Expected and unforeseen reactions of 2,3,3-trimethyl-1λ6-isothiazolidine-1,1,4-trione and their spiro derivative

Article abstract of DOI:10.1016/j.tet.2019.01.031

Herein, we present a full account of our studies with respect to the reactivity of insufficiently explored 1λ⁶-isothiazolidine-1,1,4-triones (so-called β-keto-γ-sultams). This heterocyclic system possesses two reaction centers: the EWG-activate

Full text of DOI:10.1016/j.tet.2019.01.031

Accepted Manuscript
6
Expected and unforeseen reactions of 2,3,3-trimethyl-1λ -isothiazolidine-1,1,4-trione
and their spiro derivative
Maria V. Popova, Alexey V. Dobrydnev, Viktoriya V. Dyakonenko, Irina S.
Konovalova, Svitlana V. Shishkina, Yulian M. Volovenko
PII:
S0040-4020(19)30058-4
https://doi.org/10.1016/j.tet.2019.01.031
TET 30083
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 November 2018
Revised Date: 8 January 2019
Accepted Date: 15 January 2019
Please cite this article as: Popova MV, Dobrydnev AV, Dyakonenko VV, Konovalova IS, Shishkina SV,
6
Volovenko YM, Expected and unforeseen reactions of 2,3,3-trimethyl-1λ -isothiazolidine-1,1,4-trione
and their spiro derivative, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.01.031.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Expected and unforeseen reactions of 2,3,3-
trimethyl-1λ6-isothiazolidine-1,1,4-trione and
their spiro derivative
Maria V. Popovaa, Alexey V. Dobrydnev a,b , Viktoriya V. Dyakonenkoc, Irina S. Konovalovac, Svitlana V.
Shishkinac and Yulian M. Volovenkoa
aChemistry Department, Taras Shevchenko National University of Kiev, Lva Tolstoho Street 12, Kiev 01033, Ukraine
bSMC Ecopharm Ltd., Naberezhno-Korchuvatska Street 136-B, Kiev 03045, Ukraine
cDepartment of X-ray Diffraction Studies and Quantum Chemistry, SSI “Institute for Single Crystals” National Academy of Science of Ukraine, Nauky
avenue 60, Kharkiv 61001, Ukraine

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Expected and unforeseen reactions of 2,3,3-trimethyl-1λ6-isothiazolidine-1,1,4-
trione and their spiro derivative
Maria V. Popovaa, Alexey V. Dobrydnev a,b , Viktoriya V. Dyakonenkoc, Irina S. Konovalovac, Svitlana
V. Shishkinac and Yulian M. Volovenkoa
aChemistry Department, Taras Shevchenko National University of Kiev, Lva Tolstoho Street 12, Kiev 01033, Ukraine
bSMC Ecopharm Ltd., Naberezhno-Korchuvatska Street 136-B, Kiev 03045, Ukraine
cDepartment of X-ray Diffraction Studies and Quantum Chemistry, SSI “Institute for Single Crystals” National Academy of Science of Ukraine, Nauky avenue
60, Kharkiv 61001, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we present a full account of our studies with respect to the reactivity of insufficiently
explored 1λ6-isothiazolidine-1,1,4-triones (so-called β-keto-γ-sultams). This heterocyclic system
possesses two reaction centers: the EWG-activated methylene group and the carbonyl moiety
which were investigated in the course of present study. 2,3,3-Trimethyl-1λ6-isothiazolidine-
1,1,4-trione and 4-methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione were chosen as
representatives of the given class of substances. The former is a classical spatially
uncomplicated model substance, the latter bearing a spiranic cyclopropane substituent is
interesting in terms of evaluation of strain cycle effects. Indeed, the data obtained convey
information about the impact of the highly strained substituent on the reaction centers of the
ketosultam core. Thus, in addition to less stability of the strained spiranic ketosultam, the
reactivity of its carbonyl group is suppressed whereas the activity of the methylene group is
enhanced being compared with the nonspiranic substrate. Apart from the difference in the
chemical character of the given β-keto-γ-sultams we faced unprecedented products (1,1-dioxo-5-
[2-(triphenylphosphonio)acetyl]-2,3-dihydro-1H-1λ6-isothiazol-4-olates) formed during the
course of the reaction with the Wittig reagent triphenylcarbethoxymethylenephosphorane.
Available online
Keywords:
Sulfonamides
Spiro compounds
Electrophiles
Nucleophiles
X-ray study
2009 Elsevier Ltd. All rights reserved
.
HO
Br
Br
1. Introduction
t-Bu
t-Bu
The structural and therapeutic diversity, coupled with the
commercial viability of small heterocyclic molecules has
fascinated organic and medicinal chemists for a long period of
time. Cyclic sulfonamides (sultams),1 although not found in
nature, are present in a number of biologically active compounds.
Sulfonamides are generally stable under physiological conditions
and only a few known enzymes are able to hydrolyze SO2-N
bond.2 Therefore, substituted sulfonamides are frequently used in
drug discovery projects as common starting or target materials.
Among them is S-2474, a cytokine suppressive dual inhibitor of
cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO).3 As
well, 3a,4,5,6-tetrahydro-pyrrolo[1,2-b]-isothiazole-1,1-diones
have been found to constitute a therapeutic approach to
inflammation and autoimmune diseases. They were patented4 by
Novartis Pharma GmbH in 2007 as components for treating
disorders which are mediated by interaction of LFA-1 with its
ligands involved in cell adhesion, migration and activation
(Figure 1).
O
OMe
Cl
Cl
O
O
N
N
S
S
O
S
O
O
O
O
N
O
Et
remedies for inflammation
and autoimmune diseases (ref. 4)
S-2474 (ref. 3)
Me
O
O
S
N R1
O
O
TBDMSO
H2N
N
N
O
N
OTBDMS
R2
N
O
N
Bn
S
O
OH
O
ATSAO-T derivatives (ref. 6)
anti-HIV-1 agent (ref. 5)
R1 = H, CH3, Boc
R2 = H, CH3
Figure 1. Synthetic biologically active sultams.
———
Corresponding author. Tel.: +3 8 097 339 3932; e-mail: alexey.pierrot@gmail.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
O
O
At the same time, naphthyridine bearing
a
sultam
substitution at the 3rd position of the central phenyl ring exhibits
an excellent potency and a good pharmacokinetic profile as an
HIV-1 integrase inhibitor.5 Four families of ATSAO-T
derivatives were also studied in the same manner and were found
to be HIV-1(IIIB)-specific and potent reverse transcriptase
inhibitors6 (Figure 1).
O
O
Me
Me
S
S
N
N
O
O
Me
Me
1
2
Figure 4. 1λ6-Isothiazolidine-1,1,4-triones chosen for the chemical
properties evaluation.
In medicinal chemistry and biochemistry, the sulfonamide
group is known as a bioisosteric equivalent of the carboxamide
group. Their similarity is based on the consideration of electronic
and conformational aspects and it serves as a powerful tool in
drug discovery. The most classic example is the family of
sulfonamide antibiotics. At this point, β-keto-γ-sultams are the
closest sulfur-containing bioisosters of tetramic acid (Figure 2).
The strained spirocarbocyclic substituent at the 3rd position of
the isothiazolidine-1,1,4-trione scaffold might influence the
activity of the reaction centers. Due to this reason, the difference
in the reactivity of the non-spiranic and strained spiranic
substrates towards nucleophiles and electrophiles was expected.
2. Results and discussion
O
O
In conjunction with our interest in developing efficient
syntheses of functionalized sultams14 we have already described
the preparation of 4-methyl-5λ6-thia-4-azaspiro[2.4]heptane-
5,5,7-trione (2).14a Albeit an approach to the construction of
2,3,3-trimethyl-1λ6-isothiazolidine-1,1,4-trione (1) had been
published,13a,b we envisioned an improved synthetic route
wherein isobutyric amino acid 3 was found as an appropriate
starting material.
O
S
O
N
N
O
H
H
β-keto-γ-sultam
tetramic acid
Figure 2. Tetramic acid and its sulfur-containing isoster.
Naturally occurring tetramic acids constitute a vast array of
bioactive
secondary
metabolites
among
which
are
Thus, amino isobutyric acid 3 was esterified with methanol
following the methods described in the literature.15 Subsequently,
sulfonylation of the amino acid ester 4 with MsCl in CH2Cl2 in
the presence of Et3N as a base resulted in the corresponding
methyl 1-methylsulfonamido carboxylate 5 in 84% yield. It was
found to be advantageous to allow the reaction mixture standing
at r.t. at least overnight to ensure the completion of the
sulfonylation process. Subsequent alkylation of 5 with MeI in
DMF afforded methylated sulfonamido carboxylate 6 in a nearly
quantitative yield and this was followed by treatment with tert-
BuOK in DMF to produce the target 2,3,3-trimethyl-1λ6-
isothiazolidine-1,1,4-trione (1) via sulfa-Dieckmann cyclization
in 85% yield (Scheme 1).
erythroskyrine7 and PF 1052.8 In general, tetramic acid-
containing natural products display a wide range of biological
activities, including antibiotic,9 antiviral, cytotoxicity, and
cytostatic activities.10 A great deal of attention to synthetically
occurring tetramic acids was focused by Bayer CropScience.
Eventually, they patented a series of ingredients for fungicidal
and herbicidal use11 and in 2007 released
a pesticide
spirotetramat (brand name Movento®)12 which is active against
piercing-sucking insects (Figure 3).
O
HO
Me
Me
H
O
N
O
H
HO
5
H
O
Me
H
HO
O
O
Me
H
MeSO2Cl, Et3N
O
MeOH, HCl
0°C to reflux, 4 h
Me CO2Me
N
Me CO2H
i-Pr
CH2Cl2
Me
Me
Me
erythroskyrine (ref. 7)
Me
0°C to r.t.
overnight
84% yield
Me
NH2
HCl
Me
ref. 15
s-Bu
NH
2 HCl
3
4
PF1052 (ref. 8)
Me
CO2Me
Me
Me
Me
HN
S
Me
O
O
5
O
O
Et
O
O
O
O
Me
EtO
Mel, K2CO3
DMF
r.t., 48 h
98% yield
tert-BuS
Me CO2Me
R1
N
R3
tert-BuOK, DMF
r.t., overnight
85% yield
Me
Me
O
S
Me
R2
O
Me
N
N
S
N
MeO
O
O
H
R1, R2, R3 = H, Alk
Me
Me
O
spirotetramat
(Movento®, ref. 12)
patented fungicides and herbicides
(ref. 11)
1
6
Scheme 1. An improved synthesis of 2,3,3-trimethyl-1λ6-
isothiazolidine-1,1,4-trione (1).
Figure 3. Naturally occurring and synthetic tetramic acid
derivatives.
As it will be shown below, the mother solutions remained
after recrystallization of crude 1 as well as 2 were effectively
used on the principle of non-waste production. Thus, they were
processed with an excess of DMFDMA (dimethylformamide
Although isothiazolidine-1,1,4-triones have been known since
197613a,b they are not studied sufficiently and the reported
transformations are mostly limited to condensation reactions.13a,c
At the same time, the methylene and the carbonyl groups provide
an opportunity for further modification giving access to
intermediates that are of high value for pharmaceutical-directed
organic synthesis. To this purpose, we aimed to investigate the
reactivity of both centers and chose 2,3,3-trimethyl-1λ6-
dimethyl
acetal)
to
give
the
corresponding
dimethylaminomethylene derivatives (refer to Scheme 8,
products 38,39).
We began our study of the chemical properties of ketosultams
1 and 2 with the examination of the carbonyl group reactivity.
First, the possibility of the ketonic C=O bond reduction was
explored.
isothiazolidine-1,1,4-trione
(1)
and
4-methyl-5λ6-thia-4-
azaspiro[2.4]heptane-5,5,7-trione (2) as model compounds for the
chemical properties evaluation (Figure 4).

