Dimethylaminoalkyl chalcogenolate palladium(II) complexes as an efficient copper-and phosphine-free catalyst for Sonogashira reaction

Article abstract of DOI:10.1016/j.tetlet.2013.12.004

N,N-Dimethylaminoalkyl chalcogenolate Pd(II) complexes [PdCl(E ^a∩NMe₂)]_n has been investigated as a moisture/air-stable and robust catalyst for Sonogashira cross-coupling reaction in the absence of copper and phosphine ligand. The dimeric palladium(II) complex of selenium containing ligand shows the best catalytic activity as compared with monomeric and trimeric complexes. The variety of functional groups are tolerated under optimized catalytic systems and provide excellent yields of the products.

Full text of DOI:10.1016/j.tetlet.2013.12.004

Tetrahedron Letters 55 (2014) 716–719
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dimethylaminoalkyl chalcogenolate palladium(II) complexes
as an efficient copper- and phosphine-free catalyst for Sonogashira
reaction
Bhikan J. Khairnar a, Sandip Dey b, Vimal K. Jain b, Bhalchandra M. Bhanage a,
⇑
a Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
b Chemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
N,N-Dimethylaminoalkyl chalcogenolate Pd(II) complexes [PdCl(E\NMe2)]n has been investigated as a
moisture/air-stable and robust catalyst for Sonogashira cross-coupling reaction in the absence of copper
and phosphine ligand. The dimeric palladium(II) complex of selenium containing ligand shows the best
catalytic activity as compared with monomeric and trimeric complexes. The variety of functional groups
are tolerated under optimized catalytic systems and provide excellent yields of the products.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 30 October 2013
Revised 29 November 2013
Accepted 2 December 2013
Available online 8 December 2013
Keywords:
Sonogashira reaction
Chalcogenolate
Palladium complex
Phosphine free
Copper free
The Sonogashira cross-coupling1 reaction is well-known as
being one of the most important reactions for the construction of
internal alkynes in the presence of phosphine ligand and copper re-
agent under inert conditions. The formation of internal alkynes
using Sonogashira reaction finds wide applications in various areas
such as synthesis of natural products, pharmaceuticals, and ad-
vanced materials.2 Since its discovery by Sonogashira in 1975, a
number of modifications have been made including ligand varia-
tion, Pd sources, solvents, and the amount of catalyst loading in or-
der to promote the C–C bond formation. The most common
catalytic systems used for this transformations which include
PdCl2(PPh3)2, PdCl2/PPh3, and Pd(PPh3)4 together with copper as
the co-catalyst. On the other hand, the presence of copper can also
induce a Glaser-type oxidative homocoupling of the terminal acet-
ylene to yield a diyne,3 which cannot be avoided in copper-medi-
ated reactions. These diaryldiacetylene byproducts are generally
difficult to separate from the desired products and in situ formed
copper acetylide is a potentially explosive reagent. But limiting
aspects of these reported methods are the use of air or moisture-
sensitive phosphine ligands. Considering both environmental and
economic issues, there is an urge to develop copper- and
phosphine-free palladium catalysts. In the last decade, copper-
and ligand-free palladium-catalyzed Sonogashira coupling
reactions have been evolved as efficient routes for achieving these
products.4
It is well known that the sulfur containing catalysts have been
neglected for a long time due to rapid catalyst poisoning.5 Recently
a number of palladium complexes derived from chalcogenoether
linkages (C–E–C; E@S or Se) have been shown to be efficient cata-
lysts in C–C coupling reactions.6 In Heck coupling reaction, the
cyclopalladated selenium complex [Pd(l
-OAc)(C6H4CH2SeBut)2]
has shown excellent activity than its sulfur counterpart as well
as Herrmann–Beller palladacycle.7 The palladium chalcogenolate
complexes may offer an attractive way for C–C bond forming reac-
tions owing to a strong Pd-ER linkage.8 However their utility as a
catalyst in C–C bond forming reactions remained relatively unex-
plored due to their tendency to polymerize which leads to insolu-
bility/sparing solubility in organic solvents.6
In this Letter we have explored the catalytic activity of palla-
dium containing dimeric and trimeric complexes of hemi-labile
N,N-dimethyl alkyl chalcogenolate ligands. The dimeric or trimeric
structures comprise of two or three palladium atoms bridged
through chalcogen atoms of the chelating chalcogenolate ligand
forming a four- or six-membered Pd2E2 or Pd3E3 ring, respectively.9
The chloro-ligand acts in a monodentate fashion. These complexes
have excellent air/moisture and thermal stability. In view of the
above perspective it was considered useful to examine their cata-
lytic activity in Sonogashira reaction. Herein we report a phos-
phine- and copper-free Sonogashira reaction catalyzed by
dimethylaminoalkyl chalcogenolate complexes of palladium(II)
⇑
Corresponding author. Tel.: +91 22 33612601; fax: +91 22 33611020.
E-mail addresses: bm.bhanage@ictmumbai.edu.in, bm.bhanage@gmail.com
(B.M. Bhanage).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.004

