A novel approach to the synthesis of 6-substituted uracils in three-step, one-pot reactions

Article abstract of DOI:10.1021/jo800358v

(Chemical Equation Presented) From the commercial 6-chloro-2,4- dimethoxypyrimidine (1) and by a photostimulated reaction with Me ₃Sn^- ions, 2,4-dimethoxy-6-(trimethylstannyl)pyrimidine (2) was obtained in 95% yield. By the cross-coupling reaction of 2 with 1-iodonaphthalene as electrophile catalyzed by Pd (Stille reaction), 2,4-dimethoxy-6-(naphthalen-1-yl)pyrimidine (9) was obtained in 76% yield. By hydrolysis of 9, 6-(1-naphthyl)uracil was obtained in 98% of isolated yield. When the three steps (S_RN1 reaction-cross coupling reaction-hydrolysis) were performed in a one-pot reaction, 6-substituted uracils (1-naphthyl, 4-chlorophenyl, 3-chlorophenyl, 2,3,4,5,6-pentafluorophenyl) were obtained (43-57%) of isolated pure products. When the electrophile was a benzoyl chloride, 6-benzoyl uracil (54%) and 6-(2-chlorobenzoyl) uracil (49%) were obtained in isolated pure products.

Full text of DOI:10.1021/jo800358v

A Novel Approach to the Synthesis of 6-Substituted Uracils in
Three-Step, One-Pot Reactions
Javier I. Bardag´ı and Roberto A. Rossi*
INFIQC, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Qu´ımicas, UniVersidad Nacional de
Co´rdoba, Ciudad UniVersitaria, 5000 Co´rdoba, Argentina
rossi@fcq.unc.edu.ar
ReceiVed February 12, 2008
From the commercial 6-chloro-2,4-dimethoxypyrimidine (1) and by a photostimulated reaction with
Me3Sn- ions, 2,4-dimethoxy-6-(trimethylstannyl)pyrimidine (2) was obtained in 95% yield. By the cross-
coupling reaction of 2 with 1-iodonaphthalene as electrophile catalyzed by Pd (Stille reaction), 2,4-
dimethoxy-6-(naphthalen-1-yl)pyrimidine (9) was obtained in 76% yield. By hydrolysis of 9, 6-(1-
naphthyl)uracil was obtained in 98% of isolated yield. When the three steps (SRN1 reaction-cross coupling
reaction-hydrolysis) were performed in a one-pot reaction, 6-substituted uracils (1-naphthyl, 4-chlo-
rophenyl, 3-chlorophenyl, 2,3,4,5,6-pentafluorophenyl) were obtained (43-57%) of isolated pure products.
When the electrophile was a benzoyl chloride, 6-benzoyl uracil (54%) and 6-(2-chlorobenzoyl) uracil
(49%) were obtained in isolated pure products.
Introduction
6-(Substituted phenyl)uracils and thiouracils were synthesized
by the condensation of ꢀ-(substituted phenyl)-ꢀ-oxopropionates
with thiourea.6
Lithiation of 1,3,6-trimethyluracil takes place at the methyl
in the 6-position in an essentially regiospecific manner. There-
fore this sequence was used for the preparation of several types
of 6-alkyl-substituted uracil derivates that showed activity
against Parainfluenza 1(Sendai) virus.7
Other functionalizations require the protection of carbonyl
groups, and the introduction of functionality is implemented by
directed lithiation8 or bromine-lithium exchange9 starting from
5-halo-2,4-dialkoxypyrimidines. These methods allow the prepara-
tion of various uracil derivatives. However, they require low
temperatures and preclude the presence of sensitive functional
groups. The magnesiation of 5-bromo-2,4-dialkoxypyrimidines has
Since the uracil unit is present in the DNA and related natural
products, the preparation of functionalized uracil derivatives is
of special interest. Uracils are privileged structures in drug
discovery, widely used in oncology.1 The functionalization of
uracil derivatives at the C6 position is therefore of great synthetic
importance.
6-Aminouracils were obtained by treatment of the corre-
sponding substituted 6-chlorouracil derivatives with the ap-
propriate amine.2 These substrates react with 4-(dimethylami-
no)pyridine in boiling 1,2-dichlorobenzene to afford the
uracilylpyridinium chloride.3
6-Thioether uracils were synthesized by reaction of 6-chloro
or 6-tosylate with thiols.4 Under microwave irradiation, the
nucleophilic substitution reactions of 6-halouracils with sele-
nium, sulfur, oxygen, and nitrogen nucleophiles after several
minutes were completed with good yields.5
(5) Fang, W-P.; Cheng, Y.-T.; Cheng, Y.-R.; Cherng, Y.-J. Tetrahedron 2005,
61, 3107.
(6) Clark, J.; Munawar, Z. J. Chem. Soc. (C) 1971, 1945.
(7) (a) Botta, M.; Saladino, R.; Delle Monache, G.; Gentile, G.; Nicoletti,
R. Heterocycles 1996, 43, 1687. (b) Saladino, R.; Crestini, C.; Palamara, A. T.;
Danti, M. C.; Manetti, F.; Corelli, F.; Garaci, E.; Botta, M. J. Med. Chem. 2001,
44, 4554.
