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Organic Chemistry International
Volume 2012 (2012), Article ID 956584, 5 pages
http://dx.doi.org/10.1155/2012/956584
Research Article

Regioselective Syntheses of 3-Benzyl-Substituted 7H-Thiazolo[3,2-a]pyrimidine-7-ones through Palladium-Catalyzed Heteroannulation of Acetylenic Compounds

School of Chemistry, Shahrood University of Technology, Shahrood 3619995161, Iran

Received 8 June 2012; Revised 2 August 2012; Accepted 5 August 2012

Academic Editor: Dipakranjan Mal

Copyright © 2012 Mohammad Bakherad and Farzaneh Gholipoor. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

An efficient synthesis of 3-benzyl-substituted 7H-thiazolo[3,2-a]pyrimine-7-ones in acetonitrile is accomplished via Pd- and Cu-catalyzed reaction of 2-mercaptopropargylpyrimidone with various aryl iodides in the presence of triethylamine as the base.

1. Introduction

The Sonogashira reaction is one of the most widely used C–C bond formation ones [1, 2]. It provides an efficient route to aryl alkynes, which are interesting intermediates for the preparation of a variety of target compounds with applications ranging from natural products [37] and pharmaceuticals [8] to molecular organic materials [9]. Due to the utility of the products, development of new catalyst systems has received considerable attention. Palladium-catalyzed reactions have been immensely practical for both carboannulation [10, 11] and heteroannulation [1216] processes.

Thiazole and pyrimidine nuclei are the active core of various bioactive molecules. In general, heterocycles encompassing a pyrimidine unit have found applications in a wide spectrum of biological and therapeutic areas [17, 18]. Thus, the heterocyclic system resulting from annulation of a pyrimidine ring on the biologically versatile thiazole nucleus is an attractive scaffold to be utilized for exploiting chemical diversity.

Continuing our efforts directed towards the straightforward preparation of biologically active target molecules through Sonogashira coupling reactions [1922], we performed the synthesis of new derivatives of thiazolo[3,2-a]pyrimidones via Pd- and Cu-catalyzed Sonogashira coupling reaction.

2. Results and Discussion

In this communication, we wish to report that treatment of 2-thiouracil 1 with propargyl bromide in MeONa/MeOH affords 2-propargylmercaptouracil 2 in a good yield. The 1H NMR spectrum of 2 showed a CH proton at 2.17 ppm, CH2 protons at 3.92 ppm, and a single resonance for the NH group at 13.05 ppm that disappeared on deuteration (as shown in Scheme 1).

956584.sch.001
Scheme 1

Reaction of compound 2 with various aryl iodides, 3af, in acetonitrile at room temperature led only to the formation of 3-benzyl-substituted 7H-thiazolo[3,2-a]pyrimidine-7-ones 4. The reactions were carried out under an argon atmosphere, and solvent was degassed prior to use. Presence of electron withdrawing groups such as NO2, Cl, and COMe on the aryl iodide seems to be essential. When iodobenzene was used as the aryl iodide, Sonogashira coupling could not be achieved. The results were tabulated in Table 1.

tab1
Table 1: Melting points and yields of 3-aryl-substituted 7H-thiazolo[3,2-a]pyrimidine-7-ones.

The following steps can be postulated for the mechanism of formation of either thiazolo[3,2-a]pyrimidine-7-ones 4 or thiazolo[3,2-a]pyrimidine-5-ones 5 (Scheme 2): (a) formation of ArPdI (II) through oxidative addition of Pd(0) (I) to ArI [23]; (b) transmetallation with the Cu salt of the alkyne (III) to generate the alkynyl palladium complex (IV); (c) reductive elimination results in the extrusion of Pd(0) to yield the substituted alkyne (V); (d) finally, nucleophilic attack of the nitrogen on the triple-bond intermediates (V) catalyzed by CuI led to product 4 or 5.

956584.sch.002
Scheme 2: Proposed mechanism for the formation of either 3-aryl-substituted 7H-thiazolo[3,2-a]pyrimidine-7-ones 4 or 3-aryl-substituted 5H-thiazolo[3,2-a]pyrimidine-5-ones 5 at room temperature. Reagents and conditions: (a) reduction of Pd(II) to Pd(0) with alkyne and Et3N; (b) CuI, Et3N; (c) nucleophilic attack on the triple band (V) catalyzed by CuI, Et3N to generate the product 4 or 5.

