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3.47, 3.54 (2d, J ¼ 8.0, CH2); 3.62 – 3.73 (m, CH2); 4.46 (d, J ¼ 10.5, 1 H of CH2); 5.42 (s, CH2); 5.69 (d, J ¼
10.5, 1 H of CH2); 6.97 (s, HÀC(2)); 7.05 – 7.22 (m, 4 arom. H); 7.33 – 7.38 (m, 2 arom. H); 7.43 (d, J ¼ 8.1,
1 arom. H); 7.97 (dd, J ¼ 1.3, 7.9, 1 arom. H). 13C-NMR (75 MHz, CDCl3): 14.9 (Me); 15.2 (Me); 31.8
(CH2); 63.9 (CH2); 64.9 (CH2); 75.9 (CH2); 76.9 (CH2); 100.8 (C); 108.7 (C); 109.9 (CH); 119.2 (CH);
119.9 (CH); 122.2 (CH); 127.2 (CH); 128.6 (C); 129.5 (CH); 130.1 (CH); 131.3 (CH); 136.5 (C); 140.1
(CH); 143.5 (C); 171.8 (C¼O). ESI-MS: 493 ([M þ H]þ). Anal. calc. for C22H25IN2O3: C 53.67, H 5.12, N
5.69; found: C 53.99, H 5.22, N 5.86.
5,12-Bis(ethoxymethyl)-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (7). Under N2 atmos-
phere, a suspension of 6 (246 mg, 0.5 mmol), [Pd(OAc)2] (11.2 mg, 0.05 mmol), Ph3P (26.2 mg,
0.1 mmol), and Ag2CO3 (276 mg, 1.0 mmol) in anh. DMF (10 ml) was vigorously stirred at 1008 for
30 min. After cooling, the solvent was removed under reduced pressure, the residue was taken up in
CH2Cl2, and filtered over Celite, eluting with CH2Cl2. The eluate was evaporated in vacuo, and the crude
product was purified by FC (SiO2; PE/AcOEt 9 :1) to provide 7 (167 mg, 92%). Solid. M.p. 102 – 1038
(PE/AcOEt). IR (KBr): 2980, 1680, 1460, 1365, 1340, 1085, 730. 1H-NMR (300 MHz, CDCl3): 1.16 (t, J ¼
7.0, Me); 1.25 (t, J ¼ 7.0, Me); 3.11 (d, J ¼ 13.6, CH2); 3.41 – 3.51 (m, 1 H of CH2); 3.56 – 3.70 (m, 3 H of
CH2); 3.96 (d, J ¼ 13.6, 1 H of CH2); 4.73 (d, J ¼ 10.0, 1 H of CH2); 5.39 (d, J ¼ 10.0, 1 H of CH2); 5.57 (s,
CH2); 7.21 – 7.48 (m, 4 arom. H); 7.54 (d, J ¼ 8.3, 1 arom. H); 7.73 (d, J ¼ 7.9, 1 arom. H); 7.88 (d, J ¼ 7.9, 1
arom. H); 7.95 (d, J ¼ 7.6, 1 arom. H). 13C-NMR (75 MHz, CDCl3): 15.2 (Me); 15.3 (CH2); 32.6 (CH2);
64.3 (CH2); 64.6 (CH2); 73.9 (CH2); 78.9 (CH2); 110.3 (CH); 112.9 (C); 118.9 (CH); 121.0 (CH); 123.5
(CH); 124.8 (CH); 125.3 (C); 126.0 (CH); 126.2 (C); 128.6 (CH); 129.0 (CH); 134.2 (C); 139.2 (C); 140.8
(C); 172.7 (C¼O). ESI-MS: 365 ([M þ H]þ). Anal. calc. for C22H24N2O3: C 72.51, H 6.64, N 7.69; found:
C 72.23, H 6.49, N 7.58.
7,12-Dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (1a). A soln. of 7 (30 mg, 0.08 mmol) and 1n
aq. HCl (0.75 ml) in 1,4-dioxane (2.25 ml) was stirred at 808 for 1 h. After cooling to r.t., H2O (10 ml) was
added, and the aq. layer was extracted with CH2Cl2 (3 Â 10 ml). The combined org. extracts were dried
(MgSO4), filtered, and evaporated in vacuo. The crude residue was purified by FC (SiO2; CH2Cl2/MeOH
1
99 :1) to give 1a (7.5 mg, 37%). Solid. M.p. > 2508. The H-NMR data (300 MHz, (D6)DMSO) were
identical to those described previously [7].
