LETTER
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Traceless Solid-Phase Synthesis of 2,4,5-Trisubstituted Thiazoles Solid-PhaseSynthesi of2,4Young Ill 5-TrisubstiutedThiazoles Lee,* Jin Young Lee, Hye Jin Lee, Young-Dae Gong* The Center for High Throughput Synthesis Platform Technology, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejon 305-600, Korea Fax +82(42)8611291; E-mail:
[email protected] Received 4 July 2005
Abstract: The solid-phase synthesis of trisubstituted thiazoles is described. The synthetic strategy involves the formation of a polymer-bound thiazole by reacting resin-bound cyanodithioimidocarbonic acid and a-bromoketone. The resin-bound thiazole was reacted with acyl chlorides or isocyanates. After oxidation–activation of a thioether linker to a sulfone linker, traceless cleavage was achieved with nucleophiles to give trisubstituted thiazoles.
N CN X
NH2 N
SH (path A)
R'HN
O
R'HN
Ar
S
NH
R'HN N H L = NH2, NO2, CCl3, S
known methods NH2
HN R'
N S
SYNLETT 2005, No. 16, pp 2483–248504.10205 Advanced online publication: 21.09.2005 DOI: 10.1055/s-2005-872687; Art ID: U21005ST © Georg Thieme Verlag Stuttgart · New York
O
I
L (path B)
Key words: thiazoles, traceless solid-phase synthesis, cyanodithioimidocarbonic acid
Combinatory chemistry has become fully integrated into the drug discovery process.1 Much of the early work on combinatorial chemistry relied on the direct conversion of known solution-phase syntheses into the solid phase. However, the development of new synthetic methods for functionalized heterocycles is required for the construction of drug-like molecular libraries. Thiazoles are useful heterocyclic building blocks and a prominent structural element of compounds used to treat cancer, bacterial, fungal, and viral infections.2 Recently, several solid-phase synthetic methods for thiazoles have been reported.3 Among thiazole derivatives, 5-acyl-2,4-diaminothiazole I is undergoing preclinical trials as a potential cyclin-dependent kinase (CDK)4 and glycogen synthase kinase-3 (GSK-3) inhibitor.5 The preparation of 5-acyl-2,4-diaminothiazole I is readily accomplished by reacting a-haloketone starting from acyclic thioureas as shown in Scheme 1. In the first case, the synthetic process was achieved via the reaction of N-cyanoisothioureas with an a-halo ketone (path A).6 The targeted compound can also be accessed by starting from a substituted iminothiourea, such as 1-amidinothiourea, 1-(iminonitromethyl)thiourea, 1-(2,2,2-trichloroiminoethyl)thiourea, benzylthioureidothiourea or polymer-bound thioureidothiourea (path B).7 However, these methods have limitation in the functionalization of 5-acyl-2,4-diaminothiazole. In seeking a new synthetic method for trisubstituted thiazoles II we chose traceless cleavage of the 2-sulfonyl linker of thiazole because nucleophiles can exchange a sulfonyl linker.8 In addition, this synthetic pathway in solution phase has not been reported until now. Here, we describe an efficient and new method for the solid-phase synthesis of 2,4-diaminothiazoles II via resin-bound thiazole, which has three reaction points.
Ar S
N R
S
Scheme 1
Nu
new approach
S II
R
Strategies used to make 2,4,5-trisubstituted thiazoles
The synthesis of 2,4,5-trisubstituted thiazoles 5 and 7 is outlined in Scheme 2. The general procedure starts from the reaction of commercial Merrifield resin 1 with 4 equivalents of dipotassium cyanodithioimidocarbonate, which was prepared from CS2, KOH, and cyanamide in aqueous ethanol.9 Of the various solvents (EtOH, DMSO, DMF, acetone–water = 3:1, or THF) used to prepare resin 2, DMF had the strongest CN intensity at 2168 cm–1 on ATR-FTIR and reproducibility. We also tried one-pot synthesis 2 via the reaction of Merrifield resin 1 with CS2, KOH, and cyanamide, which is similar to the solid-phase NH2 N
3
R
N R4
NH2
R1
N
d S
S 5
O
O
R1 S
O
O 4
R1 = Ph or OEt
c N Cl
a
S
1
NH2
CN
N b
SH
S
R1 S
O
3
2
e HN R2 N
R3 N R4
R1 S 7
N
c d
O 2
S
HN R2 R1 S 6
O
R = NHCOR or COR
Scheme 2 Reagents and conditions: (a) NCN=C(SK)2 (4 equiv), DMF; (b) BrCH2COR1 (3 equiv), DMF, 80 °C; (c) MCPBA (2.2 equiv), CH2Cl2; (d) R3R4NH (2 equiv), dioxane; (e) isocyanate (5 equiv), i-PrNEt2, microwave, DMSO, 150 °C or acid chloride (10 equiv), pyridine (10 equiv), MeCN, 60 °C
