Synthesis and structure of a new heterocyclic system - 7,8-dihydroimidazo- [1,2-c][1,3]thiazolo[4,5-e]pyrimidine

Article abstract of DOI:10.1007/s10593-011-0788-y

The purpose-directed synthesis of a new heterocyclic system, 7,8-dihydroimidazo[1,2-c][1,3]thiazolo[4,5-e]pyrimidine has been carried out based on the successive interaction of available 2-(aroylaminocyanomethylene) imidazolidines with hydrogen sulfide and triethyl orthoformate with subsequent intramolecular cyclocondensation of the obtained 8-aroylamino-7-thioxo-1,2,3,7- tetrahydroimidazo-[1,2-c]pyrimidines under the action of phosphorus pentasulfide or polyphosphoric acid.

Full text of DOI:10.1007/s10593-011-0788-y

Chemistry of Heterocyclic Compounds, Vol. 47, No. 4, July 2011 (Russian original Vol. 47, No. 4, April, 2011)
SYNTHESIS AND STRUCTURE OF A NEW
HETEROCYCLIC SYSTEM – 7,8-DIHYDROIMIDAZO-
[1,2-c][1,3]THIAZOLO[4,5-e]PYRIMIDINE
A. P. Kozachenko1, O. V. Shablykin1, A. N. Vasilenko1,
A. N. Chernega2, and V. S. Brovarets1*
The purpose-directed synthesis of a new heterocyclic system, 7,8-dihydroimidazo[1,2-c][1,3]thia-
zolo[4,5-e]pyrimidine has been carried out based on the successive interaction of available 2-(aroyl-
aminocyanomethylene)imidazolidines with hydrogen sulfide and triethyl orthoformate with subsequent
intramolecular cyclocondensation of the obtained 8-aroylamino-7-thioxo-1,2,3,7-tetrahydroimidazo-
[1,2-c]pyrimidines under the action of phosphorus pentasulfide or polyphosphoric acid.
Keywords: 8-aroylamino-1,2,3,7-tetrahydroimidazo[1,2-c]pyrimidines, phosphorus pentasulfide, poly-
phosphoric acid, triethyl orthoformate, heterocyclization.
N-(2-Amino-1-imidazolidin-2-ylidene-2-thioxoethyl)arylamides 1 (see Scheme), synthesized from
available 2-acylamino-3,3-dichloroacrylonitriles [1], were used previously to obtain the new heterocyclic system
4,5,7,8-tetrahydroimidazo[1,2-c][1,3]thiazolo[4,5-e][1,3,2]diazaphosphinine [2].
It was shown in the present study that compounds 1 may be applied in the synthesis of one more new
heterocyclic system 3, viz. 7,8-dihydroimidazo[1,3-c][1,3]thiazolo[4,5-e]pyrimidine. In difference to the prepa-
ration of the 7,8-dihydroimidazo[1,2-c][1,3]oxazolo[4,5-e]pyrimidine system in [3], in the present case a diffe-
rent method of design of the tricyclic heterocyclic system was used, the key stage of which was not the forma-
tion of the pyrimidine ring but annelation of the five-membered ring to a tetrahydroimidazo[1,2-c]pyrimidine
fragment. First, compounds 1a–c were condensed with triethyl orthoformate with the formation of the previous-
ly unknown 8-aroylamino-7-thioxo-1,2,3,7-tetrahydroimidazo[1,2-c]pyrimidines 2a–c (Scheme and Table 1).
NH
C
C
C(S)NH2
Similar heterocyclizations of compounds with the characteristic fragment
were
described previously in [4, 5], but the products of such reactions are as a rule monocyclic derivatives of pyrimi-
_____________
*To whom correspondence should be addressed; e-mail: brovarets@bpci.kiev.ua.
1 Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murman-
ska St., Kyiv 02660, Ukraine.
2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–620, April, 2011. Original
article submitted November 25, 2010.
0009-3122/11/4704-0507©2011 Springer Science+Business Media, Inc.
507

