A highly active and stable imidazolidine-bridged N,O-donor ligand for efficient palladium catalyzed Suzuki-Miyaura reactions in water

Article abstract of DOI:10.1007/s11243-012-9593-4

We have used the sterically hindered N,O-donor ligand 1,4-bis(2-hydroxy-3, 5-di-tert-butyl-benzyl)-imidazolidine with various Pd salts as a catalyst for the Suzuki reaction. This system exhibited excellent catalytic activity in Suzuki reactions of arylboronic acids with aryl halides, including aryl iodides, aryl bromides and activated aryl chlorides, using aqueous methanol as solvent under mild conditions. The catalytic system can be reused once without significant loss of activity. Graphical Abstract: The sterically hindered imidazolidine-bridged mixed nitrogen, oxygen ligand 1 was efficient for Pd-catalyzed Suzuki reactions involving aryl iodides, aryl bromides and activated aryl chlorides with arylboronic acid in aqueous methanol with K ₂CO₃ as a base the high catalytic activity and oxygen or moisture stable of palladium complexes maybe distribute to the bulky tert-butyl effect.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11243-012-9593-4

Transition Met Chem (2012) 37:331–335
DOI 10.1007/s11243-012-9593-4
A highly active and stable imidazolidine-bridged N,O-donor
ligand for efficient palladium catalyzed Suzuki–Miyaura reactions
in water
•
Jun Xue Zhonggao Zhou Yulan Liu
•
•
•
•
•
Li Huang Hongwei Yu Yongrong Xie
Chen Lai
Received: 21 January 2012 / Accepted: 22 February 2012 / Published online: 23 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract We have used the sterically hindered N,O-
donor ligand 1,4-bis(2-hydroxy-3,5-di-tert-butyl-benzyl)-
imidazolidine with various Pd salts as a catalyst for the
Suzuki reaction. This system exhibited excellent catalytic
activity in Suzuki reactions of arylboronic acids with aryl
halides, including aryl iodides, aryl bromides and activated
aryl chlorides, using aqueous methanol as solvent under
mild conditions. The catalytic system can be reused once
without significant loss of activity.
medicinal chemistry [4–6]. The reaction is generally cata-
lyzed by palladium complexes with or without supporting
ligands in organic solvents and, more recently, in aqueous
media [7–11]. Mixed donor ligands are very common in
such applications and can be linear, branched or cyclic,
with at least two different donor groups capable of chela-
tion to metal atoms [12–14]. The development of new
ligands bearing mixed donor atoms other than phosphorus
has been arousing more and more interest in the field of
organic chemistry, especially, in transition metal-catalyzed
coupling reactions [15–18].
Introduction
Previously, Mohanty et al. used piperazine-bridged
phenol ligands (ligands 2, 3 and 4 in Scheme 1) for Pd-
catalyzed Heck and Suzuki reactions. The presence of the
nitrogen atom in the piperazine ring seems to have a sig-
nificant effect on the catalytic activity in Pd-catalyzed C–C
bond-forming reactions [19, 20]. Our previous studies have
also revealed that ligands 2, 5 and 6 give high catalytic
activities for Suzuki reactions under mild conditions [21,
22]. Since imidazolidine-bridged bis-phenols can act as
anionic bifunctional ligands, rigid backbones that can
actually enforce a constrained geometry and, thereby, a
certain coordination mode can influence one or more
reaction steps of a catalytic cycle in several ways, for
example, stabilization or destabilization of the initial,
transition or final states [23]. Current technologies demand
new catalysts, which are inexpensive, readily accessible,
moisture- and air-stable and most importantly, highly
effective. In recent years, amine bis(phenolate) ligands
have received considerable attention in organometallic
chemistry [24]. It is expected that such ligands may have
high catalytic activity for C–C bond-forming reactions.
