Synthesis of 2-aryl and 2-hetaryl derivatives of 2′-aminospiro[(1,3- dioxane)-5,5′-thiazolin]-4′-one and spiro[(1,3-dioxane)-5,5′- thiazolidine]2′,4′-dione

Article abstract of DOI:10.1023/B:COHC.0000044576.75311.08

2-(Het)aryl derivatives of 2′-aminospiro[(1,3-dioxane)-5,5′- thiazolin]-4′-one or spiro[(1,3-dioxane)-5,5′-thiazolidine]- 2′,4′-dione are formed by the acid catalyzed interaction of 2-amino-5,5-bis(hydroxymethyl)-4-thiazolinone or its oxo analog 5,5-bis(h

Full text of DOI:10.1023/B:COHC.0000044576.75311.08

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
SYNTHESIS OF 2-ARYL AND 2-HETARYL
DERIVATIVES OF 2'-AMINOSPIRO[(1,3-DIOXANE)-
5,5'-THIAZOLIN]-4'-ONE AND SPIRO[(1,3-DIOXANE)-
5,5'-THIAZOLIDINE]-2',4'-DIONE
S. M. Ramsh1, A. G. Ivanenko2, V. A. Shpilyovy1, N. L. Medvedskiy1, and P. M. Kushakova1
2-(Het)aryl derivatives of 2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one or spiro[(1,3-dioxane)-
5,5'-thiazolidine]-2',4'-dione are formed by the acid catalyzed interaction of 2-amino-5,5-
bis(hydroxymethyl)-4-thiazolinone or its oxo analog 5,5-bis(hydroxymethyl)thiazolidine-2,4-dione with
(hetero)aromatic aldehydes.
Keywords: 2-amino-5,5-bis(hydroxymethyl)-4-thiazolinone, 2-(het)aryl derivatives of 2'-aminospiro-
[(1,3-dioxane)-5,5'-thiazolin]-4'-one and spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione, reactions with
aldehydes.
It is known that polyatomic alcohols are able to react with aldehydes and ketones under the influence of
acid catalysts to form cyclic acetals and ketals [1]. In particular derivatives of 1,3-dioxane are formed from
1,3-diols [2]. It seemed of interest to discover whether the compounds 2-amino-5,5-bis(hydroxymethyl)-4-
thiazolinone (1) and its oxo analog 5,5-bis(hydroxymethyl)-2,4-thiazolidinone (2), which we synthesized
previously [3], would undergo similar reactions. It seemed that they did not differ in their structures from other
1,3-diols and formed with aromatic and heteroaromatic aldehydes in the presence of acid 2-(het)aryl-2'-
aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-ones 3a-l or 2-(het)aryl-2'-aminospiro[(1,3-dioxane)-5,5'-thiazolidine]-
2',4'-diones 4a-l respectively (Table 1).
O
O
N
N
RCHO
CH2OH
CH2OH
O
H2N
S
H2N
S
O
O
R
R
3a–l
1
O
HN
HN
CH2OH
CH2OH
RCHO
O
O
S
O
S
O
2
4a–l
3,4 a R = Ph; b R = o-С6Н4Cl; c R = m-С6Н4Br; d R = p-С6Н4NO2; e R = m-С6Н4NO2;
f R = 3-Py; g R = 4-Py; h R = p-С6Н4NMe2; i R = p-С6Н4NEt2; j R = p-С6Н4OMe;
k R = m,p-С6Н3(OMe)2; l R = p-С6Н4Me
__________________________________________________________________________________________
1
St. Petersburg State Technological Institute (Technical University), St. Petersburg 198013, Russia;
e-mail: gsramsh@mail.wplus.net. 2 Institute of Toxicology, Ministry of Public Health of the Russian Federation,
St. Petersburg 193019, Russia; e-mail: drugs@mail.lanck.net. Translated from Khimii Geterotsiklicheskikh
Soedinenii, No. 7, 1068-1075, July 2004. Original article submitted October 12, 2003.
0009-3122/04/4007-0919©2004 Springer Science+Business Media, Inc.
919

