Copper-catalyzed N-arylation of oxindoles

Article abstract of DOI:10.1016/j.tetlet.2006.08.004

The coupling of aryl bromides or iodides with oxindoles using a copper iodide-N,N′-dimethylethylene diamine system is presented. The reaction proceeds efficiently and tolerates a variety of substitution patterns.

Full text of DOI:10.1016/j.tetlet.2006.08.004

Tetrahedron Letters 47 (2006) 7137–7138
Copper-catalyzed N-arylation of oxindoles
Dean P. Phillips, Andrew R. Hudson,* Bao Nguyen, Thomas L. Lau,
Matthew H. McNeill, Jackline E. Dalgard, Jyun-Hung Chen, Richard J. Penuliar,
Todd A. Miller and Lin Zhi
Department of Medicinal Chemistry, Ligand Pharmaceuticals, 10275 Science Centre Drive, San Diego, CA 92121, USA
Received 17 July 2006; revised 2 August 2006; accepted 2 August 2006
Available online 22 August 2006
Abstract—The coupling of aryl bromides or iodides with oxindoles using a copper iodide-N,N0-dimethylethylene diamine system is
presented. The reaction proceeds efficiently and tolerates a variety of substitution patterns.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The metal-mediated N-arylation of amines or amides
I or Br
O
CuI, MeNH(CH2)2NHMe
K2CO3, CH3CN, reflux
has received considerable interest over the past several
years.1 The Ullmann-type coupling and the related
Goldberg reaction is a straightforward method to form
the requisite carbon–nitrogen bond via coupling of
N–H containing substrate to an aryl halide.2 Recently
Buchwald et al. reported a general method for the cou-
pling of amines or amides, including heterocycles, to
aryl halides using a copper-diamine complex.3 This type
of process has been used to prepare a variety of targets
that would have otherwise been difficult to prepare.
N
O
+
N
H
Scheme 1.
to generate a number of substituted N-aryl oxindoles
from readily available starting materials (Table 1).
In general the yield of coupled product was good to
moderate (37–63%). Electron-withdrawing or donating
groups at the 3- or 4-position of the aryl bromide had
little effect on the efficiency of the reaction. Likewise
the coupling of either 5-Cl or 5-Me oxindole (Table 1,
entries 5 and 9) had no impact on the yield of coupled
product. In general, substituents adjacent to the reaction
centers of either the aryl bromide or oxindole were not
well tolerated (Table 1, entry 6). Oxindoles substituted
at the 7-position resulted in low yields or the reaction
failed altogether.
Although oxindoles are ubiquitous within the pharma-
ceutical industry only fleeting examples of the Ull-
mann-type coupling of oxindole derivatives have been
reported. Such procedures employed relatively harsh
conditions (e.g., NMP, 200 ꢁC, 24 h).4 It was speculated
that Buchwald’s conditions for the Ullmann-type cou-
pling reaction could be extended to the preparation of
N-aryl oxindoles and this would serve as a valuable syn-
thetic tool for the preparation of functionalized oxindole
targets. To the best of our knowledge the coupling of
oxindoles to aryl halides using a copper-diamine com-
plex has not been reported.
The coupling of oxindoles with aryl iodides (Table 2)
under the same conditions led to higher yields (61–92%)
than the corresponding aryl bromides. Electron-with-
drawing or donating groups at the 3-, 4-, and/or 5-posi-
tion of the aryl iodide had no impact on the efficiency
of the reaction. Substituents at the 5- or 6-position of
the oxindole were also well tolerated. In addition,
Ullmann-type coupling reaction of oxindoles with aryl
iodides required shorter reaction times (4–6 h) than the
corresponding aryl bromides (up to 21 h). Prolonged
reaction times lead to the formation of isatin and dimer-
ization side products leading to diminished yields. It is
The conditions employed are similar to that described
by Buchwald et al. (Scheme 1).3 The oxindole, aryl
bromide, copper (I) iodide, N,N0-dimethylethylene dia-
mine,5 and potassium carbonate were heated at reflux
in acetonitrile6 for 4–22 h. This procedure allowed us
*
Corresponding author. Tel.: +1 858 550 4432; fax: +1 858 550
7249; e-mail: ahudson@ligand.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.004

7138
D. P. Phillips et al. / Tetrahedron Letters 47 (2006) 7137–7138
Table 1. N-arylation of oxindoles with aryl bromidesa
iodides tend to give higher yields and shorter reaction
times than the corresponding aryl bromides.
Br
O
R
CuI, MeNH(CH2)2NHMe
K2CO3, CH3CN, reflux
N
O
R
+
Typical procedure: 1-bromo-3,4-(methylenedioxy) benz-
ene (1.2 ml, 10 mmol) was added to a suspension of
oxindole (1.49 g, 11.2 mmol) in acetonitrile (33 ml) un-
der a nitrogen atmosphere. A steady stream of nitrogen
was bubbled through the suspension as it was heated
to 40 ꢁC over 15 min. Potassium carbonate (3.09 g,
22.4 mmol), copper (I) iodide (220 mg, 1.15 mmol,
10 mol %), and N,N0-dimethylethylenediamine (0.24 ml,
2.3 mmol, 20 mol %) were added and the reaction
mixture was heated to 80 ꢁC for 21 h under a nitrogen
atmosphere. The reaction mixture was allowed to cool
to room temperature, 1 M HCl (100 ml) was added,
and the solution was extracted with ethyl acetate
(3 · 100 ml). The combined organic extracts were dried
(Na2SO4) and concentrated under reduced pressure.
Purification by flash chromatography, eluting with ethyl
acetate/hexanes, gave N-aryl oxindole 3h as a white pow-
der (1.59 g, 63%). Mp 110–111 ꢁC (from hexanes); IR
(film, cmꢀ1) 1717, 1613, 1492, and 1241; 1H NMR
(CDCl3) 300 MHz d 7.29 (d, J 7.3, 1H) 7.21 (t, J 7.8,
1H), 7.06 (t, J 7.3, 1H), 6.96–6.82 (m, 3H), 6.75 (d, J
7.9, 1H), 6.03 (s, 2H), and 3.69 (s, 2H); 13C NMR
(CDCl3) 174.7, 148.5, 147.4, 145.5, 128.0, 127.8, 124.6,
124.2, 122.8, 120.4, 109.4, 108.8, 108.0, 101.8, and 36.0;
MS (ESI) m/z 254 (MH+).
N
H
R1
R1
3a-i
Entry
R
R1
Product
% Yield
1
2
3
4
5
6
7
8
9
H
H
H
H
5-Cl
H
6-Ph
H
5-CH3
H
3a
3b
3c
3d
3e
3f
43
40
50
49
47
14
37
3-CO2CH3
4-CF3
3,4-di-Cl
4-Pr
2-F,4-CH3
3,4-di-CH3
4 + 5 = OCH2O
3,4-di-CH3
3g
3h
3i
63 (57)b
52
a Conditions: 1:1.2 equiv oxindole/aryl bromide, 2.2 equiv K2CO3,
5–10 mol % CuI, 10–20 mol % CH3NH(CH2)2NHCH3, CH3CN,
reflux 4–22 h. Yields are unoptimized.
b Microwave irradiation, 120 ꢁC, 1 h.
Table 2. N-arylation of oxindoles with aryl iodidesa
I
O
R
CuI, MeNH(CH2)2NHMe
K2CO3, CH3CN, reflux
N
O
R
+
N
H
R1
R1
Acknowledgements
3j–t
Entry
R
R1
Product
% Yield
The authors thank Catherine Gharbaoui for technical
assistance.
1
2
3
4
5
6
7
8
H
H
H
H
5-F
6-Cl
6-CF3
6-CF3
6-Cl
6-CO2CH3
6-Br
3,5-di-CH3
3,4-di-CH3
3-CO2CH3
4-OH
3-CO2CH3
3,5-di-CH3
3,4-di-CH3
3-CO2CH3
3-CO2CH3
3,4-di-CH3
3,4-di-CH3
3j
86
92
74
73
61
69
77
65
82
66
72
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
References and notes
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9
10
11
a Conditions: 1:1.2 equiv oxindole/aryl iodide, 2.2 equiv K2CO3, 5–
10 mol % CuI, 10–20 mol % CH3NH(CH2)2NHCH3, CH3CN, reflux
4–6 h. Yields are unoptimized.
worth noting that the use of microwave irradiation
reduced reaction times and thus minimized formation
of byproducts. For example, under conventional heating
the synthesis of compound 3h was complete in 21 h,
whereas under microwave irradiation (120 ꢁC) the reac-
tion time was reduced to 1 h (57% yield).
In conclusion, we have demonstrated that the Ullmann-
type coupling of oxindoles is an efficient and general
method for the preparation of substituted N-aryl oxin-
doles. The reaction works well with electron-rich and
electron-poor substrates on either reacting partner. Aryl
5. Increasing the catalytic loading of the diamine led to no
deterioration in yield.
6. CH3CN is an atypical solvent choice for this type of
reaction but was found to be optimal for this system.