A versatile synthesis of 3-substituted 4-cyano-1,2,3,4-tetrahydro-1-oxo- β-carbolines

Article abstract of DOI:10.1055/s-0030-1258282

In a project aimed at the synthesis of analogues of the cytotoxic -carboline alkaloid bauerine C with more advantageous solubility properties, a 3-amino analogue was prepared by treating ethyl 3-(cyanomethyl)indole-2- carboxylate with ammonia. Upon addition of aldehydes or ketones to the reaction mixture, 3-substituted 4-cyano-1,2,3,4-tetrahydro-1-oxo - carbolines were obtained in a one-pot condensation. When cyclic ketones are used, the procedure allows a convenient synthesis of tetracyclic spiro compounds. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258282

PAPER
3849
A Versatile Synthesis of 3-Substituted 4-Cyano-1,2,3,4-tetrahydro-1-oxo-b-
carbolines
Kilian Huber, Oliver Kast, Franz Bracher*
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstrasse 5-13, 81377 Munich,
Germany
Fax +49(89)218077171; E-mail: franz.bracher@cup.uni-muenchen.de
Received 28 June 2010; revised 19 August 2010
Encouraged by these results, we decided to further ex-
Abstract: In a project aimed at the synthesis of analogues of the cy-
plore bauerine C type 1-oxo-b-carbolines as scaffolds for
totoxic b-carboline alkaloid bauerine C with more advantageous
novel bioactive compounds. A number of synthetic ap-
solubility properties, a 3-amino analogue was prepared by treating
proaches to 1-oxo-b-carbolines have been published in lit-
ethyl 3-(cyanomethyl)indole-2-carboxylate with ammonia. Upon
addition of aldehydes or ketones to the reaction mixture, 3-substi- erature; representative examples are discussed here. For
tuted 4-cyano-1,2,3,4-tetrahydro-1-oxo-b-carbolines were obtained
in a one-pot condensation. When cyclic ketones are used, the proce-
dure allows a convenient synthesis of tetracyclic spiro compounds.
our total synthesis of bauerine C (1) we employed a Japp–
Klingemann synthesis starting from diazotized 2,3-
dichloroaniline and ethyl 2-oxopiperidine-3-carboxylate,
followed by Fischer cyclization to afford the 1,2,3,4-tet-
rahydro-1-oxo-b-carboline in good yield.3 We have also
established other efficient routes towards this ring system
using tryptamines as versatile building blocks;7 isocyan-
ates and carbamoyl chlorides prepared from tryptamines
and triphosgene are conveniently cyclized using acid ca-
talysis to give 1,2,3,4-tetrahydro-1-oxo-b-carbolines. Re-
cently, the palladium-catalyzed intramolecular olefination
of alkenyl-substituted indoles has been reported for the
preparation of 4-substituted 1-oxo-b-carbolines.8
Key words: b-carbolines, cyclizations, multicomponent reactions,
indoles, lactams
Natural products are a vital source of material for the dis-
covery and development of novel drugs enabling the treat-
ment of major diseases, e.g. cancer.1 Moreover, the broad
variety of heterocyclic ring systems provided by alkaloids
permits the structure-based design of new enhanced bio-
active compounds.
Bauerine C (1, Figure 1), a 1,2-dihydro-1-oxo-b-carbo-
line isolated from the blue-green alga Dichotrix baueri-
ana, has been reported to have strong cytotoxic as well as
antiviral activity.2 In previous studies, we presented the
first total synthesis of this alkaloid,3 and prepared hybrids
between 1 and the quinazolinocarboline alkaloid rutae-
carpine which exhibited cytotoxic activity superior to
those of both parent alkaloids.4 Recently, we successfully
combined the unique 6,7-dichloroindole substructure of
alkaloid 1 with a common kinase inhibitor scaffold to pre-
pare a new class of sirtuin (class III histone deacetylase)
inhibitors.5 Recently 1-oxo-b-carboline-derived com-
pounds, such as 2, have been shown to exert antitumoral
activity and to be potent inhibitors of protein kinases im-
plicated in the pathogenesis of various diseases.6
Due to the very poor solubility of bauerine C (1) in water,
our first intention was to prepare a derivative with superi-
or physico-chemical properties. We selected a 3-amino
analogue of 1, which would hopefully provide better sol-
ubility, and, in addition, include an additional functional
group susceptible to hydrogen bonding.
The central building block ethyl 6,7-dichloro-1H-indole-
2-carboxylate (3a) was prepared starting from 2,3-dichlo-
rophenylhydrazine and ethyl pyruvate in a Fischer cy-
clization with polyphosphoric acid.9 Subsequent
aminomethylation at C3 using Eschenmoser’s salt10 gave
the gramine derivative 4a. This amine was converted into
nitrile 5a under standard conditions upon quaternization
with dimethyl sulfate,11 followed by nucleophilic substi-
tution with potassium cyanide. N-Methylation at the in-
dole nitrogen to give 6a was performed using sodium
hydride and methyl iodide in anhydrous N,N-dimethylform-
amide. Analogous to previously published procedures,12
cyano ester 6a was converted into the target aminopyri-
done 7a by heating with liquid ammonia and ammonium
chloride in a sealed tube. The chlorine-free analogue 7b
was prepared in an analogous manner starting from phe-
nylhydrazine (Scheme 1).
