Traceless solid-phase synthesis of 2-amino-5-alkylidene-thiazol-4-ones

Article abstract of DOI:10.1016/j.tetlet.2005.02.059

2-Amino-5-alkylidene-thiazol-4-ones bearing two diversity points are prepared by a solid-phase strategy exploiting rhodanine as the starting material. Rhodanine is first loaded on bromo-Wang resin, subjected to Knovenagel condensation with aldehydes, and cleaved off the resin in a traceless manner by means of an amine.

Full text of DOI:10.1016/j.tetlet.2005.02.059

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2387–2391
Traceless solid-phase synthesis of
2-amino-5-alkylidene-thiazol-4-ones
Maurizio Pulici* and Francesca Quartieri
Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, I-20014Nerviano (MI), Italy
Received 5 January 2005; revised 10 February 2005; accepted 11 February 2005
Abstract—2-Amino-5-alkylidene-thiazol-4-ones bearing two diversity points are prepared by a solid-phase strategy exploiting rho-
danine as the starting material. Rhodanine is first loaded on bromo-Wang resin, subjected to Knovenagel condensation with alde-
hydes, and cleaved off the resin in a traceless manner by means of an amine.
Ó 2005 Elsevier Ltd. All rights reserved.
2-Amino-5-alkylidene-thiazol-4-one 1 (Fig. 1) represents
one of the privileged scaffolds in drug discovery: this
heterocyclic core is in fact found in more than 15,000
molecules synthesized so far, the biological activities of
which have been reported in approximately 150 publica-
tions, including 80 patents.1 A survey of the most recent
papers dealing with the pharmacological properties of
such compounds reveals that they may be useful for
the treatment of cystic fibrosis,2 as b-3 agonists (poten-
tially applicable to the treatment of metabolic diseases3),
as antibacterial,4 antiviral,5 cardiotonic,6 and anti-
inflammatory7 agents. Among the latter, it is worth
mentioning the case of Darbufelone mesilateÒ, reported
to have reached Phase II clinical trials as a dual inhibitor
of cellular prostaglandin and leukotriene production7d.
these compounds. The 2-amino-5-alkylidene-thiazol-4-
one nucleus can be assembled directly using acyclic
building blocks (Scheme 1) or can be attained by func-
tionalization of the thiazolone core, in turn prepared
using either acyclic or cyclic precursors (Scheme 2).
In the first case the synthetic process often involves a
substituted thiourea, which can be cyclocondensed with
an a,b-di halo carboxylic acid derivative (Route A)8 or
with an alkyl acetylenedicarboxylate (in this case R3
must be COOR, Route B)9 The targeted compounds
can also be achieved by a bromine-mediated oxidation
of propenoylthioureas (Route C)10 and by means of a
three-component reaction where the thiourea is reacted
Given this background, it is not surprising that a num-
ber of routes have been developed in order to target
O
R3
NH2
R
Route A
R1
O
X
+
N
R2
S
X
O
NH2
O
R
O
O
O
R
N
R3
R1
Route B
Route C
+
S
S
N
R2
N
O
R1
N
R3
R2
N
S
1
H
R2
R1
R3
N
N
R1
R2
Figure 1. 2-Amino-5-alkylidene-thiazol-4-one.
O
S
O
Route D
NH2
H
R
+
R1
+
O
Keywords: Solid-phase synthesis; Traceless linker; Thiazolone;
Knovenagel reaction.
