Chemoselective esterification of α-hydroxyacids catalyzed by salicylaldehyde through induced intramolecularity

Article abstract of DOI:10.1039/c2ra23068b

A new, direct and chemoselective esterification of α-hydroxyacids was developed using a reversible covalent-binding strategy. By taking advantage of acetal chemistry, simple aldehydes can be used to efficiently catalyze the esterification of α-hydroxy carboxylic acids in the presence of β-hydroxyacid moieties or other carboxylic acids in amounts equal to or in excess of the alcohols. A diverse array of α-aryl, α-alkyl, α-heteroaryl, and functionalized α-hydroxyacids were smoothly esterified with 1° and 2° alcohols catalyzed by 10 mol% inexpensive and commercially available salicylaldehyde, furnishing the resultant esterification products in 83-95% yields after a simple basic aqueous workup to remove the unreacted hydroxyacids. In addition, the salicylaldehyde can be recovered through vacuum distillation or silica gel purification, thereby meeting the standards of green chemistry. A mechanistic study proved that the formation of covalent adduct III during our proposed catalytic cycle (Scheme 1A) is responsible for the real catalysis.

Full text of DOI:10.1039/c2ra23068b

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Chemoselective esterification of a-hydroxyacids
catalyzed by salicylaldehyde through induced
Cite this: RSC Advances, 2013, 3,
1976
intramolecularity3
Shiue-Shien Weng,* Hsin-Chun Li and Teng-Mao Yang
A new, direct and chemoselective esterification of a-hydroxyacids was developed using a reversible
covalent-binding strategy. By taking advantage of acetal chemistry, simple aldehydes can be used to
efficiently catalyze the esterification of a-hydroxy carboxylic acids in the presence of b-hydroxyacid
moieties or other carboxylic acids in amounts equal to or in excess of the alcohols. A diverse array of a-aryl,
a-alkyl, a-heteroaryl, and functionalized a-hydroxyacids were smoothly esterified with 1u and 2u alcohols
catalyzed by 10 mol% inexpensive and commercially available salicylaldehyde, furnishing the resultant
esterification products in 83–95% yields after a simple basic aqueous workup to remove the unreacted
hydroxyacids. In addition, the salicylaldehyde can be recovered through vacuum distillation or silica gel
purification, thereby meeting the standards of green chemistry. A mechanistic study proved that the
formation of covalent adduct III during our proposed catalytic cycle (Scheme 1A) is responsible for the real
catalysis.
Received 26th November 2012,
Accepted 28th November 2012
DOI: 10.1039/c2ra23068b
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bimolecular reactions can be achieved through fast and
stereoselective unimolecular processes that allow for pre-
Introduction
modification of designed intermediate structures.1,2,5
Recently, a remarkable demonstration of temporary intramo-
lecularity in Cope-type hydroaminations has shown the
possibility of using simple aldehydes as catalytic tethering
functionalities to achieve highly challenging intermolecular
transformations in a catalytic and enantioinductive manner.6
Many early applications using carbonyl compounds (alde-
hydes or ketones) as catalytic platforms have focused on the
hydrolysis and transesterification of functionalized esters such
as activated esters of amino acids and a-hydroxyesters.7
However, the actual catalysis proceeded through the genera-
tion of a five-membered cyclic intermediate (dioxolanone),
triggered by the reversible nucleophilic addition of the gem-
hydroxyl group of the hemiacetal to the reacting carbonyl
group (Scheme 1A). Nevertheless, the pursuant elimination
that was conjectured as the rate-determined step strongly
relied on the leaving capability of the alcohol component of
the ester (i.e. the alkoxide). Therefore, applications using this
strategy seem limited and only applicable to activated esters;
furthermore, synergistic assistance of a general base in close
proximity to the catalytic site is required.5,7 In contrast to
those carbonyl-catalyzed enzyme-mimicking hydrolysis reac-
tions, the direct construction of ester bonds of hydroxyacids
using acidic boric and boronic acids as reversible covalently-
bonding units have shown the complementary applications of
induced intramolecularity.8 The cyclic acyloxyboronate species
is naturally, reversibly, and covalently formed as an activated
Conceptually inspired by enzymatic processes, catalysis
though induced intramolecularity utilizing a reversible multi-
ple covalent binding strategy is considered one of the
important tools and future directions for conducting sustain-
able organic syntheses.1 In reactions for which either the
catalytic functional group or functionalized substrates are
rigidly tethered through reversible covalent interactions, a
large amount of entropy must be expended in advance.
Therefore, such entropic loss can be utilized to accelerate
the subsequent chemical transformation, allowing the inter-
molecular processes to proceed in an intramolecular manner
with an inherently low energy cost and efficient energetic
discrimination of competing transition states in the rate-
determining step. This can result in high levels of regio-,
chemo-, and stereoselective induction and enhanced reaction
rates.2 By taking advantage of the high tendency of formation
and relatively low activation barriers for bond-forming
equilibration of hemiacetals, hemithioacetals, or carbinola-
mines,3 carbonyl compounds (aldehydes and ketones) can act
as enzyme-mimicking catalysts.4 This strategy provides a great
opportunity to allow pre-association of the reaction counter-
parts to form a highly reactive transient geometry and
thermodynamically stable transition state. As a consequence,
Department of Chemistry, ROC Military Academy, Taiwan, ROC.
E-mail: wengss@mail.cma.edu.tw; Fax: +886-7429442
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
3
c2ra23068b
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Scheme 1
electrophilic intermediate with very low energetic require-
ments during such equilibrating processes between bifunc-
tional a-hydroxyacids and boric (or boronic) acids, thereby
facilitating the subsequent nucleophilic acyl substitution and
water-expelling turnover processes.
Table 1 Catalyst 1 screeninga,b
In this regard, we wished to take advantage of the
glycosidic lysozyme catalysis9 associated with the related
acetal hydrolysis chemistry.10 The carboxylic acid group of the
a-hydroxyacid would serve as a general acid and self-catalyze
acetal formation with the carbonyl catalyst, which would be
followed by cyclic acylal (dioxolanone) intermediate forma-
tion with participation of the ionized carboxylate anion
(Scheme 1B). This would allow intramolecular facilitation of
Entry
Aldehyde
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Benzaldehyde
24
24
24
24
24
24
24
24
24
18
24
24
18
24
48
48
48
24
62(11)d
13
4-Nitrobenzaldehyde
Pentafluorobenzaldehyde
Pyridine-2-carboxaldehyde
2-Benzloxyacetaldehyde
2-Phenylacetaldehyde
tran-2-Hexenal
4-Methoxy-benzaldehyde
2,6-Dimethoxybenzaldehyde
Salicylaldehyde
3-Hydroxybenzaldehyde
4-Nitro-salicyladehyde
4-Methoxysalicyladehyde
2,4,6-Trihydroxybenzaldehyde
Tetrahydro-4H-pyran-4-one
Cyclohexanone
5
8
28
13
the subsequent nucleophilic esterification,11 if such
a
proposed equilibrium exists. In this article, we describe the
chemo- and site-selective catalysis of directed esterification of
a-hydroxyacids under relatively mild and metal-free condi-
tions using simple aromatic aldehydes, especially salicylalde-
hyde, by manipulating the reversible acetal bond formation
and subsequent cyclic dioxolanone-generating equilibria
between bifunctional a-hydroxyacids and carbonyl catalysts.
