A novel tert-amino effect based approach to 1,2,3,4-tetrahydroquinoline-2-spirocycloalkanes

Article abstract of DOI:10.1016/j.tet.2006.07.042

An interaction of 2-[cyclohexyl(methyl)amino]benzaldehydes with substituted acetonitriles X-CH₂CN (X=CN, Tos, hetaryl) was found to yield 1-methyl-1,2,3,4-tetrahydrospiro(quinoline-2,1′-cyclohexane)-3-carbonitriles. The corresponding spiroquino

Full text of DOI:10.1016/j.tet.2006.07.042

Tetrahedron 62 (2006) 9146–9152
A novel tert-amino effect based approach to 1,2,3,4-
tetrahydroquinoline-2-spirocycloalkanes
a
b
Anton V. Tverdokhlebov,a, Alexander P. Gorulya, Andrey A. Tolmachev,
*
Alexander N. Kostyuk,c Alexander N. Chernegac and Eduard B. Rusanovc
aEnamine Ltd, Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
bKiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
cInstitute of Organic Chemistry NAS, Murmanska str. 5, 02094 Kiev, Ukraine
Received 24 April 2006; revised 27 June 2006; accepted 13 July 2006
Available online 7 August 2006
Abstract—An interaction of 2-[cyclohexyl(methyl)amino]benzaldehydes with substituted acetonitriles X-CH2CN (X¼CN, Tos, hetaryl) was
found to yield 1-methyl-1,2,3,4-tetrahydrospiro(quinoline-2,10-cyclohexane)-3-carbonitriles. The corresponding spiroquinoline-2,10-cyclo-
pentane analogues were obtained similarly starting from 2-[cyclopentyl(methyl)amino]benzaldehydes. The reaction was assumed to proceed
via initial Knoevenagel condensation and further ring closure of the formed adduct according to the tert-amino effect mechanism. The struc-
ture of the prepared compounds was confirmed unambiguously by X-ray crystallographic study.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
N
H
R2
R1
1,2,3,4-Tetrahydroquinolines have wide pharmaceutical
applications.1,2 A number of 2,2-disubstituted tetrahydro-
quinoline derivatives occurs in the nature. Thus, the most
known are the Streptomyces alkaloid virantmycin3–10 and
its related compounds, the benzastatins.11–13 Moreover
a large family of 2-substituted tetrahydroquinoline alkaloids
has been isolated recently from the South African plant
sources.14–19 Quinoline-2-spirocycloalkanes form separate
group of 2-substituted tetrahydroquinolines. In particular,
the quinoline-2-spirocyclohexanes are especially attractive
since 1-azaspiro[5,5]undecane moiety is the core of the his-
trionicotoxines,20,21 the potent potassium channel blocka-
tors from the frog Dendrobates histrionicus (Fig. 1). So,
the 2-spirotetrahydroquinoline system consists of the sub-
structures of different natural products and, therefore, elabo-
ration of new synthetic approaches to it is the prospective
task.
HO
Figure 1. The histrionicotoxines. R1 and R2 are C3–C4 alkenyl.
bromide. It seems to be the best approach reported to date
and has been successfully applied in the preparation of var-
ious natural products analogues.29–31 However, the method
has some limitations. It only allows products unsubstituted
at position 3 of the quinoline moiety to be obtained and
spiroquinolines bearing electron-withdrawing groups in the
benzene ring are hardly available through this approach.23,25
A few other syntheses of spirocyclic tetrahydroquinolines
were also published.32–35 Furthermore, several approaches to
1,2-dihydroquinoline-2-spirocycloalkanes were reported36–41
and some of these compounds were reduced into corre-
sponding tetrahydro derivatives.37,38
The most suitable method for tetrahydroquinoline-2-spiro-
cyclohexanes preparation was developed by Kouznetsov
and co-workers.22–28 It includes electrophilic cyclization
of 1-allyl-1-anilinocyclohexanes readily available from the
cyclohexanone derived Schiff bases and allylmagnesium
The so-called tert-amino effecty is known as an efficient
method of tetrahydroquinoline system formation (Scheme
1).42–47 Thus, heating of compounds of type 1 in high-boiling
polar solvents affords tetrahydroquinoline derivatives 2 in
good yields.42–47 The reaction is assumed to proceed via sig-
matropic hydrogen 1,5-shift occurring from the canonic
structure3and further ringclosureof thebipolar intermediate
Keywords: Aldehydes; tert-Amino effect; Nitriles; Quinoline; Spiro com-
pounds.
* Corresponding author. Tel./fax: +380445586553; e-mail: atver@univ.
kiev.ua
The term was coined48,49 to describe this type and related cyclizations.
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.042

A. V. Tverdokhlebov et al. / Tetrahedron 62 (2006) 9146–9152
9147
4.44–46 The starting materials 1 are obtained easily from the
appropriate aldehydes and active methylenes X-CH2-Y.
