Intramolecular Ritter reactions of 2-(2-cyanoethyl)tetrahydrocyclopenta-[b] indole and -carbazole derivatives

Article abstract of DOI:10.1002/ejoc.200400409

Intramolecular Ritter reactions of 2-(2-cyanoethyl)tetrahydrocyclopenta[b] indole and -carbazole derivatives, prepared by a sequence of two different α-substitutions and Grignard reactions of the indole-based ketones 4-methyl-1,4-dihydrocyclopenta[b]indol-3(2H)-one and 9-methyl-2,3,4,9- tetrahydro-1H-carbazol-1-one, were used as key steps in the construction of various tetracyclic lactam compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400409

FULL PAPER
Intramolecular Ritter Reactions of 2-(2-Cyanoethyl)tetrahydrocyclopenta-
[b]indole and -carbazole Derivatives
Faye Maertens,[a] An Van den Bogaert,[a] Frans Compernolle,*[a] and
Georges J. Hoornaert[a]
Keywords: Carbazoles / Grignard reaction / Heterocyclic compounds / Indoles / Ritter reaction
Intramolecular Ritter reactions of 2-(2-cyanoethyl)tetrahydro- hydro-1H-carbazol-1-one, were used as key steps in the con-
cyclopenta[b]indole and -carbazole derivatives, prepared by
a sequence of two different α-substitutions and Grignard re-
actions of the indole-based ketones 4-methyl-1,4-dihy-
drocyclopenta[b]indol-3(2H)-one and 9-methyl-2,3,4,9-tetra-
struction of various tetracyclic lactam compounds.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
In previous work we reported the synthesis of hexahydro-
indenopyridines of type 1.[1,2] These compounds can be re-
garded as conformationally constrained analogues of the
NK1-antagonists 2 (CP-96345),[3] and 3 (CP-99994),[4] in
which the required 1,2-diamino-1-phenylethane pharmaco-
phore is incorporated in a tricyclic ring system. Further-
more, similar tricyclic diamine compounds with suitable
OH-substitution of the benzene moiety have been conceived
as potential D1-selective dopamine receptor ligands,[5]
characterized by
(hydroxyphenyl)-2-phenethylamino
a
conformationally constrained 2-
pharmacophore.[6]
Successful examples of this general approach in which re-
striction of the bioactive conformation results in improved
binding affinity and selectivity are the highly potent
and selective D1 agonists 4 [(Ϯ)-trans-10,11-dihydroxy-
Figure 1. Structures of diamine model compounds and target com-
pounds
5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine][7]
and
5,[8] in which the 2-(hydroxyphenyl)-2-phenethylamino dop-
amine pharmacophore is embedded in a polycyclic frame-
work (Figure 1).
Since the indole moiety is found in many bioactive mol-
ecules, the indole analogues 6 of tricyclic diamines 1 were
conceived as suitable target compounds of potential interest
as neurotransmitters. For the construction of the six-mem-
bered nitrogen heterocycle of 6 we envisaged an approach
(Scheme 1) similar to that used for tricyclic diamines 1.[1]
Thus, conversion of the indole-based propanenitrile precur-
sors 7 into alcohols 8 and subsequent intramolecular Ritter
reaction should provide access to the tetracyclic ester com-
pounds 9 as key intermediates; on further transformation
Scheme 1. Planned conversion of indole-based precursors 7 into
tetracyclic ester compounds 9[2]
[a]
Laboratorium voor Organische Synthese, Departement Chemie,
K. U. Leuven,
of the angular ester group these could give rise to confor-
mationally constrained indole analogues of various neuro-
transmitters. Here we deal with the sequential application
Celestijnenlaan 200F, 3001 Heverlee, Belgie¨
Fax: (internat.) ϩ 32-16-327990
E-mail: Frans.Compernolle@chem.kuleuven.ac.be
4648
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400409
Eur. J. Org. Chem. 2004, 4648Ϫ4656

Intramolecular Ritter Reactions
FULL PAPER
of Grignard and Ritter reactions to both five- and six-mem- the (OH, CO2Me) trans-disposed alcohol. No elimination
bered indole-based ketones 7.
product was detected under these conditions, although the
yield of 15b was lower (50%) than that obtained for the
combined addition/elimination in THF (60%). Therefore,
elimination probably may also proceed for the (OH,
CO2Me) cis-disposed alcohol if one takes the rather low de
value observed in Et2O into account. Again, suppression
of the elimination reaction may be due to the decreased
nucleophilicity of the O-anion, which forms a tighter ion
pair with the MgXϩ counter-ion in the less polar ether sol-
vent.
Results and Discussion
1. Grignard Reactions on Five- and Six-Membered β-Keto
Esters
The starting five-membered ring ketone 12 [4-methyl-1,4-
dihydrocyclopenta[b]indol-3(2H)-one] was prepared by N-
methylation of 3-indolepropionic acid (10),[9,10] followed by
acid-catalysed cyclisation of 3-(1-methyl-1H-indol-3-yl)pro-
panoic acid (11).[11] Subsequent methoxycarbonylation of
the electron-rich ketone 12 with dimethyl carbonate re-
quired use of a stronger base (KH) than that applied for
the analogous conversion of 1-indanone (NaH).[1] Final
Michael addition of β-keto ester 13 to acrylonitrile in
tBuOH as a solvent and with tBuOK as a base catalyst
afforded the required keto nitrile precursor 14 (Scheme 2).
Scheme 3. Reagents and conditions: (a) PhMgBr, THF, Ϫ78 °C;
(b) PhMgBr, Et2O, Ϫ78 °C, de ϭ 26%.; (c) MeMgBr, THF, Ϫ78
°C; (d) NaBH4, MeOH, phosphate buffer pH ϭ 7, de ϭ 12%
Scheme 2. Reagents and conditions: (a) (i) KOH, MeI, acetone; (ii)
KOH, H2O, reflux; (b) PPA, toluene, 110 °C; (c) KH, (CH3O)2CO,
150 °C; (d) tBuOK, acrylonitrile, tBuOH
Treatment of β-keto ester 14 with methylmagnesium bro-
The Grignard reaction between β-keto ester 14 and mide in THF furnished another alkene compound 15c, cor-
freshly prepared phenylmagnesium bromide at Ϫ78 °C in responding to elimination of the tertiary alcohol but not
THF afforded the cyclopentene product 15a instead of the the ester group. Since the ester is retained a different mecha-
expected tertiary alcohol 15b. Presumably, elimination is nism must apply, such as the formation of a stabilised car-
triggered by transfer of the methyl group of the ester to the bocation upon workup of the reaction mixture. Conversely,
vicinal O-anion centre, followed by expulsion of CO2 and such a stabilised carbocation cannot be an intermediate in
methoxide (Scheme 3). In view of the steric requirements the conversion of tertiary alcohol 15b into cyclopentene
imposed by the two bulky reaction centres, methyl transfer 15a, as it is shown further on that the carbocations formed
may proceed through an internal SN2 attack of the O-anion in the acid-catalysed Ritter reactions of 15b and 15c did not
in a six-membered transition state: for the main dia- lose their ester groups.
stereoisomer with the OH and CO2Me groups in a relative
Finally, reduction of β-keto ester 14 with NaBH4 pro-
trans configuration (see below) this would involve a pseudo- duced a mixture of the diastereoisomeric secondary al-
equatorial orientation of the vicinal substituents, while sub- cohols 15d (Scheme 3).
sequent elimination of the acid and methoxide could pro-
In a manner analogous to that described for the conver-
ceed via a diaxial orientation. Since this ester elimination sion of 3-indolepropionic acid (Scheme 2), 3-indolebutyric
reaction occurs to a much lower extent in the indanol ana- acid 16 was first converted into the corresponding six-mem-
logues obtained from Grignard reactions of the correspond- bered ring ketone 18, which was further transformed into
ing indane β-keto esters,[1] this result may be attributed to the 2-cyanoethyl keto ester 20 (Scheme 4). In this case N-
the enhanced nucleophilic properties of the O-anion formed methylation was carried out on the intermediate six-mem-
from indole keto ester 14. In fact, when the Grignard reac- bered ketone 17,[11] which could easily be isolated by col-
tion of indole keto ester 14 was carried out in Et2O instead umn chromatography, in contrast to the more polar N-un-
of THF, the expected diastereoisomeric alcohols 15b were methylated analogue of the five-membered ring ketone 12.
isolated as the only products with a de value of 26% for A subsequent Grignard reaction with phenylmagnesium
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F. Maertens, A. Van den Bogaert, F. Compernolle, G. J. Hoornaert
FULL PAPER
bromide at Ϫ78 °C in THF now produced a mixture of
alkene 21a and the isomerically pure (OH, CO2Me) trans-
disposed alcohol 21b, while treatment with methylmag-
nesium bromide furnished methylene compound 21c. Re-
duction of 21 with NaBH4 finally afforded the epimeric al-
cohols 21d.
Scheme 4. Reagents and conditions: (a) PPA, toluene, 110 °C, 85%;
(b) KOH, MeI, acetone, 65%; (c) KH, (CH3O)2CO, 150 °C, 74%;
(d) tBuOK, acrylonitrile, tBuOH, 73%; (e) PhMgBr, THF, Ϫ78 °C;
(f) MeMgBr, THF, Ϫ78 °C; (g) NaBH4, MeOH, de ϭ 30%
Scheme 5. Reagents and conditions: (a) CH3SO3H, PhCl, 100 °C;
2. Ritter Reactions
(b) CH3SO3H, as solvent, room temp.
