A versatile, unexpected, one-pot regioselective synthesis of a new class of 1,3-diazepinoindolones by reaction of pyranoindolones with monosubstituted ureas

Article abstract of DOI:10.1055/s-0029-1216868

The regioselective one-pot synthesis of a new class of 4,6-dihydro[1,3] diazepino[5,6-b]indol-3(2H)-ones, in very good yields, via reaction of pyranoindolones with monosubstituted ureas is described. Reaction of N,N′-disubstituted ureas with pyranoindolon

Full text of DOI:10.1055/s-0029-1216868

PAPER
2579
A Versatile, Unexpected, One-Pot Regioselective Synthesis of a New Class of
1,3-Diazepinoindolones by Reaction of Pyranoindolones with Monosubstituted
Ureas
O
ne-Pot Regiosele
e
ctive Synth
s
esis of 1,3
p
-Diazepinoi
i
ndolon
n
e
s
a Livadiotou, Constantinos A. Tsoleridis,* Julia Stephanidou-Stephanatou*
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
Fax +30(2310)997679; E-mail: tsolerid@chem.auth.gr; E-mail: ioulia@chem.auth.gr
Received 11 March 2009; revised 24 April 2009
give compounds 3e–h which were also isolated in very
Abstract: The regioselective one-pot synthesis of a new class of
good yields (89–92%). However, when unsubstituted urea
4,6-dihydro[1,3]diazepino[5,6-b]indol-3(2H)-ones, in very good
was used, a mixture of various unidentified products was
yields, via reaction of pyranoindolones with monosubstituted ureas
formed.
is described. Reaction of N,N¢-disubstituted ureas with pyranoindol-
ones, under similar conditions, gave the corresponding b-carbolin-
ones. The reaction mechanisms leading to both types of product are
discussed and the structures are confirmed by spectroscopic tech-
niques.
The reaction was also studied using a disubstituted urea.
Thus, reaction of pyranoindolones 1c,d with three molar
equivalents of N,N¢-dimethylurea (2c) in bromobenzene at
reflux gave b-carbolinones 4 in yields of 60–61%, instead
Key words: bisnucleophiles, carbenes, diazepinoindolones, pyra-
noindolones, substituted ureas, one-pot reaction
of the corresponding 1,3-diazepinoindolones
3
(Scheme 1, Table 1). The reaction proceeded analogously
at lower temperatures (refluxing xylenes), although
slightly longer reaction times were necessary (Table 1).
Previously, we have studied the reaction of pyranoindol-
ones with bisnucleophiles such as methyl-, phenyl- and
benzoylhydrazine. In the case of methylhydrazine, diaze-
pinoindole derivatives were isolated,1 but with phenyl- or
benzoylhydrazine, b-carbolinones were the only reaction
products.2
Table 1 Reaction Conditions and Products
Substrate Urea
Solvent
PhBr
Time (h) Product Yield (%)
1a
1b
1c
1d
1a
1b
1c
1d
1c
1c
1d
1d
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
1
3a
3b
3c
3d
3e
3f
90
91
91
93
89
91
92
91
60
63
61
57
PhBr
2
In the light of these results and in continuation of our re-
search on the synthesis of compounds containing an in-
dole ring, we decided to extend our research to the
reaction of pyranoindolones with other ambident nucleo-
philes, such as substituted ureas, since to our knowledge,
no analogous reactions have been reported in the litera-
ture. In fact, after a thorough search, the only similar reac-
tion that could be found was that between 2-pyranones
and urea, which was used to generate ammonia.3 Pyra-
noindolones are interesting in that they possess an electro-
philic center at C-1 (an enol carbon) in addition to a strong
solvent effect;1,2 this renders their study even more chal-
lenging. Moreover, it is known that medium-sized indolo-
fused azacycles constitute structural arrangements in
many natural and synthetic bioactive compounds.4,5 In the
present work we describe a one-pot method for the syn-
thesis of a new class of 1,3-diazepinoindolones in very
good yields.
