2220
K. Singh, K. Singh / Tetrahedron Letters 50 (2009) 2219–2221
Table 1
Reduction of pyrimidine-2(1H)-ones with Mg/MeOH
R3
N
Mg (5.0 equiv.)/
MeOH
500C, 26-30h
O
R1O
R2
R3
NH
O
R1O
R2
N
O
N
O
R4
R4
Entry
DHPs
R3
Biginelli DHPMs
1
R1
R2
R4
2
R1
R2
R3
R4
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Et
Me
Et
Me
Et
Et
Et
Et
Et
Me
Me
Me
Me
Ph
n-Pr
Me
Me
Me
Me
Me
Ph
Ph
Me
Me
Me
Ph
p-OMePh
Ph
H
H
H
H
H
H
H
Me
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
Et
Me
Et
Me
Et
Et
Et
Et
Et
Me
Me
Me
Me
Ph
n-Pr
Me
Me
Me
Me
Me
Ph
Ph
Me
Me
Me
Ph
p-OMePh
Ph
n-Pentyl
H
H
H
H
H
H
H
H
Me
H
H
H
24
24
26
27
24
26
24
27
30
30
27
75
64
70
69
76
74
70
62
60
62
71
n-Pentyl
H
3,4,5-(OMe)3C6H2
10
11
1j
1k
Et
Et
2j
2k
Et
Et
3,4,5-(OMe)3C6H2
a
Isolated yields.
O
R3
N
O
R3
N
O
R3
NH
O
R3
N
e-
MeOH
R1O
R1O
R1O
R1O
R2
N
O
R2
N
O
R2
N
O
R2
N
OH
R4
1
R4
R4
R4
R3
O
R3
O
R1O
NH MeOH
O
R1O
R2
NH
O
e-
R2
N
N
R4
R4
2
Scheme 1. Reductions with Mg/MeOH.
selective sodium cyanoborohydride12 and other reducing agents
such as borohydride13 and nickel sodium borohydride,14 under a
variety of conditions, unreacted starting DHPs were obtained. It
is interesting to note that magnesium/methanol has been imple-
mented in a number of chemical reductions of functionalities such
on Silica Gel-G (60–120 mesh) with ethyl acetate/hexane (3:7
v/v) as eluents.
Acknowledgements
as
a
,b-unsaturated esters,11a peroxides,11b benzothiadiazoles,11c
,b-conjugated nitriles11e and ketones11f. However,
We thank UGC, New Delhi, for the project (31-53/2005/SR) and
for a fellowship to K.S.
aziridines,11d
a
during the reduction of DHPs, enamine ester as well as uriedo link
remains unaffected, thus rendering the protocol highly chemo-
selective.
Supplementary data
The reduction potential of alkali metals is not sufficiently high
enough to add two electrons to aliphatic carbonyl group.15 Accord-
ing to the generally accepted mechanism,16 protonation of radical
anion gives a carbon radical which through its tautomer is subse-
quently reduced to a carbanion, followed by protonation provides
the DHPM 2 (Scheme 1).
In conclusion, we have demonstrated that Mg/MeOH is an effec-
tive reagent for the highly chemoselective reduction of pyrimidine-
2(1H)-one system.
References for preparation of starting materials; spectral list-
ings and NMR (1H and 13C NMR) spectra for the products are avail-
able. Supplementary data associated with this article can be found,
References and notes
1. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
2. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052; (b) Singh, K.; Arora, D.;
Singh, K.; Singh, S. Mini-Rev. Med. Chem. 2009, 9, 95–106.
3. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;
O’Reilly, B. C. J. Med. Chem. 1991, 34, 806–811.
3. Experimental
4. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.; Gilbert, K.
F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss,
D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J.
D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med.
Chem. 2000, 43, 2703–2718.
To a solution of appropriate pyrimidine-2(1H)-ones (1 mmol)
in MeOH (10 ml) were added freshly scratched Mg turnings
(5 mmol) and a tiny crystal of iodine. The resulting solution
was warmed to 50 °C until the completion of the reaction
(24–30 h). The reaction mixture was poured into cold 0.5 M
HCl and extracted with ethyl acetate. The combined ethyl ace-
tate extracts (3 Â 10 ml) were dried over Na2SO4, filtered and
concentrated. The residue was subjected to chromatography
5. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974.
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Kramer, T.; Niewohner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
Masantschek, R. N. A.; Reimann, A.; Jaeger, R.; Grob, R.; Beckermann, B.;
Schlemmer, K.-H.; Haebich, D.; Rubsamen-Waigmann, H. Science 2003, 299,
893–896.