Neopentyl 3-Triflyloxypropanesulfonate. A Reactive Sulfopropylation Reagent for the Preparation of Chemiluminescent Labels

Full text of DOI:10.1021/jo980047r

5636
J . Org. Chem. 1998, 63, 5636-5639
Sch em e 1
Neop en tyl 3-Tr iflyloxyp r op a n esu lfon a te. A
Rea ctive Su lfop r op yla tion Rea gen t for th e
P r ep a r a tion of Ch em ilu m in escen t La bels
Maciej Adamczyk,*,† Yon-Yih Chen,
Phillip G. Mattingly, You Pan, and Sushil Rege
Abbott Laboratories, Diagnostics Division, Division Organic
Chemistry (9-NM), Building AP 20, 100 Abbott Park Road,
Abbott Park, Illinois 60064
Received J anuary 9, 1998
Chemiluminescent acridinium salts by virtue of their
high quantum efficiency can be detected at the attomole
(10-18 mol) level and below1 and thus have recently been
used as labeling reagents for ultrasensitive clinical
assays.2 The N10-methyl derivatives have generally been
employed and are efficiently prepared by quarternization
of the acridine precursor with methyl fluorosulfate or
methyl triflate; poor conversion is seen with alkylating
reagents with nucleophilic leaving groups (I-, Br-, Cl-).
The aqueous solubility of N10-methylacridinium salts is
not optimal under the conditions of the assay, and we
initially sought to improve this aspect of the chemilumi-
nescent label by introducing a solubilizing substituent
at the N10-position in place of the N10-methyl group.
The sulfopropyl group has been used extensively to
improve the aqueous solubility and otherwise enhance
the hydrophilicity of a variety of surfactants,3,4 dyes,5
nucleosides,5,6 proteins7,8 and polymers9,10 and was there-
fore considered for modifying chemiluminescent acri-
dinium salts. Recently, a method to introduce the
sulfopropyl group has been described in which an allyl
group present in the substrate subsequently reacts with
bisulfite via radical initiation.3,9 Alkylation with sodium
3-chloropropylsulfonate11 has also been reported. Both
methods were unsuitable for introducing the sulfopropyl
group onto the chemiluminescent acridinium label, since
acridinium salts are reactive in radical-mediated reac-
tions and alkyl halide alkylating reagents exhibit poor
conversion to the quarternized product. For the most
part, the sulfopropyl group has been introduced by
reaction of nucleophiles with commercially available and
inexpensive, 1,3-propane sultone (1).12 Primary amines13
and sulfhydryl groups7,8 react readily at ambient tem-
perature, but heterocyclic aromatic amines (pyridine,
quinoline, acridine, etc.), amides, carboxylic acids, and
alkoxides13 require more drastic conditions, even heating
the substrate at >100 °C in neat 1,3-propane sultone.
Such drastic conditions were necessary for the synthe-
sis of the sulfopropylated chemiluminescent acridinium
label 412-17 (Scheme 1). Sulfopropylation of acridine 2
proceeded efficiently on heating in neat 1,3-propane
sultone at 125 °C for 4 h. Under these vigorous reaction
conditions, though, a mixture was produced consisting
the desired methyl ester (3, R ) O-, R′ ) OCH3) and the
sulfopropyl esters (3, R ) O-, O[(CH2)3SO3]n, R′ )
O[(CH2)3SO3]n). Rather than isolating each compound,
the mixture was separated by flash chromatography from
the starting acridine and then hydrolyzed in refluxing
aqueous hydrochloric acid to give the single compound 4
in high yield. The zwitterionic compound 4 displayed
better solubility than the corresponding positively charged
N10-methyl derivative and has subsequently been used
in the development of clinical immunoassays for a variety
of analytes.18-26
(13) Suga, K.; Miyashige, T.; Takada, K.; Watanabe, S.; Moriyama,
M. Aust. J . Chem. 1968, 21, 2333-2339.
(14) Mattingly, P. G. J . Biolumin. Chemilumin. 1991, 6, 107-14.
(15) Mattingly, P. G.; Bennett, L. U.S. Patent 5,468,646, 1995.
(16) Mattingly, P. G.; Bennett, L. G. U.S. Patent 5,543,524, 1996.
(17) Mattingly, P. G.; Bennett, L. G. U.S. Patent 5,545,739, 1996.
(18) Mattingly, P. G.; Bennett, L. G. U.S. Patent 5,565,570, 1996.
(19) Mattingly, P. G.; Bennett, L. G. U.S. Patent 5,669,819, 1997.
(20) Anawis, M.; Fico, R.; J eng, K. Y.; Quinn, F.; Ahmed, A.; Berman,
M.; Brotherton, D.; Engstrom, E.; Finley, D.; Hansen, J .; Kaplan, M.;
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M.; Nelson, M.; Scopp, R.; Vorwald, M.; Wong, M.; Grenier, F.; Trimpe,
K. Clin. Chem. 1997, 43, 301.
† Telephone: (847)937-0225. Fax: (847)938-8927. Email: maciej.
adamczyk@abbott.com.
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S0022-3263(98)00047-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/07/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5637
Sch em e 2
F igu r e 1. Low-energy rotamer conformations of acridine 5.
Sch em e 3
To address whether further enhancement of the hy-
drophilicity of the chemiluminescent label would be
advantageous, we sought to introduce a second sulfopro-
pyl group on the periphery of the acridinium label. To
our surprise, sulfopropylation of the acridine compound
5 (Scheme 2) with 1,3-propane sultone failed to yield any
of the desired bis-sulfopropylated acridinium label 6, even
after heating for days at higher temperatures. A possible
explanation of this failure may lie with the increased
steric demands of 5. All N-sulfonylacridine-9-carboxa-
mide compounds of this type studied to date exist in
ylate anions in reaction with ketones; however, their
reactivity toward epoxides was not explored. The recent
work by Roberts et al.30 and the pioneering work of
Truce29-31 indicated that the neopentyl moiety was suit-
able for protecting the sulfonic acid group yet easy to
remove. As outlined in Scheme 3, neopentyl mesylate
9, prepared straightforwardly by the reaction of neopen-
tyl alcohol and mesyl chloride, was deprotonated with
n-butyllithium and subsequently hydroxyethylated with
ethylene oxide to give the desired 3-hydroxypropane-
sulfonate ester 10. No poly(ethylene glycol) byproducts
were observed. Conversion to the triflate using triflic
anhydride in pyridine gave 11 as a tan solid in 82% yield
after an aqueous workup in greater than 95% purity by
1H NMR. Further purification by flash chromatography
yielded 11 (39%) as an analytically pure, white, low-
melting solid that was stable for at least 2 weeks in
solution at ambient temperatures as judged by 1H NMR.
Reactivity of 11 was the same in subsequent reactions
regardless of the isolation procedure. The reaction of
acridine 2 with 1 equiv of triflate 11 at room temperature
for 2 days achieved a 50% conversion to the desired
sulfopropylated acridinium compound whereas 1,3-
propane sultone is unreactive under these conditions.
Initial trials with the more sterically hindered acridine
5 (Scheme 4) showed very little sulfopropylation under
the same conditions. Heating the reaction to reflux in
dichloromethane to accelerate the reaction offered no
advantage. However, when an equivalent of an acid
scavenger, 2,6-di-tert-butyl-4-methylpyridine, was added
along with 11 at room temperature, acridine 5 was slowly
sulfopropylated to give the desired acridinium compound
12 in 96% yield based on recovered 5 (34% conversion
after 7 days). Under these conditions no ester exchange
was seen. Hydrolysis of 12 in aqueous acid removed both
1
solution as a mixture of two rotamers.14 The H NMR
showed that either the N-alkyl sulfonamide side chain
or the arylsulfonyl substituent lies in the shielding region
above the acridine nucleus. As illustrated in Figure 1,
the bulky neopentyl sulfonate and carboethoxypropyl side
chains of compound 5 can adopt low-energy conforma-
tions in which the acridine N10 nitrogen is effectively
blocked from reaction with 1,3-propane sultone. The
conversion of acridine 5 to acridinium compound 7 with
a large excess of the less sterically demanding, more
reactive methyl triflate, while slower than reaction with
2 (7 days vs overnight), was efficient. This prompted us
to investigate the preparation and use of an alternative
triflate-containing sulfopropylation reagent (11).
Manipulation of commercially available sodium 3-hy-
droxypropanesulfonate directly into the desired triflate
seemed an unlikely route, being complicated by the
insolubility of the sulfonate salt. Rather, we envisioned
starting from an alkyl 3-hydroxypropanesulfonate which
would issue from the hydroxyethylation of a mesylate
anion. Widlanski et al.29 have shown the utility of mes-
(26) Moklee, E.; Adamczyk, J .; Christensen, M.; Shipchandler, M.;
Westerberg, D.; Yao, H.; Beggs, M. Clin. Chem. 1997, 43, 183.
(27) Pennington, C.; Rudnick, S.; Simondsen, R.; Dubler, R.; J ean-
blanc, N.; J oysumpoa, J .; Kern, L.; Palafox, M.; Preisig, J .; Rupani,
H.; Sanchez, B.; Seekins, K.; Sullivan, M.; Beggs, M. Clin. Chem. 1997,
43, 791.