As a part of our interest in studying Pd-catalyzed cross-
coupling reactions and the use of mixed donor N,O-ligands
in catalytic applications [21, 22, 25], we report herein on
The discovery of the Suzuki reaction is one of the most
important landmarks of modern day organic chemistry, as
recognized by the award of a Nobel Prize to Akira Suzuki
in 2010 [1–3]. The Suzuki reaction has been used in
numerous syntheses, in the areas of materials science and
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-012-9593-4) contains supplementary
material, which is available to authorized users.
J. Xue ꢀ Z. Zhou (&) ꢀ L. Huang ꢀ Y. Xie (&) ꢀ C. Lai
College of Chemistry and Chemical Engineering,
Gannan Normal University, Ganzhou 341000,
People’s Republic of China
e-mail: zhgzhou@foxmail.com
Y. Xie
e-mail: yongrongxie@foxmail.com
Y. Liu
College of Architecture and Environment, Sichuan University,
Chengdu 610207, People’s Republic of China
H. Yu
School of Chemical Engineering, Shijiazhuang University,
Shijiazhang 050035, People’s Republic of China
123

332
Transition Met Chem (2012) 37:331–335
t
t
imidazolidine ring), 1.49 (s, 18H, Bu), 1.34 (s, 18H, Bu)
ppm. 13C NMR (100 MHz, CDCl3): d 154.16, 140.75,
135.75, 123.35, 123.12, 120.88, 74.40, 59.27, 51.80, 34.94,
1
31.73, 29.68 ppm. The H NMR spectrum of 1 shows a
broad singlet at 10.76 ppm for the phenolic OH protons,
similar to ligand 2. The presence of OH proton was con-
firmed by a D2O exchange experiment.
General procedure for the Suzuki reaction
The appropriate amounts of ligand and metal precursor were
added to the required solvent (3.0 mL). The mixture was
stirred for 5 min, and then the aryl halide (0.5 mmol),
phenylboronic acid (0.75 mmol), and base (1.0 mmol) were
added and the mixture was stirred and reacted under an inert
atmosphere. The course of the reaction was monitored by
GC–MS analysis, and yields were calculated against the aryl
halides. On completion of the reaction, the solvent was
removed under reduced pressure. The residue was diluted
with H2O (3.0 mL) and Et2O (3.0 mL), followed by
extraction with Et2O (2 9 3.0 mL). The organic fraction
was dried over anhydrous MgSO4 and then filtered, and the
solvent was evaporated under reduced pressure. The crude
product that was purified by column chromatography using
100–200 mesh silica gel and the purified products were
Scheme 1 Structures of selected ligands. 3, R1–R2 = –(CH)4–; 4,
R1 = H, R2 = tBu; 5, R3 = Me; 6, R3 = Ph
air- and moisture-stable palladium complexes of the imi-
dazolidine-bridged phenol ligand 1 in Suzuki–Miyaura
reactions of aryl iodides, aryl bromides, and activated aryl
chlorides in aqueous media under mild conditions.
Experimental
All starting materials and reagents were purchased from
Sigma-Aldrich or Alfa Aesar and used as received. Solvents
were dried with standard methods and freshly distilled prior
to use. 1,4-bis(2-hydroxy-3,5-di-tert-butyl-benzyl)-imidaz-
olidine (1) was prepared by a modification of the literature
method (see below) [24]. NMR spectra were recorded on a
Bruker Avance III 400 MHz (1H 400 MHz, 13C 100 MHz)
spectrometer. The NMR studies were carried out using
CDCl3 as solvent, and signals are quoted in ppm as d
downfield from TMS as internal standard.
1
characterized by comparing their H NMR spectra with
those found in the literature; 4-methoxybiphenyl (Table 6,
entries 1, 5 and 14) [26]; 4-methylbiphenyl (Table 6, entries
2, 3, and 12) [19]; 2-methylbiphenyl (Table 6, entries 4 and
13) [26]; 4-acetylbiphenyl (Table 6, entries 6 and 15) [19];
biphenyl (Table 6, entries
7 and 11) [27]; 4-trif-
luoromethylbiphenyl (Table 6, entries 8, 9 and 10) [21];
4,40-dimethylbiphenyl (Table 6, entries 16 and 18) [28];
4-methoxyl-40-methyl-1,10-biphenyl (Table 6, entries 17
and 19) [29].
