Unprecedented acetylation of phenols using a catalytic amount of magnesium powder

Article abstract of DOI:10.1080/00397911.2018.1459721

The acetylation of phenols with acetic anhydride was achieved using a catalytic amount of magnesium metal powder under air and solvent-free conditions to afford corresponding phenyl acetates in excellent yield (up to 98%).

Full text of DOI:10.1080/00397911.2018.1459721

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Unprecedented acetylation of phenols using a
catalytic amount of magnesium powder
Gan B. Bajracharya & Suryaman Sama Shrestha
To cite this article: Gan B. Bajracharya & Suryaman Sama Shrestha (2018) Unprecedented
acetylation of phenols using a catalytic amount of magnesium powder, Synthetic Communications,
48:13, 1688-1693, DOI: 10.1080/00397911.2018.1459721
To link to this article: https://doi.org/10.1080/00397911.2018.1459721
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1688–1693
https://doi.org/10.1080/00397911.2018.1459721
Unprecedented acetylation of phenols using a catalytic
amount of magnesium powder
Gan B. Bajracharyaa and Suryaman Sama Shresthab
b
aFaculty of Science, Nepal Academy of Science and Technology, Khumaltar, Lalitpur, Nepal; Department of
Chemistry, Tri-Chandra Multiple Campus, Tribhuvan University, Kathmandu, Nepal
ABSTRACT
ARTICLE HISTORY
Received 12 February 2018
The acetylation of phenols with acetic anhydride was achieved using a
catalytic amount of magnesium metal powder under air and solvent-
free conditions to afford corresponding phenyl acetates in excellent
yield (up to 98%).
KEYWORDS
Acetylation; free radical
mechanism; magnesium;
phenyl acetates
GRAPHICAL ABSTRACT
Introduction
Acylation (or acetylation) is a fundamental process in organic chemistry for the protection
of –OH, –SH, and –NH2 groups, which is usually achieved using acetic anhydride during
oxidation, peptide coupling, and glycosidation reactions to construct polyfunctional
molecules such as peptides, nucleosides, oligonucleotides, carbohydrates, steroids, and
other natural products.[1]
Classically, alcohols and phenols are acylated in the presence of a base (such as NaOH,
Na2CO3, pyridine, DMAP, Et3N, etc.) or an acid (such as H2SO4, H3PO4, p-TsOH, etc.).[2]
Mechanistically, the base used abstracts the acidic proton from alcohol or phenol to
generate enolate, which then attacks electrophilic carbon of the acylating agent. In the latter
case, protonation of acylating agent occurs with the aid of an acid and subsequently gen-
erates acylium ion, which then electrophilically attacks the partner. In the past two decades,
some Lewis acids such as Ce(OTf)3,[3a] Bi(OTf)3,[3b,3c] Li(OTf)3,[3d] Cu(OTf)2,[3d]
Me3SiOTf,[3e] Fe(OTs)3 · 6H2O,[3f] LiClO4,[3g] BiOClO4,[3h] RuCl3,[3i] LiCl,[3j] FePO4,[3k]
Cu(BF4) · 6H2O,[3l] Mn(bis(2-hydroxyanil)acetylacetonato)Cl,[3m] V(tetraphenylporphyri-
nato)(OTf)2,[3n] etc. have been used to achieve acetylation of phenols with acetic
anhydride. Solid acid catalysts such as monomorillonite K-10[4a] and zeolite HSZ-360,[4b]
[8]
ionic liquid,[5] heteropolyacid,[6] iodine,[7] and CBr4 are also known to promote the
reaction. Despite several catalysts have been reported, but some demerits associated in
CONTACT Gan B. Bajracharya
ganbajracharya@yahoo.com
Faculty of Science, Nepal Academy of Science and
Technology, Khumaltar, Lalitpur, Nepal.
Supplemental data (1H- and 13C-NMR spectra of compound 2j, along with literature references) can be accessed on the
publisher’s website.
© 2018 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
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these transformations are (a) hazardous condition, (b) compromising yield, (c) expensive
and readily unavailable catalyst, (d) anhydrous reaction condition, (e) additional solvent
and acylating reagent, and/or (f) tedious purification process. Therefore, the development
of inexpensive, simple, and eco-friendly acylation processes has still a great demand.
Herein, we report an efficient and convenient protocol for the acetylation of phenols with
acetic anhydride in the presence of catalytic amount of magnesium metal powder under
neat condition.
Results and discussion
In search of a suitable catalyst for the acetylation of phenols, the reactions of phenol (1a)
with 1.2 equiv. of an acetylating agent (AcOH or EtOAc or Ac2O) in the presence of
10 mol% of several catalysts (such as AlCl3, Ca3(PO4)2, CaCl2, Ce(SO4)2 · 4H2O,
Cu(OAc)2 · H2O, CoCl2, Cu, CuCl2 · 2H2O, CuSO4 · 5H2O, Fe, Fe2O3, FeCl3, (NH4)2Fe
(SO4)2 · 6H2O, FeSO4 · 7H2O, K2Cr2O7, KBrO3, KI, KIO3, Mg, MgCl2 · 6H2O,
MnCl2 · 4H2O, MnO2, MnSO4 · H2O, K2MnO4, NaAsO3, NaWo · 2H2O, (NH4)2S2O8,
(NH4)2Ni(SO4)2 · 6H2O, NH4Cl, NH4Fe(SO4)2 · 12H2O, NH4SCN, NiCl2, NiCO3 · 2Ni
(OH)2, NiSO4 · 6H2O, SnCl2 · 2H2O, Zn, ZnCl2, ZnCO3, ZnO, and ZnSO4) were performed
under neat conditions at 25 °C for 6 h. The use of either AcOH or EtOAc as an acetylating
agent was failed to promote the acetylation, while the use of Ac2O could promote the reac-
tion producing phenyl acetate (2a) with incomplete conversion. After careful analysis, we
decided to focus on the use of magnesium (a fine metallic powder) as a catalyst for further
optimization, since magnesium could be a cheap (US$ 28 for 500 g from Himedia), less
hazardous, and novel catalyst for the acylation of phenols. From extensive literature survey,
we were gratified to know that magnesium has never been used for the acylation, except
single example of acetylation of t-BuOH.[9] Since t-BuOH is a unique and highly reactive
substrate that prone to generate tert-butyl radical, it underwent acetylation in the presence
of magnesium powder under reflux conditions. Pasha et al. have used metallic zinc dust as
a reusable catalyst for the acylation of phenols with acyl chlorides.[10] In this reaction, acyl
chlorides perhaps react with zinc dust to produce ZnCl2 in situ. Acetylation of t-BuOH
with acetic anhydride using ZnCl2 is known.[11] Spassow also reported acetylation of
t-BuOH with acetyl chloride using sub-stoichiometric amount of Mg.[12] Vedejs and
Daugulis have reported MgBr2-catalyzed acylation of alcohols with acyl chlorides.[13] In
the above examples, ZnCl2 and MgBr2 were active Lewis acid catalysts for acylations.
Next, systematic optimization of the reaction conditions was performed and the results
are summarized in Table 1. The reaction of phenol (1a) with 1.2 equiv. of acetic anhydride
in the presence of 10 mol% of magnesium metal powder, at 25 °C for 18 h, afforded phenyl
acetate (2a) in 95% isolated yield (entry 1). Additional amount of acetic anhydride was
unnecessary (entries 2 and 3). The amount of magnesium can be effectively reduced to
2.5 mol% (entries 4–6). The increase in reaction temperature to 50 °C could reduce the
reaction time as shown in entries 7–9.
After obtaining optimized reaction conditions on hand, we studied the scope and
limitation of the present acetylation reaction (Table 2). 1-Naphthol (1b) was successfully
acetylated forming naphthalene-1-yl-acetate (2b). Phenols bearing electron-donating
group as in o-cresol (1c), m-cresol (1d), and thymol (1e) were acetylated to give
corresponding products 2c–e with excellent yields. A substrate vanillin (1f), possessing

