G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
169
AcP-TFA, 1H NMR ı 9.64 (s, 1H, OH), 7.45–7.32 (d, 2H), 6.70–6.65
(d, 2H), 1.97 (s, 3H).
the solid was filter and washed with a saturated solution of NaCl
and NaHCO3 at 273 K. The crude 4-HAPO was dissolved in water
and extracted with diethyl ether. After evaporation of the solvent
the solid was twice recrystallized with diethyl ether and hexane.
NMR assignments:
2.5. Beckmann rearrangement reactions
All the operations were carried out under nitrogen (charged at
atmospheric pressure) in a jacketed sealed glass reactor (10 mL)
at several temperatures and autogenous pressure. The course of
reactions was checked sampling the liquid phase by a syringe at
established intervals. All the analyses were carried out by GC and
GC–MS when APO was employed as substrate, while HPLC and
GC–MS were used when the substrate was 4-HAPO. The potential of
the method as an alternative synthetic route for obtaining different
amides has been tested on several oximes giving, in any case, high
yield in the corresponding amides (see supplementary materials).
In a typical experiment, a glass reactor was charged with
1.3 mmol of 4-HAPO, 9 mL of nitroethane and 12.5 mmol of TFA
under nitrogen. The reaction time was computed after the TFA
addition.
The first derivative at time 0 of the third order polynomial,
obtained by fitting the time decreasing concentration of 4-HAPO,
gives the overall initial reaction rate, thus allowing the control of
the influence of the operative variable on the reaction kinetics. In
this case substrate consumption and amide formation has been fol-
lowed by HPLC analysis since GC cannot be employed since either
4-HAPO or acetaminophen decompose in the GC injection system,
giving not reliable results in the quantitative analysis.
(CD3)2SO), ı 10.84 (s, 1H, N OH), 9.60 (s, 1H, OH), 7.49–7.45 (d,
2H), 6.78–6.73 (d, 2H), 2.09 (s, 3H) [31];
APO, white solid, m.p. 331-333 K, 1H NMR: (200 MHz, CDCl3), ı
9.04 (br s, 1H, OH), 7.68–7.63 (m, 2H), 7.43–7.40 (m, 3H), 2.34 (s,
3H) [32].
2.4. Synthesis of O-trifluoroacetyl oximes ester, N-trifluoroacetyl
An
attempt
to
obtain
O-trifluoroacetyl-4-hydroxy-
acetophenone oxime (4-HAPO-TFA) by following the procedure
reported for cyclohexanone oxime in previous papers does not give
satisfactorily results [27,28]. In fact, the formation of 4-HAPO-TFA
by reacting trifluoroacetic anhydride with 4-HAPO is not observed
since, the instantaneous rearrangement to acetaminophen is
observed also at 298 K.
none oxime at 353 K gives in few minutes acetanilide but,
O-trifluoroacetyl acetophenone oxime (APO-TFA) is formed at
298 K by following the procedure reported for cyclohexanone
oxime in previous papers [27,28]. The reaction occurs almost quan-
titatively in various solvent in a typical preparation 25 mmol of
APO reacts with an equimolar amount of trifluoroacetic anhydride
in 3 mL of CH2Cl2. To avoid fast decomposition of the products,
APO-TFA is maintained in a DMSO solution in the presence of an
over-stoichiometric amount of trifluoroacetic anhydride (1.1 equiv.
with respect to APO-TFA). The product is identified by 1H NMR,
GC–MS and HPLC (see supplementary materials).
The initial rate of APO rearrangement was measured by the first
derivative at time 0 of the third order polynomial obtained by fitting
the time vs. acetanilide formation data. The different methods in the
calculation of the initial rate of reaction for the two substrate is due
the fact that APO shows a complex reaction path, then acetanilide
formation appears to be a simple and reproducible parameter for
measuring the overall reaction rate.
2.6. Products, solvent and catalyst recovery
N-Trifluoroacetyl-4-hydroxyacetanilide
(AcP-TFA)
or
N-trifluoroacetyl-acetanilide (AcA-TFA) are obtained by triflu-
oroacetylation of acetaminophen or acetanilide in acetonitrile,
the products are identified via GC–MS and NMR (see supplemen-
tary materials). In a typical preparation 26 mmol of paracetamol
was dissolved with 3 mL of acetonitrile and added 26 mmol of
trifluoroacetic anhydride in a glass flask, then the reaction was
stirred for 1 h at 298 K. The solvent was eliminated under vacuum
by a rotary evaporator at 298 K; a deliquescent white solid was
obtained and analyzed by HPLC, GC–MS and NMR (see supple-
mentary materials). Analogous procedure was followed to prepare
N-trifluoroacetyl acetanilide (see supplementary materials). It
is noteworthy that all the compounds are moisture sensitive.
To avoid fast decomposition of the products, both AcP-TFA and
AcA-TFA are maintained in a DMSO or CH3CN solution in the
presence of an over-stoichiometric amount of TFA (1.1 equiv. with
respect to AcP-TFA or AcA-TFA).
The reacted mixture is transferred to a mini distillation appara-
tus equipped with membrane pump, operating at 130 Pa and with a
condenser chilled at 273 K with a circulating thermostat. The mix-
ture is heated at 353 K, than the solvent quickly distils. The solvent
recovered is over 95% of the initial solvent, the rest is in the distil-
lation apparatus. The residue is recovered and the isolated yield of
acetanilide and acetaminophen are ca. 90–95%.
3.1. Influence of the solvent on the Beckmann rearrangement of
4-HAPO and APO catalyzed by TFA
Table 1 reports the influence of the solvent on the Beckmann
rearrangement reaction of 4-HAPO and APO after 2 h of reaction.
It is noteworthy that conversions are close to completeness in
the presence of various solvents, in some cases the reaction is prac-
tically quantitative to the desired amide, except entries 4, 6 and
8 that are carried out in the presence of ethanol, DMC and DMSO,
respectively. As regard the reactivity in ethanol, the behavior is
expected, since TFA reacts almost instantly with the alcohol to
give ethyl trifluoroacetate, thus subtracting the acid to the reac-
tion environment. In the presence of DMC the reaction does not
proceed but no byproducts were observed. This strong solvent
effect is generally related to a stabilization of a charged inter-
mediate, whose stability increases the activation energy of the
overall process [35]. This strong solvent interaction inhibits also
all the reactions involved in the process (oxime hydrolysis and/or
NMR assignments:
7.54–7.26 (m, 3H), 2.51 (s, 3H);
ı 7.75–7.70 (m, 2H),
acetanilide, white solid m.p. 385–389 K, 1H NMR (200 MHz, CDCl3),
ı 8.19 (br s, 1NH), 7.55–7.51 (m, 2H), 7.33–7.25 (m, 2H), 7.13–7.06
(m, 1H), 2.15 (s, 3H) [33];
AcA-TFA, 1H NMR (200 MHz, CDCl3),
7.25–7.20 (m, 2H), 2.55 (s, 3H);
acetaminophen, white solid m.p. 440–443 K 1H NMR ((CD3)2SO,
200 MHz), ı 9.63 (s, 1H, OH), 9.12 (br s, 1H, NH), 7.36–7.31 (d,
2H), 6.69–6.65 (d, 2H), 1.98 (s, 3H) [34];