5,7-Substituted thiazolo[2,3-a]pyrimidines: Synthesis, stereochemistry and crystal structure

Article abstract of DOI:10.1016/j.molstruc.2007.03.031

Reaction of 2-aminothiazoline (1) with α,β-unsaturated carbonyl compounds 2 under mild conditions (acetone, room temperature) gives two diastereomers 5-R-7-hydroxy-5H-tetrahydrothiazolo[2,3-a]pyrimidines 3. According to ¹H NMR, major isomers of 3 have axial OH-groups whereas minor isomers have equatorial OH-groups. The X-ray investigation of compound 3i reveals only A type diastereomer in the crystal phase. The asymmetric unit contains two forms (A1 and A2) with slightly different geometrical parameters. Each of them consists of a pair of enantiomers E1 and E2. As a result, the asymmetric unit contains the centrosymmetric dimers (A1E1 ... A1E2 and A2E2 ... A2E1), due to the intermolecular hydrogen bonds. 5,7-Diaryl-5H-2,3-dihydrothiazolo[2,3-a]pyrimidines 4 were obtained via reaction of 1 with 2 under stronger conditions (DMF or chloroform, heating). Structure of product 4p was confirmed by X-ray structural analysis.

Full text of DOI:10.1016/j.molstruc.2007.03.031

Available online at www.sciencedirect.com
Journal of Molecular Structure 874 (2008) 57–63
www.elsevier.com/locate/molstruc
5,7-Substituted thiazolo[2,3-a]pyrimidines: Synthesis,
stereochemistry and crystal structure
a
b
c
a
Fedor Yaremenko , Tetyana Beryozkina , Alexander Khvat , Irina Svidlo ,
d
d
b,
*
Oleg Shishkin , Svetlana Shishkina , Valeriy Orlov
a
V. Ya. Danilevsky Institute of Endocrine Pathology Problems, Academy of Medicinal Sciences of Ukraine, 4 Artema Str., 61002 Kharkiv, Ukraine
b
V. N. Karazin Kharkiv National University, 4 Svobody Sq., 61077 Kharkiv, Ukraine
c
ChemDiv. Inc., 11558 Sorrento Valley Rd., Suites San Diego, CA 92121, USA
SSI ‘Institute for Single Crystals’ National Academy of Science of Ukraine, 60 Lenina Ave., 61001 Kharkiv, Ukraine
d
Received 15 February 2007; received in revised form 16 March 2007; accepted 19 March 2007
Available online 25 March 2007
Abstract
Reaction of 2-aminothiazoline (1) with a,b-unsaturated carbonyl compounds 2 under mild conditions (acetone, room temperature)
1
gives two diastereomers 5-R-7-hydroxy-5H-tetrahydrothiazolo[2,3-a]pyrimidines 3. According to H NMR, major isomers of 3 have
axial OH-groups whereas minor isomers have equatorial OH-groups. The X-ray investigation of compound 3i reveals only A type dia-
stereomer in the crystal phase. The asymmetric unit contains two forms (A1 and A2) with slightly different geometrical parameters. Each
of them consists of a pair of enantiomers E1 and E2. As a result, the asymmetric unit contains the centrosymmetric dimers
(A1E1. . .A1E2 and A2E2. . .A2E1), due to the intermolecular hydrogen bonds. 5,7-Diaryl-5H-2,3-dihydrothiazolo[2,3-a]pyrimidines
4 were obtained via reaction of 1 with 2 under stronger conditions (DMF or chloroform, heating). Structure of product 4p was confirmed
by X-ray structural analysis.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: 2-Aminothiazoline; Thiazolo[2,3-a]pyrimidines; NMR spectroscopy; X-ray structural analysis
1. Introduction
constant. On the other hand, the nucleophilicity of different
centers of azole molecule can vary. Thus, the direction of
the heterocyclization of aminoazoles is mainly governed
by the nature of nucleophile.
The reaction of 2-aminothiazoline (1) with a,b-unsatu-
rated carbonyl compounds 2a–r, 6–9 has been carefully
examined. This paper presents the results including syn-
thetic details, stereochemistry and X-ray analysis of the
reaction products.
