Synthesis of tetrahydropyran-4-ones and thiopyran-4-ones from donor-substituted α-bromostyrene derivatives

Article abstract of DOI:10.1002/ejoc.200600372

Tetrahydropyran-4-one and tetrahydrothiopyran-4-one derivatives with a 3-aryl substituent were synthesized by double-conjugate addition of water or H₂S to divinyl ketones. These starting materials were prepared in two steps by conversion of lit

Full text of DOI:10.1002/ejoc.200600372

FULL PAPER
DOI: 10.1002/ejoc.200600372
Synthesis of Tetrahydropyran-4-ones and Thiopyran-4-ones from Donor-
Substituted α-Bromostyrene Derivatives
Anna Rosiak,[a,b] Wolfgang Frey,[b] and Jens Christoffers*[a]
In memoriam Michael Brommer
Keywords: Alkynes / α-Bromostyrenes / Conjugate addition / Corey–Fuchs procedure / Heterocycles / Pyrans / Thiopyrans
Tetrahydropyran-4-one and tetrahydrothiopyran-4-one de-
rivatives with a 3-aryl substituent were synthesized by
double-conjugate addition of water or H2S to divinyl ketones.
These starting materials were prepared in two steps by con-
version of lithiated α-bromostyrene derivatives with acrolein
or cinnamaldehyde and subsequent oxidation of the divinyl
alcohols with MnO2. The electron-rich α-bromostyrene build-
ing blocks were prepared by addition of HBr to the respec-
tive alkyne under strictly anhydrous conditions, which works
reliably on a multigram scale. Two routes to arylacetylenes
with a specific substitution pattern have been explored; how-
ever, on a larger scale only the Corey–Fuchs sequence turned
out to be feasible.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
5 followed by oxidation of the secondary alcohol function.
Although the parent compound α-bromostyrene 4e itself is
a commercially available material, substituted congeners, in
particular 3,4-dialkoxy-substituted ones, are mostly un-
known and moreover, common routes to these building
Introduction
Successful drug development is often dependent on the
availability of heterocyclic building blocks with a specific
substitution pattern. Of particular importance are com-
pounds with aromatic and heteroaromatic side chains with
the need for a broad variety of substituents. Moreover, in
late stages of optimization and screening processes a scal-
able access to these intermediates is required. In the course
of a search program in a medicinal chemistry context tetra-
hydrothiopyran-4-ones 1 and tetrahydropyran-4-ones 2
were required as building blocks (Scheme 1). Of course,
many procedures[1] have been reported to access tetra-
hydropyran-4-one derivatives[2] and their sulfur analogs;[3]
however, our requirement for an electron-rich aromatic sub-
stituent in the 3-position has not been addressed in the lit-
erature so far. The obvious first approach to our target
structures 1 and 2 is the α-arylation of the unsubstituted
heterocyclic ketone, which failed, however, due to the de-
composition by E1cb elimination of the respective enolates.
Therefore, we envisioned to build up the heterocycle by
double-conjugate addition of water (X = O) or sulfane (X
= S) to a divinyl ketone 3[4] with the accurate substitution
pattern in the aromatic ring. Furthermore, we decided to
prepare the divinyl ketones 3 by addition of the lithiated α-
bromostyrene derivatives 4 to the α,β-unsaturated aldehydes
blocks utilize
a
bromination/dehydrobromination se-
quence,[5] which results in low yields and low purity of the
respective bromo olefin 4. Therefore, we envisioned the ad-
dition of hydrogen bromide to an alkyne 6 under anhydrous
conditions[6] to be the best alternative for the preparation
of our target α-bromostyrenes 4 on a multigram scale. An
advantage of this route might clearly be the availability of
various phenylacetylene derivatives, which should guarantee
access to a broad spectrum of these building blocks. Never-
[a] Institut für Reine und Angewandte Chemie, Carl von Ossietzky-
Universität Oldenburg, 26111 Oldenburg, Germany
Fax: +49-441-798-3873
Scheme 1. Strategy for the preparation of 3-aryl-substituted tetra-
hydrothiopyran-4-ones 1 and tetrahydropyran-4-ones 2 by double-
conjugate addition. Retrosynthesis of the divinyl ketones 3 by α-
bromostyrene derivatives 4 to alkynes 6. R = electron-rich aryl, RЈ
= H, Ph.
E-mail: jens.christoffers@uni-oldenburg.de
[b] Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
4044
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Tetrahydropyran-4-ones and Thiopyran-4-ones from α-Bromostyrene Derivatives
FULL PAPER
theless, alkynes with a 3,4-dialkyoxyphenyl residue, which protonated (LDA) and the enolate esterified with (EtO)2-
was in the focus of our efforts, required some synthetic de- P(O)Cl to give the enol phosphate, which was eliminated
velopments, as pointed out below.
with an excess of LDA to give the alkyne 6b in moderate
yield (56%). However, the reproducibility of this one-pot
sequence was limited. In some cases yields were as low as
20%. For this reason and because the total yield over three
steps was even in optimal cases only 30%, the decision was
made to establish the alkyne moiety by the most reliable
literature procedure for alkyne synthesis, the Corey–
Fuchs[10] sequence.
Results and Discussion
Route to an Alkyne via an Enol Phosphate
As a first approach to an arylacetylene 6 we investigated
the elimination of an enol phosphate generated in situ from
a corresponding acetophenone derivative 7 (Scheme 2).[7] In
order to have direct access to one of our particular target
compounds, we decided to establish the 3-ethoxy-4-meth-
oxyphenyl substitution pattern by a dealkylation/alkylation
sequence starting from veratrophenone (7a).[8] Ether cleav-
age was regioselectively achieved at the more basic meta-
methoxy group with concd. sulfuric acid to give the phenol
derivative 8 (60%), which was subsequently alkylated in an
SN2 reaction to give the ketone 7b (88%). At this stage,
the regiochemistry was undoubtedly established by single-
crystal X-ray analysis[9] (Figure 1). The ketone 7b was de-
Corey–Fuchs Sequence to Alkynes and HBr Addition
Four commercially available, electron-rich aromatic alde-
hydes 10 – including a thiophene derivative 10d as a hetero-
cyclic example – were converted with PPh3 and CBr4 into
the corresponding dibromovinyl derivatives 11 in high
yields (86–99%, Scheme 3). Products 11a and 11b are new;
yields for compounds 11c[11] and 11d[12] have been signifi-
cantly improved compared to literature reports. For com-
pounds 11a and 11b the preparation was executed on a
40-g scale, which made the chromatographic separation of
the product from phosphane oxide a little tedious. From
one of these materials single crystals could be grown and
the constitution of compound 11b was undoubtedly proven
by X-ray crystallography[9] (Figure 2).
Scheme 3. Synthesis of α-bromostyrene derivatives 4 from aromatic
aldehydes 10 via arylacetylenes 6 (Corey–Fuchs sequence). Rea-
gents and conditions: a) PPh3, CBr4, CH2Cl2, 5 °C, 40 min (for
10a–10c), 2 h (for 10d). b) nBuLi, THF, –78 °C, 1.5 h; 23 °C, 1.5 h.
c) HBr, AcOH, 23 °C, 20 min. For yields and substituents see
Table 1.
Scheme 2. From veratrophenone (7a) to alkyne 6b by dealkylation,
alkylation, and elimination. Reagents and conditions: a) H2SO4
(concd.), 65 °C, 46 h; 60% (8). b) EtBr, K2CO3, DMF, 100 °C, 6 h;
88% (7b). c) 1. LDA, THF, –78 °C, 1 h; 2. (EtO)2P(O)Cl, 23 °C,
3 h; 3. LDA, –78 °C, 23 °C, 3 h; 56 % (6b).
Table 1. Synthesis of electron-rich α-bromostyrene derivatives 4
from aromatic aldehydes.
Elimination with 2 equiv. of nBuLi and rearrangement
gave the respective alkynes 6 in 82–99% yield, for com-
pound 6a,[13] and 6b (previously unknown) on scales up to
80 g. In contrast to alkynes 6c,[14] and 6d,[15] which behave
Figure 1. ORTEP representation of the structure of compound 7b
in the solid state.
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A. Rosiak, W. Frey, J. Christoffers
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with freshly distilled acrolein (5a) or cinnamaldehyde (5b)
to yield the divinyl alcohols 12a–12f after chromatographic
purification. Thiophene derivative 4d led to unspecific de-
composition when treated with nBuLi. Therefore, no thienyl
substituents are found in further intermediates and the tar-
get structures. The alcohols 12d–12f derived from aldehyde
5b are obtained as single diastereoisomers with the double-
bond configuration being (E) as seen from the olefinic
3J(H,H) coupling constant. Oxidation to the ketones 3 was
achieved with MnO2 of commercial activity. The oxidant
was added portionwise to a suspension in CH2Cl2 until al-
most no starting materials 12 were detectable by TLC,
which normally took 20–30 equiv. of MnO2 and about 1 h.
1
The products are generally pure by H NMR spectroscopy
without further chromatography, and are again obtained
exclusively with (E) double-bond configuration in cases
with RЈ = Ph. If the conversion in this step is not complete,
the remaining starting material 12 might be hardly separa-
ble from the cyclization product of the next step (1 or 2).
On the other hand, prolonged reaction times result in an
over-oxidation to an epoxide. Therefore, monitoring of the
reaction progress by TLC is an important issue. The divinyl
ketones 3a–c, which derive from acrolein (5a), are highly
reactive and neither stable at ambient conditions nor at low
temperatures (Table 2). They even decompose significantly
upon chromatography on SiO2. Therefore, these materials
were directly converted further after filtration from MnO2
into the heterocyclic products 1 and 2.
Figure 2. ORTEP representation of the structure of compound 11b
in the solid state.
indifferent under ambient conditions, the dialkoxy conge-
ners 6a and 6b turned surprisingly out to be hygroscopic.
The latter is an important aspect with regard to the next
step of the synthesis of α-bromostyrenes 4, which is highly
sensitive to traces of moisture, yielding acetophenones as
byproducts or even major products under the reaction con-
ditions. The addition of HBr to the alkynes 6a–6d has there-
fore to be performed under strictly anhydrous conditions. A
suitable solution of HBr in glacial acetic acid is fortunately
commercially available. Starting material 6b has to be thor-
oughly dried by lyophilization in high vacuum prior to use.
The α-bromostyrene derivatives 4a, 4b, 4c,[6,16] 4d are ob-
tained in 68–94% yield as light-sensitive compounds, which
are not stable under ambient conditions. For compounds
4a and 4b, the preparation works reliable in scales up to
20 g.
Table 2. Yields and substituents R and RЈ in the synthesis of divinyl
ketones 3.
Starting materials
R
RЈ Yield of 12 Yield of 3
4e, 5a
4a, 5a
4b, 5a
4a, 5b
4b, 5b
4c, 5b
Ph
H
H
H
12a (78%) 3a (95%)
12b (62%) 3b (56%)
12c (64%) 3c (74%)
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
3,4-(MeO)2C6H3 Ph 12d (63%) 3d (70%)
3-EtO-4-MeOC6H3 Ph 12e (48%) 3e (64%)
4-MeOC6H4
Ph 12f (74%) 3f (83%)
Double-Conjugate Addition of Sulfide
Synthesis of Divinyl Ketones
First of all, the reaction conditions of the ring closure
The dienones 3 were prepared in two steps from α-bro- were optimized with model compound 3a (R = Ph, RЈ =
mostyrene derivatives 4 (Scheme 4). The parent compound H), because it was prepared from commercially available α-
4e (R = Ph) is commercially available. Lithium/bromine ex- bromostyrene 4e. Although sulfides, as soft nucleophiles,
change of compounds 4a–c and 4e with nBuLi proceeded are expected to cleanly undergo conjugate additions, yields
smoothly at –78 °C. The reaction mixtures were treated turned out to be highly dependent on the reaction condi-
Scheme 4. Synthesis of divinyl ketones 3 from α-bromostyrenes 4. Reagents and conditions: (a) 1. nBuLi, THF, 1.5 h, –78 °C; 2. aldehyde
5, 1.5 h, –78 °C; (b) excess MnO2, CH2Cl2, 60 min, 23 °C.