N
S
O
R3
X
R2
*
Corresponding author. Tel.: +39 0331 58 1216; fax: +39 0331 58
1757; e-mail: maurizio.pulici@nervianoms.com
Scheme 1. 2-Amino-5-alkylidene-thiazol-4-ones from acyclic precursors.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.059

2388
M. Pulici, F. Quartieri / Tetrahedron Letters 46 (2005) 2387–2391
O
O
O
basic conditions proceeded with 83% yield with respect
O
NH2
S
Route E
to the declared initial loading,15 and a TFA-mediated
cleavage (20% in DCM) of an analytical sample led to
the removal of rhodanine only. However, an exhaustive
piperidine-mediated cleavage led to the recovery of only
80% of the expected 2-piperidin-1-yl-thiazol-4-one,16
which suggested the presence of some isomeric benzyl
rhodanine 3b. MAS-1H NMR (CD2Cl2) spectrumof
the resin showed indeed two diagnostic signals at 4.48
and 5.05 ppm(79–21 ratio) corresponding to benzylic
methylenes. These were also in agreement with those
observed for 2a and 3a attained in the 8–2 ratio17 by
performing a model reaction in solution between
rhodanine and benzyl bromide.
R
+
R1
N
O
N
R2
O
S
S
X
R
S
O
N
Route H
Route I
R
Route G
R1
S
O
NH
R2
R1
N
+
Route F
S
HN
R2
N
S
O
HN
S
R3
N
S
R3
S
R1
N
R2
Scheme 2. 2-Amino-5-alkylidene-thiazol-4-ones by functionalization
of thiazolones.
The subsequent steps of the synthetic routes comprised a
Knovenagel condensation followed by an amine-medi-
ated cleavage off the resin (Scheme 4); the latter clearly
affects only compounds 5b, while 3b and its derivatives
remain eventually anchored to the solid support.
with an alkyl a-haloacetate and an aldehyde (Route
D).7a
The Knovenagel condensation required fine-tuning of
the experimental conditions to avoid premature cleavage
fromthe resin, a problemalways met when using nucleo-
philic bases. Permutation of base, solvent, and tempera-
ture led to the following conclusions: alkoxides, even
t-butoxide, does not work well regardless of the solvent
used. The best bases are the organic ones (TEA; DIEA;
DBU) in DCM at roomtemperature, or also phospha-
zene, in aprotic dipolar solvents. Time affects the out-
come of the reaction, as short reaction times are
associated with incomplete conversions, and, on the
other hand, long reaction times give rise to compounds
7 as side products (Fig. 2).18 The latter may arise from
the nucleophilic displacement of an alkylidene thiazo-
lone group fromthe resin by means of the anion gener-
ated on a second thiazolone moiety. Interestingly the
amount of this type of side product depended also on
The latter synthesis can be performed also in a step-wise
manner. Thus, the reaction between a thiourea and alkyl
a-haloacetate yields an aminothiazolone (Route E)11
that subsequently undergoes
a Knovenagel reac-
tion.3,4d,7b,d–f The aminothiazolone is also accessible
through a reaction between alkyl thiocyanoacetate and
an amine (Route F)12 however, most commonly, it is
synthesized starting fromrhodanine, which is reacted di-
rectly with amines (Route G)3,13 or after activation via
alkyl thioether (Route H).3a,7d–f On the other hand, this
sequence can be reversed by first condensing rhodanine
with an aldehyde (Route I)3,14 and then reacting it with
an amine3,13
Despite such a great deal of synthetic routes and of
applications in the field of medicinal chemistry, we are
not aware of solid-phase protocols enabling the high-
throughput synthesis of these compounds. Here we wish
to disclose the development and implementation of a
methodology allowing for the traceless synthesis of par-
allel arrays of two-diversity point aminothiazolones.
O
O
O
N
N
N
Ar
RR'NH
R
S
S
S
N
R'
Ar
ArCHO
Base, Solvent
S
S
Thus rhodanine was reacted with bromo-Wang resin (4-
(bromomethyl)phenoxymethyl polystyrene) to form the
thioether 2b (Scheme 3). The reaction in DMF under
DME-TFE (9/1),
70 oC, 6h
2b
5b
6
X
X
O
X =
O
O
O
N
N
S
+
X
Br
+
S
HN
S
Scheme 4. Solid-phase synthesis of 2-amino-5-alkylidene-thiazol-4-
ones.
