I2-Triggered Reductive Generation of N-Centered Iminyl Radicals: An Isatin-to-Quinoline Strategy for the Introduction of Primary Amides

Article abstract of DOI:10.1002/adsc.201701610

An efficient and alternative isatin-to-quinoline strategy illustrates the metal-like behavior of molecular iodine in the N?O reduction of ketoxime acetates. This process involves N?O/C?N bond cleavages and C?C/C?N bond formation to furnish pharmacologically significant quinoline-4-carboxamide derivatives. In this process, metal catalysts and extra oxidants are unnecessary. Mechanistic studies confirm the crucial role of molecular iodine in the iminyl radical generation process, in that molecular iodine can catalyze single-electron reduction coupling reactions in a manner similar to transition metals. (Figure presented.).

Full text of DOI:10.1002/adsc.201701610

Title: I2-Triggered Reductive Generation of N-Centered Iminyl
Radicals: An Isatin-to-Quinoline Strategy for the Introduction of
Primary Amides
Authors: Qinghe Gao, Zhao-Min Liu, Yakun Wang, Xia Wu, Jixia
Zhang, and Anxin Wu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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published online in Early View as soon as possible and may be different
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701610
Link to VoR: http://dx.doi.org/10.1002/adsc.201701610

10.1002/adsc.201701610
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
I2-Triggered Reductive Generation of N-Centered Iminyl
Radicals: An Isatin-to-Quinoline Strategy for the Introduction
of Primary Amides
Qinghe Gao,a,* Zhaomin Liu,a Yakun Wang,a Xia Wu,b Jixia Zhang,a and Anxin Wub,*
a
School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R. China.
Fax: (+86)-373-3831-652; phone: (+86)-373-3831-652; e-mail: gao_qinghe@xxmu.edu.cn
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
b
University, Wuhan 430079, P. R. China.
Fax: (+86)-027-6786-7773; phone: (+ 86)-027-6786-7773; e-mail:chwuax@mail.ccnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
arenes,[9] cleavage of C-C bonds,[10] oxidation of
Abstract. An efficient and alternative isatin-to-quinoline
strategy illustrates the metal-like behavior of molecular primary benzyl amines[11], and oxidative amidation of
benzyl alcohols, aldehydes, or methylarenes.[12]
iodine in the N-O reduction of ketoxime acetates. This
process involves N-O/C-N bond cleavages and C-C/C-N
bond formation to furnish pharmacologically significant
quinoline-4-carboxamide derivatives. In this process, metal
catalysts and extra oxidants are unnecessary. Mechanistic
studies confirm the crucial role of molecular iodine in the
iminyl radical generation process, in that molecular iodine
can catalyze single-electron reduction coupling reactions in
a manner similar to transition metals.
Currently, the synthesis of primary amides relies
heavily on transformations of specific functional
groups. Undoubtedly, as an alternative,
a
conceptually novel approach, in which the new
arenes are constructed during the amidation process,
is highly attractive. Herein, we first demonstrate an
efficient transamidation of isatins with ketoxime
acetates allowing direct formation of quinolines and
introduction of primary amides.
Keywords: Amidation; organocatalysis; iminyl radicals;
Recently, ketoxime acetates as an internal oxidant
have been widely used for the development of
transition-metal-catalyzed α-Csp3-H bond activation
reactions.[13] In most cases, these oxime esters are
known to undergo facile single-electron reduction to
generate an iminyl radicals in the presence of low-
valent Cu or Fe.[14] Because of its good capacity for
electron transfer processes, molecular iodine has
emerged as a promising replacement for these
transition metals.[15] Among these transformations,
molecular iodine in combination with peroxides (O-
O) generates active hypervalent iodine species (I+) in
situ in a basic process. Thus, we speculate that
drug design
Owing to the extraordinary properties of primary
amides in chemistry as well as biology,[1] the
introduction of primary amides into aryl and
heterocyclic rings has been used as an efficient
method in the design and fine tuning of the biological
properties of the drug candidates.[2] As a consequence,
there are many pharmaceuticals containing a primary-
amide group,[3] including the analgesic and anti-
inflammatory drug Ethenzamide, Frovatriptan for the
treatment of migraine headaches, and the oral
chemotherapy drug Temodar used in the treatment of
certain brain cancers (Figure 1). As a result, a great
deal of recent research in this field has focused on the
