Transition metal-free N-arylation of secondary amides through iodonium salts as aryne precursors

Article abstract of DOI:10.1039/c6ob01649a

By using a diaryliodonium salt as a benzyne precursor, a transition metal-free approach for N-arylation of secondary amides is developed. This novel benzyne precursor, which can be prepared easily by a one step process from an aryl iodide, shows different reactivities with previous benzyne precursors in the N-arylation reaction. Mechanistic studies confirm the involvement of benzyne species (generated in situ from the diaryliodonium salts) as key intermediates.

Full text of DOI:10.1039/c6ob01649a

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Organic & Biomolecular Chemistry
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Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Transition Metal-Free N-Arylation of Secondary Amides through
Iodonium Salts as Aryne Precursors
Ming Wang,* and Zhijian Huang
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
group (Scheme 1.2).6 The development of more versatile and
Diaryliodonium salt as the benzyne precursor, a transition
easy-prepared benzyne precursor which avoids the preparation of
difunctionalized arene is still a great necessary.7
metal-free approach for N-arylation of secondary amides is
developed. This novel benzyne precursor, which can be
prepared easily by one step process from aryl iodide, shows
e ec e or o- unc ona ze
enz ne recursors
y
p
1 S l t d th dif li d b
ti
( )
10 different reactivity with previous benzyne precursors in the
N-arylation reaction. Mechanistic studies confirm the
involvement of benzyne species (generated in situ from the
diaryliodonium salts) as key intermediates.
M Cl
g
OTf
OTf
OTf
I
r
A
OSO2
R
n
)
TMS
B i
p
(
TMS
amura
1995
,
FG
K
oso a
2013
,
noc e
H
o a as
Kit
h l 2004
,
y
K b
hi 1983
,
y
cou
Y
-
n
reac ons v a ar ne n erme a es
2 C O
li
ti
i
i t
di t
p
g
y
( )
Arynes as highly reaction intermediates have been extensively
15 applied in organic chemistry. Not only arynes are employed in
transition metal-catalyzed reactions,1 but also they are developed
in transition metal-free reactions.2 Due to arynes can donate a
aryl moieties rapidly, they are used for the formation of carbon-
carbon, carbon-heteroatom bonds by addition of nucleophiles to
20 arynes and trapping with electrophiles subsequently. Especially,
arynes are employed for the synthesis of nature products by high
efficiently construction of the key building blocks.3 Since Roberts
et al. firstly reported arynes via chlorobenzene with potassium
amide in 1953,4 the different kinds of benzyne precursors are
25 explored popularly. The ortho-difunctionalized arenes which
contain a leaving group and an activating group are the most
common benzyne precursors. For example, 2-trimethylsilylaryl
triflate, explored by Kobayashi group in 1983, is the most
comment benzyne precursor now day. After that, various ortho-
30 difunctionalized arenes were explored as elegant benzyne
precursors (Scheme 1.1).5 In spite of these ortho-difunctionalized
arenes generate benzynes in mild condition, but the synthesis of
these precursors need 3-5 steps. Recently, Tilley group reported
aryl halides coupling with alkoxides via aryne intermediates,
35 which needed the help of an inductive electron-withdrawing
Y
:
a o en
g
X H l
t
u
1
8
,
-crown-
K
O
B
6
: n uc ve e ec ron-
Y I d ti
l
y
l
t
THF 23 o
C
,
t
w
raw n rou
i
g g
p
X
u
t
i hd
O B
-
22 92
%
-
a
on o am es o ar nes
3 C N dditi
f
id
t
y
( )
O
CF3
H
H
N
OTf
N
F
3
C
s
C F
+
r
t
O
TMS
R
R
e
i ld
77
%
y
s s u
t
d
4
( )
Thi
y
O
O
OTf
Ph
t
R1
I
u
KO B
R2
R1
N
+
N
R2
r
t
Ph
H
H
-
e
60 89% i ld
y
40 Scheme 1 Different kinds of benzyne precursors and their reactions
Larock et al. reported insertion of benzene rings (via benzyne
intermediates obtained from 2-trimethylsilyl aryltriflate
precursors)
to
amide
bonds
to
eventually
give
aminobenzophenones (Scheme 1.3).8 Here, we report an N-
45 arylation of secondary amides using readily available and stable
diaryliodonium salts9-11 as benzyne precursor under transition
metal-free conditions (Scheme 1.4).12 Mechanistic studies
confirm that the reaction proceeds through
a benzyne
School of Chemistry and Molecular Engineering, East China Normal
University, 3663 North Zhongshan Road, Shanghai 200062, P. R.
