Trifluoroacetic Anhydride as an Activator in the Acylation of Aryl Methyl Ketones with Carboxylic Acids

Article abstract of DOI:10.1134/S1070428020100164

Abstract: Trifluoroacetic anhydride was used as an efficient activator of the acylation of aryl methyl ketones with carboxylic acids in the presence of Br?nsted and Lewis acids (SF₃SO₃H, MeSO₃H, 4-MeC₆H₄

Full text of DOI:10.1134/S1070428020100164

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 10, pp. 1770–1774. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 10, pp. 1605–1610.
Trifluoroacetic Anhydride as an Activator in the Acylation
of Aryl Methyl Ketones with Carboxylic Acids
E. A. Shokovaa,*, V. A. Tafeenkoa, and V. V. Kovaleva
a Faculty of Chemistry, Moscow State University, Moscow, 119991 Russia
*e-mail: shokova@petrol.chem.msu.ru
Received July 1, 2018; revised February 13, 2020; accepted February 14, 2020
Abstract—Trifluoroacetic anhydride was used as an efficient activator of the acylation of aryl methyl ketones
with carboxylic acids in the presence of Brønsted and Lewis acids (SF3SO3H, MeSO3H, 4-MeC6H4SO3H·H2O,
BF3·Et2O). In all cases, the products were the corresponding β-diketones. In the reactions in the presence of
boron trifluoride–diethyl ether complex, the products were isolated as BF2-chelates with high yields.
Keywords: 1,3-diketones, acylation, trifluoroacetic anhydride, carboxylic acids, aryl methyl ketones, acid
catalysis
DOI: 10.1134/S1070428020100164
β-Dicarbonyl compounds constitute one of the most
important classes of organic compounds and are widely
used as key building blocks in organic synthesis. They
also exhibit various kinds of biological activity, includ-
ing antitumor, antiviral, anti-inflammatory, antioxidant,
and antimicrobial activities, as well as a broad spec-
trum of ionophoric properties [1–4].
β-diketones widely needed in organic synthesis and
synthesized heterocyclic compounds from arenes and
carboxylic acids by one-pot reactions [6, 7].
The goal of the present work was to find out
whether TFAA can be used as an activating agent in the
synthesis of β-diketones in the presence of other acid
catalysts that are more accessible than trifluoro-
methanesulfonic acid. The substrates were aromatic
methyl ketones: acetophenone (1a) and 2-acetylthio-
phene (1b). Apart from CF3SO3H, Brønsted acids,
namely methanesulfonic acid (MeSO3H) and p-tolu-
enesulfonic acid (TsOH·H2O), and a Lewis acid, boron
trifluoride–diethyl ether complex (BF3·Et2O) were
used as catalysts.
We previously reported [5] for the first time the
synthesis of β-keto acids directly from carboxylic acids
without preliminary activation of the latter. Carboxylic
acids containing branched alkyl groups [such as 3.3-di-
methylbutanoic, 2-methylbutanoic, and 2-(adamantan-
1-yl)acetic acids] in the system trifluoroacetic anhy-
dride (TFAA)/trifluoromethanesulfonic acid undergo
self-acylation to produce the corresponding β-dicar-
bonyl compounds. Trifluoroacetic anhydride readily
reacts with carboxylic acids to give mixed anhydrides,
acyl trifluoroacetates, thus playing the role of an ac-
tivatng agent. Trifluoromethanesulfonic acid used as
catalyst favors enolization of carbonyl compounds and
enhances the acylating activity of acyl trifluoroacetates.
Using the system TFAA/CF3SO3H we have developed
a simple and efficient procedure for the preparation of
Acetophenone (1a) reacted with 3.3-dimethylbuta-
noic acid (2a) in TFAA in the presence of MeSO3H or
TsOH·H2O (reactant molar ratio 1a–2a–TFAA–catalyst
= 1:1:6:1) to give β-diketone 3a, as in the presence of
trifluoromethanesulfonic acid [6] (Scheme 1). The
maximum yields of 3a were achieved after heating the
reactants for 4-h in boiling nitromethane in the pres-
ence of MeSO3H (60–65%) or TsOH·H2O (57–60%).
