6232
K. H. Kim et al. / Tetrahedron Letters 52 (2011) 6228–6233
10. For our recent example of palladium-catalyzed benzoin-mediated Ullmann
type coupling of aryl bromides to biaryls Park, B. R.; Kim, K. H.; Kim, T. H.; Kim,
J. N. Tetrahedron Lett. 2011, 52, 4405–4407. and further references were cited
therein. In the reaction, biaryls and trace amount of arenes were formed but
the yields of these compounds were not determined.
bromides including electron-deficient aryl bromides. 5-Arylura-
cils were formed exclusively most likely via an electrophilic
metalation–deprotonation process while the 6-aryl derivatives
via a Heck-type mechanism as minor products. In addition,
1,3-dimethyl-6-phenyluracil (4a) was also synthesized in high
yield by oxidative arylation with benzene via a CMD mechanism.
Further studies on the reaction mechanism and the scope of this
reaction are currently underway including an intramolecular
version.
11. The use of K2CO3 afforded higher yield of product in many palladium-catalyzed
reactions with aryl bromides than Cs2CO3, see: (a) Pivsa-Art, S.; Satoh, T.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467–473;
(b) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
2000, 41, 481–483; (c) Safin, D. A.; Babashkina, M. G.; Klein, A. Catal. Lett. 2009,
129, 363–366; (d) Safin, D. A.; Babashkina, M. G. Catal. Lett. 2009, 130, 679–682.
12. Typical procedure for the synthesis of 1,3-dimethyl-5-phenyluracil (3a): A stirred
mixture of 1,3-dimethyluracil (1a, 140 mg, 1.0 mmol), bromobenzene (2a,
315 mg, 2.0 equiv), Pd(OAc)2 (22 mg, 10 mol %), PPh3 (52 mg, 20 mol %), PivOH
(30 mg, 30 mol %), K2CO3 (415 mg, 3.0 equiv) in DMF (1.5 mL) was heated to
130 °C for 12 h under nitrogen atmosphere. After the usual aqueous extractive
workup with chloroform and column chromatographic purification process
(hexanes/THF, 4:1) compounds 3a (171 mg, 79%) and 4a (21 mg, 10%) were
obtained as white solids.5 Other compounds were synthesized analogously,
and the known compounds 3a–d5,19a and 3f,5,19a 4a–d,5,19a 4f,5,19a 4g19a were
identified by comparison their mp, IR, 1H NMR and/or mass data with the
reported. The selected spectroscopic data of 3e and 3g–k are as follows.
Compound 3e:19b 71%; white solid, mp 203–204 °C; IR (KBr) 2945, 1700, 1646,
Acknowledgments
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (2011-0002570).
Spectroscopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
1450, 1346 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.43 (s, 3H), 3.44 (s, 3H), 7.25 (s,
;
References and notes
1H), 7.33 (dd, J = 6.9 and 1.2 Hz, 1H), 7.44–7.50 (m, 3H), 7.68–7.71 (m, 1H),
7.85–7.88 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 28.22, 36.90, 113.54, 125.18,
125.25, 125.90, 126.22, 128.12, 128.36, 128.97, 130.57, 132.29, 133.58, 142.13,
151.72, 162.57; ESIMS m/z 267 [M+H]+. Anal. Calcd for C16H14N2O2: C, 72.16; H,
5.30; N, 10.52. Found: C, 72.43; H, 5.57; N, 10.29.
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Z.; Chen, Y.; Huang, C. Q.; Chen, M.; Jiang, W.; Rueter, J. K.; Coon, T.; Chen, C.;
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Chen, C. Bioorg. Med. Chem. Lett. 2005, 15, 2519–2522; (d) Chen, C.; Chen, Y.;
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Seko, T.; Nemoto, H. J. Org. Chem. 1989, 54, 4734–4736.
2. For the applications of 5-aryluracil derivatives in bioanalysis or chemical
biology, see: (a) Cahova, H.; Havran, L.; Brazdilova, P.; Pivonkova, H.; Pohl, R.;
Fojta, M.; Hocek, M. Angew. Chem., Int. Ed. 2008, 47, 2059–2062; (b) Fukuda, M.;
Nakamura, M.; Takada, T.; Yamana, K. Tetrahedron Lett. 2010, 51, 1732–1735;
(c) Jacobsen, M. F.; Ferapontova, E. E.; Gothelf, K. V. Org. Biomol. Chem. 2009, 7,
905–908; (d) Wanninger-Weib, C.; Wagenknecht, H.-A. Eur. J. Org. Chem. 2008,
64–71; (e) Ehrenschwender, T.; Wagenknecht, H.-A. Synthesis 2008, 3657–
3662; (f) Amann, N.; Pandurski, E.; Fiebig, T.; Wagenknecht, H.-A. Chem. Eur. J.