Methyl 1-Benzothiophene-3-acetate (8). At 08 and under N2 atmosphere, DMAP (763 mg,
6.24 mmol) was added to a soln. of 1-benzothiophene-3-acetic acid (1.00 g, 5.20 mmol) in anh. CH2Cl2
(55 ml). After stirring at 08 for 20 min, anh. MeOH (316 ml, 7.80 mmol) was added dropwise, followed by
EDCI3) (1.20 g, 6.24 mmol). The mixture was warmed to r.t., and stirred overnight. After hydrolysis with
1n aq. HCl (15 ml) and H2O (15 ml), the layers were separated, and the aq. phase was extracted with
CH2Cl2 (3 Â 30 ml). The combined org. extracts were dried (MgSO4), filtered, and concentrated in
vacuo. The oily residue was purified by FC (SiO2; PE/AcOEt 9 :1) to give 8 (1.04 g, 97%). Colorless oil.
IR (NaCl): 3070, 1735, 1460, 1430, 1260, 1160, 1020, 760, 730. 1H-NMR (300 MHz, CDCl3): 3.72 (s, Me);
3.89 (s, CH2); 7.34 – 7.44 (m, 3 arom. H); 7.77 (dd, J ¼ 1.7, 7.0, 1 arom. H); 7.87 (dd, J ¼ 1.7, 7.0, 1 arom. H).
13C-NMR (75 MHz, CDCl3): 34.4 (CH2); 52.3 (Me); 121.9 (CH); 123.0 (CH); 124.3 (CH); 124.5 (CH);
124.7 (CH); 128.3 (C); 138.6 (C); 140.3 (C); 171.2 (C¼O). ESI-MS: 207 ([M þ H]þ). Anal. calc. for
C11H10O2S: C 64.05, H 4.89, S 15.55; found: C 64.38, H 5.02, S 15.67.
2-(1-Benzothien-3-yl)-N-(2-iodophenyl)acetamide (9). Prepared, in analogy to 5, in 82% yield from
8 after FC (SiO2; PE/AcOEt 9 :1). Solid. M.p. 163 – 1648 (CH2Cl2). IR (KBr): 3305, 3055, 1670, 1575,
1520, 1435, 1285, 1180, 1015, 780, 740, 725. 1H-NMR (300 MHz, CDCl3): 4.05 (s, CH2); 6.77 (dd, J ¼ 7.4,
7.7, 1 arom. H); 7.26 – 7.32 (m, 1 arom. H); 7.40 – 7.46 (m, 2 arom. H); 7.53 (s, HÀC(2)); 7.60 – 7.63 (m, 2
arom. H); 7.79 – 7.97 (m, 2 arom. H); 8.27 (d, J ¼ 8.1, 1 arom. H). 13C-NMR (75 MHz, CDCl3): 38.1
(CH2); 89.1 (C); 121.3 (CH); 122.1 (CH); 123.1 (CH); 124.9 (CH); 125.2 (CH); 126.0 (CH); 126.6 (CH);
128.9 (C); 129.3 (CH); 138.0 (C); 138.5 (C); 138.8 (CH); 140.9 (C); 168.3 (C¼O). ESI-MS: 394 ([M þ
H]þ). Anal. calc. for C16H12INOS: C 48.87, H 3.08, N 3.56, S 8.15; found: C 48.77, H 3.02, N 3.78, S 7.98.
2-(1-Benzothiophen-3-yl)-N-(ethoxymethyl)-N-(2-iodophenyl)acetamide (10). Prepared, in analogy
to 6, in 75% yield from 9 after FC (SiO2; PE/AcOEt 9 :1). Oil. IR (KBr): 2970, 2930, 2865, 1680, 1470,
1
1375, 1235, 1070, 1015, 935, 780, 750, 725. H-NMR (300 MHz, CDCl3): 1.20 (t, J ¼ 7.1, Me); 3.63 – 3.71
(m, 2 CH2); 4.47, 5.70 (d, J ¼ 10.5, CH2); 7.04 (s, 1 arom. H); 7.05 – 7.17 (m, 2 arom. H); 7.30 – 7.36 (m, 3
arom. H); 7.59 – 7.62 (m, 1 arom. H); 7.80 – 7.83 (m, 1 arom. H); 7.96 (dd, J ¼ 1.3, 7.9, 1 arom. H).

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13C-NMR (75 MHz, CDCl3): 15.2 (Me); 35.4 (CH2); 65.0 (CH2); 77.0 (CH2); 100.7 (C); 122.0 (CH); 122.8
(CH); 124.1 (CH); 124.3 (CH); 124.6 (CH); 128.8 (C); 129.6 (CH); 130.3 (CH); 131.3 (CH); 138.8 (C);
140.1 (C); 140.2 (CH); 143.2 (C); 170.6 (C¼O). ESI-MS: 452 ([M þ H]þ). Anal. calc. for C19H18INO2S:
C 50.56, H 4.02, N 3.10, S 7.10; found: C 50.24, H 3.98, N 3.01, S 7.00.
