Reactions of β-diketone compounds with nitriles catalyzed by Lewis acids: A simple approach to β-enaminone synthesis

Article abstract of DOI:10.1039/c4ra10879e

Aluminium chloride selectively promoted the nucleophilic attack of β-diketone compounds with nitriles to give enaminones. Moreover a plausible mechanism for this transformation was given.

Full text of DOI:10.1039/c4ra10879e

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: X. Cheng, S. Pei,
C. Xue, K. Cao, L. Hai and Y. Wu, RSC Adv., 2014, DOI: 10.1039/C4RA10879E.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, 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. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this 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 shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 5
RSC Advances
View Article Online
DOI: 10.1039/C4RA10879E
Jour nal Name
RSCPublishing
ARTICLE
Reactions of βꢀDiketone Compounds with Nitriles
Catalyzed by Lewis Acids: a simple approach to βꢀ
enaminone synthesis
Cite this: DOI: 10.1039/x0xx00000x
Xu Cheng, Shuchen Pei, a Chenchen Xue, a Kaifei Cao, b Li Hai a and Yong Wu*a
a
Received 00th January 2012,
Accepted 00th January 2012
Aluminium chloride selectively promoted the nucleophilic attack of βꢀdiketone compounds
with nitriles to give enaminones. Moreover a plausible mechanism for this transformation
was given.
DOI: 10.1039/x0xx00000x
www.rsc.org/
by Lewis acid has not been systematically researched. These
products could be a useful intermediate for the synthesis of
Introduction
bioactive heterocyclic molecules such as pyrazoles, isothiazole
and isoxazole. However, poor reaction selectivity was found
when a mixture of acetylacetone and aromatic nitrile was
treated under titanium(IV) chloride conditions. We
hypothesized that the reaction selectivity could be controlled by
using an appropriate Lewis acid catalyst. Our own interest is
looking for an efficient and general Lewis acid as a catalyst in
Enaminones are important synthetic intermediates and building
blocks for drug development1 and natural product synthesis2. For
example, they have been successfully used for synthesis of drug
(anticonvulsants3, antiꢀinflammatory agents4, and antitumor agents5)
and bioactive heterocycles (pyridinones, quinolones, pyrroles,
6
isoxazoles, indole, and polyazaheterocycles) . Moreover, they are
widely applied in functional group transformation in the field of
organic chemistry, including βꢀalkoxyvinyl ketone enamination7,
1,2ꢀaryl migration8, 1,3ꢀdicarbon enamination9, dehydrogenation10,
lithiated enamine acylation11, and the Sonochemical Blaise
reaction12. In coordination chemistry, some βꢀenaminones can be
used as good chelating ligands for main group and transition
metals13. Therefore, the development of convenient and efficient
methods for the synthesis of enaminones has attracted considerable
attention. Over the past decades, numerous techniques have been
developed for the construction of enaminones, which includes the
direct condensation reaction of 1,3ꢀdicarbonyl compounds with
amines14, and cleavage of heterocycles to some novel
unconventional routes15. In addition, the metalꢀpromoted reaction of
1,3ꢀdicarbonyl compounds to activated nitrile compounds have been
successfully employed in the synthesis of enaminones16. Despite the
success of these approaches in obtaining various enaminones, these
methods frequently suffer from certain disadvantages such as harsh
reaction conditions, unsatisfactory yields, and the need to use special
starting materials.
synthesis of βꢀenaminones 4a
.
Scheme 1. Synthetic protocols of enaminone derivatives
Several Lewis acid catalyst systems were investigated to
test this hypothesis. The reaction of benzonitrile 1a with
acetylacetone 2a was chosen as a model to optimize the
reaction conditions. The results are summarized in table 1.
Various Lewis acid catalysts such as SnCl4, CuCl2, AlCl3,
.
FeCl3, I2, BF3 Et2O, TiCl4, Ni(AcAc)2 and Co(AcAc)2 were
used. Among these catalysts, AlCl3 and BF3 exhibited the
higher catalyst selectivity (Table 1, entries 5 and 10). In
addition, the screening of different Lewis acid (Table 1, entries
1ꢀ15) led to the discovery that AlCl3 was the most effective
catalytic, forming the product 4a in an encouraging yield (Table
1, entry 5). The temperature (Table 1, entries 16ꢀ20) and
solvent (Table 1, entries 5, 21ꢀ28) were finally screened.
