Ligand- and Base-Free Copper(II)-Catalyzed C-N Bond Formation: Cross-Coupling Reactions of Organoboron Compounds with Aliphatic Amines and Anilines

Article abstract of DOI:10.1021/ol035681s

(Equation presented) A ligandless and base-free Cu-catalyzed protocol for the cross-coupling of arylboronic acids and potassium aryltrifluoroborate salts with primary and secondary aliphatic amines and anilines is described. The process utilizes catalytic copper(II) acetate monohydrate and 4 A molecular sieves in dichloromethane at slightly elevated temperatures under an atmosphere of oxygen. A broad range of functional groups are tolerated on both of the cross-coupling partners.

Full text of DOI:10.1021/ol035681s

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4397-4400
Ligand- and Base-Free
Copper(II)-Catalyzed C−N Bond
Formation: Cross-Coupling Reactions of
Organoboron Compounds with Aliphatic
Amines and Anilines
Tan D. Quach and Robert A. Batey*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received September 2, 2003
ABSTRACT
A ligandless and base-free Cu-catalyzed protocol for the cross-coupling of arylboronic acids and potassium aryltrifluoroborate salts with
primary and secondary aliphatic amines and anilines is described. The process utilizes catalytic copper(II) acetate monohydrate and 4 Å
molecular sieves in dichloromethane at slightly elevated temperatures under an atmosphere of oxygen. A broad range of functional groups
are tolerated on both of the cross-coupling partners.
Copper-mediated C-N bond formation via the cross-
coupling of arylboronic acids and nitrogen-based nucleo-
philes has become an important synthetic strategy since the
initial reports by Chan and Lam.1 Under their conditions,
the N-arylation2 of nitrogen-based nucleophiles by arylbo-
ronic acids occurs using a stoichiometric amount of Cu salt,
and several equivalents of an external base/ligand. A variety
of amines, anilines, and nitrogen heterocycles have been
N-arylated under these conditions, both in the liquid phase
and on solid support.3 Most recently, Lam reported the
arylation of amino acid ester hydrochloride salts under these
now “classical” conditions.4 Catalytic variants have also been
developed. Collman has employed a catalytic amount of [Cu-
(OH)‚TMEDA]2Cl2 complex in the arylation of imidazoles
with arylboronic acids. Unfortunately, the substrate scope
of this protocol is limited to the use of imidazole derivatives.5
Lam has shown that stoichiometric chemical oxidants
(including molecular oxygen, TEMPO, and pyridine-N-oxide)
can be used to regenerate the Cu catalyst. However, the
optimal oxidants vary with the choice of the nucleophilic
amine component; furthermore, an appreciable amount of
competitive oxidation of the boronic acid also occurs.6
(3) For a recent review on Cu(OAc)2-mediated arylation of heteroatomic
nucleophiles using aryl-B, Bi, Pb, Si, and Sn and hypervalent iodonium
reagents, see: Finet, J. P.; Fedorov, A. Y.; Combes, S.; Boyer, G. Curr.
Org. Chem. 2002, 6, 597-626.
(4) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P.
Tetrahedron Lett. 2003, 44, 1691-1694.
(1) (a) Chan, D. M. T.; Monaco, K. L.; Wang, 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.
(2) An alternative protocol for C-N bond formation is the amination of
arylhalides catalyzed by Cu(I) salts developed by Buchwald. This highly
efficient method tolerates a broad range of substrates, but reactions are
performed at elevated temperatures, and in the presence of several
equivalents of base. See: Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003,
5, 793-796 and references therein.
(5) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236. (b)
Collman, J. P.; Zhong, M.; Zeng, L.; Costano, S. J. Org. Chem. 2001, 66,
1528-1531. (c) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org.
Chem. 2001, 66, 7892-7897.
(6) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415-3418.
10.1021/ol035681s CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003

Table 1. Cu(II)-Catalyzed N-Phenylation of Aliphatic Amines, Ammonium Salts, and Anilinesa
a Reaction times are not optimized for individual substrates. b Isolated yields. c Epimerization of the stereocenter did not occur under the reaction conditions.
d Ammonium salt was pretreated with Amberlyst A-21 in MeCN for 30 min prior to addition to the reaction mixture; yield reported is over both steps.
Buchwald has reported a Cu-catalyzed cross-coupling of
arylboronic acids employing myristic acid as ligand, and 2,6-
lutidine as base.7 This protocol uses oversized reaction
vessels in an air/O2 atmosphere. Excellent yields of the
arylated product were obtained using anilines as the cross-
coupling partners, but with poorer results shown with
aliphatic amines. This trend is also observed for the
aforementioned stoichiometric Cu protocols. Following our
recent report on the Cu-catalyzed cross-coupling of potassium
organotrifluoroborate salts and boronic acids with aliphatic
alcohols,8 we now report a new set of reaction conditions,
optimized for the cross-coupling of primary and secondary
aliphatic amines with arylboron compounds.
Previous attempts at the arylation of aliphatic amines under
stoichiometric Cu conditions have reported low yields of the
(7) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079.
(b) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem. 2003, 68, 2045-
2047.
(8) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381-1384.
Org. Lett., Vol. 5, No. 23, 2003
4398