S
S
S
X
2
3
X
O
H
O
N
O
N
S
a) X = H b) X =
Ar
S
N
R
7
R'
Scheme 3. Loading of rhodanine on bromo-Wang resin: rhodanine
3.5 equiv, DIEA 5 equiv; DMF, rt, 18 h.
Figure 2. Structure of possible side products.

M. Pulici, F. Quartieri / Tetrahedron Letters 46 (2005) 2387–2391
2389
the temperature and on the strength of the bases: in both
cases the higher the greater.
wise stench thiols remain anchored to the solid support,
providing an additional advantage to the present meth-
odology. We typically used excess of reactant (3 equiv)
in DME as a solvent with 10% trifluoroethanol
(TFE) as a co-solvent at 70 °C.20 Expected products
could be isolated using chromatographic methods:
either (mass-triggered) preparative HPLC or filtration
through a silica gel plug worked well. Alternatively, in
several instances products could be obtained with
reasonable purities simply by decantation of the solid
material (taken up with ethyl ether or acetone)
obtained after evaporation of the reaction crude.
Tables 1 and 2 show representative examples of this
methodology.
Eventually the optimized conditions for the Knovenagel
condensation comprised the use of DCM as the solvent
and DIEA as the base; the reaction was carried out
using an excess of aldehyde (normally 5–8 equiv) for
about 40 h. These conditions worked well for all
aldehydes but were not effective for ketones. Only
the thermodynamically more stable Z-isomers were
obtained,3a,7f,19 while the supposed E-isomers were
occasionally observed in the HPLC trace (of final prod-
uct 6) but never isolated.
Liberation of products 6 fromresin was achieved by
reaction of 5 with an amine. With this strategy the other-
Table 1. Compounds 6: examples with various aldehydesa,b
R3 (fromR3CHO)
O
a
b
c
d
e
f
N
Br
O
*
*
*
*
*
Br
*
R1
S
N
R2
R3
F
O
OH
O
Purity
78
OH
R1R2N
Yield
64c
Purity
100
Yield
81c
Purity
94
Yield
Purity
77
Yield
70c
Purity
82
Yield
20c
Purity
91
Yield
A
B
100c
26c
N
N
100
48c
34c
95
89c
40c
92
64c
95
41c
98
85c
80
34d
N
C
89
92
100
5c
100
43d
O
a Yield is determined on weight of isolated product and calculated on the effective loading of 2b.
b Purity is evaluated by HPLC trace using UV detection at 220 nm.
c Purified by (mass triggered) preparative HPLC.
d Purified by filtration through a silica gel plug (DCM–MeOH 99:1).
Table 2. Compounds 6g: examples with various aminesa,b
R1R2N
D
E
F
G
H
I
NH
N
N
N
N
N
N
HO
OH
O
Purity
89
Yield
24c
Purity
100
Yield
24c
Purity
97
Yield
20c
Purity
96
Yield
20c
Purity
86
Yield
16c
Purity
100
Yield
22e
N
R1
J
K
L
M
N
O
S
N
R2
NH
NH
NH
N
NH
NH
F
O
Purity
76
Yield
12d
Purity
85
Yield
34e
Purity
93
Yield
27c
Purity
85
Yield
37e
Purity
100
Yield
10d
Purity
90
Yield
34e
a Yield is determined on weight of isolated product and calculated on the effective loading of 2b.
b Purity is evaluated by HPLC trace using UV detection at 220 nm.
c Purified by (mass triggered) preparative HPLC.
d Purified by filtration through a silica gel plug (DCM–MeOH 99:1).
e Purified by decantation of the crude.

2390
M. Pulici, F. Quartieri / Tetrahedron Letters 46 (2005) 2387–2391
11. (a) Seebacher, W.; Belaj, F.; Saf, R.; Brun, R.; Weis, R.
Monat. Chem. 2003, 134, 1623–1628; (b) Iwataki, I. Bull.
Chem. Soc. Jpn. 1972, 45, 3218–3220.
12. (a) Roessler, A.; Boldt, P. Synthesis 1998, 980–982; (b)
Zimmermann, T.; Fischer, G. W.; Olk, B. J. Prakt. Chem.
1990, 332, 540–546.
In conclusion we have developed a mild and practical
protocol allowing for the high-throughput solid-phase
synthesis of parallel arrays of 2-amino-5-alkylidene-
thiazol-4-ones bearing two diversity points.
13. Taylor, E. C., Jr.; Wolinsky, J.; Lee, H.-H. J. Am. Chem.
Soc. 1954, 76, 1870–1872.
Acknowledgements
14. (a) Vachal, P.; Pihera, P.; Svoboda, J. Collect. Czech.
Chem. Commun. 1997, 62, 1468–1480; (b) Tashima, T.;
Kagechika, H.; Tsuji, M.; Fukasawa, H.; Kawachi, E.;
Hashimoto, Y.; Shudo, K. Chem. Pharm. Bull. 1997, 45,
1805–1813; (c) Simpson, J.; Rathbone, D. L.; Billington,
D. C. Tetrahedron Lett. 1999, 40, 7031–7033; (d) Murata,
M.; Fujitani, B.; Mizuta, H. Eur. J. Med. Chem. 1999, 34,
1061–1070; (e) Gant, E. B.; Guiadeen, D.; Baum, E. Z.;
Foleno, B. D.; Jin, H.; Montenegro, D. A.; Nelson, E. A.;
Bush, K.; Hlasta, D. J. Bioorg. Med. Chem. Lett. 2000, 10,
2179–2182.
We thank Franco Ciprandi for the purification of prod-
`
ucts by preparative HPLC and Marco Tato for record-
ing MAS NMR spectra.
References and notes
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cas.org/SCIFINDER/) search.
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11, 981–984; (b) Hu, B.; Malamas, M.; Ellingboe, J.
Heterocycles 2002, 57, 857–870.
15. Reaction conditions were not optimized, however, in
qualitative terms, DMF was more efficient than DCM,
and DIEA gave a cleaner reaction than K2CO3 and
NaOH. Typical loading procedure: To a suspension of
bromo-Wang resin (1 g, declared loading 1.4 mmol/g) in
DMF (15 mL), rhodanine (652 mg, 3.5 equiv) is added
followed by DIEA (500 lL, 362 mg, 2 equiv). The mixture
is gently shaken for 40 h. The resin is filtered, washed with
DMF, MeOH, DCM, and dried in vacuo. Obtained
4. (a) Soltero-Higgin, M.; Carlson, E. E.; Phillips, J. H.;
Kiessling, L. L. J. Am. Chem. Soc. 2004, 126, 10532–
10533; (b) Hu, Y.; Helm, J. S.; Chen, L.; Ginsberg, C.;
Gross, B.; Kraybill, B.; Tiyanont, K.; Fang, X.; Wu, T.;
Walker, S. Chem. Biol. 2004, 11, 703–711; (c) Kocabal-
O
O
¨
¨
kanlia, A.; Ates, O.; Otukb, G. Arch. Pharm. 2001, 334,
¨
¨
35–39; (d) Ates, O.; Altintas, H.; Otukb, G. Arzneim.-
N
¨
N
¨
S
S
S
Forsch. 2000, 50, 569–575.
5. Abdel-Ghani, E. J. Chem. Res. Synop. 1999, 3, 174–
175.
6. (a) Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.;
Bossa, R.; Chiericozzi, M.; Galatulas, I.; Salvatore, G.
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Rambaldi, M.; Locatelli, A.; Leoni, A.; Bossa, R.;
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42, 1151–1160; (e) Janusz, J. M.; Young, P. A.; Ridgeway,
J. M.; Scherz, M. W.; Enzweiler, K.; Wu, L. I.; Gan, L.;
Chen, J.; Kellstein, D. E.; Green, S. A.; Tulich, J. L.;
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J. Med. Chem. 1994, 37, 322–328.
