A novel thiourea ligand applied in the Pd-catalyzed Heck, Suzuki and Suzuki carbonylative reactions

Article abstract of DOI:10.1002/adsc.200404165

A novel C₂ symmetrical and sterically bulky thiourea ligand 1 has been successfully applied to Heck, Suzuki and Suzuki-type carbonylative coupling reactions under aerobic conditions. Since the metal-sulfur bond in the thiourea complexes is stronger than the metal-phosphorus bond of typical phosphine complexes, thiourea ligands generally do not easily dissociate from the metal center under catalytic conditions, which establishes the thiourea 1-based palladium complexes as effective catalysts for the palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1002/adsc.200404165

COMMUNICATIONS
A Novel Thiourea Ligand Applied in the Pd-Catalyzed Heck,
Suzuki and Suzuki Carbonylative Reactions
a
a
a
a
a
a
Dai Mingji, Bo Liang, Cuihua Wang, Zejin You, Jing Xiang, Guangbin Dong,
a,
a, b,
Jiahua Chen, * Zhen Yang *
Key Laboratory of Bioorganic Chemistry andMolecular Engineering of Ministry of E du cation, College of Chemistry,
a
Peking University, Beijing 100871, andLaboratory of Chemical Genetics, Shenzhen Gra du ate School of Peking
University, The University Town, Shenzhen 518055, P. R. China
Fax: (þ86)-10-6275-9105, e-mail: zyang@chem.pku.edu.cn
b
VivoQuest, Inc., 711 Executive Blvd, Valley Cottage, New York 10989, USA
Fax: (þ1)-845-267-0926, e-mail: z.yang@vivoquest.com
Received: June 9, 2004; Accepted: September 3, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: A novel C symmetrical andsterically bul-
coordinate to metal centers in either the neutral state
2
[
5]
ky thiourea ligand 1 has been successfully appliedto
Heck, Suzuki andSuzuki-type carbonylative cou-
pling reactions under aerobic conditions. Since the
metal-sulfur bondin the thiourea complexes is stron-
ger than the metal-phosphorus bondof typical phos-
phine complexes, thiourea ligands generally do not
easily dissociate from the metal center under catalyt-
ic conditions, which establishes the thiourea 1-based
palladium complexes as effective catalysts for the
palladium-catalyzed cross-coupling reactions.
or as monoanion or dianion forms. Therefore, their
physical andchemical properties can be changedby
[
6]
modifying their nitrogen substituents.
We recently reportedthat our newly synthesizedthio-
urea 1(Figure 1) can be effectively utilizedin the Pd-cat-
alyzedbismethoxycarbonylation of styrene andthe
cross-coupling reaction of diazonium salts and boronic
[
7a]
[7b]
acids under oxygen and aerobic conditions. Addi-
tional work to define the scope and limitations of thiour-
ea 1 in a broadspectrum of reactions is imperative. To
this end, three types of coupling reactions have now
been profiled, and the details are described herein.
Keywords: cross-coupling; Heck reaction; palladium;
Suzuki reaction; thiourea
The Pd-catalyzed cross-coupling reaction is a well-
known methodfor CꢀC bondformation. In this context,
the design of novel ligands and transition metal catalysts Figure 1. The structure of thiourea 1.
that can affect desired transformations with both high
efficiency andhigh selectivity has been a fertile area of
[
1]
research. Phosphine-basedligan ds have playedvery
The first reaction investigatedwas the Suzuki cou-
important roles in the Pd-catalyzed cross-coupling reac- pling because of its usefulness for CꢀC bondforma-
[
8]
tions. However these ligands usually need to be handled tion. Considerable effort has been made to develop
in an inert atmosphere or in dry conditions, and some- catalyst systems that facilitate the cross-coupling andex-
[
9]
times suffer from significant PꢀC bond degradation at pandits scope. However, most Suzuki couplings need
elevated temperatures, which leads to palladium aggre- degassed solvents, and the reactions have to be carried
[
10]
gation andaffects the catalytic activity.
out under in an inert atmosphere. For this particular
Recently, phosphine-free ligands, such as N-heterocy- reason, we testedthe Suzuki coupling un de r aerobic
[2]
[3]
clic carbenes, andsulfur-containing ligansd
been appliedin some metal-catalyzedsynthetic trans-
formations, which open up new opportunities in cataly- bility.
sis. To this end, seven aryl iodides together with six arylbor-
Thioureas are compounds that are stable in air and onic acids were selected for the coupling reactions with
have conditions with a thiourea 1-ligatedpalla di um catalyst
in consideration of its beneficial air- and moisture-sta-
moisture, andare renownedfor their great tunability
by varying substituents on the nitrogen, andthey can
PdI /thiourea 1 as catalyst. As expected, good to excellent
yields of coupling products were obtained under aerobic
2
[
4]
Adv. Synth. Catal. 2004, 346, 1669–1673
DOI:10.1002/adsc.200404165
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1669

COMMUNICATIONS
Dai Mingji et al.
