Oxalic Acid Monothioester for Palladium-Catalyzed Decarboxylative Thiocarbonylation and Hydrothiocarbonylation

Article abstract of DOI:10.1021/acs.orglett.9b03701

Oxalic acid monothioester (OAM), an easily accessible and storable reagent, was reported herein as a thioester synthetic equivalent for palladium-catalyzed decarboxylative thiocarbonylation of organohalides and hydrothiocarbonylation of unsaturated carbon-carbon bonds at room temperature with high chemo- and regioselectivity. The reaction is applicable to the synthesis of cysteine-derived thioesters, thus allowing chemical modification of cysteine-containing peptides. Decarboxylation of OAM proceeds through oxidative addition of Pd(0) to the acyl-S bond, which accounts for the very mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.9b03701

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxalic Acid Monothioester for Palladium-Catalyzed Decarboxylative
Thiocarbonylation and Hydrothiocarbonylation
Bin Zhao,† Yao Fu,† and Rui Shang*,†,‡
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Oxalic acid monothioester (OAM), an easily
accessible and storable reagent, was reported herein as a
thioester synthetic equivalent for palladium-catalyzed decar-
boxylative thiocarbonylation of organohalides and hydro-
thiocarbonylation of unsaturated carbon−carbon bonds at
room temperature with high chemo- and regioselectivity. The
reaction is applicable to the synthesis of cysteine-derived
thioesters, thus allowing chemical modification of cysteine-
containing peptides. Decarboxylation of OAM proceeds through oxidative addition of Pd(0) to the acyl−S bond, which
accounts for the very mild reaction conditions.
hioesters are an important class of bioactive compounds
Tthat widely exist as intermediates in enzymatic biosyn-
thesis1 and are considered as possible precursors to life.2 In
synthetic chemistry, thioesters also act as important synthetic
intermediates3 to provide essential chemoselectivity in the
synthesis of complex bioactive molecules and natural
products,4 as evidenced by the renowned Fukuyama reaction
and coupling.5 Besides classic condensation reactions,6
chemical synthesis of thioesters generally applies transition-
metal-catalyzed thiocarbonylation from organohalides7 and
hydrothiocarbonylation from unsaturated hydrocarbons.8
These transformations generally require the use of smelly
thiol and toxic carbon monoxide under harsh reaction
conditions (100−110 °C), under which complex biomolecules
such as cysteine-containing peptides are not well tolerable. In
addition, a stoichiometric amount of thiol or thiophenol of
high affinity to transition metal (e.g., Pd) sometimes impedes
the catalytic reactivity9 to limit the scope of amenable
substrates. We posit that a new method for thioester synthesis
by using oxalic acid monothioester (OAM) through palladium-
Figure 1. Decarboxylative couplings using oxalic acid derivatives. (a)
Decarboxylation of oxalate monoester on Pd(II) to generate ester
catalyzed decarboxylative couplings10−12 may provide another
competent path that uses user-friendly reagents. Different from
decarboxylative coupling of oxalate monoester salts,12a in
which decarboxylation takes place on a Pd(II) intermediate by
overcoming a high energy barrier (Figure 1a), decarboxylation
of OAM proceeds with a much lower energy barrier by
oxidative insertion of Pd(0) species into the acyl−S bond
(Figure 1b). It is notable that oxalic acid monothioesters are
easily synthesized by condensation of oxalyl chloride with
thiols or thiolphenols, followed by hydrolysis. Oxalic acid
monothioesters are bench stable, storable crystalline solids
with much less odor than thiols. As depicted in Figure 1c, we
hypothesized that both palladium-catalyzed thiocarbonylation
synthon. (b) Decarboxylation of OAM through oxidative addition
(OA) to S−CO bond and a photo of bench-stable, crystalline,
odorless oxalic acid monothioester. (c) Working hypothesis using
OAM as a thioester synthetic equivalent for palladium-catalyzed
thiocarbonylation and hydrothiocarbonylation.
and hydrothiocarbonylation can proceed using oxalic acid
monothioesters through this new decarboxylation process.
Received: October 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Guided by this hypothesis, we discovered that Pd(PPh3)4 in
combination with Xantphos served as efficient catalyst for
decarboxylative thiocarbonylation of aryl, alkenyl, benzyl, and
alkyl halides with oxalic acid monothioesters without using any
additive or base. Oxalic acid monothioesters can also be
applied in palladium-catalyzed hydrothiocarbonylation of
alkenes and alkynes. Remarkably, thiocarbonylation with aryl
iodides proceeded smoothly under room temperature without
addition of base, thus allowing modification of cysteine-
containing peptides, which will be useful in the discovery of
peptide drugs.
