Copper-catalyzed coupling of arylboronic acids and amines.

Article abstract of DOI:10.1021/ol0160396

[reaction: see text] A general catalytic coupling of arylboronic acids and amines is reported. This room-temperature coupling was realized through the use of catalytic copper(II) acetate, 2,6-lutidine as base, and myristic acid as an additive. Functionalized aniline substrates provided the diarylamine coupling products in good yield (58-91%). A variety of alkylamines were also successfully coupled to give N-alkyl anilines in moderate yield (50-64%).

Full text of DOI:10.1021/ol0160396

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2077-2079
Copper-Catalyzed Coupling of
Arylboronic Acids and Amines
Jon C. Antilla and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received April 27, 2001
ABSTRACT
A general catalytic coupling of arylboronic acids and amines is reported. This room-temperature coupling was realized through the use of
catalytic copper(II) acetate, 2,6-lutidine as base, and myristic acid as an additive. Functionalized aniline substrates provided the diarylamine
coupling products in good yield (58−91%). A variety of alkylamines were also successfully coupled to give N-alkyl anilines in moderate yield
(50−64%).
Aromatic amines are important compounds found throughout
the pharmaceutical1 and agrochemical2 industries. Uses for
aromatic amines can range from conducting polymers3 in
material science to ligands for asymmetric homogeneous
chemistry.4 It therefore follows that catalytic aromatic
carbon-nitrogen bond forming reactions that are practical,
relatively inexpensive, and viable over a broad range of
substrates would be valued in organic synthesis.
common.7 Copper-mediated coupling of amines using alter-
nate transmetallating agents such as aryllead triacetate8 and
arylbismuth9 reagents have also been employed. A recent
series of developments by Chan and Lam10 and others11 has
shown that the amination of arylboronic acids,10a-c,11
arylsiloxanes,10d or arylstannanes10e can be effective when
stoichiometric quantities of Cu(OAc)2 were used. An im-
portant discovery by Collman12 has demonstrated that this
reaction can be rendered catalytic for the arylation of
imidazoles when [Cu(OH)‚TMEDA]2Cl2 is used as the
copper source. After the submission of this work a new
publication by Lam13 has shown that the cross-coupling of
amines, N-H heterocycles, and phenols with arylboronic
acids can be catalyzed by Cu(OAc)2 when a variety of
oxidants are employed.
The most successful C-N coupling methods in the
literature to date have utilized the palladium- or nickel-
catalyzed coupling of amines with aryl halides.5 Copper-
catalyzed or -mediated systems for the coupling of amines
with aryl halides are typically performed under Ullmann-
type6 conditions where heating, often above 130 °C, is
(1) Negwer, M. In Organic-Chemical Drugs and their Synonyms: (An
International SurVey), 7th ed.; Akademie Verlag GmbH: Berlin, 1994.
(2) Montgomery, J. H. In Agrochemicals Desk Reference: EnVironmental
Data; Lewis Publishers: Chelsea, MI 1993.
(3) D’Aprano, G.; Leclerc, M.; Zotti, G.; Schiavon, G. Chem. Mater.
1995, 7, 33-42.
(4) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. ReV.
2000, 100, 2159-2231.
(5) For reviews see: (a) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576(1-2), 125-146. (b) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (c) Hartwig, J.
F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-2067.
(6) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-2384. (b)
Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674. For a
general Ullmann review, see: (c) Lindley, J. Tetrahedron 1984, 40, 1433-
1456.
Collman found that the catalytic coupling of arylboronic
acids with imidazoles was possible when an O2 or air
atmosphere was present. We therefore decided that a
screening of copper salts for catalytic activity (20 mol %
Cu) in the coupling of p-tolylboronic acid with aniline under
an air atmosphere at ambient temperature could provide a
general catalytic system. It was initially found that CuOAc,
Cu(OAc)2, and copper(II) isobutyrate could provide 2-3
turnovers (40-55% conversion). The reaction was found to
proceed smoothly to 35-45% conversion in the first 4-5
h, and catalytic activity rapidly diminished over the next 20
10.1021/ol0160396 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/30/2001

