Bulky N-acyl-pyridylbenzamidine ligands for palladium catalyzed Suzuki-Miyaura reaction

Article abstract of DOI:10.1007/s10562-011-0625-z

In this letter, a series of bulky N-acyl-pyridylbenzamidine ligands were synthesized and characterized. Under the optimized reaction conditions, these bulky ligands were applied to catalyze Suzuki-Miyaura reactions of various aryl bromides and chlorides. The desired biaryl products were obtained in good to high yields.

Full text of DOI:10.1007/s10562-011-0625-z

Catal Lett (2011) 141:1332–1337
DOI 10.1007/s10562-011-0625-z
Bulky N-acyl-pyridylbenzamidine Ligands for Palladium
Catalyzed Suzuki–Miyaura Reaction
•
Cheng Tan Feng-Shou Liu Dong-Sheng Shen
•
•
•
Tao Cheng Zong-Zhou Zhou
Received: 9 March 2011 / Accepted: 10 May 2011 / Published online: 25 May 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In this letter, a series of bulky N-acyl-pyridyl-
benzamidine ligands were synthesized and characterized.
Under the optimized reaction conditions, these bulky
ligands were applied to catalyze Suzuki–Miyaura reactions
of various aryl bromides and chlorides. The desired biaryl
products were obtained in good to high yields.
However, most of them are air and/or moisture sensitive,
toxic and environmentally unfriendly [13–16].
On the contrary, inexpensive, easily prepared, moisture
and air stable nitrogen donor ligands have attracted great
attention recently. They have also shown excellent cata-
lytic efficiency because of strong r-donating abilities [17–
22]. To our knowledge, dipyridyl-and dipyrimidyl (I and
II, Fig. 1) ligands investigated by Buchmeiser et al.
showed fine catalytic properties for carbon–carbon and
carbon–nitrogen bond formation [23–27]. Very shortly, a
family of di-2-pyridylmethylamine (III, Fig. 1) based cat-
Keywords N-acyl-pyridylbenzamidine ligands Á
Suzuki–Miyaura reaction Á Aryl chlorides
´
alysts developed by Najera turned out to be excellent for
1 Introduction
Suzuki–Miyaura reaction and other types of cross-coupling
reactions under homogeneous conditions [28–31]. These
ligands as well as the supported catalysts exhibited high
efficiency both for aryl iodides and bromides. However,
they were found to be much less active towards the unac-
tivated aryl chlorides. Furthermore, structures of their
ligands were simple and not bulky enough. We surmised
that ligands with electron-rich substituted groups and hin-
dered structures would work well on catalyzing Suzuki–
Miyaura reactions of various aryl chlorides with phenyl-
boronic acid. Herein, in this letter, a series of designed
N-acyl-pyridylbenzamidine ligands (IV) with bulky imine
structure and different electronic substituents were reported
and employed in Suzuki–Miyaura reaction.
Suzuki–Miyaura reaction [1–3] is growing as one of the
most convenient and popular synthetic methods for car-
bon–carbon bond formation, which plays a very important
role in the synthesis of pharmaceuticals, agro-chemicals
and advanced functional materials [4–6]. Meanwhile, cat-
alysts containing different sorts of ligands have been
intensively studied by numbers of researchers during the
past two decades in this hot area [7–9]. These reported
ligands were mainly focused on phosphines [10–12].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-011-0625-z) contains supplementary
material, which is available to authorized users.
2 Experimental
C. Tan Á F.-S. Liu (&) Á D.-S. Shen (&) Á T. Cheng Á
Z.-Z. Zhou
School of Chemistry and Chemical Engineering, Guangdong
Pharmaceutical University, Zhongshan, Guangdong 528458,
People’s Republic of China
2.1 Instruments and Reagents
All the chemical reagents (AR grade) were from com-
mercial resources and used without any further purification.
GC analysis were performed on an Agilent GC-6820
e-mail: fengshou2004@126.com
D.-S. Shen
e-mail: sds8@163.com
123

