Microwave-accelerated selective acylation of (hydroxyalkyl)phenols using acid chlorides

Article abstract of DOI:10.1080/00397910802499534

Highly selective acylation of the alcoholic hydroxy group can be achieved with (hydroxyalkyl)phenols carrying both alcoholic and phenolic hydroxyls by the use of the most common acylating agents, acid chlorides, under microwave irradiation. Copyright Tayl

Full text of DOI:10.1080/00397910802499534

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Microwave-Accelerated
Selective Acylation of
(Hydroxyalkyl)phenols Using
Acid Chlorides
Toshifumi Miyazawa a , Masato Yamamoto a & Yuki
Maeda a
a Department of Chemistry , Faculty of Science and
Engineering, Konan University , Kobe, Japan
Published online: 25 Feb 2009.
To cite this article: Toshifumi Miyazawa , Masato Yamamoto & Yuki Maeda
(2009) Microwave-Accelerated Selective Acylation of (Hydroxyalkyl)phenols
Using Acid Chlorides, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:6, 1092-1099, DOI:
10.1080/00397910802499534
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Synthetic Communications1, 39: 1092–1099, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802499534
Microwave-Accelerated Selective Acylation of
(Hydroxyalkyl)phenols Using Acid Chlorides
Toshifumi Miyazawa, Masato Yamamoto, and Yuki Maeda
Department of Chemistry, Faculty of Science and Engineering, Konan
University, Kobe, Japan
Abstract: Highly selective acylation of the alcoholic hydroxy group can be
achieved with (hydroxyalkyl)phenols carrying both alcoholic and phenolic
hydroxyls by the use of the most common acylating agents, acid chlorides, under
microwave irradiation.
Keywords: Acid chlorides, (hydroxyalkyl)phenols, microwave-assisted synthesis,
selective acylation
INTRODUCTION
Acylation has been employed as the most generally useful protecting
method for the hydroxy functionalities.[1] In general, acylation is carried
out by treatment of an alcohol with an appropriate acyl halide or anhy-
dride. Acid chlorides are often used in pyridine and acid anhydrides in the
presence of such acylation promoters as 4-(dimethylamino)pyridine
(DMAP) or 4-pyrrolidinopyridine (PPY),[2] so that even hindered hydro-
xyls are smoothly acylated. The high catalytic activity of these com-
pounds is attributable to the formation of N-acylpyridinium ions as
hyperreactive intermediates. On the other hand, it is usually difficult to
conduct a selective acylation of compounds bearing multiple hydroxyls.
Therefore, a wide variety of reagents[3] and auxiliaries[4] have been
Received August 18, 2008.
Address correspondence to Dr. Toshifumi Miyazawa, Department of Chemis-
try, Faculty of Science and Engineering, Konan University, 8-9-1 Okamoto,
Higashinada-ku, Kobe 658-8501, Japan. E-mail: miyazawa@konan-u.ac.jp
1092

