Chemoselective reduction of pyrimidines. An access to enantiopure tetrahydropyrimidinones

Article abstract of DOI:10.1016/S0040-4039(01)01875-5

A synthesis of substituted 1,3-tetrahydropyrimidinones 8 starting from homochiral synthon 2 is described. Chemoselective reduction of pyrimidines 4 using BH₃·THF provides an access to regioselective N-protected tetrahydropyrimidinones 8.

Full text of DOI:10.1016/S0040-4039(01)01875-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8629–8631
Chemoselective reduction of pyrimidines. An access to
enantiopure tetrahydropyrimidinones
Claude Agami, Luc Dechoux* and Mohand Melaimi
Laboratoire de Synthe`se Asyme´trique (UMR 7611), Universite´ Pierre et Marie Curie, 4 place Jussieu, case 47,
F-75005 Paris, France
Received 3 October 2001; accepted 8 October 2001
Abstract—A synthesis of substituted 1,3-tetrahydropyrimidinones 8 starting from homochiral synthon 2 is described. Chemoselec-
tive reduction of pyrimidines 4 using BH3·THF provides an access to regioselective N-protected tetrahydropyrimidinones 8.
© 2001 Elsevier Science Ltd. All rights reserved.
nones was the subject of but a few studies: LiAlH4
reductions of two pyrimidines analogous to compounds
4 were reported8 and the yields were really unsatisfac-
tory in both cases.
In the course of our studies concerning the enantiose-
lective synthesis of a,b-substituted b-amino acids 5 we
made use of a new chiral synthon 2.1 Conjugate addi-
tions of different organocuprate reagents to this chiral
Michael acceptor occurred with complete diastereose-
lectivity and afforded compounds 3, which furnished
products 4 in good yields after hydrogenolysis2 of the
labile homobenzylic CꢀO bond3 (Scheme 1).
In order to synthesize enantiopure tetrahydropyrimidi-
nones 8, pyrimidines 4 were reduced with an excess of
LiAlH4 in THF or diethylether. In these conditions,
pyrimidine 4c afforded 4-hydroxypyrimidinone 12c
(46% yield): only traces of the expected compound 8c
was observed in the NMR spectrum of the crude mate-
rial (Scheme 3). Moreover, the reduction of pyrimidines
4c with DIBAL-H gave rise to compound 12c in 43%
yield (Scheme 3). It is noteworthy that N-substituted
hydantoins have already been shown to undergo similar
LiAlH4 reductions to give 4-hydroxy-2-imidazolidi-
nones in good yields.9
Herein, we wish to report a new entry to enantiopure
N-protected tetrahydropyrimidinones 8 starting from
homochiral template 2. Tetrahydropyrimidinones 7,
which formally would lead to 1,3-diamines 6, are poten-
tial anti-HIV agents4 (Scheme 2). The synthesis of such
1,3-diamines has attracted some attention in recent
years.5 Although less described than their 1,2-ana-
logues, which play an important role as chiral auxil-
iaries and catalysts in asymmetric synthesis,6 they are of
interest in medicinal chemistry (i.e. in cancer research).7
O
R2
HN
R1
NH
H2N
NH2
R1
This paper presents our results concerning the chemose-
lective reduction of pyrimidines 4 and describes the
synthesis of homochiral tetrahydropyrimidinones 8.
The reduction of pyrimidines into tetrahydropyrimidi-
R2
6
7
Scheme 2.
R2
O
O
N
O
OH
Ph
Ph
H2 / Pd
H2N
Ph
N
N
NH
N
N
CO2H
Ph
R1
NH2
R1
O
R1
O
O
24
2
2 3
1
R
R
5
Scheme 1.
Keywords: 1,3-diamines; tetrahydropyrimidinones; chemoselective reduction; pyrimidines.
* Corresponding author. E-mail: dechoux@ccr.jussieu.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01875-5