O
HN
NH
NH
Cl
N
N
H
N
S
Cl
Me
O
O
HN
O
1
2
Having the intermediate 6a in hand, we worked out a
completely new approach towards highly substituted
1,2,3,4-tetrahydro-1-oxo-b-carbolines. Thus, upon heat-
ing the 3-(cyanomethyl)indole ester 6a with acetone, liq-
uid ammonia, and ammonium chloride in a sealed tube,
Figure 1 Lead structures
SYNTHESIS 2010, No. 22, pp 3849–3854
Advanced online publication: 01.10.2010
DOI: 10.1055/s-0030-1258282; Art ID: T14010SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

3850
K. Huber et al.
PAPER
NMe2
OEt
N
a
b
OEt
N
OEt
R1
R1
N
H
R1
N
H
R1
H
O
R1
O
R1
O
4a: R1 = Cl 78%
4b: R1 = H
5a: R1 = Cl 88%
5b: R1 = H
3a: R1 = Cl
3b: R1 = H
NH2
N
c
d
NH
OEt
R1
N
R1
N
R1
Me
O
R1
Me
O
6a: R1 = Cl 80%
6b: R1 = H 86%
7a: R1 = Cl 77%
7b: R1 = H 80%
CN
CN
R3
R3
X
N
e
n
OEt
NH
NH
or
R1
N
R1
N
R1
N
R1
R2
O
R1
R2
O
R1
R2
O
R1 R2
Cl Me
R1 R2
R3
R1 R2
Cl Me
Cl Me
Cl Me
X
n
2
1
2
8a
8b
9
13a
13b
Me
Me
Et
Me
Me
5a
5b
6a
6b
Cl
H
H
H
10
11
12
CH2
CH2
O
H
Me
Cl Me
Cl Me
Me
Cl
H
H
H
H
CN
O
H
R
f
6b
NH
N
14: R = Me 35%
15: R = Ph 70%
Scheme 1 Reagents and conditions: (a) N,N-dimethylmethyleneiminium chloride, DMF, 100 °C, 2 h; (b) (MeO)2SO2, KCN, DMSO, r.t., 7 h;
(c) NaH, MeI, DMF, r.t., 5 h; (d) NH4Cl, NH3, 120 °C, 16 h, sealed tube; (e) ketone R3 CO, NH4Cl, NH3, 100 °C, 16 h, sealed tube, yields see
2
Table 1; (f) aldehyde RCHO, NH4Cl, NH3, 100 °C, 16 h, sealed tube.
7,8-dichloro-4-cyano-1,2,3,4-tetrahydro-3,3,9-trimethyl-
1-oxo-b-carboline (8a) was obtained in high yield (87%).
Table 1 Synthesized Oxo-b-carbolines
The formation of this product may be explained by vari-
ous mechanisms. Most likely, acetone condenses with the
acidic methylene group of the (cyanomethyl)indole to
give an a,b-unsaturated nitrile. Michael-type addition of
ammonia to this system might yield a primary amine,
which in turn forms the lactam upon nucleophilic attack at
the ester group. However, alternative pathways, e.g. ami-
nolysis of the ester prior to the Michael addition, or initial
formation of a ketimine and subsequent Mannich-type re-
action with the (cyanomethyl)indole cannot be excluded.
Entry
Starting materials
6a, acetone
Product
8a
Yield (%)
1
2
87
87
39
21
22
62
95
65
35
70
6b, acetone
8b
3
6a, pentan-3-one
6a, cyclohexanone
6a, cyclopentanone
6a, tetrahydropyran-4-one
5a, acetone
9
4
10
5
11
6
12
Excited by this smooth conversion, we investigated the
scope and limitations of this novel approach (Table 1).
Not surprisingly, pentan-3-one reacted in an analogous
manner giving the 3,3-diethyl analogue 9 (entry 3), and
cyclic ketones (cyclohexanone, cyclopentanone, tetrahy-
dropyran-4-one; entries 4–6) gave the corresponding
spiro derivatives 10, 11, and 12 in moderate to good
7
13a
13b
14
8
5b, acetone
9
6b, acetaldehyde
6b, benzaldehyde
10
15
Synthesis 2010, No. 22, 3849–3854 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 4-Cyano-1,2,3,4-tetrahydro-1-oxo-b-carbolines
3851
2 H, OCH2), 3.92 (s, 2 H, Ar-CH2), 2.29 (s, 6 H, NCH3), 1.45 (t, J =
7.1 Hz, 3 H, CH2CH3).
lacking an alkyl substituent at the indole nitrogen (entries 13C NMR (125 MHz, CDCl3): d = 161.5 (C=O), 133.8 (C7a), 129.0
yields. Further we found that this cyclization also takes
place with 3-(cyanomethyl)indole-2-carboxylates 5a,b
(C6), 128.1 (C3a), 125.8 (C2), 122.6 (C5), 122.0 (C3), 121.1 (C4),
115.4 (C7), 61.3 (OCH2), 53.2 (Ar-CH2), 45.7 (NCH3), 14.4
(CH2CH3).
7 and 8) and non-chlorinated indoles 5b and 6b (entries 2
and 8).
Replacing the ketones with aldehydes (acetaldehyde,
MS (EI, 70 eV): m/z (%) = 318 (3) [M+], 316 (15) [M+], 314 (23)
benzaldehyde; entries 9 and 10) in this cyclocondensation
with 6b led to 3-monosubstituted products 14 and 15. Due
to the generation of two stereogenic centers, the products
were obtained as racemic mixtures of diastereoisomers.