This method may provide another chance to circumvent the
inherent harshness, difficulty, and inefficiency of classical
esterification reactions.8,12 This strategy also fully demon-
strates an application contrary to traditional aldehyde
catalysis and illustrates the power of induced intramolecu-
larity. In addition, the aldehyde catalysts can be conveniently
recovered by simple distillation or chromatographic purifica-
tion, and the use of transition metal catalysts can be avoided,
thereby meeting the standards of current innovation toward
green organic synthesis.
43
75(20)d
68(12)d
92(28)d
76
60
87
79
6
11
Trifluoromethyl phenyl ketone
35
82(5)d
19e,f
20e,g
Salicylaldehyde
Salicylaldehyde
18
15
90 (1b)
92 (1c)
a
Reaction conditions: 10 mol% aldehyde, (R)-mendalic acid (1
b
mmol) in 1 mL CH3OH at 70 uC. Reaction progress was monitored
by TLC, 1H NMR spectroscopy, and GC analysis. Yield of isolated
c
d
product. Reaction was conducted at room temperature (25 uC).
e
f
Reaction was conducted at 80 uC. EtOH was used instead of
g
CH3OH. iso-PrOH was used instead of CH3OH.
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Results and discussion
Catalyst screening
Initial attempts were guided by the model esterification of (R)-
mandelic acid with methanol as the solvent in the presence of
10 mol% of aldehydes at 70 uC, and the results are shown in
Table 1. To our delight, only 10 mol% of benzaldehyde allowed
the reaction to proceed at 70 uC, albeit with a moderate yield
(62%, Table 1, entry 1), while only 11% yield of 1a was
obtained at room temperature after 24 h (Table 1, entry 1,
parentheses). Notably, esterification product 1a was obtained
as an enantiomerically pure material (determined by chiral
HPLC analysis), suggesting that no racemization occurred
under the reaction conditions. Interestingly, highly activated
electron-deficient aldehydes such as 4-nitrobenzaldehyde and
pentafluorobenzaldehyde failed to promote this condensation
to a significant extent (Table 1, entries 2 and 3). In addition,
2-formylpyridine with a basic nitrogen atom proximate to the
reaction center, which was employed to catalyze the hydroxyl-
directed methanolysis of activated glycolate,7 also proved
ineffective (Table 1, entry 4), implying that our reaction
mechanism is not through a general base or nucleophilic
mechanism. Aliphatic aldehydes activated by a-benzyloxy or
phenyl groups provided negligible activity in this condensa-
tion (Table 1, entries 5 and 6). An a,b-unsaturated alkenyl
aldehyde showed a slight improvement in yield, but was still
unsatisfactory (Table 1, entry 7). Surprisingly, electron-rich
4-methoxybenzaldehyde was found to be highly active, furnish-
ing ester 1a in 75% yield at 70 uC and 20% yield at room
temperature within 24 h (Table 1, entry 8). The dimethoxy
analog was less efficacious, yet still very active (68% yield,
Table 1, entry 9).
Scheme 2 Chemoselective esterification of mandelic acid in the presence of
2-phenylacetic acid catalyzed by salicylaldehyde
it was not very efficient at room temperature (Table 1, entry 18,
parentheses) compared with benzaldehyde, 4-methoxybenzal-
dehyde, 2,6-dimethoxybenzaldehyde, and salicylaldehyde
(entries 1, 8, 9, and 10, parentheses). Other alcohols, such as
ethanol and isopropanol, can also be used as protic
nucleophiles using salicylaldehyde as the catalyst at higher
temperature (80 uC) to furnish ethyl mandelate 1b and iso-
propyl mandelate 1c in 90% and 92% yield, respectively
(Table 1, entries 19 and 20). Interestingly, the reaction rate of
the more sterically hindered isopropanol was faster than
primary alcohols, probably because of the decreased rate of
the competing acetal (or hemiacetal) formation of isopropanol
and mandelic acid with the catalyst. However, the current
protocol did not proceed well with 3u alcohols such as tert-
butanol, even at prolonged reaction times, presumably due to
the steric hindrance of 3u alcohols. It is worth mentioning that
most of the carbonyl catalysts can be recovered through high
vacuum distillation after completion of the reaction under
mild heating (50 uC) and the pure mandelates (as judged by
spectroscopic analysis) can be obtained upon washing the
crude product with aqueous bicarbonate to remove the
unreacted carboxylic acid or via chromatographic purification,
if necessary. Ionic catalyst 2 can easily be recovered though
precipitation by addition of a less polar solvent or from the
water layer after aqueous work up. In order to examine the
chemoselectivity of the present salicylaldehyde catalysis,
equimolar amounts of mandelic acid and 2-phenyl acetic acid
were mixed with 2 mL methanol in the presence of 10 mol%
salicylaldehyde at 70 uC for 24 h. It was found that mandelic
acid was quantitatively converted to the corresponding methyl
ester 1a, while no esterification product of 2-phenyl acetic acid
was detected (Scheme 2). This result suggests that a high level
of chemoselectivity can be achieved in our catalytic system,
even in the presence of excess amounts of alcohol.
It appears that an acidic phenol group proximate to the
carbonyl does play
a significant role in this catalytic
condensation, as judged by the remarkable improvement in
the yield for the reaction using salicylaldehyde (18 h, 92%
yield, entry 10) relative to that of the analogous reaction
catalyzed by 3-hydroxybenzaldehyde (24 h, 76% yield, entry
11). However, the analog with an electron-withdrawing nitro
substituent was less efficacious than the parent salicylalde-
hyde (24 h, 60% yield, Table 1, entry 12). The salicylaldehyde
possessing an electron-donating methoxy group at C-4 and
water-soluble 2,4,6-trihydroxybenzaldehyde were catalytically
comparable to salicylaldehyde, but showed no significant
improvement in yield (Table 1, entries 13 and 14). Both
4-heterocyclohexanone and cyclohexanone, which were effi-
cient catalysts for the hydrolysis of functionalized amides
under strong alkaline conditions,13 were found to be inactive,
even at prolonged reaction times (Table 1, entries 15 and 16). A
ketone catalyst possessing a strong electron-withdrawing
trifluoromethyl group (CF3) was slightly more efficient than
the cyclic ketones and a prolonged reaction time was required
to achieve a moderate yield (48 h, 35%, Table 1, entry 17).
