Synthesis and stereochemistry of new spiro[5.5]undecane derivatives with 1,3-dioxane, 1,3-dithiane, or 1,3-oxathiane rings

Article abstract of DOI:10.1007/s11224-011-9848-2

The synthesis and the structural investigations of spiro[5.5]undecane derivatives with S and O containing heterocycles, exhibiting similar [bis(1,3-oxathiane) spiranes] or different (1,3-dioxane-1,3-dithiane spiranes) heterocycles, in the spirane units are reported. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s11224-011-9848-2

Struct Chem (2012) 23:61–69
DOI 10.1007/s11224-011-9848-2
ORIGINAL RESEARCH
Synthesis and stereochemistry of new spiro[5.5]undecane
derivatives with 1,3-dioxane, 1,3-dithiane, or 1,3-oxathiane rings
•
Alin Mihis¸ Ligia Mirabela Golban
•
•
•
•
Ciprian I. Rat¸ Elena Bogdan Anamaria Terec
Ion Grosu
Received: 26 May 2011 / Accepted: 19 July 2011 / Published online: 3 August 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The synthesis and the structural investigations
of spiro[5.5]undecane derivatives with S and O contain-
ing heterocycles, exhibiting similar [bis(1,3-oxathiane)
spiranes] or different (1,3-dioxane-1,3-dithiane spiranes)
heterocycles, in the spirane units are reported.
built). The flipping of the six-membered rings transforms
the M enantiomer into the P one and vice versa (I ¡ II),
this conformational equilibrium being an enantiomeric
inversion. The barrier of the process is not high enough for
the discrimination and separation of the enantiomers of this
compound.
Keywords Spiranes ꢀ 1,3-Diheteracyclohexanes ꢀ
Heterocycles isomerisation ꢀ Chirality ꢀ Molecular
modeling
The 3,9-disubstituted-spiro[5.5]undecane derivatives
(and the similar compounds with 1,3-dioxane or 1,3-
dithiane rings) show anancomeric structures (Scheme 2),
and the conformational equilibria are shifted toward the
conformers with the larger groups in equatorial orientation.
In these cases, the enantiomers (III and IV), generated by
the helix of the spirane skeleton, can be discriminated and
isolated, the racemization of the compounds being not
possible anymore [1].
Introduction
Spiro compounds with saturated six-membered rings
revealed intriguing conformational and configurational
aspects, and their stereochemistry was extensively inves-
tigated [1–10]. These polyspiranes exhibit helical disposi-
tion of the six-membered rings, and the helix can turn
identical with itself after each fourth six-membered ring.
Spiro[5.5]undecane, considered as the parent compound
of the series, is chiral (Scheme 1) and its chirality is due to
the helicity of the spirane skeleton (the helix begins to be
On the other hand, the 1,3-oxathiane derivatives exhibit
some peculiar stereochemistry aspects. The heterocycle is
chiral and its flipping is an enantiomeric inversion
(V ¡ VI) [11–13]. The chirality of the heterocycle can
be attributed to a virtual tricoordinated chiral center
(C*, Scheme 3, structures V and VI).
Many derivatives with 2,4,8,10-tetraheteroatom-
spiro[5.5]undecane skeleton (bearing either oxygen or
sulfur atoms in the rings, Chart 1, structures VII and VIII)
were already investigated [5–8, 14, 15], but very few data
about spiranes showing both heteroatoms in the spirane
unit such as 1,3-dioxane-1,3-dithiane spiranes (IX) or
bis(1,3-oxathiane) spiranes (X) were reported [16–20].
The most important reported results deal with the syn-
thesis of a series of non-symmetrically substituted deriva-
tives having the 1,3-dithiane-1,3-dioxane skeleton (type
IX) using acetalization (1 ? 2; 3 ? 4) and transthioace-
talization (2 ? 3) processes (Scheme 4) [16]. Further
substitutions of the 1,3-dithiane ring were carried out on
these compounds by deprotonation (BuLi) in position 3
Electronic supplementary material The online version of this
article (doi:10.1007/s11224-011-9848-2) contains supplementary
material, which is available to authorized users.
A. Mihis¸ ꢀ L. M. Golban ꢀ C. I. Ra¸t ꢀ E. Bogdan ꢀ
A. Terec (&) ꢀ I. Grosu (&)
Center of Supramolecular Organic and Organometallic
Chemistry, Babes-Bolyai University, Cluj-Napoca,
11 Arany Janos, 400028 Cluj-Napoca, Romania
e-mail: asuciu@chem.ubbcluj.ro
I. Grosu
e-mail: igrosu@chem.ubbcluj.ro
123

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Struct Chem (2012) 23:61–69
HO
HO
Br
Br
1. (CH2O)n/H+
O
O
S
S
COCH3
COCH3
2. CH3COSK/DMF
2
1
HO
S
S
O
O
S
RCHO
HCl (2N)
R
Scheme 1 Conformational equilibrium for spiro[5.5]undecane
THF, reflux
HO
S
3
4
1. BuLi
2. RCHO
3
1
O
O
S
S
2
R
CH(OH)R
11
R
R
5
5
6
4
10
9
7
Scheme 4 Synthesis of compound 5
III
IV
8
R
R
P
M
Scheme 2 Enantiomers of 3,9-disubstituted-spiro[5.5]undecane
derivatives
Chart 2 Target symmetrically substituted 1,3-dioxane-1,3-dithiane
(XI) and bis(1,3-oxathiane) (XII) compounds
C*
O
O
S
S
Results and discussions
C*
VI, R
the absent ligand
Two synthetic strategies were employed to access spiranes
with S and O atoms in the rings. The first option (named
Method A) was to carry out the synthesis of derivatives of
type XI by the methodology that was used for obtaining
non-symmetrically substituted compound 5. The next
considered possibility (Method B) was to carry out the
(thio)acetalization reaction of 2,2-bis(mercaptomethyl)-
1,3-propanediol with different aldehydes and to separate
compounds of types XI and XII which theoretically can be
formed during this reaction.
