Synthesis of Methionine-Derived Endocyclic Sulfilimines and Sulfoximines

Article abstract of DOI:10.1002/ejoc.201601515

The asymmetric synthesis of endocyclic methionine sulfilimines and sulfoximines from methionine derivatives was explored. The cyclization was performed by using phenyliodine diacetate (PIDA). In the case of l-methionine, dehydromethionine was obtained, and a deprotonation step by tBuONa was necessary to yield the corresponding sulfilimine. On the other hand, the cyclic sulfilimine of methionine methyl ester, methylthiopropylamine, and l-methioninol were synthesized in a single step by using PIDA. Owing to their instability, the sulfilimines were oxidized to their corresponding sulfoximines in good yields.

Full text of DOI:10.1002/ejoc.201601515

A Journal of
Accepted Article
Title: Synthesis of Methionine Derivatived Endocyclic Sulfilimines and
Sulfoximines
Authors: Vincent Reboul, Hamid Marzag, Marie Schuler, and Arnaud
TATIBOUËT
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601515
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601515
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
Synthesis of Methionine Derivatived Endocyclic Sulfilimines and
Sulfoximines
[
a]
[b]
[b]
[a]
Hamid Marzag, Marie Schuler, Arnaud Tatibouët, and Vincent Reboul*
Abstract: The asymmetric synthesis of endocyclic methionine
sulfilimines and sulfoximines from methionine derivatives is
reported. The cyclisation is performed using phenyliodine diacetate
Few examples described the synthesis of saturated cyclic
sulfoximines, mainly by ring closure of existing sulfoximine
[
15]
function (Figure 1).
Herein, we report a synthesis of such
(
PIDA). In the case of L-methionine, dehydromethionine was
compounds from amino sulfides, which allowed the synthesis
of both endocyclic sulfilimines and sulfoximines.
obtained and a deprotonation step by t-BuONa is necessary, to
yield the corresponding sulfilimine. On the other hand, cyclic
sulfilimine of methionine methyl ester, methylthiopropylamine and
L-methioninol were synthetized in a single step using PIDA. Due to
their instability, the sulfilimines were oxidized into corresponding
sulfoximine in good yields.
O
S
O
S
O
S
O
S
HN
HO C
R1
HN
R1
N
R1
HN
R1
2
LG
Ref. 15c,d,e
Ref. 15j
Ref. 15g,i,k
Ref. 15a,b,f
Previous work
N (O)n
This
work
S
NH2
1
Introduction
R
n = 0: sulfilimine
n = 1: sulfoximine
R1 = alkyl, aryl
S
R1
In recent years, sulfoximines have become essential
[
1]
groups in modern sulfur organic chemistry. They have found
[
2]
many applications as chiral auxiliaries, ligands in asymmetric
Figure 1. Starting material for endocyclic sulfilimine and sulfoximine
synthesis.
[
3]
catalysis,
activating groups in C–H activation or ortho-
[
4]
[5]
lithiation, precursors of heterocycles or in the preparation of
[
6]
other sulfurated functions. Surprisingly, sulfoximines have
[
7]
long been neglected in medicinal chemistry despite the early
Results and Discussion
[
8]
discovery of biological activities of methionine sulfoximine
3
[
9]
(
MSO) and buthionine sulfoximine 4 (BSO),
as glutamine
In connection with our interest in asymmetric synthesis of
synthetase inhibitor and specific and competitive inhibitor of
γ-glutamyl-cysteine synthetase, respectively (Scheme 1). Thus,
only few compounds containing sulfoximine moiety have
[16]
N,S-heterocycles, we envisioned the synthesis of endocyclic
five membered ring systems sulfilimines 6 and sulfoximines 7,
[17]
called dihydroisothiazoles and S-oxides thereof,
from L-
[
10a]
emerged, such as potent kinase inhibitor (BAY-1143572,
[18,19]
methionine derivatives 5.
In this approach, the nitrogen
[
10b]
[11]
BAY-1000394
and
AZD-6738
)
or
insecticide
atom of the compounds comes from the amino-acid. We
designed two classical approaches. The first one consists in an
intramolecular imination from sulfoxide methionine derivatives
[
12]
(
Sulfoxaflor ).
Most of the methods of the synthesis of sulfoximines
[
13]
concern the preparation of acyclic compounds.
The
(
pathway A). The second approach (pathway B) refers to an
imination reaction of methionine followed by an oxidation
Scheme 2).
synthesis of endocyclic compounds, in which sulfur-nitrogen
bond forms part of the ring system, was rarely reported and
usually involved the preparation of benzofused cyclic
(
[
14]
sulfoximines.
R2
O
O
O
NH
Pathway A
N
O
S
Pathway B
NaN3, H2SO4
CHCl3
O
HO
H N
S
HO
S
R1
imination
oxidation
R2
R1
7
0
°C to 45 °C
O
2
H N
2
H N
S
2
N
S
1
R
= Me: 1
= Bu: 2
Methionine sulfoximine (MSO): 3
Buthionine sulfoximine (BSO): 4
1
R
R2
NH2
S
1
6
oxidation
imination
Scheme 1. First synthesis of sulfoximines.
