Palladium-catalyzed decarboxylative ortho-acylation of N-nitrosoanilines with α-oxocarboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2016.03.009

A palladium-catalyzed efficient C-H acylation reaction of N-nitrosoanilines with α-oxocarboxylic acids has been developed. The reaction proceeded smoothly with potassium persulfate as the oxidant to afford acylated N-nitrosoanilines in moderate to good yi

Full text of DOI:10.1016/j.tetlet.2016.03.009

Tetrahedron Letters 57 (2016) 1687–1690
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed decarboxylative ortho-acylation
of N-nitrosoanilines with a-oxocarboxylic acids
⇑
Jia-Ping Yao, Guan-Wu Wang
Hefei National Laboratory for Physical Sciences at Microscale, iChEM, and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed efficient C–H acylation reaction of N-nitrosoanilines with a-oxocarboxylic acids
has been developed. The reaction proceeded smoothly with potassium persulfate as the oxidant to afford
Received 12 January 2016
Revised 2 March 2016
Accepted 4 March 2016
Available online 4 March 2016
acylated N-nitrosoanilines in moderate to good yields with
a broad substrate scope and good
regioselectivity.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
C–H bond activation
N-Nitrosoanilines
Decarboxylation
Acylation
7
Introduction
groups reported the Rh-catalyzed ortho-olefination and ortho-
8
9
10
alkynylation, respectively. The Zhu and Huang groups indepen-
In recent decades, transition-metal-catalyzed direct C–H bond
functionalization has been successful as a valuable tool for the
modular and facile synthesis of structurally similar, yet diversified
dently described the Rh-catalyzed cyclization of N-nitrosoanilines
11
with alkynes for the synthesis of indoles. The Sun group and
1
2
2
we disclosed the Pd(OAc) -catalyzed N-nitroso-directed ortho-
1
organic molecules. Among them, transition-metal-catalyzed
alkoxylation and ortho-acyloxylation of arenes, respectively. More
decarboxylative cross-coupling reactions involving the use of read-
recently, the Sun group also reported the Rh-catalyzed cyanation
1
3
14
ily available
a,b-unsaturated and aryl carboxylic acids as potential
of N-nitrosoanilines. Kwong, Luo and co-workers reported the
palladium-catalyzed reaction of N-nitrosoanilines with toluene
derivatives, and N-alkyl-2-aminobenzophenones were unexpect-
edly obtained. However, the palladium-catalyzed decarboxylative
acylation of N-nitrosoanilines has been unknown until now. In
recent years, our group has investigated the palladium-catalyzed
coupling partners, in place of aryl halides or organometallic
reagents, has attracted much attention. In general, directing groups
are necessary to facilitate the ortho C–H bond activation in the
presence of transition metals (e.g., Pd, Ir, Rh, Ru, Cu, Fe, etc.) and
lead to a versatile C–H bond functionalization upon trapping with
appropriate electrophiles or nucleophiles under basic or oxidative
conditions respectively.2 N-Nitroso compounds can coordinate
with transition metal catalysts, because the nitroso group pos-
sesses a lone pair of electrons.3 This character makes it possible
as a directing group to realize the C–H bond activation in the
transition-metal-catalyzed reactions.
2
12,15
sp C–H activation reactions,
, and have successfully realized
the ortho-acylation with oxime and azo as the directing
1
5i,j
2
groups.
activation, herein we report
acylation of N-nitrosoanilines using nitroso as the directing
In continuation of our interest in sp C–H bond
a
palladium-catalyzed ortho-
1
6
group with
a-oxocarboxylic acids.
N-Nitrosoanilines are a class of very useful medicinal com-
pounds and synthetic materials for the preparation of various
Results and discussion
4
nitrogen-containing compounds. They are also important precur-
5
sors to synthesize other organic compounds such as hydrazines
In our initial investigation, we chose the reaction of N-
nitrosoaniline 1a with -oxocarboxylic acid 2a as the model reac-
tion. Firstly, 1,4-dioxane was chosen as the solvent. To our delight,
product 3a was isolated in 53% yield in the presence of K and
Pd(OAc) (Table 1, entry 1). Different oxidants, such as Na
,4-benzoquinone (BQ), and PhI(OAc) were explored.
6
and sydnones. Recently, C–H activation reactions of N-nitrosoani-
a
lines have attracted interest of organic chemists. The Zhu and Li
2 2 8
S O
2
2 2 8
S O ,
⇑
Corresponding author. Tel./fax: +86 0551 63607864.
E-mail address: gwang@ustc.edu.cn (G.-W. Wang).
1
2
,
http://dx.doi.org/10.1016/j.tetlet.2016.03.009
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

