Simple and efficient preparation of reagents for thiopyran introduction: Methyl tetrahydro-4-oxo-2H-thiopyran-3-carboxylate, tetrahydro-4H-thiopyran-4- one, and 3,6-dihydro-4-trimethylsilyloxy-2H-thiopyran

Article abstract of DOI:10.1055/s-2007-965954

Tetrahydro-4H-thiopyran-4-one was prepared in >75% yield by treatment of dimethyl 3,3′-thiobispropanoate with NaOMe (generated in situ) in THF solution and decarboxylation of the resulting methyl tetrahydro-4-oxo-2H- thiopyran-3-carboxylate in refluxing 10% aqueous H₂SO₄. Reaction of tetrahydro-4H-thiopyran-4-one with Me₃SiCl and Et ₃N in CHCl₃ gave the corresponding trimethylsilyl enol ether in near quantitative yield. The prepared reagents are useful for the synthesis of thiopyran-containing compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965954

1584
PRACTICAL SYNTHETIC PROCEDURES
Simple and Efficient Preparation of Reagents for Thiopyran Introduction:
Methyl Tetrahydro-4-oxo-2H-thiopyran-3-carboxylate, Tetrahydro-4H-thio-
pyran-4-one, and 3,6-Dihydro-4-trimethylsilyloxy-2H-thiopyran
Synthesisof
T
etrah
a
ydro-4
H
-th
l
iopyra
e
n-4-one and Cong
E
eners . Ward,* M. Abdul Rasheed, H. Martin Gillis, Garrison E. Beye, Vishal Jheengut, George T. Achonduh
Department of Chemistry, University of Saskatchewan, 110 Science Place,
Saskatoon, SK, S7N 5C9, Canada
Fax +1(306)9664730; E-mail: dale.ward@usask.ca
PSP
Received 4 October 2006; revised 22 January 2007
No83
Abstract: Tetrahydro-4H-thiopyran-4-one was prepared in >75% yield by treatment of dimethyl 3,3¢-thiobispropanoate with NaOMe (gen-
erated in situ) in THF solution and decarboxylation of the resulting methyl tetrahydro-4-oxo-2H-thiopyran-3-carboxylate in refluxing 10%
aqueous H2SO4. Reaction of tetrahydro-4H-thiopyran-4-one with Me3SiCl and Et3N in CHCl3 gave the corresponding trimethylsilyl enol
ether in near quantitative yield. The prepared reagents are useful for the synthesis of thiopyran-containing compounds.
Key words: tetrahydro-4H-thiopyran-4-one, 4-thianone, heterocyclic ketone, Dieckmann cyclization, thiopyran synthesis
O
O
OSiMe3
O
NaOMe, THF
r.t., 2–4 h
10% H2SO4
reflux, 1 h
Me3SiCl, Et3N
CHCl3, r.t., 3–4 d
O
O
OMe
OMe
MeO
S
S
S
S
1
2
3
4
Scheme 1
Cyclic sulfides are an important class of compounds with reactions on much smaller scale (<0.1 mol) and the report-
numerous applications in many areas of chemistry.1 In ed yields vary widely (13–81%; most around 75%). The
particular, thiopyran-derived scaffolds have been exploit- importance of the quality of the NaOMe used has been
ed in diverse ways.2 The synthesis of such targets often in- noted9a and it is likely that the diester 1 is susceptible to
volves the elaboration of simple thiopyran-containing hydrolysis by small amounts of NaOH. It is known that
reagents such as 2–4.3 Of these, only tetrahydro-4H-thio- the reaction is accompanied by some cleavage of the sul-
pyran-4-one (3) is commercially available, albeit at a sig- fide linkage in 1, especially at higher temperatures, result-
nificant cost.4 We have been investigating aldol reactions ing in the formation of methyl 3-methoxypropionate,
of 3 for the rapid assembly of stereochemically diverse methyl 3-mercaptopropionate, and hydrogen sulfide.9a
polypropionate synthons and required large amounts of 2 Our experiments indicate that 2 readily decomposes under
and 3 for this purpose.5 Herein we report simple and cost- basic conditions in protic solution, perhaps contributing to
efficient procedures for the preparation of 2, 3, and 4 the high variation in the reported yields.
(Scheme 1).
