Synthesis of β-enaminodicarbonyl derivatives in the titanium(iv) chloride-promoted reactions of β-dicarbonyl compounds with nitriles

Article abstract of DOI:10.1039/c4ra05100a

Titanium(iv) chloride selectively promoted the nucleophilic attack of ethyl acetoacetate with nitriles to give enaminoketoesters, which were valuable intermediates for the syntheses of 2,3,4-substituted heterocyclics. Moreover a plausible mechanism for this transformation was given. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra05100a

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Synthesis of b-enaminodicarbonyl derivatives in
the titanium(IV) chloride-promoted reactions of
b-dicarbonyl compounds with nitriles†
Cite this: RSC Adv., 2014, 4, 38055
*
Shuchen Pei, Chenchen Xue, Li Hai and Yong Wu
Received 29th May 2014
Accepted 15th August 2014
Titanium(IV) chloride selectively promoted the nucleophilic attack of ethyl acetoacetate with nitriles to give
enaminoketoesters, which were valuable intermediates for the syntheses of 2,3,4-substituted heterocyclics.
Moreover a plausible mechanism for this transformation was given.
DOI: 10.1039/c4ra05100a
www.rsc.org/advances
Results and discussion
Introduction
Our study began with the C–C bonds formation of nitriles
with ethyl acetoacetate. Initially we examined direct
benzonitrile and acetoacetate in the presence of different
kinds of Lewis acid as a catalytic in toluene at 110 ꢀC. To our
surprise, the screening of different Lewis acid (Table 1,
entries 1–8) led to the discovery that TiCl4 was an effective
catalytic, forming the product in an encouraging yield of 65%
(Table 1, entry 7). Other additives such as SnCl4 (Table 1,
entry 3) and I2 (Table 1, entry 4) also promoted exclusive
generation of the product, but the yields are lower than when
TiCl4 used. However, FeCl3 (Table 1, entry 1), ZnCl2 (Table 1,
entry 2), CoCl2 (Table 1, entry 5), HgCl2 (Table 1, entry 6),
CuBr2 (Table 1, entry 8) did not activate the reaction
efficiently affording the product. With the aim of improving
the desired product yield, the equivalent of TiCl4 was
examined, and a stoichiometric amount of TiCl4 gave the
It is believed that b-enaminodicarbonyl derivatives have many
potential applications as biologically active compounds and as
precursors of substituted b-amino acids, heterocyclic systems,
and other classes of valuable compounds.1 As a consequence,
much attention has been paid to the development of an
appropriate method for the synthesis of b-enaminodicarbonyl
derivatives. Conceptually, many of these b-enaminodicarbonyl
derivatives should be available by the addition of appropriate
carbon nucleophiles to nitriles. In the past few years, promising
progress has been made in this area. Lee and coworkers2,3
demonstrated that the Blaise reaction, the addition of zinc
enolates derived from a-halo esters to nitriles, proceeded via
a zinc bromide complex of a b-enamino ester. However, this
reaction was quite limited due to the competitive
amino-acylated side product, as show in Scheme 1. So far, the
most popular route to b-enaminodicarbonyl derivatives is the
reaction of b-ketoesters with nitrile by using catalytic amounts
(1–5 mol%) of acetylacetonates of Ni(II), Co(II), Zn(II) or Cu(II),4À9
whereas tin(IV) chloride also promotes C–C bond formation.10À13
Therefore, in view of higher yield and for environmental
concern, the development of a direct synthetic method for
b-enaminodicarbonyl derivatives in the presence of Lewis acids
would be highly desirable. In this paper we reported
a
direct titanium(IV) chloride-promoted method for
b-dicarbonyl compounds with nitriles providing b-enaminodi-
carbonyl derivatives and their conversion to 3,4,5-substituted
heterocyclic.
Key Laboratory of Drug Targeting of Education Ministry, West China School of
Pharmacy, West China Hospital, Sichuan University, No. 37, GuoXue Road,
Chengdu 610041, P.R. China. E-mail: wyong@scu.edu.cn; Fax: +862885503666
† Electronic supplementary information (ESI) available: Copies of the 1H NMR
and 13C NMR spectra are required for all key intermediates and nal products;
additional information as needed. See DOI: 10.1039/c4ra05100a
Scheme 1 Synthetic protocols of enaminodicarbonyl derivatives.
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Table 1 Optimization of the reaction conditionsa
Table 2 TiCl4-promoted reactions of b-dicarbonyl compounds with
nitrilesa
Entry
Catalytic (mol)
Temperature
Solvent
Yieldb (%)
Entry
R1
R2
R3
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl3 (1.5)
ZnCl2 (1.5)
SnCl4 (1.5)
I2 (1.5)
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
C
C
C
C
C
C
C
C
C
C
C
C
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
NRc
NRc
57
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
