Synthesis of 6-alkyluridines from 6-cyanouridine via zinc(II) chloride-catalyzed nucleophilic substitution with alkyl grignard reagents

Article abstract of DOI:10.1021/jo400364p

6-Cyanouracil derivatives underwent a direct nucleophilic substitution reaction with alkyl Grignard reagents in the presence of zinc(II) chloride as a catalyst to form the corresponding 6-alkyluracils. This methodology is applicable to sugar-protected 6-cyanouridine and 6-cyano-2′-deoxyuridine without the protection at the N³-imide and provides a facile and general access to versatile 6-alkyluracil and 6-alkyluridine derivatives.

Full text of DOI:10.1021/jo400364p

Article
pubs.acs.org/joc
Synthesis of 6‑Alkyluridines from 6‑Cyanouridine via Zinc(II)
Chloride-Catalyzed Nucleophilic Substitution with Alkyl Grignard
Reagents
Yu-Chiao Shih, Ya-Ying Yang, Chun-Chi Lin, and Tun-Cheng Chien*
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
S
* Supporting Information
ABSTRACT: 6-Cyanouracil derivatives underwent a direct
nucleophilic substitution reaction with alkyl Grignard reagents
in the presence of zinc(II) chloride as a catalyst to form the
corresponding 6-alkyluracils. This methodology is applicable
to sugar-protected 6-cyanouridine and 6-cyano-2′-deoxyur-
idine without the protection at the N3-imide and provides a
facile and general access to versatile 6-alkyluracil and 6-
alkyluridine derivatives.
of 6-alkyluridines.11,12 (D) Reduction from 6-alkenyl- or 6-
INTRODUCTION
■
alkynyluridines was incompatible with unsaturated moieties in
C-Alkyl-substituted uridines are an important class of
the same molecule.6,13 The cross-coupling reactions have been
pyrimidine nucleoside analogues that have received substantial
restricted by the preparation of 6-halouridines, which suffered
attention for decades. 5-Alkyluridines have been widely utilized
from lower yields and limited scales.11 Thus, there is a need to
as naturally occurring thymidine or 5-methyluridine analogues
develop a more general and effective process for the synthesis
for a range of biological interests. There is also a growing
of 6-alkyluridines.
interest in the 6-alkyluridine derivatives for their potential
biological applications.1,2 In particular, 6-alkyluridine derivatives
RESULTS AND DISCUSSION
■
represented spatial or regioisomeric analogues of thymidine and
syn-conformation-constrained uridine/thymidine analogues
In our attempt to prepare the 6-acyluracil derivatives by
Grignard reaction, 6-cyano-1,3-dimethyluracil14 (6-CN-1,3-
which can be used to probe the interaction between
nucleoside/nucleotide substrates and targeted proteins.1−4
More recently, the introduction of alkyl-linkers at the 6-
position of the uracil base has also been employed in the
DMU, 1) was treated with methylmagnesium bromide in
THF, but surprisingly the reaction did not afford the desired 6-
Ac-1,3-DMU (2). Instead, 6-cyano-1,3-dimethyl-4-methylene-
3,4-dihydropyrimidin-2-one (4, 31%) was obtained as the major
development of intramolecular and intermolecular base−sugar
bridged uridine/thymidine analogues.5,6
Careful examination of literature revealed that the synthesis
of 6-alkyluridines has mostly been achieved by four approaches
(summarized in Scheme 1) with certain limitations: (A) specific
product, and its structure was confirmed by X-ray crystallog-
raphy. Another product was found to be 6-Me-1,3-DMU (3a,
20%), which was identical to the authentic compound prepared
from the methylation of 6-methyluracil.15 Products 4 and 3a
resulted from a 1,2- and 1,4-addition to the uracil ring carbons,
6-alkyluracils required multistep synthesis from acyclic
respectively, followed by the elimination to retain their
precursors, and direct ribosylation of the 6-alkyluracils usually
gave a mixture of N1- and N3-ribosides due to the steric and
aromaticities. When the reaction was carried out with
electronic effects.2,7 (B) Lithiation at the 6-position of uridine
ethylmagnesium bromide, the substitution reaction took place
predominantly to give 6-Et-1,3-DMU (3b) as the sole product
followed by the reaction with electrophiles has been a
in 66% yield (Scheme 2). We envisioned that the direct
straightforward approach for the synthesis of 6-substituted
uridine derivatives.8 However, the lithiated uridine could only
nucleophilic substitution reaction of 6-cyanouracil with the
Grignard reagents would provide a feasible route for the
react with less hindered alkyl halides to form simple 6-
synthesis of 6-substituted uridine derivatives.
alkyluridines with concomitant alkylation at the α-carbon of the
6-alkyl substituent as byproducts.5,9,10 (C) The palladium-
The reaction of 6-CN-1,3-DMU (1) as a non-nucleoside
model with EtMgBr was further investigated in order to
catalyzed cross-coupling reactions of 6-halouridines are effective
to introduce alkenyl (Csp2) and alkynyl (Csp) substituents at
the 6-position of uridine. Nevertheless, the Suzuki−Miyaura
and Stille reactions have only limited success in the preparation
Received: February 18, 2013
Published: March 27, 2013
© 2013 American Chemical Society
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Scheme 1. Previous Strategies for the Synthesis of 6-Alkyluridine Derivatives
Scheme 2. Initial Reaction Outcome
Table 1. Optimization for the Reaction of 6-CN-1,3-DMU
(1) with EtMgBr
a
c,d
EtMgBr
additive
(0.1 equiv)
time
(h)
yield
(%)
b
entry
(equiv)
solvent
f
1
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
g, h
g, h
THF
THF
THF
3
3
1
3
1
3
3
3
3
3
3
3
3
3
66
18
2
3
72 (3)
4
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
45 (10)
55 (38)
e
5
ZnCl2
e
f
6
ZnCl2
90
7
ZnBr2
CuCl
CuCl2
NiCl2
80 (14)
59 (6)
52 (9)
67
8
optimize the substitution reaction. Various conditions including
different temperature, time, solvent, and the amount of the
Grignard reagents were screened. The optimum conditions
were to carry out the reaction with 1.5 equiv of the Grignard
reagent in THF from 0 °C to room temperature, and the
reaction could be completed within 3 h. Subsequently, a series
of Lewis acids as additives were examined (entries 5−11 in
Table 1), and it was found that the zinc salts effectively
improved the yields (entries 6 and 7 in Table 1). The
combination of the ethyl Grignard reagent and zinc salts raised
the possibility that diethylzinc might be the reactive species in
the reaction. Thus, a catalytic amount of Et2Zn was employed,
and the reaction yield was comparable to the results with zinc
salts (entries 6, 7, and 12 in Table 1). However, only the
starting material was recovered when a stoichiometric amount
of Et2Zn was used instead of EtMgBr in the reaction (entries 13
and 14 in Table 1). We postulated that the zinc adducts played
the roles of Lewis acids to activate the carbonyl group at the 4-
position to facilitate the substitution reaction.
9
10
11
12
13
14
e
CuI/ZnCl2
59 (39)
89
g
Et2Zn
0 (83)
MgCl2
0 (82)
a
b
c
0.9 M EtMgBr in THF. Reaction concentration = 0.1 M. Unless
specified otherwise, the yields were determined by 1H NMR analysis of
the crude products using 1,3,5-trimethoxybenzene as an internal
standard. Numbers in parentheses represent the percentages for the
unreacted substrate 1. ZnCl2 (1 M) in Et2O. Isolated yield. Et2Zn
(1.5 M) in toluene. Et2Zn (1.5 equiv) was used instead of EtMgBr in
the reaction.
d
e
f
g
h
with zinc(II) chloride as an additive were examined for
comparison purposes. Under the optimized conditions (entries
1 and 6 in Table 1), 6-CN-1,3-DMU (1) reacted with most of
the alkylmagnesium halides (sp3 Grignard reagents) to form the
6-alkyluracil derivatives (3a−g,i) in good yields (entries 1−7
and 9 in Table 2), except the allylmagnesium chloride did not
afford the desired product (entry 8 in Table 2). Our
investigation has shown that the reactivity of alkylmagnesium
The reactions of 6-CN-1,3-DMU (1) with a variety of
Grignard reagents, as shown in Table 2, were investigated to
establish the scope and generality of the nucleophilic
components. Both the uncatalyzed reaction and the reaction
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Article
cyanouracils with alkyl Grignard reagents could be amenable
for the synthesis of the 6-alkyluridine derivatives.
Table 2. Reactions of 6-CN-1,3-DMU (1) with Various
Grignard Reagents
Since the model study demonstrated that the substitution
reaction was applicable to the N1,N3-disubstituted 6-cyanour-
acil, we first considered that the introduction of an appropriate
protecting group for the N3-imide would be necessary when the
reaction was intended to apply to the 6-cyanouridine
derivatives. Both p-methoxybenzyl (PMB) and benzyloxymeth-
yl (BOM) as protecting groups for the N3-imide were
anticipated to be stable toward the Grignard reagents, and
thus, N3-PMB- and N3-BOM-5′-O-(tert-butyldimethylsilyl)-
2′,3′-O-isopropylidene-6-cyanouridines (8a,b) were chosen as
the nucleoside substrates in our initial trials.
a
yield (%)
b
entry
RMgX
product
ZnCl2
no additive
c
d
1
methyl
3a
3b
3c
3d
3e
3f
53
90
60
32
20
c
2
ethyl
isopropyl
66
51
49
40
36
45
e
3
N3-Alkylation of 5′-O-TBS-2′,3′-O-isopropylidene-5-bro-
mouridine16 (5) with PMBCl or BOMCl in the presence of
DBU as a base provided the corresponding N3-PMB- and N3-
BOM-protected 5-bromouridines 6a,b.17 N3-PMB-6-cyanour-
idine 8a was then obtained from the addition−elimination
reaction of 6a with sodium cyanide in DMF. Nevertheless,
under the same condition, the reaction of 6b with NaCN only
resulted in the N3-BOM-5′-O-TBS-2′,3′-O-isopropylidene-5-
cyanouridine (8b′).14,18,19 Alternatively, the desired N3-BOM
6-cyanouridine 8b was obtained from the direct N3-alkylation of
5′-O-TBS-2′,3′-O-isopropylidene-6-cyanouridine16 (7) with
BOMCl and DBU (Scheme 3).
e
4
tert-butyl
f
g
5
n-butyl
81
h
6
cyclopentyl
44
87
c
7
3-butenyl
3g
e
i
8
allyl
ND
e
9
benzyl
3i
3j
60
24
32
16
c
10
11
12
phenyl
c
,
e
j
vinyl
NR
c
j
ethynyl
NR
a
b
c
Isolated yield. ZnCl2 (1 M) in Et2O; RMgBr in THF/MeMgBr (1
M), EtMgBr (0.9 M), 3-butenyl-MgBr (0.5 M), PhMgBr (1 M), vinyl-
MgBr (0.7 M), ethynyl-MgBr (0.5 M); 20% of 3a and 31% of 4 were
obtained from the reaction as shown in Scheme 1; RMgCl in THF/i-
PrMgCl (2 M), t-BuMgBr (1.7 M), allyl-MgCl (1.7 M), BnMgCl (20
wt %), vinyl-MgCl (1.9 M). 20 wt % of n-BuMgCl in THF/toluene.
