Unusual reactivity of dimethylsulfoxonium methylide with esters

Article abstract of DOI:10.1002/ejoc.201101031

The dimethylsulfoxonium methylide was treated with esters under mild conditions to rapidly afford the corresponding carboxylic acids at room temperature. Moreover, by performing the procedure on enantiopure substrates, it was demonstrated that the reaction occurs without racemization. ¹⁸O-labeled reagents showed that the reaction does not proceed through an ester hydrolysis mechanism. The reactions are characterized by an unusual reactivity of the dimethylsulfoxonium methylide. This methodology is general and can be considered a valid alternate route for ester cleavage when a substrate is sensitive to hydrolysis conditions.

Full text of DOI:10.1002/ejoc.201101031

FULL PAPER
DOI: 10.1002/ejoc.201101031
Unusual Reactivity of Dimethylsulfoxonium Methylide with Esters
Antonella Leggio,*[a] Rosaria De Marco,[a] Francesca Perri,[a] Mariagiovanna Spinella,[a]
and Angelo Liguori*[a]
Keywords: Synthetic methods / Amino acids / Ylides / Cleavage reactions
The dimethylsulfoxonium methylide was treated with esters
under mild conditions to rapidly afford the corresponding
carboxylic acids at room temperature. Moreover, by per-
forming the procedure on enantiopure substrates, it was
demonstrated that the reaction occurs without racemization.
18O-labeled reagents showed that the reaction does not pro-
ceed through an ester hydrolysis mechanism. The reactions
are characterized by an unusual reactivity of the dimethylsul-
foxonium methylide. This methodology is general and can be
considered a valid alternate route for ester cleavage when a
substrate is sensitive to hydrolysis conditions.
Introduction
Modifications of the carboxyl functionality in α-amino
acids are essential in peptide synthesis and for functionaliz-
ing the terminal amino acid in biologically active peptides.
The conversion of amino acid precursors into α-chlo-
roketones is of increasing interest in the syntheses of phar-
maceutical building blocks.[1] Modification of the carboxyl
functional group in N-protected α-amino acids to an epox-
ide plays a pivotal role in the syntheses of hydroxyethyl-
amine derivatives which show protease inhibitory activity.[2]
Moreover, conversions of carboxyl groups to diazoketones
are involved in the syntheses of β3-amino acids[3] which con-
stitute a vast array of natural[4] and synthetic biologically
active peptides.[5]
In this field, we attempted to generate a β-keto dimethyl-
sulfoxonium ylide on the carboxyl function of N-protected
amino acids for further modification and functionalization.
The reaction of methyl esters of N-protected α-amino ac-
ids to produce our target products is reported previously in
the literature.[6] Here, a series of aliphatic methyl esters and
three amino acid methyl esters were treated with 3 equiv. of
dimethylsulfoxonium methylide, obtained from trimethyl-
sulfoxonium chloride and the base sodium tert-butoxide.
The reaction was carried out in dry tetrahydrofuran (THF)
for several hours (Scheme 1).
Scheme 1. An example of the reactivity of dimethylsulfoxonium
methylide reported in the literature.[6]
conditions for complete conversion of the starting substrate.
In particular, methyl 4-chlorobenzoate required a longer re-
action time (more than 48 h) and a greater excess amount
of the ylide (5 equiv.). For the N-Boc-l-phenylalanine
methyl ester (Boc = tert-butoxycarbonyl), the reaction was
carried out in the absence of light, whereas the N-Cbz-l-
valine methyl ester (Cbz = benzyloxycarbonyl) was treated
with a large excess amount of the ylide (5 equiv.). In the
case of a completely inactive ester, methyl caprylate did not
produce a significant amount of the desired product (25%),
even after 72 h and 5 equiv. of the ylide.
We investigated the synthesis of β-keto dimethylsulfoxon-
ium ylide derivatives of N-Cbz-l-alanine. The protected
amino acid was treated under the reported conditions[6]
using dimethylsulfoxonium methylide prepared from the
commercially available trimethylsulfoxonium chloride and
sodium tert-butoxide. The reaction was completed with a
hydrolytic treatment and extraction by an organic solvent.
