Incorporation of an indole-containing diarylbutylamine pharmacophore into furo[2,3-a]carbazole ring systems

Article abstract of DOI:10.1016/j.tet.2004.12.049

Due to concurrent oxidation of the indole moiety in the starting carbazole alkenol, an epoxidation route aiming at incorporation of a conformationally constrained diarylbutylamine failed to give the desired furo[2,3-a]carbazole ring system. Instead, an in

Full text of DOI:10.1016/j.tet.2004.12.049

Tetrahedron 61 (2005) 1715–1722
Incorporation of an indole-containing diarylbutylamine
pharmacophore into furo[2,3-a]carbazole ring systems
*
Faye Maertens, Suzanne Toppet, Georges J. Hoornaert and Frans Compernolle
Laboratorium voor Organische Synthese, K.U.Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 6 October 2004; revised 15 December 2004; accepted 21 December 2004
Available online 15 January 2005
Abstract—Due to concurrent oxidation of the indole moiety in the starting carbazole alkenol, an epoxidation route aiming at incorporation of
a conformationally constrained diarylbutylamine failed to give the desired furo[2,3-a]carbazole ring system. Instead, an indole epoxide
intermediate was generated, which underwent rearrangement involving participation of a vicinal OH group. The required furo[2,3-a]-
carbazole could, however, be accessed via a Hg2C-induced cyclisation of a carbazole alkynol.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we reported the synthesis of various indeno-
[1,2-b]furan, indeno[1,2-b]pyran, naphtho[1,2-b]furan and
benzo[h]chromene ring systems 3 encompassing a confor-
mationally constrained diarylbutylamine pharmacophore.1
This is a general approach for improving the binding affinity
and selectivity of neurotransmitter ligands to receptor
molecules. Specifically, these compounds can be viewed
as constrained analogues of dopamine receptor ligands 1
and the antihistamine difenhydramine 2.2–4
Since the indole moiety is an essential feature of many
bioactive molecules, we conceived target structures of
furo[2,3-a]carbazole5 type 4 as constrained analogues of
2-indolylbutylamines. Similar to the strategy used for the
synthesis of tricycic compounds 3, our present approach
(Scheme 1) involves regioselective opening of the epoxide
ring in precursor 5 by the tertiary alcohol centre. This
precursor in its turn may be derived from the 2-alkenyl
substituted b-keto-ester 6 via sequential Grignard reaction
and epoxidation.
Scheme 1.
2. Results and discussion
six-membered ring ketone 8,6 which was N-methylated to
give compound 9.7,8 b-Keto ester 10 was prepared by
Our synthetic approach required the preparation of the
carbazole alkenol precursor 12 (Scheme 2). An acid-
treatment of 9 with potassium hydride and dimethyl
catalysed ring closure of 3-indolebutyric acid afforded the
carbonate.9 Subsequent allylation gave the 2-allyl-1-oxo-
1H-carbazole-2-carboxylate 11, which was submitted to a
Keywords: Heterocyclic compounds; Epoxidation; Indole; Bromo-
Grignard reaction with freshly prepared PhMgBr. Following
cyclisation.
chromatographic purification alcohol 12 was isolated as the
major diastereoisomer with a d.e. of 46%.
* Corresponding author. Tel.: C32 16 32 74 07; fax: C32 16 32 79 90;
e-mail: frans.compernolle@chem.kuleuven.ac.be
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.049

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F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
finding suggested the existence of the ring-opened indolone
structures 16 and 17, which could be formed via an acid-
catalysed retro-aldol reaction of b-hydroxy ketone 14. The
resulting enol intermediate 15 then would be converted into
the corresponding ketone 16 or oxidized to yield the 2-OH
product 17.
Scheme 2. Reagents and conditions: (a) PPA, toluene, 110 8C; (b) KOH,
MeI, acetone; (c) KH, (CH3O)2CO, reflux; (d) NaH, allyl bromide, DMF;
(e) PhMgBr, THF, K78 8C.
A NOESY analysis of 12 reveals a trans-diaxial orientation
of the phenyl and allyl groups. NOEs are observed between
H-20 of the allyl group and both H-3eq and H-4ax. Proton
H-10b shows a NOE with H-4ax, while H-10a correlates with
the tertiary alcohol proton (see geometrically optimised
conformation, Fig. 1). These findings confirm the (Ph, allyl)
trans-diaxial relation of the major product, in agreement
with our previous report regarding the diastereoselectivity
of the Grignard reaction in similar systems.10
Scheme 3. Initially suggested course of MCPBA oxidation.
Surprisingly, the HMBC spectra of the two indolone
products revealed a correlation between the N-methyl
protons (dZ3.17) and one of the carbonyl groups (dZ
176.9). This finding clearly is not consistent with 3-indolone
structures 16 and 17, but rather with the analogous 2-indo-
lone products 21 and 22. Actually these 2-indolones also
may be generated via initial epoxidation of the indole
moiety to form epoxide 18 (Scheme 4).
Figure 1. Geometrically optimised conformation of 12.
Alkenol 12 was submitted to reaction with m-chloroper-
benzoic acid (MCPBA) but the two major products isolated
from the reaction mixture clearly were not the expected
epoxide or ring-closed product. Indeed, tetrahydrocarbazole
derivatives have been reported to give 2,2-spiro-annulated
3-indolone products upon oxidation with MCPBA. Appar-
ently, these 3-indolones are generated via a pinacol-type
rearrangement, which involves a ring contraction of the
3-hydroxyindolium intermediate.11
Scheme 4. Actual course of MCPBA oxidation.
A further literature search indeed revealed that both 2- and
3-indolones can be generated upon epoxidation of 2,3-
disubstituted indoles.12–15 Instead of being converted to the
stabilised 3-hydroxyindolium ion 13 (see Scheme 3 before),
the protonated epoxide intermediate 19 is subject to an
alternative ring cleavage process, which is assisted by the
vicinal OH group. The resulting enol intermediate 20 is then
Initially, we assumed that hydroxylation at the 3-position of
the indole moiety of 12 would trigger a similar rearrange-
ment of the cation intermediate 13 to form the spiro product
14 (Scheme 3). For both compounds the presumed spiro
structure, however, was refuted based on the observation of
three carbonyl signals in each of the 13C NMR spectra. This

F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
1717
converted into the corresponding lactam carbonyl product
21 or can be further oxidized to give the 3-OH product 22.
