Preparation of peri-annulated indoles from polynitro compounds

Article abstract of DOI:10.1016/j.tet.2009.06.074

A novel peri-annulated heterocyclic system of 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indole was prepared starting from TNT via 4,6-dinitro-1-tosylindoline as a key intermediate. Base-induced C{double bond, long}C bond shift in 1,2-dihydrobenz[6,7]oxepino[4,

Full text of DOI:10.1016/j.tet.2009.06.074

Tetrahedron 65 (2009) 6868–6872
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Preparation of peri-annulated indoles from polynitro compounds
1
*
Alexander V. Samet , Alexei N. Yamskov , Yuri A. Strelenko, Victor V. Semenov
N. D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Pr., 47, Moscow, 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2009
Received in revised form 2 June 2009
Accepted 19 June 2009
Available online 24 June 2009
A novel peri-annulated heterocyclic system of 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indole was prepared
starting from TNT via 4,6-dinitro-1-tosylindoline as a key intermediate. Base-induced C]C bond shift in
1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles affords isomeric 2,11-dihydrobenz[6,7]oxepino[4,3,2-
cd]indoles.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
nucleophilic displacement, and acidic benzylic CH-protons, appar-
ently making it a promising intermediate in a synthesis of peri-
Some natural biologically active compounds feature peri-annu-
lated indole core.1 Thus, well-known lysergic acid derivatives A1b
contain an indole moiety fused with cyclohexane ring, while in the
molecules of welwitindolinones B,2 aurantioclavine,3 clavicipitic
acid4 the indole fragment is peri-annulated with seven-membered
carbo- and heterocycles (Fig. 1).
annulated systems with indole fragment C under the action of
reagents which molecules possess both nucleophilic and electro-
philic centers (Scheme 1).12
Nu
NO2
E
Nu
E
3 steps
ref. 10
-
TNT
-
NO2
O
Cl
N
Ts
N
O2N
O2N
Ts
X
1
C
N
Scheme 1.
R1
O
O
Reaction of 1 with benzaldehyde in the presence of a base (pi-
peridine) was previously shown to yield a product of Knoevenagel
condensationd3-benzylidene-4,6-dinitro-1-tosylindoline.13
N
R
N
H
B
A
2. Results and discussion
COOH
H
N
H
N
Meanwhile, the reaction with ortho-hydroxy benzaldehydes
(where the OH-group is a nucleophilic center and the CHO-group is
an electrophilic one) normally does not stop at condensation
products D and is accompanied by intramolecular nucleophilic
displacement of the nitro group with the phenolate-anion, result-
ing in oxepine ring closure (Scheme 2).14
The resulting red or orange 1,2-dihydrobenz[6,7]oxepino[4,3,2-
cd]indoles 2 under the action of a stronger base (DBU) rearrange
into colourless 2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles 3
with a shift of the C]C bond from the oxepine ring into the pyrrole
(see Scheme 3 and Table 1). Energetic gain due to formation of the
aromatic indole system is the driving force of the rearrangement.
This approach to indole synthesis, featuring an endocyclic C-C
double bond shift in 3-(alkylidene)indolines, is not very common,
though such shifts induced by acids15 or bases16 are known.
N
H
N
H
aurantioclavine
clavicipitic acid
Figure 1. Some natural biologically active compounds with peri-annulated indole core.
In the course of investigations aimed at utilization of 2,4,6-tri-
nitrotoluene (TNT)5–9 earlier we synthesized 4,6-dinitro-1-tosy-
lindoline 1.10,11 Its structure includes nitro groups, susceptible to
* Corresponding author. Fax: þ7 495 1355328.
E-mail address: sametav@server.ioc.ac.ru (A.V. Samet).
1
Deceased.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.074

A.V. Samet et al. / Tetrahedron 65 (2009) 6868–6872
6869
O-
X
HO
R
Y
CHO
OH,
CHO
NO2
NO2
,
NH
OH
Y
NH
X
R
1
1
C6H6, reflux
C6H6, reflux
N
N
Ts
O2N
O2N
Ts
Y
CHO
D
5a (59%) X=Y=Cl
,
OH
5b (61%) X=H, Y=NO2
NH
-
X
-
NO2
C6H5Cl, reflux
Y
R
X
O
C6H5Cl, reflux
O
(71%)
5a
3e
N
Ts
O2N
NH
N
Ts
O2N
2
3e (68%) X=Y=Cl
Scheme 2.
3f (66%) X=H, Y=NO2
Scheme 4.
R
R
HO
2
2'
6'
O
O
DBU
C6H6, reflux
KOH
MeOH
H
2
11H
O
NO2
NO2
N
Ts
N
H
O2N
O2N
1
N
O2N
N
O2N
3
4
Ts
Ts
Scheme 3.
5b
2a
Figure 2. Key cross peaks in 2D 1H NOESY spectra of 5b and 2a.
Table 1
Preparation of the compounds 2–4
Thus, a base-induced (Z)-(E)-isomerization should apparently
precede the cyclization of 5a,b to 3e,f (such isomerization seems
quite plausible in the phenolates like D, see Scheme 2).
An interesting transformation of the oxepinoindoles 2 consists
of their bromination and subsequent nucleophilic substitution.
