Palladium-Catalyzed Desulfurative Amide Formation from Thioureas and Arylboronic Acids

Article abstract of DOI:10.1002/cctc.202001099

The development of the reactivity on carbene complexes would lead to the creation of novel synthetic strategies. We discovered herein the Pd-catalyzed desulfurative amide formation involved Suzuki-Miyaura coupling reaction, notably the Pd complex was generated in situ from thioureas, Ag salt and Pd catalyst. Silver salt was essential for the construction of this type of carbenes from available and stable thioureas and well participated in the catalytic cycle. We report a method for the synthesis of arylamides from arylboronic acids, which greatly enriched the application of thiourea chemistry and expanded the application of the Suzuki-Miyaura coupling.

Full text of DOI:10.1002/cctc.202001099

The European Society Journal for Catalysis
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Accepted Article
Title: Palladium-Catalyzed Desulfurative Amide Formation from
Thioureas and Arylboronic Acids
Authors: Jianke Su, Wendong Li, Xin Li, Jian Xu, and Qiuling Song
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01/2020

10.1002/cctc.202001099
ChemCatChem
COMMUNICATION
Palladium-Catalyzed Desulfurative Amide Formation from
Thioureas and Arylboronic Acids
Jianke Su,[a] Wendong Li,[a] Xin Li,[a] Jian Xu [a] and Qiuling Song*[a]
ABSTRACT: The development of the reactivity on carbene
complexes would lead to the creation of novel synthetic strategies.
We discovered herein the Pd-catalyzed desulfurative amide
formation involved Suzuki−Miyaura coupling reaction, notably the Pd
complex was generated in situ from thioureas, Ag salt and Pd
catalyst. Silver salt was essential for the construction of this type of
carbenes from available and stable thioureas and well participated in
the catalytic cycle. We report a method for the synthesis of
arylamides from arylboronic acids, which greatly enriched the
application of thiourea chemistry and expanded the application of the
Suzuki−Miyaura coupling.
Introduction
Amide bonds are one of the most important functional motifs in
chemistry and biology, they are not only the key chemical
connections of proteins but also the basis for some of the most
versatile and widely used synthetic polymers.1 Because of their
Scheme 1. Different approaches for the synthesis of amides from
organoboronic acids
prevalence and stability, amides are attractive reagents for chemical
transformations and can be converted into versatile valuable
products.2 Therefore, the development of the efficient synthesis of
Along with our continuous interest on thiocarbonyl chemistry,12
amides is an ongoing research hotspot in chemistry and biology.3
we found that stable and easily-obtained thioureas could be used as
Traditionally, amides are synthesized via the condensation between
the ADC (acyclic diaminocarbene) precursors and ADC-metal
amines and carboxylic acids or amine acylation with acid derivatives,
complexes could be formed in situ in the presence of silver salts.
such as acyl chlorides, anhydrides, or active esters, using various
Moreover, it could perfectly immerse to the catalytic system in
coupling reagents.3,4 However, the production of large quantities of
coupling with aryl boronic acids (Scheme 1c). There are several
waste is the major concern using stoichiometric activating agents5.
unprecedented merits in this transformation: 1) no need to use the
Therefore, the development of green and novel catalytic methods for
activator commonly used in the past,13 such as EDC (1-ethyl-3-(3-
amide synthesis is in great demand.
dimethylaminopropyl)carbodiimide), and T3P (n-propylphosphonic
Organoboronic acids are widely used in various coupling reactions
acid anhydride), etc; 2) the complexes were compatible with both
under the catalysis of palladium.6 However, the use of arylboronic
substrate (boronic acids) and oxidant (Ag salt) although carbenes
acids in the synthesis of arylamides has been rarely reported. In the
are active species which are reported to be intolerable to either NuH
past few decades, Buchwald,7 Jiao,8 and others9 have made great
or oxidant; 3) form ADC-meta complexes in situ, the ADC-metal
achievements on transition-metal-catalyzed carbonylation of aryl
complexes were the real catalyst species in the tranformations.
halides and related compounds with carbon monoxide (CO) and
Herein, we disclose a Suzuki−Miyaura coupling of thioureas via a
amines (Scheme 1a). More recently, palladium/copper-catalyzed
palladium diaminocarbene intermediate, affording various aryl
oxidative coupling of arylboronic acids with isocyanides to amides
amides upon further hydrolysis (Scheme 1C). Compared with the
was achieved by Lei’s group10 (Scheme 1b), but the current methods
previous research on thiourea, the application of thiourea in
synthesis was further expanded.14 This reaction provides the rare
