Hydrogermylation of 5-ethynyluracil nucleosides: Formation of 5-(2-germylvinyl)uracil and 5-(2-germylacetyl)uracil nucleosides

Article abstract of DOI:10.1021/jo400590z

A stereoselective radical-mediated hydrogermylation of the protected 5-ethynyluracil nucleosides with trialkyl-, triaryl,- or tris(trimethylsilyl) germanes gave (Z)-5-(2-germylvinyl)uridine, 2′-deoxyuridine, or ara-uridine as major products. Reaction of the β-triphenylgermyl vinyl radical intermediate with oxygen and fragmentation of the resulting peroxyradical provided also 5-[2-(triphenylgermyl)acetyl]pyrimidine nucleosides in low to moderate yields. Thermal isomerization of the latter in MeOH occurred via a four-centered activated complex, and subsequent hydrolysis of the resulting O-germyl substituted enol yielded 5-acetyluracil nucleosides in quantitative yield.

Full text of DOI:10.1021/jo400590z

Note
pubs.acs.org/joc
Hydrogermylation of 5‑Ethynyluracil Nucleosides: Formation of 5‑(2-
Germylvinyl)uracil and 5‑(2-Germylacetyl)uracil Nucleosides
Yong Liang, Jean-Philippe Pitteloud,† and Stanislaw F. Wnuk*
Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States
S
* Supporting Information
ABSTRACT: A stereoselective radical-mediated hydrogermy-
lation of the protected 5-ethynyluracil nucleosides with trialkyl-,
triaryl,- or tris(trimethylsilyl)germanes gave (Z)-5-(2-
germylvinyl)uridine, 2′-deoxyuridine, or ara-uridine as major
products. Reaction of the β-triphenylgermyl vinyl radical
intermediate with oxygen and fragmentation of the resulting
peroxyradical provided also 5-[2-(triphenylgermyl)acetyl]-
pyrimidine nucleosides in low to moderate yields. Thermal
isomerization of the latter in MeOH occurred via a four-centered activated complex, and subsequent hydrolysis of the resulting
O-germyl substituted enol yielded 5-acetyluracil nucleosides in quantitative yield.
broad spectrum of biological activity has been described
for 5-substituted pyrimidine nucleosides.1 One especially
the renowned antitumor drug Ftorafur.17 The 5-trimethylgerm-
yl-2′-deoxyuridine, which is one of the few known examples of
germanium-containing nucleoside analogues, was shown to
inhibit HSV-1 replication in vitro and block incorporation of
thymidine into DNA of cancer ovarian cells.18
A
potent and selective antiviral drug of this class is (E)-5-(2-
bromovinyl)-2′-deoxyuridine (BVDU).2 Pronounced cytotoxity
and significant antiviral activity have been reported for 1-(β-D-
arabinofuranosyl)-5-ethenyluracil3 and 5-ethynyl-2′-deoxyuri-
dine.4 The synthesis of the numerous 5-substituted pyrimidine
nucleosides via Pd-assisted routes have been reviewed.5
The (E)-5-[2-(tributylstannyl)vinyl]uracil nucleosides, pre-
pared by coupling of (E)-1,2-bis(tributylstannyl)ethene with 5-
iodoracil precursors6 or via radical hydrostannylation of 5-
ethynyluracil precursors,7,8 have been developed as convenient
substrates for a mild and rapid radiohalogenation via
halodestannylation reactions.6−9 However, the tendency of
(E)-5-[2-(tributylstannyl)vinyl]arabinosyluridine8 and 5-trime-
thylstannyl araU9 to protiodestannylation was noted.
Pd(0)-catalyzed,19,20 Lewis acid-promoted,21,22 radical-medi-
ated,23 and ultrasound- and microwave-accelerated24 hydro-
germylation of alkynes provide vinylgermanes with high regio
and stereoselectivity. Germyldesulfonylation protocols has been
also developed for the synthesis of vinyl- and (α-fluoro)-
vinylgermanes.25 Herein, we report that hydrogermylation of
the 5-ethynyluracil nucleosides with trialkyl-, triaryl,- and
tris(trimethylsilyl)germanes in addition to the expected 5-(2-
germylvinyl)uracil nucleosides provides also access to 5-(2-
germylacetyl)uracil nucleosides which can be converted to 5-
acetyluracil products.
The 5-[2-(trimethylsilyl)ethynyl]uracil nucleosides, prepared
by Sonogashira coupling reactions between protected 5-
iodoracil nucleosides with (trimethylsilyl)acetylene,5,10 have
been hydrogenated to give (Z)-5-[2-(trimethylsilyl)vinyl]uracil
products.11 Solvent-dependent isomerization of the latter into
the E isomer was observed.10 The (E)-5-[2-(trimethylsilyl)-
vinyl]-2′-deoxyuridine has been also prepared by direct Pd-
catalyzed coupling of (E)-2-(tributylstannyl)-1-(trimethylsilyl)-
ethene with protected 5-iodo-2′-deoxyuridine.12 The 5-vinyl
silanes were converted to 5-(2-halovinyl)uracil products upon
treatment with XeF2 and metal halides11 and were also utilized
for the radioiodination via iododesilylations reactions10,12
The chemistry13 and biological activity of organogermanium
compounds have been reviewed.14,15 A few biologically active
germane-modified nucleoside analogues have been developed.
Among them, the 5-trimethylgermyluracil and 1-(2-tetrahy-
drofuranyl)-5-trimethylgermyluracil exhibit cytotoxicity to
melanoma B16 cells.16 The 1-(2-tetrahydrofuranyl)-6-trialkyl-
germyl-5-fluorouracil derivatives have caused inhibition of DNA
and RNA biosynthesis in Frhk cells almost twice as efficiently as
Several hydrogermylation approaches for the preparation of
5-(2-germylvinyl)uracil nucleosides of type 2 were initially
tested. Thus, treatment of the acetyl protected 1-(β-D-
arabinofuranosyl)-5-ethenyluracil26 1 with Ph3GeH in the
presence of 1,1′-azobis(cyclohexanecarbonitrile) (ACCN), as
radical initiator, in toluene at 90 °C (method A) produced
predominantly the Z-vinylgermanes 2a (E/Z, 5:95; Scheme 1).
1
The H NMR spectra established the configuration for E-2a (J
= 18.8 Hz) and Z-2a (J = 13.5 Hz) diastereomers. The
formation of the Z isomer as the major product was in
agreement with the expected23 anti-addition of germyl radical
to the triple bond. Careful purification of the reaction mixture
on a silica gel column gave not only pure Z-2a (47%) but also
led to the isolation of a new product, whose structure was
assigned (vide infra) as 5-[2-(triphenylgermyl)acetyl]uracil (β-
germyl ketone) derivative 4a (12%; Table 1, entry 1).
Received: March 24, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
lower stereoselectivity. Moreover, no 5-[2-(trialkylgermyl)-
acetyl] product 4b was isolated from the reaction mixture.
Hydrogermylation of 1 with reactive (Me3Si)3GeH (ACCN/
toluene/90 °C) stereoselectively produced the 5-[2-(TTMS-
germyl)ethenyl]uracil analogue Z-2c (68%) in a shorter
reaction time, though the acyl product 4c was also not isolated
(30 min, entry 7). Deacetylation of Z-2a with NH3/MeOH
afforded Z-3a (86%).
Scheme 1. Hydrogermylation of 1-(β-D-Arabinofuranosyl)-5-
ethenyluracil 1 with Germane Hydrides
a
The Et3B-promoted hydrogermylation of the toluoyl
protected of 5-ethynyluridine 5 with Ph3GeH/Et3B at −78
°C showed a slow conversion to 7a but warming of the reaction
mixture to 0 °C afforded vinyl triphenylgermane Z-7a (40%)
together with the 5-[2-(triphenylgermyl)acetyl] product 11a
(13%, Scheme 2; entry 8). Analogous hydrogermylation of 5
a
Reagents and conditions: (a) R3GeH/(ACCN)/toluene/90 °C
(method A), R3GeH/Et3B/THF/−78 °C (method B), or Pd-
(PPh3)4/THF/rt (method C); (b) NH3/MeOH/rt.
