Efficient aqueous-phase heck reaction catalyzed by a robust hydrophilic pyridine-bridged bisbenzimidazolylidene-palladium pincer complex

Article abstract of DOI:10.1055/s-0030-1259723

The first efficient example of NHC-palladium pincer complex catalyzed aqueous Heck reaction with extremely low catalyst loading was realized without obvious hydrolysis of products by using a robust hydrophilic pyridine-bridged bisbenzimidazolylidene-palla

Full text of DOI:10.1055/s-0030-1259723

LETTER
951
Efficient Aqueous-Phase Heck Reaction Catalyzed by a Robust Hydrophilic
Pyridine-Bridged Bisbenzimidazolylidene–Palladium Pincer Complex
Effi ci ent
A
queo
h
us-Phas e
H
e
i
c
k
Rea
x
ct ion un Wang, Xike Feng, Weiwei Fang, Tao Tu*
Department of Chemistry, Fudan University, 220 Handan Road, 200433 Shanghai, P. R. of China
Fax +86(21)55664250; E-mail: taotu@fudan.edu.cn
Received 20 December 2010
Dedicated to Prof. Xiyan Lu and Prof. Li-Xin Dai
have played crucial roles in many C–C bond-forming re-
Abstract: The first efficient example of NHC–palladium pincer
complex catalyzed aqueous Heck reaction with extremely low cat-
alyst loading was realized without obvious hydrolysis of products
by using a robust hydrophilic pyridine-bridged bisbenzimida-
actions in organic media, their application in aqueous sol-
vents is almost ignored.9 To the best of our knowledge,
there is no report on the NHC–metal complexes catalyzed
zolylidene–palladium complex as a molecular catalyst, which toler- aqueous Heck reaction. Hence, in this paper, we would
ated various electronic properties of substituted functional groups in
arenes.
like to present the first efficient example of NHC–palladi-
um-catalyzed aqueous Heck reaction.
Key words: aqueous phase, benzimidazole, Heck reaction, N-het-
Our recent work demonstrated that the robust pyridine-
erocyclic carbene, palladium
bridged palladium pincer complexes 1 (Figure 1) and their
precursors can not only gelate with a variety of solvents to
form stable gels with various potential in the gel catalysis
As one of the most versatile straightforward methodolo-
and chemical devices,10 but also exhibit their powerful
gies for C–C bond formation, palladium-catalyzed cross-
catalytic activities in homogenous coupling reactions
coupling reactions between aryl halides and olefins (Heck
even with extremely low catalyst loading.11 Further intro-
reactions1) played key roles in modern organic syntheses
ducing the carboxyl (COOH) as hydrophilic group into
the pincer skeleton, complex 2 showed excellent catalytic
with potential application in fine chemicals, pharmaceuti-
cal and material sciences.2,3 However, the most efficient
activity towards Suzuki–Miyaura coupling reactions in
reported Heck reactions are usually carried out in organic
aqueous media with a catalyst loading down to the ppm
solvents in the presence of phosphine ligands.4 In order to
scale.11a To extend our research in developing NHC–met-
minimize adverse impact of toxic solvents and air-sensi-
al complexes and their application in catalysis and mate-
tive phosphine ligands, considerable attention has been
rial sciences, we would like to explore the catalytic role of
hydrophilic palladium pincer complex 2 in the Heck reac-
tion under aqueous conditions.
focused on developing alternative ligands, nonclassical
solvents, and heterogeneous catalysts.5,6 In terms of cost,
nontoxicity, and easy processing, water is an attractive re-
action medium,6 whereas, in contrast with Suzuki–
+
X–
Miyaura coupling reactions, the examples of Heck reac-
tion carried out in aqueous phase are quite limited. In ad-
dition, most of these numbered cases required phosphine
N
N
N
ligands, and catalyst loading is usually 2–10 mol%.7 An-
other problem encountered in the aqueous Heck reaction
is hydrolysis of substrates and products when acrylates
were used, which dramatically hampered its applicability.
