Novel chiral cyclic polysulfides with a biphenyl backbone: investigation of atropisomerism and pentathiepin ring inversion

Article abstract of DOI:10.1016/j.tet.2008.02.014

Novel axially chiral benzopolysulfides were synthesized on biaryls by sulfurization of dithiastannoles. Pentathiepin, trithiole, and trithiole 2-oxide rings were observed as single isomer on 1,1′-biaryls. The rotational energy barrier of chiral axis was i

Full text of DOI:10.1016/j.tet.2008.02.014

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Tetrahedron 64 (2008) 3751e3759
www.elsevier.com/locate/tet
Novel chiral cyclic polysulfides with a biphenyl backbone: investigation
of atropisomerism and pentathiepin ring inversion
*
Ryu Sato , Ashraful Alam, Hidetoshi Ohta, Ko-ei Mori, Yuki Sato, Masayoshi Okawa,
Masashi Tada, Shiduko Nakajo, Satoshi Ogawa, Tatsuya Yamamoto
Department of Chemical Engineering, Faculty of Engineering, Iwate University, Morioka 020-8551, Japan
Received 18 December 2007; received in revised form 6 February 2008; accepted 6 February 2008
Available online 8 February 2008
Abstract
Novel axially chiral benzopolysulfides were synthesized on biaryls by sulfurization of dithiastannoles. Pentathiepin, trithiole, and trithiole
2-oxide rings were observed as single isomer on 1,10-biaryls. The rotational energy barrier of chiral axis was increased by incorporation of
a methyl group at ortho-position. In that case, both trithiole oxide and pentathiepin rings appeared as diastereomer. ortho-Tolyl functionality
was also replaced by naphthyl moiety to create more rotational hindrance. Chiral axis was incorporated at the neighborhood of polysulfide func-
tionality by SuzukieMiyaura cross-coupling reaction. Calculated rotational energy barriers were very much consistent with experimental obser-
vations to show atropisomerism. Energy barrier for the inversion of pentathiepin ring was experimentally determined by variable temperature 1H
NMR. The kinetic data suggested that pentathiepin ring inversion was prompt in solution. Insufficient rotational energy barriers of chiral axis and
pentathiepin ring inversion make substantially impossible to separate optically pure diastereomer even by chiral chromatography [Preliminary
report: Sato, R.; Ohta, H.; Yamamoto T.; Nakajo, S.; Ogawa, S.; Alam, A. Tetrahedron Lett. 2007, 48, 4991e4994.].
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Axial chirality; Diastereomer; Biphenyl backbone; Pentathiepin; Ring inversion
1. Introduction
pentathiepin ring has inspired us to make polysulfide function-
ality on selected biaryls having substituents around the locked
bond.
Rotationally hindered biaryls with rigid chiral frameworks
appeared as the most successful reagents and catalysts in mod-
ern synthetic chemistry.2 Axially chiral biaryls are of impor-
tance not only as chiral ligands in asymmetric reactions but
also for biologically active natural products. Axially chiral
molecules are widely found in nature and exhibit a broad
range of biological activities and therefore a continuous effort
has been devoted to their synthesis.3 The rotation about the
s-bond of 1,10-biaryls and its derivatives is an important de-
signing factor to generate atropisomerism. Syntheses of cyclic
polysulfides on rotationally hindered biaryls are extremely at-
tractive choice, as their polysulfide derivatives are not yet ex-
plored on rotationally hindered systems.4,5 Slow inversion of
A small number of chiral benzopolysulfides have been re-
ported so far. Varacin is the first naturally occurring benzopo-
lysulfide, which showed potential antifungal and cytotoxic
1
activities.6 It is also reported that H NMR signals assigned
to the side chain methylene proton of some varacin derivatives
are complex multiplets, rather than simple one. Pentathiepin
ring hinders the rotation around the side-chain bonds of vara-
cins. Moreover, a barrier to interconversion of the low energy
conformations of the pentathiepin ring induces asymmetry into
the molecule, causing these protons to become diastereotopic.7
Searle et al. also observed chirality for lissoclinotoxin A
derivatives. They also quoted an interesting conclusion that
asymmetric pentathiepins are chiral at least on NMR time
scale although some compounds were racemized during isola-
tion.8 The origin of the chirality for pentathiepin is best
* Corresponding author.
E-mail address: rsato@iwate-u.ac.jp (R. Sato).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.014

3752
R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
explained by slow inversion of the pentathiepin ring.7e9 Inter-
esting feature is that chirality is not yet observed for its
trithiole or other cyclic polysulfur systems. Since then, benzo-
pentathiepins have received considerable attention in the light
of structural diversity and biological activities.10,11 Almost all
chiral benzopentathiepins were found to show biological activ-
ity and therefore we appended our attention to develop benzo-
penathiepin having chiral axis at the neighborhood of the
pentathiepin ring.
Thus, it was sufficiently increased by adding one methyl group
near to rotational axis.
R
B(OH)2
R
i
i
i
i
SPr
SPr
S
S
Me
Me
R
SPr
SPr
b
a
Sn
+
I
1
Axial chirality is closely associated with the stereoisomers
resulting from the hindered rotation about the single bond,
where the barrier to rotation is high enough to allow for the
isolation of the conformers. The conditions for the existence
of stereoisomerisms have been defined as one where stereoiso-
mers can be isolated and have a half-life of at least 1000 s.12
Derivatizations of pentathiepin with chiral axis would provide
atropisomeric products, which might be detectable by spec-
troscopy. Hence, naphthalene moiety was selectively incorpo-
rated near to polysulfide ring to give axially chiral
benzopolysulfides.
2 (R = H)
3 (R = Me)
4 (R = H)
5 (R = Me)
6 (R = H)
7 (R = Me)
Scheme 1. (a)Pd(PPh3)4 (2 mol %), CsCO3 (1 equiv), DMF/H2O, 120 ꢀC, 6 h;
(b) (i) Na (excess)/pyridine, reflux, 2 h, (ii) NaBH4/THF/EtOH, (iii) H3Oþ,
(iv) Me2SnCl2.