Scheme 2. Hydrogermylation of 5-Ethenyluridine 5 and 2′-
a
Deoxy-5-ethenyluridine 6 with Germane Hydrides
Analogous treatment of 1 with Ph3GeH without ACCN also
yielded 2a and 4a (entry 2).
The Et3B-promoted addition27 of Ph3GeH to 1 in THF at
low temperature (method B) gave Z-2a as the sole isolated
product (55%, entry 3). However, analogous hydrogermylation
of 1 at higher temperature (0 °C/6 h) afforded Z-2a and 4a
(∼3:2, entry 4). Hydrogermylation of 1 with Ph3GeH in the
22
presence of B(C6F5)3 in CH2Cl2 at ambient temperature
produced 2a in lower than 10% yields (TLC, H NMR) while
1
prolonged heating (48 h, reflux) produced a complex reaction
mixture. The Pd(PPh3)4-catalyzed hydrogermylation19 of 1
with Ph3GeH in THF afforded a mixture of the expected E-
isomer of 2a and the corresponding 5-[1-(triphenylgermyl)-
ethenyl] regioisomer, produced by addition of germyl radical to
α-carbon,19 in 3:2 ratio and 73% overall yield (entry 5; method
C). The acyl product 4a was not isolated from the reaction
catalyzed by Pd(PPh3)4.
a
Reagents and conditions: (a) Ph3GeH/(ACCN)/toluene/(THF or
DMF)/90 °C or R3GeH/Et3B/THF/−78 °C; (b) MeONa/MeOH/
rt; (c) NH3/MeOH/rt.
At low temperature (−78 °C), Et3B-promoted hydro-
germylation27 of 1 with less reactive trimethylgermane failed
to give vinylgermane 2b. However, at ambient temperature the
hydrogermylation yielded 2b (E/Z, 15:85; entry 6) although in
with Me3GeH/Et3B at ambient temperature yielded only vinyl
trimethylgermane 7b (E/Z, 45:55; entry 9). Deprotection of
E/Z-7b with MeONa/MeOH afforded uridine analogue E/Z-
Table 1. Hydrogermylation of 5-Ethynyluracil and Related Nucleosides with Germane Hydrides
vinylgermanes
germyl ketones
a
b
b
b
entry
substrate
method
A
temp (°C)
90
R3GeH
Ph3GeH
product
yield (%)
ratio (E/Z)
product
yield (%)
c
1
1
2a
47
60
55
28
45
40
68
40
41
61
33
35
27
34
86
52
0:100
3:97
4a
4a
12
15
d
2
1
A
90
Ph3GeH
Ph3GeH
Ph3GeH
Ph3GeH
Me3GeH
(Me3Si)3GeH
Ph3GeH
Me3GeH
Ph3GeH
Ph3GeH
Me3GeH
Ph3GeH
Ph3GeH
Ph3GeH
Ph3GeH
2a
2a
2a
3
1
B
B
C
B
A
B
B
B
−78 → −60
0
0:100
0:100
100:0
15:85
0:100
0:100
45:55
0:100
0:100
40:60
0:100
0:100
100:0
0:100
4
1
4a
19
e
5
1
25
2a
6
1
0 → 25
90
2b
f
7
1
2c
8
5
−78 → 0
0 → 25
−78 → 0
7a
7b
9a
11a
13
9
5
10
11
12
13
14
15
16
6
12a
12a
12
17
g
h
i
6
A
100
9a
6
B
A
0 → 25
90
9b
14
14
14
14
13
13
13
13
15
15
13
20
d
A
100
100
0
d,j
A
B
a
b
Method A: R3GeH/ACCN/toluene/90 or 100 °C. Method B: R3GeH/Et3B/THF/−78 or 0 °C. Method C: Pd(PPh3)4/THF/rt. For the isolated
c
d
e
products. Crude reaction mixture (E/Z-2a, 5:95). Without ACCN. In addition to E-2a, the α-addition product was formed (∼3:2, 73% overall).
f
g
h
i
Crude reaction mixture (E/Z-2c, 4:96). Toluene/THF (20:1, v/v) was used as solvent. Oil bath. With toluene/DMF/H2O (20:1:0.1, v/v/v) as
j
solvents E-9a, Z-9a and 12a (∼2:2:1, 40% overall) were obtained. With addition of 25 μL of H2O (14 equiv).
B
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8b (71%), confirming stability28 of the C(sp2)-Ge(alkyl)3 bond
in basic conditions.
Ph3GeH in “moist” toluene interestingly yielded only the syn-
addition product E-14 (86%, entry 15; see also entry 11,
footnote i). Hydrogermylation of 13 with Ph3GeH in the
presence of Et3B/THF at 0 °C produced Z-14 as a sole product
(entry 16).
Hydrogermylation of the toluoyl protected 5-ethynyl-2′-
deoxyuridine 6 with Ph3GeH/Et3B produced the vinyl-
triphenylgermane Z-9a (61%) along with the 5-[2-
(triphenylgermyl)acetyl] product 12a (12%, entry 10). Treat-
ment of 6 with Ph3GeH/ACCN in toluene/THF (20:1, v/v)
also yielded Z-9a and 12a (entry 11). Interestingly, analogous
hydrogermylation of 6 in toluene/DMF with addition of a
“measured” amount of water (14 equiv.) produced mixture of
E/Z isomers of 9a (∼1:1) as well as 12a (entry 11, footnote i;
DMF or THF were added to increase solubility of 6 in reaction
mixture). Deprotection of Z-9a with NH3/MeOH provided 2′-
deoxyuridine analogue Z-10a (65%). Treatment of 6 with
Me3GeH/Et3B gave E/Z-9b (entry 12), but once again
hydrogermylation with alkylgermanes did not yield the germyl
ketone product.
Treatment of E/Z-9b (40:60) with N-bromosuccinimide
(NBS) followed by deprotection (NH3/MeOH) afforded a
mixture of 5-(2-bromovinyl)-2′-deoxyuridines (E/Z, ∼2:3;
70%) illustrating a potential application of vinyl 5-[2-
(trimethylgermyl)vinyl]uracil nucleosides toward the synthesis
of 5-(2-halovinyl) analogues with possible applications for
radiolabeling. Stereoselective halodegermylation of vinyl
trialkylgermanes with NBS or NIS with retention of the
double-bond geometry is known.22,28,29 It is also worth
mentioning that substitution of the trialkylgermyl group on
an sp2 carbon29,30 (as well as sp carbon30,31) with a halogen
proceed not only more easily than the substitution of the
corresponding trialkylsilyl group but also with improved
stereochemical outcome.
The structures of the (triphenylgermyl)methyl ketone (β-
germyl ketone) products were established by spectroscopic
1
analysis. Thus, the H NMR spectrum of 11a confirmed the
absence of the vinyl unit, whereas two upfield shifted doublets
at 3.76 and 3.87 ppm (J = 9.0 Hz) supported the presence of
the C(O)CH2Ge moiety. The peak at 193.3 ppm in the 13C
NMR spectrum of 11a confirmed the presence of the ketone.
The HMBC and NOE correlations also supported the
proposed structures (Figure S1, Supporting Information).
The (+)ESI-MS analyses of 15 produced the [M + Na]+ ion
as the predominant peak. The (−)ESI-MS/MS product ion
spectrum of [M − H]− (m/z 547 [74Ge]) showed a loss of 43u
(CONH) as the most abundant product ion (m/z 504[74Ge]).
Formation of the β-germyl ketones (e.g., 15) probably
involves an initial attack of the triphenylgermyl radical at the
triple bond of 13 to give a vinylic radical 16 (Figure 1).
