Pyrazole-tethered arylphosphine ligands for Suzuki reactions of aryl chlorides: How important is chelation?

Article abstract of DOI:10.1016/j.tetlet.2004.11.016

Pyrazole-derived bidentate ligands (P,N-donor) with bulky substituents at the 3-position of the pyrazole, 1b-d, were used with Pd₂(dba) ₃ to carry out efficient Suzuki coupling reactions with both aryl bromides and chlorides. Enhanced catalytic activity on account of steric crowding in the metal complex suggested participation of a chelated structure in the intermediate catalytic steps.

Full text of DOI:10.1016/j.tetlet.2004.11.016

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9525–9528
Pyrazole-tethered arylphosphine ligands for Suzuki reactions of
aryl chlorides: how important is chelation?
Anuradha Mukherjee and Amitabha Sarkar*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 30 September 2004; revised 28 October 2004; accepted 2 November 2004
Abstract—Pyrazole-derived bidentate ligands (P,N-donor) with bulky substituents at the 3-position of the pyrazole, 1b–d, were used
with Pd2(dba)3 to carry out efficient Suzuki coupling reactions with both aryl bromides and chlorides. Enhanced catalytic activity on
account of steric crowding in the metal complex suggested participation of a chelated structure in the intermediate catalytic steps.
Ó 2004 Elsevier Ltd. All rights reserved.
Palladium catalyzed activation of the Ar–Cl bond re-
mains a challenge in catalytic coupling reactions.1 While
aryl bromides or iodides react readily, less expensive aryl
chlorides are inert with respect to most catalysts and
reactions. In the pioneering studies related to catalysis
of the Suzuki reaction with aryl chlorides, Buchwald
and co-workers,2 Fu and co-workers,3a,b and others4
indicated that alkyl groups on the phosphine donor
and the steric bulk of substituents in the ligand are
crucial design elements for effective catalysis. A few
representative structures are displayed in Figure 1.
Buchwald showed that the alkylphosphine group im-
proves catalytic efficiency but the presence of an amino
function (as in A) is not essential for the ligand to be
effective. On the other hand, Fu and co-workers demon-
strated that tri(tert-butyl)phosphine, a monodentate
ligand of considerable steric bulk, effected efficient
catalysis of Suzuki and other reactions.3c–e
could activate an aryl chloride substrate if the 3-substit-
uent of the pyrazole was sufficiently bulky.
A set of pyrazole-tethered triarylphosphines,5 1a–d were
synthesized to catalyze the Suzuki reaction between phen-
ylboronic acid and a variety of aryl halides (Scheme 1)
and their effectiveness in catalysis was compared. Specif-
ically, ligands 1b, 1c and 1d were found to activate aryl
chlorides for the Suzuki reaction and 1b gave respect-
able turnover numbers. The complex derived from 1a
could only catalyze reactions of aryl bromides or iodides
but not chlorides.6
Typically, 1mol% of Pd2(dba)3 and 4mol% of ligand
(Pd:1 = 1:2) were used in toluene at 60–80°C in the pres-
ence of CsF.7 The results are summarized in Scheme 2
and Tables 1–3. Yields are reported as isolated and
chromatographically purified products.
Exploratory experiments in our laboratory on Pd-cataly-
zed Suzuki coupling with a set of pyrazole-tethered tri-
arylphosphine ligands revealed that arylphosphines
We found that Pd(OAc)2 can also be used as the source
of palladium without compromising the efficiency of the
reaction. Elevation of the temperature had a detrimental
PCy2
PCy2
P(t-Bu2)
P(t-Bu2)
Me2N
Me2N
A
D
B
C
Figure 1.
Keywords: Pyrazole; Phosphine ligand; Suzuki coupling; Palladium.
*
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.2004.11.016

9526
A. Mukherjee, A. Sarkar / Tetrahedron Letters 45 (2004) 9525–9528
R2
R1
R2
R1
R1
R2
N
N
O
O
sec-BuLi/n-BuLi
N
N
NH2NH2. H2O
PhB(OH)2
Cu(OAc)2
Pyridine
PPh2Cl
N
N
R1
H
R2
PPh2
1
Ligand
R1
R2
Yield
1a
1b
1c
1d
CH3
CH3
CH3
CH3
CH3
56%
48%
34%
26%
tert-butyl
Phenyl
Mesityl
Scheme 1.
