Palladium- and Nickel-Catalyzed Decarbonylative C-S Coupling to Convert Thioesters to Thioethers

Article abstract of DOI:10.1021/acs.orglett.7b03305

This Letter describes the development of a catalytic decarbonylative C-S coupling reaction that transforms thioesters into thioethers. Both Pd- and Ni-based catalysts are developed and applied to the construction of diaryl, aryl alkyl, and heterocycle-containing thioethers.

Full text of DOI:10.1021/acs.orglett.7b03305

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium- and Nickel-Catalyzed Decarbonylative C−S Coupling to
Convert Thioesters to Thioethers
Naoko Ichiishi, Christian A. Malapit, Łukasz Wozniak, and Melanie S. Sanford*
́
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: This Letter describes the development of a catalytic decarbonylative C−S coupling reaction that transforms
thioesters into thioethers. Both Pd- and Ni-based catalysts are developed and applied to the construction of diaryl, aryl alkyl, and
heterocycle-containing thioethers.
he aryl thioether functional group appears in a variety
T
of pharmaceuticals and agrochemicals.1 For instance, a
number of top-selling drugs,2 including Seroquel,3 Trintellix,4
Teflaro,5 and Inlyta,6 contain aryl thioether moieties (Figure 1).
Figure 2. Transition-metal-catalyzed syntheses of aryl thioethers by
(a) traditional cross-coupling reactions and (b) decarbonylation of
thioesters.
Figure 1. Examples of pharmaceuticals containing aryl thioethers.
and Ni complexes are competent catalysts for this transfor-
mation and further that they exhibit complementary reactivity
and selectivity profiles with some substrates.
Aryl thioethers are most commonly prepared via the coupling
of an aryl halide or pseudohalide with a thiol in the presence of
base.7−10 With electron-deficient aryl halides, these reactions
often proceed via an uncatalyzed SNAr pathway,7 while Pd or
Cu catalysis8 is commonly employed to forge the C−S bond
with electron-rich (hetero)aryl halides (Figure 2a).
In this Letter, we report an alternate approach to aryl thio-
ethers involving metal-catalyzed intramolecular decarbonylative
coupling of thioesters (Figure 2b). This process offers several
advantages over conventional aryl halide/thiol cross-couplings.
First, carboxylic acids (the precursors to thioesters) are often
more readily available and less expensive than their aryl halide
counterparts.11−14 Second, this transformation proceeds under
base-free conditions without the requirement for exogeneous
thiol15 nucleophiles.16 Finally, we demonstrate that both Pd
At the outset of our studies, we noted sporadic literature
reports of metal-mediated decarbonylative thioetherification
reactions.17−19 However, most prior examples employed
stoichiometric quantities of Ni or Rh complexes. Furthermore,
the reported reactions were demonstrated with a narrow scope
of unfunctionalized substrates. Our work in this area was inspired
by recent reports of Ni- and/or Pd-catalyzed intramolecular
decarbonylation of aryl esters20 and aroyl chlorides21 to form
C(sp2)−O and C(sp2)−Cl bonds, respectively. As shown in
Received: October 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Scope of Pd and Ni-Catalyzed Decarbonylative Thioetherification
a
Conditions: With [Pd]: substrate 1 (0.3 mmol, 1 equiv), Pd[P(o-tol)3]2 (0.03 mmol, 0.1 equiv), and PAd2Bn (0.06 mmol, 0.2 equiv) in p-xylene
(0.2 M) with 5 Å molecular sieves at 150 °C. With [Ni]: substrate (0.3 mmol, 1 equiv), Ni(cod)2 (0.03 mmol, 0.1 equiv), and PCy3 (0.06 mmol,
b
0.2 equiv) in toluene (0.2 M) at 130 °C. Isolated yields are shown. For experimental details, see the Supporting Information. Isolated yield from
c
d
1.0 mmol scale substrate. GC yield obtained from 0.05 mmol scale substrate using neopentyl benzene as an internal standard. Based on 1H NMR
e
and GC−MS analysis of the crude mixture. Yield based on 1H NMR analysis of the crude mixture; 2t was found inseparable with starting material.