5-(Ethoxymethyl)-5,7-dihydro-6H-[1]benzothieno[3,2-d][1]benzazepin-6-one (11). Prepared, in
analogy to 7, in 87% yield from 10 after FC (SiO2; PE/AcOEt 8 :2). Solid. M.p. 118 – 1198 (AcOEt/
PE). IR (KBr): 3055, 2970, 2920, 2865, 1670, 1485, 1445, 1375, 1295, 1095, 1070, 940, 910, 770, 750, 730.
1H-NMR (300 MHz, CDCl3): 1.19 (t, J ¼ 6.8, Me); 3.24 (m, 1 H of CH2); 3.52 (m, 1 H of CH2); 3.66 (m,
1 H of CH2); 4.10 (m, 1 H of CH2); 4.79 (m, 1 H of CH2); 5.44 (m, 1 H of CH2); 7.33 – 7.48 (m, 4 arom. H);
7.64 (d, J ¼ 7.5, 1 arom. H); 7.86 – 7.92 (m, 3 arom. H). 13C-NMR (75 MHz, CDCl3): 15.4 (Me); 34.8
(CH2); 64.8 (CH2); 78.9 (CH2); 122.0 (CH); 122.8 (CH); 124.2 (CH); 124.9 (CH); 125.3 (CH); 126.2
(CH); 128.3 (C); 129.1 (C); 129.2 (CH); 129.7 (CH); 136.0 (C); 138.3 (C); 140.3 (C); 140.5 (C); 170.1
(C¼O). ESI-MS: 324 ([M þ H]þ). Anal. calc. for C19H17NO2S: C 70.56, H 5.30, N 4.33, S 9.91; found: C
70.05, H 5.11, N 4.41, S 9.77.
5,7-Dihydro-6H-[1]benzothieno[3,2-d]benzazepin-6-one (2a). Prepared, in analogy to 1a, in 57%
yield from 11. Solid. M.p. > 2508 (H2O/1,4-dioxane). IR (KBr): 3460, 3185, 3060, 2970, 2915, 1680, 1485,
1385, 720, 725. 1H-NMR (300 MHz, (D6)DMSO): 3.63 (s, CH2); 7.27 – 7.30 (m, 2 arom. H); 7.44 – 7.52 (m,
3 arom. H); 7.65 (d, J ¼ 7.7, 1 arom. H); 8.00 (d, J ¼ 7.9, 1 arom. H); 8.06 (d, J ¼ 7.7, 1 arom. H); 10.4 (br. s,
NH). 13C-NMR (75 MHz, (D6)DMSO): 33.7 (CH2); 121.8 (CH); 122.4 (CH); 122.9 (CH); 124.3 (CH);
124.6 (C); 124.9 (CH); 125.2 (CH); 127.3 (C); 129.1 (CH); 129.2 (CH); 135.7 (C); 136.1 (C); 138.3 (C);
139.4 (C); 170.1 (C¼O). ESI-MS: 266 ([M þ H]þ). Anal. calc. for C16H11NOS: C 72.43, H 4.18, N 5.28, S
12.08; found: C 72.35, H 4.05, N 5.33, S 11.92.
N-(2-Iodophenyl)-2-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}acetamide (13). Prepared, in
analogy to 5, from 12 [13] in 98% yield after FC (SiO2; PE/AcOEt 7:3). Solid. M.p. 146 – 1478
(MeOH). IR (KBr): 3340, 1695, 1585, 1525, 1370, 1170, 1065. 1H-NMR (300 MHz, CDCl3): 2.43 (s, Me);
3.58 (s, CH2); 6.32 (dd, J ¼ 1.7, 3.0, 1 H); 6.78 (t, J ¼ 7.7, 1 arom. H); 7.23 – 7.33 (m, 5 H); 7.57 (s, NH); 7.64
(dd, J ¼ 1.3, 7.9, 1 arom. H); 7.82 (d, J ¼ 8.3, 2 arom. H); 8.25 (d, J ¼ 8.1, 1 arom. H). 13C-NMR (75 MHz,
(D6)DMSO): 21.0 (Me); 34.1 (CH2); 95.4 (C); 115.3 (CH); 118.9 (CH); 121.0 (CH); 122.6 (C); 126.6
(CH); 126.8 (2 CH); 127.4 (CH); 128.6 (CH); 130.3 (2 CH); 135.3 (C); 138.8 (CH); 139.2 (C); 145.3 (C);
168.7 (C¼O). ESI-MS: 481 ([M þ H]þ). Anal. calc. for C19H17IN2O3S: C 47.51, H 3.57, N 5.83, S 6.68;
found: C 47.66, H 3.39, N 5.88, S 6.65.
