Versatile three-component synthesis of 2'-amino-1,2-dihydrospiro[(3H)- indole-3,4'-(4'H)-pyran]-2-ones

Article abstract of DOI:10.1007/s11172-008-0338-7

A versatile method for the synthesis of 2'-amino-1,2-dihydrospiro[(3H)- indole-3,4'-(4'H)-pyran]-2-ones has been suggested consisting in the three-component reaction of isatins, cyanoacetic acid derivatives, and α-methylenecarbonyl compounds (β-dicarbonyl compounds, activated phenols, and OH-substituted heterocycles) in ethanol in the presence of triethylamine as a catalyst. The reaction proceeds selectively to form spiro[(3H)-indole-3,4'-(4'H)-pyrans].

Full text of DOI:10.1007/s11172-008-0338-7

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2373—2380, November, 2008
2373
Versatile threeꢀcomponent synthesis
of 2´ꢀaminoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones
V. Yu. Mortikov, Yu. M. Litvinov, A. A. Shestopalov, L. A. Rodinovskaya, and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: amsh@ioc.ac.ru
A versatile method for the synthesis of 2´ꢀaminoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyran]ꢀ2ꢀones has been suggested consisting in the threeꢀcomponent reaction of isatins, cyꢀ
anoacetic acid derivatives, and αꢀmethylenecarbonyl compounds (βꢀdicarbonyl compounds,
activated phenols, and OHꢀsubstituted heterocycles) in ethanol in the presence of triethylꢀ
amine as a catalyst. The reaction proceeds selectively to form spiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyrans].
Key words: threeꢀcomponent reaction, 2´ꢀaminospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyrans],
isatin, malononitrile, cyanoacetic acid esters, βꢀdicarbonyl compounds, mꢀaminophenol, 3,5ꢀ
dihydroxysorbic acid δꢀlactone, 4ꢀhydroxycoumarin, 2ꢀpyrazolones.
method).8,9 There are known both the nonannulated2,6,7
pyrans and pyrans annulated with carboꢀ and heteroꢀ
cycles.1,3—5,8,9 Pyrans can contain at position 4 such subꢀ
stituents as alkyl10 and aryl1—4,6—9 groups (including
polyalkoxyaryl attaching to pyrans the high biological
activity3), two nitrile,5 ester, and fluoroalkyl groups.11
Recently, the pyrans spiroꢀjoined with substituted
2ꢀAminoꢀ4Hꢀpyrans are of significant importance
among sixꢀmembered oxygenꢀcontaining heterocycles.
They were used as intermediate products in the synthesis
of blood anticoagulant Varfarin,1 analogs of Tachrin, i.e.,
the cholinesterases inhibitor used for the treatment of the
Alzheimer disease.2 2ꢀAminoꢀ4Hꢀpyrans themselves exꢀ
hibit anticancer3 and antibacterial4 activity.
In most cases, methods for their preparation include
the reaction of unsaturated nitriles with αꢀmethyleneꢀ
carbonyl compounds (for example, with βꢀdiketones
and βꢀketo esters), as well as with activated phenols and
OHꢀsubstituted heterocycles, which can be formally conꢀ
sidered as completely enolized carbonyl compounds1,5—7
(the soꢀcalled twoꢀcomponent method), or the oneꢀstep
reaction of aldehydes, cyanoacetic acid derivatives, and
αꢀmethylenecarbonyl compounds (the threeꢀcomponent
3
a
b
c
d
e
f
R3
Me
Ph
OMe
PriO
ButO
R4 3 R3
Me g OCH2Ph
Me h OCH2CH2OOCC(Me)=CH2 Me
Me i OEt
Me j OMe
Me k OMe
R4
Me
Pr
CH2OMe
CH2COOMe
OCH2CH=CH2 Me
4: R5 = H (a), Me (b).
1
a
b
c
d
e
R1
H
H
H
H
H
R2
H
7ꢀMe
5ꢀMe
5ꢀCl
5ꢀBr
1
f
g
h
i
R1
H
Prn
R2
5ꢀNO2
H
H
H
H
CH2CH=CH2
CH2OH
CH2N(CH2CH2)2O
j
Z = CN (a); COOMe (b); COOBut (c); COOCH2CH2OMe (d);
COOCH2Ph (e).
8: R6 = Me (a), Et (b), But (c).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2326—2332, November, 2008.
1066ꢀ5285/08/5711ꢀ2373 © 2008 Springer Science+Business Media, Inc.

