Palladium-Catalyzed Animation of Aryl Halides on Solid Support

Article abstract of DOI:10.1021/ol027119s

(Matrix Presented) The first examples of the Pd(0)-catalyzed amination of aryl halides using Rink-resins as nitrogen source are described. Pd₂dba₃/BINAP/NaO-t-Bu was found to be the most efficient catalyst/base system, while a solvent mixture of dioxane and tert-butyl alcohol was shown to enhance the selectivity toward the desired monoarylation. Moderate to good yields and excellent purities of the amination products were found with electron-poor aryl halides, while electon-rich aryl halides failed to react under these conditions.

Full text of DOI:10.1021/ol027119s

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4689-4692
Palladium-Catalyzed Amination of Aryl
Halides on Solid Support
Klaus Weigand* and Sylvie Pelka
NoVartis Research Institute, Brunner Strasse 59, A-1235 Vienna, Austria
klaus.weigand@pharma.noVartis.com
Received October 17, 2002
ABSTRACT
The first examples of the Pd(0)-catalyzed amination of aryl halides using Rink-resins as nitrogen source are described. Pd2dba3/BINAP/NaO-
t-Bu was found to be the most efficient catalyst/base system, while a solvent mixture of dioxane and tert-butyl alcohol was shown to enhance
the selectivity toward the desired monoarylation. Moderate to good yields and excellent purities of the amination products were found with
electron-poor aryl halides, while electon-rich aryl halides failed to react under these conditions.
The arylamine moiety is an ubiquitous structural element in
pharmacologically active compounds. The palladium-cata-
lyzed amination of aryl halides, which was developed by
the groups of Buchwald1 and Hartwig,2 opens an attractive
new synthetic route toward this important functional group.
While the classical method for the formation of substituted
arylamines involves a nitration-reduction and substitution
sequence that is often not compatible with other functional
groups, the Buchwald-Hartwig amination procedure is
broadly applicable to a great variety of substrates and
nitrogen donors and uses milder conditions. In 1996, Ward3
and Willoughby4 reported independently their first successful
application of the Buchwald-Hartwig amination procedure
on solid support. Both groups immobilized the aryl bromides
via an amide linkage onto the resin and added a large excess
of the amine. The undesired reduction of the aryl bromides
via â-hydride elimination could be minimized through the
use of chelating phosphine ligands such as BINAP or dppf.
The Pd-catalyzed amination of 2-chloropurines immobilized
on a solid support was described recently.5
In the course of developing synthetic routes toward an
arylamine library on solid support, we became interested in
investigating the use of amine resins as nitrogen sources in
palladium-catalyzed C-N cross-couplings (Scheme 1). In
Scheme 1
this paper, we report our initial results for the coupling of
functionalized aryl halides to acid-labile amine-based solid
supports as nitrogen donors.
In an initial study, we tested seven resins for their ability
to undergo the desired reaction. Thus, amino-functionalized
polystyrene resins with Rink,6 Knorr, Sieber,7 DCHD,8 and
2-chlorotritylamine linkers as well as TentaGel resins with
(1) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. (b) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125-146.
(5) Brill, W. K.-D.; Riva-Toniolo, C.; Mu¨ller, S. Synlett 2001, 1097-
1100.
(6) Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790. Rink amide resin
was purchased from Advanced ChemTech.
(7) Sieber, P. Tetrahedron Lett. 1987, 28, 2107-2110. Sieber amide resin
was purchased from Bachem.
(8) Ramage, R.; Irving, S. L.; McInnes, C. Tetrahedron Lett. 1993, 34,
6599-6602. DCHD resin was purchased from Advanced ChemTech.
(2) (a) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-
2067. (b) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2000.
(3) Ward, Y. D.; Farina, V. Tetrahedron Lett. 1996, 37, 6993-6996.
(4) Willoughby, C. A.; Chapman, K. T. Tetrahedron Lett. 1996, 37,
7181-7184.
10.1021/ol027119s CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/27/2002