2.2. Synthesis of trithiole ring on 1,10-biphenyl
Stannoles 6 and 7 were converted into corresponding tri-
thiole 2-oxide by a common procedure quantitatively (Scheme
2).1 Compound 8 was a single isomer. However, for increasing
the rotational energy barrier of CaryleCaryl bond by incorpora-
tion of a methyl group, its derivative 9 appeared as diastereo-
mer.15 It has been pointed out that enantiomerically stable
biaryls require at least three ortho-substituents to avoid the
racemization due to the rotation around the internal bond of
biaryls.16 Compound 9 having two ortho-substituents on the
biphenyl backbone was observed as diastereomer.17 In general,
those biphenyls in which the mono-substituted aromatic ring
had an sp3 carbon at the ortho-position were stable toward ra-
cemization.18 For example, methyl group significantly retards
racemization. On the other hand, electron withdrawing ortho-
substituent group also inhibits the racemization process.19 Sul-
finyl oxygen withdraws electron from aromatic ring. Hence,
although compound 9 is a di-ortho-substituted biphenyl, it
showed diastereomeric character. However, rotational energy
barrier was too low to separate optically pure diastereomer
by chromatography. Compound 9 lost its diastereomerism
upon reduction of sulfinyl oxygen with SmI2 in THF. The
evidences for generation of diastereomerism are shown in
Figure 1. Methyl protons of 9 showed two singlets at 2.09
and 2.19 ppm in 1H NMR. The peaks indicated that compound
11 was a single isomer due to loss of sulfinyl oxygen. Axial or
equatorial arrangements of sulfinyl oxygen in respect of
methyl group can promote the chirality. Observation of 9 in
solution for a long time reveals the variation of diastereomeric
ratio. The ring inversion of trithiole 2-oxide is not so prompt
and it seems to help the molecule to separate into two isomers.
2. Results and discussion
2.1. Synthesis of 2,2-dimethyl-4-phenyl-1,3,2-benzo-
dithiastannol
The routes for the synthesis of cyclic polysulfides on
1,10-binaphthyls are presented in Scheme 1. Reaction of 1,2-
benzenedithiol with 2-iodopropane afforded 1,2-bis(isopro-
pylthio)benzene in 79% yield.13 Selective ortho-lithiation of
1,2-bis(isopropylthio)benzene with n-BuLi in hexane/TMEDA
and successive iodination with I2/Et2O gave 1-iodo-2,3-bis-
(isopropylthio)benzene (1) in 66% yield, a suitable element
for SuzukieMiyaura cross-coupling reaction. Both asymmet-
ric and symmetric CeC cross-coupling reactions were per-
formed between 1 and boronic acid derivatives (2 or 3) in
DMF/H2O in the presence of CsCO3 as base and Pd(PPh3)4
as catalyst.14 In the case of reaction of 1 and 2, cross-coupling
product 4 was isolated in excellent yields. The 1H NMR spec-
trum of all isopropyl protons of 4 appeared as clear septet and
doublet, respectively. The results indicated that rotation of iso-
propyl group occurred freely and CaryleCaryl bond did not af-
fect on the rotation. Hence, compound 4 was a single isomer
each. After dealkylation of isopropylthio group of compound
4 with Na/pyridine, we protected unstable dithionates with
dimethyl tindichloride to give 2,2-dimethyl-4-phenyl-1,3,2-
benzo dithiastannole (6) in 47% yield. Since the cross-
coupling reaction of 1 with 2 gave successfully compound 4,
the synthesis of 2,2-dimethyl-4-(o-tolyl)-1,3,2-benzodithia-
stannole (7) was performed without thorough isolation of coup-
ling intermediate 2,3-bis(isopropylthio)-20-methylbiphenyl
(5). As a result of such procedures, we achieved the valuable
protected compound 7 from 1 and 3 in 39% yield. Spectro-
scopic data anticipated well for structural elucidation of the
generated molecules. The energy of rotational barrier is an im-
portant criterion to resolve the racemates into diastereomer.
R
R
R
a
S
S
S
S
Me
Me
b
S
S
Sn
S O
S
6 (R=H)
7 (R= Me)
8 (R=H)
9 (R= Me)
10 (R=H)
11 (R= Me)
Scheme 2. (a) SOCl2/THF, rt, 0.5 h; (b) TMSOTf/THF, SmI2, ꢁ78 ꢀC, 15 min.

R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
3753
S
S
S
S
S
a
6
12
S
S
S
S
S
S
S
S
S
S
Me
a
Me
7
rac
rac
13
Scheme 3. (a) S2Cl2 (1.5 equiv)/CH2Cl2, rt, 1 h.
One fundamental question arises about atropisomerism.
What are the determining factors for generation of diastereo-
merism for axially chiral benzopentathiepin, either rotation
hindrance or pentathiepin ring geometry? Observation of dia-
stereomerism for its different derivatives by NMR reveals that
Figure 1. 1H NMR spectra of (a) compound 9 and (b) compound 11.
Even by chiral chromatographic separation of 9, we noticed
their mutual interconversion by rotation around the biphenyl
bond. In fact, starting from one enriched fraction of 9, the
same equilibrium ratio was reached in CCl4 solution. Partial
recrystallization at low temperature also did not afford any
suitable optically pure single crystal.
