Condensed isoquinolines. 13*. Synthesis of 1,2,3,4-tetrahydro-spiro[isoquinoline-4,1′-cyclopentane]-3-imines and condensed spirocyclic systems based on them

Article abstract of DOI:10.1023/A:1020969413371

1-(2-Bromomethylphenyl]-1-cyclopentanecarbonitrile has been synthesized by the cycloalkylation of (2-methylphenyl)acetonitrile with 1,4-dibromobutane with subsequent bromination of the intermediate product with N-bromosuccinimide. The product serves as a convenient intermediate in the synthesis of derivatives of a series of heterospiro systems. Condensation of it with primary amines leads to the hydrobromides of 1,2,3,4-tetrahydrospiro[isoquinoline-4,1′-cyclopentane]-3-imines, but with vicinal eneamino carbonyl compounds derivatives results in previously undescribed condensed spirocyclic systems, viz. spiro[5H-isoquino[2,3-a]quinazoline-7,1′-cyclopentane] and spiro[4H-thieno[3′,2′:5,6]- pyrimido[1,2-b]isoquinoline-6,1′-cyclopentane].

Full text of DOI:10.1023/A:1020969413371

Chemistry of Heterocyclic Compounds, Vol. 38, No. 8, 2002
CONDENSED ISOQUINOLINES.
13*. SYNTHESIS OF 1,2,3,4-TETRAHYDRO-
SPIRO[ISOQUINOLINE-4,1'-CYCLOPENTANE]-
3-IMINES AND CONDENSED SPIROCYCLIC
SYSTEMS BASED ON THEM
V. M. Kisel, E. O. Kostyrko, and V. A. Kovtunenko
1-(2-Bromomethylphenyl)-1-cyclopentanecarbonitrile has been synthesized by the cycloalkylation of
(2-methylphenyl)acetonitrile with 1,4-dibromobutane with subsequent bromination of the intermediate
product with N-bromosuccinimide. The product serves as a convenient intermediate in the synthesis of
derivatives of a series of heterospiro systems. Condensation of it with primary amines leads to the
hydrobromides of 1,2,3,4-tetrahydrospiro[isoquinoline-4,1'-cyclopentane]-3-imines, but with vicinal
eneamino carbonyl compounds derivatives results in previously undescribed condensed spirocyclic
systems, viz. spiro[5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentane] and spiro[4H-thieno[3',2':5,6]-
pyrimido[1,2-b]isoquinoline-6,1'-cyclopentane].
Keywords: isoquinolineimines, isoquinoquinazoline, condensed isoquinolines, spirocyclic compounds,
thienopyrimidoisoquinoline, cyclopentane.
Spiro[isoquinoline-4,1'-cyclopentanes] are of practical interest due to discovery of biologically active
substances amongst them [2,3]. At the same time the available methods for building the spiro[isoquinoline-4,1'-
cyclopentane] system are limited by the single examples of synthesizing its derivatives. Consequently it seemed
promising to work on the introduction into synthetic practice of intermediates opening a route to a series of
derivatives of this system. The possibility of realization just such an approach is studied in the present work,
which is a continuation of our investigations [1,4] in the area of spirocyclic condensed isoquinoline compounds.
The cycloalkylation of (2-methylphenyl)acetonitrile (1) with 1,4-dibromobutane in anhydrous toluene in
the presence of sodium hydride as base leads to the previously undescribed 1-(2-methylphenyl)-1-
cyclopentanecarbonitrile (2). Bromination of this compound with N-bromosuccinimide leads in high yield to
1-(2-bromomethylphenyl)-1-cyclopentanecarbonitrile (3), which lies at the basis of the method proposed by us
for constructing the spiro[isoquinoline-4,1'-cyclopentane] system.
We have studied the interaction of bromo nitrile 3 with various primary amines, such as aniline,
substituted arylamines, benzylamine, (2-furyl)methylamine, and butylamine. It is evident that at the first stage of
the reaction a simple alkylation takes place, but it may be accompanied by an intramolecular interaction of
nitrile and amino groups. It was found that, independently of the basicity of the initial amine, heating a mixture
_______
* For Part 12 see [1].