Results and discussion
Recently, we reported the preparation of βꢀenaminodicarbonyl
derivatives in the titanium(IV) chlorideꢀpromoted reactions of
βꢀdicarbonyl compounds with nitriles17. However, when we
examined benzonitrile 1a with acetylacetone 2a in the presence
of titanium(IV) chloride, we found the yield of desired product
3a was low because of a side product. After separation and
confirmation of this side product, to our surprise, the side
product was deacetylated product of 3a, as show in Scheme 1.
To the best of our knowledge, the addition reaction of βꢀ
diketone to activated nitriles to produce enaminones catalyzed
o
Toluene and 100 C were identified as the best solvent and
reaction temperature, respectively. Therefore, in view of
catalytic selectivity, higher yield and for environmental
concern, the reactions of βꢀdiketone compounds with nitriles
o
were performed in the presence of AlCl3 in toluene at 100 C
for 4 h.
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 |
1

RSC Advances
Page 2 of 5
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C4RA10879E
Table 1 Reaction condition screeninga
acid catalyst for the addition reaction of ketones to activated
nitriles to produce enaminones.
Table2. The reactions of βꢀdiketone compounds with nitrilesa
Yieldb Yieldb
Entr
y
Catalyst Solvent Temperature (%)
3a
(%)
4a
1
2
3
4
5
6
7
8
9
SnCl4
NiCl2
CuCl2
ZnCl2
AlCl3
FeCl3
I2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
80oC
60oC
70oC
90oC
100oC
110oC
100oC
100oC
80oC
40oC
65oC
80oC
100oC
100oC
28
Trace
15
Trace
10
32
Trace
Trace
Trace
70
Yieldb (%) Yield (%)b
Entry
R1
Ph
R2 R3
3
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Me Me
12
8
78
80
71
67
72
56
35
68
55
38
70
67
65
71
53
45
61
35
10
4ꢀNO2C6H4 Me Me
2ꢀNO2C6H4 Me Me
Benzyl
Styryl
<10
Trace
Trace
68
60
Trace
17
<10
Trace
Trace
Trace
13
Trace
Trace
Trace
Trace
15
55
75
78
70
Trace
Trace
Trace
52
38
Trace
45
11
15
10
18
20
12
18
16
CoCl2
Me Me
Me Me
Me Me
PdCl2
.
10 BF3 Et2O Toluene
11
12
13 Ni(AcAc)2 Toluene
14 Co(AcAc)2 Toluene
15 Ce(BuAc)2 Toluene
2ꢀFuryl
TiCl4
CeCl3
Toluene
Toluene
2ꢀMeOC6H4 Me Me
Me Me Me
C2H5OCOCH2 Me Me
15
Ph
Ph
Ph
Ph Me
Trace
<10
<10
10
tꢀBu tꢀBu Trace
16
17
18
19
20
21
22
23
24
25
26
27
28
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
DMF
EtOH
DCM
THF
AcOH
Ph Ph
Me Me
Trace
12
8
21
27
2ꢀClC6H4
BrCH2CH2 Me Me
4ꢀHOC6H4 Me Me
12
<10
<10
Trace
Trace
<10
<10
Trace
Trace
Trace
p 4ꢀHOC6H4CH2 Me Me
q CH3OCOC6H4 Me Me
20
a
Reaction conditions: aluminium chloride (1 mmol), nitriles
1
o
(1 mmol), βꢀdiketone
2 (1.2 mmol) and solvent (2ml) 100 C
for 4h. b Isolated yield.
Moreover, the product
3 could be also transformed to 4 in
Dioxane
Pyridine
the presence of catalytic amounts of hydrochloric acid at room
temperature18. And when benzonitrile 1a was treated with
cyclohexanedione 2m under the optimized conditions, a
mixture of enaminone 3r (20%) and 4r (42%) were obtained
(Scheme 2).
Trace
a Reaction conditions: Lewis acid catalyst (1 mmol),
benzonitrile 1a (1 mmol), acetylacetone 2a (1.2 mmol) and
solvent (2ml) for 4 h. b Isolated yield.