2.3. Synthesis of pentathiepin ring on 1,10-biphenyl
Stannoles 6 and 7 were treated with S2Cl2 in THF to give
stable pentathiepin rings (Scheme 3). 6-Phenylbenzopentathi-
epin (12) was isolated as a single isomer in 36% yield.4,20 Pen-
tathiepin ring in 12 does not interfere about the rotation of
chiral axis. In another hand, formation of two diastereomers
(13) was observed for the reaction of 7 at 1:1 isomeric ratio
determined by NMR measurement in 53% yield. The central
bond rotation was hindered for introduction of both methyl
group and pentathiepin ring (Fig. 2). In 1H NMR, methyl pro-
tons appeared at 1.99 and 2.17 ppm as two singlets. In 13C
NMR, methyl carbons also appeared at 20.26 and
20.86 ppm. These two diastereomers were always in equilib-
rium in solution. Therefore, the isolation of diastereoisomer
as an optically active form is substantially impossible. The
products 13 have low rotational energy barrier and one isomer
exhibits fast pentathiepin ring inversion to another in the ex-
perimental conditions. Diastereomeric peaks were also calcu-
lated by B3LYP/6-31G(d) level for each optically pure isomer
and the calculations were very much consistent with the experi-
mental values. The calculated values were summarized in
Table 1. NMR time scale for the isomerization of 13 was suf-
ficient to trace diastereomer.
Figure 2. Partial 1H (upper) and 13C (lower) NMR peaks of methyl group of 13
clearly showed diastereomer due to the combination of both axial chirality and
pentathiepin ring inversion.

3754
R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
Table 1
Experimental and calculated 13C and 1H NMR chemical shift values (ppm)
of 13
1,2,3-benzotrithiole (18) in 26% yield as a single product.
Although, compound 18 was isolated as a single product but
its 2-oxide (17) was a diastereomeric mixture, as evident by
1H NMR spectra. Electron withdrawing sulfinyl functionality
generated enantiomerism as like as compound 9. Difficult in-
version behavior of 9 makes the molecule into diastereomer.
Five-membered trithiole ring has one conformational state.21
An appearance of complex multiplets of 17 in H NMR spec-
tra also implied that it existed as a diastereomeric mixture at
least in NMR time scale.
Expt.a
Calcd
13C NMR
1H NMR
a
20.25
20.86
2.17
20.33b
20.76b
2.14c
1.99
1.92c
1
The NMR spectra were measured in CDCl3 by using TMS as an internal
standard.
b
The calculated chemical shifts were difference of C magnetic shielding
tensor of 13 calculated by GIAO-HF/6-311þG(2d,p)//B3LYP/6-31G(d).
c
The calculated chemical shifts were difference of H magnetic shielding
tensor of 13 calculated by GIAO-HF/6-311þG(2d,p)//B3LYP/6-31G(d).
S
S
S
S
S
O
S
a
b
16
rotational energy barriers are vital for generation of atro-
pisomer but pentathiepin ring inversion makes it impossible
to isolate as pure form.
17
18
Scheme 5. (a) SOCl2/THF, rt, 0.5 h; (b) TMSOTf/THF, SmI2, ꢁ78 ꢀC, 15 min.
2.4. Incorporation of axial chirality on cyclic polysulfides by
naphthyl moiety
2.6. Synthesis of pentathiepin rings having axial chirality
Asymmetric SuzukieMiyaura cross-coupling reaction also
enabled for the successful features of naphthyl moiety. Com-
pound 1 was utilized as aromatic halide component for the
cross-coupling reaction. Typical reaction was performed quan-
titatively between 1 and 14 in DMF/H2O in the presence of
Our main focus was to explore pentathiepin ring having
axial chirality. Therefore, compound 16 was treated with
1.5 equiv of S2Cl2 in CH2Cl2 in the presence of BF3$OEt2 to
give 19 in overall 53% yield (Scheme 6).4,20 Diastereomeric
1
CsCO3 as base and Pd(PPh3)4 as catalyst (Scheme 4). In H
1
peaks were clearly observed for 19 by H NMR. One doublet
NMR spectra, compound 15 gave two AB type doublets at
d 1.44 and 1.46 ppm for methyl protons of one isopropyl
group, which is located adjacent to naphthalene moiety. Re-
stricted rotation of isopropyl moiety near to naphthalene
made the protons to be magnetically nonequivalent. On the
contrary, the outer isopropyl group gave only sharp doublet
for all six methyl protons due to their free rotation. After
dealkylation of isopropylthio group of compound 15 with
Na/pyridine, we protected unstable dithionates with dimethyl
tindichloride to give 2,2-dimethyl-4-naphthyl-1,3,2-benzo-
dithiastannole (16) in 53% yield.
at d 7.15 ppm and another double doublet at d 7.23 ppm ap-
peared in 45:55 isomeric ratios by indicating two distinct
products. Peaks for each optically pure isomer were assigned
after partial separation of mixture by Gel Permeation Liquid
Chromatography (GPLC). Each enriched fraction was also
tried to resolve by partial recrystallization at <ꢁ20 ꢀC. Previ-
ously, this separation technique showed effectiveness for
separation of optically active pentathiepin derivatives.9 Com-
pound 19 has low crystallinity and polarizability. Thus, partial
recrystallization failed to isolate individual isomer.
S
S
S
PriS
S
S
Me
Me
S
S
S
Sn
S
S
S
PriS
S
B(OH)2
+
a
b
c
1
16
a
rac
rac
15
14
19
16
Scheme 4. (a) Pd(PPh3)4 (2 mol %), CsCO3 (1 equiv), DMF/H2O, 120 ꢀC, 6 h;
(b) (i) Na (excess)/pyridine, reflux, 2 h, (ii) NaBH4/THF/EtOH, (iii) H3Oþ; (c)
Me2SnCl2.
Scheme 6. (a) S2Cl2 (1.5 equiv)/BF3$OEt2, CH2Cl2, rt, 1 h.
The separated enriched fraction from each chromatogram
was collected from GPLC column but the product was a mix-
ture rather than a pure diastereomer. Further attempts of partial
recrystallization also did not afford single product. In course
of time, the minor diastereomer was observed more in the so-
lution. After two days, one separated fraction was completely
back to original mixture. In solution, diastereomer (19a or
19b) cannot exist as pure state for slow reversible inversion
of the pentathiepin ring. Restricted rotation of chiral axis
2.5. Synthesis of five-membered rings having axial chirality
Stannole 16 was converted to 4-(1-naphthyl)-1,2,3-benzo-
trithiole 2-oxide (17) quantitatively according to Scheme 5.