4046
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Tetrahydropyran-4-ones and Thiopyran-4-ones from α-Bromostyrene Derivatives
FULL PAPER
tions applied, particularly on the solvent used. Best results Double-Conjugate Addition of Water
were achieved with NaHS in 2-methoxyethanol (2-ME,
For the pyranone series, various acidic and basic reaction
conditions with different solvent/water mixtures, even with
phase-transfer catalysis have been investigated with the di-
enone 3a as starting material. Surprisingly, only with the
system KOH/H2O/CH2Cl2 at 50 °C the racemic pyranones
2a and 2b were formed, although yields are not fully
satisfying (Scheme 6). They are dependent on the purity of
the respective divinyl ketone 3. Actually, the low stability of
these dienones 3 might be the major reason for the moder-
ate yields in these cases. Nevertheless, the product of spe-
cific interest 2b was batchwise prepared in total amounts of
20 g by using the conditions depicted in Scheme 6.
Scheme 5) or Na2S in THF/H2O (1:1) at moderate tempera-
tures (45–55 °C). Yields for products 1a–1f are presented in
Table 3. Compounds 1b and 1c were of particular interest
and batchwise prepared in amounts of 20 and 50 g, respec-
tively.
Scheme 5. Synthesis of 3-aryl-substituted tetrahydrothiopyran-4-
ones 1 by double-conjugate addition. For yields and substituents
see Table 3.
Scheme 6. Synthesis of 3-aryl-substituted tetrahydropyran-4-ones 2
by double conjugate addition.
Table 3. Yields and substituents R and RЈ in the synthesis of tetra-
hydrothiopyran-4-ones 1 (X = S).
Dienone
R
RЈ
Product
Yield
3a
3b
3c
3d
3e
3f
Ph
H
H
H
1a
1b
1c
1d
1e
1f
70%
67%
59%
Conclusions
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3 Ph
4-MeOC6H4 Ph
A simple access to electron-rich α-bromostyrene deriva-
tives has been developed by hydrobromination of donor-
substituted arylacetylenes under strictly anhydrous condi-
tions. The respective alkynes were prepared by the Corey–
Fuchs procedure in a straightforward manner from aro-
matic aldehydes. The latter are available in a broad variety
Ph
60% (dr 4:1)[a]
48% (dr 9:1)[a]
57% (dr 3:1)[a]
[a] The trans isomer is the major diastereoisomer in all three cases.
All compounds were of course obtained as racemates. that assures a convenient access to a large number of α-
The molecular constitution of dimethoxyphenyl derivative bromostyrenes. Particular emphasis was put on the 3,4-di-
1b was established by an X-ray single-crystal structure alkoxyphenyl derivatives, which were prepared in three steps
analysis. An ORTEP representation of the solid-state struc- from the corresponding benzaldehydes in 73% (4a) and
ture is given in Figure 3.[9] For products 1d–1f mixtures of 88% (4b) overall yields, respectively, and on multigram
two diastereoisomers were obtained with moderate stereo- scales. The α-bromostyrenes are further converted by lith-
selectivity. The relative configuration was assigned based on ium/bromine exchange and subsequent treatment with α,β-
3J(H,H) coupling constants.
unsaturated aldehydes 5 to give the divinyl alcohols 12,
Figure 3. ORTEP representation of the structure of compound 1b in the solid state.
Eur. J. Org. Chem. 2006, 4044–4054
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A. Rosiak, W. Frey, J. Christoffers
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(%) = 252 (39) [M+], 164 (100). C13H16O3S (252.33): calcd. C 61.88,
H 6.39; found C 61.76, H 6.47.
which are further oxidized to the divinyl ketones 3. These
compounds are the relevant starting materials for tetra-
hydrothiopyran-4-ones 1 with an aromatic substituent in
the 3-position, which are accessed by double-conjugate ad-
dition of the sulfide to the dienones 3. The respective oxa-
3-(3-Ethoxy-4-methoxyphenyl)tetrahydrothiopyran-4-one (1c): Ac-
cording to the procedure given for compound 1a, divinyl ketone 3c
(1.9 g, 8.2 mmol) was converted with NaHS·1.2H2O (2.7 g,
cycles 2 can be similarly prepared from compounds 3 and 34.8 mmol) to give the title compound 1c (1.24 g, 4.66 mmol, 57%)
after chromatography (SiO2; PE/EA, 2:1; Rf = 0.31) as colorless
crystals, m.p. 103–104 °C. H NMR (300 MHz, CDCl3): δ = 1.46
water, however in lower yields. Overall yields allow for the
preparation of final products on multigram scales.
1
(t, J = 7.0 Hz, 3 H, CH3), 2.76–2.92 (m, 2 H), 2.98–3.17 (m, 3 H),
3.24 (dd, J = 13.6 Hz, J = 10.6 Hz, 1 H), 3.86 (s, 3 H), 3.90 (dd, J
= 10.6 Hz, J = 4.8 Hz, 1 H), 4.04–4.13 (m, 2 H), 6.71 (d, J = 1.9 Hz,
1 H, Ar-H), 6.74 (dd, J = 8.2 Hz, J = 2.0 Hz, 1 H, Ar-H), 6.85 (d,
J = 8.2 Hz, 1 H, Ar-H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
= 14.8 (CH3), 30.8 (CH2), 36.7 (CH2), 44.2 (CH2), 55.9 (OCH3),
58.9 (CH), 64.4 (OCH2), 111.5 (CH), 113.3 (CH), 120.6 (CH),
Experimental Section
General Methods: Procedures using nBuLi, LDA, CBr4, and HBr
were performed in flame-dried glassware and with absolute solvents
under nitrogen. Acrolein was freshly distilled prior to use. Column
chromatography was carried out using Merck SiO2 60 with hexanes
129.9 (C), 148.2 (C), 148.6 (C), 207.7 (C=O) ppm. IR (ATR): ν =
˜
1
1703 (vs), 1588 (m), 1514 (s), 1444 (m), 1422 (m), 1344 (m), 1306
(m), 1243 (vs), 1182 (m), 1155 (m), 1137 (s), 1111 (m), 1042 (m),
1019 (s), 980 (m) cm–1. MS (EI, 70 eV): m/z (%) = 266 (53) [M+],
178 (100), 150 (26). C14H18O3S (266.35): calcd. C 63.13, H 6.81;
found C 62.81, H 6.89.
(PE, b.p. 40–60 °C), ethyl acetate (EA), and CH2Cl2 as eluents. H
NMR spectra were recorded with a Bruker ARX 500 (500 MHz),
a Bruker ARX 300 (300 MHz), or a Bruker AC 250 (250 MHz)
spectrometer. 13C NMR spectra were recorded with a Bruker ARX
500 (125 MHz), a Bruker ARX 300 (75 MHz), or a Bruker AC 250
(62 MHz) spectrometer. Multiplicities were determined with DEPT
experiments. Melting points were measured with a Büchi 510 appa-
ratus and are uncorrected. All starting materials were commercially
available. nBuLi (2 moldm–3 solution in pentane), CBr4, and HBr
(33% solution in glacial acetic acid) were purchased from Aldrich
Chemical Company. NaSH hydrate (72wt.-% NaSH; Aldrich) is in
accordance with the formula NaHS·1.2H2O.
5-(3,4-Dimethoxyphenyl)-2-phenyltetrahydrothiopyran-4-one (1d):
According to the procedure given for compound 1a, divinyl ketone
3d (180 mg, 0.61 mmol) was converted with NaHS·1.2H2O
(264 mg, 3.40 mmol) to give the title compound 1d (120 mg,
0.37 mmol, 60%) after chromatography (SiO2; PE/EA, 2:1; Rf =
0.33) as a light brown solid, m.p. 160–162 °C. Two signal sets are
observed in the 1H NMR spectrum (ratio 4:1), which can be as-
signed to the trans (major) and cis (minor) isomer. The signals of
the cis isomer are partly hidden by the trans isomer in the 1H NMR
spectrum. They cannot be doubtlessly assigned in the 13C NMR
spectrum. 1H NMR (250 MHz, CDCl3), trans isomer: δ = 3.06 (dd,
3-Phenyltetrahydrothiopyran-4-one (1a): NaHS·1.2H2O (138 mg,
1.78 mmol) was added to a solution of divinyl ketone 3a (50 mg,
0.32 mmol) in 2-ME (3 mL). The resulting mixture was stirred at
50 °C for 5 h, then water (15 mL) and EA (20 mL) were added
and the layers separated. The aqueous layer was extracted with EA
(3×20 mL) and the combined organic phases were washed with
water (10 mL), dried (MgSO4), and concentrated after filtration.
The residue was chromatographed on SiO2 (PE/EA, 5:1; Rf = 0.27)
to give the title compound 1a (42 mg, 0.22 mmol, 70%) as a light
yellow oil, which solidified after a while at ambient temperature,
m.p. 64–66 °C. 1H NMR (300 MHz, CDCl3): δ = 2.84–2.87 (m,
2 H, CH2), 2.99–3.15 (m, 3 H, CH2), 3.28 (dd, J = 14.5 Hz, J =
10.9 Hz, 1 H, CH2), 3.97 (dd, J = 10.9 Hz, J = 4.8 Hz, 1 H, CH),
7.16–7.28 (m, 5 H, Ph) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
= 30.8 (CH2), 36.7 (CH2), 44.3 (CH2), 59.5 (CH), 127.5 (CH), 128.5
3
2
2J = 13.1 Hz, Jeq,ax = 3.0 Hz, 1 H, 6-Heq), 3.10 (dd, J = 13.7 Hz,
3Jeq,ax = 5.0 Hz, 1 H, 2-Heq), 3.19 (t, J = Jax,ax = 12.8 Hz, 1 H,
6-Hax), 3.36 (dd, J = 13.7 Hz, Jax,ax = 12.1 Hz, 1 H, 2-Hax), 3.88
2
3
2
3
3
(s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.00 (dd, Jax,ax = 11.5 Hz,
3Jax,eq = 4.8 Hz, 1 H, 2-Hax), 4.41 (dd, Jax,ax = 12.4 Hz, Jax,eq
=
3
3
3.0 Hz, 1 H, 5-Hax), 6.70 (d, J = 2.0 Hz, 1 H, Ar-H), 6.75 (dd, J =
8.1 Hz, J = 2.0 Hz, 1 H, Ar-H), 6.88 (d, J = 8.1 Hz, 1 H, Ar-H),
7.27–7.43 (m, 5 H, Ar-H) ppm; cis isomer: δ = 2.96 (dd, J =
14.2 Hz, J = 3.9 Hz, 1 H), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
4.46 (dd, J = 9.1 Hz, J = 3.9 Hz, 1 H), 6.83 (d, J = 2.0 Hz, 1 H,
Ar-H), 6.92 (dd, J = 8.3 Hz, J = 2.0 Hz, 1 H, Ar-H), 6.98 (d, J =
8.6 Hz, 1 H, Ar-H), 7.27–7.43 (m, 5 H, Ar-H) ppm. 13C{1H} NMR
(125 MHz, CDCl3), trans isomer: δ = 37.0 (CH2), 49.8 (CH), 52.2
(CH2), 55.6 (OCH3), 55.9 (OCH3), 58.7 (CH), 111.2 (CH), 111.9
(CH), 120.8 (CH), 127.0 (2 CH), 128.2 (CH), 129.0 (2 CH), 139.7
(2 CH), 128.6 (2 CH), 137.4 (C), 207.3 (C=O) ppm. IR (ATR): ν
˜
= 1707 (vs), 1494 (m), 1448 (m), 1315 (m), 1287 (m), 1003 (m), 759
(m), 730 (m), 695 (vs), 674 (m) cm–1. MS (EI, 70 eV): m/z (%) = 192
(22) [M+], 135 (5), 104 (100). HRMS (EI, 70 eV): calcd. 192.0609
(C11H12OS); found 192.0608 [M+].