Both the alkene 15a and the tertiary alcohol 15b were
treated with methanesulfonic acid in chlorobenzene at 100
°C to effect cyclisation by an intramolecular Ritter reaction, and 15b and methyl in 15c) may account for the transform-
which involves attack of the nitrile group on a stabilised ation of cation A into C, which, especially at higher tem-
carbocation intermediate (Scheme 5).[12,13] However, ring peratures, occurs more rapidly than the ring closure in the
closure did not occur at the expected 3-position but rather 3-position.
at the 1-position of the tetrahydrocyclopenta[b]indole ring
The relative stereochemistries of the lactams obtained
system. Apparently the initially formed benzylic cation A from the Ritter reactions were revealed by 1H NMR analy-
transforms into a more stable 3-indolylmethyl type cation sis. Thus, compound 22a can be assigned as (10c,4a)-cis,
C: this probably proceeds through loss of a proton at the (4a,5)-trans on the basis of NOE correlations observed in
1
1-position to generate an ortho-quinodimethane intermedi- its H NMR spectrum. A NOE between H-4a and H-10c
ate B.
reveals a cis fusion of the tetracyclic lactam system. The
When methylene compound 15c was subjected to the trans relationship between H-5 and H-4a is demonstrated
same reaction conditions (i.e., heating with methanesulfonic by a NOE between H-5 and one of the 4-methylene protons,
acid in chlorobenzene at 100 °C), ring closure again oc- while the other 4-methylene proton correlates with H-4a
curred exclusively at the 1-position, yielding 22c as a mix- (Figure 2).
ture of diastereoisomers (de ϭ 40%). Under less drastic
Compounds 22b, 22c, 22cЈ and 22d were characterized in
conditions (use of methanesulfonic acid at room tempera- a similar manner by NOESY analysis. In all cases, ring fu-
ture), however, a mixture of lactams 22c and 22cЈ (ring clos- sion proceeds diastereoselectively in cis fashion, due to the
ure at the 3-position) was obtained. Finally, the Ritter reac- favourable syn attack of the nitrile on the planar cation in-
tion of secondary alcohol 15d resulted in exclusive ring clos- termediate. Compound 22c was isolated as a mixture of dia-
ure at the 3-position. In this case direct attack of the nitrile stereoisomers with a de of 40%. NOE difference analysis of
group on the more reactive carbocation A is enhanced over this mixture revealed that, in the major isomer, the 5-methyl
isomerisation into C as there is no substituent in the 3- is cis to proton H-10c and hence also to the ester group.
position to retard cyclisation. Thus, the steric hindrance ex- Indeed, on irradiation at the respective resonance frequenc-
erted by substituents in the 3-position (i.e., phenyl in 15a ies corresponding to the 5-methyl group of each isomer, the
4650
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Intramolecular Ritter Reactions
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Scheme 6. Reagents and conditions: (a) CH3SO3H, PhCl, 100 °C;
Figure 2. NOE correlations in the 1H NMR spectrum of lactam
22a
(b) CH3SO3H, as solvent, room temp.
NOE diff. signals detected for the major isomer were those
for H-5 and H-10c, whereas only the H-5 signal remained
for the minor isomer.
and concomitant ring closure at that site. While cyclopenta-
[b]indole 15c, with a 3-methyl substituent, reveals competi-
tive cyclisation at the 1- and 3-positions, the corresponding
carbazole 21c and the secondary alcohols 15d and 21d ex-
clusively undergo ring closure at the original cation site.
When the Ritter reaction was applied to the six-mem-
bered 2-cyanoethyl-substituted carbazole alcohols, it was to
be expected that cyclisation at the 4-position of the re-
arranged 3-indolylmethyl type cation C to form a bridged
ring system should be less likely to occur. Indeed, treatment
of alkene 21a with methanesulfonic acid in chlorobenzene
at 100 °C did not result in ring closure, but instead yielded
the amides 23 and 24. However, treatment of ester 21b with
methanesulfonic acid at room temperature afforded a 1:1
mixture of the diastereoisomeric bridged compounds 25 re-
sulting from intramolecular attack of the nitrile group at
the 4-position in rearranged cation C. The two diastereoiso-
mers of 25 were separated by column chromatography and
Experimental Section
General Remarks: Infrared spectra were recorded with
a
PerkinϪElmer 1600 Fourier transform spectrometer. Mass spectra
were run with a HewlettϪPackard 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 (δ, ppm) a Bruker AMX 400 and a
Bruker Avance 300 spectrometer were used. For column chroma-
tography 70Ϫ230 mesh silica 60 (E.M. Merck) was used as the
stationary phase. All reagents and solvents were of commercial
1
their structures were assigned by H NMR NOESY analy-
sis. On the other hand, compounds 21c and 21d were con-
verted into lactams 26 and 27, corresponding to direct tilled before use. Some signals in the H NMR spectrum of com-
cyclisation of cation A generated at the 1-position. Presum-
15b, 15d, 22b, 24 are lacking due to the spectral complexity (e.g.,
ably, the benzylic cation A formed from 21b is less reactive
quality. THF, Et2O and toluene were dried with sodium and dis-
1
pound 15b and the 13C NMR spectra of compounds 15c, 21a, 21b,
overlapping signals or the presence of an isomeric mixture).
towards attack of the nitrile, due both to the stabilising ef-
fect of the phenyl group and to its larger steric hindrance
compared to a methyl group or hydrogen.
3-(1-Methyl-1H-indol-3-yl)propanoic Acid (11): KOH (1.78 g,
31.7 mmol) and MeI (1.64 mL, 26.5 mmol) were added at 0 °C to
a solution of indolepropanoic acid (1.0 g, 5.3 mmol) in acetone
(50 mL). The mixture was stirred at room temperature for 4 h, and
the solvent was evaporated. The residue was dissolved in water
(100 mL), and KOH (1.48 g, 26.4 mmol) was added. After having
been heated at reflux for 2 h, the mixture was made acidic with
HCl (6). The precipitate was filtered off and washed with heptane.
The product was purified by crystallization from CH2Cl2/heptane.
Yield: 95%. IR (KBr, cmϪ1): ν˜ ϭ 1710 (s, CϭO). 1H NMR
(400 MHz, [D6]DMSO): δ ϭ 12.04 (s, 1 H, CO2H), 7.52 (d, J ϭ
8 Hz, 1 H, H-arom.), 7.36 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.13 (t,
J ϭ 8 Hz, 1 H, H-arom.), 7.03 (s, 1 H, H-arom.), 7.01 (t, J ϭ
8 Hz, 1 H, H-arom.), 3.72 (s, 3 H, NCH3), 2.92 (t, J ϭ 8 Hz, 2 H,
CH2CH2CO2H), 2.57 (t, J ϭ 8 Hz, 2 H, CH2CO2H) ppm. 13C
Conclusion
Intramolecular Ritter reactions of 2-cyanoethyl-substi-
tuted indole-based alcohols, encompassing cyclopentene- or
cyclohexene-fused ring moieties, were used as key steps in
the construction of lactam compounds serving as precur-
sors to conformationally constrained indole analogues of
NK-1 and dopamine receptor ligands. When phenyl groups
are present in the tertiary alcohol positions of the tricyclic
cyclopenta[b]indole and carbazole substrates, acidic Ritter
reaction conditions result in rearrangement of the original
benzylic cations to form stable 3-indolylmethyl-type cations NMR (100 MHz, [D6]DMSO): δ ϭ 174.1, 136.6, 127.2, 126.6,
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F. Maertens, A. Van den Bogaert, F. Compernolle, G. J. Hoornaert
FULL PAPER
121.0, 118.4, 118.3, 112.7, 109.5, 34.6, 32.2, 20.1 ppm. MS (EI):
°C) for 1 h, and ice-water (100 mL) was then added. The aqueous
layer was extracted three times with CH2Cl2. The combined organic
m/z (%) ϭ 203 (47) [M·ϩ], 185 (3) [M·ϩ Ϫ H2O], 144 (100) [M·ϩ
Ϫ
CH2CO2H]; exact mass calculated for C12H13NO2: 203.0946; phases were dried with MgSO4 and filtered, and the solvents were
found 203.0941.
evaporated. The residue was purified by column chromatography
(silica gel, heptane/ethyl acetate, 7:3).
General Procedure for the Synthesis of 4-Methyl-1,4-dihydrocyclo-
penta[b]indol-3(2H)-one (12) and 2,3,4,9-Tetrahydro-1H-carbazol-1- Methyl 4-Methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-2-car-
one (17): Compound 11 (1 g, 4.95 mmol) or 4-(3-indolyl)butyric
acid 16 (4.95 mmol) was added to a solution of polyphosphoric
acid (PPA) (7.24 g, 73.91 mmol) in toluene (50 mL). The mixture
was stirred at 110 °C for 4 h, and ice-water (100 mL) was added.
