Synthesis of 4-amino-substituted but-2-en-4-olides

Article abstract of DOI:10.1007/s11172-006-0201-7

Previously unknown 4-amino derivatives of spiro-annelated Δ²-butenolide were synthesized by the addition of various amines at the activated triple bond of 4-hydroxy-2-alkynoic esters.

Full text of DOI:10.1007/s11172-006-0201-7

Russian Chemical Bulletin, International Edition, Vol. 54, No. 12, pp. 2857—2866, December, 2005
2857
Synthesis of 4ꢀaminoꢀsubstituted butꢀ2ꢀenꢀ4ꢀolides
M. V. Mavrov,ꢀ L. D. Konyushkin, N. I. Simirskaya, and S. G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 137 2944. Еꢀmail: zlotin@ioc.ac.ru
2
Previously unknown 4ꢀamino derivatives of spiroꢀannelated ∆ ꢀbutenolide were syntheꢀ
sized by the addition of various amines at the activated triple bond of 4ꢀhydroxyꢀ2ꢀalkynoic
esters.
Key words: methyl 3ꢀ(1ꢀhydroxycyclohexyl)propꢀ2ꢀynoate, amines, butꢀ2ꢀenꢀ4ꢀolides,
Michael reaction, spiro compounds, 1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀones.
Certain furanꢀ2(5H )ꢀone (butꢀ2ꢀenꢀ4ꢀolide) derivaꢀ
tives are known to act on enzymes and possess bacteriꢀ
react under more drastic conditions. For example, refluxꢀ
1
,2
ing of (–)ꢀanabasine 3о in butanol selectively afforded (in
3
,4
5,6
2
cidal, fungicidal, or antibacterial properties. A series
of natural compounds (alkaloids, steroids, tetronic and
74% yield) ∆ ꢀbutenolide 7о containing a chiral center in
the α position with the respect to the nitrogen atom
7
—13
24
ascorbic acids, pheromones, and fragrances)
ꢀbutenolide fragments. Earlier,14 we have developed a
contain
([α ] –198.70 (c 1.00, CHCl )). It should be noted
D
3
2
∆
that the analogous reaction of anabasine with nitrile of
facile procedure for the synthesis of 4ꢀaminofuranꢀ2(5H )ꢀ
ones spiroꢀannelated at position 5, which are of interest
(1ꢀhydroxycyclohexyl)propiolic acid (EtOH, 40 °C) gave
2
1
only linear adduct 9 instead of iminolactone 8. Under
the aboveꢀmentioned conditions, both amino groups in
1,2ꢀdiaminopropane are involved in the reaction to give
bislactone 10.
as biologically active compounds and intermediates in the
synthesis of natural compounds.1
5—20
This procedure inꢀ
volves the reaction of esters of 4ꢀhydroxyalkꢀ2ꢀynoic acid
derivatives, in particular, of compound 1, with primary
The addition of benzoylhydrazine 2x occurs at the
C≡C bond through the terminal nitrogen atom to give
lactone 6x in 77% yield. Arylhydrazines (оꢀnitroꢀ and
оꢀmethoxyphenylhydrazines) were not involved in the reꢀ
action at room temperature, whereas refluxing of these
compounds in methanol afforded complex mixtures
of products. Apparently, high temperature promotes
Z/Eꢀisomerization of adducts 4 and 5, which is responꢀ
(
2) and secondary (3) amines (Scheme 1). Under the
reaction conditions, the initially formed linear Michael
adducts 4 and 5 undergo cyclization to give the correꢀ
sponding furanꢀ2(5H )ꢀone derivatives 6 and 7.
The aim of the present study was to examine the scope
of application of this oneꢀpot procedure and to synthesize
a series of amino derivatives of butꢀ2ꢀenꢀ4ꢀolides conꢀ
taining pharmacophoric substituents in the amine comꢀ
ponent. For this purpose, we studied the reactions of
methyl (1ꢀhydroxycyclohexyl)propiolate 1 with various
amines 2a—z and 3a—z. The reactions were carried out in
the absence of catalysts in dry diethyl ether or in a 2 : 1
diethyl ether—methanol mixture at 20—60 °C. The reacꢀ
tions with salts of amines were performed by refluxing in
methanol in the presence of sodium acetate. In most cases,
the desired amino derivatives of butꢀ2ꢀenꢀ4ꢀolides 6 and 7
were isolated in high yields. As expected, the reaction rate
depends on the structure of the starting amine, the numꢀ
ber of substituents, and their size. Benzylic amines 2a—d
and 3e,f,h are most reactive. Thus, their reactions proꢀ
ceed readily in diethyl ether at room temperature, and the
corresponding products 6 and 7 were obtained in 61—78%
yields (Tables 1 and 2). NꢀNucleophiles, which are comꢀ
ponents of heterocycles, such as piperidine (3i—l,o),
piperazine (3q,s,t), and some other heterocycles (3v,x),
2
2—24
sible for a decrease in selectivity of the process.
The
reactions of amino derivatives of imidazoles 2z and 3y
with compound 1 gave mixtures of linear and cyclic prodꢀ
ucts (4z+6z and 5y+7y, respectively). Attempts to sepaꢀ
rate these mixtures into individual components by crysꢀ
tallization or chromatography failed. Some reactions were
accompanied by partial hydrolysis of ester 1 into the corꢀ
responding acid. According to the results of IR spectroꢀ
–
1
scopy (absorption bands at 2240—2260 cm ), products
6b,k,y and 7m,n contain triple bonds due, apparently, to
the presence of impurities of propiolates of the correꢀ
sponding amines. In the reactions of ester 1 with piperidinꢀ
4ꢀone and dicyclohexylamine, hydrolysis of the ester givꢀ
ing rise to the corresponding acid becomes the main proꢀ
cess. The structures of salts 11a,b were established by
analytical and spectroscopic methods.
To summarize, we studied the influence of the strucꢀ
ture of the amine component on their reactions with meꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2761—2770, December, 2005.
066ꢀ5285/05/5412ꢀ2857 © 2005 Springer Science+Business Media, Inc.
1

2858
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Mavrov et al.
Scheme 1
thyl (1ꢀhydroxycyclohexyl)propiolate 1. The structural
features responsible for selectivity of the reaction and its
pathway were revealed. A representative series (a library)
of amino derivatives of butꢀ2ꢀenꢀ4ꢀolides 6, 7, and 10
containing pharmacophoric substituents at the nitrogen
atom of the amino group were synthesized.

