Mild alkaline hydrolysis of hindered esters in non-aqueous solution

Article abstract of DOI:10.24820/ark.5550190.p010.673

Sterically hindered esters of carboxylic acids, which are considered very resistant to saponification, were rapidly and efficiently saponified in a non-aqueous medium using NaOH in MeOH/CH2Cl2 (1:9) at room temperature. Furthermore, this reaction protocol was extended and successfully applied to the hydrolysis of tosylates and N-tosyl indoles.

Full text of DOI:10.24820/ark.5550190.p010.673

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Mild alkaline hydrolysis of hindered esters in non-aqueous solution
Vassiliki Theodorou,*a Michalis Alagiannis, Nikoleta Ntemou, Alexios Brentas, Pinelopi Voulgari, Vasiliki
Polychronidou, Marina Gogou, Marios Giannelos, and Konstantinos Skobridis
aDepartment of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
Email: vtheodor@cc.uoi.gr
Dedicated to Professor Dieter Seebach on the occasion of his 80th birthday
Received 06-29-2018
Accepted 10-08-2018
Published on line 10-27-2018
Abstract
Sterically hindered esters of carboxylic acids, which are considered very resistant to saponification, were
rapidly and efficiently saponified in a non-aqueous medium using NaOH in MeOH/CH2Cl2 (1:9) at room
temperature. Furthermore, this reaction protocol was extended and successfully applied to the hydrolysis of
tosylates and N-tosyl indoles.
Keywords: t-Butyl esters; non-aqueous conditions; saponification, hindered esters; tosylates; N-tosyl indoles
DOI: https://doi.org/10.24820/ark.5550190.p010.673
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Introduction
Alkaline hydrolysis of an ester is one of the most extensively investigated reactions. Typical methods for
saponification involve the use of aqueous solutions of water-miscible solvents, large excesses of hydroxides,
long reaction times, and high temperatures. The reaction rate is altered by steric and electronic effects1,2 as
well as the reaction solvent3-5 due to interactions of the protic solvent with the hydroxyl anions. Solvation of
the anions by water molecules through hydrogen bonding6-8 increases the energy barrier for the reactions.
Replacing the traditional polar protic solvents with non-polar aprotic solvents can also exert a profound effect
on the reaction rates.
The development of a mild-ester hydrolysis method is of great importance, especially in the synthesis of
complex molecules, the chemistry of natural compounds, and total synthesis. A need exists for a versatile and
simple process whereby esters may be hydrolysed without heating or exposure to extreme pH values.
Crowded esters, in particular, typically afford low yields due to steric hindrance which makes carbonyl attack
difficult.
In a previous work, we reported the alkaline hydrolysis of esters in non-aqueous reaction medium under
very mild conditions,9 including short reaction times at room temperature, and the use of a low concentration
of alkali in MeOH/CH2Cl2 (1:9) as a solvent. We have also developed a mild protocol for the alkaline hydrolysis
of secondary and tertiary amides10 to the corresponding acids and amines, while nitriles are converted to
primary amides (Scheme 1).
CH2Cl2 / MeOH ~9:1
RCOOR'
NaOH
RCOONa
RCOONa
R'OH
+
+
+
rt
Dioxane / MeOH ~9:1
RCONR'2 NaOH
NHR'2
+
reflux
Dioxane / MeOH ~9:1
reflux
RCN NaOH
RCONH2
+
+H2O
Scheme 1. Alkaline hydrolysis of esters and amides and hydration of nitriles in non-aqueous conditions.
A plausible mechanistic process was proposed9,10 based on the well-established observation that
hydroxide anions, when poorly solvated, attack the carbonyl groups of the esters or of the amides much more
easily than the ordinarily strongly-solvated hydroxyl anions in an aqueous environment.