Selective Acylation of (Hydroxyalkyl)phenols
1093
developed for selective acylation of polyhydric compounds, which is still
a fundamental but important topic in synthetic organic chemistry. The
regioselective properties of enzymes have also been exploited for such a
purpose. For example, the lipase-catalyzed acylation or deacylation pro-
cedure has been applied to the synthesis of selectively protected deriva-
tives of polyhydroxy compounds such as carbohydrates.[5] Recently, we
also have reported on the Candida antarctica lipase B–catalyzed regiose-
lective acylation[6] of dihydroxybenzenes and deacylation[7] of them acyla-
ted at both phenolic hydroxyls. During the course of our continuing study
on the enzyme-catalyzed selective acylation of polyhydric compounds, we
needed to prepare authentic samples by chemo-enzymatic methods and
found that with (hydroxyalkyl)phenols carrying both alcoholic and phe-
nolic hydroxyls, highly selective acylation of the alcoholic hydroxy group
can be achieved by the use of the most common acylating agents, acyl
chlorides, under microwave irradiation. This information forms the sub-
ject of the present communication.
RESULTS AND DISCUSSION
Initially, 2-(4-hydroxyphenyl)ethanol (1e) was chosen as a model
compound and its acylation was examined under various reaction condi-
tions (Fig. 1). The diol 1e can undergo acylation through two pathways
to form either the alkyl monoester (1f) or the phenyl monoester (1g) and
finally to afford the diester (1h). The distribution of products was deter-
1
mined by the H NMR analysis of the reaction mixture. The most com-
mon acylation method employing acetyl chloride (2 mol equiv) in
pyridine yielded the diester as the major product, besides a fair amount
of the alkyl ester, but no phenyl ester after 45 min needed for the com-
plete consumption of the starting diol at 25 ꢀC (1f, 16.6%; 1g, 0%; 1h,
83.4%). On the other hand, when acetyl chloride (3 mol equiv) alone
was used in tetrahydrofuran as a solvent, it was found that the alkyl ester
was formed as a sole acylation product, contrary to expectations, though
the yield was not very high (entry 1 in Table 1). In the presence of
pyridine (3 mol equiv), the outcome became different: the starting diol
was consumed completely within the same reaction time, and besides
the alkyl ester a fair amount of the diester was produced (entry 3). When
triethylamine (3 mol equiv) was employed as an additive, the major pro-
duct was the diester accompanied by a considerable amount of the phenyl
ester (entry 5). Next, we examined the effect of microwave irradiation on
the acylation reactions. Microwave-assisted organic synthesis has been
known to possess a number of advantages:[8] it is able to substantially
shorten reaction times, reduce side reactions to give cleaner reactions,

1094
T. Miyazawa, M. Yamamoto, and Y. Maeda
Figure 1. (Hydroxyalkyl)phenols examined in this study.
increase yields, and even improve reproducibility. A few examples have
revealed also that the chemo- or regioselectivity can be altered under
the action of microwave irradiation compared with conventional heat-
ing.[9] In the present case, virtually no effects of microwaves were detected
with the reaction using acetyl chloride in the presence of triethylamine
(entry 6), and a small increase of the proportion of the diester was
observed in the presence of pyridine (entry 4). On the other hand,

Selective Acylation of (Hydroxyalkyl)phenols
1095
Table 1. Acetylation of 2-(4-hydroxyphenyl)ethanol (1e) using acetyl chloride in
the absence or presence of an additive in tetrahydrofuran under conventional
heating (D) or microwave irradiation (MW)a
Products (%)
Entry
Additiveb
Mode
Time (min)
1f
1g
1h
1
2
3
4
5
6
None
None
Pyridine
Pyridine
Et3N
D
MW
D
MW
D
MW
40
40
40
40
40
40
40.7
83.6
81.0
66.6
0
0
0
0
0
30.0
31.0
0
7.4
19.0
33.3
70.0
69.0
Et3N
0
aReactions were conducted at 60 ꢀC using 3 mol equiv of acetyl chloride.
b3 equiv.
microwaves exerted a significant influence on the reaction with acyl
chloride alone (entry 2): the yield of the alkyl ester was approximately
doubled, with the concomitant production of a small amount of the
diester.
Stimulated by these facts, we set about examining the effect of micro-
wave irradiation on the acylation of (hydroxyalkyl)phenols depicted in
Fig. 1 when an acyl chloride alone was used in the solvent of tetrahydro-
furan. The results obtained under microwave irradiation were compared
with those of the reactions carried out under conventional heating under
otherwise identical conditions (Table 2). When the amount of acetyl
chloride was reduced to 1 mol equiv, no diester was produced, but the
yield of the alkyl ester was very low, though a small increase in yield
was observed upon microwave irradiation (entries 1 and 2). When the
acid chloride was used in 2 mol equiv, even a prolonged reaction afforded
only the alkyl ester in a slightly increased yield under conventional heat-
ing (entries 3 and 5); however, its yield was no more than 52% even after
24 h. When microwaves were adapted, the yield of the alkyl ester almost
doubled in 40 min, with the formation of the diester being negligible
(entry 4). After 60 min, the starting diol was completely consumed, and
the alkyl ester was obtained in 94% yield (the remainder was the diester;
entry 6). When the acylating agent was replaced by propanoyl chloride,
similar results were obtained: the yield of the alkyl monoester (1i)
attained under the action of microwave was four times higher than that
obtained under the comparable conventional heating (entries 7 and 8).
Therefore, the acid chloride was used in 2 mol equiv in the further experi-
ments. Similar yield increase upon microwave irradiation was observed in
the acetylation of (hydroxyalkyl)phenols with a shorter (1a) or longer (1l)