The reactions of βꢀdiketone compounds
2 with nitriles 1
Scheme 2.
were performed under optimized conditions to determine the
scope of βꢀdiketone substrates. The results are summarized in
Table 2. The desired product enaminone 4a was isolated in 75%
yield from the reaction of 1a with 2a (Table 2, entry 1).
Satisfactory yields similar to that of 4b
4ꢀnitrobenzonitrile 1b), 2ꢀnitrobenzonitrile
phenylacetonitrile (1d), cinnamonitrile (1e
carbonitrile 1f were tested under optimized reaction
ꢀ
4f were observed when
1c), 2ꢀ
and furanꢀ2ꢀ
(
(
)
(
)
conditions (Table 2, entries 2ꢀ6, 56ꢀ80%). The desired product
enaminone 4g was isolated in only 35% yield even prolonged
the reaction time to 12 h (Table 2, entry 7). These results
suggested that the reactivity of the nitrile substrate was
remarkably influenced by the electronic property of the
substituent of the benzene ring of nitrile. The reactivity of
aromatic nitriles could be reduced by an electronꢀdonating
group linked to a benzene ring. Enaminone 4h was obtained in
a moderate yield when acetonitrile (1h) was tested (Table 2,
entry 8, 68%). The reaction of unsymmetrical ketone 2j
regioselectively occurred on the less sterically hindered αꢀ
carbon atom (Table 2, entry 10). The enaminone products 4k
and 4l were obtained in 70% and 67% yields, respectively
(Table 2, entries 11ꢀ12). Therefore, these results clearly
demonstrated that aluminium chloride serves as a useful Lewis
Therefore, a plausible reaction mechanism for aluminium
chlorideꢀpromoted reactions of βꢀdiketones was presented in
Scheme 3. The first step of the mechanism involves the
formation of an Alꢀenolate by interaction of AlCl3 with βꢀ
diketone. Then the corresponding Alꢀenolate that formed will
attack on the nitrile to generate a NꢀAlꢀO cyclic intermediate
17. A part of intermediate 17 can be intercepted by the Alꢀ
enolate to produce the product 3. At the same time, the acetyl
groups in another part of intermediate 17 would leave first
because of the existence of hydrogen ion to form intermediate
18, which can be also intercepted by the Alꢀenolate to produce
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 5
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C4RA10879E
the product
part of product
4
. Besides, with the influence of hydrogen ion, a
could be transformed into product
We are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant numbers
81102324 and 81373259).
3
4.
Scheme 3.
Notes and references
a
Key Laboratory of Drug Targeting and Drug Delivery system of
Education Ministry, Department of Medicinal Chemistry, West China
School of Pharmacy, West China Hospital, Sichuan University, No. 37,
GuoXue
Road,
Chengdu
610041,
P.R.
China.
Eꢀmail:
wyong@scu.edu.cn; Fax: +862885503666
b
Clinical Medicine School, Chengdu university of Traditional Chinese
Medicine, No. 37 12ꢀbridge road, Chengdu, 610075, P.R.China.
‡ the synthesis of
3 and 4: To a solution of the benzonitrile (1 mmol) in
toluene (2ml), AlCl3 (1 mmol) and acetylacetone (1.2 mmol) were added
o
at room temperature with stirring. The mixture was heated at 100 C with
stirring for 4 h. Afer cooling to room temperature, saturated sodium
carbonate solution was added, and the mixture was extracted with EtOAc.
The combined organic phases were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel.
1
2
G. Negri, C. Kascheres and A. J. Kascheres, J. Heterocycl. Chem.,
2004, 41, 461.
Finally, application of this new Lewis Acids catalyzed
method in the synthesis of heterocyclic frameworks was tested.
The resulting βꢀenaminone derivatives can be transformed to
various biologically active compounds. For example, the key
intermediate 21, prepared from commercially available 2ꢀ
aminoacetonitrile 19 by two steps, proceeds smoothly under the
optimized reaction conditions, affording the desired product 23
in 72% yield, which was an important building block for the
synthesis of FGFR inhibitor derivatives (Scheme 4).
(a) N. D. Eddington, D. S. Cox, M. Khurana, N. N. Salama, J. P.
Stables, S. J. Harrison, A. Negussie, R. S. Taylor, U. Q. Tran, J. A.
