In situ generation of highly active bis(N-heterocyclic)carbene palladium as an efficient catalyst in direct S-arylation of methylphenyl sulfoxide and the Heck reaction: Ligand steric effects in product selectivity

Article abstract of DOI:10.1002/aoc.3677

The use of 1,3-bis(N-heterocyclic)carbene ligands with different alkyl wingtip groups (alkyl = methyl, isopropyl and tert-butyl) is an effective method for the palladium-catalysed direct S-arylation of methylphenyl sulfoxide and C–C coupling of various of aryl halides with alkenes. The reactions proceed in moderate to good yields. Interestingly, it is shown experimentally that, by using bulkier bidentate N-heterocyclic carbene ligands, more selective catalytic systems towards cis products in Heck coupling reactions can be achieved.

Full text of DOI:10.1002/aoc.3677

Received: 17 September 2016
DOI 10.1002/aoc.3677
Accepted: 7 October 2016
F U L L PA P E R
In situ generation of highly active bis(N‐heterocyclic)carbene
palladium as an efficient catalyst in direct S‐arylation of
methylphenyl sulfoxide and the Heck reaction: Ligand steric
effects in product selectivity
Mojtaba Bagherzadeh | Narges‐alsadat Mousavi | Sirous Jamali
Department of Chemistry, Sharif University of
The use of 1,3‐bis(N‐heterocyclic)carbene ligands with different alkyl wingtip
Technology, PO Box 11155‐3516, Tehran, Iran
groups (alkyl = methyl, isopropyl and tert‐butyl) is an effective method for the
palladium‐catalysed direct S‐arylation of methylphenyl sulfoxide and C–C coupling
of various of aryl halides with alkenes. The reactions proceed in moderate to good
yields. Interestingly, it is shown experimentally that, by using bulkier bidentate
Correspondence
Mojtaba Bagherzadeh or Sirous Jamali,
Department of Chemistry, Sharif University of
Technology, PO Box 11155‐3516, Tehran, Iran.
Email: bagherzadeh@sharif.edu; sjamali@sharif.
edu
N‐heterocyclic carbene ligands, more selective catalytic systems towards cis
products in Heck coupling reactions can be achieved.
KEYWORDS
bis(N‐heterocyclic)carbene, direct S‐arylation, Heck coupling, palladium catalysis
1
|
INTRODUCTION
an attractive synthetic strategy for the synthesis of compound
libraries of important molecules for potential applications in
Sulfoxides are important functional groups in organic synthe-
sis, and as ligands in catalysis. In addition, they are interesting
due to their function in several biologically active compounds.
Two favourite methods for the synthesis of sulfoxides are
oxidation of sulfides and nucleophilic substitution of
sulfinamidesorsulfinateesters.[1,2] Transition‐metal‐catalysed
cross‐coupling reactions are potent methods for the formation
of C─S bonds[3–5] (Scheme 1) and suggest a further approach
for the synthesis of aryl sulfoxides. Palladium‐catalysed cross‐
coupling reactions are useful methods for forming C─S bonds
and offer another approach for the formation of aryl
sulfoxides.[6–8] For a wide range of utility of sulfoxides, their
functionalization using well‐defined complexes of palladium
withN‐heterocycliccarbenes(NHCs)wasinvestigated.[6]
The palladium‐catalysed arylation of alkenes with aryl
halides (Mizoroki–Heck reaction) is a versatile method in
organic synthesis for the construction of substituted alkenes
containing aryl groups. The reaction proceeds with very high
trans selectivity of product in homogeneous systems and a
mixture of products (cis/trans and gem) in heterogeneous
systems (Scheme 2).[9–14] In recent years, many papers have
reported improvements to the Heck reaction, but it still is
medicinal and pharmaceutical chemistry. So, it is important
to expand catalytic systems for obtaining high selectivity
and high activity to aryl halides.[15–18]
Because of remarkable catalytic potential, easy synthetic
accessibility, thermal stability and relatively low toxicity,
palladacycles have become attractive organometallic catalysts
in organic synthesis. A wide variety of palladacycles obtained
from the cyclopalladation of phosphines, phosphites, amines,
imines, oximes and thioethers or NHCs have been used in
C─C coupling reactions.[19–22]
Among the poly‐NHCs, bis‐NHCs are by far the most
abundant ones. A class of bis‐NHCs is one in which the
two NHC fragments are bound with an aliphatic or aromatic
linker (Scheme 3). The easy preparation of these types of
ligands has allowed a controlled study of their coordination
to metals by modifying the length of the aliphatic or aromatic
linker and some important implications of the structural
properties and reactivity of the resulting products have been
extensively investigated.[23–27]
Mono‐NHC and bis‐NHC ligands are widely used in the
palladium‐catalysed Heck arylation of alkenes with aryl
halides. The NHCs act as a powerful σ donor ligands and
Appl Organometal Chem 2016; 1–5
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
BAGHERZADEH ET AL.
