Tuning the reactivity of oxygen/sulfur by acidity of the catalyst in Prins cyclization: Oxa-versus thia-selectivity

Article abstract of DOI:10.1021/jo402832t

An unprecedented oxa- versus thia-selectivity has been observed in Prins cyclization of 6-mercaptohex-3-en-1-ol with aldehydes. In the presence of a stoichiometric amount of strong Lewis or Bronsted acids, the reaction provides the hexahydro-2H-thieno[3,2

Full text of DOI:10.1021/jo402832t

Note
pubs.acs.org/joc
Tuning the Reactivity of Oxygen/Sulfur by Acidity of the Catalyst in
Prins Cyclization: Oxa- versus Thia-Selectivity
B. V. Subba Reddy,*,† A. Venkateswarlu,† Prashant Borkar,† J. S. Yadav,† B. Sridhar,‡ and Rene Gree§
́
́
†Natural Product Chemistry and ‡Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007,
India
§Institut des Sciences Chimiques de Rennes, Universite
́
de Rennes 1, CNRS UMR 6226, 35042 Rennes, France
S
* Supporting Information
ABSTRACT: An unprecedented oxa- versus thia-selectivity
has been observed in Prins cyclization of 6-mercaptohex-3-en-
1-ol with aldehydes. In the presence of a stoichiometric
amount of strong Lewis or Brønsted acids, the reaction
provides the hexahydro-2H-thieno[3,2-c]pyran skeleton pre-
dominantly via oxonium-Prins cyclization. In contrast, a
catalytic amount of weak Lewis or Brønsted acids provides
the hexahydro-2H-thiopyrano[4,3-b]furan preferentially
through thionium-Prins cyclization.
rins cyclization is a very useful strategy for the stereo-
2H-thiopyrano[4,3-b]furan 4a as a minor product which arises
from thionium-Prins cyclization, in moderate to high oxa-
versus thia-selectivity (entries 4−11). Among the strong acids
tested for this conversion, 1 equiv of BF3·OEt2 gave the best
result in terms of yield (85% of 3a) with 9:1 oxa/thia-selectivity
(entry 3). However, the selectivity of the reaction depends
upon the amount of acid. As seen from Table 1, the selectivity
was decreased to 1.2:1 (entry 1) when 0.1 equiv of BF3·OEt2
was used. Next, we examined the reactivity of several weak
Lewis/Brønsted acids in the above model reaction (entries 12−
24, Table 1). Surprisingly, in the presence of weak Lewis/
Brønsted acids, trans-hexahydro-2H-thiopyrano[4,3-b]furan 4a
was isolated as a major product. In the case of mild/weak acids
(at 10 mol %), a predominant formation of product 4a was
observed over 3a through thionium-Prins cyclization with
moderate to good thia- vs oxa-selectivity (entries 12−24, Table
1). Among several mild/weak acids tested, InCl3 gave excellent
results in terms of yield (75% of 4a) with 7.6:1 thia/oxa-
selectivity (entry 16, Table 1). In this case also, the selectivity
depends upon the quantity of acid but in the opposite direction.
It decreased to 1.3:1 when 1 equiv of InCl3 was used (entry
13). The two isomeric products could easily be separated by
silica gel column chromatography. In each case, the ratio of two
products was determined by crude 1H NMR spectrum.
Therefore, the selectivity of oxa versus thia and thia versus
oxa can be changed in Prins bicyclization of 6-mercaptohex-3-
en-1-ol with aldehyde by tuning the reactivity of oxygen and
sulfur with strong and weak Lewis/Brønsted acids. Next, we
examined the cooperative effect of two weaker acids.
Interestingly, a combination of a weak Lewis acid with a
P
selective synthesis of tetrahydropyran derivatives, a
skeleton which is frequently present in natural products.1
Aza- and thia-versions of Prins cyclization2 are important
approaches to generate the substituted piperidine and thia-
tetrahydropyran derivatives, respectively. In particular, thia-
tetrahydropyran plays an important role in pharmaceutical
chemistry.3−7 Though Prins cyclization is well-explored in
organic synthesis, the thia-Prins cyclization is relatively less
studied.8 Inspired by a Prins bicyclization strategy with tethered
nucleophiles,9 we have successfully demonstrated the Prins
cascade cyclization for the stereoselective synthesis of hetero-
bicycles.10 However, the scope of the reaction is still
unexplored with 6-mercaptohex-3-en-1-ol. Recently, we re-
ported the synergistic effects (cooperative catalysis) between
the Lewis acids and Brønsted acids in Prins cyclization.11 These
observations encouraged us to study the effect of acidity of the
catalyst in thia-Prins cyclization. During our study, we found
very intriguing results dealing with the nature of acid catalysts
in thia-Prins cyclization between 6-mercaptohex-3-en-1-ol and
aldehydes. Under strong acidic conditions, the hexahydro-2H-
thieno[3,2-c]pyran is formed predominantly through Prins
cyclization, whereas the weak acid provides mainly hexahydro-
2H-thiopyrano[4,3-b]furan via thia-Prins cyclization. To the
best of our knowledge, there are no reports on such oxa- versus
thia-selectivity and vice versa in Prins cyclization by tuning the
reactivity of oxygen and sulfur with acidity of the catalyst. At
first, we examined the reactivity of several Lewis and Brønsted
acids in a model reaction between (E)-6-mercaptohex-3-en-1-ol
(1) and 4-nitrobenzaldehyde in CH2Cl2 at 0 °C (entries 1−11,
Table 1).