Bromination17 of 2a affords 11-bromo derivative 6, which could be
converted to ethers 7a,b simply by refluxing it in the corresponding
alcohols (MeOH, EtOH) (Scheme 5):
R
Yield of 2 (%)
Yield of 3 (%)
Yield of 4 (%)
H (a)
75
81
68
76
82
91
92
87
68a
80
96
90
86
96
9-Br (b)
7-MeO (c)
7-allyl (d)
7,9-Cl2 (e)
a
Prepared directly from 1 in refluxing C6H5Cl, see Scheme 4.
N-Tosylindoles 3 undergo smooth detosylation by KOH in MeOH
furnishing NH-indoles 4.
O
Br
O
OR
Br2
CHCl3
ROH
2a
Under the same conditions, a reaction of the indoline 1 with 5-
nitrosalicylic and 3,5-dichlorosalycilic aldehydes affords 3-(2-
hydroxybenzylidene)indolines 5 instead of cyclization products
(Scheme 4)dobviously, because of the lower nucleophilicity of the
corresponding phenolate anions due to the electron-withdrawing
substituents in the ring. However, the cyclization does take place at
higher temperature (when refluxing chlorobenzene is used instead
of benzene as a solvent). Under these conditions, the concomitant
shift of the C]C bond occurs as well, and 2,11-dihydro-
benz[6,7]oxepino[4,3,2-cd]indoles 3e,f are formed directly (1,2-
dihydro derivatives 2 were not isolated).
N
Ts
N
Ts
O2N
O2N
6
7a (83%) R = Me
7b (81%) R = Et
Scheme 5.
Probably, such a smooth alcoholysis is due to a SN1 reaction
mechanism and the high stability of the corresponding carbocation
in the 11 position.18
2D 1H NOESY spectrum of the compound 5b provides evidence
for (Z)-configuration of 3-(2-hydroxybenzylidene)indolines
(Fig. 2). A cross-peak between the signals of H-2 (
5.11) and H-60
8.14) is observed in the spectrum, while a cross-peak between
the signals of H-2 and ]CH (
7.12) is absent (for comparison, 2D 1H
NOESY spectrum of oxepinoindole 2a features a strong cross-peak
between the corresponding signals H-1 ( 4.75) and H-11 ( 6.49).
5
d
3. Conclusion
(d
d
Reaction of 4,6-dinitro-1-tosylindoline, prepared in 3 steps from
TNT, with o-hydroxybenzaldehydes proceeds via intermediate
(Z)-3-(o-hydroxybenzylidene)indolines (which were isolated in
d
d

6870
A.V. Samet et al. / Tetrahedron 65 (2009) 6868–6872
some cases) and affords 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]in-
doles. Base-induced C]C bond shift in the latter results in isomeric
2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles, while bromination
of 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles and subsequent
nucleophilic displacement yields 11-substituted derivatives. Thus,
TNT could be used for a synthesis of a novel class of peri-annulated
indoles.
4.2.1.3. 7-Methoxy-4-nitro-2-(p-toluenesulphonyl)-1,2-dihydrobenz-
[6,7]oxepino[4,3,2-cd]indole 2c. Yield 68%. Red crystals, mp 246–
248 ꢀC (DMF). 1H NMR (DMSO-d6,
d): 2.42 (s, 3H, Ts), 3.85 (s, 3H,
OMe), 4.70 (s, 2H, H-1), 6.42 (br s, 1H, H-11), 6.61 (d, J¼8.0 Hz, 1H,
H-8), 6.95–7.00 (m, 2H), 7.38 (d, J¼8.2 Hz, 2H, Ts), 7.41 (s, 1H, H-5),
7.76 (d, J¼8.2 Hz, 2H, Ts), 7.98 (s, 1H, H-3). EIMS (70 eV) (m/z, I, %):
450 [Mþ, 56], 295 [60], 249 [100], 91 [82]. Anal. Calcd for
C23H18N2O6S: C, 61.32; H, 4.03; N, 6.22; S, 7.12. Found: C, 61.11; H,
3.90; N, 6.54; S, 7.00. IR (nmax, KBr): 1525, 1370, 1335, 1160, 1125,
1103, 665.
4. Experimental
4.1. General
4.2.1.4. 7-Allyl-4-nitro-2-(p-toluenesulphonyl)-1,2-dihydrobenz[6,7]-
1H NMR spectra were recorded on a Bruker AM-300 and Bruker
DRX500 spectrometers (300.13 and 500.13 MHz, respectively); 13C
NMR spectra were recorded on a Bruker DRX500 spectrometer
(125.75 MHz). Mass-spectra were measured on a Kratos MS-30
instrument (EI, 70 eV). IR spectra were obtained on a ‘Specord
M80–2’ spectrometer.
oxepino[4,3,2-cd]indole 2d. Yield 76%. Orange crystals, mp 240–
242 ꢀC (DMF). 1H NMR (DMSO-d6,
d): 2.41 (s, 3H, Ts), 3.48 (d,
J¼7.4 Hz, 2H), 4.69 (s, 2H, H-1), 5.03–5.08 (m, 2H), 5.94–5.97 (m,
1H), 6.42 (br s, 1H, H-11), 6.92 (d, J¼8.1 Hz, 1H, H-10), 6.98 (t,
J¼8.0 Hz, 1H, H-9), 7.12 (d, J¼8.0 Hz, 1H, H-8), 7.40 (m, 3H), 7.76 (d,
J¼8.3 Hz, 2H, Ts), 7.97 (s, 1H, H-3). 13C NMR (DMSO-d6,
d): 21.1, 55.3,
105.0, 110.9, 116.0, 125.7, 125.8, 127.2 (2CH), 128.2, 128.4, 129.8,
130.4 (2CH), 131.2, 132.5, 132.7, 136.8, 144.0, 145.4, 150.5, 152.0.
