Dihydropyran as a template for lactone synthesis

Article abstract of DOI:10.1080/00397910701557358

3,4-Dihydro-2H-pyran (DHP) was efficiently transformed into 4-thiophenyl-3,4-dihydro-2H-pyran. This intermediate was converted to the corresponding 1,3-O,S-allylic carbanion with t-butyllithium and selectively alkylated at the carbon α to the sulfur with

Full text of DOI:10.1080/00397910701557358

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Dihydropyran as a Template for Lactone
Synthesis
Matthew P. Brichacek a & Robert M. Carlson a
a Department of Chemistry and Biochemistry , University of Minnesota
Duluth , Duluth, Minnesota, USA
Published online: 05 Oct 2007.
To cite this article: Matthew P. Brichacek & Robert M. Carlson (2007) Dihydropyran as a Template for Lactone
Synthesis, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:20, 3541-3549, DOI: 10.1080/00397910701557358
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Synthetic Communicationsw, 37: 3541–3549, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557358
Dihydropyran as a Template for Lactone
Synthesis
Matthew P. Brichacek, and Robert M. Carlson
Department of Chemistry and Biochemistry, University of Minnesota
Duluth, Duluth, Minnesota, USA
Abstract: 3,4-Dihydro-2H-pyran (DHP) was efficiently transformed into 4-thiophenyl-
3,4-dihydro-2H-pyran. This intermediate was converted to the corresponding 1,3-O,S-
allylic carbanion with t-butyllithium and selectively alkylated at the carbon a to the
sulfur with alkyl halides, an epoxide, and an aldehyde. An one-pot oxidative elimin-
ation of the sulfur fragment using vanadium pentoxide generates the desired b-substi-
tuted a,b-unsaturated d-valero lactone.
b-Substituted a,b-unsaturated d-valero lactones represent potentially useful
intermediates and have a strong structural presence in natural products.
Therefore, they have been the target for new synthetic methods.[1–6] We
now report a new, straightforward approach to this lactone system using
3,4-dihydro-2H-pyran (DHP) as a readily available and inexpensive
template (Scheme 1). In our synthetic approach, the goal was to selectively
introduce a sulfide as a carbanion-stabilizing functionality at C-4 that could
be removed after an alkylation process.
The availability of the typical array of potential carbon electrophiles for
reaction with the resulting carbanion intermediate would ensure the desired
flexibility in structural design within the targeted family of unsaturated lactones.
The successful approach was to utilize dithiophenyldibutyl stannane for
the reported SN20 addition of thiophenoxide to allylic acetals.[6–8] The
requisite cyclic allylic acetal was prepared through an one-pot sequence of
bromoethoxylation of DHP and dehydrobromination (Table 1).[9–11]
Received in the USA March 30, 2007
Address correspondence to Robert M. Carlson, Department of Chemistry and
Biochemistry, University of Minnesota Duluth, 1039 University Drive, Duluth, MN
55812, USA. E-mail: rcarlson@d.umn.edu
3541

3542
M. P. Brichacek and R. M. Carlson
Scheme 1.
Table 1. NMR data: compound 2
NMR
(CDCI3)
Product
Data
2
1H NMR
d 6.1 (1H, m), 5.9 (1H, d), 5.0 (1H, s), 4.0
(1H, td), 3.9 (1H, m), 3.8 (1H, q), (1H, m),
2.3 (1H, m), 2.0 (1H, m), 1.3 (3H, t)
13C NMR
(75.5 MHz, CDCI3) d 129, 93, 63, 57, 25, 15
4-(Phenylthio)-3,4-dihydro-2H-pyran (Table 2) produced a 1,3-O,S-allylic
carbanion when treated with t-butyl lithium (Scheme 2). Alkylation of the
allylic carbanion occurred selectively a to the sulfur[12] at C-4 (Table 2).
Using a mixture of vanadium pentoxide and hydrogen peroxide for
oxidative elimination,[13] the desired b-substituted a,b-unsaturated
d-lactones[5] were generated in satisfactory yields (Scheme 2, Tables 3 and 4).
Table 2. NMR data: compound 3
NMR
(CDCI3)
Product
Data
3
1H NMR
d 7.4 (2H, m) 7.3 (3H, m), 6.5 (1H, d), 4.9 (1H, m), 4.2
(2H, td), (1H, m), 3.9 (1H, m), 2.2 (1H, m), 1.9 (1H, d)
(75.5 MHz, CDCI3) d 146, 135, 131, 129, 127, 100, 62,
38, 26
13C NMR
Scheme 2.