O
HO
R1
R2
of
ketosulfonamides 1,2 with KCN and
ACCEPTED MANtUheSCreRactIiPonTof
0°C to r.t., overnight
91% yield
MsCl, CH2Cl2,
R1
R2
NaBH4, MeOH
pyridine
(NH4)2CO3 in aqueous methanol. Thus, instead of hydantoins
19,20 formation according to the Bucherer–Bergs method we
observed the retro-Claisen reaction and CO-CH2 bond splitting
that gave the corresponding acids 21 and 22 (Scheme 4).
O
O
S
S
0°C to r.t., overnight
88% yield of 7
85% yield of 8
N
N
O
O
Me
Me
1,2
7,8
O
O
Me
O
S
NH2OH·HCl, pyridine,
THF, reflux, 3 h,
MsCl, pyridine
1) 0°C to r.t., overnight;
2) 75°C, 1 h
HON
N
pyrrolidine, benzene
reflux, 6 h
Me
Me
O
S
83% yield of 15
N
R1
R2
O
R1
R2
O
O
84% yield
S
S
64% yield of 12
69% yield of 13
NH2OH·HCl, Et3N,
MeOH,reflux, 3 h,
90% yield of 16
Me
N
N
O
O
9
Me
Me
12,13
O
H2 (0.1 MPa), Pd/C
MeOH, 20°C, 48 h
15,16
tert-BuOK, THF
0°C to r.t., overnight
99% yield
Me
Me
10
Me
Me
11
O
O
R1
R2
S
S
O
95% yield
S
N
Me
N
O
O
N
O
Me
Me
NHR3
1,2
PhHN
N
1, 7 R1 = R2 = Me; 2, 8 R1 + R2 = (CH2)2
H2N-NHR3, dioxane,
reflux, 3 h
PhNH2, benzene,
reflux, 3 h
Scheme 2. The reduction of ketosultams 1,2 and subsequent
transformations of the alcohol 7.
Me
Me
Me
Me
O
O
S
S
N
N
O
O
71% yield
74% yield of 17
79% yield of 18
Me
Me
14
17,18
Thus, the interaction of ketosultams 1,2 with NaBH4 in MeOH
led to the corresponding alcohols 7,8 in 88 and 85% yields,
respectively (Scheme 2).
1,12,15 R1 = R2 = Me; 2,13,16 R1 + R2 = (CH2)2; 17 R3 = Ph; 18 R3 = Boc
Scheme 3. The reactions of 1 and 2 with N-nucleophiles.
The carbinol 7, when reacted with MsCl, provided mesylate 9
which in turn was subjected to the action of tert-BuOK in THF.
The elimination of a mesylate-anion proceeded smoothly and the
corresponding alkene 10 was isolated in a nearly quantitative
yield. It is important to note that alkene 10 can be prepared
directly from the alcohol 7 by carrying out a mesylation reaction
in a pyridine media followed by heating of the reaction mixture
up to 75°C. Hydrogenation of alkene 10 catalyzed by palladium
on charcoal in a methanol media gave the saturated 1,3-
propanesultam 11 in 95% yield (Scheme 2).
Quite unforeseen results were obtained during the course of
the reaction of ketosultams 1,2 with a Wittig reagent the
triphenylcarbethoxymethylenephosphorane
(Ph3P=CHCO2Et).
The reaction took place under mild conditions in refluxing
toluene media using benzoic acid as a catalyst. We expected the
oxygen atom of the ketone group to be replaced with =CHCO2Et
moiety. However, the major product in the case of nonspiranic
ketosultam
1
was
2,3,3-trimethyl-1,1-dioxo-5-[2-
(triphenylphosphonio)acetyl]-2,3-dihydro-1H-1λ6-isothiazol-4-
olate (isolated as solvate 23•PhMe in 61% yield). Noteworthy
fact, the ‘acylation’ with Ph3P=CHCO2Alk16 is unprecedented
and had been hitherto unknown. The structure of this unusual
compound was mainly established by X-ray structure
determination of a single crystal (solvate 23•DMF) obtained by
slow evaporation of the solution of 23•PhMe in DMF upon
standing (Figure 5). According to XRD data, the thiazolidine
cycle adopts an envelope conformation. The deviation of the N1
atom from the mean plane of the remaining atoms of this cycle is
-0.43 Å. The N1 atom has the pyramidal configuration (the sum
of the valence angles centered at the N1 atom is 349°). The
methyl group at the atom N1 is located in an equatorial position
to the plane of the thiazolidine cycle (the C2-C1-N1-C4 torsion
angle is -170.7(4)°). The carbonyl group and the C8 atom of the
substituent at the C3 atom are coplanar to the C2-C3 endocyclic
bond (the C2-C3-C7-C8 torsion angle is 8.7(7)°). It is stabilized
additionally by the C8-H…O1 intramolecular hydrogen bond
(H…O 2.21 Ǻ, C-H…O 138º). The triphenylphosphonio
fragment is located in +sc-position relatively the carbonyl group
(the O4-C7-C8-P1 torsion angle is 57.8(5)°).
Unfortunately, the mesylation of carbinol 8 was not successful
and did not allow obtaining any identifiable product.
Then we investigated classical reactions with N-nucleophiles.
After refluxing the benzene solutions of 1,2 with excess
pyrrolidine with a Dean-Stark attachment it was isolated the
corresponding enamines 12,13 with
a pyrrolidinyl-bearing
substituent at the 4th position. The related enamine with an
aromatic substituent at the amino group was obtained only from
ketosultam 1. The spiranic derivative 2 did not react with aniline
(Scheme 3).
Refluxing the ketosultam 1 with H2NOH•HCl and pyridine in
THF led to ketoxime 15 in 83% yield. However, in the case of
spiranic sultam 2, the best result was obtained with Et3N under
reflux in a methanol media and the corresponding ketoxime 16
was isolated in 90% yield (Scheme 3). It is of note here that
attempts at the reduction of oximes 15 and 16 into the
corresponding amines were unsuccessful (LiAlH4 and
NaBH4+Et2O•BF3 were explored).
Another interesting feature was the reactivity towards
hydrazines. The interactions of ketosultam 1 with substituted
hydrazines (namely, PhNHNH2 and BocNHNH2) resulted in the
direct formation of the corresponding hydrazones 17 and 18 in
moderate (74 and 79%) yields. Whereas an analogous treatment
with NH2NH2•H2O as well as reactions of 2 with all the
mentioned hydrazines failed to give the desired hydrazones,
instead, the mixtures of unidentifiable by-products were isolated.
The minor product (22% yield) was a nearly equimolar
mixture of tautomeric sultamo esters with an exocyclic (24) and
an endocyclic (25) double C=C bonds with some predominance
of the latter (Scheme 4). At the same time, the treatment of 2
with this Wittig reagent at equal conditions resulted in the
expected 2-([E]-4-methyl-5,5-dioxo-5λ6-thia-4-azaspiro[2.4]hept-
7-ylidene)acetate 26 as a sole isomer in 57% yield. The
corresponding betaine derivative 27 was also formed, but only in
trace amounts and it was identified according to LCMS and
HRMS data.
After, we explored the reactions with C-nucleophiles. To a
certain extent, predictable result was obtained during the course

4
Tetrahedron
Ph
Ph
ACCEPTED MANUSCRIPT
H
O
P
CO2Et
CO2Et
N
Ph
(NH4)2CO3,, KCN
aq. MeOH
Ph3P=CHCO2Et
O
O
S
O
PhCO2H, toluene
HN
R1
R2
reflux, 6 h
reflux, 6 h
Me
Me
Me
S
Me
O
+
+
O
O
O
S
N
S
N
N
O
N
O
O
O
O
Me
Me
Bucherer-Bergs
reaction conditions
Wittig reaction
conditions
Me
19,20
Me
23
Me
Me
R1
R2
O
S
24 (1 eq.)
25 (1.22 eq.)
N
O
61% yield
10% yield
12% yield
(NH4)2CO3,, KCN
aq. MeOH
Me
R1
R2
Me
CO2H
1,2
Ph
reflux, 6 h
Ph
Me
O
CO2Et
P
N
S
2) aq. HCl
89% yield of 21
82% yield of 22
Ph
O
O
O
Ph3P=CHCO2Et, PhCO2H
toluene, reflux, 6 h
21,22
O
O
S
+
S
N
N
O
O
Me
26
Me
1,19,21 R1 = R2 = Me
2,20,22 R1 + R2 = (CH2)2
27
57% yield
traces
Scheme 4. The reactions of 1 and 2 with C-nucleophiles.
Ph
Ph
Ph
CO2Et
O
P
Ph
Ph
Ph
CO2Et
Ph
Ph
Ph
O
H
CO2Et
O
P
P
O
R1
R2
C
H
H
Ph
P
pathway A
CO2Et
CH
R1
R2
O
O
R1
R2
R1
R2
R1
R2
O
O
Me
23,27
O
S
+
+
Ph
S
N
S
O
S
O
- Ph3PO
N
S
O
N
Ph
O
N
N
Me
O
O
Me
triphenylcarbethoxy-
methylenephosphorane
Me
Me
1,2
24,26
i
ii
pathway B
EtO
Ph
Ph
Ph Ph
Ph Ph
Ph P
O
OEt
Ph
Ph
O
Ph
Ph
P
Ph
P
H
1,23,24 R1 = R2 = Me
2,26,27 R1 + R2 = (CH2)2
P
C
H
O
O
CO2Et
O
O
OH
H
O
R1
R2
R1
R2
R1
R2
O
O
O
-EtOH
R1
R2
S
S
S
S
N
N
N
N
O
O
O
O
Me
Me
Me
Me
vi
iii
iv
v
Scheme 5. A mechanism proposed for the formation of products 24,26 and betaines 25,27.
C–C bond of the oxaphosphetane ring splits, that is accompanied
by a proton migration from the 5th position of the isothiazole
cycle to an oxygen atom of the carbonyl moiety. Further
tautomeric rearrangement of ethylenylphosphorane iv results in
the formation of the intermediate v that cyclizes turning into
oxaphosphinino[6,5-d]isothiazole vi. The latter, due to steric
hindrances, splits the P–O bond to form the betaines 23,27.
In order to confirm the configuration of the ethyl acrylate
fragment in product 26, a single crystal of the product 26 was
obtained by slow evaporation of a dilute solution in cyclohexane.
The X-ray crystal structure determination decisively confirmed
the proposed structure. Figure 6 shows the molecular structure
together with the atomic numbering scheme of 26. According to
XRD data, the thiazolidine cycle adopts an envelope
conformation. The deviation of the N1 atom from the mean plane
of the remaining atoms of this cycle is -0.59 Å. The N1 atom has
the pyramidal configuration (the sum of valence angles centered
at the N1 atom is 332°). The methyl group at the atom N1 is
located in an axial position to the plane of the thiazolidine cycle
(the C6-C3-N1-C2 torsion angle is 88.6(3)°). The C7-C8-(O3)-
O4-C9 fragment of the ethyl acrylate substituent is coplanar to
the C1-C6 endocyclic bond (the C1-C6-C7-C8 torsion angle is
5.9(4)°). The methyl group at the atom C9 is orthogonal to the
plane of the planar fragment of this substituent (the C10-C9-O4-
C8 torsion angle is 85.9(3)°).
Figure 5. The molecular structure of compound 23 according to the
results of an X-ray diffraction study. Thermal ellipsoids are shown at
50% probability level.
We propose, that the reaction proceeds via the nucleophilic
addition of the zwitterionic phosphine ylide to the carbonyl
moiety of ketosultam 1,2 to give the oxaphosphetane
intermediate i. In the classical course of the reaction (pathway A,
Scheme 5) the intermediate conversion leads to products 24,26
that is accompanied by triphenylphosphine oxide release.
However, the isomeric product 25 is more energetically favorable
tautomer. It is formed upon heating and exists in thermodynamic
equilibrium with 24. Alternatively (pathway B, Scheme 5), the
The similarity in structures of compounds 24 and 26 permits
the supposition that the former has the same configuration of the
double C=C bond.

At the same time, both ketosulfonamides 1 and 2 successfully
ACCEPTED MANUSCRIPT
underwent an azo coupling reaction with p-tolyl diazonium
acetate and the corresponding azo compounds 29,30 were
obtained in satisfactory (64 and 58%) yields (Scheme 6).
Three tautomers of azo compounds 29,30 are possible, two of
which (B and C) feature the intramolecular hydrogen bond that
contributes to the conformational stability (Scheme 7). Howbeit,
both types of bondings (
NH···O and OH···N) are strong17 it
should be considered the persistent tendency of azo compounds
to tautomerize to hydrazones even when no through-conjugated
structures can result.18
p-Tol
p-Tol
p-Tol
Figure 6. The molecular structure of compound 26 according to the
results of an X-ray diffraction study. Thermal ellipsoids are shown at
50% probability level.
H
O
N
N
H N
O
O
N
N
N
R1
R2
R1
R2
R1
R2
O
O
O
O
S
S
S
N
N
N
O
O
Finally, apart from the synthetic utility of the C=O group we
should also mention the limitations associated with the carbonyl
group activity. Thus, we did not find appropriate conditions for
protecting group attachment: methanol, ethylene glycol,
propanedithiol et al. in acidic conditions were tried but were not
set. Then, attempts to employ Corey-Chaykovsky reagent
(Me3SO+ I-) for epoxidation of ketosultams 1 and 2 also failed,
we obtained a complex mixture of ring-opening and other side
products. The same situation was observed when 1 and 2 were
involved in the Knoevenagel reaction: the condensation products
with malononitrile, malonic acid as well as malonates were not
detected. Besides, under the Grignard reaction conditions we did
not obtain the corresponding tertiary carbinols; instead, the
starting ketosultams were recovered that occurred due to
enolization, induced by EWG-group (SO2).
To further explore the synthetic utility of 1λ6-isothiazolidine-
1,1,4-triones 1,2 we next focused on reactions of the SO2 and
CO-activated methylene group to obtain the derivatives which
would bear different substituents at the 5th position of the
heterocyclic core. So, the following step in this direction was the
study of interaction with electrophilic agents.
Me
Me
Me
A
B
C
29 R1 = R2 = Me; 30 R1 + R2 = (CH2)2
Scheme 7. The azo-tautomers of 29 and 30.
The structure of 29 was established on the basis of its spectral
data. The H NMR spectrum displayed a broad singlet at δH
1
=
13.36 ppm, typical for intramolecular hydrogen bond, and the
lack of downfield singlet, assignable to a 5-CH proton, that is
contrary to structure A. Moreover, the 13C NMR spectrum
showed two downfield signals at δC = 188.5 and 139.4 ppm
assigned to the ketone fragment and the imine moiety,
respectively. These data are therefore consistent with structure C
(Scheme 7). For the spiro derivative 30, the same pattern was
observed and the analogical structure was proposed.
Next, we turned our attention to reactions of β-keto-γ-sultams
1,2 with C-electrophiles. Among them acylating and alkylating
agents, as well as reactants for condensation reactions, were
chosen.
The behavior of the keto sultam system towards acylating
agents was investigated in order to generate β-diketone
derivatives, the widely applicable substances. However, the
direct acylation with benzoyl chloride in benzene/pyridine media
did not prove to be a regiosective method. For this reason, we
examined the acylation with benzoic acid in the presence of a
coupling agent EDC (1-ethyl-3-(3-dimethylaminopropyl)-
We first investigated classical reactions with N-electrophiles.
When β-keto-γ-sultams 1,2 reacted with a nitrosation agent
(sodium nitrite solution in aq. acetic acid) at 0-5°C only the non-
spiranic ketoxime 28 was isolated in a moderate (53%) yield
(Scheme 6). The suitable conditions for nitrosation of spiranic
ketosultam 2 were not found. Variation of temperature, amount
of the electrophile and isolation procedures, even so, resulted in
the unidentified mixtures only.
carbodiimide
hydrochloride)
and
DMAP
(4-
dimethylaminopyridine) as a base. Indeed, after 96 h standing at
20°C and a standard work-up procedure the desired products 31
and 32 were obtained, but in low (38 and 44%) yields (Scheme
8). Interestingly, the spiranic derivative 32 was isolated as a
mixture of enol and ketone tautomers in 3:1 ratio.
1λ6-Isothiazolidine-1,1,4-triones 1,2 also readily react with
phenyl isocyanate and phenyl isothiocyanate according to a
known method.19 As a result, the corresponding amides 33,34 and
thioamides 35,36 were obtained (Scheme 8).
NOH
O
O
Me
Me
NaNO2, aq. HOAc
S
1) 0-5°C during mixing
2) r.t., overnight
53% yield
N
O
Me
O
28
R1
R2
O
S
Me
N
Me
O
AcO
Me
1,2
N N
aq. HOAc
The condensation of sultam 1 with benzaldehyde in the
presence of NaOAc in HOAc has been reported.13a Again, we
decided to use an alternative method and base-mediated
conditions that gave the corresponding conjugated ketone 37 in a
better (84%) yield (Scheme 8). At once, the similar reaction
between spiranic ketosultam 2 and benzaldehyde was not fruitful.
The condensation under both acidic (NaOAc+HOAc) and basic
(pyridine) conditions gave at the best scenario the partial
recovery of the starting material and at the worst the total
decomposition of ketosultam 2.
HN
1) 0-5°C during mixing
2) 5°C to r.t., 4 h
3) 45°C, 2 h
64% yield of 29
58% yield of 30
O
N
R1
R2
S O
O
N
Me
29,30
1,29 R1 = R2 = Me; 2,30 R1 + R2 = (CH2)2
Scheme 6. The reactions of 1 and 2 with N- electrophiles.

