I2-catalyzed oxidative cross-coupling of methyl ketones and benzamidines hydrochloride: A facile access to α-ketoimides

Article abstract of DOI:10.1021/ol501029w

An iodine-catalyzed oxidative cross-coupling of C-H/N-H has been demonstrated. This simple and efficient approach constructed α-ketoimides in good to excellent yields from methyl ketones and benzamidines hydrochloride under metal-free and peroxide-free co

Full text of DOI:10.1021/ol501029w

Letter
pubs.acs.org/OrgLett
I2‑Catalyzed Oxidative Cross-Coupling of Methyl Ketones and
Benzamidines Hydrochloride: A Facile Access to α‑Ketoimides
Xia Wu, Qinghe Gao, Shan Liu, and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: An iodine-catalyzed oxidative cross-coupling of C−H/
N−H has been demonstrated. This simple and efficient approach
constructed α-ketoimides in good to excellent yields from methyl
ketones and benzamidines hydrochloride under metal-free and
peroxide-free conditions. This synthetic strategy was achieved via an in situ iodination-based oxidative coupling pathway.
ketones with amines has been established by Prabhu,7a
n recent years, direct oxidative C−H bond functionalization,
Iespecially a sp C−H bond toward the formation of C−C Wan,7b and Wang7c (Scheme 1c). However, these recent
3
advances were focused on the oxidative coupling of RH with
N−H of amines to construct α-ketoamides. Directly employing
amide compound oxidative cross-coupling with a C−H bond
has not previously been reported to build α-ketoimides, due to
the predominant limitations presented by very weak nucleo-
philicity especially of the free N−H of amides. Therefore, in
order to develop a simple and practical strategy for the
synthesis of α-ketoimides, discoveries of new N−H reagents
instead of amides as nucleophiles are desperately needed. To
the best of our knowledge, the free N−H of benzamidines
hydrochloride has not yet been directly utilized as a nucleophile
reagent for the oxidative coupling with methyl ketones for
construction of a novel α-ketoimides skeleton. In view of this,
herein the first known example of an iodine-catalyzed protocol
to access α-ketoimides via a C−H/N−H oxidative cross-
coupling is reported from methyl ketones and benzamidines
hydrochloride (Scheme 1d).
and C−heteroatom bonds, is one of the most attractive and
powerful strategies in organic synthesis.1,2 Direct C−H bond
oxidative amidation through C−H/N−H oxidative cross-
coupling has always been a fascinating topic3 since nitrogen-
containing compounds include imides, α-ketoamides, and α-
ketoimides that are potentially valuable synthetic building
blocks for the preparation of various heterocyclic ring systems
of biological interest.4 Significantly, Jiao and co-workers
presented a novel Cu-catalyzed C−H bond oxidative amidation
via oxidative coupling of aryl acetaldehydes or α-carbonyl
aldehydes or phenylacetylenes with anilines (Scheme 1a).5a−c
Recently, Cu-catalyzed direct oxidative coupling between aryl
methyl ketones and amines under ambient conditions for the
attainment of sp3 C−H bond oxidative amidation have been
developed by Ji (Scheme 1b).6 Moreover, iodine or iodide
combination of peroxide synergistic promoted sp3 C−H bond
oxidative amidation via the oxidative coupling of methyl
Initially, an optimized iodine-catalyzed oxidative cross-
coupling of aromatic methyl ketone (1a) with benzamidine
hydrochloride (2a) was examined in DMSO. To our delight,
the reaction of acetophenone (1a, 1.0 mmol) and benzamidine
hydrochloride (2a, 2.0 mmol) with I2 (1.6 mmol) could afford
the desired oxidative coupling product in 87% yield at 100 °C
in DMSO (Table 1, entry 1). The structure of the product was
unambiguously confirmed by X-ray crystallography analysis
(see Supporting Information). Encouraged by the results,
subsequent studies indicated that decreases in the equivalents
of 2a did not afford any changes in the yield (Table 1, entries
2−4). Next, various temperatures were scanned to improve the
yield, and 130 °C was determined as optimum for the oxidative
coupling reaction (Table 1, entries 5−9). To our surprise, the
reaction performed smoothly even with decreases in the
equivalents of I2 to 10 mmol % (Table 1, entries 10−13).
