Synthesis of α-enaminones from cyclic ketones and anilines using oxoammonium salt as an oxygen transfer reagent

Article abstract of DOI:10.1039/c9gc03845k

A convenient and straightforward transformation of cyclic ketones with anilines at room temperature has been developed using oxoammonium salt TEMPO⁺PF₆^- as an oxidant. This method enabled the synthesis of a broad range of α-enaminones. The ¹⁸O-labeling experiment demonstrated that oxoammonium salt served as the oxygen transfer reagent.

Full text of DOI:10.1039/c9gc03845k

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Green Chemistry
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DOI: 10.1039/C9GC03845K
COMMUNICATION
Synthesis of α-Enaminones from Cyclic Ketones and Anilines using
Oxoammonium Salt as an Oxygen Transfer Reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Biping Xu, a,b Yaping Shang,*a Xiaoming Jie, a Xiaofeng Zhang, a Jian Kan, a Subhash Laxman Yedage a
and Weiping Su *a
DOI: 10.1039/x0xx00000x
A convenient and straightforward transformation of cyclic ketones
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and its
with anilines at room temperature has been developed using corresponding oxoammonium salts are widely used as catalyst
-
oxoammonium salt TEMPO+PF6 as an oxidant. This method or oxidant in traditional synthetic organic reactions, and very
enabled synthesis of a broad range of α-enaminones. The 18O- recently in electrochemical transformations.4 Moreover,
labeling experiment demonstrated that oxoammonium salt served TEMPO could also be used as an oxygenation reagent to
as the oxygen transfer reagent.
incorporate itself into the target molecules,5 particularly in the
α-aminoxylation reactions of carbonyl compounds.6 In these
elegant studies, some of them also required a secondary
amine as catalyst to generate the reactive enamine
intermediate, which was then subject to further metal-
promoted oxidation to afford the α-aminoxylation product.
Inspired by these pioneering works, our group reported a
series of TEMPO-mediated ketone functionalization reactions,
which, by comprehensive mechanistic studies, were believed
to involve α-TEMPO-substituted ketone as the key
intermediate.7 Despite the versatile behavior of TEMPO in
organic synthesis, the example of TEMPO serving as oxygen
transfer reagent is rare.8 Base on our previous works, we
recently discovered that oxoammonium salt, the ‘true oxidant’
in many TEMPO-mediated oxidation reactions,9 could be used
as highly efficient oxidant to produce α-enaminones from
simple cyclic ketones and anilines. This will be presented and
discussed in this work.
α-enaminones are versatile structural motifs in organic
synthesis. Because of their dual electronic attitude (acting as
nucleophilic enamines and electrophilic enones), these
compounds have been used as useful intermediates for the
construction of several important heterocyclic scaffolds, which
include
quinolinones,
tetrahydron-1H-carbazol-1-ones,
pyrroles and even bicyclic N-heterocycles.1 The conventional
methods for the build of α-enaminones usually require
multiple synthetic steps or start from the corresponding
diketones (Scheme 1a).2 Recently, this conversion has been
carried out from anilines (or O-benzoylhydroxylamines) and
cyclic ketones under mild conditions, but the prefunctionalized
amination reagents and electrochemistry devices confined
their applications (Scheme 1b and 1c).3 Mechanistically, these
elegant progresses share one common reaction pathway, that
is, first α-amination to form α-amino ketones and further
oxidation to deliver the final α-enaminones. Additionally, some
of them require harsh reaction conditions or exhibit restricted
ketones or aniline substrates scope3c,8. In view of these
limitations, the development of new synthetic protocol that
directly utilize readily available simple ketones and anilines
under mild conditions, especially that operate with a unique
mechanistic avenue, would be highly desirable (Scheme 1c).