1
688
J.-P. Yao, G.-W. Wang / Tetrahedron Letters 57 (2016) 1687–1690
Table 1
Table 2
a
Optimization of the reaction conditions
Palladium-catalyzed direct ortho-acylation of N-nitrosoaniline 1a with a-oxocar-
boxylic acids 2
a,b
O
N
O
N
O
Pd(OAc) (10 mol%)
O
2
N
O
N
O
N
O
OH K S O (2.0 equiv)
N
O
OH
N
2
2
8
N
Pd(OAc)2
+
+
O
dioxane/AcOH=7:3
80 C, 12 h
O
R
1
o
R
1
1a
2
3a-o
1
a
2a
Additive
3a
Yieldb (%)
N
O
N
O
N
O
Entry
Oxidant
Solvent
N
O
N
O
N
O
1
2
3
4
5
6
7
8
9
K
Na
PhI(OAc)
BQ
2
S
2
O
8
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
53
45
Trace
Trace
39
2
2
S O
8
2
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
S
2 2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
2 2
ClCH CH Cl
CH CN
3
35
36
Cl
DMF
DMSO
NMP
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane/AcOH (9:1)
1,4-Dioxane/AcOH (7:3)
1,4-Dioxane/AcOH (5:5)
1,4-Dioxane/AcOH (7:3)
1,4-Dioxane/AcOH (7:3)
3a, 81% (95:5)
3b, 78% (96:4)
3c, 91% (94:6)
Trace
Trace
Trace
Trace
Trace
15
35
61
75
81
N
O
N
O
N
O
10
11
12
13
14
15
16
17
18
19
20
Cu(OAc)
2
N
O
N
O
N
O
Ag
Ag
2
CO
O
3
2
PTSA
TFA
AcOH
Br
CF3
3e, 80% (93:7)
Ph
3
d, 73% (93:7)
3f, 55% (94:6)
77
62
69
c
d
N
O
N
O
N
O
a
N
O
N
O
N
O
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd(OAc)
oxidant (0.2 mmol), additive (0.2 mmol), solvent (1 mL), 80 °C, 12 h.
2
(0.01 mmol),
b
Isolated yield based on 1a.
c
7
9
0 °C.
0 °C.
d
OMe
g, 71% (95:5)
Cl
Br
3i, 89% (94:6)
3
3h, 88% (94:6)
Unfortunately, it was found that they were less effective, and 3a
was obtained in lower yields (Table 1, entries 2–4 vs. entry 1).
N
O
N
O
N
O
Among all of the examined oxidants, K
catalytic reaction. Other different solvents including ClCH
CH CN, DMF, DMSO, and NMP were screened, and it was found
S
2 2
O
8
was the best for this
N
O
N
O
N
O
2
CH Cl,
2
3
OMe
Cl
that they were less effective, and deteriorated the product yield
of 3a (Table 1, entries 5–9). The addition of common additives,
such as Cu(OAc) , Ag CO , Ag O, PTSA, and TFA, to the reaction
2 2 3 2
resulted in a reduced yield of 3a (Table 1, entries 10–14). Addition
of AcOH moderately improved the yield of 3a (Table 1, entries
I
3
j, 73% (94:6)
3k, 75% (96:4)
3l, 68% (94:6)
N
O
N
O
N
O
1
5–18), indicating that AcOH was beneficial to this transformation.
N
O
N
O
N
O
After further screening of the reaction media, the yield was
increased to 81% with a 1,4-dioxane/AcOH mixture (7/3, v/v)
(Table 1, entry 17). Lower temperature suppressed the efficiency,
whereas higher temperature did not lead to a better result (Table 1,
entries 19 and 20). Therefore, the optimal conditions for the palla-
dium-catalyzed ortho-acylation of 1a with 2a were as follows:
Cl
Cl
3
m, 72% (95:5)
3n, 79% (94:6)
3o, 64% (94:6)
(0.03 mmol),
1
0 mol % of Pd(OAc)
oxidant, and 1.5 equiv of
N-nitrosoaniline. The reaction was performed best at 80 °C for
2
as the catalyst, 2.0 equiv of K
2 2 8
S O as the
a
Reaction conditions: 1a (0.3 mmol),
2
(0.45 mmol), Pd(OAc)
2
a
-oxocarboxylic acid as the partner of
K
2
S
2
O
8
(0.6 mmol), dioxane/AcOH (7:3, 3 mL), 80 °C, 12 h. Isolated yield based on 1.
Ratios of the syn to anti isomers relative to the N–N bond are shown in
parentheses, determined by the H NMR spectra.
b
1
2 h in a 1,4-dioxane/AcOH mixture (7/3, v/v).
1
With the optimized reaction conditions in hand, we next
explored the scope of the a-oxocarboxylic acid derivatives as the
simple acyl source (Table 2). The results indicated that N-
nitrosoaniline 1a could react with various phenylglyoxylic acids
to generate the corresponding products 3a–o in 55–91% yields
acids worked well in the reaction to give the desired products
3g–j in good to excellent yields (71–89%). The reaction could also
be applied to ortho-substituted phenylglyoxylic acids to afford 3k
and 3l in moderate to good yields (68–75%). Furthermore, it was
found that disubstituted phenylglyoxylic acids showed good reac-
tivity and provided products 3m and 3n in good yields (72–79%). It
should be noted that when 2-(naphthalen-1-yl)-2-oxoacetic acid
was employed as the acyl source, the corresponding product 3o
was obtained in 64% yield.
(Table 2). The reaction tolerated a variety of functional groups
including chloro, bromo, iodo, and methoxy groups. As for the sub-
stitution pattern of reagent 2, higher yields were obtained with
para-substituted phenylglyoxylic acids containing methyl, halo,
and trifluoromethyl groups in comparison with that bearing aryl
group (Table 2, 3b–e vs. 3f). Meta-substituted phenylglyoxylic

