Regiospecific synthesis of 2-halo-3-(2'-glucalyl)benzo[ b ]thiophenes

Article abstract of DOI:10.1021/jo5012762

A regiospecific synthetic strategy for the synthesis of 2-chloro-3-substituted benzo[b]thiophenes is developed via a dichlorocarbene insertion and sigmatropic rearrangement of an in situ generated ylide. The current protocol provides a reversed regiochemistry to the commonly employed electrophilic cyclization reaction for the synthesis of benzo[b]thiophenes and access to their hitherto under-represented chlorinated derivatives.

Full text of DOI:10.1021/jo5012762

Note
pubs.acs.org/joc
Regiospecific Synthesis of 2‑Halo-3-(2′-glucalyl)benzo[b]thiophenes
Henok H. Kinfe,* Felix L. Makolo, and Christian K. Adokoh
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, Republic of South Africa
S
* Supporting Information
ABSTRACT: A regiospecific synthetic strategy for the
synthesis of 2-chloro-3-substituted benzo[b]thiophenes is
developed via a dichlorocarbene insertion and sigmatropic
rearrangement of an in situ generated ylide. The current
protocol provides a reversed regiochemistry to the commonly
employed electrophilic cyclization reaction for the synthesis of benzo[b]thiophenes and access to their hitherto under-
represented chlorinated derivatives.
enzo[b]thiophenes are aromatic annulated sulfur-contain-
the ylide intermediate of a serendipitously formed aryl-S-
Bing five-membered heterocyclic derivatives. They have glucoside. Incorporation of the glucalyl moiety with its
inherently defined stereochemistry adds potential for further
structural elaborations.
attracted substantial attention due to their presence as key
structural components in a number of important compounds
that possess a wide range of biological activities including
antifungal,1−3 antibacterial,2,3 antiinflammatory,2−4 anti-
cancer,5,6 and antiallergy.7 Raloxifene, Arzoxifene, Zileuton,
and Sertaconazole are examples of benzo[b]thiophene-contain-
ing clinically used drugs. Furthermore, a sugar-linked benzo-
[b]thiophene, Ipragliflozin,8−10 has been recently approved in
Japan for the treatment of type 2 diabetes. Owing to their
important biological activities, a number of efficient method-
ologies for the synthesis of benzo[b]thiophenes have been
developed. Transition-metal-catalyzed annulations11−14 and
electrophilic cyclization15−20 are among the commonly
employed methodologies for the synthesis of such compounds.
The former methodology provides 2-substituted or 2,3-
disubstituted benzo[b]thiophenes depending on the alkyne
substrate employed, while the latter furnishes 3-halo-2-
substituted products. Considering the high cost of the
transition metal catalysts and the possibility of transforming
the halide moiety of the benzo[b]thiophenes into different
analogues using Suzuki, Sonogashira, Heck, Negishi, Kumada,
Hiyama, Fukuyama, Stille, and Buchwald−Hartwig reactions,
the electrophilic cyclization reaction is the preferred protocol
for their synthesis.19,21 Although a number of reagent systems
are reported for the synthesis of 3-iodo/bromo-2-substituted
benzo[b]thiophenes, chloro- and fluorocyclizations using
appropriate electrophiles as well as attempts to construct 2-
halo-3-substituted regioisomers (reversed regioisomers in
respect of the outcome of normal electrophilic cyclization) of
benzo[b]thiophenes are less explored.21,22 The search for the
chloro- and fluorocyclization methodologies is interesting since
the nature of halogen substituents is reported to affect the
adsorption, metabolism, distribution, and excretion properties
of bioactive molecules.21 In continuation of our previous
studies on the stereoselective synthesis of carbohydrate fused-
thiochromans and thiochromenes,23−25 we report herein the
successful synthesis of the privileged 2-chloro-3-(2′-glucalyl)-
benzo[b]thiophenes via a sigmatropic allylic rearrangement of
We recently reported that treatment of sulfoxide 1 with
NaOAc in acetic anhydride resulted in the formation of an
unexpected fused aryl-S-glucoside 2, presumably via an unusual
C → S rearrangement reaction as shown in Scheme 1,25 and
this provided the substrate for the benzothiophene synthesis in
the current study.
