Taurine isothiocyanate: a versatile intermediate for the preparation of ureas, thioureas, and guanidines. Taurine-derived cyclodextrins

Article abstract of DOI:10.1016/j.tetlet.2008.04.053

A versatile and expeditious synthesis of taurine-derived thioureas, ureas, and guanidines using taurine isothiocyanate as the key intermediate is reported. Thioureas were obtained by a one-pot two-step procedure starting from taurine by the isothiocyanation reaction with thiophosgene in aqueous THF, followed by coupling with aliphatic and aromatic amines. Desulfurization of thiourea derivatives with yellow mercury(II) oxide gave access to either taurine-containing ureas or guanidines in a one-pot three-step fashion. This methodology was successfully applied to the preparation of a cyclodextrin-derived thiourea and guanidine with a taurine residue in their structures.

Full text of DOI:10.1016/j.tetlet.2008.04.053

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3912–3915
Taurine isothiocyanate: a versatile intermediate for the preparation
of ureas, thioureas, and guanidines. Taurine-derived cyclodextrins
´
*
´
´
´
´
´
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´
Jose M. Marquez, Oscar Lopez, Ines Maya, Jose Fuentes, Jose G. Fernandez-Bolanos
˜
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain
Received 15 March 2008; revised 4 April 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
A versatile and expeditious synthesis of taurine-derived thioureas, ureas, and guanidines using taurine isothiocyanate as the key inter-
mediate is reported. Thioureas were obtained by a one-pot two-step procedure starting from taurine by the isothiocyanation reaction
with thiophosgene in aqueous THF, followed by coupling with aliphatic and aromatic amines. Desulfurization of thiourea derivatives
with yellow mercury(II) oxide gave access to either taurine-containing ureas or guanidines in a one-pot three-step fashion. This meth-
odology was successfully applied to the preparation of a cyclodextrin-derived thiourea and guanidine with a taurine residue in their
structures.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Taurine; Isothiocyanate; Thioureas; Ureas; Guanidines; Cyclodextrin
Taurine, or 2-aminoethanesulfonic acid, is a natural b-
sulfoaminoacid that is not incorporated into proteins, but
is particularly abundant as a free amino acid in all mamma-
lian electrically excitable tissues such as heart, brain, retina,
and skeletal muscles.1,2 Although it was isolated from the
animal tissues more than two hundred years ago, its biolog-
ical activities and beneficial effects have been recently redis-
covered.1,3 Taurine is involved in brain and retina
development, neurotransmission, osmoregulation, and
immunomodulation;1,2,4,5 numerous studies show that tau-
rine also exerts an antioxidant activity by scavenging reac-
tive oxygen species (ROS) such as endogenously generated
hypochlorous acid,6 nitric oxide or H2O2.7
Although the exact antioxidant mechanism still remains
unclear, the promising in vivo and in vitro studies suggest
that this sulfoaminoacid might be considered as a potential
drug to ameliorate the oxidative stress8,9 in diseases such as
diabetes.10,11 Furthermore, taurine has been described to
play a protective role in spinal cord injury12 and a detoxif-
icant role against some toxins such as heavy metals13 or
against vitamin A excess.14
The exceptional properties showed by taurine have
prompted the researchers to prepare a plethora of deriva-
tives3,15–17 among which acamprosate (calcium 3-acetyla-
minopropane-1-sulfonate) has a predominant place, as it
has recently been approved for the clinical treatment of
alcoholism.18,19 Other taurine derivatives such as taltrimide
and tauromustine are commercialized as anti-convulsant
and anti-cancer agents,3 respectively. Some different appli-
cations of taurine derivatives comprise nanosensors,20
organogelators21 or water-soluble dyes.22
In this context, we now describe a novel methodology
for the easy and practical preparation of taurine-derived
thioureas, ureas, and guanidines, families of compounds
with both synthetic and biological interests.23–26 Despite
the vast amount of taurine derivatives described so
far,3,27 reports on the synthesis of thioureas, ureas, and
guanidines are very scarce,28,29 and never involving taurine
isothiocyanate or isocyanate.