TABLE 1. 2-Aryl(hetaryl)-2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-ones
3a-l and 2-aryl(hetaryl)[spiro(1,3-dioxane)-5,5'-thiazolidine]-2',4'-diones 4a-l
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
3a
3b
3c
3d
3e
C12H12N2O3S
C12H11ClN2O3S
C12H11BrN2O3S
C12H11N3O5S
C12H11N3O5S
54.40
54.53
48.31
48.24
41.88
42.00
46.64
46.60
4.49
4.58
3.64
3.71
3.21
3.23
3.67
3.58
10.70
10.60
9.43
9.38
8.28
8.16
13.58
13.59
273-275
257-259
269-270
350-353
50
52
46
57
78
295-298
(dec.)
46.74
46.60
3.64
3.58
13.65
13.59
3f
3g
3h
3i
C11H11N3O3S
C11H11N3O3S
C14H17N3O3S
C16H21N3O3S
295-300
(dec.)
81
81
70
35
49.86
49.80
3.95
4.18
15.86
15.84
302-305
(dec.)
49.89
49.80
4.14
4.18
15.89
15.84
238-240
(dec.)
54.79
54.71
5.66
5.57
13.67
13.67
232-234
(dec.)
57.27
57.29
6.30
6.31
12.48
12.53
3j
3k
3l
C13H14N2O4S
C14H16N2O5S
C13H14N2O3S
53.18
53.05
51.85
51.84
4.71
4.79
5.01
4.97
9.59
9.52
8.59
8.64
260-262
72
38
61
258-260
263-265
(dec.)
56.05
56.10
5.11
5.07
10.01
10.06
4a
4b
4c
4d
C12H11NO4S
54.39
54.33
48.11
48.09
42.00
41.88
4.14
4.18
3.30
3.36
2.82
2.93
5.36
5.28
4.59
4.67
4.08
4.07
203-205
214-216
173-175
60
51
71
90
C12H10ClNO4S
C12H10BrNO4S
C12H10N2O6S
263-265
(dec.)
46.53
46.45
3.17
3.25
9.05
9.03
4e
4f
C12H10N2O6S
C11H10N2O4S
C11H10N2O4S
C14H16N2O4S
C16H20N2O4S
235-238
(dec.)
82
83
80
30
82
46.45
46.45
3.21
3.25
9.15
9.03
254-258
(dec.)
49.60
49.62
3.90
3.79
10.50
10.52
4g
4h
4i
272-275
(dec.)
49.43
49.62
3.58
3.79
10.47
10.52
200-203
(dec.)
54.68
54.53
5.22
5.23
9.20
9.08
206-208
(dec.)
57.17
57.12
5.92
5.99
8.29
8.33
4j
C13H13NO5S
C14H15NO6S
52.81
52.87
4.35
4.44
4.73
4.74
198-201
60
47
4k
239-241
(dec.)
51.65
51.68
4.60
4.65
4.35
4.31
4l
C13H13NO4S
55.97
55.90
4.73
4.69
4.97
5.01
212-215
68
All reactions were carried out in sulfuric acid or boron trifluoride etherate, i.e., the acid and etherate
were used as both catalysts and as reaction media. In the case of the basic aldehydes (R = p-C6H4NMe2,
p-C6H4NEt2, 3-Py, 4-Py) this facilitated the appearance of the catalytic effect by neutralization of their basicity.
The syntheses were carried out at room temperature by simple mixing of the reagents in the following
order: the aldehyde was added to a mixture of compound 1 or 2 in sulfuric acid or boron trifluoride etherate.
When the reaction mixture was heterogeneous it was subjected to intense stirring. As a rule a precipitate of the
920