The aqueous layer was extracted three times with CH2Cl2. The
combined organic phases were dried with MgSO4 and filtered, and
the solvents were evaporated. The residue was purified by column
chromatography (silica gel, heptane/ethyl acetate, 7:3).
boxylate (13): Yield: 88%. IR (KBr, cmϪ1): ν˜ ϭ 1736.4 (s, CϭO),
1676.9 (s, CϭO). H NMR (400 MHz, CDCl3): δ ϭ 7.66 (dd, J ϭ
1
8, 1 Hz, 1 H, H-arom.), 7.41 (ddd, J ϭ 9, 8, 1 Hz, 1 H, H-arom.),
7.32 (dd, J ϭ 8, 1 Hz, 1 H, H-arom.), 7.17 (ddd, J ϭ 9, 8, 1 Hz, 1
H, H-arom.), 3.97 (dd, J ϭ 7, 3 Hz, 1 H, H2), 3.86 (s, 3 H, OCH3),
3.78 (s, 3 H, NCH3), 3.39 (dd, J ϭ 17, 3 Hz, 1 H, H1), 3.24 (dd,
J ϭ 17, 7 Hz, 1 H, H1) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
187.1, 170.0, 145.3, 144.1, 137.0, 127.3, 122.6, 121.8, 120.4, 110.9,
57.8, 52.5, 29.9, 24.2 ppm. MS (EI) m/z (%) ϭ 243 (75) [M·ϩ], 211
(24) [M·ϩ Ϫ MeOH], 183 (100) [M·ϩ Ϫ HCO2CH3]; exact mass
calculated for C14H13NO3: 243.0895; found 243.0892.
4-Methyl-1,4-dihydrocyclopenta[b]indol-3(2H)-one (12): Yield: 95%.
IR (KBr, cmϪ1): ν˜ ϭ 1970 (s, CϭO). 1H NMR (400 MHz, CDCl3):
δ ϭ 7.70 (dd, J ϭ 8, 1 Hz, 1 H, H-arom.), 7.42 (dt, J ϭ 8, 1 Hz, 1
H, H-arom.), 7.35 (dd, J ϭ 8, 1 Hz, 1 H, H-arom.), 7.17 (dt, J ϭ Methyl
9-Methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazole-2-car-
8, 1 Hz, 1 H, H-arom.), 3.92 (s, 3 H, NCH3), 3.06 (m, 2 H, H2), boxylate (19): Yield: 74%. IR (KBr, cmϪ1): ν˜ ϭ 2958 (s, CH2), 1737
2.98 (m, 2 H, H1) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 194.8, (s, CO), 1666 (s, CO). H NMR (300 MHz, CDCl3): δ ϭ 7.55 (d,
1
145.0, 144.8, 138.9, 126.8, 123.1, 121.7, 120.2, 110.9, 41.2, 30.0,
J ϭ 8 Hz, 1 H, H-arom.), 7.36 (ddd, J ϭ 8, 7, 1 Hz, 1 H, H-arom.),
7.32 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.09 (ddd, J ϭ 8, 7, 1 Hz, 1 H,
H-arom.), 3.95 (s, 3 H, OCH3), 3.77 (s, 3 H, NCH3), 3.59 (dd, J ϭ
9, 4 Hz, 1 H, H2), 3.05 (m, 1 H, H4), 2.90 (m, 1 H, H4), 2.52 (m,
1 H, H3), 2.37 (m, 1 H, H3) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 187.1, 171.4, 140.6, 129.8, 128.7, 126.6, 121.7, 120.7, 119.6,
111.8, 56.5, 51.8, 32.9, 31.0, 30.3 ppm. MS (EI) m/z (%) ϭ 257
(100) [M·ϩ], 226 (5) [M·ϩ Ϫ OCH3], 198 (93) [M·ϩ Ϫ CO2CH3],
183 (28) [M·ϩ Ϫ CO2CH3 Ϫ CH3]; exact mass calculated for
C15H15NO3: 257.1052; found 257.1055.
19.6 ppm. MS (EI): m/z (%) ϭ 185 (100) [M·ϩ], 157 (53) [M·ϩ
Ϫ
CO], 142 (13) [M·ϩ Ϫ CH3 Ϫ CO]; exact mass calculated for
C12H11NO: 185.0841; found 185.0837.
2,3,4,9-Tetrahydro-1H-carbazol-1-one (17): Yield: 85%. IR (NaCl,
1
cmϪ1): ν˜ ϭ 3284 (m, NH), 2930 (s, CH2), 1637 (s, CO). H NMR
(300 MHz, CDCl3): δ ϭ 9.86 (s, 1 H, NH), 7.66 (d, J ϭ 8 Hz, 1 H,
H-arom.), 7.51 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.38 (ddd, J ϭ 8, 7,
1 Hz, 1 H, H-arom.), 7.15 (ddd, J ϭ 8, 7, 1 Hz, 1 H, H-arom.),
3.03 (t, J ϭ 6 Hz, 2 H, H2), 2.71 (t, J ϭ 7 Hz, 2 H, H4), 2.27 (m,
2 H, H3) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 192.2, 138.5, General Procedure for the Synthesis of 14 and 20: tBuOK (0.18 g,
131.6, 130.0, 127.4, 126.3, 121.8, 120.8, 113.0, 38.8, 24.4, 21.8 ppm.
1.6 mmol) and acrylonitrile (0.84 mL, 12.7 mmol) were added to a
solution of 13 (1.5 g, 6.4 mmol) or 19 (6.4 mmol) in tBuOH
MS (EI) m/z (%) ϭ 185 (100) [M·ϩ], 156 (35) [M·ϩ Ϫ CHO], 143
(19) [M·ϩ Ϫ CH2CO], 129 (77) [M·ϩ Ϫ CH2CH2CO], 77 (10) (100 mL). The mixture was stirred at room temperature for 3 h,
[C6H5ϩ]; exact mass calculated for C12H11NO: 185.0841; found and water (70 mL) was then added. The aqueous layer was ex-
185.0841.
tracted three times with CH2Cl2, the combined organic phases were
dried with MgSO4 and filtered, and the solvents were evaporated.
The residue was purified by column chromatography (silica gel,
CH2Cl2/ethyl acetate, 19:1).
9-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (18): KOH (1.64 g,
29.0 mmol) and MeI (1.5 mL, 24.0 mmol) were added at 0 °C to a
solution of 17 (1.8 g, 10.0 mmol) in acetone (100 mL). The mixture
was stirred at room temperature for 2 h, and was then acidified
Methyl
2-(2-Cyanoethyl)-4-methyl-3-oxo-1,2,3,4-tetrahydrocyclo-
with HCl (6N). The aqueous layer was extracted three times with penta[b]indole-2-carboxylate (14): Yield: 70%. IR (NaCl, cmϪ1):
CH2Cl2, the combined organic phases were dried with MgSO4 and
filtered, and the solvents were evaporated. The residue was purified
by column chromatography (silica gel, heptane/ethyl acetate, 1:1).
ν˜ ϭ 2246 (w, CN), 1733 (s, CϭO), 1691 (s, CϭO). 1H NMR
(400 MHz, CDCl3): δ ϭ 7.69 (dd, J ϭ 9, 1 Hz, 1 H, H-arom.), 7.47
(dt, J ϭ 9, 1 Hz, 1 H, H-arom.), 7.38 (dd, J ϭ 9, 1 Hz, 1 H, H-
arom.), 7.21 (dt, J ϭ 9, 1 Hz, 1 H, H-arom.), 3.91 (s, 3 H, NCH3),
Yield: 82%. IR (KBr, cmϪ1): ν˜ ϭ 2932 (s, CH2), 1646 (s, CO). H
1
NMR (300 MHz, CDCl3): δ ϭ 7.66 (d, J ϭ 8 Hz, 1 H, H-arom.), 3.72 (s, 3 H, OCH3), 3.58 (d, J ϭ 17 Hz, 1 H, H1), 3.10 (d, J ϭ
7.40 (m, 2 H, H-arom.), 7.13 (ddd, J ϭ 8,7,1 Hz, 1 H, H-arom.), 17 Hz, 1 H, H1), 2.56 (m, 2 H, CH2CN), 2.42 (m, 2 H,
4.07 (3, s, NCH3), 3.02 (t, J ϭ 6 Hz, 2 H, H2), 2.65 (t, J ϭ 6 Hz, CH2CH2CN) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 188.9,
2 H, H4), 2.22 (q, J ϭ 6 Hz, 2 H, H3) ppm. 13C NMR (75 MHz, 171.1, 145.7, 143.0, 136.7, 127.9, 122.6, 122.0, 120.5, 119.8, 111.2,
CDCl3): δ ϭ 192.7, 140.1, 130.8, 129.6, 127.0, 125.1, 121.7, 120.4,
110.6, 40.4, 31.9, 25.2, 22.2 ppm. MS (EI) m/z (%) ϭ 199 (100)
64.0, 52.9, 31.4, 30.7, 30.2, 13.0 ppm. MS (EI) m/z (%) ϭ 296 (100)
[M·ϩ], 256 (15) [M·ϩ Ϫ CH2CN], 236 (38) [M·ϩ Ϫ HCO2CH3],
[M·ϩ], 170 (40) [M·ϩ Ϫ CHO], 157 (22) [M·ϩ Ϫ CH2CO], 143 (56) 196 (61) [M·ϩ Ϫ HCO2CH3 Ϫ CH2CN]; exact mass calculated for
[M·ϩ Ϫ CH2CH2CO], 77 (7) [C6H5ϩ]; exact mass calculated for
C17H16N2O3: 296.1161; found 296.1161.
C13H13NO: 199.0997; found 199.0996.