N-(Ethoxymethyl)-N-(2-iodophenyl)-2-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}acetamide
(14a). Prepared, in analogy to 6, from 13 in 98% yield after FC (SiO2; PE/AcOEt 8 :2). Solid. M.p. 102 –
1038 (Et2O). IR (KBr): 2980, 1675, 1470, 1365, 1230, 1170, 1095. 1H-NMR (300 MHz, CDCl3): 1.18 (t, J ¼
7.0, Me); 2.39 (s, Me); 3.09, 3.17 (d, J ¼ 16.0, CH2); 3.56 – 3.71 (m, CH2); 4.39, 5.63 (d, J ¼ 10.4, CH2); 6.15
(dd, J ¼ 1.5, 3.0, 1 H); 6.83 (br. s, 1 H); 7.05 – 7.07 (m, 1 H); 7.11 (d, J ¼ 7.4, 2 arom. H); 7.26 – 7.28 (m, 2 H
arom. H); 7.34 (t, J ¼ 7.6, 1 arom. H); 7.71 (d, J ¼ 8.3, 2 arom. H); 7.92 (d, J ¼ 7.7, 1 arom. H). 13C-NMR
(75 MHz, CDCl3): 15.2 (Me); 21.7 (Me); 33.4 (CH2); 64.9 (CH2); 76.8 (CH2); 100.7 (C); 115.1 (CH);
119.1 (CH); 120.9 (CH); 121.6 (C); 127.0 (2 CH); 129.6 (CH); 130.0 (2 CH); 130.3 (CH); 131.2 (CH);
136.2 (C); 140.1 (CH); 143.2 (C); 145.0 (C); 171.2 (C¼O). ESI-MS: 539 ([M þ H]þ). Anal. calc. for
C22H23IN2O4S: C 49.08, H 4.31, N 5.20, S 5.96; found: C 49.48, H 4.22, N 5.32, S 5.87.
N-[(Benzyloxy)methyl]-N-(2-iodophenyl)-2-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}aceta-
mide (14b). Prepared, in analogy to 6, from 13 and BnOCH2Cl in 86% yield after FC (SiO2; PE/AcOEt
9 :1). Colorless oil. IR (NaCl): 3140, 3060, 2930, 1675, 1470, 1370, 1170, 1100, 1060, 675, 585, 540.
1H-NMR (300 MHz, CDCl3): 2.38 (s, Me); 3.12, 3.20 (2d, J ¼ 16.0, CH2); 4.47 (d, J ¼ 10.4, 1 H of CH2);
4.62 – 4.71 (m, CH2); 5.73 (d, J ¼ 10.4, 1 H of CH2); 6.17 – 6.18 (m, 1 H); 6.85 (br. s, 1 H); 7.06 – 7.08 (m,
1 H); 7.11 (d, J ¼ 7.5, 2 arom. H); 7.23 – 7.38 (m, 8 arom. H); 7.71 (d, J ¼ 8.7, 2 arom. H); 7.92 (d, J ¼ 7.1, 1
arom. H). 13C-NMR (75 MHz, CDCl3): 21.5 (Me); 33.2 (CH2); 71.2 (CH2); 76.6 (CH2); 100.5 (C); 114.9
(CH); 118.9 (CH); 120.7 (CH); 121.4 (C); 126.8 (2 CH); 127.5 (2 CH); 127.6 (CH); 128.3 (2 CH); 129.4
(CH); 129.8 (2 CH); 130.2 (CH); 131.1 (CH); 136.0 (C); 137.8 (C); 139.9 (CH); 142.9 (C); 143.2 (C);
144.9 (C); 171.1 (C¼O). ESI-MS: 601 ([M þ Hþ]). Anal. calc. for C27H25IN2O4S: C 54.01, H 4.20, N 4.67;
found: C 53.88, H 4.30, N 4.59.

Helvetica Chimica Acta – Vol. 90 (2007)
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6-(Ethoxymethyl)-4,6-dihydro-1-[(4-methylphenyl)sulfonyl]pyrrolo[3,2-d][1]benzazepin-5(1H)-
one (15a). Prepared, in analogy to 7, from 14a in 86% yield after FC (SiO2; PE/AcOEt 85 :15). Solid.
