Regioselective direct C-H arylations of protected uracils. Synthesis of 5- and 6-aryluracil bases

Article abstract of DOI:10.1021/jo2006494

A new regioselective synthesis of 5- and 6-aryluracil bases based on direct C-H arylations of diverse 1,3-protected uracils has been developed. Benzyl-protected uracils were selected as the most practical in terms of stability during the arylation and fac

Full text of DOI:10.1021/jo2006494

ARTICLE
pubs.acs.org/joc
Regioselective Direct CꢀH Arylations of Protected Uracils. Synthesis of
5- and 6-Aryluracil Bases
ꢀ
ꢀ
Miroslava Cerꢀnovꢁa, Igor Cerꢀna, Radek Pohl, and Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research
Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic
S Supporting Information
b
ABSTRACT: A new regioselective synthesis of 5- and 6-aryluracil bases based on direct CꢀH
arylations of diverse 1,3-protected uracils has been developed. Benzyl-protected uracils were
selected as the most practical in terms of stability during the arylation and facile cleavage of the
benzyl groups. Pd-catalyzed CꢀH arylations in the absence of CuI gave preferentially 5-aryl-,
whereas the reactions in the presence of CuI gave 6-aryl-1,3-dibenzyluracils. Final deprotec-
tion either by transfer hydrogenolysis over Pd/C or by treatment with BBr3 gave the desired
free arylated uracil bases in good yields.
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Diverse uracil bases and nucleosides bearing aryl groups at
positions 5 or 6 display a wide range of biological activities1
(cytostatic, antiviral, antagonists of GnRH, etc.). Arylation at
position 5 is often used for labeling of nucleotides and DNA for
applications in bioanalysis or chemical biology.2 The 5- or
6-aryluracils are most often prepared by heterocyclizations3 or
by cross-coupling reactions4 of halouracils with arylboronic acids
or -stannanes or metalated uracils with aryl halides. However, still
some aryluracil derivatives are difficult to prepare, and therefore,
development of alternative methodologies is of interest. In
addition, cross-couplings, N-alkylation/arylation, and other re-
actions would be desirable to be combined in regioselective
cascades in order to prepare highly substituted heterocycles.
Direct CꢀH arylations5 have recently emerged as an alternative
to cross-couplings, and we6 and others7 have repeatedly shown
that they are complementary and could be used for multiple
substitutions of diverse heterocycles. On the other hand, there
were only scarce examples of CꢀH arylations of electron-poor
pyrimidines8 (usually using the corresponding N-oxides9).
In our recent preliminary communication10 we reported
regioselective Pd-catalyzed and/or Cu-mediated direct CꢀH
arylations of 1,3-dimethyluracil. We found that reactions in the
absence of CuI provided 5-aryl-1,3-dimethyluracils as a major
products, whereas the reactions in the presence of CuI gave
preferentially 6-aryl-1,3-dimethyluracils. However, this chemis-
try did not work in unsubstituted uracil and the methyl groups at
N1 and N3 are not easily cleavable. Therefore, it was needed to
develop an efficient protection strategy for uracil CꢀH aryla-
tions. In this paper, we report on the CꢀH arylations of diverse
protected uracils and development of a practical synthesis of free
arylated uracil bases.
As mentioned before, the previously reported regioselective
CꢀH arylation was developed for 1,3-dimethyluracil (1). Three
different sets of conditions were developed (Scheme 1, Table 1)
and applied in regioselective direct arylation with 4-tolyl iodide
9a: (A) Pd(OAc)2 in combination with P(C6F5)3 in the presence
of Cs2CO3, (B) the same catalyst in combination with 3 equiv of
CuI, and (C) CuI and Cs2CO3 in the absence of Pd(OAc)2
and ligand. The reaction in the absence of CuI gave the 5-aryl-
1,3-dimethyluracil 10a as major product (entry 1), whereas the
reactions in the presence of CuI (conditions B or C, entries 2
and 3) gave mainly or exclusively 6-aryl-1,3-dimethyluracil 11a.
The explanation of the dichotomy is probably the switch of
the mechanism from concerted metalationꢀdeprotonation
(CMD)11 to the cupration/Ullmann coupling.12,7e The reactions
did not proceed for 1,3-unsubstituted uracil base, and therefore,
for the access to free aryluracil bases, we needed a suitable
protection at N1 and N3 that should be compatible with the
harsh conditions of the CꢀH arylations but should be cleavable
at the end without decomposition of the aryluracils. Thus, we
have prepared (by literature procedures) a set of protected
uracils 2ꢀ8 bearing diverse N-protecting groups: silyl
(TMS,13a TBDMS13b), benzyloxymethyl (BOM),13c benzoyl
(Bz),13d methoxyethoxymethyl (MEM),13c p-methoxybenzyl
(PMB),13e and benzyl (Bn).13e They were all tested in CꢀH
arylation reactions with 4-iodotoluene 9a in order to test the
stability of the protecting groups under the harsh CꢀH arylation
conditions either in the absence (conditions A) or in the
presence of CuI (conditions B) in the presence of Cs2CO3 at
160 °C (Scheme 1, Table 1). The Cu-catalyzed reaction in the
Received: March 30, 2011
Published: May 18, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 1. CꢀH Arylation of 1ꢀ8
Table 1. CꢀH Arylation of Diverse Protected Uracils 1ꢀ8
protecting group
products
6-isomer
entry
compound
R1
R2
method
5-isomer
yield (%)
yield (%)
ratio
1b
2b
3b
4
1
1
1
2
3
4
4
5
5
6
6
7
7
7
8
8
8
-CH3
-CH3
-CH3
TMS
TBDMS
BOM
BOM
H
-CH3
-CH3
-CH3
TMS
TBDMS
BOM
BOM
Bz
A
B
C
10a
10a
10a
53
5
11a
9
73
35
86:14
6:94
11a
0
11a
0:100
unstable
5
unstable
6
A
B
A
B
A
B
A
B
C
A
B
C
complex mixture
7
complex mixture
8
complex mixture
9
H
Bz
complex mixture
10
11
12
13
14
15
16
17
MEM
MEM
PMB
PMB
PMB
Bn
MEM
MEM
PMB
PMB
PMB
Bn
12a
12a
14a
14a
14a
16a
16a
16a
24
6
13a
13a
15a
15a
15a
17a
17a
17a
0
19
6
100:0
25:75a
88:12
14:86
10:90
86:14
14:86
9:91
47
8
46
34
7
4
45
10
4
Bn
Bn
66
42
Bn
Bn
a Ratio from 1H NMR spectra. b Taken from ref 10.
absence of Pd gave exclusively 6-substituted derivatives but in
lower conversions (Method C).
The deprotection of bis-PMB-uracil 14a was attempted by
treatment with neat refluxing TFA,14 Ce(NH4)2(NO3)6,13e and
DDQ15 (entries 1ꢀ3), but all of these reactions were unsuccess-
ful (either no reaction or complex mixtures). Catalytic transfer
hydrogenolysis16 with ammonium formate over 10% Pd/C (1.1
equiv) gave only selective cleavage of one PMB group at N1 to
afford monoprotected 3-PMB-derivative 18a in 82% (entry 4).
Only the treatment of 14a with BBr317 led to complete cleavage
of both PMB groups to give the desired 5-tolyluracil (20a) in
moderate yield of 62% (entry 5). Deprotection of benzyl-
protected uracil 16a was performed using catalytic transfer
hydrogenation with ammonium formate over 10% Pd/C.16
The use of 1.1 equiv of Pd/C provided a complete and efficient
deprotection to give uracil 20a in almost quantitative yield (entry
7). Decrease of the loading of Pd/C to 0.54 equiv led to
incomplete deprotection giving the 3-benzyluracil 19a as the
major product in 80% yield accompanied by only minor amount
of 20a (15%). The use of BBr317 in refluxing xylene converted
protected uracil (16a) to uracil 20a in 15% yield.
Silylated uracils 2 and 3 (entries 4, 5) were unstable under the
reaction conditions and quickly decomposed. The use of BOM-
protected uracil 4 and 3-benzoyluracil (5) gave inseparable
complex mixtures (entries 6ꢀ9). The MEM-protected uracil 6
was stable but gave only moderate conversions to 5-tolyl (12a)
(the only product under conditions A, entry 10) and/or 6-tolyl
(13a) (major product under conditions B, entry 11) derivatives.
The most stable and efficient protective groups were the benzyl-
type substituents: PMB or Bn. The corresponding benzylated
uracils 7 and 8 reacted in almost the same manner and efficiency as
the parent 1,3-dimethyluracil (1). The reactions in the absence of
CuI (conditions A, entries 12 and 15) gavethe 5-tolyluracils14a or
16a asmajor products (ca. 7:1) in acceptable yields (47% and 45%,
respectively). The Pd-catalyzed reactions in the presence of CuI
(conditions B, entries 13, 16) provided the 6-tolyluracils 15a or
17a as major products (ca. 6:1) in reasonable yields (46% and
66%, respectively). The Cu-mediated reactions in the absence of
Pd gave lower conversions (entries 14, 17).
On the basis of these results, we selected benzyl protection for
the preparation of arylated uracil bases. 1,3-Dibenzyluracil (8)
was used as starting compound in a series of direct CꢀH
arylations with diverse aryl halides 9aꢀ9g under the above-
mentioned conditions (A) Pd(OAc)2, P(C6F5)3 in the presence
The next task was to develop an efficient deprotection
protocol for the benzylated aryluracils. The methods were tested
on PMB- and Bn- protected 5-tolyluracils 14a and 16a (Scheme 2,
Table 2).
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ARTICLE
Table 2. Deprotection of 14a, 16a
entry
compounds
R
reagents
yield of 18a/19a (%)
yield of 20a (%)
1
2
3
4
5
6
7
8
14a
14a
14a
14a
14a
16a
16a
16a
PMB
PMB
PMB
PMB
PMB
Bn
TFAa
0
0
b
Ce(NH4)2(NO3)6
DDQc
NH4HCO2, 10% Pd/C (1.1 equiv)d
complex mixture
complex mixture
0
0
82 (18a)
0
e
BBr3
0
62
15
98
15
NH4HCO2, 10% Pd/C (0.54 equiv) f
NH4HCO2, 10% Pd/C (1.1 equiv)d
80 (19a)
Bn
0
g
Bn
BBr3
0
a TFA; reflux; 65 °C. b Ce(NH4)2(NO3)6 (4 equiv), CH3CN/H2O 3:1, rt; 3 h. c DDQ, DCM/H2O 5:1, rt, 3.5 days. d 10% Pd/C (1.1 equiv), NH4HCO2,
MeOH, 72 °C, 17 h. e BBr3, m-xylene, pressure tube 140 °C, 5 h. f 10% Pd/C (0.54 equiv), NH4HCO2, MeOH, 72 °C, 17 h. g BBr3, m-xylene, reflux,
140 °C, 19 h.
Scheme 2. Deprotection of 14a, 16a
these compounds were deprotected by treatment with BBr3
in overheated xylene (in sealed tube). Under those conditions
the deprotection of 16eꢀg and 17eꢀg proceeded readily to
afford the desired uracil bases 20f, 20g and 22eꢀg in almost
quantitative yields (apart from 22g, obtained in moderate
38% yield).
In conclusion, a new method for the synthesis of 5-aryluracil
and 6-aryluracil bases has been developed, based on the applica-
tion of regioselective CꢀH arylations to 1,3-dibenzyluracil
followed by deprotection. The Pd-catalyzed CꢀH arylations
under Pd catalysis gave preferentially 5-aryluracils, whereas in the
presence of CuI the regioselectivity reverted to 6-aryluracils. The
debenzylation was performed either by transfer hydrogenolysis
with ammonium formate over Pd/C or by treatment with BBr3
(for more bulky aryl groups).
of Cs2CO3 and (B) the same catalyst and base in the presence of
3 equiv of CuI (Scheme 3, Table 3). The reactions in the absence
of CuI (conditions A) gave 5-aryl-1,3-dibenzyluracils 16aꢀg as
major products (selectivities 4:1 to 9:1) in 19ꢀ70% yields
(entries 1,3,5,7,9,11,13). In all cases minor amounts of the other
regioisomer (6-aryluracils 17aꢀg) were also isolated. More
bulky and less reactive aryl bromides 9f and 9g gave generally
lower yields. The reactions in the presence of CuI gave pre-
dominantly (3:1ꢀ7:1) or even exclusively (for 9b) 6-aryl-1,3-
dibenzyluracils 17aꢀg in 28ꢀ66% yields (entries 2, 4, 6, 8, 10,
12, 14). The regioisomers were separable by column chroma-
tography (1% of ethyl acetate in toluene) and were assigned by
HMBC NMR spectroscopy. Both electron-rich (2-bromothio-
fene, 2-bromofurane) and electron-poor (3-iodopyridine, 9-ben-
zyl-6-iodopurine) hetaryl halides were also examined in these
reactions under conditions A and B, but in all cases the reactions
did not proceed. Apparently this methodology is only applicable
to carbocyclic aryl halides.