Recently the tert-amino effect has been employed to prepare
spirocyclic compounds using cyclic methylene components
(Scheme 1, X and Y form a ring), namely the 1,3-cyclo-
hexanedione, the Meldrum’s acid, and the barbituric acid
derivatives.50–52 However, the potential of the tert-amino
effect in the synthesis of spiro compounds is believed not
to be exhausted by the use of cyclic methylenes. It seems
possible to bring in a spiro-center in position 2 of tetra-
hydroquinoline following the scheme 1 at the expense of
replacement of the pyrrolidine or piperidine moiety by other
suitable amine.
aldehydes 5, 6 with the nitriles 7–9 in ethanol in the pres-
ence of triethylamine was found to give the target spiro-
cyclic quinolines 11–16 in 65–100% yields. In a single
case only the reaction product appeared to be Knoevenagel
adduct 10b. Nevertheless, it was also converted into the
corresponding quinoline 16b in quantitative yield by reflux-
ing in DMF. Apparently the derivatives 11–16 are formed
according to the tert-amino effect mechanism (Scheme
2).44–46 Thus, the sigmatropic hydrogen 1,5-shift occurring
from the canonic structure 17 affords the bipolar inter-
mediate 18, which undergoes further ring closure into
quinolines 11–16. Moreover, under the conditions of Knoe-
venagel condensation, the cyclization of the adducts 10
turned out to be fast enough to disable their isolation, ex-
cept the case of 10b. At the same time during the previous
studies42–47,53 on the tert-amino effect with the same
methylene compounds 7–9 and 2-pyrrolidino- or piperidino-
benzaldehydes only dinitriles 2 (X¼Y¼CN) were obtained
directly without isolation of the corresponding precursors
1. For nitriles 8, 9 the appropriate derivatives 1 were pre-
pared separately and their cyclization required more drastic
conditions.53 Hence, the cycloalkyl(methyl)amino moiety
is more reactive toward the tert-amino effect cyclization
than the pyrrolidine fragment stated hitherto as the most
active one.44–46
Y
X
X
Y
n
heating
R
R
N
X
N
( )
( )
1
2
n
Y
X
Y
-
-
H
1,5-[H]shift
H
H
H
H
n
R
R
Within the series of compounds 11–16 the five-member de-
rivatives (n¼1) were more reactive than the six-member
ones (n¼2) requiring shorter reaction times and giving
higher yields of the products. Furthermore, the nitro
substituted compounds (R¼NO2) exhibited lower reactivity
toward the cyclization than their unsubstituted analogues
(R¼H), whereas the nitriles 7–9 could be placed in the fol-
lowing reactivity order: 8>7[9. The latter observations
are in complete agreement with the reported data.44–46,53 Ac-
cordingly, compound 10b is the least reactive sample and,
therefore, a higher boiling solvent, DMF is needed for
cyclization.
N+
N+
( )
( )
n
3
4
Scheme 1. The tert-amino effect cyclization. n¼1, 2. X and Y are the
electron-withdrawing groups.
This idea was examined in the course of our research on the
tert-amino effect53 and spiro-heterocycles synthesis,54,55
and the results obtained are reported herein.
2. Results and discussion
The structure of the prepared compounds 11–16 was initially
deduced from 1H and 13C NMR spectroscopic data and then
confirmed unambiguously by X-ray crystallographic study
carried out for the derivative 14a (Fig. 2). According to the
The desired aminoaldehydes 5, 6 (Scheme 2) were pre-
pared from 2-fluoro- and 2-chloro-5-nitrobenzaldehydes
and appropriate N-methylcycloalkylamines. Treatment of
CN
X
X
X
CN
7-9
CN
( )
R
R
CHO
R
heating
EtOH / Et3N
65-100%
( )
( )
n
N
CH3
N
CH3
N
CH3
10b
n
n
5a-b
11a-b, 12a-b
13a-b, 14a-b
15a-b, 16a-b
6a-b
X = 7,11,12: CN
CN
X
-
CN
X
-
H
8,13,14: 4-CH3C6H4SO2-
R
R
H
1,5-[H]shift
H
N
( )
+
+
( )
n
N
N
n
9,10,15,16:
CH3
17
S
CH3
18
Scheme 2. Compounds 5, 11, 13, 15: n¼1; compounds 6, 10, 12, 14, 16: n¼2. R¼a: H, b: NO2.

9148
A. V. Tverdokhlebov et al. / Tetrahedron 62 (2006) 9146–9152
3.1.1. Aminobenzaldehydes 5a, 6a. Powdered K2CO3
(3.04 g, 0.022 mol) was added to a solution of 2-fluoro-
benzaldehyde (2.48 g, 0.02 mol) and appropriate amine
(0.022 mol) in DMF (10 mL) and the resulted mixture was
refluxed with stirring for 6 h. After cooling it was poured
into water (25 mL) and extracted with EtOAc (2ꢁ10 mL).
The extract was washed with saturated aqueous NH4Cl solu-
tion, dried (Na2SO4), and evaporated in vacuo to give crude
compounds 5a, 6a as red oils. Further purification by chro-
matography on silica gel with EtOAc–hexane (1:4, v/v)
mixture as eluent afforded derivatives 5a, 6a as yellow oils.
