Tetrahedron Letters
Efficient and practical synthesis of N-acetyl enamides from ketoximes
by unique iron catalytic system
Takahiro Kunishige a, Daisuke Sawada a,b,
⇑
a Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama-shi, Okayama 700-8530, Japan
b Advanced Elements Chemistry Laboratory, RIKEN-CPR, Hirosawa Wako-shi, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new procedure for the iron-catalyzed synthesis of enamides from ketoximes was developed, and its
mechanism was proposed. A unique reduction system, with the concerted use of KI and Na2S2O4, was
involved. The reaction exhibited a wide substrate scope and gave good yields in a short reaction time.
The procedure is operationally simple and also applicable for the large-scale synthesis.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 19 March 2019
Revised 17 April 2019
Accepted 7 May 2019
Available online 15 May 2019
Keywords:
Ketoxime
Enamide synthesis
Iron catalyst
One-electron reduction
N-acetyl enamides are useful synthetic intermediates, which
lead to biologically active compounds [1], pharmaceutical com-
pounds [1] and functional chiral amines [2]. A number of methods
for the synthesis of N-acetyl enamides have been reported, which
utilized nitriles [3], amides [4], and ketoximes [5–11] as the sub-
strate. Among these, ketoximes are easily prepared from ketones
and hydroxylamine, and the derivatives are also easily available.
The acylation of the hydroxy group of the ketoxime, reductive
cleavage of its NAO bond, and re-acylation via tautomerization of
the imine can proceed in a one-pot reaction and is an efficient syn-
thetic method to afford N-acetyl enamides (Scheme 1). The effec-
tive methods used to conduct the above reaction are listed
herein. The first example was reported in 1975, using stoichiomet-
ric amounts of a chromium(II) reagent [5]. Following this, a CuI-
catalyzed reaction at 120 °C for 24 h [6], Ru(II)-catalyzed reactions
[7], Rh/C-catalyzed reactions with H2 [8], phosphine-mediated sys-
tem in refluxing toluene [9], and stoichiometric amounts of Fe
powder or Fe(II)-mediated reactions were proposed [10,11]. Each
of these methods offered advantages with respect to the different
parameters, such as temperature, reaction time, reagents, substrate
scope, and yield. However, several aspects can be improved
further.
in the catalytic cycle that should be applicable to the abovemen-
tioned reaction. Iron is cheap and abundant on the earth; however,
a catalytic reaction is valuable from the environmental aspect.
Herein, we report the iron-catalyzed synthesis of N-acetyl enam-
ides, in which 5 mol% of the catalyst affords high to excellent yields
of a wide range of products in a short reaction time.
Using compound 1, we investigated the reductant in the Fe
(OAc)2 catalyzed reaction to obtain compound 2 (Table 1, see
Supporting information Table S1). All the reagents and substrate
were simply mixed in a solvent at 65 °C, and 3 equivalents of KI
was used in DCE with 5 mol% of catalyst (entry 1) [7], however,
compound 2 was given in 8% yield after 12 h. The reaction in the
presence of NaHSO3, that is often used in such reactions [6,7], gen-
erated compound 2 in low yield (entry 2). Next, we tried adding
Na2S2O4 and found an improvement in the yield, however, sub-
strate 1 was recovered after 12 h (entry 3). To overcome the low
reactivity, we considered the reduction cycle of the iron catalyst
and attempted to use of KI and Na2S2O4 simultaneously. Gratify-
ingly and expectedly, the reaction rate was dramatically improved,
and 90% yield was accomplished in only 1 h (entry 4). Reducing the
amount of catalyst (3 mol%) lowered the reactivity, giving a lower
yield (entry 5), on the other hand, a catalytic amount of KI (0.4
equivalent) worked sufficiently (entry 6). Acetic acid is an essential
promoter in the reaction, although its role and mechanism are not
clearly understood (entry 7) [11]. Tetrabutylammonium iodide
(TBAI) could be used as an iodide source, despite the low reactivity
(entry 8), while the combination of KI and NaHSO3 decreased the
reactivity and yield (entry 9). Both THF and toluene could be used
In the course of our research project, we investigated the iron-
catalyzed reaction and found a unique reduction pathway of Fe(III)
⇑
Corresponding author at: Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama University, Okayama-shi, Okayama 700-8530,
Japan.
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.