Structures 4 and 5 were characterized by comparing their spectra with those for the well-established compounds 6a [24], 6b [25], and 7 [25] (Scheme 3).The IR spectra for 4 or 5 were quite similar to that for 6. Therefore, we can conclude that the one-pot condensation, cyclization, and isomerization of acetylenic compounds regioselectively afford 4.

956584.sch.003
Scheme 3

The 1H NMR spectrum of 4a exhibited an aromatic proton at 6.70 ppm, which was characteristic of a fused thiazole ring. The other four aromatic protons appeared at 8.10–8.40 ppm. In the aliphatic region, the singlet at 4.30 ppm was due to the benzylic protons.

In conclusion, we have described a palladium-catalyzed, one-pot reaction for the regioselective syntheses of 3-aryl-substituted 7H-thiazolo[3,2-a]pyrimidine-7-ones from readily available starting materials in moderate-to-good yields.

3. Experimental

Melting points were uncorrected. The 1H NMR spectra were recorded at 400 MHz, and the 13C NMR spectra were recorded at 100 MHz in DMSO- . The J-coupling constants are reported in Hz.

3.1. Synthesis of 2-Propargylmercaptouracil 2

A mixture of sodium (1.2 mmol) and 2-thiouracile 1 (1 mmol) was stirred in methanol (5 mL). Propargyl bromide (1.2 mmol) was then added, and the mixture was stirred at room temperature for 24 h. The solid substance formed was filtered, washed with water, and recrystallized from water to afford the title compound.

Yield, 78%; m.p., 152-153°C; IR (KBr,  cm−1): 3200, 2100, 1645. 1H NMR (400 MHz, DMSO- δ ppm): 2.10 (s, 1H, CH), 3.90 (s, 2H, CH2), 6.10 (d, J = 6.4 Hz, 1H, CH of pyrimidine), 7.80 (d, J = 6.4 Hz, 1H, CH of pyrimidine), 13.05 (s, 1H, NH).

3.2. Syntheses of 3-Aryl-Substituted 7H-Thiazolo[3,2-a]pyrimidine-7-ones 4af

A mixture of aryl iodide (1 mmol), PdCl2(PPh3)2 (0.03 mmol), Cul (0.06 mmol), and triethylamine (2.0 mmol) was stirred in acetonitrile (5 mL) under an argon atmosphere. 2-Propargylmercaptouracil 2 (1.3 mmol) was then added, and the mixture was stirred at room temperature for 12 h. The solid substance formed was filtered, washed with water, and recrystallized from acetonitrile (Table 1).

3.2.1. 3-(2-Nitrobenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4a

IR (KBr,  cm−1): 1645, 1510, 1345. 1H NMR (400 MHz, DMSO- δ ppm): 4.30 (s, 2H, CH2), 6.20 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 6.70 (s, 1H, CH of thiazole), 7.84 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 8.10–8.40 (m, 4H, ArH); HRMS (ESI): 287.010.

3.2.2. 3-(3-Nitrobenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4b

IR (KBr,  cm−1): 1645, 1520, 1330. 1H NMR (400 MHz, DMSO- δ ppm): 4.36 (s, 2H, CH2), 5.72 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 6.55 (s, 1H, CH of thiazole), 7.20 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 7.80–8.10 (m, 4H, ArH); HRMS (ESI): 287.053.

3.2.3. 3-(4-Nitrobenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4c

IR (KBr,  cm−1): 1645, 1510, 1345. 1H NMR (400 MHz, DMSO- δ ppm): 4.07 (s, 2H, CH2), 6.30 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 6.35 (s, 1H, CH of thiazole), 7.45 (dd, J = 8.0, 1.6 Hz, 2H, ArH), 7.53 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 8.2 (dd, J = 8.0, 1.6 Hz, 2H, ArH); HRMS (ESI): 287.018.

3.2.4. 3-(4-Chloro-2-nitrobenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4d

IR (KBr,  cm−1): 1640, 1530, 1340; 1H NMR (400 MHz, DMSO- δ ppm): 4.27 (s, 2H, CH2), 6.20 (s, 1H, CH of thiazole), 6.34 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 7.58 (dd, J = 8.0, 2.0 Hz, 1H, ArH), 7.65 (d, J = 8.0 Hz, 2H, CH of pyrimidine and ArH), 8.10 (d, J = 2.0 Hz, 1H, ArH); HRMS (ESI): 320.966.

3.2.5. 3-(2-Methyl-4-nitrobenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4e

IR (KBr,  cm−1): 1640, 1520, 1345; 1H NMR (400 MHz, DMSO- δ ppm): 2.40 (s, 3H, CH3), 3.97 (s, 2H, CH2), 6.10 (s, 1H, CH of thiazole), 6.35 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 7.60 (d, J = 8.0, 1H, CH of pyrimidine), 7.95–8.20 (m, 3H, ArH); HRMS (ESI): 301.352.

3.2.6. 3-(4-Acetylbenzyl)-7H-thiazolo[3,2-a]pyrimidine-7-one 4f

IR (KBr,  cm−1): 1680, 1645; 1H NMR (400 MHz, DMSO- δ ppm): 2.64 (s, 3H, CH3), 4.10 (s, 2H, CH2), 6.35 (d, J = 8.0 Hz, 1H, CH of pyrimidine), 6.45 (s, 1H, CH of thiazole), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.62 (d, J = 8.0, 1H, CH of pyrimidine), 8.02 (d, J = 8.0 Hz, 2H, ArH); HRMS (ESI): 284.302.

Acknowledgment

The authors would like to thank the Research Council of Shahrood University of Technology for the support of this work.

References

  1. K. Sonogashira, “Development of Pd–Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides,” Journal of Organometallic Chemistry, vol. 653, no. 1-2, pp. 46–49, 2002. View at Publisher · View at Google Scholar
  2. R. Chinchilla and C. Najera, “The Sonogashira reaction: a booming methodology in synthetic organic chemistry,” Chemical Reviews, vol. 107, no. 3, pp. 874–922, 2007. View at Publisher · View at Google Scholar
  3. M. Toyota, C. Komori, and M. Ihara, “A concise formal total synthesis of mappicine and nothapodytine B via an intramolecular hetero Diels-Alder reaction,” The Journal of Organic Chemistry, vol. 65, no. 21, pp. 7110–7113, 2000. View at Publisher · View at Google Scholar · View at Scopus
  4. F. Yoshimura, S. Kawata, and M. Hirama, “Synthetic study of kedarcidin chromophore: atropselective construction of the ansamacrolide,” Tetrahedron Letters, vol. 40, no. 47, pp. 8281–8285, 1999. View at Publisher · View at Google Scholar · View at Scopus
  5. M. W. Miller and C. R. Johnson, “Sonogashira Coupling of 2-iodo-2-cycloalkenones: synthesis of (+)- and (−)-harveynone and (−)-tricholomenyn A,” The Journal of Organic Chemistry, vol. 62, no. 6, pp. 1582–1585, 1997. View at Publisher · View at Google Scholar
  6. A. Sakai, T. Aoyama, and T. Shioiri, “Total synthesis of vibsanol, a benzofuran-type lignan,” Tetrahedron Letters, vol. 40, no. 22, pp. 4211–4214, 1999. View at Publisher · View at Google Scholar · View at Scopus
  7. A. E. Graham, D. McKerrecher, D. H. Davies, and R. J. K. Taylor, “Sonogashira coupling reactions of highly oxygenated vinyl halides: the first synthesis of harveynone and epi-harveynone,” Tetrahedron Letters, vol. 37, no. 41, pp. 7445–7448, 1996. View at Publisher · View at Google Scholar · View at Scopus
  8. J. W. Grissom, G. U. Gunawardena, D. Klingberg, and D. Huang, “The chemistry of enediynes, enyne allenes and related compounds,” Tetrahedron, vol. 52, no. 19, pp. 6453–6518, 1996. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Wu, J. S. Schumm, D. L. Pearson, and J. M. Tour, “Convergent synthetic routes to orthogonally fused conjugated oligomers directed toward molecular scale electronic device applications,” The Journal of Organic Chemistry, vol. 61, no. 20, pp. 6906–6921, 1996. View at Scopus
  10. N. C. Ihle and C. H. Heathcock, “Palladium-catalyzed intramolecular alkyne-carbon monoxide-alkene insertion cascade for synthesis of .alpha.-methylenecyclopentenones,” The Journal of Organic Chemistry, vol. 58, no. 3, pp. 560–563, 1993. View at Publisher · View at Google Scholar
  11. R. C. Larock, M. J. Doty, and S. Cacchi, “Synthesis of indenones via palladium-catalyzed annulation of internal alkynes,” The Journal of Organic Chemistry, vol. 58, no. 17, pp. 4579–4583, 1993. View at Scopus
