Solid-phase synthesis of 2-imidazolidinethiones via Mitsunobu reaction of N-(2-hydroxyethyl)thioureas

Article abstract of DOI:10.1016/j.tetlet.2006.11.055

This letter reports the solid-phase synthesis of 2-imidazolidinethiones via the N-cyclization of N-(2-hydroxyethyl)thioureas using the Mitsunobu reaction in good yield and purity. This process employed the reductive amination of an ArgoGel-MB-CHO resin to

Full text of DOI:10.1016/j.tetlet.2006.11.055

Tetrahedron Letters 48 (2007) 439–441
Solid-phase synthesis of 2-imidazolidinethiones via
Mitsunobu reaction of N-(2-hydroxyethyl)thioureas
Hyun Suk Jeon,a Je Hwa Yoo,a Jae Nyoung Kimb and Taek Hyeon Kima,*
aDepartment of Applied Chemistry and Center for Functional Nano Fine Chemicals, College of Engineering,
Chonnam National University, Gwangju 500-757, Republic of Korea
bDepartment of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju, 500-757, Republic of Korea
Received 7 September 2006; revised 7 November 2006; accepted 10 November 2006
Available online 1 December 2006
Abstract—This letter reports the solid-phase synthesis of 2-imidazolidinethiones via the N-cyclization of N-(2-hydroxyethyl)thio-
ureas using the Mitsunobu reaction in good yield and purity. This process employed the reductive amination of an ArgoGel-
MB-CHO resin to anchor the aminoalcohols, followed by a reaction with isothiocyanates to give the resin-attached N-(2-hydroxy-
ethyl)thioureas. Cleavage of the 2-imidazolidinethiones was performed with trifluoroacetic acid.
ꢀ 2006 Published by Elsevier Ltd.
Substituted thioureas has recently gained much interest
as a wide variety of known biological active compounds
such as non-nucleoside inhibition of HIV-1 and HIV-2
reverse transcriptases,1 potent orally active antagonism
of the bradykinin B (2) receptor,2 and antioxidant active
compounds with potent anti-HIV activity.3 The solid-
phase synthesis of small heterocycles is receiving consid-
erable attention because it can be applied to the rapid
generation of diverse libraries of drug-like compounds.4
Recently, Goff and Houghten reported the synthesis of
2-imidazolidinethiones on solid support by tandem
aminoacylation/Michael addition5 and by reduction of
dipeptides/thiocarbonylation with carbonyldiimid-
azole,6 respectively. In this letter, we report the solid-
phase synthesis of 2-imidazolidinethiones using the
intramolecular cyclization of resin bound N-(2-hydroxy-
ethyl)thioureas under Mitsunobu conditions, which can
be used for the high throughput synthesis of drug
libraries for potential drug discovery.
precursors to generate 2-imidazolidinethiones, which
were conveniently prepared from various commercially
available aminoalcohols and isothiocyanates for diver-
sity generation.
Scheme 1 shows the synthetic route of the 2-imidazol-
idinethione scaffold. The first step in solid-phase reac-
tions was the coupling of various amino alcohols onto
an ArgoGel-MB-CHO resin10 via reductive amination,
followed by the protection of the free alcohol 3 with
tert-butyldimethylsilyl chloride (TBSCl) according to
the previous procedures.11 Treatment of this intermedi-
ate with isothiocyanates afforded the thioureas resin 5,
and subsequent deprotection of the silylated hydroxy
group with tetrabutyl ammonium fluoride in THF
yielded resin 6. The key reaction step in this scheme,
the intramolecular cyclization of resin 6 under Mitsu-
nobu conditions, afforded mainly the required N-cyclized
products. The desired 2-imidazolidinethiones were
released at 95% TFA (in H2O) cleavage for 4 h in high
yield and purity and characterized by the spectroscopic
methods.12 The results are summarized in Table 1. Resin
6 derived from either aliphatic (entry 8a) or aryl isothio-
cyanates (entries 8b–k) furnished the required N-alkyl-
ation products, but aminoalcohol was limited to the
primary alcohol.13
The cyclization of N-(2-hydroxyethyl)thioureas can pro-
vide different products depending on the reaction condi-
tions and substrates such as S-cyclized,7 N-cyclized,8 or
O-cyclized9 products. The cyclization of resin-attached
N-(2-hydroxyethyl)thioureas has been extended to a
solid-phase synthesis protocol for 2-imidazolidine-
thiones. Resin-bound substrates 6 were designed as
In summary, a solid-phase synthetic method was devel-
oped for the parallel synthesis of a wide range of disub-
stituted 2-imidazolidinethiones using aminoalcohols and
isothiocyanates. The final products were obtained in
*
Corresponding author. Tel.: +82 62 530 1891; fax: +82 62 530
1889; e-mail: thkim@chonnam.ac.kr
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.055