To our surprise, in the presence of 1 equiv of strong acid, a
trans-fused hexahydro-2H-thieno[3,2-c]pyran 3a was obtained
as a major product via oxonium Prins pathway and hexahydro-
Received: December 23, 2013
Published: February 24, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. Reactivity of Various Lewis and Brønsted Acids in
Prins Cyclization of (E)-6-Mercaptohex-3-en-1-ol and 4-
Nitrobenzaldehyde
Table 2. BF3·OEt2-Mediated Synthesis of Hexahydro-2H-
thieno[3,2-c]pyran Scaffolds via Oxonium-Prins Cyclization
major
product
time
(h)
yield
b
3:4
c
a
entry olefin
R
(%)
ratio Q
1
2
3
4
5
E
Z
E
Z
E
4-nitrophenyl
4-nitrophenyl
4-bromophenyl
4-bromophenyl
3a
3b
3c
3d
3e
1
85
86
82
84
80
9:1
10:1
8.5:1
10:1
8:1
1
1
1
2,5-
1.5
dimethoxyphenyl
6
Z
2,5-
3f
1.5
78
8.2:1
dimethoxyphenyl
7
8
E
Z
E
Z
4-chlorophenyl
benzyl
3g
3h
3i
1
85
75
88
70
9:1
6.5:1
10:1
10:1
2
9
styryl
0.5
2
10
n-pentyl
3j
a
Products were characterized by 1H and 13C NMR, IR, and mass
b
spectroscopy. Yield refers to pure product after column chromatog-
raphy. Ratio was determined by H NMR of the crude product.
c
1
The above examples were further studied with 10 mol % of
InCl3 for thia-selectivity. Accordingly, treatment of 6-mercapto-
hex-3-en-1-ol with different aldehydes afforded the hexahydro-
2H-thiopyrano[4,3-b]furan derivatives 4 via thionium-Prins
cyclization, and the results are illustrated in Table 3. In each
case, product 4 was obtained predominantly with high thia-
selectivity in good yields (Table 3, entries 1−9). As evident
from Tables 2 and 3, the trans-fused products were obtained
mainly from E-homoallylic substrate, while cis-fused products
were formed selectively with Z-homoallylic substrate. 2-D
NMR studies (NOESY and DQFCOSY) were used to establish
the structure and stereochemistry of 3i and 4i.14 The
characteristic NMR peaks of 3i and 4i are shown in Figure 1.
In each case, the oxathioacetal was formed rapidly from 6-
mercaptohex-3-en-1-ol and the aldehyde. It provides the clue to
elucidate the role of this oxathioacetal intermediate in the
reaction mechanism. Therefore, in order to obtain information
on the reaction pathway, the oxathioacetal A was prepared
separately from (E)-6-mercaptohex-3-en-1-ol and 4-nitro-
benzaldehyde and then studied for its reactivity in Prins
cyclization in the presence of a strong or weak Lewis/Brønsted
acid (Table 4). A similar oxa- and thia-selectivity was observed
even with this oxathioacetal, which is consistent with the results
reported in Table 1. Therefore, product 3a was formed in the
presence of a stoichiometric amount of strong acid (BF3·OEt2
or TMSOTf) by oxonium-Prins cyclization (Table 4, entries 2
and 4), whereas product 4a was formed under the influence of a
catalytic amount of weak acid (InCl3 or p-TSA) through
thionium-Prins pathway (Table 4, entries 5 and 7) with good
selectivity.
a
The reaction was performed with strong acids for 1 h and with mild/
b
c
1
weak acids for 2 h. Isolated yields. Ratio was determined by H
NMR of the crude product.
weak Brønsted acids (1:1 ratio) in most cases reversed the
selectivity in favor of the oxonium pathway (entries 25−30,
Table 1). This result is in line with our previous experimental
studies11 and the computational studies12 indicating that such
combinations could significantly increase the acidity of
Brønsted acids.
Subsequently, we examined the scope of oxa-selectivity in the
synthesis of trans/cis-fused hexahydro-2H-thieno[3,2-c]pyrans 3
by the coupling of (E)- and (Z)-6-mercaptohex-3-en-1-ols with
aldehydes in the presence of a stoichiometric amount of BF3·
OEt2, and the results are summarized in Table 2. This method
is effective with aromatic aldehydes such as 4-bromo-
benzaldehyde, 2,5-dimethoxybenzaldehyde, and 4-chloro-
benzaldehyde (entries 2−7, Table 2). Remarkably, acid-
sensitive aldehydes such as cinnamaldehyde and phenyl-
acetaldehyde participated well in this reaction (entries 8 and
9, Table 2). Aliphatic aldehyde, that is, n-hexanal, also gave the
product in good yield (entry 10, Table 2). In all cases, product
3 was obtained predominantly via oxonium-Prins cyclization in
good yields with excellent oxa- versus thia-selectivity.
Furthermore, the structure of 3e was confirmed by X-ray
crystallography.13
On the basis of these results, we propose a tentative
mechanism for the observed oxa- versus thia-selectivity in Prins
cyclization of 6-mercaptohex-3-en-1-ol with aldehydes, as
depicted in Schemes 1 and 2. Under acid catalysis, 6-
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Note
Table 3. InCl3-Catalyzed Synthesis of Hexahydro-2H-
thiopyrano[4,3-b]furan Scaffolds via Thionium-Prins
Cyclization
Table 4. Prins Cyclization of Oxathioacetal (A) with Strong
and Weak Lewis/Brønsted Acids
a
yield (%)
b
entry
acid
equiv
time (h)
3a
4a
3a:4a ratio
1
2
BF3·OEt2
BF3·OEt2
TMSOTf
TMSOTf
lnCI3
0.1
1
1
60
85
50
76
10
30
10
40
16
30
30
10
35
11
75
56
73
50
60
45
63:37
89:11
55:45
82:18
12:88
33:67
11:89
44:56
23:77
35:65
0.5
1
3
0.1
1
major
product
time
(h)
yield
b
4:3
ratio
4
0.5
2
a
c
entry olefin
R
(%)
5
0.1
1
1
2
3
4
5
E
Z
E
Z
E
4-nitrophenyl
4-nitrophenyl
4-bromophenyl
4-bromophenyl
4a
4b
4c
4d
4e
2
2
2
2
3
75
76
80
78
74
7.6:1
7.8:1
7.4:1
7.2:1
6:1
6
lnCI3
1
7
lnBr3
0.1
1
2
8
lnBr3
1
9
p-TSA
0.1
1
2
2,5-
10
p-TSA
1
dimethoxyphenyl
a
b
1
Isolated yields. Ratio was determined by H NMR of the crude
6
Z
2,5-
4f
3
72
6.2:1
product.
dimethoxyphenyl
7
8
9
E
Z
E
4-chlorophenyl
benzyl
4g
4h
4i
2
4
1
78
68
82
7.5:1
5.4:1
7.5:1
Scheme 1. Formation of Intermediate A and Bicycles 3 and 4
Starting from 6-Mercaptohex-3-en-1-ol and Aldehydes
styryl
a
Products were characterized by 1H and 13C NMR, IR, and mass
spectroscopy. Yield refers to pure product after column chromatog-
raphy. Ratio was determined by H NMR of the crude product.
b
c
1
Scheme 2. Plausible Mechanism for Oxa- and Thia-
Selectivity
Figure 1. Characteristic NMR data of 3i and 4i.
mercaptohex-3-en-1-ol and the aldehyde will give first the
intermediates hemiacetal (X) and hemithioacetal (W) and then
the corresponding oxonium ion (B) and thionium ion (C).15
Latter derivatives can afford bicycles 3 and 4 via Prins-type
reactions and/or give oxathioacetal A by intramolecular
cyclization (Scheme 1).