GC–MS analyses were carried out on an Agilent 6,890
GC with 5,973 mass spectrometer, using an AT.SE-30
column of 50 m length, 0.32 mm diameter and 0.5 lm film
thicknesses. GC parameters for Suzuki reactions were as
follows: injector temperature, 280 °C; detector tempera-
ture, 280 °C; initial temperature, 60 °C; initial time, 5 min;
temperature ramp 1, 30 °C min-1; final temperature,
200 °C; ramp 2, 20 °C min-1; final temperature, 250 °C;
run time, 25 min; inject, 1.0 lL; helium carrier gas; system
pressure, 3.5 bar.
Results and discussion
The Mannich reaction is a convenient method to synthesize
amine bridged bis(phenol)s. Shen and co-workers have
reported the synthesis of ligand 1 in methanol at 60 °C oil
bath in 65% yield [24]. We have developed an alternative
atom-economic synthesis of ligand 1, giving a yield of 91%
within 2.5 h (Scheme 2).
A mixture of ethylenediamine (1.34 mL, 0.020 mol) and
40% aqueous formaldehyde solution (6.57 mL, 0.080 mol)
was stirred at room temperature for 0.5 h, and then 2,4-di-
tert-butylphenol (8.25 g, 0.040 mol) was added and the
mixture was stirred for 2.0 h at 90 °C oil bath. The
resulting solid was washed with hot methanol (100 mL),
and the white solid precipitate was collected by vacuum
filtration; yield, 9.26 g (91%). Mp: 183.9–184.2 °C
1
(184.1–184.5 °C). H NMR (400 MHz, CDCl3): d 10.76
(br, 2H, OH), 7.29 (s, 2H, Ph), 6.90 (s, 2H, Ph), 3.95 (s, 4H,
Scheme 2 Modified experimental procedure for the preparation of
ligand 1
CH2), 3.59 (s, 2H, imidazolidine ring), 3.06 (br, 4H,
123

Transition Met Chem (2012) 37:331–335
333
Table 2 Effect of solvents on the Suzuki reaction
Entry
Solvent
Time (h)
Yield (%)a
Scheme 3 Pd-catalyzed Suzuki reaction of 4-bromotoluene with
phenylboronic acid
1
Ethanol
3
3
85
97
75
82
85
70
90
95
85
91
99
83
2
Methanol
3
Water
12
3
4
Acetone
Table 1 Effect of different bases on the Suzuki reaction
5
Toluene
24
12
3
Entry
Base
Yield (%)a
6
Chloroform
7
Ethanol ? water (5%)
Methanol ? water (5%)
Acetone ? water (5%)
Ethanol ? water (50%)
Methanol ? water (50%)
Methanol ? water (60%)
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
K3PO4
KOH
96
97
98
92
91
96
85
65
90
8
3
9
12
3
10
11
12
3
Na2CO3
t-BuONa
NaOH
LiCl
3
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst (1.0 mol%,), K2CO3 (2.0 equiv), solvent
(3.0 mL), room temperature
Et3N
a
Average of two runs, measured by GC
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst 1.0 mol %, Pd(COD)Cl2:1 = 1:1, base (2.0
equiv), methanol (3.0 mL), room temperature, 3 h
Therefore, the subsequent Suzuki reactions were performed
using this solvent/base combination.
a
Average of two runs, measured by GC
The palladium–ligand mole ratio and the palladium
source used frequently have a dramatic influence on Pd-
catalyzed Suzuki chemistry also [31–33]; thus, the best
palladium source and amount of ligand 1 added to the
Suzuki reaction were also studied. Several palladium
compounds were tested, and the best result were obtained
for Pd(COD)Cl2/1, giving 98% conversion with a 1:1.3 Pd–
ligand ratio (Table 3, entry 7). The yield decreased rapidly
when the Pd–L ratio was increased further (entries 9 and
10). Similar effects have been observed for other Pd-cat-
alyzed cross-coupling reactions [34]. We also confirmed
that the ligand-free catalytic system gave poor results (ca.