(C) 148.4 (C), 148.9 (C), 179.8 (C=O) ppm. IR (ATR): ν = 1704
˜
(s), 1591 (m), 1515 (s), 1491 (m), 1456 (m), 1417 (m), 1256 (s), 1238
(s), 1213 (m), 1147 (m), 1024 (m) cm–1. MS (EI, 70 eV): m/z (%) =
328 (38) [M+], 178 (3), 164 (100), 103 (3). C19H20O3S (328.43):
calcd. C 69.49, H 6.14; found C 69.45, H 6.21.
3-(3,4-Dimethoxyphenyl)tetrahydrothiopyran-4-one (1b): According
to the procedure given for compound 1a, divinyl ketone 3b (40 mg,
0.18 mmol) was converted with NaHS·1.2H2O (78 mg, 1.00 mmol)
to give the title compound 1b (30 mg, 0.12 mmol, 67%) after
chromatography (SiO2; PE/EA, 2:1; Rf = 0.26) as a colorless solid,
m.p. 114–118 °C. H NMR (250 MHz, CDCl3): δ = 2.83–2.88 (m,
2 H, CH2), 3.03–3.13 (m, 3 H), 3.25 (dd, J = 13.5 Hz, J = 10.7 Hz,
1 H), 3.87 (br. s, 6 H, 2 OCH3), 3.92 (dd, J = 10.6 Hz, J = 4.8 Hz,
5-(3-Ethoxy-4-methoxyphenyl)-2-phenyltetrahydrothiopyran-4-on
(1e): According to the procedure given for compound 1a, divinyl
ketone 3e (200 mg, 0.65 mmol) was converted with NaHS·1.2H2O
(280 mg, 3.60 mmol) to give the title compound 1e (105 mg,
1
1 H, CH), 6.69–6.77 (m, 2 H, Ar-H), 6.83–6.87 (m, 1 H, Ar-H) 0.31 mmol, 48%) after chromatography (SiO2; PE/EA, 2:1; Rf =
ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 30.8 (CH2), 36.7 0.47) as colorless crystals, m.p. 141–142 °C. Two signal sets are ob-
(CH2), 44.3 (CH2), 55.9 (2 OCH3), 59.0 (CH), 111.2 (CH), 111.8
(CH), 120.6 (CH), 130.0 (C), 148.4 (C), 148.9 (C), 207.7 (C=O)
served in the 1H NMR spectrum (ratio 9:1), which can be assigned
to the trans (major) and cis (minor) isomer. The signals of the cis
ppm. IR (ATR): ν = 1701 (s), 1587 (m), 1516 (s), 1439 (m), 1258 isomer are partly hidden by those of the trans isomer in the 1H
˜
(s), 1221 (m), 1138 (s), 1022 (s), 865 (m) cm–1. MS (EI, 70 eV): m/z
NMR spectrum. They cannot be doubtlessly assigned in the 13C
4048
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Eur. J. Org. Chem. 2006, 4044–4054

Tetrahydropyran-4-ones and Thiopyran-4-ones from α-Bromostyrene Derivatives
FULL PAPER
NMR spectrum. 1H NMR (500 MHz, CDCl3), trans isomer: δ = into a mixture of water (100 mL) and an aqueous solution of citric
3
1.47 (t, J = 7.0 Hz, 3 H, CH3), 3.05 (dd, 2J = 13.2 Hz, Jeq,ax
=
acid (c = 20%, 25 mL). The resulting mixture was extracted with
2
3
3.0 Hz, 1 H, 6-Heq), 3.10 (dd, J = 13.7 Hz, Jeq,ax = 4.9 Hz, 1 H, CH2Cl2 (2×80 mL). The combined organic layers were washed
2-Heq), 3.17 (t, J = Jax,ax = 12.7 Hz, 1 H, 6-Hax), 3.34 (dd, J = with water (80 mL) and dried (MgSO4). After filtration and re-
2
3
2
3
13.6 Hz, Jax,ax = 12.7 Hz, 1 H, 2-Hax), 3.87 (s, 3 H, OCH3), 3.97 moval of all volatile materials in vacuo, the residue was chromato-
(dd, 3Jax,ax = 12.0 Hz, 3Jax,eq = 4.9 Hz, 1 H, 2-Hax), 4.40 (dd, 3Jax,ax graphed on SiO2 (PE/EA, 2:1; Rf = 0.23) to give a title compound
3
= 12.3 Hz, Jax,eq = 2.9 Hz, 1 H, 5-Hax), 6.71 (d, J = 1.8 Hz, 1 H,
Ar-H), 6.74 (dd, J = 8.2 Hz, J = 1.8 Hz, 1 H, Ar-H), 6.88 (d, J =
8.1 Hz, 1 H, Ar-H), 7.30–7.42 (m, 5 H, Ar-H) ppm. 13C{1H} NMR
(125 MHz, CDCl3), trans isomer: δ = 14.9 (CH3), 37.0 (CH2), 49.8
(CH), 52.2 (CH2), 56.0 (OCH3), 58.7 (CH), 64.4 (OCH2), 111.6
2b (1.21 g, 4.83 mmol, 25%) as a light yellow oil, which solidified
after 1 d, m.p. 65–67 °C. 1H NMR (250 MHz, CDCl3): δ = 1.45 (t,
J = 7.0 Hz, 3 H, CH3), 2.59–2.65 (m, 2 H, CH2), 3.71 (dd, J =
8.2 Hz, J = 5.9 Hz, 1 H, CH), 3.85 (s, 3 H, OCH3), 3.93–4.13 (m,
4 H, 2 CH2), 4.16–4.25 (m, 2 H, CH2), 6.76–6.87 (m, 3 H, Ar-H)
(CH), 113.6 (CH), 120.8 (CH), 127.1 (2 CH), 128.2 (CH), 129.0 (2 ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 14.8 (CH3), 41.8
CH), 129.7 (C), 139.7 (C), 148.2 (C), 148.8 (C), 207.0 (C=O) ppm. (CH2), 55.9 (OCH3), 57.5 (CH), 64.4 (OCH2), 68.5 (CH2), 73.2
IR (ATR): ν = 1705 (m), 1590 (m), 1514 (m), 1255 (s), 1211 (m), (CH2), 111.6 (CH), 113.6 (CH), 121.0 (CH), 127.4 (C), 148.3 (C),
˜
1134 (m), 1022 (m), 696 (s), 589 (m) cm–1. MS (EI, 70 eV): m/z (%)
148.8 (C), 206.1 (C=O) ppm. IR (ATR): ν = 2973 (m), 1715 (vs),
˜
= 342 (37) [M+], 178 (100), 150 (14), 103 (4). C20H22O3S (342.45): 1589 (m), 1517 (vs), 1433 (m), 1389 (m), 1251 (vs), 1167 (m), 1094
calcd. C 70.14, H 6.48; found C 69.69, H 6.48.
(m), 1045 (m), 1020 (s), 969 (m), 924 (m), 887 (m), 851 (m), 822
(m), 693 (s) cm–1. MS (EI, 70 eV): m/z (%) = 250 (100) [M+], 222
(4), 178 (72), 150 (34), 107 (6). C14H18O4 (250.29): calcd. C 67.18,
H 7.25; found C 67.09, H 7.29.
5-(4-Methoxyphenyl)-2-phenyltetrahydrothiopyran-4-one (1f): Ac-
cording to the procedure given for compound 1a, divinyl ketone 3f
(130 mg, 0.49 mmol) was converted with NaHS·1.2H2O (212 mg,
2.73 mmol) to give the title compound 1f (85 mg, 0.28 mmol, 57%)
after chromatography (SiO2; PE/EA, 2:1; Rf = 0.50) as a light yel-
2-Phenyl-1,4-pentadien-3-one (3a): MnO2 (3.41 g, 39.3 mmol) was
added portionwise to a solution of 12a (300 mg, 1.87 mmol) in
CH2Cl2 (10 mL) at ambient temperature. The progress of the reac-
tion was monitored by TLC [product 3a: Rf(SiO2; PE/EA, 5:1) =
0.44]. After being stirred at 23 °C for 60 min, the reaction mixture
was filtered with vacuum through SiO2 to separate MnO2, the resi-
due was washed several times with EA (total ca. 100 mL). The fil-
1
low solid, m.p. 125–127 °C. Two signal sets are observed in the H
NMR spectrum (ratio 3:1), which can be assigned to the trans
(major) and cis (minor) isomer. The signals of the cis isomer are
hidden by those of the trans isomer in the 1H NMR spectrum.
They cannot be doubtlessly assigned in the 13C NMR spectrum.
1H NMR (500 MHz, CDCl3), trans isomer: δ = 3.06 (m, 2 H, 2- trate was concentrated under vacuum to give 3a as a yellow oil
2
3
Heq, 6-Heq), 3.18 (t, J = Jax,ax = 12.6 Hz, 1 H, 6-Hax), 3.33 (dd,
(280 mg, 1.77 mmol, 95%), which decomposed under ambient con-
3
1
2J = 13.4 Hz, Jax,ax = 12.1 Hz, 1 H, 2-Hax), 3.81 (s, OCH3), 3.99
ditions. It could not even be stored at –5 °C. H NMR (300 MHz,
(dd, 3Jax,ax = 12.1 Hz, 3Jax,eq = 4.9 Hz, 1 H, 2-Hax), 4.40 (dd, 3Jax,ax CDCl3): δ = 5.87 [dd, J = 10.4 Hz, J = 1.5 Hz, 1 H, (E)-5-H], 5.96
= 12.4 Hz, 3Jax,eq = 2.9 Hz, 1 H, 5-Hax), 6.91–6.93 (m, 2 H, Ar-H),
7.10–7.12 (m, 2 H, Ar-H), 7.22–7.41 (5 H, Ar-H) ppm. 13C{1H}
(s, 1 H, 1-H), 5.98 (s, 1 H, 1-H), 6.35 [dd, J = 17.3 Hz, J = 1.6 Hz,
1 H, (Z)-5-H], 6.75 (dd, J = 17.3 Hz, J = 10.4 Hz, 1 H, 4-H), 7.34–
NMR (125 MHz, CDCl3), trans isomer: δ = 37.0 (CH2), 49.8 (CH), 7.36 (m, 5 H, Ph) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
52.1 (CH2), 55.3 (OCH3), 58.3 (CH), 114.0 (2 CH), 127.1 (2 CH), 123.4 (CH2), 127.9 (2 CH), 128.4 (CH), 128.4 (2 CH), 130.4 (CH2),
128.1 (CH), 128.9 (2 CH), 129.3 (C), 129.7 (2 CH), 139.7 (C), 158.9
(C), 207.0 (C=O) ppm. IR (ATR): ν = 1702 (vs), 1610 (m), 1583
134.3 (CH), 136.9 (C), 148.8 (C), 193.5 (C=O) ppm. IR (ATR): ν
= 1665 (vs), 1604 (vs), 1575 (m), 1493 (s), 1445 (m), 1400 (s), 1327
˜
˜
(m), 1511 (s), 1453 (m), 1305 (m), 1246 (s), 1229 (m), 1179 (m), (m), 1307 (m), 1278 (m), 1192 (m), 1137 (m), 1037 (m), 1026 (m)
1103 (m), 1027 (m), 823 (s), 749 (m), 695 (vs) cm–1. MS (EI, 70 eV): cm–1. MS (EI, 70 eV): m/z (%) = 158 (46) [M+], 130 (19) [M+ –
m/z (%) = 298 (17) [M+], 134 (100). C18H18O2S (298.39): calcd. C
72.45, H 6.08; found C 72.57, H 6.14.