Cyclopentaindole 28 was generated from alcohol 25 by an
acid-catalysed dismutation reaction: the benzylic cation
produced from 25 (molecular mass 291) is subject to an
intermolecular hydride transfer to form the reduced product
28 (CIMS: MHC 276) together with an unstable oxidation
product (CIMS: MHC 290) that was not further
characterized.
At this point we wanted to examine further the mechanistic
course of this rearangement reaction including the role of
the vicinal hydroxyl group and the ring size of the ring
annulated onto the indole moiety. To this end, cyclopenta-
indoles 25 and 28 were prepared and submitted to reaction
with MCPBA. For compound 25, one expects a similar OH-
assisted epoxide cleavage process as observed for tetra-
hydrocarbazole 12 (see Scheme 4 before). With the latter
compound 28, however, any assistance by the (non-existent)
neighbouring OH-group is precluded, while the rearrange-
ment proceeding by ring contraction of an indolium ion
intermediate appears unlikely since this now would produce
a highly strained 4-membered spirocycle (Fig. 2).
Compound 28 also was made to react with MCPBA but this
reaction resulted in yet another rearrangement affording an
8-membered ring keto lactam, dihydrobenzo[b]azocine-2,6-
dione 29 (Scheme 6). The latter may be formed by addition
of MCPBA to the 3-hydroxyindolium intermediate 31
generated from epoxide 30, followed by expulsion of
m-chlorobenzoic acid from adduct 32. Hence the
3-hydroxyindolium ion 31 generated from cyclopentaindole
28 is unable to form a strained 4-membered spirocycle, in
contrast to the carbazole 3-hydroxyindolium ion, which
rearranges into a less strained 5-membered spirocycle.11
Figure 2. Tetrahydrocyclopentaindole derivatives 25 and 28 and possible
outcome of MCPBA oxidation of 28.
The required tertiary alcohol 25 was synthesised (Scheme 5)
by double a-methylation of cyclopentaindolone 23 followed
by Grignard reaction on ketone 24.9 Subsequent oxidation
with MCPBA afforded the 2-indolone product 26 and the
spiro-annulated 2-indolone 27. The 2-indolone structures
were confirmed by their HMBC spectra, which again
revealed a correlation between the N-Me protons and the
lactam carbonyl group. This result provides further support
to the vicinal OH-assisted epoxide cleavage process
depicted in Scheme 4. In this case, further oxidation
proceeding at the 3-position of the enolic intermediate
intially yields the 3-hydroxy-2-indolone product 27a, but
the g-hydroxy ketone moiety of 27a transforms into a five-
membered spirocycle to yield two epimeric hemiacetals 27.
Scheme 6. Reagents and conditions: (a) PTSA, toluene, reflux; (b)
MCPBA, CH2Cl2.
There is ample precedent for the oxidative cleavage of the
indole ring system to form the corresponding keto amide,
for example, tryptophan has been converted into a mixture
of products which included N-formylkynurenine,16 whereas
tetrahydrocarbazole and the octahydroindolo[2,3-a]quino-
lizine ring system afforded the corresponding nine-mem-
bered ring keto-lactams.17,18
The keto lactam structure of 29 is indicated by two relevant
carbonyl signals in the IR (1666, 1596 cmK1) and 13C NMR
spectra (d 198.4, 172.2). The correlations found in the
HMBC spectrum confirm the proposed 8-membered keto
lactam ring. Thus, amide carbon C-2 (dZ172.2) couples
with the protons of the N-Me group (dZ3.34) and with H-3
(dZ3.95), while H-3 in its turn correlates with the two
Me carbon atoms located on C-4 (dZ25.9 and 26.4) and
with C-5 (dZ57.2). Finally, the ketone carbon atom C-6
(dZ198.4) couples with both methylene protons H-5 (dZ
3.11 and 2.62).
Turning back to the synthesis of the required furo[2,3-a]-
carbazole ring system we submitted alkenol 12 to reaction
with iodine and NaHCO3 in dichloromethane, but this
attempted halocyclisation method also failed. Therefore,
a new approach was investigated (Scheme 7), which
involved the Hg2C-induced cyclisation19,20 of the 1-phenyl,
Scheme 5. Reagents and conditions: (a) KH, MeI, DMF, 70 8C; (b)
PhMgBr, THF, K78 8C; (c) MCPBA, CH2Cl2.

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F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
2-propynyl substituted carbazolol 34. This alkynol starting
material was prepared by alkylation of b-keto ester 10 with
3-bromo-1-propyne, followed by a Grignard reaction of 33
with PhMgBr.
spectrum indeed revealed a correlation between the protons
of the methyl ester and the ortho-protons of the phenyl
group. This is consistent with a pseudo-equatorial ester and
a pseudo-axial phenyl group, in accordance with a
geometrically optimised model of 36 (Fig. 3).
3. Conclusions
The indole moiety of 2-allyl-2,3,4,9-tetrahydro-1H-carba-
zol-1-ol 12 appears to be more reactive towards oxidation
with m-chloroperbenzoic acid than the sidechain allyl
group. Consequently, an attempted epoxidation of alkenol
12 was found to result in the formation of an indole epoxide
intermediate, which is subject to a further vicinal OH-
assisted rearrangement to form the corresponding ring-
opened 2-indolone products. The mechanistic course of
this rearrangement was checked by studying the MCPBA
oxidation of two analogous alkenyl substituted cyclopenta-
indoles, with and without the neighbouring OH-group.
Finally, we did succeed in the synthesis of the desired
furo[2,3-a]carbazole ring system encompassing a confor-
mationally constrained diarylalkylamine. This was accom-
plished by applying a Hg2C-induced cyclisation to alkynol
34, and by further manipulation of the resulting bromo
alkene 35.
