C - S coupling using a mixed-ligand Pd catalyst: A highly effective strategy for synthesizing arylthio-substituted heterocycles

Article abstract of DOI:10.1002/chem.201302174

C - S coupling: A variety of arylthio-substituted heterocycles can be prepared through C - S coupling of the corresponding halide-substituted heterocycles by using a mixed-ligand palladium catalyst, [Pd₂(dba) ₃]/ Xantphos/CyPF-tBu (see scheme; dba=dibenzylideneacetone). This catalytic system is extremely powerful and efficient, allowing even C - Cl bond activation.

Full text of DOI:10.1002/chem.201302174

COMMUNICATION
DOI: 10.1002/chem.201302174
À
C S Coupling Using a Mixed-Ligand Pd Catalyst: A Highly Effective
Strategy for Synthesizing Arylthio-Substituted Heterocycles
Mei Cong,[a, b] Yuting Fan,[b] Jean-Manuel Raimundo,[a] Yi Xia,[a] Yang Liu,[b]
Gilles Quꢀlꢀver,[a] Fanqi Qu,[b] and Ling Peng*[a]
À
Pd-catalyzed cross-coupling reactions that form C S
bonds have recently emerged as a powerful synthetic ap-
proach for synthesizing various sulfur-containing compounds
or structural motifs in both medicinal chemistry and materi-
al sciences.[1] Pd-catalyzed C S coupling reactions remain
À
relatively underdeveloped compared to other carbon–
heteroACHTUNGTRENNUNGatom bond-forming reactions. Indeed, many Pd cata-
lysts are highly sensitive to substrates containing the reac-
tive sulfur moieties and some sulfur-containing compounds
may function as ligands, thus forming complexes that impair
the catalytic reaction.[2] In addition, the yields of products of
such reactions are highly dependent on the electronic fea-
tures and steric environments of the thiol substrates. To
overcome these issues, judicious choice of the ligands for
the Pd catalysts is crucial.[2] However, the screening of li-
gands often requires trial and error, making it a time-con-
suming process. One rewarding way to circumvent this prob-
lem is the inventive combination of ligands with comple-
mentary features for transition-metal catalysis.[3] For in-
stance, the mixed-ligand catalyst recently developed by
Buchwald and co-workers has been successfully implement-
Scheme 1. Mixed-ligand Pd catalysts to promote cross-coupling reactions
for synthesizing triazole nucleoside analogues and heterocycles.
cross-coupling reactions and in particular those involving
À
the formation of C S bonds. Indeed, to the best of our
À
ed in C N coupling of both primary and secondary amine
knowledge, there is no report in the literature referring to
substrates.[4] The reported results clearly demonstrate the
compelling advantages of combining and harnessing the
properties of each individual ligand, thus promoting catalyt-
ic activity and dramatically broadening the substrate scope.
Taking into account these aspects, our research group has
extended this concept of mixed-ligand catalysis towards the
synthesis of various arylamine-substituted triazole nucleo-
sides, which were indeed obtained in high yields
(Scheme 1A).[5] These remarkable results have encouraged
us to further expand the scope of this approach to other
the use of mixed-ligand catalysis for C S coupling. Hence,
À
we disclose herein the first mixed-ligand Pd catalyst for such
coupling reactions based on [Pd2ACHTNUGTRENUNG(dba)3]/Xantphos/CyPF-tBu
(dba=trans,trans-dibenzylideneacetone). This new mixed-
ligand catalytic system proved to be extremely effective for
the synthesis of myriad arylthio-substituted triazole nucleo-
sides (Scheme 1B). In addition, the effectiveness of this cat-
À
alytic system for the activation of C Cl bonds on heteroaryl
rings and its versatility for use in coupling reactions involv-
ing both aryl and alkyl thiols was demonstrated.
