V. V. Kouznetsov et al. / Tetrahedron Letters 49 (2008) 5855–5857
5857
(
36), 92 (17), 77 (24). Anal. calcd for C15
H
12
2
N O
2
: C, 71.42; H, 4.79; N, 11.10.
Supplementary data
Found: C, 71.23; H, 4.95; N, 11.05.
1
1
6. General experimental procedure for the synthesis of the ketimine 9b in PEG 400:
In a round-bottom flask, the isatin 7 (2.04 mmol) was dissolved in PEG 400
(5 mL) and the arylamine 8 b was added (2.44 mmol) stirring and heating at
80 °C for 3 h. The product formation is monitored by TLC comparing to the
standard protocol of ketimine.
References and notes
0
7. General experimental procedure for the synthesis of the dihydrospiro[indoline-3,2 -
quinolin]-2-ones: In a Schlenck flask, the ketimines 9a–h (1.8 mmol) were
dissolved in anhydrous dichloromethane with inert nitrogen atmosphere. The
1
.
(a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031–
5070; (b) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl.
Chem. 1998, 35, 761–785; (c) Kouznetsov, V. V. J. Heterocycl. Chem. 2005, 42,
9–59.
1
BF
trans-isoeugenol (2.7 mmol) was added. The reaction mixture was monitored
through TLC. The reaction mass was then treated with 20 mL of NaHCO
solution and extracted with ethyl acetate (3 ꢂ 20 mL). The organic layer was
dried on anhydrous Na SO and then concentrated by vacuum. The pure
3 2
ꢀOEt (1.98 mmol) was added stirring constantly. Fifteen minutes later, the
3
3
2
.
Fisher, M. J.; Backer, R. T.; Husain, S.; Hsiung, H. M.; Mullaney, J. T.; O‘Brian, T.
P.; Ornstein, P. L.; Rothhaar, R. R.; Zgombick, J. M.; Briner, K. Bioorg. Med. Chem.
Lett. 2005, 15, 4459–4462.
2
4
compounds 6a–h were obtained after recrystallization from heptanes/AcOEt
(1/1) or silica gel column chromatography with petroleum ether and ethyl
acetate as eluents (Table 1). It is important to note that trying to heat the
reaction over the room temperature (25 °C) resulted in the ketimine rupture
and the complete failure of the synthesis.
3.
4.
5.
6.
Singer, J. M.; Barr, B. M.; Coughenour, L. L.; Gregory, T. F.; Walters, M. A. Bioorg.
Med. Chem. Lett. 2005, 15, 4560–4563.
Guo, T.; Gu, H.; Hobbs, D. W.; Rokosz, L. L.; Stauffer, T. M.; Jacob, B.; Clader, J. W.
Bioorg. Med. Chem. Lett. 2007, 17, 3010–3013.
Chen, W.; Lin, Z.; Ning, M.; Yang, C.; Yan, X.; Xie, Y.; Shen, X.; Wang, M.-W.
Bioorg. Med. Chem. 2007, 15, 5828–5836.
Eastman, R. T.; White, J.; Hucke, O.; Yokoyama, K.; Verlinde, C. L. M. J.; Hast, M.
A.; Beese, L. S.; Gelb, M. H.; Rathod, P. K.; Van Voorhis, W. C. Mol. Biochem.
Parasitol. 2007, 152, 66–71.
18. Selected spectral data for some compounds 6: 4’-(4-Hydroxy-3-methoxyphenyl)-
0
3’-methyl-3’,4’-dihydro-1’H-spiro[indoline-3,2 -quinolin]-2-one (6a): white yellow
solid, mp 280–282 °C; IR (KBr): 3455 m(NH-indol), 3336 m(NH–THQ), 1712 m ,
(NC@O)
ꢁ
1 1
1600
m
(NH), 1265
m
(ArC–O) cm
;
H NMR (400 MHz, CDCl
3
, Me
4
Si): d 7.80 (1H, s,
0
0
0
4 -OHAr), 7.27 (1H, td, J = 7.9, 0.9 Hz, 5 -HTHQ), 7.14 (1H, d, J = 7.4 Hz, 7-HIndol),
7.03–6.99 (2H, m, 4-HIndol and 7 -HTHQ), 6.91 (1H, d, J = 7.7 Hz, 6-HIndol), 6.80
(1H, d, J = 8.0 Hz, 5-HIndol), 6.75 (1H, dd, J = 8.0, 1.7 Hz, 8 -HTHQ), 6.70–6.63 (3H,
m, 6 -HTHQ, 2 -HAr and 5 -HAr), 6.59 (1H, d, J = 8.0 Hz, 6 -HAr), 5.54 (1H, s,
NHTHQ), 3.86 (1H, d, J = 11.1 Hz, 4 -H), 3.80 (3H, s, 3 -OMe), 2.64 (1H, dq,
J = 11.8, 6.6 Hz, 3 -H), 0.53 (3H, d, J = 6.6 Hz, 3 -Me) ppm. C NMR (100 MHz,
CDCl , Me Si): d 178.6 (C(O)N), 146.9, 144.5, 142.3, 139.9, 135.2, 131.5, 130.1
0
7
.
