A simple, base-free preparation of S-aryl thioacetates as surrogates for aryl thiols

Article abstract of DOI:10.1016/j.tetlet.2010.10.125

A mild method for the preparation of S-aryl thioacetates by hetero cross-coupling reactions of aryl bromides or aryl triflates with potassium thioacetate is described. The reaction proceeded smoothly in toluene at 110°C, mediated by catalytic Pd₂(dba)₃ in combination with CyPF-tBu as the ligand. Neither the presence of a base nor microwave conditions were required. The formed S-aryl thioacetate proved to be stable under flash chromatographic conditions and could be rapidly converted into the corresponding thiol under mildly basic conditions.

Full text of DOI:10.1016/j.tetlet.2010.10.125

Tetrahedron Letters 51 (2010) 6877–6881
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple, base-free preparation of S-aryl thioacetates as surrogates for
aryl thiols
⇑
Adri van den Hoogenband , Jos H. M. Lange, Raymond P. J. Bronger, Axel R. Stoit, Jan Willem Terpstra
Abbott Healthcare Products B.V., C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2010
Revised 4 October 2010
Accepted 22 October 2010
Available online 30 October 2010
A mild method for the preparation of S-aryl thioacetates by hetero cross-coupling reactions of aryl bro-
mides or aryl triflates with potassium thioacetate is described. The reaction proceeded smoothly in tol-
uene at 110 °C, mediated by catalytic Pd2(dba)3 in combination with CyPF-tBu as the ligand. Neither the
presence of a base nor microwave conditions were required. The formed S-aryl thioacetate proved to be
stable under flash chromatographic conditions and could be rapidly converted into the corresponding
thiol under mildly basic conditions.
Keywords:
Palladium
Ó 2010 Elsevier Ltd. All rights reserved.
Hetero cross-coupling
Thiol surrogate
Base-free
Thio esters and thiols constitute key chemotypes in the areas of
organic and medicinal chemistry. These related motifs are fre-
quently found in biologically active molecules1 and polymeric
material.2 Moreover, such compounds are often used as starting
materials for the synthesis of heterocyclic ring systems.3 However,
their preparation—in contrast to the corresponding oxygen- and
nitrogen-containing compounds—is generally less straightforward.
Nucleophilic substitution reactions,4 lithiation chemistry5 and,
more recently, palladium-6 or copper-catalyzed7 hetero cross-
coupling strategies constitute frequently applied methods for the
introduction of thio moieties.
Recently, a number of arylbenzyl thioethers was required for
one of our research projects. Based on our interest in palladium-
and copper-catalyzed chemistry,8 it was reasoned that there are
two ways to realize their synthesis, viz. a hetero cross-coupling
reaction of an aryl halide or aryl triflate with a benzyl thiol, or a
more classical benzylation reaction between an aryl thiol or a pro-
tected aryl thiol and a benzyl halide. In the latter option, the (pro-
tected) aryl thiol needs to be prepared from the corresponding
halide or triflate. Since functionalized benzyl halides, in general,
have a broader commercial availability in comparison with the cor-
responding benzyl thiols, it was decided to pursue the latter op-
tion. An additional advantage would be the avoidance of
malodorous benzyl thiols.
protected thiol.3d,3g,6d,7e,9 Since it is known6b that the poisoning
effect of sulfur can be troublesome in palladium-catalyzed-cross-
coupling reactions, the copper-catalyzed method described by
Sawada7e (thiobenzoic acid as a thiol surrogate) was initially inves-
tigated (Scheme 1). Although the application of this method on our
aryl iodide derivative resulted in incomplete conversion of 1a and a
low chemical yield (<40%) of 2, we managed to improve the course
of an analogous S-aryl ester formation and its yield (>70%) by sub-
stitution of thiobenzoic acid by the more easy to handle potassium
thioacetate as the thiol surrogate to furnish 3 (Scheme 1). In spite
of these initially encouraging results, several disadvantages re-
mained to be improved. The copper-catalyzed method proved only
R1
S
(a)
R1
O
yield <40%
2
X
(b)
R1
1a X = I
1b X = OTf
S
yield >70%
O
Several Letters have described the palladium- or copper-
mediated conversion of aryl halides into the corresponding
3
Scheme 1. For 1a: (a) reagents and conditions: Sawada7e: CuI/1,10-phenanthroline,
thiobenzoic acid, i-Pr2NEt, toluene, 110 °C, 24 h. For 1a: (b) reagents and conditions:
CuI/1,10-phenanthroline, potassium thioacetate, i-Pr2NEt, toluene, 110 °C, 24 h; for
1b: see the conditions described in the text.