PhBr
3.5
3
PhBr
PhBr
3
PhBr
4.5
3.5
8
PhBr
3g
3h
4c
4c
4d
4d
PhBr
PhBr
5
C6H4Me2
PhBr
6
3
C6H4Me2
5
Concerning the reaction mechanism, attack of the less
hindered unsubstituted NH2 group of the urea6 on C-1, the
reactive electrophilic center, of the pyranoindolone would
be expected, as was observed in the case of other ambi-
dent nucleophiles.1,2 However, the isolation of products 3
led to the conclusion that the reaction followed a different
pathway (Scheme 2), most probably as a result of the
weak nucleophilic character of the urea nitrogens. Ac-
cording to the proposed mechanism the reaction is initiat-
ed by electrocyclic ring-opening of the pyrone ring of 1
leading to the formation of a vinylogous acylketene inter-
Initially, pyranoindolones 1a–d were reacted with three
molar equivalents of N-methylurea in refluxing bro-
mobenzene to give 1,3-diazepinoindolones 3a–d in excel-
lent yields (90–93%, Scheme 1 and Table 1), instead of
the expected b-carbolinones 5 or 1,2-diazepinoindolones
6. Analogous reactions occurred with N-benzylurea to
SYNTHESIS 2009, No. 15, pp 2579–2583
x
x.
x
x
.
2
0
0
9
Advanced online publication: 26.06.2009
DOI: 10.1055/s-0029-1216868; Art ID: P04009SS
© Georg Thieme Verlag Stuttgart · New York

2580
D. Livadiotou et al.
PAPER
mediate 7. Subsequent decarbonylation of 7, in refluxing inserts7 into the N–H bond of the urea to form intermedi-
bromobenzene, leads to the formation of carbene 8 which ate 9 which undergoes cyclization and elimination of wa-
is stabilized by the indole nitrogen. The carbene then ter to yield product 3.
O
R3
O
N
NHR3
O
N
C
O
N
N
N
R2
R2
R1
R1
5
6
R1 R2
R3
H
1
10
N
9
3
O
3a
3b
3c
3d
3e
3f
3g
3h
4c
4d
H
Me Me
H
Et
Me Me Me
Me Et
Me
Me Bn
Et Bn
Me Bn
Bn
Me Me Me
Me Et
Me
Me
8
C6H5Br
reflux
O
N
O
R3
5
7
N
R3
R4
R2
H
H
R1
O
+
N
H
N
H
3
Me
C6H5Br
or xylene
N
R1
1
2
R2
Me Et
(when R4 = H)
reflux
R1
R2
R3
R4
O
4
5
6
3
N
R3
7
a
b
c
d
H
H
Me
Et
a
Me
Bn
Me
H
H
b
c
1
N
8
R2
Me Me
Me Et
Me
R1
4
(when R4 = Me)
Scheme 1 Reactions of pyranoindolones 1 with monosubstituted ureas 2a,b to afford 1,3-diazepinoindolones 3, and with N,N¢-dimethylurea
(2c) to give b-carbolinones 4
H
H
H
H
O
C
O
∆
∆
O
O
O
O
– CO
N
N
N
N
R2
R2
R2
R2
R1
R1
R1
R1
1
7
8
O
O
Me
Me
Me
N
H
N
H
H2N
N
H
O
O
H
H
O
Me
N
H
N
N
NHMe
NH
Me
O
CONHMe
O
O
– MeN=C=O
N
N
R2
R2
R2
R1
R1
R1
9
H
H
N
O
O
O
H
N
– H2O
OH
HO
N
N
Me
Me
N
N
N
Me
R2
R2
R2
R1
R1
R1
10
4
– H2O
H
N
O
N
N
Me
R2
R1
3
Scheme 2 Plausible mechanisms for the formation of compounds 3 and 4
Synthesis 2009, No. 15, 2579–2583 © Thieme Stuttgart · New York

PAPER
One-Pot Regioselective Synthesis of 1,3-Diazepinoindolones
2581
The formation of b-carbolinones 4 most probably occurs at 139.7 ppm (C10b) confirms their positions three bonds
via attack of the NH group of the disubstituted urea 2c on apart. The structures of compounds 4c,d were easily elu-
the intermediate ketene 7. Subsequent abstraction of cidated by analogy with the b-carbolinones discussed in
methyl isocyanate followed by ring-closure to give 10 and our previous work.2
elimination of water leads to compounds 4 (Scheme 2).
