Highly selective synthesis of 2-substituted-5-hydroxy-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid derivatives using a novel protected dihydroxyfumarate

Article abstract of DOI:10.1016/j.tetlet.2004.06.028

A high yielding (50-96%) route to 2-substituted-5-hydroxy-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid derivatives has been developed using a rationally designed dihydroxyfumarate derivative. The fully unprotected pyrimidinone heterocycle was prepared i

Full text of DOI:10.1016/j.tetlet.2004.06.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6023–6025
Highly selective synthesis of 2-substituted-5-hydroxy-6-oxo-1,6-
dihydropyrimidine-4-carboxylic acid derivatives using a novel
protected dihydroxyfumarateq
Spencer D. Dreher,* Norihiro Ikemoto, Venita Gresham, Jinchu Liu, Peter G. Dormer,
Jaume Balsells, David Mathre, Thomas J. Novak and Joseph D. Armstrong, III
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065-0900, USA
Received 22 April 2004; revised 4 June 2004; accepted 7 June 2004
Abstract—A high yielding (50–96%) route to 2-substituted-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid derivatives
has been developed using a rationally designed dihydroxyfumarate derivative. The fully unprotected pyrimidinone heterocycle was
prepared in quantitative yield upon treatment with HCl.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Pyrimidines and pyrimidinones are diazine heterocycles
that are important because of their well-documented
biological activity,1 and new or improved syntheses of
these heterocycles are important to the field of drug
design. 2-Substituted-5-hydroxy-6-oxo-1,6-dihydropyr-
imidine-4-carboxylic acid (pyrimidinone) derivatives, 1,
are a class of compounds for which no simple, high-
yielding general synthetic methodologies have been
developed. The existing syntheses of these densely
functionalized heterocycles suffer from very low yields
due to poor regio- and chemoselectivity.2;3 In the most
developed synthetic route (Scheme 1, route 1), the de-
sired pyrimidinones were prepared by the Michael
reaction of N-hydroxy amidines and acetylynic diesters,
Scheme 1.
followed by thermal Claisen rearrangement and amide
condensation, typically in 30–40% overall yield.2 An-
other route (route 2) that has been reported involves the
We were interested in further examining the synthetic
condensation of dihydroxyfumarate derivatives with
potential in the latter reaction sequence, the combina-
amidines to give the desired functionalized pyrimid-
inones.3 The yields in this methodology are also
tion of dihydroxyfumarate derivatives with amidines.
One primary concern was the regio-control in these
reported to be low, but no systematic study has been
condensations, as the fumarates’ four contiguous elec-
applied to this chemistry.
trophilic carbons could conceivably lead to five-, six-
and seven-membered ring products. In addition, it has
been reported that dihydroxyfumarate derivatives can
fragment under basic conditions.4 With these concerns
in hand, we began to study the condensation of the
Keywords: Pyrimidine; Pyrimidinone; Fumarate.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.06.028
readily available dimethoxy dihydroxyfumarate 3a5 with
benzamidine HCl 2a. When 3a is mixed in MeOH at
room temperature with benzamidine and NaOMe (as
well as DBU or Et3N), a trace amount (<10% by LCMS
* Corresponding author. Tel.: +1-732-594-7669; fax: +1-732-594-1499;
e-mail: spencer_dreher@merck.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.028