Bulky N-acyl-pyridylbenzamidine Ligands
1333
Calcd for C31H31N3O: C, 80.66; H, 6.67; N, 9.10. Found:
C, 80.44; H, 6.65; N, 9.03.
L2 (C31H30N4O3): Yellow solid: mp = 175.0–176.0 °C.
MS (ESI?) m/z: [M ? Na] 529. 1H NMR (300 MHz,
CDCl3), d (ppm): 9.16–6.42 (m, 16H, Ar–H), 3.49 (m, 2H,
CH(CH3)2), 1.36 (d, J = 6.9 Hz, 12H, CH(CH3)2). 13C
NMR (75 MHz, CDCl3), d (ppm): 172.51, 161.40, 146.29,
145.14, 139.41, 135.58, 135.20, 133.11, 132.23, 131.38,
130.12, 129.40, 128.90, 128.77, 128.37, 128.26, 127.82,
124.28, 115.54, 29.08, 24.55. IR (KBr, cm-1): m 2964,
2867, 1660, 1582, 1513, 1257, 1280, 921, 858, 837, 802,
769, 694, 649. Anal Calcd for C31H30N4O3: C, 73.50; H,
5.97; N, 11.06. Found: C, 73.48; H, 5.98; N, 11.05.
L3 (C32H33N3O): Yellow solid, mp = 167.0–168.0 °C.
MS (ESI?) m/z: [M ? Na] 498. 1H NMR (300 MHz,
CDCl3), d (ppm): 8.47–5.78 (m, 16H, Ar–H), 3.53 (m, 2H,
CH(CH3)2), 2.40 (s, 3H, CH3), 1.36 (d, J = 6.6 Hz, 12H,
CH(CH3)2). 13C NMR (75 MHz, CDCl3), d (ppm): 172.86,
161.28, 155.95, 149.07, 148.51, 146.43, 137.44, 136.79,
136.20, 131.25, 130.77, 128.88, 128.46, 127.91, 124.14,
123.39, 123.08, 122.75, 121.45, 27.93, 24.10, 21.43. IR
(KBr, cm-1): m 2955, 2864, 1666, 1634, 1610, 995, 952,
927, 869, 819, 777, 742, 727. Anal Calcd for C32H33N3O:
C, 80.81; H, 6.99; N, 8.83. Found: C, 80.65; H, 6.82; N,
8.73.
Fig. 1 Types of [N, N] ligands
chromatograph with a 30 m 9 0.32 mm 9 0.5 lm OV-17
capillary column with a FID detector. NMR were recorded
on a Bruker 300 MHz spectrometer using CDCl3 as the
solvent with tetramethylsilane (TMS) as an internal stan-
dard. IR data were measured by a Perkin Elmer FT-IR
spectrometer100. MS spectral data were recorded on an
Acquity UPLC-Q-Tof Micro MS detector. Elemental
analysis were detected by a Vario EL III instrument (Ele-
mentar Analysen Systeme Gmbh, Germany).
L4 (C33H35N3O): Yellow solid, mp = 126.0–127.0 °C.
MS (ESI?) m/z: [M ? Na] 512. 1H NMR (300 MHz,
CDCl3), d (ppm): 8.10–5.59 (m, 15H, Ar–H), 3.55 (m, 2H,
CH(CH3)2), 2.49 (s, 3H, CH3), 2.19 (s, 3H, CH3), 1.35 (d,
J = 6.6 Hz, 12H, CH(CH3)2). 13C NMR (75 MHz,
CDCl3), d (ppm): 171.71, 158.01, 156.43, 154.81, 152.12,
146.42, 143.68, 139.38, 137.39, 136.23, 134.39, 131.40,
130.85, 128.66, 127.73, 123.25, 122.70, 120.68, 119.76,
27.70, 24.23, 22.51, 21.26. IR (KBr, cm-1): m 2961, 2866,
1671, 1633, 1611, 988, 959, 932, 920, 874, 843, 818, 794,
784, 777, 751, 737, 730. Anal Calcd for C33H35N3O: C,
80.95; H, 7.20; N, 8.58. Found: C, 80.84; H, 7.25; N, 8.52.
2.2 Synthesis and Characterization of L1–4
2.2.1 Synthesis of L1–4
In a three-necked round bottom flask, benzoyl chloride
(0.4 mL, 3 mmol) and triethylamine (0.7 mL, 5 mmol)
were added to a vigorously stirred mixture of 2-pyridyl-
benzamidine (3 mmol) and THF (20 mL). The reaction
was carried out at 60 °C for 6 h. Precipitation was removed
by filtration and THF was evaporated under reduced
pressure. L1–4 (yield: 78–90%) were obtained by recrys-
tallization of the crude products in ethanol.
2.3 General Procedure for Suzuki–Miyaura Reaction
In a round bottle, Ligand (1% mmol), PdCl2 (1% mmol),
aryl halides (1 mmol), phenyl boronic acid (1.2 mmol),
K2CO3 (2 mmol) and 5 mL of solvent were added with a
magnetic stir bar. The reaction mixture was heated to the
described temperature for the required time, and then the
solvent was removed under reduced pressure. The residual
was diluted with Et2O (5 mL), followed by extraction twice
(2 9 5 mL) with Et2O. The organic layer was dried with
anhydrous MgSO4, filtered and evaporated under vacuum.
The conversion rates were determined by GC analysis, and
the crude products were purified by silica-gel column
chromatography using petroleum ether-ethyl acetate as an
2.2.2 Characterization of L1–4
L1 (C31H31N3O): Yellow solid, mp = 170.0–171.0 °C.
MS (ESI?) m/z: [M ? Na] 484. 1H NMR (300 MHz,
CDCl3), d (ppm): 8.49–5.79 (m, 17H, Ar–H), 3.54 (m, 2H,
CH(CH3)2), 1.37 (d, J = 6.6 Hz, 12H, CH(CH3)2). 13C
NMR (75 MHz, CDCl3), d (ppm): 173.73, 169.79, 146.45,
137.49, 137.34, 134.08, 130.90, 130.35, 129.45, 129.04,
128.42, 127.92, 124.15, 123.68, 123.43, 122.85, 122.78,
121.57, 121.29, 27.94, 24.47. IR (KBr, cm-1): m 2956,
2864, 1668, 1628, 1466, 1436, 1326, 1288, 1174, 1145,
994, 947, 931, 870, 772, 745, 732, 715, 697, 656. Anal
123