2002, 8, 4877–4883; (g) Okamoto, A.; Tainaka, K.; Unzai, T.; Saito, I. Tetrahedron
2007, 63, 3465–3470; (h) Capobianco, M. L.; Cazzato, A.; Alesi, S.; Barbarella, G.
Bioconjugate Chem. 2008, 19, 171–177; (i) Srivatsan, S. G.; Tor, Y. J. Am. Chem.
Soc. 2007, 129, 2044–2053; (j) Greco, N. J.; Tor, Y. J. Am. Chem. Soc. 2005, 127,
10784–10785.
3. For the palladium-catalyzed synthesis of 5-aryluracil derivatives with
arylboron reagents, see: (a) Kalachova, L.; Pohl, R.; Hocek, M. Synthesis 2009,
105–112; (b) Western, E. C.; Daft, J. R.; Johnson, E. M., II; Gannett, P. M.;
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767–6774; (c) Crisp, G. T.; Macolino,
V. Synth. Commun. 1990, 20, 413–422; (d) Pomeisl, K.; Holy, A.; Pohl, R.; Horska,
K. Tetrahedron 2009, 65, 8486–8492; (e) Pomeisl, K.; Holy, A.; Pohl, R.
Tetrahedron Lett. 2007, 48, 3065–3067; (f) Coelho, A.; Sotelo, E. J. Comb. Chem.
2005, 7, 526–529; For recent 6-arylation of uracil derivatives, see: (g) Shih, Y.-
C.; Chien, T.-C. Tetrahedron 2011, 67, 3915–3923.
4. For the palladium-catalyzed synthesis of 5-aryluracil derivatives with
arylstannane reagents, see: (a) Gutierrez, A. J.; Terhorst, T. J.; Matteucci, M.
D.; Froehler, B. C. J. Am. Chem. Soc. 1994, 116, 5540–5544; (b) Sadler, J. M.;
Ojewoye, O.; Seley-Radtke, K. L. Nucleic Acids Symp. Ser. 2008, 52, 571–572; (c)
Wigerinck, P.; Pannecouque, C.; Snoeck, R.; De Clercq, E.; Herdewijn, P. J. Med.
Chem. 1991, 34, 2383–2389; (d) Herdewijn, P.; Kerremans, L.; Wigerinck, P.;
Vandendriessche, F.; Aerschot, A. V. Tetrahedron Lett. 1991, 32, 4397–4400.
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Cernova, M.; Cerna, I.; Pohl, R.; Hocek, M. J. Org. Chem. 2011, 76, 5309–5319.
6. Palladium-catalyzed intramolecular arylations of uracil derivatives have been
reported in some cases, see: (a) Majumdar, K. C.; Sinha, B.; Maji, P. K.;
Chattopadhyay, S. K. Tetrahedron 2009, 65, 2751–2756; (b) Majumdar, K. C.;
Debnath, P.; Taher, A.; Pal, A. K. Can. J. Chem. 2008, 86, 325–332.
Compound 3g:19a 75%; white solid, mp 122–124 °C; IR (KBr) 2946, 1702, 1656,
1603, 1491, 1451, 1350 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.42 (s, 3H), 3.47 (s,
;
3H), 3.83 (s, 3H), 6.88 (d, J = 7.2 Hz, 1H), 7.00–7.12 (m, 2H), 7.22–7.36 (m, 2H);
13C NMR (CDCl3, 75 MHz) d 28.25, 37.10, 55.29, 113.57, 113.96, 114.16, 120.50,
129.41, 134.20, 140.53, 151.42, 159.56, 162.23; ESIMS m/z 247 [M+H]+. Anal.
Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.75; H, 5.96; N,
11.13.
Compound 3h: 40%; white solid, mp 180–181 °C; IR (KBr) 1707, 1651, 1607,
1279, 1112 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.43 (s, 3H), 3.50 (s, 3H), 3.92 (s,
;
3H), 7.40 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 28.25, 37.21, 52.10, 113.21, 127.97, 129.25, 129.64, 137.54,
141.13, 151.24, 161.89, 166.72; ESIMS m/z 275 [M+H]+. Anal. Calcd for
C
14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.39; H, 5.45; N, 10.06.
Compound 3i: 43%; white solid, mp 158–159 °C; IR (KBr) 2953, 1713, 1652,
1253 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.42 (s, 3H), 3.49 (s, 3H), 3.92 (s, 3H),
;
7.39 (s, 1H), 7.46 (dd, J = 7.8 and 7.8 Hz, 1H), 7.79 (ddd, J = 7.8, 1.8 and 1.2 Hz,
1H), 7.99 (ddd, J = 7.8, 1.8 and 1.2 Hz, 1H), 8.10–8.11 (m, 1H); 13C NMR (CDCl3,
75 MHz) d 28.17, 37.08, 52.13, 113.13, 128.42, 128.75, 128.86, 130.28, 132.91,
133.19, 140.86, 151.26, 162.05, 166.72; ESIMS m/z 275 [M+H]+. Anal. Calcd for
C
14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.64; H, 5.45; N, 10.13.