2374
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Mortikov et al.
piperidines at position 412,13 and 2´ꢀaminospiro[(3H)ꢀinꢀ
doleꢀ3,4´ꢀ(4´H)ꢀpyrans]14—16 have been synthesized for
the first time by the threeꢀcomponent method. Earlier,
the synthesis of 2´ꢀaminospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyrans] has been carried out only by the twoꢀcomponent
method.17
In continuation of our research on the synthesis of
2ꢀaminoꢀ4Hꢀpyrans, we decided to study possibilities and
limitations of the threeꢀcomponent reaction for preparing
2´ꢀaminospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyrans]. To carry
out the syntheses, we have chosen isatin (1a) and some of
its derivatives 1b—j substituted both at the nitrogen atom
Table 1. Characteristics and yields of pyrans 9—14
a
Comꢀ
pound
Yield
(%)
τ /
M.p./°C
Found
Calculated
Molecular
formula
(%)
min
C
H
N
9a
36
33
78
74
40
67
64
39
55
33
31
37
34
87
83
86
68
76
95
60
68
76
37
5
>260b
68.2
68.1
61.5
61.7
55.8
55.6
64.3
64.6
54.4
54.5
50.9
50.8
64.6
64.7
62.4
62.4
55.3
55.5
64.6
64.5
57.6
57.4
57.1
56.5
63.4
63.3
67.1
67.3
67.4
67.3
66.0
65.7
67.2
67.1
55.4
55.7
55.3
55.1
59.2
59.5
62.7
62.5
65.4
65.3
64.7
64.5
5.09
5.11
3.96
3.88
3.53
3.50
5.44
5.42
5.37
5.36
3.83
3.81
5.23
5.21
5.01
5.00
4.01
3.99
6.57
6.59
5.29
5.30
4.99
4.97
5.52
5.54
4.73
4.71
6.41
6.38
5.19
5.24
3.98
3.97
2.76
2.75
2.29
2.31
3.15
3.14
4.21
4.23
5.45
5.48
5.13
5.11
12.4
12.5
5.15
5.14
12.3
12.2
12.2
11.9
5.60
5.52
6.19
6.24
6.08
6.03
9.98
9.92
12.2
12.3
6.52
6.54
6.71
6.70
6.24
6.28
12.6
12.8
13.3
13.1
6.80
6.82
11.7
11.5
18.6
18.4
15.0
15.3
9.59
9.63
5.17
5.14
22.6
22.8
20.2
20.0
20.7
20.9
C19H17N3O3
C28H21BrN2O5
C16H12ClN3O4
C19H19N3O4
C23H27BrN2O6
C19H17BrN2O6
C25H24N2O7
C22H21N3O6
C21H18N4O8
C23H28N2O6
C20H22N2O8
C21H22N2O9
C23H24N4O5
C18H15N3O3
C23H26N2O5
C20H19N3O4
C17H12N4O2
C17H10N4O6
C20H10BrN3O4
C27H17BrN2O6
C16H13N5O2
C19H19N5O2
C18H17N5O2
9b
15
3
261—263b
>260b
9c
9d
3
>260b
9e
20
15
15
15
5
>260b
9f
253—256
154—156
199—200b
213—215b
232—234
161—163
179—181
255—257
>260b
9g
9h
9i
9j
45
45
15
15
2
9k
9l
9m
10a
10b
10c
11
30
2
>260b
237—239
>260b
5
12
5
>260b
13a
13b
14a
14b
14c
5
>260b
30
5
>260b
>260b
10
60
>260b
>260b
a The reaction time.
b With decomposition.

1,2ꢀDihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2375
and in the benzene ring, as well as a number of cyanoꢀ
acetic acid derivatives 2a—e.
The threeꢀcomponent reaction of isatins 1, cyanoꢀ
acetic acid derivatives 2, and compounds 3—8 was carried
out under the standard conditions: the starting compounds
were simultaneously mixed in ethanol followed by addiꢀ
tion of catalytic amount of triethylamine, the reaction
mixture was brought to boiling and refluxed for 2—60 min
(see Table 1).
The reaction of isatins 1a—g, cyanoacetic acid derivaꢀ
tives 2a—e, and acyclic carbonyl compounds 3a—k under
such conditions leads to nonannulated 2´ꢀaminoꢀ1,2ꢀ
dihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones
9—m (see Tables 1 and 2). In this case, no transesterifiꢀ
Acyclic diꢀ and tricarbonyl compounds 3a—k, cyclic
βꢀdiketones 4a,b, as well as mꢀaminophenol 5, 3,5ꢀdiꢀ
hydroxysorbic acid δꢀlactone 6, 4ꢀhydroxycoumarin 7,
and 2ꢀpyrazolones 8a—c have been chosen as the
αꢀmethylenecarbonyl compounds. Such a choice of
the reactants allowed us to significantly broaden the scope
of the threeꢀcomponent reaction and to study effects
of substituents and structure of the starting reagents on
the whole on regioselectivity and yields of the target
compounds.
