Selective acylation of phenols in boron trifluoride diethyl etherate solution and the mechanistic implication

Article abstract of DOI:10.14233/ajchem.2014.17019

In the presence of boron trifluoride diethyl etherate (BF₃ · OEt₂), direct acylation of phenols with free carboxylic acid is chemoselective and regioselective and no demethylation, if any, was observed. The para-directing effect of BF₃·OEt₂ is attributed to the large steric hindrance of the boron trifluoride-phenolic hydroxyl group complex, which blocks the ortho-acylation from occurrence. Microwave irradiation could not change the regioselectivity of BF₃·OEt₂ except the reaction time being greatly shortened.

Full text of DOI:10.14233/ajchem.2014.17019

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 8039-8042
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17019
Selective Acylation of Phenols in Boron Trifluoride Diethyl
Etherate Solution and the Mechanistic Implication
*
ZHU-PING XIAO , WEI WEI, SHEN HUANG, XIAO-YI LIN, BIN PENG, XU-DONG WANG and LEI ZHANG
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, P.R. China
*Corresponding author: Tel/Fax: + 86 74 8563911; E-mail: xiaozhuping2005@163.com
Received: 10 January 2014;
Accepted: 10 April 2014;
Published online: 15 November 2014;
AJC-16289
In the presence of boron trifluoride diethyl etherate (BF3·OEt2), direct acylation of phenols with free carboxylic acid is chemoselective
and regioselective and no demethylation, if any, was observed. The para-directing effect of BF3·OEt2 is attributed to the large steric
hindrance of the boron trifluoride-phenolic hydroxyl group complex, which blocks the ortho-acylation from occurrence. Microwave
irradiation could not change the regioselectivity of BF3·OEt2 except the reaction time being greatly shortened.
Keywords: Regioselectivity, Direct acylation of phenol, Boron trifluoride diethyl ehterate.
and solvent signals allotted as internal standards. Chemical
INTRODUCTION
shifts were reported in ppm (δ). Elemental analyses were
Hydroxyaryl ketones are versatile intermediates for syn-
performed on a CHN-O-Rapid instrument and were within
thesis of chalcones1,2, aryl pyrazoles3, flavonoids4,5 and alkyl
0.4 % of the theoretical values.
phenols6, which show interesting pharmacological properties
including antiinflammatory, telomerase inhibitory and
antimicrobial activities. In view of the preparation of hydroxy-
aryl ketones, the typical approach is cascade chlorination of a
Crystallographic studies: X-ray single-crystal diffraction
data for compound 14 was collected on a Bruker SMART
APEX CCD diffractometer at 296(2) K using MoKα radiation
(λ = 0.71073 Å) by the ω scan mode. The program SAINT was
carboxylic acid, esterification with phenols and Fries rearr-
used for integration of the diffraction profiles.All the structures
angement in the presence of a Lewis acid7,8. By comparison, a
were solved by direct methods using the SHELXS program
one pot acylation of a phenol with free carboxylic acids has
of the SHELXTL package and refined by full-matrix least-
attracted much interest9. Over the past decades, a method of
squares methods with SHELXL. All non-hydrogen atoms of
compound 14 were refined with anisotropic thermal para-
direct condensation of a phenol with a carboxylic acid in the
presence of boron trifluoride gas has been developed for this
meters. All hydrogen atoms were generated theoretically onto
end and was used in several instances10,11.A variety of strategies
the parent atoms and refined isotropically with fixed thermal
have been proposed to modify this method, including substi-
factors.
tution of boron trifluoride diethyl etherate (BF3·OEt2) for boron
trifluoride gas12 and microwave-assisted condensation13,14
.
General procedure for acylation
However, the selectivity and mechanism of these reactions are
so far lacking in detail. Herein, we report our findings.
Method A: Phenol (12-15 mmol) and aliphatic acid (10
mmol) were dissolved into 10 mL of BF3·Et2O. The mixture
was stirred and heated on the oil-bath at 80-90 °C for 2-4 h.
After cooling, the contents were poured into 200 mL of ice-
cold aqueous solution of sodium acetate (w. % = 10 %) with
stirring. Then, the precipitate was filtered and washed thrice
with water. The crude product was purified by a flash
chromatography with EtOAc-petroleum ether (v:v = 1:2 to
1:3) to afford colourless crystals.
EXPERIMENTAL
All chemicals (reagent grade) used were purchased from
Aldrich (U.S.A) and Sinopharm Chemical Reagent Co., Ltd
(China). All microwave experiments were performed using
an APEX microwave synthesizer (PreeKem, China). Melting
points (uncorrected) were determined on a XT4 MP apparatus
(Taike Corp., China). EI mass spectra were obtained on a
Method B: Phenol (10 mmol) and aliphatic acid (20-30
mmol) were dissolved into 10 mL of BF3·Et2O. The mixture
was stirred and heated on the oil-bath at 80-90 °C for 2-4 h.
1
Waters GCT mass spectrometer and H NMR spectra were
recorded on a BrukerAV-300 spectrometer at 25 °C with TMS

8040 Xiao et al.
Asian J. Chem.
After cooling, the contents were poured into 200 mL of ice-
cold aqueous solution of sodium acetate (w. % = 10 %) with
stirring. Then, the mixture was extracted with EtOAc and dried.
After removal of solvent, the crude product was from EtOAc-
petroleum (v:v = 1:1 to 1:3) to give colourless crystals.
Mthod C: The conditions and procedures are the same
as method A or B except substitution microwave irradiation
for heat and the volume of BF3·Et2O being halved.
1-(3,4-Dihydroxyphenyl)-2-(4-fluorophenyl)ethanone
(18):Yield 79 % (86 % for microwave irradiation); m.p. 187-
188 °C. 1H NMR (d6-DMSO): 4.23 (s, 2H), 8.82 (d, 1H, J =
8.4 Hz), 7.12 (t, 2H, J = 9.2 Hz), 7.26 (dd, 2H, J = 8.8 Hz, J =
5.6 Hz), 7.39 (d, 1H, J = 2.4 Hz), 7.47 (dd, 1H, J = 8.0 Hz,
J = 2.0 Hz), 9.35 (s, 1H), 9.89 (s, 1H). EI-MS C14H11FO3 (M+)
246. Anal. calc. for C14H11FO3: C, 68.29; H, 4.50; F, 7.72.
Found: C, 68.37; H, 4.49; F, 7.71.
1H, J = 8.4 Hz), 6.85 (d, 1H, J = 1.6 Hz), 6.86 (d, 1H, J = 8.0
Hz), 7.39 (d, 1H, J = 2.0 Hz), 7.46 (dd, 1H, J = 8.4 Hz, J = 2.4
Hz), 9.33 (s, 1H), 9.86 (s, 1H). EI-MS C16H16O5 (M+) 224.Anal.
calc. for C16H16O5: C, 66.66; H, 5.59. Found: C, 66.59; H, 5.59.
RESULTS AND DISCUSSION
During our drug discovery program on the synthesis of
polyphenols as urease inhibitors15-17, a series of hydroxyaryl
ketones were designed and synthesized by direct condensation
of phenols with carboxylic acids in BF3·OEt2 according to the
previous described method (Scheme-I)12. In comparison with
phenol and pyrogallol, catechol not only has ortho-, meta-
and para-positions being available but also shows a good
reactivity and was therefore selected to explore the chemo-
and regioselectivity.
1-(3,4-Dihydroxyphenyl)-2-(4-chlorophenyl)ethanone
(19):Yield 83 % (95 % for microwave irradiation); m.p. 200-
202 °C. 1H NMR (d6-DMSO): 4.24 (s, 2H), 8.82 (d, 1H, J =
8.0 Hz), 7.25 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz),
7.38 (d, 1H, J = 2.0 Hz), 7.47 (dd, 1H, J = 8.0 Hz, J = 2.0 Hz),
9.36 (s, 1H), 9.90 (s, 1H). EI-MS C14H11ClO3 (M+) 262. Anal.
calc. for C14H11ClO3: C, 64.01; H, 4.22; Cl, 13.50. Found: C,
63.96; H, 4.22; Cl, 13.52.
1-(3,4-Dihydroxyphenyl)-2-(3,4-dimethoxyphenyl)-
ethanone (20): Yield 86 % (90 % for microwave irradiation);
m.p. 179-181 °C. 1H NMR (d6-DMSO): 3.709 (s, 3H), 3.711 (s,
3H), 4.12 (s, 2H), 6.74 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz), 6.81 (d,
O
HO
HO
HO
HO
BF3 Et2O
+
R
OH
Heat,or microwave
irradiation
R
O
1
2
Scheme-I: Direct acylation of phenol with free carboxylic acid
First of all, a general reaction condition was explored and
the results are shown in Fig. 1, which disclosed that a tempe-
rature of 90 °C was sufficient to complete the condensation
reaction. This one pot procedure is particularly useful for pre-
paring ketones with long chains and leads to uniformly high
yields, usually in a range of 68 to 90 % (Table-1). It is noted
TABLE-1
ACYLATION PRODUCTS OF PHENOL
R1
R2
Method/
Yield (%)
Energy
(w)
m.p. (°C)
Found/Reported
R3
Time
Compound
O
R1
R2
R3
B/62
C/78
B/64
C/82
B/69
C/90
A/76
C/86
A/68
C/83
A/70
C/78
A/72
C/89
A/74
C/92
A/79
C/86
A/83
C/95
A/86
-
300
-
300
-
300
-
300
-
300
-
300
-
300
-
300
-
2 h
2.5 min
2.5 h
2.5 min
3 h
2.5 min
2.5 h
2.5 min
3 h
2.5 min
3 h
3 min
3 h
117-119/
114-11518
10
11
12
13
14
15
16
17
18
19
OH
OH
Methyl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Propyl
Pentyl
139-140/1396
91-93/93-9419
97-99/95.5-966
Heptyl
Nonyl
106-108/
102-10420
Undecyl
Tridecyl
108-109/97-9821
110-112/98-9921
209-210/21112
187-188
3 min
4 h
OH
3 min
3.5 h
3 min
3.5 h
3 min
3.5 h
F
300
-
300
-
Cl
200-202
OMe
20
21
22
OH
OH
179-181
156-15822
133-13523
C/90
300
3 min
OMe
A/68
C/86
A/78
C/89
-
4 h
3 min
3 h
OH
Cl
OMe
OMe
OMe
OMe
300 w
-
300 w
3 min

Vol. 26, No. 23 (2014)
Selective Acylation of Phenols in Boron Trifluoride Diethyl Etherate Solution 8041
80 oC
70 oC
50 oC
90 oC
90
80
70
60
50
40
30
20
10
0
Fig. 2. Single crystal structure of compound 14
However, to our surprise, Hossein Naeimi et al.13,14 reported
a quite different result. They claimed that acylation of phenol
and naphthol derivatives with acetic acid gave regioselectively
ortho acylated products in the presence of BF3·OEt2 under
microwave irradiation. To check their reported results, we then
treated catechol with acetic acid as the description of Hossein
Naeimi. Unfortunately, no ortho acylated product (2,3-
dihydroxyacetophenone) was observed and the isolated
product is identified as 3,4-dihydroxyace-tophenone (10, the
para acylated product), suggesting that the para-directing
effect of BF3·OEt2 would not change with whether or not having
microwave irradiation. Nevertheless, it must be admitted that
the reaction time is greatly shortened.
0
5
10
15
20
25
Time (h)
Fig. 1. Effect of reaction temperature on the yield of compound 20 at
different time
that, as for substrates containing methoxy group, demethylation
possibly caused by BF3·OEt2 was not observed20-22
.
With the above mentioned observations, we are able
to propose a plausible mechanism to understand the highly
chemoselective and regionselective acylation of catechol at
the presence of BF3·OEt2 (Scheme-II). It is well known that
the powerful electron withdrawing effect of carbonyl group
leads to a significant decrease in electron cloud around OH in
carboxylic acid. Therefore, in comparison with carboxylic acid,
BF3·OEt2 prefers to react with catechol, giving the Lewis adduct
5. Based on this hypothesis, reaction of a carboxylic acid with
BF3·OEt2 occurs only when the ratio of BF3·OEt2 to catechol
is over 1:1 and results in the formation of an acylating agent
4. This was evidenced by observations in acylation of catechol
with butanoic acid (Table-2). In the Lewis adduct 5, the rotation
of C-O single bond causes a fast migration of BF3 between
two hydroxyl groups to give species 6 with occupation numbers
of BF3 being 0.5 at both sites, which causes a significant
increase in steric hindrance around ortho-positions of hydroxyl
groups. The steric effects of the boron trifluoride catechol
complex (6) disfavor the attack of species 4 at ortho-positions,
resulting in the para-directing effect of BF3·OEt2. Therefore,
the para-isomer 2 is predominantly given and the ortho-
analogue, if any, is too little to be observed. On the other hand,
the positive charge atmosphere around hydroxyl groups in
complex 6 blocks from the access of acylium ion 4 to form O-
acylated product 9.
In theory, acylation of a phenol with a carboxyl acid could
possibly afford O-acylation and C-acylation products at the
presence of BF3·OEt2. To verify the possibility of O-acylation,
butanoic acid was then selected to react with catechol in
different ratios. The reaction was monitored by TLC and results
are shown in Table-2. Our data revealed that the para-C-acyla-
tion product is observed at the ratio of BF3·OEt2 to catechol
being over 1:1.At the ratio lower than 1:1, O-acylation product
was once expected to be given when butanoic acid is treated
with BF3·OEt2 before the addition of catechol. However, no
O-acylation product was observed in any case, indicating that
this condensation reaction is chemoselective.
As shown in Table-1, these reactions furnished 3,4-
dihydroxyphenyl ketones (10-17, 21-22) in good yields, which
were confirmed by melting points. While compounds 18-20
with melting points not reported previously were further
characterized by elemental analyses, MS and 1H NMR spectra.
In addition, the structure of compound 14 was also confirmed
by single crystal X-ray crystallography (Fig. 2). It is noted
that no 2,3-dihydroxyphenyl ketones was isolated, revealing
that the acyl radical enters predominantly the para position
under the influence of BF3·OEt2. The regioselectivity was
further supported by our literature survey. Several direct acyla-
tion of phenol and catechol, using BF3·OEt2 as a promoter,
also gave para-hydroxyaryl ketone derivatives10,12
.
TABLE-2
ACYLATION OF CATECHOL WITH BUTANOIC ACID AT 90 °C
Possible product
O
HO
O
Catechol
(mmol)
Butanoic acid
(mmol)
BF3·OEt2
(mmol)
HO
HO
Entry
Pr-n
n-Pr
O
par a-C-acylation
O-acylation
1
2
3
4
5
2
2
2
2
2
11
11
11
11
11
1
2
3
4
8
not observed
not observed
observed
observed
observed
not observed
not observed
not observed
not observed
not observed

8042 Xiao et al.
Asian J. Chem.
BF
O
3
BF
O
3
R
R
O
R
Et
Et
H
H
+
HOBF
3
O
O
O
3
4
1
BF
O
3
BF
3
O
O
O
fast
Et
Et
H
H
H
H
H
H
O
O
O
BF
3
BF
O
3
O
O
R
1/2
5
HO
HO
H
R
H
H
O
BF
para-C-acylated product
3
1/2
1/2
O
R
BF
O
R
O
3
3
1/2
1/2
R
2
7
O
H
H
O
BF
O
H
3
O
O
BF
H
H
BF
9
3
8
ortho-C-acylated product
R
O
O
6
O-Acylated product
BF
3
1/2
O
R
Scheme-II: Mechanism of para-selective acylation of phenol catalyzed by BF3·OEt2
Conclusion
Reaction of phenols with free carboxylic acid in BF3·OEt2
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shows high chemoselectivity and regioselectivity, which
predominantly give the para-C-acylated product whether or
not having microwave irradiation. This para-directing effect
of BF3·OEt2 may attribute to the large steric hindrance of the
boron trifluoride-phenolic hydroxyl group complex. Never-
theless, the reaction time is greatly shortened with the micro-
wave assistance. No demethylation was observed in the case
of phenol ethers.
ACKNOWLEDGEMENTS
16. Z.P. Xiao, T.W. Ma, W.C. Fu, X.C. Peng, A.H. Zhang and H.L. Zhu,
Eur. J. Med. Chem., 45, 5064 (2010).
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Zhou, X.J. Hu, L.J. Wu, Y. Zhou and H.L. Zhu, J. Agric. Food Chem.,
60, 10572 (2012).
This work is financed by grants from National Natural
Science Foundation (grant No. 81273382) of China and by a
Project supported by Hunan Provincial Natural Science Foun-
dation of China (grant No. 13JJ2030)
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Catal. Commun., 6, 753 (2005).
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