A mild copper-mediated intramolecular amination of aryl halides

Article abstract of DOI:10.1055/s-2002-19782

A unique combination of copper iodide and cesium acetate was found to mediate intramolecular amination of aryl halides under mild conditions. The reaction proceeds at room temperature with primary or N-benzyl amines and at moderately elevated temperatures with other amine derivatives. The reaction has been applied to the formation of 5-, 6-, and 7-membered rings. Remarkably, halogens at the meta-position were retained, providing a definitive advantage over palladium-catalyzed systems.

Full text of DOI:10.1055/s-2002-19782

LETTER
231
A Mild Copper-mediated Intramolecular Amination of Aryl Halides
A
Mild
C
opper-me
e
diated intra
n
m
olecular Aminati
Y
on of
A
ryl
H
alide
a
s
mada, Tetsuji Kubo, Hidetoshi Tokuyama, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 1 November 2001
itself mediated the reaction with improved yields in the
absence of palladium catalyst at room temperature when
cesium acetate was used as the base. While DMF was the
original choice of solvent, it was later found that DMSO
Abstract: A unique combination of copper iodide and cesium ace-
tate was found to mediate intramolecular amination of aryl halides
under mild conditions. The reaction proceeds at room temperature
with primary or N-benzyl amines and at moderately elevated tem-
peratures with other amine derivatives. The reaction has been ap- was superior.13 Intrigued by the synthetic potential of this
unusually mild14 copper-mediated amination, we
plied to the formation of 5-, 6-, and 7-membered rings. Remarkably,
halogens at the meta-position were retained, providing a definitive
advantage over palladium-catalyzed systems.
launched an investigation to establish its scope and limi-
tations.
To test the scope of the copper-mediated intramolecular15
Key words: aryl amination, cyclization, copper, cesium acetate, ni-
trobenzenesulfonamides
aryl amination, derivatives of o-bromo- and o-iodophen-
ethylamine with a variety of N-protecting groups were ex-
amined (Table 1).16
A smooth room temperature
Recent development of palladium catalysis in amination
of aryl halides seems to have overwhelmed copper-medi-
ated systems in terms of mildness, practicality and versa-
tility.1 However, there has been a resurgence of more
economical copper-mediated systems that circumvent or
overcome the limitations of classical Ullmann–Goldberg-
type couplings, which are known to require harsh reaction
conditions.2 The use of transmetalating agents such as tri-
arylbismuth,3 aryllead triacetates,4 arylboronic acids5 and
hypervalent aryl siloxanes6 in place of aryl halides have
been reported, although their preparation from advanced
synthetic intermediates may not always be straightfor-
ward. There are only a few reports on improved, direct
copper-mediated amination of aryl halides with limited
substrates, such as - and -amino acids,7 imidazoles8 and
amide-containing heterocycles.9 A recent report by Buch-
wald on versatile copper-catalyzed intermolecular amida-
tions of aryl halides has provided a major breakthrough in
the field.10 We have independently discovered a mild cop-
per-mediated intramolecular amination including amida-
tion,11 which can exhibit unprecedented chemoselectivity
not observed in usual palladium-catalyzed systems.
amination proceeded with N-benzyl derivatives, affording
the cyclization product in excellent yields (entries 4 and
9). Among the electron-withdrawing protecting groups
tested, particularly effective was nosyl (o-nitrobenzene-
sulfonyl, Ns),17 with which excellent conversions were
achieved in only 1 hour at 90 °C (entries 1 and 6). N-
Acetyl and N-Cbz derivatives gave contrasting results,
which clearly demonstrated the superiority of aryl iodides
over bromides. The conversions were complete within 24
hours with aryl iodides (entries 7 and 8), while they were
incomplete with aryl bromides (entries 2 and 3). Primary
amines reacted at room temperature with a rapid con-
sumption of the substrate, although the yield was low due
to the formation of unidentified byproducts (entries 5 and
10). It is notable that, with a much longer reaction time,
cyclization of 1a proceeded with a catalytic amount of
copper iodide, giving 2a in 90% yield (entry 11). Never-
theless, 2 equivalents of copper iodide were used in this
study to keep the reaction times within a reasonable range.
Encouraged by the promising results obtained in 5-mem-
bered ring formation, we next examined the formation of
6-membered rings (Table 2). Excellent results were ob-
tained with N-nosyl derivatives, which gave the cycliza-
tion products in near quantitative yields in less than 5
hours (entries 1 and 4). Coupled with the ease of its re-
moval,17 nosyl group seemed to be the best protecting
group for the formation of larger rings. N-Benzyl deriva-
tives underwent cyclization in good yields at 90 °C (en-
tries 2 and 5).18 Primary amines, on the other hand, could
not withstand elevated temperatures, and thus were treat-
ed at room temperature for 24 hours, at which time the
starting materials still remained (entries 3 and 6). The for-
mation of 7-membered ring was somewhat slower, the
conversion being incomplete even after heating at 120 °C
for 24 hours (entry 7). It is noteworthy that, in this case, a
higher yield was obtained when cesium benzoate was
used as the base, most likely due to the increased stability
In a typical procedure for a palladium-catalyzed intramo-
lecular aryl amination, the substrate aryl halide is treated
with a palladium catalyst, a phosphine ligand and a base
such as cesium carbonate and is heated in toluene at
100 °C.12 We attempted to apply this catalysis to a total
synthesis of an indoline alkaloid, in which cesium acetate
was used as the base and DMF as the solvent. However,
the reaction remained problematic even under optimized
conditions, prompting us to investigate the effect of vari-
ous additives. To this end, surprisingly, it was found that
copper iodide was not only an excellent additive, but it by
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0231,0234,ftx,en;Y22401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