  12. A. Arcadi, S. Cacchi, and F. Marinelli, “Palladium-catalysed coupling of aryl and vinyl triflates or halides with 2-ethynylaniline: an efficient route to functionalized 2-substituted indoles,” Tetrahedron Letters, vol. 30, no. 19, pp. 2581–2584, 1989. View at Scopus
  13. K. R. Roesch and R. C. Larock, “Synthesis of isoquinolines and pyridines via palladium-catalyzed iminoannulation of internal acetylenes,” The Journal of Organic Chemistry, vol. 63, no. 16, pp. 5306–5307, 1998. View at Scopus
  14. R. C. Larock, E. K. Yum, and M. D. Refvik, “Synthesis of 2,3-disubstituted indoles via palladium-catalyzed annulation of internal alkynes,” The Journal of Organic Chemistry, vol. 63, no. 22, pp. 7652–7662, 1998. View at Publisher · View at Google Scholar
  15. R. Larock and X. Can, “Palladium-catalyzed cross-coupling of 2,5-cyclohexadienyl-substituted aryl or vinylic iodides and carbon or heteroatom nucleophiles,” The Journal of Organic Chemistry, vol. 64, no. 6, pp. 1875–1887, 1999. View at Publisher · View at Google Scholar
  16. F. Alonso, I. P. Belestkaya, and M. Yus, “Transition-metal-catalyzed addition of heteroatom-hydrogen bonds to alkynes,” Chemical Reviews, vol. 104, no. 6, pp. 3079–3159, 2004. View at Publisher · View at Google Scholar
  17. K. Senga, T. Novinson, H. R. Wilson, and R. K. Robins, “Synthesis and antischistosomal activity of certain pyrazolo[1,5-a]pyrimidines,” Journal of Medicinal Chemistry, vol. 24, no. 5, pp. 610–613, 1981. View at Scopus
  18. J. L. Bernier, J. P. Henichart, V. Warin, and F. Baert, “Synthesis and structure-activity relationship of a pyrimido[4,5-d]pyrimidine derivative with antidepressant activity,” Journal of Pharmaceutical Sciences, vol. 69, no. 11, pp. 1343–1345, 1980. View at Scopus
  19. M. Bakherad, H. Nasr-Isfahani, A. Keivanloo, and N. Doostmohammadi, “Pd-Cu catalyzed heterocyclization during Sonogashira coupling: synthesis of 2-benzylimidazo[1,2-a]pyridine,” Tetrahedron Letters, vol. 49, no. 23, pp. 3819–3822, 2008. View at Publisher · View at Google Scholar
  20. M. Bakherad, H. Nasr-Isfahani, A. Keivanloo, and G. Sang, “Synthesis of 2-benzylimidazo[2,1-b][1,3]benzothiazoles through palladium-catalyzed heteroannulation of acetylenic compounds,” Tetrahedron Letters, vol. 49, no. 43, pp. 6188–6191, 2008. View at Publisher · View at Google Scholar
  21. T. A. Kamali, M. Bakherad, M. Nasrollahzadeh, S. Farhangi, and D. Habibi, “Synthesis of 6-substituted imidazo[2,1-b]thiazoles via Pd/Cu-mediated Sonogashira coupling in water,” Tetrahedron Letters, vol. 50, no. 39, pp. 5459–5462, 2009. View at Publisher · View at Google Scholar
  22. M. Bakherad, A. Keivanloo, Z. Kalantar, and S. Jajarmi, “Pd/C-catalyzed heterocyclization during copper-free Sonogashira coupling: synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water,” Tetrahedron Letters, vol. 52, no. 2, pp. 228–230, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. K. Sonogashira, Y. Tohda, and N. Hagihara, “A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines,” Tetrahedron Letters, vol. 16, no. 50, pp. 4467–4470, 1975. View at Scopus
  24. M. M. Heravi, A. Kivanloo, M. Rahimizadeh, M. Bakavoli, M. Ghassemzadeh, and B. Neumüller, “Regioselective synthesis of 3-benzylthiazolo[3,2-a]pyrimidones and 3-benzyl-thiazolo[3,2-c]pyrimidones through palladium-catalyzed heteroannulation of acetylenic compounds,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 180, no. 11, pp. 2407–2417, 2005. View at Publisher · View at Google Scholar · View at Scopus
  25. H. F. Andrew and C. K. Bradsher, “A new synthesis of thiazolo[3,2-a] pyrimidinones,” Journal of Heterocyclic Chemistry, vol. 24, no. 4, pp. 577–581, 1967. View at Publisher · View at Google Scholar