A facile synthesis of 2-(N-alkylamino)-pyrimidin-4-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.02.141

Substituted 2-(N-alkylamino)-pyrimidin-4-ones were synthesized from N-alkyl β-amino acid esters starting with guanidinylation using Pbf-activated thiourea. The six-membered pyrimidinones were obtained in good yields via intramolecular cyclization during T

Full text of DOI:10.1016/j.tetlet.2008.02.141

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2761–2763
A facile synthesis of 2-(N-alkylamino)-pyrimidin-4-one derivatives
a,
a
a
b
*
Jizhen Li , Jingping Kou , Xuyang Luo , Erkang Fan
a College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, PR China
b Biomolecular Structure Center, Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
Received 6 October 2007; revised 21 February 2008; accepted 26 February 2008
Available online 29 February 2008
Abstract
Substituted 2-(N-alkylamino)-pyrimidin-4-ones were synthesized from N-alkyl b-amino acid esters starting with guanidinylation
using Pbf-activated thiourea. The six-membered pyrimidinones were obtained in good yields via intramolecular cyclization during
TFA cleavage of the Pbf protecting group.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2-(N-Alkylamino)-pyrimidin-4-ones; Heterocycles
The biologically important guanidine moiety has been
incorporated into many drugs or drug candidates covering
a variety of therapeutic areas. Reported examples include
guanidine-containing cardiovascular antihistaminic, anti-
inflammatory, antidiabetic and antibacterial drugs.1 For
this widespread utility, we became interested in the synthe-
sis of six-membered dihydropyrimidines containing guan-
idine skeletons.2 Furthermore, this class of compounds
has been demonstrated to have a selectivity for the sodium
channel in the muscle membrane similar to that from
tetrodotoxin or saxitoxin3 and also are important interme-
diates in the catabolism and anabolism of pyrimidines.4
Presently, there are few reports on the synthetic method
of substituted 2-(N-alkylamino)-pyrimidin-4-ones. Among
several reported methodologies,5 the protocol reported by
Kim’s group involved the reactions of substituted guan-
idines with a,b-unsaturated ketones and methyl acrylate,
respectively.6 However, the requirement of strong base
for deprotonation of the guanidine moiety may limit the
application of this route. We present here an alternative
synthetic methodology for the substituted 2-(N-alkyl-
amino)-pyrimidin-4-ones from b-amino acid under mild
conditions.
We have previously developed protocols for the synthe-
sis of N,N0-substituted guanidines based on Pbf-activated
thiourea (Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-
sulfonyl), and utilized this protocol for the synthesis of
five-membered 1,5-substituted 2-(N-alkylamino)-imidazol-
idin-4-ones from a-amino acid.7 A pivotal step in the
synthesis of the imidazolidinone derivatives is the intra-
molecular cyclization while the Pbf group is cleaved by
TFA. We sought to extend this intramolecular cyclization
strategy for the synthesis of six-membered pyrimidinones.
In our design, Pbf-activated thioureas bearing substitutions
as shown in Figure 1 are reacted with N-alkylated b-amino
acid esters as shown in Figure 2 to form the intermediate
guanidines 3. Subsequently, the guanidine intermediates 3
are deprotected with TFA to generate pyrimidin-4-ones
as shown in Scheme 1.
Thioureas 1a–c containing the Pbf group were prepared
directly from Pbf-isothiocyanate with the corresponding
S
S
S
Pbf
Pbf
Pbf
N
N
N
N
N
N
H
H
H
H
H
H
1a
1c
1b
*
Corresponding author. Tel.: +86 431 85336227.
Fig. 1. Pbf-activated thioureas.
E-mail address: ljz@jlu.edu.cn (J. Li).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.141

