A new route to N1-substituted uracil derivatives using hypervalent iodine

Article abstract of DOI:10.1055/s-0031-1290749

In continuation of our previous study, oxidative coupling reactions of uracil with allylsilane or enol ethers were examined using diacetoxyiodobenzene. The reaction of persilylated uracil with 3,4-dihydro-2H-pyran in the presence of TMSOTf and PhI(OAc)res

Full text of DOI:10.1055/s-0031-1290749

SPECIAL TOPIC
▌1163
sApecNial etowpic Route to N1-Substituted Uracil Derivatives Using Hypervalent Iodine
Yuichi Yoshimura,* Hiroya Kan-no, Y. B. Kiran, Yoshihiro Natori, Yukako Saito, Hiroki Takahata*
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan
Fax +81(22)2752013; E-Mail: yoshimura@tohoku-pharm.ac.jp
Received: 21.02.2012; Accepted: 24.02.2012
An example of this is the use of a Pummerer-type thiogly-
Abstract: In continuation of our previous study, oxidative coupling
cosylation reaction for the synthesis of 4′-thionucleo-
reactions of uracil with allylsilane or enol ethers were examined us-
sides.4 This reaction involves two steps: 1) oxidation of a
sulfide to the corresponding sulfoxide and 2) a trimethyl-
ing diacetoxyiodobenzene. The reaction of persilylated uracil with
3,4-dihydro-2H-pyran in the presence of TMSOTf and PhI(OAc)2
resulted in the formation of a dihydropyranyluracil derivative, al- silyl trifluoromethanesulfonate (TMSOTf)-catalyzed cou-
though the yield was low. In an extension of the oxidative coupling
reaction, a novel glycosylation reaction using glycal derivatives as
substrates was also developed. The treatment of persilylated uracil
ation reaction coupled with oxidation was applied to the
and 3,4-dihydro-2H-pyran with (PhSe)2 and PhI(OAc)2 in the pres-
ence of a catalytic amount of TMSOTf gave a 2,3-anti-derivative
pling reaction of the sulfoxide with persilylated
nucleobases. Recently, the concept of the thioglycosyl-
synthesis of carbocyclic nucleosides.6 As a result, we suc-
cessfully developed a hypervalent iodine-catalyzed reac-
tion for condensing a base and a pseudosugar by which a
basic carbocyclic nucleoside skeleton was constructed.6
The reaction, as with the Pummerer-type thioglycosyl-
ation, involves 2 steps:6 1) the generation of the carboca-
tion 4 by the oxidative reaction of an allylsilane 1 with
diacetoxyiodobenzene [PhI(OAc)2] and TMSOTf, and 2)
the subsequent addition of bis(trimethylsilyl)uracil (2) as
shown in Scheme 1.
of 1-(3-phenylselanyltetrahydropyran-2-yl)uracil stereoselectively
and in good yield.
Key words: hypervalent iodine, nucleoside, oxidative coupling,
glycosylation, glycal
Nucleoside derivatives are widely used clinically as drugs
and as biological tools. There is no doubt about the impor-
tance of developing new nucleoside derivatives, since
they promise to contribute to the progress of medical
treatment and biological chemistry. The three general
methods for the synthesis of nucleoside derivatives in-
clude: 1) synthesis starting from a natural nucleoside,1 2)
construction of a nucleobase moiety on an appropriate
sugar portion after manipulation,2 and 3) glycosylation of
a base with an appropriately modified sugar.3 Although
the transformation of naturally occurring nucleosides is a
straightforward method for preparing new derivatives, it
is obvious that limitations to obtaining new compounds
with structural diversity exist. In contrast, the third meth-
od, which involves a glycosylation reaction, has an advan-
tage in that various nucleoside derivatives containing
different base moieties can be synthesized from a com-
mon sugar-intermediate in a minimum number of steps. In
the past, we synthesized a wide variety of nucleoside de-
rivatives by developing novel glycosylation reactions.4–6
In this report, some preliminary applications of the oxida-
tive coupling reaction to allylsilane or enol ether using a
TMSOTf/PhI(OAc)2 system are described. In addition,
the results triggered the development of a novel glycosyl-
ation reaction using oxidative conditions. The synthesis of
a 2′-phenylselenonucleoside from a glycal derivative us-
ing the TMSOTf/PhI(OAc)2/(PhSe)2 system is also re-
ported.
Initially, the reaction of allyltrimethylsilane (6) and
bis(trimethylsilyl)uracil (2) was examined using the con-
ditions reported in a previous report.6 Although the condi-
tions for the reaction of allyltrimethylsilane (6) were
modified slightly, 1-allyluracil (10a) was obtained in 69%
yield from 6 on treatment with 1 equivalent of PhI(OAc)2,
TMSOTf, and 2 in dichloromethane (Table 1, entry 1).
