Chemoselective and efficient carbomethoxylation of the alcoholic chain of phenols by dimethyl carbonate (DMC)

Article abstract of DOI:10.1016/j.tetlet.2007.07.109

The efficiency of dimethyl carbonate (DMC) as chemoselective carbomethoxylating agent of the alcoholic chain of phenols has been investigated. In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sulfuric acid as catalysts, new carbomethoxylated

Full text of DOI:10.1016/j.tetlet.2007.07.109

Tetrahedron Letters 48 (2007) 7000–7003
Chemoselective and efficient carbomethoxylation of the
alcoholic chain of phenols by dimethyl carbonate (DMC)
a,b
Roberta Bernini,a,b, Enrico Mincione, Fernanda Crisante,a,b Maurizio Barontini,a,b
*
Giancarlo Fabrizic and Patrizia Gentilid
a
`
Dipartimento di Agrobiologia e Agrochimica, Universita degli Studi Della Tuscia, Via S. Camillo De Lellis snc,
01100 Viterbo, Italy
b
` `
Unita di Ricerca VT2, Consorzio Interuniversitario La Chimica per l’Ambiente, Via Della Liberta 5/12,
30175 Marghera, VE, Italy
cDipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
`
Universita Degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy
`
Dipartimento di Chimica, Universita Degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy
d
Received 12 June 2007; revised 13 July 2007; accepted 24 July 2007
Available online 27 July 2007
Abstract—The efficiency of dimethyl carbonate (DMC) as chemoselective carbomethoxylating agent of the alcoholic chain of phe-
nols has been investigated. In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sulfuric acid as catalysts, new carbometh-
oxylated phenolic compounds were obtained in quantitative yields. A new efficient derivatization of the aliphatic alcoholic chain of
the precious natural hydroxytyrosol is described, which increases the lipophilicity of the hydroxytyrosol. The antioxidant activity of
this new carboxymethylated hydroxytyrosol 8 has been investigated using DPPH radical scavenging test. The results showed that
this new compound has an antioxidant activity similar to hydroxytyrosol.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Alkyl carbonates are an important class of compounds
widely used for a variety of industrial and synthetic
applications.1 They have been used in polymer chemis-
try,2 in agricultural3 as well as in biological fields.4 In
organic and pharmaceutical synthesis, they have been
used as protecting groups for the alcoholic function.
In particular, the protection of amino acids and carbo-
hydrates has been extensively studied.5 The cleavage of
the carbonate moiety can be performed under mild basic
hydrolysis.
oxymethylating agent.7 In these reactions, DMC is an
environmentally benign substitute for hazardous and
toxic phosgene, methyl halides and methyl sulfate.
Recently, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has
been successfully utilized as a nucleophilic catalyst for
the methylation of phenols, indoles, benzimidazoles
and for the esterification of carboxylic acids with
DMC.8 Protonated zeolites9 and mesoporous molecular
sieves functionalized by propyl-sulfonic groups10 show
the same high activity in the selective esterification of
salicylic acid with DMC.
The simplest of all carbonates, namely, dimethyl carbon-
ate (DMC), is an interesting chemical for its low toxicity
and chemical versatility.6 In fact, as extensively reported
by Tundo et al., DMC possess two active centres (alkyl
and carbonyl carbons) whose reactivity depends on the
experimental conditions. Thus, in the presence of a
nucleophile, it may react as a methylating or as a carb-
In the presence of NaY faujasite, DMC was a highly
chemoselective methylating agent of functionalized
anilines such as aminophenols, aminobenzyl alcohols,
aminobenzoic acids and aminobenzamides. In fact,
these compounds have been converted into the corre-
sponding N-methylanilines while other functional
groups were fully preserved from methylation and/or
carboxymethylation reactions;11 ambident nucleophiles
such as o- and p-mercaptophenols o- and p-mercapto-
benzoic acids underwent only an S-methylation reaction
Keywords: Chemoselective carbomethoxylation; Dimethyl carbonate
(DMC); Carboxymethylated hydroxytyrosol.
