Synthesis of benz[5,6]azepino[4,3-b]indoles by 1,7-electrocyclisation of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2004.11.127

A new, general route to the benz[5,6]azepino[4,3-b]indole ring system has been developed via the 1,7-dipolar electrocyclisation reactions of azomethine ylides. A new, general route to the benz[5,6]azepino[4,3-b]indole ring system has been developed via the 1,7-dipolar electrocyclisation reactions of azomethine ylides derived from easily available 3-formyl indole derivatives. The intermediacy of azomethine ylides was shown by the trapping of the proposed α,β:γ,δ-conjugated dipole with N-phenylmaleimide.

Full text of DOI:10.1016/j.tetlet.2004.11.127

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 377–380
Synthesis of benz[5,6]azepino[4,3-b]indoles by
1,7-electrocyclisation of azomethine ylides
a,
Miklos Nyerges, Aron Pinter, Andrea Viranyi, Istvan Bitter and Laszlo Toke
a
b
b
a
´
*
}
´
´
´
´
´
´
aResearch Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology,
Technical University of Budapest, H-1521 Budapest, PO Box 91, Hungary
bDepartment of Organic Chemical Technology, Technical University of Budapest, H-1521 Budapest, PO Box 91, Hungary
Received 13 October 2004; revised 15 November 2004; accepted 25 November 2004
Abstract—A new, general route to the benz[5,6]azepino[4,3-b]indole ring system has been developed via the 1,7-dipolar electrocy-
clisation reactions of azomethine ylides derived from easily available 3-formyl indole derivatives. The intermediacy of azomethine
ylides was shown by the trapping of the proposed a,b:c,d-conjugated dipole with N-phenylmaleimide.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The 1,3-dipolar cycloaddition of dipoles to an olefin or
an acetylene derivative is one of the most useful
approaches for the construction of five-membered het-
erocyclic rings.1 There are, however, many other
synthetically useful reactions of these dipoles, including
the 1,5- and 1,7-electrocyclic2,3 ring closure of appropri-
ately substituted unsaturated dipolar systems. Recently,
we4 and others5 published the first examples of the 1,7-
electrocyclisation of nonstabilised azomethine ylides
with a,b:c,d-unsaturation, followed by some examples
of 1,7-electrocyclisation of electron-withdrawing group
stabilised azomethine ylides.6
quinolines 1 resulted in the formation 1H-pyrrolo-
[3,4-c]quinolines 3 as products via a 1,5-electrocyclisa-
tions (Scheme 1).7
In this letter we describe the reactions of the analogous
azomethine ylides formed from 2-aryl-indol-3-carbalde-
hydes 7a–h and 8a,b. In these conjugated dipoles the 1,5-
electrocyclisation pathway is not accessible.
The starting materials were prepared via the appropriate
2-arylindoles 6a–h by the treatment with small excess of
Vilsmeier reagent.8 In the case of 2-phenylindole-3-carb-
aldehyde (7a) the protection of the indole nitrogen was
achieved (Scheme 2).
As a continuation of these studies our aim was to show
the generality of this method as a tool for the annelation
of a benzazepine ring to different heterocycles in one
step. Our previous experiments with 2-phenyl-3-formyl-
The nonstabilised azomethine ylides 9 R = H, CH3,
Bn, R1 = CH3, Bn, E = H (Table 1, entries 1–6) were
CH3
N
CH3
R2
R2
CHO
R2
N
i.
i.
N
N
Ph
N
Ph
R1
R1
R1
2
3
1
Scheme 1. Reagents and conditions: (i) sarcosine, xylene, reflux.
Keywords: Azomethine ylide; Cycloaddition; Electrocyclisation; Indole.
*
Corresponding author. Tel.: +361 463 2213; fax: +361 463 3648; e-mail: mnyerges@mail.bme.hu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.127

378
M. Nyerges et al. / Tetrahedron Letters 46 (2005) 377–380
O
R2
NH2
R3
Br
R1
i
+
N
R2
R1
H
R3
6
5
4
CHO
CHO
R2
iii
R1
ii
N
7a
=
N
1
2
3
=
R H
=
R
R
R
R3
H
8a R = CH3 (84 %)
8b R = Bn (88 %)
7
Scheme 2. Reagents and conditions: (i) N,N-dimethylaniline, 170 ꢁC (45–62%); (ii) POCl3, DMF, 80 ꢁC (73–91%); (ii) KOBut, MeI, tBuOH; or BnBr,
NaH, DMF.