6024
S. D. Dreher et al. / Tetrahedron Letters 45 (2004) 6023–6025
analysis) of desired pyrimidinone 4a was formed, with
complete consumption of the starting materials. Ami-
dine-incorporated products with lower than expected
mass were obtained as the major products (by LCMS),
presumably a result of base-promoted fragmentation of
the dihydroxyfumarate by a retro-Claisen mechanism.
In order to slow this fragmentation, we envisioned
blocking one or both of the free hydroxyls with pro-
tecting groups that could be removed later under mild
conditions. The benzyl protected dimethoxydihydroxy-
fumarate 3b was prepared by Claisen condensation of
methyl a-benzyloxy acetate and dimethyl oxalate.6
When 1.5 equiv of 3b was combined with benzamidine
and DBU (3 equiv) in MeOH at 60 ꢁC for 8 h, a rea-
sonable 65% yield of 4b, was obtained. A major side-
product that was identified in the reaction mixture is the
five-membered ring product 14, which would arise from
attack at the undesired methyl ester of 3b. This led us to
postulate that blocking this position as a bulky tert-
butyl ester would result in better regioselectivity and
higher yields. Compound 3c was prepared by Claisen
condensation of methyl a-benzyloxy acetate and methyl
tert-butyl oxalate using LDA6;7 in 72% yield after puri-
fication by silica-gel chromatography. Indeed, 3c reacts
cleanly with 2a using NaOMe (3 equiv) in MeOH at
room temperature, giving 4c in 89% HPLC assay yield8
and 84% isolated yield after crystallization. Only a trace
of the five-membered ring analog 14 was present (<3 A%
by HPLC) as the only side-product. A survey of bases
found that DBU (3 equiv) was equally capable of pro-
moting the reaction, and triethylamine (3 equiv) also
gave the product, but at a lower rate and less cleanly
(Table 1). Due to the higher cost of DBU, NaOMe was
used as the standard base in the remaining experiments.
A survey of commercially available amidines demon-
strated that the reaction is general (Table 1).9 Standard
alkyl (2b–d) and electron-poor (2f), electron-rich (2g),
and basic (2e) aryl amidines gave excellent yields of
the desired pyrimidinone heterocycles, and all were ea-
sily purified by crystallization from the crude reaction
mixture. Amidine analogs containing O, N and S hetero-
atoms, such as O-methylisourea 2h, 2-ethyl-2-thio-
pseudourea 2i and 1,1-dimethylguanidine 2j also reacted
Figure 1.
Scheme 2.
Table 1. Optimization and scope of dihydroxyfumarate/amidine condensation reactions (Scheme 2)
Amidines 1a–j
Fumarate
Conditions
Product R1 ¼ , R2 ¼ , R3 ¼
4a Ph, H, Me
Yielda
2a R1 ¼ Ph-, (HCl)
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
NaOMe, Et3N and DBU
DBU, 60 ꢁC, 8 h
DBU, 60 ꢁC, 8 h
Trace
65
2a R1 ¼ Ph-, (HCl)
4b Ph, Bn, Me
t
2a R1 ¼ Ph-, (HCl)
4c Ph, Bn, Bu
t
na (92)
na (82)
84 (89)
84
2a R1 ¼ Ph-, (HCl)
Et3N, 60 ꢁC, 24 h
NaOMe, rt, 24 h
NaOMe, rt, 24 h
NaOMe, rt, 24 h
NaOMe, rt, 30 h
NaOMe, rt, 30 h
NaOMe, rt, 48 h
NaOMe (2 equiv), rt, 30 h
NaOMe, rt, 36 h
NaOMe or DBU
NaOMe or DBU
4c Ph, Bn, Bu
t
2a R1 ¼ Ph-, (HCl)
4c Ph, Bn, Bu
t
2b R1 ¼ Me-, (HCl)
5 Me, Bn, Bu
t
2c R1 ¼ H-, (HCl)
6 6H, Bn, Bu
7 Cyclopropyl-, Bn, Bu
93
92
2d R1 ¼ cyclopropyl-, (HCl)
2e R1 ¼ 4-pyridine-, (HCl)
2f R1 ¼ 3-NO2Ph-, (HCl)
2g R1 ¼ 4-MeOPh-, (free base)
2h R1 ¼ MeO-, (1/2H2SO4)
2j R1 ¼ EtS-, (HBr)
t
t
8 4-Pyridine-, Bn, Bu
t
96
88
9 3-NO2Ph, Bn, Bu
t
10 4-MeOPh-, Bn, Bu
t
94
50
11 OMe, Bn, Bu
t
12 EtS-, Bn, Bu
t
13 Me2N-, Bn, Bu
Low
Low
2k R1 ¼ Me2N-, (H2SO4)
na denotes that the compound was not isolated.
a HPLC assay yield in parentheses.