Previous Work:
O
O
O
Ar
HN
O
O
N
ArNH2
morpholine
(a)
(b)
toluene,reflux
PTSA, toluene
80oC
O
O
O
NR2
rt
N
Source
ArNH2
+
R
R
O
H
N
catalysts
reflux
Ar
+
+
(c)
R
aState Key Laboratory of Structural Chemistry, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of Matter, Chinese Academy
of Sciences, Fuzhou, 350002, China
This Work:
Ar
HN
O
O
E-mail: wpsu@fjirsm.ac.cn, shangyaping@fjirsm.ac.cn
catalyst free
ArNH2
bUniversity of Chinese Academy of Sciences, Beijing 100049, People’s Republic of
China
O
TEMP salt
rt
R
R
Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data, and crystallographic data (CIF). CCDC: 1962739. For ESI and
Scheme 1 Strategies for the syntheses of α-enaminones from cyclic ketones.
crystallographic
data
in
CIF
or
other
electronic
format
see
DOI:10.1039/x0xx00000x
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Green Chemistry
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COMMUNICATION
Journal Name
Table 1 Optimization of the reaction conditionsa
View Article Online
DOI: 10.1039/C9GC03845K
Cl
Cl
O
AgSbF6 (10 mol%)
NH2
Cl
HN
TEMPO+PF-6 (1.2 equiv)
O
NH2
HN
O
R
additive
+
O
DCE (1.0 mL), 3Å MS (400 mg)
rt, N2, 24 h
R
oxidant(1.2 equiv)
+
1
2a
solvent, MS(400 mg)
rt, N2, 24 h
3
tBu
1a
Cl
tBu
3a
3i
3j
, R=COOEt,82%
Cl
Cl
3a
3b
, R=tert-butyl, 90%
, R=H, 81%
2a
, R=CH2COOEt,79%
3c
3d
,
R=Me, 85%
3k
, R=CF3,88%
HN
HN
, R=Et, 86%
Additives
(mol%)
-
Cu(OAc)2(10)
Cu(OTf)2(10)
Sc(OTf)3(10)
Yb(OTf)3(10)
B(C6F5)3(10)
TsOH(10)
AgNO3(10)
AgBF4(10)
AgPF6(10)
AgClO4(10)
AgSbF6(10)
AgSbF6(10)
AgSbF6(10)
AgSbF6(10)
AgSbF6(10)
Yield of 3a
3l
, R=CN,74%
O
Entry
Oxidants
O
3e
3f
, R=n-Prop, 90%
, R=tert-amyl, 99%
b
(%)b
3m
, R=NPhth,93%
3n
3o
, R=NHBoc,88%
, R=NMeBoc,75%
Cl
3g
3h
, R=n-Pent, 87%
, R=Ph, 91%
-
1
2
3
4
5
6
7
8
9
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
TEMPO+BF4
70
56
49
66
62
77
70
72
80
81
80
86
73
74
98(91)
80
p
3
, 63%
Cl
R
-
-
-
-
-
-
-
-
-
-
-
Cl
HN
Cl
Cl
Cl
HN
HN
HN
HN
HN
O
O
O
O
O
O
Me
Me
N
R
O
O
O
Me Me
3q
Ph CN
c
3u
,R=Ts, 63%
3w
, 66%
3s
3t
, 68%
, 87%
3r
, 91%
, 78%
3v
,R=Boc, 53%
Cl
Cl
Cl
Cl
Cl
Cl
10
HN
HN
HN
HN
HN
HN
1
1
1
2
O
O
O
O
Me
Ph
O
O
-
TEMPO+ClO4
Me Me
13
14
15
16c
Me Me
3x 3x'
3y 3y'
:
3aa
3ab
, 40%
TEMPO+TfO-
:
=2.9:1, 81%
Cl Cl
=3.6:1, 93%
, 12%
Me
O
Me
TEMPO+PF6
-
HN
H
TEMPO+PF6
-
HN
NH
H
3z 3z'
:
=10.8:1, 82%
3ac
, 95%
H
a
H
O
O
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), additive (10 mol%), 3Å molecular
Cl
sieves (400 mg), Oxoammonium salt (1.2 equiv), DCE (1.0 mL), N2, room temperature
for 24 h. Yields were determined by GC analysis using n-dodecane as an internal
b
standard, and isolated yield is listed in parentheses. c 4Å MS (400 mg) was used instead
of 3Å MS (400 mg).