Table 2. Spectroscopic data for pyrans 9—14
Comꢀ
pound
IR, ν/cm–1
ν(C≡N)
1H NMR, δ (J/Hz)
ν(NH,
ν(C=O)
NH2)
9a
9b
3356,
3300,
3176 br
2200
1704,
1684 br
2.05 (s, 3 H, CH3); 2.33 (s, 3 H, CH3); 4.26 (dd, 1 H, CH2CH=CH2,
J = 4.4, J = 13.2); 4.37 (dd, 1 H, CH2CH=CH2, J = 4.3, J = 13.2);
5.20 (d, 1 H, CH2CH=CH2ꢀcis, J = 9.6); 5.44 (d, 1 H,
CH2CH=CH2ꢀtrans, J = 17.0); 5.86 (m, 1 H, CH2CH=CH2);
6.84 (m, 3 H, NH2+ Ar); 7.02, 7.08, 7.23 (all m, 1 H each, Ar)
1.64 (s, 3 H, C(6)CH3); 4.67 (d, 1 H, CH2Ph, J = 13.7);
4.92 (d, 1 H, CH2Ph, J = 13.9); 6.40 (d, 1 H, H(7´), J = 8.3);
6.78 (m, 2 H, oꢀCH2 Ph); 7.07 (d, 1 H, H(6´), J = 8.77);
7.19 (m, 3 H, m,pꢀCH2Ph); 7.31 (s, 1 H, H(4´)); 7.45 (t, 2 H, mꢀCOPh,
J = 7.9); 7.58 (t, 1 H, pꢀCOPh, J = 7.8); 7.76 (d, 2 H, oꢀCOPh, J = 8.1);
7.86 (br.s, 2 H, NH2); 10.12 (br.s, 1 H, NH)
3352,
3308,
3172 br
—
1724,
1704,
1680 br
9c
9d
3448,
3290 br,
3172
3452,
3284 br,
3164 br
2200
2196
1724,
1700
2.34 (s, 3 H, СH3); 3.40 (s, 3 H, СH3O); 6.83 (d, 1 H, H(7´), J = 8.0);
7.08 (br.s, 2 H, NH2); 7.14 (s, 1 H, H(4´));
7.22 (d, 1 H, H(6´), J = 7.9); 10.42 (br.s, 1 H, NH)
0.54 (d, 3 H, (CH3)2CH, J = 6.0); 0.98 (d, 3 H, (CH3)2CH, J = 6.7);
2.21 (s, 3 H, C(7´)CH3); 2.32 (s, 3 H, C(6)CH3);
4.62 (m, 1 H, (CH3)2CH); 6.87 (m, 2 H, Ar); 7.04 (m, 3 H, Ar+NH2);
10.40 (br.s, 1 H, NH)
1720,
1700
9e
9f
3372,
3256,
3208 br
3372,
3272 br,
3204
—
—
1724,
1716,
1704
1732,
1704,
1688
1.07, 1.12 (both s, 9 H each, 2 C(CH3)3); 2.05 (s, 3 H, CH3);
6.64 (d, 1 H, H(7´), J = 8.0); 7.07 (s, 1 H, H(4´)); 7.30 (d, 1 H, H(6´),
J = 7.9); 7.72 (br.s, 2 H, NH2); 10.29 (br.s, 1 H, NH)
2.39 (s, 3 H, СH3); 3.37 (s, 3 H, СH3OOC); 4.32 (dd, 2 H, CH2OOC,
J = 7.3, J = 14.6); 5.07 (d, 1 H, transꢀCH2=CH, J = 7.3);
5.12 (s, 1 H, cisꢀCH2=CH); 5.63 (m, 2 H, CH2=CH); 6.64 (d, 1 H,
H(7´), J = 10.2); 7.01 (s, 1 H, H(4´)); 7.19 (d, 1 H, H(6´), J = 9.8);
7.69 (br.s, 2 H, NH2); 10.22 (br.s, 1 H, NH)
9g
3452,
3282 br,
3176
—
1720 br,
1700
2.13 (s, 3 H, CH3); 3.08 (m, 5 H, OCH3, OCH2);
3.82 (m, 2 H, COOCH2); 4.86 (ABꢀm, 2 H, PhCH2, J = 14.1);
6.63 (d, 1 H, Ar, J = 7.8); 6.82 (t, 1 H, Ar, J = 8.0);
6.93 (d, 1 H, Ar, J = 8.0); 7.03 (m, 2 H, Ph); 7.08 (t, 1 H, J = 8.0);
7.27 (m, 3 H, Ph); 7.72 (br.s, 2 H, NH2); 10.06 (br.s, 1 H, NH)
1.83 (s, 3 H, CH3C(=CH2)CO); 2.19 (s, 3 H, C(7´)CH3);