reached their inherent limits,11 such as the production of large
quantities of waste is the major concern using stoichiometric
case of thiourea arylation via formal C-N bond cleavage reaction15.
activating agents, unfriendly CO or isonitrile need to be used.
Therefore, it is necessary to develop new efficient and general
Results and Discussion
methods for amide synthesis.
By using di(piperidin-1-yl)methanethione (1a) and phenyl boronic
acid (2a) as the model substrates, we first investigated the effect of
key parameters (Pd catalysts, entries 1-5; temperature, entries 6-8).
[a]
J. Su, W. Li, X. Li, J. Xu, Prof. Q. Song
Institute of Next Generation Matter Transformation, College of
Material Sciences Engineering, Huaqiao University, Xiamen, Fujian,
361021, China
Silver salt was essential for the success of this reaction. As our
description above, it could play the role of achieving ADC via
desulfurization16 which was only accomplished by metal K17 or
oxalyl chloride,18 by the formation of Ag2S. Additionally, Ag salt is
the typical oxidants for regeneration of PdII from Pd0 to furnish the
E-mail: qsong@hqu.edu.cn
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10.1002/cctc.202001099
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COMMUNICATION
Scheme 2. Substrate scope of boronic acidesa
whole catalytic cycle. Such dual identities make it indispensable in
this reaction (entry 20). No reaction occurred if other common
oxidants were used such as BQ and copper salts (entries 9-11).
Further screening of common silver salts showed that Ag2CO3
exhibited best activity. To facilitate transmetallation of phenyl boronic
acid, a series of additional bases were also studied and Na2CO3 was
the optimal one (entries 13-17). Amount of Pd catalyst as well as the
silver salt loading and base usage highly affected the efficiency of
this transformation. When submitting them along with 10 mol% of
Pd(PPh3)2Cl2 in trifluoroethanol (TFE, without dehydration) under air
atmosphere with 1.5 equiv of Ag2CO3, a 93% yield of the amide
phenyl(piperidin-1-yl)methanone (3a) could be obtained (entry 19).
Table 1: Optimization of the reaction conditionsa
oxidant
solvent
base
yield
(%)b
entry
catalyst
t (oC)
(x equiv)
(1.5 mL)
(y equiv)
1
2
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(TFA)2
90
90
90
90
90
70
80
100
90
90
90
90
90
90
90
90
90
90
90
90
90
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
AgOAc (3)
BQ (3)
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-BuOH
TFE
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
K2CO3 (2)
15
23
39
36
60
16
21
42
18
0
3
4
PdCl2(dppf)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (2)
Ag2CO3 (1.5)
Ag2CO3 (0)
Ag2CO3 (1.5)
0
36
53
23
68
79
80
83
93
0
TFE
The nucleophiles in this Suzuki−Miyaura-type reaction could
also be extended to aryl boronate esters (Scheme 3). When
propane-1,3- diol arylboronates 4a, 4b and 4c were subjected to the
reaction with thiourea 1a, good yields of corresponding benzamides
were obtained except that acetyl on the para position. Pinacol
phenylboronate 4d could also smoothly lead to the formation of
amide 3a in 83% yield.
TFE
Na2CO3 (2)
Na2CO3 (1)
Na2CO3 (0.5)
Na2CO3 (0.5)
Na2CO3 (0.5)
Na2CO3 (0.5)
Na2CO3 (0.5)
TFE
TFE
TFE
TFE
TFE
TFE
71
a Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of 2a, 0.02 mol of Pd catalyst,
x equiv of oxidant, y equiv of base and 1.5 mL of solvent , the reaction is
carried out under air atmosphere; b Isolated yield; c 0.01 mmol PdCl2(PPh3)2.
Scheme 3. Substrate scope of boronic esters
The optimal parameters obtained were applied toward the
reaction of the thiourea 1a with a number of boronic acids (Scheme
2), giving product 3a in 93% yield. When alkyl substituents were on
the phenyl ring, desired amide products were obtained in high yields
(3b-3c). And 4-Ph substituent also can give the product 3d in 67%
yield. Electron-donating substituents led to a relatively negative
effect for this reaction (3g-3h), while halogen and other strong
electron-deficient group substituted phenyl boronic acids generally
demonstrated high activities (3f, 3i-3u). It is noteworthy, yet very
unusual in palladium chemistry, that bromo-substituted boronic acids
were tolerated well under our conditions (3j), and this provides an
extremely important choice for cross-coupling reactions and makes
the further structural elaboration feasible. To our delight, substrates
with functional groups such as the aldehyde group was intact in such
oxidative conditions (3q and 3r). Polyphenyl and vinyl boronic acids
were also compatible in this transformation (3e and 3v). However,
alkyl boronic acids failed to achieve desired products in this coupling
reaction, probably because of the low rates for reductive elimination
of groups bound to metal by sp3-hybridized carbons.
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Next, we examined the manifestation of various structures of