S. D. Dreher et al. / Tetrahedron Letters 45 (2004) 6023–6025
6025
7. Typical procedure: preparation of 2-benzyloxy-3-hydroxy-
fumarate 4-tert-butyl ester 1-methyl ester (3c). LDA was
generated by addition of n-BuLi (60 mL, 2.5 M in hexanes,
150 mmol) to diisopropylamine (21.0 mL, 150 mmol) in
THF (60 mL) at 0 ꢁC, and aged for 10 min. In a separate
flask, a mixture of methyl tert-butyl oxalate (24.0 g,
150 mmol) and methyl a-benzyloxy acetate (18.0 g,
100 mmol) in THF (240 mL) was cooled to )78 ꢁC. The
LDA was then added quickly by cannula, and the
resulting mixture stirred for 1 h at )78 ꢁC, then warmed
to room temperature over 1 h. The mixture was then
quenched with cold aqueous HCl (200 mL, 1 M), and the
reaction was diluted with EtOAc (200 mL). The layers
were separated, and the aqueous was back-washed with
EtOAc (2 · 100 mL). The resulting organics were dried
(MgSO4), filtered and stripped, then purified by column
chromatography on silica-gel (eluents 1–60% EtOAc/
hexanes) to give 22.2 g (72%) of 3c as a mixture of enol/
ketone tautomers and the ketone hydrate. 1H and 13C
NMR are complex due to keto-enol tautomers and the
ketone hydrate. NMR spectra confirming these structures
are provided in the Supplementary materials. The purified
product is a single spot by TLC analysis. We recommend
that fumarate reagent 3c be used directly after chromato-
graphic purification, due to decomposition, which can
reduce yields in the heterocycle formation. Compound 3c
can be stored for several days in a )20 ꢁC freezer, with
minimal decomposition.
Scheme 3.
to give the desired pyrimidines (by LCMS analysis), but
less cleanly. Compound 8a could be crystallized in
moderate yield, but 9a and 10a could not be isolated by
crystallization due to the low yields.10
Unambiguous structural determination for the pyr-
imidinone heterocycles was obtained by X-ray crystal
structure of the 3-nitrophenyl analogue 9 (Fig. 1).11 In
addition, both protecting groups were removed from 4c
in one step under acidic conditions to give the core
pyrimidine heterocycle, 2-phenyl-5,6-dihydroxy-pyrimi-
dine-4-carboxylic acid 15, in quantitative yield (Scheme
3).
In summary, a general synthetic method has been
developed that allows access to C2 alkyl- and aryl-
substituted pyrimidinones 1 in high yield and purity. By
understanding the inherent problems of retro-Claisen
fragmentation and regioselectivity of this reaction, a
dihydroxyfumarate derivative with an appropriate pro-
tecting scheme was devised that constrained its reactivity
to the desired path. A simple procedure for deprotection
was then found to enable further derivatization.
8. The yield was determined by quantitative HPLC by
comparison with a known amount of a purified standard.
9. Typical procedure: preparation of 5-benzyloxy-6-hydroxy-
2-cyclopropyl-pyrimidine-4-carboxylic acid tert-butyl ester
(7). To a solution of cyclopropane-1-carboximidamide
HCl 2d (1.21 g, 10.0 mmol) and 3c (4.60 g, 15.0 mmol) in
MeOH (16.6 mL) at 0 ꢁC, was added NaOMe (6.8 mL,
25 wt % solution in MeOH, 30 mmol). The mixture was
warmed to room temperature, then stirred for 30 h. After
dilution with MeOH (5 mL) and cooling to 0 ꢁC, 1 N HCl
(40 mL) was added and the product was precipitated from
the mixture. The solid was washed with 10 mL of cold 9:1
H2O/MeOH and dried giving 3.14 g of 7 (92% isolated
yield) of >98% pure (HPLC area percent purity at 210 nm)
References and notes
1. For reviews, see: (a) Brown, D. J. In The Chemistry of
Heterocylic Compounds. The Pyrimidines; Weisberger, A.,
Ed.; Wiley-Interscience: New York, 1970; Vol. 16; (b)
Hurst, D. T. An Introduction to the Chemistry and
Biochemistry of Pyrimidines, Purines and Pteridines; Wiley:
Chichester, 1980.
2. (a) Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423–
1424; (b) Cooper, J.; Irwin, W. J. J. Chem. Soc., Perkin
Trans. 1 1976, 2038–2045.
3. (a) Johnson, T. B.; Caldwell, W. T. J. Am. Chem. Soc.
1929, 51, 873; (b) Budesinsky, Z.; Jelinek, V.; Prikryl, J.
J. Collect. Czech. Chem. Commun. 1962, 27, 2550–2560; (c)
Sunderland, C. J.; Botta, M.; Aime, S.; Raymond, K. N.
Inorg. Chem. 2001, 40, 6756.
4. Huntress, E. B.; Olsen, R. T. J. Am. Chem. Soc. 1948, 70,
2856–2859.
5. Jaffe, E. E.; Matrick, H. J. Org. Chem. 1968, 33, 4004–
4010.
6. For a similar transformation, see: Bender, D. R.; Brenan,
J.; Rapoport, H. J. Org. Chem. 1978, 43, 3354–3362.
1
as a white crystalline solid, mp 164.0–164.5 ꢁC. H NMR
(400 MHz, CDCl3) d 12.98 (1H, br s), 7.46–7.49 (2H, m),
7.30–7.38 (m, 3H), 5.24 (2H, s), 1.89–1.95 (1H, m), 1.52
(9H, s), 1.24–1.29 (2H, m), 1.05–1.10 (2H, m); 13C NMR
(100 MHz, DMSO-d6) 164.3, 159.7, 159.5, 145.7, 139.4,
137.3, 128.6, 128.3 (two peaks), 82.6, 73.4, 27.9, 13.5,
10.0.
10. The pyrimidinones could not be purified in good yield by
silica-gel chromatography due to streaking of the products
on the column.
11. Crystallographic data (excluding structure factors) for the
structure in this paper, have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 236303. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).