These mixtures could not be separated by column chroma-
tography, but in the case of the 3-methyl derivative 14, a
single diastereoisomer was obtained upon crystallization
from ethyl acetate. However, the coupling constants re-
corded for H4 (14, J = 4.1 Hz; mixture of diastereoiso-
mers 15, J = 4.6 and 5.1 Hz) do not allow the
stereochemistry (cis/trans) at C3 and C4 to be assigned.
[M+], 299 (100).
Anal. Calcd for C14H16Cl2N2O2: C, 53.35; H, 5.12; N, 8.89. Found:
C, 53.47; H, 5.07; N, 8.92.
Ethyl 6,7-Dichloro-3-(cyanomethyl)-1H-indole-2-carboxylate
(5a)
Under N2, to a soln of 4a (2.30 g, 7.30 mmol) and KCN (950 mg,
14.6 mmol) in anhyd DMSO (50 mL), (MeO)2SO2 (1.84 g,
14.6 mmol) was added dropwise over 15 min. The mixture was
stirred at r.t. for 7 h, then diluted with H2O (250 mL) and extracted
with EtOAc (3 × 100 mL). The combined organic layers were
washed with 2 M HCl (2 × 100 mL) and brine (100 mL), dried
(MgSO4), and filtered, and the solvent was evaporated. The residue
was recrystallized (EtOH) to give 5a (1.90 g, 88%) as white nee-
dles; mp 177 °C.
Among all of the carbonyl compounds investigated so far,
only formaldehyde and hexafluoroacetone failed to give
the desired cyclization products.
IR (KBr): 2247 (CN) cm–1.
In conclusion, our new procedure constitutes a feasible
and efficient approach towards 3-substituted 4-cyano-
1,2,3,4-tetrahydro-1-oxo-b-carbolines starting from
readily available starting materials. Furthermore, these
compounds have the potential for further functionaliza-
tion at C4 using standard operations (hydrolysis or reduc-
tion of the nitrile; deprotonation/alkylation). Thus,
additional efforts are being undertaken to expand this syn-
thetic procedure and apply it to the preparation of more
complex systems.
1H NMR (500 MHz, CDCl3): d = 9.07 (br s, 1 H, NH), 7.65 (d, J =
8.7 Hz, 1 H, H4), 7.30 (d, J = 8.7 Hz, 1 H, H5), 4.50 (q, J = 7.1 Hz,
2 H, OCH2), 4.23 (s, 2 H, Ar-CH2), 1.48 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.6 (C=O), 133.7 (C7a), 130.0
(C6), 126.1 (C3a), 125.5 (C2), 123.6 (C5), 119.2 (C4), 117.0 (CN),
116.1 (C7), 112.0 (C3), 62.0 (OCH2), 14.4 (CH3) 13.7 (Ar-CH2).
MS (EI, 70 eV): m/z (%) = 300 (5) [M+], 298 (29) [M+], 296 (41)
[M+], 270 (12), 250 (100).
Anal. Calcd for C13H10Cl2N2O2: C, 52.55; H, 3.39; N, 9.43. Found:
C, 52.43; H, 3.35; N, 9.44.
Ethyl 6,7-Dichloro-3-(cyanomethyl)-1-methyl-1H-indole-2-car-
boxylate (6a); Typical Procedure
NMR spectra were recorded using a Jeol JNMR-GSX 400 or Jeol
JNMR-GSX 500 (Jeol, Peabody, USA). Mass spectra (EI, 70 eV)
were recorded using a Hewlett Packard 5989 A Mass Spectrometer
with a 59980 B Particle Beam LC/MS-interface (Agilent Technolo-
gies, Palo Alto, USA). HRMS were obtained using a Jeol Mstation
700 (Jeol, Peabody, USA). IR spectra were recorded as KBr discs
on a Perkin Elmer FT-IR Paragon 1000 (Perkin Elmer, Waltham,
USA) or Jasco FT/IR-410 (Jasco, Easton, USA). Melting points
were determined with a Büchi B-540 apparatus (Büchi, Flawil,
Switzerland) and are uncorrected. Elemental analyses were per-
formed using a CHN-Elementaranalysator Rapid (Heraeus, Hanau,
Germany) or Elementaranalysator Vario EL (Elementar, Hanau,
Germany). Purification by flash column chromatography (FCC)
was performed using Silica gel 60 (Merck, Darmstadt, Germany);
petroleum ether = PE. All chemicals were purchased from Sigma-
Aldrich, Fluka and Acros.
Under N2, to a suspension of NaH (77 mg, 1.91 mmol) in anhyd
DMF (15 mL), a soln of 5a (520 mg, 1.75 mmol) in anhyd DMF (5
mL) was added and the mixture stirred at 40 °C for 1 h. After cool-
ing to r.t., MeI (248 mg, 1.75 mmol) was added dropwise and the
mixture was stirred for 5 h, then poured into H2O (50 mL) and ex-
tracted with EtOAc (3 × 100 mL). The combined organic extracts
were washed with brine (2 × 100 mL), dried (MgSO4), and filtered,
and the solvent was evaporated. The residue was recrystallized
(EtOH) to give 6a (434 mg, 80%) as white needles; mp 178 °C.