It is noteworthy that hydrogermylation of the alkyl- or
arylalkynes usually provides vinylgermanes in high yields, while
the formation of the corresponding β-germyl ketones have not
been observed.23,24,27,32 We reexamined the hydrogermylation
of phenylacetylene with Ph3GeH under conditions described in
methods A and B and found no formation of the β-germyl
ketones. We also found that hydrostannylation and hydro-
silylation of alkyne 5 with Ph3SnH and Ph3SiH under analogous
conditions failed to yield 5-[2-(triphenylstannyl- or -silyl)acyl]
products of type 11a suggesting that the formation of 5-
acyluracil products is selective for germane hydrides. Intrigued
by this interesting finding, we have examined the chemistry
involving the formation of 5-ketopyrimidine nucleosides (e.g.,
4a, 11a, or 12a) employing 1-N-benzyl-5-ethynyluracil 13 as a
model substrate. Thus, hydrogermylation of the readily
available33,34 13 with Ph3GeH/ACCN in toluene (90 °C/2
h) produced the Z-vinylgermane 14 and germyl ketone 15
(∼2:1, entry 13; Scheme 3). Analogous treatment of 13 with
Ph3GeH in toluene without ACCN yielded Z-14 and 15 in 34%
and 20% yields (entry 14), whereas similar reaction of 13 with
Figure 1. Plausible pathway for the formation of β-germyl ketone 15
during radical hydrogermylation of alkyne 13 with Ph3GeH.
Abstraction of hydrogen from triphenylgermane in an anti
fashion would produce Z-vinylgermane 14 as a major product
while the syn addition could produce the E isomer (path a).
Reaction of radical 16 with residual oxygen present in the
reaction mixture might lead to peroxyl radical 17 which should
abstract hydrogen from germane hydride35 to produce
hydroperoxide. The latter can be converted to enol 18,
probably by radical mechanism, and undergo tautomerization
to yield the conjugated β-germyl ketone 15 (path b).
a
Scheme 3. Hydrogermylation of the 5-Ethenyluracil 13
Efforts have been made to further optimize conditions for the
preparation of 15 (and 14) from the reaction of 13 with
Ph3GeH. Thus, experiments under Ar vs N2 vs atmospheric
conditions as well as using dry vs reagent-grade toluene vs
“moist” toluene (with the added measured amount of H2O or
D2O) did not improve the yield of 15. In fact, they led mainly
to the formation of Z-14 or E/Z-14 and 15 albeit in different
yields and ratios. It is noteworthy that treatment of 13 with
a
Reagents and conditions: (a) Ph3GeH/(ACCN)/toluene/(H2O)/
100 or 90 °C or Ph3GeH/Et3B/THF/0 °C.
C
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
with N2 for 30 min. The mixture was then preheated at 80 °C, and
Ph3GeH (50 mg, 0.16 mmol) and ACCN (4 mg, 0.02 mmol) were
added. The temperature was increased to 90 °C, and the solution was
stirred until 1 was completely consumed (TLC; 14 h). The volatiles
were removed in vacuo, and the residue was chromatographed
(hexane/EtOAc, 2:3) to give a separable mixture of Z-2a (43 mg,
Ph3GeH in oxygenated toluene resulted in the recovery of
unchanged 13. Optimal conditions for the formation of β-
germyl ketones would require very low rate of initiation and
very low and nearly constant concentration of Ph3GeH and
oxygen, which would allow the germyl radical to react with the
vinyl group rather than oxygen and the vinylic radical 16 to
react with oxygen rather than germane. Still our experiments
employing slow addition of Ph3GeH via syringe-pump over 24
h did not improve the yield of 15.
During recrystallization of the crude 15 from MeOH, we
noticed the formation of a new byproduct whose structure was
established as 5-acetyl-1-N-benzyluracil 20 both spectroscopi-
cally and by comparison with a sample of 20 that was
independently synthesized by acid-catalyzed hydration36 of 13.
We found that heating of 15 in MeOH gave the 5-acetyl
product 20 quantitatively. Conversion of (triphenylgermyl)-
methyl ketone 15 to methyl ketone 20 most probably involves
intramolecular thermal isomerization which proceedes via a
four-centered activated complex. Hydrolysis of the resulting O-
germyl substituted enol 19 led to ketone 20 (Figure 2).
1
47%) and 4a (11 mg, 12%). Z-2a: H NMR δ 1.99 (s, 3H), 2.09 (s,
3H), 2.11 (s, 3H), 3.70 (dd, J = 13.7, 7.7 Hz, 1H), 3.91−3.98 (m, 2H),
4.97 (dd, J = 3.2, 2.0 Hz, 1H), 5.27 (dd, J = 4.1, 1.9 Hz, 1H), 5.71 (d, J
= 4.1 Hz, 1H), 6.56 (d, J = 13.5 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H),
7.36−7.52 (m, 16H), 8.30 (br s, 1H); 13C NMR δ 20.4, 20.6, 20.7,
62.3, 74.6, 76.1, 79.8, 84.4, 113.4, 128.4, 129.1, 131.7, 134.8, 136.38,
136.41, 138.2, 148.6, 161.3, 168.5, 169.4, 170.2; MS m/z 701 (100,
MH+, 74Ge), 699 (71, MH+, 72Ge) 698 (51, MH+, 70Ge). Anal. Calcd
for C35H34GeN2O9·0.25EtOH (710.81): C, 59.99; H, 5.03; N, 3.94.
1
Found: C, 59.63; H, 4.92; N, 4.00. H NMR of the crude reaction
mixture also showed presence (∼5%) of the E-2a with the
characteristic peaks at δ 6.31 (d, J = 4.0 Hz, H1′), 6.69 (d, J = 18.8
Hz, CH).
Compound 4a: 1H NMR δ 1.90 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H),
3.48 (d, J = 9.3 Hz, 1H), 4.16−4.19 (m, 1H), 4.17 (d, J = 9.3 Hz, 1H),
4.33 (dd, J = 12.1, 4.5 Hz, 1H), 4.44 (dd, J = 12.1, 4.9 Hz, 1H), 5.12
(dd, J = 3.3, 1.6 Hz, 1H), 5.33 (dd, J = 4.1, 1.6 Hz, 1H), 6.23 (d, J =
4.1 Hz, 1H), 7.21−7.55 (m, 15H), 8.08 (s, 1H), 8.49 (br s, 1H); 13C
NMR δ 20.4, 20.7, 20.8, 33.0, 62.4, 74.6, 76.6, 80.8, 83.9, 113.3, 128.4,
129.5, 135.1, 135.3, 146.6, 148.8, 160.4, 168.8, 169.6, 170.8, 194.2;
HRMS calcd for C35H3474GeN2NaO10 [M + Na]+ 739.1323, found
739.1311.
Method B. Et3B (1M/THF; 140 μL, 0.14 mmol) was added to a
stirred solution of 1 (50 mg, 0.127 mmol) and Ph3GeH (43 mg, 0.14
mmol) in anhydrous THF (5 mL) placed in screw-capped glass tube at
−78 °C. After 3 h, when TLC showed appearance of less polar spot,
and the reaction mixture was warmed up to −60 °C and was stirred for
1.5 h. The volatiles were evaporated, and the residue was
chromatographed (hexane/EtOAc, 2:3) to give Z-2a (49 mg, 55%)
as a white powder after crystallization from hexane/Et2O.
Figure 2. Plausible pathway for the thermal degradation of β-germyl
ketone 15.
Analogous thermal rearrangements of the β-silylketones into O-
silyl substituted enols have been reported.37 Heating 15 in
MeOD or MeOH-d4 provided quantitatively 1-deuteriomethyl
ketone 21, which supports the proposed degradation pathway.
In summary, we have demonstrated that radical hydro-
germylation of the 5-acetylenic derivatives of protected uracil,
uridine, 2′-deoxyuridine, and 1-(β-D-arabinofuranosyl)uracil
analogues with triphenylgermane in toluene at elevated
temperature provided vinylgermanes in good yields and high
Z-stereoselectivity. The E isomers can be formed in the
presence of an added “measured” amount of water. Hydro-
germylation of 5-ethynyluracil nucleosides with triphenylger-
mane in addition to vinylgermanes produced also 5-[2-
(triphenylgermyl)acetyl]uracil nucleosides in yields up to
20%. Thermolysis of the latter in MeOH afforded quantitatively
5-acetyluracil nucleosides via hydrolysis of the O-germyl
substituted enols. The Et3B-promoted hydrogermylation of 5-
ethynyluracil nucleosides with trimethylgermane in THF at low
temperature gave E/Z mixture of vinylgermanes. Bromode-
germylation of vinyl trimethylgermanes with NBS provides
access to 5-(2-bromovinyl) analogues.
