Polymer-supported copper complex for C-N and C-O cross-coupling reactions with aryl boronic acids

Article abstract of DOI:10.1021/ol048943e

(Chemical Equation Presented) Immobilization of copper onto modified Wang resin provided a polymer-supported copper catalyst, which is effective in cross-coupling reactions between N- or O-containing substrates and arylboronic acids. The copper catalyst is air stable and can be recycled with minimal loss of activity.

Full text of DOI:10.1021/ol048943e

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3079-3082
Polymer-Supported Copper Complex for
C−N and C−O Cross-Coupling
Reactions with Aryl Boronic Acids
Gary C. H. Chiang* and Thomas Olsson
AstraZeneca R&D Mo¨lndal, SE-431 83, Mo¨lndal, Sweden
gary.chiang@astrazeneca.com
Received June 7, 2004
ABSTRACT
Immobilization of copper onto modified Wang resin provided a polymer-supported copper catalyst, which is effective in cross-coupling reactions
between N- or O-containing substrates and arylboronic acids. The copper catalyst is air stable and can be recycled with minimal loss of
activity.
In recent years, the formation of C(aryl)-N and C(aryl)-O
bonds using copper-mediated processes has emerged as one
of the most significant classes of cross-coupling reactions.1
The initial reports of Chan2, Evans,3 and Lam4 illustrated
that arylamines, N-aryl heterocycles, and biaryl ethers can
be prepared using boronic acids and cupric acetate [Cu(OAc)2]
as the catalyst. The advantage of this method was that the
coupling reaction could be performed under milder conditions
(room temperature, weak base, and in air) compared to that
of the classical Ullmann and Goldberg arylation protocols.5
Extensions to the cupric acetate method have included other
organometalloid partners such as hypervalent siloxanes,6
hypervalent diaryliodonium salts,7 and arylstannanes.2b How-
ever, one limitation with the use of these coupling partners
(including boronic acids) was that they require stoichiometric
amounts of Cu(OAc)2. More recently, Collman reported the
first catalytic version of this reaction.8 In this system,
[Cu(OH)‚TMEDA]2Cl2 was used as the source of copper,
but this method worked for only a limited number of
substrates. Two other catalytic systems have since been
reported by Buchwald9 and Lam.10 Buchwald’s system
employed Cu(OAc)2, myristic acid as an additive, and 2,6-
lutidine as the stoichiometric base, and a number of amines
were shown to cross couple with boronic acids efficiently.
Lam’s system also employed Cu(OAc)2 as the catalyst along
with an additional co-oxidant such as pyridine N-oxide.
We sought to develop a polymer-supported copper catalyst
based upon the cupric acetate method in a way similar to
the development of polymer-supported catalysts for pal-
ladium-catalyzed cross-coupling processes such as in the
Heck11 and Suzuki couplings.12 The method would benefit
from lower costs and the improved workup procedure that
is often associated with the polymer-supported palladium
catalysts.13 This would inevitably improve its application in
(1) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-
5449.
(2) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936.
(3) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937-2940.
(4) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944.
(b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.;
Chan, D. M. T.; Combs, A. Synlett 2000, 674-676.
(5) (a) Ullman, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389-2391. (b)
Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691-1696.
(6) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R. H.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601.
(7) Kang, S. K.; Lee, S. H.; Lee, D. Synlett 2000, 1022-1024.
(8) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236. (b)
Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66,
1528-1531
(9) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079.
(10) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415-3418
10.1021/ol048943e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/13/2004