We isolated a small amount of a product mixture, but
were unable to identify the β-keto dimethylsufoxonium
ylide derivative. We therefore decided to treat the resulting
aqueous phase with a 5% aqueous potassium hydrogen sul-
fate solution. After the extraction with an organic solvent,
we recovered the N-Cbz-l-alanine with a free carboxyl
functional group in 80% yield. The reaction was repeated
three additional times and consistently produced the same
product in good yield (80–85%). All attempts to obtain the
β-keto dimethylsufoxonium ylide derivative were unsuccess-
ful.
However, the previous study did not provide a general
procedure to prepare β-keto dimethylsulfoxonium ylide de-
rivatives. Indeed, each system required different reaction
[a] Dipartimento di Scienze Farmaceutiche,
Università della Calabria, edificio polifunzionale,
87036, Arcavacata di Rende (CS), Italy
Fax: +39-0984493265
E-mail: a.leggio@unical.it
a.liguori@unical.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101031.
114
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Unusual Reactivity of Dimethylsulfoxonium Methylide with Esters
extract was recovered, however after acidification, the N-
protected amino acid 5g was obtained in quantitative yield.
Failure to obtain the β-keto dimethylsulfoxonium ylide was
balanced by this important and useful result. The treatment
of methyl esters with dimethylsulfoxonium methylide, in
fact, leads to the efficient cleavage of the ester and forma-
tion of the corresponding carboxylic acids in the absence of
water. This reaction can be considered a convenient alter-
nate route to ester hydrolysis.
In the literature, only one example of de-esterification
induced by dimethylsulfoxonium methylide has been re-
ported.[9] The carboxylic acid 6-methoxy-2,3-dihydro-
benzo[b]furan-3-acetic acid was obtained upon treatment of
the corresponding methyl ester with dimethylsulfoxonium
methylide. In a different case, the dimethylsulfoxonium
methylide cleaved the ester group in a complex lactone mo-
lecule.[10]
In the light of the interesting results and to validate this
procedure, the reaction (Scheme 3) was applied to a series
of N-protected α-amino acid esters (Table 1, 4a–j) and to a
set of carboxylic esters (Table 1, 4k–n).
In each experiment the corresponding carboxylic acid
was obtained in high yield and purity. The successful results
make this reaction a valid general procedure for ester cleav-
age.
Results and Discussion
The reaction was tested with methyl phenylacetate using
the same reaction conditions. Also in this case, we recovered
an insignificant amount of the basic extract, whereas in the
acidic extracts phenylacetic acid was formed in quantitative
yield.
In previously cited work, trimethylsulfoxonium chloride
due to its solubility in tetrahydrofuran was used rather than
the more available iodide. In our experiments, methyl-
sulfoxonium chloride showed a solubility (at 25 °C) in THF
of 340 mg/100 mL, whereas the solubility of methylsulf-
oxonium iodide was 202 mg/100 mL. However, this latter
concentration seemed sufficient to form the ylide.
As a consequence, we prepared the dimethylsulfoxonium
methylide (2) in dry THF starting from the trimethyl-
sulfoxonium iodide and used the more readily available so-
dium hydride as the base.[7]
The formation of the ylide was verified by its reaction
with phenylacetaldehyde (Scheme 2).[7] Benzyloxirane (3)
was obtained in 83% yield. The spectroscopic data of 3
matched the literature data[8] and confirmed the high qual-
ity of the ylide.
The reaction has been utilized to convert the methyl es-
ters of nosyl-, Cbz-, and Boc-protected amino acids into
the corresponding amino acids. Deprotection of the car-
boxyl group was also performed in high yield for the Nε-
Boc-protected lysine (4d), the S-trityl-protected cysteine
(4f), and the O-Bn tyrosine (4e). These results confirm the
applicability of the procedure in the presence of acid-sensi-
tive protecting groups in the side chain.
In peptide synthesis, semipermanent protection is re-
quired for the terminal carboxyl group. The protecting
groups should be kept intact throughout the chain-building
process and removed upon its completion. In general, the
C-terminal in the peptide is protected as a methyl ester
which is normally difficult to remove under basic condi-
tions and could result in racemization of the amino acid
chiral centers.
Scheme 2. Synthesis of the benzyloxirane (3) from dimethylsulf-
oxonium methylide.
