Solid-phase Suzuki cross-coupling reactions using a phosphine ligand based on a phospha-adamantane framework

Article abstract of DOI:10.1016/j.tetlet.2004.05.110

The use of a catalyst system based on Pd₂dba₃· CHCl₃ and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha- adamantane allows for Suzuki coupling aryl halides with an array of boronic acids on a solid-phase platform. The reactions can be carried out at room temperature with low palladium loadings in high yields.

Full text of DOI:10.1016/j.tetlet.2004.05.110

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5661–5663
Solid-phase Suzuki cross-coupling reactions using a phosphine
ligand based on a phospha-adamantane framework
Stephan A. Ohnmacht,a Tim Brenstrum,a Konrad H. Bleicher,b James McNultya and
Alfredo Caprettaa,*
aDepartment of Chemistry, McMaster University, Hamilton, Ontario, Canada L8S 4M1
bF. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland
Received 7 May 2004; revised 18 May 2004; accepted 20 May 2004
Available online 10 June 2004
Abstract—The use of a catalyst system based on Pd2dba3ꢀCHCl3 and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-
adamantane allows for Suzuki coupling aryl halides with an array of boronic acids on a solid-phase platform. The reactions can be
carried out at room temperature with low palladium loadings in high yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Reactions involving organopalladium cross-coupling
have become indispensable methods for carbon–carbon
bond formation.1 For example, the Suzuki–Miyaura
reaction2 (the Pd-mediated coupling of an aryl or alk-
enyl halide with an organoboron reagent) has been
widely employed in organic syntheses and its use well
documented in the chemical literature. Recently, the
scope of applicability of palladium-catalyzed cross-
coupling chemistry has been expanded as a result of the
development of synthetic protocols employing sterically
demanding, electron-rich phosphine ligands.3 Utiliza-
tion of catalytic systems incorporating these bulky
phosphines has facilitated couplings involving even the
least reactive coupling partners in the Suzuki,4 Stille,5
Sonogashira,6 aryl amination7 and ketone arylation8
reactions. For example, our work involving the devel-
opment of new phosphine ligands based on a phospha-
adamantane framework has allowed for effective Suzuki
cross-coupling of a variety of aryl halides and boronic
acids under mild conditions.9
optimization of biologically active substances. An im-
mense variety of synthetic transformations can now be
achieved on polymer support and, not surprisingly, a
number of examples exist describing the utilization of
the Suzuki reaction on a solid-phase platform.10 A range
of systems has been prepared using the reaction as a key
step.11 Many of these cases, however, describe reactions
employing PPh3 as the ligand and often require elevated
temperatures to achieve coupling of the less-reactive
coupling partners. In addition, large amounts of Pd
catalyst (as much as 10–20 mol % in some cases) are
required to achieve reasonable yields. The present paper
describes a general Suzuki reaction methodology for
solid phase that permits the coupling of aryl halides with
an array of boronic acids at room temperature with low
palladium loadings by taking advantage of a catalyst
system incorporating 1,3,5,7-tetramethyl-2,4,8-trioxa-6-
phenyl-6-phospha-adamantane (PA-Ph, Fig. 1) as a
ligand.12
p-Iodo-, p-bromo or p-chloro-benzoic acid was linked to
commercially available tritylchloride–polystyrene resin
Solid-phase synthetic methodologies, meanwhile, have
become well established in the drug discovery process
allowing for the preparation of arrays of compounds
and combinatorial libraries for the discovery and
CH3
O
P
H C
3 O
CH3
Keywords: Solid-phase synthesis; Suzuki reaction; Organopalladium
chemistry.
O
CH3
*Corresponding author. Tel.: +1-905-525-9140x27318; fax: +1-905-5-
22-2509; e-mail: capretta@mcmaster.ca
Figure 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.110