__________________________________________________________________________________________
Kiev Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: kvm@sbet.com,
v_kysil@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1079-1086,
August, 2002. Original article submitted May 22, 2000.
940
0009-3122/02/3808-0940$27.00©2002 Plenum Publishing Corporation

R1
S
R
R2
N
N
N
(5a)
N
N
O
N
H
O
10
5
6
Br
Me
R
Me
N
CN
CN
NH
CN
.
4
HBr
1
2
3
_
2-NH2
5-ClC6H3COC6H5
Cl
+
N
N
N
H
CN
CN
N
N
NH
_
.
HBr
Br
8
9
7
4 a–k R = C6H4X; l R = CH2Ph; m R = CH2-(2-furyl); n R = (CH2)3Me; a X = H; b X = 4-OMe; c X=4-CH3; d X=2-Cl; e X=3-Cl;
f X = 4-Br; g X = 3-F; h X = 4-CO2Et; i X = 4-COMe; j X = 4-NO2; k X = 3-NO2; 5 a R = H; b R = 2-Cl; c R = 3-Br;
10 a R1 = R2 = Me; b R1 = Et, R2 = H; c R1R2 = (CH2)4; d R1R2 = (CH2)3

of equimolar amounts of the starting materials in dioxane leads to 2-R-1,2,3,4-tetrahydrospiro[isoquinoline-4,1'-
cyclopentan]-3-imine hydrobromides 4 (Table 1). In their IR spectra bands for the nitrile absorption were
absent, which might have been expected for the intermediate alkylation products, but bands were observed for
the absorption of N+–H and C=N+ groups (Table 2).
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Yield,
%
Calculated, %
mp, °С
С
Н
N
Hal (S)*
64.00
63.87
6.15
5.92
7.91
7.84
22.64
22.36
223
217
179
234
226
246
224
232
242
258
282
233
255
191
224
224
254
172
163
301
291
205
217
257
42
40
79
59
57
80
62
83
61
58
56
93
82
55
88
64
49
97
42
69
55
94
75
50
4а
4b
4c
4d
4e
4f
С19Н20N2·HBr
C20H22N2O·HBr
C20H22N2·HBr
62.17
6.10
7.19
20.86
62.02
5.99
7.23
20.63
64.80
64.69
6.37
6.24
7.64
7.54
21.82
21.52
C19H19CIN2·HBr
C19H19CIN2·HBr
C19H19BrN2·HBr
C19H19FN2·HBr
C22H24N2O2·HBr
C21H22N2O·HBr
C19H19N3O2·HBr
58.40
5.25
7.40
29.22
58.26
5.15
7.15
29.45
58.35
58.26
5.25
5.15
7.07
7.15
29.47
29.45
52.49
4.82
6.56
36.97
52.32
4.62
6.42
36.64
60.00
60.81
5.42
5.37
7.87
7.46
21.38
21.29
4g
4h
4i
61.67
6.00
6.66
18.92
61.54
5.87
6.52
18.61
63.23
63.16
6.00
5.81
7.17
7.02
20.18
20.01
56.93
5.12
10.27
20.12
4j
56.73
5.01
10.45
19.86
C19H19N3O2.HBr
С20Н22N2·HBr
С18Н20N2О·HBr
C17H24N2·HBr
C20H18N2О
56.82
56.73
5.13
5.01
10.49
10.45
20.06
19.86
4k
4l
64.76
6.29
7.69
21.72
64.69
6.24
7.54
21.52
59.90
59.84
5.88
5.86
7.90
7.75
22.64
22.12
4m
4n
5a
5b
5c
6
60.63
7.62
8.38
23.68
60.54
7.47
8.31
23.69
79.60
79.44
6.13
6.00
9.30
9.26
C20H17CIN2О
C20H17BrN2О
C20H20N2О
71.43
5.15
8.52
10.30
10.53
71.32
5.09
8.32
63.10
63.01
4.55
4.49
7.58
7.35
21.08
20.96
79.03
6.76
9.17
78.92
6.62
9.20
+
C26H22ClN2 ·Br–
65.39
65.36
4.97
4.64
5.90
5.86
23.67
24.14
7
C20H19N3·HBr
C20H20N2ОS
C20H20N2ОS
C22H22N2ОS
C21H20N2ОS
62.89
5.32
11.21
21.04
9
62.84
5.27
10.99
20.90
71.52
71.40
6.13
5.99
8.16
8.33
(9.56)
(9.53)
10а
10b
10c
10d
71.54
6.07
8.23
(9.66)
71.40
5.99
8.33
(9.53)
73.03
72.90
6.24
6.12
7.87
7.73
(8.90)
(8.84)
72.43
5.85
8.17
(9.30)
72.38
5.78
8.04
(9.20)
_______
* For compounds 4d,e the combined data are given for the analysis of Cl
and Br, but for 4g data are given for the analysis of Br.
