Stereoselective synthesis of thiochroman-4-ones by ring transformation of chiral 5-ylidene-1,3-dioxan-4-ones with 2-bromothiophenol via bromo - Lithium exchange

Article abstract of DOI:10.1002/1099-0690(200102)2001:3<529::AID-EJOC529>3.0.CO;2-B

The reaction of (E)- or (Z)-5-ylidene-1,3-dioxan-4-one (1) and 2-bromothiophenol, followed by bromo-lithium exchange with nBuLi, provides a new access to optically active thiochroman-4-ones 4 and 5. Stereoselective conjugate addition occurs in the first step and the resulting 5-(1-phenylsulfanylalkyl)-1,3-dioxan-4-ones 2 and 3 undergo ring transformation to thiochroman-4-ones by attack of the lithiated phenyl ring at the dioxanone carbonyl carbon atom, cleaving off pivalaldehyde. If reactants with a (Z)-configuration are used, a retro-aldol reaction occurs in the ring transformation step, thus affording the 3-unsubstituted thiochroman-4-ones 5 rather than 3-(1-hydroxyethyl)-thiochroman-4-ones 4. This phenomenon can be rationalized by the steric congestion in the intermediate enolate 7.

Full text of DOI:10.1002/1099-0690(200102)2001:3<529::AID-EJOC529>3.0.CO;2-B

FULL PAPER
Stereoselective Synthesis of Thiochroman-4-ones by Ring Transformation of
Chiral 5-Ylidene-1,3-dioxan-4-ones with 2-Bromothiophenol via
Bromo؊Lithium Exchange
Akbar Ali,[a] Viqar Uddin Ahmad,[b] and Jürgen Liebscher*[a]
Keywords: Asymmetric synthesis / Sulfur heterocycles / Ketones / Oxygen heterocycles / Bromo-Lithium exchange
The reaction of (E)- or (Z)-5-ylidene-1,3-dioxan-4-one (1) and
2-bromothiophenol, followed by bromo-lithium exchange
with nBuLi, provides a new access to optically active thio-
ring at the dioxanone carbonyl carbon atom, cleaving off
pivalaldehyde. If reactants with a (Z)-configuration are used,
a retro-aldol reaction occurs in the ring transformation step,
chroman-4-ones 4 and 5. Stereoselective conjugate addition thus affording the 3-unsubstituted thiochroman-4-ones 5 ra-
occurs in the first step and the resulting 5-(1-phenylsulfanyl-
alkyl)-1,3-dioxan-4-ones 2 and 3 undergo ring transforma-
tion to thiochroman-4-ones by attack of the lithiated phenyl
ther than 3-(1-hydroxyethyl)-thiochroman-4-ones 4. This
phenomenon can be rationalized by the steric congestion in
the intermediate enolate 7.
Introduction
undergoes conjugate addition in Michael systems[11,12] but
has not been used further as a binucleophilic SϪCϪC
building block in these cases. On the other hand, the 5-
ylidene-1,3-dioxanones (E)-1 and (Z)-1, available from nat-
urally occurring poly-(3R)-hydroxybutyrate,[13Ϫ15] have be-
come versatile starting materials in Michael systems, al-
lowing the stereoselective synthesis of several heterocyclic
products such as benzothiazepones and pyrrolidones by re-
action with binucleophiles or by cycloadditions.[16Ϫ19] Ad-
dition reactions to the double bond follow a predictable
mode, i.e. in cases of (E)-1 attack from the re-face[15,17] (e.g.
cuprates, silanes, nitromethane) unless stereoelectronic fac-
tors force an attack from the more sterically hindered side,
i.e. the si-face of (E)-1[18] (e.g. 2-aminothiophenol, because
of hydrogen bonding of the amino group with the lone pairs
of the oxygen atoms of the dioxanone ring).
Thiochroman-4-ones are sulfur analogues of naturally
occurring chromanones and are of interest in the synthesis
of pharmacologically active compounds such as Dilthia-
zem-related chiral CNS drugs.[1,2] The existence of thiochro-
man-4-ones has been known about for a long time[3,4] and
a number of syntheses have been developed. The unsubsti-
tuted compound is commercially available. The most versat-
ile route to thiochroman-4-ones is based on the addition of
arylthiols to α,β-unsaturated carboxylic acids or their deriv-
atives, followed by intramolecular Friedel-Craft acylation of
the resulting β-arylthiopropionic acids.[3,5,6] The latter can
also be obtained in other ways such as by the ring opening
of β-lactones.[5] The only reported synthesis of optically act-
ive thiochroman-4-ones uses the cyclization of (R)-β-
phenylthiocarboxylic acids which were obtained from optic-
ally active β-hydroxy esters and thiophenol.[1] Racemic 2-
phenyl-thiochroman-4-one has been resolved by formation
of its chiral hydrazone.[7] Treatment of 2-methylthio or 2-(4- Results and Discussion
methoxybenzylthio)chalcones with acids represents another
ring closure synthesis of thiochroman-4-ones.[4,8] Finally,
The reaction of 2-bromothiophenol with 5-ylidene-1,3-
this class of heterocycles can also be obtained by addition
dioxanone (1) in the presence of 1 mol-% nBuLi in THF at
Ϫ78 °C gave a clean addition to the CϪC double bond. As
expected, the preferred mode of attack occurred from the
bottom side, i.e. from the re-face of (E)-1 and the si-face of
(Z)-1, while the protonation took place from the si-face
(anti-addition). Obviously, the stereochemical mode of pro-
tonation is governed by 1,2-asymmetric induction exerted
by the Me group at the C-6 position of the dioxanone ring.
Diastereoselectivities between 70:30 and 95:5 were
achieved. The major diastereomers, i.e. adducts 2 starting
from (E)-1 and adducts 3 starting from (Z)-1 could be ob-
tained in an analytically pure form by flash chromato-
graphy of the diastereomeric mixture (Scheme 1, Table 1).
