Synthesis of the First Representatives of Spiro-1λ6-isothiazolidine-1,1,4-triones

Article abstract of DOI:10.1055/s-0034-1380434

A strategy for the construction of spiro[cycloalkane-1,3′-1′λ⁶-isothiazolidine]-1′,1′,4′-triones through the sulfonylation of 1-aminocyclopropane- and 1-aminocyclobutanecarboxylates with methanesulfonyl chloride followed by alkylation with methyl iodide and subsequent cyclization in the presence of potassium tert-butoxide in N,N-dimethylformamide is reported. An efficient synthesis of starting 1-aminocyclopropane- and 1-aminocyclobutanecarboxylic acids was developed. The reaction of spiro[cycloalkane-1,3′-1′λ⁶-isothiazolidine]-1′,1′,4′-triones with N,N-dimethylformamide dimethyl acetal (DMF-DMA) gives 5′-[(Z)-(dimethylamino)methylene]spiro[cycloalkane-1,3′-1′λ⁶-isothiazolidine]-1′,1′,4′-triones, the structure of which was confirmed by X-ray diffraction study.

Full text of DOI:10.1055/s-0034-1380434

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2523–2528
2523
special topic
A. V. Dobrydnev et al.
Special Topic
Synthesis
Synthesis of the First Representatives of Spiro-1λ6-isothiazolidine-
1,1,4-triones
Alexey V. Dobrydnev*a,b
Maria V. Popovaa
Nathalie Saffon-Merceronc
Dymytrii Listunova,d
Yulian M. Volovenkoa
O
O
Me
N
CO2Me
DMFDMA, MeOH
3 steps
i–iii
(CH2)n
(CH2)n
(CH2)n
Me
S
O
S
O
20–65 °C, 2 h
79–85% yield
NH•HCl
N
N
O
O
Me
Me
n = 2, 3
i) MeSO2Cl, Et3N, CH2Cl2, 0–20 °C, overnight, 86–89% yield
ii) MeI, K2CO3, DMF, 0–20 °C, overnight, 92–95% yield
iii) t-BuOK, DMF, 20 °C, overnight, 75–82% yield
a Chemistry Department, Taras Shevchenko National University
of Kiev, Lva Tolstoho Street 12, Kyiv 01033, Ukraine
alexey.pierrot@gmail.com
b SMC Ecopharm Ltd., Naberezhno-Korchuvatska Street 136-B,
Kyiv 03045, Ukraine
c Université de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse
Cedex 9, France
d CNRS, LCC (Laboratoire de Chimie de Coordination),
205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4,
France
Received: 30.03.2015
Accepted after revision: 28.05.2015
Published online: 25.06.2015
Me
O
Me
Me
HO
DOI: 10.1055/s-0034-1380434; Art ID: ss-2015-t0209-st
Me
O
O
Me
O
Abstract A strategy for the construction of spiro[cycloalkane-1,3′-
1′λ6-isothiazolidine]-1′,1′,4′-triones through the sulfonylation of 1-ami-
nocyclopropane- and 1-aminocyclobutanecarboxylates with methane-
sulfonyl chloride followed by alkylation with methyl iodide and subse-
quent cyclization in the presence of potassium tert-butoxide in N,N-
dimethylformamide is reported. An efficient synthesis of starting 1-
aminocyclopropane- and 1-aminocyclobutanecarboxylic acids was de-
veloped. The reaction of spiro[cycloalkane-1,3′-1′λ6-isothiazolidine]-
1′,1′,4′-triones with N,N-dimethylformamide dimethyl acetal (DMF-
DMA) gives 5′-[(Z)-(dimethylamino)methylene]spiro[cycloalkane-1,3′-
1′λ6-isothiazolidine]-1′,1′,4′-triones, the structure of which was con-
firmed by X-ray diffraction study.
O
N
Me
O
Me
Me
Me
Me
S
R1
N
R3
R2
Me
Me
Me
PF1052
(ref. 1)
R1, R2, R3 = H, Alk
(ref. 10)
HO
O
N
O
H
H
Me
HO
Key words amino acids, sulfonamides, spiro compounds, cyclization,
X-ray structure determination
O
O
Me
H
Me
erythroskyrine
(ref. 1)
Me
Figure 1 Naturally and synthetic occurring tetramic acids
Naturally occurring tetramic acids (PF 1052 and eryth-
roskyrine)1 constitute a rich family of bioactive secondary
metabolites. All of them contain a pyrrolidine-2,4-dione
moiety and display a wide range of biological activity, in-
cluding antibiotic,2–6 antiviral, cytotoxicity, and cytostatic
activity.7–9 Some synthetic analogues of certain tetramic ac-
ids have been the subject of clinical investigations as prom-
ising antibiotic substances. Additionally, in 2005 Bayer
CropScience patented a series of substituted tetramic acids
as ingredients for fungicidal and herbicidal use (Figure 1).10
The sulfonamide group is known as a bioisosteric equiv-
alent of the carboxamide group. The similarity between
these two groups, which is based on consideration of elec-
tronic and conformational aspects, is a powerful instru-
ment in drug discovery (the most classic example is the
family of sulfonamide antibiotics).