SCHEME 1 S‐Arylation of sulfoxides
FIGURE 1 NHCs used as ligands
2
| RESULTS AND DISCUSSION
The reaction of neat N‐alkylimidazoles (alkyl = methyl,
isopropyl and tert‐butyl) with 0.5 equiv. of 1,3‐bis
(bromomethyl)benzene at 120 °C in a pressure tube gave
the corresponding bis(imidazolium) salts (methyl, L1;
isopropyl, L2; tert‐butyl, L3) in good yield. These salts were
characterized using NMR spectroscopy in DMSO‐d6
(supporting information).
SCHEME 2 Possible isomers of Heck reaction
The in situ synthesis of each complex was achieved by
sonicating of 1 equiv. of 1,3‐bis(1‐alkylimidazoliumethyl)
benzene bromide with 1 equiv. of palladium salt at 90 °C.
The reactivity of palladium complexes with sulfoxides has
been recently investigated.'[7,37,38] In the present study of
the catalytic capability of our palladium–NHC system, the
reaction between methylphenyl sulfoxide and bromobenzene
was first examined for obtaining the optimal conditions
(Table 1, entries 1–4). No α‐arylated product was
detected in this catalytic reaction mixture when Pd(dba)2
was used with L1.
SCHEME 3 Different classes of bis‐NHCs
form considerably stronger bonds to the palladium atom than
do phosphanes, whereas π back‐donation from palladium to
the NHC orbital is negligible.[28,29] Thus, they increase
electron density at the palladium centre and improve the first
step of the catalytic cycle, that is, oxidative addition of
carbon–halogen bond to the palladium centre. These lead to
better yield and turnover number of the catalytic cycle of
the Heck reaction. A large number of well‐defined
NHC–palladium complexes have been shown to efficiently
catalyse the Heck–Mizoroki reaction.[30–32]
Most of these complexes are Pd(II) species that show
excellent catalytic performance at high temperature.
However, most of the research in this area has been focused
on activity and stability of catalyst systems with pincer
(CCC) ligands of the type B[33] and C[34] (Scheme 3) and less
attention has been directed towards catalyst system with
pincer (CCC) ligands of the type A.[35] On the basis of these
precedents and continuing our interest in the palladium‐
catalysed Heck reaction,[36] we report herein a series of
palladium–NHC catalysts that are generated from palladium
acetate and bis(imidazolium) salts with a 2,6‐bis(methylene)
phenyl spacer and alkyl wingtip groups (alky = methyl,
isopropyl and tert‐butyl) (Figure 1) and a base that promotes
arylation of alkenes for which a comparison of reactivity and
selectivity of these ligands is possible.
The reaction reached better conversion when LiOtBu was
used as a base (entries 1–3). Toluene was a good medium for
this catalytic system (entries 3 and 4). At 110 °C and for 24 h,
some aryl bromides were coupled to methylphenyl sulfoxide
(entries 5–7). The results indicate that electron‐withdrawing
groups retard the catalytic reactivity (entry 7).
After preparation the catalytic system, we tested the cata-
lytic activity for the Heck reaction of aryl halides with butyl
acrylate (Table 2). It is important to notice that studies show
that formation of Pd–carbene complexes from Pd(dba)2 (bis
(dibenzylideneacetone)palladium(0)) without prior deproton-
ation of the imidazolium cation can occur through a process
of the oxidative addition to a low‐valent metal.[39] So we used
both Pd(dba)2 and Pd(OAc)2 as a Pd precursor for the Heck
reactions. Of course, the presence of excess base in the
reaction can help the formation of carbene complexes in the
Heck reactions.[39] Also, coordination of carbene ligand to
the metal centre can be confirmed by the colour change from
violet to red.[40]
In all cases the reactions afforded two products, trans and
geminal olefins, as expected[41] (except for entry 5). Compar-
ing entries 5 with 6, and 1 with 7, shows that chelating
ligands on zero‐valent Pd favour oxidative addition. This is
a consequence of a bent geometry for the M0(C^C) fragment,

BAGHERZADEH ET AL.
