Organic Syntheses, Vol. 78, pp. 169-176
Checked by Jianming Cheng and William R. Roush.
1. Procedure
C. Diethyl [(phenylsulfonyl)methyl]phosphonate. A
1-L, three-necked, round-bottomed
flask, fitted with a
reflux condenser,
thermometer,
pressure-equalizing dropping funnel and equipped with a
large
magnetic stirring bar is charged with
300
mL of acetic acid and
75.0
g (0.29 mol) of diethyl [(phenylthio)methyl]phosphonate.
The dropping funnel is charged with
90 mL
of an aqueous hydrogen peroxide, solution (30%)
and the reaction mixture is heated under stirring to 50°C (internal temperature).
The
hydrogen peroxide solution is added slowly so that the internal
temperature does not rise above 80°C (
Caution: This very exothermic reaction
has an induction period!) (Note
7). The reaction
mixture is heated to 85°C for an additional 3 hr (Note
8), cooled
to room temperature, and transferred to a
4-L beaker. Ice (1000
g) and then a
concd sodium hydroxide
solution (10 M) is added until the solution is basic, pH
8-9 (
Caution: Exothermic reaction!) The reaction mixture
is transferred to a
separatory funnel, and the water phase
is extracted five times with
200-mL portions
of dichloromethane. The combined organic phase is
washed with
50-mL portions of aqueous sodium
hydrogen sulfite solution (10%) until no
oxidizing agent remains (Note
9), and then dried over
anhydrous magnesium sulfate. After
removal of the
magnesium sulfate by filtration, the solvents
are evaporated under reduced pressure using a
rotary evaporator.
Purification of the crude product by flash chromatography (5 × 30-cm column) using
1:1
diethyl ether-hexanes to elute the non-polar impurities followed
by
100% ethyl acetate
to elute the product provides
diethyl [(phenylsulfonyl)methyl]phosphonate
(
76.3 g,
90%) as colorless crystals,
mp 51°C (Note
10).
2. Notes
1.
Paraformaldehyde
(96%) was purchased from Fisher Scientific Company
and
thiophenol (99%)
was purchased from Sigma Chemical Company. Both reagents
were used as received.
2.
Chloromethyl phenyl sulfide
shows the following physical data:
1H
NMR (400 MHz, CDCl
3) δ: 4.96 (s, 2 H), 7.35 (m,
3 H), 7.51 (m, 2 H);
13C NMR (100 MHz, CDCl
3) δ: 51.0,
127.9, 129.2, 130.9, 133.2;
IR cm
−1: 1584,
1482, 1440, 1228; HRMS calcd for C
7H
735ClS (M
+)
157.9957, found 157.9953. Anal. Calcd for C
7H
7ClS:
C, 53.00; H, 4.45. Found: C, 52.97; H, 4.49.
Chloromethyl
phenyl sulfide is also commercially available (Aldrich Chemical
Company, Inc.).
3. Volatile
ethyl chloride
is formed during the reaction, which evaporates through the
reflux condenser
and is trapped in an
ethanol-filled safety bottle.
4.
Triethyl phosphite
was purchased from Aldrich Chemical Company, Inc.,
and used without further purification.
5.
Diethyl [(phenylthio)methyl]phosphonate
shows the following physical data:
1H
NMR (400 MHz, CDCl
3) δ: 1.27 (t, 6 H, J = 7.1), 3.19
(d, 2 H, J = 14.1), 4.14 (m, 4 H), 7.26 (m, 1 H),
7.30 (m, 2 H), 7.45 (m, 2 H);
13C NMR (100 MHz, CDCl
3) δ:
16.2, 28.4 (J = 48), 62.5, 126.6,
128.8, 129.4, 135.4; IR cm
−1: 2982, 1582, 1482,
1440, 1392, 1255; HRMS calcd for C
11H
17O
3PS (M
+)
260.0636, found 260.0630. Anal. Calcd for C
11H
17O
3PS:
C, 50.76; H, 6.58. Found: C, 50.49; H, 6.51.
6. If the product does not show the required purity, a second distillation
may be necessary.
7. The checkers used a
water bath as heat
source and did not observe a significant increase in reaction temperature during the
addition of
hydrogen peroxide.
8. The internal temperature may rise for a short time up to 100°C
on heating.
9. Commercially available
peroxide test
strips (Aldrich Chemical Company, Inc.) are used to
verify the presence of oxidizing agents.
10. The compound shows the following physical data: R
f
= 0.31 (0.25-mm silica gel on glass,
diethyl ether/
methanol,
20:1, (v/v);
1H
NMR (400 MHz, CDCl
3) δ: 1.29 (td, 6 H, J = 7.0, 0.5),
3.77 (d, 2 H, J = 16.7), 4.16 (m, 4 H), 7.58 (m, 2
H), 7.68 (m, 1 H), 8.00 (m, 2 H);
13C NMR (100 MHz, CDCl
3)
δ: 16.1, 53.7 (J = 38), 63.3, 128.2,
129.0, 134.0, 139.9; IR cm
−1: 2984, 1586, 1480,
1448, 1394, 1369, 1324, 1263,
1157; HRMS calcd for
C
11H
18O
5PS (M
+ +H) 292.0613,
found 293.0602. Anal. Calcd for C
11H
17O
5PS:
C, 45.20; H, 5.86. Found: C, 45.35; H, 6.13.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Diethyl [(phenylsulfonyl)methyl]phosphonate (
1) has
served in many procedures as a versatile intermediate in synthesis. Thus
1
has been used in alkylation reactions by reaction of appropriate electrophiles with
the metalated sulfone.
6 In
addition
1 may be used as the phosphonate component in Horner-Wadsworth-Emmons
olefination reactions.
7,8,9 The olefination
step can be carried out with high (E)-selectivity, as illustrated in the accompanying
procedure.
10 α,β-Unsaturated phenyl sulfones
are in general useful as Michael acceptors in reactions with a host of nucleophilic
partners. In contrast to unsaturated carbonyl compounds, competing addition to the
sulfone functionality cannot occur and the vinyl phenyl sulfone itself acts as a "two-carbon
acceptor," which is not available using carbonyl-type Michael acceptors.
5 Furthermore, unsaturated sulfones in which the sulfone is directly
attached to an alkenyl or alkynyl group undergo a range of cycloadditions including
[2+2], [3+2]
8 and [4+2]
9 processes. However, the sulfone is
rarely required in the final target molecule and so methods for removal of the sulfone
group have been developed.
5 Finally, α,β-unsaturated
sulfones are also an effective class of cysteine protease inhibitors.
11
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Diethyl [(phenylsulfonyl)methyl]phosphonate: Phosphonic
acid, [(phenylsulfonyl)methyl]-, diethyl ester (9); (56069-39-7)
Chloromethyl phenyl sulfide: Sulfide, chloromethyl
phenyl (8); Benzene, [(chloromethyl)thio]- (9); (7205-91-6)
Paraformaldehyde (9); (30525-89-4)
Thiophenol: Aldrich: Benzethiol
(8,9); (108-98-5)
Diethyl [(phenylthio)methyl]phosphonate: Phosphonic
acid, [(phenylthio)methyl]-, diethyl ester (9); (38066-16-9)
Triethyl phosphite: Phosphorous acid, triethyl
ester (8,9); (122-52-1)
Hydrogen peroxide (8,9); (7722-84-1)
Sodium hydrogen sulfite: Sulfurous acid,
monosodium salt (8,9); (7631-90-5)
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