Fe-Catalyzed enaminone synthesis from ketones and amines

Article abstract of DOI:10.1039/c9ob01137d

We have developed an iron-catalyzed direct olefination for enaminone synthesis, with saturated ketones as a source of olefins. This direct ketone β-functionalization reaction has readily available starting materials and a wide range of substrates and requires mild reaction conditions.

Full text of DOI:10.1039/c9ob01137d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Wu, Z. Wang,
Q. Shen, Q. Liu and H. Chen, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB01137D.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Page 1 of 4
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB01137D
Organic & Biomolecular Chemistry
COMMUNICATION
Fe-Catalyzed Enaminones Synthesis from Ketones and amines
Wenfeng Wu‡, Zhuxian Wang‡, Qun Shen, Qiang Liu* and Huoji Chen*
inReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We have developed an iron-catalyzed direct olefination for iodides,10a-b Cu-catalyzed direct β-functionalization of ketones
enaminone synthesis, including saturated ketones as a source of with
a wide range of nitrogen, oxygen and carbon
olefins. This direct ketone β-functionalization reaction has readily nucleophiles,10c Rh/Cu-catalyzed direct β-arylation or ketone
available starting materials, a wide range of substrates and mild alkenylation,10d and so on.10e-i
reaction conditions.
Tandem β-amination/oxidation of saturated ketones may be a
good way to synthesize enaminones. In 2009, Ueno and
colleagues reported Ni-catalyzed enaminone formation
catalyzed by ketones and amines, but only secondary aliphatic
amines were used(Scheme 1a).11 A similar conversion was
realized by Pan's group, who led the use of copper salts as
catalysts. However, this reaction is only applicable to
sulfonamides(Scheme 1b).12
Iron is inexpensive, low in toxicity, easy to use and stable in
performance. Therefore, iron-catalyzed organic conversion has
recently attracted great interest from synthetic chemists.13 In
our previous work, we developed an aerobic Fe-catalyzed
direct formylation of imidazo[1,2-a] pyridine using DMSO as
carbon source.14 Here, we propose to synthesize a carbon-
nitrogen bond with an amine at the β-position of the β-ketone
to synthesize enaminone(Scheme 1c).
Enaminone is an important synthetic intermediate for the
synthesis of various heterocyclic compounds.1 In addition, the
enaminone skeleton is present in drug molecules and natural
products.2 Typical methods for enaminones included the
condensation of 1,3-dicarbonyl compounds with amines,3
Michael addition of alkynones with amines.4 Recently, some
new methods have also been developed. In 2012, Miura and
colleagues developed
a denitrification rearrangement of
ruthenium-catalyzed 1-(N-sulfonyl-1,2,3-triazol-4-yl)alkanol.5
In 2013, an economical step was reported to synthesize
enaminone from calcium carbide, aryl aldehydes, and amines
in Zhang's research group.6 In 2014, Li discovered four-
component synthesis of enaminone and palladium-catalyzed
cascade carbonylation.7 Kim and Hong demonstrated the NHC-
catalyzed C-C bonds to form enaminones from ketones and
isocyanates in 2017.8 However, most of these reported
methods are subject to some limitations, such as unusable
starting materials, severe reaction conditions, poor functional
group tolerance, and low yield.
