Preparation of arylmercapturic acids by S-arylation of N,N′- diacetylcystine

Article abstract of DOI:10.1002/ejoc.200900982

A simple convenient method has been developed for the preparation of N-acetyl-S-arylcysteines based on the Chan-Lam-Evans arylation of N,N′-diacetylcystine dimethyl ester with arylboronic acids and used to synthesize a series of arylmercapturic acids. Unlike copper-mediated N-arylation, the S-arylation of neither cysteine nor cystine derivatives proceeded satisfactorily in the presence of air. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900982

FULL PAPER
DOI: 10.1002/ejoc.200900982
Preparation of Arylmercapturic Acids by S-Arylation of N,NЈ-Diacetylcystine
[a]
[a]
ˇ
Jan Krouzelka and Igor Linhart*
Keywords: Arylation / Sulfides / Copper / Amino acids / Reaction mechanisms
A simple convenient method has been developed for the
preparation of N-acetyl-S-arylcysteines based on the Chan–
Lam–Evans arylation of N,NЈ-diacetylcystine dimethyl ester
with arylboronic acids and used to synthesize a series of aryl-
mercapturic acids. Unlike copper-mediated N-arylation, the
S-arylation of neither cysteine nor cystine derivatives pro-
ceeded satisfactorily in the presence of air.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
its ability to arylate aliphatic thiols in high yields by using
arylboronic acids as the starting material. Interestingly,
more than 1 equiv. of CuII was needed in this procedure.
Liebeskind and co-workers noted that thiols are easily oxi-
dised by CuII to disulfides, which are actually the ultimate
substrates for S-arylation.[9] They found that, indeed, di-
alkyl disulfides react with arylboronic acids in the presence
of at least a stoichiometric amount of CuI salts to give the
corresponding alkyl aryl sulfides and 1 equiv. of CuI thiol-
ate, which is inactive as a catalyst (Scheme 2).
Introduction
Electrophilic arene oxides react in vivo with glutathione,
a cellular tripeptide that provides first-line protection
against the attack of electrophiles and free radicals. The glu-
tathione (GSH) conjugates formed undergo subsequent
aromatization and biotransformation by the mercapturic
acid pathway (MAP) to afford N-acetyl-S-arylcysteines,
mercapturic acids, as metabolic end-products excreted in
urine (Scheme 1).[1] The presence of mercapturic acids indi-
cates internal exposure to potentially mutagenic and carcin-
ogenic compounds, for example, phenylmercapturic acid
has been used in occupational medicine as a biomarker of
exposure to benzene, reflecting its metabolic activation to
benzene oxide.[2] A traditional method for the synthesis of
arylmercapturic acids was based on the addition of arene-
thiols to 2-acetamidopropenoate.[3] Another approach used
the reaction of arenediazonium salts with N-acetylcyste-
ine.[4] However, recent developments in organometallic
chemistry have provided new possibilities for aryl–sulfur
bond-forming reactions by using palladium[5] or copper[6]
complexes. Aryl iodides can be used as substrates for cop-
per- or palladium-mediated arylation of the thiol group of
N-acetylcysteine to give mercapturic acids.[7] Over the last
two decades a wide range of arylboronic acids have become
readily commercially available so that nowadays they are
reactants of choice for various arylation reactions including
S-arylation. They have also been used successfully for CuII-
mediated S-arylation of N-protected cysteine derivatives.[8]
Although various S-arylation procedures have been devel-
oped for the preparation of unsymmetrical sulfides, that of
Guy and co-workers[8] seems to be exceptional because of
Scheme 1. In vivo formation of mercapturic acids from arene ox-
ides.
Scheme 2. Stoichiometry of the arylation of thiols with arylboronic
acids according to Liebeskind and co-workers.[9]
[a] Department of Organic Chemistry, Faculty of Chemical Tech-
nology, Institute of Chemical Technology Prague,
Technická 1905, 166 28 Prague, Czech Republic
Fax: +420-220-444-288
The aim of this work was to develop a suitable S-aryl-
ation procedure for the synthesis of mercapturic acids bear-
ing a wide range of aryl groups.
E-mail: linharti@vscht.cz
6336
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6336–6340

Arylmercapturic Acids by S-Arylation of N,NЈ-Diacetylcystine
placement of pyridine by phenanthroline as a stronger li-
gand as well as by potassium carbonate as a simple inor-
ganic base led to elimination to yield methyl 2-acetamido-
propenoate, and no arylation product was formed. Simi-
larly, increasing the amount of pyridine to 10 equiv. gave
the eliminated acetamidopropenoate.