a
Scheme 2 Substrate scope of cyclic ketones.a Reaction conditions: 1 (0.3 mmol), 2a
(0.2 mmol), additive (10 mol%), 3Å molecular sieves (400 mg), TEMPO+PF6 (1.2 eqiv),
DCE (1.0 mL), N2, room temperature, 24 h. b DCE (5 mL) was used. Reaction time was
-
We commenced our investigation by combining 4-tert-
butyl-cyclohexanone (1a) (1.5 equiv.) and 4-chloro-aniline (2a)
c
16 h.
-
together with oxoammonium salt TEMPO+BF4 (1.2 equiv.) as
oxidant, as well as molecule sieves (3Å) to remove water
generated in-situ from the condensation of cyclohexanone
with aniline. Initially, 4-methylanthranilic acid, an effective
catalyst for ketone-aniline condensation,10 is used to facilitate
the imine formation. And it turned out that the desired α-
enaminones could be obtained in 63% yield with CH3CN as
solvent at room temperature (See the supporting information
for details).11 The difference of our product with previous
report is that in this transformation, the original ketone
position has been changed via a formal oxygen 1,2-migration,
which implies a unique mechanistic pathway. Other solvent
systems such as toluene, o-DCB (1,2-dicholorobenzene), Et2O
and DCM gave inferior results as compared with CH3CN. To our
delight, DCE gave a better yield (68%)(See the SI for details).11
Unexpectedly, 70% yield can still be obtained without the
presence of 4-methylanthranilic acid (Table 1, entry 1).
Considering Lewis acid could facilitate the condensation of
amines with carbonyls and the cleavage of C-O bond between
the substrate and TEMPO,12 we turned our attention to the
effect of various Lewis acids as additives. Among them,
Cu(OAc)2, Cu(OTf)2, Sc(OTf)2 and Yb(OTf)3 showed a slightly
detrimental effect for the reaction (Table 1, entries 2-5). And
B(C6F5)3 and TsOH exhibited no improvement (Table 1, entries
6-7). Later on, we found that the employment of silver salts
could promote this transformation.13 Further screening of
silver salts revealed that AgSbF6 furnished the best result in
86% yield (Table 1, entries 8-12). Finally, we found that the
counter anion of oxoammonium salt also had an influence on
-
the reaction outcome: the use of TEMPO+PF6 instead of
-
TEMPO+BF4 gave the optimal 91% isolated yield (Table 1,
entries 13-15). Replace of 3Å molecule sieves with 4Å ones
gave a lower yield (Table 1, entry 16).
Having established the optimal reaction conditions, the
substrate scope of cyclic ketones as well as anilines were then
examined. To check the substrate scope of cyclic ketones, we
used 4-chloroaniline as a model coupling partner (Scheme 2).