46% of 3e under standard condition; 81% of 3e when the reaction
concentration was raised to 0.2 M. Cyclopentyl-MgCl (2 M) in Et2O.
d
The sugar- and N3-protected 6-cyanouridines 8a and 8b were
reacted with EtMgBr under the uncatalyzed condition (entry 1
in Table 1) and the corresponding N3-protected 6-ethyluridines
10a and 10b were obtained in 62% and 29% yields,
respectively. The low yield of 8b was attributed to partial
cleavage of the BOM group during the reaction. Furthermore,
the removal of the N3-protecting groups was also problematic.
A global deprotection to remove the PMB, isopropylidene and
TBS groups of 10a with CAN followed by our previously
developed workup protocol furnished the desired 6-ethyl-
uridine (11b) in 10% yield.11 Meanwhile, hydrogenolysis of the
N3-BOM of 10b followed by the removal of TBS and
isopropylidene groups with aqueous TFA gave 6-ethyluridine
(11b) in 24% yield. Both synthetic routes suffered from lengthy
steps and poor overall yields, and were impractical for the
synthesis of the 6-alkyluridine derivatives.
e
f
g
h
i
j
ND = no desired product under both conditions. NR = no reaction
under both conditions.
halides decreases with the increase of the steric hindrance, and
in general, the yields were improved by the addition of ZnCl2 as
a catalyst. In the reactions with sp2 and sp Grignard reagents,
phenylmagnesium bromide was found to give the substitution
product (3j) in low yields (entry 10 in Table 2), while vinyl and
ethynyl Grignard reagents could not react with 6-CN-1,3-DMU
(1) (entries 11 and 12 in Table 2). The survey of the reaction
scope suggested that the nucleophilic substitution of 6-
a
Scheme 3. Synthesis of N3-Protected 6-Ethyluridines
a
Reagents and conditions (a) PMBCl, DBU, CH3CN, 60 °C, 3 h; (b) BOMCl, DBU, DMF, 0 °C to rt; (c) NaCN, DMF, rt, 2 h; (d) EtMgBr (0.9 M
in THF; R3 = PMB or BOM: 1.5 equiv; R3 = H: 2.5 equiv), THF, 0 °C to rt, 3 h.
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The unsatisfactory results have prompted us to make a bold
attempt to subject the N3-unprotected 6-cyanouridine to the
Grignard reaction. Therefore, the sugar-protected 6-cyanour-
idine 716 was directly reacted with 2.5 equiv of EtMgBr under
the uncatalyzed conditions. An additional equivalent of the
Grignard reagent was used because the unprotected N3-imide
proton was expected to consume an equal amount of the
Grignard reagent. It was beyond our expectations that the
reaction proceeded to give 5′-O-TBS-2′,3′-O-isopropylidene-6-
ethyluridine (9b) as the sole product in 58% yield. The result
indicated that a protecting group for the reactive N3-imide is
unnecessary in this novel substitution reaction.
Scheme 4. Deprotection of Sugar-Protected 6-Alkyluridines
Afterward, the reaction of 7 with a series of alkyl Grignard
reagents, as shown in Table 3, was explored in order to expand
a
Scheme 5. Synthesis of 6-Alkyl-2′-deoxyuridines
Table 3. Reactions of Sugar-Protected 6-Cyanouridine 7
with Various Grignard Reagents
b
yield (%)
a
c
entry
RMgX
product
ZnCl2
no additive
d
1
2
3
4
5
6
7
8
methyl
ethyl
9a
9b
9c
9d
9e
9f
45
trace
58
82
57
44
isopropyl
tert-butyl
n-butyl
52
42
e
60
29
cyclopentyl
3-butenyl
benzyl
37
46
54
49
a
9g
9i
16
Reagents and conditions: (a) NaCN (2.5 equiv), DMF, rt, 6 h, 80%;
39
(b) RMgBr (R = Me: 5 equiv; R = Et or 3-butenyl: 2.5 equiv), ZnCl2
(R = Me: 0.5 equiv; R = Et or 3-butenyl: 0.1 equiv), THF, 0 °C to rt, 3
h; (c) 1 M TBAF in THF with ca. 5% water.
a
b
c
Refer to footnotes c, e, f, and h in Table 2. Isolated yield. ZnCl2 (1
d
M) in Et2O; No reaction under the standard conditions; 45% of 9a
from the reaction with 5 equiv of MeMgBr and 0.5 equiv of ZnCl2.
34% of 9e under the standard conditions; 60% of 9e when the
reaction concentration was raised to 0.2 M.
e
CONCLUSION
■
In summary, we have discovered a novel substitution reaction
of 6-cyanouracil derivatives with alkyl Grignard reagents, which
illustrated the versatile reactivity of 6-cyanouracils.14,18,19,21 Our
investigation has successfully provided a facile and general
synthesis of 6-alkyluridines from readily prepared 6-cyanour-
idines. Further application of this methodology will be
amenable to the synthesis of a variety of 6-alkyluracil derivatives
for biochemical applications.
the reaction scope to the nucleoside derivatives. Under the
uncatalyzed condition, the sugar-protected 6-cyanouridine 7
can react with the alkyl Grignard reagents to give the
corresponding sugar-protected 6-alkyluridines 9 in reasonable
yields. The reaction can also be facilitated by the addition of
ZnCl2 as the catalyst. (Table 3) Nonetheless, MeMgBr gave the
desired product only in a trace amount under both conditions.
Upon increasing the amounts of MeMgBr and ZnCl2 to 5 and
0.5 equivalents, respectively, the desired sugar-protected 6-
methyluridine 9a was obtained in 45% yield. The acid-labile
TBS and isopropylidene groups of 9a−g,i were deprotected
with aqueous TFA to give the targeted 6-alkyluridines 11a−g,i
in good yields (Scheme 4).
The success in the synthesis of 6-alkyluridines has prompted
us to broaden the scope of this strategy to the synthesis of 6-
alkyl-2′-deoxyuridine derivatives. Therefore, 3′,5′-di-O-TBS-5-
bromo-2′-deoxyuridine20 (12) was treated with NaCN to give
the sugar-protected 6-cyano-2′-deoxyuridine 13. Subjection of
13 to the optimized ZnCl2-catalyzed condition with the alkyl
Grignard reagents afforded the corresponding sugar-protected
6-alkyl-2′-deoxyuridine derivatives (14a,b,g). Subsequent re-
moval of the TBS group with TBAF gave the desired 6-alkyl-2′-
deoxyuridines (15a,b,g) (Scheme 5).
EXPERIMENTAL SECTION
■
General Chemical Procedures. The chemical shift values are
reported in δ values (parts per million, ppm) relative to the standard
chemical shift for the hydrogen residue peak and carbon-13 peak in the
deuterated solvent, CDCl3, or DMSO-d6.22 The coupling constant (J)
values are expressed in hertz (Hz). The numbers of protons directly
attached to the individual carbons were determined by 13C NMR
DEPT experiments. Thin-layer chromatography (TLC) was per-
formed on silica gel plates. Compounds on TLC were visualized by
illumination under UV light (254 nm), or dipped into 10% ethanolic
sulfuric acid followed by charring on a hot plate. Solvent systems are
expressed as a percentage of the more polar component with respect
to total volume (v/v %). Silica gel (230−400 mesh) was used for flash
column chromatography and this technique has been described by Still
et al.23 Evaporations were carried out under reduced pressure (water
aspirator or vacuum pump) with the bath temperature below 50 °C
unless specified otherwise. Materials obtained from commercial
suppliers were used without further purification.
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General Procedure for the Reaction of 6-Cyanouracil
Derivatives with Grignard Reagents (for Compounds 3, 4, 9,
10, and 14). To a solution of 6-cyanouracil derivative in THF (0.1
M) was slowly added ZnCl2 (0.1 equiv) and then the Grignard reagent
(1.5 or 2.5 equiv) at 0 °C. After the addition was completed, the
reaction mixture was stirred for 3 h, and the reaction temperature was
allowed to rise to room temperature. The reaction was quenched with
saturated aqueous NH4Cl solution, and the solvent was removed
under reduced pressure. The residue was partitioned between CHCl3
and H2O, and the aqueous layer was further extracted with CHCl3.
The organic portions were combined, washed with saturated aqueous
NaCl solution, dried over anhydrous MgSO4, and concentrated under
reduced pressure to dryness. The resulting residue was purified by
flash column chromatography to give the product.
(s, 1 H), 3.45 (s, 3 H), 3.34 (s, 3 H), 2.97−2.89 (m, 1 H), 2.06−2.02
(m, 2 H), 1.80−1.79 (m, 2 H), 1.71−1.68 (m, 2 H), 1.63−1.59 (m, 2
H); 13C NMR (CDCl3, 100 MHz) δ 162.9, 159.0, 152.9, 97.6 (CH),
41.1 (CH), 31.8 (CH2), 31.6 (CH3), 27.9 (CH3), 25.0 (CH2); MS (EI,
70 eV) m/z 167 (100), 208 (18) (M+); HRMS (EI, 70 eV, magnetic
sector) calcd for C11H16N2O2 208.1212, found 208.1218.