N,NЈ-Diacetylcystine dimethyl ester (2) was tested as an-
other starting material for the S-arylations. Its reaction with
3 equiv. of CuI acetate and 6 equiv. of pyridine (correspond-
ing to 1.5 equiv. of CuI acetate and 3 equiv. of pyridine for
each sulfur in 2) gave an almost quantitative yield with
phenylboronic acid (3a). Decreasing the amount of CuI to
2 equiv. led to a marked decrease in the yield (Table 1, en-
tries 10 and 11). With CuII acetate the reaction also pro-
ceeded satisfactorily (Table 1, entry 12). Nevertheless, the
optimum yield was obtained with cystine 2 as the starting
material and 3.0 equiv. of CuI as the mediator.
Results and Discussion
In our early attempts to arylate N-acetylcysteine methyl
ester (1) with phenylboronic acid (3a) under the conditions
of Guy and co-workers[8] (2.2 equiv. of boronic acid,
1.5 equiv. of CuII acetate and 3 equiv. of pyridine) we found
that the yield of 4a was 63% based on 1 (Table 1, entry 1).
This represents significantly more than a quantitative yield
when the stoichiometry outlined in Scheme 2 is taken into
account. To explain this discrepancy and to gain an insight
into the reaction mechanism we performed a series of ex-
periments using 1 or N,NЈ-diacetylcystine dimethyl ester (2)
with various amounts of CuI or CuII acetates (Scheme 3);
the results are shown in Table 1.
Table 1. Preparation of S-phenylmercapturic acid (4a) by copper-
mediated arylation. Optimization of the reaction conditions.[a]
Entry Starting
material
Mediator
Cu cat.
Pyridine
% Yield[b]
of 4
Although CuI thiolates were not active either as catalysts
or as mediators of the reaction, they could be used as start-
ing materials provided that an additional copper salt, CuI
acetate, was added. Thus, CuI butanethiolate and 1.5 equiv.
of phenylboronic acid with 1 equiv. of CuOAc and 3 equiv.
of pyridine gave a 47% yield of butyl phenyl sulfide. Simi-
larly, the CuI salt of 1 under the same conditions gave 62%
of 4a. The reaction appears to be rather non-selective as far
as the starting material is concerned.
Unlike copper-catalysed N-arylations, which require air
oxygen to proceed,[6a] the S-arylation required anoxic con-
ditions. In the presence of dry air the yields were much
lower (Table 1, compare entries 1 and 5 and 9 and 10). Simi-
larly, the addition of water (3% in DMF) to the reaction
mixture decreased the yield of 4d from 50 to 28%. Tolylbo-
ronic acid 3d was chosen for this experiment because it was
expected that the addition of water might improve the solu-
bility of the catalytic species and thereby measurably in-
crease the yield. A possible mechanism for the arylation of
disulfides is outlined in the Scheme 4. Pyridine ligands are
not shown for the sake of simplicity, although the reaction
did not proceed at all when pyridine was omitted from the
reaction mixture (Table 1, entries 6 and 7). Pyridine acts as
a ligand rather than a base and seems to play an important
role in tuning the reactivity of the intermediary Cu com-
plex. The reaction sequence begins with an oxidative ad-
dition of the disulfide to CuI followed by transmetallation
of the boronic acid with CuIII and reductive elimination to
yield alkyl aryl sulfide and CuI thiolate, which is arylated in
the presence of CuI acetate. The mechanism for this second
Amount
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
2
2
2
2
Cu(OAc)2
CuOAc
CuOAc
1.5 equiv.
1.0 equiv.
1.5 equiv.
2.0 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
2.0 equiv.
3.0 equiv.
3 equiv.
3 equiv.
3 equiv.
3 equiv.
3 equiv.
10 equiv.
–
63
3
53
CuOAc
55
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuOAc
CuOAc
CuOAc
13[c]
0[d]
0[e]
0[f]
23[c]
96
–
9
6 equiv.
6 equiv.
6 equiv.
6 equiv.
10
11
12
CuOAc
Cu(OAc)2
69
78
[a] The reactions were performed in DMF at 100 °C. [b] Isolated
yields. [c] In the presence of dry air. [d] Methyl 2-acetamidopro-
penoate was isolated as the sole product. [e] NaH (1 equiv.) was
added as a base. [f] K2CO3 (3 equiv.) was used instead of pyridine.