Previous work
[Ni(Cod)2], PMe3
PhCl, K3PO4
O
O
NHR1R2
R
NR1R2
(a)
(b)
+
R
dioxane, 100 oC, 40 h
R1 = alkyl
R2 = alkyl
For many years, direct functionalization of the inert C(sp3)-H
bonds has become one of the most important areas of modern
organic chemistry because of its high atomic and step
economy.9 Saturated carbonyl compounds are inexpensive and
available on the market. Recently, some transition-metal-
catalyzed direct β-functionalization reactions of saturated
ketones have been reported, such as Pd-catalyzed direct β-
arylation of ketones with diaryliodonium salts or aryl
O
S
O
R1
O
R1
O
CuTC, DMAP, 4-CH3O-TEMPO
DMSO, 110 oC, O2
S
R2
+
Ar
N
R2
N
Ar
O
O
H
This work
O
O
FeCl3, Li2CO3
DABCO,TBHP
(c)
R
NHR1R2
R
+
toluene, 100 oC, air
NR1R2
Scheme 1. Synthesis of enaminones from ketones and amines
We began our investigation by examining the reaction of
propiophenone (1a) and 2-aminopyridine (2a) with FeCl2 as
catalyst, Li2CO3 as base and TBHP (tert-Butyl Hydroperoxide)
as oxidant in toulene under air atmosphere. To our delight,
the enaminone 3a was produced in 39% isolated yield (Table 1,
entry 1). Different Fe and Cu catalysts were explored, and we
School of Traditional Chinese Medicine, Southern Medical University, 1023 South
Shatai Road, Baiyun District, Guangzhou 510515, P. R. China. E-mail:
gzlq2002@163.com; chenhuoji2005@126.com
Electronic Supplementary Information (ESI) available: Experimental section,
characterization of all compounds, Figure S1, copies of 1H and 13C NMR spectra for
all target compounds. See DOI: 10.1039/x0xx00000x
‡These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., XXXX, XX, X-X | X
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Organic & Biomolecular Chemistry
25f
FeCl3
TBHP
toulene
View 6Ar8ticle Online
found that FeCl3 promoted this reaction to 59% yield (Table 1,
entries 2-10). Next, various oxidants were evaluated, showing
that replacing TBHP with other oxidants made the yields
obviously decreased (Table 1, entries 11-14). Solvent effects
were also surveyed (Table 1, entries 15-18), while toulene was
most suitable for this transformation. Control experiments
revealed that no product was obtained in the absence of
either FeCl3 or TBHP (Table 1, entries 19-20). When Li2CO3 was
replaced by K2CO3, the yield was 38% (Table 1, entires 21).
Addition of bpy led to diminish yield of 3a, while DABCO could
enhance the yield (Table 1, entries 22-23). A increase of
reaction temperature led to a diminished product yield (Table
1, entry 24). The yield of 3a did not change much under a N2
atmosphere (Table 1, entry 25). In order to simplify the
operation, we elected to carry out our process under an air
atmosphere. Thus, the optimized reaction system was: 1a (0.5
mmol), 2a (1.0 mmol), FeCl3 (20 mol %),Li2CO3 (30 mol %),
DABCO (20 mol %), TBHP (1.5 mmol), and toulene (2 mL) at
100 oC under air atmosphere for 6 hours.
DOI: 10.1039/C9OB01137D
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2a (1.0 mmol), catalyst (20 mol%), Li2CO3
(30 mol%), oxidant (1.5 mmol) and solvent (2 mL), at 100 oC under air for
6 h. Isolated yield. K2CO3 instead of Li2CO3.
Add DABCO (20 mol %). The reaction temperature was decreased to
120 oC. f Under N2 atmosphere.
a
b
c
d
Add Bipy (20 mol %).
e
Table 2. Substrate scopea
FeCl3 (20 mol %)
Li2CO3 (30 mol %)
DABCO (20 mol %)
TBHP (3 equiv.)
O
O
R
R
NHR1R2
+
toluene, 100 oC, air
NR1R2
Br
1
3
2
Cl
O
HN
N
O
HN
N
O
HN
N
Ph
Ph
Ph
Ph
Ph
3a
, 70%
3c
, 59%
3b
, 67%
OMe
Cl
O
HN
O
HN
3e
O
HN
Ph
3d
, 74%
HN
, 77%
3f
, 62%
N
COOMe
O
O
Table 1. Optimization of reaction conditionsa
O
Ph
Ph
N
3h, 35%
Ph
Catalyst (20 mol %)
Li2CO3 (30 mol %)
Oxidant (3 equiv.)