However, the reaction was found unable to proceed in the
Scheme 1. Oxidative Cross-Coupling Reactions Between C−
H and N−H
Received: April 9, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Aryl Methyl Ketones and Benzamidine
Hydrochloride
ab
,
b
entry
I2 (equiv)
2a (equiv)
temp (°C)
yield (%)
1
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.0
0.5
0.3
0.1
2.0
1.5
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
100
100
100
100
60
87
87
87
87
29
78
82
88
90
91
90
91
91
0
2
3
4
5
6
80
7
90
8
110
130
130
130
130
130
130
9
10
11
12
13
14
a
Reaction conditions: 1a (1.0 mmol), 2a, and I2, heated in 3 mL of
b
DMSO within 3 h. Isolated yield.
absence of I2 (Table 1, entry 14), which indicated that iodine
was an important mediator in this transformation. After several
experimental optimizations, the optimized conditions were
determined as 1a (1.0 mmol) with 2a (1.0 mmol) in the
presence of I2 (0.1 mmol) in DMSO at 130 °C to afford the
desired product in 91% yield (Table 1, entry 13).
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), and I2 (0.1
b
mmol) in DMSO (3 mL) at 130 °C for 3 h. Isolated yield.
Scheme 3. Scope of Aryl Methyl Ketones and Benzamidines
Hydrochloride
ab
,
To test the substrate generality of this I2-catalyzed oxidative
coupling reaction, a series of substituted aryl methyl ketones
were investigated under the optimized reaction conditions. To
our satisfaction, the results indicated that aryl methyl ketones
bearing diverse functional groups and substitution patterns
afforded the desired products in good to excellent yields (84−
93%) as shown in Scheme 2. The electron neutral (4-H, 4-Me),
electron-donating (4-OMe, 4-OEt, 2,4-(OMe)2, 3,4-OCH2O),
and electron-deficient (3-NO2, 4-NO2) groups that were
attached to the phenyl rings of the aryl methyl ketones
exhibited excellent reactivity (85%−93%, 3aa−ha). The
electronic and steric nature of the aromatic methyl ketones
was seen to have little influence on the reaction efficiency, and
all of the corresponding products were obtained in good to
excellent yields. In addition, the scope of the substrates was
further extended to various halogenated (4-Br, 4-Cl, 3,4-Cl2)
substrates (89%−92%, 3ia−ka), which could be used as an
intermediate to synthesize more complex compounds. Mean-
while, sterically hindered 2-acetylnaphthalene 1l and 1-
acetylnaphthalene 1m also furnished the desired products 3la
and 3ma smoothly in 91% and 90% yields, respectively. The
heteroaryl methyl ketones, such as thiophenyl and benzofuryl,
were found compatible under the optimal conditions and
provided oxidative coupling products in good yields (84−89%,
3na−pa).
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), I2 (0.1 mmol) in
b
DMSO (3 mL) at 130 °C for 3 h. Isolated yield.
Halogen-substituted benzamidine hydrochloride (4-Cl) also
afforded the desired products in good to excellent yields (89−
92%, 3ae−ce).
To gain some insight into the mechanism of the reaction, a
series of control experiments were performed (Scheme 4). The
reaction of α-iodo acetophenone 1aa with benzamidine
hydrochloride 2a was found successful, and the product 3aa
was obtained in excellent yields both with I2 (10 mol %) and
without I2 (Scheme 4a). In the presence of additional iodine,
hydrated hemiacetal 1ac could react with 2a and afford the
oxidative coupling product 3aa in 97% yield (Scheme 4b).
These results clearly confirmed the intermediacy of phenacyl
iodine 1aa and phenylglyoxal 1ac in the transformation.
However, the reaction was found unable to proceed smoothly
in the absence of I2 (Scheme 4b), which emphasized the crucial
The scope of the study was extended to substituted
benzamidines hydrochloride, The results are subsequently
displayed in Scheme 3. Various substituted benzamidines
hydrochloride were found compatible in the reaction. Electron
neutral (4-CH3), electron-deficient (4-NO2), and electron-rich
(3-OMe) groups on the phenyl rings of benzamidines
hydrochloride were compatible and provided the corresponding
products in good to excellent yields (83−92%, 3ab−ad).