⇑
Corresponding author. Tel.: +31 (0)294 479605; fax: +31 (0)294 477138.
E-mail addresses: adri.vandenhoogenband@abbott.com, adri.vandenhoogen-
band@solvay.com (A. van den Hoogenband).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.125

6878
A. van den Hoogenband et al. / Tetrahedron Letters 51 (2010) 6877–6881
Method:Itoh6d
results prompted us to further investigate the scope and generality
(a)
of this mild synthetic method by reacting a number of (mostly)
commercially available aryl bromides 6–14, 16, and 19, aryl tri-
flates 15, 17, and 20–23, and the aryl chloride 18 with potassium
thioacetate. As a general procedure, all the experiments were car-
ried out with 1 mmol of aryl bromide, aryl triflate or aryl chloride,
2 mmol of potassium thioacetate, 2.5 mol % of Pd2(dba)3, and
5 mol % of CyPF-tBu in 15 ml of toluene at 110 °C for 24 h.13 The re-
sults are disclosed in Table 1.14
(Het)ArX + HS-R
(Het)ArS-R
4
X = Br, OTf
R = alkyl, aryl
Method:Lai,9d Jeges9c
O
O
(b)
Moderate to good yields were obtained using aryl- or heteroaryl
bromides 6–12, and 16. Common functional groups for example
NH2 or the base-sensitive N-acetyl moiety proved to be well-toler-
ated (entries 3 and 4). No side reactions were detected. Interest-
ingly, we observed that both the formamides 11 and 29 existed
in two conformations, based on their 1H NMR spectra. Additionally,
during the conversion of 29, the N-formyl group was partially
transformed into the corresponding N-acetyl moiety (see com-
pound 27). As both 9 and 11 did not dissolve readily in toluene
at room temperature, these compounds were dissolved at 100 °C,
followed by the simultaneous addition of potassium thioacetate,
Pd2(dba)3, and CyPF-tBu at the same temperature. Of particular
interest is the conversion of 10 into 28. The sensitive N-Cbz group
survived our neutral reaction conditions, which is in contrast with
the reported result of Lai.9c In accordance with Lai’s findings, nitro-
containing substrates were unsuitable as starting materials,
besides the starting compound, only a low yield of product was ob-
tained (entries 8 and 9). The presence of an ethyl ester moiety was
also tolerated; no trace of any saponification product was detected
(entry 11). Unexpectedly, the conversion of 19 into 34 was disap-
pointing (entry 14). Aryl triflates generally reacted smoothly under
the neutral conditions (entries 12 and 15, 16–18). Although the
conversion of 20 was troublesome, prior protection of 20 as its
N-Boc carbamate 21 raised the yield of the S-indolyl thioacetate
formation from 16% to 79% (entries 15 and 16). In accordance with
expectation, it was not possible to convert 15 into 32 (entry 10),
only starting material was recovered. The aryl chloride 18 was also
converted, in a modest yield of 36% into 33, despite the fact that
Pd2(dba)3/CyPF-tBu is generally considered to be a suitable system
for the conversion of aryl chlorides (entry 13). Substitution of tol-
uene for the higher boiling xylene and raising the temperature to
125 °C did not turn out to be beneficial for the conversion of 18.
The palladium precursor effect found during this investigation
was of interest. Substitution of Pd2(dba)3 for Pd(OAc)2 was not
beneficial. A dramatic effect was seen for the conversion of 7 into
25. The yield dropped from 80% to a negligibly low value. The anal-
ogous reaction of 13 resulted in the recovery of starting material.