The same principles were applied to the reaction of benz-
yltrimethylsilane (7), but no trace of the desired 10b was
OTMS
N
O
OAc
TMS
N
OTMS
2
I
N
NH
Ph
TMSOTf
PhI(OAc)2
O
4
3
1
5
Scheme 1 Our previous study
SYNTHESIS 42170012, 44,81163–1170
Advanced online publication: 22.03.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290749; Art ID: SS-2012-C0184-ST
© Georg Thieme Verlag Stuttgart · New York

1164
Y. Yoshimura et al.
SPECIAL TOPIC
detected (entry 2). The reason is not clear at this time. One though other metal triflates, for example, Sc(OTf)3 and
plausible explanation is that the electrophilic substitution Y(OTf)3, were found to catalyze the reaction, the yields
of the phenyl ring might preferentially occur under the were lower than that obtained using Cu(OTf)2 (data not
conditions used. The reaction of 3,4-dihydro-2H-pyran shown). The oxidative coupling reaction was also applied
(8) was examined next. As in the case mentioned above, to 2,3-dihydrofuran (9). In contrast to the results for 8, the
the reaction conditions for preparing 10c from 8 needed to reaction gave an inseparable mixture of dihydrofuryl de-
be optimized. After several attempts, it was found that a rivatives 10d and 10e8 in 5.5% yield along with O-cyclo
dihydropyranyluracil derivative 10c was produced in 31% derivative 10f in 8.9% yield (entry 5).
yield when 8 was treated with PhI(OAc)2 (1.5 equiv),
TMSOTf (0.4 equiv), and 2 (2.0 equiv) at –40 °C to room
Even though, except for 10a, none of the yields shown in
Table 1 were completely satisfactory, it is important to
temperature (entry 3). It was found that 0.2 equivalent of
note that the oxidative coupling reaction proceeded with
Cu(OTf)2, instead of TMSOTf, also catalyzed the reac-
enol ethers and gave a nitrogen-substituted product. A
tion.7 However, when 8 was reacted with 2 under the
proposed mechanism for the oxidative coupling reaction
above conditions in the presence of Cu(OTf)2 at room
temperature, 10c was formed in 24% yield (entry 4). Al-
is shown in Scheme 2.9 When the dihydropyran 8 or 9 re-
Table 1 Summary of the Oxidative Coupling of Bis(TMS)uracil 2 with Allylsilanes and Enol Ethers
O
OTMS
N
allylsilanes 6,7 or enol ethers 8,9
TMSOTf, PhI(OAc)2
CH2Cl2
NH
N
R
O
N
OTMS
2
10
Entry
Compound
Product
Yield (%)
69
O
TMS
N
NH
1
2
3
6
O
10a
O
N
NH
TMS
NDa
O
7
8
10b
O
O
O
O
N
NH
31b
O
10c
O
O
N
NH
24c
4
5
O
8
9
10c
O
O
O
O
O
N
NH
O
N
NH
N
N
5.5 (10d/10e = 3:1), 8.9 (10f)d,e
O
O
O
O
OAc
10d
10e
10f
a Not detected.
b Method A: PhI(OAc)2 (1.5 equiv), TMSOTf (0.4 equiv), and 2 (2.0 equiv) at –40 °C to r.t.
c Method B: PhI(OAc)2 (1.5 equiv), Cu(OTf)2 (0.2 equiv), and 2 (2.0 equiv) at r.t.
d Method C: PhI(OAc)2 (1.5 equiv), TMSOTf (0.4 equiv), and 2 (2.0 equiv) at 0 °C to r.t.
e The ratio was determined based on 1H NMR spectroscopy.
Synthesis 2012, 44, 1163–1170
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
A New Route to N1-Substituted Uracils
1165
acts with PhI(OAc)2 in the presence of TMSOTf, an ace- anism, we hypothesized that the instability of the interme-
toxyiodobenzene derivative 11a,b is initially produced. diate 11a,b (or competing path b) might be a factor in the
Two pathways shown in Scheme 2 are possible for the low yield of the oxidative coupling reaction and that this
conversion of 11a,b into the N1-substituted uracils 10c could be avoided if (PhSe)2 was used as a co-catalyst.
and 10d: the nucleophilic attack of bis(TMS)uracil 2 oc- When 2 and 8 were treated with PhI(OAc)2 and (PhSe)2 in
curs prior to the elimination (path a) or an allylic carboca- the presence of catalytic amounts of TMSOTf, the trans-
tion 14a,b generated from 11a,b reacts with 2 (path b). isomer of 1-(3-phenylselanyltetrahydropyran-2-yl)uracil
Since the formation of 10e and 10f from dihydrofuran 9 (15a) was selectively produced, as shown in Scheme 3.11
was observed, the preferred pathway for the oxidative The result differed from the one expected and was deemed
coupling reaction appears to involve path a, rather than to be important, since this reaction has the potential for
path b (Scheme 2). In the case of the reaction with 8, the use in producing 2′-deoxynucleosides as well as dide-
elimination would generally proceed with 10c being oxydidehydronucleosides such as 10c and 10d, which
formed via 12a as depicted in Scheme 2. In the case of 9, constitute an important class of antiviral agents12 (Scheme
however, a similar 2-iodophenyl intermediate 12b prefer- 3).
entially gives rise to the 2,2′-O-cyclo derivative 10f. The
reason why the reaction of 9 prefers the intramolecular
TMSOTf
O
(PhSe)2
nucleophilic attack to the elimination is not clear at this
time. The conformational flexibility of the tetrahydrofu-
ran ring in the reaction of 9 might make the formation of
five-membered ring system easy. The above mechanism
explains why the reaction gave only poor yields: it is like-
ly that the formation of an allyl cation like 14a,b, through
path b, may compete and this would result in the forma-
tion of dihydropyrans and furans.
