K.N. Tiwari et al. / Tetrahedron xxx (2018) 1e6
5
three times. With few isatins, solid precipitate was obtained in
reaction mixture in small amount which was found as expected
product by TLC. The precipitated solid was dissolved in combined
organic layer which was evaporated to provide light yellow solid
and purified by silica gel column chromatography using hex-
ane:ethyl acetate (6:4) as an eluent to provide 5a as white solid
(353 mg).
13.06 HRMS (ESI) m/z for C22H25N3O4 [M þ H]þ, calcd, 396.1923,
found: 397.1750.
4.2.6. Ethyl 20-amino-5-nitro -70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5f)
White solid, 65%, m.p.:218e220 ꢀC, 1H NMR (300 MHz, DMSO-
d6) d ppm 10.96 (s, 1H) 8.10e8.07 (m, 1H) 8.01 (s, 2H) 7.76e7.75 (m,
1H) 6.89 (d, J ¼ 8.69 Hz, 1H) 3.77e3.70 (q, J ¼ 7.18 Hz, 2H) 2.12e2.11
4.2.1. Ethyl 20-amino-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5a)
White solid, 69%, m.p.:214e216 ꢀC, 1H NMR (300 MHz, DMSO-
(m, 2H) 1.23 (s, 2H) 1.01 (s, 3H) 0.97 (s, 3H) 0.82 (t, J ¼ 7.08 Hz, 3H)
13C NMR (75 MHz, DMSO-d6)
d ppm 189.14, 180.38, 167.13, 163.53,
159.35, 150.88, 141.53, 137.12, 125.12, 117.66, 112.03, 108.09, 75.04,
59.71, 59.10, 50.38, 46.64, 31.59, 28.95, 27.21, 13.14 HRMS (ESI) m/z
for C21H22N4O6 [M þ H]þ, calcd, 427.1617, found: 428.1428.
d6)
d
ppm 10.12 (s, 1H) 7.84 (s, 2H) 7.06e7.01 (td, J ¼ 7.55, 1.32 Hz,
1H) 6.85e6.81 (m, 1H) 6.78e6.75 (m, 1H) 6.68e6.66 (m, 1H)
3.72e3.69 (m, 2H) 2.18e2.12 (d, J ¼ 14.73 Hz, 2H) 1.24 (s, 2H) 1.01 (s,
3H) 0.95 (s, 3H) 0.80 (t, J ¼ 7.08 Hz, 3H) 13C NMR (75 MHz, DMSO-
40.2.7. Ethyl 20-amino-05-methoxy-70,70-dimethyl-2,50-dioxo-
5 ,60,70,80-tetrahydro-1 H-spiro[indoline-3,40-quinoline]-30-
carboxylate (5g)
d6)
d ppm 194.57, 179.74, 167.62, 162.34, 159.09, 144.01, 127.12,
122.18, 120.48, 113.09, 108.09, 76.34, 58.79, 50.63, 46.60, 31.49,
27.75, 26.85, 13.07 HRMS (ESI) m/z for C21H23N3O4 [M þ H]þ, calcd,
382.1766, found: 383.1596.
White solid, 70%, m.p.:214e216 ꢀC, 1H NMR (300 MHz, DMSO-
d6) d ppm 9.95 (s, 1H) 7.84 (s, 2H) 6.63e6.61 (m, 1H) 6.65e6.60 (m,
1H) 6.45 (d, J ¼ 2.27 Hz, 1H) 3.75e3.68 (m, 2H) 3.61 (s, 3H)
4.2.2. Ethyl 20-amino-5-bromo-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5b)
White solid, 72%, m.p.:218e220 ꢀC, 1H NMR (300 MHz, DMSO-
2.20e2.12 (m, 2H) 1.23e1.15 (m, 2H) 1.01 (s, 3H) 0.96 (s, 3H) 0.82 (t,
J ¼ 7.26 Hz, 3 H) 13C NMR (75 MHz, DMSO-d6)
d ppm 194.56, 179.57,
167.67, 162.32, 159.05, 154.27, 137.65, 137.31, 113.04, 111.27, 109.73,
108.13, 76.35, 58.83, 55.23, 50.68, 47.10, 31.49, 27.74, 26.72, 13.08
HRMS (ESI) m/z for C22H25N3O5 [M þ H]þ, calcd, 412.1872, found:
413.1727.
