Copper-catalyzed one-pot multicomponent coupling reaction of phenols, amides, and 4-bromphenyl iodide

Article abstract of DOI:10.1021/ol801730g

(Chemical Equation Presented) An efficient copper-catalyzed multicomponent reaction of phenols, amides, and 4-bromphenyl iodide was developed that uses commercially available N,N-dimethylglycine as the ligand. This multicomponent reaction proceeds in moderate to good yields for a range of phenols and amides. The simple experimental procedure and high levels of functional group compatibility make this method attractive for applications on pesticides.

Full text of DOI:10.1021/ol801730g

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4565-4568
Copper-Catalyzed One-Pot
Multicomponent Coupling Reaction of
Phenols, Amides, and 4-Bromphenyl
Iodide
Wenming Chen,† Jianjun Li,† Dongmei Fang,‡ Chun Feng,† and
Chenggang Zhang*,†
Department of Chemistry and Materials, Sichuan Normal UniVersity, Chengdu 610066,
P. R. China, and Chengdu Institute of Biology, the Chinese Academy of Sciences,
Chengdu 610041, P. R. China
zhangcg2008@yahoo.com.cn
Received July 30, 2008
ABSTRACT
An efficient copper-catalyzed multicomponent reaction of phenols, amides, and 4-bromphenyl iodide was developed that uses commercially
available N,N-dimethylglycine as the ligand. This multicomponent reaction proceeds in moderate to good yields for a range of phenols and
amides. The simple experimental procedure and high levels of functional group compatibility make this method attractive for applications on
pesticides.
Copper-catalyzed cross-coupling reactions of aryl halides
with various nucleophilic compounds are now among the
most prominent synthetic methods for the formation of C-N,
C-O, and C-S bonds in the preparation of numerous
important products in the fields of biological, pharmaceutical,
and material sciences.1 During the past few years, some
exciting achievements have already appeared in this field.
For instance, Buchwald2 reported that ligands such as
1-naphthoic acid, 4,7-dimethoxy-1,10-phenanthroline, N,N-
diethylsalicylamide, ꢀ-diketones, diamines, and ethylene
glycol enabled the Ullmann-type arylation to be performed
under milder conditions and in the presence of catalytic
amounts of the copper catalyst. At the same time, other
groups also reported that the Ullmann-type arylation could
be performed under milder conditions by using oxime,3
amino alcohols,4 8-hydroxyquinoline,5 and 1,1,1-tris(hy-
(2) (a) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539–10540. (b) Altman, R. A.; Buchwald, S. L. Org. Lett.
2006, 8, 2779–2782. (c) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J.
Org. Chem. 2007, 72, 6190–6199. (d) Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2003, 5, 793–796. (e) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc.
2006, 128, 8472–8473. (f) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3940–3941. (g) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729. (h) Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844–14845. (i) Kwong,
F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–584.
(3) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695–709.
† Sichuan Normal University.
‡ Chengdu Institute of Biology of the Chinese Academy of Sciences.
(1) For reviews, see:(a) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345.
(b) Rayner, C. M. Contemp. Org. Synth. 1996, 3, 499. (c) Metal-Catalyzed
Cross Coupling Reactions; Diederich, F., Stang, P., Eds.; Wiley-VCH: New
York, 1998.
(4) Lu, Z. K.; Twieg, R. J.; Huang, S. P. D. Tetrahedron Lett. 2003,
44, 6289–6292.
10.1021/ol801730g CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