We have used the sodium salt of taurine isothiocyanate
as the key and versatile intermediate for the preparation
of these compounds. There is only one report for the
*
Corresponding author. Tel.: +34 95 4550996; fax +34 95 4624960.
´
E-mail address: bolanos@us.es (J. G. Fernandez-Bolanos).
˜
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.053

J. M. Ma´rquez et al. / Tetrahedron Letters 49 (2008) 3912–3915
3913
preparation of the potassium salt of taurine isothiocyanate,
used as an intermediate in the synthesis of thiazolines;30
however, the procedure described by the authors turns
out to be quite tedious and expensive, and consists of
sequential treatment of taurine with DBU, carbon disulfide,
N,N0-diisopropylcarbodiimide, and potassium thiocyanate
in an acetonitrile–pyridine mixture. Furthermore, no char-
obtained in a 45–86% yield for the two steps after column
chromatography.34
This one-pot procedure could be extended one more
step; thus, in situ treatment of crude taurine-containing
thioureas with yellow mercury(II) oxide as a desulfurizat-
ing agent (Scheme 1), in the presence of aromatic and ali-
phatic amines afforded guanidines 7–11 (24–61%, three
steps). It is noteworthy mentioning that zwitterionic guan-
idines were isolated as solid pure compounds without chro-
matography. Reaction must proceed through a transient
carbodiimide which spontaneously undergoes addition of
the amine.33 It is remarkable that despite using an aqueous
medium, the higher nucleophilicity of the amine toward
water affords the desired guanidines as the major com-
pounds. An example of a natural taurine-derived guanidine
is asterubine, 2-[(dimethylamino)iminomethyl]aminoe-
thanesulfonic acid, isolated from starfish, which displays
a plant growth-promoting effect.35
Following the same synthetic pathway, the addition of
yellow mercury(II) oxide to the crude thioureas 5 and 6,
without the presence of an extra amine, afforded ureas 12
and 13 in a 60% and 40% yield, respectively (Scheme 1).36
We decided to extend our methodology to the prepara-
tion of taurine-containing cyclodextrins; the latter are
macrocyclic oligosaccharides with a truncated-cone struc-
ture bearing a hydrophobic cavity capable of forming
acterization data for the title compound are included. Bult-
¨
mann and co-workers reported31 the use of the sodium salt
of taurine isothiocyanate 2 as a potential P2-purinoceptor
antagonist; this compound was synthesized from taurine
by the addition of thiophosgene, but neither experimental
nor spectroscopy data are included.
On the contrary, we have prepared crystalline isothiocy-
anate 232 in quite an effective and operative fashion by the
treatment of taurine with thiophosgene in aqueous THF in
the presence of NaHCO3 as a mild base (Scheme 1), using
similar conditions as those reported by us for the prepara-
tion of glycopyranosyl isothiocyanates.33 Purification by
column chromatography afforded compound 2 in an 87%
yield, and remarkably, the reaction could be performed
in a multi-gram scale.
Compound 2 could be in situ transformed into thioureas
3–6 by the addition of both aliphatic and aromatic amines
to the reaction medium, without the necessity of first isolat-
ing or purifying the isothiocyanate; these thioureas were
R1-NH2
H
N
CSCl2, NaHCO3
H
SCN
N
H3N
SO3Na
R1
SO3
SO3Na
4:1 H2O-THF
S
rt
Taurine (1)
2 (87%)
3
4
5
6
R1 = n-C4H9
R1 = n-C8H17
R1 = Bn
(75%)
(45%)
(60%)
(86%)
R1 = p-Tol
Yellow HgO
Yellow HgO
H2O
R2-NH2
H
N
H
N
H
N
H
N
R1
SO3
R1
SO3Na
HN
O
R2
12 R1 = Bn
13
R1 = p-Tol (40%)
(60%)
7
8
9
R1 = R2 = n-C4H9
R1 = R2 = n-C8H17
R1 = R2 = Bn
(43%)
(61%)
(51%)
(24%)
10 R1 = R2 = p-Tol
11 R1 = p-Tol, R2 = Bn (38%)
Scheme 1.