Horsfiline: (a) Jossang, A.; Jossang, P.; Hadi, H. A.; Sévent, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527–6530. Spirotryprostatin A: (b) Cui, C.-B.; Kakeya, H.;
Okada, G.; Osada, H. J. Antibiot. 1996, 49, 527–533. Pteropodine: (c) Kang, T.-H.;
Matsumoto, K.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J.
Pharmacol. 2002, 444, 39–45.
0
0
00
00
00
0
00
0
0
13
8
9
.
.
Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.;
Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J.
Am. Chem. Soc. 2005, 127, 10130–10131.
Dandia, A.; Singh, R.; Khaturia, S.; Mérienne, C.; Morgant, G.; Loupy, A. Bioorg.
Med. Chem. 2006, 14, 2409–2417.
3
4
(+), 129.1 (+), 127.3 (+), 125.0, 124.8 (+), 123.4 (+), 123.3 (+), 118.8 (+), 115.5
(+), 113.8 (+), 111.0 (+), 109.9 (+), 65.4 (spiro), 56.0 (+), 47.3 (+), 40.8 (+), 13.3
+
ꢀ
t
(+) ppm. GC–MS: R : 53.34 min; m/z (%): 386 (M , 13), 343 (4), 254 (7), 235
(100), 115 (5). Anal. calcd for C24
H
22
N
2
O
3
: C, 74.59; H, 5.74; N, 7.25. Found: C,
0
0
0
0
0
1
0. (a) Kouznetsov, V. V.; Bohórquez Romero, A. R.; Stashenko, E. E. Tetrahedron
Lett. 2007, 48, 8855–8860; (b) Kouznetsov, V. V.; Merchan Arenas, D. R.;
Bohórquez Romero, A. R. Tetrahedron Lett. 2008, 49, 3097–3100; (c)
Kouznetsov, V. V.; Mora Cruz, U.; Zubkov, F. I.; Nikitina, E. V. Synthesis 2007,
74.78; H, 5.89; N, 7.16. 4 -(4-Hydroxy-3-methoxyphenyl)-3 6 -dimethyl-3 ,4 -
0
0
dihydro-1 H-spiro[indoline-3,2 -quinolin]-2-one (6b): white yellow solid, mp
252–253 °C; IR (KBr): 3540 (NC@O), 1592
Si): d 10.46 (1H, s,
NHIndol), 8.79 (1H, s, 4 -OHAr), 7.19 (1H, td, J = 7.6, 1.1 Hz, 6-HIndol), 6.96 (1H, t,
m
(NH–indol), 3344
m
(NH–THQ), 1710
m
m
(NH),
ꢁ
1
1
1276
m
(ArC–O) cm
.
6 4
H NMR (400 MHz, DMSO-d , Me
0
0
3
75–384; (d) Kouznetsov, V. V.; Bohórquez Romero, A. R.; Astudillo Saavedra,
00
L.; Fierro Medina, R. Mol. Divers. 2006, 10, 29–37.
J = 7.0 Hz, 4-HIndol), 6.90 (1H, t, J = 7.4 Hz, 5-HIndol), 6.85 (1H, d, J = 7.7 Hz, 5 -
0 00
Ar), 6.79 (1H, d, J = 6.3 Hz, 5 -HTHQ), 6.72 (1H, d, J = 8.0 Hz, 6 -HAr), 6.66 (1H, s,
2 -HAr), 6.50 (1H, d, J = 8.0 Hz, 7 -HTHQ), 6.40–6.34 (2H, m, 6 -HTHQ and 7-
1
1
1
1. Fringuelli, F.; Taticchi, A. The Diels–Alder Reaction Selected Practical Methods;
John Wiley & Sons, Ltd: Chichester, 2002; 330 p.
