Carbohydrate derived thiosemicarbazone and semicarbazone palladium complexes: Homogeneous catalyst for C-C cross coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.06.145

Palladium complexes of carbohydrate derived thiosemicarbazone and semicarbazone were used as catalysts for Suzuki and Sonogashira cross coupling reactions at ambient temperature. The catalysts were active after 5 cycles. Activation of 4-chlorotoluene has been achieved with 0.1% catalyst loading at ambient temperature with TON of 970 in 4 h.

Full text of DOI:10.1016/j.tetlet.2013.06.145

Tetrahedron Letters 54 (2013) 4914–4917
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbohydrate derived thiosemicarbazone and semicarbazone
palladium complexes: homogeneous catalyst for C–C cross coupling
reactions
⇑
Prashant Ranjan Verma, Soumik Mandal, Parna Gupta, Balaram Mukhopadhyay
Department of Chemical Sciences, Indian Institute of Science Education and Research-Kolkata (IISER-K), Mohanpur, Nadia 741252, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium complexes of carbohydrate derived thiosemicarbazone and semicarbazone were used as
catalysts for Suzuki and Sonogashira cross coupling reactions at ambient temperature. The catalysts were
active after 5 cycles. Activation of 4-chlorotoluene has been achieved with 0.1% catalyst loading at
ambient temperature with TON of 970 in 4 h.
Received 15 May 2013
Revised 27 June 2013
Accepted 28 June 2013
Available online 4 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Thiosemicarbazone
Semicarbazone
Carbohydrate
Suzuki–Miyaura
Sonogashira
Transition metal complexes of thiosemicarbazones and semi-
carbazones attract great interest for their biological applications
as antimicrobial, antibacterial, and antitumor agents.1 Possibilities
of different binding modes of thiosemicarbazone and semicarba-
zone ligands open up scopes for interesting studies with transition
metal complex formation.2 Among them, palladium metals are of
great importance owing to their famous catalytic activities for var-
ious C–C cross coupling reactions. For example, Suzuki–Miyaura
cross coupling between aryl halide and aryl boronic acid is one
of the most extensively used C–C bond formation reactions.3 For
obvious reasons aryl bromides and iodides undergo activation in
a much faster rate than their chloride counterparts. However, since
aryl chlorides are readily available and cheap, they can make the
industrial application more economically viable. The use of aryl
chlorides for Suzuki–Miyaura cross coupling reaction came only
in late 90’s4 and only a few examples are in the literature till
date.5,6 Moreover, room temperature activation of aryl chlorides
with low catalyst loading still remains a quest.
corresponding thiosemicarbazone (4) and semicarbazone (5)
ligands respectively (Scheme 1).
Reaction of the ligands 4 and 5 with Pd(PPh3)2Cl2 in refluxing
methanol in the presence of Et3N resulted in a color change from
yellow to bright orange. The products thus formed were isolated
by column chromatography using CH2Cl2/EtOAc (4:1) as eluent.
The pure complexes 1 and 2 were characterized by mass and
NMR spectroscopy which revealed the presence of a triphenyl
phosphine and chlorine attached to the central palladium. The
complexes 1 and 2 were crystallized from MeOH/CH3CN (1:1)
Herein we report two palladium(II) complexes with carbohy-
drate derived thiosemicarbazone and semicarbazone ligands. The
known sugar aldehyde 37 was treated with either thiosemicarba-
zide or semicarbazide in dry methanol at 60 °C to furnish the
⇑
Corresponding author. Tel.: +91 9748 261742.
E-mail address: sugarnet73@hotmail.com (B. Mukhopadhyay).
Scheme 1. Synthesis of the palladium complexes 1 and 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.145

P. R. Verma et al. / Tetrahedron Letters 54 (2013) 4914–4917
4915
Figure 1. ORTEP diagram of complexes 1 and 2 with 50% probability of the thermal ellipsoids.aCCDC numbers for the crystals 1 and 2 are 904793 and 904792, respectively.
and CH2Cl2/CH3CN (1:1) respectively. The single crystal X-ray dif-
fraction clearly showed the attachment of the thiosemicarbazone
moiety to the central palladium through S1 and N1 in complex 1.
Other two sites of the central palladium are occupied by a PPh3
and a Cl. Similarly, in the semicarbazone complex 2, the semicarba-
zone moiety of the ligand is attached through N1 and O5. The
geometry around palladium was square planar in both complexes
1 and 2 (Fig. 1).
Catalytic efficiency of the iso-structural thiosemicarbazone and
semicarbazone-palladium catalysts was investigated by using
them for Suzuki–Miyaura C–C cross coupling reaction between aryl
boronic acids and aryl halides to form biaryl compounds. Since
activation of aryl chlorides at ambient temperature is our prime
target, phenyl boronic acid was reacted with 4-chlorotoluene in
the presence of complex 1 (0.2 mol %) using K2CO3 as base at
25 °C. To our satisfaction the reaction was complete within 1 h to
form the corresponding biaryl derivative in 98% yield. In a similar
reaction with complex 2 resulted in the formation of the biaryl
derivative in 98% yield with 0.2% catalyst loading revealing compa-
rable catalytic efficiency. Other aryl chlorides having different sub-
stituents at p-position resulted in the formation of biaryls in near
quantitative yields upon coupling phenyl boronic acid at ambient
temperature8 (Table 1).
Indeed the catalytic efficiency of both 1 and 2 is found to be excel-
lent for the activation of aryl chlorides at ambient temperature.
However, since the catalysts are soluble in the reaction media, it is
impossible to recover them to check the retention of catalytic activ-
ity. Thus, the only way remaining to postulate their activity is to run
several catalytic cycles in one-pot. In
a model reaction of
4-chlorotoluene with phenyl boronic acid using 0.2 mol % of catalyst
1, we added fresh batch of substrates in every 2 h interval after
confirming the consumption of the aryl halide by 1H NMR. After 5
such cycles, the desired biaryl compound was isolated in 94% yield
which demonstrates that the catalyst remains live after the catalytic
cycle.
To judge the catalytic efficiency further, 4-chlotoluene was
reacted with phenyl boronic acid with 0.1 mol % of catalyst 1.
The reaction was complete in 4 h and the desired biaryl was
obtained in 97% yield showing that the catalyst is almost equally
active in 0.1 mol % loading. Lowering of the catalyst loading to
0.05 mol % resulted in a very slow reaction and after 24 h the
desired product was obtained in 60% yield only. The results of
the reactions with lowered catalyst loading are summarized in
Table 2 with calculated TON values.
The success of the Suzuki–Miyaura cross coupling reactions
using catalysts 1 and 2 prompted us to investigate their potential

4916
P. R. Verma et al. / Tetrahedron Letters 54 (2013) 4914–4917
Table 1
Suzuki–Miyaura C–C cross coupling reactions of aryl chlorides and phenyl boronic acid at ambient temperaturea
No.
Substrate
Catalyst
Product
Time (min)
Yieldb (%)
1
2
1
2
60
60
989
98
Cl
6
3
4
1
2
50
50
9810
97
Cl
Cl
Cl
Cl
Cl
CN
CN
7
5
6
1
2
45
45
9710
98
COCH3
NH2
COCH3
NH2
8
7
8
1
2
90
90
9711
96
9
9
10
1
2
30
30
9710
97
CHO
NO2
CHO
NO2
10
11
11
12
1
2
30
30
9811
97
13
14
1
2
60
60
7612
75
Cl
12
a
Conditions: aryl chloride (1 mmol), phenyl boronic acid (1.2 mmol), K2CO3 (2 mmol), and catalyst (0.2 mol %) in 5 mL EtOH at 25 °C.
Yield after chromatographic purification.
b
Table 2
1 and 2 were found to be of equal efficiency and effective at
0.5 mol % of catalyst loading.14
Suzuki–Miyaura C–C cross coupling reactions of 4-chlorotoluene and phenyl boronic
acid with different catalyst loadings at ambient temperaturea
Encouraged by successful Sonogashira coupling of phenyl acet-
ylene with aryl halides, we tried to couple propargyl glycosides
with aryl halides. Indeed the propargyl derivatives16 undergo
coupling with the aryl halides to form the corresponding glycocon-
jugates in moderate yields (Scheme 2).
In conclusion, we have developed two palladium catalysts
with carbohydrate derived thiosemicarbazone and semicarba-
zone ligands and fully characterized them with NMR, mass,
and single crystal X-ray crystallography. The catalysts are found
to be efficient for both Suzuki–Miyaura and Sonogashira
coupling reactions. The catalysts are capable of activating aryl
chlorides in Suzuki–Miyaura coupling reaction at ambient
temperature at a low catalyst loading of 0.05 mol %. The catalysts
remain active even after 5 consecutive cycles. In addition to the
aromatic alkynes, aliphatic terminal alkynes of propargyl glyco-
sides were successfully coupled with aryl halides in Sonogashira
coupling reaction.
No.
Catalyst loading (mol %)
Time (h)
Yieldb (%)
TON
1
2
3
0.2
0.1
0.05
1
4
24
98
97
60
490
970
1200
a
Conditions: 4-chlorotoluene (1 mmol), phenyl boronic acid (1.2 mmol), K2CO3
(2 mmol), and catalyst (as mentioned) in 5 mL EtOH at 25 °C.
b
Yield after chromatographic purification.
to catalyze Sonogashira coupling reactions (Table 3).13 Different
aryl halides were reacted with phenyl acetylene in the presence
of catalyst 1 or 2 with CuI and Et3N. Reactions with aryl bromides
and iodides were complete in 12 h at 80 °C resulted in the forma-
tion of the desired product in moderate yield. However, the aryl
chlorides were found to be lethargic and only after 24 h, the de-
sired products were obtained in comparative yields. Both catalyst
Table 3
Sonogashira coupling reactions of aryl halides and phenyl acetylene using catalysts 1 and 2a
No.
Substrate
Catalyst
Product
Time (h)
Yieldb (%)
1
2
1
2
16
16
6615
65
Br
NO2
NO2
13
3
4
1
2
16
16
6415
65
I
14
5
6
1
2
24
24
67
65
Cl
15
a
Conditions: aryl halide (1 mmol), phenyl acetylene (1.5 mmol), catalyst 1 or 2 (0.5 mmol %), CuI (10 mol %), and Et3N (5 mL) at 80 °C.
Yield after chromatographic purification.
b

