Solid-phase synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.08.009

A solid-phase synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione derivatives is reported. The desired products were obtained in good purities and yields.

Full text of DOI:10.1016/j.tetlet.2009.08.009

Tetrahedron Letters 50 (2009) 5857–5859
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Tetrahedron Letters
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Solid-phase synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-
3,5[2H,6H]-dione derivatives
*
Yangmei Li, Marc Giulianotti, Richard A. Houghten
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A solid-phase synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione derivatives is
reported. The desired products were obtained in good purities and yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 24 June 2009
Revised 4 August 2009
Accepted 6 August 2009
Available online 9 August 2009
The thiazolidinone core plays an important role as a widely
exploited pharmacophore in medicinal chemistry.1 Diverse biolog-
ical activities such as antimicrobial,2 protein tyrosine phosphatase
inhibitory,3 anticancer,4 follicle-stimulating hormone (FSH) ago-
nists,5 anticonvulsant,6 antipsychotic,7 and class I phosphoinosi-
tide 3-kinases inhibitory8 have been found to be associated with
thiazolidinone derivatives. Thiazolidinone has three isomers: with
a carbonyl group at positions 2, 4, and 5. 4-Thiazolidinone repre-
sents one of the most privileged thiazolidinone scaffolds in drug
discovery among the thiazolidinone derivatives. Thus far the
majority of the thiazolidinone derivatives reported as being biolog-
ically active are 4-thiazolidinones.9 The exploitation of diversity
around this privileged core is of high demand.
Combinatorial chemistry, together with solid-phase synthetic
approaches, provides an efficient methodology for the high-speed
synthesis of large compound collections. Although the synthesis of
4-thiazolidinone derivatives in solution-phase has been largely
explored, conversely there is a paucity of solid-phase synthetic
approaches for these structures.10 Herein, we report an efficient
solid-phase synthetic approach for the synthesis of 2-alkylidene-6-
alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione derivatives, bicyclic
products of 5-alkylidene-4-thiazolidinones fused with 50-alkyl-4-
imidazolidinones.
The resin-bound 4-thiazolidinone core was synthesized by
reacting resin-bound bromoacetamide with potassium thiocya-
nate. HF cleavage of the 4-thiazolidinone derivatives from the resin
resulted in the second ring closure and thus formed the final prod-
uct, 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione
derivatives (Scheme 1).11 Starting from MBHA resin 1, a Boc-amino
acid was coupled on the resin using a standard DIC/HOBt protocol
to generate the resin-bound peptide 2. After removal of the Boc
group, a bromoacetic acid was coupled in order to generate the re-
sin-bound bromoacetamide 3. The resin-bound bromoacetamide 3
was treated with potassium thiocyanate forming the resin-bound
4-thiazolidinone 4. A Knovenagel condensation using various aryl
aldehydes catalyzed with piperidine was applied to functionalize
position 5 of the resin-bound 4-thiazolidinone ring to generate
the resin-bound 5-alkylidene-4-thiazolidinone 5. Cleavage of the
product was performed by 100% anhydrous HF at 0 °C for 1.5 h.
Simultaneous ring closure was carried out during the cleavage step
to form the second ring of 4-imidazolidinone,thus obtaining the fi-
nal products of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-
3,5[2H,6H]-dione derivatives 6 (Table 1).
The Knovenagel condensation between 4-thiazolidinone and aryl
aldehydes in solution has been reported to be catalyzed either by
acid or by base.11 Sodium acetate/acetic acid buffer solution and
piperidine were generally used as the catalyst, respectively. In our
efforts to apply Knovenagel condensation on solid phase, both con-
ditions were found satisfactory. However the two different catalytic
conditions did have an effect on the generation of the final product.
Under catalysis with piperidine the desired biheterocyclo 2-alkyl-
idene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione was found
to be the major end product. However it is interesting to point out
that under catalysis by sodium acetate/acetic acid, the monohetero-
cycle was the only product after cleavage. The second imidazolidi-
none ring could not form during the HF cleavage. The effect of the
R1 group on the ring fusing was also investigated. It was found that
the second imidazolidinone ring did not form when R1 was H. The
monoheterocycle 7 was the only product obtained (Fig. 1). The ring
fusing was also affected by the nature of aldehyde. The presence of
electron-donating substituents at the ortho and para positions of
benzyl ring of the aryl aldehyde significantly decreased the purities
and yields of the desired products. These substituents decreased the
positive charge on the carbonyl carbon atoms in aldehydes. This, in
turn, reduced the activity of carbonyl group.
Side chain-protected amino acids were also applied to increase
the diversity of R1. Serine (hydroxyl), histidine (imidazole), lysine
(amino), and glutamic acid (carboxyl) were selected to determine
their application in generating 2-alkylidene-6-alkyl-imidazo
* Corresponding author. Tel.: +1 772 345 4580; fax: +1 772 345 3649.
E-mail address: houghten@tpims.org (R.A. Houghten).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.009