6-(3-Butenyl)-1,3-dimetyluracil (3g). The reaction was purified
by flash column chromatography (Hex/EtOAc = 9:1 to 8:2) to give
the product (3g, foam, 0.1562 g, 87%, Rf = 0.3 (Hex/EtOAc = 5:5)):
1H NMR (CDCl3, 400 MHz) δ 5.86−5.76 (m, 1 H), 5.61 (s, 1 H),
5.14−5.08 (m, 2 H), 3.40 (s, 3 H), 3.33 (s, 3 H), 2.57 (t, 2 H, J = 7.6
Hz), 2.38−2.33 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 162.4,
154.1, 152.6, 135.2 (CH), 116.8 (CH2), 100.2 (CH), 31.7 (CH2), 31.2
(CH3), 30.7 (CH2), 27.8 (CH3); MS (EI, 20 eV) m/z 179 (100), 194
(44) (M+); HRMS (EI, 70 eV, magnetic sector) calcd for C10H14N2O2
194.1055, found 194.1061.
1,3,6-Trimethyluracil15 (3a) and 6-Cyano-1,3-dimethyl-4-
methylidene-3,4-dihydropyrimidin-2-one (4). The reaction was
purified by flash column chromatography (Hex/EtOAc = 9:1 to 7:3 to
1:9) to give the products (4, solid, 0.2476 g, 31%, Rf = 0.20 (Hex/
EtOAc = 9:1 and 3a, white solid, 0.1509 g, 20%, Rf = 0.19 (Hex/
6-Benzyl-1,3-dimethyluracil27 (3i). The reaction was purified by
flash column chromatography (Hex/EtOAc = 7:3 to 6:4) to give the
product (3i, solid, 0.2754 g, 60%, Rf = 0.3 (Hex/EtOAc = 5:5)): mp
95−97 °C; 1H NMR (CDCl3, 400 MHz) δ 7.37−7.30 (m, 3 H), 7.18
(d, 2 H, J = 7.2 Hz), 5.55 (s, 1 H), 3.82 (s, 2 H), 3.35 (s, 3 H), 3.32 (s,
3 H); 13C NMR (CDCl3, 100 MHz) δ 162.5, 153.2, 152.7, 134.1,
129.2 (CH), 128.6 (CH), 127.7 (CH), 102.6 (CH), 39.2 (CH2), 31.6
(CH3), 28.0 (CH3); MS (EI, 70 eV) m/z 230 (100) (M+); HRMS (EI,
70 eV, magnetic sector) calcd for C13H14N2O2 230.1055, found
230.1054.
EtOAc = 1: 9)). 3a: mp 113−115 °C (lit.15 mp 114−115 °C); H
1
NMR (CDCl3, 400 MHz) δ 5.57 (s, 1 H), 3.36 (s, 3 H), 3.28 (s, 3 H),
2.20 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 162.3, 152.5, 151.3,
101.1 (CH), 31.6 (CH3), 27.8 (CH3), 20.1 (CH3); MS (EI, 20 eV) m/
z 56 (100), 69 (39), 82 (88), 97 (59), 125 (32), 154 (79) (M+). 4: 1H
NMR (CDCl3, 400 MHz) δ 6.16 (s, 1 H), 4.07 (d, 1 H, J = 1.1 Hz),
4.01 (d, 1 H, J = 1.1 Hz), 3.27 (s, 3 H), 3.06 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 150.2, 140.3, 116.1 (CH), 114.9, 112.7, 89.3
(CH2), 33.5 (CH3), 30.5 (CH3); MS (EI, 20 eV) m/z 163 (100)
(M+); MS (FAB) m/z 164 (100) (M + H); HRMS (FAB, magnetic
sector) calcd for C8H10N3O 164.0824, found 164.0826.
6-Phenyl-1,3-dimethyluracil28,29 (3j). The reaction was purified
by flash column chromatography (Hex/EtOAc = 9.5:0.5 to 8.5:1.5) to
give the product (3j, solid, 0.0526 g, 24%, Rf = 0.25 (Hex/EtOAc =
5:5)): mp 104−106 °C (lit.28,29 mp 86−88 °C); H NMR (CDCl3,
1
1,3-Dimethyl-6-ethyluracil24 (3b). The reaction was purified by
flash column chromatography (Hex/EtOAc = 8:2 to 6:4) to give the
product (3b, white solid, 0.1509 g, 90%, Rf = 0.18 (Hex/EtOAc =
400 MHz) δ 7.47−7.44 (m, 3 H), 7.31−7.29 (m, 2 H), 5.66 (s, 1 H),
3.37 (s, 3 H), 3.19 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 162.3,
154.5, 152.6, 133.3, 130.1 (CH), 128.9 (CH), 127.6 (CH), 102.3
(CH), 34.5 (CH3), 27.9 (CH3); MS (EI, 20 eV) m/z 216 (100) (M+).
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(p-
methoxybenzyl)-5-bromouridine (6a). To a solution of 5′-O-tert-
butyldimethylsilyl-2′,3′-O-isopropylidene-5-bromouridine16 (5, 5.3147
g, 11.13 mmol) in CH3CN (50 mL) were added DBU (3.36 mL, 22.26
mmol, 2 equiv) and PMBCl (2.26 mL, 16.70 mmol, 1.5 equiv).17 The
reaction mixture was stirred at 60 °C for 3 h. The solvent was removed
under reduced pressure. The residue was partitioned between EtOAc
and H2O. The aqueous layer was further extracted with EtOAc. The
organic portions were combined, washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and concentrated under
reduced pressure to dryness. The residue was purified by flash column
chromatography (Hex/EtOAc = 9:1) to give the product (6a, solid,
5:5)): mp 50−52 °C (lit.24 mp 46−47 °C); H NMR (CDCl3, 400
1
MHz) δ 5.63 (s, 1 H), 3.40 (s, 3 H), 3.34 (s, 3 H), 2.52 (q, 2 H, J = 7.3
Hz), 1.24 (t, 3 H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 162.4,
156.1, 152.4, 98.8 (CH), 30.8 (CH3), 27.6 (CH3), 25.4 (CH2), 11.0
(CH3); MS (EI, 20 eV) m/z 82 (40), 168 (100) (M+); HRMS (EI, 70
eV, magnetic sector) calcd for C8H12N2O2 168.0899, found 168.0903.
1,3-Dimethyl-6-isopropyluracil25 (3c). The reaction was
purified by flash column chromatography (Hex/EtOAc = 8.5:1.5 to
7.5:2.5) to give the product (3c, oil, 0.5471 g, 60%, Rf = 0.25 (Hex/
EtOAc = 5: 5)): 1H NMR (CDCl3, 400 MHz) δ 5.61 (s, 1 H), 3.40 (s,
3 H), 3.28 (s, 3 H), 2.83 (sep, 1 H, J = 6.7 Hz), 1.19 (d, 6 H, J = 6.7
Hz); 13C NMR (CDCl3, 100 MHz) δ 162.9, 160.7, 152.7, 97.3 (CH),
30.9 (CH3), 29.5 (CH), 27.8 (CH3), 21.2 (CH3); MS (EI, 70 eV) m/z
167 (46), 182 (100) (M+); HRMS (EI, 70 eV, magnetic sector) calcd
for C9H14N2O2 182.1055, found 182.1055.
1
4.4276 g, 67%, Rf = 0.38 (Hex/EtOAc = 8:2)): mp 118−120 °C; H
NMR (CDCl3, 400 MHz) δ 7.88 (s, 1 H), 7.48 (d, 2 H, J = 8.6 Hz),
6.81 (d, 2 H, J = 8.7 Hz), 5.86 (d, 1 H, J = 2.5 Hz), 5.13 (d, 1 H, J =
13.5 Hz), 5.05 (d, 1 H, J = 13.5 Hz), 4.72−4.68 (m, 2 H), 4.42−4.41
(m, 1 H), 3.91 (dd, 1 H, J = 2.0 and 11.7 Hz), 3.77 (dd, 1 H, J = 2.9
and 11.6 Hz), 3.77 (s, 3 H), 1.59 (s, 3 H), 1.37 (s, 3 H), 0.85 (s, 9 H),
0.08 (s, 3 H), 0.077 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 159.3,
158.9, 150.2, 137.6 (CH), 131.2 (CH), 128.4, 113.9, 113.7 (CH), 96.4,
94.1 (CH), 87.2 (CH), 86.0 (CH), 80.7 (CH), 63.4 (CH2), 55.2
(CH3), 45.0 (CH2), 27.2 (CH3), 25.9 (CH3), 25.2 (CH3), 18.3, −5.3
(CH3), −5.5 (CH3); MS (ESI) m/z 595 (100) (M − H), 597 (89) (M
+ H); HRMS (ESI, TOF) calcd for C26H37BrN2O7Si·Na (M + Na)
619.1451, found 619.1406.
6-tert-Butyl-1,3-dimethyluracil26 (3d). The reaction was
purified by flash column chromatography (Hex/EtOAc = 8.5:1.5 to
7:3) to give the product (3d, foam, 0.0956 g, 49%, Rf = 0.3 (Hex/
EtOAc = 5: 5)): 1H NMR (CDCl3, 400 MHz) δ 5.81 (s, 1 H), 3.55 (s,
3 H), 3.34 (s, 3 H), 1.40 (s, 9 H); 13C NMR (CDCl3, 100 MHz) δ
162.9, 161.4, 153.4, 99.3 (CH), 35.7, 35.1 (CH3), 29.7 (CH3), 27.8
(CH3); MS (EI, 70 eV) m/z 181 (55), 196 (100) (M+); HRMS (EI,
70 eV, magnetic sector) calcd for C10H16N2O2 196.1212, found
196.1218.
