Direct arylation of tertiary amines via aryne intermediates using diaryliodonium salts

Article abstract of DOI:10.1016/j.tetlet.2018.03.067

With a strategy by using diaryliodonium salts as the precursors of benzynes, direct N-arylation of tertiary amines with diaryliodonium salts was reported. Thus, the desired aromatic tertiary amines with a wide range of substituents were synthesized in moderate to excellent yields of 55–91%.

Full text of DOI:10.1016/j.tetlet.2018.03.067

Accepted Manuscript
Direct Arylation of Tertiary Amines via Aryne Intermediates Using Diarylio-
donium Salts
Zhiang Zhang, Xunshen Wu, Jianwei Han, Wenju n Wu, Limin Wang
PII:
S0040-4039(18)30394-0
https://doi.org/10.1016/j.tetlet.2018.03.067
TETL 49836
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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19 March 2018
23 March 2018
Please cite this article as: Zhang, Z., Wu, X., Han, J., Wu, W.n., Wang, L., Direct Arylation of Tertiary Amines
via Aryne Intermediates Using Diaryliodonium Salts, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.067
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Direct Arylation of Tertiary Amines via Aryne
Intermediates Using Diaryliodonium Salts
Zhiang Zhang, [a] Xunshen Wu, [a] Jianwei Han,*[a, b] Wenjun Wu,[a] and Limin Wang*[a]
[a]130 Meilong Road, Shanghai 200237, P. R. China
[b]345 Ling Ling Road, Shanghai 200237, P. R. China

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Tetrahedron Letters
journal homepage: www.elsevier.com
Direct Arylation of Tertiary Amines via Aryne Intermediates Using Diaryliodonium Salts
Zhiang Zhang, [a] Xunshen Wu,[a] Jianwei Han,*[a, b] Wenjun Wu,[a] and Limin Wang*[a]
[ a]Key Laboratory for Advanced Materials, Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, P. R. China
[b]Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling
Road, Shanghai 200032, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
With a strategy by using diaryliodonium salts as the precursors of benzynes, direct N-arylation
of tertiary amines with diaryliodonium salts was reported. Thus, the desired aromatic tertiary
amines with a wide range of substituents were synthesized in moderate to excellent yields of 55-
91%.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Diaryliodonium salts
Benzyne
Arylation
Aromatic tertiary amines
 Limin Wang. Tel.: +86-021-64253881; e-mail: wanglimin@ecust.edu.cn
 Jianwei Han. Tel.: +86-021-64253040; e-mail: jianweihan@ecust.edu.cn

