Synthesis of Secondary Arylamines through Copper-Mediated Intermolecular Aryl Amination

Article abstract of DOI:10.1021/ol035942y

(Equation presented) A mild intermolecular copper-mediated amination of aryl iodides has been developed. The reaction takes place at room temperature or heating at 90°C and tolerates halogens attached to the aromatic ring. Its synthetic applications include a synthetic protocol for unsymmetrical N,N′-dialkylated phenylenediamines and both a stepwise and a general synthetic method for N-aryl secondary amines via Ns-anilides (readily obtained by reaction of the Ns-amide).

Full text of DOI:10.1021/ol035942y

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4987-4990
Synthesis of Secondary Arylamines
through Copper-Mediated Intermolecular
Aryl Amination
Kentaro Okano, Hidetoshi Tokuyama, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received October 4, 2003
ABSTRACT
A mild intermolecular copper-mediated amination of aryl iodides has been developed. The reaction takes place at room temperature or heating
at 90 °C and tolerates halogens attached to the aromatic ring. Its synthetic applications include a synthetic protocol for unsymmetrical N,N′-
dialkylated phenylenediamines and both a stepwise and a general synthetic method for N-aryl secondary amines via Ns-anilides (readily
obtained by reaction of the Ns-amide).
The copper-catalyzed Ullmann-Goldberg coupling, a well-
known reaction for the introduction of amine functionality
using aromatic halides, proceeds under severe reaction
conditions such as heating at high temperatures without a
solvent.1 While milder reactions using transmetallating agents
such as triarylbismuth,2 aryllead triacetates,3 arylboronic
acids,4 and hypervalent aryl siloxanes5 have been developed,
the utility of these variants is limited since the preparation
of highly functionalized substrates usually requires multistep
sequences. Recent improvements using palladium-catalyzed
amination of aryl halides appear to be greatly superior in
terms of practical utility and mild reaction conditions.6 For
instance, with the right choice of an efficient phosphine
ligand, N-arylation can be performed at room temperature.
More recently, mild Ullmann-type N-arylations have been
investigated, in which a variety of nitrogen substrates,
including anilines,7 amides,8 imidazoles,9 nitrogen hetero-
cycles,10 hydrazides,11 and R- or â-amino acids12 could be
(6) (a) Belfield, A. J.; Brown, G. R.; Foubister, A. J. Tetrahedron 1999,
55, 11399. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. For a review, see: (d) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (e) Zim, D.; Buchwald, S. L. Org. Lett.
2003, 5, 2413. (f) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapers,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(7) (a) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791. (b) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315. (c) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999,
64, 670. (d) Kelkar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron
Lett. 2002, 43, 7143. (e) For preparation of primary anilines using copper
catalysis in liquid ammonia, see: Lang, F.; Zewge, D.; Houpis, I. N.;
Volante, R. P. Tetrahedron Lett. 2001, 42, 3251. (f) Kwong, F. Y.; Klapars,
A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(1) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Goldberg,
I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (c) Goodbrand, H. B.; Hu, N.-
X. J. Org. Chem. 1999, 64, 670. (d) Arterburn, J. B.; Pennala, M.; Gonzalez,
A. M. Tetrahedron Lett. 2001, 42, 1475. (e) Lang, F.; Zewge, D.; Houpis,
I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42, 3251. For a review, see:
(f) Lindley, J. Tetrahedron 1984, 40, 1433.
(2) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747 and references therein.
(3) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055 and references
therein.
(8) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (d) Kang, S.-K.; Kim, D.-H.;
Park, J.-N. Synlett 2002, 427.
(4) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (b) Lam,
Y. S. P.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron
Lett. 2001, 42, 3415.
(5) 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.
(9) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
(10) (a) Kang, S.-K.; Kim, D.-H.; Park, J.-N. Synlett 2002, 427. (b)
Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2002,
58, 7943.
10.1021/ol035942y CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/02/2003