In preceding results, we have shown that (i) the intermediate
A is formed very quickly during the synthesis, and (ii) similar
results are obtained if the reaction is performed starting either
from 6-mercaptohex-3-en-1-ol or from oxathioacetal A. There-
fore, it appears logical to consider that this latter intermediate
plays a key role in the selectivity. After formation of A, the
complexation of sulfur by the acid induces the C−O bond
cleavage of the thioacetal to generate an oxonium ion, affording
the hexahydro-2H-thieno[3,2-c]pyran derivative 3. On the
other hand, complexation onto the oxygen by the acid will
cleave the C−S bond and generate a thiocarbenium ion to
provide the respective hexahydro-2H-thiopyrano[4,3-b]furan
derivative 4 (Scheme 2).16
acids such as InCl3. In the case of oxa-aza or thia-aza
homoallylic trifunctional susbstrate, no aza-Prins cyclization
was observed either by strong or by weak acid even with
stoichiometric amounts.17
In summary, we demonstrated a remarkable oxa- and thia-
selectivity in Prins cyclization by changing the acidity of the
catalyst. The reaction follows the oxonium-Prins pathway
preferentially in the presence of a strong acid to provide the
hexahydro-2H-thieno[3,2-c]pyran derivatives. Conversely, in
the presence of a weak acid as catalyst, the reaction mainly
From our results, complexation to sulfur is favored in the
case of strong acids or Lewis acids such as BF3·OEt2, while
coordination to oxygen is preferred for weaker acids or Lewis
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The Journal of Organic Chemistry
Note
mL) under a nitrogen atmosphere at 0 °C.2 The resulting mixture was
stirred at ambient temperature for 1 h, and the excess lithium
aluminum hydride was quenched by adding anhydrous sodium sulfate.
Then the mixture was filtered through Celite, and the residue was
washed with hot ethyl acetate. The filtrate was dried over anhydrous
Na2SO4 and concentrated in vacuo, and the resulting crude product
was purified by column chromatography (silica gel, 60−120 mesh)
using ethyl acetate/n-hexane gradients to afford the corresponding
pure (E)-or (Z)-6-mercaptohex-3-en-1-ol.
Typical Procedure for Prins Cyclization in the Presence of
Strong Lewis or Brønsted Acid (entries 1−12, Table 1). To a
stirred solution of (E)-6-mercaptohex-3-en-1-ol (1) (0.5 mmol, 1
equiv) and 4-nitrobenzaldehyde (2a) (0.525 mmol, 1.05 equiv) in dry
dichloromethane (5 mL) under nitrogen atmosphere was added strong
Lewis or Brønsted acid (1 mmol) at 0 °C. The reaction mixture was
stirred at room temperature for 1 h and then quenched with saturated
aqueous NaHCO3 solution (1 mL), diluted with water (2−3 mL), and
extracted with dichloromethane (2 × 5 mL). The organic phases were
combined, washed with brine (2 × 2 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The resulting crude mixture was
purified by column chromatography (silica gel of 100−200 mesh)
using ethyl acetate/n-hexane gradients to afford 3a (major) and 4a
(minor) as pure products (Table 1).
Typical Procedure for Prins Cyclization in the Presence of
Mild/Weak Lewis or Brønsted Acid (entries 13−25, Table 1). To
a stirred solution of (E)-6-mercaptohex-3-en-1-ol (1) (0.5 mmol, 1
equiv) and 4-nitrobenzaldehyde (2a) (0.525 mmol, 1.05 equiv) in dry
dichloromethane (5 mL) under nitrogen atmosphere was added mild/
weak Lewis or Brønsted acid (10 mol %) at 0 °C. The reaction mixture
was stirred at the same temperature for 2 h and then quenched with
saturated aqueous NaHCO3 solution (0.5 mL), diluted with water (2−
3 mL), and extracted with dichloromethane (2 × 5 mL). The organic
phases were combined, washed with brine (2 × 2 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting crude
mixture was purified by column chromatography (silica gel of 100−
200 mesh) using ethyl acetate/n-hexane gradients to afford 4a (major)
and 3a (minor) as pure products (Table 1).
follows the thionium-Prins pathway, affording the hexahydro-
2H-thiopyrano[4,3-b]furan derivatives. By using a combination
of two weak acids, the reaction follows again the oxonium-Prins
pathway. Further, the reaction is stereoselective to provide
useful cis- and trans-fused oxa-thia and thia-oxa bicycles in a
single-step process.
EXPERIMENTAL SECTION
■
General. Dichloromethane was dried according to a standard
literature procedure. Reactions were performed in an oven-dried
round-bottom flask; the flasks were fitted with rubber septa, and the
reactions were conducted under nitrogen atmosphere. Glass syringes
were used to transfer the solvent. Crude products were purified by
column chromatography on silica gel of 100−200 mesh. Thin layer
chromatography plates were visualized by exposure to ultraviolet light
and/or by exposure to iodine vapors and/or by exposure to
methanolic acidic solution of p-anisaldehyde (anis) followed by
heating (<1 min) on a hot plate (∼250 °C). Organic solvents were
concentrated on rotary evaporator at 35−40 °C. IR spectra were
1
recorded on a FT-IR spectrometer. H NMR and 13C NMR (proton-
decoupled) spectra were recorded in CDCl3 on 300, 500, 600, or 700
MHz NMR spectrometers. Chemical shifts (δ) were reported in parts
per million (ppm) with respect to TMS as an internal standard.