M.p. 111 – 1128 (PE/AcOEt). IR (KBr): 3125, 2980, 2930, 1690, 1375, 1310, 1175, 1115, 1075, 770, 695,
585, 545. 1H-NMR (300 MHz, CDCl3): 1.25 (t, J ¼ 7.0, Me); 2.32 (s, Me); 2.85 (d, J ¼ 13.6, 1 H of CH2);
3.39 (d, J ¼ 13.6, 1 H of CH2); 3.51 – 3.62 (m, 1 H of CH2); 3.67 – 3.78 (m, 1 H of CH2); 3.97, 5.10 (2d, J ¼
9.7, CH2); 6.31 (d, J ¼ 3.4, 1 H); 7.04 (d, J ¼ 8.3, 2 arom. H); 7.18 (d, J ¼ 8.3, 2 arom. H); 7.31 – 7.41 (m, 2
arom. H); 7.44 (d, J ¼ 3.4, 1 H); 7.72 – 7.75 (m, 1 arom. H); 7.85 – 7.88 (m, 1 arom. H). 13C-NMR (75 MHz,
CDCl3): 15.4 (Me); 21.7 (Me); 35.1 (CH2); 64.9 (CH2); 78.5 (CH2); 113.4 (CH); 123.8 (CH); 124.4 (C);
125.3 (CH); 126.7 (CH); 127.2 (CH); 127.5 (C); 128.7 (CH); 129.2 (C); 129.4 (CH); 131.5 (CH); 135.3
(C); 140.0 (C); 145.0 (C); 172.9 (C¼O). ESI-MS: 411 ([M þ H]þ). Anal. calc. for C22H22N2O4S: C 64.37,
H 5.40, N 6.82, S 7.81; found: C 64.36, H 5.14, N 6.82, S 7.72.
6-[(Benzyloxy)methyl]-4,6-dihydro-1-[(4-methylphenyl)sulfonyl]pyrrolo[3,2-d][1]benzazepin-
5(1H)-one (15b). Prepared, in analogy to 7, from 14b in 87% yield after FC (SiO2; PE/AcOEt 85 :15).
Solid. M.p. 95 – 968 (PE/AcOEt). IR (KBr): 3125, 3055, 3030, 2935, 1685, 1450, 1375, 1175, 1065, 775, 700,
585, 545. 1H-NMR (300 MHz, CDCl3): 2.22 (s, Me); 2.88, 3.41 (d, J ¼ 13.6, 1 H of CH2); 4.08 (d, J ¼ 9.8,
1 H of CH2); 4.59 (d, J ¼ 12.0, 1 H of CH2); 4.74 (d, J ¼ 12.0, 1 H of CH2); 5.13 (d, J ¼ 9.8, 1 H of CH2);
6.32 (d, J ¼ 3.4, 1 H); 6.97 (d, J ¼ 8.3, 2 arom. H); 7.16 (d, J ¼ 8.3, 2 arom. H); 7.29 – 7.40 (m, 7 arom. H);
7.44 (d, J ¼ 3.4, 1 H); 7.73 – 7.76 (m, 1 arom. H); 7.86 – 7.89 (m, 1 arom. H). 13C-NMR (75 MHz, CDCl3):
21.6 (Me); 35.1 (CH2); 71.7 (CH2); 78.5 (CH2); 113.4 (CH); 123.8 (CH); 124.4 (C); 125.3 (CH); 126.7
(2 CH); 127.2 (CH); 127.4 (C); 127.9 (2 CH); 128.6 (2 CH); 128.8 (CH); 129.2 (C); 129.4 (2 CH); 131.5
(CH); 135.2 (C); 138.0 (C); 139.9 (C); 145.1 (C); 173.1 (C¼O). ESI-MS: 473 ([M þ H]þ). Anal. calc. for
C27H24N2O4S: C 68.63, H 5.12, N 5.93, S 6.79; found: C 68.59, H 5.18, N 5.72, S 6.40.
4,6-Dihydro-1-[(4-methylphenyl)sulfonyl]pyrrolo[3,2-d][1]benzazepin-5(1H)-one (16). Prepared,
in analogy to 1a, from 15a in 42% yield after FC (SiO2; PE/AcOEt 1:1). Solid. M.p. 177 – 179 (MeOH).
IR (KBr): 3445, 3210, 3100, 2985, 1670, 1370, 1180, 1160, 760, 585. 1H-NMR (300 MHz, CDCl3): 2.31 (s,
Me); 2.88 – 2.96 (m, 1 H of CH2); 3.28 – 3.36 (m, 1 H of CH2); 6.28 (d, J ¼ 3.2, 1 H); 6.99 (dd, J ¼ 1.2, 7.8, 1
arom. H); 7.04 (d, J ¼ 8.3, 2 arom. H); 7.14 – 7.17 (m, NH and 2 arom. H); 7.29 – 7.39 (m, 2 arom. H); 7.45
(d, J ¼ 3.2, 1 H); 7.93 (dd, J ¼ 1.6, 7.8, 1 arom. H). 13C-NMR (75 MHz, CDCl3): 21.1 (Me); 34.0 (CH2);
114.8 (CH); 121.7 (C); 122.0 (CH); 122.5 (C); 126.2 (2 CH); 127.2 (C); 127.5 (CH); 128.3 (CH); 129.3
(C); 129.7 (2 CH); 131.0 (CH); 134.1 (C); 135.6 (C); 145.2 (C); 172.8 (C¼O). ESI-MS: 353 ([M þ H]þ).