Some approaches to the construction of the 2,3,3-
trimethyl-1λ6-isothiazolidine-1,1,4-trione system 2 have
been published.11 However, strategies for the synthesis of
spiro-substituted sulfur-containing isosters of tetramic acid
3a and 3b have not been previously investigated (Figure 2).
Considering the importance of applying these compounds
in medicinal chemistry and the absence of synthetic access
to these key products, we have developed a synthetic route
to 3a,b.
First, the building blocks for construction of the 1λ6-iso-
thiazolidine-1,1,4-trione system, 1-aminocyclopropanecar-
boxylic acid (4) and 1-aminocyclobutanecarboxylic acid (5),
were obtained. The starting cyclic α-amino acids were pre-
pared according to the reaction sequences shown in
Schemes 1 and 2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528

2524
A. V. Dobrydnev et al.
Special Topic
Synthesis
ing the methods described in the literature.12,13 Subse-
quently, sulfonylation of the amino acid esters 15a,b with
methanesulfonyl chloride in dry dichloromethane in the
presence of triethylamine as base resulted in corresponding
O
O
O
O
O
O
O
Me
Me
S
S
S
O
N
N
H
N
N
O
O
O
Me
3b
Me
2
Me
3a
methyl
1-(methylsulfonamido)cycloalkanecarboxylates
1
16a,b in 86–89% yield (Scheme 3). It was found to be advan-
tageous to allow the reaction mixture to stand at room
temperature at least overnight to ensure completion of the
sulfonylation process. Subsequent alkylation of 16a,b with
methyl iodide in N,N-dimethylformamide afforded methyl
1-(N-methylmethylsulfonamido)cycloalkanecarboxylates
17a,b and was followed by their treatment with potassium
tert-butoxide in dry N,N-dimethylformamide to produce
the target spiro[cycloalkane-1,3′-1′λ6-isothiazolidine]-
1′,1′,4′-triones 3a,b in 75 and 82% yields, respectively.
To confirm the structure of the synthesized compounds,
formylation of the sulfonamides 3a,b was performed by re-
action with N,N-dimethylformamide dimethyl acetal to af-
ford the crystalline derivative 18a,b (Scheme 4). Single
crystals of product 18b were obtained by slow evaporation
of a dilute solution in methanol. X-ray diffraction analysis
of enamine 18b revealed the Z configuration of the (di-
methylamino)methylene group relative to the SO2 fragment
at the C4–C3 bond (Figure 3).
Figure 2 The tetramic acid 1 and its sulfur-containing isosteres 2, 3a,b
1-Aminocyclopropanecarboxylic acid (4) was synthe-
sized starting from commercially available D,L-methionine
(6). This synthetic pathway included introduction of the
phthalimide protecting group, esterification, and alkylation
of 7 with dimethyl sulfate resulting in formation of the
methylsulfonium salt 8. The isolated intermediate under-
went a cyclization reaction to methyl 1-phthalimidocyclo-
propanecarboxylate 9 through an intramolecular alkyla-
tion. The hydrolysis of 9 upon treatment with aqueous 20%
hydrochloric acid under reflux led to the hydrochloric salt
of the acid 4·HCl in 95% yield (Scheme 1).
The amino acid 5 was prepared by an eight-step proce-
dure starting from commercially available ethyl cyanoace-
tate (10) (Scheme 2). First, ester 10 was alkylated with 1,3-
dibromopropane. The hydrolysis of the cyano ester 11, fol-
lowed by preparation of corresponding acid chloride and
Curtius rearrangement of the azide 12 with subsequent hy-
drolysis of both functional groups in the isocyanate 13
yielded crude amino acid 5, which was further purified us-
ing ion-exchange resin Amberlite IR-120 Plus. The cyclic
amino acids 4 and 5 were esterified with methanol follow-
In summary, spiro[cycloalkane-1,3′-1′λ6-isothiazoli-
dine]-1′,1′,4′-triones 3a,b were designed as isosteric ana-
logues of pharmacologically relevant tetramic acid. The
synthesis of both compounds was performed in four steps
from 1-aminocyclopropane- and 1-aminocyclobutanecar-
–
CO2H
CO2Me
NPhth
CO2Me
NPhth
1) phthalic anhydride, 160 °C, 90 min
2) SOCl2, PhH, 60–80 °C, 90 min
MeOSO3
Me2SO4, PhMe
111 °C, 2 h
Me
S+
MeS
MeS
NH2 3) MeOH, PhH, 10–65 °C, 150 min
Me
6
8
7
Me
S+
CO2Me
CO2H
Me
DMF, 20 °C, overnight
aq HCl, reflux, 8 h
NaH, DMF
30–40 °C, 2 h
95% yield
– Me2S
47% yield, 5 steps
CO2Me
C-
NPhth
NH2•HCl
4.HCl
9
NPhth
Scheme 1 The synthesis of 1-aminocyclopropanecarboxylic acid (4)
O
1) NaOH, MeOH, 65 °C, 10 h
2) HCl–H2O, to pH 1, 20 °C
CO2Et
CO2Et
CN
Br
Br
N3
K2CO3, DMF, 20 °C
overnight, 50% yield
3) SOCl2, CH2Cl2, 40 °C, 2 h
4) NaN3, H2O–dioxane
0–5 °C, 90 min
CN
CN
11
12
10
PhMe
reflux
90 min
aq HCl, reflux
10 h, 2 steps
CO2H
NCO
CN
NH2•HCl
aq HCl, reflux
64% yield, 7 steps
NH2•HCl
CN
5.HCl
14
13
Scheme 2 The synthesis of 1-aminocyclobutanecarboxylic acid (5)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528