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Lagedrost, J .; Markese, J .; Noonan, G.; Schiff, E. R.; Spronk, A. M.
Clin. Chem. 1997, 43, 617.
(30) Roberts, J . C.; Gao, H.; Gopalsamy, A.; Kongsjahju, A.; Patch,
R. J . Tetrahedron Lett. 1997, 38, 355-358.
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(29) Xie, M.; Widlanski, T. S. Tetrahedron Lett. 1996, 37, 4443-
4446.

5638 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
9-[[(3-Ca r boxyp r op yl)[(4-m eth ylp h en yl)su lfon yl]a m in o]-
ca r bon yl]-10-(3-su lfop r op yl)a cr id in iu m In n er Sa lt (4). The
mixture of the acridinium compounds (3) and 1 N HCl (500 mL)
was heated to reflux for 4.25 h under nitrogen and then cooled
at room temperature for 16 h. During this time a yellow
precipitate formed. The mixture was cooled in ice for 45 min,
and the precipitate was collected by filtration, washed with
acetonitrile (40 mL), and dried in vacuo to afford pure 4 (8.56 g,
78%): 1H NMR (CD3OD) δ 8.93 (2 H, d, J ) 9), 8.50-8.40 (2 H,
m), 8.21 (2 H, d, J ) 8), 8.10-7.78 (4 H, m), 7.63 (1 H, d, J ) 8),
7.25-7.14 (2 H, m), 5.80-5.65 (2 H, m), 4.29 (1 H, t, J ) 7),
3.54-3.46 (1 H, m), 3.27-3.14 (1 H, m), 2.70-2.52 (3 H, m), 2.38
(3 H, s), 2.32-2.20 (1 H, m), 1.92 (1 H, t, J ) 6), 1.60-1.50 (1 H,
Sch em e 4
m); ESI/MS m/z 585.5 (M
+
H)+. Anal. Calcd for
C28H28N2O8S2: C, 57.52; H, 4.83; N, 4.79; S, 10.97. Found: C,
57.38; H, 4.89; N, 4.74; S, 10.91.
9-[[[[4-(4-Eth oxy-4-oxobu tyl)p h en yl]su lfon yl][4-(2,2-d i-
m eth ylp r op oxy)-4-su lfobu tyl]a m in o]ca r bon yl]-10-m eth yl-
a cr id in iu m Tr ifla te Sa lt (7). To the stirred solution of
compound 5 (11.0 g, 16.45 mmol) in dry dichloromethane (165
mL) was added freshly opened methyl triflate (18.6 mL, 164.4
mmol) in one portion. The reaction mixture was stirred at room
temperature for 7 days. Solvents were removed under reduced
pressure on a rotary evaporator. The remaining material was
redissolved in a small amount of dichloromethane and applied
to a gravity column (1 kg silica gel). The column was eluted
with 50% ethyl acetate in hexanes (2 L), 60% ethyl acetate in
hexanes (2 L), 80% ethyl acetate in hexanes (2 L), 100% ethyl
acetate (6 L), and 5% methanol in dichloromethane. A small
amount of unreacted starting material 5 (∼0.45 g) was recovered
from the ethyl acetate/hexanes fractions. All fractions contain-
ing fluorescent material were collected, combined, and evapo-
rated in vacuo to afford the desired compound 7 (11.8 g, 14.2
mmol, 87%) as a mixture of rotamers: ESI/Ms m/z 683.8 (M+);
1H NMR (CD3OD) δ 8.80-6.80 (12 H, m), 4.91 and 4.83 (3 H, s,
1/1 ratio, N-methyl), 4.12 (2 H, m, ethyl ester), 1.24 (3 H, m,
ethyl ester), 1.03 and 0.78 (s, methyl groups of neopentyl
sulfonate); HPLC [3.9 × 300 mm µBondapak C-18, 65:35:0.1
acetonitrile/water/trifluoroacetic acid, 1 mL/min, 254 nm] tR, 4.5
min. The mixture was used in the next step without further
purification.
9-[[[[4-(3-Ca r b oxyp r op yl)p h en yl]su lfon yl][3-su lfop r o-
p yl]a m in o]ca r bon yl]-10-m eth yla cr id in iu m In n er Sa lt (8).