For comparison, the yield of 3a in the reaction cata-
Scheme 1.
O
O
O
O
TFAA, catalyst, solvent
+
R
R
Ph
Me
OH
Ph
1a
2a, 2b
3a, 3b
R = t-Bu (a), 1-Ad (b); Catalyst = CF3SO3H, MeSO3H, TsOH∙H2O; solvent: CH2Cl2, MeNO2.
1770

TRIFLUOROACETIC ANHYDRIDE AS AN ACTIVATOR
1771
Scheme 2.
F
F
B
TFAA, BF3·Et2O
CH2Cl2, r.t.
O
O
O
1a
+
t-Bu
t-Bu
OH
Ph
2a
4, 52%
Scheme 3.
O
O
O
O
TFAA, CF3SO3H
CH2Cl2, r.t.
O
S
R
O
+
2a, 2b
+
t-Bu
S
Me
S
Bu-t
1b
5a, 5b
6
R = t-Bu (a), 1-Ad (b); reaction conditions: ratio 1b–2–TFAA–CF3SO3H 1:1:6:1, reaction time 22 h (a);
1:1:3:1, 48 h (b); 1:1:1.5:1, 24 h (c); 1:2:3:1, 24 h (d).
lyzed by CF3SO3H (CH2Cl2, room temperature, 2–4 h)
was 70%. In the reactions catalyzed by MeSO3H at
room temperature (3 days), the yields of β-diketone 3a
were lower, 35% in CH2Cl2 and 23% in MeNO2.
A similar reaction of acetophenone with 2-(adamantan-
1-yl)acetic acid (2b) in nitromethane in the presence of
MeSO3H gave 25% of adamantyl-containing β-di-
ketone 3b after 2 h under reflux, though the yield of 3b
in the presence of trifluoromethanesulfonic acid was
almost twice as high (47%) [6].
previously. We were the first to carry out this reaction
in the presence of trifluoromethanesulfonic acid as
acylation catalyst. It was found that the major product
in the reaction of equimolar amounts of 1b, 2a, and
CF3SO3H was β-diketone 5a (yield 56–60%;
Scheme 3, a–c) and that 3 equiv of TFAA was suf-
ficient. When 2 equiv of 2a was used, the yield of 5a
reached 90% (Scheme 3, d). 2,5-Disubstituted thio-
phene 6 containing mono- and β-dicarbonyl substit-
uents was also formed as minor product whose yield
did not exceed 5%. In the reaction of 1b with 2-(ada-
mantan-1-yl)acetic acid (Scheme 3, c, 24 h), the only
product was adamantyl-containing β-diketone 5b; its
yield (80%) was significantly higher than in the pres-
ence of 0.5 equiv of trifluoromethanesulfonic acid [6].
The acylation of acetophenone (1a) with 2,2-di-
methylbutanoic acid (2a) in TFAA in the presence of
BF3·Et2O was quite efficient. After 48 h at room
temperature (ratio 1a–2a–TFAA–catalyst = 1:1:3:1),
the corresponding diketone was formed with a high
yield and was isolated as boron chelate 4 (Scheme 2).
Table 1 shows the results obtained in the reaction of
α-acetylthiophene (1b) with 3,3-dimethylbutanoic acid
in TFAA in the presence of MeSO3H, TsOH·H2O, and
The acylation of acetylthiophene (1b) with 3,3-di-
methylbutanoic acid (2a) in TFAA has not been studied
Table 1. Reaction of α-acetylthiophene (1b) with 3,3-dimethylbutanoic acid (2a) in TFAA in the presence of MeSO3H,
TsOH·H2O, and BF3·Et2Oa
Yield,b %
Entry no.
Catalyst
Solvent
Temperature, °C
Reaction time, h
5a
Traces
28
6
Traces
20
2a
90
40
1
MeSO3H
CH2Cl2
CH2Cl2
MeNO2
MeNO2
CH2Cl2
CH2Cl2
Reflux
3
3
2
TsOH·H2O
MeSO3H
Reflux
3
75
4
28
13
4
TsOH·H2O
TsOH·H2O
BF3·Et2O
75
4
23
7
18
23
5
6c
Room temperature
48
96
32
60d
3
Room temperature
a Amounts of reactants: 1b, 1 mmol; 2a, 1 mmol; TFA, 6 mmol; catalyst, 1 mmol.
b Isolated yield based on the initial ketone.
c 3 equiv of TFAA was used.
d The product was isolated as BF2 chelate 7 (Fig. 1).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

SHOKOVA et al.
1772
Scheme 4.
O
O
O
O
2a, TFAA, TsOH·H2O
MeNO2, 75°C, 7.5 h
Ad
Bu-t
+
6
S
S
5b
5a, 10%
50%
BF3·Et2O. It is seen that replacement of fairly expen-
sive CF3SO3H by more accessible MeSO3H and
p-toluenesulfonic acid did not change the reaction
direction. Under the given conditions (Table 1, entry
nos. 1–5), the major product was (as before) β-diketone
5a. However, the yield of 5a did not exceed 35% based
on the initial acetylthiophene. Nevertheless, the syn-
thesis of 5a in the presence of TsOH as a cheap catalyst
(3 equiv of TFAA, room temperature; Table 1, entry
no. 5) seems fairly promising.
amount of triketone 6 (50%) significantly exceeded the
amount of transacylation product 5a (10%). It should
be noted that transacylation of β-diketones is well
known and that this reaction is fairly general [8].
The ease of formation and purification and rela-
tively high yield of difluoroborate 7 in the presence of
BF3·Et2O as catalyst (Table 1, entry no. 6) are worth
noting. In this case, no 2,5-disubstituted thiophene
derivatives were formed. The structure of chelate 7 was
determined by X-ray analysis (Fig. 1).
Our results suggest higher reactivity of the CH3CO
group than of the 5-position of the thiophene ring in the
initial ketone; furthermore, elevated temperature favors
formation of disubstituted thiophene 6. Thus, the reac-
tion of 5a with 3,3-dimethylbutanoic acid (2a) in
TFAA in the presence of TsOH·H2O in boiling methy-
lene chloride afforded 40% of 6.
In summary, we have studied the possibility of
using trifluoroacetic anhydride to activate acylation of
aryl methyl ketones with carboxylic acids in the
presence of some acid catalysts (CF3SO3H, CH3SO3H,
p-MeC6H4SO3H H2O, BF3·Et2O) with a view to ob-
taining β-diketones. It has been found that the target
β-dicarbonyl compounds can be synthesized in high
yields using more accessible (than previously proposed
trifluoromethanesulfonic acid) methanesulfonic acid,
p-toluenesulfonic acid, and boron trifluoride–diethyl
ether complex. In the reactions catalyzed by BF3·Et2O,
the products were isolated as BF2 chelates.
An attempt to acylate adamantyl-containing β-di-
ketone 5b with 3,3-dimethylbutanoic acid in TFAA
(2a–5b–TFAA–TsOH = 1:1:6:1) gave unexpected
results. We isolated β-diketone 5a and disubstituted
thiophene 6 containing only fragments of 3,3-dimethyl-
butanoic acid (Scheme 4). Presumably, the reaction
involves transacylation of 5b to diketone 5a, and the
latter is acylated with 3,3-dimethylbutanoic acid. The
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400 and
100 MHz, respectively, using CDCl3 as solvent and
reference. The X-ray diffraction data for compound 7
were obtained with a STOE diffractometer equipped
with a Pilatus 100K semiconductor detector (Cu Kα
radiation, λ 1.54086 Å; multilayer focusing monochro-
mator). The data were processed using STOE X-AREA
1.67 package (STOE&Cie, Darmstadt, Germany, 2013)
and LANA program included in the X-Area package to
minimize differences in equivalent reflections (multi-
scan method). Analytical thin-layer chromatography
was performed using Merck DC Alufolien Kieselgel
60 F254 plates; spots were visualized under UV light
(λ 254 nm). Silica gel Kieselgel 40/60 (Merck) was
used for preparative column chromatography. Trifluoro-
acetic anhydride was distilled over P2O5 prior to use.
C4
C5
C3
C7
C2
S1
C9
C6
O2
C13
C10
C8
F1
O1
C11
B1
C12
F2
Fig. 1. Structure of the molecule of (5,5-dimethyl-1-(thio-
phen-2-yl)-3-oxohex-1-en-1-olato)difluoroboron (7) accord-
ing to the X-ray diffraction data. Non-hydrogen atoms are
shown with 50% probability thermal vibration ellipsoids.
General procedure for the acylation of aryl
methyl ketones 1a and 1b with carboxylic acids 2a
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

TRIFLUOROACETIC ANHYDRIDE AS AN ACTIVATOR
1773
and 2b. A mixture of reactants was kept for a required
time at a required temperature (for details, see text).
The mixture was treated with water and extracted with
methylene chloride. The extract was washed in succes-
sion with water, a 2% solution of sodium hydrogen
carbonate until weakly alkaline washings, and water
until neutral washings, dried over magnesium sulfate,
and evaporated. The residue was subjected to column
chromatography on silica gel using methylene chloride
as eluent. Boron chelates 4 and 7 were isolated by
evaporation of the reaction mixture, followed by
treatment of the residue with hexane. β-Diketones 3a,
3b, and 5b were reported previously [6].
reflux, 5 h. Yield 129 mg (40%), light yellow powder,
mp 172–174°C, Rf 0.55 (CHCl3). H NMR spectrum,
1
δ, ppm (ketone–enol ratio 2:98): enol: 1.05 s (9H,
t-Bu), 1.07 s (9H, t-Bu), 2.25 s (2H, CH2), 2.77 s (2H,
CH2), 6.00 s (1H, CH=), 7.65 d (2H, Harom, J = 3.7 Hz).
13C NMR spectrum, δC, ppm: 29.5 [C(CH3)3], 29.6
[C(CH3)3], 31.4 [C(CH3)3], 31.7 [C(CH3)3], 50.9
(CH2), 51.0 (CH2), 98.0 (CH=), 129.5 (CHarom), 131.7
(CHarom), 147.0 (Carom), 149.2 (Carom), 180.2 [=C(OH)],
190.7 (C=O), 192.7 (C=O). Found, %: C 67.33;
H 8.26; S 9.56. C18H26O3S. Calculated, %: C 67.04;
H 8.13; S 9.94. M 322.46.
(5,5-Dimethyl-1-(thiophen-2-yl)-3-oxohex-1-en-
1-olato)difluoroboron (7) was synthesized by reaction
of ketone 1b (0.105 mL, 1 mmol), acid 2a (0.13 mL,
2 mmol), TFAA (0.42 mL, 3 mmol), and TsOH·H2O
(0.19 g, 1 mmol) in 2 mL of CH2Cl2; reflux, 5 h. Yield
129 mg (60%), colorless transparent crystals, mp 138–
(5,5-Dimethyl-1-phenyl-3-oxohex-1-en-1-olato)-
difluoroboron (4) was synthesized by reaction of
ketone 1a (0.120 mL, 1 mmol) with acid 2a (0.13 mL,
1 mmol), TFAA (0.42 mL, 3 mmol), and BF3·Et2O
(0.13 mL, 1 mmol) in 2 mL of CH2Cl2; room tempera-
ture, 48 h. Yield 138 mg (52%), light yellow powder,
mp 118–119°C, Rf 0.70 (CHCl3). 1H NMR spectrum, δ,
ppm: 1.04 s (9H, t-Bu), 2.48 s (2H, CH2), 6.55 s (1H,
1
139°C, Rf 0.70 (CHCl3). H NMR spectrum, δ, ppm:
1.10 s (9H, t-Bu), 2.44 s (2H, CH2), 6.31 s (1H, CH=),
7.26 m (1H, Harom), 7.87 d (1H, Harom, J = 4.8 Hz),
8.01 d (1H, Harom, J = 3.9 Hz). 13C NMR spectrum, δC,
ppm: 29.6 [C(CH3)3], 33.1 [C(CH3)3], 50.8 (CH2), 97.9
(CH=), 129.1 (CHarom), 134.8 (CHarom), 135.9 (Carom),
137.2 (CHarom), 175.6 [=C(OB)] 192.6 (C=O).
Found, %: C 53.19; H 5.33; S 11.69. C12H16O2S.
Calculated, %: C 52.97; H 5.56; S 11.78. M 272.12.
Crystallographic data: C12H16O2S (M 272.12); triclinic
crystal system, space group P-1; unit cell parameters:
a = 6.9641(5), b = 9.6509(7), c = 11.1094(6) Å; α =
103.362(6), β = 91.794(6), γ = 109.906(6)°; V =
678.09(9) Å3; Z = 2; dcalc = 1.333 g/cm3. The X-ray
diffraction data for compound 7 were deposited to the
Cambridge Crystallographic Data Centre (CCDC entry
no. 1850382) and are available at www.ccdc.cam.
ac.uk/data_request/cif.
CH=), 7.53 t (2H, Harom, J = 7.6 Hz), 7.68 t (1H, Harom
,
J = 7.6 Hz), 8.05 d (2H, Harom, J = 7.6 Hz). 13C NMR
spectrum, δC, ppm: 29.6 [C(CH3)3], 33.2 [C(CH3)3],
51.1 (CH2), 98.5 (CH=), 128.6 (CHarom), 128.8
(CHarom), 130.9 (Carom), 135.0 (CHarom), 181.9 (=COB),
194.4 (C=O). Found, %: C 63.51; H 6.14; F 13.88.
C14H17BF2O2. Calculated, %: C 63.19; H 6.44; F 14.28.
M 266.09.
5,5-Dimethyl-1-(thiophen-2-yl)hexane-1,3-dione
(5a) was synthesized by reaction of 1b (0.105 mL,
1 mmol), 2a (0.26 mL, 2 mmol), TFAA (0.42 mL,
3 mmol), and CF3SO3H (0.088 mL, 1 mmol) in 2 mL
of CH2Cl2; room temperature, 24 h. Yield 201 mg
(90%), lustrous orange powder, mp 58–60°C, Rf 0.75
(CHCl3). 1H NMR spectrum, δ, ppm (ketone–enol ratio
4:96): enol: 1.03 s (9H, t-Bu), 2.09 s (2H, CH2), 5.94 s
(1H, CH=), 7.11 m (1H, Harom), 7.58 d (1H, Harom, J =
4.8 Hz), 7.67 d (1H, Harom, J = 3.5 Hz), 15.66 br.s (1H,
OH). 13C NMR spectrum, δC, ppm: 29.5 [C(CH3)3],
31.5 [C(CH3)3], 50.4 (CH2), 97.5 (CH=), 127.8
(CHarom), 129.8 (CHarom), 132.1 (CHarom), 142.0
(Carom), 182.5 [=C(OH)], 187.4 (C=O). Found, %:
C 64.47; H 7.36; S 14.39. C12H16O2S. Calculated, %:
C 64.25; H 7.19; S 14.29. M 224.32.
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
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