dine. Several approaches are known [6–9] for design similar bicyclic system of structure 2 but containing a
7-oxotetrahydroimidazo[1,2-c]pyrimidine fragment. However 7-thioxo derivatives of such structures were
synthesized by us for the first time.
S
S
S
H
N
H
N
Ar
Ar
N
N
NH2
HC(OEt)3
N
O
O
Ar
N
N
HN
N
HN
NH
4a–c
1a–c
2a–c
P2S5, Py
or PPA
Ar
1N
2
S 3
3a
9b
4
N
9a
5
N
6
9 N
7
8
3a–c
1–4 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-ClC6H4
A complex NMR analysis (NOESY, COSY, HMQC, HMBC) was carried out to confirm their structures.
1
A complete assignment of the signals in the H and 13C spectra of compound 2a is given in Fig. 1, and all the
correlations found are given in Table 2. The large number of correlations left no doubt as to the correctness of
assigning signals. Thus the presence of the imidazole fragment was confirmed by the HMBC correlation 3.81
HC(2b) → 147.03 C(8a) and 4.44 HC(3b) → 147.03 C(8a), and of pyrimidine by HMBC 8.21 HC(5b) → 186.58
CS and 8.21 HC(5b) → 147.03 C(8a). The tetrahydroimidazoline fragment is condensed with the pyrimidine as
shown by the NOESY correlation 4.44 HC(3b) → 8.21 HC(5b) and HMBC 3.81 HC(2b) → 47.83 C(3b). It should
be mentioned that the amide CONH bond and the imidazoline fragment are close together in space as pictured in
the Scheme and in Fig. 1 and as indicated by the found NOESY correlations 8.00 HC(2,6c) → 9.61 CONH, while
the NOESY interaction 7.71 HN(1b) → 9.61 CONH was not observed.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °C*
С
Н
N
S
2a
2b
2c
3a
3b
3c
C13H12N4OS
C14H14N4OS
C13H11ClN4OS
C13H10N4S
57.27
57.34
4.52
4.44
20.63
20.57
11.83
11.77
269–271
289–290
293–294
229–231
257–258
244–245
63
67
71
58.79
58.72
4.91
4.93
19.50
19.57
11.12
11.20
50.98
50.90
3.70
3.61
18.33
18.26
10.52
10.45
61.49
61.40
4.01
3.96
22.08
22.03
12.69
12.61
65 (А),
61 (B)
C14H12N4S
62.74
62.66
4.60
4.51
20.96
20.88
12.02
11.95
71 (А),
66 (B)
C13H9ClN4S
53.98
54.07
3.21
3.14
19.49
19.40
11.18
11.10
69 (А),
65 (B)
__________
*Solvent for recrystallization was ethanol.
508

TABLE 2. Correlations Found in the COSY, NOESY, HMQC, and
HMBC Spectra of Compound 2a*
1H, δ
NOESY
13C, δ
1H, δ
COSY
7.58
HMQC
HMBC
7.61 (H-4c)
7.58
132.66
129.38
128.28 (C-2c,6c)
7.58 (H-3c,5c)
7.61,
8.00
7.61,
8.00
134.39 (C-1c), 129.38 (C-3c,5c)
8.00 (H-2c,6c)
9.61 (CONH)
7.71 (NH)
7.58
7.58,
9.61
128.28
–
132.66 (C-4c), 128.28 (C-2c,6c)
–
8.00
147.03 (C-8ab), 165.20 (CO),
186.58 (C-7)
–
3.81
–
147.03 (C-8ab), 44.03 (C-2b),
47.83 (C-3b)
3.81 (2H-2b)
4.44 (2H-3b)
8.21 (H-5b)
4.44
3.81
–
7.71,
4.44
44.03
47.83
141.69
147.03 (C-8ab), 47.83 (C-3b)
3.81,
8.21
147.03 (C-8ab), 44.03 (C-2b),
141.69 (C-5b)
4.44
147.03 (C-8ab), 44.03 (C-2b),
186.58 (C-7), 113.02 (C-8)
_______________
*Assignment of signals in compound 2a, see Fig. 1.
Owing to the fact that compounds 2a–c contain acylamine residues and a thioxo group in vicinal posi-
tions, intramolecular cyclization under the action of phosphorus pentasulfide or polyphosphoric acid remains a
possibility. Similar reactions are well known in syntheses of thiazolopyrimidine derivatives [10–13]. It should
be noted that on carrying out this reaction it is also possible to expect the formation of tricyclic structures 4a–c
with a purine fragment (see analogies in [14–18]). However in all cases only the formation of compounds 3a–c
in fairly high yields were observed (65–71%). The formation of compounds 4 was not established even with the
aid of spectral monitoring of the reaction mixture. Moreover, purpose-directed attempts (heating in acetic
anhydride, aqueous alcoholic alkali, formic acid, or formamide) to synthesize compounds 4 were unsuccessful.
7.58
129.38
8.00
128.28
7.61
132.66
H
H
H
9.61
H
S
186.58
113.02
c
N
7
b
N
6
8
165.20
134.39
5
O
H
8a
147.03
8.21
141.69
N
H
7.71
N
4
3
1
2
H
4.44
H
H
3.81
44.03
H
47.83
1
Fig. 1. Main correlations (shown by arrows) and assignment of signals (ppm) in the H
and 13C NMR spectra of compound 2a.
509