Methyl 2-(2-Cyanoethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-car-
bazole-2-carboxylate (20): Yield: 73%. IR (KBr, cmϪ1): ν˜ ϭ 2243
General Procedure for the Synthesis of Methyl 4-Methyl-3-oxo-
1,2,3,4-tetrahydrocyclopenta[b]indole-2-carboxylate (13) and Methyl (w, CN), 1727 (s, CϭO), 1660 (s, CϭO). 1H NMR (300 MHz,
9-Methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (19): CDCl3): δ ϭ 7.63 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.40 (ddd, J ϭ 8,
A solution of 12 (1 g, 5.4 mmol) or 18 (5.4 mmol) in dimethyl car-
7, 1 Hz, 1 H, H-arom.), 7.36 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.15
bonate (50 mL) was added dropwise at 0 °C to a mixture of KH (ddd, J ϭ 8, 7, 1 Hz, 1 H, H-arom.), 4.05 (s, 3 H, OCH3), 3.72 (s,
(35% dispersion in mineral oil, 1.4 g, 11.9 mmol) in dimethyl car-
bonate (70 mL). The mixture was heated at reflux temperature (150
3 H, NCH3), 3.08 (t, J ϭ 6 Hz, 2 H, H4), 2.63 (m, 3 H, 1H3
ϩ2CH2CN), 2.30 (m, 3 H, 1H3 ϩ2CH2CH2CN) ppm. 13C NMR
4652
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4648Ϫ4656

Intramolecular Ritter Reactions
FULL PAPER
(100 MHz, CDCl3): δ ϭ 188.3, 172.2, 140.9, 129.7, 129.0, 126.7,
14 (4.3 g, 15 mmol) in dry Et2O (100 mL) was added. The stirred
122.8, 121.9, 120.7, 119.9, 111.9, 85.1, 52.2, 31.1, 29.3, 19.2, 17.5, reaction mixture was allowed to come to room temperature over-
13.9 ppm. MS (EI) m/z (%) ϭ 310 (100) [M·ϩ], 256 (74) [M·ϩ
CH2CH2CN], 251 (75) [M·ϩ Ϫ CO2CH3], 224 (83) [M·ϩ
Ϫ
night (16 h), and NH4Cl (satd. aq. solution, 150 mL) was added.
The aqueous layer was extracted three times with CH2Cl2. The
combined organic phases were dried with Na2SO4 and filtered, and
Ϫ
CH2CH2CN Ϫ MeOH], 197 (15) [M·ϩ Ϫ MeOH Ϫ CO2 Ϫ CHϭ
CHCN], 182 (13) [M·ϩ Ϫ MeOH Ϫ CO2 Ϫ CHϭCHCN Ϫ CH3]; the solvents were evaporated. The residue was purified by column
exact mass calculated for C18H18N2O3: 310.1317; found 310.1320.
chromatography (silica gel, CH2Cl2/ethyl acetate, 19:1). Yield: 50%;
mixture of diastereoisomers, de ϭ 26%. IR (NaCl, cmϪ1): ν˜ ϭ 2247
(w, CN), 1732 (s, CϭO). 1H NMR (300 MHz, CDCl3): δ ϭ
7.73Ϫ7.22 (m, 18 H major, minor isomer, H-arom.), 4.15 (dd, J ϭ
11, 3 Hz, 1 H major isomer, CH2CH2CN), 4.00 (dd, J ϭ 11, 3 Hz,
1 H minor isomer, CH2CH2CN), 3.85 (dd, J ϭ 16, 4 Hz, 1 H minor
isomer, CH2CN), 3.80 (s, 3 H major isomer, NCH3), 3.70 (dd, J ϭ
16, 4 Hz, 1 H major isomer, CH2CN), 3.55 (s, 3 H minor isomer,
NCH3), 3.18 (s, 3 H major isomer, OCH3), 3.07 (s, 3 H minor
isomer, OCH3), 3.31Ϫ2.18 (m, 4 H, 2CH2CH2CN major, minor
isomer ϩ 2CH2CN major, minor isomer ϩ 4 H1 major, minor iso-
mer) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 139.5, 139.3, 130.4,
130.3, 130.0, 129.3, 128.3, 127.9, 127.8, 126.5, 126.3, 126.2, 125.6,
125.5, 125.1, 124.1, 121.6, 121.5, 121.4, 121.3, 120.9, 120.8, 119.4,
118.9, 110.9, 110.8, 53.0, 52.6, 52.3, 43.4, 40.6, 40.5, 30.6, 30.2,
30.0, 29.9, 25.6, 25.1 ppm MS (EI): m/z (%) ϭ 374 (24) [M·ϩ], 248
General Procedure for the Synthesis of 15a, 21a and 21b: Bromoben-
zene (2.7 mL, 26 mmol) was added dropwise under argon to a
stirred mixture of magnesium turnings (0.8 g, 23 mmol) and a iod-
ine crystal in dry THF (50 mL). The mixture was heated at reflux
for 1 h, and was then cooled to Ϫ78 °C and a solution of 14
(4.3 g,15 mmol) or 20 (15 mmol) in THF (100 mL) was added. The
reaction mixture was allowed to come to room temperature over-
night (16 h), and NH4Cl (satd. aq. solution, 150 mL) was added.
The aqueous layer was extracted three times with CH2Cl2. The
combined organic phases were dried with Na2SO4, and filtered, and
the solvents were evaporated. The residue was purified by column
chromatography (silica gel, CH2Cl2/ethyl acetate, 19:1).
3-(4-Methyl-3-phenyl-1,4-dihydrocyclopenta[b]indol-2-yl)propane-
1
nitrile (15a): Yield: 60%. IR (NaCl, cmϪ1): ν˜ ϭ 2250 (w, CN). H
(100) [M·ϩ Ϫ CH2CN Ϫ HCO2CH3 Ϫ C2H4], 235 (93) [M·ϩ
Ϫ
NMR (400 MHz, CDCl3): δ ϭ 7.38Ϫ7.58 (m, 9 H, H-arom.), 3.41
(s, 2 H, H1), 3.40 (s, 3 H, NCH3), 2.75 (t, J ϭ 7 Hz, 2 H, CH2CN),
2.48 (t, J ϭ 7 Hz, 2 H, CH2CH2CN) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 142.5, 141.0, 129.2, 128.6, 128.5, 128.0, 125.1, 123.7,
120.1, 119.6, 118.0, 115.1, 109.8, 33.5, 30.6, 25.4, 18.1 ppm. MS
(EI) m/z (%) ϭ 298 (39) [M·ϩ], 258 (100) [M·ϩ Ϫ CH2CN], 243
(15) [M·ϩ Ϫ CH2CH2CN]; exact mass calculated for C21H18N2:
298.1471; found 298.1469.
CH2CH2CN Ϫ CO2CH3 Ϫ C2H2], 105 (65) [C6H5COϩ], 77 (38)
[C6H5ϩ]; exact mass calculated for C23H22N2O3: 374.1630; found
374.1634.
General Procedure for the Synthesis of 15c and 21c: MeMgBr (22
wt-% in THF, 7.82 mL, 23 mmol) was added at Ϫ78 °C under ar-
gon to a stirred solution of 14 (4.3 g, 15 mmol) or 20 (15 mmol) in
dry THF (100 mL). After further reaction at room temperature for
16 h, NH4Cl (satd. aq. solution, 150 mL) was added. The aqueous
layer was extracted three times with CH2Cl2. The combined organic
phases were dried with Na2SO4 and filtered, and the solvents were
evaporated. The residue was purified by column chromatography
(silica gel, CH2Cl2/ethyl acetate, 19:1).
3-(9-Methyl-1-phenyl-4,9-dihydro-3H-carbazol-2-yl)propanenitrile
1
(21a): Yield: 20%. IR (NaCl, cmϪ1): ν˜ ϭ 2246 (w, CN). H NMR
(300 MHz, CDCl3): δ ϭ 7.61 (dt, J ϭ 6, 1 Hz, 1 H, H-arom.), 7.50
(m, 3 H, H-arom.), 7.36 (dt, J ϭ 6, 1 Hz, 2 H, H-arom.), 7.19 (m,
3 H, H-arom.), 3.03 (s, 3 H, NCH3), 3.02 (m, 2 H, H4), 2.58 (m, 4
H, H3, CH2CH2CN), 2.43 (m, 2 H, CH2CN) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 131.2, 130.0, 128.9, 128.7, 126.3, 125.9,
123.5, 122.7, 120.4, 120.2, 119.7, 119.6, 118.9, 110.9, 109.7, 109.2,
32.0, 29.5, 20.5, 19.6, 16.8 ppm.
Methyl 2-(2-Cyanoethyl)-4-methyl-3-methylene-1,2,3,4-tetrahydro-
cyclopenta[b]indole-2-carboxylate (15c): Yield: 33%. IR (KBr,
cmϪ1): ν˜ ϭ 2244 (w, CN), 1722 (s, CϭO). 1H NMR (300 MHz,
CDCl3): δ ϭ 7.52 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.29 (m, 2 H, H-
arom.), 7.13 (ddd, J ϭ 8, 6, 2 Hz, 1 H, H-arom.), 5.44 (d, J ϭ
1 Hz, 1 H, ϭCH2), 5.05 (d, J ϭ 1 Hz, 1 H, ϭCH2), 3.84 (s, 3 H,
NCH3), 3.74 (s, 3 H, OCH3), 3.56 (d, J ϭ 16 Hz, 1 H, H3), 2.84
(d, J ϭ 16 Hz, 1 H, H3), 2.34 (m, 4 H, CH2CH2CN, CH2CN) ppm.
13C NMR (75 MHz, CDCl3): 174.5, 144.1, 143.9, 141.1, 124.2,
123.7, 123.4, 120.3, 120.2, 119.9, 110.0, 102.6, 61.3, 53.1, 34.4, 33.2,
31.1, 13.2 ppm. MS (EI) m/z (%) ϭ 294 (70) [M·ϩ], 254 (100) [M·ϩ
Methyl (1R*,2R*)-2-(2-Cyanoethyl)-1-hydroxy-9-methyl-1-phenyl-
2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (21b): Yield: 53%.