1H NMR (400 MHz, CD2Cl2): d = 7.56 (d, J = 8.6 Hz, 1 H, H4),
7.30 (d, J = 8.6 Hz, 1 H, H5), 4.47 (q, J = 7.1 Hz, 2 H, OCH2), 4.38
(s, 3 H, NCH3), 4.10 (s, 2 H, Ar-CH2), 1.47 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13C NMR (100 MHz, CD2Cl2): d = 160.9 (C=O), 134.9 (C7a), 131.1
(C6), 128.8 (C2), 126.6 (C3a), 123.1 (C5), 118.8 (C4), 117.4 (CN),
116.6 (C7), 111.8 (C3), 61.8 (OCH2), 35.2 (NCH3), 14.2 (Ar-CH2),
14.0 (CH2CH3).
Ethyl 6,7-Dichloro-3-[(dimethylamino)methyl]-1H-indole-2-
carboxylate (4a)
Ethyl 6,7-dichloro-1H-indole-2-carboxylate (3a)9 (3.10 g,
12.0 mmol) and N,N-dimethylmethyleneiminium chloride (1.46 g,
15.6 mmol) were dissolved in DMF (10 mL) and heated to 100 °C
for 2 h. The mixture was diluted with H2O (50 mL), brought to pH
>10 using 6 M NaOH and extracted with Et2O (3 × 50 mL). The or-
ganic layer was dried (MgSO4) and filtered, and the solvent was
evaporated. The residue was recrystallized (MeCN) to give 4a
(2.95 g, 78%) as white needles; mp 132 °C.
MS (EI, 70 eV): m/z (%) = 314 (7) [M+], 312 (40) [M+], 310 (65)
[M+], 281 (100).
Anal. Calcd for C14H12Cl2N2O2: C, 54.04; H, 3.89; N, 9.00. Found:
C, 53.76; H, 3.93; N, 8.92.
Ethyl 3-(Cyanomethyl)-1-methyl-1H-indole-2-carboxylate (6b)
Following the typical procedure for 6a using 5b13 (400 mg,
1.75 mmol) gave 6b (365 mg, 86%) as white crystals (PE); mp 89
°C.
1H NMR (500 MHz, CDCl3): d = 8.92 (br s, 1 H, NH), 7.74 (d, J =
8.7 Hz, 1 H, H4), 7.21 (d, J = 8.7 Hz, 1 H, H5), 4.45 (q, J = 7.1 Hz,
Synthesis 2010, No. 22, 3849–3854 © Thieme Stuttgart · New York

3852
K. Huber et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 7.86 (d, J = 8.1 Hz, 1 H, H4),
7.62 (d, J = 8.6 Hz, 1 H, H7), 7.38–7.42 (m, 1 H, H6), 7.16–7.24 (m,
1 H, H5), 4.36 (q, J = 7.2 Hz, 2 H, OCH2), 4.31 (s, 2 H, Ar-CH2),
3.99 (s, 3 H, NCH3), 1.39 (t, J = 7.2 Hz, 3 H, CH2CH3).
tracted with EtOAc (3 × 30 mL). The combined organic layers were
dried (Na2SO4) and filtered, and the solvent removed. The crude
product was purified by flash column chromatography.
(4RS)-7,8-Dichloro-3,3,9-trimethyl-1-oxo-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indole-4-carbonitrile (8a)
Following the general procedure using 6a (1.00 g, 3.21 mmol) and
acetone (5 mL) with FCC (PE–EtOAc, 1:1) gave 8a as white nee-
dles (EtOH); yield: 900 mg (87%); mp 235 °C.
13C NMR (100 MHz, DMSO-d6): d = 161.7 (C=O), 138.5 (C7a),
126.2 (C6), 126.0 (C2), 125.6 (C3a), 121.4 (C5), 120.7 (C4), 119.4
(CN), 112.1 (C3), 111.7 (C7), 61.6 (OCH2), 32.7 (NCH3), 14.5
(CH2CH3), 14.3 (Ar-CH2).
MS (EI, 70 eV): m/z (%) = 242 (64) [M+], 213 (100).
IR (KBr): 2245 cm–1 (CN).
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.31; H, 5.64; N, 11.62.
1H NMR (500 MHz, CD2Cl2): d = 7.69 (d, J = 8.5 Hz, 1 H, H5),
7.31 (d, J = 8.5 Hz, 1 H, H6), 6.01 (br s, 1 H, NH), 4.55 (s, 3 H,
NCH3), 4.18 (s, 1 H, H4), 1.61 (s, 3 H, 3-CH3), 1.51 (s, 3 H, 3-CH3).
13C NMR (125 MHz, CD2Cl2): d = 159.8 (C=O), 135.4 (C8a), 130.6
(C7), 126.8 (C9a), 124.7 (C4b), 123.2 (C6), 118.7 (C5), 116.9 (C8),
116.8 (CN), 111.8 (C4a), 55.7 (C3), 36.2 (C4), 34.5 (NCH3), 27.8
(3-CH3), 25.9 (3-CH3).
3-Amino-2,9-dihydro-1-oxo-b-carbolines 7a,b; General Proce-
dure
At –80 °C, gaseous NH3 was introduced into a glass tube containing
6a,b (3.21 mmol) and NH4Cl (6.42 mmol) until approx. 10 mL
were condensed. The tube was closed tightly and heated to 120 °C
for 16 h in an autoclave. The mixture was allowed to reach r.t. and
after evaporation of excess NH3 extracted with EtOAc (3 × 30 mL).
