Selective C-N coupling reaction of diaryliodonium salts and dinucleophiles

Article abstract of DOI:10.1039/c6nj03964b

N-Aryl-α-amino amides including their chiral isomers have demonstrated important applications as pharmaceutical drugs; however, to date, a one-step synthetic route for them still remains to be developed. Herein, an efficient ligand-free copper-catalyzed selective C-N coupling reaction of diaryliodonium salts and dinucleophiles under mild conditions was realized. Diaryliodonium salts prefer to react with dinucleophiles at the site of stronger alkalic amino groups. Thus, a general aliphatic amino-selective N-arylation of α-amino amides was disclosed. Additionally, copper-catalyzed N-arylation of diaryliodonium salts afforded the same products as obtained via palladium-catalyzed reactions of aryl halides.

Full text of DOI:10.1039/c6nj03964b

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Selective C-N coupling reaction of diaryliodonium salts and
dinucleophiles
Chang Ma,a Qingle Zeng,a* Xufeng Wu,a Lihong Zhoua and Yi Huangb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
aromatic electrophile, and they have extensive
applications in organic synthesis.[11] For example, they are
used in metal-catalyzed[12] and catalyst-free[13] C-N
coupling reactions. But to the best of our knowledge,
selective C-N coupling reaction of dinucleophiles and
diaryliodonium salts are not explored yet, so we intend to
investigate it (Scheme 1).
N-Aryl-α-amino amides including their chiral isomers have
demonstrated important applications as clinic medicines, but
there is lack of a one-step synthetic method for it. Now an
efficient ligand-free copper-catalyzed selective C-N coupling
reaction of diaryliodonium salts and dinucleophiles under mild
conditions was realized. Diaryliodonium salts prefer to react with
dinucleophiles at the site of stronger alkalic amino groups. A
general aliphatic amino-selective N-arylation of α-amino amides is
first disclosed. Additionally copper-catalyzed N-arylation of
diaryliodonium salts affords the same products as palladium-
catalyzed reactions of aryl halides.
Ar
NH
X-
I+
Cu(OAc)2, K3PO4, 1,4-dioxane
NH2
YH
YH
+
Ar
Ar
RT or 40 oC, 24 h
NH
1
2
3
NH
Selective reactions avoid protecting co-existing functional
groups, as belong to step economic, atom economic and
cost-save reactions.[1] Dinucleophiles is a class of common
organic compounds,[2] and C-N coupling reactions are
YH = CONH2, OH,
,
N
Scheme
1
Copper-catalyzed selective C-N coupling reaction of
diaryliodonium salts 1 and dinucleophiles 2.
extensively
adopted
in
pharmaceutical
and
organochemical industries,[3] so to study selective C-N
coupling reactions of dinucleophiles is of importance.
α-Amino amides are a class of basic derivatives of α-
amino acids as well as a kind of common dinucleophiles.
The amide skeleton compounds were effective C-H
activation substrates in recent years, and have received
increasing attention from the scientific and industrial
viewpoints.[14] In addition, N-aryl-α-amino amides
including chiral isomers have demonstrated their
extensive and important applications as clinic
medicines,[15] such as Enzalutamide, Spiperone,
indolactam V, Opaviraline, lotrafiban, Lyngbyatoxin A, (-)-
Benzolactam-V8, teleocidin B-4, Loviride (Fig. 1).[16] The
synthetic method of N-(2-haloaryl)-α-amino amides is
developed by our group,[10] but the general synthesis of N-
aryl-α-amino amides via C-N coupling reaction is not
developed yet. As our ongoing study on coupling
reactions,[17] after many trials, we successfully explore a
general aliphatic amino-selective N-arylation of α-amino
amides with diaryliodonium salts as aromatic electrophile.
