Cyclometallated Pd(II) thiosemicarbazone complexes: New catalyst precursors for Suzuki-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2012.10.115

Four tridentate [C,N,S] thiosemicarbazone Pd(II) complexes were applied as catalyst precursors for the Suzuki-Miyaura coupling of a variety of aryl halides and aryl boronic acids. After screening various catalytic conditions, it was found that one dinuclear complex IV containing the bis(diphenylphosphino) ferrocene spacer was able to efficiently catalyze these reactions with yields up to 99% irrespective of the type of aryl substituent on the substrate.

Full text of DOI:10.1016/j.tetlet.2012.10.115

Tetrahedron Letters 54 (2013) 154–157
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclometallated Pd(II) thiosemicarbazone complexes: new catalyst
precursors for Suzuki-coupling reactions
Hong Yan a, Prinessa Chellan b, Tingyi Li a, Jincheng Mao a, , Kelly Chibale b,c, Gregory S. Smith b,
⇑
⇑
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
b Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
c Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Four tridentate [C,N,S] thiosemicarbazone Pd(II) complexes were applied as catalyst precursors for the
Suzuki–Miyaura coupling of a variety of aryl halides and aryl boronic acids. After screening various cat-
alytic conditions, it was found that one dinuclear complex IV containing the bis(diphenylphosphino) fer-
rocene spacer was able to efficiently catalyze these reactions with yields up to 99% irrespective of the
type of aryl substituent on the substrate.
Received 28 August 2012
Revised 11 October 2012
Accepted 26 October 2012
Available online 2 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Coupling reactions
Suzuki reaction
Aryl halides
Thiosemicarbazone complexes
Arylboronic acids
Cross-coupling reactions are a set of palladium catalyzed reac-
tions that are an essential synthetic tool. The most well-known
and widely used cross-coupling reactions are the Heck, Stille, Suzu-
ki, Negishi, and Buchwald–Hartwig cross-couplings.1,2 These types
of reactions have proven useful for the syntheses of polymers,3,4
natural products,5 agrochemicals,6,7 and pharmaceuticals.8,9 Thus,
the search for a metal complex which can catalyze these types of
reactions efficiently while maintaining high chemo- and regio-
selectivities and recyclability is an ongoing process.
In cross-coupling reactions, palladium(II) complexes are gener-
ally used as catalyst precursors from which the active Pd(0) species
is generated in situ. One disadvantage of the current catalyst sys-
tems used is that the metal complex sometimes undergoes decom-
position during the reaction leading to poor recyclability of the
metal complex as well as impurities in the products making the
process a costly one.10
Thiosemicarbazones are widely known for their metal chelating
abilities to a large variety of metals.11 These compounds can be
classified as hybrid ligands as they are capable of acting as bi- or
multidentate ligands through several donor atoms.12 Studies into
the biological applications of thiosemicarbazone metal complexes
are prolific. Research into their role in catalysis however, is still a
relatively new area of interest. One of the earliest reports of
their catalytic abilities was published in 1998 by Pelagatti and
co-workers; they found that tridentate [N,N,S] thiosemicarbazone
palladium(II) complexes were able to catalyze chemoselective
homogenous hydrogenation reactions.13 More recently, a cyclo-
metallated ruthenium(II) thiosemicarbazone complex was used
for the catalytic transfer hydrogenation of substituted ketones with
high efficiency.14 Moderate activities were also observed for the
Suzuki–Miyaura coupling of aryl halides and phenylboronic acids
using tridentate [S,N,O] Ni(II) thiosemicarbazones.15
Tridentate pincer-type Pd(II) complexes are known to effi-
ciently catalyze carbon–carbon coupling reactions.16–19 Tridentate
thiosemicarbazone Pd(II) complexes may exhibit a similar behav-
ior. The thiosemicarbazone ligand occupies three of the four coor-
dination sites available on the metal and this may restrict how the
olefinic or organo-halide substrates coordinate with the metal thus
influencing the selectivity of the catalyst. These complexes are also
known to exhibit high thermal stability, both in the solid state and
in solution, making them good candidates for high temperature
homogenous catalysis. Within our group, we have investigated
the synthesis and application of tridentate [O,N,S] Pd(II) thiosemi-
carbazone complexes as anticancer and antimalarial agents.20–22
To demonstrate the versatility of these complexes, we have also
studied their catalytic activity as catalyst precursors for the Mizor-
oki–Heck coupling reaction and have recently published some of
our findings.23 These promising results along with our previous re-
search on various cross-coupling reactions24 have prompted us to
extend our catalytic studies of Pd(II) thiosemicarbazones to triden-
tate [C,N,S] systems prepared by C–H activation of the thiosemicar-
bazone aryl ortho-carbon. In this Letter we report the preliminary
⇑
Corresponding authors.
E-mail addresses: jcmao@suda.edu.cn (J. Mao), gregory.smith@uct.ac.za (G. S.
Smith).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.115

H. Yan et al. / Tetrahedron Letters 54 (2013) 154–157
155
Table 1
findings of four cyclometallated Pd(II) thiosemicarbazone com-
Screening various catalytic conditionsa
plexes containing the 3,4-dichloroacetophenonethiosemicarbaz-
one ligand as catalyst precursors for the Suzuki–Miyaura cross
couplings of a variety of aryl halides and aryl boronic acids.
The four cyclopalladated thiosemicarbazone complexes (I–IV,
Chart 1)22 were evaluated for their ability to catalyze a series of Su-
zuki–Miyaura cross coupling reactions. The first step was to screen
different catalytic conditions to optimize activity. Table 1 shows
the data ascertained for these reactions.
The palladium catalyst precursors were first screened for the
Suzuki–Miyaura cross coupling of 4-(methoxy)-iodobenzene and
phenylboronic acid in dioxane using K3PO4 as the base (Table 1, en-
tries 1–5). The mononuclear complex I (1 mol %) gave a 95% yield
of the coupled product when the reaction was carried out at
100 °C. However, a decrease in the reaction temperature to 60 °C
yielded only 20% of the coupled product (Entry 2). At 60 °C, the tet-
ranuclear complex II and dinuclear complex III also showed a low
activity while the bis(diphenylphosphino)ferrocene bridged com-
plex IV (0.5 mol %) showed a much more promising activity of
60%. Thus, this complex was chosen for further screening of cata-
lytic conditions.
With the aryl halide substrate changed to 4-(methoxy)-bromo-
benzene and using 0.5 mol % of IV at 100 °C, it was found that the
best yields were obtained when the cross coupling reactions were
carried out in DMF or dioxane (entries 6–10). Further catalytic
reactions in DMF using different bases at 100 °C (entries 11–15)
showed a significant decrease in the isolated yield when Cs2CO3
or TEA are used as a base. Varying the temperature (entries 16–
18) and carrying out the reactions under argon (entries 17 and
18) showed that better yields are obtained as the temperature
was increased with a 94% yield observed at 130 °C. Screening these
different conditions showed that complex IV exhibited the best
activity when a 0.5 mol % complex loading was used in DMF with
K3PO4 as base at 130 °C under argon. Under the same conditions,
PdCl2 or Pd(OAc)2 afforded the desired product with moderate
yields, even using PPh3 as the ligand (entries 19–20). Higher tem-
perature could not give a better result (entry 21).
Pd-cat.
+
MeO
MeO
X
B(OH)2
base, solvent
24 h, air
X = I, Br
Entry
X
Pd-cat. (mol %)
Base
K3PO4
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
I
I (1)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
DMSO
Toluene
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
60
60
60
60
95
20
19
10
60
44
43
10
34
30
25
5
I
I
I
I
I (1)
II (0.5)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
tBuOK
Et3N
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
III (0.25)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
IV (0.5)
Pd cat. (0.5)
Pd cat. (0.5)
IV (0.5)
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
100
100
100
100
100
100
100
100
100
100
120
120
130
130
130
140
9
10
11
12
13
14
15
16
17c
18c
19c,d
20c,e
21c
20
5
22
58
67
94
53,57
78
81
DMF
DMF
DMF
a
Reaction conditions: Aryl halide (0.3 mmol), phenylboronic acid (0.4 mmol), Pd-
complex (0.25–1 mol %), base (2 equiv), solvent (2 mL), 60–130 °C, 24 h, air.
b
Isolated yield (based on aryl halide).
The reaction was performed under argon atmosphere.
PdCl2 or Pd(OAc)2.
Pd(OAc)2/PPh3 (1/2).
c
d
e
to 90% (entry 4). A 31% yield is obtained for the reaction using
2-methoxy-phenylboronic acid (entry 5) and this low yield could
be due to the steric hindrance from the methoxy substituent. The
catalytic reactions using the phenylboronic acid and 4-methyl-
phenylboronic acid substrates (entries 1 and 6) both show a 93%
yield of coupled products. The complex IV was also able to effi-
ciently catalyze the coupling of the chloro substituted phenylbo-
ronic acid with bromobenzene (entry 7) but a slight decrease in
activity is observed when the halide substituent is changed to fluo-
rine (entry 8). High activity is also observed for the naphtha-
lenylboronic acid substrate (entries 10 and 11).
Using these optimal conditions, the complex IV was then
applied to the Suzuki–Miyaura cross-coupling of bromobenzene
with different arylboronic acid substrates. Figure 1 shows a
graphical representation of the product yields obtained for each
substrate.
A product yield of 95% is observed when the substrate 4-meth-
oxy-phenylboronic acid is used (entry 2) and 88% yield is obtained
when the 3-methoxy derivative is used (entry 3). When the reac-
tion is allowed to proceed for 48 hours the product yield increases
The Suzuki–Miyaura coupling reactions between phenylboronic
acid and different aryl halides using IV also show promising results
(Fig. 2). Yields of 99% are obtained when the substrates 3-bromo-
acetophenone, 3-bromopyridine, or 3-methoxy-bromobenzene
are used (entries 2, 4, and 10, Fig. 2). The coupling reactions using
aryl bromide substrates containing a chloro or fluoro substituent
also exhibited high product yields (entries 1 and 8). In contrast
to the aryl boronic acid derivative (entry 5, Fig. 1), a moderately
good yield of 70% is observed for the substrate 2-methoxy-bromo-
benzene (entry 11, Fig. 2).
When the reaction is allowed to proceed for 48 h, a yield of 77%
is obtained for the less reactive 4-nitro-chlorobenzene (entry 13).
Much lower activity is observed for the coupling reactions of other
chlorobenzenes (entries 14 and 15). With the exception of entries
14 and 15, complex IV efficiently catalyzes the coupling of phenyl-
boronic acid and different aryl bromides irrespective of the type of
substituent (electron withdrawing or electron donating) with
yields between 70–99% being attained. This moderate to excellent
activity is also upheld when the substituents are varied on the
phenylboronic acid (Fig. 1).
Cl
Cl
N
NH2
Cl
Cl
N
NH2
N
Pd
N
Pd
S
S
PPh3
4
(I)
(II)
Cl
Cl
N
NH2
N
Pd
Ph2P
S
Cl
Cl
N
NH2
N
Pd
Ph2P
S
Fe
PPh2
Pd
Cl
Cl
S
PPh2
Pd
Cl
Cl
N
S
H2N
N
N
H2N
N
(III)
(IV)
Chart 1. Structures of the catalyst precursors (I–IV) evaluated in this study.

156
H. Yan et al. / Tetrahedron Letters 54 (2013) 154–157
Figure 1. Suzuki–Miyaura coupling of bromobenzene and aryl boronic acids using IV.
Figure 2. Suzuki–Miyaura coupling reactions between phenylboronic acid and various aryl halides using IV.
This preliminary study has demonstrated the versatility of this
matography was performed using glass plates pre-coated with
200–400 mesh silica gel impregnated with a fluorescent indicator
(254 nm). NMR spectra were measured in CDCl3 on a Varian Ino-
va-400 NMR spectrometer (400 MHz) with TMS as an internal ref-
erence. The preparation and characterization of complexes I–IV
have previously been reported by us.22 For IV, 1H NMR (400 MHz,
DMSO): d (ppm) 7.40–7.58 (m, 20H, PPh2), 7.25 (s, 2H, Ar-H),
6.96 (s, 4H, NH2), 6.08 (s, 2H, Ar-H), 5.07 (br s, 4H, Cp-H), 4.27
(br s, 4H, Cp–H), 2.31(s, 6H, CH3). 13C NMR (100 MHz, DMSO): d
(ppm) 178.6, 163.8, 152.7, 136.14, 133.0–133.2, 131.1, 129.4,
128.4–128.5, 126.4, 126.3, 75.4–74.2, 13.3. 31P NMR (161.9 MHz,
complex as it is able to produce a wide variety of coupled products
and its effectiveness does not seem to be dependent on the type of
aryl substrate used. Further studies on the use of complex IV for
other coupling reactions are currently underway.
Experiment
General information
DMSO): d(ppm) 29.19 (dppf). IR (KBr, cmÀ1
) m 3479 (m, N–H),
All reactions were carried out under an argon atmosphere un-
less otherwise stated. Solvents were dried and degassed by stan-
dard methods. All aryl halides and boronic acids were purchased
from Aldrich and Alfa. Flash column chromatography was per-
formed using silica gel (300–400 mesh). Analytical thin-layer chro-
3383 (m, N–H), 1595 (s, C@N), 1574 (s, C@N), 1491 (s, C@C aromat-
ics). Elemental Analysis for C52H42Cl4FeN6P2Pd2S2: found C 49.0, H
3.5, N 6.2, S 4.1%; calculated C 48.5, H 3.3, N 6.5, S 5.0%. ESI-MS: m/z
1288.87 ([M+H]+, 50%), 644.94 ([M/2+2H]2+, 100%).

H. Yan et al. / Tetrahedron Letters 54 (2013) 154–157
157
2. For recent selected reviews, see: (a) Sonogashira, K. J. Organomet. Chem. 2002,
653, 46–49; (b) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566–1568; (c)
Jutand, A. Pure Appl. Chem. 2004, 76, 565–576.
3. Li, Y.; Yang, M. J. Mol. Catal. A: Chem. 2002, 184, 161–165.
4. Li, C.-J.; Slaven, W. T.; John, V. T.; Banerjeeb, S. Chem. Commun. 1997, 1569–
1570.
5. Bates, R. W.; Gabel, C. J.; Ji, J.; Rama-Devi, T. Tetrahedron 1995, 51, 8199–8212.
6. Hargreaves, S. L.; Pilkington, B. L.; Russell, S. E.; Worthington, P. A. Tetrahedron
Lett. 2000, 41, 1653–1656.
General procedure for Suzuki–Miyaura reactions
A Schlenk tube was charged with aryl boronic acid (0.4 mmol),
K3PO4 (0.6 mmol), and the complex IV (0.5 mol %). The tube was
connected to a vacuum line under argon and purged three times.
N,N-dimethylformamide (2 mL) and aryl halide (0.3 mmol) were
added. The reaction mixture was stirred at 130 °C between 24–
48 h. At the end of the reaction, the reaction mixture was cooled
to room temperature, diluted with diethyl ether, and washed with
water. The combined organic phase was dried over anhydrous
Na2SO4. After removal of the solvent, the residue was subjected
to column chromatography on silica gel using ethyl acetate and
petroleum ether mixtures to afford the Suzuki–Miyaura product
in high purity.
7. Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101–109.
8. Mauger, C.; Mignani, G. Adv. Synth. Catal. 2005, 347, 773–782.
9. Doucet, H.; Hierso, J. C. Curr. Opin. Drug Discovery. Dev. 2007, 10, 672–690.
10. Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173.
11. Lobana, T. S.; Sharma, R.; Bawa, G.; Khanna, S. Coord. Chem. Rev. 2009, 253, 977–
1055.
12. (a) Zhang, W.-H.; Chien, S. W.; Hor, T. S. A. Coord. Chem. Rev. 2011, 255, 1991–
2024; (b) Kostas, I. D.; Heropoulos, G. A.; Kovala-Demertzi, D.; Yadav, P. N.;
Jasinski, J. P.; Demertzis, M. A.; Andreadaki, F. J.; Vo-Thanh, G.; Petit, A.; Loupy,
A. Tetrahedron Lett. 2006, 47, 4403–4407; (c) Kovala-Demertzi, D.; Yadav, P. N.;
Demertzi, M. A.; Jasiski, J. P.; Andreadaki, F. J.; Kostas, I. D. Tetrahedron Lett.