Scheme 7. Reagents and conditions: (a) NaH, 3-bromo-1-propyne, HMPA,
THF, K10 8C; (b) PhMgBr, THF, K78 8C, d.e.Z98%; (c) HgCl2, NBS,
DMAP, CH2Cl2; (d) PTSA, H2O, THF, 80 8C; (e) Et3N, Me2NH$HCl,
THF/MeOH (2:1).
4. Experimental
4.1. General
Alkynol 34 was formed with a very high diastereoisomeric
excess (d.e.Z98%) and was submitted to reaction with
HgCl2, NBS, and DMAP in dichloromethane affording the
2-(bromomethylene) substituted hexahydro-3aH-furo[2,3-a]-
carbazole 35. In the next step, an acid-catalysed hydration
was effected on the enol–ether moiety of hydrofuran
compound 35 to give the epimeric cyclic hemiacetals 36.
Final substitution of the hidden a-bromo ketone group with
dimethylamine furnished the corresponding epimeric
amines 37.
Infrared spectra were recorded on a Perkin–Elmer 1600
Fourier transform spectrometer. Mass spectra were run
using a Hewlett–Packard MS-Engine 5989A apparatus for
EI and CI spectra, and a Kratos MS50TC instrument for
exact mass measurements performed in the EI mode at a
resolution of 10,000. For the NMR spectra (d, ppm) a
Bruker AMX 400 and a Bruker Avance 300 spectrometer
were used. For column chromatography 70–230 mesh silica
60 (E.M. Merck) was used as the stationary phase. For the
synthesis of 2,3,4,9-tetrahydro-1H-carbazol-1-one 8: see
Ref. 5, for the synthesis of 9-methyl-2,3,4,9-tetrahydro-1H-
carbazol-1-one 9, methyl 9-methyl-1-oxo-2,3,4,9-tetrahy-
dro-1H-carbazole-2-carboxylate 10 and 4-methyl-1,4-dihy-
drocyclopenta[b]indol-3(2H)-one 23 see Ref. 8. Chemicals
received from commercial sources were used without
further purification. THF was dried with sodium and
distilled before use.
A NOESY analysis of the epimeric mixture of compounds
36 confirmed their common cis-fusion to be expected from
the structure of the starting alkynol 34. The NOESY
4.2. Synthesis of 11 and 12
4.2.1. Methyl 2-allyl-9-methyl-1-oxo-2,3,4,9-tetrahydro-
1H-carbazole-2-carboxylate (11). A solution of 10 (1.0 g,
3.4 mmol) in DMF (40 mL) was added to a mixture of
sodium hydride (0.32 g, 8 mmol, 60% dispersion in mineral
oil) in DMF (30 mL). After stirring at room temperature for
15 min, allyl bromide (0.44 mL, 5 mmol) was added. The
reaction mixture was stirred for 3 h, and then water (50 mL)
was added. The aqueous layer was extracted three times
with dichloromethane. The combined organic phases were
washed with brine, dried with MgSO4, filtered and
Figure 3. Conformational structure calculated for one epimer of 36 and
corresponding NOE interactions.

F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
1719
evaporated. The residue was purified by column chroma-
tography (silica gel, heptane/ethyl acetate, 23/2). Yield:
82%; oil; IR (NaCl, cmK1): 1732 (C]O), 1659 (C]O); 1H
NMR (300 MHz, CDCl3): 2.26 (m, 1H, CH2CH]CH2),
2.95–2.68 (m, 3H, two H3CCH2CH]CH2), 3.07 (m, 2H,
H4), 3.72 (s, 3H, OCH3), 4.08 (s, 3H, NCH3), 5.16 (d, JZ10,
1 Hz, 1H, CH]CH2), 5.20 (dd, JZ17, 1 Hz, 1H,
CH]CH2), 5.90 (m, 1H, CH]CH2), 7.16 (t, JZ8 Hz,
1H, H-arom.), 7.36 (d, JZ8 Hz, 1H, H-arom.), 7.41 (t, JZ
8 Hz, 1H, H-arom.), 7.64 (d, JZ8 Hz, 1H, H-arom.); 13C
NMR (75 MHz, CDCl3): 19.2, 32.0, 23.7, 39.2, 52.9, 59.1,
110.8, 119.2, 120.7, 121.8, 124.9, 127.4, 127.4, 128.8,
130.0, 134.2, 172.6, 189.0; m/z (E.I., %): 297 (22, M%C),
226 (5, M%CKOCH3), 256 (98, M%CKCH2CH]CH2), 224
(100, M%CKCH2CH]CH2–MeOH); exact mass calculated
for C18H19NO3: 297.1365, found: 297.1360.
4.3.1. Methyl 2-benzoyl-2-[2-(1-methyl-2-oxo-2,3-dihy-
dro-1H-indol-3-yl)ethyl]-4-pentenoate (21). Mixture of
isomers (50/50); yield: 20%; oil; IR (NaCl, cmK1): 1732
1
(C]O), 1713 (C]O), 1679 (C]O); H NMR (400 MHz,
CDCl3): 1.68 (m, 1H, –CH2–), 2.16–1.81 (m, 3H, –CH2–),
2.79 (m, 2H, CH2CH]CH2), 3.16 (s, 1.5H, NCH3), 3.17 (s,
1.5H, NCH3), 3.38 (m, 1H, H3), 3.59 (s, 1.5H, OCH3), 3.61
(s, 1.5H, OCH3), 4.99 (m, 2H, CH]CH2), 5.52 (m, 1H,
CH]CH2), 6.78 (m, 2H, H-arom.), 7.21 (m, 2H, H-arom.),
7.35 (m, 2H, H-arom.), 7.51 (m, 1H, H-arom.), 7.71 (dd, JZ
7, 1 Hz, 1H, H-arom.), 7.77 (dd, JZ7, 1 Hz, 1H, H-arom.);
13C NMR (100 MHz, CDCl3): 23.6, 24.3, 26.0, 26.1, 27.7,
28.4, 36.8, 36.9, 44.9, 45.0, 52.3, 60.4, 107.8, 107.9, 119.2,
119.3, 122.2, 123.2, 123.5, 127.7, 127.8, 127.9, 128.1,
128.2, 128.5, 131.6, 131.8, 132.6, 132.7, 135.6, 135.7,
144.4, 173.1, 173.2, 176.8, 176.9, 196.1, 196.2; m/z (E.I.,
%): 391 (18, M%C), 360 (2, M%CKOCH3), 105 (100,
C6H5CO), 77 (44, C6HC5 ); exact mass calculated for
C24H25NO4: 391.1784, found: 391.1780.