A
series of selective C-N coupling reactions of
dinucleophiles were studied. For example, Buchwald and
co-workers have studied selective C-N coupling reactions
of
2-aminobenzamizoles,[4]
amino
phenols,[5]
aminobenzamides,[6] N-Boc hydrazine and benzoic
hydrazide,[7] and β-amino alcohols.[8] Zeng et al. have
disclosed selective C-N coupling reaction of chiral α-amino
amides to synthesize chiral α-amino acid anilides[9] and
chiral N-(2-haloaryl)-α-amino amides.[10] Overall, the
selective C-N coupling reaction commonly uses aryl
halides as aromatic electrophile,[4-10] however, other kinds
of aromatic electrophiles are rarely investigated.
Diaryliodonium salts are a class of highly reactive
a.State Key Laboratory of Geohazard Prevention and Geoenvironment Protection
(Chengdu University of Technology), Chengdu University of Technology, College of
Materials, Chemistry & Chemical Engineering, 1#, Dongsanlu, Erxianqiao,
Chengdu 610059, Sichuan, P. R. China.
b.Chengdu University of Technology, College of Earth Science, 1#, Dongsanlu,
Erxianqiao, Chengdu 610059, Sichuan, P. R. China.
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures as well as spectral data of all synthesized compounds. See
DOI: 10.1039/x0xx00000x
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temperature, 24 h, argon, unless otherwise noted. Yields of the isolated
NH
HN
H
F
b)
c)
d)
N
HO
OH
products are given. 8 h. 24 h. 0.5 mmol diphenyliodonium triflate 1a,
1.0 mmol L-phenylalaninamide 2a. e) 0.8 mmol diphenyliodonium triflate 1a,
0.5 mmol L-phenylalaninamide 2a.
O
N
HN
O
NH
N
N
O
N
O
Spiperone
indolactam V
OH
teleocidin B-4
Therefore, common cuprous salts used in coupling
reactions were adopted as catalyst. CuI really carried out
the coupling reaction, although a low yield of 35% of the
targeted product N-phenyl-L-phenylalaninamide was
obtained (Entry 3). Neither CuBr nor CuCl gave better
results (Entries 4 and 5). To our delight, cupric salts
afforded much higher yields. Both CuCl2 and Cu(OTf)2 gave
70% yields (Entries 6 and 7). Fortunately, Cu(OAc)2
exhibited superior catalytic performance with the highest
yield of 95% (Entry 8).
O
HN
O
NH
O
N
Cl
HN
N
HO
NH2
NH
Lyngbyatoxin A
Cl O
(-)-Benzolactam-V8
Loviride
Fig. 1 Representative bioactive α-amino amide derivatives.
Neither stronger polarity solvent such as DMSO and
DMF nor lower polarity solvents such as toluene and
dichloromethane provided better results than that in
dioxane (Entries 9 to 12 vs. 8). Carbonates such as K2CO3
and Cs2CO3 as weak bases gave a little lower yields
(Entries 13 and 14). But strong bases KOtBu and NaOH
afforded much poorer results (Entries 15 and 16).
Interestingly, this coupling reaction also carried out when
no base was added (Entry 17), perhaps L-
phenylalaninamide acts as a weak base.
First of all, diphenyliodonium triflate and L-
phenylalaninamide were adopted as the model substrates
(Table 1). Given several catalyst-free C-N coupling
reactions with diaryliodonium salts were reported, the
two reactants were performed at room temperature
under catalyst-free condition, but only trace product was
detected on TLC (Entry 1). When Pd(OAc)2 was used as
catalyst for this reaction, the yield was very low (Entry 2).
Table 1 Optimization of reaction conditions of diphenyliodonium
triflate 1a and L-phenylalaninamide 2a.a)
Other reaction temperatures including 110 oC, 90 oC
o
and 40 C were screened (Entries 18 to 20 vs. 8), but no
O
better result was got. It seemed that high temperature for
common C-N coupling reaction with aryl halides as
substrates is not applicable to the reaction with
diaryliodonium salts as substrates. Shortening the
reaction time gave lower yield (Entry 21), but prolonging
it is not necessary (Entry 22). Perhaps high reactive
diphenyliodonium triflate easily carries out some side-
reactions, such as reaction with moisture to form phenol
H2N
H2N
catalyst, base
NH2
+
I+
OTf-
HN
solvent, temp., time
O
1a
3a
2a
Entry Solvent
Catalyst
——
Base
T (oC) Yield
1
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMSO
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
trace
8
2
Pd(OAc)2
CuI
3
35
30
35
70
70
95
20
40
30
and
diphenyl
ethers,[11a,18]
so
some
excess
4
CuBr
diphenyliodonium triflate benefits this transformation
(Entries 23 and 24 vs. 8).