R2
: R2 = CO
H (c), CH
5
2
H (a), CO
2
Me (b),
=
2
OH (d)
[
a]
b]
Normandie Univ, LCMT, ENSICAEN, UNICAEN, CNRS, 14000
Caen, France. Full address: Laboratoire de Chimie Moléculaire et
Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN &
Université de Caen-Normandie, 14050 Caen, France.
vincent.reboul@ensicaen.fr; http://www.lcmt.ensicaen.fr/
Institut de Chimie Organique et Analytique, Université d’Orléans,
UMR CNRS 7311, BP 6759, F-45067 Orléans Cedex, France.
Scheme 2. Retro-synthetic pathways of cyclic sulfilimines and sulfoximines.
[
20]
The imination reaction of methionine sulfoxide 1 was first
explored (Pathway A). We investigated the metal free
cyclization with phenyliodine diacetate (PIDA), as already used
[
Supporting information for this article is given via a link at the end of
the document.
[21]
in an intermolecular reaction. Surprisingly, the reaction led to
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European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
[
22]
nitrile 8 in 58% yield instead of the expected sulfoximine 7a,
The use of NaOH afforded 6a in a moderate 48% yield (entry
4) but the formation of methionine sulfoxide 1a was not
through oxidative decarboxylation (Scheme 3). Indeed, this
[
23]
[34]
reaction usually did not occur with aliphatic amino acid.
Nitrile 8 was also isolated in a quantitative yield using NBS in
observed.
Table 2. Synthesis of cyclic sulfilimine 6a
[
24]
the presence of NaOH.
Nitrile 8 was then exploited for the
preparation of the desired cyclic sulfoximines. Using Magnier’s
O C
O C
2
2
[
25]
Base
rt
procedure, i.e.
trifluoromethanesulfonic anhydride followed
NH
S
N
by a quench with water, the desired cyclic sulfilimine 9 was
S
1
[26]
detected by H NMR on the crude.
We were not able to
(1R,3S)-11
6a
purify it because of its instability on silica gel and consequently,
[
27]
it was oxidized in-situ using mCPBA. Thus, the racemic acyl
sulfoximine 10 was isolated an overall 48% yield (Scheme 3).
entry
Base
Equiv.
h
6a
(%
[
a]
yield)
1
2
3
4
5
6
NEt
3
2
2
2
2
1
2
24
24
24
24
12
12
0
HO C
2
N
O
S
AcONa
MeONa
NaOH
t-BuONa
t-BuONa
1
0
CO H
PIDA
MeOH
NH2 58%
2
0
7a
O
Tf2O
then
H2O
O
or
NBS
NaOH
CN
O
S
K2CO3
m-CPBA
48
20
>95
O
N
N
O
1
9
9%
S
S
S
8
9
10 (48%)
Scheme 3. Synthesis of sulfoximine 10
[
a] Estimated by H NMR of the crude
Finally, a complete and clean conversion into sulfilimine 6a
The imination reaction (Pathway B) of unprotected
was achieved using t-BuONa at room temperature (entries 5
methionine derivatives 5 was next studied (Table 1). The
and 6). The use of 2 equivalents of the base is mandatory due
[
28,29]
cyclisation into dehydromethionine
11 was first realized
[35]
to the prior deprotonation of the methyl group (Scheme 4).
using the well-known oxidation reaction by iodine in the
Being highly instable, purification attempts of crude 6a on silica
gel or neutral alumina led to degradation. Consequently, it was
oxidized in-situ into sulfoximine 7a with mCPBA in the
[
30]
[31]
presence of NaOH
or MeONa
which involves a tetra-
However, although the
[
32]
coordinate sulfurane intermediate.
two diastereoisomers (dr 2/1) can be separated by column
chromatography, a disappointing 50% yield was obtained.
These results could be slightly improved (Table 1) by using
NBS (entry 1) or chloramine-T (entry 3) as the halogen
2 3
presence of K CO , in 90% overall yield (Scheme 4).
O C
t-BuONa O C
mCPBA HO C
2
2
2
(
2 eq)
K2CO3
NH
N
N
O
[
33]
rt, 2 h
rt, 1 h
source
and t-BuONa as the base (entry 2). The best result
S
S
S
9
0%
was obtained using PIDA (1 equiv.) in MeOH at room
temperature affording the major diastereoisomer (1R,3S)-
dehydromethionine 11 in 76% isolated yield (entry 4).
(1R,3S)-11
7a
Scheme 4. Synthesis of sulfoximine 7a
Table 1. Optimization of the synthesis of dehydromethionine 11.
The reaction with L-methionine methyl ester hydrochloride
5b was then explored (Table 3). NBS was first used as the
O C
O C
2
2
"
X " (1 eq)
HO C
NH2
S
2
Base (2 eq)
NH
S
NH
S
[
36]
+
oxidant, with and without MeONa (1 equiv.) (entries 1 and 2).