36% GC yield, entry 14). Next, the effect of concentration
of palladium was examined. The same experiment was
repeated using 0.5 mol% of palladium loading under
identical reaction conditions as above, where complete
consumption of the 4-bromotoluene was observed after 3 h
with 97% conversion (entry 11). However, 0.1 mol% pal-
ladium loading gave only 40% conversion (entry 12), and
raising the temperature to 100 °C only improved this to
82% (entry 13). Therefore, in all of the subsequent
experiments, a loading of 0.5 mol% of palladium and
1:1.3 mol ratio of Pd(COD)Cl2/1 was employed.
For our initial experiments, we chose 4-bromotoluene
and phenylboronic acid as standard substrates to optimize
the conditions for the Suzuki–Miyaura reaction in metha-
nol. Ligand 1 was combined with Pd(COD)Cl2 in situ to
give the catalyst (Scheme 3, Tables 1, 2). The inorganic
bases Cs2CO3, K2CO3, K3PO4, KOH and Na2CO3 and
organic bases t-BuONa and Et3N were investigated for the
coupling reaction. Most of these bases gave good to
excellent conversions (Table 1). The best yields were
obtained using K3PO4 or K2CO3 as base, and we chose
K2CO3 in the following Suzuki reactions.
Solvents have a key influence on the environmental
impact of chemical processes and also affect cost, safety
and health issues [8]. According to the green solvent
selection guide [30], water, acetone, ethanol and methanol
can be considered environmentally friendly, whereas the
use of dioxane, acetonitrile, acids, formaldehyde, toluene
and tetrahydrofuran is not recommended. To examine the
effects of solvent on the present system, a set of reactions
between 4-bromotoluene and phenylboronic acid catalyzed
by the catalyst [Pd(COD)Cl2:1 = 1:1] with a range of
solvents (Table 2) was carried out. Polar solvent such as
methanol proved to be more productive (entry 2). This may
be due to better catalyst solubility. Ligand 1 is insoluble in
cold water, and when the water content was increased from
5 to 60%, we found the optimum water content (entry 11).
Although non-polar solvents like toluene also gave good
conversions, these reactions required more time (entry 5).
To test the reusability of the catalyst system, we chose
the reaction of 4-bromotoluene with phenylboronic acid as
a model (Table 4), using methanol–water (1:1) as solvent,
After completion of each reaction without separation of the
products, the same amount of fresh substrate and reagent
was added and the reaction was completed within 3 h with
95% conversion (entry 2). Hence, the catalytic system can
123

334
Transition Met Chem (2012) 37:331–335
Table 3 Effect of palladium source and Pd:1 ratio on the Suzuki
reaction
Table 5 Suzuki reactions of aryl halides with arylboronic acids
Entry Aryl halide
Arylboronic acid
Time Yield
(%)a
Entry
Pd source
Pd:1 ratio
Yield (%)a
(h)
1
Pd(COD)Cl2
Pd(CF3COO)2
PdCl2
1:1
96
1
4-MeOC6H4I
4-MeC6H4I
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
0.5
100 (98)
100 (99)
97 (96)
95 (95)
98 (97)
99 (98)
100 (100)
75 (73)
81 (80)b
97 (94)c
83 (81)c
70 (70)c
68 (65)c
67 (65)c
75 (72)c
