Tandem cleavage of hydrogenated β- and γ-carbolines - New practical synthesis of tetrahydroazocino[4,5-b]indoles and tetrahydroazocino[5, 4-b]indoles showing acetylcholinesterase inhibitory activity

Article abstract of DOI:10.1002/ejoc.200400107

Hydrogenated γ-carbolines underwent tandem piperidine ring cleavage on treatment with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate (EP) in the presence of alcohols, producing 3-alkoxymethyl-substituted indoles in high yields. These compounds were cyclized to tetrahydroazocino[4,5-b]indoles in the presence of AlCl₃. Hydrogenated β-carbolines produced tetrahydroazocino [5,4-b]indoles directly upon treatment with EP in ethanol. The resulting azocinoindole derivatives were subjected to a preliminary evaluation of their in vitro acetylcholinesterase (AChE) inhibitory activities. Most of them were found to inhibit AChE with IC₅₀ values in the micromolar range, compound 17 being the most potent (IC₅₀ = 8.7 μm). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400107

FULL PAPER
Tandem Cleavage of Hydrogenated β- and γ-Carbolines ؊ New Practical
Synthesis of Tetrahydroazocino[4,5-b]indoles and Tetrahydroazocino[5,4-b]-
indoles Showing Acetylcholinesterase Inhibitory Activity
[
a]
[a]
[a]
Leonid G. Voskressensky,* Tatiana N. Borisova, Larisa N. Kulikova,
[a]
[b]
[b]
[b]
Alexej V. Varlamov, Marco Catto, Cosimo Altomare, and Angelo Carotti
Keywords: Acetylcholinesterase inhibition / Azocine / Fused-ring systems / Nitrogen heterocycles / Ring expansion
Hydrogenated γ-carbolines underwent tandem piperidine
dole derivatives were subjected to a preliminary evaluation
ring cleavage on treatment with dimethyl acetylenedicarbox- of their in vitro acetylcholinesterase (AChE) inhibitory activ-
ylate (DMAD) or ethyl propiolate (EP) in the presence of alco- ities. Most of them were found to inhibit AChE with IC50
hols, producing 3-alkoxymethyl-substituted indoles in high
yields. These compounds were cyclized to tetrahydroazoc- potent (IC50 = 8.7 µ
ino[4,5-b]indoles in the presence of AlCl . Hydrogenated β-
values in the micromolar range, compound 17 being the most
m).
3
carbolines produced tetrahydroazocino[5,4-b]indoles directly
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
upon treatment with EP in ethanol. The resulting azocinoin-
Germany, 2004)
roles[
11,12]
or parallel pyrroloazocine formation in low
THPP derivatives were also demonstrated to un-
Introduction
[
13]
yields.
Because of their wide occurrence in many biologically ac-
tive compounds,
dergo cleavage in alcohols on treatment with DMAD, pro-
[
1,2]
eight-membered (azocine) and larger
ducing β-alkoxy(hydroxy)alkylpyrroles in moderate to high
N-containing fused ring systems deserve more investigation
efforts from the point of view of organic chemistry. The
azocine fragment, for example, occurs in many indole
[14]
yields.
Here we report on a new practical synthesis of
tetrahydroazocino[5,4-b]indole and tetrahydroazocino[4,5-
b]indole derivatives, starting from readily obtainable hydro-
genated β- and γ-carbolines and DMAD or ethyl propiol-
ate. The preliminary results from an evaluation of their in
vitro activities as acetylcholinesterase inhibitors (AChE-Is)
are also reported.
[
3Ϫ6]
alkaloids,
but one barrier to their exploitation is a gen-
eral lack of satisfactory preparative methods. Known syn-
thetic pathways toward this class of indole derivatives in-
clude ring expansion of azetopyridoindoles through the
[
1,2]-Meisenheimer rearrangement of the corresponding N-
[
7]
oxides, Fisher indolization of the appropriate azacy-
clanones,
[
8]
[9]
cationic domino processes,
and catalytic
hydrogenation of the 2-(2-benzylaminoethyl)-3-cyanoethyl-
Results and Discussion
[
10]
indoles.
These procedures are either based on poorly
available (and thus very expensive) starting materials or re-
quire relatively inefficient, multi-step procedures. There is
The starting γ-carbolines 1Ϫ4 were obtained by the well
therefore a need for new synthetic approaches to produce known Fischer indolization of the appropriate N-alkyl-4-
azocine-containing heterocycles from readily available com- piperidones (see Scheme 1, Table 1).
pounds.
We have recently reported tandem piperidine ring cleav-
age in tetrahydropyrrolopyridines (THPPs) on treatment
with dimethyl acetylenedicarboxylate (DMAD) in aprotic
solvents, resulting in the formation of α- and β-vinylpyr-
[
a]
Organic Chemistry Department of the Russian Peoples’
Friendship University,
6
, Miklukho-Maklaya St., Moscow, 117198, Russia
Fax: (internat.) ϩ 7-095-955-0779
E-mail: lvoskressensky@sci.pfu.edu.ru
Medicinal Chemistry Department, University of Bari,
Via E. Orabona 4, 70125 Bari, Italy
[
b]
Scheme 1
3128
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400107
Eur. J. Org. Chem. 2004, 3128Ϫ3135

Tandem Cleavage of Hydrogenated β- and γ-Carbolines
FULL PAPER
Table 1. R substituents for carbolines 1Ϫ8, alkoxymethylindoles
9Ϫ15, and azocinoindoles 17Ϫ22
Carbolines Alkoxymethylindoles
Azocinoindoles
1
1
1
2
R3
R
R
R
R
R
R
R
1
2
3
4
5
6
7
8
Et
Et
iPr F
H
F
9
10
11
Et
iPr
Et
Et
Et
Et
Et
F
F
OMe
H
H
OMe
F
17 Et
18 iPr F
19 Et OMe COOMe COOMe
20 Et
21 Et
22 Et
F
COOMe COOMe
COOMe COOMe
Et OMe 12
H
H
F
COOMe COOMe
Me Ϫ
iPr Ϫ
Me Ϫ
iPr Ϫ
13
14
15
H
H
COOEt
COOEt
N-Ethyl-β-carbolines 7 and 8 were synthesized by
PictetϪSpengler condensation of tryptamine with acetalde-
hyde or isobutyraldehyde, followed by N-ethylation of the
intermediate tetrahydro-β-carbolines 5 and 6 (Scheme 2)
(Table 1). All reactions proceeded smoothly, giving the de-
sired products in good to high yields, except for the N-ethyl-
ation of 6; the isolation of the target product required col-
umn chromatography in this case. The main by-product iso-
lated was the N(9)ϪEt isomeric carboline 8a. The structure
1
of 8a was assigned from its IR and H NMR spectroscopic
data as well as its mass spectrum. The proton NMR spec-
trum of 8a lacks the N(9)ϪH signal, which in the case of 8
resonates at δ ϭ 8.21 ppm (br. s, 1 H). We relate this un-
usual alkylation to the presence of the bulky isopropyl
group in the position α to the piperidine NH in 6.