C2H4], 115 (5), 103 (100), 77 (39). HR-MS (EI, 70 eV): calcd.
158.0732 (C11H10O), found 158.0731 [M+]. C11H10O (158.20):
calcd. C 83.52, H 6.37; found C 82.99, H 6.65.
3-Phenyltetrahydropyran-4-one (2a): KOH (130 mg, 2.30 mmol) was
added to a mixture of divinyl ketone 3a (250 mg, 1.58 mmol),
CH2Cl2 (6 mL) and water (12 mL), and the mixture was stirred at
35 °C for 28 h. Water was added, the layers were separated, and
the aqueous phase was extracted with CH2Cl2 (2×30 mL). The
combined organic layers were dried (MgSO4), filtered, and the sol-
vents evaporated. Chromatography (PE/EA, 5:1; Rf = 0.16) gave
the title compound 2a (142 mg, 0.80 mmol, 51%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 2.54–2.73 (m, 2 H, CH2), 3.79
(dd, J = 8.7 Hz, J = 5.9 Hz, 1 H), 3.94–4.04 (m, 2 H), 4.20–4.29
(m, 2 H), 7.22–7.39 (m, 5 H, Ph) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ = 42.3 (CH2), 58.4 (CH), 68.9 (CH2), 73.5 (CH2), 128.0
(CH), 129.1 (2 CH), 129.5 (2 CH), 135.3 (C), 206.1 (C=O) ppm.
2-(3,4-Dimethoxyphenyl)-1,4-pentadien-3-one (3b): According to the
procedure reported for ketone 3a, divinyl alcohol 12b (220 mg,
0.99 mmol) was oxidized with MnO2 (1.81 g, 20.8 mmol) to give
the title compound 3b (122 mg, 0.56 mmol, 56%) as a yellow oil,
which could not be stored neither under ambient conditions nor at
low temperatures due to decomposition processes. Rf(SiO2; PE/EA,
2:1) = 0.37. 1H NMR (300 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3),
3.90 (s, 3 H, OCH3), 5.88 (dd, J = 10.5 Hz, J = 1.6 Hz, 1 H, 5-H),
5.90 (s, 1 H, 1-H), 5.92 (s, 1 H, 1-H), 6.35 (dd, J = 17.2 Hz, J =
1.5 Hz, 1 H, 5-H), 6.75 (dd, J = 17.3 Hz, J = 10.5 Hz, 1 H, 4-H),
6.84–6.95 (m, 3 H, Ar-H) ppm. 13C{1H} NMR (62 MHz, CDCl3):
δ = 55.9 (2 OCH3), 110.97 (CH), 111.01 (CH), 120.6 (CH), 122.1
IR (ATR): ν = 2965 (m), 2854 (m), 1714 (vs), 1206 (s), 1146 (s), (CH2), 129.5 (C), 130.4 (CH2), 134.4 (CH), 148.3 (C), 148.8 (C),
˜
1096 (m), 971 (m), 761 (m), 699 (s), 634 (m) cm–1. MS (EI, 70 eV): 149.4 (C), 193.9 (C=O) ppm. IR (ATR): ν = 1670 (m), 1605 (m),
˜
m/z (%) = 176 (10) [M+], 104 (100). C11H12O2 (176.21): calcd. C
74.98, H 6.86; found C 75.01, H 6.78.
1516 (s), 1463 (m), 1403 (m), 1256 (s), 1027 (m) cm–1. MS (EI,
70 eV): m/z (%) = 218 (92) [M+], 203 (19), 163 (100), 148 (27), 132
(17), 119 (19). HR-MS (EI, 70 eV): calcd. 218.0943 (C13H14O3),
found 218.0942 [M+].
3-(3-Ethoxy-4-methoxyphenyl)tetrahydropyran-4-one (2b): KOH
(4.34 g, 77.5 mmol) was added to a mixture of divinyl ketone 3c
(4.50 g, 19.40 mmol), CH2Cl2 (100 mL), and water (100 mL), and
the mixture was vigorously stirred at 40 °C for 50 h, then poured
2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-one (3c): MnO2
(25.0 g, 287 mmol) was added portionwise to a solution of 12c
Eur. J. Org. Chem. 2006, 4044–4054
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4049

A. Rosiak, W. Frey, J. Christoffers
FULL PAPER
(2.00 g, 8.55 mmol) in CH2Cl2 (60 mL) at ambient temperature.
The progress of the reaction was monitored by TLC [product 3c:
Rf(SiO2; PE/EA, 2:1) = 0.45]. After being stirred at 23 °C for
60 min, the reaction mixture was filtered with vacuum through
SiO2 to separate MnO2, the residue was washed several times with
EA (total ca. 600 mL). The filtrate was concentrated under vacuum
to give 3c as a yellow oil (1.47 g, 6.33 mmol, 74%) with 90–95%
12f (220 mg, 0.83 mmol) was oxidized with MnO2 (1.3 g, 15 mmol)
to give the title compound 3e (180 mg, 0.68 mmol, 83%) as green
crystals, m.p. 104–106 °C, which was not stable under ambient con-
ditions, but could be stored at lower temperature. Rf(SiO2; PE/EA,
2:1) = 0.56. 1H NMR (500 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3),
5.88 (s, 1 H, 5-H), 5.91 (s, 1 H, 5-H), 6.89–6.92 (m, 2 H, Ar-H),
7.06 (d, J = 15.9 Hz, 1 H, 2-H), 7.33–7.40 (m, 5 H, Ar-H), 7.53–
7.55 (m, 2 H, Ar-H), 7.70 (d, J = 15.9 Hz, 1 H, 5-H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 55.32 (OCH3), 113.9 (2 CH), 120.7
1
purity by H NMR spectroscopy. The product decomposed under
1
ambient conditions. H NMR (300 MHz, CDCl3): δ = 1.46 (t, J =
7.0 Hz, 3 H, CH3), 3.88 (s, 3 H, OCH3), 4.10 (q, J = 7.0 Hz, 2 H, (CH2), 124.5 (CH), 128.5 (2 CH), 128.9 (2 CH), 129.1 (2 CH),
OCH2), 5.87 [dd, J = 10.5 Hz, J = 1.5 Hz, 1 H, (E)-5-H], 5.87 (s,
1 H, 1-H), 5.89 (s, 1 H, 1-H), 6.34 [dd, J = 17.4 Hz, J = 1.6 Hz,
129.4 (C), 130.6 (CH), 134.7 (C), 144.9 (CH), 148.9 (C), 159.8 (C),
193.8 (C=O) ppm. IR (ATR): ν = 1654 (s), 1594 (vs), 1572 (m),
˜
1 H, (Z)-5-H], 6.73 (dd, J = 17.3 Hz, J = 10.5 Hz, 1 H, 4-H), 6.84– 1509 (s), 1447 (m), 1344 (m), 1293 (m), 1246 (s), 1180 (m), 1132
6.93 (m, 3 H, Ar-H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = (m), 1031 (s), 984 (m), 939 (m), 871 (m), 851 (s), 781 (m), 686 (s)
14.8 (CH3), 56.0 (OCH3), 64.4 (OCH2), 111.3 (CH), 112.4 (CH),
120.5 (CH), 121.9 (CH2), 129.4 (C), 130.4 (CH2), 134.5 (CH), 148.0
cm–1. MS (EI, 70 eV): m/z (%) = 264 (31) [M+], 236 (7), 133 (100),
103 (14), 77 (13). C18H16O2 (264.32): calcd. C 81.79, H 6.10; found
C 81.41; H 6.44.
(C), 148.3 (C), 149.6 (C), 194.0 (C=O) ppm. IR (ATR): ν = 2932
˜
(m, br.), 1671 (m), 1604 (m), 1514 (s), 1255 (s), 1141 (m), 1028 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 232 (100) [M+], 177 (89), 149 (43),
117 (5), 89 (8). HR-MS (EI, 70 eV): calcd. 232.1099 (C14H16O3);
found 232.1099 [M+].
1-Bromo-1-(3,4-dimethoxyphenyl)ethene (4a): Starting material 6a is
hygroscopic and must be carefully dried by lyophilization prior to
use. Under strict exclusion of moisture, HBr (24.7 mmol, 4.4 mL
of a 33% solution in acetic acid) was added dropwise with cooling
(ice/water bath) to arylacetylene 6a (4.00 g, 24.7 mmol). After being
stirring at room temperature for 25 min, water (40 mL) and CH2Cl2
(25 mL) were added to the dark blue reaction mixture. This mixture
was vigorously shaken until the color changed from blue to yellow-
green, and the layers were separated. The aqueous layer was ex-
tracted with CH2Cl2 (3×20 mL). The combined organic layers were
washed with a saturated aqueous solution of NaHCO3 (2×25 mL),
water (25 mL) and dried (MgSO4). After filtration and removal of
all volatile materials in vacuo (rotary evaporator), the residue was
chromatographed on SiO2 (PE/EA, 5:1; Rf = 0.41) to give the title
compound 4a (5.23 g, 21.5 mmol, 87%) as a light brown oil, which
solidified upon storage at –15 °C. The product decomposed under
ambient conditions. 1H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3 H,
OCH3), 3.90 (s, 3 H, OCH3), 5.68 (d, J = 1.9 Hz, 1 H, CHH), 6.01
(d, J = 1.9 Hz, 1 H, CHH), 6.81 (d, J = 8.4 Hz, 1 H, Ar-H), 7.10
(d, J = 2.1 Hz, 1 H, Ar-H), 7.14 (dd, J = 8.3 Hz, J = 2.0 Hz, 1 H,
Ar-H) ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 55.8 (OCH3),
55.9 (OCH3), 110.4 (CH), 110.4 (CH), 116.1 (CH2), 120.2 (CH),
(E)-4-(3,4-Dimethoxyphenyl)-1-phenyl-1,4-pentadien-3-one (3d): Ac-
cording to the procedure reported for ketone 3a, divinyl alcohol
12d (400 mg, 1.35 mmol) was oxidized with MnO2 (3.50 g,
40.5 mmol) to give the title compound 3d (280 g, 0.95 mmol, 70%)
as a yellow oil, which was not stable under ambient conditions, but
could be stored at lower temperature. Rf(SiO2; PE/EA, 2:1) = 0.31.