6
Tetrahedron
Dimethylaminomethylene derivative 37 was obtained in a
Another example of striking differences in the chemical
ACCEPTED MANUSCRIPT
similar manner to the previously described synthesis of spiranic
product 38 (Scheme 8).14a It is worthwhile to note that a tangible
amount of products 38,39 can be obtained from the combined
filtrates and wash solutions remained after purification of
ketosultams 1,2. Thus, treatment of such a mixture with the
abundance of DMFDMA gave another crop of pure crystalline
material.
behavior of 1 and 2 was found upon the Vilsmeier reaction
conditions. Thus, the chloroformylation of 1 with the Vilsmeier
reagent
(DMF/POCl3)
successfully
afforded
β-
chlorovinylaldehyde 40 in 67% yield according to the method
described by Li Tian.20 At the same time, when this procedure
was applied to 2 a quite dissatisfactory result was obtained:
complete decomposition of the starting material occurred
(Scheme 8).
A single crystal of the product 39 was obtained by slow
evaporation of the mother solution in methanol upon standing. X-
ray crystal structure determination decisively confirmed the
structure of 39 (Figure 7). According to XRD data, the
thiazolidine cycle adopts an envelope conformation. The
deviation of the N1 atom from the mean plane of the remaining
cyclic atoms is -0.29 Å. The configuration of the N1 atom is
slightly pyramidal (the sum of the valence angles centered at the
N1 atom is 345°). The methyl group at the atom N1 has an
equatorial orientation relatively to the plane of the thiazolidine
cycle (the C1-N1-S1-C4 torsion angle is -162.1(1)°). The
dimethylaminomethylene fragment lies in the plane of the planar
part of the thiazolidine cycle (the torsion angle C3-C4-C6-N2 is
180.0(1)°).
However, bearing in mind that β-chlorovinylaldehydes are
related to β-ketoenols and could be frequently replaced with each
other, we turned our attention to condensation of 1 and 2 with
triethyl orthoformate. In this way, the spiranic derivative 41 was
synthesized in
a straightforward manner in 78% yield.
Interestingly, when this methodology was tried out on 1, after
workup procedure starting materials were recovered.
Compounds 40 and 41 are expected to be useful intermediates,
as on interaction with diverse amidines they may supply a range
of fused heterocyclic systems. The successful application of this
strategy will be described later.
Finally, we subjected 1 and 2 to the action of an alkylating
agent. Despite the β-keto-γ-sultam ring has two reaction centers
at C-5 and 4-keto, respectively, the reactions of 1,2 with an
excess of MeI in the presence of K2CO3 in DMF media afforded
exclusively the C-5 dimethylated derivatives 42,43 in moderate
(68 and 56%) yields (Scheme 8). The monoalkylated products
were not readily available using equimolar amounts of the
reagents.
The dimethylaminomethylene derivatives 38 and 39 are
particularly well functionalized since they contain a ketone
moiety and
a
dimethylaminomethylene group which is
considered as a hidden carbonyl group. The scope of a literature
review demonstrates the importance of these functional groups in
the synthesis of fused heterocycles.21 From this point of view
compounds 38 and 39 looked to be promising reagents.
Therefore, interaction with C-, N-, and O-nucleophiles was next
addressed in our substrates.
Figure 7. The molecular structure of compound 39 according to the
results of an X-ray diffraction study. Thermal ellipsoids are shown at
50% probability level.
O
X
Ph
HO
R1
R2
NHPh
HO
R1
PhCO2H, EDC, DMAP, DMF, r.t., 96 h
PhNCX, DBU, DMF, r.t., overnight
O
O
S
S
67% yield of 33
77% yield of 34
38% yield of 31
44% yield of 32
70% yield of 35
82% yield of 36
N
N
R2
O
O
Me
Me
31,32
33-36
O
Ph
NMe2
O
O
R1
O
PhCHO, pyridine
DMFDMA, MeOH
r.t. to reflux, 1 h
Me
O
R1
R2
O
r.t. to reflux, 2 h
S
S
S
N
N
R2
O
N
90% yield of 38
85% yield of 39
84% yield
Me
O
O
Me
Me
Me
1,2
37
38,39
MeI, K2CO3
DMF, r.t., 48 h
68% yield of 42
56% yield of 43
Cl
OEt
.
O
O
DMF, POCl3, CH2Cl2
0°C to r.t., 30 h
67% yield
(EtO)3CH, Ac2O
reflux, 2 h, 78% yield
Me
Me
O
O
S
S
N
N
O
O
Me
O
Me
40
in case
of 2
in case
Me
Me
O
R1
R2
of 1
41
S
N
O
no reaction and
starting materials
recovering
blackening and
decomposition
of starting sultam
Me
42,43
1,31,38,42 R1 = R2 = Me
2,32,39,43 R1 + R2 = (CH2)2
34 R1 + R2 = (CH2)2, X = O
36 R1 + R2 = (CH2)2, X = S
33 R1 = R2 = Me, X = O
35 R1 = R2 = Me, X = S
Scheme 8. The reactions of 1 and 2 with C-electrophiles.

O
NMe2
O
O
NHPh
O
O
ACCEPTED MANUSCRIPT
aq. 1N NaOH
40°C, 2 h
PhNH2, dioxane, reflux, 8 h
R1
R2
R1
R2
R1
R2
R1
R2
aq. 1N NaOH
- HCO2Na
69% yield of 1
61% yield of 2
O
O
O
O
S
S
S
S
87% yield of 46
88% yield of 47
N
N
N
N
O
O
O
O
Me
Me
Me
Me
1,2
44,45
38,39
46,47
CO2Et
O
NC
CO2Et
CN
R1
R2
EtOH, reflux, 12 h
62% yield of 48
54% yield of 49
O
S
O
Me
N
Me
H2N
Me
1,38,44,46,48 R1 = R2 = Me; 2,39,45,47,49 R1 + R2 = (CH2)2
48,49
Scheme 9. The reactions of 38 and 39 with C-, N-, and O-nucleophiles.
The interaction of compounds 38,39 with 1N aq. NaOH
resulted in the formation of ketosultams 1,2 instead of the desired
aldehydes 44,45. A possible mechanism of this reaction and the
general method were described previously22 (Scheme 9).
bond (1.326 Å) and shorter than the mean value of the Csp2–Csp2
bond (1.455 Å)).
Having established the synthesis of 38,39 we turned our
attention to the preparation of other aminomethylene derivatives
by means of transamination reaction. Thus, the interaction with
aniline gave the corresponding products 46,47 in good (87 and
88%) yields (Scheme 9). Theoretically, these compounds can
exist as s-cis- and s-trans-conformers, thereby we observed a
duplicate set of signals which can be explained by a high energy
barrier of rotation of the conjugated =CH–NR1R2 bond. On the
basis of the 1H NMR spectra, we deduced that the s-trans-
conformer is characterized by a J-coupling constant with a
greater frequency value (approx. J = 15 Hz). The further
evaluation of the integral intensities of the signals allowed
proposing the predominance of the s-cis-conformers in the
mixtures. The conformer ratio s-cis/s-trans in both cases were
2.6:1.
To our disappointment, all the attempts to involve the
dimethylamino and ketonic groups of compounds 38,39 in
interaction with hydrazines in order to obtain the corresponding
fused heterocyclic systems failed. Instead, we obtained a set of
contradicting and irreproducible results (atypical transamination,
rearrangement, and condensation) that are a subject of further
Figure 8. The molecular structure of compound 48 according to the
results of an X-ray diffraction study. Thermal ellipsoids are shown at
50% probability level.
In contrast to structures 26 and 39, the heterocycle in the
carbanion is flat. The sum of the valence angles centered at the
N1 atom is 359°). The ethyl cyanoacrylate fragment lies in the
plane of the thiazolidine cycle (the torsion angle S1-C3-C7-C8 is
-3.0(3)°).
investigations.
A
suchlike result was obtained when
hydroxylamine and amidines were explored. At mild conditions
(Et3N/i-PrOH, reflux) the starting materials were recovered
whereas more stringent conditions (EtONa/EtOH, reflux)
resulted in a complex mixture of side products. The only
alternative interpretation of the observed data evident to the
authors was that, perhaps, the lability of the single C–C bond
between the ketonic moiety and the dimethylaminomethylene
group. The interaction was assumed to proceed via the initial
retro-Claisen reaction followed by other adverse reactions.
3. Conclusion
As a part of a program launched into the development of novel
methods for the preparation of synthetically occurring tetramic
acid isosters, we introduced the behavior and comparative
assessment of chemical properties of spatially uncomplicated
2,3,3-trimethyl-1λ6-isothiazolidine-1,1,4-trione
(1)
and
Continuing with the theme of the replacement of the easily
leaving dimethylamino group we envisaged a similar approach
for C-nucleophiles. This was implemented by carrying out the
reaction of 38,39 with ethyl cyanoacetate. Consequently, the
corresponding substitution products 48,49 were isolated as the
anions with dimethylammonium counterion in satisfactory (62
and 54%) yields. X-ray crystal structure determination allowed
us to confirm the structure of the product 48 (Figure 8).
According to the XRD data, the organic salt 48 exists in the
crystal phase as monohydrate. The protonation of the
dimethylammonium is confirmed by the localization of two
hydrogen atoms from electron density difference maps. The
distribution of the electron density in the carboanion allows to
presume the localization of the negative charge within the C3-
C7-C8 fragment (the C3-C7 and C7-C8 bonds (1.394(3) Å and
1.366(3) Ǻ) are longer than the mean value of the Csp2=Csp2
geometrically tensed 4-methyl-5λ6-thia-4-azaspiro[2.4]heptane-
5,5,7-trione (2) which is interesting in terms of strain cycle
effects.
An exploration of the EWG-activated methylene group and
the carbonyl function of the β-keto-γ-sultam system, on the one
hand, disclosed their potential synthetic utility providing access
to a range of derivatives, and on the other hand, revealed the
influence of the sterical tension on the chemical activity. Though
the range of investigated compounds is limited, the data
presented suggest that the size of the substituent ring and the
geometry of the resulting sultam framework have an impact on
its chemical properties. In this way, the reactivity of the carbonyl
group in 4-methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione
towards N-nucleophiles is suppressed whereas the activity of the