2525
A. V. Dobrydnev et al.
Special Topic
Synthesis
CO2H
NH2•HCl
CO2Me
NH2
CO2Me
MeSO2Cl, Et3N, CH2Cl2
0–20 °C, overnight
MeOH–HCl, 0–65 °C, 4 h
(CH2)n
(CH2)n
(CH2)n
HCl
NSO2Me
H
4.HCl, 5.HCl
15a,b
16a,b
O
15a n = 2 (58% yield)
15b n = 3 (65% yield)
16a n = 2 (86% yield)
16b n = 3 (89% yield)
17a n = 2 (95% yield)
17b n = 3 (92% yield)
3a n = 2 (75% yield)
3b n = 3 (82% yield)
CO2Me
(CH2)n
Mel, K2CO3, DMF
20 °C, overnight
t-BuOK, DMF
(CH2)n
S
O
20 °C, overnight
NSO2Me
N
O
Me
Me
3a,b
17a,b
Scheme 3 The synthesis of spiro[cycloalkane-1,3′-1λ6-isothiazolidine]-1′,1′,4′-triones 3a,b
O
O
Me
were recorded on an Agilent 1100 Series with an Agilent LC/MSD SL
detector by chemical ionization (CI). All melting points were deter-
mined in open capillary tubes in a Thiele apparatus and are uncor-
rected.
DMFDMA, MeOH
20–65 °C, 2 h
N
(CH2)n
(CH2)n
Me
S
O
S
O
N
N
O
O
Me
18a n = 2 (85% yield)
18b n = 3 (79% yield)
Me
3a, b
Methyl 1-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclopropane-
carboxylate (9); One-Pot General Procedure
Scheme 4 The reaction of spiro[cycloalkane-1,3′-1′λ6-isothiazolidine]-
1′,1′,4′-triones 3a,b with N,N-dimethylformamide dimethyl acetal
A mixture of D,L-methionine (6, 100 g, 0.67 mol) and phthalic anhy-
dride (101 g, 0.68 mol) was ground to a powder and placed in a 1-L
round-bottomed flask that was then heated in an oil bath previously
heated to 160 °C. The mixture fused and vigorous emission of water
vapor occurred; heating was continued for a further 90 min and then
the mixture was cooled to r.t. The resulting crude phthalylmethionine
was blended (in the same flask) with benzene (400 mL) and few drops
of DMF were added followed by the dropwise addition of SOCl2 (98
mL, 161 g, 1.36 mol) at 60 °C. When all the SOCl2 had been added, the
mixture was refluxed for 1 h and then cooled to r.t. Benzene and ex-
cess SOCl2 were evaporated under reduced pressure and the residue
was heated under vacuum (60–80 °C/0.4 mbar) for 90 min. The acid
chloride was dissolved in benzene (200 mL) (in the same flask),
cooled in a cold (10–15 °C) water bath then MeOH (55 mL, 43.6 g,
1.36 mol) was added dropwise to the stirred solution; the first 25 mL
of MeOH should be added with caution! When the addition of MeOH
was complete, the mixture was refluxed for 2 h. Benzene and excess
MeOH were evaporated under reduced pressure and the residue was
heated under vacuum (60–80 °C/0.4 mbar) for 90 min. Toluene (200
mL) was added to crude phthalylmethionine methyl ester 7 and the
mixture was heated (80–100 °C) with stirring for 15 min. The clear
hot solution was separated and the procedure was repeated using tol-
uene (2 × 100 mL). The combined toluene extracts were poured into a
1-L round flask followed by addition of fresh distilled Me2SO4 (70 mL,
93 g, 0.74 mol); the resulting solution was refluxed with stirring for 2
h. After approx. 30 min from the time heating began, a dark heavy oil
formed. The two-phase mixture was cooled to r.t. and the toluene
phase (top layer) was decanted. The dark viscous residue (bottom
phase) was heated under vacuum (60–80 °C/0.4 mbar) for 90 min.
The methylsulfonium salt of phthalylmethionine methyl ester 8 thus
obtained was pure and no further purification was required.