The absence from the 13C NMR spectra (in DMSO-d6) of a signal of the thioxo group characteristic of
compounds 2 (for example for compound 2a δC=S 186.58 ppm) indicates the structure of 7,8-dihydroimid-
13
azo[1,2-c][1,3]thiazolo[4,5-e]pyrimidines 3. It should be mentioned that in the C NMR spectrum of compound
3a taken in CF3COOD solution, a signal was present at δ 175.89 ppm (Table 3), which highly probably might also
have been assigned to the C=S signal of compounds 4. However, a detailed analysis of the spectra made us
consider the possibility that in CF3COOD solution protonation not only of the N(9) atom, but also of N(1) occurs
(see Scheme) as indicated by the low field (δ 175.89 ppm) displacement of the signal of the C(3a) atom of
compound 3a (Table 3). In the IR spectra of compounds 3 also broad absorption bands for the N–H group in the
3155–3240 cm–1 region were absent, which were present for compounds 2. In addition the mass spectra of
compounds 3 point to the cleavage of a molecule of water in the process of conversion of 2 → 3 (Table 3).
TABLE 3. Spectral Data of the Synthesized Compounds
Com-
pound
IR pectrum,
1Н NMR spectrum (DMSO-d6),
δ, ppm (J, Hz)
Mass spectrum,
ν, сm–1
m/z
+
2a
1644* (C=O),
3240 (NH)
3.85 (2Н, t, J = 7.6, СН2);
4.46 (2Н, t, J = 7.6, СН2);
7.52–8.00 (5Н, m, Н Ar);
7.68 (1Н, s, NH);
272 [M]
8.19 (1Н, s, Н-2);
9.76 (1Н, s, CONH)
+
2b
1644* (C=O),
3222 (NH)
2.39 (3Н, s, СН3);
286 [M]
3.81 (2Н, t, J = 7.4, СН2);
4.43 (2Н, t, J = 7.4, СН2);
7.40 (2Н, d, J = 7.5, Н Ar);
7.68 (1Н, s, NH);
7.87 (2Н, d, J = 7.5, Н Ar);
8.20 (1Н, s, Н-2);
9.60 (1Н, s, CONH)
+
2c
1649* (C=O),
3155 (NH)
3.80 (2Н, t, J = 7.4, СН2);
4.43 (2Н, t, J = 7.4, СН2);
7.62 (2Н, d, J = 7.6, Н Ar);
7.69 (1Н, s, NH);
306 [M]
8.08 (2Н, d, J = 7.6, Н Ar);
8.19 (1Н, s, Н-2 );
9.56 (1Н, s, CONH)
+
3a*2
3b
1660 (C=N),
3050–3500 (bands 4.16 (2Н, t, J = 9.2, СН2);
3.97 (2Н, t, J = 9.2, СН2);
254 [M]
absent)
7.54–7.94 (5Н, m, Н Ar);
8.13 (1Н, s, H-2 )
+
1662 (C=N),
2.36 (3Н, s, СН3);
268 [M]
3050–3500 (bands 3.96 (2Н, t, J = 9.4, СН2);
absent)
4.15 (2Н, t, J = 9.4, СН2);
7.32 (2Н, d, J = 7.5, Н Ar);
7.81 (2Н, d, J = 7.5, Н Ar);
8.01 (1Н, s, Н-2)
+
3c
1662 (C=N),
4.00 (2Н, t, J = 9.4, СН2);
288 [M]
3050–3500 (bands 4.13 (2Н, t, J = 9.4, СН2);
absent)
7.58 (2Н, d, J = 7.8, Н Ar);
7.94 (2Н, d, J = 7.8, Н Ar);
8.13 (1Н, s, Н-2)
___________
*Band with shoulder.
*
2 13C NMR spectrum (DMSO-d6), δ, ppm: 46.97 (СН2), 54.08 (СН2),
126.93 (С-2,6 Ph), 129.99 (С-3,5 Ph), 131.53 (С-4 Ph), 133.34, 134.20,
146.75 (C-5), 149.72, 157.64, 163.07 (C-5). 13C NMR spectrum
(CF3COOD), δ, ppm: 45.87 (СН2), 50.30 (СН2), 128.92 (С-2,6 Ph),
130.17, 130.66 (С-3,5 Ph), 131.17, 134.91 (С-4 Ph), 145.28 (C-5), 152.26,
164.37, 175.89 (C-3a).
510