OTMS
N
PhI(OAc)2
CH2Cl2
O
O
N
NH
+
O
SePh
N
OTMS
2
8
15a
Scheme 3
yl)uracil (15a)
Synthesis of 1-(3-phenylselanyltetrahydropyran-2-
The oxidative coupling of 2 with enol ethers and glycals
using the TMSOTf/PhI(OAc)2/(PhSe)2 system was exam-
ined and the results are summarized in Table 2. As de-
To improve the yields in the oxidative coupling reaction,
the use of a co-catalyst was examined. Very recently,
Singh and Wirth reported on a new selenium-catalyzed
cyclization of γ,δ-unsaturated carboxylic acids to 3,6-di-
hydro-2H-pyran-2-ones using hypervalent iodine as an
oxidant in the presence of catalytic amounts of diphenyl
diselenide [(PhSe)2].10 Given the proposed reaction mech-
scribed above, the reaction with
8
gave 15a
stereoselectively and in 73% yield (Table 2, entry 1). Sim-
ilarly, reaction with 9 furnished 1-(3-phenylselanyltetra-
hydrofuran-2-yl)uracil (15b) in 31% yield (entry 2). In
O
O
NH
PhI
NH
N
O
O
O
N
O
8: n = 1
9: n = 0
n
O
O
IPh
OAc
10e
O
PhI(OAc)2
TMSOTf
TMSOAc
O
O
2
O
N
NH
O
N
NH
O
OTf
n
O
O
IPh
I
n
path a
OAc
OAc
I
Ph
H
OAc
11a: n = 1
11b: n = 0
12a: n = 1
12b: n = 0
Ph
TMSOTf
PhI, TMSOAc
path b
PhI, AcOH, TMSOTf
O
TfO–
+
O
2
O
H
OTf
O
OTf
O
N
NH
n
n
n
n
IPh
O
TMSOTf
OAc
14a: n = 1
14b: n = 0
13a: n = 1
13b: n = 0
10c: n = 1
10d: n = 0
TMSOTf
Scheme 2
A proposed reaction mechanism for the oxidative coupling of 3,4-dihydro-2H-pyran (8) and dihydrofuran 9 with
TMSOTf/PhI(OAc)2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1163–1170

1166
Y. Yoshimura et al.
SPECIAL TOPIC
Table 2 Summary of the Oxidative Coupling Reaction of Bis(TMS)uracil 2 with Enol Ethers Using TMSOTf/PhI(OAc)2/(PhSe)2 System
TMSOTf
(PhSe)2
PhI(OAc)2
CH2Cl2
O
OTMS
N
NH
OR1
+
N
O
R2
N
OTMS
R2
OR1
2
8, 9, 16–18
SePh
15
Entry
Compound
Product
Yield (%)
O
O
O
N
NH
73a
1
O
SePh
8
15a
O
O
O
N
NH
31a
2
3
O
SePh
9
15b
O
O
N
NH
O
69b
O
16
PhSe
15c
O
O
O
O
N
NH
TBSO
O
N
NH
TBSO
80c
TBSO
4
5
+
(15d/15e = 2:1d)
O
SePh
O
SePh
17
15d
15e
O
NH
O
NH
O
BnO
BnO
O
N
O
N
BnO
BnO
BnO
BnO
64c
+
O
O
(15f/15g = 1:1d)
SePh
OBn
SePh
OBn
OBn
18
15f
15g
a Performed at r.t.
b Performed at –5 °C.
c Performed at –20 °C.
d The ratio was determined based on 1H NMR spectroscopy.
both cases, the reaction selectively produced the trans- 3). In all of the above cases, 1 equivalent of PhI(OAc)2
isomer and the best results were obtained when the reac- and (PhSe)2 in the presence of 0.1 equivalent of TMSOTf
tion was conducted at room temperature. In contrast, the were employed. When the same reactions were performed
reaction with the ethyl vinyl ether (16) at room tempera- with 0.5 equivalent of (PhSe)2, the isolated yields of the
ture gave 1-(1-ethoxy-2-phenylselanylethyl)uracil (15c) products were decreased (data not shown). As an exten-
in low yield (data not shown). The reaction of 2 with 16 at sion, the oxidative coupling of the glycal derivatives 1713
–5 °C, on the other hand, afforded 15c in 69% yield (entry and 18, which can be considered to constitute a new gly-
Synthesis 2012, 44, 1163–1170
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
A New Route to N1-Substituted Uracils
1167
cosylation reaction applicable to the synthesis of 2′-de-
oxy- and 2′,3′-dideoxydidehydronucleosides, were tried.
The reaction of 17 gave 15d and 15e in 80% yield with the
predominant formation of β-nucleoside 15d (entry 4).14
On the other hand, the oxidative glycosylation reaction of
D-glucal 18 gave a mixture of 15f and 15g in 64% yield
and lacked stereoselectivity (entry 5).
1) MCPBA
CH2Cl2
O
O
2) pyridine
PhMe
50 °C
O
N
NH
O
N
NH
60%
O
O
SePh
15a
10c
Scheme 5 Synthesis of 10c
A proposed reaction mechanism for the oxidative cou-
pling under TMSOTf/PhI(OAc)2/(PhSe)2 system is shown
in Scheme 4. Diphenyl diselenide is oxidized to a phenyl-
selenium derivative 19 by the action of TMSOTf and
PhI(OAc)2. The phenylselenium derivative 19 then reacts
with an enol ether, for example, dihydropyran 8, to form
an episelenium ion 21. Nucleophilic attack of 2 to 21 re-
sults in the formation of 15a along with the regeneration
of TMSOTf that can be used in the next cycle of the reac-
tion. During the course of the oxidative coupling, a hyper-
valent iodine derivative 20, formed along with 19, might
have the ability to convert 8 into 21. However, at least 1
equivalent of diphenyl diselenide was required to achieve
the yields described above. The results suggest that 20
could not act as an electrophilic selenium reagent in this
reaction.
