tert-Amino effect in heterocyclic chemistry. Synthesis of hydrogenated spiro derivatives of quinolines

Article abstract of DOI:10.1023/B:RUCB.0000042280.71728.d0

A new method was developed for the one-step synthesis of spiro derivatives of fused quinolines by the reactions of ortho-amino derivatives of benzaldehyde with Meldrum's acid, cyclohexane-1,3-dione, or N,N′-disubstituted barbituric acids.

Full text of DOI:10.1023/B:RUCB.0000042280.71728.d0

1240
Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1240—1247, June, 2004
tertꢀAmino effect in heterocyclic chemistry.
Synthesis of hydrogenated spiro derivatives of quinolines✾
E. V. D´yachenko,a T. V. Glukhareva,a E. F. Nikolaenko,a A. V. Tkachev,b and Yu. Yu. Morzherina
ꢀ
aUrals State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Eꢀmail: morjerine@htf.ustu.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Eꢀmail: atkachev@nioch.nsc.ru
A new method was developed for the oneꢀstep synthesis of spiro derivatives of fused
quinolines by the reactions of orthoꢀamino derivatives of benzaldehyde with Meldrum's acid,
cyclohexaneꢀ1,3ꢀdione, or N,N´ꢀdisubstituted barbituric acids.
Key words: tertꢀamino effect, cyclization, nitrogenꢀcontaining heterocycles, spiro derivaꢀ
tives, quinoline.
The term "tertꢀamino effect" was proposed by
MethꢀCohn and Suschitzky1 to generalize cyclization
reactions of certain derivatives of orthoꢀsubstituted
N,Nꢀdialkylanilines.2 Cyclizations occurring at the αꢀcarꢀ
bon atom in the dialkylamino group were described for
compounds with an unsaturated orthoꢀsubstituent includꢀ
ing at least one heteroatom (nitroso, nitro, azo, azoꢀ
methino, imino, or carbonyl groups).3—9 It was found
that N,Nꢀdialkylanilines containing vinyl substituents in
the ortho position also undergo cyclization.10 These reacꢀ
tions provide an original way of forming C—C bonds with
the practically nonactivated NCH2 group.11,12
The starting aminobenzaldehydes 1a—e were prepared
in 60—80% yields by the replacement of the fluorine atom
in 2ꢀfluorobenzaldehyde with cyclic amines as nucleoꢀ
philes (Scheme 1).
Knoevenagel condensation of 2ꢀdialkylaminobenzꢀ
aldehydes 1a—e with cyclohexanedione (refluxing in toluꢀ
ene for 15 h) afforded individual compounds 2a—e
(Scheme 2).
Scheme 2
The aim of the present study was to develop a method
for the synthesis of spiro derivatives of heterocycles based
on the reactions proceeding by the mechanism of the
"tertꢀamino effect". Earlier, we have proposed13 to use the
strategy of the "tertꢀamino effect" for the synthesis of spiro
compounds starting from oꢀaminobenzaldehyde and cyꢀ
clic CHꢀactive compounds, viz., cyclic βꢀdiketo comꢀ
pounds, such as cyclohexaneꢀ1,3ꢀdione, Meldrum's acid,
and barbituric acid derivatives.
Scheme 1
i. Toluene, ∆.
The mass spectra of the reaction products (Table 1)
have a peak corresponding to the calculated weight of
X = O (a); NMe (b); (CH2)n (c—e), n = 1 (c), 2 (d), 0 (e)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1191—1198, June, 2004.
