Synthesis of 3-aryl-substituted tetrahydropyran-4-ones and tetrahydrothiopyran-4-ones

Article abstract of DOI:10.1055/s-2006-941572

A series of tetrahydropyran-4-one and tetrahydrothiopyran-4-one derivatives with 3-aryl or 3,6-diaryl substituents were prepared by double conjugate addition of water or H₂S to divinyl ketones. These starting materials were accessed in two step

Full text of DOI:10.1055/s-2006-941572

1434
LETTER
Synthesis of 3-Aryl-Substituted Tetrahydropyran-4-ones and Tetrahydrothio-
pyran-4-ones
3
-Aryl-Substituted
n
Tetrahydrop
n
yran-4-ones
a
and Tetrahydroth
R
iopyran-4-ones osiak,a,b Jens Christoffers*b
a
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
b
Institut für Reine und Angewandte Chemie, Carl von Ossietzky-Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received 20 March 2006
Reaction conditions were optimized with model com-
pound 1a (R = Ph, R¢ = H). Although sulfides, as soft nu-
cleophiles, should cleanly undergo conjugate additions,
yields turned out to be highly dependent on the reaction
Abstract: A series of tetrahydropyran-4-one and tetrahydrothio-
pyran-4-one derivatives with 3-aryl or 3,6-diaryl substituents were
prepared by double conjugate addition of water or H2S to divinyl
ketones. These starting materials were accessed in two steps by
conversion of lithiated a-bromostyrene derivatives with acrolein or conditions, particularly on the solvent. Best results were
achieved with NaHS in 2-methoxyethanol (2-ME)5 or
cinnamaldehyde and subsequent oxidation of the divinylalcohols
with MnO2.
Na2S in THF–H2O (1:1) at elevated temperatures (45–
Key words: building blocks, conjugate addition, heterocyclic com-
pounds, pyran derivatives, thiopyran derivatives
55 °C). Yields for products 2a–f are collated in Table 1.
They are, however, dependent on the purity of the respec-
tive divinylketone 1 (see below).
Table 1 Yields and Substituents R and R¢ in the Synthesis of
Tetrahydropyran-4-ones 3 (X = O) and Tetrahydrothiopyran-4-ones 2
(X = S)
Successful drug development is often dependent on the
availability of heterocyclic building blocks with a specific
substitution pattern. In the course of a research program in
a medicinal chemistry context tetrahydropyran-4-ones 3
and tetrahydrothiopyran-4-ones 2 were required for the
preparation of novel enzyme inhibitors. Of course, many
procedures1 have been reported to access tetrahydro-
pyran-4-one derivatives2 and their sulfur analogues,3
however, our requirement for an electron-rich aryl sub-
stituent in the 3-position has not been addressed in the
literature so far. The obvious first approach to our target
structures is the a-arylation of the unsubstituted heterocy-
clic ketone, which failed, however, due to decomposition
by E1cb elimination of the respective enolates. Therefore,
we envisioned to build up the heterocycle by double con-
jugate addition of water (X = O) or sulfane (X = S) to a
divinylketone4 with the accurate aryl substitution pattern
(Scheme 1).
Product
2a
R
R¢
H
X
S
S
S
S
S
S
O
O
Yield (%)
Ph
70
2b
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
4-MeOC6H4
Ph
H
65
2c
H
59
2d
Ph
Ph
Ph
H
60 (dr 4:1)
48 (dr 9:1)
57 (dr 3:1)
50
2e
2f
3a
3b
3-EtO-4-MeOC6H3
H
25
All compounds were of course obtained as racemates. For
products 2d–f mixtures of two diastereoisomers were
obtained with moderate stereoselectivity. The relative
O
O
R
R
3
a or b
configuration was assigned based on J(H,H) coupling
constants. The trans isomer is the major diastereomer in
all three cases (2d: trans/cis 4:1; 2e: trans/cis 9:1; 2f:
trans/cis 3:1). For the pyranone series, various acidic and
basic reaction conditions with different solvent–water
mixtures, even with phase-transfer catalysis have been
investigated. Surprisingly, only with the system KOH–
H2O–CH2Cl2 at 50 °C the racemic pyranones 3a and 3b6
were formed, though, yields are not fully satisfying.
Nevertheless, products of specific interest were prepared
batchwise in total yields of 50 g (thiacycle 2) and 20 g
(oxacycle 3), respectively, by using the conditions de-
picted in Scheme 1.