In conclusion, in continuation of our previous study, the
development of a novel oxidative coupling reaction of
persilylated uracil with allylsilanes and enol ethers to pro-
duce a dihydropyranyluracil derivative in the presence of
TMSOTf and PhI(OAc)2 is presented. As an extension of
the oxidative coupling reaction, a novel glycosylation re-
action starting from glycal derivatives by using a
TMSOTf/PhI(OAc)2/(PhSe)2 system was also developed.
The latter promises to serve as a new route to the synthesis
of 2′-deoxynucleosides and dideoxydidehydronucleo-
sides, which are medicinally and biologically important
class of compounds.
Melting points are uncorrected. NMR spectra were recorded at 400
MHz (1H), 100 MHz (13C) using CDCl3 as a solvent. As an internal
standard, TMS was used for CDCl3. Mass spectra were recorded us-
ing EI and CI ionization modes. Isobutane was used as the reagent
gas in CI mass spectra. Silica gel used for chromatography was from
Fuji Silysia PSQ 100B. When the reagents sensitive to moisture
were used, the reaction was performed under argon atmosphere.
O
AcO
PhI(OAc)2
TMSOTf
8
I
Ph
+
(PhSe)2
Ph Se
SePh
– TMSOAc
N1-Allyluracil (10a)
AcO
TfO–
19
I
Ph
To a solution of bis(trimethylsilyl)uracil (2; 138 μL, 0.53 mmol),
PhI(OAc)2 (171 mg, 0.53 mmol), and allyltrimethylsilane (84 μL,
0.53 mmol) in CH2Cl2 (3 mL) was added TMSOTf (96 μL, 0.53
mmol) at 0 °C. The mixture was stirred at r.t. for 1 h. To the mixture
were added excess of solid NaHCO3 (ca. 1 g) and sat. aq NaHCO3
(0.5 mL). The mixture was diluted with CH2Cl2 (30 mL) and dried
(Na2SO4). After filtration, the filtrate was concentrated under re-
duced pressure, and the residue was purified by silica gel column
chromatography (50–100% EtOAc in hexane) to give 10a (55.6 mg,
69%); white crystals; mp 100–101 °C.
PhSe
20
OTMS
N
O
N
OTMS
2
O
O
N
NH
+
SePh
TMSOTf
+
O
SePh
15a
TfO–
21
IR (KBr): 921, 1201, 1466, 1688, 2927 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.36 (td, J = 1.9, 3.6 Hz, 2 H),
5.28 (d, J = 16.9 Hz, 1 H), 5.33 (d, J = 10.1 Hz, 1 H), 5.73 (dd,
J = 1.9, 8.2 Hz, 1 H), 5.93–5.83 (m, 1 H), 7.15 (d, J = 8.2 Hz, 1 H),
8.69 (br s, 1 H).
Scheme 4 Proposed reaction mechanism for the oxidative coupling
for the TMSOTf/PhI(OAc)2/(PhSe)2 system
Until now, we have not succeeded in the direct formation
of dihydropyranyluracil derivatives, for example, 10c as
originally planned. One of the reasons for this is the insta-
bility of the dihydropyranyluracil under the acidic condi-
tions of the reactions. Even in the case of the syn-
elimination of selenoxide derivatives of nucleosides, the
addition of a base is frequently required.15 Indeed, the
conversion of 15a into 10c was achieved using the two- Method A (Table 1, entry 3): To a solution of bis(trimethylsilyl)ura-
step synthesis shown in Scheme 5 and pyridine was need-
ed as an additive. We attempted to add triethylamine in
the conditions in entry 1 of Table 2. However, this result-
13C NMR (100 MHz, CDCl3): δ = 50.0, 102.5, 119.5, 131.4, 143.7,
150.8, 163.7.
EI-MS: m/z = 152 [M+].
HRMS (EI): m/z calcd for C7H8N2O2: 152.0586 [M+]; found:
152.0580.
N1-(5,6-Dihydro-2H-pyran-2-yl)uracil (10c)
cil (2; 256 μL, 1.0 mmol), PhI(OAc)2 (241 mg, 0.75 mmol), and 3,4-
dihydro-2H-pyran (8; 45.6 μL, 0.50 mmol) in CH2Cl2 (5 mL) was
added TMSOTf (36.3 μL, 0.20 mmol) at –40 °C. After allowing to
reach r.t. in 2 h, the mixture was stirred at r.t. overnight. The reac-
ed in the suppression of the reaction with decreased yields
(data not shown).
tion was quenched with sat. aq NaHCO3 (5 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with brine (10 mL) and dried (Na2SO4). After filtration, the filtrate
was concentrated under reduced pressure, and the residue was puri-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1163–1170

1168
Y. Yoshimura et al.
SPECIAL TOPIC
fied by silica gel column chromatography (75–100% EtOAc in hex-
ane) to give 10c (30.2 mg, 31%).
aq NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with brine (10 mL) and dried
(Na2SO4). After filtration, the filtrate was concentrated under re-
duced pressure, and the residue was purified by silica gel column
chromatography (Table 2).