In IR spectra, strong sulfinyl group stretching vibration was
observed at 1104 cmꢁ1. Subsequent reduction of 17 with
TMSOTf/SmI2 in THF at ꢁ78 ꢀC yielded 4-(1-naphthyl)-

R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
3755
and conformation of pentathiepin rings made each optically
1
increases the rotational energy barriers by inductive effect. De-
tailed calculations of various types of 1,10-binaphthyl having
cyclic polysulfides moieties revealed that more than 20 kcal/
mol rotational energy barrier is required for atropisomerism.
pure diastereomer (19a or 19b) into enantiomer. H and 13C
NMR spectra were, however, not perfectly assigned for these
compounds because of their difficult resolution properties. Op-
tically pure benzopentathiepin was yet resolved by any author
and all previous assignments were also on the basis of NMR
signals after partial separation.
2.8. Conformational analysis of diastereomer 19 by variable
1
temperature H NMR
2.7. Theoretical rotational energy barriers of 1,10-binaphthyl
Compound 19a and 19b are the conformational isomers.
Since the pentathiepin rings existed along with the naphthyl
moiety as chiral auxiliary, these two molecules are diastereo-
mers in respect to the conformation of pentathiepin rings and
locked axis.22 One pure isomer (19a or 19b) was almost iso-
lated by GPLC analysis but once collected from column, the
compound started to transform into mixture. But in solid state,
both isomers were found stable. Measurements of 1H NMR of
approximately pure isomer of 19a in CDCl3 solution after ev-
ery 5 h interval revealed that the compounds were isomerized
to each other in solution. Isomerization can only be stopped by
solid-state preservation or incubation of sample at low temper-
ature. Therefore, in order to verify the inversion energy of pen-
tathiepin ring experimentally and to accumulate data for
activation parameters of the molecule, its isomerization was
monitored at 303, 308, 313, and 318 K. Typically the results
of isomerization of 19 are shown in Figure 3. The calculated
kinetic parameters are presented in Table 3. The isomerization
of these compounds was first order. Furthermore, as shown in
Figure 4, the Eyring treatment of the rate constant of 19, ob-
tained at those temperatures, enabled us to calculate the acti-
vation parameters of the molecule. All thermodynamic
parameters 298DGs, DHs, and DSs of 19 are calculated.
The value of 298DG* was about 24.28 kcal/mol, suggesting
Calculated rotational energy barriers are presented in Table
2. For compound 19, the value was ca. 25.49 kcal molꢁ1 and it
was high enough to generate corresponding diastereomerism.
Naphthyl moiety acted as like as asymmetric chiral center in
respect of benzopentathiepin ring. Although for the most
part stable atropisomers are orthoeortho0 tetrasubstituted bi-
aryls,15 a sufficient high rotational barrier about the biaryl
linkage has been shown in few congested di- or trisubstituted
biphenyls. The twisting of biphenyl skeleton can be induced
by pentathiepin and trithiole oxide giving rise to optically
active atropisomers as diastereoisomeric mixtures. Rotational
energy barriers are crucial factor to generate atropisomers.
Therefore, compound 12 has very low rotational energy
(11.7 kcal/mol) barrier hence experimentally diastereoisomer-
ism was not yet observed in NMR time scale. The rotational
energy barriers are generally increased due to addition of me-
thoxy and isopropyl groups at ortho-positions. For incorpora-
tion of one methyl group in 12, the theoretical rotational
energy barrier was increased from 11.7 to 23.8 kcal/mol.
The value was high enough to form diastereomer. As a conse-
quence, the similar atropisomerisms were also observed
for 1-phenylnaphthalenepolysulfides. Sulfinyl oxygen also
Table 2
Calculated biaryl rotational energy barriers of polysulfur derivatives of
1,10-binaphthyls
Compound
Relative energy
(kcal/molꢁ1
Compound
Relative energy
(kcal/molꢁ1
)
)
MeO
19.2
11.8
iPr
S
S
S
Figure 3. The representative kinetic data for the inversion of the pentathiepin
ring of compound 19; [Xe]: equilibrium concentration; [XeꢁX]: concentration
as a function of time.
S
11.7
23.8
19.0
25.5
S
S
S
S
S
Table 3
Kinetic and thermodynamic parameters of compound 19
S
S
S
S
(1.79ꢂ0.053)ꢃ10ꢁ5 sꢁ1
(3.74ꢂ0.023)ꢃ10ꢁ5 sꢁ1
(7.08ꢂ0.017)ꢃ10ꢁ5 sꢁ1
(11.61ꢂ0.328)ꢃ10ꢁ5 sꢁ1
24.28ꢂ0.015 kcal/mol
23.32ꢂ0.021 kcal/mol
ꢁ3.199ꢂ0.123 eu
Me
303 K
308 K
313 K
318 K
DG**
DH**
DS**
S
S
S
S
S
Calculated by B3LYP/6-311þG(2d,p)//B3LYP/6-31G(d) level (energy differ-
ence between the most stable conformer and the transition state of the
arylearyl rotation).

3756
R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
of Iwate University. Chiral chromatographic separation was
attempted in Daicel Chemical Industries, Ltd., Japan.
4.2. 1,2-Bis(isopropylthio)benzene13
Colorless oil; bp 128e130 ꢀC (3.0 Torr); 1H NMR
(400 MHz, CDCl3) d 1.33 (d, 12H, J¼6.5 Hz, CH3), 3.49
(sept, 2H, J¼6.5 Hz, CH), 7.05e7.44 (m, 4H, ArH).
4.3. 1-Iodo-2,3-bis(isopropylthio)benzene (1)
1,2-Bis(isopropylthio)benzene (7.47 g, 33 mmol) was dis-
solved in the dry hexane (75 ml) in 200 ml three-neck reactor.