1066ꢀ5285/04/5306ꢀ1240 © 2004 Plenum Publishing Corporation

Synthesis of spiro derivatives of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1241
Table 1. Physicochemical characteristics of fused quinolines 2, 4, 6, and 7a—e
Compound
Yield M.p. Found
. Molecular
formula
IR (KBr),
ν/cm–1
MS,
m/z
(%)
/°C Calculated
N (%)
(Irel (%))
CH
C=O
1,2,4,4a,5,6ꢀHexahydrospiro[[1,4]oxazino[4,3ꢀa]ꢀ
quinolineꢀ5,2´ꢀcyclohexane]ꢀ1´,3´ꢀdione (2a)
2,3,4,4a,5,6ꢀHexahydroꢀ6Hꢀspiro[benzo[c]
quinolizineꢀ5,2´ꢀcyclohexane]ꢀ1´,3´ꢀdione (2c)
5,6,6a,7,8,9,10,11ꢀOctahydroꢀ5Hꢀspiro[azepino
[1,2ꢀa]quinolineꢀ6,2´ꢀcyclohexane]ꢀ1´,3´ꢀdione (2d)
1,2,3,3a,4,5ꢀHexahydrospiro[pyrrolo[1,2ꢀa]ꢀ
quinolineꢀ4,2´ꢀcyclohexane]ꢀ1´,3´ꢀdione (2e)
2,2ꢀDimethylꢀ1´,2´,4´,4a´,5´,6´ꢀhexahydrospiroꢀ
[[1,3]dioxaneꢀ5,5´ꢀ[1,4]oxazino[4,3ꢀa]quinoline]−
4,6ꢀdione (4a)
2,2,3´ꢀTrimethylꢀ2´,3´,4´,4a´ꢀtetrahydroꢀ6Hꢀ
spiro[[1,3]dioxaneꢀ5,5´ꢀpyrazino[1,2ꢀa]quinoline]−
4,6ꢀdione (4b)
2´,2´ꢀDimethylꢀ2,3,4,4a,5,6ꢀhexahydroꢀ6Hꢀ
spiro[benzo[c]quinolizineꢀ5,5´ꢀ[1,3]dioxane]ꢀ
4´,6´ꢀdione (4c)
2´,2´ꢀDimethylꢀ5,6,6a,7,8,9,10,11ꢀoctahydroꢀ5Hꢀ
spiro[azepino[1,2ꢀa]quinolineꢀ6,5´ꢀ[1,3]dioxane]ꢀ
4´,6´ꢀdione (4d)
2,2ꢀDimethylꢀ1´,2´,3´,3a´,4´,5´ꢀhexahydrospiroꢀ
[[1,3]dioxaneꢀ5,4´ꢀpyrrolo[1,2ꢀa]quinoline]ꢀ
4,6ꢀdione (4e)
1´,3´ꢀDimethylꢀ1,2,4,4a,5,6ꢀhexahydrospiroꢀ
[[1,4]oxazino[3,4ꢀa]quinolineꢀ5,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (6a)
1´,3,3´ꢀTrimethylꢀ2,3,4,4aꢀtetrahydroꢀ6Hꢀ
spiro[pyrazino[1,2ꢀa]quinolineꢀ5,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (6b)
1´,3´ꢀDimethylꢀ2,3,4,4a,5,6ꢀhexahydroꢀ6Hꢀ
spiro[benzo[c]quinolizineꢀ5,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (6c)
1´,3´ꢀDimethylꢀ5,6,6a,7,8,9,10,11ꢀoctahydroꢀ5Hꢀ
spiro[azepino[1,2ꢀa]quinolineꢀ6,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (6d)
1,3ꢀDimethylꢀ1´,2´,3´,3a´,4´,5´ꢀhexahydrospiroꢀ
[pyrimidineꢀ5,4´ꢀpyrrolo[1,2ꢀa]quinoline]ꢀ
2,4,6ꢀtrione (6e)
1´,3´ꢀDiphenylꢀ1,2,4,4a,5,6ꢀhexahydrospiroꢀ
[[1,4]oxazino[3,4ꢀa]quinolineꢀ5,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (7a)
3ꢀMethylꢀ1´,3´ꢀdiphenylꢀ2,3,4,4aꢀtetrahydroꢀ
6Hꢀspiro[pyrazino[1,2ꢀa]quinolineꢀ
5,5´ꢀpyrimidine]ꢀ2´,4´,6´ꢀtrione (7b)
1´,3´ꢀDiphenylꢀ2,3,4,4a,5,6ꢀhexahydroꢀ6Hꢀ
spiro[benzo[c]quinolizineꢀ
5,5´ꢀpyrimidine]ꢀ2´,4´,6´ꢀtrione (7c)
1´,3´ꢀDiphenylꢀ5,6,6a,7,8,9,10,11ꢀoctahydroꢀ5Hꢀ
spiro[azepino[1,2ꢀa]quinolineꢀ6,5´ꢀpyrimidine]ꢀ