Surprisingly, sulfilimine 6b was directly obtained as the major
product in a mixture with the intermediate 12. However, when 2
equivalents of base were used, only the sulfilimine 6b was
obtained as an inseparable mixture of 2 diastereoisomers
(1R,3S)
(1S,3S)
Dehydromethionine (11)
5
a
[
a]
entry
Oxidant
NBS
Base
Time
Yield (%)
(
entry 3). A screening of oxidant (entries 4-6) did not improve
1
2
3
4
NaOH
30 min
16 h
51/29
66/07
63/16
76/21
the diastereoselectivity of 6b. Finally, the use of PIDA without
base promoted the sulfilimine formation (entry 7), probably due
to the formation of the acetate anion from PIDA. When 1 or 2
I
2
t-BuONa
equivalents
diastereoselectivity of 6b was clearly enhanced (entries 8 and
). A catalytic amount (10%) of base (entry 10) was found to
of
MeONa
were
used
with
PIDA,
TsNClNa
PIDA
-
30 min
30 min
-
9
be sufficient to promote the same induction (dr 85/15). With
these optimized conditions, stable sulfilimine 6b was isolated in
high 94% isolated yield. The use of other hypervalent iodine
reagents (PIFA or DMP) did not improve this result (entries 11
and 12).
[
a] Isolated yields of (1R,3S) and (1S,3S)-dehydromethionine respectively.
The formation of cyclic sulfilimine 6a was next
investigated by the unprecedented deprotonation of (1R,3S)-
dehydromethionine 11 (Table 2). When NEt , AcONa and
MeONa were used as bases (entries 1-3), no reaction occurred.
3
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European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
Table 3. Optimization of the synthesis of sulfilimine 6b
MeO C
2
Oxidant
MeO C
2
MeO C
2
NH2 Base
NH
N
MeOH
30 min
S
S
S
MeO C
1) PIDA, MeOH
2
MeONa (10%) MeO C
MeO C
2
2
5
b
12
6b
NH2
S
rt, 30 min
N
N
O
+
O
2
) mCPBA, K CO3
[
a]
[a]
2
S
S
entry
Oxidant
NBS
Base [Equiv.]
Ratio 12/6b [%]
37/63
dr of 6b
56/44
56/44
56/44
54/46
46/54
60/40
69/31
84/16
87/13
rt, 1 h
5
b
(1S,3S)-7b
(1R,3S)-7b
10%
1
2
3
4
5
6
7
8
9
-
61%
NBS
MeONa [1]
MeONa [2]
MeONa [2]
MeONa [2]
MeONa [2]
-
28/72
Scheme 6. Sequential one-pot synthesis of 7b
NBS
0/100
I
2
0/100
Encouraged by these results, this one-pot methodology
was next successfully applied on methylthiopropylamine 5c
Br
2
0/100
[
37]
and L-methioninol 5d (Scheme 7).
Corresponding
[
38]
TsNClNa
PIDA
PIDA
PIDA
PIDA
PIFA
DMP
1
0/100
sulfoximine 7c and 7d
were obtained in 55% and 66%
overall yields, respectively.
0/100
1
) PIDA, MeOH
rt, 30 min
R
R
NH2
MeONa [2]
MeONa [1]
MeONa [0.1]
MeONa [1]
MeONa [1]
0/100
N
O
S
2) mCPBA, K CO3
rt, 1 h
S
2
0/100
5
c: R = H
7c: 55%
7d: 55% + 11%
[
b]
1
1
1
0
1
2
0/100
85/15
61/39
63/37
5d: R = CH OH
2
0/100
Scheme 7. Synthesis of endocyclic sulfoximine 7c and 7d
0/100
[
a] Estimated by H NMR on the crude product. [b] 6b was isolated in 94%
Conclusions
yield.
In conclusion, according to the imination then oxidation
approach, we have developed an asymmetric synthesis of
endocyclic sulfoximines from methionine derivatives. Moreover,
the oxidation then imination procedure of methionine afforded
unexpected sulfinyl nitrile derivative, which was cyclized into
acyl sulfoximine.
Sulfilimine 6b was next oxidized with mCPBA in the
presence of K CO into the corresponding sulfoximine 7b in
3% yield (Scheme 5). At this stage, the 2 diastereoisomers
can be separated by column chromatography.
2
3
6
MeO C
mCPBA MeO C
2
MeO C
2
2
K2CO3
N
N
N
O
+
O
S
rt, 1 h
S
S
6
b
(1S,3S)-7b
0%
(1R,3S)-7b
13%
Experimental Section
5
NaOH
1S,3S)-7a
General Experimental Information: The NMR spectra were recorded
1
13
as solutions in D
respectively. The chemical shifts are calibrated to residual proton and
carbon resonance of the solvents D O (δ 4.79 ppm) and CD OD (δ
.30 and δ 49.0 ppm). In some cases, a deuterium exchange occurred
2 3
O or CD OD, at 400 MHz ( H) and 100.6 MHz ( C)
(
2
H
3
H
Scheme 5. Synthesis of sulfoximine 7a and 7b
3
C
[
35]
on the methyl group of methionine derivatives. Mass spectra (MS)
were determined by ESI. Specific rotation was determined in water or
methanol. Flash column chromatography was performed using silica
gel 60 (230-400 mesh). Thin layer chromatography was carried out on
silica gel 60 F254 (1.1 mm) with spot detection under UV light and by
The major one, (1S,3S)-7b, was saponified with NaOH to
afford 7a. The stereochemistry observed confirmed the same
asymmetric induction sense as in the synthesis of
dehydromethionine 11.
immersion in KMnO
4
solution. All reactions were carried out in
anhydrous solvents and performed in oven-dried glassware. All other
solvents and reagents were used as received from commercial sources.
