New pyrazole-tethered Schiffs bases as ligands for the Suzuki reaction

Article abstract of DOI:10.1016/j.tetlet.2004.11.051

Pyrazole-tethered Schiffs base ligands 2 promote Suzuki coupling of aryl bromides and chlorides with phenylboronic acid efficiently under mild conditions.

Full text of DOI:10.1016/j.tetlet.2004.11.051

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 15–18
New pyrazole-tethered Schiffs bases as ligands
for the Suzuki reaction
Anuradha Mukherjee and Amitabha Sarkar*
Department of Organic Chemistry, Indian Association for The Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 8 October 2004; revised 2 November 2004; accepted 8 November 2004
Abstract—Pyrazole-tethered Schiffs base ligands 2 promote Suzuki coupling of aryl bromides and chlorides with phenylboronic acid
efficiently under mild conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
Transition metal catalyzed cross-coupling reactions are
useful tools in organic synthesis for constructing C–C
bonds.1 Among these, the coupling of an aryl halide
with an organoboron reagent, the Suzuki reaction has
emerged a favourite because of its mild conditions.1c
Pd–phosphine complexes2,3 have been the most com-
monly employed catalysts for the Suzuki reaction. The
high price associated with bulky tertiary phosphines
and difficulties associated with separation of the ligands
and their degradation products, phosphine oxides, etc.,
from coupling products have encouraged researchers
to explore alternative ligands. Recently a few nonphos-
phine ligands such as N-heterocyclic carbenes (NHCs),4
imidazol-2-ylidenes5 and diazabutadienes6 have been
used in Suzuki coupling reactions.
congestion around the metal accelerates the reductive
elimination step. Accordingly, we designed ligand sys-
tems depicted in Figure 1. There are two types of nitro-
gen donor atoms in these potentially bidentate ligands.
The pyrazole is expected to act as a hemilabile ligand7
while the Schiffs base nitrogen acts as the principal
donor. For comparison, an ortho-NMe2 group (as in 1)
instead of CH@N was also examined.8a
Ligand 1 did not catalyze the Suzuki coupling reaction at
all. Deposition of Pd black commences after 1h at room
temperature and within a few minutes at 65–70°C. This
result indicates that a low valent Pd(0) complex cannot
be stabilized by a hard donor like NMe2. The use of li-
gands 2a–d, on the other hand, effected efficient coupling.
The preparation of ligands 2 is depicted in Scheme 2.8b,c
The relative efficiency of the ligands 2a–d was assessed by
reference to results of the Suzuki coupling between 4-
bromoanisole and phenylboronic acid (Table 1).
Recent developments in this area suggest that an elec-
tron rich metal center (possibly aided by a r-donor
ligand) facilitates oxidative addition and steric
N
R1
N
N
N
N
R2
N
N
N
N
N
R1=R2=CH3
R1= R2=CH3
X = NMe2,
CH N
CH N
CH N
CH N
R1= CH3, R2=t-Bu
X=
CH=NAr
X
1
2
2b
2a
2d
2c
Figure 1.
Keywords: Pyrazole; Schiffs base; N,N-donor system; Suzuki coupling; Pd.
*
Corresponding author. Tel.: +91 33 24734971; fax: +91 33 24732805; e-mail: ocas@iacs.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.051

