Synthesis of a Novel C2-Symmetric Thiourea and Its Application in the Pd-Catalyzed Cross-Coupling Reactions with Arenediazonium Salts under Aerobic Conditions

Article abstract of DOI:10.1021/ol036182u

(Matrix presented) A novel thiourea-based C₂-symmetric ligand was synthesized, and its application in the palladium-catalyzed Heck and Suzuki coupling reactions of arenediazonium salts was evaluated. The reactions, which were performed at room temperature, without added base, and under aerobic conditions, produced product in 4 h with good yield. The corresponding arenediazonium salts were easily generated in one step from anilines.

Full text of DOI:10.1021/ol036182u

ORGANIC
LETTERS
2004
Vol. 6, No. 2
221-224
Synthesis of a Novel C -Symmetric
2
Thiourea and Its Application in the
Pd-Catalyzed Cross-Coupling Reactions
with Arenediazonium Salts under
Aerobic Conditions
,†
,†,‡
Mingji Dai,† Bo Liang,† Cuihua Wang,† Jiahua Chen,* and Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Peking UniVersity, Beijing, 100871 China, and
ViVoQuest, Inc., 711 ExecutiVe BlVd., Valley Cottage, New York 10989
zyang@chem.pku.edu.cn.
Received November 6, 2003
ABSTRACT
A novel thiourea-based C -symmetric ligand was synthesized, and its application in the palladium-catalyzed Heck and Suzuki coupling reactions
2
of arenediazonium salts was evaluated. The reactions, which were performed at room temperature, without added base, and under aerobic
conditions, produced product in 4 h with good yield. The corresponding arenediazonium salts were easily generated in one step from anilines.
The palladium-catalyzed cross-coupling reaction is a reliable
method for C-C bond formation.1 In this context, aryl or
vinyl halides or triflates have found broad utility as electro-
philic coupling partners.2
Recently, considerable attention has been focused on the
metal-catalyzed coupling reactions that incorporate arene-
diazonium tetrafluoroborate salts as aryl electrophilic com-
ponents in order to take advantage of several of their
important features.3 First, arenediazonium salts can be easily
synthesized from the corresponding aniline with high
yield.3m,q,u,w,4 Second, the arenediazonium salts are more
reactive than the corresponding aryl halides in the palladium-
catalyzed Heck and Suzuki reactions.3q,3w Third, palladium-
catalyzed reactions can usually be carried out at lower
temperature (between 20 and 50 °C)3n-w than the typical
Heck and Suzuki reactions (over 100 °C), and they can also
be carried out without added extra base or salt (such as silver
chloride or thallium ethoxide),5 which extend the reaction
scope to substrates with sensitive functional groups. Fourth,
although certain aryl halides and triflates are difficult to
synthesize, the corresponding arenediazonium salts can be
generated easily from the corresponding arylamines, and this
is a significant consideration for combinatorial synthesis.
Thus, development of an arenediazonium salt that can be
used in the metal-catalyzed coupling reaction could poten-
† Peking University.
‡ VivoQuest, Inc.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Palladium Reagents
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Chichester, 1995; p 19. (c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.
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10.1021/ol036182u CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

tially both simplify the synthesis of certain types of advanced
intermediates and reduce the steps involved in the synthesis
of pharmaceuticals and agrochemicals.6
Scheme 1. Synthesis of C2-Symmetric Thiourea 3
Previously described transition-metal-catalyzed reactions
of diazonium salts with high affinity ligands (such as
phosphines) are deficient because of their low catalytic
activity, modest yields, and loss of diazonium salts as a result
of decomposition.3n,p,s To avoid this problem, a ligand-free
catalytic process has frequently been used.3j,n,o,r-v In 1997,
the Sengupta group reported that a ligand-free palladium-
catalyzed coupling reaction using diazonium salts with aryl
boronic acids produced good yields when 10 mol % of Pd-
(OAc)2 was included in the reaction.3t Later Andrus’ group
reported a similar coupling with 2 mol % of Pd(OAc)2;
however, the yield dropped to 21%.3p
To improve this reaction, new ligand-based metal-
catalyzed reactions needed to be developed. Very recently,
two groups reported that the imidazolium carbene based
palladium complex3q,w effectively catalyzed the Heck and
Suzuki reactions with arenediazonium tetrafluoroborate. In
this report, we describe our successful efforts to synthesize
a novel type of C2-symmetric thiourea that is air-, moisture-,
and heat-stable and can be successfully used in the Suzuki
and Heck reactions at room temperature with Pd(OAc)2 (1
mol %) under aerobic conditions and without added base.
Historically, the strong coordinative and adsorptive prop-
erties of sulfur-containing compounds have rendered them
totally ineffective as catalysts, causing them to be categorized
as catalyst poisons.7 Recently, efforts have been made to
synthesize sulfur-containing ligands, and several notable
successes have been reported.8 Complexes of thiourea with
transition metals were first reported in 1894,9 followed by
their crystal study.10
synthesis, but most often their use has been restricted to the
polymer-supported palladium or rhodium catalysts.11
The pioneering work of Chiusoli demonstrated that
thiourea was a useful ligand in Pd-catalyzed carbonylations.12
On the basis of these results, we began to study the function
of thiourea in the Pd-catalyzed carbonylation.13 Encouraged
by our initial studies, we decided to attempt to synthesize a
palladium complex based on a C2-symmetric thiourea ligand,
which would be able to catalyze the arenediazonium-based
cross-coupling reaction. If these studies were successful, we
reasoned that we might have a ligand that could be used for
asymmetric synthesis of biaryl compounds.14
To this end, ligand 3 (see Scheme 1) was designed, and
synthesized from the diamine 1. Synthetically, commercially
available (1R,2R)-(-)-1,2-diaminocyclohexane 1 (Aldrich)
was coupled with o-methyl bromobenzene to give 2,15 which
was then condensed with thiophosgene to generate 3.16 Its
structure was confirmed by the X-ray analysis.
In early attempts to test the effect of ligand 3 in the Pd-
catalyzed coupling reaction of the diazonium salt 417a (Table
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Org. Lett., Vol. 6, No. 2, 2004