The diastereoselectivities were lower with the (Z)-isomer
reactions to thiochromones.[4,6,9,10]
Here we report a new stereoselective synthesis of thioch-
roman-4-ones using 2-bromothiophenol as a binucleophilic
SϪCϪC building block. Since a strongly nucleophilic car-
bon atom can be generated by bromoϪlithium exchange,
this reagent should be particularly useful for asymmetric
syntheses requiring mild conditions. 2-Bromothiophenol
[a]
Institut für Chemie, Humboldt-Universität Berlin,
Hessische Str. 1Ϫ2, 10115, Berlin, Germany
Fax: (internat.) ϩ49-30/2093-8907
E-mail: liebscher@chemie.hu-berlin.de
[b]
International Center for Chemical Sciences, HEJ Research
Institute of Chemistry, University of Karachi,
Karachi 75270, Pakistan
Eur. J. Org. Chem. 2001, 529Ϫ535
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0203Ϫ0529 $ 17.50ϩ.50/0
529

A. Ali, V. U. Ahmad, J. Liebscher
FULL PAPER
Scheme 1. (a) nBuLi (cat.), THF, Ϫ78 to 0 °C; (b) nBuLi, THF, Ϫ100 to Ϫ78 °C
Table 1. Adducts 2, 3 and thiochroman-4-ones 4 and 5
4-ones 4 by attack of the lithiated ring position at the car-
bonyl carbon atom, opening of the dioxanone ring and sub-
sequent loss of the pivalaldehyde moiety. The diastereo-
meric adducts 3, predominantly derived from the (Z)-starting
material (Z)-1, additionally lose the hydroxyethyl moiety in
the nBuLi-assisted cyclization reaction affording the 3-un-
substituted thiochroman-4-ones 5. Obviously, a retro-aldol
reaction has occurred. So far, this type of reaction has only
been observed with 1,3-dioxan-4-ones possessing a quatern-
ary carbon atom at position 5 — sterically less-congested
analogues with a tertiary carbon at position 5 keep the hy-
droxyethyl group.[16Ϫ19] In order to rationalize the different
reaction behavior of 2 and 3, the structures of the likely
enolate intermediates 6a and 7a, derived from the intramo-
lecular attack of the lithiated phenyl ring at the dioxanone
carbonyl carbon and cleaving off of pivalaldehyde, were
geometry optimized by MM2 force field calculations (see
Figure 1 and 2). It turned out that a steric repulsion be-
tween the two methyl groups exists in enolate 7a, which
would cause a retro-aldol reaction releasing the hydroxy-
ethyl group as acetaldehyde. Enolate 6a lacks this repulsive
driving force (minimum energy 17.98 kcal/mol compared to
26.50 kcal/mol in case of 7a) and the aldol structure sur-
vives.
Entry
R
Geometry Adducts
dr
Thiochromanones
of
2؉3
2/3 4 or 5 (% yield)[b]
reactant 1 (% yield)[a]
1
2
3
4
5
6
7
8
9
10
Me
E
2a/3a (92) 80:20
2a/3a (90) 30:70
2b/3b (91) 80:20
2b/3b 90 30:70
2c/3c (86) 90:10
2c/3c (85) 20:80
2d/3d (92) 90:10
2d/3d (92) 20:80
2e/3e (86) 95:05
2f/3f (85) 70:30
4a (76)
5a (76)
4b (73)
5b (75)
4c (72)
5c (78)
4d (73)
5d (75)
4e (70)
4f (78)
Me
Z
E
Z
E
Z
E
Z
E
E
Et
Et
iPr
iPr
(CH2)2Ph
(CH2)2Ph
Ph
cHex
[a]
Major isomer could be obtained in analytically pure form by
flash chromatography. Ϫ [b] Obtained from pure adducts 2 or 3, re-
spectively.
than with the corresponding (E)-isomer. After separation,
pure adducts 2 and 3 were submitted to bromoϪlithium
exchange by treatment with nBuLi in THF at Ϫ100 °C. To
our surprise, different types of cyclization products ap-
peared depending on the configuration at the 1Ј-position
of the 5-(1-phenylsulfanylalkyl)-1,3-dioxan-4-ones 2 and 3.
Adducts 2, derived as the main products from (E)-1, gave
the expected 2-substituted 3-(1-hydroxyethyl)-thiochroman-
530
Eur. J. Org. Chem. 2001, 529Ϫ535

Stereoselective Synthesis of Thiochroman-4-ones
FULL PAPER
spectra are in accordance with the cis-configuration of the
substituents in thiochromanones 4. The CHS protons of ad-
ducts 2 exhibit a slight downfield shift and a somewhat
greater coupling constant with CHCϭO than in the corres-
ponding diastereomer 3. The latter compounds possess
higher Rf values.
Figure 1. Intermediate enolate 6a (formula and MM2-optimized
structure, total energy 17.98 kcal/mol) formed in the conversion of
2a to 4a
Figure 3. X-ray crystal analysis of 2b
In summary, a new straightforward asymmetric synthesis
of thiochromanones was found by the two step-reaction of
5-alkylidene-1,3-dioxan-4-ones with 2-bromothiophenol.
Similar to the known synthesis of thiochroman-4-ones from
thiophenols with α,β-unsaturated esters, conjugate addition
occurs in the first step and the thiopyran ring is established
by nucleophilic attack of the aryl ring at the carbonyl car-
bon atom and ring transformation. However, the applica-
tion of 2-bromo-thiophenol instead of thiophenol allows
the cyclization step to run under much milder conditions
since the nucleophilicity of the aryl ring is enhanced by
bromoϪlithium exchange.
Experimental Section
Figure 2. Intermediate enolate 7a (formula and MM2-optimized
structure, total energy 26.50 kcal/mol) formed in the conversion of
3a to 5a
The structural elucidation of compounds 2Ϫ4 is based
on an X-ray crystal analysis of adduct 2b (see Figure 3)[20]
and similar CD spectra in this series (see Figure 4). The
General Remarks: 1H NMR and 13C NMR (including DEPT) spec-
tra were recorded at 300 and 75.5 MHz, respectively on a Bruker
AC-300 in CDCl3 with TMS as internal standard. 2D NMR experi-
ments include 1H,1H COSY and HMQC. Optical rotations were
determined with a PerkinϪElmer polarimeter 241 (c ϭ 1, CHCl3,
coupling constants J Ͻ 4 Hz observed in the 1H NMR d ϭ 1 mm). Circular dichroism in terms of ellipticity Theta (in deg)
Figure 4. CD spectra for compounds 2b, 2c, 2d and 2f in CH3OH
Eur. J. Org. Chem. 2001, 529Ϫ535
531

A. Ali, V. U. Ahmad, J. Liebscher
FULL PAPER
was measured on a Jasco J710 spectrometer (minimum wave length
190 nm). For preparative column chromatography, silica
(0.04Ϫ0.063 mm, Merck) was used. Starting materials 1a؊1f were
obtained following or adapting literature procedures.[13Ϫ15,18]
ChemOffice version 5 was used for MM2-force field calculations.
34.98 [C(CH3)3], 52.20 (CHS), 52.43 (CHCϭO), 72.89 (CHO),
107.31 (OCHO), 126.03 (C, Ar), 128.03, 128.36, 132.66, 133.15
(CH, Ar), 136.07 (C, Ar), 170.20 (CϭO). Ϫ C18H25BrO3S (401.36):
calcd. C 53.87, H 6.28, S 7.99, Br 19.91; found C 53.85, H 6.39, S
8.02, Br 19.70.