942

TABLE 2. Spectral Characteristics of the Compounds Synthesized
1Н NMR spectrum, δ, ppm, J (Hz)*
IR spectrum,
Com-
pound
NCH2 N+H2
ν, cm-1
–(CH2)4–
3
Other signals
6
(2Н, s) (1Н, s)
1
2
4
5
3020,
1.92-2.50 (8Н, m)
5.02
8.95,
8.35
7.35-7.75 (9Н, m, HAr)
4а
3180 (N–H);
1650 (C=N)
3120,
1.88-2.00 (4Н, m); 4.97
2.10-2.55 (4Н, m)
8.90,
8.28
7.36-7.52 (6Н, m, HAr);
7.17 (2Н, d, J = 8, HAr);
3.84 (3Н, s, ОСН3)
4b
4c
4d
4e
4f
3340 (N–H);
1645 (C=N)
3120,
1.80-2.50 (8H, m)
1.80-2.50 (8H, m)
1.80-2.50 (8H, m)
1.75-2.50 (8H, m)
4.98
4.97
5.02
5.00
8.92,
8.31
7.10-7.80 (8Н, m, HAr);
3320 (N–H);
1645 (C=N)
2.42 (3Н, s, СН3)
3020,
9.08,
8.77
7.35-7.90 (8Н, m, HAr)
3180 (N–H);
1650 (C=N)
3000,
8.98,
8.57
7.81 (1Н, t, J = 2.5, C(2")–Н);
7.35-7.75 (7Н, m, HAr)
3150 (N–H);
1650 (C=N)
3100,
8.70
7.84 (2Н, d, J = 8, C(3")–Н,
C(5")–Н); 7.52 (2Н, d,
J = 8, C(2")–Н, C(6")–Н);
7.36-7.45 (4Н, m, HAr)
3330 (N–H);
1640 (C=N)
(2Н)
3020,
1.80-2.50 (8H, m)
1.80-2.50 (8H, m)
5.03
5.07
9.00,
8.53
7.35-7.85 (8Н, m, HAr)
4g
4h
3180 (N–H);
1650 (C=N)
3030,
9.09,
8.55
8.20 (2Н, d, J = 8, C(3")–Н,
C(5")–Н); 7.74 (2Н, d,
3200 (N–H);
1640 (C=N);
1700 (C=O)
J = 8, C(2")–Н, C(6")–Н);
7.35-7.55 (4Н, m, HAr);
4.39 (2Н, q, J = 7.5, СН2CH3);
1.35 (3Н, t, J = 7.5, CH2СН3)
3080,
1.70-2.50 (8H, m)
5.04
9.04,
8.52
8.21 (2Н, d, J = 8, C(3")–Н,
C(5")–Н); 7.72 (2Н, d,
J = 8, C(2")–H, C(6")–Н);
7.35-7.55 (4Н, m, HAr);
2.66 (3Н, s, СН3)
4i
3350 (N–H);
1650 (C=N);
1675 (С=О)
3100, 3360
(N–H); 1650
(C=N); 1350,
1515 (NO2)
1.93-2.50 (m, 8Н)
5.10
5.09
8.92
8.53 (2Н, d, J = 8, C(3")–Н,
C(5")–Н); 7.94 (2Н, d,
J = 8, C(2"), C(6")–Н);
7.40-7.60 (4Н, m, HAr)
4j
(2Н)
3020,
1.83-2.50 (8H, m)
9.06
8.62 (1Н, t, J = 2, C(2")–Н);
8.44 (1Н, dt, Jm = 2, Jо = 8,
C(4")–Н); 8.08 (1Н, dt, Jm = 2,
Jо = 8, C(6")–Н); 7.93 (1Н, t,
J = 8, C(5")–Н);
4k
3200 (N–H);
1650 (C=N);
1350, 1515
(NO2)
(2Н)
7.33-7.54 (4Н, m, HAr)
3150,
1.87-2.50 (8Н, m,) 5.05
9.03
7.20-7.50 (9Н, m, HAr);
4l
3220 (N–H);
1630 (C=N)
(2Н)
4.75 (2Н, s, –СН2–Рh)
3150,
1.83-2.50 (8H, m)
5.05
9.23,
9.00
7.69 (1Н, d, J = 2.5, C(5")–Н);
7.32-7.43 (4Н, m, HAr);
6.62 (1Н, d, J = 3, C(3")–Н);
6.48 (1Н, dd, J = 3, J = 2,