d6)
d
ppm 10.29 (s, 1H) 7.91 (s, 2H) 7.24e7.20 (dd, J ¼ 8.12, 2.08 Hz,
1H) 7.00 (d, J ¼ 2.08 Hz,1H) 6.65e6.63 (d, J ¼ 8.12 Hz,1H) 3.77e3.69
(m, 2H) 2.11e2.08 (m, 2H) 1.23e1.15 (m, 2H) 1.01 (s, 3H) 0.97 (s, 3H)
0.82 (t, J ¼ 7.15 Hz, 3H) 13C NMR (75 MHz, DMSO-d6)
d ppm 194.80,
179.35, 167.41, 162.86, 159.17, 143.52, 138.49, 129.81, 125.02, 112.48,
109.97, 75.68, 58.94, 50.56, 46.84, 31.53, 27.38, 27.09, 13.11 HRMS
(ESI) m/z for C21H22BrN3O4 [M þ H]þ, calcd, 460.0871, found:
461.0700.
4.3. Typical procedure for synthesis of 6
A
solution of 200 mg (1.36 mmol) of isatin (1a), 132 mg
(1.36 mmol) of 3-aminocyclopent-2-en-1-one (2d) and 0.144 mL
(1.36 mmol) of ethyl cyanoacetate (3) was heated to 80 ꢀC in H2O for
8 h. After the TLC indicated the complete consumption of isatin
(1a), the reaction mixture was extracted with ethyl acetate three
times and the combined organic layer was dried and evaporated to
provide brown solid. The reaction mixture was purified by silica gel
column chromatography using hexane:ethyl acetate (4:6) as an
eluent to provide 6 as white solid (253 mg).
4.2.3. Ethyl 20-amino-5-chloro-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5c)
White solid, 75%, m.p.:212e214 ꢀC, 1H NMR (300 MHz, DMSO-
d6)
d
ppm 10.29 (s, 1H) 7.91 (s, 2H) 7.11e7.07 (dd, J ¼ 8.12, 2.27 Hz,
1H) 6.91e6.89 (m, 1H) 6.69 (d, J ¼ 8.12 Hz, 1H) 3.77e3.69 (m, 2H)
2.12e2.08 (m, 2H) 1.23e1.14 (m, 2H) 1.01 (s, 3H) 0.98 (br s, 3H) 0.82
(t, J ¼ 7.08 Hz, 3H) 13C NMR (75 MHz, DMSO-d6)
d ppm 194.79,
179.49, 167.43, 162.85, 159.19, 154.42, 143.13, 138.11, 126.96, 124.38,
122.36, 109.35, 75.70, 58.93, 50.57, 46.90, 31.52, 27.41, 27.08, 13.11
HRMS (ESI) m/z for C21H22ClN3O4 [M þ H]þ, calcd, 416.1377, found:
417.1198.