V, S
Scheme 3 Virtual tricoordinated chiral centers of 1,3-oxathiane
Method A (acetalization and transacetalization starting
from 2,2-dibromomethyl-1,3-propanediol 1)
This synthetic strategy was developed after the procedure
used for the preparation of 1,3-dioxane-1,3-dithianes 5
(Scheme 4) [16]. This procedure based on acetalization and
transthioacetalization processes was slightly modified as
the original reaction-path gave poor yields for the first
steps; hence thioacetylation was performed before acetal-
ization. The protected dimercaptodiol 6 (obtained from the
dibromo derivative 1 by a typical procedure) [21] was
subjected to acetalization reaction to afford the 1,3-dioxane
compounds 7 and 8 (Scheme 5). Reflux of 1,3-dioxane
derivative with HCl in THF leads to deprotection of the
mercapto group followed by transthioacetalization (proce-
dure similar to the synthesis of 3, Scheme 4) and the
obtaining of dithianes 9 and 10, respectively. In the
next step, the 1,3-dithiane compounds (9 and 10) were
Chart 1 Spirane skeletons with 1,3-dioxane (VII, IX), 1,3-dithiane
(VIII, IX), and 1,3-oxathiane (X) rings
(4 ? 5), followed by the reaction with different electro-
philes (e.g., RCHO, Scheme 4) [16, 18].
We considered of interest to study the stereochemistry
of new spiro compounds showing skeletons of types IX and
X. In view of the complexity of configurational and con-
formational aspects of such compounds, we were interested
in obtaining symmetrically substituted derivatives (XI and
XII, Chart 2) and in investigations concerning their struc-
ture carried out by NMR spectroscopy, mass spectrometry,
and molecular modeling.
123

Struct Chem (2012) 23:61–69
63
H
O
S
S
COCH3
COCH3
Br
HO
HO
S
S
COCH3
COCH3
HO
HO
O2N C6H4-CH=O
CH3COSK
PTSA,
toluene, reflux
O2N-C6H4
O
meta
para
Br
7
8
1
6
HO
HO
S H
O2N-C6H4
O
S
S
H
2N HCl
O2N C6H4-CH=O
THF,
reflux
PTSA,
toluene, reflux
S
C6H4-NO2
H
O
meta
para
C6H4-NO2
11
12
meta
para
9
10
Scheme 5 Synthesis of compounds 11 and 12 by method A
submitted to the acetalization reaction with the formation of
1,3-dioxane-1,3-dithiane compounds (11, 12), respectively.
Formation of the corresponding bis(1,3-oxathiane) deriva-
tives (XII) was not observed in this reaction; compounds 11
and 12 were purified by column chromatography.
Table 1 Results of the synthesis of compounds 11, 12, 14, and 15
using different methods
Method
Yields %
11
14
12
15
A
42
45
27
–
34
38
21
–
Method B [(thio)acetalization of 2,2-
B1 (10 h)
B2 (2 h)
\3
\3
11
bis(mercaptomethyl)-1,3-propanediol 13)]
8
The (thio)acetalization (Scheme 6) of m- or p-nitrobenz-
aldehyde with 2,2-bis(mercaptomethyl)propane-1,3-diol 13
(obtained by the reduction of 6 with LiAlH4) [19] resulted
into the mixture of 1,3-dioxane-1,3-dithiane spiranes (11
and 12) and the corresponding bis(1,3-oxathiane) deriva-
tives (14 and 15). The composition of the crude products in
1,3-dioxane-1,3-dithiane spiranes and bis(1,3-oxathiane)
derivatives could be correlated with the reaction time
(Table 1). The diminishing of the reaction time lead to
smaller overall yields but increased the ratio in bis(1,3-
oxathiane) spiranes (Table 1). Separation of the crude
mixtures by column chromatography (pentane/ethylace-
tate = 2/1) allowed the isolation of 1,3-dioxane-1,3-dithi-
ane compounds (11 and 12) along with fractions containing
mixtures of isomers of bis(1,3-oxathiane) derivatives (14
and 15).
1
2
O
3
11
10
R
4
R
O
5,7 methylene
inside groups
O
O
6 5
S
S
R
7
S
9
1,11 methylene
outside groups
S
8
R
P
M
XI
Scheme 7 Enantiomers of 11 and 12
stereochemistry. In agreement with the fact that type X
structures (Chart 1) exhibit three chiral elements (besides
the helicity of the spirane unit, there are two tricoordinated
virtual chiral centers belonging to the 1,3-oxathiane rings),
the bis(1,3-oxathianes) XII exhibit three diastereoisomers
all with the substituents at positions 3 and 9 in equatorial
orientations (Scheme 8). The –CH2S– unit (with highest
precedence) incorporated in one cycle can be considered as
a substituent of the other cycle and it can exhibit either
axial or equatorial positions. The three diastereoisomers are
Compounds 11 and 12 (type XI, Chart 2) are ananco-
meric and exhibit stable enantiomers (P or M configuration
of the helix, theoretically separable) (Scheme 7). The
bis(1,3-oxathiane) spiro compounds 14 and 15 (type XII)
are also anancomeric, but they have a more complex
Scheme 6 Synthesis of 11, 12,
14 and 15 by method B
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64
Struct Chem (2012) 23:61–69
5
4
S
3
both formed during the direct thioacetalization reaction
(Method B). The fact that compounds 11 and 12 are
obtained as major products by Method B (Table 1) could
be explained by considerably higher stability of these
compounds (see the molecular modeling results described
below). Meanwhile, the less stable bis(1,3-oxathiane)
spiranes 14 and 15 are transformed (isomerized) into the
more stable derivatives 11 and 12.