EIMS (70 eV) (m/z, I, %): 460 [Mþ, 50], 305 [54], 259 [81], 91 [100].
Anal. Calcd for C25H20N2O5S: C, 65.20; H, 4.38; N, 6.08; S, 6.96.
Found: C, 64.85; H, 4.56; N, 6.32; S, 7.19. IR (nmax, KBr): 1528, 1368,
1340, 1164, 1120, 664.
4.2. Synthetic procedures
Caution. Both we and other researchers encountered no diffi-
culties in working with multi-gram quantities of TNT19 (the same is
true for the compound 1 as well). Nevertheless, polynitroaromatic
compounds are potential explosives, so proper protective measures
(shields, glasses) should be used during experiments with these
materials. Scale-up of the reported reactions requires appropriate
chemical hazards testing.
4.2.1.5. 3-(2-Hydroxy-3,5-dichlorobenzylidene)-4,6-dinitro-1-(p-tol-
uenesulphonyl)-2,3-dihydroindole 5a. Yield 59%. Orange powder,
mp 216–217 ꢀC (MeCN). 1H NMR (DMSO-d6,
d): 2.43 (s, 3H, Ts), 4.95
(br s, 2H, H-2), 7.17–7.23 (m, 2H), 7.36 (s, 1H), 7.40 (d, J¼8.3 Hz, 2H),
4.2.1. Preparation of N-tosyl-1,2-dihydrobenz[6,7]oxepino[4,3,2-
cd]indoles 2a–d and 3-(2-hydroxybenzylidene)indolines 5a,b
(general procedure)
7.86 (d, J¼8.3 Hz, 2H), 8.28 (s, 1H), 8.43 (s, 1H), 9.90 (br s, 1H, OH).
13C NMR (DMSO-d6,
d): 21.1, 54.9, 111.0, 115.0, 122.4, 123.5, 123.7,
125.9, 127.0, 127.2, 127.5 (2CH), 128.3, 129.8, 130.5 (2CH), 132.6,
144.2, 145.3, 145.8, 147.9, 150.1. Anal. Calcd for C22H15Cl2N3O7S: C,
49.27; H, 2.82; N, 7.83; S, 5.98. Found: C, 49.25; H, 2.95; N, 8.14; S,
5.71. IR (nmax, KBr): 3504, 1536, 1372, 1344, 1172, 664.
To a suspension of indoline 1 (1.82 g, 5 mmol) and the corre-
sponding ortho-hydroxy benzaldehyde (5 mmol) in benzene
(5 mL), piperidine (0.45 g, 5.3 mmol) was added, and the mixture
was stirred at reflux for 30 min. The resulting thick suspension was
cooled to rt, diluted with MeOH, and filtered. The precipitate was
washed with MeOH (5 mL) and dried. For isolation of 3-(2-
hydroxybenzylidene)indolines, the mixture was acidified with
AcOH (1 mL) before filtration.
4.2.1.6. 3-(2-Hydroxy-5-nitrobenzylidene)-4,6-dinitro-1-(p-toluene-
sulphonyl)-2,3-dihydroindole 5b. Yield 61%. Orange powder, mp
227–230 ꢀC (MeCN). 1H NMR (DMSO-d6,
d): 2.37 (s, 3H, Ts), 5.11 (d,
J¼3.1 Hz, 2H, H-2), 7.09 (d, J¼8.9 Hz, 1H, H-30), 7.12 (t, J¼3.1 Hz, 1H,
]CH), 7.42 (d, J¼8.3 Hz, 2H, Ts), 7.83 (d, J¼8.3 Hz, 2H, Ts), 8.14 (d,
J¼2.7 Hz, 1H, H-60), 8.17 (dd, J¼8.9, 2.7 Hz,1H, H-40), 8.39 (d, J¼2.0 Hz,
1H, H-7), 8.45 (d, J¼2.0 Hz, 1H, H-5), 11.72 (br s, 1H, OH). 13C NMR
4.2.1.1. 4-Nitro-2-(p-toluenesulphonyl)-1,2-dihydrobenz[6,7]oxepino-
[4,3,2-cd]indole 2a. Yield 75%. Orange-red crystals, mp 236–238 ꢀC
(DMF).13 1H NMR (DMSO-d6,
d): 2.35 (s, 3H, Ts), 4.75 (s, 2H, H-1),
(DMSO-d6, d): 21.0, 54.9, 110.9, 114.8, 115.9, 122.2, 122.6, 124.7, 126.4,
6.49 (br s, 1H, H-11), 7.06 (d, J¼8.0 Hz, 1H, H-7), 7.09–7.14 (m, 2H),
127.1, 127.2 (2CH), 128.0, 130.4 (2CH), 132.5, 139.6, 144.1, 145.3, 145.6,
147.7, 161.5. Anal. Calcd for C22H16N4O9S: C, 51.56; H, 3.15; N, 10.93; S,
6.26. Found: C, 51.35; H, 2.97; N, 11.10; S, 6.49. IR (nmax, KBr): 3497,
1534, 1515, 1370, 1338, 1168, 665.