Therefore, it is very imperative and challenging to devel-
op suitable efficient phosphine-free catalytic systems and
apply them in the aqueous Heck reaction.
Pd
X
N
R
N
R
1, X = I, Br;
R = C4H9, C8H17 or C16H33
+
COOH
In contrast to phosphine ligands, N-heterocylic carbenes
(NHC) act as stronger s-donors and weaker p-acceptors,8
which can further increase electronic density at the metal
center and improve the catalytic activity. Moreover, the
stable carbon–metal bonds enforce their robustness
against air, moisture, and heat, which indicates NHC–
metal complexes as a preference option in the catalytic
aqueous reactions. Although, NHC–palladium complexes
Br–
N
N
N
Pd
Br
N
N
Bu
Bu
2
SYNLETT 2011, No. 7, pp 0951–0954
Advanced online publication: 10.03.2011
x
x.
x
x.
2
0
1
1
Figure 1 Pyridine-bridged palladium pincer complexes
DOI: 10.1055/s-0030-1259723; Art ID: W34810ST
© Georg Thieme Verlag Stuttgart · New York

952
Z. Wang et al.
LETTER
Initially, the standard reaction conditions for Suzuki–
Miyaura coupling reactions were applied directly in aque-
ous Heck reaction. However, with 50 ppm catalyst load-
ing and K2CO3 as a base, the reaction between
iodobenzene and tert-butyl acrylate at 100 °C turned out
in a disappointed yield (2%, Table 1, entry 1), which may
be aroused by the low solubility and hydrolysis of the tert-
butyl acrylate. In order to transfer the substrates into the
aqueous phase and enhance the reaction rate, quaternary
ammonium salts, tetrabutylammonium halides (TBAX),
were involved as an additive.7c Whereas, hydrolysis of the
substrates and product still occurred and resulted in low
isolated yields when inorganic bases, such as K2CO3,
were applied (33%, Table 1, entry 2). Then, various or-
ganic bases were examined, and the results were compiled
in Table 1 (entries 3–11). In the presence of tetrabutylam-
monium iodide (TBAI), Et3N (2.5 equiv) gave the best re-
sult (97%, Table 1, entry 5); more bulky (Table 1, entries
9 and 10) and basic organic (Table 1, entry 11) bases also
turned out to be less effective. Bromobenzene was not an
active substrate under this optimal reaction conditions and
resulted in a low yield (4%, Table 1, entry 6). Further de-
creasing the amount of TBAI or Et3N led to an unsatisfied
lower yield [Tables 1, 78% (entry 7) and 64% (entry 8) vs.
97% (entry 5)]. When n-butyl or methyl acrylate was ap-
plied in the standard reaction conditions, lower yields
were obtained [Tables 1, 87% (entry 12) and 51% (entry
13)]. Then efficiency of the catalyst was demonstrated in
the coupling of iodobenzene and tert-butyl acrylate using
a steadily reduced catalyst loading. When 5 ppm catalyst
loading was applied under the optimal conditions
(Table 1, entry 14), the reaction still gave a 41% yield
within 24 hours (TON: 8.2×105). Further reducing the cat-
alyst loading to 5 ppb resulted in still 5% isolated yield
with extended reaction time to 48 hours (TON: 1.1×107,
Table 1, entry 15).
Table 1 Optimization of Bases and Additives for the Heck Reaction
between Aryl Halides and Acrylates Catalyzed by Palladium Pincer
Complex 2 in Watera
O
complex 2
X
R
O
(0.005 mol%)
O
+
R
base, additive,
H2O, 100 °C
O
3a R = t-Bu
4
5
R = Bu
R = Me
Entry
1
X
I
Additive
none
Base
Time (h) Yield (%)b
K2CO3
K2CO3
Et3N
5
5
3a 2
2
I
TBAI
none
3a 33
3a 7
3
I
5
4
I
TBAB
TBAI
TBAI
TBAIc
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
Et3N
5
3a 60
3a 97
3a 4
5
I
Et3N
5
6
Br
I
Et3N
8
7
Et3N
5
3a 78
3a 64
3a 39
3a 16
3a trace
4 87
8
I
Et3Nd
i-Pr2NEt
DABCO
DBU
Et3N
5
9
I
8
10
11
12
13
14e
15f
I
8
I
8
I
5
I
Et3N
5
5 51
I
Et3N
24
48
3a 41
I
Et3N
3a 5
a Reaction conditions: aryl halide (1 mmol), acrylate (1.5 equiv), base
(2.5 equiv), TBAX (1 equiv), H2O (2 mL), palladium pincer complex
2 (50 ppm), 100 °C, air.
