Regioselective arylation of uracil and 4-pyridone derivatives via copper(I) bromide mediated C-H bond activation

Article abstract of DOI:10.1016/j.tet.2012.11.001

A facile and effective synthesis of 6-aryluracil derivatives was accomplished by the direct C-H bond activation for arylation. A series of 6-aryl-1,3-dimethyluracils were synthesized from the reaction of 1,3-dimethyluracil with various phenyl iodides in DMF, in the presence of copper(I) bromide as the catalyst and lithium tert-butoxide as the base. This methodology is applicable to a variety of 5-substituted uracils as well as 4-pyridone to provide direct accesses to versatile uracil and 4-pyridone derivatives.

Full text of DOI:10.1016/j.tet.2012.11.001

Tetrahedron 69 (2013) 1387e1396
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Regioselective arylation of uracil and 4-pyridone derivatives via
copper(I) bromide mediated CeH bond activationq
,
a,
*
Chien Cheng a, Yu-Chiao Shih a, Hui-Ting Chen b , Tun-Cheng Chien
*
a Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
b Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Received in revised form 21 October 2012
Accepted 2 November 2012
Available online 8 November 2012
A facile and effective synthesis of 6-aryluracil derivatives was accomplished by the direct CeH bond
activation for arylation. A series of 6-aryl-1,3-dimethyluracils were synthesized from the reaction of 1,3-
dimethyluracil with various phenyl iodides in DMF, in the presence of copper(I) bromide as the catalyst
and lithium tert-butoxide as the base. This methodology is applicable to a variety of 5-substituted uracils
as well as 4-pyridone to provide direct accesses to versatile uracil and 4-pyridone derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
CeH activation
Uracil
4-Pyridone
Arylation
Catalysis
1. Introduction
Direct activation of CeH bond for arylation has become
a promising method for the synthesis of C-arylated heterocycles in
C-Aryl-substituted uracils are an important class of pyrimidine
derivatives that have received substantial attention for decades. 5-
Aryluracils and, in particular, their nucleoside derivatives, owing to
their structural resemblance to thymine, have been shown to
possess a wide variety of biological activities and have been ex-
tensively utilized as biosensors1e8 or dimensional analogs9e15 for
various biological targets. There has also been a growing interest in
the 6-aryluracil derivatives for their potential biological
applications.16e28 Except limited structures could be obtained by
the de novo synthesis from acyclic precursors,17,19,20,22,25,29e36 the
synthesis of 5- or 6-aryluracils has mostly been achieved by the
palladium-catalyzed cross-coupling reactions from the corre-
sponding halouracils, in which both SuzukieMiyaura26e28,37 and
Stille18,38e43 reactions were applicable. However, the synthesis of 6-
aryluracils has been restricted by the preparation of 6-halouracil
derivatives from uracil27,44 or barbituric acid derivatives,45,46
which suffered from lower yields, limited scales and harsh condi-
tions. Thus, there is a need to develop a more effective process for
the synthesis of 6-aryluracils.
recent years.47e57 Nevertheless, a thorough survey of the literature
revealed that only few examples utilizing the direct activation of
the uracil CeH bond for functionalization have been doc-
umented.58e65 In 1986, Itahara first reported that both sugar-
protected uridine derivatives and 1,3-dimethyluracil (1,3-DMU,
1a) underwent the CeC bond formation reaction at the 5-position
with maleimides in the presence of a stoichiometric amount of
palladium acetate in acetic acid.65 In 2009, a Pd(OAc)2 catalyzed
direct arylation of N-substituted uracils with aryl iodides was re-
ported by Hocek et al., in which the regiochemistry was switchable
by the addition of copper(I) iodide.62,64 In the absence of CuI, the
reaction led preferentially to the 5-aryluracils, while the reaction
gave 6-aryluracils as the major products with a large excess of CuI.
Later on, an improved protocol for Pd(OAc)2 catalyzed 5-arylation
of 1,3-DMU (1a) was reported by Kim et al. in 2011.60 Only very
recently in 2012, Kim et al. also reported that the 6-aryluracils could
be obtained as the major products by the palladium(II)
trifluoroacetate-catalyzed double CeH activation between 1,3-
DMU (1a) and the arene solvents, such as benzene and xylenes,
in the presence of an excess of silver acetate and pivalic acid.59
The formation of 6-aryluracils from 1,3-DMU (1a) and aryl io-
dides reported by Hocek et al. has received our attention.64 When
1,3-DMU (1a) was reacted with aryl iodides in the presence of
3 equiv of CuI and cesium carbonate as a base in DMF, without any
Pd catalyst and ligand, the reaction proceeded over two days with
q
This paper is dedicated to Professor Ji-Wang Chern on the occasion of his 60th
birthday
* Corresponding authors. E-mail address: tcchien@ntnu.edu.tw (T.-C. Chien).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.001

1388
C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
moderate yields but afforded exclusively the 6-aryluracils. In ad-
dition, Daugulis and Do reported a general approach that hetero-
cycles possessing CeH bonds with pKa lower than 35 could be
activated for arylation by CuI and 1,10-phenanthroline (1,10-Phen)
in combination with various bases and solvents.55 They also dem-
onstrated a single example that the 6-aryluracil could be obtained
in 61% yield from the copper-catalyzed cross-coupling reaction
between 1,3-DMU (1a) and 3-methylanisole.61 The reaction used
10 mol % of CuI/1,10-Phen as the catalyst, potassium phosphate as
the base, iodine as the oxidant, and pyridine as an additive in 1,2-
dichlorobenzene, but required two days for the completion. All
reports suggested that copper is amenable for the CeH bond acti-
vation at the 6-position of uracil. In our effort to explore the
chemical synthesis and biological significance of 6-substituted
uracil derivatives, we have also embarked on the investigation of
the direct activation of uracil CeH bond for functionalization.
Herein, we report our synthesis of 6-aryluracil and 2-aryl-4-
pyridone derivatives via a copper(I) bromide catalyzed regiose-
lective activation of CeH bond for arylation.
CeH bond at the 6-position of uracil derivatives. The screening of
the reaction conditions started with 20 mol % of copper(I) ha-
lides55,57 as the catalyst with various solvents, bases, arylating re-
agents, temperature, and ligands/additives (part of the results is
summarized in Table 1). The maximal yield was obtained when the
reaction was carried out in DMF with phenyl iodide (2a) as the
arylating reagent, copper(I) bromide as the catalyst, and lithium
tert-butoxide as the base (entry 3 in Table 1). The survey of the
conditions also concluded that both the copper catalyst and the
alkoxide base were required for the reaction, and the reaction
yields were presumably the same in open air and under an argon
atmosphere. The use of an inexpensive copper catalyst allowed the
catalyst loading to be increased to 40 mol % to further improve the
yield. Hence, this optimized condition (entry 19 in Table 1) was
used as the standard condition for the subsequent studies. It is
noteworthy that this reaction protocol is highly regioselective at
the 6-position of 1,3-DMU (1a). Only 6-Phe1,3-DMU (3aa) was
isolated from the reaction while 5-Phe1,3-DMU (1g) was almost
negligible (0e0.5% among all the conditions) and 5,6-diPhe1,3-
DMU (3ga) was not observed from the 1H NMR of the reaction
mixture.
2. Results and discussion
The reactions of 1,3-DMU (1a) with a variety of phenyl iodides
(2aei) possessing o-, m- or p-substituents, as shown in Table 2,
were examined to establish the scope of the aryl iodide
1,3-Dimethyluracil (1,3-DMU, 1a) was chosen as a model sub-
strate to investigate the direct arylation via the activation of the
Table 1
Examination and optimization of the reaction conditionsa
O
O
catalyst
base
Me
O
H
H
Me
O
H
N
N
(ligand/additive)
solvent (0.5 M)
temperature
1 h
N
Me
1a
N
Me
3aa
Entry
Catalyst (equiv)
Base (equiv)
Ligand/additive (equiv)
Arylating reagent (2 equiv)
Solventb
Yieldc (%)
1
2
3
4
5
6
7
8
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.1)
CuBr (0.2)
CuBr (0.4)
CuCl (0.4)
CuI (0.4)
Cs2CO3 (2)
LiOH (2)
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheB(OH)2
PheBr
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
PheI
DMF
DMF
DMF
DMF
THF
DME
Dioxane
Toluene
tert-Amyl-OH
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
N.R.d
N.R.d
76
21
5
20
41
30
LiOtBu (2)
NaOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (4)
LiOtBu (4)
LiOtBu (4)
LiOtBu (4)
LiOtBu (4)
LiOtBu (4)
d
9
10
10e
11
12
13
14
15
16
17
18i
19
20
21
22
23
24
25
26
N.D.f
67
PPh3 (0.2)
1,10-Pheng (0.1)
62
57
L-Proline (0.1)
TMEDAh (0.1)
60
N.R.d
6
63
15
87 (82)j
79
79
70
78
CuCN (0.4)
Cu(OAc)2 (0.4)
CuSO4 (0.4)
CuBr (0.4)
d
DMF
DMF
DMF
34
N.R.d
N.D.f
LiOtBu (4)
a
Temperature¼reflux (unless specified otherwise); time¼1 h; under air atmosphere.