Anal. calc. for C19H16N2O3S: C 64.76, H 4.58, N 7.95; found: C 65.11, H 4.65, N 8.04.
4,6-Dihydropyrrolo[3,2-d][1]benzazepin-5(1H)-one (2b). A soln. of 15b (47 mg, 0.1 mmol) and
[Pd(OH)2] (50% (w/w); 23 mg) in EtOH/THF 4 :1 (5 ml) was stirred under H2 (1 bar) for 2 h at r.t. After
filtration over Celite and evaporation of the solvent, the crude residue was dissolved in 1,4-dioxane
(4 ml), and then treated with 1n aq. NaOH soln. (1 ml). The mixture was stirred at 808 for 1 h, cooled to
r.t., and treated with H2O (10 ml). The aq. layer was extracted with AcOEt (3 Â 10 ml), the combined
org. extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by
FC (SiO2; CH2Cl2/MeOH 98 :2) to afford 2b (14.3 mg, 72%). Colorless solid. M.p. > 2108 (MeOH). IR
(KBr): 3445, 3210, 3085, 3040, 1641, 1565, 1410, 1145, 755, 730. 1H-NMR (300 MHz, (D6)DMSO): 3.18 (s,
CH2); 6.06 (t, J ¼ 2.5, 1 H); 6.93 (t, J ¼ 2.5, 1 H); 7.13 – 7.23 (m, 3 arom. H); 7.52 (d, J ¼ 7.5, 1 arom. H);
9.86 (s, NH); 11.33 (s, NH). 13C-NMR (75 MHz, (D6)DMSO): 34.6 (CH2); 108.1 (CH); 115.7 (C); 120.3
(CH); 122.0 (CH); 123.4 (CH); 123.5 (C); 125.6 (CH); 125.8 (C); 126.1 (CH); 133.9 (C); 171.7 (C¼O).
ESI-MS: 199 ([M þ H]þ). Anal. calc. for C12H10N2O: C 72.71, H 5.08, N 14.13; found: C 72.99, H 4.88, N
13.91.
Methyl 3-[1-(Ethoxymethyl)-1H-indol-3-yl]propanoate (18). This compound was prepared by the
following three-step sequence. a) At 08 and under N2 atmosphere, NaH (60% dispersion in mineral oil;
390 mg, 9.69 mmol) was added portionwise to a soln. of 1H-indole-3-carbaldehyde (17; 1.08 g, 7.45 mmol)
in anh. THF (35 ml). After 30 min at 08, EtOCH2Cl (1.05 ml, 11.2 mmol) was added dropwise, and the
final soln. was stirred for 2 h at r.t. After addition of H2O (15 ml), the mixture was extracted with CH2Cl2
(3 Â 30 ml), the combined org. extracts were dried (MgSO4), filtered, and concentrated in vacuo. The
crude product was purified by FC (SiO2; PE/AcOEt 8 :2) to afford 1-(ethoxymethyl)-1H-indole-3-
carbaldehyde (1.39 g, 92%). Colorless solid. M.p. 79 – 808 (Et2O). IR (KBr): 3115, 2975, 2880, 2830, 1650,
1530, 1470, 1375, 1245, 1095, 1030, 840, 785, 670. 1H-NMR (300 MHz, CDCl3): 1.18 (t, J ¼ 7.0, Me); 3.48

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Helvetica Chimica Acta – Vol. 90 (2007)
(q, J ¼ 7.0, CH2); 5.56 (s, CH2); 7.33 – 7.38 (m, HÀC(5), HÀC(6)); 7.53 (dd, J ¼ 2.5, 6.0, HÀC(4)); 7.80 (s,
HÀC(2)); 8.31 (dd, J ¼ 2.5, 6.0, HÀC(7)); 10.1 (s, CHO). 13C-NMR (75 MHz, CDCl3): 14.9 (Me); 64.7
(CH2); 76.9 (CH2); 110.8 (CH); 119.0 (C); 122.2 (CH); 123.4 (CH); 124.6 (CH); 125.6 (C); 137.3 (C);
138.3 (CH); 185.0 (CHO). ESI-MS: 204 ([M þ H]þ). Anal. calc. for C12H13NO2: C 70.92, H 6.45, N 6.89;
found: C 70.79, H 6.33, N 6.99.
