Platinum-catalyzed cyclization reaction of alkynes: Synthesis of azepino[3,4-b]indol-1-ones

Article abstract of DOI:10.1039/c0ob00728e

Novel azepino[3,4-b]indol-1-ones were synthesized from alkyne-substituted indole-2-carboxamides by catalytic intramolecular cyclization in the presence of PtCl₂. The scope and limitations of this straightforward protocol are reported.

Full text of DOI:10.1039/c0ob00728e

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PAPER
Platinum-catalyzed cyclization reaction of alkynes: synthesis of
azepino[3,4-b]indol-1-ones†
Marina Gruit, Anahit Pews-Davtyan and Matthias Beller*
Received 15th September 2010, Accepted 26th October 2010
DOI: 10.1039/c0ob00728e
Novel azepino[3,4-b]indol-1-ones were synthesized from alkyne-substituted indole-2-carboxamides by
catalytic intramolecular cyclization in the presence of PtCl2. The scope and limitations of this
straightforward protocol are reported.
or platinum-catalyzed cycloisomerization and hydroarylation,6,9–11
Introduction
offer a straightforward preparation of this class of compounds.
As an example, recently we reported that the intramolecular
cyclization of pyrrole-2-carboxamide alkyne 1 catalyzed by PtII,
PtIV or AuIII complexes gave two pyrroloazepinones 2 and 3
(Scheme 1).12 In the presence of either H2PtCl6·H2O at 120 ◦C
or AuCl3 at room temperature new pyrrolo[3,2-c]azepin-4-ones 3
were mainly formed in up to 76% yield. Due to the efficiency of this
straightforward synthesis we decided to extend this methodology
to the preparation of indoloazepinones (R = aryl, Scheme 1). Here,
we report for the first time our results in this area.
Pyrrolo-azepinones represent an interesting structural motif found
in a variety of bio-active natural products such as hymenialdisine,
stevensine, latonduine, and the paullones. In the last decade
synthetic hymenialdisine derivatives have emerged as promising
therapeutic molecules for the treatment of a range of diseases,
including cancer.1–4 For example, hymenialdisine derivative B
and paullone derivatives C (Fig. 1) have been found to inhibit
selectively different kinases and cytokines.2,3 Recently, structurally
related indolobenzazepin-7-ones D also showed cytotoxic and
anti-tumor properties as inhibitors of tubulin polymerization.4
Scheme 1 Strategy for the synthesis of pyrrolo and indoloazepinones
from 2-propargylamide-substituted pyrroles or indoles.
Results and discussion
At the start of our investigations, we studied the influence of dif-
ferent solvents and temperatures on platinum- and gold-catalyzed
cyclization of the model reaction using 1-methyl-1H-indole-2-
carboxylic acid methyl-(3-p-tolyl-prop-2-ynyl)-amide (5a) (Ta-
ble 1). Compound 5a was easily formed in two steps from
commercially available 1-methylindole-2-carboxylic acid. Ami-
dation with N-methylpropargylamine in the presence of 4-
(dimethylamino)pyridine (DMAP) and 1,1¢-carbonyldiimidazole
(CDI) at 40 ◦C in tetrahydrofuran (THF) gave 1-methyl-1H-
indole-2-carboxylic acid methyl-prop-2-ynyl-amide (4a) in 98%
yield. Subsequent Sonogashira reaction (2 mol% PdCl2(PPh3)2,
4 mol% CuI, 20 h at 60 ◦C in triethylamine/THF) using 4-
iodotoluene led to 5a in 62% overall yield.
Fig. 1 Hymenialdisine and indoloazepinone derivatives.
Due to their biological properties, the synthesis of in-
doloazepinones has attracted significant interest in recent years.5,6
For some time our laboratory has also been involved in the
development of novel catalytic methods for the synthesis of
potential bio-active hymenialdisine derivatives, e.g. E (Fig. 1)7
and indoles.8 Among the different catalytic methods especially
transition-metal-catalyzed cyclizations of aromatic and heteroaro-
matic compounds with alkynes, in particular, intramolecular gold-
Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, D-18059 Rostock, Germany. E-mail: matthias.beller@
catalysis.de; Fax: +49 381 1281 51113; Tel: +49 381 1281 113
† Electronic supplementary information (ESI) available: Scans of NMR
spectra are available. See DOI: 10.1039/c0ob00728e
Among the tested catalysts H2PtCl6·6H2O, K2PtCl6, PtCl2,
AuCl3 and AuCl all led to 2,10-dimethyl-5-p-tolyl-3,10-dihydro-
2H-azepino[3,4-b]indol-1-one (6a) as the main product (Table 1).
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Table 1 Catalyst (Pt or Au-salts) and solvent screening reaction for indole synthesisa
Entry
Catalyst
Solvent
T/◦C
Convb [%]
6a Yieldb [%]
7a Yieldc [%]
8a Yieldc [%]
1
2
3
4
5
6
7
8
H2PtCl6·6H2O
H2PtCl6·6H2O
H2PtCl6·6H2O
K2PtCl6
K2PtCl6
K2PtCl6
PtCl2
PtCl2
PtCl2
PtCl2
AuCl3
AuCl3
AuCl3
AuCl
AuCl
AuCl
AuCl(PPh3)
Toluene
Dioxane
DCM
Toluene
Dioxane
DCM
Toluene
Toluene
Dioxane
DCM
Toluene
Dioxane
DCM
120
60
RT
120
60
RT
140
120
60
RT
120
60
RT
120
60
RT
120
100
99
100
63
25
0
100
100
100
100
66
100
100
97
42
58
97
30
2
19
< 1
1
15
< 1
0
27
18
13
1
9
5
1
13
0
4
2
2
0
1
0
7
3
7
1
5
2
3
6
3
1
0
0
39
35
80
98
24
93
96
52
6
9
10
11
12
13
14
15
16
17
Toluene
Dioxane
DCM
18
84
12
82
1
1
0
Toluene
a Reaction conditions: 5 mol% catalyst, 0.2 mmol compound 5a, 10 mL solvent, 20 h. b Determined by GC with hexadecane as internal standard. c Ratio
determined by 1H NMR.
High activity and full conversion are observed in the presence of
H2PtCl6·6H2O, PtCl2 and AuCl3 as catalyst in dichloromethane at
room temperature (Table 1, entries 3, 10 and 13). Under these mild
conditions the product 6a is formed in 96–98% yield. On the other
hand K2PtCl6, AuCl or AuCl(PPh3) showed no or low activity for
the cyclization process (Table 1, entries 5, 6, 15 and 17). As shown
in Table 1, in most cases only a small amount of the two other iso-
mers 2,6-dimethyl-5-p-tolyl-3,6-dihydro-2H-azepino[4,3-b]indol-
1-one (7a) and 2,9-dimethyl-4-(4-methyl-benzyl)-2,9-dihydro-b-
carbolin-1-one (8a) was observed. It appears that the ratio of
6a and 7a depends strongly upon the temperature and solvent.
Indeed, we observed that using harsh◦(Table 1, entries 1, 4, 7, 8 and
14) reaction conditions (120 or 140 C) promoted the formation
of 7a
studies of the scope and limitations of the cyclization with different
arylated substrates (Table 2).
Hence, the Sonogashira coupling of various substituted aryl
or heteroaryl iodides and bromides with 1-methyl-1H-indole-2-
carboxylic acid methyl-prop-2-ynyl-amide (4a) was performed to
give indole-substituted alkynes 5a–m in up to 94% isolated yield.
Apart from the N-methylated derivatives the N-benzyl-protected
alkyne (5o) was also obtained by Sonogashira reaction between N-
benzylpropargylamine and 4-iodotoluene followed by amidation
of benzyl-(3-p-tolyl-prop-2-ynyl)-amine with indole-2-carboxylic
acid.
As shown in Table 2, the cyclization reaction of compounds
5a–o in the presence of 5 mol% of PtCl2 in dichloromethane at
◦
50 C formed three different products 6, 7 or 8. Contrary to the
Based on previous investigations of related cyclizations,6,10,11,13
we propose the following mechanism of this Au- or Pt-catalyzed
cycloisomerization reaction (Scheme 2). Treatment of the indole-
substituted alkyne 5 with a AuIII, PtII or PtIV catalyst results in
an initial activation of the triple bond by the electrophilic metal
species (I). Then, in principle three modes of cycloisomerization
reactions are possible depending on the reaction conditions
(Table 1 and Scheme 2). Seven-membered-ring compounds 6
and 7 can be formed by a 7-endo-dig cyclization which might
require a 6-endo-dig process to form the spiro-intermediate II,
already described in the literature.6,10 On the other hand, the initial
activation of the triple bond (I) can also give the cation V which
might be involved in the formation of b-carbolines 8 by a 6-exo-dig
cyclization.11
model reaction, the reaction temperature needed to be increased
to obtain full conversion. In most cases the cycloisomerization
formed 4-substituted azepino[3,4-b]indol-1-ones 6a–e, g, i–k, m,
o as the main products in up to 80% isolated yield (Table 2,
entries 1–5, 7, 9–11, 13 and 15). Notably, we observed that
the formation of the isomeric 4-substituted b-carbolin-2-one 8
depended on the aryl moieties. More specifically, the presence of
an acceptor group on the arylated substrate gave 6-membered-
ring products 8d–h by a 6-exo-dig process (Table 2, entries 4–8).
Furthermore, it is interesting to note that cyclization of the initial
indole alkyne 4a gave product 8n in 95% isolated yield.11 This
result clearly showed the importance of the aryl substituent in the
cycloisomerization mechanism. We also observed the formation of
azepino[4,3-b]-indol-1-one isomers 7m and 7o when the arylated
substrate owned a donor and an acceptor group (Table 2, entry
13). Similar results were obtained in the case of an N-benzyl
On the basis of the catalyst optimization, we choose PtCl2
as catalyst in dichloromethane (Table 1, entry 10) for further
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Scheme 2 General synthesis of azepino[3,4-b]indol-1-one 6, azepino[4,3-b]indol-1-one 7 and b-carbolin-2-one 8 derivatives.
protecting group instead of the N-methyl substituent (Table 2,
entry 15).
Agilent 6890 chromatograph with a 30 m HP5 column. HRMS
was performed on MAT 95XP (EI) and Agilent 6210 Time-of-
Flight LC/MS (ESI). GC-MS was performed on Agilent 5973
chromatograph Mass Selective Detector.
Conclusion
The analyses of compounds 4a and 8n have been already
described in earlier publication.11
In summary, we have prepared a variety of novel azepin[3,4-
b]indol-1-ones 6 in a straightforward manner. The key step is the
platinum-catalyzed 7-endo-dig cyclization process which proceeds
in good isolated yields under optimized conditions. Contrary to
our previous work with pyrrole-substituted alkynes, in general no
rearrangement of the amide substituent took place. Nevertheless,
the formation of the three different cyclization products 6, 7
and 8 strongly depends on the catalyst, solvent, temperature, N-
protecting group and aryl substituents.
General procedure for the synthesis of
1-methyl-1H-indole-2-carboxylic acid methyl-prop-2-ynyl-amide
(4a)
1-Methylindole-2-carboxylic acid (1.5 g, 8.56 mmol, 1 equiv), 4-
dimethylaminopyridine (DMAP, 0.105 g, 0.86 mmol) and 1,1¢-
carbonyldiimidazole (CDI, 1.39 g, 8.56 mmol, 1 equiv) were in-
troduced into 30 mL of tetrahydrofuran (THF). The solution was
stirred 90 min at room temperature and N-methylpropargylamine
(0.87 mL, 10.28 mmol, 1.2 equiv) was then added. The brown
mixture was stirred overnight at 40 ◦C. After removal of the solvent
in vacuo, the residue was purified by column chromatography (Rf
0.51, solvent heptane–ethyl acetate 1 : 1) to give indole 4a as a light
yellow powder (1.89 g, 98%).
1H NMR (300 MHz; CDCl3): d = 7.66 (d, J = 8.0 Hz, 1H), 7.35
(m, 1H), 7.32 (ddd, J = 8.3 Hz, J = 6.7 Hz, J = 1.2 Hz, 1H), 7.16
(ddd, J = 8.0 Hz, J = 6.7 Hz, J = 1.3 Hz, 1H), 6.82 (br, 1H), 4.38
(s, 2H, CH2), 3.86 (s, 3H, NCH3), 3.25 (s, 3H, OCNCH3), 2.38
(br, 1H, CH ); 13C NMR (75.5 MHz, CDCl3): d = 164.0 (CO),
138.0 (C), 130.9 (C), 126.2 (C), 123.5 (CH), 121.7 (CH), 120.3
(CH), 109.8 (CH), 104.3 (CH), 78.4 ( CH), 31.2 (NCH3), not
displayed: NCH2, OCNCH3, C CH.
Experimental
General information
All reactions were carried out under an argon atmosphere.
Chemicals were purchased from Aldrich, Fluka and Acros and
unless otherwise noted were used without further purification.
All compounds were characterized by 1H NMR, 13C NMR, GC-
MS, HRMS and IR spectroscopy. 1H and 13C NMR spectra
were recorded on Bruker AV 300 and AV 400 spectrometers
with chloroform solutions of the compounds at a temperature
1
of 300 K. The H and 13C NMR chemical shifts are reported
relative to the chloroform resonances (d (1H) = 7.26, d (13C) =
77.0). Due to dynamic effects (restricted rotation in the amide
moiety) some signals of compounds 5 appeared in the spectra at
room temperature as broadened or were not displayed. IR spectra
were recorded on FT-IR ALPHA (Bruker) with Platinum-ATR
(Bruker). EI (70 eV) mass spectra were recorded on MAT 95XP
(Thermo ELECTRON CORPORATION). GC was performed on
General procedure for Sonogashira reactions
[PdCl2(PPh3)2] (16 mg, 0.022 mmol, 2 mol%) and CuI (8.5 mg,
0.044 mmol, 4 mol%) were placed in an ACE pressure tube under
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Table 2 Sonogashira and cyclization reactions with various arylated substratesa
Entry
1
R1, R2
Ar-X
5 [%]b
5a: 62
Product 6
6 [%]b
Product/s 7 and/or 8
7a + 8a
7 and/or 8 [%]b
< 5
CH3,CH3
76
2
3
CH3,CH3
5b: 60
68
78
7b
8c
< 5
CH3,CH3
5c: 31
< 5
4
5
CH3,CH3
5d: 82
61
45
12
29
CH3,CH3
5e: 77
6
7
CH3,CH3
5f: 66
6f
< 5
20
14
CH3,CH3
5g: 85
21
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Table 2 (Contd.)
Entry
8
R1, R2
Ar-X
5 [%]b
5h: 88
Product 6
6 [%]b
Product/s 7 and/or 8
7 and/or 8 [%]b
CH3,CH3
25d
25d
9
CH3,CH3
5i: 67
80
8i
< 5
10
11
CH3,CH3
CH3,CH3
5j: 39
65
45
8j
< 5
5k: 65
7k + 8k
< 5
12
13
CH3,CH3
CH3,CH3
5l: 94
6l
0
8l
0
5m: 73
60
23
14
15
CH3,CH3
CH3,Bn
—
—
6n
0
9511
5o: 78c
77d
17d
a Sonogashira conditions: 2 mol% [PdCl2(PPh3)2], 4 mol% CuI, 1.15 mmol compound 4a, 1.27 mmol aryl halide, 8 mL THF/TEA (1 : 1), 60 ◦C, 20 h.
Cyclization conditions: 5 mol% PtCl2, 0.2 mmol compound 5, 10 mL CH2Cl2, 50 ◦C, 24 h. b Yield of isolated product. c Yield of isolated product after
amide formation. d Yield determined by 1H NMR.
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an argon atmosphere. The N,N¢-dimethyl-N-(prop-2-ynyl)-1H-
indole-2-carboxamide 4a (250 mg, 1.10 mmol, 1 equiv) and the
aryl halogenide (1.22 mmol, 1.1 equiv) were added and a solution
of THF/TEA (1 : 1, 7 mL) was then injected. The pressure tube was
sealed and the reaction mixture was heated at 65 ◦C for 20 h. After
removal of the solvent in vacuo, the residue was purified by column
chromatography (dichloromethane–ethyl acetate or heptane–ethyl
acetate) to give indoles 5a–m.
FT-IR (ATR, cm-1): 3118, 3055, 3015, 2934, 1729, 1621, 1521,
1507, 1458, 1396, 1281, 1172, 1062, 1028, 833, 733, 664; GC-MS
(EI, 70 eV): m/z (%): 332 (14) [M+], 303 (13), 288 (9), 275 (100),
260 (13), 246 (7), 225 (8), 197 (4), 158 (24), 145 (11), 131 (24), 114
(4), 102 (9), 89 (34), 77 (4), 63 (3), 42 (4); HRMS (EI): calcd for
C21H20O2N2: 332.15193; found: 332.15262.
1-Methyl-1H-indole-2-carboxylic acid [3-(4-chloro-phenyl)-
prop-2-ynyl]-methyl-amide (5d)
1-Methyl-1H-indole-2-carboxylic acid methyl-(3-p-tolyl-prop-
2-ynyl)-amide (5a)
Yield: 304 mg, 82%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (80 : 20); 1H NMR (300 MHz; CDCl3): d =
7.67 (d, J = 7.7 Hz, 1H), 7.36 (m, 6H), 7.17 (ddd, J = 8.0 Hz, J =
6.8 Hz, J = 1.2 Hz, 1H), 6.85 (br, 1H), 4.60 (s, 2H, CH2), 3.89 (s, 3H,
NCH3), 3.31 (s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3):
d = 164.0 (CO), 138.0 (C), 134.6 (C), 133.0 (2 CH), 131.0 (C),
128.7 (2 CH), 126.2 (CH), 123.5 (CH), 121.6 (CH), 120.2 (CH),
109.8 (CH), 104.3 (C), 84.8 (C C), 31.2 (NCH3), not displayed:
NCH2, OCNCH3, C C; FT-IR (ATR, cm-1): 3053, 2920, 1629,
1520, 1487, 1464, 1397, 1345, 1229, 1089, 1059, 827, 751, 738,
3104, 2930, 1701, 1618, 1532, 1487, 1390, 1243, 1089, 1069, 1013,
827, 729, 607; GC-MS (EI, 70 eV): m/z (%): 336 (10) [M+], 308
(16), 292 (10), 279 (100), 265 (21), 243 (13), 225 (6), 197 (8), 168
(3), 158 (40), 149 (8), 131 (35), 122 (8), 114 (8), 101 (4), 89 (52), 77
(6), 63 (3), 42 (5); HRMS (ESI, [M+H]+): calcd for C20H18ON2Cl:
337.1102; found: 337.1101.
Yield: 216 mg, 62%; white powder; purification conditions:
CH2Cl2–ethyl acetate (90 : 10); 1H NMR (300 MHz; CDCl3): d =
7.67 (d, J = 7.9 Hz, 1H), 7.35 (m, 4H), 7.17 (m, 3H), 6.88 (br, 1H),
4.59 (s, 2H, CH2), 3.89 (s, 3H, NCH3), 3.31 (s, 3H, OCNCH3),
2.38 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d = 164.1 (CO),
138.8 (C), 138.0 (C), 131.6 (2 CH), 131.3 (C), 129.1 (2 CH), 126.3
(C), 123.5 (CH), 121.7 (CH), 120.2 (CH), 109.8 (CH), 104.2 (C),
83.0 (C C), 31.2 (NCH3), 21.5 (CH3), not displayed: NCH2,
OCNCH3, C C; FT-IR (ATR, cm-1): 3051, 3024, 2915, 2850,
1609, 1525, 1509, 1465, 1396, 1357, 1231, 1145, 1056, 819, 811,
732, 529; GC-MS (EI, 70 eV): m/z (%): 316 (13) [M+], 301 (4), 288
(9), 272 (11), 259 (100), 244 (23), 225 (6), 211 (6), 197 (3), 183 (1),
158 (24), 131 (25), 115 (6), 102 (4), 89 (38), 77 (5), 63 (4), 42 (4);
HRMS (EI): calcd for C21H20ON2: 316.15701; found: 316.15673.
1-Methyl-1H-indole-2-carboxylic acid [3-(3,4-dimethyl-phenyl)-
1-Methyl-1H-indole-2-carboxylic acid methyl-[3-(4-
prop-2-ynyl]-methyl-amide (5b)
trifluoromethyl-phenyl)-prop-2-ynyl]-amide (5e)
Yield: 218 mg, 60%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (80 : 20); 1H NMR (300 MHz; CDCl3): d =
7.65 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.3 Hz, J = 0.8 Hz, 1H),
7.35–7.19 (m, 3H), 7.15 (ddd, J = 8.0 Hz, J = 6.8 Hz, J = 1.2 Hz,
1H), 7.10 (d, J = 7.8 Hz, 1H), 6.88 (br, 1H), 4.58 (s, 2H, CH2),
3.88 (s, 3H, NCH3), 3.29 (s, 3H, OCNCH3), 2.28 (s, 3H, CH3),
2.26 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d = 164.1 (CO),
138.0 (C), 137.6 (C), 136.7 (C), 132.8 (CH), 131.3 (C), 129.6 (CH),
129.2 (CH), 126.3 (CH), 123.5 (CH), 121.7 (CH), 120.2 (CH),
119.6 (C), 109.8 (CH), 104.2 (C), 82.7 (C C), 31.2 (NCH3), 19.7
(CH3), 19.6 (CH3), not displayed: NCH2, OCNCH3, C C; FT-IR
(ATR, cm-1): 3118, 3045, 2917, 2861, 1623, 1518, 1461, 1398, 1340,
1285, 1155, 1063, 803, 732; GC-MS (EI, 70 eV): m/z (%): 330 (12)
[M+], 301 (9), 286 (12), 273 (100), 258 (27), 244 (5), 225 (7), 211
(5), 158 (21), 143 (11), 131 (22), 121 (3), 115 (7), 89 (31), 77 (4),
63 (2), 44 (5), 32 (4); HRMS (ESI, [M+H]+): calcd for C22H23ON2:
331.1805; found: 331.1806.
Yield: 314 mg, 77%; yellow syrup; purification conditions:
heptane–ethyl acetate (80 : 20); 1H NMR (400 MHz; CDCl3): d =
7.65 (dt, J = 8.0 Hz, J = 0.9 Hz, 1H), 7.59 (dd, J = 8.7 Hz, J =
4.8 Hz, 4H), 7.38 (dd, J = 8.4 Hz, J = 0.9 Hz, 1H), 7.32 (m, 1H),
7.16 (ddd, J = 8.0 Hz, J = 6.8 Hz, J = 1.2 Hz, 1H), 6.82 (br, 1H),
4.63 (s, 2H, CH2), 3.88 (s, 3H, NCH3), 3.31 (s, 3H, OCNCH3);
13C NMR (100.6 MHz, CDCl3): d = 164.1 (CO), 138.1 (C), 132.0
(2 CH), 131.0 (C), 130.1 (C), 126.3 (CH), 125.6 (C), 125.4 (CH),
125.3 (CH), 123.6 (CH), 122.0 (C), 121.7 (CH), 120.3 (CH), 109.9
(CH), 104.5 (C), 86.4 (C C), 31.3 (NCH3), not displayed: NCH2,
OCNCH3, C C; FT-IR (ATR, cm-1): 3056, 2931, 1630, 1615,
1521, 1465, 1399, 1319, 1164, 1120, 1104, 1063, 1016, 841, 751,
735; GC-MS (EI, 70 eV): m/z (%): 370 (14) [M+], 342 (20), 326 (9),
313 (100), 299 (21), 244 (2), 225 (4), 211 (6), 183 (6), 158 (26), 131
(6), 133 (24), 116 (4), 89 (35), 77 (3), 63 (3), 42 (3); HRMS (EI):
calcd for C21H17ON2F3: 370.12875; found: 370.12877.
1-Methyl-1H-indole-2-carboxylic acid [3-(4-cyano-phenyl)-
1-Methyl-1H-indole-2-carboxylic acid [3-(4-methoxy-phenyl)-
prop-2-ynyl]-methyl-amide (5f)
prop-2-ynyl]-methyl-amide (5c)
Yield: 238 mg, 66%; yellow syrup; purification conditions:
heptane–ethyl acetate (60 : 40); 1H NMR (300 MHz; CDCl3): d =
7.64 (m, 3H), 7.55 (m, 2H), 7.34 (m, 2H), 7.16 (ddd, J = 8.0 Hz, J =
6.8 Hz, J = 1.2 Hz, 1H), 6.81 (br, 1H), 4.64 (s, 2H, CH2), 3.88 (s, 3H,
NCH3), 3.31 (s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3): d =
164.1 (CO), 138.1 (C), 132.3 (2 CH), 132.1 (2 CH), 130.8 (C), 128.8
(C), 127.2 (C), 126.2 (CH), 123.7 (CH), 121.7 (CH), 120.4 (CH),
118.3 (C), 112.0 (C), 109.9 (CH), 88.4 (C C), 31.3 (NCH3), not
displayed: NCH2, OCNCH3, C C; FT-IR (ATR, cm-1): 3054,
2927, 2226, 1717, 1627, 1603, 1520, 1464, 1396, 1344, 1228, 1058,
1
Yield: 114 mg, 31%; light yellow powder; H NMR (300 MHz;
CDCl3): d = 7.65 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.34
(m, 2H), 7.16 (ddd, J = 8.0 Hz, J = 6.8 Hz, J = 1.2 Hz, 1H), 6.87 (br
d, J = 8.8 Hz, 3H), 4.58 (br, 2H, CH2), 3.88 (s, 3H, OCH3), 3.81 (s,
3H, NCH3), 3.29 (s, 3H, OCNCH3); 13C NMR(75.5MHz, CDCl3):
d = 164.1 (CO), 159.8 (CO), 138.0 (C), 133.2 (2 CH), 132.1 (C),
131.3 (C), 126.3 (CH), 123.5 (CH), 121.7 (CH), 120.8 (C), 120.2
(CH), 114.0 (2 CH), 109.8 (CH), 104.3 (C), 82.3 (C C), 55.3
(OCH3), 31.2 (NCH3), not displayed: NCH2, OCNCH3, C C;
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838, 750, 735, 555; GC-MS (EI, 70 eV): m/z (%): 327 (15) [M+],
299 (23), 283 (9), 270 (100), 256 (22), 242 (3), 225 (5), 211 (8), 168
(4), 158 (32), 140 (7), 131 (26), 116 (5), 89 (46), 77 (4), 63 (5), 42
(3); HRMS (ESI, [M+Na]+): calcd for C21H17ON3Na: 350.1264;
found: 350.1266.
(CH), 104.3 (C), 88.6 (C C), 31.3 (NCH3), not displayed: NCH2,
OCNCH3, C C; FT-IR (ATR, cm-1): 3054, 2921, 1627, 1519,
1463, 1394, 1343, 1228, 1143, 1057, 799, 773, 750, 735, 527; GC-
MS (EI, 70 eV): m/z (%): 352 (64) [M+], 323 (24), 308 (23), 295
(100), 281 (35), 267 (4), 252 (5), 225 (7), 211 (8), 194 (4), 178 (9),
165 (33), 158 (44), 154 (13), 147 (7), 139 (11), 131 (40), 116 (6),
89 (60), 77(5), 63 (5), 42 (5); HRMS (ESI, [M+Na]+): calcd for
C24H20ON2Na: 375.1468; found: 375.1472.
1-Methyl-1H-indole-2-carboxylic acid [3-(4-acetyl-phenyl)-
prop-2-ynyl]-methyl-amide (5g)
Yield: 322 mg, 85%; yellow syrup; purification conditions:
heptane–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
7.93 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 6.55 (d, J =
8.4 Hz, 2H), 7.38 (m, 1H), 7.32 (m, 1H), 7.16 (ddd, J = 8.0 Hz,
J = 6.9 Hz, J = 1.2 Hz, 1H), 6.84 (br, 1H), 4.64 (s, 2H, CH2), 3.88
1-Methyl-1H-indole-2-carboxylic acid (3-furan-2-yl-prop-2-ynyl)-
methyl-amide (5j)
Yield: 126 mg, 39%; yellow syrup; purification conditions:
CH2Cl2–ethyl acetate (90 : 10); 1H NMR (300 MHz; CDCl3): d =
7.65 (d, J = 7.9 Hz, 1H), 7.35 (m, 3H), 7.15 (ddd, J = 8.0 Hz,
J = 6.9 Hz, J = 1.0 Hz, 1H), 6.81 (br, 1H), 6.64 (dd, J = 3.4 Hz,
J = 0.5 Hz, 1H), 6.41 (dd, J = 3.4 Hz, J = 1.9 Hz, 1H), 4.63 (s,
2H, CH2), 3.87 (s, 3H, NCH3), 3.29 (s, 3H, OCNCH3); 13C NMR
(75.5 MHz, CDCl3): d = 164.1 (CO), 143.7 (CH), 138.1 (C), 131.0
(C), 126.3 (C), 123.6 (CH), 121.7 (CH), 120.3 (CH), 115.7 (CH),
110.9 (CH), 109.9 (2 CH), 104.4 (C), 88.3 (C C), 31.2 (NCH3),
not displayed: CH2, OCNCH3, C C; FT-IR (ATR, cm-1): 3115,
3055, 2937, 2227, 1733, 1629, 1519, 1464, 1396, 1344, 1240, 1211,
1146, 1058, 736, 592; GC-MS (EI, 70 eV): m/z (%): 292 (18) [M+],
263 (11), 248 (5), 235 (100), 220 (19), 206 (30), 192 (9), 180 (5),
167 (4), 158 (24), 131 (16), 116 (4), 103 (4), 89 (48), 77 (10), 63
(5), 51 (7), 42 (3); HRMS (ESI, [M+H]+): calcd for C18H17O2N2:
293.1285; found: 293.1286.
(s, 3H, NCH3), 3.32 (s, 3H, OCNCH3), 2.61 (s, 3H, CH3CO); 13
C
NMR (75.5 MHz, CDCl3): d = 197.3 (CO), 164.1 (CO), 138.1 (C),
136.4 (C), 131.9 (2 CH), 131.0 (C), 128.3 (2 CH), 126.2 (CH), 123.6
(CH), 121.7 (CH), 120.3 (CH), 119.0 (C), 109.9 (CH), 104.5 (C),
87.2 (C C), 31.3 (NCH3), 26.6 (CH3CO), not displayed: NCH2,
OCNCH3, C C; FT-IR (ATR, cm-1): 3109, 3092, 3080, 2936,
1677, 1633, 1600, 1524, 1463, 1397, 1345, 1262, 1240, 1229, 954,
839, 755, 588; GC-MS (EI, 70 eV): m/z (%): 344 (16) [M+], 316
(14), 300 (8), 287 (100), 273 (14), 244 (13), 230 (6), 211 (6), 158
(25), 143 (5), 131 (26), 114 (8), 89 (37), 77 (3), 63 (4), 43 (3); HRMS
(ESI, [M+H]+): calcd for C22H21O2N2: 345.1598; found: 345.1603.
4-{3-[Methyl-(1-methyl-1H-indole-2-carbonyl)-amino]-prop-1-
ynyl}-benzoic acid ethyl ester (5h)
Yield: 363 mg, 88%; yellow syrup; purification conditions:
heptane–ethyl acetate (60 : 40); 1H NMR (300 MHz; CDCl3): d =
8.02 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.53 (dd, J =
8.3 Hz, J = 1.6 Hz, 2H), 7.34 (m, 2H), 7.16 (ddd, J = 8.0 Hz, J =
6.9 Hz, J = 1.0 Hz, 1H), 6.84 (br, 1H), 4.63 (s, 2H, CH2), 4.39 (q, J =
7.1 Hz, 2H, OCH2), 3.88 (s, 3H, NCH3), 3.32 (s, 3H, OCNCH3),
1.41 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d =
165.9 (CO), 164.1 (CO), 138.1 (C), 131.7 (2 CH), 131.0 (C), 130.2
(C), 129.5 (2 CH), 126.9 (C), 126.3 (CH), 123.6 (CH), 121.7 (CH),
120.3 (CH), 109.9 (CH), 104.5 (C), 86.7 (C C), 61.2 (OCH2), 31.2
(NCH3), 14.3 (CH3), not displayed: NCH2, OCNCH3, C C; FT-
IR (ATR, cm-1): 3107, 3038, 2987, 2966, 2925, 2870, 1707, 1626,
1523, 1464, 1396, 1272, 1154, 1104, 1067, 1018, 851, 766, 737, 693,
524; GC-MS (EI, 70 eV): m/z (%): 374 (16) [M+], 346 (10), 330 (9),
317 (100), 303 (9), 288 (9), 275 (8), 244 (10), 225 (6), 211 (5), 188
(5), 168 (7), 158 (31), 143 (7), 131 (35), 114 (7), 89 (46), 63 (2), 44
(2); HRMS (ESI, [M+Na]+): calcd for C23H22O3N2Na: 397.1523;
found: 397.1526.
1-Methyl-1H-indole-2-carboxylic acid methyl-(3-thiophen-
2-yl-prop-2-ynyl)-amide (5k)
Yield: 221 mg, 65%; orange syrup; purification conditions:
CH2Cl2–ethyl acetate (90 : 10); 1H NMR (300 MHz; CDCl3): d =
7.66 (d, J = 7.9 Hz, 1H), 7.31 (m, 3H), 7.16 (ddd, J = 8.0 Hz,
J = 6.9 Hz, J = 1.1 Hz, 1H), 7.00 (dd, J = 5.1 Hz, J = 3.6 Hz,
1H), 6.82 (br, 1H), 4.62 (s, 2H, CH2), 3.88 (s, 3H, NCH3), 3.29
(s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3): d = 164.1
(CO), 138.0 (C), 132.5 (CH), 131.1 (C), 127.4 (C), 127.0 (CH),
126.3 (C), 123.5 (2 CH), 121.7 (CH), 120.3 (CH), 109.9 (CH), 87.7
(C C), 31.2 (NCH3), not displayed: CH2, OCNCH3, C C; FT-
IR (ATR, cm-1): 3055, 2926, 2223, 1732, 1627, 1518, 1463, 1396,
1342, 1228, 1189, 1057, 847, 751, 736, 700; GC-MS (EI, 70 eV):
m/z (%): 308 (22) [M+], 279 (9), 264 (8), 251 (100), 237 (17), 218
(29), 204 (4), 158 (28), 131 (20), 121 (9), 116 (4), 102 (4), 89 (52), 77
(8), 63 (5), 42 (4); HRMS (ESI, [M+H]+): calcd for C18H175ON2S:
309.1056; found: 309.1062.
1-Methyl-1H-indole-2-carboxylic acid methyl-(3-naphthalen-
1-yl-prop-2-ynyl)-amide (5i)
1-Methyl-1H-indole-2-carboxylic acid methyl-(3-pyridin-
2-yl-prop-2-ynyl)-amide (5l)
Yield: 260 mg, 67%; yellow syrup; purification conditions:
heptane–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
8.32 (d, J = 8.1 Hz, 1H), 7.88 (m, 2H), 7.69 (m, 2H), 7.57 (m,
2H), 7.41 (m, 3H), 7.17 (ddd, J = 8.0 Hz, J = 6.8 Hz, J = 1.1 Hz,
1H), 6.95 (br, 1H), 4.76 (s, 2H, CH2), 3.91 (s, 3H, NCH3), 3.39 (s,
3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3): d = 164.2 (CO),
138.1 (C), 133.3 (C), 133.1 (C), 131.2 (C), 130.8 (CH), 129.1 (CH),
128.4 (CH), 127.8 (C), 126.9 (CH), 126.5 (CH), 126.3 (CH), 125.8
(CH), 125.2 (CH), 123.6 (CH), 121.7 (CH), 120.3 (CH), 109.9
Yield: 314 mg, 94%; yellow syrup; purification conditions:
CH2Cl2–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
8.61 (br, 1H), 7.70 (dd, J = 7.8 Hz, J = 1.6 Hz, 1H), 7.65 (dt, J =
7.9 Hz, J = 1.0 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.32 (m, 3H), 7.15
(ddd, J = 8.0 Hz, J = 6.9 Hz, J = 1.1 Hz, 1H), 6.84 (br, 1H), 4.65 (s,
2H, CH2), 3.88 (s, 3H, NCH3), 3.32 (s, 3H, OCNCH3); 13C NMR
(75.5 MHz, CDCl3): d = 164.1 (CO), 150.1 (CH), 138.1 (C), 136.3
(CH), 130.9 (C), 127.3 (C), 126.3 (CH), 123.6 (2 CH), 123.3 (C),
1154 | Org. Biomol. Chem., 2011, 9, 1148–1159
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121.7 (CH), 120.3 (CH), 109.9 (2 CH), 83.9 (C C), 31.3 (NCH3),
not displayed: CH2, OCNCH3, C C; FT-IR (ATR, cm-1): 3052,
2928, 2236, 1733, 1628, 1580, 1520, 1461, 1427, 1396, 1344, 1229,
1146, 1058, 778, 751, 736; GC-MS (EI, 70 eV): m/z (%): 303 (100)
[M+], 288 (14), 274 (15), 260 (22), 245 (64), 231 (43), 225 (17), 211
(18), 197 (6), 183 (3), 168 (10), 158 (38), 145 (57), 131 (36), 117
(28), 104 (8), 89 (91), 77 (9), 63 (10), 51 (5), 39 (4); HRMS (EI):
calcd for C19H17ON3: 303.13661; found: 303.13605.
7.23 (m, 7H), 7.12 (br d, J = 7.9 Hz, 2H), 3.95 (s, 2H, CH2), 3.65 (s,
2H, CH2), 3.35 (s, 3H, NCH3); 13C NMR (75.5 MHz, CDCl3): d =
138.1 (2 C), 131.5 (2 CH), 129.0 (2 CH), 128.4 (4 CH), 127.1 (CH),
120.1 (C), 83.8 (C C), 52.5 (NCH2), 31.3 (NCH3), 21.4 (CH3),
not displayed: CH2, C C; FT-IR (ATR, cm-1): 3308, 3028, 2924,
2907, 2864, 2839, 1603, 1507, 1496, 1451, 1323, 1107, 1073, 907,
815, 798, 782, 731, 694, 544; GC-MS (EI, 70 eV): m/z (%): 234
(100) [M - H], 220 (9), 205 (4), 272 (5), 192 (15), 178 (2), 158 (38),
144 (45), 129 (66), 115 (41), 106 (11), 91 (71), 77 (12), 65 (13),
51(8), 39 (9); HRMS (EI): calcd for C17H16N1: 234.12773; found:
234.12725.
4-Methoxy-3-{3-[methyl-(1-methyl-1H-indole-2-carbonyl)-
amino]-prop-1-ynyl}-benzoic acid methyl ester (5m)
Yield: 314 mg, 73%; light yellow powder; purification conditions:
heptane–ethyl acetate (1 : 1); H NMR (400 MHz; CDCl3): d =
1-Methyl-1H-indole-2-carboxylic acid benzyl-(3-p-tolyl-prop-
2-ynyl)-amide (5o)
1
8.12 (d, J = 2.2 Hz, 1H), 8.02 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H),
7.65 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.3 Hz, J = 0.7 Hz, 1H),
7.31 (ddd, J = 8.0 Hz, J = 6.9 Hz, J = 1.1 Hz, 1H), 7.15 (ddd,
J = 8.0 Hz, J = 6.9 Hz, J = 1.0 Hz, 1H), 6.96 (br, 1H), 6.92 (d,
J = 8.8 Hz, 1H), 4.64 (s, 2H, CH2), 3.96 (s, 3H, OCH3), 3.90 (s,
3H, OCOCH3), 3.88 (s, 3H, NCH3), 3.31 (s, 3H, OCNCH3); 13C
NMR (100.6 MHz, CDCl3): d = 166.1 (CO), 164.1 (CO), 163.6
(CO), 138.1 (C), 135.2 (CH), 131.9 (CH), 131.2 (C), 126.4 (C),
123.5 (CH), 122.6 (C), 121.7 (CH), 120.2 (CH), 111.8 (C), 110.2
(CH), 109.9 (CH), 104.4 (C), 88.6 (C C), 56.0 (OCH3), 52.0
(OCH3), 31.2 (NCH3), not displayed: CH2, OCNCH3, C C; FT-
IR (ATR, cm-1): 3232, 3090, 3018, 2970, 2942, 2838, 1718, 1630,
1604, 1523, 1499, 1460, 1437, 1401, 1291, 1273, 1242, 1220, 1140,
1104, 1061, 1018, 830, 753, 726, 699; GC-MS (EI, 70 eV): m/z (%):
390 (17) [M+], 359 (100), 346 (9), 333 (59), 318 (31), 302 (45), 288
(6), 274 (5), 258 (7), 243 (4), 225 (11), 213 (24), 207 (15), 189 (6),
171 (7), 158 (48), 131 (41), 115 (13), 102 (5), 89 (51), 77 (5), 63 (4),
42 (3); HRMS (ESI, [M+H]+): calcd for C23H23O4N2: 391.1652;
found: 391.1659.
To a stirred solution of 1-methyl-1H-indole-2-carboxylic acid
(294 mg, 1.68 mmol, 2 equiv) in benzene (8.4 mL) was added
oxalyl chloride (2 M in CH2Cl2, 220 mL, 2.52 mmol, 3 equiv).
The resulting solution was stirred at RT for 3 h, after which time
the solvent was removed under reduced pressure and then taken
up in 3 mL of THF. In a separate schlenk, to a suspension of
NaH (60% in oil, 40.3 mg, 1 mmol, 1.2 equiv) in THF (4.2 mL)
cooled to 0 ◦C was added a solution of benzyl-(3-p-tolyl-prop-
2-ynyl)-amine (197.5 mg, 0.84 mmol, 1 equiv) in THF (2.5 mL).
The suspension was allowed to stir at 0 ◦C for 30 min, after which
time, the preformed acid chloride was added. 1.2 mL of THF
was used to clean the schlenk with the preformed acid chloride
and was added. The resulting yellow suspension was allowed to
warm to RT overnight (18 h). The solution was then quenched with
water and extracted with ethyl acetate. The combined organic layer
was washed with brine (NaCl), dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (heptane–ethyl acetate: 70/30) affording
the indole 5o as an orange syrup (258 mg, 78%).11 1H NMR
(300 MHz; CDCl3): d = 7.64 (br d, J = 7.5 Hz, 1H), 7.44–7.29
(m, 9H), 7.15 (m, 3H), 6.98 (br, 1H), 5.00 (s, 2H, CH2), 4.49
(s, 2H, CH2), 3.91 (s, 3H, NCH3), 2.38 (s, 3H, CH3); 13C NMR
(75.5 MHz, CDCl3): d = 138.8 (C), 138.1 (C), 136.6 (C), 131.7
(4 CH), 131.2 (C), 129.1 (4 CH), 128.8 (CH), 127.7 (CH), 126.3
(C), 123.5 (CH), 121.8 (CH), 120.3 (CH), 109.9 (CH), 103.9 (C),
83.2 (C C), 31.3 (NCH3), 21.4 (CH3), not displayed: CO, 2 CH2,
OCNCH3, C C; FT-IR (ATR, cm-1): 3109, 3082, 3055, 3028,
2919, 1630, 1509, 1464, 1448, 1409, 1344, 1240, 1225, 1170, 994,
815, 734, 699, 527; GC-MS (EI, 70 eV): m/z (%): 392 (8) [M+], 364
(6), 301 (8), 272 (5), 259 (100), 244 (18), 230 (2), 170 (3), 158 (25),
131 (16), 117 (5), 102 (3), 89 (27), 77 (3), 65 (2); HRMS (EI): calcd
for C27H24ON2: 392.18831; found: 392.18777.
Procedure for the synthesis of 1-methyl-1H-indole-2-carboxylic
acid benzyl-(3-p-tolyl-prop-2-ynyl)-amide (5o) and corresponding
starting materials
Benzyl-(prop-2-ynyl)-amine. To a stirred solution of benzy-
lamine (10 mL, 91.6 mmol, 6 equiv) was added propargyl
◦
bromide (1.64 mL, 15.3 mmol, 1 equiv) dropwise at 0 C during
30 min. The mixture was stirred overnight at room temperature.
The resulting solution was then quenched with water and ex-
tracted with Et2O. The combined organic layer was washed with
brine (NaHCO3), dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography (heptane–ethyl acetate: 60/40) affording the N-
benzylpropargylamine as colourless liquid (1.654 g, 75%).
Benzyl-(3-p-tolyl-prop-2-ynyl)-amine.
[PdCl2(PPh3)2]
General procedure for cyclization reactions
(40.4 mg, 0.058 mmol, 2 mol%) and CuI (21.9 mg, 0.115 mmol,
4 mol%) were placed in an ACE pressure tube under an argon
atmosphere. A solution of N-benzylpropargylamine (500.9 mg,
3.45 mmol, 1.2 equiv) in THF/TEA (1 : 1, 20 mL) was injected and
the 4-iodotoluene (626.8 mg, 2.875 mmol, 1 equiv) was then added.
The pressure tube was sealed and the reaction mixture was heated
at 65 ◦C for 20 h. After removal of the solvent in vacuo, the residue
was purified by column chromatography (heptane–ethyl acetate:
60/40) to give benzyl-(3-p-tolyl-prop-2-ynyl)-amine as light brown
PtCl2 (0.01 mmol, 5 mol%) was placed in an ACE pressure
tube under an argon atmosphere. A solution of product 5a–m,
o (0.2 mmol, 1 equiv) in 10 mL of dichloromethane was then
injected into the tube. The pressure tube was sealed and the
reaction mixture was heated at 50 ◦C for 24 h. Solvent was
removed under reduced pressure and the residue purified by
column chromatography to give azepino[3,4-b]indol-1-ones 6a–
k, m, o indolo[4,3-b]azepin-1-ones 7a, m, o and carbolin-1-ones
8d–h, n (Table 1, and 2).
1
powder (372 mg, 55%). H NMR (300 MHz; CDCl3): d = 7.42–
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2,10-Dimethyl-5-p-tolyl-3,10-dihydro-2H-azepino[3,4-b]indol-1-
one (6a)
7.41 (br d, J = 8.4 Hz, 1H), 7.33–7.25 (m, 1H), 7.16 (br, 1H), 7.10
(m, 2H), 6.95–6.87 (m, 1H), 6.78 (br d, J = 8.1 Hz, 1H), 6.17 (t,
J = 7.1 Hz, 1H), 4.10 (s, 3H, NCH3), 3.80 (br, 2H, CH2), 3.24 (s,
3H, OCNCH3), 2.31 (s, 3H, CH3), 2.24 (s, 3H, CH3); 13C NMR
(75.5 MHz, CDCl3): d = 162.2 (CO), 142.1 (C), 138.2 (C), 137.8
(C), 136.4 (2 C), 133.4 (C), 129.6 (CH), 129.5 (CH), 125.9 (CH),
124.6 (C), 124.2 (CH), 122.8 (CH), 120.7 (CH), 119.9 (CH), 117.2
(C), 109.8 (CH), 47.5 (CH2), 34.7 (NCH3), 31.9 (OCNCH3), 19.7
(CH3), 19.6 (CH3); FT-IR (ATR, cm-1): 3503, 3402, 3033, 3018,
2921, 2899, 1614, 1504, 1467, 1386, 1330, 1231, 1081, 828, 757,
744; GC-MS (EI, 70 eV): m/z (%): 330 (100) [M+], 315 (19), 301
(31), 287 (6), 273 (51), 258 (7), 242 (5), 225 (19), 215 (3), 202 (3),
197 (10), 165 (4), 136 (3), 128 (3), 121 (4), 115 (3), 108 (2), 42 (3);
HRMS (ESI, [M+H]+): calcd for C22H23ON2: 331.1805; found:
331.1809.
Yield: 48 mg, 76%; white powder; purification conditions:
1
heptane–ethyl acetate (1 : 1); H NMR (300 MHz; CDCl3): d =
7.42 (d, J = 8.4 Hz, 1H), 7.34–7.25 (m, 3H), 7.16 (d, J = 7.8 Hz,
2H), 6.92 (ddd, J = 8.0 Hz, J = 7.0 Hz, J = 1.1 Hz, 1H), 6.76 (dt
J = 8.1 Hz, J = 0.9 Hz, 1H), 6.19 (t, J = 7.0 Hz, 1H), 4.11 (s, 3H,
NCH3), 3.81 (br, 2H, CH2), 3.26 (s, 3H, OCNCH3), 2.41 (s, 3H,
CH3); 13C NMR (75.5 MHz, CDCl3): d = 162.2 (CO), 142.0 (C),
138.3 (C), 137.8 (C), 137.3 (C), 133.5 (C), 129.0 (2 CH), 128.3 (2
CH), 124.6 (C), 124.2 (CH), 122.7 (CH), 120.8 (CH), 120.0 (CH),
117.1 (C), 109.8 (CH), 47.5 (CH2), 34.7 (NCH3), 31.9 (OCNCH3),
21.2 (CH3); FT-IR (ATR, cm-1): 3026, 2917, 2853, 1632, 1506,
1466, 1383, 1329, 1226, 1166, 1060, 805, 757, 744, 526; GC-MS
(EI, 70 eV): m/z (%): 316 (100) [M+], 301 (13), 287 (33), 274 (7),
259 (52), 244 (7), 225 (21), 202 (5), 197 (12), 158 (8), 121 (6), 115
(4), 89 (2), 77 (1), 63 (1), 42 (4); HRMS (EI): calcd for C21H20ON2:
316.15701; found: 316.15725.
5-(4-Methoxyphenyl)-2,10-dimethyl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6c)
Yield: 52 mg, 78%; white powder; purification conditions: CH2Cl2–
1
ethyl acetate (80 : 20); H NMR (300 MHz; CDCl3): d = 7.41 (d,
2,6-Dimethyl-5-p-tolyl-3,6-dihydro-2H-azepino[4,3-b]indol-1-one
J = 8.3 Hz, 1H), 7.33–7.26 (m, 3H), 6.95–6.84 (m, 3H), 6.76 (dt
J = 8.1 Hz, J = 0.8 Hz, 1H), 6.14 (t, J = 7.0 Hz, 1H), 4.01 (s,
3H, NCH3), 3.85 (s, 3H, OCH3), 3.75 (br, 2H, CH2), 3.24 (s, 3H,
OCNCH3); 13C NMR (75.5 MHz, CDCl3): d = 162.1 (CO), 159.5
(CO), 141.6 (C), 138.3 (C), 133.5 (C), 132.8 (C), 129.6 (2 CH),
124.6 (C), 124.2 (CH), 122.7 (CH), 120.1 (CH), 119.9 (CH), 117.2
(C), 113.6 (2 CH), 109.9 (CH), 55.3 (OCH3), 47.5 (CH2), 34.7
(NCH3), 31.9 (OCNCH3); FT-IR (ATR, cm-1): 3110, 3035, 2992,
2929, 2835, 1704, 1625, 1506, 1465, 1384, 1280, 1243, 1166, 1033,
839, 810, 740; GC-MS (EI, 70 eV): m/z (%): 332 (100) [M+], 317
(7), 303 (29), 290 (8), 275 (40), 260 (16), 245 (4), 231 (3), 225 (13),
217 (5), 204 (3), 197 (9), 190 (3), 176 (2), 166 (2), 144 (2), 137 (3),
130 (3), 122 (4), 115 (3), 94 (3), 42 (4); HRMS (ESI, [M+H]+):
calcd for C21H21O2N2: 333.1598; found: 333.1599.
(7a)
White powder, purification conditions: heptane–ethyl acetate
(1 : 1); 1H NMR (300 MHz; CDCl3): d = 8.32 (m, 1H), 7.38–7.22
(m, 3H), 7.16 (m, 4H), 6.42 (t, J = 7.5 Hz, 1H), 3.79 (br, 2H, CH2),
3.26 (s, 3H, OCNCH3), 3.24 (s, 3H, NCH3), 2.38 (s, 3H, CH3); 13
C
NMR (75.5 MHz, CDCl3): d = 165.6 (CO), 138.5 (C), 138.2 (C),
137.8 (C), 137.5 (C), 136.3 (C), 129.6 (2 CH), 127.3 (CH), 127.2
(2 CH), 126.8 (C), 123.7 (CH), 122.4 (CH), 121.4 (CH), 114.4
(C), 109.1 (CH), 47.1 (CH2), 35.1 (NCH3), 32.7 (OCNCH3), 21.2
(CH3); FT-IR (ATR, cm-1): 3052, 3012, 2962, 2913, 2854, 1612,
1463, 1385, 1260 1073, 1016, 855, 810, 795, 749, 738, 705, 522;
GC-MS (EI, 70 eV): m/z (%): 316 (100) [M+], 301 (11), 287 (73),
274 (17), 259 (27), 244 (9), 225 (48), 202 (6), 197 (7), 182 (3), 158
(4), 150 (4), 136 (4), 128 (6), 115 (5), 108 (5), 77 (2), 63 (1), 42 (4);
HRMS (EI): calcd for C21H20ON2: 316.15701; found: 316.15756.
5-(4-Chlorophenyl)-2,10-dimethyl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6d)
2,9-Dimethyl-4-(4-methylbenzyl)-2,9-dihydro-b-carbolin-1-one
Yield: 41 mg, 61%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
7.42 (d, J = 8.3 Hz, 1H), 7.35–7.27 (m, 5H), 6.93 (ddd, J = 8.0 Hz,
J = 7.0 Hz, J = 1.0 Hz, 1H), 6.72 (dt J = 8.2 Hz, J = 0.8 Hz,
1H), 6.19 (t, J = 7.0 Hz, 1H), 4.10 (s, 3H, NCH3), 3.81 (br, 2H,
CH2), 3.25 (s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3): d =
162.0 (CO), 141.0 (C), 138.6 (C), 138.2 (C), 133.9 (C), 133.6 (C),
129.7 (2 CH), 128.5 (2 CH), 124.4 (CH), 124.2 (C), 122.4 (CH),
121.7 (CH), 120.2 (CH), 116.3 (C), 110.0 (CH), 47.4 (CH2), 34.8
(NCH3), 32.0 (OCNCH3); FT-IR (ATR, cm-1): 3045, 2996, 2929,
2906, 1634, 1511, 1467, 1383, 1329, 1226, 1088, 1012, 839, 804,
757, 748, 554; GC-MS (EI, 70 eV): m/z (%): 336 (100) [M+], 307
(33), 294 (8), 279 (55), 264 (4), 258 (4), 244 (5), 225 (28), 214 (5),
197 (17), 168 (5), 128 (3), 114 (4), 101 (3), 42 (5); HRMS (ESI,
[M+H]+): calcd for C20H18ClON2: 337.1102; found: 337.1102.
(8a)
Purification conditions: heptane–ethyl acetate (1 : 1); NMR data
from inseparable mixture of compounds 7a and 8a; H NMR
1
(400 MHz; CDCl3): d = 7.90 (dt, J = 8.1 Hz, J = 0.9 Hz, 1H), 7.46
(dd, J = 4.4 Hz, J = 0.9 Hz, 1H), 7.21–7.07 (m, 5H), 6.64 (s, 1H),
4.38 (s, 3H, NCH3), 4.29 (br, 2H, CH2), 3.63 (s, 3H, OCNCH3),
2.32 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3): d = 156.2 (CO),
141.0 (C), 136.4 (C), 135.8 (C), 135.8 (C), 129.3 (2 CH), 128.5 (2
CH), 127.6 (CH), 127.0 (C), 126.2 (CH), 124.3 (C), 123.0 (CH),
120.0 (CH), 115.3 (C), 110.0 (CH), 36.6 (NCH3), 36.1 (CH2), 31.3
(OCNCH3), 21.0 (CH3); GC-MS (EI, 70 eV): m/z (%): 316 (100)
[M+], 301 (5), 287 (4), 259 (3), 231 (3), 225 (7), 211 (2), 184 (3), 158
(4), 150 (2), 128 (2), 115 (2); HRMS (EI): calcd for C21H20ON2:
316.1570; found: 316.15744.
5-(3,4-Dimethylphenyl)-2,10-dimethyl-3,10-dihydro-2H-
azepino[3,4-b]indol-1-one (6b)
4-(4-Chlorobenzyl)-2,9-dimethyl-2,9-dihydro-b-carbolin-1-one (8d)
Yield: 8 mg, 12%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
7.79 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.29–7.24 (m,
Yield: 45 mg, 68%; light yellow powder; purification conditions:
heptane–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
1156 | Org. Biomol. Chem., 2011, 9, 1148–1159
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2H), 7.22–7.10 (m, 3H), 6.67 (s, 1H), 4.38 (s, 3H, NCH3), 4.29 (s,
2H, CH2), 3.65 (s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3):
155.9 (CO), 145.8 (C), 141.0 (C), 137.5 (2 C), 131.1 (C), 129.9 (2
CH), 128.8 (2 CH), 127.8 (CH), 126.9 (C), 126.3 (CH), 122.8 (CH),
120.1 (CH), 114.4 (C), 110.1 (CH), 36.7 (NCH3), 37.9 (CH2), 31.3
(OCNCH3); FT-IR (ATR, cm-1): 3071, 2923, 2853, 1725, 1652,
1599, 1488, 1477, 1287, 1093, 1014, 814, 790, 731, 587, 533; GC-
MS (EI, 70 eV): m/z (%): 336 (100) [M+], 321 (2), 307 (3), 231
(2), 225 (9), 216 (3), 211 (3), 184 (4), 168 (3), 128 (3), 115 (2);
HRMS (ESI, [M+H]+): calcd for C20H18ClON2: 337.1102; found:
337.1106.
132.5 (2 CH), 129.2 (2 CH), 128.1 (CH), 127.2 (C), 126.4 (CH),
123.6 (C), 122.4 (CH), 121.0 (C), 120.3 (CH), 118.8 (C), 112.9 (C),
110.5 (C), 110.3 (CH), 36.7 (NCH3), 36.6 (CH2), 31.3 (OCNCH3);
FT-IR (ATR, cm-1): 3059, 2992, 2922, 2853, 2225, 1732, 1648,
1588, 1567, 1457, 1435, 1333, 1293, 1155, 1102, 821, 742, 594, 546;
GC-MS (EI, 70 eV): m/z (%): 327 (100) [M+], 298 (3), 241 (2),
225 (7), 211 (2), 184 (3), 164 (5), 140 (2), 128 (2); HRMS (ESI,
[M+H]+): calcd for C21H18ON3: 328.1444; found: 328.1444.
5-(4-Acetylphenyl)-2,10-dimethyl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6g). Yield: 15 mg, 21%; yellow powder; pu-
rification conditions: heptane–ethyl acetate (70 : 30); 1H NMR
(300 MHz; CDCl3): d = 7.94 (d, J = 8.4 Hz, 2H), 7.46 (d, J =
8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.30 (ddd, J = 8.2 Hz, J =
7.0 Hz, J = 1.1 Hz, 1H), 6.90 (ddd, J = 8.0 Hz, J = 7.0 Hz, J =
0.9 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.29 (t, J = 7.0 Hz, 1H),
4.11 (s, 3H, NCH3), 3.85 (br, 2H, CH2), 3.26 (s, 3H, OCNCH3),
2.63 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d = 197.8 (CO),
162.0 (CO), 144.8 (C), 141.3 (C), 138.3 (C), 136.5 (C), 133.6 (C),
128.7 (2 CH), 128.5 (2 CH), 124.5 (CH), 124.2 (C), 122.9 (CH),
122.3 (CH), 120.2 (CH), 116.0 (C), 110.1 (CH), 47.4 (CH2), 34.9
(NCH3), 32.0 (OCNCH3), 26.7 (CH3); FT-IR (ATR, cm-1): 3050,
2921, 2852, 1678, 1624, 1600, 1503, 1466, 1400, 1378, 1355, 1331,
1262, 1231, 1075, 1060, 847, 806, 739, 594; GC-MS (EI, 70 eV):
m/z (%): 344 (100) [M+], 329 (4), 315 (28), 301 (8), 287 (46), 272
(4), 260 (7), 244 (7), 225 (24), 214 (3), 202 (4), 197 (13), 189 (3),
182 (2), 172 (3), 136 (4), 121 (4), 114 (2), 101 (2), 43 (5); HRMS
(EI): calcd for C22H20O2N2: 344.15193; found: 344.1514.
2,10-Dimethyl-5-(4-trifluoromethylphenyl)-3,10-dihydro-2H-
azepino[3,4-b]indol-1-one (6e)
Yield: 33 mg, 45%; yellow powder; purification conditions:
CH2Cl2–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
7.61 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.43 (d, J =
8.4 Hz, 1H), 7.31 (ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.1 Hz, 1H), 6.93
(ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.0 Hz, 1H), 6.65 (dt J = 8.1 Hz,
J = 0.8 Hz, 1H), 6.27 (t, J = 7.0 Hz, 1H), 4.11 (s, 3H, NCH3),
3.85 (br, 2H, CH2), 3.26 (s, 3H, OCNCH3); 13C NMR (75.5 MHz,
CDCl3): d = 162.0 (CO), 143.7 (C), 141.0 (C), 138.3 (C), 133.7
(C), 128.7 (2 CH), 125.4 (C), 125.3 (CH), 125.3 (CH), 124.5 (CH),
124.1 (C), 122.9 (CH), 122.3 (CH), 120.3 (CH), 116.0 (C), 110.1
(CH), 47.5 (CH2), 34.9 (NCH3), 32.0 (OCNCH3), not displayed:
C-CF3, CF3; FT-IR (ATR, cm-1): 3059, 2957, 2929, 2860, 1725,
1622, 1501, 1465, 1324, 1158, 1101, 1068, 1016, 852, 740; GC-MS
(EI, 70 eV): m/z (%): 370 (100) [M+], 355 (4), 341 (33), 326 (7),
313 (61), 298 (6), 285 (4), 257 (2), 244 (2), 225 (27), 197 (15), 185
(5), 168 (3), 42 (4); HRMS (ESI, [M+H]+): calcd for C21H18ON2F3:
371.1366; found: 371.1365.
4-(4-Acetylbenzyl)-2,9-dimethyl-2,9-dihydro-b-carbolin-1-one (8g)
Yield: 10 mg, 14%; yellow syrup; purification conditions: heptane–
ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d = 7.89 (dt,
J = 8.4 Hz, J = 1.9 Hz, 2H), 7.75 (dt, J = 8.1 Hz, J = 0.8 Hz, 1H),
7.47 (d, J = 0.9 Hz, 1H), 7.45 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H),
7.11 (ddd, J = 8.1 Hz, J = 5.0 Hz, J = 3.1 Hz, 1H), 6.71 (s, 1H),
4.38 (s, 5H, CH2 + NCH3), 3.66 (s, 3H, OCNCH3), 2.56 (s, 3H,
CH3); 13C NMR (75.5 MHz, CDCl3): d = 197.8 (CO), 156.3 (CO),
144.8 (C), 140.9 (C), 135.6 (C), 128.8 (2 CH), 128.7 (2 CH), 127.9
(CH), 127.1 (C), 126.3 (CH), 123.9 (C), 122.7 (CH), 121.1 (C),
120.2 (CH), 113.8 (C), 110.1 (CH), 36.7 (NCH3), 36.5 (CH2), 31.3
(OCNCH3), 26.6 (CH3); FT-IR (ATR, cm-1): 3050, 2921, 2852,
1678, 1649, 1588, 1565, 1472, 1411, 1355, 1333, 1293, 1264, 1102,
957, 823, 739, 600; GC-MS (EI, 70 eV): m/z (%): 344 (100) [M+],
315 (3), 301 (4), 244 (1), 225 (8), 184 (3), 165 (9), 128 (2), 114 (1), 89
(1), 43 (3); HRMS (EI): calcd for C22H20O2N2: 344.15193; found:
344.15115.
2,9-Dimethyl-4-(4-trifluoromethyl-benzyl)-2,9-dihydro-b-carbolin-
1-one (8e)
Yield: 22 mg, 29%; yellow syrup; purification conditions: CH2Cl2–
ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d = 7.75 (dt,
J = 8.2 Hz, J = 0.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.47 (m, 2H),
7.37 (d, J = 8.0 Hz, 2H), 7.17–7.09 (m, 1H), 6.70 (s, 1H), 4.38 (s,
5H, NCH3 + CH2), 3.66 (s, 3H, OCNCH3); 13C NMR (75.5 MHz,
CDCl3): d = 156.3 (CO), 143.3 (C), 140.9 (C), 128.8 (2 CH), 128.6
(C), 127.9 (CH), 127.1 (C), 126.3 (CH), 126.0 (C), 125.6 (CH),
125.5 (CH), 123.8 (C), 122.6 (CH), 121.1 (C), 120.2 (CH), 113.7
(C), 110.2 (CH), 36.7 (NCH3), 36.3 (CH2), 31.3 (OCNCH3); FT-
IR (ATR, cm-1): 3068, 2958, 2927, 2860, 1725, 1655, 1596, 1460,
1322, 1283, 1153, 1111, 1065, 1021, 862, 822, 734; GC-MS (EI,
70 eV): m/z (%): 370 (100) [M+], 351 (4), 285 (2), 225 (8), 211
(3), 184 (4), 175 (2), 150 (2); HRMS (ESI, [M+H]+): calcd for
C21H18ON2F3: 371.1366; found: 371.1367.
4-(2,10-Dimethyl-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-
yl)-benzoic acid ethyl ester (6h)
Yield: 19 mg, 25%; yellow powder; purification conditions:
heptane–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
8.03 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.7 Hz,
1H), 7.30 (m, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 8.2 Hz,
1H), 6.28 (t, J = 7.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 1H), 4.11 (s, 3H,
NCH3), 3.84 (br, 2H, CH2), 3.26 (s, 3H, OCNCH3), 2.41 (t, J =
7.1 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d = 166.5 (CO),
162.0 (CO), 144.6 (C), 141.4 (C), 138.3 (C), 133.6 (C), 129.9 (C),
129.6 (2 CH), 128.4 (2 CH), 124.4 (CH), 124.2 (C), 122.8 (CH),
4-(2,9-Dimethyl-1-oxo-2,9-dihydro-1H-b-carbolin-4-ylmethyl)-
benzonitrile (8f)
Yield: 13 mg, 20%; yellow powder; purification conditions:
1
heptane–ethyl acetate (1 : 1); H NMR (400 MHz; CDCl3): d =
7.66 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.46 (m, 2H),
7.36 (d, J = 8.1 Hz, 2H), 7.15–7.07 (m, 1H), 6.74 (s, 1H), 4.38
(s, 3H, NCH3), 4.375 (br, 2H, CH2), 3.67 (s, 3H, OCNCH3); 13C
NMR (100.6 MHz, CDCl3): d = 156.3 (CO), 144.9 (C), 140.9 (C),
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122.4 (CH), 120.2 (CH), 116.2 (C), 110.1 (CH), 61.0 (OCOCH2),
47.4 (CH2), 34.9 (NCH3), 32.0 (OCNCH3), 14.3 (CH3); GC-MS
(EI, 70 eV): m/z (%): 374 (100) [M+], 345 (22), 329 (5), 317 (5), 301
(11), 289 (8), 273 (2), 260 (6), 242 (5), 225 (26), 214 (3), 202 (5),
197 (11), 187 (3), 136 (4), 128 (2), 121 (3), 115 (2), 42 (2); HRMS
(ESI, [M+H]+): calcd for C23H23O3N2: 375.1703; found: 375.1706.
(CH2), 34.8 (NCH3), 31.9 (OCNCH3); FT-IR (ATR, cm-1): 3154,
3116, 3058, 2909, 1620, 1511, 1464, 1385, 1332, 1231, 1212, 1064,
1008, 851, 737, 687; GC-MS (EI, 70 eV): m/z (%): 292 (100) [M+],
277 (3), 263 (47), 248 (8), 235 (79), 220 (13), 206 (11), 191 (7), 180
(4), 165 (5), 152 (4), 139 (2), 117 (4), 110 (2), 102 (2), 42 (4); HRMS
(ESI, [M+H]+): calcd for C18H17O2N2: 293.1285; found: 293.1290.
4-(2,9-Dimethyl-1-oxo-2,9-dihydro-1H-b-carbolin-4-ylmethyl)-
benzoic acid ethyl ester (8h)
2,10-Dimethyl-5-thiophen-2-yl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6k)
Yield: 19 mg, 25%; yellow syrup; purification conditions: heptane–
ethyl acetate (70 : 30); NMR data from inseparable mixture of
compounds 8h:6h (9 : 1). H NMR (300 MHz; CDCl3): d = 7.97
Yield: 28 mg, 45%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (90 : 10); 1H NMR (300 MHz; CDCl3): d =
7.42 (dt, J = 8.4 Hz, J = 0.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.09-6.96
(m, 4H), 6.32 (t, J = 7.1 Hz, 1H), 4.09 (s, 3H, NCH3), 3.80 (br,
2H, CH2), 3.25 (s, 3H, OCNCH3); 13C NMR (75.5 MHz, CDCl3):
d = 162.0 (CO), 142.6 (C), 138.2 (C), 134.9 (C), 133.3 (C), 127.3
(CH), 127.1 (CH), 125.1 (CH), 124.4 (CH), 124.3 (C), 122.6 (CH),
121.4 (CH), 120.1 (CH), 116.5 (C), 110.0 (CH), 47.3 (CH2), 34.8
(NCH3), 31.9 (OCNCH3); FT-IR (ATR, cm-1): 3102, 3057, 2927,
2902, 1620, 1503, 1463, 1382, 1331, 1229, 1060, 850, 739, 705, 665,
613; GC-MS (EI, 70 eV): m/z (%): 308 (100) [M+], 279 (32), 266
(8), 251 (59), 236 (7), 225 (9), 218 (3), 209 (2), 204 (3), 197 (8), 190
(3), 165 (2), 154 (4), 139 (2), 42 (3); HRMS (ESI, [M+H]+): calcd
for C18H17ON2S: 309.1056; found: 309.1061.
1
(d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 4.1 Hz,
1H), 7.32 (d, J = 8.1 Hz, 2H), 7.11 (m, 1H), 6.68 (s, 1H), 4.38 (s, 5H,
CH2 + NCH3), 4.35 (q, J = 7.1 Hz, 1H), 3.65 (s, 3H, OCNCH3),
1.34 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3):
d = 166.5 (CO), 156.3 (CO), 144.4 (C), 140.9 (C), 129.9 (2 CH),
128.8 (C); 128.5 (2 CH), 127.9 (CH), 127.1 (C), 126.3 (CH), 123.9
(C), 122.7 (CH), 121.2 (C), 120.1 (CH), 113.9 (C), 110.1 (CH),
60.9 (OCOCH2), 36.7 (NCH3), 36.5 (CH2), 31.3 (OCNCH3), 14.3
(CH3); GC-MS (EI, 70 eV): m/z (%): 374 (100) [M+], 346 (20), 329
(6), 301 (4), 286 (2), 271 (3), 242 (2), 231 (3), 225 (8), 211 (3), 202
(3), 184 (5), 164 (25), 154 (3), 149 (3), 144 (3), 135 (6), 129 (5), 121
(3), 115 (3), 108 (2); HRMS (ESI, [M+H]+): calcd for C23H23O3N2:
375.1703; found: 375.1702.