Table 1. Benz[5,6]azepino[4,3-b]indoles produced via Scheme 3
Entry
Starting aldehyde
R
R1
R2
R3
R4
E
Reaction time (h)
Product
Yield %
1
7a
7a
8a
8a
8b
8b
7a
8a
8b
7b
7c
7d
7e
7f
H
H
H
H
CH3
Bn
H
6
10
18
16
18
96
15
20
60
6
11a
11b
11c
11d
11e
11f
11g
11h
11i
54
46
46
38
40
41a
15
18
—
52
58
55
59
55
54
61
2
H
H
H
H
H
3
CH3
CH3
Bn
Bn
H
H
H
H
CH3
Bn
H
4
H
H
H
H
5
H
H
H
CH3
Bn
H
6
H
H
H
H
CO2CH3
7
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
8
CH3
Bn
H
H
H
H
CO2CH3
CO2CH3
9
H
H
H
10
11
12
13
14
15
16
CH3
Cl
CH3O
H
H
H
H
H
H
H
H
H
H
11j
H
H
H
8
11k
11l
H
H
H
6
H
CH3O
CH3O
H
H
6
11m
11n
11o
11p
H
Br
H
H
8
7g
7h
H
CH3
CH3
6
H
Br
H
6
a
ꢀ20% Starting material recovered.
generated from the aldehydes in refluxing xylene using
the method of decarboxylative condensation with sarco-
sine or N-benzyl-glycine.9 The azomethine ylide interme-
diates reacted via the expected 1,7-electrocyclisation
reaction to the azepines 10 and finally by a 1,5-hydrogen
shift to give the products 11a–f (Scheme 3). The prod-
ucts were isolated in acceptable yields after column
chromatography. As can be seen from the table beside
the very similar yields, the reaction times depended on
the N substituent of the indole and the glycine. The fast-
est reaction was observed in the case of unprotected in-
dole aldehyde 7a with sarcosine, while the reaction of 8b
with N-benzyl-glycine was not complete after four days
boiling in xylene.
1,7-electrocyclisation to give benzazepines 11g,h, how-
ever in low yields. In the reaction of 8b and N-benzyl
glycine there was no product observed by TLC after
refluxing for 60 h in xylene.
In a few examples, we investigated the effect of the addi-
tional substituents on the indole nucleus and/or 2-aryl
ring on the course of the electrocyclisation process. In
the reactions of the unprotected indoles 7b–h and sarco-
sine, azepines 11j–p were again isolated in acceptable
yields, with no visible effects of the substituents of the
starting materials on the yield, or the reaction times.
The intermediacy of azomethine ylides was shown in one
case by trapping the dipole 9 (R = CH3, E = H) with N-
phenylmaleimide to give the two isomeric cycloadducts
12 and 13 (ratio ꢀ 5:1) in good yield. The stereochemis-
try of the major isomer (12) was proved by NOE experi-
ments (Scheme 4).
In our early studies we found significant differences
between the reactivity of a,b:c,d-unsaturated, nonstabi-
lised and a,b:c,d-unsaturated, ester-stabilised azome-
thine ylides. The former dipoles react via a 1,7-
electrocyclisation to yield dihydrobenzazepines,10 whilst
the latter give other products via novel rearrange-
ments.11,12 We have also investigated the reactions of
7a and 8a,b aldehydes with methyl sarcosinate. The
ester-stabilised azomethine ylides 9 (R = H, CH3,
R1 = CH3, E = CO2CH3) in this case reacted again via
In summary we have explored a convenient reaction
sequence which provides a useful route to the benzo[c]-
indolo[2,3-e]azepine ring system13 via the 1,7-dipolar
electrocyclisation reactions of azomethine ylides derived
from easily available 3-formylindole derivatives.14

M. Nyerges et al. / Tetrahedron Letters 46 (2005) 377–380
379
4
R
N
E
CHO
2
2
R
R
[1,7]
i
1
1
R
R
N
N
R
3
R
3
R
R
7a-h R = H
8a R = CH3
8b R = Bn
9
4
R
4
R
E
N
E
N
2
R
2
R
[1,5]
1
R
N
1
R
N
R
3
R
R
3
R
11
10
Scheme 3. Reagents and conditions: (i) E = H: sarcosine or N-benzyl glycine, xylene, reflux; E = CO2CH3:CH3NCH2CO2CH3ÆHCl, Et3N, xylene,
reflux.
7 % n.O.e.
O
O
H
H
H
CHO
Ph
CH3N
H
CH3N
NPh
NPh
i
+
H
O
O
NH
Ph
Ph
O
O
NH
12
NH
13
N
Ph
7a
Scheme 4. Reagents and conditions: (i) sarcosine, toluene, reflux (92%).