3.1.1.1. 2-[Cyclopentyl(methyl)amino]benzaldehyde
(5a). Yield 48%. Yellow oil; nmax (KBr) 2931, 2855, 1685,
1595, 1477, 1452, 1386, 1293, 1272, 1191, 1148, 1081,
1003, 942, 832, 760 cmꢀ1. dH 1.54–1.84 (8H, m, 4CH2),
2.79 (3H, s, NCH3), 3.64 (1H, m, N-CHo), 7.08 (1H, t,
J¼7.6, 5-H), 7.19 (1H, d, J¼7.6, 3-H), 7.49 (1H, t, J¼7.6,
4-H), 7.80 (1H, d, J¼7.6, 6-H), 10.37 (1H, s, CHO). dC
23.1 (2CH2), 29.3 (2CH2), 38.2 (CH3), 62.3 (NCHo),
111.7 (3-C), 122.9 (5-C), 131.4 (6-C), 132.2 (4-C), 134.3
(1-C), 157.1 (2-C), 197.8 (CO). Found: 76.92 C, 8.40 H,
7.04 N; C13H17NO requires 76.81 C, 8.43 H, 6.89 N.
Figure 2. X-ray molecular structure of compound 14a with the atom num-
bering used in the crystallographic analysis.
crystal dataz the cyclohexane ring adopts chair confor-
mation. The tetrahydropyridine moiety is slightly twisted.
Thus, the atoms N1, C3, C4, and C5 are almost coplanar
˚
(with precision of 0.05 A). The atoms C2 and C1 are devi-
˚
˚
ated from this plane at +0.54 A and ꢀ0.28 A, respectively.
3.1.1.2. 2-[Cyclohexyl(methyl)amino]benzaldehyde
(6a). Yield 57%. Yellow oil; nmax (KBr) 2919, 2882, 1680,
1588, 1467, 1447, 1342, 1293, 1251, 1155, 1138, 1081,
991, 987, 871, 797 cmꢀ1. dH 1.01–1.02 (3H, m, c-hexyl),
1.41–1.50 (2H, m, c-hexyl), 1.54–1.57 (1H, m, c-hexyl),
1.70–1.78 (4H, m, c-hexyl), 2.73 (3H, s, NCH3), 2.94 (1H,
m, N-CHo), 6.97 (1H, t, J¼8.4, 5-H), 7.05 (1H, d, J¼8.4,
3-H), 7.41 (1H, t, J¼8.4, 4-H), 7.73 (1H, d, J¼8.4, 6-H),
10.15 (1H, s, CHO). dC 24.1 (CH2), 25.4 (2CH2), 26.8
(2CH2), 42.6 (CH3), 59.1 (NCHo), 115.2 (3-C), 123.7 (5-
C), 133.1 (6-C), 133.6 (4-C), 136.4 (1-C), 157.3 (2-C),
198.7 (CO). Found: 77.51 C, 8.66 H, 6.35 N; C14H19NO
requires 77.38 C, 8.81 H, 6.45 N.
To resume, the present investigation has resulted in a novel
approach to 1,2,3,4-tetrahydroquinoline-2-spirocyclopen-
tanes and -cyclohexanes. The cycloalkylamino moiety has
been shown to be applicable in the tert-amino effect and
its reactivity has been compared with that of pyrroli-
dine.44–46 A spiro-center has been first generated at the
expense of amine fragment during the tert-amino effect
process. The present synthesis complements well the Kouz-
netsov’s procedure22–28 since it allows preparation of spiro-
quinolines substituted at the position 3 unavailable through
the known approach.22–28 Further research on the scope of
this method for the preparation of quinolines spiro-fused
with other carbo- and heterocycles of different sizes is being
carried out and the results will be reported.
3.1.2. 2-Amino-5-nitrobenzaldehydes 5b, 6b. Powdered
K2CO3 (3.04 g, 0.022 mol) was added to a solution of 2-chlo-
ro-5-nitrobenzaldehyde (3.71 g, 0.02 mol) and appropriate
amine (0.022 mol) in DMF (10 mL) and the resulted mixture
was refluxed with stirring for 4 h. After cooling it was poured
into water (25 mL) and the solid formed was filtered and
recrystallized from i-PrOH to yield compounds 5b, 6b.
3. Experimental
3.1. General
N-Methylcyclopentylamine56 and 2-benzothiazole-aceto-
nitrile 957 were prepared as reported. Other reagents were
commercially available. All melting points were determined
in open capillary tubes in a Thiele apparatus and were uncor-
rected. 1H and 13C NMR spectra were recorded on a Varian
3.1.2.1. 2-[Cyclopentyl(methyl)amino]-5-nitrobenz-
aldehyde (5b). Yield 63%. Yellow powder; mp 79 ꢂC (from
i-PrOH); nmax (KBr) 2964, 2864, 1677, 1598, 1507, 1316,
1256, 1158, 1072, 949, 823, 748 cmꢀ1. dH 1.55 (2H, m,
CH2), 1.71 (4H, m, 2CH2), 1.94 (2H, m, CH2), 2.91 (3H,
s, NCH3), 4.14 (1H, m, N-CHo), 7.22 (1H, d, J¼9.2, 3-H),
8.16 (1H, dd, J3¼9.2, J4¼2.4, 4-H), 8.48 (1H, d, J4¼2.4,
6-H), 9.95 (1H, s, CHO). dC 21.3 (2CH2), 24.2 (2CH2),
38.0 (CH3), 63.8 (NCHo), 126.9 (2-C), 128.4 (1-C), 129.5
(4-C), 134.7 (6-C), 138.6 (5-C), 155.5 (2-C), 193.7 (CO).
