1,5-Diketones Synthesis via Three-Component Cascade Reaction

Article abstract of DOI:10.1002/adsc.201500691

A mild and efficient cascade synthesis of 1,5-diketones from readily available N,N-dicyclohexylmethylamine, 1,3-dicarbonyl compounds, and trifluoromethyl β-diketones has been developed. This cascade reaction occurs via an oxidation/Mannich reaction/Cope elimination/Michael addition/retro-Claisen reaction sequence, and provides multiple C-C bond formations in one pot. In addition, exquisite chemoselectivity is achieved in the reaction between 1,3-dicarbonyl compounds and trifluoromethyl β-diketones.

Full text of DOI:10.1002/adsc.201500691

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DOI: 10.1002/adsc.201500691
1,5-Diketones Synthesis via Three-Component Cascade Reaction
Li-Juan Xing,a Tao Lu,a Wei-Li Fu,a Mei-Mei Lou,a Bo Chen,a Zhi-Shen Wang,a
Yang Jin,a Dan Li,a and Bin Wanga,b,*
a
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300071,
Peopleꢀs Republic of China
b
Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
Fax: (+86)-22-2350-7760; phone: (+86)-22-2350-6290; e-mail: wangbin@nankai.edu.cn
Received: July 20, 2015; Revised: August 17, 2015; Published online: October 13, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500691.
Abstract: A mild and efficient cascade synthesis of
1,5-diketones from readily available N,N-dicyclo-
hexylmethylamine, 1,3-dicarbonyl compounds, and
trifluoromethyl b-diketones has been developed.
This cascade reaction occurs via an oxidation/Man-
nich reaction/Cope elimination/Michael addition/
retro-Claisen reaction sequence, and provides mul-
age, the final products are limited to symmetrical ad-
ducts.[2,3] The synthesis of unsymmetrical adducts by
this method is still challenging. To realize this goal,
the carbon nucleophile Nu2 must be able to react ex-
clusively with an iminium ion in the step of the Man-
nich reaction and another nucleophile Nu3 must be
able to react exclusively with a Michael acceptor in
the step of addition. Thus the nucleophiles Nu2 and
Nu3 have to be carefully selected to achieve such
a chemoselectivity. Recently, trifluoromethyl b-dike-
tones Nu2 were found to be highly reactive nucleo-
À
tiple C C bond formations in one pot. In addition,
exquisite chemoselectivity is achieved in the reac-
tion between 1,3-dicarbonyl compounds and tri-
fluoromethyl b-diketones.
À
philes, which allowed the easy construction of C C
À
Keywords: cascade reaction; 1,5-diketones; metal-
free conditions; N-methylamine; trifluoroacetate re-
lease
and C X bonds via the facile release of trifluoroace-
tate.[4] We envisioned that the use of these substrates
would furnish
a
selective cascade reaction
(Scheme 1). Herein, we report a one-pot, three-com-
ponent cascade reaction that allows the synthesis of
methylene-bridged unsymmetrical adducts from N-
methyl tertiary aliphatic amines, trifluoromethyl b-di-
Starting from the early 1960s, the chemistry of multi- ketones, and 1,3-dicarbonyl compounds. This reaction
component cascade or domino reactions has experi-
enced a rapid development.[1] This interest in multi-
component cascade reactions is mainly due to their
excellent atom economy and overall efficiency. The
major challenge of a cascade reaction is achieving
high selectivity, such as chemo-, regio- and stereose-
lectivity.[1c–e,j] In 2009, Li and co-workers reported an
efficient synthesis of methylene-bridged bis-1,3-dicar-
bonyl compounds via iron-catalyzed oxidative reac-
tions of N,N-dimethylaniline and 1,3-dicarbonyl com-
pounds.[2] A cascade reaction pathway of oxidation/
Mannich reaction/Cope elimination/Michael addition
has been proposed, in which 1,3-dicarbonyl compound
Nu1 first participates in a Mannich reaction as carbon
nucleophile and then reacts with a Michael acceptor
to afford the methylene-bridged symmetrical adduct
(Scheme 1). Very recently, a number of reports have
described similar oxidative cascade reactions of N-
methylamines.[3] Although these processes enable
À
À
multiple C C bond formation and C N bond cleav- Scheme 1. Cascade reaction of N-methylamine.