4.2.2. Methyl 2-allyl-1-hydroxy-9-methyl-1-phenyl-
2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (12).
Bromobenzene (0.64 mL, 6 mmol) was added dropwise to
magnesium turnings (0.16 g, 5 mmol) and a crystal of iodine
in dry THF (30 mL) under argon. After being refuxed for
60 min, the mixture was cooled down to K78 8C. Then a
solution of 11 (0.79 g, 3 mmol) in dry THF (50 mL) was
added. After stirring at room temperature for 16 h, NH4Cl
(sat. aq. solution, 50 mL) was added. The aqueous layer was
extracted three times with dichloromethane. The combined
organic phases were dried with MgSO4, filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, heptane/ethyl acetate, 23/2). Yield:
78%, d.e.Z46%.
4.3.2. Methyl 2-benzoyl-2-[2-(3-hydroxy-1-methyl-2-
oxo-2,3-dihydro-1H-indol-3-yl)ethyl]-4-pentenoate (22).
Yield: 64%; oil; IR (NaCl, cmK1): 3331 (OH), 1739
1
(C]O), 1698 (C]O), 1672 (C]O); H NMR (400 MHz,
CDCl3): 1.70 (m, 1H, –CH2–), 2.01–1.78 (m, 3H, –CH2–),
2.74 (d, JZ7 Hz, 2H, CH2CH]CH2), 3.14 (s, 3H, OCH3),
3.57 (s, 3H, NCH3), 4.90 (d, JZ17 Hz, 1H, CH]CH2), 4.95
(d, JZ10 Hz, 1H, CH]CH2), 5.39 (m, 1H, CH]CH2),
6.81 (d, JZ7 Hz, 1H, H-arom.), 7.06 (t, JZ7 Hz, 1H,
H-arom.), 7.32 (m, 4H, H-arom.), 7.48 (t, JZ7 Hz, 1H,
H-arom.), 7.71 (dd, JZ7, 1 Hz, 2H, H-arom.); 13C NMR
(100 MHz, CDCl3): 25.8, 26.2, 32.2, 36.9, 52.3, 60.1, 76.1,
108.6, 119.4, 123.1, 123.7, 128.1, 128.5, 129.4, 129.7,
130.1, 131.4, 132.8, 133.2, 135.6, 143.3, 173.0, 177.8,
195.9; m/z (E.I., %): 407 (17, M%C), 389 (1, M%CKH2O),
159 (43, C12H1C5), 105 (100, C6H5COC), 77 (C6HC5 ); exact
mass calculated for C24H15NO5: 407.1733, found:
407.1730.
Major isomer methyl (1R*,2R*)-2-allyl-1-hydroxy-9-
methyl-1-phenyl-2,3,4,9-tetrahydro-1H-carbazole-2-car-
boxylate. Mp 144–146 8C; IR (KBr, cmK1): 3492 (OH),
1713 (C]O); 1H NMR (400 MHz, CDCl3): 2.09 (ddd, JZ
15, 6, 2 Hz, 1H, H3), 2.22 (dddd, JZ15, 12, 6, 1 Hz, 1H,
H3), 2.58 (dd, JZ14, 8 Hz, 1H, CH2CH]CH2), 2.85 (ddd,
JZ17, 12, 6 Hz, 1H, H4), 2.92 (ddd, JZ17, 6, 2 Hz, 1H,
H4), 3.11 (ddd, JZ14, 6, 1 Hz, 1H, CH2CH]CH2), 3.42 (s,
6H, OCH3CNCH3), 4.42 (s, 1H, OH), 5.09 (d, JZ10 Hz,
1H, CH]CH2), 5.15 (d, JZ16 Hz, 1H, CH]CH2), 5.68
(m, 1H, CH]CH2), 7.07 (m, 2H, H-arom.), 7.13 (m, 1H,
H-arom.), 7.22 (m, 5H, H-arom.), 7.58 (d, JZ8 Hz, 1H,
H-arom.); 13C NMR (100 MHz, CDCl3): 16.9, 23.6, 31.2,
36.0, 51.7, 56.6, 77.9, 109.2, 110.4, 118.5, 118.7, 118.9,
121.9, 125.7, 127.2, 127.5, 127.6, 134.3, 134.6, 138.3,
142.3, 175; m/z (E.I., %): 375 (100, M%C), 343 (13,
4.4. Synthesis of 24 and 25
4.4.1. 2,2,4-Trimethyl-1,4-dihydro-2H-cyclopenta[b]-
indol-3-one (24). A solution of 23 (3 g, 16.2 mmol) in
DMF (30 mL) was added to a mixture of potassium hydride
(35% dispersion in mineral oil, 5.6 g, 48.6 mmol) in DMF
(20 mL) at 0 8C. After stirring at room temperature for
15 min, MeI (3.0 mL, 48.6 mmol) was added dropwise. The
reaction mixture was stirred at 70 8C for 2 h, then ice water
(50 mL) was added. The aqueous layer was extracted three
times with diethyl ether. The combined organic phases were
dried with Na2SO4, filtered and evaporated. The residue was
purified by column chromatography (silica gel, heptane/
ethyl acetate, 23/2). Yield: 71%; mp 64–65 8C; IR (KBr,
M
M
%CKMeOH), 298 (5, M%CKH2O–CO2CH3), 249 (84,
%CKH2O–MeOH–HOCO2CH3).
4.3. Synthesis of 21 and 22
1
cmK1): 1676 (CO); H NMR (400 MHz, CDCl3): 1.33 (s,
MCPBA (0.6 g, 3.47 mmol) was added to a solution of 12
(0.44 g, 1.17 mmol) in dichloromethane (40 mL). After
stirring at room temperature for 20 min, Na2CO3 (sat. aq.
solution, 50 mL) was added. The aqueous layer was
extracted three times with dichloromethane. The combined
organic phases were dried with Na2SO4, filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, heptane/ethyl acetate, 1/1) to give
0.10 g of 21 and 0.31 g of 22.