Found: 62.80 C, 6.56 H, 11.20 N; C13H16N2O3 requires
62.89 C, 6.50 H, 11.28 N.
1
UNITYplus 400 (400 MHz for H and 100 MHz for 13C)
spectrometer in DMSO-d6 or CDCl3 solutions. Chemical
shifts (d) are given in parts per million downfield from inter-
nal Me4Si. J values are in hertz. The purity of all compounds
prepared was checked by 1H NMR and LC/MS on an Agilent
1100 instrument.
z
Crystallographic data (excluding structural factors) for the structure in
this paper have been deposited at the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 604539. Copies of
the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
3.1.2.2.
2-[Cyclohexyl(methyl)amino]-5-nitrobenz-
aldehyde (6b). Yield 78%. Yellow powder; mp 68 ꢂC (from
i-PrOH); nmax (KBr) 2925, 2853, 1681, 1602, 1571, 1494,
1328, 1257, 1166, 1069, 1001, 955, 745 cmꢀ1. dH 1.17 (1H,

A. V. Tverdokhlebov et al. / Tetrahedron 62 (2006) 9146–9152
9149
m, c-hexyl), 1.36 (2H, m, c-hexyl), 1.66 (3H, m, c-hexyl),
1.86 (4H, m, c-hexyl), 2.91 (3H, s, NCH3), 3.43 (1H, m,
N-CHo), 7.08 (1H, d, J¼9.6, 3-H), 8.15 (1H, d, J¼9.6,
4-H), 8.48 (1H, s, 6-H), 9.90 (1H, s, CHO). dC 21.5 (CH2),
24.1 (2CH2), 33.5 (2CH2), 37.4 (CH3), 66.5 (NCHo), 126.1
(3-C), 128.4 (4-C), 132.2 (6-C), 133.1 (1-C), 136.5 (5-C),
155.4 (2-C), 192.6 (CO). Found: 64.22 C, 6.90 H, 10.77 N;
C14H18N2O3 requires 64.11 C, 6.92 H, 10.68 N.
1338, 1319, 1279, 1186, 961, 937, 750 cmꢀ1. dH 1.88 (4H,
m, c-pentane), 2.09 (4H, m, c-pentane), 3.06 (3H, s,
NCH3), 3.86 (2H, s, 4-CH2), 6.96 (1H, d, J¼9.2, 8-H),
8.05 (2H, m, 5,7-H). dC 25.6 (30,40-C), 33.3 (4-C), 34.0
(20,50-C), 36.0 (NCH3), 40.5 (3-C), 70.9 (2-C), 113.0 (CN),
114.9 (8-C), 115.3 (4a-C), 124.7 (5-C), 124.8 (7-C), 137.3
(6-C), 148.9 (8a-C). Found: 64.70 C, 5.40 H, 18.93 N;
C16H16N4O2 requires 64.85 C, 5.44 H, 18.91 N.
3.1.3. Spiroquinoline-3,3-dicarbonitriles 11a, 12a. Tri-
ethylamine (0.1 mL, 0.7 mmol) was added to a solution of
the aldehyde 5a or 6a (4 mmol) and malonodinitrile 7
(0.26 g, 4 mmol) in EtOH (5 mL) and the resulted mixture
was refluxed for 3 h. After cooling it was diluted with water
(15 mL) and a viscous oily material precipitated. The liquid
was decanted and the precipitate was chromatographed on
silica gel using EtOAc–hexane (1:4, v/v) mixture as eluent.
Evaporation of the appropriate fraction and drying the resi-
due in vacuo afforded compounds 11a, 12a as yellowish
vitreous solids.
3.1.4.2. 1-Methyl-6-nitro-1,2,3,4-tetrahydrospiro-
(quinoline-2,10-cyclohexane)-3,3-dicarbonitrile (12b).
Yield 75%. Yellow powder; mp 159 ꢂC (from EtOH);
nmax (KBr) 2936, 2245, 1607, 1585, 1511, 1493, 1323,
1288, 1274, 1077, 958, 920, 821, 749 cmꢀ1. dH 1.37
(1H, m, c-hexane), 1.54 (2H, m, c-hexane), 1.81 (5H, m,
c-hexane), 2.11 (2H, m, c-hexane), 3.35 (3H, s, NCH3),
3.68 (2H, s, 4-CH2), 7.02 (1H, d, J¼9.2, 8-H), 8.05 (2H,
m, 5,7-H). dC 22.3 (30,50-C), 24.7 (40-C), 31.5 (20,60-C),
32.8 (4-C), 38.1 (NCH3), 40.8 (3-C), 62.0 (2-C), 115.4
(8-C), 116.6 (4a-C), 117.3 (CN), 124.6 (5-C), 125.1 (7-
C), 138.7 (6-C), 150.5 (8a-C). Found: 65.70 C, 5.65 H,
18.02 N; C17H18N4O2 requires 65.79 C, 5.85 H, 18.05 N.
3.1.3.1. 1-Methyl-1,2,3,4-tetrahydrospiro(quinoline-
2,10-cyclopentane)-3,3-dicarbonitrile (11a). Yield 76%.