While basic 2-formylpyridine showed poor catalytic ability,
ionic, water soluble, methylated N-methylpyridinium-2-carbox-
aldehyde iodide salt 2 was found to have catalytic efficiency
comparable to that of salicylaldehyde, furnishing product 1a
in 82% yield at 70 uC within 24 h (Table 1, entry 18). However,
The scope of functional group compatibility
With these promising results in hand, our attention turned to
the examination of the substrate scope of the reaction
(Table 2). Salicylaldehyde readily promoted the esterification
of a range of mandelic acid derivatives with various electronic
and steric demands in concentrated methanolic solution at 70
uC (Table 2, entries 1–7). In general, substrates bearing
electron-withdrawing groups (e.g. 4-Cl, 4-NO2, and 4-CF3,
entries 3–5) were more reactive than those with electron-
donating groups (e.g. 4-CH3 and 4-CH3O, entries 1 and 2). The
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Table 2 Substrate scopea,b
Entry
1
Product
Time (h)
18
Yield (%)c
90
Entry
11
Product
Time (h)
12
Yield (%)c
95
2
3
4
24
14
14
91
93
90
12
13d
12
8
91
93
85
14d,e
28
5
6
12
20
93
92
15f
36
14
92
89
16d,e
7
8
9
16
18
48
90
89
48
17d,e
36
20
30
89
90
23
18
19
10
30
82
20
48
,5
a
b
Reaction conditions: 10 mol% aldehyde, a-hydroxyacid (1 mmol) in 1 mL CH3OH at 70 uC. Reaction progress was monitored by TLC and
1H NMR spectroscopy analysis. Yield of isolated product. Reaction was conducted at 80 uC. EtOH was used instead of CH3OH. n-BuOH
was used instead of CH3OH and the reaction was conducted at 100 uC.
c
d
e
f
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influence of steric hindrance on the reaction rate was
pronounced for 2-substituted phenyl derivatives (compare
entries 1 and 3 with entries 6 and 7). The esterification rates of
the 2-chloro- and 2-methyl-substituted mandelic acids were
slightly lower than the corresponding 4-substituted analogs.
The reaction was also compatible with a heteroaryl-containing
mandelic acid system to afford the highly biologically active 3h
within 18 h (89% yield, entry 8).14 However, the esterification
of a pyridyl-derived substrate was somewhat sluggish, prob-
ably because the basic nitrogen atom neutralized the acidic
proton of the phenol group of salicylaldehyde or the mandelic
acid, thus inhibiting the proposed acetal formation equili-
brium and minimizing the yield (48%, entry 9). It was found
that a slightly longer reaction time was required in the case of
the ortho-substituted phenol substrate, owing to the compet-
ing reaction between the phenol group of the substrate and
the carboxylic acid group of the a-hydroxyacid with the catalyst
(30 h, 82%, entry 10).
The substrate class was further extended to a-hydroxyacids
possessing a-benzyl, a-alkenyl, a-alkynyl, and a-alkyl groups.
In general, a-benzyl, a-alkenyl (trans-PhCHLCH), and a-alkynyl
(PhCMC) analogs were more reactive than a-aryl and a-alkyl
analogs (entries 11, 12, and 13). Their salicylaldehyde-
catalyzed esterifications could be completed in 8–12 h.
Furthermore, the conjugated alkene and triple bond remained
intact without isomerization or rearrangement. In marked
contrast, substrates bearing a-alkyl groups, such as lactic acid
and 2-hydroxy-2-methylpropanoic acid, were less reactive in
methanol; however, ethyl lactate 3n (80 uC, 28h, 85% yield,
entry 14) and n-butyl 2-hydroxy-2-methylpropanoate 3o (100
uC, 36h, 92% yield, entry 15) could be obtained, albeit with
prolonged reaction times and elevated temperatures, in the
corresponding higher-boiling alcohols. With dicarboxylic acids
framework, L-malic acid, the ethylation was ultimately
regioselective for the carboxylic group proximate to the
a-hydroxy moiety to provide monoester 3p in 89% yield within
14 h (entry 16). It is notable that neither a significant
improvement of the yield of monoester 3p nor diester
formation were observed when the reaction was extended to
24 h, which fully demonstrates the unique chemoselectivity of
this aldehyde catalysis for a-hydroxyacids. In contrast, the
esterification of tartaric acid was slower, even at 80 uC (36 h,
89% yield, entry 17), probably because of the fast formation of
the acetal of the diol moiety of tartaric acid and the carbonyl
group, which inhibited the formation of the proposed reactive
intermediate III. Furthermore, the esterification of pharma-
ceutically active N-benzoyl-3-phenylisoserine (i.e. the taxol C-13
side chain)15 led to methylated ester 3r in 90% yield within 20
h, suggesting that b-branching substitution did not influence
the catalytic efficiency of salicylaldehyde (compare entry 18
with entry 11). Notably, the methylation of phenyl glycine
derivative 2-(4-nitrophenylamino)-2-phenylacetic acid was inef-
ficacious, even though the amino group was protected with an
electron-deficient para-nitrophenyl group, and amino ester 3s
was obtained in only 23% yield after a prolonged reaction time
(entry 19). Finally, the reaction of a b-hydroxyacid (tropic acid)
was inefficient with a long reaction time (,5% yield, 48h,
entry 20), which again demonstrates the promising chemos-
electivity of our catalytic system.
Concentration effects
It was found that the concentration and solvent effects largely
influenced the yields of the direct esterification of a-hydro-
xyacids catalyzed by boronic acids. Whereas excess a-hydro-
xyacid accelerated the reaction, excess alcohol suppressed the
reaction because of the competing coordination of both
substrates and alcohols with the boron center.8 Thus, we
evaluated the solvent and concentration effects in our system
using 10 mol% salicylaldehyde as the catalyst with different
ratios of mandelic acid and alcohols (Table 3). The evaluation
of other solvents in the esterification reaction of mandelic acid
catalyzed by 10 mol% salicylaldehyde was undertaken at 80 uC
and the amount of n-butanol was reduced to 5 equivalents. We
found that nonpolar solvents such as toluene, cyclohexane,
and heptane were tolerated at high molar concentration (2
M),16 and toluene was optimal (Table 3, entries 1–3). On the
effects of the concentration of the alcohol, expectedly, the
reaction rate and yield increased when the amount of the
alcohol used in toluene was decreased. The best molar ratio of
mandelic acid to n-butanol was 1 : 1 (Table 3, entry 5), whereas
the reaction rate was inhibited when the mandelic acid/
n-butanol molar ratio was less than 1 : 1 (Table 3, compare
entries 1 and 4 with 5). This phenomenon was probably due to
the competition between formation of the hemiacetal of
mandelic acid and that of excess n-butanol with the carbonyl
group of the catalyst.7 In contrast, the reactions of bulky
alcohols proceeded more smoothly with a 1 : 1 molar ratio of
mandelic acid to alcohol (Table 3, compare entries 5 and 6),
and the rate of competition of mandelic acid for aldehyde
decreased as the size of the alcohol moiety increased. The
esterification of less nucleophilic benzyl alcohol was also
proved efficacious in 14 h with nearly quantitative conversion
(Table 3, entry 7), while a more basic long-chain aliphatic
alcohol required an elevated temperature (100 uC) and a
prolonged reaction time (Table 3, entry 8). The reaction of a
sterically hindered 2u alcohol also proceeded smoothly to
Table 3 Concentration effectsa
Entry Solvent/R2OH
Time (h) Yield (%)b
1
2
3
Toluene/n-BuOH (5 eq)
Cyclohexane/n-BuOH (5 eq)
Heptane/n-BuOH (5 eq)
16
24
18
14
12
10
14
30
20
87 (1d)
80 (1d)
84 (1d)
89 (1d)
93 (1d)
95 (1e)
94 (1f)
81 (1g)
90 (1h)
87 (1i)
4
5
6
7
Toluene/n-BuOH (2 eq)
Toluene/n-BuOH (1.0 eq)
Toluene/i-Armyl (1.0 eq)
Toluene/BnOH (1.0 eq)
8c
9c
10d
Toluene/CH3(CH2)16CH2OH (1.0 eq)
Toluene/Ph2CHOH (1.0 eq)
Toluene/cis-PhCHLCHCH2OH (1.0 eq) 24
a
All reactions were conducted in 1 mL solvent in the presence of 10
b
mol% salicylaldehyde and 2 mmol mandelic acid at 80 uC. Isolated
c
d
yield. Reaction temperature: 100 uC. Reaction temperature: 120 uC
(reflux).