C(4")–Н); 4.79 (2Н, s,
–CH2–(2-furyl))
4m
3260 (N–H);
1650 (C=N)
3060,
1.83-2.50 (8H, m)
4.78
8.75
7.36 (4Н, s, HAr); 3.68 (2Н, t ,
4n
5a
3240 (N–H);
1650 (C=N)
(2Н)
J = 7.5, –NСН2(CH2)2CH3);
1.40 (4Н, centre m, –(СН2)2СН3);
0.91 (3Н, t, J = 7.5, (CH2)3СН3)
1590 (C=N); 1.70-2.15 (6H, m); 5.45
1625 (C=O) 2.30-2.90 (2H, m)
7.30-7.60 (4Н, m, HAr);
7.77-8.20 (4Н, m, HAr)
943

TABLE 2 (continued)
1
2
3
4
5
6
1585 (C=N); 1.70-2.15 (6H, m); 5.44
1635 (C=O) 2.40-2.75 (2H, m)
8.10 (1Н, d, Jp = 8, C(4")–Н);
8.08 (1Н, d, Jm = 2.5, C(1")–Н);
7.54 (1Н, dd, Jp = 8, Jm= 2.5,
C(3")–Н); 7.30-7.50 (4Н, m, HAr)
5b
1580 (C=N); 1.75-2.20 (6Н, m); 5.44
1630 (C=O) 2.40-2.75 (2Н, m)
8.19 (1Н, d, Jm = 2, C(4'')–Н);
7.90-8.03 (2Н, m, C(1'')–H,
C(2")–H); 7.23-7.55 (4Н, m, HAr)
5c
6
3080 (N–H); 1.35-2.25 (8Н, m) 4.89*2, 8.12
1650 (C=O) 4.40
7.70 (1H, dd, Jо = 8, Jm = 2.5,
C(4")–Н); 7.34 (1Н, centre m,
Jо = 8, Jm = 2.5, C(2")–H);
7.17-7.25 (4Н, m, HAr);
6.90 (1Н, d, Jо = 8, C(1")–H);
6.70 (1Н, t, Jо = 8, C(3")–H); 4.99
(1H, d, J = 3, C(6a)–Н)
1575 (C=N) 1.90-2.03 (4Н, m); 6.32
2.12-2.79 (4Н, m)
8.95 (1Н, d, J = 8, C(1")–Н);
8.68 (1Н, dd, Jо = 8, Jm =2.5,
C(2")–Н); 8.44 (1Н, d, J = 2.5,
C(4")–Н); 7.46-8.11 (9Н, m, HAr)
7
9
3020,
1.75-2.21 (6Н, m); 5.76
9.92,
9.75
8.61 (1Н, d, J = 8, C(4")–Н);
8.41 (1Н, d, J = 8, C(1")–Н);
8.21 (1Н, t, J = 8, C(2")–Н);
7.85 (1Н, t, J = 8, C(3")–Н);
7.33-7.65 (4Н, m, HAr)
3220 (N–H); 2.50-2.80 (2Н, m)
1650 (C=N)
1575 (C=N); 1.80-2.10 (6Н, m); 5.26
7.30-7.55 (4Н, m, HAr);
10а
1625 (C=O)
2.45-2.60 (2Н, m)
2.38 (6Н, s, 2СН3 )
1570 (C=N); 1.70-2.15 (6Н, m); 5.30
7.30-7.60 (4H, m, HAr);
7.05 (1Н, s, C(3")–Н);
2.88 (2Н, q, J = 7.5,
–СН2CH3); 1.29 (3Н, t,
J = 7.5, CH2СН3)
10b
1620 (C=O) 2.50-2.70 (2Н, m)
1570 (C=N); 2.02 (4Н, centre, m); 5.63
1620 (C=O) 2.63 (4Н, centre, m)
7.50-7.65 (4Н, m, HAr);
10c
10d
2.85-3.25 (4Н, m, C(11")–Н2,
C(8")–Н2); 2.25 (4Н, centre m,
C(9")–Н2, C(10")–Н2)
7.45-7.65 (4Н, m, HAr);
3.10-3.30 (4Н, m, C(8")–Н2,
C(10")–Н2); 2.62 (2H, centre m,
C(9")–H2)
1570 (C=N); 2.20-2.40 (4Н, m); 5.64
1620 (C=O)
2.50-2.80 (4Н, m)
_______
* Compounds 4-7, 9, and 10a,b in DMSO-d6, 10c,d in deuterotrifluoroacetic