A one-pot sequential procedure starting from methionine
methyl ester hydrochloride 5b also was investigated (Scheme
Methionine sulfoxide (1a): To a suspension of L-methionine (1.0 g,
6
). Thus, (1S,3S)-7b and (1R,3S)-7b were obtained in 61%
6
.57 mmol) in water (100 mL) was added phenyliodine diacetate (2.37
and 10% overall yields, respectively.
g, 7.23 mmol, 1.1 equiv.) and p-toluenesulfonic acid (127 mg, 0.66
mmol, 0.1 equiv.). The reaction mixture was stirred overnight at room
temperature. The volume of the mixture was reduced to 20 mL under
vacuum then pH of the solution was adjusted to 5 by addition of HCl
(
10%). Acetone was added slowly until complete precipitation of
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European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
1
methionine sulfoxide. After cooling at 0°C for 2 h, the precipitate was
collected, washed with acetone then dried under vacuum to afford
slightly yellow powder (976 mg, 90%) as a mixture of two inseparable
diastereoisomers (dr = 50:50).
H NMR (D
2
3
O, 400 MHz): δ = 4.36 (dd, J = 7.4 and 5.8 Hz, 1H, H ),
3.81 (dt, J = 13.2 and 8.3 Hz, 1H, H
Hz, 1H, H ), 2.90-2.80 (m, 1H, H ), 2.81 (s, 3H, Me), 2,45 (ddt, J = 13.7,
8.3 and 5.4 Hz, 1H, H ). C NMR (D O, 100.6 MHz): δ = 176.0 (C=O),
7.1 (C ), 47.0 (C ), 31.4 (SMe), 30.9 (C
NO SNa]: 170.0252; found: 170.0248. [α]
O). (1S,3S)-11: H NMR (D
), 3.80 (ddd, B part of ABMPX system, JAB = 13.2 and J
11.4, 7.2 Hz, 1H, H ), 3.71 (dddd, A part of ABMPX system, JAB = 13.2
), 2.91 (ddt, J = 13.9, 2.6 and 7.1 Hz, 1H,
), 2.81 (s, 3H, Me), 2.59 (dddd, J = 13.9, 11.2, 9.4 and 6.9 Hz, 1H,
5
), 3.60 (ddd, J = 13.2, 7.3 and 5.0
5
4
1
3
4
2
+
6
3
5
4
). HRMS (ESI ): calc. for
2
0
[
C
5
H
9
2
D
= 72.45 (c = 0.52,
(
S)-Methionine (S)-sulfoxide (1a): To a solution of (1R,3S)-
1
H
2
2
O, 400 MHz): δ = 4.36 (dd, J = 9.4 and
dehydromethionine 11 (0.1 g, 0.67 mmol) in water (1.75 mL) was added
aqueous lithium hydroxide (0.25 mL of 3.3 M solution, 0.83 mmol). After
stirring for 15 min at room temperature, the pH of the solution was
adjusted to 7 by the addition of 2 M hydrochloric acid. Acetone was
slowly added, and the white solid was allowed to settle for 20 min. The
white crystalline precipitate was collected at the pump, washed with
7
.1 Hz, 1H, H
3
=
5
and J = 6.9, 2.6, 0.6 Hz, 1H, H
5
H
H
4
1
3
4
). C NMR (D
2
O, 100.6 MHz): δ = 177.7 (C=O), 67.9 (C
3
), 47.9 (C
5
),
+
3
1.8 (SMe), 30.0 (C
4
). HRMS (ESI ): calc. for [C
5
H
10NO
2
S]: 148.0432;
acetone (2 × 5 mL), and dried in vacuum to give (S)-methionine (S)-
2
0
1
2
found: 148.0425. [α]D = –21.09 (c = 0.3, H O).
sulfoxide 1a (0.18 g, 73%) as white crystals. (2S,S
S
)-1a: H NMR (D
2
O,
), 2.72
O, 100.6 MHz): δ =
), 36.5 (SMe), 23.7 (C ). HRMS
)-1a:
), 3.11 (ddd, J =
), 2.92 (ddd, J = 13.4, 9.0 and 6.8 Hz, 1H,
4
00 MHz): δ = 3.87 (t, J = 6.3 Hz, 1H, H
2
), 3.07-2.94 (m, 2H, H
). C NMR (D
4
1
3
(
s, 3H, SMe), 2.32-2.27 (m, 2H, H
3
2
1-Methyl-4,5-dihydro-3H-isothiazole-3-carboxylic acid (6a): To a
solution of (1R,3S)-dehydromethionine 11 (50 mg, 0.27 mmol) in
methanol (1 mL) was added sodium tert-butoxide (54 mg, 0.54 mmol,
2.0 equiv.) in one portion. The reaction mixture was stirred at room
temperature for 2 h. The product cannot be purified by chromatography
1
73.20 (C=O), 53.3 (C
2
), 48.22 (C
4
3
–
(
1
ESI ): calc. for [C
5
H
10NO
3
S]: 164.0381; found: 164.0377. (2S,S
O, 400 MHz): δ = 3.85 (t, J = 6.4 Hz, 1H, H
3.4, 9.5 and 7.0 Hz, 1H, H
R
H NMR (D
2
2
1
4
1
3
H
4
), 2.73 (s, 3H, SMe), 2.34-2.23 (m, 2H, H
3
). C NMR (D
2
O, 100.6
).