6H, 2!CH3), 2.96 (s, 2H, H1), 3.94 (s, 3H, NCH3), 7.19
(ddd, JZ8, 7, 1 Hz, 1H, H-arom.), 7.05 (m, 2H, H-arom.),
7.68 (dd, JZ8, 1 Hz, 1H, H-arom.); 13C NMR (100 MHz,
CDCl3): 26.2, 30.5, 36.9, 52.0, 110.4, 111.3, 120.5, 122.2,
123.6, 125.7, 127.1, 137.3, 141.6, 145.6, 200.6; m/z (E.I.,
%): 213 (100, M%C), 198 (72, M%CKCH3), 184 (18, M%CK
CHO), 181 (14, M%CKCH3O), 170 (16, M%CKCH3–CO),
144 (22, C10H10NC); exact mass calculated for C14H15NO:
213.1154, found: 213.1163.

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F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
4.4.2. 2,2,4-Trimethyl-3-phenyl-1,2,3,4-tetrahydrocyclo-
penta[b]indol-3-ol (25). Bromobenzene (0.52 mL,
4.9 mmol) was added dropwise to magnesium turnings
(0.15 g, 4.4 mmol) and a crystal of iodine in dry THF
(10 mL) under argon. After being refluxed for 60 min, the
mixture was cooled down to K78 8C. Then a solution of 24
(0.6 g, 2.8 mmol) in dry THF (20 mL) was added. After
stirring at room temperature for 16 h, NH4Cl (sat. aq.
solution, 50 mL) was added. The aqueous layer was
extracted three times with dichloromethane. The combined
organic phases were dried with MgSO4, filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, heptane/ethyl acetate, 23/2). Yield:
64%; mp 121–129 8C; IR (KBr, cmK1): 3521 (OH), 2659
(CH2); 1H NMR (300 MHz, CDCl3): 0.90 (s, 3H, CH3), 1.47
(s, 3H, CH3), 2.30 (s, 1H, OH), 2.84 (d, JZ15 Hz, 1H, H1),
2.94 (d, JZ15 Hz, 1H, H1), 3.58 (s, 3H, NCH3), 7.49–7.24
(m, 8H, H-arom.), 7.70 (d, JZ8 Hz, 1H, H-arom.); 13C
NMR (75 MHz, CDCl3): 25.1, 28.3, 31.0, 39.3, 54.2, 85.3,
110.4, 118.8, 119.8, 120.2, 122.1, 124.5, 127.0, 127.7,
128.4, 142.1, 142.5, 146.2; m/z (E.I., %): 291 (65, M%C),
273 (21, M%CKH2O), 258 (11, M%CKH2O–CH3), 248
(100, M%CKC3H7), 231 (17, M%CKC3H8O), 77 (13,
C6HC5 ); exact mass calculated for C20H21NO: 291.1623,
found: 291.1656.
H-arom.), 7.54–7.76 (m, 3H, H-arom.); 13C NMR
(100 MHz, CDCl3): 23.3, 23.4, 26.7, 27.0, 27.4, 28.9,
48.5, 49.1, 49.4, 50.0, 82.4, 83.4, 108.4, 109.4, 110.8, 111.1,
123.7, 124.3, 125.2, 125.8, 126.4, 127.2, 127.7, 127.9,
128.0, 128.1, 128.2, 128.7, 129.8, 130.4, 130.6, 132.7,
139.9, 140.7, 144.0, 144.1, 172.3, 177.1, 180.5; m/z (E.I.,
%): 323 (13, M%C), 267 (58, M%CK2!CO), 201 (61,
M
%CKC6H5CO2), 105 (100, C6H5COC), 77 (50, C6HC5 ).
4.6. Synthesis of 28 and 29
4.6.1. 2,2,4-Trimethyl-3-phenyl-1,2,3,4-tetrahydrocyclo-
penta[b]indole (28). PTSA (0.6 g, 0.3 mmol) was added to
a solution of 25 (0.19 g, 0.7 mmol) in toluene (10 mL). The
reaction mixture was refluxed for 1 h and was worked up by
addition of water (10 mL). The aqueous layer was extracted
three times with dichloromethane. The combined organic
phases were dried with Na2SO4, filtered and evaporated.
The residue was purified by column chromatography (silica
gel, heptane/ethyl acetate, 19/1). Yield: 52%; oil; IR (NaCl,
1
cmK1): 2954 (CH2); H NMR (300 MHz, CDCl3): 0.85 (s,
3H, CH3), 1.46 (s, 3H, CH3), 2.75 (d, JZ15 Hz, H1), 2.86
(d, JZ15 Hz, H1), 3.43 (s, 3H, NCH3), 4.00 (s, 1H, H3),
7.36–6.87 (m, 8H, H-arom.), 7.57 (d, JZ7 Hz, 1H,
H-arom.); 13C NMR (75 MHz, CDCl3): 27.3, 31.0, 32.7,
40.4, 50.3, 56.8, 109.9, 117.1, 119.3, 120.6, 150.0, 127.0,
128.7, 129.0, 132.8, 141.2, 141.7, 146.6; m/z (E.I., %): 275
(100, M%C), 260 (11, M%CKCH3), 232 (56, M%CKC3H7),
217 (16, M%CKC4H10), 184 (22, C14H14N); exact mass
calc. for C20H21N: 275.1674, found: 275.1680.
4.5. Synthesis of 26 and 27
MCPBA (0.18 g, 1.02 mmol) was added to a solution of 25
(0.10 g, 0.34 mmol) in dichloromethane (10 mL). After
stirring at room temperature for 20 min, Na2CO3 (sat. aq.
solution, 10 mL) was added. The aqueous layer was
extracted three times with dichloromethane. The combined
organic phases were dried with Na2SO4, filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, heptane/ethyl acetate, 3/22) to give
0.019 g of 26 and 0.068 g of 27.
