Straightforward synthesis of α,β-unsaturated thioesters via ruthenium-catalyzed olefin cross-metathesis with thioacrylate

Article abstract of DOI:10.1021/jo800879e

(Chemical Equation Presented) The cross-metathesis reaction of S-ethyl thioacrylate with a variety of olefins is effectively catalyzed by using a ruthenium benzylidene olefin metathesis catalyst. This reaction provides a convenient and versatile route to substituted α,β-unsaturated thioesters, key building blocks in organic synthesis.

Full text of DOI:10.1021/jo800879e

catalyzed coupling reactions6 among others.7 R,ꢀ-Unsaturated
thioesters show important differences in their reactivity as
Michael acceptors compared to oxoesters.3d,8 They have been
found to be excellent substrates for enantioselective Cu-
catalyzed conjugate additions of Grignard reagents9 and their
reactivity has proven exceptionally versatile in the synthesis of
several natural products.9b,10
Straightforward Synthesis of r,ꢀ-Unsaturated
Thioesters via Ruthenium-Catalyzed Olefin
Cross-Metathesis with Thioacrylate
Anthoni W. van Zijl, Adriaan J. Minnaard,* and
Ben L. Feringa*
Although a highly useful intermediate, occasionally difficul-
ties are encountered in the synthesis of R,ꢀ-unsaturated thioesters
through classic methods,11 such as DCC/DMAP-coupling of
acids with thiols and transesterification with trimethylsilyl
thioethers, due to 1,4-addition of thiolate to the product. As
routine application of R,ꢀ-unsaturated thioesters relies on
methods that give ready access to these compounds, we were
interested in whether it was possible to synthesize these
compounds via cross-metathesis with a thioacrylate.
Stratingh Institute for Chemistry, UniVersity of Groningen,
Nijenborgh 4, 9747AG, Groningen, The Netherlands
a.j.minnaard@rug.nl; b.l.feringa@rug.nl
ReceiVed April 23, 2008
Ruthenium-catalyzed olefin metathesis has emerged as one
of the most versatile of synthetic methods over the past decade.12
It is frequently the method of choice for the construction of
carbon-carbon double bonds. In particular, cross-metathesis
allows for the formation of highly complex products from much
simpler precursors.13 The increased functional group tolerance
as a result of the development of new catalysts (Figure 1), their
commercial availability, and the Grubbs model to predict the
selectivity14 have enhanced greatly the utility of cross-metathesis
reactions.
The cross-metathesis reaction of S-ethyl thioacrylate with a
variety of olefins is effectively catalyzed by using a
ruthenium benzylidene olefin metathesis catalyst. This reac-
tion provides a convenient and versatile route to substituted
R,ꢀ-unsaturated thioesters, key building blocks in organic
synthesis.
The use of electron-deficient terminal olefins as cross-
metathesis partners, such as acrylates and vinyl ketones, which
are type II or type III olefins according to the Grubbs model, is
now relatively widespread. Although the use of other sulfur-
containing alkenes has been described previously, to the best
of our knowledge the use of thioacrylate compounds has so far
not been reported.15
Thioesters are highly relevant compounds due to their
distinctive chemical properties: the reduced electron delocal-
ization provides for enhanced reactivity compared to oxoesters.1
The importance of thioesters in the cell is well established:
biological systems use their relative reactivity in many enzymatic
reactions by employing, for example, acetyl coenzyme A,
cysteine proteases, or polyketide and fatty acid synthases.2 Their
enhanced reactivity compared to that of oxoesters has been
employed successfully in a wide range of synthetic organic
transformations, some inspired directly by related biosynthetic
pathways. Stereoselective aldol reactions often depend on the
distinctive reactivity of thioesters3 and their synthetic versatility
is further illustrated by many other well-known transformations
including R-alkylations,4 selective reductions,4,5 and Pd-
Thioacrylates are not commercially available and the current
preparative methods are either unsafe or expensive.16 However,
(6) (a) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003,
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11260–11261.