Method B (Table 1, entry 4): To a solution of bis(trimethylsilyl)ura-
cil (2; 256 μL, 1.0 mmol), PhI(OAc)2 (241 mg, 0.75 mmol) and 3,4-
dihydro-2H-pyran (8; 45.6 μL, 0.50 mmol) in CH2Cl2 (3 mL) was
added TMSOTf (36.3 μL, 0.20 mmol) at 0 °C. After stirring at r.t.
for 2 h, the reaction was quenched with sat. aq NaHCO3 (5 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were washed with brine (10 mL) and dried (Na2SO4). After filtra-
tion, the filtrate was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography (75–
100% EtOAc in hexane) to give 10c (25.3 mg, 24%); white crystals;
mp 113–115 °C.
N1-[trans-3-(Phenylselanyl)tetrahydro-2H-pyran-2-yl]uracil
(15a)
By the general procedure described above, compound 15a (128.6
mg, 73%) was obtained from 3,4-dihydro-2H-pyran (8; 45.6 μL,
0.50 mmol) after purification by silica gel column chromatography
(33 → 50 → 75% EtOAc in hexane); white foam.
IR (KBr): 744, 1066, 1257, 1688, 3056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.81–1.67 (m, 3 H), 2.44 (d,
J = 13.0 Hz, 1 H), 3.23 (dt, J = 3.9, 10.6 Hz, 1 H), 3.64 (t, J = 12.1
Hz, 1 H), 4.08 (d, J = 13.0 Hz, 1 H), 5.36 (dd, J = 1.9, 8.2 Hz, 1 H),
5.69 (d, J = 10.1 Hz, 1 H), 6.98 (d, J = 8.2 Hz, 1 H), 7.34–7.22 (m,
3 H), 7.53 (d, J = 6.8 Hz, 2 H), 8.14 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.9, 30.8, 43.6, 68.6, 85.6,
102.4, 126.8, 128.6, 129.3, 135.8, 139.2, 150.3, 162.7.
IR (KBr): 820, 1243, 1385, 1676, 3019 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.01–2.34 (m, 2 H), 3.86–3.96 (m,
2 H), 5.64 (d, J = 10.6 Hz, 1 H), 5.72 (d, J = 8.2 Hz, 1 H), 6.36–6.40
(m, 2 H), 7.42 (d, J = 8.2 Hz, 1 H), 9.00 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.4, 61.7, 77.6, 102.1, 123.7,
133.1, 140.9, 150.7, 163.1.
EI-MS: m/z = 194 [M+].
HRMS (EI): m/z calcd for C9H10N2O3: 194.0691 [M+]; found:
EI-MS: m/z = 352 [M+].
HRMS (EI): m/z calcd for C15H16N2O3Se: 352.0326 [M+]; found:
194.0695.
352.0320.
N1-[trans-3-(Phenylselanyl)tetrahydrofuran-2-yl]uracil (15b)
By the general procedure described above, compound 15b (52 mg,
31%) was obtained from dihydrofuran 9 (37.8 μL, 0.53 mmol) after
purification by silica gel column chromatography (33 → 50 → 75%
EtOAc in hexane); white foam.
1-(2,3-Dihydrofuran-5-yl)uracil (10d)
Method C (Table 1, entry 5): To a solution of bis(trimethylsilyl)ura-
cil (2; 256 μL, 1.0 mmol), PhI(OAc)2 (241 mg, 0.75 mmol), and di-
hydrofuran 9 (37.8 μL, 0.50 mmol) in CH2Cl2 (5 mL) was added
TMSOTf (36.3 μL, 0.20 mmol) at 0 °C. After allowing to reach r.t.,
the mixture was stirred at r.t. for 4 h. The reaction was quenched
with sat. aq NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 15
mL). The combined organic layers were washed with brine (10 mL)
and dried (Na2SO4). After filtration, the filtrate was concentrated
under reduced pressure, and the residue was purified by silica gel
column chromatography (50 → 75 → 100% EtOAc in hexane) to
give a mixture of 10d and 10e (5 mg, 10d/10e = 3:1, 5.5%) as less
polar products and 10f (8 mg, 8.9%) as a more polar product.
IR (KBr): 744, 1066, 1257, 1688, 3056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.10–2.17 (m, 1 H), 2.36–2.43 (m,
1 H), 3.81–3.87 (m, 1 H), 4.12 (q, J = 7.8 Hz, 1 H), 4.20–4.25 (m, 1
H), 5.62 (d, J = 8.3 Hz, 1 H), 5.93 (d, J = 3.9 Hz, 1 H), 7.14 (d,
J = 8.3 Hz, 1 H), 7.28–7.34 (m, 3 H), 7.64 (d, J = 4.2 Hz, 2 H), 8.09
(br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 31.2, 43.5, 69.0, 92.9, 102.1,
126.8, 126.6, 129.3, 135.6, 139.6, 150.0, 163.2.
EI-MS: m/z = 338 [M+].
HRMS (EI): m/z calcd for C14H14N2O3Se: 338.0170 [M+]; found:
338.0160.
10d and 10e
1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 0.75 H), 2.14–2.17 (m,
0.25 H), 2.26–2.36 (m, 0.25 H), 4.15 (td, J = 6.7, 9.2 Hz, 0.25 H),
4.34 (td, J = 3.5, 8.7 Hz, 0.25 H), 4.71–4.76 (m, 0.75 H), 4.81–4.87
(m, 0.75 H), 5.37 (dt, J = 1.9, 4.4 Hz, 0.25 H), 5.71–5.74 (m, 1.25
H), 5.83–5.85 (m, 0.75 H), 6.44–6.46 (m, 0.75 H), 7.00–7.02 (m,
0.75 H), 7.08 (d, J = 8.2 Hz, 0.75 H), 7.23 (d, J = 8.2 Hz, 0.25 H),
8.67 (br s, 0.25 H), 8.73 (br s, 0.25 H).