development of more efficient and practical
approaches to introduce this primary amide motif.[4]`
For example, ammonolysis of carboxylic acids
species,[5] hydration of nitriles,[6] rearrangement of
aldoximes,[7] aminocarbonylation of aryl halides or
phenols,[8] Friedel–Crafts carboxamidation of
Figure 2. I2-triggered reductive generation of N-
Centered Radicals.
Figure 1. Selected examples of primary amide drugs.
1
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10.1002/adsc.201701610
Advanced Synthesis & Catalysis
molecular iodine can take the place of these low-
valent transition metals in the construction of N-
containing heterocycles without peroxides, wherein
oxime derivatives (N-O) serve as both internal
oxidants and reactants. In this paper, we report our
progress in the I2-triggered redox-neutral reaction of
ketoxime acetates with isatins for the synthesis of
diverse quinoline-4-carboxamides (Figure 2), which
are potential precursors of the privileged medicinal
structures found use in a wide spectrum of medicinal
targets: GPCRs, protein-protein interactions, ion
channels and enzyme inhibitors.[16]
transformation. Therefore, different solvents such as
DMF, anisole, chlorobenzene, toluene, 1,4-dioxane,
and water were also investigated. Indeed, the
quinoline-4-carboxamide product 3a was obtained in
the best yield when using chlorobenzene as a solvent
(entries 2−7). It is noteworthy that both I2 and Et3N
were essential to this reaction, based on the blank
experiments (entries 8−9). Unexpectedly, this
reaction could also work well in the absence of L-
proline (entry 10), which was generally used to
enhance electrophilic nature of 2a C3 carbon.[18]
When other bases such as Et2NH, DABCO, DBU,
N,N-dimethylaniline, quinolone, and pyridine, were
applied instead of Et3N, the yield of the desired
product more or less decreased (entries 11−16).
Further examination of the temperature showed that
130 °C proved to be the best, affording 3a in 86%
isolated yield (entries 17−20).
Table 1. Optimization of the reaction conditions.[a]
Temp Yield[b]
Entry
Base
Additive Solvent
L-proline DMSO
(°C)
(%)
1
2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
120
n.d.
L-proline
L-proline anisole
L-proline PhCl
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
110
130
140
n.d.
54
3
4
80
5
L-proline toluene
L-proline dioxane
78
6
65
7
8[c]
L-proline
L-proline
L-proline
H2O
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
n.d.
n.r.
trace
84
9
10
11
12
13
14
15
16
17
18
19
20
Et3N
Et2NH
DABCO
DBU
67
trace
trace
19
Scheme 1. Scope of ketoxime acetates. All yields are of
isolated products. [a] Conducted on 10 mmol scale
DMA
quinoline
Py
48
With the optimized reaction conditions in hand, the
generality and scope of this efficient and alternative
isatin-to-quinoline strategy for the introduction of
primary amides was explored. The reaction
demonstrated a wide substrate scope of the ketoxime
acetates (Scheme 1). Aryl ketone O-acetyloximes
bearing electron-neutral (e.g., 4-Me), electron-rich
(e.g., 4-OMe, 3,4-OCH2O), and electron-deficient
(e.g., 3-NO2) on the phenyl ring were converted to the
corresponding products in satisfactory yields
(41−90%; 3b−3e). In general, acetophenone oxime
acetates with an electron-donating group showed
higher reactivity than those with an electron-
withdrawing group. Much to our satisfaction, the
optimized conditions were mild enough to allow a
broad range of halogenated (e.g., 4-Cl, 4-Br)
substrates to be reacted (73−78%; 3f−3g).
Naphthalen-2-yl ethanone oxime acetate was also a
suitable substrate for this reaction to provide the
expected product (3h) in 77% yield. Meanwhile, the
optimized conditions could be applied to heteroarene
oxime acetates such as furanyl and thienyl, delivering
57
Et3N
64
Et3N
79
Et3N
86
Et3N
86
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5mmol), I2
(0.25 mmol), Et3N (0.25 mmol), additive (0.05 mmol),
solvent (2 mL). [b] Isolated yields; n.d. = no desired
product; n.r. = no reaction. [c] In the absence of I2.
Based on our previous works on oxidative cross-
coupling in the I2-DMSO system,[17] our initial efforts
were focused on the model reaction of acetophenone
oxime acetate 1a with isatin 2a in the presence of
Et3N and L-proline (Table 1). Disappointingly, no
desired 3a was observed when the reaction was
carried out in DMSO (entry 1). We speculate that
solvent might play an important role in this
2
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10.1002/adsc.201701610
Advanced Synthesis & Catalysis
the corresponding products in 49% and 67% yields,
respectively (3i–3j). Notably, oxime acetates derived
from propiophenone, 1,2-diphenylethanone, and 3,4-