O
3g
, 57%
3i, 57%
O
HN
N
O
Solvent, 100 o
C
N
NH2
O
HN
N
O
HN
N
Cl
Ph
N
1a
2a
3a
O
Entry
1
Catalyst
FeCl2
FeCl3
FeBr2
FeBr3
Fe(NO3)3
Cu(OTf)2
CuCl2
CuCl
Oxidant
Solvent
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
toulene
DMSO
DCE
Yield (%)
39
Br
3j
3k, 61%
3l
, 59%
, 64%
O
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
(t-BuO)2
TPB
O
O
HN
N
N
2
59
N
H
N
H
3
40
MeO
O
3n
, 72%
3m
, 73%
3o
, 69%
O
O
O
4
46
OMe
Cl
5
35
N
N
N
N
H
H
O
6
34
3p
3q
3r, 54%
3s
, 49%
, 73%
, 58%
7
28
a Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), FeCl3 (20 mol %), Li2CO3 (30
mol %), DABCO (20 mol %), TBHP (1.5 mmol), toluene (2 mL), under air, 100
oC for 6 h. Isolated yields.
8
36
9
CuBr
25
10
11
12
13
14
15
16
17
18
19
20
21b
22c
23d
24e
CuI
29
With the optimized conditions in hand, we tested various
ketones and amines and the results were summarized in Table
2. Halo-substituted 2-aminopyridines were good coupling
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
--
26
31
partners
with
propiophenone,
and
the
BQ
49
corresponding enaminones were obtained in moderate yields
(Table 2, 3b, 3c). Anilines bearing chloro, methy, methoxy or
ester functionalities smoothly underwent the reaction to
produce the desired products (Table 2, 3d-3g). The N-
methylaniline gave the corresponding product in lower yield
(Table 2, 3h). Gratifyingly, the method was also suitable for
secondary aliphatic amines such as piperidine and morpholine,
the corresponding products were obtained in 57% and 64%
yields, respectively (Table 2, 3i, 3j). While a primary aliphatic
amine such as n-butylamine didn’t give the target product due
to the decomposition of substrate in the conditions.
Additionally, substituted propiophenone could be smoothly
transformed into the enaminone products with 2-
aminopyridine (Table 2, 3k-3m). However, 1-phenylbutan-1-
one failed to afford corresponding product with 2-
O2
trace
21
TBHP
TBHP
TBHP
TBHP
TBHP
--
32
DMF
28
1,4-dioxane
toulene
toulene
toulene
toulene
toulene
toulene
13
n.d.
n.d.
38
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
TBHP
TBHP
TBHP
TBHP
24
70
57
Org. Biomol. Chem, XXXX, XX, X-X
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Organic & Biomolecular Chemistry
COMMUNICATION
aminopyridine and most of the raw material was recovered.
To investigate the reaction mechanism, several control
View Article Online
The different stereoselectivity occured between primary and experiments were conducted. When 1aDwOaI:s10s.u10b3j9e/cCt9eOdBt0o113th7De
secondary amines. The products derived from primary amine standard reaction conditions, α,β-unsaturated ketone 4 was
were Z-type due to the intramolecular hydrogen-bond isolated in yield of 38% (Scheme 3, eq 1). Compound 4 could
interaction. While the products derived from secondary amine react with 2a and produce the 3a in 75% yield under the
were E-type due to the steric hindrance. Significantly, standard reaction conditions. Those results reveal that
cyclohexanone was suitable for the reaction, and coupled with compound 4 may be an intermediate (Scheme 3, eq 2). The
various amines to offer the corresponding products in coupling product 5 was obtained when 1a reacted with TEMPO
acceptable yields (Table 2, 3n-3r).
(Scheme 3, eq 3). Based on previous reports and the control
experiments, a possible mechanism is illustrated in Scheme 3.
To further enhance the utility of this catalytic process, we A iron II/III catalytic cycle with TBHP produces tert-butoxyl and
15a-b
utilize the enaminone product to rapidly transport tert-butylperoxy radicals.