À
We were motivated to develop Pd-catalyzed C S coupling
by our discovery of the appealing biological activities of
aryl-appended triazole nucleosides and by our desire to syn-
thesize their S-arylthiotriazole nucleoside analogues, as part
of our general search for novel antiviral and anticancer drug
candidates and efforts to better understand structure–activi-
ty relationships.[6] Throughout our studies, the synthesis of
the arylthio-substituted triazole nucleosides has proven chal-
lenging. Indeed, our first attempt to achieve direct thiolation
employed the conventional nucleophilic aromatic substitu-
tion reaction (SNAr), which showed very limited nucleoside
substrate scope: only the 5-bromotriazole nucleoside 1’ was
able to afford the corresponding target (Scheme 2A),[6b] and
[a] M. Cong, Dr. J.-M. Raimundo, Dr. Y. Xia, Dr. G. Quꢀlꢀver,
Dr. L. Peng
Aix-Marseille Universitꢀ
CNRS UMR 7325
Centre Interdisciplinaire de Nanoscience de Marseille
13288 Marseille (France)
E-mail: ling.peng@univ-amu.fr
[b] M. Cong, Y. Fan, Y. Liu, Prof. F. Qu
College of Chemistry and Molecular Sciences
Wuhan University, 430072 Wuhan (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302174.
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À
one of the rare ligands that has been reported for the C S
coupling of aryl halides with electron-deficient thiols.[9]
Taking this into consideration, we tried the first attempt of
À
C S coupling with a mixed-ligand system using Xantphos
and CyPF-tBu in a 1:1 molar ratio, successfully obtaining
the product in an extremely encouraging yield of 68%
(Table 1, entry 3). This dramatically improved yield was
indeed the direct consequence of the mixed-ligand Pd cata-
lytic system because neither the single-ligand systems,
A
E
ACHTUGTNRENNGU[Pd2ACHTUNGTERN(NUGN dba)3]/Xantphos, could
afford the corresponding product with acceptable yields
(Table 1, entries 1 and 2). By systematically varying the
ligand ratio, we found that the best yield was obtained with
Xantphos and CyPF-tBu at a ratio of 3:1 (Table 1, entries 3–
7). Moreover, we further examined several bases and sol-
vents as both base and solvent often impact the course of
the reaction (see the Supporting Information, Tables S2 and
S3). The best combination turned out to be Et3N as base
and toluene as solvent for the mixed-ligand system,
Scheme 2. Nucleophilic aromatic substitution for synthesizing arylthiol-
substituted triazole nucleosides.
no product could be achieved with the isomeric substrate
1 (Scheme 2B).[7] Therefore, we turned our attention to the
A
2ACHTUNGRTEN(NUNG dba)3]/Xantphos/CyPF-tBu.
À
Pd-catalyzed C S coupling reaction. However, only a few
reaction conditions based on single-ligand Pd catalysts could
a wide range of aryl thiols (Scheme 3), leading to excellent
product yields with aryl thiols bearing both electron-defi-
cient and electron-rich substituents at various positions. Fur-
thermore, reactions with alkyl thiols led to very high yields
(Scheme 3, 2h and 2l) and even the extremely sterically hin-
dered substrate, 2-methyl-2-propanethiol, could be trans-
formed into product (Scheme 3, 2m). Therefore, the mixed-
ligand catalyst [Pd2ACHTNUTRGNE(NUG dba)3]/Xantphos/CyPF-tBu appears par-
ticularly effective with an exceptionally broad thiol substrate
scope.