X-Ray structural analysis of one of the compounds 3 provided an unequivocal confirmation of the pro-
posed structure of the final products. The general shape of the 3c molecule is given in Fig. 2, its main bond
lengths and valence angles are given in Table 4. The central tricyclic system S(1)N(1-4)C(1-7) is almost planar,
the deviation of atoms from the mean square plane does not exceed 0.107 Å. The benzene ring C(8)–C(13) is
practically coplanar with this system (dihedral angle was 4.6o).
Fig. 2. General form of the compound 3c molecule.
Hence not only were new derivatives of 7-thioxotetrahydroimidazo[1,2-c]pyrimidines 2 synthesized, but
also conditions were found for the regiospecific cyclization of the latter into representatives of a new
heterocyclic system, viz. 7,8-dihydroimidazo[1,2-c][1,3]thiazolo[4,5-e]pyrimidine 3.
TABLE 4. Main Bond Lengths (l) and Valence Angles (ω) of Compound 3c
Main bond lengths
l, Å
Valence angles
, deg
S(1)–C(1)
S(1)–C(3)
N(1)–C(1)
N(1)–C(2)
N(2)–C(3)
N(2)–C(4)
N(3)–C(4)
N(3)–C(5)
N(3)–C(7)
N(4)–C(5)
N(4)–C(6)
C(2)–C(3)
1.747(3)
1.719(3)
1.297(3)
1.370(3)
1.376(3)
1.297(4)
1.346(4)
1.405(3)
1.467(4)
1.272(4)
1.472(4)
1.376(3)
C(1)S(1)C(3)
C(1)N(1)C(2)
C(3)N(2)C(4)
C(4)N(3)C(5)
C(5)N(4)C(6)
88.81(12)
110.4(2)
113.3(2)
124.4(2)
107.2(2)
511

