Synthesis of new 2-amino-5-hydroxymethyl-2-thiazolines

Article abstract of DOI:10.1007/s10593-007-0054-5

A simple and convenient method is proposed for the synthesis of 2-amino-5-hydroxymethylthiazolines with various substituents in the amino group, which is based on hydrolysis of the corresponding 5-halomethyl derivatives of thiazoline in the presence of divalent lead oxide.

Full text of DOI:10.1007/s10593-007-0054-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
SYNTHESIS OF NEW 2-AMINO-5-HYDROXYMETHYL-2-THIAZOLINES
T. P. Trofimova1, A. N. Pushin2, A. N. Proshin2, A. I. Stash3,
A. A. Mandrugin1, V. M. Fedoseev1, and S. Ya. Proskuryakov4
A simple and convenient method is proposed for the synthesis of 2-amino-5-hydroxymethylthiazolines
with various substituents in the amino group, which is based on hydrolysis of the corresponding
5-halomethyl derivatives of thiazoline in the presence of divalent lead oxide.
Keywords: 2-amino-5-hydroxymethyl-2-thiazoline, nitric oxide, hydrolysis, X-ray structural analysis,
NMR.
It is familiar [1] that 2-amino-2-thiazoline derivatives provide radiation protection. Recently, interest has
been shown in their capacity to act selectively on certain enzymes (e.g., NO synthase isoforms) [2, 3]. This has
led to a search for a convenient method of synthesizing previously unknown 2-amino-5-hydroxymethyl-
2-thiazolines with alkyl, benzyl, alkylbenzyl, dibenzyl, and hetaryl substituents in the amino group. The
literature bears isolated items of information on the synthesis of such compounds from the corresponding
5-haloderivatives of thiazoline in the presence of silver salts [4, 5], but unfortunately they lack descriptions of
the experimental methods and proof of the structures of the substances.
We have examined the hydrolysis of the hydrohalides of 2-amino-substituted 5-halomethyl-2-thiazolines 1a-
h made by traditional methods: iodination of the corresponding N'-derivatives of N-allylthiourea or reaction of N-
(2,3-dibromopropyl)isothiocyanate with amines [6-8].
Previous studies have shown that isomeric six-membered rings (thiazines) are formed in these reactions as
well as thiazolines [9, 10]. However, these reactions are usually performed in polar media with heating, and from the
reaction mixtures one isolates only five-membered thiazoline rings, because under these conditions there is an easy
dihydrothiazine-thiazoline rearrangement [11]. There is published evidence for the reversibility of that rearrangement
[12], so particular attention has been given to establishing the structures of the resulting hydroxyl derivatives.
In order to choose the hydrolysis conditions, we examined the behavior of compounds 1a-h at various pH;
according to [13] and our studies, these compounds are unstable in the presence of bases and may give rise to
polymeric compounds of variable composition. Therefore, for the hydrolysis we examined the systems PbO-H2O or
PbO-H2O-EtOH as appropriate to the solubility of the initial hydrogen halides of the 2-aminothiazolines 1a-h. The
lead halides formed in the reaction are virtually insoluble in water, i.e., the halogen ions are removed from the
reaction sphere and the equilibrium is displaced towards the formation of 2-amino-5-hydroxy-2-methylthiazolines.
We found that the best conditions for the experiments were pH from 4 to 7.
__________________________________________________________________________________________
1M. V. Lomonosov Moscow State University, Chemical Faculty, Moscow 119992, Russia; e-mail:
2
trof@radio.chem.msu.ru. Institute of Physiologically Active Compounds, Russian Academy of Sciences,
3
Chernogolovka 142432, Moscow Region. Karpov Institute of Physical Chemistry, Moscow 105064, Russia;
4
e-mail: center@cc.nifhi.ac.ru. Medical Radiological Research Center, Russian Academy of Medical Sciences,
Obninsk 249036, Moscow Region; e-mail: noo@mrrc.obninsk.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 456-463, 2007. Original article submitted November 22, 2005.
370
0009-3122/07/4303-0370©2007 Springer Science+Business Media, Inc.