N1-[1-Ethoxy-2-(phenylselanyl)ethyl]uracil (15c)
By the general procedure described above, compound 15c (125 mg,
69%) was obtained from ethyl vinyl ether (16; 138 μL, 0.53 mmol)
after purification by silica gel column chromatography (9% EtOAc
in CH2Cl2); whitish brown solid; mp 99.0–101.0 °C.
EI-MS: m/z = 180 [M+] (10d).
CI-MS: m/z = 241 [M+ + 1] (10e).
IR (KBr): 762, 1332, 1626, 1701, 3057 cm–1.
10f
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 3 H), 3.17 (dd,
J = 5.7, 12.9 Hz, 1 H), 3.27 (dd, J = 5.7, 12.9 Hz, 1 H), 3.56 (q,
J = 7.2 Hz, 2 H), 5.67 (dd, J = 1.5, 7.8 Hz, 1 H), 5.88 (t, J = 5.7 Hz,
1 H), 7.25–7.27 (m, 3 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.51–7.53 (m,
2 H), 9.07 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.6, 31.7, 53.4, 65.4, 84.6,
102.5, 127.5, 129.2, 133.1, 138.6, 150.8, 163.3.
White crystals; mp 248–250 °C (sublimed).
1H NMR (400 MHz, CDCl3): δ = 2.17–2.24 (m, 1 H), 2.48 (d,
J = 4.6, 14.3 Hz, 1 H), 4.23–4.30 (m, 2 H), 5.41 (t, J = 5.3 Hz, 1 H),
6.12 (d, J = 7.2 Hz, 1 H), 6.50 (d, J = 5.3 Hz, 1 H), 7.71 (d, J = 7.2
Hz, 1 H).
EI-MS: m/z = 180 [M+].
HRMS (EI): m/z calcd for C8H8N2O3: 180.0535 [M+]; found:
180.0536.
EI-MS: m/z = 340 [M+].
HRMS (EI): m/z calcd for C14H16N2O3Se: 340.0329 [M+]; found:
340.0321.
Oxidative Coupling Reaction of Bis(TMS)uracil (2) with Enol
Ethers Using TMSOTf/PhI(OAc)2/(PhSe)2 System; General
Procedure
To a solution of bis(trimethylsilyl)uracil (2; 138 μL, 0.53 mmol),
PhI(OAc)2 (171 mg, 0.53 mmol), PhSe)2 (165 mg, 0.53 mmol), and
enol ether (0.53 mmol) in CH2Cl2 (3 mL) was added TMSOTf (9.6
μL, 0.053 mmol) at the temperature shown in Table 2. After stirring
at the same temperature for 1 h, the reaction was quenched with sat.
1-[(2R*,3R*,6S*)-6-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-
(phenylselanyl)tetrahydro-2H-pyran-2-yl]uracil (15d) and 1-
[(2S*,3S*,6S*)-6-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-
(phenylselanyl)tetrahydro-2H-pyran-2-yl]uracil (15e)
By the general procedure described above, compounds 15d (135
mg, 51%) and 15e (75 mg, 29%) were obtained from 1713 (121 mg,
Synthesis 2012, 44, 1163–1170
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
A New Route to N1-Substituted Uracils
1169
0.53 mmol) after purification by silica gel column chromatography
(33% EtOAc in hexane).
References
(1) Recent reports: (a) Fan, X.; Wang, Y.; Qu, Y.; Xu, H.; He,
Y.; Zhang, X.; Wang, J. J. Org. Chem. 2011, 76, 982.
(b) Peacock, H.; Maydanovych, O.; Beal, P. A. Org. Lett.
2010, 12, 1044. (c) Plant, A.; Thompson, P.; William, D. M.
J. Org. Chem. 2009, 74, 4870. (d) Smith, D. B.; Kalayanov,
G.; Sund, C.; Winqvist, A.; Pinho, P.; Maltseva, T.;
Morisson, V.; Leveque, V.; Rajyaguru, S.; Le, Pogam. S.;
Najera, I.; Benkestock, K.; Zhou, X.-X.; Maag, H.;
Cammack, N.; Martin, J. A.; Swallow, S.; Johansson, N. J.;
Klumpp, K.; Smith, M. J. Med. Chem. 2009, 52, 219.
(e) Spitale, R. C.; Heller, M. G.; Pelly, A. J.; Wedekind, J. E.
J. Org. Chem. 2007, 72, 8551.
15d
White crystals; mp 174.0–176.0 °C.
IR (KBr): 689, 776, 1386, 1667, 1703, 2953 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.89 (s, 9 H), 1.46–
1.55 (m, 1 H), 1.72–1.80 (m, 2 H), 2.42–2.45 (m, 1 H), 3.16 (s, 1 H),
3.55 (dd, J = 1.9, 10.2 Hz, 1 H), 3.61–3.69 (m, 2 H), 5.40 (dd,
J = 1.9, 8.2 Hz, 1 H), 5.82 (d, J = 10.2 Hz, 1 H), 7.00 (d, J = 8.2 Hz,
1 H), 7.22–7.30 (m, 3 H), 7.54–7.55 (m, 2 H), 9.16 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = –5.3, 18.2, 25.7, 28.7, 30.2, 43.5,
65.4, 78.8, 85.2, 102.2, 126.7, 128.5, 129.3, 135.8, 139.2, 150.3,
162.8.