Two different cleavage procedures D (10% Pd/C, ammonium
formate, CH3OH, refux 72 °C, 17 h) and E (BBr3, m-xylene,
140 °C, pressure tube, 5 h) were further used in deprotection of
5- and 6-aryl-1,3-dibenzyluracils. The 5-aryl isomers 16aꢀd and
6-aryl isomers 17aꢀd bearing small electron-rich aryl groups
were readily deprotected by transfer hydrogenolysis by ammo-
nium formate over Pd/C (conditions D) to give the desired free
5-aryl- 20aꢀd and 6-aryluracil bases 22aꢀd in quantitative
yields. The transfer hydrogenation of the 4-fluorophenyl deriva-
tives 16e and 17e gave inseparable mixtures with the products of
dehalogenation. Therefore, we used the treatment with BBr3
which afforded quantitatively the fully deprotected 6-aryluracil
22e. The corresponding 5-(fluorophenyl)uracil was unstable
under these conditions and decomposed. In the case of com-
pounds bearing bulky aromatic substituents at position 5 and 6
(16f, 16g, 17f, and 17g), we observed only partial deprotection
under conditions D giving 3-benzyluracils 19f, 19g, 21f, and 21g
as major products. The catalytic hydrogenolysis over Pd/C was
not improved by the use of H2 or cyclohexadiene. Therefore,
’ EXPERIMENTAL SECTION
General. All starting aryl halides 9aꢀg, Pd(OAc)2, P(C6F5)3,
copper(I) iodide (purum), Cs2CO3, and other reagents were purchased
from commercial suppliers and used without any further treatment. Dry
DMF, methanol, and m-xylene was used as received from supplier.
Cs2CO3 is extremely hygroscopic and must be kept away from moisture.
Cs2CO3 was dried at 500 °C under vacuum for 10 min prior to each use.
All CꢀH arylations were carried out in evacuated flame-dried glassware
with magnetic stirring under argon atmosphere. All compounds were
fully characterized by NMR, and spectra were recorded on a 600 MHz
(1H at 600 MHz, 13C at 151 MHz) or on a 500 MHz (500 MHz for 1H
1
and 125.7 MHz for 13C) spectrometer. H and 13C resonances were
1
assigned by analysis of H, 13C-APT, H,C-HSQC and H,C-HMBC
spectra. For monoprotected derivatives, H,C-HMBC measurements
showed characteristic cross-peaks between CH2-Ph and C-2,6 (1-benzyl
derivative), and CH2-Ph and C-2,4 (3-benzyl derivative). The samples
were measured in CDCl3 and chemical shifts (in ppm, δ scale) were
referenced to TMS as internal standard or in DMSO-d6 referenced to the
residual solvent signal (1H NMR δ 2.50 ppm, 13C NMR 39.7 ppm).
Coupling constants (J) are given in Hz. IR spectra (wavenumbers
in cmꢀ1) were recorded using KBr technique (Bruker IFS 88 spectro-
meter) or using ATR technique (Bruker Alpha FT-IR spectrometer).
High resolution mass spectra were measured on a LTQ Orbitrap XL
(Thermo Fisher Scientific) spectrometer using EI or ESI ionization
technique. Melting points were determined on a Kofler block and are
uncorrected. Elemental analyses were measured on PE 2400 Series II
CHNS/O (Perkin-Elmer, USA, 1999).
Method A. General Procedure for CꢀH Arylation of 1,3-
Dibenzyluracil 8 with Aryl Halides 9aꢀg at the C-5 Position.
DMF (6 mL) was added through a septum to an argon-purged vial
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Table 3. CꢀH Arylations of 1,3-Dibenzyluracil 8 with Diverse Aryl Halides and Following Deprotection of 5- and 6-Regioisomers
ARTICLE
(16aꢀg) as a major product and regioisomer at the C-6 position
(17aꢀg) as a minor product.
Scheme 3. Preparative CꢀH Arylations of 8 and Subsequent
Deprotectiona
Method B. General Procedure for CꢀH Arylation of 1,3-
Dibenzyluracil 8 with Aryl Halides 9aꢀg at the C-6 Position.
DMF (6 mL) was added through a septum to an argon-purged vial
containing a 1,3-dibenzyuracil (8, 292 mg, 1 mmol), aryl halide (9aꢀg, 2
mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %), P(C6F5)3 (53.2 mg,
0.1 mmol, 10 mol %), CuI (571 mg, 3 mmol) and Cs2CO3 (814 mg, 2.5
mmol). Reaction mixture was stirred at 160 °C for 48 h. After cooling to
rt, the mixture was diluted with chloroform (20 mL), and solvents were
evaporated under reduced pressure. The crude product was chromatographed
by column chromatography on 120 g of silica gel in gradient toluene to
1% ethyl acetate in toluene to give regioisomer substituted in the C-6
position (17aꢀg) as a major product and regioisomer at the C-5
position (16aꢀg) as a minor product.
Method C. General Procedure for CꢀH Arylation of Pro-
tected Uracils 7, 8 with 4-Iodotoluene 9a at the C-6 Position
in the Absence of Pd Catalyst and Ligand. DMF (3 mL) was
added through a septum to an argon-purged vial containing protected
uracils (7, 8, 0.5 mmol), 4-iodotoluene (9a, 218 mg, 1 mmol), CuI (286
mg, 1.5 mmol) and Cs2CO3 (407 mg, 1.25 mmol). Reaction mixture was
stirred at 160 °C for 48 h. After cooling to rt, the mixture was diluted with
chloroform (20 mL), and solvents were evaporated under reduced
pressure. The crude product was chromatographed by column chroma-
tography on 60 g of silica gel in gradient toluene to 1% ethyl acetate in
toluene to give regioisomer substituted in the C-6 position (15a, 17a) as
a major product and regioisomer at the C-5 position (14a, 16a) as a
minor product.
Method D. General Procedure for the Removal of the
Benzyl Protecting Groups Using Transfer Hydrogenation. A
mixture of dibenzyluracil derivative 16aꢀd, 17aꢀd (0.3 mmol), ammo-
nium formate (7.5 mL of a 0.4 N solution in dry MeOH) and 10%
palladiumꢀcharcoal (0.33 mmol of Pd) was refluxed at 72 °C for 17 h.
a Reagents and conditions. (i) Method A: Ar-X (9aꢀg, 2 equiv),
Pd(OAc)2 (0.05 equiv), P(C6F5)3 (0.1 equiv), Cs2CO3 (2.5 equiv),
DMF, 160 °C, 48 h. (ii) Method B: Ar-X (9aꢀg, 2 equiv), Pd(OAc)2
(0.05 equiv), P(C6F5)3 (0.1 equiv), CuI (3 equiv), Cs2CO3 (2.5 equiv),
DMF, 160 °C, 48 h. (iii) Method D: 10% Pd/C, NH4HCO2, CH3OH,
refux 72 °C, 17 h. (iv) Method E: BBr3, m-xylene, 140 °C, pressure
tube, 5 h.
containing a 1,3-dibenzyluracil (8, 292 mg, 1 mmol), aryl halide (9aꢀg,
2 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %), P(C6F5)3 (53.2
mg, 0.1 mmol, 10 mol %) and Cs2CO3 (814 mg, 2.5 mmol). Reaction
mixture was stirred at 160 °C for 48 h. After cooling to rt, the mixture was
diluted with chloroform (20 mL), and solvents were evaporated under
reduced pressure. The crude product was chromatographed by column
chromatography on 120 g of silica gel in gradient toluene to 1% ethyl
acetate in toluene to give regioisomer substituted in the C-5 position
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ARTICLE
The mixture was filtered through Celite, and the solid residue was
extensively washed with MeOH and CHCl3 (ca. 250 mL). Removal of
solvents under reduced pressure and following column chromatography
on 40 g of silica gel in gradient chloroform to 2% methanol in chloroform
gave the pure debenzylated products (20aꢀd, 22aꢀd).
162.1 (C-4). IR (KBr): 2820, 1715, 1666, 1516, 1453, 1353, 1279,
1103. MS (ESIþ), m/z (% relative intensity): 379 (Mþ þ H, 26), 401
(Mþ þ Na, 100). HR MS (Mþ þ Na): 401.1685 (calcd for C19H26N2-
NaO6 401.1683).
1,3-Bis(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione (7).
Compound 7 was prepared from uracil according to published proce-
dure and experimental data are in accordance to literature.13e Yield 99%
yield, as a white powder, mp 96ꢀ97 °C. 1H NMR (600.1 MHz, CDCl3):
3.78 (s, 3H, CH3O-3); 3.80 (s, 3H, CH3O-1); 4.83 (s, 2H, CH2N-1); 5.07
(s, 2H, CH2N-3); 5.71 (d, 1H, J5,6 = 7.9, H-5); 6.83 (m, 2H, H-m-
C6H4OMe-3); 6.88 (m, 2H, H-m-C6H4OMe-1); 7.07 (d, 1H, J6,5 = 7.9,
H-6); 7.21 (m, 2H, H-o-C6H4OMe-1); 7.46 (m, 2H, H-o-C6H4OMe-3).
13C NMR (150.9 MHz, CDCl3): 43.8 (CH2N-3); 51.8 (CH2N-1); 55.2
(CH3O-3); 55.3 (CH3O-1); 102.1 (CH-5); 113.7 (CH-m-C6H4OMe-3);
114.4 (CH-m-C6H4OMe-1); 127.1 (C-i-C6H4OMe-1); 129.1 (C-i-
C6H4OMe-3); 129.7 (CH-o-C6H4OMe-1); 130.7 (CH-o-C6H4OMe-
3); 141.5 (CH-6); 151.7 (C-2); 159.0 (C-p-C6H4OMe-3); 159.7 (C-p-
C6H4OMe-1); 162.9 (C-4). IR (KBr): 2837, 1711, 1667, 1611, 1585,
1514, 1454, 1388, 1256, 1026. MS (ESIþ), m/z (% relative intensity): 353
(Mþ þ H, 14), 375 (Mþ þ Na, 100), 391 (Mþ þ K, 30). HR MS (Mþ þ
H): 353.1496 (calcd for C20H21N2O4 353.1496).
1,3-Bis(4-methoxybenzyl)-5-p-tolylpyrimidine-2,4(1H,3H)-
dione (14a). DMF (3 mL) was added through a septum to an argon-
purged vial containing a 1,3-dimethoxybenzyluracil (7, 176 mg, 0.5
mmol), 4-iodotoluene (9a, 218 mg, 1 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol, 5 mol %), P(C6F5)3 (26.6 mg, 0.05 mmol, 10 mol %) and
Cs2CO3 (407 mg, 1.25 mmol). Reaction mixture was stirred at 160 °C
for 48 h. After cooling to rt, the mixture was diluted with chloroform
(20 mL), and solvents were evaporated under reduced pressure. The
crude product was chromatographed by column chromatography on 50
g of silica gel in gradient hexane to 20% ethyl acetate in hexane to give
regioisomer 14a substituted in the C-5 position as a major product in
47% yield, as a yellow oil. 1H NMR (500.0 MHz, CDCl3): 2.27 (s, 3H,
CH3); 3.70 (s, 3H, CH3O-PMB-3); 3.73 (s, 3H, CH3O-PMB-1); 4.84
(s, 2H, CH2-1); 5.08 (s, 2H, CH2-3); 6.76 (m, 2H, H-m-PMB-3); 6.81
(m, 2H, H-m-PMB-1); 7.09 (m, 2H, H-m-C6H4Me); 7.18 (m, 2H, H-o-
PMB-1); 7.19 (s, 1H, H-6); 7.24 (m, 2H, H-o-C6H4Me); 7.45 (m, 2H,
H-o-PMB-3). 13C NMR (125.7 MHz, CDCl3): 21.2 (CH3); 44.3 (CH2-
3); 51.9 (CH2-1); 55.2, 55.3 (CH3O-PMB-1,3); 113.7 (CH-m-PMB-3);
114.5 (CH-m-PMB-1); 115.0 (C-5); 127.3 (C-i-PMB-1); 128.2
(CH-o-C6H4Me); 129.1 (CH-m-C6H4Me); 129.2 (C-i-PMB-3); 129.7
(CH-o-PMB-1); 130.0 (C-i-C6H4Me); 131.0 (CH-o-PMB-3); 137.8
(C-p-C6H4Me); 138.7 (CH-6); 151.4 (C-2); 159.1 (C-p-PMB-3); 159.7
(C-p-PMB-1); 162.0 (C-4). IR (KBr): 2835, 1701, 1652, 1612, 1513,
1453, 1249, 1033. MS (ESIþ), m/z (% relative intensity): 443 (Mþ þ H,
10), 465 (Mþ þ Na, 100). HR MS (Mþ þ H): 443.1964 (calcd for
C27H27N2O4 443.1965).
Method E. General Procedure for the Removal of the
Benzyl Protecting Groups with Boron Tribromide. Boron
tribromide (1.5 mmol) was added to dibenzyluracil derivate 16eꢀg,
17eꢀg (0.3 mmol) in m-xylene (6 mL). The mixture was heated ina
pressure tube at 140 °C for 5 h and cooled, and MeOH (1.5 mL) was
added. The mixture was stirred at room temperature for 30 min. Solvents
were evaporated under reduced pressure, and products 20f,g and 22eꢀg
were isolated by column chromatography on 60 g of silica gel in gradient
chloroform to 5% methanol in chloroform.