Reaction concentration¼0.5 M.
b
c
d
e
f
The yields were determined by 1H NMR analysis of the crude products using caffeine as an internal standard.
N.R.¼no reaction.
Temperature¼180 ꢀC.
N.D.¼no desired product (complicated result).
1,10-Phen¼1,10-phenanthroline.
TMEDA¼N,N,N0,N0-tetramethylethylenediamine.
Temperature¼120 ꢀC.
g
h
i
j
Isolated yield.

C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
1389
Table 2
O
The reactions of 1,3-dimethyluracil derivatives (1aeg) with various phenyl iodides
(2aei)
Me
O
N
I
N
Me
R (2a-i)
(2 eq)
O
O
Me
O
R5
Me
O
R5
N
CuBr (0.4 eq)
N
4
N
Me
1a-g
N
Me
3a-g
Fig. 1. The benzynoid (or ‘hetaryne’) 4 formed from 5-Bre1,3-DMU (1e).
LiOtBu (4 eq)
DMF (0.5 M)
reflux, 1 h
R
reaction of 5-Fe1,3-DMU (1c) and 5-Cle1,3-DMU (1d) under the
same condition. Moreover, the 5-halo-1,3-DMUs (R5¼F, Cl, Br, 1cee,
respectively) did not undergo the classic Ullmann-type reaction68
under the standard condition as neither the 5-arylated 1,3-DMU
nor the bis-uracil adducts (5) were observed.
The synthesis of 5,6-diphenyl-1,3-dimethyluracil (3ga) has also
been demonstrated. 5-Phe1,3-DMU (1g) could be prepared by
well-established palladium-catalyzed cross-coupling reactions
from 5-Bre1,3-DMU (1e),27 or by a more recently developed
palladium-catalyzed direct CeH bond activation reactions from 1,3-
DMU (1a).60,64 The 6-phenyl substituent was then installed by our
methodology to afford the 5,6-diphenyl adduct (3ga) in 47% yield
(entry 25 in Table 2).
Meanwhile, the reactivity of the 6-substituted 1,3-DMU (6a,b)
toward the arylation condition was also examined. The reaction of
6-Cle1,3-DMU (6a) with p-iodotoluene (2b) under the standard
condition gave no arylated product at either the 5- or 6-position (7a
or 3ab). 6-Mee1,3-DMU (6b) was subjected to the standard con-
dition with p-iodotoluene (2b) but the arylation did not occur at
either the 5-position (7b) or the 6-methyl group (8) (Scheme 1).
The investigation further confirmed that the arylation under our
optimized condition did not occur at the 5-position of uracil. Fur-
thermore, the standard condition did not activate the 5- and 6-
chlorouracils (1d and 6a) for homo- or cross-coupling reactions.59
In an effort to evaluate the substituent effects on the uracil ni-
trogens, fully and partially N-unsubstituted uracil (9a,b), as well as
uracil derivatives bearing removable protecting groups at the N1- and
N3-positions62 (9c,d), including uracil (9a), 1-methyluracil (9b), 1,3-
di-(p-methoxybenzyl)uracil (9c), and 1,3-di-(benzyloxymethyl)ura-
cil (9d), were subjected to the standard conditionwith p-iodotoluene
(2b). It was found that only the reaction of 1,3-di-(p-methoxybenzyl)
uracil (9c) could proceed to afford the desired 6-(4-tolyl)uracil
product (10c). The results indicated that the protection or sub-
stitution at both nitrogens of uracil is required for the reaction
(Table 3). Since the removal of the PMB (p-methoxybenzyl) group has
been demonstrated,62 this approach would provide a facile access to
the N-unsubstituted 6-aryluracil derivatives.
Entry
Reactant
R5
AreI
R
Product, yielda
(1aeg recovered)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1f
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
F
F
F
Cl
Cl
Cl
Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
2a
2b
2c
2d
2a
2b
2d
2a
2b
2c
2d
2a
2b
2d
2a
2a
H
4-Me
3aa, 82%
3ab, 58% (15%)
3ac, 54% (19%)
3ad, 55% (21%)
3ae, 28% (24%)
3af, 20%c
3ag, 85%
3ah, 72%
3ai, 66%
3ba, 21% (45%)
3bb, 46% (29%)
3bc, 31% (40%)
3bd, 29% (60%)
3ca, 47%
3cb, 41% (6%)
3cd, 42% (8%)
3da, 68%
3db, 44% (9%)
3dc, 45% (6%)
3dd, 35% (10%)
3ea, 39%þ3aa, 23%
3eb, 32%þ3ab, 9%
3ed, 24%þ3ad, 12%
N.D.d
4-MeO
4-Cl
4-Br
4-NO2
2-Me
3-MeO
2-MeO
H
4-Me
4-MeO
4-Cl
H
4-Me
4-Cl
H
4-Me
4-MeO
4-Cl
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Br
Br
Br
NO2
Ph
4-Me
4-Cl
H
1g
H
3ga, 47%
a
Isolated yields.
b
c
Numbers in parentheses represent the recovered reactants 1aeg, if denoted.
4-Nitrophenyl iodide (2f, 5 equiv), reaction time¼5 h (only 6.3% of 3af was
obtained and 58% of 1a was recovered under the standard condition).
d
N.D.¼no desired product.
components for the reaction. Under the standard condition (entry
19 in Table 1),1,3-DMU (1a) reacted with most of the phenyl iodides
to form the 6-aryluracil derivatives 3aaeai in 28e85% yields, ex-
cept the strong electron-withdrawing p-nitrophenyl iodide (2f)
gave a very low yield. The yield was improved by extending the
reaction time and increasing the amount of p-nitrophenyl iodide
(2f) (entry 6 and note c in Table 2).
The reaction was then applied to a series of 5-substituted uracil
derivatives, including 5-methyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-
nitro-, and 5-phenyl-1,3-dimethyluracil derivatives (1beg, re-
spectively), in order to explore the generality of the uracil sub-
strates. Most of their 6-arylated products were obtained in
moderate to good yields (entries 11e23 and 25 in Table 2), except
the reaction of 5-NO2e1,3-DMU (1f) gave no desired product but
a complicated result (entry 24 in Table 2). The slight decrease in
yields for the 5-substituted 1,3-DMU derivatives (1bee and 1g) was
possibly attributed to both the steric and electronic effects of the
substituents at the 5-position of 1,3-DMU.
Me
O
O
2b
4-MePh-I ( , 2 eq)
Me
O
Me
O
CuBr (0.4 eq)
N
N
LiO Bu (4 eq)
t
N
R6
N
Me
7a-b
R6
DMF (0.5 M)
reflux, 1 h
Me
R6 = Cl
6a
R6 = Me
O
not observed
O
6b
O
When 5-Bre1,3-DMU (1e) was used as the reactant, the for-
mation of the debrominated 6-aryluracil by-products (3aa, 3ab,
and 3ad) has received our attention (entries 21e23 in Table 2). We
rationalized that the debromination possibly involved an elimi-
nationeaddition mechanism in which a ‘hetaryne (4)’ could be
formed by the deprotonation followed by the elimination of HBr
from 5-Bre1,3-DMU (1e) in prior to the arylation55,57,66,67 (Fig. 1).
However, the dehalogenated 6-aryluracils were not observed in the
Me
Me
O
Me
O
Me
N
N
N
O
N
Me
N
N
Me
C
H2
Me
5
8
bis(uracil)
not observerd from
not observerd from
6a
the reaction of 6b
the reaction of
Scheme 1.

