Synthesis and spectroscopic analysis of substituted 2-aminothiazolines

Article abstract of DOI:10.1016/j.molstruc.2012.12.031

2-Aminothiazolines can exist in two tautomeric species, amino and imino forms, which can theoretically exist as two stereoisomers. Several methods and techniques have been used to evaluate tautomeric process, but in this case ¹⁵N NMR spectrosco

Full text of DOI:10.1016/j.molstruc.2012.12.031

Journal of Molecular Structure 1037 (2013) 186–190
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Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and spectroscopic analysis of substituted 2-aminothiazolines
⇑
Renan B. Ferreira, Claudio F. Tormena, Wanda P. Almeida
Department of Organic Chemistry, Institute of Chemistry, University of Campinas, PO Box 6154, ZC 13083 970 Campinas, SP, Brazil
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
"
Synthesis and spectrometric
characterization of four new
aminothiazolines.
"
"
Study of the tautomerism
phenomenon by 1H-15N HMBC.
Theoretical calculation was
performed and suggested that amino
tautomer is around 1 kcal molÀ1more
stable than iminoform.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 October 2012
Received in revised form 18 December 2012
Accepted 19 December 2012
Available online 16 January 2013
2-Aminothiazolines can exist in two tautomeric species, amino and imino forms, which can theoretically
exist as two stereoisomers. Several methods and techniques have been used to evaluate tautomeric pro-
cess, but in this case 15N NMR spectroscopy was used due to tautomeric process involves two nitrogen
atoms. In this paper, we present the synthesis and a HMBC 1H-15N study of four 2-substituted amino-
thiazolines. It was observed from HMBC contour plot correlation between five membered ring CH2 groups
with sp2 nitrogen around 250 ppm, while aliphatic hydrogen correlates with sp3 nitrogen around 90 ppm,
suggesting that amino form is the major or the unique tautomer present in solution. Theoretical calcula-
tions at the M06-2X/cc-pVDZ level were performed and indicated that amino tautomer is slightly more
stable (ꢀ1 kcal molÀ1) than imino one.
Keywords:
Aminothiazolines
Synthesis
Tautomerism
15NMR data
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
The matter of tautomerism of aminothiazolines has been exten-
sively discussed in the literature, raising some controversy. The
Tautomerism has been a topic of constant interest, particularly
involving 1,3-dicarbonyl compounds (keto-enol) [1], imine-
enamine [2] and amidine-imidate [3]. This phenomenon has been
studied by a series of spectroscopic methods, including infrared
[4], NMR [5], UV [6] and mass spectra [7].
Aminothiazoline moieties I and their imino tautomers II and III
(Fig. 1) are present in the structure of a variety of compounds with
antidepressant [8] and anti-hypertensive activities. Furthermore,
aminothiazoline isosters had been a central role in the develop-
ment of anti-hypertensive agents displaying selective stimulus to
I1 receptors [9].
products of the reaction of amines and thiocyanates were de-
scribed by Gabriel and Colman [10] as the iminothiazolidines (imi-
no tautomer), as well Mousseron et al. [11]. In contrast, Wohl and
Headley [4] pointed to amino tautomer as being the most stable,
since a characteristic endocyclic C@N (1640 cmÀ1) absorption
was observed in the infrared spectra. Later, Weitzberg et al. [12]
confirmed the predominance of the aminothiazoline by 1H NMR
and infrared studies. Theoretically, E/Z isomerism (II and III) may
exist in the imino form (R – H), but they could interconvert via
amino tautomer (I) as depicted in Fig. 1. According to Avalos and
coworkers [13], the Z-isomer predominates for alkyliminothiazoli-
dine (DE = 1.47 kcal/mol). Despite the calculated low energy differ-
ence for aryliminothiazolidine (ca. 0.2 kcal/mol) these authors
suggested that in this case, the E-isomer is predominant.
⇑
Corresponding author. Tel.: +55 1935213016; fax: +55 1935213023.