8. Von Angerer, E.; Prekajac, J.; Strohmeier, J. J. Med.
Chem. 1984, 27, 1439.
Acknowledgements
9. (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull.
Chem. Soc. Jpn. 1987, 60, 4079; (b) Grigg, R. Chem. Soc.
This work was financially supported by the National
Fund for Science and Research, Hungary (OTKA Pro-
ject No. T 046196). N.M. thanks the Hungarian Acad-
emy of Sciences for a Bolyai J. fellowship. A grant
´
from the Jozsef Varga Foundation provided to A.V. is
gratefully appreciated.
´
Rev. 1987, 16, 89; (c) Nyerges, M.; Balazs, L.; Bitter, I.;
Ko¨vesdi, I.; Toke, L. Tetrahedron 1995, 51, 6783.
}
10. Arany, A.; Bendell, D.; Groundwater, P. W.; Garnett, I.;
Nyerges, M. J. Chem. Soc., Perkin Trans. 1 1999, 2605.
11. Nyerges, M.; Arany, A.; Fejes, I.; Groundwater, P. W.;
}
Zhang, W.; Bendell, D.; Anderson, R. J.; Toke, L.
Tetrahedron 2002, 58, 845.
References and notes
12. Groundwater, P. W.; Sharif, T.; Arany, A.; Hibbs, D. E.;
Hurthouse, M. B.; Garnett, I.; Nyerges, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 2837.
1. (a) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989,
45, 232; (b) Synthetic Applications of 1,3-Dipolar Cyclo-
addition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; John Wiley
& Sons, 2002.
2. For excellent reviews on 1,5-dipolar cyclisations, see: (a)
Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181; (b)
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
3. (a) Zecchi, G. Synthesis 1991, 181; (b) Groundwater, P.
W.; Nyerges, M. Adv. Heterocycl. Chem. 1999, 73, 97.
4. Arany, A.; Groundwater, P. W.; Nyerges, M. Tetrahedron
Lett. 1998, 38, 3267.
13. General procedure for the preparation of compounds 11a–f:
the corresponding indole aldehyde (1 mmol) was dissolved
in hot xylene (50 ml) and sarcosine (0.27 g, 3.0 mmol) or
sarcosine methyl ester (0.3 g, 3.0 mmol) was added. The
reaction mixture was refluxed and further portions of
sarcosine (0.09 g, 1.0 mmol) or sarcosine methyl ester
(0.10 g, 1 mmol) were added every 2 h until the starting
aldehyde completely disappeared (6–18 h, judged by TLC
except for 11f). All the solvent was removed in vacuo and
the residue was purified by column chromatography
(eluent: chloroform–methanol 8:1).
5. Marx, K.; Eberbach, W. Tetrahedron 1997, 53,
14687.
14. All new compounds afforded correct elemental analyses and
spectroscopic data. Selected examples: 6-benzyl-5,6,7,12-
tetrahydro-benz[c]azepino[4,3-b]indole (11b): 1H NMR
(250 MHz, CDCl3): 10.68 (s, 1H), 7.84 (d, 2H, J = 7.6 Hz),
7.44–6.94 (m, 11H), 4.26 (s, 2H), 3.89 (s, 2H), 3.76 (s, 2H);
13C NMR (62.5 MHz, CDCl3): 138.3 (q), 136.8 (q), 135.8
´
6. Nyerges, M.; Viranyi, A.; Pinter, A.; Toke, L. Tetrahedron
}
´
Lett. 2003, 44, 793.
´
´
7. Pinter, A.; Nyerges, M.; Viranyi, A.; Toke, L. Tetrahedron
´
Lett. 2003, 44, 2343.
