Cesium (Z)-2-carbomethoxyethenethiolate: A reagent for the preparation of (Z)-2-carbomethoxyethenyl thioethers including selected cysteine and homocysteine derivatives

Article abstract of DOI:10.1002/ejoc.200801025

As a means to circumvent the standard and sometimes troubling conjugate addition reaction of thiols to alkyl propiolates, a new reagent, cesium (Z)-2-carbomethoxyethenethiolate, is introduced. The cesium carbonate mediated methanolysis of ( Z)-2-carbometh

Full text of DOI:10.1002/ejoc.200801025

FULL PAPER
DOI: 10.1002/ejoc.200801025
Cesium (Z)-2-Carbomethoxyethenethiolate: A Reagent for the Preparation of
(Z)-2-Carbomethoxyethenyl Thioethers Including Selected Cysteine and
Homocysteine Derivatives
Jennifer S. O’Donnell,[a] Suneel P. Singh,[a] Thomas A. Metcalf,[a] and Adrian L. Schwan*[a]
Keywords: Cesium / Amino acids / Sulfur / Synthetic methods
As a means to circumvent the standard and sometimes troub-
ling conjugate addition reaction of thiols to alkyl propiolates,
a new reagent, cesium (Z)-2-carbomethoxyethenethiolate, is
introduced. The cesium carbonate mediated methanolysis of
(Z)-2-carbomethoxyethenyl thiolacetate at low temperature
creates cesium (Z)-2-carbomethoxyethenethiolate in solu-
tion. For base-insensitive and solvolytically stable electro-
duction to the electrophile. The conditions were adapted to
accommodate base-sensitive cysteine derivatives, and the
use of DMF as a cosolvent permits the isolation of (Z)-2-car-
bomethoxyethenyl cysteinyl thioethers in high enantiomeric
purity (Ͼ99:1 er) and with good Z/E ratios. There was no evi-
dence of carbon substitution reactions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
philes, efficient substitution can be achieved by direct intro- Germany, 2009)
stable cis form of the adduct was targeted on the basis of
Introduction
our needs and the existing ready access to trans addition
products. Moreover, (Z)-2-carboalkoxyethenyl thioethers
are useful in the synthesis of β-lactam analogs[16–19] and in
the preparation of dienophiles.[10] Given our needs and the
established value of (Z)-2-carboalkoxyethenyl thioethers,[20]
we report herein our study leading to cesium (Z)-2-
carbomethoxyethenethiolate, which serves to prepare (Z)-2-
carbomethoxyethenyl thioethers, including some vinylic
cysteine and homocysteine derivatives.
There has been considerable interest in the conjugate ad-
dition of thiols to alkynoate esters. The reaction has been
used to prepare sulfur heterocycles[1–3] and potential drug
candidates,[4] and it also serves as a general tool in organic
synthesis.[3,5–10] The addition reaction often gives a mixture
of double-bonded isomers and a solvent dependence on the
E/Z ratio of products has been observed[11,12] and ex-
plained.[13]
We have been interested in this reaction for eventual ac-
cess to selected vinylic sulfoxides, which in turn are con-
verted into α,β-unsaturated sulfinyl chlorides.[14] Also, the
addition of thiols to methyl propiolate gives thioethers,
which after oxidation serve as a general source of alkane-
and arenesulfenic acid anions.[15] For the latter reason we
had an opportunity to react protected cysteine derivatives
with methyl propiolate. Related reactions have been studied
in detail previously,[11] with yields varying from 40 to 75%.
Looking to improve on past results, we re-evaluated
some of the past chemistry[11] (vide infra) and as a result
sought to develop a new protocol for the preparation of
carboalkoxyethenyl thioethers, one that creates the vinylic
C–S bond at an earlier stage and one that precludes the
requirement of a selection of thiols. As many thiols are pre-
pared through manipulation of halides anyway, this was
viewed as a useful exercise. The thermodynamically less
Results and Discussion
The conjugate addition of Boc-Cys-OEt (1a) to methyl
propiolate (MP) parallels closely addition reactions re-
ported by Crisp and Millan,[11] who studied the reactions
of Cbz-Cys-OMe with ethyl propiolate (EP) in various sol-
vents. Under neutral conditions, in a variety of solvents,
those authors found the desired Michael product and a de-
hydroalanine derivative, but the E/Z ratio of the addition
products was typically not synthetically useful. Our reac-
tions were done with numerous bases,[21,22] in a variety of
solvents,[23] and with varying nitrogen protection (although
PG = Boc is detailed here).[24] Analysis of our reaction mix-
ture led to the isolation of Michael adduct 2 (0–68%) in
addition to dehydroalanine 3 and bisvinylic thioether 4
(Scheme 1).[25] Those products suggested that the Michael
addition could proceed in a satisfactory manner but the im-
mediate desired cysteine/MP adduct was prone to loss of
the sulfur group through an elimination reaction from the
amino acid. The resulting enethiolate then underwent sub-
sequent Michael addition to unreacted MP.
[a] Department of Chemistry, University of Guelph,
Guelph, ON, N1G 2W1, Canada
Fax: +1-519-766-1499
E-mail: schwan@uoguelph.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 547–553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
547

J. S. O’Donnell, S. P. Singh, T. A. Metcalf, A. L. Schwan
FULL PAPER
Scheme 3. Formation of cesium (Z)-2-carbomethoxyethenethiolate
and its general alkylation chemistry.
A wide variety of conditions for the conversion of 7 into
its cesium enethiolate were evaluated. Cs2CO3-mediated
methanolysis of the thiolacetate provided some suitability.
The mixtures were quenched with nBuI as a representative
electrophile. Good E/Z selectivity was observed when the
reaction temperature was kept below –10 °C. If the tem-
perature was raised to 50 °C, near-complete isomerization
to the E isomer was observed. Overall, several representa-
tive thioacrylates could be formed, as shown in Table 1.
Scheme 1. The sensitivity of direct conjugate addition of MP with
protected cysteines.
Although were we able to show that thioether 4 could
be treated with alkoxide to recover an equivalent of 5 for
alkylation chemistry,[24] the overall plan was viewed as
inefficient. Nevertheless, the alkylation chemistry of
(ECH=CHS–) prompted us to explore the direct use of
(ECH=CHS–) as an enethiolate alternative (Scheme 2, path
b) to the problematic conjugate addition reactions
(Scheme 2, path a). The use of enethiolates as a source of
vinylic thioethers is rare in comparison to the use of thiol
addition reactions. As such, only sporadic examples exist in
the literature.[10,17,26] As we sought to prepare 2-(Z)-
carbomethoxyethenyl cysteines from alaninyl halides, and
given the base sensitivity of the α-H of amino acids, we
decided to pursue the heretofore unknown cesium (Z)-
carbomethoxyethenethiolate (6), as it is recognized that
cesium thiolates do not perturb the chirality of selected
α-amino acid derivatives.[27–29] Although sodium (Z)-
carbomethoxyethenethiolate is known,[10,17] its preparation
requires aqueous NaOH, which we presumed would have a
deleterious effect on the amino acid chemistry.[30]
Table 1. Yields and stereoselectivities of substitution products 2
and 8.