8
Tetrahedron
ACCEPTED MANUSCRIPT
EWG-activated methylene group towards electrophiles is
at 1176 V. LC-HRMS analysis was performed with an LTQ
enhanced being compared with ones in 2,3,3-trimethyl-1λ6-
isothiazolidine-1,1,4-trione all arising from the steric and
conformational effects caused by
substituent. Additionally, it should be noted that the geometric
tension and rigidity of this structure cause less stability which is
the reason for adverse reactions.
Orbitrap MS system, consisting of a Surveyor autosampler model
Plus, a Surveyor quaternary gradient LC-pump, and LTQ-
Orbitrap mass-spectrometer (Thermo Electron GmbH, Bremen,
Germany). Separation was achieved using a C18 column (50×4.6
mm; Polaris Varian) in isocratic mode at a constant flow rate of
0.35 mL/min (70/30 methanol:water). Analyzes were carried out
in positive mode with ESI, using an ion spray voltage of 4000 V
and the capillary temperature 350 °C. Accurate masses (50 to 650
Da) were obtained at high resolution (60,000 FWHM), AGC=1.6
and processed using Xcalibur v.2.0. software. Elemental analysis
was performed on a CHNOS elementary Vario MICRO Cube
analyzer. All melting points were determined in open capillary
tubes in a Thiele apparatus and are uncorrected.
a strained spirocyclic
Toward the end of the present work, we would like to make
the suppositions regarding the chemical behavior of spiranic β-
keto-γ-sultams with unstrained angles and bond lengths. In
general such compounds might react similarly to 2,3,3-trimethyl-
1λ6-isothiazolidine-1,1,4-trione (1), as the spiranic feature of the
system enhances the reactivity towards electrophiles while being
more stable than 2. Analogous conclusions on the activity of non-
spiranic and spiranic substrates were drawn in respect to the β-
amino-γ-sultone scaffold.23 However, each individual case has
some specific peculiarities, caused by the chemical nature of the
substrates and the reagents.
Methyl 2-methyl-2-[(methylsulfonyl)amino]propanoate (5)
Methyl 2-amino-2-methylpropanoate hydrochloride 4 (30.72
g, 0.2 mol) was added to a stirred solution of Et3N (60.72 g,
84.30 mL, 0.6 mol) in CH2Cl2 (950 mL). As soon as the solid
phase was dissolved (approximately 30 min. required) the
mixture was cooled with an ice water bath. Then the solution of
CH3SO2Cl (27.5 g, 18.51 mL, 0.24 mol) in CH2Cl2 (150 mL) was
added dropwise, maintaining the temperature below 5°C. The ice
water bath was allowed to melt, and the mixture was stirred at
room temperature overnight. The excess CH2Cl2 and Et3N were
evaporated at reduced pressure, the residue was diluted with
water (300 mL) and acidified with 2N HCl to pH = 3. The crystal
precipitate formation occurred, the mixture was allowed to stand
for 1 h. and then it was filtered, resulting in 13.45 g of pure
methyl 2-methyl-2-[(methylsulfonyl)amino]propanoate (5). The
mother solution was extracted with EtOAc (6×60 mL). The
combined extracts were dried over Na2SO4 and evaporated at
reduced pressure yielding additionally 19.20 g of spectrally pure
title compound 5. Yield 32.65 g (0.17 mol), 84%; m.p. = 86-87°C
(can be recryst. from cyclohexane/EtOAc 2:1); [Found: C, 36.97;
H, 6.45; N, 7.47; S, 16.14. C6H13NO4S requires C, 36.91; H,
6.71; N, 7.17; S, 16.42%]; nmax (KBr) 3271, 2990, 1747, 1315,
1127, 982, 521 cm−1; dH (400 MHz, DMSO-d6) 1.41 (s, 6H,
2×CH3), 2.90 (s, 3H, SO2CH3), 3.66 (s, 3H, CO2CH3), 7.46 (s,
1H, NH); dC (100 MHz, DMSO-d6) 26.53, 43.88, 52.15, 58.40,
174.46; m/z 194.0 [М-Н]-.
These results pave the way for the more detailed study of β-
keto-γ-sultams and other relative compounds, especially with the
β-keto-sulfone fragment. With the reported syntheses we believe
that sultam and sultone derivatives will find practical application
in drug discovery projects, especially in those where tetramic
acid is involved.
4. Experimental section
X-ray diffraction study of compounds 23, 26, 39, and 48
Intensities of reflections were measured on an automatic
‘Xcalibur 3’ diffractometer (graphite monochromated MoKα
radiation, CCD-detector ω scanning). All structures were solved
by the direct method using the SHELXTL package.24 Positions of
the hydrogen atoms were located from electron density difference
maps and refined by ‘riding’ model with Uiso = nUeq of carrier
non-hydrogen atom (n = 1.5 for methyl groups and water
molecule and n = 1.2 for other hydrogen atoms). Structures were
refined by full-matrix least-squares method against F2 in
anisotropic approximation for non-hydrogen atoms. Final atomic
coordinates, geometrical parameters, and crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44
1223 336033; e-mail: deposit@ccdc.cam.ac.uk). CCDC
deposition numbers for structures 23, 26, 39 and 48 are 1876821,
1838623, 1838624 and 1838625, respectively. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/products/csd/request/.
Methyl 2-methyl-2-[methyl(methylsulfonyl)amino]propanoate (6)
Methyl 2-methyl-2-[(methylsulfonyl)amino]propanoate
5
(20.8 g, 0.11 mol) was dissolved in dry DMF (250 mL). K2CO3
(35.6 g, 0.165 mol) and MeI (23.43 g, 10.28 mL, 0.165 mol)
were added to the stirred solution in consecutive order at ambient
temperature. The flask was equipped with a Dimroth condenser
and sealed with a rubber balloon. A slight exotherm occurred.
The mixture was allowed to equilibrate to room temperature and
left for 48 h. with stirring. The precipitate was filtered and twice
washed with DMF (20 mL). The excess DMF was evaporated at
reduced pressure, the residue was diluted with water (150 mL)
and the crystal precipitate formation occurred. The mixture was
allowed to stand for 1 h. and then it was filtered, resulting in
General
Reactions requiring anhydrous conditions were performed
with the usual precautions for the rigorous exclusion of air and
moisture. N,N-Dimethylformamide was dried by distillation from
phosphorus pentoxide. The other chemicals were purchased from
Aldrich or Fluka and, when necessary, chemicals were purified
according to the reported procedures.25 1H, 13C, and 31P NMR
spectra were obtained on a Varian Mercury 400 spectrometer at
400.45 MHz, 100.61 MHz, 161.97 MHz, respectively, and
Bruker Avance 500 instrument at 500.13 MHz, 125.76 MHz,
202.46 MHz, respectively, using DMSO-d6 or CDCl3 as solvents
and Me4Si (1H, 13C) or H3PO4 (31P) as an internal standards. IR
spectra were recorded on a Perkin Elmer BX II spectrometer in
KBr pellets and are reported in cm-1. LCMS spectra were
recorded on Agilent 1100 Series with an Agilent LC/MSD SL
detector by chemical ionization (CI) and GCMS spectra were
recorded with Agilent 7890 using electron impact ionization
14.88
g
of pure methyl 2-methyl-2-[methyl(methylsul-
fonyl)amino]propanoate (6). The mother solution was extracted
with CH2Cl2 (5×50 mL). The combined extracts were dried over
Na2SO4 and evaporated at reduced pressure yielding the crude
product, which was twice washed with i-PrOH (5 mL), obtaining
additional 7.80 g of spectrally pure title compound 6. Yield 22.68
g (0.108 mol), 98%; m.p. = 84-86°C (can be recryst. from
cyclohexane/EtOAc 3:1); [Found: C, 40.51; H, 7.09; N, 7.02; S,
15.62. C7H15NO4S requires C, 40.18; H, 7.22; N, 6.69; S,

15.32%]; nmax (KBr) 3012, 2957, 1736, 1309, 1137, 960, 534
[Found: C, 41.05; H, 6.25; N, 7.50; S, 18.07. C6H11NO3S requires
C, 40.66; H, 6.26; N, 7.90; S, 18.09%]; nmax (KBr) 3497, 3028,
2942, 1466, 1295, 1131, 789 cm−1; dH (400 MHz, DMSO-d6)
0.69-0.77 (m, 1H, cyclopropyl), 0.83-1.01 (m, 3H, cyclopropyl),
2.58 (s, 3H, NCH3), 3.09 (d, J 12.4 Hz, 1H, CH2), 3.63 (dd, J
14.0, 7.2 Hz, 1H, CH2), 4.19 (m, 1H, CH-OH), 5.56 (br. s, 1H,
OH); dC (100 MHz, DMSO-d6) 4.77, 9.08, 31.35, 48.87, 56.52,
71.64; m/z 178.2 [М+Н]+.
ACCEPTED MANUSCRIPT
cm−1; dH (400 MHz, DMSO-d6) 1.43 (s, 6H, 2×CH3) , 2.79 (s,
3H, NCH3), 2.90 (s, 3H, SO2CH3), 3.66 (s, 3H, CO2CH3); dC (100
MHz, DMSO-d6) 25.36, 30.93, 40.41, 52.53, 63.00, 174.45; m/z
210.2 [М+Н]+.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione (1)
Methyl 2-methyl-2-[methyl(methylsulfonyl)amino]propanoate
6 (20.93 g, 0.10 mol) was dissolved in dry DMF (75 mL) and the
resulting solution was added dropwise to a stirred solution of t-
BuOK (23.56 g, 0.21 mol) in DMF (250 mL). A slight exotherm
occurred. The mixture was allowed to equilibrate to room
temperature and left overnight with stirring. HOAc (33.50 mL)
was added dropwise then the mixture was evaporated to dryness
in vacuo at the temperature not higher than 60°C. The residue
was triturated with water (100 mL) and extracted with CH2Cl2
(6×50 mL). The combined extracts were dried over Na2SO4 and
evaporated in vacuo yielding the light-brown product. The pure
title product, the colorless crystals, was obtained by vacuum
sublimation (at 0.3 mbar and 70°C in an oil bath). Yield 15.06 g
(85.0 mmol), 85%; m.p. = 79-80°C (lit.13a,b m.p. = 76°C, from
EtOH); [Found: C, 41.00; H, 6.05; N, 8.3; S, 17.92. C6H11NO3S
requires C, 40.66; H, 6.26; N, 7.90; S, 18.09%]; nmax (KBr) 3006,
2942, 1758, 1308, 1233, 1108, 960 cm−1; dH (400 MHz, DMSO-
d6) 1.33 (s, 6H, 2×CH3), 2.69 (s, 3H, NCH3), 4.28 (s, 2H, CH2);
dC (125 MHz, CDCl3) 21.08, 22.23, 53.22, 69.48, 200.71; m/z
178.2 [М+Н]+.
2,3,3-Trimethyl-1,1-dioxo-1λ6-isothiazolidin-4-yl
methanesulfonate (9)
4-Hydroxy-2,3,3-trimethyl-1λ6-isothiazolidine-1,1-dione
7
(1.00 g, 5.58 mmol) was added to a stirred solution of pyridine
(0.57 g, 0.59 mL, 7.25 mmol) in CH2Cl2 (50 mL). As soon as the
solid phase was dissolved the mixture was cooled with an ice
water bath. Then the solution of CH3SO2Cl (0.77 g, 0.52 mL,
6.70 mmol) in CH2Cl2 (5 mL) was added dropwise, maintaining
the temperature below 5°C. The ice water bath was allowed to
melt, and the mixture was stirred at room temperature overnight.
The excess CH2Cl2 and pyridine were evaporated at reduced
pressure and temperature below 40°C, the residue was diluted
with water (10 mL) acidified with 2N HCl to pH = 3 and
extracted with CH2Cl2 (6×6 mL). The combined extracts were
dried over Na2SO4 evaporated at reduced pressure at the
temperature below 40°C and the residue was recrystallized from
i-PrOH yielding spectrally pure title compound 9. Yield 1.30 g
(5.05 mmol), 91 %; m.p. = 99-100°C; [Found: C, 32.34; H, 5.70;
N, 5.29; S, 24.88. C7H15NO5S2 requires C, 32.67; H, 5.88; N,
5.44; S, 24.92%]; nmax (KBr) 3023, 2972, 1352, 1301, 1174,
1139, 960, 528 cm−1; dH (400 MHz, DMSO-d6) 1.25 (s, 3H,
CH3), 1.27 (s, 3H, CH3), 2.52 (s, 3H, NCH3), 3.23 (s, 3H,
OSO2CH3), 3.53 (dd, J 14.3, 4.3 Hz, 1H, CH2), 3.87 (dd, J 14.3,
7.0 Hz, 1H, CH2), 5.11 (dt, J 2.4, 4.3 Hz, 1H, CH-OMs); dC (100
MHz, DMSO-d6) 19.95, 22.60, 23.54, 38.43, 51.39, 63.32, 79.17;
m/z 258.0 [М+Н]+.
4-Hydroxy-2,3,3-trimethyl-1λ6-isothiazolidine-1,1-dione (7)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.2 g, 1.13
mmol) was dissolved in 10 mL of MeOH and cooled with an ice
water bath. NaBH4 (0.15 g, 4 mmol) was added portion-wise with
vigorous stirring during 2 h, maintaining the reaction temperature
below 10°C. The mixture was allowed to equilibrate to room
temperature and left overnight without stirring. The solvent was
evaporated in vacuo, the residue was triturated with water (4
mL), acidified to pH 5-6 with 2N HCl and extracted with CH2Cl2
(4×5 mL). The combined extracts were dried over Na2SO4,
filtered and evaporated in vacuo. The residue was sublimated in
vacuo (0.1 Torr and 100-110°C in an oil bath) giving the title
compound 7 as white crystals. Yield 0.18 g (1.0 mmol), 88%;
m.p. = 64-65°C; [Found: C, 40.24; H, 7.57; N, 7.50; S, 18.17.
C6H13NO3S requires C, 40.21; H, 7.31; N, 7.81; S, 17.89%]; nmax
(KBr) 3457, 2981, 2947, 1291, 1130, 962, 569 cm−1; dH (400
MHz, DMSO-d6) 1.08 (s, 3H, CH3), 1.19 (s, 3H, CH3), 2.47 (s,
3H, NCH3), 2.98 (dd, J 13.4, 8.2 Hz, 1H, CH2), 3.47 (dd, J 13.1,
7.6 Hz, 1H, CH2), 4.08 (dt, J 7.6, 5.5 Hz, 1H, CH-OH), 5.71 (d, J
5.2 Hz, 1H, OH); dC (100 MHz, DMSO-d6) 16.96, 23.17, 24.07,
52.09, 63.78, 71.58; m/z 180.1 [М+Н]+.
2,3,3-Trimethyl-2,3-dihydro-1H-1λ6-isothiazole-1,1-dione (10)
Method A. 2,3,3-Trimethyl-1,1-dioxo-1λ6-isothiazolidin-4-yl
methanesulfonate 9 (0.50 g, 1.94 mmol) was added portion-wise
to cold (0°C) solution of tert-BuOK (0.26 g, 2.33 mmol) in dry
THF (10 mL). The resulting clear solution gradually became
cloudy and precipitate formation occurred. The mixture was
allowed to equilibrate to room temperature and left overnight
with stirring. The solvent was evaporated in vacuo, the residue
was triturated with water (7 mL) and extracted with CH2Cl2 (5×7
mL). The combined extracts were dried over Na2SO4, filtered and
evaporated in vacuo affording the pure title compound 10 as
white crystals. Yield 0.31 g (1.92 mmol), 99 %.
Method B. 4-Hydroxy-2,3,3-trimethyl-1λ6-isothiazolidine-1,1-
dione 7 (1.00 g, 5.58 mmol) was dissolved in pyridine (10 mL)
and the resulting solution was cooled with an ice water bath.
Then the solution of CH3SO2Cl (0.77 g, 0.52 mL, 6.70 mmol) in
CH2Cl2 (5 mL) was added dropwise, maintaining the temperature
below 5°C. The ice water bath was allowed to melt, and the
mixture was stirred at room temperature overnight. Then solution
was heated at 75°C with stirring during 1 h. The volatiles were
evaporated at reduced pressure, the residue was triturated with
water (10 mL) and extracted with EtOAc (5×10 mL). The
combined extracts were dried over Na2SO4, filtered and
evaporated in vacuo affording pure title compound 10 as white
crystals. Yield 0.75 g (4.69 mmol), 84%; m.p. = 90-91°C;
[Found: C, 44.55; H, 6.54; N, 8.33; S, 19.65. C6H11NO2S requires
C, 44.70; H, 6.88; N, 8.69; S, 19.89%]; nmax (KBr) 3084, 2981,
1464, 1277, 1127, 762, 566 cm−1; dH (400 MHz, DMSO-d6) 1.27
(s, 6H, 2×CH3), 2.59 (s, 3H, NCH3), 6.91 (d, J 7.0 Hz, 1H, H-5),
7-Hydroxy-4-methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5-dione
(8)
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.2
g, 1.14 mmol) was dissolved in 10 mL of MeOH and cooled with
an ice water bath. NaBH4 (0.15 g, 4 mmol) was added portion-
wise with vigorous stirring during 2 h, maintaining the reaction
temperature below 10°C. The mixture was allowed to equilibrate
to room temperature and left overnight without stirring. The
solvent was evaporated in vacuo, the residue was triturated with
water (7 mL), acidified to pH 5-6 with 2N HCl and extracted
with CH2Cl2 (4×5 mL). The combined extracts were dried over
Na2SO4, filtered and evaporated in vacuo. The residue was heated
in vacuum (50°C in an oil bath and 0.1 Torr) for 30 min to give
the title compound 8 as a light yellow oil that solidified upon
standing. Yield 0.17 g (0.96 mmol), 85%; m.p. = 66-67°C;