232
K. Yamada et al.
LETTER
Table 2 Formation of 6-, 7-, and 8-Membered Rings
Table 1 The Formation of 5-Membered Rings
H
CuI (2 equiv)
CsOAc (5 equiv)
CuI (2 equiv)
CsOAc (5 equiv)
R
N
n
N
R
n
H
N
R
N
R
DMSOa
DMSOa
X
X
3
1
2
4
Entry
X
R
Temp
(°C)
Time
(h)
Yieldb
(%)
Entry
n
X
R
Temp Time Yieldb
(°C)
(h)
(%)
98
71c
54d
99
54
56
39
0f
1
2
a
Br
Br
Br
Br
Br
I
Ns
Ac
Cbz
Bn
H
90
1
24
24
5
92
66c
64d
87
47
87
96
95
87
44
90
1
a
1
1
1
1
1
1
2
3
Br
Br
Br
I
Ns
Bn
H
90
4.5
b
c
d
e
f
90
90
r.t.
r.t.
90
90
90
r.t.
r.t.
90
2
b
c
d
e
f
90
9
24
4
3
3
r.t.
90
4
4
Ns
Bn
H
5
1
5
I
90
9
6
Ns
Ac
Cbz
Bn
H
1
6
I
r.t.
120
120
24
24
24
7
g
h
i
I
24
24
4
7e
8e
g
h
I
Ns
Ns
I
8
I
a,b See Table 1.
9
I
c With 9% substrate recovery.
d With 4% substrate recovery.
10
11
j
I
1
e Cesium benzoate was used as the base.
24e
f Substrate was completely consumed, resulting in the formation of
unidentified product.
a
I
Ns
a Degassed by freeze-pump-thaw cycle.
b Isolated yields.
c With 12% substrate recovery.
d With 9% substrate recovery.
crucial for the reaction.21 No amination occurred when
non-carboxylate bases such as cesium carbonate or sodi-
um tert-butoxide was used, while the reaction proceeded
sluggishly when potassium acetate was used. Further-
more, removing air from the solvent through freeze-
pump-thaw cycle dramatically improved the yield and the
reproducibility,22 whereas oxygen bubbling completely
inhibited the reaction, suggesting an in situ formation of
an air-sensitive, active species. In addition, use of a large
excess of cesium acetate appeared to stabilize the copper
species and a reasonable conversion was attained without
degassing procedure.23 Addition of phosphine or amine
ligands24 or use of alternative copper species25 did not pro-
vide any improvements.
e A catalytic amount (10 mol%) of CuI was used.
of the generated copper species.19 Unfortunately, the reac-
tion could not be extended to the formation of 8-mem-
bered ring (entry 8).
To test the selectivity of our intramolecular amination re-
action, a halogen was introduced at a position meta to the
tether. Remarkably, the halogen was largely retained un-
der the amination condition (Scheme), providing a strik-
ing difference from the palladium-catalyzed systems.20
Aryl iodide is expected to be the preferred site of oxida-
tive addition if the process is analogous to palladium sys-
tems. The retention of the halogen enhances the versatility
of this reaction by leaving a handle for further synthetic
elaboration.
The necessity for the acetate base agrees with Ma’s report
on the marked accelerating effect of carboxylates in inter-
molecular amination with - and - amino acids7 as well
as Buchwald’s explanation for the rate enhancing effect of
myristic acid due to the increased solubility in copper-cat-
alyzed coupling of arylboronic acids and amines.5a We
speculate that the air-sensitive, active catalyst formed in
situ is copper(I) acetate. Its coordination to the amine
would be followed by oxidative addition to form a tran-
sient Cu(III) species which then reductively eliminates to
give the amination product, thereby regenerating the ac-
tive catalyst (Figure).26 The directive effect of the amine
on the site of oxidative addition is a plausible explanation
for the selective amination of 5 in the presence of aryl io-
dide, which would almost certainly be the first site of ox-
idative addition in palladium-catalyzed systems.
During the optimization process, it was revealed that the
coincidental use of cesium acetate as the base was in fact
I
CuI (2 equiv)
CsOAc (5 equiv)
I
Ns
N
H
N
DMSO
Br
90 °C, 5 h
Ns
5
6
81%a
aaccompanied with deiodinated product (10%).
Scheme
Synlett 2002, No. 2, 231–234 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Mild Copper-mediated intramolecular Amination of Aryl Halides
233
(6) 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.
(7) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459.
NHR
n
X
(8) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657.
(9) Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45, 719.
(10) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
(11) The term amidation refers to coupling specifically with N-
acyl amines. The term amination, in our case, includes
coupling with N-free, N-alkyl, N-acyl, N-alkoxycarbonyl,
and N-sulfonyl amines.
NHR
Cu
O
n
CuOAc
O
X
R'
n
N
R
(12) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.
(13) The reaction also proceeded in acetonitrile and DME, but did
