N-alkylation of N-arylsulfonyl-α-amino acid methyl esters by trialkyloxonium tetrafluoroborates

Article abstract of DOI:10.1016/j.tet.2011.10.042

In this work we present the results obtained for the N-alkylation of a series of N-arylsulfonyl-α-amino acid methyl esters bearing different substituents at the 4-position of the sulfonamide aromatic ring. In particular, we compare the reactivity of these

Full text of DOI:10.1016/j.tet.2011.10.042

Tetrahedron 67 (2011) 9708e9714
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Alkylation of N-arylsulfonyl-
tetrafluoroborates
a-amino acid methyl esters by trialkyloxonium
*
*
Rosaria De Marco, Maria Luisa Di Gioia, Angelo Liguori , Francesca Perri, Carlo Siciliano ,
Mariagiovanna Spinella
ꢀ
Dipartimento di Scienze Farmaceutiche, Universita della Calabria, Edificio Polifunzionale, I-87036 Arcavacata di Rende (CS), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2011
Received in revised form 23 September 2011
Accepted 10 October 2011
Available online 19 October 2011
In this work we present the results obtained for the N-alkylation of a series of N-arylsulfonyl-a-amino
acid methyl esters bearing different substituents at the 4-position of the sulfonamide aromatic ring. In
particular, we compare the reactivity of these species with diazomethane and trimethyloxonium tetra-
fluoroborate in N-methylation processes. Diazomethylation is unsuccessful for N-arylsulfonamide de-
rivatives containing electron-releasing groups on the aromatic ring. In these cases trimethyloxonium
tetrafluoroborate is the reagent of choice for the direct and quantitative N-methylation. Further we
extend our evaluation to the use of triethyloxonium tetrafluoroborate. This reagent shows to be very
efficient in order to prepare N-ethyl derivatives of N-arylsulfonyl-a-amino acid methyl esters. An ex-
perimental protocol similar to that used for N-methylation with trimethyloxonium tetrafluoroborate is
applied for the N-ethylation.
Keywords:
Amino acids
N-Alkylation
N-Arylsulfonamides
Trimethyloxonium tetrafluoroborate
Triethyloxonium tetrafluoroborate
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
the treatment of these compounds with strong bases followed by
the quenching of the intermediate anionic nucleophiles with the
N-Alkyl-
a
-amino acids are a class of amino acid derivatives.
desired alkyl halides, however, sometimes racemization due to the
use of strong bases takes place.10 This two-step procedure works
well for the preparation of N-methylated derivatives, but it fails
when N-ethylated products are to be obtained in satisfying overall
yields.11 Alternatively, only a few protocols can be found in the
They find application as synthetic building blocks in medicinal
chemistry as well as molecular probes in studies related to the
structural properties and biological activities of N-alkylated pep-
tides and peptidomimetics.1 These are species largely represented
in nature, especially in marine organisms.2 N-Alkyl-
a
-amino acids
are not only biologically active; the substitution of N-alkyl- -amino
acids and their
3 homologs3 into biologically relevant peptides has
literature for N-ethylation of
of N,O-protected a-amino acids represents another route to N-
a
-amino acids.12 N-Chloromethylation
a
b
ethylated species.13 In this procedure however the use of cuprates is
needed to create the reactive anionic intermediates in situ.
One of the most widely employed processes of N-methylation of
led to important insights into the backbone characteristics required
for the expression of their bioactivities,4 allowing the design of
analogues with improved biological profiles.5 N-Methyl-
a
-amino
a
-amino acids by alkylation under various conditions is to utilize
their N-arylsulfonyl protected derivatives. The sulfonamide pro-
tection in fact greatly enhances the acidity of the
-NH function,14
acids are found in nature as free compounds and as structural
constituents of various peptides belonging to the cyclosporine,6
dolastatin,7 and didemnin families.8 The incorporation of N-
a
allowing a rapid deprotonation under basic conditions. In the
presence of the required alkylating reagent it furnishes the desired
methyl and in general of different N-alkyl-a-amino acids into
peptide chains often improves proteolytic stability, conformational
N-arylsulfonyl-N-methyl-
protocol could be used to achieve the N-alkylation of N-sulfonamide
-amino acid derivatives.15 In these applications the tosyl residue,
a-amino acids. Alternatively, a Mitsunobu
rigidity, lipophilicity, and transport properties.9
A wide arsenal of highly chemoselective and efficient method-
ologies have been sought and reported for the preparation of N-
a
a widely used protecting group for the a-amino function of natural
alkyl-
a
-amino acid derivatives.10 Among them, some procedures
and synthetic amino acids,16 has been employed.17 The two-step
Mitsunobu procedure requires the generation of the nitrogen nu-
cleophile and then the reactionwith the alkylating agents. However,
the use of strong deprotonating reagents could induce racemization
to variable extents. Moreover, tedious chromatographic
directed at the N-methylation of
a-amino acids generally describe
* Corresponding authors. E-mail address: A.Liguori@unical.it (A. Liguori).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.042

R. De Marco et al. / Tetrahedron 67 (2011) 9708e9714
9709
purifications must be applied in order to isolate and purify the final
products from the phosphinoxide by-product, especially upon
scale-up.
tetrafluoroborate for the direct N-ethylation of N-nosyl protected
-amino acid methyl esters.
