2512
L. Zhang et al. / Tetrahedron Letters 57 (2016) 2511–2514
R''
R'
NO
R''
NO
R''
Under the established reaction conditions, the scope of the Pd-
catalyzed ortho-acylation of N-methyl-N-Nitrosoaniline with
O
N
N
O
NH
O
OH
Pd
H
a-
+
R'''
+
R''' R'
R'
R'''
O
Oxidant
oxocarboxylic acids was investigated (Table 2). The coupling of
benzoylformic acids with electron-donating and withdrawing
groups at the phenyl ring all underwent the intended transforma-
tion smoothly and good to excellent yields were obtained in most
cases. The substitution on the aromatic ring of benzoylformic acids
demonstrated that no significant electronic effect was present. For
example, the substrates with an electron donation methyl group
and methoxyl group afforded the desired N-Nitroso ketones in
good yields, while electron-withdrawing group-substitute on phe-
nyl ring, such as F, Cl, Br, and CF3 provided comparative results. It is
worth noting that this chemistry was sensitive to the steric hin-
drance when ortho-disubstituted benzoylformic acid was involved
in the reaction, and the corresponding ketone was isolated in 42%
yields (3ae). It’s worth noticing that, the chloro and bromo groups
remained intact in this procedure with good yields (3ai–3aj, 3am–
3ao), which offer versatile synthetic functionality for further trans-
formations into other significant structures. Much to our pleasure,
this transformation can also be successfully extended to hetero-
yields: up to 89%
Not observed
Scheme 1. Site-selective ortho-acylation of Nitrosoanilines.
result, the effect of solvents on this transformation was examined,
and Diglyme proved to be crucial (Table 1, entry 1–7). It was found
that K2S2O8 was superior to other oxidants including (NH4)2S2O8,
Na2S2O8, and Oxone, affording the desired N-Nitroso ketone 3aa
in 83% isolated yield, while other oxidants such as BQ and AgOAc
were not effective and no N-Nitroso ketone product was isolated
from those attempts (Table 1, entry 8–12). Further catalyst screen-
ing showed that a noticeable (6%) increase in yield was observed
when Pd(TFA)2 was involved in the reaction, and the corresponding
product was achieved in 89% yield (Table 1, entry 15).23 Addition-
ally, no reaction took place in the absence of a palladium catalyst
even at high temperatures and longer reaction times (Table 1,
entry 16). It should be noted that increasing the loading of catalyst
could not enhance the yield of the corresponding ketone obviously,
while lowering the amount of Pd(TFA)2 to 5 mol % suppressed the
efficiency (Table 1, entry 17). Moreover, changing the reaction
temperature and reducing the stoichiometry of oxidant did not
favor the acylation progress (Table 1, entry 18–20). In summary,
the optimized reaction conditions for the ortho-CAH acylation of
N-Nitroso compounds were obtained as follows: 10 mol % Pd
(TFA)2 as the catalyst, 2.0 equiv of K2S2O8 as the oxidant, and
Diglyme as the solvent, at 80 °C under argon for 20 h.
cyclic-substituted
a-keto acids with moderate yields (3ap–3aq),
which proved a broad range of substrates in this highly effective
process.
We next examined the scope of different N-Nitroso compounds
with a-oxocarboxylic acids under our best conditions (Table 3). It
was found that this transformation also showed good tolerance
toward the N-Nitrosoaniline with either electron-rich or elec-
tron-deficient groups, and various halogen groups are tolerated,
for example F (3fa), Cl (3ga), and Br (3ha) groups, utilizing as the
handle for further functionalization. Notably, a strong electron
donating group (OMe) at the para-position of aromatic ring of N-
Nitroso compounds furnished 3ea in a relatively lower yield with
some unidentified by-products, while a para-trifluoromethyl sub-
stituted N-methyl-N-Nitrosoarylamine also provided moderated
yield, probably due to its low reactivity. As expected, the N-
ethyl-N-Nitroso ketone and N-isopropyl-N-Nitroso ketone can also
be obtained by this protocol, although both cis and trans isomers
were obtained in the products due to the restricted rotation around
the N-Nitroso NAN bond.
A possible pathway was proposed to account for this ortho-acy-
lation of N-Nitroso compounds, which was described in
Scheme 2.12,13,22 N is generally considered to be a better coordinat-
ing atom than O. It is believed that this transformation is probably
initiated by N-assisted ortho-palladation on the arene ring by Pd
(TFA)2, providing the highly reactive palladacycle I,23 followed by
Table 1
Optimization of the reaction conditionsa
NO
O
N
O
catalyst 10 mol%
oxidant, solvent
N
H
OH
NO
+
O
1a
Entry
2a
3aa
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2S2O8
Na2S2O8
Oxone
Ag2CO3
BQ
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Dioxane
DCE
Toluene
DME
DMSO
CH3CN
65
56
63
68
0
40
83
66
41
34
0
reaction with
a-keto acid to afford cyclopalladated complex II
along with release of CF3COOH. Subsequently, the obtained active
complex II underwent a decarboxylation procedure to form com-
plex III,24 which further underwent reductive elimination to afford
the corresponding acylated product 3aa and Pd(0). Finally, the gen-
erated Pd(0) catalyst can be reoxidized to the active Pd(II) catalyst
in the presence of K2S2O8.
To demonstrate the synthetic utility of this method, the further
transformation of the acylated N-Nitrosoanilines into 3-aryl-inda-
zoles was examined. Albeit their scarcity in nature, 3-aryl-inazole
is an important class of heterocycles that is being evaluated in
medicinal and agrochemical research.25 Previously reported syn-
thesis of these compounds involves harsh reagents (e.g., explosive
or toxic reagents, expensive catalysts) therefore they are less than
satisfactory.26 Much to our pleasure, when the commercially avail-
able Zn powder was used to reduce N-Nitroso ketones in AcOH at
room temperature, the transformation of acylated N-Nitrosoaniline
into 3-substituted indazoles was completed in 24 h with nearly
quantitative yields (Table 4).
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
9
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
0
30
10
89
0
77
74
66
58
76
PdCl2(MeCN)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
a
All the reactions were carried out in the presence of 0.2 mmol of 1a, 0.4 mmol of
2a, and 0.4 mmol of oxidants in 1.0 mL of solvents at 80 °C for 20 h under Ar.
b
Isolated yields.
5 mol % Pd(TFA)2 was used.
1.5 equiv of K2S2O8 was used.
At 100 °C.
At 60 °C.
Under air condition.
c
d
e
f
In summary, we have developed a novel catalytic system for Pd-
catalyzed decarboxylative ortho-acylation of N-Nitroso compounds
g