product appeared after 4h to 10 d, it was filtered off and was treated with NaHCO3 solution. If a precipitate did
not occur after prolonged standing or appeared in only small amounts, it was either precipitated with diglyme or
absolute ether or it was isolated after neutralization with excess NaHCO3.
In sulfuric acid the reaction proceeded sufficiently for isolation of the reaction products only with
pyridinealdehydes, nitro- and amino-substituted benzaldehydes, i.e. in those cases in which the aryl substituent
in the aldehyde itself possessed strong acceptor properties (p-C6H4NO2, m-C6H4NO2), or acquired them by
protonation of the substituent (p-C6H4NMe2, m-C6H4NEt2), or of the hetaryl ring (3-Py, 4-Py). With the
remaining benzaldehydes the electrophilicity of carbonyl carbon with respect to the protonic acid is evidently
insufficient for condensation with the alcohol, however when a Lewis acid was used – boron trifluoride etherate
– the reaction proceeded with acceptable yields.
The acid-base properties of the heterocyclic fragment of the diol (for compound 1 pKa of the conjugate
acid is probably close to the pKa of 2-amino-2-thiazolinone, ~2.1[4]; the estimated value of the pKa of the acid
ionization for compound 2, based on potentiometric titration with aqueous base, is ~6.0) probably do not affect
the reaction under the reaction conditions, and the other diols can condense with aromatic and heteroaromatic
aldehydes in any case.
Because of the high acidity of compound 2 the amino-substituted benzaldehydes form salts with it which
are difficult to dissolve and make it difficult to separate the reaction products. We observed a similar difficulty
for these aldehydes in carrying out the reaction with boron trifluoride etherate, evidently because of formation of
poorly soluble complexes with the etherate. In all these cases sulfolan was added to homogenize the reaction
mixture. A similar method was used to obtain derivatives of veratraldehyde (3,4-dimethoxybenzaldehyde) which
apparently also forms a poorly soluble complex with boron trifluoride etherate.
Compounds 3a-l and 4a-l are high melting crystalline compounds, which im most cases decompose on
melting (Table 1), the composition and structure of which were determined via spectroscopic data (Table 2).
The characteristic signals in the 1H NMR spectra of compounds 3a-l and 4a-l are found in narrow ranges
of chemical shifts. Thus the proton signals for the NH2 groups in compounds 3 fall in the range 9.1-8.9, while
those for the NH groups in compounds 4 fall in the range 12.4-12.1 ppm. The signals for proton H-2 of the 1,3-
dioxane rings are found in the range 6.0-5.5, and those of H-4 and H-6 in the range 4.5-4.2 ppm for all of the
compounds 3 and 4. As a rule the signals of the protons H-4 and H-6 are split into a geminal AB quartet, but in
the spectra of compounds 4b,d, and l these signal are singlets.
In the 1H NMR spectra of compounds 3g and 4g two sets of proton signals were observed. On the basis
of the pattern of the spectrum, the integrated intensities of the observed signals, and the elemental analyses, it
can be concluded that these are individual compounds, nut which exist under the conditions of recording the
spectra as a mixture of two geometric isomers in the ratios of 2.9:1 and 9:1 respectively, which probably differ in
the conformation of the dioxane rings.
EXPERIMENTAL
IR spectra of KBr disks were recorded on UR-20 spectrometer. 1H NMR spectra of DMSO-d6 solutions
with TMS internal standard were recorded on Bruker AC-200 (200 MHz) (compound 4b), Bruker AM-300
(300 MHz) (compounds 3a,c-h,j-l, 4a,c-g,k,l), and Bruker AM-500 (500 MHz) (3b,i, 4h-j) instruments. TLC
was carried out on Silufol UV-254 strips with 5:1 benzene–2-propanol as eluent.
2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone (1) and 5,5-bis(hydroxymethyl)thiazolidine-2,4-
dione (2) were prepared by a previousl described method [3].
921

