2
678
Synthesis
B. Bennua-Skalmowski, H. Vorbrueggen
Paper
Oxidation of 5 with Oxone in water afforded the crystal-
line and chemically stable sulfone 11 in 68% yield, whereas
From 2 by Reaction with the S-Oxide 9: Me S (6; 8.87 mL, 100 mmol)
2
2
in CH Cl (50 mL) was cooled to 0 °C and a suspension of 80% m-chlo-
2
2
roperbenzoic acid (21.56 g, 100 mmol) in CH Cl (200 mL) was added
reaction of 5 with aqueous NaIO furnished 76% of the race-
2
2
4
within 1 h with stirring. After 5 h additional reaction time at 0 °C, the
suspension was filtered and the filtrate dried (Na SO ), and evaporat-
mic sulfoxide 12, which is readily oxidized in 47% yield by
2
4
NaOCl in H O–acetonitrile to the desired sulfone 11
2
ed to give 9.85 g crude S-oxide 9, which was distilled in a Kugelrohr
apparatus at 70–90 °C/12 mmHg; yield: 8.2 g (74%). To a solution of
the S-oxide 9 (1.32 g, 12 mmol) and dihydropyran (2; 1.83 mL, 20
mmol) in anhydrous CH Cl (25 mL) was added dropwise a solution of
(Scheme 2). The described exploring experiments are not as
yet optimized.
2
2
SO2Me
SMe
NaIO4, H2O
SOMe
trifluoroacetic acid anhydride (1.38 mL, 10 mmol) in CH Cl (5 mL) at
2 2
Oxone, H2O
r.t. with stirring while cooling in a water bath. After 2 h at r.t., a solu-
tion of DBU (3.22 mL, 22 mmol) in CH Cl (5 mL) was added to the
O
NaH2PO4
68%
O
5
76%
O
2
2
brown reaction mixture, whereupon the dark mixture turned to yel-
low. After keeping the reaction mixture for 2 d, it was shaken with
sat. aq NaHCO , dried (Na SO ), filtered, and evaporated. The crude
11
12
aq 10% NaOCl
aq 2 M NaOH
r.t., 47%
3
2
4
product (3.98 g) was distilled in a Kugelrohr apparatus at 80–90 °C/12
mmHg to give pure 5 as a colorless oil; yield: 0.99 g (38%).
12
5-(Methylsulfonyl)-3,4-dihydro-2H-pyran (11)
Scheme 2
By Oxidation of Sulfide 5: A solution of NaH PO (2.07 g 15 mmol) in
2
4
H O (10 mL) was diluted with MeOH (25 mL) and combined with a
The high biological potency of our prostacyclin(carba-
2
11
solution of KHSO
5
(6.45 g, 10.5 mmol) in H O (30 mL) and cooled to
2
cyclin) analogues iloprost and the even more potent cica-
0
°C. A solution of 5 (0.65 g, 5 mmol) in MeOH (15 mL) was added
12
prost caused us then to abandon the synthesis of further
dropwise with stirring within 1 h and the stirring was continued for 3
new prostacyclin analogues such as 1c and 1d.
h at 0 °C. After warming up to r.t. overnight, H O was added to the
2
mixture and extracted with CH Cl (5 × 100 mL). The combined ex-
2
2
tracts were dried (Na SO ), filtered, and evaporated to give crude 11
2
4
1
(0.55 g, 68%). On extraction of the crude product repeatedly with Et O
The H NMR spectra were measured in CDCl with a 90 MHz instru-
2
3
and concentration of the Et O, the sulfone 11 crystallized as colorless
ment. TLC was performed on glass plates precoated with silica gel.
2
crystals; yield: 0.45
g (28%); mp 76–77 °C; Rf = 0.34 (EtOAc–
MeOH, 8:2).
5
-(Methylthio)-3,4-dihydro-2H-pyran (5)
1
H NMR (90 MHz, CDCl ): δ = 7.48 (s, 1 H, =CH), 4.15 (t, J = 5 Hz, 2 H,
3
By Reaction of 2 with Dimethylmethylmercaptosulfonium Tetrafluoro-
borate: To a stirred solution of dimethylmethylmercaptosulfonium
tetrafluoroborate (3; 5.88 g, 30 mmol) in anhydrous MeCN (50 mL)
OCH ), 2.95 (s, 3 H, SCH ), 1.80–2.50 (2 m, 4 H, OCH CH CH ).