Scheme 3. Arylation of N-acetylcysteine methyl and N,NЈ-di-
acetylcystine dimethyl esters.
DMF was used as the solvent and pyridine (3 equiv.) was arylation is not clear but it has been proved that CuI thio-
added to act as a ligand. Thiol 1 with 1.0 equiv. of CuI gave lates can be arylated under the reaction conditions used.
only 3% of 4a due to the strong binding of CuI to the cyste- The role of CuI acetate seems to be crucial and can be ex-
ine thiol group leading to an inactive CuI thiolate. The opti- plained by the formation of a six-membered-ring complex
mal amount of CuI for this reaction appears to be 1.5 equiv. followed by oxidative addition of arylboronic acid and re-
Addition of more than 1.5 equiv. of CuI did not further ductive elimination of the aryl sulfide, as outlined in
improve significantly the yield of 4a (Table 1, entries 2–4). Scheme 4. With most of the arylboronic acids used this sec-
These results strongly suggest that CuI thiolate formed ond arylation step apparently did not proceed well so that
upon reaction with CuI acetate in the presence of pyridine the yields were only around 50% when the arylation of both
as the base serves as a substrate for arylation, however, ad- sulfur atoms in 2 is considered. Nevertheless, yields of more
ditional CuI ions are needed to catalyse the reaction. Re- than 50%, which represents more than 100% when a single
Eur. J. Org. Chem. 2009, 6336–6340
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6337

J. Krouzelka, I. Linhart
ˇ
FULL PAPER
arylation step is considered, were obtained with eight out of aliphatic compound in this series. Its arylation by phenylbo-
the thirteen boronic acids tested, two of them giving nearly ronic acid yielded 29% of butyl phenyl sulfide.[10] Under
quantitative yields (Table 2). Theoretically, 2 equiv. of CuI the same conditions (DMSO/H2O, 2:1, 5 mol-% CuI-bpy,
should suffice for the arylation of 2, however, an excess of 24 h in air), the reaction of 2 with 3a yielded nearly 20%
CuI acetate led to a better yield (Table 1, entries 10 and 11). of 4a, as determined analytically by 1H NMR spectroscopy.
A precipitate of CuI thiolate and/or Cu0 was formed in the The isolated yield was 9%, which indicates some catalytic
course of reaction, which may explain this observation. Part turnover but, anyway, such a result is unsatisfactory.
of the catalytic species may be removed with the precipitate
and thereby made unavailable for the reaction.
The procedure described in this paper appears to be, de-
spite the need for an excess of CuI, more suitable for the
preparation of arylmercapturic acids than the catalytic pro-
cess of Taniguchi.[10] It is also a convenient alternative to
the Pd-catalysed arylation of N-acetylcysteine by aryl io-
dides.[7a]
Conclusions
Copper-mediated arylation of disulfides by arylboronic
acids is an efficient tool for the preparation of arylmercap-
turic acids. Although both thiols and disulfides can be aryl-
ated by arylboronic acids in the presence of either CuOAc
or Cu(OAc)2, the use of disulfides as the starting materials
and CuOAc as the mediator proved to be the most suitable
for achieving high yields of arylmercapturic acids.
Scheme 4. Proposed mechanism for the arylation of disulfides and
the overall stoichiometry of the reaction.
Experimental Section
General: Column chromatography was performed on silica gel 60
purchased from Fluka, particle size 0.063–0.200 mm. For thin-layer
chromatography Merck silica gel 60 F254 plates were used. Reten-
tion factors (Rf) are given for chloroform/methanol (40:1) unless
otherwise noted. N,NЈ-Dimethylformamide (DMF) was dried by
distillation from phosphorus pentoxide in a vacuum and stored
over molecular sieves. Other chemicals obtained from commercial
sources were of analytical or synthetic grade and were used as re-
Table 2. Arylation of N,NЈ-diacetylcystine dimethyl ester (2) by ar-
ylboronic acids ArB(OH)2 3a–3m in DMF at 100 °C in the pres-
ence of Cu(OAc) (3 equiv.) and pyridine (6 equiv.).[a]
.