the parallel synthesis of libraries requiring this type of
transformation.
immobilization of copper onto the solid support was ac-
complished by adding Cu(OAc)2 in THF at 40 °C, thus
revealing a strongly colored dark green resin of proposed
structure 5 (0.8 mmol/g).
Our initial experiment using catalyst 5 was performed with
phthalimide. We found that, using the conditions outlined
in Table 1, the yield obtained for this substrate was
Herein we report the synthesis of a polymer-supported
copper catalyst and illustrate its application in a number of
cross-coupling reactions between boronic acids and N-
containing substrates or phenols. Our strategy was to attach
a ligand to a polymer support and then allow it to bind to
copper through ligand exchange. The resulting binding
interaction also needs to be strong enough to prevent the
copper from dissociating from the polymer support under
the reaction conditions. To realize this strategy, we believed
that a polystyrene support with a â-ketoester terminus would
be ideal. Hence, using Cu(OAc)2 as the source of copper,
displacement of acetate would provide a copper-bound
polymer-supported catalyst.14
Table 1. Copper-Mediated Coupling of N- and O-Containing
Compounds with Aryl Boronic Acidsa
Starting from Wang resin (1.2 mmol/g), esterification with
terephthaloyl chloride gave 2 (Scheme 1). Treatment of 2
Scheme 1. Synthesis of the Solid-Phase Copper Catalyst
a All reactions were performed with 3 equiv of boronic acid. b Recycled
catalyst. c Reaction time was extended to 48 h, and an extra 3 equiv of
boronic acid was added after the first 24 h. d Pyridine was used as the base.
e Performed with 4 equiv of boronic acid.
comparable to the literature value of the homogeneous system
(entry 1). Moreover, we noticed a significant improvement
in the reaction time, taking 24 h compared to 48 h.2 Using
these conditions, we tested whether the reaction could be
performed catalytically. With 0.25 equiv of catalyst, the
coupling between 4-phenylpiperidine and p-tolylboronic acid
(entry 2) gave a 35% isolated yield of the coupled product
over 24 h, thus showing that our system was catalytic since
the yield was greater than 25%. With 1.5 equiv of catalyst,
the isolated yield was 51% after 24 h, indicating that the
reaction time is slower using substoichiometric amounts. This
deduction was further supported by the coupling reaction of
ethyl 4-amino benzoate with p-tolylboronic acid (entry 3).
The results show that with 0.25 equiv of catalyst, a 33%
isolated yield was obtained after 24 h. With 1.5 equiv of
catalyst, the isolated yield was 54%. With a 48 h reaction
with diethyl malonate provided a tricarbonyl-functionalized
resin 3. Confirmation of the tricarbonyl moiety was achieved
by cleavage of the resin with trifluoroacetic acid (TFA) to
give the ester 4. With the identity of the resin confirmed,
(11) (a) Andersson, C. M.; Karabelas, K.; Hallberg, A.; Andersson, C.
J. Org. Chem. 1985, 50, 3891-3895. (b) Zhang, Z. Y.; Pan, Y.; Hu, H.
W.; Kao, T. Y. Synth. Commun. 1990, 20, 3563-3574. (c) Liao, Y.; Zhang,
Z. Y.; Hu, H. W. Synth. Commun. 1995, 25, 595-601. (d) Kaneda, K.;
Terasawa, M.; Imanaka, T.; Teranishi, S. J. Organomet. Chem. 1978, 162,
403.
(12) (a) Jang, S. B. Tetrahedron Lett. 1997, 38, 1793-1796. (b) Fenger,
I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287-4290.
(13) (a) Atrash, B.; Reader, J.; Bradley, M. Tetrahedron Lett. 2003, 44,
4779-4782. (b) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
3412-3413. (c) Okamoto, K.; Akiyama, R.; Kobayashi, S. J. Org. Chem.
2004, 69, 2871-2873.
(14) For examples of other copper catalysts on solid supports, see:
Rechavi, D.; Lemaire, M. Chem. ReV. 2002, 102, 3467-3494 and references
therein.
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Org. Lett., Vol. 6, No. 18, 2004