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H. S. Jeon et al. / Tetrahedron Letters 48 (2007) 439–441
H
O
(i)
(ii)
N
N
OH
OH
R1
R1
OMe
OMe
OMe
2
3
1
R2
NH
S
H
(iv)
(iii)
(v)
N
N
OTBS
OTBS
R1
R1
OMe
OMe
4
5
R2
R2
N
NH
S
S
S
R2
(vii)
(vi)
N
N
HN
R1
N
OH
R1
R1
OMe
OMe
6
7
2-imidazolidinethione (8)
Scheme 1. Solid-phase synthesis approach to 2-imidazolidinethiones. Reagents and conditions: (i) trimethylorthoformate/MeOH = 1/4,
H2NCH(R1)CH2OH (2 equiv), 24 h; (ii) boran–pyridine complex (3 equiv), AcOH (3 equiv), 24 h; (iii) TBSCl (3 equiv), DMAP (0.1 equiv), TEA
(3 equiv); (iv) R2NCS (5 equiv), THF; (v) tetrabutyl ammonium fluoride (5 equiv), THF; (vi) DEAD (5 equiv), Ph3P (5 equiv), CH2Cl2, o/n; (vii) 95%
TFA/H2O, 4 h.
Table 1. Synthesis of 2-imidazolidinethione derivatives (8a–k) from
the solid-phase as outlined in Scheme 1
Stuart, D. I.; Stammers, D. K. J. Biol. Chem. 2000, 275,
5633.
2. Dziadulewicz, E. K.; Ritchie, T. J.; Hallett, A.; Snell, C.
R.; Ko, S. Y.; Wrigglesworth, R.; Hughes, G. A.;
Dunstan, A. R.; Bloomfield, G. C.; Drake, G. S.; Brown,
M. C.; Lee, W.; Burgess, G. M.; Davis, C.; Yaqoob, M.;
Perkins, M. N.; Campbell, E. A.; Davis, A. J.; Rang, H. P.
J. Med. Chem. 2000, 43, 769.
3. Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49.
4. Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
5. Goff, D. Tetrahedron Lett. 1998, 37, 5309.
6. (a) Nefzi, A.; Giulianotti, M. A.; Ong, N. A.; Houghten,
R. A. Org. Lett. 2000, 2, 3349; (b) Nefzi, A.; Ostresh, J.
M.; Giulianotti, M.; Houghten, R. A. J. Comb. Chem.
1999, 1, 195; (c) Nefzi, A.; Ostresh, J. M.; Meyer, J.-P.;
Houghten, R. A. Tetrahedron Lett. 1997, 38, 931.
7. For a review to see: D’hooghe, M.; De Kimpe, N.
Tetrahedron 2006, 62, 513.
Entry R1
R2
Yielda (%) Purityb (%)
8a
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
H
H
Me
i-Pr
C6H5
45
52
61c
50
66
40
59
71
72
74
81
99
82
90
94
93
95
96
92
4-MeC6H4
4-NO2C6H4
4-ClC6H4
3-CF3C6H4
4-CNC6H4
2-Cl, 4-NO2C6H3
8g
8h
8i
2-MeO, 4-NO2C6H3 75
4-NO2C6H4
8j
8k
54
63
(S)-i-Pr 4-NO2C6H4
a Overall yields from the ArgoGel-MB-CHO resin 1 having loading
capacity of 0.41 mmol/g.
b Purity was determined by HPLC after short-pass silica gel column
chromatography.
8. Kim, T. H.; Lee, N.; Kim, J. N. Bull. Korean Chem. Soc.
2001, 22, 761.
c Mp of free base, 111–112 ꢁC (Ref. 14, mp = 112–113 ꢁC).
9. For cyclodesulfurization of thioureas using the super
oxide radical anion, see: (a) Kim, Y. H.; Kim, Y. I. Synlett
1997, 1324; For that using DCC, see: (b) You, S.-W.; Lee,
K.-J. Bull. Korean Chem. Soc. 2001, 22, 1270; For that
using TsCl and NaOH, see: (c) Kim, T. H.; Lee, N.; Lee,
G.-J.; Kim, J. N. Tetrahedron 2001, 57, 7137.
seven steps in high purity with moderate to good yield.
This synthetic methodology is ideally suited for auto-
mated applications, because all the reactions were car-
ried out under ambient conditions.
10. ArgoGel-MB-CHO resin was purchased from Argonaut
Technologies Inc.
11. Kung, P.-P.; Swayze, E. Tetrahedron Lett. 1999, 40, 5651.
12. Typical synthetic approach of 2-imidazolidinethione is as
follows: For the synthesis of 4,5-dihydro-N-(2-chloro-4-
nitrophenyl)-2-thiazolamine 8h, the coupling of the
ethanolamine (2.0 equiv) to ArgoGel-MB-CHO resin
(0.1 mmol), which had been swollen with trimethylortho-
formate/MeOH = 4/1 (5 mL), via reductive amination
using borane–pyridine in acetic acid, followed by protec-
tion of the free alcohol with TBSCl, gave the silylated resin
4 according to the previous method.11 The dried resin 4 in
dry tetrahydrofuran (5 mL) was then reacted with 2-
chloro-4-nitrophenyl isothiocyanate (5 equiv) for 24 h.
The resulting resin was washed thoroughly with DMF
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2004-041-C00208). The spectroscopic
data was obtained from the Korea Basic Science Insti-
tute, Gwangju branch.
References and notes
1. Ren, J. S.; Diprose, J.; Warren, J.; Esnouf, R. M.; Bird, L.
E.; Ikemizu, S.; Slater, M.; Milton, J.; Balzarini, J.;