7.30–7.33 (m, 1H), 7.43 (d, J¼8.3 Hz, 2H, Ts), 7.50 (s,1H, H-5), 7.78 (d,
J¼8.3 Hz, 2H, Ts), 7.92 (s, 1H, H-3). 13C NMR (DMSO-d6,
d): 21.1, 55.3,
105.0,110.7, 122.2,125.3, 126.1, 127.3 (2CH), 127.8, 128.1, 130.5 (2CH),
131.5, 131.6 (2CH), 132.5, 144.1, 145.4, 150.7, 152.3, 152.9. EIMS
(70 eV) (m/z, I, %): 420 [Mþ, 42], 265 [29], 219 [100], 91 [40]. Anal.
Calcd for C22H16N2O5S: C, 62.85; H, 3.84; N, 6.66; S, 7.63. Found, %: C,
63.13; H, 3.66; N, 6.68; S, 7.78. IR (nmax, KBr): 1524, 1368, 1336, 1160,
1124, 1100, 672.
4.2.2. Preparation of N-tosyl-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]-
indoles 3a–d (general procedure)
To a suspension of 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indole
2a–d (4 mmol) in benzene (10 mL), DBU (0.10 g, 0.65 mmol) was
added and the mixture was refluxed for 1 h. The resulting homo-
geneous solution was evaporated to dryness, to the residue MeOH
(5 mL) was added, the precipitate filtered off, washed with MeOH
(5 mL), and dried.
4.2.1.2. 9-Bromo-4-nitro-2-(p-toluenesulphonyl)-1,2-dihydrobenz[6,7]-
oxepino[4,3,2-cd]indole 2b. Yield 81%. Bright-yellow needles, mp
268–270 ꢀC (DMF). 1H NMR (DMSO-d6,
d): 2.43 (s, 3H, Ts), 4.68 (s, 2H,
H-1), 6.34 (br s, 1H, H-11), 6.87 (d, J¼8.0 Hz, 1H, H-7), 7.20 (s, 1H, H-
10), 7.32 (d, J¼8.0 Hz, 1H, H-8), 7.35–7.42 (m, 3H), 7.75 (d, J¼8.3 Hz,
4.2.2.1. 4-Nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz[6,7]oxepino-
2H, Ts), 7.97 (s,1H, H-3). 13C NMR (DMSO-d6,
d): 21.0, 55.3,105.1,110.5,
[4,3,2-cd]indole 3a. Yield 82%. Mp 196–198 ꢀC (benzene).13 1H NMR
117.8, 123.6, 124.1, 127.2 (2CH), 130.2, 130.4 (2CH), 132.5, 133.0, 133.2,
133.5, 144.3, 145.4, 150.9, 152.0. EIMS (70 eV) (m/z, I, %): 500 [Mþ, 24],
498 [Mþ, 26], 345 [58], 343 [58], 299 [78], 297 [100], 91 [77]. Anal.
Calcd for C22H15BrN2O5S: C, 52.92; H, 3.03; N, 5.61; S, 6.42. Found: C,
53.25; H, 2.88; N, 5.60; S, 6.20. IR (nmax, KBr): 1536, 1368, 1340, 1168,
1104, 664, 580.
(DMSO-d6,
d
): 2.36 (s, 3H, Ts), 4.16 (s, 2H, H-11), 7.11 (t, J¼8.1 Hz, 1H),
7.20–7.30 (m, 2H), 7.33 (d, J¼8.0 Hz, 1H), 7.37 (d, J¼8.2 Hz, 2H, Ts),
7.80 (s,1H), 7.84 (s,1H), 7.88 (d, J¼8.2 Hz, 2H, Ts), 8.45 (s,1H, H-3). 13C
NMR (DMSO-d6, d): 21.1, 28.8, 105.2, 107.7, 118.7, 122.2, 125.6, 125.9,
126.9 (2CH), 127.3, 128.3, 128.7, 130.7 (2CH), 131.8, 133.8, 134.1, 145.5,
146.3, 150.4, 156.9. Anal. Calcd for C22H16N2O5S: C, 62.85; H, 3.84; N,

A.V. Samet et al. / Tetrahedron 65 (2009) 6868–6872
6871
6.66; S, 7.63. Found: C, 62.98; H, 4.13; N, 6.39; S, 7.51. IR (nmax, KBr):
1525, 1338, 1245, 1181, 1082, 675.
56.77; H, 3.25; N, 9.03; S, 6.89. Found: C, 56.62; H, 3.40; N, 8.82; S,
7.15. IR (nmax, KBr): 1532, 1512, 1344, 1296, 1236, 1180, 1084, 672.
Using the same procedure, the compound 3e could be prepared
from 5a in 71% yield.
4.2.2.2. 9-Bromo-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
[6,7]oxepino[4,3,2-cd]indole 3b. Yield 91%. Mp 192–195 ꢀC (ben-
zene). 1H NMR (DMSO-d6,
d
): 2.38 (s, 3H, Ts), 4.17 (s, 2H, H-11), 7.21
4.2.4. Preparation of NH-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]-
indoles 4a–e (general procedure)
A suspension of N-tosyl-2,11-dihydrobenz[6,7]oxepino[4,3,2-
cd]indole 3a–e (4 mmol) and KOH (0.84 g, 15 mmol) in MeOH
(20 mL) was refluxed for 40 min and poured into 1 N HCl (50 mL).
The resulting precipitate was filtered off and dried.
(d, J¼8.2 Hz, 1H), 7.32–7.40 (m, 3H), 7.52 (s, 1H, H-10), 7.82 (s, 2H,
H-1 and H-5), 7.88 (d, J¼8.3 Hz, 2H, Ts), 8.48 (s, 1H, H-3). 13C NMR
(DMSO-d6, d): 21.0, 28.3, 105.4, 107.7, 117.6, 117.8, 124.5, 125.9, 126.8
(2CH), 130.6 (2CH), 131.3, 133.0, 133.7, 134.0, 134.3, 145.4, 146.3,
149.8, 156.1. EIMS (70 eV) (m/z, I, %): 500 [Mþ, 95], 498 [Mþ, 100],
299 [43], 297 [36], 155 [48], 91 [74]. Anal. Calcd for C22H15BrN2O5S:
C, 52.92; H, 3.03; N, 5.61; S, 6.42. Found: C, 53.15; H, 2.91; N, 5.77;
S, 6.26. IR (nmax, KBr): 1524, 1336, 1240, 1176, 1124, 1088, 672, 580.
4.2.4.1. 4-Nitro-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indole 4a. Yield
80%. Mp 242–243 ꢀC (MeCN). 1H NMR (DMSO-d6,
d): 4.21 (s, 2H, H-
11), 7.14 (t, J¼8.2 Hz, 1H), 7.28 (t, J¼8.1 Hz, 1H), 7.35–7.39 (m, 2H), 7.55
4.2.2.3. 7-Methoxy-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
(s, 1H), 7.58 (s, 1H), 8.08 (s, 1H), 11.59 (s, 1H, NH). 13C NMR (DMSO-d6,
[6,7]oxepino[4,3,2-cd]indole 3c. Yield 92%. Mp 229–231 ꢀC (ben-
d): 29.5, 101.8, 104.9, 112.2, 122.3, 124.6, 125.2, 126.3, 128.2, 130.5,
zene). 1H NMR (DMSO-d6,
d): 2.37 (s, 3H, Ts), 3.86 (s, 3H, OMe), 4.14
133.8, 135.4, 142.7, 149.9,157.2. Anal. Calcd for C15H10N2O3: C, 67.67; H,
3.79; N, 10.52. Found: C, 67.59; H, 3.93; N, 10.80. IR (nmax, KBr): 3342,
1515, 1470, 1356, 1335.
(s, 2H, H-1), 6.86 (d, J¼8.0 Hz, 1H, H-10), 6.91 (d, J¼8.1 Hz, 1H, H-8),
7.03 (t, J¼8.0 Hz, 1H, H-9), 7.37 (d, J¼8.3 Hz, 2H, Ts), 7.80 (s, 2H, H-1
and H-5), 7.86 (d, J¼8.3 Hz, 2H, Ts), 8.44 (s, 1H, H-3). 13C NMR
(DMSO-d6,
d): 21.1, 28.7, 56.1, 105.5, 107.8, 112.0, 118.7, 121.6, 125.7,
4.2.4.2. 9-Bromo-4-nitro-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indole
126.0,126.8 (2CH),128.0,130.7 (2CH),133.3,133.8,134.1,145.4,145.7,
146.3, 150.3, 152.2. Anal. Calcd for C23H18N2O6S: C, 61.32; H, 4.03; N,
6.22; S, 7.12. Found, %: C, 61.08; H, 3.95; N, 6.37; S, 6.90. IR (nmax, KBr):
1522, 1335, 1240, 1185, 1085, 671.
4b. Yield 96%. Mp 235–237 ꢀC (MeCN). 1H NMR (DMSO-d6,
d): 4.21 (s,
2H, H-11), 7.33 (d, J¼8.2 Hz, 1H, H-7), 7.45 (d, J¼8.2 Hz, 1H, H-8), 7.55
(s, 1H), 7.59 (s, 1H), 7.63 (s, 1H, H-10), 8.09 (s, 1H), 11.62 (s,1H, NH). 13C
NMR (DMSO-d6, d): 28.9, 101.9, 105.1, 111.3, 116.9, 124.2, 124.6, 126.6,
130.8, 132.8, 135.4, 136.4, 142.6, 149.3, 156.5. Anal. Calcd for
C15H9BrN2O3: C, 52.20; H, 2.63; N, 8.12. Found: C, 52.31; H, 2.64; N,
7.89. IR (nmax, KBr): 3368, 1516, 1472, 1348, 1332.
4.2.2.4. 7-Allyl-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz[6,7]-
oxepino[4,3,2-cd]indole 3d. Yield 87%. Mp 163–164 ꢀC (benzene). 1H
NMR (DMSO-d6,
d
): 2.37 (s, 3H, Ts), 3.60 (d, J¼7.4 Hz, 2H), 4.15 (s, 2H,
H-11), 5.02–5.08 (m, 2H), 5.95–5.98 (m, 1H), 7.03 (t, J¼8.0 Hz, 1H, H-
9), 7.09 (d, J¼8.1 Hz, 1H), 7.19 (d, J¼8.0 Hz, 1H, H-8), 7.38 (d, J¼8.3 Hz,
2H, Ts), 7.81 (s, 2H, H-1 and H-5), 7.88 (d, J¼8.3 Hz, 2H, Ts), 8.45 (s,
1H, H-3). Anal. Calcd for C25H20N2O5S: C, 65.20; H, 4.38; N, 6.08; S,
6.96. Found: C, 65.00; H, 4.49; N, 6.23; S, 7.25. IR (nmax, KBr): 1525,
1332, 1237, 1182, 1080, 672.
4.2.4.3. 7-Methoxy-4-nitro-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]in-
dole 4c. Yield 90%. Mp 234–238 ꢀC (MeCN) (decomp.). 1H NMR
(DMSO-d6,
1H), 7.00 (d, J¼8.0 Hz, 1H), 7.06 (t, J¼8.0 Hz, 1H), 7.51 (s, 1H), 7.53 (s,
1H), 8.07 (s, 1H), 11.53 (s, 1H, NH). 13C NMR (DMSO-d6,
): 29.3, 56.1,
d): 3.85 (s, 3H, OMe), 4.19 (s, 2H, H-11), 6.93 (d, J¼8.0 Hz,
d
102.1, 105.0, 111.6, 112.1, 121.6, 125.2, 125.3, 126.3, 135.3, 135.4, 142.5,
145.9, 149.7, 152.4. EIMS (70 eV) (m/z, I, %): 296 [Mþ, 100], 265 [59],
249 [55], 235 [31]. Anal. Calcd for C16H12N2O4: C, 64.86; H, 4.08; N,
9.46. Found: C, 65.01; H, 4.14; N, 9.20. IR (nmax, KBr): 3328, 1512,
1472, 1332, 1296, 1080, 760.
4.2.3. Preparation of N-tosyl-2,11-dihydrobenz[6,7]oxepino[4,3,2-
cd]indoles 3e,f from indoline 1
To a suspension of indoline 1 (1.82 g, 5 mmol) and the corre-
sponding ortho-hydroxy benzaldehyde (5 mmol) in chlorobenzene
(5 mL), piperidine (0.45 g, 5.3 mmol) was added, and the mixture
was stirred at reflux for 2 h. The resulting thick suspension was
cooled to rt, diluted with MeOH (5 mL), and filtered. The precipitate
was washed with MeOH (5 mL) and dried.
4.2.4.4. 7-Allyl-4-nitro-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indole
4d. Yield 86%. Mp 165–166 ꢀC (MeCN). 1H NMR (DMSO-d6,
d): 3.63
(d, J¼7.4 Hz, 2H), 4.19 (s, 2H, H-11), 5.05 (m, 2H), 6.01 (m, 1H), 7.06
(t, J¼8.0 Hz, 1H, H-9), 7.14 (d, J¼8.1 Hz, 1H), 7.24 (d, J¼8.0 Hz, 1H),
7.53 (s, 1H), 7.59 (s, 1H), 8.08 (s, 1H), 11.56 (s, 1H, NH). Anal. Calcd for
C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C, 70.30; H, 4.82; N,
8.88. IR (nmax, KBr): 3354, 1522, 1455, 1346, 1335, 1075.
4.2.3.1. 7,9-Dichloro-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
[6,7]oxepino[4,3,2-cd]indole 3e. Yield 68%. Mp 240–242 ꢀC (benzene).
1H NMR (DMSO-d6,
d
): 2.37 (s, 3H, Ts), 4.23 (s, 2H, H-11), 7.34–7.43 (m,
4H), 7.86–7.92 (m, 4H), 8.51 (s, 1H, H-3). 13C NMR (DMSO-d6,
d): 21.1,
4.2.4.5. 7,9-Dichloro-4-nitro-2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]in-
28.5, 106.1, 107.9, 117.0, 126.4, 126.9 (2CH), 127.1, 127.8, 128.4, 129.2,
129.8, 130.7 (2CH), 133.7, 134.0, 135.7, 145.4, 146.4, 148.7, 151.0. Anal.
Calcd for C22H14Cl2N2O5S: C, 54.00; H, 2.88; N, 5.72; S, 6.55. Found: C,
53.71; H, 2.84; N, 6.09; S, 6.72. IR (nmax, KBr): 1525, 1340, 1234, 1180,
1085, 670.
dole 4e. Yield 96%. Mp 295–298 ꢀC (MeCN). 1H NMR (DMSO-d6,
d
):
4.27 (s, 2H, H-11), 7.52 (d, J¼2.4 Hz, 1H), 7.57 (s, 1H), 7.59 (d, J¼2.4 Hz,
2H), 7.62 (s, 1H), 8.12 (s, 1H), 11.67 (s, 1H, NH). 13C NMR (DMSO-d6,
):
d
29.0, 102.3, 105.7, 110.4, 124.2, 126.9, 127.7, 128.9, 129.0, 135.3, 137.7,
142.5, 148.1, 151.2. Anal. Calcd for C15H8Cl2N2O3: C, 53.76; H, 2.41; N,
8.36. Found: C, 53.56; H, 2.49; N, 8.67. IR (nmax, KBr): 3424,1528,1448,
1352, 1336.
4.2.3.2. 4,9-Dinitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz[6,7]-
oxepino[4,3,2-cd]indole 3f. Yield 66%. Mp 270–275 ꢀC (DMF)
(decomp.). 1H NMR (DMSO-d6,
d
): 2.32 (s, 3H, Ts), 4.38 (s, 2H, H-
4.2.5. Preparation of N-tosyl-11-alkoxy-2,11-dihydrobenz[6,7]-
oxepino[4,3,2-cd]indoles 7 (general procedure)
11), 7.43 (d, J¼8.3 Hz, 2H, Ts), 7.66 (d, J¼8.8 Hz, 1H), 7.95 (d,
J¼8.3 Hz, 2H, Ts), 8.02 (d, J¼1.8 Hz, 1H, H-5), 8.04 (s, 1H, H-1), 8.19
(dd, J¼8.8, 2.8 Hz, 1H), 8.36 (d, J¼2.8 Hz, 1H), 8.50 (d, J¼1.8 Hz, 1H,
To a suspension of 2a (4 mmol) in CHCl3 (10 mL), Br2 (0.64 g,
4 mmol) was added dropwise for 15 min under stirring. The re-
action mixture was stirred for a further 10 min, then Et3N (0.40 g,
4 mmol) was added to the resulting solution, and stirring was
continued for 5 min. The reaction mixture was filtered, the filtrate
evaporated to dryness, and the residual oily bromide 6 was
H-3). 13C NMR (DMSO-d6,
d): 21.1, 28.5, 105.7, 108.0, 117.2, 123.9,
124.2, 126.1, 126.6, 126.9 (2CH), 130.7 (2CH), 133.4, 133.6, 134.0,
144.3, 145.5, 146.4, 149.0, 161.4. EIMS (70 eV) (m/z, I, %): 465 [Mþ,
49], 218 [30], 155 [77], 91 [100]. Anal. Calcd for C22H15N3O7S: C,

6872
A.V. Samet et al. / Tetrahedron 65 (2009) 6868–6872
2. Brown, L. E.; Konopelski, J. P. Org. Prep. Proced. Int. 2008, 40, 411.
3. (a) May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262; (b) Yamada, F.; Makita, Y.;
Suzuki, T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162; (c) Kozlovskii, A. G.;
Soloveva, T. F.; Sakharovskii, V. G.; Adanin, V. M. Dokl. Akad. Nauk SSSR 1981,
260, 230.
4. (a) Ku, J.; Jeong, B.; Jew, S.; Park, H. J. Org. Chem. 2007, 72, 8115; (b)
Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y.
Eur. J. Org. Chem. 2004, 6, 1244; (c) Kozikowski, A. P.; Greco, M. N. J. Org.
Chem. 1984, 49, 2310.
dissolved in MeOH or EtOH (10 mL), refluxed for 30 min, and the
solvent was evaporated. The residue was crystallized from MeCN.
4.2.5.1. 11-Bromo-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
[6,7]oxepino[4,3,2-cd]indole 6. Yield of the crude product 94%.
Brown oil. 1H NMR (CDCl3,
d): 2.38 (s, 3H), 6.19 (s, 1H), 7.16 (t,
J¼7.8 Hz, 1H), 7.30–7.40 (m, 5H), 7.80 (s, 1H), 7.84 (d, J¼8.3 Hz, 2H),
5. Yamskov, A. N.; Samet, A. V.; Semenov, V. V. Mendeleev Commun. 2008, 18, 320.
6. Samet, A. V.; Kislyi, K. A.; Marshalkin, V. N.; Strelenko, Y. A.; Raihstat, M. M.;
Nelyubina, Y. V.; Semenov, V. V. Tetrahedron 2008, 64, 11763.
7.98 (s, 1H), 8.57 (s, 1H).
4.2.5.2. 11-Methoxy-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
7. Kislyi, K. A.; Samet, A. V.; Strelenko, Y. A.; Semenov, V. V. J. Org. Chem. 2008,
73, 2285.
8. (a) Samet, A. V.; Marshalkin, V. N.; Kislyi, K. A.; Chernysheva, N. B.; Strelenko, Y.
A.; Semenov, V. V. J. Org. Chem. 2005, 70, 9371; (b) Samet, A. V.; Lislyi, K. A.;
Marshalkin, V. N.; Strelenko, Y. A.; Nelyubina, Yu. V.; Lyssenko, K. A.; Semenov,
V. V. Russ. Chem. Bull. 2007, 56, 2089.
9. Zlotin, S. G.; Kislitsin, P. G.; Samet, A. V.; Serebryakov, E. A.; Konyushkin, L. D.;
Semenov, V. V.; Buchanan, A. C., III; Gakh, A. A. J. Org. Chem. 2000, 65, 8430.
10. Samet, A. V.; Zakharov, E. P.; Semenov, V. V.; Gakh, A. A.; Buchanan, A. C., III.
Synth. Commun. 2001, 31, 1441.
11. Compound 1 has already been used for the preparation of biologically active
indoles: Pullagurla, M.; Siripurapu, U.; Kolanos, R.; Bondarev, M. L.; Dukat, M.;
Setola, V.; Roth, B. L.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2005, 15, 5298.
12. Some alternative approaches to peri-annulated heterocyclic systems starting
from polynitroaromatic compounds are described in: (a) Bastrakov, M. A.;
Starosotnikov, A. M.; Kachala, V. V.; Nesterova, E. N.; Shevelev, S. A. Russ.
Chem. Bull. 2007, 56, 1603; (b) Zlotin, S. G.; Kislitsin, P. G.; Kucherov, F. A.;
Gakh, A. A. Heterocycles 2006, 68, 1109; (c) Kozikowski, A. P.; Greco, M. N.;
Springer, J. P. J. Am. Chem. Soc. 1982, 104, 7622.
13. Yamskov, A. N.; Samet, A. V.; Semenov, V. V. Russ. Chem. Bull. 2003, 52, 759.
14. For a similar reaction of 2,3-dihydro-2-methyl-4,6-dinitrobenzo[b]furan, see: TNT
itself reacts with 2-hydroxybenzaldehydes in a similar way to afford 1,3-dini-
trodibenz[b,f]oxepines: Hoyer, H.; Vogel, M. Monatsh. Chem. 1962, 93, 766; Yam-
skov, A. N.; Samet, A. V.; Semenov, V. V. Chem. Heterocycl. Compd. 2005, 41, 796.
15. (a) Murphy, J. A.; Khan, T. A.; Zhou, S.-Z.; Thomson, D. W.; Mahesh, M. Angew.
Chem., Int. Ed. 2005, 44, 1356; (b) Bergman, J.; Janosik, T.; Koch, E.; Pelcman, B.
J. Chem. Soc., Perkin Trans. 1 2000, 2615; (c) Tietze, L. F.; Grote, T. J. Org. Chem.
1994, 59, 192.
16. (a) Suarez-Castillo, O. R.; Contreras-Martinez, Y. M. A.; Beiza-Granados, L.;
Melendez-Rodriguez, M.; Villagomez-Ibarra, J. R.; Torres-Valencia, J. M.;
Morales-Rios, M. S.; Joseph-Nathan, P. Tetrahedron 2005, 61, 8809; (b) Kawasaki,
T.; Nonaka, Y.; Watanabe, K.; Ogawa, A.; Higuchi, K.; Terashima, R.; Masuda, K.;
Sakamoto, M. J. Org. Chem. 2001, 66, 1200; (c) Morales-Rios, M. S.; Bucio, M. A.;
Joseph-Nathan, P. Tetrahedron 1996, 52, 5339.
[6,7]oxepino[4,3,2-cd]indole 7a. Yield 83%. Mp 115–120 ꢀC (benzene).
1H NMR (DMSO-d6,
d): 2.32 (s, 3H, Ts), 3.22 (s, 3H), 5.40 (s, 1H, H-11),
7.23 (t, J¼7.9 Hz, 1H), 7.36–7.40 (m, 2H), 7.43 (d, J¼8.3 Hz, 2H, Ts), 7.48
(d, J¼8.1 Hz, 1H), 7.89 (s, 1H), 7.94 (d, J¼8.3 Hz, 2H, Ts), 8.24 (s, 1H),
8.45 (s, 1H, H-3). 13C NMR (DMSO-d6,
d): 21.1, 55.8, 75.8, 104.9, 107.7,
119.3, 122.9, 125.4, 125.8, 126.9 (2CH), 128.3, 130.5, 130.6, 130.7 (2CH),
132.0, 133.5, 134.3, 145.8, 146.5, 150.0, 155.5. EIMS (70 eV) (m/z, I, %):
450 [Mþ, 25], 419 [48], 155 [58], 91 [100]. Anal. Calcd for
C23H18N2O6S: C, 61.32; H, 4.03; N, 6.22; S, 7.12. Found: C, 61.05; H,
3.84; N, 5.90; S, 7.17. IR (nmax, KBr): 1528, 1340, 1192, 1180, 1088, 672.
4.2.5.3. 11-Ethoxy-4-nitro-2-(p-toluenesulphonyl)-2,11-dihydrobenz-
[6,7]oxepino[4,3,2-cd]indole 7b. Yield 81%. Mp 185–186 ꢀC (ben-
zene). 1H NMR (DMSO-d6,
d
): 1.07 (t, J¼7.3 Hz, 3H), 2.32 (s, 3H, Ts),
3.44 (q, J¼7.3 Hz, 2H), 5.56 (s,1H, H-11), 7.22–7.25 (m,1H), 7.34–7.39
(m, 2H), 7.43 (d, J¼8.3 Hz, 2H, Ts), 7.47 (d, J¼8.2 Hz, 1H), 7.89 (s, 1H),
7.93 (d, J¼8.3 Hz, 2H, Ts), 8.17 (s,1H), 8.45 (s,1H, H-3). Anal. Calcd for
C24H20N2O6S: C, 62.06; H, 4.34; N, 6.03; S, 6.90. Found: C, 61.92; H,
4.45; N, 5.70; S, 7.12. IR (nmax, KBr): 1528,1380,1340,1180,1100, 672.
Acknowledgements
We are grateful to Chemical Block Ltd. Company (www.chem-
block.com) for financial support of this research.
17. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164.
18. Jones, R. A. Pyrroles and their Benzo Derivatives: (ii) Reactivity. In Compre-
hensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 4, p 201.
19. For a large-scale synthesis with TNT, see: Organic Syntheses; Wiley & Sons: New
York, NY, 1941; Collect. Vol. I, p. 543 (no special safety precautions were rec-
ommended by the submitters or checkers of this procedure). Moreover, TNT
was successfully used for industrial production of phloroglucinol: Castens, M.
L.; Kaplan, J. F. Ind. Eng. Chem. 1950, 42, 402.
References and notes
1. (a) Gribble, G. W. Pyrroles and their Benzo Derivatives: Applications. In Com-
prehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.,
Eds.; Pergamon: New York, NY, 1996; Vol. 2, p 207; (b) Sundberg, R. J. Pyrroles
and their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 4, p 313.