The freshly prepared ylide, generated using the new pro-
cedure, was treated with N-Cbz-l-alanine methyl ester (4g,
see Scheme 3 and Table 1). A negligible amount of the basic
Scheme 3. Reaction of esters 4a–n with dimethylsulfoxonium meth-
ylide.
Table 1. Results of the reaction of esters 4a–n with dimethylsulfoxonium methylide.
Ester
R1
R2
R3
R4
Product
(% Yield)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
NosNH
NosNH
NosNH
NosNH
NosNH
NosNH
CbzNH
BocNH
NosNH
Cbz-d-alanylNH
H
CH3
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
CH3
CH3
Ph
CH2Ph
5a (95)
5b (80)
5c (81)
5d (75)
5e (97)
5f (70)
5g (94)
5h (99)
5a (70)
5i (80)
5j (90)
5k (91)
5j (72)
5j (70)
CH(CH3)CH2CH3
H
(CH2)4NH(Boc)
CH2C6H4O(Bn)
CH2S(Trt)
CH3
CH2Ph
CH3
CH2Ph
Ph
CH3(CH2)10
Ph
CH(CH3)CH2CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
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A. Leggio, R. De Marco, F. Perri, M. Spinella, A. Liguori
FULL PAPER
1
1
For this reason, as we developed the deprotecting pro- was analyzed by H NMR spectroscopy. The obtained H
cedure, we also verified that the configuration of the amino NMR spectroscopic data was identical to that of the start-
acid chiral center was retained by using N-nosyl-l-iso- ing ester (4j), confirming that no inversion of configuration
leucine methyl ester [(2S,3S)-N-nosylisoleucine, 4b] as a occurred at the chiral centers.
starting substrate. Ester 4b was treated with ylide 2 under
The methodology was then applied to methyl esters of
the conditions adopted for this methodology. The reaction carboxylic acids. Methyl phenylacetate (4k) and methyl
was complete in 30 min and provided N-nosyl-l-isoleucine laurate (4l) were selected as model systems. In both cases,
(5b) as a unique product.
the reaction with ylide 2 provided the corresponding acid
When N-nosyl-d-alloisoleucine methyl ester [(2R,3S)-N- in good yield with a short reaction time (see Scheme 3 and
nosylisoleucine, 4c] was treated with methylide 2 under the Table 1).
same conditions, the corresponding N-nosyl-d-alloisoleuc-
As a result of the success with the methyl esters, our at-
1
ine (5c) was the only reaction product. The H NMR spec- tention shifted to more complex esters. As a first attempt,
troscopic data of 5b and 5c did not show any signals from we chose to perform the reaction using triolein (6). Ad-
possible epimers resulting from an inversion of the configu- justing the stoichiometry of the reaction for the three ester
ration at the α-carbon atom. Also the GC–MS analysis of functional groups in the starting material, triolein was al-
each of the two crude products (5b and 5c) revealed the lowed to heat at reflux with 7 equiv. of dimethylsulfoxon-
presence of only one diastereomer. Moreover, a sample con- ium methylide (2) for 3 h (Scheme 4). The completion of
taining a mixture of crude 5b (20 mg) and 5c (10 mg) was the reaction was monitored by TLC. After acidification and
analyzed by GC–MS, and the corresponding chromatogram extraction with ethyl acetate, the expected oleic acid (8) was
confirmed the complete separation of the two products obtained in 80% yield.
(Figure 1).
Scheme 4. Reaction of triolein with dimethylsulfoxonium meth-
ylide.
Encouraged by this result, the methodology was applied
to other alkyl and aryl esters. In particular, the ethyl ester
of N-nosyl-l-alanine (4i) was treated with ylide 2 to obtain
N-nosyl-l-alanine (5a) with a free carboxyl group in 70%
yield (see Scheme 3 and Table 1).
With the same purpose, the procedure was attempted
with benzyl phenylacetate (4n) and phenyl phenylacetate
(4m). Ester 4n was treated with ylide 2 under the usual con-
ditions to provide phenylacetic acid (5j) in 70% yield.
Benzyl alcohol was present in the basic extract. Monitored
by TLC, the reaction showed formation of the benzyl
alcohol prior to workup. This data suggests that ester cleav-
age does not occur during workup.
Next, the reaction was applied to phenyl phenylacetate
(4m). In this case, phenylacetic acid (5j) was isolated in 72%
yield, and phenol was detected in the slightly basic solu-
tions. The substrate 4m lacks a sp3-hybridized carbon atom
in the alcohol moiety which is necessary for nucleophilic
substitution to occur. As a consequence, the mechanism
Figure 1. GC–MS analysis of (a) 5b, (b) 5c, and (c) a mixture of 5b
(20 mg) and 5c (10 mg).
To give the adopted procedure greater applicability, the does not proceed through a nucleophilic attack of methylide
deprotection reaction was extended to simple peptide sys- 2 on the carbon atom in the alcohol moiety. This is con-
tems. With this aim, the peptide N-Cbz-d-alanine-l-phenyl- firmed by data from the benzyl phenylacetate reaction
alanine methyl ester (4j) was treated with dimethylsulfoxon- which produced the benzyl alcohol, but not the hypotheti-
ium methylide (2) using the same reaction conditions. The cal adduct resulting from the nucleophilic attack of ylide 2
corresponding N-Cbz-d-alanine-l-phenylalanine (5i) with on the methylene group of the benzylic moiety. Indirectly,
the deprotected carboxyl group was recovered in good yield this experiment also excludes that the reaction proceeds by
(80%) after 20 min (Table 1). Carboxylic acid 5i was then nucleophilic attack of the iodide ion formed as a sodium
treated with diazomethane, and the corresponding product salt together with the ylide.
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Unusual Reactivity of Dimethylsulfoxonium Methylide with Esters
In the light of these results, we performed a series of the reaction the intermediate evolves into a carboxylic acid
experiments to exclude that the formation of carboxylic which includes the oxygen atom of the ylide.
acid from the corresponding ester and dimethylsulfoxonium
A last experiment involving 18O-labeled water (isotopic
methylide was due to a hydrolysis reaction related to the composition 1:1, 18O/16O) as an isotopic label in the reac-
sodium hydroxide eventually present in the sodium hydride tion products provided important evidence about the reac-
used or formed during the reaction.
tion mechanism. The reaction of methyl phenylacetate with
In previous experiments, we observed that the addition methylide 2 was carried out under the usual conditions.
of sodium hydroxide to the reaction mixture containing However, the hydrolytic treatment in the final workup was
phenylacetic acid methyl ester and dimethylsulfoxonium performed using H218O. The product analysis by mass spec-
methylide decreased the reaction rate. In these cases, in fact, trometry showed that the phenylacetic acid contained in the
the reaction was complete in 6 h.
acidic extracts had not incorporated the 18O atom. This ex-
For this reason, we conducted an additional experiment perimental data is compatible with the formation of an in-
by treating the methyl phenylacetate with dimethylsulf- termediate (Scheme 5) consisting of a molecular adduct of
oxonium methylide in presence of an excess amount of the ylide and ester. This intermediate is formed after a nu-
18O-labeled sodium hydroxide. The expectation is that if a cleophilic attack of the ylide oxygen atom on the carbon
hydrolysis reaction is occurring then 18O would be incor- atom of the carbonyl group. First, the intermediate loses
porated into the reaction product phenylacetic acid. In the the alkoxy group and then, after action of a base which
reaction, the sodium hydroxide was a mixture of sodium could be the alkoxy group or another ylide molecule, proba-
hydroxide containing 16O (Na16OH) and 18O (Na18OH) in bly forms the carboxylate by incorporating the oxygen atom
a 1:1 molar ratio. This mixture was obtained by treating from the ylide. The attack of the nucleophilic oxygen atom
sodium hydride with a commercial sample of 18O-labeled in dimethylsulfoxonium ylide is probably promoted by the
water (H218O) which according to MS analysis had a com- high electrophilic character of the carbonyl group when it
position of about 50% of 16O-labeled water. The isotopic is coordinated to the positively charged sulfur atom.
composition of the sodium hydroxide was further studied
by the hydrolysis reaction with phenylacetic chloride
which resulted in phenylacetic acid containing 50% 18O
and 50% 16O.
The sodium hydroxide with a defined isotopic composi-
tion was used as a possible isotopic label in the reaction
of the ylide with phenylacetic acid methyl ester. An excess
amount of the labeled sodium hydroxide (5:1 with respect
to the methyl ester) was added to the reaction mixture.
However the reaction afforded only the carboxylic acid con-
Scheme 5. Hypothetical reaction mechanism between dimethylsul-
taining 16O which confirms that the acid is not obtained by
foxonium methylide and a carboxylic ester.
reaction of the hydroxide with the methyl ester.
None of the attempts to isolate the residue containing
The same experiment was performed using a sample of
lithium hydroxide labeled with 18O, formed by treating the
same 18O-labeled water with butyllithium. The results are
consistent with those obtained from the labeled sodium hy-
droxide. In fact, in this case as well, the reaction product
was exclusively the phenylacetic acid containing 16O. There-
fore, we assume that the carboxylic acid does not result
from a hydrolysis reaction, and that the oxygen atom con-
tained in the carboxylic acid does not stem from the hy-
droxide.
Additional evidence was furnished by the reaction of
phenylacetic acid benzyl ester with dimethylsulfoxonium
methylide in presence of an excess amount of sodium meth-
oxide. Also in this case, we recovered the corresponding car-
boxylic acid exclusively without evidence of the presence of
the corresponding methyl ester formed by nucleophilic at-
tack of methoxide ion on benzyl phenylacetate.
the sulfur atom were successful. Neither the GC–MS nor
the H NMR spectroscopic analysis of the crude reaction
products showed the presence of any byproducts containing
a sulfur atom besides the trimethylsulfoxonium ion.
1
Conclusions
The reaction of methylides with esters highlights a new
aspect in the reactivity of ylides. Resulting in the cleavage
of the ester functionality and simulating a hydrolysis pro-
cess, the reaction is general and proceeds with complex es-
ters. Occurring rapidly under mild conditions, the reaction
appears useful for solution-phase peptide synthesis when
the final cleavage of the C-terminal amino acid ester func-
tion is required. Moreover, the configuration of the chiral
center is maintained during the reaction. All these consider-
ations make this a valid and important procedure for ester
cleavage in organic chemistry.
On the basis of the obtained results and considering that
the alcohol moiety is generated prior to workup, we hypo-
thesized that conversion could proceed through an interme-
diate formed from the two reagents with subsequent loss of
the alcohol. This adduct could hydrolyze to the carboxylic
Experimental Section
General Methods: The solvents were purified and dried by standard
acid in the final workup. Another hypothesis is that during procedures and distilled prior to use. H218O, a solution of butyllith-
Eur. J. Org. Chem. 2012, 114–118
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117

A. Leggio, R. De Marco, F. Perri, M. Spinella, A. Liguori
FULL PAPER
ium (1.6 m in n-hexane), sodium methoxide, potassium tert-butox-
ide, trimethylsulfoxonium iodide, and trimethylsulfoxonium chlor-
ide used in the procedures are commercially available. Melting
points were recorded with a Kofler hot-stage apparatus. The 1H
and 13C NMR spectroscopic data were recorded at 300 and
75 MHz, respectively, using CDCl3 or [D6]DMSO (deuterated di-
methyl sulfoxide) as solvents. Chemical shifts are reported in units
of parts per million, and all coupling constants are reported in
Hertz. GC–MS analyses were performed with an HP-5MS
(30 mϫ0.25 mm, PhMe siloxane, 5%) capillary column. The mass
detector was operated in the electron impact ionization mode (EI-
MS) with an electron energy of 70 eV and in the chemical ioniza-
tion mode (CI-MS) using methane as the gaseous reagent. All reac-
tions were monitored by thin layer chromatography using silica gel
60-F254 precoated glass plates. When required, the reactions were
carried out under an inert atmosphere (N2). The dichloromethane
solution of diazomethane was prepared from N-methyl-N-ni-
trosourea using a classical procedure.[11] The concentration of the
diazomethane solution (0.66 m) was obtained by a back titration
performed with a standard solution of benzoic acid. Caution,[11]
diazomethane is highly toxic, and hence, must be handled carefully.
Dichloromethane solutions of diazomethane are stable for long
periods if stored on KOH pellets at –20 °C.
(chloroform/methanol, 90:10, v/v), was completed after 20 min.
The mixture was evaporated to dryness under reduced pressure,
and the residue was dissolved in water (10 mL). The aqueous solu-
tion was extracted with ethyl acetate (3ϫ10 mL) and then acidified
to pH = 2 using a solution of HCl (1 n). The resulting aqueous
solution was extracted with ethyl acetate (3ϫ10 mL). The com-
bined organic layers were dried with Na2SO4, and the solvent was
evaporated under reduced pressure to afford phenylacetic acid (5j,
1
138.3 mg, 90%); m.p. 76–78 °C. H NMR (300 MHz, CDCl3): δ =
9.81 (br. s, 1 H, COOH), 7.29–7.41 (m, 5 H, Ar), 3.67 (s, 2 H,
CH2Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.23, 133.450,
129.31, 128.12, 127.30, 41.04 ppm. MS (CI): m/z (%) = 137 (45)
[M – H]+, 119 (25), 91 (100). C8H8O2 (136.15): calcd. C 70.57, H
5.92; found C 70.35, H 5.90.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, structural data and 1H NMR and
13C NMR spectra of compounds.
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Preparation of Dimethylsulfoxonium Methylide (2): Sodium hydride
(1.1 mmol) in a 50% mineral oil dispersion was placed in a three-
necked round-bottomed flask (100 mL) and washed with hexane
(3ϫ10 mL) by swirling to allow the hydride to settle and then de-
canting to remove the mineral oil. The flask was immediately fitted
with a sealed mechanical stirrer and reflux condenser. Trimethyl-
sulfoxonium iodide (220 mg, 1 mmol) and dry tetrahydrofuran
(15 mL) were introduced, and the system was placed under nitro-
gen. The mixture was heated to reflux and stirred for 2 h. During
the reaction, the evolution of hydrogen and subsequent formation
of a milky-white suspension was observed. The mixture was cooled
to room temperature and used directly for the reaction with esters.
Synthesis of Benzyloxirane (3) Using Dimethylsufoxonium Methylide
(2): Phenyl acetaldehyde (1, 298.8 mg, 2.49 mmol) was added to the
solution of the dimethylsufoxonium methylide (3.24 mmol), and the
mixture was stirred at 50 °C under an inert N2 atmosphere. The
reaction, monitored by TLC (chloroform/ethyl acetate, 95:5, v/v),
was completed after 1 h. The mixture was evaporated to dryness
under reduced pressure, and the residue was dissolved in water
(10 mL). The aqueous solution was extracted with ethyl acetate
(3ϫ10 mL). The organic layers were collected, dried with Na2SO4,
and filtered. Evaporation of the solvents afforded benzyloxirane (3,
1
277.0 mg, 83%). H NMR (300 MHz, CDCl3): δ = 7.25–7.39 (m,
5 H, Ar), 3.15–3.23 (m, 1 H, CHCH2O), 2.81–2.98 (m, 3 H,
CHCH2O and CH2Ph), 2.59 (dd, J = 2.7, J = 4.8 Hz, 1 H,
CHCH2O) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.21, 129.02,
128.24, 126.68, 52.48, 46.92, 38.78 ppm. MS (EI): m/z (%) = 134
(60) [M]·+, 105 (44), 104 (36), 91 (100), 78 (22), 77 (17), 65 (12), 51
(11). C9H10O (134.18): calcd. C 80.56, H 7.51; found C 80.30, H
7.54.
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89–91.
Reaction of Methyl Phenylacetate (4k) with Dimethylsufoxonium
Methylide (2): Methyl phenylacetate (4k, 169.5 mg, 1.13 mmol) was
added to the solution of the dimethylsufoxonium methylide
(2.26 mmol), and the mixture was stirred under an inert atmo-
sphere at room temperature. The reaction, monitored by TLC
[10] K. Beautement, J. M. Clough, Tetrahedron Lett. 1984, 25,
3025–3028.
[11] F. Arndt, Org. Synth. 1943, 2, 165–167.
Received: July 15, 2011
Published Online: November 3, 2011
118
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Eur. J. Org. Chem. 2012, 114–118