Various aryl-S-glucosides were prepared by the C → S
rearrangement reaction in order to assess the scope and
generality of our approach. In all cases complete conversion of
the starting sulfoxides to their corresponding fused aryl-S-
1
glucosides was achieved, and products were identified by H
and 13C NMR as well as HRMS spectra after chromatographic
purification. Although a range of different protecting groups on
the sugar moiety and substituents on the arylthiol moiety were
found to be compatible, the synthesis of the diastereomeric
galactosyl analogues could not be achieved, presumably due to
the 1,3-diaxial strain experienced during substitution of the
iodide with the arylthiolate to prepare the thiochroman
substrate.23
After establishing the generality of the rearrangement
reaction with glucosyl sugar analogues, our attention turned
to the application of the resulting aryl-S-glucosides in the
synthesis of benzo[b]thiophenes. Parham et al. and later Moss
et al. reported that dichlorocarbene, phenylchlorocarbene, and
phenylfluorocarbene react with acyclic allylic sulfides to
produce C−S insertion products via initial formation of
sulfonium ylides that subsequently undergo [2,3] sigmatropic
rearrangement in preference to cyclopropanation of the allylic
double bond, which is the case with allylic ethers.26−29
Although the methodology is unique and efficient, it has not,
to the best of our knowledge, been extensively applied in the
synthesis of complex organic molecules. These interesting
results prompted us to attempt the dichlorocarbene reaction on
Received: June 7, 2014
Published: July 21, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. C → S Rearrangement Reaction
our aryl-S-glucosides. It was envisioned that the nucleophilic
sulfur in the highly conjugated system of the aryl-S-glucoside 2
would react with the electrophilic dichlorocarbene with
subsequent sigmatropic rearrangement to provide the benzo-
[b]thiophenes. In pursuit of this goal, aryl-S-glucoside 2a was
treated with a 1:1 mixture of 50% aqueous NaOH and CHCl3,
in the presence of benzyltriethylammonium chloride as a phase-
transfer catalyst to provide benzo[b]thiophene 3a in 67% yield.
The structure of the benzo[b]thiophene 3a was established
using NMR and HRMS spectra. Evidence included the
appearance of the downfield singlet for the anomeric proton
at δH 6.52 and the resonances of C-1′ and C-2′ at δC 145.6 and
106.0, respectively, representing a typical pattern of a glucal
system. The HMBCAD (heteronuclear multiple bond
correlation adibatic) spectrum displayed correlation of H-1′
with C-2′, C-3′, and C-5′ of the glucal moiety as well as the C-3
of the benzo[b]thiophene group, suggesting the cleavage of the
bond between the anomeric carbon and the sulfur. The upfield
shift of the AB system of the CH2 protons that corresponds to
the benzyl protecting group at C-3′ suggest the restricted free-
rotation of the benzoloxy group due to the close proximity of
the highly aromatized benzo[b]thiophene moiety and aniso-
tropy shielding as they lie below this aromatic ring. The mass
spectrometry exhibited a molecular ion of [M + Na] 605.1537,
which corresponds to the calculated value of 605.1529. The [M
+ Na]+ (605.1537) and [M + Na]+ + 2 (607.1515) pattern of
the mass spectrometer also suggests the presence of one
chlorine atom in the molecule.
variety of aromatic substituents. In all cases complete
conversion of the starting glucoside to the corresponding
benzo[b]thiophenes was achieved, and products were identified
by 1H and 13C NMR spectroscopy after chromatographic
purification. It was interesting to note that no deacetylated
product was isolated during the reaction of the monoacetylated
glucoside 2f.