3-(2,10-Dimethyl-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-
yl)-4-methoxy-benzoic acid methyl ester (6m)
2,10-Dimethyl-5-naphthalen-1-yl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6i)
Yield: 47 mg, 60%; white powder; purification conditions: CH2Cl2–
ethyl acetate (80 : 20); 1H NMR (300 MHz; CDCl3): d = 8.09 (dd,
J = 8.7 Hz, J = 2.2 Hz, 1H), 8.00 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H),
7.24 (ddd, J = 8.2 Hz, J = 7.0 Hz, J = 1.1 Hz, 1H), 6.91 (d, J =
8.7 Hz, 1H), 6.82 (ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.0 Hz, 1H),
6.57 (d, J = 8.1 Hz, 1H), 6.19 (t, J = 7.0 Hz, 1H), 4.08 (s, 3H,
NCH3), 3.87 (s, 3H, OCH3), 3.83 (d, J = 6.9 Hz, 2H, CH2), 3.53
(s, 3H, OCOCH3), 3.26 (s, 3H, OCNCH3); 13C NMR (75.5 MHz,
CDCl3): d = 168.8 (CO), 162.1 (CO), 161.0 (CO), 138.2 (2 C), 132.6
(CH), 131.6 (CH), 129.7 (C), 124.5 (C), 124.2 (CH), 123.5 (CH),
122.5 (2 C), 121.2 (CH), 120.0 (CH), 118.0 (C), 110.6 (CH), 109.8
(CH), 55.7 (OCH3), 51.9 (OCOCH3), 47.4 (CH2), 34.9 (NCH3),
32.0 (OCNCH3); FT-IR (ATR, cm-1): 3052, 2947, 2839, 1713,
1626, 1601, 1500, 1466, 1435, 1303, 1263, 1224, 1132, 1106, 1021,
768, 739, 631; GC-MS (EI, 70 eV): m/z (%): 390 (100) [M+], 375
(5), 361 (15), 345 (4), 333 (19), 318 (7), 302 (3), 287 (2), 274 (4), 258
(3), 244 (2), 230 (3), 225 (20), 216 (3), 202 (2), 197 (7), 189 (2), 179
(5), 165 (3), 158 (3), 151 (7), 144 (2), 136 (2); HRMS (EI): calcd
for C23H23O4N2: 391.1652; found: 391.1656.
Yield: 57 mg, 80%; light yellow powder; purification conditions:
CH2Cl2–ethyl acetate (70 : 30); 1H NMR (300 MHz; CDCl3): d =
7.88 (m, 2H), 7.78 (br, 1H), 7.51 (d, J = 4.7 Hz, 2H), 7.45–7.21
(m, 3H), 7.17 (ddd, J = 8.1 Hz, J = 7.1 Hz, J = 1.1 Hz, 1H), 6.65
(ddd, J = 8.1 Hz, J = 7.0 Hz, J = 0.9 Hz, 1H), 6.25 (dt, J = 8.2 Hz,
J = 0.9 Hz, 1H), 6.24 (t, J = 6.9 Hz, 1H), 4.13 (s, 3H, NCH3),
3.95 (d, J = 6.3 Hz, 2H, CH2), 3.31 (s, 3H, OCNCH3); 13C NMR
(75.5 MHz, CDCl3): d = 162.1 (CO), 138.6 (C), 138.4 (2 C), 133.5
(C), 131.7 (C), 128.5 (CH), 128.1 (CH), 127.4 (CH), 126.2 (CH),
125.8 (CH), 125.6 (CH), 125.4 (CH), 124.4 (CH), 124.2 (C), 123.8
(CH), 121.7 (CH), 120.2 (CH), 118.7 (C), 109.7 (CH), 47.6 (CH2),
35.0 (NCH3), 32.1 (OCNCH3); FT-IR (ATR, cm-1): 3049, 2926,
1733, 1634, 1503, 1456, 1386, 1330, 1232, 1017, 797, 780, 739, 676,
614; GC-MS (EI, 70 eV): m/z (%): 352 (100) [M+], 323 (24), 208
(7), 295 (30), 278 (7), 266 (5), 253 (4), 239 (3), 225 (15), 197 (5),
154 (9), 145 (5), 139 (5), 132 (3), 127 (2); HRMS (ESI, [M+H]+):
calcd for C24H21ON2: 353.1648; found: 353.1651.
5-Furan-2-yl-2,10-dimethyl-3,10-dihydro-2H-azepino[3,4-b]indol-
3-(2,6-Dimethyl-1-oxo-1,2,3,6-tetrahydro-azepino[4,3-b]indol-5-
1-one (6j)
yl)-4-methoxy-benzoic acid methyl ester (7m)
Yield: 38 mg, 65%; light orange powder; purification conditions:
CH2Cl2–ethyl acetate (90 : 10); 1H NMR (300 MHz; CDCl3): d =
7.43 (m, 2H), 7.39–7.29 (m, 2H), 7.07 (ddd, J = 8.1 Hz, J = 6.8 Hz,
J = 1.1 Hz, 1H), 6.51 (t, J = 7.2 Hz, 1H), 6.45 (dd, J = 3.3 Hz,
J = 1.9 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.08 (s, 3H, NCH3),
3.81 (br, 2H, CH2), 3.24 (s, 3H, OCNCH3); 13C NMR (75.5 MHz,
CDCl3): d = 162.1 (CO), 152.6 (CO), 142.1 (CH), 138.1 (C), 133.5
(C), 130.9 (C), 124.4 (CH), 124.2 (C), 122.4 (CH), 120.1 (CH),
119.7 (CH), 114.9 (C), 111.3 (CH), 110.0 (CH), 109.7 (CH), 47.2
Yield: 18 mg, 23%; white powder; purification conditions: CH2Cl2–
ethyl acetate (80 : 20); 1H NMR (300 MHz; CDCl3): d = 8.31 (m,
1H), 8.06 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.90 (br, 1H), 7.36-
7.21 (m, 3H), 6.94 (d, J = 8.7 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H),
3.87 (s, 3H, NCH3), 3.81 (d, J = 7.5 Hz, 2H, CH2), 3.27 (s, 3H,
OCNCH3), 3.19 (s, 3H, OCH3); 13C NMR (75.5 MHz, CDCl3): d =
166.5 (CO), 165.7 (CO), 160.2 (CO), 138.8 (C), 137.4 (C), 131.8
(CH), 131.7 (CH), 130.7 (C), 128.2 (C), 126.9 (CH), 123.5 (CH),
122.9 (2 C), 122.4 (CH), 121.3 (CH), 119.6 (C), 110.5 (CH), 108.9
1158 | Org. Biomol. Chem., 2011, 9, 1148–1159
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(CH), 56.0 (OCH3), 52.0 (OCOCH3), 47.1 (CH2), 35.2 (NCH3),
31.8 (OCNCH3); FT-IR (ATR, cm-1): 2922, 2851, 1712, 1603,
1463, 1435, 1392, 1295, 1264, 1227, 1165, 1129, 1018, 768, 750,
735, 712; GC-MS (EI, 70 eV): m/z (%): 390 (100) [M+], 361 (43),
348 (3), 333 (7), 315 (6), 301 (5), 287 (4), 274 (4), 258 (3), 244 (4),
225 (28), 217 (3), 202 (3), 195 (5), 189 (2), 179 (4), 165 (4), 158 (2),
150 (2), 144 (3), 135 (2), 121 (3), 95 (2), 42 (2); HRMS (EI): calcd
for C23H23O4N2: 391.1652; found: 391.1660.
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3631.
2,4,9-Trimethyl-2,9-dihydro-b-carbolin-1-one (8n)
Yield: 43 mg, 95%; white powder: purification conditions: ethyl
1
acetate; H NMR (400 MHz; CDCl3): d = 8.10 (dt, J = 8.1 Hz,
J = 1.0 Hz, 1H), 7.54–7.45 (m, 2H), 7.25 (ddd, J = 8.1 Hz, J =
6.5 Hz, J = 1.6 Hz, 1H), 6.80 (d, J = 1.1 Hz, 1H), 4.36 (s, 3H,
NCH3), 3.65 (s, 3H, OCNCH3), 2.57 (d, J = 1.1 Hz, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3): d = 156.3 (CO), 140.9 (C), 126.8 (C),
126.4 (CH), 126.2 (CH), 124.7 (C), 122.7 (CH), 122.0 (C), 120.0
(CH), 112.2 (C), 110.0 (CH), 36.5 (NCH3), 31.2 (OCNCH3), 16.9
(CH3); FT-IR (ATR, cm-1): 3060, 2923, 2890, 2855, 1652, 1596,
1475, 1437, 1333, 1291, 991, 811, 728, 620, 539, 508; GC-MS (EI,
70 eV): m/z (%): 226 (100) [M+], 211 (15), 197 (4), 181 (4), 168 (4),
154 (4), 140 (4), 128 (3), 113 (6); HRMS (ESI, [M+H]+): calcd for
C14H15ON2: 227.1179; found: 227.1184.
2-Benzyl-10-methyl-5-p-tolyl-3,10-dihydro-2H-azepino[3,4-
b]indol-1-one (6o)
Yield: 61 mg, 77%; white powder; purification conditions:
heptane–ethyl acetate (70 : 30); NMR data from inseparable mix-
1
ture of compounds 6o:7o (5.7 : 1); H NMR (300 MHz; CDCl3):
d = 7.43 (dt, J = 8.6 Hz, J = 0.8 Hz, 1H), 7.40–7.23 (m, 8H), 7.16
(m, 2H), 6.91 (ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.0 Hz, 1H), 6.75
(dt, J = 8.1 Hz, J = 0.8 Hz, 1H), 6.00 (t, J = 7.0 Hz, 1H), 4.95
(br, 2H, CH2), 4.15 (s, 3H, NCH3), 3.77 (d, J = 7.0 Hz, 2H, CH2),
2.41 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): d = 162.4 (CO),
141.9 (C), 138.4 (C), 137.7 (C), 137.4 (C), 133.2 (C), 129.0 (2 CH),
128.7 (2 CH), 128.4 (2 CH), 128.2 (C), 128.0 (2 CH), 127.5 (CH),
124.6 (C), 124.3 (CH), 122.8 (CH), 121.4 (CH), 120.0 (CH), 117.3
(C), 109.9 (CH), 50.4 (CH2), 45.1 (CH2), 32.1 (NCH3), 21.2 (CH3);
GC-MS (EI, 70 eV): m/z (%): 392 (100) [M+], 377 (5), 301 (41),
288 (26), 274 (14), 259 (56), 242 (5), 230 (6), 216 (3), 202 (5), 189
(2), 168 (2), 115 (2), 91 (15), 65 (2); HRMS (ESI, [M+H]+): calcd
for C27H25ON2: 393.1961; found: 393.1971.
Acknowledgements
This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF (Bundesministerium fu¨r Bil-
dung und Forschung) and the Deutsche Forschungsgemeinschaft
(Leibniz-price; GRK 1113). We also thank Drs D. Michalik,
W. Baumann, C. Fischer, and Mrs S. Buchholz, Mrs S. Schareina,
Mrs A. Lehmann, and Mrs K. Mevius (all LIKAT) for their
excellent analytical support.
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Notes and references
1 R. Martinez, J. G. Avila, M. T. Ramirez, A. Pe´rez and A. Martinez,
Bioorg. Med. Chem., 2006, 14, 4007.
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The Royal Society of Chemistry 2011
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©