1390
C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
Table 3
O
O
The reactions of various N-substituted uracil derivatives 9aed with p-iodotoluene
(2b)
Me
O
H
H
Me
O
D
D
N
N
+
O
O
N
Me
1a
N
Me
1a-5,6-d2
4-MePh-I (2b, 2 eq)
R3
O
R3
O
CuBr (0.4 eq)
N
N
LiOtBu (4 eq)
DMF (0.5 M)
reflux, 1 h
N
N
1a / 1a-5,6-d2 = 1 : 1
R1
9a-d
R1
10a-d
O
O
Me
Me
H
Me
O
D
Ph-I
N
N
+
Entry
Reactant
R1
R3
Product (yield)a
standard
condition
87%
O
N
Me
3aa
Ph
N
Me
3aa-5-d
Ph
1
2
3
4
9a
9b
9c
9d
H
Me
PMB
BOM
H
H
N.R.b
N.D.c
PMB
BOM
10c (43%)
N.D.c
3aa / 3aa-5-d = 0.77 : 0.23
a
Isolated yields.
Scheme 2.
b
c
N.R.¼no reaction.
N.D.¼no desired product.
Ph-I
The success in uracil derivatives prompted us to further expand
1a-5,6-d2
3aa
+
3aa-5-d
the scope of this methodology to the 4-pyridone derivatives. 1-(p-
Methoxybenzyl)-4-pyridone (11) was employed in the reaction
with various phenyl iodides (2a,b and 2d) under the standard
condition. The arylation regioselectively took place at the 2-
position to give the corresponding 2-aryl-1-(p-methoxybenzyl)-4-
pyridones (12a,b and d) in 28e33% yields without any modifica-
tion of the reaction condition (Table 4). The structure of 12d was
confirmed by intensive NMR studies including 1H, 13C, DEPT-135,
COSY, HMQC, HMBC, and NOESY experiments to identify the loca-
tion of the arylation.
standard
condition
85%
3aa / 3aa-5-d = 0.52 : 0.48
Scheme 3.
distinguish the proton source, a reaction of 1,3-DMU (1a) with PhI
(2a) was carried out in the presence of one drop of D2O under the
standard condition and the product was obtained in 74% yield
with 17% of deuterium incorporation at the 5-position. Similarly,
when one drop of acetic acid-d4 was used instead of D2O in the
reaction, the product was obtained in 81% yield with 18% of
deuterium incorporation (Table 5). The addition of D2O or acetic
acid-d4 only slightly decreased the yields but did not affect
the proceeding of the reaction. However, the deuterium in-
corporation level was much lower than the proton exchange
observed in the reaction of 1a-5,6-d2. The observation has
prompted us to speculate that the proton was abstracted from
DMF during the reaction in Scheme 3. Hence, the reaction
of 1,3-DMU (1a) with PhI (2a) in DMF-d7 under the standard
condition was carried out to give the arylated product in 82%
yield with 41% of deuterium incorporation, which was compa-
rable to the loss of deuterium in the reaction of 1a-5,6-d2. The
investigation confirmed the proton source and the participation
of DMF in the reaction, which was, to our knowledge, un-
precedented in the literature although the tert-butoxide base in
DMF has been widely used.55,57
Table 4
The reactions of 1-(p-methoxybenzyl)-4-pyridone (11) with various phenyl iodides
(2a,b and d)
I
(2a-b, 2d)
R
O
O
(2 eq)
CuBr (0.4 eq)
N
PMB
11
N
PMB
12
LiOtBu (4 eq)
DMF (0.5 M)
reflux, 1 h
R
Entry
AreI
R
Product (yield)a
1
2
3
2a
2b
2d
H
4-Me
4-Cl
12a (28%)
12b (33%)
12d (31%)
a
Isolated yields.
Preliminary deuterium isotope studies were carried out in order
to gain insight into the reaction details. An intermolecular com-
petition reaction using an equimolar mixture of 1,3-DMU (1a) and
5,6-di-deuterated 1,3-DMU69e71 (1a-5,6-d2) with PhI (2a) under
the standard condition afforded the product in 87% yield with the
ratio of 3aa/3aa-5-d¼3.35 (Scheme 2). When the 5,6-di-deuterated
1,3-DMU (1a-5,6-d2) alone was subjected to the same condition, the
desired 6-phenyl-substituted product was obtained in 85% yield.
Unexpectedly, analysis of the proton NMR spectrum of the product
indicated that only 48% of deuterium retained at the 5-position
(3aa-5-d) (Scheme 3). Since the partial proton-deuterium ex-
change at the 5-position occurred during the reaction, the kinetic
isotope effect appears to be greater than 3.35 and suggests that the
CeH bond cleavage at the 6-position was involved in the rate-
limiting step.
Table 5
Identification of the proton source in the reaction
Ph-I (2 eq)
d-source
CuBr (0.4 eq)
1a
3aa
+
3aa-5-d
LiOtBu (4 eq)
solvent
reflux, 1 h
Entry
d-Source/solventa
Yieldb
Deuterium contentc
(3aa/3aa-5-d)
1
2
3
A
B
C
74%
81%
82%
0.83:0.17
0.82:0.18
0.59:0.41
a
Deuterium source/solvent: A¼1 drop of D2O in DMF; B¼1 drop of acetic acid-d4
in DMF; C¼DMF-d7.
The loss of deuterium at the 5-position of 3aa-5-d was due to
deprotonation followed by reprotonation from which was origi-
nally thought to be the water residue in the solvent. To
b
Isolated yields.
c
Determined by 1H NMR.

C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
1391
Based upon the preliminary isotope effect data, a Ullmann-type
reaction68 mechanism involving the formation of the uracil 6-
carbanion as an intermediate was sketched.57 (mechanism A in
Scheme 4) In this proposed mechanism, the catalytic cycle started
1e3 and 6e8 in Table 6). Accordingly, these investigations sug-
gested that the formation of the uracil carbanion at either 5- or 6-
position was irrelevant to the regioselectivity of the reaction and
did not support the proposed mechanism A (Table 6).
O
Me
O
H
N
Ph
2a
I
N
Me
3aa
Ph
O
H
Cu(III)BrI
Ph
Me
O
N
C-H bond
cleavage
N
H
Cu(I)Br
Me
18
O
O
N
X
mechanism A
mechanism B
- H
+H
Me
+
Me
O
H
N
Cu(III)
N
-
Cu(III)X (X = Br or I)
O
N
Me
I
Me Ph
15
Ph Cu(III)
17
O
N
Br
13
Me
O
H
N
Cu(III)PhX (X = Br or I)
H
Me
16
O
O
N
C-H bond
cleavage
Me
N
H
H
Me
O
H
N
O
N
Me
1a
Me
14
Scheme 4.
with an oxidative addition of CuBr to PhI (2a) to form the phenyl
copper(III) complex 13. Meanwhile, regioselective deprotonation
by LiOtBu at the 6-position of 1,3-DMU (1a) formed the uracil 6-
carbanion intermediate 14. We rationalize that the regiose-
lectivity of the reaction was attributed to the pKa difference be-
tween the 5-CH and the 6-CH of 1,3-DMU (1a). Subsequently, the
uracil 6-carbanion (14) replaced the halide from the copper(III)
complex 13 by transmetallation to afford the diaryl copper(III)
complex 15, which then underwent a reductive elimination to give
the coupled product 3aa and regenerated the active copper(I)
species.57 Although the pKa for the 6-CH of 1,3-DMU (1a) has been
estimated to be approximately 30e34,72e75 it still remained to be
further elucidated whether the uracil 6-carbanion was formed in
the reaction.