2.33 (s, 3H, C(6)CH3); 3.88—4.15 (m, 4 H, OCH2CH2O);
5.64 (s, 1 H, CH=C); 5.93 (s, 1 H, CH=C); 6.83 (m, 2 H, H(5´), H(6´));
6.95 (d, 1 H, H(4´)); 7.02 (br.s, 2 H, NH2); 10.31 (br.s, 1 H, NH)
1.79 (s, 3 H, CH3C(=CH2)CO); 2.40 (s, 3 H, C(6)CH3);
3.95—4.26 (m, 4 H, OCH2CH2O); 5.59 (s, 1H, CH=C);
5.86 (s, 1 H, CH=C); 6.99 (d, 1 H, H(7´), J = 8.0);
9h
9i
3380,
3284,
3156
2196
2200
1728,
1708
3432,
3334,
3304 br
1756,
1716,
1676
7.27 (br.s, 2 H, NH2); 7.99 (d, 1 H, H(4´), J = 2.4);
8.13 (dd, 1 H, H(6´), J = 8.7, J = 2.2); 11.06 (br.s, 1 H, NH)
(to be continued)

2376
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Mortikov et al.
Таблица 2 (continued)
Comꢀ
pound
IR, ν/см–1
ν(C≡N)
1H NMR, δ (J/Hz)
ν(NH,
ν(C=O)
NH2)
9j
3392,
3280,
3164
—
—
—
1724,
1716,
1704
0.91 (m, 6 H, CH3CH2 + CH3CH2CH2); 1.08 (s, 9 H, (CH3)3C); 1.62
(m, 2 H, CH3CH2CH2); 2.38 (t, 2 H, CH3CH2CH2, J = 7.7); 3.75 (m,
2 H, CH3CH2); 6.67 (d, 1 H, Ar, J = 7.8); 6.88 (m, 2 H, Ar);7.09 (d,
1 H, Ar, J = 7.2); 7.60 (br.s, 2 H, NH2); 10.03 (br.s, 1 H, NH)
3.08 (m, 5 H, OCH3, OCH2); 3.26 (s, 3 H, OCH3); 3.33 (s, 3 H, OCH3);
3.81 (m, 2 H, COOCH2); 4.15 (ABꢀm, 2 H, C(6´)—CH2, J = 14.2); 6.72
(d, 1 H, Ar, J = 7.6); 6.85 (t, 1 H, Ar, J = 8.0); 6.92 (d, 1 H, Ar, J = 7.8);
7.10 (t, 1 H, Ar, J = 8.0); 7.76 (br.s, 2 H, NH2); 10.12 (br.s, 1 H, NH)
3.14 (m, 5 H, CH3OCH2CH2); 3.35 (s, 3 H, CH3OOC); 3.55 (ABꢀm, 1 H,
C(6)—CH2COO, J = 16.0); 3.71 (ABꢀm, 1 H, C(6)—CH2COO, J = 15.8);
3.72 (s, 3 H, CH3OOC); 3.83 (m, 2 H, CH3OCH2CH2); 6.71 (d, 1 H,
Ar, J = 7.9); 6.82 (t, 1 H, Ar, J = 7.8); 6.92 (d, 1 H, Ar, J = 7.9);
7.06 (t, 1 H, Ar, J = 7.9); 7.61 (br.s, 2 H, NH2); 9.95 (br.s, 1 H, NH)
2.49 (s, 3 H, СH3); 2.62 (m, 4 H, 2 CH2 N(CH2CH2O)); 3.59 (m, 4 H,
2CH2 N(CH2CH2O)); 4.22 (d, 1 H, CH2OOC, J = 11.4); 4.25 (s, 2 H,
NCH2N); 4.46 (d, 1 H, CH2OOC, J = 11.5); 4.98 (d, 1 H, transꢀCH2=CH,
J = 17.6); 5.03 (s, 1 H, cisꢀCH2=CH); 5.43 (m, 2 H, CH2=CH);
6.87 (br.s, 2 H, NH2); 7.05 (m, 3 H, Ar); 7.26 (t, 1 H, Ar, J = 7.9)
2.02 (m, 2 H, CH2); 2.27 (m, 5 H, CH2 + CH3); 2.71 (m, 2 H, CH2);
6.68 (d, 1 H, H(7´), J = 8.4); 6.76 (s, H(4´));
9k
9l
3448,
3290 br,
3172
1728,
1720,
1704
3428,
3304,
3176
1740,
1708,
1676
9m
3316 br,
3176 br
2200
1716,
1704
10a
10b
3360 br,
3144 br
2200
—
1712,
1680