H
0
0
0
0
0
0
0
2. Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.;
Wiley-VCH: Weinheim, 2002; pp 187–209.
HIndol), 5.75 (1H, s, NHTHQ), 3.80 (1H, d, J = 12.0 Hz, 4 -H), 3.68 (3H, s, 3 -OMe),
0
0
0
2.32 (1H, dq, J = 12.0, 6.6 Hz, 3 -H), 2.01 (3H, s, 8 -Me), 0.31 (3H, d, J = 6.6 Hz, 3 -
0
0
0
0
0
0
13
3. Unique synthesis of spiro[indoline-3,2 -(1 ,2 ,3 ,4 -tetrahydroquinoline)]-2,4 -
6 4
Me) ppm. C NMR (100 MHz, DMSO-d , Me Si): d 178.1 (C(O)N), 147.5, 144.9,
diones derivatives has been reported, see: Al-Thebeiti, M. S. Heterocycles 1998,
141.7, 141.4, 134.6, 132.4, 128.2 (+), 128.0 (+), 127.1 (+), 123.7 (+), 123.5, 121.7
(+), 121.6 (+), 121.0, 115.8 (+), 115.4 (+), 112.9 (+), 109.2 (+), 64.2 (spiro), 55.5
4
8, 145–150.
4. General experimental procedure for the synthesis of the ketimines: Isatin
6.8 mmol) was dissolved in anhydrous methanol (50 mL) and the proper
arylamines 8a–h were added (8.16 mmol) and then, the acid catalyst, AcOH
0.1–7.4 mL). The reaction mixture was refluxed, stirring constantly, for 3–8 h
1
7
(+), 46.4 (+), 39.9 (+), 17.6 (+), 13.1 (+) ppm. Anal. calcd for C25
24 2 3
H N O : C,
(
74.98; H, 6.04; N, 7.00. Found: C, 74.74; H, 6.23; N, 7.13.
0
0
19. 2D-NMR data of 1 H-spiro[indoline-3,2 -quinolin]-2-one 6d: COSY correlations:
0
0
0
0
(
0.32 (3 -Me)/2.33; 2.02 (6 -Me)/6.32; 2.33 (3 -H)/0.32/3.76; 3.76 (4 -H)/
0
monitoring through TLC. After the reaction mixture reached room temperature,
the precipitated solid was filtered and washed with petroleum ether, and then
vacuum dried to get the ketimines 9a–h in good to excellent yields (50–86%).
2.33/6.32; 6.32 (5 -H)/2.02/3.76; 6.86 (5-H)/7.20; 6.90 (6-H)/6.86/7.20; 6.96
0
(4-H)/6.86; 7.20 (7-H)/6.86/6.90. HMQC correlations: 0.32 (3 -Me)/13.2;
2.02 (6 -Me)/20.2; 2.33 (3 -H)/33.8; 3.70 (3 -OMe)/55.6; 3.76 (4 -H)/46.5;
6.32 (5 -H)/129.4; 6.45 (8 -H)/114.2; 6.56 (6 -H)/121.4; 6.86 (5-H)/109.3; 6.90
(6-H)/121.8; 6.96 (4-H)/123.8; 7.20(7-H)/128.3. HMBC correlations: 0.32(3 -
Me)/38.8/46.5; 2.02 (6 -Me)/124.6/128.3; 2.33 (3 -H)/13.1/33.8/46.5/64.1/
132.1/177.7; 3.70 (3 -OMe)/147.4; 3.76 (4 -H)/ 13.1/33.8/46.5/64.1/113.0/
129.4/134.6; 6.25 (NHTHQ)/ 33.8/64.1/114.2/177.7; 6.32 (5 -H)/20.2/46.5/
127.4; 8.83 (4 -OH)/115.5/147.4; 6.45 (8 -H)/124.6/146.8; 6.56 (6 -H)/46.5/
113.0/144.9; 6.86 (5-H)/132.1; 6.90 (6-H)/109.3/132.1; 6.96 (4-H)/64.1/
128.3/141.5; 7.20 (7-H)/109.3/123.8/141.5; 10.50 (NHIndol)/64.1/132.1/141.5/
177.7.