Thus, two sets of experiments using the deuterium source (D2O,
acetic acid-d4, and DMF-d7) to trace the existence of the uracil 6-
carbanion 14 in the reaction were conducted. In one set of the ex-
periments, 1,3-DMU (1a) was subjected to the standard condition
except in the absence of PhI (2a), while in the other set, PhI (2a) and
CuBr were omitted from the standard condition. Both sets were
added one drop of either D2O or acetic acid-d4 in DMF or carried out
in DMF-d7 as the deuterium source. The levels of the deuterium
incorporation were anticipated to reflect the formation of the
carbanion in the reaction (Table 6). Nevertheless, all the experi-
mental results showed no significant differences in deuterium in-
corporation between the 5- and 6-positions in the recovered 1,3-
DMU (1a-dn). In particular, when the experiments were carried
out in DMF-d7 in the absence of PhI (2a), the levels of the deuterium
incorporation at the 5- and 6-positions were all above 70% and
indicated that the deprotonation at the 5- and 6-positions took
place at the same probability under the reaction conditions (entries
Table 6
Identification of the formation of uracil carbanions
O
O
d-source
(additive)
Me
O
H
H
Me
O
H/D
H/D
N
N
N
Me
1a
N
Me
1a-dn
LiOtBu (4 eq)
solvent (0.5 M)
reflux, 1 h
Entry
d-Source/solventa
Additive
(equiv)
Recovered
yieldb
5-H/Dc
6-H/Dc
1
2
3
4
5
6
7
8
9
10
A
B
C
CuBr (0.4)
CuBr (0.4)
CuBr (0.4)
CuBr (0.4)
CuBr (0.4)
d
67%
96%
65%
75%
75%
35%
57%
41%
81%
42%
0.86:0.14
0.80:0.20
0.30:0.70
0.80:0.20
0.67:0.33
0.76:0.24
0.88:0.12
0.12:0.88
0.81:0.19
0.30:0.70
0.88:0.12
0.85:0.15
0.22:0.78
0.74:0.26
0.56:0.44
0.78:0.22
0.90:0.10
0.18:0.82
0.76:0.24
0.30:0.70
Cd
D
A
B
d
C
d
Cd
D
d
d
a
Deuterium source/solvent: A¼1 drop of D2O in DMF; B¼1 drop of acetic acid-d4
in DMF; C¼DMF-d7 [DCON(CD3)2]; D¼DMF-d [DCON(CH3)2].
b
Isolated yields.
c
Determined by 1H NMR.
d
Reaction temperature¼120 ꢀC.
The investigations also raised a question on which deuterium
from DMF-d7 was transferred to the substrate. We presumed that
DMF decomposes at reflux temperature to form (CD3)2N-D/H,
which acts as the deuterium/proton source in the reaction. To test
this hypothesis, the same set of reactions was carried out in DMF-d7

1392
C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
at 120 ꢀC and the deuterium incorporation was found to be much
lower than at reflux temperature (entries 4 and 9 in Table 6). In
order to further illuminate the deuterium/proton source, the same
set of reactions were carried out in DMF-d at reflux temperature
and the results clarified that the deuterium was mainly abstracted
from the formyl proton due to the decomposition of DMF-d7 (en-
tries 5 and 10 in Table 6).
will be amenable to the synthesis of a variety of uracil and 4-
pyridone derivatives.
4. Experimental section
4.1. General chemical procedures
Therefore, an alternative mechanism was proposed (mechanism
B in Scheme 4), in which the 5,6-double bond of the 1,3-DMU (1a)
first coordinated to the copper center of the phenyl copper(III)
complex (13) followed by a migratory insertion in a syn fashion
to form the cis-5,6-dihydro-6-phenyluracil copper(III) complex
(18). The addition of the phenyl copper(III) complex (13) across the
5,6-double bond of the 1,3-DMU (1a) was the determinative step
for the regioselectivity. We rationalized that the selectivity was
attributed to the intrinsic bond polarity matching between the
C5eC6 double bond of 1,3-DMU (1a) and the phenylecopper bond
of 13 (transition state 17 in Scheme 4). As a result, the electrophilic
copper center of the phenylecopper(III) complex (13) attached to
the more nucleophilic C5-position in 1,3-DMU (1a), and then the
phenyl group migrated to the C6-position to provide the cis-5,6-
dihydro-6-phenyluracil copper(III) complex (18).
Nuclear magnetic resonance (NMR) spectra were obtained with
Bruker Avance-400 or Avance-500 instruments. The chemical shift
values are reported in
d values (parts per million, ppm) relative to
the standard chemical shift for the deuterated solvent, CDCl3, or
DMSO-d6.76 The coupling constant (J) values are expressed in hertz
(Hz). Mass spectrometry was acquired by the Advanced Instrument
Center, Department of Chemistry, National Taiwan University, Tai-
pei, Taiwan. Thin-layer chromatography (TLC) was performed on
silica gel GHLF-254 plates (Merck Reagents). Compounds on thin-
layer chromatography were visualized by illumination under UV
light (254 nm). Solvent systems are expressed as a percentage of
the more polar component with respect to total volume (v/v%).
Merck Silica gel (230e400 mesh) was used for flash column chro-
matography and this technique has been described by Still et al.77
Evaporations were carried out under reduced pressure (water as-
pirator) with the bath temperature below 50 ꢀC unless specified
otherwise. Materials obtained from commercial suppliers were
used without further purification.
Afterward, the base abstracted the 6-proton to promote an anti
elimination to afford the desired product 3aa and regenerated the
active copper(I) species (mechanism B1 in Scheme 5). Alternatively,
a b-hydride elimination mechanism similar to the Heck reaction was
also possible, although this mechanism may require the trans-5,6-
dihydro-6-phenyluracil copper(III) complex (180). Subsequently,
the formation of the 6-Phe1,3-DMUecopper complex (19) followed
by the dissociation of the product 3aa and the reductive elimination
of the copper(I) catalyst accomplished the catalytic cycle (mecha-
4.2. General procedure for the CuBr catalyzed CeH bond ac-
tivation for arylation
To a mixture of 1,3-dimethyluracil (0.140 g, 1 mmol), CuBr
(0.057 g, 0.4 mmol, 0.4 equiv), and the aryl iodide (2 mmol, 2 equiv)
in DMF (2 mL) was added LiOtBu (0.320 g, 4 mmol, 4 equiv). The
reaction mixture was heated at reflux temperature for 1 h. After
cooling to the room temperature, the reaction was quenched by
adding saturated aqueous NH4Cl solution. The solvent was removed
under reduced pressure. The residue was partitioned between
EtOAc and H2O. The organic layer was washed with saturated
aqueous NaCl solution, dried over anhydrous MgSO4, and then
concentrated under reduced pressure to dryness. The residue was
purified by flash column chromatography to give the product.
nism B2 in Scheme 5). The postulated
b-elimination of the cop-
per(III) complex 18 (mechanism B1) and the
b
-hydride elimination
of the copper(III) complex 180 (mechanism B2) both involved the
CeH bond breaking at the 6-positionwhich were consistent with the
deuterium isotope effect observed in the experiment (Scheme 5).
O
N
O
N
CuX
H
H
Me
O
H
Cu(III)BrI
Ph
Me
O
N
N
4.2.1. 1,3-Dimethyl-6-phenyluracil27,59,60,64,78 (3aa). Compound 3aa
was prepared by the general procedure and purified by flash column
chromatography (82%, Hex/EtOAc¼7:3, Rf¼0.28 (Hex/EtOAc¼5:5)).
An analytical sample was recrystallized from Hex/EtOAc. Mp
-elemination
Ph
Me
3aa
Me
18
mechanism B1
CuX
104e106 ꢀC (Hex/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
7.43e7.41 (m,
3H, Ph), 7.28e7.26 (m, 2H, Ph), 5.62 (s,1H, 5-H), 3.32 (s, 3H, CH3), 3.15
(s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
162.4, 154.6, 152.6, 133.4,
epimerization
at 5-position
d
O
O
N
130.2 (CH),129.0 (CH),127.8 (CH),102.4 (CH), 34.6 (CH3), 28.0 (CH3).
MS (EI, 20 eV) m/z 84 (37), 118 (35), 215 (65), 216 (100) (Mþ). HRMS
calcd for C12H12N2O2 (Mþ): 216.0899. Found: 216.0895.
H
-hydride
shift
Cu(III)BrI
Ph
Me
O
Me
O
H
N
N
Cu(III)BrI
H
Ph
N
Me
18'
H
4.2.2. 1,3-Dimethyl-6-(p-tolyl)uracil60,62,64,79 (3ab). Compound 3ab
was prepared by the general procedure and purified by flash col-
umn chromatography (58%, Hex/EtOAc¼7:3, Rf¼0.33 (Hex/
EtOAc¼5:5)). Mp 110e112 ꢀC (from column); 1H NMR (CDCl3,
Me
19
mechanism B2
Scheme 5.
