Mechanism of isomerization and acid-induced transformations of 3′-hydroxy-4,4′-dimethoxy- 3′-methyl-3-oxo-7,7′- bis(piperidino- carbonyloxy)-2,2′-spirobi- [2H,2'H,3H,3′H-benzo[b] thiophene]. unusual equilibrium between the Spiro and 3-hydroxy- benzothioph

Full text of DOI:10.1246/bcsj.82.600

600
Bull. Chem. Soc. Jpn. Vol. 82, No. 5, 600–602 (2009)
Short Articles
existed as a mixture of two diastereoisomers.1 Further studies
demonstrated that in aprotic solvents (DMSO-d6, acetone-d6,
and CDCl3) the ratio between the two forms was almost
constant and close to 2:1, but after addition of water or in
MeOD-d3 it changed to around 5:1.4.2 The existence of two
isomers was not surprising as there are two asymmetric carbon
atoms in the molecule, however the mechanism by which the
diastereoisomers equilibrated was not so obvious. Now, we
wish to report some reactions which were aimed at explanation
of the phenomena. Until now only three reports1,3,4 on 1,6-
dithiaspiro[4,4]nonane or its derivatives have been published
and their chemistry is still unexplored, and the results could be
of interest also for this reason.
While studying the isomerization of 1 in various solvents by
1H NMR, it was found that in CDCl3 a slow dehydration,
leading to formation of compound 2, took place. After two days
about 80% of the compound 1 was transformed into 2. The
dehydration was not observed in other solvents (DMSO,
acetone, and methanol) nor in acid-free chloroform (freshly
filtered through basic alumina).
Apparently, the reaction was catalyzed by traces of acids
usually present in dry chloroform, and indeed, compound 2 was
obtained preparatively by stirring of 1 in methylene chloride
with catalytic amounts of hydrochloride or methanesulfonic
acid (1 © 10¹1 mmol of methanesulfonic acid per 1 mmol of 1).
Surprisingly, reaction of 1 or 2 with a larger amount of
methanesulfonic acid (10 mmol of the acid per 1 mmol of 1)
resulted in formation of the carboxylic acid 3 (Scheme 1).
1H NMR of compound 3 demonstrated protons of the benzoic
acid part of the molecule as a broad singlet (Figure 1) but
addition of one drop of TFA transformed the broad singlet into
two doublets.
Apparently, the free carboxylic acid group was involved in
the line broadening, probably by hydrogen-bond formation
with the nonheterocyclic sulfur atom,5 as the corresponding
ester 4, obtained by methylation of the acid 3, did not
demonstrate any line broadening in NMR.
Mechanism of Isomerization and
Acid-Induced Transformations
of 3¤-Hydroxy-4,4¤-dimethoxy-
3¤-methyl-3-oxo-7,7¤-bis(piperidino-
carbonyloxy)-2,2¤-spirobi-
[2H,2¤H,3H,3¤H-benzo[b]thiophene].
Unusual Equilibrium between
the Spiro and 3-Hydroxy-
benzothiophene Systems
Marek T. Konieczny*1 and Paweł Sowiński2
1Department of Organic Chemistry, Medical University
of Gdańsk, 80-416 Gdańsk, Poland
2Laboratory of Nuclear Magnetic Resonance Spectroscopy,
Gdańsk University of Technology, 80-952 Gdańsk, Poland
Received August 22, 2008; E-mail: markon@amg.gda.pl
Mechanistic investigations show that two diastereo-
isomers of 3¤-hydroxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-7,7¤-
bis(piperidinocarbonyloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-ben-
zo[b]thiophene] (1) equilibrate via an open ring compound: a
3-hydroxybenzothiophene derivative. The result indicates
that the spiro form is more stable than the related, aromatic
benzothiophene. Acid-catalyzed transformations of 1 are also
reported.
3¤-Hydroxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-7,7¤-bis(piperi-
dinocarbonyloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-benzo[b]thio-
phene] (1) was obtained from reaction of 4-acetyl-5-methoxy-
1,3-benzoxathiol-2-one with piperidine or piperidine acetate in
DMSO.1 1H NMR spectra of compound 1 demonstrated that it
Based on the observed formation of compound 2, it seemed
that the interconversion of diastereoisomers of 1 took place
through a reversible dehydration-hydration process, via the
intermediate 2. However, incubation of compound 1 in acetone
or in acid-free chloroform with deuterated water for one week
O
O
N
N
O
O
CH2 OCH3
OCH3
H3C
S
OH
S
H+ catalytic
CH2Cl2
more H+
S
CH2Cl2
S
O
O
CH3O
CH3O
O
N
O
N
2
1
O
O
O
O
O
N
N
O
CH3 OCH3
CH3 OCH3
CH3I / K2CO3
DMF
S
S
S
OH
S
OCH3
O
O
CH3O
CH3O
O
N
O
N
4
3
O
O
Scheme 1. Acid-induced transformations of the spiro compound 1.