acid.
*2 1H, d, J = 17 Hz.
The interaction of bromo nitrile 3 with arylamines having a functional group in the ortho position
capable to amination is completed by the formation of derivatives of a new heterocyclic system,
spiro(isoquino[2,3-a]quinazoline-7,1'-cyclohexane). In the case of methyl anthranilate the reaction product is
7,12-dihydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentan)-5-one (5a). Similarly on using 4-chloro- and
5-bromoanthranilic acids the corresponding 2-chloro- and 3-bromo-7,12-dihydrospiro(5H-isoquino[2,3-a]-
quinazoline-7,1'-cyclopentan)-5-ones were obtained (5b,c). In all cases the reaction was accompanied by
deprotonation but the products were free bases. Their structures confirmed by spectral characteristics were in
good agreement with the data obtained previously in [1,5] for their structural analogs. In the IR spectra bands
were observed for the absorption of C=O and C=N groups in the absence of bands corresponding to the
vibrations of ester, carboxyl, nitrile, salts of amino or imino groups, which would be expected for the
intermediate interaction products. The C(6a)=N(6) double bond of the isoquinoquinoxaline fragment in
compound 5a is readily subjected to reduction by sodium borohydride with the formation of
944

6,6a,7,12-tetrahydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentan)-5-one (6). In the IR spectrum of this
compound an absorption band was observed for the N–H group, but the band for the C=O group undergoes the
1
regular high-frequency shift of 25 cm-1 as compared with the spectrum of the starting material. In the H NMR
spectrum of compound 6 the protons of the methylene group at C(12) and the fragment H–C(6a)–N(6)–H are
displayed as AB and AX spin systems respectively. In the presence of D2O the doublet for the N(6) proton
disappears and the doublet for the proton at C(6a) is converted into a singlet.
The interaction of bromo nitrile 3 with 2-amino-5-chlorobenzophenone is completed with the formation
of 3-chloro-5-phenyl-7,12-dihydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentan)-13-ium bromide (7).