Method C. Ph3GeH (59 mg, 0.2 mmol) and Pd(PPh3)4 (8 mg,
0.08) were added to a stirred suspension of 1 (70 mg, 0.18 mmol) in
THF (3 mL) in a flamed-dried round bottle flask at rt under N2. After
5 h, the volatiles were evaporated in vacuo, and the residue was
chromatographed (hexane/EtOAc, 1:1) to give inseparable mixture of
the E-isomer of 2a and the α-addition product (90 mg, 73%; E-2a/α-
addition product, 3:2): MS (ESI) m/z 701 (100, MH+, 74Ge), 699 (70,
1
MH+, 72Ge), 697 (50, MH+, 70Ge). E-2a: H NMR δ 1.88 (s, 3H),
1.98 (s, 3H), 2.14 (s, 3H), 4.23 (m, 2H), 4.35−4.39 (m, 1H), 5.09
(dd, J = 3.4, 1.5 Hz, 1H), 5.43 (dd, J = 3.9, 1.5 Hz, 1H), 6.31 (d, J =
4.0 Hz, 1H), 6.69 (d, J = 18.8 Hz, 1H), 7.33−7.55 (m, 16H), 7.60 (s,
1H), 9.29 (br s, 1H). The α-addition product 1-(2,3,5-tri-O-acetyl-β-D-
arabinofuranosyl)-5-[1-(triphenylgermyl)ethenyl]uracil: 1H NMR δ
1.80 (s, 3H), 2.07 (s, 3H), 2.11 (s, 3H), 4.00−4.23 (m, 2H), 4.45−
4.49 (m, 1H), 4.98 (dd, J = 3.5, 1.9 Hz, 1H), 5.35 (dd, J = 4.1, 1.5 Hz,
1H), 5.72 (d, J = 2.0 Hz, 1H), 6.17 (d, J = 4.1 Hz, 1H), 6.41 (d, J = 2.0
Hz, 1H), 7.33−7.55 (m, 16H), 8.98 (br s, 1H).
1-(2,3,5-Tri-O-acetyl-β-D-arabinofuranosyl)-5-(E/Z)-[2-
(trimethylgermyl)ethenyl]uracil (2b). Nucleoside 1 (50 mg, 0.13
mmol) was treated with Me3GeH (30 mg, 29.6 μL, 0.25 mmol) in dry
THF (5 mL) as described in method B (with injection of Me3GeH
into the reaction mixture via syringe and progressive warming from 0
°C to rt) for 14 h. The volatiles were removed under reduced pressure,
and the residue was chromatographed (hexane/EtOAc, 2:3) to give E/
1
Z-2b (27 mg, 40%; E/Z, 15:85): H NMR δ 0.26 (s, 7.65H), 0.28 (s,
EXPERIMENTAL SECTION
■
1H (Me4Si) NMR spectra at 400 MHz and 13C (Me4Si) at 100.6 MHz
were determined in CDCl3 unless otherwise noted. Mass spectra (MS)
were obtained with atmospheric pressure chemical ionization (APCI)
technique and HRMS in ESI TOF mode unless otherwise noted.
1-(2,3,5-Tri-O-acetyl-β-D-arabinofuranosyl)-5-(E/Z)-[2-
(triphenylgermyl)ethenyl]uracil (2a) and 1-(2,3,5-Tri-O-acetyl-
β-D-arabinofuranosyl)-5-[2-(triphenylgermyl)acetyl]uracil (4a).
Method A. Nucleoside 126 (50 mg, 0.13 mmol) was added to freshly
distilled toluene (6 mL) and the suspension was stirred and degassed
1.35H), 2.02 (s, 3H), 2.12 (s, 2.55H), 2.15 (s, 0.45H), 2.16 (s, 2.55H),
2.17 (s, 0.45H), 4.19−4.25 (m, 1H), 4.34 (dd, J = 11.9, 6.2 Hz,
0.85H), 4.37−4.45 (m, 0.15H), 4.44 (dd, J = 11.9, 4.2 Hz, 0.85H),
4.52 (dd, J = 11.9, 6.2 Hz, 0.15H), 5.11 (dd, J = 3.8, 1.4 Hz, 0.85H),
5.15 (dd, J = 3.4, 1.6 Hz, 0.15H), 5.44−5.48 (m, 1H), 6.10 (d, J = 13.8
Hz, 0.85H), 6.24 (d, J = 3.8 Hz, 0.85H), 6.33 (d, J = 4.0 Hz, 0.15H),
6.60 (d, J = 18.9 Hz, 0.15H), 6.80 (d, J = 19.0 Hz, 0.15H), 6.98 (dd, J
= 13.8, 1.0 Hz, 0.85H), 7.45 (d, J = 1.0 Hz, 0.85H), 7.59 (s, 0.15H),
8.97 (br s, 0.15H), 9.09 (br s, 0.85H); 13C NMR δ −1.7, −0.2, 20.5,
D
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
20.6, 20.8, 20.87, 20.92, 62.7, 63.2, 74.7, 74.8, 76.4, 76.5, 80.4, 80.8,
84.6, 112.9, 114.2, 132.1, 133.6, 134.3, 136.1, 136.4, 137.6, 149.2,
149.6, 161.8, 162.2, 168.6, 168.7, 169.7, 169.8, 170.5; HRMS calcd for
C20H2874GeNaN2O9 [M + Na]+ 537.0899, found 537.0888.
J = 8.0 Hz, 2H), 7.31−7.55 (m, 15H), 7.80 (d, J = 8.2 Hz, 4H), 7.96
(d, J = 8.2 Hz, 2H), 8.09 (br s, 1H); 13C NMR δ 21.67, 21.69, 21.72,
63.5, 70.5, 73.6, 79.9, 89.8, 115.0, 125.9, 126.0, 126.7, 128.5, 129.1,
129.2, 129.3, 129.7, 129.8, 129.9, 131.4, 134.7, 136.6, 137.0, 138.2,
144.2, 144.4, 144.5, 148.8, 161.4, 165.0, 165.1, 166.1; HRMS calcd for
C53H4674GeN2NaO9 [M + Na]+ 951.2307, found 951.2315.
1-(2,3,5-Tri-O-acetyl-β-D-arabinofuranosyl)-5-(Z)-[2-(tris-
(trimethylsilyl)germyl)ethenyl]uracil (2c). Nitrogen gas was
bubbled through a heterogeneous mixture of 1 (127 mg, 0.32
mmol) in dry toluene (10 mL) for 30 min. The suspension was
preheated to 90 °C (∼5 min), and (Me3Si)3GeH (115 mg, 123 μL,
0.39 mmol) was added via syringe followed by ACCN (8 mg, 0.04
mmol) dissolved in degassed toluene (1 mL). The reaction mixture
was heated at 90 °C for 30 min. Volatiles were evaporated, and the
residue was chromatographed (hexane/EtOAc, 3:2) to give Z-2c (152
Compound 11a had: UV (MeOH) λmax = 282 nm; 1H NMR δ 2.35
(s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 3.76 (d, J = 9.0 Hz, 1H), 3.87 (d, J
= 9.0 Hz, 1H), 4.67−4.75 (m, 3H), 5.66 (dd, J = 5.9, 5.1 Hz, 1H), 5.83
(“t”, J = 5.7 Hz, 1H), 6.01 (d, J = 5.0 Hz, 1H), 7.16−7.55 (m, 21H),
7.83 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 8.2 Hz,
2H), 8.05 (s, 1H); 13C NMR δ 21.7, 33.0, 63.5, 71.0, 73.9, 80.9, 90.4,
113.7, 125.7, 126.0, 126.6, 128.2, 129.21, 129.24, 129.3, 129.4, 129.8,
129.9, 135.0, 135.1, 144.1, 144.5, 144.7, 146.6, 148.5, 160.2, 165.19,
165.21, 166.3, 193.3; HRMS calcd for C53H4774GeN2O10 [M + H]+
945.2437, found 945.2456.
