Synthesis of vinyl-functionalized oxazoles by olefin cross-metathesis

Article abstract of DOI:10.1021/jo702305g

(Chemical Equation Presented) A ruthenium-based catalyzed olefin cross-methathesis reaction involving 2- and 4-vinyl-functionalized oxazoles was developed. A wide range of olefinic partners was coupled in good to excellent yields and high stereoselectivities under mild conditions. This methodology offers new opportunities for the synthesis of a plethora of biologically active natural products.

Full text of DOI:10.1021/jo702305g

and the commercial availability of several well-defined catalysts,
such as [Ru]-I (Grubbs first-generation catalyst),6 [Ru]-II
(Grubbs second-generation catalyst),7 and [Ru]-III (Hoveyda-
Grubbs catalyst)8 (Figure 2), has brought olefin metathesis to
the forefront of one of the most widely used synthetic methods
in carbon-carbon bond construction.9
Synthesis of Vinyl-Functionalized Oxazoles by
Olefin Cross-Metathesis
Thomas J. Hoffman,†,‡ James H. Rigby,‡
Stellios Arseniyadis,† and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI, CNRS,
10 rue Vauquelin, 75231 Paris Cedex 05, France, and
Department of Chemistry, Wayne State UniVersity,
Detroit, Michigan 48202-3489
Recent studies in our group have focused on developing an
efficient CM process applied to vinyl-functionalized thiazoles.
Our initial findings in the field were reported as a communica-
tion10 earlier this year and later resulted in the convergent total
synthesis of melithiazole C, a powerful fungicide isolated from
Melittangium lichenicola.11 Herein, we report the results of our
endeavor toward extending the substrate scope to 2- and 4-vinyl-
functionalized oxazoles.
janine.cossy@espci.fr
ReceiVed October 24, 2007
The initial study focused on the development of an effective
CM process applied to 2- and 4-vinyl-functionalized thiazoles.10
Hence, by subjecting these two compounds to various CM
experiments, it was found that the efficiency of the coupling
was highly catalyst-dependent as [Ru]-II and [Ru]-III appeared
to be more effective than [Ru]-I. Moreover, the CM reactions
were highly stereoselective in favor of the (E)-isomer as, for
most of the substrates engaged, the (Z)-isomer could barely be
detected by either H or 13C NMR.
1
A ruthenium-based catalyzed olefin cross-methathesis reac-
tion involving 2- and 4-vinyl-functionalized oxazoles was
developed. A wide range of olefinic partners was coupled
in good to excellent yields and high stereoselectivities under
mild conditions. This methodology offers new opportunities
for the synthesis of a plethora of biologically active natural
products.
Following these promising results, we subsequently turned
our attention toward the CM of 2- and 4-vinyl-functionalized
oxazoles, which, to the best of our knowledge, had never been
previously reported (Scheme 1).
The requisite 2-vinyl-functionalized oxazole 1 was readily
prepared from ethyl bromopyruvate (6) and acrylamide (7) by
using Holzapfel’s modified Hantzsch procedure12 as outlined
in Scheme 2. Under these reaction conditions, compound 1 was
isolated in 72% yield.
During the last two decades, the isolation of a wide range of
natural products containing the oxazole subunit has stimulated
considerable synthetic efforts. This interest has arisen from the
fact that many of these compounds, among them ulapualide A,1
mycalolide A,2 phorboxazole A,3 and calyculin A,4 have been
found to possess significant biological activities as cytotoxic,
antifungal, antibacterial, antitumor, and antiviral agents (Figure
1).5
Olefin cross-metathesis (CM) catalyzed by ruthenium carbene
complexes has been widely utilized as an advantageous method
in synthesizing various alkenes that would be otherwise difficult
to obtain. In addition, the relative ease of running such reactions
In order to validate the methodology on 2-vinyloxazoles, we
initially performed a series of test experiments on two types of
olefins we suspected would display very different reactivity
patterns. The two coupling partners chosen were type I7b olefin
3e and type II7b olefin 3j, while initial conditions involved the
(6) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c) Belderrain, T.
R.; Grubbs, R. H. Organometallics 1997, 16, 4001-4003.
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J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179.
† ESPCI.
‡ Wayne State University.
(1) (a) Roesner, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986, 108, 846-
847. (b) Matsusunaga, S.; Fusetani, K.; Hashimoto, K.; Koseki, K.; Norma,
M. J. Am. Chem. Soc. 1986, 108, 847-848. (c) Allingham, J. S.; Tanaka,
J.; Marriott, G.; Rayment, I. Org. Lett. 2004, 6, 597-599. (d) Pattenden,
G.; Ashweek, N. J.; Baker-Glenn, C. A. G.; Walker, G. A.; Yee, J. G. K.
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8131. (b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422-9423.
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10.1021/jo702305g CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/22/2008
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J. Org. Chem. 2008, 73, 2400-2403