R
R
S
R
11
10
9
O
O
2
1
S
R
6
7
S
1,7 inside
5,11 outside
O
O
8
R
eq-eq
ax-ax
RMR
SPS
2
O
1
3
O
R
7
S
S
4
O
R
5
6
8 O
5,11 inside
1,7 outside
When Method B was used, the reaction was stopped
before the entire amount of 14 or 15 was isomerized into 11
or 12.
11
9
S
S
R
10
SMS
RPR
3
1
2
O
Structural investigations
R
R
S
O
11
10
9
S
6 5
7
O
S
R
4
S
R
5,7 inside
1,11 outside
The optimized geometries of the 1,3-dioxane-1,3-dithiane
12 and of the isomers of the bis(1,3-oxathiane) 15 were
obtained using DFT methods. Details regarding the soft-
ware packages, the functionals, the basis sets, the number
of imaginary frequencies, as well as the Cartesian coordi-
nates of equilibrium arrangements are included in the
Supporting Information. The representations of the equi-
librium structures obtained by calculations at the BP86/
TZ2P level of theory are shown in Fig. 1.
O
8
eq-ax
XII
SPR
RMS
Scheme 8 Stereoisomers of 14 and 15
denoted as equatorial–equatorial (eq–eq), axial–equatorial
(ax–eq), or axial–axial (ax–ax) (Scheme 8).
The results of theoretical calculations on 12 and 15 are
consistent with the experimental data. In the gas phase, 12
with ca. 3 kcal/mol is more stable than the isomers of 15
(Table 2). The values of the energy differences between the
isomers of the bis(1,3-oxathiane) 15 are small and depen-
dent on the chosen functional and basis sets, respectively.
Still, a higher stability induced by the equatorial orientation
of the CH2S groups can be suggested. Considering the
experimental data, the proposed order of stability for
structures XI and XII is XI ꢁ XII(eq–eq) [ XII(eq–ax) [
XII(ax–ax).
Two of the three isomers of 15 could be isolated
by a second column chromatography separation (pentane/
dichloromethane = 1/2) of the isomeric mixture and they
were identified by the NMR spectra as being the equato-
rial–equatorial (eq–eq) and equatorial–axial (eq–ax) iso-
mers. All column chromatography attempts to separate the
isomers of 14 were unsuccessful.
In order to determine the ratios at equilibrium between
compounds with 1,3-dioxane-1,3-dithiane (11 or 12) and
bis(1,3-oxathiane) (14 or 15) structures, compound 11 (or
12) was refluxed for 2 days in toluene (PTSA was used as
acidic catalyst). Investigation of the crude (TLC and NMR)
showed the recovery of spirane 11 (12, respectively) and
no formation of 14 (15) could be observed. However, when
a mixture of isomers of 14 (or 15) was submitted to the
same equilibration procedure, the total transformation of
14 (15) into compound 11 (12, respectively) was noticed
(Scheme 9). Transformation of 14 or 15 into the more
stable 11 or 12 was observed even for samples stored in the
refrigerator.
The structure of compounds 11 and 12 in solution was
investigated by NMR spectroscopy. 1H NMR spectra
exhibit different signals for the protons at positions 3 and 9
and for the protons of the two aromatic units. The CH2
groups of the 1,3-dioxane ring (positions 1 and 5) as well as
those of the 1,3-dithiane ring (7 and 11) are diastereotopic
(Scheme 7). Positions 5 and 7 represent methylene inside
groups being oriented toward the other heterocycle of the
spirane, while positions 1 and 11 are considered methylene
outside groups (Scheme 7). The equatorial protons of the
methylene inside positions are strongly deshielded by
the influence (through space) of the two heteroatoms of the
It is to suppose that the two types of compounds [1,3-
dioxane-1,3-dithiane and bis(1,3-oxathiane) spiranes] are
Scheme 9 1,3-Dioxane-1,3-
dithiane and bis(1,3-oxathiane)
derivatives equilibrium
O2N-C6H4
H
S
S H
O2N-C6H4 O
H O
S H
S C6H4-NO2
O
O C6H4-NO2
meta 11
12
meta 14
15
para
para
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Struct Chem (2012) 23:61–69
65
Fig. 1 Equilibrium structures for 12 (a) and 15 (eq–eq) (b), 15 (ax–ax) (c), and 15 (eq–ax) (d)
outside groups. The equatorial protons of the methylene
inside –CH2O– groups are very deshielded (de =
5.19 ppm, Fig. 2b) in agreement with the data obtained for
the similar protons in 12 (de = 5.29 ppm, methylene inside
–CH2O– group) and with the previously reported
NMR investigations carried out with 2,4,8,10-tetraoxa-
spiro[5.5]undecane derivatives [1, 2, 4, 22, 23]. The pro-
tons of positions 3 and 9 in 15 (eq–eq) are equivalent and
they give a unique signal (d = 5.86 ppm, Fig. 2b). The
assignment of this spectrum (Fig. 2b) to the eq–eq isomer
and not to the ax–ax isomer (which should exhibit a similar
1H NMR pattern) was based on the chemical shifts (desh-
ielding) of the signals. In the ax–ax isomer of 15, both
–CH2–O– groups are methylene outside, while the –CH2S–
groups are both methylene inside. The signals for the
methylene outside –CH2–O– group in 12 appear at
de = 3.99 and da = 3.87 ppm), while the signals pertain-
ing to the methylene inside –CH2S– in 12 give the signals
de = 3.59 and da = 3.04 ppm (for NMR data on 2,4,
8,10-tetrathia-spiro[5.5]undecane derivatives see [8]).