Scheme 3
In the case of carboline 1, the target azocinoindoles 20
and 21 were isolated as almost the only products; the for-
mation of the corresponding β-alkoxymethylindoles 12 and
13 in the course of the reaction was demonstrated with the
aid of LCMS analysis of the crude reaction mixture. We
presume that the reaction proceeds via the intermediate
zwitterion A, the result of Michael addition of the tertiary
nitrogen to DMAD or EP. The cleavage of the C(1)ϪN
bond occurs through the formation of the six-membered
transition state B, in which a molecule of alcohol facilitates
1
the S reaction. The electronic effects of R define the sym-
N
metry of the transition state (loose or tight) and the direc-
tion of further transformations: the formation of alkoxyme-
thylindoles or azocinoindoles. EP is more active than
DMAD in the reaction with carbolines; this may be ex-
plained in terms of different delocalization of the negative
charge in the anionic part of B. The proton NMR spectra
of indoles 9Ϫ11 and 14 and 15 have similar characteristics:
the enamine protons of 9Ϫ11 resonate at δ ϭ 4.50Ϫ4.70
ppm, whereas the enamine protons of 14 and 15 appear as
Scheme 2
γ-Carbolines, unlike THPP derivatives, are cleaved by two doublets at δ ϭ 4.70Ϫ4.82 ppm and δ ϭ 7.45Ϫ7.62
DMAD in aprotic solvents, producing multicomponent ppm with J ϭ 13.0Ϫ13.8 Hz, such high vicinal coupling
mixtures of products, which were not identified. Com- constant values indicating the trans configuration of the
pounds 1Ϫ4 and 7 and 8 were treated with DMAD or ethyl enamine fragment. This observation is in agreement with
propiolate (EP) at room temperature in absolute methanol the data on cleavage of tetrahydropyrrolopyridines (THPPs)
[
14]
or ethanol. In the case of γ-carbolines 1Ϫ4 a tandem cleav- on treatment with DMAD in protic solvents.
age process involving one molecule of solvent took place
Compounds 9Ϫ11 and 15 underwent intramolecular
(Scheme 3).
cyclization on treatment with AlCl in acetonitrile to give
3
Eur. J. Org. Chem. 2004, 3128Ϫ3135
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3129

L. G. Voskressensky et al.
˚
FULL PAPER
the target azocinoindoles 17Ϫ19 and 22 in good (except for shorter than the N(1)ϪC(3) (1.364 and 1.469 A respec-
19) yields (Scheme 4).
tively), indicating the presence of conjugation in the
enamine [N(1)ϪC(4)ϪC(5)] fragment. β-Carbolines 7 and
8, upon treatment with EP in absolute ethanol, directly pro-
vided target tetrahydroazocino[5,4-b]indoles 23 and 24 in
good yield; in the case of 8 the corresponding α-(ethoxy)iso-
butylindole derivative 16 was also isolated (Scheme 5).
Scheme 4
Our attempts to isolate the target azocinoindole failed in
the case of the cyclization of 14. The reaction was ac-
companied by significant tarring, and a multicomponent re-
action mixture was formed.
We relate this result (along with the low yield of azocine
in the case of 11) to the presence of the OCH group at
3
the C(8) position. This can be alternatively attacked by the
molecule of AlCl , thus destabilizing the transition state B
3
and activating the methoxy group towards intermolecular
nucleophilic displacement.
An X-ray crystallographic analysis was carried out on the
tricyclic tetrahydroazocino[4,5-b]indole 17, obtained as a Scheme 5
suitable monocrystal by recrystallisation from ethyl acetate
through slow evaporation at room temperature, to obtain
The three-dimensional structure of compound 24 was
unequivocal structural assignment and to elucidate its
three-dimensional structure. The refined X-ray crystal
structure of 17 is shown in Figure 1.
also investigated by X-ray diffraction method. The mono-
crystal was obtained by recrystallisation from an ethyl acet-
ate/hexane mixture by slow evaporation at room tempera-
ture, and the refined X-ray crystal structure of 24 is shown
in Figure 2. The conformation of the eight-membered ring
is a flat boat, in which the C(7), C(13), N(2), and C(10)
atoms are coplanar, whilst the C(9), C(11), C(12), and C(19)
atoms are located on the same side of this plane, within
˚
1
.09, 0.41, 0.90 and 2.42 A, respectively.
The isopropyl group in azocine moiety is pseudoaxially
oriented. The N(2)ϪC(10) bond is shorter than the
˚
N(2)ϪC(9) (1.364 and 1.469 A, respectively), once again
indicating the presence of conjugation in the enamine
[N(2)ϪC(10)ϪC(11)] fragment.
We evaluated the synthesized azocinoindoles for their
abilities to inhibit AChE, in the context of a research pro-
gram aimed at testing the neuroprotective potential of new
[
15]
heterocyclic candidates.
AChE inhibition represents a
major pharmacological approach to the treatment of Alz-
[
16]
heimer’s disease (AD).
Our azocinoindoles were preliminarily tested as inhibi-
[
17]
tors of bovine AChE, by Ellman’s method,
and their
mean inhibitory concentrations (IC s) were estimated from
50
the best-fitting inhibition-concentration curves, as shown in
Figure 3 for compound 17. The biological data showed
compound 17 to be the best AChE inhibitor of the tetrahy-
Figure 1. X-ray crystal structure of 17
The conformation of the eight-membered ring is a droazocino[4,5-b]indole derivatives tested, its IC50 value be-
twisted boat, in which the C(1), C(7), N(1), and C(4) atoms ing 8.7 µ. The other derivatives, including tetrahydroazoc-
are almost coplanar, whilst the C(2), C(3), C(5), and C(6) ino[5,4-b]indoles 23 and 24, showed IC s ranging from 20
50
atoms are located on the same side of this plane within 0.78, to 50 µ. Detailed kinetic studies and structure-activity re-
˚
1
.26, 0.45, and 0.84 A, respectively. The N(1)ϪC(4) bond is lationships will be reported elsewhere in due course.
3130
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3128Ϫ3135

Tandem Cleavage of Hydrogenated β- and γ-Carbolines
FULL PAPER
Figure 2. X-ray crystal structure of 24
Experimental Section
General Remarks: All solvents were distilled and dried before use;
DMAD and EP were purchased from Acros Organics and were
used without any additional purification. Column chromatography
1
13
was performed with alumina oxide 60 from Fluka. H and
NMR spectra were recorded in CDCl solutions, at 25 °C or in
]DMSO solutions at 40 °C, with a Bruker WM 400 NMR spec-
C
3
[D
6
trometer operating at 400 and 100 MHz, respectively; peak posi-
tions are given in parts per million (δ) with tetramethylsilane as the
internal standard. For the protons indexes for compounds 9Ϫ11
1
1
and 14, 15 see Scheme 3. H- H COSY experiments were used for
the assignment of the signals in the spectra of compounds 16 and
Figure 3. AChE inhibition curve for compound 17; interpolation
of the best-fitting curve gave an IC50 value of 8.7 µ; data points
and error bars represent means and s.d. (n ϭ 3Ϫ5), respectively
24. Mass spectra were obtained by the EI technique (Finnigan-
MAT 95 XL engine) or the ESI method (Agilent 1100 Series LC/
MSD Trap System VL). IR spectra were recorded with a
PerkinϪElmer Spectrum One instrument. Only noteworthy IR ab-
Ϫ1
sorptions (cm ) are listed. Melting points were determined in a
Conclusion
capillary tube and are uncorrected.