16
A. Mukherjee, A. Sarkar / Tetrahedron Letters 46 (2005) 15–18
R1
Ar
R1
Ligand
R2
Yield
R2
R1
R1
R2
R2
C6H5
CH3
CH3
CH3
2a
2b
2c
CH3
CH3
86%
86%
N
N
N
N
N
N
2,6-(i-Pr)2C6H3
n-BuLi, DMF
ArNH2
C(CH3)3 C6H5
C(CH3)3
88%
78%
CHO
CH NAr
2d CH3
2,6-(i-Pr)2C6H3
2
Scheme 2.
Table 1. Influence of ligands 2 on the palladium-catalyzed Suzuki coupling of 4-bromoanisole with phenyl boronic acida
Pd2(dba)3/Ligand 2
MeO
Br
+
B(OH)2
OMe
CsF, Dioxane
Pd:2=1:1
Entry
Ligand
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
2a
2b
2b
2c
2d
2d
45
rt
7
10
3
68 (71)
77 (47)
78 (49)
71 (71)
78 (31)
81 (49)
45
45
rt
7
10
3
45
a Reaction conditions: Pd2(dba)3: 1mol%, Ligand 2: 2mol%, Pd:2 = 1:1, Dioxane: 3mL, CsF: 3mmol, Time: 3–10h.
b Yield in parentheses refer to ratio of Pd:ligand 2 = 1:2. Results are based upon isolated material, average of two runs.
Coupling was observed at room temperature when the
ligands 2b or 2d were used (Table 2, entries 2 and 5).
At 45°C the reaction was complete within 3h and the
yield was improved. Neither ligand 2a nor 2c promoted
coupling at room temperature. This trend in reactivity is
in agreement with the stronger donating ability of the t-
butyl group of the pyrazole ring and the iso-propyl
group on the benzene ring, making the ligands 2b and
2d more electron rich. Sensitivity to the Pd:ligand ratio
was observed for the sterically demanding ligands 2b
and 2d but not with 2a and 2c (see Table 1). Dioxane
was found to be superior to toluene as solvent (Table
2). Both CsF and Cs2CO3 gave comparable yield of
products.9
well. In case of a neutral aryl bromide (Table 3, entry
2), the reaction can be performed at room temperature,
though it required a longer time. ortho-Substituted and
sterically congested substrates also led to excellent yields
in the presence of ligands 2b and 2d (Table 3, entries
5–8). Activated and neutral aryl chlorides in the pres-
ence of ligands 2b and 2d afforded good yields of the de-
sired products (Table 3, entries 10–13), whereas
attempts to couple the electron rich 4-chloroanisole were
not successful.
In summary, we have developed a new and efficient cata-
lyst system for Suzuki coupling reactions. To the best of
our knowledge this is the first report of pyrazole-teth-
ered nonphosphine ligands being explored for catalysis
of Suzuki reactions.10,11 We have shown that the cata-
lytic activity depends considerably on the donor atoms
and the steric environment around the metal present in
the ligand system. These nonphosphine ligands consti-
tute interesting alternatives to traditional phosphine
ligands. Schiffs base structures also promote the ready
All the ligands 2a–d appear to be useful in the reactions
of aryl bromides. However, with an activated aryl chlo-
ride, only ligands 2b and 2d were effective (Table 3).
As is evident from Table 3, the Pd-catalyzed Suzuki cou-
pling reactions with the ligands 2 proceeded extremely
Table 2. Effect of solvent on the Pd2(dba)3/ligand 2-catalyzed cross-coupling reaction of 4-bromoanisole with phenylboronic acida
Pd2(dba)3/Ligand 2
CsF, Toluene
MeO
Br
+
B(OH)2
OMe
Entry
Ligand
Solvent
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2d
Toluene
Dioxane
Toluene
Dioxane
Toluene
Dioxane
Toluene
Dioxane
53
68
61
78
31
71
63
81
a Reaction conditions: Aryl bromide: 1mmol, Phenyl boronic acid: 1.5mmol, CsF: 3mmol, Pd2(dba)3: 1mol%, Ligand 2: 2mol%, Toluene: 3mL,
Temp: 45°C. Results are based upon isolated material, average of two runs.