(2) Recent reports: (a) Dalençon, S.; Youcef, R. A.; Pipelier,
M.; Maisonneuve, V.; Dubreuil, D.; Huet, F.; Legoupy, S.
J. Org. Chem. 2011, 76, 8059. (b) Saneyoshi, H.;
EI-MS: m/z = 496 [M+].
HRMS (EI): m/z calcd for C22H32N2O4SeSi: 496.1308 [M+]; found:
Deschamps, J. R.; Marquez, V. E. J. Org. Chem. 2010, 75,
7659. (c) Jiang, M. X.-W.; Jin, B.; Gage, J. L.; Priour, A.;
Savela, G.; Miller, M. J. J. Org. Chem. 2006, 71, 4164.
(3) Recent reports: (a) Huang, Q.; Herdewijin, P. J. Org. Chem.
2011, 76, 3742. (b) Reddy, P. G.; Chun, B.-W.; Zhang, H.-
R.; Rachakonda, S.; Ross, B. S.; Sofia, M. J. J. Org. Chem.
2011, 76, 3782. (c) Seth, P. P.; Vasquez, G.; Allerson, C. A.;
Berdeja, A.; Gaus, H.; Kinberger, G. A.; Prakash, T. P.;
Migawa, M. T.; Bhat, B.; Swayze, E. E. J. Org. Chem. 2010,
75, 1569. (d) Prévost, M.; St-Jean, O.; Guindon, Y. J. Am.
Chem. Soc. 2010, 132, 12433. (e) Stauffer, C. S.; Datta, A.
J. Org. Chem. 2008, 73, 4166. (f) Sabatino, D.; Damha, M.
J. J. Am. Chem. Soc. 2007, 129, 8259. (g) Jean-Baptiste, L.;
Yemets, S.; Legay, R.; Lequeux, T. J. Org. Chem. 2006, 71,
2352. (h) Neogi, A.; Majhi, T. P.; Mukhopadhyay, R.;
Chattopadyay, P. J. Org. Chem. 2006, 71, 3291.
496.1295.
15e
White crystals; mp 165.0–167.0 °C.
IR (KBr): 649, 775, 1387, 1666, 1705, 2952 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.82 (s, 9 H), 1.80–
1.97 (m, 3 H), 2.16–2.21 (m, 1 H), 3.14–3.21 (m, 1 H), 3.71 (dd,
J = 5.3, 10.5 Hz, 1 H), 3.79 (dd, J = 6.7, 10.5 Hz, 1 H), 3.98 (s, 1
H), 5.32 (dd, J = 1.9, 8.2 Hz, 1 H), 6.02 (d, J = 10.5 Hz, 1 H), 6.96
(d, J = 8.2 Hz, 1 H), 7.14–7.23 (m, 3 H), 7.46–7.47 (m, 2 H), 8.52
(br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = –5.5, 18.1, 25.8, 26.1, 26.5, 43.6,
62.7, 74.9, 81.5, 102.1, 126.9, 128.5, 129.3, 135.6, 139.2, 150.0,
162.6.
EI-MS: m/z = 496 [M+].
HRMS (EI): m/z calcd for C22H32N2O4SeSi: 496.1308 [M+]; found:
(i) Gagneron, J.; Gosselin, G.; Mathé, C. J. Org. Chem.
2005, 70, 6891.
496.1299.
(4) (a) Yoshimura, Y.; Yamazaki, Y.; Saito, Y.; Natori, Y.;
Imamichi, T.; Takahata, H. Bioorg. Med. Chem. Lett. 2011,
21, 3313. (b) Yoshimura, Y.; Yamazaki, Y.; Saito, Y.;
Takahata, H. Tetrahedron 2009, 65, 9091. (c) Yoshimura,
Y.; Yamazaki, Y.; Kawahata, M.; Yamaguchi, K.; Takahata,
H. Tetrahedron Lett. 2007, 48, 4519. (d) Yoshimura, Y.;
Kuze, T.; Ueno, M.; Komiya, F.; Haraguchi, K.; Tanaka, H.;
Kano, F.; Yamada, K.; Asami, K.; Kaneko, N.; Takahata, H.
Tetrahedron Lett. 2006, 47, 591. (e) Yoshimura, Y.; Kitano,
K.; Yamada, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62, 3140.
(f) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.;
Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem.
1996, 61, 822.
(5) (a) Yoshimura, Y.; Asami, K.; Imamichi, T.; Kuroda, T.;
Shiraki, K.; Tanaka, H.; Takahata, H. J. Org. Chem. 2010,
75, 4161. (b) Yoshimura, Y.; Asami, K.; Matsui, H.; Tanaka,
H.; Takahata, H. Org. Lett. 2006, 8, 6015.
(6) Yoshimura, Y.; Ohta, M.; Imahori, T.; Imamichi, T.;
Takahata, H. Org. Lett. 2008, 10, 3449.
(7) During the course of our investigation, the intramolecular
oxidative C–N bond forming reaction using Cu(OTf)2 and
PhI(OAc)2 has been reported: Cho, S. H.; Yoon, J.; Chang,
S. J. Am. Chem. Soc. 2011, 133, 5996.
(8) The H-H COSY spectrum of 10d and 10e showed that there
is no cross peak corresponding to the correlation between
H1′ and H2′ of 10e. This revealed that a dihedral angle of
H1′-C1′-C2′-H2′ should be around 90°. From this result, 10e
was determined to be a 1′,2′-trans-isomer.