2´,4´,6´ꢀtrione (7d)
73
66
100
150
5.00
4.91
5.08
4.94
4.70
4.71
5.26
5.20
4.60
4.41
C17H19NO3
C18H21NO2
C19H23NO2
C17H19NO2
С17Н19NO5
3010,
2910
3010,
2915
3010,
2910
3000,
2915
3000,
2915
1740,
1725
1735,
1725
1740,
1725
1740,
1725
1740,
1725
285
(90)
283
(85)
297
(95)
175
(96)
317
(64)
73 149—150
60 100—102
36
32
68
53
130
170
150
170
8.09
8.48
С18Н22N2O4
С18Н21NO4
С19Н23NO4
С17Н19NO4
С17Н19NO5
С18Н22N4O3
С18Н21N3O3
С19Н23N3O3
С17Н19N3O3
С27Н23N3O4
С28Н26N4O3
С28Н25N3O3
С29Н27N3O3
С27Н23N3O3
3000,
2940
1740,
1725
330
(100)
4.82
4.44
3010,
2915
1735,
1725
315
(95)
4.40
4.25
3000,
2940
1740,
1725
329
(100)
56 139—141
5.12
4.65
2975,
2940
1780,
1730
301
(81)
36
55
30
33
60
50
25
130
180
190
200
160
120
150
4.60
4.41
3000,
2915
1740,
1725,
1680
1760,
1700,
1680
1735,
1725,
1685
1740,
1725,
1695
1745,
1680,
1660
1740,
1725,
1695
1760,
1700,
1685
1735,
1725,
1685
317
(64)
16.33
16.37
3000,
2940
342
(100)
12.84
12.84
3010,
2915
327
(100)
12.60
12.31
3000,
2940
341
(100)
13.77
13.41
3020,
2955
313
(100)
9.59
9.27
3000,
2915
453
(100)
11.90
12.00
3060,
3000,
2940
3090,
3010,
2915
3000,
2900,
2750
3035,
2985,
2920
466
(100)
42 177—180
9.28
9.31
451
(100)
60
40
200
200
9.20
9.03
1740,
1725,
1690
1750,
1695,
1685
465
(100)
1,3ꢀDiphenylꢀ1´,2´,3´,3a´,4´,5´ꢀhexahydrospiroꢀ
[pyrimidineꢀ5,4´ꢀpyrrolo[1,2ꢀa]quinoline]−
2,4,6ꢀtrione (7e)
9.57
9.60
437
(90)

Table 2. 1H NMR spectra of fused quinolines 2, 4, 6, and 7a—e
Comꢀ
pound
δ, J/Hz
H(1)
H(2)
H(3)
H(4)
ArC(5)H
3.03 (d,
ArC(5)H
NC(6)H
NC(7)H
NC(8)H
Other signals
2a*
6.85 (d,
J = 8.0)
7.01
(dd,
6.66
(dd,
7.06 (d,
J = 7.4) J = 16.8)
2.69 (d,
J = 16.8)
4.43
(dm,
3.98
(ddd,
2.99
(ddd,
2.00—2.10 (m, 1 H, C(5´)H); 2.40 (dddd,
1 H, C(4´)H, J = 15.1, 3.6, 2.1, 4.9);
J = 8.2,
8.0)
J = 7.4,
8.2)
J = 9.6)
J = 12.6,
9.1, 1.6)
J = 12.6,
8.6, 8.6)
2.56 (dddd, 1 H, C(6´)H, J = 15.0, 3.6,
2.2, 5.6); 3.30—3.40 (m, 6 H, C(9)H,
C(6´)H, C(4´)H); 3.57 (ddd, 1 H, C(10)H,
J = 9.1, 8.4, 2.2)
2с*
6.78 (d,
J = 8.0)
6.97
(dd,
J = 8.5,
8.0)
6.62
(dd,
J = 7.4,
8.5)
7.04 (d,
J = 7.4) J = 16.6)
3.11 (d,
2.66 (d,
J = 16.6)
4.38
(dm,
J = 9.9)
3.99
(dm,
J = 14.2)
3.12
(ddd,
J = 14.2,
8.6, 2.6)
1.02—1.15 (m, 2 H, 2 C(X)H); 1.25—1.41 (m,
2 H, C(5´)H, C(10)H); 1.48—1.56 (m, 1 H,
C(5´)H); 1.65—1.82 (m, 2 H, C(9)H, C(10)H);
2.05—2.15 (m, 1 H, C(5´)H); 2.29 (dm, 1 H,
C(4´)H, J = 13.7); 2.44 (dm, 1 H, C(6´)H,
J = 14.6); 3.06 (ddd, 1 H, C(9)H, J = 12.0,