1
ceived. H and 13C NMR spectra were recorded with a Bruker Av-
Entry Ar
Boronic acid Product % Yield[a]
ance DRX500 (500 MHz for 1H) or Varian Mercury 300 (300 MHz
for 1H) Fourier transform NMR spectrometer. High-resolution
mass spectra were measured on a Q-TOF Micromass instrument.
1
2
3
4
5
6
7
8
phenyl
2-tolyl
3-tolyl
4-tolyl
3-vinylphenyl
4-vinylphenyl
4-methoxyphenyl
3-chlorophenyl
4-chlorophenyl
4-cyanophenyl
2-methoxycarbonylphenyl
3-methoxycarbonylphenyl
4-methoxycarbonylphenyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
96
48
53
50
56
56
48
52
63
36
24
98
56
N,NЈ-Diacetylcystine Dimethyl Ester (2):[11] A mixture of N-acetyl-
cysteine methyl ester (1) (2 mmol) and copper(II) acetate (4 mmol)
in pyridine (10 mL) was heated in an oil bath at 40 °C for 1 h.
During this time the colour of the solution turned from green to
dark blue. Pyridine was then distilled off in a vacuum, dichloro-
methane (25 mL) was added and the resulting solution was washed
three times with water. The organic layer was dried with magne-
sium sulfate, filtered and the solvent was evaporated in a vacuum.
The crude product was purified by column chromatography on sil-
ica gel using CHCl3/MeOH (20:1) to yield 61% of 2. Crystallization
from chloroform/cyclohexane afforded white crystals. Rf = 0.41
(CHCl3/MeOH, 20:1); m.p. 125–126 °C. 1H NMR (CDCl3): δ =
2.07 (s, 6 H, CH3CO), 3.21 (m, 4 H, CH2), 3.78 (s, 6 H, COOCH3),
4.88 (m, 1 H, CHCOOCH3), 6.59 (d, J = 7.2 Hz, 1 H, NH) ppm.
13C NMR (CDCl3): δ = 23.1 (CH3CO), 40.7 (CH2), 51.7 (CH), 52.8
(CH3O), 170.0 (COOCH3), 170.9 (CH3CO) ppm. C12H20N2O6S2
(352.42): calcd. C 40.90, H 5.72, N 7.95, S 18.20; found C 40.90,
H 5.94, N 7.94, S 18.32.
9
10
11
12
13
3j
3k
3l
4j
4k
4l
3m
4m
[a] Isolated yields.
Unlike the reactions with N-arylsulfanylsuccinimides,
which were used by Liebeskind and co-workers[9] as disul-
fide equivalents, the reactions with disulfides do not pro-
ceed catalytically, requiring at least 2 equiv. of CuI acetate,
that is, 1 equiv. for each sulfur of the disulfide. Undoubt-
edly, this is a disadvantage of our procedure. Therefore, we
tested another S-arylation process, that described by Tanig-
uchi.[10] This procedure was reported to give good yields
General Procedure for the Arylation of 2: A mixture of N,NЈ-di-
acetylcystine dimethyl ester (2; 0.2 mmol), arylboronic acid
with diverse diaryl disulfides. Dibutyl disulfide was the only (0.6 mmol), copper(I) acetate (0.6 mmol) and pyridine (1.2 mmol)
6338
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Eur. J. Org. Chem. 2009, 6336–6340

Arylmercapturic Acids by S-Arylation of N,NЈ-Diacetylcystine
in DMF (2.5 mL) was heated in an oil bath at 100 °C under argon
for 3 h. DMF was then distilled off in a vacuum, methanol was
added to the residue and the resulting suspension was filtered
through a paper filter. After evaporation of the solvent in a vac-
uum, column chromatography on silica gel using CHCl3/MeOH
(40:1) or CHCl3/EtOAc (3:1) as eluent afforded the corresponding
N-acetyl-S-arylcysteinates 4a–m. A further purification step by col-
umn chromatography on silica gel was needed in several cases to
obtain pure samples. As most of the mercapturic acid esters ob-
tained were oils the sample homogeneity was checked by 1H and
13C NMR spectroscopy rather than by elemental analysis.
Ar-H) ppm. 13C NMR (CDCl3): δ = 22.8 (CH3CO), 36.2 (CH2),
52.3 and 52.4 (CH and CH3O), 115.0 (=CH2), 124.9, 128.4, 129.1,
130.0 (Ar C-H), 135.0 (Ar C-S), 135.9 (=CH), 138.4 (Ar C-C),
169.8 (COOCH3), 170.7 (CH3CO) ppm. HRMS (EI): calcd. for
C14H17NO3S 279.0929; found 279.0928.