Yellowish vitreous solid becoming fluid at 30–35 ꢂC; nmax
(KBr) 2955, 2878, 2246, 1601, 1580, 1496, 1456, 1342,
1312, 1178, 763, 748 cmꢀ1. dH 1.75–2.20 (8H, m,
20,30,40,50-CH2), 3.05 (3H, s, NCH3), 3.54 (2H, s, 4-CH2),
6.82 (2H, m, 6,8-H), 7.05 (1H, d, J¼7.2, 5-H), 7.23 (1H, t,
J¼7.2, 7-H). dC 25.0 (30,40-C), 34.3 (4-C), 35.0 (20,50-C),
35.8 (NCH3), 40.0 (3-C), 70.3 (2-C), 115.0 (8-C), 115.4
(CN), 115.5 (4a-C), 118.6 (6-C), 128.7 (5-C), 128.8 (7-C),
144.0 (8a-C). Found: 76.60 C, 6.74 H, 16.66 N; C16H17N3
requires 76.46 C, 6.82 H, 16.72 N.
3.1.4.3. 1-Methyl-3-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydrospiro(quinoline-2,10-cyclopentane)-3-carbo-
nitrile (13a). Yield 98%. White crystals; mp 92 ꢂC (from
EtOH); nmax (KBr) 2956, 2928, 2865, 1594, 1492, 1456,
1327, 1300, 1150, 1084, 818, 749, 660, 577 cmꢀ1. dH 1.65
(1H, m, c-pentane), 1.82 (2H, m, c-pentane), 1.98 (2H, m,
c-pentane), 2.22 (1H, m, c-pentane), 2.40 (3H, s, CH3),
2.52 (2H, m, c-pentane), 2.96 (3H, s, NCH3), 3.25 (1H, d,
J¼18.0, 4-H), 3.53 (1H, d, J¼18.0, 4-H), 6.57 (1H, d,
J¼8.4, 8-H), 6.70 (1H, t, J¼8.4, 6-H), 6.88 (1H, d, J¼8.4,
5-H), 7.07 (1H, t, J¼8.4, 7-H), 7.25 (2H, d, J¼8.0, Tos),
7.73 (2H, d, J¼8.0, Tos). dC 21.7 (CH3), 23.0 (30-C), 24.2
(40-C), 33.7 (20-C), 34.4 (4-C), 34.7 (50-C), 37.4 (NCH3),
67.1 (3-C), 70.8 (2-C), 115.1 (8-C), 117.4 (4a-C), 117.5
(CN), 118.1 (6-C), 127.7 (5-C), 128.1 (7-C), 129.3 (2,6-
CTos), 130.4 (3,5-CTos), 133.5 (4-CTos), 144.5 (8a-C), 146.0
(1-CTos). Found: 69.50 C, 6.33 H, 7.50 N, 8.33 S;
C22H24N2O2S requires 69.44 C, 6.36 H, 7.36 N, 8.43 S.
3.1.3.2. 1-Methyl-1,2,3,4-tetrahydrospiro(quinoline-
2,10-cyclohexane)-3,3-dicarbonitrile (12a). Yield 67%.
Yellowish vitreous solid becoming fluid at 35–40 ꢂC; nmax
(KBr) 2953, 2931, 2862, 2850, 2246, 1603, 1578, 1496,
1456, 1448, 1318, 1043, 767 cmꢀ1. dH 1.31 (1H, m, c-hex-
ane), 1.53 (2H, m, c-hexane), 1.74 (5H, m, c-hexane), 2.10
(2H, m, c-hexane), 3.25 (3H, s, NCH3), 3.44 (2H, s,
4-CH2), 6.82 (1H, t, J¼8.4, 6-H), 6.93 (1H, d, J¼8.4,
8-H), 7.00 (1H, d, J¼8.4, 5-H), 7.20 (1H, t, J¼8.4, 7-H).
dC 22.3 (30,50-C), 25.0 (40-C), 31.2 (20,60-C), 33.3 (4-C),
38.0 (NCH3), 40.3 (3-C), 61.4 (2-C), 116.2 (8-C), 117.6
(CN), 118.5 (4a-C), 119.5 (6-C), 128.5 (5-C), 128.9 (7-C),
145.1 (8a-C). Found: 76.76 C, 7.30 H, 15.86 N; C17H19N3
requires 76.95 C, 7.22 H, 15.84 N.
3.1.4.4. 1-Methyl-3-[(4-methylphenyl)sulfonyl]-6-nitro-
1,2,3,4-tetrahydrospiro(quinoline-2,10-cyclopentane)-3-
carbonitrile (13b). Yield 91%. Yellow crystals; mp 189–
190 ꢂC (from dioxane); nmax (KBr) 2967, 1603, 1588, 1509,
1497, 1313, 1272, 1147, 810, 671, 584 cmꢀ1. dH 1.56 (1H,
m, c-pentane), 1.70 (2H, m, c-pentane), 1.85–2.01 (3H, m,
c-pentane), 2.30 (3H, s, CH3), 2.37 (2H, m, c-pentane), 2.88
(3H, s, NCH3), 3.70 (1H, d, J¼18.8, 4-H), 3.80 (1H,
d, J¼18.8, 4-H), 6.55 (1H, d, J3¼9.6, 8-H), 7.27 (2H,
d, J¼8.0, Tos), 7.64 (2H, d, J¼8.0, Tos), 7.83 (1H, dd, J3¼
9.6, J4¼2.0, 7-H), 7.93 (1H, d, J4¼2.0, 5-H). dC 21.1 (CH3),
22.8 (30-C), 24.4 (40-C), 32.9 (20-C), 33.4 (50-C), 34.1 (4-C),
38.1 (NCH3), 67.9 (3-C), 70.4 (2-C), 113.3 (CN), 116.7 (4a-
C), 117.2 (8-C), 123.4 (5-C), 124.3 (7-C), 129.0 (2,6-CTos),
130.2 (3,5-CTos), 132.4 (4-CTos), 137.4 (6-C), 146.5 (1-
CTos), 149.2 (8a-C). Found: 62.11 C, 5.45 H, 10.03 N, 7.60
S; C22H23N3O4S requires 62.10 C, 5.45 H, 9.88 N, 7.54 S.