E-mail address: wanda@iqm.unicamp.br (W.P. Almeida).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.12.031

R.B. Ferreira et al. / Journal of Molecular Structure 1037 (2013) 186–190
187
2.2.1. 3-Pentylisothiocyanate (3a)
27% yield. Colorless oil. IR (film,
m
max): 2970, 2935, 2114, 1740,
1460, 1348, 1242, 1047, 912, 822, 735 cmÀ1 1H NMR (250 MHz,
.
CDCl3) d 3.51 (qt, J = 6.5 Hz, 1H, CH), 1.64 (qt, J = 7.2 Hz, 4H, CH2),
1.02 (t, J = 7.4 Hz, 6H, CH3). 13C NMR (62.5 MHz, CDCl3): d 129.99
(C), 62.07(CH), 28.76(CH2), 10.74(CH3). HRMS (EI TOF): Calculated
for C6H11NS: 129.0612, Found: M+: 129.0621.
2.2.2. 3-(Isothiocyanatomethyl)heptane (3b)
81% yield. Colorless oil. IR (film,
2094, 1460, 1335 cmÀ1 1H NMR (250 MHz, CDCl3): d 3.46 (d,
J = 5.3 Hz, 2H), 1.7–1.2 (m, 9H), 0.90 (t, J = 7.5 Hz, 6H). 13C NMR
(62.5 MHz, CDCl3): 129.46(C), 47.84(CH2), 40.32 (CH),
mmax): 2958, 2930, 2874, 2183,
.
Fig. 1. Tautomerism in aminothiazolines: I, amino tautomer; II and III imino
tautomers.
d
30.89(CH2), 28.75(CH2), 24.29(CH2), 22.77(CH2), 13.95(CH3),
10.87(CH3). HRMS (EI TOF): Calculated for C9H17NS: 171.1082,
Found: M+: 171.0893.
As a part of a research program aimed at the development of
new anti-hypertensive drug candidates, we have planned to syn-
thesize a series of substituted 2-aminothiazolines (Fig. 2). In order
to unequivocally determine their structure and study the tautom-
erism phenomenon in this class of compounds, two dimensional
1H-15N NMR spectroscopy experiments were performed, in addi-
tion to usual methods for characterization. High Resolution Mass
Spectrometry (HRMS) was also included for the new compounds.
To the best of our knowledge these compounds were not synthe-
sized or studied before.
2.2.3. (1-Isothiocyanatoethyl)benzene (3c)
77% yield. Slightly yellow oil. IR (film,
m
max): 3032, 2984, 2931,
1H NMR
2091, 1495, 1454, 1346, 1308, 1022, 949, 758, 698 cmÀ1
.
(250 MHz, CDCl3): d 7.4–7.2 (m, 5H), 4.92 (q, J = 6.8 Hz, 1H), 1.68
(d, J = 6.8 Hz, 3H). 13C NMR (62.5 MHz, CDCl3): d 140.16 (C),
132.90 (C), 128.20 (CH), 125.41 (CH), 57.04 (CH), 24.96 (CH3).
2.2.4. 1-Bromo-4-(1-isothiocyanate)ethylbenzene (3d)
72% yield. Pale yellow oil. IR (film,
2133, 2089, 2046, 1489, 1404, 1329, 1306, 1099, 1074, 1011,
824, 781 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.51 (d, J = 8.5 Hz,
2H), 7.20 (d, J = 8.5 Hz, 2H), 4.89 (q, J = 6.8 Hz, 1H), 1.65 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
139.26(C),
mmax): 2984, 2931, 2850,
2. Experimental
.
2.1. General
d
133.37(C), 132.09(C), 127.22(CH), 122.26(CH), 56.55(CH); 24.92
(CH3). HRMS (EI TOF): Calculated for C9H8BrNS: 240.9561, Found:
M+: 240.9553.