This method has subsequently been used to prepare sensitive compounds in excellent yields, without
racemization, isomerization or other undesirable reactions. It is worth noting also that, in some of these cases,
conventional methods for hydrolysis of carboxylic esters in aqueous solution did not take place under basic
conditions.11-19 Moreover, the method has been applied to the hydrolysis of several sulfonates.20
Very recently, in an attempt to hydrolyse a methyl-ester moiety on a substrate also possessing a tert-butyl
ester group using our methodology, we were surprised to find that the tert-butyl group was also removed.
This observation motivated us to investigate further our reaction system, using a series of sterically-hindered
carboxylic esters to extend our previously-published methodology and further demonstrate its applicability to
a large number of compounds.
To the best of our knowledge, there are several reports on the alkaline hydrolysis of hindered esters in
non-aqueous conditions.21-25 These include, among others, the use of potassium tert-butoxide in DMSO,21-22
the use of a KOH complex in the presence of a phase-transfer catalyst,23 and the transesterification of
sterically-hindered steroid esters to methyl esters in MeOH/Et3N under high-pressure conditions.24 Cleavage
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of tert-butyl benzoates has been attempted with NaH in DMF or, alternatively, with KOH/THF/crown ethers at
high temperature.25 The tert-butyl moiety is widely used as a valuable protecting group for acids and alcohols
in organic synthesis, since tert-butyl esters are remarkably stable to basic hydrolysis, but labile to acid
hydrolysis.
Herein, we report, for the first time, the applicability and potency of our method in the alkaline hydrolysis of
hindered esters and tosylates with very good yields.
Results and Discussion
In order to establish our methodology, a diverse set of hindered esters was selected and submitted to
saponification, including esters of crowded secondary or tertiary alcohols, some of them natural products or
their derivatives. For an approximate experimental comparison, parallel reactions were performed under
classical conditions using 0.3 N NaOH in 80% MeOH/H2O at rt (Scheme 2).
1. NaOH, rt./CH2Cl2: CH3OH ~9:1
RCOOR'
RCOOH + R'OH
2. H3O
Scheme 2. General reaction scheme for study of saponification of diverse hindered esters using new protocol.
The study was extended to other substrates including several tosylates which were submitted to the mild-
alkaline hydrolysis according to this protocol. The reaction progress was monitored by TLC. After hydrolysis,
the resulting alcohol or acid or both can be recovered. The conversion reactions were nearly quantitative, as
revealed by the TLC analysis, unless otherwise noted. The results are summarized in Table 1. In all cases, the
reactions gave rapidly the acid and/or alcohol hydrolysis products quantitatively in high purity (isolated yields
80-96%) by the use of 0.3 N NaOH in 10% MeOH/CH2Cl2 at rt. Sodium hydroxide was used in excess, in most of
the cases, in a ratio of ester/NaOH of 1:3. By addition of the methanolic solution of NaOH to the ester (or
other substrate) dissolved in dichloromethane, a white, finely-dispersed precipitate of sodium salt begins to
form slowly and increases over time. For some entries (6, 7, 12, 14, and 15), yields were not determined (nd),
as the reaction products were soluble in water and/or of not special interest. Yields are not shown in column 2
of Table 1 since our primary interest was the comparison of the reaction-completion times using both
methods, as observed by TLC analysis. Obviously, the classical procedure was very much slower when the
esters were sterically hindered.
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Table 1. Results of examples for the alkaline hydrolysis of hindered esters and other substrates.
Reagents, solvents, conditionsa
0.3 N NaOH/DCM:MeOH
Ester/ NaOH
0.3 N NaOH/H2O:MeOH
(2:8)b
(9:1)b
Time,c yield, temp., mp
(lit.mp)
Entry
Ester
(mmol/mmol)
Time,c temp.