6.95 (m, 3 H, H(6´) + NH2); 10.18 (br.s, 1 H, NH)
0.93, 0.98 (both s, 3 H each, CH3); 1.07 (s, 9 H, C(CH3)3);
2.04 (ABꢀsystem, 2 H, CH2, J = 18.3); 2.51 (overlaps with the signal
for DMSO, АВꢀsystem, 2 H, CH2, J = 18.0); 6.63 (d, 1 H, Ar, J = 8.6);
6.75 (m, 2 H, Ar); 7.02 (t, 1 H, Ar, J = 8.5); 7.60 (br.s, 2 H, NH2);
9.88 (br.s, 1 H, NH)
3372,
3256,
3208 br
1724,
1716,
1680
10c
3400 br*,
3332,
3244,
2200
1732,
1680
1.02, 1.05 (both s, 3 H, CH3); 2.12 (s, 2 H, CH2); 2.57 (s, 2 H, CH2);
5.02 (m, 1 H, NCH2O); 5.13 (m, 1 H, NCH2O); 6.15 (t, 1 H, Ar, J = 8.0);
6.95—7.13 (m, 5 H, Ar + NH2 + OH); 7.24 (t, 1 H, Ar, J = 8.5)
3204
11
12
3468,
3364,
3296 br
3456,
3424,
2184
2200
1720 br
5.05 (br.s, 2 H, C(7)—NH2); 6.18 (m, 2 H, H(5´), H(6´));
6.27 (s, 1 H, H(8)); 6.77 (br.s, 2 H, C(2)—NH2); 6.85—6.99 (m, 3 H, Ar);
7.19 (m, 1 H, Ar), 10.25 (br.s, 1 H, NH)
2.26 (s, 3 H, CH3); 6.34 (s, 1 H, H(8´)); 7.07 (d, 1 H, H(7), J = 9.3);
7.41 (br.s, 2 H, NH2); 8.12 (s, 1 H, H(4));
1752,
1700
3356,
8.19 (d, 1 H, H(6´), J = 9.1); 11.17 (br.s, 1 H, NH)
3332 br
3432 br,
3300,
3172
3440 br,
3296,
13a
13b
2200
—
1716 br,
1692
6.83 (d, 1 H, Ar, J = 9.5); 7.39 (dd, 1 H, Ar, J = 2.1, J = 9.0);
7.53 (m, 3 H, Ar); 7.67 (br.s, 2 H, NH2); 7.78 (t, 1 H, Ar, J = 7.9);
7.96 (d, 1 H, Ar, J = 8.1); 10.77 (br.s, 1 H, NH)
4.76 (d, 1 H, CH2Ph, J = 14.2); 5.01 (d, 1 H, CH2Ph, J = 13.6);
6.59 (d, 1 H, Ar, J = 8.2); 6.83 (m, 2 H, Ar); 7.22 (m, 3 H, CH2Ph);
7.29 (m, 2 H, CH2Ph); 7.44 (d, 1 H, Ar, J = 9.1); 7.52 (t, 1 H, Ar,
J = 8.1); 7.73 (t, 1 H, Ar, J = 8.5); 8.02 (d,1 H, Ar, J = 8.2);
8.12 (br.s, 2 H, NH2); 10.50 (br.s, 1 H, NH)
1720 br,
1688
3168
14a
14b
14c
3404 sh,
3316 br,
3128 br
3316 br,
3172 br
2200
2200
2204
1712
1.56 (s, 3 H, C(3´)CH3); 2.27 (s, 3 H, C(7)CH3); 6.88 (m, 2 H,
H(5), H(6)); 7.06 (d, 1 H, H(4), J = 7.3); 7.13 (br.s, 2 H,
NH2); 10.58 (br.s, 1 H, H(1)); 12.22 (br.s, 1 H, H(1´))
0.66 (t, 3 H, CH3CH2, J = 7.2); 0.94 (t, 3 H, CH3CH2CH2N, J = 7.3);
1.66 (m, 2 H, CH3CH2CH2N); 1.83 (k, 2 H, CH3CH2, J = 7.2); 3.68 (m,
2 H, CH3CH2CH2N); 7.13 (m, 6 H, Ar + NH2); 12.26 (br.s, 1 H, NH)
0.91 (s, 9 H, C(CH3)3); 6.80 (br.s, 2 H, NH2); 6.88 (m, 1 H, Ar);
6.99 (m, 2 H, Ar); 7.20 (m, 1 H, Ar); 10.25 (br.s, 1 H, H(2´));
12.06 (br.s, 1 H, H(1))
1700 br
1720 br
3460,
3308 br,
3180 br
* ν(OH, NH, NH2).