b) A soln. of 1-(ethoxymethyl)-1H-indole-3-carbaldehyde (1.07 g, 5.28 mmol) and [(ethoxycarbo-
nyl)methylidene]triphenylphosphorane (EtOC(O)C(H)¼PPh3; 3.68 g, 10.57 mmol) in anh. toluene
(50 ml) was heated under reflux overnight. The mixture was poured into H2O (30 ml) and extracted with
AcOEt (3 Â 30 ml). The combined org. extracts were dried (MgSO4), filtered, and concentrated in
vacuo. The crude compound was purified by FC (SiO2; PE/AcOEt 8 :2) to provide methyl (2E)-3-[1-
(ethoxymethyl)-1H-indol-3-yl]prop-2-enoate (1.3 g, 90%). Colorless solid. M.p. 87 – 888 (PE/AcOEt). IR
1
(KBr): 3105, 2975, 2895, 1705, 1635, 1535, 1470, 1370, 1300, 1195, 835, 740, 620. H-NMR (300 MHz,
CDCl3): 1.16 (t, J ¼ 7.2, Me); 1.35 (t, J ¼ 7.2, Me); 3.44 (q, J ¼ 7.2, CH2); 4.27 (q, J ¼ 7.2, CH2); 5.50 (s,
CH2); 6.46 (d, J ¼ 15.8, HC ¼ ); 7.27 – 7.35 (m, 3 arom. H); 7.45 (s, HÀC(2)); 7.53 (d, J ¼ 7.5, HÀC(4));
7.88 (d, J ¼ 15.8, HC¼); 7.94 (d, J ¼ 6.4, HÀC(7)). 13C-NMR (75 MHz, CDCl3): 14.5 (Me); 14.9 (Me);
60.2 (CH2); 64.3 (CH2); 76.3 (CH2); 110.8 (CH); 113.3 (C); 114.0 (CH); 120.7 (CH); 121.9 (CH); 123.5
(CH); 126.6 (C); 132.0 (CH); 137.5 (C); 137.7 (CH); 168.1 (C¼O). ESI-MS: 274 ([M þ H]þ). Anal. calc.
for C16H19NO3: C 70.31, H 7.01, N 5.12; found: C 70.33, H 6.95, N 5.17.
c) A soln. of methyl (2E)-3-[1-(ethoxymethyl)-1H-indol-3-yl]prop-2-enoate (1.21 g, 4.44 mmol) in
MeOH/THF 6 :1 (70 ml) was stirred with a cat. amount of 10% Pd/C (120 mg) in a stainless-steel reactor
under H2 (20 atm) for 3 h at r.t. After filtration over Celite and solvent removal, the crude product was
purified by FC (SiO2; PE/AcOEt 8 :2) to afford 18 (1.21 g, 99%). Oil. IR (NaCl): 2975, 1735, 1465, 1370,
1
1160, 1090, 740. H-NMR (300 MHz, CDCl3): 1.14 (t, J ¼ 7.0, Me); 1.24 (t, J ¼ 7.1, Me); 2.71 (t, J ¼ 7.5,
CH2); 3.09 (t, J ¼ 7.5, CH2); 3.40 (q, J ¼ 7.0, CH2); 4.13 (q, J ¼ 7.1, CH2); 5.45 (s, CH2); 7.00 (s, HÀC(2));
7.15 (dd, J ¼ 7.3, 8.0, HÀC(5)); 7.24 (dd, J ¼ 7.3, 7.9, HÀC(6)); 7.46 (d, J ¼ 8.0, HÀC(4)); 7.59 (d, J ¼ 7.9,
HÀC(7)). 13C-NMR (75 MHz, CDCl3): 14.2 (Me); 14.8 (Me); 20.5 (CH2); 34.8 (CH2); 60.3 (CH2); 63.7
(CH2); 75.7 (CH2); 109.8 (CH); 114.9 (C); 118.9 (CH); 119.7 (CH); 122.2 (CH); 125.3 (CH); 128.4 (C);
136.7 (C); 173.2 (C¼O). ESI-MS: 276 ([M þ H]þ). Anal. calc. for C16H21NO3: C 69.79, H 7.69, N 5.09;
found: C 70.08, H 7.53, N 5.17.
3-[1-(Ethoxymethyl)-1H-indol-3-yl]-N-(2-iodophenyl)propanamide (19). Prepared, in analogy to 5,
from 18 in 92% yield after FC (SiO2; PE/AcOEt 8 :2). Solid. M.p. 114.5 – 115.58 (PE/AcOEt). IR (KBr):
1
3275, 2970, 2910, 1655, 1575, 1525, 1465, 1435, 1355, 1325, 1285, 1200, 1095, 1015, 755, 730. H-NMR
(300 MHz, CDCl3): 1.07 (t, J ¼ 7.0, Me); 2.84 (t, J ¼ 7.4, CH2); 3.23 (t, J ¼ 7.4, CH2); 3.34 (q, J ¼ 7.0, CH2);
5.43 (s, CH2); 6.81 (t, J ¼ 7.5, 1 arom. H); 7.05 (s, HÀC(2)); 7.14 – 7.35 (m, 3 arom. H); 7.47 (d, J ¼ 8.2, 1
arom. H); 7.64 (d, J ¼ 7.8, 1 arom. H); 7.71 (d, J ¼ 7.9, 1 arom. H); 8.22 (d, J ¼ 7.9, 1 arom. H). 13C-NMR
(75 MHz, CDCl3): 14.9 (Me); 21.2 (CH2); 38.4 (CH2); 63.9 (CH2); 75.8 (CH2); 89.9 (C); 110.2 (CH);
114.3 (C); 118.9 (CH); 119.9 (CH); 122.1 (CH); 122.4 (CH); 125.8 (CH); 125.9 (CH); 128.3 (CH); 129.2
(CH); 137.0 (C); 138.2 (C); 138.8 (CH); 170.9 (C¼O). ESI-MS: 449 ([M þ H]þ). Anal. calc. for
C20H21IN2O2: C 53.58, H 4.72, N 6.25; found: C 53.40, H 4.57, N 6.18.
