2-Amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one and its spirodioxane compounds in the Mannich reaction

Article abstract of DOI:10.1007/s10593-006-0207-y

It was found that the aminomethylation of 2-amino-5,5-bis(hydroxymethyl)-1, 3-thiazol-4(5H)-one and its spiro analogs using primary amines is accompanied by cyclization at the amidine fragment of the molecule with annelation of a tetrahydrotriazine ring.

Full text of DOI:10.1007/s10593-006-0207-y

Chemistry of Heterocyclic Compounds, Vol. 42, No. 8, 2006
2-AMINO-5,5-BIS(HYDROXYMETHYL)-
1,3-THIAZOL-4(5H)-ONE AND ITS SPIRODIOXANE
COMPOUNDS IN THE MANNICH REACTION
S. M. Ramsh1, A. G. Ivanenko2, N. L. Medvedskiy1, D. G. Lagerev1, D. B. Lazarev1,
and L. N. Belobrzeckaja Costa3
It was found that the aminomethylation of 2-amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one and its
spiro analogs using primary amines is accompanied by cyclization at the amidine fragment of the
molecule with annelation of a tetrahydrotriazine ring. When using secondary amines the
aminomethylation occurs at the exocyclic nitrogen atom.
Keywords: 2-amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one, 2-'amino-2-aryl(hetaryl)spiro-
[1,3-dioxan-5,5'(4'H)-1',3'-thiazol]-4'-ones, 5-methyl- and 2-amino-5-ethyl-1,3-thiazol-4(5)-ones,
aminomethylation.
We have previously been able to prepare a 5,5-bis(hydroxymethyl) derivative of 2-amino-1,3-thiazol-
4(5H)-one (pseudothiohydantoin) (1a) [1] and synthesize a series of spiro-[1,3-dioxan-5,5'(4'H)-1',3'-thiazole]
derivatives (2a-e) from it [2]. Compound 1a is a "truncated" (fragmented) part of the compound 3a molecule
which shows high biological activity [3]. This encouraged us to develop a novel method for the preparation of
active compound 3a by the aminomethylation of the bis(hydroxymethyl) derivative 1a. This was particularly in
view of the fact that the preparation of compound 3a, initially proposed via the direct aminomethylation of
pseudothiohydantoin [3, 4] is accompanied by the formation of a side reaction product and the yield of the target
compound 3a does not exceed 30%. It also seemed suitable for developing a method of preparing homologs of
compound 3a through the variation of the amino component in the aminomethylation reaction of compound 1a.
With the aim of subsequently studying the biological activity of the newly obtained compounds and
revealing a structure-activity relationship we have also synthesized in the work the monohydroxymethyl and
spiro analogs of compound 3a using the 1b,c or spiro compounds 2a-e as substrates in the Mannich reaction and
tert-butylamine or methylamine as the amino component. The aminomethylation of substrate 1a with secondary
cyclic amines also gave the Mannich bases 5a,b, differing from compound 3a in the acyclic structure of the
aminomethyl fragment of the molecule. Finally, the hydroxymethylation of the thiazolo[3,2-a]pyrimidine
derivative 6 gave compound 7 as the "desaminated" analog of compounds 3a.
__________________________________________________________________________________________
1
St. Petersburg State Technical University, St. Petersburg 198013, Russia; e-mail:
2
gramsh@mail.wplus.net. Institute Toxicology, Ministry of Public Health of Russia, St. Petersburg 193019, e-
mail: drugs@mail.lanck.net. 3 Genoa State University, Genoa, Italy; e-mail: belobrzeckaja@libero.it. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1252-1260, August, 2006. Original article submitted
August 10, 2005.
1086
0009-3122/06/4208-1086©2006 Springer Science+Business Media, Inc.