5 h 30 min, 93% (RCOOH), rt
mp 236-239 (lit. 237-240) oC26
1
2
1:3
1:4
30 h, rt
t-butyl p-nitrobenzoate
3 h, 84% (RCOOH), rt
mp 127-129 (128-130) oC26
>28 h, rte
di-t-butyl 2-methylmalonate
CH3(CH2)13CH2COOCMe3
t-butyl palmitate
25 min, 95% (RCOOH), rt
mp 59-61 (61-62.5) oC26
20 min, 94% (R´OH), rt
mp 64-66 (65-67) oC26
3
4
1:3
1:3
~30 h, rt
3 h, rt
CH3(CH2)13CH2COOCHPh2
diphenylmethyl palmitate
3 h 30 min, 96% (R´OH), rt
Viscous liquid
5
6
1:3
1:5
~30 h, rt
~48 h, rt
dimethylbenzylcarbinyl acetate
4.5 h, nd,d rt
5 h, nd, rt
Fmoc–L-Glu(OtBu)–OH
Fmoc–L-Asp(OtBu)–OH
7
8
1:5
1:3
~50 h, rt
1 h, 80% (RCOOH), 30 oC
viscous
~25 h, 30 oC
t-butyl N-methacryloyl-L-
prolinate
2 h 30min, 91% (R´OH), rt
mp 210-213 (212-214) oC26
9
1:3
1:4
~24 h, rt
isobornyl acetate
linalyl benzoate
5 h 30 min, 93% (R´OH), 30 oC
10
~ 3 d, 30 oC
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45 min, 95% (R´OH), rt
mp 41-43 (41-44) oC26
11
1:3
~ 24 h, rt
(-)-menthyl acetate
12
1:10
10-15 min, nd., rt
21 h, rt
α-D(+)-glucose pentaacetate
3 h 45 min, 80% (PhOH), rt
50 min, 30 oC
~4 d, rt
~9 h , 30 oC
13
14
15
1:3
1:3
1:4
phenyl tosylate
ethyl tosylate
~6 h, nd, 30 oC
~7 h, nd, 30 oC
~20 h, 30 oC
>30 h, 30 oCe
N-tosyl pyrrole
4 h 30 min, 82% (indole),
30 oC, mp 50-52 (51-54) oC26
16
17
1:4
1:3
>24 h, 30 oCe
No reaction
N-tosyl indole
No reaction
N-ethyl-N-tosyl-aniline
18
1:3
Salt formation
Salt formation
N-tosyl-aniline
aReaction conditions: ester (1 mmol), 0.3 N NaOH (3 mmol), solvent (10 mL, CH3OH:CH2Cl2 1:9) or (10 mL, CH3OH:H2O
b
8:2). Each mL of the solution corresponds to 0.3 mmol of NaOH. The same volume of the solvent is used for both
solvent systems. cMonitored by TLC until the starting material was consumed. dnd: not determined. eIncomplete reaction
(~ 50%).
It is clear from all of the examples that our hydrolysis protocol is efficient, and much faster with milder
conditions than conventional methods, producing high yields of the desired products. In addition, it is
particularly useful to note that the precipitated sodium carboxylates or tosylates can be easily separated by
filtration or extraction. In selected cases (8, 10, 13-16), the temperature was maintained at ~30 °C to speed up
slow reactions.
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1
The H NMR data of the isolated hydrolysis products were identical with those of authentic samples. The
disappearance of the proton peaks attributed to the acid or alcohol moieties of the ester following hydrolysis
provided evidence that the hydrolysis reactions were complete. The asterisk denotes the peaks that disappear
after hydrolysis (see Supplementary Material, Figure S5-S16).).
The optical purity of optically-active compounds was determined by comparison with reported values.
Specific rotation and HPLC analyses have proven the lack of racemization, thus establishing the non-
racemization feature of the saponification protocol (Supplementary Material, Figure S1-S4).
Specifically, the saponification of tert-butyl p-nitrobenzoate, di-tert-butyl 2-methylmalonate, the two
palmitates, and dimethylbenzylcarbinyl acetate (1-5) proceeded relatively rapidly. The racemic mixtures of
isobornyl acetate and linalyl benzoate (9, 10) were saponified after 2.5 and 5.5 hours, instead of 1 and 3 days,
respectively.