2-Aminothiazolines is the well known class of chemicals
exhibiting various types of biological activity. Several
derivatives of 2-aminothiazoline (1) were characterized as
nitric oxide synthetase inhibitors [2], spermagenesis modu-
lators [3], potential cancer chemopreventive agents [4] and
specific monovalent ligands for the cholera toxin [5]. Thiaz-
olo[2,3-a]pyrimidines that can be obtained via the cycliza-
tion of 2-aminothiazoline (1) with a,b-unsaturated
Reactions of a,b-unsaturated ketones with aminoazoles
is the most favourable way to the series of natural-like par-
tially hydrogenated azolopyrimidines [1]. These transfor-
mations usually proceed under mild reaction conditions
with high regio- and stereoselectivity. This can be explained
not only by the difference in the electrophilicity of carbonyl
and b-carbon center of the ketone but also by significant
differences in the nucleophilicity of amino group and adja-
cent endo-reaction center of azole. The distribution of the
electron density and electrophilicity of carbon centers in
the molecules of a,b-unsaturated ketones are relatively
*
Corresponding author. Tel.: +38 057 707 5292; fax: +38 057 705 12 61.
E-mail address: orlov@univer.kharkov.ua (V. Orlov).
0022-2860/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2007.03.031

58
F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
ketones were reported as potent antagonists of specific che-
mokine (CXCR2) receptors [6] and prospective anticancer
agents [7].
was kept in cold for 24 h. The precipitate of 5p was fil-
tered and washed with chloroform. The filtrate was
diluted with acetone and kept in cold for 24 h. The pre-
cipitated solid of 4p was filtered off, washed with acetone
and dried.
Even though 2-aminothiazoline (1) and its derivatives
have been investigating for many years, surprisingly limited
information is available on the heterocyclization of 1 with
a,b-unsaturated carbonyl compounds. We know paper [8]
and patent [9], but the synthetic information described in
them lack important structural details. Authors of [8]
inform about the possibility to oxidize the 7-hydroxy group
to keto group in the reaction of MnO2 with 5-R-7-hydroxy-
5H-2,3,6,7-tetrahydrothiazolo[2,3-a]pyrimidines which has
no second substituent in position 7. Surprisingly, nothing
is mentioned about both the formation of diastereomers
and the dehydratation. According to our experience, these
processes are very difficult to avoid.
Compound 5p. 1H NMR (DMSO-d6) d: 3.30 (m, 4H, C2-
H), 3.70 (m, 4H, C3-H), 3.86 (s, 6H, OCH3), 7.12–8.30 (m,
12H, CHarom.), 8.37–8.40 (m, 4H, CHarom.).
2.2. Instruments
1H and 13C NMR spectra were recorded on Bruker AM-
300 spectrometer using CDCl3 or DMSO-d6 as the solvent
at 25 °C and TMS as the internal standard. Mass spectra
were recorded on FINNIGAN MAT. INCOS 50 instru-
ment at 70 eV. Microanalyses were carried out on LECO
CHNS-900 elemental analyzer.
2. Experimental
2.3. X-ray diffraction study
2.1. Synthesis
Crystals of compounds 3i and 4p for X-ray diffraction
experiments were grown in acetone at 20 °C.
The general procedure for the preparation of 5-R-7-
hydroxy-7-R0-5H-2,3,6,7-tetrahydrothiazolo[2,3-a]pyrimidines
3a–j, 5,7-diaryl-5H-2,3-dihydrothiazolo[2,3-a]pyrimidines 4k,
m,o and 5,50-bis-5-(4-fluorophenyl)-7-phenyl-2,3-dihydro-
thiazolo[2,3-a]pyrimidine 5r. Amine 1 (0.80 g, 8.0 mmol)
was added to the acetone solution of a corresponding alde-
hyde or ketone 2. The mixture was stirred until complete
dissolution of 1 and kept at room temperature in dark
(time of the reaction is 1 day for 3c, 2 days for 3a,f, 4 days
for 3b,d, 5 days for 3g, 13 days for 3i, 17 days for 3e, 20
days for 3h, 30 days for 3j and 5r). The precipitate formed
was filtered off, washed with acetone and dried.
Crystals of 3i are triclinic. At 293 K a = 10.001(2),
˚
b = 11.247(2), c = 13.904(3) A, a = 90.42(2)°, b = 109.94
´
3
˚
(2(8)°, c = 104.39(2)°, V = 1426(2) A , Mr = 262.37, Z =
4, the space group is P1, dcalc = 1.218 g/cm3, l(MoKa) =
0.218 mmꢀ1, F(000) = 560. Intensity of 8003 reflections
(4774 independent, Rint = 0.047) were measured on the
ꢁXcalibur-3ꢂ diffractometer (graphite monochromated
MoKa radiation, CCD detector, x-scaning, 2Hmax = 50°).