The solution was cooled down to 0 ꢀC. TMEDA (8.6 ml,
59 mmol) was added into the reaction mixture. n-BuLi
(2.67 M, 18.5 ml, 49.5 mmol) was slowly added into the reac-
tion mixture under constant stirring. The reaction mixture was
stirred for 2 h at the same temperature. Iodine (12.56 g,
49.5 mmol) was dissolved in dry ether. The iodine solution
was slowly added into the reaction mixture. The reaction mix-
ture was further stirred for 18 h at room temperature. The so-
lution was neutralized and extracted with CH2Cl2. Running
a silica gel column chromatography by using hexane as eluent
gave product 1 (7.90 g) in 66% yield. Colorless oil, bp 122e
125 ꢀC (0.5 Torr); 1H NMR (400 MHz, CDCl3) d 1.29 (d,
6H, J¼6.7 Hz, CH3), 1.38 (d, 6H, J¼6.7 Hz, CH3), 3.42
(sept, 1H, J¼6.7 Hz, CH), 3.58 (sept, 1H, J¼6.7 Hz, ArH),
6.90 (dd, 1H, J¼7.9, 7.9 Hz, ArH), 7.19 (dd, 1H, J¼7.9,
0.9 Hz, ArH), 7.70 (dd, 1H, J¼7.9, 0.9 Hz, ArH); 13C NMR
(101 MHz, CDCl3) d 22.5, 22.9, 36.5, 40.5, 112.5, 126.0,
130.0, 135.8, 136.4, 146.0; IR (neat) 2962, 2922, 2864,
1538, 1420, 1239, 1190, 1154, 1051, 768, 737 cmꢁ1; MS
(70 eV) m/z 352 [M]þ. Anal. Calcd for C12H17IS2: C, 40.91;
H, 4.86. Found: C, 41.30; H, 4.97.
Figure 4. Eyring treatment with the standard deviation for the inversion of the
pentathiepin ring of 19.
that the inversion of pentathiepin ring proceeds at room tem-
perature. The value of DSs also suggested that the isomeriza-
tion was due to the pentathiepin ring inversion. The inversion
of the ring proceeded fast at higher temperature in polar sol-
vents. Therefore, chiral chromatographic separation method
was also unable to isolate diastereomer.9
3. Conclusion
Two reasons are notable concerning generation of diaste-
reomerism. The energy barriers for the inversion of pentathi-
epin ring in solution and the NMR time scale are adequate
to recognize them. Secondary, high rotational energy barrier
of central bond acted as chiral auxiliary to resolve them into
diastereomer. In addition, theoretical calculations and variable
1
temperature H NMR experiments provided sufficient support
to trace the atropisomers for all axially chiral cyclic
benzopolysulfides.
4. Experimental
4.4. 2,3-Bis(isopropylthio)biphenyl (4)
4.1. General
Compound 1 (1.58 g, 4.5 mmol), phenylboronic acid
(0.54 g, 4.5 mmol), CsCO3 (1.46 g, 4.5 mmol), and Pd(PPh3)4
(0.26 g, 0.23 mmol) were placed in a reactor fitted with a con-
denser under nitrogen atmosphere. Predried DMF (15 ml) was
added into the reaction mixture. The reaction mixture was re-
fluxed for 24 h by placing it in oil bath. The reactor was cooled
down to room temperature and quenched with water. The
product was extracted with CH2Cl2 after acidification by dilute
HCl. The extracted solution was dried over MgSO4 and excess
solvent was removed by evaporation. The remaining DMF was
separated by distillation. Running a silica gel column chroma-
tography by using hexane as eluent gave pure product 4
(1.11 g, 82% yield). Colorless oil; bp 134.0e135.2 ꢀC
(0.4 Torr); 1H NMR (400 MHz, CDCl3) d 0.97 (d, 6H,
J¼6.8 Hz, CH3), 1.42 (d, 6H, J¼6.7 Hz, CH3), 2.93 (sept,
1H, J¼6.8 Hz, CH), 3.51 (sept, 1H, J¼6.7, CH), 7.06e7.39
(m, 8H, ArH); 13C NMR (101 MHz, CDCl3) d 22.7, 22.8,
35.9, 39.0, 125.1, 126.8, 126.9, 127.5, 128.3, 129.7, 130.9,
141.8, 145.0, 148.2; IR (neat) 2961, 1549, 788 cmꢁ1; MS
Melting points were measured with a MEL-TEMP capillary
1
melting point apparatus and are uncorrected. H (400 MHz)
and 13C (101 MHz) NMR spectra were recorded on a Bruker
AC-400PinstrumentwithCDCl3 as asolvent. 1H NMRchemical
shifts are given in relative parts per million from internal TMS.
13C NMR chemical shifts are given in relative parts per million
from the internal CDCl3. Mass spectra are recorded with a
Hitachi M-2000 or JEOL JMS SX 102 spectrometer under elec-
tron ionization (70 eV). IR spectra were recorded on KBr disk
with a JASCO FT/IR-7300 spectrometer. Hexane, CH2Cl2,
THF, and DMF were freshly distilled according to standard lab-
oratory procedure prior to use. Commercial grade TMEDA was
purified by atmospheric distillation before use. All chemicals
were reagent grades and were used without further purification
unless otherwise stated. Wakogel C-200 was used for silica gel
column chromatography. Elemental analyses were recorded
using Yanaco MT-5 apparatus at the elemental analysis division

R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
3757
(70 eV) m/z 302 [M]þ; Anal. Calcd for C18H22S2: C, 71.47; H,
7.33. Found: C, 71.84; H, 7.48.
was slowly added into the reaction mixture under constant stir-
ring. The mixture was stirred for 0.5 h, extracted with CH2Cl2,
dried over anhydrous MgSO4. The solvent was removed under
vacuum. The product was separated by silica gel column chro-
matography by using CHCl3 as solvent (0.26 g, 98% yield).