Figure 3 Molecular structure of compound 18b according to results of
X-ray diffraction study
boxylic acids. New methods for the syntheses of cyclic ami-
no acids were developed, employing inexpensive commer-
cially available reagents. With the reported rapid synthesis
we believe that spiro[cycloalkane-1,3′-1′λ6-isothiazoli-
dine]-1′,1′,4′-triones 3a,b will find practical application in
drug discovery projects, especially in those where tetramic
acid is involved.
Reactions requiring anhydrous conditions were performed with the
usual precautions for the rigorous exclusion of air and moisture. DMF
was dried by distillation from P2O5. The other chemicals were pur-
chased from Aldrich or Fluka and, when necessary, chemicals were
purified according to the reported procedure.14 1H and 13C NMR spec-
tra were recorded on a Varian Mercury 400 spectrometer at 400.45
MHz and 100.61 MHz respectively using DMSO-d6 or CDCl3 as sol-
vents and TMS as an internal standard. IR spectra were obtained on a
Perkin Elmer BX II spectrophotometer in KBr pellets. Mass spectra
A 60% suspension of NaH in oil (40 g, 1 mol) was weighed into a 2-L
two-necked flask equipped with a thermometer and a dropping fun-
nel and covered with anhyd DMF (250 mL). A solution of methylsulfo-
nium salt 8 in anhyd DMF (500 mL) was added dropwise with vigor-
ous stirring, maintaining the temperature at 30–40 °C. The mixture
became orange and gas evolution (Me2S) occurred. When the addi-
tion of methylsulfonium salt was complete, the mixture was allowed
to stir at r.t. overnight. The orange-brown suspension was quenched
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528

2526
A. V. Dobrydnev et al.
Special Topic
Synthesis
with AcOH (86 mL, 90 g, 1.5 mol) (Caution! Exotherm and foaming
occurred.) DMF and excess AcOH were evaporated under reduced
pressure and the residue was heated under vacuum (60–80 °C/0.4
mbar) for 90 min. The resulting brown viscous mass was triturated
with water (700 mL) and the resulting precipitate was filtered, se-
quentially washed with water (3 × 50 mL) and hexane (3 × 50 mL)
then recrystallized (50% aq i-PrOH) to give pale yellow crystals; yield:
77.2 g (0.31 mol, 47%); mp 140–141 °C (i-PrOH–H2O, 1:1) [Lit.15 mp
139–141 °C (Et2O–hexane)].
M NaOH to pH 7. The solution was passed through a Amberlite IR-120
Plus column (5% aq NH3). The residue obtained on evaporation of the
eluate was dried under vacuum (80 °C/0.4 mbar) for 90 min. The
product thus obtained was pure and no further purification was re-
quired to give the product as white crystals; yield: 2.21 g (19.2 mmol,
64%); mp >300 °C (Lit.12 >300 °C).
IR (KBr): 3433, 3020, 2800, 1728, 1492, 1213, 1158, 865 cm–1
.
1Н NMR (400 MHz, D2O): δ = 2.09–2.30 (m, 2 H, cyclobutyl), 2.43–
2.51 (m, 2 H, cyclobutyl), 2.67–2.74 (m, 2 H, cyclobutyl).
13C NMR (100 MHz, DMSO-d6): δ = 14.4, 29.3, 56.3, 172.3.
MS (APCI): m/z = 116.0 [М + Н]+.
IR (KBr): 3100, 2954, 1731, 1409, 1314, 1142, 720 cm–1
.
1Н NMR (400 MHz, DMSO-d6): δ = 1.51 (m, 2 H, cyclopropyl), 1.67 (m,
2 H, cyclopropyl), 3.61 (s, 3 H, OCH3), 7.90 (m, 4 H, Phth).
13C NMR (100 MHz, DMSO-d6): δ = 16.4, 31.4, 53.2, 123.7, 131.5,
135.2, 167.9, 171.3.
MS (APCI): m/z = 246.2 [М + Н]+.
Methyl 1-(Methylsulfonamido)cycloalkanecarboxylates 16a,b;
General Procedure
Methyl 1-aminocycloalkanecarboxylate hydrochloride 15a,b (50
mmol) was added to a magnetically stirred solution of Et3N (15.2 g,
20.9 mL, 150 mmol) in CH2Cl2 (250 mL). As soon as the solid phase
dissolved (approx. 30 min required), the mixture was cooled with an
ice-water bath. Then the solution of MeSO2Cl (6.8 g, 60 mmol) in
CH2Cl2 (50 mL) was added dropwise, maintaining the temperature be-
low 5 °C. The ice-water bath was allowed to melt, and the mixture
was stirred at r.t. overnight. Excess CH2Cl2 and Et3N were evaporated
under reduced pressure, the residue was diluted with water (150 mL),
acidified with HCl to pH 3, and extracted with EtOAc (5 × 50 mL). The
combined extracts were dried (Na2SO4) and evaporated under re-
duced pressure to yield the crude oily product. The pure product, a
colorless oil, was obtained by vacuum distillation.