The combined organic layers were dried (Na2SO4) and filtered, and
the solvent was removed. The crude product was purified by flash
column chromatography.
MS (EI, 70 eV): m/z (%) = 325 (5) [M+], 323 (32) [M+], 321 (47)
[M+], 264 (73), 236 (100).
Anal. Calcd for C15H13Cl2N3O: C, 55.92; H, 4.07; N, 13.04. Found:
C, 55.70; H, 4.13; N, 12.94.
(4RS)-3,3,9-Trimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-4-carbonitrile (8b)
Following the general procedure using 6b (778 mg, 3.21 mmol) and
acetone (5 mL) with FCC (PE–EtOAc, 1:1) gave 8b as white crys-
tals (EtOAc); yield: 707 mg (87%); mp 218 °C (dec).
3-Amino-7,8-dichloro-9-methyl-2,9-dihydro-1H-pyrido[3,4-
b]indol-1-one (7a)
Following the general procedure using 6a (1.00 g, 3.21 mmol) with
FCC (EtOAc–MeOH–concd NH3, 90:5:5) gave 7a as green crystals
(EtOH); yield: 700 mg (77%); mp 256 °C.
1H NMR (400 MHz, DMSO-d6, 40 °C): d = 10.74 (br s, 1 H, 2-NH),
7.81 (d, J = 8.5 Hz, 1 H, H5), 7.25 (d, J = 8.5 Hz, 1 H, H6), 5.85 (s,
1 H, H4), 5.37 (br s, 2 H, 3-NH2), 4.46 (s, 3 H, NCH3).
13C NMR (100 MHz, DMSO-d6, 40 °C): d = 155.5 (C=O), 145.7
(C3), 137.9 (C8a), 131.1 (C7), 129.8 (C4a), 123.3 (C4b), 121.8
(C5), 121.3 (C9a), 121.0 (C6), 115.2 (C8), 76.7 (C4), 34.3 (NCH3).
IR (KBr): 2240 cm–1 (CN).
1H NMR (400 MHz, DMSO-d6): d = 8.02 (s, 1 H, NH), 7.73 (d, J =
8.0 Hz, 1 H, H5), 7.57 (d, J = 8.5 Hz, 1 H, H8), 7.32–7.38 (m, 1 H,
H7), 7.15–7.23 (m, 1 H, H6), 4.72 (s, 1 H, H4), 4.02 (s, 3 H, NCH3),
1.45 (s, 3 H, CH3), 1.29 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 165.0 (C1), 143.4 (C8a),
130.2 (C9a), 129.7 (C7), 128.0 (C4b), 125.7 (C6), 124.5 (C5), 123.4
(C4a), 116.0 (C8), 59.8 (C3), 39.5 (C4), 35.9 (NCH3), 32.0 (CH3),
30.9 (CH3).
MS (EI, 70 eV): m/z (%) = 285 (12) [M+], 283 (66) [M+], 281 (100)
[M+].
Anal. Calcd for C12H9Cl2N3O: C, 51.09; H, 3.22; N, 14.89. Found:
C, 50.00; H, 3.18; N, 14.03.
MS (CI): m/z (%) = 214 (100) [M + H]+.
Anal. Calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59. Found: C,
70.67; H, 5.83; N, 16.71.
3-Amino-9-methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one
(7b)
Following the general procedure using 6b (778 mg, 3.21 mmol)
with FCC (EtOAc–MeOH–concd NH3, 90:5:5) gave 7b as a yellow
solid; yield: 548 mg (80%); mp 184 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 10.64 (s, 1 H, NH), 7.83 (d, J =
7.9 Hz, 1 H, H5), 7.45 (d, J = 8.4 Hz, 1 H, H8), 7.39–7.43 (m, 1 H,
H7), 7.06–7.10 (m, 1 H, H6), 5.88 (s, 1 H, H4), 5.25 (s, 2 H, NH2),
3.39 (s, 3 H, NCH3).
13C NMR (100 MHz, DMSO-d6): d = 155.7 (C1), 144.8 (C3), 141.6
(C8a), 129.4 (C4a), 127.0 (C7), 121.9 (C5), 121.3 (C4b), 120.1
(C9a), 118.9 (C6), 110.5 (C8), 77.5 (C4), 31.3 (NCH3).
(4RS)-7,8-Dichloro-3,3-diethyl-9-methyl-1-oxo-2,3,4,9-tetrahy-
dro-1H-pyrido[3,4-b]indole-4-carbonitrile (9)
Following the general procedure using 6a (1.00 g, 3.21 mmol) and
pentan-3-one (5 mL) with FCC (PE–EtOAc, 1:1) gave 9 as white
crystals (EtOH); yield: 436 mg (39%); mp 245 °C.
IR (KBr): 2241 cm–1 (CN).
1H NMR (500 MHz, DMSO-d6): d = 8.29 (br s, 1 H, NH), 7.87 (d,
J = 8.5 Hz, 1 H, H5), 7.45 (d, J = 8.5 Hz, 1 H, H6), 4.90 (s, 1 H,
H4), 4.47 (s, 3 H, NCH3), 1.93 (dq, J = 14.4, 7.6 Hz, 1 H, CH2), 1.76
(dq, J = 14.4, 7.6 Hz, 1 H, CH2), 1.63 (dq, J = 14.4, 7.4 Hz, 1 H,
CH2), 1.47 (dq, J = 14.4, 7.4 Hz, 1 H, CH2), 0.96 (t, J = 7.6 Hz, 3 H,
CH2CH3), 0.81 (t, J = 7.4 Hz, 3 H, CH2CH3).
