Highly chemoselective methylation and esterification reactions with dimethyl carbonate in the presence of NaY faujasite. The case of mercaptophenols, mercaptobenzoic acids, and carboxylic acids bearing OH substituents

Article abstract of DOI:10.1021/jo0520792

In the presence of NaY faujasite, the reactions of dimethyl carbonate (DMC) with several ambident nucleophiles such as o- and p-mercaptophenols (1a,b), o- and p-mercaptobenzoic acids (2a,b), o- and p-hydroxybenzoic acids (3a,b), mandelic and phenyllactic acids (4, 5), have been explored under batch conditions. Highly chemoselective reactions can be performed: at 150 °C, compounds 1 and 2 undergo only a S-methylation reaction, without affecting OH and CO₂H groups; at 165 °C, acids 3-5 form the corresponding methyl esters, while both their aromatic and aliphatic OH substituents are fully preserved from methylation and/or transesterification processes. Typical selectivities are of 90-98% and isolated yields of products (S-methyl derivatives and methyl esters, respectively) are in the range of 85-96%. A comparative study with K₂CO₃ as a catalyst is also reported. Although the base (K₂CO₃) turns out to be more active than the zeolite, the chemoselectivity is elusive: compounds 2a,b undergo simultaneous S-methylation and esterification reactions, and acids 3-5 yield complex mixtures of products of O-methylation, O-methoxycarbonylation, and esterification of their OH and CO₂H groups, respectively. Overall, the combined use of a nontoxic reagent/solvent (DMC) and a safe promoter (NaY) imparts a genuine ecofriendly nature to the investigated synthesis.

Full text of DOI:10.1021/jo0520792

Highly Chemoselective Methylation and Esterification Reactions
with Dimethyl Carbonate in the Presence of NaY Faujasite. The
Case of Mercaptophenols, Mercaptobenzoic Acids, and Carboxylic
Acids Bearing OH Substituents
Maurizio Selva* and Pietro Tundo
Dipartimento di Scienze Ambientali dell’UniVersita` Ca’ Foscari, and Consorzio InteruniVersitario “La
Chimica per l’Ambiente” (INCA), UdR di Venezia, Calle Larga S. Marta, 2137-30123 Venezia, Italy
selVa@uniVe.it
ReceiVed October 4, 2005
In the presence of NaY faujasite, the reactions of dimethyl carbonate (DMC) with several ambident
nucleophiles such as o- and p-mercaptophenols (1a,b), o- and p-mercaptobenzoic acids (2a,b), o- and
p-hydroxybenzoic acids (3a,b), mandelic and phenyllactic acids (4, 5), have been explored under batch
conditions. Highly chemoselective reactions can be performed: at 150 °C, compounds 1 and 2 undergo
only a S-methylation reaction, without affecting OH and CO2H groups; at 165 °C, acids 3-5 form the
corresponding methyl esters, while both their aromatic and aliphatic OH substituents are fully preserved
from methylation and/or transesterification processes. Typical selectivities are of 90-98% and isolated
yields of products (S-methyl derivatives and methyl esters, respectively) are in the range of 85-96%. A
comparative study with K2CO3 as a catalyst is also reported. Although the base (K2CO3) turns out to be
more active than the zeolite, the chemoselectivity is elusive: compounds 2a,b undergo simultaneous
S-methylation and esterification reactions, and acids 3-5 yield complex mixtures of products of
O-methylation, O-methoxycarbonylation, and esterification of their OH and CO2H groups, respectively.
Overall, the combined use of a nontoxic reagent/solvent (DMC) and a safe promoter (NaY) imparts a
genuine ecofriendly nature to the investigated synthesis.
Introduction
ation of CH2-active compounds and primary aromatic amines2-3
and in the synthesis of methyl carbamates as well.4
In recent years, an increasing interest has been focused on
dimethyl carbonate (DMC) as a reagent for safer and selective
methylation and/or carboxymethylation protocols.1 DMC in fact
is a nontoxic compound that allows catalytic processes with
unprecedented high selectivity (up to 99%) in the monomethyl-
(2) (a) Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc., Perkin Trans.
1 1994, 1323-1328. (b) Fu, Z.-H.; Ono, Y. J. Catal. 1994, 145, 166-170.
(d) Selva, M.; Tundo, P.; Perosa, A.; Memoli, S. J. Org. Chem. 2002, 67,
1071-1077.
(3) (a) Fu, Z.-H.; Ono, Y. Catal. Lett. 1993, 22, 277-281. (b) Selva,
M.; Bomben, A.; Tundo, P. J. Chem. Soc., Perkin Trans. 1 1997, 1041-
1045. (c) Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 2001, 66, 677-
680. (d) Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 2002, 67, 9238-
9247.