Figure 2b, we hypothesized that a similar process involving:
(i) oxidative addition of a thioester to form an acylmetal thio-
late (A), (ii) decarbonylation to form an aryl thiolate inter-
mediate (B), and finally (iii) C−S bond-forming reductive elimi-
nation would enable the catalytic formation of diverse thioether
products.
diphenyl sulfide (2a), in 28% yield in xylene at 150 °C. We next
explored the use of Pd[P(o-tol)3]2 in conjunction with various
mono- and bisphosphine ligands.22 As shown in Table 1, many
of these ligands afforded improvements in the yield, and the
best result (78% yield) was obtained with the sterically bulky
monophosphine PAd2Bn (entry 7).
We initiated our studies with S-phenyl benzenethioate (1a)
as the substrate. Our previous work on the decarbonylative
coupling of aroyl chlorides showed that Pd complexes bearing
bulky monophosphine ligands (e.g., P(o-tol)3 and BrettPhos)
were the most effective catalysts. Thus, we initially explored the
use of 10 mol % Pd[P(o-tol)3]2 as the catalyst. As shown in
Table 1, entry 1, these conditions afforded the desired product,
We also pursued an analogous Ni-catalyzed reaction, since
Ni-based catalysts have been much more widely used for decar-
bonylative couplings than their Pd analogues.23 The combina-
tion of 10 mol % Ni(cod)2 and 20 mol % PAd2Bn (the optimal
ligand for the Pd system) in toluene at 130 °C afforded 2a in
85% yield. Furthermore, switching to PCy3 resulted in the for-
mation of 2a in nearly quantitative yield (entry 10).
B
DOI: 10.1021/acs.orglett.7b03305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Evaluation of Ligands for Pd- and Ni-Catalyzed
Decarbonylative Thioetherification
Table 2. Competition Experiments with Various Thioesters
under Pd and Ni Catalysis
a
a
b
entry
[M]
ligand (mol %)
none
Brettphos (10)
dppe (20)
yield of 2a (%)
1
2
3
Pd[P(o-tol3)]2
28
58
19
4
5
dppf (20)
61
15
tBuXantphos (20)
PAd2n-Bu (20)
PAd2Bn (20)
PAd2Bn (20)
P(n-Bu)3 (20)
PCy3 (20)
6
7
8
9
67
78
85
92
Ni(cod)2
10
>99
a
Conditions: 1a (0.05 mmol), [M] (0.005 mmol, 0.1 equiv), and
ligand (0.01 mmol, 0.2 equiv). Entries 1−7 were performed in p-xylene
(0.2 M), 150 °C, 20 h; entries 8−10 were performed in toluene,
130 °C, 20 h. See the Supporting Information for additional details.
b
GC yields obtained using neopentylbenzene as an internal standard.
We next examined the scope of these Pd- and Ni-catalyzed
C−S coupling reactions. As shown in Scheme 1, substrates
bearing electron-donating and electron-withdrawing substitu-
ents on the thiol-derived fragment underwent high-yielding
decarbonylative thioetherification to afford products 2i−l under
both Pd and Ni catalysis. A wide variety of substituents were
well-tolerated on the carboxylic acid-derived portion of the
substrate. For instance, benzylic C−H bonds (2b), carboxylic
acid esters (2e), and boronate esters (2f) were compatible with
the reaction conditions. Notably, the low yield observed with
4-anisoyl phenylthiolate (2c) under Pd catalysis (27%) is due
to the formation of diaryl sulfides as byproducts.24 In contrast,
under Ni catalysis 2c was obtained in 75% yield. Sterically hin-
dered thioesters also reacted to form the corresponding thio-
ether products (2g, 2h), and the Ni catalyst provided higher
yields with these substrates. Finally, heterocycles including
thiophene (2m), pyridine (2n), and chromenone (2o) were
well-tolerated, particularly with the Ni catalyst.
The decarbonylation of S-phenyl (E)-3-phenylprop-2-ene-
thioate proceeded to form 2p under both Pd and Ni catalysis
with retention of the olefin geometry. However, the E/Z ratio
in the product varied significantly as a function of the metal.
Under Pd catalysis, 2p was obtained as a 9:1 E/Z mixture, while
the Ni catalyst afforded the product with an E/Z ratio of >20:1.