1-Aminocyclopropanecarboxylic Acid Hydrochloride (4·HCl)
Phthalimidocyclopropanecarboxylate 9 (30.0 g, 122.3 mmol) was cov-
ered with 20% aq HCl (400 mL) and the mixture was refluxed with
stirring for 8 h. The solid phase gradually dissolved and a clear solu-
tion formed. The mixture was allowed to equilibrate to r.t. and left
overnight without stirring. The precipitate was filtered off and the fil-
trate was extracted with CH2Cl2 (5 × 60 mL). The aqueous phase was
evaporated to dryness, the residue was heated under vacuum
(60 °C/0.4 mbar) for 90 min, triturated (i-PrOH, 20 mL) and filtered to
give pure product as white crystals that required no further purifica-
tion; yield: 18.1 g (116.2 mmol, 95%); mp 221–222 °C (dec.) [Lit.13,15
mp 220–222 °C (H2O–acetone)].
IR (KBr): 3402, 2980, 2923, 1733, 1531, 1189, 834, 551 cm–1
.
Methyl 1-(Methylsulfonamido)cyclopropanecarboxylate (16a)
1Н NMR (400 MHz, DMSO-d6): δ = 1.27 (s, 2 H, cyclopropyl), 1.37 (s, 2
H, cyclopropyl), 8.90 (br s, 3 H, NH3).
13C NMR (100 MHz, DMSO-d6): δ = 13.1, 33.7, 171.5.
MS (APCI): m/z = 102.0 [М + Н]+.
Using 15a (9.00 g, 60 mmol); yield: 9.81 g (51 mmol, 86%); bp 115–
119 °C/0.4 mbar).
IR (KBr): 3280, 3028, 2957, 1733, 1318, 1148, 522 cm–1
.
1Н NMR (400 MHz, CDCl3): δ = 1.62 (s, 2 H, cyclopropyl), 1.64 (s, 2 H,
cyclopropyl), 3.15 (s, 3 H, SO2CH3), 3.88 (s, 3 H, CO2CH3), 6.27 (br s, 1
H, NH).
13C NMR (100 MHz, CDCl3): δ = 18.0, 36.3, 42.5, 52.6, 173.1.
MS (APCI): m/z = 194.2 [М + Н]+.
1-Aminocyclobutanecarboxylic Acid Hydrochloride (5·HCl)
Ethyl 1-cyanocyclobutanecarboxylate16 (11, 4.60 g, 30 mmol) was
added to solution of NaOH (1.32 g, 33 mmol) in MeOH (40 mL) and
the resulting mixture was refluxed for 10 h. The excess MeOH was
evaporated under reduced pressure, and the residue was diluted with
water (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The aqueous
phase was acidified with HCl to pH 1 and extracted into CH2Cl2 (5 ×
10 mL). The combined extracts were dried (Na2SO4), filtered, and
poured into a round-bottom flask (100 mL). A few drops of DMF were
added to the magnetically stirred solution followed by addition of
fresh distilled SOCl2 (4.35 mL, 7.14 g, 60 mmol). When the addition of
SOCl2 was complete, the mixture was refluxed for 2 h, and then the
volatiles were removed under vacuum at a temperature no higher
than 60 °C. The residue was dissolved in dry dioxane (20 mL) and
added dropwise to a stirred solution of NaN3 (7.8 g, 120 mmol) in wa-
ter (50 mL), maintaining the temperature at 0–5 °C. Stirring was con-
tinued for an additional 75 min, the mixture was diluted with water
(50 mL), and the acid azide 12 was extracted with toluene (5 × 25 mL).
The combined toluene phases were dried (Na2SO4), filtered, and addi-
tionally dried (CaCl2) overnight. The filtered clear solution was care-
fully heated and refluxed for 90 min; gas evolution (N2) occurred.
Then 20% aq HCl (150 mL) was added to the hot toluene solution and
the two-phase mixture was refluxed with vigorous stirring for a fur-
ther 10 h. The aqueous phase was separated and evaporated to dry-
ness. The residue was dissolved in water (50 mL) and alkalized with 1
Anal. Calcd for C6H11NO4S: C, 37.30; H, 5.74; N, 7.25. Found: C, 37.49;
H, 5.68; N, 7.14.
Methyl 1-(Methylsulfonamido)cyclobutanecarboxylate (16b)
Using 15b (1.75 g, 11 mmol); yield 2.09 g (9.4 mmol, 89%); bp 120–
125 °C/0.4 mbar.
IR (KBr): 3281, 3006, 2958, 1732, 1304, 1142, 979, 524 cm–1
.
1Н NMR (400 MHz, CDCl3): δ = 1.99–2.10 (m, 2 H, cyclobutyl), 2.36–
2.44 (m, 2 H, cyclobutyl), 2.56–2.63 (m, 2 H, cyclobutyl), 3.02 (s, 3 H,
SO2CH3), 3.81 (s, 3 H, CO2CH3), 6.03 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): δ = 15.4, 32.4, 43.4, 52.5, 60.5, 173.4.