N
2b
4
X
1.058 g (calculated loading 1.092 mmol/g, theoretical
loading 1.303 mmol/g, 83%).
16. The resin obtained as reported in Ref. 15 (150 mg,
0.1638 mmol) was treated with excess piperidine (150 lL,
9.3 equiv) in DME–TFE (9:1) at 70 °C for 3 h. The
product was then isolated by silica gel chromatography
(DCM–MeOH 98:2): 24.7 mg (0.134 mmol, 82 %). No
further product was recovered on reiteration.
17. Compounds 2a and 3a have been separated by silica gel
chromatography (hexane–ethyl acetate 7:3). Compound
1
2a: H NMR (300 MHz, CDCl3) d ppm3.99 (s, 2H) 4.58
(s, 2H) 7.25–7.32 (m, 5H); 13C NMR (75 MHz CDCl3) d
ppm38.6, 40.0, 128.6, 129.4, 129.7, 135.3, 187.7, 201.8.
1
Compound 3a: H NMR (300 MHz, CDCl3) d ppm3.98
(s, 2H) 5.18 (s, 2H) 7.25–7.33 (m, 5H); 13C NMR (75 MHz
CDCl3) d ppm35.8, 48.0, 128.4, 128.9, 129.5, 135.2, 174.0,
201.3. In addition only 2a (and not 3a) reacts completely
with pyrrolidine (DME–TFE 9:1, 70 °C, 1 h) according to
O
JH-C3 = 6 Hz
N
8. Khare, R. K.; Srivastava, M. K.; Singh, H. Indian J.
Chem., Sect. B 1995, 34, 828–831.
H
N
S
O
9. (a) Hendrickson, J. B.; Rees, R.; Templeton, J. F. J. Am.
Chem. Soc. 1964, 86, 107–111; (b) Hurst, D. T.; Atcha, S.;
Marshall, K. L. Aust. J. Chem. 1991, 44, 129–134; (c)
Sarodnick, G.; Heydenreich, M.; Linker, T.; Kleinpeter,
E. Tetrahedron 2003, 59, 6311–6321.
Br
10. Dzurilla, M.; Kristian, P.; Imrich, J.; Stec, J. Collect.
Czech. Chem. Commun. 1983, 48, 3134–3139.
the scheme of Ref. 16.
18. (a) Compounds with this general structure are known:
Kandeel, K. A.; Youssef, A. M.; El-Bestawy, H. M.;

M. Pulici, F. Quartieri / Tetrahedron Letters 46 (2005) 2387–2391
2391
Omar, M. T. J. Chem. Res. Synop. 2003, 682; (b) Kandeel,
K. A.; Youssef, A. M.; El-Bestawy, H. M.; Omar, M. T.
Monat. Chem. 2002, 133, 1211–1219.
aldehyde (100 mg or lL) was added. Next DIEA
(100 lL) was added and the mixture gently shaken for
40 h. The resin was washed successively with DMF,
MeOH, and DCM (three times each). The resin was then
slurried in DME–TFE (9:1) and treated with the amine
(100 mg or lL) and heated at 70 °C for 6 h. The cleaved
material was then isolated and the resin rinsed once with
DCM–MeOH (9:1). Solvent was removed in vacuo
yielding the reaction crude that was purified as mentioned
in the text.
19. Calculation of the H–C coupling constant is in good
agreement with this stereochemistry:
20. The whole synthetic sequence has been carried out using
either vials, Argonaut Quest 210, or Bohdan Miniblocks.
Typical procedure for the 2-amino-5-alkylidene-thiazol-4-
ones synthesis: 150 mg of the resin obtained as reported
in Ref. 15 was suspended in DCM (3 mL) and the