1H NMR (300 MHz, CDCl3): δ = 3.89 (s, 3 H, OCH3), 3.90 (s, 3
H, OCH3), 5.89 (s, 1 H, 5-H), 5.93 (s, 1 H, 5-H), 6.87 (d, J = 8.2 Hz,
1 H, Ar-H), 6.95 (d, J = 2.0 Hz, 1 H, Ar-H), 6.96 (dd, J = 8.2 Hz,
J = 2.0 Hz, 1 H, Ar-H), 7.07 (d, J = 15.9 Hz, 1 H, 2-H), 7.38–7.40
(m, 3 H, Ar-H), 7.53–7.55 (m, 2 H, Ar-H), 7.71 (d, J = 15.9 Hz,
1 H, 1-H) ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 55.9 (2
OCH3), 110.9 (CH), 111.0 (CH), 120.6 (CH), 121.0 (CH2), 124.5
(CH), 128.5 (2 CH), 129.0 (2 CH), 130.6 (CH), 134.6 (C), 145.0
(CH), 148.8 (C), 149.1 (C), 149.3 (C), 162.4 (C), 193.7 (C=O) ppm.
IR (ATR): ν = 1732 (m), 1682 (m), 1595 (m), 1511 (s), 1447 (m),
˜
1411 (m), 1250 (s), 1137 (s), 1099 (m), 1022 (s) cm–1. MS (EI,
70 eV): m/z (%) = 294 (63) [M+], 235 (23), 163 (100), 131 (28),
77 (25). HR-MS (EI, 70 eV): calcd. 294.1256 (C19H18O3), found
294.1255 [M+].
130.7 (C), 131.3 (C), 148.3 (C), 149.7 (C) ppm. IR (ATR): ν = 1601
˜
(m), 1515 (s), 1460 (m), 1269 (s), 1143 (m), 1026 (m) cm–1. MS (EI,
70 eV): m/z (%) = 242 (28) [M+], 180 (14), 163 (100). C10H11BrO2
(243.10): calcd. C 49.41, H 4.56; found C 49.29, H 4.59.
(E)-4-(3-Ethoxy-4-methoxyphenyl)-1-phenyl-1,4-pentadien-3-one
(3e): According to the procedure reported for ketone 3a, divinyl
alcohol 12e (0.80 g, 2.6 mmol) was oxidized with MnO2 (6.7 g,
77 mmol) to give the title compound 3e (0.52 g, 1.69 mmol, 65%)
as a yellow oil, which was not stable under ambient conditions, but
could be stored at lower temperature. Rf(SiO2; PE/EA, 2:1) = 0.34.
1H NMR (500 MHz, CDCl3): δ = 1.45 (t, J = 7.0 Hz, 3 H, CH3),
3.89 (s, 3 H, OCH3), 4.10 (q, J = 7.0 Hz, 2 H, OCH2), 5.87 (s, 1
H, CHH), 5.91 (s, 1 H, CHH), 6.87 (d, J = 8.9 Hz, 1 H, Ar-H),
6.95 (br. s, 1 H, Ar-H), 6.96 (dd, J = 8.9 Hz, J = 1.9 Hz, 1 H, Ar-
H), 7.06 (d, J = 15.8 Hz, 1 H, 4-H), 7.36–7.39 (m, 3 H, Ph), 7.52–
7.54 (m, 2 H, Ph), 7.70 (d, J = 15.9 Hz, 1 H, 5-H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 14.8 (CH3), 56.0 (OCH3), 64.4
(OCH2), 111.3 (CH), 112.4 (CH), 120.5 (CH), 120.8 (CH2), 124.5
(CH), 128.5 (2 CH), 128.7 (CH), 128.9 (2 CH), 130.6 (CH), 134.7
(C), 144.9 (CH), 148.1 (C), 149.2 (C), 149.7 (C), 193.7 (C=O) ppm.
1-Bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (4b): Starting mate-
rial 6b is hygroscopic and must be carefully dried by lyophilization
prior to use. According to the procedure reported for compound
4a, acetylene 6b (15.0 g, 85.2 mmol) was converted with HBr
(85.2 mmol, 15.4 mL of a 33% solution in acetic acid) to give the
title compound 4b (19.5 g, 75.8 mmol, 89%) after chromatography
on SiO2 (PE/EA, 2:1; Rf = 0.56) as a light brown solid, m.p. 32–
34 °C. The product decomposed under ambient conditions. 1H
NMR (300 MHz, CDCl3): δ = 1.48 (t, J = 7.0 Hz, 3 H, CH3), 3.88
(s, 3 H, OCH3), 4.08–4.17 (m, 2 H, OCH2), 5.68 (d, J = 2.0 Hz,
1 H, CHH), 6.01 (d, J = 2.0 Hz, 1 H, CHH), 6.82 (d, J = 8.4 Hz,
1 H, Ar-H), 7.11 (d, J = 2.2 Hz, 1 H, Ar-H), 7.17 (dd, J = 8.4 Hz,
J = 2.2 Hz, 1 H, Ar-H) ppm. 13C{1H} NMR (125 MHz, CDCl3):
δ = 14.7 (CH3), 56.0 (OCH3), 64.5 (OCH2), 110.7 (CH), 112.1
(CH), 116.0 (CH2), 120.2 (CH), 130.8 (C), 131.4 (C), 147.7 (C),
IR (ATR): ν = 1664 (m, br.), 1598 (s), 1575 (m), 1511 (s), 1448 (m),
˜
1329 (m), 1251 (s), 1140 (m), 1027 (m) cm–1. MS (EI, 70 eV): m/z
(%) = 308 (97) [M+], 177 (100), 149 (8), 131 (17), 103 (10). HR-MS
(EI, 70 eV): calcd. 308.1412 (C20H20O3), found 308.1412 [M+].
150.2 (C) ppm. IR (ATR): ν = 1670 (m), 1586 (m), 1510 (s), 1425
˜
(m), 1258 (s), 1137 (s), 1019 (s), 810 (m), 775 (m) cm –1. MS (EI,
70 eV): m/z (%) = 256 (21) [M+], 177 (100), 149 (29), 117 (11).
C11H13BrO2 (257.13): calcd. C 51.38, H 5.10; found C 51.28, H
5.16.
(E)-4-(4-Methoxyphenyl)-1-phenyl-1,4-pentadien-3-one (3f): Ac-
cording to the procedure reported for ketone 3a, divinyl alcohol
4050
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4044–4054

Tetrahydropyran-4-ones and Thiopyran-4-ones from α-Bromostyrene Derivatives
FULL PAPER
1-Bromo-1-(4-methoxyphenyl)ethene (4c): According to the pro-
cedure reported for compound 4a, acetylene 6c (1.58 g, 11.9 mmol)
was converted with HBr (11.9 mmol, 2.14 mL of a 33% solution in
acetic acid) to give the title compound 4c (1.73 g, 8.12 mmol, 68%)
after chromatography on SiO2 (PE/EA, 2:1; Rf = 0.59) as a light
brown solid, m.p. 35–36 °C. The product decomposed under ambi-
ent conditions. 1H NMR (500 MHz, CDCl3): δ = 3.82 (s, 3 H,
OCH3), 5.67 (d, J = 1.9 Hz, 1 H, CHH), 6.00 (d, J = 1.9 Hz, 1 H,
CHH), 6.84–6.87 (m, 2 H, Ar-H), 7.52–7.55 (m, 2 H, Ar-H) ppm.
ambient temperature for 3 h. LDA (30.2 mmol, 15.1 mL of a
2 mol·dm–3 solution) was added dropwise at –78 °C over 30 min,
and the reaction mixture was then warmed and stirred at ambient
temperature for 3 h. Water (10 mL) was added at 0 °C, and the
reaction mixture stirred at 0 °C for 20 min. The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2
(3×50 mL). The combined extracts were washed with hydrochloric
acid (40 mL, 1 mol·dm–3), water (3×100 mL) and dried (MgSO4).
After filtration, the solvent was removed in vacuo, and the residue
13C{1H} NMR (125 MHz, CDCl3): δ = 55.4 (OCH3), 113.5 (2 CH), chromatographed on SiO2 (PE/EA, 5:1; Rf = 0.31) to give the com-
115.9 (CH2), 128.7 (2 CH), 130.7 (C), 131.1 (C), 160.2 (C) ppm. pound 6b as a colorless solid (1.33 g, 7.60 mmol, 56%), m.p. 95–
1
IR (ATR): ν = 1600 (s), 1569 (m), 1504 (s), 1456 (m), 1437 (m), 96 °C. H NMR (500 MHz, CDCl3): δ = 1.46 (t, J = 7.0 Hz, 3 H,
˜
1410 (m), 1303 (s), 1246 (br. s), 1177 (m), 1058 (s), 1022 (s), 876
CH3), 2.99 (s, 1 H, CH), 3.87 (s, 3 H, OCH3), 4.09 (q, J = 7.0 Hz,
2 H, OCH2), 6.80 (d, J = 8.3 Hz, 1 H, Ar-H), 6.99 (d, J = 1.8 Hz,
(s), 825 (vs) cm–1. MS (EI, 70 eV): m/z (%) = 212 (22) [M+], 133
(100), 118 (8), 89 (9). C9H9BrO (213.07): calcd. C 50.73, H 4.26; 1 H, Ar-H), 7.09 (dd, J = 8.3 Hz, J = 1.8 Hz, 1 H, Ar-H) ppm.
found C 50.88, H 4.30.
13C{1H} NMR (125 MHz, CDCl3): δ = 14.7 (CH3), 55.9 (OCH3),
64.3 (OCH2), 75.5 (CH), 83.8 (C), 111.2 (CH), 114.1 (C), 116.1
1-Bromo-1-(2-thienyl)ethene (4d): According to the procedure re-
ported for compound 4a, acetylene 6d (1.28 g, 11.9 mmol) was con-
verted with HBr (11.9 mmol, 2.1 mL of a 33% solution in acetic
acid) to give the title compound 4d (1.63 g, 8.62 mmol, 72%) after
chromatography on SiO2 (PE/EA, 2:1; Rf = 0.68) as a brown oil,
which decomposed under ambient conditions. 1H NMR (500 MHz,
(CH), 125.4 (CH), 147.9 (C), 150.1 (C) ppm. IR (ATR): ν = 3258
˜
(m), 1509 (m), 1458 (m), 1442 (m), 1412 (m), 1319 (m), 1233 (s),
1152 (m), 1129 (s), 1044 (m), 1018 (s) cm –1. MS (EI, 70 eV): m/z
(%) = 176 (100) [M+], 148 (57), 133 (79), 105 (22), 91 (10).
C11H12O2 (176.12): calcd. C 74.93, H 6.85; found C 74.98, H 6.86.
CDCl3): δ = 5.85 (d, J = 2.4 Hz, 1 H, CHH), 6.08 (d, J = 2.4 Hz, 4-Methoxyphenylacetylene (6c): According to the procedure re-
1 H, CHH), 6.97 (dd, J = 5.1 Hz, J = 3.7 Hz, 1 H, Ar-H), 7.21–
ported for 6a, dibromo compound 11c (10.0 g, 34.3 mmol) was
7.29 (m, 2 H, Ar-H) ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = converted with nBuLi (72 mmol, 36 mL of a 2 mol·dm–3 solution
115.8 (CH2), 122.3 (C), 126.7 (CH), 127.3 (CH), 128.4 (CH), 142.0 in pentane) to yield the title compound 6c (3.7 g, 28 mmol, 82%)
(C) ppm. IR (ATR): ν = 2917 (s), 2849 (m), 1743 (m), 1534 (m), after chromatography on SiO2 (PE/EA, 5:1; Rf = 0.44) as a color-
˜
1
1501 (m), 1335 (s), 1118 (m), 743 (m) cm–1. MS (CI, CH4): m/z (%) less solid, m.p. 25 °C. H NMR (500 MHz, CDCl3): δ = 3.00 (s, 1
= 189 (100) [M+H+], 110 (88). C6H5BrS (189.07): calcd. C 38.12,
H 2.67; found C 38.36, H 2.97.
