NBu4NI-Catalyzed oxidative imidation of ketones with imides: Synthesis of α-amino ketones

Article abstract of DOI:10.1039/c3cc48887j

nBu₄NI-Catalyzed oxidative imidation of ketones and imides for the synthesis of α-amino ketones were realized for the first time. The methodology is characterized by its wide substrate scope even for acetone with readily available phthalimide, saccharin and succinimide, which opens a new pathway for direct imidation of ketones. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc48887j

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nBu4NI-Catalyzed oxidative imidation of ketones
with imides: synthesis of a-amino ketones†
Cite this: Chem. Commun., 2014,
50, 2367
Yunhe Lv, Yan Li, Tao Xiong, Yu Lu, Qun Liu and Qian Zhang*
Received 21st November 2013,
Accepted 8th January 2014
DOI: 10.1039/c3cc48887j
www.rsc.org/chemcomm
nBu4NI-Catalyzed oxidative imidation of ketones and imides for the
synthesis of a-amino ketones were realized for the first time. The
methodology is characterized by its wide substrate scope even for
acetone with readily available phthalimide, saccharin and succinimide,
which opens a new pathway for direct imidation of ketones.
a-Amino ketones are an important class of biologically relevant
molecules.1 Additionally, these compounds are useful precursors for
the synthesis of heterocycles2 and 1,2-amino alcohols.3 a-Amino Scheme 1 Methods for the synthesis of a-amino ketones from ketone
derivatives.
ketones are traditionally prepared by the substitution reaction of
a-halo/hydroxyl ketones with nucleophilic nitrogen sources4 or
a-amination of carbonyl compounds with electrophilic nitrogen were pleased to find that with acetone as the solvent, the aminated
sources.5 For the synthesis of a-amino ketones via a nucleophilic product 3a was obtained in 46% yield with Pd(OAc)2 as the catalyst
amination reaction, prefunctionalization of the a-position of ketones and 1,10-phenanthroline as the ligand (eqn (1)). Then some other
is needed (for example, Scheme 1, path a).4 For an electrophilic potential radical nitrogen sources8 containing N–H bonds as well
amination reaction, pre-preparation of electrophilic nitrogen sources as catalytic systems were investigated. Recently, Ishihara and
is required (for example, Scheme 1, path b).5 Obviously, the most co-workers9 reported
a remarkable n-butylammonium iodide
simple and efficient route for the synthesis of a-amino ketones (nBu4NI) catalyzed enantioselective oxidative cycloetherification and
might be the oxidative C–N bond coupling reaction between N–H a-oxyacylation of carbonyl compounds with carboxylic acids. To our
bonds in nitrogen sources and sp3 C–H bonds in the a-position of delight, with saccharin 2b as the nitrogen source and acetone as the
ketones. In this communication, nBu4NI-catalyzed direct oxidative solvent, the combination of nBu4NI (0.2 equiv.) and tert-butyl-
imidation reactions of various simple ketones, including the parent hydroperoxide (TBHP, 2 equiv.) was extraordinarily efficient and gave
acetone, with a diverse range of imides, such as phthalimide, the desired aminated product 3b in 95% yield (Table 1, entry 1).
saccharin and succinimide, were realized for the first time Remarkably, it was not necessary to use acetone as the solvent in this
(Scheme 1, path c).
reaction. Ethyl acetate and dichloromethane (DCM) were effective in
As part of our continuing interest in employing various nitrogen providing 3b in 91% and 71% yields, respectively (Table 1, entries 2
sources for efficient construction of C–N bonds directly from C–H and 3). Instead of nBu4NI, the use of some other catalysts such as
bonds,6 the reaction between acetone and N-fluorobenzene- NaI, NH4I, nBu4NBr, nBu4NCl, I2, and NIS decreased the yields of 3b
sulfonimide (NFSI) was tested. In fact, we discovered that NFSI could dramatically, or no 3b was observed (Table 1, entries 5–10). As shown
be utilized as an effecient radical nitrogen source for benzylic C–H in Table 1, TBHP was the most effective peroxide in the process.
amination6b and aminative difunctionalization of alkenes,6g and the Other oxidants such as K2S2O8, di-tert-butylperoxide (TBP), O2 and
nitrogen-based radical addition reactions of NFSI to aromatic rings 30% H2O2 did not perform well (Table 1, entries 11–14). 3b could
were also realized by Ritter and co-workers very recently.7 Initially, we also be obtained in 71% yield when 70% TBHP was employed as the
peroxide (Table 1, entry 15). In addition, when the reaction was
performed at 70 1C or 100 1C, 3b was isolated in 55% or 82% yield.