10
Tetrahedron
7.02 (d, J 7.0 Hz, 1H, H-4); dC (100 MHz, DMSO-d6) 23.03,
1H, H-4’), 7.22 (d, J 7.9 Hz, 2H, H-2’ and H-6’), 7.33 (t, J 7.6
ACCEPTED MANUSCRIPT
24.00, 63.28, 125.39, 146.25; m/z 162.0 [М+Н]+.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1-dione (11)
Hz, 2H, H-3’ and H-5’), 8.36 (s, 1H, NH); dC (100 MHz, DMSO-
d6) 23.32, 63.52, 89.97, 121.86, 124.18, 129.56, 140.97, 156.12;
m/z 253.2 [М+Н]+.
2,3,3-Trimethyl-2,3-dihydro-1H-1λ6-isothiazole-1,1-dione 10
(0.16 g, 1 mmol), Pd/C (10 wt. % loading, 0.05 g) and MeOH (5
mL) were placed in a dried Schlenk tube. The mixture was septa-
sealed, evacuated to exclude the presence of air and then
hydrogenated at 0.1 MPa for 48 h at r.t. Then the resulting
mixture was filtered through Celite and washed with MeOH (10
mL). Concentration of the filtrate in vacuo afforded pure title
compound 11 as yellowish oil. Yield 0.15 g (0.95 mmol), 95%;
[Found: C, 43.95; H, 7.82; N, 8.62; S, 19.87. C6H13NO2S requires
C, 44.15; H, 8.03; N, 8.58; S, 19.64%]; nmax (KBr) 2974, 1295,
1192, 1129, 919, 796, 503 cm−1; dH (400 MHz, CDCl3) 1.59 (s,
6H, 2×CH3), 2.19 (t, J 7.5 Hz, 2H, SO2CH2CH2), 2.54 (s, 3H,
NCH3), 3.08 (t, J 7.5 Hz, 2H, SO2CH2CH2); dC (100 MHz,
CDCl3) 23.54, 25.69, 34.33, 45.26, 58.23; m/z 164.2 [М+Н]+.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 4-oxime (15)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.2 g, 1.13
mmol) was dissolved in a mixture of THF (3 mL) and pyridine (3
mL) then NH2OHꢀHCl (0.1 g, 1.32 mmol) was added. The
resulting solution was refluxed with stirring for 3 hours. The
volatiles were evaporated in vacuo and the residue was triturated
with water (3 mL). After a while the bottom viscous phase
crystallized. The resulting white crystals were filtered and
washed consequently with minimal amount of aq. 2N HCl and
water affording pure title compound 15. Yield 0.18 g (0.94
mmol), 83%; m.p. = 136-137°C; [Found: C, 37.29; H, 6.62; N,
14.53; S, 16.69. C6H12N2O3S requires C, 37.49; H, 6.29; N,
14.57; S, 16.68%]; nmax (KBr) 3438, 3360, 2980, 1440, 1287,
1121, 962, 865 cm−1; dH (400 MHz, DMSO-d6) 1.44 (s, 6H,
2×CH3), 2.62 (s, 3H, NCH3), 3.99 (s, 2H, CH2), 11.35 (s, 1H,
NOH); dC (100 MHz, DMSO-d6) 22.62, 24.78, 46.73, 62.81,
151.85; m/z 193.2 [М+Н]+.
2,3,3-Trimethyl-4-(1-pyrrolidinyl)-2,3-dihydro-1H-1λ6-
isothiazole-1,1-dione (12)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.20 g,
1.13 mmol) and pyrrolidine (0.40 g, 5.62 mmol) were dissolved
in benzene (7 mL). The mixture was refluxed with Dean-Stark
trap for 6 hours and then it was evaporated to dryness. The
recrystallization of crude product from i-PrOH gave the title
compound 12 as cream-colored crystals. Yield 0.17 g (0.72
mmol), 64%; m.p. = 225-226°C; [Found: C, 52.47; H, 7.63; N,
12.56; S, 13.72. C10H18N2O2S requires C, 52.15; H, 7.88; N,
12.16; S, 13.92%]; nmax (KBr) 3099, 2974, 1579, 1250, 1109,
883, 576 cm−1; dH (400 MHz, CDCl3) 1.46 (s, 6H, 2×CH3), 1.95
(m, 4H, 2×NCH2CH2), 2.65 (s, 3H, NCH3), 3.31 (m, 4H,
2×NCH2CH2), 4.94 (s, 1H, CH); dC (100 MHz, DMSO-d6) 22.26,
22.43, 25.14, 49.66, 62.97, 88.34, 158.03; m/z 231.3 [М+Н]+.
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 7-oxime
(16)
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.2
g, 1.14 mmol) was dissolved in MeOH (10 mL) then
NH2OHꢀHCl (0.1 g, 1.32 mmol) and Et3N (0,5 mL, 3.5 mmol)
were added consequently. The resulting solution was refluxed
with stirring for 3 hours. MeOH was evaporated in vacuo; the
residue was triturated with saturated aqueous NaHCO3 (7 mL)
and extracted into CH2Cl2 (4×5 mL). The combined extracts were
dried over Na2SO4, filtered and evaporated in vacuo. The residue
was heated in vacuum (at 50°C and 0.3 Torr) for 30 min to give
the title compound 16 as colorless crystals. Yield 0.20 g (1.0
mmol), 90%; m.p. = 95-96°C; [Found: C, 37.55; H, 5.04; N,
14.46; S, 17.06. C6H10N2O3S requires C, 37.88; H, 5.30; N,
14.73; S, 16.86%]; nmax (KBr) 3390, 2980, 2929, 1458, 1307,
1129, 951 cm−1; dH (400 MHz, DMSO-d6) 1.19 (m, 2H,
cyclopropyl), 1.30 (m, 2H, cyclopropyl), 2.61 (s, 3H, NCH3),
4.07 (s, 2H, CH2), 11.20 (s, 1H, NOH); dC (100 MHz, DMSO-d6)
13.50, 32.72, 46.40, 47.08, 150.59; m/z 189.2 [М-Н]-.
4-Methyl-7-(1-pyrrolidinyl)-5λ6-thia-4-azaspiro[2.4]hept-6-ene-
5,5-dione (13)
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.10
g, 0.57 mmol) and pyrrolidine (0.20 g, 2.82 mmol) were
dissolved in benzene (5 mL). The mixture was refluxed with
Dean-Stark trap for 6 hours and then it was evaporated to
dryness. The recrystallization of crude product from dioxane-
cyclohexane (3:1) gave the title compound 13 as cream-colored
crystals. Yield 0.09 g (0.39 mmol), 69%; m.p. = 203-205°C;
[Found: C, 52.36; H, 7.00; N, 12.22; S, 14.42. C10H16N2O2S
requires C, 52.61; H, 7.06; N, 12.27; S, 14.04%]; nmax (KBr)
3110, 2974, 1570, 1249, 1103, 833, 594 cm−1; dH (400 MHz,
DMSO-d6) 1.30 (m, 2H, cyclopropyl), 1.48 (m, 2H, cyclopropyl),
1.90 (m, 4H, 2×NCH2CH2), 2.46 (s, 3H, NCH3), 3.19 (m, 4H,
2×NCH2CH2), 5.19 (s, 1H, CH); dC (100 MHz, DMSO-d6) 9.99,
25.16, 31.36, 47.03, 49.43, 90.75, 156.05; m/z 229.2 [М+Н]+.
General method for the preparation of hydrazones 17 and 18
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.20 g,
1.13 mmol) was dissolved in dioxane (4 mL) then substituted
hydrazine was added. The resulting solution was refluxed with
stirring for 3 hours. The volatiles were evaporated in vacuo and
the residue was recrystallized from the corresponding solvent,
affording the title compounds 17,18. as colorless crystals.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 4-(N-
phenylhydrazone) (17)
4-Anilino-2,3,3-trimethyl-2,3-dihydro-1H-1λ6-isothiazole-1,1-
dione (14)
Using 2 (0.20 g, 1.14 mmol) and PhNH-NH2 (0.18 g, 0.17
mL, 1.70 mmol). Yield 0.22 g (0.84 mmol), 74%; m.p. = 173-
174°C (i-PrOH); [Found: C, 53.90; H, 6.58; N, 15.68; S, 12.02.
C12H17N3O2S requires C, 53.91; H, 6.41; N, 15.72; S, 11.99%];
nmax (KBr) 3334, 2973, 1604, 1310, 1123, 961, 749 cm−1; dH (400
MHz, DMSO-d6) 1.47 (s, 6H, 2×CH3), 2.65 (s, 3H, NCH3), 4.15
(s, 2H, CH2), 6.74 (t, J 7.0 Hz, 1H, H-4’), 7.02 (d, J 7.6 Hz, 2H,
H-2’ and H-6’), 7.16 (t, J 7.6 Hz, 2H, H-3’ and H-5’), 9.09 (s,
1H, NH); dC (100 MHz, DMSO-d6) 22.52, 24.69, 46.96, 64.12,
112.81, 119.44, 128.80, 138.55, 145.60; m/z 268.0 [М+Н]+.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.20 g,
1.13 mmol) and aniline (0.21 g, 0.21 mL, 2.26 mmol) were
dissolved in dry benzene (5 mL). The mixture was refluxed with
Dean-Stark trap for 6 hours and then it was evaporated to
dryness. The recrystallization of crude product from i-PrOH gave
the title compound 14 as cream-colored crystals. Yield 0.20 g
(0.80 mmol), 71%; m.p. = 203-204°C; [Found: C, 57.46; H, 6.49;
N, 11.35; S, 12.63. C12H16N2O2S requires C, 57.12; H, 6.39; N,
11.10; S, 12.71%]; nmax (KBr) 3280, 2979, 1617, 1595, 1536,
1238, 1098, 757 cm−1; dH (400 MHz, DMSO-d6) 1.46 (s, 6H,
2×CH3), 2.59 (s, 3H, NCH3), 5.67 (s, 1H, CH), 7.06 (t, J 7.0 Hz,
tert-Butyl 2-(2,3,3-trimethyl-1,1-dioxo-1λ6-isothiazolidin-4-
ylidene)-1-hydrazine-carboxylate (18)