The β- and γ-tert-butyl esters of N-fluorenylmethyloxycarbonyl (Fmoc) amino acids N-Fmoc-L-glutamic and
20
N-Fmoc-L-aspartic, 6 and 7, respectively (specific optical rotation for N-Fmoc-L-Glu-OH: [α]D -5, c 1 in
AcOH/H2O, 4:1, and for N-Fmoc-L-Asp-OH: [α]D20 -24, c 1 in DMF), were hydrolysed without racemization, and
20
with simultaneous Fmoc-deprotection (specific optical rotation for L-Glu-OH: +30, lit. [α]D +31.5, c 2 in 5N
20
HCl26 and for L-Asp-OH: +24, lit. [α]D +25, c 2 in 5N HCl).26 HPLC results (Figure S1 and S2) showed the
presence of one product after the alkaline hydrolysis of both, Fmoc-L-Asp(-OtBu)-OH and Fmoc-L-Glu(-OtBu)-
OH. The enantiomeric purity was determined by HPLC analysis using Chirobiotic T column
(water/methanol/formic acid: 30/70/0.02, flow rate 1.0 mL/min). The L-Asp was eluted at 4.32 min, while the
D-Asp was eluted at 5.28 min (Figure S1. A. and B). The L-Glu and D-Glu were eluted at 4.23 and 5.43 min
(Figure S2. A. and B), respectively. These results clearly suggest that their saponification took place with
retention of configuration.
Importantly, t-butyl N-methacryloyl-L-prolinate (8) was saponified after 1 hour to afford N-methacryloyl-L-
proline, without hydrolysis of the amide bond, instead of 25 h under the classical conditions. The N-
methacryloyl-L-proline had a specific rotation of -136.2, lit. [α]D20 -137.8, c 1.2 in chloroform,27 confirming the
absence of racemization. HPLC analysis showed the presence of only one product (enantiomer) after the
1
alkaline hydrolysis of the ester during all of the different flows (Figure S3 and S4). The H NMR data of N-
methacryloyl-L-proline and its t-butyl ester are consistent with the cis and trans isomers, existing in solution,
due to restricted rotation about the amide bond, and depending on the solvent. In chloroform, the trans
isomer is favored, because of the γ-turn, the intramolecular H-bonding in the acid form between the CO
oxygen and the COOH hydrogen (trans 91%, cis 9%), while the cis isomer of the t-butyl ester increases to
about 33% (trans about 67%), (1H NMR spectrum, Figure S10).
The alkaline hydrolysis of optically active (-)-menthyl acetate (11) was completed in 45 minutes, instead of
1
24 hours under normal conditions. Based on the H NMR spectrum (Figure S13) and the specific optical
rotation of the recovered (-)-menthol {-48, lit. (-)-menthol [α]D20 -50, c 10 in ethanol},26 after hydrolysis of the
(-)-menthyl acetate, it was concluded that the reaction proceeded without racemization via the BAC2
mechanism. The absolute configuration of the carbon atom bearing the OH group of (-)-menthol (1R, 2S, 5R)
1
did not change to give the epimer (+)-neomenthol (1S, 2S, 5R), as verified by its H NMR spectrum, which is
different from that of (+)-neomenthol. No inversion of the configuration at C-1 took place during the alkaline
hydrolysis. The more characteristic proton (CHOH) of (+)-neomenthol resonates at 4.10 ppm and that of (-)-
menthol at 3.41 ppm (1H NMR spectrum, Figure S13).
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We subsequently explored the potential application of our developed protocol to peracetylated glucose
(α-D-pentaacetyl glucose). The corresponding D-(+)-glucose was formed, quantitatively, as a mixture of α-and
β-anomers within 15 min at rt (12); under normal conditions, the reaction was very slow (21 h).
The above methodology was also applied to the hydrolysis of tosylates and N-tosyl amides28, 29 (13-18),
(Scheme 3, eq. 1-4).
1. NaOH, r.t. / CH2Cl2:CH3OH ~9:1
(1)
RSO2OR'
RSO OH
+ R'OH
2
2. H3O
NaOH, r.t. / CH2Cl2:CH3OH ~9:1
no reaction (2)
RR'NSO2R''
RNHSO2R'
NaOH, r.t. / CH2Cl2:CH3OH ~9:1
RNSO2R' Na
(3)
+ H2O
NaOH, r.t. / CH2Cl2:CH3OH ~9:1
N-indolyl-SO2R''
N-indolyl-H + R''SO2ONa (4)
Scheme 3. Reactions for the alkaline hydrolysis of tosylates and N-tosyl amides.
Indole derivatives are extensively explored molecules with significant biological activities, and a wide
range of applications. For their synthesis, protection of the indole NH was necessary, followed by removal of
the protective group. Sulfonamides, prepared easily with sulfonyl chloride, are between the best nitrogen
protective groups. Tosyl group is one such blocking group; its deprotection usually requires harsh conditions.
Introduction of a sulfonyl group on the nitrogen of pyrrole, indole and derivatives for N-sulfonyl protection, as
well as the relatively harsh conditions of alkaline hydrolysis for N-sulfonyl deprotection,30 encouraged us to try
our alternative method. It is of interest to note that phenyl tosylate (13) was completely hydrolysed after ~3.5
h, compared with ~4 d using the classical methodology (and 50 min and ~9 h, respectively, at 30 °C). Ethyl
tosylate (14) was hydrolysed at 30 °C after 6 h and 20 h, respectively. With our protocol, N-tosyl pyrrole (15)
and N-tosyl indole (16) were hydrolysed after 7 h and 4.5 h at 30 °C, respectively. Under normal reaction
conditions, approximately 50% of the N-protected compounds reacted after 30 h and 24 h, respectively
(according to TLC). The alkaline hydrolysis of N-tosyl-N-ethylaniline (17) was impossible, even following
refluxing with 0.3 N NaOH (6 equiv.) in dioxane/methanol (9:1) for 2 days. On the other hand, N-tosyl-aniline
(18) immediately gave the corresponding sodium salt, due to its acidic proton on N-1. These differences in the
reaction completion times are expected, due to the higher electrophilicity of the sulfonyl group of compounds
13 and 16.
Alkaline hydrolysis has been widely studied, and it is commonly accepted that the majority of the esters
are saponified via a two-step BAC2 mechanism.31-37 In the non-aqueous solvent reaction, unsolvated or
“naked” hydroxyl anions approach and attack the carbonyl carbon of the hindered esters much more easily
than solvated ions to afford the hydrolysis products (Scheme 4).
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O
O
C
C
R
CH3OH
HO
R
RCOOH
+
R'O
R'OH
+
RCOO
+
.
HO
.
.
.
.
OR'
R'O
CH3OH
O
O
C
HO
.
.
C
R
CH3OH
HO
+
R
RCOOH
+
R' N
2
R'2NH
+
RCOO
+
.
.
.
R'2N
NR'2
CH3OH
NR'R''
Ar
O
NR'R''
Ar
O
S
R'R''NH
ArSO2OH R'R''N
CH3OH
ArSO3
+
+
S
O
HO
HO
.
.
.
O
.
.
CH3OH
Scheme 4. Suggested mechanism for the alkaline hydrolysis in non-aqueous conditions.
Conclusions
In conclusion, our saponification methodology constitutes an advantageous mild, non-racemizing alternative
to existing methods. It is shown to be available for the alkaline hydrolysis of crowded esters which are
normally resistant to saponification, and for detosylation of tosylates and N-tosyl protected pyrroles and
indoles. This protocol may be useful, as well, for other substrates.
Experimental Section
General. All chemicals were obtained from commercial suppliers and used without further purification. TLC
plates were from Merck Silica gel 60 F254. Optical rotations were measured on an automatic digital
1
polarimeter. H NMR spectra were recorded on a Bruker (AV500 MHz) at ambient temperature, using
tetramethylsilane (TMS) as an internal standard. HPLC experiments were performed at 25 oC using a Shimadzu
system, consisting of a DGU-20A controller, a LC-20AD pump, a SPD-M20A photodiode-array detector and a
CTO-10AS column oven, controlled with Schimadzu Class-VP, version 6, software. Elemental analyses were
performed on a Heraeus CHN-Rapid Analyzer. The hydrolysis products are known compounds and were
identified by comparison with authentic samples, derived from the pure products suppliers.
General experimental procedure. To a solution of the ester (1 mmol) in CH2Cl2 (9 mL) was added a methanolic
solution of 3 N NaOH (1 mL, 3 mmol), with the final concentration of the alkali being 0.3 N, and the solvent
mixture CH2Cl2/CH3OH (9:1, v/v, 10 mL). Esters bearing more than one ester moiety needed more equivalents
of NaOH (Table 1). After stirring, the solution became cloudy and the sodium salt of the carboxylic acid began
to precipitate. The progress of the reaction was monitored by thin layer chromatography (TLC). The mixture
was stirred until the ester was consumed (Table 1), the solvents were then removed under vacuum, the
residue was diluted with water (10 mL) and extracted with ethyl acetate or diethyl ether (2x20 mL) to isolate
the water-insoluble alcohol, and/or to remove unreacted ester. The aqueous phase was cooled, acidified to pH
~2 with dilute HCl and extracted with AcOEt (2x20 mL). The combined organic layers were dried (Na2SO4) and
the solvent removed to afford the acid. Alternatively, the RCOONa precipitated during the reaction can be
isolated by filtration, washed with CH2Cl2 (10 mL), dried and weighed (Yields: 80-96%).
Sodium palmitate precipitates after the addition of diethyl ether (20 mL) to the reaction mixture.
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In the case of the saponification of the Fmoc-protected amino acids {Fmoc-Asp (O-t-Bu)-OH and Fmoc-Glu(O-t-
Bu)-OH}, 9-methylenefluorene, derived from the Fmoc group, was extracted first with diethyl ether (2x20 mL).
The amino acid was isolated by freeze drying of the aqueous solution of its sodium salt, followed by
preparative chromatographic separation of the amino acids, using a solvent mixture of 1-propanol, acetic acid
and water in the ratio 12:3:5 by volume. Two additional equivalents of NaOH were required for hydrolysis, due
to the COOH group and Fmoc deprotection. Increased equivalents of NaOH were also required with very
crowded or unreactive compounds (2, 10, 12, 15, and 16). N-Tosyl indole (16) gave sodium tosylate and indole.
The alkaline aqueous phase was first neutralised with dilute HCl and then extracted with ether.
General procedure for saponification using classical conditions. To a solution of the ester (1 mmol) in CH3OH
(7 mL) and H2O (2 mL), a methanolic solution of 3 N NaOH (1 mL, 3 mmol) was added with stirring; the final
concentration of the alkali being 0.3 N and the solvent mixture CH3OH/H2O (8:2, v/v, 10 mL). The progress of
the reaction was monitored by TLC. The mixture was stirred until the ester was consumed (TLC) (Table 1), and
then the solvents were removed under vacuum. The residue was diluted with water (10 mL), and subsequently
extracted with ethyl acetate or diethyl ether (2x20 mL) to isolate the water-insoluble alcohol and/or to
remove unreacted ester. The aqueous phase was cooled, acidified to pH ~2 with dilute HCl and extracted with
AcOEt (2x20 mL). The combined organic layers were dried (Na2SO4) and the solvent removed to afford the
acid. Yields for the resulting acids or alcohols were not determined as our interest was to measure and
compare the completion times of the reactions (by TLC) of the two methodologies.
t-Butyl esters syntheses. The esters 1-3 had been prepared by reaction of tert-butanol (2-4 mmol) in dry
dichloromethane (DCM) (20 mL) and the appropriate acid chloride (2 mmol). To the stirring mixture was
added triethylamine (5 mmol) in dry dichloromethane (5 mL) at 0 °C under argon. After addition was
complete, the mixture was stirred for an additional 1-2 h at room temperature, then refluxed until
completion (approximately 1 h). At the end of the reaction (as determined by TLC), the reaction mixture
was cooled and evaporated to dryness. The residue was diluted with CH2Cl2 and extracted with H2O, 5%
NaHCO3 and H2O. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column
chromatography (CH2Cl2/hexane) on silica to afford the desired products (overall yields 74-80%). Their
1
identities were confirmed by H NMR spectroscopy.