No 3b was observed when either nBu4NI or TBHP was absent. It
Department of Chemistry, Northeast Normal University, Changchun, 130024,
China. E-mail: zhangq651@nenu.edu.cn; Fax: +86-431-5099759
should be noted that this imidation reaction was performed under
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc48887j
environmentally benign conditions (with tert-butyl alcohol and water
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Table 3 Imidation of ketones 1 with saccharin 2aa,b
as by-products) without utilizing metal or stoichiometric amounts of
hypervalent iodine(III) species.6f,10
(1)
To explore the generality and scope of the direct a-imidation of
acetone, a variety of imide nitrogen sources were investigated. As
shown in Table 2, sulfimides with different substituents at the
aromatic ring could be converted to the desired products 3c–f in high
to excellent yields. To our delight, phthalimide could also give the
a-amino carbonyl compound 3g in 81% yield. In addition, substituted
phthalimides reacted smoothly with acetone to give products 3h–j
in high to excellent yields. Furthermore, succinimide (2k) and
Table 1 Optimization of the reaction conditionsa
a
Standard reaction conditions: 1 (1.5 mmol), 2b (0.3 mmol), TBHP
(0.6 mmol, 5.5 M in decane), nBu4NI (0.06 mmol), EtOAc (3.0 mL),
Entry
Oxidantb
Catalyst
Solvent
Yieldc (%)
b
130 1C, 3 h. Yield of the isolated products.
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
TBP
nBu4NI
nBu4NI
nBu4NI
nBu4NI
NaI
Acetone
EtOAc
DCM
95
91
71
1,2-cyclohexanedicarboximide (2l) were effective substrates under these
conditions, the yields of the corresponding 3k and 3l were up to 92%
and 94%, respectively. Remarkably, starting from 1,8-naphthalimide
(2m), the imidation product 3m was obtained in 85% yield. As we
know naphthalimide derivatives possess interesting properties, and
they could be widely used as tunable dye lasers, polymerizable
materials, fluorescent chemical sensors and electroluminescent
organic diodes in thin films.11 However, amines such as pyrrolidine
and morpholine did not give the desired aminated products.
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
54d
Trace
63
NH4I
nBu4NBr
nBu4NCl
I2
47
53
0
0
Trace
Trace
0
0
71
9
10
11
12
13
14
15
NIS
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
O2
H2O2
e
TBHP f
To further explore the potential of this efficient imidation
reaction, several ketones as well as 1,3-dicarbonyl compounds were
examined as substrates to react with saccharin (2b) under the
optimized reaction conditions. Aryl ketones with various functional
groups were effective. Aryl ketone substrates bearing electron-
donating substituents were converted into the corresponding
products in higher yields compared with substrates with electron-
withdrawing substituents on the aromatic ring (Table 3, 4b–k). Halo-
substituted aryl ketones (1c, 1d, 1j–l) were tolerated in the
a-imidation reaction, and could be very useful for further transfor-
mations. In addition, starting from 1-acetylnaphthalene (1m),
2-acetylthiophene (1n) and 2-acetylfuran (1o), 4m, 4n and 4o could
be obtained in good yields. Cycloketones such as cyclopentanone
(1p), cyclohexanone (1q), cycloheptanone (1r) and 4-methylcyclo-
hexanone (1s) were also effective in providing 4p–s in 48–69% yields.
