An efficient synthesis of pyrimidines from beta-amino alcohols.

Article abstract of DOI:10.1021/ol991385x

[reaction: see text] Pyrimidinones 3 were chemoselectively reduced by using metal-catalyzed hydrogenation and stereoselectively substituted by various nucleophiles. Starting from beta-amino alcohols 1, the overall process allows efficient access to substi

Full text of DOI:10.1021/ol991385x

ORGANIC
LETTERS
2000
Vol. 2, No. 5
633-634
An Efficient Synthesis of Pyrimidines
from â-Amino Alcohols
Claude Agami, Luc Dechoux,* and Mohand Melaimi
Laboratoire de Synthe`se Asyme´trique (UMR 7611), UniVersite´ P. et M. Curie,
4 place Jussieu, 75005 Paris, France
dechoux@ccr.jussieu.fr
Received December 22, 1999
ABSTRACT
Pyrimidinones 3 were chemoselectively reduced by using metal-catalyzed hydrogenation and stereoselectively substituted by various nucleophiles.
Starting from â-amino alcohols 1, the overall process allows efficient access to substituted pyrimidines 4 and 6.
The emergence of Acyclovir1 as a successful antiviral agent
has stimulated the synthesis of a wide variety of acyclic
nucleosides.2 However, no structure-activity relationship has
been reported so far for this new potential antiviral agent.
Therefore, new pyrimidine acyclonucleosides are of great
interest.
this reaction afforded either pyrimidines 4 or dihydropyri-
midines 5 (Scheme 2). Results are collected in Table 1.
Scheme 2
We present here an efficient access to acyclonucleosides
4 and 6 starting from â-amino alcohols 1 in three high-
yielding steps. Reaction of the â-amino alcohol with cyano-
gen bromide followed by condensation of the resulting
heterocycle 2 with ethyl propiolate or ethyl butynoate led to
pyrimidinones 3 (Scheme 1).3
Scheme 1
Palladium- and rhodium-mediated catalysis was investi-
gated in order to cleave the oxazolidine C-O bond. When
rhodium was used (entries 7 and 8), hydrogenation affected
only the ethylenic double bond, affording compound 5, thus
leaving the C-O bond untouched. On the other hand,
palladium catalysis4 was satisfactory except in the case of
We first studied catalytic hydrogenation of substituted
pyrimidinones 3 according to the experimental conditions;
(1) Shaeffer, H. J.; Beauchamp, L.; De Miranda, P.; Elion, G. B.; Bauer,
D. J.; Collins, P. Nature 1978, 272, 583.
(3) (a) Agami, C.; Cheramy, S.; Dechoux, L.; Kadouri-Puchot, C. Synlett
1999, 727. (b) Agami, C.; Cheramy, S.; Dechoux, L. Synlett 1999, 1838.
Selected data for compound 3a: 1H NMR (250 MHz, CDCl3) 4.49 (dd, J
) 7.8 and 9.2 Hz, 1H), 5.01 (t, J ) 9.2 Hz, 1H), 5.23 (dd, J ) 7.8 and 9.2
Hz, 1H), 5.95 (d, J ) 7.5 Hz, 1H), 6.90 (d, J ) 7.5 Hz, 1H), 7.23-7.31
(m, 5H); 13C NMR (63 MHz, CDCl3) 61.9, 73.9, 109.8, 127.1, 129.7, 130.1,
135.1, 135.8, 160.9, 172.0; mp 186 °C.
(2) (a) Campos, J.; Pineda, M. J.; Gomez, J. A.; Entrena, A.; Trujillo,
M. A.; Gallo, M. A.; Espinosa, A. Tetrahedron 1996, 52, 8907. (b) Gomez,
J. A.; Campos, J.; Marchal, J. A.; Trujillo, M. A.; Melguizo, C.; Prados, J.;
Gallo, M. A.; Aranega, A.; Espinosa, A. Tetrahedron 1997, 53, 7319. (c)
Chu, C. K.; Cutler, S. J. Heterocycl. Chem. 1986, 23, 289. (d) Hossain, N.;
Rozenski, J.; De Clercq, E.; Herdewijn, P. Tetrahedron 1996, 52, 13655.
10.1021/ol991385x CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/05/2000