China, E-mail: wangming@chem.ecnu.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental
procedures and characterization of the new products. See DOI:
10.1039/b000000x/.
intermediate generated in situ from diaryliodonium salt (Scheme
50 2). It is noteworthy that use of diaryliodonium salt as benzyne
precursor shows different reactivity compared to 2-
trimethylsilylaryltriflates used by Larock group (Schemes 1.3 and
1.4).
We started by using N-benzylbenzamide 1a as a model
55 secondary amide substrate. Our initial attempts to obtain N-
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DOI: 10.1039/C6OB01P64a9gAe 2 of 5
arylated product in reaction with 2-trimethylsilyl aryltriflates as
30 acetamide all reacted smoothly with diphenyliodonium leading to
benzyne precursor in presence of different bases remained
unsuccessful (Scheme 2). We next explored diphenyliodonium
salt 2a as the arylating reagent (Table 1). With NaH as the base in
THF, N-arylated product 3a was obtained in 12% yield at room
temperature (entry 1). The use of other strong bases led to either
trace or poor yield of 3a (entries 2-5). When KOtBu was used in
THF, we were fortunate to observe 3a in 41% yield (entry 6).
Further studies on the solvent effects did not lead to better
10 solvents (entries 7). We then chose to stay with KOtBu as the
base and THF as the solvent for additional optimizations. When
the amount of KOtBu was increased (from two to three
equivalents), product 3a was obtained in 65% yield (entry 8). The
reaction yield could be further consistently improved when the
products in 60-68% isolated yields (3i-k).
In another set of experiments, we examined the scope of the
diaryliodonium reagents (Table 3). When diaryliodonium salt 2b
was used for p-Me-phenylation of amide 1a, interestingly, two
35 regio-isomers were obtained (3l and 4l). The two regio-isomers
(p-Me-phenylation product 3l and m-Me-phenylation product 4l)
were formed in about 1:1 ratio. Other diaryliodonium reagents
with para-substituents (e.g., Cl, Br, F) on the phenyl unit were all
tolerated in the reactions with different amides (Table 3). The
40 ratios of the two regio-isomers ranged from 50:50 to 86:14 (Table
3).13
5
Table 2 N-Arylation of various amides using diphenyliodonium
Ph
Tf
O
t
H
u
K
B
O
N
O
N
I
O
+
R1
R1
Ph
Ph
THF 0 o
,
t
o r
t
C
n
B
n
B
-crown-
e
q
)
KF 18
/
6 2
(
R2
TM
R2
S
or
s
e
q
)
F 2
(
C
a
HN
O
2
N
O
3
1
+
Ph
N 60 o 12 h
e
M
C
C
,
,
Tf
O
Ph
Ph
a
3
a
1
race ro uc
<
1
0%
t
d
t
,
p
e
M
e
O
Ph
N
M
15
Ph
N
Ph
N
Scheme 2 N-arylation of 2-trimethylsilylaryl triflate as benzyne precursor
O
n
B
O
O
Ph
Ph
Ph
c
3
3b
81
a
Table 1 Optimization of the model reaction
3
84
89%
n
%
%
B
n
B
X
ase
so ven
l
t 2
. mmo
0 4
l
)
(
HN
O
b
(
l
C
l
C
N
O
+
F
I
Ph
N
m
Ph
N
L
)
Ph
Ph
Ph
Ph
Ph
O
O
Ph
N
O
r
t 5 h
,
a
1
a
2
a
3
e
3
3d
77
Ph
.
mmo
.
mmo
Ph
0 2
l
0 24
l
3f
82
Ph
%
74
%
%
entry
1
base
NaH
solvent
X
yield (%)a
Ph
N
Ph
Ph
N
Ph
N
Ph
N
THF
THF
THF
THF
THF
THF
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
PF6
12
<10
28
N
O
O
O
O
O
n
n
u
B
Ph
n
B
u
B
2
KOH
Ph
Ph
3
g
3
j
3h
3k
68
3i
68
3
KHMDS
NaHMDS
NaOMe
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
1
a
a
a
a
a
63
%
65
%
%
60
%
%
4
15
5
<10
41
Reaction conditions are same as in Table 1, entry 9, unless otherwise
noted. All yields are isolated yields. a Substrates were added at rt and 2.0
equiv of KOtBu was used.
