Mendeleev Commun., 2014, 24, 260–261
1
a–c
compound 6b gave product 7b in high yield. The (RS,RS)-con-
figuration of the spiro-center and nitrile group was confirmed
by a signal of the HCCN proton at 2.82 ppm with J 4 Hz observed
in the NMR spectrum. The syn position of the nonbornane bridge
relative to the benzene ring in compound 7b was determined by
the NOE experiment (Figure S1, Online Supplementary Materials).
In the final step, hydrogenation of compound 7b in AcOH/
i
Me
Me
HOOC
CN
O
CN
COOH
R
R
v
O
N
N
2
4
H
H
Ac O system in the presence of Adams catalyst proceeded
2
4
a–c
8a–c
simultaneously with the acylation of the amino group (see
Scheme 2). Product 9b was identified by mass spectrometry.
To summarize, the developed strategy is versatile and can be
used to synthesize various spirocyclic analogues of melatonin
starting from simple reactants.
a R = H
b R = OMe
c R = NO2
ii
CN
COOH
CN
COOH
O
R
iii MeO
for 5b
iv
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.09.003.
O
N
N
H
H
5
a–c
6b
References
1
S.-L. Zhu, Sh.-J. Jia and Y. Zhang, Tetrahedron, 2007, 63, 9365.
2 P. Kutschy, A. Salayová and Z. Curillová, Bioorg. Med. Chem., 2009,
7, 3698.
B. Lippa, G. Pan, M. Corbett, Ch. Li and G. S. Kauffman, Bioorg. Med.
Chem. Lett., 2008, 18, 3359.
H
CN
O
NHAc
MeO
vi
MeO
1
O
3
N
N
H
H
4
5
H. Sch. Eidam and P. A. Haile, US Patent 2008/0318990 A1, 2008.
Y. C. Tsai, J. P. Liou, R. Liao, C. Y. Cheng and P. L. Tao, Bioorg. Med.
Chem. Lett., 1998, 8, 1813.
7
b
9b
Scheme 2 Reagents and conditions: i, NCCH COOH, Et N, 1,4-dioxane,
h, then HCl aq.; ii, cyclopentadiene, EtOH, 78°C; iii, N H ·H O, H O ,
–5°C, methanol; iv, EtO(CH ) OH, reflux, 2.5 h; v, 2,3-dimethylbutadiene,
EtOH, reflux; vi, H (1 atm), PtO , AcOH, Ac O, 25°C, 4 h.
2
3
6
D. W. Robertson, J. H. Krushinski and G. D. Pollock, J. Med. Chem.,
4
0
2 4 2 2 2
1
987, 30, 824.
2
2
7
8
9
D. P. Zlotos, Arch. Pharm. Chem. Life Sci., 2005, 338, 229.
2
2
2
D. X. Tan, R. J. Reiter and L. D. Chen, Carcinogenesis, 1994, 15, 215.
M. A. Pappolla, Y. J. Chyan, B. Poeggeler, B. Frangione, G. Wilson,
J. Chiso and R. J. Reiter, J. Neural. Transm., 2000, 107, 203.
case of indole derivatives containing either electron-donating or
electron-withdrawing groups in the 5-position of indole moiety.
Attempted decarboxylation of compound 5b was accom-
panied by the retro-Diels–Alder fragmentation. To preserve the
polycyclic skeleton, we performed the hydrogenation of its double
1
0 M. A. Pappolla, M. Sos, R. A. Omar, R. J. Bick, D. L. M. Hickson-Bick,
R. J. Reiter, S. Efthimiopoulos and N. K. Robakis, J. Neurosci., 1997, 17,
1683.
1
1 S. M. Armstrong, Experientia, 1989, 45, 932.
‡
12 D. J. Kennaway and H. Wright, Curr. Top. Med. Chem., 2002, 2, 199.
bond by using diimide. The decarboxylation of thus obtained
1
1
3 O. Uchikawa, K. Fukatsu, R. Tokunoh, M. Kawada, K. Matsumoto,
Y. Imai, S. Hinuma, K. Kato, K. Nishikawa, K. Hirai, M. Miyamoto and
S. Ohkawa, J. Med. Chem., 2002, 45, 4222.
4 G. Spadoni, C. Balsamini, G. Diamantini, B. D. Giacomo, G. Tarzia,
M. Mor, P. V. Plazzi, V. Lucini, R. Nonno, M. Pannacci, F. Fraschini and
B. Stankov, J. Med. Chem., 1997, 40, 1990.
‡
3
-Cyano-5'-methoxy-2'-oxo-1',2'-dihydrospiro{bicyclo[2.2.1]heptane-
,3'-indole}-3-carboxylic acid 6b. A suspension of 5b (1 g, 0.003 mol) in
2
methanol (20 ml) was placed in a three-neck flask, and a 85% hydrazine
hydrate solution (9.6 ml) was added. The mixture was cooled to 0–5°C,
and a 35% hydrogen peroxide solution (34 ml) was added within 4 h at a
temperature below 30°C. The mixture was kept overnight and then hydro-
chloric acid (15 ml) was added dropwise. The light-yellow precipitate that
formed was washed with water (40 ml) and diethyl ether (15 ml) and dried.