The structure was solved by the direct method using SHEL-
XTL package [10]. Positions of hydrogen atoms were calcu-
lated geometrically and refined using the ‘‘riding’’ model
with Uiso = nUeq of a non-hydrogen atom bonded with
the given hydrogen atom (n = 1.5 for methyl and hydroxyl
groups and n = 1.2 for other hydrogen atoms). The full-
matrix least-squares refinement against F2 in the anisotropic
approximation using 4533 reflections was converged to
R1 = 0.056 (for 1686 reflections with F > 4r(F)),
wR2 = 0.088, S = 0.746. Atomic coordinates and crystallo-
graphic parameters have been deposited to the Cambridge
Crystallographic Data Centre (CCDC 636587).
Compound 5r. 1H NMR (DMSO-d6) d: 3.30 (m, 4H, C2-
H), 4.0 (m, 4H, C3-H), 7.10–7.70 (m, 10H, CHarom.), 7.97–
8.20 (m, 8H, CHarom.).
7-Hydroxy-7-methyl-5-phenyl-5H-2,3,6,7-tetrahydro-
thiazolo[2,3-a]pyrimidine (3d). The mixture of amine 1 (15
mmol, 1.50 g) and benzalacetone (2d) (15 mmol, 1.50 g) in
DMF (3 ml) was heated on water-bath for 4 h. Then the
reaction mixture cooled down and poured into the 100 ml
of ice water. Resulting precipitate was recrystallized from
acetone.
7-(4-Methoxyphenyl)-5-phenyl-5H-2,3-dihydrothiazol-
o[2,3-a]pyrimidine (4l). The mixture of amine 1 (15 mmol,
1.50 g) and chalcone 2l (10 mmol, 2.40 g) in DMF (5 ml)
was refluxed for 0.5 h. The resulting solution cooled down,
diluted with acetone (40 ml) and kept in cold for 24 h. The
precipitate formed was filtered off, washed with acetone
and dried.
Crystals of 4p are orthorhombic. At 293 K a = 8.637(2),
´
3
˚
˚
b = 10.878(2), c = 18.003(4) A, V = 1691.4(6) A , Mr =
367.42, Z = 4, the space group is P212121, dcalc = 1.443 g/
cm3, l(MoKa) = 0.217 mmꢀ1, F(000) = 768. Intensity of
1734 reflections were measured on an automatic four circles
Siemens P3/PC diffractometer (graphite monochromated
MoKa radiation, H/2H scaning, 2Hmax = 50°). The struc-
ture was solved by the direct method using SHELXTL
package [10]. Positions of hydrogen atoms were calculated
geometrically and refined using the ‘‘riding’’ model with
Uiso = nUeq of a non-hydrogen atom bonded with the given
hydrogen atom (n = 1.5 for methyl group and n = 1.2 for
other hydrogen atoms). The full-matrix least-squares refine-
ment against F2 in the anisotropic approximation using
1697 reflections was converged to R1 = 0.066 (for 1122
7-(4-Methoxyphenyl)-5-(4-nitrophenyl)-5H-2,3-dihydro-
thiazolo[2,3-a]pyrimidine 4p and 5,50-bis-5-(4-nitrophenyl)-
7-(4-methoxyphenyl)-2,3-
dihydrothiazolo[2,3-a]pyrimi-
dine 5p. The mixture of amine 1 (15 mmol, 1.50 g) and
chalcone 2p (10 mmol, 2.40 g) in chloroform (50 ml) was
refluxed for 18 h. Then the reaction mixture was evapo-
rated down to volume of 10 ml and the resulting solution

F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
59
reflections with F > 4r(F)), wR2 = 0.138, S = 1.113. Atomic
coordinates and crystallographic parameters have been
deposit to the Cambridge Crystallographic Data Centre
(CCDC 636586).
produced dihydroderivatives 4k,m,o with the low yield
even at room temperature in acetone. In general, dihydro-
thiazolopyrimidines 4k–p were obtained from correspond-
ing chalcones with the better yield under stronger
conditions, e.g. reflux in corresponding solvent (Table 2).
2.4. Quantum-chemical calculations
For example, dihydrothiazolopyrimidines 4l, p were
obtained after reflux either in DMF or chloroform, respec-
tively. But all our attempts to obtain thiazolopyrimidine
derivatives from corresponding 4-nitrochalcone, 4-fluor-
ochalcone, and benzalpinacoline failed.
Ketones with rigid s-cis-configuration of a,b-unsatu-
rated fragment, e.g. 16-benzylidene-3b-hydroxyandrost-5-
en-17-one 6, 2-benzylidene derivatives of cyclopentanone
7, indanone 8, and tetralone 9, were inert in the reaction
with 1, as expected. In all cases starting ketones were
recovered.