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Table 4 Esterification of equal amounts of benzyl alcohol and a-hydroxyacidsa
Table 4 (Continued)
Entry
1
Product
Time (h)
10
Yield (%)b
90 (4a)
Entry
13c
Product
Time (h)
20
Yield (%)b
87 (4m)
14c
15d
24
8
91 (4n)
93 (4o)
2
3
12
8
91 (4b)
93 (4c)
a
4
5
8
8
92 (4d)
94 (4e)
All reactions were conducted in 1 mL toluene in the presence of 10
b
c
mol% salicylaldehyde at 80 uC. Isolated yield. Reaction
temperature: 100 uC. The dilute benzylthiol in toluene (10 mL) was
slowly added to the reaction mixture of mandelic acid and
salicylaldehyde over 7 h at 60 uC via syringe pump.
d
furnish product 1h in 90% yield within 20 h at 100 uC (Table 3,
entry 9). The more challenging a,b-unsaturated cinnamyl
alcohol also afforded a high product yield, albeit at the cost
of a higher reaction temperature (Table 3, entry 10). Based on
these results, it is noteworthy that the use of excess alcohol is
not necessary, and more complex alcohols were applicable
using our protocol.
6
14
90 (4f)
7
8
10
12
94 (4g)
90 (4h)
We further demonstrated the more challenging benzylation
of a series of a-hydroxyacids under the optimal conditions (2
M in toluene, 80 uC) catalyzed by 10 mol% salicylaldehyde in
the presence of 1.0 equivalents benzyl alcohol (Table 4). In all
cases, except those involving a-alkyl-substituted hydroxyacids,
benzylation proceeded smoothly at 80 uC to afford the
corresponding benzyl esters 4a–4j in 90–95% yields at short
reaction times (8–14 h, entries 1–10). In general, similar to the
corresponding methylation (Table 2), a-aryl substrates bearing
electron-withdrawing groups were more reactive than those
with electron-donating groups. Also, the ortho-substituted aryl
substrates were less reactive than the para-substituted
substrates (compare entry 1 with entry 2). The steric effect
was also pronounced for naphthyl-containing analogs; the
2-naphthyl (i.e. 3,4-/m,p-benzo-fused) system was more reactive
than the 1-naphthyl (i.e. 2,3-/o,m-benzo-fused) system (entries
7 and 8). The benzylation of heteroaryl-containing systems
such as the thiophene and furfural derivatives (entries 9 and
10) are even faster than a-aryl systems, presumably because of
their high solubilities under such reaction conditions.
Although a higher temperature (100 uC) was required for
a-alkyl substituted systems, higher product yields were
obtained, even in the cases of sterically hindered isobutyl
9
8
95 (4i)
93 (4j)
10
10
11c
12c
18
15
85 (4k)
88 (4l)
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and cyclohexyl systems (85–91% yield, entries 11–14).
Moreover, the thioesterification was also compatible, even at
60 uC to afford thioester 4o in 93% yield within 8 h (entry 15).
However, slow addition of the dilute toluene solution of
benzylthiol (0.1 M) was essential to avoid formation of the
extremely stable thioacetal of salicylaldehyde, which would
interrupt the proposed catalytic equilibrium during the
reaction.
IV is produced and dissociation of the a-hydroxyester from IV
liberates product V, regenerating the carbonyl catalyst. A
similar hydrolysis of a dioxolanone intermediate promoted by
an acidic proton was also observed in a detailed mechanistic
study of the alcoholysis of activated esters catalyzed by
2-formylpyridine (general base), which coincides with our
observations in eqn (2).7 It should be noted that the final
product-releasing step is irreversible, since the released
a-hydroxyester did not undergo hydrolysis or transesterifica-
tion at 80 uC in the presence of 10 mol% salicylaldehyde in
aqueous ethanol.18
In view of the previous studies on the detailed mechanism
concerning substituent effects in the intramolecular hydrolysis
of hydroxyacid-derived acetals, electron-donating substituents
on the aromatic ring of the acetal (i.e. a methoxy group)
accelerate the hydrolysis rates, owing to the resonance
stabilization of the oxocarbonium transition state.19 In
contrast, electron-withdrawing substituents (such as nitro or
halide groups) strongly decelerate the hydrolysis because they
deactivate the partially positive intermediate (Fig. 1, A). In
addition, the ortho-hydroxy substituent can serve as a general
acid itself, spontaneously catalyzing the hydrolysis of the
phenolic acetal through an intramolecular hydrogen-bonding
activation from the acidic phenolic proton. This leads to the
development of a resonance-assisted equilibration between
the phenol and o-quinone methide,20 thereby remarkably
accelerating the hydrolysis of the phenolic acetal (Fig. 1, B).
These results are consistent with our observations of the
electronic effect of the catalyst; that is, electron-rich aromatic
aldehydes, especially salicylaldehyde with an ortho-hydroxy
group, proved most efficient, as summarized in Table 1. We
further postulate that in the case of salicylaldehyde catalysis,
the phenolic proton also acts as a general acid and can
intramolecularly activate the carbonyl group of the aldehyde
and dioxolanone intermediate III synergistically with the
a-hydroxyacid (Fig. 2), thus more efficiently catalyzing the
formation of dioxolanone III and the subsequent nucleophilic
acyl substitution of III with the alcohol. Moreover, the
resonance-assisted equilibrium between the phenol and
o-quinone methide facilitates the expulsion of water from II,
release of the product V from IV, and regeneration of the
catalyst. Although cationic pryridyl-derived catalyst 2 does not
possess any Brønsted-acid characteristics, it is comparable to
the efficient catalyst salicylaldehyde in the esterification
reaction. This is probably because its cationic pyridinium
structure stabilizes the oxonium ion proximate to the aromatic
nitrogen atom by inductive electron-withdrawing or resonance
effects,21 thereby facilitating the manipulation of our proposed
esterification using acetal chemistry.
ð1Þ
ð2Þ
Mechanistic study
With these results in hand, we were keen to validate our
proposed reaction mechanism in Scheme 1B. In order to
examine whether the designed equilibrium actually exists, we
first set about trying to validate the existence of the
intermediary dioxolanone, III. We conducted a reaction with
a 1 : 1 ratio of benzaldehyde/mandelic acid in refluxing
cyclohexane (70 uC) in the absence of any acidic catalyst or
alcohol for 10 h (eqn (1)). Gratifyingly, the corresponding
dioxolanone III was isolated with 46% yield as a spectro-
scopically pure solid, after extracting the unreacted mandelic
acid with basic aqueous solution (see the Experimental
section). This result had several mechanistic implications:
(1) the hydroxyl group of the bifunctional mandelic acid serves
as a directing group that rapidly and reversibly reacts with the
carbonyl group of the catalyst to generate hemiacetal I; (2) the
neighboring carboxylic acid group of mandelic acid then acts
as
a general acid and protonates the gem-hydroxyl of
hemiacetal I to generate protonated species II; (3) the resulting
ionized carboxylate reversibly and covalently participates in
the next water-expelling step, which consequently facilitates
the formation of kinetically competent cyclic dioxolanone III.
However, such productive equilibrium is not favored at room
temperature; therefore, a moderate energy requirement (heat-
ing) is essential to achieve this equilibrium.17
We further examined the reactivity of dioxolanone III toward
alcoholysis with n-butanol (1.0 equivalent) in the presence or
absence of mandelic acid in toluene. In the absence of
mandelic acid, the alcoholysis was quite slow even at 80 uC,
whereas esterification product 1d was obtained in 94% yield at
80 uC and 31% yield at room temperature within 10 h when a
catalytic amount of mandelic acid (1 mol%) was added to the
reactions (eqn (2)). These results again suggested that a
general acid catalysis provided by the carboxylic acid group of
mandelic acid is crucial for the subsequent nucleophilic acyl
substitution of III by the alcohols. Consequently, hemiacetal
Conclusion
In summary, we have documented a successful example using
simple and inexpensive salicylaldehyde for the efficient and
highly chemoselective direct esterification of functionalized
a-hydroxyacids with excess amounts of volatile alcohols. We
have also demonstrated that the current method is applicable
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Experimental
The H and 13C NMR spectra were recorded in CDCl3 using a
JEOL JVM EX400 spectrometer (400 MHz, 1H; 100 MHz, 13C)
and Bruker AVANCE 500 spectrometer (500 MHz, 1H; 125 MHz,
13C), with CHCl3 as an internal reference. Electron-impact
(ESI) mass spectra were recorded using a Thermo Finnigan
spectrometer equipped with LCQ Advantage ionization and a
SpectraSYSTEM detector system. Analytical GC was carried out
using an Agilent 6890C GC system equipped with an Agilent
DB-WAX column (30 m 6 0.25 mm 6 0.25 mm). Analytical
TLC plates were visualized under UV light, or by spraying with
phosphomolybdic acid (PMA) or KMnO4 staining agents. All
the reactions were performed under a nitrogen or argon
atmosphere, and the end products were isolated as pure
materials. Aldehyde 2,22 racemic N-benzoyl-3-phenylisoser-
ine,23 2-(4-nitrophenylamino)-2-phenylacetic acid,24 and a-sub-
stituted a-hydroxyacids25 were prepared according to the
literature reports. (R)-Mandelic acid, racemic 4-bromomande-
lic acid, (R)-lactic acid, racemic 2-hydroxyl-2-methyl-propanoic
acid, racemic tropic acid, L-tartaric acid, and L-malic acid were
purchased from Aldrich or Acros and used without further
purification. All the liquid aldehydes and alcohols used in this
study were distilled under reduced pressure from anhydrous
CaSO4 or activated magnesium metal before use. All products
except 1i are known compounds,26 and they were identified by
comparing their physical and spectra data with those reported
1
Fig. 1 Stabilization of the oxocarbonium transition state though resonance-
assisted equilibration.
in an atom-efficient version of the reaction performed with
equimolar amounts of a-hydroxyacids and complex alcohols in
concentrated solutions in toluene. Application involving
chemoselective esterification of a-hydroxyacid in the presence
of b-hydroxyacid backbones in the same molecule (malic acid)
or other simple acids fully demonstrates the potential value of
this enzyme-mimicking catalytic protocol in the synthesis of
other complex multifunctionalized esters. Mechanistic studies
indicate that the turnover step is likely the formation of
dioxolanone III during the reaction, which was triggered by
self-catalysis of the a-hydroxyacid (general acid catalysis). In
addition, the ortho-phenolic proton assistance of the salicy-
laldehyde and the resonance-assisted equilibration between
the phenol and o-quinone methide are both responsible for
the catalytic turnover. Notably, the catalyst is easily recovered
via high-vacuum distillation or chromatographic purification
after the reaction. Thus, the new approach meets the criteria
for green chemical reactions, and this augurs well for its
potential application in pharmaceutical chemistry and asym-
metric catalysis.
in the literature (see ESI for details).
3
Representative procedure for the esterification of
a-hydroxyacids catalyzed by salicylaldehyde (Table 2)
(R)-Mandelic acid (1, 153 mg, 1 mmol) was dissolved in
methanol (1.0 mL) in a 5 mL single-neck round-bottomed
flask. Salicylaldehyde (12.2 mg, 11 mL, 0.10 mmol) was added
to the flask via a syringe, at room temperature under a
nitrogen atmosphere. The resulting mixture was heated to 70
1
uC, and the reaction progress was monitored by TLC, H NMR
spectroscopy, and GC analysis. After completion of the
reaction, the mixture was gradually cooled to room tempera-
ture, and the organic solvent was evaporated to give the crude
product. The salicylaldehyde was recovered through vacuum
distillation using a Ku¨gelrohr apparatus (1 torr, 50 uC). The
remaining material was extracted with ethyl acetate (20 mL)
and the organic layer was washed with saturated aqueous
NaHCO3 (10 mL 6 2), dried with Na2SO4, and filtrated.