Methyl N-Acetyl-S-(4-vinylphenyl)cysteinate (4f): Yellowish liquid
(31 mg, 56%); Rf = 0.35. 1H NMR (CDCl3): δ = 1.81 (s, 3 H,
CH3CO), 3.28 (dd, J = 4.5, 14.3 Hz, 1 H, CH2), 3.41 (dd, J =
4.5, 14.3 Hz, 1 H, CH2), 3.51 (s, 3 H, COOCH3), 4.80 (m, 1 H,
CHCOOCH3), 5.18 (d, J = 10.9 Hz, 1 H, =CH2), 5.66 (d, J =
17.6 Hz, 1 H, =CH2), 6.17 (d, J = 5.9 Hz, 1 H, NH), 6.59 (dd, J =
10.9, 17.6 Hz, 1 H, CH=CH2), 7.26 (d, J = 8.4 Hz, 2 H, Ar-H),
7.29 (d, J = 8.4 Hz, 2 H, Ar-H) ppm. 13C NMR (CDCl3): δ = 22.9
(CH3CO), 36.5 (CH2), 52.4 and 52.5 (CH and CH3O), 114.4
(=CH2), 126.8, 131.0 (Ar C-H), 134.0 (Ar C-S), 135.9 (=CH), 136.5
(Ar C-C), 169.7 (COOCH3), 170.7 (CH3CO) ppm. HRMS (EI):
calcd. for C14H17NO3S 279.0929; found 279.0937.
Methyl N-Acetyl-S-phenylcysteinate (4a): A mixture of N-acetylcys-
teine methyl ester (1; 76 mg, 0.4 mmol), phenylboronic acid (3a;
107 mg, 0.88 mmol), copper(II) acetate (110 mg, 0.6 mmol) and
pyridine (95 mg; 1.2 mmol) in DMF (2.5 mL) was heated with an
oil bath at 100 °C under argon for 3 h. DMF was then distilled
off in vacuum, the residue was suspended in methanol and filtered
through a paper filter. Evaporation of the solvent in vacuum fol-
lowed by column chromatography on silica gel with CHCl3/EtOAc
(20:1) as eluent yielded 67 mg (63%) of a yellowish liquid. Com-
pound 4a (48.5 mg, 96%) was obtained by arylation of 1 or 2 with
3a as described in the general procedure and identified by compar-
ing its NMR spectra with published data.[12] Compound 4a (48.5 g,
96%) was also obtained from 2 as described in the general pro-
cedure.
Methyl N-Acetyl-S-(4-methoxyphenyl)cysteinate (4g): Yellowish li-
quid (27 mg, 48%); Rf = 0.28. 1H NMR (CDCl3): δ = 1.84 (s, 3 H,
CH3CO), 3.17 (dd, J = 4.9, 14.2 Hz, 1 H, CH2), 3.27 (dd, J = 4.9,
14.2 Hz, 1 H, CH2), 3.49 (s, 3 H, COOCH3), 3.71 (s, 3 H, CH3-O-
Ar), 4.74 (m, 1 H, CHCOOCH3), 6.22 (d, J = 6.7 Hz, 1 H, NH),
6.77 (d, J = 8.9 Hz, 2 H, Ar-H), 7.31 (d, J = 8.9 Hz, 2 H, Ar-
H) ppm. 13C NMR (CDCl3): δ = 22.9 (CH3CO), 38.0 (CH2), 52.2
and 52.4 (CH and CH3O), 55.3 (CH3-O-Ar), 114.6 (Ar C-H), 124.7
(Ar C-S), 134.3 (Ar C-H), 159.4 (Ar C-O), 169.7 (COOCH3), 170.8
(CH3CO) ppm. HRMS (EI): calcd. for C13H17NO4S 283.0878;
found 283.0867.