We previously reported a simplified procedure for the
Several methods for the synthesis of 3 are known,3,6–9 conversion of 1 into 2 (2 equiv of NaOMe in Et2O–THF;
most commonly by the decarboxylation of 2.7–9 The b- 93 5% on 0.5 mol scale).5b Subsequently, we optimized
keto ester 2 is also a versatile reagent for synthesis of thi- several reaction parameters and have now developed a
opyran-containing compounds and numerous reports on very robust, scalable, and cost-effective procedure. The
its preparation by Dieckmann cyclization of 110 or an anal- amount of NaOMe used can be reduced to 1.3
ogous diester have been published.7,8,11 Most of these equivalents12 and its quality is easily controlled with in
methods involve the use of NaOMe or NaH in various situ generation by addition of anhydrous methanol to a
modifications of Fehnel and Carmack’s improvement of suspension of Na metal in THF. Addition of 1 to the re-
the original procedure by Bennet and Scorah.7 Compared sulting NaOMe/THF mixture results in complete conver-
to the Fehnel and Carmack protocol (2 equiv of ‘alcohol- sion to 2 in 2–4 hours at room temperature. The use of
free’ NaOMe in refluxing diethyl ether; 64% yield of 2 on THF as solvent (compared to diethyl ether or benzene) is
1.4 mol scale), the modified procedures typically describe highly advantageous because it gives a homogenous reac-
tion mixture, permits higher reaction concentrations (2.5
M in 1), and results in shorter reaction times. Neutraliza-
SYNTHESIS 2007, No. 10, pp 1584–1586
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965954; Art ID: M06106SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
tion of the cold reaction mixture followed by standard
aqueous work-up affords 2 in high yield (ca. 95%)
(Scheme 1). On larger scales (>100 g of 1) the above

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Tetrahydro-4H-thiopyran-4-one and Congeners
1585
work-up involves processing a considerable amount of alents of Me3SiCl to give 4 in near quantitative yield
solvent. More conveniently, the reaction mixture can be (Scheme 1).
quenched by addition of 50% H2SO4 (1.0 equiv of H+ with
respect to Na); simple filtration of the precipitated Na2SO4
hydrate and concentration gives 2 in 92–98% yield (0.1–
0.6 kg scale).
In summary, we have developed scalable, efficient, and
cost-effective procedures for the preparation of 2, 3, and 4
from the commercially available and inexpensive 1.10 In
view of already widespread use of 3 and its derivatives in
The decarboxylation of 2 to give 3 can be achieved under synthesis, these procedures should facilitate additional ap-
basic conditions or more efficiently by refluxing in aque- plications.
ous H2SO4.7a Several closely related procedures have ap-
peared with reported yields varying from 60–91%.7,8
Anhydrous solvents were distilled under argon as follows: THF
Similarly, a number of ‘one-pot’ procedures (NaOMe
then H2SO4) for preparation of 3 from 1 without isolation
of the intermediate 2 have been described (39–58% over-
all yield).9 In many of the reported procedures, the yields
obtained represent ‘crude’ 3 of uncertain purity; ‘pure’ 3
(the mp reported varies from 58–60 to 65–67 °C) has been
obtained by sublimation6a or recrystallization.7a,8a–d,9c We
were unable to obtain good yields of pure 3 using any of
the above procedures. The ketone 3 is quite volatile7a and
readily sublimes even on a rotary evaporator (especially
on heating). Also, the solubility of 3 in water is surprising-
ly high and the usual work up procedures involving aque-
ous washes necessarily reduce the yield. In control
experiments, we established that 3 decomposes to uniden-
tified products in refluxing aqueous H2SO4 at the rate of
ca. 2–3% per hour and these products are not effectively
removed by washing with aqueous base. Moreover, the
decarboxylation of 2 in refluxing aqueous H2SO4 is much
slower in the presence of Na2SO4 (i.e., as in the ‘one-pot’
procedures) or at higher concentrations (perhaps due to
the limited solubility of 2 in water) and these slower de-
carboxylations produce a significantly greater amount of
yellow oily by-products that complicate the purification
of 3. These results can help to explain the wide range in
the yield of 3 obtained by various researchers.
from benzophenone sodium ketyl and MeOH from Mg(OMe)2. Re-
agent grade CHCl3 was passed through basic alumina prior to use;
Et3N and Me3SiCl were distilled from CaH2 and Bu3N, respectively.
All other reagents and solvents were commercially available and
unless otherwise noted, were used as received. Concentration refers
to removal of volatiles at water aspirator pressure on a rotary evap-
orator with the final traces of solvent removed at high vacuum (ca.