Coupling constants (J) are quoted in hertz (Hz). Mass spectra were
recorded on mass spectrometer by gas chromatography electron
impact mass spectrometry (GC-EI-MS) or electrospray ionization
mass spectrometry (ESI-MS) technique.
Procedure. To a stirred solution of (E)- or (Z)-6-(tetrahydro-2H-
pyran-2-yloxy)hex-3-enyl 4-methylbenzenesulfonate [obtained via
tosylation of (E)- or (Z)-6-(tetrahydro-2H-pyran-2-yloxy)hex-3-en-1-
ol]1 (15 mmol) in N,N-dimethylformamide (30 mL) was added
potassium thioacetate (23 mmol) (Scheme 3). The reaction mixture
a
Scheme 3. Preparation of the Starting Material
Typical Procedure for Prins Cyclization in the Presence of
Mild/Weak Lewis and Brønsted Acid (entries 26-31, Table 1).
To a stirred solution of (E)-6-mercaptohex-3-en-1-ol (1) (0.5 mmol, 1
equiv) and 4-nitrobenzaldehyde (2a) (0.525 mmol, 1.05 equiv) in dry
dichloromethane (5 mL) under nitrogen atmosphere were added
mild/weak Lewis (1.0 equiv) and Brønsted acid (1.0 equiv) at 0 °C.
The reaction mixture was stirred at same temperature for 2 h and then
quenched with saturated aqueous NaHCO3 solution (0.5 mL), diluted
with water (2−3 mL), and extracted with dichloromethane (2 × 5
mL). The organic phases were combined, washed with brine (2 × 2
mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude mixture was purified by column chromatography (silica
gel of 100−200 mesh) using ethyl acetate/n-hexane gradients to afford
pure products (Table 1).
a
Reagents and conditions: (a) (i) TsCl, Et3N, DMAP, dichloro-
methane, rt, 4−5 h (90%); (ii) CH3COSK, N,N-dimethylformamide,
rt, 3 h (80−82%); (b) (i) Amberlyst-15, methanol, 1 h (90%); (ii)
lithium aluminium hydride, dry THF, 0 °C to rt, 1 h (82−85%).
was stirred at room temperature for 3 h. After completion of the
reaction as indicated by TLC, the reaction mixture was diluted with
water and extracted with ether (3 × 40 mL). The organic layer was
washed with brine (2 × 15 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting crude product was purified by
column chromatography (silica gel, 60−120 mesh) using ethyl
acetate/n-hexane gradients to afford the pure thioacetic acid esters,
(E)- or (Z)-S-6-(tetrahydro-2H-pyran-2-yloxy)hex-3-enyl esters as a
liquid in 80−82% yields, respectively. To a stirred solution of the
above thioacetic acid ester in methanol (15 mL) was added Amberlyst-
15 (2 g), and the mixture was stirred for 2−3 h at ambient
temperature. After completion, the mixture was filtered, washed with
methanol, and the filtrate was concentrated in vacuo. The resulting
crude product was purified by column chromatography (silica gel, 60−
120 mesh) using ethyl acetate/n-hexane gradients to afford the pure
(E)- or (Z)-S-6-hydroxyhex-3-enyl ethanethioate as a liquid in 90%
yield. The above hydroxy compound was dissolved in 5 mL of
anhydrous tetrahydrofuran and was added dropwise to a suspension of
lithium aluminum hydride (2 equiv) in anhydrous tetrahydrofuran (15
Procedure for the Synthesis of Hexahydro-2H-thieno[3,2-
c]pyrans (3, Table 2). To a stirred solution of (E)- or (Z)-6-
mercaptohex-3-en-1-ol (1) (0.5 mmol, 1 equiv) and aldehyde (2)
(0.525 mmol, 1.05 equiv) in dry dichloromethane (5 mL) under
nitrogen atmosphere was added BF3·Et2O (1 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for specified time.
After completion, as indicated by TLC, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution (1 mL), diluted
with water (2−3 mL), and extracted with dichloromethane (2 × 5
mL). The organic phases were combined, washed with brine (2 × 2
mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude product was purified by column chromatography (silica
gel of 100−200 mesh) using ethyl acetate/n-hexane gradients to afford
3 as a pure product (Table 2).
Procedure for the Synthesis of Hexahydro-2H-thiopyrano-
[4,3-b]furans (4, Table 3). To a stirred solution of (E)-6-
mercaptohex-3-en-1-ol (1) (0.5 mmol, 1 equiv) and 4-nitro-
benzaldehyde (2a) (0.525 mmol, 1.05 equiv) in dry dichloromethane
(5 mL) under nitrogen atmosphere was added InCl3 (10 mol %) at 0
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Note
°C. The reaction mixture was stirred at room temperature for specified
time. After completion, as indicated by TLC, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution (0.5 mL), diluted
with water (2−3 mL), and extracted with dichloromethane (2 × 5
mL). The organic phases were combined, washed with brine (2 × 2
mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude product was purified by column chromatography (silica
gel of 100−200 mesh) using ethyl acetate/n-hexane gradients to afford
4 as a pure product (Table 3).
and 1.3 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.58 (dt, J = 11.9 and 2.3
Hz, 1H), 3.18−3.05 (m, 1H), 2.89−2.68 (m, 2H), 2.13−2.03 (m, 1H),
1.91−1.48 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 154.0, 150.3,
130.7, 113.6, 112.4, 111.6, 76.9, 67.6, 56.2, 56.0, 55.8, 49.6, 33.1, 30.8,
28.6; IR (KBr) νmax 2924, 2853, 1498, 1463, 1279, 1232, 1048, 1022,
794, 709 cm−1; GC-EI-MS m/z 280 (M)+; HRMS (TOF GC-EI) calcd
for C15H20O3S 280.1133 (M)+, found 280.1143.