Published on the web May 13, 2009; doi:10.1246/bcsj.82.600

M. Konieczny et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 5 (2009)
601
O
O
N
N
O
O
OCH3
OCH3
H3C
S
H3C
S
O
O
_
S
S
_
O
O
CH3O
CH3O
O
N
O
N
9
O
O
7.30 7.20 7.10 7.00 6.90 6.80 6.70
ppm
7.30 7.20 7.10 7.00 6.90 6.80 6.70
ppm
Figure 2. Mesomeric forms of anion 9.
Figure 1. Influence of TFA on the shape of the aromatic
1
protons peaks in H NMR of 3: DMSO-d6 (left), DMSO-
d6 + 1 drop TFA (right) (To view the original spectra, see
Supporting Information, part 1, pages 11-15).
O
O
N
O
N
O
OCH3
CH2 OCH3
CH3
S
OH
-H2O
S
S
S
O
O
CH3O
CH3O
O
N
O
N
path A
O
O
1
2
+ OH-
path B
O
N
O
path C
N
O
O
OCH3
OCH3
CH3
S
CH3
S
OH
O
S
S
OH
OH
CH3O
CH3O
O
N
O
N
O
O
O
5
6
Scheme 2. The considered ways of isomerization of the spiro compound 1.
O
O
OCH3
O
O
OCH3
H3C
S
N
N
H3C
O
O
S
S
CH3I
1
+
6
S
O
N
K2CO3 / DMF
CH3
O
OCH3
O
N
CH3O
CH3O
O
O
8
7
Scheme 3. Methylation of the spiro compound 1.
did not change the integration of the methyl group in NMR,
which made the dehydration-hydration mechanism of isomer-
ization improbable (Scheme 2, path A). It was then speculated
that the isomerization could be due to nucleophilic attack of
water on the carbonyl group, as during formation of 3, leading
to ring opening and formation of sulfur atoms stabilized
carbanion 5 (Scheme 2, path B). However, after three days
incubation of 1 in acetone with 18O-labeled water no
incorporation of the 18O isotope into the molecule was found
(by calculations of isotopic peaks ratios for molecular ions in
MS), which made also a pathway B hardly possible.
To determine a potential participation of the free hydroxy
group in the isomerization of 1, the compound was methylated
with methyl iodide in DMF in the presence of potassium
carbonate. To our surprise, the reaction resulted in formation
of two products of methylation, 7 and 8 in the ratio 7:1,
respectively (Scheme 3).
The result suggests that two diastereoisomers of spiro
compound 1 are in equilibrium, either by deprotonation-
protonation or [1,5] hydrogen shift mechanism, via 3-hydroxy-
benzothiophene 6. Fast changes of the equilibrium in protic
solvents suggest that it is rather the ionic mechanism. In
alkaline solution, the intermediate 6 forms an anion 9, well
stabilized by spreading the negative charge at the dithioacetal
carbon and carbonyl group (Figure 2).
A relative distribution of the negative charge between the
oxygen and carbon atoms can be estimated, based on the
reported above results of methylation, as 7:1, respectively.
Concluding, it seems to be highly possible that the observed
equilibration of two diastereoisomers of 1 takes place via a
reversible ring opening to 6. Noteworthy, the intermediate 6
was not observed in NMR spectra, which means that equi-
librium between spiro compound 1 and aromatic compound 6
was shifted almost completely toward 1. Similar aldol-retro-

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Bull. Chem. Soc. Jpn. Vol. 82, No. 5 (2009)
© 2009 The Chemical Society of Japan
(M + Na), 667 (M + K). Anal. Calcd for C31H36N2O8S2: C, 59.22;
H, 5.77; N, 4.46; S, 10.20%. Found: C, 59.52; H, 6.10; N, 4.19; S,
9.93%. H NMR (CDCl3, 500 MHz): ¤ 7.17 (d, 1H, J = 9.0 Hz),
aldol equilibrium was already proposed for isomerization of a
cyclic ¢-keto sulfide,6 but to the best of our knowledge it was
not observed for a spiro system.
1
7.03 (d, 1H, J = 8.6 Hz), 6.93 (d, 1H, J = 9.0 Hz), 6.67 (d, 1H,
J = 8.6 Hz), 3.88 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.63 (br s,
2H), 3.50 (br s, 2H), 3.39 (br s, 4H), 2.61 (s, 3H), 1.70-1.50 (m,
12H). IR (KBr, cm¹1): 2936, 2855, 1722, 1421, 1224.