Spiroꢀannelated aminobutenolides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2859
Table 1. Physicochemical characteristics of compounds 6a—z and 10
Comꢀ
pound
Method of Yield
M.p./°C
Found
Calculated
Molecular
formula
MS,
m/z (I (%))
(
%)
synthesis
(%)
and isolation
С
Н
N
6
6
6
6
6
6
6
6
6
6
6
6
6
6
а
b
с
d
е
f
A, a
A, a
B, a
C, b
B, b
B, a
B, a
B, a
B, a
B, b
B, a
A, a
A, a
D, b
61*
65
67
61
49
67
68
62
80
58
62
74*
69*
43
198—199
186—187
262—263
247—248
217—218
210—211
305—306
305—306
264—265
185—186
115—116
162—163
150—151
222—223
69.55
7.12
7.02
5.19
5.25
9.16
9.27
6.72
6.88
8.59
8.53
7.96
7.92
9.85
9.68
8.63
8.50
7.05
6.95
6.42
6.59
6.89
6.33
7.43
7.60
8.08
8.13
7.65
7.74
—
9.26
9.05
3.37
3.74
7.47
7.33
5.29
5.37
8.98
8.90
7.51
7.69
9.39
9.41
6.76
6.72
6.41
6.34
—
10.86
10.85
4.31
4.29
4.53
4.44
8.53
8.69
7.81
7.90
7.91
7.86
4.01
4.08
3.45
3.58
4.12
4.20
4.63
4.58
7.44
7.99
4.38
4.23
3.98
3.90
8.39
8.28
—
4.24
4.05
6.28
6.11
15.93
16.08
10.14
10.16
9.41
9.52
15.54
15.26
10.15
10.06
4.93
4.90
9.79
9.78
—
С15Н N О
2
258 (5.2)
326 (2.1)
315 (13.4)
322 (6.7)
354 (5.4)
356 (4.3)
343 (7.4)
391 (18.5)
333 (8.4)
305 (9.2)
350 (6.0)
331 (11.8)
359 (17.9)
338 (12.3)
18
2
6
9.74
59.00
8.91
76.21
6.15
74.71
4.51
74.48
4.54
70.47
0.76
77.01
6.92
79.68
9.75
79.38
9.25
66.85
6.77
57.96
8.26
69.01
8.86
70.23
0.17
74.61
С Н С1 NО
2
1
6
17
2
5
С20Н29NО2
С20Н22N О
7
2
2
2
3
7
С22Н30N О
2
7
С21Н28N O
2
7
g
h
i
С22Н33NО2
С26Н33NО2
С22Н23NО2
7
7
7
j
С17Н20С1NО2
6
k
l
С17Н22N O S
2
4
5
С Н25NО4
1
9
6
m
n
С Н29NО4
21
7
С21Н26N О
2
2
2
7
4.52
—
6
6
о**
р
D, b
A, a
27
70
89—90***
221—222
С22Н28N О
352 (9.4)
345 (2.1)
2
72.62
3.00
44.80
4.48
64.41
4.34
55.18
5.15
65.34
5.28
65.68
5.43
68.91
9.03
54.63
4.66
67.23
С21Н NО
31 3
7
6
6
6
6
6
6
6
6
q
r
B, a
B, a
B, a
A, a
B, b
B, b
C, b
C, b
58
52
64
63
41
61
51
77
206—207
175—175.5
174—175
143—144
175—176
171—172
308—309
294—295
С17Н С1 N О
2
458 (19.6)
261 (—)
17
5
2
4
С Н N О
2
1
4
19
3
6
s
С Н F N О
4
413 (—)
1
9
22
3
3
5
t
С Н N О
294 (4.4)
275 (4.9)
278 (4.2)
285 (14.3)
286 (18.7)
1
6
26
2
3
2
2
6
u
v
w
х
С15Н N О
21 3
6
С Н N О
1
6
26
2
6
С Н NО S
1
3
19
4
5
C H N O
1
6
18
2
3
6
7.11
—
6
4
1
у**
z+6z
0
D, b
D, b
B, b
23
22
58
>355
99—101
>365
C H27NO2
301 (21.3)
—
374 (2.2)
1
9
—
—
8.11
8.16
—
15.04
15.12
—
68.19
8.08
С21Н30N О
2
4
6
*
*
*
Upon storage of the reaction mixture at room temperature for 1.5—3 months, the yields were increased by 7—12%.
* Compounds 6o and 6y contained an impurity (3—5%) of the corresponding salt 11 (νC≡C ~2240 cm– ).
1
** An amorphous compound, the purity was ~93%.

2860
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Mavrov et al.
Table 2. Physicochemical characteristics of compounds 7a—y
Comꢀ
pound
Method of Yield
M.p./°C
Found
Calculated
Molecular
formula
MS,
m/z (I (%))
(
%)
synthesis
(%)
and isolation
С
Н
N
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
а
B, b
В, b
А, b
B, b
A, a
A, b
B, b
А, а
A, b
B, b
A, a
B, b
B, a
B, b
56
43
76
46
78
79
67
78
82
69
74
67*
55*
57
128—129
91—92
72.88
10.63
10.46
10.93
10.81
10.21
10.03
8.47
8.50
7.99
7.80
8.15
8.12
7.57
7.69
7.35
7.25
9.31
9.30
9.64
9.57
9.24
9.30
8.36
8.20
8.01
7.97
8.73
8.73
7.79
7.74
8.67
8.63
8.12
8.01
7.85
7.74
6.53
6.48
7.13
7.02
9.34
9.25
8.85
8.74
5.83
5.92
9.85
9.63
—
5.01
5.01
4.51
4.56
5.53
5.57
6.29
6.22
5.19
5.16
4.97
4.91
4.81
4.65
4.06
4.03
5.57
5.62
5.43
5.32
5.63
5.62
4.41
4.56
10.01
10.07
8.04
8.09
8.69
8.97
10.08
9.99
14.19
14.52
9.08
8.97
11.57
11.76
8.33
8.48
7.43
7.56
5.41
5.28
6.51
6.33
4.51
4.62
—
C H NО
279 (17.0)
307 (22.0)
263 (29.4)
225 (25.1)
271 (11.7)
285 (39.0)
287 (—)
1
7
29
2
2
2
3
2
7
3.07
74.12
4.22
71.38
1.67
64.01
3.97
75.17
5.24
75.63
5.75
71.79
1.73
79.52
9.50
72.39
2.25
72.81
2.96
72.38
2.25
66.45
6.42
64.81
4.72
69.01
9.33
b
C H NО
19 33
7
c
86—87
C H NО
16 25
7
d
99—100
118—119
82—83
C H NО
12 19
6
e
C H NО
17 21
7
f
C H23NО2
18
7
g
128—129
161—162
134—135
112—113
136—137
150—151
236—237
184—185
221—222
156—158
C H23NО3
18
7
h
C23H25NО2
С Н23NО2
347 (29.6)
249 (31.3)
263 (10.6)
249(47.2)
307 (100)
278 (56.2)
346 (36.4)
312 (62.3)
280 (11.4)
289 (53.6)
312 (65.4)
357 (100)
330 (38.3)
370 (43.4)
265 (100)
442 (1.0)
303 (37.8)
—
7
i
1
5
7
j
С Н NО
16 25 2
7
k
С Н23NО2
15
7
l
С Н25NО4
17
6
m
С Н N О
15 22 2
3
3
2
3
2
2
4
6
n
С20Н30N О
2
6
о
D, b
C, b
B, b
74
62
63
72.84
73.04
64.51
64.26
66.22
С Н N О
19 24 2
р
С Н N О
15 24 2
(
decomp.)
q
B, b
B, b
B, b
A, a
B, b
C, b
D, b
B, b
B, b
69
151—152
С Н N О
16 23 3
6
6.41
72.91
3.04
63.91
3.85
69.15
9.07
74.59
4.55
67.81
7.89
73.21
3.28
75.15
r
47
206—207
268—269
191—192
242—243
187.5—189
264—265
144—145
125—135
С Н N О
19 24 2
7
s
72
С Н N О
19 23 3
6
t
70*
69
С Н FN О
19 23 2 2
6
u
С23Н34N О
2
2
7
v
49
С Н23NО3
15
6
w
36
С27Н N О
26 2
4
7
х
49*
43*
С Н NО
19 29 2
7
5.20
—
5
у+7у
—
*
Upon storage of the reaction mixture at room temperature for 1.5—3 months, the yields were increased by 7—12%.

Spiroꢀannelated aminobutenolides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2861
tion of propiolate 1 (1.18 g, 7 mmol) and the corresponding
amine (9—10 mmol) in dry diethyl ether (20 mL) was kept at
room temperature for 10—12 days.
Method B. A solution of propiolate 1 (7 mmol) and the correꢀ
sponding amine (9—10 mmol) in a ~2 : 1 diethyl ether—methanol
mixture (20 mL) was kept at room temperature for 2 days and
then heated at 55—60 °C for 10—12 h.