These results indicated that the in situ reduction of Pd(II) into
Pd(0) did not occur under our reaction conditions. Using
(Het)ArS
(Het)ArX +
X = Br, OTf
KS
5
Scheme 2. (a) Pd2(dba)3/Xantphos, i-Pr2NEt, 1,4-dioxane, reflux; (b) Pd2(dba)3/
Xantphos, i-Pr2NEt, 1,4-dioxane, microwave, 160 °C.
to be successful with aryl iodides as starting materials. Therefore,
further attention was focused on a palladium-catalyzed conversion
of aryl triflates—which can be easily prepared from the corre-
sponding phenols10—and readily available aryl bromides. Our
starting point was the procedure of Itoh6d who described the con-
version of aryl bromides or aryl triflates into the corresponding
thioethers 4 by reacting them with a suitable aryl or alkyl thiol
using Pd2(dba)3/Xantphos, i-Pr2NEt, and 1,4-dioxane as optimal
conditions (Scheme 2). More recently, a variation of Itoh’s method
was applied by Lai9c and Jeges,9b applying potassium thioacetate as
the thiol source to deliver compounds of general formula 5. How-
ever, this reaction was reported to be successful only under micro-
wave heating conditions at 160 °C (Scheme 2). As many synthetic
chemists still prefer oil bath heating above microwave heating,
and given the fact that many laboratories are not equipped with
dedicated microwave instruments, triflate 1b was reacted with
potassium thioacetate using oil bath heating and the conditions
of Lai.9c Unfortunately, an incomplete conversion into 3 was found.
Moreover, the reproducibility of this particular reaction proved to
be troublesome, thereby precluding its general use.
Therefore, it was decided to shift our attention to the pioneering
work of Hartwig in the area of palladium-catalyzed thioetherifica-
tion of aryl halides and aryl triflates.6a,9a,11 Key to his success
was the use of the commercially available (R)-1-[(Sp)-2-(dicyc-
lohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine as the
ligand12 (further abbreviated as CyPF-tBu, Fig. 1) in combination
with a suitable Pd precursor, base, and solvent. Very recently,
Hartwig also reported this method for the preparation of a number
of phenyl triisopropylsilyl sulfides (ArS-TIPS) as thiol surrogates.9a
However, in some cases their ArS-TIPS derivatives suffered from a
lack of stability during purification. Moreover, the high costs of the
required TIPS-SH reagent in comparison with potassium thioace-
tate prompted us to further explore the hetero cross-coupling reac-
tion between the triflate 1b and potassium thioacetate, mediated
by Pd2(dba)3/CyPF-tBu. A brief survey of reaction conditions re-
vealed a clean conversion in toluene at a temperature of 110 °C
within 16 h. In contrast to other literature methods, no additional
base was required. It is also interesting to note that 3 remained sta-
ble during flash chromatographic purification. These encouraging
10 mol % of phenylboronic acid as
Pd(OAc)2 for the conversion of 17 into 33 was not successful,
and no reaction was observed.
a possible reductor for
15
Finally, we briefly investigated the conversion of 6 into 24 using
microwave conditions (50 min, 160 °C in 1,4-dioxane). Surpris-
ingly, no improvement was found. Besides 24 (37 mol % based on
LC–MS), bromide 6 was still present (50 mol % based on LC–MS)
together with the dimeric 3-(quinolin-3-ylsulfanyl)quinoline (13
mol % based on LC–MS).
The development of our general and mild procedure to convert
aryl bromides and aryl triflates into their corresponding S-aryl thi-
oacetates 24–38 prompted their further transformations into the
corresponding thiols under mild basic conditions. Deprotection of
24, followed by in situ benzylation of the so formed 3-quinolinyl-
mercaptan, at 0 °C with benzyl bromide in ethanol (containing
1.1 mol equivalents of NaOH), resulted in clean and rapid conver-
sion into sulfide 39 in an overall yield of 72% (Scheme 3).16 In this
respect, the S-aryl thioacetate moiety is preferable over S-TIPS as a
P-tBu2
PCy2
Fe
Figure 1.