(1) Newkome, G. R.; Pandler, W. W. Contemporary Heterocyclic Chemistry;
Wiley: New York, 1982.
(2) (a) Klein, R. S.; Lenzi, M.; Lim, T. H.; Hotchkiss, K. A.; Wilson, P.;
Schwartz, E. L. Biochem., Pharmacol. 2001, 62, 1257. (b) Nencka, R.; Votruba,
I.; Hrebabecky´, H.; Tloustova´, E.; Horska´, K.; Masoj´ıdkova´, M.; Holy´, A. Bioorg.
Med. Chem. Lett. 2006, 16, 1335.
(8) Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841.
(9) (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.
(3) Schmidt, A.; Kindermann, M. K. J. Org. Chem. 1997, 62, 3910.
(4) Benhida, R.; Aubertin, A.-M.; Grierson, D. S.; Monneret, C. Tetrahedron
Lett. 1996, 37, 1031.
10.1021/jo800358v CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4491–4495 4491

Bardag´ı and Rossi
TABLE 1.
expt 1, 10-3 mol Me3Sn-Na+, 10-3 mol conditions 2, yield (%)b
S
RN1 Reactions of 1 with Me3Sn- Ionsa
also been described.10 Recently a novel route for the synthesis of
5,6-difunctionalized uracils by using a chemo- and regioselective
bromine/magnesium exchange reaction on 5-bromo-6-halo-2,4-
dimethoxypyrimidines has been developed.11
1
0.50
0.55
0.26
0.55
0.26
0.26
hν
95
7
0
20
39
2
0.25 (73%)c
0.50 (80%)c
0.23 (80%)c
0.24 (37%)c
dark
dark
hν
3d
4d
5e
In the present study, we explore the synthesis of 6-substituted
uracils by SRN1 reactions of 6-chloro-2,4-dimethoxypyrimidine
with Me3Sn- ion, followed by cross-coupling reactions of the
stannane obtained and finally by the hydrolysis of these products.
The unimolecular radical nucleophilic substitution, or SRN1
reaction, is a process through which an aromatic nucleophilic
substitution is achieved. Since the scope of this process has
increased considerably over the last decades, nowadays it serves
as an important synthetic strategy.12 The wide variety of
nucleophiles that can be used, the great functional group
tolerance, and the fact that many carbon-carbon and carbon-
heteroatom bonds can be obtained make the SRN1 reaction a
powerful synthetic tool.
hν
a All reactions were performed in liquid ammonia during 15 min; the
substrate was added in
1 mL of Et2O. Photostimulated reactions
employed two water-cooled medium-pressure Hg lamps. b Product yields
were determined by CG analysis, using authentic samples as references.
c Yield of substrate recovered. d 30% of di-tert-butyl nitroxide was
added. e 30 mol % of 1,4-dinitrobenzene was added.
Substrate 6-bromo-2,4-dimethoxypyrimidine only afforded the
reduction product 2,4-dimethoxypyrimidine by a halogen metal
exchange reaction.
Prior to the next step in our synthesis, we decided to study
the Stille reaction with stannane 4 (eq 2) as a model substrate.
There is a fast reaction (15 min) of Me3Sn- ions and 2-chlo-
ropyrazine 3 to obtain 4 in excellent yield (97%) (eq 2).
We have described the photostimulated reactions of Me3Sn-
ions with several chloroarenes in liquid ammonia that afford
ArSnMe3 from very good to excellent yields, and these reactions
occur by the SRN1 mechanism.13
These reactions are an alternative route to the synthesis of
stannanes, by which the use of Grignard reagents or organo-
lithium compounds could be avoided. In addition, the SRN1
reactions of Me3Sn- ions with chloroarenes are quite versatile.
The products are of synthetic relevance and can be employed
as intermediates in several reactions, such as the Stille reaction.14
With stannane 4 thus obtained we performed the cross-
coupling reaction with 1-iodonaphthalene 5 as a model elec-
trophile under different conditions (Table 2) to obtain 2-(1-
naphthyl)pyrazine 6 (eq 3).
Results and Discussion
In the photostimulated reaction of 6-chloro-2,4-dimethoxy-
pyrimidine 1 (0.50 × 10-3 mol dissolved in 1 mL of ether)
with Me3Sn- ions (prepared with Me3SnCl and Na metal in
liquid ammonia) (0.55 × 10-3 mol) the stannane 2 was obtained
in 95% yield (76% isolated) (eq 1) (expt 1, Table 1). When the
reaction was performed in the dark, the yield was 7%, and 73% of
the substrate remained unaltered. The photostimulated reactions
are also inhibited by 1,4-dinitrobenzene, a well-known inhibitor
of SRN1 reactions and di-tert-butyl nitroxide (a known radical
The nonpolar solvent (PhMe) was better than polar ones
(DMF and NMP, Table 2, expts 1, 6 and 7). Under the best
conditions 6 was obtained in 79% yield when CsF, CuI, and
Ph3P were added (Table 2, expt 3). 4-Iodoacetophenone 7 was
another electrophile studied, and good yields of the cross-
coupling product 8 were obtained (Table 2, expt 8) (eq 4).