(3aR*,4R*,7aS*)-4-(2,5-Dimethoxyphenyl)hexahydro-2H-thieno-
[3,2-c]pyran (3f; Table 2, entry 6): 114 mg, yield 78%; solid; mp 96−
98 °C; 1H NMR (300 MHz, CDCl3) δ 7.04−6.98 (m, 1H), 6.83−6.71
(m, 2H), 5.02 (br s, 1H), 4.17−4.07 (m, 1H), 3.77 (s, 6H), 3.64−3.53
(m, 1H), 3.49−3.39 (m, 1H), 2.95−2.86 (m, 1H), 2.79−2.68 (m, 1H),
2.66−2.56 (m, 1H), 2.05−1.87 (m, 2H), 1.85−1.75 (m, 1H), 1.51−
1.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 153.7, 149.4, 131.5,
112.5, 111.9, 110.9, 74.1, 68.3, 55.8, 47.1, 44.2, 33.5, 29.3, 26.4; IR
(KBr) νmax 2928, 2841, 1500, 1464, 1276, 1216, 1086, 1047, 1023, 793,
711 cm−1; GC-EI-MS m/z 280 (M)+; HRMS (TOF GC-EI) calcd for
C15H20O3S 280.1133 (M)+, found 280.1136.
1
(E)-6-Mercaptohex-3-en-1-ol: 1.22 g, yield 85%; liquid; H NMR
(300 MHz, CDCl3) δ 5.62−5.42 (m, 2H), 3.65 (t, J = 6.8 Hz, 2H),
2.75−2.60 (m, 2H), 2.43−2.35 (m, 2H), 2.33−2.24 (m, 2H), 1.70 (br
s, 1H), 1.46 (t, J = 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 131.1,
128.4, 61.8, 38.6, 35.9, 32.2; IR (neat) νmax 2924, 2854, 1373, 1165,
1085, 811, 662 cm−1; GC-EI-MS m/z 132 (M)+; HRMS (TOF GC-
EI) calcd for C6H12OS 132.0609 (M)+, found 132.0607.
6(Z)-6-Mercaptohex-3-en-1-ol: 1.18 g, yield 82%; liquid; 1H NMR
(300 MHz, CDCl3) δ 5.60−5.45 (m, 2H), 3.67 (t, J = 6.8 Hz, 2H),
2.63−2.54 (m, 2H), 2.46−2.30 (m, 4H), 1.76 (br s, 1H), 1.44 (t, J =
7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 130.2, 127.9, 62.1, 31.5,
30.9, 24.5; IR (neat) νmax 2924, 2854, 1373, 1165, 1085, 811, 662
cm−1; GC-EI-MS m/z 132 (M)+; HRMS (TOF GC-EI) calcd for
C6H12OS 132.0609 (M)+, found 132.0608.
(3aS*,4R*,7aS*)-4-(4-Chlorophenyl)hexahydro-2H-thieno[3,2-
c]pyran (3g; Table 2, entry 7): 113 mg, yield 85%; solid; mp 76−78
1
°C; H NMR (300 MHz, CDCl3) δ 7.39−7.23 (m, 4H), 4.29−4.19
(m, 1H), 4.15 (d, J = 9.3 Hz, 1H), 3.57 (dt, J = 11.9 and 2.1 Hz, 1H),
3.13−3.01 (m, 1H), 2.92−2.70 (m, 2H), 2.14−2.04 (m, 1H), 1.91−
1.62 (m, 3H), 1.54−1.38 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
139.6, 133.6, 128.6, 127.7, 83.8, 67.6, 55.7, 49.6, 32.8, 30.9, 28.4; IR
(KBr) νmax 2922, 2855, 1485, 1251, 1080, 1019, 819 cm−1; GC-EI-MS
m/z 254 (M)+; HRMS (TOF GC-EI) calcd for C13H15ClOS 254.0532
(M)+, found 254.0533.
(3aS*,4R*,7aS*)-4-(4-Nitrophenyl)hexahydro-2H-thieno[3,2-
c]pyran (3a; Table 2, entry 1): 118 mg, yield 85%; solid; mp 100−102
1
°C; H NMR (300 MHz, CDCl3) δ 8.28−8.18 (m, 2H), 7.56−7.46
(m, 2H), 4.35−4.23 (m, 2H), 3.61 (dt, J = 12.1 and 2.3 Hz, 1H),
3.17−3.05 (m, 1H), 2.94−2.84 (m, 1H), 2.83−2.70 (m, 1H), 2.17−
2.07 (m, 1H), 1.94−1.45 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
149.3, 148.3, 127.1, 123.7, 83.4, 67.6, 55.7, 49.5, 32.8, 30.8, 28.3; IR
(KBr) νmax 2925, 2855, 1519, 1350, 1247, 1069, 852, 695 cm−1; GC-
EI-MS m/z 265 (M)+; HRMS (TOF GC-EI) calcd for C13H15NO3S
265.0772 (M)+, found 265.0773.
(3aR*,4S*,7aS*)-4-Benzylhexahydro-2H-thieno[3,2-c]pyran (3h;
1
Table 2, entry 8): 92 mg, yield 75%; viscous liquid; H NMR (500
MHz, CDCl3) δ 7.36−7.16 (m, 5H), 3.96−3.91 (m, 1H), 3.91−3.85
(m, 1H), 3.36 (dt, J = 12.5 and 2.1 Hz, 1H), 3.28−3.22 (m, 1H),
3.08−3.01 (m, 1H), 2.97−2.80 (m, 2H), 2.73−2.66 (m, 1H), 2.25−
2.03 (m, 3H), 1.88−1.77 (m, 1H), 1.76−1.66 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 138.5, 128.9, 128.4, 126.3, 78.7, 68.2, 47.6, 44.7, 41.3,
33.4, 29.6, 25.1; IR (neat) νmax 2924, 2851, 1452, 1161, 1084, 700
cm−1; GC-EI-MS m/z 234 (M)+; HRMS (TOF GC-EI) calcd for
C14H18OS 234.1078 (M)+, found 234.1085.
(3aS*,4S*,7aS*)-4-Styrylhexahydro-2H-thieno[3,2-c]pyran (3i;
Table 2, entry 9): 113 mg, yield 88%; solid; mp 90−92 °C; 1H
NMR (300 MHz, CDCl3) δ 7.44−7.20 (m, 5H), 6.64 (d, J = 15.9 Hz,
1H), 6.23 (dd, J = 15.9 and 6.8 Hz, 1H), 4.18 (ddd, J = 12.1, 4.5, and
1.5 Hz, 1H), 3.89−3.80 (m, 1H), 3.52 (dt, J = 12.1 and 2.3 Hz, 1H),
3.06−2.94 (m, 1H), 2.93−2.80 (m, 2H), 2.24−2.12 (m, 1H), 2.09−
1.98 (m, 1H), 1.85−1.39 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
136.5, 131.7, 128.5, 127.8, 126.5, 82.7, 67.1, 54.4, 49.5, 32.8, 30.9, 28.6;
IR (KBr) νmax 2927, 2855, 1443, 1239, 1071, 9970, 749, 692 cm−1;
GC-EI-MS m/z 246 (M)+; HRMS (TOF GC-EI) calcd for C15H18OS
246.1078 (M)+, found 246.1079.