1,2ꢀDihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2377
cation of the ester groups of the cyanoacetic ester or
acetoacetic ester fragments is observed. The low yields
of compounds 9a,b can be explained by the high ability of
acyclic βꢀdiketones (in contrast to βꢀketo esters) to the
side Knoevenagel reaction with malononitrile 2a, whereas
in the case of compounds 9h,j,k—m, by steric hindrance
for the cyclization created by bulky alkyl groups.
The reaction of isatins 1a,c,i, cyanoacetic acid derivaꢀ
tives 2a,c, and cyclic βꢀdicarbonyl compounds 4a,b leads
to 2ꢀaminoꢀ1´,2´,5,6,7,8ꢀhexahydrospiro[(4H)ꢀ1ꢀbenzoꢀ
pyranꢀ4,3´ꢀ(3´H)ꢀindole]ꢀ2´,5ꢀdiones 10a—c. In contrast
to the reactions of βꢀketo esters, the reactions of cycloꢀ
hexanedione 4a and dimedone 4b proceed much readily,
and sometimes (for example, with malononitrile 2a,
Scheme 1
9
a
b
c
d
e
f
g
h
i
R1
R2
H
R3
COMe
COPh
COOMe
R4
Z
CN
COOCH2Ph
CN
CN
COOBut
COOMe
COOCH2CH2OMe
CN
10 R1
R2
5ꢀMe
H
R5
H
Me
Me
Z
CN
COOBut
CN
CH2CH=CH2
Me
Me
Me
Me
Me
Me
Me
a
b
c
H
H
H
H
H
H
H
H
H
H
H
H
H
5ꢀBr
5ꢀCl
7ꢀMe COOPri
5ꢀBr
5ꢀBr
H
7ꢀMe COOCH2CH2OOCC(Me)=CH2 Me
5ꢀNO2 COOCH2CH2OOCC(Me)=CH2 Me
H
H
H
CH2OH
H
COOBut
COOCH2CH=CH2
COOCH2Ph
13: Z = CN (a), COOCH2Ph (b).
14 R1 R2 R6
a
b
c
H
Pr
H
7ꢀMe Me
H
H
CN
Et
But
j
k
l
COOEt
COOMe
COOMe
COOCH2CH=CH2
Prn
CH2OMe
CH2COOMe COOCH2CH2OMe
Me CN
COOBut
COOCH2CH2OMe
m
CH2N(CH2CH2)2OH

2378
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Mortikov et al.
Z = CN), the target product precipitates from the refluxꢀ
ing reaction mixture. The reactions of isatins with
mꢀaminophenol 5, 3,5ꢀdihydroxysorbic acid δꢀlactone 6,
and 4ꢀhydroxycoumarin 7 also proceed when heated for a
short time (except the reaction with 2e, Z = COOCH2Ph)
and resulted in 2ꢀaminoꢀ3ꢀcyanoꢀ1´,2´ꢀdihydrospiroꢀ
[(4H)ꢀ1ꢀbenzopyranꢀ4,3´ꢀ(3´H)ꢀindole]ꢀ2´ꢀone (11),
2´ꢀaminoꢀ3´ꢀcyanoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ
(4´H)ꢀpyrano[4,3ꢀb]pyran]ꢀ2,5´ꢀdione (12), and 2´ꢀaminoꢀ
1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyranoꢀ
[3,2ꢀc]chromene]ꢀ2,5´ꢀdiones 13a,b. 3ꢀAlkylpyrazolinꢀ
5ꢀones 8a,b possess high nucleophilicity and in the reacꢀ
tions with malononitrile 2a and isatins 1a,b,g easily form
6´ꢀaminoꢀ5´ꢀcyanoꢀ1´,2´ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ
(4´H)ꢀpyrano[2,3ꢀc]pyrazol]ꢀ2ꢀones 14a,b. In the case of
3ꢀtertꢀbutylpyrazolinꢀ5ꢀone 8c, the reaction proceeds with
difficulties: a prolonged heating is required (60 min) with
the yield of pyran 14c reducing to 37%. Such a reactivity
of compound 8c can be explained by the influence of
bulky tertꢀbutyl group creating steric hindrance during
formation of the spiroꢀjoined pyran ring. The formation
of different classes of 2´ꢀaminoꢀ1,2ꢀdihydrospiro[(3H)ꢀ
indoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones 9—14 is illustrated in
Scheme 1.