1
mg, 68%): H NMR δ 0.20 (s, 27H), 2.01 (s, 3H), 2.10 (s, 3H), 2.14
(s, 3H), 4.17−4.24 (m, 1H), 4.34 (dd, J = 12.0, 5.5 Hz, 1H), 4.38 (dd,
J = 12.0, 5.2 Hz, 1H), 5.14 (dd, J = 3.8, 1.6 Hz, 1H), 5.47 (dd, J = 3.8,
1.7 Hz, 1H), 6.16 (d, J = 3.9 Hz, 1H), 6.28 (d, J = 13.5 Hz, 1H), 6.90
(dd, J = 13.5, 1.4 Hz, 1H), 7.29 (d, J = 1.4 Hz,1H), 8.27 (br s, 1H);
13C NMR δ 1.95, 20.7, 20.9, 21.0, 63.1, 75.0, 76.5, 80.7, 85.4, 116.1,
133.9, 134.1, 136.2, 149.6, 162.0, 168.9, 169.7, 170.6; HRMS calcd for
C26H4774GeN2O9Si3 [M + H]+ 689.1801, found 689.1798. 1H NMR of
the crude reaction mixture showed 4:96 mixture of E/Z isomers of 2c.
The E-2c had the characteristic peaks on the 1H NMR spectrum at: δ
6.36 (d, J = 3.5 Hz, H1′), 6.63 (d, J = 18.7 Hz, CH), 6.86 (d, J = 18.5
Hz, CH).
1-(β-D-Arabinofuranosyl)-5-(Z)-[2-(triphenylgermyl)ethenyl]-
uracil (3a). A saturated solution of NH3/MeOH (3 mL) was added to
a suspension of Z-2a (40.0 mg, 0.057 mmol) in MeOH (2 mL) and
the reaction mixture stirred for 6 h at 0 °C and then for 2 h at rt.
Volatiles were evaporated and the residue was chromatographed
(EtOAc/MeOH, 98:2) to give Z-3a (28.2 mg, 86%): 1H NMR
(MeOH-d4) δ 3.28 (dd, J = 11.3, 4.0 Hz, 1H), 3.37 (dd, J = 11.3, 5.6
Hz, 1H), 3.76 (ddd, J = 5.8, 4.1, 2.1 Hz, 1H), 3.98−4.02 (m, 2H), 5.59
(d, J = 3.3 Hz, 1H), 6.50 (d, J = 13.2 Hz, 1H), 7.30 (d, J = 13.3 Hz,
1H), 7.35−7.51 (m, 16H); 13C NMR (MeOH-d4) δ 62.6, 76.6, 78.4,
87.0, 88.3, 113.8, 129.3, 130.0, 131.5, 136.0, 138.2, 139.9, 140.7, 151.3,
165.0; HRMS calcd for C29H2874GeNaN2O6 [M + Na]+ 597.1051,
found 597.1076. Anal. Calcd for C29H28GeN2O6·CH3OH·H2O
(623.24): C, 57.81; H, 5.50; N, 4.49. Found: C, 57.84; H, 5.41; N,
4.69.
5-(E/Z)-[2-(Trimethylgermyl)ethenyl]-2′,3′,5′-tri-O-p-toluoy-
luridine (7b). Nucleoside 5 (50.0 mg, 0.08 mmol) was treated with
Me3GeH (19.0 mg, 18.8 μL 0.16 mmol) in dry THF (5 mL) as
described in method B (with injection of Me3GeH into the reaction
mixture via syringe and progressive warming from 0 °C to rt) for 10 h.
The volatiles were evaporated and the residue was chromatographed
(hexane/EtOAc, 3:2) to give E/Z-7b (24.5 mg, 41%; E/Z, 45:55): 1H
NMR δ 0.12 (s, 4.05H), 0.20 (s, 4.95H), 2.40, 2.43, 2.44 (singlets,
9H), 4.68−4.82 (m, 3H), 5.72 (“t”, J = 6.0 Hz, 0.55H), 5.78 (“t”, J =
6.3 Hz, 0.45H), 5.82 (dd, J = 6.1, 3.9 Hz, 0.55H), 5.88 (dd, J = 5.8, 2.8
Hz, 0.45H), 5.98 (d, J = 13.7 Hz, 0.55H), 6.34 (d, J = 5.9 Hz, 0.55H),
6.37 (d, J = 19.0 Hz, 0.45H), 6.50 (d, J = 6.8 Hz, 0.45H), 6.69 (d, J =
19.0 Hz, 0.45H), 6.72 (dd, J = 13.7, 1.0 Hz, 0.55H), 7.16−7.32 (m,
6H), 7.34 (d, J = 1.0 Hz, 0.55H), 7.54 (s, 0.45H), 7.83−8.04 (m, 6H),
8.24 (br s, 0.45H), 8.27 (br s, 0.55H); 13C NMR δ −2.0, −0.2, 21.7,
63.7, 64.2, 71.1, 71.5, 73.45, 73.53, 80.7, 81.0, 86.9, 88.0, 114.4, 116.0,
125.65, 125.70, 125.96, 125.97, 126.3, 126.5, 129.24, 129.25, 129.29,
129.4, 129.6, 129.71, 129.73, 129.88, 129.9, 129.95, 130.0, 131.8,
134.1, 134.4, 135.1, 135.8, 138.7, 144.3, 144.5, 144.57, 144.63, 144.64,
144.7, 149.3, 149.7, 161.3, 161.7, 165.3, 165.35, 165.38, 165.5, 166.1;
MS (ESI+) m/z 765 (100, MNa+, 74Ge), 763 (71, MNa+, 72Ge), 762
(52 MNa+, 70Ge). Anal. Calcd for C38H40GeN2O9·H2O (759.39): C,
60.10; H, 5.57; N, 3.69. Found: C, 60.39; H, 5.38; N, 3.87.
5-(E/Z)-[2-(Trimethylgermyl)ethenyl]uridine (8b). A 0.1 N
solution of MeONa in MeOH (2.5 mL) was added to 7b (18.8 mg,
0.025 mmol; E/Z, ∼45:55) and the resulting mixture was stirred at rt
for 12 h. The reaction mixture was neutralized to pH ∼6.2 by addition
of Dowex 50WX2-200(H+). Dowex resin was filtered off and the
filtrate was evaporated and residue partitioned between Et2O/H2O.
The organic layer was extensively washed with water and the
combined aqueous layer was evaporated to yield E/Z-8b (7 mg,
71%; E/Z, ∼40:60): 1H NMR (D2O) δ 0.27 (s, 5.4H), 0.32 (s, 3.6H),
3.84−3.91 (m, 1H), 3.95 (dd, J = 12.7, 2.7 Hz, 0.6H), 4.05 (dd, J =
12.9, 2.4 Hz, 0.4H), 4.18−4.24 (m, 1H), 4.29 (“t”, J = 5.0 Hz, 0.6H),
4.34 (“t”, J = 5.7 Hz, 0.4H), 4.39−4.44 (m, 1H), 6.00 (d, J = 3.8 Hz,
0.4H), 6.05 (d, J = 5.3 Hz, 0.6H), 6.36 (d, J = 13.6 Hz, 0.6H), 6.70 (d,
J = 19.0 Hz, 0.4H), 6.83 (d, J = 19.0 Hz, 0.4H), 6.93 (d, J = 13.6 Hz,
0.6H), 7.77 (s, 0.6H), 8.20 (s, 0.4H); 13C NMR (MeOH-d4) δ −2.9,
−1.2, 60.1, 61.0, 68.9, 69.8, 73.7, 74.1, 84.0, 84.7, 88.8, 89.7, 113.8,
115.7, 132.1, 134.1, 134.7, 137.6, 137.8, 140.8, 151.1, 151.6, 164.6,
165.3; HRMS calcd for C14H2374GeN2O6 [M + H]+ 389.0762, found
389.0775.