due to his instability on silica gel. Consequently, the product was
1
MHz): δ = 173.16 (C=O), 53.5 (C
2
), 48.19 (C ), 36.4 (SMe), 23.8 (C
4
3
characterized on the crude. H NMR (D
2
O, 400 MHz): δ = 3.33 (t, J =
6
.6 Hz, 1H, H
3
), 2.90 (ddd, A part of ABMX system, JAB= 13.3 and J =
), 2.85 (ddd, B part of ABMX system, JAB= 13.3
), 2.67 (s, 3H, Me), 1.99 (ddt, A part of
ABMX system, JAB= 13.7 and J = 10.2, 6.0 Hz, 1H, H ), 1,89 (ddt, B
part of ABMX system, JAB= 13.7 and J = 10.1, 6.6 Hz, 1H, H
NMR (D O, 100.6 MHz): δ = 181.7 (C=O), 55.0 (C3), 48.9 (C4), 36.5
Me), 27.6 (C5).
1
0.1 and 6.5 Hz, 1H, H
5
3
-(Methylsulfinyl) propanenitrile (8): To a suspension of methionine
and J = 9.9 and 5.7 Hz, 1H, H
5
sulfoxide 1a (300 mg, 1.78 mmol) in methanol (9 mL) was added
sodium hydroxide (145 mg, 3.56 mmol, 2.0 equiv.) in one portion. The
reaction mixture was stirred until complete solubilization of methionine
sulfoxide then N-bromosuccinimide (970 mg, 5.34 mmol, 3.0 equiv.)
was added in one portion. Carbon dioxide liberation occurs immediately.
After 15 min of stirring, the reaction mixture was filtered then
concentrated under vacuum. The crude product was purified by
chromatography on silica gel (AcOEt 100% to AcOEt/MeOH: 95/5) to
afford nitrile 8 as yellow-orange oil (207 mg, 99%). IR (neat): ν = 2249
4
1
3
4
).
C
2
(
1-Methyl-4,5-dihydro-3H-isothiazole-1-oxide-3-carboxylic acid (7a):
To a solution of (1R,3S)-dehydromethionine 11 (150 mg, 0.82 mmol) in
ethanol (3 mL) was added sodium tert-butoxide (160 mg, 1.63 mmol,
2.0 equiv.). The reaction mixture was left under stirring and the reaction
-
1
1
(
CN), 1038 (S=O) cm . H NMR (CD
3
OD, 400 MHz): δ = 3.21 (dt, J =
), 3.05 (ddd, J = 12.8, 7.4 and 5.7 Hz, 1H, H ),
OD, 100.6
1
1
3
2.8 and 7.7 Hz, 1H, H
.02-2.90 (m, 2H, H ), 2.73 (s, 3H, SMe). C NMR (CD
), 49.18 (C ), 38.2 (SMe), 11.5 (C ). HRMS (ESI ):
NOSNa]: 140.0146; found: 140.0145.
3
3
was monitored by TLC and H NMR. After completion, potassium
1
3
2
3
carbonate (288 mg, 2.04 mmol, 2.5 equiv.) and m-chloroperbenzoic
+
MHz): δ = 119.0 (C
calc. for [C
1
3
2
acid (402 mg, 1.63 mmol, 2.0 equiv.) were added successively. The
4
H
7
reaction mixture was stirred for 1 h then was filtered. After
concentration, the crude yellow product was dissolved in small amount
of methanol then purified by chromatography on silica gel
1
-Methyl-4,5-dihydro-3H-isothiazol-3-one-1-oxide (10): To a solution
1
(
acetone/MeOH 9:1) to give 7a (120 mg, 90%) as a yellowish solid.
