Direct N- and C-vinylation with trimethoxyvinylsilane

Article abstract of DOI:10.1016/j.mencom.2011.11.011

Treatment of nucleobases, nucleosides, 5-membered N-heterocycles and terminal alkynes with trimethoxyvinylsilane in the presence of copper(II) acetate-TBAF system as catalyst affords the vinylation products.

Full text of DOI:10.1016/j.mencom.2011.11.011

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 326–328
Direct N- and C-vinylation with trimethoxyvinylsilane
Pavel Arsenyan,* Alla Petrenko, Edgars Paegle and Sergey Belyakov
Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia. Fax: +371 6755 0338; e-mail: pavel@osi.lv
DOI: 10.1016/j.mencom.2011.11.011
Treatment of nucleobases, nucleosides, 5-membered N-heterocycles and terminal alkynes with trimethoxyvinylsilane in the presence
of copper(ii) acetate–TBAF system as catalyst affords the vinylation products.
The development of new methods for catalytic C–N bond forma-
tion is highly challenging.1 Notably, copper promoted C–N cross-
coupling of amides with organometalloids have received a great
deal of attention since initial reports.2 Recently, Lam3 reported very
impressive results for the arylation of heteroarylcarboxamides
with phenyl trimethoxysilane and tributylphenyltin under mild
conditions. Lam’s method is based on the a-nitrogen activating
effect in the Cu-promoted N-arylation. Previously, very simple
reaction conditions [(MeO)3SiCH=CH2, Cu(OAc)2, TBAF, solvent]
have been developed for the direct vinylation of aryl and hetaryl
carboxamides. Note that formation of N,N-divinyl carboxamides
was not observed, whereas the yield of N-vinyl amides strongly
depended on the structure of initial amide and solvent nature.4
Treating of 5-fluorouracil with acetylene in dioxane in the presence
of cadmium(ii) acetate at 220°C and 9120 Torr within 2 h leads
to the formation of the mixture of 1-vinyl- and 1,3-divinyl-
5-fluorouracil in moderate yields.5 1-Vinyl-5-fluorouracil was
obtained in 74% yield by elimination of HCl from 1-(2-chloro-
ethyl)-5-fluorouracil with potassium tert-butoxide in DMSO.6
More or less convenient procedure was described7 for direct vinyl-
ation of trimethylsilyl-protected nucleobases with vinyl acetate
as the reagent and the solvent in the presence of Hg(OAc)2 and
hydroquinone. Herein, we report a convenient method for the
N-vinylation of nucleobases with trimethoxyvinylsilane under
mild base-free conditions.
imide followed by reaction with activated trimethoxyvinylsilane
[(MeO)3SiCH=CH2 + TBAF] furnished the intermediate 1a. Then
1a in the presence of oxygen was subjected to reductive elimina-
tion with the formation of the desired N-vinylphthalimide 2.
In dichloromethane, the yield of 2 was as low as 17%. However,
addition of 20% of methanol to the reaction mixture raised the
yield of 2 as twofold. Notably, according to our experimental
data DMF is not appropriate solvent for N-vinylation of imides
under current reaction conditions.