À
promote the corresponding C S bond formation with low
yields (see the Supporting Information, Table S1); triazole
heterocyclic aromatic rings are notoriously uncooperative
for Pd catalysis.[6a]
To address this issue, we aimed to develop mixed-ligand
Pd catalysts (Table 1). It has been reported that the Josi-
phos-type ligand CyPF-tBu is an extremely active ligand in
Pd-catalyzed thiolation.[8] Xantphos, on the other hand, is
We further examined the substrate scope using different
triazole nucleoside analogues. Interestingly, we found that
aryl thiolation was also effective with sterically hindered 3-
À
Table 1. Evaluation of Pd/Xantphos/CyPF-tBu systems for C S coupling
by using the triazole nucleoside 1 and 4-(trifluoromethyl)thiophenol.[a]
Entry
Xantphos/CyPF-tBu[b]
Yield of 2i
Recovery of 1
[%][c]
[%][c]
1
2
3
4
5
6
7
1:0
0:1
1:1
1:2
2:1
3:1
4:1
17
5
59
0
19
16
8
68
51
71
89
53
0
27
Scheme 3. Synthesis of arylthio-substituted triazole nucleosides by using
[a] Reaction conditions:
1
(0.10 mmol), 4-(trifluoromethyl)thiophenol
[ligand]=1:1.1, K2CO3
the Pd/Xantphos/CyPF-tBu system with 1 and various thiols. Reaction
(0.12 mmol), [Pd2A(dba)3] (0.010 mmol), [Pd]/
R
E
conditions: 1 (0.10 mmol), thiol (0.12 mmol), [Pd
[Pd]/[ligand]=1:1.1, [Xantphos]/[CyPF-tBu]=3:1, Et3N (0.70 mmol), tol-
uene (2.0 mL), reflux at 1158C, 4 h.
2ACHTUNGTREN(NNUG dba)3] (0.0050 mmol),
(0.26 mmol), toluene (2.0 mL), reflux at 1158C, 3 h. [b] Molar ratio.
[c] Yield of isolated product.
A
ACHTUNGTRENNUNG
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À
C S Coupling
COMMUNICATION
those signals corresponding to
the complex [(Xant
ACHTUNGTRENNUNGphos)ACHTUNGTRENNUNGPd-
AHCTUNGERTG(NNUN dba)] were observed (Fig-
ure 1A, IV). Clearly, these re-
sults indicate that Xantphos is
a
highly efficient ligand in
forming the complex with
[Pd2A(dba)3] compared with
G
CHTUNGTRENNUNG
CyPF-tBu. Most interestingly,
free CyPF-tBu was no longer
detected in the mixed-ligand
system (Figure 1A, V), thus
suggesting that Xantphos pro-
moted the ligation of CyPF-tBu
to Pd, probably through rapid
ligand exchange.
Further 31P NMR studies
were carried out on the oxida-
tive-addition step after adding
the substrate 1 into solutions of
both the two individual single-
ligand systems and into a solu-
tion of the mixed-ligand system
(Figure 1B). In the single-
ligand system of [Pd2ACHTUNGTRENNUNG(dba)3]/
Xantphos/1 (Figure 1B, II), we
observed that the NMR signals
for the [(Xantphos)PdACHTUNGTRENNUNG(dba)]
complex disappeared, whereas
a new signal corresponding to
the oxidative complex [(Xant-
phos)Pd(1)] emerged. Notably,
the NMR signal of free Xant-
Scheme 4. Aryl thiolation of heteroaryl substrates using the Pd/Xantphos/CyPF-tBu mixed-ligand system. Re-
action conditions (exceptions, see below): aryl halide (0.10 mmol), thiol (0.12 mmol), [Pd
(0.0050 mmol), [Pd]/[ligand]=1:1.1, [Xantphos]/[CyPF-tBu]=3:1, Et3N (0.70 mmol), toluene (2.0 mL), reflux
at 1158C, 4 h. [a] Double the catalyst loading, 20 h. [b] N,N-Diethylmethylamine (1.0 mmol) instead of Et3N,
16 h. [c] Scale-up synthesis with aryl halide (0.50 mmol), thiol (0.60 mmol), [Pd2A(dba)3] (0.025 mmol), [Pd]/[li-
gand]=1:1.1, [Xantphos]/[CyPF-tBu]=3:1, Et3N (3.5 mmol), toluene (10 mL), reflux at 1158C, 24 h.