[a]
Table 1. Suzuki reaction of iodides with boronic acids.
Table 2. Suzuki reaction of bromides with boronic acids.
[
[
a]
b]
Reactions between arylboronic acid(1.0 mmol), aryl io-
dide (1.0 mmol) and base K CO (3.0 mmol) carriedout
2
3
at 808C for 5 hours in the presence of PdI (1 mol %), li-
2
gand 1 (2 mol %) andsolvent (10 mL).
Isolatedyieldafter silica gel chromatography.
[a]
Isolatedyieldafter silica gel chromatography.
[
11s]
conditions, and the results are shown in Table 1. Interest- at 1 atm CO. The beneficial effect of thiourea 1 to in-
ingly, in these coupling reactions, the ratio of PdI to thio- corporate CO into the palladium complex in our previ-
2
urea 1 (1:2) is an important parameter to achieve goodre-
sults, changing the ratio ledto decreasedyields.
ous study of the bismethoxycarbonylation of sty-
rene promptedus to apply thiourea 1 to this unsym-
[7b]
We then ran similar reactions with the less reactive metrical ketone synthesis.
aryl bromides with boronic acids. To our delight, all re-
actions workedwell un de r the con di tions listedin Ta-
ble 2, both electron-poor andelectron-rich aryl bro-
mides gave similar results under aerobic conditions.
The metal-catalyzedthree-component reaction with
Thus, eight diazonium salts were reacted with several
arylboronic acids under the conditions listed in Table 3.
Fortunately, all substrates gave the desired products.
However, the nitro-basedsalts (see entries 17–23)
[
11s]
gave lower yields than Andrusꢁ method.
It should
[
11]
arylmetal (B, Zn, Cu, Al, Si, In), carbon monoxide be notedthat only trace amounts of biaryl coupling
(
CO), andaryl electrophile is a valuable methodfor
products were obtained in most of our coupling reac-
tions, which indicated the favorable effect of thiourea
the synthesis of unsymmetrical ketones as opposedto
the Lewis acid-catalyzed FriedelꢀCrafts acylation. 1 in the Pd-catalyzed carbonylative reaction.
However, one problem associatedwith this reaction is To further extendthe scope of these carbonylative re-
the formation of a significant amount of biaryl products actions, aryl iodides were reacted with boronic acids in
[
12a]
when electron-deficient aryl halides were used, presum- anisole
ably because the halides react too quickly with arylme- better results were obtained(see Table 4).
tals without insertion of CO.
Miyaura andco-workers have resolvedthis issue by
at 808C under balloon pressure of CO, and
[
11m]
Our final investigation was the Heck coupling. When
the active aryl iodides were reacted with methyl acryl-
applying CO at higher pressures to get the high yields ate, goodto excellent yiel ds of coupling pro du cts were
[
11m]
of coupling products.
Andrus and co-workers recent- obtained (see Table 5). But no desired products were
ly achieved good yields by the imidazolium-based Pd- generatedwhen the less active aryl bromi de s were ap-
catalyzed coupling of diazonium salts and boronic acids pliedin this reaction.
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Thiourea Ligandin P d- CatalyzedHeck, Suzuki andSuzuki Reactions
COMMUNICATIONS
Table 3. Suzuki-carbonylative reaction of diazonium salts
Table 4. Suzuki carbonylative reaction of aryl iodides with
with arylboronic acids.
arylboronic acids.
[a]
Isolatedyieldafter silica gel chromatography.
In summary, we have illustratedthe utilization of our
newly synthesizedthiourea 1 in a variety of Pd-catalyzed
cross-coupling reactions, andsatisfactory results were
obtained. In consideration of its thermal stability, insen-
sitivity to air andmoisture, andtunability by modifying
its nitrogen substituents, thiourea 1 is worthy of further
investigation.
Experimental Section
[
[
[
a]
b]
c]
Reactions between arylboronic acid(1.0 mmol), CO (bal-
loon pressure), and di azonium salt (1.0 mmol) were car-
riedout at 50 8C for 10 hours in the presence of Pd(OAc)2
General Information
All reagents were purchasedfrom Al dr ich andusedwithout
further purification. All solvents were distilled prior to use.