The molecular structure of the isomers A and B for com-
pound 3i was optimized using Density Functional Theory
with B3LYP functional [11–14]. The standard cc-pvdz basis
set [15] was used. All calculations were performed using the
PC GAMESS program [16].
3. Results and discussion
3.1. Synthesis
Unexpected product with high melting point was iso-
lated from the reaction of 2-aminothiazoline (1) with chal-
cones 2p and 2r. The only difference in the NMR spectra
of the isolated compound in comparison with correspond-
ing spectra of dihydrothiazolopyrimidines 4 was the
absence of C-5 and C-6 protons. The mass-spectra of these
compounds showed molecular ion [(2M-2)+1]+, where M
is the molecular weight of corresponding dihydroderiva-
tive. Based on these data we assigned 5,50-bis-5,7-diaryl-
2,3-dihydrothiazolo[2,3-a]pyrimidine structures 5p, r to
the isolated compounds. For the present we have not con-
firmed the mechanistic hypothesis about the formation of
dimers 5.
In comparison to dihydroderivatives 4 all 7-hydroxytet-
rahydropyrimidines 3 were unstable at elevated tempera-
tures. All attempts to recrystallize compounds 3 from hot
acetone or alcohols led to the complex mixture of products
where starting amine and unsaturated component were
detected by HPLC and NMR. The same results were
obtained after dissolution of tetrahydroderivatives in
DMSO. These results clearly confirmed the instability of
Several solvents were proposed for the heterocyclization
of a,b-unsaturated ketones or aldehydes with 2-amino-
thiazoline (1), e.g. acetone, methanol, xelene and their cor-
responding mixtures [9]. We expanded the range of solvent
and also explored various reaction conditions. The solvent
(acetone, alcohols, chloroform, DMF, DMSO), tempera-
ture (ambient temperature or reflux in the appropriate sol-
vent) and reaction time were varied in our experiments.
The best protocol for the synthesis of tetrahydrothiazolo-
purimidines 3 (Scheme 1) was found to include the treat-
ment of 2-aminothiazoline (1) with unsaturated aldehydes
2a–c or arylidenacetones 2d–i in acetone at room tempera-
ture. The reaction proceeds very slowly, from 1 to 17 days,
and 7-hydroxy-5H-2,3,6,7-tetrahydrothiazolo[2,3-a]pyrimi-
dines 3a–j crystallized directly from the mixture as large
well shaped crystals (Table 1).
Majority of chalcones 2j–p failed to react in these condi-
tions to form tetrahydrothiazolopyrimidines except 2j that
reacts with 1 very slowly to afford the target tetrahydro-
thiazolopyrimidine 3j with 12% yield. Compounds 2k,m,o
O
Me
no reaction
Me
R
Ph
Ph
OH
R'
N
acetone
rt
HO
6
no reaction
7
O
N
S
3a-j
R
R
N
acetone, CHCl3
or DMF
N
NH2
R'
Ph
S
R'
O
N
S
1
2a-r
4k-p
S
N
R
O
8
R'
N
acetone
Ph
no reaction
R
O
9
or CHCl3
N
no reaction
R'
N
5p,r
S
Scheme 1. Reaction of 2-aminothiazoline (1) with a,b-unsaturated carbonyl compounds.

60
F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
the tetrahydroderivatives 3 and reversible nature of the
reaction. Based on these results we related the observed
instability of compounds 3 not to the electronic properties
of compounds 2 but to the stereochemistry of formed
tetrahydrothiazolopyrimidines.
All compounds 3 and 4 were characterized by NMR
(1H, 13C) spectroscopy (Tables 3–5). The structures of com-
pounds 3i and 4p were confirmed by single crystal X-ray
analysis (Figs. 1 and 2).
diastereomeric pairs. The detailed analysis of 1H NMR
spectra of synthesized compounds clarifies this point.