Table 2 Calculated relative energies between 12 and the isomers of
15 at different levels of theory
Compd.
Earel [kcal/mol]
Ebrel [kcal/mol]
Ecrel [kcal/mol]
15 (ax–ax)
15 (ax–eq)
15 (eq–eq)
12
3.07
3.06
3.57
0
3.35
3.02
3.13
0
3.45
3.18
3.06
0
a
ADF BP86/TZ2P; b GAMESS B3LYP/6-31G(d); c ORCA B3LYP/
6-31G(d,p)
other heterocycle (Table 3). The relevant fragment of the
1H NMR spectrum of 12 is presented in Fig. 2a.
As expected, the NMR spectra of isomeric 15 (eq–eq)
and 15 (eq–ax) are quite different. In the spectrum of the
eq–eq isomer, the two –CH2O– groups (positions 1 and 7)
and the two –CH2S– groups (positions 5 and 7) have
similar pattern in NMR. The methylene groups connected
to the oxygen atoms (–CH2O–) are both methylene inside,
while those of the –CH2S– moieties are both methylene
Table 3 1H NMR data (selected, d, ppm) for compounds 11, 12, and 15
Compound 3-H 9-H –O–CH2– (inside)
–S–CH2– (inside)
–O–CH2– (outside)
–S–CH2– (outside)
Heq
Hax
Heq
Hax
Heq
Hax
Heq
Hax
11
5.55 5.19 5.30 (5)
5.54 5.18 5.29 (5)
3.71 (5)
3.70 (5)
3.59 (7)
3.59 (7)
–
3.05 (7)
3.04 (7)
–
3.99 (1)
3.99 (1)
–
3.88 (1)
3.87 (1)
–
2.54 (11)
2.53 (11)
2.90 (11)
2.90 (11)
12
15 (eq–eq) 5.86
15 (eq-ax) 5.81; 5.85
5.19 (1,7) 3.53 (1,7)
5.28 (7) 3.03 (7)
2.56 (5, 11) 3.18 (5, 11)
3.58–3.61 (5) 3.91–3.93 (5) 3.91–3.93 (1) 3.58–3.61 (1) 2.41 (11)
3.16 (11)
The numbering of the inside and outside positions in different structures is shown inside the brackets
123

66
Struct Chem (2012) 23:61–69
Fig. 2 1H NMR spectra
(fragments) of compounds 12
(a), 15 (eq–eq) (b), and 15
(eq–ax) (c)
A
B
C
The spectrum in Fig. 2b was assigned to the eq–eq isomer
on the basis of the very deshielded signal (de = 5.19 ppm)
which belongs to equatorial protons of methylene inside
–CH2O– groups and such groups exist only in the eq–eq
isomer.
modelling and the equilibration experiments showed that
bis(1,3-oxathiane) spiranes are less stable than the isomeric
spiranes bearing both 1,3-dioxane and 1,3-dithiane rings.
The synthesis based on the (thio)acetalization reaction of
2,2-bis(mercaptomethyl)-1,3-propanediol 6 leads to the
initial formation of both bis(1,3-oxathiane) (XII) and 1,3-
dioxane-1,3-dithiane (XI) spiranes, but during the process
the bis(1,3-oxathiane) derivative (XII) can be totally
isomerized into the more stable spirane with different
heterocycles (XI). The structures of the compounds were
deduced based on important differences between the NMR
spectra of spiranes XI and the isomers belonging to spir-
anes XII.
1
The H NMR spectrum of the eq–ax isomer of 15 is
more complicated, for either –CH2O– or –CH2S– frag-
ments there are methylene inside and methylene outside
groups. The protons at positions 3 and 9 give different
signals (d = 5.81 and 5.85 ppm, Fig. 2c) as one of them is
connected to the ring having methylene inside group of
–CH2O– moiety and the other one is attached to the ring in
which the methylene inside group belongs to the –CH2S–
fragment. The protons at positions 1 and 7 as well as those
at positions 5 and 11 give different signals. The more
deshielded signal belongs to the equatorial proton of the
–CH2O– methylene inside fragment (de = 5.28 ppm),
while the equatorial proton of the methylene outside
–CH2S– moiety is the most shielded one (Fig. 2c; Table 3).
Experimental
1H NMR and 13C NMR spectra were recorded on Bruker
AVANCE 300 or 400 spectrometers operating at 300 (400)
MHz for proton and 75 (100) MHz for carbon atoms; d are
given in ppm (relative to TMS) and coupling constants
(J) in Hz. Mass spectra were recorded under ESI ion trap
mass spectrometer (Agilent 6320) in positive mode and/
or under EI mode (70 eV) on a VG-Autospec mass spec-
trometer. Melting points were measured with a Kleinfeld
melting point apparatus and are uncorrected. Elemental
Conclusions
Spiro[5.5]undecane derivatives with O and S atoms in the
rings exhibit different stabilities in correlation with the
nature of the constituent heterocycles. The molecular
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Struct Chem (2012) 23:61–69
67
5,5-Bis(mercaptomethyl)-2-p-nitrophenyl-1,3-dioxane 8
analyses were determined at Babes-Bolyai University,
Cluj-Napoca. Thin-layer chromatography was performed
on Merck silica gel 60 F 254 sheets. Silica gel Merck
(40–63 lm) was used for flash chromatography.