Moore, J. C. Barrow and K. R. Scott, Eur. J. Med. Chem., 2003, 38
,
49; (b) M. M. Abdelkhalik, A. M. Eltoukhy, S. M. Agamy and M.
H. Elnagdi, J. Heterocycl. Chem., 2004, 41, 431.
3
(a) I. O. Edafiogho, C. N. Hinko, H. Chang, J. A. Moore, D.Mulzac,
J.M. Nicholson and K. R. Scott, J. Med. Chem., 1992, 35, 2798; (b)
K. R. Scott, I. O. Edafiogho, E. L. Richardson, V. A. Farrar, J. A.
Moore, E. I. Tietz, C. N. Hinko, H. Chang, A. ElꢀAssadi and J. M.
Nicholson, J. Med. Chem., 1993, 36, 1947; (c) K. R. Scott, G.O.
Rankin, J. P. Stables, M. S. Alexander, I. O. Edafiogho, V. A.
Farrar, K. R. Kolen, J. A. Moore, L. D. Sims and A. D. Tonnu, J.
Med. Chem., 1995, 38, 4033.
O
O
OH2N
CN
a
b
c
N
H2N
CN
N
O
O
20
19
21
O
O
N
O
N
O
4
5
6
G. Dannhardt, A. Bauer and U. Nowe, J. Prakt. Chem./Chem.-Ztg.,
1998, 340, 256.
N
d
O
HN
N
N
H2N
D. L. Boger, T. Ishizaki, J. R. J. Wysocki, S. A. Munk, P. A. Kitos
and O. Suntornwat, J. Am. Chem. Soc., 1989, 111, 6461.
HN
N
NH
22
23
N
I
(a) A. Alberola, L. A. Calvo, A. G. Ortega, M. C. S. Ruı´z and P.
Yustos, J. Org. Chem., 1999, 64, 9493; (b) R. Bernini, S. Cacchi, G.
Fabrizi and A. Sferrazza, Synthesis, 2009, 1209; (c) M. N. Eberlin
and C. Kascheres, J. Org. Chem., 1988, 53, 2084; (d) F. AlꢀOmran
and A. A. ElꢀKhair, J. Heterocycl. Chem., 2005, 42, 307; (e) A.
Mu¨ller, A. Maier, R. Neumann and G. Maas, Eur. J. Org. Chem.,
1998, 1177; ( f ) E. Bejan, H. Aı¨tꢀHaddou, J. C. Daran and G. G. A.
Balavoine, Eur. J. Org. Chem., 1998, 2907.
24
Scheme 4. (a) phthalic anhydride, TEA, CHCl3, 60 oC, 6 h; (b)
acetylacetone, AlCl3, 100 oC, 4 h; (c) NH4OH.HCl, EtOH, 80 oC, 1 h;
o
(d) N2H4, EtOH, 80 C, 2 h.
Conclusions
In conclusion, we have successfully developed the Lewis
acid catalyzed reaction of βꢀdiketone compounds with nitriles
using the readily available reagent AlCl3. The reaction could be
carried out under mild conditions and was compatible with
7
(a) M. A. P. Martins, A. F. C. Flores, G. P. Bastos, A. Sinhorin, H. G.
Bonacorso and N. Zanatta, Tetrahedron Lett., 2000, 41, 293; (b) H.
G. Bonacorso, R. V. Lourega, A. D. Wastowski, A. F. C. Flores, N.
Zanatta and M. A. P. Martins, Tetrahedron Lett., 2002, 43, 9315; (c)
N. Zanatta, D. M. Borchhardt, S. H. Alves, H. S. Coelho, A. M. C.
Squizani, T. M. Marchi, H. G. Bonacorsoa and M. A. P. Martinsa,
Bioorg. Med. Chem., 2006, 14, 3174; (d) S. V. Druzhinin, E. S.
Balenkova and V. G. Nenajdenko, Tetrahedron, 2007, 63, 7753.
many functional groups. This reaction will provide
a
straightforward, practically useful way to prepare various
enaminones derivatives.
Acknowledgements
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 |
3

RSC Advances
Page 4 of 5
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA10879E
8
9
N. Jiang, Z. Qu and J. Wang, Org. Lett., 2001, 3, 2989.
(a) B. Rechsteiner, F. TexierꢀBoullet and J. Hamelin, Tetrahedron
Lett., 1993, 34, 5071; (b) A. Amougay, O. Letsch, J. P. Pete and O.