Manipulations and reactions were performed under dry atmo-
spheres or employing dry solvents, Purification and separations
by column chromatography were performed on silica gel, using
flash chromatography. TLC visualization was achieved by spraying
with 5% ethanolic phosphomolybdic acid and heating. All reagents
were purchased from Aldrich and were used without previous
purification. Melting points were measured in open capillary tubes
using a Nicolet Impact 410 apparatus and are uncorrected. Mass
spectra were acquired in a Xevo Q-Tof WatersÒ (ESI) and GCT-
Premier WatersÒ (EI) equipment. Uncorrected melting points were
determined in a GehakaÒ PF 1500 equipment.
2.3. General procedure to obtain N-(2-hydroxyethyl)thioureas
To a stirred solution of ethanolamine (85 lL, 1.4 mmol) in 3 mL
of dry THF, at room temperature and under N2, a solution of isothi-
ocyanate (1.24 mmol) in dry THF (1.5 mL) was slowly added using
a syringe (5 min adding). The resulting mixture was stirred at the
same conditions for 15 h. After this period, the mixture was filtered
through a pad of silica gel, using hexanes to remove the recovered
isothiocyanate. Then, ethyl acetate was used as eluent. After sol-
vent removal, the N-(2-hydroxyethyl)thiourea was obtained and
used in the next step without additional purification.
2.2. General procedure to prepare isothiocyanates
To a stirred solution of amine (5.0 mmol) in dry CH2Cl2 (20 mL)
at À10 °C, under N2 atmosphere, CS2 (1.5 mL, 25 mmol) and dicy-
clohexylcarbodiimide (1.03 g, 5.0 mmol) were successively added.
The resulting mixture was then slowly warmed to room tempera-
ture and stirring was continued for additional 18 h. Solvent was re-
moved by evaporation in vacuum and the residue purified by
column chromatography (eluent: hexanes).
2.3.1. 3-(2-Hydroxyethyl)-1-(pentan-3-yl)-thiourea (4a)
71% yield. White solid. Melting point: 68–69 °C. IR (KBr,
3381, 3292, 3223, 3051, 2970, 2876, 1553, 1462, 1348, 1217,
1151, 1057, 995, 901, 681 cmÀ1 1H NMR (500 MHz, CD3OD): d
4.12 (brs, 1H), 3.74–3.47 (m, 4H), 1.69–1.35 (m, 4H), 0.91 (t,
J = 7.4 Hz, 6H); 13C NMR (125 MHz, CD3OD):
182.51(C),
mmax):
.
d
60.58(CH2), 56.69 (CH), 46.04(CH2); 26.78(CH2), 9.15(CH3). HRMS
(ESI+ TOF): Calculated for C8H19N2OS+: 191.1218, Found (M + H)+:
191.1239.
2.3.2. 1-(2-Ethylhexyl)-3-(2-hydroxyethyl)thiourea (4b)
91% yield. Viscous oil. IR (film, mmax): 3284, 3074, 2958, 2928,
2872, 1556, 1462, 1348, 1286, 1057 cmÀ1. 1H NMR (400 MHz, CD3-
OD): d 3.68 (t, J = 7.5 Hz, 2H), 3.61 (br s, 2H), 3.44 (br s, 2H), 1.60
(m, 1H), 1.45–1.25 (m, 8H), 0.94 (t, J = 7.0 Hz, 3H), 0.93 (t,
J = 7.5 Hz, 3H). 13C NMR (125 MHz, CD3OD):
d 184.45 (C),
62.09(CH2), 49.93(CH2), 47.66(CH2), 40.52(CH), 32.25(CH2),
30.17(CH2), 25.44(CH2), 24.25(CH2), 14.59(CH3), 11.39(CH3). HRMS
(ESI+ TOF): Calculated for C11H25N2OS+: 233.1682, Found (M + H)+:
233.1696.
Fig. 2. Substituted 2-aminothiazolines that were synthesized this work.