All these reactions demonstrate the high regioselecꢀ
tivity. From several possible directions of the reaction,
only one is implemented in practice, viz., the formation
of 2ꢀaminoꢀ4Hꢀpyran. This can be explained by the strict
sequence of the reactions taken place: the Knoevenagel
reaction → the Michael reaction → the Thorpe—Ziegler
reaction. Such a sequence of the reaction course is proꢀ
vided by the difference in reactivity of the CHꢀacids
(cyanoacetic acid derivatives 2 and αꢀmethylenecarbonyl
compounds 3 and 4) toward isatins 1 (Scheme 2).
Apparently, in the first step cyanoacetic acid derivaꢀ
tive 2 undergoes the Knoevenagel condensation with isatin
1 giving rise to unsaturated nitrile 15. Further, the Michael
reaction takes place between the unsaturated nitrile and
carbonyl compound 3 or 4 to form adduct 16. Finally, the
intramolecular cyclization occurs in the Michael adduct
16. 2´ꢀAminoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyran]ꢀ2ꢀones 9 and 10 are formed, apparently, from the
intermediate iminopyrans 17 by the [1,3]ꢀsigmatropic proꢀ
ton shift. The reaction with carbonyl compounds 3 and 4,
Scheme 2
Conditions: i, the Knoevenagel reaction; ii, the Michael reaction; iii, the Thorpe—Ziegler reaction.

1,2ꢀDihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ2ꢀones Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2379
by thinꢀlayer chromatography (TLC) on Silufol UVꢀ254 plates,
the light petroleum—acetone (5 : 3) mixture was used as the
eluent with the iodine vapors being the visualization agent.
Melting points of compounds obtained were measured on a
Koffler apparatus. Elemental analysis was performed on a Perkinꢀ
Elmer 2400 microanalyzer. Commercially available starting
compounds 1—8 (Lancaster) were used in the synthesis.
2´ꢀAminoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyran]ꢀ
2ꢀones 9a—m (general procedure). Isatin 1a—j (6 mmol),
cyanoacetic acid derivative 2a—e (6 mmol), and one of the
βꢀdicarbonyl compounds 3a—k (7 mmol) were dissolved in
ethanol (20 mL) with heating followed by addition of triethylꢀ
amine (0.3 mL). The reaction mixture was refluxed from 2 to
45 min (TLC monitoring, see Table 1) and left for 16 h at 4 °C
for crystallization. A precipitate was filtered off, washed with
ethanol (2×5 mL) and light petroleum (5 mL) and recrystallized
from ethanol. The products obtained were dried in a drying oven
at 60—70 °C.
2ꢀAminoꢀ1´,2´,5,6,7,8ꢀhexahydrospiro[(4H)ꢀ1ꢀbenzopyranꢀ
4,3´ꢀ(3´H)ꢀindole]ꢀ2´,5ꢀdiones 10a—c (general procedure).
Isatin 1a—j (6 mmol), cyanoacetic acid derivative 2a,c (6 mmol),
and one of the βꢀdicarbonyl compounds 4a,b (7 mmol) were
dissolved in ethanol (20 mL) with heating followed by addition
of triethylamine (0.3 mL). The reaction mixture was refluxed
from 2 to 30 min (TLC monitoring, see Table 1) and left for 16 h
at 4 °C for crystallization. A precipitate was filtered off, washed
with ethanol (2×5 mL) and light petroleum (5 mL) and recrysꢀ
tallized from nitromethane. The products obtained were dried in
a drying oven at 60—70 °C.
2ꢀAminoꢀ3ꢀcyanoꢀ1´,2´ꢀdihydrospiro[(4H)ꢀ1ꢀbenzopyranꢀ
4,3´ꢀ(3´H)ꢀindole]ꢀ2´ꢀone (11). Isatin 1a (6 mmol), malonoꢀ
nitrile 2a (6 mmol), and mꢀaminophenol 5 (7 mmol) were
dissolved in ethanol (20 mL) with heating followed by addition
of triethylamine (0.3 mL). The reaction mixture was refluxed for
5 min (TLC monitoring) and treated further as described
for compounds 10.