* To whom correspondence should be addressed. Fax: +39 041 234 8620.
(1) (a) Shaik, A.-A. G.; Sivaram, S. Chem. ReV. 1996, 96, 951-976. (b)
Tundo, P.; Selva, M. Acc. Chem Res. 2002, 35, 706-716. (c) Shieh, W.-
C.; Dell, S.; Repic, O. J. Org. Chem. 2002, 67, 2188-2191. (d) Shieh,
W.-C.; Dell, S.; Bach, A.; Repic, O.; Balcklock, T. J. J. Org. Chem. 2003,
68, 1954-1957.
(4) (a) Aresta, M.; Quaranta, E. Tetrahedron 1991, 47, 9489-9502. (b)
Selva, M.; Tundo, P.; Perosa, A.; Dall’Acqua, F. J. Org. Chem. 2005, 70,
2771-2777.
10.1021/jo0520792 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/25/2006
1464
J. Org. Chem. 2006, 71, 1464-1470

ChemoselectiVe Syntheses using DMC/Faujasite
TABLE 1. Reactions of Compounds 1a,b with DMC
products
A further added value of the use of DMC is that derivatization
(protection/deprotection) sequences may be avoided. In par-
ticular, we have recently reported that in the presence of sodium-
exchanged Y-zeolite (NaY faujasite) as a catalyst, the reaction
of dimethyl carbonate with ambident nucleophiles such as
amino-phenols, -benzyl alcohols, -benzoic acids, and -benza-
mides not only showed a very high mono-N-methyl selectivity
(up to 99%), but it proceeded with complete chemoselectivity
toward the amino group (Scheme 1).5 The other nucleophilic
(%, GC)
NaY: K2CO3:
isolated
yield,
substrate
sub sub (mol/
t
T
conv
entry (XC6H4SH) (w/w)a mol)b (h) (°C) (%) c
6
7
8
6 (%)
1
2
3
4
5
6
7
X)o-OH(1a)
20 130
20 150 15
15
59
61
0.5
0.5
2
3
150 66
7
20 150 75 14
20 150 93 76
13 150 100 94
16 60d
3
6
95e
0.2
0.2
3
130 100 100
20 150 67 36 2 29
20 150 96 72 10 14 60d
13 150 99 90
90d
130 85 85
SCHEME 1. X ) OH, CO2H, CH2OH, CONH2
8
9
10
11
X) p-OH(1b)
1
2
3
1
8
3
a Weight ratio NaY:substrate. b Molar ratio K2CO3:substrate. c Conver-
sion (%) by GC. d Yields of products 6a,b purified by FCC (eluant:
petroleum ether/diethyl ether, 4:1 v/v). e Yield of crude product 6a isolated
after filtration of the zeolite and vacuum distillation of DMC.
functionalities (OH, CO2H, CH2OH, CONH2) were fully
preserved from alkylation and/or transesterification reactions.
With the aim of further exploring the potential of the DMC/
faujasite system for chemoselective green syntheses, other
bifunctional substrates such as mercaptophenols (1a,b), mer-
captobenzoic acids (2a,b), and carboxylic acids bearing OH
substituents (3a,b, 4, and 5) (Scheme 2) were considered.
TABLE 2. Reactions of Compounds 2a,b with DMC
products
NaY: K2CO3:
sub sub (mol/
isolated
yield,
(% GC)
substrate
(XC6H4SH)
t
T
conv
entry
(wt/wt)a mol)b (h) (°C) (%)c
9
10 9 (%)d
1
2
3
4
X)o-CO2H(2a)
2
3
20 150 95 85 10b
15 150 93 90 2b
87
SCHEME 2
2
0.2
3
1
130 99 22 77
130 100 51 49
5
6
X)p-CO2H(2b)
3
3
13 150 69e 64
26 150 100 90 10
2
85
a Weight ratio NaY:substrate. b Molar ratio K2CO3:substrate. c Conver-
sion (%) by GC. d Yield of products 9a (entry 3) and 9b (entry 7) purified
by FCC (eluant: petroleum ether/diethyl ether, 4:1 v/v). e Methyl p-
mercaptobenzoate (p-SHC6H4CO2Me, 3%) was also observed.
K2CO3:substrate in the range of 0.2-2) in place of NaY. These
experiments were performed at a lower temperature of 130 °C.
Tables 1 and 2 report the results for mercaptophenols (1a,b)
and for mercaptobenzoic acids (2a,b), respectively. To allow
an inspection of the chemoselectivity, the chosen reaction times
and temperatures of both tables mostly refer to high, if not
quantitative, substrates conversions.