droxymethyl)ethane6 as the ligands. Among these reports,
Ma’s work has attracted our attention. In 1998, Ma7 reported
that the structures of R- and ꢀ-amino acids could induce
acceleration of Ullmann-type arylation which led to the
coupling reaction of aryl halides with R- or ꢀ-amino acids
at relatively low temperatures. Soon after these reports,
milder Ullmann-type processes for C-N bond formation
such as N-arylation of amides,8 amines,9 unsaturated
heterocycles,9b and C-O bond formation such as O-arylation
of phenols10 which use amino acids as supporting ligands
have been reported by Ma and co-workers. Because these
copper-catalyzed coupling reactions could be carried out at
a much lower temperature than the traditional copper-
mediated Ullmann coupling protocols, these results repre-
sented a major advance in the development of Ullmann-type
arylation methodology.
On the other hand, a multicomponent reaction plays an
important role in modern organic chemistry since it exhibits
generally a higher atom economy and selectivity, as well as
lower costs, time, and energy. Furthermore, this methodology
allows molecular complexity and diversity to be created by
the facile formation of several new covalent bonds in a one-
pot transformation quite closely approaching the concept of
an ideal synthesis. Inspired by the work of Ma and colleagues
on the copper-catalyzed cross-coupling reactions and en-
deavoring us to develop useful organic transformations taking
advantage of the multicomponent reaction, we were prompted
to construct an aryl C-N bond and a C-O bond in one pot
via copper-catalyzed cross-coupling. Thus, a competitive
experiment was undertaken (Scheme 1) in which a mixture
this case not only 50% yield of the product but also N-(4-
bromphenyl)-proline was isolated. This result clearly indi-
cated that L-proline could couple with 4-bromphenyl iodide
during the reaction, thereby reducing the activity of the
catalytic system. Encouraged by this result, we examined
several amino acids as the ligands. As shown in Table 1,
Table 1. Coupling Reaction of Phenol, Caprolactam, and
4-Bromphenyl Iodide under the Catalysis of CuI and Ligandsa
entry
ligand
solvent
base
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
L-proline
glycine
dioxane K3PO4
dioxane K3PO4
50
42
65
23
34
55
78
43
41
70c
82d
69e
78f
N,N-dimethylglycine dioxane K3PO4
2-aminoethanol
1,2-ethandiol
dioxane K3PO4
dioxane K3PO4
N,N-dimethylglycine DMF
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
N,N-dimethylglycine DMSO
K3PO4
K3PO4
K2CO3
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
a Reaction conditions: 4-bromphenyl iodide (1.0 mmol), caprolactam
(1.2 mmol), CuI (0.1 mmol, 10 mol %), ligand (0.2 mmol, 20 mol %), and
base (5.0 mmol) in 3 mL of solvent were stirred at 100 °C for 48 h. Then
phenol (1.2 mmol) was added and stirred at 120 °C for another 48 h.
b Isolated yield. c Using 10 mol % of CuI and 30 mol % of ligand. d Using
15 mol % of CuI and 20 mol % of ligand. e The time of the second reaction
step: 24 h. f The time of the second reaction step: 36 h.
glycine gave a similar result (entry 2), and then we employed
N,N-dimethylglycine as the ligand because this amino acid
is unable to process the N-aryl amination. As expected, N,N-
dimethylglycine gave better conversion in comparison with
L-proline and glycine (compare entries 1 and 3, as well as
entries 2 and 3). Besides the above amino acids, other
bidentate O,O and O,N ligands such as 1,2-ethanediol and
2-aminoethanol were also tested, but these ligands led to a
lower catalytic activity (entries 5 and 4). Using N,N-
dimethylglycine as the ligand, we changed the solvent
dioxane to DMSO, DMF. To our delight, the use of DMSO
gave excellent yield of the product (entry 7). Base effects
were preliminarily surveyed, and K3PO4 was found to be
effective as base; however, K2CO3 and Na2CO3 gave inferior
results (entries 8 and 9). Further optimization of the reaction
conditions revealed that the best ratio between CuI and N,N-
dimethylglycine was 1.5:2 (compare entries 7 and 11, as well
as entries 10 and 11). In addition, we evaluated the effect of
reaction time. The results showed that lower yields of 1-(4-
bromophenyl)azepan-2-one were observed if the time of the
first reaction step was reduced to 24 or 36 h, and lower yields
of product were obtained if the time of the second reaction
step was shortened (entries 12 and 13).
Scheme 1
of CuI catalyst (10 mol %), L-proline (20 mol %), capro-
lactam (1.2 equiv), 4-bromphenyl iodide (1.0 equiv), and
K3PO4 (5.0 equiv) was stirred in dioxane at 100 °C for 48 h,
and then phenol (1.2 equiv) was added into the mixture and
stirred at 120 °C for another 48 h.
The sequence of the reaction was based on that phenol
exhibits higher activity than amide.10,11 It was found that in
(5) Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider,
P. J. J. Org. Chem. 2005, 70, 10135–10138.
(6) Chen, Y. J.; Chen, H. H. Org. Lett. 2006, 8, 5609–5612.
(7) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459–12467. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583–
2586.
The optimized reaction conditions, CuI (15 mol %), N,N-
dimethylglycine (20 mol %), and 5.0 equiv of K3PO4 in
DMSO under nitrogen, were tested by a number of different
amides and phenols. The results were summarized in Table
2. As can be seen, for most cases, the desired products were
(8) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809–1812.
(9) (a) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455. (b)
Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173.
(10) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799–3802.
4566
Org. Lett., Vol. 10, No. 20, 2008

