Synthesis of unsymmetrically 2,6-disubstituted 2,3-dihydrothiopyran-4-ones

Article abstract of DOI:10.1016/j.tetlet.2006.05.080

A series of 2,3-dihydrothiopyran-4-one derivatives with unequal substituents in the 2- and 6-position have been prepared by double conjugate addition of sulfide to enynones. These starting materials were accessed in two steps from terminal alkynes and α,β

Full text of DOI:10.1016/j.tetlet.2006.05.080

Tetrahedron Letters 47 (2006) 5095–5097
Synthesis of unsymmetrically 2,6-disubstituted
2,3-dihydrothiopyran-4-ones
Anna Rosiak and Jens Christoffers*
Institut fu¨r Reine und Angewandte Chemie, Carl von Ossietzky-Universita¨t Oldenburg, D-26111 Oldenburg, Germany
Received 20 March 2006; revised 10 May 2006; accepted 15 May 2006
Available online 6 June 2006
Abstract—A series of 2,3-dihydrothiopyran-4-one derivatives with unequal substituents in the 2- and 6-position have been prepared
by double conjugate addition of sulfide to enynones. These starting materials were accessed in two steps from terminal alkynes and
a,b-unsaturated aldehydes.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Dihydrothiopyran-4-one derivatives 5 are important
building blocks for the synthesis of heterocyclic com-
pounds1 and organic materials for electronic applica-
tions.2 They have been accessed by oxidation of the
respective tetrahydrothiopyran-4-ones by a halogena-
tion–dehydrohalogenation sequence with various chlori-
nating3 and fluorinating4 reagents. Since this oxidation
was reported to proceed without any significant regio-
selectivity, only symmetrically substituted compounds
of this class have been reported in the literature so far.
In the course of a project related to the pharmaceutical
application we were looking for dihydrothiopyran-
4-ones 5 with unsymmetrical 2,6-disubstitution as
heterocyclic building blocks. An obvious retrosynthetic
approach to these compounds is the double conjugate
addition of sulfide to an enynone 4 with the appropriate
substitution pattern. It was however not clear whether
an initial conjugate addition to the triple bond of these
starting materials would lead to a Z-configurated do-
nor–acceptor substituted olefin, which of course would
be the precondition for the formation of the heterocyclic
ring in the second conjugate addition to the C–C double
bond. Conjugate addition reactions of nitrogen nucleo-
philes have been reported in the literature to give enami-
nones with a E-configurated C–C double bond,5 which
is of course the thermodynamically more favoured situ-
ation. And indeed, in our hands, the conversion of eny-
nones 4 with primary amines led to the exclusive
formation of enaminones with two C–C double bonds.
No piperidone derivatives were detected. Therefore we
conclude, that at least for N-nucleophiles the conjugate
addition to the C–C triple bond is the predominating
process.
Enynones 4 (Scheme 1) were prepared starting from a ser-
ies of terminal alkynes 1 by deprotonating them with one
equivalent of n-BuLi in THF and further conversion with
cinnamaldehyde 2a or acroleine 2b. After aqueous work-
up and chromatographic purification allylic alcohols
OH
1. n-BuLi, -78 ºC, THF
R
2. R'-CH=CH-CHO
R
R'
2a R' = Ph
2b R' = H
1
3
xs. MnO2
23 ºC, CH2Cl2
O
O
NaSH, 2-ME, 40 ºC
R
R
S
R'
R'
5
4
Keywords: Thiopyrane derivatives; Heterocyclic compounds; Sulfur
Scheme 1. Synthesis of dihydrothiopyrones 5 from alkynes 1 via
allylalcohols 3 and vinylketones 4, for yields and substituents R and R0
see Table 1. 2-ME = 2-methoxyethanol.
compounds; Alkynes; Conjugate addition.
*
Corresponding author. Tel.: +49 441 798 4744; fax: +49 441 798
3873; e-mail: jens.christoffers@uni-oldenburg.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.080

5096
A. Rosiak, J. Christoffers / Tetrahedron Letters 47 (2006) 5095–5097
3 were obtained,6 which were subsequently oxidized
with an excess (10–30 equiv) MnO2 at 23 ꢁC in CH2Cl2.