*
Corresponding author. Tel.: +39 761 357452; fax: +39 761 357230;
e-mail: berninir@unitus.it
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.109

R. Bernini et al. / Tetrahedron Letters 48 (2007) 7000–7003
7001
without affecting OH and CO2H groups; o- and p-
hydroxybenzoic acids have been chemoselectively con-
verted into the corresponding methyl esters.12
98%).14a When the reaction was performed in the pres-
ence of sulfuric acid (20%), a similar experimental proce-
dure was followed.
Nevertheless, to the best of our knowledge, there are no
examples about the use of DMC as a reagent for the
selective carbomethoxylation of the alcoholic chain in
the presence of phenolic hydroxyls. On the other hand,
the selective protection of the alcoholic group in pheno-
lic compounds is an important goal in organic synthesis
but only few selective procedures for acylation have
been reported.13
Considering the high selectivity obtained in the carbo-
methoxylation reaction of 2-(20-hydrophenyl)ethanol 1,
we extended the same experimental procedures to other
phenolic compounds such as 2-(30-hydroxyphenyl)etha-
nol 3, 2-(40-hydroxyphenyl)ethanol (tyrosol) 5, 2-(30,40-
dihydroxyphenyl)ethanol 7 (hydroxytyrosol) and 2-(4-
hydroxy-3-methoxyphenyl)ethanol (homovanillyl alco-
hol) 9. Reaction conditions, conversions and yields are
reported in Table 1. All reactions proceeded with com-
plete substrate conversion and resulted in good product
yield of the corresponding new methyl carbonates 4, 6, 8
and 10.14b–e Under these controlled experimental condi-
tions, no phenolic groups were methylated. Only by
increasing reaction times (24 h), were these groups deriv-
atized in the presence of DBU.
We describe here two simple and efficient procedures to
obtain new methyl carbonates of aliphatic alcohols of
phenolic compounds by utilizing DMC/1,8-diazabicyclo-
[5.4.0]undec-7-ene or DMC/sulfuric acid (Scheme 1).
In a typical experiment, a mixture of 2-(20-hydrophen-
yl)ethanol 1 (1.0 mmol), DBU (1.2 mmol) and DMC
(8.0 mL) was heated to reflux (T = 90 ꢁC). The reaction
was monitored by thin layer chromatography (TLC)
and by gas–mass analysis (GC–MS). After the disap-
pearance of the substrate, the work-up of the reaction
was achieved. The reaction mixture was cooled to room
temperature and DMC was evaporated under vacuum
as an azeotropic mixture with methanol (DMC/
CH3OH = 1:3) boiling at 64 ꢁC.7d The residue was solu-
bilized in ethyl acetate and washed with a solution of
HCl 1 N. The organic extracts were treated with satu-
rated solution and dried over Na2SO4, filtered and con-
centrated under vacuum. Purification of crude mixture
by chromatography on silica gel using hexane/ethyl ace-
tate (4:1) as eluent give exclusively the methyl carbonate
2, characterized by spectroscopic analysis (Table 1, yield
To increase the environmentally friendly character of
this reaction, as an example, we performed the carboxy-
methylation reaction of tyrosol 5 using a lower
amount of DBU (0.1 mmol). Also in this case, the reac-
tion proceeded in quantitative yield even if a longer
time reaction was needed (compare entry 5 with entry
11).
Of particular interest was the selective carbomethoxyl-
ation of the hydroxytyrosol 7, one of the major phenolic
compound present in olive leaves,15 olive oil16 and in
olive mill wastewaters (OMWW).17 Hydroxytyrosol
has been reported to have a high antioxidant and radical
scavenging activity for the presence of the free o-diOH
substitution on the aromatic ring18 and is widely used
O
CH3
OH
O
O
R1
R1
R2
1, 2: R1=OH, R2=R3=H
3, 4 : R1=R3=H; R2=OH
5, 6 : R1=R2=H; R3=OH
7, 8 : R1=H; R2=R3=OH
9, 10 : R1=H; R2=OCH3; R3=OH
DMC/DBU
or DMC/H2SO4
R2
R3
R3
2, 4, 6, 8, 10
1, 3, 5, 7, 9
Scheme 1. Selective carbomethoxylation of phenols 1, 3, 5, 7 and 9 with DMC/DBU or DMC/H2SO4.