The possibility of using this methodology for the synthesis of
the bromo analogues was demonstrated by replacement of
CHCl3 with CHBr3 in reactions of glucosides 2a and 2f
(Scheme 2 and Table 1, entries 7 and 8), though the yields
were relatively lower than those obtained for the chloro
analogues. In contrast to the attempted cyclopropanation of
glycals with dibromocarbenes reported by Nagarajan et al.,30
the insertion of the dibromocarbene to substrates 2a and 2f
followed by the rearrangement reaction to yield the brominated
benzothiophenes proceeded smoothly without the reaction
mixture turning black and viscous.
The proposed mechanism for the formation of the
benzo[b]thiophenes 3 is outlined in Scheme 3. The reaction
is proposed to proceed via initial formation of the ylide I.26
Sigmatropic rearrangement facilitates the cleavage of the C−S
bond to form the dichlorinated benzothiophane II. Abstraction
of the acidic proton by the base present in the reaction mixture
with the subsequent elimination of one of the chlorine atoms
provides the aromatized benzo[b]thiophene 3.
In conclusion, the unusual C → S rearrangement reaction of
sulfoxides 1a−f to provide aryl-S-glucosides 2a−f was realized.
The aryl-S-glucosides so obtained are successfully employed in
the synthesis of novel 2-halo-3-glucalyl substituted benzo[b]-
thiophenes 3a−h. The current protocol provides alternative
access to the under-represented synthesis of chlorinated
benzo[b]thiophenes as well as the 2-halo-3-substituted
regioisomers. Considering the ease of preparation of the
substrates and possibilities for further elaboration of the
carbohydrate moieties with their well-defined inherent stereo-
chemistry, the current strategy for synthesis of benzo[b]-
thiophene derivatives would be of great benefit to medicinal
chemists.
In order to evaluate the generality and scope of the proposed
synthesis of the benzo[b]thiophene derivatives, the reaction
was monitored with a number of aryl-S-glucosides. The reaction
provided the corresponding glucal derived 2-chloro-3-substi-
tuted benzo[b]thiophenes in moderate yields, and the results
are summarized in Table 1. The reaction conditions are tolerant
of both O-acetate and O-benzyl protecting groups as well as a
Table 1. Synthesis of 2-Halo-3-(2′-
glucalyl)benzo[b]thiophenes 3a−h
yield
(%)
entry
aryl-S-glucosides 2a−f
benzo[b]thiophenes 3a−h
EXPERIMENTAL SECTION
2a R1 = R2 = H, R3 = Bn 3a R1 = R2 = H, R3 = Bn, X = Cl
67
68
■
1
2
2b R1 = H, R2 = CH3,
3b R1 = H, R2 = CH3, R3 = Bn,
All solvents were dried by appropriate techniques reported by Perrin
and Armarego.31 Sulfoxides 1a−e and aryl-S-glycosides 2a−e were
synthesized according to previously published protocols.25 All
reactions were monitored by thin layer chromatography (TLC) on
aluminum-backed silica gel 60 F254 plates using an ascending
technique. The plates were visualized by spraying with a 1:1 solution
of 5% p-anisaldehyde in ethanol and 10% sulfuric acid in ethanol and
then baking at 150 °C. Gravity column chromatography was done on
silica gel 60 (70−230 mesh). Optical rotations were determined in
chloroform solutions at 25 °C. The concentration c refers to g/100
mL. All proton and carbon-13 nuclear magnetic resonance spectra
R3 = Bn
X = Cl
3
4
5
2c R1 = H, R2 = OCH3,
3c R1 = H, R2 = OCH3, R3 = Bn,
65
72
64