(7) For a review on thioester chemistry developed in the last 10 years, see:
Fujiwara, S.-I.; Kambe, N. Top. Curr. Chem. 2005, 251, 87–140.
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* Corresponding author. Fax: +31 50 363 4296. Phone: +31 50363 4235.
(1) (a) Yang, W.; Drueckhammer, D. G. J. Am. Chem. Soc. 2001, 123, 11004–
11009. (b) Wiberg, K. B. J. Chem. Educ. 1996, 73, 1089–1095. (c) Cronyn,
M. W.; Chang, M. P.; Wall, R. A. J. Am. Chem. Soc. 1955, 77, 3031–3034.
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Stryer, L. Biochemistry, 4th ed.; Freeman: New York, 1995. (c) Bruice, T. C.;
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Minnaard, A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123–5126. (b) Des Mazery,
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Information of ref 9b.
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10.1021/jo800879e CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5651–5653 5651

TABLE 1. Cross-Metathesis Reactions with S-Ethyl Thioacrylate
and 1-Octenea
entry
cat.
T
time
20 h
20 h
20 h
20 h
20 h
60 min
120 min
24 h
yield (%)
1
2
3
4
5
6
7
8
G-1 (2 mol %)
HG-1 (2 mol %)
G-2 (2 mol %)
HG-2(2 mol %)
Gre-2 (2 mol %)
HG-2(2 mol %)
HG-2(1 mol %)
HG-2 (0.5 mol %)
rt
rt
rt
rt
rt
ndb
ndb
76
93
72
94
94
42
reflux
reflux
reflux
FIGURE 1. Ruthenium-based metathesis catalysts: Grubbs 1st genera-
tion (G-1), Hoveyda-Grubbs 1st generation (HG-1), Grubbs 2nd
generation (G-2), Hoveyda-Grubbs 2nd generation (HG-2), and
Grela’s catalyst (Gre-2).
a Reaction conditions: 2 (1.0 mmol), 1-octene (2.5 equiv), catalyst
(0.5-2.0 mol %), CH2Cl2 (c ) 0.4 M). b Only formation of tetradec-
7-ene observed.
SCHEME 1. Preparation of S-Ethyl Thioacrylate through a
Wittig Reaction
only 72% yield. In all cases, only traces of the Z-isomer of 3
were detected, which were removed readily by column
chromatography.
With the best catalyst, HG-2, the reaction temperature and
catalyst loading were varied (Table 1, entries 6-8). The reaction
can be accelerated substantially by elevating the reaction
temperature: heating the mixture at reflux for 60 min yielded
94% of compound 3. With only 1 mol % catalyst, the same
excellent yield was obtained in 120 min, but the use of 0.5 mol
% of HG-2 led to incomplete conversion after 1 d and only a
42% yield of 3.
These optimized conditions for the cross-metathesis reaction
can be applied to a wide range of substrates to provide various
R,ꢀ-unsaturated thioesters (Table 2).21 The reactions were
performed in CH2Cl2 heated to reflux with 2 mol % HG-2. Most
cross-metathesis partners with a terminal olefin and which were
not branched on the allylic position led to fast reactions, which
provided the products in excellent yields (Table 2, entries 1-4).
Thioesters with a phenyl ring or trimethylsilyl group at the
γ-position (products 4 and 5) or a more remote oxoester group
(products 6 and 7) were thus obtained.
Reaction with styrene, featuring a conjugated double bond,
required an extended reaction time (Table 2, entry 5) providing
the cinnamic acid thioester 8 in 72% yield after 18 h. In the
case of linear terminal olefins with a carboxylic acid, an
unprotected alcohol, an aldehyde, or a bromide functionality a
second portion of catalyst was needed to bring the reaction to
completion (Table 2, entries 6-9); the same held for secondary
and tertiary unprotected allylic alcohols and allyl tosylamide
(Table 2, entries 10-12). The products 9-15 were all obtained
in good yield after 24 h.
it was found that compound 2 (Scheme 1) could be prepared
from Wittig reagent 1, which is readily available from bro-
moacetic acid, through DCC/DMAP-coupling followed by
reaction with PPh3.17 We could obtain 2 in 73% yield after
refluxing 1 in CH2Cl2 with 5 equiv of paraformaldehyde.18 The
reaction could be performed on a synthetically useful scale,
yielding up to 25 mL of pure thioacrylate. This new method
provides an excellent protocol to prepare thioacrylates on a large
scale.
