CuI/Oxalic Diamide Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amines

Article abstract of DOI:10.1021/jacs.5b08411

A class of oxalic diamides are found to be effective ligands for promoting CuI-catalyzed aryl amination with less reactive (hetero)aryl chlorides. The reaction proceeds at 120 °C with K₃PO₄ as the base in DMSO to afford a wide range of (hetero)aryl amines in good to excellent yields. The bis(N-aryl) substituted oxalamides are superior ligands to N-aryl-N′-alkyl substituted or bis(N-alkyl) substituted oxalamides. Both the electronic nature and the steric property of the aromatic rings in ligands are important for their efficiency.

Full text of DOI:10.1021/jacs.5b08411

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Communication
CuI/oxalic diamides catalyzed coupling
reaction of (hetero)aryl chlorides and amines
wei zhou, Mengyang Fan, Junli Yin, Yongwen Jiang, and Dawei Ma
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08411 • Publication Date (Web): 09 Sep 2015
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CuI/Oxalic Diamides Catalyzed Coupling Reaction of
(Hetero)Aryl Chlorides and Amines
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Wei Zhou,†§ Mengyang Fan,†§ Junli Yin,‡ Yongwen Jiang† and and Dawei Ma†‡*
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech, 319 Yueyang Road, Shanghai 200031, China
Supporting Information Placeholder
(hetero)aryl chlorides could proceed under mild conditions
with CuI as the catalyst.
ABSTRACT: A class of oxalic diamides are found to be ef-
fective ligands for promoting CuI-catalyzed aryl amination
with less reactive (hetero)aryl chlorides. The reaction proceeds
o
at 120 C with K3PO4 as the base in DMSO to afford a wide
range of (hetero)aryl amines in good to excellent yields. The
bis(N-aryl) substituted oxalamides are superior ligands to N-
aryl-N’-alkyl substituted or bis(N-alkyl) substituted oxa-
lamides. Both the electronic nature and the steric property of
the aromatic rings in ligands are important for their efficiency.
N-Aryl amine moieties are important structural features that
Scheme 1. Coupling reactions of (hetero)aryl halides with amines
under the catalysis of palladium and copper complexes
are ubiquitously found in numerous natural products, pharma-
ceuticals, agrochemicals, and material molecules.1 A typical
approach for preparing N-aryl amines is the copper-catalyzed
In search of effective ligands for Cu-catalyzed coupling
Ullmann coupling reaction of aryl halides with amines.2 Tradi-
reactions, we realized that the electronic nature of the ligands
are particularly important for their efficiency.19 We therefore
tionally, the reaction required a high reaction temperature and
the stoichiometric amount of copper reagent, which greatly
became interested in developing aromatic bidentate ligands
limited the reaction scope.2 During the past two decades, two
because their electronic nature can be finely tuned by
introducing different substituents on the aromatic rings.19b-d In
breakthroughs have appeared to overcome these drawbacks.
One is the development of palladium-catalyzed coupling of
2012, we revealed that 2-(2,6-dimethylphenylamino)-2-
aryl halides with amines using sterically hindered phosphine
oxoacetic acid (DMPAO) effectively promoted CuI-catalyzed
ligands (Buchwald-Hartwig reaction).3 Another one is the dis-
N-arylation of acyclic secondary amines that were considered
as the difficult substrates previously,19b but as well as primary
covery of efficient bidentate ligands that have promoted cop-
per-catalyzed Ullmann-type reactions.4-16 These progresses
amines even at low catalytic loadings. Its excellent reactivity
have greatly extended the reaction scope of aryl aminations
prompted us to challenge the Cu-catalyzed aryl amination of
and allowed these reactions to proceed under mild conditions.
aryl chlorides. Accordingly, we conducted a CuI/DMPAO
Thanks to these advances, the aryl aminations have been in-
catalyzed coupling of 4-methylphenylchloride with
o
tensively applied in the synthesis of functional molecules by
benzylamine, and found that reaction occurred at 120 C in
DMSO under the assistance of K3PO4, albeit with a low
researchers in both academia and industry.3f-k,16,17 However,
further breakthroughs are required to make these reactions
conversion (Table 1, entry 1). Changing the ligand with a
more attractive. In Cu/ligand-catalyzed aryl amination reaction,
more
electron-rich
2-(2,4,6-trimethoxyphenylamino)-2-
similar result (entry 2).
