Palladium-catalyzed direct arylation of 5-halouracils and 5-halouracil nucleosides with arenes and heteroarenes promoted by TBAF

Article abstract of DOI:10.1021/jo500602p

The 1-N-benzyl-5-iodo(or bromo)uracil undergoes Pd-catalyzed [Pd ₂(dba)₃] direct arylation with benzene and other simple arenes in the presence of TBAF in DMF without the necessity of adding any ligands or additives to give 5-arylate

Full text of DOI:10.1021/jo500602p

Article
pubs.acs.org/joc
Palladium-Catalyzed Direct Arylation of 5‑Halouracils and
5‑Halouracil Nucleosides with Arenes and Heteroarenes Promoted
by TBAF
Yong Liang, Jennifer Gloudeman, and Stanislaw F. Wnuk*
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States
S
* Supporting Information
ABSTRACT: The 1-N-benzyl-5-iodo(or bromo)uracil undergoes Pd-catalyzed
[Pd2(dba)3] direct arylation with benzene and other simple arenes in the presence
of TBAF in DMF without the necessity of adding any ligands or additives to give 5-
arylated uracil analogues. The TBAF-promoted coupling also occurs efficiently with
electron rich heteroarenes at 100 °C (1 h) even with only small excess of
heteroarenes. The protocol avoids usage of the arylboronic acid or stannane
precursors for the synthesis of 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)uracil nucleosides,
which are used as important RNA and DNA fluorescent probes. The fact that 1-N-
benzyl-3-N-methyl-5-iodouracil did not undergo the TBAF-promoted couplings with arenes or heteroarenes suggests that the
C4-alkoxide (enol form of uracil) facilitates coupling by participation in the intramolecular processes of hydrogen abstraction
from arenes. TBAF-promoted arylation was extended into the other enolizable heterocyclic systems such as 3-bromo-2-pyridone.
The π-excessive heteroarenes also coupled with 5-halouracils in the presence of Pd(OAc)2/Cs2CO3/PivOH combination in
DMF (100 °C, 2 h) to yield 5-arylated uracils.
compete with traditional Pd-catalyzed cross-couplings13 as a
tool for the synthesis of biaryls. Direct arylations, in which
INTRODUCTION
■
The 5-substituted pyrimidine nucleosides are important
arene-derived organometallic components are replaced by
synthetic intermediates, which also show a broad spectrum of
simple arenes, can proceed efficiently intra-14 or intermolecu-
biological activity.1 Highly potent and selective antiviral drugs
larly14b,15 and are especially efficient with electron-rich
of this class include (E)-5-(2-bromovinyl)-2′-deoxyuridine
heteroaromatics.12d The Pd-catalyzed direct arylation reactions
(BVDU)2 and bicyclic furanopyrimidine-2-one nucleoside
of aryl halides are postulated to occur via electrophilic aromatic
analogues, which display remarkable antiviral potency against
the Varicella-Zoster virus.3 Uracil and uracil nucleosides
substitution (electrophilic palladation with nucleophilic arenes)
or concerted palladation-deprotonation involving proton
substituted with aryl groups at positions 5 and/or 6 also
abstraction by halide or carboxylate ligands.12,14c,16
display a wide range of biological activities.4
Syntheses of the 5-(alkenyl or alkynyl) modified pyrimidines
Direct arylation of the electron-poor pyrimidines17 and
pyridine oxides15a,18 with aryl halides as well as intramolecular
have been achieved by organometallic and/or Pd-assisted cross-
couplings with 5-halopyrimidine nucleosides1,5 and by dehy-
arylation at C6 or C5 of the 5-(or 6)-[N-(2-bromobenzyl)-N-
methylamino]-1,3-dimethyluracil derivatives19 have been re-
drogenative alkenylation of uracils with alkenes.6 The arylation
ported. Hocek and co-workers developed regioselective Pd-
and heteroarylation of the uracil ring at the 5 position have
been accomplished efficiently using Suzuki,7 Stille,8 and other
coupling reactions.1 The 5-(2-furyl)uridine and 5-(2-thienyl)-
2′-deoxyuridine analogues, which were prepared in these ways,
have been incorporated into RNA and DNA fragments using
solid support and used as fluorescent probes.9 Hocek and co-
workers showed that 5-aryl and 5-(2-thienyl) modified dU(or
C)TPs are substrates for DNA polymerases and can be used for
DNA staining and electrochemical labels.10 The Stille
procedure was also successful on a polyuridine RNA strand
bearing 5-iodouridine base, although 60 equiv of 2-
(tributylstannyl)furan reagent and 15 equiv of Pd2(dba)3
catalyst along with 30 equiv of P(furyl)3 ligand were required.11
Direct arylation of aromatic rings with Pd-activated aryl
halides has been recently established as an excellent set of
protocols for the synthesis of biaryls.12 These protocols, which
eliminate the use of organometallics substrates, have begun to
catalyzed direct C−H arylation of 1,3-diprotected uracil
derivatives at the 5 or 6 position controlled by the presence
or absence of CuI.20 Kim and co-workers recently reported Pd-
catalyzed 5-arylation of 1,3-dimethyluracil with aryl bromides as
well as oxidative homocoupling of the 1,3-dimethyluracil
derivatives.21 The 6-aryluracil derivatives were also prepared
by CuBr-mediated arylation of the 1,3-dimethyluracil with aryl
iodides.22
Direct arylation of the 3-N unprotected uracil analogues,
which allows for enolization between 4-oxo group and the
hydrogen at 3-N position is underdeveloped. This tautomeriza-
tion is critical in the biology and chemistry of RNA/DNA and
in the nucleoside-derived drug metabolism. The currently
Received: March 13, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of the Arylation of 1-N-Benzyl-5-iodouracil 1a with Toluene
b
cd
,
d
entry
reagent/solvent
toluene
Pd
TBAF (equiv)
base (2 equiv)
time (h)
2a yield (%)
3 yield (%)
e
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
7
7
6
5
3
7
7
−
−
−
−
−
−
−
−
−
−
6
45
3
f
2
toluene
0.75
1
75 (71)
5
3
toluene
60
15
17
8
g
4
toluene
1
48
5
toluene
1
30
h
6
toluene
1
70 (68)
7
i
j
7
toluene/DMF
toluene/DMF
1
82 (65)
7
k
l
8
7
1
65 (50)
19
10
46
11
25
80 (65)
17
23
33
14
i
9
toluene/DMA
7
1
20
40
−
−
−
−
−
−
−
i
10
11
12
13
14
15
16
17
18
toluene/dioxane
7
1
j
m
toluene/DMF
−
−
−
−
−
KF
2
j
n
toluene/DMF
Cs2CO3
2
j
toluene/DMF
KOSiMe3
2
j
o
toluene/DMF
Ag2CO3
2
toluene/DMF/H2O
K2CO3
2
j
p
toluene/DMF
TBAI
−
CsF
2
j
q
toluene/DMF
TBAI
2
2
j
r
toluene/DMF
Cs2CO3
2
10
8
a
b
Couplings were performed on 0.14 mmol scale of 1a [0.05 M (entries 1−10) or 0.07 M (entries 11−18)] with 0.05 equiv of Pd catalyst. Mixture
c
d
e
of o/m/p isomers (3:2:1, GC−MS). Overall yield for o/m/p isomers. Determined by GC−MS. Isolated yield in parentheses. Also 4 (35%) was
formed. After 18 h the yield of 4 was 85%. 70% yield at 90 °C for 1.5 h. 40% yield at 80 °C for 4 h. 35% with 4 equiv of TBAF. 69% yield at 90 °C
for 1.5 h. 1:1 (v/v). 1:9 (v/v). When neat TBAF·3H2O (7 equiv) was used 2a (67%) and 3 (20%) were produced. 25% yield in toluene/DMF
(1:20, v/v). Reaction with CsF or Ag2CO3 or K2CO3 also did not yield 2a. Attempts with different equivalents of base (0.5−4.0) or prolonged
reaction time (4 h) were also unsuccessful. Couplings also did not proceed in the presence of Cs2CO3 or AgOAc and their combination with pivalic
f
g
h
i
j
k
l
m
n
o
p
q
acid. Couplings in the presence of tetrabutylammonium chloride, bromide, or hydroxide also failed. With 65% HF·pyridine coupling also failed.
r
Also couplings in the presence of CsF did not improve yield of 2a.
available methods for direct 5-arylation of the uracil analogues
were noted to be either not suitable for the natural (3-N-
unsubstituted) uracils20b or caused cleavage of the nucleoside
glycosidic bond.21a Moreover, there have been no reports of
direct arylation of 5-halopyrimidine nucleosides with arenes,
which would supplement the well-established Suzuki and Stille
approaches. Herein, we report Pd-catalyzed direct arylation of
5-halouracils with arenes and electron-excessive heterocycles
promoted by TBAF or bases that provide access to 5-arylated
uracils and uracil nucleosides. The protocol avoids usage of
arylboronic acid or stannane precursors and is applicable to the
natural nucleosides.