Entry RX, temp[a]
Cond.[b] Prod./
%Yield
E/Z
er[e]
1
2
3
4
5
6
7
8
nBuI, r.t.
nBuI, r.t. (one step)
nBuI
nBuI, r.t. to 50 °C
BnBr
3-ClBnBr
iPrI
A
A
A
A
A
A
A
A
A
B
8a/76
8a/73
8a/70
8a/56
8b/83
8c/90
8d/0
1:2.6
1:4.2
1:16.7
13.3:1
1:20.7
1:14.7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
c-C6H11
I
8e/0
–
1:5.9
9
PMBBr
8f/30
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PMBBr[c]
8f/92 Ͻ1:49[f]
DPMBr[c]
B
8g/40
1:10.9
BnO2CCH2Br
EtO2CCH2I
EtO2CCH2I
A
A
C
A
A
A
C
A
C
A
C
A
C
C
8h/81 Ͻ1:49[f]
8h/83 Ͻ1:49[f]
8i/71
8j/76
1:8.2
1:19.5 Ͼ99:1
1:19.1 Ͼ99:1
(S)-Bz-homoAla(I)-OMe (9a)
(S)-Cbz-homoAla(I)-OMe (9b)
(R)-Boc-Ala(I)-OEt (10a)
(R)-Boc-Ala(I)-OEt[d]
(R)-Cbz-Ala(I)-OEt (10b)
(R)-Cbz-Ala(I)-OEt[d]
(R)-Bz-Ala(I)-OEt (10c)
(R)-Bz-Ala(I)-OEt[d]
(R)-Fmoc-Ala(I)-OEt (10d)
(R)-Fmoc-Ala(I)-OEt
(R)-Fmoc-Ala(Br)-OEt (10e)
8k/67
2a/62
2a/75
2b/75
2b/78
2c/75
2c/76
2d/52
2d/78
2d/81
1:25.0
1:8.7
1:11.8
1:6.0
1:4.7
1:4.3
1:2.4
1:6.6
1:3.6
41:59
Ͼ99:1
46:54
Ͼ99:1
43:58
Ͼ99:1
63:37
Ͼ99:1
Ͼ99:1
Scheme 2. Options for the preparation of 2-carboalkoxyethenyl
thioethers.
[a] All reactions were performed at –10 °C unless otherwise indi-
cated. [b] Reaction conditions, see Experimental Section. [c] Three
equivalents of the electrophile were employed. [d] Reactions were
performed at –40 °C. [e] Enantiomeric ratio of the Z isomer (only)
obtained by chiral HPLC by using a Chiralcel OJ-H column.
[f] Minor isomer was not detected.
We chose to access the target compound through (Z)-2-
carbomethoxyethenyl thiolacetate (7), a compound that has
not been addressed in the primary literature since
1968.[31–34] Targeting the cis isomer, we were able to find
conditions to effect the addition of thiolacetic acid to MP
in good yield and in a Ͼ20:1 Z/E ratio (NMR spectroscopic
analysis). Specifically, the use of a catalytic amount of imid-
Typical benzyl bromides reacted effectively with high
azole as the base provided the favorable double bond ratio Z/E ratios. The reaction of 6 with secondary alkyl iodides
(Scheme 3). Pure 7 was obtained through flash chromatog- did not proceed (Table 1, Entries 7 and 8), but benzhydryl
raphy in 79% yield on a multigram scale (Scheme 3).[35]
bromide reacted to afford 8g in low yield. Usually, the elec-
548
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 547–553

Reagent for the Preparation of (Z)-2-Carbomethoxyethenyl Thioethers
trophile is introduced in MeOH, but if the electrophile is able conditions based on established protocols of Cs2CO3
solvolysis prone, THF is an adequate replacement (condi- in DMF were eventually found.[27,28] Specifically, 6 is pro-
tions B). In particular, PMBBr only gave a high yield of duced as usual in MeOH at –40 °C. That solution is then
thioether when introduced in THF. If MeOH was em- transferred to a solution of iodide 10 in DMF at –40 °C
ployed, PMBOMe was clearly evident in the reaction mix- and stirred for 3 h. Under these conditions, improved yields
ture. Product 8f from this reaction is particularly note- of the product were obtained and there was no evidence of
worthy, as this is a useful precursor to α,β-unsaturated sulf- racemization at the α-position. Strangely, in some cases, the
inyl chlorides,[14] and the reaction at hand represents a more Z/E double-bond ratio suffered slightly. In the example of
efficient reaction than through the thiol (Figure 1).
2d, the yield, the Z/E ratio, and the α-carbon stereochemis-
try were all improved, but the electrophilic iodide is clearly
superior to the bromide.
These useful reaction conditions prompted us to revisit
the reaction of 6 with α-halo esters (Table 1, Entry 14). A
good yield and Z/E ratio were obtained, and the ethyl ester
was unperturbed.
In general, Entries 18–25 of Table 1 exhibit lower Z/E
ratios in comparison to earlier entries in the Table. The
reason may be based on the degree of substitution near the
halide-bearing carbon atom. Clearly, the two protecting
groups on substrates 10 create a steric impedance, which
retards direct substitution of the halide. Few, if any, of the
other electrophiles reported herein possess comparable hin-
drance. It follows then that slower substitution of 6 permits
more time for its isomerization, and moreover, the E ver-
sion of 6 may be expected to have less steric demands. The
Fmoc and Bz groups offer the lowest Z/E ratios. The result
obtained with the Fmoc group may be due to its large size
in relation to the other carbamate-based Cbz and Boc
groups. As to the ratio obtained with the benzoyl moiety,
the aryl group is two atoms closer to the reaction site than
the aryl group in the Cbz moiety, which may add additional
steric retardation to the substitution reaction.
With regard to products 2a–d, conditions A and C offer
complementary products, depending on one’s needs. Condi-
tions A tend to preserve the geometry of the double bond,
but clearly the stereochemistry of the amino acid is sacri-
ficed. In contrast, conditions C fully preserve the configura-
tion at the α-carbon while providing a Z/E ratio that is
slighted reduced; in many cases, however, it is still prefera-
ble than the ratio obtained under the conditions used for
Michael addition.
Figure 1. Alkylation products of cesium (Z)-2-carbomethoxy-
ethenethiolate.
α-Halo esters are also reactive electrophiles (Table 1, En-
tries 12 and 13), but transesterification occurred under con-
ditions A. Nevertheless, these two examples were indicative
of clean substitution α to the carbonyl group. Moreover,
there was no detectable E isomer in the mixture. In none of
these reactions did we observe any C-alkylation products.
The reaction of 6 with protected homoalaninyl iodides 9
occurred in good yield with high double-bond selectivity
and with preservation of chirality of the substrate; no race-
mization was detected. However, successful application of
these conditions to the more-sensitive alaninyl iodides 10
failed. Although good double-bond stereochemistry could
be maintained in some cases, there was significant racemi-
zation. A control experiment demonstrated that 6 was suffi-
ciently reactive to add to Cbz-Dha-OEt, which resulted the
formation of rac-2b (Scheme 4). Presumably, conditions A
induced some elimination of HI from compounds 10 and
subsequent conjugate addition produced products of atten-
uated stereogenicity.
Conclusions
In this paper we present the new enethiolate reagent ce-
sium (Z)-carbomethoxyethenethiolate (6). This reagent is
conveniently prepared from thiolacetate 7, which in turn
arises from the reaction of thiolacetic acid and methyl pro-
piolate. The Z stereochemistry of 6 is maintained at low
temperature, and the reagent exhibits sulfur nucleophilicity
exclusively with a variety of electrophiles. The compounds
prepared have value in the preparation of sulfenate
Scheme 4. Reaction of cesium (Z)-2-carbomethoxyethenethiolate
with a dehydroalanine.