B. J. Khairnar et al. / Tetrahedron Letters 55 (2014) 716–719
717
Table 2
[PdCl(E NMe2)]n
I
Optimization of reaction parametersa
+
Et3N, Dioxane
100oC, 12h
I
'Pd' catalyst 1d
+
Base, Solvent
3a
2a
4a
Time (h)
N
Cl
E
PPh3
Cl
Pd
Entry
Solvent
Base
Temp (°C)
Yieldb (%)
Cl
N
E
N
E
Pd
Cl
Pd
Pd
N
Se
Pd
Cl
Pd
N
Effect of solvent:
E
E
Cl
N
1
2
3
4
Toluene
DMF
DMSO
Dioxane
Et3N
Et3N
Et3N
Et3N
100
100
100
100
12
12
12
12
48
26
Trace
96
E = S 1a
E = Se 1b
E = S 1c
E = Se 1d
1e
Effect of base:
Scheme 1. Chalcogenolate ligated Pd(II) complexes [PdCl(E\NMe2)]n used as
catalysts in Sonogashira reaction.
5
6
7
Dioxane
K2CO3
100
100
100
100
100
100
12
12
12
12
12
12
76
82
80
68
90
78
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
NaHCO3
K3PO4
8
tBuOK
9
Pyrolidine
Et3N
10c
Table 1
Effect of catalyst screening and loading on Sonogashira reactiona
Effect of temperature and time:
Entry
‘Pd’ catalyst
‘Pd’ (mol %)
Yieldb (%)
11
12
13
14
Dioxane
Dioxane
Dioxane
Dioxane
Et3N
Et3N
Et3N
Et3N
90
90
100
110
12
15
10
12
82
86
88
96
1
2
3
4
5
6
7
[PdCl(SCH2CH2NMe2)]3 1a
4
4
4
4
4
3
2
56
64
78
97
76
96
84
[PdCl(SeCH2CH2NMe2)]3 1b
[PdCl(SCH2CH2CH2NMe2)]2 1c
[PdCl(SeCH2CH2CH2NMe2)]2 1d
[PdCl(SeCH2CH2NMe2)(PPh3)] 1e
[PdCl(SeCH2CH2CH2NMe2)]2 1d
[PdCl(SeCH2CH2CH2NMe2)]2 1d
a
Reaction conditions: Iodobenzene (1 mmol), phenyl acetylene (1.2 mmol), base
(2 mmol), ‘Pd’ catalyst 1d (3 mol %).
b
GC yield.
Base (1 mmol).
c
a
Reaction conditions: Iodobenzene (1 mmol), phenyl acetylene (1.2 mmol), tri-
ethyl amine (2 mmol), solvent-1,4-dioxane (4 ml), 100 °C, 12 h.
b
GC yield.
which gives moderate to good yields under aerobic conditions
(Scheme 1).
Having optimized the reaction conditions in hand, we next set
out to explore the substrate scope of 1d catalyzed Sonogashira
reaction.10
At the onset of the research, we made a conscious effort to devel-
op a catalytic system that would address the limitations of the pre-
viously reported palladium catalyzed Sonogashira reaction. During
preliminary studies, iodobenzene 2a was reacted with phenyl acet-
ylene 3a and used as the model system. A series of experiments
were performed to optimize various reaction parameters, such as
the nature of the catalyst, effect of catalyst loading, base,
solvent, temperature, and time. Initially we screened various
N,N-dimethylalkyl chalcogenolate ligands chelated palladium cata-
lyst such as [PdCl(SCH2CH2NMe2)]3 1a, [PdCl(SeCH2CH2NMe2)]3 1b,
[PdCl(SCH2CH2CH2NMe2)]2 1c, [PdCl(SeCH2CH2CH2NMe2)]2 1d, and
[PdCl(SeCH2CH2NMe2)(PPh3)] 1e (Table 1, entries 1–5) for the
present Sonogashira protocol. The complex 1d was the best catalyst
giving excellent yield of the desired product 4a (Table 1, entry 4).
We further studied catalyst loading ranging from 2 to 4 mol %,
wherein increasing catalyst concentration from 2 to 3 mol %
showed increase in the yield of the desired product and further in-
crease in catalyst concentration has no profound effect on the yield
of the product (Table 1, entries 4, 6 and 7).
Various aryl halides containing different functional groups
were investigated (Table 3). We observed that electron donating
(Table 3, entries 2–4) as well as electron withdrawing (Table 3,
entries 5–9) substituents provided remarkable yield of products.
Gratifyingly this protocol tolerated a variety of common func-
tional groups such as alkyl, ether, halogen, and nitro groups
regardless of the positions. We also found that the heteroaryl
halides also gave moderate to good yields of the desired
products (Table 3, entries 10–14). Next we attempted to widen
the scope of chalcogenolate Pd catalyst for aryl bromide and aryl
chloride; among these, aryl bromides were well tolerated
(Table 3, entries 1, 2 and 8) and gave good yields. It should be
noted that the coupling reactions of the aryl chlorides also took
place under similar copper- and phosphine-free conditions, after
increasing the catalyst loading up to 5 mol % and increasing the
reaction temperature to 120 °C for 15 h, though the reactivity
was much lower than their iodo and bromo counterparts
(Table 3, entries 1 and 8).
As the nature of the base is assumed to have a marked impact
on the overall process the effect of different bases such as, K2CO3,
A small library of heteroaryl halides and substituted aryl acety-
lenes was tested and the provided corresponding products were
obtained in good yields (Table 3, entries 12–14).
t
K3PO4, NaHCO3, BuOK, pyrolidine, and Et3N were examined. The
best results were obtained with Et3N affording 4a in excellent yield
(Table 2, entries 4–10). We studied the effect of different solvents
in the standard reaction. It was found that 1,4-dioxane was a better
solvent to yield the desired product in good yield (Table 2, entries
1–4). While studying the effect of temperature, the yield of the de-
sired product increased with increasing the reaction temperature
from 90 °C to 100 °C. The latter appears to be the optimum temper-
ature for the reaction. The reaction time is also optimized and
maximum yield of the desired product was obtained after 12 h
(Table 2, entries 4, 11–14).
In conclusion, we have developed a protocol for the Sono-
gashira coupling using N,N-dimethylaminoalkyl chalcogenolate
palladium(II) complexes as catalyst to give various biarylacety-
lene derivatives. The reactions work under copper- and phos-
phine-free conditions in air. It was found that the catalyst
exhibited good activity and selectivity for the Sonogashira
reaction.
The activity of chalcogenolate Pd-complexes, [PdCl(E\NMe2)]n
is influenced by the nature and number of (E\N) group and follows