A. van den Hoogenband et al. / Tetrahedron Letters 51 (2010) 6877–6881
6879
Table 1
Reagents and conditions: (a) 1 mol equivalent of (Het)ArX, 2 mol equivalent of KSAc, 2.5 mol % Pd2(dba)3, 5 mol % CyPF-tBu, 15 ml of toluene, 110 °C, 24 h
O
O
O
a)
KS
(Het)ArS
(Het)ArX
+
Entry
1
(Het)ArX
Product
Yielda (%)
Br
S
6
24
25
90b
80
N
N
S
Br
O
2
7
N
N
O
H2N
Br
3
4
8
9
26
27
60
72
H2N
S
O
O
H
N
Br
Br
S
S
N
H
O
O
CbzHN
5
6
10
11
28
29
55
CbzHN
O
OHCHN
Br
90c,d
OHCHN
S
O
Br
7
8
9
12
13
14
30
31
32
70
15
13
S
O
O
O
O2N
O2N
Br
O2N
O2N
S
O
S
Br
O2N
O2N
O
10
15
32
0
OTf
S
O
EtOOC
EtOOC
EtOOC
CH3O
Br
11
12
13
14
16
17
18
19
33
33
33
34
67e
58f
36f
20
EtOOC
EtOOC
EtOOC
CH3O
S
O
OTf
Cl
S
O
S
O
Br
S
OTf
OTf
O
O
S
15
16
20
21
35
36
16
N
H
N
H
S
N
79
N
Boc
Boc
(continued on next page)

6880
A. van den Hoogenband et al. / Tetrahedron Letters 51 (2010) 6877–6881
Table 1 (continued)
Entry
(Het)ArX
Product
Yielda (%)
69
OTf
O
S
17
22
37
38
N
O
N
O
O
18
23
67
OTf
S
a
Isolated yield of pure compounds.
b
c
d
e
f
Running the reaction in 1,4-dioxane resulted in incomplete conversion.
Product exists in two conformations in the ratio 3:2.
Contaminated with 15 mol % of 27.
Contaminated with 4 mol % of dibenzylideneacetone.
Contaminated with 30 mol % of dibenzylideneacetone.
O
Chem. 2007, 50, 3046–3053; (g) Llauger, L.; He, H.; Kim, J.; Aguirre, J.; Rosen, N.;
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S
S
(a), (b)
N
N
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39
24
Scheme 3. Reagents and conditions: (a) 1 mol equivalent of 24, 1.1 mol equivalent
of NaOH, EtOH, 0 °C, 10 min; (b) 1.1 mol equivalent of BnBr, 0 °C, 10 min, 72%.
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thiol surrogate since the S-TIPS moiety was reported to require
four equivalents of CsF for deprotection.9a Finally, this procedure
was successfully applied within our research projects resulting in
a large number of arylbenzyl thioethers (unfortunately, for patent
reasons, we are not able to report these data).
In conclusion, a novel and mild palladium-catalyzed method is
described for the smooth conversion, under neutral conditions, of a
variety of aryl bromides and aryl triflates into the corresponding
S-aryl thioacetates, which can be regarded as thiol surrogates. All
the prepared S-aryl thioacetates were purified by flash chromatog-
raphy over silica gel without concomitant deprotection to the thiol.
In contrast with the existing method, microwave heating was not
needed. Moreover, during our investigation, it was found that the
yield in some cases could be increased by adding more
Pd2(dba)3/CyPF-tBu (data not shown). Therefore, our procedure
constitutes a straightforward, mild, and cheap alternative to
Hartwig’s9a S-TIPS methodology. It can be anticipated that besides
a benzylation after the deprotection step, alkylations, acylations,
ketone synthesis17 or new cross-coupling reactions with a variety
of aryl bromides or aryl triflates should be feasible. Such chemistry
will be investigated in more detail in the near future.