H, CH), 3.81 (s, 3 H, OCH3), 6.83–6.85 (m, 2 H, Ar-H), 7.42–7.44
(m, 2 H, Ar-H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 55.3
(OCH3), 75.8 (CH), 83.7 (C), 113.9 (2 CH), 114.1 (C), 133.6 (2
3,4-Dimethoxyphenylacetylene (6a): nBuLi (162 mmol, 81 mL of a
2 mol·dm–3 solution in pentane) was added to a solution of di-
bromo compound 11a (24.7 g, 76.7 mmol) in THF (300 mL) at
–78 °C over a period of 45 min. Stirring was continued at –78 °C
for 1.5 h, then the reaction mixture, while being stirred, was
warmed to 23 °C over a period of 1.5 h. After dilution with satu-
rated aqueous NH4Cl solution (300 mL) and extraction with
CH2Cl2 (2 × 80 mL), the combined organic layers were dried
(MgSO4), filtered, and the solvents evaporated. The residue was
chromatographed on SiO2 (PE/EA, 2:1; Rf = 0.35) to yield the title
compound 6a (11.6 g, 71.5 mmol, 93%) as colorless crystals, m.p.
71–72 °C. 1H NMR (250 MHz, CDCl3): δ = 3.02 (s, 1 H, CH), 3.85
(s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.78 (d, J = 8.3 Hz, 1 H, Ar-
H), 6.98 (d, J = 1.9 Hz, 1 H, Ar-H), 7.09 (dd, J = 8.3 Hz, J =
CH), 159.9 (C) ppm. IR (ATR): ν = 3255 (m), 1604 (s), 1504 (vs),
˜
1465 (m), 1442 (m), 1289 (s), 1243 (vs), 1170 (s), 1109 (m), 1026
(vs), 833 (vs), 639 (br. s) cm–1. MS (EI, 70 eV): m/z (%) = 132 (100)
[M+], 117 (24), 89 (28), 63 (9). C9H8O (132.16): calcd. C 81.79, H
6.10; found C 81.86, H 6.00.
2-Ethynylthiophene (6d): According to the procedure reported for
6a, the dibromo compound 11d (4.00 g, 14.9 mmol) was converted
with nBuLi (30 mmol, 15 mL of a 2 mol·dm–3 solution in pentane)
to yield the title compound 6d (1.1 g, 10 mmol, 68%) after distil-
lation (b.p. 31–34 °C/13 mbar) as a colorless liquid. Rf(SiO2; PE/
EA, 2:1) = 0.72. 1H NMR (500 MHz, CDCl3): δ = 3.33 (s, 1 H,
CH), 6.93 (dd, J = 5.1 Hz, J = 3.8 Hz, 1 H, Ar-H), 7.22 (dd, J =
5.1 Hz, J = 1.1 Hz, 1 H, Ar-H), 7.25 (dd, J = 3.8 Hz, J = 1.0 Hz,
1.9 Hz, 1 H, Ar-H) ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 1 H, Ar-H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 77.0
55.8 (2 OCH3), 75.8 (CH), 83.8 (C), 110.9 (CH), 114.2 (C), 114.7 (CH), 81.2 (C), 122.1 (C), 126.9 (CH), 127.5 (CH), 133.1 (CH)
(CH), 125.5 (CH), 149.6 (C), 149.8 (C) ppm. IR (ATR): ν = 3248 ppm. IR (ATR): ν = 3298 (s), 2957 (s), 2926 (s), 2870 (m), 1239
˜
˜
(m), 1578 (m), 1507 (m), 1444 (m), 1406 (m) cm–1. MS (EI, 70 eV): (m), 928 (m), 852 (m) cm–1. MS (EI, 70 eV): m/z (%) = 108 (100)
m/z (%) = 162 (100) [M+], 147 (29). C10H10O2 (162.19): calcd. C
[M+], 82 (17).
74.06, H 6.21; found C 73.97, H 6.30.
3-Ethoxy-4-methoxyacetophenone (7b): A suspension of phenol 8
(4.00 g, 24.1 mmol) and K2CO3 (4.77 g, 48.1 mmol) in DMF
(20 mL) was heated at 100 °C for 30 min and then cooled to ambi-
ent temperature. Ethyl bromide (5.25 g, 48.14 mmol) was slowly
added dropwise, and the reaction mixture heated at 100 °C for 6 h.
After cooling to ambient temperature and removal of the solvent,
the residue was dissolved in water (40 mL) and extracted with
CH2Cl2 (3×50 mL). The combined extracts were dried (MgSO4),
filtered and concentrated. The crude product was recrystallized
from 2-propanol (25 mL) to give ketone 7b as fine colorless needles
(4.09 g, 21.1 mmol, 88 %), m.p. 66–67 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.48 (t, J = 7.0 Hz, 3 H, CH3), 2.56 (s, 3 H, CH3), 3.94
(s, 3 H, OCH3), 4.16 (q, J = 7.0 Hz, 2 H, OCH2), 6.88 (d, J =
3-Ethoxy-4-methoxyphenylacetylene (6b). a) Corey–Fuchs Protocol:
According to the procedure reported for 6a, dibromo compound
11b (32.0 g, 95.2 mmol) was converted with nBuLi (210 mmol,
105 mL of a 2 mol·dm–3 solution in pentane) to yield the title com-
pound 6b (16.60 g, 94.25 mmol, 99%) after chromatography on
SiO2 (PE/EA, 2:1; Rf = 0.54) as a colorless, hygroscopic solid. b)
Via Enol Phosphate: A solution of ketone 7b (2.60 g, 13.4 mmol)
in THF (7 mL) was slowly added to LDA (14.1 mmol, 7.05 mL
of a 2 mol·dm–3 solution in ethylbenzene/THF/heptane) in THF
(10 mL) at –78 °C, and the reaction mixture was further stirred at
–78 °C for 1 h. Then diethyl chlorophosphate (2.51 g, 14.1 mmol)
was added, and the reaction mixture was warmed and stirred at
Eur. J. Org. Chem. 2006, 4044–4054
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4051

A. Rosiak, W. Frey, J. Christoffers
FULL PAPER
8.4 Hz, 1 H, Ar-H), 7.52 (d, J = 1.9 Hz, 1 H, Ar-H), 7.57 (dd, J = (m), 868 (s), 815 (m), 795 (s), 721 (m), 628 (m), 612 (m) cm–1. MS
8.4 Hz, J = 1.9 Hz, 1 H, Ar-H) ppm. 13C{1H} NMR (125 MHz, (EI, 70 eV): m/z (%) = 334 (100) [M+], 306 (41), 291 (53), 263 (9),
CDCl3): δ = 14.7 (CH3), 26.2 (CH3), 56.1 (OCH3), 64.4 (OCH2),
110.2 (CH), 111.4 (CH), 123.1 (CH), 130.5 (C), 148.3 (C), 153.6
176 (11), 148 (21), 133 (27), 105 (21), 76 (14). C11H12Br2O2
(336.02): calcd. C 39.32, H 3.60; found C 39.32, H 3.62.
(C), 196.8 (C=O) ppm. IR (ATR): ν = 1668 (vs), 1583 (vs), 1508
˜
1,1-Dibromo-2-(4-methoxyphenyl)ethene (11c): According to the
procedure reported for compound 11a, the aldehyde 10c (3.0 g,
22 mmol), PPh3 (11.6 g, 44.2 mmol) and CBr4 (7.3 g, 22 mmol)
were converted to yield title compound 11c (5.54 g, 19.0 mmol,
86%) after chromatography (SiO2; CH2Cl2; Rf = 0.74) as a yellow
(vs), 1469 (m), 1422 (s), 1396 (m), 1355 (m), 1341 (m), 1290 (m),
1257 (m, br.), 1213 (br. s), 1180 (m), 1105 (m), 1081 (m), 1042 (s),
1012 (vs) cm–1. MS (EI, 70 eV): m/z (%) = 194 (62) [M+], 179 (45),
151 (100). C11H14O3 (194.23): calcd. C 68.02, H 7.26; found C
67.90, H 7.36.
1
solid, m.p. 34–36 °C. H NMR (250 MHz, CDCl3): δ = 3.80 (s, 3
H, OCH3), 6.88 (d, J = 8.9 Hz, 2 H, Ar-H), 7.39 (s, 1 H, 2-H), 7.49
(d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 55.3 (OCH3), 87.2 (C), 113.8 (2 CH), 127.8 (C), 129.9
3-Hydroxy-4-methoxyacetophenone (8): A solution of ketone 7a
(15 g, 83 mmol) in concd. H2SO4 (75 mL) was stirred at 65 °C for
46 h. After cooling to ambient temperature, the reaction mixture
was poured on ice (300 g) and the mixture stirred for 1 h. The pre-
cipitate was filtered off, washed with water, and redissolved in
NaOH (0.19 mol, 190 mL of a 1 mol·dm–3 solution in water). The
mixture was extracted with CH2Cl2 (80 mL). The aqueous layer
was acidified (cooling with ice/water bath) with concd. hydrochloric
acid (30 mL), stirred for 1.5 h, and the precipitate filtered off to
give phenol 8 as a light brown solid (8.291 g, 49.89 mmol, 60%),
m.p. 88–90 °C. 1H NMR (500 MHz, CDCl3): δ = 2.55 (s, 3 H,
CH3), 3.93 (s, 3 H, OCH3), 5.94 (s, 1 H, OH), 6.90–6.92 (m, 1 H,
Ar-H), 7.56–7.57 (m, 2 H, Ar-H) ppm. 13C{1H} NMR (62 MHz,
CDCl3): δ = 26.7 (CH3), 56.5 (OCH3), 110.3 (CH), 114.9 (CH),
122.2 (CH), 131.4 (C), 145.8 (C), 151.2 (C), 197.4 (C=O) ppm. IR
(2 CH), 136.3 (CH), 159.7 (C) ppm. IR (ATR): ν = 1602 (m), 1565
˜
(m), 1506 (m), 1454 (m), 1329 (m), 1305 (m), 1253 (m), 1176 (m),
1025 (s), 862 (s), 802 (s), 730 (m) cm–1. MS (EI, 70 eV): m/z (%) =
290 (100) [M+], 276 (16), 132 (30). C9H8Br2O (291.80): calcd. C
37.02, H 2.76; found C 37.12, H 2.78.
1,1-Dibromo-2-(2-thienyl)ethene (11d): According to the procedure
reported for compound 11a, the aldehyde 10d (4.00 g, 35.7 mmol),
PPh3 (23.4 g, 89.2 mmol) and CBr4 (14.8 g, 44.6 mmol) were con-
verted to yield title compound 11d (9.50 g, 35.4 mmol, 99%) after
chromatography on SiO2 (CH2Cl2; Rf = 0.78) as light brown crys-
1
tals, m.p. 55–56 °C. H NMR (500 MHz, CDCl3): δ = 7.03 (dd, J
= 5.0 Hz, J = 3.8 Hz, 1 H, Ar-H), 7.25 (d, J = 4.3 Hz, 1 H, Ar-H),
7.38 (d, J = 5.0 Hz, 1 H, Ar-H), 7.65 (s, 1 H, 2-H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 86.9 (C), 126.5 (CH), 127.1 (CH),
(ATR): ν = 3169 (m, br.), 1665 (m), 1574 (m), 1509 (m), 1361 (m),
˜
1272 (m, br.), 1204 (s), 1122 (m), 1017 (m), 820 (m) cm–1. MS (EI,
70 eV): m/z (%) = 166 (45) [M+], 151 (100), 123 (19). C9H10O3
(166.18): calcd. C 65.05, H 6.07; found C 64.70, H 6.08.