The progress of this reaction was followed by TLC, and
after full conversion as achieved (5–30 min), materials
containing manganese were simply removed by filtration
to yield the double Michael acceptors 4, which were ana-
lytically pure without further purification.7 Yields for
both steps are generally very good, in some cases even
quantitative (Table 1). Alcohols 3a–i and ketones 4a–i
originating from cinnamaldehyde 2a (R0 = H) are
exclusively obtained with the C–C double bond in
E-configuration.
were achieved with 2-ME at moderate temperatures
(40–55 ꢁC) within a few hours (4–16 h). After aqueous
workup, products were purified by column chromato-
graphy on SiO2.8 The yields of derivatives with R0 = Ph
(5a–i) range from satisfying (60% for 5g) to excellent
(96% for 5b). For R = Ph (5a) and electron rich aromat-
ics (5b and 5c) yields are reaching 90%. Electron defi-
cient phenyl (5d and 5e) and electron rich (5f) and
poor heteroaryl (5g) as well as an aliphatic (5h) gave
yields from 60% to 85%. If trimethylsilyl acetylene
1i is used as starting material, the R = TMS group is
retained in alcohol 3i and ketone 4i. Cyclization with
NaSHÆ9H2O leads to ring closure, but the TMS group
is lost presumably due to the strong nucleophilicity of
sulfide. In this case the final product 5i is unsubstituted
in the 6-position (R = H).
Whereas vinylketones 4a–i with R0 = Ph show reason-
able stability, their congeners 4j–k deriving from acro-
leine (R0 = H) tend to decompose within an hour at
ambient conditions and can even not be stored at lower
temperatures and must therefore be further converted
directly after filtration.
Yields for compounds 5j–l without a substituent in the
2-position are not satisfying at all (8–36%). This might
actually originate from the low stability of the respective
starting materials 4j–l, which decompose under the reac-
tion conditions.
The result of the double thia-Michael reaction was
highly dependent on the solvent applied. Best results
In conclusion, 2,3-dihydrothiopyran-4-one derivatives
with unequal substituents in the 2- and 6-position (R,
R0) are conveniently accessed from terminal alkynes
and a,b-unsaturated aldehydes in a three step sequence.
The ring closure is achieved from enynones with sulfide.
Electron rich and deficient aromatic and heteroaromatic
as well as aliphatic substituents have been introduced in
the 6-position (R). The yields over three steps range
from 40% to 80%. Congeners without a substituent in
the 2-position (R0 = H) are more difficult to prepare,
which is mainly due to the instability of the enynone
intermediate product. Overall yields in these cases are
much lower (6–20%).
Table 1. Yields and substituents R and R0 in the synthesis of
dihydrothiopyrones 5
Entry
R
R0
Yield of Yield of Yield of
3 (%)
4 (%)
5 (%)
a
b
Ph
Ph 89
96
94
MeO
Ph 94
84
99
99
96
92
84
MeO
EtO
c
Ph 79
Ph 78
MeO
d
CF3
Acknowledgements
e
f
Ph 66
Ph 51
Ph 92
99
99
75
65
81
60
We thank the ALTANA Pharma Konstanz, Germany,
for support of this work.
F
F
S
References and notes
g
N
1. (a) Ried, W.; Bopp, H. Synthesis 1978, 211; (b) Yamamoto,
K.; Yamazaki, S.; Osedo, H.; Murata, I. Angew. Chem.
1986, 98, 636; Angew. Chem., Int. Ed. Engl. 1986, 25, 635;
(c) Yamamoto, K.; Yamazaki, S.; Murata, I. J. Org. Chem.
1987, 52, 5239.
2. (a) Reynolds, G. A.; Chen, C. H.; Van Allan, J. A. J. Org.
Chem. 1979, 44, 4456; (b) Chen, C. H.; Reynolds, G. A. J.
Org. Chem. 1980, 45, 2449; (c) Nakasuji, K.; Nakasuka, M.;
Murata, I. J. Chem. Soc., Chem. Commun. 1981, 1143; (d)
Chen, C. H.; Reynolds, G. A.; Luss, H. R.; Perlstein, J. H.
J. Org. Chem. 1986, 51, 3282; (e) Fox, J. L.; Chen, C. H.;
Luss, H. R. J. Org. Chem. 1986, 51, 3551.
3. (a) Chen, C. H.; Reynolds, G. A.; Van Allan, J. A. J. Org.
Chem. 1977, 42, 2777; (b) Chen, C. H. Heterocycles 1977, 7,
231; (c) Van Allan, J. A.; Reynolds, G. A.; Chen, C. H. J.
Heterocycl. Chem. 1977, 14, 1399; (d) Chen, C. H.;
Reynolds, G. A. J. Org. Chem. 1979, 44, 3144.
h
i
t-Bu
Ph 85
Ph 98
99
97
85
70
TMS, Ha
MeO
j
H
H
H
71
67
71
77
62
99
36
16
8
MeO
EtO
k
l
MeO
F
F
a TMS acetylene 1i was used as starting material. The TMS group was
retained in alcohol 3i and ketone 4i (R = TMS), but lost in the final
product 5i (R = H).
4. Zupan, M. J. Fluorine Chem. 1976, 8, 305.

A. Rosiak, J. Christoffers / Tetrahedron Letters 47 (2006) 5095–5097
5. (a) Karpov, A. S.; Rominger, F.; Muller, T. J. J. J. Org.
