Efficient preparation of S-aryl thioacetates from aryl halides and potassium thioacetate

Article abstract of DOI:10.1016/j.tetlet.2007.02.128

A method for the preparation of S-aryl thioacetates using palladium-mediated couplings of aryl bromides and aryl triflates with potassium thioacetate as an inexpensive thiol source was developed. Electron withdrawing groups, electron donating groups and heterocyclic substrates were tolerated in the reaction conditions, affording the corresponding products in good to excellent yields. This method was applied to the preparation of novel sulfone-containing DPP-IV inhibitors.

Full text of DOI:10.1016/j.tetlet.2007.02.128

Tetrahedron Letters 48 (2007) 3033–3037
Efficient preparation of S-aryl thioacetates from aryl halides
and potassium thioacetate
Chunqiu Lai* and Bradley J. Backes
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064-6098, USA
Received 3 October 2006; revised 24 February 2007; accepted 26 February 2007
Available online 2 March 2007
Abstract—A method for the preparation of S-aryl thioacetates using palladium-mediated couplings of aryl bromides and aryl tri-
flates with potassium thioacetate as an inexpensive thiol source was developed. Electron withdrawing groups, electron donating
groups and heterocyclic substrates were tolerated in the reaction conditions, affording the corresponding products in good to excel-
lent yields. This method was applied to the preparation of novel sulfone-containing DPP-IV inhibitors.
Ó 2007 Elsevier Ltd. All rights reserved.
Compounds that possess arylsulfur-containing func-
tional groups have found use in multiple applications,
including those in biological, pharmaceutical and mate-
rials areas.1 Accordingly, methods to construct the aryl–
sulfur bond are of high utility. In spite of this, relatively
few efficient and general methods to prepare versatile
arylthiol equivalents from readily available starting
materials have been developed. Classical preparations
generally feature the trapping of metalated aryl groups
with elemental sulfur to afford arylthiols.2 However,
these transformations cannot be applied for those aryl
substrates bearing sensitive functionalities such as alde-
hyde, ketone and ester groups. More modern procedures
utilize specialized sulfur reagents that can be coupled
with aryl halides to afford stable intermediates. A second
step is used to reveal the arylthiol functionality.3 For
example, iso-octyl-3-mercaptopropionate3e and 2-(4-
pyridyl)ethanethiol3f can be coupled to aryl bromides
to furnish intermediates that are susceptible to b-elimi-
nation. Treatment with sodium tert-butoxide then gives
the corresponding arylthiol products.3h While effective,
these specialized sulfur reagents are not simple and
low cost thiol sources. We reasoned that the coupling
of inexpensive thioacetic acid with aryl halides would
be a powerful alternative to form the aryl–sulfur bond
(Scheme 1).4 The resulting S-aryl thioacetates are versa-
tile intermediates from which a number of sulfur-con-
taining functional groups including arylthiols (ArSH),5
aryl sulfenyl chlorides (ArSCl),6 aryl sulfinyl chlorides
(ArSOCl)7 and aryl alkyl sulfides (ArSR)8 can be
accessed in a straightforward manner. Here, we report a
general Pd-catalyzed coupling of aryl bromides/triflates
with inexpensive potassium thioacetate to give S-aryl
thioacetates under microwave conditions (Scheme 1).
We used the catalyst system (Pd2(dba)3–Xantphos)
reported by Ioth and Mase3h as a starting point to
investigate the coupling efficiency of bromobenzene with
potassium thioacetate (Table 1). Under refluxing condi-
tions with 1,4-dioxane as solvent (100 °C), we were
O
S-K+
ArSH
ArSR
ArSCl
ArSOCl
Me
X
S
Me
1-Step
R
R
O
S
-Aryl
X = Br, OTf
Scheme 1. Preparation of versatile S-aryl thioacetates.
thioacetates
*
Corresponding author. Tel.: +1 847 935 6567; fax: +1 847 938 1674; e-mail: chunqiu.lai@abbott.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.128