b Isolated yield.
c 0.5 equiv TBAI.
Under the optimal reaction conditions, the substrate scope
was investigated with various electronic and steric prop-
erties of aryl halides (Table 2, entries 1–12).12 p-Iodotolu-
ene gave 94% isolated yield within 5 hours (Table 2, entry
1). Further extending the reaction time to 18 hours, a
quantitative yield was observed without obvious hydroly-
sis of the product under reflux conditions (Table 2, entry
2). The relative position of the substituent in arenes slight-
ly affected the efficiency of the coupling process; in con-
trast with o- and p-iodotoluene (96% and >99%), m-
iodotoluene afforded 61% yield (Table 2, entries 2 and 4
vs. entry 3). Other substrates with an electronic-donating
group like o-iodoanisole also resulted in a good yield
(85%, Table 2, entry 5). When p-chloroiodobenzene was
used, the reaction only occurred at the iodic side in a good
yield (93%, Table 2, entry 6), which clearly indicated that
chloroarenes are not suitable substrates in such low cata-
lyst loading. To our delight, the standard protocol also tol-
erated electronic-deficient substituents, good isolated
yields were afforded by o-trifluoromethyl-, p-fluoro-, and
acetyl-iodoarenes (79–96%, Table 2, entries 7–9). In ad-
dition, the hydro-sensitive substrate, for example, ethyl-
d With 1.2 equiv base.
e With 5 ppm catalyst loading.
f. With 5 ppb catalyst loading.
iodobenzonate, still endured aqueous reflux conditions
and turned out a good yield (87%, Table 2, entry 10).
However, when more sterically demanding and heterocyl-
ic substrates, such as 1-iodonaphthalene and 3-iodopyri-
dine, were applied, low yields were found (29% and 3%,
Table 2, entries 11 and 12).
Our study on the Suzuki–Miyaura couplings indicated
that palladium pincer complex 2 acts as molecular catalyst
other than palladium nanoparticle.11a With 50 ppm cata-
lyst loading of complex 2, our protocol exhibited slightly
less powerful in Heck reactions than in Suzuki–Miyaura
coupling reactions, however, we still expect a molecular
catalytic active species containing the pincer ligand that
was involved in the transformation, similar to that previ-
ously reported by Crabtree13 and us. Therefore, a set of
mercury tests was involved in the poisoning experiments
under the standard conditions with iodobenzene and tert-
Synlett 2011, No. 7, 951–954 © Thieme Stuttgart · New York

LETTER
Efficient Aqueous-Phase Heck Reaction
953
Table 2 Heck Reaction of Iodoarenes with tert-Butyl Acrylate Catalyzed by Palladium Pincer Complex 2 in Aqueous Phasea
O
I
O
complex 2 (0.005 mol%)
+
R
O
Et3N, TBAI, H2O, 100 °C
O
R
3b–l
Entry
1
Iodoarene
Time (h)
Yield (%)b
3b 94
3b >99
3c 61
3d 96
3e 85
3f 93
4-iodotoluene
4-iodotoluene
3-iodotoluene
2-iodotoluene
2-iodoanisole
5
18
8
2
3
4
18
8
5
6
1-chloro-4-iodobenzene
1-fluoro-4-iodobenzene
24
18
5
7
3g 96
3h 80
3i 79
8
1-iodo-2-(trifluoromethyl)benzene
4-iodoacetophone
9
12
8
10
11
12
ethyl 4-iodobenzoate
1-iodonaphthalene
3j 87
8
3k 29
3-iodopyridine
8
3l
3
a Reaction carried out in H2O under air.