13C NMR (125 MHz, DMSO-d6): d = 159.2 (C=O), 134.4 (C8a),
129.0 (C7), 127.5 (C9a), 124.9 (C4b), 122.8 (C6), 119.9 (C5), 117.8
(CN), 115.7 (C8), 112.3 (C4a), 59.9 (C3), 34.1 (NCH3), 31.5 (C4),
27.4 (CH2), 26.3 (CH2), 7.7 (CH2CH3), 7.1 (CH2CH3).
MS (CI): m/z (%) = 214 (100) [M + H]+.
Anal. Calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C,
66.88; H, 5.30; N, 19.14.
Cyclization of Ethyl 3-(Cyanomethyl)indole-2-carboxylates
5a,b and 6a,b; General Procedure
MS (EI, 70 eV): m/z (%) = 353 (7) [M+], 351 (34) [M+], 349 (50)
Compound 5a,b and 6a,b (3.21 mmol) and NH4Cl (6.42 mmol)
were suspended in the given amount of aldehyde or ketone in a glass
tube. After cooling to –80 °C, gaseous NH3 was introduced into the
tube until approx. 10 mL were condensed. The tube was closed
tightly and heated to 100 °C for 16 h in an autoclave. The mixture
was allowed to reach r.t., excess NH3 was evaporated, and it was ex-
[M+], 264 (100).
Anal. Calcd for C17H17Cl2N3O: C, 58.30; H, 4.89; N, 12.00. Found:
C, 58.04; H, 4.75; N, 11.84.
Synthesis 2010, No. 22, 3849–3854 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 4-Cyano-1,2,3,4-tetrahydro-1-oxo-b-carbolines
3853
(4¢RS)-7¢,8¢-Dichloro-9¢-methyl-1¢-oxo-1¢,2¢,4¢,9¢-tetrahydro-
spiro[cyclohexane-1,3¢-pyrido[3,4-b]indole]-4¢-carbonitrile (10)
Following the general procedure using 6a (1.00 g, 3.21 mmol) and
cyclohexanone (5 mL) with FCC (PE–EtOAc, 1:1) gave 10 as white
crystals (EtOH); yield: 244 mg (21%); mp 290 °C.
(4RS)-7,8-Dichloro-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-4-carbonitrile (13a)
Following the general procedure using 5a (954 mg, 3.21 mmol) and
acetone (5 mL) with FCC (PE–EtOAc, 1:1) gave 13a as white nee-
dles (EtOH); yield: 996 mg (95%); mp 248 °C.
IR (KBr): 2238 cm–1 (CN).
IR (KBr): 2239 cm–1 (CN).
1H NMR (500 MHz, DMSO-d6): d = 8.22 (br s, 1 H, H2¢), 7.91 (d,
J = 8.5 Hz, 1 H, H5¢), 7.44 (d, J = 8.5 Hz, 1 H, H6¢), 5.06 (s, 1 H,
H4¢), 4.46 (s, 3 H, NCH3), 1.99–1.33 (m, 10 H, H2/H3/H4/H5/H6).
13C NMR (125 MHz, DMSO-d6): d = 159.3 (C=O), 134.4 (C8a¢),
129.0 (C7¢), 127.6 (C9a¢), 125.0 (C4b¢), 122.9 (C6¢), 119.9 (C5¢),
117.9 (CN), 115.7 (C8¢), 112.0 (C4a¢), 56.6 (spiro C), 34.55 (C2 or
C6), 34.59 (C2 or C6), 34.1 (NCH3), 30.8 (C4¢), 24.7 (C4), 21.3 (C3
or C5), 20.5 (C3 or C5).
1H NMR (500 MHz, DMSO-d6): d = 12.72 (br s, 1 H, 9-NH), 8.21
(br s, 1 H, 2-NH), 7.75 (d, J = 8.5 Hz, 1 H, H5), 7.41 (d, J = 8.5 Hz,
1 H, H6), 4.83 (s, 1 H, H4), 1.51 (s, 3 H, 3-CH3), 1.35 (s, 3 H, 3-
CH3).
13C NMR (125 MHz, DMSO-d6): d = 159.5 (C=O), 135.6 (C8a),
129.2 (C9a), 127.9 (C7), 125.0 (C4b), 123.0 (C6), 119.9 (C5), 118.7
(CN), 116.4 (C8), 112.6 (C4a), 55.9 (C3), 34.9 (C4), 27.8 (3-CH3),
26.5 (3-CH3).
MS (EI, 70 eV): m/z (%) = 365 (9) [M+], 363 (42) [M+], 361 (79)
MS (EI, 70 eV): m/z (%) = 311 (11) [M+], 309 (66) [M+], 307 (100)
[M+], 264 (93), 236 (100).
[M+].
Anal. Calcd for C18H17Cl2N3O: C, 59.68; H, 4.73; N, 11.60. Found:
C, 59.34; H, 4.78; N, 11.41.
Anal. Calcd for C14H11Cl2N3O: C, 54.57; H, 3.60; N, 13.64. Found:
C, 54.39; H, 3.51; N, 13.61.