3914
J. M. Ma´rquez et al. / Tetrahedron Letters 49 (2008) 3912–3915
N
3
NH
2
H2, Pd/C
β
β
β-Cyclodextrin
MeOH
(OAc)
(OAc)
20
20
15
14
2
MeOH
H
N
H
N
H
N
H
N
SO
SO Na
3
3
HN
S
BnNH2
HgO
β
β
DMF
(OAc)
(OAc)
20
20
17 (68%)
16 (28%, from 14)
Scheme 2.
inclusion complexes.37 This property makes these com-
pounds to be very valuable carbohydrate derivatives in
supramolecular chemistry, with interesting practical appli-
cations such as drug carriers, catalysts, chiral separations
or food additives.38
the Ministerio de Educacion y Ciencia for the award of a
fellowship.
´
References and notes
Monoazido derivative 14 is easily available39 in three
steps starting from b-cyclodextrin; this compound can be
subjected to Pd-catalyzed hydrogenation to afford transient
amine 15 which can be used without further purification for
the coupling reaction with taurine isothiocyanate 2 to
afford thiourea 16 in a 28% yield from 14.40 (Scheme 2).
The low yield obtained for compound 16 can be explained
considering a partial acetyl migration to the amino group
of 15.
1. Schuller-Levis, G. B.; Park, E. FEMS Microbiol. Lett. 2003, 226, 195–
202.
2. Rijssenbeek, A. L.; Melis, G. C.; Oosterling, S. J.; Boelens, P. G.;
Houdijk, A. P. J.; Richir, M. C.; van Leeuwen, P. A. M. Curr. Nutr.
Food Sci. 2006, 2, 381–388.
3. Gupta, R.; Win, T.; Bittner, S. Curr. Med. Chem. 2005, 12, 2021–
2039.
4. Bouckenooghe, T.; Remacle, C.; Reusens, B. Curr. Opin. Clin. Nutr.
Metab. Care 2006, 9, 728–733.
5. Albrecht, J.; Schousboe, A. Neurochem. Res. 2005, 30, 1615–1621.
´
6. Ramos, D. R.; Garcıa, M. V.; Canle, L. M.; Santaballa, J. A.;
The transformation of 16 into guanidine 1741 was
achieved by the treatment of the former with yellow mer-
cury(II) oxide in DMF in the presence of benzylamine, in
a 68% yield.
Furtmueller, P. G.; Obinger, C. Arch. Biochem. Biophys. 2007, 466,
¨
221–233.
7. Saransaari, P.; Oja, S. S. Amino Acids 2004, 26, 91–98.
8. Kim, B.-H.; Oh, J. M.; Yun, K. U.; Kim, C. H.; Kim, S. K. J. Toxicol.
Public Health 2007, 23, 263–269.
In conclusion, we have developed an easy and practical
methodology for the preparation of taurine-derived thio-
ureas, ureas, and guanidines, using taurine isothiocyanate
as a versatile intermediate. The most highlighting aspect
of this procedure is that final compounds can be obtained
in a one-pot procedure starting from taurine, without inter-
mediate purifications. The same methodology was success-
fully applied to the preparation of a cyclodextrin-derived
thiourea and guanidine, compounds of interest in the
supramolecular chemistry field.
9. Yu, X.; Chen, K.; Wei, N.; Zhang, Q.; Liu, J.; Mi, M. Br. J. Nutr.
2007, 98, 711–719.
10. Kim, S.-J.; Gupta, R. C.; Lee, H. W. Curr. Diabetes Rev. 2007, 3, 165–
175.
11. Tas, S.; Sarandol, E.; Ayvalik, S. Z.; Serdar, Z.; Dirican, M. Arch.
Med. Res. 2007, 38, 276–283.
12. Gupta, R. C.; Seki, Y.; Yosida, J. Curr. Neurovasc. Res. 2006, 3, 225–
235.