Table 3. Results of electrophilic additions to 1,3-O,S-allylic carbanion
Strating material Electrophile Product Yield (%) Rx time (min)
NMR (CDCI3)
1H NMR
Data
CH3I
4a
88
5
d 7.5 (2H, m) 7.3 (3H, m), 6.4 (1H, d),
4.7 (1H, d), 4.3 (1H, td), 4.0 (1H, m),
2.0 (1H, m), 1.3 (3H, s)
13C NMR
1H NMR
d 145, 138, 133, 130, 129, 108, 64, 45,
36, 30
n-BuBr
4b
4c
96
90
10
60
d 7.5 (2H, m) 7.3 (3H, m), 6.4 (1H, d),
4.6 (1H, d), 4.3 (1H, m), 4.0 (1H, m),
1.9 (2H, m), 1.5 (4H, m) 1.5(4H, m)
1.3 (2H, m), 0.9 (3H, t)
13C NMR
1H NMR
d 145, 138, 131, 130, 129, 106, 107, 64,
49, 41, 34, 27, 24, 15
d 7.5 (2H, m) 7.3 (3H, m), 6.4 (1H, d)
4.4 (1H, d), 4.3 (1H, td), 4.0 (1H, m),
2.2 (1H, td), 1.8 (2H, m), 1.1(3H, d),
1.0 (3H, d)
13C NMR
d 145, 138, 131, 130, 129, 106, 64, 55,
36, 31, 19, 18
(continued)

Table 3. Continued
Strating material
Electrophile
Product Yield (%) Rx time (min)
NMR (CDCI3)
1H NMR
Data
4d
95
5
d 7.6 (2H, m) 7.4 (3H, m), 6.4 (1H, d),
4.6 (1H, d), 4.4 (1H, td), 4.1 (1H, m),
3.5 (2H, m), 3.4 (1H, d), 3.3(1H, d)
2.1 (1H, td), 1.8 (1H, m), 1.2 (3H, t)
d 146, 138, 132, 130, 129, 104, 75, 67,
63, 49, 31, 16
13C NMR
4e
85
15
Two isomers
(1.1:1)1H NMR
d 7.6 (2H, m) 7.3 (3H, m), 6.5 & 6.3
(1H, d), 4.8 & 4.5 (1H, d), 4.4 (1H,
m), 4.2 (1H, m), 4.0 (1H, m) 3.2 & 3.1
(1H, borad s) 3.1 & 2.9 (1H, m) 2.1 &
2.0 (1H, m), 2.0 (1H, m) 1.9 & 1.8
(1H, m), 1.6 (1H, t), 1.2 & 1.1 (3H, d)
d 146, 145, 138, 131, 130, 129, (106,
105), (66, 65), (63, 62), (50, 49), (48,
47), (35, 34), (25, 24)
13C NMR
CH3CHO
4f
65
5
Two isomers
(1.1:1)1H NMR
d 7.5 (2H, m) 7.3 (3H, m), 6.5 & 6.4
(1H, d), 4.6 & 4.2 (1H, d), 4.5–4.4
(1H, m), 4.2 (1H, m), 3.6 (1H, m) 3.0
(1H, borad s) 2.3 & 2.0 (1H, td), 1.8
(1H, t), 1.2 & 1.1 (3H, d)
13C NMR
d 148, 145, 138, 131 130, 129, (103,
100), (70, 69), (64, 63), (57, 56), (29,
28), (17, 16)