Reactions at 90 °C for 1.5 h and at 80 °C for 4 h produced 2a
in 70 and 40% yields, respectively. Remarkably, no alkylation
(butylation) at the N-3 position was observed (GC−MS) on
heating for up to 1.5 h at 100 °C or 3 h at 90 °C. At least 7
equiv of TBAF (1 M/THF) were required to produce 2a in
highest yields with the best 2a to 3 ratios (entries 2−5). Among
the other Pd catalysts tested, Pd(OAc)2 also produced 2a in
similar yields (entry 6).
In an effort to lower the ratio of arene (toluene) to 1a, we
sought for the inert solvents suitable for this arylation reaction.
Thus, couplings proceeded efficiently in 1:1 and 1:9 (v/v)
mixture of toluene/DMF (entries 7 and 8). Arylation in
toluene/DMA and toluene/dioxane (1:1, v/v) also gave 2a but
in lower yields (entries 9 and 10), while no product was formed
in toluene/THF (1:1; v/v) at reflux.
Replacement of the 1 M TBAF/THF solution with neat
TBAF·3 H2O also yielded 2a (entry 8, footnote k) with similar
yield. It is noteworthy that each of these fluoride reagents
introduced approximately the same amount of water to the
reaction mixture. Water is known to play multiple roles in
enhancing the efficiency of the couplings including the
formation of the reactive hydroxypalladium intermediates.23
Heating of 1a in a mixture of toluene/DMF (1:9, v/v) in the
presence of either other fluoride sources such as CsF or KF (2
equiv) or bases such as Cs2CO3, Ag2CO3, K2CO3, or KOSiMe3,
instead of TBAF, failed to produce 2a leading mainly to 3
(entries 11−15). The outcome was not improved by varying
RESULTS AND DISCUSSION
■
Heating of 1-N-benzyl-5-iodouracil 1a in toluene (6 h, 100 °C)
in the presence of Pd2(dba)3 and TBAF (1 M/THF containing
5% of water) afforded a mixture of 5-(o,m,p-methylphenyl)
uracil products 2a [45% overall yield for o/m/p (3:2:1)
isomers]. In addition to the isomeric mixture of 2a, the reduced
substrate 3 (3%) and 3-N-butylated byproducts 4 were also
detected in the crude reaction mixture (35%; Table 1, entry 1).
The ratio for the o/m/p isomers of 2a was established by
comparison with authentic samples prepared by Suzuki
coupling7c between 1a and the corresponding tolylboronic
acids (see Experimental Section). Careful investigation of
reaction time and temperature revealed that arylation of 1a was
completed in less than 1 h (45 min) at 100 °C (entry 2).
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the bases, Pd catalysts, and reaction times (entry 12) or by
addition of the pivalic acid (entry 14). Likewise carrying out
couplings using a mixture of DMF/H2O (5:1, v/v), to improve
the solubility of salts, was unsuccessful (entry 15).
Arylations were also unsuccessful either in the presence of
tetrabutylammonium hydroxide or chloride, bromide, or iodide
(entry 16) or in the combination of the latter with other
fluoride sources (CsF or HF; entry 17). Coupling with 2 equiv
of TBAF with other bases or fluoride sources produced 2a in
low yields (e.g., entry 18).
Direct arylation of the 5 position of the uracil ring promoted
by TBAF has general applicability; hence, reaction of 5-
halouracils 1a or 1b with various arenes and heterocyclic arenes
are presented in Table 2. Thus, heating of 5-iodouracil 1a in
benzene/DMF (1:9, v/v) in the presence of TBAF (7 equiv) at
100 °C for 1 h (ratio of benzene to 1a, 16:1) produced 5-
phenyluracil 2b as a single product in addition to the reduced
substrate 3 (Table 2, entry 1). Arylation of 1a with xylene gave
a mixture of the three regioisomers (88%) from which the 2,4-
dimethylphenyl isomer 2c was isolated in 55% yield (entry 2).
Arene bearing the electron-donating methoxy group on the
phenyl ring produced 2d as a mixture of o/m/p regioisomers
(entry 3). The ratio for the o/m/p isomers of 2d was
established by comparison with authentic samples prepared by
Suzuki coupling7c between 1a and the corresponding
methoxyphenylboronic acids (see Experimental Section).
However, arenes with EWG either failed (nitrobenzene) or
gave the corresponding 5-arylated products in low yields
(1,2,3,4,5-pentafluorobenzene, 15%, GC−MS). Arylation of 5-
bromouracil 1b, prepared by bromination of 1-N-benzyluracil
with 1,3-dibromo-5,5-dimethylhydantoin in the presence of
TMSOTf,24 with benzene proceeded smoothly to afford 2b in
78% yield but needed 14 equiv of TBAF (entry 4).
The arylation of 5-iodouracil 1a with electron rich
heteroaromatics requires only 3.5 equiv of TBAF and also
occurs efficiently at 90 °C. Thus, 1a coupled with furan to give
5-(2-furyl)uracil 2e (95%) without any reduction product 3
(entry 5). Arylation of 1a with benzo[b]furan proceeded in
good yield even with only slight excess of benzo[b]furan to 1a
(1.5:1, mol/mol; benzo[b]furan/DMF, 1:100, v/v; entry 6).
Reaction of 1a with thiophene gave 5-(2-thienyl)uracil 2g
quantitatively (entry 7), while coupling with 2-substituted
thiophenes provided single products 2h or 2i (entries 8 and 9).
The 5-bromouracil 1b also coupled efficiently with furan under
similar conditions to give 2e (entry 10). Interestingly, TBAF-
promoted couplings between 3-N-methyl-5-iodouracil 1c and
toluene or thiophene (or furan) was unsuccessful yielding only
the reduced product 6 (entries 11−12).
Table 2. Arylation of 5-Halouracils 1 with Arenes and
a
Electron-Rich Heteroaromatics Promoted by TBAF
In contrast to the simple arenes (Table 1, entries 11−18), the
π-excessive heteroarenes did couple successfully with 5-
halouracils under TBAF-free conditions in the presence of
bases (Table 3). For example on heating of 1a with thiophene
(15 equiv) in DMF (2 h, 100 °C) in the presence of Pd(OAc)2
and K2CO3 (2 equiv) only reduced product 3 was formed
(Table 3, entry 1). However, when the reaction was carried out
in a mixture of DMF/H2O (5:1, v/v) product 2g was obtained
in 75% yield (entry 2). Apparently the increased solubility of
K2CO3 in the DMF/H2O mixture changed the outcome of the
reaction dramatically. The very low solubility of K2CO3 in
organic solvents (e.g., less than 1% in DMA after 30 min
heating at 120 °C) is known.16b Coupling yields were only
slightly affected when 1 or 4 equiv of K2CO3 was used (entry
3). Direct arylation in the presence of NaOH or CsF or
Ag2CO3 gave 2g in lower yields (entries 4−6) but proceeded
efficiently with Cs2CO3 (entry 7). Arylation at 80 °C (2 h) gave
2g in lower yield (53%) but with an increased ratio relative to 3
(entry 8), while reaction at 60 °C (4 h) produced 2g in only
15% (entry 9). As expected because of the solubility difference
between K2CO3 and Cs2CO3, the heteroarylation in the
presence of Cs2CO3 was also successful in neat DMF (entry
10). Addition of the pivalic acid16b to the reaction mixture not
only increased the yields but also the ratio of 2g to 3 (entry
11). In the presence of pivalic acid coupling proceeded at 80 °C
(entry 12) but gave 2g in low yield at 60 °C. It is worth
mentioning that, in general, direct arylation of 1a promoted by
TBAF gave the best results with the Pd2(dba)3 catalyst, while
base-promoted coupling proceeded more efficiently with
Pd(OAc)2.
a
Couplings were performed on 0.14 mmol scale of substrates 1 (0.07
M) in the presence of 7 equiv of TBAF and 0.05 equiv of Pd catalyst
with Ar−H to DMF ratio of 1:9 (v/v) unless otherwise noted.
b
c
d
Determined by GC−MS. Isolated yield in parentheses. Overall
e
yield for three possible isomers (ratio, 14:5:1). Yield for 2,4-
dimethylphenyl isomer of 2c. Overall yield for mixture of o/m/p
(ratio, 4:1:1) isomers. With 14 equiv of TBAF. With 3.5 equiv of
f
g
h
i
j
TBAF. 77% at 90 °C. 47% with benzofuran:1a ratio (1.5:1).
k
Coupling with furan instead of thiophene also produced 6 (60%).