one key problem is that less expensive aryl chlorides are still
poor substrates,5,18 which has been considered for years as the
weakness of such method in comparison with Buchwald-
Hartwig reaction.3k,16 In consideration of the relative low cost
of catalysts and ligands in copper-catalyzed aryl aminations, it
is highly desirable that a copper catalyst can sufficiently acti-
vate aryl chloride substrates. Herein, we wish to disclose our
results by discovering oxalic diamides as powerful ligands for
copper catalysis. With these ligands, the amination of
oxoacetic acid (L2) gave
a
Surprisingly, its methyl ester (L3) could dramatically increase
the conversion to afford arylamine 3a in 74% yield (entry 3).
Since the corresponding potassium salt L4 still gave a low
yield of 3a (entry 4), we thought that this salt should not be the
active ligand. After examining the reaction mixture carefully,
we found that L3 was indeed converted into the corresponding
diamide L5 during the coupling reaction. When L5 was
directly used, coupling product 3a was obtained in 75% yield
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o
b
1
(entry 5), indicating that this oxalic diamide is a real ligand for
coupling reaction.
mL), 120 C, 24 h. The yield was determined by H NMR
analysis of crude products using CH2Br2 oas the internal stand-
c
ard. The reaction was conducted at 115 C with 5 mol% CuI,
Table 1. CuI-catalyzed coupling of 4-methylphenyl chloride
d
with benzylamine under the assistance of different ligands.a
10 mol% ligand and 110 mol% K3PO4. DMF as the solvent.
eDMA as the solvent. MeCN as the solvent. t-BuOH as the
f
g
10 mol% CuI
h
i
j
Cl
NHBn
solvent. Cs2CO3 as the base. K2CO3 as the base. Na2CO3 as
20 mol% ligand
K3PO4, DMSO
120 oC, 24 h
k
+ BnNH2
the base. 5 mol% CuI, 5 mol% ligand and 100 mol% K3PO4
were used. lIsolated yield.
Me
Me
2a
9
3a
1a
In response to this exciting result, we explored the
structure-efficiency relationship of
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OMe
O
MeO
Me
O
a number of oxalic
O
diamides. Thus, L6-L13 were synthesized from the
corresponding mono-substituted anilines. Screening of these
ligands demonstrated that 2-methoxyaniline derived diamide
L6 was still active to provide 3a in 62% yield (entry 6), while
improved yields were obtained by employing isopropoxy and
benzoxy substituted ligands (entries 7 and 8), presumely
because their larger substituents at the ortho-position of
anilines could prevent the hydrolysis of the ligands.20
N
CONHBn
N
COR
N
CO2H
H
H
H
R
OMe
Me
L1 (DMPAO)
L6: R = OMe
L7: R = OPr-i
L8: R = OPh
L2
L3
L4
L5
: R = OH
: R = OMe
: R = OK
O
N
: R = NHBn
O
R
2
O
H
N
CONHMe
R
H
OPh
R
N
L10: R = OPh (BBPO)
L11: R = Et
L12: R = Bu-t
Changing the N-benzyl of L8 to N-methyl led to formation
of 3a in a decreased yield (entry 9). However, complete con-
version was observed when N,N’-bis(2-benzoxyphenyl)-
oxalamide (BBPO, L10) was utilized (entry 10), which im-
plied that bis(N-aryl) substituted oxalamides are more effec-
tive ligands. Further investigations indicated that electronic
nature of the aromatic ring in ligands played an important role
for their efficiency. When the benzoxy group in L10 was re-
placed with less electron-rich ethyl and t-butyl groups, ligands
L11 and L12 gave poor results (compare entries 10-12). The
similar trend could be seen from the performance of ligands
L13-L16 (entries 13-16). The better result obtained by L15 in
comparison with L14 showed again that increased steric hin-
drance is necessary to get more effective ligands, while the
best result was observed in case of more electron-rich N,N’-
bis(2,4,6-trimethoxyphenyl)oxalamide (BTMPO, L16) as the
ligand (entry 16). To fully demonstrate the importance of the