O
O
R
R1
N
R1
N
N
CH2O, RNH2
H2N
S
R2
N
S
CH2OH
3a–h
1a–c
1 a R1 = R2 = CH2OH; b R1 = Me, R2 = H; c R1 = Et, R2 = H;
3 a R = t-Bu, b R = Me, c R = Et, d R = c-Hex, e R = Bn, f R = Ph2CH;
g, h R = t-Bu; a–f R1 = CH2OH, g R1 = Me, h R1 = Et
O
O
Me
N
N
N
CH2O, MeNH2
O
O
H2N
S
N
S
O
R
O
R
2a–e
4a–e
4 a R = Ph, b R = p-C6H4NO2, c R = p-C6H4Me, d R = 3-Py, e R = 4-Py
O
N
CH2O,
NH
X
CH2OH
CH2OH
1a
N
N
S
H
X
5a,b
5 a X = CH2, b X = O
O
O
N
CH2O
N
+
N
H
OH
S
NaHCO3, NEt3
N
S
–
Cl
OH
6
7
As expected, the aminomethylation of compounds 1a-c and 2a-e gave the target Mannich bases
[1,3]thiazolo[3,2-a][1,3,5]triazines 3a-h and spiro[1,3-dioxan-5,7'(6'H)-[1,3]thiazolo[3,2-a][1,3,5]triazines 4a-e
respectively (Table 1).
A feature of the proposed method for aminomethylating compound 1a (with the exclusion of the
preparation of compound 3f), which distinguishes it from the known method of aminomethylating a
pseudothiohydantoin [4] is the absence of a specifically added solvent, water in this case being added in the
reaction mixture as part of one of the reagents viz. formaldehyde (in the case of compound 3b contained in the
methylamine). Another feature distinguishing this method of preparing thiazolotriazines is the addition of
potassium carbonate to the reaction mixture. Its role is in homogenization of the reaction mass and, possibly, in a
base catalysis of the aminomethylation [5, 6]. A third difference for the proposed method is the use of an almost
stoichiometric ratio of substrate to amine to formaldehyde since in the method for preparing thiazolotriazines by
method [4] acceptable yields are achieved with a 1.5 to 2.5 fold excess of formaldehyde. For the preparation of
compounds 3a,b and 3d the amine is added with cooling of the reaction mixture to 0-3°C.
Only in the preparation of compound 3f is the reaction mixture heated to reflux and the product
separated from it needs recrystallization. In the remaining examples the reaction takes place at room temperature
and the reaction product is quite pure and does not need recrystallization. The yields of compounds 3a-f varied
from 46 to 98% (Table 1).
The yield of the thiazolotriazine 3a by this new method reaches 70% which is more than twice the yield
using the known method, i.e. by the direct aminomethylation of the pseudothiohydantoin [3, 4]. It should also be
noted that the direct aminomethylation of the pseudothiohydantoin using methylamine as the amino component
1087

TABLE 1. Characteristics of Compounds 3 and 4
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
70
С
Н
N
3a
С11Н19N3O3S
48.41
48.33
6.97
7.01
15.38
15.37
159-60
(159 [4])
3b
3c
3d
3e
С8Н13N3O3S
С9Н15N3O3S
С13Н21N3O3S
С14Н17N3O3S
41.49
41.55
44.09
44.07
52.18
52.15
54.78
54.71
5.64
5.67
6.09
6.16
7.01
7.07
5.54
5.57
18.20
18.17
17.19
17.13
13.94
14.04
13.63
13.67
166-171 (dec.)
71
40
76
46
131-133
135-137
146-147
(136-138 [4])
3f
С20Н21N3O3S
C11H19N3O2S
C12H21N3O2S
С15Н17N3O3S
С15Н16N4O5S
С16Н19N3O3S
С14Н16N4O3S
С14Н16N4O3S
62.56
62.64
51.54
51.34
53.14
53.11
56.35
56.41
49.33
49.44
57.71
57.64
52.44
52.49
52.36
52.49
5.54
5.52
7.53
7.44
7.85
7.80
5.39
5.37
4.46
4.43
5.70
5.74
5.27
5.03
5.24
5.03
11.02
10.96
16.41
16.33
15.41
15.48
13.10
13.16
15.34
15.38
12.64
12.60
17.25
17.49
17.19
17.49
230-233
98
58
25
83
77
75
50
46
3g
3h
4a
4b
4c
4d
4e
138-140
108-110
176-179
210-220 (dec.)