a
N-Arylsulfonyl groups are also used as pharmacophores, espe-
cially when substituted with halogens at the 4-position of the aryl
2. Results and discussion
portion.18 N-Arylsulfonyl-
a-amino acids are in fact constituents of
In the present investigation, and in order to assess the main
advantages of the use of trialkyloxonium salts over the existing
procedures, we undertook the study of the reactivity of a series of
N-arylsulfonyl-a-amino acid methyl esters containing differently 4-
substituted aromatic rings on the protective group moiety. This
aimed at further considering any possibilities in modulating the
metalloproteases and carbonic anhydrase inhibitors.19 Further-
more, N-alkyl-sulfonamides have been found to possess a wide-
spread spectrum of bioactivities, including antibacterial,
antidiabetic, diuretic, and antithyroid effects.20 Recently, these
compounds have been tested as HIV protease inhibitors in retro-
viral therapy,21 and many of them are still under clinical evaluation
for their antitumor potential.22 Thus, the knowledge of the reactive
acidity and nucleophilicity of the a-NH proton, two characteristics
required for an efficient N-alkylation process. The increased acidity
of the sulfonamide NH functionality can allow the chemoselective
N-methylation in a peptide structure.31 Thus, the reactivity of the
properties of N-arylsulfonyl-a-amino acids under different N-al-
kylation conditions, either for the N-methyl or the N-ethyl func-
tionalization, is of great importance for the development of new
classes of metalloprotease inhibitors.23 It is also relevant in QSAR
studies concerning these particular families of interesting
pharmaceuticals.
NH residue in
lated by having a substituted sulfonyl group attached to it. Co-
ordination studies on N-tosyl- -amino acids have also
a-amino acids can sensibly be enhanced or modu-
a
demonstrated that, since the sulfonamide NH residue can become
an excellent nucleophile, a sulfonyl group having strong electronic
effects is able to exert a modulation of the reactive properties of the
NH functionality.32
We started our evaluation by subjecting the series of N-aryl-
sulfonyl-a-amino acid methyl esters 1aei to the N-methylation
Various 4-substituted N-arylsulfonamides can be N-alkylated on
solid support by using a modification of the Kenner safety-catch
strategy.24 This approach, however, requires a large excess of
alkylating reagents and bases and it is not adequate for large scale
preparation. The N-alkylation of N-monosubstituted arylsulfona-
mides containing amino acidic frames has been conducted in ionic
liquids by alkyl halides in reactions assisted by strong bases.25 The
FukuyamaeMitsunobu reaction is another method to realize the
chemospecific N-alkylation of secondary arylsulfonamides con-
taining substituents strongly deactivating on the aromatic ring.15
The use of Lewis acids and ruthenium-catalyzed processes has
been reported to be effective in the N-alkylation of N-arylsulfona-
mides.26 More recently, the use of alcohols in processes assisted by
copper(II) species has been proposed at high temperature and in
the presence of air.27
with diazomethane (Scheme 1), according to the synthetic pro-
cedure previously used for the process performed on the N-nosyl
protected derivatives 1aed.28a N-Arylsulfonyl-
a
-amino acid methyl
esters 1aei have been prepared in excellent yields by reacting the
corresponding -amino acid methyl ester hydrochloride with the
a
required arylsulfonyl chloride in the presence of triethylamine and
applying a well known general experimental protocol.30
O
S
O
R2
O
S
O
R2
CH2N2
O
O
The synthesis of N-methyl and N-ethyl-a-amino acids by nu-
N
H
N
DCM, r.t.
cleophilic substitution should generally be represented by a short
sequence, applying simple chemical techniques, which can also
offer the advantage of a minimal manipulation of the starting
materials. From the standpoint of the total synthesis of bi-
ologically active natural products, mild, and effective methods for
O
O
R1
R1
1a-i
2a-i
Scheme 1. Diazomethylation of 1aei under neutral conditions.
the N-alkylation of
a-amino acid derivatives are very appealing
and they may represent the most frequently used reactions. In our
previously published papers, we have proposed a ‘one-pot’ pro-
cedure based on the use of diazomethane as the methylating re-
Our first aim was to compare the reactivity of a series of N-
arylsulfonyl- -amino acid methyl esters containing electron-
a
agent in order to obtain N-methyl-
homologs in a fast and clean way, using N-arylsulfonyl derivatives
of natural
-amino acids.28 In those works, the nosyl group has
been used to drastically enhance the -NH function acidity. Al-
though the use of diazomethane presents important improve-
ments in the N-methylation of -amino acid methyl esters, it is to
a
-amino acids and their b3
withdrawing (F, Cl), and electron-releasing (CH3, OCH3) groups at
the 4-position of the aromatic portion of the sulfonamide moiety,
as opposed to their N-nosyl protected analogues.
a
a
Diazomethylation under neutral conditions28 allows a mild,
clean, and quantitative N-methylation of N-nosyl-
a-amino acid
a
methyl esters 1aed. Thus, we selected -alanine methyl ester as an
L
be used with great caution because of its explosive and toxic
nature, especially if preparative scales are entertained. Recently,
trimethylsilyldiazomethane has been proposed by our research
group as an alternative to diazomethane.29 Trialkyloxonium salts
ideal molecular model in order to evaluate the influence on the
diazomethylation process exerted by the different substituents at
the 4-position of the sulfonamide aromatic ring. The electronic
effects exerted by the 4-substituents on the reactivity of sulfon-
amides 1aei during their N-methylation can easily be recognized
from the data showed in Table 1. Diazomethane presents optimal
could play an important role in the preparation of N-alkyl-
amino acids and derivatives. However, the treatment of natural or
synthetic -amino acids with trialkyloxonium species has been
a-
a
properties for quantitative N-methylation of the a-amino acid de-
confined by the literature in a very few reports. For example,
triethyloxonium tetrafluoroborate has been used to promote N-
rivatives 1aed, without need of other reagent assistance in a ‘one-
pot’ process. However, it is worth to note that, in the case of the N-
arylsulfonyl derivatives 1eei containing 4-substituents, which are
different from the NO2 group (Table 1), this alkylating reagent gives
variable overall yields in the corresponding final products 2eei.