6-n-Butyl-1,3-dimethyluracil11 (3e). The reaction was purified
by flash column chromatography (Hex/EtOAc = 7:3) to give product
1
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(ben-
zyloxymethyl)-5-bromouridine (6b). To a solution of 5′-O-tert-
butyldimethylsilyl-2′,3′-O-isopropylidene-5-bromouridine16 (5, 2.6083
g, 5.46 mmol) in DMF (6 mL) were added DBU (1.7 mL, 10.92
mmol, 2.0 equiv) and BOMCl (1.14 mL, 8.19 mmol, 1.5 equiv) at 0
°C.17 The reaction temperature was allowed to rise to room
temperature, and the reaction mixture was stirred for 2 days. The
solvent was removed under reduced pressure. The residue was purified
by flash column chromatography (Hex/EtOAc = 9:1) to give the
product (6b, foam, 2.1338 g, 65%, Rf = 0.50 (Hex/EtOAc = 7: 3)): 1H
NMR (CDCl3, 400 MHz) δ 7.87 (s, 1 H), 7.36−7.25 (m, 5 H), 5.86
(3e, oil, 0.790 g, 81%, Rf = 0.16 (Hex/EtOAc = 7: 3)): H NMR
(CDCl3, 400 MHz) δ 5.53 (s, 1 H), 3.33 (s, 3 H), 3.25 (s, 3 H), 2.40
(t, 2 H, J = 7.7 Hz), 1.56−1.47 (m, 2 H), 1.42−1.32 (m, 2 H), 0.90 (t,
3 H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 162.5, 155.0, 152.6,
99.9 (CH), 32.1 (CH2), 31.1 (CH3), 28.9 (CH2), 27.7 (CH3), 22.0
(CH2), 13.5 (CH3); MS (EI, 20 eV) m/z 55 (83), 69 (83), 82 (56), 97
(100), 127 (27), 154 (63), 196 (51) (M+).
6-Cyclopentyl-1,3-dimethyluracil (3f). The reaction was
purified by flash column chromatography (Hex/EtOAc = 8.7:1.3 to
8.5:1.5) to give the product (3f, foam, 0. 0925 g, 44%, Rf = 0.3 (Hex/
1
EtOAc = 5:5)): mp 51−55 °C; H NMR (CDCl3, 400 MHz) δ 5.69
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(d, 1 H, J = 2.6 Hz), 5.55 (d, 1 H, J = 9.8 Hz), 5.51 (d, 1 H, J = 9.8
Hz), 4.73−4.62 (m, 4 H), 4.43−4.40 (m, 1 H), 3.92 (dd, 1 H, J = 1.9
and 11.6 Hz), 3.78 (dd, 1 H, J = 2.7 and 11.6 Hz), 1.59 (s, 3 H), 1.37
(s, 3 H), 0.89 (s, 9 H), 0.11 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
159.0, 150.1, 138.4 (CH), 137.8, 128.2 (CH), 127.62 (CH), 127.55
(CH), 113.9, 96.2, 93.9 (CH), 87.1 (CH), 85.8 (CH), 80.7 (CH), 72.5
(CH2), 71.6 (CH2), 63.4 (CH2), 27.2 (CH3), 25.9 (CH3), 25.2 (CH3),
18.3, −5.3 (CH3), −5.5 (CH3); MS (ESI) m/z 619 (100) (M + Na),
621 (89) (M + Na + 2); HRMS (ESI, TOF) calcd for
C26H37Br1N2O7Si·Na (M + Na) 619.1451, found 619.1449.
1.60 (s, 3 H), 1.37 (s, 3 H), 0.88 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H);
13C NMR (CDCl3, 100 MHz) δ 158.9, 149.3, 146.6 (CH), 137.5,
128.3 (CH), 127.8 (CH), 127.7 (CH), 113.8, 113.0, 95.1 (CH), 88.0
(CH), 86.3 (CH), 80.9 (CH), 72.7 (CH2), 70.9 (CH2), 63.5, 27.1
(CH3), 25.8 (CH3), 25.1 (CH3), 18.2, −5.4 (CH3), −5.6 (CH3); MS
(ESI) m/z 566 (100) (M + Na); HRMS (ESI, TOF) calcd for
C27H37N3O7Si·Na (M + Na) 566.2298, found 566.2303.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-meth-
yluridine5 (9a). To a solution of 716 (0.5808 g, 1.3713 mmol) in
THF (13.7 mL) were slowly added ZnCl2 (1 M solution in Et2O, 0.69
mL, 0.69 mmol, 0.5 equiv) and MeMgBr (1 M solution in THF, 6.86
mL, 6.86 mmol, 5 equiv) at 0 °C. After the addition was completed,
the reaction mixture was stirred for 3 h and the reaction temperature
was allowed to rise to room temperature. The reaction was quenched
with saturated aqueous NH4Cl solution, and the solvent was removed
under reduced pressure. The residue was partitioned between CHCl3
and H2O. The aqueous layer was further extracted with CHCl3. The
organic portions were washed with saturated aqueous NaCl solution,
combined, dried over anhydrous MgSO4, and concentrated under
reduced pressure to dryness. The reaction was purified by flash column
chromatography (Hex/ether = 5:5) to give the product (9a, oil, 0.2551
g, 0.6183 mmol, 45%, Rf = 0.11 (Hex/ether = 5:5)): 1H NMR
(CDCl3, 400 MHz) δ 9.54 (bs, 1 H), 5.70 (s, 1 H), 5.56 (s, 1 H), 5.21
(d, 1 H, J = 6.4 Hz), 4.82 (dd, 1 H, J = 4.6 and 6.1 Hz), 4.15−4.11 (m,
1 H), 3.82−3.78 (m, 2 H), 2.33 (s, 3 H), 1.53 (s, 3 H), 1.33 (s, 3 H),
0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 162.9,
153.2, 150.5, 113.7, 103.0 (CH), 91.7 (CH), 89.5 (CH), 84.2 (CH),
82.0 (CH), 64.2 (CH2), 27.2 (CH3), 25.9 (CH3), 25.3 (CH3), 20.4
(CH3), 18.4, −5.28 (CH3); MS (ESI) m/z 435 (100) (M + Na);
HRMS (ESI, TOF) calcd for C19H31N2O6Si (M − H) 411.1951, found
411.1943.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(p-
methoxybenzyl)-6-cyanouridine (8a). To a solution of 6a (4.0204
g, 6.73 mmol) in DMF (60 mL) was added NaCN (0.4908 g, 10.1
mmol, 1.5 equiv), and the reaction mixture was stirred at room
temperature for 2.5 h.16 The solvent was removed under reduced
pressure. The residue was partitioned between CHCl3 and H2O. The
aqueous layer was further extracted with CHCl3. The organic portions
were combined, washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and concentrated under reduced pressure to
dryness. The residue was purified by flash column chromatography
(Hex/EtOAc = 9:1) to give the product (8a, oil, 1.7037 g, 3.13 mmol,
1
47%, Rf = 0.43 (Hex/EtOAc = 8:2)): H NMR (CDCl3, 400 MHz) δ
7.39 (d, 2 H, J = 8.6 Hz), 6.82 (d, 2 H, J = 8.7 Hz), 6.31 (s, 1 H), 6.04
(d, 1 H, J = 2.1 Hz), 5.11 (dd, 1 H, J = 2.1 and 6.7 Hz), 4.98 (s, 2 H),
4.82 (dd, 1 H, J = 4.6 and 6.6 Hz), 4.19−4.15 (m, 1 H), 3.86 (dd, 1 H,
J = 5.2 and 10.9 Hz), 3.81−3.77 (m, 3 H), 3.77 (s, 3 H), 1.57 (s, 3 H),
1.35 (s, 3 H), 0.89 (s, 9 H), 0.051 (s, 3 H), 0.048 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 159.7, 159.4, 149.3, 130.9 (CH), 127.6, 125.6,
114.7, 113.8 (CH), 112.6 (CH), 110.9, 94.5 (CH), 88.7 (CH), 83.7
(CH), 81.5 (CH), 63.4 (CH2), 55.2 (CH3), 44.2 (CH2), 27.1 (CH3),
25.9 (CH3), 25.4 (CH3), 18.4, −5.35 (CH3), −5.38 (CH3); MS (ESI)
m/z 566 (100) (M + Na). HRMS (ESI, TOF) calcd for
C27H37N3O7Si·Na (M + Na) 566.2298, found 566.2260.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-ethyl-
uridine30 (9b). The reaction was purified by flash column
chromatography (Hex/EtOAc = 9:1 to 8:2) to give the product (9b,
oil, 0.9115 g, 58%, Rf = 0.13 (Hex/EtOAc = 7:3)): 1H NMR (CDCl3,
400 MHz) δ 9.20 (bs, 1 H), 5.72 (s, 1 H), 5.58 (s, 1 H), 5.19 (dd, 1 H,
J = 0.6 and 6.2 Hz), 4.81 (dd, 1 H, J = 4.6 and 6.3 Hz), 4.15−4.11 (m,
1 H), 3.82−2.80 (m, 2 H), 2.62 (q, 2 H, J = 7.3 Hz), 1.54 (s, 3 H),
1.33 (s, 3 H), 1.28 (t, 3 H, J = 7.3 Hz), 0.87 (s, 9 H), 0.04 (s, 6 H);
13C NMR (CDCl3, 100 MHz) δ 163.0, 158.2, 150.6, 113.7, 101.0
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(ben-
zyloxymethyl)-6-cyanouridine (8b). To a solution of 5′-O-tert-
butyldimethylsilyl-2′,3′-O-isopropylidene-6-cyanouridine16 (7, 0.9221
g, 2.18 mmol) in DMF (10 mL) was added DBU (0.66 mL, 4.36
mmol, 2.0 equiv) and then BOMCl (0.45 mL, 3.27 mmol, 1.5 equiv)
at 0 °C. After the addition was completed, the reaction mixture was
stirred for 3.5 h, and the reaction temperature was allowed to rise to
room temperature. The solvent was removed under reduced pressure.