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LETTER
I. Y. Lee et al.
Table 1
Solid-Phase Synthesis of 5
Table 2
HN R2
NH2 N
R3 N
R1 S
R4
Solid-Phase Synthesis of 7
N
R3 N
O
R1 S
R4
O
Compound
R1
R3R4N
Yield (%)a
Compound
R1
R2
R3R4N
Yield (%)a
5a
Ph
PrNH
35
7a
Ph
PhNHCO
PrNH
25
5b
Ph
BnNH
28
7b
Ph
PhNHCO
Et2N
36
5c
Ph
32
7c
Ph
PhNHCO
7d
Ph
BnNHCO
7e
Ph
BnNHCO
N
5d
NH
NH
Ph
NH
28
PrNH
28 28
N
5f
Ph
5g
Ph
Et2N
32
5h
Ph
(i-Pr)2N
42
5i
Ph
5j
Ph
5k
OEt
O
28
NH F
NH
25 38
O
5l
38
N
41 PhN
N
N
7f
Ph
CH3CO
PrNH
30
7g
Ph
PhCO
PrNH
29
7h
Ph
Et2N
32
S
CO
7i
Oet
PhNHCO
7j
OEt
PhCO
N
OEt
25 O
O
N
O
N
30 29
a
Isolated yield of purified material over four steps based on the loading of the Merrifield resin used. Purities were >95% as evaluated by 1 H NMR.
a
Isolated yield of purified material over four steps based on the loading of the Merrifield resin used. Purities were >95% as evaluated by 1 H NMR.
synthesis of triazole.10 However, the deduced loading was about 40% based on comparison of the CN peak areas on IR with the above stepwise pathway. The obtained resin needs to be washed with water because the salt form of resin-bound cyanodithioimidocarbonic acid 2 is difficult to filter with organic solvents. The subsequent reaction of resin 2 with 2-bromoacetophenone or ethyl bromoacetate and triethylamine in DMF at 80 °C gave the polymerbound 4-aminothiazole 3. To determine the reactivity of sulfanyl resin 3 (R1 = Ph) with amines, the reaction of resin 3 (R1 = Ph) with two equivalents of n-propylamine in dioxane produced no detectable (4-amino-2-propylaminothiazol-5-yl)phenylmethanone (5a) at room temperature even through on heating at 80 °C for six hours. After that, the sulfonyl resin 4 (R1 = Ph) was obtained by MCPBA oxidation as an application of solution-phase thiazole synthesis.8,11 The desired thiazole 5a was liberated from resin 4 (R1 = Ph) by nucleophilic addition of npropylamine in dioxane at room temperature. To establish the scope of this reaction on solid support, a variety of amines and anilines were investigated (Table 1). When the primary and secondary amines (2 equiv) reacted with resin-bound thiazole 4 (R1 = Ph) at room temperature, the desired thiazoles were obtained in 28–42% yields based on the original loading of Merrifield resin 1 for four steps (5a–h). Nucleophilic addition of anilines (2 equiv) was Synlett 2005, No. 16, 2483–2485
© Thieme Stuttgart · New York
achieved by heating at 80 °C (5i,j). The respective 4-carboxylated 2,4-diaminothiazles were also obtained from 4 (R1 = OEt) in good yield (5k,l). This approach allows the possibility of introducing other substituent groups into thiazoles. The solution-phase reaction of aminothiazole and isocyanate is a known synthetic method for thiazoleureas.12 Therefore, these methods of functionalizing thiazoles were applied in our system to obtain unknown compounds as shown in Scheme 2 and Table 2. The reaction of thiazole resin 3 with five equivalents of phenyl isocyanate in DMSO at 150 °C for ten hours gave the desired resin-bound thiazolurea 6 (R2 = NHCOR). Recently, microwaveassisted organic synthesis has proven to be a powerful tool for promoting a variety of chemical reactions.13 When we tried synthesis of resin 6 (R2 = NHCOR) under microwave irradiation condition, the reaction was completed within 30 minutes. Thiazolureas were obtained by the oxidation of 6 (R2 = NHCOR) followed by amines addition (7a–e). The solution-phase acylation of aminothiazole is also a common method of derivatizing thiazole.14 The acylation of resin 3 was achieved with ten equivalents of acyl chloride and pyridine in acetonitrile to get resin 6 (R2 = COR). Then, oxidation and amines addition gave the corresponding thiazoles (7f–h). Moreover, the urea formation or acylation reaction of the 5-carboxylated 2,4diaminothiazole gave each functionalized thiazole (7i,j).
LETTER
In summary, we have developed a useful method for the solid-phase synthesis of trisubstituted thiazoles.15,16 This protocol was easily adapted for automated library synthesis. The synthesis of drug-like fused thiazole compounds from resin-bound thiazoles would be especially interesting. The complete results will be reported in due course.
Acknowledgment We are grateful to the Center for Biological Modulators and the Ministry of Commerce, Industry and Energy of Korea for financial support for this research.
References (1) (a) Nicolaou, K. C.; Hanko, R.; Hatwig, W. Handbook of Combinatorial Chemistry; Wiley-VCH: Washington, 2002. (b) Dolle, R. E. J. Comb. Chem. 2003, 6, 693. (2) (a) Boyle, P. H. In Comprehensive Heterocyclic Chemistry, 2nd ed., Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier: New York, 1996, 373. (b) Lewis, J. R. Nat. Prod. Rep. 1999, 16, 389. (3) (a) Goff, D.; Fernandez, J. Tetrahedron Lett. 1999, 40, 423. (b) Kazzouli, S. E.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron Lett. 2002, 43, 3193. (c) Stieber, F.; Mazitschek, R.; Soric, N.; Giannis, A.; Waldmann, H. Angew. Chem. Int. Ed. 2002, 41, 4757. (d) Katrizky, A. R.; Cai, X.; Rogovoy, B. V. J. Comb. Chem. 2003, 5, 392. (4) Chen, L.; Ding, Q.; Gillespie, P.; Kim, K.; Lovey, A. J.; Mccomas, W. W.; Mullin, J. G. Jr.; Perrotta, A. PCT Int. Appl. WO02057261, 2002. (5) Bowler, A. N.; Hansen, B. F. PCT Int. Appl. WO03011843, 2003. (6) (a) Gompper, R.; Gang, M.; Saygin, F. Tetrahedron Lett. 1966, 7, 1885. (b) Gewald, K.; Blauschimit, P.; Mayer, R. J. Prakt. Chem. 1967, 35, 97. (7) (a) Rajasekharan, K. N.; Nair, K. P.; Jenardanan, G. C. Synthesis 1986, 353. (b) Binu, R.; Thomas, K. K.; Jenardannan, G. C.; Rajasekharan, K. N. Org. Prep. Proced. Int. 1998, 30, 93. (c) Romero-Ortega, M.; Aviles, A.; Raymundo, C.; Fuentes, A.; Gomez, R. M.; Plata, A. J. Org. Chem. 2000, 65, 7244. (d) Masquelin, T.; Obrecht, D. Tetrahedron 2001, 57, 153. (e) Baer, R.; Masquelin, T. J. Comb. Chem. 2001, 3, 16. (8) (a) Yamanaka, H.; Ohba, S.; Sakamoto, T. Heterocycles 1990, 31, 1115. (b) Konno, S.; Masaki, A.; Mataichi, S.; Hiroshi, Y. Yakugaku Zasshi 1990, 110, 105. (9) Timmons, R. J.; Wittenbrook, L. S. J. Org. Chem. 1967, 32, 1566. (10) Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.; Yoo, S.-e.; Gong, Y.D. J. Comb. Chem. 2005, 7, 136. (11) Vernin, G.; Siv, C.; Metzger, J. J. Heterocycl. Chem. 1978, 15, 1361. (12) (a) Walchshofer, N.; Minjat, M.; Tinland, B.; Jaussaud, P.; Petavy, A. F.; Paris, J. Eur. J. Med. Chem. 1986, 59. (b) Yamamoto, K.; Kondoh, K.; Horiuchi, K.; Matsui, Y.; Nagamine, M. Eur. Pat. Appl. EP 761658, 1997.