arylated under mild conditions. In addition, copper-catalyzed
aminations using easily prepared, efficient ligands have been
reported.13
Table 1. Amination of Monosubstituted Aryl Iodides with
Butylaminea
During the course of our synthetic studies on indole
alkaloids, we have discovered an exceptionally mild copper-
mediated intramolecular amination of aryl halides, which was
effected by a combination of copper iodide and cesium
acetate without ligands.14 Use of this reaction allowed
asymmetric total syntheses of the duocarmycins to be
achieved.15 The unusually facile amination might be at-
tributed to the use of soluble CuOAc, generated in situ, and
appropriate solvents without using ligands. To examine the
generality of this reaction, we turned our attention to its
application to an intermolecular process. In this paper, we
describe a copper-mediated intermolecular amination of aryl
iodides. In addition, we report its application to a general
protocol for the synthesis of secondary N-arylalkylamines,
exploiting o-nitrobenzenesulfonamide (Ns-amide) chemistry.
First, n-butylamine and iodobenzene were chosen as the
test substrates and subjected to the conditions previously
established,14,15 namely, 1.0 equiv of CuI and 2.5 equiv of
CsOAc in degassed DMSO.16 Unfortunately, the reaction
afforded only a minute amount of the desired product (1a).
After extensive optimization, we found that a relatively high
concentration (ca. 1.0 M) in DMSO or DMF was essential
for obtaining satisfactory yields. Thus, the reaction at room
temperature for 18 h afforded 70% yield of N-butylaniline
(Table 1, entry 1), which was improved to 93% by elevating
the reaction temperature to 90 °C (entry 2). In the case of a
large-scale reaction with several grams of substrate, use of
inexpensive lower grade CuI (95% purity) and nondegassed
DMSO provided 1a at the same level of yield, indicating
the practical utility of this condition (entry 3).17 Furthermore,
a limited amount (1.2 equiv) of amine and a substoichio-
metric amount (20 mol %) of CuI provided acceptable results
(entries 4, 5).
a Reaction conditions: 0.50 mmol of aryl iodide, 1.0 mmol of butylamine,
0.50 mmol of CuI, 1.25 mmol of CsOAc, degassed DMF (0.50 mL), under
Ar. b Room temperature. c DMSO was used as a solvent. d Iodobenzene (18
mmol), CuI (1.0 equiv, 95% purity). e Iodobenzene (9.8 mmol), butylamine
(1.2 equiv). f Iodobenzene (6.9 mmol), CuI (20 mol %), 48 h. g Inseparable
butyl-(4-iodo-phenyl)amine (4%) was observed by 1H NMR. h 2,2′-
Dimethoxy-1,1′-biphenyl (26%; homocoupling product) was obtained. i 2,2′-
Dinitro-1,1′-biphenyl (25%; homocoupling product) was obtained.
place. On the other hand, the reaction was strongly hampered
by ortho-substituents, and ortho-substituted iodobenzenes
afforded the desired compounds (entries 14-17) in only
modest yields. Steric rather than electronic effects may be
the principal factor for these low yields.
Taking advantage of the selective monoamination that
occurs when using diiodobenzenes, we then applied this
process to successive diamination to construct unsymmetrical
N,N′-dialkylated phenylenediamines (Scheme 1). Following
Having established the optimal conditions, we then
investigated the substitution effects of aryl iodides (Table
1). All of the para-substituted compounds, including those
bearing electron-donating and electron-withdrawing substit-
uents, gave good to excellent yields of the products (entries
2, 6-10). One advantage over palladium-mediated reactions14
was that a selective monoamination took place in the cases
of the 4-bromoiodobenzene and 1,4-diiodobenzene, and the
4-bromo or 4-iodo substituent was mostly retained after the
reaction. The amination reaction of the meta-substituted
iodobenzenes also gave the corresponding secondary amines
in good yields (entries 11-13).18 As observed in para-
substituted diiodobenzene, selective monoamination took
Scheme 1. Successive Amination of 1,3-Diiodobenzene
(11) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(12) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459.
(13) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (b) Ma,
D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(14) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231.
(15) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am.
Chem. Soc. 2003, 125, 6630.
(16) Use of 1 equiv of CuOAc instead of CuI and CsOAc afforded
N-butylaniline in 70% yield.
(17) For the large-scale procedure, see Supporting Information.
4988
Org. Lett., Vol. 5, No. 26, 2003