a PAL9 and a Rink linker (TentaGel S AM and TentaGel S
RAM, respectively)10 were reacted with excess 4-bromoben-
zonitrile (1a) under the conditions given in Table 1.
Table 2. Evaluation of Ligand and Solvent for Coupling of
4-Bromobenzonitrile (1a) to Rink Resina
Table 1. Coupling of 4-Bromobenzonitrile to Amine Resinsa
4-aminobenzonitrile
linker
yieldb (%)
purityc (%)
Rink
63d
64
28
36
49
87
92
53
86
90
92
Knorr
Sieber
DCHD
Tentagel S AM
Tentagel S RAM
2-chlorotritylamine
31
tracese
a Reaction performed on 0.03-0.07 mmol scale with respect to the amino
groups. b Quantitated by calibrated HPLC. c Determined by HPLC of the
crude product. d No product was formed in the absence of Pd. e Reaction
performed with 10 mol % Pd on a 0.3 mmol scale.
After 20 h reaction time in dioxane, all resins gave a
negative Kaiser test, indicating complete consumption of free
amino groups. The resin was thoroughly washed, dried, and
submitted to TFA cleavage. Gratifyingly, polystyrene resins
fitted with the Rink or the Knorr linker gave the expected
4-aminobenzonitrile (2a) in good yield and purity. The less
hindered Sieber xanthydrylamine polystyrene and DCHD
solid supports gave only a minor yield of 2a. From the two
Tentagel resins tested, only the SAM resin fitted with the
PAL-linker gave a medium yield. In contrast to the poly-
styrene-based Rink-amide, the Tentagel S RAM resin with
the Rink-amide linker gave an unsatisfactory yield of 2a.
No product could be isolated from the 2-chlorotritylamine
resin. In some cases, minor amounts (up to 5 mol % with
respect to the active sites of the resins) of benzonitrile,
formed by â-hydride elimination, could be detected in the
washing solutions. A second cycle of TFA-treatment did not
yield any additional product. We therefore assume that
degradation of the resin under the reaction conditions
accounts for the incomplete mass balance.11 To confirm that
the reaction does not proceed via an SNAr mechanism we
also submitted the Rink amide resin to the reaction without
adding a palladium source. We could not detect any aniline
product under these conditions.
a Reaction performed on 0.03-0.07 mmol scale with respect to the amino
groups on the resin. b Quantitated by calibrated HPLC. c In parentheses:
purity determined by HPLC of the crude product. d 83% isolated yield.e 20
mol % Pd(OAc)2 used instead of Pd2dba3.
NaO-t-Bu was again used as the base. A large excess of
both bromide and base (10 equiv of each with respect to the
amino groups of the resin) were used to ensure complete
reaction. Both BINAP12 and dppf efficiently catalyzed the
desired coupling of 1a to the resin, with BINAP leading to
somewhat higher yields.
In addition, a series of monodentate alkylphosphine
ligands13,14 were tested (entries 4-6) but found to be inferior
to BINAP. The two carbene ligands15 we tested (entries 7
and 8) were found to be as effective as the BINAP ligand.
Not unexpectedly, the high amount of aryl bromide in the
reaction mixture led to the formation of minor quantities of
the doubly arylated product bis(4-cyanophenyl)amine (3a)
We next investigated the most suitable combination of
ligand and solvent. Table 2 summarizes the conversion of
our standard substrate 1a with the polystyrene Rink amine
resin using different types of ligands.
(12) For a review on the Pd/BINAP-system in the amination of aryl
bromides see: Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-
1157.
(13) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722-9723. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158-1174.
(14) Wolfe, J. P.; Buchwald, S. L. Angew. Chem. 1999, 111, 2570-
2573. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
(9) Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; L.; Masada, R.
I.; Huson, D.; Barany, G.J. Org. Chem. 1990, 55, 3730-3743.
(10) TentaGel resins were purchased from Advanced ChemTech.
(11) Gauzy, L.; Le Merrer, Y.; Depezay, J.-C.; Clerc, F.; Mignani, S.
Tetrahedron Lett. 1999, 40, 6005-6008.
4690
Org. Lett., Vol. 4, No. 26, 2002