However, its yield decreased when the best condition found for
5 was used (Table 2, expt 9).
trap).12 This indicates that the reaction occurs by the SRN
1
mechanism. The fact that the yield of the dark reactions fell to
zero in the presence of di-tert-butyl nitroxide led us to conclude
that the dark component came from the same mechanism, through
a spontaneous electron transfer (thermal initiation).
(10) (a) Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Masataka, Y. J.
Org. Chem. 1998, 63, 7207. (b) Shimura, A.; Momotake, A.; Togo, H.;
Yokoyama, M. Synthesis 1999, 495.
The possibility of performing the synthesis of 4 and the Stille
reaction in a two-step, one-pot reaction was also explored.
Therefore, we carried out the SRN1 reaction employing 3 (0.97
× 10-3 mol), in 50 mL of dry liquid ammonia and Me3Sn-
ions (0.97 × 10-3 mol), under an atmosphere of nitrogen during
15 min to obtain stannane 4. Then the ammonia was allowed
to evaporate, PhMe was added (20 mL), and iodoarene 5 (0.97
× 10-3 mol) and the catalyst system PdCl2(Ph3P)2 (5 mol %)
were added, the reaction was refluxed for 4 h, and product 6
was obtained in 57% yield (duplicate experiments).15 However,
(11) Boudet, N.; Knochel, P. Org. Lett. 2006, 8, 3737.
(12) For reviews, see: (a) Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B. Chem.
ReV. 2003, 103, 71. (b) Rossi, R. A.; Pierini, A. B.; Santiago, A. N. In Organic
Reactions; Paquette, L. A., Bittman, R., Eds.; Wiley & Sons: New York, 1999;
pp 1-271. (c) Rossi, R. A. In Synthetic Organic Photochemistry; Griesberck,
A. G., Mattay, J., Eds.; Marcel Dekker: New York, 2005; Vol. 12, Chapter 15,
pp 495-527.
(13) (a) Yammal, C. C.; Podesta, J. C.; Rossi, R. A. J. Org. Chem. 1992,
57, 5720. (b) Corsico, E. F.; Rossi, R. A. Synlett 2000, 227. (c) Santiago, A. N.;
Basso, S. M.; Montan˜ez, J. P.; Rossi, R. A. J. Phys. Org. Chem. 2006, 19, 829.
(14) (a) Corsico, E. F.; Rossi, R. A. Synlett 2000, 230. (b) Corsico, E. F.;
Rossi, R. A. J. Org. Chem. 2002, 67, 3311. (c) Dol, G. C.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Eur. J. Org. Chem. 1998, 359.
(15) There was no substrate left.
4492 J. Org. Chem. Vol. 73, No. 12, 2008

A NoVel Synthesis of 6-Substituted Uracils
TABLE 2. Cross-Coupling Reactions of 4 with 5a
SCHEME 1. Three-Step, One-Pot Synthesis of 6-Substituted
Uracils
expt 2, 10-3 mol 5, 10-3 mol
conditions
4, yield (%)b
1
2
0.23
0.30
0.20
0.21
0.25
0.26
0.25
0.22
0.21
0.23
0.31
0.21
0.22
0.26
0.27
0.26
0.24
0.23
PhMe, 4 mL, reflux, 18 h
PhMe, 5 mL, 60 °C, 5 days
PhMe, 2 mL, 80 °C, 24 h
PhMe, 2 mL, 80 °C, 13 h
PhMe, 5 mL, 85 °C, 3 h
DMF, 5 mL, 80 °C, 3 h
NMP, 2 mL, 80 °C, 3 h
PhMe, 10 mL, reflux, 10 h
PhMe, 10 mL, 80 °C, 24 h
70c
25d
79c
19c
42c
12h
50c
88c
78c
3e
4f
5g
6
7f
8i
9i, e
extraction of the final mixture the solid products were obtained
in high purity in good yields, after being washed with Et2O.
Surprisingly, eletrophile 7, which worked well in the cross-
coupling of the model reaction (Table 2, expt 8), only gave a
low yield (30%) of the desired product. In view of these results,
we performed the Stille reaction of 2 with electrophile 7 and
obtained a 60% yield of product 11 (eq 7).
a The catalyst was PdCl2(Ph3P)2 (5 mol %). In addition to the
cross-coupling product 4, small amounts of homocoupling products were
detected, but not quantified. b Quantified by GC, using the internal
standard method. c There was no substrate left. d Substrate was
e
recovered in 43% yield. CsF (0.4 × 10-3 mol), CuI (10 mol %), and
f
Ph3P (10 mol %) were added. CsF (0.4 × 10-3 mol), CuI (10 mol %),
and Ph3P (20 mol %) were added. g The catalyst was Pd(Ph3P)4.
h Substrate was recovered in 60% yield. i The electrophile was 7.
when the optimized reaction conditions obtained for the Stille
reaction (conditions of Table 2, expt 3) were used, 6 was formed
in 55% yield, the same yield when no additive was used.
These results, and the fact that the use of additives seems to
be deleterious for other electrophiles in the Stille reactions (see
Table 2, expt 8 and 9), prompted us to perform the Stille reaction
without additives in the “one-pot” synthesis of uracil derivates.
After studying the Stille reaction, we resumed our target
synthesis and performed the reaction with stannane 2 (0.25 ×
10-3 mol) and electrophile 5 (0.32 × 10-3 mol) in the presence
of PdCl2(Ph3P)2 as catalyst (5 mol %) in refluxing toluene (5
mL) during 15 h; 2,4-dimethoxy-6-(naphthalen-1-yl)pyrimidine
9 was obtained in 67% yield (eq 5).
However, with this yield of the Stille reaction, a yield of about
50% of the global reaction SRN1-Stille-hydrolysis is expected;
therefore it is believed that there has been some problem in the
conditions of the last step for the synthesis of this compound.
Yet, its reasons are still unclear.
Conclusions
In summary, we have shown that the reactions of commercial
6-chloro-2,4-dimethoxypyrimidine (1) in liquid ammonia afford
6-substituted uracils with good yields in a three-step, one-pot
reaction. Considering the availability/simplicity of the starting
materials, the readiness and mild reaction conditions of the
procedure, we believe that this procedure might become a
general method for the synthesis of this family of compounds.
The SRN1-Stille sequence was performed in a two-step, one-
pot reaction as indicated before for the model reaction. The SRN1
reaction was carried out with 1 (0.50 × 10-3 mol), and Me3Sn-
ions (0.51 × 10-3 mol), 5 (0.51 × 10-3 mol), and the catalyst
system PdCl2(Ph3P)2 (5 mol %): product 9 was obtained in 61%
yield (duplicate experiments).
To end the reaction sequence to yield 6-subtituted uracil,
product 9 (0.23 × 10-3 mol) was hydrolyzed with HCl-MeOH
(1:1, 10 mL) and boiled for 18 h, and 6-(naphthalen-1-
yl)pyrimidine-2,4(1H,3H)-dione 10a was obtained quantitatively
(98% isolated yield, eq 6).
Experimental Section
2,4-Dimethoxy-6-(trimethylstannyl)pyrimidine (2). Reactions
of Me3Sn-Na+ in liquid ammonia: Ammonia (150 mL), previ-
ously dried with Na metal under nitrogen, was condensed into a
three-necked, 250-mL round-bottomed flask equipped with a
coldfinger condenser charged with ethanol, a nitrogen inlet, and a
magnetic stirrer. ClSnMe3 (109.6 mg, 0.55 mmol) was then added,
and Na metal (30.6 mg, 1.33 mmol) in small pieces was introduced,
waiting for total discoloration between each addition. A lemon
yellow solution of Me3Sn- ions is obtained. Then 6-chloro-2,4-
dimethoxypyrimidine (87.3 mg, 0.50 mmol) was dissolved in 1 mL
of dried ethyl ether and added to the solution. The reaction mixture
was irradiated for 15 min with use of two medium-pressure mercury
lamps emitting maximally at 350 nm. The reaction was quenched
by adding ammonium nitrate in excess. The ammonia was allowed
to evaporate, and water (50 mL) was added. The aqueous phase
was extracted with Et2O (3 × 40 mL), the organic phase was dried
(magnesium sulfate), and the solvent was evaporated in vacuum.
The product was purified by radial thin-layer chromatography on
aluminum oxide eluting with petroleum ether/ethylic ether 90:10.
Colorless oil was isolated in 76% yield (115.1 mg, 0.38 mmol).
1H NMR (400 Mhz, CCl3D) δ 6.56 (s, H-SnJ ) 12.4, 1H), 3.98 (s,
3H), 3.92 (s, 3H), 0.31 (s, H-SnJ ) 27.7, 9H). 13C NMR (100.6
MHz, CCl3D) δ 184.8, 169.5, 164.1, 110.1, 54.4, 53.1, -9.6. CG/
Finally, we studied the possibility of performing a three-step,
one-pot reaction SRN1-Stille-hydrolysis from the commercial
pyrimidine 1 to obtain 6-aryl and 6-acyl substituted uracils
(Scheme 1) without the need to isolate the intermediate product
(Table 3).