220-227 (dec.)
184-186
189-191
gave the des hydroxymethyl analog of compound 3b [4] and use of ethyl- and cyclohexylamine did not generally
give the Mannich bases.
The monohydroxymethylated analogs of compound 3a (thiazolotriazines 3g and 3h) were prepared from
the pseudothiohydantoin homologs 1b or 1c by direct aminomethylation using a known method for the
aminomethylation of pseudothiohydantoin [4].
Due to the low solubility of the starting compounds 2a-e the preparation of the spiro[1,3-dioxan-
5,7'(6'H)-[1,3]thiazolo[3,2-a][1,3,5]triazines] 4a-e is heterophasic even though, in the majority of cases (with the
exclusion of the preparation of 4a) ethanol was introduced as solvent and the reaction mixture was refluxed for
several minutes. None the less, with an approximately 2-fold excess of formaldehyde and 2.5-fold excess of
methylamine the reaction occurs quite readily and completely. The compounds obtained have acceptable quality
and do not need recrystallization. Their yields were from 46-83% (Table 1).
The 1H NMR spectra of compounds 3a-h and 4a-e are given in Table 2.
In the reactions of polydentate nucleophilic substrates (to which compound 1a can be assigned) with
electrophilic reagents the central question is the regioselectivity of the process [7]. Through the
aminomethylation of compound 1a using aqueous formaldehyde and secondary amines using the method
proposed in [8] for the aminomethylation of pseudothiohydantoin with aqueous formaldehyde and piperidine, we
have separated pure monoaminomethyl derivatives and the indicated question reduces to the structure of the
compounds produced. The 1H NMR spectroscopic analysis unambiguously shows that they are substituted at the
exocyclic nitrogen atom as compounds 5a and 5b. The most characteristic spectroscopic indication for these
compounds is the complex nature of the protons of the NH, NCH2N, and hydroxyl protons, "sensitive" to both
hindered rotation around the C(2)–Nexo bond and to an intramolecular association of one of the conformers via a
hydroxymethyl group. A further confirmation of substitution at the exocyclic nitrogen atom is the relatively low
frequency for the C(2)=N(3) bond absorption (1590-1595 cm-1) in the IR spectra [9, 10].
1088

TABLE 2. Spectroscopic Characteristics of Compounds 3a-h
IR spectrum
Com-
pound
1Н NMR spectrum (DMSO-d6), δ, ppm*
(in KBr), ν, cm-1
С=О
С=N
СН2ОН*2
2Н-2
2Н-4
СН2ОН*3
R
3a
3b
3c
1710
1700
1720
1630
1625
1640
5.64 (t)
5.39 (t)
4.92
4.50
4.54
4.66
4.22
4.26
3.94, 3.88
3.67
1.34
2.38
5.36 (br.)
3.67
2.52 (m);
1.08 (m)
3d
3e
1720
1690
1625
1635
5.45 (br.)
5.48 (t)
4.59
4.42
4.36
4.36
3.68
3.68
2.48 (m);
1.63 (m);
1.11 (m)
7.35
(m, C6H5);
3.66
(C6H5CН2)
3f
1715
1620
5.37 (br.)
4.47
4.26
3.73
7.50-7.05
(m C6H5);
4.81
((C6H5)2CH)
3g*4,*5
3h*6,*5
1723
1730
1650
1630
5.31 (br.)
5.47 (br.)
4.69
4.69
4.40
4.41
3.66, 3.49
3.69, 3.55
1.15
1.09
_______
* Multiplicities indicated for non singlet signals.
*2 For all hydroxyl triplets the spin spin coupling J = 5 Hz.