General Procedure for the Michael Addition of 2-Bromothiophenol:
(1ЈS,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sufanylpropyl]-2-tert-butyl-6-
A solution of 2-bromothiophenol (378 mg, 2 mmol) in dry THF methyl-1,3-dioxan-4-one (3b): Yield: 253 mg (63%). Ϫ Rf ϭ 0.44
(5 mL) was added to an ice-cold solution of nBuLi (1.6  in hexane,
(hexane/Et2O, 4:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ ϩ40.6 (c ϭ 1,
0.04 mmol) in dry THF (5 mL). The resulting solution was stirred CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.88 [s, 9 H,
at 0 °C for 45 min and then cooled to Ϫ78 °C. A solution of the
ylidenedioxanone 1 (1 mmol) in THF (10 mL) was added dropwise
over a period of 20 min. The reaction mixture was slowly warmed
to 0 °C overnight, quenched with aqueous 2  NaOH (10 mL)
solution and was extracted with CH2Cl2 (3 ϫ 30 mL). The com-
bined organic extracts were dried over MgSO4 and evaporated to
give a pale yellow oil, which was purified by flash chromatography
(silica gel, n-hexane/Et2O, 5:1).
C(CH3)3], 1.03 (t, J ϭ 7.1 Hz, 3 H, CH3CH2), 1.30 (d, J ϭ 6.0 Hz,
3 H, CH3CHO), 1.74Ϫ1.99 (m, 2 H, CH2), 2.70 (dd, J ϭ 2.2,
9.8 Hz, 1 H, CHCϭO), 3.52 (ddd, J ϭ 2.2, 6.8, 8.6 Hz, 1 H, CHS),
3.96 (dq, J ϭ 6.0, 9.8 Hz, 1 H, CHO), 4.91 (s, 1 H, OCHO), 7.01
(ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.22 (ddd, J ϭ 1.5, 7.9,
9.0 Hz, 1 H, ArH), 7.39 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH), 7.50 (dd,
J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ
12.78 (CH3CH2), 21.12 (CH3CHO), 23.86 [C(CH3)3], 26.57 (CH2),
35.12 [C(CH3)3], 49.18 (CHS), 51.21 (CHCϭO), 72.99 (CHO),
108.0 (OCHO), 125.15 (C, Ar), 127.74, 128.12, 130.59, 133.44 (CH,
Ar), 136.67 (C, Ar), 169.20 (CϭO). Ϫ C18H25BrO3S (401.36):
calcd. C 53.87, H 6.28, S 7.99, Br 19.91; found C 53.63, H 6.43, S
7.78, Br 19.84.
(1ЈR,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanylethyl]-2-tert-butyl-6-
methyl-1,3-dioxan-4-one (2a): Yield: 286 mg (74%). Ϫ Rf ϭ 0.32
(hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 52Ϫ53 °C. Ϫ [α]2D0
ϭ
ϩ8.5 (c ϭ 1, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.88 [s,
9 H, C(CH3)3], 1.33 (d, J ϭ 6.0 Hz, 3 H, CH3CHO), 1.37 (d, J ϭ
7.1 Hz, 3 H, CH3CHS), 2.67 (dd, J ϭ 3.0, 9.0 Hz, 1 H, CHCϭO),
(1ЈR,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanylisobutyl]-2-tert-butyl-
3.82 (dq, J ϭ 3.0, 7.1 Hz, 1 H, CHS), 4.06 (dq, J ϭ 6.4, 9.0 Hz, 1 6-methyl-1,3-dioxan-4-one (2c): Yield: 321 mg (77%). Ϫ Rf ϭ 0.44
H, CHO), 4.94 (s, 1 H, OCHO), 7.03 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 (hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 125Ϫ126 °C. Ϫ [α]D20
H, ArH), 7.19 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.46 (dd, J ϭ ϭ ϩ61.4 (c ϭ 1, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
1.5, 7.9 Hz, 1 H, ArH), 7.50 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ
0.88 [s, 9 H, C(CH3)3], 0.98 and 1.02 [each d, J ϭ 6.4 Hz, 2 ϫ 3
H, CH(CH3)2], 1.37 (d, J ϭ 6.0 Hz, 3 H, CH3CHO), 1.88 [m, 1 H,
13C NMR (75.5 MHz, CDCl3): δ ϭ 20.60 (CH3CHS), 22.09
(CH3CHO), 23.84 [C(CH3)3], 35.01 [C(CH3)3], 44.31 (CHS), 53.89 CH(CH3)2], 2.98 (dd, J ϭ 3.0, 9.0 Hz, 1 H, CHCϭO), 3.74 (dd,
(CHϭO), 73.01 (CHO), 107.47 (OCHO), 127.42 (C, Ar), 127.98, J ϭ 3.0, 10.5 Hz, 1 H, CHS), 4.15 (dq, J ϭ 6.0, 9.0 Hz, 1 H, CHO),
128.96, 133.33, 133.75 (CH, Ar), 135.46 (C, Ar), 169.35 (CϭO). Ϫ 5.0 (s, 1 H, OCHO), 6.96 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH),
C17H23BrO3S (387.33): calcd. C 52.72, H 5.99, S 8.28, Br 20.63; 7.20 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.45 (dd, J ϭ 1.5,
found C 52.53, H 6.19, S 8.19, Br 20.50.
7.9 Hz, 1 H, ArH), 7.51 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C
NMR (75.5 MHz, CDCl3): δ ϭ 21.33 and 21.63 [CH(CH3)2], 22.13
(CH3CHO), 23.85 [C(CH3)3], 33.58 [CH(CH3)2], 34.97 [C(CH3)3],
51.04 (CHCϭO), 58.74 (CHS), 73.25 (CHO), 107.17 (OCHO),
124.44 (C, Ar), 127.71, 128.14, 131.46, 133.03 (CH, Ar), 137.24 (C,
Ar), 170.99 (CϭO). Ϫ C19H27BrO3S (415.39): calcd. C 54.94, H
6.55, S 7.72, Br 19.24; found C 55.26, H 6.62, S 7.40, Br 19.04.
(1ЈS,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanylethyl]-2-tert-butyl-6-
methyl-1,3-dioxan-4-one (3a): Yield: 244 mg (63%). Ϫ Rf ϭ 0.38
(hexane/Et2O, 4:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ ϩ47.5 (c ϭ 1,
CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.89 [s, 9 H,
C(CH3)3], 1.32 (d, J ϭ 6.0 Hz, 3 H, CH3CHO), 1.45 (d, J ϭ 7.1 Hz,
3 H, CH3CHS), 2.67 (dd, J ϭ 2.6, 9.4 Hz, 1 H, CHCϭO), 3.86
(dq, J ϭ 2.6, 7.1 Hz, 1 H, CHS), 4.01 (dq, J ϭ 6.4, 9.4 Hz, 1 H, (1ЈS,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanylisobutyl]-2-tert-butyl-
CHO), 4.89 (s, 1 H, OCHO), 7.02 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, 6-methyl-1,3-dioxan-4-one (3c): Yield: 283 mg (68%). Ϫ Rf ϭ 0.48
ArH), 7.23 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.40 (dd, J ϭ
1.5, 7.9 Hz, 1 H, ArH), 7.51 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ
13C NMR (75.5 MHz, CDCl3): δ ϭ 18.78 (CH3CHS), 21.58
(hexane/Et2O, 4:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ ϩ19.6 (c ϭ 1,
CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.87 [s, 9 H,
C(CH3)3], 1.05 and 1.12 [each d, J ϭ 6.8 Hz, 2 ϫ 3 H, CH(CH3)2],
(CH3CHO), 23.84 [C(CH3)3], 35.13 [C(CH3)3], 41.63 (CHS), 52.19 1.25 (d, J ϭ 6.0 Hz, 3 H, CH3CHO), 2.35 [m, 1 H, CH(CH3)2], 2.80
(CHCϭO), 72.60 (CHO), 107.97 (OCHO), 125.47 (C, Ar), 128.08, (dd, J ϭ 1.5, 10.1 Hz, 1 H, CHCϭO), 3.06 (dd, J ϭ 1.5, 10.5 Hz, 1
128.12, 131.14, 133.46 (CH, Ar), 135.83 (C, Ar), 169.25 (CϭO). Ϫ H, CHS), 3.85 (dq, J ϭ 6.0, 10.1 Hz, 1 H, CHO), 4.96 (s, 1 H,
C17H23BrO3S (387.33): calcd. C 52.72, H 5.99, S 8.28, Br 20.63; OCHO), 6.97 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.21 (ddd, J ϭ
found C 52.46, H 6.23, S 8.10, Br 20.42.
1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.33 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH),
7.48 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz,
CDCl3): δ ϭ 20.29 and 21.66 [CH(CH3)2], 22.14 (CH3CHO), 23.91
[C(CH3)3], 32.06 [CH(CH3)2], 35.08 [C(CH3)3], 51.51 (CHCϭO),
55.34 (CHS), 73.46 (CHO), 107.88 (OCHO), 124.40 (C, Ar),
127.28, 128.09, 129.78, 133.45 (CH, Ar), 138.37 (C, Ar), 168.73
(CϭO). Ϫ C19H27BrO3S (415.39): calcd. C 54.94, H 6.55, S 7.72,
Br 19.24; found C 54.73, H 6.75, S 7.52, Br 19.06.
(1ЈR,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanylpropyl]-2-tert-butyl-
6-methyl-1,3-dioxan-4-one (2b): Yield: 292 mg (73%). Ϫ Rf ϭ 0.37
(hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 75Ϫ76 °C. Ϫ [α]2D0
ϭ
1
ϩ41.6 (c ϭ 1, CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.88
[s, 9 H, C(CH3)3], 0.98 (t, J ϭ 7.1 Hz, 3 H, CH3CH2), 1.33 (d, J ϭ
6.0 Hz, 3 H, CH3CHO), 1.61Ϫ1.80 (m, 2 H, CH2), 2.77 (dd, J ϭ
2.6, 9.0 Hz, 1 H, CHCϭO), 3.81 (ddd, J ϭ 2.6, 7.1, 8.6 Hz, 1 H,
CHS), 4.10 (dq, J ϭ 6.0, 9.0 Hz, 1 H, CHO), 4.99 (s, 1 H, OCHO), (1ЈR,2R,5R,6R)-5-{1Ј-[(2-Bromophenyl)sulfanyl]-3Ј-phenylpropyl}-
6.99 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.18 (ddd, J ϭ 1.5, 7.9, 2-tert-butyl-6-methyl-1,3-dioxan-4-one (2d): Yield: 396 mg (83%). Ϫ
9.0 Hz, 1 H, ArH), 7.46 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH), 7.49 (dd,
Rf ϭ 0.35 (hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 114Ϫ115
J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ °C. Ϫ [α]2D0 ϭ ϩ11.9 (c ϭ 1, CHCl3). Ϫ 1H NMR (300 MHz,
12.44 (CH3CH2), 22.21 (CH3CHO), 23.83 [C(CH3)3], 28.86 (CH2), CDCl3): δ ϭ 0.87 [s, 9 H, C(CH3)3], 1.28 (d, J ϭ 6.4 Hz, 3 H,
532
Eur. J. Org. Chem. 2001, 529Ϫ535

Stereoselective Synthesis of Thiochroman-4-ones
FULL PAPER
CH3CHO), 1.86Ϫ2.08 (m, 2 H, CH2CH2Ph), 2.55 (ddd, J ϭ 6.4, Ar), 127.53, 128.09, 131.18, 132.99 (CH, Ar), 137.35 (C, Ar),
9.0, 13.5 Hz, 1 H, CH2CH2Ph), 2.78 (dd, J ϭ 2.6, 9.0 Hz, 1 H, 171.10 (CϭO). Ϫ C22H31BrO3S (455.45): calcd. C 58.02, H 6.86, S
CHCϭO), 2.82 (ddd, J ϭ 5.2, 9.0, 13.5 Hz, 1 H, CH2CH2Ph), 3.84 7.04, Br 17.54; found C 58.18, H 6.97, S 6.88, Br 17.46.
(ddd, J ϭ 2.6, 5.6, 8.6 Hz, 1 H, CHS), 4.08 (dq, J ϭ 6.0, 9.0 Hz, 1
General Procedure for the Ring Transformation of Adducts 2 and 3:
A solution of the adduct 2 or 3 (1 mmol) in dry THF (30 mL) was
H, CHO), 4.97 (s, 1 H, OCHO), 6.96Ϫ7.02 (m, 3 H, ArH),
7.08Ϫ7.20 (m, 4 H, ArH), 7.40 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH),
cooled to Ϫ100 °C under an argon atmosphere. nBuLi (1.6  in
hexane, 0.88 mL, 1.4 mmol) was added rapidly carefully main-
taining the reaction temperature below Ϫ90 °C. The reaction mix-
ture was stirred at Ϫ100 °C for 2 h and then it was warmed slowly
to Ϫ78 °C. Stirring was continued for a further 4 h before the reac-
tion was quenched with a saturated NH4Cl solution (10 mL) and
the mixture extracted with diethyl ether (3 ϫ 30 mL). The com-
bined organic extracts were dried over MgSO4 and evaporated to
give a pale yellow oil, which was purified by flash chromatography
(silica gel, n-hexane/Et2O, 4:1 for 4 and 9:1 for 5).
7.48 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz,
CDCl3):
δ
ϭ
22.13 (CH3CHO), 23.86 [C(CH3)3], 33.71
(CH2CH2Ph), 35.03 [C(CH3)3], 37.71 (CH2CH2Ph), 49.71 (CHS),
53.07 (CHCϭO), 72.97 (CHO), 107.44 (OCHO), 126.08 (C, Ar),
126.25, 128.11, 128.43 (ϫ 2), 128.48, 128.55 (ϫ 2), 132.76, 133.21
(CH, Ar), 136.04, 140.57 (C, Ar), 169.84 (CϭO). Ϫ C24H29BrO3S
(477.46): calcd. C 60.37, H 6.12, S 6.71, Br 16.74; found C 60.05,
H 6.16, S 6.86, Br 16.80.
(1ЈS,2R,5R,6R)-5-{1Ј[(2-Bromophenyl)sufanyl]-3Ј-phenylpropyl}-2-
tert-butyl-6-methyl-1,3-dioxan-4-one (3d): Yield: 352 mg (74%). Ϫ
Rf ϭ 0.42 (hexane/Et2O, 4:1). Ϫ Colorless oil. Ϫ [α]2D0ϭ ϩ42.6 (c ϭ
1, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.87 [s, 9 H,
C(CH3)3], 1.21 (d, J ϭ 6.4 Hz, 3 H, CH3CHO), 2.12 and 2.27 (each
m, 2 ϫ H, CH2CH2Ph), 2.65Ϫ2.85 (m, 2 H, CH2CH2Ph), 2.70 (dd,
J ϭ 1.9, 9.8 Hz, 1 H, CHCϭO), 3.52 (ddd, J ϭ 1.9, 6.4, 8.3 Hz, 1
H, CHS), 3.91 (dq, J ϭ 6.0, 9.8 Hz, 1 H, CHO), 4.88 (s, 1 H,
OCHO), 6.98 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.05Ϫ7.23 (m,
7 H, ArH), 7.48 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR
(75.5 MHz, CDCl3): δ ϭ 20.95 (CH3CHO), 23.90 [C(CH3)3], 33.75
(CH2CH2Ph), 35.02 (CH2CH2Ph), 35.16 [C(CH3)3], 49.53 (CHS),
51.49 (CHCϭO), 73.14 (CHO), 108.07 (OCHO), 125.32 (C, Ar),
126.29, 127.91, 128.15, 128.50 (ϫ 2), 128.55 (ϫ 2), 130.79, 133.51
(CH, Ar), 136.41, 140.50 (C, Ar), 168.92 (CϭO). Ϫ C24H29BrO3S
(477.46): calcd. C 60.37, H 6.12, S 6.71, Br 16.74; found C 60.13,
H 6.37, S 6.50, Br 16.59.
(؉)-(1ЈR,2R,3R)-3-(1Ј-Hydroxyethyl)-2-methylthiochroman-4-one
(4a): Yield: 169 mg (76%). Ϫ Rf ϭ 0.30 (hexane/Et2O, 3:1). Ϫ Col-
orless crystals. M.p. 35Ϫ36 °C. Ϫ [α]2D0 ϭ ϩ81.9 (c ϭ 1, CHCl3).
Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 1.24 (d, J ϭ 6.4 Hz, 3 H,
CH3CHO), 1.29 (d, J ϭ 7.1 Hz, 3 H, CH3CHS), 2.97 (dd, J ϭ 3.7,
7.9 Hz, 1 H, CHCϭO), 3.39 (dq, J ϭ 3.7, 7.1 Hz, 1 H, CHS), 3.81
(br s, 1 H, OH), 4.18 (dq, J ϭ 6.4, 7.9 Hz, 1 H, CHO), 7.10 (ddd,
J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 7.15 (dd, J ϭ 1.1, 7.9, Hz, 1 H,
ArH), 7.34 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 7.98 (dd, J ϭ
1.1, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ
15.92 (CH3CHS), 19.50 (CH3CHO), 37.43 (CHS), 59.05 (CHCϭ
O), 66.35 (CHO), 124.72, 127.84, 128.80 (CH, Ar), 130.34 (C, Ar),
134.09 (CH, Ar), 139.69 (C, Ar), 198.34 (CϭO). Ϫ C12H14O2S
(222.30): calcd. C 64.84, H 6.35, S 14.42; found C 64.85, H 6.65,
S 14.18.
(؉)-(1ЈR,2R,3R)-2-Ethyl-3-(1Ј-hydroxyethyl)thiochroman-4-one
(4b): Yield: 173 mg (73%). Ϫ Rf ϭ 0.33 (hexane/Et2O, 3:1). Ϫ Col-
orless oil. Ϫ [α]2D0 ϭ ϩ101.6 (c ϭ 1, CHCl3). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.96 (t, J ϭ 7.1 Hz, CH3CH2), 1.23 (d,
J ϭ 6.4 Hz, 3 H, CH3CHO), 1.35Ϫ1.48 (m, 1 H, CH2), 1.50Ϫ1.61
(m, 1 H, CH2), 3.03 (dd, J ϭ 3.7, 7.5 Hz, 1 H, CHCϭO), 3.09
(ddd, J ϭ 3.7, 6.8, 11.0 Hz, 1 H, CHS), 3.76 (br s, 1 H, OH), 4.27
(dq, J ϭ 6.4, 7.5 Hz, 1 H, CHO), 7.09 (ddd, J ϭ 1.1, 7.1, 8.3 Hz,
1 H, ArH), 7.15 (dd, J ϭ 1.1, 7.9, Hz, 1 H, ArH), 7.33 (ddd, J ϭ
1.1, 7.1, 8.3 Hz, 1 H, ArH), 7.97 (dd, J ϭ 1.1, 7.9 Hz, 1 H, ArH).
(1ЈS,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanyl(phenyl)methyl]-2-
tert-butyl-6-methyl-1,3-dioxan-4-one (2e): Yield: 368 mg (82%). Ϫ
Rf ϭ 0.34 (hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 61Ϫ62 °C.
1
Ϫ [α]2D0 ϭ Ϫ70.2 (c ϭ 1, CHCl3). Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 0.81 (d, J ϭ 6.0 Hz, 3 H, CH3CHO), 0.88 [s, 9 H, C(CH3)3],
3.03 (dd, J ϭ 3.7, 9.0 Hz, 1 H, CHCϭO), 4.01 (dq, J ϭ 6.0, 9.0 Hz,
1 H, CHO), 4.86 (s, 1 H, OCHO), 4.99 (d, J ϭ 3.7 Hz, 1 H, CHS),
6.88Ϫ6.94 (m, 1 H, ArH), 6.97Ϫ7.08 (m, 2 H, ArH), 7.15Ϫ7.28
(m, 3 H, ArH), 7.42Ϫ7.45 (m, 3 H, ArH). Ϫ 13C NMR (75.5 MHz,
CDCl3): δ ϭ 21.24 (CH3CHO), 23.85 [C(CH3)3], 35.02 [C(CH3)3],
52.75 (CHS), 55.45 (CHCϭO), 73.09 (CHO), 107.54 (OCHO),
125.26 (C, Ar), 127.88, 128.02, 128.20 (ϫ 2), 128.88 (ϫ 2), 129.39,
131.39, 133.01 (CH, Ar), 135.88, 138.39 (C, Ar), 169.07 (CϭO). Ϫ
C22H25BrO3S (449.40): calcd. C 58.80, H 5.61, S 7.13, Br 17.78;
found C 58.78, H 5.66, S 6.16, Br 17.76.
Ϫ
13C NMR (75.5 MHz, CDCl3): δ ϭ 13.08 (CH3CH2), 19.60
(CH3CHO), 21.61 (CH2), 45.81 (CHS), 59.24 (CHCϭO), 66.21
(CHO), 124.72, 127.81, 128.74 (CH, Ar), 130.86 (C, Ar), 133.98
(CH, Ar), 139.79 (C, Ar), 198.20 (CϭO). Ϫ C13H16O2S (236.33):
calcd. C 66.07, H 6.82, S 13.57; found C 66.02, H 6.94, S 13.42.
(1ЈR,2R,5R,6R)-5-[1Ј-(2-Bromophenyl)sulfanyl(cyclohexyl)methyl]-
2-tert-butyl-6-methyl-1,3-dioxan-4-one (2f): Yield: 271 mg (59%). Ϫ
Rf ϭ 0.54 (hexane/Et2O, 4:1). Ϫ Colorless crystals. M.p. 84Ϫ85 °C.
(؉)-(1ЈR,2R,3R)-3-[1Ј-Hydroxyethyl]-2-isopropylthiochroman-4-one
(4c): Yield: 180 mg (72%). Ϫ Rf ϭ 0.35 (hexane/Et2O, 3:1). Ϫ Col-
orless oil. Ϫ [α]2D0 ϭ ϩ149.6 (c ϭ 1, CHCl3). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.78 and 0.94 [each d, J ϭ 6.8 Hz, 2 ϫ 3
1
Ϫ [α]2D0 ϭ ϩ47.7 (c ϭ 1, CHCl3). Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 0.72Ϫ0.77 (m, 1 H, cyclohexyl), 0.93 [s, 9 H, C(CH3)3], H, CH(CH3)2], 1.27 (d, J ϭ 6.4 Hz, 3 H, CH3CHO), 2.05 [m, 1 H,
1.05Ϫ1.24 (m, 4 H, cyclohexyl), 1.39 (d, J ϭ 6.0 Hz, 3 H, CH(CH3)2], 3.02 (dd, J ϭ 3.7, 7.9 Hz, 1 H, CHCϭO), 3.33 (dd,
CH3CHO), 1.46Ϫ1.56 (m, 1 H, cyclohexyl), 1.59Ϫ1.80 (m, 4 H,
J ϭ 3.7, 11.6, Hz, 1 H, CHS), 3.70 (br s, 1 H, OH), 4.41 (dq, J ϭ
cyclohexyl), 2.18Ϫ2.22 (m, 1 H, cyclohexyl), 3.10 (dd, J ϭ 2.6, 6.4, 7.9 Hz, 1 H, CHO), 7.06 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH),
9.0 Hz, 1 H, CHCϭO), 3.83 (dd, J ϭ 2.6, 10.5 Hz, 1 H, CHS), 4.19 7.17 (dd, J ϭ 1.1, 7.9, Hz, 1 H, ArH), 7.29 (ddd, J ϭ 1.1, 7.1,
(dq, J ϭ 6.0, 9.0 Hz, 1 H, CHO), 5.07 (s, 1 H, OCHO), 7.0 (ddd,
J ϭ 1.5, 7.9, 9.0 Hz, 1 H, ArH), 7.25 (ddd, J ϭ 1.5, 7.9, 9.0 Hz, 1 NMR (75.5 MHz, CDCl3): δ ϭ 18.46 (CH3CHO), 20.31 and 20.81
8.3 Hz, 1 H, ArH), 7.94 (dd, J ϭ 1.1, 7.9 Hz, 1 H, ArH). Ϫ 13C
H, ArH), 7.49 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH), 7.55 (dd, J ϭ 1.5,
7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 22.03
(CH3CHO), 23.86 [C(CH3)3], 25.90, 25.96, 26.16, 31.42, 31.60
[CH(CH3)2], 29.55 [CH(CH3)2], 50.49 (CHS), 56.82 (CHCϭO),
66.25 (CHO), 124.54, 126.71, 128.50 (CH, Ar), 131.34 (C, Ar),
133.56 (CH, Ar), 141.53 (C, Ar), 198.24 (CϭO). Ϫ C14H18O2S
(CH2, cyclohexyl), 34.96 [C(CH3)3], 42.43 (CH, cyclohexyl), 50.10 (250.36): calcd. C 67.17, H 7.25, S 12.81; found C 67.11, H 7.48,
(CHCϭO), 57.36 (CHS), 73.26 (CHO), 107.12 (OCHO), 124.20 (C,
Eur. J. Org. Chem. 2001, 529Ϫ535
S 12.68.
533

A. Ali, V. U. Ahmad, J. Liebscher
FULL PAPER
(؉)-(1ЈR,2R,3R)-3-[1Ј-Hydroxyethyl]-2-phenylethyl)thiochroman-4-
one (4d): Yield: 228 mg (73%). Ϫ Rf ϭ 0.34 (hexane/Et2O, 3:1). Ϫ
(hexane/Et2O, 6:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ Ϫ205.7 (c ϭ 1,
1
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.99 (t, J ϭ 7.1 Hz,
Colorless crystals. M.p. 67Ϫ68 °C. Ϫ [α]2D0 ϭ ϩ194.4 (c ϭ 1, 3 H, CH3), 1.69 (m, 2 H, CH3CH2), 2.73 (dd, J ϭ 10.9, 16.2 Hz, 1
1
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.94 (d, J ϭ 6.4 Hz, H, CH2CϭO), 2.98 (dd, J ϭ 3.0, 16.2 Hz, 1 H, CH2CϭO), 3.36
3 H, CH3CHO), 1.72Ϫ1.80 (m, 2 H, CH2CH2Ph), 2.56Ϫ2.66 (m,
(ddt, J ϭ 3.0, 7.1, 10.9 Hz, 1 H, CHS), 7.09 (ddd, J ϭ 1.1, 7.1,
2 H, CH2CH2Ph), 2.96 (dd, J ϭ 3.7, 7.9 Hz, 1 H, CHCϭO), 3.06 8.3 Hz, 1 H, ArH), 7.20 (dd, J ϭ 1.5, 7.9, Hz, 1 H, ArH), 7.31
(ddd, J ϭ 3.7, 5.6, 9.4 Hz, 1 H, CHS), 3.72 (br s, 1 H, OH), 4.15 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 8.0 (dd, J ϭ 1.5, 7.9 Hz, 1
(dq, J ϭ 6.4, 7.9 Hz, 1 H, CHO), 6.97Ϫ7.13 (m, 4 H, ArH),
7.17Ϫ7.22 (m, 3 H, ArH), 7.33 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H,
H, ArH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 11.35 (CH3), 27.62
(CH3CH2), 43.28 (CHS), 45.90 (CH2CϭO), 124.83, 127.64, 128.88
ArH), 7.96 (dd, J ϭ 1.1, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (CH, Ar), 130.64 (C, Ar), 133.44 (CH, Ar), 141.64 (C, Ar), 194.75
(75.5 MHz, CDCl3): δ ϭ 19.13 (CH3CHO), 29.67 (CH2CH2Ph), (CϭO). Ϫ C11H12OS (192.28): calcd. C 68.71, H 6.29, S 16.67;
33.68 (CH2CH2Ph), 42.11 (CHS), 58.96 (CHCϭO), 66.14 (CHO), found C 68.76, H 6.49, S 16.42.
124.88, 126.38, 127.94, 128.55(ϫ 2), 128.61 (ϫ 2), 128.85 (CH, Ar),
(؊)-(2S)-2-Isopropylthiochroman-4-one (5c): Yield: 161 mg (78%).
130.83 (C, Ar), 134.09 (CH, Ar), 139.51, 140.26 (C, Ar), 198.10
(CϭO). Ϫ C19H20O2S (312.43): calcd. C 73.04, H 6.45, S 10.26;
found C 72.84, H 6.46, S 9.98.
Ϫ Rf ϭ 0.56 (hexane/Et2O, 6:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ Ϫ191.5
(c ϭ 1, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.99 and 1.01
[each d, J ϭ 6.8 Hz, 2 ϫ 3 H, CH(CH3)2], 1.88 [m, 1 H, CH(CH3)2],
(؉)-(1ЈR,2S,3R)-3-[1Ј-Hydroxyethyl]-2-phenylthiochroman-4-one
(4e): Yield: 199 mg (70%). Ϫ Rf ϭ 0.30 (hexane/Et2O, 3:1). Ϫ Col-
orless crystals. M.p. 125Ϫ126 °C. Ϫ [α]2D0 ϭ ϩ211.4 (c ϭ 1, CHCl3).
2.77 (dd, J ϭ 12.0, 16.2 Hz, 1 H, CH2CϭO), 2.94 (dd, J ϭ 3.0,
16.2 Hz, 1 H, CH2CϭO), 3.30 (ddd, J ϭ 3.0, 6.4, 12.0 Hz, 1 H,
CHS), 7.07 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 7.20 (dd, J ϭ
1.5, 7.9, Hz, 1 H, ArH), 7.29 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH),
7.99 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C NMR (75.5 MHz,
CDCl3): δ ϭ 19.60 and 19.79 [CH(CH3)2], 31.99 [CH(CH3)2], 43.76
(CH2CϭO), 48.46 (CHS), 124.71, 127.69, 128.84 (CH, Ar), 130.59
(C, Ar), 133.35 (CH, Ar), 142.07 (C, Ar), 195.22 (CϭO). Ϫ
C12H14OS (206.30): calcd. C 69.86, H 6.84, S 15.54; found C 69.66,
H 7.06, S 15.32.
Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 1.14 (d, J ϭ 6.8 Hz, 3 H,
CH3), 3.37 (dd, J ϭ 3.8, 9.8 Hz, 1 H, CHCϭO), 3.54 (br s, 1 H,
OH), 3.82 (dq, J ϭ 6.8, 9.8 Hz, 1 H, CHO), 4.56 (d, J ϭ 3.8 Hz, 1
H, CHS), 7.10Ϫ7.18 (m, 2 H, ArH), 7.23Ϫ7.30 (m, 3 H, ArH),
7.33Ϫ7.38 (m, 3 H, ArH), 8.0 (dd, J ϭ 1.5, 8.6 Hz, 1 H, ArH). Ϫ
13C NMR (75.5 Hz, CDCl3): δ ϭ 19.09 (CH3), 47.70 (CHS), 58.86
(CH2CϭO), 66.81 (CHO), 125.26, 126.94, 127.83 (ϫ 2), 128.51,
129.07 (ϫ 2), 129.39 (CH, Ar), 130.95 (C, Ar), 133.99 (CH, Ar),
137.33, 141.44 (C, Ar), 197.48 (CϭO). Ϫ C17H16O2S (284.37):
calcd. C 71.80, H 5.67, S 11.27; found C 71.77, H 5.78, S 11.51.
(؊)- (2S)-2-Phenethylthiochroman-4-one (5d): Yield: 201 mg (75%).
Ϫ Rf ϭ 0.42 (hexane/Et2O, 6:1). Ϫ Colorless oil. Ϫ [α]2D0 ϭ Ϫ178
(c ϭ 1, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.89Ϫ1.97
(m, 2 H, CH2CH2Ph), 2.58Ϫ2.77 (m, 3 H, CH2CH2Ph and CH2Cϭ
O), 2.95 (dd, J ϭ 3.0, 16.2 Hz, 1 H, CH2CϭO), 3.35 (m, 1 H,
CHS), 7.02Ϫ7.11 (m, 4 H, ArH), 7.15Ϫ7.20 (m, 3 H, ArH), 7.27
(ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 7.97 (dd, J ϭ 1.5, 7.9 Hz, 1
(؉)-(1ЈR,2R,3R)-2-Cyclohexyl-3-[1Ј-hydroxyethyl]thiochroman-4-
one (4f): Yield: 226 mg (78%). Ϫ Rf ϭ 0.38 (hexane/Et2O, 3:1). Ϫ
Colorless crystals. M.p. 92Ϫ93 °C. Ϫ [α]2D0 ϭ ϩ178.8 (c ϭ 1,
1
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.87Ϫ1.03(m, 3 H,
H, ArH).
Ϫ δ ϭ 32.76
13C NMR (75.5 MHz, CDCl3):
cyclohexyl), 1.13Ϫ1.19 (m, 1 H, cyclohexyl), 1.26 (d, J ϭ 6.4 Hz,
3 H, CH3), 1.35Ϫ1.54 (m, 4 H, cyclohexyl), 1.65Ϫ1.69 (m, 3 H,
cyclohexyl), 3.0 (dd, J ϭ 3.7, 7.6 Hz, 1 H, CHCϭO), 3.29 (dd, J ϭ
3.7, 11.2 Hz, 1 H, CHS), 3.82 (br s, 1 H, OH), 4.39 (dq, J ϭ 6.4,
7.6 Hz, 1 H, CHO), 7.06 (ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH),
7.17 (dd, J ϭ 1.5, 7.9, Hz, 1 H, ArH), 7.30 (ddd, J ϭ 1.1, 7.1,
8.3 Hz, 1 H, ArH), 7.94 (dd, J ϭ 1.5, 7.9 Hz, 1 H, ArH). Ϫ 13C
NMR (75.5 MHz, CDCl3): δ ϭ 20.36 (CH3), 25.71, 25.92 (ϫ 2),
26.16, 31.53 (CH2, cyclohexyl), 39.42 (CH, cyclohexyl), 49.80
(CHS), 57.52 (CH2CϭO), 66.26 (CHO), 124.50, 126.72, 128.50
(CH, Ar), 131.36 (C, Ar), 133.55 (CH, Ar), 141.43 (C, Ar), 198.19
(CϭO). Ϫ C17H22O2S (290.42): calcd. C 70.31, H 7.64, S 11.04;
found C 70.28, H 7.95, S 10.84.
(CH2CH2Ph), 35.94 (CH2CH2Ph), 40.69 (CHS), 46.10 (CH2CϭO),
124.99, 126.29, 127.73, 128.44 (ϫ 2), 128.60 (ϫ 2), 128.93 (CH,
Ar), 130.66 (C, Ar), 133.54 (CH, Ar), 140.52, 141.23 (C, Ar),
194.37 (CϭO). Ϫ C17H16OS (268.37): calcd. C 76.08, H 6.01, S
11.95; found C 75.81, H 6.28, S 11.72.
X-ray Crystal Analysis of 2b:[20] A single crystal of 2b with the
dimensions 0.80 ϫ 0.80 ϫ 0.40 mm was measured on a STOE Ipds
˚
diffractometer using Mo-Kα radiation (λ ϭ 0.71073 A). Crystal
data: C18H25BrO3S, M ϭ 401.36, orthorhombic space group
˚
˚
˚
P212121, a ϭ 7.3753 (9) A, b ϭ 10.617 (3) A, c ϭ 24.180 (3) A,
3
˚
α ϭ 90°, β ϭ 90°, γ ϭ 90°, V ϭ 1893.4 (6) A , Z ϭ 5, Dc ϭ 1.408 g/
cm3, F (000) ϭ 832, µ(Mo-Kα) ϭ 2.293 mmϪ1. At 180 (2) K in the
range 1.68 Ͻ θ Ͻ 25.23°, 2276 reflections were measured, 1990
(؊)-(2S)-2-Methyl-2,3-thiochroman-4-one (5a): Data for the ra-
cemic 5a[5,6,9] and (2R)-5a[1] have been reported earlier. Yield:
135 mg (76%). Ϫ Rf ϭ 0.43 (hexane/Et2O, 6:1). Ϫ Colorless oil. Ϫ
were unique (Rint ϭ 0.0143). The final residuals were wR2(all)
ϭ
0.0661, R1(all) ϭ 0.0400 and R1(obs) ϭ 0.0286. The maximum and
minimum peaks in the final difference map were 0.330 and Ϫ0.243
1
[α]2D0 ϭ Ϫ200.5 (c ϭ 1, CHCl3). Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 1.37 (d, J ϭ 6.8 Hz, 3 H, CH3), 2.69 (dd, J ϭ 11.3, 16.2 Hz,
1 H, CH2CϭO), 2.95 (dd, J ϭ 3.0, 16.2 Hz, 1 H, CH2CϭO), 3.56
(ddq, J ϭ 3.0, 6.8, 11.3 Hz, 1 H, CHS), 7.09 (ddd, J ϭ 1.1, 7.1,
8.3 Hz, 1 H, ArH), 7.18 (dd, J ϭ 1.5, 7.9, Hz, 1 H, ArH), 7.31
(ddd, J ϭ 1.1, 7.1, 8.3 Hz, 1 H, ArH), 8.02 (dd, J ϭ 1.5, 7.9 Hz, 1
H, ArH). Ϫ 13C NMR: (75.5 Hz, CDCl3): δ ϭ 20.45 (CH3), 36.43
(CHS), 47.82 (CH2CϭO), 124.91, 127.48, 128.96 (CH, Ar), 130.36
(C, Ar), 133.47 (CH, Ar), 141.79 (C, Ar), 194.66 (CϭO). Ϫ
C10H10OS (178.25): calcd. C 66.38, H 5.65, S 17.99; found C 66.21,
H 5.69, S 17.82.
e AϪ3, respectively.
˚
Acknowledgments
We gratefully acknowledge the financial support from the
Deutscher Akademischer Austauschdienst (DAAD) and the Fonds
der Chemischen Industrie. We thank Dr. Burkhard Ziemer and Dr.
Joachim Leistner, Institut für Chemie, Humboldt-Universität
Berlin for the X-ray crystal analysis and CD-spectra, respectively.
[1]
(؊)-(2S)-2-Ethylthiochroman-4-one (5b): Data for the racemic 5b
have been reported earlier.[9] Ϫ Yield: 144 mg (75%). Ϫ Rf ϭ 0.50
A. Kumar, D. H. Ner, S. Dike, Indian J. Chem. Sect. B 1992,
31, 803Ϫ809.
534
Eur. J. Org. Chem. 2001, 529Ϫ535

Stereoselective Synthesis of Thiochroman-4-ones
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[9]
Crystallographic data (excluding structure factors) for the
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Received July 27, 2000
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535