Numerous experiments were performed to improve the anions[15] and in some cases sulfinyl chlorides.[14]
outcome of the reactions of 6 with iodides 10, including the Most importantly, thiolate 6 reacts with protected
use of substoichiometric amounts of Cs2CO3, neutraliza- alaninyl and homoalaninyl iodides to produce the equiva-
tion methods, and attempts to isolate the cesium enethiol- lent of the Z Michael addition product of protected cysteine
ate, but these efforts did not offer any viable solutions. Suit- with methyl propiolate. The reaction occurs in good yield
Eur. J. Org. Chem. 2009, 547–553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
549

J. S. O’Donnell, S. P. Singh, T. A. Metcalf, A. L. Schwan
FULL PAPER
raphy (10% EtOAc/hexanes) in 79% yield. Data for the Z isomer:
M.p. 51–53 °C (ref.[32] 58–59 °C). 1H NMR (400 MHz): δ = 7.80
(d, J = 10.3 Hz, 1 H), 6.10 (d, J = 10.3 Hz, 1 H), 3.78 (s, 3 H),
2.48 (s, 3 H) ppm. 13C NMR (75.5 MHz): δ = 191.8, 166.5, 137.3,
with high double-bond stereoselectivity, all while preserving
the integrity of the α-carbon configuration. This is an im-
portant achievement given our difficulty and fair yields ob-
tained with base-induced conjugate additions of protected
cysteine derivatives. Moreover, the preserved stereogenicity
permits further elaboration in target-oriented synthe-
sis.[36–38]
116.2, 51.7, 30.8 ppm. IR (CHCl ): ν = 2849, 1710, 1600, 1359,
˜
3
1126 cm–1.
General Procedures for the Synthesis of (Z)-2-Carbomethoxyethenyl
Alkyl Thioethers
Method A: Cs2CO3 (1.02 equiv.) was added to a solution of thiol-
acetate 7 (1 equiv.) dissolved in MeOH (6 mL) at –10 °C, followed
by the immediate addition of a solution of RX (1 equiv.) in MeOH
(1–2 mL). The reaction mixture was allowed to stir overnight and
a 5% solution of HCl was added until the solution was acidic by
litmus. CH2Cl2 was added, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3ϫ), and the com-
bined organic layer was washed with brine, dried with MgSO4, fil-
tered, and concentrated under reduced pressure to give the crude
thioether, which was purified by flash chromatography through sil-
ica gel (EtOAc/hexanes). Thioether yields were calculated from thi-
olacetate 7.
Experimental Section
General: Melting points were determined with a MEL-TEMP melt-
ing point apparatus and are uncorrected. Infrared (IR) spectra were
obtained with a Bomen FT-IR spectrometer. 1H and 13C NMR
spectra were recorded with a Bruker model spectrometer at the
frequency indicated in CDCl3 unless otherwise noted. Chemical
shifts are referenced to CHCl3 or tetramethylsilane and are re-
corded in parts per million (ppm). Mass spectra (MS) were per-
formed at either the McMaster Regional Centre for Mass Spec-
trometry, McMaster University, or the WATSPEC Mass Spectrom-
etry Facility, University of Waterloo. Elemental analyses were per-
formed by MHW Laboratories of Pheonix, AZ. Solvents were dis-
tilled and dried. Chemicals were purchased from Aldrich unless
otherwise specified. All air- and water-sensitive reagents were trans-
ferred by oven-dried, nitrogen-purged syringes into flame-dried
flasks. Flash chromatography was performed on virgin or recycled
200–450 mesh Type 60 Å silica gel. Analytical thin-layer
chromatography (TLC) was performed by using 0.25-mm Merck
Kieselgel 60 F254 precoated glass-backed silica-gel plates or Silicy-
cle 0.25-mm, extra hard layer, 60 Å F254 glass-backed silica-gel
plates. HPLC experiments were performed with a Waters 600–2487
(λ = 254 nm) system by using a Chiralcel OJ-H (0.46ϫ25 cm) col-
umn and iPrOH/hexane as the eluent. Optical rotations were mea-
sured with a Rudolph Research Autopol III automatic polarimeter
in 1-dm tubes.
Method B: This method mirrors method A, except three equivalents
of electrophile were introduced in THF.
Method C:
A cooled (–40 or –10 °C) solution of Cs2CO3
(1.02 equiv.) in MeOH (6 mL) was added to a cooled (–40 or
–10 °C) solution of thiolacetate 7 (1.0 equiv.) in MeOH (6 mL) un-
der a nitrogen atmosphere. The mixture was stirred for 5 min. and
added to a cooled solution (–40 or –10 °C) of RX (1.1 equiv.) in
DMF (13 mL). The reaction mixture was allowed to stir 3 h, and
the volatiles were removed under reduced pressure. The remaining
organic layer was added to 10% aqueous citric acid and extracted
with diethyl ether (3ϫ50 mL). The combined organic layer was
washed with H2O (1ϫ20 mL) and brine (2ϫ20 mL), dried with
MgSO4, filtered, and concentrated under reduced pressure. The re-
sulting thioether was purified as per method A.
Sample Reaction of 1a with MP: A solution of (R)-Boc-Cys-OEt
(Z)-2-Carbomethoxyethenyl Butyl Thioether (8a) (Method A): Thi-
(1a; 1.92 g, 7.72 mmol) was prepared in CH2Cl2 (10 mL) and olacetate 7 (100 mg, 0.625 mmol) in MeOH (5 mL) at –10 °C was
cooled to 0 °C. Methyl propiolate (890 µL, 10.0 mmol) was added,
followed by the slow addition of triethylamine (1.18 mL,
8.49 mmol), upon which the solution turned dark brown. The mix-
ture was stirred for 60 min, allowing the ice bath to warm to room
temperature. A 5% solution of HCl was added, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(3ϫ), and the combined organic layer washed with H2O and brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. The resulting thioether was isolated by flash chromatography
(silica gel, 10% EtOAc/hexanes). Thioether yields were calculated
from the thiol. Thioether (2a, data presented later) was obtained
in 38% yield, accompanied by Boc-Dha-OEt (3a)[39] and bisvinylic
thioether 4 in variable yields. Data for 4: M.p. 140–142 °C (MeOH).
1H NMR (400 MHz): δ = 7.70 (d, J = 15.4 Hz, 1 H), 6.09 (d, J =
15.4 Hz, 1 H), 3.77 (s, 3 H) ppm. 13C NMR (100.6 MHz): δ =
treated with Cs2CO3 (208 mg, 0.637 mmol), followed by the imme-
diate addition of a solution of nBuI (85.3 µL, 0.750 mmol) in
MeOH (1 mL). Thioether 8a (76.5 mg, 70%) was isolated as a pale-
yellow oil after flash chromatography (5% EtOAc/hexanes) as a
1
mixture of E/Z isomers (1:16.7). Data for the Z isomer: H NMR
(400 MHz): δ = 7.70 (d, J = 15.2 Hz, 1 H), 7.11 (d, J = 10.2 Hz, 1
H), 5.85 (d, J = 10.2 Hz, 1 H), 5.75 (d, J = 15.2 Hz, 1 H), 3.74 (s,
3 H), 3.72 (s, 3 H), 2.79 (t, J = 7.4 Hz, 2 H), 2.77 (t, J = 7.4 Hz, 2
H), 1.66 (p, J = 7.4 Hz, 4 H), 1.45 (sextet, J = 7.4 Hz, 4 H), 0.94
(t, J = 7.4 Hz, 3 H), 0.93 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75.5 MHz): δ = 166.7, 150.5, 112.2, 50.8, 35.4, 32.1, 21.3,
13.3 ppm. IR (CDCl ): ν = 2961, 2875, 1697, 1581 cm–1. MS (EI):
˜
3
m/z (%) = 174 (100) [M]+, 149 (62), 143 (58), 117 (55), 114 (32), 86
(42), 69 (27), 57 (40). HRMS (EI): calcd. for C8H14O2S 174.0715;
found 174.0714.