(3aR*,4R*,7aS*)-4-(4-Nitrophenyl)hexahydro-2H-thieno[3,2-
c]pyran (3b; Table 2, entry 2): 119 mg, yield 86%; solid; mp 118−120
1
°C; H NMR (300 MHz, CDCl3) δ 8.27−8.17 (m, 2H), 7.54−7.44
(m, 2H), 4.88 (d, J = 3.0 Hz, 1H), 4.18 (ddd, J = 12.1, 4.5, and 1.5 Hz,
1H), 3.59 (dt, J = 12.1 and 3.0 Hz, 1H), 3.53−3.42 (m, 1H), 3.00−
2.89 (m, 1H), 2.76 (dt, J = 10.6 and 7.6 Hz, 1H), 2.54−2.42 (m, 1H),
2.02−1.79 (m, 3H), 1.46−1.34 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 149.2, 147.0, 125.8, 123.6, 78.0, 68.3, 49.4, 44.3, 32.9, 29.1, 25.7; IR
(KBr) νmax 2925, 2850, 1520, 1346, 1249, 1084, 855, 708 cm−1; GC-
EI-MS m/z 265 (M)+; HRMS (TOF GC-EI) calcd for C13H15NO3S
265.0771 (M)+, found 265.0772.
(3aS*,4R*,7aS*)-4-(4-Bromophenyl)hexahydro-2H-thieno[3,2-
c]pyran (3c; Table 2, entry 3): 128 mg, yield 82%; solid; mp 68−70
1
°C; H NMR (300 MHz, CDCl3) δ 7.52−7.45 (m, 2H), 7.25−7.18
(m, 2H), 4.24 (ddd, J = 12.1, 4.5, and 1.5 Hz, 1H), 4.14 (d, J = 9.8 Hz,
1H), 3.57 (dt, J = 12.1 and 2.3 Hz, 1H), 3.13−3.01 (m, 1H), 2.91−
2.70 (m, 2H), 2.13−2.04 (m, 1H), 1.91−1.62 (m, 3H), 1.55−1.37 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 140.2, 131.6, 128.1, 121.8, 83.9,
67.6, 55.8, 49.6, 32.9, 31.0, 28.4; IR (KBr) νmax 2938, 2860, 1491,
1344, 1228, 1156, 1087, 1024, 818, 763, 664 cm−1; GC-EI-MS m/z
298 (M)+; HRMS (TOF GC-EI) calcd for C13H15BrOS 298.0027
(M)+, found 298.0014.
(3aR*,4S*,7aS*)-4-Pentylhexahydro-2H-thieno[3,2-c]pyran (3j;
1
Table 2, entry 10): 78 mg, yield 70%; viscous liquid; H NMR (500
MHz, CDCl3) δ 3.97−3.90 (m, 1H), 3.61−3.55 (m, 1H), 3.37 (dt, J =
12.5 and 2.1 Hz, 1H), 3.32−3.24 (m, 1H), 3.06−2.99 (m, 1H), 2.93−
2.83 (m, 1H), 2.14−1.91 (m, 3H), 1.85−1.65 (m, 2H), 1.50−1.17 (m,
8H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 77.8,
68.0, 48.1, 44.7, 35.0, 33.7, 31.9, 29.7, 25.7, 25.1, 22.6, 14.0; IR (neat)
νmax 2928, 2860, 1459, 1376, 1261, 1088, 768 cm−1; GC-EI-MS m/z
214 (M)+; HRMS (TOF GC-EI) calcd for C12H22OS 214.1391 (M)+,
found 214.1390.
(3aR*,4R*,7aS*)-4-(4-Bromophenyl)hexahydro-2H-thieno[3,2-
c]pyran (3d; Table 2, entry 4): 131 mg, yield 84%; solid; mp 72−74
1
°C; H NMR (300 MHz, CDCl3) δ 7.50−7.43 (m, 2H), 7.22−7.14
(m, 2H), 4.74 (d, J = 2.8 Hz, 1H), 4.14 (ddd, J = 11.8, 4.7, and 1.5 Hz,
1H), 3.56 (dt, J = 11.8 and 2.6 Hz, 1H), 3.49−3.39 (m, 1H), 2.98−
2.88 (m, 1H), 2.81−2.68 (m, 1H), 2.47−2.34 (m, 1H), 2.03−1.75 (m,
3H), 1.55−1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 141.0, 131.3,
126.7, 120.7, 78.2, 68.3, 49.8, 44.2, 33.1, 29.2, 25.7; IR (KBr) νmax
2925, 1487, 1046, 1007, 835, 729 cm−1; GC-EI-MS m/z 298 (M)+;
HRMS (TOF GC-EI) calcd for C13H15BrOS 298.0027 (M)+, found
298.0020.
(3aR*,4R*,7aS*)-4-(4-Nitrophenyl)hexahydro-2H-thiopyrano-
[4,3-b]furan (4a; Table 3, entry 1): 104 mg, yield 75%; solid; mp
1
118−120 °C; H NMR (300 MHz, CDCl3) δ 8.23−8.17 (m, 2H),
7.57−7.51 (m, 2H), 3.91 (d, J = 10.7 Hz, 1H), 3.86−3.81 (m, 2H),
3.19−3.12 (m, 1H), 3.02−2.95 (m, 1H), 2.88−2.82 (m, 1H), 2.55−
2.48 (m, 1H), 2.16−2.07 (m, 1H), 1.88−1.76 (m, 2H), 1.56−1.45 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 148.1, 147.0, 128.7, 124.0, 82.2,
65.0, 50.6, 32.4, 29.8, 29.5; IR (KBr) νmax 2925, 1516, 1345, 1117,
1029, 860, 731 cm−1; GC-EI-MS m/z 265 (M)+; HRMS (TOF GC-
EI) calcd for C13H15NO3S 265.0772 (M)+, found 265.0774.
(3aS*,4R*,7aS*)-4-(2,5-Dimethoxyphenyl)hexahydro-2H-thieno-
[3,2-c]pyran (3e; Table 2, entry 5): 117 mg, yield 80%; solid; mp
1
104−106 °C; H NMR (300 MHz, CDCl3) δ 7.06−7.00 (m, 1H),
6.83−6.74 (m, 2H), 4.71 (d, J = 8.9 Hz, 1H), 4.23 (ddd, J = 11.9, 4.5,
2720
dx.doi.org/10.1021/jo402832t | J. Org. Chem. 2014, 79, 2716−2722

The Journal of Organic Chemistry
Note
(3aS*,4R*,7aS*)-4-(4-Nitrophenyl)hexahydro-2H-thiopyrano-
[4,3-b]furan (4b; Table 3, entry 2): 105 mg, yield 76%; solid; mp
135−137 °C; H NMR (300 MHz, CDCl3) δ 8.23−8.16 (m, 2H),
HRMS (TOF GC-EI) calcd for C14H18OS 234.1078 (M)+, found
234.1069.
1
(3aR*,4S*,7aS*)-4-Styrylhexahydro-2H-thiopyrano[4,3-b]furan
1
(4i; Table 2, entry 9): 105 mg, yield 82%; solid; mp 74−76 °C; H
7.54−7.46 (m, 2H), 4.54 (d, J = 3.8 Hz, 1H), 4.20−4.00 (m, 2H),
3.85−3.73 (m, 1H), 2.85−2.58 (m, 3H), 2.48−2.31 (m, 1H), 2.12−
2.00 (m, 1H), 1.85−1.70 (m, 1H), 1.51−1.38 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 148.3, 147.1, 128.5, 123.8, 76.9, 66.4, 46.9, 44.7, 28.0,
26.2, 23.9; IR (KBr) νmax 2930, 2888, 1514, 1346, 1258, 1045, 850, 705
cm−1; GC-EI-MS m/z 265 (M)+; HRMS (TOF GC-EI) calcd for
C13H15NO3S 265.0772 (M)+, found 265.0773.
(3aR*,4R*,7aS*)-4-(4-Bromophenyl)hexahydro-2H-thiopyrano-
[4,3-b]furan (4c; Table 3, entry 3): 125 mg, yield 80%; solid; mp 92−
94 °C; 1H NMR (300 MHz, CDCl3) δ 7.51−7.41 (m, 2H), 7.29−7.20
(m, 2H), 3.87−3.74 (m, 3H), 3.18−3.07 (m, 1H), 3.01−2.88 (m, 1H),
2.85−2.75 (m, 1H), 2.54−2.43 (m, 1H), 2.19−2.00 (m, 1H), 1.91−
1.70 (m, 2H), 1.57−1.40 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
138.7, 131.8, 129.4, 121.5, 82.4, 65.0, 50.9, 50.7, 32.6, 29.9, 29.4; IR
(KBr) νmax 2925, 2875, 1484, 1072, 1000, 844, 750 cm−1; GC-EI-MS
m/z 298 (M)+; HRMS (TOF GC-EI) calcd for C13H15BrOS 298.0027
(M)+, found 298.0029.
(3aS*,4R*,7aS*)-4-(4-Bromophenyl)hexahydro-2H-thiopyrano-
[4,3-b]furan (4d; Table 3, entry 4): 116 mg, yield 78%; solid; mp 74−
76 °C; 1H NMR (300 MHz, CDCl3) δ 7.50−7.41 (m, 2H), 7.24−7.16
(m, 2H), 4.40 (d, J = 3.6 Hz, 1H), 4.15−3.99 (m, 2H), 3.83−3.71 (m,
1H), 2.80−2.53 (m, 3H), 2.48−2.27 (m, 1H), 2.09−1.97 (m, 1H),
1.82−1.66 (m, 1H), 1.55−1.42 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 140.0, 131.6, 129.2, 121.1, 77.0, 66.5, 46.8, 45.1, 28.1, 26.3, 24.0; IR
(KBr) νmax 2923, 2849, 1482, 1246, 1132, 1085, 1004, 824, 726, 663
cm−1; GC-EI-MS m/z 298 (M)+; HRMS (TOF GC-EI) calcd for
C13H15BrOS 298.0027 (M)+, found 298.0025.
NMR (300 MHz, CDCl3) δ 7.45−7.20 (m, 5H), 6.62 (d, J = 15.9 Hz,
1H), 6.13 (dd, J = 15.9 and 9.1 Hz, 1H), 3.90−3.81 (m, 2H), 3.55 (t, J
= 9.8 Hz, 1H), 3.11−3.00 (m, 1H), 2.91 (dt, J = 13.6 and 3.0 Hz, 1H),
2.75 (td, J = 13.6 and 3.4 Hz, 1H), 2.47−2.37 (m, 1H), 2.20−2.07 (m,
1H), 1.92−1.52 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 136.4, 132.5,
128.5, 127.8, 127.5, 126.4, 81.8, 65.1, 50.4, 49.7, 32.3, 30.3, 28.6; IR
(KBr) νmax 2929, 2878, 1446, 1068, 963, 761, 690 cm−1; GC-EI-MS
m/z 246 (M)+; HRMS (TOF GC-EI) calcd for C15H18OS 246.1078
(M)+, found 246.1079.
(E)-2-(4-Nitrophenyl)-4,5,8,9-tetrahydro-1,3-oxathionine (A;
Table 4) (Spectral Data Represents a Crude Oxathioacetal): To a
stirred solution of (E)-6-mercaptohex-3-en-1-ol (1) (0.5 mmol, 1
equiv) and 4-nitrobenzaldehyde (2a) (0.525 mmol, 1.05 equiv) in dry
dichloromethane (5 mL) under nitrogen atmosphere was added strong
Lewis or Brønsted acid (0.05 mmol) at 0 °C. The reaction mixture was
stirred at room temperature for 25 min and then quenched with
saturated aqueous NaHCO3 solution (1 mL), diluted with water (2−3
mL), and extracted with dichloromethane (2 × 5 mL). The organic
phases were combined, washed with brine (2 × 2 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo to afford the
1
oxathioacetal A in quantitative yield: H NMR (500 MHz, CDCl3)
δ 8.20 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H)5.57−5.42 (m, 2H),
4.97 (s, 1H), 3.63 (t, J = 6.8 Hz, 2H), 2.76−2.53 (m, 2H), 2.35−2.22
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 147.8, 147.2, 130.9, 128.5,
123.8, 61.7, 52.9, 38.5, 35.7, 32.1: IR (KBr) νmax 2930, 2988, 1564,
1336, 1258, 945, 850, 705 cm−1; GC-EI-MS m/z 265 (M)+; HRMS
(TOF GC-EI) calcd for C13H15NO3S 265.0872 (M)+, found 265.0873.
(3aR*,4R*,7aS*)-4-(2,5-Dimethoxyphenyl)hexahydro-2H-thio-
pyrano[4,3-b]furan (4e; Table 3, entry 5): 108 mg, yield 74%; solid;
ASSOCIATED CONTENT
* Supporting Information
1
■
mp 90−92 °C; H NMR (300 MHz, CDCl3) δ 7.01 (d, J = 3.0 Hz,
S
1H), 6.86−6.72 (m, 2H), 4.42 (d, J = 11.0 Hz, 1H), 3.88−3.74 (m,
2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.23−3.11 (m, 1H), 3.04−2.90 (m,
1H), 2.84−2.73 (m, 1H), 2.53−2.42 (m, 1H), 2.19−2.01 (m, 1H),
1.95−1.71 (m, 2H), 1.61−1.44 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 153.9, 150.9, 129.0, 114.3, 113.0, 112.1, 82.5, 65.0, 56.4, 55.7, 50.9,
42.5, 32.8, 29.7, 29.3; IR (KBr) νmax 2932, 2830, 1500, 1482, 1227,
1181, 1074, 1046, 813, 711 cm−1; GC-EI-MS m/z 280 (M)+; HRMS
(TOF GC-EI) calcd for C15H20O3S 280.1133 (M)+, found 280.1126.
(3aS*,4R*,7aS*)-4-(2,5-Dimethoxyphenyl)hexahydro-2H-thio-
pyrano[4,3-b]furan (4f; Table 3, entry 6): 105 mg, yield 72%; solid;
Copies of 1H and 13C NMR spectra of products (3a−3j, 4a−4i,
E1,Z1, and A), NOESY and DQFCOSY study of compounds
(3i and 4i), ORTEP diagram of 3e, and X-ray data of
compounds 3e are provided in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: basireddy@iict.res.in. Fax: 91-40-27160512.
■
1
mp 84−86 °C; H NMR (300 MHz, CDCl3) δ 6.96−6.93 (m, 1H),
Notes
6.80−6.78 (m, 1H), 6.76−6.73 (m, 1H), 4.93 (d, J = 3.8 Hz, 1H),
4.16−3.97 (m, 2H), 3.83−3.73 (m, 8H), 2.76−2.64 (m, 2H), 2.50−
2.30 (m, 1H), 2.09−1.97 (m, 1H), 1.80−1.66 (m, 1H), 1.51−1.39 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 153.4, 150.1, 130.3, 114.8, 112.1,
111.2, 77.0, 66.5, 55.9, 55.7, 42.7, 39.9, 28.4, 26.5, 24.3; IR (KBr) νmax
2943, 2833, 1498, 1461, 1276, 1219, 1247, 1076, 1049, 1023, 877, 799,
713 cm−1; GC-EI-MS m/z 280 (M)+; HRMS (TOF GC-EI) calcd for
C15H20O3S 280.1132 (M + H)+, found 280.1133.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research has been performed as part of the Indo-French
“Joint Laboratory for Sustainable Chemistry at Interfaces”. We
thank CNRS and University of Rennes 1, France and CSIR,
India, for support. A.V. and P.B. thank the Council of Scientific
and Industrial Research (CSIR), New Delhi, for the award of
fellowships.
(3aR*,4R*,7aS*)-4-(4-Chlorophenyl)hexahydro-2H-thiopyrano-
[4,3-b]furan (4g; Table 3, entry 7): 104 mg, yield 78%; solid; mp 80−
1
82 °C; H NMR (300 MHz, CDCl3) δ 7.30 (s, 4H), 3.86−3.77 (m,
3H), 3.17−3.09 (m, 1H), 3.02−2.88 (m, 1H), 2.85−2.75 (m, 1H),
2.54−2.43 (m, 1H), 2.19−2.00 (m, 1H), 1.92−1.71 (m, 2H), 1.58−
1.40 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 138.2, 133.4, 129.1,
128.8, 82.4, 65.0, 50.9, 50.6, 32.6, 29.9, 29.4; IR (KBr) νmax 2926, 2878,
1488, 1077, 1032, 844, 753 cm−1; GC-EI-MS m/z 254 (M)+; HRMS
(TOF GC-EI) calcd for C13H15ClOS 254.0532 (M)+, found 254.0534.
(3aS*,4S*,7aS*)-4-Benzylhexahydro-2H-thiopyrano[4,3-b]furan
(4h; Table 3, entry 8): 83 mg, yield 68%; viscous liquid; 1H NMR (300
MHz, CDCl3) δ 7.36−7.16 (m, 5H), 4.09−4.00 (m, 1H), 3.99−3.89
(m, 1H), 3.88−3.76 (m, 1H), 3.54−3.45 (m, 1H), 2.87−2.67 (m, 2H),
2.66−2.55 (m, 1H), 2.53−2.22 (m, 3H), 1.99−1.88 (m, 2H), 1.75−
1.60 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 138.7, 128.8, 128.4,
126.6, 76.7, 66.3, 44.1, 41.9, 40.4, 28.3, 25.3, 23.4; IR (neat) νmax 2923,
1450, 1267, 1128, 1054, 756, 700 cm−1; GC-EI-MS m/z 234 (M)+;
REFERENCES
■
(1) For an excellent recent review on Prins reaction, see: (a) Adams,
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́
,
́
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respective ORTEP diagram of 3e are provided in Supporting
Information.
(14) The discussion on NMR and NOE studies of these compounds
has been provided in Supporting Information.
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(16) We have further established that this research occurs under
kinetic control, neither epimerization nor transformation are (3⇋4)
observed under strong or weak acidic conditions.
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