400 MHz)
d
7.22 (d, 2H, J¼8.0 Hz, Ph), 7.16 (d, 2H, J¼8.0 Hz, Ph), 5.60
3. Conclusion
(s, 1H, 5-H), 3.32 (s, 3H, CH3), 3.16 (s, 3H, CH3), 2.35 (s, 3H, CH3); 13
NMR (CDCl3, 100 MHz) 162.5, 154.8, 152.7, 140.4, 130.5, 129.6 (CH),
C
d
In summary, our investigation has provided a facile and practical
synthesis of 6-aryluracil and 2-aryl-4-pyridone derivatives, which
utilized inexpensive copper(I) bromide as a catalyst to regiose-
lectively activate the CeH bond for arylation at the 6-position of
uracil and 2-position of 4-pyridone. The reaction protocol is con-
venient to carry out under ambient atmosphere without the ex-
clusion of moisture and air. Further application of this methodology
127.7 (CH), 102.3 (CH), 34.6 (CH3), 28.0 (CH3), 21.3 (CH3). MS (EI,
20 eV) m/z 72 (84), 132 (36), 229 (75), 230 (100) (Mþ). HRMS calcd
for C13H14N2O2 (Mþ): 230.1055. Found: 230.1050.
4.2.3. 1,3-Dimethyl-6-(p-methoxyphenyl)uracil60,64,79 (3ac). Compo-
und 3ac was prepared by the general procedure and purified by flash
column chromatography (54%, Hex/EtOAc¼7:3, Rf¼0.23 (Hex/

C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
1393
EtOAc¼5:5)). Mp 98e100 ꢀC (from column); 1H NMR (CDCl3,
column chromatography (66%, Hex/EtOAc¼7:3, Rf¼0.33 (Hex/
EtOAc¼5:5)). Mp 116e118 ꢀC (from column); 1H NMR (CDCl3,
400 MHz)
d
7.22 (dd, 2H, J¼6.9, 1.8 Hz, Ph), 6.93 (dd, 2H, J¼7.0, 1.8 Hz,
Ph), 5.61 (s, 1H, 5-H), 3.81 (s, 3H, CH3), 3.33 (s, 3H, CH3), 3.19 (s, 3H,
400 MHz)
d
7.39e7.34 (m, 1H, Ph), 7.08 (dd, 1H, J¼7.2, 1.6 Hz, Ph),
CH3); 13C NMR (CDCl3,100 MHz)
d
162.5,161.0,154.7,152.8,129.4 (CH),
6.93 (t, 1H, J¼7.4 Hz, Ph), 6.89 (d, 1H, J¼8.4 Hz, Ph), 5.53 (s, 1H, 5-H),
125.6,114.4 (CH),102.3 (CH), 55.5 (CH3), 34.7 (CH3), 28.0 (CH3). MS (EI,
3.74 (s, 3H, CH3), 3.27 (s, 3H, CH3), 3.03 (s, 3H, CH3); 13C NMR
20 eV) m/z 72 (46),148 (28), 245 (72), 246 (100) (Mþ). HRMS calcd for
(CDCl3, 100 MHz) d 162.5, 155.9, 152.7, 152.3, 131.8 (CH), 129.5 (CH),
C
13H14N2O3 (Mþ): 246.1004. Found: 246.0995.
122.3, 121.0 (CH), 110.9 (CH), 102.3 (CH), 55.4 (CH3), 33.0 (CH3), 27.8
(CH3). MS (EI, 20 eV) m/z 158 (25), 246 (100) (Mþ). HRMS (EI) calcd
for C13H14N2O3 (Mþ): 246.1004. Found: 246.1002.
4.2.4. 1,3-Dimethyl-6-(p-chlorophenyl)uracil (3ad). Compound 3ad
was prepared by the general procedure and purified by flash column
chromatography (55%, Hex/EtOAc¼7:3, Rf¼0.25 (Hex/EtOAc¼5:5)).
4.2.10. 1,3,5-Trimethyl-6-phenyluracil (3ba). Compound 3ba was
prepared by the general procedure and purified by flash column
chromatography (21%, Hex/EtOAc¼7:3, Rf¼0.38 (Hex/EtOAc¼5:5)).
Mp 126e130 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
d 7.41 (d,
2H, J¼8.3 Hz, Ph), 7.24 (d, 2H, J¼8.4 Hz, Ph), 5.6 (s, 1H, 5-H), 3.31 (s,
3H, CH3), 3.15 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
162.2,153.5,
Mp104e106 ꢀC(fromcolumn);1HNMR(CDCl3, 400MHz)
d7.49e7.47
152.5,136.5,131.8,129.4 (CH),129.2 (CH),102.6 (CH), 34.6 (CH3), 28.0
(CH3). MS (EI, 20 eV) m/z 72 (52), 152 (50), 249 (94), 250 (100) (Mþ),
251 (19), 252 (10) (Mþ2). HRMS calcd for C12H11N2O2Cl (Mþ):
250.0509. Found: 250.0503.
(m, 3H, Ph), 7.18 (d, 2H, J¼7.4 Hz, Ph), 3.40 (s, 3H, CH3), 3.04 (s, 3H,
CH3),1.66 (s, 3H, CH3); 13C NMR (CDCl3,100 MHz)
d
163.9, 152.2, 149.8,
133.2,129.7 (CH),129.4 (CH),128.0 (CH),108.6, 34.6 (CH3), 28.4 (CH3),
12.9 (CH3). MS (EI, 20 eV) m/z 229 (100), 230 (60) (Mþ). HRMS (ESI)
calcd for C13H14N2O2 (MþH): 231.1134. Found: 231.1134.
4.2.5. 1,3-Dimethyl-6-(p-bromophenyl)uracil (3ae). Compound 3ae
was prepared by the general procedure and purified by flash col-
umn chromatography (28%, Hex/EtOAc¼7:3, Rf¼0.28 (Hex/
EtOAc¼5:5)). Mp 116e120 ꢀC (from column); 1H NMR (CDCl3,
4.2.11. 1,3,5-Trimethyl-6-(p-tolyl)uracil (3bb). Compound 3bb was
prepared by the general procedure and purified by flash column
chromatography (46%, Hex/EtOAc¼7:3, Rf¼0.40 (Hex/EtOAc¼5:5)).
400 MHz)
d
7.56 (d, 2H, J¼8.4 Hz, Ph), 7.17 (d, 2H, J¼8.4 Hz, Ph), 5.60
Mp 156e160 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
d 7.30 (d,
(s, 1H, 5-H), 3.30 (s, 3H, CH3), 3.14 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) 162.1, 153.4, 152.5, 132.3 (CH), 132.2, 129.4 (CH), 124.7,
2H, J¼7.8 Hz, Ph), 7.07 (d, 2H, J¼8.0 Hz, Ph), 3.42 (s, 3H, CH3), 3.06 (s,
d
3H, CH3), 2.41 (s, 3H, CH3), 1.68 (s, 3H, CH3); 13C NMR (CDCl3,
102.6 (CH), 34.5 (CH3), 28.0 (CH3). MS (EI, 20 eV) m/z 72 (93), 196
(73), 198 (70), 293 (95), 294 (100) (Mþ), 295 (97), 296 (98) (Mþ2).
HRMS calcd for C12H11N2O2Br (Mþ): 294.0004. Found: 293.9993.
100 MHz) d 164.0, 152.4, 150.1, 139.8, 130.4, 130.1 (CH), 128.0 (CH),
108.7, 34.6 (CH3), 28.5 (CH3), 21.5 (CH3), 12.9 (CH3). MS (EI, 20 eV)
m/z 243 (100), 244 (83) (Mþ). HRMS (ESI) calcd for C14H16N2O2
(MþH): 245.1290. Found: 245.1309.
4.2.6. 1,3-Dimethyl-6-(p-nitrophenyl)uracil27 (3af). Compound 3af
was prepared by the general procedure and purified by flash column
chromatography (20%, Hex/EtOAc¼7:3, Rf¼0.28 (Hex/EtOAc¼5:5)).