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Table 3. Optimization of the Base-Promoted Arylation of 1-
N-Benzyl-5-iodouracil 1a with Thiophene
Table 4. Arylation of 5-Halouracils 1 with Electron-Rich
a
a
Heteroarenes Promoted by Cs2CO3
T
yield 2g
bc
yield 3
b
,
entry
solvent
DMF
base
equiv (°C)
(%)
(%)
1
2
K2CO3
K2CO3
2
2
100
100
−
80 (74)
20
e
DMF/
75 (60)
d
H2O
f
3
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF
K2CO3
NaOH
CsF
1
2
2
2
2
2
2
2
2
2
100
100
100
100
100
80
73 (61)
16
17
30
35
8
4
5
37
6
Ag2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
20
7
61 (53)
53 (41)
15
32
8
8
9
60
2
10
11
12
100
100
80
76 (65)
82 (76)
51 (43)
11
4
g
h
DMF
Cs2CO3
Cs2CO3
g
DMF
8
a
Couplings were performed on 0.14 mmol scale of 1a (0.07 M) in the
presence of 0.05 equiv of Pd(OAc)2 with thiophene to DMF ratio of
b
1:9 (v/v). Determined by GC−MS of the crude reaction mixture.
c
d
e
Isolated yield in parentheses. DMF/H2O (5:1, v/v). Pd2(dba)3 gave
f
2g in 36% isolated yield. 4 equiv of K2CO3 gave 2g in 50% isolated
yield. With addition of PivOH (1.25 equiv). 80% yield with addition
of PivOH (1.25 equiv) and Ag2CO3 (1.0 equiv).
g
h
a
Couplings were performed on 0.14 mmol scale of 1 (0.07 M) with
Cs2CO3 (2 equiv), PivOH (1.25 equiv), and Pd(OAc)2 (0.005 equiv)
Base-promoted direct arylation of the 5 position of the uracil
ring with other electron-rich heteroarenes are presented in
Table 4. Thus, heating of 1a with furan (ratio of furan to 1a,
15:1) in DMF in the presence of Cs2CO3 (2 equiv) and PivOH
at 100 °C for 2 h produced 2e in addition to 3 (entry 1).
Arylation proceeded smoothly with thiophene (entry 2) but
failed with pyrrole (entry 3). The coupling of 5-bromouracil 1b
with furan and thiophene gave products but in lower yields
(entries 4 and 5). Interestingly, contrary to the unsuccessful
TBAF-promoted coupling of 3-N-methyl-5-iodouracil 1c with
heteroarenes (Table 2, entry 12), the base-promoted arylation
of 1c with furan or thiophene gave coupling products 5e and 5g
(entries 6 and 7). Attempted 5-arylations of the 3-N
unprotected 1a and 3-N protected 1c uracil substrates with
simple arenes in the presence of Cs2CO3 were unsuccessful
(entries 8 and 9).
Our methodology, which not only avoids the use of toxic
tributyl(2-furyl)stannne9a,b,11 but also works efficiently with the
3-N unprotected uracil substrates,20b,21a,22 was applied to the
synthesis of 5-heteroarylated uracil nucleosides. Thus, reaction
of 2′,3′,5′-tri-O-acetyl-1-(β-D-arabinofuranosyl)-5-iodouracil 7
with furan in DMF (1:9, v/v) in the presence of TBAF (3.5
equiv) and Pd2(dba)3 afforded 5-(2-furyl)uracil analogue 12
(61%; Table 5, entry 1). Similarly, the protected 2′-deoxy-5-
iodouridine 8 was converted to 13 (entry 2), confirming that
direct arylation conditions are compatible with the commonly
used acyl protection group.
b
with Ar−H to DMF ratio of 1:9 (v/v). Determined by GC−MS of
c
d
the crude reaction mixture. Isolated yield in parentheses. Coupling
without addition of PivOH gave 2e in 65% yield.
3−5). Coupling of 11 proceeded also with only a small excess
of furan (1.75 equiv) affording 16 in 41% isolated yield (entry
5, footnote c). Deacetylation of 12 or 13 with methanolic
ammonia also gave 14 (92%) and 15 (95%).
The 5-iodouridine 11 coupled efficiently with thiophene and
2-methylthiophene to give products 17 or 18 (entries 6 and 7).
We found that the pyrrole also coupled with 11 to produce 5-
(2-pyrrolyl)uridine 19 (entry 8), which can be purified on silica
gel column but is somewhat unstable during storage and when
exposed to air. Coupling of 2′-deoxyuridine 9 with
benzimidazole failed to give 5-benzimidazolyl-2′-deoxyuri-
dine.25 Base-promoted 5-arylation of 11 with furan or
thiophene preceded less efficiently giving products 16 or 17
in 23 and 17% isolated yield (entries 9 and 10). Instability of
the glycosidic bond was noted during the 5-arylation of 3-N-
benzyl-1-(tetrahydrofuran-2yl)uracil with bromobenzene.21a
Subjection of 5-iodocytidine or 4-N-acetyl-2′,3′,5′-tri-O-acetyl-
5-iodocytidine26 to the TBAF- or base-promoted direct
arylation with furan failed to provide 5-(2-furyl)cytidine
products.
On the basis of the established mechanisms for the
substitution of hydrogen in the arenes by Pd-activated aryl
halides,12b,d it is expected that arylation of 5-iodouracils would
occur via either electrophilic aromatic substitution (palladation)
or direct proton abstraction (σ-bond metathesis). We do not
have sufficient data to speculate on the mechanism or the role
of TBAF. However, the fact that 1-N-benzyl-3-N-methyl-5-
Arylation proceeded also with the unprotected nucleosides.
Thus, subjection of 1-(β-D-arabinofuranosyl)-5-iodouracil 9, 2′-
deoxy-5-iodouridine 10, and 5-iodouridine 11 to TBAF-
promoted/Pd-catalyzed coupling with furan gave the corre-
sponding 5-(2-furyl) analogues 14−16 in high yields (entries
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which have also possibility of tautomerization between oxo
group and the hydrogen at the adjacent nitrogen atom, we
subjected 3-bromo-2-pyridone 20 to our direct arylation
protocol. Thus, heating of 20 with furan in the presence of
TBAF and Pd2(dba)3 without other additives added gave
product 21 in moderate yield (41%) in addition to unchanged
20 (35%, Scheme 1). Arylation of 20 with thiophene was also
Table 5. Arylation of 5-Iodouracil Nucleosides with
Electron-Rich Heteroaromatics
a
Scheme 1. Arylation of 3-Bromo-2-pyridone
successful to give 22 (37%) but essentially failed with benzene
(5−10%, GC−MS). Also coupling of 20 with furan or
thiophene in the presence of Cs2CO3/PivOH produced 21 or
22 in 68 and 63% isolated yields, respectively. Products 21 and
22 have UV (MeOH) λ maxima at 332 and 346 nm and are
good candidates for development as fluorescence probes (λem
397 and 410 nm). There have been few reports on the arylation
and/or vinylation of the N-alkylated 3-halo-2-pyridones at 3
position using Suzuki27 or Stille28 protocols as well as Negishi29
reactions.
Hocek20 and Kim21a and their co-workers recently reported
the base-promoted direct C−H arylation of 1,3-N-diprotected
uracils at C5 and/or C6 position(s) with aryl halides under the
conditions that usually required higher temperature (130−160
°C) and longer reaction time (12−48 h) with noted instability
of the glycosidic bond.21a In view of those results, we carried
out direct C−H arylation of 1-N-benzyluracil 3 with aryl halides
in the presence of TBAF. Thus, treatment of 3 with 4-
iodoanisole with TBAF/Pd2(dba)3/DMF/100 °C/16 h failed
to give arylated uracil products. However, heating (DMF/100
°C/16 h) of 3 with 4-iodoanisole (3 equiv) in the presence of
TBABr/Pd(OAc)2/AgCl15f produced mixture of the 5 and 6
arylated products p-2d (23%) and 23 (33%) in addition to the
unchanged 3 (41%, Scheme 2).
a
Couplings were performed on 0.14 mmol scale of nucleosides (0.07
M) in the presence of 3.5 equiv of TBAF and 0.05 equiv of Pd catalyst
with Ar−H to DMF ratio of 1:9 (v/v). Ratio of Ar−H to substrate
b
c
nucleosides 15−20:1. Isolated yields. 41% yield with 1.75:1 ratio of
d
furan to 11. Coupling on 1 mmol scale of 11 gave 16 in 88% yield.
iodouracil (1c), which lacks the possibility to tautomerize to
the enol form, did not undergo TBAF-promoted coupling with
arenes indicates that the C4-alkoxide (enol form of uracil) may
participate in the intramolecular processes of hydrogen
abstraction as depicted in structures A and B (Figure 1).
Fagnou and co-workers showed that direct arylation was
facilitated by using Pd-coordinated carboxylate group, which
assisted in intramolecular proton abstraction.16
Scheme 2. Direct C−H Arylation of Uracil with 4-
Iodoanisole
In order to expand the TBAF-promoted arylation method-
ology of the uracil ring into the other heterocyclic systems,
In summary, we have demonstrated that 1-N-benzyl-5-
iodo(or bromo)uracil undergoes Pd-catalyzed direct arylation
with simple arenes and electron rich heteroarenes in the
presence of TBAF in DMF to give 5-arylated uracil analogues.