The optimal reaction conditions and some key reaction
parameters of palladium-catalyzed decarboxylative thiocarbo-
nylation and hydrothiocarbonylation are shown in Scheme 1
(see the Supporting Information for more details). Thio-
carbonylation with aryl iodide proceeds at room temperature
(Scheme 1a). Xantphos is essential for the high catalytic
reactivity. Pd(II) precatalysts such as Pd(OTFA)2 and
Pd(PPh3)2Cl2 were ineffective, suggesting the reaction was
initiated by Pd(0) catalyst. Interestingly, the reaction did not
require addition of base, as addition of K2HPO4 significantly
lowered the yield of thioester product. Pd(PPh3)4 (5 mol %) in
combination with Xantphos (6 mol %) catalyzes decarbox-
ylation of 1 to generate p-toluenethiol completely within 3 h at
room temperature in DMA, while oxidative addition of aryl
iodide with the same Pd(0) catalyst under identical conditions
proceeded at a much slower rate (see the Supporting
Information for details). Decarboxylative thiocarbonylation
with aryl bromides requires elevated reaction temperature to
overcome the energy barrier for oxidative addition with less
reactive aryl bromides (Scheme 1b).13 Aryl chloride and aryl
mesylate were unsuccessful substrates. Xantphos is the most
effective ligand among other phosphine ligands tested, possibly
because of its effect to destabilize Pd−CO bonding.14 It is
worthwhile to notice that a small amount of di-p-tolylsulfane
was detected in the reaction using p-tolyl bromide under 100
°C, suggesting a competing decarbonylation process under
reaction condition of high temperature. Decarboxylative
hydrothiocarbonylation of alkene also proceeds smoothly
with linear selectivity using Pd(PPh3)4/Xantphos as catalyst
under room temperature in toluene solvent (Scheme 1c).
Decarboxylative hydrothiocarbonylation required the use of
Pd(0) complex as catalyst. Pd(II) complexes as Pd(OTFA)2,
PdCl2, and Pd(PPh3)2Cl2 were all ineffective. Decarboxylative
hydrothiocarbonylation required addition of sodium iodide,
which probably acts as coordinative anion on palladium
catalyst to dictate desired reactivity and selectivity (cf. Figure
1c). The amount of sodium iodide additive can be reduced to
50 mol % with a slight decrease of the yield of the desired
product.
Scheme 1. Palladium-Catalyzed Thiocarbonylation and
Hydrothiocarbonylation Using OAM under Various
Conditions
The scope of thiocarbonylation with respect to aryl and
alkenyl halides is shown in Scheme 2. The reaction proceeds
well with both electron-rich aryl halides (3, 9) and electron-
deficient aryl halides (2, 10). A variety of functional groups
such as halides (5−7), acetyl (2), aldehyde (8), ether (9), aryl
pinacol boronate (13), amide (15), nitro (22), cyano (23),
and ester (27) were all compatible. The reaction also
proceeded with tolerance of ortho steric hindrance (14, 18).
Besides aryl halides, halogenated heteroarenes such as furan
(11), pyridine (16), quinoline (17), and benzothiophene (25)
were all suitable substrates. Alkenyl halide reacted smoothly to
produce alkene thioate (29). Entries 19 and 20 shows that the
reaction worked well for iodinated estrone derivatives,
demonstrating the ability to introduce thioester functionality
onto complex molecules.
The amenable substrate scope of different oxalic acid
monothioesters for synthesis of different S-substituted
thioesters is shown in Scheme 3. Both S-aryl thioesters and
S-alkyl thioesters could be synthesized using oxalic acid
monothioesters of thiophenols and thiols. For S-aryl
substituents, a variety of electron-rich and electron-deficient
aryl groups were all compatible (30−36). For S-alkyl
substituents, primary alkyl (37, 38), secondary alkyl (41),
tertiary alkyl (39, 42), and benzyl (40) were all tolerable.
The advantage of thioester synthesis using oxalic acid
monothioesters under mild conditions was further demon-
strated by applying this method to synthesize cysteine-derived
thioesters (43) and to modify the cysteine unit in cysteine-
containing peptides (44−49) (Scheme 4). We anticipate that
these short peptides containing thioester functionality will find
their utility in medicinal chemistry.15
a
Reaction conditions for aryl halide: 1 (0.75 mmol), 4′-
iodoacetophenone or 4-bromotoluene (0.5 mmol), Pd(PPh3)4 (5
mol %), Xantphos (6 mol %), DMA (5 mL), reaction performed at
room temperature (25
atmosphere. Reaction conditions for olefin: 1 (0.75 mmol), 4-phenyl-
1-butene (0.5 mmol), Pd(PPh3)4 (5 mol %), Xantphos (6 mol %),
NaI (150 mol %), toluene (5 mL), reaction performed at room
3 °C) or 100 °C for 8 h under argon
b
temperature (25 3 °C) for 8 h under argon atmosphere. Yield of
c
isolated product. Yield determined by 1H NMR using diphenyl-
methane as an internal standard.
B
DOI: 10.1021/acs.orglett.9b03701
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Organic Letters
Letter
Scheme 2. Scope of Thiocarbonylation with Different Aryl
and Alkenyl Halides
Scheme 3. Scope of Thiocarbonylation with Different Oxalic
Acid Monothioesters
a
Reaction conditions: 4-iodotoluene (0.5 mmol), oxalic acid
monothioester, (0.75 mmol), Pd(PPh3)4 (5 mol %), Xantphos (6
mol %), DMA (5 mL), reaction performed at room temperature (25
b
3 °C) for 8 h under argon atmosphere. Reaction conditions: 4-
bromoacetophenone (0.5 mmol), oxalic acid monothioester, (0.75
mmol), Pd(PPh3)4 (5 mol %), Xantphos (6 mol %), DMA (5 mL),
c
reaction performed at 100 °C for 8 h under argon atmosphere. 4-
a
Reaction conditions: 1 (0.75 mmol), aryl halide (0.5 mmol),
Iodoacetophenone instead of 4-bromoacetophenone, reaction per-
Pd(PPh3)4 (5 mol %), Xantphos (6 mol %), DMA (5 mL), reaction
conditions for aryl iodides performed at room temperature (25
formed at 80 °C for 8 h under argon atmosphere.
3
°C) for 8 h under argon atmosphere. Reaction conditions for aryl
bromides performed at 100 °C for 8 h under argon atmosphere.
Scheme 4. Synthesis of Cysteine-Derived Thioesters and
Modification of Cysteine-Containing Peptides
Besides aryl and alkenyl halides, the thiocarbonylation
reaction also proceeded with benzyl chloride (eq 1). The
reaction did not proceed when primary and secondary alkyl
bromides were tested. However, testing tertiary butyl bromide
gave 3-methylbutanethioate as the product in high yield
(Scheme 5, 51). Other 1,1′-dimethylalkyl bromides also gave
similar types of isomerized 3-methyl primary alkanethioate as
products (52, 53). Considering the high propensity of β-H
elimination of tertiary alkyl palladium species,16 3-methyl-
butanethioate is suggested to be generated by a hydro-
thiocarbonylation process from alkene after β-H elimination.
The utility of OAM in palladium-catalyzed decarboxylative
hydrothiocarbonylation of alkene and alkyne is demonstrated
in Scheme 6. Aliphatic terminal alkenes (4, 54), styrenes (55,
56), cyclic alkene (57), acrylamide (58), and acrylate (59)
were all amenable substrates to deliver hydrothiocarbonylation
products with linear selectivity. It is noteworthy that branched
product was also obtained in 15% isolated yield for acrylate
substrate (59), while the branched product was not observed
for aliphatic terminal alkenes and styrenes. Reaction of
phenylacetylene produced 3-phenylpropenethioate with E-
selectivity (60), while a mixture of Z/E isomers were obtained
a
Reaction conditions: aryl bromide (0.5 mmol), OAM (0.75 mmol),
Pd(PPh3)4 (5 mol %), Xantphos (6 mol %), DMA (5 mL), reaction
performed at 100 °C for 8 h under argon atmosphere. Reaction
conditions: aryl iodide (0.5 mmol), OAM (0.75 mmol), Pd(PPh3)4 (5
mol %), Xantphos (6 mol %), DMA (5 mL), reaction performed at 80
°C for 8 h under argon atmosphere. Aryl iodide (0.75 mmol), OAM
(0.5 mmol).
b
c
C
DOI: 10.1021/acs.orglett.9b03701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
monothioester as synthetic equivalent for thioester will find
further application in other transition-metal-catalyzed thio-
carbonylation and hydrothiocarbonylation reactions as well as
enantioselective thiocarbonylation17 processes of branched
selectivity.
Scheme 5. Decarboxylative Thiocarbonylation of Tertiary
Alkyl Halides
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03701.
a
Reaction conditions: 1 (0.75 mmol), alkyl halide (0.5 mmol),
Experimental details and characterization data for all
products (PDF)
Pd(PPh3)4 (5 mol %), Xantphos (6 mol %), DMA (5 mL), reaction
performed at 80 °C for 8 h under argon atmosphere. 2-Iodo-2-
methylpropane instead of 2-bromo-2-methylpropane, reaction per-
formed at room temperature (25
atmosphere.
b
Accession Codes
3 °C) for 8 h under argon
CCDC 1958954 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Decarboxylative Hydrothiocarbonylation of
Alkene and Alkyne
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rui@chem.s.u-tokyo.ac.jp.
ORCID
Yao Fu: 0000-0003-2282-4839
Rui Shang: 0000-0002-2513-2064
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by KY(2060000119), National Key
R & D P r o g r a m o f C h in a ( 20 18 Y F B1 5 01 60 0 ,
2017YFA0303502), and Strategic Priority Research Program
o f C A S ( X D B 2 0 0 0 0 0 0 0 , X D A 2 1 0 6 0 1 0 1 ) ,
HCPST(2017FXZY001).
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