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1,5-Diketones Synthesis via Three-Component Cascade Reaction
proceeds through an oxidation/Mannich reaction/ 4aa (Table 1, entry 4 and 5). Instead, they afforded
Cope elimination/Michael addition/retro-Claisen reac- the symmetrical methylene-bridged bis-1,3-dicarbonyl
À
tion sequence that includes C N bond cleavage of the compounds in very low yields as in our previous
amine, C C bond cleavage of the trifluoromethyl b- report.[7] Interestingly, by using a sterically hindered
À
diketone, and the chemoselective formation of two tertiary amine, N,N-dicyclohexylmethylamine 1f, the
C C bonds. Notably, 1,5-diketones can be readily pre- yield was significant improved to 75% (Table 1,
À
pared through this cascade reaction under mild and entry 6). Replacing aqueous TBHP with the solution
metal-free conditions. 1,5-Diketone derivatives serve TBHP in n-decane led to a lower yield of 4aa
as useful synthetic intermediates for the preparation (Table 1, entry 7). It is noteworthy that the symmetri-
of cyclopentenes, piperidines, pyridines, hydrazines, cal adduct was not observed when the reaction was
ketolactones and many other heterocyclic compounds, performed using N-methylamines such as 1a–1c and
which exhibit various potential biological and phar- 1f.
macological activity. Consequently, the feasible con-
On the basis of the results achieved with N,N-dicy-
clohexylmethylamine 1f and 4,4,4-trifluoro-1-(thio-
struction of such structures is of great value.[5]
We chose ethyl benzoylacetate 2a as one nucleo- phen-2-yl)butane-1,3-dione 3a, a range of 1,3-dicar-
phile and 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3- bonyl substrates 2 was next examined under the opti-
dione 3a as another nucleophile to evaluate various mal conditions described in Table 1, entry 6. As
tertiary amines in the presence of TBHP. In the previ- shown in Table 2, when b-keto esters 2 were substitut-
ous report, N,N-dimethylanline 1a was frequently ed with electron-withdrawing groups on the aromatic
used as carbon partner or carbon source in oxidative ring, including halides, nitro and cyano groups, the
coupling reactions.[2,6] However, it only afforded the corresponding products 4ba–4ea were obtained in 35–
desired product 4aa in 20% yield in this transforma- 88% yield (Table 2, 4ba–4ea). Electron-donating
tion (Table 1, entry 1). N,N-Dimethylbenzylamine 1b groups such as p-methyl, p-methoxy, m-methoxy and
slightly improved the yield of 4aa to 30% (Table 1, methylenedioxy groups were also allowed the forma-
entry 2). The secondary anline N-methylaniline 1c tion of 4fa–4ia in moderate to good yields (Table 2,
was also investigated, but a messy result was observed 4fa–4ia, 59–74%). The naphthyl group substituted b-
and product 4aa was not detected (Table 1, entry 3). keto esters could also give products in good yields
We recently reported that tertiary N-ethylamines (Table 2, 4ja, 4ka). When heterocyclic 1,3-dicarbonyl
could be used for oxidative coupling reactions.[7] How- compounds, such as thiophene, furan and pyrrole 1,3-
ever, the reactions of N,N-diisopropylethylamine 1d keto esters were subjected to the conditions, the reac-
and N,N-dicyclohexylethylamine 1e could not yield tions furnished the corresponding oxidative-coupling
products in moderate yields (Table 2, 4la–4na). Be-
sides 1,3-keto esters, we found that 1,3-diphenyl-1,3-
propanedione 2o could also transformed into the
Table 1. Screening studies for various amines.[a]
target compound 4oa in 32% yield (Table 2, 4oa).
Moreover, the substrate scope was extended to dia-
lkyl malonates and ethyl acetoacetate, which were
converted to the desired products 4pa–4sa in moder-
ate to good yields (Table 2, 4pa–4sa, 56–77%). These
substrates are readily available carbon synthons in or-
ganic synthesis. Thus we anticipate that the present
cascade reaction will be valuable for the synthesis of
complex molecules.