4.2.12. 1,3,5-Trimethyl-6-(p-methoxyphenyl)uracil (3bc). Compound
3bc was prepared by the general procedure and purified by flash
column chromatography (31%, Hex/EtOAc¼7:3, Rf¼0.25 (Hex/
EtOAc¼5:5)). Mp 144e148 ꢀC (from column); 1H NMR (CDCl3,
Mp 136e140 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
d 8.37 (d,
2H, J¼8.7 Hz, Ph), 7.56 (d, 2H, J¼8.8 Hz, Ph), 5.71 (s, 1H, 5-H), 3.40 (s,
3H, CH3), 3.21 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
162.1, 152.5,
400 MHz)
d
7.09 (d, 2H, J¼8.8 Hz, Ph), 6.98 (d, 2H, J¼8.7 Hz, Ph), 3.84
152.3,149.1,139.5,129.3 (CH),124.5 (CH),103.3 (CH), 34.8 (CH3), 28.4
(CH3). MS (EI, 20 eV) m/z 163 (48), 260 (95), 261 (100) (Mþ). HRMS
calcd for C12H11N3O4 (Mþ): 261.0750. Found: 261.0742.
(s, 3H, CH3), 3.39 (s, 3H, CH3), 3.05 (s, 3H, CH3), 1.67 (s, 3H, CH3); 13
NMR (CDCl3, 100 MHz) 163.9, 160.4, 152.3, 149.8, 129.5 (CH), 125.4,
C
d
114.8 (CH), 108.9, 55.5 (CH3), 34.6 (CH3), 28.4 (CH3), 12.9 (CH3). MS
(EI, 20 eV) m/z 259 (100), 260 (78) (Mþ). HRMS (ESI) calcd for
4.2.7. 1,3-Dimethyl-6-(o-tolyl)uracil60,64,79 (3ag). Compound 3ag
was prepared by the general procedure and purified by flash col-
umn chromatography (85%, Hex/EtOAc¼7:3, Rf¼0.33 (Hex/
EtOAc¼5:5)). Mp 128e130 ꢀC (from column); 1H NMR (CDCl3,
C14H16N2O3 (MþH): 261.1239. Found: 261.1255.
4.2.13. 1,3,5-Trimethyl-6-(p-chlorophenyl)uracil (3bd). Compound
3bd was prepared by the general procedure and purified by flash
column chromatography (29%, Hex/EtOAc¼7:3, Rf¼0.43 (Hex/
EtOAc¼5:5)). Mp 168e178 ꢀC (from column); 1H NMR (CDCl3,
400 MHz) d 7.32e7.28 (m, 1H, Ph), 7.22e7.19 (m, 2H, Ph), 7.08 (d,1H,
J¼8.0 Hz, Ph), 5.55 (s, 1H, 5-H), 3.31 (s, 3H, CH3), 2.98 (s, 3H, CH3),
2.16 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
162.4, 154.0, 152.4,
400 MHz)
d
7.50 (d, 2H, J¼8.1 Hz, Ph), 7.15 (d, 2H, J¼8.3 Hz, Ph), 3.42
135.1, 132.9, 130.6 (CH), 130.0 (CH), 127.9 (CH), 126.4 (CH), 101.9
(CH), 33.1 (CH3), 27.9 (CH3), 19.2 (CH3). MS (EI, 20 eV) m/z 144 (40),
215 (50), 230 (100). HRMS (EI) calcd for C13H14N2O2: 230.1055.
Found: 230.1049.
(s, 3H, CH3), 3.06 (s, 3H, CH3), 1.68 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) 163.7, 152.2, 148.6, 136.0, 131.6, 130.0 (CH), 129.6 (CH),
d
109.0, 34.7 (CH3), 28.5 (CH3), 12.9 (CH3). MS (EI, 20 eV) m/z 263
(100), 264 (68) (Mþ), 265 (20), 266 (25) (Mþ2). HRMS (ESI) calcd for
C13H13N2O2Cl (MþH): 265.0744. Found: 265.0720.
4.2.8. 1,3-Dimethyl-6-(m-methoxyphenyl)uracil60,79 (3ah). Compo-
und 3ah was prepared by the general procedure and purified by
flash column chromatography (72%, Hex/EtOAc¼7:3, Rf¼0.38 (Hex/
EtOAc¼5:5)). Mp 100e108 ꢀC (from column); 1H NMR (CDCl3,
4.2.14. 1,3-Dimethyl-5-fluoro-6-phenyluracil (3ca). Compound 3ca
was prepared by the general procedure and purified by flash col-
umn chromatography (47%, Hex/EtOAc¼7:3, Rf¼0.45 (Hex/
EtOAc¼5:5)). Mp 104e108 ꢀC (from column); 1H NMR (CDCl3,
400 MHz)
d
7.32 (t, 1H, J¼8.0 Hz, Ph), 6.95 (dd,1H, J¼8.3, 2.3 Hz, Ph),
6.83 (d,1H, J¼7.6 Hz, Ph), 6.78 (d,1H, J¼2.0 Hz, Ph), 5.62 (s,1H, 5-H),
400 MHz) d 7.55e7.53 (m, 3H, Ph), 7.35e7.33 (m, 2H, Ph), 3.45 (s,
3.77 (s, 3H, CH3), 3.31 (s, 3H, CH3), 3.15 (s, 3H, CH3); 13C NMR (CDCl3,
3H, CH3), 3.15 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d 157.3 (d,
100 MHz)
d
162.4, 159.8, 154.5, 152.6, 134.5, 130.2 (CH), 119.9 (CH),
J¼27 Hz), 151.0, 139.2 (d, J¼25 Hz), 137.6 (d, J¼230 Hz), 130.9 (CH),
129.5 (CH), 128.9 (d, J¼2 Hz, CH), 127.5, 34.4 (CH3), 28.8 (CH3). MS
(EI, 20 eV) m/z 234 (100) (Mþ). HRMS (ESI) calcd for C12H11N2O2F
(MþH): 235.0883. Found: 235.0891.
115.5 (CH), 113.6 (CH), 102.2 (CH), 55.4 (CH3), 34.5 (CH3), 28.0 (CH3).
MS (EI, 20 eV) m/z 72 (92), 245 (60), 246 (100) (Mþ). HRMS calcd for
C
13H14N2O3 (Mþ): 246.1004. Found: 246.0994.
4.2.9. 1,3-Dimethyl-6-(o-methoxyphenyl)uracil79 (3ai). Compound
3ai was prepared by the general procedure and purified by flash
4.2.15. 1,3-Dimethyl-5-fluoro-6-(p-tolyl)uracil (3cb). Compound 3cb
was prepared by the general procedure and purified by flash column

1394
C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
chromatography (41%, Hex/EtOAc¼7:3, Rf¼0.48 (Hex/EtOAc¼5:5)).
Mp 128e132 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
7.32 (d,
2H, J¼8.2 Hz, Ph), 7.21 (d, 2H, J¼8.0 Hz, Ph), 3.43 (s, 3H, CH3), 3.14 (s,
3H, CH3), 2.42 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
157.3 (d,
J¼26 Hz), 151.0, 141.2, 139.4 (d, J¼25 Hz), 137.6 (d, J¼228 Hz), 130.1
(CH), 128.7 (d, J¼2 Hz, CH), 124.4, 34.3 (CH3), 28.7 (CH3), 21.6 (CH3).
MS (EI, 20 eV) m/z 248 (100) (Mþ). HRMS (ESI) calcd for C13H13N2O2F
(MþH): 249.1039. Found: 249.1044.
flash column chromatography (Hex/EtOAc¼8:2, then CHCl3; com-
pound 3aa: 23%, Rf¼0.28 (Hex/EtOAc¼5:5); 3ea: 39%, Rf¼0.45 (Hex/
EtOAc¼5:5)). Compound 3ea: mp 124e128 ꢀC (from column); 1H
d
d
NMR (CDCl3, 400 MHz) d 7.54e7.52 (m, 3H, Ph), 7.27e7.24 (m, 2H,
Ph), 3.48 (s, 3H, CH3), 3.14 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
159.5, 152.5, 151.7, 133.8, 130.4 (CH), 129.6 (CH), 127.8 (CH), 98.6,
35.9 (CH3), 29.7 (CH3). MS (EI, 20 eV) m/z 118 (92), 294 (100) (Mþ),
296 (78) (Mþ2). HRMS (EI) calcd for C12H11N2O2Br: 294.0004.
Found: 293.9998.