164.8, 140.9, 119.0, 51.8 ppm. IR (CDCl ): ν = 3002, 2953, 1716,
˜
3
(Z)-2-Carbomethoxyethenyl Benzyl Thioether (8b) (Method A): Thi-
olacetate 7 (120 mg, 0.750 mmol) in MeOH (7 mL) at –10 °C was
treated with Cs2CO3 (249 mg, 0.765 mmol), followed by the imme-
diate addition of a solution of BnBr (107 µL, 0.900 mmol) in
MeOH (3 mL). Thioether 8b (129 mg, 83%) was isolated as an oil
after flash chromatography (5% EtOAc/hexanes) as a mixture of
E/Z isomers (1:20.3). Data for the mixture of isomers: M.p. 47–
51 °C. Data for the Z isomer:[40] 1H NMR (400 MHz): δ = 7.71 (d,
J = 15.1 Hz, 1 H), 7.30 (m, 10 H), 7.06 (d, J = 10.2 Hz, 1 H), 5.83
(d, J = 15.0 Hz, 1 H), 5.82 (d, J = 10.3 Hz, 1 H), 4.00 (s, 2 H), 3.95
1582 cm–1. MS (EI): m/z (%) = 202 (100) [M]+, 171 (41), 143 (57),
127 (56), 117 (43), 99 (13), 85 (22), 59 (28), 58 (15). HRMS (EI):
calcd. for C8H10O4S 202.0300; found 202.0298.
(Z)-2-Carbomethoxyethenyl Thiolacetate (7): Methyl propiolate
(8.0 mL, 89.4 mmol) in CH3CN (50 mL) was added dropwise over
2 h to a stirred solution of thiolacetic acid (4.4 mL, 61.8 mmol) and
imidazole (210 mg, 3.0 mmol) in CH3CN (170 mL) at 45 °C. The
reaction mixture was stirred overnight at 45 °C. Acetonitrile was
removed under vacuum. Pure 7 was obtained by flash chromatog-
550
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 547–553

Reagent for the Preparation of (Z)-2-Carbomethoxyethenyl Thioethers
(s, 2 H), 3.71 (s, 3 H), 3.70 (s, 3 H) ppm. 13C NMR (100.6 MHz): δ (19), 126 (37), 117 (100), 99 (16), 84 (11), 59 (17). C7H10O4S
= 166.8, 148.8, 137.0, 128.9, 128.7, 127.4, 113.0, 51.1, 39.3 ppm.
(190.22): calcd. C 44.23, H 5.26; found C 44.40, H 5.09.
IR (CDCl ): ν = 3066, 3032, 2951, 2846, 1708, 1585, 1496, 1435,
˜
3
Ethyl [(Z)-2-Carbomethoxyethenylsulfanyl]acetate (8i) (Method C):
A cooled (–10 °C) solution of Cs2CO3 (416 mg, 1.27 mmol) in
1312, 1042, 828 cm–1.
(Z)-2-Carbomethoxyethenyl 3-Chlorobenzyl Thioether (8c) (Method methanol (6 mL) was added to a cooled (–10 °C) solution of thiola-
A): Thiolacetate 7 (120 mg, 0.750 mmol) in MeOH (7 mL) at cetate 7 (200 mg, 1.25 mmol) in MeOH (6 mL). The mixture was
–10 °C was treated with Cs2CO3 (249 mg, 0.765 mmol), followed stirred for 5 min and then added to a cooled solution (–10 °C) of
by the immediate addition of a solution of 3-chlorobenzyl bromide
(118 µL, 0.900 mmol) in MeOH (3 mL). Thioether 8c (165 mg,
90%) was isolated as a pale-yellow oil after flash chromatography
RX (148.0 µL, 1.25 mmol) in DMF (13 mL). Thioether 8i (180 mg,
71%) was obtained as a pale-yellow oil as a mixture of E/Z isomers
(1:8.2). Data for the Z isomer: H NMR (300 MHz): δ = 7.12 (d,
1
(5% EtOAc/hexanes) as a mixture of E/Z isomers (1:14.6). Data
for the Z isomer: H NMR (400 MHz): δ = 7.33 (s, 1 H), 7.23 (m, 2 H), 3.61 (s, 3 H), 3.30 (s, 2 H), 1.14 (t, J = 7.2 Hz, 3 H) ppm.
J = 10.2 Hz, 1 H), 5.79 (d, J = 9.9 Hz, 1 H), 4.06 (q, J = 7.2 Hz,
1
3 H), 7.02 (d, J = 10.2 Hz, 1 H), 5.85 (d, J = 10.2 Hz, 1 H), 3.93
13C NMR (75.5 MHz): δ = 169.1, 166.6, 148.4, 113.9, 61.4, 51.1,
(s, 2 H), 3.73 (s, 3 H) ppm. 13C NMR (75.5 MHz), δ = 166.8, 148.2, 36.3, 13.9 ppm. IR (KBr): ν = 3433, 2983, 2943, 1734, 1694, 1580,
˜
139.2, 134.5, 130.0, 128.9, 127.6, 127.0, 113.5, 51.2, 38.8 ppm. IR
1219, 1167, 801 cm–1. HRMS (TOF EI+): calcd. for C8H12O4S
(CDCl ): ν = 2952, 1697, 1579, 1224, 1172, 1009, 802 cm–1. MS [M]+ 204.0456; found 204.0445.
˜
3
(EI): m/z (%) = 242 (49) [M]+, 211 (14), 127 (32), 117 (60), 89 (15).
(S)-Bz-homoCys[(Z)-2-carbomethoxyethenyl]-OMe (8j) (Method A):
Thiolacetate 7 (85.0 mg, 0.531 mmol) in MeOH (5 mL) was treated
with Cs2CO3 (177 mg, 0.542 mmol), followed by the immediate ad-
C11H11ClO2S (242.72): calcd. C 54.46, H 4.53; found C 54.56, H
4.32.
(Z)-2-Carbomethoxyethenyl p-Methoxybenzyl Thioether (8f) dition of
a solution of Bz-homoAla(I)-OMe (9a; 184 mg,
(Method B): Thiolacetate 7 (120 mg, 0.750 mmol) in MeOH (7 mL)
at –10 °C was treated with Cs2CO3 (249 mg, 0.765 mmol), followed
by the immediate addition of a solution of PMBBr (452 mg,
2.25 mmol) in THF (3 mL). Thioether 8f (164 mg, 92%) was iso-
lated as an oil after flash chromatography (5% EtOAc/hexanes) as
the Z isomer exclusively (no E isomer detected). Data for the Z
0.531 mmol) in MeOH (2 mL). Thioether 8j (136 mg, 76%, er
Ͼ99:1) was isolated as a white solid after flash chromatography
(30% EtOAc/hexanes, then 50% EtOAc/hexanes) as a mixture of
E/Z isomers (1:19.5). Data for the Z isomer: M.p. 102–103 °C.