´
}

380
M. Nyerges et al. / Tetrahedron Letters 46 (2005) 377–380
(q), 131.7 (q), 131.2 (q), 129.0 (CH), 127.9 (CH), 127.5 (q),
109.7 (CH), 109.4 (q), 57.3 (CH2), 47.7 (CH3), 43.9 (CH2);
42.6 (CH3); 31.2 (CH3); IR (KBr, cmÀ1): 3404, 2963, 2515,
2361, 1708, 1635, 1542, 1497, 1468, 1388, 1355, 1262, 1096,
1030. Methyl, 3-bromo-9-methoxy-6-methyl-5,6,7,12-tetra-
hydro-benz[c]azepino[4,3-b]indole (11l): 1H NMR
(300 MHz, DMSO-d6): 11.11 (s, 1H), 7.75 (d, 1H,
J = 8.3 Hz), 7.56 (d, 1H, J = 8.3 Hz), 7.48 (s, 1H), 7.30
(d, 1H, J = 8.7 Hz), 6.93 (s, 1H), 6.82 (d, 1H, J = 8.7 Hz),
4.08 (s, 2H), 3.78 (s, 3H), 3.45 (s, 2H), 2.42 (s, 3H); 13C
NMR (75 MHz, DMSO-d6): 153.5 (q), 140.1 (q), 132.3
(CH), 131.8 (q), 131.3 (q), 130.1 (CH), 127.9 (q),
127.1 (CH), 119.5 (q), 113.1 (CH), 112.9 (q), 112.1 (CH),
99.9 (CH), 60.1 (CH2), 55.5 (CH3), 43.9 (CH3), 40.0(CH2);
IR (KBr, cmÀ1): 3222, 3054, 2968, 2791, 1489, 1353, 1327,
1304, 1280, 1259, 1233, 1110, 1050. Cycloadduct 12: 1H
NMR (250 MHz, CDCl3): 8.59 (s, 1H), 7.79 (d, 1H,
J = 7.5 Hz), 7.57–7.08 (m, 13 H), 3.88 (dd, 1H, J = 6.9 and
13.8 Hz), 3.77 (d, 1H, J = 7.7 Hz), 3.64 (m, 3H), 2.06 (s,
3H); 13C NMR (62.5 MHz, CDCl3): 176.7 (q), 173.3 (q),
161.8 (q), 138.2 (q), 133.5 (2 · CH), 132.1 (q), 130.8 (q),
129.1 (CH), 128.6 (2 · CH), 128.0 (CH), 126.1 (2 · CH),
125.6 (q), 125.6 (2 · CH), 121.6 (CH), 119.6 (CH), 111.1
(CH), 108.0 (CH), 65.3 (CH), 57.3 (CH2), 50.7 (CH), 43.9
(CH), 38.4 (CH3); IR (KBr, cmÀ1): 2944, 2843, 1708, 1593,
1492, 1481, 1389, 1320, 1188, 1144, 1089, 1024.
127.2 (2 · CH), 126.4 (CH), 126.0 (2 · CH), 124.4 (CH),
121.5 (CH), 118.0 (CH), 117.1 (CH), 111.7 (q), 110.3
(CH), 58.6 (CH2), 57.8 (CH2), 52.4 (CH2); IR (KBr,
cmÀ1): 3401, 3029, 2945, 2917, 2780, 1451, 1340, 1314,
1248, 1116, 1065. 6,12-Dimethyl-5,6,7,12-tetrahydro-
benz[c]azepino[4,3-b]indole (11c): 1H NMR (250 MHz,
CDCl3): 7.73 (d, 1H, J = 7.8 Hz), 7.55 (m, 2H), 7.51 (t, 1H,
J = 7.3 Hz), 7.46 (d, 1H, J = 8.2 Hz), 7.43 (t, 1H, J =
7.4 Hz), 7.34 (t, 1H, J = 7.7 Hz), 7.25 (t, 1H, J = 7.4 Hz),
3.93 (s, 3H), 3.66 (s, 2H), 3.48 (s, 2H), 2.54 (s, 3H); 13C
NMR (62.5 MHz, CDCl3): 137.9 (q), 137.8 (q), 137.7 (q),
132.6 (q), 131.0 (CH), 127.5 (CH), 127.3 (CH), 127.2 (CH)
127.1 (q), 121.9 (CH), 119.7 (CH), 118.1 (CH), 111.6 (q),
109.5 (CH), 58.3 (CH2), 48.4 (CH2), 43.8 (CH3), 31.1
(CH3); IR (KBr, cmÀ1): 3446, 3044, 2933, 2777, 1930,
1681, 1600, 1488, 1467, 1352, 1258, 1241, 1200, 1130, 1090,
1034, 1008. Methyl, 6,12-dimethyl-5,6,7,12-tetrahydro-
benz[c]azepino[4,3-b]indole-5-carboxylate
(11g):
1H
NMR (250 MHz, CDCl3): 7.68 (d, 1H, J = 7.7 Hz), 7.58
(d, 1H, J = 7.4 Hz), 7.52–7.18 (m, 6H); 3.89 (s, 3H), 3.78
(s, 2H), 3.60 (s, 1H), 3.56 (s, 3H), 2.58 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): 177.5 (q), 137.9 (q), 135.6 (q), 132.4
(q), 131.7 (CH), 130.7 (q), 128.5 (q), 128.1 (CH), 127.8
(CH), 127.7 (CH), 122.4 (CH), 120.2 (CH), 117.9 (CH),