Pd2(dba)3.CHCl3
4-bromonitrobenzene and phenylboronic acid, while lig-
and 1b afforded the coupling product in 81% isolated
yield (Table 1, entries 9 and 10). Similarly, reaction of
the sterically congested halide, 2-bromomesitylene, af-
forded much higher yield of coupling product in the
presence of ligand 1b than ligand 1a (Table 1, entries 7
and 8). The catalytic efficiency remained practically un-
changed when the ligand 1b was used and the catalyst
concentration was reduced by three orders of magnitude
as shown by the reaction of 4-bromoacetophenone4b,g
(Table 2). The coupling reaction between phenylboronic
acid and 4-bromoacetophenone in the presence of
Pd2(dba)3 (1mol%) alone at 80°C for 12h gave only
15% of the cross-coupled product.
Ligand 1a/ 1b/ 1c/ 1d
Br
Ph
PhB(OH)2, CsF
R
R
2
3
Scheme 2.
effect on the reaction presumably due to rapid catalyst
decomposition. Although the efficiency of the reaction
is high at 65°C (for ligand 1b) and at 80–85°C for
1a, no significant reaction took place at ambient
temperature. The use of 0.5mol% of Pd2(dba)3 with
ligand 1a resulted in a diminished yield of coupling
product compared to the original conditions (Table 1,
entry 1).
Presented in Table 3 are the results obtained from cou-
pling reactions of aryl chlorides with phenylboronic
acid. While ligand 1a did not promote coupling of the
aryl chloride with phenylboronic acid, ligands 1b, 1c
The reactivity difference between Pd(0)-complexes of lig-
ands 1a and 1b is evident from the examples in Table 1.
Ligand 1a did not furnish any coupling product between
Table 1. Suzuki coupling reactions of aryl bromides with phenylboronic acid in the presence of Pd2(dba)3 and ligand 1a/1b/1c/1da
Entry
Substrate 2
Ligand
Temp (°C)
Time (h)
Product 3
Yield (%)
1
4-Bromoanisole
4-Bromoanisole
1a
1b
1c
1d
1a
1b
1a
1b
1a
1b
1a
85
65
80
80
85
65
85
70
80
60
80
8 (12)a
4-Methoxybiphenyl
4-Methoxybiphenyl
4-Methoxybiphenyl
4-Methoxybiphenyl
2-Methylbiphenyl
2-Methylbiphenyl
2,4,6-Trimethylbiphenyl
2,4,6-Trimethylbiphenyl
4-Nitrobiphenyl
80 (61%)b
2
3
8
97 (91%)b
61
3
4-Bromoanisole
4-Bromoanisole
4
8
61
65
5
2-Bromotoluene
2-Bromotoluene
2-Bromomesitylene
2-Bromomesitylene
4-Bromonitrobenzene
4-Bromonitrobenzene
4-Bromotoluene
7
6
3
95
31
7
10
8
8
62
9
10
3
0
81
82 (74)c
10
11
4-Nitrobiphenyl
4-Methylbiphenyl
6
a Reaction conditions: aryl bromide (1mmol), phenylboronic acid (1.5mmol), Pd2(dba)3 (1mol%), ligand (4mol%), Pd:1 = 1:2, CsF (3mmol),
toluene (3mL), temperature 65–80°C, reaction time 2.5–10h. Yields given here represent yields of isolated product (average of two runs).
b 0.5mol% Pd2(dba)3 was used.
c 2mol% of Pd(OAc)2 was used.
Table 2. Influence of low catalyst loading on the coupling reactiona
Aryl halide
Product
Pd (mol%)
Yield (%)
2
100
99
99
1
0.1
0.01
0.001
Br
COCH3
COCH3
98
97
a Reactants were heated to 65°C for 2h using 1mmol of aryl bromide, 1.5mmol of phenylboronic acid, 3mmol of CsF, 1mol%
Pd2(dba)3(Pd:1b = 1:2), and toluene (3mL). Results are based upon isolated material (average of two runs).