A. Mukherjee, A. Sarkar / Tetrahedron Letters 46 (2005) 15–18
Table 3. Pd2(dba)3/ligand 2 catalyzed coupling of aryl halides with phenyl boronic acida
17
Pd2(dba)3/Ligand 2
X
+
B(OH)2
CsF, Dioxane
Pd:2=1:1
R
R
Entry
Ligand
Aryl halide
Time (h)
Product
Yield (%)
1
2a
2b
2c
2d
2b
2d
2b
2b
2b
2b
2d
2b
2d
2b
4-Bromotoluene
4-Bromotoluene
7
3
4-Methylbiphenyl
4-Methylbiphenyl
4-Methylbiphenyl
4-Methylbiphenyl
2-Methylbiphenyl
2-Methylbiphenyl
2-Acetylbiphenyl
2,4,6-Trimethylbiphenyl
4-Acetylbiphenyl
4-Methylbiphenyl
4-Methylbiphenyl
4-Acetylbiphenyl
4-Acetylbiphenyl
4-Methoxybiphenyl
79
88 (81)b
81
2
3
4-Bromotoluene
4-Bromotoluene
7
4
2
95
87
5
2-Bromotoluene
2-Bromotoluene
3
6
3
91
7
2-Bromoacetophenone
2-Bromomesitylene
4-Bromoacetophenone
4-Chlorotoluene
5
89
8
10
1
73c
93 (91)d
69e
67
9
10
11
12
13
14
10
10
8
4-Chlorotoluene
4-Chloroacetophenone
4-Chloroacetophenone
4-Chloroanisole
75
79
8
12
0
a Reaction conditions: Aryl halide (1mmol), Phenyl boronic acid (1.5mmol), Pd2(dba)3: 1mol%, Ligand 2: 2mol%, Base: CsF (for aryl bromide),
K3PO4 (for aryl chloride): 3mmol. Dioxane: 3mL, Temp: 45–55°C.
b Reaction was performed at room temperature for 12h.
c Temp: 55°C.
d Reaction was performed at room temperature for 2h.
e For chloro substrate the temperature was fixed at 55°C.
7. (a) Bader, A.; Linder, E. Coord. Chem. Rev. 1991, 108, 27;
(b) Newkome, G. R. Chem. Rev. 1993, 93, 2067.
synthesis of a large number of enantiopure chiral li-
gands. The utility of the Pd2(dba)3/ligand 2 catalysts in
other coupling reactions such as Heck, Sonogashira
and amination is being explored in our laboratory.
8. (a) When 4-bromoanisole and phenylboronic acid were
treated with N-phenylpyrazole as the ligand instead of
ligand 2, below 65°C, no coupling was observed. Above
65°C rapid precipitation of Pd-black was observed.; (b)
General procedure for synthesizing ligands 2: the pyrazole-
tethered aldehyde (1equiv) and aromatic amine (1equiv)
in dry ethanol were refluxed in the presence of one drop of
acetic acid until the starting material was completely
consumed (monitored by TLC). After removal of solvent,
the product was obtained either as a solid or a semi-solid,
which was purified by crystallization using hot ethanol. (c)
Spectral and analytical data for ligands 1 and 2a–d: ligand
1: (Liquid). Yield: 66%. 1H NMR (300MHz, CDCl3) d:
7.28–7.19 (2H, m, PhH), 6.94–6.89 (2H, m, PhH) 5.91 (1H,
s, PzH), 2.46 (6H, s, N(CH3)2), 2.26 (3H, s, CH3), 2.06
(3H, s, CH3). 13C NMR (50.32MHz, CDCl3) d: 148.5,
140.9, 130.6, 129.4, 128.9, 120.2, 117.3, 105.0, 41.5, 13.3,
10.8. Microanalysis: C13H17N3 (215): calcd: C: 72.56%, H:
7.91%, N: 19.53%. Found: C: 72.44%, H: 7.88%, N:
19.43%.
Acknowledgements
One of us (A.M.) would like to thank CSIR, India, for a
research fellowship.
References and notes
1. (a) Heck, R. F. Palladium Reagents In Organic Syntheses;
Academic: London, 1985; (b) Principle and Applications of
Organotransition Metal Chemistry; Collman, J. P., Hege-
dus, L. S., Norton, J. R., Finke, R. G., Eds.; University
Science: Mill Valley, CA, 1987; (c) Miyaura, N.; Suzuki,
A. Chem. Rev. 1995, 95, 2457–2483.
2. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722–9723; (b) Wolfe, J. P.; Buchwald, S.
L. Angew. Chem., Int. Ed. 1999, 38, 2413–2416; (c) Wolfe,
J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550–9561; (d) Yin, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2000, 122, 12051–12052; (e) Yin, J.;
Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1162–1163.
Ligand 2a: (Yellow solid). Mp: 65–67°C. IR (KBr, cmÀ1):
1552, 1496. 1H NMR (300MHz, CDCl3): d 8.40–8.37 (1H,
m, CH@N), 8.05 (1H, s, PhH), 7.54–7.52 (3H, m, PhH),
7.37–7.31 (3H, m, PhH), 7.14–7.12 (2H, m, PhH), 6.02
(1H, s, PzH), 2.32 (3H, s, CH3), 2.11 (3H, s, CH3). 13C
NMR (75.47MHz, CDCl3): d 156.3, 151.7, 149.3, 141.4,
140.1, 133.3, 131.5, 129.0, 128.2, 127.8, 127.6, 120.9, 106.1,
13.5, 11.6. Microanalysis: C18H17N3 (275): calcd: C:
78.54%, H: 6.18%, N: 15.27%. Found: C: 78.29%, H:
5.91, N: 15.25%.
3. (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387–3388; (b) Adam, F. L.; Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 4020–4028.
Ligand 2b: (Yellow solid). Mp: 104–107°C. IR (KBr,
4. (a) Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186–
190; (b) Navarro, O.; Kelly, R. A., III; Nolan, S. P. J. Am.
Chem. Soc. 2003, 125, 16194–16195.
5. Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804–3805.
1
cmÀ1): 1552, 1498. H NMR (200MHz, CDCl3): d 8.45–
8.41 (1H, m, CH@N), 7.72 (1H, s, PhH), 7.63–7.59 (2H,
m, PhH), 7.39–7.34 (1H, m, PhH), 7.13 (3H, bs, PhH),
5.94 (1H, s, PzH), 3.00–2.87 (2H, m, CH(CH3)2), 2.22 (3H,
s, CH3). 2.12 (3H, s, CH3), 1.14 (12H, d, J = 6Hz,
CH(CH3)2).13C NMR (50.32MHz, CDCl3): 159.7, 158.4,
149.1, 140.8, 140.3, 137.6, 133.9, 131.4, 129.2, 128.1, 127.6,
6. Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001,
3, 1077–1080.

18
A. Mukherjee, A. Sarkar / Tetrahedron Letters 46 (2005) 15–18
124.2, 123.0, 105.9, 27.8, 23.4, 13.3, 11.3. Microanalysis:
argon and charged with Pd2(dba)3.CHCl3 (1mol%),
ligand 2 (2mol%), phenyl boronic acid (1.5mmol) and
base (3mmol). The flask was evacuated and flushed with
argon once again. Aryl halide (1mmol) and dioxane
(3mL) were added to the reaction mixture by a syringe.
The reaction mixture was heated (45–55°C) with stirring
for the specified time. Reaction was monitored by TLC.
The reaction mixture was then cooled to room tempera-
ture, filtered through Celite and washed with dichlorom-
ethane. The crude material was purified by flash
chromatography. The identity of every product was
confirmed by comparison with literature spectroscopic
data: 4-methoxybiphenyl,12a 2-methylbiphenyl,12b 2,4,6-
C24H29N3 (359): calcd: C: 80.22%, H: 8.07%, N: 11.69%.
Found: C: 80.12%, H: 8.03%, N: 11.59%.
Ligand 2c: (Yellow semi-solid). IR (Neat, cmÀ1): 1550,
1
1480. H NMR (300MHz, CDCl3): d 8.39–8.37 (1H, m,
CH@N), 7.99 (1H, s, PhH), 7.57–7.53 (2H, m, PhH), 7.40–
7.35 (3H, m, PhH), 7.23–7.12 (2H, m, PhH), 6.08 (1H, s,
PzH), 2.14 (3H, s, CH3), 1.35 (9H, s, C(CH3)3). 13C NMR
(75.47MHz, CDCl3): 162.5, 157.1, 151.9, 140.9, 140.3,
134.1, 133.5, 131.4, 129.0, 126.9, 127.8, 127.7, 126.1, 120.9,
102.9, 32.0, 30.5, 11.7. Microanalysis: C21H23N3 (317):
calcd: C: 79.49%, H: 7.25%, N: 13.25%. Found: C: 79.31%,
H: 7.38%, N: 13.20%.
Ligand 2d: (Yellow semi-solid). IR (Neat, cmÀ1): 1552,
1496. 1H NMR (300MHz, CDCl3):d 8.46–8.42 (1H, m,
CH@N), 7.73 (1H, s, PhH), 7.62–7.58 (2H, m, PhH), 7.40–
7.38 (1H, m, PhH), 7.15–7.06 (3H, m, PhH), 6.00 (1H, s,
PzH), 3.03–2.86 (2H, m, CH(CH3)2), 2.09 (3H, s, CH3),
1.26 (9H, s, C(CH3)3), 1.10 (12H, d, J = 6Hz, CH(CH3)2).
13C NMR (75.47MHz, CDCl3): d 162.3, 158.1, 149.0,
140.4, 137.3, 133.6, 131.6, 129.3, 128.5, 127.3, 124.1, 122.9,
102.5, 30.4, 27.8, 23.4, 22.4, 11.4. Microanalysis:
C27H35N3 (401): calcd: C: 80.79%, H: 8.72%, N: 10.47%.
Found: C: 81.41%, H: 8.90%, N: 10.33%.
trimethylbiphenyl,12c
acetylbiphenyl.12d
4-methylbiphenyl,2a
and
4-
10. For use of pyrazole-derived P,N-ligands in Suzuki and
amination reaction: Mukherjee, A.; Sarkar, A. Arkivoc
2003, 87–95.
11. For use of pyrazole and pyrrole-derived P,N-ligands in
amination reaction: Singer, R. A.; Caron, S.; McDermott,
R. E.; Arpin, P.; Do, N. M. Synlett 2003, 1727–1731.
12. (a) Rao, M. S. C.; Rao, G. S. K. Synthesis 1987, 231; (b)
Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.;
Peterson, J. L. J. Org. Chem. 1999, 64, 6797–6803; (c)
Anderson, J. C.; Namli, H.; Roberts, C. A. Tetrahedron
1997, 53, 15123–15134; (d) Barba, I.; Chinchilla, R.;
Gomez, C. Tetrahedron 1990, 46, 7813–7822.
9. (a) Pd2(dba)3 is a better catalyst precursor than Pd(OAc)2
for this reaction. (b) General procedure for Suzuki coupling:
an oven dried round bottomed flask was cooled under