FIGURE 1. Natural products containing the oxazole/thiazole subunit.
use of [Ru]-II and [Ru]-III as the ruthenium carbene catalyst
(10 mol %) in refluxing CH2Cl2 (Table 1).
study to broaden the substrate scope of the reaction. As a con-
sequence, a series of CM experiments was performed exclu-
sively using [Ru]-III as the carbene catalyst (10 mol %) and
1.5 equiv of the appropriate olefinic coupling partner in refluxing
CH2Cl2.12 The results are depicted in Table 1.
Interestingly, under these reaction conditions, both substrates
appeared to couple smoothly. While CM between p-methoxy-
benzyl-protected homoallylic alcohol 3e and 2-vinyloxazole 1
afforded the corresponding coupled product 4e in 67% and 87%
yield when using [Ru]-II and [Ru]-III (Table 1, entries 5 and
6), ethyl vinyl ketone (3j) led to disubstituted vinyloxazole 4l
in up to 65% yield after purification (Table 1, entries 13 and
14). Moreover, [Ru]-III appeared to be superior to [Ru]-II as
shorter reaction times along with greater yields and conversions
were obtained under otherwise identical conditions. These
interesting yet unexpected results set the ground rules for our
2-Vinyloxazole 1 appeared to readily undergo CM when
coupled to 4-methylpent-1-ene (3a), as the desired coupled
product 4a was isolated in both high yield (68%) and high
stereoselectivity (E/Z ) 11/1) (Table 1, entry 1). For olefins
such as allyltrimethylsilane (3b), allyl bromide (3c), and allyl
dimethylmalonate (3d), CM afforded the corresponding products
4b, 4c, and 4d with chemical yields ranging from 43% to 73%,
while the E/Z ratio varied from 6/1 to 10/1 in favor of the (E)-
isomer (Table 1, entries 2-4). Likewise, when olefin 3f was
used, the coupled product 4f was isolated in 59% yield as an
8/1 mixture of stereoisomers (Table 1, entry 7). High yields
were also accessed for substrates such as 3g (72%, Table 1,
entry 8) and 3h (77%, Table 1, entry 9) with selectivities ranging
from 7/1 to 11/1 in favor of the (E)-isomer in both cases.
The coupling efficiency of oxazole 1 with a series of styrene
derivatives showed a high dependency on the type of substituent
at the para position of the phenyl ring. Hence, p-fluoro-
substituted styrene (3i) gave the best yields (80%) (Table 1,
entry 10) when compared to styrene (3j) and p-methoxystyrene
(3k), which afforded the corresponding coupled products in 37%
and 26% yield, respectively (Table 1, entries 11 and 12). These
results suggest that electron-poor styrene derivatives such as 3i
are more prone to undergo CM with 1 in comparison to more
electron-rich styrene derivatives.
FIGURE 2. Commonly used metathesis catalysts.
SCHEME 1. Synthesis of 2- and 4-Vinyl-Functionalized
Oxazoles by Olefin CM
Finally, the reactions between 2-vinyloxazole 1 and electron-
deficient olefins such as methyl acrylate (3m) and tert-butyl
acrylate (3n) were also investigated. In both cases, CM appeared
to be very sluggish as only 52% of 4m and 24% of 4n were
isolated after 48 h (Table 1, entries 15 and 16). However, the
reactions did proceed to afford the desired coupled products in
contrast to the thiazole series tested previously which did not
undergo any CM, and the ratio of (Z)-isomer increased compared
to all the other olefins (E/Z ) 3/1, Table 1, entries 15 and 16).
Along with investigating the CM of 2-vinyloxazole 1, the
utility of the reaction was extended to oxazoles featuring a vinyl
group at the 4 position of the ring. The substrate examined, 2,
was readily prepared in 57% overall yield in two steps starting
from benzamide (8). The synthesis involved a one-pot trimeth-
ylsilyldiazomethane addition to the acyl isocyanate prepared in
SCHEME 2. Synthesis of 2-Vinyl-Functionalized Oxazole 1
J. Org. Chem, Vol. 73, No. 6, 2008 2401

TABLE 1. Olefin Cross-Metathesis Reaction of 2-Vinyloxazole 1a
a All reactions were carried out on a 0.11 mmol scale using 1.5 equiv of the selected olefin (unless otherwise specified) in CH2Cl2 at 40 °C. b Conversion
1
1
determined by H NMR of the crude reaction mixture. c Isolated yield in major isomer. d E/Z ratio determined by H NMR of the crude reaction mixture.
e Reaction performed using 3 equiv of the olefinic partner.
2402 J. Org. Chem., Vol. 73, No. 6, 2008

TABLE 2. Olefin Cross-Metathesis Reaction of 4-Vinyloxazole 2a
SCHEME 3. Synthesis of 4-Vinyl-Functionalized Oxazole 2
situ13 leading to an oxazolidinone, which was converted to the
corresponding enol triflate 9. The latter was then coupled with
vinyltributyltin under Stille conditions to introduce the vinyl
moiety and thus generate 4-vinyloxazole 2 in 57% yield overall
yield (Scheme 3).
a All reactions were carried out on a 0.11 mmol scale using 1.5 equiv of
the selected olefin (unless otherwise specified) in CH2Cl2 at 40 °C.
b Conversion determined by 1H NMR of the crude reaction mixture.
4-Vinyloxazole 2 was then subjected to an initial CM
experiment using [Ru]-III as the ruthenium carbene catalyst (10
mol %) and 4-methylpent-1-ene (3a) (3 equiv) as the olefinic
coupling partner in refluxing CH2Cl2. Surprisingly, under these
reaction conditions, the corresponding coupled product, 5a, was
isolated in low yield (36%) as a single stereoisomer (Table 2,
entry 1). The same result was observed with allyldimethylma-
lonate (3d), which upon coupling with 2 led to only 27% yield
of the desired coupled product 5d (Table 5, entry 2). However,
electron-poor olefins such as ethyl vinyl ketone (3l) and methyl
acrylate (3m) both coupled suitably well in comparison to
activated olefins, as after 36 h, 5l and 5m were both isolated in
72% and 60% yield, respectively, as single stereoisomers (Table
2, entries 3 and 4).
By closely examining the results obtained in the CM
involving thiazoles10 and oxazoles, both similarities and contrasts
in terms of reactivity and selectivity were observed. This was
typically the case for the 2-phenyl-4-vinyl systems, which could
be directly compared. First, the oxazoles appeared to be less
reactive than the thiazoles as higher yields/conversions along
with shorter reaction times were observed with the latter. This
feature may well be due to the fact that homodimerization of
the oxazole system was prevalent (type I olefin), while ho-
modimerization was not observed with the 4-vinylthiazole
system. Another striking aspect was the discrepancies observed
in the reactivity toward deactivated type II olefins such as
acrylates and enones. Indeed, in the case of vinyloxazoles 1
and 2, CM proceeded satisfactorily with enone 3l and tolerably
well with acrylates 3m and 3n, whereas vinylthiazoles failed
to provide any coupling product under similar conditions. Hence,
however closely related the two structures are, they both appear
to have a completely different reactivity pattern.
1
c Isolated yield. d E/Z ratio determined by H NMR of the crude reaction
mixture. e Reaction performed using 3 equiv of the olefinic partner.
systems with a variety of olefinic coupling partners. The fact
that many known biological active molecules exhibit motifs of
this type aroused interest in the use of this method toward new
synthetic targets. Implementation of this methodology in this
field is currently underway in our laboratory.
Experimental Section
General Procedure for the CM of Vinyl-Functionalized
Oxazoles with Various Olefins. To a stirred solution of 2- or
4-vinyl-functionalized oxazole (0.11 mmol) and the selected
olefin (0.17 mmol, 1.5 equiv) in CH2Cl2 (1 mL) was added either
[Ru]-II or [Ru]-III (0.01 mmol, 10 mol %). The reaction mixture
was heated under an argon atmosphere at 40 °C until completion
(the reactions were monitored by TLC). The solvent was then
removed under reduced pressure, and the crude residue was
purified by flash column chromatography on silica gel using a
gradient of eluent (Et2O/n-pentane: 1/9 to 5/5) or (EtOAc/
hexanes: 5/95 to 5/5) to provide the corresponding products
(see Tables 1 and 2).
Acknowledgment is made to the Ministe`re de l’Enseignement
Supe´rieur et de la Recherche for a grant to T.J.H.
Note Added after ASAP Publication. Hoveyda-Grubbs
catalyst was misspelled in the version published ASAP February
22, 2008; the corrected version was published February 25,
2008.
Overall, the use of the CM reaction has proven its potential
as a versatile method for coupling vinyl-functionalized oxazole
Supporting Information Available: General methods, experi-
mental procedures, and reproductions of 1H and 13C NMR data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) (a) Hari, Y.; Iguchi, I.; Aoyama, T. Synthesis 2004, 1359-1362.
(b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495-
2498.
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