Table 1. Experimental data of the reactions depicted in Scheme 1
Entry
Substrate
Experimental conditions
Conversion (%)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
3
3
5
5
7
7
9
9
5
DBU (1.2 mmol), 90 ꢁC, 2 h
H2SO4 (20%), 90 ꢁC, 1.5 h
DBU (1.2 mmol), 90 ꢁC, 4.5 h
H2SO4 (20%), 90 ꢁC, 4.5 h
DBU (1.2 mmol), 90 ꢁC, 7.5 h
H2SO4 (20%), 90 ꢁC, 7 h
DBU (1.2 mmol), 90 ꢁC, 1 h
H2SO4 (20%), 90 ꢁC, 6.5 h
DBU (1.2 mmol), 90 ꢁC, 7.5 h
H2SO4 (20%), 90 ꢁC, 7 h
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
2
>98
90
2
4
>98
>98
>98
>98
>98
>98
>98
>98
>98
4
6
6
8
8
10
10
6
10
11
DBU (0.1 mmol), 90 ꢁC, 12 h

7002
R. Bernini et al. / Tetrahedron Letters 48 (2007) 7000–7003
Chem. 2002, 67, 2188–2191; (c) Shieh, W.-C.; Dell, S.;
Repic, O. Tetrahedron Lett. 2002, 43, 5607–5609.
9. Kirunakki, S. R.; Nagaraju, N.; Murthy, K. V. V. S. B. S.
R.; Narayanan, S. Appl. Cat. A—Gen. 2002, 226, 175–
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10. Zheng, Y.; Li, J.; Zhao, N.; Wei, W.; Sun, Y. Micropor.
Mesopor. Mater. 2006, 92, 195–200.
11. Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 2003, 68,
7374–7378.
for pharmacological, food, nutraceutical and cosmetic
applications.19
The antioxidant activity of this new carboxymethylated
hydroxytyrosol 8 has been determined by the DPPH
reduction method,20 by plotting, as indicated in note,21
the remaining percentage of DPPH as a function of
the molar ratios of 8 over DPPH. An EC50 (efficient
concentration) of 0.11 0.02 (mmol 8/mmol DPPH)
was determined, which is comparable to that of the well
known hydroxytyrosol.22 On the basis of these results,
the compound 8 having an increased lipophilicity com-
pared to hydroxytyrosol appeared as a new antioxidant
useful for cosmetic and nutraceutical purposes.
12. Selva, T.; Tundo, P. J. Org. Chem. 2006, 71, 1464–
1470.
13. (a) Breton, G. W. J. Org. Chem. 1997, 62, 8952–8954; (b)
Sabitha, G.; Reddy, B. V. S.; Reddy, G. S. K. K.; Yadav,
J. S. New J. Chem. 2000, 24, 63–64; (c) Biswanatha, D.;
Venkataiah, B.; Madhusudhan, P. Synth. Commun. 2002,
32, 249–252.