5662
S. A. Ohnmacht et al. / Tetrahedron Letters 45 (2004) 5661–5663
to provide the solid-supported aryl halides required.13
The loading was determined to be roughly 1.00 mmol/g
based on weight change. Given the established rates of
oxidation addition of the aryl halides to palladium,
attention was first directed to the Suzuki couplings
involving the aryl bromide resin as this represented the
intermediate case with respect to coupling difficulty.
Initial screening revealed that Pd2dba3ꢀCHCl3 was the
best palladium source for the reaction and that optimum
conditions were achieved when using metal to phospha-
adamantane ligand in a 1:1 ratio. While the reactions
proceed using various bases (CsF, CsCO3, KF) or sol-
vents (toluene, toluene/THF mixtures), the best results
were obtained using potassium phosphate as the base
and THF as the solvent. Furthermore, in the absence of
the PA-Ph ligand, couplings involving the aryl bromide
resin and phenyl boronic acid resulted in very low yields
(generally less than 5%).
With optimum conditions in hand,14 the scope of the
developed solid-phase Suzuki coupling was determined
via the screening of a variety of boronic acids. The
couplings involving the aryl bromide resin were found to
proceed smoothly using 2% Pd2dba3ꢀCHCl3 and 4% PA-
Ph at room temperature over a period of 15 h. The
benzoate was cleaved from the polymer support using
10% TFA in dichloromethane and provided the prod-
ucts shown in Table 1.15 The purity of the cleaved
1
biaryls was confirmed by HPLC and H NMR. Percent
conversion was then calculated by comparing the rela-
tive amounts of uncoupled benzoic acid with biaryl
product. As seen in Table 1, a diverse array of boronic
acids could be coupled to the resin using the described
Table 1.
1. 2% Pd2dba3.CHCl3
4% Ph-PA, 2.5 eq. K3PO4
THF, r.t.
O
O
Ar
Ar B(OH)2
X
+
HO
Y
O
Y
2. cleave from resin
Entry
Boronic acid
Biaryl product
% Conversions
Y ¼ CH
X ¼ Br
Y ¼ N
X ¼ Cl
O
1
2
96
91
B(OH)2
HO
O
Y
B(OH)2
92
90
HO
O
Y
Y
3
4
100
100
89
93
O
O
B(OH)2
O
HO
O
O
O
O
B(OH)2
B(OH)2
HO
O
Y
Y
5
6
91
42
96
83
HO
O
B(OH)2
HO
O
Y
Y
Y
7
8
91
84
56
78
CF3
B(OH)2
CF3
Cl
HO
O
Cl
O
B(OH)2
HO
O
9
58
76
62
68
B(OH)2
HO
O
Y
Y
O
S
S
10
B(OH)2
HO