in some cases, especially with BINAP and the carbene
ligands (Table 2, entries 1, 7, and 8). When phosphines were
used as ligands, this side reaction could be minimized by
utilizing a 1:1 mixture of dioxane and tert-butyl alcohol as
the solvent. The beneficial effect of tert-butyl alcohol as
cosolvent was found to be even more pronounced with
4-bromobenzophenone (1b) as the electrophile (Table 3).
alcohol while NMP and DMF in general gave poor results
(data not shown).
Having established a suitable combination of solvent, resin,
additive and catalyst, we explored the scope of the new
protocol. A diverse series of aryl bromides bearing functional
groups for further elaboration were attached to the resin using
the conditions given in Table 4.17 Aryl bromides with
Table 4. Palladium-Catalyzed Coupling of Aryl Halides with
Diverse Functional Groups to Polystyrene Rink Amine Resin
Table 3. Effect of Cosolvent and Stoichiometry on the Ratio
of Mono- and Diarylation of 4-Bromobenzophenone (1b)
%
equiv
yield 2bb
entry DVB of 1b
solvent
dioxane
dioxane/t-BuOH (1:1)
dioxane/t-BuOH (1:1) 100:0
dioxane 94:6
dioxane/t-BuOH (1:1) 100:0
2b/3ba
(%)
1
2
3
4
5
1
1
1
2
2
2
10
2
10
10
57:43
80:20
50
71
73
60
76
a Determined by HPLC analysis of the crude product. b Quantitated by
calibrated HPLC.
This bromide showed a high tendency toward double
arylation of Rink amine resin. Using only 2 equiv of 1b with
respect to the amino groups on the resin in pure dioxane as
solvent resulted in a 57:43 mixture of 2b and the diarylation
product 3b. In contrast, in a 1:1 dioxane/tert-butyl alcohol
solvent mixture, even with a 10-fold excess of 1b, an
improved ratio of 4:1 in favor of 2b was found. The
formation of 3b could be completely inhibited by applying
only 2 equiv of 1b in a 1:1 dioxane/tert-butyl alcohol
mixture. With carbene ligands, no product could be isolated
when tert-butanol was applied as cosolvent, probably due
to the competitive formation of a complex with the alcohol.16
We speculated that the reduced swelling of the resin in
the more polar solvent mixture might lead to a less accessible
environment in which a second arylation is more difficult
due to steric reasons. This was supported by a control
experiment in which the rink amine was attached to a support
with reduced swelling capacity (polystyrene cross-linked with
2% divinylbenzene). Using this resin indeed gave an
improved ratio of mono- and diarylation (Table 3, entries 4
and 5). Other solvents such as THF, toluene, or DME served
similarly well when used as a 1:1 mixture with tert-butyl
a Quantitated by calibrated HPLC. b Purity determined by HPLC of the
crude product. c 83% yield and 91% purity with THF as solvent and
Pd(OAc)2 instead of Pd2dba3. d 2 equiv of 4-bromobenzophenone were used.
e In addition, 21% p-aminobenzoic acid was formed. f Toluene was used
as solvent.
(15) Arduengo, A. J.; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523-14534. Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 2001, 3,
119-122. Zhang, C.; Huang, J.; Trudell, M. T.; Nolan, S. P. J. Am. Chem.
Soc. 1999, 121, 2674-2678. Huang, J.; Stevens, E. D.; Nolan, S. P.;
Petersen, J. L. Org. Lett. 1999, 1, 1307-1309. Huang, J.; Grasa, G.; Nolan,
S. P. Org. Lett. 1999, 1, 1307-1309. Grasa, G. A.; Mihai S. V.; Huang, J.
Nolan, S. P. J. Org. Chem. 2001, 66, 7729-7737. Stauffer, S. R.; Lee, S.;
Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423-
1426.
electron-withdrawing groups in meta or para-position could
be coupled efficiently under Buchwald-Hartwig conditions
to give, after TFA-cleavage, the expected anilines in moder-
ate to good yield and excellent purity. The comparatively
low yield in the coupling of 3- and 4-bromobenzoic acid
(16) Hocker, J.; Merten, R. Chem. Ber. 1972, 105, 1651-1663.
Org. Lett., Vol. 4, No. 26, 2002
4691