Diphenylmethyl palmitate synthesis (4). The ester 4 has been prepared as above, from diphenyl
methanol and palmitoyl chloride (Yield 75%).
t-Butyl N-methacryloyl-L-prolinate synthesis (8). To a solution of the methacrylic acid (2 mmol) in dry
DCM (5 mL), t-butyl-L-prolinate (2 mmol), N,N'-Dicyclohexylcarbodiimide (DCC) (2 mmol) and Et3N (5
mmol) in DCM (2 mL) was added. The mixture was allowed to stir at 0 °C for 5 minutes. Stirring was
continued overnight at rt until completion of the reaction (by TLC). After completion, it was concentrated
to dryness. The residue was diluted with AcOEt (50 mL) and extracted with H2O (20 mL), then with a
solution of NaHCO3 (2x15 mL), H2O, and finally with a solution of KHSO4. The organic layer was dried over
MgSO4 and the crude product was purified by column chromatography (CH2Cl2/hexane) on silica gel. Yield:
64%.
Syntheses of tosylates and N-tosylamines (13, 14, 17, 18).38 To a solution of the suitable alcohol, phenol or
amine (2 mmol) in dry DCM (10 mL), and cooled to 0 ◦C, was added, portion-wise and drop-wise, 4-
dimethylaminopyridine (0.4 mmol), p-toluenesulfonyl chloride (2.4 mmol) and triethylamine (3.00 mmol). The
reaction mixture was stirred at 0 oC until TLC showed complete consumption of starting material. The resulting
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suspension was diluted with diethyl ether (25 mL), stirred for a further 30 min, and the precipitate removed by
filtration. The solution was then washed sequentially with water (40 mL), 10% NaHCO3 (2x25 mL) and a
saturated aqueous NaCl solution (10 mL). The combined organic layers were dried over MgSO4, filtered,
concentrated in vacuo, and purified by column chromatography (CH2Cl2/hexane).
Syntheses of N-tosyl pyrrole and N-tosyl indole (15, 16).39 A mixture of the indole or the pyrrole (1 mmol), p-
toluenesulfonyl chloride (2 mmol), K2CO3 (4 mmol) and toluene (15 mL) was heated at reflux with stirring.
After 15 h, the resulting suspension was filtered hot and the solution was concentrated under reduced
pressure. The residue was diluted with diethyl ether (15 mL) and triturated with hexane. The precipitate was
removed by filtration and crystallised from EtOH-hexane to yield 85% and 75% of products 15 and 16,
respectively.
1
t-Butyl p-nitrobenzoate (1). White solid (80%, 0.36 g), mp 107-108 °С; H NMR (CDCl3, 500 MHz): δH 1.62
3
3
(s, 9H, t-Bu), 8.14 (d, 2H, JHH 8.5 Hz, CH aromatic), 8.26 (d, 2H, JHH 8.5 Hz, CH aromatic); Anal. Calcd. for
C11H13NO4: C, 59.19; H, 5.87; N, 6.27; found: C, 59.03; H, 5.91; N, 6.17%.