[α]2D5 = +43.0 (c = 1.05, CHCl3). 1H NMR (400 MHz): δ = 7.82 (d,
J = 7.2 Hz, 2 H), 7.47 (m, 3 H), 7.06 (d, J = 10.2 Hz, 1 H), 7.03
(s, 1 H), 5.87 (d, J = 10.2 Hz, 1 H), 4.90 (dt, J = 5.1, 7.6 Hz, 1 H),
3.79 (s, 3 H), 3.72 (s, 3 H), 2.86 (m, 2 H), 2.37 (m, 1 H), 2.19 (m,
1 H) ppm. 13C NMR (100.6 MHz): δ = 172.2, 167.2, 166.9, 149.4,
145.9, 133.4, 131.9, 128.6, 127.1, 113.4, 52.8, 51.8, 51.3, 33.4, 31.8,
1
isomer: H NMR (400 MHz): δ = 7.24 (d, J = 8.7 Hz, 2 H), 7.06
(d, J = 10.2 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2 H), 5.81 (d, J =
10.2 Hz, 1 H), 3.91 (s, 2 H), 3.78 (s, 3 H), 3.71 (s, 3 H) ppm. 13C
NMR (75.5 MHz): δ = 166.8, 158.8, 148.8, 130.0, 128.9, 114.0,
112.8, 55.1, 51.1, 38.7 ppm. IR (CDCl ): ν = 3007, 2952, 1698,
27.8 ppm. IR (CDCl ): ν = 3429, 2952, 1739, 1697, 1666, 1223,
˜
˜
3
3
1512, 1172, 833 cm–1. C12H14O3S (238.30): calcd. C 60.53, H 5.88;
1172, 802 cm–1. MS (EI): m/z (%) = 337 (3) [M]+, 220 (13), 216
(18), 193 (50), 184 (14), 161 (44), 105 (100), 77 (24). C16H19NO5S
(337.39): calcd. C 56.66, H 5.60; found C 56.86, H 5.57. HPLC
(8% iPrOH/hexanes, 1 mLmin–1 flow rate): tR = 52.6 min.
found C 60.74, H 5.64.
(Z)-2-Carbomethoxyethenyl Diphenylmethyl Thioether (8g) (Method
B): Thiolacetate 7 (120 mg, 0.750 mmol) in MeOH (7 mL) at
–10 °C was treated with Cs2CO3 (249 mg, 0.765 mmol), followed (S)-Cbz-homoCys[(Z)-2-carbomethoxyethenyl]-OMe (8k) (Method
by the immediate addition of a solution of DPMBr (185 mg,
2.25 mmol) in THF (3 mL). Thioether 8g (97.7 mg, 40%) was iso-
lated as a white solid after flash chromatography (5% EtOAc/hex-
A): Thiolacetate 7 (594 mg, 3.71 mmol) in MeOH (36 mL) was
treated with Cs2CO3 (1.23 mg, 3.79 mmol), followed by the imme-
diate addition of a solution of Cbz-homoAla(I)-OMe (9b; 1.40 g,
anes) as a mixture of E/Z isomers (1:10.9). Data for the Z isomer: 3.71 mmol) in MeOH (12 mL). Thioether 8k (911 mg, 67%, er
1
M.p. 109–110 °C (EtOAc/hexanes). H NMR (400 MHz): δ = 7.33
(m, 10 H), 6.98 (d, J = 10.3 Hz, 1 H), 5.79 (d, J = 10.3 Hz, 1 H),
5.42 (s, 1 H), 3.73 (s, 3 H) ppm. 13C NMR (75.5 MHz): δ = 165.6,
145.6, 139.5, 128.9, 128.3, 127.8, 115.1, 55.2, 51.4 ppm. IR
Ͼ99:1) was isolated as an oil after flash chromatography (25%
EtOAc/hexanes, then 50% EtOAc/hexanes) as a mixture of E/Z
isomers (1:19.1). Data for the Z isomer: [α]2D5 = +21.6 (c = 1.04,
CHCl3). 1H NMR (400 MHz): δ = 7.35 (m, 5 H), 7.01 (d, J =
10.2 Hz, 1 H), 5.88 (d, J = 10.2 Hz, 1 H), 5.38 (br. d, J = 7.6 Hz,
1 H), 5.12 (s, 2 H), 4.48 (dt, J = 5.3, 7.6 Hz, 1 H), 3.76 (s, 3 H),
3.74 (s, 3 H), 2.79 (m, 2 H), 2.24 (m, 1 H), 2.04 (m, 1 H) ppm. 13C
NMR (75.5 MHz): δ = 172.0, 166.9, 155.9, 149.4, 136.0, 128.5,
128.2, 128.1, 113.3, 67.1, 53.0, 52.6, 51.2, 33.5, 31.6 ppm. IR
(CDCl ): ν = 3029, 2951, 1696, 1576, 1438, 1227, 1170, 803 cm–1.
˜
3
MS (EI): m/z (%) = 284 (2) [M]+, 168 (15), 167 (100), 166 (9), 165
(25), 152 (12). C17H16O2S (284.37): calcd. C 71.85, H 5.63; found
C 72.00, H 5.66.
Methyl [(Z)-2-Carbomethoxyethenylsulfanyl]acetate (8h) (Method
A): Thiolacetate 7 (100 mg, 0.625 mmol) in MeOH (8 mL) at
–10 °C was treated with Cs2CO3 (208 mg, 0.637 mmol), followed
by the immediate addition of a solution of ethyl 2-iodoacetate
(74.0 µL, 0.625 mmol) or benzyl 2-bromoacetate (99.0 µL,
0.625 mmol) in MeOH (2 mL). Transesterified methyl ester thio-
ether 8h (95.9 mg, 81%) was isolated as a pale-yellow oil after flash
chromatography (15% EtOAc/hexanes) as the Z isomer exclusively
(CH Cl ): ν = 3409, 2956, 1742, 1725, 1698, 1218, 1172, 803 cm–1.
˜
2
2
C17H21NO6S (367.42): calcd. C 56.61, H 5.72; found C 55.72, H
5.53. HPLC (8% iPrOH/hexanes, 1 mLmin–1 flow rate): tR
=
47.1 min.
(R)-Boc-Cys[(Z)-2-carbomethoxyethenyl]-OEt (2a) (Method C): A
cooled (–40 °C) solution of Cs2CO3 (416 mg, 1.27 mmol) in MeOH
(6 mL) was added to a cooled (–40 °C) solution of thiolacetate 7
(no E isomer detected). Data for the Z isomer: 1H NMR (200 mg, 1.25 mmol) in MeOH (6 mL). The mixture was stirred for
(400 MHz): δ = 7.23 (d, J = 10.1 Hz, 1 H), 5.94 (d, J = 10.1 Hz, 1
5 min and then added to a cooled solution (–40 °C) of Boc-Ala(I)-
H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.44 (s, 2 H) ppm. 13C NMR OEt (10a; 471 mg, 1.37 mmol) in DMF (13 mL). Workup and puri-
(75.5 MHz): δ = 169.8, 166.8, 148.1, 113.9, 52.6, 51.3, 36.2 ppm.