The residue was partitioned between CHCl3 and H2O. The aqueous
layer was further extracted with CHCl3. The organic portions were
washed with saturated aqueous NaCl solution, combined, dried over
anhydrous MgSO4, and concentrated under reduced pressure to
dryness. The resulting residue was purified by flash column
chromatography (Hex/EtOAc = 8:2) to give the product (8b, foam,
(CH), 91.2 (CH), 89.5 (CH), 84.3 (CH), 82.1 (CH), 64.2 (CH2),
27.2 (CH3), 26.1 (CH2), 25.9 (CH3), 25.3 (CH3), 18.4, 12.1 (CH3),
−5.3 (CH3); MS (ESI) m/z 449 (100) (M + Na); HRMS (ESI, TOF)
calcd for C20H34N2O6Si·Na (M + Na) 449.2084, found 449.2097.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-iso-
propyluridine (9c). The reaction was purified by flash column
chromatography (Hex/EtOAc = 9:1 to 8.5:1.5) to give the product
1
0.5619 g, 1.03 mmol, 47%, Rf = 0.40 (Hex/EtOAc = 7:3)): H NMR
1
(9c, foam, 0.2406 g, 52%, Rf = 0.20 (Hex/EtOAc = 7: 3)): H NMR
(CDCl3, 400 MHz) δ 7.37−7.28 (m, 5 H), 6.25 (s, 1 H), 6.01 (d, 1 H,
J = 1.7 Hz), 5.45 (d, 1 H, J = 9.8 Hz), 5.40 (d, 1 H, J = 9.9 Hz), 5.10
(dd, 1 H, J = 1.7 and 6.5 Hz), 4.82−4.79 (m, 1 H), 4.67 (s, 2 H),
4.20−4.15 (m, 1 H), 3.89−3.81 (m, 2 H), 1.58 (s, 3 H), 1.36 (s, 3 H),
0.89 (s, 9 H), 0.06 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 159.8,
149.3, 137.4, 128.4 (CH), 127.9 (CH), 127.6 (CH), 126.4, 114.8,
112.5 (CH), 110.7, 94.5 (CH), 88.7 (CH), 83.6 (CH), 81.4 (CH),
72.7 (CH2), 70.8 (CH2), 63.5 (CH2), 27.2 (CH3), 25.9 (CH3), 25.4
(CH3), 18.4, −5.31 (CH3), −5.33 (CH3); MS (ESI) m/z 566 (100)
(M + Na); HRMS (ESI, TOF) calcd for C27H38N3O7Si (M + H)
544.2479, found 544.2466.
(CDCl3, 400 MHz) δ 9.30 (bs, 1 H), 5.80 (s, 1 H), 5.64 (s, 1 H), 5.19
(dd, 1 H, J = 0.8 and 6.6 Hz), 4.81 (dd, 1 H, J = 4.7 and 6.4 Hz),
4.15−4.11 (m, 1 H), 3.83−3.81 (m, 2 H), 3.01−2.94 (m, 1 H), 1.54
(s, 3 H), 1.33 (s, 3 H), 1.29 (d, 3 H, J = 6.7 Hz), 1.26 (d, 3 H, J = 6.7
Hz), 0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
163.3, 162.6, 150.8, 113.8, 98.9 (CH), 90.8 (CH), 89.5 (CH), 84.5
(CH), 82.1 (CH), 64.3 (CH2), 29.6 (CH), 27.3 (CH3), 25.9 (CH3),
25.3 (CH3), 22.1 (CH3), 21.2 (CH3), 18.4, −5.24 (CH3), −5.25
(CH3); MS (ESI) m/z 463 (100) (M + Na); HRMS (ESI, TOF) calcd
for C21H37N2O6Si (M + 1) 441.2421, found 441.2434.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(ben-
zyloxymethyl)-5-cyanouridine (8b′). Compound 8b′ was obtained
from the reaction of 6b (0.7374 g, 1.23 mmol) with NaCN (0.0604 g,
1.23 mmol, 1 equiv) in DMF (15 mL) at 0 °C to room temperature as
described for 8a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 8:2) to give the product (8b′,
foam, 0.3049 g, 46%, Rf = 0.25 (Hex/EtOAc = 7:3)). 1H NMR
(CDCl3, 400 MHz) δ 8.21 (s, 1 H), 7.35−7.26 (m, 5 H), 5.81 (d, 1 H,
J = 2.4 Hz), 5.51 (d, 1 H, J = 10.1 Hz), 5.47 (d, 1 H, J = 9.8 Hz),
4.69−4.68 (m, 3 H), 4.65−4.64 (m, 1 H), 4.54−4.52 (m, 1 H), 3.95
(dd, 1 H, J = 1.7 and 11.8 Hz), 3.78 (dd, 1 H, J = 2.3 and 11.9 Hz),
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-tert-
butyluridine (9d). The reaction was purified by flash column
chromatography (Hex/EtOAc = 9:1 to 8.5:1.5) to give the product
1
(9d, foam, 0.9043 g, 42%, Rf = 0.23 (Hex/EtOAc = 7:3)): H NMR
(CDCl3, 400 MHz) δ 9.03 (bs, 1 H), 6.17 (s, 1 H), 5.76 (s, 1 H), 5.17
(d, 1 H, J = 6.6 Hz), 4.82−4.80 (m, 1 H), 4.11 (dd, 1 H, J = 5.8 and
11.1 Hz), 3.85−3.83 (m, 2 H), 1.54 (s, 3 H), 1.45 (s, 9 H), 1.33 (s, 3
H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
163.7, 163.4, 151.4, 113.8, 100.6 (CH), 92.5 (CH), 89.3 (CH), 84.7
(CH), 82.4 (CH), 64.3 (CH2), 36.0, 30.5 (CH3), 27.3 (CH3), 25.9
(CH3), 25.4 (CH3), 18.4, −5.19 (CH3), −5.23 (CH3); MS (ESI) m/z
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477 (100) (M + Na); HRMS (ESI, TOF) calcd for C22H38N2O6Si·Na
(M + Na) 477.2397, found 477.2412.
= 7.3 Hz), 1.53 (s, 3 H), 1.34 (s, 3 H), 1.25 (t, 3 H, J = 7.3 Hz), 0.88
(s, 9 H), 0.01 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 162.2, 159.0,
155.5, 151.2, 130.6 (CH), 128.9, 113.7 (CH), 113.6, 100.9 (CH), 91.9
(CH), 89.6 (CH), 84.4 (CH), 82.4 (CH), 64.2 (CH2), 55.2 (CH3),
43.4 (CH2), 27.3 (CH3), 25.93 (CH3), 25.85 (CH2), 25.4 (CH3), 18.5,
12.0 (CH3), −5.27 (CH3), −5.31 (CH3); MS (ESI) m/z 569 (100)
(M + Na); HRMS (ESI, TOF) calcd for C28H42N2O7Si·Na (M + Na)
569.2659, found 569.2651.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-n-bu-
tyluridine (9e). The reaction was purified by flash column
chromatography (Hex/EtOAc = 8:2) to give the product (9e, oil,
1.4454 g, 60%, Rf = 0.19 (Hex/EtOAc = 7: 3)): 1H NMR (CDCl3, 400
MHz) δ 9.73 (bs, 1 H), 5.68 (s, 1 H), 5.56 (s, 1 H), 5.18 (d, 1 H, J =
6.3 Hz), 4.80 (dd, 1 H, J = 4.6 and 6.2 Hz), 4.14 (dd, 1 H, J = 6.0 and
10.9 Hz), 3.82−3.80 (m, 2 H), 2.55 (t, 2 H, J = 7.7 Hz), 1.66−1.58
(m, 2 H), 1.53 (s, 3 H), 1.47−1.38 (m, 2 H), 1.32 (s, 3 H), 0.96 (t, 3
H, J = 7.3 Hz), 0.87 (s, 9 H), 0.03 (s, 6 H); 13C NMR (CDCl3, 100
MHz) δ 163.3, 157.0, 150.8, 113.7, 101.8 (CH), 91.5 (CH), 89.6
(CH), 84.3 (CH), 82.1 (CH), 64.3 (CH2), 32.6 (CH2), 29.5 (CH2),
27.2 (CH3), 25.9 (CH3), 25.3 (CH3), 22.1 (CH2), 18.4, 13.6 (CH3),
−5.25 (CH3), −5.28 (CH3); MS (ESI) m/z 477 (M + Na); HRMS
(ESI, TOF) calcd for C22H37N2O6Si (M − H) 453.2421, found
453.2417.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-cyclo-
pentyluridine (9f). The reaction was purified by flash column
chromatography (Hex/EtOAc = 7.5:2.5) to give the product (9f, foam,
0.5257 g, 49%, Rf = 0.23 (Hex/EtOAc = 7:3)): 1H NMR (CDCl3, 400
MHz) δ 9.39 (bs, 1 H), 5.84 (s, 1 H), 5.66 (s, 1 H), 5.18 (d, 1 H, J =
6.4 Hz), 4.81 (dd, 1 H, J = 4.9 and 6.1 Hz), 4.13 (dd, 1 H, J = 5.8 and
11.2 Hz), 3.82−3.81 (m, 2 H), 3.03−2.96 (m, 1 H), 2.13−2.02 (m, 2
H), 1.85−1.77 (m, 2 H), 1.76−1.56 (m, 4 H), 1.53 (s, 3 H), 1.33 (s, 3
H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
163.4, 160.7, 150.8, 113.7, 98.9 (CH), 91.3 (CH), 89.6 (CH), 84.5
(CH), 82.2 (CH), 64.3 (CH2), 41.2 (CH), 32.6 (CH2), 31.8 (CH2),
27.3 (CH3), 25.9 (CH3), 25.3 (CH3), 24.8 (CH2), 24.7 (CH2), 18.4,
−5.23 (CH3), −5.24 (CH3); MS (ESI) m/z 489 (100) (M + Na);
HRMS (ESI, TOF) calcd for C23H39N2O6Si (M + 1) 467.2580, found
467.2577.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(ben-
zyloxymethyl)-6-ethyluridine (10b). The reaction was purified by
flash column chromatography (Hex/EtOAc = 8:2) to give the product
(10b, foam, 0.1543 g, 29%, Rf = 0.30 (Hex/EtOAc = 8: 2)): 1H NMR
(CDCl3, 400 MHz) δ 7.37−7.24 (m, 5 H), 5.70 (s, 1 H), 5.58 (s, 1 H),
5.46 (d, 1 H, J = 9.9 Hz), 5.38 (d, 1 H, J = 9.9 Hz), 5.17 (d, 1 H, J =
6.5 Hz), 4.86 (dd, 1 H, J = 4.7 and 6.2 Hz), 4.67 (s, 2 H), 4.15−4.11
(m, 1 H), 3.86−3.78 (m, 2 H), 2.59 (q, 2 H, J = 7.3 Hz), 1.54 (s, 3 H),
1.34 (s, 3 H), 1.26 (t, 3 H, J = 7.3 Hz), 0.86 (s, 9 H), 0.02 (s, 6 H);
13C NMR (CDCl3, 100 MHz) δ 162.3, 156.5, 151.2, 137.9, 128.3
(CH), 127.7 (CH), 127.6 (CH), 113.6, 100.7 (CH), 91.6 (CH), 89.5
(CH), 84.3 (CH), 82.1 (CH), 72.2 (CH2), 70.1 (CH2), 64.2 (CH2),
27.2 (CH3), 26.0 (CH2), 25.9 (CH3), 25.4 (CH3), 18.4, 12.0 (CH3),
−5.27 (CH3), −5.29 (CH3); MS (ESI) m/z 569 (100) (M + Na);
HRMS (ESI, TOF) calcd for C28H42N2O7Si·Na (M + Na) 569.2659,
found 569.2661.