0.7 mbar). All reported compounds were homogenous by thin-layer
chromatography (TLC) and 1H NMR spectra.
Methyl Tetrahydro-4-oxo-2H-thiopyran-3-carboxylate (2)
Anhyd MeOH (41 mL, 32 g, 1.0 mol) was added via a dropping fun-
nel over 30 min to a stirred suspension of Na metal (21.7 g, 0.95
mol)15 in THF (300 mL) at 0 °C (ice bath) under argon (Caution!
H2 evolution). The ice bath was removed and stirring continued at
r.t. for 15–20 h, at which point most of the Na was consumed (ca.
90%)15 leaving a grayish-white mixture of NaOMe in THF. The
mixture was cooled in an ice bath and the diester 1 (150 g, 0.728
mol) was added via a dropping funnel over 1 h (the dropping funnel
was rinsed with 15 mL of THF). The ice bath was removed and the
mixture, initially a thick slurry, became a homogeneous amber so-
lution.16 After stirring for 3 h at r.t., the reaction was complete by
TLC analysis (30% EtOAc in hexane). The mixture was transferred
to a beaker equipped with a mechanical stirrer and cooled in an ice
bath. Aq H2SO4 (0.475 mol; prepared by adding 47.5 g of 98%
H2SO4 to ca. 45 g of ice) was added slowly with stirring maintaining
the temperature below 20 °C; the final pH was 6–7. To the resulting
creamy yellow mixture, CH2Cl2 (400 mL) was added after which
the Na2SO4 hydrate precipitated as granules that readily settle, leav-
ing a pale yellow solution; occasionally, a small amount of H2O (2–
10 mL) must be added to achieve the desired consistency. Na2SO4
(20 g) and solid NaHCO3 (21 g) were added with stirring and after
30 min, the supernatant was filtered through cotton wool and the
residue was washed with CH2Cl2 (200 mL). The combined filtrate
and washings were concentrated to give the titled compound as a
pale yellow oil (stench!); yield: 124.5 g (98%); >95% purity17 by
NMR. The oil solidified (keto form) on standing for several days at
5 °C.
We have found that adding 2 to ten times its mass of re-
fluxing 10% aqueous H2SO4 leads to complete transfor-
mation to 3 within one hour. The remarkable water
solubility of 3 provides a simple purification method. On
cooling, a yellow oil separates from the reaction mixture
and the oil is washed with warm water. The dichloro-
methane extracts of the combined aqueous layers are di-
rectly passed through a short pad of basic alumina (to
remove the polar by-products) and concentrated to give
white crystalline 3 of high purity in 76–80% yield (50–
200 g scale) (Scheme 1).
IR (diffuse reflectance): 3100 (br), 1745, 1720, 1658, 1617 cm–1.
1H NMR (500 MHz, CDCl3): d (for the enol tautomer) = 12.5 (s, 1
H), 3.79 (s, 3 H), 3.36 (s, 2 H), 2.80 (app t, J = 5.5 Hz, 2 H), 2.60
Trialkylsilyl enol ethers of 3, particularly 4, are also use- (app t, J = 5.5 Hz, 2 H); d (for the keto tautomer) = 3.80 (s, 3 H),
ful reagents.5b,13 These compounds have been prepared
3.70 (dd, J = 4, 8.5 Hz, 1 H), 3.31 (dd, J = 8.5, 14 Hz, 1 H), 3.06 (dd,
J = 4, 14 Hz, 1 H), 2.99–2.94 (m, 2 H), 2.91–2.85 (m, 1 H), 2.77–
2.72 (m, 1 H).
13C NMR (125 MHz, CDCl3): d (for the enol tautomer) = 172.0,
169.3, 97.4, 51.9, 30.9, 24.6, 23.4; d (for the keto tautomer) = 203.7,
172.6, 58.7, 52.7, 43.7, 32.6, 30.5.
HRMS-EI: m/z [M+] calcd for C7H10O3S: 174.0351; found:
174.0348.
from 3 in yields of ca. 80% using the method of House et
al.14 (e.g., from reaction of the LDA-generated lithium
enolate with Me3SiCl).13 We reported that 4 can be pre-
pared in 95% yield by reaction of 3 with Me3SiCl and
Et3N in CH2Cl2.5b The long reaction time (10 d) and large
excess of reagents (5 equiv of Me3SiCl) required in that
procedure are disadvantages, especially on large scale.