R1
N
R1
R2
Br
H
N
N
C
S
R2
+
HN
S
Br
I2
Hal
Hal
+
S
N
S
N
HHal
HHal
N
N
R1
R2
R1
R2
Hal
–
OH , pH >7.0
S
N
S
N
N
HHal
R2
N
R1
R1
R2
1a–h
PbO–H2O–EtOH 50–100 oC
Hb
polymer
Ha
HO
4
5
H
S1 3N
2
N
R1
R2
2a–h
а R1 = H, R2 = Me, Hal = I; b R1 = H, R2 = Et, Hal = I; с R1 = H, R2 = Bn, Hal = I;
d R1 = Me, R2 = Bn, Hal = Br; e N + R1 + R2 = pyrrolidin-1-yl, Hal = I;
f N + R1 + R2 = piperidin-1-yl, Hal = Br; g R1 = H, R2 = dibenzo[b,d]furan-3-yl, Hal = I;
h R1 = R2 = Bn, Hal = I
The use mainly of 5-iodomethyl-2-thiazolines not only reduced the reaction times but also simplified the
purification of the final compound because the solubility of the lead iodide formed in the reaction is less by an order
of magnitude than that of lead bromide. We also used water-alcohol mixtures instead of water with various alcohol
contents because of the solubility differences of the initial hydrogen halides of the 2-amino-5-halomethyl-2-
thiazolines 1a-h. The stabilities of the initial and final compounds on heating were examined to choose the best
reaction temperature for each substance and provided yields of 60-96% of the 5-hydroxymethyl derivatives 2a-h
(Table 1).
Most of the compounds synthesized were oils difficult to crystallize. All the 5-hydroxymethyl-2-thiazolines
2a-h were obtained as bases, but on the hydrolysis of unsubstituted 2-amino-5-bromomethyl-2-thiazoline
hydrobromide (1i) in the presence of PbO we were able to isolate the 2-amino-5-hydroxymethyl-2-thiazoline (2i) as
the hydrobromide with almost quantitative yield. Previously, that compound had been obtained with a low (25%)
yield by the hydrolysis of 2-amino-5-bromomethyl-2-thiazoline hydrobromide 1i in the presence of NaHCO3 [14].
371

TABLE 1. Reaction Conditions
Reaction
Reaction
temperature, ºС
Reaction
time, h
Medium
product
Yield 2, %
2a
2b
2c
2d
2e
2f
Вода
50
60
80
60
60
100
55
80
3
5
66
64
63
96
77
60
64
96
Вода
Water–alcohol, 1:1
Water–alcohol, 5:1
Water–alcohol, 5:1
Water
6
2
4
2.5
10.5
4
2g
2h
Water–alcohol, 1:1
Water–alcohol, 5:2
Table 2 gives spectral data on compounds 2a-h.
The fragments X–CH2–CH(S)–CH2N of all the compounds given in Table 2 appear in the 1H NMR spectrum
as two ABX systems with common X parts. Sometimes, the CH-S signal overlaps with one of the signals from the
CH2N group protons. It is also difficult to analyze the spectra because of the hindered rotation around the exocyclic
C-N bond, which leads to considerable broadening of the lines, so the coupling coefficients are given only for those
groups where it occurs explicitly. In some cases we observed signals from two rotational isomers (with respect to the
exocyclic C-N bond). Although the five-membered and six-membered isomers have a common type of spin system
(two AB systems with a common X part), the forms of the spectra are different. In particular, in the salts and bases of
the six-membered heterocyclics one gets spin-spin interaction through four bonds between the H-6 and H-4 protons,
which has not been observed in any of the spectra for compounds 2a-h.
Fig. 1. General view of compound 2d molecule with numbering of the atoms.
The X-ray data for thiazoline 2d (Fig. 1) provide a further confirmation of the structures of these compounds.
The XRD show that compound 2d in the crystalline state is a 2-amino derivative of 2-thiazoline, which has a 5-
hydroxomethyl substituent.
The maximum deviation of the N(2) atom from the plane formed by the atoms С(1),С(2),С(3) is -0.34, while that
for the S atom is -0.62 Å, and the angle between the plane of the heterocycle and the benzene ring is 96.7°. Table 3
gives the bond lengths and valence angles for compound 2d.
372