4.3.1. Ethyl 2-amino-20,5-dioxo-1,5,6,7-tetrahydrospiro[cyclopenta
[b]pyridine-4,30-indoline]-3-carboxylate (6)
White solid, 55%, m.p.:204e206 ꢀC, 1H NMR (400 MHz, DMSO-
d6)
d ppm 10.31 (s, 1H) 8.05 (br s, 2H) 7.11e7.07 (m, 1H) 6.98e6.97
(m,1H) 6.82e6.79 (m,1H) 6.74e6.73 (m,1H) 3.73 (q, J ¼ 7.11 Hz, 2H)
4.2.4. Ethyl 20-amino-5-iodo-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5d)
White solid, 63%, m.p.:220e222 ꢀC, 1H NMR (300 MHz, DMSO-
2.92e2.88 (m, 2H) 2.09e2.05 (m, 2H) 0.73 (t, J ¼ 7.03 Hz, 3H) 13C
NMR (100 MHz, DMSO-d6)
d ppm 200.06, 176.22, 169.42, 168.17,
143.65, 135.20, 127.98, 123.20, 121.44, 117.46, 108.93, 75.48, 59.37,
49.32, 33.60, 31.75, 13.53. HRMS (ESI) m/z for C18H17N3O4 [M þ H]þ,
calcd., 340.1297, found:340.1294.
d6)
d
ppm 10.28 (s, 1H) 7.91 (s, 2H) 7.40e7.37 (dd, J ¼ 8.03, 1.79 Hz,
1H) 7.12 (d, J ¼ 1.70 Hz, 1H) 6.53 (d, J ¼ 7.93 Hz, 1H) 3.77e3.69 (m,
2H) 2.11e2.10 (m, 2H) 1.26e1.17 (m, 2H) 1.01 (s, 3H) 0.97 (s, 3H)
0.82 (t, J ¼ 7.08 Hz, 3H) 13C NMR (75 MHz, DMSO-d6)
d
ppm 194.80,
4.4. Typical procedure for synthesis of 7
179.14, 167.41, 162.82, 159.14, 143.99, 138.76, 135.70, 130.47, 112.54,
110.67, 82.79, 75.74, 58.94, 50.56, 46.62, 31.53, 27.39, 27.04, 13.10
HRMS (ESI) m/z for C21H22IN3O4 [M þ H]þ, calcd, 508.0733, found:
509.0551.
A solution of 200 mg (1.10 mmol) of 5-chloroisatin (1c), 153 mg
(1.10 mmol) of 3-amino-5,5-dimethylcyclohex-2-enone (2b) was
heated to 80 ꢀC in H2O for 6 h. After the TLC indicated the complete
consumption of 5-chloroisatin (1c), the reaction mixture was
extracted with ethyl acetate three times. The combined organic
layer was dried over Na2SO4 and evaporated on rotatory evaporator
to provide light yellow solid which was purified by silica gel column
chromatography using hexane:ethyl acetate (2:8) as an eluent to
provide 7 as white solid (239 mg).
4.2.5. Ethyl 20-amino-5-methyl-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carboxylate (5e)
Isolated as a white solid, 60%, m.p.:216e218 ꢀC, 1H NMR
(300 MHz, DMSO-d6) d ppm 10.01 (s, 1H) 7.83 (s, 2H) 6.85e6.82 (m,
1H) 6.64 (s, 1H) 6.57e6.54 (m, 1H) 3.74e3.67 (q, J ¼ 7.18 Hz, 2H)
2.15e2.11 (m, 2H) 2.05e1.98 (m, 3H) 1.23 (s, 2H) 1.01 (s, 3H) 0.96 (s,
3H) 0.82 (t, J ¼ 7.18 Hz, 3H) 13C NMR (75 MHz, DMSO-d6)
d
ppm
4.4.1. 3-(2-amino-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-5-
chloro-3-hydroxyindolin-2-one (7)
194.56, 179.71, 167.67, 162.23, 159.05, 141.63, 136.02, 129.02, 127.36,
113.19, 107.81, 76.46, 58.83, 50.67, 46.65, 31.51, 27.63, 26.84, 20.62,
White solid, 68%, m.p.:174e176 ꢀC. 1H NMR (300 MHz, MeOH-
Please cite this article in press as: Tiwari KN, et al., An expeditious access of 2,50-dioxo-50,60,70,80-tetrahydro-10H-spiro[indoline-3,40-quinoline]-
30-carboxylate by reaction of isatin, ethyl cyanoacetate and enaminone in water, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.020