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Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.; Koch, M.; Visser, G. M.;
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Acknowledgments
We thank Hugo Morren and Willem Gorter for the analytical
support, Harry Mons and Sjoerd van Schaik for experimental con-
tributions, and Hicham Zilaout for helpful suggestions.
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6881
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132.70, 132.98, 133.89, 137.15, 138.03, 192.76, 195.86. HRMS (ES+): calcd for
C
15H13O2S (M+H)+: 257.0636; found: 257.0619. Compound 33: 1H NMR
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13. General procedure for the hetero cross-coupling with potassium thioacetate (Table
1, entry 1): A dried 50 ml, three-necked reaction vessel was charged with
degassed toluene (15 ml) followed by the addition of 6 (208 mg, 1 mmol)
resulting in a clear solution. After addition of Pd2(dba)3 (23 mg, 0.025 mmol)
and CyPF-tBu (27.7 mg, 0.05 mmol), the mixture was stirred under a nitrogen
atmosphere for 5 min at room temperature. KSAc (228 mg, 2 mmol) was added
and the mixture was heated in a pre-heated oil bath at 110 °C for 24 h. After
cooling to room temperature, Et2O was added. Undissolved salts were removed
by filtration and the remaining organic layer was concentrated in vacuo. The
obtained crude 24 was further purified by flash chromatography [silica gel 60
(0.040–0.063 nm, Merck)] eluting with CH2Cl2–acetone, 95:5 (v/v), to give
183 mg of pure 24 (90%).
(400 MHz, CDCl3): d 1.40 (t, J = 8 Hz, 3H), 2.45 (s, 3H), 4.36–4.42 (m, 2H),
7.49 (d, J = 8 Hz, 2H), 8.07 (d, J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 13.28,
29.40, 60.21, 129.36, 130.15, 132.37, 132.96, 164.88, 191.71. HRMS (ES+): calcd
for C11H13O3S (M+H)+: 225.0585; found: 225.057. Compound 35: 1H NMR
(400 MHz, CDCl3): d 2.41 (s, 3H), 6.54 (m, 1H), 7.15–7.19 (m, 2H), 7.33 (d,
J = 8 Hz, 1H), 7.01 (br s, 1H), 8.35 (br s, 1H). HRMS (ES+): calcd for C10H10NOS
(M+H)+: 192.0483; found: 192.0502. 13C NMR data not available. Compound 36:
1H NMR (400 MHz, CDCl3): d 1.67 (s, 9H), 2.42 (s, 3H), 6.57 (d, J = 4 Hz, 1H),
7.33 (dd, J = 8 and 2 Hz, 1H), 7.61–7.65 (m, 2H), 8.18 (br d, J = 8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d 28.27, 30.06, 84.17, 107.08, 115.96, 121.31, 126.89,
127.57, 130.29, 131.42, 135.62, 149.47, 195.22. HRMS (ES+): calcd for
C
15H18NO3S (M+H)+: 292.1007; found: 292.1010. Compound 37: 1H NMR
(400 MHz, CDCl3): d 2.48 (s, 3H), 7.44 (dd, J = 8 and 4 Hz, 1H), 7.69 (dd, J = 8 and
2 Hz, 1H), 7.94 (br s, 1H), 8.15 (t, J = 8 Hz, 2H), 8.95 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 29.33, 120.66, 125.39, 127.39, 129.37, 133.10, 133.51, 134.99, 147.08,
150.51, 192.57. HRMS (ES+): calcd for C11H10NOS (M+H)+: 204.0483; found:
204.0466. Compound 21 (starting material for 36): 1H NMR (400 MHz, CDCl3): d
1.68 (s, 9H), 6.60 (d, J = 4 Hz, 1H), 7.21 (dd, J = 8 and 2 Hz, 1H), 7.48 (d, J = 2 Hz,
1H), 7.70 (d, J = 4 Hz, 1H), 8.21 (br d, J = 8 Hz, 1H). 13C data and HRMS data not
available.