IR (KBr, cmϪ1): ν˜ ϭ 3420 (b, OH), 2246 (w, CN), 1704 (s, CϭO).
1H NMR (300 MHz, CDCl3): δ ϭ 7.64 (d, J ϭ 8 Hz, 1 H, H-
arom.), 7.43Ϫ7.18 (m, 8 H, H-arom.), 6.10 (s, 1 H, OH), 3.86 (s, 3
H, OCH3), 3.51 (s, 3 H, NCH3), 3.05 (ddd, J ϭ 17, 6, 2 Hz, 1 H,
H4), 2.95 (ddd, J ϭ 17, 11, 6 Hz, 1 H, H4), 2.76 (ddd, J ϭ 17, 9,
6 Hz, 1 H, CH2CN), 2.47 (ddd, J ϭ 17, 9, 7 Hz, 1 H, CH2CN),
2.32 (ddd, J ϭ 14, 6, 2 Hz, 1 H, H3), 2.19 (ddd, J ϭ 14, 11, 6 Hz,
1 H, H3), 1.95 (ddd, J ϭ 15, 9, 7 Hz, 1 H, CH2CH2CN), 1.86 (ddd,
J ϭ 15, 9, 6 Hz, 1 H, CH2CH2CN) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 177.9, 140.9, 138.9, 137.9, 130.1, 128.5, 126.3, 122.6,
120.7, 120.0, 119.6, 119.2, 115.9, 110.8, 109.8, 78.9, 55.1, 54.1, 53.3,
31.3, 30.8, 19.2, 14.4 ppm. MS (EI) m/z (%) ϭ 388 (100) [M·ϩ],
371 (8) [M·ϩ Ϫ OH], 312 (10) [M·ϩ Ϫ OH Ϫ CO2CH3], 105 (90,)
[C6H5COϩ], 77 (63) [C6H5ϩ]; exact mass calculated for
C24H24N2O3: 388.1787; found 388.1793.
Ϫ CH2CN], 241 (25) [M·ϩ Ϫ CH2ϭCHCN], 235 (13) [M·ϩ
Ϫ
CO2CH3], 194 (58) [M·ϩ Ϫ HCO2CH3 Ϫ CH2CN]; exact mass cal-
culated for C18H18N2O2: 294.1368; found 294.1362.
Methyl 2-(2-Cyanoethyl)-9-methyl-1-methylene-2,3,4,9-tetrahydro-
1H-carbazole-2-carboxylate (21c): Yield: 33%. IR (KBr, cmϪ1): ν˜ ϭ
1
2242 (w, CN), 1717 (s, CϭO). H NMR (400 MHz, CDCl3): δ ϭ
7.51 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.28 (m, 2 H, H-arom.), 7.12
(ddd, J ϭ 8, 6, 1 Hz, 1 H, H-arom.), 5.50 (s, 1 H, ϭCH2), 5.08 (s,
1 H, ϭCH2), 3.85 (s, 3 H, NCH3), 3.74 (s, 3 H, OCH3), 3.04 (dt,
J ϭ 17, 6 Hz, 1 H, H4), 2.83 (ddd, J ϭ 17, 9, 6 Hz, 1 H, H4), 2.57
(m, 2 H, 1H3 ϩ1CH2CN), 2.43 (ddd, J ϭ 17, 10, 6 Hz, 1 H,
Methyl 2-(2-Cyanoethyl)-3-hydroxy-4-methyl-3-phenyl-1,2,3,4-tetra-
hydrocyclopenta[b]indole-2-carboxylate
(2.7 mL, 26 mmol) was added dropwise to a stirred mixture of mag-
nesium turnings (0.8 g, 23 mmol) and an iodine crystal in dry Et2O 1 H, H3) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 174.4, 139.8,
(15b):
Bromobenzene CH2CN), 2.28 (ddd, J ϭ 14, 10, 6 Hz, 1 H, CH2CH2CN), 2.19
(ddd, J ϭ 14, 10, 6 Hz, 1 H, CH2CH2CN), 2.00 (dt, J ϭ 14, 6 Hz,
(50 mL) under argon. After having been heated at reflux tempera-
138.0, 137.7, 125.9, 123.3, 119.6, 119.5, 119.0, 113.0, 109.5, 109.4,
ture for 1 h, the mixture was cooled to Ϫ78 °C, and a solution of
52.7, 52.3, 32.4, 31.0, 30.3, 18.2, 13.5 ppm. MS (EI) m/z (%) ϭ 308
Eur. J. Org. Chem. 2004, 4648Ϫ4656
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4653

F. Maertens, A. Van den Bogaert, F. Compernolle, G. J. Hoornaert
FULL PAPER
(93) [M·ϩ], 277 (7) [M·ϩ Ϫ OCH3], 248 (28) [M·ϩ Ϫ HCO2CH3], (400 MHz, CDCl3): δ ϭ 7.51 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.31 (d,
220 (13) [M·ϩ Ϫ HCO2CH3 Ϫ C2H4], 195 (23) [M·ϩ Ϫ CH2CH2CN J ϭ 8 Hz, 1 H, H-arom.), 7.27 (t, J ϭ 8 Hz, 1 H, H-arom.), 7.12
Ϫ CO2CH3], 167 (100) [M·ϩ Ϫ CH2CH2CN Ϫ CO2CH3 Ϫ C2H4], (t, J ϭ 8 Hz, 1 H, H-arom.), 4.88 (d, J ϭ 8 Hz, 1 H, H1), 3.86 (s,
77 (14) [C6H5ϩ]; exact mass calculated for C19H20N2O2: 308.1525;
found 308.1536.
3 H, OCH3), 3.80 (s, 3 H, NCH3), 2.92 (ddd, J ϭ 17, 6, 3 Hz, 1 H,
H4), 2.62 (ddd, J ϭ 17, 11, 6 Hz, 1 H, H4), 2.51 (d, J ϭ 8 Hz, 1 H,
OH), 2.44Ϫ2.22 (m, 3 H, 2CH2CN, 1 H3), 2.14 (ddd, J ϭ 15, 6,
3 Hz, 1 H, H3), 2.05 (dt, J ϭ 15, 7 Hz, 1 H, CH2CH2CN), 1.90
(ddd, J ϭ 15, 9, 7 Hz, 1 H, CH2CH2CN) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 174.6, 138.0, 133.0, 125.7, 122.7, 119.3,
119.0, 118.7, 110.0, 109.3, 67.4, 52.5, 52.0, 29.4, 28.5, 22.8, 17.4,
13.5 ppm.
Methyl
2-(2-Cyanoethyl)-3-hydroxy-4-methyl-1,2,3,4-tetrahydro-
cyclopenta[b]indole-2-carboxylate (15d): NaBH4 (0.046 g, 1.2 mmol)
was added to a solution of 14 (0.36 g, 1.2 mmol) in a 3:1 mixture
of MeOH/phosphate buffer (pH ϭ 7, 50 mL) at 0 °C. The mixture
was stirred at 0 °C for 1 h, and NH4Cl (satd. aq. solution, 50 mL)
was added. The aqueous layer was extracted three times with
CH2Cl2. The combined organic phases were dried with Na2SO4
and filtered, and the solvents were evaporated. The residue was
purified by column chromatography (silica gel, CH2Cl2/ethyl acet-
ate, 19:1). Yield: 49%; mixture of diastereoisomers, de ϭ 12%. IR
General Procedure A for the Ritter Reaction with CH3SO3H and
Chlorobenzene at 100 °C: The alcohol or alkene (5 mmol) was dis-
solved in a chlorobenzene/CH3SO3H mixture (1:1, 20 mL). The
mixture was stirred at 100 °C for 4 h, and ice-water (50 mL) was
added. The aqueous layer was extracted three times with CH2Cl2.
The combined organic phases were dried with MgSO4 and filtered,
and the solvents were evaporated. The residue was purified by col-
umn chromatography (silica gel, eluent: see data of individual com-
pounds).
1
(KBr, cmϪ1): ν˜ ϭ 3397 (b, OH), 2251 (w, CN), 1730 (s, CϭO). H
NMR (300 MHz, CDCl3): δ ϭ 7.47 (dd, J ϭ 8, 1 Hz, 1 H, H-
arom.), 7.33Ϫ7.06 (m, 3 H, H-arom.), 5.60 (d, J ϭ 8 Hz, 0.56 H,
H1), 5.11 (d, J ϭ 8 Hz, 0.44 H, H1), 3.80 (s, 1.32 H, NCH3), 3.76
(s, 1.68 H, NCH3), 3.75 (s, 1.32 H, OCH3), 3.72 (s, 1.68 H, OCH3),
3.58 (d, J ϭ 15 Hz, 0.44 H, H3), 3.41 (d, J ϭ 15 Hz, 0.56 H, H3),
2.93 (d, J ϭ 8 Hz, 1 H, OH), 2.87 (d, J ϭ 15 Hz, 0.44 H, H3), 2.72
(d, J ϭ 15 Hz, 0.56 H, H3), 2.57Ϫ2.17 (m, 4 H, CH2CH2CN) ppm. General Procedure B for the Ritter Reaction with CH3SO3H at
13C NMR (100 MHz, CDCl3): δ ϭ 175.9, 174.2, 144.2, 144.1, 143.6, Room Temperature: The alcohol or alkene (5 mmol) was dissolved
143.5, 142.5, 142.4, 142.2, 142.1, 123.7, 123.6, 122.6, 122.5, 120.2, in CH3SO3H (20 mL) at 0 °C. The mixture was stirred at room
120.0, 119.7, 119.6, 117.7, 117.6, 110.5, 110.3, 64.1, 62.9, 53.1, 53.0,
temperature for 8 h, and ice-water (50 mL) was added. The aque-
ous layer was extracted with CH2Cl2. The combined organic phases
33.7, 33.6, 30.9, 30.8, 30.3, 14.3, 14.1 ppm. MS (EI) m/z (%) ϭ 298
(100) [M·ϩ], 280 (9) [M·ϩ Ϫ H2O], 267 (7) [M·ϩ Ϫ OCH3], 198 (39) were dried with MgSO4 and filtered, and the solvents were evapo-
[M·ϩ Ϫ HCO2CH3 Ϫ CH2CN], 184 (12) [M·ϩ Ϫ HCO2CH3
Ϫ
rated. The residue was purified by column chromatography (silica
CH2CH2CN], 77 (8) [C6H5ϩ]; exact mass calculated for gel, eluent: see data of individual compounds).