In conclusion, we have developed a direct method for the
The assignment of the molecular structures of novel com- synthesis of a new class of 1,3-diazepinoindoles via reac-
pounds 3 and 4 was based on rigorous spectroscopic anal- tion of pyranoindolones with bisnucleophiles. Full assign-
ysis including IR and NMR spectroscopy [1H, 13C, ment of the H and 13C NMR chemical shifts of the
1
correlation spectroscopy (COSY), nuclear Overhauser ex- products has been achieved unambiguously. Although
change spectroscopy (NOESY), heteronuclear chemical- some [1,3]diazepino[4,5-b]indol-6-ones have been re-
shift correlation (HETCOR) and correlation through long- ported in the literature,8 our procedure constitutes the first
range coupling (COLOC)], mass spectrometry and ele- example of the synthesis of [1,3]diazepino[5,6-b]indol-3-
mental analysis. As an example, the structural assignment ones. While bis-diazepinones have demonstrated promis-
of 1,3-diazepinoindole 3c is described. The elemental ing biological activity8,9 further investigations are compli-
analysis and mass spectrum established that one molecule cated by the lack of efficient methods for their
of pyranoindolone 1c had reacted with one molecule of N- preparation. Work in this area is continuing in our labora-
methylurea with the loss of a molecule of formic acid. tory using other bisnucleophiles, and we will report our
This was also confirmed from the 13C NMR spectrum results in due course.
where 14 different signals were observed. Moreover, in
the IR spectrum, the N–H and carbonyl absorptions were
Melting points were measured using a Kofler hot-stage apparatus
identified at 3451, 3400, 3195 (N–H), and 1685 and 1659
and are uncorrected. Column chromatography was carried out using
(NC=O) cm–1, respectively. The presence and positions of
Merck silica gel (0.063–0.200 mm). TLC was performed on pre-
coated silica gel glass plates containing a fluorescent indicator (Ma-
cherey–Nagel UV254, 0.25 mm) using PE–EtOAc (3:1). PE refers to
the fraction boiling between 60–80 °C. NMR spectra were recorded
at r.t. on a Bruker AM 300 spectrometer at 300 MHz (1H) and 75
MHz (13C), respectively, using CDCl3 as the solvent . In the case of
insoluble products, 5–20% of DMSO-d6 was added to the CDCl3 so-
lution. CD3OD was used as solvent in the case 3k. 1H NMR chem-
ical shifts are expressed in d values (ppm) relative to TMS (0.00
ppm) as internal standard. 13C NMR spectra are expressed in d val-
ues (ppm) relative to the CDCl3 solvent signal at 77.05 ppm, and at
49.0 ppm in the case of CD3OD. Coupling constants nJ are reported
in Hz. IR spectra were recorded on a Perkin-Elmer 1600 series FTIR
spectrometer and are reported in wavenumbers (cm–1). Low-resolu-
tion electron impact mass spectra were recorded using a 6890N
GC–MS system (Agilent Technology); LC-MS (ESI, 1.65 eV)
spectra were recorded on an LCMS-2010 EV instrument (Shimad-
zu). Elemental analyses were recorded using a Perkin-Elmer 2400-
II CHN analyzer.
the four indole-aromatic protons were proven unequivo-
cally from their 1H NMR splitting patterns and long-range
correlations (COLOC). The long-range C–H correlation
spectra were optimized for J = 10 Hz, with aromatic pro-
tons showing 3J correlations, and protons on saturated car-
bons demonstrating COLOC via J and J couplings.
Consequently, the C5-methyl group protons showed cor-
relations with the carbon at 128.1 ppm (C5) and with the
quaternary carbon at 127.8 ppm (C5a) whereas the indole
N-methyl protons correlated with the same quaternary
carbon (C5a) and with the quaternary carbon at 147.7 ppm
(C6a). The N4-methyl protons correlated with the carbon
at 128.1 ppm (C5) and the carbonyl carbon at 161.5 ppm
(C3), thus confirming its position. Finally, proton H1 cor-
related with carbon C5a and the quaternary carbon at
120.6 ppm (C10a) which established the complete carbon
skeleton of product 3c (Figure 1).