We proceeded as indicated before for the SRN1-Stille one-
pot reactions, then toluene was evaporated, MeOH/HCl was
added, and the mixture was refluxed for 20-24 h. After
MS (m/z) 304 (M+ 120Sn), 1), 289 (isotopic cluster, M+ 120Sn) -
( (
CH3, 100), 259 (43), 165 (15), 163 (12), 162 (10), 151 (15), 149
J. Org. Chem. Vol. 73, No. 12, 2008 4493

Bardag´ı and Rossi
product (yield %)b
TABLE 3. Three-Step, One-Pot Synthesis of 6-Substituted Uracilsa
expt
1 (10-3 mol)
Me3Sn- Na+ (10-3 mol)
ArI or ArCOCl (10-3 mol)
1
2
3
4
5
6
7
0.42
0.47
0.37
0.50
0.39
0.48
0.37
0.44
0.50
0.39
0.57
0.43
0.50
0.40
5 (0,44)
7 (0.58)
10a(57)
10b(30)
10c(55)
10d(43)
10e(50)
10f (54)
10g(49)
1-chloro-4-iodobenzene (0.49)
1-chloro-3-iodobenzene (0.58)
1,2,3,4,5-pentafluoro-6-iodobenzene (0.46)
benzoyl chloride (0.65)
2-chlorobenzoyl chloride (0.46)
a The SRN1 reactions were performed in ca. 50 mL of liquid ammonia. The Stille reaction was in PhMe (ca. 10 mL) at reflux during 16-20 h. The
catalyst was PdCl2(Ph3P)2 (5 mol %). The hydrolysis was performed with HCl(c)/MeOH (1:3, 13 mL) at reflux during 20-24 h. b Isolated yield (>95%
1
purity by H NMR).
(14), 135 (33), 134 (11), 133 (26), 131 (17), 72 (10), 66 (11). ESI/
APCI-HRMS Anal. calcd for C9H16N2O2Sn 304.0234, found
304.0225.
ether to yield 44.6 mg (0.17 mmol, 67%) of a white solid. Mp
78-80 °C. 1H NMR (400 MHz, CCl3D) δ 8.25 (m, 1H), 7.91 (m,
2H), 7.65 (dd, 3J ) 7.09 Hz, 4J )1.16 Hz, 1H), 7.51 (m, 3H), 6.67
(s, 1H), 4.07 (superimposed s, 3H), 4.06 (superimposed s, 3H).
13C NMR (100.6 MHz, CCl3D) δ 172.0, 168.4, 165.2, 136.2, 133.8,
130.6, 129.9, 128.4, 127.3, 126.5, 126.0, 125.4, 125.1, 102.4, 54.9,
53.9. CG/MS (m/z) 267 (M+ + 1, 10), 266 (M+, 61), 265 (100),
250 (13), 194 (12), 193 (38), 166 (13), 165 (14), 152 (9), 126 (10),
83 (10). ESI/APCI-HRMS Anal. calcd for C16H14N2O2 266.1055,
found 266.1057.
2-(Trimethylstannyl)pyrazine16 (4). To a lemon yellow solution
of Me3Sn- ions (0.55 mmol) was added 2-chloropyrazine (57.3
mg, 0.50 mmol) dissolved in 1 mL of dried ethyl ether. The reaction
mixture was allowed to react for 15 min and treated as previously
described. The product was purified by radial thin-layer chroma-
tography on aluminum oxide eluting with petroleum ether/diethyl
ether 90:10. A colorless oil was isolated (78.9 mg, 0.33 mmol, yield
65%). 1H NMR (400 MHz, CCl3D) δ 8.69 (dd, 3J ) 2.27 Hz, 4J )
1-(4-(2,4-Dimethoxypyrimidin-6-yl)phenyl)ethanone (11). Tolu-
ene (4 mL), 2 (60.6 mg, 0.20 mmol), 4-iodoacetophenone (51.7
mg, 0.21 mmol), and 5 mol % (7 mg, 0.01 mmol) of the catalyst
(dichlorobis(triphenylphosphine)palladium(II)) were added and the
mixture was refluxed for 16 h. The product was purified by column
chromatography on silica gel eluting with a petroleum ether/diethyl
ether mixture, and 31 mg (0.12 mmol, 60%) of a white solid was
4
3
1.73 Hz, 1H), 8.58 (d, J ) 1.58 Hz, 1H), 8.39 (d, J ) 2.51 Hz,
1H), 0.42 (s, H-SnJ ) 27.8 Hz, 9H). 13C NMR (100.6 MHz, CCl3D)
δ 169.0, 150.6, 146.6, 143.2, -9.4. CG/MS (m/z) 244 (isotopic
cluster, M+ 120Sn), 12), 229 (isotopic cluster, M+ - CH3 (120Sn),
(
100), 199 (39), 165 (25), 164 (26), 163 (21), 162 (21), 161(16),
160 (10), 146(11), 145 (10), 135 (54), 134 (17), 133 (43), 132 (15),
131(25), 120 (13), 118 (10), 52(11).