Solid-Phase Synthesis of 2,4,5-Trisubstituted Thiazoles
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(13) (a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (b) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberin, R. J. Comb. Chem. 2002, 4, 95. (d) Lee, I. Y.; Lee, J. Y.; Gong, Y.-D. Synthesis 2005, DOI: 10.1055/5-2005-872099. (14) (a) Hirai, K.; Sugimoto, H.; Ishiba, T. J. Org. Chem. 1980, 45, 253. (b) Wamhoff, H.; Berressem, R.; Herrmann, S. Synthesis 1993, 107. (15) A Typical Procedure for Preparing Compound 5. Merrifield resin 1 (2.50 g, from Advanced ChemTech, loading 0.94 mmol/g) was treated with dipotassium cyanodithioimidocarbonate (1.94 g, 10 mmol) in DMF (20 mL). The mixture was stirred at r.t. for 6 h, and then filtered and washed with H2O, DMF, MeOH, and CH2Cl2 several times. The resin was dried under vacuum, and then treated with 5 mL of 2-bromoacetophenone (2 M) and 5 mL of Et3N (2 M) in DMF, the resulting slurry was heating at 80 °C for 3 h to get resin 3 which was filtered and washed with H2O, DMF, MeOH, and CH2Cl2 several times and dried at r.t. The dried resin 3 was then treated 6 mL of MCPBA (1 M) in CH2Cl2 to get resin 4 which was filtered and washed with DMF, MeOH, and CH2Cl2 several times. The resin 5 (each 250 mg) loaded into the Mettler–Toledo MiniBlock synthesizer. To each block was added dioxane (1 mL) and amine (0.5 mmol). The reaction was then shaken 12 h, filtered and concentrated under reduced pressure in a Genevac HT-4X. The residue was purified on a Biotage Quad 3+ using a flash 12 M column. Analytical data of 5a:7b 1H NMR (500 MHz, CDCl3): d = 11.67 (s, 1 H), (m, 2 H), 7.40–7.45 (m, 3 H), 3.17–3.20 (m, 2 H), 1.65 (q, 2 H, m), 0.96 (t, 3 H, J = 7.4 Hz). LCMS: m/z = 262 [M + 1]. (16) A Typical Procedure for Preparing Compound 7. To a microwave reaction vessel was added dried resin 4 (1 g), isocyanate (5 mmol) and DMSO (3 mL). The reaction vessel was irradiated at 150 °C for 30 min (Emrys Creator from Personal Chemistry). The resin 6 (R2 = NHCOR) was collected by filtration and washed with H2O, DMF, MeOH, and CH2Cl2 several times and dried in a vacuum. Thiazolureas were prepared in the same manner from resin 6 (R2 = NHCOR) as described in the preparation of 5 from resin 4. Analytical data of 7a: 1H NMR (500 MHz, CDCl3): d = 11.67 (br s, 1 H), 7.76–7.79 (m, 2 H), 7.66 (d, 2 H, J = 7.8 Hz), 7.43–7.47 (m, 3 H), 7.33 (dd, 2 H, J1 = 7.6 Hz, J2 = 8.3Hz), 7.06 (dd, 1 H, J1 = 7.4 Hz, J2 = 7.4 Hz), 5.88 (br s, 1 H), 3.22–3.28 (m, 2 H), 1.67–1.73 (m, 2 H), 1.00 (t, 3 H, J = 7.4 Hz). 13C NMR (125 MHz, CDCl3): d = 183.5, 162.1, 130.5, 141.8, 139.7, 130.5, 129.0, 128.4, 127.2, 123.0, 120.2, 47.5, 22.4, 11.4. LCMS: m/z = 403 [M + Na]. The resin 4 (250 mg) was treated with acyl chloride (2.5 mmol) and pyridine (2.5 mmol) in MeCN (1 mL) to yield 6 (R2 = COR). After shaking for 6 h at r.t., the resin 6 (R2 = COR) was collected by filtration and washed with H2O, DMF, MeOH, and CH2Cl2 several times and dried in a vacuum. N-Acylthiazoles were prepared in the same manner from resin 6 (R2 = COR) as described in the preparation of 5 from resin 4. Analytical data of 7f: 1H NMR (500 MHz, CDCl3): d = 12.93 (s, 1 H), 8.15 (d, 2 H, J = 7.2 Hz), 7.80–8.14 (m, 2 H), 7.49– 7.57 (m, 6 H), 3.21–3.26 (m, 2 H), 1.70 (m, 2 H), 1.00 (t, 3 H, J = 7.4 Hz). 13C NMR (125 MHz, CDCl3): d = 186.7, 174.2, 164.0, 158.0, 140.9, 133.8, 132.5, 131.5, 128.9, 128.6, 128.0, 127.5, 102.7, 48.0, 22.1, 11.3. LCMS: m/z = 366 [M + 1].
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© Thieme Stuttgart · New York
