Synthesis of vinyl-functionalized thiazoles by cross-metathesis and tandem stille coupling/cross-metathesis

Article abstract of DOI:10.1002/adsc.200600509

The application of olefin cross-metathesis to vinyl-functionalized thiazoles and the tandem Stille coupling/cross-metathesis of bis-trifloylthiazoles are reported. These processes offer new opportunities for the synthesis of complex natural products.

Full text of DOI:10.1002/adsc.200600509

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DOI: 10.1002/adsc.200600509
Synthesis of Vinyl-Functionalized Thiazoles by Cross-Metathesis
and Tandem Stille Coupling/Cross-Metathesis
a
a
a,
Jyotirmayee Dash, Stellios Arseniyadis, and Janine Cossy *
a
Laboratoire de Chimie Organique associØ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax : (+33)-1-40-79-46-60; e-mail: Janine.Cossy@espci.fr
Received: October 5, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The application of olefin cross-metathesis
to vinyl-functionalized thiazoles and the tandem
Stille coupling/cross-metathesis of bis-trifloylthia-
zoles are reported. These processes offer new op-
portunities for the synthesis of complex natural
products.
chemistry. As a consequence, olefin CM has been
widely used in the synthesis of complex natural prod-
ucts.
[
6]
Whereas metathesis reactions on substrates bearing
a large range of functionalities and heteroatoms are
fully documented in the literature, to our knowledge,
no examples of substrates containing vinyl-functional-
ized thiazoles have been reported to date. Functional-
ized thiazole substructures are present in numerous
Keywords: alkenes; heterocycles; homogeneous cat-
alysis; metathesis; Stille coupling; tandem reactions
[
7]
[8]
biologically active natural and non-natural prod-
ucts such as epothilone B or HDAC inhibitor I
(
Figure 2). It is therefore important to be able to
In the last decade, olefin cross-metathesis (CM) has
emerged as a powerful tool for the construction of
[
1]
carbon-carbon double bonds. The commercial avai-
lablity of well-defined catalysts such as [Mo]-I
[
2]
(
Schrockꢀs catalyst), [Ru]-I (Grubbsꢀ first generation
[3]
catalyst), [Ru]-II (Grubbsꢀ second generation cata[5-]
[4]
lyst), and [Ru]-III (Hoveyda–Grubbsꢀ catalyst)
Figure 1) has expanded the variety of functional
(
groups amenable to CM and thus made olefin meta-
thesis practical for application in synthetic organic
Figure 2. Thiazole-containing natural products.
build such substructures in a very versatile and effi-
cient way starting from simple and readily available
compounds. Herein, we report a CM reaction involv-
ing vinyl-functionalized thiazoles using [Ru]-II and
[
Ru]-III catalysts, and a “one-pot” Stille coupling/CM
leading to bis-substituted thiazoles of type
Scheme 1).
The synthesis of compound 2 was achieved starting
A
(
[9]
from the corresponding 2,4-bis-trifloylthiazole 1 in
[10]
7
6% yield using the standard Stille conditions [vi-
nylstannane (1 equiv.), Pd(PPh ) (5 mol%), LiCl
5 equivs.), dioxane, 808C, 4 h]. In order to determine
AHCTREUNG
3
4
(
the best conditions for the CM reaction, compound 2
was then subjected to a series of CM experiments in
the presence of carbene ruthenium complexes [Ru]-I,
[Ru]-II, and [Ru]-III, and 4-methylpent-1-ene 3a
