Selective cleaving the N–P bond of difluoromethylene phosphabetaines for effective synthesis of β-ketoamides

Article abstract of DOI:10.1016/j.tetlet.2019.06.036

An unprecedent transition-metal-free protocol for the synthesis of β-ketoamides from β-ketoesters is described. This method involves selective cleaving N–P bond of an unusual aminating reagent, [tris(dimethylamino)phosphonio]difluoroacetate (ADFA), which

Full text of DOI:10.1016/j.tetlet.2019.06.036

Tetrahedron Letters 60 (2019) 1934–1937
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Tetrahedron Letters
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Selective cleaving the NAP bond of difluoromethylene phosphabetaines
for effective synthesis of b-ketoamides
a
a
a
a
a
a
a,
Yingle Liu a, , Tao Yang , Yuting Dong , Junjie Cai , Gen Luo , Xia Tong , Yan Jiang , Yi Yang
⇑
⇑
,
Xiu-Hua Xu b,
⇑
a Key Laboratory of Green Catalysis of Higher Education Institutes of Sichuan, Sichuan University of Science & Engineering, Zigong 643000, China
b Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedent transition-metal-free protocol for the synthesis of b-ketoamides from b-ketoesters is
described. This method involves selective cleaving NAP bond of an unusual aminating reagent, [tris
(dimethylamino)phosphonio]difluoroacetate (ADFA), which is well known as the difluoromethylene ylide
precursor. The process is notable for its operational simplicity and good functional group tolerance.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 17 April 2019
Revised 28 May 2019
Accepted 18 June 2019
Available online 20 June 2019
Keywords:
Difluoromethylene phosphabetaines
b-Ketoamides
b-Ketoester
Aminating reagent
Introduction
b-ketonitriles was developed by Crochet and Cadierno for the
preparation of b-ketoamides [19]. However, the use of precious
The b-ketoamides and their derivatives represent important
class of units in modern organic synthesis and medicinal chemistry
[1]. They are also very important and useful building blocks for the
synthesis of various heterocycles including lactams [2], furans [3],
pyrans [4], isoquinolines [5], oxocyclohexenones [6], spiroindo-
lines [7], tetrahydropyridines [8], bridged heterocycles [9] and
spiroaminals [10]. Furthermore, they can be conveniently con-
verted into b-hydroxyamides [11] and c-ketoamides [12]. Conse-
quently, a variety of methods have been developed for the
synthesis of b-ketoamides. The traditional methods include
transition metals made these processes less applicable to large-
scale synthesis. From this point of view, it is deeply worthy to
explore broadly applicable methods for the synthesis of
b-ketoamides.
In 2013, Xiao and co-workers reported the preparation of [tris
(dimethylamino)phosphonio]difluoroacetate (ADFA) as a difluo-
romethylene phosphonium ylide precursor [20]. The general
application of ADFA is to react with ketones for the preparation of
gem-difluoroalkenes (Scheme 1, left) [21]. Herein, we demonstrate
an unusual application of ADFA as a novel aminating reagent in
the amination of b -ketoesters to b -ketoamides (Scheme 1, right).
aminolysis of b-ketoesters [13],
a-acylation of amides [14], addi-
tion of enolates to isocyanates [15], Wolff Rearrangement of cyclic
2-diazo-1,3-diketones [16] and oxidation b-hydroxy amide [17].
However, most of these approaches often suffer from narrow
substrate scope and/or harsh reaction conditions. Recently, the
transition-metal-catalyzed methods have been developed for the
preparation of b-ketoamides. In 2014, Skrydstrup and Lindhardt
reported a mild and effective synthetic route via Pd-catalyzed
Result and discussion
Recently, we reported an unprecedent reaction of indoline-2,3-
diones and (triphenylphosphonio)difluoroacetate (PDFA) [20,22] to
afford novel 3-fluoroalkenyl-3-trifluoromethyl-2-oxindoles in
moderate to excellent yields [23]. To extend the scope of this
unique reaction, we examined the reaction of b-ketoester 1a with
PDFA (Table 1, entry 1). However, no reaction was detected. To our
surprise, treatment of 1a with more nucleophilic ADFA in NMP
gave tautomeric mixture of b-ketoamide 4a and enol forms 4a0 in
49% total yield (entry 2). No gem-difluoroalkene 3a was observed
in this reaction. In continuation of our research interest in the
carbonylative
a-arylation of acetoacetamides and subsequent
deacetylation [18]. The ruthenium-catalyzed hydration of
⇑
Corresponding authors.
E-mail addresses: liuyingleyou@163.com (Y. Liu), yangyiyoung@163.com
(Y. Yang), xuxiuhua@sioc.ac.cn (X.-H. Xu).
https://doi.org/10.1016/j.tetlet.2019.06.036
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