Table 1. Copper-Catalyzed Coupling of Anilines with
p-Tolylboronic Acida
Table 2. Copper-Catalyzed Coupling of Amines with
Arylboronic Acidsa
a,b See Table 1.
transformed. Sterically demanding anilines (entries 9 and
10) required 10 mol % copper but were also efficiently
arylated.
A series of substituted arylboronic acids, shown in Table
2, were subjected to these cross-coupling conditions to further
explore the reaction scope. Substitution in the para position
gave satisfactory coupling when methoxy or acetyl groups
(entries 2 and 3) were used, but the yields dropped off
precipitously with the analogous chloride (entry 4). It was
soon discovered that substitution ortho to boron had a
dramatic influence on the reaction rate. The relatively
unhindered 2-methyl-phenylboronic acid (entry 5) gave only
a 50% yield when 20 mol % catalyst was used. Cundy11a
reported a similar drop-off in yield for the coupling of 2-,
3-, and 4-substituted arylboronic acids with p-tert-butyl
aniline, with only the reaction of phenyl- and p-tolylboronic
acids being moderately successful.
a Reaction conditions: 1.0 equiv of the aniline, 1.5 equiv of the boronic
acid, 1.0 equiv of 2,6-lutidine, ambient temperature (22 °C) with 2 mL of
toluene (0.5 M in amine) for 24 h. b Isolated yields are the average of two
runs and are estimated to be >95% pure by 1H NMR and GC analysis. All
previously unknown compounds gave satisfactory 1H NMR, 13C NMR, IR,
and compustion analysis data.
h. It was then discovered that by using vigorous stirring in
flasks with a large volume (100 mL) relative to that of the
solvent volume (2 mL) the complete conversion of aniline
could be achieved. Presumably, these conditions allowed
improved oxygen uptake and therefore more efficient oxida-
tion of a reduced copper intermediate.14 A second discovery
was that the addition of myristic acid to the reaction mixture
provided an enhanced reaction rate. This additive may
operate by coordination to the copper center, thereby
increasing the solubility of the catalyst.
Using conditions outlined in Table 1, a series of substituted
anilines were subjected to the copper-catalyzed arylation with
p-tolylboronic acid.15 It was initially found that 5-10 mol
% of Cu(OAc)2 was sufficient to promote full conversion to
arylated product. We were pleased to find that both electron-
withdrawing and -donating substituents in the para position
are tolerated in the reaction (entries 2-6). Substrates
containing functional groups that have been problematic in
the palladium-catalyzed amination chemistry16 such as
amides (entry 6) and alcohols (entry 8) were successfully
The application of this reaction to the coupling of
alkylamines with arylboronic acids was also briefly explored.
Such coupling was found to give the desired N-alkyl aniline
products in moderate yield, as depicted in Table 3. Branched
and unbranched primary and secondary amines were suc-
(7) For an Ulmann-type coupling of heterocyclic amines and aryl halides
under relatively mild conditions, see: Kiyomori, A.; Marcoux, J.-F.;
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2640.
(8) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 20, 3055-3057 and
references therein.
(9) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747-7749 and references
therein.
(10) (a) Chan, D. M. T.; Monaca, K. L.; Wanag, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936. (b) 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. (c) Combs, A. P.; Saubern, S.;
Rafalski, M.; Lam, P. Y. S. Tetrahedron Lett. 1999, 1623-1626. (d) Lam,
P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark,
C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601. (e) Lam, P. Y. S.; Clark,
C. G.; Subern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A.
Synlett 2000, 5, 674-676.
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Org. Lett., Vol. 3, No. 13, 2001

a side product, p-tolylamine, was observed in up to a 29%
GC yield. This side product was possibly formed by arylation
of aniline followed by C-N bond scission.
Table 3. Copper-Catalyzed Coupling of Amines with
p-Tolylboronic Acidsa
In summary, we have built on the results of Chan and
Lam and of Collman and have developed a copper-catalyzed
coupling of arylboronic acids and amines in moderate to good
yields. This method shows good substrate generality while
using relatively nontoxic, inexpensive reagents under mild
conditions.
Acknowledgment. This work was supported by the NIH
(grant GM46059). We thank Pfizer and Merck for additional
unrestricted support. J.C.A. was partially supported as a
postdoctoral trainee of the National Cancer Institute (NCI
training grant CI T32CA09112).
Supporting Information Available: Experimental pro-
cedures and characterization data for all unknown com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0160396
(11) (a) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979-
7982. (b) Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D.
Tetrahedron 1999, 55, 12757-12770. (c) Collot, V.; Bovy, P. R.; Rault,
S. Tetrahedron Lett. 2000, 9053-9057.
(12) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 9, 1233-1236. (b)
Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66,
1528-1531.
(13) Lam, Y. S. P.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415-3418.
a,b See Table 1.
(14) Evans has proposed a mechanism for a similar system utilizing Cu-
(OAc)2 that involves a reduced Cu(I) or Cu(0) intermediate: Evans, D. A.;
Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 2937-2940.
(15) Typical Experimental Procedure. Arylboronic acid (1.5 mmol),
Cu(OAc)2 (5-20 mol %), and myristic acid (10-40 mol %) were combined
in a 100-mL round-bottom flask with a large stir bar. A rubber septum was
attached, and dry toluene (2 mL), 2,6-lutidine (1.0 mmol), and the amine
(1.0 mmol) were successively added by syringe. The resulting mixture was
stirred at a high rate for 24 h, diluted with ethyl acetate (10 mL), filtered
through a plug of silica gel, and then purified by column chromatography
to give the desired product (see Supporting Information).
cessful as substrates. It was found that substrates containing
olefin moieties could also be cleanly arylated (entries 4 and
8).
It should be noted that bis-arylated products were never
detected during the course of the reported reactions. It is
also of interest that in the reaction of p-tolylboronic acid
and aniline with excess base (neat in 2,6-lutidine or pyridine)
(16) Brief attempts to arylate imidazoles with this method resulted in
low yields (32%) of the desired product.
Org. Lett., Vol. 3, No. 13, 2001
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