Novel bulky pyrazolylphosphine ligands for the Suzuki coupling of aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2009.10.056

Bulky 1-(3,5-di-tert-butyl)pyrazolyl-dicyclohexylphosphine and 1-(3,5-di-tert-butyl)pyrazolyl-di-tert-butylphosphine were prepared from the reactions of 3,5-di-tert-butylpyrazolide and corresponding chlorodialkylphosphines. They were successfully employed

Full text of DOI:10.1016/j.tetlet.2009.10.056

Tetrahedron Letters 50 (2009) 7217–7219
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel bulky pyrazolylphosphine ligands for the Suzuki coupling
of aryl chlorides
*
Jenifer Jackson, Aibing Xia
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada B3M 2J6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2009
Revised 9 October 2009
Accepted 11 October 2009
Available online 29 October 2009
Bulky 1-(3,5-di-tert-butyl)pyrazolyl-dicyclohexylphosphine and 1-(3,5-di-tert-butyl)pyrazolyl-di-tert-
butylphosphine were prepared from the reactions of 3,5-di-tert-butylpyrazolide and corresponding
chlorodialkylphosphines. They were successfully employed as ligands in the Suzuki coupling reactions
of phenylboronic acid and various aryl bromides and chlorides.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Unsymmetrical ligands
Pyrazolylphosphines
Aryl chlorides
The Suzuki reaction
Palladium-catalyzed cross-coupling reactions,1,2 such as the Su-
zuki coupling of arylboronic acid and aryl halides,3 are powerful
and versatile tools for carbon–carbon bond formation in organic
synthesis. The efficiency of the catalysts depends largely on the
ancillary ligands. Among the most commonly used ligands are
electron-rich and sterically hindered tertiary phosphines. Func-
tionalized phosphines, such as N-substituted aminophosphines,
have attracted considerable interest as potential ligands and have
demonstrated high activities.4 Recently, unsymmetrical pyrazole-
tethered tridentate PCN-type and bidentate PN-type phosphine li-
gands have been successfully employed in cross-coupling reac-
tions.5,6 Pyrazolylphosphines (Fig. 1), with a single P–N bond
between one phosphino group and one pyrazolyl group (R = Me
or H), have been known for over thirty years.7 However, due to
air- and moisture-sensitivity, their use as ancillary ligands was
limited to metal complexes containing electron-withdrawing
groups such as CO.8,9 We recently reported a pyrazolylphosphine
ligand, 1-(3,5-di-tert-butyl)pyrazolyldiphenylphosphine (1), and
its stable Au(I) complex that did not contain an electron-with-
drawing group.10 The ligand contained sterically hindered tert-bu-
tyl groups on the pyrazolyl moiety and showed improved stability
over its smaller methyl analogues. Here we wish to report the syn-
thesis and catalytic applications of novel bulky pyrazolyldialkyl-
phosphines based on 3,5-di-tert-butylpyrazole.11
R
N
Ph
Ph
N
P
R
Figure 1. Pyrazolylphosphines.
2
12 and 313 (Eq. 1). The compounds showed improved stability over
their smaller methyl analogues7 as both can be handled in air. In
GC/MS analysis, the compounds showed peaks of 376 and 324
which corresponded to the molecular ions of 2 and 3, indicative
of their thermal stability. The results of elemental analysis were
in good agreement with calculated values. Their IR spectra showed
the P–N stretches at 796 and 800 cmꢀ1, within the range of
reported values for m
(P–N) in N-substituted aminophosphines.14
The 1H spectra of both compounds showed a doublet (4JP,H = 2.0
and 2.4 Hz) at 6.0 ppm for the hydrogen on the pyrazolyl moiety,
reflecting the long range interaction between hydrogen and phos-
phorus nuclei. Similar interaction was also observed for the hydro-
gen atoms in the di-tert-butylphosphino group, PtBu2 (3JP,H
=
12.2 Hz) in 3. The 31P{1H} NMR resonances for 2 and 3 were ob-
served at 68.45 and 89.23 ppm, respectively. The chemical shifts
are significantly different from those of pyrazole-tethered phos-
phine compounds without a direct P–N bond, in which the 31P
shifts are often in the upfield region with negative values.6 The
downfield chemical shifts in 2 and 3 suggested that the electroneg-
ative nitrogen atom decreased the electron density on the phos-
phorus atom.