Experimental
Reaction of 3¤-Hydroxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-7,7¤-
bis(piperidinocarbonyloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-benzo-
[b]thiophene] (1) with Traces of HCl.
3¤-Hydroxy-4,4¤-
Reaction of 3¤-Hydroxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-
7,7¤-bis(piperidinocarbonyloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-
benzo[b]thiophene] (1) with Methyl Iodide. 3¤-Hydroxy-4,4¤-
dimethoxy-3¤-methyl-3-oxo-7,7¤-bis(piperidinocarbonyloxy)-2,2¤-
spirobi[2H,2¤H,3H,3¤H-benzo[b]thiophene] (1) (245 mg, 0.4
mmol), anhydrous K2CO3 (500 mg, 3.6 mmol), and methyl iodide
(0.7 mL, 11 mmol) in dry DMF (4 mL) were stirred at rt for 3 h. An
excess of methyl iodide was evaporated and the residue was
quenched with icy water to give a bright violet solid (200 mg).
1H NMR (CD3COCD3, 500 MHz) of the product demonstrated a
mixture of compounds 7 and 8 in a 7:1 ratio. Separation on silica
gel column in CHCl3-EtOAc 20:1 solution gave two products: 2-
[2¤-Acetyl-3¤-methoxy-6¤-(piperidinocarbonyloxy)phenylthio]-3,4-
dimethoxy-7-(piperidinocarbonyloxy)benzo[b]thiophene (7) (100
mg, 39%) as a colorless solid, mp 154-155 °C. MS (MALDI
TOF): 667 (M + K), 651 (M + Na), 628 (M). Anal. Calcd for
C31H36N2O8S2: C, 59.22; H, 5.77; N, 4.46; S, 10.20%. Found: C,
59.25; H, 5.63; N, 4.22; S, 10.30%. 1H NMR (CD3COCD3,
500 MHz): ¤ 7.20 (d, 1H, J = 9.0 Hz), 7.18 (d, 1H, J = 9.0 Hz),
7.10 (d, 1H, J = 8.6 Hz), 6.88 (d, 1H, J = 8.6 Hz), 3.97 (s, 3H),
3.90 (s, 3H), 3.78 (s, 3H), 3.66 (br s, 2H), 3.48 (br s, 4H), 3.24
(br s, 2H), 2.50 (s, 3H), 1.74-1.48 (m, 12H). IR (KBr, cm¹1): 2934,
2853, 1716, 1416, 1219.
dimethoxy-3¤-methyl-3-oxo-7,7¤-bis(piperidinocarbonyloxy)-2,2¤-
spirobi[2H,2¤H,3H,3¤H-benzo[b]thiophene] (1) (50 mg, 0.082
mmol) was dissolved in CHCl3 (2 mL), a small amount of HCl
(about 1 mL of gases from a concd hydrochloric acid bottle) was
pipetted over the solution, and the mixture was stirred at rt for 24 h.
The obtained product was purified on a silica gel column in
CHCl3-EtOAc 3:1 solution to give 4,4¤-dimethoxy-3¤-methylene-
3-oxo-7,7¤-bis(piperidinocarbonyloxy)-2,2¤-spirobi(2H,2¤H,3H,3¤H-
benzo[b]thiophene) (2) (28 mg, 57%) as a colorless glass, mp 120-
122 °C. MS (MALDI TOF): 635 (M + K), 619 (M + Na), 597
(M + H). Anal. Calcd for C30H32N2O7S2: C, 60.38; H, 5.41; N,
4.69; S, 10.75%. Found: C, 59.99; H, 5.38; N, 4.58; S, 10.84%.
1H NMR (CDCl3, 500 MHz): ¤ 7.44 (d, 1H, J = 8.8 Hz), 7.11 (d,
1H, J = 8.8 Hz), 6.71 (d, 1H, J = 8.8 Hz), 6.67 (d, 1H, J =
8.8 Hz), 6.37 (s, 1H), 5.41 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.63-
3.40 (m, 8H), 1.61 (m, 12H). IR (KBr, cm¹1): 2937, 2855, 1722,
1487, 1424, 1224.
Reaction of 3¤-Hydroxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-
7,7¤-bis(piperidinocarbonyloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-
benzo[b]thiophene] (1) with Methanesulfonic Acid.