3.1.4. Spiroquinolines 11b, 12b, 13a–b, 14a–b, 15a–b,
16a. General procedure. A solution of the aldehydes 5a–
b, 6a–b (4 mmol), the nitriles 7–9 (4 mmol), and triethyl-
amine (0.1 mL) in EtOH (5 mL) was heated at reflux for
3–5 h until complete disappearance of the starting aldehyde
by TLC data. After cooling the precipitate formed was fil-
tered, washed with cold i-PrOH, and recrystallized from an
appropriate solvent to give compounds 11b, 12b, 13a–b,
14a–b, 15a–b, 16a.
3.1.4.1.
1-Methyl-6-nitro-1,2,3,4-tetrahydrospiro-
(quinoline-2,10-cyclopentane)-3,3-dicarbonitrile (11b).
Yield 79%. Yellow powder; mp 164 ꢂC (from EtOH); nmax
(KBr) 2970, 2947, 2882, 1604, 1583, 1504, 1489, 1425,
3.1.4.5. 1-Methyl-3-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydrospiro(quinoline-2,10-cyclohexane)-3-carbo-
nitrile (14a). Yield 95%. White crystals; mp 204 ꢂC (from

9150
A. V. Tverdokhlebov et al. / Tetrahedron 62 (2006) 9146–9152
acetonitrile); nmax (KBr) 2947, 2919, 2858, 1594, 1492,
1453, 1325, 1153, 1079, 756, 664, 597, 578 cmꢀ1. dH 1.39
(2H, m, c-hexane), 1.52 (1H, m, c-hexane), 1.64 (1H, m,
c-hexane), 1.76 (1H, m, c-hexane), 1.87 (2H, m, c-hexane),
2.03 (1H, m, c-hexane), 2.40 (2H, m, c-hexane), 2.51 (3H, s,
CH3), 2.63 (1H, d, J¼17.2, 4-H), 3.22 (3H, s, NCH3), 3.37
(1H, d, J¼17.2, 4-H), 6.70 (1H, t, J¼7.2, 6-H), 6.85 (2H,
m, 5,8-H), 7.09 (1H, t, J¼7.2, 7-H), 7.47 (2H, d, J¼7.6,
Tos), 7.84 (2H, d, J¼7.6, Tos). dC 21.7 (CH3), 22.1 (30-C),
22.9 (50-C), 25.3 (40-C), 30.5 (20-C), 32.4 (4-C), 32.9 (60-
C), 38.2 (NCH3), 64.7 (2-C), 67.0 (3-C), 117.8 (CN),
118.4 (8-C), 118.5 (4a-C), 119.4 (6-C), 128.2 (5-C), 128.8
(7-C), 130.5 (2,6-CTos), 130.6 (3,5-CTos), 133.4 (4-CTos),
145.5 (8a-C), 146.8 (1-CTos). Found: 70.13 C, 6.60 H, 7.22
N, 8.19 S; C23H26N2O2S requires 70.02 C, 6.64 H, 7.10 N,
8.13 S.
J¼9.6, 8-H), 7.45 (1H, t, J¼8.0, HX), 7.54 (1H, t, J¼8.0,
HX), 8.05 (4H, m, 2HX, 5,7-H). dC 25.2 (30-C), 25.3 (40-C),
34.1 (NCH3), 34.7 (20-C), 36.3 (50-C), 36.9 (4-C), 49.7
(3-C), 71.3 (2-C), 113.0 (CN), 117.6 (8-C), 120.0 (4a-C),
122.3 (4-CX), 123.1 (7-CX), 124.5 (6-CX), 124.8 (5-CX),
126.0 (5-C), 126.8 (7-C), 135.0 (7a-CX), 137.4 (6-C),
149.7 (8a-C), 151.6 (3a-CX), 165.5 (2-CX). Found: 65.30
C, 4.90 H, 13.80 N, 7.86 S; C22H20N4O2S requires 65.33
C, 4.98 H, 13.85 N, 7.93 S.
3.1.4.9. 3-(Benzothiazol-2-yl)-1-methyl-1,2,3,4-tetra-
hydrospiro(quinoline-2,10-cyclohexane)-3-carbonitrile
(16a). Yield 69%. Yellowish powder; mp 112 ꢂC (from di-
oxane); nmax (KBr) 2934, 2856, 1601, 1494, 1454, 1435,
1316, 970, 754, 730 cmꢀ1. dH 1.23 (1H, m, c-hexane),
1.50 (2H, m, c-hexane), 1.67 (4H, m, c-hexane), 1.88
(1H, m, c-hexane), 2.02 (1H, m, c-hexane), 2.18 (1H, m,
c-hexane), 3.15 (3H, s, NCH3), 3.53 (1H, d, J¼17.2,
4-H), 3.64 (1H, d, J¼17.2, 4-H), 6.76 (1H, t, J¼7.6,
6-H), 6.88 (1H, d, J¼7.6, 8-H), 7.03 (1H, d, J¼7.6, 5-H),
7.17 (1H, t, J¼7.6, 7-H), 7.38 (1H, t, J¼8.0, HX), 7.48
(1H, t, J¼8.0, HX), 7.87 (1H, d, J¼8.0, HX), 8.02 (1H, d,
J¼8.0, HX). dC 22.5 (30-C), 22.7 (50-C), 25.2 (40-C), 30.3
(20-C), 32.4 (4-C), 36.2 (60-C), 37.8 (NCH3), 51.0 (3-C),
61.6 (2-C), 116.7 (8-C), 118.8 (4a-C), 119.5 (CN), 121.4
(6-C), 122.6 (7-CX), 123.5 (4-CX), 126.1 (5-CX), 127.0
(6-CX), 128.3 (5-C), 129.0 (7-C), 135.7 (7a-CX), 145.6
(8a-C), 151.7 (3a-CX), 167.2 (2-CX). Found: 73.83 C, 6.25
H, 11.34 N, 8.48 S; C23H23N3S requires 73.96 C, 6.21 H,
11.25 N, 8.58 S.
3.1.4.6. 1-Methyl-3-[(4-methylphenyl)sulfonyl]-6-nitro-
1,2,3,4-tetrahydrospiro(quinoline-2,10-cyclohexane)-3-car-
bonitrile (14b). Yield 86%. Yellow crystals; mp 201 ꢂC
(from acetonitrile); nmax (KBr) 2931, 1602, 1507, 1486,
1317, 1288, 1269, 1143, 1133, 919, 752, 544 cmꢀ1. dH 1.39
(2H, m, c-hexane), 1.60 (1H, m, c-hexane), 1.67 (1H, m,
c-hexane), 1.80 (2H, m, c-hexane), 2.15 (2H, m, c-hexane),
2.30 (2H, m, c-hexane), 2.52 (3H, s, CH3), 2.88 (1H, d,
J¼18.8, 4-H), 3.32 (3H, s, NCH3), 3.49 (1H, d, J¼18.8,
4-H), 6.94 (1H, d, J¼9.2, 8-H), 7.49 (2H, d, J¼8.0, Tos),
7.84 (2H, d, J¼8.0, Tos), 7.90 (1H, s, 5-H), 8.00 (1H, d,
J¼9.2, 7-H). dC 21.7 (CH3), 22.3 (30-C), 22.4 (50-C), 22.5
(20-C), 25.0 (40-C), 30.8 (60-C), 32.4 (4-C), 38.4 (NCH3),
64.4 (2-C), 67.2 (3-C), 116.4 (8-C), 117.2 (CN), 118.9
(4a-C), 124.1 (5-C), 125.0 (7-C), 130.6 (2,6-CTos), 130.7
(3,5-CTos), 133.0 (4-CTos), 138.6 (6-C), 147.1 (1-CTos), 151.2
(8a-C). Found: 62.73 C, 5.84 H, 9.50 N, 7.35 S;
C23H25N3O4S requires 62.85 C, 5.73 H, 9.56 N, 7.29 S.
3.1.5. 2-(Benzothiazol-2-yl)-3-{2-[cyclohexyl(methyl)-
amino]-5-nitrophenyl}-2-propenenitrile (10b). Triethyl-
amine (0.1 mL, 0.7 mmol) was added to a solution of the
aldehyde 6b (1.67 g, 4 mmol) and the nitrile 9 (0.7 g,
4 mmol) in EtOH (5 mL) and the resulted mixture was
refluxed for 3 h. After cooling the precipitated solid was fil-
tered and recrystallized from EtOH to yield compound 10b.
Yield 94%. Yellow powder; mp 179–180 ꢂC; nmax (KBr)