Method C. A solution of a mixture of compound 1 (7 mmol),
the corresponding amine hydrochloride (5 mmol), and sodium
acetate (10 mmol) in methanol (20 mL) was refluxed for
1
5—20 h.
Method D. The mixture was refluxed in butanol (20 mL) for
1
2—15 h analogously to the method B.
All expected compounds were isolated and purified accordꢀ
ing to one of procedures described below.
a) The solid product that precipitated was filtered off, thorꢀ
(
oughly washed on a filter with a saturated sodium bicarbonate
solution, water, and petroleum ether with small additives
(
2—5%) of ethyl acetate and methanol, dried in air, and recrysꢀ
tallized from a petroleum ether—ethyl acetate mixture.
b) The hot reaction mixture was filtered and the filtrate was
(
concentrated in vacuo. The residue (solid and oily) was refluxed
in petroleum ether (10—15 mL) for 7—10 min, and the unꢀ
consumed starting compounds were removed by decantation.
The solid residue was filtered off and worked up analogously to
the procedure a. In the case of oily products (6l,о), the residues
were subjected to silica gel flash chromatography using a soluꢀ
tion of methanol in ethyl acetate (5—12%) as the eluent.
The following compounds were synthesized according to the
procedure A, a: 4ꢀ(3ꢀpyridyl)methylaminoꢀ (6a), 4ꢀ(3,4ꢀdiꢀ
chlorobenzylamino)ꢀ (6b), 4ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethylꢀ
amino]ꢀ (6l), 4ꢀ[2ꢀ(3,4ꢀdiethoxyphenyl)ethylamino]ꢀ (6m),
4ꢀ[2ꢀ(adamantanꢀ1ꢀyloxy)ethylamino]ꢀ (6p), 4ꢀ(3ꢀmorpholinoꢀ
propylamino)ꢀ (6t), 4ꢀ(NꢀbenzylꢀNꢀmethylamino)ꢀ (7e),
The resulting butꢀ2ꢀenꢀ4ꢀolides will be tested for antiꢀ
tumor activity at the M. M. Shemyakin and Yu. A.
Ovchinnikov Institute of Bioorganic Chemistry of the
Russian Academy of Sciences. The database of their physiꢀ
cochemical and spectroscopic properties (Tables 1—5)
can be used for identification of biologically active comꢀ
pounds belonging to furan derivatives.
4
4
2
ꢀdibenzylaminoꢀ (7h), 4ꢀ(4ꢀmethylpiperidinꢀ1ꢀyl)ꢀ (7k), and
ꢀ[4ꢀ(4ꢀfluorophenyl)piperazinꢀ1ꢀyl]ꢀ1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ
ꢀone (7t).
The procedure A, b was used to synthesize 4ꢀ(Nꢀcycloꢀ
Experimental
propylmethylꢀNꢀpropylamino)ꢀ (7c), 4ꢀ(NꢀbenzylꢀNꢀethylꢀ
amino)ꢀ (7f), and 4ꢀ(2ꢀmethylpiperidinꢀ1ꢀyl)ꢀ1ꢀoxaspiꢀ
ro[4.5]decꢀ3ꢀenꢀ2ꢀone (7i).
1
The H NMR spectra were recorded on a Bruker DRXꢀ500
instrument (500.13 MHz) in DMSOꢀd with Me Si as the interꢀ
The following compounds were synthesized according to
the procedure B, a: 4ꢀ(adamantanꢀ1ꢀyl)methylaminoꢀ (6c),
4ꢀ[1ꢀ(4ꢀmorpholinophenyl)ethylamino]ꢀ (6f), 4ꢀ[1ꢀ(adamanꢀ
tanꢀ1ꢀyl)propylamino]ꢀ (6g), 4ꢀ[αꢀ(adamantanꢀ1ꢀyl)benzylꢀ
amino]ꢀ (6h), 4ꢀbenzhydrylaminoꢀ (6i), 4ꢀ[2ꢀ(4ꢀaminosulfonylꢀ
phenyl)ethylamino]ꢀ (6k), 4ꢀ[2ꢀ(pentachlorophenylamiꢀ
no)ethylamino]ꢀ (6q), 4ꢀ[2ꢀ(pyrazolꢀ1ꢀyl)ethylamino]ꢀ (6r),
4ꢀ[3ꢀ(2ꢀnitroꢀ4ꢀtrifluoromethylanilino)propyl]ꢀ (6s), and
4ꢀ[4ꢀaminocarbonylpiperidinꢀ1ꢀyl)ꢀ1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀ
one (7m).
The following compounds were synthesized according to the
procedure B, b: 4ꢀ[1ꢀ(4ꢀpiperidinophenyl)ethylamino]ꢀ (6e),
4ꢀ[2ꢀ(4ꢀchlorophenyl)ethylamino]ꢀ (6j), 4ꢀ[3ꢀ(imidazolꢀ1ꢀ
yl)propylamino]ꢀ (6u), 4ꢀ(1ꢀethylpiperidinꢀ3ꢀyl)aminoꢀ (6v),
4ꢀdiisobutylaminoꢀ (7a), 4ꢀdipentylaminoꢀ (7b), 4ꢀ[Nꢀ(2ꢀhydrꢀ
oxyethyl)ꢀNꢀmethylamino]ꢀ (7d), 4ꢀ[NꢀbenzylꢀNꢀ(2ꢀhydroxyꢀ
6
4
nal standard. The UV spectra were measured on a Specord Mꢀ40
spectrometer in ethanol. The IR spectra were recorded on a
Specord Mꢀ80 instrument in KBr pellets. The mass spectra were
obtained on a Finnigan MAT.INCOS 50 instrument (EI, 70 eV)
using a direct inlet system.
The melting points were measured on a Boetius hotꢀstage
apparatus and are uncorrected.
The reagents were purchased from Acros Organics and
Chemical Blocks. The specific rotation was measured on a PUꢀ7
polarimeter. The specific rotation is given in deg mL g– dm
1
–1
,
and the concentrations of solutions in chloroform are given
–
1
in g (100 mL)
.
Elemental analysis was carried out on a Perkin—Elmer 2400
C,H,N analyzer.
The course of the reactions was monitored by TLC on Silufol
(
UVꢀ254) in a 9 : 1 : 1 chloroform—methanol—ethyl acetate
ethyl)amino]ꢀ
(7g),
4ꢀ(2ꢀethylpiperidinꢀ1ꢀyl)ꢀ
(7j),
mixture; spots were visualized with iodine vapor.
Addition of amines 2a—z and 3a—y to methyl 3ꢀ(1ꢀhydroxyꢀ
cyclohexyl)propiolate (1) (general procedure). Method A. A soluꢀ
4ꢀ[(4ꢀethoxycarbonyl)piperidinꢀ1ꢀyl]ꢀ (7l), 4ꢀ[4ꢀ(piperidinoꢀ
carbonyl)piperidinꢀ1ꢀyl]ꢀ (7n), 4ꢀ[4ꢀ(2ꢀhydroxyethyl)piperazinꢀ
1ꢀyl]ꢀ (7p), 4ꢀ[4ꢀ(2ꢀcyanoethyl)piperazinꢀ1ꢀyl]ꢀ (7q),

2862
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Mavrov et al.
