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Chemistry Letters Vol.33, No.3 (2004)
Facile One-pot Syntheses of Amidines and Enamines from Oximes via Beckmann
Rearrangement Using Trifluoromethansulfonic Anhydride
Tomofumi Takuwa,y;yy Tomofumi Minowa,y;yy Jim Yoshitaka Onishi,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received December 8, 2003; CL-031201)
Table 1. Syntheses of amidines by trapping with amines
Facile one-pot syntheses of amidines and enamines were
R1
H
N
achieved by trapping carbocation intermediates that were formed
by Beckmann rearrangement of oximes with amines and carbon
nucleophiles, respectively, under mild conditions.
OH
R2
N
R3
R4
Tf2O, Et3N
N
R3
R2
Toluene
−78°C
R1
N
R4
3
H
Beckmann rearrangement1 is a well-known useful tool having
a wide range of applications in organic synthesis for the construc-
tion of nitrogen-containing compounds2 such as ꢀ-alkylated
amines3 via imines, amidines,4 thioimidates,5 imidoyl halides,6
imidoyl cyanides,5 iminophosphonates,7 and enaminones.8 Ami-
dines were synthesized by trapping the iminocarbocation inter-
mediates of Beckmann rearrangement derived from oximes,9,10 ox-
ime sulfonates,4 oxime carbonates, and oxime phosphonium salts11
with primary or secondary amines. There are also some reports on
the formations of amines3 or enamines8 by trapping the intermedi-
ates with the carbon nucleophiles. In some cases, however, these
reported procedures require isolation of oxime sulfonates or high
reaction temperature, and products yields are low. Then, it was
considered that if the oximes having a strong leaving group such
as trifluoromethanesulfonate were to be used, Beckmann rear-
rangement would proceed smoothly under milder conditions to
provide a convenient procedure. Among the Beckmann type reac-
tions of ketoximes that form nitriles, dehydrated products, or the
rearranged products of common amides by the use of trifluorome-
thanesulfonic anhydride,12 no reaction that traps the iminocarboca-
tion intermediates with amines or carbon nucleophiles is known.
Here, we would like to report facile one-pot syntheses of ami-
dines and enamines under mild conditions by trapping the inter-
mediates, generated from oximes by Beckmann rearrangement,
with amines or carbon nucleophiles.
R1
Ph
R2
Product
3a
Entry
1
Yield /%a,b
N
R3
R4
H
N
95c
99
Ph
Me
1
Me
2
3
Ph
3b
Ph
N
H
2
3c
87
HN
O
4
5
1
2
3d
3e
89
86
Ph
Me
Et
Me
Me
Et
6
1
3f
93
7
8
1
2
3g
3h
99
99
- (CH2)5 -
9
1
3i
83
aIsolated yield. bAll products were obtained as a single isomer and the geom-
etry of them were not determined. cThe yield was determined by 1H NMR anal-
ysis using 1,1,2,2-tetrachloroetahne as an internal standard.
cations and successive reaction of thus formed carbocations with
carbon nucleophiles afforded the enamines under mild conditions.
A similar example was reported by Yamamoto and co-workers, in
which enaminones8 were obtained from oxime sulfonates and enol
silyl ethers in the presence of Lewis acid such as diethylaluminum
chloride.
In the first place, the carbocation intermediate of Beckmann
rearrangement generated from benzophenone oxime and trifluoro-
methanesulfonic anhydride was studied to see if it was trapped by
N-methylaniline. The carbocation intermediate was generated by
adding trifluoromethanesulfonic anhydride to the toluene solution
of benzophenone oxime and triethylamine at ꢁ78 ꢂC. Then, N-
methylaniline was added to the reaction mixture and was warmed
up to room temperature. After aqueous work up, the desired prod-
uct was obtained in 95% yield. Various amidines were similarly
prepared by the above-mentioned one-pot procedure from the cor-
responding oximes. For example, treatment of aromatic oximes
with aromatic or aliphatic amines gave the corresponding amidines
in good yields (Table 1, Entries 1–5). The reactions proceeded
smoothly also in the case of less reactive aliphatic oximes and gave
the desired products in high yields (Entries 6–8). According to this
procedure, the yield of rearranged product of cyclic oxime was im-
proved compared with that by the ordinary method4 (Entry 9).
Next, the trapping of iminocarbocation intermediates with car-
bon nucleophiles was tried. The reaction was thought to provide a
new method for the formation of enamines by one-pot procedure:
namely, Beckmann rearrangement of oximes to form iminocarbo-
The reactions of acetophenone oxime and sodium methylmal-
onate were tried as the model. It was revealed that at least 3.0
equivalents of nucleophile were necessary in order to obtain the
desired product in high yield (Table 2, Entry 3).
The reaction was further examined by using various aromatic
and aliphatic oximes (Table 3 Entries 1–5), and it became clear
that all the reactions proceeded smoothly to afford the correspond-
ing enamines in good to high yields. It was considered that thus ob-
tained enamines derived from aromatic oximes would be convert-
ed to 2-substituted 4-oxo-3-qunorinecarboxylic acid derivatives13
which possess antibacterial activities by subsequent intramolecular
Friedel–Crafts acylation.14 Similar reactions using other nucleo-
philes were further studied and a mixture of C- and O-alkylated
products was obtained in 94% yield in the case using sodium eno-
late of ꢁ-ketoester as a nucleophile (Entry 7). When sodium eno-
late of methyl cyanoacetate was used together with two ketoximes,
respective reactions gave only one product in high yields (Entries 8
and 9). Furthermore, phenylsulfonylacetonitrile was also used as a
nucleophile together with DBU, a base, and the corresponding
product was obtained in 72% yield (Entry 10). On the other hand,
Copyright Ó 2004 The Chemical Society of Japan
Takuwa, Tomofumi