White crystals, m.p. = 134–135 °C. Rf = 0.21 (hexane/
CH2Cl2 = 1/1). Yields 32%. Found: C, 49.64; H, 4.77; N,
3.79; S, 16.74, C16H19N2O6S2 requires C, 49.86; H, 4.97; N,
3.63; S, 16.64. 1H NMR (300 MHz, CDCl3) d = 2.08 (3H, s,
CH3e), 2.10 (3H, s, CH3a), 2.84 (2H, d, J = 14.4 Hz, 4-Ha,
6-Ha), 3.03 (2H, d, J = 14.4 Hz, 4-He, 6-He), 4.04 [2H, s,
5(50)-CH2e-], 4.64 [2H, s, 5(50)-CH2a-], 5.15 (1H, s, 2-Ha),
7.67 (2H, d, J = 8.7 Hz, 20-H, 60-H), 8.20 (1H, d, J = 8.7 Hz,
30-H, 50-H), 13C NMR (75 MHz, CDCl3) d = 20.75 (5-CH3e),
20.83 (5-CH3a), 31.99 (C5), 35.09 (C4,6), 50.39 (C2), 62.63
(5-CH2e–), 67.56, (5-CH2a–), 124.02; 128.94 (tertiary aro-
matic carbon atoms), 144.95, 147.85 (quaternary aromatic
carbon atoms), 170.54, 170.59 (–S–CO–).
Procedure for the synthesis of 2,2-
bis(acetylthiomethyl)-1,3-propandiol 6
To a stirred solution of 2,2-bis(bromomethyl)-1,3-propan-
diol 1 (6.5 g, 25 mmol) in anhydrous DMF (190 mL)
under argon, potassium thioacetate (13.11 g, 115 mmol)
was added at room temperature (RT). The stirring was
continued for 6 days (TLC control), then the mixture was
concentrated to 20 mL volume. CH2Cl2 (150 mL) is added
and the organic solution was washed with brine
(4 9 90 mL). The separated organic phase was dried over
sodium sulfate and concentrated. The crude product was
subjected to column chromatography (n-hexane/ethylace-
tate = 2/1). Compound 6 was obtained as white solid in
38% yield (2.4 g) [21].
Procedure for the synthesis of 5,5-bis(hydroxymethyl)-
2-(m- or p-)nitrophenyl-1,3-dithianes 9 and 10
A solution of 1,3-dioxanes 7 or 8 (0.20 g, 0.519 mmol) in
THF (40 mL) and 2 N HCl (10 mL) was refluxed for 24 h.
The mixture was cooled to RT, neutralized with 5%
Na2CO3 to pH = 8–9 with stirring (1 h). The solution was
extracted with dichloromethane (3 9 50 mL), the sepa-
rated organic phase was dried over sodium sulfate and
concentrated. The solid residue was purified by column
chromatography (pentane/dichloromethane = 1/4).
Procedure for the synthesis of 5,5-bis(mercaptomethyl)-
2-(m- or p-)nitrophenyl-1,3-dioxanes 7 and 8
A solution of 2,2-bis(acetylthiomethyl)-1,3-propandiol 6
(0.22 g, 0.872 mmol), m- or p-nitrobenzaldehyde (0.16 g,
1.05 mmol), and PTSA (0.05 g, 0.3 mmol) in toluene
(30 mL) was refluxed for 12 h using a Dean-Stark trap.
The mixture was cooled to RT and neutralized with sodium
acetate (0.2 g). The mixture was washed with water
(2 9 50 mL), the organic layer was separated and dried
over sodium sulfate and concentrated. The solid residue
was purified by column chromatography (hexane/dichlo-
romethane = 1/1).
5,5-Bis(hydroxymethyl)-2-m-nitrophenyl-1,3-dithiane 9
White crystals, m.p. = 143–144 °C. Rf = 0.18 (pentane/
CH2Cl2 = 1/4). Yields 48%. Found: C, 47.54; H, 4.92; N,
4.79; S, 21.04, C12H15NO4S2 requires C, 47.82; H, 5.02; N,
4.65; S, 21.28. 1H NMR (400 MHz, CDCl3) d = 2.91 (4H, s,
4-H, 6-H), 3.67 (2H, s, 5-CH2e–) 4.29 (2H, s, 5-CH2a–), 5.16
(1H, s, 2-Ha), 7.53 (1H, t, J & J0 & 8.0 Hz, 50-H), 7.84 (1H,
d, J = 8.0 Hz, 60-H), 8.18 (1H, d, J = 7.8 Hz, 40-H) 8.39
(1H, s, 20-H), 13C NMR (100 MHz, CDCl3) d = 33.41 (C5),
34.31 (C4,6), 49.49 (C2), 60.42 (5-CH2e–), 66.61 (5-CH2a–),
122.32; 122.83, 129.65, 133.87 (tertiary aromatic carbon
atoms), 139.22, 147.65 (quaternary aromatic carbon atoms).
5,5-Bis(mercaptomethyl)-2-m-nitrophenyl-1,3-dioxane 7
White crystals, m.p. = 117–118 C. Rf = 0.14 (hexane/
CH2Cl2 = 1/1). Yields 70%. Found: C, 50.07; H, 4.80; N,
3.78; S, 16.38, C16H19N2O6S2 requires C, 49.86; H, 4.97;
1
N, 3.63; S, 16.64. H NMR (300 MHz, CDCl3) d = 2.09
(3H, s, CH3e), 2.11 (3H, s, CH3a), 2.85 (2H, d, J =
14.5 Hz, 4-Ha, 6-Ha), 3.04 (2H, d, J = 14.5 Hz, 4-He,
6-He), 4.05 [2H, s, 5(50)-CH2e–], 4.64 [2H, s, 5(50)-CH2a–],
5.17 (1H, s, 2-Ha), 7.55 (1H, t, J & J0 & 8.0 Hz, 50-H),
7.87 (1H, d, J = 7.8 Hz, 60-H), 8.18 (1H, d, J = 8.3 Hz,
40-H), 8.36 (1H, s, 20-H), 13C NMR (75 MHz, CDCl3)
d = 20.73 (5-CH3e), 20.80 (5-CH3a), 32.03 (C5), 35.08
(C4,6), 50.19 (C2), 62.72 (5-CH2e–), 67.52, (5-CH2a–),
123.04; 123.64, 129.85, 133.95 (tertiary aromatic carbon
atoms), 140.02, 148.35 (quaternary aromatic carbon
atoms), 170.52, 170.54 (–S–CO–).