13. Sinha, M.; Manna, P.; Sil, P. C. Toxicol. In Vitro 2007, 21, 1419–
1428.
14. Yeh, Y.-H.; Lee, Y.-T.; Hsieh, H.-S.; Hwang, D.-F. Food Chem. 2008,
106, 260–268.
15. Sapronov, N. S.; Bul’on, V. V.; Krylova, I. B.; Gavroskaya, L. K.;
Selina, E. N.; Evdokimova, N. R. Bull. Exp. Biol. Med. 2006, 141, 44–
47.
Acknowledgments
16. Sapronov, N. S.; Khnychenko, L. K.; Polevshchikov, A. V. Bull. Exp.
Biol. Med. 2001, 131, 142–144.
17. van Gelder, N. M.; Bowers, R. J. Neurochem. Res. 2001, 26, 575–578.
18. Johnson, B. A. Biochem. Pharmacol. 2008, 75, 34–56.
´
´
We thank the Direccion General de Investigacion of
´
Spain and the Junta de Andalucıa (Grant Nos. CTQ
2005-01830/BQU and FQM 134). J.M. Marquez thanks
´

J. M. Ma´rquez et al. / Tetrahedron Letters 49 (2008) 3912–3915
3915
19. Tambour, S.; Quertemont, E. Fundam. Clin. Pharmacol. 2007, 21, 9–
39. Schaschke, N.; Musiol, H.-J.; Assfalg-Machleidt, I.; Machleidt, W.;
Rudolph-Bo¨hner, S.; Moroder, L. FEBS Lett. 1996, 391, 297–
301.
28.
´
20. Capone, R.; Blake, S.; Ricon Restrepo, M.; Yang, J.; Mayer, M. J.
Am. Chem. Soc. 2007, 129, 9737–9745.
21. Suzuki, M.; Nakajima, Y.; Sato, T.; Shirai, H.; Hanabusa, K. Chem.
Commun. 2006, 377–379.
22. Mikhalenko, S. A.; Solov’eva, L. I.; Luk’‘yanets, E. A. Russ. J. Gen.
Chem. 2004, 74, 1775–1800.
23. Koketsu, M.; Ishihara, H. Curr. Org. Synth. 2006, 3, 439–455.
24. Gallou, I. Org. Prep. Proc. Int. 2007, 39, 355–383.
25. Blondeau, P.; Segura, M.; Perez-Fernandez, R.; De Mendoza, J.
Chem. Soc. Rev. 2007, 36, 198–210.
26. Suhs, T.; Koenig, B. Mini-Rev. Org. Chem. 2006, 3, 315–331.
27. Seeberger, S.; Griffin, R. J.; Hardcastle, I. R.; Golding, B. T. Org.
Biomol. Chem. 2007, 5, 132–138.
28. Garrigues, B.; Mulliez, M. Synthesis 1988, 810–813.
29. Langhals, E.; Balli, H. Helv. Chim. Acta 1985, 68, 1782–1797.
30. Armand, M.; Hammami, A.; Cavalie-Kosheiry, H. Preparation of
2,20-azinobis(thiazolines) as air- and water-stable radical precursors,
WO 2005026136, 2005.