6
7
8c
9c,d
10c,d
11c,d
Solventsb
<10
65
88 (84)e
THF
Table 3 Scope of the arylating substratesa
THF
R1
N
R1
N
OTf
R1
HN
THF
o r
THF
70
O
0 o
R
I
O
t
C
t
O
es
M
+
+
THF
78
t
R2
u
KO B
R2
R2
R
R
a Estimated via H NMR analysis of crude reaction mixture. Solvents
such as (CH2Cl)2, CH3CN and DMSO gave 3a in <10% yield, BuOMe
gave 24% yield, toluene gave 14% yield. 3.0 equiv of base. 1a and
2a was added at 0 oC, then the mixture was warmed to rt and stirred for
5 h. e Isolated yield based on 1a.
b
1
2
3
4
t
re o- somer o
i
i
f 3
)
g
(
c
d
3:4b
yield
3
1
2
(R)
(R1, R2)
(%)c
81
3l
3m
3n
1a
Me, 2b
Cl, 2c
Br, 2d
F, 2e
50:50
66:34
70:30
86:14
65:35
addition of diphenyliodonium reagent (2a) was performed at 0 oC
(84% isolated yield, entry 9). Variations of the counter anions of
the diphenyliodonium salts (from OTf- to BH4 or PF6 ) resulted
1a
86
1a
72
-
-
3o
3pd
1a
54
20 in a slight diminish on reaction yields (entries 10-11).
1i
2c
63
Having established an optimal condition, the generality of the
reaction was examined. A variety of N-bezylbenzamides were
used in reactions with diphenyliodonium 2a (3a-f; Table 2).
Substituents on the phenyl ring of the benzyl group did not
25 influence the reaction outcomes, and the corresponding products
were isolated in good to excellent yields (3a-f). With N-
alkylbenzamides, products 3 could be obtained in good yield (63-
65%) after a slight modification of the above optimized condition
(3g and 3h). Acetanilide, N-benzylacetamide, and N-alkyl
Ph, Me
1i
3qd
3rd
2d
2b
67:33
53:47
65
72
1k
nBu, Me
3sd
3td
1k
2c
64:36
64:36
67
65
1k
2d
a
b
Reactions conditions are same as in Table 1, entry 9. The ratios
were determined by GC-MS. c Isolated yields. d Substrates were added
at rt and 2.0 equiv of KOtBu was used.
2
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Organic & Biomolecular Chemistry
Diaryliodonium salts have been broadly used as arylating
The cycloaddition product 6 was afforded in 56% yield when
agents in a substantial set of reactions.10 However, to the best of 40 furan was treatment with diaryliodonium salt 2a under the
our knowledge, regio-isomer generations were not observed
before.11 Our observation of regio-isomers suggests that the
reactions likely proceed through a benzyne intermediate. Similar
benzyne intermediates generated from diaryliodonium salts were
proposed in 1974.5b To further elucidate the reaction mechanism,
a deuterated diphenyliodonium salt (2g) was subjected to a
reaction with amide 1k (Scheme 2). Only product 3u with a
condition of KOtBu, which further proved the formation of
benzyne intermediate in current reaction (Scheme 4).
5
Tf
O
I
t
u e
2
(
K
O
B
q
)
es
M
+
O
y
o uene r
T l
t
,
O
e
M
e
M
e
i l
d
2b
6 5
6%
,
10 deuterium (at the ortho-phenyl carbon) replaced by a proton was
observed. Product 3u' without proton incorporation was not
formed. These results further suggested that the reaction did not
go through a direct nucleophilic aromatic substitution involving
aryl cation intermediate (aromatic SN1) or the addition-
15 elimination SNAr mechanism. Instead, a nucleophilic addition of
amide14 to a benzyne intermediate (A, Scheme 2) followed by a
protonation is likely the reaction pathway.
Scheme 4 Cycloaddition reaction of diaryliodinium salt with furan
45
In summary, we have developed a transition metal-free
approach for N-arylation of challenging acyclic secondary amides.
The reaction proceeds under mild conditions at room temperature.
Mechanistically, the transition metal-free reaction proceeds
50 through a benzyne intermediate generated in situ from readily
available diaryliodonium salt. Diaryliodonium salt as benzyne
precursor shows different reactivity compared to 2-trimethylsilyl
aryltriflate. This N-arylation approach proceeds in highly
chemoselective manner for amides and amines. Further
55 explorations of diaryliodonium salt as benzyne precursor are
under progress in our laboratory.
Tf
O
D
D
D
I
D
D
D5
C6
t
u
THF
,
K
B
O
D
D
t
-
u
-
O
D
, C6
K
O
Tf
B
D I
,
(
)