373

The length of the endocyclic N(2)–С(1) bond is 1.273(5) Å, which corresponds to a standard N(sp2)=C(sp2)
double bond for these heterocycles (1.28 Å) [15, 16]. The exocyclic bond N(1)–С(1) (1.346(5) Å) is somewhat shorter
than a single one С(sp2)–N (1.37–1.38 Å) [15, 17, 18]. The molecule contains two single S–C(sp3) bonds and S–
C(sp2), where the difference between the lengths of these bonds is only 0.014 Å. The S–С(3) bond of 1.794(4) Å
agrees well with the published data (1.79 [15] and 1.803 Å [19]), while the S–C(1) – 1.780(4) Å bond is somewhat
longer (1.77 [15], 1.741 Å [19]). The С(1)–S–С(3) angle is 88.9° (17), which agrees well with the data for the 2-
aminothiazolines (88°) [15].
Fig. 2. Dimer formation in the crystal of compound 2d (hydrogen bonds shown dotted).
The hydroxymethyl group in position 5 of the thiazoline molecule 2d leads to the formation of layers of
dimers in the crystal, which are joined by intermolecular OH...N hydrogen bonds (Fig. 2). The parameters of the
hydrogen bond are d O–H 0.84(7), H...N(2) 2.03(7), O...N(2) 2.831(5) Å, angle (OH…N(2)) 161(6)°.
The compounds were tested for NOS-inhibiting activity in vivo with white mice. The best results were
obtained with compounds 2c and 2g.
TABLE 3. Bond Lengths d and Valence Angles ω in the Molecule of Compound 2d
Bondь
d, Å
Angle
C(1)–S–C(3)
ω, deg
S–C(1)
S–C(3)
O–C(4)
1.780(4)
1.794(4)
1.411(5)
1.346(5)
1.439(5)
1.453(6)
1.273(5)
1.472(5)
1.509(6)
1.521(6)
1.520(6)
1.370(6)
1.375(6)
1.380(6)
1.348(7)
1.372(8)
1.383(7)
88.6(17)
124.0(4)
119.6(4)
116.4(4)
110.1(3)
124.1(4)
117.1(3)
118.9(3)
109.3(3)
113.6(4)
103.6(3)
111.1(3)
111.0(4)
113.5(4)
118.8(4)
121.6(4)
119.6(4)
120.6(4)
120.6(5)
119.5(5)
120.4(5)
120.0(5)
C(1)–N(1)–C(6)
C(1)–N(1)–C(5)
C(6)–N(1)–C(5)
C(1)–N(2)–C(2)
N(2)–C(1)–N(1)
N(2)–C(1)–S
N(1)–C(1)
N(1)–C(6)
N(1)–C(5)
N(2)–C(1)
N(2)–C(2)
C(2)–C(3)
C(3)–C(4)
C(6)–C(7)
C(7)–C(8)
C(7)–C(12)
C(8)–C(9)
C(9)–C(10)
C(10)–C(11)
C(11)–C(12)
N(1)–C(1)–S
N(2)–C(2)–C(3)
C(2)–C(3)–C(4)
C(2)–C(3)–S
C(4)–C(3)–S
O–C(4)–C(3)
N(1)–C(6)–C(7)
C(8)–C(7)–C(12)
C(8)–C(7)–C(6)
C(12)–C(7)–C(6)
C(7)–C(8)–C(9)
C(10)–C(9)–C(8)
C(9)–C(10)–C(11)
C(10)–C(11)–C(12)
C(7)–C(12)–C(11)
374