b Isolated yield.
butyl acrylate. With 50 ppm catalyst loading, one drop of strain the process. Therefore, overdose PVPy (300 equiv
Hg (with excess amount respect to the palladium species) in respect to the palladium source) was also included in
was added onto reaction mixture after 0, 1, and 3 hours, the catalyst-poisoning experiments. A 69% isolated yield
and after 18 hours reflux, the reaction resulted in 9%, without obvious hydrolysis after 18 hours further con-
18%, and 61% isolated yields, respectively, with obvious firmed that the molecular catalyst played the real role in
hydrolysis of the byproduct (Table 3, entries 1–4), which the reaction, although 3-iodopyridine is not a good sub-
indicated that mercury may not inhibit the reaction pro- strate for the transformation (Table 2, entry 12).
cess completely, and the transformation may involve the
In summary, we presented the first example of NHC–pal-
molecular catalytic route. In order to avoid hydrolysis
ladium complex catalyzed aqueous Heck reaction with
possibly aroused by Hg droplets, poly(4-vinylpridine)
extremely low catalyst loading by using hydrophilic pyri-
(PVPy) was then involved in the catalyst-poisoning ex-
dine-bridged bisbenzimidazolylidene–palladium pincer
complex 2 as an efficient molecular catalyst. In the pres-
ence of Et3N and TBAI, the protocol tolerated various
periment. Because pyridine-type ligands possess the abil-
ity to efficiently chelate metallic palladium nanoparticles,
and the resulting coordinated complex could totally re-
electronic properties of substituted functional groups in
arenes. In addition, the hydrolysis of the substrates and
products could be efficiently inhibited in the reflux condi-
tions, which further extend the aqueous reaction scope of
pincer complex 2.
Table 3 Catalyst Poisoning Experiments in Aqueous Conditionsa
Entry
Additive
Time (h) Yield (%)b
1
2
3
4
5
Hg (1 drop after 0 min)
Hg (1 drop after 0 min)
Hg (1 drop after 1 h)
Hg (1 drop after 3 h)
5
18
18
18
5
9
Acknowledgment
Financial support from the National Science Foundation of China
(No. 20902011), the Shanghai Municipal Science and Technology
Commission (Qimingxing Program No. 10QA1400500), the
Shanghai Leading Academic Discipline Project (B108), and Shang-
hai Key Laboratory of Molecular Catalysts and Innovative Materi-
als (2010MCIMKF04), Department of Chemistry, Fudan
University is gratefully acknowledgement. We thank Prof. Shu-Li
You and Mingli Deng for technical support (GC-MS and CEM Dis-
cover microwave instrument).
18
61
69
PVPy (300 equiv of Pd after 0 min) 18
a Reaction carried out in H2O under air.
b Isolated yield.
Synlett 2011, No. 7, 951–954 © Thieme Stuttgart · New York

954
Z. Wang et al.
LETTER
(8) For recent reviews, see: (a) Hahn, F. E.; Jahnke, M. C.
References and Notes
Angew. Chem. Int. Ed. 2008, 47, 3122. (b) Crabtree, R. H.
Coord. Chem. Rev. 2007, 251, 596. (c) N-Heterocyclic
Carbenes in Transition Metal Catalysis, In Topics in
Organometallic Chemistry, Vol. 21; Glorius, F., Ed.;
Springer: Berlin, 2007, 1–218. (d) Marion, N.; Díez-
González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46,
2988. (e) Kühl, O. Chem. Soc. Rev. 2007, 36, 592. (f)Hahn,
F. E. Angew. Chem. Int. Ed. 2006, 45, 1348.
(1) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) Heck,
R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37, 2320.
(c) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
1971, 44, 581.
(2) For selected recent reviews of Heck reaction, see:
(a) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351,
3027. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. Int. Ed. 2005, 44, 4442. (c) Dounay, A. B.; Overman,
L. E. Chem. Rev. 2003, 103, 2945. (d) Whitcombe, N. J.;
Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
(e) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009.