In conclusion, we offer a new, two-step procedure for the Starting Materials: γ-Carbolines 1Ϫ4 were synthesized by the pre-
viously described method,[ and β-carbolines 5 and 6 were synthe-
18]
synthesis of azocino[4,5-b]indoles and azocino[5,4-
[19]
sized by a previously described procedure.
compounds 1Ϫ6 were confirmed by H NMR and MS data.
The structures of
b]indoles, starting from readily available γ- and β-carbol-
ines. This reaction could represent a new powerful tool for
the construction of fused azocine derivatives, shown to be
1
2
-Ethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (7): Ethyl iodide
endowed with different degrees of inhibitory activity to- (1.3 g, 8 mmol) was added to a stirred solution of 5 (1.0 g,
ward AChE.
5.4 mmol) and K
2
CO
3
(1.6 g, 16 mmol) in DMF (10 mL), and stir-
Eur. J. Org. Chem. 2004, 3128Ϫ3135
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3131

L. G. Voskressensky et al.
FULL PAPER
ring was continued at 50 °C for 5 h. The crude reaction mixture 59 (15). C20
H25FN
2
O
5
(392.42): calcd. C 61.21, H 6.42, N 7.14;
was poured into water (20 mL) and extracted with CH
2 2
Cl (3 ϫ 70 found C 61.30, H 6.51, N 7.35.
mL). Solvents were evaporated under reduced pressure to give 7
1
Dimethyl
(2E)-2-[{2-[5-Fluoro-3-(methoxymethyl)-1H-indol-2-yl]-
(
600 mg, 52%) as a light brown oil. H NMR (CDCl
J ϭ 7.3 Hz, 3 H, CH ϪCH ), 1.40 (d, J ϭ 6.7 Hz, 3 H, CH
.61Ϫ2.95 (m, 5 H, CH ϪCH , CH -3, 4-H), 3.18Ϫ3.20 (m, 1 H,
-H), 3.85 (q, J ϭ 7.3 Hz, 1 H, 1-H), 7.06Ϫ7.1 (m, 2 H, 6-H, 7-
3
): δ ϭ 1.16 (t,
ethyl}(isopropyl)amino]but-2-enedioate (10): White crystals, m.p.
3
2
3
ϪCH),
1
1
00Ϫ102 °C (ethyl acetate/hexane), yield 230 mg (56%). H NMR
CDCl ): δ ϭ 0.95 (d, J ϭ 6.4 Hz, 3 H, CH iPr), 1.01 (d, J ϭ 6.4
Hz, 3 H, CH iPr), 3.05 (t, J ϭ 7.2 Hz, 2 H, NϪCH -α), 3.32 (t,
J ϭ 7.2 Hz, 2 H, NϪCH -β), 3.40 (s, 3 H, OCH ), 3.54 (sept, J ϭ
.4 Hz, 1 H, CH iPr), 3.65 (s, 3 H, OCH ), 3.94 (s, 3 H, OCH ),
.55 (s, 2 H, OϪCH ), 4.79 (s, 1 H, H-ε), 6.87 (ddd, J ϭ 10.5 Hz,
2
4
2
3
2
(
3
3
3
2
H), 7.3 (d, J ϭ 7.9 Hz, 1 H, 5-H), 7.50 (d, J ϭ 7.6 Hz, 1 H, 8-H),
ϩ
2
3
7
.75 (br. s, 1 H, NH) ppm. EI MS: m/z (%) ϭ 214 (20) [M ], 199
6
4
8
3
3
(
100), 157 (40), 144 (10), 130 (15). C14 (214.31): calcd. C
18 2
H N
2
78.46, H 8.47, N 13.07; found C 78.32, H 8.53, N 12.95.
.9 Hz, 2.3 Hz, 1 H, CH6Ј-indolyl), 7.23Ϫ7.19 (m, 2 H, CH4Ј-indolyl
,
2-Ethyl-1-isopropyl-1,2,3,4-tetrahydro-β-carboline (8) and 9-Ethyl-1-
CH7Ј-indolyl), 8.38 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ 20.1, 20.1,
2
isopropyl-1,2,3,4-tetrahydro-β-carboline (8a): Ethyl iodide (1.1 g, 23.9, 43.6, 50.9, 52.5, 57.8, 65.0, 65.0, 86.2, 103.3 (d,
C,F
J ϭ
2
3
7
mmol) was added to a stirred solution of 6 (1.0 g, 4.7 mmol) and 24 Hz), 110.0 (d, JC,F ϭ 24 Hz), 110.1, 111.2 (d, JC,F ϭ 9 Hz),
1
K
2
CO
tinued at 50 °C for 6 h. The crude reaction mixture was poured
into water (20 mL) and extracted with CH Cl (3 ϫ 70 mL). Sol-
vents were evaporated under reduced pressure, and the residue
750 mg) was purified by column chromatography with ethyl acet-
ate/heptane (1:3) as eluent. The first fraction provided 8 (590 mg,
3
(1.4 g, 14 mmol) in DMF (10 mL), and stirring was con-
128.7, 131.9, 136.6, 153.3, 158.1 (d, JC,F ϭ 234 Hz), 166.8, 168.1
ppm. EI MS: m/z (%) ϭ 406 (5) [M ], 375 (8), 347 (12), 315 (5),
271 (5), 214 (100), 174 (15), 172 (18), 161 (25), 140 (50), 112 (20),
2 5
44 (15). C21H27FN O (406.45): calcd. C 62.06, H 6.65, N 6.90;
ϩ
2
2
(
found C 62.30, H 6.51, N 6.45.
