2-Substituted-5-halo-2,3-dihydro-4(H)-pyrimidin-4-ones
SCHEME 1. Enantioselective Synthesis of â-Amino Acids
via Chiral Pyrimidinones
FIGURE 1. Structural similarity between haloenones 3 and biologically
relevant 5-halouracils.
Treatment of perhydropyrimidinone-6-carboxylic acids 1a-c
with DIB (2 equiv) and iodine (1 equiv) in CH2Cl2 during 4.5
h afforded a mixture of the expected5 enones 4 and iodoenones
3 (cf. Scheme 2). We were pleased to find that addition of BF3‚
Et2O (2 equiv) to the resulting reaction mixture resulted in the
fast conversion of the enone into the corresponding iodoenone,
which becomes the sole reaction product (Scheme 3).
Because acetic acid is formed in the reaction medium upon
reduction of DIB, it is likely that acetic acid reacts with the
DIB/I2 reagent to produce acetyl hypoiodite,11 which is activated
by BF3 to liberate iodonium ion (Scheme 4a). Finally, iodonium
ion adds to enones 4 to give, after â-elimination of a proton,
the desired iodoenones 3 (Scheme 4b).
SCHEME 2. Preparation of Enone (S)-4a
In addition, bromoenones 5a-c were prepared from enones
4a-c by bromination with pyridine perbromide hydrobromide
(Pyr‚HBr‚Br2)12 (Scheme 5). The mechanism for the bromina-
tion reaction is anticipated to be similar to that presented in the
iodination reaction (cf. Scheme 4b), with bromonium, Br+,
instead of iodonium ion.
Crystals of (S)-5b were obtained by recrystallization from
CH2Cl2 and ethyl acetate, and the crystal structure was
determined by X-ray diffraction crystallography (Figure 2,
Supporting Information).
For the preparation of bromoenones 5a-c (Scheme 5),
starting enones 4a-c were prepared in good yields following
our recently reported decarboxylation/â-iodination/hydrodeio-
dination tandem protocol (1a-c f 4a-c, cf. Scheme 2b).6 A
single crystal of 1-benzoyl-2(S)-phenyl-2,3-dihydro-4(H)-pyri-
midin-4-one, (S)-4c, could be obtained, and Figure 3 (Supporting
Information) shows its molecular structure.
antiviral activity (Figure 1),7 we sought to develop reaction
conditions for the decarboxylation/â-iodination of (2S,6S)-1a
to provide (S)-3a as the single product.
The structural similarity of haloenones 3 and 5-halouracils
(Figure 1) suggested that they should present the same chemical
reactivity. For example, there are successful reports of the
application of Sonogashira couplings to substitute the halogen
in 5-halouracils.8 Thus, compounds (S)-3 presented themselves
as interesting substrates for this kind of coupling. Furthermore,
the expected products could prove to be suitable precursors to
enantiomerically pure â-amino acids.9
(9) For monographs, see: (a) Juaristi, E., Ed. EnantioselectiVe Synthesis
of â-Amino Acids; Wiley: New York, 1997. (b) Juaristi, E.; Soloshonok,
V. Second Edition of EnantioselectiVe Synthesis of â-Amino Acids; Wiley:
New York, 2005. For additional review articles, see: (c) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3-11. (d) Cole, D.
C. Tetrahedron 1994, 50, 9517-9582. (e) Cardillo, G.; Tomasini, C. Chem.
Soc. ReV. 1996, 25, 117-128. (f) Juaristi, E.; Lo´pez-Ruiz, H. Curr. Med.
Chem. 1999, 6, 983-1004. (g) Abele, S.; Seebach, D. Eur. J. Org. Chem.
2000, 1-15. (h) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
(i) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603-1623. (j) Ma, J.-A.
Angew. Chem., Int. Ed. 2003, 42, 4290-4299. (k) Sewald, N. Angew. Chem.,
Int. Ed. 2003, 42, 5794-5795. (l) Palko, M.; Lorand, K.; Fu¨lo¨p, F. Curr.
Med. Chem. 2005, 12, 3063-3083. (m) Garrido, N. M.; Diez, D.;
Dom´ınguez, S. H.; Garc´ıa, M.; Sa´nchez, M. R.; Davies, S. G. Tetrahe-
dron: Asymmetry 2006, 17, 2183-2186.
(10) (a) Juaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992, 3, 723-
726. (b) Juaristi, E. Handbook of Reagents for Organic Synthesis. Chiral
Reagents for Asymmetric Synthesis; Paquette, L. A., Ed.; Wiley: Chichester,
2003; pp 53-56. (c) Hopkins, S. A.; Ritsema, T. A.; Konopelski, J. P. J.
Org. Chem. 1999, 64, 7885-7889.
(11) (a) Concepcio´n, J. I.; Francisco, C. G.; Freire, R.; Herna´ndez, R.;
Salazar, J. A.; Sua´rez, E. J. Org. Chem. 1986, 51, 402-404. (b) de Armas,
P.; Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.; Salazar, J. A.; Sua´rez,
E. J. Chem. Soc., Perkin Trans. 1 1989, 405-411.
Results and Discussion
Diastereomerically pure perhydropyrimidinone-6-carboxylic
acids 1a-c were prepared by condensation of (S)-asparagine
with pivalaldehyde, isobutyraldehyde, or benzaldehyde, respec-
tively, followed by in situ N-benzoylation3a,10 (Scheme 3).
(6) Iglesias-Arteaga, M. A.; Castellanos, E.; Juaristi, E. Tetrahedron:
Asymmetry 2003, 14, 577-580.
(7) (a) Shealy, Y. F.; O’Dell, C. A.; Shannon, W. M.; Arnett, G. J. Med.
Chem. 1983, 26, 156-161. (b) Howell, H. G.; Brodfuehrer, P. R.;
Brundidge, S. P.; Benigni, D. A.; Sapino, C. J. Org. Chem. 1988, 53, 85-
88. (c) Beauchamp, L. M.; Serling, B. L.; Kelsey, J. E.; Biron, K. K.; Collins,
P.; Selway, J.; Lin, J-C.; Schaeffer, H. J. J. Med. Chem. 1988, 31, 144-
149.
(8) (a) Tanaka, H.; Haraguchi, K.; Koizumi, Y.; Fukui, M.; Miyasaka,
T. Can. J. Chem. 1986, 64, 1560-1563. (b) Hobbs, F.W. J. Org. Chem.
1989, 54, 3420-3422. (c) Robins, M. J.; Barr, P. J. Tetrahedron Lett. 1981,
22, 421-424. (d) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854-
1862. (e) Hudson, R. H. E.; Li, G.; Tse, J. Tetrahedron Lett. 2002, 43,
1381-1386.
(12) (a) Fieser, M.; Fieser, L. Reagents for Organic Synthesis; Wiley:
New York, 1967; p 967. (b) Barili, P. L.; Bellucci, G.; Marioni, F.; Morelli,
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