Table 3. Main spectroscopic characteristics of compounds 6a—y and 10
Comꢀ
poꢀ
und
IR, ν/cm–1
UV,
λmax/nm
(ε•10–3
)
1H NMR, δ (J/Hz)
С=С
NH
HC=
(s)
Signals of other protons
[
C=O]
6
6
а
b
1608
3308
255
(25.2)
4.52 1.24, 1.47—1.55, 1.71, 1.86 (all m, 1 H, 4 H, 3 H, 2 H, СН of cyclohexane);
2
[
1704]
4.33 (d, 2 H, NCH , J = 5.6); 7.39 (dd, 1 H, Н of pyridine, J = 6.0, J = 4.0);
2
7
1
.69 (d, 1 H, Н of pyridine, J = 6.0); 7.83 (t, 1 H, NH, J = 5.6); 8.49 (d,
H, Н of pyridine, J = 4.0); 8.54 (s, 1 H, Н of pyridine)
1608
3080,
3260,
255
(27.3)
4.49 1.24, 1.47—1.56, 1.69, 1.85 (all m, 1 H, 4 H, 3 H, 2 Н, СН of cyclohexane);
2
[
1700]
4.28 (d, 2 H, NCH , J = 6.0); 7.38 (dd, 1 H, H arom., J = 8.0, J = 0.4);
2
3
276
7.59 (d, 1 H, H arom., J = 0.4); 7.64 (d, 1 H, H arom., J = 8.0);
7
.86 (t, 1 H, NH, J = 6.0)
4.46 1.26, 1.33—1.72, 1.49, 1.94 (two m, s, m, 1 H, 13 H, 6 H, 2 H,
CH of cyclohexane, CH , Ad); 1.94 (s, 3 H, CH, Ad); 2.73 (d, 2 H,
6
6
6
c
d
e
1608
3084,
3248
258
(19.6)
[
1700]
2
2
NCH , J = 5.4); 7.06 (t, 2 H, NH, J = 5.4)
2
1604 sh,
616
3064,
3224
255
(24.2)
4.21 1.22, 1.42—1.60, 1.66, 1.84 (all m, 1 H, 4 H, 3 H, 2 H, СН of cyclohexane);
2
1
4.09 (d, 2 H, NCH , J = 6.0); 6.26, 7.01 (both s, 2 H each, H of pyrrole);
2
[1692]
1604
7.34 (m, 1 H, H arom.); 7.43 (m, 3 H, H arom.); 7.35 (t, 1 H, NH, J = 6.0)
3060,
3268
258
(29.0)
4.21 1.17—1.74, 1.93 (both m, 14 H, 2 H, CH of cyclohexane, СН of piperidine);
2 2
[
1696]
1.40 (d, 3 H, Ме, J = 7.0); 3.09 (t, 4 H, NCH , J = 7.0); 4.26 (quint, 1 H,
2
NCH, J = 7.0); 6.89, 7.12 (both d, 2 H each, H arom., J = 8.0);
7
.53 (d, 1 H, NH, J = 7.0)
6
f
1604
3056,
3268
258
(37.8)
4.21 1.27, 1.51, 1.67, 1.83 (all m, 2 H, 3 H, 3 H, 2 H, СН of cyclohexane);
2
[
1700]
1.40 (d, 3 Н, Ме, J = 7.0); 3.07 (t, 4 H, NCH , J = 5.5); 3.72 (t, 4 H, ОCH ,
2
2
J = 5.5); 4.28 (quint, 1 H, NCH, J = 7.0); 6.90, 7.16 (both d, 2 H each,
H arom., J = 8.0); 7.55 (d, 1 H, NH, J = 7.0)
6
6
6
6
g
h
i
1603
3088,
3253
258
(27.2)
4.43 0.81 (t, 3 H, Ме, J = 7.0); 1.30, 1.36—1.72 (both m, 20 H, СН of cyclohexane,
2
[
[
[
[
1696]
CH , Ad); 1.93 (s, 3 H, CH, Ad); 1.91, 2.05 (both t, 2 H, CH СН , J = 7.0);
2
2
3
6
.62 (d, 1 H, NH, J = 7.0)
1600
1700]
3060,
3292
257
(23.9)
4.37 1.17, 1.36, 1.40—1.75, 1.53, 2.07 (three m, s, m, 1 H, 1 H, 12 H, 6 H, 2 H,
CH of cyclohexane, CH , Ad); 1.92 (s, 3 H, CH, Ad); 3.91 (d, 2 H, NCH,
2
2
J = 8.0); 7.06 (d, 1 H, NH, J = 8.0); 7.22—7.33 (m, 5 H, H arom.)
4.41 1.25, 1.43, 1.53, 1.68, 2.06 (all m, 1 H, 2 H, 2 H, 3 Н, 2 H,
1600
1700]
3244
257
(29.5)
СН of cyclohexane); 5.62 (d, 1 H, NH, J = 7.0); 7.28—7.32 (m, 6 H,
2
H arom.); 7.36—7.39 (m, 4 Н, H arom.); 7.98 (d, 1 H, NH, J = 7.0)
j
1604
1704]
3068,
3228
220
(12.5),
4.40 1.24, 1.38, 1.52—1.81 (all m, 1 H, 2 Н, 7 H, СН of cyclohexane);
2
2.81 (t, 2 H, J = 7.0); 3.27 (q, 2 H, NCH , J = 7.0);
2
2
57
7.12 (br.s, 1 H, NH); 7.23 (d, 2 H, H arom., J = 8.0);
7.29 (d, 2 H, H arom., J = 7.0)
4.53 1.19, 1.43, 1.54, 1.60—1.81 (all m, 1 H, 2 H, 2 H, 5 H, СН of cyclohexane);
2
(
29.7)
256
6
6
k
l
1616
3064,
3320,
[
1700]
(26.1)
2.87 (t, 2 Н, СН Аr, J = 6.8); 3.30 (q, 2 H, NCH , J = 6.8); 7.32 (br.s, 3 H,
2 2
NН , NH); 7.44, 7.75 (both d, 2 H each, H arom., J = 7.0)
2
3
572
1608
3080,
3276
257
(26.5)
4.42 1.22, 1.43, 1.52—1.75, 1.79 (all m, 1 H, 2 H, 5 H, 2 H, СН of cyclohexane);
2
[
1700]
2.74 (t, 2 Н, СН Аr, J = 6.8); 3.24 (q, 2 H, NCH , J = 6.8); 3.73, 3.77 (both s,
2
2
6
6
H, ОМе); 6.72 (d, 1 H, H arom., J = 8.0); 6.83 (s, 1 H, H arom.);
.86 (d, 1 H, H arom., J = 8.0); 7.12 (br.s, 1 H, NH)
6
6
m
n
1604
3064,
3232
256
(28.0)
4.48 1.20, 1.40, 1.33, 1.67, 1.78 (all m, 1 H, 2 H, 2 H, 3 H, 2 H,
СН of cyclohexane); 1.31 (t, 6 H, Ме, J = 6.4); 2.72 (t, 2 H, СН Ar, J = 6.8);
[
1700]
2
2
3
6
.22 (q, 2 H, NCH , J = 6.8); 3.90—4.10 (both t, 4 H, ОСН , 2 J = 6.4);
2 2
.71 (dd, 1 H, H arom., J = 8.0, J = 2.0); 6.83 (t*, H arom.); 6.86 (br.s, 1 H,
H arom.); 7.27 (t, 1 H, NH, J = 6.8)
1604
3076,
3272
229
(36.9),
4.43 1.21, 1.43, 1.55, 1.67, 1.76 (all m, 1 H, 2 H, 2 H, 3 H, 2 H,
[
1700]
СН of cyclohexane); 2.33 (s, 3 H, МеС=); 2.86 (t, 2 H, СН C=, J = 7.0);
2
2
2
58
3.21 (q, 2 H, NCH , J = 7.0); 3.64 (s, 3 H, NМе); 6.99, 7.07 (both t, 1 H each,
2
(
25.7)
H arom., J = 6.0); 7.35 (d, 1 H, H arom., J = 6.0); 7.36 (br.s, 1 H, NH);
7
.44 (d, 1 H, H arom., J = 6.0)
(
to be continued)

Spiroꢀannelated aminobutenolides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2863
Table 3 (continued)
Comꢀ
poꢀ
und
IR, ν/cm–1
UV,
λmax/nm
(ε•10–3
)
1H NMR, δ (J/Hz)
С=С
NH
HC=
(s)
Signals of other protons
[
C=O]
6
о
1608
3064,
3284
226
(38.4),
4.42 1.22 (t, 3 H, СН СН , J = 8.0); 1.40—1.82 (m, 10 H, СН of cyclohexane);
2 3 2
[
1712]
2.32 (s, 3 H, MeС=); 2.80 (m, 4 H, NСН СН С=); 3.21 (q, 2 H, CH , Ar,
2 2 2
2
58
J = 8.0); 6.82 (d, 1 H, H arom., J = 8.0); 6.88 (t, 1 H, H arom., J = 8.0);
7.22 (d, 1 H, H arom., J = 8.0); 7.37 (t, 1 H, NH, J = 6.0);
(
25.5)
1
0.60 (s, 1 H, NH of pyrrole)
4.46 1.22, 1.43, 1.56—1.73, 1.61, 1.82 (three m, s, m, 1 H, 2 Н, 11 H, 6 H, 2 H,
СН of cyclohexane, CH , Ad); 2.08 (s, 3 H, CH, Ad); 3.13 (q, 2 H, NCH ,
6
6
р
q
1604,
616 sh
3084,
3256
255
(28.0)
1
2
2
2
[
1700]
J = 6.0); 3.45 (t, 2 H, ОСН , J = 6.0); 7.31 (t, 1 H, NH, J = 6.0)
2
1608
3072,
3240,
227
(32.1),
255
(28.8)
254
4.47 1.18, 1.37, 1.51, 1.65 (all m, 1 Н, 2 Н, 2 Н, 5 H,
[
[
1700]
СН of cyclohexane); 3.20, 3.53 (both q, 2 H each,
2
3
3
276,
340
NCH , J = 6.7); 5.47, 7.18 (both t, 1 H each,
2
NH, J = 6.7)
6
6
r
s
1614
1718]
3026,
3121,
4.46 1.25, 1.40—1.74, 1.81 (all m, 1 Н, 7 Н, 2 H, СН of cyclohexane);
2
(25.3)
2.96 (q, 2 H, HNCH , J = 6.8); 4.02 (t, 2 H, СН N of pyrazole, J = 6.8);
2 2
6.86, 7.21, 7.59 (all s, 1 H, 1 Н, 1 H, Н of pyrazole);
7.31 (t, 1 Н, NH, J = 6.8)
3
3
145,
214
1604,
640 sh
3088,
3288,
3384
351
(38.9)
4.42 1.25, 1.47, 1.52—1.83, 1.91 (all m, 1 H, 2 H, 7 H, 2 H, СН of cyclohexane,
2
1
NCH СН СН N); 3.26 (d, 2 H, NCH , J = 7.0); 3.49 (q, 2 H, NCH ,
2 2 2 2 2
[
1696]
J = 7.0); 7.12 (br.s, 1 H, NH); 7.26, 7.74 (d, 1 H, H arom., J = 8.0);
.32 (s, 1 H, H arom.); 8.43 (br.s, 1 H, NH)
4.42 1.23, 1.44, 1.46—1.74, 1.78 (all m, 1 H, 2 H, 7 Н, 2 H, СН of cyclohexane,
8
6
6
t
1608
3060,
3232
256
(23.2)
2
[
[
1700]
NCH СН СН N); 2.25—2.38 (m, 6 H, NCH ); 3.08 (q, 2 H, NCH , J = 6.8);
2 2 2 2 2
3
.55 (t, 4 H, ОСН , J = 7.0); 7.22 (t, 1 H, NH, J = 6.8)
2
u
1612
1720]
3212
255
(21.1)
4.41 1.22, 1.42, 1.56, 1.68, 1.82 (all m, 1 H, 2 H, 2 H, 3 H, 2 H,
СН of cyclohexane); 1.92 (quint, 2 H, СН , J = 7.0); 2.94 (q, 2 Н, NCH ,
2
2
2
J = 6.8); 3.98 (t, 2 Н, NCH , J = 6.8); 6.89, 7.18, 7.61 (all s, 1 H each,
2
Н of imidazole); 7.25 (t, 1 H, NH, J = 6.8)
6
6
v
1604
3080,
3248
255
(23.7)
4.38 1.02 (t, 3 H, Me, J = 7.0); 1.26, 1.38—1.98 (both m, 2 H, 14 H,
[
1700]
CH of cyclohexane, CH of piperidine); 2.38 (q, 2 H, NCH );
2
2
2
2
6
.71, 2.86 (both d, 2 H, NCH ); 3.16 (br.s, 3 H, NCH, NCH );
2 2
.79 (br.s, 1 H, NH)
w
1604
3272
253
4.63 1.22, 1.39—1.58, 1.68, 1.80 (all m, 1 H, 4 H, 3 H, 2 H, СН of cyclohexane);
2
[
1696]
(7.8)
2.11 (sextet, 1 H, β´ꢀCH of sulfolane, J = 7.5); 2.47 (q, 1 H,
2
β´ꢀCH of sulfolane, J = 6.6); 2.93 (dd, 1 H, αꢀCH S, J = 13.7, J = 6.2);
2
2
3
3
.14 (dt, 1 H, α´ꢀCH S, J = 8.5, J = 7.8); 3.32 (q, 1 H, αꢀCH S, J = 8.1);
2
2
.57 (dd, 1 H, αꢀCH S, J = 13.7, J = 8.1); 7.44 (d, 1 H, NH, J = 6.6)
2
6
x
1608
3008,
3244
248
(14.7)
4.51 1.12, 1.27, 1.32, 1.92 (all m, 1 H, 4 H, 3 H, 2 H, СН of cyclohexane);
2
[
1700]
7.54 (t, 2 H, H arom., J = 8.0); 7.61 (t, 1 H, H arom., J = 8.0); 7.81 (d, 2 H,
H arom., J = 8.0); 9.38, 9.74 (both s, 1 H each, NH)
6
1
y
1600
1700]
1608
1700]
3068,
3300
3080,
3272
258
(27.6)
260
4.62 1.18, 1.42—1.72, 1.85, 1.92 (two m, s, m, 2 H, 12 H, 6 H, 2 H,
[
[
CH of cyclohexane, CH , Ad); 2.06 (s, 3 H, CH, Ad); 6.54 (s, 1 H, NH)
2
2
0
4.42, 1.14 (d, 3 H, Me, J = 7.6); 1.19, 1.37, 1.51, 1.56—1.76 (all m, 2 H, 4 H, 4 H,
4.51 10 H, СН of cyclohexane); 3.00—3.16 (m, 2 H, NCH ); 3.44 (septet, 1 H,
(35.1)
2
2
NCH, J = 7.6); 6.97 (d, 1 H, NH, J = 7.6); 7.24 (t, 1 H, NH, J = 6.8)
*
The degenerate triplet.
4
ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ꢀ (7r), 4ꢀ[4ꢀ(4ꢀnitrophenyl)piperꢀ
noꢀ (6w), 4ꢀN´ꢀbenzoylhydrazinoꢀ (6x), 4ꢀ[(S)ꢀ2ꢀ(3ꢀpyridyl)piꢀ
peridinꢀ1ꢀyl]ꢀ (7o), and 4ꢀ(2,6ꢀdimethylmorpholinꢀ4ꢀyl)ꢀ1ꢀ
oxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀone (7v).
azinꢀ1ꢀyl]ꢀ (7s), 4ꢀ[4ꢀ(adamantanꢀ1ꢀyl)piperazinꢀ1ꢀyl]ꢀ (7u),
ꢀ(1,3,3ꢀtrimethylꢀ6ꢀazabicyclo[3.2.1]octꢀ6ꢀyl)ꢀ1ꢀoxaspiꢀ
4
ro[4.5]decꢀ3ꢀenꢀ2ꢀone (7x), and N,Nꢀbis(2ꢀoxoꢀ1ꢀoxaspiꢀ
ro[4.5]decꢀ3ꢀenꢀ4ꢀyl)ꢀ1,2ꢀdiaminopropane (10).
The C, b was used to synthesize 4ꢀ[2ꢀ(pyrrolꢀ1ꢀyl)benꢀ
zylamino]ꢀ (6d), 4ꢀ(1,1ꢀdioxotetrahydrothiophenꢀ3ꢀyl)amiꢀ
The following compounds were synthesized according to the
procedure D, b: 4ꢀ[2ꢀ(1,2ꢀdimethylindolꢀ3ꢀyl)ethylamino]ꢀ (6n),
4ꢀ[2ꢀ(8ꢀethylꢀ2ꢀmethylindolꢀ3ꢀyl)ethylamino]ꢀ (6o), 4ꢀ(adaꢀ
mantanꢀ1ꢀyl)aminoꢀ (6y), and 4ꢀ[(1ꢀphthalimidomethyl)ꢀ

2864
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Mavrov et al.
Table 4. Main spectroscopic characteristics of compounds 7a—x
Comꢀ
poꢀ
und
IR, ν/cm–1
UV,
λmax/nm
(ε•10–3
)
1H NMR, δ (J/Hz)
С=С
Other
HC=
(s)
Signals of other protons
[
C=O]
groups
7
7
7
а
b
c
1584
271
(29.7)
4.53
0.87 (d, 12 H, CH(CH ) , J = 7.6); 1.31, 1.57—1.74, 1.93 (all m, 1 H,
3 2
7 H, 2 H, СН of cyclohexane); 2.04 (septet, 2 H, CHMe , J = 7.6);
2 2
[
1720]
3
.11 (d, 4 H, NCH , J = 7.6)
2
1576
—
—
270
(28.2)
4.43,
4.52
0.82—1.03, 1.16, 1.38—1.92, 2.06 (all m, 12 H, 1 H, 14 H, 1 H,
CH of cyclohexane, CH CH CH CH );
[
1716]
2
2
2
2
3
(
1 H) 3.09—3.29 (m, 4 H, NCH2)
1588
269
4.53
0.30, 0.54 (both q, 2 H, 2 H, CH of cyclopropane, J = 4.4); 0.86 (t, 3 H, Me,
2
[
1724]
(24.9)
J = 7.4); 0.92 (t, 1 H, CH of cyclopropane, J = 7.2); 1.33, 1.54—1.72,
1
.93 (all m, 1 H, 9 H, 2 H, CH of cyclohexane, NCH CH CH ); 3.18 (d, 2 H,
2 2 2 3
NCH CH, J = 7.0); 3.26 (t, 2 H, NCH CH , J = 7.0)
2
2
2
7
7
7
d
e
f
1592
3368
(OH)
267
(20.8)
4.42
4.59
4.50
1.32, 1.53—1.75, 2.02 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
[
[
[
1696]
2.96 (s, 3 H, Me); 3.35 (t, 2 H, NCH , J = 7.2); 3.62 (q, 2 H, OCH , J = 7.2);
2
2
4
.68 (t, 1 H, OH, J = 7.2)
1588
1716]
—
—
266
(33.5)
1.33, 1.52—1.71, 2.04 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
2.94 (s, 9 H, NMe); 4.59 (s, 2 H, NCH ); 7.19 (d, 2 H, H arom., J = 8.0);
2
7
.31 (t, 1 H, H arom., J = 8.0); 7.39 (t, 2 H, H arom., J = 8.0)
1584
1720]
266
(30.2)
1.28, 1.63, 2.01 (all m, 1 H, 7 H, 2 H, СН of cyclohexane); 1.09 (t, 3 H, Me,
2
J = 8.0); 3.32 (br.s, 2 H, NCH ); 4.55 (s, 2 H, NCH Ar); 7.22 (d, 2 H,
2
2
H arom., J = 8.0); 7.29 (t, 1 H, H arom., J = 8.0);
7
.38 (t, 2 H, H arom., J = 8.0)
7
g
1580
3388
267
4.52
1.30, 1.61, 2.03 (all m, 1 H, 7 H, 2 H, СН of cyclohexane); 3.35 (br.s,
2
[
1692]
(OH)
(29.9)
2 H, NCH ); 3.55 (q, 2 H, OCH , J = 5.4); 4.64 (br.s, 2 H, NCH Ar);
2
2
2
4
.87 (br.s, 1 H, OH); 7.19 (d, 2 H, H arom., J = 8.0); 7.30 (t, 1 H,
H arom., J = 8.0); 7.39 (t, 2 H, H arom., J = 8.0)
1.31, 1.60, 2.00 (all m, 1 H, 7 H, 2 H, СН of cyclohexane); 4.55 (br.s,
7
7
7
h
i
1596
1572
(Ar)
267
(25.3)
4.72
4.59
4.62
2
[
1724]
4 H, NCH Аr); 7.20 (d, 4 H, H arom., J = 8.0); 7.28 (t, 2 H,
2
H arom., J = 8.0); 7.38 (t, 4 H, H arom., J = 8.0)
1.16 (d, 3 H, Ме, J = 7.6); 1.36, 1.49—1.71, 1.95 (all m, 2 H, 12 H, 2 H,
1584,
708
—
—
—
270
(27.6)
1
CH of cyclohexane, CH of piperidine); 3.11 (td, 1 H, NCH , J = 7.0,
2
2
2
J = 1.9); 3.54 (d, 1 H, NCH , J = 7.0); 3.91 (br.s, 1 H, NCH)
2
j
1572
270
(30.3)
0.84 (t, 3 H, Ме, J = 7.2); 1.35, 1.50—1.75, 1.95 (all m, 2 H, 14 H, 2 H,
[
1720]
CH of cyclohexane, CH of piperidine, CH CH ); 3.08 (t, 1 H, NCH ,
2 2 2 3 2
J = 7.6); 3.63 (m, 2 H, NCH, NCH2)
0.89 (d, 3 H, Me, J = 7.2); 1.09, 1.37, 1.50—1.72, 1.96 (all m, 2 H, 1 H,
10 H, 2 H, CH of cyclohexane, СН , СН of piperidine)
7
7
k
l
1584
1717]
1580
1720]
270
(29.1)
268
4.64
4.74
[
[
2
2
1736
(COOEt)
1.19 (t, 3 H, Me, J = 7.6); 1.36, 1.47—1.71, 1.85—2.02 (all m, 1 H, 9 H,
4 H, СН of cyclohexane, СН of piperidine); 2.67 (m, 1 Н, СН of piperidine);
(27.7)
2
2
3
.12 (td, 2 H, NCH , J = 12.0, J = 2.0); 3.69, 3.73 (both t, 2 H, NCH ,
2 2
J = 2.0); 4.08 (q, 2 H, ОСН , J = 7.6)
2
7
7
m
n
1576,
684,
1696 sh]
1580
3180,
3376
(NH2)
1724,
1424,
268
(26.6)
4.69
4.66
1.35, 1.45—1.82, 1.96 (all m, 1 H, 11 H, 2 H, СН of cyclohexane,
2
СН of piperidine); 2.42 (m, 1 H, СН of piperidine); 3.04 (t, 2 H, NCH ,
2 2
J = 12.0); 3.76 (d, 2 H, NCH , J = 12.0); 6.85, 7.32 (both с, 2 H, NH )
2 2
1
[
268
(30.4)
1.27—1.72, 1.91 (both m, 18 H, 2 H, CH of cyclohexane, СН of piperidine);
2
2
[
1624]
2.92 (br.t, 1 H, СН of piperidine, J = 13.0); 3.11 (br.t, 2 H, NCH2,
J = 13.0); 3.42, 3.49 (both t, 4 H, NCH , J = 6.0);
1
204
2
(
amide)
—
3.78 (br.d, 2 H, NCH , J = 13.0)
1.38, 1.49—1.75, 1.82—2.02, 2.12, 2.36 (all m, 2 H, 10 H, 2 Н, 1 H,
2
7
о
1580
268
4.70
[
1712]
(25.7)
1 H, СН of cyclohexane, СН of piperidine); 3.08 (t, 1 H, NCH ,
2 2 2
J = 13.0); 3.76 (d*, 1 H, NCH ); 5.18 (br.s, 1 H, NCH); 7.43 (dd, 1 H,
2
Н of pyridine, J = 8.0, J = 4.0); 7.63 (d, 1 H, Н of pyridine, J = 8.0);
8
.46 (s, 1 H, H of pyridine); 8.51 (d, 1 H, Н of pyridine, J = 4.0)
(
to be continued)

Spiroꢀannelated aminobutenolides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2865
Table 4 (continued)
Comꢀ
poꢀ
und
IR, ν/cm–1
UV,
λmax/nm
(ε•10–3
)
1H NMR, δ (J/Hz)
С=С
Other
HC=
(s)
Signals of other protons
[
C=O]
groups
7
7
7
7
p
q
r
1584
3190
(OH)
266
(13.0)
4.67
4.70
4.76
4.73
1.32, 1.50—1.73, 1.91 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
2.40—2.70 (br.s, 6 H, NCH ); 3.35 (br.s, 4 H, NCH ); 3.54 (q, 2 H,
2 2
[
1728]
ОСН , J = 5.4); 4.42 (br.s, 1 H, NH)
2
1592
2248
(C≡N)
267
(30.8)
1.32, 1.53—1.72, 1.90 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
2.47 (t, 4 H, CH CN, NCH , J = 4.6); 2.62, 2.69 (both t, 2 H each,
2 2
[
1720]
NCH , J = 4.6); 3.38 (t, 4 H, NCH , J = 4.6)
2
2
1592
—
—
267
(37.9)
1.35, 1.54—1.74, 2.01 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
[
1720]
3.39, 3.53 (both t, 4 H each, NCH , J = 4.6); 6.83 (t, 1 H, H arom.,
2
J = 8.0); 6.97 (d, 2 H, H arom., J = 8.0); 7.50 (t, 2 H, H arom., J = 8.0)
1.34, 1.54—1.75, 2.01 (all m, 1 H, 7 H, 2 H,
s
1596,
604
266
(26.5),
376
18.8)
268
1
СН of cyclohexane); 3.21 (s, 2 H, NCH ); 3.60 (s, 6 H, NCH );
2
2
2
[
[
[
[
1712]
7.01, 8.09 (both d, 2 H each,
H arom., 2 J = 8.0)
(
7
7
7
t
1588
1716]
—
—
—
4.78
4.51
4.64,
1.35, 1.60, 1.67, 2.01 (all m, 1 H, 4 H, 3 H, 2 H, СН of cyclohexane);
2
(30.2)
3.11, 3.53 (both t, 4 H each, NCH , 2 J = 4.6); 6.80, 6.98 (both d, 2 H each,
2
H arom., 2 J = 6.0); 7.09 (t, 2 H, H arom., J = 9.0)
u
v
1584
1728]
268
(29.7)
1.28, 1.56—1.79, 1.93 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
1.69 (s, 12 H, CH , Ad); 2.11 (s, 3 H, CH, Ad); 2.64, 3.32 (both br.s,
2
4
H each, NCH2)
1580
1716]
268
(26.2)
A: 1.22 (d, 6 H, Me, J = 7.2); 1.36, 1.55—1.72, 1.95 (all m, 1 H, 7 H,
4.70** 2 H, СН of cyclohexane); 3.12 (dd, 2 H, NCH , J = 12.0, J = 4.0);
2
2
3
.43 (d, 2 H, NCH , J = 12.0); 3.96 (t, 2 H, OCH, J = 4.0)
2
B: 1.20 (d, 6 H, Me, J = 7.2); 1.36, 1.55—1.72, 1.95 (all m, 1 H, 7 H,
2
3
H, СН of cyclohexane); 2.68 (t, 2 H, NCH , J = 12.0);
2
2
.55 (m, 2 H, OCH); 3.61 (d, 2 H, NCH , J = 12.0)
2
7
w
x
1568
1724
(amide)
220
(33.5),
4.52
—
1.08, 1.32—1.70, 1.96 (all m, 1 H, 7 H, 2 H, СН of cyclohexane);
2
2.82 (m, 2 H, CH Ar); 3.78 (m, 1 H, NCH ); 3.96 (m, 2 H, NCH );
2 2 2
[
1712]
2
67
4.13 (br.t, 1 H, NCH , J = 12.0); 5.01 (br.s, 1 H, NCH of piperidine);
2
(
11.8)
270
7.26 (br.s, 4 H, H arom.); 7.88 (m, 4 H, H arom.)
0.89, 0.94, 1.09 (all с, 3 H each, Ме); 1.18—2.20 (m, 16 H,
7
1584
—
[
1720]
(28.1)
СН of cyclohexane, СН of bicyclic fragment); 3.55—3.95 (both m, 2 H,
2
2
NCH ); 4.25—4.55 (m, 2 H, СН=, NCH)
2
*
*
The unresolved doublet.
* Diastereomers A and B in a ratio of ~1 : 5.
1
,2,3,4ꢀtetrahydroisoquinolinꢀ2ꢀyl]ꢀ1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀ
one (7w).
The yields, elemental analysis data, and the melting
signals characteristic of compound 7y (δ): 6.54 (s, 1 H, CH=);
7.21, 7.89, and 8.49 (all s, 3 H, H of imidazole).
Methyl 3ꢀ(1ꢀhydroxycyclohexyl)ꢀ3ꢀ[3ꢀ(2ꢀmethylimidazolꢀ1ꢀ
yl)propylamino]propꢀ2ꢀenoate (4z) and 4ꢀ[3ꢀ(2ꢀmethylimidazolꢀ
1ꢀyl)propylamino]ꢀ1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀone (6z) (see
Table 1). A mixture of compounds 4z+6z was obtained in a
points for compounds 6a—z and 10 are given in Table 1;
for compounds 7a—y, in Table 2. The IR, UV, and
1
H NMR spectroscopic data are presented, respectively, in
–
1
Tables 3 and 4. The massꢀspectrometric data are listed in
Tables 1, 2, and 5.
ratio of 1 : 5, m.p. 99—102 °C. IR, ν/cm : 1612, 1656, 1728,
1
3048, 3210. Compound 4z. H NMR, δ: 1.89 (s, 3 H, MeC=);
Methyl 3ꢀ(1ꢀhydroxycyclohexyl)ꢀ3ꢀ(imidazolꢀ1ꢀyl)propꢀ2ꢀ
enoate (5y) and 4ꢀ(imidazolꢀ1ꢀyl)ꢀ1ꢀoxaspiro[4.5]decꢀ3ꢀenꢀ2ꢀone
3.07 (q, 2 H, NC(1)H , J = 6.7 Hz); 3.22 (s, 3 H, ОMe); 3.86
2
(br.t, 2 H, NC(3)H , J = 6.2 Hz); 5.05 (br.s, 1 H, ОH); 6.71 and
2
(
7y) (see Table 2). A mixture of compounds 5y+7y was obtained
7.91 (both s, 2 H, H of imidazole); 6.72 (t, 1 H, NH, J =
6.7 Hz). In addition, the spectrum showed characteristic signals
of compound 6z (δ, J/Hz): 2.52 (s, 3 H, MeC=); 3.00 (q, 2 H,
NC(1)H , J = 6.7 Hz); 3.91 (t, 2 H, NC(1)H , J = 6.4 Hz);
6.74 and 7.05 (both s, 2 H, H of imidazole), 7.37 (t, 1 H, NH,
J = 6.7 Hz).
1
in a ratio of 14 : 3. Recrystallization of this mixture ( H NMR
data) led to enrichment with γꢀlactone 7y to form a mixture of
5
ether—diethyl ether, 2 : 1). IR, ν/cm : 1632, 1660, 1732, 1748,
3
5
y+7y in a ratio of 12 : 5, m.p. 125—132 °C (petroleum
2
2
–
1
1
112, 3152. Compound 5y. H NMR, δ: 3.52 (s, 3 H, ОMe);
.27 (s, 1 H, ОH); 6.39 (s, 1 H, CH=); 6.95, 7.19, and 7.47
4ꢀOxopiperidinium (1ꢀhydroxycyclohexyl)ethynylcarboxylate
(11a). The yield was 47%, m.p. 253—254 °C. Found (%): N, 5.31.
(
all s, 3 H, H of imidazole). In addition, the spectrum showed

2866
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Mavrov et al.
Table 5. Mass spectra of compounds 6a,c,g,m,u,w, 7n,o,t, and 10
4. A. A. Avetisyan and G. G. Tokmadzhyan, Khim. Geterotsikl.
Soedin., 1987, 723 [Chem. Heterocycl. Compd., 1987 (Engl.
Transl.)].
Comꢀ
pound
m/z (I (%))*
5
6
. Eur. Pat. 266 182; Chem. Abstr., 1988, 109, 110243h.
. B. Gabriele, G. Salerno, P. Plastina, M. Costa, and
A. Crispini, Adv. Synth. Catal., 2004, 346; 351.
6
6
6
6
6
6
7
7
а
c
215 (27.7), 202 (41.0), 132 (45.1), 93 (33.4),
9
2 (100), 68 (38.1)
189 (24.1), 135 (100), 107 (26.8), 93 (49.3),
9 (62.2), 68 (40.0)
208 (46.6), 207 (21.1), 135 (100), 93 (40.2),
9 (62.2), 68 (35.1)
192 (88.0), 180 (31.9), 179 (100), 151 (50.2),
23 (65.4)
149 (77.3), 109 (39.8), 95 (74), 82 (100),
8 (31.5)
229 (22.9), 137 (23.6), 68 (34.7), 55 (100),
1 (84.0)
234 (90.3), 190 (100), 140 (85.3), 84 (44.1),
9 (43.0)
268 (50.2), 213 (30.9), 185 (39.3), 176 (56.3),
32 (45.3), 106 (44), 68 (30.0), 41 (100)
7. R. S. Vartanyan, Sintez osnovnykh lekarstvennykh sredstv
[Synthesis of Main Drugs], Meditsinskoe informatsionnoe
agentstvo, Moscow, 2005, 845 pp. (in Russian).
8. G. M. Dyson and P. May, May´s Chemistry of Synthetic
Drugs, Longman, London, 1959.
9. M. Negwer, Organischꢀchemische Arzneimittel and ihre
Synonima, Acad. Verlag, Berlin, 1971.
10. A. A. Semenov, Ocherki khimii prirodnykh soedinenii [Essays
of Chemistry on Natural Compounds], Nauka, Novosibirsk,
2000, 664 pp. (in Russian).
7
g
7
m
u
w
n
o
1
6
4
11. J. S. Rao, Chem. Rev., 1976, 76.
12. I. Paltenden, Fortschr. Chem. Org. Naturst., 1978, 35, 133.
13. I. Ohloff, Fortschr. Chem. Org. Naturst., 1978, 35, 431.
14. M. V. Mavrov and N. I. Simirskaya, Khim. Geterotsikl.
Soedin., 1999, 1330 [Chem. Heterocycl. Compd., 2000, 1150
(Engl. Transl.)].
6
1
7
1
t
0
150 (100), 137 (22.8), 123 (67.9), 122 (58.2)
194 (35.9), 181 (39.6), 91 (35.2), 55 (43.5),
15. E. D. de Silva and P. J. Scheuer, Tetrahedron Lett., 1980,
21, 1611.
4
4 (100)
1
6. B. C. M. Potts, D. J. Faulkner, M. S. de Carvalho, and R. S.
Jacobs, J. Am. Chem. Soc., 1992, 114, 5093.
*
The signals with intensities of no lower than 20% are given.
1
7. H. He, P. Kulanthaivel, and B. J. Baker, Tetrahedron Lett.,
1
994, 35, 7189.
18. N. Fusetani, M. Takahashi, and S. Matsunaga, Tetrahedron,
996, 37, 3951.
C H NO . Calculated (%): N, 5.24. IR, ν/cm–1: 1560, 1640,
14
21
4
1
1
660, 2208 (C≡C); 3420. H NMR, δ: 1.08—1.24 and 1.38—1.83
1
(
both m, 3 H, 7 H, CH of cyclohexane); 2.52 and 2.74 (both m,
2
19. E. W. Schmidt and D. J. Faulkner, Tetrahedron Lett., 1996,
37, 3951.
20. S. P. Gunasckera, P. J. McCarthy, M. KellyꢀBorges,
E. Lolkousky, and J. Clardy, J. Am. Chem. Soc., 1996,
2
H each, CH C=О); 3.09 (t, 2 H, NCH , J = 7.2 Hz); 3.52
2 2
(
br.s, 2 H, NCH ); 6.23 (s, 1 H, ОH); 8.52 (br.s, 2 H,
2
NH, CООH).
Dicyclohexylammonium (1ꢀhydroxycyclohexyl)ethynylcarbꢀ
oxylate (11b). The yield was 39%, m.p. 206—207 °C. Found (%):
1
18, 8759.
2
1. B. A. Trofimov, L. V. Andriyankova, R. T. Tlegenov, A. G.
Mal´kina, A. V. Afonin, L. N. Il´icheva, and L. P. Nikitina,
Mendeleev Commun., 2005, 33.
22. R. E. Valter, Kol´chatoꢀtsepnaya izomeriya v organicheskoi
khimii [RingꢀChain Isomerism in Organic Chemistry], Zinatne,
Riga, 1978, 238 pp. (in Russian).
–
1
N, 4.01. C H NO . Calculated (%): N, 4.01. IR, ν/cm
:
21
35
3
1
1
3
548, 1632, 2224 (C≡C); 3280. H NMR, δ: 1.02—2.05 (m,
0 H, CH of cyclohexane); 2.98 (br.t, 2 H, NCH); 4.90—5.30
2
(
br.s, 2 H, ОH, NH); 8.50—10.60 (br.s, 1 H, CООH).
2
3. R. E. Valters and W. Flitsch, RingꢀChain Tautomerism,
Plenum Press, New York, 1985, No. 4, 278.
References
2
4. Ya. F. Freimanis, Khimiya enaminoketonov, enaminoiminov,
enaminotionov [Chemistry of Enamino Ketones, Enamino Imiꢀ
nes, and Enamino Thiones], Zinatne, Riga, 1974, 278 pp. (in
Russian).
1
2
. V. L. Sparnins, J. Chuan, and L. W. Wattenberg, Cancer
Res., 1982, 42, 1205; Chem. Abstr., 1982, 96, 178894q.
. V. L. Sparnins, P. L. Venegas, and L. W. Wattenberg,
J. Natl. Cancer Inst., 1982, 68, 493; Chem. Abstr., 1982, 96,
2
10536n.
Received September 23, 2005;
3
. Jpn Pat. 63 211 276; Chem. Abstr., 1989, 110, 94978q.
in revised form November 7, 2005