Tetrahedron Letters
A new ligand for copper-catalyzed amination of aryl halides to primary
(hetero)aryl amines
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Shang Jiang, Xinrui Dong, Yatao Qiu, Dong Chen, Xiaoxing Wu , Sheng Jiang
Key Laboratory of Natural Medicines and Department of Medical Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
N,N0-Bis(3,5-dimethoxyphenyl)cyclopentane-1,1-dicarboxamide was found as a new ligand for copper-
catalyzed amination of aryl iodides, bromides and chlorides to afford various primary (hetero)aryl
amines. These reactions proceeded efficiently under mild conditions when inexpensive aqueous ammo-
nia (28% NH3 in H2O) was used as the amino source.
Article history:
Received 12 November 2019
Revised 23 January 2020
Accepted 27 January 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
Amination
New ligand
Cyclopentane-1,1-dicarboxamide
Introduction
ligand were needed to proceed this amination reaction at room
temperature. Other ligands such as 2-pyridinyl-b-ketones [30]
Primary (hetero)aryl amines are present in a number of biolog-
ically active natural products and privileged building blocks in
pharmaceuticals, agrochemicals, and material molecules [1].
Although transition-metal catalyzed cross-coupling reactions are
among the most common methods to prepare substituted arylami-
nes [2–4], the direct synthesis of primary (hetero)aryl amines are
rare until recently [5,6].
Buchwald [7] and Hartwig [8] independently reported palla-
dium-catalyzed cross-coupling reaction of aryl halides with
ammonia. These methods demonstrate the effectiveness of palla-
dium catalysts to access primary arylamines. However, the devel-
opment of less expensive copper catalysts with readily available
ligands for such transformation is desirable.
and pyridydiketone derivatives [31] were identified as efficient
ligands for copper-catalyzed amination reaction of aryl iodides at
room temperature.
In 2011, CuI nanoparticles-nBu4NOH system was used for the
amination of aryl iodides at room temperature [32]. No additional
ligand is required. Page and co-worker disclosed the use of 1 mol%
ascorbic acid as the ligand to achieve the cross-coupling of aryl
iodides and ammonia [33]. However, liquid ammonia should be
the ammonia source.
Herein we describe a mild copper catalyst system for the direct
amination of aryl iodides at room temperature, and of aryl bro-
mides and aryl chlorides at higher temperatures by utilizing N,
N’-bis(3,5-dimethoxyphenyl)cyclopentane-1,1-dicarboxamide as
the new ligand (Fig. 1).
Earlier copper-catalyzed examples that converted aryl halides
into primary arylamines often suffer from high reaction tempera-
ture, limited substrate scope, or the use of ammonia gas/liquid
ammonia as nitrogen source [9–28].
Results and discussion
The first room-temperature method for the coupling of aryl
iodides with ammonia has been developed by Chang and co-work-
ers [29]. In this methodology, cheap ammonium chloride (NH4Cl)
We initially selected 4-methyliodobenzene as a model substrate
for optimization of the reaction conditions. With the newly-pre-
pared ligand L1 employed, the desired coupling product 4-methy-
laniline was obtained in 44% yield at room temperature (Table 1,
entry 1). The replacement of base K3PO4 with CsOH led to
decreased yield, while Cs2CO3 improved the reaction efficiency
(Table 1, entry 2–3). Among the ligands screened, N,N0-bis(3,5-
dimethoxyphenyl)cyclopentane-1,1-dicarboxamide L2 turned out
to be the best, affording the product in 87% yield (Table 1, entry
4). This suggests the importance of the electronic effect of ligand
was utilized as an ammonia surrogate. -Proline has been found
L
as the effective ligand. However, 20% mol copper and 40 mol%
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Corresponding authors at: Department of Pharmacy, China Pharmaceutical
University, 24 Tong Jia Xiang, Nanjing 210009, China.
(S. Jiang).
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Jiang, X. Dong, Y. Qiu et al., A new ligand for copper-catalyzed amination of aryl halides to primary(hetero)aryl amines, Tetra-