PAPER
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid
1117
1H NMR (600 MHz, DMSO-d6): d = 9.65 (s, 1 H), 8.32 (d, J = 5.0
Hz, 1 H), 7.94 (s, 1 H), 7.49 (s, 1 H), 6.88 (s, 1 H), 6.72 (d, J = 5.0
Hz, 1 H), 2.32 (s, 3 H), 2.21 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 168.2, 160.2, 158.1, 142.9,
140.6, 124.8, 122.0, 118.6, 118.5, 113.0, 24.3, 21.6.
(13) Edo, K.; Yamanaka, H.; Sakamoto, T. Heterocycles 1978, 9,
271.
(14) Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem.
1995, 32, 1177.
(15) Schomaker, J. M.; Delia, T. J. J. Heterocyl. Chem. 2000, 37,
1457.
(16) Peng, Z.-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8,
395.
HRMS (EI): m/z calcd for C12H13BrN3: 278.0293; found: 278.0307
(M + H).
(17) Zeng, Z.-S.; Liang, Y.-H.; Feng, X.-Q.; Chen, F.-E.;
Pannecouque, C.; Balzarini, J.; De Clercq, E.
6-Bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-
amine (68)33
ChemMedChem 2010, 5, 837.
To a round-bottomed flask equipped with a large stir bar was added
67 (5 g, 18.1 mmol), 42 (3.32 g, 21.7 mmol), and PivOH (35 mL).
The resulting mixture was heated to an internal temperature of
100 °C and stirred for 1 h. Heating was discontinued, the reaction
mixture cooled to 70 °C, and a mixture of EtOH–hexanes (1:1, 70
mL) was added dropwise over 20 min. The slurry was stirred at r.t.
for 1 h, then filtered, and the resulting cake washed with EtOH–
hexanes (1:1, 35 mL). The dried solid was transferred to a round-
bottomed flask, diluted with 5% MeOH–CH2Cl2 (250 mL) and
treated with sat. aq NaHCO3 (250 mL) and stirred until both layers
were clear. The layers were separated, the aqueous portion extracted
a second time with 5% MeOH–CH2Cl2 (250 mL), and the combined
organics were dried (MgSO4), filtered, and concentrated in vacuo.
The crude residue was purified by flash chromatography to afford
the desired product; yield: 6.25 g (17.9 mmol, 99%); beige solid;
mp 165 °C. Compound 68 showed satisfactory spectroscopic data
in agreement with that reported in the literature.
(18) Bamborough, P.; Angell, R. M.; Bhamra, I.; Brown, D.;
Bull, J.; Christopher, J. A.; Cooper, A. W. J.; Fazal, L. H.;
Giordano, I.; Hind, L.; Patel, V. K.; Ranshaw, L. E.; Sims,
M. J.; Skone, P. A.; Smith, K. J.; Vickerstaff, E.;
Washington, M. Bioorg. Med. Chem. Lett. 2007, 17, 4363.
(19) Waelchi, R.; Bollbuck, B.; Bruns, C.; Buhl, T.; Eder, J.;
Feifel, R.; Hersperger, R.; Janser, P.; Revesz, L.; Zerwes, H.-
G.; Schlapbach, A. Bioorg. Med. Chem. Lett. 2006, 16, 108.
(20) Manley, P. J.; Balitza, A. E.; Bilodeau, M. T.; Coll, K. E.;
Hartman, G. D.; McFall, R. C.; Rickert, K. W.; Rodman, L.
D.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2003, 13, 1673.
(21) 2-Methylthio-4-pyrimidinone may also be readily prepared
from 2-thiouracil: Barrett, H. W.; Goodman, I.; Dittmer, K.
J. Am. Chem. Soc. 1948, 70, 1753.
(22) (a) Spychala, J. Synth. Commun. 1997, 27, 1943. For a
recent report using refluxing BuOH, see: (b) Grigoryan, L.
A.; Kaldrikyan, M. A.; Melik-Ogandzhanyan, R. G.;
Arsenyan, F. G. Pharm. Chem. J. 2011, 45, 137.
(23) Conversion of thioethers into the corresponding sulfone is a
common strategy to increase reactivity of the electrophile,
but used rarely in the context of 2-methylthio-4-pyrimidi-
nones, for example, see: Gibson, C. L.; Huggan, J. K.;
Kennedy, A.; Kiefer, L.; Lee, J. H.; Suckling, C. J.;
Clements, C.; Harvey, A. L.; Hunter, W. N.; Tulloch, L. B.
Org. Biomol. Chem. 2009, 7, 1829.
Supporting Information for this article is available online at
Acknowledgment
The authors would like to thank Bridget Becker and Bruce Adams
for NMR support, and in addition Chuck Ross and Adam Beard for
HRMS analysis.
(24) For example, see example 2, page 15, of: Djung, J. F.-J.;
Golebiowski, A.; Hunter, J. A.; Shrum, G. P. US Patent
Appl. Publ. US 20070293525 A1, 2007; Chem. Abstr. 2008,
148, 79042.
(25) Feng, X.-Q.; Liang, Y.-H.; Zeng, Z.-S.; Chen, F.-E.;
Balzarini, J.; Pannecouque, C.; De Clercq, E.
References
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cited therein.
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ChemMedChem 2009, 4, 219.
(26) Reactions performed on 1 mmol scale in sealed vials.
(27) Three examples have been previously reported in which
AcOH was used as a solvent for SNAr reactions of 2-
methylthio-4-pyrimidinones (see ref. 1).
(28) Pivalic acid (bp 164 °C/760 Torr) offers the additional
advantage of a wider convenient temperature operating
range relative to AcOH (bp 119 °C/760 Torr).
(29) Methanethiol is generated during the course of the reaction;
a nitrogen sweep is recommended especially on large scale
with the outlet bubbled through a bleach scrubber.
(30) Efficient stirring is recommended and should it become
ineffective additional PivOH can be added.
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Patent PCT Int. Appl. WO 2010068257 A1, 2010; Chem.
Abstr. 2010, 153, 87827.
(34) Variable levels of pivalic acid (up to 1 molar equiv) were
observed in the isolated 2-anilinopyrimidinones. This was
not found to be problematic in subsequent halogenation at
the 4- or 5-position.
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Synthesis 2012, 44, 1109–1118