dihydro-naphthalen-1(2H)-one could be accessed
using this route to generate the ring-expansion
condensation of amines and carboxylic acids from the
Pfitzinger reaction requires very harsh conditions in
order to circumvent the unreactive carboxylate-
ammonium salt formation for the desired amide bond
formation. We reasoned that this intrinsic difficulty
product in good yields (79−90%; 3k−3m). In addition, might be mitigated by preinstalling a nitrogen atom
the structure of 3k was unambiguously confirmed by
as well as an internal oxidant in the reactant.
X-ray crystallography.[19]
Scheme 2. Scope of isatins. All yields are of isolated
products.
Scheme 3. Control experiments.
The scope of this reaction was subsequently
extended to the representative isatins (Scheme 2).
Isatins substituted with various useful substituents
such as methyl, methoxy, and halogens (F, Cl, Br,
and I) at the C-5 position showed good reactivity with
acetophenone oxime acetate 1a, leading to the
corresponding primary amides 3n–3s in 67−74%
yields. However, a strong electron-withdrawing
moiety (5-NO2) prevented the reaction from
proceeding under the standard conditions. Similarly,
isatins substituted at the C6 and C7positions were
also found to be effectual under the present reaction
Although the exact reaction mechanism is unclear,
one possible mechanism has been proposed using
acetophenone oxime acetate 1a and isatin 2a as
examples (Scheme 4). Initially, 1a could be reduced
by molecular iodine or iodine radical to generate the
iminyl radical intermediate A and hypervalent iodine
species (I+). Subsequently, the highly active iminyl
radical A was reductively quenched by Et3N to
produce the corresponding anion B which could
isomerize to a strong nucleophile α-carbanion C.[20]
This might explain why Et3N was indispensable in
this reaction system. Then, nucleophilic addition of C
to carbonyl of 2a formed intermediate D, followed by
a ring-reconstruction to afford the bridged bicyclic
intermediate E.[21] Finally, intermediate E underwent
ring-opening and eliminated hydroxyl anion to access
the desired product 3a.
conditions,
furnishing
the
chloro-substituted
quinoline-4-carboxamides (55−92%; 3t–3u). Notably,
the quinoline scaffolds were formed with a diverse
range of halogen atoms, providing enormous
possibilities for further modification.
To understand the role of molecular iodine in this
transamidation process, we applied different kinds of
iodine source in the model reaction (Scheme 3a). As
expected, an iodine radical source, NIS, showed a
reactivity similar to that of molecular iodine.
However, the commonly used iodide catalysts such as
TBAI, KI, and NaI were less efficient for the
formation of the desired product. Generally, the
oxime could be converted to the corresponding
iminyl radical in the presence of low-valent transition
metal. Therefore, an inhibiton experiment for radical
was carried out. When TEMPO was introduced into
the reaction system, the formation of 3a was
completely suppressed (Scheme 3b). These results
indicated that molecular iodine or iodine radical was
capable of reducing the N-O bond of oxime via a
single-electron transfer (SET) process. Finally, a
Pfitzinger-type reaction of acetophenone with isatin
and ammonium acetate gave the desired quinoline
product in 21% yield (Scheme 3c). The direct
Scheme 4. A possible mechanism.
In conclusion, we have demonstrated that
molecular iodine behave as a metal in the reductive
3
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10.1002/adsc.201701610
Advanced Synthesis & Catalysis
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generating of N-centered iminyl radicals. This
strategy provides an efficient and alternative method
for the synthesis of biologically useful quinoline-4-
carboxamide derivatives from ketoxime acetates and
isatins. The reaction was accomplished through N-
O/C-N bond cleavages and new C-C/C-N bond
formations, along with the activation of Csp3-H bond.
Importantly, this work provides an example for
applying molecular iodine as a promising alternative
to transition metal catalysts for single-electron
reduction coupling reactions. Detailed mechanistic
investigations and exploring new transformations of
oxime acetates with molecular iodine are underway in
our laboratory and will be reported in due course.
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This work was supported by the National Natural Science
Foundation of China (Grant 21602070). We also acknowlege the
University Key Research Projects of Henan Province (Grant
16A150022).
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