1
Dimethyl (2E)-2-(Ethyl{2-[5-methoxy-3-(methoxymethyl)-1H-indol-
5
3
3%) as a yellow oil. H NMR (CDCl
H, CH ϪCH), 1.13 (t, J ϭ 7.3 Hz, 3 H, CH
ϪCH), 2.0 (m, 1 H, CH iPr), 2.45Ϫ2.60 (m,
, 4-H), 2.90 (m, 1 H, 4-H), 3.05 (m, 1 H, 3-H),
.20Ϫ3.30 (m, 2 H, 1-H, 3-H), 7.10 (t, J ϭ 7.6 Hz, 1 H, 6-H), 7.15
3
): δ ϭ 1.05 (d, J ϭ 6.8 Hz,
2
-yl]ethyl}amino)but-2-enedioate (11): Pale yellow oil. Yield 280 mg
3
3
ϪCH ), 1.21 (d,
2
1
(
70%). H NMR (CDCl
3
): δ ϭ 1.05 (t, J ϭ 6.7 Hz, 3 H,
), 2.95 (q, J ϭ 6.7 Hz, 2 H, CH ϪCH ), 3.06 (t, J ϭ 7.2
ϪCH ), 3.38 (s, 3 H, OCH ), 3.41 (t, J ϭ 7.2 Hz,
), 3.66 (s, 3 H, OCH ), 3.85 (s, 3 H, OCH ), 3.95 (s,
), 4.58 (s, 2 H, OϪCH ), 4.73 (s, 1 H, H-ε), 6.81 (dd,
J ϭ 6.8 Hz, 3 H, CH
3
3
3
CH
3
ϪCH
2
2
3
2 3
H, CH ϪCH
Hz, 2 H, NϪCH
2
2
3
2
3
H, NϪCH
H, OCH
2
3
3
(t, J ϭ 7.6 Hz, 1 H, 7-H), 7.25 (d, J ϭ 7.6 Hz, 1 H, 5-H), 7.50 (d,
3
2
J ϭ 7.6 Hz, 1 H, 8-H), 7.71 (br. s, 1 H, NH) ppm. ESI MS: m/z ϭ
ϩ
J ϭ 8.7 Hz, 1.9 Hz, 1 H, CH6Ј-indolyl), 7.04 (d, J ϭ 1.9 Hz, 1 H,
CH4Ј-indolyl), 7.22 (d, J ϭ 8.7 Hz, 1 H, CH7Ј-indolyl), 8.21 (br. s, 1 H,
NH) ppm. C NMR (CDCl ): δ ϭ 12.8, 24.9, 46.7, 50.7, 51.2,
3
2
22 2
43 [M ϩ 1]. C16H N (242.36): calcd. C 79.29, H 9.15, N 11.56;
found C 78.98, H 9.13, N 11.32.
1
3
Further elution provided 8a (100 mg, 9%) as light yellow crystals,
53.4, 56.4, 58.1, 65.5, 85.1, 100.1, 110.0, 111.8, 112.2, 129.2, 130.9,
1
m.p. 142Ϫ143 °C. H NMR (CDCl
3
): δ ϭ 0.85 (d, J ϭ 6.6 Hz, 3
ϪCH
ϪCH), 1.85 (td, J ϭ 13.2, 4.2 Hz, 1 H, 4-H
.27Ϫ2.28 (m, 2 H, CH ϪN), 2.45 (m, 1 H, CH iPr), 2.60Ϫ2.71 N 6.93; found C 62.02, H 7.12, N 6.90.
, 3-H ), 3.07 (d, J ϭ 11.0 Hz, 1 H, 1-H), 3.51 (td,
J ϭ 12.3, 2.8 Hz, 1 H, 3-H ), 7.20 (t, J ϭ 7.4 Hz, 1 H, 6-H),
.30Ϫ7.40 (m, 2 H, 5-H, 7-H), 7.52 (d, J ϭ 7.6 Hz, 1 H, 8-H) ppm.
135.5, 153.7, 154.9, 166.9, 168.6 ppm. EI MS: m/z (%) ϭ 404 (5)
ϩ
H, CH
3
ϪCH), 1.01 (t, J ϭ 7.1 Hz, 3 H, CH
3
2
), 1.08 (d, J ϭ [M ], 373 (8), 372 (20), 345 (15), 313 (25), 200 (100), 173 (85), 158
6
2
.6 Hz, 3 H, CH
3
a 28 2 6
), (20), 96 (15), 45 (15). C21H N O (404.46): calcd. C 62.36, H 6.98,
2
(
m, 2 H, 4-H
e
a
Ethyl (2E)-3-[{2-[3-(Ethoxymethyl)-5-methoxy-1H-indol-2-yl]ethyl}-
e
1
(
ethyl)amino]acrylate (14): Pale yellow oil. Yield 230 mg (61%). H
NMR: δ ϭ 1.05 (t, J ϭ 7.2 Hz, 3 H, NϪCH ϪCH ), 1.22 (t, J ϭ
.0 Hz, 3 H, OϪCH ϪCH ), 1.25 (t, J ϭ 7.1 Hz, 3 H,
OϪCH ϪCH ), 2.95 (t, J ϭ 7.5 Hz, 2 H, CH -α), 3.05 (q, J ϭ 7.2
Hz, 2 H, NϪCH ϪCH ), 3.48 (t, J ϭ 7.5 Hz, 2 H, NϪCH -β),
3.52 (q, J ϭ 7.0 Hz, 2 H, OϪCH ϪCH ), 3.85 (s, 3 H, OϪCH ),
4.25 (q, J ϭ 7.1 Hz, 2 H, OϪCH ϪCH ), 4.52 (s, 2 H, OϪCH
γ), 4.54 (d, J ϭ 13.2 Hz, 1 H, H-ε), 6.80 (dd, J ϭ 8.7 Hz, 1.9 Hz,
7
ϩ
2
3
22 2
ESI MS: m/z ϭ 243 [M ϩ 1]. C16H N (242.36): calcd. C 79.29,
7
2
3
H 9.15, N 11.56; found C 79.13, H 9.18, N 11.64.
2
3
2
General Synthetic Procedure for the Synthesis of Alkoxyindoles
2
3
2
9Ϫ11, 14, and 15: DMAD or EP (1.2 mmol) was added to a solu-
2
3
3
tion of the carboline derivative 2Ϫ4 (1 mmol) in methyl (ethyl) al-
cohol (10 mL). The reaction mixture was stirred for 4Ϫ6 h at room
2
3
2
-
temperature (TLC monitoring). The solvent was evaporated under 1 H, CH6Ј-indolyl), 7.04 (d, J ϭ 2.2 Hz, 1 H, CH4Ј-indolyl), 7.19 (d,
reduced pressure. The resulting residue was purified by column J ϭ 8.7 Hz, 1 H, CH7Ј-indolyl), 7.42 (d, J ϭ 13.2 Hz, 1 H, H-δ), 8.22
chromatography with ethyl acetate/hexane (1:2) as eluent. The first (br. s, 1 H, NH) ppm. C NMR (CDCl
1
3
3
): δ ϭ 13.4, 14.6, 15.4,
fraction provided the corresponding β-alkoxy derivatives 9Ϫ11 and
4 and 15.
24.7, 55.9, 55.9, 59.0, 63.2, 63.2, 65.3, 84.5, 100.6, 109.7, 111.3,
111.6, 128.9, 130.5, 135.2, 150.7, 154.3, 169.9 ppm. ESI MS: m/z ϭ
1
3
30 2 4
75 [M ϩ 1]. C21H N O (374.47): calcd. C 67.35, H 8.07, N 7.48;
Dimethyl (2E)-2-(Ethyl{2-[5-fluoro-3-(methoxymethyl)-1H-indol-2-
found C 67.39, H 8.31, N 7.25.
yl]ethyl}amino)but-2-enedioate (9): Colorless oil. Yield 270 mg
1
(
70%). H NMR (CDCl
3
): δ ϭ 1.07 (t, J ϭ 7.3 Hz, 3 H, CH
ϪCH
), 3.42 (t, J ϭ 6.7 Hz, 2 H, NϪCH
), 3.95 (s, 3 H, OCH ), 4.56 (s, 2 H, OϪCH
.74 (s, 1 H, H-ε), 6.90 (ddd, J ϭ 11.7 Hz, 9.2 Hz, 2.4 Hz, 1 H,
CH6Ј-indolyl), 7.20Ϫ7.27 (m, 2 H, CH4Ј-indolyl, CH7Ј-indolyl), 8.32 (br. Hz, 2 H, NϪCH
s, 1 H, NH) ppm. 13C NMR: δ ϭ 12.5, 22.1, 46.3, 51.2, 52.3, 55.0, 2 H, NϪCH
-β), 4.15 (q, J ϭ 7.3 Hz, 2 H, OϪCH
(s, 2 H, OϪCH -γ), 4.68 (bd, J ϭ 13.1 Hz, 1 H, H-ε), 6.90 (td, J ϭ
8.9, 2.4 Hz, 1 H, CH6Ј-indolyl), 7.17Ϫ7.27 (m, 2 H, CH4Ј-indolyl
CH7Ј-indolyl), 7.44 (d, J ϭ 13.1 Hz, 1 H, H-δ), 8.21 (br. s, 1 H, NH)
3
ϪCH
2
)
Ethyl (2E)-3-[(Ethyl){2-[5-fluoro-3-(methoxymethyl)-1H-indol-2-yl]-
2
.95 (q, J ϭ 7.3 Hz, 2 H, CH
CH -α), 3.39 (s, 3 H, OCH
β), 3.67 (s, 3 H, OCH
2
3
), 2.95 (t, J ϭ 6.7 Hz, 2 H, ethyl}amino]acrylate (15): Yellow crystals. M.p. 83Ϫ84 °C (ethyl
1
2
3
2
-
acetate). Yield 255 mg (73%). H NMR (CDCl
), 7.2 Hz, 3 H, NϪCH ϪCH ), 1.26 (t, J ϭ 7.0 Hz, 3 H,
OϪCH ϪCH ), 2.95 (t, J ϭ 8.3 Hz, 2 H, CH -α), 3.01 (q, J ϭ 7.3
ϪCH ), 3.39 (s, 3 H, OCH ), 3.41 (t, J ϭ 8.3 Hz,
ϪCH ), 4.55
3
): δ ϭ 1.07 (t, J ϭ
3
3
2
2
3
4
2
3
2
2
3
3
2
2
3
2
2
5
7.1, 66.3, 86.2, 103.2 (d,
J
C,F ϭ 26 Hz), 107.9 (d, JC,F ϭ 26 Hz),
2
3
1
10.4 (d, JC,F ϭ 9 Hz), 110.5, 131.4, 135.2, 136.8, 150.7, 157.3 (d,
C,F ϭ 230 Hz), 168.2, 169.1 ppm. EI MS: m/z (%) ϭ 392 (6) [M ],
,
1
ϩ
J
1
3
3
33 (21), 301 (79), 271 (18), 241 (10), 200 (100), 185 (15), 133 (11), ppm. C NMR (CDCl
3
): δ ϭ 15.1, 19.4, 30.8, 52.1, 58.2, 59.5,
Eur. J. Org. Chem. 2004, 3128Ϫ3135
3132
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

Tandem Cleavage of Hydrogenated β- and γ-Carbolines
FULL PAPER
6
3
0.1, 65.5, 85.2, 97.8, 103.8 (d, J 2C ,F ϭ 37 Hz), 110.5 (d, 2JC,F
ϭ
Dimethyl 8-Fluoro-3-isopropyl-2,3,6,11-tetrahydro-1H-azocino[4,5-
3
7 Hz), 111.2 (d, JC,F ϭ 14 Hz), 129.3, 132.7, 136.8, 151.2, 158.6
b]indole-4,5-dicarboxylate (18): Yield 135 mg (60%), yellow crystals,
1
ϩ
1
(d, JC,F ϭ 240 Hz), 170.4 ppm. EI MS: m/z (%) ϭ 348 (10) [M ], m.p. 160Ϫ162 °C (ethyl acetate/hexane). H NMR (CDCl
3
): δ ϭ
2
61 (5), 161 (7), 156 (100), 142 (5), 128 (20), 82 (10). C19
H
25FN
2
O
3
1.13 (d, J ϭ 6.6 Hz, 6 H, 2 ϫ CH
CH -1), 3.40 (m, 1 H, CH iPr), 3.70 (s, 3 H, OCH
OCH ), 3.90 (t, J ϭ 6.0 Hz, 2 H, CH -2), 3.93 (s, 2 H, CH
.83 (td, J9H,F ϭ J9H,10H ϭ 8.6, J9H,7H ϭ 2.5 Hz, 1 H, 9-H),
.30Ϫ7.21 (m, 2 H, 7-H, 10-H), 7.76 (br. s, 1 H, NH) ppm. IR
3
iPr), 3.15 (t, J ϭ 6.0 Hz, 2 H,
), 3.77 (s, 3 H,
-6),
(348.41): calcd. C 65.50, H 7.23, N 8.04; found C 65.34, H 7.33,
2
3
N 8.42.
3
2
2
6
7
Use of the same procedure in the case of the carboline 1 resulted
in the isolation of the azocinoindoles 20 and 21 (LCMS analysis
of the crude reaction mixtures carried out within 2 h of the start
of the reaction showed small peaks corresponding to 12 and 13).
Ϫ1
(
KBr): ν˜ ϭ 3395.9, 2952.0, 1715.8, 1669.5, 1546.3 cm . ESI MS:
ϩ
m/z ϭ 375 [M ϩ 1]. C20
2 4
H23FN O (374.41): calcd. C 64.16, H
6.19, N 7.48; found C 64.11, H 6.15, N 7.09.
Dimethyl 3-Ethyl-8-methoxy-2,3,6,11-tetrahydro-1H-azocino[4,5-b]-
Dimethyl 3-Ethyl-2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole-4,5-
dicarboxylate (20): Yield 170 mg (50%), m.p. 116Ϫ118 °C (ethyl
1
indole-4,5-dicarboxylate (19): Yield 60 mg (25%), yellow oil,
NMR (CDCl ): δ ϭ 1.01 (t, J ϭ 7.1 Hz, 3 H, CH ϪCH ), 3.01 (q,
J ϭ 7.1 Hz, 2 H, CH ϪCH ), 3.16 (t, J ϭ 6.2 Hz, 2 H, CH -1),
), 3.75 (s, 3 H, OCH ), 3.86 (s, 3 H, OCH ),
-6), 6.76 (dd,
H
3
2
3
1
acetate/hexane). H NMR (CDCl
3
): δ ϭ 1.00 (t, J ϭ 7.1 Hz, 3 H,
ϪCH ), 3.17 (t, J ϭ 6.0
), 3.74 (s, 3 H, OCH ), 3.94
-2), 4.04 (s, 2 H, CH -6), 7.07Ϫ7.01 (m,
H, 8-H, 9-H), 7.25 (m, 1 H, 7-H), 7.41 (m, 1 H, 10-H), 7.95 (br.
2
3
2
CH
2
ϪCH
3
), 3.00 (q, J ϭ 7.1 Hz, 2 H, CH
-1), 3.73 (s, 3 H, OCH
t, J ϭ 6.0 Hz, 2 H, CH
2
3
3
3
.73 (s, 3 H, OCH
.93 (t, J ϭ 6.2 Hz, 2 H, CH
3
3
3
Hz, 2 H, CH
2
3
3
2
-2), 4.00 (s, 2 H, CH
2
(
2
2
J ϭ 8.7 Hz, 2.3 Hz, 1 H, 9-H), 7.09 (d, J ϭ 2.3 Hz, 1 H, 7-H), 7.12
d, J ϭ 8.7 Hz, 1 H, 10-H), 7.75 (br. s, 1 H, NH) ppm. ESI MS:
2
(
13
s, 1 H, NH) ppm. C NMR (CDCl
3
): δ ϭ 14.4, 21.6, 27.9, 45.6,
8.2, 51.7, 52.3, 103.0, 110.0, 110.1, 118.1, 119.2, 121.1, 129.0,
32.5, 135.8, 152.5, 167.8, 169.5 ppm. EI MS: m/z (%) ϭ 342 (15)
ϩ
24 2 5
m/z ϭ 373 [M ϩ 1]. C20H N O (372.42): calcd. C 64.50, H 6.50,
4
1
[
N 7.52; found C 64.87, H 6.35, N 7.53.
ϩ
M ], 297 (10), 283 (50), 214 (15), 200 (20), 143 (100). C19
H
22
N
2
O
4
Ethyl 3-Ethyl-8-fluoro-2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole-
5-carboxylate (22): Yield 125 mg (65%), white crystals, m.p.
(342.39): calcd. C 66.65, H 6.48, N 8.18; found C 66.54, H 6.09,
1
N 8.25.
218Ϫ220 °C (ethyl acetate/hexane). H NMR (CDCl ) :δ ϭ 1.17
3
(
t, J ϭ 7.2 Hz, 3 H, NϪCH
2
ϪCH
3
), 1.30 (t, J ϭ 7.1 Hz, 3 H,
ϪCH ), 3.20 (t,
-6, CH -2), 4.17 (q,
Ethyl
3-Ethyl-2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole-5-car-
OϪCH CH ), 3.16 (q, J ϭ 7.2 Hz, 2 H, NϪCH
2
3
2
3
boxylate (21): Yield 135 mg (45%), m.p. 122Ϫ124 °C (ethyl acetate/ J ϭ 5.4 Hz, 2 H, CH
2
-1), 3.98 (m, 4 H, CH
2
2
1
hexane). H NMR: δ ϭ 1.19 (t, J ϭ 7.2 Hz, 3 H, NϪCH
2
ϪCH
), 3.00 (q, J ϭ 7.2 Hz, 2
), 3.22 (t, J ϭ 5.7 Hz, J ϭ 6.2 Hz, 2 H, CH
-2), 4.06 (s, 2 H, CH
), 7.01Ϫ7.11 (m, 2 H, 8-H, 9-H), 7.23 (m, 1 H, 7-H),
3
2
), J ϭ 7.1 Hz, 2 H, OϪCH ), 6.9 (td, J9H,F ϭ J9H,10H ϭ 8.6, J9H,7H ϭ
2.5 Hz, 1 H, 9-H), 7.09 (dd, J10H,9H ϭ 8.6, J10H,F ϭ 4.3 Hz, 1 H,
-1), 10-H), 7.32 (dd, J7H,F ϭ 9.7, J7H,9H ϭ 2.5 Hz, 1 H, 7-H), 7.35 (s,
1
.29 (t, J ϭ 7.1 Hz, 3 H, OϪCH
H, NϪCH ϪCH
.92 (bt, 2 H, CH
2
ϪCH
3
2
3
2
1
3
3
2
2
-6), 4.14 (q, J ϭ 7.1 Hz, 2 1 H, 4-H), 7.87 (br. s, 1 H, NH) ppm. C NMR (CDCl
3
): δ ϭ
14.7, 14.8, 18.9, 30.3, 44.9, 51.6, 59.6, 97.2, 103.4 (d, 2JC,F
ϭ
H, OϪCH
2
2
3
7
.39 (s, 1 H, 4-H), 7.41 (m, 1 H, 10-H), 7.77 (br. s, 1 H, NH) ppm. 23 Hz), 109.3 (d, JC,F ϭ 23 Hz), 110.4 (d, JC,F ϭ 9 Hz), 113.4,
13
1
C NMR ([D
6
]DMSO): δ ϭ 15.3, 15.6, 19.1, 30.3, 45.3, 51.6, 59.2,
129.3, 132.2, 133.6, 149.2, 157.7 (d, JC,F ϭ 240 Hz), 170.0 ppm.
ESI MS: m/z ϭ 317 [M ϩ 1]. C18H21FN O (316.37): calcd. C
2 2
68.34, H 6.69, N 8.85; found C 68.31, H 6.42, N 8.63.
ϩ
9
1
6.6, 110.7, 112.0, 117.9, 118.6, 120.7, 129.1, 133.7, 136.2, 149.8,
69.5 ppm. EI MS: m/z (%) ϭ 298 (38) [M ], 269 (8), 253 (15), 225
ϩ
(
7
20), 167 (18), 156 (60), 143 (100). C18
2.46, H 7.43, N 9.39; found C 73.21, H 7.55, N 9.52.
H
22
N
2
O
2
(298.38): calcd. C
Ethyl 3-Ethyl-6-methyl-1,2,3,6-tetrahydroazocino[5,4-b]indole-5-car-
boxylate (23): A solution of β-carboline 7 (200 mg, 0.9 mmol) and
ethyl propiolate (110 mg, 1.1 mmol) in absolute ethanol (10 mL)
was stirred at room temp. for 5 h. The solvent was evaporated un-
der reduced pressure, and dry diethyl ether (10 mL) was added to
General Synthetic Procedure for the Synthesis of Azocinoindoles
7Ϫ19 and 22: Anhydrous AlCl (3 mg, 23 µmol) was added to a
stirred solution of the alkoxy indole derivative 9Ϫ11 or 15
0.6 mmol) in dry acetonitrile (10 mL), and stirring was continued
1
3
the oily residue. White crystals of 23 (150 mg, 52%) were filtered
(
1
off and dried, m.p. 188Ϫ190 °C. H NMR (CDCl
3
) :δ ϭ 1.16 (t,
for 24 h at room temperature (TLC monitoring: alufoil, hexane/
ethyl acetate, 1:1). The reaction mixture was concentrated under
reduced pressure, and the resulting dark, oily residue was dissolved
in ethyl acetate (200 mL) and percolated through a short column
of alumina oxide (h ϭ 3 cm, d ϭ 3 cm). Evaporation of the solvent
provided the target azocinoindole derivatives 17Ϫ19 and 22.