Using 2 (0.20 g, 1.14 mmol) and BocNH-NH2 (0.15 g, 1.13
A mixture of ethyl 2-(2,3,3-trimethyl-1,1-dioxo-1λ6-isothiazolidin-
4-ylidene)acetate (24) and ethyl 2-(2,3,3-trimethyl-1,1-dioxo-2,3-
dihydro-1H-1λ6-isothiazol-4-yl)acetate (25)
ACCEPTED MANUSCRIPT
mmol). Yield 0.26 g (0.89 mmol), 79%; m.p. = 245-246°C
(water) with decomposition; [Found: C, 45.47; H, 7.23; N, 14.20;
S, 11.04. C11H21N3O4S requires C, 45.34; H, 7.26; N, 14.42; S,
11.01%]; nmax (KBr) 3191, 2980, 1698, 1560, 1314, 1130, 886
cm−1; dH (400 MHz, DMSO-d6) 1.40 (s, 6H, 2×CH3), 1.48 (s, 9H,
tert-Bu), 2.61 (s, 3H, NCH3), 4.08 (s, 2H, CH2), 9.87 (s, 1H,
NH); dC (100 MHz, DMSO-d6) 22.50, 24.23, 28.36, 47.34, 64.27,
79.81, 152.51; m/z 290.2 [М-Н]-.
The mother and washing solutions remained after isolation of
23 were combined and evaporated in vacuo. The crude residue
was directly subjected to silica gel column chromatography using
MTBE-hexane (1:1) as the eluting solvent. Evaporation of the
eluate in vacuo afforded the sum of title compounds 24 and 25
(1:1.22 ratio) as yellowish oil. Yield 0.31 g (1.24 mmol), 22%;
[Found: C, 48.30; H, 7.12; N, 5.29; S, 13.34. C10H17NO4S
requires C, 48.56; H, 6.93; N, 5.66; S, 12.97%]; nmax (KBr) 2979,
2937, 1734, 1713, 1463, 1285, 1022 cm−1; 24 dH (500 MHz,
CDCl3) 1.27 (m, 3H, CH2CH3), 1.43 (s, 6H, 2×CH3), 2.67 (s, 3H,
NCH3), 4.19 (m, 2H, CH2CH3), 4.40 (s, 2H, CH2SO2), 6.04 (s,
1H, CH); 25 dH (500 MHz, CDCl3) 1.27 (m, 3H, CH2CH3), 1.30
(s, 6H, 2×CH3), 2.72 (s, 3H, NCH3), 3.25 (s, 2H, CH2CO2Et),
4.19 (m, 2H, CH2CH3), 6.72 (s, 1H, CH); 24 dC (125 MHz,
CDCl3) 14.15, 22.75, 25.72, 50.63, 60.87, 63.76, 117.09, 154.22,
165.27; 25 dC (125 MHz, CDCl3) 14.07, 22.64, 23.05, 32.86,
61.76, 65.13, 122.75, 150.74, 168.07; m/z 248.2 [М+Н]+.
General method for the preparation of acids 21 and 22 (The
unsuccessful synthesis of hydantoins 19 and 20)
The mixture of ketosultam 1,2 (0.20 g), KCN (0.15 g, 2.3
mmol) and (NH4)2CO3 (0.5 g, 5.2 mmol) in aqueous methanol
(1:1) (6 mL) was refluxed for 6 h. The solvent was evaporated in
vacuo, the residue was diluted with water (4 mL), acidified with
2N HCl to pH = 1 and extracted into CH2Cl2 (6×5 mL). The
combined extracts were dried over Na2SO4 and evaporated in
vacuo yielding the light brown precipitate. The recrystallization
of the crude product from toluene gave the title compound 21,22
as colorless crystals.
Ethyl 2-([E]-4-methyl-5,5-dioxo-5λ6-thia-4-azaspiro[2.4]hept-7-
ylidene)acetate (26)
N,2-Dimethyl-N-(methylsulfonyl)alanine (21)
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.10
g, 0.57 mmol) and triphenylcarbethoxymethylenephospho-rane
(0.20 g, 0.57 mmol) were dissolved in dry toluene (10 mL) and a
pair of crystals of benzoic acid (approx. 0.75 mg) were added.
The resulting mixture was refluxed for 6 h and then it was
evaporated to dryness. The crude residue was directly subjected
to silica gel column chromatography using MTBE-hexane (1:1)
as the eluting solvent. Evaporation of the eluate in vacuo afforded
the title compound 26 as colorless crystals. Yield 0.08 g (0.33
mmol), 57%; m.p. = 117-118°C; [Found: C, 48.77; H, 6.25; N,
6.08; S, 13.34. C10H15NO4S requires C, 48.96; H, 6.16; N, 5.71;
S, 13.07%]; nmax (KBr) 3016, 2939, 1702, 1654, 1335, 1195,
1145, 760 cm−1; dH (400 MHz, CDCl3) 0.96 (m, 2H,
cyclopropyl), 1.05 (t, J 7.0 Hz, 3H, CH2CH3), 1.28 (m, 2H,
cyclopropyl), 2.42 (s, 3H, NCH3), 3.95 (q, J 7.0 Hz, 2H,
CH2CH3), 4.19 (s, 2H, CH2SO2), 5.27 (s, 1H, CH); dC (100 MHz,
CDCl3) 13.81, 16.67, 32.78, 48.24, 51.36, 60.37, 110.58, 154.22,
164.80; m/z 245.0 [М]+.
Using 1 (0.20 g, 1.13 mmol). Yield 0.20 g (1.01 mmol), 89%;
m.p. = 167-169°C; [Found: C, 37.13; H, 6.67; N, 7.24; S, 16.70.
C6H13NO4S requires C, 36.91; H, 6.71; N, 7.17; S, 16.42%]; nmax
(KBr) 3416, 2999, 2671, 1710, 1321, 1137, 960, 818 cm−1; dH
(400 MHz, DMSO-d6) 1.45 (s, 6H, 2×CH3), 2.81 (s, 3H, NCH3),
2.92 (s, 3H, SO2CH3), 12.47 (broad singlet, 1H, CO2H); dC (100
MHz, DMSO-d6) 25.32, 30.86, 40.04, 62.69, 175.27; m/z 194.2
[М-Н]-.
1-[Methyl(methylsulfonyl)amino]cyclopropanecarboxylic
acid
(22)
Using 2 (0.20 g, 1.14 mmol). Yield 0.18 g (0.93 mmol), 82%;
m.p. = 134-135°C; [Found: C, 37.50; H, 5.83; N, 7.46; S, 16.24.
C6H11NO4S requires C, 37.30; H, 5.74; N, 7.25; S, 16.60%]; nmax
(KBr) 3450, 3037, 2613, 1709, 1328, 1150, 965 cm−1; dH (400
MHz, DMSO-d6) 1.25-1.65 (broad singlet, 4H, cyclopropyl),
2.93 (s, 3H, NCH3), 2.98 (s, 3H, SO2CH3); dC (100 MHz, DMSO-
d6) 17-22 (broad singlet), 35.86, 39.43, 42.28, 174.02; m/z 192.0
[М-Н]-.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4,5-tetrone 5-oxime (28)
2,3,3-Trimethyl-1,1-dioxo-5-[2-(triphenylphosphonio)acetyl]-
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.2 g, 1.13
mmol) was dissolved in aq. 95% HOAc (4 mL) and the resulting
solution was cooled with an ice water bath. Then the solution of
NaNO2 (0.09 g, 1.36 mmol) in water (2 mL) was added dropwise
upon stirring maintaining the temperature below 5°C. The
resulting mixture was septa-sealed, allowed to equilibrate to r.t.
and left to react overnight with stirring. Then it was diluted with
water (6 mL) and extracted with CH2Cl2 (5×5 mL). The
combined organic layers were dried over Na2SO4 and evaporated
in vacuo. The residue was dissolved in i-PrOH (3 mL), filtered
and evaporated in vacuo affording the title compound 28 as
yellow crystals. Yield 0.12 g (0.60 mmol), 53%; m.p. = 123-
125°C; [Found: C, 34.68; H, 4.93; N, 13.28; S, 15.20.
C6H10N2O4S requires C, 34.95; H, 4.89; N, 13.58; S, 15.55%];
nmax (KBr) 3580, 3473, 2807, 1751, 1499, 1292, 1152, 929 cm−1;
dH (500 MHz, CDCl3) 1.45 (s, 6H, 2×CH3), 2.81 (s, 3H, NCH3);
dC (125 MHz, CDCl3) 21.21, 21.94, 68.04, 141.39, 189.98; m/z
207.0 [М+Н]+.
2,3-dihydro-1H-1λ6-isothiazol-4-olate
(23•PhMe)
toluene
monosolvate
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (1.0 g, 5.64
mmol) and triphenylcarbethoxymethylenephosphorane (2.95 g,
7.61 mmol) were dissolved in dry toluene (75 mL). Then benzoic
acid (5 mg) was added. The resulting mixture was refluxed for 6
h and then it was cooled. The precipitate was filtered and washed
with toluene (2×4 mL) affording the title compound 23•PhMe as
colorless crystals. Yield 1.97 g (3.44 mmol), 61%; dec. = 267-
268°C; nmax (KBr) 2960, 1593, 1406, 1256, 1102, 741, 690 cm−1;
dH (500 MHz, DMSO-d6) 1.02 (s, 6H, 2×CH3), 2.30 (s, 3H, CH3
[toluene]), 2.42 (s, 3H, NCH3), 5.33 (d, J 14.2 Hz, 2H, CH2P),
7.14 (t, J 7.0 Hz, 1H, H-4 [toluene]), 7.17 (d, J 7.2 Hz, 2H, H-2
and H-6 [toluene]), 7.25 (t, J 7.0 Hz, 2H, H-3 and H-5 [toluene]),
7.67-7.76 (m, 12H, 3×(H-2’, H-3’, H-5’, H-6’)), 7.84 (t, J 6.6 Hz,
3H, 3×H-4’); dC (126 MHz, DMSO-d6) 21.05, 21.67, 22.26,
33.28 (d, J 52.4 Hz), 64.24, 105.34 (d, J 4.5 Hz), 119.18, 119.88,
125.31, 128.65 (d, J 87.3 Hz), 129.77 (d, J 12.5 Hz), 133.78 (d, J
10.5 Hz), 134.44 (d, J 2.5 Hz), 137.34, 175.78 (d, J 6.0 Hz),
187.26; dP (202 MHz, DMSO-d6) 23.08; m/z 480.0 [М+Н]+;
HRMS (ESI): M+H+, found 480.1391. C26H27NO4PS requires
480.1393.
General method for the azo coupling of keto sultams 1 and 2
NaNO2 (0.08 g, 1.12 mmol) was dissolved in water (5 mL)
and then it was added dropwise to stirred cold (0°C) solution of