5
D
D
A
2
g
O
O
O
n
n
n
u
B
u
u
B
B
N
N
N
K
Acknowledgements
H
D
D
D
D
t
u
H
-
H
B
d
O
+
We thank the generous financial supports from the National
Science Foundation of China (No. 21502054) and East China
60 Normal University (ECNU).
an
O
)
(
2
D
D
D
e reac on m x ure
th
was no
ti
r
i t
was
[
D
D
u
u
3
3 '
H
t d
p
2O
]
;
y
e
i ld
64
%
y
resen
e
0%
i ld
y
t
20 Scheme 2 Postulated mechanism and supporting evidence
Notes and references
Our approach for amide-arylations could also be extended for
chemoselective N-arylation of amide in presence of amine and
vice versa (Scheme 3). For instance, when amide 1l containing a
primary amine was subjected to our optimized reaction condition,
25 the selective N-arylation of amide proceeded smoothly to give 5a
in 45% yield without formation of regio-isomer 5b or diarylated
products. Further, N-arylation of amine in 1l could exclusively be
achieved in 72% yield with diaryliodinium salt in presence of
CuBr/Na2CO3, without any trace of either 5a or diarylated
30 products. In part due to the relatively strong acidity of amide
(compared to amine), it was easier to form the anion of amide in a
strong base condition, which is more suitable for the selectivity
N-arylation of amide. In a weak base or neutral condition, the N-
arylation of amine was prior to amide due to the relatively high
35 nucleophilicities of amine (compared to amide).15
1
For selected examples, see: (a) D. Peña, D. Pérez, E. Guitián and L.
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65
70
75
80
85
90
2
O
t
u
B
K
O
O
Ph
N
THF 0 o
C
,
Ph
Ph
N
NH2
a
e
i ld
y
5
45
%
,
H
1l
NH2
O
+
a
N
2CO3
mo
l
%
)
Tf
O
Ph
N
H
u
C
r
B
I
10
(
Ph
Ph
Ph
r
H
t
2C 2
,
l
C
N
a
2
e
72
i ld
%
y
5b
,
H
3
4
5
For a review, see: P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012,
112, 3550.
J. D. Roberts, H. E. Jr. Simmons, L. A. Carlsmith and C. W.
Vaughan, J. Am. Chem. Soc., 1953, 75, 3290.
Scheme 3 Chemoselective N-arylation of amide and amine
(a) Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983,
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C6OB01P64a9gAe 4 of 5
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2806.
5
6
Y. Dong, M. I. Lipschutz and T. D. Tilley, Org. Lett., 2016, 18,
1530.
10 7
In the preparation of our manuscript, diaryliodinium salt as benzyne
precursor was reported in a cycloaddition reaction with furan: S. K.
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Int. Ed., 2016, 55, 8431.
8
(a) Z. Liu and R. C. Larock, J. Am. Chem. Soc., 2005, 127, 13112;
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15
9
For the preparation of diaryliodonium salts, see: (a) M. D. Hossain,
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20
25
10 For recent reviews, see: (a) V. V. Grushin, Chem. Soc. Rev., 2000,
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2012, 18, 1591; (k) L. Chan, A. McNally, Q. Y. Toh, A. Mendoza
and M. J. Gaunt, Chem. Sci., 2015, 6, 1277.
30
35
40 11 Benzyne precursors were mentioned in diaryliodonium salt: (a) T.
Akiyama, Y. Iwasaki and M. Kawanishi, Chem. Lett., 1974, 229; (b)
J. I. G. Cadogan, A. G. Rowley, J. T. Sharp, B. Sledzinski and N. H.
Wilson, J. Chem. Soc., Perkin Trans. 1, 1975, 1072. (c) T. Kitamura,
M. Yamane, K. Inoue, M. Todaka, N. Fukatsu, Z. Meng and Y.
45
50
55
Fujiwara, J. Am. Chem. Soc., 1999, 121, 11674. For a review on
benzyne, see: (d) L. Ackermann, Mordern Arylation Methods,
Weinheim: Wiley-VCH, 2009.
12 Metal-free N-arylation of secondary amides, see: (a) A. P.
Antonchick, R. Samanta, K. Kulikov and J. Lategahn, Angew. Chem.
Int. Ed., 2011, 50, 8605; (b) R. Samanta, J. Lategahn and A. P.
Antonchick, Chem. Commun., 2012, 48, 3194. (c) F. Tinnis, E.
Stridfeldt, H. Lundberg, H. Adolfsson and B. Olofsson, Org. Lett.,
2015, 17, 2688.
13 The substituent (e.g. F) at the ortho-position of the phenyl ring led
to lower yields but higher ratios of the two regiomers.
F
n
F
B
a
t
e
1
T bl
en r
F
OTf
n
B
9
N
O
y
I
HN
O
n
B
+
es
M
+
N
Ph
Ph
O
Ph
o
v
3
4
2f
a
1
o: v >
:
95 5
e
i ld
4
,
3
43
%
y
14 The Na anion of amide, see: C. L. Perrin, C. P. Lollo and C. S. Hahn,
J. Org. Chem., 1985, 50, 1405.
60 15 The N-arylation of amines with arynes, see: (a) Z. Liu and R. C.
Larock, J. Org. Chem., 2006, 71, 3198. (b) D. C. Rogness and R. C.
Larock, J. Org. Chem., 2010, 75, 2289.
4
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB01649A
A transition metal-free approach for N-arylation of secondary amides was developed
via diaryliodonium salts as aryne precursors.