2
3
4,6-Dihydro[1,3]diazepino[5,6-b]indol-3(2H)-ones (3a–h);
General Procedure
NOESY
To a refluxing solution of pyranoindolone 1 (1.5 mmol) in bro-
mobenzene (15 mL) was added monosubstituted urea 2a,b (4.5
mmol) and heating was continued until 1 was consumed. The reac-
tion mixture was allowed to cool (5–10 °C) and the precipitated
product was filtered off, washed with Et2O (15 mL) and recrystal-
lized from EtOH. If crystallization was not possible the solvent was
removed by distillation and the residue was purified by column
chromatography on silica gel using PE–EtOAc (5:1) as eluent,
slowly increasing the polarity up to 1:5 to give the products.
H
H
H
H
H
H
H
H
N
N
O
O
H
H
N
N
Me
Me
N
N
H
H
Me
Me
Me
Me
NOESY
3c
3c
Figure 1 Correlations (COLOC) between the protons and carbons
(via 2JC–H and 3JC–H) in compound 3c. NOESY correlations were ob-
served between protons H7 and 6-Me and between H1 and H10. Ben-
zylic-type coupling (J = 0.6 Hz) between protons H1 and 5-Me were
also observed
4,5-Dimethyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-3(2H)-one
(3a)
Yellow crystals; yield: 0.204 g (90%); mp >350 °C (EtOH).
IR (KBr): 3407, 3371, 3276, 3171 (NH), 1686, 1670 (NC=O) cm–1.
1H NMR (CDCl3 containing DMSO-d6): d = 2.63 (s, 3 H, 5-Me),
3.71 (s, 3 H, 4-Me), 5.72 (br s, 1 H, H2), 6.99 (s, 1 H, H1), 7.08 (ddd,
J = 1.0, 7.2, 8.0 Hz, 1 H, H9), 7.28 (dd, J = 1.0, 8.0 Hz, 1 H, H7),
7.45 (ddd, J = 1.0, 7.2, 8.0 Hz, 1 H, H8), 7.88 (dd, J = 1.0, 8.0 Hz,
1 H, H10), 9.04 (br s, 1 H, H6).
For compounds 3e–h the benzylic protons appear as broad
signals which are indicative of rotational restriction about
this group. In compound 3h, the correlation (COLOC) be-
tween proton H10 at 7.89 ppm and the quaternary carbon
Synthesis 2009, No. 15, 2579–2583 © Thieme Stuttgart · New York

2582
D. Livadiotou et al.
PAPER
4-Benzyl-5-methyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-
3(2H)-one (3e)
13C NMR (CDCl3, containing DMSO-d6): d = 15.8 (5-Me), 32.0 (4-
Me), 102.5 (C1), 111.1 (C7), 119.0 (C9), 121.0 (C10a), 122.9
(C10), 125.9 (C5a), 129.1 (C5), 130.1 (C8), 138.1 (C10b), 145.1
(C6a), 161.5 (C3).
Yellow crystals; yield: 0.269 g (89%); mp 225–226 °C (EtOH).
IR (KBr): 3420, 3225 (NH), 1710, 1690, 1670, 1650 (NC=O) cm–1.
LC-MS (ESI, 1.65 eV): m/z (%) = 267 (100) [M + 1+ K+].
1H NMR (CDCl3): d = 2.38 (s, 3 H, 5-Me), 5.38 (s, 2 H, 4-CH2),
7.00–7.07 (m, 3 H, H1, H7, H4¢), 7.11 (dd, J = 7.2, 8.0 Hz, 1 H, H9),
7.17–7.30 (m, 4 H, H2¢, H3¢, H5¢, H6¢), 7.45 (dd, J = 7.2, 8.4 Hz, 1
H, H8), 7.87 (d, J = 8.0 Hz, 1 H, H10), 8.27 (br s, 1 H, H6).
Anal. Calcd for C13H13N3O: C, 68.70; H, 5.77; N, 18.49. Found: C,
68.85; H, 5.83, N, 18.57.
5-Ethyl-4-methyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-3(2H)-
one (3b)
Yellow crystals; yield: 0.219 g (91%); mp 149–150 °C (EtOH).