1,3-Diketones 1t and 1u gave the corresponding a-amino carbonyl
compounds in high yields. Next, the chemo- and regio-selectivity of
this imidation reaction were tested. Although from 1-cyclopropyl-
ethanone (1v) and 2-methylpentan-3-one (1w), the only aminated
product 4v and 4w was obtained in 90% and 73% yields, respectively,
for other ketones tested (1x–z), the corresponding chemo- and regio-
selective imidation products were observed. Imidation products
4x, 4x0 and 4x00 were obtained starting from butan-2-one (1x).
a
Reaction conditions: 1a (1.5 mmol), 2b (0.3 mmol), oxidant
b
(0.6 mmol), catalyst (0.06 mmol), solvent (3.0 mL), 130 1C, 3 h. TBHP
c
d
(5.5 M in decane). Yield of the isolated product. 1a (0.9 mmol).
e
f
H2O2 (30% in water). TBHP (70% in water).
Table 2 Imidation of acetone with imides 2a,b
a
Standard reaction conditions: 1a (1.5 mmol), 2 (0.3 mmol), TBHP
(0.6 mmol, 5.5 M in decane), nBu4NI (0.06 mmol), EtOAc (3.0 mL),
130 1C, 3 h. Yield of the isolated products.
b
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For pentan-3-one (1y), imidation and oxidation products 4y and 4y0
Financial support for this research by the SRFDP
were obtained in 77% and 20% yields, respectively. 4-Methylpentan- (20110043110002), the NNSFC (21372041, 21302017) and the
2-one (1z) gave the regio-isomers 4z and 4z0.
Fundamental Research Funds for the Central Universities
Several control experiments were performed to probe the reac- (11GJHZ001 and 11QNJJ015) is greatly acknowledged.
tion mechanism (see ESI†). The competitive imidations involving 1a
and its deuterated derivative 1a-d6 were performed and obvious
kinetic isotope effect (kH/kD = 5/1) was observed. This result showed
Notes and references
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that the enol form of ketone was formed during this imidation
process.12 When the radical scavenger 2,2,6,6-tetramethylpiperidine
N-oxide (TEMPO, 2.0 equiv.) was added to the imidation reaction of
pentan-3-one (1y) under the optimal conditions, after 3 h, a trace
amount of 4y was observed. Starting from acetone, 3b and 5 were
obtained in 47% and 21% yields, respectively (eqn (2)). Furthermore,
when 3b reacted with saccharin (1.0 equiv.) and TEMPO (2.0 equiv.)
in the presence of nBu4NI (0.2 equiv.) and TBHP (2.0 equiv.) for 9 h,
5 was obtained in 37% yield along with 51% 3b recovered (eqn (3)).
This result showed that the radical addition of enol to provide the
a-functionalized ketone was possible in this catalytic system. Inter-
estingly, no reaction occurred for the above reaction but without
adding 1.0 equiv. of saccharin. In addition, ESI-MS analysis of the
reaction system of 1a (see ESI,† reacted for 40 minutes) and 50 mL of
the mixture was used for the negative ion ESI analysis in CH3CN,
which showed the presence of I2. In the work of Wei,13 [IO2]ꢀ was
detected in the nBu4NI–H2O2 reaction system. However, as
described in Table 1, entry 14, no desired imidation product was
formed with H2O2 as the oxidant. Therefore, we do not propose that
[nBu4N]+[IO]ꢀ or [nBu4N]+[IO2]ꢀ generated in situ from nBu4NI and a
co-oxidant involved in this catalytic cycle.9 No reactions occur
between acetone and saccharin under the optimal conditions but
with stoichiometric NIS or molecular iodine (I2) instead of using
nBu4NI as the catalyst and TBHP as the oxidant.14 Furthermore, no
ketone iodinated products were detected in these imidation reac-
tions and morpholine and pyrrolidine were not effective for this
imidation reaction only with the starting materials recovered.
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In conclusion, we have described the first example of an nBu4NI-
catalyzed C–N cross coupling imidation reaction of sp3 C–H bonds of
simple ketones and N–H bonds in imides with TBHP as an
environmentally benign oxidant. Various ketones including the
simplest acetone and a diverse range of imides such as phthalimide,
saccharin and succinimide were efficient, which made this
imidation reaction very attractive. This methodology promises
to provide a new pathway for direct imidation of ketones.
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Chem. Commun., 2014, 50, 2367--2369 | 2369