P. R. Verma et al. / Tetrahedron Letters 54 (2013) 4914–4917
4917
AcO
AcO
O
1 (0.5 mol%), CuI (10 mol%)
AcO
O
O
AcO
+
I
O
AcO
Et3N, 80 oC, 16h
AcO
OAc
OAc
16
63%
15
OAc
O
COCH3
AcO
AcO
OAc
O
AcO
AcO
2 (0.5 mol%), CuI (10 mol%)
Br
COCH3
Et3N, 80 oC, 16h
+
AcO
AcO
O
65%
O
17
18
Scheme 2. Sonogashira coupling reaction with propargyl glycosides.
Bedford, R. B.; Buttsa, C. P.; Hurst, T. E.; Lidström, P. Adv. Synth. Catal. 2004, 346,
1627–1630; (e) Karimi, B.; Akhavan, P. F. Inorg. Chem. 2011, 50, 6063–6072.
6. (a) Datta, S.; Seth, D. K.; Halder, S.; Sheldrick, W. S.; Mayer-Figge, H. M.; Drew,
G. B.; Bhattacharya, S. RSC Adv. 2012, 2, 5254–5264; (b) Sau, S. C.; Santra, S.;
Sen, T. K.; Mandal, S. K.; Koley, D. Chem. Commun. 2012, 48, 555–557; (c)
Diebolt, O.; Braunstein, P.; Nolan, S. P.; Cazin, C. S. J. Chem. Commun. 2008,
3190–3192; (d) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G.
A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 12, 4743–4748;
(e) Navarro, O.; Marion, N.; Mei, J.; Nolan, S. P. Chem. Eur. J. 2006, 12, 5142–
5148; (f) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004, 248,
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8. General procedure for Suzuki–Miyaura coupling reactions: To a solution of
catalyst 1 or 2 (0.2 mol %) in EtOH (3 mL) were added phenylboronic acid
(146 mg, 1.2 mmol), aryl halide (1 mmol) and K2CO3 (276 mg, 2.0 mmol) and
the mixture was allowed to stir at ambient temperature for minutes as
described in Table 1. After completion of the reaction, water (15 mL) was added
and the organic materials were extracted with CH2Cl2. The organic layer was
washed with water, dried over anhydrous Na2SO4 and filtered. Solvent was
removed under vacuum and the residue was purified by flash chromatography
using n-hexane–EtOAc to afford pure biaryl compound.
Acknowledgments
PRV is thankful to IISER-Kolkata and SM is thankful to CSIR,
New Delhi for Senior Research Fellowships. The work is supported
by the research grant 01(2370)/10/EMR-II from CSIR, New Delhi to
BM.
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