Analogues coupling of 1-(β-D-arabinofuranosyl)-5-iodouracil,
2′-deoxy-5-iodouridine, and 5-iodouridine with heteroarenes
afforded the corresponding 5-(2-furyl, or 2-thienyl, or 2-
pyrrolyl)uracil nucleosides that are important RNA and DNA
fluorescent probes. The TBAF-promoted protocol developed
here differs from the existing routes to 5-aryluracils in at least
one of the following: (i) it avoids usage of the arylboronic acid
or stannane precursors necessary for Suzuki or Stille couplings,
Figure 1. The plausible intermediates for the Pd-catalyzed direct
arylation of 5-halouracils: (A) electrophilic aromatic palladation
assisted by C4-alkoxide; (B) direct proton abstraction assisted by
C4-alkoxide.
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Article
348, M+); H NMR δ 0.92 (t, J = 7.3 Hz, 3H), 1.36 (“sextet”, J = 7.4
Hz, 2H), 1.67 (“quint”, J = 7.6, Hz, 2H), 2.18 (s, 1.5H, o-4), 2.30 (s,
0.5H, p-4), 2.32 (s, 1H, m-4), 4.00 (“t”, J = 7.6 Hz, 2H), 4.94 (s, 1H, o-
4), 4.95 (s, 0.33H, p-4), 4.96 (s, 0.67H, m-4), 7.02−7.37 (m, 10H);
HRMS calcd for C22H25N2O2 [M + H]+ 349.1911, found 349.1920.
1-N-Benzyl-5-(3-methylphenyl)uracil (m-2a). Suzuki cou-
pling:7c 3-Tolylboronic acid (29 mg, 0.21 mmol) and PPh3 (9 mg,
0.034 mmol) were added to a stirring solution of 1-N-benzyl-5-
iodouracil (1a, 46 mg, 0.14 mmol) in CH3CN/H2O (3 mL; v/v, 2:1)
under the N2 atmosphere at ambient temperature, followed by the
addition of Na2CO3 (22 mg, 0.21 mmol) and Pd(OAc)2 (3 mg, 0.013
mmol). The resulting suspension was stirred for 4 h at 80 °C (oil
bath). Volatiles were evaporated, and the residue was partitioned
between EtOAc and H2O. The organic layer was then washed (brine),
dried (Na2SO4) and evaporated. Column chromatography (hexane/
1
(ii) it proceeds without the necessity of adding any ligands and
additives, (iii) it works efficiently with the natural 3-N-
unsubstituted uracils and uracil nucleosides, and (iv) it is
compatible with the stability of the nucleoside glycosidic bond.
The π-excessive heteroarenes couple also with 5-halouracils in
the presence of Cs2CO3 in DMF. The yields for the 5-arylated
products were improved with the addition of pivalic acid. The
Pd2(dba)3 was the catalyst of choice for TBAF-promoted
arylation of 5-halouracils, whereas Pd(OAc)2 gave the best
results for base-promoted couplings. Heteroarylation was
extended into the other enolizable heterocyclic systems such
as 3-bromo-2-pyridone
1
EXPERIMENTAL SECTION
EtOAc, 6:4 → 5:5) gave m-2a (21.7 mg, 53%): H NMR δ 2.38 (s,
■
1H NMR spectra at 400 MHz and 13C NMR at 100.6 MHz were
recorded in CDCl3 unless otherwise noted. All chemical shift values
are reported in parts per million (ppm) and referenced to the residual
3H), 5.01 (s, 2H), 7.16 (dt, J = 6.8, 2.0 Hz, 1H), 7.23−7.29 (m, 2H),
7.30 (t, J = 1.7 Hz, 1H), 7.32 (s, 1H), 7.34−7.46 (m, 5H), 9.35 (s,
1H); 13C NMR δ 21.6, 51.5, 116.1, 125.3, 128.2, 128.5, 128.7, 128.97,
129.01, 129.3, 132.1, 135.4, 138.3, 141.2, 150.9, 162.5; GC−MS (tR
32.38 min) m/z 292 (85, M+), 91 (100); HRMS calcd for C18H17N2O2
[M + H]+ 293.1285, found 293.1293.
1
solvent peaks [CDCl3 (7.26 ppm) or DMSO-d6 (2.54 ppm)] for H
NMR and the CDCl3 (77.16 ppm) or DMSO-d6 (39.52 ppm) for 13
C
NMR spectra, with coupling constant (J) values reported in Hz.
HRMS were obtained in TOF (ESI) mode. TLC was performed on
Merck kieselgel 60-F254, and products were detected with 254 nm light
or by development of color with I2. Merck kieselgel 60 (230−400
mesh) was used for column chromatography. Purity, yields and ratio of
the products (crude and/or purified) were established using a GC−
MS (EI) system [capillary column (30 m × 0.25 mm × 25 μm)] using
calibrated standards. The 1.0 M TBAF solution in THF (catalog
number: 216143) were purchased from Aldrich-Sigma Co., LLC.
1-N-Benzyl-3-N-methyl-5-iodouracil (1c). Freshly distilled
diazomethane solution in ether (10 mL), generated from Diazald
(3.0 g, 14.0 mmol), was added dropwise to a stirred solution of 1a30
(357 mg, 1.09 mmol) in CH2Cl2 (20 mL) at 0 °C. After 18 h, the
volatiles were evaporated to give 1c (354 mg, 95%) as white powder:
1H NMR δ 3.34 (s, 3H), 4.86 (s, 2H), 7.21−7.30 (m, 5H), 7.57 (s,
1-N-Benzyl-5-(4-methylphenyl)uracil (p-2a). Suzuki coupling:7c
Treatment of 1a (46 mg, 0.14 mmol) with 4-tolylboronic acid (29 mg,
0.21 mmol), as described above for m-2a, gave p-2a (20.0 mg, 49%):
1H NMR δ 2.34 (s, 3H), 4.98 (s, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.28
(s, 1H), 7.32−7.41 (m, 7H), 9.03 (s, 1H); 13C NMR δ 21.3, 51.5,
115.9, 128.1, 128.2, 128.7, 129.2, 129.3, 129.4, 135.4, 138.2, 140.8,
150.8, 162.4; GC−MS (tR 32.70 min) m/z 292 (85, M+), 91 (100);
HRMS calcd for C18H17N2O2 [M + H]+ 293.1285, found 293.1291.
1-N-Benzyl-5-phenyluracil (2b). Treatment of 1a (46 mg, 0.14
mmol) with benzene (0.2 mL, 175 mg, 2.24 mmol) by procedure A
gave 2b (25.3 mg, 59%): 1H NMR δ 4.99 (s, 2H), 7.32 (s, 1H), 7.33−
7.49 (m, 10H), 9.02 (s, 1H); 13C NMR δ 51.6, 115.9, 128.2, 128.3,
128.7, 128.8, 129.4, 132.2, 135.3, 141.2, 150.7, 162.3; GC−MS (tR
24.52 min) m/z 278 (80, M+), 91 (100); HRMS calcd for
C17H14N2NaO2 [M + Na]+ 301.0947, found 301.0945.
1H); 13C NMR δ 29.7, 52.7, 68.0, 128.2, 128.8, 129.3, 135.0, 146.4,
151.5, 160.2; GC−MS (tR 21.70 min) m/z 342 (85, M+), 91 (100);
HRMS calcd for C12H12IN2O2 [M + H]+ 342.9938, found 342.9935.
1-N-Benzyl-5-(2-, 3-, and 4-methylphenyl)uracil (o/m/p-2a).
Procedure A. Toluene (0.2 mL, 173 mg, 1.89 mmol), TBAF (1M/
THF solution containing ca. 5 wt % of water; 980 μL, 0.98 mmol) and
Pd2(dba)3 (6.4 mg, 0.007 mmol) were added to a stirring solution of
1-N-benzyl-5-iodouracil30 (1a, 46 mg, 0.14 mmol) in DMF (1.8 mL)
under the N2 atmosphere at ambient temperature. The resulting
suspension was stirred for 1 h at 100 °C (oil bath). Volatiles were
evaporated, and the oily residue was dissolved in EtOAc or MeOH and
filtrated through Celite or Whatman GF/A filter paper. The filtrate
was partitioned (EtOAc/H2O). The organic layer was then washed
(brine), dried (Na2SO4) and evaporated. GC−MS of this material
showed peaks at tR 31.46, 32.38, and 32.70 min (m/z 292, M+) for the
three isomers of 2a (ortho/meta/para with relative intensities of
∼3:2:1, respectively). Column chromatography (hexane/EtOAc, 8:2
→ 6:4) gave a mixture of o/m/p-2a (o/m/p, 3:2:1; 29 mg, 71% overall
yield) followed by 3 (1 mg, 4%; see Supporting Information, p S5).
Mixture of o/m/p-2a: GC−MS tR 31.46 (o-2a), 32.38 (m-2a) and
32.70 (p-2a) min (m/z 292, M+); 1H NMR δ 2.21 (s, 1.5H, o-2a), 2.35
(s, 0.5H, p-2a), 2.36 (s, 1H, m-2a), 4.97 (s, 1H, o-2a), 4.985 (s, 0.33H,
p-2a), 4.990 (s, 0.67H, m-2a), 7.07−7.41 (m, 10H), 8.91 (s, 1H);
HRMS calcd for C18H17N2O2 [M + H]+ 293.1285, found 293.1294.