Next, we investigated the applicability of the elaborated pro-
cedure in the vinylation of imide moieties of nucleobases. In the
case of 5-fluorouracil 3, a mixture of 1-vinyl-5-fluorouracil 85,6
and 1,3-divinyl-5-fluorouracil 95,6 was obtained (27% and 33%
yields, respectively) (Scheme 2). Molecular structure of the com-
pound 9 is outlined in Figure 1.‡ The vinyl groups are slightly
unfolded to the pyrimidine cycle. The torsion angles C(8)–C(7)–
N(1)–C(6) and C(11)–C(10)–N(3)–C(4) are equal to 5.2(5)
O
O
O
N
F
H
R'
R'
N
O
N
N
+
O
N
O
N
O
8 R' = F, 27%
10 R' = Me, 22%
9 R' = F, 33%
11 R' = Me, 25%
Initially, to improve the procedure, we studied N-vinylation
of phthalimide 1 as a model compound with trimethoxyvinyl-
silane (Scheme 1).† Addition of copper(ii) acetate to phthal-
12, 47%
R = H
O
O
O
N
O
H
N
F
Me
R'
Cu(OAc)2
N
O
Bu4N+
Si
+
N
H
OMe
OMe
– (MeO)3SiF
MeO
N
R
O
O
N
O
N
O
OH
1
O
3 R = H, R' = F
4 R = H, R' = Me
O
O
N
OAc
HO
OH
14, 81%
HO
OH
13, 74%
O2
N
Cu
5 R =
, R' = F
– Cu(OAc)2
O
~
OAc
O
O
OH
O
O
1a
2
6 R =
, R' = H
Scheme 1
HO
OH
~
†
General procedure for N-vinylation. 1 m TBAF solution in dioxane
(2 mmol) was added to a mixture of imide (1 mmol), trimethoxyvinyl-
silane (2 mmol), and copper(ii) acetate (1 mmol) in 10 ml of dichloro-
methane–methanol (5:1). The reaction mixture was stirred at 30°C and
monitored by TLC until complete disappearance of the starting compound.
The pure product was isolated by column chromatography on silica gel
using chloroform–ethanol (15:1 or 10:1) as an eluent.
7 R =
, R' = Me
HO
OH
Scheme 2 Reagents and conditions: (MeO)3SiCH=CH2, Cu(OAc)2, TBAF,
CH2Cl2–MeOH (5:1).
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 326–328
O(10)
C(4)
C(8)
C(7)
O(13)
C(6)
F(11)
F(12)
C(8)
C(9)
C(5)
N(3)
C(2)
C(5)
N(1)
C(2)
C(6)
N(1)
C(4)
O(7)
N(3)
O(9)
O(1')
C(1')
C(10)
C(2')
C(11)
C(3')
C(4')
Figure 1 ORTEP molecular structure of 1,3-divinyl-5-fluorouracil 9.
Figure 2 ORTEP molecular structure of 3-vinylftorafur 12.
and –21.7(5)°, respectively. In the crystal structure of 9 there is
a shortened intermolecular contact O(13)···H(4), which can be
described as a weak hydrogen bond of CH···O type [C···O,
3.190(7) Å; H···O, 2.26 Å; C–H···O, 157°]. Vinylation of thymine
4 proceeds similarly, the corresponding 1-vinylthymine 107 and
1,3-divinylthymine 11§ were obtained in 22% and 25% yields. Use
of Ftorafur 5 as substrate under the same conditions (Scheme 2)
gave 3-vinylftorafur 12§ in 47% yield, which was dropped to 27%
while performing the procedure in DMF. Molecular structure of
compound 12 is given in Figure 2.‡ Five-membered cycle is char-
acterized by the envelope conformation: atom C(3') is deviated
from the plane of C(2')–C(1')–O(1)–C(4') by 0.529(17) Å. Like-
wise 9, in the crystal structure of 12 there is a weak intermole-
cular hydrogen bond of CH···O type between atoms O(10) and
H(6) [C···O, 3.163(18) Å; H···O, 2.39 Å; C–H···O, 137°]. Since
Ftorafur is a known anticancer agent, we investigated in vitro
the formation of a copper(ii) acetate intermediate complex. To
verify scope and limitations of trimethoxyvinylsilane as a source of
vinyl group, we investigated its interaction with five-membered
heterocycles such as indole, imidazole and benzimidazole in the
presence of copper(ii) acetate and TBAF in DMF and dichloro-
methane. The corresponding N-vinyl derivatives 15,8(a),(b) 16,8(c)–(f)
and 178(f),(g) were obtained in moderate yields. Therefore, the
presence of carbonyl group in a substrate is not crucial for the
current procedure.
N
N
N
N
N
15
16
17
DMF
CH2Cl2
50%
45%
38%
29%
60%
34%
a
ctivity of 12 on human fibrosarcoma (HT-1080) and mice hepatoma
(MG 22A) tumor cell lines, and normal fibroblast cells (NIH 3T3),
as well as in vivo antitumor activity on sarcoma S-180 on mice.