TABLE 2. Spectroscopic Characteristics of Compounds 3a-l and 4a-l
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm
Com-
pound
С=О
С=N
NH
4
Ph(Py), m
5
C(2)H, s
C(4(6))HA*
7
C(4(6))HB*
8
R
9
1
2
3
6
—
3a
3b
3c
3d
3e
3f
1680
1675
1675
1690
1700
1690
1650
1640
1650
1650
1670
1650
9.2, 9.0
9.2, 9.0
9.0
7.4*2
7.8-7.2
5.8
6.0
5.8
6.0
5.9
5.9
4.4
4.4
4.4
4.5
4.5
4.5
4.2
4.2
4.2
4.2
4.2
4.2
—
—
—
—
—
8.1-7.0
9.1, 9.0
9.2, 8.9
9.2, 8.9
8.3, 7.7
8.3-7.6
8.6, 7.8, 7.4
8.64 (2),
8.57 (1), 7.43 (2),
7.39 (1)
9.2 (1+2),
8.9 (1), 8.8 (2)
5.9 (2),
5.8 (1)
4.5 (1),
4.2 (2)
3g*3
1660
1620
4.2 (1), 4.0 (2)
—
3h
3i
1700
1700
1650
1625
9.1, 8.9
9.0, 8.8
7.2, 6.6
5.6
5.5
4.4
4.4
4.1
4.1
2.9, s
3.4, q*4;
7.2, 6.6
1.2, t*5
3j
3k
3l
1665
1670
1620
1640
1650
1640
9.1, 8.9
9.1, 8.9
9.1, 8.9
12.2
7.3, 6.9
7.0-6.8
7.3, 7.2
7.4*2
5.7
5.6
5.7
5.7
4.4
4.4
4.4
4.5
4.2
4.1
4.1
4.4
3.8, s
3.8, s
2.3, s
—
1690
4a
1770, 1690

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
4b
1760, 1715
1760, 1710
1750, 1700
1750, 1700
1790, 1710
1610
1615
1620
1630
1610
12.4
12.2
7.4-7.6
7.3-7.7
6.0
5.7
6.0
5.9
5.8
4.5*2
4.5*2
—
—
—
—
—
4c
4d
4e
4f
4.4
4.3
12.2
8.2, 7.7
12.2
8.2, 7.8, 7.7
8.8-7.3
4.6
4.5
4.4
4.4
12.2 (1+2)
12.2 (1),
12.0 (2)
8.59 (1+2),
7.44 (2), 7.37 (1)
5.8 (1),
5.7 (2)
4.5 (1),
4.4 (2)
4.4 (1),
4.2 (2)
4g*3
1750, 1710
1750, 1710
1760, 1700
1620
1625
1630
—
4h
12.2
7.2, 6.6
5.5
4.4
4.4
3.0, s
3.4, q*4;
4i
12.1
7.2, 6.6
5.5
4.4
4.3
1.1, t*5
4j
4k
1775, 1700
1755, 1710
1750, 1700
1630
1615
1620
12.3
12.2
12.2
7.3, 6.9
7.0-6.8
7.3, 7.2
5.7
5.6
5.7
4.5
4.5
4.4
4.4
3.8, s
3.8, s
2.3, s
4l
4.4*2
_______
* Protons H-4, H-6 absorb as a geminal AB quartet. From the chemical shifts of HA and HB, JgemAB = 11 Hz.
*2 Singlet signal.
*3 In the 1H NMR spectra there are two sets of signals, corresponding to two conformers, a major (1) and a minor (2).
*4 Signal of methylene protons.
*5 Signal of methyl protons.

2'-Amino-2-phenylspiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3a). Benzaldehyde (0.69 g, 0.66 ml,
6.5 mmol) was added with stirring to a mixture of the monohydrate of compound 1 (1.0 g, 5.1 mmol) and boron
trifluoride etherate (2 ml). The initial compound 1 dissolved partially and then a new precipitate appeared and
the reaction mixture thickened by degrees. After dilution with an equal volume of absolute ether, stirring was
continued for 10 h, the solid was then filtered off, washed with absolute ether, treated with 10% aqueous
NaHCO3, and washed with water.
Compounds 3b, c, j, and l were obtained analogously from compound 1 and o-chlorobenzaldehyde,
m-bromobenzaldehyde, p-methoxybenzaldehyde, and p-methylbenzaldehyde respectively.
2'-Amino-2-(3-nitrophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3e). m-Nitrobenzaldehyde
(3.2 g, 21.2 mmol) was added to a solution of compound 1 (4.0 g, 20.6 mmol) in sulfuric acid (12 ml). The
reaction mixture was diluted over 2 d with 1.5 volumes of absolute ether and then kept in a refrigerator for a
week. The precipitate was filtered off, washed with diglyme, treated with 10% aqueous NaHCO3, and washed
with water.
Compound 3d was obtained analogously from compound 1 and p-nitrobenzaldehyde.
2'-Amino-2-(3-pyridyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3f). 3-Pyridinecarbaldehyde (3.7 g,
3.3 ml, 34.5 mmol) was added to a mixture of compound 1 (6.8 g, 35.0 mmol) and sulfuric acid (12 ml). After 4
d the reaction mixture was poured into 10% aqueous NaHCO3 (350 ml). After evolution of CO2 had ceased, the
precipitate which formed was filtered off and washed with water.
Compounds 3g (from compound 1 and the hydrate of 4-pyridinecarbaldehyde), 4f (from compound 2
and 3-pyridinealdehyde), and 4g (from compound 2 and the hydrate of 4-pyridinecarbaldehyde) were prepared
analogously.
2'-Amino-2-(4-dimethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3h). p-Dimethyl-
aminobenzaldehyde (1.4 g, 9.4 mmol) was added to a solution of compound 1 (2.0 g, 10.3 mmol) in sulfuric acid
(3 ml). After 4-5 d a precipitate formed an additional amount of which was formed by diluting the reaction
mixture with diglyme. After standing for 4 d in the refrigerator, the precipitate was filtered off, washed with
diglyme, treated with 10% aqueous NaHCO3 until evolution of CO2 ceased, filtered again, boiled with a mixture
of 10% aqueous NaHCO3 (10 ml) and i-PrOH (10 ml) for 30 min, filtered hot and washed with water.
2'-Amino-2-(4-diethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one (3i). p-Diethylamino-
benzaldehyde (1.5 g, 8.5 mmol) was added to a solution of compound 1 (2.0 g, 10.3 mmol) in sulfuric acid
(3 ml). After 3 days the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml), the precipitate was
filtered off and recrystallized from ethanol.
2-Phenylspiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4a). Benzaldehyde (0.69 g, 0.66 ml,
6.5 mmol) was added to an intensely stirred mixture of compound 2 (1.0 g, 5.6 mmol) and boron trifluoride
etherate (2 ml). Along with the dissolution of compound 2, the gradual formation of a new precipitate was
observed. After 2h stirring the reaction mixture was diluted with an equal volume of absolute ether, stirring was
continued for a further 10 h, the precipitate formed was filtered off, washed with absolute ether, treated with
10% aqueous NaHCO3, and washed with water.
Compounds 4b,c,j, and l were obtained analogously to compound 4a from compound 2 and
o-chlorobenzaldehyde,
m-bromobenzaldehyde,
p-methoxybenzaldehyde,
and
p-methylbenzaldehyde
respectively.
2-(4-Nitrophenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4d). p-Nitrobenzaldehyde (3.2 g,
21.2 mmol) was added to a mixture of compound 2 (4.0 g, 22.6 mmol) and sulfuric acid (12 ml). After 2 d the
reaction mixture was diluted with 1.5 volumes of diglyme and kept in the refrigerator for a week. The precipitate
was filtered off, washed with diglyme, treated with 10% aqueous NHCO3, and washed with water.
Compound 4e was prepared analogously from compound 2 and m-nitrobenzaldehyde.
2-(4-Diethylaminophenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4i). Boron trifluoride
etherate (8 ml) and compound 2 (1.7 g, 9.6 mmol) were added to a solution of p-dimethylaminobenzaldehyde in
sulfolane (10 ml). The reaction mixture was shaken periodically and compound 2 dissolved progressively. After
924

10 d the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml), the precipitate was filtered off and
washed successively with water and ethanol.
Compound 4h was obtained from compound 2 and p-dimethylaminobenzaldehyde analogously.
2-(3,4-Dimethoxyphenyl)spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione (4k). Boron trifluoride
etherate (6 ml) and compound 2 (3.0g, 16.9 mmol) were added successively with stirring to a solution of
3,4-dimethoxybenzaldehyde (2.8 g, 16.8 mmol) in sulfolane (30 ml). Stirring was continued until compound 2
had dissolved. After 4 h the reaction mixture was poured into 10% aqueous NaHCO3 (100 ml). The precipitate
was filtered off and washed successively with water and ethanol.
Compound 3k was obtained analogously from compound 1 and 3,4-dimethoxybenzaldehyde.
All of the precipitated compounds were dried initially in air and then in vacuum to constant weight.
The authors thank D. B. Lazarev for help in preparing this paper.
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2.
3.
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925