NMR (CD OD, 400 MHz): δ = 4.18 (t, J = 6.7, 1H, H
.0 Hz, 1H, H ), 3.39 (ddd, J = 13.0, 7.7 and 5.4 Hz, 1H, H
H, Me), 2.57 (dddd, J = 12.7, 9.0, 6.7 and 5.4 Hz, 1H, H ), 2.32 (dddd,
OD, 100.6 MHz):
), 42.5 (t, J C-D= 21.1 Hz, SCH D),
). HRMS (ESI ): calc. for [C NO S]: 162.0225; found:
H
of nitrile 8 (50 mg, 0.43 mmol) in dichloromethane (2 mL) was added
trifluromethanesulfonic anhydride (84 µL, 0.50 mmol, 1.2 equiv.). The
reaction mixture was stirred at room temperature for 30 min then water
3
3
), 3.59 (dt, J = 13.0,
), 3.20 (s,
9
5
5
3
4
(
2 mL) was added. The biphasic mixture was left under high stirring for
0 min. The aqueous phase was separated from the organic phase
1
3
4 3
J = 12.7, 9.0, 7.7 and 6.7 Hz, 1H, H ). C NMR (CD
1
1
3
δ = 181.0 (C=O), 72.1 (C
3
–
), 53.7 (C
5
2
then concentrated under vacuum. The crude product was solubilized in
methanol (5 mL) and potassium carbonate (146 mg, 1.05 mmol, 2.5
equiv.) and m-chloroperbenzoic acid (206 mg, 0.84 mmol, 2.0 equiv.)
were added successively and the mixture was left under stirring for 1 h.
The reaction mixture was concentrated under vacuum and the crude
was purified by chromatography on silica gel (AcOEt 100% to
AcOEt/MeOH: 9/1) to afford sulfoximine 10 as slightly yellow oil (27 mg,
3
1
1.1 (C
4
5
H
8
1
3
-
20
62.0224. IR (neat): ν = 1587 (C=O) cm . [α]
D
= 28.18 (c = 0.27,
MeOH).
1-Methyl-4,5-dihydro-3H-isothiazole-3-carboxylic acid methyl ester
(6b): To a solution of L-methionine methyl ester hydrochloride (100 mg,
0.49 mmol) in dry methanol (2.5 mL) was successively added sodium
methoxide (3 mg, 0.05 mmol, 0.1 equiv.) then phenyliodine diacetate
(169 mg, 0.52 mmol, 1.05 equiv.) in one portion. The reaction mixture
was left under stirring for 30 min and was quenched with water (2 mL).
The aqueous phase was washed with hexane (3 × 5 mL) to remove the
iodobenzene. The aqueous-methanol layer was concentrated under
-
1
1
4
8%). IR (neat): ν = 1672 (C=O) cm . H NMR (D
δ = 4.13 (ddd, J = 14.3, 10.7 and 6.6 Hz, 1H, H ), 3.66 (ddd, J = 14.3,
.7 and 4.6 Hz, 1H, H ), 3.48 (s, 3H, SMe), 3.08 (ddd, A part of ABMX
system, JAB = 16.9, 9.7 and J = 6.6 Hz, 1H, H ), 2.93 (ddd, B part of
ABMX system, JAB = 16.9, 10.7 and J = 4.6 Hz, 1H, H
2
O, 400 MHz):
5
9
5
4
1
3
4
1
). C NMR (D
2
O,
), 42.1 (quint, J C-D = 21.1 Hz, S-
). HRMS (ESI ): calc. for [C NO SNa]: 158.0221;
found: 158.0213.
3
1
00.6 MHz): δ = 183.6 (C=O), 50.9 (C
5
+
CHD
2
), 34.0 (C
4
4
H
5
D
2
2
vacuum to afford sulfilimine 6b as an inseparable mixture of 85/15 of
1
diastereoisomers, as yellowish oil (74 mg, 94%). H NMR (CD
3
OD, 400
),
Me), 3.72 (ddd, B part of ABMX
system, JAB= 13.3 Hz and J = 7.2, 3.8 Hz, 1H, H ), 2.99-2.89 (m, 1H,
), 2.88 (s, 3H, SMe), 2.62 (ddt, J = 13.7, 8.0 and 4.0 Hz, 1H, H ).
1S,3S)-6b (minor product): 4.58 (t, J = 8.0 Hz, 1H, H ), 4.00-3.88 (m,
), 2.88 (s, 3H, SMe),
MHz): (1R,3S)-6b (major product): 4.66 (dd, J = 7.6 and 4.4 Hz, 1H, H
.90-3.82 (m, 1H, H ), 3.81 (s, 3H, CO
3
3
5
2
Dehydromethionine (11): To a solution of L-methionine 5a (100 mg,
.66 mmol) in dry methanol (5 mL) was added phenyliodine diacetate
227 mg, 0.69 mmol, 1.05 equiv.) in one portion. The reaction mixture
0
5
H
4
4
(
(
3
was left under stirring for 30 min then was concentrated under vacuum.
The resulting crude product was purified by chromatography on silica
gel (Acetone/MeOH: 7/3 to 5/5) to yield (1R,3S)-dehydromethionine (73
mg, 76%) and (1S,3S)-dehydromethionine (20 mg, 21%). (1R,3S)-11:
2
2
1
H, H
.76 (dddd, J = 13.9, 10.7, 8.3 and 7.1 Hz, 1H, H
00.6 MHz): (1R,3S)-6b (major product): 170.8 (C=O), 64.3 (C
5 2 4
), 3.80 (s, 3H, CO Me), 2.99-2.84 (m, 1H, H
1
3
4
). C NMR (CD
3
OD,
3
), 52.3
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European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
(
CO
2
Me), 46.2 (C
4
), 31.8 (SMe), 29.4 (C
5
). (1S,3S)-6b (minor product):
Me), 47.9 (C ), 31.9 (SMe), 29.1 (C ).