(4¢RS)-7¢,8¢-Dichloro-9¢-methyl-1¢-oxo-1¢,2¢,4¢,9¢-tetrahydro-
spiro[cyclopentane-1,3¢-pyrido[3,4-b]indole]-4¢-carbonitrile
(11)
Following the general procedure using 6a (1.00 g, 3.21 mmol) and
cyclopentanone (5 mL) with FCC (PE–EtOAc, 1:1) gave 11 as
white crystals (EtOH); yield: 250 mg (22%); mp 253 °C.
(4RS)-3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-4-carbonitrile (13b)
Following the general procedure using 5b (733 mg, 3.21 mmol) and
acetone (5 mL) with FCC (PE–EtOAc, 1:1) gave 13b as white crys-
tals (EtOAc); yield: 499 mg (65%); mp 267 °C.
IR (KBr): 2243 cm–1 (CN).
IR (KBr): 2239 cm–1 (CN).
1H NMR (400 MHz, DMSO-d6): d = 12.08 (s, 1 H, 9-NH), 8.02 (s,
1 H, 2-NH), 7.74 (d, J = 8.1 Hz, 1 H, H5), 7.48 (d, J = 8.2 Hz, 1 H,
H8), 7.27–7.35 (m, 1 H, H7), 7.08–7.15 (m, 1 H, H6), 4.76 (s, 1 H,
H4), 1.52 (s, 3 H, CH3), 1.36 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 159.9 (C1), 137.2 (C8a),
126.6 (C9a), 124.6 (C7), 124.1 (C4b), 120.4 (C6), 119.5 (C4), 118.6
(CN), 113.0 (C8), 110.4 (C4a), 55.5 (C3), 34.6 (C4), 27.4 (CH3),
26.1 (CH3).
1H NMR (500 MHz, CDCl3): d = 7.60 (d, J = 8.5 Hz, 1 H, H5¢), 7.30
(d, J = 8.5 Hz, 1 H, H6¢), 6.34 (br s, 1 H, NH), 4.56 (s, 3 H, NCH3),
4.17 (s, 1 H, H4¢), 2.16–2.24 (m, 1 H, H2 or H5), 2.01–2.08 (m, 1 H,
H2 or H5), 1.80–1.96 (m, 6 H, H2, 2 H3, 2 H4, H5).
13C NMR (125 MHz, CDCl3): d = 160.6 (C=O), 135.5 (C8a¢), 131.2
(C7¢), 127.3 (C9a¢), 124.5 (C4b¢), 123.6 (C6¢), 118.6 (C5¢), 117.2
(C8¢), 117.1 (CN), 112.8 (C4a¢), 66.3 (spiro C), 39.2 (C2 or C5),
37.8 (C2 or C5), 34.8 (NCH3), 34.5 (C4¢), 23.6 (C3 or C4), 23.3 (C3
or C4).
MS (EI, 70 eV): m/z (%) = 239 (48) [M+], 154 (96), 127 (100).
Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56. Found: C,
69.79; H, 5.80; N, 17.39.
MS (EI, 70 eV): m/z (%) = 351 (11) [M+], 349 (61) [M+], 347 (100)
[M+].
Anal. Calcd for C17H15Cl2N3O: C, 58.63; H, 4.34; N, 12.07. Found:
C, 58.46; H, 4.41; N, 11.93.
(3RS,4RS)-3,9-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indole-4-carbonitrile (14)
Following the general procedure using 6b (778 mg, 3.21 mmol) and
acetaldehyde (5 mL) with FCC (PE–EtOAc, 1:1). Crystallization
(EtOAc) gave a single diastereoisomer as white crystals; yield:
269 mg (35%); mp 245 °C.
(4¢RS)-7¢,8¢-Dichloro-9¢-methyl-1¢-oxo-1¢,2,2¢,3,4¢,5,6,9¢-octa-
hydrospiro[pyran-4,3¢-pyrido[3,4-b]indole]-4¢-carbonitrile (12)
Following the general procedure using 6a (1.00 g, 3.21 mmol) and
tetrahydropyran-4-one (5 mL) with FCC (PE–EtOAc, 1:1) gave 12
as white crystals (EtOH); yield: 720 mg (62%); mp 316 °C.
IR (KBr): 2233 cm–1 (CN).
1H NMR (400 MHz, DMSO-d6): d = 8.04 (s, 1 H, NH), 7.74 (d, J =
8.2 Hz, 1 H, H5), 7.59 (d, J = 8.8 Hz, 1 H, H8), 7.36–7.42 (m, 1 H,
H7), 7.18–7.24 (m, 1 H, H6), 4.71 (d, J = 4.1 Hz, 1 H, H4), 4.04 (s,
3 H, NCH3), 4.03–4.10 (m, 1 H, H3), 1.39 (d, J = 6.6 Hz, 3 H, 3-CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.1 (C1), 138.5 (C8a),
126.9 (C9a), 125.1 (C7), 122.5 (C4b), 120.9 (C6), 119.9 (C5), 117.9
(CN), 112.9 (C4a), 111.1 (C8), 49.3 (C3), 31.1 (NCH3), 29.7 (C4),
17.7 (3-CH3).
IR (KBr): 2239 cm–1 (CN).