H. S. Jeon et al. / Tetrahedron Letters 48 (2007) 439–441
441
(3 · 5 mL), MeOH (3 · 5 mL), THF (3 · 5 mL), and
CH2Cl2 (3 · 5 mL) and dried in vacuum to give resin 5.
The deprotection of the silyl group in resin 5 with
tetrabutyl ammonium fluoride (5 equiv) was carried out
for 15 h, washed with the same solvent system and dried in
vacuum for 30 min. Resin 6 in CH2Cl2 (5 mL) was
incubated in diisopropyl azodicarboxylate (5 equiv) and
triphenyl phosphine (5 equiv) for 24 h and washed thor-
oughly to give resin 7. Finally, the dried resin was cleaved
in a 95% TFA/H2O solution (5 mL). The cleavage solution
was collected by filtration, dried by evaporation and
analyzed by HPLC to a purity of 93% after short-pass
silica gel column chromatography. 1-(2-Chloro-4-nitro-
phenyl)imidazolidine-2-thione (8h) was characterized as
1
TFA salts: Rf = 0.6 (ethyl acetate); H NMR (300 MHz,
CDCl3): d 8.4–7.99 (m, 3H), 4.12 (br s, 2H), 3.59 (br s,
2H); ESMS (M+) 257.
13. Further experimental work to examine scope and limita-
tion in aminoalcohols revealed that the secondary alcohol
was not working.
14. Hirashima, A.; Shinkai, K.; Kuwano, E.; Taniguchi, E.
Biosci. Biotechnol. Biochem. 1998, 62, 1179.