2004, 45, 2923–2926; (d) Kostas, I. D.; Andreadaki, F. J.; Kovala-Demertzi, D.;
Prentjas, C.; Demertzis, M. A. Tetrahedron Lett. 2005, 46, 1967–1970.
13. Pelagatti, P.; Venturini, A.; Leporat, A.; Carcelli, M.; Costa, M.; Bacchi, A.; Pelizzi,
G.; Pelizzi, C. J. Chem. Soc., Dalton Trans. 1998, 2715–2721.
Acknowledgments
We gratefully thank the University of Cape Town and the
National Research Foundation (NRF) of South Africa for financial
support. We thank the AngloPlatinum Corporation and Johnson
Matthey for the kind donation of palladium salts. In addition, we
are grateful to the grants from the International S&T Cooperation
Program of Jiangsu Province (BZ2010048), the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State Edu-
cation Ministry, the Priority Academic Program Development of
Jiangsu Higher Education Institutions, and the Key Laboratory of
Organic Synthesis of Jiangsu Province, PR China.
14. Pandiarajan, D.; Ramesh, R. Inorg. Chem. Commun. 2011, 14, 686–689.
15. Datta, S.; Seth, D. K.; Butcher, R. J.; Bhattacharya, S. Inorg. Chim. Acta 2011, 377,
120–128.
16. Bonnet, S.; Lutz, M.; Spek, A. L.; Koten, G. Van; Gebbink, R. J. M. K.
Organometallics 2010, 29, 1157–1167.
17. Pijnenburg, N. J. M.; Lutz, M.; Siegler, M. A.; Spek, A.; Koten, G. Van; Gebbink, R.
J. M. K. New J. Chem. 2011, 35, 2356–2365.
18. Gerber, R.; Blacque, O.; Frech, C. M. Dalton Trans. 2011, 40, 8996–9003.
19. Kozlov, V. A.; Aleksanyan, D. V.; Nelyubina, Y. V.; Lyssenko, K. A.; Petrovskii, P.
V.; Vasil’ev, A. A.; Odinets, I. L. Organometallics 2011, 30, 2920–2932.
20. Stringer, T.; Chellan, P.; Therrien, B.; Shunmoogam-Gounden, N.; Hendricks, D.
T.; Smith, G. S. Polyhedron 2009, 28, 2839–2846.
21. Chellan, P.; Shunmoogam-Gounden, N.; Hendricks, D. T.; Gut, J.; Rosenthal, P.
J.; Lategan, C.; Smith, P. J.; Chibale, K.; Smith, G. S. Eur. J. Inorg. Chem. 2010,
3520–3528.
Supplementary data
22. Chellan, P.; Nasser, S.; Vivas, L.; Chibale, K.; Smith, G. S. J. Organomet. Chem.
2010, 695, 2225–2232.
23. Xie, G.; Chellan, P.; Mao, J.; Chibale, K.; Smith, G. S. Adv. Synth. Catal. 2010, 352,
1641–1647.
24. (a) Li, T.; Qu, X.; Xie, G.; Mao, J. Chem. Asian J. 2011, 6, 1325–1330; (b) Li, T.; Qu,
X.; Zhu, Y.; Sun, P.; Yang, H.; Shan, Y.; Zhang, H.; Liu, D.; Zhang, X.; Mao, J. Adv.
Synth. Catal. 2011, 353, 2731–2738; (c) Qu, X.; Sun, P.; Li, T.; Mao, J. Adv. Synth.
Catal. 2011, 353, 1061–1066; (d) Mao, J.; Xie, G.; Zhan, J.; Hua, Q.; Shi, D. Adv.
Synth. Catal. 2009, 351, 1268–1272; (e) Mao, J.; Hua, Q.; Xie, G.; Guo, J.; Yao, Z.;
Shi, D.; Ji, S. Adv. Synth. Catal. 2009, 351, 635–641; (f) Mao, J.; Xie, G.; Wu, M.;
Guo, J.; Ji, S. Adv. Synth. Catal. 2008, 350, 2477–2482.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.115.
References and notes
1. (a) Diederic, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reaction; Wiley-VCH:
Weinheim, 1998; (b) Tsuji, J. Palladium Reagents and Catalysts; John Wiley and
Sons: Chichester, 1995.