5-Ethynyl-2′,3′,5′-tri-O-p-toluoyluridine (5). The p-toluoyl
chloride (86 μL, 101 mg, 0.65 mmol) was added to a stirred solution
of 5-ethynyluridine38 (50 mg, 0.19 mmol) in pyridine (5 mL). After 24
h, volatiles were evaporated and the residue was partitioned
(NaHCO3/H2O//CHCl3). The organic layer was washed with HCl/
H2O, NaHCO3/H2O and brine, dried (MgSO4), and evaporated. The
residue was chromatographed (hexane/EtOAc, 7:3 → 6:4) to give 5
(85 mg, 73%): 1H NMR δ 2.40 (s, 3H), 2.44 (s, 6H, 2 x Me), 2.94 (s,
1H), 4.69−4.76 (m, 2H), 4.78−4.84 (m, 1H), 5.70 (“t”, J = 6.0 Hz,
1H), 5.84 (dd, J = 5.9, 3.6 Hz, 1H, H3), 6.37 (d, J = 6.1 Hz, 1H), 7.18
(d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H),
7.81 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 8.02
(d, J = 8.2 Hz, 2H), 8.18 (s, 1H); 13C NMR δ 21.8, 21.9, 63.8, 71.5,
73.76, 73.77, 81.4, 82.5, 87.9, 100.6, 125.7, 126.1, 126.5, 129.4, 129.5,
129.7, 129.9, 130.1, 130.2, 143.2, 144.6, 144.8, 144.9, 148.8, 160.6,
165.4, 165.5, 166.3; HRMS calcd for C35H31N2O9 [M + H]+ 623.2024,
found 623.2033.
5-(Z)-[2-(Triphenylgermyl)ethenyl]-2′,3′,5′-tri-O-p-toluoylur-
idine (7a) and 5-[2-(Triphenylgermyl)acetyl]-2′,3′,5′-tri-O-p-
toluoyluridine (11a). Nucleoside 5 (49 mg, 0.08 mmol) was treated
with Ph3GeH (26 mg, 0.085 mmol) in dry THF (5 mL) as described
in method B. After 6 h at −78 °C, the reaction mixture was slowly
warmed to 0 °C (∼24 h). The volatiles were evaporated, and the
residue was chromatographed (hexane/EtOAc, 1:1) to give a separable
mixture of Z-7a (29 mg, 40%) and 11a (10 mg, 13%). Z-7a: 1H NMR
δ 2.40 (s, 6H), 2.42 (s, 3H), 4.34 (dd, J = 12.2, 5.4 Hz, 1H), 4.40 (dd,
J = 12.2, 3.4 Hz, 1H), 4.47 (ddd, J = 5.8, 5.4, 3.5 Hz, 1H), 5.38 (dd, J =
6.2, 4.5 Hz, 1H), 5.51 (“t”, J = 6.0 Hz, 1H), 5.52 (d, J = 4.4 Hz, 1H),
6.50 (d, J = 13.6 Hz, 1H), 7.11 (d, J = 0.9 Hz, 1H), 7.16 (d, J = 8.1 Hz,
2H), 7.19 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 13.5, 0.9 Hz, 1H), 7.24 (d,
1-(2-Deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-
5-(Z)-[2-(triphenylgermyl)ethenyl]uracil (9a) and 1-(2-Deoxy-
3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-5-[2-
(triphenylgermyl)acetyl]uracil (12a). Nucleoside 610 (44 mg, 0.09
mmol) was treated with Ph3GeH (30 mg, 0.1 mmol) in dry THF (5
mL) as described in method B. After 6 h at −78 °C, the reaction
mixture was slowly warmed to 0 °C and stirred for 3 h. The volatiles
were evaporated, and the residue was chromatographed (hexane/
EtOAc, 3:2) to give a separable mixture of Z-9a (43 mg, 61%) and 12a
1
(9 mg, 12%). Z-9a: H NMR δ 1.68 (ddd, J = 14.9, 8.1, 7.0 Hz, 1H),
2.31 (ddd, J = 14.5, 5.7, 1.8 Hz, 1H), 2.41 (s, 3H), 2.45 (s, 3H), 4.16
(dd, J = 11.1, 3.5 Hz, 1H), 4.26−4.30 (m, 1H), 4.32 (dd, J = 11.1, 5.0
E
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 1H), 5.15 (“dt”, J = 6.8, 1.8 Hz, 1H), 5.84 (dd, J = 8.1, 5.7 Hz,
1H), 6.51 (d, J = 13.5 Hz, 1H), 7.11 (d, J = 1.0 Hz, 1H), 7.21−7.56
(m, 20H), 7.88 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H); 13C
NMR δ 21.68, 21.72, 37.3, 63.9, 74.5, 82.3, 85.5, 114.8, 126.4, 126.7,
128.5, 129.2, 129.25, 129.28, 129.6, 129.8, 131.0, 134.8, 135.6, 136.6,
138.8, 144.2, 144.5, 149.3, 161.7, 165.8, 166.0; HRMS calcd for
C45H4174GeN2O7 [M + H]+ 795.2120, found 795.2131.
h. The volatiles were evaporated, and the residue was chromato-
graphed (hexane/EtOAc, 1:1) to give Z-14 (61 mg, 52%) as a white
powder: mp 202−204 °C (MeOH); UV (MeOH) max 296 nm (ε 11
000), min 255 (ε 3500); 1H NMR δ 4.03 (s, 2H), 6.30 (d, J = 13.5 Hz,
1H), 6.69 (“d”, J = 7.0 Hz, 2H), 6.84 (s, 1H), 7.09 (“t”, J = 7.5 Hz,
2H), 7.16 (“t”, J = 7.1 Hz, 1H), 7.23−7.35 (m, 10H), 7.37−7.46 (m,
6H), 8.51 (br s, 1H); 13C NMR δ 51.2, 113.7, 128.3, 128.3, 128.4,
128.8, 129.1, 129.5, 134.8, 135.0, 136.7, 138.7, 141.0, 150.1, 162.4;
HRMS calcd for C31H2674GeN2NaO2 [M + Na]+ 555.1105, found
555.1113.
1-N-Benzyl-5-(E)-[2-(triphenylgermyl)ethenyl]uracil (14).
Ph3GeH (118.6 mg, 0.38 mmol) and H2O (25 μL, 25 mg, 1.4
mmol) were added to a stirred solution of 13 (80 mg, 0.35 mmol) in
toluene (5 mL) at rt. The resulting mixture was heated at 100 °C for
12 h. The volatiles were evaporated, and the residue was chromato-
graphed (CH2Cl2/EtOAc, 10:1) to give E-14 (126 mg, 86%) as a
white solid. Recrystallization (MeOH) gave white crystals: mp 185−
186 °C; UV (MeOH) max 300 nm (ε 13900), 251 nm (ε 15500), min
272 (ε 7100); 1H NMR δ 4.92 (s, 2H), 6.56 (d, J = 18.7 Hz, 1H), 7.21
(s, 1H), 7.28−7.30 (m, 2H), 7.33 (d, J = 18.7 Hz, 1H), 7.35−7.51 (m,
18H), 8.78 (br s, 1H); 13C NMR δ 51.5, 113.8, 127.2, 127.9, 128.3,
128.6, 129.1, 129.2, 135.1, 135.2, 136.1, 136.9, 141.7, 150.1, 161.8;
HRMS calcd for C31H2674GeN2NaO2 [M + Na]+ 555.1105, found
555.1111. Anal. Calcd for C31H26GeN2O2 (531.19): C, 70.09; H, 4.93;
N, 5.27. Found: C, 69.82; H, 4.64; N, 5.35.
Compound 12a had: 1H NMR δ 2.18−2.27 (m, 1H), 2.36 (s, 3H),
2.45 (s, 3H), 2.64 (ddd, J = 14.3, 5.7, 1.8 Hz, 1H), 3.81 (d, J = 9.1 Hz,
1H), 3.85 (d, J = 9.1 Hz, 1H), 4.53−4.60 (m, 2H), 4.74−4.80 (m,
1H), 5.54 (“d”, J = 6.6 Hz, 1H), 6.16 (dd, J = 8.3, 5.7 Hz, 1H), 7.16 (d,
J = 8.0 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.32−7.57 (m, 15H), 7.94
(d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 8.15 (s, 1H); 13C NMR δ
21.70, 21.73, 32.8, 38.4, 63.8, 74.5, 83.2, 86.2, 113.6, 126.3, 126.6,
128.2, 129.25, 129.28, 129.3, 129.8, 135.1, 135.2, 144.1, 144.5, 145.2,
148.8, 160.3, 165.8, 166.2, 193.5; HRMS calcd for C45H4174GeN2O8
[M + H]+ 811.2075, found 811.2063.