5,5-Bis(hydroxymethyl)-2-p-nitrophenyl-1,3-dithiane 10
White crystals, m.p. = 203–204 °C. Rf = 0.17 (pentane/
CH2Cl2 = 1/4). Yields 60%. Found: C, 47.61; H, 5.15; N,
4.37; S, 21.11, C12H15NO4S2 requires C, 47.82; H, 5.02; N,
4.65; S, 21.28. 1H NMR (400 MHz, CD3OD) d = 2.79
(2H, d, J = 14.3 Hz, 4-Ha, 6-Ha), 3.07 (2H, d, J =
14.3 Hz, 4-He, 6-He), 3.52 (2H, s, 5-CH2e–) 4.09 (2H, s,
5-CH2a–), 5.34 (1H, s, 2-Ha), 7.75 (2H, d, J = 8.7 Hz, 20-H,
60-H), 8.23 (2H, d, J = 8.7 Hz, 30-H, 50-H), 13C NMR
(100 MHz, CD3OD) d = 33.48 (C5), 34.31 (C4,6), 49.82
123

68
Struct Chem (2012) 23:61–69
(C2), 60.42 (5-CH2e–), 66.61 (5-CH2a–), 123.42, 128.79
(tertiary aromatic carbon atoms), 144.73, 146.21 (quater-
nary aromatic carbon atoms).
(eq–eq) and (eq–ax) isomers of 15 were separated from this
mixture by a subsequent column chromatography (pentane/
dichloromethane = 1/2).
Procedure for the synthesis of 2,2-bis(mercaptomethyl)-
Procedure for the isomerization of bis(1,3-
oxathiane)spiranes 9b and 10b into spiro-1,3-dioxane-
1,3-dithiane 9a and 10a
1,3-propandiol 13
To a stirred solution of 2,2-bis(acetylthiomethyl)-1,3-prop-
andiol 6 (0.22 g, 0.872 mmol) in anhydrous THF (22 mL)
under argon, LiAlH4 (0.165 g, 4.348 mmol) was added at
RT. The stirring was continued for 16 h, then the mixture
was cooled on an ice bath and a solution of HCl 18% was
added to pH = 1.5–2. The solution was extracted with
diethylether (5 9 50 mL), and then the combined organic
phase was washed with brine (2 9 15 mL). The separated
organic phase was dried over sodium sulfate and concen-
trated. Compound 13 was obtained as strong-smelling white
crystals in 52% yield. The synthesis of this compound by
other procedures has already been reported [19, 20].
The solution of the mixture of isomers of 14 or 15 (0.020 g)
and PTSA (0.001 g, catalytic amounts) in toluene (10 mL)
was refluxed for 2 days. After cooling at RT, 1 mL KOH
0.1 M was added and the toluene solution was stirred for 1 h.
The toluene solution was washed with water (2 9 5 mL)
then the organic layer was separated and dried over anhy-
drous Na2SO4. The solvent was removed by vacuum distil-
lation, and the crude product was investigated by
chromatographical methods and by NMR spectra and the
entire transformation of 14 or 15 into 11 or 12 was observed.
3,9-Bis(m-nitrophenyl)-2,4-dioxa-8,10-dithia-spiro[5.5]
undecane (11)
Procedures for the synthesis of spiro-1,3-dioxane-1,3-
dithiane 11 and 12 and of bis(1,3-oxathiane)spiranes 14
and 15
White crystals, m.p. = 171–172 °C, Rf = 0.19 (pentane/
ethylacetate = 1/2). Yields 45% (A1). Found: C, 52.31; H,
4.31; N, 6.63; S, 14.92, C19H18N2O6S2 requires C, 52.52;
Method A
1
H, 4.18; N, 6.45; S, 14.76. H NMR (400 MHz, CDCl3) d
A solution of 2-(m- or p-)-nitrophenyl-5,5-bis(hydroxy-
methyl)-1,3-dithiane (9 or 10; 0.100 g, 0.33 mmol), m- or
p-nitrobenzaldehyde (0.060 g, 0.4 mmol), and PTSA
(0.010 g, 0.06 mmol) in toluene (10 mL) was refluxed for
10 h using a Dean-Stark trap. After the mixture was cooled
to RT, the unreacted mercapto derivative was neutralized
with KOH 0.1 M (1.5 mL). The mixture was washed with
water (2 9 10 mL), the organic layer was separated and
dried over sodium sulfate and concentrated. The crude
product was crystallized from methanol to afford 1,3-
dioxane-1,3-dithiane spiranes 11 or 12.
ppm: 2.54 (1H, dd, J = 14.3, 1.8 Hz, 11-He), 2.90 (1H, d,
J = 14.3 Hz, 11-Ha), 3.05 (1H, d, J = 14.2, 7-Ha), 3.59
(1H, dd, J = 14.2, 1.8 Hz, 7-He), 3.71 (1H, d, J = 11.6,
Hz, 5-Ha), 3.88 (1H, d, J = 11.5 Hz, 1-Ha), 3.99 (1H, dd,
J = 11.5, 2.7 Hz, 1-He), 5.19 (1H, s, 9-Ha), 5.30 (1H, dd,
J = 11.6, 2.7 Hz, 5-He), 5.55 (1H, s, 3-Ha), 7.56–7.58 (2H,
overlapped peaks, 50-H, 500-H), 7.85–7.87 (2H, overlapped
peaks, 60-H, 600-H), 8.20–8.23 (2H, overlapped peaks, 40-H,
400-H), 8.39–8.41 ppm (2H, overlapped peaks, 20-H, 200-H).