Results refer to the yields in isolated products after a maximum
reaction time of 40 min. It is important to note that conversion of
the starting materials 1aed is complete after this time, while it is
evident that N-arylsulfonyl derivatives 1eei are showed to be much
ethylation of Boc- and Z-protected a
-amino acids.11 However, in
this case it is necessary to bypass the poor reactivity imposed by
the low acidity of the NH residue and to produce nucleophilic
double anions, which can further be N-ethylated. As a conse-
quence, the reported method suffers from the need of a pre-
treatment of the starting materials with lithium bases. In our
previous
paper30
we
have
proposed
triethyloxonium

9710
R. De Marco et al. / Tetrahedron 67 (2011) 9708e9714
Table 1
nosyl protected a-amino acid methyl esters. Our approach relied
N-Methylation of N-arylsulfonyl-
a-amino acid methyl esters 1aei: use of
upon an in situ ‘one-pot’ ethylation at the nitrogen atom, avoiding
any previous step necessary to generate the required nucleophile.
The treatment proceeds smoothly in DCM solution and in the
presence of N,N-diisopropylethylamine (DIPEA). Pure N-nosyl-N-
ethyl derivatives are recovered in excellent to quantitative yields
after a simple work-up protocol. The alkylation of the hindered
tertiary amine by trialkyloxonium reagents is quite slow,30 and
does not influence the course of reaction. However in our data al-
ready published we did not use different N-arylsulfonyl groups
besides the nosyl for the protection of the NH functionality. On the
basis of these preliminary results we thought that trimethyloxo-
nium tetrafluoroborate could be useful also for the N-methylation
diazomethane
Entry
R1
R2
Product
Yieldsa (%)
Yieldsb (%)
1a
1b
1c
1d
1e
1f
NO2
NO2
NO2
NO2
F
CH3
CH(CH3)2
CH(CH3)CH2CH3
CH2Ph
CH3
CH3
CH3
CH3
CH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
100
100
100
100
23
19
12
7
15
d
d
d
d
62
59
50
47
55
Cl
1g
1h
1i
CH3
OCH3
H
a
Isolated yields after 40 min.
Isolated yields after 120 h. Entries 1aed have already been published by the
b
of N-arylsulfonyl-a-amino acid methyl esters containing different
substituent groups at the 4-position of the sulfonamide aromatic
ring.
authors.28a
less reactive than the 4-NO2 substituted analogues. In the case of
sulfonamides 1eei in fact very low yields in isolated products are
obtained after 40 min. Moreover the amount of the respective N-
methylated derivatives does not appreciably increase even after
longer times of treatment. Conversions of the less acidic N-aryl-
sulfonyl derivatives containing a halogen atom (F, Cl), or electron-
releasing groups (CH3, OCH3), or featuring no substitution at the
4-position of the aromatic ring, are not complete also after 120 h
(Table 1). In the case of 1h, a 47% overall yield in recovered product
is obtained after flash column chromatography. For the other N-
arylsulfonamides 1eeg and 1i yields in isolated product 2eeg and
2i were 62, 59, 50, and 55%, respectively. Note that in the case of the
treatment of sulfonamides 1eei flash column chromatography
needed for the recovery and purification of the corresponding N-
methyl derivatives 2eei. Furthermore, it should be considered that
additions of 10 mL of fresh diazomethane every 6 h were needed in
order to obtain 2eei in fair yields.
Scheme 2 displays the results obtained by reacting the series of
compounds 1aei with trimethyloxonium tetrafluoroborate. The N-
methylation was performed in dichloromethane and in the pres-
ence of DIPEA, at room temperature. The reaction was found to be
fast and chemospecific in all the analyzed cases (Table 2). It also
showed a complete conversion of all the sulfonamide precursors
1aei in a variable time between 15 and 110 min. The corresponding
N-methylated derivatives 2aei were recovered by a simple hy-
drolytic work-up of the reaction mixture. No flash column chro-
matography was needed in order to purify the final compounds
2aei, which were isolated in quantitative yields.
O
S
O
R2
O
S
O
R2
Me3OBF4
O
O
N
H
N
DIPEA
O
O
R1
R1
DCM, r.t.
From the data collected for the diazomethylation under neutral
conditions, it can further be argued that the electronic nature of
these various 4-substituents should be the main effect responsible
for the observed reactivity order showed by sulfonamides 1aei. The
1a-i
2a-i
Scheme 2. Reaction of 1aei with trimethyloxonium tetrafluoroborate.
reactivity of the NH function in the N-arylsulfonyl-a-amino acid
methyl esters 1aei appears to be correlated closely with the elec-
tronic effects imposed by the nature of each of the different 4-
substituents featured by the N-arylsulfonyl moiety. The acidity of
the sulfonamide NH proton is a crucial factor toward the effec-
tiveness of diazomethylation: the pKa value 10 of the methylating
species33 requires the presence of strongly electron-withdrawing
substituents (such as NO2) at the 4-position of the sulfonamide
aromatic ring, able to drastically enhance the NH acidity, which
determines the high reactivity observed for 1aed. The acidity of the
same functionality is sensibly reduced by the 4-substituents
exerting an electron-releasing effect, such as CH3 and OCH3 in
compounds 1geh. Moderate modulation of the NH reactivity to-
ward diazomethane is, instead, observed in the case of sulfon-
amides 1e,f bearing a halogen substituent.
The unsatisfying yields observed for the less reactive N-aryl-
sulfonamides 1eei, the need for a repeated addition of large
amounts of methylating reagent, its chemical nature, and the
slow kinetics of reaction strongly limit the usefulness of
diazomethylation.
The failure of diazomethane led us to direct our attention to
different and more efficient N-alkylating ‘one-pot’ methodologies.