4.5. 2,3-Bis(isopropylthio)-20-methylbiphenyl (5)
1
The synthetic procedure of 5 was as same as that of product
1
4 from products 1 and 3. H NMR (60 MHz, CDCl3) d 1.05e
1.40 (m, 12H, CH3,), 2.08 (s, 3H, CH3), 3.07e3.47 (m, 2H,
CH), 6.95e7.58 (m, 7H, ArH); IR (neat) 3057, 2961, 1738,
1550, 1444, 1238, 754 cmꢁ1. This compound was used to
the next reaction without further purification.
Yellow powder; mp 120.6e121.2 ꢀC; H NMR (400 MHz,
CDCl3) d 7.39 (dd, 1H, J¼1.0, 7.8 Hz, ArH), 7.41e7.46 (m,
5H, ArH), 7.43 (t, 1H, J¼7.8 Hz, ArH), 7.59 (dd, 1H,
J¼1.0, 7.8 Hz, ArH); 13C NMR (101 MHz, CDCl3) d 123.4,
127.8, 128.1, 128.4, 128.6, 128.7, 135.5, 136.2, 139.7,
140.8; IR (KBr) 1102 cmꢁ1 (S]O); MS (70 eV) m/z 264
[M]þ. Anal. Calcd for C12H8OS3: C, 54.51; H, 3.05. Found:
C, 54.35; H, 3.10.
4.6. 2,2-Dimethyl-4-phenyl-1,3,2-benzodithiastannole (6)
Product 4 (0.90 g, 3.0 mmol) was taken in a reactor fitted
with a condenser under nitrogen atmosphere. Pyridine
(20 ml) was added into the reactor. Carefully cut metallic so-
dium (0.31 g, 13.5 mmol) was also placed in it. The reaction
mixture was refluxed for 2 h by placing in oil bath. The reactor
was cooled down to 0 ꢀC and the reaction mixture was
quenched with methanol and water. The reaction mixture
was further acidified with dilute HCl and extracted with ether.
The remaining solvent was removed by evaporation. The gen-
erated dithiol was again dissolved in dry THF and the reaction
mixture was reduced with NaBH4 at room temperature. The
reaction mixture was further quenched with water, acidified
with HCl up to pH¼7e8 and protected with Me2SnCl2. The
generated stannole was extracted with CH2Cl2 and dried
over anhydrous MgSO4. Running a silica gel column chroma-
tography by using solvent CHCl3/hexane at 1:1 ratio gave
product 6 (0.53 g, 47% yield). Colorless powder; mp 208.3e
4.9. 4-(o-Tolyl)-1,2,3-benzotrithiole 2-oxide (9)
The synthetic procedure from 7 was as same as that of
product 8 (97% yield).
Yellow powder; mp 79.9e81.5 ꢀC; 1H NMR (400 MHz,
CDCl3) d 2.09e2.19 [sꢃ2, 6H (2.09:2.19 ppm¼1:1.5), CH3],
7.12 (d, 1H, J¼7.4 Hz, ArH), 7.20 (dd, 2H, J¼0.7, 7.4 Hz,
ArH), 7.27e7.37 (m, 8H, ArH), 7.42 (dd, 1H, J¼1.5,
7.9 Hz, ArH), 7.44 (dd, 1H, J¼1.5, 7.4 Hz, ArH), 7.58 (d,
2H, J¼7.9 Hz, ArH); IR (KBr) 1123 cmꢁ1 (S]O); MS
(70 eV) m/z [278]þ. Anal. Calcd for C13H10OS3: C, 56.08;
H, 3.62. Found: C, 56.28; H, 3.66.
4.10. 4-Phenyl-1,2,3-benzotrithiole (10)
The product 8 (0.22 g, 0.75 mmol) was dissolved in dry
THF (20 ml). The solution was cooled down to ꢁ78 ꢀC.
TMSOTf (0.13 ml, 0.75 mmol) solution was added into the re-
actor and the reaction mixture was stirred for 10 min at the
same temperature. A solution of SmI2 in dry THF (0.1 M)
was added into the reaction mixture. The solution was stirred
for more than 1.0 h at the same temperature. After checking
the progress of reaction by TLC, the mixture was quenched
with water and the product was extracted with CH2Cl2. Run-
ning a silica gel column chromatography by using hexane as
solvent gave pure product (0.04 g, 16% yield).
1
209.1 ꢀC; H NMR (400 MHz, CDCl3) d 0.94 (s, 6H, CH3),
6.85e6.96 (m, 2H, ArH), 7.32e7.48 (m, 6H, ArH); 13C
NMR (101 MHz, CDCl3) d 2.3, 123.9, 126.3, 127.3, 127.9,
129.0, 129.1, 137.4, 139.0, 143.3, 143.4; IR (KBr) 3052,
1381, 781 cmꢁ1; MS (70 eV) m/z 366 [M]þ. Anal. Calcd for
C14H14S2Sn: C, 46.06; H, 3.87. Found: C, 45.88; H, 3.86.
4.7. 2,2-Dimethyl-4-(o-tolyl)-1,3,2-benzodithiastannole (7)
The synthetic procedure of stannole 7 from compound 5
was as same as that of product 6 (39% yield). Colorless nee-
dles; mp 200.7e201.1 ꢀC; 1H NMR (400 MHz, CDCl3)
d 0.93 (s, 6H, CH3), 2.13 (s, 3H, CH3), 6.77 (dd, J¼0.9,
7.4 Hz, 1H, ArH), 6.96 (dd, J¼7.4, 7.7 Hz, 1H, ArH), 7.12e
7.30 (m, 4H, ArH), 7.48 (dd, J¼0.9, 7.7 Hz, 1H, ArH); 13C
NMR (101 MHz, CDCl3) d 2.1, 2.3, 19.8, 123.9, 125.6,
127.6, 128.8, 129.0, 129.8, 135.9, 138.1, 138.5, 142.9; IR
(KBr) 3456, 1383, 754 cmꢁ1; MS (70 eV) m/z 381 [M]þ.
Anal. Calcd for C15H16S2Sn: C, 47.52; H, 4.25. Found: C,
47.58, H, 4.31.
