PEG350-based di-(2-pyridyl)methylamine as a ligand in the Pd-catalyzed water Suzuki-Miyaura reaction of aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2008.10.018

The synthesis of new hydrosoluble PEG-based ligand derived from di-(2-pyridyl)methylamine has been developed. The catalytic performance of this ligand is demonstrated in Suzuki-Miyaura reactions between aryl chlorides and arylboronic acids and using water as solvent.

Full text of DOI:10.1016/j.tetlet.2008.10.018

Tetrahedron Letters 49 (2008) 7217–7219
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PEG350-based di-(2-pyridyl)methylamine as a ligand in the Pd-catalyzed
water Suzuki–Miyaura reaction of aryl chlorides
Ouissam Adidou a,b, Catherine Goux-Henry a, Mohamed Safi b, Mohamed Soufiaoui c, Eric Framery a,
*
a ICBMS, UMR-CNRS 5246, Equipe Synthèse Asymétrique, Université de Lyon, Université Lyon 1, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France
b Faculté des Sciences et Techniques, BP 146, Cité Yasmina, Mohammedia, Morocco
c Université Mohamed V, Faculté des Sciences, Avenue Ibn Batouba, Rabat, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new hydrosoluble PEG-based ligand derived from di-(2-pyridyl)methylamine has been
developed. The catalytic performance of this ligand is demonstrated in Suzuki–Miyaura reactions
between aryl chlorides and arylboronic acids and using water as solvent.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 June 2008
Revised 30 September 2008
Accepted 3 October 2008
Available online 8 October 2008
Keywords:
Hydrosoluble ligand
Suzuki–Miyaura reaction
PEG
Di-(2-pyridyl)methylamine
The biaryl compounds constitute one of the most important
building blocks for the synthesis of pharmaceuticals, herbicides,
polymers, materials, liquid crystals, and ligands. And one of the
most attractive synthetic routes for the preparation of these com-
pounds is the palladium-catalyzed cross-coupling reaction of aryl
halides with boronic acids, so-called Suzuki–Miyaura reaction.1
From an environmental as well from an economic point of view,
an alternative to the organic solvents is the use of water,2 or the
immobilization of the catalyst in a liquid phase such as ionic liq-
uids.3 The ionic liquids are very expensive, and their toxicity and
environmental effect are for the most part unknown. The catalytic
reactions performed in water require water-soluble catalysts.
Among numerous water-soluble ligands,4 sulfonated ligands are
probably the most known. Another way is the use of poly(ethylene
glycol) (PEG) and its monomethyl ethers.5 They are known to be
inexpensive, thermally stable, and nontoxic. They can be used to
recover catalysts and ligands in organic synthesis,6 or used as an
COR
N
NHCOR
N
N
N
N
2
1
Figure 1. Bipyridine ligands.
or aqueous solvent under homogeneous conditions.11 This last type
of Pd-complexes have been anchored to an organic or inorganic
matrix like styrene-maleic anhydride copolymer12 or silica ma-
trix.13 These functionalized materials provide recyclable catalysts
for these C–C bond formation reactions.
Prompted by the results of the ligands based on di-2-pyridyl-
methylamine, we propose to functionalize the same ligand with
a PEG arm, in order to use it in the Suzuki–Miyaura reaction with
water as solvent. Here, we describe the preparation of the PEG350
based di-2-pyridylmethylamine ligand 3 from commercial di-(2-
pyridyl)methanone 4 (Scheme 1).
-
7
8
9
alternative solvent. For example, PEG400, PEG2000, and PEG6000
have been used as solvent in the Suzuki–Miyaura reactions with
catalysts derived or not from PEG.
According to literature,14 the di-2-pyridylmethylamine 5 was
prepared in two steps from derivative 4: preparation of the oxime
followed by Zn-reduction of the oxime. After Jones’ oxidation of
polyethylene glycol monomethylether with an average molecular
weight of 350 g/mol (PEG350, purchased to Alfa Aesar Company),
the corresponding carboxylic acid was coupled with amino com-
pound 5 in a THF–CH2Cl2 solution in the presence of 1-[3-dimeth-
ylaminopropyl]-3-ethylcarbodiimide hydrochloride (EDCꢀHCl), 1-
hydroxybenzotriazole (HOBT), and NaHCO3, afforded PEG350-based
The N,N-ligands (Fig. 1), like di-2-pyridylamine-derived ligands
1,10 have proven to be efficient catalysts for C–C and C–N bond
forming reactions. And the Pd-complexes based on ligand 2 de-
rived from di-2-pyridylmethylamine are also efficient catalysts
for Heck, Suzuki–Miyaura, and Sonogashira reactions in organic
* Corresponding author. Tel.: +33 472 446 263; fax: +33 472 448 160.
E-mail address: framery@univ-lyon1.fr (E. Framery).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.018

7218
O. Adidou et al. / Tetrahedron Letters 49 (2008) 7217–7219
base, and of 0.5 equiv of tetrabutylammonium bromide (TBAB) as
O
NH2
an additive as described in the literature.11a Since the molecular
weight of the PEG350 is not well defined, in order to prepare the
Pd-catalyst, the amount of ligand 3 was determined from the nitro-
gen analysis.
N
N
N
N
N
Ref. 14
4
5
Before testing the potential of the PEG350-based di-2-pyridyl-
methylamine ligand 3, we studied the cross-coupling of 1-chloro-
4-nitrobenzene (Table 1, entry 1) with 1.1 equiv of phenylboronic
acid using a ‘ligandless’ palladium catalyst. No reaction occurred.
It is well known that the ligand-free Pd(OAc) is able to catalyze
the coupling reaction of aryl iodides and activated or desactivated
aryl bromides;18 however, in the case of aryl chlorides, tempera-
tures higher than 150 °C or microwave assistance are necessary
in order to perform efficiently this cross-coupling reaction.19 Using
ligand 3, aryl chlorides bearing electron-withdrawing or electron-
donating groups reacted with various arylboronic acids affording
the corresponding biaryl compounds in excellent yields (>85%) (Ta-
ble 1, entries 2–12). When compared with the ligands derived from
di-2-pyridylmethylamine described in the literature,11a,b,12,13 the
same reactivity was observed, with good TON values up to 9800
when the reaction was performed with 0.01 mol % of Pd-catalyst
(Table 1, entry 5).
NH2
+ PEG350-CO2H
EDC.HCl / HOBT
NaHCO3
THF - CH2Cl2
N
5
O
HN
PEG350
N
N
3
Scheme 1. Preparation of PEG-based di-2-pyridylmethylamine ligand 3.
In the literature,12,13 the study of the recycling Pd-catalyst is
only described when the catalyst is anchored to organic or inor-
ganic matrix. Whatever the type of support used for the Pd-cata-
lyst, in the case of the cross-coupling reaction with aryl chlorides
and arylboronic acids, a significant decrease of conversion is
observed from the second run. The recycling of the Pd-catalyst
di-2-pyridylmethylamine ligand 3 in 76% yield evaluated from the
elemental analysis.15 On the 1H and 13C NMR spectra, the signals
corresponding to the proton and carbon of the di-2-pyridylmethyl-
amine were observed in addition to the signals of the PEG, and sev-
eral changes before and after condensation can be cited
(seeSupplementary data). The chemical shifts of the proton linked
to C-1 of di-(2-pyridyl)methylamine’s unit moved d 5.32 to
6.29 ppm. The chemical shifts of both carbons C-1 and C-2 of di-
(2-pyridyl)methylamine’s unit moved d 62.5 to 59.2 ppm and d
162.8 to 159.3 ppm, respectively, confirming that the di-(2-pyri-
dyl)methylamine’s part and the PEG arm were well linked
together.
Knowing that the water influences favorably the activity of Su-
zuki–Miyaura catalyst,16 the cross-coupling reaction in this solvent
was investigated using various aryl halides and arylboronic acids.
The results are summarized in Table 1. The reactions17 were car-
ried out in water (0.08 M) at 100 °C for 15 h, and were catalyzed
with 0.1 or 0.01 mol % of Pd-catalyst prepared in situ from
Pd(OAc)2 and ligand 3, in the presence of 2 equiv of K2CO3 as a
derived from PEG350-based di-2-pyridylmethylamine ligand
3
was also studied in the case of the Suzuki–Miyaura reaction with
1-chloro-4-nitrobenzene and phenylboronic acid. Unfortunately,
the yield of the coupling product decreased drastically to 30% from
the second cycle. We explain it by the high solubility of Pd-catalyst
in the both organic and aqueous phases. And after the first treat-
ment, a large amount of Pd-catalyst was lost.
In conclusion, the synthesis of new hydrosoluble PEG-based li-
gand derived from di-(2-pyridyl)methylamine has been described.
This ligand has been used in the palladium Suzuki–Miyaura cross-
coupling reactions. The efficiency of this ligand has been demon-
strated in a wide range of couplings between aryl chlorides and
arylboronic acids. With only 1.1 equiv of arylboronic acid in rela-
tion to aryl chloride, the conversions and the chemical yields are
generally high, with excellent TON up to 9800 when 0.01 mol %
Pd-catalyst is used. Work is in progress actually in order to study
recycling Pd-catalyst from new ligand derived of di-(2-pyr-
idyl)methylamine with a PEG arm having an higher molecular
weight in order to increase its solubility in water, and so to have
a better extraction.
Table 1
Suzuki–Miyaura cross-coupling reactions of aryl chlorides and arylboronic acids with
Pd(OAc)2/3a
[Pd]
Ar-Cl
+
Ar'-B(OH)2
Ar-Ar'
100 °C,15 h
Acknowledgment
Entry
Ar–Cl
Ar0–B(OH)2
Yieldb (%)
TON
We are grateful for financial support from the Rhône Alpes
state.
1c
2
3
4-NO2
4-NO2
4-MeCO
4-CN
4-CN
2-NO2
4-Me
4-NO2
4-NO2
4-CN
2-NO2
2-NO2
H
H
H
H
H
H
H
0
99
98
99
98
99
90
99
93
86
85
85
0
990
980
990
9800
990
900
990
930
860
850
850
4
Supplementary data
5d
6
Supplementary data (1H and 13C NMR spectra of compounds 3
and 5) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2008.10.018.
7
8
9
10
11
12
4-MeO
4-Me
4-Me
4-Me
2-Me
References and notes
a
[Ar–Cl] = 0.08 M,
[Ar–Cl]/[Ar–B(OH)2]/[K2CO3]/[Pd(OAc)2]/[Ligand]/[TBAB] =
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
2. (a) Sinou, D. Adv. Synth. Catal. 2002, 344, 221–237; (b) Manabe, K.; Kobayashi, S.
Chem. Eur. J. 2002, 8, 4095–4101; (c) Franzén, R.; Xu, Y. Can. J. Chem. 2005, 83,
1.0:1.1:2.0:0.001:0.001:0.5.
b
Isolated chemical yield after column chromatography.
Reaction performed without ligand.
c
d
Reaction performed with 0.01 mol % of Pd-catalyst.

O. Adidou et al. / Tetrahedron Letters 49 (2008) 7217–7219
7219
266–272; (d) Li, C.-J. Chem. Rev. 2005, 105, 3095–3165; (e) Hailes, H. C. Org.
Process Res. Dev. 2007, 11, 114–120.
3. Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH:
Weinheim, 2003.
15. A mixture of 5 (4.3 mmol, 0.79 g), PEG350–CO2H (4.3 mmol, 1.50 g), EDCꢀHCl
(6.9 mmol, 1.32 g), HOBT (8.6 mmol, 1.16 g), NaHCO3 (6.9 mmol, 0.58 g),
CH2Cl2 (5 mL), and THF (10 mL) was stirred at room temperature for 48 h.
The solvents were evaporated, and the residue was dissolved in CH2Cl2
(30 mL), washed with 5% NaOH (10 mL) and with HCl 0.5 M (5 mL), then dried
over MgSO4. After filtration and evaporation, the residue was purified by flash
chromatography on silica gel (CHCl3/EtOH 10:1) to give compound 3 (1.85 g,
76%, based on elemental analysis) as a yellow oil (Found: C, 57.38; H, 7.54; N
7.40 giving a formula of C27.1H42.8N3.0O9.8); dH (300 MHz; CDCl3; Me4Si) 8.74
(1H, br d, J 7.0, NH), 8.52 (2H, d, J 4.7, H-6 of pyridine), 7.61 (2H, td, J 7.7 and
1.7, H-4 of pyridine), 7.42 (2H, d, J 7.7, H-3 of pyridine), 7.16 (2H, td, J 6.2 and
1.6, H-5 of pyridine), 6.29 (1H, d, J 7.0, CHNH), 4.08 (2H, s, CH2 of PEG unit),
3.74–3.50 (30H, m, CH2 of PEG unit), 3.35 (3H, s, CH3O of PEG unit); dC
(75 MHz; CDCl3) 169.8, 159.3, 149.6, 137.2, 122.8, 122.5, 72.3, 71.6, 71.3, 71.1,
71.0, 70.9, 59.4, 59.0.
4. (a) Aqueous-Phase Organometallic Chemistry; Cornils, B., Herrmann, W. A., Eds.;
Wiley-VCH: Weinheim, 2004; (b) Anderson, K. W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2005, 44, 6173–6177; (c) Billingsley, K. L.; Anderson, K. W.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484–3488; (d) Kudo, N.;
Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282–1284; (e)
Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2007, 13, 2701–2716.
5. Polyethylene Glycol Chemistry: Biotechnological and Biomedical Application;
Harris, J. M., Ed.; Plenum: New York, 1992.
6. (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489–509; (b) Dickerson, T. J.;
Reed, N. N.; Janda, K. D. Chem. Rev. 2002, 102, 3325–3344; (c) Bergbreiter, D. E.
Chem. Rev. 2002, 102, 3345–3384; (d) Uozumi, Y. Top. Curr. Chem. 2004, 242,
77–112.
16. (a) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.;
Hursthouse, M. E.; Light, M. E. Organometallics 2003, 22, 987–999; (b) van der
Heiden, M.; Plenio, H. Chem. Eur. J. 2004, 10, 1789–1797.
7. Li, J. H.; Liu, W. J.; Xie, Y. X. J. Org. Chem. 2005, 70, 5409–5412.
8. Mai, W.; Gao, L. Synlett 2006, 2553–2558.
9. Corma, A.; Garcia, H.; Leyva, A. J. Catal. 2006, 240, 87–99.
10. (a) Buchmeiser, M. R.; Wurst, K. J. Am. Chem. Soc. 1999, 121, 11101–11107; (b)
Silberg, J.; Schareina, T.; Kempe, R.; Wurst, K.; Buchmeiser, M. R. J. Organomet.
Chem. 2001, 622, 6–18.
11. (a) Nájera, C.; Gil-Moltó, J.; Karlström, S.; Falvello, L. R. Org. Lett. 2003, 5, 1451–
1454; (b) Nájera, C.; Gil-Moltó, J.; Karlström, S. Adv. Synth. Catal. 2004, 346,
1798–1811; (c) Gil-Moltó, J.; Nájera, C. Eur. J. Org. Chem. 2005, 4073–4081; (d)
Gil-Moltó, J.; Nájera, C. Adv. Synth. Catal. 2006, 348, 1874–1882.
12. Gil-Moltó, J.; Karlström, S.; Nájera, C. Tetrahedron 2005, 61, 12168–12176.
13. (a) Trilla, M.; Pleixats, R.; Wong Chi Man, M.; Bied, C.; Moreau, J. J. E.
Tetrahedron Lett. 2006, 47, 2399–2403; (b) Trilla, M.; Pleixats, R.; Wong
Chi Man, M.; Bied, C.; Moreau, J. J. E. Adv. Synth. Catal. 2008, 350, 577–
590.
17. Typical cross-coupling procedure: A flask was charged with Pd(OAc)2 (1.3 mg,
6 lmol), 3 (3.4 mg, 18 lmol of nitrogen based on analysis), K2CO3 (1.66 g,
12.0 mmol), aryl chloride (6.0 mmol), arylboronic acid (6.6 mmol), TBAB
(0.83 g, 3.0 mmol), and water (75 mL). The mixture was heated at 100 °C and
stirred during 15 h. The mixture was cooled at room temperature, extracted
with diethyl ether (2 ꢁ 50 mL), dried over MgSO4, concentrated, and purified
by flash chromatography on silica gel to afford the pure coupling product.
18. (a) Klingensmith, L. M.; Leadbeater, N. E. Tetrahedron Lett. 2003, 44, 765–768;
(b) Tao, X.; Zhao, Y.; Shen, D. Synlett 2004, 359–361.
19. (a) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973–2976; (b) Arvela, R. K.;
Leadbeater, N. E. Org. Lett. 2005, 7, 2101–2104; (c) Miao, G.; Ye, P.; Yu, L.;
Baldino, C. M. J. Org. Chem. 2005, 70, 2332–2334; (d) Liu, L.; Zhang, Y.; Wang, Y.
J. Org. Chem. 2005, 70, 6122–6125; (e) Cravotto, G.; Beggiato, M.; Penoni, A.;
Palmisano, G.; Tollari, S.; Lévêque, J.-M.; Bonrath, W. Tetrahedron Lett. 2005, 46,
2267–2271.
14. Chang, J.; Plummer, S.; Berman, E. S. F.; Striplin, D.; Blauch, D. Inorg. Chem.
2004, 43, 1735–1742.