5097
6.91–6.99 (m, 2H, Ar–H), 7.43–7.47 (m, 3H, Ar–H),
7.59–7.67 (m, 3H, Ar–H), 7.99 (d, J = 16.1 Hz, 1H, 5-H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): d = 83.74 (s, C,
C-2), 90.95 (t, 3J = 2.4 Hz, C, C-1), 104.81 (dd, 2J =
25.1 Hz, 2J = 24.5 Hz, CH, C-30), 105.58 (dd, 2J = 15.9 Hz,
4J = 4.0 Hz, C, C-10), 112.35 (dd, 2J = 22.5 Hz,
4J = 5.9 Hz, CH, C-50), 128.34 (s, CH), 128.80 (s, 2CH),
129.12 (s, 2CH), 131.33 (s, CH), 134.03 (s, C), 135.84 (dd,
¨
Chem. 2003, 68, 1503; (b) Karpov, A. S.; Muller, T. J. J.
¨
Org. Lett. 2003, 5, 3451; (c) Dediu, O. G.; Yehia, N. A. M.;
Oeser, T.; Polborn, K.; Muller, T. J. J. Eur. J. Org. Chem.
¨
2005, 1834.
6. Representative experimental procedure, (E)-1-(2,4-difluoro-
phenyl)-3-hydroxy-5-phenyl-4-penten-1-yne (3e): n-BuLi
(3.62 mmol, 1.80 ml of a solution in pentane, 2.0 mol dmꢀ3
)
3
was added at ꢀ78 ꢁC to a solution of 2,4-difluorophenyl-
acetylene (1e, 500 mg, 3.62 mmol) in abs. THF (9 ml). After
further stirring (ꢀ78 ꢁC, 90 min), cinnamaldehyde (2a,
530 mg, 3.98 mmol) was added, and the resulting mixture
stirred for 90 min at ꢀ78 ꢁC. Then a saturated, aqueous
NH4Cl-solution (20 ml) was added, the layers were sepa-
rated, and the aqueous phase extracted with CH2Cl2
(20 ml). The combined organic layers were dried (MgSO4),
filtered and the solvent stripped off. The residue was
chromatographed (SiO2, hexanes/EtOAc 2:1, Rf = 0.50) to
yield the title compound 3e (642 mg, 2.38 mmol, 66%) as
light yellow crystals, mp 64–66 ꢁC. 1H NMR (250 MHz,
CDCl3): d = 2.82 (br s, 1H, OH), 5.29 (d, J = 5.6 Hz, 1H, 3-
H), 6.36 (dd, J = 15.8, 6.0 Hz, 1H, 4-H), 6.81 (t, J = 8.2 Hz,
1H, Ar–H), 6.83 (d, J = 15.6 Hz, 1H, 5-H), 6.84 (d,
J = 1.9 Hz, 1H, Ar–H), 7.21–7.45 (m, 6H, Ar–H) ppm.
13C{1H} NMR (62 MHz, CDCl3): d = 63.41 (s, CH, C-4),
3J = 10.0 Hz, J = 1.7 Hz, CH, C-60), 149.33 (s, CH),
164.35 (d, 1J = 256.7 Hz, C, C–F), 164.45 (d, 1J =
256.7 Hz, C, C–F), 177.91 (s, C@O, C-3) ppm. IR (ATR):
kꢀ1 = 2215 (m), 1632 (m), 1604 (m), 1496 (m), 1446 (w),
1425 (w), 1317 (m), 1267 (m), 1224 (m), 1174 (m), 1139 (w),
1093 (m), 1000 (w), 973 (m), 963 (m), 847 (m), 756 (m)