Y. Liu et al. / Tetrahedron Letters 60 (2019) 1934–1937
1935
Table 2
Amination of b -ketoesters with ADFA.a,b
Scheme 1. Applications of ADFA.
Table 1
Reaction condition optimization.a
Entry
2
Solvent
Temperature (oC)
4 Yield (%)b
1
2
3
4
5
6
7
8
PDFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
ADFA
NMP
NMP
DMF
DMA
1,4-dioxane
toluene
NMP
NMP
NMP
NMP
NMP
NMP
NMP
120
120
120
120
120
120
140
130
110
120
120
120
120
ND
49
32
20
27
trace
34
47
41
21
68
83
73
9
10c
11d
12e
13f
a
Reaction conditions: 1a (0.5 mmol), difluoromethylene phosphabetaine
(1.0 mmol), solvent (1.0 mL), temperature, under N2, 12 h.
b
Isolated yields.
ADFA (1.5 mmol).
NMP (2.5 mL).
NMP (5.0 mL). NMP (7.5 mL).
c
d
e
f
development of new applications of fluoroalkylphosphoniums
[23,24], we decided to further explore the amination reaction with
ADFA. We continued to optimize the reaction conditions started
with the screening of other solvents including DMF, DMA, 1,4-
dioxane, and toluene (entries 3–6), but none of them gave better
results. Further screening of reaction temperature showed that
120 °C was optimal (entries 2, 7–9). Given the unsatisfactory reac-
tion yield, three equivalents of ADFA was also used in this reaction
system (entries 10). To our surprise, this reaction gave out b-ketoa-
mide 4a and enol forms 4a0 in lower yields than the one obtained
with two equivalent ADFA (entries 10 vs. 2). We therefore specu-
lated that the concentration of ADFA could play important roles
in determining the yield of the product. To our delight, the yield
of 4a and 4a0 was sharply improved when the reaction concentra-
tion was decreased (entries 11–13). Finally, the optimal reaction
conditions were defined as 1 equiv of 1a (0.1 mol/ L) and 2 equiv
of ADFA(0.2 mol/ L) in NMP (5 mL) at 120 °C (entry 12).
With the optimized reaction conditions in hand, the substrate
scope of this reaction was surveyed. As shown in Table 2, this reac-
tion is compatible with a wide range of electron-donating (Me,
OMe, and phenyl; 1b-1d) and electron-withdrawing (F, Cl, Br, CN,
and NO2; 1f-1j) groups on benzene ring of b -ketoesters. In general,
the substitution of electron-donating groups is favored for this
reaction. Moreover, allyl functional group that is commonly
employed in cross coupling reactions was also tolerated giving
the corresponding 4e and 4e0 in moderate yields, thus providing
opportunities for additional transformations. The substituent on
aReaction conditions: 1 (0.5 mmol), ADFA (1.0 mmol), NMP (5.0 mL), 120 °C, under
N2, 12 h, all reaction yields are isolated yields.
bKeto/enol ratios are determined by 1H NMR spectroscopy in CDCl3.
cEthyl 3-oxo-3-phenylpropanoate (1 s) as the substrate.
d1a (8.0 mmol), ADFA (16.0 mmol), NMP (80.0 mL).
the para, meta or ortho position of aromatic ring had no obvious
effect on the reaction yield (1c vs. 1k; 1h vs. 1l; 1g vs. 1m). Further-
more, this procedure was also applicable to polycyclic (1n), hetero-
cyclic aromatic-substituted (1o-1q), and even a-alkyl substituted
(1r) b-ketoesters, albeit the yield was slightly reduced. Lastly, ethyl
3-oxo-3-phenylpropanoate (1s) was also investigated under stan-
dard conditions. The corresponding tautomeric mixture 4a and
4a0 were obtained in 88% yields. It was noteworthy that this reac-
tion can also be used to gram scale synthesis b-ketoamides without
significant reduction in yield and the structure of product 4 was
confirmed by X-ray crystallographic analysis of compound 4a0
(see the Supporting information).
Besides b-ketoesters, other compounds could also be aminated
by ADFA. For example, the Morita–Baylis–Hillman adduct
5
reacted with ADFA in NMP to give an allylic amine 6 in 53% yield
and a moderate stereoselectivity (Scheme 2) [25].
To gain insight into the reaction mechanism, the following
experiments were performed. Firstly, methyl benzoate 7 and
methyl 3-phenyl propanoate 8 were examined to react with ADFA,
and the amination reaction did not happen (Scheme 3a and 3b).

