K. D. Otley et al.
Experimental
(1,1,2-2H3)Propane-1,2-diol (6b)
Lithium aluminum deuteride (2.5 g, 59.5 mmol) was suspended
in THF (50 mL) in a three-neck flask equipped with a pressure
equalizing addition funnel, a mechanical stirrer and a reflux
condenser and the mixture was cooled in an ice bath under
argon. A solution of ethyl pyruvate (5) (5.1 mL, 5.3 g, 45.6 mmol)
in THF (10 mL) was added dropwise to this mixture over a one
hour period. The reaction was warmed to room temperature
and then stirred for 24 h. The reaction was quenched by careful
addition of water (20 mL), 1 M sodium hydroxide (30 mL) and
water (40 mL). The resulting mixture was refluxed for 1 h. The
mixture was cooled to room temperature, diluted with THF
(90 mL) and filtered. The filtrate was dried over MgSO4 and the
General methods
Commercially available starting materials were purchased from
Acros or Aldrich unless otherwise specified. Anhydrous THF and
dichloromethane were obtained by passing solvents through a
pair of alumina columns under argon pressure using a PureSolv
MD-3 solvent purification system. NMR spectra were recorded at
298 K on a Bru¨ker Avance 500 Spectrometer using residual
solvent peaks as internal standards (CHCl3 at 7.26 ppm for 1H
and 77.0 ppm for 13C). Peaks in the 13C spectra for deuterium-
labeled carbons are given, with coupling information, only when
the peaks were clearly distinguishable from the baseline noise.
1
TLC was performed using Whatman silica gel plates (F254
,
solvent was removed to give a yellow oil (1.48 g, 41%). H NMR
(CDCl3, 500 MHz) d 3.56 (br s, 2H), 1.14 (s, 3H). 13C NMR (CDCl3,
125 MHz) d 67.7 (t, JC-D = 22 Hz), 66.9 (quintet, JC-D = 21 Hz), 18.5.
0.25 mm) and compounds were visualized using UV light at
254 nm or by charring with either 10% phosphomolybdic acid in
ethanol or vanillin with 1% H2SO4 in ethanol. Flash chromato-
˚
graphy was carried out using MP Silica 32-63, 60 A.
1-(Benzyloxy)(3,3,3-2H3)propan-2-ol (10)
2-Oxo(2H5)propyl 4-methylbenzenesulfonate (2)
A solution of d3-methylmagnesium iodide in THF (0.5M; 73.6mL,
36.8mmol) was added to a stirred solution of 2-benzyloxyace-
taldehyde (9) (4.60 g, 30.7mmol) in THF (77 mL) at 01C under
argon and the solution was stirred for 2 h. Saturated ammonium
chloride (10 mL) was added, the THF was removed under reduced
pressure and the mixture was partitioned between ether (140mL)
and saturated ammonium chloride (140mL). The organic layer
was washed with sat. NaCl (100mL), dried over MgSO4, and the
solvent was removed under reduced pressure to yield a clear,
colorless oil (3.86 g, 75%). 1H NMR (CDCl3, 500MHz) d 7.36 (m, 5H),
4.59 (s, 2H), 4.01 (br d, J = 7.7 Hz, 1H), 3.49 (dd, J = 9.4, 3.1 Hz, 1H),
3.32 (dd, J = 9.4, 8.1 Hz, 1H), 2.53 (s, 1H); 13C NMR (CDCl3, 125 MHz)
d 138.0, 128.4, 127.8, 127.7, 75.8, 73.3, 66.3.