15 M. N. Elinson, A. I. Ilovaisky, V. M. Merkulova, T. A. Zaimovskaya and
G. I. Nikishin, Mendeleev Commun., 2012, 22, 143.
16 Ch. Browning, I. Beresford, N. Fraser and H. Giles, Br. J. Pharmacol.,
2000, 129, 877.
1
Yield 0.71 g (71%), mp 235–236°C. H NMR (400.13 MHz, DMSO-d )
17 P. Tang and Y. Qin, Synthesis, 2012, 44, 2969.
6
1
1
2
8 C. J. Thibodeaux, W. Chang and H. Lu, Chem. Rev., 2012, 112, 1681.
9 F. Brackmann and A. de Meijere, Chem. Rev., 2007, 107, 4493.
0 Yu. G. Gololobov, A. N. Nesmeyanov, V. P. Lysenko and I. E. Boldeskul,
Tetrahedron, 1987, 43, 2609.
1 H. Lebel, J. F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev.,
2003, 103, 977.
d: 1.21 (m, 1H), 1.62 (m, 1H), 1.69 (d, 1H, J 10.3 Hz), 2.07 (m, 1H), 2.18
(
6
(
m, 1H), 2.25 (m, 1H), 2.32 (m, 1H), 2.83 (d, 1H, J 10.8 Hz), 3.72 (s, 3H),
.78 (d, 1H, J 8.3 Hz), 6.85 (dd, 1H, J 1.5 and 8.3 Hz), 7.1 (s, 1H), 10.50
s, 1H). 13C NMR (400.13 MHz, DMSO-d ) d: 22.41, 24.19, 39.90, 46.19,
6
2
2
4
1
1
9.98, 55.92, 57.58, 58.78, 109.98, 113.21, 113.31, 119.96, 133.07, 135.29,
54.90, 167.01, 176.01. IR (n/cm ): 1490 [NHC(O)], 1500 [C(O)OH],
–1
2 G. B. Bennett, R. B. Mason and M. J. Shapiro, J. Org. Chem., 1978, 43,
640 [NHC(O)], 1740 [C(O)OH], 2250 (CN), 2440–2500 (OH) 3370
4
383.
+
+
(
NH). MS, m/z: 312 (M ), 268 (M – CO ). Found (%): C, 64.39; H, 5.16;
2
2
2
3 F. Arndt, Org. Synth., 1943, 2, 165.
1
N, 8.86. Calc. for C H N O · / H O (%): C, 64.45; H, 5.25; N, 8.84.
17
16
2
4
4
2
4 N. A. Lozinskaya, S. E. Sosonyuk, M. S. Volkova, M. Yu. Seliverstov,
5
'-Methoxy-2'-oxo-1',2'-dihydrospiro{bicyclo[2.2.1]heptane-2,3'-indole}-
-carbonitrile 7b.A mixture of 6b (0.71 g, 2.3 mmol) and 2-ethoxyethanol
20 ml) was refluxed for 2.5 h and then concentrated. The product was
M. V. Proskurnina, S. E. Bachurin and N. S. Zefirov, Synthesis, 2011,
3
(
2
, 273.
i
recrystallized from a mixture of Pr OH and water (1:1); the yield 0.61 g
1
(
84%); mp 195–196°C. H NMR (400.13 MHz, DMSO-d ) d: 1.21 (m,
6
1
2
3
H), 1.61 (m, 1H), 1.70 (d, 1H, J 11.3 Hz), 2.07 (m, 1H), 2.17 (s, 1H),
.33 (m, 1H), 2.32 (d, 1H, J 10.6 Hz), 2.50 (s, 1H), 2.82 (d, 1H, J 4.0 Hz),
.72 (s, 3H), 6.77 (d, 1H, J 8.3 Hz), 6.84 (dd, 1H, J 2.2 and 8.6 Hz), 7.09
(
s, 1H), 10.50 (s, 1H). 13C NMR (400.13 MHz, DMSO-d ) d: 22.45, 24.20,
6
4
1
3
0.53, 40.94, 46.24, 49.99, 57.55, 58.94, 109.97, 113.20, 113.22, 120.07,
–1
33.12, 154.90, 166.97, 176.01. IR (n/cm ): 1700 [C(O)NH], 2270 (CN),
+
+
370 [C(O)NH]. MS, m/z: 268 (M ), 253 (M –Me). Found (%): C, 71.40,
H, 5.98; N, 10.50. Calc. for C H N O (%): C, 71.62; H, 6.01; N, 10.44.
16
16
2
2
For experimental details, see Online Supplementary Materials.
Received: 3rd February 2014; Com. 14/4300
261 –
–