Evaporation of the organic solvent provided pure methyl
mandelate 1a (153 mg, 92% yield). 1H NMR (400 MHz, CDCl3):
d 7.43–7.33 (m, 5H), 5.18 (d, J = 5.2, 1H), 3.76 (s, 3H), 3.45 (d, J
= 5.6, 1H, OH); 13C NMR (100 MHz, CDCl3): d 174.1, 138.2,
128.6, 128.5, 126.6, 72.9, 53.0; MS C9H10O3 (EI, 166) 166 (M+,
13), 107 (100), 79 (51), 77 (43), 40 (12); TLC Rf 0.32 (EtOAc/
hexane, 1/3); GC conditions: Agilent DB-WAX column (30 m 6
0.25 mm 6 0.25 mm), flow rate: 1 mL min21; 90 uC, 1 min; 10
uC min21 to 140 uC; retention time (tR) 19.78 min; internal
standard: 1,3,5-trimethylbenzene. HPLC for racemic methyl
mandelate: tR 27.4 min (R, 50%), 31.2 min (S, 50%)
(CHIRALCEL AD-H, i-PrOH/hexane, 6 : 94, 1.0 mL min21, l =
254 nm). [a]2D4 2142 (c 1.0, MeOH) for 99% ee (lit. [a]D20 -144 (c
Fig. 2 Synergistic activation of the carbonyl of dioxolanone III through
intramolecular hydrogen bonding of the phenolic proton and intermolecular
hydrogen bonding of the carboxyl group of the a-hydroxyacid.
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1.0, MeOH) for (R)). The absolute configuration was deduced
to be R according to the sign of the optical rotation.26
and unreacted benzaldehyde were evaporated under vacuum
to give the crude product. The crude product was dissolved in
ether (30 mL) and washed with saturated aqueous NaHCO3 (10
mL 6 2) to remove the unreacted mandelic acid. The organic
layer was dried with Na2SO4 and filtrated. Evaporation of the
organic solvent provided pure 2,5-diphenyl-[1,3]dioxolan-4-one
(dioxolanone III, 442 mg, 46% yield), with 99.6% cis isomers.
1H NMR (400 MHz, CDCl3): d 7.61–7.43 (m, 10H), 6.57 (s, H),
5.43 (s, 1H); 13C NMR (100 MHz, CDCl3): d 171.3, 134.3, 133.3,
130.7, 129.3, 128.79, 128.75, 127.0, 126.8, 103.2, 77.19; MS
Representative procedure for the esterification of mandelic
acid with n-butanol catalyzed by salicylaldehyde in toluene
(concentration study, Table 3, entry 5)
To a 5 mL single-necked round-bottomed flask was added
mandelic acid (306 mg, 2 mmol) in 1 mL toluene at room
temperature under
a nitrogen atmosphere. Solutions of
n-butanol (149 mg, 184 mL, 2 mmol) and salicylaldehyde
(24.4 mg, 22 mL, 0.20 mmol, 10 mol%) were added successively
via syringe. The resulting mixture was heated to 70 uC and the
reaction progress was monitored by TLC and 1H NMR
spectroscopy analysis. After completion of the reaction, the
salicylaldehyde was recovered through vacuum distillation
using a Ku¨gelrohr apparatus (1 torr, 50 uC). The remaining
material was extracted with ethyl acetate (20 mL) and the
organic layer was washed with saturated aqueous NaHCO3 (10
mL 6 2), dried with Na2SO4, and filtrated. Evaporation of the
organic solvent provided pure n-butyl mandelate 1d (387 mg,
93% yield). 1H NMR (400 MHz, CDCl3): d 7.43–7.34 (m, 5H),
5.16 (d, J = 5.2, 1H), 4.15 (m, 2H), 3.57 (d, J = 5.6, 1H, OH), 1.56
(m, 2H), 1.26 (m, 2H), 0.85 (t, J = 7.2, 3H); 13C NMR (100 MHz,
CDCl3): d 173.7, 138.4, 128.5, 128.3, 126.5, 72.8, 66.0, 30.3,
18.8, 13.5; MS C12H16O3 (EI, 208) 208 (M+, 21), 191 (58), 107
(100), 79 (62), 77 (47); TLC Rf 0.28 (EtOAc/hexane, 1 : 5).26
C
15H12O3 (EI, 240) 240 (M+, 16), 151(32) 105 (100), 93(23),
90(24), 79(43), 77(76); Mp: 102–104 uC.27
Synthesis of n-butyl mandelate 1d from dioxolanone III (eqn
(2))
To a dry 25 mL, two-necked round-bottomed flask was added
2,5-diphenyl-[1,3]dioxolan-4-one (dioxolanone III, 240 mg, 1.0
mmol), n-butanol (82 mg, 102 mL, 1.1 mmol), and 1 mol%
mandelic acid (1.5 mg, 0.01 mmol) in anhydrous toluene (10
mL) under a nitrogen atmosphere. The reaction mixture was
heated at 80 uC for 10 h. The mixture was cooled to room
temperature, washed with saturated aqueous NaHCO3 (10 mL
6 2), dried with Na2SO4, and filtrated. Evaporation of the
organic solvent gave pure n-butyl mandelate 1d (196 mg, 94%
yield).
Representative procedure for the esterification of
a-hydroxyacids with benzyl alcohol catalyzed by
salicylaldehyde in concentrated toluene (Table 4)
Acknowledgements
We acknowledge the financial contribution extended by the
National Science Council of the Republic of China (NSC-100-
2113-M-145-001-MY2). We also thank the mass laboratory of
National Taiwan Normal University and the NMR laboratory of
National Sun Yat-sen University for assistance in the NMR
spectra measurements.
To a 5 mL single-necked round-bottomed flask was added
a-hydroxyacid (2 mmol) in 1 mL toluene at room temperature
under a nitrogen atmosphere. Solutions of benzyl alcohol
(216mg, 208 mL, 2 mmol) and salicylaldehyde (24.4 mg, 22 mL,
0.20 mmol, 10 mol%) were added successively via syringe. The
resulting mixture was heated to 70 uC and the reaction
progress was monitored by TLC and 1H NMR spectroscopy
analysis. The salicylaldehyde was recovered through vacuum
distillation using Ku¨gelrohr apparatus (1 torr, 50 uC). The
remaining material was extracted with ethyl acetate (20 mL)
and the organic layer was purified by column chromatography
on a shot pad of silica gel (hexane/EtOAc = 1 : 5) to provide the
References
1 For reviews of induced intramolecularity strategy, see: (a)
K. L. Tan, ACS Catal., 2011, 1, 877–886; (b) R. Pascal, Eur. J.
Org. Chem., 2003, 10, 1813–1824; (c) R. Pascal, J. Phys. Org.
Chem., 2002, 15, 566–569; (d) M. Bols and T. Skrydstrup,
Chem. Rev., 1995, 95, 1253–1277. For recent devotions on
this issue, see (e) A. D. Worthy, C. L. Joe, T. E. Lightburn
and K. L. Tan, J. Am. Chem. Soc., 2010, 132, 14757–14759; (f)
T. E. Lightburn, M. T. Dombrowski and K. L. Tan, J. Am.
Chem. Soc., 2008, 130, 9210–9211; (g) X. Sun, A. D. Worthy
and K. L. Tan, Angew. Chem., Int. Ed., 2011, 50, 8167; (h) A.