3-Benzoylpyrimidine-2,4(1H,3H)-dione (5). Compound 5
was prepared from uracil according to published procedure13d in 61%
yield, as a white crystals from CHCl3/MeOH, mp 203ꢀ204 °C (lit.18
mp 200ꢀ202 °C). 1H NMR (500.0 MHz, DMSO-d6): 5.74 (d, 1H, J5,6
=
7.7, H-5); 7.60 (m, 2H, H-m-Ph); 7.66 (d, 1H, J6,5 = 7.7, H-6); 7.77 (m,
1H, H-p-Ph); 7.96 (m, 2H, H-o-Ph); 11.61 (bs, 1H, NH). 13C NMR
(125.7 MHz, DMSO-d6): 100.3 (CH-5); 129.7 (CH-m-Ph); 130.4
(CH-o-Ph); 131.5 (C-i-Ph); 135.6 (CH-p-Ph); 143.5 (CH-6); 150.3
(C-2); 163.1 (C-4); 170.2 (CO). IR (KBr): 1765, 1748, 1706, 1656,
1597, 1416, 1390, 1231, 1181. MS (ESIþ), m/z (% relative intensity):
239 (Mþ þ Na, 100). HR MS (Mþ þ H): 239.0426 (calcd for C11H8-
N2NaO3 239.0427).
1,3-Bis((2-methoxyethoxy)methyl)pyrimidine-2,4(1H,3H)-
dione (6). To a mixture of uracil (336 mg, 3 mmol) and anhydrous
K2CO3 (2.07 g, 15 mmol) in dry DMF (5 mL) was added dropwise
ClCH2OC2H5 (1.12 g, 9 mmol) below 0 °C. The mixture was allowed to
warm to room temperature and was stirred overnight. Inorganic salts
were removed by filtration, and the filtrate was concentrated under
reduced pressure. The protected compound 6 were isolated by column
chromatography on 60 g of silica gel in gradient chloroform to 1%
methanol in chloroform in 35% yield, as a colorless oil. 1H NMR (500.0
MHz, CDCl3): 3.36, 3.37 (2 ꢁ s, 2 ꢁ 3H, H-60,600); 3.53 (m, 2H, H-400);
3.54 (m, 2H, H-40); 3.75 (m, 2H, H-30); 3.80 (m, 2H, H-300); 5.23 (s, 2H,
H-10); 5.47 (s, 2H, H-100); 5.80 (d, 1H, J5,6 = 8.0, H-5); 7.33 (d, 1H, J6,5
=
8.0, H-6). 13C NMR (125.7 MHz, CDCl3): 59.0, 59.0 (CH3-60,600); 69.0
(CH2-30); 69.8 (CH2-300); 71.0 (CH2-100); 71.5 (CH2-400); 71.6 (CH2-
40); 77.9 (CH2-10); 102.6 (CH-5); 141.8 (CH-6); 151.9 (C-2); 162.8
(C-4). IR (KBr): 2821, 1719, 1671, 1638, 1452, 1103, 1089. MS (ESIþ),
m/z (% relative intensity): 289 (Mþ þ H, 6), 311 (Mþ þ Na, 100),
599 (2Mþ þ Na, 25). HR MS (Mþ þ Na): 311.1213 (calcd for
C12H20N2NaO6 311.1214).
1,3-Bis((2-methoxyethoxy)methyl)-5-p-tolylpyrimidine-
2,4(1H,3H)-dione (12a). DMF (2 mL) was added through a septum
to an argon-purged vial containing compound 6 (86.5 mg, 0.3 mmol),
4-iodotoluene (9a, 131 mg, 0.6 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol,
5 mol %), P(C6F5)3 (16 mg, 0.03 mmol, 10 mol %) and Cs2CO3 (244
mg, 0.75 mmol). Reaction mixture was stirred at 160 °C for 48 h. After
cooling to rt, the mixture was diluted with chloroform (20 mL), and
solvents were evaporated under reduced pressure. The crude product
was chromatographed by column chromatography on 40 g of silica gel in
gradient chloroform to 1% metanol in chloroform to give regioisomer
12a substituted in C-5 position as a major product in 24% yield, as a
yellow oil. 1H NMR (500.0 MHz, CDCl3): 2.37 (s, 3H, CH3); 3.36, 3.37
(2 ꢁ s, 2 ꢁ 3H, H-60,600); 3.54 (m, 2H, H-400); 3.55 (m, 2H, H-40); 3.79
(m, 2H, H-30); 3.84 (m, 2H, H-300); 5.30 (s, 2H, H-10); 5.56 (s, 2H,
H-100); 7.20 (m, 2H, H-m-Ph); 7.40 (m, 2H, H-o-Ph); 7.47 (s, 1H, H-6).
13C NMR (125.7 MHz, CDCl3): 21.2 (CH3); 59.0, 59.0 (CH3-60,600);
69.1 (CH2-30); 69.9 (CH2-300); 71.5 (CH2-400); 71.5 (CH2-100); 71.7
(CH2-40); 78.0 (CH2-10); 115. Five (C-5); 128.1 (CH-o-Ph); 129.1
(CH-m-Ph); 129.4 (C-i-Ph); 138.0 (C-i-Ph); 138.7 (CH-6); 151.5 (C-2);
1,3-Bis(4-methoxybenzyl)-6-p-tolylpyrimidine-2,4(1H,3H)-
dione (15a). DMF (3 mL) was added through a septum to an argon-
purged vial containing a 1,3-dimethoxybenzyluracil (7, 176 mg,
0.5 mmol), 4-iodotoluene (9a, 218 mg, 1 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol, 5 mol %), P(C6F5)3 (26.6 mg, 0.05 mmol, 10 mol %), CuI
(286 mg, 1.5 mmol) and Cs2CO3 (407 mg, 1.25 mmol). Reaction
mixture was stirred at 160 °C for 48 h. After cooling to rt, the mixture was
diluted with chloroform (20 mL), and solvents were evaporated under
reduced pressure. The crude product was chromatographed by column
chromatography on 50 g of silica gel in gradient hexane to 20% ethyl
acetate in hexane to give regioisomer 15a substituted in the C-6 position
as a major product in 46% yield, as a yellow oil. 1H NMR (500.0 MHz,
CDCl3): 2.32 (s, 3H, CH3); 3.69 (s, 3H, CH3O-PMB-3); 3.72 (s, 3H,
CH3O-PMB-1); 4.80 (bs, 2H, CH2-1); 5.06 (s, 2H, CH2-3); 5.59 (s, 1H,
H-5); 6.67 (m, 2H, H-m-PMB-1); 6.74 (m, 2H, H-o-PMB-1); 6.78 (m,
2H, H-m-PMB-3); 6.98 (m, 2H, H-o-C6H4Me); 7.11 (m, 2H, H-m-
C6H4Me); 7.43 (m, 2H, H-o-PMB-3). 13C NMR (125.7 MHz, CDCl3):
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21.3 (CH3); 44.0 (CH2-3); 48.8 (CH2-1); 55.2 (CH3O-PMB-1,3);
103.4 (CH-5); 113.7 (CH-m-PMB-3); 113.9 (CH-m-PMB-1); 127.9
(CH-o-C6H4Me); 128.3 (CH-o-PMB-1); 128.6 (C-i-PMB-1); 129.3
(C-i-PMB-3); 129.3 (CH-m-C6H4Me); 130.4 (C-i-C6H4Me); 130.8
(CH-o-PMB-3); 140.3 (C-p-C6H4Me); 152.5 (C-2); 154.9 (C-6); 158.9
(C-p-PMB-3); 159.1 (C-p-PMB-1); 162.1 (C-4). IR (KBr): 2836, 1703,
1660, 1613, 1513, 1441, 1248, 1034. MS (ESIþ), m/z (% relative
intensity): 465 (Mþ þ Na, 100). HR MS (Mþ þ Na): 465.1783
(calcd for C27H26N2NaO4 465.1785).
C6H4Me); 129.1 (CH-m-1Bn); 129.4 (CH-o-3Bn); 129.8 (C-i-
C6H4Me); 135.3 (C-i-1Bn); 136.9 (C-i-3Bn); 137.8 (C-p-C6H4Me);
138.9 (CH-6); 151.4 (C-2); 162.0 (C-4). IR (KBr): 1704, 1652, 1584,
1515, 1495, 1451, 1379, 1284, 1219, 1083. MS (ESIþ), m/z (% relative
intensity): 383 (Mþ þ H, 10), 405 (Mþ þ Na, 100), 421 (Mþ þ K, 12).
HR MS (Mþ þ H): 383.1754 (calcd for C25H23N2O2 383.1754).
1,3-Dibenzyl-6-p-tolylpyrimidine-2,4(1H,3H)-dione (17a).
Compound 17a was prepared from 8 according to general procedure
1
(Method B) in 66% yield, as a yellowish oil. H NMR (499.8 MHz,
3-(4-Methoxybenzyl)-5-p-tolylpyrimidine-2,4(1H,3H)-dione
(18a). A mixture of compound 14a (50 mg, 0.113 mmol), ammonium
formate (2.8 mL of a 0.4 N solution in dry MeOH) and 10%
palladiumꢀcharcoal (132 mg 10% Pd/C, 0.124 mmol of Pd, 1.1 equiv
of Pd) was refluxed at 72 °C for 17 h. The mixture was filtered through
Celite, and the solid residue was extensively washed with MeOH and
CHCl3 (ca. 120 mL). Removal of solvents under reduced pressure and
following column chromatography on 40 g of silica gel in gradient
chloroform to 1% methanol in chloroform gave the pure monodepro-
tected product 18a in 82% yield, as a white powder, mp 175ꢀ177 °C. 1H
NMR (500.0 MHz, CDCl3): 2.36 (s, 3H, CH3); 3.77 (s, 3H, CH3O);
5.13 (s, 2H, CH2Ph); 6.83 (m, 2H, H-m-C6H4OMe); 7.20 (m, 2H, H-m-
C6H4Me); 7.26 (d, 1H, J6,NH = 5.9, H-6); 7.38 (m, 2H, H-o-C6H4Me);
7.49 (m, 2H, H-o-C6H4OMe); 9.62 (bs, 1H, NH). 13C NMR (125.7
MHz, CDCl3): 21.18 (CH3); 43.63 (CH2); 55.22 CH3O); 113.70 (CH-
m-C6H4OMe); 115.09 (C-5); 128.18 (CH-o-C6H4Me); 128.90 (C-i-
C6H4OMe); 129.15 (CH-m-C6H4Me); 129.75 (C-i-C6H4Me); 130.81
(CH-o-C6H4OMe); 135.25 (CH-6); 137.87 (C-p-C6H4Me); 152.53
(C-2); 159.13 (C-p-C6H4OMe); 162.31 (C-4). IR: 2920, 1713, 1628,
1611, 1512, 1440, 1292, 1245, 1150, 1038. MS (ESIþ), m/z (% relative
intensity): 323 (Mþ þ H, 30), 345 (Mþ þ Na, 100), 667 (2Mþ þ Na,
15). HR MS (Mþ þ H): 323.1390 (calcd for C19H19N2O3 323.1390).
1,3-Dibenzylpyrimidine-2,4(1H,3H)-dione (8). Anhydrous
DMF (35 mL) was added through a septum to an argon-purged flask
containing a uracil (930 mg, 8.29 mmol) and K2CO3 (2.75 g, 19.89
mmol), and the mixture was stirred for 18 h, resulting in a thick gel.
Benzyl bromide (2.99 mL [4.3 g], 24.87 mmol) was added, and the
reaction was stirred for another 3 days. The reaction mixture was
concentrated and redissolved in water and extracted with EtOAc. The
combined organic layers were washed with water and brine, dried over
MgSO4, filtered, and concentrated. Purification by column chromatog-
raphy on a 150 g of silica gel (1:4 EtOAc/hexanes) afforded the product
(8) in 89% yield, as a white crystals from hexane/ethylacetate, mp
67ꢀ69 °C (lit.19 67ꢀ68 °C). 1H NMR (499.8 MHz, CDCl3): 4.91 (s,
2H, CH2-1); 5.15 (s, 2H, CH2-3); 5.74 (d, 1H, J5,6 = 7.9, H-5); 7.11 (d,
1H, J6,5 = 7.9, H-6); 7.26 (m, 1H, H-p-3Bn); 7.27 (m, 2H, H-o-1Bn);
7.31 (m, 2H, H-m-3Bn); 7.36 (m, 1H, H-p-1Bn); 7.37 (m, 2H, H-m-
1Bn); 7.48 (m, 2H, H-o-3Bn). 13C NMR (125.7 MHz, CDCl3): 44.41
(CH2-3); 52.24 (CH2-1); 102.16 (CH-5); 127.58 (CH-p-3Bn); 128.01
(CH-o-1Bn); 128.38 (CH-m-3Bn); 128.49 (CH-p-1Bn); 128.97 (CH-o-
3Bn); 129.11 (CH-m-1Bn); 135.20 (C-i-1Bn); 136.77 (C-i-3Bn);
141.70 (CH-6); 151.74 (C-2); 162.81 (C-4). IR (KBr): 1700, 1663,
1605, 1585, 1495, 1452, 1393, 1218. MS (ESIþ), m/z (% relative
intensity): 315 (Mþ þ Na, 100). HR MS (Mþ þ H): 293.1285
(calcd for C18H17N2O2 293.1285).