4.6.2. 1,4,4-Trimethyl-3-phenyl-4,5-dihydro-1H,3H-
benzo[b]azocine-2,6-dione (29). MCPBA (0.047 g,
0.27 mmol) was added to a solution of 28 (0.025 g,
0.09 mmol) in dichloromethane (10 mL). After stirring at
room temperature for 20 min, Na2CO3 (sat. aq. solution,
10 mL) was added. The aqueous layer was extracted three
times with dichloromethane. The combined organic phases
were dried with Na2SO4, filtered and evaporated. The
residue was purified by column chromatography (silica gel,
heptane/ethyl acetate,1/4). Yield: 76%; mp 40–42 8C; IR
(KBr, cmK1): 2931 (CH2), 1666 (CO), 1596 (CO); 1H NMR
(400 MHz, CDCl3): 0.74 (s, 3H, CH3), 1.06 (s, 3H, CH3),
2.62 (d, JZ14 Hz, 1H, CH2), 3.11 (d, JZ14 Hz, 1H, CH2),
3.34 (s, 3H, NCH3), 3.95 (s, 1H, CHPh), 7.15 (m, 3H,
H-arom.), 7.19 (dt, JZ7, 2 Hz, 1H, H-arom.), 7.36 (dt, JZ7,
1 Hz, 1H, H-arom.), 7.44 (m, 2H, H-arom.), 7.53 (dt, JZ8,
2 Hz, 1H, H-arom.), 8.08 (dd, JZ8, 1 Hz, 1H, H-arom.); 13C
NMR (100 MHz, CDCl3): 25.9, 26.4, 37.5, 38.9, 53.7, 57.2,
77.9, 127.4, 127.7, 127.9, 128.0, 131.3, 131.8, 134.7, 135.3,
144.7, 172.2, 198.4; m/z (E.I., %): 307 (56, M%C), 267 (29,
4.5.1. 3-(2,2-Dimethyl-3-oxo-3-phenylpropyl)-1-methyl-
1,3-dihydroindol-2-one (26). Yield: 18%; mp 95–97 8C;
1
IR (KBr, cmK1): 2987 (CH2), 1715 (CO), 1613 (CO); H
NMR (400 MHz, CDCl3): 1.49 (s, 3H, CH3), 1.50 (s, 3H,
CH3), 2.28 (dd, JZ19, 6 Hz, 1H, CH2), 2.51 (dd, JZ19,
9 Hz, 1H, CH2), 3.19 (s, 3H, NCH3), 3.48 (dd, JZ9, 6 Hz,
1H, H3), 6.80 (d, JZ10 Hz, 1H, H-arom.), 7.03 (t, JZ
10 Hz, 1H, H-arom.), 7.25 (m, 2H, H-arom.), 7.42 (m, 3H,
H-arom.), 7.66 (2!d, JZ9 Hz, 2H, H-arom.); 13C NMR
(100 MHz, CDCl3): 26.6, 26.7, 27.8, 41.6, 43.0, 47.8, 108.2,
122.8, 124.9, 128.2, 128.3, 128.4, 130.2, 131.1, 139.5,
144.5, 178.5, 209.4; m/z (E.I., %): 307 (8, M%C), 267 (16,
M
%CKC2O), 201 (23, M%CKC6H5COH), 160 (91, M%CK
H2CO–C6H5CO), 105 (100, C6H5COC), 77 (56, C6H5C).
M
%CKC2O), 201 (32, M%CKC6H5COH), 189 (89, M%CK
C6H5CH2CO), 105 (100, C6H5COC), 77 (65, C6H5C).
4.5.2. Spiro compound 27. Mixure of isomers (60/40);
yield: 62%; mp 136–140 8C; IR (KBr, cmK1): 3398 (OH),
2960 (CH2), 1703 (CO); 1H NMR (400 MHz, CDCl3): 0.99
(s, 1.2H, CH3), 1.08 (s, 1.8H, CH3), 1.34 (s, 1.8H, CH3),
1.38 (s, 1.2H, CH3), 2.20 (d, JZ13 Hz, 0.4H, CH2), 2.38 (d,
JZ13 Hz, 0.6H, CH2), 2.67 (d, JZ13 Hz, 0.6H, CH2), 2.71
(d, JZ13 Hz, 0.4H, CH2), 2.22 (s, 1.8H, NCH3), 3.23 (s,
1.2H, NCH3), 6.80 (d, JZ8 Hz, 0.6H, H-arom.), 6.88 (d,
JZ8 Hz, 0.4 H, H-arom.), 7.09 (t, JZ7 Hz, 0.6H, H-arom.),
7.19 (t, JZ7 Hz, 0.4H, H-arom.), 7.32–7.43 (m, 4H,
4.7. Synthesis of furo[2,3-a]carbazole compounds
4.7.1. Methyl 9-methyl-1-oxo-2-(2-propynyl)-2,3,4,9-
tetrahydro-1H-carbazole-2-carboxylate (33). A solution
of 10 (1.3 g, 5 mmol) in THF (30 mL) was added dropwise
to a mixture of sodium hydride (60% dispersion in mineral
oil, 0.27 g, 6.5 mmol) in THF (30 mL) at K10 8C. After
stirring at room temperature for 1 h, HMPA (0.89 mL,
5 mmol) and propargyl bromide (80 wt%, 0.74 mL,

F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
1721
6.5 mmol) were added. The reaction mixture was stirred at
room temperature for 2 h, then NH4Cl (sat. aq. solution,
20 mL) was added. The aqueous layer was extracted three