5.6, 2.0); 3.30—3.40 (m, 2 H, C(6´)H, C(4´)H)
1.30—1.70 (m, 8 H, C(10)H, C(9)H, 2 C(X)H2,
C(5´)H2); 2.05—2.25 (m, 2 H, C(10)H, C(9)H);
2.51 (dddd, 1 H, C(4´)H, J = 14.4, 4.4, 2.7, 1.5);
2.62 (dddd, 1 H, C(6´)H, J = 14.6, 4.4, 2.8, 1.5);
2.80 (ddd, 1 H, C(6´)H, J = 14.1, 14.1, 6.6);
3.06 (ddd, 1 H, C(4´)H, J = 15.2, 11.3, 5.6)
2d** 6.53 (d,
J = 8.2)
7.00
(dd,
J = 8.2,
7.8)
6.67
(dd,
J = 7.4,
7.4)
7.12 (d,
J = 7.4) J = 17.3)
3.30 (d,
2.92 (d,
J = 17.3)
4.06
(dd,
J = 9.1,
5.1)
3.98
(ddd,
J = 15.2,
5.1, 1.6)
3.03
(ddd,
J = 14.1,
9.1, 6.4)
2e* 6.40—6.47
7.00
(dd,
J = 8.0,
7.3)
6.40—6.47 6.92 (d,
3.36 (d,
2.85 (d,
J = 15.2)
3.82
(dd,
J = 10.1,
5.8)
3.49
(dd,
J = 7.9,
6.7)
1.50—2.21 (m, 6 H, 3 CH2);
(m)
(m)
J = 7.9) J = 15.2)
2.25 (ddd, 1 H, С(4´)Н, J = 15.2, 5.6, 4.8);
2.54 (ddd, 1 H, С(6´)Н, J = 15.0, 4.9, 4.3);
2.75—3.10 (m, 3 H, С(6´)H, C(4´)Н, NC(8)H)
4a** 7.01 (d,
J = 7.4)
7.18
(dd,
J = 8.0,
7.4)
6.80
(dd,
J = 8.0,
8.3)
6.89
(d,
J =
8.3)
3.61 (d,
J = 16.8)
2.99 (d,
J = 16.8)
3.92
(dd,
J = 11.7,
3.2)
3.86
(dm,
J = 12.2)
3.69
(ddd,
J = 11.6,
12.2, 2.7)
1.74, 1.77 (both s, 2 H each, Me);
2.70 (ddd, 1 H, C(9)H, J = 11.6, 10.2, 3.6);
3.28 (dd, 1 H, C(10)H, J = 11.0, 10.6);
3.46 (dd, 1 H, C(9)H, J = 10.2, 3.1);
3.77 (ddd, 1 H, C(10)H, J = 11.0, 3.1, 2.9)
(to be continued)

Table 2 (continued)
Comꢀ
δ, J/Hz
pound
H(1)
H(2)
H(3)
H(4)
ArC(5)H
3.35 (d,
ArC(5)H
NC(6)H
NC(7)H
NC(8)H
Other signals
4b** 7.00 (d,
J = 7.4)
7.08
(dd,
J = 8.4,
7.4)
6.70
(dd,
J = 8.0,
8.4)
6.93 (d,
J = 8.0) J = 17.0)
3.29 (d,
J = 17.0)
3.92
(dd,
J = 12.4,
4.0)
1.74 (s, 3 H, Me); 1.75 (dd, 1 H, CН, J = 10.7, 4.5); 1.77 (s, 3 H, Me);
2.00 (ddd, 1 H, СН, J = 11.8, 4.0, 3.1); 2.20 (s, 3 H, NMe); 2.63 (d, 1 H,
СН, J = 10.8); 2.80 (d, 1 H, СН, J = 9.9); 2.82 (dd, 1 H, СН, J = 11.2, 3.8);
3.41 (dd, 1 H, CН, J = 10.8, 3.1)
4с*
6.91 (d,
J = 8.0)
6.66
(ddd,
7.05
(ddd,
6.99
(dd,
3.30 (d,
J = 16.9)
3.25 (d,
J = 16.9)
4.05
(dm,
3.42
(dd,
2.78
(ddd,
1.22 (ddd, 1 H, СН, J = 11.7, 5.8, 4.0);
1.38—1.66 (m, 4 H, 4 CH);
J = 8.5,
8.0, 1.2) 7.8, 1.4)
J = 8.5,
J = 7.8,
1.2)
J = 12.3)
J = 12.2,
2.4)
J = 12.2,
3.2, 2.9)
1.74—1.78 (m, 1 H, СН);
1.76, 1.77 (both s, 2 H each, Me)
4d** 6.53 (d,
J = 8.2)
7.00
(dd,
6.67
(dd,
7.12 (d,
J = 7.4) J = 17.3)
3.25 (d,
3.15 (d,
J = 17.3)
3.42—3.65 3.29—3.38
1.30—1.70 (m, 8 H, C(10)H, C(9)H, 2 C(X)H2, C(9)H, C(8)H);