cross-coupled product from primary amines and moderate
yields from secondary amines, though no further descriptions
of the outcome of those reactions have been offered.1a,3,6 In
our hands, the treatment of 1 equiv of n-butylamine or
isopropylamine with 2 equiv of PhB(OH)2 under Chan and
Lam’s original conditions gave diphenylamine as the sole
product in almost quantitative yield (Scheme 1). In this
Table 2. Comparison of Cu(II)-Catalyzed Methods
Scheme 1. Reaction of Primary Amines Using Stoichiometric
Cu(II) Salts
a Reaction conditions: A ) Cu(OAc)2‚H2O (10 mol %), CH2Cl2, 4 Å
MS, 40 °C, O2, 24 h; B ) Cu(OAc)2 (10 mol %), myristic acid (20 mol
%), 2,6-lutidine (1 equiv), toluene, rt, air (ref 7a). b Isolated yields.
The scope and limitations of this protocol were examined
using a series of primary and secondary amines, and anilines
with both PhBF3-K+ 10 and PhB(OH)2 (Table 1).11 In general,
phenylboronic acid 1a gave slightly greater yields than
potassium phenyltrifluoroborate 2a. This may be due to its
greater solubility in CH2Cl2, although we observed the
reverse behavior in the cross-coupling reactions of aliphatic
alcohols.8 When compared to their alcohol analogues,
aliphatic amines give greater yields; in fact, whereas tertiary
alcohols do not undergo cross-coupling, tertiary alkyl
substituted amines undergo arylation, albeit in low yields
(Table 1, entries 2-5). A variety of functional groups on
the amines are tolerated, including alkenes, esters, ketones
and ketals. Interestingly, both alkyl and aryl halide func-
tionality is also tolerated, without nucleophilic displacement
or cross-coupling being observed (Table 1, entries 12 and
22). Substrates bearing chelating substituents on the aliphatic
chain typically did not undergo complete conversion at room
temperature but gave better results when heated to 40 °C
(Table 1, entry 8). R-Amino acid derivatives underwent
reaction without detectable epimerization (Table 1, entries
14 and 19). In the case of ammonium salts, in situ activation
of the ammonium salt with 1 equiv of Et3N or pyridine as
per Lam’s conditions,4 afforded only low yields of the
arylated product. However, pretreatment of the ammonium
salt with the weakly basic resin, Amberlyst A-21, prior to
addition to the reaction mixture overcomes this problem
(Table 1, entries 12-14, 18, and 19).
manner, simple aliphatic amines can be used as a surrogate
for ammonia, in symmetrical diarylation reactions. Presum-
ably, primary amines undergo the expected cross-coupling
reaction to form the alkylarylamine, which then undergoes
subsequent Cu-promoted N-dealkylation. The resultant aniline
then participates in a second cross-coupling with another
equivalent of the arylboronic acid, thereby affording the
diarylated product. This hypothesis is supported by the results
of Tolman, who observed that bis(µ-oxo)dicopper complexes
promote the oxidative C-N bond scission of aliphatic
amines.9
We concluded from these results that N-dealkylation is a
potentially serious side reaction, a feature which undoubtedly
negatively impacted earlier attempts at N-arylations of
aliphatic amines using arylboronic acids. N-Dealkylation side
reactions could be minimized by preventing bis(µ-oxo)-
dicopper complex formation, either by dilution of the reaction
mixture, or by decreasing the amount of Cu present (i.e.,
rendering the reaction catalytic in Cu salts). Application of
our earlier reported conditions for the cross-coupling of
aliphatic alcohols, to the reaction of 1 equiv of the model
-
amine, n-BuNH2, with 2 equiv of PhBF3 K+, 10 mol % Cu-
(OAc)2‚H2O, 20 mol % DMAP, and powdered 4 Å MS in
CH2Cl2 under an atmosphere of dry O2 at room temperature
for 24 h, gave an excellent yield of the monoarylated product
(89%). No trace of the diarylated product, n-butyldiphenyl-
amine, or the N-dealkylated product, diphenylamine, was
observed. Further optimization revealed that the presence of
the DMAP ligand (required for O-arylation) was unnecessary
for the cross-coupling of aliphatic amines. This is probably
because the amine nucleophile is a much better ligand for
Cu. The presence of molecular sieves was again found to
be essential for efficient cross-coupling to occur.
Anilines proved to be poorer cross-coupling partners under
these conditions, affording only low to moderate yields of
the unsymmetrical diarylamine products (Table 1, entries
22-25). Additionally, competitive oxidative homocoupling
of the anilines to azobenzene derivatives occurred under these
conditions.12 A comparison of our conditions with those of
Buchwald’s revealed that the two are complementary (Table
(9) (a) Mahapatra, S.; Halfen, J. A.; Wilkinson, E. C.; Pan, G.; Wang,
X.; Young, V. G.; Cramer, C. J.; Que, L.; Tolman, W. B. J. Am. Chem.
Soc. 1996, 118, 11555-11574. (b) Mahapatra, S.; Halfen, J. A.; Tolman,
W. B. J. Am. Chem. Soc. 1996, 118, 11575-11586.
(10) Potassium organotrifluoroborate salts are readily synthesized from
their boronic acid derivatives by treatment with KHF2, and several are now
commercially available. See: Vedejs, E.; Fields, S. C.; Schrimpf, M. R. J.
Am. Chem. Soc. 1993, 115, 11612-11613.
Org. Lett., Vol. 5, No. 23, 2003
4399