times with dichloromethane. The combined organic phases
were dried with MgSO4, filtered and evaporated. The
residue was purified by column chromatography (silica gel,
heptane/ethyl acetate, 22/3). Yield: 98%; mp 88–91 8C; IR
(KBr, cmK1): 3270 (C^CH), 1735.5 (C]O), 1660
54%; mp 37–39 8C; IR (KBr, cmK1): 2942 (CH2), 1729
(CO); H NMR (400 MHz, CDCl3): 2.08 (ddd, JZ15, 5,
1
2 Hz, 1H, H4), 2.57 (ddd, JZ15, 12, 6 Hz, 1H, H4), 2.79
(ddd, JZ17, 12, 5 Hz, 1H, H5), 2.90 (dd, JZ16, 2 Hz, 1H,
H3), 3.07 (d, JZ16 Hz, 1H, H3), 3.16 (ddd, JZ17, 6, 2 Hz,
1H, H5), 3.25 (s, 3H, OCH3), 3.35 (s, 3H, NCH3), 4.97 (s,
1H, ]CHBr), 7.60–7.09 (m, 9H, H-arom.); 13C NMR
(100 MHz, CDCl3): 17.3, 25.4, 30.6, 35.2, 51.8, 56.9, 88.7,
109.1, 109.3, 111.1, 119.0, 119.1, 122.4, 122.7, 125.2,
127.9, 128.1, 128.3, 133.2, 138.3, 138.7, 156.0, 172.7; m/z
(E.I., %): 451C453 (8, M%C), 372 (4, M%CKHBr), 340 (13,
1
(C]O); H NMR (300 MHz, CDCl3): 2.07 (t, JZ3 Hz,
1H, C^CH), 2.60 (ddd, JZ14, 10, 6 Hz, 1H, H3), 2.76
(ddd, JZ14, 10, 5 Hz, 1H, H3), 2.96 (d, JZ3 Hz, 2H,
CH2C^CH), 3.16 (m, 2H, H4), 3.72 (s, 3H, OCH3), 4.09 (s,
3H, NCH3), 7.18 (dt, JZ7, 1 Hz, 1H, H-arom.), 7.31 (d, JZ
8 Hz, 1H, H-arom.), 7.44 (dt, JZ7, 1 Hz, 1H, H-arom.),
7.65 (d, JZ8 Hz, 1H, H-arom.); 13C NMR (75 MHz,
CDCl3): 19.3, 24.9, 32.0, 32.8, 53.2, 58.4, 71.7, 70.4,
110.8, 120.7, 121.9, 124.9, 127.7, 129.4, 129.8, 140.8,
171.8, 187.4; m/z (E.I., %): 295 (43, M%C), 256 (100,
M
%CKHBr–MeOH), 312 (12, M%CKHBr–HCO2CH3);
exact mass calculated for C24H22O3NBr: 451.0783 and
453.0763, found: 451.0793 and 453.0760.
4.7.4. Methyl (3aS*,10bR*)-2-(bromomethyl)-2-
hydroxy-10-methyl-10b-phenyl-2,3,4,5,10,10b-hexa-
hydro-3aH-furo[2,3-a]carbazole-3a-carboxylate (36). To
a solution of 35 (0.30 g, 0.66 mmol) in THF (20 mL) was
added PTSA (0.019 g, 0.10 mmol) and a few drops of water.
After stirring at 80 8C for 12 h, the solvent was evaporated
and the residue purified by column chromatography (silica
gel, heptane/CH2Cl2, 3/7). Yield: 45%, mp 81–82 8C; IR
(KBr, cmK1): 2946 (OH), 1703 (CO); 1H NMR (400 MHz,
CDCl3): 2.03 (ddd, JZ15, 6, 1 Hz, 1H, H4), 2.52 (ddd, JZ
15, 12, 6 Hz, 1H, H4), 2.55 (d, JZ14 Hz, 1H, H3), 2.67 (d,
JZ14 Hz, 1H, H3), 2.81 (ddd, JZ17, 12, 6 Hz, 1H, H5),
2.88 (d, JZ10 Hz, 1H, CH2Br), 3.07 (ddd, JZ17, 6, 1 Hz,
1H, H5), 3.13 (s, 3H, OCH3), 3.29 (s, 3H, NCH3), 3.32 (d,
JZ10 Hz, 1H, CH2Br), 6.40 (d, JZ1 Hz, 1H, OH), 6.70 (d,
JZ7 Hz, 1H, H-arom.), 7.29–7.11 (m, 5H, H-arom.), 7.40
(t, JZ7 Hz, 1H, H-arom.), 7.59 (d, JZ8 Hz, 1H, H-arom.),
7.81 (d, JZ8 Hz, 1H, H-arom.); 13C NMR (100 MHz,
CDCl3): 17.2, 24.8, 30.6, 38.6, 41.9, 52.5, 60.6, 87.5, 104.4,
109.3, 110.5, 119.0, 122.6, 125.3, 127.2, 128.1, 138.2,
139.7, 176.6; m/z (E.I.,%): 471 (63, M%C), 469 (63, M%C),
389 (20, M%CKHBr), 376 (15, M%CKCH2Br), 371 (7,
M
%CKC3H3), 236 (12, M%CKCO2CH3), 224 (88, M%CK
C3H3–MeOH), 197 (21, M%CKC3H3–CO2CH3); exact
mass calculated for C18H17NO3: 295.1208, found:
295.1203.
4.7.2. Methyl (1R*,2R*)-1-hydroxy-9-methyl-1-phenyl-
2-(2-propynyl)-2,3,4,9-tetrahydro-1H-carbazole-2-car-
boxylate (34). Bromobenzene (1.77 mL, 17 mmol) was
added dropwise to magnesium turnings (0.52 g, 15 mmol)
and a crystal of iodine in dry THF (40 mL) under argon.