2
Tetrahedron Letters
2. Results and Discussion
1. Introduction
Initially,
we
used
N,N-dimethylaniline
1a
and
Direct N-arylation, a convenient approach for construction of C(sp2)-
N bonds, has been extensively investigated in the synthesis of aromatic
amines.[1] Among them, diaryliodonium salts played an important role
in the development of N-arylations in an efficient manner.[2] In recent
years, direct N-arylation of secondary aliphatic amines, aromatic
amines, amides, sulfoximines and various N-heterocyclic aromatics
with diaryliodonium salts had been recorded under mild conditions.[3]
In general, the nitrogen containing substrates were employed as N-
nucleophiles in these reactions, which the N-nucleophiles reacted with
aryl cations or aryl radicals for producing aryl amines. Since the year of
2012, our group had reported N-arylation methodologies in the
preparation of N-arylcarbazoles, N-arylated 1,8-naphthalimides, N’ N-
diarylsulfonamides and N-arylated hydroxylamines under metal-catalysis
or harsh basic reaction conditions.[4] However, N-arylation of substrates
containing nitrogen atom without N-H has rarely been reported. For the
cases of N-heterocyclic aromatics with no N-H bond (Scheme 1, (1)),
Gao and You et al. used diaryliodonium salts for directly quaternization
of N-substituted imidazoles in the synthesis of aryl imidazolium salts as
well as aryl triazolium salts in moderate to excellent yields.[5] Later, the
research group of Hollis extended this methodology to di-imidazolium
systems to obtain diarylated pincer ligand precursors in a single step.[6]
Recently, the research group of Mo reported a metal-free N-arylation of
oximes with diaryliodonium salts to produce α,β-unsaturated N-aryl
ketonitrones under mild conditions.[7] Furthermore, this method of N-
arylation was attempted to prepare 2,3-quaternary fused indolines in good
yields with high diastereoselectivity from alkynyl tethered oximes.[8] In the
case of direct aryl quaternization of N-alkyl imidazoles, Yoshida and Kunai
have reported a methodology by using aryne intermediates in 2002, in which
the arynes were generated from a Kobayashi precursor of silylaryl triflate in
the presence of CsF.[9] The strategy was widely employed to react with a
variety of nitrogen-based nucleophiles.[10] For example, the research group of
Biju described a monoselective N-arylation of aromatic tertiary amines using
a transition-metal-free approach using silylaryl triflate with KF in the
presence of crown ether.[11] Very recently, Stuart group and Wang group [12]
independently found that benzynes can be generated by simple
diaryliodonium salts comparing with the phenyl[o-(trimethylsilyl)phenyl]-
iodonium triflate by Kitamura in 1995.[13] Inspired by these excellent works,
we reported herein a transition-metal-free N-arylation of tertiary amines by
using diaryliodonium salts as the precursor of benzynes to access aromatic
tertiary amines (Scheme 1, (2)).
phenyl(mesityl)iodonium tosylate 2a as starting materials for the
optimization of the reaction conditions, the results were shown in Table 1.
Screening of several bases showed that LiHMDS was the most suitable
base (Table 1, entry 1-11). The desired product 3aa was afforded in 65%
yield, while other bases such as KOH, K2CO3, Cs2CO3, NaNH2, and NaH
proved to be ineffective (Table 1, entries 1-5). The strong bases of
KOtBu, NaOtBu, NaOMe and KHMDS led to decreased yields of 7-45%
(Table 1, entry 6-10). The yield of 3aa was improved to 70% when the
temperature was elevated to 110 oC. We then investigated the influence
of the excess of 2a and LiHMDS on the yield of 3aa. When two
equivalents of 2a and two equivalents of LiHMDS was used in this
reaction, an excellent yield of 91% was achieved (Table 1, entry 14).
The solvent effect was also examined, toluene was found to be superior
to other solvents such as THF, CH3CN (Table 1, entries 17 and 18). no
desired product was observed in CH3CN as solvent (Table 1, entry 18).
Table 1. optimization for the Reaction of N,N-dimethylaniline (1a) with
diaryliodonium salt (2a).[a]
Temperature
(oC)
Yield
(%)[b]
Entry
2a (equiv.)
Base (equiv.)
Solvent
1
2
3
4
5
6
1.2
1.2
1.2
1.2
1.2
1.2
KOH (1)
K2CO3 (1)
Cs2CO3 (1)
NaH (1)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
100
100
100
100
100
100
0
0
0
0
NaNH2 (1)
KOtBu (1)
0
15
7
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2
KOtBu (1.5)
NaOtBu (1.5)
NaOMe (1.5)
KHMDS (1.5)
LiHMDS (1.5)
LiHMDS (1.5)
LiHMDS (1.5)
LiHMDS (2)
LiHMDS (2.5)
LiHMDS (2)
LiHMDS (2)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
100
100
100
100
100
110
110
110
110
110
60
18
7
8
9
23
45
65
70
74
91
85
90
52
10
11
12
13
14
15
16
17
2
2.5
2
18
2
LiHMDS (2)
MeCN
80
0
[a]
Reaction conditions: 1a (0.4 mmol, 1 equiv.), base (0.4-1 mmol, 1-2.5 equiv.),
[b]
solvents (4 mL), 16 h.
Isolated yields. Mes = 2,4,6-trimethylphenyl. OTs = 4-
toluenesulfonate.
Scheme 1. N-arylations with diaryliodonium salts; Mes = 2,4,6-trimethylphenyl.
With the optimal conditions in hand, we next investigated the scope of
the N-arylation reaction, as shown in Table 2. A range of tertiary amines
1 was applied in this reaction under the identified optimized conditions.
It was found that the electronic properties of substituents on the anilines
affected reaction efficiency. For example, anilines with electron-donating
OTs = 4-toluenesulfonate.

3
i
1
(Me, OMe, Pr) groups are well tolerated to give products 3aa-3ag in
3bb, both two isomers in different ratio were determined by H NMR
good yields of 80-91% (Table 2, entries 1-7). However, the anilines with
electron-withdrawing (4-F, 4-CHO) groups gave moderate yields of 63-
70% (Table 2, entries 8-9). We also investigated the reactions of N,N-
diethylaniline and N,N-dibutylaniline with diaryliodonium salt 2a, the
reaction afforded the expected products 3aj-3ak in good yields (Table 2,
entries 10-11). As can be seen, the aliphatic tertiary amines such as
triethylamine, tripropylamine and tributylamine with diaryliodonium salt
2a was also examined, the reactions proceeded well under the optimal
conditions to give the desired aromatic amines in excellent yields of 68-
80% (Table 2, entries 12-14). Furthermore, the reaction of N-isobutyl-N-
methylaniline with diaryliodonium salt 2a was investigated under the
optimal conditions (Table 2, entry 15). The experiments revealed that
only the demethylated products 3ao was obtained in the moderate yield
of 76%. Therefore, the results indicated that both aromatic and aliphatic
tertiary amines provided desired products in good to excellent yields with
this method. However, the arylamines bearing electron withdrawing
groups of 4-nitro, 3,5-ditrifluoromethyl were failed to give the desired
products (Table 2, entries 16-17).
spectra according to the formed benzyne intermediates. the regioisomeric
products were not separable by column chromatography on silica gel.
However, only one isomer of 3be was obtained as suggested by NMR
spectra, which might be due to the steric effect. The diaryliodonium salts
with electron-withdrawing groups (4-F, 4-CF3, 4-OCF3) only give the
moderate yields of 55-67% (Table 3, entries 6-11). The results indicated
that diaryliodonium salts with electron-donating groups favored this
reaction. Interestingly, only one isomer was obtained in these cases of
3bf, 3bg, 3bh and 3bk (Table3, entries 6-11).
Table 3. Reaction of N,N-dimethylaniline 1a with diaryliodonium salts 2. [a]
Entry
1[c]
2
3
The structures of 3
Yield
(%)[b]
89
3ba
Table 2. Reaction of tertiary amine 1 with diaryliodonium salt 2a. [a]
2[c]
87
84
3bb
3bc
R1
R2
R3
Product
Yield
(%)[b]
Entry
3
1
2
3
4
5
6
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
CH3-
C6H5-
3aa
3ab
3ac
3ad
3ae
3af
91
2-MeC6H4-
3-MeC6H4-
4-MeC6H4-
3-MeOC6H4-
4-MeOC6H4-
82
4
5
6
80
90
55
3bd
3be
3bf
80
90
83
88
7
8
CH3-
CH3-
CH3-
Et-
CH3-
CH3-
CH3-
Et-
4-iPrC6H4-
4-CHOC6H4-
4-FC6H4-
C6H5-
3ag
3ah
3ai
89
70
63
81
75
68
80
75
76
0
7
8
71
65
67
58
3bg
3bh
3bi
9
10
11
12[c]
13
14
15
16
3aj
nBu-
Et-
nBu-
Et-
C6H5-
3ak
3al
9
Et-
10
3bj
nPr-
nPr-
nPr-
3am
3an
3ao
3ap
3aq
nBu-
CH3-
CH3-
CH3-
nBu-
iBu-
CH3-
CH3-
nBu-
11
61
3bk
C6H5-
4-NO2C6H4-
3,5-(CF3)2C6H3-
[a]
Reaction conditions: 1 (0.4 mmol), 2a (0.8 mmol, 2 equiv.), LiHMDS (1M in THF,
0.8 mL, 2 equiv.), Toluene (4 mL), 110 oC, 16 h. [b] Isolated yields. [c] The ratio of two
isomers was determined by 1H NMR spectroscopy. Mes = 2,4,6-trimethylphenyl. OTs =
4-toluenesulfonate.
17
0
[a]
Reaction conditions: 1 (0.4 mmol), 2a (0.8 mmol, 2 equiv.), LiHMDS (1M in THF,
0.8 mL, 2 equiv.), Toluene (4 mL), 110 oC, 16 h. Isolated yields. 1 (0.8 mmol, 2
equiv.), 2a (0.4 mmol). Mes = 2,4,6-trimethylphenyl. OTs = 4-toluenesulfonate.
To further explore the generality of this reaction, the scope of
aryl(mesityl)iodonium salts 2 was also examined (Table 3). The reaction
of N, N-dimethylaniline 1a with a variety of substituted diaryliodonium
salts 2 were conducted under the optimal conditions. We investigated the
steric and electronic effects on the N-arylation reaction. As shown in
Table 3, when iodonium salts 2 have electron-donating (Me, Bu) groups
on the aryl moiety the reaction gave the desired products 3ba-3be in
excellent yields of 80-90% (Table 3, entries 1-5); In the cases of 3ba and
[b]
[c]
To further validate the mechanism of the reaction, we used a deuterated
diaryliodonium salt 2n as the reactant for the arylation with triethylamine
(Scheme 2). We observed a deuterium at the ortho-phenyl carbon was
replaced by a proton. This experiment suggested that the benzyne
intermediate was formed during the reaction process. We therefore
proposed a possible mechanism of the reaction as shown in Figure 1.
First of all, the diaryliodonium salt generated benzyne intermediate under
the condition of alkali, and then triethylamine as the nucleophile attacks
the benzyne intermediate to generate amphoteric ion intermediate.
t