1096
T. Miyazawa, M. Yamamoto, and Y. Maeda
Table 2. Acylation of (hydroxyalkyl)phenols using acid chlorides in tetrahydro-
furan under conventional heating (D) or microwave irradiation (MW)a
Products (%)
Starting
diol
Entry
Mode Time (min) Alkyl ester Phenyl ester
Diester
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1eb
1eb
1ec
1e
D
MW
D
MW
D
MW
D
MW
D
MW
D
MW
D
MW
D
MW
40
40
40
40
60
60
60
60
10
10
20
20
30
30
40
40
30
30
1f, 19.4
1f, 31.8
1f, 37.7
1f, 68.4
1f, 38.6
1f, 94.0
1i, 21.4
1i, 89.6
1b, 29.9
1b,100
1m, 23.3
1m, 94.5
2b, 62.2
2b, 100
3b, 32.6
3b, 98.1
4b, 43.4
4b, 100
1 g, 0
1 g, 0
1 g, 0
1 g, 0
1 g, 0
1 g, 0
1j, 0
1 h, 0
1 h, 0
1 h, 0
1 h, trace
1 h, 0
1 h, 6.0
1k, 0
1k, 2.8
1d, 0
1d, 0
1ec
1e
1ed
1ed
1a
1a
1 l
1j, 0
1c, 0
1c, 0
1n, 0
1n, 0
2c, 0
2c, 0
3c, 0
3c, 0
4c, 0
4c, 0
1o, 0
1 l
1o, 5.5
2d, 0
2d, 0
2a
2a
3a
3a
4a
4a
3d, 0
3d, 1.9
4d, 0
4d, 0
D
MW
aReactions were conducted at 60 ꢀC. Acetyl chloride (2 mol equiv) was used
unless otherwise noted.
bAcetyl chloride (1 mol equiv) was used.
cThe product yields after 24 h were as follows: 1f, 52.3%; 1 g, 0%; 1 h, 0%.
dPropanoyl chloride (2 mol equiv) was used.
alkyl chain between the benzene ring and the alcoholic hydroxy group
(entries 9 and 10, entries 11 and 12, respectively). The result obtained
with 1a was the most satisfactory: only the alkyl ester (1b) was produced
quantitatively in 10 min under microwave irradiation, whereas conven-
tional heating afforded it in only a 30% yield in the same reaction time.
The diol 1 l gave similar results to those obtained with 1e: the yield of the
alkyl ester (1m) increased four times with the action of microwaves,
together with the formation of a limited amount (6%) of the diester
(1o). With the diol 2a bearing a substituent ortho to the phenolic hydroxyl
in 1a, the conventional heating afforded the alkyl ester (2b) in a moderate
yield, whereas its yield was augmented to a quantitative level in 30 min
under microwave irradiation (entries 13 and 14). With the compound
3a having the meta reciprocal position between a phenolic hydroxyl

Selective Acylation of (Hydroxyalkyl)phenols
1097
and the alkyl chain in a benzene ring, acetylation was a little retarded
compared to the corresponding compound 1a, whereas the microwave
ameliorated the yield of the alkyl ester (3b), though a limited amount
of the diester (3d) was produced (entries 15 and 16). The introduction
of a substituent into 3a accelerated the acylation reaction, and moreover
the microwave irradiation resulted in the sole formation of the alkyl ester
(4b) in a quantitative yield (entries 17 and 18).
In summary, we found that in the acylation of (hydroxyalkyl)phenols
carrying both an alcoholic and a phenolic hydroxyl, a highly selective
acylation of the alcoholic hydroxy group can be achieved without resort-
ing to the use of specially developed reagents and=or auxiliary
compounds, but by using the most conventional reagents, acyl chlorides,
under microwave irradiation.
EXPERIMENTAL
Instruments and Reagents
The microwave-assisted reactions were performed using a monomode
Green-motif reactor (300 W) from IDX (Japan). The reactor has a
single-mode cavity with temperature regulation, and the reaction condi-
tion is not expressed by the power generated from the magnetron, thus
giving the possibility of operating with rather similar profiles of tempera-
ture increases in microwave and conventional heating.
1H and 13C NMR spectra were recorded on a Varian Inova 500 spec-
trometer at 500 MHz and 125.7 MHz, respectively, with tetramethylsi-
lane (TMS) as an internal standard. Assignments of signals were made
by correlation spectroscopy (COSY), DEPT, heteronuclear multiple
quantum correlation (HMQC), and heteronuclear multiple bond correla-
tion (HMBC) techniques.
(Hydroxyalkyl)phenols used in this studies were purchased from
Tokyo Chemical Industry or Aldrich Chemical Co. Other chemicals were
obtained from Wako Pure Chemical Industries, Tokyo Chemical Indus-
try, or Aldrich Chemical Co. All organic solvents were distilled following
standard protocols and dried over molecular sieves prior to use.
Authentic Samples of Monoesters and Diesters of
(Hydroxyalkyl)phenols
The isomeric monoesters and the diester of each (hydroxyalkyl)phenol
were isolated through preparative thin-layer chromatography (TLC) or

1098
T. Miyazawa, M. Yamamoto, and Y. Maeda
column chromatography of the reaction products obtained under some
different reaction conditions. The methylene protons attached to the
benzene ring were mainly employed for the quantification of reaction
1
products by H NMR. Selected data for 1f–h are shown as examples.
Selected Data for 1f–h
Compound 1f: Mp 60–61 ꢀC; 1H NMR (DMSO-d6) d1.98 (3H, s,
CH3CO), 2.75 (2H, t, J ¼ 7.0 Hz, CH2Ar), 4.12 (2H, t, J ¼ 7.0 Hz,
OCH2), 4.90 (1H, s, OH), 6.68 (2H, d, J ¼ 8.5 Hz, H-3 and H-5), 7.03
(2H, d, J ¼ 8.5 Hz, H-2 and H-6), 9.24 (1H, s, OH). Compound 1g: Oil;
1H NMR (DMSO-d6) d 2.25 (3H, s, CH3CO), 2.71 (2H, t, J ¼ 6.7 Hz,
CH2Ar), 3.60 (2H, d of t, J ¼ 6.7 and 5.3 Hz, OCH2), 4.67 (1H, t,
J ¼ 5.3 Hz, OH), 7.01 (2H, d, J ¼ 8.5 Hz, H-3 and H-5), 7.24 (2H, d,
1
J ¼ 8.5 Hz, H-2 and H-6). Compound 1h: Oil; H NMR (DMSO-d6) d
1.99 (3H, s, CH3COOCH2), 2.25 (3H, s, CH3COOAr), 2.88 (2H, t,
J ¼ 7.0 Hz, CH2Ar), 4.21 (2H, t, J ¼ 7.0 Hz, OCH2), 7.05 (2H, d,
J ¼ 8.5 Hz, H-3 and H-5), 7.28 (2H, d, J ¼ 8.5 Hz, H-2 and H-6).
Typical Acylation Procedures
Under Microwave Irradiation
A solution of a (hydroxyalkyl)phenol (0.5 mmol) and acetyl chloride (1.0
mmol) in tetrahydrofuran (7 mL) was subjected to microwave irradiation
at 60ꢀC for the specified time. The solvent was removed at less than ambi-
ent temperature under reduced pressure. The residual oil was dissolved in
1
dimethyl sulfoxide-d6 (DMSO-d6) and subjected to H NMR (500 MHz)
analysis for the quantification of the reaction products. The methylene pro-
tons attached to the benzene ring were mainly employed for the purpose.
The whole content of the reaction mixture was used up for one analysis,
and several discrete reaction mixtures were used at different reaction times.
Under Conventional Heating
To clarify the microwave effect, the reactions with conventional heating
were carried out under conditions otherwise identical to those with
microwave irradiation and not by the conventional manipulation, as fol-
lows: A solution of a (hydroxyalkyl)phenol (0.5 mmol) in tetrahydro-
furan (7 mL) was preheated at 60 ꢀC (thermostated oil bath) for 5 min,
acetyl chloride (1.0 mmol) was added, and then the reaction mixture

Selective Acylation of (Hydroxyalkyl)phenols
1099
was heated at this temperature for the specified time. The same workup
was adopted for the quantification of the reaction products.
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