electronic nature in the ligands, we also examined two series
of ligands L17-L24 and L25-L30. The results clearly showed
that ligands generated from more electronic-rich anilines are
more effective (compare entries 17-24 and entries 25-30). Ad-
ditionally, decreased yields were obtained by using L31 and
L32 indicating that aniline-derived diamides were better than
aliphatic amine-derived diamides (entries 31 and 32), and such
subtle change in electronic nature of the ligands provided sig-
nificant influence on their efficiency. Noteworthy is that no
coupling occurred under similar conditions if the oxalic dia-
mide ligands were switched with other ligands such as amino
acids,4 diamines,5 salicylaldoxime.6 1,10-phenanthroline7 di-
ethyl-salicylamide,8 1,3-diketones,9 pyrrole 2-carboxylic ac-
id,10 rac-BINOL,11 2-dimethylaminoethanol,12 β-keto esters,13
8-hydroxyqunioline14 and 2-pyridinyl-β-ketones.15
L9
2
H
Ph
L17
L18
: R = H
: R = CF3
L19: R = F
L20: R = CO2Me
L21: R = Ph
L22: R = Me
L23: R = OMe
L24: R = NEt2
Me
O
L13: R = OMe
R
R'
N
O
2
H
Me
N
H
L25: R = CO2Me
L26: R = F
2
OMe
L27
L28
L29
: R = H
: R = Me
: R = OMe
L14: R = OMe, R' = H
L15: R = H, R' = OMe
L16: R = R' = OMe (BTMPO)
L30: R = NMe2
L31
L32
)
(BnNHCO)2
(
), (MeNHCO)2
(
Entry Ligand
Yield
(%)b
Entry
Ligand
Yield
(%)b
1
2
L1
L2
15
16
74
10
75
62
74
73
56
86
45
17
66
73
82
92
76
23
61
48
21
22
L21
L22
L23
L24
L25
L26
L27
L28
L29
L30
L31
L32
L16
L16
L16
L16
L16
L16
L16
L16
77
87
3
L3
23
88
4
L4
24
92
5
L5
25c
26c
27c
28c
29c
30c
31
21
6
L6
49
7
L7
65
8
L8
69
9
L9
92
10
11
12
13
14
15
16
17
18
19
20
L10
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
94
61
32
11
33d
34e
35f
36g
37h
38i
39j
40k
84
78
Using L16 as the ligand, we tested other solvents and bases.
Using DMF and DMA only slightly decreased the reaction
yields, while much lower yields were observed in cases of
MeCN and t-BuOH as the solvents (entries 33-36). Change of
the base to Cs2CO3, K2CO3 and Na2CO3 also gave poorer re-
sults (entries 37-39). Thus, we concluded that the best condi-
tions are K3PO4 as the base and DMSO as the solvent. To our
delight, under these conditions a 89% isolated yield was ob-
tained even the loadings of both catalyst and ligand were re-
duced to 5 mol% (entry 40).
49
29
65
48
38
91 (89)l
aGeneral conditions: 1a (0.5 mmol), 2a (0.75 mmol), CuI
(0.05 mmol), ligand (0.1 mmol), base (1 mmol), solvent (1.0
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Table 2. Scope of CuI/BTMPO catalyzed coupling reaction of
worked well, delivering the coupling products 3b-3k in 60-
96% yields. Three meta-substituted aryl chlorides were also
good substrates, affording 3l-3n in 70-97% yields. The for-
mation of 3m as a single product implied that chemoselectivi-
ty could be obtained between aromatic amines and aliphatic
amines. Coupling with sterically hindered ortho-substituted
aryl chlorides was found to be relatively difficult and increas-
ing the ligand loading and prolonging reaction time were re-
quired to ensure a good yield (for 3o). The similar trend was
also observed from the reactivity difference between 1-
naphthyl chloride (3s) and 2-naphthyl chloride (3t).
(hetero)aryl chlorides with amines.a
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A variety of biologically interesting heteroaryl amines could
be assembled from the corresponding heteroaryl chlorides us-
ing the present method. These aromatic heterocycles include
pyridine (3u, 3v), thiophene (3w), protected indole (3x), ben-
zothiophene (3y), benzothiazole (3z), quinoline (3aa), as well
as quinoxaline (3ab). Furthermore, two aryl chlorides with the
additional heterocycles underwent the coupling smoothly,
providing arylamines 3ac and 3ad in 78% and 93% yields, re-
spectively.