718
B. J. Khairnar et al. / Tetrahedron Letters 55 (2014) 716–719
Table 3
Substrate study for Sonogashira reactiona
X
1d
'Pd' catalyst
R1
+
Et3N, Dioxane
100oC, 12h
R1
R
R
Entry
1
Aryl halide
Alkyne
Product
Yield (%)b
X
X = I, 92
Br, 58
Cl, 14c
3a
4a
2a
X
H3C
X = I, 89
Br, 48
2
3
4
3a
3a
3a
H3C
4b
2b
I
78
76
82
88
67
CH3
CH3
4c
2c
I
OCH3
OCH3
4d
4e
2d
F
I
5
6
3a
3a
3a
3a
3a
3a
3a
F
2e
I
F3C
F3C
4f
2f
I
7
Br
Br
4g
2g
X
I
O2N
O2N
X = I, 93
Br, 64
8
O2N
O2N
Cl, 18c
4h
2h
9
81
80
78
4i
2i
I
N
10
11
N
4j
2j
I
N
N
2k
4k
CH3
12
13
14
2j
76
63
74
N
N
3b
3c
4l
H3C
H3CO
2j
4m
4n
OCH3
CH3
2k
3b
N
a
b
c
Reaction conditions: Aryl halide (1 mmol), aryl acetelyne (1.2 mmol), Pd catalyst 1d (3 mol %), triethyl amine (2 mmol), 100 °C, 12 h.
Isolated yield.
Reaction conditions for chloro-substrate 120 °C, 15 h.