R3 = Bn
X = Cl
2d R1 = H, R2 = C(CH3)3, 3d R1 = H, R2 = C(CH3)3,
R3 = Bn
R3 = Bn, X = Cl
3e R1 = CH3, R2 = H, R3 = Bn,
2e R1 = CH3, R2 = H,
R3 = Bn
X = Cl
6
7
8
2f R1 = R2 = H, R3 = Ac 3f R1 = R2 = H, R3 = Ac, X = Cl
2a R1 = R2 = H, R3 = Bn 3g R1 = R2 = H, R3 = Bn, X = Br
2f R1 = R2 = H, R3 = Ac 3h R1 = R2 = H, R3 = Ac, X = Br
68
61
60
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The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of 2-Halo-3-(2′-glucalyl)-benzo[b]thiophenes
with CH2Cl2. The resulting solution was washed successively with
saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and
evaporated. The residue product was purified by column chromatog-
raphy on silica gel (ethyl acetate/hexane, 10:90) to provide the title
compound 2f: 210 mg, 60% yield; colorless oil; IR (neat cm−1) 1736,
Scheme 3. Proposed Mechanism for the Synthesis of the
Benzo[b]thiophenes
1
1087, 733, 696; [α]D (c 0.5, CHCl3) −65.7; H NMR (CDCl3, 400
MHz) δ 7.51−7.06 (m, 14H), 6.78 (s, 1H), 5.26 (s, 1H), 4.98 (d, J =
10.8 Hz, 1H), 4.90 (d, J = 11.6 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H),
4.60 (d, J = 10.8 Hz, 1H), 4.30 (bd, J = 7.6 Hz, 1H), 4.25 (dd, J = 2.0
and 12.2 Hz, 1H), 4.16 (dd, J = 5.2 and 12.2 Hz, 1H), 3.78 (ddd, J =
2.0, 5.2, and 9.6 Hz, 1H), 3.50 (dd, J = 8.6 and 9.6 Hz, 1H), 1.96 (s,
3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.8, 137.6, 129.7, 128.6,
128.5, 128.4, 128.2, 128.0, 127.8, 127.7, 127.4, 125.7, 125.4, 120.7,
85.0, 81.6, 78.4, 75.4, 75.3, 72.8, 63.5, 20.9; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C29H29O5S 489.1736, found 489.1746.
General Procedure for the Synthesis of Benzothiophenes 3.
50% aq NaOH (5 mL) was added to a vigorously stirred solution of
aryl-S-glucoside 2 (0.28 mmol) in CHCl3 or CHBr3 (5 mL) containing
BnEt3NCl (0.088 mmol). After stirring at 35 °C for 6 h (for the
CHCl3 solution) or 3 h (for the CHBr3 solution), the reaction mixture
was diluted with water, and the aqueous phase was extracted with
CH2Cl2 (4 × 15 mL). The combined organic phases were dried over
MgSO4, filtered, and evaporated in vacuo. Chromatography on silica
gel (ethyl acetate/hexane, 3:97) of the residue gave the corresponding
benzo[b]thiophenes 3:
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2-
chlorobenzo[b]thiophen-3-yl)-3,4-dihydro-2H-pyran (3a). 111
mg, 67% yield; colorless oil; IR (neat cm−1) 1652, 1065, 731, 695;
[α]D (c 0.5, CHCl3) +20.2; 1H NMR (CDCl3, 400 MHz) δ 7.70−7.65
(m, 1H, Ar), 7.64−7.58 (m, 1H, Ar), 7.40−7.22 (m, 12H, Ar), 7.19−
7.01 (m, 3H, Ar), 6.77 (d, J = 6.4 Hz, 2H, Ar), 6.52 (s, 1H, H-1′), 4.78
(d, J = 11.6 Hz, 1H, CHAHBPh), 4.68 (d, J = 11.6 Hz, CHAHBPh), 4.63
(d, J = 12.0 Hz, 1H, CHAHBPh), 4.59 (d, J = 12.0 Hz, 1H, CHAHBPh),
4.47−4.41 (m, 2H, H-3′ and H-5′), 4.28 (d, J = 11.6 Hz, 1H,
CHAHBPh), 4.12 (d, J = 11.6 Hz, 1H, CHAHBPh), 4.03 (t, J = 5.6 Hz,
1H, H-4′), 3.99 (dd, J = 6.2 and 10.6 Hz, 1H, H-6a′), 3.81 (dd, J = 3.4
and 10.6 Hz, 1H, H-6b′); 13C{1H} NMR (CDCl3, 100 MHz) δ 145.6,
139.3, 137.9, 137.7, 137.0, 129.9, 129.6, 128.5, 128.4, 128.0, 127.9,
127.8, 127.7, 127.6, 127.4, 124.8, 124.7, 123.0, 121.6, 106.0, 76.8, 74.9,
74.1, 73.5, 73.1, 72.3, 68.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C35H31ClNaO4S 605.1529, found 605.1537; [M + NH4]+ calcd for
C35H35ClNO4S 600.1975, found 600.1973.
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2-
chloro-5-methyl benzo[b]thiophen-3-yl)-3,4-dihydro-2H-pyran
(3b). 115 mg, 68% yield; colorless oil; IR (neat cm−1) 1650, 1095, 733,
696; [α]D (c 0.5, CHCl3) +12.6; 1H NMR (CDCl3, 400 MHz) δ 7.54
(d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.40−7.20 (m, 11H), 7.14−7.02 (m,
3H), 6.83−6.75 (m, 2H), 6.50 (s, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.67
(d, J = 11.6 Hz, 1H), 4.63−4.56 (m, 2H), 4.48−4.38 (m, 2H), 4.28 (d,
J = 11.2 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 4.04 (dd, J = 5.0 and 6.6
Hz, 1H), 3.97 (dd, J = 5.8 and 10.6 Hz, 1H), 3.82 (dd, J = 3.6 and 10.6
Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 145.6,
139.4, 137.9, 137.8, 134.5, 134.1, 129.5, 128.5, 128.4, 128.3, 128.2,
128.0, 127.8, 127.7, 127.6, 127.3, 126.4, 122.9, 121.3, 106.1, 76.8, 75.2,
74.2, 73.5, 73.2, 72.3, 68.2, 21.4; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C36H33ClNaO4S 619.1686, found 619.1667; [M + NH4]+
calcd for C36H37ClNO4S 614.2132, found 614.2132.
were recorded as deuteriochloroform solutions using tetramethylsilane
as an internal standard. All chemical shifts are reported in ppm.
( ( 2 R , 3 S , 4 R ) - 3 , 4 - B i s ( b e n z y l o x y ) - 2 , 3 , 4 , 1 0 a -
tetrahydrothiochromeno[2,3-b]pyran-2-yl)methyl Acetate (2f).
To a solution of (2R,3S,4R,4aR,10bR)-3,4-bis(benzyloxy)-2-(benzylox-
ymethyl)-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran23 (500
mg, 0.928 mmol) in Ac2O (3 mL) was added a solution of H2SO4
in Ac2O (2% v/v, 3.5 mL), and the reaction mixture was stirred at
room temperature for 15 min. The reaction mixture was then poured
into an ice-cold saturated aqueous NaHCO3 with vigorous stirring.
The aqueous solution was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with water, dried over MgSO4,
filtered, and concentrated to dryness. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane, 1:9) to
obtain the monoacetylated (2R,3S,4R,4aR,10bR)-3,4-bis(benzyloxy)-
2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran-2-yl)methyl ace-
tate: 400 mg, 88% yield; colorless oil; IR (neat cm−1) 1737, 1072,
1
733, 696; [α]D (c 0.5, CHCl3) +28.1; H NMR (CDCl3, 400 MHz) δ
7.47−6.99 (m, 14H), 4.92 (d, J = 10.8 Hz, 1H), 4.76 (d, J = 11.6 Hz,
1H), 4.63 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 10.8 Hz, 1H), 4.37 (s, 1H),
4.28−4.21 (m, 2H), 3.94 (dd, J = 5.2 and 8.8 Hz, 1H), 3.68 (ddd, J =
2.4, 3.6, and 9.4 Hz, 1H), 3.61 (t, J = 9.4 Hz, 1H), 3.23 (t, J = 12.8 Hz,
1H), 2.97 (dd, J = 1.4 and 12.8 Hz, 1H), 2.63 (ddd, J = 2.4, 5.2, and
10.4 Hz, 1H), 1.98 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ
170.8, 137.9, 137.8, 134.0, 133.2, 130.6, 129.0, 128.5, 128.2, 127.9,
127.7, 126.5, 124.3, 82.8, 75.1, 74.3, 73.8, 71.2, 63.7, 38.8, 21.1, 20.9;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H30Na05S 513.1712,
found 513.1716. This monoacetylated product (350 mg, 0.71 mmol)
was then added to a vigorously stirring suspension of wet alumina
(1.11 g wetted with 117 μL of water) and OXONE (437 mg, 0.71
mmol) in CH2Cl2 (5 mL). After 3 h of stirring at room temperature,
the adsorbent was filtered over a Celite bed and washed several times
with CH2Cl2. The filtrate was evaporated in vacuo. NaOAc (8 mg, 0.06
mmol) was added to a solution of the solid residue in Ac2O (2 mL),
and the reaction mixture was stirred overnight at 140 °C. The reaction
mixture was then allowed to cool to room temperature and diluted
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The Journal of Organic Chemistry
Note
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2-
chloro-5-methoxybenzo[b]thiophen-3-yl)-3,4-dihydro-2H-
pyran (3c). 113 mg, 65% yield; colorless oil; IR (neat cm−1) 1069,
73.5, 73.1, 72.4, 68.2; HRMS (ESI-TOF) m/z [M + NH4]+ calcd for
C35H35BrNO4S 644.1470, found 644.1465.
((2R,3S,4R)-3,4-Bis(benzyloxy)-5-(2-bromobenzo[b]-
thiophen-3-yl)-3,4-dihydro-2H-pyran-2-yl)methyl Acetate (3h).
99 mg, 60% yield; pale yellow oil; IR (neat cm−1) 1739, 1027, 732,
696; [α]D (c 0.5, CHCl3) +1.4; 1H NMR (CDCl3, 400 MHz) δ 7.78−
7.61 (m, 2H) 7.46−7.21 (m, 7H), 7.11−7.01 (m, 3H), 6.83−6.71 (m,
2H), 6.48 (s, 1H), 4.79 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H),
4.61 (dd, J = 6.4 and 12.0 Hz, 1H), 4.49−4.34 (m, 3H), 4.25 (d, J =
11.2 Hz, 1H), 4.10 (d, J = 11.2 Hz, 1H), 3.93 (dd, J = 4.6 and 5.8 Hz,
1H), 2.10 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.9, 145.2,
139.7, 137.5, 132.9, 128.8, 128.6, 128.5, 128.1, 127.9, 127.8, 127.7,
127.6, 127.5, 126.4, 124.9, 123.4, 121.7, 107.2, 77.2, 75.2, 74.2, 73.9,
73.0, 72.5, 62.6, 21.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C30H27BrNaO5S 601.0660, found 601.0653; [M + NH4]+ calcd for
C30H31BrNO5S 596.1106, found 596.1099.
1
734, 696; [α]D (c 0.5, CHCl3) +4.4; H NMR (CDCl3, 400 MHz) δ
7.52 (d, J = 8.8 Hz, 1H), 7.39−7.20 (m, 11H), 7.14−7.01 (m, 3H),
6.94 (dd, J = 2.4 and 8.8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 2H), 6.52 (s,
1H), 4.76 (d, J = 11.6 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.60 (s, 2H),
4.46 (bq, J = 5.6 and 9.2 Hz, 1H), 4.40 (bd, J = 4.4 Hz, 1H), 4.30 (d, J
= 11.2 Hz, 1H), 4.15 (d, J = 11.2 Hz, 1H), 4.04 (bt, J = 5.6 Hz, 1H),
3.99 (dd, J = 6.0 and 10.6 Hz, 1H), 3.82 (dd, J = 3.4 and 10.6 Hz, 1H),
3.66 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 157.7, 145.6, 140.2,
138.2, 137.8, 137.7, 130.5, 129.7, 129.0, 128.8, 128.4, 128.3, 128.1,
128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 122.3, 114.7, 105.9, 105.3,
76.5, 74.6, 74.0, 73.5, 72.9, 72.2, 68.2, 55.3; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C36H33ClNaO5S 635.1635, found 635.1656; [M +
NH4]+ calcd for C36H37ClNO5S 630.2081, found 630.2073.
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(5-
(tert-butyl)-2-chlorobenzo[b]thiophen-3-yl)-3,4-dihydro-2H-
pyran (3d). 131 mg, 72% yield; colorless oil; IR (neat cm−1) 1653,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1069, 732, 695; [α]D (c 0.5, CHCl3) +6.1; H NMR (CDCl3, 400
1H and 13C {H} spectra on all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
MHz) δ 7.59 (d, J = 8.8 Hz, 2H), 7.40−7.24 (m, 11H), 7.11−6.98 (m,
3H), 6.77 (d, J = 6.4 Hz, 2H), 6.52 (s, 1H), 4.77 (d, J = 11.8 Hz, 1H),
4.66 (d, J = 11.6 Hz, 1H), 4.60 (s, 2H), 4.48 (bq, J = 5.6 and 9.2 Hz,
1H), 4.37 (d, J = 4.4 Hz, 1H), 4.26 (d, J = 11.6 Hz, 1H), 4.11 (d, J =
11.6 Hz, 1H), 4.07−3.80 (m, 2H), 3.82 (dd, J = 3.6 and 10.8 Hz, 1H),
1.28 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 148.0, 145.4, 139.0,
137.9, 137.8, 134.2, 130.1, 129.5, 128.5, 128.4, 127.9, 127.8, 127.7,
127.6, 127.3, 123.0, 121.2, 119.0, 106.0, 77.2, 76.4, 74.2, 73.8, 73.6,
72.7, 72.0, 68.3, 34.7, 31.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C39H39ClNaO4S 661.2155, found 661.2156; [M + NH4]+ calcd for
C39H43ClNO4S 656.2601, found 656.2589.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hhkinfe@uj.ac.za.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2-
chloro-7-methylbenzo[b]thiophen-3-yl)-3,4-dihydro-2H-pyran
(3e). 109 mg, 64% yield; colorless oil; IR (neat cm−1) 1651, 1069, 730,
We thank the University of Johannesburg, Research Centre for
Synthesis and Catalysis of the Department of Chemistry at UJ
and Prof David Gammon (UCT) for proofreading and his
valuable suggestions.
1
695; [α]D (c 0.5, CHCl3) +15.4; H NMR (CDCl3, 400 MHz) δ 7.47
(d, J = 8.0 Hz, 1H), 7.40−7.20 (m, 12H), 7.18−7.01 (m, 3H), 6.78 (d,
J = 6.4 Hz, 2H), 6.51 (s, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.66 (d, J =
11.6 Hz, 1H), 4.63−4.57 (m, 2H), 4.47−4.40 (m, 2H), 4.25 (d, J =
11.6 Hz, 1H), 4.11 (d, J = 11.6 Hz, 1H), 4.04−3.94 (m, 2H), 3.80 (dd,
3.4 and 10.6 Hz, 1H), 2.48 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz) δ 145.6, 139.2, 138.0, 137.9, 137.7, 137.6, 137.4, 137.2, 131.1,
130.6, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6, 127.3, 125.2, 125.1,
120.6, 106.3, 76.8, 74.9, 74.2, 73.5, 73.1, 72.3, 68.2, 20.1; HRMS (ESI-
TOF) m/z [M + NH4]+ calcd for C36H37ClNO4S 614.2132, found
614.2094.
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1
[α]D (c 0.5, CHCl3) +7.0; H NMR (CDCl3, 400 MHz) δ 7.78−7.62
(m, 2H), 7.40−7.26 (m, 7H), 7.15−7.01 (m, 3H), 6.84−6.74 (m, 2H),
6.49 (s, 1H), 4.78 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H),
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(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2-
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