The boiling point of petroleum ether is between 60–90 C. Sili-
(
2 mol %), ligand 1 (2 mol %) andsolvent (10 mL).
Reactions between arylboronic acid(1.0 mmol), CO (bal-
loon pressure), and di azonium salt (1.0 mmol) were car-
riedout at 20 8C for 10 hours in the presence of Pd(OAc)2
0
ca gel (200–300 mesh) for purification was purchasedfrom
Qing Dao Hai Yang Chemical Industry Co. of China.
(
5 mol %), ligand 1 (2 mol %) andsolvent (10 mL).
1
13
H NMR and C NMR were recorded at 300 MHz and
Isolatedyieldafter silica gel chromatography.
7
4
5 MHz with a Varian Mercury 300 spectrometer or at
00 MHz and100.6 MHz with a Bruker ARX400 spectrome-
ter. Mass spectrometric data were obtained using a ZAB-HS
mass spectrometer. The purity of the synthesizedcompounds
1
13
was checkedby H and C NMR spectroscopy.
Adv. Synth. Catal. 2004, 346, 1669–1673
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COMMUNICATIONS
Dai Mingji et al.
Table 5. Heck cross-coupling reaction of aryl iodides with
methyl acrylate.
bottom flask. Anhydrous THF (10 mL) was added and the
flask was chargedwith CO (balloon), andthe reaction mixture
was stirredat 50 8C for 10 hours. The reaction mixture was
workedup by removing the solvent under vacuum andthe res-
idue was purified by a flash chromatography on silica gel.
[a]
General Procedure for the Syntheses of
Unsymmetrical Ketones by the Carbonylative
Coupling of Aryl Iodide with Arylboronic Acid
(
1d–4d)
Aryl iodide (1.0 mmol), arylboronic acid (1.0 mmol), K CO3
2
(
(
(
3.0 mmol), PdI2 (0.01 mmol, 1 mol %) andthiourea
0.02 mmol, 2 mol %) were mixedin anhy rdo us anisole
10 mL) under balloon pressure of CO, and the reaction mix-
1
ture was stirredat 80 8C for 10 hours. The reaction mixture
was workedup by removing the solvent un de r vacuum and
the residue was purified by flash chromatography on silica gel.
General Procedure for the Synthesis of Compounds
1e–9e by Coupling of Aryl Halides and Methyl
Acrylate
Aryl iodides (1.0 mmol), methyl acrylate (1.2 mmol), Et N
3
(
(
3.0 mmol), PdI2 (0.01 mmol, 1.0 mol %) andthiourea
0.02 mmol, 2.0 mol %) were mixedin DMF (10 mL), andthe
1
reaction mixture was stirredat 80 8C for 5 hours under aerobic
conditions. The reaction was worked up by extraction of the re-
action mixture with ethyl acetate, washedwith saturatedNaCl
solution, and dr iedover Na SO . After removing the solvent
under vacuum, the residue was purified by flash chromatogra-
phy on silica gel.
2
4
[
[
a]
b]
Reactions between methyl acrylate (1.2 mmol), aryl iodide
1.0 mmol) andEt N (3.0 mmol) carriedout at 80 8C for 5
(
3
hours in the presence of PdI2 (1 mol %), ligand 1
2 mol %) andDMF (10 mL).
Isolatedyieldafter silica gel chromatography.
(
Acknowledgements
General Procedure for the Synthesis of Biaryl
We gratefully acknowledge financial support of this work by the
Compounds by Coupling of Aryl Iodides or Bromides National Science Foundation of China (grants 20272003 and
and Arylboronic Acid (1a–8a, and 1b–10b)
20325208), and VivoQuest Inc. through the sponsored research
program.
Aryl iodides or bromides (1.0 mmol), arylboronic acid
(
1.0 mmol), K CO (3.0 mol), PdI (0.015 mmol, 1.5 mol %)
2 3 2
andthiourea 1 (0.03 mmol, 3 mol %) were mixedin isopropyl
alcohol/H O (10 mL/1.5 mL) under aerobic conditions, and
2
References and Notes
the reaction mixture was stirredat 80 8C for 5 hours. The reac-
tion mixture was first passedthrough a silica gel plug, andthen
washedwith ethyl acetate. The filtrate was concentratedunder
vacuum andthe residue was purifiedby flash chromatography
on silica gel.
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