After being refluxed for 60 min, the mixture was cooled
down to K78 8C. Then 33 (1.5 g, 5 mmol) in dry THF
(40 mL) was added. After stirring at room temperature for
16 h, NH4Cl (sat. aq. solution, 50 mL) was added. The
aqueous layer was extracted three times with dichloro-
methane. The combined organic phases were dried with
Na2SO4, filtered and evaporated. The residue was puri-
fied by column chromatography (silica gel, heptane/ethyl
acetate, 23/2). Yield: 86%; mp 36–38 8C; IR (KBr, cmK1):
1
2943 (OH), 1712 (CO); H NMR (400 MHz, CDCl3): 2.04
M
%CKHBr–H2O), 257 (100, C19H15NC), 105 (54,
(t, JZ3 Hz, 1H, C^CH), 2.32 (m, 1H, H3), 2.50 (ddd, JZ
15, 6, 2 Hz, 1H, H3), 2.76 (dd, JZ17, 3 Hz, 1H,
CH2C^CH), 2.93 (ddd, JZ17, 11, 6 Hz, 1H, H4), 3.01
(ddd, JZ17, 7, 2 Hz, 1H, H4), 3.34 (ddd, JZ17, 7, 3 Hz,
1H, CH2C^CH), 3.41 (s, 3H, NCH3), 3.48 (s, 3H, OCH3),
4.40 (s, 1H, OH), 7.43–7.06 (m, 8H, H-arom.), 7.60 (d, JZ
8 Hz, 1H, H-arom.); 13C NMR (100 MHz, CDCl3): 17.1,
22.4, 24.2, 31.2, 52.1, 56.5, 71.0, 77.6, 80.8, 118.8, 119.0,
122.1, 126.9, 127.5, 127.7, 128.3, 128.4, 128.5, 129.7,
132.3, 133.9, 138.3, 141.9; m/z (E.I., %): 373 (47, M%C),
341 (3, M%CKMeOH), 296 (7, M%CKC6H5), 268 (24,
C6H5COC); exact mass calculated for C24H24O4NBr:
471.0868 and 469.0889, found: 471.0869 and 469.0913.
4.7.5. Methyl (3aS*,10bR*)-2-[(dimethylamino)methyl]-
2-hydroxy-10-methyl-10b-phenyl-2,3,4,5,10,10b-hexa-
hydro-3aH-furo[2,3-a]carbazole-3a-carboxylate (37). To
a solution of 36 (0.064 g, 1.14 mmol) in THF/MeOH (2:1,
10 mL) was added Me2NH$HCl salt (0.088 g, 1.1 mmol)
and Et3N (0.19 mL, 1.4 mmol). The mixture was stirred at
room temperature for 2 days. Then Na2CO3 (sat. aq.
solution, 15 mL) was added. The aqueous layer was
extracted three times with dichloromethane. The combined
organic phases were dried with Na2SO4, filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, MeOH/CH2Cl2, 1/9). Yield: 53%;
mixture of isomers (50/50); oil; IR (NaCl, cmK1): 2946
M
%CKC7H5O), 250 (100, C17H16NOC), 249 (99,
C17H15NOC), 105 (34, C7H5OC); exact mass calculated
for C24H23NO3: 373.1678, found: 373.1679.
4.7.3. Methyl (3aS*,10bR*)-2-(bromomethylene)-10-
methyl-10b-phenyl-2,3,4,5,10,10b-hexahydro-3aH-
furo[2,3-a]carbazole-3a-carboxylate (35). HgCl2 (0.15 g,
0.55 mmol), NBS (0.20 g, 1.1 mmol) and DMAP (0.27 g,
2.2 mmol) were added to a solution of 34 (0.41 g, 1.1 mmol)
in dichloromethane (40 mL). After being stirred at room
temperature for 13 h, the mixture was filtered. The solids
were washed three times with dichloromethane. The filtrate
was evaporated and the residue purified by column
chromatography (silica gel, heptane/CH2Cl2, 3/7). Yield:
1
(OH), 1727 (CO); H NMR (400 MHz, CDCl3): 2.02 (m,
2H, H4), 2.21 (s, 3H, NCH3), 2.46 (dd, JZ14, 2 Hz, 1H, H3),
2.50 (s, 3H, NCH3), 2.59 (2!d, JZ8 Hz, 1H, H3), 2.80 (d,
JZ13 Hz, 1H, CH2N(CH3)2), 2.90 (m, 1H, H5), 3.04 (2!
dd, JZ4, 2 Hz, 1H, H5), 3.10 (s, 1.5H, OCH3), 3.11 (s, 1.5H,
OCH3), 3.24 (d, JZ13 Hz, 1H, CH2N(CH3)2), 3.26 (s, 1.5H,
NCH3), 3.28 (s, 1.5H, NCH3), 6.71 (d, JZ8 Hz, 1H,
H-arom.), 7.26–7.04 (m, 5H, H-arom.), 7.38 (t, JZ7 Hz,
1H, H-arom.), 7.58 (dd, JZ8, 1 Hz, 1H, H-arom.), 7.84 (d,

1722
F. Maertens et al. / Tetrahedron 61 (2005) 1715–1722
JZ8 Hz, 1H, H-arom.); 13C NMR (100 MHz, CDCl3): 17.2,
17.5, 25.1, 25.8, 30.5, 30.6, 41.9, 42.8, 46.8, 47.1, 51.4,
52.3, 60.0, 60.9, 66.9, 67.6, 86.7, 86.9, 103.9, 106.1, 108.9,
109.1, 110.2, 110.4, 118.6, 118.9, 119.0, 121.8, 122.2,
125.3, 125.4, 125.8, 127.2, 127.6, 127.8, 127.9, 128.1,
134.6, 135.5, 138.1, 140.4, 141.0, 174.6, 176.6; m/z (E.I.,
%): 434 (3, M%C), 416 (2, M%CKH2O), 376 (9, M%CK
CH2N(CH3)2), 316 (4, M%CKCH2N(CH3)2–HCO2CH3),
58 (100, CH2N(CH3)C2 ); exact mass calculated for
C23H30O4N2: 434.2206, found: 434.2217.
Rational Design, Mechanistic Study & Therapeutic Appli-
cation of Chemical Compounds. Pergamon: New York, 1991;
Vol. 3.
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5. For a recent review on furocarbazoles, see Frohner, W.; Krahl,
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8. Buttery, C. D.; Jones, R. G.; Knight, D. W. J. Chem. Soc.,
Perkin Trans. 1 1993, 1425–1432.
9. Maertens, F.; Van den Bogaert, A.; Compernolle, F.;
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Acknowledgements
The authors wish to thank the F.W.O. (Fonds voor
Wetenschappelijk Onderzoek-Flanders) and the Johnson &
Johnson Pharmaceutical Research Foundation for finan-
cial support. They are also grateful to R. De Boer and
K. Duerinckx for mass and NMR measurements.
´
11. Williams, R. M.; Sanz Cervera, J. F.; Sanceron, F.; Marco,
J. A.; Halligan, K. J. Am. Chem. Soc. 1998, 120, 1090–1091.
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