4.2.16. 1,3-Dimethyl-5-fluoro-6-(p-chlorophenyl)uracil (3cd). Com-
pound 3cd was prepared by the general procedure and purified
by flash column chromatography (42%, Hex/EtOAc¼7:3, Rf¼0.48
(Hex/EtOAc¼5:5)). Mp 178e182 ꢀC (from column); 1H NMR (CDCl3,
4.2.22. 5-Bromo-1,3-dimethyl-6-(p-tolyl)uracil (3eb). Compounds
3ab and 3eb were obtained from the reaction of 5-bromo-1,3-
dimethyluracil (3e) with the general procedure and purified by
flash column chromatography (Hex/EtOAc¼8:2, then CHCl3; com-
pound 3ab: 9%, Rf¼0.28 (Hex/EtOAc¼5:5); compound 3eb: 32%,
Rf¼0.48 (Hex/EtOAc¼5:5)). Compound 3eb: mp 222e224 ꢀC (from
400 MHz)
d
7.53 (d, 2H, J¼8.4 Hz, Ph), 7.29 (d, 2H, J¼8.4 Hz, Ph), 3.44
(s, 3H, CH3), 3.16 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d 157.1 (d,
J¼26 Hz), 150.9, 138.1 (d, J¼25 Hz), 137.7 (d, J¼230 Hz), 137.4, 130.4
(d, J¼1 Hz, CH), 129.9 (CH), 125.8, 34.4 (CH3), 28.8 (CH3). MS (EI,
20 eV) m/z 267 (78), 268 (100) (Mþ), 269 (27), 270 (41) (Mþ2). HRMS
(ESI) calcd for C12H10N2O2FCl (MþH): 269.0493. Found: 269.0512.
column); 1H NMR (CDCl3, 400 MHz)
d
7.33 (d, 2H, J¼7.8 Hz, Ph), 7.13
(d, 2H, J¼8.0 Hz, Ph), 3.47 (s, 3H, CH3), 3.13 (s, 3H, CH3), 2.43 (s, 3H,
CH3); 13C NMR (CDCl3, 100 MHz)
159.5, 152.7, 151.7, 140.6, 130.9,
d
130.2 (CH), 127.6 (CH), 98.6, 35.9 (CH3), 29.7 (CH3), 21.6 (CH3). MS
(EI, 20 eV) m/z 132 (58), 308 (60) (Mþ), 310 (100) (Mþ2).
HRMS (ESI) calcd for C13H13N2O2Br (MþH): 309.0239. Found:
309.0577.
4.2.17. 5-Chloro-1,3-dimethyl-6-phenyluracil80 (3da). Compound 3da
was prepared by the general procedure and purified by flash column
chromatography (68%, Hex/EtOAc¼8:2, Rf¼0.45 (Hex/EtOAc¼5:5)).
Mp 122e126 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
d
7.53e7.51 (m, 3H, Ph), 7.27e7.25 (m, 2H, Ph), 3.45 (s, 3H, CH3), 3.11
4.2.23. 5-Bromo-1,3-dimethyl-6-(p-chlorophenyl)uracil (3ed). Com-
pounds 3ad and 3ed were obtained from the reaction of 5-bromo-
1,3-dimethyluracil (3e) with the general procedure and purified by
flash column chromatography (Hex/EtOAc¼8:2 then CHCl3; com-
pound 3ad: 12%, Rf¼0.28 (Hex/EtOAc¼5:5); compound 3ed: 24%,
Rf¼0.45 (Hex/EtOAc¼5:5)). Compound 3ed: mp 188e190 ꢀC (from
(s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
159.4, 151.3, 150.7, 131.8,
130.4 (CH), 129.5 (CH), 127.9 (CH), 108.4, 35.4 (CH3), 29.4 (CH3). MS
(EI, 20 eV) m/z 118 (82), 250 (100) (Mþ), 252 (38) (Mþ2). HRMS (ESI)
calcd for C12H11N2O2Cl (MþH): 251.0587. Found: 251.0566.
4.2.18. 5-Chloro-1,3-dimethyl-6-(p-tolyl)uracil (3db). Compound 3db
was prepared by the general procedure and purified by flash column
chromatography (45%, Hex/EtOAc¼8:2, Rf¼0.40 (Hex/EtOAc¼5:5)).
column); 1H NMR (CDCl3, 400 MHz)
d
7.51 (d, 2H, J¼8.5 Hz, Ph), 7.21
(d, 2H, J¼8.4 Hz, Ph), 3.45 (s, 3H, CH3), 3.13 (s, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 159.2, 151.5, 151.3, 136.7, 132.0, 130.0 (CH), 129.3
Mp 182e186 ꢀC (from column); 1H NMR (CDCl3, 400 MHz)
d
7.34 (d,
(CH), 98.8, 35.9 (CH3), 29.7 (CH3). MS (EI, 20 eV) m/z 152 (81), 327
(41), 328 (72) (Mþ), 329 (79), 330 (100) (Mþ2), 331 (59), 332 (10)
(Mþ4). HRMS (EI) calcd for C12H10N2O2ClBr: 329.9594. Found:
329.9589.
2H, J¼7.9 Hz, Ph), 7.16 (d, 2H, J¼8.1 Hz, Ph), 3.47 (s, 3H, CH3), 3.13 (s,
3H, CH3), 2.43 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
159.5, 151.5,
151.0, 140.8, 130.2 (CH), 128.9, 127.9 (CH), 108.6, 35.5 (CH3), 29.5
(CH3), 21.7 (CH3). MS (EI, 20 eV) m/z 132 (58), 264 (100) (Mþ), 266
(38) (Mþ2). HRMS (ESI) calcd for C13H13N2O2Cl (MþH): 265.0744.
Found: 265.0759.
4.2.24. 1,3-Dimethyl-5,6-diphenyluracil78 (3ga). Compound 3ga was
prepared by the general procedure and purified by flash column
chromatography (47%, Hex/EtOAc¼8:2 then CHCl3, Rf¼0.50 (Hex/
EtOAc¼5:5)). Mp 172e174 ꢀC (from column); 1H NMR (CDCl3,
4.2.19. 5-Chloro-1,3-dimethyl-6-(p-methoxyphenyl)uracil (3dc). Com-
pound 3dc was prepared by the general procedure and purified by
flash column chromatography (44%, Hex/EtOAc¼8:2, Rf¼0.28 (Hex/
EtOAc¼5:5)). Mp 126e132 ꢀC (from column); 1H NMR (CDCl3,
400 MHz) d 7.27e7.26 (m, 3H, Ph), 7.10e7.09 (m, 5H, Ph), 6.99e6.97
(m, 2H, Ph), 3.47 (s, 3H, CH3), 3.16 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) 162.7, 152.3, 151.5, 133.3, 132.7, 131.2 (CH), 129.4 (CH),
d
400 MHz)
d
7.20 (d, 2H, J¼8.7 Hz, Ph), 7.04 (d, 2H, J¼8.7 Hz, Ph), 3.87
128.9 (CH), 128.7 (CH), 127.8 (CH), 127.1 (CH), 114.9, 35.0 (CH3), 28.6
(CH3). MS (EI, 20 eV) m/z 118 (71), 291 (100), 292 (85) (Mþ). HRMS
(EI) calcd for C18H16N2O2: 292.1212. Found: 292.1203.
(s, 3H, CH3), 3.47 (s, 3H, CH3), 3.15 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) 161.1, 159.5, 151.5, 150.8, 129.6 (CH), 123.9, 114.9 (CH),
d
108.9, 55.6 (CH3), 35.6 (CH3), 29.5 (CH3). MS (EI, 20 eV) m/z 148 (38),
279 (50), 280 (100) (Mþ), 282 (36) (Mþ2). HRMS (ESI) calcd for
4.2.25. 1,3-Di(4-methoxybenzyl)-6-(p-tolyl)uracil62 (10c). Compo-
und 3ga was prepared by the general procedure and purified by
flash column chromatography (43%, Hex/EtOAc¼8:2 then CHCl3,
C13H13N2O3Cl (MþH): 281.0693. Found: 281.0691.