Table 1. Pd-Catalyzed Coupling of Arenediazonium Salts with
Table 2. Pd-Catalyzed Coupling of Arenediazonium Salts with
Styrene under Aerobic Conditions
Methyl Acrylate under Aerobic Conditions
1) with styrene, six solvents (MeOH, 1,4-dioxane, THF, CH2-
Cl2, CH3CN, toluene) were screened, and methanol turned
out to be the best solvent, producing 69% yield of coupling
product 4a (see Table 1, entry 1).17b
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in Table 1) were tested. Interestingly, the diazonium salts
9-11 with NO2 groups gave better results than the diazonium
salts 4-6. This observation was significant since low yields
of coupling products were obtained by both Kikukawa3c and
(15) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225.
(16) Lo´pez, OÅ .; Maya, I.; Ulgar, V.; Robina, I.; Fuentes, J.; Ferna´ndez-
Bolan˜os, J. G. Tetrahedron Lett. 2002, 43, 4313.
(17) (a) General procedure for the synthesis of the arenediazonium
tetrafluoroborate salts employed Doyle’s method;4 see Supporting Informa-
tion for detail. (b) General procedure for the Pd-catalyzed coupling
reactions: Pd(OAc)2 (0.005 mmol), ligand 3 (0.005 mmol), olefin or
arylboronic acid (0.6 mmol), and arenediazonium tetrafluoroborate salt (0.5
mmol) were mixed in methanol (5.0 mL), and the reaction mixture was
stirred at room temperature for 4 h under aerobic conditions. The reaction
was worked up by removing the solvent under vacuum, and the residue
was purified by chromatography on silica gel.
Org. Lett., Vol. 6, No. 2, 2004
223

Encouraged by these results, we began to evaluate the
coupling reaction of arenediazonium salts with methyl
acrylate,3p and the results are shown in Table 2. Notably,
most of the reactions gave good results, and the halogen-
based salts 7 and 8 and 12-14 underwent chemoselective
couplings to generate the organohalides 7b and 8b and 12b-
14b. The remaining halides can undergo further chemical
modification to generate structurally more complex mol-
ecules. Once again, the nitro-based diazonium salts 9-11
(see Table 2) produced good to excellent yields of coupling
products 9b-11b.
Table 3. Pd-Catalyzed Coupling of Aryldiazonium Salts with
Aryl Boronic Acids under Aerobic Conditions
To extend the applicability of ligand 3 for use in the
coupling reaction, additional studies in the Suzuki-type
coupling was conducted. Nine arenediazonium salts were
reacted with five arylboronic acids under the identical
conditions listed in Table 1. The results, listed in Table 3,
indicate that moderate to good yields of coupling products
were obtained. It is also important to point out that good
chemoselectivity was achieved in these coupling reactions
using halogen-based diazonium salts, which suggests their
potential utility in additional synthetic chemistry applications.
In summary, these results represent the first report of the
synthesis of a novel C2-symmetric thiourea 3 and its
application in the palladium-catalyzed Heck and Suzuki
coupling reactions with arenediazonium salts under aerobic
conditions without added base. The results demonstrate the
utility of ligand 3 in the palladium-catalyzed Heck and
Suzuki coupling reactions that incorporate arenediazonium
salt as an eletrophilic coupling partner. Further evaluation
of chiral ligand 3 in the palladium-catalyzed asymmetric
synthesis of biaryl molecules is currently underway.
Acknowledgment. We thank Dr. Maryann Donovan for
her assistance in editing this manuscript and Mr. Guangbin
Dong and Mr. Liang Zhao for their efforts in obtaining the
X-ray structure of ligand 3. Financial support from the NSFC
(grants 20142004 and 20242002), and the sponsored research
program of VivoQuest, Inc. is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedure and H NMR and 13C NMR spectra for the known
product compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Sengupta3h and colleagues when they utilized the nitro-based
diazonium salts in their ligand-free palladium-catalyzed
coupling reactions.
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