To this aim, we selected trialkyloxonium species. We predicted that
the utilization of trialkyloxonium tetrafluoroborates for the N-al-
Table 2
N-Methylation of N-arylsulfonyl-
thyloxonium tetrafluoroborate
a-amino acid methyl esters 1aei: use of trime-
Entry
R1
R2
Product
Yielda (%)
Timeb
1a
1b
1c
1d
1e
1f
1g
1h
1i
NO2
NO2
NO2
NO2
F
CH3
CH(CH3)2
2a
2b
2c
2d
2e
2f
2g
2h
2i
Quantitative
Quantitative
Quantitative
Quantitative
Quantitative
Quantitative
Quantitative
Quantitative
Quantitative
15
15
15
15
60
75
90
110
90
CH(CH3)CH2CH3
CH2Ph
CH3
CH3
CH3
CH3
Cl
CH3
OCH3
H
CH3
a
Isolated products.
Time are expressed in min.
b
From the data displayed in Table 2, it is once again evident the
effect exerted by the strong electron-withdrawing substituent NO2
in nosyl sulfonamides 1aed. The sulfonamide proton acidity is
drastically influenced by the electronic characteristics of the sub-
stituent placed on the aromatic ring, and the enhanced reactivity of
the NH functionality determines the fast kinetics observed for the
N-methylation process.
kylation of N-arylsulfonyl-a-amino acid methyl esters could afford
a method general in its applicability, convenient, mild, and which
would not require the use of hazardous reagents. As recently pro-
posed by our research group,30 triethyloxonium tetrafluoroborate
can successfully be used for the chemospecific N-ethylation of N-
Compounds 2aed are formed in 15 min at room temperature,
and reactions proceed with complete consumption of the pre-
cursors 1aed. We used
L-alanine methyl ester as a model, similarly
to the study performed on the diazomethylation under neutral

R. De Marco et al. / Tetrahedron 67 (2011) 9708e9714
9711
Table 3
conditions, as previously discussed. The presence of a halogen atom
N-Ethylation of N-arylsulfonyl-
tetrafluoroborate
a
-amino acid methyl esters: use of triethyloxonium
at the 4-position of the sulfonamide aromatic ring led to larger
reaction times, as verified for sulfonamides 1eef. Longer reaction
times are required in the case of the less acidic sulfonamide de-
rivative 1h bearing the strong electron-releasing group OCH3. In all
cases the corresponding products were recovered in quantitative
yields avoiding chromatographic purification of the crude reaction
mixtures. It could be concluded that the chemospecific N-methyl-
Entry
R1
R2
Product
Yielda (%)
Timeb
1a
1b
1c
1d
1g
1h
1i
NO2
NO2
NO2
NO2
CH3
OCH3
H
CH3
3a
3b
3c
3d
3g
3h
3i
96
89
95
99
91
90
93
94
93
10
10
10
10
90
120
85
65
CH(CH3)2
CH(CH3)CH2CH3
CH2Ph
CH3
CH3
CH3
ation of N-arylsulfonyl-a-amino acid methyl esters can straight-
forwardly be realized by using trimethyloxonium tetrafluoroborate.
This represents an effective methylating reagent, which, contrary to
diazomethane, can be safely handled and offers great advantages in
terms of effectiveness and applicability for the N-methylation of
differently reactive N-arylsulfonamides.
1l
1m
F
Cl
CH(CH3)2
CH2CH(CH3)2
3l
3m
70
a
Isolated products.
Time are expressed in min.
b
While diazomethane can easily be prepared in the laboratory
scale, diazoethane is less available. Triethyloxonium salts could
successfully allow the preparation of N-ethyl derivatives of a-amino
3. Conclusion
acids. Hence our work continued with the exploitation of the po-
tentialities of trialkyloxonium salts in obtaining N-alkylated de-
rivatives of N-arylsulfonyl-a-amino acid methyl esters in which the
We exploited the possible use of different methods for the N-
alkylation of 4-substituted N-arylsulfonyl- -amino acid methyl
a
esters. Diazomethane and trimethyloxonium tetrafluoroborate
showed a significantly different behavior in the N-methylation. For
both methylating agents, the reaction seemed to be controlled by
the acidity of the sulfonamide NH functionality. Systems charac-
terized by a drastically enhanced acidity of the NH residue, e.g., N-
nosyl derivatives, can efficiently be N-methylated either by trime-
thyloxonium tetrafluoroborate or diazomethane. The latter showed
to be basic enough to generate the conjugated base of the sulfon-
amide derivatives, allowing diazomethylation under neutral con-
ditions. However, the protocol based on the use of diazomethane
fails when the acidity of the sulfonamide NH moiety is sensibly
reduced. In the cases of N-arylsulfonamides not containing sub-
stituents at the 4-position of the aromatic ring, or bearing electron-
releasing groups at the same carbon atom, the treatment with
diazomethane is ineffective. In these circumstances, the base
DIPEA, able to assists the N-methylation when combined with tri-
methyloxonium tetrafluoroborate, allowed the rapid, clean, and
aromatic ring is substituted with groups other than NO2. This fur-
ther test was triggered by our interest in the biological implications
that some N-ethyl derivatives of a-amino acids and peptides can
have.34 The aim was, again, to propose an easy, mild, efficient, and
direct chemospecific N-ethylation, which could minimize synthetic
manipulations on the initial amino acid materials.
The N-arylsulfonyl-a-amino acid methyl esters 1aed, 1gem
were subjected to treatment with trialkyloxonium tetra-
fluoroborate at room temperature, in dichloromethane and in the
presence of the base DIPEA (Scheme 3). Sulfonamides 1aed, con-
taining the strongly electron-withdrawing group NO2, were
smoothly N-ethylated, as already reported30 (Table 3), confirming
the effects exerted by that kind of 4-substitution on the en-
hancement of the acidity of the sulfonamide NH residue. The re-
actions were complete in 10 min, and the final products 3aed were
recovered in excellent to quantitative yields without the need for
flash column chromatography. Relatively lower reactivity was ob-
served for the less acidic N-arylsulfonamides 1gei, for which there
was either no substitution or an electron-releasing group placed at
the 4-position of the aromatic ring. The reaction proceeded with
complete consumption of the respective N-arylsulfonamide pre-
cursors 1gei in a time ranging between 85 and 120 min. This
allowed the recovery of the corresponding pure N-ethylated de-
rivatives 3gei in excellent yields without flash column chroma-
tography. N-Arylsulfonamides 1lem were, finally, selected in order
to assess the possible effects deriving from the steric hindrance
quantitative reaction also in the presence of N-arylsulfonyl-a-
amino acid methyl esters containing a less acidic NH functionality.