Table 4. Result of oxidations to produce lactones
Starting material Lactone
Product Yield (%)
NMR (CDCI3)
1HNMR
Data
5a
47
d 5.8 (1H), 4.4 (2H, td), 2.4 (2H, td),
2.0 (3H, s)
d 157, 117, 67, 54, 29, 24
13CNMR
1HNMR
5b
52
d 5.7 (1H, s), 4.4 (2H, td), 2.4 (2H, t)
2.2 (2H, t) 1.5 (2H, m) 1.3 (2H, m)
0.9 (3H, t)
13CNMR
1HNMR
d 165, 162, 116, 66, 36, 29, 28, 22, 13
d 5.8 (1H, s) 4.4 (2H, td), 2.5 (1H, m),
2.4 (2H, t), 1.2 (3H, d), 1.1 (3H, d)
d 168, 166, 114, 67, 34, 26, 20
5c
50
54
13CNMR
5d
1HNMR
13CNMR
d 6.1 (1H, s), 4.4 (2H, t), 4.1 (2H, s),
3.5 (2H, q), 2.4 (2H, t), 1.3 (3H, m)
d 164, 159, 115, 95, 71, 66, 25, 15
5g
48
1HNMR
13CNMR
d 7.0 (1H, m), 6.0 (1H, m), 4.4 (2H, t),
2.3 (2H, m)
d 164, 146, 122, 67, 25

3546
M. P. Brichacek and R. M. Carlson
EXPERIMENTAL
One-Pot Synthesis of 2-Ethoxy-5,6-dihydro-2H-pyran (2)
3,4-Dihydro-2H-pyran (45.6 mL, 0.500 mol) was added to a three-necked
flask (1 L) containing absolute ethanol (400 mL). The solution was cooled
to 08C, and N-bromo succinimide (89.0 g, 0.50 mol) added over 3 h. The
resulting faint yellow solution was stirred for an additional 30 min at 08C.
Potassium hydroxide flakes (125 g, 2.0 mol) were added, and the solution
was stirred as it warmed to room temperature. The solution was then
refluxed until none of the initial bromoethoxy addition product could be
detected by GC-MS (10 h). The reaction mixture was filtered on a sintered-
glass funnel, extracted with diethyl ether (500 mL), and washed with water
(3 ꢀ 500 mL). The dried (anhydrous sodium sulfate) solution was filtered
and evaporated, and the 2-ethoxy-5,6-dihydro-2H-pyran was distilled (2,
152–1558C, atm, 33.3 g, 52% yield).
Synthesis of 4-(Phenylthio)-3,4-dihydro-2H-pyran (3)
To a solution of 2-ethoxy-5,6-dihydro-2H-pyran (2, 10 g, 0.078 mol) in
toluene (500 mL, 2808C, N2 atmosphere), Bu2Sn(SPh)2 in toluene
.
(24.1 mL, 1.62 M, 0.039 mol) was added. BF3 OEt2 (34.6 mL, 0.273 mol)
was added rapidly, and the solution was allowed to stir (2808C, 2 h).
Pyridine (22.1 mL, 0.273 mol) and NaOH (1 M, 50 mL, 0.10 mol) were
added, and the reaction mixture warmed to room temperature slowly over
3 h. The solution was filtered on a sintered-glass funnel and then washed
with 1 M NaOH (3 ꢀ 300 mL). The organic layer was dried with anhydrous
Na2SO4, and the solvent was removed in vacuo (98% yield). The product
was distilled (908C, 3 mm Hg) to yield 4-(phenylthio)-3,4-dihydro-2H-
pyran (3, 12.6 g, 84% yield).
Addition of Electrophiles to 4-Lithio-4-thiophenyl Pyran:
Preparation of 4-Methyl-4-thiophenyl Pyran (4a)
4-(Phenylthio)-3,4-dihydro-2H-pyran 3 (1.0 g, 0.0052 mol) was added to
anhydrous THF (25 mL) and HMPA (5 mL) at 2808C under an atmosphere
of N2. t-BuLi (3.37 mL, 1.7 M in hexane, 0.057 mol) was added dropwise
over 1 h. The solution turned dark and was allowed to stir for an additional
30 min at 280 8C. When methyl iodide (0.35 mL, 0.057 mol) was added
slowly, the solution turned light yellow. The reaction mixture was then
allowed to warm to room temperature over 1 h, extracted with ether
(2 ꢀ 25 mL), and washed several times with water. The organic layer was
dried with anhydrous Na2SO4, and the solvent was removed in vacuo (92%