3034
C. Lai, B. J. Backes / Tetrahedron Letters 48 (2007) 3033–3037
Table 1. Evaluation of reaction conditions for the formation of S-phenyl thioacetate
O
conditions
Br
Me
+
S
S-K+
Me
O
Entry
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
8
Pd2(dba)3, Xantphos, i-Pr2NEt, 1,4-dioxane, 100 °C, 1d
Pd2(dba)3, Xantphos, i-Pr2NEt, diglyme, 150 °C, 1d
Pd2(dba)3, Xantphos, i-Pr2NEt, DMF, 150 °C, 1d
Pd2(dba)3, Xantphos, i-Pr2NEt, NMP, 150 °C, 1d
Pd2(dba)3, Xantphos, i-Pr2NEt, 1,4-dioxane, microwave, 160 °C, 25 min
1,4-Dioxane, microwave, 160 °C, 25 min
30
nd
nd
nd
89
nd
nd
5
Pd2(dba)3, i-Pr2NEt, 1,4-dioxane, microwave, 160 °C, 25 min
Pd2(dba)3, Xantphos, 1,4-dioxane, microwave, 160 °C, 25 min
a Reactions were performed using 2.5 mol % catalyst, 5 mol % ligand, 1.5 equiv of potassium thioacetate, 2.0 equiv of Hunig’s base and 3.6 mL of
solvent with 1.0 mmol of bromobenzene.
b Isolated yield.
pleased to observe partial conversion to give S-phenyl
thioacetate (30%) (entry 1). This result was encouraging
and we reasoned that the conversion could be increased
through better dissolution of potassium thioacetate. To
this end, various aprotic solvents and reaction tempera-
tures were screened. Diglyme at 150 °C gave no detect-
able amount of the desired product (entry 2). Similarly
poor results were observed for DMF and NMP (entries
3, 4). However, the subjection of the reaction mixture to
microwave heating at 160 °C with 1,4-dioxane as solvent
afforded the desired product in an excellent yield (entry
5, 89%).
Table 2. Pd-catalyzed coupling of aryl bromides/triflates potassium thioacetate under microwave conditions
2.5 mol% Pd2(dba)3,
5 mol% Xantphos,
O
X
Me
S
+
2 eq -Pr2NEt,
i
R
R
S
S-K+
Me
1,4-dioxane, microwave
MW 160 oC, 25 min
O
X = Br, OTf
Entry
1
ArX
Product
Yielda (%)
75
Br
Me
Me
Me
O
S
Me
Br
Me
2
3
4
72
51
85
O
Me
Me
Br
S
MeO
MeO
MeO
O
MeO
S
Me
Br
N
N
O
S
Me
Me
BocHN
CbzHN
5
6
7
71
—
65
Br
BocHN
O
O
S
Br
CbzHN
O
O
S
Me
Br
Me
Me
O

C. Lai, B. J. Backes / Tetrahedron Letters 48 (2007) 3033–3037
3035
Table 2 (continued)
Entry
ArX
Product
Yielda (%)
88
Br
S
Me
8
9
EtOOC
O
EtOOC
O2N
Me
S
Br
—
91
—
O
O2N
S
S
Me
10
OTf
Cl
O
O
Me
11
a Isolated yield.
In order to investigate the requirements of the transfor-
mation, we performed reactions in the absence of
Pd2(dba)3–Xantphos and Hunig’s base (entry 6), ligand
Xantphos (entry 7), or Hunig’s base (entry 8). None of
these reaction conditions were effective. Finally, it
should be noted that the use of thioacetic acid, rather
than potassium thioacetate, employing our best condi-
tions (Pd2(dba)3, Xantphos, i-Pr2NEt, 1,4-dioxane,
microwave, 160 °C, 25 min) did not yield any product.
dered ortho-bromotoluene provided the correspond-
ing product in good yield (entry 2). Electron rich
3,4-dimethoxybromobenzene coupled with moderate
efficiency (entry 3, 51%), while the electron poor hetero-
cycle 3-bromopyridine gave a good yield of thioacetate
product (entry 4, 85%). Common functional groups
such as N-Boc carbamates, ketones and ethyl esters
proved to be well-tolerated under our reaction condi-
tions, as exemplified by entries 5, 7 and 8. However,
both N-Cbz carbamate (entry 6) and nitro-containing
substrates (entry 9) provided no reaction products due
to either cross-reaction of these functionalities with
potassium thioacetate or decomposition. In addition,
the protocol can be applied with aryl triflates (entry
With the optimized reaction conditions in hand, we then
explored the scope of the transformation by coupling
various functionalized aryl bromides and aryl triflates
with potassium thioacetate (Table 2).9 Sterically hin-
F
F
F
F
NHBoc
F
NHBoc
+
F
a
Cl
N
N
Br
N
N
N
N
N
Br
N
2
3
4
F
F
F
F
F
NHBoc
NH3Cl
F
b
c, d, e
Me
N
N
N
O
O
N
N
N
S
S
N
N
Me
O
5
1
Scheme 2. Reagents and conditions (a) CH3CN, 80 °C, 0.5 h, 83%; (b) CH3COSK, Pd2(dba)3, Xantphos, i-Pr2NEt, 1,4-dioxane, microwave, 160 °C,
25 min, 87%; (c) CH3I, NaOH (1 N), EtOH, 0 °C, 1 h; (d) m-CPBA, CH2Cl2, rt, 50 min; (e) HCl/1,4-dioxane (4 N), rt, 2 h, (84%—three steps).