3¤-Hy-
droxy-4,4¤-dimethoxy-3¤-methyl-3-oxo-7,7¤-bis(piperidinocarbon-
yloxy)-2,2¤-spirobi[2H,2¤H,3H,3¤H-benzo[b]thiophene] (1) (150
mg, 0.25 mmol) was dissolved in CH2Cl2 (5 mL), and methane-
sulfonic acid (0.2 mL) was added to the stirred solution. The
solution was stirred for 2 h, diluted with CH2Cl2 (50 mL),
washed with water and dried (Na2SO4). Evaporation of solvent
gave a noncrystalline residue which was purified on silica gel
column in CHCl3-MeOH 10:1 solution to give 6-methoxy-2-(4¤-
methoxy-3¤-methyl-7¤-(piperidinocarbonyloxy)benzo[b]thiophen-
2-ylthio)-3-(piperidinocarbonyloxy)benzoic acid (3) (130 mg,
86%) as a yellow glass, mp 139-143 °C. MS (MALDI TOF):
597 (M ¹ OH), 614 (M), 637 (M + Na), 653 (M + K). Anal.
Calcd for C30H34N2O8S2¢1.5H2O: C, 56.14; H, 5.81; N, 4.37; S,
9.99%. Found: C, 56.24; H, 5.64; N, 4.28; S, 9.70%. 1H NMR
(DMSO-d6 + 1 drop TFA, 500 MHz): ¤ 7.22 (d, 1H, J = 9.0 Hz),
7.18 (d, 1H, J = 9.0 Hz), 7.04 (d, 1H, J = 8.6 Hz), 6.84 (d, 1H,
J = 8.6 Hz), 3.87 (s, 3H), 3.80 (s, 3H), 3.60-3.25 (m, 8H), 2.56 (s,
3H), 1.65-1.35 (m, 12H). IR (KBr, cm¹1): 3448, 2936, 2855, 1722,
1421, 1224.
2-[2¤-Acetyl-3¤-methoxy-6¤-(piperidinocarbonyloxy)phenylthio]-
4-methoxy-2-methyl-7-(piperidinocarbonyloxy)-2H-benzo[b]thio-
phen-3-one (8) (15 mg, 6%) as cream solid, mp 74-76 °C. MS
(MALDI TOF): 679 (M + 51), 667 (M + K), 651 (M + Na), 639
(M + K ¹ CO), 627 (M ¹ H). Anal. Calcd for C31H36N2O8S2: C,
59.22; H, 5.77; N, 4.46; S, 10.20%. Found: C, 59.58; H, 6.05; N,
1
4.25; S, 9.87%. H NMR (CD3COCD3, 500 MHz): ¤ 7.40 (d, 1H,
J = 8.9 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 8.8 Hz),
6.89 (d, 1H, J = 8.9 Hz), 3.96 (s, 3H), 3.88 (s, 3H), 3.64-3.36 (m,
8H), 2.43 (s, 3H), 1.77 (s, 3H), 1.73-1.50 (m, 12H). IR (KBr,
cm¹1): 2928, 2853, 1722, 1423, 1224.
We thank the Polish Ministry of Science and Higher
Education for the grant no 2 PO5F 055 28 and the Medical
University of Gdańsk for the grant no W-60.
Supporting Information
1H NMR spectra (aromatic region) of compound 1 in various
solvents. 1H NMR, 13C NMR, gHMBC, gHSQC, and ROESY
spectra of compounds 2, 3, 4, 7, and 8.
Reaction of 6-Methoxy-2-(4¤-methoxy-3¤-methyl-7¤-(piperi-
dinocarbonyloxy)benzo[b]thiophen-2-ylthio)-3-(piperidinocar-
bonyloxy)benzoic Acid (3) with Methyl Iodide. 6-Methoxy-2-
(4¤-methoxy-3¤-methyl-7¤-(piperidinocarbonyloxy)benzo[b]thio-
phen-2-ylthio)-3-(piperidinocarbonyloxy)benzoic acid (3) (123
mg, 0.2 mmol), anhydrous K2CO3 (138 mg, 1 mmol), and MeI
(0.18 mL, 3 mmol) were stirred in anhydrous DMF (1 mL) at rt for
1.5 h. The reaction mixture was diluted with water and extracted
with ether (50 mL). The ethereal layer was washed with water (3©)
and brine (1©), dried (Na2SO4) and evaporated. The residue was
purified on silica gel column in CHCl3-EtOAc 5:1 solution to give
6-methoxy-2-(4¤-methoxy-3¤-methyl-7¤-(piperidinocarbonyloxy)-
benzo[b]thiophen-2-ylthio)-3-(piperidinocarbonyloxy)benzoic acid
methyl ester (4) (84 mg, 67%) as a colorless, noncrystalline solid,
mp 70-72 °C. MS (MALDI TOF): 597 (M ¹ OCH3), 628 (M), 651
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5
Supporting Information, paragraph 1.
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6