Compound 3j:19c 35%; white solid, mp 198–200 °C; IR (KBr) 1693, 1650, 1483,
1350 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.43 (s, 3H), 3.51 (s, 3H), 7.28–7.38 (m,
;
1H), 7.39 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.57 (br s, 1H), 8.65 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) d 28.25, 37.24, 111.02, 123.14, 129.00, 136.07, 140.68, 148.30,
148.88, 151.26, 162.03; ESIMS m/z 218 [M+H]+. Anal. Calcd for C11H11N3O2: C,
60.82; H, 5.10; N, 19.34. Found: C, 60.64; H, 5.49; N, 19.12.
Compound 3k: 55%; sticky oil; IR (film) 3060, 2960, 2892, 1702, 1658, 1494,
1458, 1440, 1291, 1076 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.85–2.14 (m, 3H)
;
2.37–2.49 (m, 1H), 3.95–4.02 (m, 1H), 4.17–4.23 (m, 1H), 5.14 (d, J = 13.5 Hz,
1H), 5.23 (d, J = 13.5 Hz, 1H), 6.08 (dd, J = 6.3 and 3.3 Hz, 1H), 7.22–7.42 (m,
6H), 7.44 (s, 1H), 7.46–7.57 (m, 4H); 13C NMR (CDCl3, 75 MHz) d 23.90, 33.11,
44.54, 70.19, 88.05, 114.14, 127.62, 127.78, 128.36, 128.41 (2C), 129.41,
133.39, 134.71, 136.85, 150.43, 161.83; ESIMS m/z 349 [M+H]+. Anal. Calcd for
C
21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.23; H, 5.96; N, 7.89.
13. We also examined the reaction of 1a under the modified condition A, by simply
replacing PPh3 with tris(pentafluorophenyl)phosphine;5 however, the results
were not satisfactory (3a: 73% and 4a: 18%). Replacement of PPh3 with an
electron-poor triethyl phosphite ligand was also examined in order to make
the arylpalladium intermediate more electrophilic, however, the yield and
selectivity were similar (3a: 74% and 4a: 16%) with those of (C6F5)3P. In
addition, the reaction of 1a and iodobenzene produced biphenyl as a major
product along with a low yield of 3a (<15%).
14. Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003,
5, 301–304.
15. For the synthesis and synthetic applications of N1-protected uracil derivatives
with a tetrahydrofuranyl moiety, see: (a) Maruyama, T.; Kozai, S.; Demizu, Y.;
Witvrouw, M.; Pannecouque, C.; Balzarini, J.; Snoecks, R.; Andrei, G.; De Clercq,
E. Chem. Pharm. Bull. 2006, 54, 325–333; (b) Dolman, N. P.; More, J. C. A.; Alt, A.;
Knauss, J. L.; Pentikainen, O. T.; Glasser, C. R.; Bleakman, D.; Mayer, M. L.;
Collingridge, G. L.; Jane, D. E. J. Med. Chem. 2007, 50, 1558–1570; (c) Dolman, N.
P.; More, J. C. A.; Alt, A.; Knauss, J. L.; Troop, H. M.; Bleakman, D.; Collingridge,
G. L.; Jane, D. E. J. Med. Chem. 2006, 49, 2579–2592; (d) Engel, D.; Nudelman, A.;
Tarasenko, N.; Levovich, I.; Makarovsky, I.; Sochotnikov, S.; Tarasenko, I.;
Rephaeli, A. J. Med. Chem. 2008, 51, 314–323.
7. For the palladium-catalyzed arylation of indole derivatives, see: (a) Lebrasseur,
N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926–2927; (b) Wang, X.; Gribkov, D.
V.; Sames, D. J. Org. Chem. 2007, 72, 1476–1479; (c) Lane, B. S.; Sames, D. Org.
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471–483.
8. For the 1,2-palladium migration, see: (a) Kirchberg, S.; Frohlich, R.; Studer, A.
Angew. Chem., Int. Ed. 2009, 48, 4235–4238; (b) Lane, B. S.; Brown, M. A.; Sames,
D. J. Am. Chem. Soc. 2005, 127, 8050–8057.
9. In the papers of Hocek,5 an electron-deficient tris(pentafluorophenyl)-
phosphine might be helpful for the increase of the electrophilicity of an
arylpalladium intermediate.
16. For the palladium-catalyzed oxidative arylation of indoles, see: (a) Stuart, D. R.;
Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072–12073; (b) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172–1175; (c) Potavathri, S.; Pereira, K. C.;