5858
Y. Li et al. / Tetrahedron Letters 50 (2009) 5857–5859
O
O
O
O
N
S
H
N
H
N
NH2
c
α
b
NH2
1
N
H
N
H
N
H
Br
R1
R1
R1
O
3
4
2
O
O
O
O
N
S
H
d
e
N
N
N
H
R1
R1
R2
N
S
R2
6
5
Scheme 1. Synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]thiazole-3,5[2H,6H]-dione derivatives. Reagents and conditions: (a) Boc-AA-OH, DIC, HOBt; 55% TFA/DCM; (b)
bromoacetic acid/DIC; (c) KSCN/DMF, 65 °C, overnight; (d) RCHO/piperidine/DMF, 65 °C, 48 h; and (e) anhydrous HF, 0 °C, 1.5 h.
Table 1
Individual products of imidazo[2,1-b]thiazole-3,5-dione derivatives
Entry
R1
R2
Puritya (%)
Yieldb (%)
MWc (fd)
6a
6b
6c
6d
6e
6f
6g
6h
6i
–CH3
–CH3
–CH3
–CH2CH(CH3)2
–CH2C6H5
–CH2C6H5
–CH2C6H5
–CH2OH
–CH(CH3)2
–CH(CH3)2
–C6H5
85
50
75
84
72
80
54
70
60
62
73
75
72
85
74
87
82
74
80
80
259.0 (M+H)
289.1 (M+H)
293.0 (M+H)
381.0 (M+H)
369.0 (M+H)
403.1 (M+H)
414.9 (M+H)
289.1 (M+H)
287.1 (M+H)
355.1 (M+H)
–C6H4(p-OCH3)
–C6H4(m-Cl)
–C6H4(o-Br)
–C6H4(m-Cl)
–C6H4(p-CF3)
–C6H4(o-Br)
–C6H4(m-CH3)
–C6H5
6j
–C6H4(p-CF3)
N
NH
6k
–C6H4(p-OH)
52
83
341.1 (M+H)
a
b
c
Purity (in%) is determined by the peak area of HPLC at 214 nm.
Yields (in%) are based on the weight of the crude product and are relative to the substitution of the resin (1.1 mmol/g).
Determined by ESI-MS.
O
Development, National Science Foundation (R.A.H. CHE 0455072),
1P41GM079590, 1P41GM081261, and U54HG03916-MLSCN.
H
N
O
N
HN
O
O
O
O
N
S
H
N
N
O
S
H2N
N
References and notes
S
H2N
R2
R2
R2
7
8
9
1. Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. Rev. 1981, 81, 175.
2. (a) Kline, T.; Felise, H. B.; Barry, K. C.; Jackson, S. R.; Nguyen, H. V.; Miller, S. I. J.
Med. Chem. 2008, 51, 7065; (b) Küçükgüzel, Sß. G.; Kocatepe, A.; Clercq, E. D.;
Sßahin, F.; Güllüce, M. Euro. J. Med. Chem. 2006, 41, 353; (c) Vicini, P.; Geronikaki,
A.; Anastasia, K.; Incerti, M.; Zani, F. Bioorg. Med. Chem. 2006, 14, 3859.
3. Ottanà, R.; Maccari, R.; Ciurleo, R.; Paoli, P.; Jacomelli, M.; Manao, G.; Camici,
G.; Laggner, C.; Langer, T. Bioorg. Med. Chem. 2009, 17, 1928.
Figure 1.
4. (a) Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Zaprutko, L.; Gzella, A.;
Lesyk, R. Euro. J. Med. Chem. 2009, 44, 1396; (b) Zhou, H.; Wu, S.; Zhai, S.; Liu, A.;
Sun, Y.; Li, R.; Zhang, Y.; Ekins, S.; Swaan, P. W.; Fang, B.; Zhang, B.; Yan, B. J.
Med. Chem. 2008, 51, 1242.
[2,1-b]thiazole-3,5[2H,6H]-dione under these synthetic conditions.
It was found that the use of lysine generated a biheterocyclo
byproduct 8 that formed by attacking the carbonyl by the e-amino
5. Wrobel, J.; Jetter, J.; Kao, W.; Rogers, J.; Di, L.; Chi, J.; Perez, M. C.; Chen, G.;
Shen, E. S. Bioorg. Med. Chem. 2006, 14, 5729.
of lysine (Fig. 1). The use of glutamic acid had a similar problem.
The side chain carboxyl group of glutamic acid reacted preferen-
tially during the HF cleavage, resulting in the biheterocyclo prod-
uct 9.
In summary, we present here an efficient solid-phase synthetic
approach for the synthesis of biheterocyclo 2-alkylidene-6-alkyl-
6. Dwivedi, C.; Gupta, S. S.; Parmar, S. S. J. Med. Chem. 1972, 15, 553.
7. Hrib, N. J.; Jurcak, J. G.; Bregna, D. E.; Dunn, R. W.; Geyer, H. M.; Hartman, H. B.;
Roehr, J. E.; Rogers, K. L.; Rush, D. K. J. Med. Chem. 1992, 35, 2712.
8. Pomel, V.; Klicic, J.; Covini, D.; Church, D. D.; Shaw, J. P.; Roulin, K.; Burgat-
Charvillon, F.; Valognes, D.; Camps, M.; Chabert, C.; Gillieron, C.; Franon, B.;
Perrin, D.; Leroy, D.; Gretener, D.; Nichols, A.; Vitte, P. A.; Carboni, S.; Rommel,
C.; Schwarz, M. K.; Rckle, T. J. Med. Chem. 2006, 49, 3858.
imidazo[2,1-b]thiazole-3,5[2H,6H]-dione
derivatives.
Various
9. Verma, A.; Saraf, S. K. Euro. J. Med. Chem. 2008, 43, 897.
amino acids and aryl aldehydes have been used, resulting in high
product yields and purities under optimized conditions. The meth-
odology is of value for high throughput synthesis of these poten-
tially bioactive molecules.
10. (a) Caille, S.; Bercot, E. A.; Cui, S.; Faul, M. M. J. Org. Chem. 2008, 73, 2003; (b)
Blanchet, J.; Zhu, J. Tetrahedron Lett. 2004, 45, 4449; (c) Pulici, M.; Quartieri, F.
Tetrahedron Lett. 2005, 46, 2387.
11. General procedure for the synthesis of 2-alkylidene-6-alkyl-imidazo[2,1-b]
thiazole-3,5[2H,6H]-dione derivatives: 100 mg of MBHA resin (loading:
1.1 mmol/g) was sealed within a polypropylene mesh packet.12 Reactions
were carried out in polypropylene bottles. A solution of N-Boc-amino acid
(5 equiv, 0.1 M in DMF), HOBt (5 equiv, 0.1 M in DMF), and DIC (5 equiv, 0.1 M
in DMF) was added to the reaction vessel. The reaction mixture was shaken at
room temperature for 2 h, followed by washing with DMF (3 times). Upon
removal of the Boc group with 55% TFA in DCM for 30 min, the resin was
Acknowledgments
This work was supported by the State of Florida, Executive
Officer of the Governor’s Office of Tourism, Trade, and Economic

Y. Li et al. / Tetrahedron Letters 50 (2009) 5857–5859
5859
washed and neutralized with 5% DIEA in DCM. The resin-bound amine was
reacted with bromoacetic acid (5 equiv, 0.1 M in DCM), and DIC (5 equiv, 0.1 M
in DCM) overnight. After washing with DCM (2 times), DMF (1 time), DCM (2
times), and air dried, potassium thiocyanate (10 equiv, 0.1 M in DMF) was
added into the reaction vessel. The Knovenagel condensation was performed at
65 °C for 24 h, followed by DMF wash (3 times). Piperidine (10 equiv, 0.1 M in
DMF) and aryl aldehyde (25 equiv, 0.25 M in DMF) were added and allowed to
react at 65 °C for 24 h. This condensation was performed twice. The resin
packet was then washed with DMF (3 times), DCM (3 times), and MeOH (3
times). The cleavage of the product was carried out by the treatment with 100%
anhydrous HF at 0 °C for 1.5 h, followed by nitrogen gas flow to remove the HF.
The product was extracted by 95% acetic acid. After lyophilization, the product
of 2-alkylidene-6-alkyl-imidazo[2,1-b] thiazole-3, 5[2H,6H]-dione was
obtained. The product was characterized by electrospray LC-MS under ESI
conditions and 1H and 13C NMR. ESI-MS (m/z) of 6a: 259.0 [M+H]; 1H NMR of
compound 6a: (500 MHz, DMSO-d6): d 1.53 (3H, d, J = 7.1 Hz), 4.58 (1H, q,
J = 7.1 Hz), 7.55–7.61 (3H, m), 7.72–7.74 (2H, m), 8.02 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 13.6, 56.7, 122.3, 129.5, 129.6, 130.0, 130.2, 131.2,
132.4, 135.5, 159.9, 181.7, 188.6.
12. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.