In the case of mercaptophenols (1a,b) (Table 1), reactions
showed the formation of the corresponding S-methyl derivatives
(6a,b, usually main products; 75-100% at complete conver-
sions), along with compounds 7a,b that derived from the
simultaneous S- and O-methylation of the substrates, and the
disulfides 8a,b (Scheme 3). Compounds 6a,b were isolated, and
We wish to report herein that in the presence of NaY, also
reactions of compounds 1-5 do proceed with a very high
selectivity. In particular, at 150 °C, compounds 1 and 2 undergo
only S-methylation, hydroxyl and carboxylic groups being
unaffected, whereas at 165 °C acids 3-5 yield the corresponding
methyl esters without any side reactions (methylation/methoxy-
carbonylation) of OH substituents. To further elucidate the scope
and limitations of the method, a comparison between NaY and
a conventional basic catalyst (K2CO3) for DMC-mediated
methylations is also described.
SCHEME 3. Reactions of Mercaptophenols 1a,b with DMC
Results
Mercapto-Derivatives 1 and 2. Initially, compounds 1 and
2 were investigated. Solutions of 1 and 2 in DMC (5 × 10-2
M, 30 mL; DMC serving both as a reagent and the solvent)
were prepared to react at 150 °C, in a stainless steel autoclave
(90 mL), in the presence of different amounts of the faujasite
NaY [weight ratio NaY:substrate (Q) in the range of 0.5-4].
All reactions were carried out under a N2 atmosphere and were
monitored by GLC and GC-MS.
The same procedure was also used to carry out reactions of
substrates 1a,b and 2a with K2CO3 as a catalyst (molar ratio
yields of 60-95% were obtained.6
J. Org. Chem, Vol. 71, No. 4, 2006 1465

Selva and Tundo
TABLE 3. Reactions of Carboxylic Acids 3-5 with DMC
entry
substrate
Fau/basea
t (h)
T (°C)
conv (%)
products (% GC)
Y (%)b
1
2
o-OHC6H4CO2H (3a)
NaY
K2CO3
15
10
165
150
100
80
13a: o-OHC6H4CO2Me (98)
16a: o-OMeC6H4CO2Me (80)
93
3
4
p-OHC6H4CO2H (3b)
PhCH(OH)CO2H (4)
NaY
K2CO3
24
17
165
150
100
70
13b: p-OHC6H4CO2Me (100)
16b: p-OMeC6H4CO2Me (70)
87c
96
5
6
NaY
K2CO3
24
9
165
150
100
85
14: PhCH(OH)CO2Me (92)
14: PhCH(OH)CO2Me (10)
17: PhCH(OMe)CO2Me (13)
18: PhCH(OCO2Me)CO2Me (62)
7
8
(s)PhCH(OH)CO2H
NaY
NaY
22
24
165
165
96
96
(s)PhCH(OH)CO2Me (93)
85
95
PhCH2CH(OH)CO2H (5)
15: PhCH2CH(OH)CO2Me (92)
PhCHdCHCO2Me (4)
a Fau ) NaY faujasite. Entries 1, 3, 5, 7, and 8: reactions were carried out using a NaY:substrate weight ratio of 3. Entries 2, 4, and 6: reactions were
carried out using a K2CO3:substrate molar ratio of 1.5. b Y ) isolated yields of crude methyl esters 13a, 14, and 15 (entries 1, 5, 7, and 8, respectively).
c Yield of 13b purified by FCC (eluant: petroleum ether/diethyl ether, 4:1 v/v).
SCHEME 5
Two recycling tests were also carried out. Once experiments
of entries 6 and 10 of Table 1 were completed, the solid NaY
was filtered, dried at 90 °C overnight, and finally, reused to
repeat the two reactions. No appreciable variations of either
conversion of 1a,b or selectivity were observed.
In the case of mercaptobenzoic acids (2a,b) over NaY (Table
2), the corresponding S-methyl derivatives 9a,b were still the
major products (up to 90%, Scheme 4). They were isolated in
Carboxylic Acids Bearing OH Substituents (3-5). Ac-
cording to the procedure above-described for compounds 1 and
2, solutions of hydroxybenzoic acids (3a,b), racemic and
enantiomerically pure [(s)-form] mandelic acid (4), and racemic
phenyllactic acid (5) in DMC (5 × 10-2 M, 30 mL) were made
to react at 165 °C, in the presence of the faujasite NaY [weight
ratio NaY:substrate (Q) of 3]. The corresponding methyl esters
(13-15, Scheme 6, right) were obtained in >90% purity (by
GC-MS). They were isolated in 85-96% yields, by simple
filtration of the zeolite and removal of DMC under vacuum.8
SCHEME 4. Reactions of Compounds 2a,b with DMC
85-87% yields. Methyl esters 10 a,b were also observed (2-
10%).