130.0 (CH), 130.9 (CH), 138.1 (C) ppm. IR (ATR): ν = 1420 (m),
˜
1346 (m), 1208 (s), 1077 (m), 1050 (m), 855 (s), 816 (s) 741 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 266 (100) [M+], 189 (10), 108 (67).
C6H4Br2S (268.00): calcd. C 26.89, H 1.51; found C 27.10, H 1.61.
1,1-Dibromo-2-(3,4-dimethoxyphenyl)ethene (11a): Ph3P (31.6 g,
120 mmol) was added to a cooled (ice/water bath) and well-stirred
solution of CBr4 (20.0 g, 60.2 mmol) in abs. CH2Cl2 (150 mL). The
mixture was stirred with cooling for further 5 min, then aldehyde
10a (10.0 g, 60.0 mmol) was added portionwise (exothermic reac-
tion). The resulting solution was stirred for 30 min, then extracted
with water (250 mL). The organic layer was separated and dried
with MgSO4. After filtration, the solvent was stripped off and the
residue chromatographed on SiO2 (CH2Cl2; Rf = 0.55) to give the
title compound 11a in the first fraction as a light yellow oil (17.9 g,
2-Phenyl-1,4-pentadien-3-ol (12a): Under N2, nBuLi (68.30 mmol,
40.2 mL of a 1.7 mol·dm–3 solution in pentane) was added drop-
wise at –78 °C to a solution of the bromo olefin 4e (5.00 g,
27.3 mmol) in abs. THF (100 mL) over a period of 30 min. The
reaction mixture was further stirred at –78 °C for 1.5 h. Then
freshly distilled acrolein 5a (4.59 g, 81.9 mmol) was added dropwise
over a period of 10 min. After being stirred at –78 °C for a further
1.5 h, the reaction mixture was warmed to room temperature and
washed with saturated aqueous NH4Cl (150 mL) and water
(50 mL). The layers were separated, and the combined aqueous lay-
ers were extracted with CH2Cl2 (2×50 mL). The combined organic
layers were dried with MgSO4. After filtration and removal of sol-
vent, the residue was chromatographed on SiO2 (PE/EA, 5:1; Rf =
1
55.6 mmol, 92%). H NMR (250 MHz, CDCl3): δ = 3.87 (s, 6 H,
2 OCH3), 6.82 (d, J = 8.4 Hz, 1 H, Ar-H), 7.09 (dd, J = 8.4 Hz, J
= 1.7 Hz, 1 H, Ar-H), 7.17 (d, J = 1.7 Hz, 1 H, Ar-H), 7.39 (s, 1
H, 2-H) ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 55.89 (OCH3),
55.92 (OCH3), 87.4 (C), 110.8 (CH), 111.1 (CH), 121.9 (CH), 127.9
1
(C), 136.4 (CH), 148.6 (C), 149.3 (C) ppm. IR (ATR): ν = 1600
˜
0.35) to give 12a (3.40 g, 21.2 mmol, 78%) as a light yellow oil. H
(m), 1515 (s), 1462 (m), 1269 (s), 1142 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 320 (100) [M+], 305 (20), 198 (10), 162 (19), 118 (30).
C10H10Br2O2 (322.00): calcd. C 37.30, H 3.13; found 37.05, H 3.15.
NMR (500 MHz, CDCl3): δ = 3.0 (br. s, 1 H, OH), 5.06 (d, br., J
Ϸ 6 Hz, 1 H, 3-H), 5.09 [dt, J = 10.3 Hz, J = 1.4 Hz, 1 H, (E)-5-
H], 5.26 [dt, J = 17.2 Hz, J = 1.4 Hz, 1 H, (Z)-5-H], 5.34–5.36 (m,
br., 1 H, 1-H), 5.37 (t, J = 1.1 Hz, 1 H, 1-H), 5.90 (ddd, J =
17.2 Hz, J = 10.3 Hz, J = 5.8 Hz, 1 H, 4-H), 7.19–7.32 (m, 3 H,
Ph), 7.36–7.41 (m, 2 H, Ph) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 75.0 (CH), 114.0 (CH2), 116.3 (CH2), 127.4 (2 CH),
128.1 (CH), 128.7 (2 CH), 139.4 (CH), 139.8 (C), 150.4 (C) ppm.
1,1-Dibromo-2-(3-ethoxy-4-methoxyphenyl)ethene (11b): According
to the procedure reported for compound 11a, the aldehyde 10b
(24.0 g, 133 mmol), PPh3 (69.6 g, 266 mmol) and CBr4 (44.4 g,
133 mmol) were converted to yield title compound 11b (42.8 g,
127 mmol, 96 %) after chromatography on SiO2 (CH2Cl2; Rf =
0.55) as a pale yellow solid, m.p. 41–42 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.46 (t, J = 7.0 Hz, 3 H, CH3), 3.86 (s, 3 H, OCH3),
4.08 (q, J = 7.0 Hz, 2 H, OCH2), 6.83 (d, J = 8.4 Hz, 1 H, Ar-H),
7.10 (dd, J = 8.4 Hz, J = 2.0 Hz, 1 H, Ar-H), 7.18 (d, J = 2.0 Hz,
IR (ATR): ν = 3390 (br. s), 3110 (m), 3100 (m), 2957 (m), 1501
˜
(m), 1489 (m), 1018 (s), 951 (s) cm–1. MS (EI, 70 eV): m/z (%) =
160 (30) [M+], 142 (24), 103 (100), 77 (39). HRMS (EI, 70 eV):
calcd. 160.0888 (C11H12O); found 160.0889 [M+].
1 H, Ar-H), 7.38 (s, 1 H, 2-H) ppm. 13C{1H} NMR (62 MHz, 2-(3,4-Dimethoxyphenyl)-1,4-pentadien-3-ol (12b): According to the
CDCl3): δ = 14.8 (CH3), 55.9 (OCH3), 64.4 (OCH2), 87.1 (C), 110.9 procedure reported for compound 12a, nBuLi (8.65 mmol, 4.3 mL
(CH), 112.5 (CH), 121.9 (CH), 127.8 (C), 136.4 (CH), 147.8 (C), of a 2 mol·dm–3 solution in pentane), bromo olefin 4a (1.00 g,
149.5 (C) ppm. IR (ATR): ν = 1596 (m), 1511 (s), 1428 (m), 1387
4.12 mmol), and acrolein 5a (685 mg, 12.3 mmol) were converted
˜
(m), 1302 (m), 1262 (s), 1236 (s), 1145 (s), 1045 (m), 1021 (m), 991 to give the title compound 12b (560 mg, 2.54 mmol, 62%) after
4052
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4044–4054

Tetrahydropyran-4-ones and Thiopyran-4-ones from α-Bromostyrene Derivatives
FULL PAPER
chromatography [SiO2; PE/EA, 5:1; Rf(PE/EA, 2:1) = 0.21] as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ = 1.95 (br. s, 1 H,
OH), 3.88 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.10 (d, J = 5.5 Hz,
1 H, 3-H), 5.19 [dt, J = 10.4 Hz, J = 1.2 Hz, 1 H, (E)-5-H], 5.34
= 6.2 Hz, 1 H, 3-H), 5.37 (s, 1 H, 5-H), 5.38 (s, 1 H, 5-H), 6.31
(dd, J = 16.0 Hz, J = 6.2 Hz, 1 H, 2-H), 6.67 (d, J = 16.5 Hz, 1 H,
1-H), 6.82 (d, J = 8.2 Hz, 1 H, Ar-H), 7.01 (d, J = 1.9 Hz, 1 H,
Ar-H), 7.03–7.04 (m, 1 H, Ar-H), 7.22–7.36 (m, 5 H, Ph) ppm.
(s, 1 H, 1-H), 5.35 (s, 1 H, 1-H), 5.35 (dt, J = 18.1 Hz, J = 1.2 Hz, 13C{1H} NMR (125 MHz, CDCl3): δ = 14.5 (CH3), 55.9 (OCH3),
1 H, 5-H), 5.97 (ddd, J = 17.1 Hz, J = 10.3 Hz, J = 5.7 Hz, 1 H,
64.3 (OCH2), 74.5 (CH), 111.2 (CH), 112.0 (CH), 112.6 (CH2),
4-H), 6.82–6.84 (m, 1 H, Ar-H), 7.00–7.02 (m, 2 H, Ar-H) ppm. 119.4 (CH), 126.5 (2 CH), 127.7 (CH), 128.6 (2 CH), 130.5 (CH),
13C{1H} NMR (62 MHz, CDCl3): δ = 55.85 (2 OCH3), 74.7 (CH), 131.1 (CH), 132.0 (C), 136.6 (C), 148.0 (C), 149.2 (C), 149.7 (C)
110.4 (CH), 110.9 (CH), 112.6 (CH2), 115.7 (CH2), 119.3 (CH),
ppm. IR (ATR): ν = 3344 (m, br.), 1578 (m), 1515 (m), 1465 (m),
˜
132.1 (C), 139.2 (CH), 148.7 (C), 148.8 (C), 149.5 (C) ppm. IR 1392 (m), 1331 (m), 1254 (s), 1216 (s), 1180 (m), 1145 (s), 1124 (m),
(ATR): ν = 1516 (m), 1256 (m), 1025 (m) cm–1. MS (EI, 70 eV):
1098 (m), 1020 (s), 959 (s), 898 (m), 755 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 310 (47) [M+], 206 (7), 177 (100), 149 (8), 91 (8). HRMS
(EI, 70 eV): calcd. 310.1569 (C20H22O3), found 310.1568 [M+].
˜
m/z (%) = 220 (34) [M+], 163 (100), 148 (4), 91 (6). C13H16O3
(220.26): calcd. C 70.89, H 7.32; found C 70.73, H 7.56.