IR (CH Cl ): ν = 2953, 1738, 1698, 1582, 1172, 1009, 803 cm–1.
fication gave thioether 2a (320 mg, 77%, er Ͼ99:1) as an oil as a
mixture of E/Z isomers (1:8.7). Data for the Z isomer: [α]2D5 = +50.5
(c = 0.80, CH2Cl2). 1H NMR (400 MHz): δ = 7.02 (d, J = 10.1 Hz,
˜
2
2
MS (EI): m/z (%) = 190 (40) [M]+, 159 (21), 158 (59), 131 (18), 130
Eur. J. Org. Chem. 2009, 547–553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
551

J. S. O’Donnell, S. P. Singh, T. A. Metcalf, A. L. Schwan
FULL PAPER
1 H), 5.85 (d, J = 10.1 Hz, 1 H), 5.39 (br. d, J = 6.4 Hz, 1 H), 4.60 mixture was separated by flash chromatography (10% EtOAc/hex-
(m 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.74 (s, 3 H), 3.29 (br. m, 2 H),
anes, then 15% EtOAc/hexanes). Data for the Z isomer: [α]2D5
=
1
1.45 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100.6 MHz), +83.5 (c = 0.96, CH2Cl2). M.p. 91–92 °C. H NMR (400 MHz): δ
δ = 169.9, 165.4, 154.9, 146.3, 114.8, 80.4, 62.1, 53.1, 51.4, 35.2,
= 7.80 (m, 2 H), 7.51 (m, 3 H), 7.10 (br. d, J = 6.6 Hz, 1 H), 7.03
(d, J = 10.1 Hz, 1 H), 5.81 (d, J = 10.1 Hz, 1 H), 5.06 (dt, J = 4.3,
6.6 Hz, 1 H), 4.28 (q, J = 6.6 Hz, 2 H), 3.72 (s, 3 H), 3.45 (ABX,
28.2, 14.0 ppm. IR (KBr): ν = 3432, 2987, 1747, 1718, 1690 cm–1.
˜
MS (TOF CI+): m/z (%) = 334.1 (0.6) [M + H]+, 278.1 (20). 277.1
(16), 260.1 (39), 234.1 (100), 228.0 (59), 216.0 (77), 160.0 (78). JAX = 4.7 Hz, JBX = 4.0 Hz, JAB = 14.3 Hz, 2 H), 1.32 (t, J =
C14H23NO6S (333.40): calcd. C 50.47, H 6.90; found C 50.60, H
6.6 Hz, 3 H) ppm. 13C NMR (75.5 MHz), δ = 169.9, 167.2, 149.9,
6.88. HPLC (8% iPrOH/hexanes, 1 mLmin–1 flow rate): tR
=
133.4, 132.1, 128.7, 127.1, 113.5, 62.4, 53.3, 51.4, 38.1, 14.2 ppm.
17.3 min. Data for the E isomer: 1H NMR (400 MHz): δ = 7.51 (d,
J = 15.3 Hz, 1 H), 5.79 (d, J = 15.3 Hz, 1 H), 5.34 (br. d, J =
IR (CDCl ): ν = 3426, 3032, 2952, 1737, 1698, 1665, 804 cm–1. MS
˜
3
(EI): m/z (%) = 337 (14) [M]+, 216 (59), 143 (14), 105 (100), 77
6.4 Hz, 1 H), 4.58 (m 1 H), 4.16 (q, J = 6.3 Hz, 2 H), 3.64 (s, 3 H), (30). C16H19NO5S (337.39): calcd. C 57.00, H 5.63; found C 56.90,
3.34 (ABX, JAX = 4.7 Hz, JBX = 4.8 Hz, JAB = 14.1 Hz, 2 H), 1.38
(s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz): δ
= 169.9, 165.4, 154.9, 146.3, 80.4, 62.2, 53.1, 51.4, 35.2, 28.2,
H 5.67. HPLC (8% iPrOH/hexanes, 1 mLmin–1 flow rate): tR
=
52.1 min. Data for the E isomer: M.p. 84–85 °C. 1H NMR
(400 MHz): δ = 7.78–7.76 (m, 2 H), 7.55 (d, J = 15.3 Hz, 1 H),
14.0 ppm. IR (KBr): ν = 3367, 2979, 1716, 1584, 1524, 1255, 7.52–7.48 (m, 1 H), 7.44–7.40 (m, 2 H), 6.98 (br. d, J = 5.7 Hz, 1
˜
1165 cm–1. MS (ES+): m/z (%) = 356.1 (21) [M + Na]+, 351.2 (66)
[M + NH4]+, 334.1 (8) [M + H]+, 278.0 (15), 234.0 (32), 219.9 (20),
202.9 (7). HRMS (TOF ESI+): calcd. for C14H27NO2S [M +
NH4]+ 351.1590; found 351.1590. HPLC (8% iPrOH/hexanes,
1 mLmin–1 flow rate): tR = 10.9 min.
H), 5.86 (d, J = 15.3 Hz, 1 H), 5.06 (dt, J = 4.3, 6.7 Hz, 1 H), 4.26
(q, J = 7.1 Hz, 2 H), 3.61 (s, 3 H), 3.56–3.34 (ABX, JAX = 4.6 Hz,
JBX = 4.2 Hz, JAB = 14.1 Hz, 2 H), 1.31 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (100.6 MHz): δ = 169.8, 167.1, 165.2, 146.2, 133.3, 132.0,
128.6, 127.1, 115.2, 62.5, 52.4, 51.4, 34.8, 14.0 ppm. IR (KBr): ν =
˜
3339, 2951, 1701, 1580, 1523, 1219, 1169 cm–1. MS (ES+): m/z (%)
= 360.1, (42) [M + Na]+, 338.1 (100) [M + H]+, 306.1 (11), 242
(18). HRMS (TOF ESI+): calcd. for C16H20NO6S [M + H]+
338.1062; found 338.1053. HPLC (8% iPrOH/hexanes, 1 mLmin–1
flow rate): tR = 42.5 min.
(R)-Cbz-Cys[(Z)-2-carbomethoxyethenyl]-OEt (2b) (Method C): A
cooled (–40 °C) solution of Cs2CO3 (416 mg, 1.27 mmol) in MeOH
(6 mL) was added to a cooled (–40 °C) solution of thiolacetate 7
(200 mg, 1.25 mmol) in MeOH (6 mL). The mixture was stirred for
5 min and then added to a cooled solution (–40 °C) of Cbz-Ala(I)-
OEt (10b; 518 mg, 1.37 mmol) in DMF (13 mL). Workup and puri-
fication gave thioether 2b (360 mg, 78%, er Ͼ99:1) as a white solid
as a mixture of E/Z isomers (1:5.4). The isomeric mixture was sepa-
rated by careful flash chromatography (15% EtOAc/hexanes). Data
for the Z isomer: [α]2D5 = +65.0 (c = 0.96, CH2Cl2). M.p. 76–77 °C.