Methyl N-Acetyl-S-(2-tolyl)cysteinate (4b): Yellowish liquid (26 mg,
48%); Rf = 0.31. 1H NMR (CDCl3): δ = 1.90 (s, 3 H, CH3CO),
2.41 (s, 3 H, CH3-Ar), 3.32 (dd, J = 4.7, 14.0 Hz, 1 H, CH2), 3.44
(dd, J = 4.7, 14.0 Hz, 1 H, CH2), 3.57 (s, 3 H, COOCH3), 4.85 (m,
1 H, CHCOOCH3), 6.36 (d, J = 6.7 Hz, 1 H, NH), 7.16 (m, 3 H,
Ar-H), 7.39 (m, 1 H, Ar-H) ppm. 13C NMR (CDCl3): δ = 20.5
(CH3-Ar), 22.8 (CH3CO), 35.7 (CH2), 52.3 and 52.4 (CH and
CH3O), 126.5, 127.1, 130.4, 130.9 (Ar C-H), 133.6 (Ar C-C), 139.1
(Ar C-S), 169.8 (COOCH3), 170.7 (CH3CO) ppm. HRMS (EI):
calcd. for C13H17NO3S 267.0929; found 267.0938.
Methyl N-Acetyl-S-(3-chlorophenyl)cysteinate (4h): Colorless liquid
1
(30 mg, 52%); Rf = 0.50. H NMR (CDCl3, 25 °C): δ = 1.92 (s, 3
H, CH3CO), 3.37 (dd, J = 4.4, 14.1 Hz, 1 H, CH2), 3.51 (dd, J =
4.4, 14.1 Hz, 1 H, CH2), 3.62 (s, 3 H, COOCH3), 4.88 (m, 1 H,
CHCOOCH3), 6.22 (br. s, 1 H, NH), 7.16–7.29 (m, 3 H, Ar-H),
7.37 (s, 1 H, Ar-H) ppm. 13C NMR (300 MHz, CDCl3, 25 °C): δ =
23.2 (CH3CO), 36.3 (CH2), 52.5 and 52.9 (CH and CH3O), 127.3,
128.7, 130.2, 130.3 (Ar C-H), 134.9 and 137.2 (Ar C-S and Ar C-
Cl), 170.0 (COOCH3), 170.8 (CH3CO) ppm. HRMS (EI): calcd.
for C12H14ClNO3S 287.0383; found 287.0374.
Methyl N-Acetyl-S-(3-tolyl)cysteinate (4c): Yellowish liquid (28 mg,
53%); Rf = 0.30. 1H NMR (CDCl3): δ = 1.81 (s, 3 H, CH3CO),
2.25 (s, 3 H, CH3-Ar), 3.28 (dd, J = 4.5, 14.2 Hz, 1 H, CH2), 3.40
(dd, J = 4.5, 14.2 Hz, 1 H, CH2), 3.51 (s, 3 H, COOCH3), 4.80 (m,
1 H, CHCOOCH3), 6.16 (d, J = 6.0 Hz, 1 H, NH), 6.96 (m, 1 H,
Ar-H), 7.13 (m, 3 H, Ar-H) ppm. 13C NMR (CDCl3): δ = 21.2
(CH3-Ar), 22.9 (CH3CO), 36.6 (CH2), 52.4 and 52.4 (CH and
CH3O), 127.9, 127.9, 128.9, 131.5 (Ar C-H), 134.4 (Ar C-C), 138.9
(Ar C-S), 169.7 (COOCH3), 170.7 (CH3CO) ppm. HRMS (EI):
calcd. for C13H17NO3S 267.0929; found 267.0940.
Methyl N-Acetyl-S-(4-chlorophenyl)cysteinate (4i): White solid
1
(36 mg, 63%); Rf = 0.49. H NMR (CDCl3, 25 °C): δ = 1.91 (s, 3
H, CH3CO), 3.32 (dd, J = 4.4, 14.4 Hz, 1 H, CH2), 3.47 (dd, J =
4.4, 14.4 Hz, 1 H, CH2), 3.59 (s, 3 H, COOCH3), 4.85 (m, 1 H,
CHCOOCH3), 6.22 (br. s, 1 H, NH), 7.24 (d, J = 8.8 Hz, 2 H Ar-
H), 7.35 (d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR (CDCl3,
25 °C): δ = 23.2 (CH3CO), 36.9 (CH2), 52.5 and 52.8 (CH and
CH3O), 129.4 (Ar C-H), 132.5 (Ar C-H), 133.4 and 133.5 (Ar C-S
and Ar C-Cl), 170.0 (COOCH3), 170.9 (CH3CO) ppm. HRMS
(EI): calcd. for C12H14ClNO3S 287.0383; found 287.0372.