1936
Y. Liu et al. / Tetrahedron Letters 60 (2019) 1934–1937
On the basis of the above results, we proposed a plausible
mechanism (Fig. 1). The ADFA underwent decarboxylation process
under the mild heating to generate transient difluoromethylene
phosphonium ylide 12 [20]. Then, ylide 12 was trapped by enol
10 to form a five-coordinate phosphorus intermediate 13. Subse-
quently, an intramolecular nucleophilic substitution [26] hap-
pened via a selective cleavage of the NAP bond of ADFA to give
intermediate 15. Finally, protonation of 15 furnished the desired
product b-ketoamide 4.
Scheme 2. Amination of Morita–Baylis–Hillman adduct 5.
Conclusion
In summary, we have developed an efficient method for the
preparation b-ketoamides from b-ketoesters via a selective cleav-
age of the NAP bond of difluoromethylene phosphabetaines. Com-
pared with other methods, this current one has some advantages,
such as wide substrate scope, operational simplicity, transition-
metal-free, and no need to add base. Thus, the difluoromethylene
phosphabetaines might be expected to become a unique and effi-
cient aminating reagent for the formation of CAN bond. Further
exploration of this protocol and development of other reagents will
be carried on in our group.
Acknowledgments
We thank Sichuan University of Science
& Engineering
(No. 2014RC07), Science and Technology Department of Sichuan
Province (No. 2016JY0246), Education Department of Sichuan
Province (No. 16ZB0247), Key Laboratory of Green Chemistry of
Sichuan Institutes of Higher Education (No. LZJ1505), Opening
Project of Sichuan Province Key Laboratory of Natural Products
and Small Molecule Synthesis (No. TRCWYXFZCH2016005) and
Shanghai Pujiang Program (No. 15PJ1410300) for financial support.
Scheme 3. Mechanism experiments.
This result demonstrated that the carbonyl of b-ketoester played
an important role in this reaction. In contrast, treatment of methyl
2-hydroxybenzoate 9 with ADFA gave the corresponding amide 10,
Appendix A. Supplementary data
albeit in low yield (Scheme 3c). Furthermore, when a-dialkyl sub-
stituted b-ketoester 11 was subjected to the standard conditions,
the corresponding amide was not obtained (Scheme 3d). These
results confirmed that enolization of b-ketoester was the key step
for this reaction. Lastly, we also used GC–MS to identify the reac-
tion solution and no dimethyl amine can be observed from the
spectra. Base on this, we believe dimethyl amine generated from
decomposition of ADFA should be not involving in this reaction
system.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.06.036.
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