not proceed in toluene, methylene chloride, dioxane, THF or
methanol. Addition of water as co-solvent retarded the
reaction.
(14) Buchwald indicated one example of room temperature
amidation, although elevated temperature was generally
needed (ref. 10).
n
HX
N
R
Cu
O
O
R'
Figure Proposed Mechanism
(15) Attempts at intermolecular amination with CuI/CsOAc
system have not been successful.
(16) Typical Procedure. A pyrex test tube was charged with
CsOAc (213 mg, 1.11 mmol, 5 equiv), CuI (84 mg, 441
mol, 2 equiv) and a small amount of dry benzene. The tube
was evacuated and backfilled with argon. The substrate 1d
(64 mg, 221 mol, 1 equiv) in degassed DMSO (1.1 mL) was
then added. The mixture was stirred magnetically under
argon atmosphere (balloon) for 5 h. To the resulting solution
were added ether and ammoniacal aq NaCl. The mixture was
shaken vigorously to dissolve the precipitate. The aq layer
was extracted three times with ether. The combined ether
layer was dried over MgSO4, filtered and concentrated in
vacuo. Preparative TLC (5% EtOAc–hexanes) provided 40
mg (191 mol, 87% yield) of 2d.
In summary, we have developed a new protocol for cop-
per-mediated intramolecular amination, which tolerates a
variety of N-protecting groups and proceeds under mild
conditions with inexpensive reagents. The reaction is es-
pecially useful when the substrate contains palladium-la-
bile functional groups, serving as a complement to the
widely used palladium-catalyzed systems. Further studies
to expand the generality of the reaction and to develop ef-
ficient catalytic system are currently in progress.
Acknowledgement
(17) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.;
Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831.
(18) When 3e was treated at r.t. for 9 h, 4e was obtained in 39%
yield with substantial recovery of the unreacted 3e.
(19) CsOBz has an additional advantage of being significantly
less hygroscopic than CsOAc, facilitating its handling. Also,
use of cesium salicylate vastly improved the stability of the
copper species, but the decreased reactivity rendered its use
impractical.
(20) A treatment of 5 with Pd2(dba)3 (20 mol%), (S)-BINAP (30
mol%), Cs2CO3 (1.4 equiv) in toluene at 100 °C gave
multiple products from which a mixture of 6 and the
deiodinated product was isolated in less than 3% yield.
(21) Interestingly, a reported example of modified copper-
mediated intramolecular amidation of aryl halide utilized
sodium hydride as the base, which was heated in DMF at
80 °C for 12 h: Kametani, T.; Ohsawa, T.; Ihara, M.
Heterocycles 1980, 45, 277.
This work was partly supported by CREST, The Japan Science and
Technology Corporation, and the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We thank Mr. Toshiki Ku-
rokawa for helpful discussions.
References
(1) For reviews, see: (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. (d) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046.
(2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 37, 2382.
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(22) Initially, poor reproducibility was a problem, sometimes
resulting in seemingly spontaneous decomposition of the
soluble copper species into green precipitate.
(23) When 1a was treated with 2 equiv of CuI and 20 equiv of
CsOAc in non-degassed DMSO for 21 h, the desired product
1b was obtained in 79% yield.
(24) No reaction was observed when triethylamine, DBU or
EDTA was used as the base, resulting in the formation of
deep-blue Cu-amine complex. For the use of diamine ligand
in copper catalysis, see ref. 10.
(3) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747; and references
therein.
(4) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 20, 3055; and
references therein.
(5) (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.
Synlett 2002, No. 2, 231–234 ISSN 0936-5214 © Thieme Stuttgart · New York

234
K. Yamada et al.
LETTER
(25) CuBr and (Thienyl)Cu were almost equally effective. No
reaction was observed when Cu(II) species were used.
(26) A catalytic cycle through alternation between Cu(I) and
Cu(III) oxidation states has been proposed: (a) Barton, D.
H. R.; Finet, J.-P.; Khamsi, J. Tetrahedron Lett. 1987, 28,
887. (b) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P.;
Guiry, P. J. J. Chem. Soc., Perkin Trans. 1 1991, 2095.
(c) For a list of possible mechanisms in Cu(I)-mediated
amination of aryl halides, see ref. 2f.
Synlett 2002, No. 2, 231–234 ISSN 0936-5214 © Thieme Stuttgart · New York