The cascade reaction was also applicable to a varie-
Entry
Amine
Yield [%]
ty of trifluoromethyl-1,3-dicarbonyl compounds 3b–n
(Table 3). The aryl halide-substituted substrates gave
the desired products 4gb–4ge in 46–73% yields. When
the aromatic ring is substituted with electron-donating
groups, such as methoxy, methylenedioxy and benzyl-
oxy groups, the reaction proceeded smoothly to
afford the products (Table 3, 4gf–4gj, 4aj, 37–84%
yield). It is noteworthy that the para-methoxy sub-
strate gave a better result than the meta- and ortho-
methoxy isomers (Table 3, 4gf–4gh). The trifluoro-
methyl-1,3-dicarbonyl compound bearing a larger aryl
substituent such as a naphthyl group was successfully
transformed to the corresponding 1,5-diketones
1
2
3
4
5
6
7
N,N-dimethylaniline 1a
N,N-dimethylbenzylamine 1b
N-methylaniline 1c
N,N-diisopropylethylamine 1d
N,N-dicyclohexylethylamine 1e
N,N-dicyclohexylmethylamine 1f
N,N-dicyclohexylmethylamine 1f
20
33
0
0
0
75
62[b]
[a]
Unless otherwise noted, reaction conditions were as fol-
lows: amine (2.0 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
TBHP (4.0 mmol, 70% aqueous), MeCN (2 mL), 808C,
12 h, isolated yield.
[b]
TBHP (5.5M in n-decane)
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Li-Juan Xing et al.
Table 2. Substrate scope of various 1,3-dicarbonyl substrates.[a]
[a]
Reactions were carried out with 1f (2.0 mmol) 2 (0.5 mmol), 3a (0.5 mmol), and
TBHP (4.0 mmol, 70% aqueous) in MeCN (2 mL) at 808C for 12 h; yield as indi-
cated.
(Table 3, 4gk, 4ak). Furthermore, we were pleased to
On the basis of earlier studies and our results,[2,4a,d,8]
find that even the aliphatic substrate 1,1,1-trifluoro- we propose a possible mechanism for the cascade re-
pentane-2,4-dione could be used in our procedure to action (Scheme 2). The first step is the oxidation of
afford 4gl in 58% yield (Table 3, 4gl). However, the N,N-dicyclohexylmethylamine 1f with TBHP afford-
nitro substituent on the aromatic ring led to a low ing an iminium ion A, which undergoes a Mannich re-
yield of 27% (Table 3, 4am). The furan substituted tri- action with trifluoromethyl b-diketone to generate
fluoromethyl b-diketone was also tolerated in this re- a Mannich base B. Upon oxidation, Cope elimination
action, and 1,5-diketone 4an was obtained in 79% of B occurs to produce a Michael acceptor C. Subse-
yield.
quently, C converts to the final product 4 through
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1,5-Diketones Synthesis via Three-Component Cascade Reaction
Table 3. Substrate scope of various trifluoromethyl b-diketones.[a]
[a]
Reactions were carried out with 1f (2.0 mmol), b-keto esters substrates 2 (0.5 mmol), trifluoromethyl
b-diketones 3 (0.5 mmol), and TBHP (4.0 mmol, 70% aqueous) in MeCN (2 mL) at 808C for 12 h;
yield as indicated.
a Michael reaction/retro-Claisen reaction sequence.[8] other 1,5-diketones and heterocycles is underway in
Another alternative pathway, which involves firstly our laboratory.
the Knoevenagel condensation between formaldehyde
and trifluoromethyl b-diketone, and then a Michael
reaction/retro-Claisen reaction, is also possible.
Experimental Section
In conclusion, we have developed a mild and effi-
cient cascade reaction for the synthesis of 1,5-dike-
tones employing readily available N,N-dicyclohexyl-
methylamine, 1,3-dicarbonyl compounds, and trifluor-
omethyl b-diketones. In addition, the selective reac-
tion of trifluoromethyl b-diketone and 1,3-dicarbonyl
compound is achieved in one pot. Further investiga-
General Procedure for the Synthesis of 4
A Schlenk tube was charged with 1,3-dicarbonyl compound
2 (0.5 mmol) and trifluoromethyl b-diketone 3 (0.5 mmol)
under air at room temperature, then N,N-dicyclohexylme-
thylamine 1f (2.0 mmol) and tert-butyl hydroperoxide
(TBHP, 4.0 mmol, 70% aqueous solution) were added. The
tion of this strategy focusing on the construction of mixture was stirred at 808C for 12 h. The resulting reaction
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Li-Juan Xing et al.
Scheme 2. Proposed mechanism for the cascade reaction.
mixture was purified by flash column chromatography on
silica gel with ethyl acetate/petroleum ether (1:20, v/v) as
eluent to give the desired product 4.
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (No. 21172120, 21472093),Tianjin Municipal Sci-
ence and Technology Commission (No. 14 JCYBJC20600)
and National University Student Innovation Program (No.
201510055118) for the funding support.
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