A. Mukherjee, A. Sarkar / Tetrahedron Letters 45 (2004) 9525–9528
Table 3. Suzuki coupling aryl chloride with ligand 1a, 1b, 1c and 1da
9527
Entry
Substrate
Ligand
Temp (°C)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
4-Chloroacetophenone
4-Chloroacetophenone
4-Chloroacetophenone
4-Chloroacetophenone
4-Chlorotoluene
1a
1b
1c
1d
1b
1b
1b
1b
85
65
10
4
4-Acetylbiphenyl
4-Acetylbiphenyl
4-Acetylbiphenyl
4-Acetylbiphenyl
4-Methylbiphenyl
4-Formylbiphenyl
4-Methoxybiphenyl
4-Nitrobiphenyl
0
89
31
29
83
69
69
75
70–75
70–75
70
10
10
4
4-Chlorobenzaldehyde
4-Chloroanisole
4-Chloronitrobenzene
70
75
5
5
70
4
a Reaction conditions: aryl chloride (1mmol), phenylboronic acid (1.5mmol), CsF (3mmol), toluene (3mL), Pd2(dba)3 (1mol%) and ligand
(4mol%). Results are based upon isolated material (average of two runs).
and 1d were useful ligands for the reaction. Among 1b–
d, ligand 1b with a tert-butyl group at the 3-position of
pyrazole was the most effective (Table 3, entries 1, 2, 3
and 4).
acids. Exploration of other pyrazole-based ligand struc-
tures as well as mechanistic details of this reaction are
being studied.
Acknowledgments
Both electron rich and electron deficient aryl chlorides
were activated by ligand 1b, while ligands 1c and 1d
worked only for electron deficient aryl chlorides where
yields were not good. We conclude that ligand 1b com-
bines steric and electronic factors favorable for all the
catalytic steps (oxidative addition, transmetalation and
reductive elimination) of the Suzuki reaction despite
being a triarylphosphine.
One of us (A.M) would like to thank CSIR, India, for a
research fellowship.
References and notes
1. (a) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047–
1062; (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176–4211.
The similarity of the structures of ligands 1a–d with Buch-
waldÕs A–D cannot be overlooked, but significant dif-
ferences merit discussion. The phosphorus atom in the
set of ligands, 1a–d, is attached to three aryl rings unlike
BuchwaldÕs, hence the donor characteristics of the phos-
phine is different. Secondly, a crystal structure of Buch-
waldÕs complex reveals an unusually short contact
between the metal atom and the carbon of the aromatic
substituent, a feature that is said to induce the observed
rate accelerating effect.8 One can visualize a coordinat-
ing interaction with palladium via N1 of the pyrazole,
in the same manner as the ipso carbon of a phenyl ring
was shown to coordinate in BuchwaldÕs catalyst. Alter-
natively, we can invoke an g2-coordination by the N1–
N2 bond of pyrazole as characterized by Winter9 for
early transition metal complexes. In both of these
assumptions, a chelate structure rather than monoden-
tate ligand behavior is implied. We believe that involve-
ment of a chelated intermediate is also indicated by the
dramatic change in catalyst activation for chloride when
a 3-methyl group was changed to a 3-tert-butyl group on
the pyrazole. For a monodentate ligand where only
phosphorus is the coordinating atom, steric perturba-
tion on pyrazole would not have made such a great dif-
ference. Chelation might stabilize a Ôresting stateÕ where
coordinative unsaturation is temporarily contained by
the participation of pyrazole.10 The bulkier the pyrazole,
the faster is the dissociation when the metal enters the
next catalytic cycle. This can also explain the steric
acceleration effect as observed.
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.
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; (c) Hundertmark, T.;
Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000,
2, 1729–1731; (d) Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2001, 123, 2719–2724; (e) Littke, A. F.; Schwarz, L.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 6343–6348.
4. (a) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R.,
Jr. Org. Lett. 2001, 3, 1555–1557; (b) Grasa, G. A.; Hillier,
A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077–1080; (c)
Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 16194–16195; (d) Hu, Q.-S.; Lu, -Y.; Tang,
Z.-Y.; Yu, H.-B. J. Am. Chem. Soc. 2003, 125, 2856–2857;
(e) LeBlond, C. R.; Andrews, A. T.; Sowa, J. R., Jr.; Sun,
Y. Org. Lett. 2001, 3, 1555–1557; (f) Jensen, J. F.;
Johannsen, M. Org. Lett. 2003, 5, 3025–3028; (g) Albis-
son, D. A.; Bedford, R. B.; Lawrence, S. E.; Scully, P. N.
Chem. Commun. 1998, 2095–2096.
5. Typical procedure:
Ligand 1b: n-BuLi (2.3mL of 1.6M, 2.55mmol) was added
dropwise to N-phenyl-3-t-butyl-5-methylpyrazole (0.53g,
2.48mmol) in 3mL THF at 0°C. The ice bath was
removed after addition of n-buLi. The color of the
reaction mixture gradually changed into yellow then
brown and stirring was continued for 6h. PPh2Cl
(0.56mL, 2.55mmol) was added at 0°C and stirring was
continued for another 4h. After the usual work up a semi-
solid product was obtained which was purified by column
chromatography on silica gel (eluting with acetone/pet
In summary, we have established that steric modulation
of the structure of a set of pyrazole-based bidentate
ligands for Pd(0) can provide efficient catalysts for the
Suzuki reaction between aryl chlorides and arylboronic

9528
A. Mukherjee, A. Sarkar / Tetrahedron Letters 45 (2004) 9525–9528
ether, 1:10). Yield: 0.47g (48%). mp: 99.5°C. IR (Neat):
(b) General procedure for Suzuki coupling: An oven dried
round bottomed flask was evacuated and flushed with
argon and charged with Pd2(dba)3. CHCl3 (1mol%),
ligand 1 (4mol%), phenylboronic acid (1.5mmol) and
base (3mmol). The flask was evacuated and flushed with
argon. Aryl halide (1mmol) and toluene (3–5mL) were
added to the reaction mixture by a syringe. The reaction
mixture was heated (65–85°C) with stirring for 2–10h and
the reaction was monitored by TLC. The reaction mixture
was then cooled to room temperature, filtered through
Celite and washed with dichloromethane. The crude
material was purified by flash column chromatography.
The identity of each product was confirmed by compar-
ison with literature spectroscopic data: 4-methoxybiphen-
yl,11a 2-methylbiphenyl,11b 2,4,6-trimethylbiphenyl,11c 4-
nitrobiphenyl,11d 4-methylbiphenyl,2a 4-acetylbiphenyl,11e
and 4-formylbiphenyl.11f
1
1552cmÀ1. H NMR (CDCl3, 200MHz) d: 7.46–7.29 (m,
14H, PhH), 6.04 (s, 1H, PzH), 2.21 (s, 3H, CH3), 1.22 (s,
9H, C(CH)3). 13C NMR (CDCl3, 50.32MHz): d 161.3,
144.1, 143.6, 139.3, 137.9, 137.6, 136.9, 134.7, 134.2, 133.7,
129.3, 128.5, 128.2, 127.8, 102.2, 31.8, 30.3, 11.9. 31P
NMR (CDCl3, 81.02MHz): d: À13.23ppm. Anal. Calcd
for C26H27N2P(398) Cal: C, 78.39%; H, 6.78%; N, 7.03%.
Found: C, 78.32%; H, 6.67%; N, 6.98%.
Spectral and analytical data for ligands 1a, 1c and 1d:
1
Ligand 1a: mp: 110°C. IR (Nujol): 1552cmÀ1. H NMR
(CDCl3, 200MHz): d 7.31 (br s, 14H, PhH), 5.86 (s, 1H,
PzH) 2.19 (s, 3H, CH3), 2.00 (s, 3H, CH3) ppm. 13C NMR
(CDCl3, 50.32MHz): d 147.7, 143.2, 142.8, 139.9, 137.8,
137.4, 136.1, 135.9, 134.0, 133.9, 133.5, 129.1, 128.4, 128.1,
127.9, 127.7, 105.1, 13.2, 11.4ppm. 31PNMR (CDCl
,
3
81.02MHz): d À23.89ppm. Anal. Calcd for C23H21N2P
(356): C, 77.52%; H, 5.89%; N, 7.86%. Found: C, 77.29%;
H, 5.64%; N, 7.24%. Ligand 1c: mp: 103°C. 1H NMR
(CDCl3, 300MHz) d: 7.54–7.15 (m, 19H, PhH), 6.36 (s,
1H, PzH), 2.22 (s, 3H, CH3). 13C NMR (CDCl3,
75.47MHz) d: 150.8, 141.6, 135.6, 135.5, 132.9, 132.0,
131.8, 131.7, 131.5, 131.4, 131.3, 131.1, 129.2, 129.1, 129.0,
128.3, 128.2, 128.1, 128.0, 127.8, 127.5, 125.4, 103.5, 11.6.
31PNMR (CDCl 3, 81.02MHz): d À18.14ppm. Anal.
Calcd for C28H23N2P(418) Cal: C, 80.38%; H, 5.50%; N,
6.69%. Found: C, 80.21%; H, 5.57%; N, 6.91%.
8. Kocovsky, P.; Vyskocil, S.; Cisarova, I.; Sejbal, J.;
Tislerova, I.; Smrcina, M.; Lloyd-Jones, G. C.; Stephen,
S. C.; Butts, C. P.; Murray, M.; Langer, V. J. Am. Chem.
Soc. 1999, 121, 7714–7715.
9. (a) Guzei, I. A.; Baboul, A. G.; Yap, G. P. A.; Rheingold,
A. L.; Schlegel, H. B.; Winter, C. H. J. Am. Chem. Soc.
1997, 119, 3387–3388; (b) Guzei, I. A.; Winter, C. H.
Inorg. Chem. 1997, 36, 4415–4420; (c) Yelamos, C.; Heeg,
M. J.; Winter, C. H. Inorg. Chem. 1999, 38, 1871–1878.
10. Ligand 1a has been used for making complexes with other
late transition metals such as, Ni(II) [CCDC No 250554]
and Cu(I) [CCDC No 250553]. In both cases the pyrazole
nitrogen and phosphine act as bidentate ligands as proved
Ligand 1d: mp: 107°C. 1H NMR (CDCl3, 300MHz) d:
7.52–7.10 (14H, m, PhH),6.85 (2H, s, PhH), 6.04 (1H, s,
PzH), 2.28 (3H, s, CH3), 2.13 (3H, s, CH3), 2.02 (6H, s,
2CH3). 13C NMR (CDCl3, 75.47MHz) d: 150.9, 149.2,
141.4, 140.2, 139.9, 138.7, 138.3, 137.3, 137.0, 130.8, 129.3,
128.8, 128.5, 128.4, 128.2, 127.9, 126.9, 126.0, 125.9, 124.4,
by their crystal structure.
preparation.
A manuscript is under
11. (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) Zapf, A.; Beller, M. Chem. Eur.
J. 2000, 6, 1830–1833; (e) Barba, I.; Chinchilla, R.;
Gomez, C. Tetrahedron 1990, 46, 7813–7822; (f) Dupuis,
C.; Adiey, K.; Charruault, L.; Michelet, V.; Savignac, M.;
Genet, J.-P. Tetrahedron Lett. 2001, 42, 6523–6526.
122.3, 108.1, 20.9, 20.5, 12.6. 31PNMR (CDCl
,
3
81.02MHz) d: À20.70ppm. Anal. Calcd for C31H29N2P
(460) Cal: C, 80.86%; H, 6.30%; N, 6.08%. Found: C,
80.53%; H, 5.97%; N, 6.23%.
6. Mukherjee, A.; Sarkar, A. Arkivoc 2003, 87–95.
7. (a) We found that CsF was a more effective base than Cs2-
CO3 and K3PO4. Toluene was a better solvent than THF
or dioxane.