12
Tetrahedron
ACCEPTED MANUSCRIPT
p-toluidine (0.12 g, 1.12 mmol) in 95% aqueous acetic acid (5
C13H13NO4S requires C, 55.90; H, 4.69; N, 5.01; S, 11.48%]; nmax
mL) maintaining the temperature below 5°C. After the addition
was completed the mixture was allowed to stir for 30 min. Thus
obtained solution of diazonium salt was added dropwise to stirred
cold (0°C) solution of keto sultam 1,2 (0.2 g) in aq. 95% HOAc
(7 mL) maintaining the temperature below 5°C. The resulting
solution was allowed to stir at room temperature for 4 h and then
at 45°C for 2h. The precipitate that formed upon cooling to r.t.
was filtered and washed with water. The recrystallization of
crude product from i-PrOH gave the title compound 29,30 as
dark red prisms.
(KBr) 3429, 2919, 1742, 1603, 1334, 1158, 1097, 741 cm−1;
enol/ketone ratio 3:1; enolic tautomer dH (400 MHz, DMSO-d6)
1.13 (s, 2H, cyclopropyl), 1.28 (s, 2H, cyclopropyl), 2.55 (s, 3H,
NCH3), 7.45 (m, 2H, H-3’ and H-5’), 7.55 (m, 1H, H-4’), 7.67
(m, 2H, H-2’ and H-6’), 10.19 (br s, 1H, OH) ; ketonic tautomer
(rotamers are present) dH (400 MHz, DMSO-d6) 1.36 (m, 2H,
cyclopropyl), 1.52 (m, 1H, cyclopropyl), 1.82 (m, 1H,
cyclopropyl), 2.85 (s, 3H, NCH3), 4.58 (m, 1H, CH), 7.45 (m,
2H, H-3’ and H-5’), 7.55 (m, 1H, H-4’), 7.67 (m, 2H, H-2’ and
H-6’); enolic tautomer dC (125 MHz, DMSO-d6) 11.88, 14.63,
32.03, 50.32, 128.39, 129.22, 132.33, 136.53, 181.51; ketonic
tautomer (rotamers are present) dC (125 MHz, DMSO-d6)
20.16+20.53, 21.64+21.98, 34.13+34.42, 54.19, 59.57+59.88,
128.39, 129.22, 132.33, 136.53, 203.71+204.05; m/z 280.0
[М+Н]+.
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4,5-tetrone
methylphenyl)hydrazone] (29)
5-[N-(4-
Using 1 (0.20 g, 1.13 mmol). Yield 0.21 g (0.73 mmol), 64%;
m.p. = 183-185°C; [Found: C, 53.09; H, 5.90; N, 14.13; S, 11.15.
C13H17N3O3S requires C, 52.86; H, 5.80; N, 14.23; S, 10.86%];
nmax (KBr) 3452, 2990, 1657, 1542, 1458, 1292, 1098, 820 cm−1;
dH (400 MHz, DMSO-d6) 1.37 (s, 6H, 2×CH3), 2.35 (s, 3H, CH3),
2.71 (s, 3H, NCH3), 7.20 (d, J 7.3 Hz, 2H, H-3’ and H-5’), 7.52
(d, J 7.9 Hz, 2H, H-2’ and H-6’), 13.36 (broad s, 1H, NH); dC
(100 MHz, DMSO-d6) 21.38, 21.59, 22.87, 65.43, 117.57,
127.61, 130.40, 136.81, 139.43, 188.47; m/z 296.2 [М+Н]+.
General method for the preparation of 4-hydroxy-2-methyl-1,1-
dioxo-N-phenyl-2,3-dihydro-1H-1λ6-isothiazole-5-carboxamides
33,34 and 4-hydroxy-2-methyl-1,1-dioxo-N-phenyl-2,3-dihydro-
1H-1λ6-isothiazole-5-carbothioamides 35,36
The solution of ketosultam 1,2 (1.38 mmol) and PhNCO or
PhNCS (1.38 mmol) in dry DMF (2 mL) was added to the stirred
solution of DBU (0.21 g, 1.38 mmol) in dry DMF (2 mL). The
resulting mixture was stirred overnight at r.t. and then poured
onto aq. 4M HCl (12 mL). The resulting precipitate was filtered
and washed with water (3×1 mL) affording the title compound
33-36. The product thus obtained was pure. If necessary, it can be
recrystallized from n-BuOH.
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,6,7-tetrone 6-[N-
(4-methylphenyl)hydrazone] (30)
Using 2 (0.20 g, 1.14 mmol). Yield 0.19 g (0.65 mmol), 58%;
m.p. = 191-192°C; [Found: C, 52.98; H, 5.41; N, 14.29; S, 11.11.
C13H15N3O3S requires C, 53.23; H, 5.15; N, 14.32; S, 10.93%];
nmax (KBr) 3435, 3154, 1676, 1534, 1444, 1289, 1110, 592 cm−1;
dH (400 MHz, DMSO-d6) 1.39 (s, 2H, cyclopropyl), 1.52 (s, 2H,
cyclopropyl), 2.35 (s, 3H, CH3), 2.69 (s, 3H, NCH3), 7.20 (d, J
5.2 Hz, 2H, H-3’ and H-5’), 7.51 (d, J 6.0 Hz, 2H, H-2’ and H-
6’), 13.17 (broad s, 1 H, NH); dC (100 MHz, DMSO-d6) 13.70,
20.74, 31.88, 50.82, 116.63, 128.93, 129.76, 135.80, 138.93,
187.31; m/z 294.2 [М+Н]+.
4-Hydroxy-2,3,3-trimethyl-1,1-dioxo-N-phenyl-2,3-dihydro-1H-
1λ6-isothiazole-5-carboxamide (33)
Using 1 (0.24 g, 1.38 mmol) and PhNCO (0.19 g, 1.38 mmol).
Yield 0.27 g (0.92 mmol), 67%; m.p. = 179-180°C; [Found: C,
52.76; H, 5.54; N, 9.30; S, 10.65. C13H16N2O4S requires C, 52.69;
H, 5.44; N, 9.45; S, 10.82%]; nmax (KBr) 3485, 3295, 2981, 1646,
1527, 1276, 1146, 1089 cm−1; dH (400 MHz, DMSO-d6) 1.31 (s,
6H, 2×CH3), 2.58 (s, 3H, NCH3), 7.01 (t, J = 7.3 Hz, 1H, H-4’),
7.27 (t, J = 7.6 Hz, 2H, H-3’ and H-5’), 7.56 (d, J = 7.9 Hz, 2H,
H-2’, and H-6’), 9.75 (br. s, 1H, NH) , 9.95 (br. s, 1H, OH); dC
(100 MHz, DMSO-d6) 22.33, 23.16, 63.59, 120.36, 123.61,
129.10, 139.22, 160.16; m/z 297.2 [М+Н]+.
General method for the preparation of 5-benzoyl-4-hydroxy-2-
methyl-2,3-dihydro-1H-1λ6-isothiazole-1,1-dione 31 and 32
Ketosultam 1,2 (0.18 g, 1.00 mmol), PhCO2H (0.12 g, 1.00
mmol), ЕDC (0.20 g, 1.00 mmol) and DMAP (0.12 g, 1.00
mmol) in the indicated order were dissolved in DMF (3 mL) and
the resulting mixture was left to react upon stirring at r.t. for 96 h.
Then it was evaporated in vacuo at the temperature not higher
than 60°C and the residue was triturated with water (5 mL). The
resulting precipitate was filtered and successively washed with
aq. 1M HCl (1 mL) and water (3×1 mL) affording the title
compound 31,32 as white powder.
7-Hydroxy-4-methyl-5,5-dioxo-N-phenyl-5λ6-thia-4-
azaspiro[2.4]hept-6-ene-6-carboxamide (34)
Using 2 (0.08 g, 0.46 mmol) and PhNCO (0.06 g, 0.46 mmol).
Yield 0.10 g (0.35 mmol), 77%; m.p. = 188-189°C; [Found: C,
52.76; H, 4.54; N, 9.67; S, 11.15. C13H14N2O4S requires C, 53.05;
H, 4.79; N, 9.52; S, 10.89%]; nmax (KBr) 3333, 3092, 1642, 1536,
1446, 1259, 761 cm−1; dH (400 MHz, DMSO-d6) 1.38 (s, 4H,
cyclopropyl), 2.71 (s, 3H, NCH3), 7.03 (t, J = 6.1 Hz, 1H, H-4’),
7.28 (t, J = 7.0 Hz, 2H, H-3’ and H-5’), 7.55 (d, J = 7.0 Hz, 2H,
H-2’, and H-6’), 10.46 (br. s, 1H, NH); dC (100 MHz, DMSO-d6)
7.75, 28.07, 48.76, 96.73, 118.79, 121.56, 128.61, 140.30,
161.65, 180.67; m/z 295.0 [М+Н]+.
5-Benzoyl-4-hydroxy-2,3,3-trimethyl-2,3-dihydro-1H-1λ6-
isothiazole-1,1-dione (31)
Using 1 (0.18 g, 1.00 mmol). Yield 0.11 g (0.38 mmol), 38%;
m.p. = 141-142°C; [Found: C, 55.21; H, 5.01; N, 4.87; S, 11.28.
C13H15NO4S requires C, 55.50; H, 5.37; N, 4.98; S, 11.40%]; nmax
(KBr) 3451, 2983, 1602, 1568, 1288, 1151, 698 cm−1; dH (400
MHz, DMSO-d6) 1.22 (s, 6H, 2×CH3), 2.55 (s, 3H, NCH3), 7.42
(t, J = 6.5 Hz, 2H, H-3’ and H-5’), 7.50 (t, J = 6.5 Hz, 1H, H-4’),
7.65 (d, J = 6.5 Hz, 2H, H-2’ and H-6’), 7.84 (br s, 1H, OH); dC
(125 MHz, DMSO-d6) 22.03, 23.03, 63.80, 128.11, 129.03,
131.79, 138.46, 184.06; m/z 282.2 [М+Н]+.
4-Hydroxy-2,3,3-trimethyl-1,1-dioxo-N-phenyl-2,3-dihydro-1H-
1λ6-isothiazole-5-carbothioamide (35)
Using 1 (0.24 g, 1.38 mmol) and PhNCS (0.19 g, 1.38 mmol).
Yield 0.30 g (0.97 mmol), 70%; m.p. > 300°C; [Found: C, 49.63;
H, 4.96; N, 9.15; S, 20.36. C13H16N2O3S2 requires C, 49.98; H,
5.16; N, 8.97; S, 20.53%]; nmax (KBr) 3440, 2969, 1608, 1536,
1396, 1211, 1133, 766 cm−1; dH (400 MHz, DMSO-d6) 1.20 (s,
6H, 2×CH3), 2.54 (s, 3H, NCH3), 7.04 (t, J = 6.4 Hz, 1H, H-4’),
7.27 (t, J = 7.2 Hz, 2H, H-3’ and H-5’), 7.81 (d, J = 6.4 Hz, 2H,
H-2’, and H-6’), 12.97 (s, 1H, NH); dC (100 MHz, DMSO-d6)
6-Benzoyl-7-hydroxy-4-methyl-5λ6-thia-4-azaspiro[2.4]hept-6-
ene-5,5-dione (32)
Using 2 (0.18 g, 1.00 mmol). Yield 0.12 g (0.44 mmol), 44%;
m.p. = 98-100°C; [Found: C, 55.90; H, 4.41; N, 4.72; S, 11.09.

4-Chloro-2,3,3-trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ6-
isothiazole-5-carbaldehyde (40)
22.28, 22.97, 62.16, 106.68, 122.76, 123.69A, 1C28C.1E0,P1T4E0.5D3, MANUSCRIPT
182.75, 183.03; m/z 313.2 [М+Н]+.
7-Hydroxy-4-methyl-5,5-dioxo-N-phenyl-5λ6-thia-4-
azaspiro[2.4]hept-6-ene-6-carbothioamide (36)
To a cold (0°C) solution of POCl3 (1.04 g, 0.63 mL, 6.78 mol)
in CH2Cl2 (5 mL) was added dropwise a solution of DMF (0.51
g, 0.54 mL, 7.0 mmol) in CH2Cl2 (3 mL) maintaining the
temperature below 5°C. The ice water bath was removed and the
mixture was allowed to stirr at r.t. for 0.5 h. Then it was cooled
(0°C) again and the solution of 2,3,3-trimethyl-1λ6-
isothiazolidine-1,1,4-trione 1 (0.2 g, 1.13 mmol) in CH2Cl2 (4
mL) was added dropwise at 0-5°C. The ice water bath was
allowed to melt and the resulting mixture was stirred at room
temperature overnight. Then it was poured on the crushed ice (10
g) in water (20 mL), stirred for 1 h and divided. The water phase
was extracted with CH2Cl2 (5×7 mL), the combined organic
layers were dried over Na2SO4 and evaporated at reduced
pressure. The solid remainder was recrystallized from EtOAc
affording the title compound 40 as colorless crystals. Yield 0.17 g
(0.76 mmol), 67%; m.p. = 184-185°C; [Found: C, 37.40; H, 4.52;
N, 6.40; S, 14.26. C7H10ClNO3S requires C, 37.59; H, 4.51; N,
6.26; S, 14.34%]; nmax (KBr) 2900, 1692, 1618, 1287, 1144, 882,
551 cm−1; dH (400 MHz, CDCl3) 1.47 (s, 6H, 2×CH3), 2.77 (s,
3H, NCH3), 9.88 (s, 1H, CHO); dC (125 MHz, CDCl3) 22.74,
23.54, 65.47, 131.67, 161.40, 179.96; m/z 223.0 [М]+.
Using 2 (0.10 g, 0.57 mmol) and PhNCS (0.08 g, 0.57 mmol).
Yield 0.14 g (0.46 mmol), 81%; m.p. > 300°C; [Found: C, 50.12;
H, 4.59; N, 8.93; S, 20.86. C13H14N2O3S2 requires C, 50.31; H,
4.55; N, 9.03; S, 20.66%]; nmax (KBr) 3451, 3048, 1631, 1541,
1413, 1242, 1105, 912 cm−1; dH (400 MHz, DMSO-d6) 1.03 (m,
4H, cyclopropyl), 2.41 (s, 3H, NCH3), 7.04 (t, J = 7.3 Hz, 1H, H-
4’), 7.27 (t, J = 7.27 Hz, 2H, H-3’ and H-5’), 7.80 (d, J = 7.6 Hz,
2H, H-2’, and H-6’), 12.80 (s, 1H, NH); dC (100 MHz, DMSO-
d6) 8.49, 29.32, 47.47, 109.19, 122.67, 123.57, 128.06, 140.61,
179.89, 182.24; m/z 309.0 [М-Н]-.
2,3,3-Trimethyl-5-[(Z)-phenylmethylidene]-1λ6-isothiazolidine-
1,1,4-trione (37)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.2 g, 1.13
mmol) was dissolved in pyridine (5 mL) then PhCHO (0.3 g,
0.29 mL, 2.83 mmol) was added to the stirred solution in one
portion. The mixture was refluxed for 2 h and then it was
evaporated to dryness. The solid remainder was recrystallized
from i-PrOH affording the title compound 37 as colorless
crystals. Yield 0.25 g (0.95 mmol), 84%; m.p. = 93-94°C (lit.13a
m.p. = 92°C, from EtOH); [Found: C, 58.66; H, 5.91; N, 5.37; S,
11.92. C13H15NO3S requires C, 58.85; H, 5.70; N, 5.28; S,
12.09%]; nmax (KBr) 2979, 1729, 1609, 1296, 1142, 1109, 773
cm−1; dH (400 MHz, DMSO-d6) 1.41 (s, 6H, 2×CH3), 2.80 (s, 3H,
NCH3), 7.57 (t, J 7.3 Hz, 2H, H-3’ and H-5’), 7.64 (t, J 7.0 Hz,
1H, H-4’), 7.97 (s, 1H, CHPh), 8.09 (d, J 7.0 Hz, 2H, H-2’ and
H-6’); dC (100 MHz, DMSO-d6) 21.68, 22.76, 68.00, 126.86,
129.60, 130.82, 134.09, 134.24, 145.57, 192.97; m/z 266.1
[М+Н]+.
6-[(Z)-Ethoxymethylidene]-4-methyl-5λ6-thia-4-
azaspiro[2.4]heptane-5,5,7-trione (41)
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.2
g, 1.14 mmol) was dissolved in Ac2O (4 mL) then HC(OEt)3
(0.84 g, 0.95 mL, 5.70 mmol) was added in one portion. The
resulting solution was refluxed for 3 h. The volatiles were
evaporated in vacuo and the solid remainder was sublimated in
vacuum (0.1 Torr and 100-110°C in an oil bath) giving the title
compound 41 as white powder (Note: This compound is quite
sensitive to moisture! Being left in air it decomposes in a few
hours!). Yield 0.21 g (0.89 mmol), 78%; m.p. = 121-122°C;
[Found: C, 46.98; H, 5.67; N, 5.70; S, 14.02. C9H13NO4S
requires C, 46.74; H, 5.67; N, 6.06; S, 13.87%]; nmax (KBr) 3104,
2980, 1712, 1614, 1326, 1010, 730 cm−1; dH (400 MHz, CDCl3)
1.36 (m, 2H, cyclopropyl), 1.47 (m, 2H, cyclopropyl), 1.51 (t, J =
7.2 Hz, 3H, CH2CH3), 2.71 (s, 3H, NCH3), 4.45 (q, J = 7.2 Hz,
2H, CH2CH3), 7.74 (s, 1H, CH); dC (125 MHz, CDCl3) 14.81,
15.24, 33.85, 53.24, 75.10, 112.46, 162.52, 193.21; m/z 202.2
[М-Et]-.
5-[(Z)-(Dimethylamino)methylidene]-2,3,3-trimethyl- 1λ6-
isothiazolidine-1,1,4-trione (38)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (1.77 g, 10
mmol) was dissolved in warm anhydrous MeOH (15 mL) then
DMFDMA (1.79 g, 1.99 mL, 15 mmol) was added to the stirred
solution in one portion. The crystal precipitate formation was
occurred and the mixture was allowed to stir for 30 min. After,
the reaction mixture was refluxed for 1 h and then it was
evaporated to dryness. The solid remainder was recrystallized
from i-PrOH affording the title compound 38 as colorless
crystals. Yield 2.09 g (9.0 mmol), 90%; m.p. = 164-165°C (lit.13a
m.p. = 162°C, from EtOH); [Found: C, 46.56; H, 7.27; N, 12.28;
S, 13.73. C9H16N2O3S requires C, 46.53; H, 6.94; N, 12.06; S,
13.80%]; nmax (KBr) 2976, 1679, 1618, 1257, 1103, 946, 602
cm−1; dH (400 MHz, DMSO-d6) 1.24 (s, 6H, 2×CH3), 2.62 (s, 3H,
NCH3), 3.42 (s, 3H, N(CH3)2), 3.44 (s, 3H, N(CH3)2), 7.59 (s,
1H, CH); dC (100 MHz, DMSO-d6) 21.78, 22.61, 41.56, 47.94,
66.29, 98.96, 151.99, 190.54; m/z 233.2 [М+Н]+.
2,3,3,5,5-Pentamethyl-1λ6-isothiazolidine-1,1,4-trione (42)
2,3,3-Trimethyl-1λ6-isothiazolidine-1,1,4-trione 1 (0.20 g,
1.13 mmol) was dissolved in DMF (5 mL) then K2CO3 (0.47 g,
3.39 mmol) and MeI (0.48 g, 0.21 mL, 3.39 mmol) were added
consequently. The resulting mixture was stirred at room
temperature for 48 h, after the precipitate was filtered and twice
washed with DMF (1 mL). The combined DMF layer was
evaporated in vacuo, the residue was diluted with water (5 mL)
and extracted with CH2Cl2 (5×4 mL). The combined extracts
were dried over Na2SO4, evaporated at reduced pressure and
sublimated in vacuum (0.1 Torr and 50°C in an oil bath) giving
the title compound 42 as white crystals which had been washed
with mixture cyclohexane/i-PrOH (9:1) before scraping from
cold finger. Yield 0.16 g (0.77 mmol), 68%; m.p. = 71-72°C;
[Found: C, 47.14; H, 7.44; N, 6.78; S, 15.69. C8H15NO3S
requires C, 46.81; H, 7.37; N, 6.82; S, 15.62%]; nmax (KBr) 2992,
2941, 1754, 1466, 1301, 1116, 1035 cm−1; dH (400 MHz, DMSO-
d6) 1.35 (s, 6H, 2×CH3-3), 1.44 (s, 6H, 2×CH3-5), 2.75 (s, 3H,
NCH3); dC (100 MHz, DMSO-d6) 19.95, 22.49, 22.88, 61.04,
67.60, 208.75; m/z 206.2 [М+Н]+.
General procedure for the recycling of mother solutions after
keto sultams 1 and 2. Another crop of dimethylaminomethylene
derivative 38,39.
The combined mother solution remained after recrystallization
and washing of keto sultam 1,2 was treated with DMFDMA (the
quantity was calculated from the ratio of 0.75 eq. of DMFDMA
to 1 eq. of isolated keto sultam 1,2), the resulting mixture was
allowed to stand overnight then filtered and washed with minimal
amount of i-PrOH. The product thus obtained was spectrally pure
and can be used without further purification. In this way, from
0.05 to 0.12 eq. (based on amount of isolated keto sultam 1,2) of
the title compound 38,39 can be obtained.