Deprotonation of 3,5-di-tert-butylpyrazole with potassium hy-
dride, followed by treatment of the potassium pyrazolide with
chlorodialkylphosphines, afforded the corresponding compounds
* Corresponding author. Tel.: +1 902 457 6543; fax: +1 902 457 6134.
E-mail address: aibing.xia@msvu.ca (A. Xia).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.056

7218
J. Jackson, A. Xia / Tetrahedron Letters 50 (2009) 7217–7219
Table 2
Suzuki coupling of aryl chloridesa
N
N
R
Pd(OAc)2,
ligand
a) KH, THF
b) PR2Cl
N
H
N
P
R
Cl +
B(OH)2
R
Ph
Cs2CO3,
Dioxane
R
ð1Þ
Entry
R
Ligand
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
NO2
NO2
NO2
CH3CO
CH3CO
CH3CO
CHO
CHO
CHO
Me
Me
Me
CHO
CHO
Me
1
2
3
1
2
3
1
2
3
1
2
3
2
3
2
3
2
3
26
93 (86)c
89
R = cyclohexyl (2) or tert-butyl (3)
5
78 (70)c
43
Next we evaluated the efficiency of the ligands in the Suzuki
coupling reactions of aryl halides and phenylboronic acid. As the
solvent and base may have profound effects on the catalytic effi-
ciency,1 we examined several solvents and bases commonly used
in the Suzuki reactions. 4-Bromoanisole, a deactivated bromide
and a fairly inert halide, was chosen as the aryl halide substrate.15
Compound 1 was used as the ligand for screening purposes. At
100 °C in 1,4-dioxane, with 1 mol % Pd(OAc)2 and ligand loading,
the yield was excellent (91%) when cesium carbonate was used
as the base (Table 1, entry 3). Under similar conditions, the yield
was only 48% without any ligand (entry 9) and 61% when triphen-
ylphosphine was employed as the ligand (entry 10). Thus ligand 1
is essential for the high yield. The yield was also good (81%) in tet-
rahydrofuran (THF) (entry 4). We chose to use dioxane as the sol-
vent and Cs2CO3 as the base for subsequent investigation.
6
44
30
Trace
12
50
93d
57d
27d
85d
10d
54d
Me
MeO
MeO
a
1.0 mmol aryl halide, 1.5 mmol phenylboronic acid, 2.0 mmol Cs2CO3,
0.010 mmol Pd(OAc)2, 0.010 mmol ligand, 3 mL 1,4-dioxane, refluxing, 21 h.
b
GC yields based on aryl chlorides.
Isolated yields.
0.030 mmol Pd(OAc)2, 0.030 mmol ligand.
c
d
We then investigated the efficiency of the catalysts in the cou-
pling reactions of aryl chlorides, which are more abundant and
economically desirable yet less reactive than aryl bromides. A vari-
ety of aryl chlorides were examined, including activated aryl
chlorides such as 1-chloro-4-nitrobenzene, a neutral aryl chloride,
4-chlorotoluene, and a deactivated aryl chloride, 4-chloroanisole.
At 1 mol % catalyst loading, the pyrazolyldiphenylphosphine ligand
1 was largely inefficient in the coupling of aryl chlorides (Table 2,
entries 1, 4, 7, and 10). However, the more electron-rich and steri-
cally hindered dialkylphosphines 2 and 3 gave good to excellent
yields (entries 2, 3, and 5). The coupling of neutral and deactivated
aryl chlorides required a higher catalyst loading (3 mol %). Ligand 2
was the most efficient in the coupling of activated aryl chlorides
(entries 5, 6, 8, 9, 13, and 14), whereas the most sterically hindered
ligand 3 was the most efficient in the coupling of neutral and deac-
tivated aryl chlorides (entries 15–18). For example, a yield of 85%
was obtained for the coupling of 4-chlorotoluene with 3 at
3 mol % catalyst loading. Even though directly P–N-bonded pyraz-
olylphosphine ligands are not as electron-rich as the pyrazole-teth-
ered phosphines,6 the electron-rich tert-butyl groups on the
phosphorus atom and the pyrazolyl moiety can improve the phos-
phines’ donating ability and enhance the oxidative addition of aryl
chloride to the palladium center. Furthermore, the bulky tert-butyl
groups will facilitate the reductive elimination of the biphenyl
product in the catalytic cycle. These factors rendered the bulky
pyrazolylphosphines efficient ligands in the Suzuki coupling of aryl
chlorides.
In conclusion, novel bulky pyrazolylphosphines have been pre-
pared and characterized. The ligands showed improved stability
over previously reported smaller methyl analogues. They demon-
strated good to excellent activity in the Suzuki coupling reactions
of various aryl chlorides. The ease of preparation and improved sta-
bility make them viable ligands for late transition metal com-
plexes. We are currently exploring the applications of the bulky
ligands in other catalytic transformations.
Acknowledgments
Table 1
Screening of base and solventa
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC) and Canada Foundation for Innovation (CFI)
for financial support.
Pd(OAc)2, 1
H3CO
Br +
PhB(OH)2
H3CO
Ph
Base,
Solvent
Entry
Solvent
Base
Yieldb (%)
References and notes
1
2
3
4
5
6
7
8
9
Toluene
DMF
1,4-Dioxane
THF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
K3PO4
K2CO3
NaOAc
Cs2CO3
Cs2CO3
29
19
91
82
75
77
63
27
48c
61d
1. (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester, UK, 2004. p 105;
(b) Negishi, E.. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley: Chichester, UK, 2002; Vol. 1. p 215.
2. For reviews, see: (a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555; (b) Marion, N.;
Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440; (c) Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674; (d) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord.
Chem. Rev. 2004, 248, 2283; (e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 4176.
3. (a) Martin, B.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461; (b) Doucet, H. Eur.
J. Org. Chem. 2008, 2013; (c) Suzuki, A. Chem. Commun. 2005, 4759.
4. Recent reviews on aminophosphines: (a) Alajarín, M.; López-Leonardo, C.;
Llamas-Lorente, P. Top. Curr. Chem. 2005, 250, 77; (b) Zubiri, M. R.; Woollins, J.
D. Comments Inorg. Chem. 2003, 24, 189.
5. (a) Inés, B.; SanMartin, R.; Churruca, F.; Domínguez, E.; Urtiaga, M. K.; Arriortua,
M. I. Organometallics 2008, 27, 2833; (b) Gong, J.-F.; Zhang, Y.-H.; Song, M.-P.;
Xu, C. Organometallics 2007, 26, 6487.
10
a
1.0 mmol bromoanisole, 1.5 mmol phenylboronic acid, 2.0 mmol base,
0.010 mmol Pd(OAc)2, 0.010 mmol ligand, 3 mL 1,4-dioxane, 100 °C, 21 h.
b
GC yields based on 4-bromoanisole.
Without any ligand.
PPh3 used as a ligand.
c
d

J. Jackson, A. Xia / Tetrahedron Letters 50 (2009) 7217–7219
7219
6. (a) Sun, Y.; Thiel, W. R. Inorg. Chim. Acta 2006, 359, 4807; (b) Sun, Y.; Hienzsch,
A.; Grasser, J.; Herdtweck, E.; Thiel, W. R. J. Organomet. Chem. 2006, 691, 291; (c)
Mukherjee, A.; Sarkar, A. Tetrahedron Lett. 2004, 45, 9525; (d) Singer, R. A.;
Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis 2003, 1727; (e)
Mukherjee, A.; Sarkar, A. Arkivoc 2003, 9, 87–95; (f) Caiazzo, A.; Dalili, S.; Yudin,
A. K. Org. Lett. 2002, 4, 2597.
1493 w, 1477 m, 1361 s, 1309 m, 1267 w, 1249 m, 1227 w, 1196 w, 1129 s,
1051 w, 990 m, 889 w, 849 m, 796 m, 712 w, 515 m. 1H (C6D6, 500.13 MHz,
ppm): d 5.98 (d, 1H, JP,H = 2.0 Hz, CH of pyrazolyl), 2.51 (m, 2H, cyclohexyl),
1.87 (m, 2H, cyclohexyl), 1.67 (m, 4H, cyclohexyl), 1.55 (m, 4H, cyclohexyl),
1.51 (s, 9H, tBu), 1.3 (s, 9H, tBu), 1.22 (m, 10H, cyclohexyl). 31P{1H} (C6D6,
202.47 MHz, 85% H3PO4 as external reference, ppm): d 68.45.
4
7. (a) Fischer, S.; Peterson, L. K.; Nixon, J. F. Can. J. Chem. 1976, 54, 2710; (b)
Fischer, S.; Hoyano, J.; Peterson, L. K. Can. J. Chem. 1974, 52, 3981.