1334
C. Tan et al.
Scheme 1 The synthesis route
of the ligands
eluent. The isolated corresponding products were charac-
1
conditions using K2CO3 as a base, and the results are
presented in Table 1. As expected, the ligand played an
important role in the electronically demanding reaction.
Meanwhile, L4 was found to be the most effective. How-
ever, L1–3 with less bulky or electron with-drawing sub-
stitution groups allowed moderate conversion rates of the
starting materials and were less efficient than L4 (Table 1,
entries 1–6). It indicated that ligands with stronger elec-
tron-donating substituents rendered a promotion of the
oxidative addition process and stabilized the palladium
complexes. What’s more, bulky hindrance on ligands could
further facilitate the reductive elimination in the catalytic
cycle [33, 34]. Therefore, L4 was applied in the following
palladium catalyzed Suzuki–Miyaura reactions.
terized by H NMR and 13C NMR.
These N-acyl-pyridylbenzamidine ligands were pre-
pared in one step through the acylation of pyridylbenz-
amidines with benzoyl chloride (Scheme 1), and the
synthesis route of pyridylbenzamidines has been recently
reported by our research group [32]. All of the N-acyl-
pyridylbenzamidine ligands (L1–4) were characterized by
1H NMR, 13C NMR, MS, IR and elemental analysis.
Besides, L1 was further confirmed by X-ray diffraction
analysis (see Supplementary data).
3 Results and Discussion
With the optimized reaction conditions in hand, the
cross-coupling reactions of various aryl bromides and
phenylboronic acid were performed in the presence of
1 mol% of L4 and 1 mol% PdCl2. As summarized in
Table 2, electron-deficient aryl bromides such as
In order to evaluate their catalytic efficacy, the selected
ligands were screened using 4-bromoanisole and phenyl-
boronic acid in the model reaction. The coupling reaction
was initially performed in EtOH/H2O under aerobic
Table 1 Optimization of reaction conditions
Entry
Ligand
Pd (mol%)
Solvent
T (h)
Conv. (%)a
Yield (%)b
1
L1
L2
L3
L3
L4
L4
L4
L4
L4
L4
L4
L4
1
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
DMF/H2O
Acetone/H2O
Toluene/H2O
THF/H2O
1
1
1
1
1
1
1
I
90
51
94
75
87
97
96
96
16
71
35
80
85
40
81
64
79
93
91
89
5
2
1
3
1
4
0.5
0.5
1
5
6
7
1
8
1
9
1
1
1
1
1
10
11
12
1
65
11
72
1
Dioxane/H2O
EtOH
1
Reaction conditions: 4-bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2.0 mmol), EtOH:H2O = 4 mL:1 mL, under aerobic
a
b
atmosphere at 60 °C. Conversions determined by GC. Isolated yields
123

Bulky N-acyl-pyridylbenzamidine Ligands
1335
Table 2 Suzuki–Miyaura reaction of ArBr with ArB(OH)2 under aerobic conditions
Reaction conditions: ArBr (1.0 mmol), ArB (OH)2 (1.2 mmol), K2CO3 (2.0 mmol), Solvent: EtOH:H2O = 4 mL:1 mL, under aerobic atmo-
a
sphere. Conversions determined by GC. Isolated yields. Under nitrogen atmosphere
b
c
4-bromonitrobenzene and 4-bromochlorobenzene afforded
excellent yields at room temperature (entries 1–3). Fur-
thermore, aryl bromides containing electron-rich or mono-
ortho-substituted groups (entries 5–8) also gave good
yields at 60 °C. The coupling product of sterically hindered
mesitylbromide with phenylboronic acid was obtained in a
satisfied yield by prolonging the reaction time (entry 9). In
order to further evaluate the activity of the catalyst, more
hindered substrates such as mesitylbromide and o-tolybo-
ronic acid, o-tolybromide and mesitylboronic acid were
also coupled under the same reaction conditions for 16 h.
The results showed that o-tolybromide and mesitylboronic
acid provided a much higher yield (92%) than that of
mesitylbromide and o-tolyboronic acid (69%). As expec-
ted, the more hindered mesitylbromide is much less reac-
tive than o-tolybromide. It was probably that the steric
effect might prevent its effective oxidative addition process
[35].
The excellent results of hindered aryl bromides inspired
us to further investigate its tolerance on more challenging
aryl chlorides. Surprisingly, we found that EtOH/H2O led
serious homo-coupling of phenylboronic acid when deac-
tivated arylchlorides were tested. It was previously repor-
ted that oxygen [36] would accelerate side reactions.
Meanwhile, low reactivity of arylchlorides is resulted
from their difficult oxidative addition to palladium species
123

1336
C. Tan et al.
Table 3 Suzuki–Miyaura reaction of ArCl with PhB(OH)2 under aerobic conditions
Reaction conditions: ArCl (1.0 mmol), PhB(OH)2 (1.2 mmol), K2CO3 (2.0 mmol), DMF:H2O = 4 mL:1 mL, under aerobic atmosphere.
a
b
EtOH:H2O = 4 mL:1 mL. Conversions determined by GC. Isolated yields
c
[37–39]. Therefore, a higher reaction temperature is needed
in order to activate the aryl chlorides. Further study indi-
cated that solvent with a higher boiling point is preferred.
And we found the reactions of chlorinated substrates
with phenylboronic acid could be taken successfully in
DMF/H2O.
5 Supplementary Data
Supplementary data (CIF and crystal structure of L1,
compound characterization data) associated with this arti-
cle can be found, in the online version.
Acknowledgements We are sincerely grateful for the financial
support from the National Natural Science Foundation of China (No.
21004014).
As shown in Table 3, these ligands could be used to
couple electron-deficient aryl chlorides with phenylboronic
acid. For example, the corresponding biaryl products were
given in good to high yields ranging from 74 to 99% in 6 h
(entries 4–7). Moreover, the desired coupling products of
electron-rich aryl chlorides (e.g. 4-chlorotoluene and
4-chloroanisole) were also obtained in moderate yields of
52% and 35%, respectively.
References
1. Suzuki A (1982) Acc Chem Res 15:178
2. Suzuki A (1994) Pure Appl Chem 66:213
3. Miyaura N, Suzuki A (1995) Chem Rev 95:2457
4. Stanforth SP (1998) Tetrahedron 54:263
5. Chen Y, Wu CS (2009) Macromolecules 42:3729
6. Spencer J, Baltus CB, Patel H, Press NJ, Callear SK, Male L,
Coles SJ (2011) Comb Sci 13:24
4 Conclusions
In summary, four N-acyl-pyridylbenzamidine ligands with
different steric and electronic substituents (L1–4) have
been prepared and characterized. The ligands complexed
with PdCl2 in situ under aerobic conditions proved to be
highly efficient for Suzuki–Miyaura reactions of a variety
of aryl bromides and chlorides.
7. Dupont J, Consorti CS, Spencer J (2005) Chem Rev 105:2527
8. Liebscher J, Yin LX (2007) Chem Rev 107:133
9. Guiry PJ, Hargaden GC (2009) Chem Rev 109:2505
10. So CM, Lau CP, Kwong FY (2007) Org Lett 9:2795
11. So CM, Chan ASC, Kwong FK (2008) J Org Chem 73:7731
12. Yang DX, Colletti SL, Wu K, Song MY, Shen HC (2009) Org
Lett 11:381
123