Piva, Tetrahedron, 1996, 52, 2405; (c) C. Calvet, O. David, C.
VanucciꢀBacque´, M. C. Fargeau Bellassoued and G. Lhommet,
Tetrahedron, 2003, 59, 6333; (d) A. R. Khosropour, M. M. Khodaei
and M. Kookhazadeh, Tetrahedron Lett., 2004, 45, 1725; (e) Z. H.
Zhang, L. Yin and Y. M. Wang, Adv. Synth. Catal., 2006, 348, 184;
( f ) F. Epifano, S. Genovese and M. Curini, Tetrahedron Lett.,
2007, 48, 2717.
10 S. Fustero, B. Pina, M. G. de la Torre, A. Navarro, C. R. de Arellano
and A. Simo´n, Org. Lett., 1999, , 977.
1
11 G. Bartoli, C. Cimarelli, R. Dalpozzo and G. Palmieri, Tetrahedron
,
1995, 51, 8613.
12 A. S. Y. Lee, R. Y. Cheng and O. G. Pan, Tetrahedron Lett, 1997, 38
,
443.
13 X. Xu, P. Du, D. Cheng, H. Wanga and X. Li, Chem. Commun.,
2012, 48, 1811.
14 (a) G. Hamid; R. Ehsan; B. Giuseppeh; R. H. Amiri, Inorganica
Chim Acta., 2013, 394, 1ꢀ9, ; (b) K. Ryuichi; F. Masahiro; H.
Mariko; F, Masafumi; K, Tomoji; N, Matsuhisa; F, Toshio., Chem
Pharm Bull., 1995, 43, 450ꢀ60, ; (c) X. S. Liang; L. C. Ping; L. J.
Hua., Synlett, 2009, 5, 818ꢀ822, ; (d) S. Xiaoqian; L. Youran; Z.
Daisy; D. Yunfei; Z. Kang., Org. Lett, 2013, 15, 6222ꢀ6225; (e) H.
Paul; B. Sarah; R. HansꢀUlrich., Synthesis, 2013, 45, 3288ꢀ3294; (f)
S. Masaharu; K. Mako; N. Makoto., Chem. Commun, 2009, 24
,
3585ꢀ3587.
15 (a) S. Petr; Bertolasi, V. P. Marketa; M. Vladimir; L. Antonin., Org
Biomol Chem, 2005, , 1217ꢀ1226; (b) A. Kinya; K. Kohichi; O.
3
Yoshihiko; Y. Yohsuke; O. Katsuo., J Am Chem Soc, 1985, 107
,
,
2721ꢀ30; (c) K. Szabolcs and N. Zoltan., Tetrahedron, 2013, 69
8987ꢀ8993; (d) S. Sergey I.; V. Andrei A.; S. Sergey V.,
Tetrahedron, 2007, 63, 12195ꢀ12201.
16 (a) Y. Xiaoqiang, W. Longxiang, F. Xiujuan; B. Ming, Y. Yoshinori,,
Chem. Commun, 2013, 49, 2885ꢀ2887; (b) Basato, M., Corain, B.,
Veronese, A. C., D'Angeli, F., Valle, G., Zanotti, G. J. Org. Chem.
,
1984, 49, 4696ꢀ700; (c) C. V. Augusto, G. Vittorio, C. Benedetto, B.
Marino., J Mol Catal, 1986, 36, 339ꢀ41; (d) M. Raimondo, B.
Giovanna, G. Stefano, O. Chiara, S. Giovanni.. Green Chem, 2005,
7, 182ꢀ184; (e) C. Ben, H. Eric G., St. Alison M., Chem. Commun,
2003. 19, 2430ꢀ2431.
17 P. Shuchen, X. Chenchen, H. Li, W. Yong. RSC Adv., 2014, 4, 38055
18 (a) C. Ying, Z. Min, W. Meixiang, W. Liben, H. Zhitang. Synthetic
communications, 1995, , 1339ꢀ1351; (b) T. Oishi, M. Nagai, T.
9
Onuma, H. Moriyama, K. Tsutae, M. Ochiai, Y. Ban. Chem. Pharm.
Bull, 1969, 17, 2306ꢀ2313
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C4RA10879E
286x60mm (96 x 96 DPI)