100 (99)
97 (96)
86 (85)c
69 (68)c
2
1:1
86
2
0.5
3
3
1:1
43
3
4-MeC6H4Br
2-MeC6H4Br
4-MeOC6H4Br
4
Pd2(dba)3
1:1
85
4
3
5
Pd(OAc)2
1:1
81
5
3
6
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
1:0.9
1:1.3
1:1.5
1:2.0
1:3.0
1:1.3
1:1.3
1:1.3
1:0
78
6
4-MeCOC6H4Br C6H5B(OH)2
3
7
98
7
C6H5Br
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
3
8
85
8
4-CF3C6H4Cl
4-CF3C6H4Cl
4-CF3C6H4Cl
C6H5Cl
6
9
56
9
6
10
11
12
13
14
15
37
10
11
12
13
14
15
16
17
18
19
6
97b
40c
82d
36
24
4-MeC6H4Cl
2-MeC6H4Cl
4-MeOC6H4Cl
24
24
24
24
3
0:1
Trace
4-MeCOC6H4Cl C6H5B(OH)2
4-MeC6H4Br
4-MeC6H4Br
4-MeC6H4Cl
4-MeC6H4Cl
4-MeC6H4B(OH)2
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst (Pd/1, 1.0 mol%), K2CO3 (2.0 equiv), metha-
nol–water (1:1, 3.0 mL), room temperature
4-MeOC6H4B(OH)2
4-MeC6H4B(OH)2
3
24
a
Average of two runs, measured by GC
4-MeOC6H4B(OH)2 24
b
Catalyst 0.5 mol%
Reaction conditions: aryl halide (0.5 mmol), arylboronic acid
(0.75 mmol), K2CO3 (2.0 equiv), catalyst (0.5 mol %), methanol–
water (1:1, 3.0 mL), room temperature
c
Catalyst 0.1 mol%
d
Catalyst 0.1 mol%, 100 °C
a
Average of two runs, isolated yields given in parentheses
b
Catalyst 1.0 mol%, 100 °C
Catalyst 2.0 mol%, 100 °C
c
Table 4 Reusability of the catalyst in the Suzuki reaction
Entry
Run
Time (h)
Yield (%)a
1
2
3
4
5
1
2
3
4
5
3
3
97
10), when the reaction was performed at 100 °C in the
presence of 2.0 mol% of catalyst. Chlorobenzene yields
biphenyl in 83% GC yield under the same conditions (entry
11); however, other aryl chlorides only gave moderate
yields.
95
12
12
12
76
55
Trace
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst (Pd(COD)Cl2:1 = 1:1.3, 0.5 mol %), metha-
nol–water (1:1, 3.0 mL), room temperature
Conclusion
a
Average of two runs, measured by GC
In summary, we have developed a new synthesis of ligand 1
and investigated the Pd(COD)Cl2/1 system for Suzuki
reactions. This bulky imidazolidine-bridged mixed N,O-
ligand proved to be an efficient catalyst for Suzuki chemistry,
and the stability toward oxygen and moisture explained by
the bulky tert-butyl substituents. Applications of this catalyst
for other C–C bond-forming reactions are currently being
investigated.
be reused once without significant loss of activity. How-
ever, the yield deceased in subsequent experiments.
Finally, the scope of the reaction was explored with a
range of aryl iodides, aryl bromides and aryl chlorides
under the optimized conditions (Table 5). Generally, aryl
iodides and bromides were converted to the corresponding
biaryl derivatives quantitatively, even at room temperature.
The reactions of aryl chlorides with arylboronic acids in the
presence of higher loadings of catalyst were carried out at
100 °C. A good yield was obtained with an activated aryl
chloride, namely 4-(trifluoromethyl) chlorobenzene (entry
Acknowledgments Financial support for this work was provided by
the National Natural Science Foundation of China (Contract No.
20861001 and 21061001), the Key Laboratory of Jiangxi University
for Functional Materials Chemistry and Gannan Normal University.
123

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335
19. Mohanty S, Suresh D, Balakrishna MS, Mague JT (2008) Tet-
rahedron 64:240–247
References
20. Mohanty S, Suresh D, Balakrishna MS, Mague JT (2009)
J Organomet Chem 694:2114–2121
21. Zhou ZG, Shi JC, Hu QS, Xie YR, Du ZY, Zhang SY (2011)
Appl Organomet Chem 25:616–619
22. Zhou ZG, Du ZY, Hu QS, Shi JC, Xie YR, Liu YL (2012)
Transition Met Chem 37:149–153
23. Kamer PCJ, van Leeuwen PWNM, Reek JNH (2001) Acc Chem
Res 34:895–904
24. Xu X, Yao Y, Zhang Y, Shen Q (2007) Inorg Chem 46:
3743–3751
25. Zheng J, Zhou ZG, Tong QS, Jiang F, Jia L, Lin JH, Shi JC
(2011) Chin J Org Chem 31:324–327
26. Yu HW, Shi JC, Zhang H, Yang PY, Wang XP, Jin ZL (2006)
J Mol Catal A Chem 250:15–19
27. Hanhan M, Senemoglu Y (2012) Transition Met Chem 37:
109–116
28. Carrettin S, Guzman J, Corma A (2005) Angew Chem Int Ed
44:2242–2245
29. Kitamura Y, Sakurai A, Udzu T, Maegawa T, Monguchi Y, Sajiki
H (2007) Tetrahedron 63:10596–10602
30. Capello C, Fischer U, Hungerbu¨hler K (2007) Green Chem
9:927–934
31. Bedford RB, Cazin CSJ, Coles SJ, Gelbrich T, Horton PN,
Hursthouse MB, Light ME (2003) Organometallics 22:987–999
32. Littke AF, Fu GC (1998) Angew Chem Int Ed 37:3387–3388
33. Grasa GA, Viciu MS, Huang JK, Zhang CM, Trudell ML, Nolan
SP (2002) Organometallics 21:2866–2873
1. The Nobel Prize in Chemistry 2010-Press Release. http://nobelprize.
org/nobel_prizes/chemistry/laureates/2010/press.html
2. Miyaura N, Yamada K, Suzuki A (1979) Tetrahedron Lett
20:3437–3440
3. Suzuki A (2011) Angew Chem Int Ed 50:6722–6737
4. Magano J, Dunetz JR (2011) Chem Rev 111:2177–2250
´
5. Ard Molnar (2011) Chem Rev 111:2251–2320
6. Lakshmi V, Ravikanth M (2011) J Org Chem 76:8466–8471
7. Leadbeater NE, Marco M (2003) J Org Chem 68:888–892
8. Polshettiwar V, Decottignies A, Len C, Fihri
ChemSusChem 3:502–522
A (2010)
9. Tang WJ, Capacci AG, Wei XD, Li WJ, White A, Patel ND,
Savoie J, Gao JJ, Rodriguez S, Qu B, Haddad N, Lu BZ,
Krishnamurthy D, Yee NK, Senanayake CH (2010) Angew Chem
Int Ed 49:5879–5883
10. Lipshutz BH, Abela AR, Bo kovi V, Nishikata T, Duplais C,
Krasovskiy A (2010) Top Catal 53:985–990
11. Adrio LA, Nguyen BN, Guilera G, Livingston AG, Hii KK
(2012) Catal. Sci Technol 2:316–323
12. Lawrance GA (2005) Encyclopedia of Inorganic Chemistry
13. Bianchini C, Meli A (2002) Coord Chem Rev 225:35–66
14. Zeng FL, Yu ZK (2006) J Org Chem 71:5274–5281
15. Grach G (2011) Pieters Gg, Dinut A, Terrasson V, Medimagh R,
Bridoux A, Razafimahaleo V, Gaucher A, Marque S, Marrot Jrm,
Prim D, Gil R, Planas JG, Vin˜as C, Thomas I, Roblin J-P, Troin
Y. Organometallics 30:4074–4086
16. Mohanty S, Punji B, Balakrishna MS (2006) Polyhedron 25:
815–820
17. Fortman GC, Nolan SP (2011) Chem Soc Rev 40:5151–5169
18. Yang W, Liu C, Qiu J (2010) Chem Commun 46:2659–2661
34. Patil SA, Weng CM, Huang PC, Hong FE (2009) Tetrahedron
65:2889–2897
123