3
*
The diastereotopic methylene protons of the hydroxymethyl group
CHAHBOH resonate as an AB-geminal quadruplet (dd) with
JgemAB = 12-13 Hz. In addition each signal of the quadruplet is split by the
hydroxyl proton with J = 5 Hz [4]. Because of overlap of signals the
analysis of this part of the spectrum is difficult. For this reason the geometric
mean of the signal chemical shifts are given.
*4 The 7-CH3 protons absorb at 1.48 ppm.
5
*
The diastereotopic methylene protons of the hydroxymethyl group
CHAHBOH resonate as an AB- quadruplet (dd) with JgemAB = 11 Hz.
*6 The ethyl group signals are at 1.78 (2H, m, CH2CH3) and 0.86 ppm (3H, t,
J = 7, CH2CH3).
It should be noted that monosubstituted derivatives at an exocyclic nitrogen atom were also separated in
the reactions of hydroxymethylation with aqueous formaldehyde and aminomethylation using aqueous
formaldehyde and piperidine which are near in structure, i.e. a pseudothiohydantoin [11, 8] and its 5-aryl
derivatives [12]. In the case of the aminomethylation of the pseudothiohydantoin there were separated a mixed
hydroxymethylpiperidinomethyl derivative like 5a but with two piperidinomethyls in positions Nexo and C(5) and
one hydroxymethyl in position 5. The compound thus separated had similar spectroscopic features to those noted
above, even with the simplest pseudothiohydantoins monosubstituted at the exocyclic nitrogen atom, i.e. 2-
methylamino-1,3-thiazol-4(5H)-one [14] and its 5-benzylidene analog [15].
A feature of carrying out the aminomethylation reaction of substrate 1a by secondary amines is the
selection of an unusual ratio of reagents and, in fact, a marked excess of the aminomethylating reagents. The
ratio of substrate to formaldehyde to amine was 1:2.7:2.5 in the case of piperidine and 1:4.1:2 for morpholine.
We associate this with the proposed stage of the process leading to the separation of 5a and 5b. Evidently during
the process compound 1a undergoes bisaminomethylation at both the cyclic and exocyclic nitrogen atoms. In
fact a possible route of formation of compounds 3a-h, 4a-e by aminomethylation of compounds 1a,
1089

TABLE 3. Spectroscopic Characteristics of Compounds 4a-e
IR spectrum
1Н NMR spectrum, δ, ppm*
(in KBr), ν, cm-1
Com-
pound
C6H5
(Py)
HАHВ-4(6)*2
С=О
С=N
Н-2
2Н-2'
2Н-4' NCH3
HА
HВ
4a
1690
1685
1620
1625
7.42-7.34 (m)
5.67
5.94
4.54
4.55
4.52
4.54
4.28
4.35
4.25
4.25
2.48
2.45
4b*3
8.25 (d);
7.70 (d)
4c*3
1715
1700
1630
1640
7.30 (d);
7.17 (d)
5.69
5.88
4.54
4.55
4.48
4.53
4.28
4.33
4.24
4.25
2.44
2.44
4d
8.59 (m);
7.79 (m);
7.42 (m)
4e
1695
1615
8.61 (m);
7.40 (m)
5.80
4.54
4.54
4.32
4.24
2.45
_______
* Multiplicities indicated for non singlet signals.
*2 The diastereotopic methylene group proton signals for HAHB-4(6) appear
as a geminal AB-quadruplet with JgemAB = 11-12 Hz.
*3 Aromatic coupling constants Jarom = 8 Hz, δ (H-4) = 2.34 ppm.
2a-e by primary amines is also formation of an intermediate bisaminomethylated derivative and its subsequent
cyclization. Experimentally the choice of the ratio of reagents chosen for the non catalyzed course of similar
reactions [4] is close to that used by us to prepared compounds 5a and 5b. In the case of the aminomethylation of
compound 1a by secondary amines these suggested bisaminomethylated derivatives, via gentle heating of the
reaction mixture in ethanol, undergo solvolysis with fission of an aminomethyl group from the cyclic nitrogen
atom and the formation of monoaminomethyl derivatives at the exocyclic nitrogen 5a and 5b.