[Hydroxy(tosyloxy)iodo]benzene (15.0 g, 38.2 mmol) was sus-
pended in acetonitrile (160 mL). The suspension was heated to
501C and acetone-d6 (5.1 mL, 4.4 g, 69.4 mmol) was added to the
hot mixture while the solution was stirred. The mixture was
refluxed for 30 min, cooled to room temperature and stirred for
10 additional minutes. The solvent was removed under reduced
pressure and the residue was dissolved in dichloromethane
(160 mL). The solution was washed with water (2 Â 100 mL) and
the organic layer was dried over MgSO4. The solvent was
removed under reduced pressure to yield the crude product
(12.7 g). The crude product was purified by flash chromato-
graphy on silica, eluting first with 10% EtOAc/hexanes to
remove the iodobenzene byproduct then with 100% EtOAc to
isolate the product. The solvent was removed under reduced
pressure to yield the purified product (7.45 g, 46% yield). 1H
NMR (CDCl3, 500MHz) d 7.82 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz,
2H), 2.47 (s, 3H). 13C NMR (CDCl3, 125 MHz) d 201.2, 145.5, 132.3,
1-(Benzyloxy)(3,3,3-2H3)propan-2-one (11)
DMSO (5.5 mL, 6.1 g, 78.1 mmol) was added dropwise, under
argon, to a solution of oxalyl chloride (3.3 mL, 5.0 g, 39.4 mmol)
in dichloromethane (175 mL) at À781C and the solution was
allowed to stir for 5 min. 1-(Benzyloxy)(3,3,3-2H3)propan-2-ol (10)
(3.26 g, 19.3 mmol) in dichloromethane (36 mL) was added and
the resulting solution was allowed to stir at À781C for 1 h.
Triethylamine (16.0 mL, 11.6 g, 114.6 mmol) was added to the
reaction mixture, which was warmed to room temperature and
stirred for 1 h. The reaction was then quenched with the slow
addition of saturated ammonium chloride solution (250 mL)
and the aqueous layer was extracted with dichloromethane
(3 Â 200 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure.
The crude product was purified via flash chromatography (20 %
ethyl acetate in hexanes) to yield the product as a clear, colorless
130.2, 128.0, 71.5 (quintet, JC-D = 23 Hz), 25.8 (septet, JC-D
20 Hz), 21.87.
=
2-Hydroxy(1,1,3,3,3-2H5)propyl 4-methylbenzenesulfonate (3a)
2-Oxo(2H5)propyl
4-methylbenzenesulfonate (2) (12.7 g,
54.4 mmol) was dissolved in methanol-d (25 mL) and the flask
was cooled in an ice bath. While the solution was stirred, sodium
borohydride (1.03 g, 27.2 mmol) was added slowly. Upon
completion of the addition, the solution was stirred at 01C for
5 min then the ice bath was removed and the solution was
stirred for an additional 30 min as it warmed to room
temperature. Saturated ammonium chloride (25 mL) was added
and the mixture was stirred for 10 min at room temperature. The
methanol was removed under reduced pressure and the
resulting aqueous solution was extracted with dichloromethane
(4 Â 50 mL). The combined organic layers were dried over
MgSO4, filtered and the solvent was removed under reduced
1
oil (2.71 g, 84%). H NMR (CDCl3, 500 MHz) d 7.38 (m, 5H), 4.62
(s, 2H), 4.08 (s, 2H). 13C NMR (CDCl3, 125 MHz) d 206.8, 137.1,
128.5, 128.0, 127.8, 75.3, 73.3.
1-(Benzyloxy)(2,3,3,3-2H4)propan-2-ol (12)
pressure yielding the product as a clear oil which solidified to a 1-(Benzyloxy)(3,3,3-2H3)propan-2-one (11) (2.35 g, 14.1 mmol)
white powder upon drying at high vacuum (9.28 g, 73%). 1H was dissolved in methanol (77 mL) and stirred for 10 min at
NMR (CDCl3, 500 MHz) d 7.81 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 01C. NaBD4 (0.29 g, 6.9 mmol) was added, and the resulting
2H), 4.02 (s, 1H), 2.46 (s, 3H), 2.39 (br s, 1H). 13C NMR (CDCl3, solution was stirred for 20 min at 01C then for 40 min at room
125 MHz) d 145.0, 132.7, 129.9, 127.9, 74.2 (quintet, JC-D = 23 Hz), temperature. Saturated ammonium chloride (40 mL) was added
65.4, 21.6, 17.7 (septet, JC-D = 19 Hz).
to the solution, which was allowed to stir for 10 min. The solvent
J. Label Compd. Radiopharm 2011, 54 308–311
Copyright r 2011 John Wiley & Sons, Ltd.