14. Carboxymethylated compounds 2, 4, 6, 8 and 10 are
colourless oils. Spectroscopic data are given below. (a)
2-(20-Hydrophenyl)ethyl methyl carbonate 2. 1H NMR
(CDCl3): d (ppm) 2.99 (t, 2H, J = 7.0 Hz, CH2CH2O-
CO2CH3), 3.76 (s, 3H, OCO2CH3), 4.33 (t, 2H,
J = 7.0 Hz, CH2CH2OCO2CH3), 6.77–6.88 (m, 2H,
CHar), 7.07–7.11 (m, 2H, CHar); 13C NMR (CDCl3): d
(ppm) 30.1, 54.9, 67.7, 115.8, 120.7, 123.3, 128.3, 131.0,
154.3, 156.0; MS (EI) m/z 196 (M+). Anal. Calcd for
C10H12O4 (196.20): C, 61.22; H, 6.16; O, 32.62. Found: C,
61.18; H, 6.18; O, 32.64; (b) 2-(30-Hydrophenyl)ethyl
In conclusion, the present Letter describes a new eco-
friendly procedure for the chemoselective carbometh-
oxylation of the alcoholic chain in phenolic compounds
using a cheap and green carboxymethylating agent such
as dimethyl carbonate (DMC). The reactions proceed in
good yields in presence of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) or sulfuric acid as catalysts. A new antiox-
idant hydroxytyrosol derivative useful for industrial
applications has been synthesized in quantitative yield.
1
methyl carbonate 4. H NMR (CDCl3): d (ppm) 2.91 (t,
2H, J = 7.1 Hz, CH2CH2OCO2CH3), 3.75 (s, 3H,
OCO2CH3), 4.31 (t, 2H, J = 7.1 Hz, CH2CH2OCO2CH3),
5.12 (1H, OH), 6.68–6.79 (m, 3H, CHar), 7.11–7.19 (m,
1H, CHar); 13C NMR (CDCl3): d (ppm) 34.9, 54.7, 68.3,
113.7, 115.8, 121.3, 129.8, 139.7, 155.8, 155.9. MS (EI) m/z
196 (M+). Anal. Calcd for C10H12O4 (196.20): C, 61.22; H,
6.16; O, 32.62. Found: C, 61.25; H, 6.18; O, 32.57; (c) 2-
(40-Hydrophenyl)ethyl methyl carbonate 6. 1H NMR
(CDCl3): d (ppm) 2.88 (t, 2H, J = 7.1 Hz, CH2CH2O-
CO2CH3), 3.75 (s, 3H, OCO2CH3), 4.28 (t, 2H,
J = 7.1 Hz, CH2CH2OCO2CH3), 5.37 (s, 1H, OH), 6.75
(d, 2H, J = 8.6 Hz, CHar), 7.06 (d, 2H, J = 8.5 Hz, CHar);
13C NMR (CDCl3): d (ppm) 34.2, 54.8, 68.7, 115.4, 129.1,
130.0, 154.4, 155.8. MS (EI) m/z 196 (M+). Anal. Calcd
for C10H12O4 (196.20): C, 61.22; H, 6.16; O, 32.62. Found:
C, 61.15; H, 6.22; O, 32.63; (d) 2-(3,4-Dihydrophenyl)ethyl
methyl carbonate 8: 1H NMR(CDCl3): d (ppm) 2.82 (t,
2H, J = 7.1 Hz, CH2CH2OCO2CH3), 3.75 (s, 3H,
OCO2CH3), 4.26 (t, 2H, J = 7.1 Hz, CH2CH2OCO2CH3),
6.60 (dd, 1H, J1 = 2.0 Hz, J2 = 8.0 Hz, CHar), 6.70 (d, 1H,
J = 2.0 Hz, CHar), 6.76 (d, 1H, J = 8.0 Hz, CHar). 13C
NMR (CDCl3): d (ppm) 34.4, 54.8, 68.7, 115.4, 115.9,
121.3, 130.0, 142.4, 143.6, 155.9. MS (EI) m/z 212 (M+).
Anal. Calcd for C10H12O5 (212.20): C, 56.60; H, 5.70; O,
37.70. Found: C, 56.70; H, 5.75; O, 37.55; (e) 2-(4-
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Hydroxy-3-methoxyphenyl)ethyl methyl carbonate 10. H
NMR (CDCl3):
d (ppm) 2.88 (t, 2H, J = 7.1 Hz,
CH2CH2OCO2CH3), 3.74 (s, 3H, OCH3), 3.85 (s, 3H,
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