We have thus developed a synthesis methods in the search for compounds with NO modulating activity for
the synthesis of previously unknown 5-hydroxymethyl derivatives of thiazoline 2a-h by hydrolysis of the
corresponding 5-halomethyl derivatives 1a-h in the presence of lead oxide. The method gives heterocyclic
1
aminoalcohols 2a-h in preparative amounts and with good yield. The H NMR spectra and X-ray data reliably
confirm the structures of the compounds.
EXPERIMENTAL
1
The H NMR spectra were recorded with a Bruker CXP-200 spectrometer '200 MHz), internal standard
TMS. The course of the reactions was monitored and the individuality of the compounds was established by TLC on
Silufol UV-254 plates in the system butanol-acetone-formic acid 1:1:1.
X-ray structure analysis of compound 2d. Crystals of compound 2d formed from alcohol are platy and at
293 K: a = 6.1070(10), b = 8.996(2), c = 11.367(2) Å, a = 99.79(3), b = 103.05(3), g= 95.60(3)°, V = 593.45(19) Å3,
d
calc = 1.323 g/cm3, space group P-1, Z = 2. The measurements were made with an Enraf-Nonius CAD-4 automatic
diffractometer by θ/2θ scanning in MoKα radiation, wavelength 0.71073 Å. The intensities of three standard
reflections measured every 60 min remain stable within a range of 0.3%. A correction was applied for the X-ray
absorption, absorption coefficient 0.253 mm-1. The experimental data were processed and the subsequent calculations
were performed on the SHELXT program. In the calculation we used 1002 reflections having I > 2σ(I). The structure
was interpreted by a direct method and refined by least-squares fitting in the full-matrix anisotropic approximation for
the non-hydrogen atoms. All the hydrogen atoms were included in the refinement with fixed parameters in the
isotropic approximation. The final value for the divergence factor was R = 0.0401. The full XRD data have been
deposited in the Cambridge database: depositor CCDC 297910.
Hydrohalides of 2-amino-5-halomethyl-2-thiazolines 1a-i. These were made by iodinating N' derivatives
of N-allylthiourea (compounds 1a, b, c, e, g, and h) or by bromination of N-allylthiourea (compound 1i) or reaction
of N-(2,3-dibromopropyl)isothiocyanate with the corresponding amines (compounds 1d and f) [6-8].
5-Hydroxymethyl-2-methylamino-2-thiazoline (2a). We dissolve (1.0 g, 2.6 mmol) of 5-iodomethyl-
2_methylamino-2-thiazoline hydroiodide (1a) at 50° in 75 ml of water and gradually add (0.87 g, 3.9 mmol) of lead
oxide. The mixture is stirred at that temperature for 3 h. The precipitate is filtered off and the solvent is evaporated
under vacuum, with the resulting oil treated with ether and stored in the cold. It crystallizes within 1-3 days and gives
0.25 g of thiazoline 2a, m.p. 102-104°C. Found, %: С 41.09; H 6.99; N 19.01. C5H10N2OS. Calculated, %: C 41.07;
H 6.89; N 19.16.
Compounds 2b-h were made similarly with modification of certain aspects of the methods 'Table 1).
2-Ethylamino-5-hydroxymethyl-2-thiazoline (2b), mp 81-83°C. Found, %: С 45.24; H 7.76; N 17.80.
C6H12NOS. Calculated, %: C 44.97; H 7.55; N 17.48.
2-(N-Benzyl)amino-5-hydroxymethyl-2-thiazoline (2c), mp 151-153°C. Found, %: С 59.57; H 6.13;
N 12.98. C11H14N2OS. Calculated, %: C 59.43; H 6.35; N 12.60.
2-(N,N-Methylbenzyl)amino-5-hydroxymethyl-2-thiazoline (2d), mp 117-119°C. Found, %: С 60.97;
H 6.57; N 11.88. C12H16N2OS. Calculated, %: С 60.97; H 6.57; N 11.88.
5-Hydroxymethyl-2-pyrrolidin-1-yl-2-thiazoline (2e), mp 104-106°C. Found, %: С 51.65; H 7.28; N
15.35. C8H14N2OS. Calculated, %: C 51.58; H 7.58; N 15.04.
5-Hydroxymethyl-2-piperidin-1-yl-2-thiazoline (2f), mp 82-84°C. Found, %: С 53.89; H 8.17; N 14.12.
C9H16N2OS. Calculated, %: C 53.97; H 8.05; N 13.99.
2-(N-dibenzo[b,d]furan-3-yl)amino-5-hydroxymethyl-2-thiazoline (2g), mp 181-183°C. Found, %: С
64.32; H 5.69; N 9.14. C16H16N2O2S. Calculated, %: 63.98; H 5.37; N 9.33.
2-(N,N-Dibenzyl)amino-5-hydroxymethyl-2-thiazoline (2h), mp 112-113°C. Found, %: С 69.23; H 6.48;
N 9.01. C18H20N2OS. Calculated, %: C 69.20; H 6.45; N 8.97.
375