1H NMR (400 MHz, DMSO-d6): d = 8.51 (br s, 1 H, NH), 7.83 (d,
J = 8.6 Hz, 1 H, H5¢), 7.46 (d, J = 8.6 Hz, 1 H, H6¢), 5.11 (s, 1 H,
H4¢), 4.46 (s, 3 H, NCH3), 3.88–3.96 (m, 1 H, H2 or H6), 3.70–3.78
(m, 1 H, H2 or H6), 3.58–3.66 (m, 1 H, H2 or H6), 3.50–3.58 (m,
1 H, H2 or H6), 1.90–2.05 (m, 2 H, H3 or H5), 1.62–1.74 (m, 2 H,
H3 or H5).
13C NMR (100 MHz, DMSO-d6): d = 159.3 (C=O), 134.5 (C8a¢),
129.1 (C7¢), 127.7 (C9a¢), 124.9 (C4b¢), 123.0 (C6¢), 119.8 (C5¢),
117.5 (CN), 115.8 (C8¢), 111.6 (C4a¢), 62.5 (C2 or C6), 61.8 (C2 or
C6), 54.2 (spiro C), 35.0 (C3 or C5), 34.3 (C3 or C5), 34.2 (NCH3),
32.1 (C4¢).
MS (EI, 70 eV): m/z (%) = 239 (54) [M+], 196 (53), 168 (100).
Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56. Found: C,
69.78; H, 5.48; N, 17.49.
(3RS,4RS)-9-Methyl-1-oxo-3-phenyl-2,3,4,9-tetrahydro-1H-py-
rido[3,4-b]indole-4-carbonitrile (15)
Following the general procedure using 6b (778 mg, 3.21 mmol) and
benzaldehyde (5 mL) with FCC (PE–EtOAc, 2:1) gave 15 as ~1:1
mixture of diastereoisomers as white crystals (EtOAc); yield:
677 mg (70%); mp 255 °C.
MS (EI, 70 eV): m/z (%) = 367 (8) [M+], 365 (46) [M+], 363 (66)
[M+], 264 (100).
Anal. Calcd for C17H15Cl2N3O2: C, 56.06; H, 4.15; N, 11.54. Found:
C, 55.82; H, 4.24; N, 11.34.
Synthesis 2010, No. 22, 3849–3854 © Thieme Stuttgart · New York

3854
K. Huber et al.
PAPER
M.; Tuccinardi, T.; Martinelli, A.; Penco, S.; Zunino, F.
IR (KBr): 2236 cm–1 (CN).
J. Med. Chem. 2008, 51, 7777. (c) Wu, J.-P.; Wang, J.;
Abeywardane, A.; Andersen, D.; Emmanuel, M.; Gautschi,
E.; Goldberg, D. R.; Kashem, M. A.; Lukas, S.; Mao, W.;
Martin, L.; Morwick, T.; Moss, N.; Pargellis, C.; Patel, U.
R.; Patnaude, L.; Peet, G. W.; Skow, D.; Snow, R. J.; Ward,
Y.; Werneburg, B.; White, A. Bioorg. Med. Chem. Lett.
2007, 17, 4664.
1H NMR (400 MHz, DMSO-d6): d = 8.54 (d, J = 3.3 Hz, 1 H, NH),
8.39 (s, 1 H, NH), 7.78 (d, J = 8.0 Hz, 1 H, H5), 7.74 (d, J = 8.0 Hz,
1 H, H5), 7.61–7.12 (m, 16 H), 5.25 (d, J = 4.6 Hz, 1 H, H3), 5.18–
5.21 (m, 1 H, H3), 5.05 (d, J = 5.1 Hz, 1 H, H4), 4.98 (d, J = 4.6 Hz,
1 H, H4), 4.09 (s, 3 H, NCH3), 4.07 (s, 3 H, NCH3).
13C NMR (100 MHz, DMSO-d6): d = 163.0 (C1), 161.7 (C1), 140.0,
139.6, 139.4, 138.0, 129.5, 129.4, 129.3, 129.0, 128.4, 127.8, 127.0,
126.8, 126.2, 126.0, 123.6, 123.4, 121.8, 121.1, 120.8, 120.2, 118.7,
113.6, 112.10, 112.07, 111.2, 58.6 (C3), 58.4 (C3), 33.0 (C4), 32.1
(NCH3), 31.8 (C4).
(7) (a) Bracher, F.; Hildebrand, D. Pharmazie 1993, 48, 695.
(b) Bracher, F.; Hildebrand, D.; Häberlein, H. Nat. Prod.
Res. 2004, 18, 391. (c) For a very recent application of this
methodology, see: La Ferla, B.; Orsato, A.; Zona, C.; Cervi,
G.; Papeo, G.; Felder, E. R.; Nicotra, F. Synthesis 2010, 601.
(8) (a) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
10250. (b) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2004, 126, 3700.
MS (EI, 70 eV): m/z (%) = 301 (52) [M+], 196 (54), 168 (100).
Anal. Calcd for C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C,
75.66; H, 5.09; N, 14.00.
(9) Preparation of substituted indoles for treatment of a disease
or condition mediated by monocyte chemoattractant protein-
1 (MCP-1): Barker, A. J.; Kettle, J. G.; Faull, A. W. WO
9,907,351, 1999.
(10) Kozikowski, A. P.; Ishida, H. Heterocycles 1980, 14, 55.
(11) Snyder, H. R.; Smith, C. W.; Stewart, J. M. J. Am. Chem.
Soc. 1944, 66, 200.
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Synthesis 2010, No. 22, 3849–3854 © Thieme Stuttgart · New York