Attempted purification of the o/m/p-2a mixture on a long silica gel
column (hexane/EtOAc, 8:2 → 7:3) gave partial separation of the o/
m/p isomers of 2a but failed to yield single isomers.
Analogues treatment of 1-N-benzyl-5-bromouracil31 (1b, 39 mg,
0.14 mmol) with benzene (0.2 mL, 175 mg, 2.24 mmol) by procedure
A (14 equiv of TBAF) gave 2b (27.6 mg, 71%) with spectroscopic data
as described above.
1-N-Benzyl-5-(2,4-dimethylphenyl)uracil (2c). Treatment of 1a
(46 mg, 0.14 mmol) with m-xylene (0.2 mL, 172 mg 1.62 mmol) by
procedure A gave the desired product, which was recrystallized from
hexane/EtOAc to give a single isomer 2c (23.6 mg, 55%): 1H NMR δ
2.16 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.99
(br d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30−7.41 (m, 5H),
8.30 (s, 1H); 13C NMR δ 20.1, 21.2, 51.4, 116.5, 126.8, 128.3, 128.7,
128.8, 129.4, 130.5, 131.4, 135.3, 137.6, 138.8, 142.2, 150.8, 161.9;
GC−MS (tR 27.34 min) m/z 306 (70, M+), 91 (100); HRMS calcd for
C19H19N2O2 [M + H]+ 307.1441, found 307.1442.
GC−MS of the crude reaction mixture showed peaks for three
isomers with tR at 27.34, 27.90, and 28.33 min with relative intensities
of 14:5:1 (m/z 306, M+).
1-N-Benzyl-5-(2-, 3-, and 4-methoxyphenyl)uracil (o/m/p-
2d). Treatment of 1a (46 mg, 0.14 mmol) with anisole (0.2 mL, 199
mg, 1.84 mmol) by procedure A gave 2d (o/m/p, 4:1:1; 29.3 mg,
68%): GC−MS tR 25.52 (o-2d), 26.68 (m-2d) and 27.31 (p-2d) min
(m/z 308, M+); H NMR δ 3.73 (s, 2H, o-2d), 3.80 (s, 0.5H, p-2d),
1
3.81 (s, 0.5H, m-2d), 4.96 (s, 1.3H, o-2d), 4.98 (s, 0.7H, m,p-2d),
6.86−7.34 (m, 10H), 9.01(s, 0.67H, o-2d) 9.14(s, 0.33H, m,p-2d);
HRMS calcd for C18H17N2O3 [M + H]+ 309.1234, found 309.1247.
1-N-Benzyl-5-(3-methoxyphenyl)uracil (m-2d). Suzuki cou-
pling:7c Treatment of 1a (46 mg, 0.14 mmol) with 3-methoxyphe-
nylboronic acid (32 mg, 0.21 mmol), as described above for m-2a, gave
m-2d (22 mg, 51%): 1H NMR δ 3.80 (s, 3H), 4.98 (s, 2H), 6.88 (dd, J
= 8.8, 2.5 Hz, 1H), 7.03 (“dt”, J = 7.6, 2.0 Hz, 1H), 7.10 (“t”, J = 2.0
Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.33−7.40 (m, 6H), 9.33 (s, 1H);
13C NMR δ 51.4, 55.3, 113.6, 114.0, 115.5, 121.4, 128.1, 128.6, 129.2,
129.5, 133.4, 135.2, 141.3, 150.7, 159.6, 162.2; GC−MS (tR 26.68
Note: Treatment of 1a (46 mg, 0.14 mmol) with toluene/TBAF/
Pd2(dba)3 in DMF for 18 h at 100 °C, as described above (column
chromatography; hexane/EtOAc, 98:2 → 95:5) gave mixture of 1-N-
benzyl-3-N-butyl-5-(2-methylphenyl)uracil (o-4), 1-N-benzyl-3-N-
butyl-5-(3-methylphenyl)uracil (m-4) and 1-N-benzyl-3-N-butyl-5-(4-
methylphenyl)uracil (p-4) (36.6 mg, 75% overall yield; o-4/m-4/p-4,
3:2:1): GC−MS tR 27.29 (o-4), 28.27 (m-4) and 28.74 (p-4) min (m/z
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min) m/z 308 (75, M+), 91 (100); HRMS calcd for C18H17N2O3 [M +
H]+ 309.1234, found 309.1238.
3.6, 1.1 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.30−7.40 (m, 5H), 7.42 (s,
1H), 9.06 (s, 1H); 13C NMR δ 15.3, 51.7, 110.9, 125.0, 125.5, 128.2,
128.8, 129.4, 130.8, 135.2, 138.2, 140.4, 152.2, 161.4; HRMS calcd for
C16H14N2O2SNa [M + Na]+ 321.0668, found 321.0674.
1-N-Benzyl-5-(4-methoxyphenyl)uracil (p-2d). Suzuki cou-
pling:7c Treatment of 1a (46 mg, 0.14 mmol) with 4-methoxyphe-
nylboronic acid (32 mg, 0.21 mmol), as described above for m-2a, gave
p-2d (23.7 mg, 55%): 1H NMR δ 3.80 (s, 3H), 4.98 (s, 2H), 6.90 (d, J
= 8.8 Hz, 2H), 7.25 (s, 1H), 7.32−7.39 (m, 7H), 8.64 (s, 1H); 13C
NMR δ 51.5, 55.5, 114.2, 115.7, 124.5, 128.2, 128.7, 129.3, 129.5,
135.4, 140.3, 150.8, 159.7, 162.5; GC−MS (tR 27.31 min) m/z 308
(80, M+), 91 (100); HRMS calcd for C18H17N2O3 [M + H]+ 309.1234,
found 309.1241.
1-N-Benzyl-5-(5-acetylthiophen-2-yl)uracil (2i). Treatment of
1a (46 mg, 0.14 mmol) with 2-acetylthiophene (0.2 mL, 234 mg, 2.1
mmol) by procedure A (3.5 equiv of TBAF) gave 2i (25 mg, 54%): 1H
NMR (DMSO-d6) δ 2.50 (s, 3H), 4.99 (s, 2H), 7.29−7.34 (m, 1H),
7.37 (d, J = 4.3 Hz, 4H), 7.59 (d, J = 4.1 Hz, 1H), 7.87 (d, J = 4.1 Hz,
1H), 8.76 (s, 1H), 11.89 (s, 1H); 13C NMR (DMSO-d6) δ 26.4, 51.2,
107.1, 123.0, 127.4, 127.7, 128.6, 133.1, 136.5, 141.9, 142.5, 143.2,
149.7, 161.5, 190.6; GC−MS (tR 31.00 min) m/z 326 (20, M+), 91
(100); HRMS calcd for C17H15N2O3S [M + H]+ 327.0798, found
327.0801.
1-N-Benzyluracil (3). Treatment of 1a (46 mg, 0.14 mmol) with
toluene (0.2 mL, 173 mg, 1.89 mmol) by procedure A [using
KOSiMe3 (53.8 mg, 0.42 mmol) instead of TBAF] gave 333 (18.4 mg,
65%): 1H NMR δ 4.92 (s, 1H), 5.70 (dd, J = 7.9, 1.5 Hz, 1H), 7.16 (d,
J = 7.9 Hz, 1H), 7.25−7.44 (m, 3H), 9.46 (s, 1H); 13C NMR δ 51.4,
102.8, 128.2, 128.7, 129.3, 135.2, 144.0, 151.3, 163.7; GC−MS (tR
24.38 min) m/z 202 (35, M+), 91 (100); HRMS calcd for C11H11N2O2
[M + H]+ 203.0815, found 203.0817.
1-N-Benzyl-5-(fur-2-yl)uracil (2e). Method A. Treatment of 1a
(46 mg, 0.14 mmol) with furan (0.2 mL, 187 mg, 2.75 mmol) by
procedure A (3.5 equiv of TBAF) gave 2e (30.4 mg, 81%): 1H NMR δ
5.01 (s, 2H), 6.43 (dd, J = 3.0, 1.9 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H),
7.28−7.43 (m, 6H), 7.69 (s, 1H), 9.19 (s, 1H); 13C NMR δ 51.9,
107.6, 109.7, 112.1, 128.2, 128.8, 129.3, 135.3, 137.7, 141.3, 145.7,
150.2, 160.4; GC−MS (tR 27.41 min) m/z 268 (60, M+), 91 (100);
HRMS calcd for C15H13N2O3 [M + H]+ 269.0921, found 269.0934.
Analogues treatment of 1b (39 mg, 0.14 mmol) with furan (0.2 mL,
187 mg, 2.75 mmol) by procedure A (14 equiv of TBAF) gave 2e
(31.9 mg, 85%) with spectroscopic data as described above.