MS (APCI): m/z = 206.1 [М – Н]–.
Anal. Calcd for C7H13NO4S: C, 40.57; H, 6.32; N 6.76. Found: C, 40.61;
H, 6.28; N 6.66.
Methyl 1-(N-Methylmethylsulfonamido)cycloalkanecarboxylates
17a,b; General Procedure
Methyl 1-(methylsulfonamido)cycloalkanecarboxylate 16a,b (10
mmol) was dissolved in dry DMF (35 mL). K2CO3 (2.76 g, 20 mmol)
and MeI (2.84 g, 1.25 mL, 20 mmol) were added to the magnetically
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528

2527
A. V. Dobrydnev et al.
Special Topic
Synthesis
stirred solution consecutively at r.t. The flask was equipped with a
Dimroth condenser and sealed with a rubber balloon; a slight exo-
therm occurred. The mixture was allowed to equilibrate to r.t. and
stirred overnight. The precipitate was filtered and washed with DMF
(2 × 5 mL). Excess DMF was evaporated under reduced pressure and
the residue was diluted with water (15 mL) and extracted with CH2Cl2
(5 × 15 mL). The combined organic extracts were dried (Na2SO4) and
evaporated under reduced pressure yielding crude oily product. The
pure product, a light yellow oil, was obtained by vacuum distillation.
5-Methyl-6λ6-thia-5-azaspiro[3.4]octane-6,6,8-trione (3b)
A solution of 17b (1.0 g, 4.5 mmol) in DMF (5 mL) was added drop-
wise to a magnetically stirred solution of t-BuOK (1.1 g, 9.6 mmol) in
DMF (20 mL); a slight exotherm occurred. The mixture was allowed
to equilibrate to r.t. and left overnight with stirring. AcOH (1.5 mL)
was added dropwise then mixture was evaporated to dryness under
reduced pressure and at a temperature no higher than 60 °C. The resi-
due was triturated with water (10 mL) and extracted into CH2Cl2 (5 ×
5 mL). The combined organic extracts were dried (Na2SO4) and evapo-
rated under reduced pressure yielding a light-brown oily product. The
pure product was obtained by hot extraction into cyclohexane and
subsequent vacuum sublimation to give colorless crystals; yield: 0.70
g (3.7 mmol, 82%); bp 98–103 °C/0.4 mbar; mp 50–51 °C.
Methyl 1-(N-Methylmethylsulfonamido)cyclopropanecarboxylate
(17a)
From 16a (9.5 g, 49 mmol); yield: 9.8 g (47 mmol, 95%); bp 98–
103 °C/0.4 mbar.
IR (KBr): 2998, 2948, 1756, 1317, 1222, 1135, 1057 cm–1
.
IR (KBr): 3019, 2956, 1732, 1335, 1147, 522 cm–1
1Н NMR (400 MHz, CDCl3): δ = 1.48–1.76 (br s, 4 H, cyclopropyl), 3.02
.
1Н NMR (400 MHz, CDCl3): δ = 1.84–1.94 (m, 1 H, cyclobutyl), 2.04–
2.16 (m, 1 H, cyclobutyl), 2.41–2.53 (m, 4 H, cyclobutyl), 2.91 (s, 3 H,
NCH3), 3.72 (s, 2 H, CH2).
(s, 3 H, NCH3), 3.04 (s, 3 H, SO2CH3), 3.78 (s, 3 H, CO2CH3).
13C NMR (100 MHz, DMSO-d6): δ = 14.4, 24.2, 28.9, 54.6, 71.8, 202.5.
MS (APCI): m/z = 190.1 [М + Н]+.
13C NMR (100 MHz, CDCl3): δ = 17–23 (br s), 35.7, 39.0, 42.4, 52.3,
172.4.
MS (APCI): m/z = 208.2 [М + Н]+.
Anal. Calcd for C7H11NO3S: C, 44.43; H, 5.86; N, 7.40. Found: C, 44.28;
H, 5.83; N, 7.27.
Anal. Calcd for C7H13NO4S: C, 40.57; H, 6.32; N 6.76. Found: C, 40.45;
H, 6.24; N, 6.81.
(Dimethylamino)methylidene-Substituted Thiaazaspiroalkanetri-
ones 18a,b; General Procedure
Methyl 1-(N-Methylmethylsulfonamido)cyclobutanecarboxylate
(17b)
Cyclic sulfonamide 3a,b (1 mmol) was dissolved in warm anhyd
MeOH (5 mL) at r.t. DMFDMA (0.24 g, 0.27 mL, 2 mmol) was added to
the stirred solution in one portion; a crystalline precipitate formed
and the mixture was stirred for 30 min. The mixture was refluxed for
90 min to ensure completion of the reaction and then it was evapo-
rated to dryness. Recrystallization (i-PrOH) afforded the pure product
as white crystals.