thioureas in this reaction (Scheme 4). When a symmetric thiourea
(1b-1f) was used, sole product was obtained. High yields of
benzamides were achieved whatever the thiourea substrate was
derived from a tertiary aliphatic amine or an aromatic one (3w-3aa).
Release of an amine from thiourea that owns high boiling point could
be detected by GC-MS (See SI). Thiocarbonyldiimidazole (1g),
which possesses the fine leaving group, was unreactive under the
standard conditions (3bb), indicating this reaction unlikely proceeds
through the typical nucleophilic addition-elimination mechanism.
Asymmetric thiourea would lead to a couple of possible products.
According to the discrimination in iminium salt formation step, a
regioselectivity can be observed (1h-1j). The results obtained
showed that the thioureas bearing more electron-rich amine-moiety
tend to donate its electron pair to form iminium salt, further
hydrolysis of which transferred to an amine, thus driving the
reductive elimination of ADC complex. The electron-deficient part
was apt to reserve in the amide product with the selectivity between
2:1 and 4:1, approximately (3cc-3ff). Thioureas bearing primary or
secondary amino moiety lead to unknown mixtures, according to the
detection by GC-MS.
dual roles in this transformation: it acts as a reagent for desulfuration
to form ADC-metal complexes, at the same time, it also serves as an
oxidant to oxidize Pd(0) to Pd(II) to furnish the catalytic cycle. When
urea 1a’ was exposed to the standard conditions, there was no
reaction occurred, suggesting the unique structure of thioureas for
the success of the transformation (eq. 1). In order to understand the
origins of oxygen in the product, 18O labeling experiment were
performed with H218O under standard conditions, the 18O-labeled
product 3a-18O was obtained (eq. 2), which demonstrated that
oxygen atom in carbonyl group of the final product was from water.
The low 18O incorporation might stem from the residual water which
was contained in reagents, catalysts or glassware. Direct reaction of
thiourea 1a with equivalent amount of PdCl2(PPh3)2 was
subsequently conducted. After filtration of inorganic solids and
addition of ether solvent, yellow crystal 5 was precipitated and
separated (eq. 3). All these operations were conducted under air
atmosphere. Complex 5 catalyzed the Suzuki−Miyaura reaction
under standard condition in the presence of Ag2CO3 delivering 3a in
high yield, suggesting the plausible intermediacy of it in the catalytic
cycle (eq. 4). Not surpringly, in the absence of Ag2CO3, there was no
product 3a detected. These results further demonstrated the key role
of Ag salt in the transformation. The reaction between stoichiometric
amount of complex 5 and arylboronic acid 2a were performed
subsequently under standard conditions, rendering 3a in 81% yield
(eq. 5), which further confirmed that complex 5 might be the key
intermediate in our transformation.
Scheme 4. Substrate scope of thioureasa
Scheme 5. Control experiments
Conclusions
In summary,
we have
developed the Pd-catalyzed
Suzuki−Miyaura coupling of thioureas with the formal C-N bond
activation to afford aryl amides. Silver salts assisted the formation of
Pd-ADC complex in a facile and direct manner, which is believed to
undergo reductive elimination to result in the C-C coupling. This
reaction is mild under air atmosphere and tolerant of a variety of
functional groups with high yields, and can be expanded to thioureas
to achieve aryl amides. It proved that thioureas can be harnessed as
To demonstrate the detailed reaction process that established in
Scheme 1C, several control experiments were performed (Scheme
5). As we mentioned in condition screenings, Ag salt plays a key and
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Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
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Financial support from the National Natural Science Foundation
(21772046 and 2193103) are gratefully acknowledged. We also
thank the Instrumental Analysis Center of Huaqiao University for
analysis support. J. S. thanks the Subsidized Project for Cultivating
Postgraduates’ Innovative Ability in Scientific Research of Huaqiao
University.
Keywords: amide formation • arylboronic acids • desulfurative •
Suzuki−Miyaura coupling • thioureas
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From thiourea to amide. We
disclosed a desulfurative reaction
which provides the rare case of
thiourea arylation from arylboronic
acids via formal C-N bond
cleavage, which greatly enriched
Jianke Su, Wendong Li, Xin
Li, Jian Xu and Qiuling
Song*
Page No. – Page No.
Palladium-Catalyzed
Desulfurative Amide
Formation from Thioureas
and Arylboronic Acids
the
application
of
thiourea
chemistry and expanded the
application of the Suzuki−Miyaura
cross couplings.
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