Method B. Procedure B. Furan (0.2 mL, 187 mg, 2.75 mmol),
Cs2CO3 (91.2 mg, 0.28 mmol) and Pd(OAc)2 (1.6 mg, 0.007 mmol)
were added to a stirring solution of 1a (46 mg, 0.14 mmol) in DMF
(1.8 mL) under the N2 atmosphere at ambient temperature. The
resulting suspension was stirred for 2 h at 100 °C (oil bath) and after
cooling down to ambient temperature was diluted with EtOAc (3 mL).
The resulting mixture was vacuum filtered using Whatman GF/A filter
paper, and the filtrates were evaporated. The oily residue was dissolved
in EtOAc and partitioned (EtOAc/H2O). The organic layer was then
washed (brine), dried (Na2SO4) and evaporated. Column chromatog-
raphy (hexane/EtOAc, 8:2 → 6:4) gave 2e (24.5 mg, 65% yield) with
the spectroscopic data as above and 6 (4 mg, 12%).
Procedure C. Analogous treatment of 1a (46 mg, 0.14 mmol) with
furan (0.2 mL, 187 mg, 2.75 mmol) and Cs2CO3 (91.2 mg, 0.28
mmol) in the presence of PivOH (17.9 mg, 0.175 mmol) and
Pd(OAc)2 (1.6 mg, 0.007 mmol) by procedure B gave 2e (27 mg, 73%
yield).
Analogues treatment of 1b (39 mg, 0.14 mmol) with furan (0.2 mL,
187 mg, 2.75 mmol) by procedure B gave 2e (5 mg, 13% yield) with
the spectroscopic data as above.
1-N-Benzyl-5-(benzo[b]fur-2-yl)uracil (2f). Treatment of 1a (46
mg, 0.14 mmol) with benzo[b]furan (23.1 μL, 24.8 mg, 0.21 mmol) by
procedure A (3.5 equiv of TBAF) gave 2f (29.4 mg, 66%): 1H NMR δ
5.06 (s, 2H), 7.2 (td, J = 7.3, 1.2 Hz, 1H), 7.26 (dt, J = 7.3, 1.4 Hz,
1H), 7.37−7.42 (m, 6H), 7.47 (d, J = 0.6 Hz, 1H), 7.56 (ddd, J = 7.3,
1.5, 0.8 Hz, 1H), 7.95 (s, 1H), 8.67 (s, 1H); 13C NMR δ 52.2, 106.1,
107.0, 110.7, 121.6, 123.3, 124.8, 128.2, 128.9, 129.3, 129.4, 135.1,
139.5, 147.6, 149.9, 153.9, 160.1; HRMS calcd for C19H15N2O3 [M +
H]+ 319.1077, found 319.1081.
1-N-Benzyl-5-(thiophen-2-yl)uracil (2g). Method A. Treat-
ment of 1a (46 mg, 0.14 mmol) with thiophene (0.2 mL, 210 mg, 2.5
mmol) by procedure A (3.5 equiv of TBAF) gave 2g32 (36.2 mg,
91%): 1H NMR (DMSO-d6) δ 4.98 (s, 2H), 7.06 (dd, J = 5.1, 3.7 Hz,
1H), 7.29−7.32 (m, 1H), 7.34−7.37 (m, 4H), 7.44−7.47 (m, 2H),
8.45 (s, 1H), 11.72 (s, 1H); 13C NMR (DMSO-d6) δ 50.8, 108.1,
122.7, 125.6, 126.4, 127.4, 127.6, 128.6, 133.7, 136.7, 140.9, 149.9,
161.7; HRMS calcd for C15H13N2O2S [M + H]+ 285.0692, found
285.0691.
1-N-Benzyl-3-N-methyl-5-(fur-2-yl)uracil (5e). Treatment of 1c
(48 mg, 0.14 mmol) with furan (0.2 mL, 187 mg, 2.75 mmol) by
procedure C (column chromatography; hexane/EtOAc, 8:2 → 7:3)
gave 5e (26 mg, 65% yield): GC−MS (tR 17.67 min) m/z 282 (75,
1
M+), 91 (100); H NMR δ 3.45 (s, 3H), 5.03 (s, 2H), 6.45 (dd, J =
3.4, 1.8 Hz, 1H), 7.06 (d, J = 3.3 Hz, 1H), 7.35 (d, J = 5.9 Hz, 1H),
7.33−7.39 (m, 3H), 7.36 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H); 13C NMR
δ 28.5, 53.0, 106.6, 109.3, 112.0, 128.1, 128.7, 129.3, 135.4, 136.0,
141.2, 146.3, 151.0, 160.2; HRMS calcd for C16H15N2O3 [M + H]+
283.1077, found 283.1065.
1-N-Benzyl-3-N-methyl-5-(thiophen-2-yl)uracil (5g). Treat-
ment of 1c (48 mg, 0.14 mmol) with thiophene (0.2 mL, 210 mg,
2.5 mmol) by procedure C (column chromatography; hexane/EtOAc,
8:2 → 7:3) gave 5g (26 mg, 62% yield): GC−MS (tR 23.66 min) m/z
1
298 (75, M+), 91 (100); H NMR δ 3.46 (s, 3H), 5.03 (s, 2H), 7.02
(dd, J = 5.1, 3.7 Hz, 1H), 7.28−7.39 (m, 7H), 7.55 (s, 1H). 13C NMR
δ 28.7, 52.8, 109.6, 124.0, 125.8, 126.9, 128.2, 128.8, 129.3, 134.9,
135.3, 137.0, 151.1, 161.4; HRMS calcd for C16H15N2O2S [M + H]+
299.0849, found 299.0852.
1-N-Benzyl-3-N-methyluracil (6). Treatment of 1c (48 mg, 0.14
mmol) with toluene (0.2 mL, 173 mg, 1.89 mmol) by procedure A
(column chromatography; hexane/EtOAc, 6:4 → 4:6) gave 634 (29
mg, 73%): 1H NMR δ 3.36 (s, 3H), 4.94 (s, 2H), 5.75 (d, J = 7.9 Hz,
1H), 7.17 (d, J = 7.9 Hz, 1H), 7.2−7.48 (m, 5H); 13C NMR δ 28.0,
52.4, 102.0, 128.1, 128.6, 129.2, 135.4, 141.7, 152.0, 163.2; GC−MS
(tR 20.49 min) m/z 216 (50, M+), 91 (100); HRMS calcd for
C12H13N2O2 [M + H]+ 217.0972, found 217.0976.
Analogous treatment (TBAF 3.5 equiv) of 1c (48 mg, 0.14 mmol)
with furan (0.2 mL, 187 mg, 2.75 mmol) by procedure A gave 634 (24
mg, 60%).
1-(2,3,5-Tri-O-acetyl-β-D-arabinofuranosyl)-5-(fur-2-yl)uracil
(12). Treatment (TBAF 3.5 equiv) of 1-(2,3,5-tri-O-acetyl-β-D-
arabinofuranosyl)-5-iodouracil35 (7, 69.5 mg, 0.14 mmol) with furan
(0.2 mL, 187 mg, 2.75 mmol) by procedure A (column
chromatography; hexane/EtOAc, 6:4 → 5:5) gave 12 (37.3 mg,
1
61%) as a slightly yellow solid: H NMR δ 2.01 (s, 3H), 2.18 (s 3H),
2.19 (s, 3H), 4.24 (dt, J = 5.2, 3.9 Hz, 1H), 4.44 (dd, J = 12.0, 5.2 Hz,
1H), 4.53 (dd, J = 12.0, 4.2 Hz, 1H), 5.22 (dd, J = 3.6, 1.7 Hz, 1H),
5.48 (dd, J = 4.1, 1.7 Hz, 1H), 6.43 (d, J = 4.1 Hz, 1H), 6.49 (dd, J =
3.4, 1.8 Hz, 1H), 7.09 (d, J = 3.2 Hz, 1H), 7.39 (dd, J = 1.8, 0.6 Hz,
1H), 7.97 (s, 1H), 9.39 (s, 1H); 13C NMR δ 20.4, 20.65, 20.68, 62.7,
74.7, 76.5, 80.5, 84.2, 106.6, 109.7, 112.0, 134.1, 141.3, 145.5, 149.0,
159.6, 168.6, 169.6, 170.5; HRMS calcd for C19H21N2O10 [M + H]+
437.1191, found 437.1176.
Method B. Analogues treatment of 1a (46 mg, 0.14 mmol) with
thiophene (0.2 mL, 210 mg, 2.5 mmol) by procedure C gave 2g (30.2
mg, 76% yield) with the spectroscopic data as above.
Analogues treatment of 1b (39 mg, 0.14 mmol) with thiophene (0.2
mL, 210 mg, 2.5 mmol) by procedure C gave 2g (6 mg, 16% yield)
with the spectroscopic data as above.