With a new route to thioacrylate 2 in hand, the compound
was studied in a cross-metathesis reaction with a type I cross-
metathesis partner, 1-octene, and five well-known catalysts
(Figure 1). The results are summarized in Table 1, entries 1-5.
As expected according to the Grubbs model,14 both the Grubbs
and the Hoveyda-Grubbs first generation catalysts (G-1 and
HG-1) were found to be unsuitable for the reaction, since only
dimerization of the 1-octene was observed.
When using 2 mol % of the Grubbs second generation catalyst
(G-2), full conversion of the thioacrylate was observed after
20 h at rt and product 3 could be isolated in 76% yield.
However, the Hoveyda-Grubbs second generation catalyst
(HG-2)19 gave a cleaner reaction and under the same conditions
3 was obtained in 93% with this catalyst. The Gre-2 catalyst,
reported by Grela,20 was tested also, due to its known potential
in metathesis reactions with electron-deficient olefins. This did
not result in full conversion, however, and 3 was obtained in
Reactions with olefins containing an internal double bond,
such as 1,4-diacetoxy-cis-but-2-ene or 1,4-dibromo-trans-but-
2-ene, were performed with only 1.5 equiv of the cross-
metathesis partner and again two portions of the catalyst were
needed (Table 2, entries 13 and 14). Crotonic acid thioesters
with an acetoxy or bromo substituent at the γ-position (products
16 and 17, respectively) were obtained in good yield after 24 h.
In conclusion, a mild and scalable new route to S-ethyl
thioacrylate is presented. The feasibility of the use of this olefin
in cross-metathesis reactions with the Hoveyda-Grubbs second
(15) (a) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K. Chem. Eur.
J. 2008, 14, 806–818. (b) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic,
G.; Ling, T.; Yamada, Y.; Tang, W.; Frederick, M. O. Angew. Chem., Int. Ed.
2004, 43, 4318–4324. (c) Katayama, H.; Nagao, M.; Ozawa, F. Organometallics
2003, 22, 586–593. (d) Shi, Z.; Harrison, B. A.; Verdine, G. L. Org. Lett. 2003,
5, 633–636. (e) Spagnol, G.; Heck, M.-P.; Nolan, S. P.; Mioskowski, C. Org.
Lett. 2002, 4, 1767–1770. (f) Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H.
Pure Appl. Chem. 2002, 74, 7–10.
(16) (a) Schaumann, E.; Mergardt, B. J. Chem. Soc., Perkin Trans. 1 1989,
1361–1363. (b) Braude, G. J. Org. Chem. 1957, 22, 1675–1678. (c) Marvel,
C. S.; Jacobs, S. L.; Taft, W. K.; Labbe, B. G. J. Polym. Sci. 1956, 19, 59–72.
(17) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50, 709–
710.
(18) See the Supporting Information.
(19) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 791–799.
(21) Cross-metathesis with 3,3-dimethyl-1-butene was attempted but product
formation was not observed. The reaction was performed under the regular
conditions (as specified in Table 2), although with 3,3-dimethyl-1-butene as
cosolvent.
(20) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed.
2002, 41, 4038–4040.