1H NMR (400 MHz): δ = 7.35 (m, 5 H), 6.95 (d, J = 10.1 Hz, 1
H), 5.78 (d, J = 10.1 Hz, 1 H), 5.65 (br. d, J = 6.6 Hz, 1 H), 5.12
(ABq, J = 12.2 Hz, 2 H), 4.66 (m, 1 H), 4.23 (q, J = 7.2 Hz, 2 H),
3.73 (s, 3 H), 3.30 (d, J = 4.4 Hz, 2 H), 1.29 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (75.5 MHz), δ = 169.7, 166.8, 155.6, 149.7, 136.1,
128.5, 128.3, 128.1, 113.5, 67.1, 62.2, 54.4, 51.3, 38.3, 14.1 ppm. IR
(R)-Fmoc-Cys[(Z)-2-carbomethoxyethenyl]-OEt (2d) (Method C): A
cooled (–10 °C) solution of Cs2CO3 (204 mg, 0.625 mmol) in
MeOH (2.5 mL) was added to a cooled (–10 °C) solution of thiol-
acetate 7 (100 mg, 0.625 mmol) in MeOH (2.5 mL) under a nitro-
gen atmosphere. The mixture was stirred for 5 min and then added
to a cooled solution (–10 °C) of Fmoc-Ala(I)-OEt (10d; 319 mg,
0.687 mmol) or Fmoc-Ala(Br)-OEt (10e; 274 mg, 0.656 mmol) in
DMF (6 mL). Workup and purification gave thioether 2d (222 mg,
78% from 10d; 231 mg, 81% from 10e; er Ͼ99:1) as a white solid
as a mixture of E/Z isomers (1:6.6 from 10d; 1:3.6 from 10e). The
isomeric mixture was separated by flash chromatography (10%
EtOAc/hexanes). It should be noted that the reaction was not com-
plete after 3 h when the experiment was performed at –40 °C. Data
for the Z isomer: [α]2D5 = +29.7 (c = 0.8, CH2Cl2). 1H NMR
(400 MHz): δ = 7.74 (d, J = 7.4 Hz, 2 H), 7.57 (d, J = 7.4 Hz, 2
H), 7.38 (t, J = 7.4 Hz, 2 H), 7.30 (t, J = 7.4 Hz, 2 H), 6.96 (d, J
= 10.1 Hz, 1 H), 5.81 (d, J = 10.1 Hz, 1 H), 5.80 (br. s, 1 H), 4.67
(m, 1 H), 4.40 (m, 2 H), 4.21 (m, 3 H), 3.71 (s, 3 H), 3.27 (br. d, J
= 4.5 Hz, 2 H), 1.27 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(75.5 MHz), δ = 169.6, 166.7, 155.5, 149.4, 143.5, 141.1, 127.6,
127.0, 124.9, 119.9, 113.5, 67.0, 62.1, 54.2, 51.2, 46.9, 38.2,
(CDCl ): ν = 3425, 3035, 2952, 1748, 1719, 1701, 805, 602 cm–1.
˜
3
MS (TOF CI+): m/z (%) = 368.1 (49) [M + H]+, 324.1 (61), 277.1
(43), 260.0 (100), 243.1 (49), 228.0 (94), 216.0 (90), 183.1 (55), 117.0
(70), 108.1 (60), 91.0 (87). C17H21NO6S (367.42): calcd. C 55.61, H
5.72; found
C 55.38, H 5.52. HPLC (8% iPrOH/hexanes,
1 mLmin–1 flow rate): tR = 48.9 min. Data for the E isomer: M.p.
58–59 °C. 1H NMR (400 MHz): δ = 7.55 (d, J = 15.2 Hz, 1 H),
7.33–7.29 (m, 5 H), 5.84 (d, J = 15.2 Hz, 1 H), 5.65 (br. d, J =
6.0 Hz, 1 H), 5.13 (ABq, J = 12.1 Hz, 2 H), 4.66 (m, 1 H), 4.23 (q,
J = 7.1 Hz, 2 H), 3.67 (s, 3 H), 3.31 (ABX, JAX = 4.7 Hz, JBX
=
4.8 Hz, JAB = 14.0 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (100.6 MHz): δ = 168.3, 164.1, 154.2, 144.8, 134.6, 127.2,
127.0, 126.8, 113.7, 66.0, 61.1, 52.2, 50.2, 23.8, 12.7 (CH3) ppm.
14.0 ppm. IR (CH Cl ): ν = 3417, 1723, 1698, 1172 cm–1. MS (CI,
˜
2
2
NH3): m/z (%) = 473 (100) [M + NH4]+, 456 (11), 372 (13), 277
(19), 234 (20), 179 (16), 178 (20). HRMS (EI). calcd. for
C24H25NO6S [M]+ 455.1404; found 455.1412. HPLC (30% iPrOH/
hexanes, 0.7 mLmin–1 flow rate): tR = 49.6 min. Data for the E
IR (KBr): ν = 3325, 1728, 1713, 1693, 1583, 1274, 1167 cm–1. MS
˜
(ESI+): m/z (%) = 390.2 (100) [M + Na]+, 385.2 (7) [M + NH4]+,
242.5 (56). HRMS (TOF ESI+): calcd. for C17H25N2O6S [M +
NH4]+ 385.1433; found 385.1454. HPLC (8% iPrOH/hexanes,
1 mLmin–1 flow rate): tR = 23.5 min.
1
isomer: H NMR (400 MHz): δ = 7.74 (d, J = 7.5 Hz, 2 H), 7.59–
7.55 (m, 3 H), 7.38 (t, J = 7.4 Hz, 2 H), 7.32–7.27 (m, 2 H), 5.86
(d, J = 15.3 Hz, 1 H), 5.65 (d, J = 7.2 Hz, 1 H), 4.68 (m, 1 H),
4.45–4.32 (m, 2 H), 4.26–4.19 (m, 3 H), 3.62 (s, 3 H), 3.42–3.24
(ABX, JAX = 4.6 Hz, JBX = 4.7 Hz, JAB = 14.0 Hz, 2 H), 1.30 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (100.6 MHz): δ = 169.6, 165.3,
155.5, 146.0, 143.6, 141.2, 127.7, 127.0, 125.0, 119.9, 115.0, 67.3,
(R)-Bz-Cys[(Z)-2-carbomethoxyethenyl]-OEt (2c) (Method C): A
cooled (–40 °C) solution of Cs2CO3 (204 mg, 0.625 mmol) in
MeOH (2.5 mL) was added to a cooled (–40 °C) solution of thiol-
acetate 7 (100 mg, 0.625 mmol) in MeOH (2.5 mL). The mixture
was stirred for 5 min and then added to a cooled solution (–40 °C)
of Bz-Ala(I)-OEt (10c; 238 mg, 0.687 mmol) in DMF (6 mL).
Workup and purification gave thioether 2c (160 mg, 76%, er Ͼ99:1)
as a white solid as a mixture of E/Z isomers (1:4.3). The isomeric
62.4, 53.4, 51.4, 47.0, 34.9, 14.0 ppm. IR (KBr): ν = 3325, 1710,
˜
1583, 1268, 1167 cm–1. MS (ESI+): m/z (%) = 478.1 (100) [M +
Na]+, 473.1 (54) [M + NH4]+, 456.1 (9) [M + H]+, 449.4 (44), 425.2
(37), 390.1 (57), 385.1 (45), 368.2 (14), 192.1 (10), 102.1 (13).