Bulky N-acyl-pyridylbenzamidine Ligands
1337
13. Baillie C, Zhang LX, Xiao JL (2004) J Org Chem 69:7779
14. Iwasana T, Komano T, Tajima A, Tokunaga M, Obata Y,
Fujihara T, Tsuji Y (2006) Organometallics 25:4665
15. Plentio H, Fleckenstein CA (2008) Organometallics 27:3924
16. Kantam ML, Srinivas P, Yadar J, Likhar PR, Bhargava S (2009)
J Org Chem 74:4882
27. Buchmeiser MR (2002) Bioorg Med Chem Lett 12:1837
´
´
¨
28. Najera C, Gil-Molto J, Karlstrom S (2004) Adv Synth Catal
346:1798
´
´
¨
29. Najera C, Gil-Molto J, Karlstrom S, Falvello LR (2003) Org Lett
5:1451
30. Gil-Molto J, Karlstrom S, Najera C (2005) Tetrahedron 61:12168
´
´
¨
´
´
17. Li JH, Liu WJ (2004) Org Lett 6:2809
18. Mino T, Shirae Y, Sakamoto M, Fujita T (2005) J Org Chem
70:2191
31. Gil-Molto J, Najera C (2005) Eur J Org Chem 4073
32. Liu FS, Gao HY, Song KM, Zhang L, Zhu FM, Wu Q (2009)
Polyhedron 28:1386
19. Li SH, Lin YJ, Gao JG, Zhang SB (2007) J Org Chem 72:4067
20. Marion N, Nolan SP (2008) Acc Chem Res 41:1440
21. Chalker JM, Wood CS, Davis BG (2009) J Am Chem Soc
131:16346
33. Zhang HC, Kwong FY, Tian Y, Chan KS (1998) J Org Chem
63:6886
34. Braga AAC, Morgon NH, Ujaque G, Maseras F (2005) J Am
Chem Soc 127:9298
´
22. Zhou ZZ, Liu FS, Shen DS, Tan C, Luo LY (2011) Inorg Chem
Commun 14:659
35. Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M (2002)
Chem Rev 102:1359
23. Sinner F, Buchmeiser MR, Tessadri R, Mupa M, Wurst K, Bonn
GK (1998) J Am Chem Soc 120:2790
36. Adamo C, Amatore C, Ciofini I, Jutand A, Lakmini H (2006) J
Am Chem Soc 128:6829
24. Buchmeiser MR, Wurst K (1999) J Am Chem Soc 121:11101
25. Buchmeiser MR, Schareina T, Kempe R, Wurst K (2001)
J Organomet Chem 634:39
26. Silberg J, Schareina T, Wurst K, Buchmeiser MR (2001)
J Organomet Chem 622:6
37. Milstein D, Portnoy M (1993) Organometallics 12:1665
38. Ahlquist M, Norrby PO (2007) Organometallics 26:550
39. Ochi N, Nakao Y, Sato H, Mantano Y, Imahori H, Sakaki S
(2009) J Am Chem Soc 131:10955
123