1
obtained. Mp 121-123 °C. H NMR (400 MHz, CCl3D) δ 8.14
2-(Naphthalen-1-yl)pyrazine17 (6). General procedure for
cross-coupling reactions: Into a 2-necked round-bottomed flask
equipped with a nitrogen inlet and magnetic stirrer were added 4
mL of toluene, 2-(trimethylstannyl)pyrazine (55.9 mg, 0.23 mmol),
and 1-iodonaphthalene (58.4 mg, 0.23 mmol). Then cesium fluoride
(69.9 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium(II)
(8.4 mg, 0.012 mmol, 5 mol %), and triphenylphosphine (6.3 mg,
0.024 mmol, 10 mol %) were introduced and the reaction mixture
was stirred for 5 min. Copper(I) iodide (4.6 mg, 0.024 mmol, 10
mol %) was added and the mixture was warmed at the temperature
and the time indicated (see Table 2). Water was added (30 mL)
and the aqueous phase was extracted with CH2Cl2 (3 × 50 mL),
the organic phase was dried (magnesium sulfate), and the solvent
was evaporated in vacuum. The product was separated and isolated
by radial thin-layer chromatography on silica gel eluting with
petroleum ether/diethyl ether. A colorless oil was isolated. Spectral
data for 6 (1H and 13C NMR, MS) agree with those previously
reported.17
1-(4-(Pyrazin-2-yl)phenyl)ethanone (8). Toluene, 4, 4-iodoac-
etophenone (7), and the catalyst (and additives) were added and
refluxed for 10 h. Product 8 was isolated as a yellow oil. 1H NMR
(400 MHz, CCl3D) δ 9.09 (d, J ) 1.44 Hz, 1H), 8.68 (dd, J )
2.32 Hz, 1.64 Hz, 1H), 8.57 (d, J ) 2.45 Hz, 1H), 8.11 (m, 4H),
2.66 (s, 3H). 13C NMR (100.6 MHz, CCl3D) δ 197.5, 151.5, 144.3,
143.7, 142.4, 140.4, 137.8, 128.9, 127.0, 26.7. CG/MS (m/z) 199
(M+ + 1, 5), 198 (M+, 38), 184 (13), 183 (100), 155 (45), 128
(10), 102 (10), 101 (11), 43 (11). ESI/APC -HRMS Anal. calcd
for C12H10N2O 198.0793, found 198.0787.
(m, 2H), 8.04 (m, 2H), 6.83 (m, 1H), 4.09 (s, 3H), 4.02 (s, 3H),
2.64 (s, 3H). 13C NMR (100.6 MHz, CCl3D) δ 197.5, 172.6, 165.5,
164.6, 140.9, 138.4, 128.6, 127.2, 98.0, 54.8, 54.0, 26.7. CG/MS
(m/z) 260 (M+ + 2, 2), 259 (M+ + 1, 15), 258 (M+, 100), 257
(57), 244 (13), 243 (75), 229 (16), 228 (34), 215 (21), 172 (12),
143 (35), 115 (12), 99 (17), 72 (12), 43 (22). ESI/APCI-HRMS
Anal. calcd for C14H14N2O3 258.1004, found 258.1011.
6-(Naphthalen-1-yl)uracil (10a). General procedure for hy-
drolysis: To a solution of MeOH (10 mL) was added 9 (61.2 mg,
0.23 mmol) and the mixture was stirred for 5 min until total
dissolution, then HCl concentrate (36%, 10 mL) was introduced
and the mixture was refluxed until 9 was completely consumed
(18 h). A saturated solution of NaHCO3 was carefully introduced
to neutralize the acid, water was added (20 mL), and the aqueous
phase was extracted with AcOEt (3 × 50 mL), the organic phase
was dried (magnesium sulfate), and the solvent was evaporated in
vacuum. A pure product was obtained as a white solid in 98% (53.7
mg, 0.22 mmol) isolated yield. Mp 317 °C dec. 1H NMR (400 MHz,
d6-DMSO) δ 11.26 (superimposed s, 1H), 11.23 (superimposed s,
1H), 8.03 (m, 3H), 7.61 (m, 4H), 5.57 (s, 1H). 13C NMR (100.6
MHz, d6-DMSO) δ 163.9, 152.5, 151.4, 132.9, 130.6, 130.1, 129.7,
128.3, 127.1, 126.6, 126.4, 125.1, 124.6, 101.4. CG/MS (m/z) 239
(M+ + 1, 4), 238 (M+, 59), 237 (19), 222 (15), 221 (100), 194
(13), 179 (15), 168 (12), 167 (75), 166 (59), 140 (15), 139 (27),
127 (26), 126 (13), 84 (12), 84(13), 70 (12), 63 (10). ESI/APCI-
HRMS Anal. calcd for C14H10N2O2 238.0742, found 238.0739.
General Procedure for Three-Step, One-Pot Reactions
(SRN1-Stille-Hydrolysis). Ammonia (50 mL), previously dried
with Na metal under nitrogen, was condensed into a 3-necked, 100-
mL round-bottomed flask equipped with a coldfinger condenser
charged with ethanol, a nitrogen inlet, and a magnetic stirrer.
Me3SnCl was then added, and Na metal in small pieces was
introduced, waiting for total discoloration between each addition.