Treatment of 6 (50 mg, 0.10 mmol) with Ph3GeH (36 mg, 0.12
mmol) in toluene (4 mL) as described in Method A [DMF (0.2 mL)
and water (25 μL, 25 mg, 1.4 mmol) were added to the preheated
reaction mixture] gave partially separated E-9a (13 mg, 16%), 12a (6.5
mg, 8%), and Z-9a (13 mg, 16%). Compound E-9a had characteristic
peaks for vinylic protons at δ 6.63 (d, J = 18.8 Hz, 1H) and within the
envelope of aromatic protons at δ 7.20−7.50 (Cosy).
1-(2-Deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-
5-(E/Z)-[2-(trimethylgermyl)ethenyl]uracil (9b). Nucleoside 610
(45.0 mg, 0.092 mmol) was treated with Me3GeH (21.8 mg, 21.6 μL,
0.18 mmol) in dry THF (5 mL) as described in method B (with
injection of Me3GeH into the reaction mixture via syringe and
progressive warming from 0 °C to rt) for 10 h. The volatiles were
evaporated, and the residue was chromatographed (hexane/EtOAc,
1-N-Benzyl-5-[2-(triphenylgermyl)acetyl]uracil (15). Alkyne
13 (50 mg, 0.22 mmol) was suspended in dry toluene (5 mL), and
the suspension was degassed with N2 for 45 min at ambient
temperature. Ph3GeH (73 mg, 0.24 mmol) and ACCN (10 mg,
0.041 mmol) were added, and the suspension was heated at 90 °C for
2 h. The volatiles were evaporated, and residue was chromatographed
(hexane/EtOAc, 3:2) to give 15 (15 mg, 13%) followed by Z-14 (31
mg, 27%). Compound 15 was recrystallized (MeOH) to give colorless
crystals: mp 205−207 °C; UV (MeOH) max 294 nm (ε 10 600), min
1
1:1) to give E/Z-9b (16.5 mg, 35%; E/Z, 40:60): H NMR δ 0.14 (s,
3.6H), 0.21 (s, 5.4H), 2.25−2.34 (m, 1H), 2.42, 2.43, 2.45 (singlets,
6H), 2.78 (ddd, J = 14.2, 5.5, 1.6 Hz, 0.6H), 2.80 (ddd, J = 14.3, 5.1,
1.2 Hz, 0.4H), 4.56−4.61 (m, 1H), 4.65 (dd, J = 12.2, 3.2 Hz, 0.6H),
4.73−4.77 (m, 0.8H), 4.75 (dd, J = 12.2, 3.8 Hz, 0.6H), 4.59 (“dt”, J =
4.9, 1.9 Hz, 0.6H), 4.63 (“d”, J = 6.4 Hz, 0.4H), 6.00 (d, J = 13.7 Hz,
0.6H), 6.40 (dd, J = 8.7, 5.4 Hz, 0.6H), 6.41 (d, J = 19.2 Hz, 0.4H),
6.46 (d, J = 8.9, 5.2 Hz, 0.4H), 6.72 (d, J = 19.0 Hz, 0.4H), 6.78 (dd, J
= 13.7, 1.0 Hz, 0.6H), 7.22−7.32 (m, 4H), 7.48 (d, J = 1.0 Hz, 0.6H),
7.67 (s, 0.4H), 7.85−7.99 (m, 4H), 8.51 (br s, 0.4H), 8.57 (br s,
0.6H); 13C NMR δ −2.0, −0.2, 21.70, 21.73, 38.5, 64.1, 64.4, 74.7,
75.0, 82.9, 83.1, 85.6, 113.9, 115.4, 126.3, 126.4, 126.5, 129.30, 129.34,
129.50, 129.54 129.6, 129.8, 131.9, 133.9, 134.2, 134.9, 135.1, 138.3,
144.4, 144.5, 144.6, 149.2, 149.7, 161.5, 161.9, 166.0, 166.1; HRMS
calcd for C30H3474GeN2NaO7 [M + Na]+ 631.1470, found 631.1482.
Note: Treatment of 9b (E/Z, 40:60; 12 mg; 0.02 mmol) with NBS
(5 mg, 0.028 mmol) in CHCl3/CH2Cl2 (1:1.5, v/v; 2.5 mL) for 6 h at
0 °C followed by deprotections with NH3/MeOH (0 °C to rt, 12 h)
gave 5-(2-bromovinyl)-2′-deoxyuridine39,40 (E/Z, 2:3; 70% from 9b).
1-(β-D-Erythro-pentofuranosyl)-5-(Z)-[2-(triphenylgermyl)-
ethenyl]uracil (10a). A saturated solution of NH3/MeOH (2 mL)
was added to a suspension of Z-9a (33 mg, 0.042 mmol) in MeOH (2
mL), and the resulting mixture was stirred for 24 h at rt. The volatiles
were evaporated, and the residue was chromatographed (EtOAc) to
give Z-10a (15 mg, 65%): 1H NMR (MeOH-d4) δ 1.44 (ddd, J = 14.2,
7.9, 6.6 Hz, 1H), 1.87 (ddd, J = 13.6, 5.9, 2.7 Hz, 1H), 3.38 (“d”, J =
4.4 Hz, 2H), 3.70 (“q”, J = 3.8 Hz, 1H), 3.97 (ddd, J = 6.0, 3.3, 2.8 Hz,
1H), 5.81 (dd, J = 8.0, 6.0 Hz, 1H), 6.52 (d, J = 13.3 Hz, 1H), 7.28 (d,
J = 1.1 Hz, 1H), 7.31 (dd, J = 13.3, 1.1 Hz, 1H), 7.36−7.54 (m, 15H);
13C NMR (MeOH-d4) δ 40.3, 63.0, 72.3, 86.3, 88.6, 115.8, 129.5,
1
255 (ε 3800); H NMR δ 3.81 (s, 2H), 4.77 (s, 2H), 7.24−7.54 (m,
20H), 7.79 (br s, 1H), 7.85 (s, 1H); 13C NMR δ 33.1, 52.4, 113.3,
128.3, 128.5, 129.1, 129.3, 129.5, 134.5, 135.2, 135.3, 149.7, 149.9,
160.7, 194.3; HRMS calcd for C31H2674GeN2NaO3 [M + Na]+
571.1054, found 571.1068. Anal. Calcd for C31H26GeN2O3 (547.2):
C, 68.04; H, 4.79; N, 5.12. Found: C, 68.26; H, 4.60; N, 4.81.
1-N-Benzyl-5-acetyluracil (20). A solution of 15 (15 mg, 0.03
mmol) in CH3OH (3 mL) was heated for 12 h at 65 °C. Volatiles were
evaporated, and the residue was chromatographed (CH2Cl2/EtOAc,
2:1) to give 2041 (6.5 mg, 95%) as a white powder: UV (MeOH) max
1
290 nm (ε 12200), 226 nm (ε 8100), min 249 (ε 1400); H NMR δ
2.61 (s, 3H), 5.01 (s, 2H), 7.33−7.41 (m, 5H), 8.28 (s, 1H), 8.59 (br
s, 1H); 13C NMR δ 30.6, 52.5, 112.8, 128.3, 129.0, 129.3, 134.3, 150.2,
150.6, 161.2, 193.9; GC−MS (tR 26.87 min) m/z 244 (20, M+), 91
(100; HRMS calcd for C13H12N2NaO3 [M + Na]+ 267.0740, found
267.0739.
Analogous treatment of 15 (10 mg, 0.02 mmol) using MeOD or
MeOH-d4 instead of MeOH gave 1-N-benzyl-5-(2-deuterioacetyl)-
uracil (21; 4.2 mg, 94%): GC−MS (tR 26.87 min) m/z 245 (20, M+),
91 (100). 1H NMR spectrum of 21 corresponded to this of the above
20 with 1/3 reduction of the integrated intensity for the signal from
methyl group at 2.61 ppm.
ASSOCIATED CONTENT
■
S
* Supporting Information
130.2, 131.8, 135.9, 138.1, 138.2, 140.8, 151.6, 164.7; MS (ESI+) m/z
581 (100, MNa+, 74Ge), 579 (70, MNa+, 72Ge), 577 (49, MNa+, 70Ge).
Anal. Calcd for C29H28GeN2O5 (557.18): C, 62.51; H, 5.07; N, 5.03.
Found: C, 62.14; H, 5.28; N, 4.86.