Note that antitumor activity of 3-vinylftorafur 12 is comparable
with that of Ftorafur, however, 12 exhibits much lower acute
toxicity (LD50 = 1940 mg kg–1).
Encouraged by these results we studied the possibility of
C-vinylation of terminal alkynes 18a–c using the here developed
procedure¶ (Scheme 3, Table 1). In the most of conventional
solvents (entries 1–7) the reaction of phenylacetylene 18a was
accompanied by formation of side diyne 20a. Luckily, in dioxane
(entry 8) the yield of the target enyne 19a was as high as 81%,
while the fraction of homocoupled alkyne 20a was low. On
Then we tried to adopt this method for vinylation of unpro-
tected nucleosides. Direct vinylation of uridine 6 and thymidine 7
with trimethoxyvinylsilane led to 3-vinyl derivatives 13 and 14§
in very good yields (74% and 81%, respectively). Surprisingly,
these compounds were obtained as sole products; sugar hydroxy
groups remained intact.
+
R
C
CH
R
C
C
R
C
C
C
C R
According to Lam’s theory3 and our investigations,4 the pres-
ence of carbonyl group near the reaction centre is necessary for
18a–c
19a–c
20a
a R = Ph
b R = C(OH)Me2
c R = 1-hydroxycyclohexyl
‡
Diffraction data were collected on a Nonius KappaCCD diffractometer
using graphite monochromated MoKa radiation (l = 0.71073 Å). The
crystal structures of 9 and 12 were solved by direct methods9 and refined
by full-matrix least squares.10
Scheme 3 Reagents ans conditions: (MeO)3SiCH=CH2, Cu(OAc)2, TBAF,
solvent.
Crystal data for 9: C8H7FN2O2, monoclinic, a = 6.6735(4), b =
= 11.7772(8) and c = 10.5198(8) Å, V = 825.8(1) Å3, Z = 4, m = 0.122 mm–1,
dcalc = 1.465 g cm–3, space group P21/a. A total of 1900 independent reflec-
tion intensities (2qmax = 55°) was collected at room temperature. For
structure refinement, 1104 reflections with I > ns(I) were used. The final
R-factor is 0.071.
Crystal data for 12: C10H11FN2O3, orthorhombic, a = 9.310(1), b =
= 9.711(2) and c = 11.385(2) Å, V = 1029.4(3) Å3, Z = 4, m = 0.120 mm–1,
dcalc = 1.460 g cm–3, space group P21nb. A total of 1186 independent
reflection intensities (2qmax = 55°) was collected at 253 K. For structure
refinement, 702 reflections with I > ns(I) were used. The final R-factor
is 0.074.
Table 1 Vinylation of terminal alkynes 18a–c with trimethoxyvinylsilane.
Entry Substrate Solvent
Yield of 19 (%) Yield of 20 (%)
1
2
3
4
5
6
7
8
9
18a
18a
18a
18a
18a
18a
18a
18a
18b
18c
DMF
CH2Cl2
CH2Cl2–MeOH (5:1)
MeCN
Toluene
Acetone
DMSO
Dioxane
Dioxane
Dioxane
36
32
5
38
17
33
38
81
47
52
45
56
22
36
22
42
34
4
CCDC 762232 and 762233 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2011.
—
—
10
§
For characteristics of compounds 11–14, see Online Supplementary
¶
Some previous methods for enyne synthesis are given under ref. 11.
Materials.
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Mendeleev Commun., 2011, 21, 326–328
moving to aliphatic a-hydroxyalkynes 18b,c, the corresponding
enyne alcohols 19b,c were obtained as sole products in 47% and
52% yields, respectively.
In summary, the herein developed very simple reaction con-
ditions [(MeO)3SiCH=CH2, Cu(OAc)2, TBAF, solvent] for direct
vinylation of nucleobases, nucleosides, 5-membered N-hetero-
cycles and terminal acetylenes can promote wider use of such an
important transformation in fine organic synthesis.
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This work was supported by the Latvian Council of Science
(09.1588) and ESF project no. 2009/0197/1DP/1.1.1.2.0/09/
APIA/VIAA/014.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.11.011.
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Received: 4th April 2011; Com. 11/3713
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