Detrifluoroacetylation Reaction of Trifluoromethyl-β-diketones: Facile Method for the Synthesis of Succinimide Derivatives and 1,4-Diketones

Article abstract of DOI:10.1002/ejoc.201800680

Currently, a great deal of research efforts are focused on C–C bond activation for development of novel synthetic methodology. In this paper, a detrifluoroacetylation of trifluoromethyl-β-diketones is described, which allows for the synthesis of succinimides and 1,4-diketones through cascade Michael addition/retro-Claisen reaction and nucleophilic substitution/retro-Claisen reaction. The readily available trifluoromethyl-β-diketones, wide substrate scope, and mild conditions make this method very practical.

Full text of DOI:10.1002/ejoc.201800680

DOI: 10.1002/ejoc.201800680
Communication
C–C Bond Cleavage
Detrifluoroacetylation Reaction of Trifluoromethyl-ꢀ-diketones:
Facile Method for the Synthesis of Succinimide Derivatives and
1,4-Diketones
Li-Hua Wang[a] and Jing Zhao*[a]
Abstract: Currently, a great deal of research efforts are focused dition/retro-Claisen reaction and nucleophilic substitution/
on C–C bond activation for development of novel synthetic retro-Claisen reaction. The readily available trifluoromethyl-ꢀ-
methodology. In this paper, a detrifluoroacetylation of trifluoro- diketones, wide substrate scope, and mild conditions make this
methyl-ꢀ-diketones is described, which allows for the synthesis method very practical.
of succinimides and 1,4-diketones through cascade Michael ad-
Introduction
Organofluorine compounds are of great importance in the
pharmaceutical and agrochemical industries, as well as in mate-
rials sciences. In the last decades, a great deal of research efforts
was focused on the new methodologies for the synthesis of
organofluorine compounds. Many C–F bond forming reactions
and fluorinated building blocks are available.[1] However, reac-
tions allowing the cleavage of C–F bond or the release of fluor-
inated moieties had been largely unexplored.[2] Recently, the
synthetic utility of 1,1,1,3,3-pentafluoro-2,4-dione 1 and 1,1,1,3-
tetrafluoro-2,4-dione 2 was investigated due to their unique re-
activity (Scheme 1). These organofluorine compounds are easily
accessible from a wide range of available simple ketones and
fluorine reagents. As shown in Scheme 1, the synthetic strategy
relied on the haloform-type reaction, which led to the
C–C bond cleavage and detrifluoroacetylation.[3] New C–C or
C–heteroatom bonds were formed simultaneously through
Aldol addition, Mannich addition, Michael addition, substitution
Scheme 1. The C–C bond cleavage of organofluorine compounds.
Results and Discussion
or halogenation. Although these novel transformations of com-
pounds 1 and 2 have been reported, the direct detrifluoroacet-
ylative reactions of 1,1,1-trifluoromethyl-ꢀ-diketone 3 are rare.[4]
Compound 3 can be easily prepared by Claisen reaction with
various ketones and trifluoroacetates. Therefore, the synthetic
methodology based on the application of compound 3 will be
attractive. Herein, we present an efficient synthetic approach to
succinimide derivatives and 1,4-diketons utilizing trifluoro-
methyl-ꢀ-diketones synthons. The succinimide derivatives are a
well-known class of compounds, they serve as important inter-
mediates in organic synthesis, and moreover, they frequently
display potent and diverse biological activity.[5]
At the outset, we explored the reaction using 4,4,4-trifluoro-1-
phenyl-ꢀ-butanedione 3a and N-phenylmaleimide 4a as model
substrates (Table 1). In the presence of NaOH (2.0 equiv.) in
CH2Cl2 at 60 °C, the desired product 5aa was obtained in 32 %
isolated yield. The reaction afforded 5aa in low to moderate
yields by use of weak bases such as K2CO3, (NH4)2CO3 and
AcONa (Entries 2–4). To our delight, an improved yield of 5aa
was observed using NaHCO3 (Entry 5). We further found that
phase-transfer catalyst (PTC) nBu4NI promoted the reaction effi-
ciently and the yield of 5aa could be enhanced to 85 % (entry
5). Other PTCs such as nBu4NBr and (nBu4N)2SO4 could also
catalyze this Michael addition/detrifluoroacetylation reaction to
give comparable yields (Entries 7 and 8). However, when the
reaction was performed in other solvents including DCE, THF
and AcOEt, the decreased yields of 5aa were observed and the
starting materials were reclaimed. (Entries 9–11). In order to
obtain high yields and complete consumption of starting mate-
[a] Tianjin Vocational College Of Bioengineering,
Tianjin 300462, P. R. China
E-mail: jingzhao20080823@126.com
http://www.tjbio.cn
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800680.