14
Tetrahedron
4,6,6-Trimethyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione
conformer dC (100 MHz, DMSO-d6) 11.71, 31.25, 51.13, 105.52,
ACCEPTED MANUSCRIPT
(43)
118.10, 125.61, 129.36, 138.42, 144.33, 191.05; s-trans
conformer dC (100 MHz, DMSO-d6) 12.48, 33.12, 52.06, 104.09,
118.67, 125.23, 129.21, 139.87, 141.70, 189.89; m/z 279.1
[М+Н]+.
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione 2 (0.2
g, 1.14 mmol) was dissolved in DMF (5 mL) then K2CO3 (0.48 g,
3.39 mmol) and MeI (0.47 g, 0.21 mL, 3.39 mmol) were added
consequentially and the resulting mixture was stirred at room
temperature for 48 h. The precipitate was filtered and twice
washed with DMF (1 mL). The combined DMF layer was
evaporated in vacuo, the residue was diluted with water (5 mL)
and extracted with CH2Cl2 (5×4 mL). The combined extracts
were dried over Na2SO4 and evaporated in vacuo. The residue
was distilled in vacuo giving the title compound 43 as colorless
oil. Yield 0.13 g (0.64 mmol), 56%; b.p. = 70-75°C (0.1 Torr);
[Found: C, 47.63; H, 6.45; N, 7.09; S, 16.16. C8H13NO3S
requires C, 47.27; H, 6.45; N, 6.89; S, 15.78%]; nmax (KBr) 2987,
1745, 1462, 1333, 1194, 1126, 731 cm−1; dH (500 MHz, CDCl3)
1.41 (m, 2H, cyclopropyl), 1.43 (m, 2H, cyclopropyl), 1.51 (s,
6H, 2×CH3), 2.72 (s, 3H, NCH3); dC (125 MHz, CDCl3) 14.18,
19.29, 28.79, 51.30, 62.94, 206.46; m/z 204.0 [М+Н]+.
General method for the preparation of dimethylammonium salt
of
ethyl
(E)-2-cyano-3-(4-hydroxy-2-methyl-1,1-dioxo-2,3-
dihydro-1H-1λ6-isothiazol-5-yl)-2-propenoates 48 and 49
Dimethylaminomethylideneketosultam 38,39 (0.25 g, 1.07
mmol) was dissolved in EtOH (5 mL), ethyl 2-cyanoacetate (0.15
g, 0.14 mL, 1.28 mmol) was added and the resulting mixture was
refluxed for 10 h. Then the mixture was cooled to r.t. and filtered.
The mother solution was evaporated in vacuo and the residue was
recrystallized from EtOAc affording the title compound 48•H2O,
49 as colorless crystals.
Dimethylammonium salt of ethyl (E)-2-cyano-3-(4-hydroxy-2,3,3-
trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ6-isothiazol-5-yl)-2-
propenoate monohydrate (48•H2O)
General
method
for
the
preparation
of
5-[(Z)-
Using 38 (0.25 g, 1.07 mmol). Yield 0.24 g (0.66 mmol),
62%; m.p. = 88-89°C; [Found: C, 46.04; H, 7.21; N, 11.27; S,
8.87. C14H25N3O6S requires C, 46.27; H, 6.93; N, 11.56; S,
8.82%]; nmax (KBr) 3532, 3076, 2200, 1700, 1634, 1534, 1226,
1119 cm−1; dH (400 MHz, DMSO-d6) 1.17 (s, 6H, 2×CH3), 1.27
(t, J 7.1 Hz, 3H, CH2CH3), 2.62 (s, 3H, NCH3), 2.59 (s, 6H,
H2N+(CH3)2), 4.15 (q, J 6.7 Hz, 2H, CH2CH3), 7.72 (s, 1 H, CH),
8.10 (broad s, 2H, H2N+(CH3)2); dC (100 MHz, DMSO-d6) 14.73,
22.04, 22.59, 34.80, 59.86, 65.47, 101.78, 118.11, 141.07,
166.33; m/z 244.1 [М-C2Н5-HCN]-.
anilinomethylidene]-2-methyl-1λ6-isothiazolidine-1,1,4-triones
46 and 47
Dimethylaminomethylideneketosultam 38,39 (0.23 g, 1.0
mmol) was dissolved in dioxane (6 mL) then PhNH2 (0.37 g,
0.37 mL, 4 mmol) was added and the resulting mixture was
refluxed for 8 h. The volatiles were evaporated in vacuo and the
residue was recrystallized from i-PrOH affording the title
compound 46,47 as colorless crystals.
5-[(Z)-Anilinomethylidene]-2,3,3-trimethyl-1λ6-isothiazolidine-
1,1,4-trione (46)
Dimethylammonium salt of ethyl (E)-2-cyano-3-(7-hydroxy-4-
methyl-5,5-dioxo-5λ6-thia-4-azaspiro[2.4]hept-6-en-6-yl)-2-
propenoate (49)
Using 38 (0.23 g, 1.0 mmol). Yield 0.24 g (0.87 mmol), 87%;
m.p. = 176-178°C; [Found: C, 56.00; H, 5.66; N, 10.36; S, 11.70.
C13H16N2O3S requires C, 55.70; H, 5.77; N, 9.99; S, 11.44%];
nmax (KBr) 3255, 3148, 3075, 2980, 1655, 1624, 1432, 1314,
1271, 1148, 754 cm−1; s-cis/s-trans ratio 2.6:1; s-cis conformer
dH (400 MHz, DMSO-d6) 1.33 (s, 6H, 2×CH3), 2.65 (s, 3H,
NCH3), 7.21 (t, J 7.0 Hz, 1H, H-4’), 7.39 (t, J 7.6 Hz, 2H, H-3’
and H-5’), 7.54 (d, J 7.6 Hz, 2H, H-2’ and H-6’), 8.62 (d, J 9.8
Hz, 1H, CH-NH), 11.48 (d, J 8.5 Hz, 1H, NH); s-trans conformer
dH (400 MHz, DMSO-d6) 1.30 (s, 6H, 2×CH3), 2.67 (s, 3H,
NCH3), 7.21 (t, J 7.0 Hz, 1H, H-4’), 7.36 (t, J 7.9 Hz, 2H, H-3’
and H-5’), 7.49 (d, J 7.9 Hz, 2H, H-2’ and H-6’), 7.94 (br s, 1H,
CH-NH), 11.14 (br s, 1H, NH); s-cis conformer dC (100 MHz,
DMSO-d6) 21.86, 23.08, 66.52, 104.33, 118.92, 126.47, 130.01,
138.90, 146.03, 193.25; s-trans conformer dC (100 MHz, DMSO-
d6) 21.97, 22.78, 67.43, 102.65, 119.58, 126.11, 129.83, 140.52,
143.04, 191.04; m/z 281.2 [М+Н]+.
Using 39 (0.25 g, 1.07 mmol). Yield 0.17 g (0.58 mmol),
54%. m.p. = 140-141°C; [Found: C, 49.17; H, 6.48; N, 12.02; S,
9.18. C14H21N3O5S requires C, 48.97; H, 6.16; N, 12.24; S,
9.34%]; nmax (KBr) 3218, 2986, 2201, 1686, 1620, 1554, 1254,
1113 cm−1; dH (400 MHz, DMSO-d6) 1.06 (s, 4H, cyclopropyl),
1.28 (t, J 7.0 Hz, 3H, CH2CH3), 2.46 (s, 3H, NCH3), 2.58 (s, 6H,
H2N+(CH3)2), 4.15 (q, J 7.0 Hz, 2H, CH2CH3), 7.74 (s, 1 H, CH);
dC (125 MHz, CDCl3) 10.57, 14,97, 27.31, 31.12, 34.87, 51.24,
60.34, 76.37, 104.82, 118.24, 140.69, 166.85; m/z 297.0 [М-H]-.
Acknowledgments
Alexey Dobrydnev acknowledges Prof. Dr. Demid. S.
Milokhov for a fellowship and theoretical support. We would
also like to show our gratitude to Mr. Mit Dapple for sharing his
pearls of wisdom with us during the course of this research.
6-[(Z)-Anilinomethylidene]-4-methyl-5λ6-thia-4-
azaspiro[2.4]heptane-5,5,7-trione (47)
References and notes
Using 39 (0.23 g, 1.0 mmol). Yield 0.24 g (0.88 mmol), 88%;
m.p. = 209-210°C; [Found: C, 56.13; H, 5.34; N, 10.04; S, 11.91.
C13H14N2O3S requires C, 56.10; H, 5.07; N, 10.06; S, 11.52%];
nmax (KBr) 3053, 2992, 1650, 1586, 1435, 1312, 1275, 1150
cm−1; s-cis/s-trans ratio 2.6:1; s-cis conformer dH (400 MHz,
DMSO-d6) 1.28 (s, 4H, cyclopropyl), 2.58 (s, 3H, NCH3), 7.19 (t,
J 6.7 Hz, 1H, H-4’), 7.38 (t, J 6.7 Hz, 2H, H-2’ and H-6’), 7.52
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(400 MHz, DMSO-d6) 1.34 (s, 4H, cyclopropyl), 2.62 (s, 3H,
NCH3), 7.19 (t, J 6.7 Hz, 1H, H-4’), 7.38 (t, J 6.7 Hz, 2H, H-2’
and H-6’), 7.47 (d, J 8.2 Hz, 2H, H-3’ and H-5’), 7.98 (d, J 14.6
Hz, 1H, CH-NH), 11.03 (d, J 15.0 Hz, 1H, CH-NH); s-cis
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