0
0
00
0
0
0
00
1
5. Selected spectral data of ketimines 9: Ketimine 9b, R
ether/ethyl acetate); mp 184–185 °C; IR (KBr): 3251
f
= 0.43 (2:1 petroleum
(NH), 1747 (NC@O), 1666
0
m
m
ꢁ
1
1
0
0
m
Me
(NH), 1612
m
(C@N), 1461
m
(C@C), 1338
m
(C–N) cm
;
H NMR (400 MHz, CDCl
3
,
0
00
0
4
Si): d 9.72 (1H, br. s, H–N), 7.32–7.28 (2H, m, 6-HIndol, 5 -HAr), 7.23 (1H, d,
0
0
J = 7.5 Hz, 6 -HAr), 7.16 (1H, dd, J = 7.8, 7.3 Hz, 5-HIndol), 6.95 (1H, d, J = 7.8 Hz,
4
0
0
00
0
00
-HIndol), 6.85 (1H, d, J = 7.6 Hz, 3 -HAr), 6.74 (1H, dd, J = 7.6, 8.3 Hz, 4 -HAr), 6.5
1
3
(
1H, d, J = 7.7 Hz, 7-HIndol), 2.16 (3H, s, Me) ppm. C NMR (100 MHz, CDCl
Me Si): d 165.4, 154.7, 149.1, 145.4, 134.3 (+), 130.9, 126.7 (+), 126.2 (+), 126.1
+), 125.3 (+), 123 (+), 116.6 (+), 111.8 (+), 17.7 (+) ppm. GC–MS: R : 23.54 min;
m/z (%): 236 (M , 51), 208 (100), 180 (16), 118 (6), 91 (19), 65 (26). Anal. calcd
for C15 O: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.49; H, 5.03; N, 11.67.
Ketimine 9c, R = 0.33 (2:1 petroleum ether/ethyl acetate); mp 177–179 °C; IR
(NH), 1735 (NC@O), 1654 (NH), 1612 (C@N), 1461
H NMR (400 MHz, CDCl , Me Si): d 9.78 (1H, br. s, H–N), 7.29 (1H, dd,
3
,
4
(
t
+
20. The configuration of the oxindole moiety was assigned with aid of the NOE-
0
H
12
N
2
experiments (the irradiation of protons 3 -H
a
and 4-HIndol was carried out). The
similar case of the stereochemistry at the quaternary spiro and adjacent alkyl
f
0
(
cm
KBr): 3170
m
m
m
4
m
m
(C@C), 1334
m
(C–N)
centers of spiro[pyrroline-3,3 -oxindoles] has been reported, see: Miyake, F. Y.;
ꢁ
1 1
;
3
Yakushijin, K.; Horne, D. A. Org. Lett. 2004, 6, 711–713.
21. See, recent works on complex isatin-3-spiranes: (a) Sridhar, G.; Gunasundari,
T.; Raghunathan, R. Tetrahedron Lett. 2007, 48, 319–322; (b) Kumar, R. S.;
Perumal, S. Tetrahedron Lett. 2007, 48, 7164–7168; (c) Kumar, R. S.; Perumal, S.
Tetrahedron 2007, 63, 12220–12231.
J = 8.0, 6.9 Hz, 6-HIndol), 7.23 (1H, dd, J = 6.2, 8.0 Hz, 5-HIndol), 6.93 (1H, d,
0
0
0
0
J = 7.8 Hz, 3 -HAr), 7.0–6.9 (3H, m, 4-HIndol, 4 - and 5 -HAr), 6.76–6.75 (2H, m, 7-
13
H
Indol and 4 -HAr), 3.76 (3H, s, OMe) ppm. C NMR (100 MHz, CDCl
65.3, 155.3, 148.1, 145.2, 134.2 (+), 126.5 (+), 125.8 (+), 122.7 (+), 121.2 (+),
21.0 (+), 119.3 (+), 117.1 (+), 111.8 (+), 111.6 (+), 55.6 (+) ppm. GC–MS: R
3 4
, Me Si): d
1
1
2
t
:
22. Their antifungal and cytotoxic properties are under way. These results will be
published soon elsewhere.
+
ꢀ
4.67 min; m/z (%): 252 (M , 67), 237 (9), 224 (36), 195 (100), 180 (34), 117