A lemon yellow solution of Me3Sn- ions was obtained. Then
6-chloro-2,4-dimethoxypyrimidine was dissolved in 1 mL of dried
ethyl ether and added to the solution. The reaction mixture was
2,4-Dimethoxy-6-(naphthalen-1-yl)pyrimidine (9). Toluene (5
mL), 2 (75.7 mg, 0.25 mmol), 1-iodonaphthalene (81.3 mg, 0.32
mmol), and 5 mol % (8.8 mg, 0.0125 mmol) of the catalyst
(dichlorobis(triphenylphosphine)palladium(II)) were added and the
mixture was refluxed for 15 h. The product was purified by column
chromatography on silica gel eluting with petroleum ether/diethyl
(16) Yang, Y.; Martin, A. R. Synth. Commun. 1992, 22, 1757.
(17) Molander, G. A.; Biolatto, B. J. Org. Chem. 2007, 68, 4302.
4494 J. Org. Chem. Vol. 73, No. 12, 2008

A NoVel Synthesis of 6-Substituted Uracils
irradiated for 15 min with use of two medium-pressure mercury
lamps emitting maximally at 350 nm. The ammonia was allowed
to evaporate under N2. Then toluene (10 mL) was added followed
by the addition of electrophile (ArI or ArCOCl) and the catalyst
(PdCl2(PPh3)2). The reaction was refluxed overnight. Then MeOH
was added (20 mL) and the solution was evaporated in vacuum.
MeOH (10 mL) was added and the solution was stirred for 5 min,
HCl (36%, 3 mL) was introduced, and the mixture was refluxed
for 20-24 h. A saturated solution of NaHCO3 was carefully added
to neutralize the acid. Water (20 mL) was added and the aqueous
phase was extracted with AcOEt (3 × 50 mL), the organic phase
was dried (magnesium sulfate), and the solvent was evaporated in
vacuum. The solid residue was washed with boiling ethyl ether (5
mL) and the product was isolated with >95% purity (H1 RMN).
6-(Naphthalen-1-yl)uracil (10a). Substrate 1 (73.3 mg, 0.42
mmol) was used with 1-iodonaphthalene (111.8 mg, 0.44 mmol)
as the electrophile. The product was obtained as a yellow solid.
Isolated yield 57% (57 mg, 0.24 mmol). Recrystallization from
MeOH gave a white solid. Mp: 317 °C decomposed.
6-(Perfluorophenyl)uracil (10e). Substrate 1 (68.1 mg, 0.39
mmol) was used with 1,2,3,4,5-pentafluoro-6-iodobenzene (135.2
mg, 0.46 mmol) as the electrophile. The product was obtained as
a yellow solid. Isolated yield 50% (54.2 mg, 0.20 mmol). 10e was
purified by short column chromatography on silica gel eluting with
ethyl ether. White solid. Mp: 64-267 °C dec. 1H NMR (400 MHz,
d6-DMSO) δ 11.46 (superimposed s, 1H), 11.44 (superimposed s,
1H), 5.82 (d, J ) 1.58 Hz, 1H). 19F NMR (376.4 MHz, d6-DMSO)
δ -139.14 (d, J ) 18.39 Hz, 2F), -151.08 (t, J ) 22.43 Hz, 1F),
-161.48 (m, 2F). 13C NMR (100.6 MHz, d6-DMSO) δ18 163.2,
151.0, 139.0, 104.0. CG/MS (m/z) 279 (M+ + 1, 4), 278 (M+, 38),
277 (100), 201 (12), 199 (21), 183 (14), 152 (11), 77 (18), 51 (12).
ESI/APCI-HRMS Anal. calcd for C10H3F5N2O2 278.0115, found
278.0117.
6-Benzoyluracil (10f). Substrate 1 (83.8 mg, 0.48 mmol) was
used with benzoyl chloride (91.4 mg, 0.65 mmol) as the electrophile.
The product was obtained as a light brown solid. Isolated yield
54% (56.0 mg, 0.26 mmol). Filtration over silica gel followed by
recrystallization from EtOH gave a white solid. Mp: 221 °C dec.
1H NMR (400 MHz, d6-DMSO) δ 11.37 (superimposed s, 1H),
11.21 (superimposed s, 1H), 7.92 (m, 2H), 7.76 (m, 1H), 7.60 (t,
3J ) 7.76 Hz, 2H), 5.70 (s, 1H). 13C NMR (100.6 MHz, d6-DMSO)
δ 189.3, 164.2, 151.4, 148.1, 135.0, 134.5, 130.3, 129.4, 103.9.
CG/MS (m/z) 217 (M+ + 1, 7), 216 (M+, 54), 188 (17), 145 (29),
105 (100), 77 (78), 68 (46), 51 (30). ESI/APCI-HRMS Anal. calcd
for C11H8N2O3 216.0535, found 216.0532.