R'
R'
X
2 (X = S)
3 (X = O)
1
Scheme 1 Synthesis of 3-aryl-substituted tetrahydropyran-4-ones 3
and -thiopyran-4-ones 2 by double conjugate addition. Reagents and
conditions: (a) for 2: NaHS-hydrate, 2-methoxyethanol (2-ME),
50 °C, 5 h; (b) for 3: KOH, H2O, CH2Cl2, 40 °C, 2–3 d. For yields and
substituents, see Table 1.
SYNLETT 2006, No. 9, pp 1434–1436
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1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941572; Art ID: G09806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Aryl-Substituted Tetrahydropyran-4-ones and Tetrahydrothiopyran-4-ones
1435
In conclusion, tetrahydrothiopyran-4-ones 2 with an
aromatic substituent in the 3-position are conveniently
accessed by double conjugate addition of sulfide to the re-
spective divinylketone 1. The respective oxacycles 3 can
be similarily achieved from compounds 1 and water, how-
ever, in lower yields. The divinylketones 1 are accessed
from a-bromostyrene derivatives 4 with a specific
aromatic substitution pattern. Overall yields allow for the
preparation of final products on multigram scale.
O
OH
R
Br
R'
R
R
a
b
CHO
R'
R'
4
5a (R' = H)
5b (R' = Ph)
6
1
Scheme 2 Synthesis of divinylketones 1 from a-bromostyrenes 4.
Reagents and conditions: (a) 1. n-BuLi, THF, 1.5 h, –78 °C; 2. alde-
hyde 5, 1.5 h, –78 °C; (b) excess MnO2, CH2Cl2, 60 min, 23 °C.
Acknowledgment
Table 2 Yields and Substituents R and R¢ in the Synthesis of
Divinylketones 1
We are grateful to the ALTANA Pharma Konstanz, Germany for
support of this work.
R
R¢
H
Product 6
6a (78%)
6b (62%)
6c (64%)
6d (63%)
6e (48%)
6f (74%)
Product 1
1a (90%)
1b (56%)
1c (74%)
1d (72%)
1e (64%)
1f (83%)
References and Notes
Ph
(1) Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. Rev.
1983, 83, 379.
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
3,4-(MeO)2C6H3
3-EtO-4-MeOC6H3
4-MeOC6H4
H
(2) (a) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.;
Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061.
(b) Wang, J.-K.; Zong, Y.-X.; An, H.-G.; Xue, G.-Q.; Wu,
D.-Q.; Wang, Y.-S. Tetrahedron Lett. 2005, 46, 3797.
(c) Ruijter, E.; Schültingkemper, H.; Wessjohann, L. A. J.
Org. Chem. 2005, 70, 2820. (d) Kulesza, A.; Ebetino, F. H.;
Mishra, R. K.; Cross-Doersen, D.; Mazur, A. W. Org. Lett.
2003, 5, 1163. (e) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett.
1996, 37, 141. (f) Hatam, N. A. R.; Whiting, D. A. J. Chem.
Soc. C 1969, 1921.
(3) (a) Faulkner, S.; Whitehead, R. C.; Aarons, R. J. Science of
Synthesis, Vol. 14; Thomas, E. J., Ed.; Thieme: Stuttgart,
2003, 771–786. (b) Rule, N. G.; Detty, M. R.; Kaeding, J. E.;
Sinicropi, J. A. J. Org. Chem. 1995, 60, 1665. (c) Pantaleo,
N. S.; van der Helm, D.; Ramarajan, K.; Bailey, B. R.;
Berlin, K. D. J. Org. Chem. 1981, 46, 4199. (d) Ried, W.;
Bopp, H. Synthesis 1978, 211. (e) Schönberg, A.; van
Ardenne, R. Chem. Ber. 1966, 99, 3316.
(4) (a) Grotjahn, D. B.; Hoerter, J. M.; Hubbard, J. L. J. Am.
Chem. Soc. 2004, 126, 8866. (b) Kuroda, C.; Koshio, H.;
Koito, A.; Sumiya, H.; Murase, A.; Hirono, Y. Tetrahedron
2000, 56, 6441. (c) Kopinski, R. P.; Pinhey, J. T. Aust. J.
Chem. 1983, 36, 311. (d) Jones, T. K.; Denmark, S. E. Helv.
Chim. Acta 1983, 66, 2377. (e) Steinfels, M. A.; Krapf, H.
W.; Riedl, P.; Sauer, J.; Dreiding, A. S. Helv. Chim. Acta
1972, 55, 1759.