CDCl3): 2.38 (s, 3H, CH3); 4.94 (bs, 2H, CH2-1); 5.20 (s, 2H, CH2-3);
5.70 (s, 1H, H-5); 6.90 (m, 2H, H-o-1Bn); 7.05 (m, 2H, H-o-C6H4Me);
7.16 (m, 2H, H-m-C6H4Me); 7.22 (m, 3H, H-m,p-1Bn); 7.29 (m, 1H,
H-p-3Bn); 7.33 (m, 2H, H-m-3Bn); 7.53 (m, 2H, H-o-3Bn). 13C NMR
(125.7 MHz, CDCl3): 21.3 (CH3); 44.5 (CH2-3); 49.4 (CH2-1); 103.4
(CH-5); 126.7 (CH-o-1Bn); 127.5 (CH-p-1Bn); 127.6 (CH-p-3Bn);
127.8 (CH-o-C6H4Me); 128.4 (CH-m-3Bn); 128.5 (CH-m-1Bn); 129.1
(CH-o-3Bn); 129.3 (CH-m-C6H4Me); 130.2 (C-i-C6H4Me); 136.6 (C-
i-1Bn); 136.9 (C-i-3Bn); 140.3 (C-p-C6H4Me); 152.5 (C-2); 155.0 (C-
6); 162.1 (C-4). IR: 1703, 1658, 1580, 1549, 1513, 1492, 1451, 1383,
1279, 1243, 1181, 1083. MS (ESIþ), m/z (% relative intensity): 383
(Mþ þ H, 4), 405 (Mþ þ Na, 100), 421 (Mþ þ K, 16). HR MS (Mþ þ
H): 383.1754 (calcd for C25H23N2O2 383.1754).
3-Benzyl-5-p-tolylpyrimidine-2,4(1H,3H)-dione (19a). A
mixture of compound 16a (50 mg, 0.131 mmol), ammonium formate
(3.3 mL of a 0.4 N solution in dry MeOH) and 10% palladiumꢀcharcoal
(77 mg 10% Pd/C, 0.072 mmol of Pd, 0.55 equiv of Pd) was refluxed at
72 °C for 17 h. The mixture was filtered through Celite, and the solid
residue was extensively washed with MeOH and CHCl3 (ca. 120 mL).
Removal of solvents under reduced pressure and following column
chromatography on 40 g of silica gel in gradient chloroform to 1%
methanol in chloroform gave the pure monodeprotected product 19a in
80% yield, as a white powder, mp 205ꢀ208 °C. 1H NMR (500.0 MHz,
CDCl3): 2.28 (s, 3H, CH3); 5.11 (s, 2H, CH2Ph); 7.12 (m, 2H, H-m-
C6H4Me); 7.19 (m, 2H, H-6, H-p-Bn); 7.22 (m, 2H, H-m-Bn); 7.30 (m,
2H, H-o-C6H4Me); 7.44 (m, 2H, H-o-Bn), 9.97 (bs, 1H, NH). 13C
NMR (125.7 MHz, CDCl3): 21.18 (CH3); 44.19 (CH2Ph); 115.02 (C-
5); 127.68 (CH-p-Bn); 128.17 (CH-o-C6H4Me); 128.40 (CH-m-Bn);
129.11, 129.15 (CH-m-C6H4Me, CH-o-Bn); 129.70 (C-i-C6H4Me);
135.34 (CH-6); 136.61 (C-i-Bn); 137.89 (C-p-C6H4Me); 152.59 (C-2);
162.30 (C-4). IR: 3179, 1703, 1628, 1515, 1494, 1434, 1289, 1210, 1152.
MS (ESIþ), m/z (% relative intensity): 315 (Mþ þ Na, 100). HR MS
(Mþ þ H): 315.1104 (calcd for C18H16N2NaO2 315.1104).
5-p-Tolylpyrimidine-2,4(1H,3H)-dione (20a). Compound 20a
was prepared from 16a (100 mg, 0.261 mmol) according to general
procedure (Method D), in 98% yield, as a white powder, mp 228ꢀ
230 °C. 1H NMR (600.1 MHz, DMSO-d6): 2.29 (s, 3H, CH3); 7.15 (m,
2H, H-m-C6H4Me); 7.42 (m, 2H, H-o-C6H4Me); 7.56 (s, 1H, H-6);
11.21 (bs, 2H, NH-1,3). 13C NMR (150.9 MHz, DMSO-d6): 20.95
(CH3); 112.3 (C-5); 128.0 (CH-o-C6H4Me); 128.8 (CH-m-C6H4Me);
130.6 (C-i-C6H4Me); 136.4 (C-p-C6H4Me); 139.4 (CH-6); 151.2 (C-
2); 163.4 (C-4). IR: 3079, 1747, 1718, 1665, 1618, 1515, 1444, 1423,
1230, 1109. MS (ESIþ), m/z (% relative intensity): 203 (Mþ þ H,
16), 225 (Mþ þ Na, 100), 427 (2Mþ þ Na, 37). HR MS (Mþ þ H):
203.0815 (calcd for C11H11N2O2 203.0815). Anal. Calcd for C11H10-
N2O2 1H2O: C, 59.99; H, 5.49; N, 12.72. Found: C, 60.14; H, 5.12;
N, 12.63.
1,3-Dibenzyl-5-p-tolylpyrimidine-2,4(1H,3H)-dione (16a).
Compound 16a was prepared from 8 according to general procedure
(Method A) in 45% yield, as a yellowish oil. H NMR (600.1 MHz,
CDCl3): 2.34 (s, 3H, CH3); 4.99 (s, 2H, CH2-1); 5.23 (s, 2H, CH2-3);
7.17 (m, 2H, H-m-C6H4Me); 7.25 (s, 1H, H-6); 7.26 (m, 1H, H-p-3Bn);
7.31 (m, 4H, H-o-1Bn, H-m-3Bn); 7.33 (m, 2H, H-o-C6H4Me); 7.36 (m,
1H, H-p-1Bn); 7.37 (m, 2H, H-m-1Bn); 7.55 (m, 2H, H-o-3Bn). 13C
NMR (150.9 MHz, CDCl3): 21.2 (CH3); 44.9 (CH2-3); 52.4 (CH2-1);
115.1 (C-5); 127.6 (CH-p-3Bn); 128.0 (CH-o-1Bn); 128.2 (CH-o-
C6H4Me); 128.4 (CH-m-3Bn); 128.5 (CH-p-1Bn); 129.1 (CH-m-
3
1
6-p-Tolylpyrimidine-2,4(1H,3H)-dione (22a). Compound 22a
was prepared from 17a (100 mg, 0.261 mmol) according to general
procedure (Method D), in 97% yield, as a white powder, mp >300 °C
(lit.20 mp 315ꢀ318 °C). 1H NMR (600.1 MHz, DMSO-d6): 2.35 (s, 3H,
CH3); 5.78 (d, 1H, J = 1.7, H-5); 7.30 (m, 2H, H-m-C6H4Me); 7.62 (m,
2H, H-o-C6H4Me); 11.08, 11.12 (2 ꢁ bs, 2 ꢁ 1H, NH-1,3). 13C NMR
(150.9 MHz, DMSO-d6): 21.1 (CH3); 97.6 (CH-5); 127.0 (CH-o-
C6H4Me); 128.9 (C-i-C6H4Me); 129.6 (CH-m-C6H4Me); 141.3 (C-p-
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ARTICLE
C6H4Me); 152.1 (C-2); 152.6 (C-6); 164.3 (C-4). IR (KBr): 3132,
1698, 1667, 1618, 1517, 1493, 1406, 1385, 1238, 1191. MS (ESIþ), m/z
(% relative intensity): 203 (Mþ þ H, 28), 225 (Mþ þ Na, 81), 427
(2Mþ þ Na, 100). HR MS (Mþ þ H): 203.0815 (calcd for C11H11-
5.40 (s, 1H, H-5); 7.28 (m, 1H, H-5-C6H4Me); 7.31 (m, 2H, H-3,6-
C6H4Me); 7.39 (td, 1H, J4,3 = J4,5 = 7.4, J4,6 = 1.8, H-4-C6H4Me), 11.03,
11.14 (2 ꢁ bs, 2 ꢁ 1H, NH-1,3). 13C NMR (150.9 MHz, DMSO-d6):
19.6 (CH3); 100.6 (CH-5); 126.2 (CH-5-C6H4Me); 128.7 (CH-6-
C6H4Me); 130.1 (CH-4-C6H4Me); 130.7 (CH-3-C6H4Me); 133.2 (C-
1-C6H4Me); 135.7 (C-2-C6H4Me); 151.7 (C-2); 153.9 (C-6); 164.3
(C-4). IR: 3158, 1731, 1656, 1600, 1577, 1485, 1385, 1292. MS (ESIþ),
m/z (% relative intensity): 203 (Mþ þ H, 23), 225 (Mþ þ Na, 100),
427 (2Mþ þ Na, 65). HR MS (Mþ þ H): 203.0815 (calcd for
C11H11N2O2 203.0815).
N2O2 203.0815). Anal. Calcd for C11H10N2O2 1H2O: C, 59.99; H,
3
5.49; N, 12.72. Found: C, 59.65; H, 5.09; N, 12.57.
1,3-Dibenzyl-5-o-tolylpyrimidine-2,4(1H,3H)-dione (16b).
Compound 16b was prepared from 8 according to general procedure
(Method A) in 70% yield, as a white powder, mp 115ꢀ116 °C. 1H NMR
(499.8 MHz, CDCl3): 2.17 (s, 3H, CH3); 4.97 (s, 2H, CH2-1); 5.22 (s,
2H, CH2-3); 7.06 (dd, 1H, J6,5 = 7.6, J6,4 = 1.4, H-6-C6H4Me); 7.12 (s,
1H, H-6); 7.16 (m, 1H, H-5-C6H4Me); 7.21 (m, 1H, H-3-C6H4Me);
7.25 (ddd, 1H, J4,3 = 7.6, J4,5 = 7.0, J4,6 = 1.4, H-4-C6H4Me); 7.26ꢀ7.40
(m, 8H, H-o,m,p-1Bn, H-m,p-3Bn); 7.54 (m, 2H, H-o-3Bn). 13C NMR
(125.7 MHz, CDCl3): 20.1 (CH3); 44.9 (CH2-3); 52.3 (CH2-1); 115.6
(C-5); 125.8 (CH-5-C6H4Me); 127.6 (CH-p-3Bn); 128.1 (CH-o-1Bn);
128.4 (CH-m-3Bn); 128.5, 128.5 (CH-4-C6H4Me, CH-p-1Bn); 129.2
(CH-m-1Bn); 129.4 (CH-o-3Bn); 130.1 (CH-3-C6H4Me); 130.5 (CH-
6-C6H4Me); 132.3 (C-1-C6H4Me); 135.3 (C-i-1Bn); 137.0 (C-i-3Bn);
137.7 (C-2-C6H4Me); 140.2 (CH-6); 151.6 (C-2); 161.7 (C-4). IR
(KBr): 1703, 1649, 1634, 1586, 1495, 1446, 1379, 1294, 1217. MS
(ESIþ), m/z (% relative intensity): 383 (Mþ þ H, 93), 405 (Mþ þ Na,
100), 421 (Mþ þ K, 30). HR MS (Mþ þ H): 383.1753 (calcd for
C25H23N2O2 383.1754).
1,3-Dibenzyl-6-o-tolylpyrimidine-2,4(1H,3H)-dione (17b).
Compound 17b was prepared from 8 according to general procedure
(Method B) in 28% yield, as a white crystals from hexane/ethylacetate,
mp 131ꢀ132 °C. 1H NMR (499.8 MHz, CDCl3): 1.97 (s, 3H, CH3);
4.69 and 4.91 (2 ꢁ bd, 2 ꢁ 1H, Jgem = 14.9, CH2-1); 5.22 and 5.26 (2 ꢁ
d, 2 ꢁ 1H, Jgem = 13.7, CH2-3); 5.65 (s, 1H, H-5); 6.78 (m, 2H, H-o-
1Bn); 6.98 (dd, 1H, J6,5 = 7.6, J6,4 = 1.4, H-6-C6H4Me); 7.16 (m, 1H,
H-5-C6H4Me); 7.18 (m, 2H, H-m-1Bn); 7.19 (m, 2H, H-p-1Bn); 7.20
(m, 1H, H-3-C6H4Me); 7.29 (m, 1H, H-p-3Bn); 7.35 (m, 3H, H-4-
C6H4Me and H-m-3Bn); 7.55 (m, 2H, H-o-3Bn). 13C NMR (125.7
MHz, CDCl3): 19.2 (CH3); 44.7 (CH2-3); 49.0 (CH2-1); 103.2 (CH-
5); 125.9 (CH-5-C6H4Me); 127.4 (CH-o-1Bn); 127.6 (CH-p-3Bn);
127.7 (CH-p-1Bn); 128.4, 128.4 (CH-m-1Bn and CH-m-3Bn); 128.5
(CH-6-C6H4Me); 129.1 (CH-o-3Bn); 130.1 (CH-4-C6H4Me); 130.5
(CH-3-C6H4Me); 132.4 (C-1-C6H4Me); 135.8 (C-2-C6H4Me); 136.2
(C-i-1Bn); 136.9 (C-i-3Bn); 152.7 (C-2); 154.0 (C-6); 162.2 (C-4). IR
(KBr): 1698, 1660, 1621, 1585, 1495, 1438, 1395, 1344, 1216. MS
(EIþ), m/z (% relative intensity): 65 (19), 77 (13), 91 (100), 103 (7),
115 (15), 132 (21), 149 (5), 186 (32), 220 (3), 248 (7), 289 (10), 367
(46), 382 (Mþ, 33). HR MS (Mþ): 382.1674 (calcd for C25H22N2O2
382.1681).