40. Data for compound 16: A suspension of monoazido 14 (80 mg,
0.040 mmol) and 10% Pd/C (25 mg) in MeOH (1.5 mL) was hydro-
genated at atmospheric pressure and rt for 3 h. Then, it was filtrated
through a Celite pad and the filtrate was concentrated to dryness to
give crude 15, which was used for the next step without further
purification. The residue was dissolved in a 2:1 H2O–THF mixture
(3 mL), and to the corresponding solution was added isothiocyanate 2
(7.6 mg, 0.040 mmol). The reaction was kept stirring at rt for 12 h,
and then the solvent was eliminated under reduced pressure and the
residue was purified by column chromatography (CH2Cl2?10:1
25
CH2Cl2–MeOH) to afford 16 (24 mg, 28%, 2 steps). ½aꢁD +68 (c 1.3,
CH2Cl2); IR mmax 2926, 2360, 1748, 1653, 1541, 1373, 1236, 1043,
901 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 5.44–5.23 (m, 7H, H-3A–G),
5.15 (br s, 1H, NH), 5.10 (d, 1H, J1,2 = 3.7 Hz, H-1), 5.08 (d, 1H,
J1,2 = 3.8 Hz, H-1), 5.05 (d, 1H, J1,2 = 3.1 Hz, H-1), 5.10–4.99 (m,
4H, H-1), 4.85 (dd, 1H, J2,3 = 10.6 Hz, H-2), 4.83 (dd, 1H,
J2,3 = 9.0 Hz, H-2), 4.73 (dd, 1H, J2,3 = 9.9 Hz, H-2), 4.86–4.73 (m,
4H, H-2), 4.67–4.47 (m, 7H, H-6aB–G, NH), 4.42–4.27 (m, 6H, H-6bB–
G), 4.17–4.08 (m, 6H, H-5B–G), 3.93 (m, 1H, H-5A), 3.83 (m, 1H, H-
6aA), 3.75–3.64 (m, 10H, H-4A–G, H-6bA, CH2N), 3.11 (m, 2H,
CH2S), 2.15–2.00 (20s, 60H, 20Ac); 13C NMR (125.7 MHz, CDCl3) d
183.2 (C@S), 171.5–170.2, 169.8–169.2 (20 CO), 97.8–96.2 (C1A–G),
77.8–76.5 (C4A–G), 72.0–69.0 (C2A–G, C3A–G, C5A–G), 63.2–62.1
(C6B–G), 50.2 (CH2S), 45.8 (C6A), 40.4 (CH2N), 20.9–20.7 (20OAc);
HRLSIMS: [M+Na]+ calcd for C85H115N2Na2O57S2, 2185.5398;
found, 2185.5341.
31. Bultmann, R.; Pause, B.; Wittenburg, H.; Kurz, G.; Starke, K.
¨
Naunyn-Schmiedeberg’s Arch. Pharmacol. 1996, 354, 481–490.
32. Data for compound 2: To a solution of taurine (100 mg, 0.799 mmol)
in 4:1 water–THF (10 mL) NaHCO3 was added (228 mg, 2.72 mmol)
and the mixture was stirred for 15 min at rt. Then, thiophosgene (73
lL, 0.96 mmol) was added and the mixture was stirred for 40 min at
rt. The mixture was concentrated to dryness and the residue was
purified by column chromatography (CH2Cl2?5:1 CH2Cl2–MeOH),
to give 2 as a solid. mp: 230 °C (desc.); IR mmax 3605, 3518, 2207, 2120,
1609, 1352, 1209, 1053, 806 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6)
41. Data for compound 17: To a solution of thiourea 16 (46 mg, 0.021
mmol) in DMF (1 mL) were added benzylamine (2.3 lL, 0.021 mmol)
and mercury(II) oxide (18 mg, 0.083 mmol), and the corresponding
mixture was vigorously stirred in the darkness for 48 h. Then, it was
filtrated through a Celite pad and the filtrate was concentrated to
dryness; the residue was purified by column chromatography
d 3.85 (t, 2H, JH,H = 6.9 Hz, CH2NCS), 2.79 (t, 2H, CH2SO3Na);
13C NMR (75.5 MHz, DMSO-d6) d 127.3 (NCS), 50.1 (CH2SO3Na),
41.5 (CH2NCS); HRLSIMS: [M+Na]+ calcd for C3H4NNa2O3S2,
211.9428; found, 211.9427.
´
´
´
33. Lopez, O.; Maya, I.; Fuentes, J.; Fernandez-Bolanos, J. G. Tetrahe-
˜
25
dron 2004, 60, 61–72.