2´ꢀAminoꢀ3´ꢀcyanoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyrano[4,3ꢀb]pyran]ꢀ2,5´ꢀdione (12). Isatin 1f (6 mmol), malonoꢀ
nitrile 2a (6 mmol), and 3,5ꢀdihydroxysorbic acid δꢀlactone 6
(7 mmol) were dissolved in ethanol (20 mL) with heating
followed by addition of triethylamine (0.3 mL). The reaction
mixture was refluxed for 5 min (TLC monitoring) and treated
further as described for compounds 10.
as well as with mꢀaminophenol 5 and heterocycles 6—8,
by all appearances, proceeds through the analogous
sequence of steps. When the adduct has both a nitrile and
an ester groups, the nucleophilic addition of the enolic
oxygen takes place selectively at the nitrile rather than the
ester group to form 2ꢀaminopyrans.1—17 Probably, this
results from both the higher electrophilicity of the nitrile
group and the lower steric hindrance for the nucleophilic
addition than in the case of the ester group. Possibly,
when two nitrile groups are present, the same factors
operate to reduce the reaction time and to increase the
yields of pyrans.
All pyrans 9—14 are colorless or light cream crystalline
compounds with high melting points. Their structures were
1
confirmed by IR and H NMR spectroscopy. In the IR
spectra, an absorption in the region 3156—3444 cm–1 is
observed which corresponds to the stretching vibrations
of the NH and NH2 groups. The assignment of bending
vibrations of the NH and NH2 groups is difficult since
there are several intensive overlapping absorption bands
in the region 1660—1600 cm–1 (the double bonds). In the
spectra of compounds 9a,c,d,h,i,m, 10a,c, 11, 12, 13a,
and 14a—c, the intensive absorption band in the region
2204—2184 cm–1 confirms the presence in the molecule
of the nitrile group conjugated with the enamine fragꢀ
ment. In the region 1756—1680 cm–1, there are intensive
absorption bands of the carbonyl group (the carbonyl
groups of the substituents and the CO—N group of the
1
oxindole fragment). In the H NMR spectra of all the
compounds, a broad singlet at 6.84—7.76 ppm related to
the pyran C(2´)—NH2 group and the signals for the aroꢀ
matic protons in the region 6.60—8.19 ppm are observed.
In the spectra of all the compounds unsubstituted at the
oxindole nitrogen (except 9a,m, 10c, and 14b), the signal
for the NH appears in the region 9.88—11.17 ppm as a
broad singlet. (a typical value is 10.10—10.30 ppm).
Chemical shifts of other signals (the protons of the alkyl
substituents, the aryl protons, and the NH of the pyrazole
fragment) also confirm the structures of pyrans 9—14
obtained (see Table 1, 2). In conclusion, in the present
work it was found that a simple and convenient threeꢀ
component reaction of isatins, cyanoacetic acid derivaꢀ
tives, and αꢀmethylenecarbonyl compounds is a versatile
method for the synthesis of 2´ꢀaminoꢀ1,2ꢀdihydrospiroꢀ
[indoleꢀ3,4´ꢀ(4H)ꢀpyran]ꢀ2ꢀones, which has high synꢀ
thetic potential.
2´ꢀAminoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀpyranoꢀ
[3,2ꢀc]chromene]ꢀ2,5ꢀdiones 13a,b. Isatin 1e (6 mmol), malonoꢀ
nitrile 2a (6 mmol), and 3,5ꢀdihydroxysorbic acid δꢀlactone 6
(7 mmol) were dissolved in ethanol (20 mL) with heating
followed by addition of triethylamine (0.3 mL). The reaction
mixture was refluxed for 5 (13a) or 30 min (13b) (TLC moniꢀ
toring) and treated further as described for compounds 10.
6´ꢀAminoꢀ5´ꢀcyanoꢀ1,2ꢀdihydrospiro[(3H)ꢀindoleꢀ3,4´ꢀ(4´H)ꢀ
pyrano[2,3ꢀc]pyrazol]ꢀ2´ꢀones 14a—c (general procedure). One
of isatins 1a,b,g (6 mmol), malononitrile 2a (6 mmol), and
one of pyrazolones 8a—c (7 mmol) were dissolved in ethanol
(20 mL) with heating followed by addition of triethylamine
(0.3 mL). The reaction mixture was refluxed from 5 to 60 min
(TLC monitoring, see Table 1) and treated further as described
for compounds 10.
Experimental
1H NMR spectra were recorded on a Bruker WMꢀ250 and
Bruker AMꢀ300 spectrometers (250 and 300 MHz, respectively)
in DMSOꢀd6, chemical shifts are given in the δ scale relatively
to SiMe4, IR spectra were recorded on a Specord M82 Fourier
spectrometer in KBr pellets (1 : 200 w/w). Monitoring of the
processes and purities of compounds synthesized was performed
The constants, yields, and spectral characteristics of comꢀ
pounds 9—14 obtained are given in Tables 1 and 2.

2380
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Mortikov et al.
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Received March 4, 2008;
in revised form May 13, 2008