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J. Li et al. / Tetrahedron Letters 49 (2008) 2761–2763
idine intermediates 3a–m. All intermediates 3a–m are white
H
N
H
N
solids isolated through column chromatography eluted
with ethyl acetate and petroleum ether. The sterically bulky
N-alkyl group such as isobutyl seemed to give lower but
still reasonable isolated yields (Table 1, entries 1 and 6)
than the benzyl or n-butyl counter parts.
CO2Et
CO2Et
2a
2b
2d
H
N
H
N
CO2Me
CO2Me
The target 1- or 1,5-alkyl 2-(N-alkylamino)-pyrimidin-4-
ones 4 were easily obtained with high yields when com-
pounds 3 were treated with 95% aqueous TFA solution
at room temperature to remove Pbf and promote cycli-
zation (Scheme 1).11 The formation of the crude products
4 were monitored by TLC on silica gel eluting with ethanol
and ethyl acetate. It was necessary to add Et3N to the crude
compound after the last reaction step and evaporated most
part of solvent before purification. All compounds were
obtained after chromatographic purification as white solid,
and confirmed by 1H NMR and electrospray MS. Yields of
the purified products were high (72–94%, Table 1). The
ester group of ethyl or methyl had little influence on reac-
tion yield, and so did other substituted groups in this key
intramolecular cyclization step. Moreover, no racemization
occurred in the reactions of guanidinylation and intra-
molecular cyclization during TFA cleavage of the Pbf
protecting group.12
In conclusion, we have demonstrated an efficient route
to 1- or 1,5-alkyl-2-(N-alkylamino)-pyrimidin-4-ones via
guanidine intermediates with high yields. Compared to
other methods reported in the literature, our procedure
allows for a mild guanidinylation and cyclization towards
the products with the preservation of stereochemistry.
Secondly, b-amino acid bearing various functional groups
are easily obtained as starting materials from commercial
2c
H
N
H
N
CO2Me
CO2Et
2e
(R)-(+)-2f
Fig. 2. N-Alkylated b-amino acid esters.
alkylamine and aniline when stirred in dichloromethane.8
Methyl or ethyl esters of b-amino acid (3-aminopropanoic
acid) and branched b-amino acid (2-methyl 3-aminopro-
panoic acid) that are commercially available were selected
as starting materials. In order to assess the preservation
of chirality during the reaction, we also prepared optically
pure (R)-(+)-2-phenyl 3-aminopropanoic acid based on the
literature report9 in 75% ee. This non-racemic sample
subsequently gave us the corresponding ethyl ester. These
b-amino acid esters were reacted with benzaldehyde, isobu-
tylaldehyde or n-butylaldehyde under NaBH3CN condition
to produce N-alkylated b-amino acid esters 2a–f through
the classic N-alkylation reaction.10 At room temperature,
substituted thioureas 1a–c were treated with N-alkylated
b-amino acid esters 2a–f in THF/DMF mixed solvent
followed by the Mukaiyama reagent to produce the guan-
O
R3
S
HN R1
R3
Pbf
N
N
Mukaiyama reagent
CO2Me ( Et )
TFA/H2O
CO2Me ( Et )
H
R3
+
R1
Pbf
N
R1
N
N
H
R2
DMF/THF
N
N
N
H
R2
H
R2
1a-1c
2a-2f
3a-3m
4a-4m
Scheme 1. Strategy for the synthesis of substituted 2-(N-alkylamino)-pyrimidin-4-ones.
Table 1
Summary of the reaction compounds and yields obtained in the synthesis of substituted 2-(N-alkylamino)-pyrimidin-4-ones referred to Scheme 1
Entry
R1
R2
R3
Compound 3
Isolated yield (%)
Product 4
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
Ph
i-Bu
PhCH2
n-Bu
n-Bu
PhCH2
i-Bu
PhCH2
n-Bu
n-Bu
PhCH2
PhCH2
n-Bu
H
H
H
CH3
CH3
H
H
H
CH3
CH3
H
CH3
Ph
3a
3b
64
94
88
95
71
71
92
89
80
80
82
85
80
4a
4b
93
86
92
91
84
94
72
72
80
85
86
88
80
3c
3d
4c
4d
3e
4e
3f
3g
4f
4g
3h
3i
4h
4i
3j
3k
4j
4k
Ph
Ph
3l
4l
PhCH2
(R)-(+)-3m
(R)-(+)-4m

