of aliphatic amines, however, has been realized only in the
1
2
context of chelating substrates such as R- and â-amino
13
acids or in strategies utilizing less convenient or more costly
14,15,16
arylating agents.
Thus, a simple and general procedure
for the copper-catalyzed coupling of alkylamines and aryl
halides has remained elusive. We previously disclosed that
trans-1,2-diaminocyclohexane serves as an excellent sup-
porting ligand in the Cu-catalyzed amidation of aryl halides
9
and the N-arylation of nitrogen heterocycles. The success
of these processes as well as a recent report by a Merck
group17 prompted us to examine whether O-donor ligands
could be used for C-N bond formation reactions. Herein,
we report a mild, practical Cu-catalyzed amination of
functionalized aryl iodides using air-stable CuI as the catalyst,
ethylene glycol as ligand and unpurified 2-propanol as the
solvent; these reactions can be performed without protection
from air or moisture.
A variety of diol ligands were examined using iodobenzene
and benzylamine as model substrates (Table 1). Neat ethylene
glycol can be used as solvent instead of 2-propanol (Table
1, entry 5). However, the highly viscous ethylene glycol
made stirring difficult, and the solubility of certain substrates
in ethylene glycol was poor. Moreover, the yield of the
reaction was higher when 2-propanol was used as solvent
as compared to the reaction performed in ethylene glycol
(entry 5).
Dramatic differences in yield were observed in reactions
using ethylene, propylene and butylene glycols as ligands
Table 1, entries 5-7). Presumably, ethylene glycol acts as
(
a ligand that is more effective in stabilizing or solubilizing
the copper complex. Control experiments revealed that no
reaction was observed in the absence of ethylene glycol.
Substituted diols such as pinacol and cis- and trans-1,2-
cyclohexanediol gave poor conversions and yields compared
with ethylene glycol (Table 1, entries 8-12). 2-Methoxy-
a
Reaction conditions: 1.0 mmol of iodobenzene, 1.2 mmol of benzyl-
amine, 10 mol % CuI, 2.0 mmol of diol, 2.0 mmol of K3PO4, i-PrOH (1
(
10) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-
mL), 80 °C under Ar. b Calibrated GC yield. c Diol used as solvent.
3
805.
(11) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
1
19, 10539-10540.
(
12) (a) Arai, S.; Yamagishi, T.; Ototake, S.; Hida, M. Bull. Chem. Soc.
Jpn. 1977, 50, 547-548. (b) Kalinin, A. V.; Bower, J. F.; Riebel, P.;
Snieckus, V. J. Org. Chem. 1999, 64, 2986-2987. (c) Vedejs, E.;
Trapencieris, P.; Suna, E. J. Org. Chem. 1999, 64, 6724-6729. (d)
Arterburn, J. B.; Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001,
ethanol, diethyleneglycol, and glycerol proved to be signifi-
cantly less effective (Table 1, entries 13-15).
Preliminary results showed that Cu salts such as CuI,
CuBr, CuCl, and CuOAc were effective precatalysts. Among
the copper(I) sources investigated, CuI and CuOAc were the
most efficient. Air-stable and inexpensive CuI was used in
experiments designed to examine the effect of base and
4
2, 1475-1477.
(
13) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1
998, 120, 12459-12466. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583-
2
586. (c) Clement, J.-B.; Hayes, J. F.; Sheldrake, H. M.; Sheldrake, P. W.;
Wells, A. S. Synlett 2001, 1423-1427.
(14) (a) Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022-1024. (b)
Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683-5705. (c) 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. (d) Lam, P. Y. S.; Clark,
C. G.; Subern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A.
Synlett 2000, 674-676.
solvent in the amination reaction. Both K
proved effective, however, some O-arylated ethylene glycol
CO was used. 2-Propanol
3 4 2 3
PO and Cs CO
was obtained (∼9%) when Cs
2
3
and n-butanol were found to be the solvents of choice, while
toluene, dioxane, and DMF were much less effective. That
the process is fairly insensitive to water is demonstrated by
the observation that a small decrease in reaction rate occurred
when 2 equivalents of water (relative to aryl iodide) was
added to the reaction mixture. Thus, no special precautions
to exclude small amounts of moisture from this reaction are
required.
(
15) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079,
and references therein. (b) Lam, P. Y. S.; Vincent, G.; Clark, C. G, Deudon,
S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418.
(16) For the use of stoichiometric Cu reagents, see: (a) Chan, D. M. T.;
Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1988, 39,
2
933-2936. (b) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1988, 39,
7
979-7982. (c) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236.
(
d) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001,
6
6, 1528-1531.
17) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett.
001, 42, 3251-3254.
(
2
582
Org. Lett., Vol. 4, No. 4, 2002