We have found that the reaction is considerably faster in
CHCl3 and goes to completion in 3–4 days with 1.5 equiv-
Tetrahydro-4H-thiopyran-4-one (3)
Keto ester 2 (100 g, 0.57 mol) was added via a dropping funnel over
3–5 min to a well-stirred solution of 10% aq H2SO4 (1 L) heated un-
Synthesis 2007, No. 10, 1584–1586 © Thieme Stuttgart · New York

1586
D. E. Ward et al.
PRACTICAL SYNTHETIC PROCEDURES
der reflux. After ca. 1 h, the reaction was complete by TLC analysis
(30% EtOAc in hexane) and the mixture was cooled to 40 °C with
the aid of an ice bath. The aqueous layer was decanted from a yel-
low oil that separated and settled. The yellow oil was washed with
H2O (500 mL) at 40 °C and the combined aqueous layers were ex-
tracted with CH2Cl2 (3 × 200 mL) with each extract passed through
a column of basic Al2O3 (Brockmann I, ca. 150 mesh; 200 g). The
column was finally eluted with CH2Cl2 (600 mL) and the combined
eluates were concentrated and then reconcentrated from hexane to
give the titled compound as a white, freely flowing, crystalline solid
(52 g, 78%); mp 59–60 °C.
IR (diffuse reflectance): 1704 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.99–2.94 (m, 4 H), 2.72–2.68 (m,
4 H).
13C NMR (125 MHz, CDCl3): d = 210.0, 44.7, 30.6.
HRMS-EI: m/z [M+] calcd for C5H8OS: 116.0296; found: 116.0293.
(5) (a) Ward, D. E.; Guo, C.; Sasmal, P. K.; Man, C. C.; Sales,
M. Org. Lett. 2000, 2, 1325. (b) Ward, D. E.; Sales, M.;
Man, C. C.; Shen, J.; Sasmal, P. K.; Guo, C. J. Org. Chem.
2002, 67, 1618. (c) Ward, D. E.; Jheengut, V.; Akinnusi, O.
T. Org. Lett. 2005, 7, 1181. (d) Ward, D. E.; Gillis, H. M.;
Akinnusi, O. T.; Rasheed, M. A.; Saravanan, K.; Sasmal, P.
K. Org. Lett. 2006, 8, 2631.
(6) From N-methyl-4-piperidone: (a) Johnson, P. Y.; Berchtold,
G. A. J. Org. Chem. 1970, 35, 584. (b) Unkovskii, B. V.;
Psal’ti, F. I. Khim. Geterotsikl. Soedin., Sb. 1970, 2, 174;
Chem. Abstr. 1972, 77, 114188. (c) Garst, M. E.; McBride,
B. J.; Johnson, A. T. J. Org. Chem. 1983, 48, 8. From 1,5-
dibromo-3-pentanone: (d) Sviridov, S. V.; Vasilevskii, D.
A.; Kulinkovich, O. G. Zh. Org. Khim. 1991, 27, 1431.
(7) (a) Bennett, G. M.; Scorah, L. V. D. J. Chem. Soc. 1927,
194. (b) Fehnel, E. A.; Carmack, M. J. Am. Chem. Soc. 1948,
70, 1813.
(8) (a) Naylor, R. F. J. Chem. Soc. 1949, 2749. (b) Onesta, R.;
Castelfranchi, G. Gazz. Chim. Ital. 1959, 89, 1127.
(c) Casy, G.; Sutherland, A. G.; Taylor, R. J. K.; Urben, P.
G. Synthesis 1989, 767. (d) Rule, N. G.; Detty, M. R.;
Kaeding, J. E.; Sinicropi, J. A. J. Org. Chem. 1995, 60,
1665. (e) Matsuyama, H.; Miyazawa, Y.; Takei, Y.;
Kobayashi, M. J. Org. Chem. 1987, 52, 1703.
(f) Chowdhury, A. Z. M. S.; Khandker, M. M. R.; Bhuiyan,
M. M. H.; Hossain, M. K. Pak. J. Sci. Ind. Res. 2001, 44, 63.
(9) (a) Barkenbus, C.; Midkiff, V. C.; Newman, R. M. J. Org.
Chem. 1951, 16, 232. (b) Traverso, G. Chem. Ber. 1958, 91,
1224. (c) Parham, W. E.; Christensen, L.; Groen, S. H.;
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K.; Suginose, R.; Kashiwagi, K. Japanese Patent 99198350,
1999; Chem. Abstr. 2001, 134: 131428.