1.71, 1.78 (both s, 2 H each, Me); 1.85—2.00 (m, 1 H, С(10)Н)
(m)
(m)
J = 8.2,
7.8)
J = 7.4,
7.8)
4e* 6.54—6.60, 7.03—7.11 (both m, 2 H each, ArH)
3.33 (s, 2 Н)
3.84
(dd,
J = 8.9,
6.1)
3.58
(dd,
J = 16.5,
5.8)
3.10
(dd,
J = 16.5,
8.2)
1.50—1.62 (m, 1 H, СН);
1.72, 1.79 (both s, 2 H each, Ме);
1.87—1.98 (m, 2 H, 2 СН);
2.01—2.19 (m, 1 H, СН)
6a*
6.83 (d,
J = 9.0)
6.68
(dd,
J = 8.1,
9.0)
7.04
(dd,
J = 7.9,
8.1)
6.92 (d,
J = 7.9) J = 16.8)
3.33 (d,
3.10 (d,
J = 16.8)
3.84 (d,
J = 14.2)
2.93 (ddd, 1 H, CH, J = 11.9, 3.6, 3.5); 3.10—3.25 (m, 1 H, CH);
3.13, 3.14, 3.22 (all s, 2 H each, Me); 3.41 (dd, 1 H, CH, J = 10.3, 3.2);
3.54 (ddd, 1 H, CH, J = 11.4, 2.8, 2.3); 3.63 (dd, 1 H, CH, J = 11.0, 2.9);
3.78 (dd, 1 H, CH, J = 12.2, 2.3)
6b** 6.90 (d,
J = 8.0)
6.67
(ddd,
J = 7.1,
8.0, 1.4)
7.04
(dd,
J = 7.1,
7.5)
6.96
(dd,
J = 7.5,
1.4)
3.24 (d,
J = 17.0)
3.15 (d,
J = 17.0)
3.92
(ddd,
J = 12.7,
2.2, 2.9)
3.48
(dd,
J = 10.8,
3.1)
2.45—2.55
(m)
1.69 (dd, 1 H, CН, J = 11.8, 10.8);
1.98 (ddd, 1 H, СН, J = 11.8, 2.9, 3.4);
2.14 (s, 3 H, Me); 2.70 (dm, 1 H, CH, J = 9.9);
2.82 (ddd, 1 H, СН, J = 12.0, 1.3, 2.5);
3.11, 3.19 (both s, 2 H each, NMe)
6c*
6.83 (d, 6.97—7.05 6.97—7.05
J = 8.1) (m) (m)
6.63
(dd,
J = 6.3,
0.9)
3.29 (d,
J = 17.0)
3.00 (d,
J = 17.0)
3.99 (d,
J = 13.9)
3.48
(ddd,
J = 9.2,
7.3, 4.4)
2.81
(ddd,
J = 9.2,
7.4, 4.4)
1.10—1.17 (m, 1 H, СН);
1.26—1.55 (m, 4 Н, 2 СН2);
1.70 (d, 1 H, СН, J = 12.6);
3.12 (d, 6 H, 2 Me, J = 5.0)
(to be continued)

Table 2 (continued)
Comꢀ
δ, J/Hz
pound
H(1)
H(2)
H(3)
H(4)
ArC(5)H
3.41 (d,
ArC(5)H
NC(6)H
NC(7)H
NC(8)H
Other signals
6d* 6.59—6.60
6.94
(dd,
6.59—6.60 7.00 (d,
2.71 (d,
J = 17.3)
3.51—3.65 (m, 2 H)
1.35—1.70 (m, 6 H, 6 CH); 1.85—2.01 (m, 1 H, СН);
2.95—3.10 (m, 2 H, СН); 3.13, 3.16 (both s, 2 H each, Me)
(m)
(m)
J = 6.1) J = 17.3)
J = 8.0,
7.6)
6e*
7a*
6.48 (d,
J = 8.3)
7.00
(dd,
J = 8.3,
7.9)
6.53
(dd,
J = 7.3,
7.9)
6.92 (d,
J = 7.3) J = 10.0)
3.38 (d,
3.20 (d,
J = 10.0)
3.68
(dd,
J = 6.4,
2.7)
3.41—3.55
(m)
1.41—1.58 (m, 1 H, СН); 1.85—2.11 (m, 3 H, 3 СН);
3.08 (s, 3 H, Ме); 3.15—3.20 (m, 1 H, СН);
3.24 (s, 3 H, Ме)
6.91 (d,
J = 8.0)
6.71
(dd,
J = 8.0,
7.2)
7.02—7.09 (m, 2 H)
3.45 (d,
J = 16.9)
3.36 (d,
J = 16.9)
3.96
(dd,
J = 11.2,
2.7)
3.09 (ddd, 1 H, CH, J = 11.2, 9.8, 3.7); 3.59 (d, 1 H, CH, J = 9.7);
3.64 (d, 1 H, CH, J = 11.1); 3.74—3.80 (m, 1 H, CH);
3.83—3.90 (m, 2 H, 2 CH); 7.30—7.35 (m, 2 H, Ph);