From 16b (1.47 g, 7.1 mmol); yield: 1.47 g (6.7 mmol, 92%); bp 100–
105 °C/0.4 mbar.
IR (KBr): 3008, 2958, 1731, 1337, 962, 768, 526 cm–1
1Н NMR (400 MHz, CDCl3): δ = 1.80–1.88 (m, 1 H, cyclobutyl), 2.02–
2.14 (m, 1 H, cyclobutyl), 2.43–2.58 (m, 4 H, cyclobutyl), 2.79 (s, 3 H,
NCH3), 2.84 (s, 3 H, SO2CH3), 3.79 (s, 3 H, CO2CH3).
.
13C NMR (100 MHz, CDCl3): δ = 14.7, 31.6, 32.4, 39.0, 52.0, 64.6, 173.4.
MS (APCI): m/z = 222.0 [М + Н]+.
6-[(Z)-(Dimethylamino)methylidene]-4-methyl-5λ6-thia-4-
azaspiro[2.4]heptane-5,5,7-trione (18a)
Using 3a (0.20 g, 1.14 mmol); yield: 0.22 g (0.96 mmol, 85%); mp
203–204 °C.
Anal. Calcd for C8H15NO4S: C, 43.43; H, 6.83; N, 6.33. Found: C, 43.32;
H, 6.79; N, 6.27.
IR (KBr): 3092, 2949, 1680, 1614, 1361, 1259, 957 cm–1
.
4-Methyl-5λ6-thia-4-azaspiro[2.4]heptane-5,5,7-trione (3a)
1Н NMR (400 MHz, DMSO-d6): δ = 1.18 (s, 2 H, cyclopropyl), 1.20 (s, 2
H, cyclopropyl), 2.56 (s, 3 H, NMe), 3.41 (s, 6 H, NMe2), 7.62 (s, 1 H,
CH).
13C NMR (100 MHz, DMSO-d6): δ = 11.8, 32.9, 41.3, 47.4, 51.3, 155.4,
189.3.
A solution of 17a (9 g, 43.4 mmol) in DMF (40 mL) was added drop-
wise to a magnetically stirred solution of t-BuOK (10.7 g, 95.6 mmol)
in DMF (200 mL); a slight exotherm occurred. The mixture was al-
lowed to equilibrate to r.t. and stirred overnight. AcOH (15 mL) was
added dropwise then the mixture was evaporated to dryness under
reduced pressure and at a temperature no higher than 60 °C. The resi-
due was triturated with water (80 mL) and extracted with CH2Cl2 (5 ×
40 mL). The combined organic extracts were dried (Na2SO4) and evap-
orated under reduced pressure yielding a dark oily product. The pure
product was obtained by hot extraction into cyclohexane and subse-
quent recrystallization (i-PrOH) to give colorless crystals; yield: 5.7 g
(32.5 mmol, 75%); mp 78–79 °C (cyclohexane–i-PrOH).
MS (APCI): m/z = 231.2 [М + Н]+.
Anal. Calcd for C9H14N2O3S: C, 46.94; H, 6.13; N, 12.16. Found: C,
46.77; H, 6.00; N, 12.11.
7-[(Z)-(Dimethylamino)methylidene]-5-methyl-6λ6-thia-5-
azaspiro[3.4]octane-6,6,8-trione (18b)
Using 3b (0.20 g, 1.05 mmol); yield 0.20 g (0.83 mmol, 79%); mp 167–
168 °C.
IR (KBr): 3022, 2957, 1735, 1332, 1211, 1102, 832 cm–1
.
IR (KBr): 2995, 2951, 1678, 1610, 1359, 1281, 955 cm–1
.
1Н NMR (400 MHz, DMSO-d6): δ = 1.43 (s, 2 H, cyclopropyl), 1.50 (s, 2
1Н NMR (400 MHz, DMSO-d6): δ = 1.71 (m, 1 H, cyclobutyl), 1.94 (sex-
tet, J = 9.2 Hz, 1 H, cyclobutyl), 2.19 (m, 2 H, cyclobutyl), 2.40 (q, J =
8.8 Hz, 2 H, cyclobutyl), 2.74 (s, 3 H, NMe), 3.41 (s, 6 H, NMe2), 7.60 (s,
1 H, CH).
13C NMR (100 MHz, DMSO-d6): δ = 13.7, 23.6, 28.1, 41.3, 47.7, 68.0,
151.3, 189.6.
H, cyclopropyl), 2.76 (s, 3 H, NCH3), 4.24 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 17.2, 34.4, 54.2, 55.3, 202.6.
MS (APCI): m/z = 174.0 [М – Н]–.
Anal. Calcd for C6H9NO3S: C, 41.13; H, 5.18; N, 7.99. Found: C, 40.99;
H, 5.07; N, 7.83.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528

2528
A. V. Dobrydnev et al.
Special Topic
Synthesis
MS (APCI): m/z = 245.2 [М + Н]+.