S]: 162.0589; found: 162.0582. IR
purification on silica gel (cyclohexane/AcOEt: 4/6 to AcOEt/MeOH: 9/1)
1
71.7 (C=O), 64.8 (C
3
), 52.1 (CO
2
4
5
sulfoximine (1S,3S)-7d (60 mg, 55%) and (1R,3S)-7d (12 mg, 11%)
+
1
HRMS (ESI ): calc. for [C
6
H
12NO
2
both as yellowish oil. (1S,3S)-7d: H NMR (CD
3
OD, 400 MHz): δ = 3.85
), 3.65 (dd, J =
1.0 and 4.6 Hz, 1H, CHOH), 3.52 (dd, J = 11.0 and 6.1 Hz, 1H,
CHOH), 3.46 (ddd, J = 13.0, 4.4 and 8.2 Hz, 1H, H ), 3.29 (s, 3H, SMe),
), 2.15 (dddd, J = 13.0,
OD, 100.6 MHz): δ = 69.5
), 42.3 (q, J C-D= 21.7 Hz, S-CHD ), 28.1
). HRMS (ESI ): calc. for [C 10DNO SNa]: 173.0471; found:
-
1
(
neat): ν = 1741 (C=O), 1006 (S=N) cm .
3 5
(dq, J = 4.7 and 6.4 Hz, 1H, H ), 3.71-3.63 (m, 1H, H
1
1
-Methyl-4,5-dihydro-3H-isothiazole-1-oxide-3-carboxylic
acid
5
2
1
.45 (dddd, J = 13.0, 9.1, 6.4 and 4.1 Hz, 1H, H
4
methyl ester (7b): To a solution of sulfilimine 6b (85 mg, 0.45 mmol) in
dry methanol (1 mL) was added potassium carbonate (158 mg, 1.12
mmol, 2.5 equiv.) and m-chloroperbenzoic acid (221 mg, 0.896 mmol,
1
3
4 3
0.1, 7.8 and 7.0 Hz, 1H, H ). C NMR (CD
1
3
(
(
C
3
), 67.2 (CH
2
OH), 54.2 (C
5
2
+
C
4
5
H
2
2
.0 equiv.) successively. The reaction mixture was stirred for 1 h then
2
0
1
1
73.0470. [α]
D
= –10.25 (c = 0.23, MeOH). (1R,3S)-7d: H NMR
), 3.70 (dq, J = 13.0, 9.5
), 3.54 and 3.43 (AB part of ABX system, JAB = 10.9 Hz, JAX
3.6 Hz, JBX = 5.2 Hz, 2H, CH OH), 3.33-3.25 (m, 1H, H ), 3.25 (s, 3H,
SMe), 2.42 (dddd, J = 13.1, 9.3, 8.5 and 6.6 Hz, 1H, H ), 2.20 (ddt, J =
OD, 100.6 MHz): δ = 69.6 (C ),
), 42.4 (t, J C-D= 21.0 Hz, S-CDH ), 28.4 (C ).
11DNO S]: 151.0652; found: 151.0651.
was filtered. The solvent was removed under vacuum. The resulting
crude yellow solid was dissolved in a small amount of ethyl acetate and
methanol then purified by chromatography on silica gel
(
CD
3 3
OD, 400 MHz): δ = 4.07-4.02 (m, 1H, H
Hz, 1H, H
5
=
2
5
(
cyclohexane/AcOEt: 4/6 to AcOEt/MeOH: 95/5) to give (1S,3S)-7b (40
mg, 50%) as colourless oil and (1R,3S)-7b (11 mg, 13%) as colourless
4
1
3
1
1
6
3.3, 9.1, 4.4 Hz, 1H, H
7.4 (CH OH), 54.2 (C
4
). C NMR (CD
3
3
oil. (1S,3S)-7b: H NMR (CD
3
OD, 400 MHz): δ = 4.36 (dd, J = 7.0 and
), 3.73 (s, 3H, CO Me), 3.69 (dt, J = 13.3, 9.0 Hz, 1H, H ),
.43 (ddd, J = 13.3, 7.7 and 5.8 Hz, 1H, H ), 3.24 (s, 3H, SMe), 2.59
), 2.45 (ddt, J = 13.1, 5.6
OD, 100.6 MHz): δ = 175.4 (C=O),
Me), 43.0 (SMe), 29.7 (C ). HRMS
S]: 178.0538; found: 178.0537. IR (neat): ν =
1
3
5
3
.9 Hz, 1H, H
3
2
5
2
5
2
4
+
HRMS (ESI ): calc. for [C
5
H
2
5
2
0
[
α]
D
= 23.84 (c = 0.11, MeOH).