1
Di-t-butyl 2-methylmalonate (2). White viscous liquid (80%, 0.37 g); H NMR (CDCl3, 500 MHz): δH 1.32 (d,
3
3
3H, CHCH3, JHH 7 Hz), 1.46 (s, 18H, 2x-t-Bu), 3.22 (q, 1H, CHCH3, JHH 7.0 Hz); Anal. Calcd. for C12H22O4: C,
62.58; H, 9.63; found: C, 62.30; H, 9.82%.
t-Butyl palmitate (3). White viscous liquid (74%, 0.46 g); 1H NMR (CDCl3, 500 MHz): δH 0.88 (t, 3H, CH3, 3JHH 7.0
Hz), 1.22-1.35 (m, 24H, {CH2}12), 1.44 (s, 9H), 1.54-1.60 (m, 2H, CH2CH2COO-t-Bu), 2.19 (t, 2H, CH2CH2COO-t-Bu
J 7.5 Hz); Anal. Calcd. for C20H40O2: C, 76.86; H, 12.90; found: C, 76.91; H, 12.78%.
1
Diphenylmethyl palmitate (4). White viscous liquid (75%, 0.64 g). H NMR (CDCl3, 500 MHz): δH 0.88 (t, 3H,
3
3
CH3, JHH 7.0 Hz), 1.20-1.35 (m, 24H,{CH2}12), 1.62-1.69 (m, 2H, CH2CH2COOAr), 2.42 (t, 2H, CH2CH2COOAr, JHH
7.5 Hz), 7.26-7.34 (m, 10H, CH aromatic); Anal. Calcd. for C29H42O2: C, 82.41; H, 10.02; found: C, 82.28; H,
9.98%.
1
t-Butyl N-methacryloyl-L-prolinate (8). White viscous liquid (64%, 0.30 g); H NMR (CDCl3, 500 MHz): δH 1.46
(s, 9H, t-Bu), 1.80-2.20 (m, 6H), 2.22-2.25 (m, 1H), 3.57-3.64 (m, 2H), 4.38 (m, 1H), 5.05-5.27 {2H for two
rotamers, each one pair of singlets (trans ~67% and cis ~33%), vinyl moiety (=CH2)}; Anal. Calcd. for C13H21NO3:
C, 65.25; H, 8.84; N, 5.85; found: C, 65.13; H, 8.90; N, 5.78%.
1
Phenyl tosylate (13). White solid (89%, 0.44 g), mp 93-94 °С; H NMR (CDCl3, 500 MHz): δH 2.45 (s, 3H,
3
3
CH3), 6.98 (d, 2H, CH aromatic, JHH 8.0 Hz), 7.24-7.31 (m, 5H, CH aromatic), 7.70 (d, 2H, CH aromatic, JHH
8.0 Hz); Anal. Calcd. for C13H12O3S: C, 62.88; H, 4.87; found: C, 63.05; H, 4.72%.
1
N-tosyl-indole (16). Brown solid (85%, 0.46 g), mp 81-83 °С (EtOH/hexane); H NMR (CDCl3, 500 MHz): δH
3
2.33 (s, 3H, CH3), 6.65 (d, 1H, CH aromatic, JHH 3.5 Hz), 7.20-7.32 (m, 4H, CH aromatic), 7.52 (d, 1H, CH
3
3
3
3
aromatic, JHH 8.0 Hz), 7.56 (d, 1H, CH aromatic, JHH 3.5 Hz), 7.76 (d, 2H, JHH 8.0 Hz), 7.99 (d, 2H, JHH 8.5
Hz); Anal. Calcd. for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16; found: C, 66.26; H, 4.89; N, 5.10%.
Acknowledgements
We are grateful to Dr. Nikitas Ragoussis (Vioryl, S.A., Greece) for providing us with samples. We thank also the NMR
1
Center of the University of Ioannina for taking the H NMR spectra. This research has been financially supported partly
by the General Secretariat for Research and Technology (GSRT) and the Hellenic Foundation for Research and Innovation
(HFRI) (Scholarship Code: 2000)
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Theodorou, V. et al.
Supplementary Material
1
Chiral HPLC analysis for hydrolysis of esters of L-amino acids and copies of H NMR spectra of esters and
corresponding hydrolysis products are provided in the online Supplementary Material file associated with this
manuscript.
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