Dihydropyran as a Template for Lactone Synthesis
3547
yield). The product was purified by column chromatography on silica (Fisher,
60–200 mesh, 85% petroleum ether–15% CH2Cl2) to yield 4-methyl-4-(phe-
nylthio)-3-4-dihydro-2H-pyran (4a, 0.94 g, 88% yield).
Oxidation and Elimination to Lactone (5a, Anhydromevalonolactone)
4-Methyl-4-(phenylthio)-3,4-dihydro-2H-pyran 4a (1 g, 0.0049 mol) was
added to methanol (25 mL). The solution was cooled to 08C, and HClO4
(70%, 0.25 mL, 0.0029 mol), was introduced. Vanadium pentoxide (0.089 g,
0.0005 mol) was added to a 08C hydrogen peroxide solution (35% in water,
1.61 mL, 0.0196 mol) and stirred until the V2O5 dissolved and produced a
red solution. The V2O5/hydrogen peroxide solution was added dropwise to
the reaction mixture containing the pyran. Stirring was maintained at ꢀ58C
until no starting material was lift, as monitored by thin-layer chromatography
(TLC). The solution was extracted with ethyl acetate (2 ꢀ 25 mL) and washed
with saturated sodium bicarbonate. The organic layer was dried, and the
solvent was removed in vacuo (5a, 0.26 g, 47% yield).
All new compounds (3, 4a–f, and 5c,d) exhibited high resolution mass
spectra (MAT95, Mass Spectral Services, Department of Chemistry,
UMTC) from samples of .90% purity by HPLC. All mass spectra were con-
sistent (+0.0005 amu) with the molecular weight of the proposed structures.
The NMR spectrum of 5 g was identical to one obtained from a commercially
available sample (Sigma-Aldrich), and the reported values for 5a and 5b
match those found in the literature.[3,5]
RESULTS AND DISCUSSION
4-(Thiophenyl)-3,4-dihydro-2H-pyran
Dithiophenyldibutyl stannane was produced from dibutyl tin oxide[6] and used
directly as a solution in toluene. The tin reagent was stable over several weeks
but reacted readily under the acidic conditions used for addition to the allylic
acetal. Using a rapid introduction of boron trifluoride etherate (3.5 equiv;
2808C) nearly eliminated the production of unwanted by-products. The
yield and purity of the addition products were improved when pyridine and
sodium hydroxide were added to the cold (2808C) reaction mixture before
it was allowed to come slowly to room temperature. Removal of the fine
precipitate of tin oxide was most effective if both the organic and aqueous
layer were filtered. A further filtration of tin oxide from the organic layer
may be necessary after additional washes with aqueous sodium hydroxide.
A final distillation of the product was necessary to obtain material of
suitable purity for anion generation.

3548
M. P. Brichacek and R. M. Carlson
Anion Generation and Subsequent Addition
Considerable effort at experimental optimization of the reaction conditions for
anion generation and subsequent addition resulted in the recommended use of
a THF/hexane solution of t-butyllithium in the presence of HMPA. Electro-
phile reactivity followed generally predictable patterns, with methyl iodide
reacting in a few minutes and n-butyl bromide, chloromethylethyl ether,
propylene oxide, and 2-bromopropane reacting more slowly but completely.
Benzyl bromide, benzaldehyde, and styrene oxide reactions were slow
(styrene oxide) or generated considerable by-products. Although an addition
product was observed with acetaldehyde, no addition was observed with
3-pentanone or cyclohexanone, presumably because the rate of addition is
slower than the removal of the proton a to the ketone carbonyl.
Purification of the addition products can be effectively accomplished by
column chromatography on silica (Fisher, 60–200 mesh, 85% petroleum
ether–15% methylene chloride). Under these conditions, the aldehyde and
epoxide addition products were transformed to the bicyclic acetals. A deacti-
vated alumina column (Fisher, 60–325 mesh, activity grade II) proved
effective (15% petroleum ether–85% methylene chloride) in avoiding
cyclization.
Conversion to the Unsaturated g-Lactone
Of the variety of methods that were evaluated for the generation of the desired
unsaturated lactones, the most satisfying protocol used hydrolytic conditions
(aqueous perchloric acid) in the presence of vanadium pentoxide and
hydrogen peroxide. Purification of the products could be accomplished by dis-
tillation, flash chromatography, or preparative-layer chromatography on silica
(E.M. Reagents, Kieselgel 60 –Preparative 254/366, short UV visualization
of the unsaturated lactone).
CONCLUSION
A set of experimental protocols has now resulted in an attractive process for
the generation of b-substituted a,b-unsaturated d-valero lactones with
varying functionality at the b-position, using DHP as an inexpensive
synthetic template.
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Dihydropyran as a Template for Lactone Synthesis
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