N-(Ethoxymethyl)-3-[1-(ethoxymethyl)-1H-indol-3-yl]-N-(2-iodophenyl)propanamide (20). Pre-
pared, in analogy to 6, from 19 in 63% yield after FC (SiO2; PE/AcOEt 8 :2). Oil. IR (NaCl): 3055,
2975, 2925, 2885, 1665, 1580, 1470, 1380, 1230, 1090, 1015, 740. 1H-NMR (300 MHz, CDCl3): 1.13 (t, J ¼
7.1, Me); 1.20 (t, J ¼ 7.1, Me); 2.37 (t, J ¼ 7.4, CH2); 3.08 (t, J ¼ 7.4, CH2); 3.40 (q, J ¼ 7.1, CH2); 3.64 (q, J ¼
7.1, CH2); 4.41 (d, J ¼ 10.4, 1 H of CH2); 5.40 (s, CH2); 5.69 (d, J ¼ 10.4, 1 H of CH2); 6.91 (s, 1 arom. H);
7.01 – 7.09 (m, 3 arom. H); 7.18 – 7.31 (m, 2 arom. H); 7.36 – 7.44 (m, 2 arom. H); 7.90 (d, J ¼ 7.9, 1 arom.
H). 13C-NMR (75 MHz, CDCl3): 14.9 (Me); 15.2 (Me); 20.7 (CH2); 35.5 (CH2); 63.8 (CH2); 64.6 (CH2);
75.7 (CH2); 76.5 (CH2); 100.5 (C); 109.8 (CH); 115.1 (C); 119.0 (CH); 119.6 (CH); 122.1 (CH); 125.5
(CH); 128.4 (C); 129.5 (CH); 130.0 (CH); 130.9 (CH); 136.7 (C); 139.9 (CH); 143.3 (C); 173.3 (C¼O).
ESI-MS: 507 ([M þ H]þ). Anal. calc. for C23H27IN2O3: C 54.55, H 5.37, N 5.53; found: C 54.79, H 5.21, N
5.70.
5,13-Bis(ethoxymethyl)-5,7,8,13-tetrahydro-6H-indolo[3,2-e][1]benzazocin-6-one (21). Prepared, in
analogy to 7, from 20 in 82% yield after FC (SiO2; PE/AcOEt 8 :2). Solid. M.p. 158 – 1598 (PE/AcOEt).
IR (KBr): 3035, 2970, 2880, 1660, 1495, 1465, 1400, 1170, 1090, 1060, 745. 1H-NMR (300 MHz, CDCl3):

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0.86 (t, J ¼ 7.0, Me); 1.15 (t, J ¼ 7.0, Me); 2.40 – 2.47 (m, 1 H of CH2); 2.84 – 2.95 (m, CH2); 3.03 – 3.10 (m,
1 H of CH2); 3.29 – 3.54 (m, 2 CH2); 5.04 (s, CH2); 5.13, 5.26 (d, J ¼ 10.5, CH2); 7.15 – 7.26 (m, 1 arom. H);
7.43 – 7.62 (m, 7 arom. H). 13C-NMR (75 MHz, CDCl3): 15.0 (Me); 15.2 (Me); 22.4 (CH2); 31.8 (CH2);
63.9 (CH2); 64.4 (CH2); 73.1 (CH2); 76.8 (CH2); 109.7 (CH); 114.1 (C); 119.0 (CH); 120.5 (CH); 123.3
(CH); 127.2 (CH); 127.5 (CH); 128.3 (C); 129.9 (CH); 130.9 (C); 132.4 (C); 132.7 (CH); 137.7 (C); 141.8
(C); 174.5 (C¼O). ESI-MS: 379 ([M þ H]þ). Anal. calc. for C23H26N2O3: C 72.99, H 6.92, N 7.40; found:
C 73.30, H 7.12, N 7.55.
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Received January 17, 2007