Methyl N-Acetyl-S-(4-tolyl)cysteinate (4d): Yellowish liquid (27 mg,
50%); Rf = 0.33. 1H NMR (CDCl3): δ = 1.89 (s, 3 H, CH3CO),
2.30 (s, 3 H, CH3-Ar), 3.30 (dd, J = 4.7, 14.2 Hz, 1 H, CH2), 3.41
(dd, J = 4.7, 14.2 Hz, 1 H, CH2), 3.56 (s, 3 H, COOCH3), 4.83 (m,
1 H, CHCOOCH3), 6.40 (d, J = 7.0 Hz, 1 H, NH), 7.10 (d, J =
8.0 Hz, 2 H Ar-H), 7.31 (d, J = 8.0 Hz, 2 H, Ar-H) ppm. 13C NMR
(CDCl3): δ = 21.0 (CH3-Ar), 22.8 (CH3CO), 37.0 (CH2), 52.4 and
52.4 (CH and CH3O), 129.9 (Ar C-H), 130.9 (Ar C-C), 131.6 (Ar
C-H), 137.4 (Ar C-S), 170.0 (COOCH3), 170.8 (CH3CO) ppm.
HRMS (EI): calcd. for C13H17NO3S 267.0929; found 267.0928.
Methyl N-Acetyl-S-(4-cyanophenyl)cysteinate (4j): White solid
(20 mg, 36%); Rf = 0.29 (CHCl3/EtOAc, 3:1). 1H NMR (CDCl3,
25 °C): δ = 1.93 (s, 3 H, CH3CO), 3.42 (dd, J = 4.7, 14.1 Hz, 1 H,
CH2), 3.59 (dd, J = 5.0, 14.1 Hz, 1 H, CH2), 3.68 (s, 3 H, CO-
OCH3), 4.88 (m, 1 H, CHCOOCH3), 6.40 (br. d, J = 6.4 Hz, 1 H,
NH), 7.4 (d, J = 8.2 Hz, 2 H Ar-H), 7.55 (d, J = 8.2 Hz, 2 H, Ar-
H) ppm. 13C NMR (CDCl3): δ = 23.2 (CH3CO), 34.7 (CH2S), 52.3
(CH3O), 53.1 (CHCH2), 118.7 (CN), 128.6, 132.6 (Ar C-H), 142.9
(Ar C-S), 109.6 (Ar C-CN), 170.1, 170.7 (CO) ppm. HRMS (EI):
calcd. for C13H14N2O3S 278.0725; found 278.0729.
Methyl N-Acetyl-S-(3-vinylphenyl)cysteinate (4e): Yellowish liquid
(31 mg, 56%); Rf = 0.33. 1H NMR (CDCl3): δ = 1.81 (s, 3 H,
CH3CO), 3.30 (dd, J = 4.5, 14.3 Hz, 1 H, CH2), 3.41 (dd, J =
4.5, 14.3 Hz, 1 H, CH2), 3.50 (s, 3 H, COOCH3), 4.81 (m, 1 H,
CHCOOCH3), 5.22 (d, J = 10.9 Hz, 1 H, =CH2), 5.70 (d, J =
Methyl N-Acetyl-S-(2-methoxycarbonylphenyl)cysteinate (4k):
1
17.6 Hz, 1 H, =CH2), 6.25 (d, J = 6.5 Hz, 1 H, NH), 6.59 (dd, J = White solid (15 mg, 24%); Rf = 0.45. H NMR (CDCl3, 25 °C): δ
10.9, 17.6 Hz, 1 H, CH=CH2), 7.21 (m, 3 H, Ar-H), 7.37 (s, 1 H,
= 1.91 (s, 3 H, CH3CO), 3.40 (dd, J = 5.0, 13.8 Hz, 1 H, CH2),
Eur. J. Org. Chem. 2009, 6336–6340
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Krouzelka, I. Linhart
ˇ
FULL PAPER
Angerer, U. Ewers, M. Wilhelm, Int. J. Hyg. Environ. Health
2007, 210, 201–228.
3.48 (dd, J = 5.0, 13.8 Hz, 1 H, CH2), 3.67 (s, 3 H, COOCH3), 3.91
(s,
3 H, Ar-COOCH3), 4.90 (dt, J = 5.0, 7.6 Hz, 1 H,
[2]
[3]
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35.