Figure 1. Commonly used metathesis catalysts.
152
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Synthesis of Vinyl-Functionalized Thiazoles
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Scheme 1. CM and tandem Stille coupling/CM of bis-functionalized thiazoles.
(
3 equivs.) as the coupling partner. The results are re- to 5 mol%, 4a was isolated in 81% (Table 1, entry 5).
ported in Table 1.
Similar yields were obtained when the reaction was
When 10 mol% of [Ru]-I were used and the reac- performed with 5 mol% of [Ru]-III in CH Cl as the
2
2
tion performed at room temperature for 24 h, the di- quasi complete disappearance of 2 took place in 12 h
substituted olefin 4a was isolated in 53% yield as a at room temperature and in 1 h in refluxing CH Cl to
2
2
single isomer (Table 1, entry 1). The (Z)-isomer was produce 4a in 83% and 84% yield respectively
1
13
not detected by either H or C NMR thus suggesting (Table 1, entries 6 and 7).
a selectivity superior to 95/5 in favor of the (E)-
The above experiments led us to select [Ru]-II and
isomer. It is noteworthy that under these conditions [Ru]-III over [Ru]-I as the catalyst candidates. A
only 66% of the starting material 2 were converted. series of CM experiments was therefore carried out
By performing the reaction in refluxing CH Cl under between 2 and a series of electron-rich olefinic part-
2
2
otherwise identical conditions, the conversion of 2 ners in order to explore the scope and limitation of
was increased to 90%, while the yield in 4a was in- the reaction. Typically, the CM were performed in re-
creased to 67% (Table 1, entry 2). The use of 10 fluxing CH Cl using 10 mol% of [Ru]-II and 5
2
2
[
11]
mol% of [Ru]-II at room temperature led to com- mol% of [Ru]-III. The results are summarized in
plete conversion of the starting material after only Table 2.
0.5 h, and compound 4a was isolated in 92% yield as
The reaction of compound 2 with 3 equivalents of
the (E)-isomer (Table 1, entry 3). To allow direct com- 3b using the two selected catalysts, [Ru]-II and [Ru]-
parison with the previous set of conditions, the reac- III, afforded the desired product 4b in 79% to 82%
tion was run in refluxing CH Cl in the presence of 10 isolated yield as the (E)-isomer (Table 2, entries 1 and
2
2
mol% of [Ru]-II. Under these conditions, 4a was iso- 2). Similarly, 2 reacted with 3c to give the desired
lated in 91% yield as the (E)-isomer (Table 1, product 4c in 86% to 89% yield (Table 2, entries 3
entry 4). By decreasing the amount of [Ru]-II catalyst and 4). For olefins such as allyltrimethylsilane 3d, bu-
[a]
Table 1. Olefin cross-metathesis reaction of 2-vinyl-4-trifloylthiazole.
[b]
[c]
[d]
Entry
Catalyst
Temperature [8C]
Time [h]
Conversion [%]
Yield [%]
E/Z
1
2
3
4
5
6
7
I (10 mol%)
I (10 mol%)
II (10 mol%)
II (10 mol%)
II (5 mol%)
III (5 mol%)
III (5 mol%)
24
40
24
40
24
24
40
24
18
0.5
0.5
12
12
1
66
90
100
100
95
53
67
92
91
81
83
84
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
100
[
[
[
[
a]
b]
c]
d]
All reactions were carried out on a 0.11 mmol scale using 3 equivs. of 3a in CH Cl .
Conversion determined by H NMR of the crude reaction mixture.
2
2
1
Isolated yield.
1
E/Z ratio determined by H NMR of the crude reaction mixture.
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153