13C NMR (CDCl3): d = 15.5 (5-Me), 47.8 (4-CH2), 103.0 (C1),
111.4 (C7), 119.6 (C9), 121.2 (C10a), 123.0 (C10), 126.1 (C5a),
126.3 (C2¢, C6¢), 127.3 (C4¢), 128.6 (C5), 128.8 (C3¢, C5¢), 130.7
(C8), 136.7 (C1¢), 138.8 (C10b), 145.3 (C6a), 161.6 (C3).
IR (KBr): 3421, 3338, 3200 (NH), 1663, 1643 (NC=O), 1614 (NH)
cm–1.
LC-MS (ESI, 1.65 eV): m/z (%) = 303 (100) [M+].
1H NMR (CDCl3, containing DMSO-d6): d = 1.34 (t, J = 7.5 Hz, 3
H, 5-CH2CH3), 3.12 (q, J = 7.5 Hz, 2 H, 5-CH2), 3.75 (s, 3 H, 4-Me),
5.50 (br s, 1 H, H2), 6.94 (s, 1 H, H1), 7.05 (dd, J = 7.0, 7.5 Hz, 1
H, H9), 7.33 (d, J = 8.4 Hz, 1 H, H7), 7.45 (ddd, J = 1.0, 7.0, 8.4 Hz,
1 H, H8), 7.87 (dd, J = 1.0, 7.5 Hz, 1 H, H10), 10.40 (br s, 1 H, H6).
Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found: C,
75.15; H, 5.53; N, 13.63.
4-Benzyl-5-ethyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-3(2H)-
one (3f)
Yellow crystals; yield: 0.288 g (91%); mp 219–220 °C (EtOH).
13C NMR (CDCl3, containing DMSO-d6): d = 14.6 (5-CH2CH3),
22.0 (5-CH2), 31.2 (4-Me), 101.2 (C1), 110.8 (C7), 118.0 (C9),
119.9 (C10a), 120.0 (C10), 125.1 (C5a), 129.6 (C8), 132.7 (C5),
137.5 (C10b), 144.8 (C6a), 160.8 (C3).
IR (KBr): 3430, 3270 (NH), 1690, 1665, 1630 (NC=O) cm–1.
1H NMR (CDCl3): d = 1.22 (t, J = 7.5 Hz, 3 H, 5-CH2CH3), 2.84 (q,
J = 7.5 Hz, 2 H, 5-CH2), 4.39 (d, J = 6.0 Hz, 1 H, H2), 5.58 (br s, 2
H, 4-CH2), 7.07 (s, 1 H, H1), 7.08–7.14 (m, 3 H, H7, H9, H4¢), 7.20–
7.30 (m, 4 H, H2¢, H3¢, H5¢, H6¢), 7.40 (br s, 1 H, H6), 7.47 (ddd,
J = 1.1, 7.2, 8.4 Hz, 1 H, H8), 7.90 (dd, J = 1.1, 8.0 Hz, 1 H, H10).
LC-MS (ESI, 1.65 eV): m/z (%) = 281 (66) [M + 1+ K+], 227 (100).
Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C,
69.85; H, 6.43; N, 17.59.
13C NMR (CDCl3): d = 12.9 (5-CH2CH3), 22.7 (5-CH2), 47.3 (4-
CH2), 102.7 (C1), 111.5 (C7), 119.4 (C9), 120.7 (C10a), 122.9
(C10), 125.8 (C5a), 126.0 (C2¢, C6¢), 127.2 (C4¢), 128.7 (C3¢, C5¢),
130.7 (C8), 133.2 (C5), 137.0 (C1¢), 138.7 (C10b), 145.3 (C6a),
161.2 (C3).
4,5,6-Trimethyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-3(2H)-
one (3c)
Yellow crystals; yield: 0.219 g (91%); mp 188–189 °C (EtOH).
IR (KBr): 3451, 3400, 3195 (NH), 1685, 1659 (NC=O) cm–1.