3
TABLE 1 Palladium–NHC‐catalysed direct S‐arylation of methylphenyl sulfoxidea
Entry
Aryl halide
Base
Solvent
Dioxane
Yield (%)
1
2
3
4
5
6
7
Bromobenzene
NaH
10
43
61
82
73
82
35
Bromobenzene
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Dioxane
Dioxane
Toluene
Toluene
Toluene
Toluene
Bromobenzene
Bromobenzene
1‐Bromonaphthalene
4‐Bromotoluene
4‐Bromoacetophenone
a1 equiv. of methylphenyl sulfoxide, 2 equiv. of aryl halide, 3 equiv. of base, 10 mol% Pd(dba)2 and 20 mol% NHCs as ligand at 110 °C on 0.1 mmol scale for 24 h.
TABLE 2 Pd–(bis‐NHC)‐catalysed Heck reaction of aryl halides with n‐butyl acrylatea
Selectivity (%)
Entry
Aryl halide
Pd salt
Base
K2CO3
GC yield. (%)
cis
trans
gem
1
4‐Bromobenzaldehyde
4‐Chlorobenzaldehyde
4‐Bromoacetophenone
4‐Bromoanisole
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
76
77
78
93
55
70
92
0
100
98
0
2
2
K2CO3
K2CO3
K2CO3
NEt3
0
0
0
2
0
0
3
100
98
0
4
5b
2
Benzyl chloride
98
0
6
4‐Bromotoluene
NaOAc
NaOAc
5
95
0
7
4‐Bromobenzaldehyde
100
a1 mmol of aryl halide, 1.5 mmol of butyl acrylate, 1.3 mmol of base, 0.01 mol% Pd salt, 0.01 mol% ligand, 3 ml of DMA, under argon atmosphere.
bReaction conditions reported by Heck and Nolley:[45] Pd(OAc)2, 0.01 mol%; benzyl chloride, 1 mmol; methyl acrylate, 1.3 mmol; NEt3, 1 mmol; 100 °C, 15 h, no sol-
vent, except for L1.
which has a high d‐orbital energy relative to linear M(L1).[39]
An unexpected selectivity to gem product was observed for
the coupling of butyl acrylate with 4‐bromotoluene (entry 6).
The formation of 2% of cis product (Table 2, entry 5)
persuaded us to examine the Heck reaction between benzyl
chloride and butyl acrylate in the presence of ligands L1 to
L3 to determine role of steric effect of the substituents on
the carbene ligands in selectivity of the reaction (Table 3).
Although previous studies of some analogous
palladium–NHC complexes show that different substituents
on carbene group have no effect on selectivity towards cis
product in the Heck reaction,[42] the results of the present
TABLE 3 Heck reaction between benzyl chloride and n‐butyl acrylate
Selectivity (%)
GC yield
Entry
Ligand
(%)
cis
trans
1
2
3
4
None
52
55
56
54
0
100
98
1
2
3
2
8
92
15
85

4
BAGHERZADEH ET AL.
the trans product should be obtained. Data in Table 3 show
that by increasing the steric effect of NHC ligands, the
selectivity towards cis product was improved, as predicted
by theoretical calculations.[34]
To provide support for the formation of gem isomer for
p‐bromotoluene substrate (Table 2, entry 6), DFT calcula-
tions have been performed. Two different intermediates, 4
and 5, were explored on the potential energy surface. The
intermediate 3 has the possibility of forming either inser-
tion product 4 or 5. But, the DFT studies showed that for
p‐bromotoluene the formation of 4 is more favourable than
of 5 (99 kcal mol−1). It seems that the difference between
theoretical data and our experiment can arise from the fact
this gem isomer is a kinetic product.[44]
SCHEME
4
Proposed mechanism for Pd–(bis‐NHC)‐catalysed Heck
reaction
3
| CONCLUSIONS
study (Table 3) indicate selectivity towards cis product is
increased with increasing steric effect of ligands
(L3 > L2 > L1).
Palladium salts and bidentate NHC ligands appear to be good
media for S‐arylation of methylphenyl sulfoxide and Heck
reactions. NMR analysis was employed to identify bis‐NHC
as ligand and the palladium complex. A variety of functional
groups of aryl halides were used in these coupling reactions.