The common features of NMR spectra of compounds 3
were complex multiplets of thiazoline ring protons at 2.90–
3.50 ppm, multiplet (3a–c) or two doublets of doublets
(3d–j) for C-6 proton at 1.70–2.20 ppm and doublet of dou-
blets for C-5 proton at 3.70–4.60 ppm (Table 3). The spectra
of compounds 3a–c also contained doublet of doublets for
C-7 protons at 7.19–7.40 ppm. The OH proton appeared
at 3.90–4.30 ppm as a broad signal. It should be noted that
spectra of all compounds contained the double set of pyrim-
idine ring protons which was the clear indication of the dia-
stereomers formation. The signals from both sets were well
resolved and the ratio of diastereomers can be extracted
from the integral intensities of corresponding signals (Table
3). The analysis of the coupling constant was used to assign
the stereochemistry of the isomers. The coupling constants
3.2. Stereochemistry
Especial attention was paid to the stereochemistry of the
reaction 2-aminothiazoline (1) with a,b-unsaturated car-
bonyl compounds. During the cyclization of 1 into 3 two
new chiral centers are formed. Depending on the outcome
of the reaction we can expect the formation of two or one
Table 1
Characterization data of compounds 3a–j
Compound
R
R0
H
M.p. (°C)
145–146 (138–140)a 53
Yield (%) Elemental analysis (%)
3a
Me
Found: C, 48.83; H, 6.99; N, 16.27; S, 18.60. Calcd. for C7H12N2OS (172.25):
C, 48.81; H, 7.02; N, 16.26; S, 18.62
Found: C, 61.50; H, 6.00; N, 11.98; S, 13.67. Calcd. for C12H14N2OS (235.32):
C, 61.51; H, 6.02; N, 11.96; S, 13.68
3b
3c
3d
3e
3f
3g
3h
3i
Ph
H
H
153–154 (160–161)a 52
4-NO2C6H4
Ph
145–147
42
Found: C, 51.63; H, 4.68; N, 15.04; S, 11.49. Calcd. for C12H13N3O3S (279.31):
C, 51.60; H, 4.69; N, 15.04; S, 11.48
Me 135–138 (129–134)a 61
Found: C, 62.84; H, 6.53; N, 11.25; S, 12.93. Calcd. for C13H16N2OS (248.34):
C, 62.87; H, 6.49; N, 11.28; S, 12.91
4-MeOC6H4
4-ClC6H4
4-FC6H4
Me 143–145
Me 138–139
Me 137–138
60
43
69
41
40
Found: C, 60.39; H, 6.51; N, 10.07; S, 11.50. Calcd. for C14H18N2O2S (278.37):
C, 60.41; H, 6.52; N, 10.06; S, 11.52
Found: C, 55.19; H, 5.34; N, 9.87; S, 11.35. Calcd. for C13H15ClN2OS (282.79):
C, 55.21; H, 5.35; N, 9.91; S, 11.34
Found: C, 58.66; H, 5.72; N, 10.48; S, 12.01. Calcd. for C13H15FN2OS (266.33):
C, 58.63; H, 5.68; N, 10.52; S, 12.04
Found: C, 61.79; H, 7.28; N, 14.40; S, 11.03. Calcd. for C15H21N3OS (291.41):
C, 61.82; H, 7.26; N, 14.42; S, 11.00
4-Me2NC6H4 Me 119–121
Ph
Ph
Et
133–135
Found: C, 64.11; H, 6.94; N, 10.69; S, 12.22. Calcd. for C14H18N2OS (262.37):
C, 64.09; H, 6.91; N, 10.68; S, 12.22
3j
Ph 117–119 (111–115)a 12
Found: C, 69.62; H, 5.83; N, 9.04; S, 10.31. Calcd. for C18H18N2OS (310.41):
C, 69.65; H, 5.84; N, 9.02; S, 10.33
a
Literature melting point [9].
Table 2
Characterization data of compounds 4k–p and 5p, r
Compound
R
R0
M.p. (°C)
Yield(%)
32
Elemental analysis (%)
4k
Ph
4-MeC6H4
197–198
Found: C, 74.46; H, 5.95; N, 9.16; S, 10.44. Calcd. for C19H18N2S (306.42):
C, 74.47; H, 5.92; N, 9.14; S, 10.46