time and 0.25 equiv of catalyst, the isolated yield was 58%,
but additional boronic acid (3 equiv) had to be added after
24 h, as all the boronic acid had been consumed.15 From
these results, we decided that larger amounts of catalyst,
which benefit the reaction time, would be better for the
purposes of developing a general method.
Table 2. Copper-Mediated Coupling of N- and O-Containing
Compounds with Aryl Boronic Acids Using the Generalized
Conditionsa
The reusability of catalyst 5 was assessed with both
phthalimide and isatin (entries 1 and 4). The catalyst 5 was
recycled twice to give isolated yields of 72, 70, and 87%
with phthalimide and 62,, 67, and 54% with isatin. This
showed that the catalyst retained activity through recycling,
and it was also surprising to see that in the case of
phthalimide, the yield actually improved in the third cycle.
It was necessary to carry out a control experiment to confirm
that the copper catalyst 5 promoted the cross-coupling
reaction as opposed to leached copper in solution. After
suspending 5 in CH2Cl2 overnight and then filtering off the
catalyst, the cross-coupling reaction of isatin and phenyl-
boronic acid was performed in the same reaction solvent.
After 24 h, no conversion to product was detected by thin-
layer chromatography or liquid chromatography/mass spec-
troscopy. The catalyst 5 was then added to the reaction
mixture, and complete conversion to product was effected
within 24 h. This illustrates that the cross-coupling reaction
is indeed promoted by the polymer-supported copper catalyst
5.
We also briefly explored the effect of changing the base
from NEt3 to pyridine. It has been shown that pyridine can
be used to improve the low yields in reactions with NEt3. It
is hypothesized that pyridine plays a dual role in the reaction,
one as a base and the other as a ligand to copper.4b We tested
the effect of the base change to pyridine by looking at a
phenol and an aniline example (entries 5 and 6). With
trimethylaniline, coupling to phenylboronic acid gave isolated
yields of 51 and 54% for NEt3 and pyridine, respectively.
With tert-butylphenol, the yields were 81 and 99%. Although
the yields appear to be better with pyridine, they were still
comparable, and therefore we decided that NEt3 would be
the better choice for a general method due to toxicity reasons.
Under our generalized conditions, a series of N-containing
substrates and phenols were tested using both fresh and
recycled batches of catalyst 5 (Table 2).16 We were pleased
to find that for all the N-containing substrates tested, the
reactions were complete after 24 h, with yields varying
between 48 and 93%. The reaction also appeared to work
well with both electron-donating and electron-withdrawing
groups in the para position of the anilines (entries 4-7).
However, it appears that the reaction is not general for
a All reactions were run using conditions outlined in Table 1 with 1.5
equiv of catalyst 5, 3 equiv of arylboronic acid, and NEt3 as the base.
b Recycled catalyst. c Performed with 4 equiv of boronic acid.
amides, and only starting material was recovered (entries 8
and 9). Nevertheless, we were able to use this chemoselec-
tivity to account for the reaction of an amine in the presence
of an amide (entry 7), and functional groups such as alcohols
were well tolerated (entry 10). With phenols, we found that
the reactions were complete after 24 h/ 4 equiv of boronic
acid were required, and yields ranged between 50 and 83%.
Both electron-withdrawing and -donating phenols worked
well (entries 11-13). Furthermore, the phenolic OH group
can be arylated in the presence of an amide group (entry
14).
(15) Competing side reactions convert the excess boronic acid into the
homocoupled biaryl products, but these are easily removed by flash
chromatography.
(16) General procedure for the copper-catalyzed coupling of arylboronic
acids with N- or O-containing substrates. The amine or phenol (0.34 mmol)
was placed in a 25 mL round-bottomed flask (RBF). The catalyst 5 (0.64
g, 0.8 mmol/g, 0.52 mmol), aryl boronic acid (1 mmol), 4 Å crushed
molecular sieves, NEt3 (0.88 mmol), and dichloromethane (8 mL) were
added. The RBF was equipped with a vacuum adaptor, and the reaction
mixture was agitated vigorously for 24 h, open to air. The reaction mixture
was diluted with methanol (4 mL) and filtered to remove the catalyst and
sieves. Purification was accomplished by flash chromatography to give the
desired product.
A possible mechanism for N- or O-arylation is outlined
in Scheme 2. The mechanism is based upon those proposed
by Collman,8a Lam,17 and Demir.18 Coordination of the
Org. Lett., Vol. 6, No. 18, 2004
3081

is catalytic, the copper catalyst 8 should also be able to effect
the transformation to product. Hence, regeneration of the
copper(III) intermediate 6b can possibly be achieved by
coordination of the phenol/amine and oxidation by oxygen.
This suggests that, after one cycle, the actual catalyst is
copper(I) in nature.19 We believe that a copper(I)/copper(III)
catalytic system is in place because reductive elimination of
a copper(II) intermediate to copper(0) would dissociate the
copper from the polymer resin, rendering it nonrecyclable.
Scheme 2. Possible Mechanism of Catalysis
In summary, we have developed a solid-phase variant for
Cu(OAc)2 and have shown that it can be successfully applied
in a number of cross-coupling reactions between N-contain-
ing compounds or phenols and boronic acids. The solid-phase
catalyst 5 can be recycled with minimal loss of activity and
was able to promote the reaction catalytically. The easy
workup procedure provides a method that is well suited
toward the synthesis of parallel libraries based upon this type
of transformation. Further assessment of the scope and
limitations are currently underway.
Supporting Information Available: Experimental pro-
cedures and characterization for all unknown compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
phenol/amine and oxidation by oxygen gives a copper(III)
intermediate (6a). Transmetalation of (6a) with the aryl-
boronic acid gives (7), which undergoes reductive elimination
to product and also provides the copper(I)-bound catalyst 8.
Since our earlier experiments have shown that the reaction
OL048943E
(17) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P.
Tetrahedron Lett. 2003, 44, 1691-1694.
(18) Demir, A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003, 68,
10130-10134 and references therein.
(19) We have independently synthesized the copper(I) catalyst 8 by
reacting CuI with resin 3. The coupling reaction of isatin and phenylboronic
acid was subsequently tested with this catalyst, and the yield obtained was
66%, comparable to the results given in Table 1.
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Org. Lett., Vol. 6, No. 18, 2004