1-N-Benzyl-5-(5-methylthiophen-2-yl)uracil (2h). Treatment
of 1a (46 mg, 0.14 mmol) with 2-methylthiophene (0.2 mL, 203 mg,
2.1 mmol) by procedure A (3.5 equiv of TBAF) gave 2h (29.2 mg,
70%): 1H NMR δ 2.46 (d, J = 0.8 Hz, 3H), 4.98 (s, 2H), 6.66 (dd, J =
3′,5′-Di-O-acetyl-5-(fur-2-yl)-2′-deoxyuridine (13). Treatment
of 3′,5′-di-O-acetyl-2′-deoxy-5-iodouridine36 (8, 61.3 mg, 0.14 mmol)
with furan (0.2 mL, 187 mg, 2.75 mmol) by procedure A (column
chromatography; hexane/EtOAc, 6:4 → 5:5) gave 1337 (38.1 mg,
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72%): 1H NMR δ 2.12 (s, 3H), 2.15 (s, 3H), 2.54 (ddd, J = 14.4, 6.5,
2.1 Hz, 1H), 2.54 (ddd, J = 14.2, 5.6, 1.6 Hz, 1H), 4.31 (“q”, J = 2.7
Hz, 1H), 4.38−4.39 (m, 2H), 5.28 (dt, J = 6.6, 1.7 Hz, 1H), 6.44 (dd, J
= 6.5, 5.6 Hz, 1H), 6.45 (dd, J = 3.4, 1.8 Hz, 1H), 7.08 (d, J = 3.2 Hz,
1H), 7.32 (dd, J = 1.8, 0.6 Hz, 1H), 7.99 (s, 1H), 9.63 (s, 1H); 13C
NMR δ 20.8, 21.0, 38.1, 64.2, 74.6, 82.7, 85.4, 107.9, 109.9, 112.2,
132.5, 141.2, 145.8, 149.6, 160.0, 170.4, 170.5; HRMS calcd for
C17H19N2O8 [M + H]+ 379.1136, found 379.1136.
hexane gave analytical sample of 17: UV (MeOH) λmax = 318 nm; 1H
NMR (DMSO-d6) δ 3.64 (ddd, J = 12.0, 4.4, 2.3 Hz, 1H), 3.76 (ddd, J
= 12.0, 4.7, 2.8 Hz, 1H), 3.92 (dt, J = 4.8, 2.7 Hz, 1H), 4.06 (“q”, J =
5.1 Hz, 1H), 4.13 (“q”, J = 4.8 Hz, 1H), 5.09 (d, J = 5.5 Hz, 1H), 5.42
(t, J = 4.6 Hz, 1H), 5.46 (d, J = 5.3 Hz, 1H), 5.84 (d, J = 4.2 Hz, 1H),
7.05 (dd, J = 5.1, 3.7 Hz, 1H), 7.40 (dd, J = 3.7, 1.1 Hz, 1H), 7.46 (dd,
J = 5.1, 1.1 Hz, 1H), 8.65 (s, 1H), 11.69 (s, 1H); 13C NMR (DMSO-
d6) δ 60.2, 69.4, 74.3, 84.7, 88.7, 108.3, 122.5, 125.7, 126.4, 133.9,
135.7, 149.6, 161.3; HRMS calcd for C13H14N2NaO6S [M + Na]+
349.0465, found 349.0465.
1-(β-D-Arabinofuranosyl)-5-(fur-2-yl)uracil (14). Method A.
Treatment of 1-(β-D-arabinofuranosyl)-5-iodouracil38 (9, 52 mg, 0.14
mmol) with furan (0.2 mL, 187 mg, 2.75 mmol) by procedure A
(column chromatography; CH2Cl2/MeOH, 15:1 → 10:1) gave 14
(30.5 mg, 70%) as off-white solid. The analytical sample was obtained
by precipitation from minimum amount of MeOH:CH2Cl2 (1:1, v/v)
Method B. Treatment of 11 (52 mg, 0.14 mmol) with thiophene
(0.2 mL, 210 mg, 2.5 mmol) by procedure C (column chromatog-
raphy; CH2Cl2/MeOH, 15:1 → 10:1) gave 17 (8 mg, 17% yield) with
the spectroscopic data as above.
1
with hexane: H NMR (DMSO-d6) δ 3.60 (dt, J = 10.3, 5.0 Hz, 1H),
5-(5-Methylthiophen-2-yl)uridine (18). Treatment of 5-iodour-
idine (11, 52 mg, 0.14 mmol) with 2-methylthiophene (0.2 mL, 203
mg, 2.1 mmol) by procedure A (column chromatography; CH2Cl2/
MeOH, 15:1 → 10:1) gave 18 (36.5 mg, 76%) as off-white solid.
Precipitation of 18 from MeOH:CH2Cl2 (1:1, v/v) solution with
3.68 (dt, J = 10.3, 5.1 Hz, 1H), 3.78 (“q”, J = 4.6 Hz, 1H), 3.97 (dd, J =
7.3, 3.8 Hz, 1H), 4.04 (dt, J = 7.8, 3.9 Hz, 1H), 5.09 (t, J = 5.2 Hz,
1H), 5.51 (d, J = 4.4 Hz, 1H), 5.64 (d, J = 5.0 Hz, 1H), 6.07 (d, J = 4.3
Hz, 1H), 6.52 (dd, J = 3.3, 1.9 Hz, 1H), 6.85 (dd, J = 3.3, 0.5 Hz, 1H),
7.63 (dd, J = 1.8, 0.7 Hz, 1H), 8.07 (s, 1H), 11.65 (s, 1H); 13C NMR
(DMSO-d6) δ 60.7, 75.3, 75.6, 84.8, 85.3, 104.0, 107.6, 111.5, 136.5,
141.4, 146.5, 149.4, 160.2. HRMS calcd for C13H15N2O7 [M + H]+
311.0784, found 311.0811.
Method B. Compound 12 (43.6 mg, 0.10 mmol) was dissolved in
NH3/MeOH (3 mL) at 0 °C (ice bath), and the resulting solution was
stirred overnight. Volatiles were removed under the reduced pressure
and the residue was column chromatographed (CH2Cl2/MeOH, 15:1
→ 10:1) to give 14 (28.5 mg, 92%) with the spectroscopic data as
above.
5-(Fur-2-yl)-2′-deoxyuridine (15). Method A. Treatment of 2′-
deoxy-5-iodouridine36 (10, 49.6 mg, 0.14 mmol) with furan (0.2 mL,
187 mg, 2.75 mmol) by procedure A (column chromatography;
CH2Cl2/MeOH, 15:1 → 10:1) gave 1537 (30.1 mg, 73%) as yellow
solid: 1H NMR (DMSO-d6) δ 2.18 (dd, J = 6.6, 4.8 Hz, 2H), 3.61 (dd,
J = 8.8, 5.0 Hz, 2H), 3.84 (q, J = 3.3 Hz, 1H), 4.28 (“quint”, J = 4.0 Hz,
1H), 5.08 (t, J = 4.8 Hz, 1H), 5.27 (d, J = 4.2 Hz, 1H), 6.22 (t, J = 6.7
Hz, 1H), 6.52 (dd, J = 3.3, 1.8 Hz, 1H), 6.85 (dd, J = 3.3, 0.5 Hz, 1H),
7.61 (dd, J = 1.8, 0.7 Hz, 1H), 8.33 (s, 1H), 11.62 (s, 1H); 13C NMR
(DMSO-d6) δ 40.1, 61.1, 70.4, 84.7, 87.6, 105.6, 107.8, 111.5, 134.6,
141.5, 146.4, 149.4, 160.1. HRMS calcd for C13H13N2O6 [M − H]−
293.0779, found 293.0788.
1
hexane gave analytical sample of 18: H NMR (DMSO-d6) δ 2.42 (s,
3H), 3.63 (ddd, J = 12.0, 4.4, 2.3 Hz, 1H), 3.74 (ddd, J = 12.0, 4.6, 2.8
Hz, 1H), 3.91 (“dt”, J = 4.8, 2.4 Hz, 1H), 4.05 (“q”, J = 5.0 Hz, 1H),
4.11 (“q”, J = 4.8 Hz, 1H), 5.08 (d, J = 5.4 Hz, 1H), 5.38 (t, J = 4.6 Hz,
1H), 5.44 (d, J = 5.4 Hz, 1H), 5.83 (d, J = 4.4 Hz, 1H), 6.72 (dd, J =
3.6, 1.1 Hz, 1H), 7.19 (d, J = 3.6 Hz, 1H), 8.53 (s, 1H), 11.63 (s, 1H);
13C NMR (DMSO-d6) δ 14.7, 60.2, 69.4, 74.2, 84.7, 88.6, 108.6, 122.6,
124.7, 131.5, 134.9, 138.8, 149.5, 161.3; HRMS calcd for
C14H17N2O6S [M + H]+ 341.0802, found 341.0803.