B. J. Khairnar et al. / Tetrahedron Letters 55 (2014) 716–719
719
Lett. 2010, 51, 2758–2761; (f) Wang, X.; Qin, W.; Kakusawa, N.; Yasuike, S.;
Kurita, J. Tetrahedron Lett. 2009, 50, 6293–6297; (g) Yang, F.; Cui, X.; Li, Y.;
Zhang, J.; Ren, G.; Wu, Y. Tetrahedron 2007, 63, 1963–1969.
the trend: E = Se > S and dimeric > trimeric in Sonogashira cross
coupling reaction.
4. (a) Gladysz, J. A.; Curran, D. P.; Horváth, Y. I. T. Handbook of Fluorous Chemistry;
Willey: New York, 2004; pp 175–365. Chapter 10; (b) Aggarwarl, V. K.; Mereu,
A.; Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183–7189.
5. Dunleavy, J. K. Platinum Met. Rev. 2006, 50, 110.
Acknowledgments
The author (B.J.K.) is thankful to the Council of Scientific and
Industrial Research (CSIR) India for providing junior research
fellowship (JRF).
6. (a) Kostas, I. D.; Steele, B. R.; Terzis, A.; Amosova, S. V.; Martynov, A. V.;
Makhaeva, N. A. Eur. J. Inorg. Chem. 2006, 2642–2646; (b) Bai, S. Q.; Hor, T. S. A.
Chem. Commun. 2008, 3172–3174; (c) Wang, H.; Zhong, R.; Guo, X. Q.; Feng, X.
Y.; Hou, X. F. Eur. J. Inorg. Chem. 2010, 174–178; (d) Yuan, D.; Huynh, H. V.
Organometallics 2010, 29, 6020–6027; (e) Rao, G. K.; Kumar, A.; Ahmed, J.;
Singh, A. K. Chem. Commun. 2010, 5954–5956; (f) Das, D.; Singh, P.; Singh, M.;
Singh, A. K. Dalton Trans. 2010, 39, 10876–10882; (g) Rao, G. K.; Kumar, A.;
Kumar, B.; Kumar, D.; Singh, A. K. Dalton Trans. 2012, 41, 1931–1937; (h)
Chakraborty, T.; Srivastava, K.; Singh, H. B.; Butcher, R. J. J. Organomet. Chem.
2011, 696, 2559–2564.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.004.
7. (a) Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Org. Lett. 2000,
18, 2881–2884; (b) Yao, Q.; Kinney, E. P.; Zheng, C. Org. Lett. 2004, 6, 2997–
2999.
8. (a) Paluru, D. K.; Dey, S.; Wadawale, A.; Jain, V. K. J. Organomet. Chem. 2013, 728,
52–56; (b) Vivekananda, K. V.; Dey, S.; Wadawale, A.; Bhuvanesh, N.; Jain, V. K.
Dalton Trans. 2013, 42, 14158–14167.
9. (a) Dey, S.; Jain, V. K.; Chaudhury, S.; Knoedler, A.; Lissner, F.; Kaim, W. J. Chem.
Soc., Dalton Trans. 2001, 723–728; (b) Dey, S.; Jain, V. K.; Varghese, B.; Schurr,
T.; Niemeyer, M.; Kaim, W.; Butcher, R. J. Inorg. Chim. Acta 2006, 359, 1449–
1457.
10. Typical experimental procedure: In an oven dried 25 ml Schlenk tube was added
a mixture of aryl halide (1 mmol), arylacetylene (1.2 mmol), Pd catalyst 1d
(3 mol %), and triethyl amine (2 mmol) in 4 ml of dioxane. The reaction mixture
was heated in an oil bath at 100 °C for 12 h with continuous stirring. After 12 h
the reaction mixture was cooled to room temperature and the product was
extracted into ethyl acetate (3 ꢀ 10 ml). After drying over anhydrous Na2SO4,
the combined ethyl acetate layer was concentrated by rotary evaporation. All
the prepared compounds were characterized by by GC–MS and NMR
techniques.
References and notes
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–
4470; (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49.
2. For application of Sonogashira reaction: (a) Chinchilla, R.; Nájera, C. Chem. Rev.
2007, 107, 874–922; (b) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173; (c)
Doucet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46, 834–871; (d) Odlo, K.;
Klaveness, J.; Rongved, P.; Hansen, T. V. Tetrahedron Lett. 2006, 47, 1101–1103;
(e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442–
4489; (f) Pedersen, J. M.; Bowman, W. R.; Elsegood, M. R. J.; Fletcher, A. J.;
Lovell, P. J. J. Org. Chem. 2005, 70, 10615–10618.
3. (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422–424; (b) Arques, A.; Auñon, D.;
Molina, P. Tetrahedron Lett. 2004, 45, 4337–4340; (c) Consorti, C. S.; Flores, F. R.;
Rominger, F.; Dupont, J. Adv. Synth. Catal. 2006, 348, 133–141; (d) Likhar, P. R.;
Subhas, M. S.; Roy, M.; Roy, S.; Kantam, M. L. Helv. Chim. Acta 2008, 91, 259–
264; (e) Sawant, D. N.; Tambade, P. J.; Wagh, Y. S.; Bhanage, B. M. Tetrahedron