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R.B. Ferreira et al. / Journal of Molecular Structure 1037 (2013) 186–190
2.3.3. 3-(2-Hydroxyethyl)-1-(1-phenylethyl)thiourea (4c)
92% yield. Viscous, slightly yellow oil. IR (film,
3063, 2970, 2930, 2876, 1549, 1450, 1348,1257, 1055, 760,
698 cmÀ1 1H NMR (400 MHz, CD3OD): d 4.88 (br s, 1H), 3.66 (dd,
J = 4.0 and 7.0 Hz, 2H), 3.61 (brs, 2H), 1.50 (d, J = 7.0 Hz, 3H). 13C
NMR (125 MHz, CD3OD): 182.01(C), 143.90(C), 128.36(CH),
m
max): 3279,
.
d
126.92(CH), 126.04(CH), 60.66 (CH2), 53.33 (CH), 46.39 (CH2),
21.54 (CH3). HRMS (ESI+ TOF): Calculated for C11H17N2OS+:
225.1056, Found (M + H)+: 225.1087.
2.3.4. 1-[1-(4-Bromophenyl)ethyl]-3-(2-hydroxyethyl)thiourea (4d)
86% yield. Slightly yellow solid. Melting point: 71–74 °C. IR
(KBr,
m
max): 3290, 3236, 3090, 2935, 2885, 1572, 1516, 1406,
1348, 1242, 1055, 1011, 955, 820, 762, 716, 592, 521 cmÀ1
.
1H
Scheme 1. Preparation of 2-Aminothiazolines. Reagents and Conditions: (i) CS2,
CH2Cl2, À10 °C; DCC, À10 °C ? room temperature; (ii) NH2CH2CH2OH, THF, room
temperature; (iii) POCl3-DMF, room temperature, THF.
NMR (400 MHz, CD3OD): d 7.46 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H), 5.43 (br s, 1H), 3.68–3.53 (m, 4H), 1.46 (d,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, CD3OD):
d 183.43(C),
144.56(C), 132.50(CH), 129.25(CH), 121.59(C), 61.79(CH2), 53.97
(CH), 47.53(CH2), 22.47(CH3). HRMS (ESI+ TOF): Calculated for C11-
H15BrN2OSNa+: 324.9986, Found (M + Na)+: 325.0055.
Table 1
Conversion of amines into aminothiazolines.
Amines Isothiocyanates
(% yield)
Hydroxythioureas
(% yield)
Aminothiazolines
(% yield)
Overall
yield
(%)
2.4. General procedure for the preparation of 2-aminothiazolines
2a
2b
2e
2d
3a (27)
3b (81)
3c (77)
3d (72)
4a (71)
4b (91)
4c (92)
4d (86)
1a (46)
1b (57)
1c (42)
1d (53)
9
42
17
33
A stirred mixture of DMF (0.741 mmol, 86
lL) and POCl3 (0.741
mmol, 100 L) was diluted with dry THF (5.0 mL), at room temper-
l
ature, under N2, and then a solution of thiourea (0.494 mmol) in
5.0 mL of dry THF was added. After stirring for 18 h, the reaction
mixture was partitioned with brine (30 mL) and ethyl acetate
(30 mL). The aqueous phase was extracted twice with 30 mL of ethyl
acetate and the organic phases were combined, dried over Na2SO4,
filtered off and concentrated at reduced pressure. The crude residue
was purified by flash chromatography using 10% ethyl acetate–hex-
ane as eluent in all cases.
Table 2
15N NMR chemical shifts (ppm) of aminothiazolines 1 in CDCl3.
15
15
Compound
N
N
HA
HB
exo
end
1a
1b
1c
1d
98
91
106
106
206
182
205
202
3.46
3.19
3.95
3.92
3.97
3.34
4.94
4.78
2.4.1. N-(Pentan-3-yl)-4,5-dihydro-1,3-thiazol-2-amine (1a)
46% yield. White solid. Melting point: 113–114 °C. IR (KBr, mmax):
3180, 2961, 2858, 1606, 1553, 1464, 1385, 1321, 1250, 1136, 1032,
613, 488 cmÀ1. 1H NMR (250 MHz, CDCl3): d 3.97 (t, J = 7.3 Hz, 2H),
3.46 (qt, J = 6.3 Hz, 1H), 3.28 (t, J = 7.3 Hz, 2H), 1.67–1.32 (m, 4H),
0.91 (t, J = 7.4 Hz, 6H). 13C NMR (62.5 MHz, CDCl3): d 161.54(C),
60.07(CH2), 58.15(CH), 34.88(CH2), 27.45(CH2), 10.05(CH3). HRMS
(EI TOF): Calculated for C8H16N2S: 172.1034, Found M+: 172.1045.