J. Li et al. / Tetrahedron Letters 49 (2008) 2761–2763
2763
7. (a) Li, J. Z.; Zhang, Z. F.; Fan, E. Tetrahedron Lett. 2004, 45, 1267–
1269; (b) Li, J. Z.; Zhang, G. T.; Zhang, Z. S.; Fan, E. J. Org. Chem.
2003, 68, 1611–1614.
8. (a) Zhang, Z. S.; Pickens, J. C.; Fan, E. Org. Lett. 2004, 6, 1377–1380;
(b) Flemer, S.; Madalengoitia, J. S. Synthesis 2007, 12, 1848–1860.
9. (a) PonSinet, R.; Chassaing, G.; Lavielle, S. Tetrahedron: Asymmetry
1998, 9, 865–871; (b) Bower, J. F.; Williams, J. M. J. Synlett 1996,
685–686.
sources in comparison to a,b-unsaturated ketones or
methyl acrylate. Furthermore, substituted group variations
can be introduced directly to b-amino acid through N-
alkylation reaction, and the existence of N-substituted
group from reductive amination may enhance the intra-
molecular cyclization process. This synthetic methodology
is in principle suitable for large scale synthesis.
10. (a) Thompson, C. M.; Frick, J. A.; Green, D. L. C. J. Org. Chem.
1990, 55, 111–116; (b) Santagada, V.; Frecentese, F.; Perissutti, E. J.
Comb. Chem. 2005, 7, 618–621.
Acknowledgements
11. A representative procedure is given here. For compound 3b, the
corresponding N-alkylated b-amino acid ester 2b (1.25 mmol) was
added to thiourea 1a (0.5 mmol) dissolved in a solution mixture of
DMF/THF (1:4 2.5 mL) followed by the Mukaiyama reagent
(1.25 mmol), and the reaction mixture was stirred for 2 h at room
temperature. Solvent was removed under vacuum and then 10 mL
water was added. The residue was extracted with DCM (20 mL ꢀ 2).
Then the combined organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica (300–400 mesh, EtOAc/petroleum ether) to
give white solid 3b in 94% yield. 1H NMR (CDCl3, 300 MHz). d
(ppm): 7.29–7.27 (m, 3H), 7.18–7.16 (m, 2H), 6.80 (s, 1H), 4.47 (s,
2H), 4.09 (t, J = 7.2 Hz, 2H), 3.47 (t, J = 6.9, 2H), 3.17 (m, 2H), 2.95
(s, 2H), 2.57 (s, 3H), 2.54 (t, J = 6.9, 2H), 2.51 (s, 3H), 2.08 (s, 3H),
0.90 (t, J = 7.35, 3H). 13C NMR (CDCl3, 75 MHz). d (ppm): 171.81,
160.06, 158.65, 138.40, 136.57, 132.36, 128.73, 127.63, 127.35, 124.50,
117.40, 86.34, 60.76, 53.19, 45.99, 44.34, 43.19, 32.33, 28.54, 19.87,
19.25, 18.04, 14.12, 13.65, 12.38.
This work is supported by the Scientific Research foun-
dation for the Returned Overseas Chinese Scholars, State
Education Ministry, PR China.
References and notes
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For compound 4b, compound 3b (0.35 mmol) was added into a
mixture of TFA/H2O (95:5 2 mL), and stirred for 24 h at room
temperature, the solvent was removed under vacuum and then Et3N
was dropped into the residue until pH 8–9 checked by pH paper, and
the crude product was purified by column chromatography on silica
gel (300–400 mesh EtOAc/EtOH) to give white solid 4b in 86% yield.
ESI-MS (m/z) 260.2 ([M+H]+). 1H NMR (CDCl3, 300 MHz). d
(ppm): 7.44–7.42 (m, 3H), 7.25–7.23 (m, 2H), 4.52 (s, 2H), 3.61 (t,
J = 6.9 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 6.9 Hz, 2H),
1.42 (m, 2H), 1.19 (m, 2H), 0.85 (t, J = 7.2, 3H). 13C NMR (CDCl3,
75 MHz). d (ppm): 176.82, 158.87, 134.94, 129.35, 128.31, 126.24,
109.72, 53.68, 47.64, 41.47, 31.70, 31.58, 19.74, 13.66.
12. Following the literature reported route (Ref. 9a), N-Boc protected
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20
(R)-(+)-2-phenyl-3-aminopropanoic acid was obtained with ½aꢁD
20
+66.4 (c 0.247, CHCl3), which has 75% ee based on Ref. 9b (½aꢁD
+88 (c 1.25, CHCl3)). Using this non-racemic sample, (R)-(+)-2f was
20
subsequently obtained with ½aꢁD +60.2 (c 0.166, CHCl3); (R)-(+)-3m:
20
20
½aꢁD +50.0 (c 0.204, CHCl3); and (R)-(+)-4m: ½aꢁD +58.2 (c 0.175,
CHCl3). This clearly indicates that no significant racemization
occurred during the transformation from 2f to 4m.