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C. Agami et al. / Tetrahedron Letters 42 (2001) 8629–8631
1) LiAlH4 or DIBAL-H (5eq.)/ THF
O
O
2) Aqueous solution of tartaric
sodium potassium salt
Ph
N
NH
OH
Ph
N
NH
O
Me
Me
12c
4c
Scheme 3.
In conclusion, it was found that BH3·THF reduces
chemoselectively pyrimidines into tetrahydro-
pyrimidinones 8. The homochiral template 2 affords an
easy access to enantiopure mono- and disubstituted
tetrahydropyrimidinones 8 in three or four steps,
respectively.
In order for the expected reaction to succeed another
reducing agent was used. Reduction with BH3·THF
afforded the tetrahydropyrimidinones 8 in good yields.
The results are presented in Table 1.
4
All reactions were performed with an excess of
BH3·THF (5 equiv.). Tetrahydropyrimidinones 8 were
obtained in good yields by chemoselective reduction of
the carbonyl on C-4 using BH3·THF at room tempera-
ture. Compound 8a was also obtained in good yield by
using 1.2 equiv. of BH3·THF in the same experimental
conditions. No epimerization could be detected when
the reaction was applied to substrates 4d and 4e bearing
a stereogenic center a to the carbonyl function. When
the reaction was conducted at reflux with the same
reducing agent, pyrimidine 4b led to the N-methylated
diamine 9 (Scheme 4). It is noteworthy that in this case,
the carbonꢀnitrogen bond was selectively cleaved and
no 1,3-diazepine 10 could be obtained (Scheme 4) as
observed in the reduction of cyclic ureas with LiAlH4.10
The introduction of a third substituent by diastereose-
lective alkylation of a-hydroxypyrimidinones 12, which
are masked acyliminium ions, is currently underway.
Experimental procedure for the preparation of tetra-
hydropyrimidinones 8
A typical experimental procedure is provided for the
synthesis of tetrahydropyrimidinone 8b. To a solution
of pyrimidine 4b (160 mg, 0.58 mmol) in THF (10 mL)
was added dropwise, at room temperature, a solution
of BH3·THF (2.9 mL of a 1 M solution in THF). The
reaction mixture was stirred for 4 h and then quenched
with a saturated solution of ammonium chloride. The
resulting mixture was extracted with dichloromethane
(3×20 mL). The combined organic phases were then
dried over magnesium sulfate. After filtration and con-
centration under vacuum, chromatography on silica gel
(EtOAc/MeOH 95/5) afforded 92 mg (61%) of com-
pound 8b.
The regioselectivity of formation of the N-methylated
products 9 was determined by converting the 1,3-
diamines 9 into the N-methylated dihydropyrimidinone
11, using triphosgene in basic medium (Scheme 4).
Compound 11 was correlated with the product arising
from N-methylation of tetrahydropyrimidinone 4b.
In order to synthesize 1,3-diamine 13, pyrimidinones 8b
was submitted to hydrolysis under basic conditions
(NaOH, reflux), but these conditions leave the starting
material unreacted. In contrast acidic hydrolysis pro-
vides debenzylated tetrahydropyrimidinone 7b (Scheme
5).11
[h]2D0=+84 (c 0.38, CHCl3); 1H NMR (CDCl3, 250
MHz): l 0.58 (t, 3H, J=6 Hz), 0.87 (m, 4H), 1.11 (m,
2H), 1.43 (d, 3H, J=7 Hz), 1.58 (m, 1H), 1.72 (m, 1H),
3.21 (m, 3H), 4.98 (sl, 1H, NH), 5.68 (q, 1H, J=7 Hz),
7.22 (m, 5H); 13C NMR (CDCl3, 62.5 MHz): l 13.8,
16.1, 22.1, 24.2, 28.1, 31.2, 36.6, 49.8, 52.0, 127.3, 128.2,
141.5, 155.8.
Table 1. Chemoselective reduction of pyrimidines 4
Experimental procedure for the preparation of 4-hydroxy-
dihydropyrimidinones 12c
O
O
1) BH3.THF (5eq.) / THF / RT
2) aqueous NH4Cl
Ph
N
NH
Ph
N
NH
To a solution of pyrimidine 4c (120 mg, 0.517 mmol) in
THF (5 mL) was added dropwise, at room temperature,
a solution of DIBAL-H (2.58 mL of a 1 M solution in
hexanes). The reaction mixture was stirred for 4 h and
then quenched with an aqueous solution of tartaric acid
sodium potassium salt and further stirred for 1 h. The
resulting mixture was extracted with dichloromethane
(3×20 mL). The combined organic phases were then
dried over magnesium sulfate. After filtration and con-
centration under vacuum, chromatography on silica gel
(CH2Cl2/MeOH 95/5) afforded 52 mg (43%) of com-
pound 12c.
R1
R1
O
R2
R2
4
8
Entry
Substrate
R1
R2
Product
Yield (%)
1
2
3
4
5
4a
4b
4c
4d
4e
H
H
H
H
Me
Me
8a
8b
8c
8d
8e
87
61
69
76
64
n-Bu
Me
Me
H

C. Agami et al. / Tetrahedron Letters 42 (2001) 8629–8631
8631
O
(CCl3O)2CO,
O
BH3.THF (15eq.),
THF/reflux
74%
Me
Me
O
NaOH, CH2Cl2
Ph
n-Bu
78%
Ph
n-Bu
N
N
Ph
n-Bu
NH HN
N
NH
96%
O
11
1) NaH/THF
2) MeI
4b
9
O
BH3.THF, reflux
Ph
n-Bu
Ph
n-Bu
N
NH
N
NH
O
10
4b
Scheme 4.
Scheme 5.
O
O
H2SO4 / reflux
NaOH / reflux
Ph
n-Bu
Ph
n-Bu
HN
n-Bu
NH
NH NH2
N
NH
100%
7b
8b
13
1H NMR (CDCl3, 250 MHz): l 0.78 (d, 3H, J=6.75
Hz), 1.44 (d, 3H, J=7 Hz), 1.81 (m, 2H), 3.52 (m, 1H),
4.62 (ls, 1H, NH), 5.23 (m, 1H), 5.65 (q, 1H, J=7 Hz),
6.51 (ls, 1H, OH), 7.30 (m, 5H); 13C NMR (CDCl3,
62.5 MHz): l 16.4, 20.5, 35.1, 45.6, 52.0, 73.9, 127.2,
127.7, 128.1, 141.2, 154.6.
135–152; (c) De Lucca, G. V. J. Org. Chem. 1998, 63,
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