552
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 547–553

Reagent for the Preparation of (Z)-2-Carbomethoxyethenyl Thioethers
HRMS (TOF ESI+): calcd. for C24H26NO6S [M + H]+ 456.1481;
found 456.1502. HPLC (30% iPrOH/hexanes, 0.7 mLmin–1 flow
rate): tR = 27.2 min.
[17] H. R. Pfaendler, J. Gosteli, R. B. Woodward, J. Am. Chem. Soc.
1979, 101, 6306–6310.
[18] P. H. Crackett, C. W. Greengrass, R. J. Stoodley, Tetrahedron
Lett. 1986, 27, 1301–1304.
[19] N. D. Pearson, T. C. Smale, R. Southgate, Tetrahedron Lett.
1995, 36, 4493–4496.
Supporting Information (see footnote on the first page of this arti-
cle): Preparation of the amino acid based electrophiles.
[20] Under IUPAC nomenclature, the targets (products) of this
chemistry are known as methyl (2Z)-3-(alkylsulfanyl)prop-2-
enoates.
[21] N. D. Smith, M. Goodman, Org. Lett. 2003, 5, 1035–1037.
[22] C. Dugave, A. Menez, J. Org. Chem. 1996, 61, 6067–6070.
[23] O. Arjona, R. Medel, J. Rojas, A. M. Costa, J. Vilarrasa, Tetra-
hedron Lett. 2003, 44, 6369–6373.
[24] J. S. O’Donnell, PhD Thesis, University of Guelph, 2005.
[25] M. Hashemi, M. Akhbari, S. Arianfar, J. Sulfur Chem. 2004,
25, 95–99.
[26] For more examples of ethenethiolate chemistry, see: a) M. Och-
iai, M. Hirobe, K. Miyamoto, J. Am. Chem. Soc. 2006, 128,
9046–9047; b) A. L. Schwan, M. D. Refvik, Synlett 1998, 96–
98; c) V. A. Potapov, N. K. Gusarova, B. A. Trofimov, S. V.
Amosova, A. S. Kashik, Sulfur Lett. 1985, 3, 151–154; d) K.
Kpegba, P. Metzner, Tetrahedron Lett. 1990, 31, 1853–1856; e)
E. Block, S.-H. Zhao, J. Org. Chem. 1992, 57, 5815–5817; f)
S. V. Amosova, G. M. Gavrilova, A. V. Afonin, Russ. J. Org.
Chem. 2005, 41,402–405.
Acknowledgments
The authors wish to thank the Natural Sciences and Engineering
Research Council of Canada for funding this research. Acknowl-
edgment is also made to the Donors of the American Chemical
Society Petroleum Research Fund for partial support of this re-
search. J. S. O. thanks the Ontario Government for a Science and
Technology Graduate Fellowship.
[1] A. A. Esmaili, M. Ghereghloo, M. R. Islami, H. R. Bijanza-
deh, Tetrahedron 2003, 59, 4785–4788.
[2] V. A. Bakulev, V. S. Berseneva, N. P. Belskaia, Y. Y. Morzherin,
A. Zaitsev, W. Dehaen, I. Luyten, S. Toppet, Org. Biomol.
Chem. 2003, 1, 134–139.
[3] M. Journet, A. Rouillard, D. Cai, R. D. Larsen, J. Org. Chem.
1997, 62, 8630–8631.
[4] M. Mitsukuchi, T. Ikemoto, M. Taguchi, S. Higuchi, S. Abe,
H. Yasui, K. Hatayama, K. Sota, Chem. Pharm. Bull. 1989, 37,
3286–3293.
[5] N. Maezaki, S. Yagi, R. Yoshigami, J. Maeda, T. Suzuki, S.
Ohsawa, K. Tsukamoto, T. Tanaka, J. Org. Chem. 2003, 68,
5550–5558.
[27] H. Shao, S. H. H. Wang, C.-W. Lee, G. Oesapay, M. Goodman,
J. Chem. Soc. 1995, 60, 2956–2957.
[28] C. Dugave, A. Menez, Tetrahedron: Asymmetry 1997, 8, 1453–
1465.
[29] R. N. Salvatore, R. A. Smith, A. K. Nischwitz, T. Gavin, Tetra-
hedron Lett. 2005, 46, 8931–8935.
[6] Y. V. Bilokin, A. Melman, V. Niddam, B. Benhamu, M. D. Ba-
chi, Tetrahedron 2000, 56, 3425–3437.
[7] J. Zhang, S. Saito, T. Koizumi, J. Org. Chem. 1998, 63, 9375–
9384.
[8] L. N. Sobenina, A. P. Demenev, A. b. I. Mikhaleva, V. N. Elo-
khina, A. G. MalЈkina, O. g. A. Tarasova, I. A. Ushakov, B. A.
Trofimov, Synthesis 2001, 293–299.
[9] Y. Arai, Y. Hayashi, M. Yamamoto, H. Takayema, T. Koizumi,
J. Chem. Soc. Perkin Trans. 1 1988, 3133–3140.
[10] O. De Lucchi, M. Buso, G. Modena, Tetrahedron Lett. 1987,
28, 107–110.
[11] G. T. Crisp, M. J. Millan, Tetrahedron 1998, 54, 637–648.
[12] P. D. Halphen, T. C. Owen, J. Org. Chem. 1973, 38, 3507–3510.
[13] M. E. Jung, K. R. Buszek, J. Am. Chem. Soc. 1988, 110, 3965–
3969.
[14] A. L. Schwan, R. R. Strickler, Y. Lear, M. L. Kalin, T. E. Riet-
veld, T.-J. Xiang, D. Brillon, J. Org. Chem. 1998, 63, 7825–
7832.
[30] Silver (Z)-carbomethoxyethenethiolate is also known, but its
preparation also requires hydroxide. M. Giffard, I. Léauté, J.
Chem. Res. (S) 1990, 320–321.
[31] L. N. Owen, M. U. S. Sultanbawa, J. Chem. Soc. 1949, 3109–
3113.
[32] W. H. Mueller, J. Org. Chem. 1966, 31, 3075–3079.
[33] G. Dallas, J. W. Lown, J. C. N. Ma, J. Chem. Soc. C 1968,
2510–2514.
[34] D. T. Witiak, M. C. Lu, J. Org. Chem. 1968, 33, 4451–4454.
[35] The separability of 7 from its E isomer is important, as in our
experience, the chromatographic separation of E/Z isomers of
alkyl carbomethoxyethenyl thioethers can be challenging.
[36] X. Moreau, J.-M. Campagne, J. Org. Chem. 2003, 68, 5346–
5350.
[37] C. P. Sar, J. Jeko, P. Fajer, K. Hideg, Synthesis 1999, 1039–1045.
[38] G. T. Crisp, M. J. Millan, Tetrahedron 1998, 54, 649–666.
[39] J. L. Adams, T. M. Chen, B. W. Metcalf, J. Org. Chem. 1985,
50, 2730–2736.
[15] J. S. O’Donnell, A. L. Schwan, Tetrahedron Lett. 2003, 44,
[40] U. Koelle, C. Rietmann, J. Tjoe, T. Wagner, U. Englert, Organo-
metallics 1995, 14, 703–713.
6293–6296.
[16] H. R. Pfaendler, J. Gosteli, R. B. Woodward, J. Am. Chem. Soc.
1980, 102, 2039–2043.
Received: October 20, 2008
Published Online: Decmeber 9, 2008
Eur. J. Org. Chem. 2009, 547–553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
553