34. Selected data for 6: IR mmax 3449, 1534, 1485, 1262 cmꢀ1
(CH2Cl2?20:1 CH2Cl2–MeOH) to afford 17 (32 mg, 68%). ½aꢁD
;
1H NMR
+90 (c 1.2, CH2Cl2); IR mmax 2931, 1748, 1653, 1541, 1373, 1235, 1042,
(300 MHz, DMSO-d6) d 9.67 (s, 1H, PhNH), 7.86 (br t, 1H,
JNH,CH = 5.2 Hz, NHCH2CH2), 3.75 (q, 2H, JH,H = 6.2 Hz,
NHCH2CH2), 2.71 (t, 2H, JH,H = 6.2 Hz, CH2SO3); 13C NMR
(75.5 MHz, DMSO-d6) d 179.8 (C@S); HRLSIMS: [M+Na]+ calcd
for C10H13N2Na2O3S2 , 319.0163; found, 319.0159.
668 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.36–7.28 (m, 5H, Ar-H),
;
5.34–5.23 (m, 7H, J2,3 = 9.6 Hz, H-3A–G), 5.12 (d, 1H, J1,2 = 4.0 Hz,
H-1), 5.10 (d, 1H, J1,2 = 4.0 Hz, H-1), 5.08 (d, 1H, J1,2 = 4.0 Hz, H-
1), 5.06 (d, 2H, J1,2 = 3.8 Hz, H-1), 5.05 (d, 2H, J1,2 = 3.8 Hz, H-1),
4.92 (dd, 1H, H-2), 4.83 (dd, 1H, H-2), 4.79 (dd, 1H, H-2), 4.76 (dd,
1H, H-2), 4.74 (dd, 1H, H-2), 4.73 (dd, 2H, H-2), 4.70 (m, 1H, H-6a),
4.57–4.42 (m, 7H, H-6a, CH2Ph), 4.36–4.20 (m, 5H, J5,6b = 4.2 Hz,
J6a,6b = 13.0 Hz, H-6b), 4.14–3.98 (m, 8H, H-5, H-6b), 3.91 (m, 1H,
H-6aA), 3.77–3.60 (m, 10H, H-4, H-6bA, CH2N), 3.04 (m, 2H, CH2S),
2.14–1.99 (20s, 60H, 20Ac); 13C NMR (125 MHz, CDCl3) d 171.2,
171.0, 170.9, 170.8, 170.7, 170.6, 170.5, 170.4, 169.7, 169.6, 169.5,
169.4, (CO), 156.8 (C@N), 136.1, 129.2, 128.8, 127.6 (Ar), 97.3, 97.1,
97.0, 96.8, 96.7, 96.4 (C-1A–G), 77.4, 76.5, 76.3 (C-4A–G), 71.5–69.3
(21C, C-2A–G, C-3A–G, C-5A–G), 62.6–62.3 (6C, C-6B–G), 49.8 (CH2S),
45.8 (CH2Ph), 42.0 (C-6A), 39.8 (CH2N), 20.9 (20 OAc); HRLSIMS:
[M+Na]+ calcd for C92H123N3NaO57S, 2236.6437; found, 2236.6619.
35. Ishii, T.; Okino, T.; Mino, Y.; Tamiya, H.; Matsuda, F. Plant Growth
Regul. 2007, 52, 131–139.
36. Selected data for 12: IR mmax 3377, 1700, 1630 cmꢀ1; H NMR (300
1
MHz, DMSO-d6) d 6.73 (t, 1H, JH,H = 6.0 Hz, NHBn), 6.09 (t, 1H,
JH,H = 5.6 Hz, NHCH2), 3.30 (q, 2H, JH,H = 6.4 Hz, CH2N), 2.56 (t,
2H, CH2S) ppm; 13C NMR (75.5 MHz, DMSO-d6) d 158.0 (CO);
HRLSIMS: [M+Na]+ calcd for C10H13N2Na2O4S, 303.0391; found,
303.0388.
37. D’Souza, V. T.; Lipkowitz, K. B. Chem. Rev. 1998, 98, 1741–1742.
38. Cyclodextrins and their Complexes; Dodziuk, H., Ed.; Wiley-VCH:
Weinheim, 2006.