2ACHTUNGTNER(NUNG dba)3]
A
ACHTUNGTRENNUNG
C
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
bromotriazole ribonucleoside 3 (Scheme 4, 7a–c). Addition-
ally, and more importantly, the exceedingly challenging
chlorinated heteroaryl substrates 4–6 could also afford the
corresponding products in good to excellent yields
(Scheme 4, 7c, 8a–c, 9a–c).[10] Collectively, these data dem-
onstrate the extraordinary power of this mixed-ligand cata-
phos also reappeared, thus suggesting that free Xantphos
was released from Pd complexes upon the addition of 1.
This conclusion was further supported by the large amount
of free Xantphos observed in the mixed-ligand system (Fig-
ure 1B, III). On the contrary, there was no free CyPF-tBu
observed in the mixed-ligand system, thus highlighting that
1 preferentially reacts to form the oxidative-addition inter-
À
lyst for C S coupling in general.
To gain more insight into how the two ligands work in
harmony to boost the catalytic activity, we undertook
31P NMR analysis to investigate the different catalytic sys-
tems based on the knowledge that both Xantphos and
CyPF-tBu are phosphine ligands and have characteristic sig-
nals in 31P NMR spectra. We found that considerable
amounts of free CyPF-tBu remained in the single-ligand
mediate with the [(CyPF-tBu)Pd
ACHTUNGERTN(NUNG dba)] complex rather than
with the [(Xantphos)Pd(dba)] complex. This result implies
AHCTUNGTRENNUNG
that ligand exchange at the level of Pd complexes involved
in the oxidative-addition steps also favors the formation of
an adduct containing CyPF-tBu, and consequently enhances
the whole reaction. Notably, oxidative addition of a substrate
onto [(CyPF-tBu)PdACTHNUTRGNEUNG
(dba)] is usually fast.[2a] Taking all argu-
system of [Pd
G
ments together, we postulate a general mechanism for this
C-S cross coupling reaction catalyzed by the mixed-ligand
Pd catalyst where Xantphos favorably promotes the forma-
tion of the active Pd catalyst while CyPF-tBu plays a major
role in the catalytic reaction (Figure 2).
To support the above hypothesis, we performed cyclic vol-
tammetry (CV) studies on both the single-ligand and mixed-
ligand catalytic systems.[12] CV allows a more precise and de-
scriptive investigation of the mechanistic features because
unlike NMR spectroscopy, it can routinely be used to detect
NMR signals corresponding to free CyPF-tBu (Figure 1A,
III). Consequentially, only a small amount of the catalytic
complex [(CyPF-tBu)Pd
(dba)3]/CyPF-tBu system, a behavior that was revealed by
the weak NMR signals corresponding to [(CyPF-tBu)Pd-
ACHTUNGTRENNUNG
(dba)].[11] Clearly, these data reflect that the Pd complex for-
mation with CyPF-tBu alone was not efficient. Unlike
CyPF-tBu, no NMR signal for free Xantphos was observed
in the spectrum of the CATHUNGTREN[NNUG Pd2ACHTUNREGTG(NNUN dba)3]/XantACTHUNGTRENpNUGN hos system; only
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L. Peng et al.
formation of the radical cation for Xantphos together with
two irreversible waves and one reversible wave (O2, O3, and
O4) for CyPF-tBu (Figure 3A, II).[14] When CV was carried
out on the [Pd2ACTHNUTRGNEUNG(dba)3]/Xantphos system (Figure 3A, III),
a new oxidation peak, O5, at a lower potential than that of
free Xantphos (O1) was observed, corresponding to the for-
mation of the [(Xantphos)Pd
tant disappearance of the Xantphos oxidation peak (O1) im-
plies that the formation of the [(Xantphos)Pd(dba)] com-
plex is really fast and efficient. On the contrary, a different
feature was observed in the case of the [Pd2A(dba)3]/CyPF-
ACHTUNGTNER(NUNG dba)] complex. The concomi-
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
tBu system (Figure 3A, IV). The three oxidation peaks of
free CyPF-tBu (O2, O3, and O4) remained mainly unchanged
except for their decreased intensity. Nevertheless, a new
weak oxidation potential peak O6, corresponding to the
A
(dba)] complex appeared.[14] The weak cur-
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Figure 1. 31P NMR study on single-ligand and mixed-ligand systems.