7.37—7.53 (m, 8 H, Ph);
7b** 6.99—7.08
6.68
(ddd,
J = 7.3,
7.1, 0.7)
6.99—7.08 6.91 (d,
3.42 (d,
3.30 (d,
J = 14.9)
3.94
(dm,
J = 11.6)
3.76
(dd,
J = 10.1,
3.1)
3.1—3.31
(m)
2.08—2.22 (m, 2 H, CH); 2.28 (s, 3 H, Me);
2.72 (dm, 1 H, СН, J = 9.6); 2.81 (dm, 1 H,
СН, J = 8.6); 7.27—7.32 (m, 2 H, ArH);
7.34—7.53 (m, 8 H, ArH)
(m)
(m)
J = 8.0) J = 14.9)
7c*
7d*
7e*
6.85 (d,
J = 8.2)
7.00
(ddd,
J = 8.2,
6.5, 1.5)
6.63
(dd,
J = 7.4,
6.5)
7.07
(dd,
J = 7.4,
1.5)
3.46 (d,
J = 17.2)
3.02 (d,
J = 17.2)
4.26 (d,
J = 10.8)
4.00 (d,
J = 12.7)
3.21
(ddd,
J = 11.8,
11.2, 0.9)
1.13—1.48 (m, 4 H, CH);
1.71—1.99 (m, 2 H, СН2);
7.23—7.54 (m, 10 H, 2 Ph)
7.03 (d, 6.48—6.63 (m, 2 H)
J = 7.3)
6.94
(dd,
J = 7.5,
1.22)
3.60 (d,
J = 17.7)
3.00 (d,
J = 17.7)
4.22—4.41 3.79—4.00
(m) (m)
1.35—2.20 (m, 8 H, 8 CH);
3.30—3.50 (m, 1 H, СН);
7.12—7.58 (m, 10 H, 2 Ph)
6.44 (d, 6.91—7.06
J = 8.2) (m)
6.52
(dd,
J = 7.3,
6.7)
6.91—7.06 3.56 (d,
(m) J = 16.7)
3.33 (d,
J = 16.7)
3.73—3.85 3.20—3.30 2.90—3.00
(m) (m) (m)
1.98—2.20 (m, 3 Н, 3 СН);
2.23—2.50 (m, 1 H, СН);
7.12—7.24 (m, 2 H, ArH);
7.28—7.55 (m, 8 H, ArH)
* In DMSOꢀd6.
** In CDCl3.

Synthesis of spiro derivatives of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1245
to form spiro derivatives of [1,2ꢀa]quinolineꢀ2´ꢀcycloꢀ
hexaneꢀ1´,3´ꢀdione 2a—e.
The reactions of 2ꢀdialkylaminobenzaldehydes 1a—e
with 2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione (Meldrum's
acid) proceeded analogously. It was demonstrated that
the reactions were completed in 10 h to give spiroꢀfused
[1,2ꢀa]quinolines 4a—e, whereas vinyl derivatives 5 were
also not isolated (Scheme 3). The structures of compounds
4a—e were confirmed by NMR, IR, and mass spectra
as well as by the results of elemental analysis (see
Tables 1—3).
Scheme 3
condensation product 2. For example, the molecular ion
of compound 2d was observed as a doublet with 299
[M + 2]+ and 297 [M]+, peaks; the ratio between the [M]
and [M + 2] peaks was 100 : 2.66. The NMR spectral
patterns appeared to be much more complicated than
those expected for compounds 3, but they correspond to
structure 2 (Tables 2 and 3).
Therefore, as distinct from the reactions of benzaldeꢀ
hydes 1 with acyclic derivatives of malonic acid, intermeꢀ
diates 3a—e were not isolated but underwent cyclization
Table 3. 13C NMR spectra (CDCl3) of fused quinolines 2d, 4a,
6d, and 7d
Atom
δ*
i. Toluene, ∆.