1,3-Dibenzyl-5-(4-methoxyphenyl)pyrimidine-2,4(1H,3H)-
dione (16c). Compound 16c was prepared from 8 according to general
procedure (Method A) in 45% yield, as a yellowish oil. 1H NMR (499.8
MHz, CDCl3): 3.80 (s, 3H, OCH3); 4.99 (s, 2H, CH2-1); 5.23 (s, 2H,
CH2-3); 6.89 (m, 2H, H-m-C6H4OMe); 7.22 (s, 1H, H-6); 7.26 (m, 1H,
H-p-3Bn); 7.31 (m, 4H, H-o-1Bn, H-m-3Bn); 7.36 (m, 1H, H-p-1Bn);
7.37 (m, 4H, H-m-1Bn, H-o-C6H4OMe); 7.55 (m, 2H, H-o-3Bn). 13
C
NMR (150.9 MHz, CDCl3): 45.0 (CH2-3); 52.4 (CH2-1); 55.3 (CH3);
113.9 (CH-m-C6H4OMe); 114.8 (C-5); 125.1 (C-i-C6H4OMe); 127.6
(CH-p-3Bn); 128.0 (CH-o-1Bn); 128.4 (CH-m-3Bn); 128.5 (CH-p-
1Bn); 129.1 (CH-m-1Bn); 129.3 (CH-o-3Bn); 129.5 (CH-o-
C6H4OMe); 135.4 (C-i-1Bn); 136.9 (C-i-3Bn); 138.5 (CH-6); 151.4
(C-2); 159.4 (C-p-C6H4OMe); 162.1 (C-4). IR (KBr): 1702, 1651, 1609,
1515, 1495, 1451, 1380, 1249, 1179, 1049. MS (ESIþ), m/z (% relative
intensity): 399 (Mþ þ H, 100), 421 (Mþ þ Na, 88), 819 (2Mþ þ Na,
37). HR MS (Mþ þ H): 399.1704 (calcd for C25H23N2O3 399.1703).
1,3-Dibenzyl-6-(4-methoxyphenyl)pyrimidine-2,4(1H,3H)-
dione (17c). Compound 17c was prepared from 8 according to general
procedure (Method B) in 38% yield, as a yellowish oil. 1H NMR (600.1
MHz, CDCl3): 3.82 (s, 3H, OCH3); 4.95 (bs, 2H, CH2-1); 5.20 (s, 2H,
CH2-3); 5.70 (s, 1H, H-5); 6.86 (m, 2H, H-m-C6H4OMe); 6.91 (m, 2H,
H-o-1Bn); 7.09 (m, 2H, H-o-C6H4OMe); 7.22 (m, 3H, H-m,p-1Bn);
7.28 (m, 1H, H-p-3Bn); 7.33 (m, 2H, H-m-3Bn); 7.53 (m, 2H, H-o-
3Bn). 13C NMR (150.9 MHz, CDCl3): 44.6 (CH2-3); 49.4 (CH2-1);
55.4 (CH3O); 103.5 (CH-5); 114.0 (CH-m-C6H4OMe); 125.3 (C-i-
C6H4OMe); 126.6 (CH-o-1Bn); 127.5 (CH-p-1Bn); 127.6 (CH-p-
3Bn); 128.4 (CH-m-3Bn); 128.6 (CH-m-1Bn); 129.1 (CH-o-3Bn);
129.4 (CH-o-C6H4OMe); 136.6 (C-i-1Bn); 136.9 (C-i-3Bn); 152.6 (C-
2); 154.8 (C-6); 160.8 (C-p-C6H4OMe); 162.1 (C-4). IR (KBr): 1702,
1651, 1514, 1495, 1449, 1378, 1248, 1178, 1070. MS (ESIþ), m/z
(% relative intensity): 399 (Mþ þ H, 35), 421 (Mþ þ Na, 100), 437
(Mþ þ K, 30), 819 (2Mþ þ Na, 10). HR MS (Mþ þ H): 399.1703
(calcd for C25H23N2O3 399.1703).
5-(4-Methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (20c).
Compound 20c was prepared from 16c (128 mg, 0.321 mmol)
according to general procedure (Method D), in 95% yield, as a white
powder, mp > 300 °C. The experimental data are in accordance to
literature.22 1H NMR (499.8 MHz, DMSO-d6): 3.75 (s, 3H, OCH3);
6.91 (m, 2H, H-m-C6H4OMe); 7.46 (m, 2H, H-o-C6H4OMe); 7.52 (s,
1H, H-6); 11.14 (bs, 2H, NH-1,3). 13C NMR (125.7 MHz, DMSO-d6):
55.3 (OCH3); 112.2 (C-5); 113.7 (CH-m-C6H4OMe); 125.8 (C-i-
C6H4OMe); 129.4 (CH-o-C6H4OMe); 138.9 (CH-6); 151.2 (C-2);
158.6 (C-p-C6H4Me); 163.6 (C-4). IR (KBr): 3080, 1762, 1711, 1672,
1616, 1579, 1518, 1492, 1450, 1301, 1255, 1183, 1078. MS (ESIþ), m/z
(% relative intensity): 219 (Mþ þ H, 98), 241 (Mþ þ Na, 100), 257
(Mþ þ K, 32), 459 (2Mþ þ Na, 35). HR MS (Mþ þ H): 219.0764
(calcd for C11H11N2O3 219.0764).
5-o-Tolylpyrimidine-2,4(1H,3H)-dione (20b). Compound 20b
was prepared from 16b (100 mg, 0.261 mmol) according to general
procedure (Method D), in 97% yield, as a white powder, mp 265ꢀ
268 °C. The experimental data are in accordance with literature.21 1H
NMR (499.8 MHz, DMSO-d6): 2.15 (s, 3H, CH3); 7.10 (dd, 1H,
J6,5 = 7.4, J6,4 = 1.6, H-6-C6H4Me); 7.17 (m, 1H, H-5-C6H4Me); 7.21
(m, 2H, H-3-C6H4Me); 7.24 (ddd, 1H, J4,3 = 7.5, J4,5 = 6.7, J4,6 = 1.6,
H-4-C6H4Me); 7.36 (s, 1H, H-6); 11.00, 11.19 (2 ꢁ bs, 2 ꢁ 1H, NH-
1,3). 13C NMR (125.7 MHz, DMSO-d6): 19.9 (CH3); 113.5 (C-5);
125.7 (CH-5-C6H4Me); 127.9 (CH-4-C6H4Me); 129.8 (CH-3-
C6H4Me); 130.8 (CH-6-C6H4Me); 133.5 (C-1-C6H4Me); 137.6 (C-
2-C6H4Me); 140.4 (CH-6); 151.5 (C-2); 163.1 (C-4). IR (KBr): 3100,
1748, 1699, 1662, 1603, 1574, 1490, 1385, 1233. MS (ESIþ), m/z (%
relative intensity): 203 (Mþ þ H, 6), 225 (Mþ þ Na, 100), 427 (2Mþ þ
Na, 77). HR MS (Mþ þ H): 203.0814 (calcd for C11H11N2O2 203.0815).
6-o-Tolylpyrimidine-2,4(1H,3H)-dione (22b). Compound
22b was prepared from 17b (80 mg, 0.209 mmol) according to general
procedure (Method D), in 94% yield, as a white powder, mp
6-(4-Methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (22c).
Compound 22c was prepared from 17c (100 mg, 0.251 mmol)
according to general procedure (Method D), in 92% yield, as a yellowish
1
powder, mp 286ꢀ288 °C (lit.23 mp 288 °C). H NMR (500.0 MHz,
DMSO-d6): 3.81 (s, 3H, OCH3); 5.76 (s, 1H, H-5); 7.03 (m, 2H, H-m-
C6H4OMe); 7.71 (m, 2H, H-o-C6H4OMe); 11.01, 11.06 (2 ꢁ bs, 2 ꢁ
1H, NH-1,3). 13C NMR (125.7 MHz, DMSO-d6): 55.7 (OCH3); 996.8
1
185ꢀ187 °C. H NMR (600.1 MHz, DMSO-d6): 2.30 (s, 3H, CH3);
5315
dx.doi.org/10.1021/jo2006494 |J. Org. Chem. 2011, 76, 5309–5319

The Journal of Organic Chemistry
ARTICLE
(CH-5); 114.4 (CH-o-C6H4OMe); 123.7 (C-i-C6H4OMe); 128.8 (CH-
m-C6H4OMe); 152.1, 152.2 (C-2,6); 161.7 (C-p-C6H4OMe); 164.3
(C-4). IR (KBr): 3140, 1714, 1677, 1653, 1609, 1572, 1521, 1491, 1446,
1297, 1263, 1183, 1082. MS (ESIþ), m/z (% relative intensity): 219
(Mþ þ H, 100), 241 (Mþ þ Na, 75), 257 (Mþ þ K, 27), 459 (2Mþ þ
Na, 80). HR MS (Mþ þ H): 219.0764 (calcd for C11H11N2O3
219.0764).
1,3-Dibenzyl-5-phenylpyrimidine-2,4(1H,3H)-dione (16d).
Compound 16a was prepared from 8 according to general procedure
(Method A) in 47% yield, as a white powder, mp 125ꢀ126 °C. 1H NMR
(500.0 MHz, CDCl3): 5.00 (s, 2H, CH2-1); 5.24 (s, 2H, CH2-3); 7.28 (s,
1H, H-6); 7.28ꢀ7.40 (m, 11H, H-o,m,p-1Bn, H-m,p-3Bn, H-m,p-Ph);
7.44 (m, 2H, H-o-Ph); 7.56 (m, 2H, H-o-3Bn). 13C NMR (125.7 MHz,
CDCl3): 45.0 (CH2-3); 52.4 (CH2-1); 115.1 (C-5); 127.7 (CH-p-3Bn);
127.9 (CH-p-Ph); 128.0 (CH-o-1Bn); 128.3 (CH-o-Ph); 128.4 (CH-m-
3Bn); 128.4 (CH-m-Ph); 128.5 (CH-p-1Bn); 129.2 (CH-m-1Bn); 129.4
(CH-o-3Bn); 132.8 (C-i-Ph); 135.3 (C-i-1Bn); 136.9 (C-i-3Bn); 139.3
(CH-6); 151.4 (C-2); 161.9 (C-4). IR (KBr): 1698, 1648, 1602, 1581,
1495, 1455, 1439, 1378, 1337, 1280, 1206, 1181, 1078. MS (ESIþ), m/z
(% relative intensity): 369 (Mþ þ H, 11), 391 (Mþ þ Na, 100). HR MS
(Mþ þ H): 369.1597 (calcd for C24H21N2O2 369.1598).
45ꢀ47 °C. 1H NMR (499.8 MHz, CDCl3): 5.00 (s, 2H, CH2-1); 5.23
(s, 2H, CH2-3); 7.04 (m, 2H, H-m-C6H4F); 7.25 (s, 1H, H-6);
7.26ꢀ7.34 (m, 5H, H-o-1Bn, H-m,p-3Bn); 7.34ꢀ7.43 (m, 5H, H-m,p-
1Bn, H-o-C6H4F); 7.54 (m, 2H, H-o-3Bn). 13C NMR (125.7 MHz,
CDCl3): 45.0 (CH2-3); 52.5 (CH2-1); 114.2 (C-5); 115.4 (d, JC,F
=
21.6, CH-m-C6H4F); 127.7 (CH-p-3Bn); 128.0 (CH-o-1Bn); 128.4
(CH-m-3Bn); 128.6 (CH-p-1Bn); 128.7 (d, JC,F = 3.3, C-i-C6H4F);
129.2 (CH-m-1Bn); 129.3 (CH-o-3Bn); 130.1 (d, JC,F = 8.1, CH-o-
C6H4F); 135.2 (C-i-1Bn); 136.8 (C-i-3Bn); 139.1 (CH-6); 151.3 (C-2);
161.9 (C-4); 162.5 (d, JC,F = 247.7, C-p-C6H4F). 19F{1H} NMR (470.3
MHz, CDCl3): ꢀ109.95. IR: 1701, 1646, 1602, 1510, 1495, 1448, 1408,
1378, 1222, 1159, 1080. MS (ESIþ), m/z (% relative intensity):
387 (Mþ þ H, 54), 409 (Mþ þ Na, 100), 425 (Mþ þ K, 35), 795
(2Mþ þ Na, 8). HR MS (Mþ þ H): 387.1503 (calcd for C24H20FN2O2
387.1503).