H
Ph
Ph
Ph
Starting divinylketones 1 were prepared by a two-step
sequence from a-bromostyrene derivatives 4 (Scheme 2,
Table 2). Whereas the parent compound 4a (R = Ph) is
commercially available, donor-substituted congeners 4b
[R = 3,4-(MeO)2C6H3], 4c (R = 3-EtO-4-MeOC6H3) and
4f (R = 4-MeOC6H4) were prepared by addition of HBr to
the respective alkyne under strictly anhydrous conditions.
Lithium–bromine exchange of compounds 4 with n-BuLi
proceeded smoothly at –78 °C and was followed by treat-
ment of the reaction mixture with freshly distilled acrolein
(5a) or cinnamaldehyde (5b) to yield the divinylalcohols
6a–f in good to reasonable yields after chromatographic
purification.7 Compounds 6d–f are obtained as single
diastereoisomers with the double bond configuration be-
3
ing E [olefinic J(H,H)]. Oxidation to the ketones was
achieved with MnO2 (commercial activity). The oxidant
was added portionwise to a suspension in CH2Cl2 until al-
most no starting material 6 was detectable by TLC, which
normally took one hour and 20–30 equivalents of MnO2.8
The products are generally pure by 1H NMR without fur-
ther chromatography, and are again obtained exclusively
with E double-bond configuration. If the conversion is not
complete, the remaining starting material 6 might be hard-
ly separable from the product of the next step (2 or 3). On
the other hand, prolonged reaction times result in over-
oxidation to an epoxide. Divinylketones 1a–c, which
derive from acrolein (5a) are highly reactive and neither
stable at ambient conditions nor at low temperatures.
They even decompose significantly upon chromatography
on SiO2. Therefore, they were directly converted further
to the heterocyclic products 2 and 3. Actually, the low
stability of divinylketones 1 might be the major reason for
the moderate yields of compounds 3a and 3b.
(5) 3-(3-Ethoxy-4-methoxyphenyl)tetrahydrothiopyran-4-
one (2c).
NaHS·9H2O (2.7 g, 13 mmol) was added to a solution of
dienone 1c (1.9 g, 8.2 mmol) in 2-methoxyethanol (120 mL).
The reaction mixture was stirred at 50 °C for 5 h and then
poured onto H2O (80 mL). After extraction with EtOAc (4 ×
80 mL) the combined organic layers were washed with H2O
(80 mL), dried (MgSO4), and all volatile materials removed
in vacuum. Chromatography of the residue on SiO2 (PE–
EtOAc, 2:1, Rf = 0.31) gave the title compound 9 (1.29 g,
4.84 mmol, 59%) as a colorless solid, mp 103–104 °C. 1H
NMR (300 MHz, CDCl3): d = 1.46 (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): d = 14.82 (CH3), 30.75 (CH2), 36.74 (CH2), 44.23
(CH2), 55.93 (OCH3), 58.90 (CH), 64.36 (CH2), 111.47
(CH), 113.30 (CH), 120.55 (CH), 129.86 (C), 148.19 (C),
Synlett 2006, No. 9, 1434–1436 © Thieme Stuttgart · New York

1436
A. Rosiak, J. Christoffers
LETTER
combined organic layers were dried over MgSO4. After
148.64 (C), 207.69 (C=O) ppm. IR (ATR): 2926 (w), 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), 857 (w) cm–1. MS (EI, 70 eV): m/z
(%) = 266 (53) [M+], 178 (100), 150 (26), 91 (5), 77 (7), 28
(9). Anal. Calcd for C14H18O3S (266.35): C, 63.13; H, 6.81.
Found: C, 63.01; H, 6.79.
filtration and removal of solvent, the residue was
chromatographed on SiO2 [PE–EtOAc, 5:1, Rf (PE–EtOAc,
2:1) = 0.31] to give 6c (10.5 g, 44.8 mmol, 64%) as a
colorless solid, mp 30–32 °C. 1H NMR (300 MHz, CDCl3):
d = 1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.18 (br d, 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 (br t, 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): d = 14.83 (CH3), 55.94 (OCH3),
64.35 (OCH2), 74.75 (CH), 111.25 (CH), 112.01 (CH),
112.51 (CH2), 115.73 (CH2), 119.38 (CH), 132.03 (C),
139.19 (CH), 148.02 (C), 149.22 (C), 149.55 (C) ppm. IR
(ATR): = 3435 (br m), 2934 (w), 1579 (w), 1511 (s), 1441
(w), 1249 (s), 1211 (m), 1178 (w), 1137 (m), 1025 (s), 921
(w), 810 (w), 775 (w) cm–1. MS (EI, 70 eV): m/z (%) = 234
(48) [M+], 177 (100), 149 (14), 117 (7), 77 (6). Anal. Calcd
for C14H18O3 (234.29): C, 71.77; H, 7.74. Found: C, 71.44;
H, 8.09.