6-Methyluridine4,31 (11a). Compound 9a (1.0011 g, 2.4266
mmol) was dissolved in aqueous trifluoroacetic acid (H2O/TFA = 1
mL:11 mL) at 0 °C and then stirred at room temperature for 1 h. The
solvents were removed under reduced pressure. The residue was
coevaporated with a small amount of MeOH and then purified by flash
column chromatography (CHCl3/MeOH = 9:1, Rf = 0.21) to give the
product (11a, solid, 0.5594 g, 2.1663 mmol, 89%). The compound was
recrystallized from MeOH/EtOAc to give an analytical sample (11a,
white solid, 0.2526 g, 0.9782 mmol, 40%): mp 171−173 °C (lit.31 mp
177−178 °C); 1H NMR (DMSO-d6, 400 MHz) δ 11.23 (s, 1 H), 5.56
(s, 1 H), 5.46 (d, 1 H, J = 4.2 Hz), 5.19 (d, 1 H, J = 5.4 Hz), 4.93 (d, 1
H, J = 6.4 Hz), 4.66 (t, 1 H, J = 5.8 Hz), 4.54 (dd, 1 H, J = 5.4 and
10.2 Hz), 4.06 (dd, 1 H, J = 6.1 and 12.2 Hz), 3.72−3.68 (m, 1 H),
3.63−3.58 (m, 1 H), 3.47−3.41 (m, 1 H), 2.26 (s, 3 H); 13C NMR
(DMSO-d6, 100 MHz) δ 162.8, 154.0, 151.2, 102.9 (CH), 92.2 (CH),
85.2 (CH), 71.4 (CH), 70.1 (CH), 62.3 (CH2), 20.2 (CH3); MS
(ESI) m/z 281 (100) (M + Na); HRMS (ESI, TOF) calcd for
C10H14N2O6·Na (M + Na) 281.0750, found 281.0742.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-(3-
butenyl)uridine5 (9g). The reaction was purified by flash column
chromatography (Hex/EtOAc = 9:1 to 8.5:1.5) to give the product
1
(9g, oil, 0.1236 g, 16%, Rf = 0.23 (Hex/EtOAc = 7:3)): H NMR
(CDCl3, 400 MHz) δ 9.31 (bs, 1 H), 5.85−5.75 (m, 1 H), 5.68 (s, 1
H), 5.56 (s, 1 H), 5.19 (d, 1 H, J = 6.4 Hz), 5.15−5.08 (m, 2 H), 4.81
(dd, 1 H, J = 4.7 and 6.2 Hz), 4.16−4.12 (m, 1 H), 3.82−3.80 (m, 2
H), 2.67 (t, 2 H, J = 7.6 Hz), 2.44−2.38 (m, 2 H), 1.54 (s, 3 H), 1.33
(s, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ
162.7, 156.0, 150.6, 135.1 (CH), 117.1 (CH2), 113.8, 102.2 (CH),
91.5 (CH), 89.5 (CH), 84.3 (CH), 82.1 (CH), 64.2 (CH2), 32.3
(CH2), 31.4 (CH2), 27.2 (CH3), 25.9 (CH3), 25.4 (CH3), 18.4, −5.24
(CH3), −5.26 (CH3); MS (ESI) m/z 453 (100) (M + H); HRMS
(ESI, TOF) calcd for C22H36N2O6Si·Na (M + Na) 475.2240, found
475.2256.
6-Ethyluridine32 (11b). Compound 11b was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.5:0.5 to 9:1) to give the product
(11b, foam, 0.4389 g, 91%, Rf = 0.18 (CHCl3/MeOH = 9:1)): mp
62−72 °C (lit.32 mp 119−121 °C); 1H NMR (DMSO-d6, 400 MHz) δ
11.25 (s, 1 H), 5.52 (s, 1 H), 5.39 (d, 1 H, J = 3.8 Hz), 5.19 (d, 1 H, J
= 5.3 Hz), 4.94 (d, 1 H, J = 6.3 Hz), 4.63 (t, 1 H, J = 5.7 Hz), 4.55 (dd,
1 H, J = 5.2 and 9.6 Hz), 4.07 (dd, 1 H, J = 6.0 and 12.0 Hz), 3.73−
3.69 (m, 1 H), 3.63−3.58 (m, 1 H), 3.47−3.41 (m, 1 H), 2.56 (q, 2 H,
J = 7.3 Hz), 1.17 (t, 3 H, J = 7.3 Hz); 13C NMR (DMSO-d6, 100
MHz) δ 162.5, 158.3, 150.7, 100.7 (CH), 91.6 (CH), 84.8 (CH), 71.0
(CH), 69.8 (CH), 62.1 (CH2), 25.4 (CH2), 12.4 (CH3); MS (ESI) m/
z 295 (100) (M + Na); HRMS (ESI, TOF) calcd for C11H16N2O6·Na
(M + Na) 295.0906, found 295.0915.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-6-ben-
zyluridine (9i). The reaction was purified by flash column
chromatography (Hex/EtOAc = 7.5:2.5 to 7:3) to give the product
1
(9i, foam, 0.6495 g, 54%, Rf = 0.18 (Hex/EtOAc = 7:3)): H NMR
(CDCl3, 400 MHz) δ 9.57 (bs, 1 H), 7.37−7.28 (m, 3 H), 7.17 (d, 2
H, J = 6.9 Hz), 5.80 (s, 1 H), 5.31 (s, 1 H), 5.16 (d, 1 H, J = 6.4 Hz),
4.78 (dd, 1 H, J = 4.5 and 6.2 Hz), 4.12 (dd, 1 H, J = 6.0 and 10.8 Hz),
3.90 (s, 2 H), 3.81 (d, 2 H, J = 6.3 Hz), 1.46 (s, 3 H), 1.28 (s, 3 H),
0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 163.0,
155.8, 150.6, 133.8, 129.2 (CH), 129.1 (CH), 127.8 (CH), 113.6,
103.9 (CH), 91.5 (CH), 89.5 (CH), 84.1 (CH), 82.0 (CH), 64.2
(CH2), 38.7 (CH2), 27.1 (CH3), 25.9 (CH3), 25.4 (CH3), 18.5, −5.2
(CH3); MS (ESI) m/z 511 (100) (M + Na); HRMS (ESI, TOF) calcd
for C25H36N2O6Si·Na (M + Na) 511.2240, found 511.2234.
6-Isopropyluridine2 (11c). Compound 11c was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.7:0.3 to 9:1) to give the product
(11c, solid, 0.2524 g, 94%). The compound was recrystallized from
MeOH/H2O to give an analytical sample (11c, white solid, 0.1356 g,
50%, Rf = 0.15 (CHCl3/MeOH = 9:1)): mp 161−163 °C (lit.2 mp
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-N3-(p-
methoxybenzyl)-6-ethyluridine (10a). The reaction was purified
by flash column chromatography (Hex/EtOAc = 9.5:0.5 to 9:1) to
give the product (10a, oil, 0.8612 g, 62%, Rf = 0.18 (Hex/EtOAc =
8:2)): 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, 2 H, J = 8.6 Hz), 6.81
(d, 2 H, J = 8.6 Hz), 5.71 (s, 1 H), 5.62 (s, 1 H), 5.17 (dd, 1 H, J = 0.8
and 6.4 Hz), 5.01 (d, 1 H, J = 13.7 Hz), 4.95 (d, 1 H, J = 13.7 Hz),
4.88 (dd, 1 H, J = 4.4 and 6.3 Hz), 4.15−4.11 (m, 1 H), 3.83 (dd, 1 H,
J = 5.4 and 10.7 Hz), 3.77 (s, 3 H), 3.77−3.72 (m, 1 H), 2.58 (q, 2 H, J
1
204−206 °C); H NMR (DMSO-d6, 400 MHz) δ 11.27 (s, 1 H),
5.50−5.49 (m, 2 H), 5.20 (d, 1 H, J = 5.2 Hz), 4.93 (d, 1 H, J = 6.6
Hz), 4.64 (t, 1 H, J = 5.7 Hz), 4.52 (dd, 1 H, J = 5.3 and 9.6 Hz), 4.08
(dd, 1 H, J = 6.4 and 12.7 Hz), 3.72−3.68 (m, 1 H), 3.63−3.58 (m, 1
H), 3.47−3.41 (m, 1 H), 2.98−2.91 (m, 1 H), 1.19 (d, 6 H, J = 6.6
Hz); 13C NMR (DMSO-d6, 100 MHz) δ 163.2, 162.9, 151.3, 98.9
(CH), 91.6 (CH), 85.2 (CH), 71.7 (CH), 70.2 (CH), 62.6 (CH2),
29.4 (CH), 22.4 (CH3), 21.6 (CH3); MS (ESI) m/z 309 (100) (M +
4033
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Article
Na); HRMS (ESI, TOF) calcd for C12H18N2O6·Na (M + Na)
309.1063, found 309.1051. Anal. Calcd for C12H18N2O6: C, 50.35; H,
6.34; N, 9.79. Found: C, 50.51; H, 6.38; N, 9.43.