5652 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 2. Cross-Metathesis Reactions with S-Ethyl Thioacrylate
temperature. The mixture was concentrated in vacuo and the residue
was suspended in pentane (100 mL) and filtered over silica. The
filtercake was washed (10:90 Et2O/pentane, 250 mL) and the filtrates
combined. Hydroquinone (ca. 30 mg) was added to the solution to
prevent polymerization and the solvents were removed by distil-
lation at atmospheric pressure, using an efficient fractionating
column. The crude thioacrylate was further purified by distillation
at reduced pressure (50 mbar, 56-58 °C), which afforded 2 (6.93
g, 73% yield) as a colorless oil. The compound was stored without
stabilizer and used as such in the metathesis reactions; to prevent
decomposition it was shielded from light and stored at 5-8 °C. 1H
NMR δ 6.37 (dd, J ) 17.2, 9.7 Hz, 1H), 6.28 (dd, J ) 17.2, 1.6
Hz, 1H), 5.66 (dd, J ) 9.7, 1.6 Hz, 1H), 2.96 (q, J ) 7.4 Hz, 2H),
1.29 (t, J ) 7.4 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 190.0,
134.9, 125.7, 22.9, 14.4; MS (EI) m/z 116 (M+, 37), 91 (6), 89 (6),
86 (17), 84 (25), 62 (10), 61 (16), 55 (100); HRMS calcd for
C5H8OS 116.0296, found 116.0299.
and a Range of Olefinsa
Typical Procedure for the Cross-Metathesis Reaction with
Thioacrylate: Synthesis of (E)-S-Ethyl Non-2-enethiolate (3). A
flame-dried Schlenk flask under N2 atmosphere was charged with
S-ethyl thioacrylate 2 (1.0 mmol, 116 mg), 1-octene (2.5 mmol,
395 µL), and CH2Cl2 (2.5 mL). Hoveyda-Grubbs second genera-
tion catalyst (2 mol %, 20 µmol, 12.5 mg) was added and the
resulting solution was stirred for 60 min at reflux temperature. The
mixture was then concentrated in vacuo and the residue purified
by flash column chromatography (SiO2, 0.5: 99.5 to 5: 95 Et2O/
pentane gradient, Rf (2:98) 0.45), which afforded 3 (188 mg, 94%
yield) as a colorless oil; 1H NMR δ 6.89 (dt, J ) 15.5 and 7.0 Hz,
1H), 6.10 (dt, J ) 15.5, 1.6 Hz, 1H), 2.94 (q, J ) 7.4 Hz, 2H),
2.22-2.14 (m, 2H), 1.50-1.38 (m, 2H), 1.35-1.24 (m, 9H), 0.88
(t, J ) 6.9 Hz, 1H); 13C NMR δ 190.0, 145.3, 128.5, 32.1, 31.5,
28.7, 27.8, 22.9, 22.4, 14.7, 13.9; MS (EI) m/z 200 (M+, 11), 140
(10), 139 (100), 81 (6), 69 (36), 68 (11), 67 (7), 55 (66), 53 (9);
HRMS calcd for C11H20OS 200.1235, found 200.1236.
a Reaction conditions:
Hoveyda-Grubbs 2nd generation catalyst (2.0 mol %), CH2Cl2 (c ) 0.4
M), reflux; b Hoveyda-Grubbs 2nd generation catalyst (4.0 mol %)
added in 2 portions. c CM-partner (1.5 equiv).
2 (1.0 mmol), CM-partner (2.5 equiv),
Acknowledgment. We thank the NRSC-Catalysis for finan-
cial support. T. D. Tiemersma-Wegman and A. Kiewiet are
thanked for technical assistance and Dr. W. R. Browne for
valuable suggestions.
generation catalyst is demonstrated. The high functional group
tolerance of the reaction allows the preparation of a broad range
of versatile functionalized R,ꢀ-unsaturated thioesters.
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
S-Ethyl Thioacrylate (2). A flame-dried Schlenk flask under
N2 atmosphere was charged with Wittig reagent 1 (29.8 g, 82
mmol), paraformaldehyde (12.3 g, 410 mmol), and CH2Cl2 (200
mL). The resulting suspension was stirred for 30 min at reflux
JO800879E
J. Org. Chem. Vol. 73, No. 14, 2008 5653