cmꢀ1. MS (EI, 70 eV): m/z (%) = 267 (100) [M+ꢀH], 249
(55), 239 (59), 220 (17), 165 (45), 137 (14), 102 (33), 77 (21),
51 (5). Anal. Calcd for C17H10F2O (268.26): C, 76.11; H,
3.76. Found: C, 76.01; H, 3.83.
8. Representative experimental procedure, 6-(2,4-difluorophen-
yl)-2,3-dihydro-2-phenylthiopyran-4-one (5e): NaHSÆ9H2O
(194 mg, 0.76 mmol) was added to a solution of ketone 4e
(100 mg, 0.37 mmol) in 2-ME (13 ml). The mixture was
stirred for 3 h at 55 ꢁC, then washed with a saturated,
aqueous solution of NH4Cl (40 ml). The organic layer was
extracted with EtOAc (3 · 25 ml), and the combined
organic phases dried (MgSO4). After filtration, the solvent
was stripped off, and the residue purified by chromatogra-
phy (SiO2, hexanes/EtOAc 2:1, Rf = 0.56) to yield the title
2
78.88 (s, C, C-2), 93.03 (s, C, C-1), 104.31 (t, J = 25.8 Hz,
2
4
CH, C-30), 107.40 (dd, J = 15.9 Hz, J = 4.0 Hz, C, C-10),
111.63 (dd, 2J = 21.9 Hz, 4J = 3.8 Hz, CH, C-50), 126.91 (s,
2CH), 127.62 (s, CH), 128.23 (s, CH), 128.67 (s, 2CH),
1
compound 5e (74 mg, 0.24 mmol, 65%) as a brown oil. H
3
3
132.37 (s, CH), 134.53 (dd, J = 9.7 Hz, J = 2.6 Hz, CH,
NMR (500 MHz, CDCl3): d = 2.99 (dd, J = 16.4, 3.3 Hz,
1H, 3-H), 3.18 (dd, J = 16.4, 13.9 Hz, 1H, 3-H), 4.78 (dd,
J = 13.9, 3.3 Hz, 1H, 2-H), 6.48 (d, J = 1.6 Hz, 1H, 5-H),
6.86–6.97 (m, 2H, Ar–H), 7.33–7.45 (m, 5H, Ar–H), 7.51–
7.60 (m, 1H, Ar–H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): d = 44.01 (s, CH2, C-3), 47.14 (s, CH, C-2),
1
3
C-60), 136.05 (s, C), 162.91 (dd, J = 252 Hz, J = 11.3 Hz,
C, C–F), 163.19 (dd, 1J = 266 Hz, 3J = 10.9 Hz, C, C–F)
ppm. IR (ATR): kꢀ1 = 3298 (w, br), 1649 (w), 1610 (w),
1587 (w), 1502 (m), 1424 (m), 1322 (w), 1294 (w), 1267 (m),
1217 (m), 1140 (m), 1101 (m), 1075 (w), 1057 (w), 1007 (m),
964 (m), 891 (w), 852 (m), 819 (m), 754 (m) cmꢀ1. MS (EI,
70 eV): m/z (%) = 270 (100) [M+], 251 (46), 220 (30), 193
(8), 165 (76), 151 (19), 138 (48), 127 (52), 104 (55), 91 (43),
77 (30). Anal. Calcd for C17H12F2O (270.28): C, 75.55; H,
4.47. Found: C, 75.54; H, 4.48.
105.07 (t, J = 26.0 Hz, CH, C-30), 111.90 (dd, 2J =
2
4
21.6 Hz, J = 4.1 Hz, CH, C-50), 121.42 (dd, J = 13.4,
4
4.9 Hz, C, C-10), 124.56 (d, J = 5.1 Hz, CH, C-5), 127.58
(s, 2CH), 128.75 (s, CH), 129.12 (s, 2CH), 131.21 (dd,
3J = 9.9 Hz, J = 3.4 Hz, CH, C-60), 137.46 (s, C), 153.01
3
7. Representative experimental procedure (E)-1-(2,4-difluoro-
phenyl)-3-oxo-5-phenyl-4-penten-1-yne (4e): MnO2 (2.9 g,
33 mmol) was portionwise added to a solution of alcohol
3e (450 mg, 1.66 mmol) in CH2Cl2 (15 ml). The suspension
was stirred for 30 min at 23 ꢁC, then filtered through
SiO2. The residue was washed several times with EtOAc
and the combined filtrates were evaporated to yield the
analytically pure title compound 4e (440 mg, 1.64 mmol,
99%) as a light yellow solid, mp 110–112 ꢁC. 1H NMR
(250 MHz, CDCl3): d = 6.86 (d, J = 16.1 Hz, 1H, 4-H ),
(d, 3J = 1.9 Hz, C, C-6), 159.75 (dd, 1J = 255.9 Hz, 3J =
1
3
12.4 Hz, C, C–F), 163.92 (dd, J = 254.1 Hz, J = 12.0 Hz,
C, C–F), 194.65 (s, C@O, C-4) ppm. IR (ATR): kꢀ1 = 3062
(w), 1650 (vs), 1608 (s), 1558 (m), 1496 (s), 1453 (w), 1425
(m), 1264 (br s), 1143 (s), 1100 (s), 975 (m), 917 (w), 850
(m), 813 (w), 733 (m), 698 (m), 619 (w) cmꢀ1. MS (EI,
70 eV): m/z (%) = 302 (84) [M+], 274 (13), 225 (5), 198 (51),
170 (100), 126 (9), 104 (32), 91 (6), 77 (7), 28 (14). Anal.
Calcd for C17H12F2OS (302.34): C, 67.54; H, 4.00. Found:
C, 67.30; H, 4.09.