C17H18N2O3: 298.1317; found 298.1315.
(4aR*,5R*,10cR*)-6-Methyl-5-phenyl-3,4,4a,5,6,10c-hexahydro-
pyrido[2Ј,3Ј:3,4]cyclopenta[1,2-b]indol-2(1H)-one (22a): Eluent:
CH2Cl2/ethyl acetate, 1:1; yield: 17% by procedure B, 60% by pro-
cedure A. IR (KBr, cmϪ1): ν˜ ϭ 1664 (s, CϭO). 1H NMR
(400 MHz, CDCl3): δ ϭ 7.52 (d, J ϭ 8 Hz, 1 H, H-arom.),
7.34Ϫ7.13 (m, 8 H, H-arom.), 6.22 (s, 1 H, NH), 5.18 (d, J ϭ 7 Hz,
1 H, H10c), 4.29 (d, J ϭ 5 Hz, 1 H, H5), 3.32 (s, 3 H, NCH3), 3.15
(m, 1 H, H4a), 2.50 (m, 1 H, H3), 2.39 (m, 1 H, H3), 2.16 (m, 1 H,
H4), 2.06 (m, 1 H, H4) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
172.7, 146.3, 142.1, 141.8, 129.1, 127.4, 122.6, 121.5, 121.4, 120.1,
118.9, 118.2, 109.9, 53.4, 52.9, 49.6, 30.5, 29.4, 24.1 ppm. MS (EI)
m/z (%) ϭ 316 (100) [M·ϩ], 258 [M·ϩ Ϫ CH2CONH2], 245 (27)
[M·ϩ Ϫ CH2ϭCHCONH2]; exact mass calculated for C21H20N2O:
316.1576; found 316.1574.
Methyl
2-(2-Cyanoethyl)-1-hydroxy-9-methyl-2,3,4,9-tetrahydro-
1H-carbazole-2-carboxylate (21d): NaBH4 (0.06 g, 1.7 mmol) was
added to a solution of 20 (0.53 g, 1.7 mmol) in methanol (50 mL).
The mixture was stirred at room temperature for 1 h, and NH4Cl
(satd. aq. solution, 50 mL) was added. The aqueous layer was ex-
tracted three times with CH2Cl2. The combined organic phases
were dried with Na2SO4 and filtered, and the solvents were evapo-
rated. The residue was purified by column chromatography (silica
gel, CH2Cl2/ethyl acetate, 19:1). Yield: 51%; mixture of dia-
stereoisomers, de ϭ 30%. IR (KBr, cmϪ1): ν˜ ϭ 2945 (b, OH), 2244
(w, CN), 1726 (s, CϭO) ppm. MS (EI) m/z (%) ϭ 312 (35) [M·ϩ],
294 (1) [M·ϩ Ϫ H2O], 281 (4) [M·ϩ Ϫ OCH3], 253 (6) [M·ϩ
CO2CH3], 235 (6) [M·ϩ Ϫ CO2CH3 Ϫ H2O], 226 (6) [M·ϩ Ϫ H2O
Ϫ
Ϫ CH2CH2CN Ϫ CH3], 194 (8) [M·ϩ Ϫ H2O Ϫ HCO2CH3
Ϫ
CH2CN], 173 (100) [M·ϩ Ϫ CO2CH3 Ϫ CH2CH2CN Ϫ C2H2]; ex-
act mass calculated for C18H20N2O3: 312.1474; found 312.1464;
major Isomer: (Methyl (1S*,2S*)-2-(2-cyanoethyl)-1-hydroxy-9-
Methyl (4aS*,5S*,10cS*)-6-Methyl-2-oxo-5-phenyl-1,3,4,5,6,10c-
hexahydropyrido[2Ј,3Ј:3,4]cyclopenta[1,2-b]indole-4a(2H)-carb-
methyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate): 1H NMR oxylate (22b): Eluent: CH2Cl2/ethyl acetate, 1:1; yield: 45% by pro-
(400 MHz, CDCl3): δ ϭ 7.49 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.30 (d,
cedure A. IR (KBr, cmϪ1): ν˜ ϭ 3433 and 3182 (s, NH), 1725 (s,
1
J ϭ 8 Hz, 1 H, H-arom.), 7.26 (dt, J ϭ 8, 1 Hz, 1 H, H-arom.), CϭO), 1671 (s, CϭO). H NMR (400 MHz, CDCl3): δ ϭ 7.64 (d,
7.10 (dt, J ϭ 8, 1 Hz, 1 H, H-arom.), 5.15 (d, J ϭ 9 Hz, 1 H, H1), J ϭ 8 Hz, 1 H, H-arom.), 7.26Ϫ7.13 (m, 6 H, H-arom.), 6.98 (d,
3.78 (s, 3 H, NCH3), 3.64 (s, 3 H, OCH3), 2.84 (ddd, J ϭ 17, 6,
J ϭ 2 Hz, 1 H, NH), 6.93 (m, 2 H, H-arom.), 5.85 (d, J ϭ 2 Hz, 1
2 Hz, 1 H, H4), 2.72 (ddd, J ϭ 17, 11, 6 Hz, 1 H, H4), 2.57 (ddd, H, H10c), 4.37 (s, 1 H, H5), 3.35 (s, 3 H, NCH3), 3.22 (s, 3 H,
J ϭ 16, 9, 6 Hz, 1 H, CH2CN), 2.41 (ddd, J ϭ 16, 9, 6 Hz, 1 H, OCH3), 2.65 (dt, J ϭ 9, 5 Hz, 1 H, H4), 2.38 (m, 2 H, 1H4 ϩ1H3),
CH2CN), 2.33Ϫ2.20 (m, 2 H, 1CH2CH2CNϩ1H3), 2.12 (ddd, J ϭ 2.24 (dt, J ϭ 13, 5 Hz, 1 H, H3) ppm. 13C NMR (100 MHz,
14, 9, 6 Hz, 1 H, CH2CH2CN), 1.86 (ddd, J ϭ 14, 11, 6 Hz, 1 H, CDCl3): δ ϭ 172.0, 171.9, 142.7, 141.7, 137.5, 128.4, 127.9, 122.9,
H3), 1.66 (d, J ϭ 9 Hz, 1 H, OH) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 173.5, 137.9, 134.7, 125.8, 122.6, 119.4, 119.2, 119.1,
110.7, 109.3, 62.7, 52.2, 51.0, 31.7, 29.3, 26.9, 18.5, 12.6; minor
Isomer: (Methyl (1R*,2S*)-2-(2-cyanoethyl)-1-hydroxy-9-methyl-
121.7, 120.1, 118.8, 117.5, 109.9, 63.3,56.0, 55.5, 51.8, 30.5, 30.3,
29.4 ppm. MS (EI) m/z (%) ϭ 374 (68) [M·ϩ], 359 (13) [M·ϩ
Ϫ
CH3], 343 [M·ϩ Ϫ OCH3], 325 (24) [M·ϩ Ϫ OCH3 Ϫ H2O], 315
(100) [M·ϩ Ϫ CO2CH3]; exact mass calculated for C23H22N2O3:
2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate):
1H
NMR 374.1630; found 374.1633.
4654
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4648Ϫ4656

Intramolecular Ritter Reactions
FULL PAPER
Methyl (4aS*,5R*,10cS*)-5,6-Dimethyl-2-oxo-1,3,4,5,6,10c-hexa-
MS (EI) m/z (%) ϭ 330 (100) [M·ϩ], 285 (5) [M·ϩ Ϫ HCONH2],
hydropyrido[2Ј,3Ј:3,4]cyclopenta[1,2-b]indole-4a(2H)-carboxylate 272 (42) [M·ϩ Ϫ CH2CONH2], 258 (88) [M·ϩ Ϫ CH2CH2CONH2];
(22c): Eluent: CH2Cl2/ethyl acetate, 1:1; yield: 49% by procedure
B, 71% by procedure A; mixture of diastereoisomers, de ϭ 40%.
IR (KBr, cmϪ1): ν˜ ϭ 3182 (m, NH), 1726 (s, CϭO), 1697 (s, Cϭ
exact mass calculated for C22H22N2O: 330.1732; found 330.1732.