4l
Ph
4-MeOC6H4
Ph
150–151
137–139
130–132
190–191
299–301
227–229
17
30
40
34
7
Found: C, 70.80; H, 5.60; N, 8.72; S, 9.95. Calcd. for C19H18N2OS (322.42):
C, 70.78; H, 5.63; N, 8.69; S, 9.94
Found: C, 74.49; H, 5.95; N, 9.13; S, 10.44. Calcd. for C19H18N2S (306.42):
C, 74.47; H, 5.92; N, 9.14; S, 10.46
Found: C, 66.18; H, 4.67; N, 8.53; S, 9.80. Calcd. for C18H15ClN2S (326.84):
C, 66.15; H, 4.63;N, 8.57; S, 9.81
Found: C, 62.12; H, 4.64; N, 11.47; S, 8.70. Calcd. for C19H17N3O3S (367.42):
C, 62.11; H, 4.66;N, 11.44; S, 8.73
Found: C, 62.25; H, 4.44; N, 11.50; S, 8.73. Calcd. for C38H32N6O6S2 (732.83):
C, 62.28; H, 4.40;N, 11.47; S, 8.75
Found: C, 69.90; H, 4.52; N, 9.02;S, 10.37. Calcd. for C36H28F2N4S2 (618.76):
C, 69.86; H, 4.56; N, 9.05; S, 10.36
4m
4o
4p
5p
5r
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-FC6H4
Ph
4-MeOC6H4
4-MeOC6H4
Ph
7

F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
61
Table 3
1H NMR spectral characteristics of the synthesized compounds 3a–ja (CDCl3, d, ppm)
Compound H-2, H-3 H-5
2.90–3.50 3.73 (m,1H) [3.73 (m,1H)]
(m,4H)
H-6
R
R0
Ratio of isomers
3:1
3a
3b
3c
3d
3e
3f
3g
3h
3i
1.50–1.80(m,1H)
[1.80–2.10 (m,1H)] (d,3H)]
1.19 (d,3H) [1.22
5.00 (t,1H) [5.10(dd,1H)]
2.90–3.50 4.45 (dd,1H) [4.34 (dd,1H)] 1.90–2.20 (m,1H)
(m,4H)
3.00–3.50 4.55 (dd,1H) [4.45 (dd,1H)] 1.90–2.20 (m,1H)
(m,4H)
2.90-3.50 4.47 (dd,1H) [4.25 (dd,1H)] 1.77 (t,1H)
7.20–7.40 (m,5H)
7.48 (d,2H), 8.25 (d,2H) 5.03 (t,1H) [5.27(dd,1H)]
7.10–7.30 (m,5H) 1.41 (s,3H)
5.04 (dd,1H) [5.25(dd,1H)] 4:1
4:1
5:1
5:1
5:1
5:1
5:1
5:1
3:1
(m,4H)
2.90–3.50 4.40 (dd,1H) [4.21 (dd,1H)] 1.76 (dd, 1H)
(m,4H) [2.15 dd, 1H)]
2.90–3.50 4.44 (dd,1H) [4.23 (dd,1H)] 1.75 (t,1H)
(m,4H) [2.15 (dd,1H)]
2.90–3.50 4.47 (dd,1H) [4.25 (dd,1H)] 1.74 (t, 1H)
(m,4H) [2.16, dd, 1H)]
2.90–3.50 4.40 (dd,1H) [4.25 (dd,1H)] 1.76 (t, 1H)
(m,4H) [2.14 (dd,1H)]
2.90–3.40 4.47 (dd,1H) [4.22 (dd,1H)] 1.70 (t, 1H)
(m,4H) [2.11 (dd,1H)]
2.90–3.50 4.58 (dd,1H) [3.80 (dd,1H)] 1.81 (dd,1H)
(m,4H) [2.33 (dd,1H)]
[2.19 (dd,1H)
3.83 (s,3H), 6.91 (d,2H), 1.50 (s,3H)
7.25 (d,2H)
7.27 (d,2H), 7.36 (d,2H) 1.50 (s,3H)
7.06 (d, 2H), 7.30 (d,2H) 1.51 (s,3H)
6.71 (d,2H),7.17 (d,2H)
7.30–7.50 (m,5H)
1.50 (s,3H)
0.96 (t,3H), 1.85 (m,2H)
[1.05 (t,3H), 1.85 (m,2H)]
7.20–7.60 (m,10H)
3j
a
In square brackets gave signals of minor diastereomers.
Table 4
chemistry of the major isomer is represented by structure
A (Fig. 3). The intramolecular hydrogen bond is likely to
play a key role in the stabilization of the isomer A in compar-
ison with structure B where no hydrogen bonding was
possible.
According to experimental data the ratio of isomers A
and B varied from 3:1 to 5:1 throughout the series (Table
3). The results of the quantum-chemical calculations
(B3LYP/cc-pvdz) revealed that isomer A is more stable
than isomer B (energy difference is 1.06 kcal/mol).
The major isomer A for compound 3i was isolated by
crystallization from acetone and the structure was con-
firmed by single crystal X-ray analysis.
13C NMR spectral data of the synthesized compounds 3b–h and 4k, p
(CDCl3, d, ppm)
Compound
C-2
C-3
C-5
C-6
C-7
C-8a
3b
3c
3d
3g
3h
4k
4o
36.3
36.4
42.4
42.2
42.2
25.4
25.5
51.9
52.0
51.4
51.5
51.5
51.6
51.6
56.2
60.5
57.0
56.4
56.4
61.7
61.1
25.9
25.0
25.6
25.6
25.7
75.7
75.5
80.2
80.4
80.6
162.6
164.5
160.2
164.8
164.3
–
100.8
101.1
142.5
142.7
163.1
of H-7 to H-6a and H-6e in the spectrum of compound 3a
were 3.9 and 4.6 Hz, respectively. This is characteristic to
3Jaa and 3Jae type of constants. This was the clear indication
of the equatorial configuration of the proton at C-7 center in
the major isomer. Based on this analysis we can assign struc-
ture A to the major isomer formed in the reaction of 2-
aminothiazoline (1) with crotonic aldehyde. Another isomer
was assigned with structure B. The ratio of the isomers in the
case of compound 3a was 3:1. The same result was obtained
for 3b and 3c. The signal of C-5 proton exhibited the same
multiplicity, coupling constant and chemical shift through-
out the series. This proved the assumption that the stereo-
3.3. X-ray structural analysis
The X-ray investigation of the crystals of compound 3i
demonstrated that in the crystal phase only A type diaste-
reomer is present. The asymmetric unit contains two forms
(A1 and A2) with slightly different geometrical parameters.
Each of them consists of a pair of enantiomers E1 and E2.
As a result, the asymmetric unit contains four molecules;
they will be donated A1E1, A1E2, A2E1 and A2E2.
Table 5
1H NMR spectral data of the synthesized compounds 4k–p (CDCl3, d, ppm)
Compound
H-2
H-3
H-5
H-6
R
R0
4k
4l
4ma
4o
4p
a
3.10 (m,2H)
3.10 (m,2H)
3.43 (m,2H)
3.10 (m,2H)
3.20 (m,2H)
3.40 (m,2H)
3.20 (m,2H)
3.51 (m,2H)
3.30 (m,2H)
3.50 (m,2H)
5.26 (d,1H)
5.28 (d,1H)
5.29 (d,1H)
5.15 (d,1H)
5.41 (d,1H)
5.32 (d,1H)
5.32 (d,1H)
5.48 (d,1H)
5.25 (d,1H)
5.53 (d,1H)
7.40 (m,5H)
7.35 (m,5H)
2.34 (s,3H), 7.12 (d,2H), 7.62 (d,2H)
3.71 (s,3H), 6.84 (d,2H), 7.58 (d,2H)
2.28 (s,3H), 7.20–7.29 (m,7H), 7.68 (d,2H)
7.25 (d,2H), 7.63 (d,2H)
7.64 (d,2H), 8.28 (d,2H)
7.20–7.23 (m,5H)
3.73 (s,3H), 6.86 (d,2H), 7.62 (d,2H)
The spectrum was recorded in DMSO-d6.

62
F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
both molecules A1 and A2. The tetrahydropyrimidine ring
adopts a conformation which is intermediate between the
sofa and half-chair (the puckering parameters [17] are
S = 0.71, H = 30.5°, W = 13.2° for molecule A1 and
S = 0.71, H = 28.5°, W = 11.3° for A2). Deviation of the
C(5) and C(6) atoms from the mean plane of remaining
˚
atoms of the ring are ꢀ0.48 and 0.17 A for A1 and ꢀ0.48
˚
and 0.15 A for A2, respectively. The phenyl substituent
has a pseudoequatorial orientation (the C(3)–N(1)–C(6)–
C(9) torsion angle is ꢀ157.4(3)° for molecule A1 and
156.0(3)° for molecule A2 and is turned relatively to the
N(1)–C(6) bond (the N(1)–C(6)–C(9)–C(10) torsion angle
is 38.1(5)° for A1 and ꢀ39.5(5)° for A2). The ethyl substi-
tuent has a pseudoequatorial orientation (the C(3)–N(2)–
C(4)–C(7) torsion angle is 147.2(3)° for A1 and
ꢀ147.7(3)° for A2). The C(7)–C(8) bond has antiperiplanar
orientation with respect to the N(2)–C(4) bond (the N(2)–
C(4)–C(7)–C(8) torsion angle is ꢀ178.4(3)° for A1 and
ꢀ179.4(3)° for A2). The hydroxy group has a pseudoaxial
orientation (the C(3)–N(2)–C(4)–O(1) torsion angle is
ꢀ93.7(3)° for A1 and 92.9(3)° for A2).
Fig. 1. Molecular structure of tetrahydrothiazolo[2,3-a]pyrimidine 3i.
In the crystal phase each enantiomer of 3i forms the cen-
trosymmetric dimers with an opposite enantiomer possess-
ing the same geometrical parameters (A1E1. . .A1E2 and
A2E2. . .A2E1 dimers). The intermolecular hydrogen
bonds are O(1c)–H(1Oc)ꢃ ꢃ ꢃN(2c)0 (1ꢀx,ꢀy,1ꢀz) Hꢃ ꢃ ꢃN
0
˚
1.82 A O–Hꢃ ꢃ ꢃN 163° and O(1d)–H(1Od)ꢃ ꢃ ꢃN(2d) (1ꢀx,
˚
1ꢀy, 2ꢀz) Hꢃ ꢃ ꢃN 1.78 A O–Hꢃ ꢃ ꢃN 174°.