1,3-Dibenzyl-6-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione
(17e). Compound 17e was prepared from 8 according to general
procedure (Method B) in 24% yield, as a yellowish oil. 1H NMR
(499.8 MHz, CDCl3): 4.92 (bs, 2H, CH2-1); 5.22 (s, 2H, CH2-3);
5.69 (s, 1H, H-5); 6.86 (m, 2H, H-o-1Bn); 7.04 (m, 2H, H-m-C6H4F);
7.11 (m, 2H, H-o-C6H4F); 7.22 (m, 3H, H-m,p-1Bn); 7.30 (m, 1H, H-p-
3Bn); 7.33 (m, 2H, H-m-3Bn); 7.54 (m, 2H, H-o-3Bn). 13C NMR
(125.7 MHz, CDCl3): 44.7 (CH2-3); 49.4 (CH2-1); 103.9 (CH-5);
115.9 (d, JC,F = 22.0, CH-m-C6H4F); 126.5 (CH-o-1Bn); 127.7 (CH-p-
1Bn); 127.7 (CH-p-3Bn); 128.4 (CH-m-3Bn); 128.7 (CH-m-1Bn);
129.1 (d, JC,F = 3.6, C-i-C6H4F); 129.2 (CH-o-3Bn); 130.0 (d, JC,F = 8.5,
CH-o-C6H4F); 136.3 (C-i-1Bn); 136.8 (C-i-3Bn); 152.5 (C-2); 153.8
(C-6); 161.9 (C-4); 163.5 (d, JC,F = 251.5, C-p-C6H4F). 19F NMR
(470.3 MHz, CDCl3): ꢀ105.64. IR (KBr): 1705, 1665, 1621, 1600,
1511, 1496, 1441, 1392, 1345, 1226, 1160, 1071. MS (ESIþ), m/z (%
relative intensity): 387 (Mþ þ H, 42), 409 (Mþ þ Na, 100), 425 (Mþ þ
K, 25), 795 (2Mþ þ Na, 8). HR MS (Mþ þ H): 387.1504 (calcd for
C24H20FN2O2 387.1503).
6-(4-Fluorophenyl)pyrimidine-2,4(1H,3H)-dione (22e).
Compound 22e was prepared from 17e (120 mg, 0.311 mmol)
according to general procedure (Method E), in 98% yield, as a white
powder, mp > 300 °C (lit.20 mp 311ꢀ313 °C). 1H NMR (600.1 MHz,
DMSO-d6): 5.81 (s, 1H, H-5); 7.34 (m, 2H, H-m-C6H4F); 7.79 (m, 2H,
H-o-C6H4F); 11.15, 11.16 (2 ꢁ bs, 2 ꢁ 1H, NH). 13C NMR (150.9
MHz, DMSO-d6): 98.3 (CH-5); 116.0 (d, JC,F = 21.9, CH-m-C6H4F);
128.3 (d, JC,F = 3.1, C-i-C6H4F); 129.8 (d, JC,F = 8.9, CH-o-C6H4F);
151.7 (C-6); 152.0 (C-2); 163.8 (d, JC,F = 249.0, C-p-C6H4F); 164.2 (C-
4). 19F{1H} NMR (376.5 MHz, DMSO-d6): ꢀ109.94. IR: 3115, 1699,
1652, 1647, 1601, 1488, 1452, 1422, 1356, 1231, 1166, 1081. MS
(ESIþ), m/z (% relative intensity): 229 (Mþ þ Na, 100), 435
(2Mþ þ Na, 20). HR MS (Mþ þ H): 229.0383 (calcd for C10H7FN2-
NaO2 229.0384).
1,3-Dibenzyl-6-phenylpyrimidine-2,4(1H,3H)-dione (17d).
Compound 17d was prepared from 8 according to general procedure
(Method B) in 42% yield, as a white powder, mp 76ꢀ78 °C. The
experimental data are in accordance with literature.24 1H NMR (600.1
MHz, CDCl3): 4.93 (bs, 2H, CH2-1); 5.21 (s, 2H, CH2-3); 5.71 (s, 1H,
H-5); 6.86 (m, 2H, H-o-1Bn); 7.14 (m, 2H, H-o-Ph); 7.21 (m, 3H, H-m,p-
1Bn); 7.29 (m, 1H, H-p-3Bn); 7.33 (m, 2H, H-m-3Bn); 7.35 (m, 2H,
H-m-Ph); 7.44 (m, 1H, H-p-Ph); 7.54 (m, 2H, H-o-3Bn). 13C NMR
(150.9 MHz, CDCl3): 44.6 (CH2-3); 49.4 (CH2-1); 103.5 (CH-5); 126.7
(CH-o-1Bn); 127.5 (CH-p-1Bn); 127.6 (CH-p-3Bn); 127.9 (CH-o-Ph);
128.4 (CH-m-3Bn); 128.5 (CH-m-1Bn); 128.6 (CH-m-Ph); 129.2 (CH-
o-3Bn); 130.1 (CH-p-Ph); 133.0 (C-i-Ph); 136.55 (C-i-1Bn); 136.9 (C-i-
3Bn); 152.5 (C-2); 154.8 (C-6); 162.0 (C-4). IR (KBr): 1705, 1659,
1604, 1574, 1496, 1450, 1437, 1389, 1349, 1242, 1205, 1192, 1075. MS
(ESIþ), m/z (% relative intensity): 369 (Mþ þ H, 7), 391 (Mþ þ Na,
100). HR MS (Mþ þ H): 369.1597 (calcd for C24H21N2O2 369.1598).
5-Phenylpyrimidine-2,4(1H,3H)-dione (20d). Compound
20d was prepared from 16d (100 mg, 0.271 mmol) according to general
procedure (Method D), in 97% yield, as a white powder, mp > 300 °C
(lit.25 mp >350 °C). 1H NMR (600.1 MHz, DMSO-d6): 7.26 (m, 1H,
H-p-Ph); 7.35 (m, 2H, H-m-Ph); 7.53 (m, 2H, H-o-Ph); 7.61 (s, 1H,
H-6); 11.15, 11.25 (2 ꢁ bs, 2 ꢁ 1H, NH-1,3). 13C NMR (150.9 MHz,
DMSO-d6): 112.3 (C-5); 127.2 (CH-p-Ph); 128.2 (CH-o-Ph); 128.2
(CH-m-Ph); 133.5 (C-i-Ph); 139.9 (CH-6); 151.2 (C-2); 163.4 (C-4).
IR (KBr): 3062, 1749, 1688, 1676, 1631, 1605, 1498, 1448, 1353, 1236,
1078. MS (ESIþ), m/z (% relative intensity): 189 (Mþ þ H, 35), 211
(Mþ þ Na, 100). HR MS (Mþ þ H): 189.0657 (calcd for C10H9N2O2
189.0659).
6-Phenylpyrimidine-2,4(1H,3H)-dione (22d). Compound
22d was prepared from 17d (100 mg, 0.271 mmol) according to general
procedure (Method D), in 94% yield, as a white powder, mp 268ꢀ
271 °C (lit.26 mp 270 °C). 1H NMR (600.1 MHz, DMSO-d6): 5.81 (s,
1H, H-5); 7.49 (m, 2H, H-m-Ph); 7.54 (m, 1H, H-p-Ph); 7.72 (m, 2H,
H-o-Ph); 11.14, 11.16 (2 ꢁ bs, 2 ꢁ 1H, NH-1,3). 13C NMR (150.9
MHz, DMSO-d6): 98.3 (CH-5); 127.2 (CH-o-Ph); 129.0 (CH-m-Ph);
131.3 (CH-p-Ph); 131.8 (C-i-Ph); 152.1 (C-2); 152.1 (C-6); 164.3 (C-
4). IR (KBr): 3098, 1721, 1652, 1600, 1578, 1489, 1446, 1354, 1239,
1079. MS (ESIþ), m/z (% relative intensity): 189 (Mþ þ H, 34), 211
(Mþ þ Na, 100), 399 (2Mþ þ Na, 100). HR MS (Mþ þ H): 189.0658
(calcd for C10H9N2O2 189.0659).
1,3-Dibenzyl-5-(naphthalen-2-yl)pyrimidine-2,4(1H,3H)-
dione (16f). Compound 16f was prepared from 8 according to general
procedure (Method A) in 19% yield, as yellowish powder, mp
1
62ꢀ64 °C. H NMR (499.8 MHz, CDCl3): 5.04 (bs, 2H, CH2-1);
5.27 (s, 2H, CH2-3); 7.28 (m, 1H, H-p-3Bn); 7.33 (m, 2H, H-m ꢀ3Bn);
7.35 (m, 2H, H-o-1Bn); 7.37 (m, 1H, H-p-1Bn); 7.40 (m, 2H, H-m-
1Bn); 7.41 (s, 1H, H-6); 7.46 (m, 1H, H-6-naphth); 7.48 (m, 1H, H-7-
naphth); 7.56 (dd, 1H, J3,4 = 8.5, J3,1 = 1.9, H-3-naphth); 7.58 (m, 2H,
H-o-3Bn); 7.81 (m, 1H, H-8-naphth); 7.82 (m, 2H, H-4,5-naphth); 7.94
(m, 1H, H-1-naphth). 13C NMR (150.9 MHz, CDCl3): 45.0 (CH2-3);
52.5 (CH2-1); 115.1 (C-5); 126.1 (CH-3-naphth); 126.2 (CH-6,7-
naphth); 127.2 (CH-1-naphth); 127.6 (CH-8-naphth); 127.7 (CH-p-
3Bn); 128.0 (CH-4 or 5-naphth); 128.0 (CH-o-1Bn); 128.1 (CH-4 or
5-naphth); 128.4 (CH-m-3Bn); 128.6 (CH-p-1Bn); 129.2 (CH-m-
1Bn); 129.3 (CH-o-3Bn); 130.3 (C-2-naphth); 132.8 (C-4a-naphth);
133.2 (C-8a-naphth); 135.3 (C-i-1Bn); 136.8 (C-i-3Bn); 139.6 (CH-6);
151.4 (C-2); 162.0 (C-4). IR (KBr): 1703, 1652, 1600, 1586, 1495,
1,3-Dibenzyl-5-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione
(16e). Compound 16e was prepared from 8 according to general
procedure (Method A) in 49% yield, as a yellow powder, mp
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ARTICLE
1449, 1380, 1280, 1219, 1081, 1050. MS (ESIþ), m/z (% relative
intensity): 419 (Mþ þ H, 84), 441 (Mþ þ Na, 100), 457 (Mþ þ K,
9), 859 (2Mþ þ Na, 28). HR MS (Mþ þ H): 419.1758 (calcd for
C28H23N2O2 419.1754).
naphth); 7.99 (m, 1H, H-5-naphth); 8.01 (m, 1H, H-8-naphth); 8.04
(m, 1H, H-4-naphth); 8.43 (d, 1H, J1,3 = 2.0, H-1-naphth). 13C NMR
(125.7 MHz, DMSO-d6): 42.9 (CH2Ph); 98.1 (CH-5); 124.0 (CH-3-
naphth); 127.2 (CH-7-naphth); 127.3 (CH-p-Bn); 127.5 (CH-1-
naphth); 127.7 (CH-o-Bn); 127.8 (CH-5-naphth); 128.1 (CH-6-
naphth); 128.5 (CH-m-Bn); 128.7 (CH-4-naphth); 128.7 (C-2-
naphth); 129.0 (CH-8-naphth); 132.5 (C-8a-naphth); 134.1 (C-4a-
naphth); 137.5 (C-i-Bn); 151.2 (C-6); 152.0 (C-2); 163.0 (C-4). IR:
3165, 1722, 1711, 1698, 1625, 1483, 1466, 1439, 1377, 1244, 1213, 1150,
1128, 1081. MS (ESIþ), m/z (% relative intensity): 329 (Mþ þ H, 70),
351 (Mþ þ Na, 100). HR MS (Mþ þ H): 329.1283 (calcd for C21H17-
N2O2 329.1285).
1,3-Dibenzyl-6-(naphthalen-2-yl)pyrimidine-2,4(1H,3H)-
dione (17f). Compound 17f was prepared from 8 according to general
procedure (Method B) in 33% yield, as yellowish powder, mp
1
55ꢀ58 °C. H NMR (499.8 MHz, CDCl3): 4.97 (bs, 2H, CH2-1);
5.24 (s, 2H, CH2-3); 5.81 (s, 1H, H-5); 6.86 (m, 2H, H-o-1Bn); 7.19 (m,
3H, H-m,p-1Bn); 7.23 (dd, 1H, J3,4 = 8.5, J3,1 = 1.9, H-3-naphth); 7.30
(m, 1H, H-p-3Bn); 7.35 (m, 2H, H-m-3Bn); 7.54 (ddd, 1H, J7,8 = 8.2,
J7,6 = 6.9, J7,5 = 1.4, H-7-naphth); 7.55 (m, 2H, H-o-3Bn); 7.58 (ddd, 1H,
J6,5 = 8.2, J6,7 = 6.9, J6,8 = 1.4, H-6-naphth); 7.63 (d, 1H, J1,3 = 1.9, H-1-
naphth); 7.74 (m, 1H, H-8-naphth); 7.83 (d, 1H, J4,3 = 8.5, H-4-
naphth); 7.87(m, 1H, H-5-naphth). 13C NMR (125.7 MHz, CDCl3):
44.63 (CH2-3); 49.70 (CH2-1); 103.76 (CH-5); 124.58 (CH-3-
naphth); 126.72 (CH-o-1Bn); 127.18 (CH-7-naphth); 127.56 (CH-p-
1Bn); 127.63 (CH-6-naphth); 127.65 (CH-p-3Bn); 127.80 (CH-5-
naphth); 128.10 (CH-1-naphth); 128.35 (CH-8-naphth); 128.42
(CH-m-3Bn); 128.53 (CH-4-naphth); 128.55 (CH-m-1Bn); 129.16
(CH-o-3Bn); 130.31 (C-2-naphth); 132.46 (C-8a-naphth); 133.47
(C-4a-naphth); 136.54 (C-i-1Bn); 136.90 (C-i-3Bn); 152.56 (C-2);
154.93 (C-6); 162.05 (C-4). IR (KBr): 1705, 1662, 1617, 1495, 1472,
1440, 1392, 1340, 1273, 1187, 1070. MS (ESIþ), m/z (% relative
intensity): 419 (Mþ þ H, 59), 441 (Mþ þ Na, 100), 457 (Mþ þ K,
10), 859 (2Mþ þ Na, 22). HR MS (Mþ þ H): 419.1756 (calcd for
C28H23N2O2 419.1754).
5-(Naphthalen-2-yl)pyrimidine-2,4(1H,3H)-dione (20f).
Compound 20f was prepared from 16f (100 mg, 0.239 mmol) according
to general procedure (Method E), in 63% yield, as a yellowish powder,
mp > 300 °C. 1H NMR (499.8 MHz, DMSO-d6): 7.49 (ddd, 1H, J6,5
=
8.8, J6,7 = 6.8, J6,8 = 1.7, H-6-naphth); 7.70 (ddd, 1H, J7,8 = 8.8, J7,6 = 6.8,
J7,5 = 1.7, H-7-naphth); 7.70 (dd, 1H, J3,4 = 8.5, J3,1 = 1.8, H-3-naphth);
7.77 (bd, 1H, J6,NH = 5.6, H-6); 7.87ꢀ7.91 (m, 3H, H-4,5,8-naphth);
8.12 (m, 1H, H-1-naphth); 11.23 (bd, 1H, JNH,6 = 5.6, NH-1); 11.31 (bs,
1H, NH-3). 13C NMR (125.7 MHz, DMSO-d6): 112.2 (C-5); 126.1
(CH-6-naphth); 126.3 (CH-7-naphth); 126.5 (CH-1-naphth); 126.6
(CH-3-naphth); 127.4 (CH-4-naphth); 127.6 (CH-5-naphth); 128.1
(CH-8-naphth); 131.2 (C-2-naphth); 132.1 (C-4a-naphth); 133.0 (C-
8a-naphth); 140.4 (C-6); 151.2 (C-2); 163.5 (C-4). IR: 3135, 1748,
1664, 1597, 1509, 1445, 1330, 1228, 1127, 1075. MS (ESIþ), m/z (%
relative intensity): 239 (Mþ þ H, 30), 261 (Mþ þ Na, 100). HR MS
(Mþ þ H): 239.0814 (calcd for C14H11N2O2 239.0815).
3-Benzyl-5-(naphthalen-2-yl)pyrimidine-2,4(1H,3H)-dione
(19f). A mixture of compound 16f (60 mg, 0.143 mmol), ammonium
formate (4 mL of a 0.4 N solution in dry MeOH) and 10% palladiumꢀ
charcoal (168 mg 10% Pd/C, 0.158 mmol of Pd, 1.1 equiv of Pd) was
refluxed at 72 °C for 17 h. The mixture was filtered through Celite and
the solid residue was extensively washed with MeOH and CHCl3 (ca.
120 mL). Removal of solvents under reduced pressure and following
column chromatography on 40 g of silica gel in gradient hexane to 20%
ethylacetate in hexane gave the pure monodebenzylated product 19f in
42% yield, as a white powder, mp 200ꢀ202 °C. 1H NMR (500.0 MHz,
DMSO-d6): 5.08 (bs, 2H, CH2Ph); 7.26 (m, 1H, H-p-Bn); 7.32 (m, 2H,
H-m-Bn); 7.33 (m, 2H, H-o-Bn); 7.49 (m, 1H, H-6-naphth); 7.51 (m,
1H, H-7-naphth); 7.70 (dd, 1H, J3,4 = 8.6, J3,1 = 1.9, H-3-naphth); 7.86
(s, 1H, H-6); 7.90 (m, 3H, H-4,5,8-naphth); 8.14 (d, 1H, J1,3 = 1.9, H-1-
naphth). 13C NMR (125.7 MHz, DMSO-d6): 43.4 (CH2Ph); 111.8 (C-
5); 126.2 (CH-6-naphth); 126.3 (CH-7-naphth); 126.7 (CH-3-
naphth); 126.8 (CH-1-naphth); 127.3 (CH-p-Bn); 127.4 (CH-8-
naphth); 127.6 (CH-4 or 5-naphth); 127.9 (CH-o-Bn); 128.1 (CH-4
or 5-naphth); 128.6 (CH-m-Bn); 131.3 (C-2-naphth); 132.2 (C-4a-
naphth); 133.0 (C-8a-naphth); 137.5 (C-i-Bn); 139.2 (CH-6); 151.1
(C-2); 162.4 (C-4). IR (KBr): 3173, 1724, 1711, 1688, 1627, 1597,
1496, 1439, 1364, 1213, 1189, 1081. MS (ESIþ), m/z (% relative
intensity): 329 (Mþ þ H, 48), 351 (Mþ þ Na, 100). HR MS (Mþ þ
H): 329.1285 (calcd for C21H17N2O2 329.1285).
3-Benzyl-6-(naphthalen-2-yl)pyrimidine-2,4(1H,3H)-dione
(21f). A mixture of compound 17f (110 mg, 0.263 mmol), ammonium
formate (6.6 mL of a 0.4 N solution in dry MeOH) and 10%
palladiumꢀcharcoal (308 mg 10% Pd/C, 0.289 mmol of Pd, 1.1 equiv
of Pd) was refluxed at 72 °C for 17 h. The mixture was filtered through
Celite and the solid residue was extensively washed with MeOH and
CHCl3 (ca. 200 mL). Removal of solvents under reduced pressure and
following column chromatography on 70 g of silica gel in gradient
hexane to 20% ethylacetate in hexane gave the pure monodebenzylated
product 21f in 98% yield, as a white powder, mp 183ꢀ185°. 1H NMR
(500.0 MHz, DMSO-d6): 5.03 (bs, 2H, CH2Ph); 6.18 (s, 1H, H-5); 7.26
(m, 1H, H-p-Bn); 7.33 (m, 4H, H-o,m-Bn); 7.61 (m, 1H, H-7-naphth);
7.64 (m, 1H, H-6-naphth); 7.84 (dd, 1H, J3,4 = 8.6, J3,1 = 2.0, H-3-
6-(Naphthalen-2-yl)pyrimidine-2,4(1H,3H)-dione (22f).
Compound 22f was prepared from 17f (100 mg, 0.261 mmol) according
to general procedure (Method E), in 70% yield, as a yellowish powder,
mp > 300 °C. 1H NMR (500.0 MHz, DMSO-d6): 5.98 (d, 1H, J = 1.9,
H-5); 7.61 (ddd, 1H, J6,5 = 8.7, J6,7 = 6.9, J6,8 = 1.9, H-6-naphth); 7.63
(ddd, 1H, J7,8 = 8.7, J7,6 = 6.9, J7,5 = 1.9, H-7-naphth); 7.81 (dd, 1H, J3,4
=
8.7, J3,1 = 2.0, H-3-naphth); 7.99 (m, 1H, H-5-naphth); 8.01 (m, 1H,
H-8-naphth); 8.02 (m, 1H, H-4-naphth); 8.39 (m, 1H, H-1-naphth);
11.19, 11.23 (2 ꢁ bs, 2 ꢁ 1H, NH-1,3). 13C NMR (125.7 MHz, DMSO-
d6): 98.63 (CH-5); 124.00 (CH-3-naphth); 127.16 (CH-6-naphth);
127.28 (CH-1-naphth); 127.80 (CH-5-naphth); 127.96 (CH-7-
naphth); 128.62 (CH-4-naphth); 128.96 (CH-8-naphth); 129.00
(C-2-naphth); 132.47 (C-8a-naphth); 134.02 (C-4a-naphth); 152.06
(C-2); 152.47 (C-6); 164.27 (C-4). IR (KBr): 3132, 1722, 1650, 1613,
1594, 1517, 1494, 1447, 1424, 1337, 1217, 1082. MS (ESIþ), m/z (%
relative intensity): 239 (Mþ þ H, 10), 261 (Mþ þ Na, 28), 399 (2Mþ þ
Na, 100). HR MS (Mþ þ H): 239.0814 (calcd for C14H11N2O2 239.0815).
1,3-Dibenzyl-5-(pyren-1-yl)pyrimidine-2,4(1H,3H)-dione
(16g). Compound 16g was prepared from 8 according to general
procedure (Method A) in 25% yield, as a yellow powder, mp 82ꢀ84 °C.
1H NMR (499.8 MHz, CDCl3): 5.05 (bs, 2H, CH2-1); 5.31 (s, 2H,
CH2-3); 7.30 (m, 1H, H-p-3Bn); 7.35 (m, 2H, H-m-3Bn); 7.37 (m, 3H,
H-o,p-1Bn); 7.40 (m, 2H, H-m-1Bn); 7.41 (s, 1H, H-6); 7.62 (m, 2H,
H-o-3Bn); 7.86 (d, 1H, J2,3 = 7.8, H-2-pyrenyl); 7.87 (d, 1H, J10,9 = 9.2,
H-10-pyrenyl); 8.00 (t, 1H, J7,6 = J7,8 = 7.6, H-7-pyrenyl); 8.01 (d, 1H,
J9,10 = 9.2, H-9-pyrenyl); 8.04 (d, 1H, J4,5 = 8.9, H-4-pyrenyl); 8.08 (d,
1H, J5,4 = 8.9, H-5-pyrenyl); 8.15 (d, 1H, J3,2 = 7.8, H-3-pyrenyl); 8.16
(dd, 1H, J8,7 = 7.6, J8,6 = 1.1, H-8-pyrenyl); 8.19 (dd, 1H, J6,7 = 7.6, J6,8
=
1.1, H-6-pyrenyl). 13C NMR (125.7 MHz, CDCl3): 45.1 (CH2-3); 52.5
(CH2-1); 114.4 (C-5); 124.4 (CH-10-pyrenyl); 124.6 (CH-3-pyrenyl);
124.6 (C-10c-pyrenyl); 124.9 (CH-10b-pyrenyl); 125.2 (CH-8-
pyrenyl); 125.4 (CH-6-pyrenyl); 126.1 (CH-7-pyrenyl); 127.2 (CH-
4-pyrenyl); 127.4 (C-1-pyrenyl); 127.7 (CH-p-3Bn); 127.8 (CH-9-
pyrenyl); 127.9 (CH-5-pyrenyl); 128.2 (CH-o-1Bn); 128.3 (CH-2-
pyrenyl); 128.5 (CH-m-3Bn); 128.6 (CH-p-1Bn); 129.2 (CH-m-
1Bn); 129.6 (CH-o-3Bn); 129.8 (C-10a-pyrenyl); 130.8 (C-8a-
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ARTICLE
pyrenyl); 131.2 (C-5a-pyrenyl); 131.4 (C-3a-pyrenyl); 135.3 (C-i-1Bn);
136.9 (C-i-3Bn); 141.7 (CH-6); 151.6 (C-2); 162.4 (C-4). IR: 1700,
1649, 1602, 1584, 1495, 1432, 1389, 1341, 1179, 1070. MS (ESIþ), m/z
(% relative intensity): 493 (Mþ þ H, 15), 515 (Mþ þ Na, 100). HR MS
(Mþ þ H): 493.1909 (calcd for C34H25N2O2 493.1911).
chromatography on 40 g of silica gel in gradient 10% ethylacetate in
hexane to 50% ethylacetate in hexane gave the pure monodebenzylated
product 21g in 83% yield, as a yellow powder, mp 291ꢀ293 °C. H
1
NMR (500.0 MHz, DMSO-d6): 5.10 (s, 2H, CH2Ph); 5.92 (s, 1H, H-5);
7.30 (m, 1H, H-p-Bn); 7.38 (m, 2H, H-m-Bn); 7.43 (m, 2H, H-o-Bn);
8.15 (t, 1H, J7,6 = J7,8 = 7.7, H-7-pyrenyl); 8.16 (d, 1H, J2,3 = 7.9, H-2-
pyrenyl); 8.26 (d, 1H, J9,10 = 9.1, H-9-pyrenyl); 8.31 (m, 3H, H-4,5,10-
pyrenyl); 8.39 (m, 3H, H-3,6,8-pyrenyl); 11.81 (bs, 1H, NH). 13C NMR
(125.7 MHz, DMSO-d6): 43.0 (CH2Ph); 101.9 (C-5); 123.7 (C-10c-
pyrenyl); 123.9 (CH-10b-pyrenyl); 124.2 (CH-10-pyrenyl); 124.8
(CH-3-pyrenyl); 126.1, 126.3 (CH-6,8-pyrenyl); 126.8 (CH-9-
pyrenyl); 127.0 (CH-7-pyrenyl); 127.35, 127.38 (CH-2-pyrenyl, CH-
p-Bn); 127.6 (C-1-pyrenyl); 128.0 (CH-o-Bn); 128.1 (C-10a-pyrenyl);
128.6 (CH-m-Bn); 128.9 (CH-4,5-pyrenyl); 130.4, 130.9 (C-5a,8a-
pyrenyl); 132.2 (C-3a-pyrenyl); 137.6 (C-i-Bn); 151.7 (C-2); 151.8
(C-6); 162.9 (C-4). IR (KBr): 3154, 1711, 1636, 1584, 1488, 1437,
1422, 1357, 1236, 1179, 1089, 1050. MS (ESIꢀ), m/z (% relative
intensity): 401 (Mꢀ ꢀ H, 100), 825 (2[Mꢀ ꢀ H] þ Na, 66). HR
MS (Mꢀ ꢀ H): 401.1293 (calcd for C27H17N2O2 401.1296). Anal.