4.2.20. 5-Chloro-1,3-dimethyl-6-(p-chlorophenyl)uracil (3dd). Com-
pound 3dd was prepared by the general procedure and purified by
flash column chromatography (35%, Hex/EtOAc¼8:2, Rf¼0.48 (Hex/
EtOAc¼5:5)). Mp 156e160 ꢀC (from column); 1H NMR (CDCl3,
Rf¼0.63 (Hex/EtOAc¼5:5)). 1H NMR (CDCl3, 400 MHz)
d 7.52 (d, 2H,
J¼8.6 Hz, Ph), 7.18 (d, 2H, J¼7.9 Hz, Ph), 7.06 (d, 2H, J¼8.0 Hz, Ph),
6.86 (d, 2H, J¼8.7 Hz, Ph), 6.83 (d, 2H, J¼8.8 Hz, Ph), 6.74 (d, 2H,
J¼8.7 Hz, Ph), 5.68 (s, 1H, 5-H), 5.15 (s, 2H, CH2), 4.89 (s, 2H, CH2),
3.78 (s, 3H, CH3), 3.75 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C NMR
400 MHz)
d
7.53 (d, 2H, J¼8.5 Hz, Ph), 7.24 (d, 2H, J¼8.4 Hz, Ph), 3.47
(s, 3H, CH3), 3.14 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d
159.3,
(CDCl3,100 MHz) d 162.2,159.1,159.0,155.0,152.6,140.3,130.8 (CH),
151.3, 149.6, 136.9, 130.1, 130.03 (CH), 129.55 (CH), 108.8, 35.5 (CH3),
29.5 (CH3). MS (EI, 20 eV) m/z 152 (78), 283 (81), 284 (100) (Mþ),
285 (45), 286 (41) (Mþ2), 287 (2), 288 (0.5) (Mþ4). HRMS (EI) calcd
for C12H10N2O2Cl2: 284.0119. Found: 284.0109.
130.4, 129.4 (CH), 128.7, 128.4 (CH), 128.0 (CH), 113.9 (CH), 113.8
(CH), 103.5, 55.3 (2ꢁ CH3), 48.9 (CH2), 44.0 (CH2), 21.4 (CH3). MS (EI,
20 eV) m/z 121 (100), 442 (75) (Mþ). HRMS (ESI) calcd for
C27H26N2O4 (MþH): 443.1971. Found: 443.1964.
4.2.21. 5-Bromo-1,3-dimethyl-6-phenyluracil20 (3ea). Compounds
3aa and 3ea were obtained from the reaction of 5-bromo-1,3-
dimethyluracil (3e) with the general procedure and purified by
4.2.26. 1-(4-Methoxybenzyl)-2-phenyl-4-pyridone (12a). Compo-
und 12a was prepared by the general procedure and purified by
flash column chromatography (28%, CHCl3/MeOH¼99:1, Rf¼0.40

C. Cheng et al. / Tetrahedron 69 (2013) 1387e1396
1395
(CHCl3/MeOH¼9:1)). 1H NMR (CDCl3, 400 MHz)
d
7.39e7.30 (m, 4H,
References and notes
CH), 7.16 (d, 2H, J¼7.0 Hz, CH), 6.73 (m, 4H, CH), 6.36 (d, 1H,
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J¼5.8 Hz, CH), 6.27 (s, 1H, CH), 4.77 (s, 2H, CH2), 3.69 (s, 3H, CH3);
13C NMR (CDCl3, 100 MHz)
d 179.0, 159.5, 152.2, 141.3 (CH), 134.1,
129.6 (CH), 128.7 (CH), 128.6 (CH), 128.2 (CH), 127.6, 120.2 (CH),
118.3 (CH), 114.4 (CH), 56.2 (CH2), 55.3 (CH3). MS (EI, 20 eV) m/z 121
(100), 291 (10) (Mþ). HRMS (ESI) calcd for C19H17NO2 (MþNa):
314.1157. Found: 314.1159.
4.2.27. 1-(4-Methoxybenzyl)-2-(p-tolyl)-4-pyridone (12b). Compo-
und 12b was prepared by the general procedure and purified by
flash column chromatography (33%, CHCl3/MeOH¼99:1, Rf¼0.35
(CHCl3/MeOH¼9:1)). 1H NMR (CDCl3, 400 MHz)
d 7.36 (d, 1H,
J¼7.5 Hz, CH), 7.17 (d, 2H, J¼7.6 Hz, CH), 7.10 (d, 2H, J¼7.2 Hz, CH),
6.80e6.77 (m, 4H, CH), 6.37 (d, 1H, J¼7.4 Hz, CH), 6.29 (s, 1H, CH),
4.79 (s, 2H, CH2), 3.72 (s, 3H, CH3), 2.33 (s, 3H, CH3); 13C NMR
14. Herdewijn, P.; Kerremans, L.; Wigerinck, P.; Vandendriessche, F.; Van Aerschot,
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(CDCl3, 100 MHz) d 179.1, 159.6, 152.5, 141.2 (CH), 139.8, 131.3, 129.4
15. Wigerinck, P.; Pannecouque, C.; Snoeck, R.; Claes, P.; De Clercq, E.; Herdewijn, P.
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(CH),128.5 (CH), 128.2 (CH),127.8,120.3 (CH),118.4 (CH),114.4 (CH),
56.0 (CH2), 55.4 (CH3), 21.3 (CH3). MS (EI, 20 eV) m/z 121 (100), 305
(20) (Mþ). HRMS (ESI) calcd for C20H19NO2 (MþH): 306.1494.
Found: 306.1506.
16. Zhang, Z.-Y.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.-H.; Lee, B.-
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4.2.28. 1-(4-Methoxybenzyl)-2-(p-chlorophenyl)-4-pyridone (12d).
Compound 12d was prepared by the general procedure and puri-
fied by flash column chromatography (31%, CHCl3/MeOH¼99:1,
Rf¼0.50 (CHCl3/MeOH¼9:1)). 1H NMR (CDCl3, 400 MHz)
d 7.39 (d,
1H, J¼7.6 Hz, CH), 7.35 (d, 2H, J¼8.1 Hz, CH), 7.15 (d, 2H, J¼8.2 Hz,
CH), 6.77 (m, 4H, CH), 6.41 (d, 1H, J¼7.5 Hz, CH), 6.28 (s, 1H, CH),
4.78 (s, 2H, CH2), 3.74 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
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22. Baker, B. R.; Kawazu, M.; Santi, D. V.; Schwan, T. J. J. Med. Chem. 1967, 10, 304.
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d
179.0, 159.8, 151.1, 141.6 (CH), 136.1, 132.6, 130.1 (CH), 129.1 (CH),
128.1 (CH), 127.5, 120.6 (CH), 118.6 (CH), 114.6 (CH), 56.4 (CH2), 55.4
(CH3). MS (EI, 20 eV) m/z 121 (100), 325 (10) (Mþ), 327 (2) (Mþ2).
HRMS (ESI) calcd for C19H16NO2Cl (MþH): 326.0948. Found:
326.0942.
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To a mixture of 4-hydroxypyridine (0.953 g, 10 mmol) and DBU
(2.3 mL, 15 mmol, 1.5 equiv) in DMF (20 mL) was added p-
methoxybenzyl chloride (2.0 mL, 15 mmol, 1.5 equiv). The reaction
mixture was stirred at 66 ꢀC for 4 h. After cooling to the room
temperature, the solvent was removed under reduced pressure.
The residue was partitioned between CHCl3 and H2O. The organic
layer was washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and then concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy (CHCl3/MeOH¼9:1, Rf¼0.30) to give the white solid (11,
1.89 g, 8.8 mmol, 88%). Mp 166e168 ꢀC (from column); 1H NMR
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(CDCl3, 400 MHz)
CH), 6.88 (d, 2H, J¼8.8 Hz, CH), 6.31 (d, 2H, J¼7.6 Hz, CH), 4.87 (s,
2H, CH2), 3.77 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
178.8,
d
7.35 (d, 2H, J¼7.6 Hz, CH), 7.12 (d, 2H, J¼8.8 Hz,
d
44. Bello, A. M.; Poduch, E.; Fujihashi, M.; Amani, M.; Li, Y.; Crandall, I.; Hui, R.; Lee,
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5036.
159.9, 139.9 (CH), 129.1 (CH), 126.7, 118.5 (CH), 114.5 (CH), 59.5
(CH2), 55.3 (CH3).
46. King, F. E.; King, T. J.; Spensley, P. C. J. Chem. Soc. 1947, 1247.
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