D. Worthy, X. Sun and K. L. Tan, J. Am. Chem. Soc., 2012,
134, 7321; (i) T. E. Lightburn, O. De Paolis, K. A. Cheng and
K. L. Tan, Org. Lett., 2011, 13, 2686–2689; (j) A. D. Worthy,
M. M. Gagnon, M. T. Dombrowski and K. L. Tan, Org. Lett.,
2009, 11, 2764–2767; (k) C. Gouliaras, D. Lee, L. Chan and
M. S. Taylor, J. Am. Chem. Soc., 2011, 133, 13926; (l) D. Lee
and M. S. Taylor, J. Am. Chem. Soc., 2011, 133, 3724; (m) R.
B. Bedford, S. J. Coles, M. B. Hursthouse and M.
E. Limmert, Angew. Chem., Int. Ed., 2003, 42, 112.
1
pure benzyl mandelate 1f (455 mg, 94% yield). H NMR (400
MHz, CDCl3): d 7.43–7.30 (m, 7H), 7.21–7.19 (m, 2H), 5.24 (d, J
= 12.0, 1H), 5.22 (d, J = 5.2, 1H), 5.14 (d, J = 12.0, 1H), 3.41 (d, J
= 5.2,1H, OH); 13C NMR (100 MHz, CDCl3): d 173.5, 138.2,
135.0, 128.6, 128.5, 128.4, 127.9, 126.6, 73.0, 67.6; MS
C15H14O3 (EI, 242) 242 (M+, 4), 226 (12), 107 (100), 92(18),
90(24), 80(12), 79(19), 77(11); TLC Rf 0.34 (EtOAc/hexane, 1 : 5);
Mp: 96–98 uC.26
Synthesis of dioxolanone III from mandelic acid and
benzaldehyde (eqn (1))
Mandelic acid (608 mg, 4 mmol) was placed in a 10 mL single-
neck round-bottom flask and benzaldehyde (415 mL, 2 mmol)
in cyclohexane (5 mL) was added to the flask via a syringe, at
room temperature under nitrogen atmosphere. The resulting
mixture was refluxed (70 uC) for 10 h. The reaction mixture was
gradually cooled to room temperature, and the organic solvent
2 For reviews of substrate-directable reactions and removable
catalytic directing groups, see: (a) G. Rousseau and B. Breit,
1984 | RSC Adv., 2013, 3, 1976–1986
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Paper
Angew. Chem., Int. Ed., 2011, 50, 2450–2494; (b) C.
U. Gru¨nanger and B. Breit, Angew. Chem., Int. Ed., 2008,
47, 7346–7349; (c) B. Breit, Synthesis, 2001, 1, 1–36; (d) A.
H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93,
1307; (e) M. T. Reetz, Acc. Chem. Res., 1993, 26, 462–468; (f)
X. Sun, K. Frimpong and K. L. Tan, J. Am. Chem. Soc., 2010,
132, 11841–11843; (g) C. L. Joe and K. L. Tan, J. Org. Chem.,
2011, 76, 7590; (h) Y. J. Park, J. W. Park and C. H. Jun, Acc.
Chem. Res., 2008, 41, 222.
3 (a) W. P. Jencks, Prog. Phys. Org. Chem., 1964, 2, 63–128; (b)
N. C. Melchior, J. Am. Chem. Soc., 1968, 90, 6154–6162; (c)
E. W. Adams and H. Adkins, J. Am. Chem. Soc., 1925, 47,
1358–1367.
12 For reviews on esterification, see: (a) J. Otera, Esterification:
Methods Reactions, and Applications, Wiley-VCH Verlag-
GmbH, Weinheim, Germany, 2003; (b) J. Otera, Chem. Rev.,
1993, 93, 1449; (c) J. Otera, Acc. Chem. Res., 2004, 37, 288;
(d) G. A. Grasa, R. Singh and S. P. Nolan, Synthesis, 2004,
971, 985; (e) D. Enders, O. Niemeier and A. Henseler, Chem.
Rev., 2007, 107, 5606; (f) H. E. Hoydonckx, D. E. De Vos, S.
A. Chavan and P. A. Jacobs, Top. Catal., 2004, 27, 83; (g)
K. Ishihara, S. Ohara and H. Yamamoto, Science, 2000, 290,
1140; (h) K. Ishihara, S. Ohara and H. Yamamoto, J. Org.
Chem., 1996, 61, 4196–4197; (i) K. Ishihara, S. Ohara and
H. Yamamoto, Org. Synth., 2002, 79, 176–185; (j) T. Maki,
K. Ishihara and H. Yamamoto, Synlett, 2004, 1355–1358; (k)
K. Ishihara, S. Nakagawa and A. Sakakura, J. Am. Chem.
Soc., 2005, 127, 4168–4169; (l) C.-T. Chen, J.-H. Kuo, C.-
H. Ku, S.-S. Weng and C.-Y. Liu, J. Org. Chem., 2005, 70,
1328; (m) T. Funatomi, K. Wakasugi, T. Misaki and
Y. Tanabe, Green Chem., 2006, 8, 1022.
4 (a) G. Lukatela, N. Krauss, K. Theis, T. Seliner,
V. Gieselmarm, K. von Figura and W. Saenger,
Biochemistry, 1998, 37, 3654–3664; (b) W. P. Jencks,
Catalysis in Chemistry and Enzymology, Dover
Publications, New York, 1987.
13 M. Ghosh, J. L. Conroy and C. T. Seto, Angew. Chem., Int.
Ed., 1999, 38, 514.
14 Y. T. Chen, M.B. Onaran, C. J. Doss and C. T. Seto, Bioorg.
Med. Chem. Lett., 2001, 11, 1935–1938.
5 For carbonyl catalyzed hydrolysis of amino esters, see:(a)
B. Capon and R. Capon, Chem. Commun., 1965, 502–503; (b)
R. W. Hay and L. Main, Aust. J. Chem., 1968, 21, 155–169.
For nitriles hydrolysis (c) R. Pascal, J. Taillades and
A. Commeyras, Tetrahedron, 1980, 36, 2999; (d) R. Pascal,
M. Lasperas, J. Taillades and A. Commeyras, New J. Chem.,
1987, 11, 235; (e) M. Paventi and J. T. Edward, Can. J.
Chem., 1987, 65, 282–289; (f) M. Paventi, F. L. Chubb and J.
T. Edward, Can. J. Chem., 1987, 65, 2114; (g) Z. Tadros, P.
H. Lagriffoul, L. Mion, J. Taillades and A. Commeyras, J.
Chem. Soc., Chem. Commun., 1991, 1373.
6 M. J. MacDonald, D. J. Schipper, P. J. Ng, J. Moran and A.
M. Beauchemin, J. Am. Chem. Soc., 2011, 133, 20100–20113.
7 (a) T. Sammakia and T. B. Hurley, J. Am. Chem. Soc., 1996,
118, 8967; (b) T. Sammakia and T. B. Hurley, J. Org. Chem.,
1999, 64, 4652; (c) T. Sammakia and T. B. Hurley, J. Org.