The effect of the different types of substituent placed at the 4-
position of the N-arylsulfonamide moiety is crucial for the NH
properties also when N-methylated derivatives have to be prepared
by using trimethyloxonium tetrafluoroborate. This reagent can
successfully replace diazomethane. In fact, trimethyloxonium tet-
rafluoroborate is more efficient than diazomethane in the N-
methylation of less reactive substrates and it is much safer. The data
collected about the N-ethylation with triethyloxonium tetra-
fluoroborate of the same systems further demonstrate the validity
of the discussed methodology in providing N-ethylated derivatives
caused by the side-chain size of the a-amino acid frame on the N-
ethylation process. From the data obtained, it seems that bulkier
amino acid side-chains were not interfering with the N-alkylation
performed with triethyloxonium tetrafluoroborate. In the latter
cases, the kinetics observed for the processes still remained fast
(the reaction was completed in 65 and 70 min, for 1l and 1m,
respectively), and the corresponding N-ethylated derivatives 3lem
were recovered pure in excellent yields without the need for flash
column chromatography.
of N-arylsulfonyl-a-amino acid methyl esters.
4. Experimental
4.1. General
Solvents were purified and dried by standard procedures and
distilled prior to use. Commercially available reagents were pur-
chased from Aldrich Chemical Co. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, on a Bruker Avance 300
O
S
O
R2
O
S
O
R2
Et3OBF4
O
O
spectrometer by using CDCl3 as the solvent. Chemical shifts (d) are
N
H
N
reported in parts per million. Coupling constants (J) are reported in
hertz (Hz). Reaction mixtures were monitored by TLC using Merck
Silica gel 60-F254 precoated glass plates, and UV light (254 nm) or
0.2% ninhydrin in ethanol and charring as visualizing agent. Kie-
selgel 60H without gypsum was used for flash column chroma-
tography. Reactions were performed using flame dried glassware
DIPEA
O
O
R1
R1
DCM, r.t.
1a-d, 1g-m
3a-d, 3g-m
Scheme 3. Reaction with triethyloxonium tetrafluoroborate.

9712
R. De Marco et al. / Tetrahedron 67 (2011) 9708e9714
and under an inert atmosphere (dry N2). GCeMS analyses were
performed by HP-5MS (30 mꢀ0.25 mm, PhMesiloxane capillary
column). The mass detector was operated in the electron impact
ionization mode (EIMS) with an electron energy of 70 eV. The in-
jection port was heated to 250 ꢁC. The oven temperature program
was initially set at 100 ꢁC with a hold of 2 min and ramped to 280 ꢁC
at 14 ꢁC/min with a hold of 10 min. Methane gas at a pressure of ca.
2 Torr was used as the CI reagent gas. The DCM solution of diazo-
methane was prepared from N-methyl-N-nitrosourea using a clas-
sical procedure.35 The concentration of the diazomethane solution
(0.66 M) was obtained by back-titration performed with a standard
benzoic acid solution. (Caution: diazomethane is highly toxic.
Hence, this reagent must be handled carefully). DCM solutions of
diazomethane are stable for long periods if stored on KOH pellets at
methyl ester 1e (100 mg, 0.383 mmol) in dry DCM (20 mL) with
DIPEA (0.233 mL, 1.34 mmol) and trimethyloxonium tetra-
fluoroborate (142 mg, 0.958 mmol) for 60 min afforded the title
compound 2e (105 mg, quantitative yield) as a colorless oil; [Found:
C, 47.79; H, 5.14; N, 5.11. C11H14FNO4S requires C, 47.99; H, 5.13; N,
5.09%]; 1H NMR (300 MHz, CDCl3):
(3H, s, N-CH3), 3.56 (3H, s, OCH3), 4.77 (1H, q, J 7.3 Hz,
7.22e7.14 (2H, m, ArH o-F), 7.86e7.80 (2H, m, ArH m-F) ppm; 13C
NMR (75 MHz, CDCl3):
d
1.38 (3H, d, J 7.3 Hz, CH3), 2.84
-CH),
a
d
15.6, 29.9, 52.1, 54.6, 116.1 (d, JC,F¼22.5 Hz),
129.9 (d, JC,F¼9.0 Hz), 135.3 (d, JC,F¼3.0 Hz), 165.1 (d, JC,F¼252.7 Hz),
171.3. MS (CI) (rel int.): m/z 304 (2, MC2Hþ5 ), 276 (28, MHþ), 256 (2),
244 (3), 216 (100), 202 (2), 152 (5%).
4.2.6. N-Methyl-N-4-chlorophenylsulfonyl-
(2f). Treatment of a solution of N-4-chlorophenylsulfonyl-L
L
-alanine methyl ester
-alanine
e20 ꢁC. N-Nosyl-
a
-amino acid methyl esters 1aed, and N-methyl-
N-nosyl-
a
-amino acid methyl esters 2aed were prepared by diaz-
methyl ester 1f (100 mg, 0.360 mmol) in dry DCM (20 mL) with
DIPEA (0.219 mL, 1.26 mmol) and trimethyloxonium tetra-
fluoroborate (133 mg, 0.900 mmol) for 75 min afforded the title
compound 2f (105 mg, quantitative yield) as a colorless oil; [Found:
C, 45.09; H, 4.85; N, 4.79. C11H14ClNO4S requires C, 45.28; H, 4.84; N,
omethylation according to our previously published protocol.28
Spectral data for 2aed are already reported.28a N-Ethyl-N-nosyl-
a
-amino acid methyl esters 3aed were prepared as reported
elsewhere.30
4.80%]; 1H NMR (300 MHz, CDCl3):
(3H, s, NCH3), 3.56 (3H, s, OCH3), 4.76 (1H, q, J 7.3 Hz,
(2H, d, J 8.8 Hz, ArH o-Cl), 7.75 (2H, d, J 8.8 Hz, ArH m-Cl) ppm. 13C
NMR (75 MHz, CDCl3): 15.4, 29.8, 52.2, 54.6, 128.6, 129.0, 137.6,
d
1.38 (3H, d, J 7.3 Hz, CH3), 2.84
-CH), 7.48
4.2. General procedure for the reaction of N-arylsulfonyl-
amino acid methyl esters 1aei with trimethyloxonium
tetrafluoroborate
a
-
a
d
138.9, 171.1 ppm. MS (EI) (rel int.): m/z 234 (39), 232 (100), 177 (18),
To a solution of 1aei (1 mmol), in DCM (20 mL) were added
DIPEA (3.5 mmol) and solid trimethyloxonium tetrafluoroborate
(2.5 mmol). The reaction mixture was stirred for 15e110 min at
room temperature and under an inert atmosphere. The mixture
was then quenched with 1 N aqueous HCl until pH 2, and extracted
with DCM (3ꢀ10 mL). The organic layer was washed with 1 N
aqueous NaOH (3ꢀ10 mL) and then brine (10 mL). The combined
organic layers were dried with Na2SO4, and evaporated to dryness
under reduced pressure conditions to give the respective N-meth-
ylated derivatives 2aei as colorless oils in quantitative yields.
175 (50), 113 (14), 111 (45), 75 (12%).
4.2.7. N-Methyl-N-4-methylphenylsulfonyl-
(2g). Treatment of a solution of N-4-methylphenylsulfonyl-
L
-alanine methyl ester
-ala-
L
nine methyl ester 1g (100 mg, 0.389 mmol) in dry DCM (20 mL)
with DIPEA (0.237 mL, 1.36 mmol) and trimethyloxonium tetra-
fluoroborate (144 mg, 0.973 mmol) for 90 min afforded the title
compound 2g (106 mg, quantitative yield) as a colorless oil; [Found
C, 52.90; H, 6.33; N, 5.14. C12H17NO4S requires C, 53.12; H, 6.32; N,
5.16%]; 1H NMR (300 MHz, CDCl3):
d
1.32 (3H, d, J 7.3 Hz, CH3), 2.42
(3H, s, ArCH3), 2.83 (3H, s, NCH3), 3.55 (3H, s, OCH3), 4.76 (1H, q, J
7.3 Hz, -CH), 7.31 (2H, d, J 8.3 Hz, ArH o-CH3), 7.68 (2H, d, J 8.3 Hz,
ArH m-CH3) ppm. 13C NMR (75 MHz, CDCl3):
15.2, 21.3, 29.7, 51.9,
4.2.1. N-Methyl-N-4-nitrophenylsulfonyl-
L
-alanine
methyl
ester
a
(2a). Treatment of a solution of N-4-nitrophenylsulfonyl-
L-alanine
d
methyl ester (1a) (100 mg, 0.347 mmol) in dry DCM (20 mL) with
DIPEA (0.212 mL, 1.21 mmol) and trimethyloxonium tetra-
fluoroborate (128 mg, 0.868 mmol) for 15 min afforded the title
compound 2a (105 mg, quantitative yield).
54.4, 127.1, 129.4, 135.9, 143.2, 171.4 ppm. MS (EI) (rel int): m/z 271
(1), 212 (100), 155 (60), 139 (2), 116 (3), 91 (75), 65(10%).
4.2.8. N-Methyl-N-4-methoxyphenylsulfonyl-
(2h). Treatment of a solution of N-4-methoxyphenylsulfonyl-
L
-alanine methyl ester
-al-
L
4.2.2. N-Methyl-N-4-nitrophenylsulfonyl-
(2b). Treatment of a solution of N-4-nitrophenylsulfonyl-
methyl ester (1b) (100 mg, 0.316 mmol) in dry DCM (20 mL) with
DIPEA (0.193 mL, 1.11 mmol) and trimethyloxonium tetra-
fluoroborate (117 mg, 0.790 mmol) for 15 min afforded the title
compound 2b (104 mg, quantitative yield).
L
-valine
methyl
ester
-valine
anine methyl ester 1h (100 mg, 0.366 mmol) in dry DCM (20 mL)
with DIPEA (0.223 mL, 1.28 mmol) and trimethyloxonium tetra-
fluoroborate (135 mg, 0.915 mmol) for 110 min afforded the title
compound 2h (105 mg, quantitative yield) as a colorless oil; [Found
C, 49.97; H, 5.98; N, 4.85. C12H17NO5S requires C, 50.16; H, 5.96; N,
L
4.87%]; 1H NMR (300 MHz, CDCl3):
d
1.33 (3H, d, J 7.3 Hz, CH3), 2.82
(3H, s, NCH3), 3.57 (3H, s, OCH3), 3.86 (3H, s, ArOCH3), 4.76 (1H, q, J
7.3 Hz, -CH), 6.97 (2H, d, J 9.0 Hz, ArH o-OCH3), 7.74 (2H, d, J 9.0 Hz,
ArH m-OCH3) ppm. 13C NMR (75 MHz, CDCl3):
15.3, 29.7, 51.3,
4.2.3. N-Methyl-N-4-nitrophenylsulfonyl-
(2c). Treatment of a solution of N-4-nitrophenylsulfonyl-
L
-isoleucine methyl ester
-iso-
a
L
d
leucine methyl ester (1c) (100 mg, 0.303 mmol) in dry DCM (20 mL)
with DIPEA (0.185 mL, 1.10 mmol) and trimethyloxonium tetra-
fluoroborate (111 mg, 0.75 mmol) for 15 min afforded the title
compound 2c (104 mg, quantitative yield).