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G. B. BAJRACHARYA AND S. S. SHRESTHA
Table 1. Optimization of reaction conditions for the acetylation of phenol (1a).
Entry
Mg (mol%)
Ac2O (equiv.)
Temp (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
10
10
5
2.5
1
5
1.2
1.8
2.4
1.2
1.2
1.2
1.2
1.2
1.2
25
25
25
25
25
25
50
50
50
18
18
18
18
18
21
4.5
4.5
4.5
95
96
95
95
94
88
96
94
82
2.5
1
both electron-donating and electron-withdrawing groups, was acetylated providing
4-formyl-2-methoxyphenyl acetate (2f). Both the hydroxyl groups in hydroquinone (1g),
resorcinol (1h), and 2-methyl resorcinol (1i) were acetylated under optimized reaction
conditions to yield the corresponding products 2g–i in high yields. The reaction of
2-hydroxy acetophenone was halted even after prolonged heating at 50 °C and a significant
amount of the substrate (>85%) was recovered indicating intervention of hydrogen bond-
ing between the phenolic proton and the keto group. This protocol is equally effective in
Table 2. Scope of the acetylation reaction using magnesium metal powder.
aTemp 25 °C.
bTemp 50 °C.
cSubstrate (5 mmol), Mg (0.25 mmol) and Ac2O (12 mmol) were used.
dQuercetin (1 mmol), Mg (0.125 mmol) and Ac2O (12 mmol) were used.