Table 2. Coupling Reaction of Phenols and Amides with 4-Bromphenyl Iodide under the Catalysis of CuI and N,N-Dimethylglycinea
a Reaction conditions: 4-bromphenyl iodide (1.0 mmol), amide (1.2 mmol), CuI (0.15 mmol), N,N-dimethylglycine (0.2 mmol), and K3PO4 (5.0 mmol)
in 3 mL of DMSO were stirred at 80 °C for the indicated time. Then phenol (1.2 mmol) was added and stirred at 120 °C for the indicated time. b Isolated
yield. c The first step was carried out at 100 °C. d No product was determined. e The second step was carried out at 130 °C. f Using 2.5 mmol of K3PO4.
Org. Lett., Vol. 10, No. 20, 2008
4567

readily obtained in moderate to good yields. Functional
groups such as methoxy, chloro, and keto were found to be
compatible in these reaction conditions (Table 2, entries
3-6). Caprolactam, acetamide, benzamide, and acetanilide
were suitable substrates, while with acetamide, benzamide,
and acetanilide the temperature of the first step could be
reduced to 80 °C and the reaction time could be reduced to
24 h (entries 8-22). Benzamide gave only moderate yields
under the action of the second step at 120 °C (entry 13),
while good yields were obtained by carrying out the second
step at higher temperature to overcome their lack of reactivity
(entries 13-17). The reaction of acetanilide was inefficient
in the condition using 5.0 equiv of K3PO4, but it also could
be more efficient in the condition by using 2.5 equiv of
K3PO4 and the reaction time of the second step could be
reduced to 24 h (entries 18-22).
For phenols, electron-neutral, -rich, (entries 1, 3, and 4),
and -deficient (entry 5) substrates were efficiently trans-
formed to the desired products in good yields. Naphthalene-
2-ol also worked well. It is noteworthy that the hindered
2-methoxyphenol gave a slightly lower yield in comparison
with that of less-hindered phenol (compare entries 3 and 4).
On the contrary, substrates bearing strong electron-withdraw-
ing groups behaved poorly. For example, 4′-hydroxyac-
etophenone delivered a lower yield (entry 6), and 2-hydrox-
ybenzoic acid even yielded no coupling product at all (entry
7). This phenomenon may be due to the lower activity of
the substrates or their related byproducts formed during the
coupling reaction. These poor results are however quite
general in the literature.10,12 All previous unknown com-
Figure 1. ORTEP diagram of the single-crystal X-ray structure of
compound 3s.
catalyst is easily formed in situ by combining air-stable CuI
with N,N-dimethylglycine. With the exception of phenols
bearing strong electron-withdrawing groups, the catalyst
allows for a number of substrates to be transformed into the
desired products in moderate to good yields. A simple
experimental procedure, satisfactory atom economy, and
tolerance with diverse functional groups make the present
methodology very attractive. The application of this method
to the synthesis of pesticides is in progress.
1
pounds were fully identified by their H NMR, 13C NMR,
IR, and HRMS spectra. Moreover, the structure of 3s (entry
20) was unambiguously confirmed by X-ray diffraction
analysis (Figure 1).13
In summary, a facile, economic, and green protocol for a
one-pot multicomponent coupling reaction of phenols,
amides, and 4-bromphenyl iodide has been described. The
Acknowledgment. The authors are grateful to the Natural
ScienceFoundationofSichuanProvince(Grant2006J13-002-2)
and the Scientific Research Fund of Sichuan Provincial
Education Department (Grant 2006A070) for financial sup-
port.
(11) Deng, W.; Wang, Y. F.; Zou, Y.; Liu, L.; Guo, Q. X. Tetrahedron.
Lett. 2004, 45, 2311–2315.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for the reaction
products, as well as X-ray crystallographic data for 3s in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante,
R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623–1626. (b) Quali, A.; Spindler,
J. F.; Cristau, H. J.; Taillefer, M. AdV. Synth. Catal. 2006, 348, 499–505
.
(13) Crystallographic data (including structure factors) for compound
3s (CCDC694124) reported in this paper have been deposited with the
Cambridge Crystallographic Data Center. See Supporting Information for
details.
OL801730G
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Org. Lett., Vol. 10, No. 20, 2008