(10) (a) Commercially available (e.g., Aldrich Chemical Co.,
2005–2006: Cdn $70/L) or readily prepared from methyl
acrylate and H2S: Gershbein, L. L.; Hurd, C. D. J. Am. Chem.
Soc. 1947, 69, 241. (b) See also ref. 8e.
(11) (a) Kashiwagi, T.; Murakami, M.; Isaka, I.; Ozasa, T.
Japanese Patent 74 108119, 1974; Chem. Abstr. 1976, 85:
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(f) Ghosh, A. K.; Liu, W. J. Org. Chem. 1995, 60, 6198.
(g) Conroy, J. L.; Sanders, T. C.; Seto, C. T. J. Am. Chem.
Soc. 1997, 119, 4285. (h) Li, C.-J.; Chen, D.-L. Synlett
1999, 735.
3,6-Dihydro-4-trimethylsilyloxy-2H-thiopyran (4)
Et3N (27.8 mL, 20.2 g, 0.20 mol) and Me3SiCl (19.2 mL, 16.3 g,
0.15 mol) were sequentially added to a stirred solution of 3 (11.6 g,
0.10 mol) in CHCl3 (116 mL) under argon and the mixture was al-
lowed to stand in the dark at r.t. in a well-stoppered flask. The reac-
1
tion progress was monitored by H NMR (a small sample was
withdrawn and processed as described below) and when complete
(3–4 d), the mixture was concentrated, diluted with hexane (200
mL), and filtered through Celite. The combined filtrate and hexane
washings were concentrated to give 3 as yellow oil (18.4 g, 98%
1
yield) that was homogenous by H NMR spectrum and was used
without further purification. The material slowly decomposed
(mainly by hydrolysis) upon storage under argon even at –15 °C. If
not used promptly, a convenient method5b of storage involves mak-
ing a solution of known concentration in benzene (ca. 1 M) contain-
ing Et3N (2 equiv). This solution can be stored for at least three
months at –15 °C with negligible decomposition. The product is re-
covered as required by concentrating aliquots.
1H NMR (300 MHz, CDCl3): d = 5.06–5.04 (m, 1 H), 3.15–3.14 (m,
2 H), 2.76–2.72 (m, 2 H), 2.27–2.23 (m, 2 H), 0.17 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 151.3, 102.2, 31.2, 25.7, 25.1, 0.3.
HRMS-EI: m/z [M+] calcd for C8H16OSSi: 188.0708; found:
188.0705.
Acknowledgment
(12) A reaction using 1.1 equiv of NaOMe did not go to
Authors thank the Natural Sciences and Engineering Research
Council (Canada) and the University of Saskatchewan for financial
support.
completion within 5 h (ca. 90% conversion).
(13) (a) Aoki, S.; Fujimura, T.; Nakamura, E. J. Am. Chem. Soc.
1992, 114, 2985. (b) Evans, P. A.; Modi, D. P. J. Org. Chem.
1995, 60, 6662. (c) Biondi, S.; Piga, E.; Rossi, T.; Vigelli, G.
Bioorg. Med. Chem. Lett. 1997, 7, 2061. (d) Karisalmi, K.;
Rissanen, K.; Koskinen, A. M. P. Org. Biomol. Chem. 2003,
1, 3193. (e) Karisalmi, K.; Koskinen, A. M. P.; Nissinen,
M.; Rissanen, K. Tetrahedron 2003, 59, 1421.
References
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(2) For an overview and list of references, see: (a) Samuel, R.;
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(3) Review: Vartanyan, R. S. Arm. Khim. Zh. 1985, 38, 166.
(4) Aldrich Chemical Co., 2005–2006: Cdn $174/5 g of 3. Using
the procedure described herein, we estimate the cost of
materials (solvents, reagents and other materials) for the
preparation of 3 to be ca. $1/g (50 g scale).
(14) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org.
Chem. 1969, 34, 2324.
(15) Na metal was cut into pieces weighing ca. 50–100 mg (3–5
mm per side). The rate of Na consumption depends on the
size of pieces; with larger pieces, more time is required to
reach 90% conversion.
(16) A few specks of Na metal may remain at this point.
(17) The presence of small amounts of 1 (<1%) and its
corresponding half-acid (1–2%) were detected by 13C NMR
and confirmed by spiking with authentic samples.
Synthesis 2007, No. 10, 1584–1586 © Thieme Stuttgart · New York