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acetylation of polyphenolic natural products. For example, quercetin (1j) was tetraacety-
lated to afford quercetin-30,40,5,7-tetraacetate (2j) with a free 3-OH in excellent yields.
To get insight into the reaction mechanism of the present acetylation reaction, we set up
two stoichiometric reactions. First, phenol (1a) was treated with 1 equiv. of magnesium
powder at 50 °C. Both magnesium and 1a were persisted in the mixture even after stirring
for 24 h. Second, when acetic anhydride was stirred with 1 equiv. of magnesium powder at
25 °C, a white precipitate was gradually appeared indicating that acetic anhydride (not
phenol) makes complexation with magnesium. To this complex was added 1 equiv. of
1a and the mixture was stirred at 50 °C for 30 min. After usual workup, the product 2a
was obtained in 50.6% isolated yield. Since we were aware of the report of Norris and Rigby
on acetylation of t-BuOH with the involvement of tert-butyl radical,[9] we have performed
the present acetylation reaction in the presence of 2,2,6,6-tetrtamethyl-1-piperidinyloxy
(TEMPO) free radical. The reactions of phenol (1a) with 1.2 equiv. of acetic anhydride
and 2.5 mol% of magnesium at 25 °C for 24 h in the presence of 0.2, 0.5, 1, or 2 equiv.
of TEMPO allowed us to isolate 2a in 49, 1.3, 0.8, and 0.3% yields, respectively, after silica
gel column chromatography. These results clearly indicated that the presence of another
free radical hampered the transformation. Therefore, a free radical mechanism of the
present acetylation reaction is proposed (Scheme 1). The reaction may proceed through
SRN-1 process (substitution, radical-nucleophile, unimolecular). A single electron transfer
from magnesium to acetic anhydride would form an anionic radical in the initiation step.
In the propagation step, loss of the leaving group (CH3COO–) forms a neutral radical.
Since phenols are prone to scavenge free radicals, this neutral radical would be attacked
to form a new radical anion. This new radical anion serves as an electron source for the
Scheme 1. A plausible mechanism.

1692
G. B. BAJRACHARYA AND S. S. SHRESTHA
single electron transfer and forms the product together with formation of initial anionic
radical.
Conclusion
In conclusion, we have developed a new catalytic and solvent-free route for the acetylation
of phenols using magnesium metal powder. A plausible free radical mechanism of this
transformation is given. Acetylation of alcohols, thiols, and amines are under progress
in our laboratory.
Experimental
Materials and methods
Chemicals and solvents were obtained from Qualigens, Merck and Himedia, and were used
as received. Magnesium metal powder (GRM726, Lot no. 0000138967) was procured from
Himedia Laboratories Pvt. Ltd. Quercetin (1j) and TEMPO free radical was purchased
from Aldrich. For thin-layer chromatography (TLC), precoated TLC plates (0.2 mm
thickness, Kieselgel 60 F254) were procured from Merck. Melting and boiling points were
determined using a Thile’s tube and were uncorrected. Gas chromatography–mass
spectrometry was performed using an Agilent 7890A GC system coupled with a mass spec-
trometer (Agilent 5975 C). The separation was performed using a fused silica capillary
column HP-5MS (5% phenyl methyl siloxane, Agilent 19091S-433, 30 m � 250 µm
internal diameter, 0.25 µm film thickness). Helium was used as a carrier gas at a flow rate
1
of 1 mL/min. H- and 13C-NMR spectra were recorded with JEOL JMN ESC400 FT NMR
spectrophotometer.
General procedure for acetylation
A mixture of phenol (1a, 470.5 mg, 5 mmol), acetic anhydride (0.6 mL, 1.2 equiv., 6 mmol),
and 2.5 mol% of magnesium metal powder (3.0 mg, 0.125 mmol) was stirred at 25 °C for
18 h (or at 50 °C for 4.5 h in another experiment). After the completion of reaction, the
mixture was diluted with EtOAc (60 mL). The reaction mixture was washed with saturated
NaHCO3 (30 mL � 2) and brine (30 mL), dried over Na2SO4, filtered, concentrated, and
finally vacuum dried. The product phenyl acetate (2a) was directly obtained in a pure form
with the yield of 640.3 mg, 94% (the yield of the product 2a at 50 °C reaction condition was
1
640.0 mg, 94%). H-NMR (CDCl3, 400 MHz) δ ppm: 7.39–7.34 (m, 2H), 7.23–7.19 (m,
1H), 7.08 (d, J ¼ 7.6 Hz, 2H), 2.27 (s, 3H). 13C-NMR (CDCl3, 100 MHz) δ ppm: 169.66,
150.86, 129.58, 125.98, 121.73, 21.27.
Acknowledgments
We are sincerely grateful to Prof. Dr Hiroaki Sasai, The Institute of Scientific and Industrial Research
(ISIR), Osaka University, Japan for providing us NMR and DART-MS recording facility.
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