2d**
4a
6d
7d
Spiroꢀfused quinolinepyrimidines 6a—e and 7a—e can
be synthesized according to two procedures. One of them
involves Knoevenagel condensation of 2ꢀdialkylaminoꢀ
benzaldehydes 1a—e with malonic ester, cyclization of
the resulting benzylidenemalonic esters 8 to fused quinoꢀ
lines 9,11,22 and condensation of the latter with disubstiꢀ
tuted urea to give the target products. Another procedure
involves the reaction of 2ꢀdialkylaminobenzaldehydes
1a—e with barbituric acids, where Knoevenagel condenꢀ
sation is accompanied by intramolecular cyclization of
the intermediate vinyl derivatives (Scheme 4). Taking into
account the results obtained in the earlier studies, it can
be assumed that this reaction proceeds in one step to give
spiroꢀfused quinolines 6a—e and 7a—e.
The synthesis of spiro derivatives of quinolines acꢀ
cording to the first method involves difficulties associꢀ
ated, in particular, with the formation of byꢀproducts. In
this connection, isolation of the pure target spiroꢀfused
quinolines presents a problem. The total yield was 15%
(for 7e).
C(1)
C(1a)
C(2)
C(3)
C(4)
C(4a)
ArC(5)
NC(6)
NC(7)
C(9)
C(10)
C(1´)
C(2´)
C(3´)
C(5´)
110.8
141.4
126.5
117.1
129.1
119.8
23.6
64.2
50.5
27.0
29.9
112.6
144.1
127.6
119.0
128.7
119.2
27.85
67.3
48.5
59.4
46.4
168.7
67.3
113.4
144.5
126.6
117.4
128.2
120.4
26.0
67.2
50.5
29.6
30.1
112.5
143.1
128.2
117.9
129.3
119.7
26.0
67.1
51.0
28.8
30.2
205.2
70.0
203.8
10.6
170.1
53.2
168.7
151.2
169.4
54.7
168.3
151.2
164.8
66.7
* Other signals: 2d: 25.4, 25.7 (C(X)); 37.8 (C(4´)); 38.1 (C(6´));
4a: 30.2, 34.6 (Me); 6d: 27.2 (C(X)); 28.9 (Me); 29.5 (C(X));
7d: 26.68, 28.11 (C(X)); 126.79, 128.26, 128.75, 128.97, 129.17,
129.41, 129.48, 134.43 (Ph).
** In DMSOꢀd6.

1246
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
D´yachenko et al.
Scheme 4
R = Ph (6), Me (7)
Table 4. Physicochemical characteristics of oꢀdialkylaminoꢀ
benzaldehydes 1a—e
The second method is preparatively more convenient
because it involves one step. We demonstrated that the
reactions of 2ꢀdialkylaminobenzaldehydes 1a—e with
dimethylꢀ and diphenylbarbituric acids afforded spiro
compounds 6a—e and 7a—e. Their structures were conꢀ
Comꢀ Yield Found
. Molecular
IR,
MS,
m/z
poꢀ (%)
und*
Calculated formula
N (%)
(KBr),
ν/cm–1
C=O
(Irel (%))
1
firmed by H and 13C NMR and IR spectroscopy, mass
spectrometry, and elemental analysis (see Tables 1—3). It
should be noted that cyclization gave spiroꢀfused quinoꢀ
lines 6 and 7 in good yields on refluxing in toluene for 3 h.
An increase in the reaction time led to a decrease in the
yield and resinification of the products. In this approach,
the total yield of the target products 6a—e and 7a—e
varied from 26 to 70%.
To summarize, we developed a oneꢀstep method for
the synthesis of new heterocyclic systems, viz., spiro deꢀ
rivatives of pyrrolo[1,2ꢀa]quinoline, benzo[c]quinolizine,
[1,4]oxazino[1,2ꢀa]quinoline, and azepino[1,2ꢀa]quiꢀ
noline.
1a
1b
1c
1d
1e
87
88
87
82
95
7.50
7.32
13.20
13.72
7.62
7.40
6.56
6.89
7.50
7.99
C11H13NO2
C12H16N2O
C12H15NO
C13H17NO
C11H13NO
1745,
1720
1690
191
(94)
204
(79)
189
(100)
203
(100)
175
1680
1675
1680
(96)
* Oil.
Experimental
Synthesis of oꢀdialkylaminoꢀsubstituted benzaldehydes 1a—e
(general procedure). Dialkylamine (9.88 mmol) and potassium
carbonate (1.38 g, 9.88 mmol) were added to a solution of
2ꢀfluorobenzaldehyde (1.0 mL, 9.49 mmol) in DMF (8.0 mL).