1
NOE and HMBC interactions observed for 11a, and H and
13C NMR spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1-N-Benzyl-5-(Z)-[2-(triphenylgermyl)ethenyl]uracil (14). Al-
kyne 1333,34 (50 mg, 0.22 mmol) was dissolved in anhydrous THF (5
mL), and the resulting solution was stirred for 20 min under N2 at 0
°C. Ph3GeH (73 mg, 0.24 mmol) and Et3B (1M/THF 265 μL, 0.265
mmol) were added, and the resulting solution was stirred at 0 °C for 7
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wnuk@fiu.edu.
F
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Present Address
Note
(25) Wnuk, S. F.; Garcia, P. I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047−
2049.
(26) Sharma, R. A.; Kavai, I.; Hughes, R. G.; Bobek, M. J. Med. Chem.
†(J.-P.P.) Torrey Pines Institute for Molecular Studies, Port St.
Lucie, FL 34987.
1984, 27, 410−412.
Notes
(27) Ichinose, Y.; Nozaki, K.; Wakamatsu, K.; Oshima, K.; Utimoto,
K. Tetrahedron Lett. 1987, 28, 3709−3712.
The authors declare no competing financial interest.
(28) Wnuk, S. F.; Sacasa, P. R.; Restrepo, J. Nucleosides, Nucleotides
Nucleic Acids 2009, 28, 537−549.
ACKNOWLEDGMENTS
(29) Oda, H.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1984, 25, 3221−3224.
■
We thank NIGMS/NCI for financial support
(1SC1CA138176) and FIU University Graduate School for a
Dissertation Year Fellowship (J.-P.P.). We are grateful to Dr.
Jodie V. Johnson from the University of Florida for his critical
analysis of our mass spectra.
(30) Oda, H.; Oshima, K.; Nozaki, H. Chem. Lett. 1985, 53−56.
(31) Cai, C.; Vasella, A. Helv. Chim. Acta 1996, 79, 255−268.
(32) Wang, Z.; Wnuk, S. F. J. Org. Chem. 2005, 70, 3281−3284.
(33) Prachayasittikul, S.; Sornsongkhram, N.; Pingaew, R.;
Worachartcheewan, A.; Ruchirawat, S.; Prachayasittikul, V. Molecules
2009, 14, 2768−2779.
(34) Fahrig, R.; Eger, K.; Fuehrer, M.; Heinze, N.; Klemm, M.;
Heinrich, J.-C., 2009, WO 2009156182; Chem. Abstr. 2009, 152,
119663.
(35) (a) Chatgilialoglu, C.; Newcomb, M. Adv. Organomet. Chem.
1999, 44, 67−112. (b) Chatgilialoglu, C.; Timokhin, V. I.;
Zaborovskiy, A. B.; Lutsyk, D. S.; Prystansky, R. E. J. Chem. Soc.,
Perkin Trans. 2 2000, 577−582.
REFERENCES
■
(1) Machida, H.; Sakata, S. In Nucleosides and Nucleotides as
Antitumor and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum
Press: New York, 1993; pp 245−264.
(2) De Clercq, E.; Descamps, J.; De Somer, P.; Barr, P. J.; Jones, A.
S.; Walker, R. T. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2947−2951.
(3) Machida, H.; Kuninaka, A.; Yoshino, H.; Ikeda, K.; Mizuno, Y.
Antimicrob. Agents Chemother. 1980, 17, 1030−1031.
(4) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854−1862.
(5) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103,
1875−1916.
(6) Dougan, H.; Rennie, B. A.; Lyster, D. M.; Sacks, S. L. Appl.
Radiat. Isot. 1994, 45, 795−801.
(7) Yu, C.-S.; Oberdorfer, F. Synlett 2000, 86−88.
(8) Yu, C.-S.; Wu, C.-H.; Chiang, L.-W.; Wang, R.-T.; Wang, H.-Y.;
Yeh, C.-H.; Lin, K.-I. Chem. Lett. 2005, 34, 1390−1391.
(9) Yu, C.-S.; Chiang, L.-W.; Wu, C.-H.; Wang, R.-T.; Chen, S.-W.;
Wang, H.-Y.; Yeh, C.-H. Nucl. Med. Biol. 2006, 33, 367−370.
(10) Robins, M. J.; Manfredini, S.; Wood, S. G.; Wanklin, R. J.;
Rennie, B. A.; Sacks, S. L. J. Med. Chem. 1991, 34, 2275−2280.
(11) Robins, M. J.; Manfredini, S. Tetrahedron Lett. 1990, 31, 5633−
5636.
(36) Barr, P. J.; Chananont, P.; Hamor, T. A.; Jones, A. S.; O’Leary,
M. K.; Walker, R. T. Tetrahedron 1980, 36, 1269−1273.
(37) Lutsenko, I. F.; I. Baukov, Y.; Dudukina, O. V.; Kramarova, E. N.
J. Organomet. Chem. 1968, 11, 35−48.
(38) Barr, P. J.; Jones, A. S.; Serafinowski, P.; Walker, R. T. J. Chem.
Soc., Perkin Trans. 2 1978, 1, 1263−1267.
(39) Jones, A. S.; Verhelst, G.; Walker, R. T. Tetrahedron Lett. 1979,
20, 4415−4418.
(40) Jones, A. S.; Rahim, S. G.; Walker, R. T.; De Clercq, E. J. Med.
Chem. 1981, 24, 759−760.
(41) Nair, V.; Chi, G.; Uchil, V. R., 2007, WO 2007106450; Chem.
Abstr. 2007, 147, 385768.
(12) Morin, K. W.; Atrazheva, E. D.; Knaus, E. E.; Wiebe, L. I. J. Med.
Chem. 1997, 40, 2184−2190.
(13) The Chemistry of Organic Germanium, Tin and Lead Compounds;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, UK,
1995; Vol. 1; 2002; Vol. 2.
(14) Lukevics, E.; Ignatovich, L. In Metallotherapeutic Drugs and
Metal-Based Diagnostic Agents; Gielen, M., Tiekink, E. R. T., Eds.;
Wiley: New York, 2005; pp 279−295.
(15) Lukevics, E.; Ignatovich, L. In The Chemistry of Organic
Germanium, Tin and Lead Compounds; Rappoport, Z., Ed.; Wiley: New
York, 2002; pp 1653−1683.
́
(16) Trushule, M.; Kupche, E.; Augustane, I.; Verovskii, N.; Lukevits,
́
E.; Baumane, L.; Gavar, R.; Stradyn, Y. Chem. Heterocycl. Compd. 1991,
27, 1358−1364.
(17) Lukevics, E.; Ignatovich, L.; Shilina, N.; Kemme, A.; Sjakste, N.
Metal-Based Drugs 1994, 1, 65−72; Chem. Abstr. 1992, 121, 134303.
(18) Mel’nik, S. l.; Bakhmedova, A. A.; Nedorezova, T. P.; Iartseva, I.
V.; Zhukova, O. S.; Dobrynin, Y. V.; Preobrazhenskaya, M. N.;
Kolesnikov, S. P.; Li, V. Y. Bioorg. Khim. 1985, 11, 1248−1252; Chem.
Abstr. 1985, 105, 79283.
(19) Ichinose, Y.; Oda, H.; Oshima, K.; Utimoto, K. Bull. Chem. Soc.
Jpn. 1987, 60, 3468−3470.
(20) Kinoshita, H.; Nakamura, T.; Kakiya, H.; Shinokubo, H.;
Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 2521−2524.
(21) Nozaki, K.; Ichinose, Y.; Wakamatsu, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. Jpn. 1990, 63, 2268−2272.
(22) Schwier, T.; Gevorgyan, V. Org. Lett. 2005, 7, 5191−5194.
(23) Bernardoni, S.; Lucarini, M.; Pedulli, G. F.; Valgimigli, L.;
Gevorgyan, V.; Chatgilialoglu, C. J. Org. Chem. 1997, 62, 8009−8014.
(24) David-Quillot, F.; Thiery, V.; Abarbri, M.; Thibonnet, J.; Besson,
T.; Duchene, A. Main Group Met. Chem. 2007, 30, 235−244.
G
dx.doi.org/10.1021/jo400590z | J. Org. Chem. XXXX, XXX, XXX−XXX