Chem., 2000, 65, 974; (d) F. M. Menger and L. G. Whitesell,
J. Am. Chem. Soc., 1985, 107, 707; (e) F. M. Menger and R.
A. Persichetti, J. Org. Chem., 1987, 52, 3451; (f) K. Bowden,
Chem. Soc. Rev., 1995, 24, 431.
8 (a) T. A. Houston, B. L. Wilkinson and J. T. Blanchfield,
Org. Lett., 2004, 6, 679–681; (b) T. Maki, K. Ishihara and
H. Yamamoto, Org. Lett., 2005, 7, 5047–5050; (c) T. Maki,
K. Ishihara and H. Yamamoto, Org. Lett., 2005, 7,
5043–5047.
9 (a) M. L. Sinnott, Chem. Rev., 1990, 90, 1171–1202; (b)
B. Henrissat and G. Davies, Structure, 1995, 3, 853–859; (c)
B. Henrissat, I. Callebaut, J. P. Mornon, S. Fabrega, P. Lehn
and G. Davies, Proc. Natl. Acad. Sci. U. S. A., 1995, 92,
7090–7094; (d) D. J. Vocadlo, G. J. Davies, R. Laine and S.
G. Withers, Nature, 2001, 412, 835–838.
15 G. I. Georg, Z. S. Cheruvallath, R. H. Himes, M. R. Mejillano
and C. T. Burke, J. Med. Chem., 1992, 35, 4230–4237.
16 Polar solvents such as diethyl ether, diisopropyl ether,
tetrahydrofuran, N,N-dimethylformamide and a,a,a-tri-
fluorotoluene were somewhat inhibited reactions. It
should be noted that although mandelic acid was poorly
dissolved in cyclohexane or heptane, however, it was
gradually merged with salicylaldehyde and n-butanol and
formed an emulsion on the bottom of the reaction flask. As
such, the esterifying product 1d was released from the
emulsion into the hot solution.
17 There is little literature reported in the dehydrative
condensation of formaldehyde with a-hydroxyesters in
the absence of an acid catalyst, whereas a high reaction
pressure and temperature (.100 uC) is required to achieve
high conversions. For direct cyclic acylal formation
between formaldehyde and a-hydroxyacids catalyzed by
a-hydroxyacid itself, see: (a) C. A. Brown, E. B. Nau and J.
R. Bailey, J. Am. Chem. Soc., 1925, 102, 292; (b) B.-H. Lee
and M. J. Miller, J. Org. Chem., 1983, 48, 24–31.
18 The methyl mandelate 1a remained intact in 25% (v/v)
aqueous ethanol solution in the presence of 10 mol% of
salicylaldehyde at 80 uC for 24 h.
19 (a) T. J. Przystas and T. H. Fife, J. Am. Chem. Soc., 1981, 103,
´
4884; (b) M. L. Bender, F. J. Kezdy and B. Zerner, J. Am.
Chem. Soc., 1963, 85, 3017; (c) T. H. Fife and L. K. Jao, J. Am.
Chem. Soc., 1968, 90, 4081; (d) T. H. Fife and L. H. Brod, J.
Am. Chem. Soc., 1970, 92, 1681; (e) E. Anderson and
B. Capon, J. Chem. Soc. B, 1969, 1033; (f) B. Capon and
K. Nimmo, J. Chem. Soc., Perkin Trans. 2, 1975, 1113.
20 (a) M. L. Bender and M. S. Silver, J. Am. Chem. Soc., 1963,
85, 3006; (b) D. A. Blackadder and C. Hinshewood, J. Chem.
Soc., 1958, 2720.
10 (a) B. Capon, M. C. Smith, E. Anderson, R. H. Dahm and G.
H. Sankey, J. Chem. Soc. B, 1969, 1038; (b) B. M. Dum and T.
C. Bruice, J. Am. Chem. Soc., 1970, 92, 2410–6589; (c) T.
H. Fife, S. H. Jaffe and R. Natarajan, J. Am. Chem. Soc.,
1991, 113, 7646.
11 (a) T. H. Fife and E. Anderson, J. Am. Chem. Soc., 1971, 93,
6610; (b) E. Anderson and T. H. Fife, J. Am. Chem. Soc.,
1973, 95, 6437; (c) T. H. Fife and T. J. Przystas, J. Am. Chem.
Soc., 1977, 99, 6693; (d) T. H. Fife and T. J. Przystas, J. Am.
Chem. Soc., 1979, 101, 1202; (e) T. H. Fife and T. J. Przystas,
J. Am. Chem. Soc., 1980, 102, 292.
¨
21 (a) C. Albayrak, M. Odabasoglu, O. Bu¨yu¨kgu¨ngor and
¨
P. Lonnecke, Acta Crystallogr., 2004, C60, 318; (b) R. Gust
¨
and H. Schonenberger, Eur. J. Med. Chem., 1993, 28, 103.
22 M. D. Soutullo, R. A. O’Brien, K. E. Gaines and J. H. Davis,
Chem. Commun., 2009, 18, 2529–2531.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 1976–1986 | 1985

View Article Online
Paper
RSC Advances
23 K. B. Wang, H. C. Kolb and K. B. Sharpless, J. Org. Chem.,
1994, 59, 5104–5105.
24 Y. Wang, Y. Zhu, Z. Chen, A. Mi, W. Hu and M. P. Doyle,
Org. Lett., 2003, 5, 3923–3926.
25 (a) M. Norie and Y. Hisashi, J. Am. Chem. Soc., 2005, 127,
1080–1081; (b) S. Weist, C. Kittel, D. Bischoff, B. Bister,
V. Pfeifer, G. J. Nicholson, W. Wohlleben and R.
D. Suessmuth, J. Am. Chem. Soc., 2004, 126, 5942–5943;
(c) R. F. Campbell, K. Fitzpatrick, T. Inghardt, O. Karlsson,
K. Nilsson, J. E. Reilly and L. Yet, Tetrahedron Lett., 2003,
44, 5477–5482; (d) D. Basavaiah and P. R. Krishna,
Tetrahedron, 1995, 51, 2403–2416; (e) C.-H. Zhou, D.-
Q. Yuan and R.-G. Xie, Synth. Commun., 1994, 24, 43–46.
26 (a) S.-S. Weng, M.-W. Shen, G.-Q. Kao, Y. S. Munot and C.-
T. Chen, Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 3522–3527;
(b) K. A. Santosh and S. Govindasamy, Chem. Commun.,
2010, 46, 7235–7237.
27 T. B. Cameron, F. M. El-Kabbani and H. W. Pinnick, J. Am.
Chem. Soc., 1981, 103, 5414–5417.
1986 | RSC Adv., 2013, 3, 1976–1986
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