J.-P. Yao, G.-W. Wang / Tetrahedron Letters 57 (2016) 1687–1690
1689
Table 3
Next, the performance of some representative N-nitrosoanilines
were examined under the optimized reaction conditions, and the
results are shown in Table 3. N-Nitrosoaniline with no functional
group reacted with phenylglyoxylic acid 2a to provide product
3p in 76% yield. When halo, methyl, and ester groups were intro-
duced into the phenyl rings of N-nitrosoanilines, acylated products
3q–u were obtained in moderate yields (50–65%). It is worthy
mentioning that 3u was exclusively formed, indicating that the
reaction was very selective and did not occur at the ortho position
of the chloro atom due to steric hindrance. In addition, substrates
with N-ethyl and N-isopropyl groups instead of N-methyl could
also be employed to react with 2a, providing 3v and 3w in 62%
and 56% yields, respectively.
It should be pointed out that there are two isomers, that is, syn
and anti isomers for N-nitrosoanilines including both starting
materials and products. The isomer is defined as the syn configura-
tion when the N-alkyl group is cis to the N-nitroso oxygen atom.
The syn to anti isomeric ratios of products 3a–w are shown in
the parenthesis for each product in Tables 2 and 3. Compared with
3p, 3v and 3w showed decreasing syn to anti isomeric ratios due to
the increasing steric hindrance between the N-alkyl and N-nitroso
oxygen atom.
Palladium-catalyzed direct ortho-acylation of N-nitrosoanilines
boxylic acid 2a
1
with
a
-oxocar-
a,b
R
N
3
R
N
3
O
O
Pd(OAc)2 (10 mol%)
O
N
O
OH
N
2 2 8
K S O (2.0 equiv)
+
O
dioxane/AcOH=7:3
R
2
R
2
o
80
C, 12 h
1
2a
3p-w
N
O
N
O
N
O
N
O
N
O
N
O
Cl
Br
Cl
3
p, 76%c (95:5)
3q, 50% (95:5)
3r, 51% (96:4)
N
O
N
O
N
O
N
O
N
O
N
O
MeOOC
On the basis of our experimental results and the previous liter-
7
,9,13,17
ature,
this transformation is believed to start with the ortho-palladation
of 1 with Pd(OAc) to provide the five-membered palladacycle
which subsequently undergoes anion exchange with 2 to
afford intermediate II, followed by oxidation in the presence of
and concurrent decarboxylation to furnish the Pd(III) or
a plausible mechanism is shown in Scheme 1. Firstly,
3
s, 52% (96:4)
3t, 65% (84:16)
3u, 55% (96:4)
2
7
,9,13
I,
N
O
N
O
N
O
N
O
2 2 8
K S O
Pd(IV) intermediate III. Finally, product 3 is generated by reductive
elimination with the simultaneous release of a Pd(II) species to
complete the catalytic cycle. Alternatively, the reaction mechanism
involving a Pd(0/II) catalytic cycle cannot be excluded.18
3v, 62% (84:16)
3w, 56% (46:54)
c2a (0.45 mmol), 80 °C.
a
Conclusion
2 2 2 8
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Pd(OAc) (0.03 mmol), K S O
(
0.6 mmol), dioxane/AcOH (7:3, 3 mL), 100 °C, 12 h. Isolated yield based on 1.
b
Ratios of the syn to anti isomers relative to the N–N bond are shown in
In summary, we have developed a novel Pd-catalyzed decar-
boxylative ortho-acylation of N-nitrosoaniline compounds with
1
parentheses, determined by the H NMR spectra.
a-oxocarboxylic acids using K
2
2
S O
8
as a convenient oxidant. The
H
N
O
N
R1
R2
1
Pd(II)
R1
O
N
O
Pd
N
R1
L
2
N
N
O
3
O
OH
I
R2
O
2
R1
R2
N
R1
N
Pd(II)
O
L
Pd
L
Pd(III) or Pd(IV)
O
II
O
O
O
N
N
2 2 8
K S O
O
III
R2
CO
2
Scheme 1. Plausible catalytic cycle for the Pd-catalyzed reaction of N-nitrosoanilines with
a
-oxocarboxylic acids.

1
690
J.-P. Yao, G.-W. Wang / Tetrahedron Letters 57 (2016) 1687–1690
reactions of N-nitrosoaniline compounds with a variety of
a
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Supplementary data
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