Hz), 3.99 (d, 1 H, J = 16.6 Hz), 3.93 (d, 1 H, J = 16.7 Hz), 3.65−3.55
(m, 2 H), 3.45−3.39 (m, 1 H); 13C NMR (DMSO-d6, 100 MHz) δ
162.2, 155.6, 150.7, 135.5, 128.9 (CH), 128.8 (CH), 127.1 (CH),
103.3 (CH), 91.8 (CH), 84.7 (CH), 71.1 (CH), 69.7 (CH), 61.9
(CH2), 37.5 (CH2); MS (ESI) m/z 357 (100) (M + Na); HRMS
(ESI, TOF) calcd for C16H17N2O6 (M − H) 333.1087, found
333.1084.
6-tert-Butyluridine (11d). Compound 11d was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.5:0.5 to 9:1) to give the product
(11d, 0.4754 g, 89%). The compound was recrystallized from MeOH/
H2O to give an analytical sample (11d, white solid, 0.2425 g, 47%, Rf =
0.13 (CHCl3/MeOH = 9:1)): mp 181−183 °C; 1H NMR (DMSO-d6,
400 MHz) δ 11.34 (s, 1 H), 5.78 (d, 1 H, J = 2.9 Hz), 5.55 (s, 1 H),
5.15 (d, 1 H, J = 5.0 Hz), 4.92 (d, 1 H, J = 6.8 Hz), 4.59 (t, 1 H, J = 5.7
Hz), 4.52−4.48 (m, 1 H), 4.12 (dd, 1 H, J = 6.8 and 13.5 Hz), 3.69−
3.59 (m, 2 H), 3.49−3.42 (m, 1 H), 1.38 (s, 9 H); 13C NMR (DMSO-
d6, 100 MHz) δ 162.9, 162.7, 151.3, 100.1 (CH), 92.8 (CH), 84.5
(CH), 71.9 (CH), 69.8 (CH), 62.2 (CH2), 35.6, 30.1 (CH3); MS
(ESI) m/z 323 (100) (M + Na); HRMS (ESI, TOF) calcd for
C13H20N2O6·Na (M + Na) 323.1219, found 323.1202. Anal. Calcd for
C13H20N2O6: C, 51.99; H, 6.71; N, 9.33. Found: C, 51.92; H, 6.75; N,
9.54.
3′,5′-Di-O-tert-butyldimethylsilyl-6-cyano-2′-deoxyuridine
(13). Compound 13 was prepared from 3′,5′-di-O-tert-butyldimethyl-
silyl-5-bromo-2′-deoxyuridine20 (12) by the method described for 8a.
The reaction was purified by flash column chromatography (Hex/
EtOAc = 8:2, Rf = 0.23) to give the product (13, white solid, 1.0719 g,
1
2.2251 mmol, 80%): H NMR (CDCl3, 400 MHz) δ 9.59 (bs, 1 H),
6.40 (t, 1 H, J = 7.1 Hz), 6.31 (s, 1 H), 4.43−4.40 (m, 1 H), 3.88−3.83
(m, 3 H), 2.63−2.55 (m, 1 H), 2.28−2.21 (m, 1 H), 0.90 (s, 9 H), 0.89
(s, 9 H), 0.07 (s, 12 H); 13C NMR (CDCl3, 100 MHz) δ 160.2, 148.7,
126.5, 113.8 (CH), 111.2, 88.1 (CH), 85.9 (CH), 71.7 (CH), 63.0
(CH2), 39.2 (CH2), 26.0 (CH3), 25.7 (CH3), 18.5, 17.8, −4.7 (CH3),
−4.9 (CH3); MS (ESI) m/z 504 (100) (M + Na); HRMS (ESI, TOF)
Calcd for C22H38N3O5Si2 (M − H) 480.2350, found 480.2350.
3′,5′-Di-O-tert-butyldimethylsilyl-6-methyl-2′-deoxyuri-
dine33 (14a). To a solution of 13 (0.6756 g, 1.4024 mmol) in THF
(13.7 mL) were slowly added ZnCl2 (1 M solution in Et2O, 0.70 mL,
0.70 mmol, 0.5 equiv) and MeMgBr (1 M solution in THF, 7.01 mL,
7.01 mmol, 5 equiv) at 0 °C. After the addition was completed, the
reaction mixture was stirred for 3 h, and the reaction temperature was
allowed to rise to room temperature. The reaction was quenched with
saturated aqueous NH4Cl solution, and the solvent was removed
under reduced pressure. The solvent was removed under reduced
pressure. The residue was partitioned between CHCl3 and H2O. The
aqueous layer was further extracted with CHCl3. The organic portions
were combined, washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and concentrated under reduced pressure to
dryness. The resulting residue was purified by flash column
chromatography (Hex/EtOAc = 7:3, Rf = 0.17) to give the product
6-n-Butyluridine11 (11e). Compound 11e was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9:1, Rf = 0.24) to give the product
(11e, oil, 0.5746 g, 87%): 1H NMR (DMSO-d6, 400 MHz) δ 11.25 (s,
1 H), 5.52 (s, 1 H), 5.37 (d, 1 H, J = 3.8 Hz), 5.21 (d, 1 H, J = 5.3 Hz),
4.95 (d, 1 H, J = 6.1 Hz), 4.65 (t, 1 H, J = 5.6 Hz), 4.54 (dd, 1 H, J =
5.2 and 9.5 Hz), 4.07 (dd, 1 H, J = 5.8 and 11.6 Hz), 3.73−3.69 (m, 1
H), 3.63−3.58 (m, 1 H), 3.47−3.40 (m, 1 H), 2.55−2.50 (m, 2 H),
1.59−1.52 (m, 2 H), 1.39−1.30 (m, 2 H), 0.90 (t, 3 H, J = 7.3 Hz);
13C NMR (DMSO-d6, 100 MHz) δ 162.6, 157.0, 150.8, 101.6 (CH),
91.9 (CH), 84.9 (CH), 71.1 (CH), 69.9 (CH), 62.1 (CH2), 31.8
(CH2), 29.5 (CH2), 21.6 (CH2), 13.6 (CH3); MS (ESI) m/z 323
(100) (M + Na); HRMS (ESI, TOF) calcd for C13H20N2O6·Na (M +
Na) 323.1219, found 323.1210.
6-Cyclopentyluridine (11f). Compound 11f was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.9:0.1 to 9:1) to give the product
(11f, foam, 0. 3949 g, 62%, Rf = 0.18 (CHCl3/MeOH = 9:1)): mp
1
(14a, white solid, 0.1021 g, 0.2169 mmol, 33%): H NMR (CDCl3,
400 MHz) δ 8.87 (bs, 1 H), 6.09 (t, 1 H, J = 7.0 Hz), 5.52 (s, 1 H),
4.55−4.50 (m, 1 H), 3.84−3.73 (m, 3 H), 2.87−2.81 (m, 1 H), 2.32
(s, 3 H), 2.10−2.04 (m, 1 H), 0.89 (s, 18 H); 0.07 (s, 6 H), 0.06 (s, 3
H), 0.05 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 162.5, 153.7, 150.3,
103.2 (CH), 87.4 (CH), 85.2 (CH), 71.7 (CH), 63.1 (CH2), 38.4
(CH2), 26.0 (CH3), 25.7 (CH3), 20.7 (CH3), 18.5, 17.9, −4.7 (CH3),
−4.8 (CH3), −5.3 (CH3); MS (ESI) m/z 493 (100) (M + Na);
HRMS (ESI, TOF) calcd for C22H43N2O5Si2 (M − H) 471.2711,
found 471.2716.
3′,5′-Di-O-tert-butyldimethylsilyl-6-ethyl-2′-deoxyuridine
(14b). The reaction was purified by flash column chromatography
(Hex/EtOAc = 7:3, Rf = 0.24) to give the product (14b, oil, 0.7066 g,
68%): 1H NMR (CDCl3, 400 MHz) δ 9.51 (bs, 1 H), 5.97 (dd, 1 H, J
= 5.9 and 7.8 Hz), 5.54 (s, 1 H), 4.54−4.50 (m, 1 H), 3.82−3.73 (m, 3
H), 2.98−2.91 (m, 1 H), 2.63−2.56 (m, 2 H), 2.05−1.99 (m, 1 H),
1.23 (t, 3 H, J = 7.3 Hz), 0.88 (s, 18 H); 0.07 (s, 3 H), 0.06 (s, 3 H),
0.04 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 163.3, 158.7, 150.4,
101.1 (CH), 87.9 (CH), 85.1 (CH), 72.4 (CH), 63.7 (CH2), 38.2
(CH2), 26.1 (CH2), 26.0 (CH3), 25.7 (CH3), 18.4, 17.8, 12.4 (CH3),
−4.7 (CH3), −4.8 (CH3), −5.28 (CH3), −5.31 (CH3); MS (ESI) m/z
507 (100) (M + Na); HRMS (ESI, TOF) calcd for C23H44N2O5Si2·Na
(M + Na) 507.2686, found 507.2683.
1
63−70 °C; H NMR (DMSO-d6, 400 MHz) δ 11.27 (s, 1 H), 5.53−
5.52 (m, 2 H), 5.17 (d, 1 H, J = 5.2 Hz), 4.93 (d, 1 H, J = 6.2 Hz), 4.64
(t, 1 H, J = 5.6 Hz), 4.51 (dd, 1 H, J = 5.3 and 9.0 Hz), 4.08 (dd, 1 H, J
= 6.0 and 12.0 Hz), 3.72−3.68 (m, 1 H), 3.63−3.58 (m, 1 H), 3.47−
3.41 (m, 1 H), 3.02−2.95 (m, 1 H), 2.09−1.99 (m, 1 H), 1.99−1.90
(m, 1 H), 1.76−1.46 (m, 6 H); 13C NMR (DMSO-d6, 100 MHz) δ
162.6, 160.2, 150.8, 98.6 (CH), 91.6 (CH), 84.7 (CH), 71.2 (CH),
69.8 (CH), 62.1 (CH2), 40.7 (CH), 32.3 (CH2), 31.4 (CH2), 24.4
(CH2), 24.3 (CH2); MS (ESI) m/z 335 (100) (M + Na); HRMS
(ESI, TOF) calcd for C14H20N2O6·Na (M + Na) 335.1219, found
335.1216.