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Communication
rials, the addition of 10 equiv. of water is necessary. Decreasing ety of functional groups, including halides, ester, ether, nitro or
or increasing the amounts of water led to the low efficiency cyano groups, and gave the corresponding products 5 in 58–
(Table 1, Entries 12 and 13).
98 % yield. It was observed that phenyl containing electron-
withdrawing substituents lead to better yields, while the posi-
tion on the phenyl had no notable influence. The scope was
also extended to the heterocycle-substituted 1,1,1-trifluoro-
methyl-ꢀ-diketones, including furan and thiophene, which af-
forded the desired products 5ra–sa in good to excellent yields
(78–98 %). When N-methyl and N-benzyl maleimides were sub-
jected to the reaction conditions, the desired products were
obtained in 92 % and 98 % yield, respectively (Table 2, 5rb and
5rc).
1,4-Diketones and their derivatives represent interesting
classes of natural and synthetic compounds that display a wide
range of biological properties. Moreover, they serve as impor-
tant intermediates for the synthesis of cyclopentenones, diols,
and some heterocycles, such as furans, pyrroles, pyridazine,
thiophenes, and pyrrolidines.[6] We next investigated the substi-
tution/detrifluoroacetylation strategy for the synthesis of 1,4-
diketones using α-bromo ketones as electrophilic reagents. As
shown in Table 3, the cascade reactions of phenacyl bromide 6
with a range of trifluoromethyl-ꢀ-diketones 3 took place
smoothly by using K2CO3 in a combination ethyl acetate and
water, affording the desired products 7 in 30–95 % yield. The
Table 1. Screening of reaction conditionsa.
Entry
Base
PTC
Solvent
Yield
1
NaOH
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
32
45
29
49
73
85
82
80
69
51
63
60
71
2
K2CO3
–
3
4
(NH4)2CO3
AcONa
–
–
5
6
7
8
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
–
nBu4NI
nBu4NBr
(nBu4N)2SO4
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
9
10
11
12[b]
13[c]
THF
AcOEt
CH2Cl2
CH2Cl2
[a] Reaction conditions: 3a (1.0 mmol), 4a (0.5 mmol), Base (1.0 mmol), PTC
(20 mol-%) and H2O (5.0 mmol) in 3.0 mL of solvent; isolated yields. [b] H2O
(4.0 mmol). [c] H2O (6.0 mmol).
Table 3. Substrate scope of trifluoromethyl-ꢀ-diketones and α-bromo ke-
tonesa.
With the optimized reaction conditions in hand, the sub-
strate scope of the reaction was evaluated by conversion of
various 1,1,1-trifluoromethyl-ꢀ-diketones 3 with maleimides 4
(Table 2). The reaction conditions were compatible with a vari-
Table 2. Substrate scope of trifluoromethyl-ꢀ-diketones and maleimides.[a]
[a] Reaction conditions: 3 (1.0 mmol), 4 (0.5 mmol), NaHCO3 (1.0 mmol),
nBu4NI (20 mol-%) and H2O (5 mmol) in CH2Cl2 (3.0 mL); isolated yields.
[a] Reaction conditions: 3 (2.0 mmol), 6 (0.5 mmol), K2CO3 (1.25 mmol) in
mixtures of AcOEt (1.8 mL) and H2O (0.2 mL); isolated yields.
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Communication
reaction conditions were mild, and 1,1,1-trifluoromethyl-ꢀ-di- basic conditions. A retro-Claisen reaction takes place from A to
ketones containing electron-donating (EDG) and electron-with- the final product 5.[3k,7] First, A isomerizes to the enolate B,
drawing aryl groups (EWG) were both tolerated. Compared with which then undergoes intramolecular addition to the acyl
EWGs, substrates with EDGs could give the products in better group to give intermediate C.[4c] The C–C bond cleavage and
yields. Unfortunately, EWGs such as cyano and nitro only af- isomerization of C affords intermediate D. Finally, D gives prod-
forded the corresponding products in low yields (Table 3, 7ia uct 5 through hydrolysis. Similarly, a cascade substitution/retro-
and 7ja). The substrates bearing a larger aryl substituent such Claisen reaction can account for the pathway of synthesis of
as a naphthyl group was also successfully transformed to the 1,4-diketones. Under basic conditions, the direct nucleophilic
corresponding 1,4-diketones (7ta and 7ua). We were pleased addition of hydroxyl ion to trifluoroacetyl groups of A and E to
to find that even the aliphatic substrate 1,1,1-trifluoropentane- form corresponding intermediates B′ and E′ is also possible.