5
CuCl
6
CuCl2
With the optimized reaction conditions in hand, various
α-amino amides were evaluated to react with
diphenyliodonium triflate (Table 2). Surprisingly, all of the
C-N cross coupling reactions of α-amino amides gave not
amino acid anilides, but only N-aryl-α-amino amides with
moderate to high yields (Entries 1-14), as demonstrates
that this reaction has high selectivity. Interestingly, for
copper-catalyzed C-N coupling reactions, diaryliodonium
salts are completely complementary with aryl halides,
which give amino acid anilides under CuI-catalyzed
conditions.[9] It seems that this reaction is much like
aromatic nucleophilic reaction, and the reason perhaps is
due to highly reactivity of diphenyliodonium triflate.
Racemic isomers of α-amino amides got approximate
high yields to that of L-form isomers (Entries 1,3,5 vs.
2,4,6). For most chiral bioactive compounds, chirality has
an important influence on their bioactivity.[19] The
eutomer generally has much higher bioactivity than the
corresponding racemic one,[20] thus synthesis of high
enantiomer-rich N-aryl α-amino amides is of importance.
7
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
8
9
10
11
DMF
Toluene
12
DCM
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K3PO4
K2CO3
Cs2CO3
KOtBu
NaOH
——
RT
RT
RT
RT
RT
RT
110
90
40
RT
RT
RT
RT
trace
88
70
40
30
50
80
82
85
75
93
30
70
13
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
14
15
16
17
18
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
19
20
21b)
22c)
23d)
24e)
a)
Reaction conditions: 1.0 mmol diphenyliodonium triflate 1a, 0.5 mmol L-
phenylalaninamide 2a, 0.1 mmol copper salt, 1 mmol base, solvent (5 mL),
2 | J. Name., 2012, 00, 1-3
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Luckily, chirality of L-phenylalaninamide was highly
Next, various diaryliodonium salts were examined to
retained during the C-N coupling reaction (Entry 2). While react with L-phenylalaninamide (Table 3). First of all,
the coupling products of L-phenylglycine and L-alanine diphenyliodonium salts with other counteranions were
also kept high ee values (Entries 4 and 6), which means screened (Entries 2 to 6 vs. 1). Diphenyliodonium
only little racemization of α-amino amides took place hexafluorophosphate gave moderate yield (Entry 2), and
under the reaction conditions.
diphenyliodonium nitrate and chloride gave rather low
yields (Entries 3 and 4). Even worse, diphenyliodonium
Table 2 Reactions of diphenyliodonium triflate 1a and α-amino bromide and iodide gave nothing (Entries 5 and 6). Thus,
amides 2 for synthesis of N-aryl-α-amino amides 3.a)
non-nucleophilic counteranions, i.e. triflate,
hexafluorophosphate, is much better than nucleophilic
counteranions, i.e. Cl−, Br−, I−, and diaryliodonium triflates
were the best type of substrate for the C-N coupling
reaction.
H2N
H2N
R
O
Cu(OAc)2, K3PO4,
NH NH2
+
I+
OTf-
1a
1,4-dioxane, RT or 40 oC, 24 h
R
O
3
2
Entry
1
α
-Amino amide
Product
DL-3a
L-3a
DL-3b
L-3b
DL-3c
L-3c
3d
Yield (%)
92
Table 3 Reactions of L-phenylalaninamide 2a and diaryliodonium
salts 1. a)
DL-Phe-NH2
2
L-Phe-NH2
95 (99%ee)
3
DL-Phg-NH2
L-Phg-NH2
93
O
H2N
H2N
Cu(OAc)2, K3PO4,
4
94 (97%ee)
NH2
Ar2I X
+
1,4-dioxane, RT or 40 oC, 24 h
HN
5
DL-Ala-NH2
L-Ala-NH2
93
O
Ar
1
2a
3
6
92 (94%ee)
Entry Ar
X−
OTf−
Product Yield (%)
7
L-Leu-NH2
89
65
80
52
70
80
93
35
8 b
9
L-Val-NH2
3e
1
C6H5
3a
3a
3a
3a
3a
3a
3l
95
−
L-2-Aminobutanamide
Gly-NH2.HCl
L-Pro-NH2
3f
2
C6H5
C6H5
C6H5
C6H5
C6H5
PF6
45
10 b
11
12
13
14
3g
−
3
NO3
Cl−
Br−
I−
OTf−
OTf−
OTf−
OTf−
OTf−
16
3h
4
10
5
NRb)
NRb)
89
L-Trp-NH2
3i
L-Tyr-NH2
3j
6
7 c)
8
4-CH3C6H4
L-Threoninamide
3k
a) Reaction conditions: 0.5 mmol α-amino amide, 1 mmol diaryliodonium salt,
0.1 mmol anhydrous Cu(OAc)2, 1 mmol K3PO4, dioxane (5 mL), room
4-t-C4H9C6H4
3,4-(CH3)2C6H3
2,4-(CH3)2C6H3
2,5-(CH3)2C6H3
2-CH3-5-t-C4H9C6H3 OTf−
4-BrC6H4
OTf−
3m
3n
3o
3p
3q
3r
75
9 c)
10 c)
11
12
89
b)
temperature, argon, 24 h. Yields of the isolated products are given.
Reactions of Entries 8 and 10 were performed at 40 oC.
91
92
82
13c)
83
Glycinamide afforded moderate yield (Entry 10), perhaps
due to formation of strong coordination between
glycinamide and the catalyst Cu(OAc)2, thus slows down
the reaction rate, and larger hydrophilicity of the N-
arylated product, as deteriorates the efficiency of
extracting product from water.
a)
Reaction conditions: 0.5 mmol L-phenylalaninamide, 1.0 mmol
diaryliodonium salt, 0.1 mmol anhydrous Cu(OAc)2, 1 mmol K3PO4, dioxane
(5 mL), room temperature, argon, 24 h. Yields of the isolated products are
given. b) NR denotes no reaction. c) Reaction temperature for Entries 7, 9, 10,
13 was 40 oC.
L-Prolinamide with a secondary amino group also gave
the expected N-phenyl-L-prolinamide in reasonable yield
(Entry 11), as means that secondary amino group may
proceed N-phenylation with phenyliodonium triflate.
Most surprisingly, α-amino amides with the third
functional groups, such as indolyl, phenolic hydroxyl,
aliphatic hydroxyl, also selectively afforded N-phenyl-α-
amino amides (Entries 12 to 14). It is obvious that
aliphatic amino group among the four kinds of functional
groups in these α-amino amides holds the highest
alkalinity, thus these results further support that alkalinity
of functional group is the key factor for diaryliodonium
salts to carry out the C-N coupling reaction. L-
Threoninamide gave far lower yield (Entry 14), perhaps
because of formation of strong coordination between L-
threoninamide with three coordination sites and catalyst
center metal Cu(II), which heavily slows down the reaction
rate.
Diaryliodonium triflates with a para-substituted alkyl
group gave good to high yields (Entries 7 and 8).
Surprisingly, di(3,4-xylyl)iodonium triflate, di(2,4-
xylyl)iodonium triflate and di(2,5-xylyl)iodonium triflate all
furnished the corresponding C-N coupling products with
comparable yields (Entries 9 to 11), as indicates the steric
hindrance of diaryliodonium triflates was not a problem
for the reactions. Fairly good yield of bulky di(2-methyl-5-
t-butylphenyl)iodonium triflate further supports this point
(Entry 12). Interestingly, diaryliodonium triflates with
electron-rich and -poor aryl groups, the arylation
proceeded smoothly with similar yields (Entries 7 to 12 vs.
13). The bromo substituent, which can be further
functionalized, survived under the reaction conditions
(Entry 13). On the whole, various diaryliodonium triflates
afforded good to high yields (Entries 1, 7 to 13), and steric
hindrance has little effect on the coupling reaction.
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In order to further explore the reactivity of C-N coupling reactions of amines, which often carry out at
diaryliodonium triflate, in addition to α-amino amides, higher temperature.[13]
other classes of dinucleophiles were studied (Table 4).
Based on the above results and literature reports, a
plausible mechanism of Cu(OAc)2-catalyzed selective C-N
Table 4 Selective C-N coupling reactions of dinucleophiles 2 and coupling reaction of diphenyliodonium triflate and α-
diphenyliodonium triflate 1a.a)
amino amides is proposed in Scheme 2.
Cu(OAc)2, K3PO4,
YH
YH
+
HN Ph
dioxane, 40 oC, 24 h
NH2
I+
H2N
H2N
R
O
I
OTf-
2
3
1
+
+H2N
R
O
I+
Entry
1
Product
O
Product No.
Yield (%)
OTf-
OTf-
H2N
1a
2
3s
70
NH2
Ph
K3PO4
4
NH
O
2
3t
73
NH
H2N
Ph
R
KOTf, K2HPO4
O
O
Ph
NH
NH
3
4
3u
3v
74
82
NH2
H2N
I
3
H
N
Cu(OAc)2
HN
R
NH
N
Ph
H2N
O
R
O
5
3w
62
HO
HO
NH
Ph
5
Ph
NH
NH2
6
7
3x
3y
60
50
N
H
Cu
AcO
OAc
HO HN Ph
7
a) Reaction conditions: 0.5 mmol dinucleophile, 1 mmol Ph2I+.OTf−, 0.1 mmol
anhydrous Cu(OAc)2, 1 mmol K3PO4, dioxane (5 mL), 40 oC, argon, 24 h.
Yields of the isolated products are given.
I
NH
AcO
Cu
R
AcO
I
N
O
H2
6
Firstly, the reaction of diphenyliodonium triflate and 2-,
3- and 4-aminobenzamides were performed. And similar
to the N-arylation of α-amino amides, the amide group
did not react, but aromatic amino group carried out the C-
N coupling reaction (Entries 1 to 3). Very interestingly, our
cheap, ligand-free copper(II)-catalyzed method afforded
just the same C-N coupling products as expensive
Buchwald’s Pd2dba3/XPhos-catalyzed protocol.[6]
Scheme 2 A proposed mechanism of nucleophilic attack /
copper(II) induced aryl transfer.
First, direct nucleophilic attack of diphenyliodonium
triflate and α-amino amides affords compound 4, which is
transformed into compound 5 with the help of the base
K3PO4, whose analogues Ar(Ar′)I-NR(R’) are reported by
four independent group.[23] Cui have detected it by NMR
and Q-TOF HRMs.[23d] Coordination of compound 5 and
Secondly,
2-aminobenzimidazole
gave
2-
phenylaminobenzimidazole (Entry 4), which is the same
product as Buchwald’s Pd2(dba)3/t-BuBrettPhos-catalyzed
protocol obtained.[4] Thirdly, 4-aminophenol also carried
out selective C-N coupling reaction (Entry 5). It is reported
that Buchwald et al adopted BrettPhos precatalyst to
fulfill this transformation.[21]
Forthly, amino alcohols also proceeded N-arylation,
and moderate yields were achieved (Entries 6 and 7). This
kind of products is reported to be synthesized via copper-
catalyzed C-N coupling reaction of amino alcohols and aryl
halides.[21]
2+
Cu(OAc)2 gives complex 6. As we know, CuL4 complexes
like complex 6 are very common.[24] Due to Lewis acid
Cu2+ induction, phenyl is transferred from iodine atom to
amino group. At the same time, iodobenzene is released,
and complex 7 is formed, which is just a complex of the
product 3 and Cu(OAc)2. The product 3 is dissociated from
the complex 7 and Cu(OAc)2 is restored.
Various dinucleophiles carried out the C-N coupling
reaction at their amino groups, which demonstrate
stronger alkalinity. It seems that alkalinity of the
functional groups is the key factor to promote the
coupling reaction. This phenomenon conforms to other
chemists’ statement: Iodine(III) compounds are
electrophilic at iodine, and they react with various
nucleophiles (abbreviated to “Nu” ) by initial Nu-I bond
formation.[11a,11b,23] And no catalyst is permitted for some
Conclusions
In summary, a new protocol of ligand-free cupric
acetate-catalyzed selective C-N coupling reaction of
dinucleophiles and diaryliodonium salts under mild
conditions was realized. The dinucleophiles including α-
amino amides, aminobenzamides, amino alcohols, 2-
aminobenzimidazole, and aminophenol are evaluated.
4 | J. Name., 2012, 00, 1-3
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13 (a) M. A. Carroll, R. A. Wood. Tetrahedron 2007, 63, 11349-
11354; (b) D. Wang, B. Ge, L. Li. J. Org. Chem. 2014, 79, 8607-
8613; (c) X. Pang, Z. Lou, M. Li, L. Wen, C. Chen. Eur. J. Org.
Chem. 2015, 3361-3369; (d) J. Li, X. Zheng, W. Li, W. Zhou,
W. Zhu, Y. Zhang. New J. Chem., 2016, 40, 77-80.
Especially the first general N-arylation of α-amino amides
is fulfilled with diaryliodonium salts as aromatic
electrophile, and α-amino amides with the third
functional groups, such as indolyl, phenolic hydroxyl,
aliphatic hydroxyl, also aliphatic amino-selectively
afforded N-phenyl-α-amino amides. Diaryliodonium salts
with strong electrophilicity prefer to react with
dinucleophiles at the site of stronger alkalic amino group.
In addition, for some dinucleophiles, such as
aminobenzamides, amino imidazole, and aminophenol,
our cheap copper-catalyzed reaction of diaryliodonium
salts afforded the same coupling products as expensive
palladium-catalyzed reaction of aryl halides. This
convenient procedure is simple, mild and practical.
14 (a) D. Wang, X. Yu, X. Xu. Chem. Eur. J. 2016, 22, 8663-8668;
(b) D. Wang, X. Yu, W. Yao. Chem. Eur. J. 2016, 22, 5543-
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Acknowledgements
We thank the Ministry of Science and Technology of the
People’s Republic of China (No. 2013DFA21690), the
National Natural Science Foundation of China (No.
21372034), the Department of Science and Technology
of Sichuan Province (No. 2016HH0074), the Education
Department of Sichuan Province (No. 16ZA0084),
Chengdu Science and Technology Bureau (No. 2015-
HM01-00362-SF) and the State Key Laboratory of
Geohazard Prevention and Geoenvironment Protection
Independent Research Project (No. SKLGP2016Z004).
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DOI: 10.1039/C6NJ03964B
COMMUNICATION
Journal Name
Graphic Abstract
Selective C-N coupling reaction of diaryliodonium salts and dinucleophiles
Chang Ma, Qingle Zeng,* Xufeng Wu, Lihong Zhou and Yi Huang
Ligand-free copper-catalyzed selective N-arylation of dinucleophiles including chiral
α-amino amides with
diaryliodonium salts as aryl electrophile equivalents was realized. Diaryliodonium salts prefer to react with
dinucleophiles at the site of stronger alkalic amino groups.
Ar
NH
X-
I+
Cu(OAc)2, K3PO4, 1,4-dioxane
NH2
YH
YH
+
Ar
Ar
RT or 40 oC, 24 h
NH
NH
,
YH = CONH2, OH,
N
6 | J. Name., 2012, 00, 1-3
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