In the reaction with anthranilic acid nitrile 2-[2-(1-cyanocyclopentyl)benzylamino]benzonitrile (8) is formed
unexpectedly as the free base. Its structure was confirmed by the IR spectrum in which a band was observed for
a secondary N–H group and two bands for conjugated and unconjugated nitrile groups.The presence in the
1H NMR spectrum of an A2X spin system of signals with Jvic = 6 Hz corresponding to a CH2–NH structural
fragment, converted into an A2 spin system in the presence of D2O, is also in good agreement with the structure
proposed. On heating an alcoholic solution of amino dinitrile 8 in the presence of conc. HBr it readily cyclizes
into 7,12-dihydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentane)-5-imine hydrobromide (9). The
absence of nitrile group absorption at 2200-2250 cm-1 and the presence of strong absorption bands for N+–H and
C=N+ groups indicates the formation of the tetracyclic structure.
Like methyl anthranilate its heterocyclic analogs the ethyl esters of 4,5-dimethyl- and 2-amino-5-ethyl-
3-thiophenecarboxylic acids react with bromonitrile 3 to form 2,3-dimethyl- and 2-ethyl-6,11-dihydrospiro(4H-
thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-6,1'-cyclopentan)-4-ones (10a,b) respectively. The analogous
condensation
of
ethyl
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
leads
to
5,8,9,10,11,14-hexahydrospiro(7H-benzo[4',5']thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-5,1'-cyclopentan)-7-
one (10c), and of ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate to 2,3,6,11-
tetrahydrospiro(cyclopentane-1,6'-1H,4H-cyclopenta[4',5']thieno[3',2':5,6]pyrimido[1,2-b]isoquinolin)-4-one (10d).
The spectral characteristics of products 10a-d (see Table 2) and their structural analogs 5a-c are close, which
confirms the structures of compounds 10a-d.
The newly available intermediate 3 proposed in the present study therefore makes possible the synthesis
of 1,2,3,4-tetrahydrospiro[isoquinoline-4,1'-cyclopentane]-3-imine hydrobromides with ready variation of the
substituent at the nitrogen atom of the isoquinoline ring. These compounds are interesting as spirocyclic analogs
of 1,2,3,4-tetrahydroisoquinoline-3-imines, which display antimicrobial activity [6]. In addition the obtained
compounds 5-7, 9, and 10 are derivatives of spiroheterocyclic systems on which there is no information in the
literature at the present time.
EXPERIMENTAL
1
The IR spectra were recorded on a Pye Unicam SP3-300 instrument in KBr tablets. The H NMR
spectra were obtained on a Bruker WP 100 SY (100 MHz) instrument in deuterotrifluoroacetic acid for
compounds 10c,d and in DMSO-d6 for compounds 3-9 and 10a,b, internal standard was TMS. Compound 4j
was recrystallized from water, 4l,m from ethanol–dioxane, 1:3, 4n from dioxane, 5a-c, 6, and 9 from ethanol,
compound 10b from DMF, and the remainder from 2-propanol.
1-(2-Bromomethylphenyl)-1-cyclopentanecarbonitrile (3). Anhydrous toluene (50 ml) and an 80%
emulsion of sodium hydride (10 g, 0.33 mol) in nujol were placed in an apparatus protected from moisture. A
mixture of nitrile 1 (18.5 ml, 0.15 mol) and 1,4-dibromobutane (17.9 ml, 0.15 mol) was slowly added dropwise
to the reaction mixture while cooling with ice and stirring. Stirring was continued until the end of hydrogen
evolution (3-4 h) and then for 1 h further, after which the excess of sodium hydride was decomposed by adding
2-propanol (10 ml). Water (100 ml) was added to the mixture, the organic layer was separated, and the aqueous
was extracted with toluene. The combined organic extracts were dried over Na2SO4, evaporated under reduced
945

pressure, and the residue was distilled in vacuum on an oil pump, collecting the fraction of bp 115-130°C
(0.5 mm Hg). Compound 2 (12.5 g, 45%) was obtained as a colorless oily substance. IR spectrum (thin film),
1
ν, cm-1: 2230 (C≡N); 2860, 2940 (C–H). H NMR spectrum (CDCl3), , ppm: 1.70-2.20 (8H, m, (CH2)4); 2.59
δ
(3H, s, CH3); 7.21 (4H, s, HAr).