5-hydroxymethyl-2-amino-2-thiazoline hydrobromide (2i) was obtained by analogy with compound 2a, reaction
performed for 14 h at 80°C. This gave 3.53 g (91%) of thiazoline 2i, mp 85-86°C (mp 84°C [14]).
The research was performed with financial support from the Russian Fund for Basic Research (grants No.
05-04-48794 and No. 05-03-01840 ofi-a).
REFERENCES
1.
2.
3.
4.
V. G. Vladimirov, I. I. Krasil'nikov, and O. V. Arapov, in: V. G. Vladimirov (editor), Radio Protectors:
Structure and Functions) [in Russian], Naukova Dumka, Kiev (1989), p. 241.
C. L. M. Goodyer, E. Chinje, M. Jaffar, I. J. Stratford, and M. D. Threadgill, Bioorg. Med. Chem., 11, 4189
(2003).
S. Ya. Proskuryakov, A. G. Konoplyannikov, V. G. Skvortsov, A. A. Mandrugin, and V. M. Fedoseev,
Biokhimiya, 70, 14 (2005).
E. Fromm, R. Kapeller-Adler, W. Friedenthal, L. Stangel, J. Edlitz, E. Braumann, and J. Nissbaum, Liebigs
Ann. Chem., 467, 240 (1928).
5.
6.
P. I. Creek and J. M. Mellor, Tetrahedron Lett., 30, 4435 (1989).
E. Dixon, J. Chem. Soc., 69, 17 (1896).
7.
8.
V. M. Fedoseev and Yu. M. Evdokimov, Zh. Obshch. Khim., 34, 1551 (1964).
A. N. Proshin, MSc Thesis [in Russian], Moscow (2004).
9.
S. E. Tkachenko, A. N. Pushin, and V. M. Fedoseev, Zh. Obshch. Khim., 57, 2400 (1987).
V. N. Zontova, T. I. Koroleva, N. N. Mel’nikov, and A. F. Grapov, Zh. Obshch. Khim., 60, 798 (1990).
V. M. Fedoseev, V. S. Churilin, and S. E. Tkachenko, Dokl. AN, 197, 1351 (1971).
V. M. Fedoseev, V. S. Churilin, S. E. Tkachenko, and A. V. Kamaev, Khim.Geterotsikl. Soedin., 997 (1987)
[Chem. Heterocycl. Comp., 14, 805 (1978)].
10.
11.
12.
13.
14.
15.
A. N. Pushin, S. E. Tkachenko, and V. M. Fedoseev, Izv. AN SSSR, Ser. Khim., 733 (1986).
V. M. Fedoseev, V. S. Churilin, and Ya. I. Lys, Vestn. MGU, Ser. 2, Khim., 5, 611 (1971).
R. A. L. Miller, J. M. Robertson, G. A. Sim, R. C. Clap, L. Long, Jr., and T. Hasselstrom, Nature, 202,
287 (1964).
16.
17,
18.
19.
E. Shuter, H. R. Hoveyda, V. Karunaratne, S. G. Retting, and C. Orvig, Inorg. Chem., 35, 368 (1996).
M. Remko, O. A. Walsh, and W. G. Richards, Chem. Phys. Lett., 336, 156 (2001).
F. B. Stocker, P. Fadden, S. Dreher, and D. Britton, Inorg. Chem., 38, 3251 (1999).
L. D'Ornelas, T. Castrillo, B. L. de Hernandez, A. Narayan, and R. Atencio, Inorg. Chim. Acta, 342,
1 (2003).
376