14. The compounds described in Table 1, which are known in the literature (25–27,
31, 32, 34, 38) exhibited spectral properties consistent with the assigned
structures. Spectral data are given for the compounds described in Table 1,
which to the best of our knowledge are unknown in the literature. Compound
24: 1H NMR (400 MHz, CDCl3): d 2.52 (s, 3H), 7.60 (br t, J = 8 Hz,1H), 7.76–7.81
(m, 1H), 7.83 (d, J = 8 Hz, 1H), 8.13 (d, J = 8 Hz, 1H), 8.26 (d, J = 2 Hz, 1H), 8.82
(d, J = 2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 29.36, 120.94, 126.24, 126.83,
126.99, 128.39, 129.64, 141.10, 146.65, 152.72, 191.86. HRMS (ES+): calcd for
15. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapers, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653–6655.
16. Typical procedure for the preparation of compound 39: A dried 50 ml reaction
vessel was charged with thioacetate 24 (115 mg, 0.55 mmol). Under ice-bath
cooling, a solution of NaOH (25 mg, 0.62 mmol) in anhydrous EtOH (5 ml) was
added. The obtained solution was stirred under a nitrogen atmosphere at 0 °C
until deprotection of the S-acetyl moiety was complete (10 min, monitored by
LC–MS). Benzyl bromide (106 mg, 0.62 mmol) was added, and after additional
stirring at 0 °C for 10 min, repeated LC–MS indicated total conversion into 39.
The reaction mixture was diluted with EtOAc, followed by washing with brine
(2 Â 10 ml). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography [silica gel 60 (0.040–0.063 nm,
Merck)] eluting with CH2Cl2–acetone, 95:5 (v/v) gave 100 mg of pure 39 (72%).
1H NMR (400 MHz, CDCl3): d 4.19 (s, 2H), 7.21–7.31 (m, 5H), 7.53 (t, J = 8 Hz,
1H), 7.65–7.70 (m, 2H), 7.98 (d, J = 2 Hz, 1H), 8.05 (d, J = 8 Hz, 1H), 8.81 (s, 1H).
13C NMR (100 MHz, CDCl3): d 39.35, 127.11, 127.13, 127.50, 128.06, 128.65,
128.88, 129.27, 129.33, 129.86, 136.66, 136.77, 146.52, 152.15. HRMS (ES+):
calcd for C16H14NS (M+H)+ 252.0487; found: 252.0825.
C
11H11NOS (M+H)+: 204.0483; found: 204.0479. Compound 28: 1H NMR
(400 MHz, CDCl3): d 2.40 (s, 3H), 5.21 (s, 2H), 6.74 (br s, 1H), 7.32–7.41 (m,
7H), 7.45 (br d, J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 29.00, 66.16, 117.97,
120.60, 127.32, 127.42, 127.63, 134.42, 134.79, 138.18, 152.00, 193.98. HRMS
(ES+): calcd for C16H16NO3S (M+H)+: 302.0851; found: 302.0832. Compound 29,
exists as two conformations according to NMR data: (a) 60 mol %, 1H NMR
(400 MHz, CDCl3): d 2.42 (s, 3H), 7.36 (d, J = 8 Hz, 2H), 7.58 (d, J = 8 Hz, 2H),
8.05 (br s, 1H), 8.35 (d, J = 2 Hz, 1H). (b) 40 mol %, 1H NMR (400 MHz, CDCl3): d
2.45 (s, 3H), 7.11 (d, J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 8.09 (br s, 1H), 8.82 (d,
J = 2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 30.16, 118.84, 120.46, 123.01,
123.90, 135.41, 136.09, 138.08, 138.31, 159.24, 162.18, 194.57, 195.26. HRMS
(ES+): calcd for C9H10NO2S (M+H)+: 196.0432; found: 196.0419. Compound 30:
1H NMR (400 MHz, CDCl3): d 2.48 (s, 3H), 7.47–7.56 (m, 4H), 7.58–7.64 (m, 1H),
17. Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. J. Am. Chem. Soc. 1974, 96,
3654–3655.