In terms of amine coupling partners, the use of substrates
with a long alkyl chain (3ae), hydroxyl (3af, 3ao, 3ar), furanyl
(3ag, 3am), cyclic alkyl (3ah-3ak, 3ap-3as), vinyl (3al), ketal
(3an) and carbamate (3ap) groups were found to give the aryl
amination products in good to excellent yields. This fact, to-
gether with its compatibility with a wide range of functional
groups such as amide, thioether, cyano, ketone, ester, trifluoro,
amine, and heterocycles that was observed during varying
(hetero)aryl chlorides, make the present method to be a relia-
ble and attractive approach for assembling (hetero)aryl amines.
The present reaction was quite sensitive to steric hindrance
of amines, as evident from the different reactivity displayed by
linear alkylamines and cyclic alkylamines (compare 3ae, 3af
with 3ah, 3aj). For cyclic alkylamines, reactions needed high-
er ligand loadings and longer times to give complete conver-
sion. Another evidence came from the aryl amination with
secondary amines. Only 50% yield of 3au was observed when
coupling of 4-methylphenyl chloride with pyrrolidine, a rather
reactive secondary amine. Further improvements by using
suitable ligands are required to solve this problem. Interesting-
ly, when sterically hindered amines were utilized, electron-
poor aryl chlorides were found to be more reactive than elec-
tron-rich aryl chlorides (compare 3ah with 3as, and 3at with
3au).
In conclusion, oxalic diamides are discovered to be effec-
tive ligands that have enabled the CuI-catalyzed amination of
less reactive (hetero)aryl chlorides under relative mild condi-
tions. A wide range of functionalized (hetero)aryl chlorides
and amines were compatible with the present reaction condi-
tions, thereby allowing the synthesis of (hetero)aryl amines
with diverse structural features. More importantly, oxalic dia-
mide ligands are quite cheap, conveniently available and easi-
ly tunable. These remarkable features makes this method very
attractive for the preparation of (hetero)aryl amines. Unlike
previous investigations on ligand-promoted copper-catalyzed
Ullmann-type reactions where only limited ligands were em-
ployed from commercial resources and little or no information
was able to be collected for its structure-activity relationship,21
the present investigation has demonstrated the potential to gain
the structure-activity relationship of ligand for copper-
aGeneral conditions: 1 (1 mmol), 2 (1.5 mmol), CuI (0.05
mmol), BTMPO (0.05 mmol), K3PO4 (1.0 mmol), DMSO (1.0
mL), 120 oC, 24 h, isolated yield. bThe reaction was conducted
c
with 5 mol% CuI and 10 mol% BTMPO for 48 h. Reaction
was conducted with 20 mmol of aryl chloride, 2.5 mol% CuI
and 2.5 mol% BTMPO at 120 oC.
With the optimized conditions in hand, we next explored the
reaction scope and limitations by varying aryl chlorides and
amines, and the results are summarized in Table 2. We were
pleased that a series of para-substituted aryl chlorides bearing
either electron-donating or electron-withdrawing groups
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reactions. The mechanistic studies and application of these
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ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*madw@sioc.ac.cn
Author Contributions
§W.Z. and M. F. contributed equally.
ACKNOWLEDGMENT
The authors are grateful to Chinese Academy of Sciences and the
National Natural Science Foundation of China (grant 21132008 &
20921091) for their financial support, and Xiangyang Feng and Xi
Jiang for synthesizing some ligands.
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views, see: (b) Linsley, J. Tetrahedron 1984, 40, 1433-1456. (c)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
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(3) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem. Int. Ed. Engl. 1995, 34, 1348-1350. (b) Louie, J.; Hartwig, J. F.
Tetrahedron Lett. 1995, 36, 3609-3612. For reviews, see: (c) Hartwig,
J. F. Angew. Chem. Int. Ed. 1998, 37, 2046-2067. (d) Wolfe, J. P.;
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31, 805. (e) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860. (f)
Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem. Int.
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Chem. Int. Ed. 2008, 47, 6338-6361. (h) Hartwig, J. F. Acc. Chem.
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(21) Buchwald and coworkers have briefly studied the structure-
efficiency relationship of substituted phenanthrolines in their Cu-
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