(3) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A.; Diederich, F., Eds.; John Wiley and Sons:
New York, 2004. (b) Transition Metals for Organic
Synthesis Building Blocks and Fine Chemicals, Vol. 1;
Beller, M.; Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998.
(c) Comprehensive Organic Synthesis, Vol. 4; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991. (d) Heck,
R. F. Org. React. 1982, 27, 345.
(4) Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M.
Chem. Soc. Rev. 2009, 38, 1099; and references therein.
(5) (a) Alonso, D. A.; Nájera, C. Chem. Soc. Rev. 2010, 39,
2891. (b) Pan, D.; Jiao, N. Synlett 2010, 1577. (c) Modern
Arylation Methods; Ackermann, L., Ed.; Wiley-VCH:
Weinheim, 2009.
(9) Fleckenstein, C.; Roy, S.; Leuthäußer, S.; Plenio, H. Chem.
Commun. 2007, 2870.
(10) (a) Tu, T.; Bao, X.; Assenmacher, W.; Peterlik, H.; Daniels,
J.; Dötz, K. H. Chem. Eur. J. 2009, 15, 1853. (b) Tu, T.;
Assenmacher, W.; Peterlik, H.; Schnakenburg, G.; Dötz, K.
H. Angew. Chem. Int. Ed. 2008, 47, 7127. (c) Tu, T.;
Assenmacher, W.; Peterlik, H.; Weisbarth, R.; Nieger, M.;
Dötz, K. H. Angew. Chem. Int. Ed. 2007, 46, 6368.
(11) (a) Tu, T.; Feng, X.; Wang, Z.; Liu, X. Dalton Trans. 2010,
10598. (b) Tu, T.; Mao, H.; Herbert, C.; Xu, M.; Dötz, K. H.
Chem. Commun. 2010, 46, 7796. (c) Tu, T.; Malineni, J.;
Bao, X.; Dötz, K. H. Adv. Synth. Catal. 2009, 351, 1029.
(d) Tu, T.; Malineni, J.; Dötz, K. H. Adv. Synth. Catal. 2008,
350, 1791.
(12) General Procedure for the Aqueous Heck Reactions
Catalyzed by Palladium Complex 2
Palladium pincer complex 2 (50 ppm) was added to the 5 mL
flask containing iodoarene (1 mmol), acrylate (1.5 mmol),
Et3N (2.5 mmol), and TBAI (1 mmol) in H2O (2 mL) under
air. After heating at 100 °C for certain time (monitored by
TLC), the reaction mixture was allowed to cool to r.t., and
the aqueous layer was extracted with EtOAc (5 × 3 mL). The
combined organic extracts were dried over anhydrous
Na2SO4. After evaporation under vacuum, the crude product
was purified by flash column chromatography (hexane–
EtOAc, 100:1).
(6) (a) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
(b) Carril, M.; SanMartin, R.; Dominguez, E. Chem. Soc.
Rev. 2008, 37, 639. (c) Comprehensive Organic Reactions
in Aqueous Media, 2nd ed.; Li, C. J.; Chan, T. H., Eds.;
Wiley: New York, 2007. (d) Li, C. J. Chem. Rev. 2005, 105,
3095. (e) Aqueous-Phase Organometallic Catalysis:
Concepts and Applications, 2nd ed.; Cornils, B.; Herrmann,
W. A., Eds.; Wiley-VCH: Weinheim, 2004. (f) Organic
Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional: London, 1998.
(13) (a) Peris, E.; Crabtree, R. H. Coord. Chem. Rev. 2004, 248,
2239. (b) Peris, E.; Loch, J. A.; Mata, J.; Crabtree, R. H.
Chem. Commun. 2001, 201.
(7) (a) Mauger, C. C.; Mignani, G. A. Aldrichimica Acta 2006,
39, 17. (b) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(c) Jeffery, T. Tetrahedron Lett. 1994, 35, 3051.
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