6-(3-Butenyl)uridine (11g). Compound 11g was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.9:0.1 to 9:1) to give the product
(11g, oil, 0.4593 g, 86%, Rf = 0.15 (CHCl3/MeOH = 9:1)): 1H NMR
(DMSO-d6, 400 MHz) δ 11.26 (s, 1 H), 5.87−5.77 (m, 1 H), 5.53 (s,
1 H), 5.38 (d, 1 H, J = 3.4 Hz), 5.22 (bs, 1 H), 5.12−5.02 (m, 2 H),
4.95 (bs, 1 H), 4.65 (bs, 1 H), 4.56−4.54 (m, 1 H), 4.07 (t, 1 H, J =
6.0 Hz), 3.71 (dd, 1 H, J = 5.9 and 9.3 Hz), 3.60 (dd, 1 H, J = 3.1 and
11.7 Hz), 3.46−3.42 (m, 1 H), 2.64 (t, 2 H, J = 7.3 Hz), 2.40−2.32
(m, 2 H); 13C NMR (DMSO-d6, 100 MHz) δ 162.3, 155.9, 150.7,
136.3 (CH), 116.1 (CH2), 101.9 (CH), 91.7 (CH), 84.8 (CH), 71.0
(CH), 69.8 (CH), 62.0 (CH2), 31.3 (CH2), 31.1 (CH2); MS (ESI) m/
z 321 (100) (M + Na); HRMS (ESI, TOF) calcd for C13H17N2O6 (M
− H) 297.1087, found 297.1091.
3′,5′-Di-O-tert-butyldimethylsilyl-6-(3-butenyl)-2′-deoxyuri-
dine (14g). The reaction was purified by flash column chromatog-
raphy (Hex/EtOAc = 8.5:1.5 to 5:5) to give the product (14g, oil,
1
0.1355 g, 43%, Rf = 0.275 (Hex/EtOAc = 7:3)): H NMR (CDCl3,
400 MHz) δ 9.94 (bs, 1 H), 5.92−5.89 (m, 1 H), 5.82−5.72 (m, 1 H),
5.52 (s, 1 H), 5.11−5.05 (m, 2 H), 4.53−4.49 (m, 1 H), 3.83−3.72
(m, 3 H), 2.99−2.93 (m, 1 H), 2.70−2.56 (m, 2 H), 2.38−2.31 (m, 2
H), 2.04−1.98 (m, 1 H), 0.87 (s, 18 H), 0.064 (s, 3 H), 0.055 (s, 3 H),
0.03 (s, 6 H); 13C NMR (CDCl3, 100 MHz) δ 163.4, 156.4, 150.4,
135.2 (CH), 116.8 (CH2), 102.2 (CH), 88.0 (CH), 85.4 (CH), 72.5
(CH), 63.8 (CH2), 38.1 (CH2), 32.5 (CH2), 31.8 (CH2), 25.9 (CH3),
25.7 (CH3), 18.4, 17.8, −4.8 (CH3), −4.9 (CH3), −5.28 (CH3), −5.32
6-Benzyluridine (11i). Compound 11i was prepared by the
method described for 11a. The reaction was purified by flash column
chromatography (CHCl3/MeOH = 9.5:0.5 to 9:1) to give the product
(11i, foam, 0.2342 g, 83%, Rf = 0.20 (CHCl3/MeOH = 9:1)): mp 64−
1
72 °C; H NMR (DMSO-d6, 400 MHz) δ 11.33 (s, 1 H), 7.39−7.35
(m, 2 H), 7.31−7.25 (m, 3 H), 5.50 (d, 1 H, J = 3.7 Hz), 5.28 (s, 1 H),
5.05 (d, 1 H, J = 5.5 Hz), 4.91 (d, 1 H, J = 6.5 Hz), 4.62 (t, 1 H, J = 5.7
Hz), 4.50 (dd, 1 H, J = 5.5 and 9.7 Hz), 4.06 (dd, 1 H, J = 6.2 and 12.4
4034
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(CH3); MS (ESI) m/z 533 (100) (M + Na); HRMS (ESI, TOF) calcd
for C25H45N2O5Si2 (M − 1) 509.2867, found 509.2897.
REFERENCES
■
6-Methyl-2′-deoxyuridine9 (15a). To a solution of 14a (0.0839
g, 0.1782 mmol) in THF (1.7 mL) was added TBAF (1 M in THF,
0.39 mL, 2.2 equiv) at room temperature. The solution was stirred at
room temperature for 5 h. The solvent was removed under reduced
pressure. The resulting residue was purified by flash column
chromatography (CHCl3/MeOH = 9:1, Rf = 0.11) to give the
product (15a, oil, 0.0375g, 0.1548 mmol, 87%): 1H NMR (DMSO-d6,
400 MHz) δ 11.16 (s, 1 H), 6.05 (dd, 1 H, J = 6.1 and 8.0 Hz), 5.50 (s,
1 H), 5.13 (d, 1 H, J = 5.0 Hz), 4.65 (t, 1 H, J = 5.6 Hz), 4.29−4.23
(m, 1 H), 3.64−3.57 (m, 2 H), 3.50−3.44 (m, 1 H), 2.72−2.65 (m, 1
H), 2.28 (s, 3 H), 2.04−1.98 (m, 1 H); 13C NMR (DMSO-d6, 100
MHz) δ 162.3, 153.7, 150.6, 102.3 (CH), 87.1 (CH), 84.7 (CH), 70.3
(CH), 61.7 (CH2), 37.6 (CH2), 19.8 (CH3); MS (ESI) m/z 265 (100)
(M + Na); HRMS (ESI, TOF) calcd for C10H13N2O5 (M − H)
241.0824, found 241.0828.
(1) (a) Bello, A. M.; Konforte, D.; Poduch, E.; Furlonger, C.; Wei, L.;
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6-Ethyl-2′-deoxyuridine9,32 (15b). Compound 15b was pre-
pared by the method described for 15a. The reaction was purified by
flash column chromatography (CHCl3/EtOH = 95:5, Rf = 0.05) to
(4) Schweizer, M. P.; Witkowski, J. T.; Robins, R. K. J. Am. Chem. Soc.
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1
give the product (15b, oil, 0.2067 g, 91%): H NMR (DMSO-d6, 400
MHz) δ 11.16 (s, 1 H), 5.97 (dd, 1 H, J = 5.7 and 8.1 Hz), 5.46 (s, 1
H), 5.14 (d, 1 H, J = 5.0 Hz), 4.61 (t, 1 H, J = 5.6 Hz), 4.31−4.25 (m,
1 H), 3.63−3.57 (m, 2 H), 3.50−3.43 (m, 1 H), 2.74−2.69 (m, 1 H),
2.63−2.56 (m, 2 H), 2.06−2.00 (m, 1 H), 1.13 (t, 1 H, J = 7.3 Hz);
13C NMR (DMSO-d6, 100 MHz) δ 163.1, 159.0, 151.1, 100.9 (CH),
87.9 (CH), 85.2 (CH), 71.1 (CH), 62.5 (CH2), 38.1 (CH2), 25.8
(CH2), 12.9 (CH3); MS (ESI) m/z 255 (M − H); HRMS (ESI, TOF)
calcd for C11H15N2O5 (M − H) 255.0981, found 255.0983.
891.
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give the product (15g, oil, 0.0139 g, 68%, Rf = 0.23 (CHCl3/EtOH =
4755.
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Synlett 2007, 111.
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1
9:1)): H NMR (DMSO-d6, 400 MHz) δ 11.18 (bs, 1 H), 6.00−5.94
(m, 1 H), 5.88−5.74 (m, 1 H), 5.48 (s, 1 H), 5.15−5.01 (m, 3 H), 4.61
(t, 1 H, J = 5.6 Hz), 4.31−4.24 (m, 1 H), 3.68−3.56 (m, 2 H), 3.50−
3.42 (m, 1 H), 2.75−2.65 (m, 3 H), 2.34−2.26 (m, 2 H), 2.09−2.00
(m, 1 H); 13C NMR (DMSO-d6, 100 MHz) δ 162.4, 156.2, 150.6,
136.5 (CH), 116.2 (CH2), 101.7 (CH), 87.4 (CH), 84.8 (CH), 70.6
(CH), 62.0 (CH2), 37.8 (CH2), 31.4 (CH2), 31.2 (CH2); MS (ESI)
m/z 305 (100) (M + Na); HRMS (ESI, TOF) calcd for
C13H18N2O5·Na (M + Na) 305.1113, found 305.1115.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of all synthesized
compounds and X-ray structural data of compounds 4 and
11d (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tcchien@ntnu.edu.tw.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(25) Botta, M.; Saladino, R.; delle Monache, G.; Gentile, G.;
Nicoletti, R. Heterocycles 1996, 43, 1687.
This work was supported by Research Grant Nos. 100-2113-M-
003-007-MY2 and 97-2113-M-003-001-MY2 from the National
Science Council, Taiwan, and NTNU100-D-06 from National
Taiwan Normal University. We also thank Mr. Ting-Shen Kuo
for his assistance with X-ray crystallographic analysis.
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2013, 69, 1387.
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DEDICATION
■
This paper is dedicated to Professor Leroy B. Townsend on the
occasion of his 80th birthday.
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dx.doi.org/10.1021/jo400364p | J. Org. Chem. 2013, 78, 4027−4036

The Journal of Organic Chemistry
Article
(33) Armstrong, R. W.; Gupta, S.; Whelihan, F. Tetrahedron Lett.
1989, 30, 2057.
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dx.doi.org/10.1021/jo400364p | J. Org. Chem. 2013, 78, 4027−4036