A) 31P NMR spectra of the systems containing (I) free CyPF-tBu, (II)
N
CHTUNGTRENNUNG
new oxidation peak was detected (as confirmed by the de-
convoluted CV). This result implies that no new catalytic
species was formed in the mixed-ligand system. Moreover,
free Xantphos, (III) [Pd
and (V) [Pd2A
(dba)3]/CyPF-tBu/Xantphos. B) 31P NMR spectra of the sys-
tems containing (I) [Pd2A(dba)3]/CyPF-tBu/1, (II) [Pd2A(dba)3]/Xantphos/
1 and (III) [Pd2A(dba)3]/Xantphos/CyPF-tBu/1.
2CAHUTNGTREN(NUG dba)3]/CyPF-tBu, (IV) [Pd2HCATUNGTERNN(UGN dba)3]/Xantphos,
CHTUNGTRENNUNG
G
CHTUNGTRENNUNG
CHTUNGTRENNUNG
the current intensity of the oxidation peak of
tBu)Pd(dba)] was stronger in the mixed-ligand system than
in the single-ligand system, thus highlighting that the forma-
tion of the [(CyPF-tBu)Pd(dba)] complex was effectively
ACHTUNGTRENNUNG[(CyPF-
AHCTUNGTRENNUNG
reactive species with short lifetimes.[13] Cyclic voltammo-
grams of the free ligands (Figure 3A, I) revealed an irrever-
sible one-electron redox system (O1) corresponding to the
A
ACHTUNGTRENNUNG
promoted by Xantphos in the mixed-ligand system (con-
firmed by the deconvoluted
CV). Altogether, these data are
in perfect agreement with the
31P NMR results and support
our hypothesis that the pres-
ence of Xantphos favors the
formation of the [(CyPF-
tBu)PdACTHNUGRTENUNG(dba)] complex in the
mixed-ligand system. Further-
more, the corresponding cyclic-
voltammetry investigation on
the oxidative addition of the
substrate 1 to the two single-
ligand systems of
Xantphos and
CyPF-tBu and the mixed-ligand
system [Pd2A(dba)3]/Xantphos/
A
2A
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
CyPF-tBu (Figure 3B), unveiled
that all the oxidation potentials
observed in the single-ligand
systems were observed in the
mixed-ligand system. This fur-
Figure 2. Proposed mechanism used by the [Pd2ACTHNUTRGNEUNG(dba)3]/Xantphos/CyPF-tBu mixed-ligand catalytic system to
À
promote C S coupling reaction.
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À
C S Coupling
COMMUNICATION
Figure 3. A) Cyclic voltammograms of the systems containing Xantphos
(I), CyPF-tBu (II), [Pd
(IV), and [Pd2A(dba)3]/Xantphos/CyPF-tBu (V). B) Cyclic voltammograms
of the oxidation addition of the substrate 1 to the single-ligand systems,
[Pd2A(dba)3]/Xantphos/1 (I) and [Pd2A(dba)3]/CyPF-tBu/1 (II) and the
mixed-ligand system [Pd2A(dba)3]/Xantphos/CyPF-tBu/1 (III). Cyclic vol-
2CAHUTNGTREN(NUG dba)3]/Xantphos (III), [Pd2CAHTUNGTERN(NUGN dba)3]/CyPF-tBu
CTHUNGTRENNUNG
C
CHTUNGTRENNUNG
CTHUNGTRENNUNG
tammetry was performed in THF solutions using nBu4NBF4 (0.30m) as
the electrolyte at a stationary gold-disk electrode (0.50 mm diameter) at
293 K with scan rate=100 mVsÀ1
.
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L. Peng et al.