J ϭ 7.2 Hz, 3 H, CH
CH CH ϪO), 1.59 (d, J ϭ 7.3 Hz, 3 H, CH
4.5 Hz, 2.8 Hz, 1 H, 1-H ), 3.25 (m, 3 H, NϪCH
dt, J ϭ 14.5, 2.8 Hz, 1 H, 2-H ), 4.08 (td, J ϭ 14.5, 2.8 Hz, 1 H,
), 4.18 (q, J ϭ 7.1 Hz, OCH CH ), 4.69 (q, J ϭ 7.3 Hz, 1 H,
3
CH
2
ϪN), 1.28 (t, J ϭ 7.1 Hz, 3 H,
ϪCH), 3.05 (dt, J ϭ
CH , 1-H ), 3.57
3
2
3
1
e
2
3
a
(
e
2
6
1
-H
a
2
3
-H), 7.05Ϫ7.16 (m, 2 H, 9-H, 10-H), 7.25 (d, J ϭ 7.6 Hz, 1 H,
1-H), 7.45 (d, J ϭ 7.6 Hz, 1 H, 8-H), 7.61 (s, 1 H, 4-H), 7.95 (br.
Dimethyl
3-Ethyl-8-fluoro-2,3,6,11-tetrahydro-1H-azocino[4,5-b]-
13
6
s, 1 H, NH) ppm. C NMR ([D ]DMSO): δ ϭ 15.4, 15.6, 26.4,
indole-4,5-dicarboxylate (17): Yield 130 mg (60%), white crystals,
2
1
2
2
7.1, 31.6, 49.8, 51.8, 59.5, 98.6, 107.4, 111.1, 118.0, 118.7, 121.0,
1
m.p. 141Ϫ143 °C (ethyl acetate/hexane). H NMR (CDCl
.01 (t, J ϭ 7.4 Hz, 3 H, CH ϪCH ), 3.00 (q, J ϭ 7.4 Hz, 2 H,
CH ϪCH ), 3.19 (t, J ϭ 6.7 Hz, 2 H, CH -1), 3.75 (s, 6 H, 2 ϫ
OCH ), 3.85 (t, J ϭ 6.7 Hz, 2 H, CH -2), 3.95 (s, 2 H, CH -6), 6.9
td, J9H,F ϭ J9H,10H ϭ 8.7, J9H,7H ϭ 2.0 Hz, 1 H, 9-H), 7.17 (dd,
3
): δ ϭ
30.0, 134.8, 139.0, 151.6, 169.7 ppm. IR (KBr): ν˜ ϭ 3295.0,
1
2
3
Ϫ1
ϩ
974.1, 1647.6, 1598.0 cm . EI MS: m/z (%) ϭ 312 (100) [M ],
2
3
2
97 (27), 267 (20), 255 (13), 239 (54), 223 (9), 209 (9), 194 (16), 182
3
2
2
(
25), 170 (61), 143 (64), 122 (50). C19
H
24
N
2
O
2
(312.41): calcd. C
(
J
73.05, H 7.74, N 8.97; found C 73.18, H 7.87, N 8.59.
10H,9H ϭ 8.7, J10H,F ϭ 4.5 Hz, 1 H, 10-H), 7.24 (dd, J7H,F ϭ 8.7,
J
7H,9H ϭ 2.0 Hz, 1 H, 7-H), 7.90 (br. s, 1 H, NH) ppm. EI MS: Ethyl 3-Ethyl-6-isopropyl-1,2,3,6-tetrahydroazocino[5,4-b]indole-5-
ϩ
m/z (%) ϭ 360 (35) [M ], 328 (10), 301 (62), 271 (12), 185 (20), 161 carboxylate (24): A solution of β-carboline 8 (0.20 g, 0.8 mmol)
(
5
100), 133 (11), 59 (15). C19
.87, N 7.77; found C 63.30, H 6.01, N 7.45.
H
21FN
2
O
4
(360.38): calcd. C 63.32, H
and ethyl propiolate (100 mg, 1 mmol) in absolute ethanol (10 mL)
was heated at reflux for 4 h. The solvent was evaporated under
Eur. J. Org. Chem. 2004, 3128Ϫ3135
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3133

L. G. Voskressensky et al.
FULL PAPER
reduced pressure, and dry diethyl ether (10 mL) was added to the
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
oily residue, causing precipitation of 24 (120 mg, 44%); white crys-
1
tals, m.p. 222Ϫ224 °C. H NMR (CDCl
3
): δ ϭ 0.89 (t, J ϭ 6.2 Hz, Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: ϩ44-1223/
iPr), 1.16 (t, J ϭ 7.2 336-033; E-mail: deposit@ccdc.cam.ac.uk].
ϪN), 1.26 (t, J ϭ 7.1 Hz, 3 H, CH CH ϪO),
.04 (m, 1 H, CH iPr), 2.99 (dt, J ϭ 16.1 Hz, 2.6 Hz, 1 H, 1-H ),
.23 (m, 3 H, NϪCH CH , 1-H ), 3.46 (ddt, J ϭ 14.1, 2.9, 1.8 Hz,
H, 2-H ), 4.09 (td, J ϭ 14.1, 2.9 Hz, 1 H, 2-H ), 4.18Ϫ4.11 (m,
H, 6-H, CH ϪO), 7.11Ϫ7.08 (m, 2 H, 9-H, 10-H), 7.25 (d, J ϭ
.6 Hz, 1 H, 11-H), 7.46 (d, J ϭ 7.5 Hz, 1 H, 8-H), 7.64 (s, 1 H,
3
H, CH
3
iPr), 1.06 (t, J ϭ 6.8 Hz, 3 H, CH
CH
3
Hz, 3 H, CH
3
2
3
2
AChE Inhibition Measurements: Enzyme inhibitory activities were
determined by Ellman’s[ general method, with AChE from bov-
ine erythrocytes (EC. 3.1.1.7, C-5021 from Sigma). The AChE ac-
tivity was determined in a reaction mixture containing a solution
of AChE (200 µL, 0.415 U/mL in 0.1  phosphate buffer, pH 8.0),
a solution of 5,5Ј-dithiobis(2-nitrobenzoic acid) (100 µL, 3.3 m in
2
3
1
3
7
4
1
1
e
17]
2
3
a
e
a
2
13
3
-H), 8.07 (br. s, 1 H, NH) ppm. C NMR (CDCl ): δ ϭ 14.7,
5.0, 20.4, 22.6, 26.3, 39.2, 45.2, 48.7, 52.0, 59.8, 96.9, 106.9, 110.4,
0.1  phosphate-buffered solution pH 7.4), an aqueous solution of
the substrate (5 m, 100 µL), a solution of the inhibitor (100 µL)
and phosphate buffer (pH 8, 0.1 , 500 µL). Acetylthiocholine was
used as the substrate, and five to seven concentrations of the
17.5, 118.8, 120.9, 130.0, 134.2, 137.9, 151.0, 171.0 ppm. IR
Ϫ1
(
KBr): ν˜ ϭ 3395.9, 2952.0, 1715.8, 1669.5, 1546.3 cm . ESI MS:
ϩ
28 2 2
m/z ϭ 341 [M ϩ 1]. C21H N O (340.46): calcd. C 74.08, H 8.29,
Ϫ7
Ϫ4
examined compounds, ranging from 1ϫ10 to 1ϫ10 , were
spectrophotometrically tested for AChE inhibition (measurements
of increase in absorbance at 412 nm was taken over 3.0 min
at 25 °C).
N 8.23; found C 73.93, H 8.63, N 8.01. The solvent was evaporated
from the mother liquor, and the residue was dissolved in ethyl acet-
ate/hexane (1:10) and percolated through a short column with alu-
mina oxide. Evaporation of the solvent provided 16 as white crys-
1
tals (77 mg, 25%), m.p. 88Ϫ90 °C (ethyl acetate/hexane). H NMR
(
CDCl
Hz, 3 H, CH
J ϭ 7.1 Hz, 3 H, CH
.00 (m, 1 H, CH iPr), 3.00 (m, 2 H, CH
m, 2 H, N-CH CH ), 3.30Ϫ3.42 (m, 4 H, CH
3
): δ ϭ 0.82 (d, J ϭ 6.6 Hz, 3 H, CH
iPr), 1.15 (t, J ϭ 7.2 Hz, 3 H, CH
CH O), 1.27 (t, J ϭ 7.1 Hz, 3 H, CH
3
iPr), 1.10 (d, J ϭ 6.6
CH N), 1.16 (t,
CH O),
ϪN), 3.15Ϫ3.17
N, OCH
3
3
2
3
2
3
2
Acknowledgments
2
2
ϪCH
2
(
(
2
3
2
CH
2
2
), 4.14 This work was supported by the Russian Foundation for Basic
CH ),
Research (grant no. 02-03-32941).
.70 (d, J ϭ 12.2 Hz, 1 H, CHϭCHϪN), 7.11 (t, J ϭ 8.0 Hz, 1 H,
-H), 7.15 (t, J ϭ 8.0 Hz, 1 H, 4-H), 7.34 (d, J ϭ 8.0 Hz, 1 H, 6-
d, J ϭ 7.1 Hz, 1 H, CHϪO), 4.14 (q, J ϭ 7.1 Hz, 2 H, OCH
2
3
4
5
H), 7.48 (d, J ϭ 12.2 Hz, 1 H, CHϭCHϪN), 7.53 (d, J ϭ 8.0 Hz,
1
1
8
1
H, 7-H), 8.21 (br. s, 1 H, NH) ppm. 13C NMR (CDCl
4.6, 15.2, 15.2, 19.0, 19.2, 20.4, 34.3, 58.8, 58.8, 64.9, 64.9, 79.5,
3
): δ ϭ
[
1]
C. M. Bertha, M. Ellis, J. L. Flippen-Anderson, F. Porreca, R.
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4.2, 110.4, 111.0, 118.2, 119.4, 121.9, 127.9, 135.2, 135.5, 150.8,
ϩ
69.9. ESI MS: m/z ϭ 387 [M ϩ 1]. C23
H
34
N
2
O
3
(386.53): calcd.
H. Rojas, M. Nidia, P. Diaz, C. Celina, O. Perez, Revista Cub-
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[
[
3]
4]
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F. Abe, R. Fu Chen, T. Yamauchi, N. Marubayashi, I. Ueda,
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5
α
radiation,
[5]
3, 12661Ϫ12670.
[
[
[
6]
7]
8]
T. Kam, K. Yoganathan, Cheng-Hock Chuakh, Tetrahedron
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C
19
H21FN
2
O
4
,
M
r
ϭ
60.38 g·molϪ1, monoclinic, space group P2
3
1
/c, a ϭ 8.7731(19),
˚
˚
b ϭ 17.636(4), c ϭ 11.738(3) A, β ϭ 104.458(4) A, V ϭ 1758.6(7)
˚
3
3
Ϫ1
A , Z ϭ 4, ρ ϭ 1.361 g·cm , µ ϭ 0.103 cm , F(000) ϭ 760. A
total of 9800 reflections (2.13 Ͻ θ Ͻ 30.02°) were collected, of
which 4145 were unique [R(int.) ϭ 0.0337]. The structure was
[9]
5
92Ϫ604.
[
21]
solved with the program SHELXS-97
SHELXL-97
reflections with I Ͼ 2σ(I); max.\min. residual electron density 0.930
and Ϫ0.293e·A
and refined by use of
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[
22]
2
1
to R ϭ 0.0735 and wR(F ) ϭ 0.1830 for 4145
[
[
11]
12]
A. V. Varlamov, T. N. Borisova, L. G. Voskressensky, B. Nsabi-
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˚
Ϫ3
.
461Ϫ464.
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Crystal Structure Analysis for 24:
C
21
H
28
N
2
O
2
,
M
r
ϭ
3
1
40.45 g·molϪ1, monoclinic, space group P2
1
/c, a ϭ 10.432(2), b ϭ
8.175(4), c ϭ 11.302(2) A, β ϭ 113.62(3) A, V ϭ 1963.5(7) A ,
1
62Ϫ163.
˚
˚
˚
3
[13]
A. V. Varlamov, T. N. Borisova, L. G. Voskressensky, L. N.
Kulikova, T. A. Soklakova, A. I. Chernyshev, G. G. Alexand-
rov, Tetrahedron Lett. 2002, 43, 6767Ϫ6769.
3
Ϫ1
Z ϭ 4, ρ ϭ 1.152 g·cm , µ ϭ 0.103 cm , F(000) ϭ 736. A total of
592 reflections (2.13 Ͻ θ Ͻ 27.96) were collected, of which 4323
were unique [R(int.) ϭ 0.1185]. The structure was solved with the
program SHELXS-97 and refined by use of SHELXL-97 to R
4
[
[
[
14]
15]
16]
T. N. Borisova, L. G. Voskressensky, L. N. Kulikova, T. A.
Soklakova, A. V. Varlamov, Molecular Diversity 2003, 6,
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Leonetti, C. Altomare, A. Carotti, J. Med. Chem. 2001, 44,
1
ϭ
2
0.0683 and wR(F ) ϭ 0.1877 for 4097 reflections with I Ͼ 2σ(I);
˚
Ϫ3
max./min. residual electron density 0.324 and Ϫ0.269e·A
.
3
195Ϫ3198.
CCDC-218170 (for 17) and -229769 (for 24) contain the sup-
plementary crystallographic data for this paper. These data can be
E. Scarpini, P. Scheltsen, H. Feldman, Lancet Neurol. 2003,
2, 539Ϫ547.
3134
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3128Ϫ3135

Tandem Cleavage of Hydrogenated β- and γ-Carbolines
FULL PAPER
[
[
[
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[20]
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[22]
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5.0 Bruker AXS Inc., Madison, WI, 1997.
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G. M. Sheldrick SHELXL, Program for crystal structure refine-
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Received February 17, 2004
Eur. J. Org. Chem. 2004, 3128Ϫ3135
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3135