EXPERIMENTAL
1
The IR spectra of substances were recorded on a Vertex 70 spectrometer in KBr disks. H and 13C NMR
spectra were recorded on a Varian 300 (at 300 and 75 MHz respectively) in DMSO-d6 or CF3COOD, and the
1
NMR heteronuclear H–13C correlation spectra of compound 2a were taken on a Mercury 400 (at 400 and 100
MHz respectively) in DMSO-d6, internal standard was TMS. Chromato-mass spectra were obtained using a
liquid chromato-mass spectrometric system on a high performance liquid chromatograph of the Agilent 1100
Series fitted with a diode matrix and an Agilent LC/MSD SL mass selective detector. The parameters of the
chromato-mass analysis were: column Zorbax SB-C18 1.8 μm 4.6×15 mm (PN 821975-932); solvent A was
acetonitrile–water, 95:5, 0.1% trifluoroacetic acid, B 0.1% aqueous trifluoroacetic acid, eluent flow rate was
3 ml/min; injection volume 1 μliter; UV detector at 215, 254, and 285 nm; chemical ionization at atmospheric
pressure (APCI), scanning range m/z 80–1000. Melting points were measured on a Fisher–Johns instrument.
8-Aroylamino-7-thioxo-1,2,3,7-tetrahydroimidazo[1,2-c]pyrimidines 2a–c. A suspension of com-
pound 1a–c (2 mmol) and triethyl orthoformate (15 ml) was boiled for 3 h. After cooling, the solid was filtered
off, washed with diethyl ether, and purified by recrystallization.
2-Aryl-7,8-dihydroimidazo[1,2-c][1,3]thiazolo[4,5-e]pyrimidines 3a–c. A. Phosphorus pentasulfide
(0.49 g, 2.2 mmol) was added to a solution of one of the compounds 2a–c (2 mmol) in anhydrous pyridine
(10 ml). The mixture was boiled with stirring for 5 h, cooled, water (40–50 ml) was added, the precipitated solid
was filtered off, washed with water, and purified by recrystallization.
B. A mixture of one of the compounds 2a–c (2 mmol) and polyphosphoric acid (10 ml) was heated for
5 h on an oil bath at 160oC, then cooled, the mixture was poured onto ice, the precipitated solid filtered off,
washed with 5% aqueous NaHCO3 solution, and purified by recrystallization.
X-ray Structural Investigation of a monocrystal of compound 3c (0.13×0.15×0.49 mm) was carried
out at room temperature on a Bruker Apex II automatic CCD diffractometer (MoKα radiation, λ = 0.71073 Å,
θ
max = 26.3o, –8 ≤ h ≤ 8, –12 ≤ k ≤ 12, –13 ≤ l ≤13). In total 8762 reflections were collected (1808 independent
reflections, Rint = 0.003). Crystals of compound 3c were triclinic, a = 7.0498(9), b = 10.393(1), c = 11.075(1) Å,
α = 102.349(4)o, β = 96.043(4)o, γ = 91.436(4)o, V = 787.3(2) Å3, M = 334.83, Z = 2, dcalc = 1.41 g/cm3, μ = 3.82
–
cm–1, F(000) = 348, space group P1 (N 2). The structure was solved by the direct method and refined by the
least squares method in a full matrix anisotropic approximation using the CRYSTALS set of programs [19]. In
the refinement 1808 reflections with I > 3σ(I) were used. All the hydrogen atoms were made apparent by an
electron density difference synthesis and were included in the refinement with fixed positions and thermal
parameters (with the exception of atom H-1, which was refined isotropically). The Chebyshev weighting factor
[20] was used in the refinement with five parameters: 2.10, 2.19, 1.97, 0.49, and 0.35. The final values of the
divergence factor R = 0.039 and Rw = 0.047, GooF 0.908. The residual electron density from the Fourier
difference series was 0.30 and –0.38 e/Å3. A complete set of the X-ray structural data for compound 3c has been
deposited in the Cambridge Structural Database (deposit CCDC 768487).
REFERENCES
1.
2.
B. S. Drach, E. P. Sviridov, and T. Ya. Lavrenyuk, Zh. Org. Khim., 10, 1271 (1974).
A. P. Kozachenko, O. V. Shablykin, A. A. Gakh, E. B. Rusanov, and V. S. Brovarets, Heteroatom
Chem., 21, 492 (2010).
3.
4.
A. P. Kozachenko, O. V. Shablykin, E. B. Rusanov, and V. S. Brovarets, Khim. Geterotsikl. Soedin.,
1384 (2010). [Chem. Heterocycl. Comp., 46, 1116 (2010)].
A. S. Ivanov, N. Z. Tugusheva, L. M. Alekseeva, and V. G. Granik, Izv. Akad. Nauk, Ser. Khim., 837
(2004).
5.
6.
A. V. Kadushkin, I. F. Faermark, G. Ya. Shvarts, and V. G. Granik, Khim.-farm. Zh., 62, 870 (1992).
M. Dreyfus, G. Dodin, O. Bensaude, and J. E. Dubois, J. Am. Chem. Soc., 99, 7027 (1977).
512

7.
8.
9.
10.
11.
12.
13.
W. L. F. Armarego and P. Waring, Austral. J. Chem., 34, 1921 (1981).
R. A. Coburn and M. D. Taylor, J. Heterocycl. Chem., 19, 567 (1982).
H. Griengl, W. Hayden, and A. Plessing, J. Heterocycl. Chem., 21, 333 (1984).
M. Ishidate, S. Tsukagoshi, and H. Yuki, Chem. Pharm. Bull., 8, 131 (1960).
T. Ueda, T. Tsuji, and H. Monoma, Chem. Pharm. Bull., 11, 912 (1963).
S.-C. Y. Fu, E. Chinoporos, and H. Terzion, J. Org. Chem., 30, 1916 (1965).
S. Ram, W. Evans, D. S. Wise, Jr, L. B. Townsend, and J. W. McCall, J. Heterocycl. Chem., 26, 1053
(1989).
14.
15.
K. E. Andersen, M. Hammad, and E. B. Pedersen, Liebigs Ann. Chem., 1255 (1986).
H. He, D. Latorska, J. Kim, J. Agnirre, L. Llauger, Y. She, N. Wu, R. M. Immormino, D. T. Gewirth,
and G. Chiosis, J. Med. Chem., 49, 381 (2006).
16.
17.
N. Ibrahim, M. Legraverend, and L. Mouawad, Eur. J. Med. Chem., 45, 3389 (2010).
L. Aguardo, E.-M. Priego, M.-J. Camarasa, M.-J. Perez, H. J. Thibaut, J. Neyts, and M.-L. Jimeno,
J. Med. Chem., 53, 316 (2010).
18.
19.
C. Cesario, L. P. Tardibono, and M. J. Miller, Tetrahedron Lett., 51, 3053 (2010).
D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, CRYSTALS, Issue 10, Chemical
Crystallography Laboratory, Univ. Oxford (1996).
20.
J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979).
513