54.4, 55.3, 114.0, 129.2, 162.4, 171.5, ppm. MS (EI) (rel int.): m/z¼287
(1), 228 (81), 214 (14), 171 (100), 155 (3), 123 (13), 107 (27), 92 (13),
77 (17%).
4.2.9. N-Methyl-N-phenylsulfonyl-
L
-alanine
methyl
ester
4.2.4. N-Methyl-N-4-nitrophenylsulfonyl-
L
-phenylalanine methyl es-
(2i). Treatment of a solution of N-phenylsulfonyl-
L-alanine methyl
ter (2d). Treatment of a solution of N-4-nitrophenylsulfonyl-
L
-
ester 1i (100 mg, 0.411 mmol) in dry DCM (20 mL) with DIPEA
(0.251 mL, 1.44 mmol) and trimethyloxonium tetrafluoroborate
(152 mg, 1.03 mmol) for 90 min afforded the title compound 2i
(106 mg, quantitative yield) as a colorless oil; [Found C, 51.53; H,
5.85; N, 5.43. C11H15NO4 requires C, 51.35; H, 5.88; N, 5.44%]; 1H
phenylalanine methyl ester (1d) (100 mg, 0.274 mmol) in dry DCM
(20 mL) with DIPEA (0.167 mL, 0.959 mmol) and trimethyloxonium
tetrafluoroborate (99 mg, 0.67 mmol) for 15 min afforded the title
compound 2d (103 mg, quantitative yield).
NMR (300 MHz, CDCl3):
NCH3), 3.46 (3H, s, OCH3), 4.71 (1H, q, J 7.2 Hz,
m, ArH), 7.77e7.72 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3):
d
1.28 (3H, d, J 7.3 Hz, CH3), 2.79 (3H, s,
4.2.5. N-Methyl-N-4-fluorophenylsulfonyl-
(2e). Treatment of a solution of N-4-fluorophenylsulfonyl-
L
-alanine methyl ester
-alanine
a
-CH), 7.43e7.57 (3H,
L

R. De Marco et al. / Tetrahedron 67 (2011) 9708e9714
9713
d
15.1, 51.8, 54.4, 126.9, 128.7, 132.3, 138.8, 171.1 ppm; MS (EI) (rel
DIPEA (0.211 mL,1.21 mmol) and triethyloxonium tetrafluoroborate
(164 mg, 0.865 mmol) for 65 min afforded the title compound 3l
(105 mg, 94% yield) as a colorless oil; [Found C, 52.77; H, 6.37; N,
4.41. C14H20FNO4S requires C, 52.98; H, 6.35; N, 4.41%]; 1H NMR
int.): m/z¼198 (80), 184 (4), 156 (28), 141 (52), 118 (33), 91 (28), 77
(100), 65 (3), 41 (37%).
4.3. General procedure for the synthesis of N-ethyl-N-
arylsulfonyl amino acid methyl esters 3gei, 3lem
(300 MHz, CDCl3): d 0.93 [3H, d, J 6.6 Hz, CH(CH3)2], 1.05 [3H, d, J
6.6 Hz, CH(CH3)2], 1.22 (3H, t, J 7.3 Hz, NCH2CH3), 2.09 [1H, m,
CH(CH3)2], 3.45 (3H, s, OCH3), 3.54e3.40 (2H, m, NCH2CH3), 4.05
To a solution of 1gei, and 1lem (1 mmol), in DCM (20 mL) were
added DIPEA (3.5 mmol) and solid triethyloxonium tetra-
fluoroborate (2.5 mmol). The reaction mixture was stirred for
15e120 min at room temperature and under an inert atmosphere.
The mixture was then quenched with 1 N aqueous HCl until pH 2,
and extracted with DCM (3ꢀ10 mL). The organic layer was washed
with 1 N aqueous NaOH (3ꢀ10 mL) and then once with brine
(10 mL). Finally the combined organic layers were dried with
Na2SO4. Evaporation of the solvent gave the N-ethyl derivatives
3gei and 3lem in 90e94% overall yields.
(1H, d, J 10.5 Hz,
a
-CH), 7.19e7.10 (2H, m, ArH o-F), 7.88e7.80 (2H,
16.3, 19.4, 19.6, 28.7,
m, ArH m-F), ppm; 13C NMR (75 MHz, CDCl3):
d
40.3, 51.4, 65.7, 115.8 (d, JC,F¼22.5 Hz), 130.1 (d, JC,F¼9.0 Hz), 136.2
(d, JC,F¼3.0 Hz), 164.9 (d, JC,F¼252.8 Hz), 170.9 ppm. MS (CI) (rel
int.): m/z¼346 (9, MC2Hþ5 ), 318 (19, MHþ), 258 (100), 239 (3), 194
(7), 158 (3%).