Jyotirmayee Dash et al.
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[a]
Table 2. Olefin cross-metathesis of 2-vinyl-4-trifloylthiazole.
[b]
[c]
[d]
Entry Olefin
Catalyst
Time [h] Conversion [%]
Product
Yield [%]
E/Z
1
2
II (10 mol%)
III (5 mol%)
4
8
100
100
82
79
>20:1
>20:1
3
4
II (10 mol%) 12
III (5 mol%) 24
100
100
89
86
>20:1
>20:1
5
6
II (10 mol%)
III (5 mol%) 12
2
100
100
89
83
5:1
5:1
7
8
II (10 mol%) 18
III (5 mol%) 24
80
67
63
58
8:1
7:1
9
II (10 mol%) 24
III (5 mol%) 24
50
42
43
37
5:1
7:1
10
1
1
1
2
II (10 mol%) 24
III (5 mol%) 24
50
67
46
54
4:1
3:1
1
1
3
4
II (10 mol%) 24
III (5 mol%) 24
27
25
22
19
4:1
3:1
1
1
5
6
II (10 mol%) 12
III (5 mol%) 24
80
100
65
83
>20:1
>20:1
1
1
7
8
II (10 mol%) 18
86
77
57
51
>20:1
>20:1
III (5 mol%)
8
[
a]
All reactions were carried out on a 0.11 mmol scale using 1.5 equivs. of olefin (unless otherwise specified) in CH Cl at
2
2
4
08C.
[
[
[
[
b]
1
Conversion determined by H NMR of the crude reaction mixture.
Isolated yield.
E/Z ratio determined by H NMR of the crude reaction mixture.
c]
d]
e]
1
Reaction performed using 3 equivs. of the olefin partner.
tenyl acetate 3e, allyl diethylphosphonate 3f, and allyl bearing a free hydroxy group led to low yields of the
dimethylmalonate 3g, chemical yields were ranging desired coupled product, as 4h was isolated in only
from 37% to 89% while the E/Z stereoselectivity of 19% to 22% yield as a mixture of (E)- and (Z)-ste-
products 4d–g ranged from 3/1 to 8/1 in favor of the reoisomers (Table 2, entries 13 and 14). In compari-
(
E)-isomer (Table 2, entries 5–12). Interestingly, 3h son, the corresponding tert-butyldimethylsilyl protect-
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Synthesis of Vinyl-Functionalized Thiazoles
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ed alcohol 3i gave the desired coupled product as a (Scheme 4). Thus, treatment of 1 with 5 mol% of Pd-
single isomer in 83% yield when [Ru]-III was used (PPh ) in the presence of LiCl (4 equivs.) and vinyl-
Table 2, entry 16). Similarly, olefin 3j gave the de- tributylstannane (1.0 equiv.) at 808C followed, after
AHCTREUNG
3
4
(
sired CM-product 4j in both good yield and good ste- complete conversion of the starting material, by the
reoselectivity (51% to 57% yield) (Table 2, entries 17 addition of 5 mol% of [Ru]-III and olefin 3a led,
and 18). It is worth noting that vinyl-functionalized
thiazole 2 behaves as an olefin substituted with an
electron-withdrawing group and does not undergo
any homodimerization under the reaction conditions.
The CM could also be applied to 4-substituted vi-
nylthiazoles such as 6 which was prepared from bis-
trifloylthiazole 1 following two subsequent Stille cou-
plings in 30% overall yield (Scheme 2). Thus, the re-
Scheme 4. Tandem Stille coupling/CM of bis-trifloylthiazole
1
.
after 12 h at 408C, to the desired product 4a in mod-
erate to good yield depending on the nature of the
solvent used. Thus, when the reaction was performed
Scheme 2. Synthesis of 4-vinyl-functionalized thiazole.
action of 4-vinylthiazole 6 with olefin 3a and 3c in the in either dioxane or THF, 4a was isolated with yields
presence of 10 mol% of [Ru]-III in refluxing CH Cl ranging from 31% to 36%. On the other hand, when
for 12 h afforded the desired products 7a and 7c in the reaction was performed in toluene, 4a was isolat-
2
2
83% and 81% isolated yield respectively (Scheme 3). ed in 51% yield which can be compared favorably
The sequential use of reactions, also called “tandem with the standard two-step procedure.
reactions”, allows to circumvent the time and yield
In conclusion, we have shown that vinyl-functional-
loss associated with the isolation and purification of ized thiazoles could undergo CM with a variety of
[
12]
[1c]
intermediates in a multistep sequence.
In a more electron-rich olefins of Type 1 using ruthenium cat-
practical sense, it allows one to perform multiple alysts [Ru]-II and [Ru]-III to afford the desired cou-
transformations in a single reaction vessel thus lead- pled products in good to excellent yield. Moreover,
ing to a more environmentally friendly chemistry. In we have developed a very selective tandem Stille cou-
this context, we were able to perform a “one-pot” pling/CM process which provides an easy access to
Stille coupling/CM starting from bis-trifloylthiazole 1 functionalized thiazoles. The application of this meth-
odology to the synthesis of natural products is cur-
rently underway in our laboratory and the results will
be reported in due course.
Experimental Section
Typical Procedure for the CM of Vinyl-
Functionalized Thiazoles with Various Olefins
To a stirred solution of vinyl-functionalized thiazole 2
(
0.11 mmol) and olefin 4 (0.165 mmol, 1.5 equivs.) in CH Cl2
2
Scheme 3. CM of 4-vinyl-functionalized thiazole.
(1 mL) was added either [Ru]-II (0.01 mmol, 10 mol%) or
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155

Jyotirmayee Dash et al.
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[
Ru]-III (0.005 mmol, 5 mol%). The reaction mixture was
b) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hov-
eyda, J. Am. Chem. Soc. 2000, 122, 8168–8179.
heated under N at 408C (the reaction was monitored by
2
TLC). The solvent was then removed under reduced pres-
sure, and the residue purified by flash column chromatogra-
phy on silica gel (EtOAc/hexanes = 1/99 to 5/95).
Fully detailed experimental procedures and compound
characterization data can be found in the electronic Sup-
porting Information.
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Adv. Synth. Catal. 2007, 349, 152 – 156