First FeCl3 enolizes saturated
heterocycles. As shown in Scheme 2, imidazo[1,2-a]pyridine ketone 1a to give complex A, then the tert-butoxyl or tert-
and 1,2,3-triazole can be easily obtained.
butylperoxy radical abstracts β-hydrogen of intermediate A,
resulting in formation of α,β-unsaturated ketone 4.15c-d Finally,
2a and 4 proceed sequential Michael-Addition/oxidation
process to form the product 3a.15c
N
N
(i), 77%
O
4a
Ph
In summary, we have developed a new iron catalyzed
process for the synthesis of enaminones from ketones and
amines. Both aryl ketone and cyclohexanone undergo a β-
functionalization reaction with a variety of amines in moderate
to good yields. This topic is currently being further studied in
our laboratory.
O
HN
3a
N
(ii), 80%
N
N
N
Ph
N
O
5a
Ph
Scheme 2. Conditions: (i) 3a (0.3 mmol), 20 mol % CuI, DMSO (2
mL), 100 oC, 12 h, open air. (ii) 3a (0.3 mmol), TsN3 (0.4 mmol), and t-
BuONa (0.45 mmol) in 2 mL of MeCN were stirred for 2 h at rt.
Acknowledgements
The authors thank the Natural Science Foundation of
Guangdong Province (2017A030310021), the Science and
O
O
O
standard conditions
+
(1)
Ph
Ph
4 (
Ph
1a
Technology
Program
of
Guangdong
Province
)
38%
1a
(50 %, recovered)
(2017A050506027, 2017B090912005) and the Science and
Technology Program of Guangzhou (201807010053).
O
O
HN
N
standard conditions
FeCl3 (20 mol%)
+
(2)
(3)
Ph
N
NH2
Ph
4
3a (
)
75%
2a
Notes and references
O
1
(a) A. Noole, M. Borissova, M. Lopp and T. Kanger, J. Org.
Chem., 2011, 76, 1538; (b) J.-P. Wan, C. C. J. Loh, F. Pan and
D. Enders, Chem. Commun., 2012, 48, 10049; (c) C. Wang, C.
Dong, L. Kong, Y. Li and Y. Li, Chem. Commun., 2014, 50,
2164; (d)E. M. Afsah, E.-S. I. El-Desoky, H. A. Etman, I.Youssef
and A. M. Soliman, J. Heterocyclic Chem., 2018, 55, 2959; (e)
Y. Zhao, Q. Duan, Y. Zhou, Q. Yao and Y. Li, Org. Biomol.
Chem., 2016, 14, 2177; (f) H. Xu, B. Zhou, P. Zhou, J. Zhou, Y.
Shen, F.-C. Yu and L.-L. Lu, Chem. Commun., 2016, 52, 8002;
(g) J.-P. Wan, S. Cao and Y. Liu, Org. Lett., 2016, 18, 6034.
(a) M. S. Alexander , K. R. Scott, J. Harkless, R. J. Butcher, P. L.
Jackson-Ayotunde, Bioorg. Med. Chem., 2013, 21, 3272; (b)
D. J. Hogenkamp, T. B. C. Johnstone, J.-C. Huang, W.-Y. Li, M.
Tran, E. R. Whittemore, R. E. Bagnera and K. W. Gee, J. Med.
Chem., 2007, 50, 3369; (c) O. M. Ghoneima, A. Billa, J.
Dhugurua, D. E. Szollosia and I. O. Edafiogho, Bioorg. Med.
Chem., 2018, 26, 3890.
O
Ph
TEMPO
2 equive
+
Ph
1a
toluene, 100 oC, air
O
N
5
(60%)
FeIII
tBuOOH
+ OH-
tBuO
2
tBuOO
tBuOOH
+ H
FeII
O
or t
t
BuO
BuOO
FeCl2
O
O
FeCl3
Ph
Ph
Ph
+
Fe
4
1a
HCl
or tBuOOH
t
Cl
Cl
BuOH
A
3
4
5
6
7
H. Zhang, Z. Wang, C. Wang, H. Wang, T. Chengand L. Wang,
RSC Adv., 2014, 4, 19512
D. R. Chisholm, R. Valentine, E. Pohl and A. Whiting, J. Org.
Chem., 2016, 81, 755.
T. Miura, Y. Funakoshi, M. Morimoto, T. Biyajima and M.
Murakami, J. Am. Chem. Soc., 2012, 134, 17440.