6-(4-Acetylphenyl)uracil (10b). Substrate 1 (82.0 mg, 0.47
mmol) was used with 4-iodoacetophenone (142.7 mg, 0.58) as the
electrophile. The product was obtained as a yellow solid. Isolated
yield 30% (32.4 mg, 0.14 mmol). Recrystallization from EtOH gave
a white solid. Mp: up to 390 °C (at this temperature the solid turned
brown). 1H NMR (400 MHz, d6-DMSO) δ 11.20 (superimposed s,
1H), 11.17 (superimposed s, 1H), 8.03 (d, 3J ) 8.36 Hz, 2H), 7.86
(d, 3J ) 8.37 Hz, 2H), 5.89 (s, 1H), 2.62 (s, 3H).13C NMR (100.6
MHz, d6-DMSO) δ 197.9, 164.3, 152.2, 151.8, 138.9, 136.1, 128.8,
127.8, 99.6, 27.3. ESI/APCI-HRMS Anal. calcd for C12H10N2O3
230.0691, found 230.0696.
6-(2-Chlorobenzoyl)uracil (10g). Substrate 1 (64.6 mg, 0.37
mmol) was used with 2-chlorobenzoyl chloride (80.5 mg, 0.46
mmol) as the electrophile. The product was obtained as a light
brown solid. Isolated yield 49% (45.4 mg, 0.18 mmol). Filtration
over silica gel followed by recrystallization from EtOH gave a white
6-(4-Chlorophenyl)uracil6 (10c). Substrate 1 (64.6 mg, 0.37
mmol) was used with 1-chloro-4-iodobenzene (116.8 mg, 0.49
mmol) as the electrophile. The product was obtained as a yellow
solid. Isolated yield 55% (45.3 mg, 0.22 mmol). Recrystallization
1
solid. Mp ∼215 °C dec. H NMR (400 MHz, d6-DMSO) δ 11.50
(br s, 1H), 11.30 (br s, 1H), 7.67 (m, 3H), 7.53 (m, 1H), 5.55 (d,
J ) 1.54 Hz, 1H). 13C NMR (100.6 MHz, d6-DMSO) δ 188.9,
164.3, 151.2, 146.5, 134.9, 133.8, 131.1, 130.9, 130.7, 127.9, 107.2,
CG/MS (m/z) 253 (M+ + 3, 2), 252 (M+ + 2, 15), 251 (M+ + 1,
5), 250 (M+, 43), 215 (39), 179 (16), 172 (19), 144 (27), 141 (31),
139 (100), 113 (13), 111 (38), 75 (31), 68 (74), 50 (12). ESI/APCI-
HRMS Anal. calcd for C11H7ClN2O3 250.0145, found 250.0142.
1
from EtOH gave a white solid. Mp: 325 °C dec. H NMR (400
3
MHz, d6-DMSO) δ 11.17, (br s, 2H), 7.74 (d, J ) 8.64 Hz, 2H),
3
7.56 (d, J ) 8.63 Hz, 2H), 5.84 (d, J ) 1.52 Hz, 1H). 13C NMR
(100.6 MHz, d6-DMSO) δ 163.8, 151.6, 151.2, 135.7, 130.3, 128.8,
128.7, 98.3. CG/MS (m/z) 225 (M+ + 3, 4), 224 (M+ + 2, 37),
223 (M+ + 1, 16), 222 (M+, 100), 181 (19), 180 (15), 179 (52),
151 (21), 140 (25), 139 (12), 138 (78), 137 (11), 111 (13), 102
(13), 89 (12), 76 (13), 75 (25), 68 (15), 50(11).
Acknowledgment. This work was supported in part by the
Agencia Co´rdoba Ciencia, the Consejo Nacional de Investiga-
ciones Cient´ıficas y Te´cnicas (CONICET), SECYT, Universidad
Nacional de Co´rdoba, and FONCYT, Argentina. J.I.B. gratefully
acknowledges receipt of a fellowship from CONICET.
6-(3-Chlorophenyl)uracil6 (10d). Substrate 1 (87.3 mg, 0.50
mmol) was used with 1-chloro-3-iodobenzene (138.3 mg, 0.58
mmol) as the electrophile. The product was obtained as a yellow
solid. Isolated yield 43% (47.9 mg, 0.22 mmol). Recrystallization
1
from EtOH gave a white solid. Mp: 280-283 °C. H NMR (400
1
Supporting Information Available: General methods, H
MHz, d6-DMSO) δ 11.20 (superimposed s, 1H), 11.17 (superim-
posed s, 1H), 7.81 (br s, 1H), 7.68 (m, 1H), 7.60 (m, 1H), 7.52 (t,
2J ) 7.90 Hz, 1H), 5.88 (s, 1H). 13C NMR (100.6 MHz, d6-DMSO)
δ 163.9, 151.6, 150.9, 133.6, 133.4, 130.7, 130.5, 126.8, 125.7,
98.8. CG/MS (m/z) 225 (M+ + 3, 3), 224 (M+ + 2, 35), 223 (M+
+ 1, 16), 222 (M+, 100), 181 (20), 180 (13), 179 (61), 151 (18),
140 (22), 138 (70), 111 (17), 89 (11), 75 (21), 68 (16).
NMR, and 13C NMR. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO800358V
(18) The aromatic carbons were not observed due to the low relaxations of
the C system and the large coupling C-F.
J. Org. Chem. Vol. 73, No. 12, 2008 4495