2,4-dione 6v was smoothly transformed to 1,4-diketone 7va in
74 % yield. The substitution/detrifluoroacetylation reactions of
various α-bromo ketones with thiophenyl trifluoromethyl-ꢀ-di-
Conclusions
ketone 3r were then investigated. Both aryl and alkyl α-bromo
In summary, we have developed a facile method for the synthe-
ketones were converted to desired 1,4-diketones in good to
sis of succinimide derivatives and 1,4-diketones through detri-
excellent yields (7ra–7rl). It is noteworthy that para-bromo-
fluoroacetylation reaction of trifluoromethyl-ꢀ-diketones. The
phenacyl bromide 6h gave a better result than the meta-and
cascade detrifluoroacetylation/Michael addition and detri-
ortho-bromo isomers (7ri–7rj). Finally, the substrate scope was
fluoroacetylation/substitution are compatible with a variety of
extended to readily available bromoacetone 6m, which gave
functional groups. A retro-Claisen reaction pathway for the
the desired product 7rm in 67 % yield.
C–C bond cleavage is suggested. Other novel applications of
trifluoromethyl-ꢀ-diketones as synthons in organic synthesis is
underway in our laboratory.
A plausible mechanism for this transformation is illustrated
in Scheme 2. Initially, Michael addition of trifluoromethyl-ꢀ-di-
ketone 3 with maleimide produces an enolic adduct A under
Experimental Section
Synthesis of Succinimide Derivatives 5aa: A 50 mL round-
bottomed flask with a magneton was charged with trifluoromethyl-
ꢀ-diketones 3a (6.0 mmol, 2.0 equiv.) and NaHCO3 (6.0 mmol,
2.0 equiv.) under air at room temperature, and then N-phenyl
maleimide 4a (3.0 mmol, 1.0 equiv.), nBu4NI (20 mol-%), H2O
(5.0 mmol) and in CH2Cl2 (10.0 mL) were added. After the mixture
was stirred at 60 °C for 15 h, the resulting residue was mixed with
silica gel and concentrated. The resulting mixture was purified by
silica gel column chromatography on silica gel with petroleum
ether/ethyl acetate (15:1) as eluent to give the desired product 5aa
(72 %).
Synthesis of 1,4-Diketones (7aa): To a mixture of 3a (4.0 mmol,
2 equiv.), K2CO3 (2.5 mmol), 6a (2.0 mmol, 1 equiv.) in a Schlenk
tube was added EtOAc (3.6 mL) and H2O (0.4 mL). The mixture was
stirred at 60 °C for 8 h. After cooling to room temperature, the
reaction mixture was diluted with HCl aqueous solution (3 %,
20 mL) and extracted with EtOAc (15 mL × 3). The combined ex-
tracts were washed with brine (15 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (ethyl acetate/petroleum
ether, v/v1:20 to v/v = 1:5) to give product 7aa (76 %).
Acknowledgments
We gratefully acknowledge Tianjin Vocational College of Bio-
engineering for the funding support (No. 201610055).
Keywords: Synthetic methods · Cleavage reactions ·
Detrifluoroacetylation · Retro-Claisen reaction ·
Succinimides · 1,4-Diketones
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Received: May 3, 2018
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Communication
C–C Bond Cleavage
L.-H. Wang, J. Zhao* ......................... 1–5
Detrifluoroacetylation Reaction of
Trifluoromethyl-ꢀ-diketones: Facile
Method for the Synthesis of Succin-
imide Derivatives and 1,4-Diketones
A detrifluoroacetylation of trifluoro- through cascade Michael addition/
methyl-ꢀ-diketones has been devel- retro-Claisen reaction and nucleophilic
oped, which allows for the synthesis of substitution/retro-Claisen reaction.
succinimides
and
1,4-diketones
DOI: 10.1002/ejoc.201800680
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim