Strong axial preference of 2-S substituents in 3,4-dihydro-2H-1-benzopyrans

Article abstract of DOI:10.1080/10426500210244

The synthesis and crystal structure of a O,S,S-acetal derivative (1R*,2R*,2′S*)-1-(3,4-dihydro-2H-1-benzopyran-2- ylthio)-2-phenyl-1-phenylthiopropan-2-ol 4 are reported. The 2-S-sidechain orientation in solution determined by OCHS signals in ¹

Full text of DOI:10.1080/10426500210244

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Phosphorus, Sulfur, and Silicon and the Related
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Strong Axial Preference of 2-S Substituents in 3,4-
Dihydro-2 H -1-Benzopyrans
Kaija Sipilä a & Jarno Kansikas b
a Laboratory of Organic Chemistry, Department of Chemistry , University of Helsinki ,
University of Helsinki, PO Box 55, FIN-00014, Finland
b Laboratory of Inorganic Chemistry, Department of Chemistry , University of Helsinki , PO
Box 55, FIN-00014 University of Helsinki, Finland
Published online: 27 Oct 2010.
To cite this article: Kaija Sipilä & Jarno Kansikas (2002) Strong Axial Preference of 2-S Substituents in 3,4-Dihydro-2 H -1-
Benzopyrans, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:2, 437-446, DOI: 10.1080/10426500210244
To link to this article: http://dx.doi.org/10.1080/10426500210244
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Phosphorus, Sulfur and Silicon, 2002, 177:437–446
C
Copyright 2002 Taylor & Francis
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STRONG AXIAL PREFERENCE
OF 2-S SUBSTITUENTS
IN 3,4-DIHYDRO-2H-1-BENZOPYRANS
Kaija Sipila¨a and Jarno Kansikasb
Laboratory of Organic Chemistry, Department of Chemistry,
University of Helsinki, PO Box 55, FIN-00014 University of
Helsinki, Finlanda and Laboratory of Inorganic Chemistry,
Department of Chemistry, University of Helsinki, PO Box 55,
FIN-00014 University of Helsinki, Finlandb
(Received August 14 2001.)
The synthesis and crystal structure of a O,S,S-acetal derivative
(1R ,2R ,20S )-1-(3,4-dihydro-2H-1-benzopyran-2-ylthio)-2-phenyl-1-
phenylthiopropan-2-ol 4 are reported. The 2-S-sidechain orientation in
solution determined by OCHS signals in 1H NMR spectra is mainly
axial in all the 3,4-dihydro-2H-1-benzopyran derivatives. Compound 4
¯
crystallizes in the triclinic space group P 1 with an axial 2-S-sidechain
and an intramolecular hydrogen bond between the OH and the ether
. . .
˚
oxygen with the O O distance of 2.799(3) A.
Keywords: Conformation; crystal structure; 2-S-3,4-dihydro-2H-1-
benzopyran synthesis; O,S,S-acetal
INTRODUCTION
We have studied the syntheses and structures of crystalline O,S,S-
acetal derivatives where the O-atom belongs to a tetrahydropyran
ring. When 2-(phenylthiomethylthio)tetrahydropyran was lithiated
at 78 C in tetrahydrofuran and treated with benzaldehyde, ap-
proximately equal amounts of all the four possible diastereoisomers
3
of 1-phenyl-2-phenylthio-2-(tetrahydropyran-2-ylthio)ethanol1 were
formed. Conformations and crystallizabilities of these hydroxyalkyla-
tion products varied considerably. Crystalline products were also
Address correspondence to Kaija Sipila¨, Laboratory of Organic Chemistry,
Department of Chemistry, University of Helsinki, PO Box 55, FIN-00014.
437

438
K. Sipila¨ and J. Kansikas
obtained in the reaction where acetophenone was used as an electro-
phile.4 5 However, in alkylations of lithiated 2-(phenylthiomethylthio)-
tetrahydropyran diastereoselectivities up to 90:10 were found
but all the products were noncrystalline because of the flexibility
of the molecules.3 The O,S,S-acetal structure was modified by
changing the substituent at sulphur from phenyl to naphthyl
in order to facilitate the crystallizability. Investigations on 2-(2-
naphthylthiomethylthio)tetrahydropyran derivatives are underway.6
To slow down the conformational exchange the tetrahydropyran ring
was replaced by the 3,4-dihydro-2H-1-benzopyranyl group. In this
article the synthesis and crystal structure of a hydroxyalkylated
2-(phenylthiomethylthio)-3,4-dihydro-2H-1-benzopyran derivative,
(1R ,2R ,20S )-1-(3,4-dihydro-2H-1-benzopyran-2-ylthio)-2-phenyl-1-
phenylthiopropan-2-ol 4 are reported.
RESULTS AND DISCUSSION
The syntheses of compounds 1–4 are presented in Scheme 1. The
starting material 3,4-dihydro-2H-1-benzopyran-2-ol7 was prepared by
applying a slightly modified literature method8 using commercially
available 3,4-dihydro-2H-1-benzopyran-2-one and 1 M lithium tri-
tert-butoxyaluminohydride in tetrahydrofuran at 0 C under argon
atmosphere. 3,4-Dihydro-2H-1-benzopyran-2-ol was chlorinated with
SOCl2 by applying the method of Grob et al.9 for the preparation of
glycosyl chlorides to obtain 3,4-dihydro-2-chloro-2H-1-benzopyran 1.
Ringom and Benneche10 have mentioned 1 as an unisolated in-
termediate product. Indeed, compound 1 was very sensitive and
the product was used immediately without further purification for
SCHEME 1 The syntheses of compounds 1–4.

Dihydro-Benzopyrans
439
FIGURE 1 The X-ray single-crystal structures of compound 4 with crystallo-
graphic atom labels.
the preparation of thioacetic acid S-3,4-dihydro-2H-1-benzopyran-
2-yl ester 2. The O,S,S-acetal 2-(phenylthiomethylthio)-3,4-dihydro-
2H-1-benzopyran 3 was prepared from hydrolysed 2 and commer-
cially available chloromethyl phenyl sulfide in a one-pot reaction.4 In
the synthesis of 1-(3,4-dihydro-2H-1-benzopyran-2-ylthio)-2-phenyl-1-
phenylthiopropan-2-ol 4 from lithiated 3 and acetophenone four di-
astereomers were formed. One solid diastereomer was obtained from
the mixture of products by flash chromatography (Silica gel, CH2Cl2)
and recrystallized several times from ethanol to obtain crystals suitable
for X-ray studies. The crystallographic atom labels for 4 are presented
in Figure 1 and crystallographic and refinement data in Table I. Some
selected interatomic distances and angles are listed in Table II. Com-
¯
pound 4 crystallizes in the triclinic space group P 1 with an intramolec-
ular hydrogen bond between the hydroxyl group and the O atom of the
. . .
˚
3,4-dihydro-1-benzopyran ring with the O O distance of 2.799(3) A.
The earlier reported, closely related compound 2-phenyl-1-phenylthio-
1-(tetrahydropyran-2-ylthio)propan-2-ol 54 has the same relative
configuration. This tetrahydropyran derivative also has a similar
. . .
˚
intramolecular hydrogen bond with the O O distance of 2.816(3) A,
but however, the 2-S-sidechain is equatorially oriented. We assumed
that in 5 the hydrogen bond decreases the electron density at the ether

440
K. Sipila¨ and J. Kansikas
TABLE I The Crystallographic Data and Data Refinement for 4
Empirical formula
Formula weight
C24H24O2S2
408.55
Temperature
Wavelength
Crystal system, space group
193(2) K
0.71073 A
¯
Triclinic, P1
˚
˚
Unit cell dimensions
a = 9.7130(19) A
˚
b = 10.756(2) A
˚
c = 11.312(2) A
= 108.98(3)
= 109.19(3)
= 95.91(3)
3
˚
Volume
1025.9(4) A
Z, Calculated density
Absorption coefficient
F(000)
2, 1.323 Mg/m3
1
0.277 mm
432
Crystal size
Theta range for data collection
Index ranges
0.32 0.28 0.24 mm
2.69 to 25.50
11
h
11, 0
k
13, 13
l
12
Reflections collected/unique
Observed reflections [I > 2 (I)]
Completeness to 2 = 25.50
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2 (I)]
R indices (all data)
3995/3782 [R = 0.0332]
int
3078
99.1%
Full-matrix least-squares on F2
3782/0/253
1.020
R1 = 0.0547, wR2 = 0.1613
R1 = 0.0694, wR2 = 0.1708
3
˚
0.559 and 0.454 e.A
Largest diff. peak and hole
oxygen and hinders the p-orbital overlap with O C2 bond thus di-
minishing the anomeric effect which otherwise would favour the ax-
ial orientation.11 The same effect is evident in 1-phenyl-2-phenylthio-
2-(tetrahydropyran-2-ylthio)ethanol where the two intramolecularly
hydrogen bonded diastereomers 61 and 73 have equatorial S-sidechains
at the anomeric carbon. However, compound 4 shows remarkable pref-
erence for the axial S-sidechain orientation in spite of the hydrogen
bonding. This phenomenon might be due to the crystal packing forces.
The crystal packing of 4 is centrosymmetric triclinic with only two
molecules in the unit cell. The molecules form sheets with the thick-
ness of one b-axis length parallel to the a-c-plane. This kind of layer
forming is possible when the 2-S-sidechain is axially oriented allowing
the two-molecule thick wafer-like packing shown in Figure 2.
Most of the 3,4-dihydro-2H-1-benzopyran compounds found in the
Cambridge Structural Database (CSD 5.20 October 2000)12 are multi-
substituted. Four compounds where the ring system is monosubstituted

Dihydro-Benzopyrans
441
TABLE II Some Selected Interatomic Distances
and Angles for 4
˚
Bond lengths (A)
S1 C1
S1 C16
S2 C1
S2 C4
O2 C16
O2 C24
1.836(3)
1.819(3)
1.815(3)
1.770(3)
1.436(4)
1.389(3)
2.799(3)
O
H O
Bond angles ( )
C1 S1 C16
C1 S2 C4
104.71(14)
104.51(13)
113.27(14)
S1 C1 S2
Torsion angles ( )
C1 S1 C16 O2
C16 S1 C1 S2
C16 S1 C1 C2
C4 S2 C1 S1
C4 S2 C1 C2
S1 C1 C2 O1
S2 C1 C2 O1
C24 O2 C16 S1
68.4(2)
52.02(17)
74.3(2)
73.11(16)
155.61(18)
81.6(2)
47.4(2)
77.5(3)
15
only at C-2 were found13
each of them with a C-sidechain in an
equatorial orientation, which is the normal steric preference for a
bulky sidechain. In all of these four compounds the 3,4-dihydropyran
ring adopts a half-chair conformation. In compound 4 the 3,4-
dihydrobenzopyran ring with the half-chair conformation has torsion
angles t1, C18 C19 C24 02 of 0.6(4) and t2, O2 C16 C17 C18 of
60.3(3) . The corresponding torsion angles at the tetrahydropyran
group with the chair conformation in compounds 5–7 vary from 52.9(3)
to 56.9(7) for t1 and from 52.9(3) to 58.8(7) for t2, respectively.
˚
The axially oriented C16 S1 bond of 1.819(3) A in 4 is longer for
˚
sterical reasons than the corresponding bond of 1.794 (4)–1.810 (2) A
in 5–7 with the equatorial side chain. The distance of S1 from the central
˚
carbon atom C1 of 1.836(3) A is also somewhat longer than that of the
comparison compounds.
The conformation of the tetrahydropyran ring with the 2-SR
sidechain was reported to slightly favour the axial orientation
in solvent due to the anomeric effect.11 The S-sidechain orienta-
tions of 2-alkylthiotetrahydropyrans were approximated from the
OCHS signals of 1H NMR spectra by comparing the separation be-
tween the outer peaks J = JAX + JBX to that of trans- and cis-4-
methyl-2-methylthiotetrahydropyran, because in these compounds the

442
K. Sipila¨ and J. Kansikas
FIGURE 2 The molecular packing scheme for compound 4.
methylthio group is respectively axially (J = 5.4 Hz) and equatorially
(J = 12.7 Hz) oriented to an extent greater than 98%.16 In the 200 MHz
spectra of compounds 2–4 the OCHS signals resemble a triplet and
the sum of the coupling constants varies between 6 Hz in compound
3 to 8 Hz in compound 4, thus indicating a strong preference for the
axial orientation in CDCl3.
It is obvious that the intramolecular hydrogen bond in 4 strongly con-
tributes to the ready crystallizability. The work to separate the rest of
the diastereomers formed in the reaction of acetophenone with lithiated

Dihydro-Benzopyrans
443
3 and to define their structures and the diastereomeric ratios is under-
way in our laboratory.
EXPERIMENTAL
Thioacetic acid (97%) was purchased from Fluka and chloromethyl
phenyl sulfide (97%) and 3,4-dihydro-2H-1-benzopyran-2-one (99%)
from Aldrich and used without further purification. Acetophenone
was distilled before use. Toluene was dried by azeotropic distillation.
Tetrahydrofuran (THF) was dried by refluxing in the presence of sodium
and benzophenone and distilled. Dimethyl formamide (DMF) was pu-
rified by refluxing with CaH2 and distilled in vacuo. Flash chromatog-
raphy was carried out using Merck Silica gel 60 230–400 mesh. The
concentration of n-BuLi in hexane was determined by a literature
procedure.17 The NMR spectra were recorded on a Varian Gemini 200
spectrometer (chemical shifts in ; ppm, J; Hz). The assignments are
based on chemical shift data and DEPT measurements. The mass spec-
trum was run on a JEOL JMS-SX 102 instrument (70eV). The melting
points were determined in an open capillary tube with an Electrother-
mal apparatus and are uncorrected.
2-Chloro-3,4-dihydro-2H-1-benzopyran 1
Zinc chloride (5.2 g, 0.038 mol) was activated by melting it three times
in vacuum and allowing it to cool under argon atmosphere, 3,4-Dihydro-
2H-1-benzopyran-2-ol7 (0.55 g, 0.0037 mol) in 40 ml of dry toluene and
freshly distilled SOCl2 (3.4 g, 0.029 mol) were added at 0 C and the
mixture was stirred at room temperature over night. The precipitation
was filtered off with the aid of Celite and the solvent was evaporated to
obtain 0.5 g (80%) of 1 as a yellowish liquid.
1H NMR (200 MHz, CDCl3, ): 2.2–2.3 (m, CH2), 2.6–2.7, and 3.1–
3.3 (m, PhCH2), 6.5 (s-like m, OCHCl), 6.8–7.2 (m, arom. H); 13C NMR
(50 MHz, CDCl3, ): 20.0 (CH2), 30.4 (PhCH2), 89.9 (OCCl), 118.0, 122.9,
128.2, 130.0, 150.6 (arom. C); MS: no M+. observed (m/z 168).
Thioacetic acid S-3,4-dihydro-2H-1-benzopyran-
2-yl ester 2
Thioacetic acid (1.7 g, 0.022 mol) was slowly added to the mixture of
KOH (1.3 g, 0.023 mol) in 100 ml of DMF. The solution was cooled in an
ice bath and 3.5 g (0.021 mol) of 2-chloro-3,4-dihydro-2H-1-benzopyran
in 2 ml of DMF was added and the mixture was stirred overnight at

444
K. Sipila¨ and J. Kansikas
room temperature. Water was added and the reaction mixture was ex-
tracted with diethyl ether. The organic phase was washed with sat-
urated NaHCO3/H2O, water, and brine, dried with Na2SO4, and the
solvent was evaporated. The oily, brownish residue (3.6 g, 82%) was
purified with flash chromatography (Silica gel, CH2Cl2) to obtain 1.9 g
(43%) of 2 as a reddish brown syrup. The crude product was used with-
out further purification.
1H NMR (200 MHz, CDCl3, ): 2.10–2.25 and 2.28–2.50 (m, CH2),
2.36 (s, CH3), 2.70–3.00 (m, PhCH2), 6.3 (t, J 3.8, OCHS), 6.80–6.95
and 7.0–7.15 (m, arom. H); 13C NMR (50 MHz, CDCl3, ): 22.3 (CH2),
27.2 (PhCH2), 31.1 (CH3), 78.3 (OCHS), 117.5, 121.1, 121.3, 127.5, 129.5
(arom. C), 152.2 (arom. C O), 193.8 (C O); HRMS: 208.0566, calc. for
C11H12O2S 208.0558.
2-(Phenylthiomethylthio)-3,4-dihydro-
2H-1-benzopyran 3
Thioacetic acid S-3,4-dihydro-2H-1-benzopyran-2-yl ester (1.35 g,
6.5 mol) was hydrolyzed by the solution of 0.77 g (14 mmol) of KOH
in dimethyl sulfoxide-water (30 + 10 ml) in an ice bath. After stirring
for 1 h at the same temperature chloromethyl phenyl sulfide (1.03 g,
6.5 mol) was added and the mixture was allowed to reach room tempera-
ture by stirring overnight. After usual work up the evaporation residue
(1.35 g) was purified with flash chromatography (Silica gel, CH2Cl2 +
hexane 1:1) to obtain 0.70 g (37%) of 3.
1H NMR (200 MHz, CDCl3, ): 2.00–2.35 (m, CH2), 2.65–3.00
(m, PhCH2), 4.22 (ABq, J 13.5, SCH2S), 5.85–5.88 (t-like m, OCHS),
6.8–7.0 and 7.0–7.2 (m, arom. H); 13C NMR (50 MHz, CDCl3, ): 22.1
(CH2), 26.6 (PhCH2), 35.3 (SCH2S), 78.6 (OCHS), 117.5, 121.5, 126.8,
127.3, 128.9, 129.5, 130.2, 152.0 (arom. C); HRMS 288.0632, calc. for
C16H16OS2 288.0643.
1-(3,4-Dihydro-2H-1-benzopyran-2-ylthio)-2-phenyl-
1-phenylthiopropan-2-ol 4
2-(Phenylthiomethylthio)-3,4-dihydro-2H-1-benzopyran(0.25 g, 0.00087
mol) in 7.0 ml of THF under argon atmosphere was treated with
1.4 ml of 1.2 M n-BuLi in hexane (0.0017 mol) at 78 C. After stirring
for three hours at temperatures 78 35 C, 0.104 g (0.00087 mol)
of acetophenone was added and the mixture was stirred overnight
allowing it slowly to reach the room temperature. The reaction
mixture was poured into water, extracted with diethyl ether and
washed with saturated NaHSO3/H2O, NaHCO3/H2O, and water,
dried with NaH2SO4, and the solvent was evaporated. The yellowish

Dihydro-Benzopyrans
445
evaporation residue was purified with flash chromatography (silica
gel, dichloromethane) to obtain 0.18 g (51%) of 4 as a mixture of
diastereomers. A solid diastereomer was separated from the mix-
ture of products by flash chromatography (Silica gel, CH2Cl2) and
recrystallized several times from ethanol.
1
M.p. 73 C; H NMR (200 MHz, CDCl3, ): 1.67 (s, CH3), 1.95–2.35
(m, CH2), 2.65–3.05 (m, PhCH2), 4.27 (s, OH), 4.58 (s, SCHS), 5.74 (t, J 4,
OCHS), 6.8–7.0 and 7.0–7.2 (m, arom. H); 13C NMR (50 MHz, CDCl3, ):
22.4, 27.3, 29.4, 69.7 (SCHS), 79.3 (OCHS), 117.5, 121.5, 125.2, 127.1,
127.6, 128.0, 128.8, 129.7, 132.4, 145.4 (arom. C).
Crystal Structure
X-ray data for compound 4 were collected on a Nicolet AFC-7S four-
circle diffractometer at 193 K. The crystal was mounted on a glass fiber
using a viscose oil drops method18 and applying some grease as an ad-
hesive. Data reduction was done using the Texsan program system.19
The structure was solved by the SHELXS program20 using direct meth-
ods and refinement was done by the SHELXL software.21 H-atoms were
positioned at calculated locations using the XP program package22 and
they were refined using a riding model where their distances and angels
to the C- or O-atoms were fixed and their isotropic thermal parameters
were 1.2 and 1.5 the equivalent isotropic U-value of C or O, respec-
tively. The XP-program was also used for producing the illustrations.
ACKNOWLEDGMENTS
We thank Jorma Matikainen, Ph.D. for running the mass spectra.
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