(E)-4-(4-Methoxyphenyl)-1-phenyl-1,4-pentadien-3-ol (12f): Accord-
ing to the procedure reported for compound 12a, nBuLi
(3.10 mmol, 1.55 mL of a 2 mol·dm–3 solution in pentane), bromo
olefin 4c (550 g, 2.58 mmol), and aldehyde 5b (400 mg, 3.03 mmol)
were converted to give the title compound 12f (511 g, 1.92 mmol,
74%) after chromatography (SiO2; PE/EA, 2:1; Rf = 0.37) as a yel-
low oil, which slowly solidified at ambient temperature, m.p. 56–
58 °C. 1H NMR (500 MHz, CDCl3): δ = 2.00 (br. s, 1 H, OH), 3.79
(s, 3 H, OCH3), 5.25 (d, br. J = 5.4 Hz, 1 H, 3-H), 5.37 [s, 1 H,
(Z)-5-H], 5.38 [s, 1 H, (E)-5-H], 6.31 (dd, J = 16.1 Hz, J = 6.2 Hz,
1 H, 2-H), 6.65 (d, J = 15.8 Hz, 1 H, 1-H), 6.84–6.87 (m, 2 H, Ar-
H), 7.20–7.24 (m, 1 H, Ar-H), 7.27–7.30 (m, 2 H, Ar-H), 7.34–7.36
(m, 2 H, Ar-H), 7.39–7.42 (m, 2 H, Ar-H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 55.3 (OCH3), 74.4 (CH), 112.4 (CH2),
113.8 (2 CH), 126.6 (2 CH), 127.7 (CH), 128.1 (2 CH), 128.5 (2
CH), 130.4 (CH), 131.2 (CH), 131.6 (C), 136.6 (C), 149.4 (C), 159.3
2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-ol (12c): According
to the procedure reported for compound 12a, nBuLi (154 mmol,
77.0 mL of a 2 mol·dm–3 solution in pentane), bromo olefin 4b
(18.0 g, 70.0 mmol), and acrolein 5a (10.5 g, 187 mmol) were con-
verted to give the title compound 12c (10.5 g, 44.8 mmol, 64%)
after chromatography [SiO2; PE/EA, 5:1; Rf(PE/EA, 2:1) = 0.31] as
1
a colorless solid, m.p. 30–32 °C. H NMR (300 MHz, CDCl3): δ =
1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.18 (d, br., J = 3.5 Hz, 1 H, OH),
3.87 (s, 3 H, OCH3), 4.06–4.15 (m, 2 H, OCH2), 5.08 (br. s, 1 H,
3-H), 5.17 [dt, J = 10.3 Hz, J = 1.4 Hz, 1 H, (E)-5-H], 5.32 (t, br.,
J = 1.0 Hz, 1 H, 1-H), 5.33 (br. s, 1 H, 1-H), 5.34 [dt, J = 17.2 Hz,
J = 1.4 Hz, 1 H, (Z)-5-H], 5.96 (ddd, J = 17.2 Hz, J = 10.4 Hz, J
= 5.6 Hz, 1 H, 4-H), 6.81–6.84 (m, 1 H, Ar-H), 6.98–7.01 (m, 2 H,
Ar-H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.8 (CH3),
55.9 (OCH3), 64.35 (OCH2), 74.8 (CH), 111.3 (CH), 112.0 (CH),
112.5 (CH2), 115.7 (CH2), 119.4 (CH), 132.0 (C), 139.2 (CH), 148.0
(C) ppm. IR (ATR): ν = 3327 (m, br.), 1605 (s), 1574 (m), 1513 (s),
˜
(C), 149.2 (C), 149.6 (C) ppm. IR (ATR): ν = 3435 (m, br.), 1511
˜
1448 (m), 1290 (m), 1246 (vs), 1184 (s), 1068 (m), 1030 (s), 970 (m),
906 (m), 832 (s), 727 (m), 691 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 266 (35) [M+], 162 (8), 133 (100). C18H18O2 (266.32): calcd. C
81.17, H 6.81; found C 81.08, H 6.74.
(s), 1249 (s), 1211 (m), 1137 (m), 1025 (s) cm–1. MS (EI, 70 eV):
m/z (%) = 234 (48) [M+], 177 (100), 149 (14), 117 (7). C14H18O3
(234.29): calcd. C 71.77, H 7.74; found C 71.44, H 8.09.
(E)-4-(3,4-Dimethoxyphenyl)-1-phenyl-1,4-pentadien-3-ol (12d): Ac-
cording to the procedure reported for compound 12a, nBuLi
(16.0 mmol, 8.0 mL of a 2 mol·dm–3 solution in pentane), bromo
olefin 4a (1.60 g, 6.58 mmol), and aldehyde 5b (1.33 mL,
10.5 mmol) were converted to give the title compound 12d (1.20 g,
4.10 mmol, 63%) after chromatography (SiO2; PE/EA, 2:1; Rf =
Acknowledgments
This work was generously supported by the ALTANA Pharma AG,
Konstanz, Germany.
1
0.23) as a yellow oil. H NMR (500 MHz, CDCl3): δ = 2.15 (br. s,
1 H, OH), 3.85 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 5.25 (d, br., [1] V. Baliah, R. Jeyaraman, L. Chandrasekaran, Chem. Rev. 1983,
83, 379–423.
J = 6.0 Hz, 1 H, 3-H), 5.38 [br. s, 1 H, (Z)-5-H], 5.40 [br. s, 1 H,
(E)-5-H], 6.33 (dd, J = 16.0 Hz, J = 6.0 Hz, 1 H, 2-H), 6.67 (dd, J
= 16.0 Hz, J = 1.0 Hz, 1 H, 1-H), 6.81 (d, J = 8.9 Hz, 1 H, Ar-H),
7.00–7.07 (m, 2 H, Ar-H), 7.19–7.40 (m, 5 H, Ar-H) ppm. 13C{1H}
NMR (62 MHz, CDCl3): δ = 55.8 (OCH3), 55.9 (OCH3), 74.5
(CH), 110.4 (CH), 110.9 (CH), 112.7 (CH2), 119.4 (CH), 126.5 (2
CH), 127.7 (CH), 128.6 (2 CH), 130.5 (CH), 131.1 (CH), 132.0 (C),
[2] a) P. A. Clarke, W. H. C. Martin, J. M. Hargreaves, C. Wilson,
A. J. Blake, Chem. Commun. 2005, 1061–1063; b) J.-K. Wang,
Y.-X. Zong, H.-G. An, G.-Q. Xue, D.-Q. Wu, Y.-S. Wang, Tet-
rahedron Lett. 2005, 46, 3797–3799; c) E. Ruijter, H. Schülting-
kemper, L. A. Wessjohann, J. Org. Chem. 2005, 70, 2820–2823;
d) A. Kulesza, F. H. Ebetino, R. K. Mishra, D. Cross-Doersen,
A. W. Mazur, Org. Lett. 2003, 5, 1163–1166; e) N. A. Petasis,
S.-P. Lu, Tetrahedron Lett. 1996, 37, 141–144; f) N. A. R.
Hatam, D. A. Whiting, J. Chem. Soc. C 1969, 1921–1932.
[3] a) S. Faulkner, R. C. Whitehead, R. J. Aarons, Sci. Synth. 2003,
14, 771–786; b) N. G. Rule, M. R. Detty, J. E. Kaeding, J. A.
Sinicropi, J. Org. Chem. 1995, 60, 1665–1673; c) N. S. Pantaleo,
D. van der Helm, K. Ramarajan, B. R. Bailey, K. D. Berlin, J.
Org. Chem. 1981, 46, 4199–4204; d) W. Ried, H. Bopp, Synthe-
sis 1978, 211–212; e) A. Schönberg, R. von Ardenne, Chem.
Ber. 1966, 99, 3316–3326.
[4] a) D. B. Grotjahn, J. M. Hoerter, J. L. Hubbard, J. Am. Chem.
Soc. 2004, 126, 8866–8867; b) C. Kuroda, H. Koshio, A. Koito,
H. Sumiya, A. Murase, Y. Hirono, Tetrahedron 2000, 56, 6441–
6455; c) R. P. Kopinski, J. T. Pinhey, Aust. J. Chem. 1983, 36,
311–316; d) T. K. Jones, S. E. Denmark, Helv. Chim. Acta
1983, 66, 2377–2396; e) M. A. Steinfels, H. W. Krapf, P. Riedl,
J. Sauer, A. S. Dreiding, Helv. Chim. Acta 1972, 55, 1759–1771.
136.6 (C), 148.7 (C), 148.8 (C), 149.7 (C) ppm. IR (ATR): ν = 1513
˜
(s), 1462 (m), 1250 (s), 1174 (m), 1143 (m), 1025 (m) cm–1. MS (EI,
70 eV): m/z (%) = 296 (45) [M+], 192 (12), 163 (100), 148 (7), 133
(10). C19H20O3 (296.37): calcd. C 77.00, H 6.80; found C 76.93, H
7.03.
(E)-4-(3-Ethoxy-4-methoxyphenyl)-1-phenyl-1,4-pentadien-3-ol
(12e): According to the procedure reported for compound 12a,
nBuLi (13 mmol, 6.5 mL of a 2 mol·dm–3 solution in pentane),
bromo olefin 4b (1.67 g, 6.49 mmol), and aldehyde 5b (1.2 mL,
9.75 mmol) were converted to give the title compound 12e (968 mg,
3.12 mmol, 48%) after chromatography (SiO2; PE/EA, 2:1; Rf =
0.44) as a yellow solid, m.p. 73–76 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H, CH3), 2.10 (br. s, 1 H, OH),
3.86 (s, 3 H, OCH3), 4.07 (q, J = 7.0 Hz, 2 H, OCH2), 5.24 (d, J
Eur. J. Org. Chem. 2006, 4044–4054
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4053

A. Rosiak, W. Frey, J. Christoffers
FULL PAPER
[5] a) R. Gronheid, H. Zuilhof, M. G. Hellings, J. Cornelisse, G.
Lodder, J. Org. Chem. 2003, 68, 3205–3215; b) M. S. Malamas,
E. S. Manas, R. E. McDevitt, I. Gunawan, Z. B. Xu, M. D.
Collini, C. P. Miller, T. Dinh, R. A. Henderson, J. C. Keith,
H. A. Harris, J. Med. Chem. 2004, 47, 5021–5140.
[6] a) C. A. Grob, G. Cseh, Helv. Chim. Acta 1964, 47, 194–203;
b) Z. Rappoport, A. Gal, Tetrahedron Lett. 1970, 11¸3233–3236;
c) Z. Rappoport, Y. Apeloig, J. Am. Chem. Soc. 1974, 96, 6428–
6436.
[12] J.-P. Beny, S. N. Dhawan, J. Kagan, S. Sundlass, J. Org. Chem.
1982, 47, 2201–2204.
[13] a) S. Kano, T. Yokomatsu, S. Shibuya, J. Org. Chem. 1978, 43,
4366–4367; b) A. Pelter, R. S. Ward, G. M. Little, J. Chem.
Soc., Perkin Trans. 1 1990, 2775–2790.
[14] a) M. Matsumoto, K. Kuroda, Tetrahedron Lett. 1980, 21,
4021–4024; b) J. C. Gilbert, U. Weerasooriya, J. Org. Chem.
1982, 47, 1837–1845; c) R. A. Aitken, S. Seth, Synlett 1990,
211–211; d) K. Miwa, T. Aoyama, T. Shioiri, Synlett 1994, 107–
108; e) S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Syn-
lett 1996, 521–522; f) J. Carran, R. Waschbüsch, A. Marinetti,
P. Savignac, Synthesis 1996, 1494–1498.
[15] a) A. Carpita, R. Rossi, C. A. Veracini, Tetrahedron 1985, 41,
1919–1929; b) P. Michel, D. Gennet, A. Rassat, Tetrahedron
Lett. 1999, 40, 8575–8578; c) J. G. Rodriguez, A. Lafuente, L.
Rubio, Tetrahedron Lett. 2004, 45, 5685–5688.
[7] E.-i. Negishi, A. O. King, J. M. Tour, Org. Synth. 1985, 64, 44–
49.
[8] a) A. Brossi, H. Gurien, A. I. Rachlin, S. Teitel, J. Org. Chem.
1967, 32, 1269–1270; b) P. Bose, J. Banerji, Phytochemistry
1991, 30, 2438–2439.
[9] CCDC-605912 (1b), -601623 (7b) and -601624 (11b) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] a) E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–
3772; b) D. M. Perrine, J. Kagan, Heterocycles 1986, 24, 365–
368.
[16] a) H. J. Bestmann, H. Frey, Liebigs Ann. Chem. 1980, 2061–
2071; b) P. G. Gassmann, C. K. Harrington, J. Org. Chem.
1984, 49, 2258–2273; c) P. H. Lee, K. Lee, Angew. Chem. 2005,
117, 3317–3320; Angew. Chem. Int. Ed. 2005, 44, 3253–3256;
d) P. H. Lee, D. Seomoon, K. Lee, Org. Lett. 2005, 7, 343–345.
Received: April 28, 2006
[11] a) V. Galamb, M. Gopal, H. Alper, Organometallics 1983, 2,
801–805; b) D. H. Huh, J. S. Jeong, H. B. Lee, H. Ryu, Y. G.
Kim, Tetrahedron 2002, 58, 9925–9932.
Published Online: July 10, 2006
4054
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4044–4054