References
Anal. Calcd for C10H16N2O3S: C, 49.16; H, 6.60; N, 11.47. Found: C,
48.97; H, 6.51; N, 11.53.
(1) Royles, B. J. L. Chem. Rev. 1995, 95, 1981.
(2) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203.
(3) Tuske, S.; Sarafianos, S. G.; Wang, X.; Hudson, B.; Sineva, E.;
Mukhopadhyay, J.; Birktoft, J. J.; Leroy, O.; Ismail, S.; Clark, A. D.
Jr.; Dharia, C.; Napoli, A.; Laptenko, O.; Lee, J.; Borukhov, S.;
Ebright, R. H.; Arnold, E. Cell 2005, 122, 541.
(4) Aoki, S.; Higuchi, K.; Ye, Y.; Satari, R.; Kobayashi, M. Tetrahedron
2000, 56, 1833.
(5) Phillips, N. J.; Goodwin, J. T.; Fraiman, A.; Cole, R. J.; Lynn, D. G.
J. Am. Chem. Soc. 1989, 111, 8223.
(6) Marfori, E. C.; Kajiyama, S.; Fukusaki, E.-I.; Kobayashi, A. Z.
Naturforsch. 2002, 57, 465.
(7) Holtzel, A.; Ganzle, M. G.; Nicholson, G. J.; Hammes, W. P.; Jung,
G. Angew. Chem. Int. Ed. 2000, 39, 2766.
Collection of Crystallographic Data and Structure Determination
for 18b
The data were collected at low temperature (193 K) on a Bruker-AXS
APEX II QUAZAR diffractometer equipped with a 30-W air-cooled mi-
crofocus source, using MoKα radiation (λ = 0.71073 Å). Phi and omega
scans were used. The data were integrated with SAINT,17 and an em-
pirical absorption correction with SADABS was applied.18 The struc-
ture was solved by direct methods (SHELXS-97)19 and refined using
the least-squares method on F2 (SHELXL-97).19 All non-H atoms were
refined with anisotropic displacement parameters. The H atoms were
refined isotropically at calculated positions using a riding model.
(8) Marquardt, U.; Schmid, D.; Jung, G. Synlett 2000, 1131.
(9) Athanasellis, G.; Igglessi-Markopoulou, O.; Markopoulos, J.
CCDC-1051098 (18b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Bioinorg.
Chem.
Appl.
2010,
Article
ID
315056;
http://www.hindawi.com/journals/bca/,
DOI:10.1155/2010/315056.
Selected data for 18b: C10H16N2O3S, M = 244.31, monoclinic, space
group P21/c, a = 12.8541(4) Å, b = 16.1078(6) Å, c = 11.2684(4) Å, α =
γ = 90°, β = 95.7363(13)°, V = 2321.45(14) Å3, Z = 8, crystal size 0.220 ×
0.200 × 0.200 mm3, 34181 reflections collected (5285 independent,
Rint = 0.0273), 295 parameters, R1 [I >2σ(I)] = 0.0331, wR2 [all data] =
(10) Fischer, R.; Lehr, S.; Feucht, D.; Loesel, P.; Malsam, O.; Bojack, G.;
Auler, T.; Hills, M. J.; Kehne, H.; Rosinger, C. H. WO 2005048710,
2005.
(11) Stachel, H.-D.; Drasch, G. Arch. Pharm. (Weinheim, Ger.) 1985,
318, 304.
0.0965, largest diff. peak and hole: 0.393 and –0.354 e Å–3
.
(12) Tsang, J. W.; Schmied, B.; Nyfeler, R.; Goodman, M. J. Med. Chem.
1984, 27, 1663.
(13) Palacin, S.; Chin, D. N.; Simanek, E. E.; MacDonald, J. C.;
Whitesides, G. M.; McBride, M. T.; Palmore, G. T. R. J. Am. Chem.
Soc. 1997, 119, 11807.
(14) Perrin, D. D.; Armarego, I. F.; Perrin, D. R. Purification of Labora-
tory Chemicals, 2nd ed.; Pergamon: New York, 1980.
(15) Logusch, E. W. Tetrahedron Lett. 1986, 27, 5935.
(16) Van Hende, E.; Verniest, G.; Thuring, J.-W.; Macdonald, G.;
Deroose, F.; De Kimpe, N. Synlett 2009, 1765.
Acknowledgment
Alexey Dobrydnev acknowledges Patricia Dobrydneva for a fellowship
and technical support.
Primary Data
(17) SAINT, Program for data reduction, Bruker–AXS.
(18) SADABS, Program for data correction, Bruker–AXS.
(19) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
Primary data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000084 and can
be cited using the following DOI: 10.4125/pd0069th.
P
m
riaryDat
P
m
riaryDat
1
04.1
2
5
p/
d
0
0
6
9
htP
m
r.iary
D
at
Z
a
heln
1
0
1
C
h
e
mstiry
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2523–2528