the preparation of N-butyl-3-iodoaniline 1 by selective
monoamination, the second amination was carried out
smoothly to give the phenylenediamine derivative 2 in good
yield. This protocol could be quite useful since, to the best
of our knowledge, the synthesis of unsymmetrical N,N′-
dialkylated phenylenediamines has not been well-established.
For example, an approach starting with phenylenediamines
would have difficulty in discriminating the two amines, and
starting with the corresponding nitroanilines would require
a lengthy synthesis involving protection and deprotection of
the nitrogens.
Although we have established the conditions in which to
introduce amines to the aromatic ring, amines, especially
functionalized amines, are not always commercially avail-
able. The most widely used preparations of amines include
the Gabriel method19 or reduction of alkyl azides,20 both of
which are easily accessible from halides or alcohols. In
addition to these conventional methods, we have reported a
method for the synthesis of primary21 and secondary amines22
using 2-nitrobenzenesulfonamides (NsNH2). We thought that
a combination of the amination reported here and Ns
chemistry could lead to a general protocol for the synthesis
of aromatic amines. Thus, a nitrogen function would be
introduced into the aromatic ring by the amination of NsNH2
with aromatic iodides to afford Ns-anilides, to which various
residues would be introduced by the Ns protocol to provide
a range of functionalized anilines.
The substrates in our amination reaction are not limited
to primary alkylamines (Table 2). Cyclic secondary amines,
Table 2. Amination of Functionalized Aryl Halides with
Various Aminesa
First, we examined the intermolecular amination of aryl
iodides with NsNH2 using our reaction conditions (Table 3).
Table 3. Selection of Bases on Introduction of an Ns Groupa
entry
base
yieldb (%)
recovered NsNH2 (%)
1
2
3
4
5
CsOAc
K3PO4
K2CO3
Cs2CO3
Cs2CO3
30
53
26
70
91c
69
45
72
25
none
a Reaction conditions: 1.0 mmol of iodobenzene, 0.50 mmol of NsNH2,
0.50 mmol of CuI, 1.25 mmol of a base, degassed DMSO (0.50 mL), under
Ar. b Yields are based on NsNH2. c Performed with 1.0 mmol of CuI and
2.5 mmol of Cs2CO3.
The conventional conditions using CsOAc provided the
desired Ns-anilide (4) in only 30% yield with a recovery of
69% of NsNH2 (entry 1). To address this problem, we briefly
screened bases and found that Cs2CO3 was the best choice
(entry 4). Finally, the yield of 4 was improved to 91% by
use of 2-fold amounts of CuI and Cs2CO3 (entry 5).
Then, an alkyl side chain could be efficiently introduced
either by alkylation with alkyl halides or by the Mitsunobu
reaction.23 After amination with Ns-amide, we conducted a
one-pot N-alkylation and deprotection. The Ns-anilide 5,
derived from methyl 4-iodobenzoate, was treated with
phenylpropyl bromide in the presence of K2CO3 and a
catalytic amount of Bu4NI in DMF, followed by addition of
PhSH, to furnish methyl 4-(3-phenylpropylamino)benzoate
(6) in 85% yield over two steps (Scheme 2).
a Reaction conditions: 0.50 mmol of aryl iodide, 1.0 mmol of amine,
0.50 mmol of CuI, 1.25 mmol of CsOAc, degassed DMF (0.50 mL), under
Ar. b Performed with 2.5 mmol of an amine. c T ) 120 °C. d T ) 150 °C.
and even an indole nitrogen, could be introduced to the
aromatic ring in good yields (entries 1, 2). However, less
reactive amines, e.g., aniline and allylamine, provided the
amination product in moderate yields (entries 3, 4). In
addition to the iodobenzene derivatives, 2-iodopyridine is
amenable to amination, and the 2-amino pyridine derivative
was obtained in 80% yield (entry 6).
(18) Typical Procedure. An oven-dried Pyrex screw-tube was charged
with CsOAc (2.02 g, 10.5 mmol, 2.5 equiv), CuI (801 mg, 4.21 mmol, 1.0
equiv), and ca. 0.3 mL of dried benzene. The tube was evacuated and back-
filled with argon. To the mixture was added degassed DMF (4.2 mL), 1,3-
diiodobenzene (1.39 g, 4.21 mmol, 1.0 equiv), and n-butylamine (0.82 mL,
8.4 mmol, 2.0 equiv). After stirring at room temperature for 23 h, the mixture
was partitioned between EtOAc and 5% NaCl in 10% NH4OH. The aqueous
layer was extracted with EtOAc three times. The combined organic extracts
were dried over Na2SO4, filtered, and concentrated to give a crude material.
Purification by flash column chromatography on silica gel (20-50% CH2Cl2
in hexanes, gradient) gave 3-iodo-N-butylaniline (730 mg, 2.65 mmol, 63%).
(19) Gibson, H. S.; Bradshaw, R. W. Angew. Chem., Int. Ed. Engl. 1968,
7, 919.
(20) Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 5865.
(21) For a review on Ns-chemistry, see: Kan, T.; Fukuyama, T. J. Synth.
Org. Chem., Jpn. 2001, 59, 779.
(22) (a) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301. (b)
Kurosama, W.; Kan, T.; Fukuyama, T. Org. Synth. 2002, 79, 186.
(23) Mitsunobu, O. Synthesis 1981, 1.
Org. Lett., Vol. 5, No. 26, 2003
4989

Scheme 2. Synthesis of an N-Aryl Secondary Amine
Scheme 3. Synthesis of a Chiral â-Diamine
ditions and the chemoselectivity, we believe that this reac-
tion will be useful for the synthesis of a variety of
N-arylamines.
In another approach utilizing the Ns strategy, N-alkylation
by the Mitsunobu reaction was performed (Scheme 3). The
Mitsunobu reaction of the relatively less reactive Ns-anilide
(4) with N-Boc-(R)-phenylglycinol took place on heating,
and the subsequent deprotection of the Ns group gave the
chiral â-diamine derivative (8) in high yield. This method
is applicable to the general synthesis of chiral N-aryl-1,2-
diamines since various chiral amino alcohols are easily
accessible by reduction of R-amino acids.
Acknowledgment. We thank Dr. K. Yamada and Mr.
T. Kubo for their valuable discussions and some pre-
liminary experiments. This work was supported in part by
the Ministry of Education, Science, Sports, and Culture,
Japan, and PRESTO, the Japan Science and Technology
Corporation.
In summary, we have developed a copper-mediated
intermolecular amination. Furthermore, Ns-anilides, which
were obtained by amination using Ns-amides, have proven
to be particularly useful for the stepwise synthesis of
functionalized N-aryl secondary amines. Finally, we devel-
oped a synthetic protocol for unsymmetrical phenylene-
diamine derivatives. Because of the mild reaction con-
Supporting Information Available: Experimental de-
tails, characterization data details, synthetic procedures, and
characterization of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL035942Y
4990
Org. Lett., Vol. 5, No. 26, 2003