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15917.
ther endorses the proposed mechanism relying on the coex-
istence and interplay of two catalytic cycles mediated by
two individual ligands, between which Pd is shuttled to pro-
mote the catalysis (Figure 2). This mechanism matches that
[4–5]
À
proposed for C N coupling reaction,
thus suggesting that
[5] Y. Fan, Y. Xia, J. Tang, F. Ziarelli, F. Qu, P. Rocchi, J. L. Iovanna, L.
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catalytic systems, opening new opportunities and perspec-
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[6] a) Y. Xia, F. Qu, L. Peng, Mini. Rev. Med. Chem. 2010, 10, 806–821;
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[7] Under the same reaction conditions for SNAr substitution of sub-
strate 1’, isomeric 3-bromo-5-methoxycarbonyl (1) did not undergo
substitution with thiol and over 90% of the starting material 1 was
recovered even after 3 days at 808C in the presence of weak base
(K2CO3 or triethylamine) in CH3CN. We also tried numerous other
reaction conditions such as those involving stronger bases (DBU,
Cs2CO3, NaOtBu) and higher temperatures (up to 1308C) as well as
those using polar solvents such as DMF and high concentrations of
thiols; unfortunately, in all cases, the starting material 1 decomposed
after several hours and no thiolation product could be observed or
identified.
In summary, we have developed a novel and efficient
mixed-ligand catalyst [Pd2ACHTNUTRGENNUG(dba)3]/Xantphos/CyPF-tBu for
synthesizing S-arylthiotriazole nucleoside analogues with ex-
tremely high efficiency. This catalyst boasts unparalleled
broad substrate scope with high product outputs including
diverse heteroaryl systems and thiols. Moreover, the catalyt-
À
ic system can also strongly activate C Cl bonds in heteroar-
yl rings for C S bond formation. 31P NMR and cyclic-vol-
À
tammetry investigations revealed a general mechanism for
[8] a) M. A. Fernꢃndez-Rodrꢄguez, J. F. Hartwig, J. Org. Chem. 2009,
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[10] We did control experiments with substrates 1 and 3–6 under the re-
action conditions presented in the manuscript in the absence of
the thiolation as mediated by the [Pd2ACTHNUTRGNE(UNG dba)3]/Xantphos/
CyPF-tBu catalytic system in which the two mixed ligands
cooperate ingeniously and advantageously. To our knowl-
edge, this is the first example of a mixed-ligand system used
À
for a Pd-catalyzed C S coupling reaction. We now expect to
uncover a broad spectrum of applications for mixed-ligand
systems in other transition-metal-catalyzed reactions and are
working actively in this direction.
ACHUTNGERN[NUG Pd2ACHUTNGTREN(NGUN dba)3]. No thiolation product could be identified even after 8 h
and over 90% starting material was recovered. Therefore, there was
no SNAr reaction under these reaction conditions with substrates 5
or 6, neither with 1, 3, and 4.
Acknowledgements
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[12] All the NMR and CV experiments for investigating the catalytic
mechanism were performed under reaction conditions similar to
those used for the synthesis. Consequently, all samples for 31P NMR
measurement were subjected to reflux at 1158C for 1 h, thus follow-
ing the same procedure as for the synthetic reaction, then cooled
down to 258C for 31P NMR recording. Likewise, all samples for CV
measurement were refluxed at 808C for 1 h. We could not heat the
samples for CV experiments to 1108C owing to the use of THF, tolu-
ene being a poor solvent for CV investigation.
Financial support from Canceropꢂle PACA, INCa, CNRS, Wuhan Uni-
versity, and Aix-Marseille University. MC is supported by the China
Scholarship Council, and YX by la Fondation pour la Recherche Mꢀdi-
cale. We thank Damien Hꢀrault, Roseline Rosas, Fabio Ziarelli, Chao
Chen, and Yang Wang for their help in the 31P NMR experiments.
À
Keywords: C S cross-coupling · cyclic voltammetry · mixed-
ligand catalysts · nucleosides · triazoles
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Received: June 7, 2013
Revised: September 13, 2013
Published online: November 7, 2013
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