S. A. Ohnmacht et al. / Tetrahedron Letters 45 (2004) 5661–5663
5663
5. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38,
2411.
6. Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566;
Hundertmark, T.; Littke, A. F.; Buchwald, L. S.; Fu,
G. C. Org. Let. 2000, 2, 1729; Bohm, V. P. W.; Herrmann,
W. A. Eur. J. Org. Chem. 2000, 22, 3679.
7. Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38,
4807; Also see: Wolfe, J. P.; Buchwald, S. L. Angew.
Chem., Int. Ed. 1999, 38, 2413; Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67,
5553.
8. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234.
9. Adjabeng, G.; Brenstrum, T.; Wilson, J.; Frampton, C.;
Robertson, A.; Hillhouse, J.; McNulty, J.; Capretta, A.
Org. Lett. 2003, 5, 953.
10. Uozumi, Y.; Hayashi, T. In Handbook of Combinatorial
Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W.,
Eds.; Wiley-VCH: New York, 2002; Vol. 1, Chapter
19; Lorsbach, B. A.; Kurth, M. J. Chem. Rev. 1999, 99,
1549.
11. For examples see: Ferguson, R. D.; Su, N.; Smith, R. A.
Tetrahedron Lett. 2003, 44, 2939; Bork, J. T.; Lee, J. W.;
Chang, Y.-T. Tetrahedron Lett. 2003, 44, 6141; Backes,
B. J.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116,
11171.
protocol. Most interesting are those involving the
deactivated systems such as entries 7–10 or sterically
demanding substrates such as 4 and 6. In all cases, the
boronic acids were efficiently coupled in high yields. It is
worth pointing out that while the reactions were allowed
to take place over 15 h, in some cases coupling could be
achieved in less time. For example, cleavage of entry 3
after 2 h afforded an 85% yield of the biaryl benzoate.
As previously described by Guiles et al.,16 polymer
bound p-iodobenzoic acid can be coupled in high yields
at room temperature using 5–10 mol % of a suitable
palladium catalyst (such as Pd2dba3) with no additional
ligand. Repeating these reactions with our optimized
conditions, we found that the addition PA-Ph resulted
in no appreciable gain in either yield (quantitative with
each boronic acid listed in Table 1) or the rate of Suzuki
coupling. It should be noted, however, that the immo-
bilized aryl iodide used in the both our study and that of
Guiles represents an activated Suzuki coupling partner.
While the addition of the PA-Ph ligand had a minor
influence in this case, its effect is likely to be more pro-
nounced in systems wherein the immobilized aryl iodide
contains electron donating groups. Work to confirm this
is ongoing in our laboratory.
12. Available from Cytec Canada, PO Box 240, Niagara Falls,
Ontario, Canada L2E 6T4.
13. General procedure for resin loading: Tritylchloride-poly-
styrene resin (2.00 g, 2.88 mmol, available from PepChem,
Reutlingen, Germany, loading 1.44 mmol/g) was treated
with the appropriate p-halobenzoic acid (1.5 equiv), diiso-
propylethyl amine (3 equiv, 1.48 mL) in dry CH2Cl2
(20 mL). Dry DMF (0.5 mL) was added to fully dissolve
the starting material. Reactions were carried out at room
temperature over 18 h. The resin was then washed succes-
sively with MeOH (20 mL), DMF (2 · 20 mL), MeOH
(2 · 20 mL), CH2Cl2 (2 · 20 mL), and tert-butylmethyl
ether (20 mL). The resin was dried over-night under high
vacuum until a constant weight was obtained. Loadings
were determined by weight increase.
14. General procedure for the Suzuki coupling: The resin
loaded with the p-halobenzoic acid (0.19 mmol, based on a
loading of 0.94 mmol/g), K3PO4 (100 mg, 0.47 mmol),
boronic acid (0.75 mmol), phenyl-phospha-adamantane
(2.2 mg, 0.004 mmol), and Pd2dba3ꢀCHCl3 (3.9 mg,
0.002 mmol) were placed in the reaction vessel and flushed
with argon for 10 min. Tetrahydrofuran (7 mL) and
distilled water (150 lL) were added and reaction vessel
agitated at room temperature for 15 h. The resin was then
washed successively with MeOH (7 mL), DMF (7 mL),
7 mL of a quench solution (containing 50 mg of sodium-
diethylthiocarbamate, 50 mL of N-ethyldiisopropylamine
and 10 mL of DMF), MeOH (7 mL) and CH2Cl2
(2 · 7 mL) before being dried under vacuum for 18 h at
elevated temperature.
Attempts to couple the analogous aryl chloride resin
resulted in low yields even at elevated temperatures.
When 6-chloronicotinic acid was used in place of
p-chloro-benzoic acid, however, the resultant polysty-
rene resin readily underwent the Suzuki reaction at
room temperature in the presence of 2% Pd2dba3ꢀCHCl3
and 4% PA-Ph in excellent yields. The results appear in
Table 1.
The Suzuki protocol described above is readily appli-
cable to parallel synthesis, requiring less catalyst and
facilitating couplings at lower temperatures than previ-
ously published procedures. Applications involving the
palladium/PA-Ph catalyst system in other organopalla-
dium cross-coupling reactions on a solid-phase platform
are currently being developed.
Acknowledgements
The authors wish to thank F. Hoffmann-La Roche AG,
McMaster University, Cytec Canada Inc. and the Nat-
ural Sciences and Engineering Research Council of
Canada for their financial support.
15. General procedure for the cleavage of the product from
the resin: Cleavage of the product from the resin was
achieved by treatment with the resin with a solution of
freshly prepared 10% TFA in dry CH2Cl2 for 1.5 h at
room temperature. The spent resin was filtered off and the
solvent evaporated under reduced pressure. The pure
products were obtained after heating under vacuum for
12 h to remove residual Hunig’s base and DMF. Com-
pound identity and purity was determined by 1H NMR
and HPLC.
References and notes
1. Metal-Catalyzed Cross Coupling Reactions; Diederich, F.,
Stang, P., Eds.; Wiley-VCH: New York, 1998.
2. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
3. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
4. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020; Yin, J.; Rainka, M. P.; Zhang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1162.
16. Guiles, J. W.; Johnson, S. G.; Murray, W. V. J. Org.
Chem. 1996, 61, 5169.