B
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Letter
Scheme 4. Control Experiments
role of iodine in the subsequent domino process. Moreover, the
universality and mechanism of the reaction was further
examined through the reaction of acetophenone 1a and
benzamide 2aa in the presence of I2 (10 mol %) in DMSO.
However, the target product 3aa could not be obtained under
optimum condition (Scheme 4c). Furthermore, it was found
that 2a could not produce 2aa under the standard conditions
(Scheme 4d). The results suggested that benzamidine hydro-
chloride may be reacted with acetophenone first and then
underwent hydrolysis to obtain the target product.
Figure 1. Reaction process of 1a (0.10 mmol), 2a (0.20 mmol), and I2
(0.16 mmol) at 130 °C was monitored by 1H NMR spectroscopy (400
MHz, DMSO-d6, 298 0.5 K).
Scheme 5. Proposed Mechanism
We also monitored the reaction of 1c (0.10 mmol) and 2a
1
(0.20 mmol) with I2 (0.16 mmol) in DMSO-d6 by H NMR
spectroscopy to further investigate the reaction process. Based
on previous reports,8 the signal at 4.53 ppm was assigned to the
-CH2- group of α-iodo aryl methyl ketone 1ca at 5−10 min. In
addition, the signals at 9.54 and 5.66 ppm were assigned to the
phenylglyoxal aldehyde group (1cb) and the hemiacetal group
(1cc), respectively. With the consumption of 1c, the
intermediate 1cb and 1cc appeared and the concentration
subsequently increased over time. The signals at 3.83 and 3.85
ppm were assigned to the -OCH3 group of the phenylglyoxal
(1cb) or hydrated hemiacetal (1cc) and the -OCH3 group of
N-(2-(4-methoxyphenyl)-2-oxoacetyl)benzamide (3ca), respec-
tively. With the addition of 2a, the characteristic peaks of 1ca
and 1cc were seen to disappear immediately. Meanwhile, by
comparison with an authentic sample, the characteristic peaks
of 3ca was seen to appear (N−H at δ = 12.32). As shown in
Figure 1, the reaction was achieved in 75 min with high
conversion. These results demonstrated that phenacyl iodine
(1ca) and phenylglyoxal (1cb) were important intermediates in
the whole transformation.
According to the aforementioned information and based on
previous reports,9 a proposed mechanism for this I2-catalyzed
C−H/N−H oxidative cross-coupling is outlined in Scheme 5.
Initially, the substrate acetophenone 1a reacted with I2 to afford
the intermediate α-iodo acetophenone 1aa, which converted
into phenylglyoxal 1ab and released HI after a subsequent
Kornblum oxidation. The aldehyde group of phenylglyoxal 1ab
was activated by regenerated Lewis acid I2. Then, benzamidine
hydrochloride 2a attacked the activated aldehyde group of
phenylglyoxal 1ab to give the intermediate A, which was
followed by further rapid oxidation by I2 to afford intermediate
B.5c,10 Hydrolysis could then be undertaken to provide the
desired product 3aa.
Fortunately, some active methylene groups of 1,3-diketo
compounds could react with benzamidines hydrochloride and
give desired products in good to excellent yields when we tried
to further expand the substrate. Variously substituted ethyl 3-
oxo-3-phenylpropanoate and 1,3-diphenylpropane-1,3-dione
were found compatible in the reaction, as shown in Scheme
6. The related mechanism is shown in the Supporting
Information.
In summary, a molecular iodine-catalyzed sp3 C−H bond
oxidative amidation has been described for the construction of
α-ketoimides through the oxidative coupling of aryl methyl
ketones and benzamidine hydrochloride derivatives. This
method has provided a new strategy for sp3 C−H bond
C
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Scheme 6. Scope of Variously Substituted Ethyl 3-Oxo-3-
phenylpropanoate and 1,3-Diphenylpropane-1,3-dione
a b
,
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), I2 (0.1 mmol) in
b
DMSO (3 mL) at 130 °C for 3 h. Isolated yield.
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(10) (a) Xue, W.-J.; Li, Q.; Zhu, Y.-P.; Wang, J.-G.; Wu, A.-X. Chem.
Commun. 2012, 48, 3485. (b) Togo, H.; Iida, S. Synlett 2006, 2159.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21032001, 21272085). We
also thank Dr. Chuanqi Zhou, Hebei University, for analytical
support.
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