1,3-Dibenzyl-6-(pyren-1-yl)pyrimidine-2,4(1H,3H)-dione
(17g). Compound 17g was prepared from 8 according to general
procedure (Method B) in 50% yield, as a yellow powder, mp 78ꢀ80 °C.
1H NMR (600.1 MHz, CDCl3): 4.49, 5.12 (2 ꢁ d, 2 ꢁ 1H, Jgem = 15.5,
CH2-1); 5.30, 5.37 (2 ꢁ d, 2 ꢁ 1H, Jgem = 13.3, CH2-3); 5.94 (s, 1H,
H-5); 6.58 (m, 2H, H-o-1Bn); 6.99 (m, 2H, H-m-1Bn); 7.08 (m, 2H,
H-m-1Bn); 7.34 (m, 1H, H-p-3Bn); 7.40 (m, 2H, H-m-3Bn); 7.63 (d,
1H, J2,3 = 7.9, H-2-pyrenyl); 7.64 (m, 2H, H-o-3Bn); 7.82 (d, 1H, J10,9
9.1, H-10-pyrenyl); 8.08 (m, 3H, H-3,4,5-pyrenyl); 8.09 (t, 1H, J7,6
=
=
J7,8 = 7.7, H-7-pyrenyl); 8.18 (d, 1H, J9,10 = 9.1, H-9-pyrenyl); 8.25 (dd,
1H, J8,7 = 7.7, J8,6 = 1.2, H-8-pyrenyl); 8.29 (dd, 1H, J6,7 = 7.7, J6,8 = 1.2,
H-6-pyrenyl). 13C NMR (150.9 MHz, CDCl3): 44.8 (CH2-3); 49.5
(CH2-1); 105.0 (C-5); 123.1 (CH-10-pyrenyl); 124.2 (C-10c-pyrenyl);
124.3 (CH-10b-pyrenyl, CH-3-pyrenyl); 126.2 (CH-8-pyrenyl); 126.3
(CH-7-pyrenyl); 126.3 (CH-6-pyrenyl); 126.6 (CH-1-pyrenyl); 126.7
(CH-4-pyrenyl); 127.0 (CH-o-1Bn); 127.1 (CH-5-pyrenyl); 127.5
(CH-p-1Bn); 127.7 (CH-p-3Bn); 128.3 (CH-m-1Bn); 128.4 (C-10a-
pyrenyl); 128.5(CH-m-3Bn);129.0(CH-9-pyrenyl); 129.3(CH-o-3Bn);
129.4 (CH-2-pyrenyl); 130.6 (C-8a-pyrenyl); 131.1 (C-5a-pyrenyl);
132.4 (C-3a-pyrenyl); 136.3 (C-i-1Bn); 136.9 (C-i-3Bn); 152.7 (C-2);
153.8 (C-6); 162.1 (C-4). IR: 1700, 1652, 1601, 1584, 1494, 1430, 1389,
1340, 1179, 1070. MS (ESIþ), m/z (% relative intensity): 493 (Mþ þ H,
16), 515 (Mþ þ Na, 100), 531 (Mþ þ K, 30), 1007 (2Mþ þ Na, 13). HR
MS (Mþ þ H): 493.1910 (calcd for C34H25N2O2 493.1911).
Calcd for C27H18N2O2 0.75H2O: C, 77.96; H, 4.73; N, 6.73. Found: C,
3
78.21; H, 4.72; N, 6.35.
5-(Pyren-1-yl)pyrimidine-2,4(1H,3H)-dione (20g). Compound
20g was prepared from 16g (95 mg, 0.193 mmol) according to general
procedure (Method E), in 98% yield, as a white powder, mp > 300 °C.
1H NMR (499.8 MHz, DMSO-d6): 7.67 (d, 1H, J6,NH = 5.8, H-6); 7.93
(d, 1H, J2,3 = 7.8, H-2-pyrenyl); 8.02 (d, 1H, J10,9 = 9.2, H-10-pyrenyl);
8.08 (t, 1H, J7,6 = J7,8 = 7.6, H-7-pyrenyl); 8.16 (d, 1H, J9,10 = 9.2, H-9-
pyrenyl); 8.20 (s, 2H, H-4,5-pyrenyl); 8.28ꢀ8.32 (m, 3H, H-3,6,8-
pyrenyl); 11.23 (bdd, 1H, JNH,6 = 5.5, JNH,NH = 2.0, NH-1); 11.39 (bd,
1H, JNH,NH = 2.0, NH-3). 13C NMR (125.7 MHz, DMSO-d6): 112.5 (C-
5); 124.0 (C-10c-pyrenyl); 124.1 (CH-10b-pyrenyl); 124.7 (CH-3-
pyrenyl); 125.3, 125.5 (CH-6,8-pyrenyl); 125.6 (CH-10-pyrenyl);
126.5 (CH-7-pyrenyl); 127.3 (CH-9-pyrenyl); 127.5, 127.6 (CH-4,5-
pyrenyl); 129.1 (CH-2-pyrenyl); 129.2 (C-1-pyrenyl); 129.7 (C-10a-
pyrenyl); 130.6, 130.7 (C-3a,8a-pyrenyl); 131.0 (C-5a-pyrenyl); 141.9
(CH-6); 151.7 (C-2); 163.9 (C-4). IR: 3140, 1721, 1698, 1636, 1555,
1480, 1437, 1363, 1344, 1236, 1179, 1089. MS (ESIþ), m/z (% relative
intensity): 313 (Mþ þ H, 30), 335 (Mþ þ Na, 100). HR MS (Mþ þ H):
313.0972 (calcd for C20H13N2O2 313.0972).
3-Benzyl-5-(pyren-1-yl)pyrimidine-2,4(1H,3H)-dione (19g).
A mixture of compound 16g (50 mg, 0.102 mmol), ammonium formate
(2.6 mL of a 0.4 N solution in dry MeOH) and 10% palladiumꢀcharcoal
(120 mg 10% Pd/C, 0.113 mmol of Pd, 1.1 equiv of Pd) was refluxed at
72 °C for 17 h. The mixture was filtered through Celite, and the solid
residue was extensively washed with MeOH and CHCl3 (ca. 120 mL).
Removal of solvents under reduced pressure and following column
chromatography on 40 g of silica gel in gradient 10% ethylacetate in
hexane to 50% ethylacetate in hexane gave the pure monodebenzylated
product 19g in 67% yield, as a yellow powder, mp > 300 °C. 1H NMR
(499.8 MHz, DMSO-d6): 5.11 (bs, 2H, CH2-3); 7.28 (m, 1H, H-p-Bn);
7.36 (m, 2H, H-m-Bn); 7.38 (m, 2H, H-o-Bn); 7.78 (d, 1H, J6,NH = 5.5,
H-6); 7.96 (d, 1H, J2,3 = 7.8, H-2-pyrenyl); 8.01 (d, 1H, J10,9 = 9.2, H-10-
6-(Pyren-1-yl)pyrimidine-2,4(1H,3H)-dione (22g). Compound
22g was prepared from 17g (100 mg, 0.203 mmol) according to general
procedure (Method E), in 38% yield, as a yellow powder, mp > 300 °C.
1H NMR (499.8 MHz, DMSO-d6): 71 (d, 1H, J5,NH = 1.8, H-5); 8.12 (d,
1H, J2,3 = 7.9, H-2-pyrenyl); 8.15 (t, 1H, J7,6 = J7,8 = 7.6, H-7-pyrenyl);
8.26 (d, 1H, J4,5 = 9.1, H-4-pyrenyl); 8.27 (d, 1H, J9,10 = 9.3, H-9-
pyrenyl); 8.308 (d, 1H, J5,4 = 9.1, H-5-pyrenyl); 8.314 (d, 1H, J10,9 = 9.3,
H-10-pyrenyl); 8.38 (d, 1H, J3,2 = 7.9, H-3-pyrenyl); 8.39 (d, 2H,
pyrenyl); 8.08 (t, 1H, J7,6 = J7,8 = 7.6, H-7-pyrenyl); 8.15 (d, 1H, J9,10
=
9.2, H-9-pyrenyl); 8.21 (s, 2H, H-4,5-pyrenyl); 8.30 (d, 1H, J3,2 = 7.8,
H-3-pyrenyl); 8.31 (m, 2H, H-6,8-pyrenyl); 11.65 (bd, 1H, JNH,6 = 5.5,
NH). 13C NMR (125.7 MHz, DMSO-d6): 43.5 (CH2Ph); 112.0 (C-5);
124.0 (C-10c-pyrenyl); 124.1 (CH-10b-pyrenyl); 124.8 (CH-3-
pyrenyl); 125.4 (CH-10-pyrenyl); 125.5, 125.6 (CH-6,8-pyrenyl);
126.5 (CH-7-pyrenyl); 127.4 (CH-p-Bn); 127.4 (CH-9-pyrenyl);
127.5 (CH-4-pyrenyl); 127.7 (CH-5-pyrenyl); 127.9 (CH-o-Bn);
128.6 (CH-m-Bn); 129.2 (CH-2-pyrenyl); 129.3 (C-1-pyrenyl); 129.7
(C-10a-pyrenyl); 130.6 (C-8a-pyrenyl); 130.7 (C-3a-pyrenyl); 131.0
(C-5a-pyrenyl); 137.6 (C-i-Bn); 140.7 (CH-6); 151.6 (C-2); 162.9 (C-
4). IR (KBr): 3169, 1711, 1635, 1583, 1495, 1440, 1417, 1329, 1281,
1212, 1150, 1068. MS (ESIꢀ), m/z (% relative intensity): 401 (Mꢀ ꢀ H,
100), 825 (2[Mꢀ ꢀ H] þ Na, 19). HR MS (Mꢀ ꢀ H): 401.1296 (calcd
for C27H17N2O2 401.1296).
3-Benzyl-6-(pyren-1-yl)pyrimidine-2,4(1H,3H)-dione (21g).
A mixture of compound 17g (50 mg, 0.102 mmol), ammonium formate
(2.6 mL of a 0.4 N solution in dry MeOH) and 10% palladiumꢀcharcoal
(120 mg 10% Pd/C, 0.113 mmol of Pd, 1.1 equiv of Pd) was refluxed at
72 °C for 17 h. The mixture was filtered through Celite, and the solid
residue was extensively washed with MeOH and CHCl3 (ca. 120 mL).
Removal of solvents under reduced pressure and following column
J6 and 8,7 = 7.6, H-6,8-pyrenyl); 11.29, 11.41 (2 ꢁ bs, 2 ꢁ 1H, NH). 13
C
NMR (125.7 MHz, DMSO-d6): 102.40 (C-5); 123.75 (C-10c-pyrenyl);
123.84 (CH-10b-pyrenyl); 124.17 (CH-10-pyrenyl); 124.82 (CH-3-
pyrenyl); 126.06, 126.28 (CH-6,8-pyrenyl); 126.60 (CH-2-pyrenyl);
126.96 (CH-7-pyrenyl); 127.37 (CH-4-pyrenyl); 127.97 (C-1-pyrenyl);
128.09 (C-10a-pyrenyl); 128.82, 128.84 (CH-5,9-pyrenyl); 130.41 (C-
8a-pyrenyl); 130.89 (C-5a-pyrenyl); 132.07 (C-3a-pyrenyl); 151.81 (C-
2); 153.06 (C-6); 164.16 (C-4). IR: 3138, 1721, 1699, 1636, 1580, 1488,
1436, 1422, 1357, 1344, 1236, 1170, 1081. MS (ESIþ), m/z (% relative
intensity): 313 (Mþ þ H, 33), 335 (Mþ þ Na, 100). HR MS (Mþ þ
H): 313.09714 (calcd for C20H13N2O2 313.09715).
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of all NMR spectra.
b
This material is available free of charge via the Internet at
http://pubs.acs.org.
5318
dx.doi.org/10.1021/jo2006494 |J. Org. Chem. 2011, 76, 5309–5319

The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
D.; Wang, W.; Lian, S.; Yang, F.; Lan, J.; You, J. Chem.—Eur. J. 2009,
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Corresponding Author
*E-mail: hocek@uochb.cas.cz.
’ ACKNOWLEDGMENT
This work was supported by the Academy of Sciences of the
Czech Republic (Z4 055 0506), Ministryof Education (LC06077)
and by Gilead Sciences, Inc. (Foster City, CA, U.S.).
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