2.4.4. N-[1-(4-Bromophenyl)ethyl]-4,5-dihydro-1,3-thiazol-2-amine
(1d)
53% yield; slightly yellow solid. Melting point: 133–134 °C. IR
(KBr,
1643, 1485, 1408, 1344, 1211, 1155, 1070, 1030, 930, 822, 779,
690, 608, 557, 480 cmÀ1 1H NMR (250 MHz, CDCl3): d 7.45 (d,
mmax): 3439, 3250, 3130, 3047, 2974, 2897, 2849, 1906,
;
J = 8.5 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 4.78 (q, J = 6.8 Hz, 1H), 3.92
(t, J = 7.5 Hz, 2H), 3.28 (t, J = 7.4 Hz, 2H), 1.47 (d, J = 6.8 Hz, 3H);
13C NMR (62.5 MHz, CDCl3): d 160.54 (C), 143.28(C), 131.59(CH),
127.73(CH), 120.82(C), 59.48(CH2), 54.32(CH), 34.99(CH2),
23.30(CH3); HRMS (ESI+ TOF): Calculated for C11H13BrN2SH+:
285.0061, Found (M + H)+: 285.0102.
2.4.2. N-(2-Ethylhexyl)-4,5-dihydro-1,3-thiazol-2-amine (1b)
57% yield. Viscous, slight yellow oil. IR (film,
2958, 2928, 2858, 1711, 1622, 1543, 1460, 1377, 1315, 1244,
1149, 1026 cmÀ1 1H NMR (500 MHz, CDCl3): d 3.96 (t, J = 7.4 Hz,
mmax): 3207,
.
2H), 3.25 (t, J = 7.4 Hz, 2H), 1.47–1.25 (m, 9H), 0.86 (d, J = 6.0 Hz,
2H), 0.86 (t, J = 7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3):d
162.07(C), 60.26(CH2), 48.21(CH2), 39.54(CH), 35.19 (CH2),
30.90(CH2), 28.80(CH2), 24.13(CH2), 23.00(CH2), 14.03(CH3),
10.80(CH3); HRMS (EI TOF): Calculated for C11H22N2S: 214.1504,
Found M+: 214.1506.
2.5. NMR measurements
The 1H and 13C spectra were recorded on a Bruker DPX at 250
and 62.5 MHz, respectively and in a Varian Inova at 500 MHz for
1H and 125 MHz for 13C. The HMBC 1H-15N spectra were acquired
at temperature of 25 °C for several substituted 2-aminothiazolines
using CDCl3 as solvent in a Bruker Avance III 400 equipment using
5 mm TBI probe.15N NMR chemical shifts were determined relative
to ammonia.
2.4.3. N-(1-Phenylethyl)-4,5-dihydro-1,3-thiazol-2-amine (1c)
42% yield. Viscous, slight yellow oil. IR (film,
2966, 2930, 2889, 1647, 1605, 1547, 1450, 1338, 1028, 762,
700 cmÀ1 1H NMR (250 MHz, CDCl3): d 7.39–7.20 (m, 5H), 4.84
mmax): 3450, 3169,
.
(q, J = 6.8 Hz, 1H), 3.95 (t, J = 7.3 Hz, 2H), 3.27 (t, J = 7.3 Hz, 2H),
1.51 (d, J = 7.0 Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d 160.76 (C),
144.11 (C), 128.55 (CH),127,14 (CH),125.99 (CH), 59.85(CH2),
54.71 (CH), 35.05(CH2), 23.04(CH3). HRMS (EI TOF): Calculated
for C11H14N2S: 206.0878, Found M+: 206.0901.