1H NMR (CDCl3): d = 2.73 (d, J = 0.7 Hz, 3 H, 5-Me), 3.66 (s, 3 H,
4-Me), 3.73 (s, 3 H, 6-Me), 6.91 (q, J = 0.7 Hz, 1 H, H1), 7.08 (ddd,
J = 0.8, 7.2, 7.8 Hz, 1 H, H9), 7.12 (dd, J = 0.8, 7.9 Hz, 1 H, H7),
7.50 (ddd, J = 0.7, 7.2, 7.9 Hz, 1 H, H8), 7.82 (dd, J = 0.7, 7.8 Hz,
1 H, H10).
LC-MS (ESI, 1.65 eV): m/z (%) = 357 (100) [M + 1 + K+].
Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C,
75.76; H, 6.15; N, 13.48.
4-Benzyl-5,6-dimethyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-
3(2H)-one (3g)
Yellow crystals; yield: 0.291 g (92%); mp 128–130 °C (EtOH).
13C NMR (CDCl3): d = 16.5 (5-Me), 32.1 (4-Me), 34.0 (6-Me),
102.8 (C1), 109.1 (C7), 119.2 (C9), 120.6 (C10a), 122.6 (C10),
127.8 (C5a), 128.1 (C5), 130.5 (C8), 138.8 (C10b), 147.7 (C6a),
161.5 (C3).
IR (Nujol®): 3323, 3214 (NH), 1699, 1662 (NC=O) cm–1.
1H NMR (CDCl3): d = 2.60 (s, 3 H, 5-Me), 3.65 (s, 3 H, 6-Me), 5.44
(br s, 2 H, 4-CH2), 6.13 (br s, 1 H, 2H), 6.93 (s, 1 H, H1), 7.02–7.11
(m, 4 H, H7, H9, H2¢, H6¢), 7.18–7.28 (m, 3 H, H3¢, H4¢, H5¢), 7.49
(ddd, J = 1.0, 7.0, 7.5 Hz, 1 H, H8), 7.80 (dd, J = 1.0, 7.5 Hz, 1 H,
10-H).
MS (EI, 70 eV): m/z (%) = 242 (80) [M + 1+], 214 (25), 185 (14),
157 (100).
Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C,
69.78; H, 6.15; N, 17.60.
13C NMR (CDCl3): d = 16.3 (5-CH3), 34.1 (6-CH3), 47.8 (4-CH2),
103.5 (C1), 109.1 (C7), 119.3 (C9), 120.7 (C10a), 122.7 (C10),
126.3 (C2′, C6′), 127.2 (C4′), 127.97 (C5a), 128.04 (C5), 128.8
(C3′, C5′), 130.7 (C8), 137.0 (C1′), 139.5 (C10b), 148.0 (C6a),
161.7 (C3).
5-Ethyl-4,6-dimethyl-4,6-dihydro[1,3]diazepino[5,6-b]indol-
3(2H)-one (3d)
Yellow crystals; yield: 0.237 g (93%); mp 145–146 °C (EtOH).
IR (KBr): 3441, 3343, 3300, 3231 (NH), 1759, 1716, 1656 (NC=O)
cm–1.
LC-MS (ESI, 1.65 eV): m/z (%) = 317 (100) [M+].
1H NMR (CDCl3): d = 1.40 (t, J = 7.5 Hz, 3 H, 5-CH2CH3), 3.18 (q,
J = 7.5 Hz, 2 H, 5-CH2), 3.75 (s, 3 H, 4-Me), 3.77 (s, 3 H, 6-Me),
5.10 (br s, 1 H, H2), 7.00 (s, 1 H, H1), 7.10 (dd, J = 7.0, 7.5 Hz, 1
H, H9), 7.16 (d, J = 8.5 Hz, 1 H, H7), 7.52 (ddd, J = 1.0, 7.0, 8.5 Hz,
1 H, H8), 7.87 (dd, J = 1.0, 7.5 Hz, 1 H, H10).
Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C,
75.76; H, 6.15; N, 13.08.
4-Benzyl-5-ethyl-6-methyl-4,6-dihydro[1,3]diazepino[5,6-b]in-
dol-3(2H)-one (3h)
Yellow crystals; yield: 0.301 g (91%); mp 205–206 °C (EtOH).
13C NMR (CDCl3): d = 13.9 (5-CH2CH3), 20.6 (5-CH2), 32.7 (4-
Me), 34.3 (6-Me), 102.7 (C1), 108.7 (C7), 118.8 (C9), 120.1
(C10a), 122.1 (C10), 126.4 (C5a), 130.2 (C8), 133.1 (C5), 138.7
(C10b), 147.0 (C6a), 161.1 (C3).
IR (KBr): 3383, 3278, 3188 (NH), 1720, 1692, 1654 (NC=O) cm–1.
1H NMR (CDCl3): d = 1.32 (t, J = 7.6 Hz, 3 H, 5-CH2CH3), 1.80 (br
s, 0.5 H, H2), 3.06 (q, J = 7.6 Hz, 2 H, 5-CH2), 3.78 (s, 3 H, 6-Me),
4.38 (br s, 0.5 H, H2), 5.60 (br s, 2 H, 4-CH2), 7.09 (s, 1 H, H1),
7.06–7.10 (m, 2 H, H2¢, H6¢), 7.10 (ddd, J = 1.0, 7.2, 7.8 Hz, 1 H,
H9), 7.17 (dd, J = 1.0, 8.3 Hz, 1 H, H7), 7.24 (t, J = 6.9 Hz, 1 H,
MS (EI, 70 eV): m/z (%) = 254 (100) [M – 1+].
Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.67; H, 6.53; N, 16.58.
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One-Pot Regioselective Synthesis of 1,3-Diazepinoindolones
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H4¢), 7.22–7.31 (m, 2 H, H3¢, H5¢), 7.53 (ddd, J = 1.2, 7.2, 8.3 Hz,
1 H, H8), 7.89 (dd, J = 1.2, 7.8 Hz, 1 H, H10).
13C NMR (CDCl3, containing DMSO-d6): d = 14.3 (1-CH2CH3),
22.2 (1-CH2), 29.0 (2-Me), 31.6 (9-Me), 103.1 (C4), 109.0 (C8),
119.3 (C6), 120.5 (C4b), 122.6 (C5), 127.3 (C9a), 130.7 (C7), 133.4
(C1), 139.3 (C4a), 147.6 (C8a), 160.3 (C3).
13C NMR (CDCl3): d = 15.0 (5-CH2CH3), 21.9 (5-CH2), 32.7 (6-
Me), 47.1 (4-CH2), 103.8 (C1), 108.9 (C7), 119.2 (C9), 120.5
(C10a), 122.6 (C10), 126.0 (C2¢, C6¢), 126.9 (C5a), 127.1 (C4¢),
128.7 (C3¢, C5¢), 130.7 (C8), 133.4 (C5), 137.3 (C1¢), 139.7 (C10b),
147.5 (C6a), 161.4 (C3).
LC-MS (ESI, 1.65 eV): m/z (%) = 241 (100) [M + 1+].
Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C,
74.81; H, 6.58; N, 11.55.
LC-MS (ESI, 1.65 eV): m/z (%) = 371 (100) [M + 1 + K+].
Anal. Calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68. Found: C,
76.25; H, 6.19; N, 12.78.
Acknowledgment
The authors thank Professor Philip Kocienski for proposing the
mechanism given in Scheme 2.
b-Carbolin-3-ones 4c,d; General Procedure
To a refluxing solution of pyranoindolone 1c,d (1.5 mmol) in bro-
mobenzene (15 mL) was added N,N¢-dimethylurea 2c (4.5 mmol)
and heating was continued until 1 was consumed. The reaction mix-
ture was allowed to cool (5–10 °C) and the precipitated product was
filtered off, washed with Et2O (15 mL) and recrystallized from
EtOH. If crystallization was not possible the solvent was removed
by distillation and the residue was purified by column chromatogra-
phy on silica gel using EtOAc as eluent, to give products 4c,d.
References and notes
(1) Hatzimimikou, D.; Livadiotou, D.; Tsoleridis, C. A.;
Stephanidou-Stephanatou, J. Synlett 2008, 1773.
(2) Livadiotou, D.; Hatzimimikou, D.; Neochoritis, C.; Terzidis,
M. A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.
Synthesis 2008, 3273.
(3) Goel, A.; Singh, F. V.; Sharon, A.; Maulik, P. R. Synlett
2005, 623.
(4) (a) Sundberg, R. J. Indoles; Academic Press: New York,
1996. (b) Joule, J. A. In Science of Synthesis, Houben-Weyl
Methods of Molecular Transformations, Vol. 10; Thomas,
E. J., Ed.; Thieme: Stuttgart, 2000, 361–652.
1,2,9-Trimethyl-2,9-dihydro-3H-b-carbolin-3-one (4c)
Yellow crystals; yield: 0.142 g (63%); mp 225–226 °C (EtOH).
IR (KBr): 1663 (C=O) cm–1.
1H NMR (CDCl3): d = 2.74 (s, 3 H, 1-Me), 3.65 (s, 3 H, 2-Me), 3.75
(s, 3 H, 9-Me), 6.90 (s, 1 H, H4), 7.09 (dd, J = 7.2, 8.0 Hz, 1 H, H6),
7.13 (d, J = 8.0 Hz, 1 H, H8), 7.51 (ddd, J = 1.3, 7.2, 8.0 Hz, 1 H,
H7), 7.80 (dd, J = 1.3, 8.0 Hz, 1 H, H5).
(c) Rommelspacher, H.; May, T.; Salewsky, B. Eur. J.
Pharmacol. 1994, 252, 51. (d) Kim, H.; Sablin, S. O.;
Ramsay, R. R. Arch. Biochem. Biophys. 1997, 337, 137.
(e) Herraiz, T.; Chaparro, C. Biochem. Biophys. Res.
Commun. 2005, 326, 378.
13C NMR (CDCl3): d = 16.5 (1-Me), 32.1 (2-Me), 34.0 (9-Me),
102.8 (C4), 109.1 (C8), 119.2 (C6), 120.6 (C4b), 122.5 (C5), 127.9,
128.0 (C1, C9a), 130.4 (C7), 138.8 (C4a), 147.7 (C8a), 161.5 (C3).
(5) (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.
(b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 761.
(6) (a) Buscemi, S.; Pace, A.; Piccionello, A. P.; Pibiri, I.;
Vivona, N.; Giorgi, G.; Mazzanti, A.; Spinelli, D. J. Org.
Chem. 2006, 71, 8106. (b) Touzot, A.; Soufyane, M.;
Berber, H.; Toupet, L.; Mirand, C. J. Fluorine Chem. 2004,
125, 1299.
LC-MS (ESI, 1.65 eV): m/z (%) = 249 (100) [M + Na+].
Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.34; H, 6.38; N, 12.45.
1-Ethyl-2,9-dimethyl-2,9-dihydro-3H-b-carbolin-3-one (4d)
Yellow crystals; yield: 0.146 g (61%); mp 104–105 °C (EtOH).
(7) Mieusset, J.-L.; Bespokoev, A.; Pacar, M.; Abraham, M.;
Arion, V. B.; Brinker, U. H. J. Org. Chem. 2008, 73, 6551.
(8) Yu, Q.-S.; Greig, N. H.; Holloway, H. W.; Flippen-
Anderson, J. L.; Brossi, A. Med. Chem. Res. 2000, 10, 186.
(9) (a) Shutalev, A. D.; Fesenko, A. A.; Cheshkov, D. A.;
Guliguzov, D. V. Tetrahedron Lett. 2008, 49, 4099.
(b) Reisinger, A.; Koch, R.; Wentrup, C. J. Chem. Soc.,
Perkin Trans. 1 1998, 2247.
IR (KBr): 1634 (C=O) cm–1.
1H NMR (CDCl3, containing DMSO-d6): d = 1.43 (t, J = 7.5 Hz, 3
H, 1-CH2CH3), 3.22 (q, J = 7.5 Hz, 2 H, 1-CH2), 3.78 (s, 3 H, 2-Me),
3.82 (s, 3 H, 9-Me), 6.99 (s, 1 H, H4), 7.11 (dd, J = 7.0, 7.5 Hz, 1
H, H6), 7.19 (d, J = 8.5 Hz, 1 H, H8), 7.53 (dd, J = 7.0, 8.5 Hz, 1 H,
H7), 7.87 (d, J = 7.5 Hz, 1 H, H5).
Synthesis 2009, No. 15, 2579–2583 © Thieme Stuttgart · New York