(
dddd, J = 13.1, 9.0, 7.2 and 5.8 Hz, 1H, H
4
1
3
and 8.0 Hz, 1H, H
4
). C NMR (CD
), 52.7 (CO
3
6
8.7 (C
3
), 53.5 (C
5
2
4
+
(
ESI ): calc. for [C
6
H
12NO
20
3
Acknowledgements
-
1
1
1
731 (C=O) cm . [α]
D
= 15.91 (c = 0.12, MeOH). (1R,3S)-7b:
H
NMR (CD
3
OD, 400 MHz): δ = 4.62 (dd, J = 7.4 and 2.4 Hz, 1H, H
.71 (s, 3H, CO Me), 3.65 (ddd, J = 13.3, 11.6 and 8.7 Hz, 1H, H
.38 (ddd, J = 13.3, 8.2 and 2.9 Hz, 1H, H
.51 (m, 1H, H ), 2.44 (ddt, B part of ABMPX system, JAB= 13.4 and J =
.7 and 2.6 Hz, 1H, H
), 51.3 (CO
HRMS (ESI ): calc. for [C
IR (neat): ν = 1730 (C=O) cm . [α]
3
),
The authors thank the CNRS, Normandie Université, Labex
Synorg (ANR-11-LABX-0029), the Conseil Régional de
Normandie and the European FEDER fundings for financial
support. The authors also thank Prof. A.-C. Gaumont, the head
of the group, for helpful discussions.
3
3
2
8
2
5
),
5
), 3.34 (s, 3H, SMe), 2.62-
4
1
3
4
). C NMR (CD
Me), 51.1 (C
NO SNa]: 202.0492; found: 202.0483.
3
OD, 100.6 MHz): δ = 174.3
(
C=O), 67.0 (C
3
2
5
), 42.2 (SMe), 27.9 (C ).
4
+
6
H
9
-
D
2
3
20
1
D
= 17.18 (c = 0.26, MeOH).
Keywords: L-Methionine • PIDA • Sulfoxides • Sulfilimine •
Sulfoximine
General procedure for cyclisation reaction with PIDA followed by
oxidation: To a solution of methionine derivative 5 (0.49 mmol) in
methanol (2 mL) was successively added sodium methoxide (0.05
mmol, 0.1 equiv.) then phenyliodine diacetate (0.51 mmol, 1.05 equiv.)
in one portion. The reaction mixture was left under stirring at room
temperature for 30 min. After complete conversion into the
[1]
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1
corresponding sulfilimine (TLC analysis and H NMR analysis), sodium
carbonate (1.23 mmol, 2.5 equiv.) and m-chloroperbenzoic acid (0.98
mmol, 2 equiv.) were added successively and the mixture was left
under stirring for 1 h. After the completion of the reaction (TLC analysis),
the reaction mixture was filtered. The solvent was removed under
vacuum and the crude product was purified by chromatography on
silica gel.
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1
-Methyl-4,5-dihydro-3H-isothiazole-1-oxide-3-carboxylic
acid
methyl ester (7b): The reaction was carried out according to the
general procedure by using 100 mg of L-methionine methyl ester
hydrochloride 5b (100 mg, 0.49 mmol) to provide after purification on
silica gel (cyclohexane/AcOEt: 4/6 to AcOEt/MeOH: 95/5) sulfoximines
(
1S,3S)-7b (53 mg, 61%) and (1R,3S)-7b (9 mg, 10%), both as
colorless oil.
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1
-Methyl-4,5-dihydro-3H-isothiazole-1-oxide (7c): The reaction was
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carried out according to the general procedure by using 3-
methylthiopropylamine 5c (100 mg, 0.93 mmol) to provide after
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purification on silica gel (cyclohexane/AcOEt: 4/6 to AcOEt/MeOH: 9/1)
1
sulfoximine 7c as yellowish oil (61 mg, 55%). H NMR (CD
3
OD, 400
),
), 3.22 (s,
OD, 100.6 MHz): δ =
), 42.1 (quint, J C-D = 21.4 Hz, S-CHD ), 26.2 (C ).
NOSNa]: 142.0303; found: 142.0299.
MHz): δ = 3.78-3.71 (m, 1H, H
3
), 3.58 (dt, J = 13.2 and 9.1 Hz, 1H, H
.50 (dt, J = 10.3 and 6.7 Hz, 1H, H ), 3.33-3.25 (m, 1H, H
). C NMR (CD
5
3
3
5
3
5
1
3
H, Me), 2.37-2.21 (m, 2H, H
5.2 (C ), 54.0 (C
4
3
1
3
3
5
2
4
+
4 9
HRMS (ESI ): calc. for [C H
1
-Methyl-4,5-dihydro-3H-isothiazole-3-hydroxymethyl-1-oxide-
7d): The reaction was carried out according to the general procedure
by using L-methioninol 5d (100 mg, 0.72 mmol) to provide after
(
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
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2
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European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601515
SHORT COMMUNICATION
SHORT COMMUNICATION
Cyclic Sulfoximines
Hamid Marzag, Marie Schuler, Arnaud
Tatibouet, and Vincent Reboul*
Page No. – Page No.
The one-pot two steps asymmetric synthesis of endocyclic methionine sulfilimines
and sulfoximines from methionine derivatives is reported.
Synthesis of Methionine Derivatived
Endocyclic Sulfilimines and
Sulfoximines
This article is protected by copyright. All rights reserved.