3-(9-Methyl-1-phenyl-9H-carbazol-2-yl)propanamide (24): Eluent:
ethyl acetate; yield: 17% by procedure A. IR (KBr, cmϪ1): ν˜ ϭ 3341
(m, CONH2), 1660 (s, CϭO). 1H NMR (300 MHz, CDCl3): δ ϭ
8.06 (d, J ϭ 8 Hz, 1 H, H-arom.), 8.02 (d, J ϭ 8 Hz, 1 H, H-arom.),
7.50Ϫ7.36 (m, 6 H, H-arom.), 8.28 (d, J ϭ 8 Hz, 1 H, H-arom.),
7.24 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.17 (d, J ϭ 8 Hz, 1 H, H-
arom.), 5.52 (s, 1 H, NH), 5.14 (s, 1 H, NH), 3.13 (s, 3 H, NCH3),
2.86 (t, J ϭ 7 Hz, 2 H, CH2CH2CONH2), 2.38 (t, J ϭ 7 Hz, 2 H,
CH2CONH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 174.9, 142.4,
139.3, 138.6, 137.2, 131.3, 128.7, 128.3, 128.2, 128.0, 125.9, 120.4,
120.2, 119.9, 119.4, 109.0, 38.3, 32.2, 29.8 ppm. MS (EI) m/z (%) ϭ
1
O). H NMR (400 MHz, CDCl3): δ ϭ 7.54 (d, J ϭ 7 Hz, 1 H, H-
arom.), 7.27 (d, J ϭ 7 Hz, 1 H, H-arom.), 7.20 (t, J ϭ 7 Hz, 1 H,
H-arom.), 7.13 (t, J ϭ 7 Hz, 1 H, H-arom.), 6.83 (s, 0.7 H, NH),
6.63 (s, 0.3 H, NH), 5.67 (d, J ϭ 3 Hz, 0.7 H, H5a), 5.46 (d, J ϭ
3 Hz, 0.3 H, H5a), 3.84 (s, 2.1 H, OCH3), 3.80 (s, 0.9 H, OCH3),
3.74 (m, 0.3 H, H1), 3.72 (s, 0.9 H, NCH3), 3.68 (s, 2.1 H, NCH3),
3.27 (q, J ϭ 7 Hz, 0.7 H, H1), 2.48Ϫ2.03 (m, 4 H, H2, H3), 1.50
(d, J ϭ 7 Hz, 0.9 H, CH3), 1.22 (d, J ϭ 7 Hz, 2.1 H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 175.0, 173.1, 172.6, 171.7, 145.3,
144.8, 141.6, 141.3, 123.1, 122.8, 121.4, 121.3, 120.0, 118.5, 118.3,
115.4, 115.2, 109.7, 109.6, 60.8, 59.9, 56.7, 55.8, 52.6, 52.4, 42.8,
40.4, 30.6, 30.3,29.5, 29.2, 29.1, 24.0, 16.6, 14.6 ppm. MS (EI) m/z
(%) ϭ 312 (100) [M·ϩ], 297 (38) [M·ϩ Ϫ CH3], 256 (40) [M·ϩ Ϫ CO
Ϫ C2H4], 253 (98) [M·ϩ Ϫ CO2CH3], 225 (32) [M·ϩ Ϫ HCO2CH3 Ϫ
328 (100) [M·ϩ], 284 (18) [M·ϩ Ϫ CONH2], 270 (44) [M·ϩ
Ϫ
CH2CONH2], 255 (54) [C19H13Nϩ], 254 (56) [C19H12Nϩ]; exact
mass calculated for C22H20N2O: 328.1576; found 328.1580.
H2O], 197 (24) [M·ϩ Ϫ CO2CH3 Ϫ CO Ϫ C2H4], 182 (23) [M·ϩ
CO2CH3 HNCO C2H4]; exact mass calculated for
C18H20N2O3: 312.1474; found 312.1474.
Ϫ
Bridged Compounds 25: Eluent: CH2Cl2/ethyl acetate, 1:1; yield:
57% by procedure B; a mixture of diastereoisomers (50:50) was
separated. IR (KBr, cmϪ1): ν˜ ϭ 3189 (m, NH), 1721 (s, CϭO),
1653 (s, CϭO) ppm. ppm. MS (EI) m/z (%) ϭ388 (100) [M·ϩ], 345
Ϫ
Ϫ
(6) [M·ϩ Ϫ HNCO], 329 (9) [M·ϩ Ϫ CO2CH3], 312 (17) [M·ϩ
Ϫ
Methyl (4aR*,10bS*)-10,10b؊Dimethyl-2-oxo-1,3,4,5,10,10b-
Hexahydropyrido[3Ј,2Ј:4,5]cyclopenta[1,2-b]indole-4a(2H)-carb-
oxylate (22cЈ): Eluent: CH2Cl2/ethyl acetate, 1:1; yield: 15% by pro-
cedure B. IR (KBr, cmϪ1): ν˜ ϭ 3443 (m, NH), 1732 (s, CϭO), 1659
(s, CϭO). 1H NMR (400 MHz, CDCl3): δ ϭ 7.99 (s, 1 H, NH),
7.49 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.29 (d, J ϭ 8 Hz, 1 H, H-
arom.), 7.22 (dt, J ϭ 8, 1 Hz, 1 H, H-arom.), 7.12 (dd, J ϭ 8, 1 Hz,
1 H, H-arom.), 3.82 (s, 3 H, OCH3), 3.76 (s, 3 H, NCH3), 3.63 (d,
J ϭ 15 Hz, 1 H, H5), 2.83 (d, J ϭ 15 Hz, 1 H, H5), 2.57 (m, 1 H,
H3), 2.29 (m, 3 H, 1 ϫ H3 , 2 ϫ H4), 1.85 (s, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): 173.8, 173.7, 144.3, 141.6, 123.5, 121.6,
119.6, 119.2, 113.2, 109.7, 63.1, 59.8, 52.1, 33.5, 31.0, 29.9, 28.8,
CO2CH3 Ϫ NH3], 286 (15) [M·ϩ Ϫ CO2CH3 Ϫ CONH], 220 (36)
[M·ϩ Ϫ CO2CH3 Ϫ NHCO Ϫ C6H6]; exact mass calculated for
C24H24N2O3: 388.1787; found 388.1785. Isomer with Ph trans to
Ester Group: 1H NMR (400 MHz, CDCl3): δ ϭ 7.58 (d, J ϭ 8 Hz,
1 H, H-arom.), 7.37 (dt, J ϭ 7, 1 Hz, 1 H, H-arom.), 7.25 (m, 5 H,
H-arom.), 7.17 (dt, J ϭ 7, 2 Hz, 1 H, H-arom.), 7.05 (d, J ϭ 7 Hz,
1 H, H-arom.), 6.99 (d, J ϭ 6 Hz, 1 H, NH), 5.05 (s, 1 H, H5), 4.73
(t, J ϭ 6 Hz, 1 H, H10c), 3.78 (s, 3 H, OCH3), 3.15 (s, 3 H, NCH3),
2.81 (t, J ϭ 6 Hz, 1 H, H3), 2.70 (dd, J ϭ 14, 6 Hz, 1 H, H11), 2.37
(m, 2 H, H11, H3), 1.86 (m, 2 H, H4) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 177.4, 176.2, 138.2, 138.1, 137.2, 129.6, 129.1, 128.6,
128.3, 127.7, 125.5, 122.0, 120.1, 118.2, 109.7, 109.3, 52.5, 50.7,
47.2, 43.4, 39.1, 33.5, 31.9, 25.7 ppm. Isomer with Ph cis to Ester
24.4 ppm. MS (EI) m/z (%) ϭ 312 (100) [M·ϩ], 297 (60) [M·ϩ
Ϫ
CH3], 284 (15) [M·ϩ Ϫ CO], 255 (96) [M·ϩ Ϫ NCO Ϫ CH3], 237
(15) [M·ϩ Ϫ HCO2CH3 Ϫ CH3], 223 (26) [M·ϩ Ϫ CO2CH3 Ϫ C2H4
Ϫ H2]; exact mass calculated for C18H20N2O3: 312.1474; found
312.1462.
1
Group: H NMR (400 MHz, CDCl3): δ ϭ 7.63 (d, J ϭ 8 Hz, 1 H,
H-arom.), 4.76 (d, J ϭ 6 Hz, NH), 7.21 (m, 5 H, H-arom.), 7.10
(ddd, J ϭ 8, 7, 2 Hz, 1 H, H-arom.), 6.99 (m, 2 H, H-arom.), 4.87
(t, J ϭ 6 Hz, 1 H, H-arom.), 4.26 (s, 1 H, H5), 3.37 (s, 3 H, OCH3),
3.26 (s, 3 H, NCH3), 2.82 (dd, J ϭ 15, 6 Hz, 1 H, H11), 2.57 (m, 1
H, H4), 2.42 (m, 2 H, H3), 2.21 (d, J ϭ 15 Hz, 1 H, H11), 2.17 (m,
1 H, H4) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 176.8, 174.5,
138.0, 137.8, 136.7, 129.3, 128.3, 127.5, 124.8, 121.9, 119.8, 118.6,
109.8, 109.0, 51.6, 51.0, 46.8, 42.9, 33.3, 33.0, 31.6, 29.3 ppm.