CHCOOCH3), 6.57 (d, J = 7.6 Hz, 1 H, NH), 7.22 (m, 1 H Ar-H),
7.44 (m, 2 H, Ar-H), 7.84 (m, 1 H Ar-H) ppm. 13C NMR
(300 MHz, CDCl3, 25 °C): δ = 23.2 (CH3CO), 35.3 (CH2), 52.0,
52.6 and 52.9 (CH, CH3O and CH3O), 125.7, 128.8 (Ar C-H),
130.4 (Ar C-C), 131.0, 132.5 (Ar C-H), 138.5 (Ar C-S), 167.5 (Ar
C-COO), 170.2 (COOCH3), 170.9 (CH3CO) ppm. HRMS (EI):
calcd. for C14H17NO5S 311.0827; found 311.0825.
Methyl N-Acetyl-S-(3-methoxycarbonylphenyl)cysteinate (4l): White
solid (61 mg, 98%); Rf = 0.26 (CHCl3/EtOAc, 3:1). 1H NMR
(CDCl3, 25 °C): δ = 1.89 (s, 3 H, CH3CO), 3.28 (dd, J = 4.3,
14.2 Hz, 1 H, CH2), 3.50 (dd, J = 4.7, 14.2 Hz, 1 H, CH2), 3.55 (s,
3 H, COOCH3), 3.80 (s, 3 H, Ar-COOCH3), 4.84 (m, 1 H,
CHCOOCH3), 6.39 (d, J = 7.1 Hz, 1 H, NH), 7.35 (t, J = 7.8 Hz,
1 H Ar-H), 7.55 (dt, J = 1.9, 7.8 Hz, 1 H, Ar-H), 7.85 (d, J =
7.8 Hz, 1 H Ar-H), 8.02 (t, J = 1.9 Hz, 1 H, Ar-H) ppm. 13C NMR
(CDCl3, 25 °C): δ = 23.1 (CH3CO), 36.5 (CH2), 52.5, 52.6 (CH3O),
52.8 (CHCH2), 128.3, 129.3, 131.5, 135.0 (Ar C-H), 131.2 (Ar C-
C), 135.9 (Ar C-S), 166.5 (Ar-CO), 170.1 and 170 (COOCH3 and
CH3CO) ppm. HRMS (EI): calcd. for C14H17NO5S 311.0827;
found 311.0835.
[4]
[5]
Methyl N-Acetyl-S-(4-methoxycarbonylphenyl)cysteinate (4m):
1
[6]
[7]
a) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42,
5400–5449; b) J.-P. Finet, A. Y. Fedorov, S. Combes, G. Boyer,
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2180–2181; f) M. Carril, R. SanMartin, E. Domínguez, I. Tel-
litu, Chem. Eur. J. 2007, 13, 5100–5105.
White solid (35 mg, 56%); Rf = 0.44. H NMR (CDCl3, 25 °C): δ
= 1.86 (s, 3 H, CH3CO), 3.41 (dd, J = 4.7, 14.4 Hz, 1 H, CH2),
3.56 (dd, J = 4.7, 14.4 Hz, 1 H, CH2), 3.60 (s, 3 H, COOCH3), 3.87
(s,
3 H, Ar-COOCH3), 4.88 (dt, J = 4.7, 7.4 Hz, 1 H,
CHCOOCH3), 6.36 (d, J = 7.4 Hz, 1 H, NH), 7.36 (d, J = 8.2 Hz,
2 H Ar-H), 7.91 (d, J = 8.3 Hz, 2 H, Ar-H) ppm. 13C NMR
(CDCl3, 25 °C): δ = 23.2 (CH3CO), 35.0 (CH2), 52.4, 52.4 and 52.9
(CH, CH3O and CH3O), 128.1 (Ar C-C), 128.6, 130.2 (Ar C-H),
142.0 (Ar C-S), 166.7 (Ar C-COO), 170.1 and 170.8 (COOCH3
and CH3CO) ppm. HRMS (EI): calcd. for C14H17NO5S 311.0827;
found 311.0818.
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Acknowledgments
[10] a) N. Taniguchi, Synlett 2006, 1351–1354; b) N. Taniguchi, J.
Org. Chem. 2007, 72, 1241–1245.
Financial support from the Ministry of Education, Youth and
Sports of the Czech Republic (grant nos. LC06070, MSM 604 613
73 01 and 2B08051) is gratefully acknowledged.
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Received: August 28, 2009
Published Online: November 11, 2009
6340
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6336–6340