2933, 2222, 1601, 1583, 1493, 1328, 1313, 1278, 1172,
1076, 1003, 758 cmꢀ1. dH 1.13 (3H, m, c-hexyl), 1.54
(1H, m, c-hexyl), 1.65–1.78 (4H, m, c-hexyl), 1.90 (2H, m,
c-hexyl), 2.94 (3H, s, NCH3), 3.19 (1H, m, N-CHo), 7.17
(1H, d, J¼9.2, 30-H), 7.45 (1H, t, J¼7.8, HX), 7.53 (1H, t,
J¼7.8, HX), 8.01 (2H, m, 2HX), 8.20 (2H, m, 40,60-H),
8.86 (1H, s, 3-H). dC 23.0 (CH2), 26.7 (2CH2), 28.8
(2CH2), 41.5 (CH3), 61.6 (NCHo), 99.2 (2-C), 116.0 (20-C),
118.6 (CN), 119.1 (10-C), 120.9 (7-CX), 122.4 (60-C), 125.3
(4-CX), 125.5 (40-C), 129.2 (6-CX), 129.3 (5-CX), 136.5
(50-C), 140.6 (7a-CX), 152.1 (3-C), 153.7 (30-C), 157.5
(4a-CX), 164.6 (2-CX). Found: 66.20 C, 5.36 H, 13.40 N,
7.69 S; C23H22N4O2S requires 66.01 C, 5.30 H, 13.39 N,
7.66 S.
3.1.4.7. 3-(Benzothiazol-2-yl)-1-methyl-1,2,3,4-tetra-
hydrospiro(quinoline-2,10-cyclopentane)-3-carbonitrile
(15a). Yield 81%. Yellowish powder; mp 121 ꢂC (from di-
oxane); nmax (KBr) 2954, 2915, 2872, 1600, 1578, 1496,
1483, 1454, 1432, 1339, 1312, 760, 729 cmꢀ1. dH 1.75
(5H, m, c-pentane), 2.07 (3H, m, c-pentane), 2.90 (3H, s,
NCH3), 3.50 (1H, d, J¼17.2, 4-H), 3.79 (1H, d, J¼17.2,
4-H), 6.73 (1H, t, J¼7.2, 6-H), 6.86 (1H, d, J¼7.2, 8-H),
7.03 (1H, d, J¼7.2, 5-H), 7.15 (1H, t, J¼7.2, 7-H), 7.42
(1H, t, J¼8.0, HX), 7.51 (1H, t, J¼8.0, HX), 8.01 (1H, d,
J¼8.0, HX), 8.05 (1H, d, J¼8.0, HX). dC 24.9 (30-C), 25.0
(40-C), 32.9 (4-C), 34.4 (20-C), 35.6 (50-C), 37.3 (NCH3),
50.3 (3-C), 69.6 (2-C), 113.9 (8-C), 117.8 (4a-C), 118.0
(6-C), 120.9 (CN), 122.1 (4-CX), 122.9 (7-CX), 125.7 (6-CX),
126.4 (5-CX), 128.1 (5-C), 128.8 (7-C), 135.5 (7a-CX),
144.1 (8a-C), 150.7 (3a-CX), 166.7 (2-CX). Found: 73.60
C, 5.84 H, 11.86 N, 8.74 S; C22H21N3S requires 73.50 C,
5.89 H, 11.69 N, 8.92 S.
3.1.6. 3-(Benzothiazol-2-yl)-1-methyl-6-nitro-1,2,3,4-tet-
rahydrospiro(quinoline-2,10-cyclohexane)-3-carbonitrile
(16b). A solution of the compound 10b (0.84 g, 2 mmol) in
DMF (5 mL) was heated at reflux for 3 h. After cooling it
was poured into water (15 mL) and the precipitate separated
was filtered. Recrystallization from dioxane afforded deriv-
ative 16b. Yield 99%. Yellow powder; mp 215–216 ꢂC; nmax
(KBr) 2947, 1604, 1584, 1506, 1492, 1320, 1289, 1260,
768, 753 cmꢀ1. dH 1.23 (1H, m, c-hexane), 1.50 (2H, m,
3.1.4.8. 3-(Benzothiazol-2-yl)-1-methyl-6-nitro-1,2,3,4-
tetrahydrospiro(quinoline-2,10-cyclopentane)-3-carboni-
trile (15b). Yield 64%. Yellow powder; mp 146 ꢂC (from
dioxane); nmax (KBr) 2932, 1604, 1584, 1505, 1494, 1335,
1313, 1262, 1182, 766 cmꢀ1. dH 1.55 (1H, m, c-pentane),
1.75 (3H, m, c-pentane), 1.99 (2H, m, c-pentane), 2.23
(2H, m, c-pentane), 3.05 (3H, s, NCH3), 3.78 (1H, d,
J¼17.6, 4-H), 3.90 (1H, d, J¼17.6, 4-H), 6.98 (1H, d,

A. V. Tverdokhlebov et al. / Tetrahedron 62 (2006) 9146–9152
9151
947–952; Chem. Heterocycl. Compd. (Engl. Transl.) 1991,
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1993, 29, 671–675.
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Kouznetsov, V. J. Heterocycl. Chem. 1999, 36, 675–680.
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c-hexane), 1.74 (4H, m, c-hexane), 1.90 (1H, m, c-hexane),
2.09 (1H, m, c-hexane), 2.19 (1H, m, c-hexane), 3.28 (3H, s,
NCH3), 3.64 (1H, d, J¼16.8, 4-H), 3.82 (1H, d, J¼16.8,
4-H), 7.00 (1H, d, J¼9.2, 8-H), 7.42 (1H, t, J¼8.0, HX),
7.51 (1H, t, J¼8.0, HX), 7.92 (1H, d, J¼8.0, HX), 8.02
(2H, m, 5-H, HX), 8.08 (1H, d, J¼9.2, 7-H). dC 22.4
(30-C), 22.7 (50-C), 24.9 (40-C), 30.4 (20-C), 32.9 (4-C),
35.5 (60-C), 38.4 (NCH3), 51.0 (3-C), 62.7 (2-C), 115.8 (8-C),
119.6 (CN), 120.7 (4a-C), 122.8 (7-CX), 123.6 (4-CX),
124.5 (5-C), 125.3 (7-C), 126.4 (6-CX), 127.2 (5-CX), 135.5
(7a-CX), 138.4 (6-C), 151.4 (8a-C), 151.7 (3a-CX), 166.1
(2-CX). Found: 65.84 C, 5.39 H, 13.40 N, 7.62 S;
C23H22N4O2S requires 66.01 C, 5.30 H, 13.39 N, 7.66 S.
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