13C NMR (100 MHz, CDCl3), 27.21 (C7,11), 36.08 (C6),
50.79 (C9), 71.14, 76.13 (C1,5), 100.54 (C3), 121.49,
123.11, 123.91, 124.07, 128.96, 129.33, 129.87, 133.98
(tertiary aromatic carbon atoms), 139.64, 140.12, 148.18,
148.42 (quaternary aromatic carbon atoms), MS (APCI);
m/z = 435.1.
Method B
A solution of 2,2-bis(mercaptomethyl)-1,3-propanediol 13
(0.100 g, 0.59 mmol), m- or p-nitrobenzaldehyde (0.218 g,
1.44 mmol), and PTSA (0.015 g, 0.09 mmol) in toluene
(20 mL) was refluxed for 10 h (A1) or 2 h (A2) using a
Dean-Stark trap. After the mixture was cooled to RT, the
unreacted mercapto derivative was neutralized with KOH
0.1 M (3 mL). The mixture was washed with water
(2 9 10 mL), the organic layer was separated and dried
over sodium sulfate and concentrated. The crude product
was subjected to column chromatography (pentane/ethyl-
acetate = 1/2). Pure samples of 1,3-dioxane-1,3-dithiane
(11 or 12) were thus obtained along with a diastereomeric
mixture of bis(1,3-oxathiane)spiranes (14 or 15). The
3,9-Bis(p-nitrophenyl)-2,4-dioxa-8,10-dithia-spiro[5.5]
undecane (12)
White crystals, m.p. = 250–251 °C, Rf = 0.80 (pentane/
ethylacetate = 1/2). Yields 38% (A1). Found: C, 52.43; H,
4.51; N, 6.62; S, 14.58, C19H18N2O6S2 requires C, 52.52;
1
H, 4.18; N, 6.45; S, 14.76. H NMR (400 MHz, CDCl3) d
ppm: 2.53 (1H, d, J = 14.2, 11-He), 2.90 (1H, d,
J = 14.2 Hz, 11-Ha), 3.04 (1H, d, J = 15.0 Hz, 7-Ha),
3.59 (1H, d, J = 15.0 Hz, 7-He), 3.70 (1H, d, J = 11.9 Hz,
5-Ha), 3.87 (1H, d, J = 11.6 Hz, 1-Ha), 3.99 (1H, dd,
123

Struct Chem (2012) 23:61–69
69
J = 11.6, 1.6 Hz, 1-He), 5.18 (1H, s, 9-Ha), 5.29 (1H, dd,
J = 11.9, 1.6 Hz, 5-He), 5.54 (1H, s, 3-Ha), 7.65–7.72 [4H,
overlapped peaks, 20(200)-H, 60(600)-H], 8.20–8.24 [4H,
overlapped peaks, 30-H, 300-H, 50-H, 500-H], 13C NMR
(100 MHz, CDCl3) 27.27, 29.74 (C7,11), 36.15 (C6), 50.79
(C9), 71.15, 76.17 (C1,5), 100.70 (C3), 123.55, 124.13,
127.24, 128.99 (tertiary aromatic carbon atoms), 117.28,
131.07, 144.07, 145.08 (quaternary aromatic carbon
atoms), MS (APCI); m/z = 435.1.
J = 12.2, 2.0 Hz, 7-He), 5.81 (1H, s, 3-H), 5.85 (1H, s,
9-H), 7.62–7.65 (4H, overlapped peaks, 20-H, 200-H, 60-H,
600-H), 8.21–8.24 (4H, overlapped peaks, 30-H, 300-H, 50-H,
500-H), 13C NMR (100 MHz, CDCl3) d ppm: 34.28, 36.89
(C5,11), 43.76 (C6), 68.85, 72.78 (C1,7), 83.62, 83.82 (C3,9),
123.66, 123.71 126.89, 126,99 (tertiary aromatic carbon
atoms), 140.93, 141.10, 144.19, 145.52 (quaternary aro-
matic carbon atoms). MS (APCI); m/z = 435.1.
Acknowledgments This work was supported by CNCSIS-UEFI-
SCSU, projects number PNII-IDEI 570/2007 and 2278/2008. We are
grateful to the Sectoral Operational Programme for Human Resources
Development 2007–2013 (co-financed by the European Social Fund,
project number POSDRU/107/1.5/S/77946) for the fellowship given
to MLG.
3,9-Bis(m-nitrophenyl)-2,8-dioxa-4,10-dithia-spiro[5.5]
undecane (14, mixture of isomers)
White crystals, Rf = 0.25 (pentane/ethylacetate = 1/2).