2
3
2
2
2
3
Anal. Calcd for C H O S (162.21): C, 44.43; H, 6.21; S, 19.77. Found C,
6 10 3
was added dropwise at –20 °C within 20 min a solution of dihydropy-
44.33; H, 6.10; S, 19.53.
ran (2; 1.83 mL, 20 mmol) in anhydrous MeCN (20 mL). The stirring at
By Oxidation of Sulfoxide 12: To a solution of aq 10% NaOCl (1.5 mL, 2
mmol) and aq 2 N NaOH (0.5 mL, 2 mmol) was added 5-(methyl-
sulfinyl)-3,4-dihydro-2H-pyran (12; 0.29 g, 2 mmol) and the mixture
stirred overnight at r.t. Then, a further amount of aq 10% NaOCl (1 mL)
was added and the mixture was kept again overnight, whereupon no
starting material 12 could be detected anymore by TLC (eluent:
EtOAc–MeOH, 8:2). After the addition of CH Cl (50 mL) and a small
–
20 °C was continued for 2.5 h and a solution of i-Pr NEt (4; 38 mmol,
2
6.6 mL) in MeCN (10 mL) was added within 20 min at –20 °C. After
removing the cooling bath, the mixture was warmed up to r.t. over-
night and the reaction mixture was diluted with CH Cl (25 mL) and
2
2
washed with H O (2 × 15 mL). After drying (Na SO ), filtration, and
2
2
4
removal of the solvent, the foul smelling residual oil (5.79 g) was dis-
tilled in a Kugelrohr apparatus at 80–90 °C/12 mmHg to give pure 5 as
2
2
amount of H O, the organic phase was dried (Na SO ), filtered, and
2
2
4
a colorless oil; yield: 1.49 g (57%); R = 0.68 (toluene–EtOAc, 5:1).
f
evaporated to give crude 11 (0.25 g), which was crystallized from Et O
2
1
H NMR (90 MHz, CDCl ): δ = 6.70 (s, 1 H, =CH), 3.95 [t, J = 5 Hz, 2 H,
to give pure 11 in two crops; yield: 0.15 g (47%); colorless crystals;
3
OCH ], 2.1 (s, 3 H, SCH ), 1.8–2.3 (m, 4 H, OCH CH CH ).
mp 76–77 °C.
2
3
2
2
2
Anal. Calcd for C H10OS (130.21): C, 55.35; H, 7.74; S, 24.63. Found:
C,55.25; H, 7.64; S, 24.16.
6
5-(Methylsulfinyl)-3,4-dihydro-2H-pyran (12)
To an ice cold stirred solution of 5 (2.6 g, 20 mmol) in MeOH (100 mL)
From 2 via the Chloride 8: To a cooled (–50 °C) solution Me S (6; 4.45
2
2
was added dropwise a solution of NaIO (4.28 g, 20 mmol) in H O (60
mL, 50 mmol) in anhydrous CH Cl (25 mL) was added a solution of
4
2
2
2
mL), whereupon the solution turned yellow and a colorless precipi-
tate formed. After stirring overnight at r.t., the mixture was filtered,
and the filtrate concentrated in vacuo. The residue was dissolved in
SO Cl (4.07 mL, 50 mmol) in anhydrous CH Cl (15 mL) with stirring
within 10 min. After further 5 min, a solution of dihydropyran (2;
2
2
2
2
9
–
.15 mL, 100 mmol) in CH Cl (20 mL) was added with stirring at
2 2
CH Cl (50 mL), dried (Na SO ), and evaporated to give the crude oily
50 °C. Subsequently, a solution of DBU (16.1 mL, 110 mmol) in CH Cl
2
2
2
4
2
2
racemic 12 (2.88 g). Distillation at 120 °C/600 mmHg afforded puri-
fied 12 as a colorless oil; yield: 2.23 g (76%).
(25 mL) was added at –50 °C. After warming up to r.t. overnight, the
mixture was washed with sat. aq NaHCO3 (2 × 25 mL), the organic
phase dried (Na SO ), filtered, and concentrated. Distillation of the
1
2
4
H NMR (90 MHz, CDCl ): δ = 7.50 (s, 1 H, =CH), 4.10 (t, J = 6 Hz, 2 H,
3
crude product in a Kugelrohr apparatus at 80–90 °C/12 mmHg afford-
OCH ), 2.90 (s, 3 H, SCH ), 1.80–2.50 (2 m, 4 H, OCH CH CH ).
2
3
2
2
2
ed 5 as a colorless oil; yield: 4 g (31%).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2677–2679