8. (a) Peterson, L. K.; Davis, H. B.; Leung, P. Y. Inorg. Chim. Acta 1981, 47, 63; (b)
Davis, H. B.; Hoyano, J. K.; Leung, P. Y.; Peterson, L. K.; Wolstenholme, B. Can. J.
Chem. 1980, 58, 151; (c) Cobbledick, R. E.; Dowdell, L. R. J.; Einstein, F. W. B.;
Hoyano, J. K.; Peterson, L. K. Can. J. Chem. 1979, 57, 2285.
9. (a) Tribó, R.; Pons, J.; Yáñez, R.; Piniella, J. F.; Alvarez-Larena, A.; Ros, J. Inorg.
Chem. Commun. 2000, 3, 545; (b) Tribó, R.; Ros, J.; Pons, J.; Yáñez, R.; Alvarez-
Larena, A.; Piniella, J.-F. J. Organomet. Chem. 2003, 676, 38.
13. Preparation of 3: compound 3 was prepared in a similar fashion to that of 2.
However, the mixture was refluxed after the addition of chlorodi-tert-
butylphosphine. Yield: 56%. Mp: 38–40 °C. Anal. Calcd for C19H37N2P: C,
70.33; H, 11.49; N, 8.63. Found: C, 70.58; H, 11.33; N, 8.67. GC/MS (EI): 324
(M+). IR (KBr, cmꢀ1): 2956 s, 2899 m, 2862 m, 1537 s, 1498 w, 1475 m, 1359 s,
1299 m, 1249 w, 1225 w, 1205 w, 1178 m, 1128 m, 1110 w, 991 m, 934 w, 807
w, 800 m, 648 w, 516 m. 1H (C6D6, 500.13 MHz, ppm): 6.01 (d, 1H,
4JP,H = 2.4 Hz, CH of pyrazolyl), 1.49 (s, 9H, tBu), 1.40 (s, 9H, tBu), 1.29 (d,
3JP,H = 12.2 Hz, 18H, tBu2P). 31P{1H} (C6D6, 202.47 MHz, 85% H3PO4 as external
reference, ppm): d 89.23.
10. Xia, A.; Voges, M.; Seward, C. Inorg. Chem. Commun. 2007, 10, 1339.
11. Elguero, J.; Gonzalez, E.; Jacquuier, R. Bull. Soc. Chim. Fr. 1968, 4176.
14. Sisler, H. H.; Smith, N. L. J. Org. Chem. 1961, 26, 611.
12. Preparation of 2: Potassium hydride (0.44 g, 11.0 mmol) was added to
a
15. General procedures for Suzuki reactions: A 20-mL reaction tube was charged with
an aryl halide, phenylboronic acid, Pd(OAc)2, a ligand, and a base in 3 mL of
solvent under argon and heated to 100 °C for 21 h. The mixture was then cooled
to room temperature. The volatiles were removed under a reduced pressure. The
organic product was extracted with ether and analyzed on an Agilent 6890 GC-
FID instrument. The GC yields were calculated based on the unreacted aryl halide
and calibrated relative to standards containing the aryl halide starting material
and biphenyl product. Pure products were obtained by flash column
chromatography on silica gel using 5% ethyl acetate–hexane as an eluent.
solution of 3,5-di-tert-butylpyrazole (1.00 g, 5.55 mmol) in 30 mL of THF. The
mixture was stirred at room temperature for three hours and filtered.
Chlorodicyclohexylphosphine (1.29 g, 5.55 mmol) was added to the filtrate.
After stirring for two days at room temperature, the mixture was filtered. The
volatiles were removed under vacuum. Recrystallization of the crude product
from hexane afforded crystalline solids. Yield: 1.50 g (72%). Mp: 86–88 °C.
Anal. Calcd for C23H41N2P: C, 73.36; H, 10.97; N, 7.44. Found: C, 73.24; H, 10.71;
N, 7.75. GC/MS (EI): 376 (M+). IR (KBr, cmꢀ1): 2956 s, 2927 s, 2950 s, 1537 s,