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Tetrahedron Letters
8.
Ma, X.-P.; Li, K.; Wu, S.-Y.; Liang, C.; Su, G.-F.; Mo, D.-
L. Green Chem. 2017, 19, 5761-5766.
Finally the Zwitterionic intermediate undergoes a proton transfer to
form the desired product and a molecule of ethylene.
9.
Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767-2769.
10. Liu, Z.; Larock. R. C. J. Org. Chem. 2006, 71, 3198-3209.
11. Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Org. Lett. 2013, 15,
5452-5455.
12. a) Sundalam, S. K.; Nilova, A.; Seidl, T. L.; Stuart, D. R. Angew.
Chem. Int. Ed. 2016, 55, 8431-8434; b) Wang, M.; Huang, Z. Org.
Biomol. Chem. 2016, 14, 10185-10188.
13. Kitamura, T.; Yamane, M. J. Chem. Soc. Chem. Commun. 1995,
983-984.
Scheme 2.
A deuterated diaryliodonium salt was involved in the reaction with
triethylamine.
Figure 1. Plausible reaction mechanism.
3. Conclusions
In conclusion, we have developed a direct N-arylation of aromatic and
aliphatic tertiary amines with diaryliodonium salts under transition-
metal-free conditions. A variety of tertiary amines and diaryliodonium
salts proceeded well and afforded the desire aromatic tertiary amines in
excellent yields of 55-91%. The experimental results indicated that the
diaryliodonium salts transform into benzyne during the reaction process.
Therefore, this method also provides a new way for the synthesis of
aromatic amines
Acknowledgments
The work was supported by National Key Program (2016YFA0200302,
Study on application and preparation of aroma nanocomposites), the
National Nature Science Foundation of China (NSFC 21472213,
21772039), and the Fundamental Research Funds for the Central
Universities, Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
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5.
6.
7.

5
Highlights
 A synthetic method of N-arylation
of tertiary amines via benzynes
with diaryliodonium salts was
developed.
 The desire aromatic tertiary amines
were synthesized in good yields of
55-91%.
 Diaryliodonium salts was used as
the precursors of benzynes.

6
Tetrahedron Letters