entries 1-4). Electron-poor heterocyclic boronic acids, such
as 3-pyridylboronic acid, also participate in the reaction
(Table 3, entry 5). Substitution at the ortho positions of the
aryl boronic acids has a profound effect on the outcome of
the reaction. 2-Methylphenylboronic acid gave only a moder-
ate yield of cross-coupled product; whereas, the more
sterically hindered 2,6-dimethylphenylboronic acid generated
only trace amounts of the arylated amine (identified through
Table 3. Cu(II)-Catalyzed N-Arylation of
1,4-Dioxa-8-azaspiro[4.5]decanea
1
crude H NMR) (Table 3, entries 6 and 7).
In conclusion, we have developed an efficient Cu-catalyzed
protocol for the arylation of primary and secondary aliphatic
amines, a class of nucleophiles that have been problematic
under previous cross-coupling protocols with arylboronic
acids. The transformation can be affected under an atmos-
phere of molecular oxygen without the need of a ligand for
the Cu-catalyst or base to activate the amine. This procedure
further extends the utility of the Cu catalyzed cross-coupling
protocols in the rapidly growing field of N-arylations, and
we anticipate its use in a diverse range of synthetic
applications. Further studies along these lines, including a
mechanistic investigation probing the influence of additives
and molecular sieves, will be reported in due course.
Acknowledgment. The Natural Science and Engineering
Research Council (NSERC) of Canada, the Ontario Research
and Development Challenge Fund (ORDCF), and Merck-
Frosst funded this work. T.D.Q. acknowledges the receipt
of an Ontario Graduate Scholarship in Science and Technol-
ogy and the Walter C. Sumner Foundation for funding.
R.A.B. gratefully acknowledges receipt of a Premier’s
Research Excellence Award. We thank Dr. A. B. Young for
mass spectroscopic analysis.
a Reaction times are not optimized for individual substrates. b Isolated
yields.
2). While Buchwald’s conditions give excellent yields of the
arylated anilines, the arylation of n-butylamine produces only
47% of the product. The lower yields obtained under the
Buchwald protocol using aliphatic amines is due, at least in
part, to the fact that the higher concentration of Cu present
results in undesired N-dealkylation side reactions. Indeed,
in our hands, 26% of diphenylamine was isolated in the
reaction of butylamine under Buchwald’s conditions. The
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds isolated.
1H and 13C spectra of all novel compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035681S
-
failure of the PhBF3 K+ salt to react under Buchwald’s
(11) Typical Experimental Procedure. A suspension of PhBXn (2.0
mmol), Cu(OAc)2‚H2O (10 mol %), and powdered 4 Å MS (0.75 g) in
CH2Cl2 (8.0 mL) was stirred for 5 min at room temperature. To this mixture
was added the amine (1.0 mmol). The reaction vessel was then sealed with
a rubber septum and stirred at room temperature (or 40 °C) under O2 for
24 h. The reaction mixture was then filtered through a plug of Celite and
the product isolated by column chromatography (see the Supporting
Information).
conditions is due to its insolubility in toluene at room
temperature.
Finally, the nature of the boronic acid component of the
reaction was examined using 1,4-dioxa-8-azaspiro[4.5]decane
as a model amine (Table 3). The reaction tolerates both
electron-donating and electron-withdrawing substituents in
the meta or para positions of the arylboronic acid (Table 3,
(12) (a) Kinoshita, K. Bull. Chem. Soc. Jpn. 1959, 32, 777-780. (b)
Kinoshita, K. Bull. Chem. Soc. Jpn. 1959, 32, 780-783. (c) Kinoshita, K.
Bull. Chem. Soc. Jpn. 1959, 32, 783-787.
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