When NaY was replaced with K2CO3 (1.5 molar equiv with
respect to the substrate), even though experiments were carried
out at a lower temperature (150 °C), the esterification of acids
3 and 4 was always accompanied by simultaneous O-methyla-
tion and O-methoxycarbonylation reactions of the OH substit-
uents (compounds 16-18; Scheme 6, left).
Table 3 reports the results. As for Tables 1 and 2, the chosen
reaction times and temperatures of both tables mostly refer to
high, if not quantitative, substrates conversions.
In the presence of K2CO3, however, the reaction of 2a with
DMC gave the ester 10a as the predominant product (50-77%).
In a separate experiment, also 2-mercaptobenzyl alcohol (11)
was made to react with DMC in the presence of NaY (conditions
of entry 7, Table 2). After 26 h, the conversion was of 98%
and 2-(methylthio)benzyl alcohol (12) was observed in 88%
amount by GC. (Scheme 5). Compound 12 was then isolated
in 67% yield.7
SCHEME 6. Reactions of Compounds 3-5 with DMC in the Presence of NaY (Right) and of K2CO3 (Left)
1466 J. Org. Chem., Vol. 71, No. 4, 2006

ChemoselectiVe Syntheses using DMC/Faujasite
In a separate experiment, also tropic acid (19) was converted
with DMC in the presence of NaY (conditions of entry 1, Table
3). After 15 h, the conversion was substantially quantitative;
the major product, however, was methyl 2-phenylpropenoate
(20) which derived from the simultaneous dehydration and
esterification of the reagent (Scheme 7). Compound 20 was
isolated in a 82% yield.
amounts of the zeolite are used.12 Accordingly, in the present
case (entries 3-6 and 8-10), the methylation reaction can
proceed faster than the competitive oxidation process.13
In addition, since alkali metal exchanged faujasites are
amphoteric solids,14 they may induce a slight nucleophilic
activation. In fact, nucleophiles such as phenols, thiophenols,
amines, etc. are adsorbed over NaY and NaX, through the
formation of H-bonds with basic oxygen atoms of the zeolite
framework.15 Scheme 9 depicts the case of compounds 1b. The
methylation reaction is most possibly of an SN2 type.
SCHEME 7. Reaction of Tropic Acid with DMC
SCHEME 9. Pictorial View of the S-Methylation of
p-Hydroxythiophenol (1b) with DMC over NaY
It should be noted that the dehydration product was also
observed in the case of phenyllactic acid, though it was formed
to a much lesser extent (4%; entry 8, Table 3).
Discussion
Mercaptophenols 1a,b. In the absence of catalysts/promoters,
solutions of o-mercaptophenol (1a) in DMC do not react below
150 °C (entries 1 and 2, Table 1); under these conditions, only
a small amount (15%) of disulfide 8a is observed after a
prolonged reaction time (20 h, entry 2). This reaction is
reasonably due to traces of dissolved oxygen. In fact, the
synthesis of both disulfides 8a,b is reported to occur through
facile oxidation of phenols 1a,b in air.9
In the presence of NaY (Q ) 0.5-1), the formation of
disulfides 8 appears favored (entries 3 and 8, Table 1) for the
initial period (3 h); then, it substantially stops even for a
prolonged reaction time (entry 4).10 As the amount of the zeolite
is increased (Q ratio of 2-3), the S-methylation of phenols 1a,b
takes over and the corresponding hydroxythioanisoles 6a,b are
obtained in 90% and 95% isolated yields, respectively (entries
6 and 10, Table 1). This behavior can be ascribed to the modes
of interactions of DMC with the faujasite. IR and Raman
investigations demonstrate that acid-base complexes (I and II)
are formed between DMC and the Lewis acidic sites (Na+
cations) of the zeolite (Scheme 8).11
Potassium carbonate is often reported as a highly active
catalyst for DMC-mediated methylations; these reactions pro-
ceed through a BAl2 mechanism (Scheme 10, path a).1-3 A BAc2
mechanism is also possible (Scheme 10, path b), though at
temperatures g130 °C, the reversibility of this reaction often
leads to the methyl derivative (NuMe) as the sole product.
In the presence of K2CO3, also the S-methylation of com-
pounds 1a,b with DMC proceeds efficiently (entries 7 and 11,
(9) (a) Greenwood, D.; Stevenson, H. A. J. Chem. Soc. 1953, 1514-
1518. (b) Schaefer, T.; Salman, R.; Wildman, T. A.; Clark, P. D. Can. J.
Chem. 1982, 60, 342-348. (c) Mahfouz, A. M. M.; Metcalf, R. L.; Fukuto,
T. R. J. Agric. Food Chem. 1969, 17, 917-922.
(10) The oxidation of mercaptophenols to the corresponding disulfides
can be catalyzed by Lewis acidic compounds (i.e., FeCl2; see Oae, S.;
Yoshihara, M. Bull. Chem. Soc. Jpn. 1968, 41, 2082-2086). This suggests
that also small Lewis acidic cations of Y-faujasites (such as Li+, Na+; see
Barthomeuf, D. J. Phys. Chem. 1984, 88, 42-45) can promote the formation
of compounds 8a,b. The oxidation however apparently stops when dissolved
oxygen is consumed.
SCHEME 8. Interactions of DMC with Na+ of Y-Faujasites
(11) (a) Beutel, T. J. Chem. Soc., Faraday Trans. 1998, 94, 985. (b)
Bonino, F.; Damin, A.; Bordiga, S.; Selva, M.; Tundo, P.; Zecchina, A.
Angew. Chem., Int. Ed. Engl. 2005, 44, 4774-4777.
(12) From the general formula Na56[(AlO2)56(SiO2)136]‚250H2O of a NaY
faujasite, it contains ∼7.5% sodium. However, since metal cations occupy
four different positions within the framework of the Y-zeolites, only one-
third of the total sodium of a NaY, i.e., ∼ 2.3%, corresponds to active Na+
involved in adsorption and/or catalytic phenomena; the other cations, being
deeply embedded into the structure, are hardly accessible. (Gates, B. C. In
Catalytic Chemistry; Wiley: New York, 1992). In the investigated reaction
of compounds 1a,b with DMC, the 6-fold increase of the zeolite amount
(entries 4-6 and 8-10, Table 1) corresponds to an increase of the molar
ratio between active Na+ and DMC, from 0.14 to 0.86.
(13) Although disulfides 8a,b may also behave as nucleophiles, it seems
rather unlikely that they act as intermediates in the formation of the final
products 6a,b. In fact, once compounds 8a,b are formed, their amounts
remain substantially constant even though S-methyl derivatives 6a,b increase
throughout the reaction (entries 3 and 4, Table 1). Moreover, in the reaction
of mercaptobenzoic acids 2a,b (Table 2), the corresponding disulfides are
never observed.
In both I and II species, the O-CH3 bonds are weakened. This
implies that, after adsorption over NaY, DMC undergoes an
electrophilic activation that may be favored if increasing
(5) (a) Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 2003, 68, 7374-
7378. (b) Selva, M.; Tundo, P.; Foccardi, T. J. Org. Chem. 2005, 70, 2476-
2485.
(6) Compound 6a was simply isolated by filtration of the zeolite and
removal of DMC under vacuum. No further purification was necessary (see
Experimental Section).
(7) The FCC purification of compound 12 was made difficult by the
presence of some unidentified byproducts (10%) in the reaction mixture.
For this reason, a moderate yield of 12 (67% compared to the higher GC
amount of 88%) was obtained.
(8) Only compound 13b was further purified by FCC (see Experimental
Section).
(14) Su, B.; Barthomeuf, D. Stud. Surf. Sci. Catal. 1995, 94, 598 (see
also refs in note 8).
(15) (a) Czjzek, M.; Vogt, T.; Fuess, H. Zeolites 1991, 11, 832. (b) Beutel,
T.; Peltre, M.-J.; Su, B. L. Colloids Surf., A 2001, 187-188, 319-325. (c)
Fu, Z.-H.; Ono, Y. Catal. Lett. 1993, 21, 43-47.
J. Org. Chem, Vol. 71, No. 4, 2006 1467

Selva and Tundo
SCHEME 10. Mechanisms of DMC-Promoted Reactions
Carried Out Over K2CO3 as a Catalyst; NuH ) Generic
Nucleophile
Compounds III act as nucleophiles via direct SN2 displace-
ments (BAl2 mechanism) or through a nucleophilic catalysis.
Carboxylic Acids Bearing OH Substituents (3-5). A
number of methods are reported for the selective synthesis of
methyl esters of acids 3-5.21 These procedures normally allow
good yields but also pose concerns from both the environmental
and safety standpoints, as strong acids (H2SO4, HCl) as well as
harmful reagents (MeI, MeOSO3Me, CH2N2, SOCl2) have to
be used.
Despite the results shown in Table 2, the selective esterifi-
cation of compounds 3-5 with DMC can also be promoted by
the NaY faujasite. In fact, a simple increase of the reaction
temperature from 150 °C (Table 2) to 165 °C (Table 3) allows
the formation of methyl esters 13a,b, 14, and 15 with a
selectivity up to 100%, at substantially quantitative conversions
(entries 1, 3, 5, 7, and 8, Table 3). The reaction rate, however,
is rather sensitive to the amount of the zeolite. For instance, if
a weight ratio NaY:acid (Q) of 3 is used, the esterification of
mandelic acid is completed after 24 h at 165 °C (entry 5, Table
3). Instead, when the Q ratio is decreased to 0.5, the same
reaction shows a conversion of only 12% after 13 h. Methyl
mandelate is the sole observed product in both cases.
Table 1). With respect to NaY, the formation of hydroxythio-
anisoles 6a,b is faster even at a lower reaction temperature (3
h at 130 °C), and most importantly, the base can be used in a
catalytic amount (0.2 molar equiv with respect to compounds
1). The nucleophilic activation of 1a,b with a base is apparently
more important than the activation of DMC within NaY,
according to Scheme 8. Conventional procedures for the
alkylation of mercaptophenols with alkyl halides also claim the
use of basic promoters (KHCO3).16
However, although NaY is effective only in a relatively high
quantity, it can be easily reactivated and recycled.
In light of the amphoteric properties of NaY, the adsorption
of carboxylic acids possibly occurs via either interactions with
Na+ cations (similarly to DMC, Scheme 9) or H-bonds with
the oxygen atoms of the aluminosilicate structure (Scheme 12,
a, b).22
It should be finally noted that, regardless of the nature of the
promoter/catalyst, the S-methylation of phenols 1a,b is the sole
observed reaction. The higher polarization of the thiol group
with respect to the hydroxyl one accounts for such a chemose-
lectivity.
Mercaptobenzoic acids 2a,b. To avoid the formation of
disulfides as side products (see Table 1), reactions of compounds
2a,b with DMC are always carried out with relatively high
amounts of NaY (entries 1 and 2, 5 and6, Table 2).
SCHEME 12. Possible Modes of Adsorption of Carboxylic
Acids on NaY
Table 2 shows that the reaction outcome is greatly affected
by the type of the promoter/catalyst. At 150 °C, in the presence
of NaY, methylthiobenzoic acids 9a,b are obtained with a
selectivity of 90-98%. The esterification of acid functions, as
well as the transesterification of alcoholic groups (Scheme 5),17
do not take place. This is consistent with our previous findings
on the selective mono-N-methylations of aminobenzoic acids
and aminobenzyl alcohols with DMC and NaY as a catalyst.5
On the contrary, the use of K2CO3 allows simultaneous
methylation and esterification reactions of SH and of CO2H
groups, respectively. Both processes occur notwithstanding that
a lower temperature is applied (130 °C; entries 3-4, Table 2).
Under these conditions, the striking drop in chemoselectivity
reflects the general reactivity of carboxylate anions with
alkylating agents to yield the corresponding esters;18 this is
especially true when methyl halides are involved.19 In the
reaction with DMC, carboxylate salts may be generated by both
inorganic and organic bases (Scheme 11).20
(17) It should be noted that in the presence of a base the transesterification
of primary alcohols with DMC is a facile reaction: (a) Selva, M.; Trotta,
F.; Tundo, P. J. Chem. Soc., Perkin Trans. 2 1992, 4, 519-522. (b) Selva,
M. Marques, C. A. Tundo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1889-
1893. (c) Veldurthy, B.; Clacens, J.-M.; Figueras, F. J. Catal. 2005, 229,
237-242.
(18) Pfeffer, P. E.; Silbert, L. S. J. Org. Chem. 1976, 41, 1373-1379.
(19) Ozaki, S.-I.; Yang, H.-I.; Matsui, T.; Goto, Y.; Watanabe, Y.
Tetrahedron: Asymmetry 1999, 10, 183-192.
(20) (a) Loosen, P.; Tundo, P.; Selva, M. U.S. Patent 5,278,333, 1994.
(b) Shieh, W.-C.; Dell, S.; Repic, O. J. Org. Chem. 2002, 67, 2188-2191.
(21) 1. (a) Elsenbaumer, R. L.; Mosher, H. S. J. Org. Chem. 1979, 44,
600-604. (b) Kolasa, T.; Miller, M. J. J. Org. Chem. 1987, 52, 4978-
4984. (c) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J. Org. Chem.
1988, 53, 3865-3868. (d) Huszthy, P.; Bradshaw, J. S.; Zhu, C. Y.; Izatt,
R. M.; Lifson, S. J. Org. Chem. 1991, 56, 3330-3336. (e) Robertson, D.
W.; Lacefield, W. B.; Bloomquist, W.; Pfeiffer, W, Simon, R. L.; Cohen,
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H. Tetrahedron Lett. 1996, 37, 6375-6378. (g) Parmar, S. V.; Kumar, A.;
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C. E. Tetrahedron 1997, 53, 2163-2176. (h) Killian, J. A.; Van Cleve, M.
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(i) Chakaborti, A. K.; Basak, A.; Grover, V. J. Org. Chem. 1999, 64, 8014-
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Chem. Lett. 2002, 12, 2391-2394.
SCHEME 11. Base-Catalyzed Esterification of Carboxylic
Acids with DMC
(22) Based upon spectroscopic investigations, refs 9 and 11 detail the
adsorption pattern of phenols and amines over NaY and NaX faujasites.
Since no data are available for carboxylic acids, Scheme 12 is only a
reasonable hypothesis. For clarity, the interactions of OH substituents of
acids 3-5 with NaY (see Scheme 9) are omitted.
(16) Kalgutkar, A. S.; Kozak, K. R. Crews, B. C.; Hochsang, G. P.;
Marnett, L. J. J. Med. Chem. 1998, 41, 4800-4818.
1468 J. Org. Chem., Vol. 71, No. 4, 2006

ChemoselectiVe Syntheses using DMC/Faujasite
The tuning of the reaction temperature may affect both modes
(a and b) of adsorption. Accordingly, tetrahedral or SN2-type
(BAl2) or both mechanisms account for the esterification process.
Whatever the mechanism, aromatic and aliphatic OH sub-
stituents of acids 3-5 are substantially preserved. Such a high
chemoselectivity in the synthesis of esters with DMC has been
reported only in the preparation of methyl salicylate over
protonic zeolites (Hâ and HZSM5).23
is due only to its acid-base properties or if a shape-selectivity
operates as well.
The green features of the reported protocol should also be
mentioned: (i) a nontoxic compound (DMC) is used as both a
reagent and a solvent, (ii) an eco-safe solid (NaY) is involved,
and (iii) thanks to the high chemoselectivity, derivatization
sequences can be avoided. Finally, although the zeolite must
be used in a relatively high amount (weight ratios of NaY:
substrate up to 3), it can be easily separated by filtration,
reactivated, and recycled without any loss of activity and/or
selectivity.
The unusual behavior observed for tropic acid 19 (whose
alcoholic group undergoes a rapid dehydration, Scheme 7) can
presently not be explained.
Table 3 also shows that a dramatic drop of chemoselectivity
occurs when K2CO3 is the catalyst. In addition to the esterifi-
cation of acid functions of compounds 3-5, the methylation of
aromatic and aliphatic OH substituents and the transesterification
of DMC with alcoholic groups (entries 2, 4, and 6, Table 3)
take place through BAl2 and BAc2 mechanisms, respectively.1
Under basic conditions, solvation phenomena can also play a
role on the overall selectivity. For instance, the reaction of
mandelic acid with MeI in a suspension of NaHCO3/DMF is
claimed to produce the methyl ester 4 in a 85% yield,19b whereas
only the formation of (R)-2-methoxymandelic acid [(R)-PhCH-
(OMe)CO2H] is reported when (R)-mandelic acid reacts with
dimethyl sulfate in an aqueous alkaline (NaOH) solution.24
Apparently, the two competitive esterification and O-methylation
processes can be mainly discriminated by the reaction medium.
Experimental Section
Compounds 1a,b, 2a, 3a,b, 4, and 5 and DMC were ACS grade
and were employed without further purification. The zeolite NaY
was from Aldrich (no. 334448), and before each reaction it was
dried under vacuum (65 °C; 8 mbar) overnight. GLC and GC-
MS (70 eV) analyses were run using HP5 and HP5/MS capillary
1
columns (30 m), respectively. H NMR spectra were recorded on
a 300 MHz spectrometer, using CDCl3 or CD3OD as solvents.
Compound 2b (4-mercaptobenzoic acid) was not commercially
available; it was prepared according to reported procedures (Scheme
13).25-27 Starting from methyl 4-hydroxybenzoate (5.2 g, 34.2
SCHEME 13. Synthesis of 4-Mercaptobenzoic Acid 2b
Conclusions
The combination of dimethyl carbonate and NaY faujasite
makes it possible to set up methylation and esterification
processes of bifunctional substrates such as mercaptophenols
1a,b, mercaptobenzoic acids 2a,b, and OH-substituted carbox-
ylic acids 3-5.
mmol), after three steps, compound 2b was isolated as a pale yellow
solid (51%, 2.7 g, 17.4 mmol). Spectroscopic and physical
properties were in agreement with literature data: mp 218 (lit.20
222 °C); 1H NMR (300 MHz, CDCl3) δ 3.66 (s, 1H, SH), 7.32 (d,
J ) 8.5 Hz, 2H, Ar), 7.96 (d, J ) 8.4 Hz, 2H, Ar). GC-MS m/z:
154 (M+, 100%), 137 ([M - OH]+, 60), 109 ([M - CO2H]+, 36),
108 (10), 65 (19), 65 (19), 45 (12).
Reactions Carried Out in Autoclave. General Procedure.
(Tables 1-3) A stainless steel autoclave (150 mL internal volume)
was charged with a solution (5 × 10-2 M; 30 mL) of the chosen
substrate (1a,b, 2a,b, 3-5, 11, and 19; 1.5 mmol), dimethyl
carbonate (0.36 mol), and NaY (NaY:substrate in a 0.5-4 weight
ratio; see Tables 1-3 for details). At room temperature and before
the reaction, air was removed by a purging valve with a N2 stream.
The autoclave was then heated by an oil-circulating jacket, while
the mixture was kept under magnetic stirring throughout the
reaction. A thermocouple fixed onto the autoclave head checked
the temperature (150-165 °C). After different time intervals (13-
24 h), the autoclave was cooled to room temperature, purged from
CO2, and finally opened. The reaction mixture was analyzed by
GC and GC-MS.
Under the investigated conditions, the comparison between
K2CO3 (a typical basic catalyst for DMC-mediated reactions)
and NaY faujasite shows that the zeolite is always less active
than the base. However, NaY is by far superior for chemose-
lectivity: at 150 °C, mercaptobenzoic acids undergo S-methyl-
ation reactions without affecting the acid groups, whereas the
increase of the temperature (165 °C) allows the exclusive
esterification of hydroxybenzoic acids (ortho and para isomers),
mandelic acid, and phenyllactic acid, their aromatic and aliphatic
OH substituents being fully preserved from methylation and/or
methoxycarbonylation side reactions. Typical selectivities for
such processes are in the range of 90-100%. On the contrary,
in the presence of K2CO3, competitive reactions of O- and
S-methylation, esterification, and O-methoxycarboylation take
place simultaneously.
K2CO3 and NaY allow a comparable selectivity only in the
case of mercaptophenols, where hydroxythioanisoles are the only
products in yields of g90%.
The same procedure was also used for reactions carried out in
the presence of K2CO3. In these cases (entries 6 and 11, Table 1;
entries 3-4, Table 2; entries 2, 4, and 6, Table 3), the temperature
was set to 130 °C (Tables 1 and 2) and to 150 °C (Table 3), and
the molar ratio K2CO3:substrate was in the range of 0.2-2.
All products 6a,b, 9a,b, 13a,b, 14, 15, and 20 were simply
isolated by filtration of the zeolite and removal of DMC under
vacuum (35 °C/250 mm). Compounds 6b, 9a,b, 12, and 13b were
The amphoteric nature of NaY suggests that two major points
should account for such results: (i) the electrophilic activation
of DMC over NaY and (ii) a possible nucleophilic activation
of reagents 1-5 that may take place through H-bonds with basic
oxygen atoms of the framework of the aluminosilicate. However,
the data gathered so far do not allow further substantiation of
these effects or determination of whether the action of the zeolite
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J. Org. Chem, Vol. 71, No. 4, 2006 1469

Selva and Tundo
further purified by FCC on silica gel F60 (eluant: petroleum ether/
diethyl ether 4:1 v/v).
Methyl 4-hydroxybenzoate 13b: mp 124-126 °C (white solid)
[lit.32-33 mp 124-125 °C]. Methyl mandelate 14: mp 52-54 °C
(yellow solid) [lit.34 bp 118-9 °C/8 mm]. Methyl phenyllactate
15: mp 27-29 °C (pale yellow solid) [lit.35 mp 33 °C]. Methyl
2-phenylpropenoate 20: yellow oil [lit.36 colorless oil].
Spectroscopic and physical properties were in agreement with
those reported in the literature. 2-Hydroxythioanisole 6a: pale-
yellow liquid [lit.28 bp 81-82 °C/0.5 mm]. 4-Hydroxythioanisole
6b: mp 83-85 °C (yellow solid) [lit.28 mp 84-85 °C]. 2-Meth-
ylthiobenzoic acid 9a: mp 165-167 °C (yellow solid) [lit.29 mp
168-169 °C]. 4-Methylthiobenzoic acid 9b: mp 190-191 °C
(white solid) [lit.30 mp 187-190 °C]. 2-Methylthiobenzyl alcohol
12: pale yellow liquid [lit.31 bp 105-110 °C/0.05 Torr]. Methyl
2-hydroxybenzoate 13a: pale yellow oil [lit.32 bp 40-50 °C/3 mm].
Acknowledgment. MIUR (Italian Ministry of University and
Research) is gratefully acknowledged for financial support. We
also thank Dr. A. Perosa for his helpful comments and Dott. F.
Dall’Acqua for his help in the experimental work.
Supporting Information Available: 1H NMR and GC-MS
spectra for compounds 6a,b, 9a,b, 13a,b, 14, 15, and 20. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
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1470 J. Org. Chem., Vol. 71, No. 4, 2006