(6) 3-(3-Ethoxy-4-methoxyphenyl)tetrahydropyran-4-one
(3b).
KOH (4.34 g, 77.5 mmol) was added to a solution of 1c (4.50
g, 19.4 mmol) in CH2Cl2–H2O (1:1, 200 mL). The reaction
mixture was vigorously stirred at 40 °C for 3 d and then
poured into a mixture of H2O (100 mL) and aq solution of
citric acid (c = 20%, 25 mL). The resulting mixture was
extracted with CH2Cl2 (2 × 80 mL). The combined organic
layers were washed with H2O (30 mL) and dried (MgSO4).
After removal of all volatile materials in vacuum, the residue
was chromatographed on SiO2 (PE–EtOAc, 2:1, Rf = 0.23)
to give title compound 3b (1.21 g, 4.83 mmol, 25%) as a
light-yellow oil, which solidified after one day, mp 65–
67 °C. 1H NMR (250 MHz, CDCl3): d = 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) ppm. 13C{1H}-NMR (62 MHz, CDCl3): d = 14.81 (CH3),
41.84 (CH2), 55.94 (OCH3), 57.48 (CH), 64.39 (CH2), 68.52
(CH2), 73.20 (CH2), 111.62 (CH), 113.57 (CH), 120.99
(CH), 127.39 (C), 148.29 (C), 148.77 (C), 206.11 (C=O)
ppm. IR (ATR): 2973 (m), 2934 (w), 1715 (vs), 1589 (m),
1517 (vs), 1474 (w), 1433 (m), 1424 (w), 1389 (m), 1339
(w), 1309 (w), 1251 (vs), 1167 (m), 1094 (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), 91 (5), 77 (7), 28 (12). Anal.
Calcd for C14H18O4 (250.29): C, 67.18; H, 7.25. Found: C,
67.09; H, 7.29.
(8) 2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-one (1c).
MnO2 (25.0 g, 287 mmol) was added portionwise to a
solution of 6c (2.00 g, 8.55 mmol) in CH2Cl2 (60 mL) at
ambient temperature. The progress of the reaction was
monitored by TLC [product 1c: Rf (SiO2, PE–EtOAc,
2:1) = 0.45]. After being stirred for 60 min at 23 °C, the
reaction mixture was filtered with vacuum through SiO2 to
separate MnO2, the residue was washed several times with
EtOAc (total ca. 600 mL). The filtrate was concentrated
under vacuum to give 1c as a yellow oil (1.47 g, 6.33 mmol,
74%) with 90–95% purity by 1H NMR. The product
decomposes under ambient conditions. 1H NMR (300 MHz,
CDCl3): d = 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, 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, 1 H; Z-5-H), 6.73
(dd, J = 17.3 Hz, J = 10.5 Hz, 1 H, 4-H), 6.84–6.93 (m, 3 H,
ArH) ppm. 13C{1H}-NMR (75 MHz, CDCl3): d = 14.77
(CH3), 55.97 (OCH3), 64.40 (OCH2), 111.25 (CH), 112.44
(CH), 120.50 (CH), 121.93 (CH2), 129.44 (C), 130.35 (CH2),
134.45 (CH), 148.04 (C), 148.30 (C), 149.64 (C), 193.97
(C=O) ppm. IR (ATR): 2932 (br m), 2186 (w), 1671 (m),
1604 (m), 1514 (s), 1398 (w), 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), 77 (4), 55 (16). HRMS (EI, 70 eV):
m/z calcd for C14H16O3: 232.1099; found: 232.1099 [M+].
(7) 2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-ol (6c).
Under an inert atmosphere (N2) n-BuLi (154 mmol, 77.0 mL
of a 2 M solution in pentane) was added dropwise at –78 °C
to a solution of bromoolefin 4c (18.0 g, 70.0 mmol) in abs.
THF (250 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, 10.5 g, 187 mmol) was dropwise added over a
period of 10 min. After being stirred for a further 1.5 h at
–78 °C, the reaction mixture was allowed to warm up to r.t.
and washed with sat. aq NH4Cl (300 mL) and with H2O (100
mL). The layers were separated, and the combined aqueous
layers were extracted with CH2Cl2 (2 × 100 mL). The
Synlett 2006, No. 9, 1434–1436 © Thieme Stuttgart · New York