Yellow powder; mp 71.4e73.6 ꢀC; 1H NMR (400 MHz,
CDCl3) d 7.10e7.15 (m, 2H, ArH), 7.38e7.46 (m, 6H,
ArH); 13C NMR (101 MHz, CDCl3) d 122.6, 126.9, 128.1,
128.30, 128.33, 128.5, 139.4, 141.1, 141.3, 142.3; IR (KBr):
3449, 1438, 799, 756 cmꢁ1; MS (70 eV) m/z 248 [M]þ.
Anal. Calcd for C12H8S3: C, 58.03; H, 3.25. Found: C,
58.28; H, 3.26.
4.11. 4-(o-Tolyl)-1,2,3-benzotrithiole (11)
The synthetic procedure from trithiole 2-oxide 9 was as
same as that of product 10 (13% yield). Yellow powder; mp
1
4.8. 4-Phenyl-1,2,3-benzotrithiol 2-oxide (8)
152.0e153.3 ꢀC; H NMR (400 MHz, CDCl3) d 2.21 (s, 3H,
CH3), 6.93e6.95 (m, 1H, ArH), 7.10e7.15 (m, 2H, ArH),
7.21e7.37 (m, 4H,ArH); 13C NMR (101 MHz, CDCl3)
d 122.8, 126.8, 128.1, 128.2, 128.7, 128.5, 139.4, 140.1,
141.3, 142.5; IR (KBr) 3449, 1438, 799, 756 cmꢁ1; MS
Product 6 (0.36 g, 1.0 mmol) was dissolved in dry THF
(4.0 ml) under air and the reaction mixture was cooled down
to 0 ꢀC. Under constant stirring, SOCl2 (0.078 ml, 1.1 mmol)

3758
R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
(70 eV) m/z 262 [M]þ; Anal. Calcd for C13H10S3: C, 59.50; H,
3.84. Found: C, 59.55; H, 3.94.
ArH), 7.44e7.48 (m, 1H, ArH), 7.50e7.58 (m, 3H, ArH),
7.86e7.89 (m, 2H, ArH); 13C NMR (101 MHz, CDCl3)
d 2.04, 123.9, 125.4, 125.7, 125.9, 126.3, 126.7, 127.0,
127.9, 128.2, 129.3, 131.6, 133.7, 139.0, 139.1, 141.1,
141.7; IR (KBr): 3048, 1383, 779 cmꢁ1; MS (70 eV) m/z
416 [M]þ. Anal. Calcd for C18H16S2Sn: C, 52.07; H, 3.88.
Found: C, 52.38; H, 4.00.
4.12. 6-Phenyl-1,2,3,4,5-benzopentathiepin (12)
Stannole 6 (0.36 g, 1.0 mmol) was dissolved in CH2Cl2
(10 ml) in 50 ml reactor under nitrogen atmosphere. The reac-
tion mixture was cooled down to 0 ꢀC. Sulfur chloride
(0.12 ml, 1.5 mmol) was slowly added into the reaction mix-
ture at the same temperature. The reaction mixture was stirred
for 1 h at room temperature. The mixture was quenched with
water and acidified with HCl. The generated product was ex-
tracted with CH2Cl2 and dried over MgSO4. The excess sol-
vents were removed by vacuum. Running a silica gel
column chromatography by using hexane as solvent afforded
product 12 (0.11 g, 36% yield).Yellow powder; mp 88.1e
4.16. 4-(1-Naphthyl)-1,2,3-benzotrithiole 2-oxide (17)
The synthetic procedure was as same as that of product 8
(98% yield). Yellow solid; mp 185e186 ꢀC; 1H NMR
(400 MHz, CDCl3) d 7.35e7.56 (m, 3H, ArH), 7.64e7.69 (m,
5H, ArH), 7.91e7.95 (m, 2H, ArH); IR (KBr) 1392, 1104
(S]O), 782 cmꢁ1; MS (70 eV) m/z 314 [M]þ. Anal. Calcd for
C16H10OS3: C, 61.11; H, 3.21. Found: C, 61.11; H, 3.32.
1
89.6 ꢀC; H NMR (400 MHz, CDCl3) d 7.26e7.30 (m, 2H,
ArH), 7.32e7.37 (m, 2H, ArH), 7.39e7.45 (m, 3H, ArH),
7.84e7.87 (m, 1H, ArH); 13C NMR (101 MHz, CDCl3)
d 127.7, 128.0, 128.1, 128.5, 129.62, 129.68, 132.6, 135.1,
145.3, 149.1; IR (neat): 3368, 1439, 800, 757 cmꢁ1; MS
(70 eV) m/z 312 [M]þ. Anal. Calcd for C12H8S5: C, 46.12;
H, 2.58. Found: C, 46.40; H, 2.95.
4.17. 4-(1-Naphthyl)-1,2,3-benzotrithiole (18)
The synthetic procedure was as same as that of product 10
1
(26% yield). Orange needles; mp 107e109 ꢀC (decomp.); H
NMR (400 MHz, CDCl3) d 7.10e7.12 (m, 1H, ArH), 7.16e
7.20 (m, 1H, ArH), 7.35e7.37 (m, 1H, ArH), 7.45e7.54 (m,
4H, ArH), 7.60e7.63 (m, 1H, ArH), 7.90e7.93 (m, 2H,
ArH); 13C NMR (101 MHz, CDCl3) d 122.7, 125.2, 125.6,
126.2, 126.5, 126.6, 128.4, 128.9, 129.3, 129.3, 130.6,
133.6, 137.3, 138.8, 141.0, 142.7; IR (KBr) 3043, 1387,
777 cmꢁ1; UV (n-C6H14) lmax 222 (3 5.7ꢃ104), 284 (3
1.1ꢃ104) nm; MS (70 eV) m/z 298 [M]þ. Anal. Calcd for
C16H10S3: C, 64.39; H, 3.38. Found: C, 64.41; H, 3.65.
4.13. 6-(o-Tolyl)-1,2,3,4,5-benzopentathiepin (13)
The synthetic procedure was as same as that of product 12
(53% yield). Diastereomeric mixture; yellow powder; mp
88.2e89.0 ꢀC (decomp.); 1H NMR (400 MHz, CDCl3)
d 1.99 (s, CH3), 2.17 (s, CH3), 6.91e7.37 (m, ArH), 7.87e
7.89 (m, ArH); IR (KBr): 3449, 1379, 750 cmꢁ1; MS
(70 eV) m/z [326]þ. Anal. Calcd for C13H10S5: C, 47.82; H,
3.09. Found: C 48.02, H, 3.20.
4.18. 6-(1-Naphthyl)-1,2,3,4,5-benzopentathiepin (19)1
Stannole 16 (0.20 g, 0.48 mmol) was dissolved in CH2Cl2
(10 ml) containing BF3$OEt2 (0.48 mmol, 0.06 ml) in 50 ml
reactor under nitrogen atmosphere. The reaction mixture was
cooled down to 0 ꢀC. Sulfur chloride (0.06 ml, 0.72 mmol)
was slowly added into the reaction mixture at the same tem-
perature. The reaction mixture was stirred for 1 h at room tem-
perature. The mixture was quenched with water and acidified
with HCl. The generated product was extracted with CH2Cl2
and dried over MgSO4. The excess solvents were removed
by vacuum. Running a silica gel column chromatography by
using hexane as solvent afforded product 19 (0.09 g, 53%
yield). Yellow solid; mp 60e63 ꢀC; 1H NMR (400 MHz,
CDCl3) d 7.15e7.17 (m, 1H, ArH), 7.34e7.44 (m, 1H, ArH),
7.40e7.44 (m, 1H, ArH), 7.47e7.53 (m, 4H, ArH), 7.90e7.93
(m, 2H, ArH), 7.97e7.98 (m, 1H, ArH); IR (KBr) 3043, 1507,
1393, 799, 775 cmꢁ1; UV (n-C6H14) lmax 213 (3 5.1ꢃ104),
217 (3 5.1ꢃ104), 285 (3 7.7ꢃ103) nm; MS (70 eV) m/z 362
[M]þ. Anal. Calcd for C16H10S5: C, 53.00; H, 2.78. Found:
C, 52.84; H, 3.02.
4.14. 1-[2,3-Bis(isopropylthio)phenyl]naphthalene (15)
The synthetic procedure was as same as that of product 4
1
(95% yield). Colorless solid; mp 87 ꢀC; H NMR (400 MHz,
CDCl3) d 0.90 (d, 6H, J¼6.7 Hz, CH3), 1.44 (d, 3H,
J¼4.6 Hz, CH3), 1.46 (d, 3H, J¼4.6 Hz, CH3), 3.05 (sept,
1H, J¼6.7 Hz, CH), 3.56 (sept, 1H, J¼6.7 Hz, CH), 7.09e
7.11 (m, 1H, ArH), 7.33e7.37 (m, 4H, ArH), 7.42e7.51 (m,
3H, ArH), 7.84e7.88 (m, 2H, ArH); 13C NMR (101 MHz,
CDCl3) d 22.7, 22.8, 23.0, 35.9, 38.9, 124.8, 125.5, 125.5,
125.8, 126.2, 127.2, 127.5, 127.6, 128.0, 128.2, 132.2,
132.5, 133.2, 139.6, 145.0, 146.8; IR (neat) 3053, 2962,
2924, 2864, 1551, 1444, 1385, 1241, 1154, 803, 783, 734,
635 cmꢁ1; MS (70 eV) m/z 352 [M]þ. Anal. Calcd for
C22H24S2: C, 74.95; H, 6.86. Found: C, 74.94; H, 6.98.
4.15. 2,2-Dimethyl-4-(1-naphthyl)- 1,3,2-benzodithia-
stannole (16)
The synthetic procedure was as same as that of product 6
1
4.19. Attempts for isolation of diastereomer
(53% yield). Colorless solid; mp 219e221 ꢀC (decomp.); H
NMR (400 MHz, CDCl3) d 0.87 (s, 6H, CH3), 6.89e6.91
(m, 1H, ArH), 6.99e7.03 (m, 1H, ArH), 7.36e7.42 (m, 2H,
All the diastereomers were attempted to separate by partial
recystallization at cryogenic temperature. GPLC column was

R. Sato et al. / Tetrahedron 64 (2008) 3751e3759
3759
Litaudon, M.; Trigalo, F.; Martin, M.-T.; Frappier, F.; Guyot, M. Tetra-
hedron 1994, 50, 5323e5334.
also run to separate the diastereomeric mixture and after a long
recycling time two fractions were almost separated. The iso-
lated each enriched fraction was subjected to recrystallize at
<ꢁ20 ꢀC but the process did not afford any single isomer.
However, in course of time, the minor diastereomer appeared
more in the solution. Observation of one enriched fraction for
24 h in solution gave 1:1 diastereomeric mixture again. The
mixture was also attempted to separate by chiral chromatogra-
phy in Daicel Chemical Industries Ltd., Japan but the attempts
were also unable to separate the diastereomer.
8. (a) Kimura, T.; Hanzawa, M.; Horn, E.; Kawai, Y.; Ogawa, S.; Sato, R.
Tetrahedron Lett. 1997, 38, 1607e1610; (b) Kimura, T.; Hanzawa, M.;
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Y.; Ogawa, S.; Sato, R. Chem. Lett. 1999, 1305e1306.
9. Chenard, B. L.; Dixon, D. A.; Harlow, R. L.; Roe, D. C.; Fukunaga, T.
J. Org. Chem. 1987, 52, 2411e2420.
10. (a) Sato, R. Pure Appl. Chem. 1999, 71, 489e494; (b) Sato, R. Rev.
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Supplementary data
12. Sato, R.; Ohyama, T.; Kawagoe, T.; Baba, M.; Nakajo, S.; Kimura, T.;
Ogawa, S. Heterocycles 2001, 55, 145e154.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.014.
13. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483; (b)
Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723e1724;
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