For the first time, our report shows experimentally that by
using bulkier bidentate NHC ligands, catalytic systems can
be achieved with more selectivity towards cis products in
Heck coupling reactions.
The mechanism for the palladium‐catalysed Heck
arylation of butyl acrylate in the presence of palladium–
NHC catalyst is proposed as shown in Scheme 4. Here the
oxidative addition of aryl bromide to active palladium
catalyst 1 results in the formation of a σ‐arylpalladium
species (2). Insertion of butyl acrylate into palladium–aryl
bond gives the intermediate 4 or 5 (path 1 or 2) and finally
syn‐elimination from these intermediates affords the arylated
products and simultaneous regeneration of the initial
palladium active catalyst. It seems that the stereoselectivity
of the reaction toward gem or trans/cis products is caused
by the formation of the key intermediate 4 or 5. 1,2‐Insertion
of butyl acrylate into palladium–aryl bond from path 1 gives
the intermediate 4, whereas 1,2‐insertion of butyl acrylate
into palladium–aryl bond through path 2 affords intermediate
5. However, stereoselectivity toward cis or trans isomers is
caused by the reductive elimination from two different
conformations of 4 as shown in Scheme 5.
ACKNOWLEDGMENT
M.B. acknowledges the Research Council of Sharif University
of Technology for the research funding of this project.
REFERENCES
[1] E. Wojaczynska, J. Wojaczynski, Chem. Rev. 2010, 110, 4303.
[2] C. Bolm, Coord. Chem. Rev. 2003, 237, 245.
[3] I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111, 1596.
[4] I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337.
[5] C. C. Eichman, J. P. Stambuli, Molecules 2011, 16, 590.
[6] A. Chartoire, S. P. Nolan, ACS Catal. 2013, 3, 2190.
Two new bonds are formed in species 4 and, during this
bond formation, the R group can end up in the cis position
or the trans position. This intermediate has the ability to
freely rotate, as seen in Scheme 5. Density functional theory
(DFT) calculations show that the energy for the cis elimina-
tion is higher because of steric repulsion, as the aryl rings
are forced into an eclipsed position.[34] According to studies
of phosphine ligands,[43] it was predicted that if more bulky
ligands are used, so relatively more of the cis and less of
[7] T. Jia, M. Zhang, I. K. Sagamanova, C. Y. Wang, P. J. Walsh, Org. Lett.
2015, 17, 1168.
[8] T. Jia, A. Bellomo, S. Montel, M. Zhang, K. El Baina, B. Zheng, P. J. Walsh,
Angew. Chem. Int. Ed. 2014, 53, 260.
[9] M. Bagherzadeh, M. Amini, P. G. Derakhshandeh, M. M. Haghdoost, J.
Iranian Chem, Soc. 2014, 11, 441.
[10] M. Amini, M. Bagherzadeh, S. Rostamnia, Chinese Chem. Lett. 2013, 24, 433.
[11] N. T. S. Phan, M. Van Der Sluys, C. W. Jones, Adv. Synth. Catal. 2006,
348, 609.
[12] A. Barau, V. Budarin, A. Caragheorgheopol, R. Luque, D. J. Macquarrie, A.
Prelle, V. S. Teodorescu, M. Zaharescu, Catal. Lett. 2008, 124, 204.
[13] N. Meric, M. Aydemir, U. Isik, Y. S. Ocak, K. Rafikova, S. Pasa, C. Kayan,
F. Durap, A. Zazybin, H. Temel, Appl. Organometal. Chem. 2014, 28, 818.
[14] S. Demir, I. Özdemir, B. Çetinkaya, Appl. Organometal. Chem. 2006,
20, 254.
[15] A. Slamani, S. Demir, İ. Özdemir, Catal. Commun. 2012, 29, 141.
SCHEME 5 Two different conformations of intermediate 4. Reductive
elimination from conformations a and b gives the trans and cis isomers,
respectively
[16] P. Zhou, H. Wang, J. Yang, J. Tang, D. Sun, W. Tang, Ind. Eng. Chem. Res.
2012, 51, 5743.

BAGHERZADEH ET AL.
5
[17] Q. Du, W. Zhang, H. Ma, J. Zheng, B. Zhou, Y. Li, Tetrahedron 2012, 68,
[36] M. Bagherzadeh, F. Ashouri, L. Hashemi, A. Morsali, INOCHE 2014,
44, 10.
3577.
[37] G. Maitro, G. Prestat, D. Madec, G. Poli, J. Org. Chem. 2006, 71, 7449.