N-Bromosuccinimide (16 g, 0.09 mol) and the dinitrile of azodiisobutyric acid (100 ml) was added to a
solution of compound 2 (12.5 g, 0.07 mol) in CCl4 (100 ml). The mixture was refluxed with stirring for 14 h,
cooled, and filtered. The filtrate was evaporated at reduced pressure, and the residue triturated with hexane. The
solid substance was filtered off and washed with hexane. Colorless crystalline product 3 (12.9 g, 70%) was
1
obtained; mp 64°C (2-propanol). IR spectrum, ν, cm-1: 2230 (C≡N); 2860, 2940 (C–H). H NMR spectrum
(CDCl3), , ppm: 1.9-2.8 [8H, m, (CH2)4]; 4.85 (2H, s, CH2–Br); 7.30-7.55 (4H, m, HAr). Found:, %: Br 30.40;
δ
N 5.38. C13H14BrN. Calculated, %: Br 30.25; N 5.34.
Hydrobromides of 2-R-1,2,3,4-Tetrahydrospiro[isoquinoline-4,1'-cyclopentane]-3-imines (4a-n). A
mixture of bromo nitrile 3 (0.79 g, 3 mmol) and arylamine (3 mmol) in dioxane (10 ml) was refluxed for 8 h.
After cooling the precipitated crystalline substance was filtered off, washed with dioxane, and recrystallized.
Condensed Spiro[isoquinoline-4,1'-cyclopentanes] 5, 7, and 10. A mixture of bromo nitrile 3 (0.79 g,
3 mmol) and enaminocarbonyl compound (3.5 mmol) in dioxane (10 ml) was refluxed for 12 h. The solid
precipitated from the cooled reaction mixture was filtered off, washed on the filter with dioxane, and
recrystallized.
6,6a,7,12-tetrahydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentan)-5-one (6). A mixture of
compound 5a (0.20 g, 0.66 mmol) and NaBH4 (0.15 g, 3.96 mmol) in dioxane (5 ml) was refluxed for 2.5 h,
cooled, and diluted with two volumes of water. The precipitated solid was filtered off, washed with water, and
recrystallized.
2-[2-(1-Cyanocyclopentyl)benzylamino]benzonitrile (8). A mixture of bromo nitrile 3 (0.79 g,
3 mmol) and anthranilonitrile (0.41 g, 3.5 mmol) in dioxane (10 ml) was refluxed for 6 h. The solid precipitated
on cooling the reaction mixture was filtered off, washed on the filter with dioxane, and recrystallized from
2-propanol. A colorless crystalline product (0.42 g, 47%) was obtained, mp 167°C. IR spectrum, ν, cm-1: 2200,
1
2220 (C≡N), 3380 (N–H). H NMR spectrum, (DMSO-d6), , ppm, J (Hz): 1.70-2.15 (6H, m) and 2.50-2.75
δ
(2H, m) ((CH2)4); 4.69 (2H, d, Jvic = 6, NCH2); 7.25-7.60 (6H, m, HAr); 6.84 (1H, t, Jvic = 6, NH); 6.66 (1H, t,
Jo = 8, C(5)–H); 6.47 (1H, d, Jo = 8. C(3)–H). Found, %: C 79.82; H 6.42; N 13.91. C20H19N3. Calculated, %:
C 79.70; H 6.42; N 13.94.
Hydrobromide of 7,12-Dihydrospiro(5H-isoquino[2,3-a]quinazoline-7,1'-cyclopentan)-5-imine (9).
A mixture of dinitrile 8 (0.6 g, 2 mmol), conc. HBr (2 ml), and ethanol (8 ml) was refluxed for 0.5 h. The solid
precipitated on cooling was filtered off, washed with water, and with ethanol.
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