2.6. Computational methods
The geometries of both tautomers were fully optimized at the
M06-2X [14] functional and cc-Pvdz [15] basis set were applied.

R.B. Ferreira et al. / Journal of Molecular Structure 1037 (2013) 186–190
189
Fig. 3. The 1H-15N HMBC contour plot for the N-(1-phenylethyl)-4,5-dihydro-1,3-thiazol-2-amine (1c).
Fig. 4. Optimized structures of N-substituted-2-aminothiazoline tautomers and transition state.
All stable tautomers were characterized as minima due to their po-
sitive values for vibrational frequencies. The zero-point energy was
used to correct the electronic energies, all calculation were per-
formedusing Gaussian 09 program. [16].

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R.B. Ferreira et al. / Journal of Molecular Structure 1037 (2013) 186–190
between five membered ring CH2 groups with sp2 nitrogen be-
3. Results and discussion
tween 200 and 250 ppm was observed, while exocyclic aliphatic
protons correlates with sp3 nitrogen around 90 ppm. Based on
NMR spectra analyses we concluded that the amino tautomer is
unique or the only detectable. Despite the small energy difference
between imino and amino tautomers, the energy related to the
transition state suggests that the interconversion process is not ob-
served at 25 °C.
3.1. Synthesis
Aminothiazolines were synthesized by S-cyclization of thioure-
ias as depicted in Scheme 1. The synthesis started with the reaction
of amines 2 with carbon disulfide in dichloromethane at À10 °C,
followed by treatment with dicyclohexylcarbodiimide (DCC), to
give 3. Isothiocyanates 3 were prompted converted into the corre-
sponding hydroxythioureas 4 by treatment with 2-ethanolaminein
THF, according to the procedure described by Kim et al. [17],
hydroxythioureas were activated to selectively S-cyclize, leading
to the corresponding aminothiazolines 1.
Acknowledgments
W.P. Almeida and C.F. Tormena are grateful to CNPq for
research fellowships. Renan B. Ferreira also thanks Fapesp (2010/
030242-8). Authors are grateful to Fapesp for financial support
(2008/06397-1).
All compounds were characterized by IR, 1H and 13C NMR and
HRMS and yields after purification are shown in Table 1.
3.2. NMR studies
Appendix A. Supplementary material
It has been observed from 1H NMR spectra of substituted
2-aminothiazolines in CDCl3, a set of narrow peaks suggesting a fast
exchange process between two possible tautomers or the presence
of only one tautomeric form in solution. The imino tautomer can ex-
ist as E/Z stereoisomers as previously mentioned, but 1H and 13C
NMR spectra showed a unique signal corresponding to the substitu-
ent of the N-exocyclic. These observations suggest the presence of a
unique isomer or a fast isomerization via amino tautomer as pre-
sented in Fig. 1. However, no information about which isomer exists
in solution could be obtained from 1H and 13C NMR spectra.
To deep insight about the contribution of each tautomer for the
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.
12.031.
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3.3. Theoretical studies
In order to corroborate with these observations, a theoretical
calculation at the M06-2X/cc-pVDZ level using Gaussian 09 pack-
age of program was performed and it has been found amino tauto-
mer is around 1 kcal molÀ1 more stable than (Z) imino form, while
(E) imino form is 2.3 kcal/mol less stable than the amino tautomer.
(Fig. 4) Tautomerism may occur via intra or intermolecular proto-
tropy, depending on the media and properties of the compounds.
To calculate the energy of the state transition we chose the intra-
molecular model, according to other examples presented in litera-
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ture [5,13,20]. The energy related to the state transition (D
E#) is
48.2 kcal/mol, suggesting that interconversion process is not
occurring at 25 °C.
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4. Conclusion
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We synthesized a series of N-substituted-2-aminothiazolines,
that were studied by HMBC 1H-15N spectroscopy. A correlation