In order to prepare 2,2-bis(hydroxymethyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-3(2H)-one (7)
(the desaminated analog of compound 3) the hydrochloride 6 was neutralized in situ with sodium bicarbonate in
a minimal amount of water followed by treatment with aqueous formaldehyde in the presence of a catalytic
amount of triethylamine according to method [1].
EXPERIMENTAL
IR spectra were taken on a UR-20 spectrometer as a thin layer and 1H NMR spectra on Bruker AC-200
(200 MHz), AM-300 (300 MHz), and AM-500 (500 MHz) spectrometers using DMSO-d6 and with TMS as
internal standard. TLC was performed on Silufol UV-254 plates with acetone–hexane (1:1) or benzene-isopropyl
alcohol (5:1) as eluent.
The bis(hydroxymethyl) derivative of pseudothiohydantoin 1a was prepared as the monohydrate by
method [1], compounds 1b,c by [16], the spiro[1,3-dioxan-5,5'(4'H)-1',3'-thiazoles] 2a-e by [2], and compound 6
by [17].
3-tert-Butyl-7,7-bis(hydroxymethyl)-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one
(3a). 37% Formalin (2.0 ml, 24.9 mmol) and potassium carbonate (1 g) were added to compound 1 monohydrate
(2.0 g, 10.3 mmol). The mixture was stirred until full solution of compound 1 (1-1.5 h) and, with continued
stirring, the solution was cooled in an ice bath to 0-3°C. tert-Butylamine (0.835 g, 1.2 ml, 11.5 mmol) was
added. After some time a precipitate appeared in the bulk of the solution. After 2 h the mixture was again cooled
and the precipitate was filtered off and washed three times with portions of iced water.
1090

7,7-Bis(hydroxymethyl)-3-methyl-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (3b)
was prepared similarly to compound 3a from compound 1 monohydrate (3.0 g, 15.4 mmol), formalin (3.0 ml,
37.4 mmol), potassium carbonate (1 g), and 25% aqueous methylamine solution (2.1 ml, 17.1 mmol).
3-ethyl-7,7-Bis(hydroxymethyl)- 3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (3c).
37% Formalin (3.0 g, 37.4 mmol) and potassium carbonate (1 g) were added to compound 1 monohydrate
(3.00 g, 15.4 mmol). The mixture was stirred until full solution of compound 1 (1-1.5 h) and, with continued
stirring, the solution was cooled and ethylamine hydrochloride (1.40 g, 17.2 mmol) and, portionwise, potassium
carbonate (0.954 g, 9.0 mmol) were added. After 1 day the reaction mixture was cooled in an ice bath and the
precipitate was filtered off, washed three times with portions of iced water, and dried in vacuo. The dried
product was washed with benzene and twice with acetone.
3-cyclohexyl-7,7-Bis(hydroxymethyl)- 3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one
(3d) was prepared similarly to compound 3a. The dried material was washed with benzene.
3-Benzyl-7,7-bis(hydroxymethyl)-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one (3e).
Formalin (1 ml, 12.5 mmol) and potassium carbonate (1 g) were added to compound 1 monohydrate (0.999 g,
5.67 mmol). After 1 h benzylamine (0.608 g, 0.62 ml, 5.7 mmol) was added to the homogenous reaction mass.
The reaction product was periodically agitated and the precipitate formed was triturated. After 3 h the precipitate
was filtered off, washed three times with portions of water, and dried in vacuo. The dried product was washed
twice with benzene.
3-Benzhydryl-7,7-bis(hydroxymethyl)-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-one
(3f). 37% Formalin (2.0 ml, 24.9 mmol) and benzhydrylamine (2.09 g, 11.4 mmol) were added to compound 1
monohydrate (2.00 g, 10.3 mmol). The thickening mixture was stirred for 2 h and then periodically heated to
reflux for a further 1 h. The precipitate formed on cooling was twice washed with methanol and recrystallized
from butanol.