In this context, a variety of substitutes on the ring of
cyclohexanones, such as alkyl (3a-3g), phenyl (3h), ester (3i,
3j), trifluoromethyl (3k), cyano (3l) and protected amino
groups (3m-3o), are well tolerated. Furthermore,
unfunctionalized cyclopentanone (3p), 4,4- and 3,3-
disubstituted cyclohexanones (3q-3t), as well as the ones with
heteroatom-substitutes on the ring of cyclohexanones (3u-3w)
also underwent the reaction smoothly. Interestingly, for the
ketones possess substitutes at the 3-position of original
carbonyls, usually two isomers were obtained, in which the
major product is the one with oxygen migrated to the less
hindered position (3x-3z). By comparison, ketones bearing
substitutes at the 2-position of original carbonyls only offered
one isomer, albeit in moderate yields (3aa, 3ab). Pleasingly, a
2 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
COMMUNICATION
Control Experiments
R
View Article Online
DOI: 10.1039/C9GC03845K
O
O
O
AgSbF6 (10 mol)
NH2
Cl
Cl
H
N
HN
TEMPO+PF-6 (1.2 equiv)
O
Standard Conditions
w/o MS
+
+
(a)
Cl
+
H2N
R
DCE (1.0 mL), 3Å MS (400 mg)
rt, N2, 24 h
1b
2a
3b
, 5%
Ph
1h
Ph
O
H
2
O
O
4
N
N
O
b
Standard Conditions
(b)
Cl
b
4j
4a
4b
4c
4d
4e
, R=4-(2-Py), 80%
, R=4-H, 70%
R
O
O
b
a
H2N
4k
, R=4-SMe, 79%
, R=4-F, 76%
, R=4-Br, 91%
Cl
HN
5a
2a
3a'
3a, 5%
b
a
4l
, R=4-SCF3, 73%
HN
O
b
O
a
4m
, R=3-OCF3, 86%
, R=4-I, 82%
H
N
O
O
H
b
a
a
Standard Conditions
4n
4o
4p
, R=3-OMe, 76%
, R=4-CF3, 89%
N
a
(c)
(d)
4f
, R=3-NO2, 59%
, R=4-Bpin, 80%
Cl
Ph
a
b
4g
4h
, R=3-Cl, 79%
Cl
O
, R=4-tBu, 86%
5b
3b(trace)
Ph
a
b
4q
a
, R=2-Cl, 87%
, R=4-Ac, 75%
b
4r
, 56%
4i
, R=4-COOEt, 81%
O
Cl
O
1).Standard Conditions for 15 min
2). 15% HCl, 4 h
Br
N
I
+
+
H
Me
HN
N
OMe
HN
H2N
N
N
1b
2a
5c,
11%
HN
HN
HN
O
O
O
O
O
O
I
+PF6
-
18O
TEMP
HN
(e)
18O
Standard Conditions
H2N
Ph
Ph
Ph
Ph
18O-4d
90% isolated yield
Ph
4w
b
b
b
b
a
Ph
1h
4s
4t
4u
4v
, 73%
, 72%
, 72%
, 89%
, 46%
2d
Ph
a
Scheme 3 Substrate scope of anilines.a Method A: 1h (0.3 mmol), 2a (0.2 mmol),
additive (10 mol%), 3Å molecular sieves (400 mg), TEMPO+PF6-(1.2 equiv), DCE (1.0
mL), N2, room temperature, 24 h. Method B: 1h (0.3 mmol), 2a (0.2 mmol), additive
Plausible Mechanism
b
Ar
O
HN
R
O
(10 mol%), 3Å molecular sieves (400 mg), DCE (1.0 mL), N2, room temperature,
TEMPO+PF6-(1.2 equiv) was added after pre-stirring for 1h and then reacted for further
23 h before workup.
ArNH2
+
3
1
2
R
Lewis Molecular
(f)
Acid
Sieves
H2O
steroid compound containing cyclohexanone subunit is also
suitable for the transformation, affording the desired product
in 95% yield (3ac).14
Ar
Ar
Ar
Ar
Ar
HN
R
HN
N
R
N
HN
H
O
TEMP
O
O
TEMP
O+PF
N
TEMP
6
[Ag]
In respect of anilines, a broad range of primary amines,
either electron-rich or electron-poor, are fully compatible with
current reaction conditions, affording the desired products in
good to excellent yields (Scheme 3). Both halide substitutes
and pharmaceutically relevant trifluoromethyl group are well
tolerated (4a-4e). Moreover, aniline bearing pinacolborane
functionality is also feasible substrate (4f), which offered a lot
of space for further manipulations with other orthogonal
C
D
E
A
B
R
R
R
Scheme 4 Control experiments and mechanism Investigation.
imine in work-up step (Scheme 4d). Also, 18O-labled
oxoammonium salt TEMPO+PF6 gave the 18O-containing 4d in
-
90% yield, which revealed that the oxygen atom of carbonyl
group in the α-enaminones product originated from the
oxidant-oxoammonium salt (Scheme 4e). Based on these
mechanistic investigations, we proposed a possible reaction
pathway as illustrated in Scheme 4f. As demonstrated, the
reaction started with molecular sieves facilitated imine
condensation (A), and then the in-situ formed tautomerizable
imine intermediate (B) reacted with TEMPO+PF6- in its enamine
form to generate α-aminoxylated imine (C), which next
underwent TMP-elimination to afford the desired α-
enaminones (3). Notably, the application of our strategy is
highlighted by the fact that chiral tetrahydrocarbazoles (HPVs
inhibitor) and tjipanazoles D&I could be accessed starting from
our product 3b and 6a via only two synthetic steps (Scheme 5).
metal-catalyzed
transformations
(e.g.
Suzuki-Miyaura
coupling). Additionally, other commonly encountered
functionalities such as tert-butyl, ester, pyridine, sulfur ether,
trifluoromethoxy, methoxy and nitro groups exhibited
excellent reactivity (4g-4o). The substituted positions of
anilines had subtle effect for the reaction outcome (4p-4q).
Besides mono-substituted anilines, multi-substituted as well as
heterocyclic anilines served as competent substrates (4r-4w),
demonstrating the generality of our reaction conditions.
To further elucidate the mechanism of this reaction, we
performed an array of control experiments (Scheme 4). Firstly,
the model reaction conducted without molecular sieves gave
only 5% product, which indicated the crucial role of molecular
sieves in this transformation (Scheme 4a). Next, the use of
diketone as starting material only gave trace amount of 3a
(Scheme 4b). And the independently prepared α-amino-
substituted ketone also failed to give the desired product
(Scheme 4c). These results imply that our reaction doesn’t
involve intermediates of diketone or α-amino- substituted
ketone. Α-aminoxylated ketone (5c) was obtained in 11% yield
when the standard reaction of cyclohexanone and 4-
chloroaniline was quenched after 15 min, and this α-
aminoxylated ketone likely resulted from the α-aminoxylated
H
H
N
N
H
O
Cl
R
N
O
X
tjipanazole deriatives(R=H or Cl)
2 Steps
Standard Condition
Me
+
H2
N
X
H
HN
Ph
N
1a
(2.0 eq)
2
3b
6a
,X=Cl, 82%
,X=Br, 86%
Br
HPV inhibitor
Scheme 5 Gram-scale synthetic applications.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Green Chemistry
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COMMUNICATION
Journal Name
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Conclusions
In conclusion, we have developed a concise and general
strategy to synthesize α-enaminones. In this transformation,
the oxoammonium salt TEMPO+PF6 acted as both oxidant and
3
4
5
6
-
oxygen transfer reagent. The reaction tolerated a broad range
of substrate scope with respect to both ketones and anilines,
while operating under simple and mild conditions (room
temperature). We believe this study could give more
inspirations for the use of TEMPO and its corresponding
oxoammonium salts in organic synthesis. Further explorations
about using oxoammonium salts as oxidant in ketone
functionalization reactions are currently ongoing in our lab.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
The authors thank gratefully Dr. Fa-Jie Chen, Mr. Jianchen Shen and
Mr. Yangjing Xu for helpful discussions. We also thank Dr. Meng Xi
for NMR assistance. This work was supported by the National Key
Research and Development Program of China (2018FYA0704502,
2017YFA0206801), the National Natural Science Foundation of
China (Grants no. 21931011, 21702205, 21431008 and u1505242),
the Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000 and XDB10040304), the Key Research
Program of Frontier Sciences, CAS (QYZDJ-SSW-SLH024) and the Key
Research Program of the Chinese Academy of Sciences (ZDRW-CN-
2016-1).
7
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2016, 138, 5623; (b) Y. Shang, X. Jie, K. Jonnada, S. N. Zafar
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4 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
TOC
COMMUNICATION
View Article Online
A convenient α-enaminones synthesis from cyclic ketones
with anilines under room temperature via an oxygen-atom-
transfer pathway of the oxoammonium salt.
DOI: 10.1039/C9GC03845K
Ar
O
HN
54 examples
up to 99% yeild
O
catalyst free
+ ArNH2
O
TEMP salt
room temp.
chemo- and regio-selective
catalyst free
mild condition
scalable
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