Methyl (4aR*,10bS*)-10-Methyl-2-oxo-1,3,4,5,10,10b-hexahydropy-
rido[3Ј,2Ј:4,5]cyclopenta[1,2-b]indole-4a(2H)-carboxylate (22d): Elu-
ent: ethyl acetate; yield: 43% by procedure A. IR (KBr, cmϪ1): ν˜ ϭ
1731 (s, CϭO), 1666 (s, CϭO). 1H (300 MHz, CDCl3): δ ϭ 7.51
(d, J ϭ 8 Hz, 1 H, H-arom.), 7.27Ϫ7.06 (m, 3 H, H-arom.), 6.91
(s, 1 H, NH), 5.42 (s, 1 H, H10b), 3.79 (s, 3 H, NCH3), 3.65 (s, 3
H, OCH3), 3.53 (d, J ϭ 16 Hz, 1 H, H5), 2.99 (d, J ϭ 16 Hz, 1 H,
H5), 2.43Ϫ2.02 (m, 4 H, H3, H4) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 175.9, 173.3, 142.5, 141.9, 123.3, 121.7, 120.4, 118.7,
117.2, 110.1, 57.6, 56.7, 53.2, 35.8, 31.2, 30.9, 29.2 ppm. MS (EI)
m/z (%) ϭ 298 (100) [M·ϩ], 283 (40) [M·ϩ Ϫ CH3], 242 (72) [M·ϩ
Methyl (4aS*,10bS*)-11,11b؊Dimethyl-2-oxo-1,2,3,4,5,6,11,11b-
octahydro-4aH-pyrido[2,3-a]carbazole-4a-carboxylate (26): Eluent:
CH2Cl2/ethyl acetate, 1:1; yield: 68% by procedure A. IR (KBr,
cmϪ1): ν˜ ϭ 1882 (s, CϭO), 1664 (s, CϭO). 1H NMR (400 MHz,
CDCl3): δ ϭ 8.37 (s, 1 H, NH), 7.49 (d, J ϭ 8 Hz, 1 H, H-arom.),
7.32 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.26 (dt, J ϭ 8, 1 H, H-arom.),
7.15 (t, J ϭ 8 Hz, 1 H, H-arom.), 3.88 (s, 3 H, NCH3), 3.82 (s, 3
H, OCH3), 2.94 (dt, J ϭ 16, 6 Hz, 1 H, H6), 2.83 (ddd, J ϭ 16, 10,
Ϫ CO Ϫ C2H4], 239 (44) [M·ϩ Ϫ CO2CH3], 227 (12) [M·ϩ
Ϫ
HNCO Ϫ C2H4]; exact mass calculated for C17H18N2O3: 298.1317;
found 298.1316.
3-(9-Methyl-1-phenyl-4,9-dihydro-3H-carbazol-2-yl)propanamide 5 Hz, 1 H, H6), 2.59 (m, 2 H, H3), 2.26 (ddd, J ϭ 14, 10, 6 Hz, 1
(23): Eluent: ethyl acetate; yield: 35% by procedure A. IR (KBr,
H, H5), 2.15 (m, 2 H, H4), 2.05 (ddd, J ϭ 14, 14, 6 Hz, 1 H, H5),
cmϪ1): ν˜ ϭ 3402 (m, CONH2), 1651 (s, CϭO). 1H NMR 1.69 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 174.5,
(300 MHz, CDCl3): δ ϭ 7.54Ϫ7.04 (m, 9 H, H-arom.), 5.76 (s, 1 173.6, 138.0, 136.9, 125.6, 122.0, 119.2, 118.5, 109.0, 107.9, 56.7,
H, NH), 5.37 (s, 1 H, NH), 2.96 (s, 3 H, NCH3), 2.90 (m, 2 H, 52.0, 48.9, 31.4, 29.0, 28.0, 26.1, 24.7, 21.2 ppm. MS (EI) m/z (%) ϭ
H4), 2.53 (m, H, H3, CH2CH2CONH2), 2.31 (m, 326 (100) [M·ϩ], 311 (61) [M·ϩ Ϫ CH3], 268 (35) [M·ϩ Ϫ COCH2],
H,
CH2CONH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 175.2, 138.9, 253 (97) [M·ϩ Ϫ CO2CH3 Ϫ CH3], 208 (39) [M·ϩ Ϫ HCO2CH3 Ϫ
138.6, 136.9, 136.4, 131.3, 130.2, 129.3, 129.2, 128.7, 127.8, 125.9,
H2NCOCH2], 194 (26) [M·ϩ Ϫ HCO2CH3 Ϫ H2NCOCH2CH2];
121.4, 119.7, 118.6, 110.4, 109.6, 35.5, 31.9, 30.2, 29.9, 20.5 ppm. exact mass calculated for C19H22N2O3: 326.1630; found 326.1636.
4
2
Eur. J. Org. Chem. 2004, 4648Ϫ4656
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4655

F. Maertens, A. Van den Bogaert, F. Compernolle, G. J. Hoornaert
FULL PAPER
Methyl (4aR*,10bR*)-11-Methyl-2-oxo-1,2,3,4,5,6,11,11b-octahy-
R. De Boer and Professor S. Toppet for mass and NMR measure-
ments.
dro-4aH-pyrido[2,3-a]carbazole-4a-carboxylate
(27):
Eluent:
CH2Cl2/MeOH, 19:1; yield: 51% by procedure A. IR (KBr, cmϪ1):
1
[1]
ν˜ ϭ 3189 and 3055 (s, CONH), 1731 (s, CϭO), 1661 (s, CϭO). H
K. Van Emelen, T. De Wit, G. J. Hoornaert, F. Compernolle,
Org. Lett. 2000, 2, 3083Ϫ3086.
NMR (400 MHz, CDCl3): δ ϭ 7.48 (d, J ϭ 8 Hz, 1 H, H-arom.),
7.29 (d, J ϭ 8 Hz, 1 H, H-arom.), 7.25 (t, J ϭ 8 Hz, 1 H, H-arom.),
7.12 (t, J ϭ 8 Hz, 1 H, H-arom.), 6.05 (s, 1H NH), 5.14 (s, 1 H,
H11b), 3.72 (s, 3 H, NCH3), 3.63 (s, 3 H, OCH3), 2.84 (ddd, J ϭ
16, 6, 2 Hz, 1 H, H6), 2.75 (ddd, J ϭ 16, 11, 6 Hz, 1 H, H6), 2.46
(ddd, J ϭ 17, 6, 5 Hz, 1 H, H3), 2.34 (ddd, J ϭ 17, 10, 6 Hz, 1 H,
H3), 2.25 (ddd, J ϭ 14, 10, 6 Hz, 1 H, H4), 2.14 (ddd, J ϭ 13, 6,
2 Hz, 1 H, H5), 1.99 (m, 2 H, H4, H5) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 174.5, 170.5, 137.8, 132.1, 126.1, 122.5, 119.4, 118.9,
110.4, 109.3, 52.4, 48.8, 45.0, 30.8, 29.5, 27.7, 25.4, 18.6 ppm. MS
(EI) m/z (%) ϭ 312 (74) [M·ϩ], 256 (36) [M·ϩ Ϫ CO Ϫ C2H4], 253
(100) [M·ϩ Ϫ CO2CH3], 197 (20) [M·ϩ Ϫ CO Ϫ CO2CH3 Ϫ C2H4],
157 (26) [M·ϩ Ϫ CO Ϫ CO2CH3 Ϫ C2H4 Ϫ C2H2N]; exact mass
calculated for C18H20N2O3: 312.1474; found 312.1467.
[2]
T. De Wit, K. Van Emelen, F. Maertens, G. J. Hoornaert, F.
Compernolle, Tetrahedron Lett. 2001, 42, 4919Ϫ4922.
R. M. Snider, J. W. Constantine, J. A. Lowe III, K. P. Longo,
W. S. Lebel, H. A. Woody, S. E. Drozda, M. C. Desai, F. J.
Vinick, R. W. Spencer, H.-J. Hess, Science 1991, 251, 435Ϫ437.
M. C. Desai, S. L. Lefkowitz, P. F. Thadeio, K. P. Longo, R.
M. Snider, J. Med. Chem. 1992, 35, 4911Ϫ4913.
T. A. Knoerzer, D. E. Nichols, W. K. Brewster, V. J. Watts, D.
Mottola, R. B. Mailman, J. Med. Chem. 1994, 37, 2453Ϫ2460.
K. Van Emelen, T. De Wit, G. J. Hoornaert, F. Compernolle,
Tetrahedron 2002, 58, 4225Ϫ4236.
W. K. Brewster, D. E. Nichols, V. J. Watts, R. M. Riggs, D.
Mottola, R. B. Mailman, J. Med. Chem. 1995, 38, 318Ϫ327.
F. Claudi, G. M. Cingolani, A. Di Stefano, G. Giorgini, F.
Amenta, P. Barili, F. Ferrari, D. Giuliani, J. Med. Chem. 1996,
39, 4238Ϫ4246.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
Y. Kikugawa, Y. Miyake, Synthesis 1981, 461Ϫ462.
C. D. Buttery, R. G. Jones, D. W. Knight, J. Chem. Soc., Perkin
[10]
Trans. 1 1993, 1425Ϫ1431.
[11]
Acknowledgments
K. Ishizumi, T. Shioiri, S. I. Yamada, Chem. Pharm. Bull. 1967,
15, 836Ϫ872.
The authors wish to thank the F.W.O. (Fonds voor Wetenschap-
pelijk Onderzoek-Flanders) for financial support and for a fellow-
ship to F. M. and the Johnson & Johnson Pharmaceutical Research
Foundation for financial support. They are also grateful to
[12]
L. I. Krimen, D. J. Cota, Org. React. 1969, 17, 213Ϫ325.
[13]
S.-J. Chang, Organic Process Research & Development 1999, 3,
232Ϫ234.
Received June 9, 2004
4656
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4648Ϫ4656