[18] M. Kranenburg, Y. E. M. van der Burgt, P. C. J. Kamer, P. W. N. M. van
Leeuwen, K. Goubitz, J. Fraanje, Organometallics 1995, 14, 3081.
[38] T. Jia, A. Bellomo, K. E. L. Baina, S. D. Dreher, P. J. Walsh, J. Am. Chem.
Soc. 2013, 135, 3740.
[19] S. Nadri, M. Joshaghani, E. Rafiee, Organometallics 2009, 28, 6281.
[39] D. S. Mcguinness, N. Saendig, B. F. Yates, K. J. Cavell, Society 2001,
123, 4029.
[20] W. A. Herrmann, C. Brossmer, C.‐P. Reisinger, T. H. Riermeier, K. Öfele, M.
Beller, Chem. Eur. J. 1997, 3, 1357.
[40] W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G. R. J. Artus, Angew.
Chem. Int. Ed. Engl. 1995, 34, 2371.
[21] W. A. Herrmann, V. P. W. Böhm, C.‐P. Reisinger, J. Organometal. Chem.
1999, 576, 23.
[41] S. Gründemann, M. Albrecht, J. A. Loch, J. W. Faller, R. H. Crabtree,
[22] I. P. Beletskaya, A. N. Kashin, N. B. Karlstedt, A. V. Mitin, A. V. Cheprakov,
Organometallics 2001, 20, 5485.
G. M. Kazankov, J. Organometal. Chem. 2001, 629, 9393618.
[42] T. Yagyu, A. Tsubouchi, Y. Nishimura, J. Organometal. Chem. 2014, 767, 1.
[23] M. Kline, R. L. Harlow, J. Am. Chem. Soc. 1991, 113, 361.
[43] G. P. F. Van Strijdonck, M. D. K. Boele, P. C. J. Kamer, J. G. De Vries, P.
[24] D. Bourissou, O. Guerret, F. P. Gabbaï, G. Bertrand, Chem. Rev. 2000,
100, 39.
Van Leeuwen, Eur. J. Inorg. Chem. 1999, 1073.
[44] R. Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am Chem, Soc. 2011,
133, 19020.
[25] J. Schwarz, V. P. W. Böhm, M. G. Gardiner, M. Grosche, W. A. Herrmann,
W. Hieringer, G. Raudaschl‐Sieber, Chem. Eur. J. 2000, 6, 1773.
[45] R. F. Heck, J. P. Nolley Jr., J. Org. Chem. 1972, 37, 2320.
[26] J. Huang, G. Grasa, S. P. Nolan, Org. Lett. 1999, 1, 1307.
[27] H. M. Lee, T. Jiang, E. D. Stevens, S. P. Nolan, Organometallics 2001,
20, 1255.
SUPPORTING INFORMATION
Additional supporting information can be found in the online
[28] G. van Koten, Pure Appl, Chem. 1989, 61, 1681.
version of this article at the publisher’s website.
[29] M. Albrecht, G. van Koten, Angew. Chem. Int. Ed. Engl. 2001, 40, 3750.
[30] A. C. Hillier, S. P. Nolan, Platinum Met. Rev. 2002, 46, 50.
[31] W. A. Herrmann, V. P. W. Böhm, C. W. K. Gstöttmayr, M. Grosche, C.‐P.
Reisinger, T. Weskamp, J. Organometal. Chem. 2001, 617, 616.
How to cite this article: Bagherzadeh, M., Mousavi,
N.‐a., and Jamali, S. (2016), In situ generation of
highly active bis(N‐heterocyclic)carbene palladium as
an efficient catalyst in direct S‐arylation of
methylphenyl sulfoxide and the Heck reaction: Ligand
steric effects in product selectivity, Appl Organometal
Chem, doi: 10.1002/aoc.3677
[32] M. C. Done, T. Rüther, K. J. Cavell, M. Kilner, E. J. Peacock, N. Braussaud,
B. W. Skelton, A. White, J. Organometal. Chem. 2000, 607, 78.
[33] M. V. Baker, D. H. Brown, P. V. Simpson, B. W. Skelton, A. H. White, C. C.
Williams, J. Organometal. Chem. 2006, 691, 5845.
[34] C. Allolio, T. Strassner, J. Org. Chem. 2014, 79, 12096.
[35] N. Ghavale, S. T. Manjare, H. B. Singh, R. J. Butcher, Dalton Trans. 2015,
44, 11893.