The reaction mixture was refluxed on a glycerol bath at 150 °C
for 20 h. The completion of the reaction was judged from the
TLC data. Then the reaction mixture was cooled to ~20 °C,
water (75 mL) was added, and the product was extracted with
ethyl acetate (3×60 mL). The combined organic extract was
washed with a solution of ammonium chloride. The organic
layer was dried with Na2SO4 and the solvent was removed
in vacuo.
The 1H and 13C NMR spectra were recorded on a Bruker
WPꢀ250 spectrometer (250 MHz for 1H) and a Bruker DRXꢀ400
instrument (400 MHz for 1H and 100 MHz for 13C) in DMSOꢀd6
and CDCl3 with Me4Si as the internal standard. The IR spectra
were measured on a URꢀ20 spectrometer in KBr pellets. The
mass spectra were obtained on a MAT11 instrument (EI, 70 eV).
The course of the reactions and purity of the compounds synꢀ
thesized was monitored by TLC on DCꢀPlastikfolien Kieselgel
60 F 254 plates using the 15 : 1 dichloromethane—hexane sysꢀ
tem. The melting points are uncorrected. Compounds 1a,14 1b,15
1c,e, 8e, and 9e 16 were synthesized according to known proceꢀ
dures. The physicochemical characteristics and spectroscopic
data for the compounds synthesized are given in Tables 1—5.
Synthesis of spiro derivatives of fused quinolines (general proꢀ
cedure). Cyclic CHꢀactive compounds (2.3 mmol) were added
to a solution of 2ꢀdialkylaminobenzaldehyde 1a—e (2.3 mmol)

Synthesis of spiro derivatives of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1247
1
Table 5. H NMR spectra (DMSOꢀd6) of oꢀdialkylaminobenzaldehydes 1a—e
Comꢀ
pound
δ (J/Hz)
CHO
ArH
Dialkylamino group
1a
1b
1c
1d
1e
10.22
(s)
10.20
(s)
10.19
(s)
10.10
(s)
7.06
7.01 (dd,
6.85
(d, J = 8.0)
7.13
6.66 (dd,
J = 7.4, 8.2)
7.09 (dd,
2.50—2.57, 3.00—3.11 (both m,
4 H each, N(CH2) + O(CH2))
2.27 (s, 3 Н, СН3); 2.50—2.61,
3.00—3.10 (both m, 4 H each, 4 СН2)
1.30—1.81 (m, 6 Н, 3 СН2);
(d, J = 7.4)
7.64—7.65
(m)
7.66 (dd,
J = 6.1, 1.5)
7.60
(d, J = 7.4)
7.65 (dd,
J = 7.2, 6.4)
J = 8.2, 8.0)
7.50—7.51
(m)
7.54—7.55
(m)
7.45 (dd,
J = 8.1, 7.5)
7.65 (dd,
J = 8.0, 7.3)
(d, J = 7.7)
J = 10.3, 7.6)
7.00—7.15 (m, 2 Н)
2.87—3.05 (m, 4 Н, 2 СН2)
2.60, 2.76 (both s, 6 H each, 6 СН2)
7.15
(d, J = 8.2)
6.90 (dd,
J = 7.8, 7.2)
10.02
(s)
6.65—6.90 (m, 2 Н)
2.76 (s, 4 Н, 2 СН2);
2.89 (s, 4 Н, 2 NСН2)
in toluene (20 mL). The reaction mixture was refluxed for 3 h.
The completion of the reaction was determined by TLC. Then
the reaction mixture was cooled to ~20 °C and concentrated in
vacuo. The residue was triturated with ethanol.
7. W. H. N. Nijhuis, W. Verboom, S. Harkema, and D. N.
Reinhoudt, Recl. Trav. Chim. PaysꢀBas, 1989, 108, 147.
8. Y. Cheng, H.ꢀL. Ye, Y.ꢀH. Zhan, and O. MethꢀCohn, Synꢀ
thesis, 2001, 904.
9. Y. Cheng, H.ꢀB. Yang, B. Liu, O. MethꢀCohn, D. Watkin,
and S. Humphries, Synthesis, 2002, 906.
10. W. Verboom and D. N. Reinhoudt, Rec. Trav. Chim.
PayꢀBas, 1990, 109, 311.
11. O. MelhꢀCohn and H. Suschiizky, Adv. Heterocycl. Chem.,
1996, 65, 1.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ32733ꢀ
a) and the US Civilian Research and Development Founꢀ
dation (CRDF, Grants RECꢀ005 and RC1ꢀ2393ꢀEKꢀ02).
12. V. Ojea, I. Muinelo, and J. M. Quintela, Tetrahedron, 1998,
54, 927.
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Received October 28, 2003