Table 1. Chemoselective Reductions of Pyrimidinones 3
Table 2. Regioselective Reactions of Pyrimidinones 3
entry
substrate
catalyst
yield (%)
ratio 4/5
entry substrate
R1
R2
R3
conditions
Nu
Cl
OMe
OH
I
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3d
3a
3e
Pd/C
70
91
84
95
95
65
74
78
>95/5
>95/5
>95/5
>95/5
>95/5
<5/95
<5/95
<5/95
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3e
3f
3f
3f
Ph
Ph
Ph
Ph
Ph
Ph
Me Ph
Me Ph
Me Ph
H
H
H
H
H
H
H
H
H
H
H
TMSCl/THF
MeOH/PTSA
H2O/THF/PTSA
TMSI/THF
Pd/BaSO4
Pd (OH)2
Pd/BaSO4
Pd/BaSO4
Pd/BaSO4
Rh, Al2O3
Rh, Al2O3
PhSH/THF/PTSA PhS
Me TMSCl/THF
Cl
Cl
OH
OMe
H
H
H
TMSCl/THF
H2O/THF/PTSA
MeOH/PTSA
substrates 3d and 3e. Substrate 3d was stable unless the
experimental conditions are forced:5 in that case the ethylenic
bond was hydrogenated (entry 6). This result indicates that
a methylene group R to the oxazolidine C-O bond is
necessary to achieve the formation of pyrimidines 4. Pal-
ladium catalysis applied to substrate 3e resulted in hydro-
genolysis of the benzylic carbon-nitrogen bond.
Perusal of the literature showed that 2,2′-anhydronucleo-
sides can be substituted with nucleophiles such as azide
anion6 and halides.7 To obtain functionalized pyrimidines
6, we investigated the reactivity of compounds 3 with such
nucleophiles in acidic conditions (Scheme 3). To this aim,
whose substitution with three nucleophiles (entries 7-9)
afforded only one diastereoisomer. In contrast, trimethylsilyl
azide and cyanide were ineffective in these experimental
conditions, even in the presence of added fluoride ion.
In summary, a concise and practical synthesis of pyrim-
idines 4 and 6 has been developed starting from â-amino
alcohols. This procedure has a wide scope and should allow
for the synthesis of a large variety of acyclonucleosides
which are potential antiviral and antitumoral agents.
OL991385X
(4) . General procedure for the hydrogenolysis on palladium. Pd/
BaSO4 (100 mg) was added, at room temperature, to a solution of compound
3a (0.47 mmol) in MeOH (10 mL) under an atmosphere of hydrogen. The
reaction mixture was stirred at room temperature for 4 h. The suspension
was then filtered on Celite and methanol was evaporated. The residue was
chromatographed on silica gel (AcOEt/MeOH 98/2) to afford compound
4a (91 mg). Selected data for 4a: 1H NMR (250 MHz, CDCl3) 1.63 (d, J
) 7.1 Hz, 3H), 5.58 (d, J ) 8.0 Hz, 1H), 5.91 (q, J ) 7.1 Hz, 1H), 6.94
(d, J ) 8.0 Hz, 1H), 7.26 (m, 5H); 13C NMR (63 MHz, CDCl3): 18.4,
53.3, 102.7, 127.2, 128.5, 129.1, 138.6, 141.1, 151.2, 163.0
Scheme 3
(5) Reaction was performed with Pd/BaSO4 (5 equiv) over 2 days.
(6) Costa, A. M.; Faja, M.; Farras, J.; Vilarrasa, J. Tetrahedron Lett.
1998, 39, 1835.
(7) (a) Mercer, J. R.; Knaus, E. E.; Wiebe, L. I. J. Med. Chem. 1987,
30, 670. (b) Kumar, A.; Walker, R. T. Tetrahedron 1990, 46, 3101.
(8) General procedure for the substitution of 3a by trimethylsilyl
halides. To a solution of 3a (100 mg, 0.47 mmol) in 10 mL of THF was
added TMSCl (0.09 mL, 0.70 mmol). The reaction mixture was stirred at
room temperature for 4 h. The reaction was quenched with a saturated
solution of NaHCO3 and extracted twice with 20 mL of dichloromethane.
The organic phase was concentrated at reduced pressure to afford
quantitatively compound 6a (Nu ) Cl). Selected data for 6a (Nu ) Cl):
1H NMR (250 MHz, CDCl3) 4.07 (m, 2H), 5.63 (d, J ) 8.3 Hz, 1H), 5.94
(t, J ) 6.5 Hz, 1H), 7.03 (d, J ) 8.3 Hz, 1H), 7.28 (m, 5H); 13C NMR (63
MHz, CDCl3) 43.2, 59.1, 102.5, 128.6, 129.2, 129.4, 134.7, 141.7, 151.2,
163.1.
H2O, MeOH, thiophenol, and trimethylsilyl halides were
reacted with pyrimidinones 3. Results are presented in Table
2.8
As shown in Table 2, the reaction was effective for all
substrates in nearly quantitative yields (>90%). These
nucleophilic substitutions are chemo- and diastereoselective
as well. The stereoselectivity was proven for substrate 3f,
634
Org. Lett., Vol. 2, No. 5, 2000