82
88
92
74
56
68
70
85
76
78
70
65
60
80
2-NO2C6H4
4-NO2C6H4
2-MeOC6H4
2,4-Dimethoxy phenyl
2-ClC6H4
2-Methoxy-3-pyridyl
2-Furly
Benzyl
Styryl
Me
BrCH2CH2
Ph
23
CoCl2 (1.5)
HgCl2 (1.5)
TiCl4 (1.5)
CuBr2 (1.5)
TiCl4 (0.5)
TiCl4 (1.0)
TiCl4 (2.0)
TiCl4 (3.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
NRc
NRc
65
NRc
45
9
10
11
12
13
14
15
16
17
18
19
20
21
22
72
40
9
10
11
12
13
14
18
50 ꢀ
60 ꢀ
70 ꢀ
80 ꢀ
90 ꢀ
C
C
C
C
C
NRc
25
66
82
80
75
Ph
OC2H5
a
The reaction were carried out with 1 (1 mmol), 2 (1.2 mmol), solvent
(2 mL). b Isolated yield.
100 ꢀ
C
80 ꢀ
80 ꢀ
80 ꢀ
40 ꢀ
C
52
C
DMF
EtOH
DCM
NRc
30
C
C
45
(Table 2, entries 1–8) as well as aliphatic nitriles such as
benzyl cyanide acetonitrile, and 3-bromopropanenitrile
(Table 2, entries 9–12) were converted to their corresponding
b-enaminodicarbonyl derivatives 1a–14n in moderate to
excellent yield. Electron-decient aryl nitriles gave the
expected b-enaminodicarbonyl products in good-to-excellent
yield, which was much better than electron-rich one (Table 2,
entries 2–7). Many synthetically important functional groups,
such as alkoxy, alkyl, nitro and halogen were well-tolerated
under the optimal conditions. Moreover, adjacent
heteroatom substituted aryl nitriles reacted with ethyl
acetoacetate under our conditions to give the products in
higher yield, up to 85% (Table 2, entries 8). In the case of
other active b-dicarbonyl compounds such as acetyl acetone
and diethyl malonate, the yield was also desirable (Table 2,
entries 13 and 14). Therefore, these results clearly demon-
strated that titanium(IV) chloride serves as a useful Lewis acid
catalyst for the reaction of nucleophilic attack of ethyl
acetoacetate with nitriles.
Finally, application of this new metal-promoted method
in the synthesis of heterocyclic was tested. The resulting
b-enaminodicarbonyl derivatives were transformed to
pyrazoles, isoxazoles and isothiazoles, which are important
pharmacophores in various biologically active compounds.14
As show in Scheme 2, reaction of 3 with hydrazine hydrate,
hydroxylamine hydrochloride and phosphorus pentasulde
in appropriate solvent afforded the corresponding
3,4,5-trisubstituted pyrazoles, isoxazoles and isothiazoles in
good to excellent yields. These encouraging results indicated
a
The reaction were carried out with 1 (1 mmol), 2 (1.2 mmol), solvent
(2 mL). b Isolated yield based on 1a. c No reaction.
best yield compared with others (Table 1, entries 9–12).
Increase or decrease the equivalent of TiCl4 would reduce the
reaction yield. Given that temperature might play an
important role in this reaction, we tested the temperature
from 50 ꢀC to 100 ꢀC (Table 1, entries 13–18). It was found out
that this rꢀeaction could provide the most efficient yield of
82% at 80 C. At higher temperatures the by-products would
show up, however, the remaining ingredients were the key
factors affecting the yield at lower temperatures. Interest-
ingly, the choice of solvent exerted great inuence on the
reaction yield (Table 1, entries 19–22). Evaluation of various
organic solvents in the presence of TiCl4 revealed that
toluene provided the best yield. Polar aprotic solvents, such
as DMF and DMSO did not effectively improve the reaction
yields. Running the reaction in polar protic solvent such as
ethanol only afforded a small amount of desired product.‡
With these optimized conditions in hand, we proceeded
to investigate the substrates of nitriles. Aromatic nitriles
‡ A representative procedure for the synthesis of 3a: To a solution of the
benzonitrile (1 mmol), TiCl4 (1 mmol) and ethyl acetacetate (1.2 mmol) were
added at room temperature with stirring. The mixture was reuxed with stirring
for
2 h. Aer 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 puried by ash column chromatography on silica gel.
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Notes and references
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involves the formation of a Ti-enolate by interaction of TiCl4
with ethyl acetoacetate and in this step the HCl will go out
rst. Then corresponding Ti-enolate that formed will
attack on the nitrile to generate a N–Ti–O cyclic intermediate
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Conclusions
In conclusion, we have successfully developed the metal-
promoted reaction of b-dicarbonyl compounds with nitriles
using the readily available reagent TiCl4. The reaction could
be carried out under mild conditions and was compatible
with many functional groups. This reaction provides a
straightforward, practically useful way to prepare various
b-enaminodicarbonyl derivatives.
Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (NSFC) (grant numbers 81102324
and 81373259).
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