Chemo- and regioselective functionalization of uracil derivatives. Applications to the synthesis of oxypurinol and emivirine

Article abstract of DOI:10.1021/ol061295+

A novel route for the synthesis of 4,5-difunctionalized uracils using a chemo- and regioselective bromine/magnesium exchange reaction on 5-bromo-4-halogeno-2,6-dimethoxypyrimidines has been developed. Applications to the synthesis of pharmaceuticals such as oxypurinol and emivirine are reported.

Full text of DOI:10.1021/ol061295+

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3737-3740
Chemo- and Regioselective
Functionalization of Uracil Derivatives.
Applications to the Synthesis of
Oxypurinol and Emivirine
Nade`ge Boudet and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received May 27, 2006
ABSTRACT
A novel route for the synthesis of 4,5-difunctionalized uracils using a chemo- and regioselective bromine/magnesium exchange reaction on
5-bromo-4-halogeno-2,6-dimethoxypyrimidines has been developed. Applications to the synthesis of pharmaceuticals such as oxypurinol and
emivirine are reported.
The preparation of functionalized uracil derivatives is of
interest because the uracil unit is present in DNA and related
natural products, such as the marine alkaloid rigidin 1 (Figure
1).1Uracils are privileged structures in drug discovery2 and
widely used in oncology. Oxypurinol 24 is a xanthine oxidase
inhibitor, which is the active metabolite of the drug allo-
purinol. In recent years, several pathways for the synthesis
of analogues from emivirine 3,5 belonging to a nonnucleoside5b
class (NNRTIs) of inhibitors that target the retrovirus HIV-
1, were developed. The functionalizations of uracil deriva-
tives at the C4 or C5 position are therefore of great synthetic
importance. Generally, these functionalizations require the
protection of the carbonyl groups, and the introduction of
functionality is implemented by directed lithiation6 or
bromine-lithium exchange7 starting from 5-halogeno-2,6-
dialkoxypyrimidines. These methods allow the preparation
(2) Newkome, G. R.; Pandler, W. W. Contemporary Heterocyclic
Chemistry; Wiley: New York, 1982.
(3) Cai, T. B.; Tang, X.; Nagorski, J.; Brauschweiger, P. G.; Wang, P.
G. Bioorg. Med. Chem. 2003, 11, 4971.
(4) Nagamatsu, T.; Fujita, T.; Endo, K. J. Chem. Soc., Perkin Trans. 1
2000, 33. Allopurinol is a well-known drug clinically used for the treatment
of gout and hyperuricemia. Oxypurinol is currently being developed by
Cardiome Pharma for the treatment of allopurinol-intolerant hyperuricemia
(gout) and is in phase III trials for the treatment of congestive heart failure.
(5) (a) Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye,
N.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. J.
Med. Chem. 1995, 38, 2860. (b) Pedersen, O. S.; Pedersen, E. B. AntiViral
Chem. Chemother. 1999, 10, 2860.
Figure 1. Uracil derivatives.
display a broad spectrum of biological activities. For
example, 5-fluorouracil3 is an important anticancer agent
(1) (a) Sakamoto, T.; Kondo, Y.; Sato, S.; Yamanaka, H. J. Chem. Soc.,
Perkin Trans. 1 1996, 5, 459. (b) Lagoja, I. M. Chem. BiodiVersity 2005,
2, 1.
(6) (a) Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841. (b)
Chan, S. A.; Chen, G.; Guo, R.; Wu, J. PCT Int. Appl. 2005, 2005108377.
10.1021/ol061295+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/18/2006

of various uracil derivatives, but they require low temper-
atures and preclude the presence of sensitive functional
groups. The magnesiation of 5-bromo-2,6-dialkoxypyrim-
idines has also been described.8,9
Table 1. Products of Type 8 and 9
Recently, we have found a LiCl-catalyzed Br/Mg ex-
change10 reaction using i-PrMgCl‚LiCl.11 This reagent con-
siderably accelerates the bromine/magnesium exchange
reaction on aryl and heteroaryl bromides. Herein, we wish
to report a general preparation of difunctionalized uracil
derivatives at the C4 and C5 positions, starting from
5-bromo-4-halogeno-2,6-dimethoxypyrimidines (4 and 5).
The utility of this method is demonstrated by performing
the synthesis of oxypurinol 2 and emivirine 3.
Thus, the addition of i-PrMgCl‚LiCl to 5-bromo-4-chloro-
2,6-dimethoxypyrimidine12 (4) at 20 °C in THF furnished
quantitatively,13 within 15 min, the magnesiated N-hetero-
cycle 6 (Scheme 1, Table 1). This magnesium reagent reacted
Scheme 1. Chemo- and Regioselective Functionalizations of
5-Bromo-4-halogeno-2,6-dimethoxypyrimidines at the C5
Position
with a wide range of electrophiles providing new 5-func-
tionalized 4-chloro-2,6-dimethoxypyrimidines of type 8a-g
in high yields, after quenching with an electrophile (Scheme
1, Table 1, entries 1-7).
Addition of benzaldehyde or 2-methoxybenzaldehyde on
metalated species 6 led to the corresponding alcohols 8a and
8b in, respectively, 91 and 83% yield (entries 1 and 2). The
reaction with acid chlorides such as PhCOCl or a carbamoyl
chloride provided the ketone 8c in 86% yield and the amide
8d in 85% yield (entries 3 and 4). Treatment of the
magnesiated derivative 6 with TsCN afforded the heterocy-
clic nitrile 8e in 89% yield (entry 5). The introduction of an
ester group was best performed by the reaction with
NC-CO2Et leading to the ester 8f in 87% yield (entry 6).
The reaction with an activated bromide, such as benzyl
bromide, provided the expected product 8g in 75% yield
(entry 7).
Similarly, starting from 4,5-dibromo-2,6-dimethoxypyri-
midine14 (5), the Br/Mg exchange reaction occurred regio-
(7) (a) De Corte, B. L.; Kinney, W. A.; Liu, L.; Ghosh, S.; Brunner, L.;
Hoekstra, W. J.; Santulli, R. J.; Tuman, R. W.; Baker, J.; Burns, C.; Proost,
J. C.; Tounge, B. A.; Damiano, B. P.; Maryanoff, B. E.; Johnson, D. L.;
Galemmo, R. A. Bioorg. Med. Chem. Lett. 2004, 14, 5227. (b) Reese, C.
B.; Wu, Q. Org. Biomol. Chem. 2003, 1, 3160.
(8) Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Masataka, Y. J.
Org. Chem. 1998, 63, 7207.
(9) Shimura, A.; Momotake, A.; Togo, H.; Yokoyama, M. Synthesis 1999,
495.
a X ) Cl‚LiCl. b Isolated yield of analytically pure product.
(10) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333.
(11) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(12) Okafor, C. J. Org. Chem. 1973, 38, 4386.
(13) The completion of the Br-Mg exchange was checked by GC
analysis of reaction aliquots quenched with saturated NH4Cl (aqueous).
selectively at C5, providing the corresponding magnesium
species 7 (Scheme 1, Table 1). The reaction of the Grignard
reagent intermediate 7 with various electrophiles gave the
3738
Org. Lett., Vol. 8, No. 17, 2006

expected products 9a-e in very high yields (Scheme 1, Table
1, entries 8-12). The silylation and the direct allylation of
the magnesium derivative 7 can be accomplished, respec-
tively, with TMSCl and allyl bromide, leading to pyrimidines
9a and 9b with 91% yield (entries 8 and 9). Trapping the
magnesium species 7 with ethyl cyanoformate, benzaldehyde,
or 4-morpholinecarbonyl chloride furnished the highly cor-
responding functionalized products 9c-e in 70-95% yields
(entries 10-12).
The pyrimidines of type 8 can be converted into various
annelated heterocycles. Thus, the reaction between the
chloroketone 8c and the hydroxylamine hydrochloride in a
1:1 mixture of H2O/MeOH gave, within 4 h, the desired
product 10 in 83% yield (Scheme 2). Interestingly, the
provided the aldehyde 12 in 83% yield. Treatment of 12 with
an excess of hydrazine monohydrate16 led to the bicyclic
N-heterocycle 13 in 91% yield (80 °C, 0.5 h). Deprotection
using concentrated HCl led to oxypurinol 2 in 81% yield
(Scheme 3).
A successive introduction of two different electrophiles
in positions C4 and C5 can be performed. Thus, the reaction
of 4-bromo-2,6-dimethoxy-5-(trimethylsilyl)pyrimidine (9a)
with i-PrMgCl‚LiCl at -15 °C for 12 h furnished the
corresponding Grignard reagent which could be trapped with
allyl bromide and gave the expected product 14 in 81% yield
(Scheme 4).
Scheme 4. Difunctionalizations of
4,5-Dibromo-2,6-dimethoxypyrimidine via Successive One-Pot
Br/Mg Exchange Reactions
Scheme 2. Synthesis of Annelated Heterocycles
addition of methyl mercaptoacetate on 8c, in the presence
of triethylamine,15 provided the bicyclic S,N-heterocycle 11
in 69% yield (Scheme 2).
As an application, we also used an intramolecular cycliza-
tion to prepare the drug oxypurinol 2 (Scheme 3). Thus, the
Interestingly, difunctionalizations with two successive Br/
Mg exchange reactions using a “one-pot” procedure could
also be performed. Thus, by using successively c-HexCHO
and N-morpholinecarbonyl chloride as electrophiles, we
obtained the desired product 15 in 69% overall yield.
Similarly, by using allyl bromide and MeI, we prepared the
4,5-disubstituted pyrimidine 16 in 81% yield (Scheme 4).
To illustrate the versatility of this method, a synthesis of
emivirine 3 was performed (Scheme 5). Treatment of 4,5-
dibromo-2,6-dimethoxypyrimidine (5) with i-PrMgCl‚LiCl
followed by the reaction with acetone in the presence of a
solution of LaCl3‚2LiCl in THF17 led to the corresponding
alcohol 17 in 87% yield. This compound was dehydroxylated
using triethylsilane with trifluoroacetic acid.18 A mixture of
the expected 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine
(18) and the corresponding dehydrated product was ob-
Scheme 3. Synthesis of Oxypurinol 2
(15) Rahman, L. K. A.; Scrowston, R. M. J. Chem. Soc., Perkin Trans.
1 1984, 3, 385.
(16) Nagamatsu, T.; Fujita, T.; Endo, K. J. Chem. Soc., Perkin Trans. 1
reaction of pyrimidine 4 with i-PrMgCl‚LiCl (1.05 equiv,
rt, 15 min) followed by the reaction with N-formylmorpholine
2000, 33.
(14) For the preparation of 4-bromo-2,6-dimethoxypyrimidine: White,
J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963.
(17) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 497.
Org. Lett., Vol. 8, No. 17, 2006
3739