tert-butyl ester is due to the concomitant cleavage of the
tert-butyl ester during TFA-treatment. Ortho-substituted aryl
bromides could also be coupled (entries 8 and 9), albeit
giving significantly reduced yields compared to their meta-
and para-isomers. Unexpectedly, even the electron-poor
4-chlorobenzonitrile could be coupled efficiently to the Rink
amine resin under Pd-BINAP catalysis (entry 10).
desired amination products, while a negative Kaiser test
indicated the absence of amino groups on the resin after the
reaction was stopped. Although BINAP is known to be
effective for the amination of heterocyclic aryl halides,18 we
could not couple nitrogen and sulfur heterocycles (e.g.,
2-chloropyridine, 2- and 3-bromothiophene, 5-bromopyri-
midine) to the resin under these conditions.
In summary, we have developed a novel strategy to attach
electron-poor aromatics to amine resins which should be
useful for the design and synthesis of combinatorial libraries
containing arylamine moieties. Investigations into the exten-
sion of this methodology to electron-rich aromatics using
modified linkers are under way.
Electron-rich aryl halides (entries 11 and 12) gave complex
product mixtures containing only minor amounts of the
(17) General Procedure for the Amination of Amine Resins. The
amination of Rink resin is representative: For Fmoc-deprotection, 100 mg
of Rink resin (0.6 mmol/g) was suspended in 2 mL of 20% piperidine/
DMF at room temperature for 30 min. The resin was washed with DMF,
and the deprotection was repeated for additional 30 min. The resin was
washed thoroughly with DMF, CH2Cl2, MeOH and CH2Cl2 and dried in
vacuo. In an oven-dried Schlenk tube purged with argon, the deprotected
resin was suspended in 1.5 mL of anhydrous dioxane/tert-butyl alcohol 1:1.
After 5 min of stirring, 109 mg (0.6 mmol, 10 equiv) of 4-bromobenzonitrile
was added. After 10 min of stirring, a mixture of 5.6 mg (0.006 mmol, 0.2
equiv based on Pd) of Pd2dba3, 11.2 mg (0.018 mmol, 0.3 equiv) of BINAP,
and 57.6 mg (0.6 mmol, 10 equiv) of NaO-t-Bu were added as solid. The
flask was purged with argon for a few minutes, and the mixture was stirred
in an oil bath at 80 °C for 18-20 h. The reaction mixture was then
transferred to a frit and washed with CH2Cl2, MeOH, CH2Cl2, DMF, THF,
CH2Cl2, MeOH, and CH2Cl2. The product was cleaved from the solid
support by treatment with 5% TFA/CH2Cl2 for 45 min. The resin was filtered
off and washed twice with 2 mL of CH2Cl2, and the combined solutions
were evaporated to dryness. The crude product was dissolved in ethyl acetate
and washed twice with saturated NaHCO3 and brine. The organic layer
was dried with MgSO4, evaporated, and dried in vacuo. The residue was
dissolved in acetonitrile to give a 1 mg/mL solution that was then analyzed
by HPLC.
Acknowledgment. We thank Prof. Johannes Fro¨hlich,
Technical University of Vienna, for support and helpful
discussions.
Supporting Information Available: Text giving repre-
sentative procedures, a detailed description of the HPLC
calibration method, HPLC analyses of the crude products
from Tables 1 and 3, and selected NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL027119S
(18) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240-7241.
4692
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