Benzylic (2q) and allylic (2r) thioethers were formed in
moderate to high yields from S-phenyl 2-phenylethanethioate
and S-phenyl (E)-4-phenylbut-3-enethioate, respectively. With
these two substrates, the Pd catalyst afforded significantly
higher yields than the Ni catalyst. Alkyl thioesters were also
found to be compatible with the Pd catalysis, forming alkyl
thioether products 2s and 2t in good yields. However, these
reactions did not proceed under Ni catalysis.
a
Conditions: (a) 1c (0.05 mmol), 1d (0.05 mmol), [M] (0.002
mmol), ligand (0.004 mmol), toluene-d8, 130 °C, 0.5 and 2 h. (b) 1g
(0.1 mmol), [M] (0.002 mmol), ligand (0.004 mmol), toluene-d8,
b
1
130 °C, 0.5 and 2 h. Ratio and yield analyses were obtained by H
c
and 19F NMR spectroscopy. Unwanted biarylsulfide byproducts
(∼5%) were observed (ref 24). See the Supporting Information for
additional details.
A final set of experiments was conducted to probe the rela-
tive reactivities of thioester substrates with the two different
catalyst systems. First, a 1:1 mixture of 1c and 1d was heated at
130 °C under Pd or Ni catalysis (Table 2a). The reactions were
analyzed by 1H and 19F NMR spectroscopy after 0.5 and 2 h to
assay both the yield and ratio of aryl thioether products at each
time point. As summarized in Table 2, 1d (bearing an electron-
withdrawing p-trifluoromethyl substituent) reacted faster than
1c (bearing an electron-donating p-methoxy substituent) under
both Pd and Ni catalysis. However, the Pd catalyst afforded
lower overall yield and higher selectivity for 1d at both time
points. We next examined the o-methyl-substituted thioester
substrate 1g with both catalysts (Table 2b). These studies
revealed that this relatively sterically hindered substrate under-
goes much faster reaction with the Pd catalyst, affording >99%
yield of thioether 2g after just 0.5 h. In contrast, the Ni catalyst
afforded 2g in just 40% yield under analogous conditions.
These studies provide preliminary insights into the different
electronic/steric preferences of the two catalyst systems.
We also applied this method to the functionalization of the
carboxylic acid-containing drug probenecid.25 A series of pro-
benecid thioesters (1u−w) were prepared and then subjected
to the optimal Ni and Pd catalytic conditions. As summarized in
Scheme 1, these transformations afforded thioether derivatives
2u−w in good to excellent yields, highlighting the potential of
this transformation for the late-stage derivatization of bioactive
carboxylic acids.
In summary, this Letter has described the development, opti-
mization, and scope of the Pd- and Ni-catalyzed intramolec-
ular decarbonylative conversion of thioesters to thioethers.
This method provides access to diaryl thioethers, heteroaryl
thioethers, and aryl alkyl thioethers under base- and thiol-free
C
DOI: 10.1021/acs.orglett.7b03305
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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conditions. In general, the Pd and Ni catalysts exhibit similar
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ASSOCIATED CONTENT
■
S
* Supporting Information
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see: (a) Gooßen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2002, 41,
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A. Eur. J. Org. Chem. 2015, 2015, 5546. (h) Pu, X.; Hu, J.; Zhao, Y.;
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(13) For examples of decarbonylative coupling reactions of amides,
see: (a) Shi, S.; Szostak, M. Org. Lett. 2017, 19, 3095. (b) Meng, G.;
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(14) For an example of the decarbonylation of thioesters and
formation of C−B bonds, see: Ochiai, H.; Uetake, Y.; Niwa, T.;
Hosoya, T. Angew. Chem., Int. Ed. 2017, 56, 2482.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03305.
Experimental details, characterization, and NMR data for
isolated compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mssanfor@umich.edu.
ORCID
Christian A. Malapit: 0000-0002-8471-4208
Melanie S. Sanford: 0000-0001-9342-9436
Notes
The authors declare no competing financial interest.
(15) For examples of thiol-free thioetherifications, see: (a) Reeves, J.
T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, C. A.; Senanayake,
C. H. Org. Lett. 2014, 16, 1196. (b) Li, Y.; Pu, J.; Jiang, X. Org. Lett.
2014, 16, 2692. (c) Lin, Y.-M.; Lu, G.-P.; Wang, G.-X.; Yi, W.-B. J. Org.
Chem. 2017, 82, 382.
ACKNOWLEDGMENTS
■
We acknowledge financial support from NIH NIGMS
(GM073836) as well as the Danish National Research Founda-
tion (Carbon Dioxide Activation Center; CADIAC). Ł.W. thanks
the UM-ICIQ Global Engagement Program for a fellowship.
(16) (a) Fernan
Eur. J. 2006, 12, 7782. (b) Fernan
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DOI: 10.1021/acs.orglett.7b03305
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