(9) The C2-acylglycosylation of glycals with PhI(OCOR)2 in
the presence of Et2O·BF3 was reported to proceed via a C2-
phenyliodonium (IIII) intermediate: Shi, L.; Kim, Y.-J.; Gin,
D. Y. J. Am. Chem. Soc. 2001, 123, 6939.
N1-(3,4,6-Tri-O-benzyl-2-deoxy-2-O-phenylselanyl-β-D-gluco-
pyranosyl)uracil (15f) and N1-(3,4,6-Tri-O-benzyl-2-deoxy-2-O-
phenylselanyl-α-D-gluco-pyranosyl)uracil (15g)
By the general procedure described above, compounds 15f,g (231
mg, 64%) were obtained as an inseparable mixture from tri-O-ben-
zyl-D-glucal (18; 220 mg, 0.53 mmol) after purification by silica gel
column chromatography (33% EtOAc in hexane).
1H NMR (400 MHz, CDCl3): δ = 3.30 (t, J = 10.1 Hz, 0.5 H), 3.60–
3.88 (m, 4.5 H), 4.24 (s, 0.5 H), 4.39 (t, J = 6.8 Hz, 0.5 H), 4.42–
4.55 (m, 3.5 H), 4.60–4.64 (m, 1 H), 4.86 (d, J = 10.6 Hz, 0.5 H),
4.91 (d, J = 10.1 Hz, 0.5 H), 4.99 (d, J = 10.1 Hz, 0.5 H), 5.13 (dd,
J = 2.2, 8.0 Hz, 0.5 H), 5.33 (dd, J = 1.9, 7.8 Hz, 0.5 H), 5.91 (d,
J = 10.6 Hz, 0.5 H), 6.29 (d, J = 10.6 Hz, 0.5 H), 6.83–6.88 (m, 1
H), 7.16–7.53 (m, 20 H), 8.61 (br s, 0.5 H), 9.01 (br s, 0.5 H).
13C NMR (100 MHz, CDCl3): δ = 46.6, 51.4, 67.4, 68.2, 71.1, 71.7,
73.0, 73.3, 73.4, 75.1, 76.1, 76.2, 77.4, 78.7, 79.0, 82.5, 101.8,
102.5, 127.6, 127.7, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.2,
128.3, 128.4, 128.4, 128.5, 128.6, 129.3, 129.4, 134.6, 135.1, 136.6,
137.4, 137.7, 137.7, 137.8, 137.8, 139.5, 150.1, 150.2, 162.6, 162.7.
EI-MS: m/z = 684 [M+].
HRMS (EI): m/z calcd for C37H36N2O6Se: 684.1739 [M+]; found:
684.1752.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research (No. 21590119), JSPS (Y.Y.) and by a grant of Strategic
Research Foundation Grant-aided Project for Private Universities
from Ministry of Education, Culture, Sport, Science, and Technolo-
gy, Japan (MEXT).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1163–1170

1170
Y. Yoshimura et al.
SPECIAL TOPIC
(13) Imanieh, H.; Quayle, P.; Voaden, M.; Conway, J.
(10) Singh, F. V.; Wirth, T. Org. Lett. 2011, 13, 6504.
(11) In contrast, the reaction of glycal derivatives with (PhSe)2,
PhI(OAc)2, and NaN3 gave 2-azido-1-phenylseleno-
glycoside selectively: (a) Litjens, R. E. J. N.; den Heeten, R.;
Timmer, M. S. M.; Overkleeft, H. S.; van der Marel, G. A.
Chem.–Eur. J. 2005, 11, 1010. (b) Jiaang, W.-T.; Chang,
M.-Y.; Tseng, P.-H.; Chen, S.-T. Tetrahedron Lett. 2000,
41, 3127. (c) Santoyo-Gonzalez, F.; Calvo-Flores, F. G.;
García-Mendoza, P.; Hernández-Mateo, F.; Isac-García, J.;
Robles-Díaz, R. J. Org. Chem. 1993, 58, 6122.
Tetrahedron Lett. 1992, 33, 543.
(14) The stereochemistries of 15d,e were determined by NOE
experiments: 15d showed a NOE (3.1%) between H-6 of the
uracil ring and one of the methylene protons on the
siloxymethyl group on C6 of tetrahydropyran. On the other
hand, in the case of 15e, NOEs (9.9% and 2.3%) were found
between the H-2 of tetrahydropyran (anomeric proton) and
the methylene protons of the siloxymethyl group. The
stereochemistries of 15f,g were estimated by comparison
with the 1H NMR spectra of 15d,e.
(12) For example, see: (a) De Clercq, E. Biochem. Pharmacol.
2011, 82, 99. (b) Esté, J. A.; Cihlar, T. Antiviral Res. 2010,
85, 25. (c) Meadows, D. C.; Gervey-Hague, J.
(15) (a) Díaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillón, S.
J. Org. Chem. 1997, 62, 1501. (b) Wilson, L.; Lotta, D.
Tetrahedron Lett. 1990, 31, 1815.
ChemMedChem 2006, 1, 16. (d) Imamichi, T. Curr. Pharm.
Design 2004, 10, 4039.
Synthesis 2012, 44, 1163–1170
© Georg Thieme Verlag Stuttgart · New York