aryloxyamines have been prepared using halobenzenes
substituted with several electron-withdrawing groups facili-
tating a nucleophilic aromatic substitution by the conjugate
base of N-hydroxyphthalimide (1).6 Activated arene com-
plexes, especially diphenyl iodonium chloride and the
tricarbonyl (chloroarene) complexes, facilitate nucleophilic
attack by PhthN-O-, which upon hydrazinolysis affords the
aryloxyamine.7 Another route involves nitrogen transfer to
a phenoxide. However, some of the best N-transfer reagents
donor, although a few others were evaluated.13 Three
equivalents of phenylboronic acid, 1 equiv of 1, and 1 equiv
of CuII(OAc)2 were allowed to react at room temperature in
methylene chloride, while varying the amine. This revealed
that pyridine was by far the best amine evaluated and similar
yields were observed irrespective of the excess utilized
between 1 and 10 equiv (Table 1, entries 1-4). Both Et3N
(e.g.,
(2,4,-dinitrophenoxy)amine)
are
themselves
Table 1. Optimization of the Amine for the Cross Couplinga
aryloxyamines which are difficult to prepare and unstable
to long term storage. Furthermore, the N-transfer reaction is
not general for all phenoxides, especially electron rich
phenoxides.8
Several groups have reported the use of CuII(OAc)2 in the
presence of an amine base to cross-couple a phenylboronic
acid with a variety of coupling partners including phenols,9
amines,10 alkanethiols,11 or the like.12 As shown in Scheme
1, N-hydroxyimides (e.g., 1) can now be added to the long
yield (%)
entry
amine
equiv
CuII(OAc)2
CuICl
1b
2
3
4
5
6
7
8
9
pyridine
pyridine
pyridine
pyridine
Et3N
1
1
5
10
1
5
10
1
5
10
5
5
58
92
84
88
33
13
6
40
0
0
NA
93
70
64
37
13
0
75
0
0
Et3N
Et3N
DMAP
DMAP
DMAP
Cs2CO3
DABCO
Scheme 1
10
11
12
0
0
0
0
a Reaction conditions: 1 mmol CuII(OAc)2, 3 mmol phenylboronic acid,
1 mmol 1, ∼250 mg of 4 Å molecular sieves (freshly activated), and the
amine base in CH2Cl2, at room temperature for 24 h under an ambient
atmosphere. Yields refer to those determined via the integrated area of the
3a RP-HPLC peak compared to a 3a calibration curve. Each yield is an
average of two experiments. b 1 mmol phenylboronic acid, everything else
as in footnote a. NA: not available.
and DMAP are inferior and inhibit the reaction at higher
concentrations (Table 1, entries 5-10). Interestingly, under
an atmosphere of argon the reaction gave slightly depressed
yields in comparison to an ambient atmosphere, a phenom-
enon also observed in other copper-mediated cross-
couplings.9,10d,12b
list of partners that participate in these arylboronic acid
coupling processes. Examples of this new method for the
synthesis of aryloxyamines are reported below.
The initial conditions explored were those reported
simultaneously by Chan12a and Evans et al.9 for the CuII-
(OAc)2-mediated cross-couplings of arylboronic acids. N-
Hydroxyphthalimide (1) was chosen as the hydroxyamine
A rationale for the enhancement of the reaction by O2 has
been offered by Lam et al. for the N-arylation of saturated
heterocycles.10d The copper complex coordinates 1 and
presumably transmetalates the arylboronic acid releasing
boric acid. Molecular oxygen could then oxidize the pyridine-
coordinated copper complex to Cu(III), facilitating the
reductive elimination of the N-aryloxyphthalimide.10d,12b The
oxidizing reaction conditions likely promote peroxide forma-
tion. The resultant peroxide would decompose the arylbo-
ronic acid. This would explain the lower yields when 1 equiv
of phenylboronic acid (Table 1, entry 1), is employed.
Several common copper(I) and (II) salts were evaluated
for the desired reactivity (Table 2). While selected copper-
(I) and (II) sources effect the cross-coupling reaction, there
is not a direct correlation between the effectiveness of a
specific salt and its oxidation state. For example, CuICl very
(6) Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. Org. Prep. Proced. Int.
1977, 29, 594.
(7) (a) Cadogan, J. I. G.; Rowley, A. G. Synth. Comm. 1977, 7, 365. (b)
Baldoli, C.; Del Bettero, P.; Licandro, E.; Maiorana, S. Synthesis 1988,
344.
(8) (a) Castellino, A. J.; Rapoport, H. J. Org. Chem. 1984, 49, 1348. (b)
Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M. Synthesis
1977, 1.
(9) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(10) (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623. (b) Cundy, D. J.; Forsyth, S. A.
Tetrahedron Lett. 1998, 39, 7979. (c) 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. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams,
J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 5, 674.
(11) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Organic Lett. 2000, 2,
2019.
(13) Several other N-hydroxylamine sources were also evaluated. N-
Hydroxynaphthalimide and endo-N-hydroxy-5-norbornene-2,3-dicarbox-
imide were viable N-hydroxylamine sources but afforded inferior yields
relative to 1. Cross-couplings with N-hydroxy succinimide and N-hydroxy
carbamate were unsuccessful.
(12) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Collman, J. P.; Zhong, M. Organic
Lett. 2000, 2, 1233.
140
Org. Lett., Vol. 3, No. 1, 2001