20 was preliminarily silylated using BSA in MeCN and then
N-alkylated21 with diethoxymethane to furnish 6-benzyl-1-
(ethoxymethyl)-5-isopropyluracil (3, emivirine) in 90% yield
(Scheme 5).
Scheme 5. Synthesis of Emivirine 3
In summary, we have developed a selective functional-
ization method22 of uracils in the C4 and C5 positions via
successive Br/Mg exchanges allowing the synthesis of
various new polyfunctionalized uracils. We have applied this
method to the synthesis of biologically active uracils, such
as oxypurinol and emivirine, and opened a new route to the
synthesis of their analogues.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support and Sanofi-Aventis for a
fellowship to N.B.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061295+
(21) Therkelsen, F. D.; Hansen, A.-L. L.; Pedersen, E. B.; Nielsen, C.
Org. Biomol. Chem. 2003, 1, 2908.
(22) (a) Procedure for the Br/Mg exchange reaction at C5 (synthesis
of 9a): A dry and argon-flushed 10 mL flask, equipped with a magnetic
stirrer and a septum, was charged with a solution of 4,5-dibromo-2,6-
dimethoxypyrimidine (5) (596 mg, 2 mmol) in dry THF (3 mL). i-PrMgCl‚
LiCl (1.0 M/THF, 2.1 mmol, 1.05 equiv) was added slowly (within 5 min)
at room temperature, and the resulting mixture was stirred for 15 min to
complete the bromine-magnesium exchange (checked by GC-MS analysis
of reaction aliquots). Trimethylsilyl chloride (240 mg, 2.2 mmol, 1.1 equiv)
was added dropwise. The mixture was stirred at room temperature for 24
h and was quenched with saturated aqueous NH4Cl solution. The aqueous
phase was extracted with ethyl acetate (3 × 10 mL). The organic fractions
were dried (Na2SO4) and concentrated in vacuo. Purification by flash
chromatography (n-pentane/diethyl ether ) 4:1) yielded 529 mg (91% yield)
of 9a as a white solid (mp: 71.1-72.2 °C). (b) Procedure for the Br/Mg
exchange reaction at C4 (synthesis of 14): A dry and argon-flushed 10
mL flask, equipped with a magnetic stirrer and a septum, was charged with
a solution of 4-bromo-2,6-dimethoxy-5-(trimethylsilyl)pyrimidine (9a) (291
mg, 1.0 mmol) in dry THF (2 mL). i-PrMgCl‚LiCl (1.0 M/THF, 1.05 mmol,
1.05 equiv) was added very slowly at -15 °C, and the resulting mixture
was stirred for 12 h at this temperature to complete the bromine-magnesium
exchange (checked by GC-MS analysis of reaction aliquots). Then, allyl
bromide (145 mg, 1.2 mmol, 1.2 equiv) was added dropwise. After 30 min,
3 drops of CuCN‚2LiCl (cat., 1 M in THF) were added. The mixture was
warmed at room temperature for 6 h and was quenched with saturated
aqueous NH4Cl solution. The aqueous phase was extracted with ethyl acetate
(3 × 5 mL). The organic fractions were dried (Na2SO4) and concentrated
in vacuo. Purification by flash chromatography (n-pentane/diethyl ether )
3:2) yielded 204 mg (81% yield) of 14 as a colorless oil.
tained.19 The product mixture was directly hydrogenated
using PtO2 (1 bar, 30 min), and we obtained 18 in 91%
yield.
The second Br/Mg exchange was performed at room
temperature for 5 h, followed by the benzyl bromide addition,
leading to the 4,5-dialkylated-2,6-dimethoxypyrimidine spe-
cies (19) (20 h, rt, 87% yield). An acidic hydrolysis in
aqueous MeOH gave the corresponding uracil 20 in 92%
yield after recrystallization from aqueous MeOH. Compound
20
(18) Albert, J. S.; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P.
R.; Bialecki, R. A.; Dedinas, R.; Dembofsky, B. T.; Hill, D.; Kirkland, K.;
Koether, G. M.; Kosmider, B. J.; Ohnmacht, C.; Palmer, W.; Potts, W.;
Rumsey, W.; Shen, L.; Shenvi, A.; Sherwood, S.; Warwick, P. J.; Russell,
K. J. Med. Chem. 2002, 45, 3972.
(19) A mixture of 17% of 18 and 83% of the corresponding dehydrated
1
product was obtained by H NMR analysis of the crude product.
(20) Tilley, J. W.; LeMahieu, R. A.; Carson, M.; Kierstead, R. W. J.
Med. Chem. 1980, 23, 92.
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