3-tert-Butyl-7-(hydroxymethyl)-7-methyl-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-
one (3g) was prepared from compound 1b similarly to compound 3a from pseudothiohydantoin [4]. It was
recrystallized from benzene.
3-tert-Butyl-7-ethyl-7-(hydroxymethyl)-3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-
one (3h). tert-Butylamine (1.53 g, 2.2 ml, 21.0 mmol) was added with stirring to compound 1c (2.0 g,
13.9 mmol) in formalin (4.9 ml, 61 mmol) and stirred for 2.5 h. It was diluted with benzene (10 ml) and stirring
was continued for a further 2 h and then left at room temperature for 2 days. The benzene layer was separated
and the aqueous layer was stirred and extracted with more benzene (10 ml). The benzene extracts were combined
and dried over sodium sulfate after which solvent was distilled off in vacuo with a bath temperature of 40-50°C.
The oily residue crystallized with vigorous and prolonged grinding in hexane and the precipitate formed was
filtered off and recrystallized from a mixture of benzene and hexane (1:10).
3'-Methyl-2-phenyl-3',4'-dihydro-2'H-spiro[1,3-dioxan-5,7'(6H')-[1,3]thiazolo[3,2-a][1,3,5]triazin-
6'-one] (4a). 37% Formalin (0.55 ml, 6.85 mmol) and 25% aqueous methylamine (0.55 ml, 4.47 mmol) were
added with vigorous stirring to compound 2a (0.45 g, 1.7 mmol) in water (2 ml). The reaction product was held
at room temperature for 1 day. The precipitate was filtered off and washed with water.
3'-Methyl-2-(4-nitrophenyl)-3',4'-dihydro-2'H-spiro[1,3-dioxan-5,7'(6H')-[1,3]thiazolo[3,2-a][1,3,5]-
triazin-6'-one] (4b) Formalin (1.0 ml, 12.4 mmol) and an aqueous solution of methylamine (1.0 ml, 8.13 mmol)
were added to compound 2b (1.0 gm 3.23 mmol) in ethanol (15 ml) and refluxed for 5 min. After 2 h the
precipitate formed on cooling the reaction product was filtered and washed twice with ethanol.
3'-Methyl-2-(4-methylphenyl)-3',4'-dihydro-2'H-spiro[1,3-dioxan-5,7'(6H')-[1,3]thiazolo[3,2-a]-
[1,3,5]-triazin-6'-one] (4c) was prepared similarly to compound 4b from compound 2c.
3'-Methyl-2-pyridin-3-yl-3',4'-dihydro-2'H-spiro[1,3-dioxan-5,7'(6H')-[1,3]thiazolo[3,2-a][1,3,5]-
triazin-6'-one] (4d). Formalin (1.2 ml, 14.9 mmol) and an aqueous solution of methylamine (1.2 ml, 9.8 mmol)
1091

were added to compound 2d (1.0 g, 3.77 mmol) in ethanol (4 ml) and refluxed for 3 min. The product was
cooled to room temperature and left for 1 day in the fridge. The precipitate was filtered off and washed with
water.
3'-Methyl-2-pyridin-4-yl-3',4'-dihydro-2'H-spiro[1,3-dioxan-5,7'(6H')-[1,3]thiazolo[3,2-a][1,3,5]-
triazin-6'-one] (4e). Formalin (1.2 ml, 14.9 mmol) and an aqueous solution of methylamine (1.2 ml, 9.8 mmol)
were added to compound 2e (1.0 g, 3.77 mmol) in ethanol (3 ml) and refluxed for 3 min. The product was cooled
to room temperature and poured into a Petri dish. The precipitate formed after 1 h was washed out with water,
filtered, and twice washed with water.