The X-ray investigation of the crystals of compound 4p
demonstrated that the thiazoline ring adopts the twist con-
formation. Deviation of the C(1) and C(2) atoms from the
˚
plane of remaining atoms of the ring is ꢀ0.32 and 0.23 A,
respectively. The tetrahydropyrimidine ring adopts a con-
formation which is intermediate between the sofa and
half-chair (the puckering parameters [17] are S = 0.34,
H = 33.8°, W = 17.6°). Deviation of the C(5) and C(6)
atoms from the plane of remaining atoms of the ring are
˚
ꢀ0.24 and ꢀ0.43 A, respectively.
˚
The length of the N(1)–C(3) bond (1.362(7) A) indicates
the conjugation between the lone pair of the nitrogen atom
and p-system of the azomethyne group despite the trigonal-
pyramidal configuration of the N(1) atom. The substituent
at the C(6) atom has pseudoequatorial orientation (the
C(4)–C(5)–C(6)–C(13) torsion angle is 137.3(6)°). This
position of the substituent results in the appearance of
Fig. 2. Molecular structure of dihydrothiazolo[2,3-a]pyrimidine 4p.
2
2
˚
the shortened intramolecular contact H(14)ꢃ ꢃ ꢃN(1) 2.58 A
3
3
1
1
S
S
(the sum of the corresponding Van der Waals radii [18] is
N4
N4
8
8
´
5
5
˚
2.67 A). The nitro group is coplanar to the aromatic ring
CH3
CH3
N
(e)H
N
HO
6
6
(the O(2)–N(3)–C(16)–C(17) torsion angle is 0.3(9)°). It
7
7
H(a)
H(a)
can be assumed that this orientation of the nitro group is
OH
H(e)
˚
B
A
stabilized by the H(15)ꢃ ꢃ ꢃO(3) 2.44 A and H(17)ꢃ ꢃ ꢃO(2)
˚
2.42 A attractive interactions.
Fig. 3. Diastereomeric pair of 7-hydroxytetrahydropyrimidine 3a.
The methoxyphenyl substituent is slightly turned rela-
tively to the C(4)–C(5) double bond (the C(5)–C(4)–C(7)–
C(8) torsion angle is 7.8(9)°) because of the repulsion
between the bicyclic fragment and aromatic ring (the short-
The thiazoline ring adopts the envelope conformation in
both enantiomers. Deviation of the C(1) atom from the
mean plane of remaining atoms of the ring is 0.52 A for
˚
˚
˚
ened intramolecular contacts H(5)ꢃ ꢃ ꢃC(8) 2.65 A (2.87 A),

F. Yaremenko et al. / Journal of Molecular Structure 874 (2008) 57–63
63
˚
˚
˚
˚
˚
˚
H(5)ꢃ ꢃ ꢃH(8) 2.09 A (2.34 A), H(8)ꢃ ꢃ ꢃC(5) 2.67 A (2.87 A),
References
H(12)ꢃ ꢃ ꢃN(2) 2.45 A (2.67 A)). The methoxy group is almost
coplanar to the benzene ring (the C(19)–O(1)–C(10)–C(9)
torsion angle is ꢀ3.3(9)°) in spite of the shortened intramo-
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˚
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˚
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4. Conclusions
Reactions of 2-aminothiazoline (1) with a,b-unsaturated
carbonyl compounds 2 in different reaction conditions have
been investigated. We discovered that 7-hydroxytetrahy-
drothiazolo[2,3-a]pyrimidines 3 can be obtained with rea-
sonable yields under mild conditions (acetone, room
temperature). Two diastereoisomers, A (with axial OH-
group) and B (with equatorial OH-group), of tetrahydro-
thiazolo[2,3-a]pyrimidine products have been identified
and the structures and the ratio of the isomers were deter-
mined using NMR spectroscopy. Structure A, confirmed
by X-ray structural analysis in the case of 3i, has been
shown to be the major isomer in all cases. The intramolec-
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the isomer A in solutions compared to structure B where no
hydrogen bonding is possible. Under stronger reaction
conditions (DMF or chloroform, heating) the formation
of 2,3-dihydrothiazolo[2,3-a]pyrimidines 4 is much more
preferable. Molecular structure of 4p was confirmed by
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