Yields 8% (A2). 1H NMR (400 MHz, CDCl3) d ppm:
2.52–2.58 (1H, overlapped peaks, 11-He), 3.13–3.19 (2H,
overlapped peaks, 7-Ha, 11-Ha), 3.52–3.89 (4H, overlapped
peaks, 1-Ha, 5-He, 1-He, 5-Ha), 5.19–5.21 (1H, overlapped
peaks, 7-He), 5.49, 5.86 (2H, s, 3-H, 9-H), 7.55–7.57 (2H,
overlapped peaks, 50-H, 500-H), 7.82–7.84 (2H, overlapped
peaks, 60-H, 600-H), 8.21–8.24 (2H, overlapped peaks, 40-H,
400-H), 8.36–8.39 (2H, overlapped peaks, 20-H, 200-H), MS
(APCI); m/z = 435.1
References
1. Cismas¸ C, Terec A, Mager S, Grosu I (2005) Curr Org Chem
9:1287–1314
´
2. Opris D, Grosu I, Toupet L, Ple G, Terec A, Mager S, Muntean L
(2001) J Chem Soc Perkin Trans 1:2413–2420
´
3. Terec A, Grosu I, Condamine E, Breau L, Ple G, Ramondenc Y,
Rochon FD, Peulon-Agasse V, Opris D (2004) Tetrahedron
60:3173–3189
´
¨
4. Grosu I, Mager S, Ple G, Turos I, Mesaros E, Schirger I (1998)
Monatsh Chem 129:59–68
´
3,9-Bis(p-nitrophenyl)-2,8-dioxa-4,10-dithia-
spiro[5.5]undecane (15, eq–eq isomer)
5. Grosu I, Bogdan E, Ple G, Toupet L, Ramondenc Y, Condamine
M (2003) Eur J Org Chem
E, Peulon-Agasse V, Balog
16:3153–3161
´
6. Balog M, Grosu I, Ple G, Ramondenc Y, Toupet L, Condamine E,
Lange C, Loutelier-Bourhis C, Peulon-Agasse V, Bogdan E
(2004) Tetrahedron 60:4789–4799
White crystals, m.p. = 244–245 °C, Rf = 0.36 (pentane/
CH2Cl2 = 1/2). Yields 7% (A2). Found: C, 52.67; H, 4.29;
N, 6.28; S, 14.92, C19H18N2O6S2 requires C, 52.52; H,
´
7. Mihis¸ A, Condamine E, Bogdan E, Terec A, Kurtan T, Grosu I
(2008) Molecules 10:2848–2858
8. Gaz SA, Condamine E, Bogdan N, Terec A, Bogdan E,
Ramondenc Y, Grosu I (2008) Tetrahedron 64:7295–7300
9. Grosu I, Ple G, Mager S, Martinez R, Mesaros C, Camacho BC
(1997) Tetrahedron 53:6215–6232
1
4.18; N, 6.45; S, 14.76. H NMR (400 MHz, CDCl3) d
ˆ
ppm: 2.56 (2H, dd, J = 14.2, 1.0 Hz 5-He, 11-He), 3.18
(2H, d, J = 14.2 Hz, 5-Ha, 11-Ha), 3.53 (2H, d,
J = 15.0 Hz, 1-Ha, 7-Ha), 5.19 (2H, dd, J = 15.0 Hz,
1.0 Hz, 1-He, 7-He), 5.86 (2H, s, 3-H, 9-H), 7.68 (4H, d,
J = 8.5 Hz, 20-H, 200-H, 60-H, 600-H), 8.24 (4H, d,
J = 8.5 Hz, 30-H, 300-H, 50-H, 500-H), 13C NMR (100 MHz,
CDCl3) d ppm: 26.53 (C5,11), 37.67 (C6), 69.81 (C1,7),
88.82 (C3,9), 123.68, 127.00 (tertiary aromatic carbon
atoms), 144.34, 147.37 (quaternary aromatic carbon
atoms). MS (APCI); m/z = 435.1.
´
´
10. Grosu I, Mager S, Ple G, Martinez R, Horn M, Gavino RR (1995)
Monatsh Chem 126:1021–1030
´
11. Grosu I, Mager S, Ple G, Martinez R (1996) Chirality 8:311–315
12. Terec A, Grosu I, Muntean L, Toupet L, Ple G, Socaci C, Mager
S (2001) Tetrahedron 57:8751–8758
´
13. Terec A, Grosu I, Ple G, Muntean L, Mager S (2003) Hetero-
cycles 60:1477–1519
14. Lemcoff NG, Fuchs B (2002) Org Lett 4:731–734
15. Sun XQ, Yu SL, Li ZY, Yang Y (2010) J Mol Struct
973:152–156
´
16. Mitkin O, Wan Y, Kurchan A, Kutateladze A (2001) Synthesis
1133–1142
17. Kryczka B, Descotes G (1986) Bull Pol Acad Sci Chem
33:475–482
3,9-Bis(p-nitrophenyl)-2,8-dioxa-4,10-dithia-
spiro[5.5]unde cane (15, eq–ax isomer)
White crystals, m.p. = 233–234 °C, Rf = 0.25 (pentane/
CH2Cl2 = 1/2). Yields 4% (A2). Found: C, 52.30; H, 4.03;
N, 6.67; S, 14.59, C19H18N2O6S2 requires C, 52.52; H,
18. Wan Y, Mitkin O, Barnhurst L, Kurchan A, Kutateladze A (2000)
Org Lett 2:3817–3819
19. Backer T (1938) Rec Trav Chim Pays-Bas 57:1183–1199
20. Bladon O (1950) J Chem Soc 591–594
21. Tsukatani T, Fujihara H (2005) Langmuir 21:12093–12095
1
4.18; N, 6.45; S, 14.76. H NMR (400 MHz, CDCl3) d
ppm: 2.41 (1H, dd, J = 13.7, 2.0 Hz, 11-He), 3.03 (1H, d,
J = 14.0 Hz, 7-Ha), 3.16 (1H, d, J = 13.7 Hz, 11-Ha),
3.58–3.61 (2H, overlapped peaks, 1-Ha, 5-He), 3.91–3.93
(2H, overlapped peaks, 1-He, 5-Ha), 5.28 (1H, dd,
´
22. Grosu I, Mager S, Ple G, Horn M (1995) J Chem Soc Chem
Commun 167–168
23. Grosu I, Mager S, Ple G (1995) J Chem Soc Perkin Trans
2:1351–1357
´
123