4.3.5. N-Ethyl-N-4-chlorophenylsulfonyl-
(3m). Treatment of a solution of N-4-chlorophenylsulfonyl-
L
-leucine
methyl
ester
L-leu-
cine methyl ester 1m (100 mg, 0.313 mmol) in dry DCM (20 mL)
with DIPEA (0.192 mL, 1.10 mmol) and triethyloxonium tetra-
fluoroborate (149 mg, 0.783 mmol) for 70 min afforded the title
compound 3m (102 mg, 94% yield) as a colorless oil; [Found C,
51.59; H, 6.39; N, 4.04.C15H22ClNO4S requires C, 51.79; H, 6.37; N,
4.3.1. N-Ethyl-N-4-methylphenylsulfonyl-
(3g). Treatment of a solution of N-4-methylphenylsulfonyl-
L
-alanine methyl ester
-ala-
L
nine methyl ester 1g (100 mg, 0.389 mmol) in dry DCM (20 mL)
with DIPEA (0.237 mL, 1.36 mmol) and triethyloxonium tetra-
fluoroborate (185 mg, 0.973 mmol) for 90 min afforded the title
compound 3g (101 mg, 91% yield) as a colorless oil; [Found C, 54.93;
H, 6.68; N, 4.90. C13H19NO4S requires C, 54.72; H, 6.71; N, 4.91%]; 1H
4.03%]; 1H NMR (300 MHz, CDCl3):
d 0.95 [3H, d, J 6.9 Hz, CH(CH3)2],
0.97 [3H, d, J 6.9 Hz, CH(CH3)2], 1.20 (3H, t, J 7.1 Hz, NCH2CH3),
1.70e1.62 (2H, m, CHCH2), 1.75 [1H, m, CH(CH3)2], 3.40e3.10 (2H,
m, NCH2CH3), 3.45 (3H, s, OCH3), 4.55 (1H, dd, J 8.8, 5.3 Hz,
7.48 (2H, d, J 8.1 Hz, ArH o-Cl), 7.75 (2H, d, J 8.1 Hz, ArH m-Cl) ppm;
13C NMR (75 MHz, CDCl3):
12.3, 21.7, 21.8, 23.4, 38.4, 39.8, 50.9,
a-CH),
NMR (300 MHz, CDCl3):
J¼7.5 Hz, CH3), 2.41 (3H, s, ArCH3), 3.21 (1H, m, NCH2CH3), 3.34 (1H,
m, NCH2CH3), 3.53 (3H, s, OCH3), 4.65 (1H, q, J 7.3 Hz, -CH), 7.27
(2H, d, J 8.4 Hz, ArH o-CH3), 7.69 (2H, d, J 8.4 Hz, ArH m-CH3) ppm;
13C NMR (75 MHz, CDCl3):
16.5, 16.6, 21.5, 40.4, 52.0, 54.9, 127.2,
d 1.21 (3H, t, J 6.9 Hz, NCH2CH3), 1.41 (3H, d,
d
a
57.2, 128.3, 127.8, 137.6, 137.9, 170.8 ppm. MS (CI) (rel int.): m/z¼376
(7, MC2Hþ5 ), 348 (21, MHþ), 288 (100), 208 (5%).
d
129.4, 137.3, 143.1, 172.1 ppm; MS (CI) (rel int.): m/z¼314 (7,
Supplementary data
MC2Hþ5 ), 286 (45, MHþ), 226 (100), 155 (3%).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.10.042.
4.3.2. N-Ethyl-N-4-methoxyphenylsulfonyl-
(3h). Treatment of a solution of N-4-methoxyphenylsulfonyl-
L-alanine methyl ester
L
-
alanine methyl ester 1h (100 mg, 0.366 mmol) in dry DCM (20 mL)
with DIPEA (0.223 mL, 1.28 mmol) and triethyloxonium tetra-
fluoroborate (174 mg, 0.915 mmol) for 120 min afforded the title
compound 3h (100 mg, 90% yield) as a colorless oil; [Found C,
52.01; H, 6.33; N, 4.63. C13H19NO5S requires C, 51.81; H, 6.35; N,
References and notes
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4.65%]; 1H NMR (300 MHz, CDCl3):
d 1.22 (3H, t, J 7.1 Hz, NCH2CH3),
1.43 (3H, d, J 7.3 Hz, CH3), 3.21 (1H, m, NCH2CH3), 3.34 (1H, m,
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7.3 Hz,
a
-CH), 6.96 (2H, d, J 8.9 Hz, ArH o-OCH3), 7.76 (2H, d, J
16.5, 16.6,
8.9 Hz, ArH m-OCH3), ppm; 13C NMR (75 MHz, CDCl3):
d
40.3, 52.1, 54.7, 55.5, 113.9, 129.3, 162.7, 172.1 ppm. MS (EI) (rel
int.): m/z¼301 (1), 242 (100), 171 (95), 155 (2), 123 (9), 107 (18), 92
(7), 77 (9%).
4.3.3. N-Ethyl-N-phenylsulfonyl-
L
-alanine
methyl
ester
(3i).
Treatment of a solution of N-phenylsulfonyl-L-alanine methyl ester
1i (100 mg, 0.411 mmol) in dry DCM (20 mL) with DIPEA (0.251 mL,
1.44 mmol) and triethyloxonium tetrafluoroborate (196 mg,
1.03 mmol) for 85 min afforded the title compound 3i (104 mg, 93%
yield) as a colorless oil; [Found C, 53.33; H, 6.29; N, 5.17.C12H17NO4S
requires C, 53.12; H, 6.32; N, 5.16%]; 1H NMR (300 MHz, CDCl3):
ꢁ
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d
1.28 (3H, t, J 7.1 Hz, NCH2CH3), 1.47 (3H, d, J 7.4 Hz, CH3), 3.25 (1H,
m, NCH2CH3), 3.40 (1H, m, NCH2CH3), 3.54 (3H, s, OCH3), 4.70 (1H,
q, J 7.3 Hz, -CH), 7.50e7.64 (3H, m, ArH), 7.88e7.83 (2H, m, ArH)
ppm; 13C NMR (75 MHz, CDCl3):
16.5, 16.6, 40.4, 51.9, 54.9, 127.1,
a
d
11. Hansen, D. W.; Pilipauskas, D. J. Org. Chem. 1985, 50, 945e950.
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McDermott, J. R.; Benoiton, N. L. Can. J. Chem. 1973, 51, 1915e1919; (c) Cheung,
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4.3.4. N-Ethyl-N-4-fluorophenylsulfonyl-
(3l). Treatment of a solution of N-4-fluorophenylsulfonyl-
methyl ester 1l (100 mg, 0.346 mmol) in dry DCM (20 mL) with
L
-valine
methyl
ester
L-valine

9714
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