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C. Lai, B. J. Backes / Tetrahedron Letters 48 (2007) 3033–3037
2. Patai, S. The Chemistry of the Thiol Group; John Wiley &
Sons: London, 1974; Chapter 4, Part 1, pp 163–269.
3. (a) Testaferri, L.; Tingoli, M.; Tiecco, M. Tetrahedron
Lett. 1980, 21, 3099–3100; (b) Pinchart, A.; Dallaire, C.;
Bierbeek, A. V.; Gingras, M. Tetrahedron Lett. 1999, 40,
5479–5482; (c) Takagi, K. Chem. Lett. 1985, 1307–1308;
(d) Flatt, A. K.; Tour, J. M. Tetrahedron Lett. 2003, 44,
6699–6702; (e) Becht, J.-M.; Wangner, A.; Mioskowski, C.
J. Org. Chem. 2003, 68, 5758–5761; (f) Katritzky, A. R.;
Khan, G. R.; Schwarz, O. A. Tetrahedron Lett. 1984, 25,
1223–1226; (g) Rane, A. M.; Miranda, E. I.; Soderquist, J.
A. Tetrahedron Lett. 1994, 35, 3225–3226; (h) Itoh, T.;
Mase, T. Org. Lett. 2004, 6, 4587–4590.
4. S-Aryl thioacetates were prepared in 40–60% yield by the
treatment of arenediazonium tetrafluoroborates with
commercial potassium thioacetate. Petrillo, G.; Novi,
M.; Garbarino, G.; Filiberti, M. Tetrahedron Lett. 1988,
29, 4185–4188.
5. (a) MacCoss, R. N.; Henry, D. J.; Brain, C. T.; Ley, S. V.
Synlett 2004, 675–678; (b) Jin, C. K.; Jeong, H. J.; Kim,
M. K.; Kim, J. Y.; Yoon, Y.-J.; Lee, S.-G. Synlett 2001,
1956–1958.
10, 91%). Aryl chlorides did not couple under these con-
ditions, thus defining the limits of reactivity (entry 11).
These methods were applied to the development of pyr-
rolidine-constrained phenethylamine DPP-IV inhibitors
such as 1.10 A flexible and efficient synthesis of com-
pound 1 is shown in Scheme 2.11 Briefly, pyrrolidine
2
3
10 was treated with bromo-substituted triazine chloride
12 to provide 4 in high yield (83%). This efficient trans-
formation proceeded with quaternization of the amine
followed by debenzylation.13 Compound 4 was then
coupled with potassium thioacetate under our optimized
reaction conditions to form key intermediate 5 in 87%
yield. Compound 5 was cleanly converted to the corre-
sponding methyl sulfide via one-pot deacylation/alkyl-
ation with MeI.8 Finally, oxidation of the methyl
sulfide with m-chloroperoxybenzoic acid followed by a
deprotection step provided the desired product 1 in high
yield (84% from 5).
6. Thea, S.; Cevasco, G. Tetrahedron Lett. 1988, 29, 2865–
2866.
7. Thea, S.; Cevasco, G. Tetrahedron Lett. 1987, 28, 5193–
5194.
In summary, we have developed an efficient and func-
tional group compatible method for the formation of
aryl–sulfur bonds through the coupling of aryl bromides
and aryl triflates with an inexpensive thiol source. The
S-aryl thioacetate products that this method provides
are versatile intermediates for the preparation of a range
of sulfur-containing functional groups. We have applied
these methods to the synthesis of DPP-IV inhibitors that
contain sensitive functionality. Further improvement
and applications of this protocol will be reported in
due course.
8. Sawicki, E. J. Org. Chem. 1956, 21, 271–273.
9. All microwave reactions were performed using a Personal
Chemistry EmrysTM Optimizer in a septa capped 2–5 mL
BiotageTM microwave tube with magnetic stirring. Power
required to maintain target temperature was controlled by
EmrysTM Optimizer Software. The synthesis of represent-
ative compound thioacetic acid S-(4-tert-butoxycarbonyl-
amino-phenyl) ester (Table 2, entry 5): (4-Bromo-
phenyl)carbamic acid tert-butyl ester (270 mg, 1.0 mmol),
potassium thioacetate (170 mg, 1.5 mmol), Pd2(dba)3
(23 mg, 0.025 mmol) and Xantphos (29 mg, 0.050 mmol)
were placed in a 2–5 mL BiotageTM microwave tube capped
with a rubber septum. The tube was evacuated under
vacuum and refilled with nitrogen three times. i-Pr2NEt
(350 lL, 2.0 mmol) and degassed dry 1,4-dioxane (3.6 mL)
were added to the tube and the rubber septum was quickly
replaced with a microwave tube cap. The reaction mixture
was heated in a microwave at 160 °C for 25 min. The
reaction mixture was partitioned between EtOAc and
water. The aqueous phase was extracted again with
EtOAc. The combined organic phase was dried over
Na2SO4 and concentrated in vacuo. The crude material
was purified by flash chromatography on silica gel (0–20%
EtOAc/hexanes) to give thioacetic acid S-(4-tert-butoxy-
carbonylaminophenyl) ester (190 mg, 71%). 1H NMR
(300 MHz, CD3OD) d 7.43–7.51 (m, 2H), 7.24–7.31 (m,
2H), 2.35 (s, 1H), 1.51 (s, 9H) ppm. 13C NMR (100 MHz,
CD3OD) d 196.75, 154.88, 142.14, 136.31, 122.01, 119.98,
81.15, 29.85, 28.66 ppm. MS (+ESI) m/z 285.0
(M þ NH4þ). Anal. Calcd for C13H17NO3S: C, 58.4; H,
6.41; N, 5.24. Found: C, 58.35; H, 6.20; N, 5.18.
Acknowledgements
The authors thank the staff of Abbott Structural Chem-
istry Department for obtaining the spectral data, and
Dr. Andrew J. Souers and Dr. Thomas W. von Geldern
for their valuable comments.
References and notes
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11. Preparation of 1: A mixture of 2 (1.30 g, 4.80 mmol) and 3
(2.0 g, 4.80 mmol) in CH3CN (16 mL) was stirred at 80 °C
for 30 min.13 After cooling to room temperature, the solids
were collected and washed with hexanes three times.
Compound 4 was obtained as a white solid (2.20 g, 83%
yield). Using our coupling procedure (Ref. 9), 4 (110 mg,

C. Lai, B. J. Backes / Tetrahedron Letters 48 (2007) 3033–3037
3037
0.20 mmol) was coupled with potassium thioacetate to
afford intermediate 5 (95 mg, 87%). A mixture of 5 (27 mg,
0.050 mmol), CH3I (8.5 mg, 0.060 mmol) and NaOH (1 N,
60 lL, 0.060 mmol) in EtOH (0.3 mL) was stirred at 0 °C
for 1 h. The reaction mixture was partitioned between
EtOAc and water. The organic phase was dried over
Na2SO4 and concentrated in vacuo to provide the corre-
sponding methyl sulfide (27 mg, 100%). To a solution of
the methyl sulfide (27 mg, 0.050 mmol) in CH2Cl2
(0.6 mL) was added m-CPBA (70–75%, 26 mg,
0.10 mmol). After stirring at 50 °C for 50 min, the reaction
mixture was quenched with NaHCO3 (1 N) and extracted
with ethyl acetate. The organic extracts were washed with
brine, dried (Na2SO4) and concentrated. The crude
material was purified by flash chromatography on silica
gel (30–80% EtOAc/hexanes) to give the methyl sulfoxide
(23 mg, 84%). A solution of the methyl sulfoxide (23 mg,
0.042 mmol) in HCl/1,4-dioxane (4 N, 0.1 mL) was stirred
at room temperature for 2 h. The reaction mixture was
concentrated under vacuum to afford 1 (21 mg, 100%). 1H
NMR (300 MHz, CD3OD) d 8.86–8.95 (m, 1H), 8.78–8.85
(m, 1H), 8.63–8.74 (m, 1H), 8.17–8.27 (m, 1H), 7.78–7.89
(m, 1H), 7.55–7.65 (m, 1H), 7.26–7.37 (m, 1H), 4.39–4.61
(m, 2H), 4.24–4.37 (m, 1H), 3.55–4.14 (m, 5H), 3.14–3.26
(m, 3H) ppm. MS (+ESI) m/z 450 (M+H+). Anal. Calcd
for C20H18F3N5O2SÆ2.65HClÆ1.35CH3OH: C, 43.60; H,
4.35; N, 11.77. Found: C, 43.51; H, 4.46; N, 11.88.
12. Harris, R. L. N. Synthesis 1980, 841–842.
13. Hamilton, G. L.; Backes, B. J. Tetrahedron Lett. 2006, 47,
2229–2231.