D. Yu, Y. N. Sum, A. C. C. Ean, M. P. Chin and Y. Zhang,
Angew. Chem. Int. Ed., 2013, 52, 5125.
N
NH2
Oxidation
N
NH
O
3a
Michael-Addition
B
Ph
Scheme 3. Control experiments and Possible reaction
mechanism
L. Shi, L. Xue, R. Lang, C. Xia and F. Li, ChemCatChem, 2014,
6, 2560.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., XXXX, XX, X-X | X
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Organic & Biomolecular Chemistry
8
9
J. Kim and S. H. Hong, Chem. Sci., 2017, 8, 2401.
View Article Online
DOI: 10.1039/C9OB01137D
(a) C.-J. Li, Acc. Chem. Res., 2009, 42,335; (b) O. Baudoin,
Chem. Soc. Rev., 2011, 40, 4902; (c) S.-R. Guo, P. S. Kumar
and M. Yang, Adv. Synth. Catal., 2017, 359, 2; (d) X.-Q. Chu,
D. Ge, Z.-L. Shen and T.-P. Loh, ACS Catal., 2018, 8, 258; (e) R.
R. Karimov and J. F. Hartwig, Angew. Chem. Int. Ed., 2018,
57, 4234.
10 (a) Z. Huang, Q. P. Sam and G. Dong, Chem. Sci., 2015, 6,
5491; (b) Z. Huang and G. Dong, J. Am. Chem. Soc., 2013,
135, 17747; (c) X. Jie, Y. Shang, X. Zhang and W. Su, J. Am.
Chem. Soc., 2016, 138, 5623; (d) H. Li, Q. Jiang, X. Jie, Y.
Shang, Y. Zhang, L. J. Gooßen and W. Su, ACS Catal., 2018, 8,
4777; (e) W. Guo, D. Liu, J. Liao, F. Ji, W. Wu, H. Jiang, Org.
Chem. Front., 2017, 4, 1107; (f) M. Tian, X. Shi, X. Zhang and
X. Fan, J. Org. Chem., 2017, 82, 7363; (g) Z. Yang, C. Liu, Y.
Zeng, J. Zhang, Z. Wang, Z. Fang and K. Guo, RSC Adv., 2016,
6, 89181; (h) Y. Shang, X. Jie, J. Zhou, P. Hu, S. Huang and W.
Su; Angew. Chem. Int. Ed., 2013, 52, 1299; (i) C. Wang and G.
Dong, J. Am. Chem. Soc., 2018, 140, 6057.
11 S. Ueno, R. Shimizu and R. Kuwano, Angew. Chem. Int. Ed.,
2009, 48, 4543.
12 X. Liang, X. Huang, M. Xiong, K. Shen and Y. Pan, Chem.
Commun., 2018, 54, 8403.
13 (a) F. Jia and Z. Li, Org. Chem. Front., 2014, 1, 194; (b) X.-H.
Yang, R.-J. Song, Y.-X. Xie and J.-H. Li; ChemCatChem, 2016,
8, 2429; (c) A. Piontek, E. Bisz and M. Szostak, Angew. Chem.
Int. Ed., 2018, 57, 11116; (d) R. Sreedevi, S. Saranya, K. R.
Rohit and G. Anilkumar, Adv. Synth. Catal., DOI:
10.1002/adsc.201801471.
14 S. Xiang, H. Chen and Q. Liu, Tetrahedron Lett., 2016, 57,
3870.
15 (a) Y. Wei, H. Ding, S. Lin and F. Liang, Org. Lett., 2011, 13,
1674; (b) J. K. Tucker and M. D. Shair, Org. Lett., 2019, 21,
2473; (c) Z. Wang, G. Chen, X. Zhang and X. Fan, Org. Chem.
Front., 2017, 4, 612; (d) D. K. Tiwari, M. Phanindrudu, S. B.
Wakade, J. B. Nanubolu and D. K. Tiwari, Chem. Commun.,
2017, 53, 5302.
Org. Biomol. Chem, XXXX, XX, X-X
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins