8
70
Note
Chem. Pharm. Bull. 61(8) 870–872 (2013)
Vol. 61, No. 8
The Effect of Indium(III) Triflate in Oxone-Mediated Oxidative Methyl
Esterification of Aldehydes
,
a
a
a
a
b
Tomoko Mineno,* Mai Sakai, Akira Ubukata, Kazuhide Nakahara, Hitoshi Yoshimitsu, and
Hisao Kansui*
,
c
a
Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare; 60 Nakaorui,
b
c
Takasaki, Gunma 370–0033, Japan: Laboratory of Natural Medicines, Sojo University; and Laboratory of
Organic Chemistry, Faculty of Pharmaceutical Sciences, Sojo University; 4–22–1 Ikeda, Kumamoto 860–0082,
Japan.
Received January 24, 2013; accepted June 4, 2013
An oxidative methyl esterification of aldehydes was effectively achieved. The trivalent indium reagent,
indium(III) triflate, was revealed to accelerate the reactions in many cases. Aromatic aldehydes with various
substituents were subjected to this method, and each produced the corresponding methyl esters in good to
excellent yields within a relatively short reaction time.
Key wordsꢀ indium(III)ꢀtriflate;ꢀaldehyde;ꢀmethylꢀesterification
Methyl esters of carboxylic acids are one of the most funda- detailsꢀ ofꢀourꢀstudyꢀ onꢀtheꢀefficientꢀoxidativeꢀmethylꢀesterifi-
mental chemical components. Methyl ester moieties are con- cation of aldehydes using In(OTf) . As the effective oxidant,
3
®
veniently utilized as masking units for carboxylates, which, Oxone monopersulfate compound (Oxone), a triple salt of
when left in their unmasked free carboxylate forms, may exert potassium composed of potassium peroxymonosulfate, which
anꢀ untowardꢀ influenceꢀ onꢀ moleculesꢀ uponꢀ implementationꢀ ofꢀ is a versatile oxidant developed by DuPont, was chosen after a
theꢀintendedꢀchemicalꢀreactions.ꢀInꢀtheꢀfieldꢀofꢀchemotherapy,ꢀ couple of tentative experiments.
methyl esters often serve as a prodrug in order to improve
Initially, we attempted the use of para-tolualdehyde as the
bioavailability. Methyl esters are generally converted to their starting material for the oxidative chemical transformation, after
2
0,21,28)
active acid form in the body via the function of esterase.
consulting the previously reported reaction conditions
t
t
Generally, methyl esters can be synthesized by the conden- (Table 1). Initially, H O and BuOO Bu were selected as the
2
2
sation reaction of carboxylic acids with methanol in the pres- oxidants, and the reaction mixtures were stirred in the pres-
ence of an acid or a base, and there are a number of methods ence of 10mol % of In(OTf) at room temperature for 40h
3
available.ꢀWeꢀpreviouslyꢀreportedꢀanꢀefficientꢀmethodꢀofꢀhigh- in MeOH (Table 1, Entries 1 and 2). However, sterile results
yieldingꢀ methylꢀ esterificationꢀ thatꢀ isꢀ catalyzedꢀ byꢀ aꢀ trivalentꢀ were obtained since the reaction did not proceed, and in-
1)
indium reagent under mild reaction conditions. Likewise, stead, most of the starting material of para-tolualdehyde was
methyl esters can be practically prepared by treating carbox- recovered intact. Seeing the inorganic oxidant in the next
ylic acids in methanol that contains a catalytic amount of vision, Oxone was subsequently tested for its reaction in the
2)
trimethylsilyl chloride.
presence of 10mol % of In(OTf) , as well as other trivalent
3
Meanwhile,ꢀ theꢀ directꢀ oxidativeꢀ methylꢀ esterificationꢀ ofꢀ indium reagents, such as InCl and InBr (Table 1, Entries
3
3
aldehydesꢀhasꢀcommandedꢀaꢀgreatꢀdealꢀofꢀinterestꢀinꢀtheꢀfieldꢀ 3–5). Surprisingly, despite the identical reaction conditions, at
of organic synthesis. Although a couple of the esterifying room temperature and for the elongated reaction time of 3d,
transformations of aldehydes using metal-based reagents have only the entry of 10mol % of In(OTf) produced encouraging
3
3
–5)
6)
7)
been reported, including iridium,
rhodium, palladium,
rhenium, ruthenium,
results in a 52% yield (Table 1, Entry 5). The result prompted
us to search for more suitable reaction conditions. The reac-
those heavy/transition tion was dramatically improved when the temperature was in-
8)
9,10)
11)
12)
13)
14)
manganese, iron, copper, tin,
and pyridinium dichromate (PDC),
15,16)
metalꢀ oxidantsꢀ mightꢀ notꢀ beꢀ sufficientlyꢀ environmentallyꢀ be- creasedꢀtoꢀreflux,ꢀandꢀtheꢀreactionꢀtimeꢀwasꢀalsoꢀconsiderablyꢀ
nign.ꢀAsꢀaꢀconsequence,ꢀesterificationꢀmethodologiesꢀemploy- shortened to a 3h time of completion (Table 1, Entry 6). For
ing H O and catalytic amounts of metal-based reagents, such the assurance, the reaction was carried out with 5mol % of
2
2
1
7)
18,19)
as titanosilicate, vanadium pentoxide,
iron salt, and zinc In(OTf) , which furnished only a 32% yield (Table 1, Entry 7).
3
2
0,21)
salt,
have been introduced. However, in many cases, the Theꢀreactionꢀwasꢀalsoꢀconfirmedꢀusingꢀ10ꢀmolꢀ%ꢀofꢀZn(OTf)2
reagents are limited by the use of H O with the combination and Mg(OTf) , and the result was moderately diminished
2
2
2
of fourth-row transition elements. Thus, it is worthwhile to de- yields in both cases (Table 1, Entries 8 and 9). The blank ex-
velop methodologies that incorporate useful and convenient al- periment without Lewis acid was then followed, which yielded
ternativesꢀforꢀtheꢀoxidativeꢀmethylꢀesterificationꢀofꢀaldehydes.
56%ꢀ atꢀ refluxꢀ andꢀ 55%ꢀ atꢀ roomꢀ temperatureꢀ basedꢀ onꢀ ourꢀ
In recent years, we have studied the usage of trivalent indi- reaction method and isolating procedure (Table 1, Entries 10
2
2,23)
24–27)
um reagents,
andꢀ reportedꢀ theꢀ catalyticꢀ applicationꢀ ofꢀ indium(III)ꢀ triflateꢀ
In(OTf) ) in the one-step chemical transformations. As part ous aromatic aldehydes were subjected to this method of
as well as indium metal-based reagents,
and 11).
With the optimized reaction conditions in hand, vari-
(
3
of our ongoing investigations, herein we wish to report the oxidativeꢀmethylꢀesterification.ꢀTableꢀ2ꢀshowsꢀthatꢀtheꢀreactionꢀ
proceeded to give the corresponding methyl esters in good
Theꢀauthorsꢀdeclareꢀnoꢀconflictꢀofꢀinterest.
to excellent yields. In particular, the entry of the aromatic
*
To whom correspondence should be addressed. e-mail: mineno@takasaki-u.ac.jp;
© 2013 The Pharmaceutical Society of Japan