5,5-Bis(hydroxymethyl)-2-[(piperidinomethyl)amino]-1,3-thiazol-4(5H)-one (5a). A mixture of
compound 1b (2.0 g,11.4 mmol), formalin (2.3 ml, 28.6 mmol), and piperidine (2.24 g, 2.6 ml, 26.3 mmol) was
stirred at room temperature for 2.5 h and then left overnight. The liquid phase was distilled to dryness in vacuo
at 40-50°C and the residual glassy mass was dissolved in ethanol with moderate heating and stirring. The
solution obtained was left at room temperature for 2 days. The precipitate was filtered off and dried in vacuo
over CaCl2. Yield 2.65 g (85%); mp 158-159°C (acetonitrile). IR spectrum, ν, cm-1: 1685 (C=O), 1595 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 9.15 (0.7H, s, NHE); 8.56 (0.3H, s, NHZ); 5.05 (0.35H, t, J = 5, OHass); 4.86
(1.65H, m, OHE+Z); 4.52 (0.29H, s, CH2NHass); 4.24 (1.1H, s, CH2NHE); 3.98 (0.61H, d, J = 17, CH2NHZ);
3.72-3.62 (8H, m, CH2OH, piperidino H-2,6); 1.56-1.33 (6H, m, piperidino H-3,4,5). Found, %: C 48.44;
H 6.97, N 15.39. C11H19N3O3S. Calculated, %: C 48.33; H 7.01; N 15.37.
5,5-Bis(hydroxymethyl)-2-[(morpholinomethyl)amino]-1,3-thiazol-4(5H)-one (5b) was prepared
similarly to compound 5a from compound 1a (4.0 g, 22.7 mmol), formalin (7.4 ml, 92.1 mmol), and morpholine
(4.0 g, 4 ml, 45.9 mmol). Yield 6.05 g (97%); mp 162-163°C with decomp. (from acetonitrile or a 1:10 mixture
1
of ethanol and benzene). IR spectrum, ν, cm-1: 1705 (C=O), 1590 (C=N). H NMR spectrum, δ, ppm (J, Hz):
9.40 (0.58H, s, NHE); 8.82 (0.19H, s, NHass); 8.70 (0.23H, s, NHZ); 5.41 (0.21H, t, J = 5, OHass); 5.16 (1.79H, m,
OHE+Z); 4.52 (0.24H, s, CH2NHass); 4.24 (1.19H, d, J = 4, CH2NHE); 4.00 (0.57H, s, CH2NHZ); 3.70-3.37 (12H,
m, CH2OH, morpholino H-2,3,5,6). Found, %: C 43.74; H 6.29; N 15.43. C10H17N3O4S. Calculated, %: C 43.62;
H 6.22; N 15.26.
2,2-Bis(hydroxymethyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-3(2H)-one (7). Compound 6
(5.2 g, 27.0 mmol) was added portionwise to a mixture of sodium bicarbonate (2.27 g, 27.0 mmol) in water
(2 ml) using a magnetic follower as stirrer. Stirring was continued and formalin (10.0 ml, 125 mmol) and
triethylamine (0.335 g, 0.46 ml, 3.3 mmol) were added to the homogeneous solution obtained. Stirring was
continued at room temperature for a further 3 h. The finely crystalline precipitate was filtered off and
recrystallized from a mixture of i-PrOH and CCl4 (1:4). Yield 3.72 g (64%); mp 157-159°C. IR spectrum,
1
ν, cm-1: 1725 (C=O), 1641 (C=N). H NMR spectrum, δ, ppm (J, Hz): 5.33 (2H, s, OH); 3.70 (2H, d,
JgemAB = 13, CHAHB); 3.63 (2H, d, JgemAB = 13, CHACHB); 3.52 (2H, t, J = 7, H-7); 3.40 (2H, t, J = 7, H-5); 1.70
(2H, m, H-6). Found, %: C 44.38; H 5.63; N 13.04. C8H12N2O3S. Calculated, %: C 44.43; H 5.59; N 12.95.
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