5-(Pyrrol-2-yl)uridine (19). Treatment of 5-iodouridine (11, 52
mg, 0.14 mmol) with pyrrole (0.2 mL, 193 mg, 2.88 mmol) by
procedure A [reaction was carried out in a flask covered in aluminum
foil under N2 atmosphere; column chromatography (CH2Cl2/MeOH,
15:1 → 10:1)] gave 19 (19.4 mg, 45%) as brownish amorphous
powder. This material is stable when stored in refrigerator under the
1
inert condition for at least 1 month: H NMR (DMSO-d6) δ 3.60
(ddd, J = 12.0, 4.4, 3.3 Hz, 1H), 3.70 (ddd, J = 11.8, 4.6, 3.5 Hz, 1H),
3.87 (“q”, J = 3.5 Hz, 1H), 4.03 (“q”, J = 4.7 Hz, 1H), 4.14 (“q”, J = 5.2
Hz, 1H), 5.10 (d, J = 5.2 Hz, 1H), 5.27 (t, J = 4.8 Hz, 1H), 5.42 (d, J =
5.6 Hz, 1H), 5.83 (d, J = 5.1 Hz, 1H), 6.03 (dd, J = 5.8, 2.6 Hz, 1H),
6.39 (dd, J = 4.5, 2.7 Hz, 1H), 6.76 (dd, J = 4.1, 2.5 Hz, 1H), 8.22 (s,
1H), 10.85 (s, 1H), 11.54 (bs, 1H); 13C NMR (DMSO-d6) δ 60.6,
69.6, 73.6, 84.7, 88.2, 105.5, 107.2, 108.0, 118.2, 123.8, 133.6, 149.7,
162.0; HRMS calcd for C13H16N3O6 [M + H]+ 310.1034, found
310.1034.
Method B. Treatment of 13 (38 mg, 0.10 mmol) with NH3/
MeOH, as described for 14 (Method B), gave 15 (28.0 mg, 95%) with
the spectroscopic data as above.
5-(Fur-2-yl)uridine (16). Method A. Treatment of 5-iodour-
idine36 (11, 52 mg, 0.14 mmol) with furan (0.2 mL, 187 mg, 2.75
mmol) by procedure A (column chromatography; CH2Cl2/MeOH,
15:1 → 10:1) gave 169b (34.7 mg, 80%) as off-white solid.
Precipitation of 16 from MeOH:CH2Cl2 (1:1, v/v) solution with
hexane gave analytical sample of 16: UV (MeOH) λmax = 314 nm; 1H
NMR (DMSO-d6) δ 3.60 (ddd, J = 11.9, 4.6, 2.9 Hz, 1 H), 3.68 (ddd, J
= 11.9, 4.7, 2.9 Hz, 1H), 3.90 (“q”, J = 3.2 Hz, 1H), 4.02 (“q”, J = 4.5
Hz, 1H), 4.12 (“q”, J = 5.1 Hz, 1H), 5.11 (d, J = 5.0 Hz, 1H), 5.21 (t, J
= 4.7 Hz, 1H), 5.43 (d, J = 5.5 Hz, 1H), 5.87 (d, J = 5.1 Hz, 1H), 6.52
(dd, J = 3.3, 1.8 Hz, 1H), 6.86 (dd, J = 3.3, 0.6 Hz, 1H), 7.60 (dd, J =
1.8, 0.7 Hz, 1H), 8.42 (s, 1H), 11.64 (s, 1H); 13C NMR (DMSO-d6) δ
60.6, 69.9, 74.0, 85.0, 88.2, 105.7, 108.0, 111.6, 134.9, 141.6, 146.4,
149.7, 160.1; HRMS calcd for C13H13N2O7 [M − H]− 309.0728,
found 309.0734.
Analogous treatment of 11 (310 mg, 1.0 mmol) with furan (1.1 mL,
1.03 g, 15 mmol) by procedure A gave 16 (273 mg, 88%).
Method B. Treatment of 11 (52 mg, 0.14 mmol) with furan (0.2
mL, 187 mg, 2.75 mmol) by procedure C (column chromatography;
CH2Cl2/MeOH, 15:1 → 10:1) gave 16 (10 mg, 23% yield) with the
spectroscopic data as above.
5-(Thiophen-2-yl)uridine (17). Method A. Treatment of 5-
iodouridine (11, 52 mg, 0.14 mmol) with thiophene (0.2 mL, 210 mg,
2.5 mmol) by procedure A (column chromatography; CH2Cl2/
MeOH, 15:1 → 10:1) gave 17 (44.7 mg, 98%) as off-white solid.
Precipitation of 17 from MeOH:CH2Cl2 (1:1, v/v) solution with
3-(Fur-2-yl)pyridin-2(1H)-one (21). Method A. Treatment of 20
(24.36 mg, 0.14 mmol) with furan (0.2 mL, 187 mg, 2.75 mmol) by
procedure A (14 equiv of TBAF) gave 2139 (9.3 mg, 41%) followed by
1
20 (8.5 mg, 35%). Compound 21: UV (MeOH) λmax = 332 nm; H
NMR (CD3CN) δ 6.33 (t, J = 6.9 Hz, 1H), 6.53 (dd, J = 3.3, 1.8 Hz,
1H), 7.27−7.29 (m, 2H), 7.54 (dd, J = 1.8, 0.7 Hz, 1H), 7.89 (dd, J =
7.1, 2.0 Hz, 1H), 10.33 (s, 1H); 13C NMR (CD3CN) δ 106.5, 111.1,
112.7, 122.2, 133.7, 134.6, 143.0, 150.4, 160.2; HRMS calcd for
C9H8NO2 [M + H]+ 162.0550, found 162.0553.
Method B. Treatment of 20 (24.36 mg, 0.14 mmol) with furan
(0.2 mL, 187 mg, 2.75 mmol) by procedure C gave 21 (15.3 mg, 68%
yield) with the spectroscopic data as above.
3-(Thiophen-2-yl)pyridin-2(1H)-one (22). Treatment of 20
(24.36 mg, 0.14 mmol) with thiophene (0.2 mL, 210 mg, 2.5
mmol) by procedure A (14 equiv of TBAF) gave 2239 (9 mg, 37%)
followed by 20 (8 mg, 33%). Compound 22: UV (MeOH) λmax = 346
nm; 1H NMR (CD3CN) δ 6.32 (dd, J = 7.0, 6.6 Hz, 1H), 7.09 (dd, J =
5.1, 3.8 Hz, 1H), 7.28 (dd, J = 6.5, 1.9 Hz, 1H), 7.40 (dd, J = 5.1, 1.1
Hz, 1H), 7.67 (dd, J = 3.8, 1.1 Hz, 1H), 7.97 (dd, J = 7.1, 1.9 Hz, 1H),
9.98 (s, 1H); 13C NMR (CD3CN) δ 105.4, 123.6, 126.2, 126.4, 128.2,
129.2, 132.4, 134.5, 159.6; HRMS calcd for C9H8NOS [M + H]+
178.0321, found 178.0320.
Method B. Treatment of 20 (24.36 mg, 0.14 mmol) with
thiophene (0.2 mL, 210 mg, 2.5 mmol) by procedure C gave 22
(15.6 mg, 63% yield) with the spectroscopic data as above.
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1-N-Benzyl-6-(4-methoxyphenyl)uracil (23). AgCl (60 mg,
0.42 mmol), Pd(OAc)2 (3.2 mg, 0.014 mmol) and tetrabutylammo-
nium bromide (TBABr, 67.7 mg, 0.21 mmol) were added to a stirred
solution of 1-N-benzyluracil33 (3, 28.3 mg, 0.14 mmol) and 4-
iodoanisole (98.3 mg, 0.42 mmol) in DMSO (1 mL) under the N2
atmosphere at ambient temperature. The resulting suspension was
stirred for 16 h at 100 °C (oil bath). Volatiles were evaporated, and the
oily residue was dissolved in EtOAc and filtrated through Whatman
GF/A filter paper. The filtrate was column chromatographed (hexane/
EtOAc, 5:5 → 4:6) to give p-2d (10 mg, 23%) and 23 (14 mg, 33%)
followed by 3 (12 mg, 41%). Compound 23: 1H NMR δ 3.84 (s, 1H),
4.96 (s, 1H), 5.65 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.90−6.95 (m,
1H), 7.08 (d, J = 8.5 Hz, 1H), 7.19−7.26 (m, 1H), 9.73 (s, 1H); 13C
NMR δ 48.6, 55.5, 104.1, 114.2, 125.3, 127.0, 127.7, 128.7, 129.5,
136.5, 152.3, 157.3, 161.0, 163.1; GC−MS (tR 24.77 min) m/z 308
(70, M+), 91 (100); HRMS calcd for C18H17N2O3 [M + H]+ 309.1234,
found 309.1229.
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ASSOCIATED CONTENT
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* Supporting Information
1H and 13C NMR spectra for all compounds and GC−MS
spectra for 2a and 2d. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wnuk@fiu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH (1SC1CA138176) for financial support and
FIU University Graduate School for Dissertation Year Fellow-
ship (Y.L.). J.G. was sponsored by MBRS RISE program
(NIGMS; R25 GM61347).
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