The acridinium neopentyl sulfonate 7 (11.8 g) was heated to
reflux with 1 N HCl (400 mL) for 4.25 h. The hot yellow solution
was decanted away from the insoluble tar material and allowed
to cool to room temperature. A precipitate quickly formed upon
cooling. The precipitate was collected by filtration, washed with
a small amount of distilled water, and dried over phosphorus
pentoxide in vacuo to afford pure product 8 (8.38 g, 14.2 mmol,
87%): ESI/MS m/z 585.6 (M + H)+; 1H NMR (pyridine-d5) δ 8.77
(2 H, d, J ) 9), 8.55 (2 H, d, J ) 8), 8.26 (2 H, t, J ) 8), 8.04 (2
H, d, J ) 8), 7.82 (2 H, t, J ) 7), 7.64 (2 H, d, J ) 8), 4.92 (3 H,
s), 4.32 (2 H, t, J ) 8), 2.86 (2 H, t, J ) 8), 2.58 (2 H, m), 2.16
(4 H, m), 2.04 (2 H, m). Anal. Calcd for C28H28N2O8S2(H2O):
C, 55.80; H, 5.02; N, 4.64; S, 10.64. Found: C, 55.65; H, 4.93;
N, 4.42; S, 10.48.
the neopentyl sulfonate protecting groups and the ethyl
ester to afford 13 quantitatively. Whereas acridinium
compound 4 precipitated out of the hydrolysis mixture,
bis-sulfopropylated 13 was completely soluble. Evalua-
tion of chemiluminescent bis-sulfopropylated acridinium
salt 13 as a label in an immunoassay format is ongoing.
In summary, neopentyl 3-triflyloxypropanesulfonate 11
was easily prepared and was shown to be much more
reactive than 1,3-propane sultone in the preparation of
sterically hindered sulfopropylated acridinium chemilu-
minescent labels. Whereas 1,3-propane sultone failed to
react with the acridine 5 under forcing conditions (>125
°C, neat), triflate 11 was sufficiently reactive at room
temperature to quarternize the acridine at the N10
nitrogen, yielding gram quantities of a chemiluminescent
acridinium labeling reagent with the most desirable
solubility characteristics yet described. Since this re-
agent worked so well under these “worst case” conditions,
it is expected that this reactive sulfopropylating reagent
will find use in the functionalization of a wide range of
heterocylic bases, and other substrates that react poorly
with 1,3-propane sultone, and do so under much milder
conditions.
Exp er im en ta l Section
Reagents were obtained from Aldrich Chemical Co. (Milwau-
kee, WI) unless otherwise noted. 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were recorded at on a Varian Gemini
2300 spectrometer (Palo Alto, CA). Chemical shifts are reported
in ppm (δ) using tetramethylsilane (TMS) as the internal
reference; coupling constants (J ) are in hertz. Elemental
analyses were performed by Robertson Microlit Laboratories,
Inc. (Madison, NJ ). Melting points were performed on an
Electrothermal model 9100 digital melting point apparatus
(Gillette, NJ ) and are uncorrected. Electrospray ionization mass
spectrometry ESI/MS was carried out on a Perkin-Elmer (Nor-
walk, CT) Sciex API 100 Benchtop system employing the Turbo
IonSpray ion source.
9-[[(4-Met h oxy-4-oxob u t yl)[(4-m et h ylp h en yl)su lfon yl]-
a m in o]ca r bon yl]-10-(3-su lfop r op yl)a cr id in iu m In n er Sa lt
(3). A mixture of compound 2 (9.0 g, 18.9 mmol) and 1,3-propane
sultone (25.0 g, 205 mmol) in a 250 mL round-bottomed flask
covered with aluminum foil was heated at 125 °C in an oil bath
for 5 h under nitrogen. The reaction mixture was then cooled
to room temperature, dissolved in a small amount of methanol,
added to silica gel (100 g), and evaporated in vacuo. The
compound adsorbed on silica gel was loaded onto a flash column
(600 g silica gel). The column was eluted with dichloromethane
(500 mL), 5% methanol in dichloromethane (3.5 L), and 15%
methanol in dichloromethane (6 L). The fractions which showed
strong fluorescent yellow spots on TLC (silica gel, 15% methanol
in dichloromethane) were combined and evaporated in vacuo to
afford the mixture 3 (15.2 g). It was used directly in the
hydrolysis reaction without further characterization.
Neop en tyl Mesyla te (9).33 To the cooled (0 °C), stirred
solution of neopentyl alcohol (25.1 g, 0.285 mol) and methane-
sulfonyl chloride (20.5 mL, 0.265 mol) in dichloromethane (500
mL) was added dropwise triethylamine (112 mL, 0.804 mol). The
internal reaction temperature was kept below 10 °C (immersed
thermometer). Addition was complete in 2 h. The reaction
mixture was stirred at 0 °C for an additional 2.5 h and then
washed with saturated sodium bicarbonate (500 mL), dried over
anhydrous magnesium sulfate, filtered, and evaporated in vacuo.
The crude oil was purified by bulb-to-bulb distillation using a
Kugelrohr apparatus under diminished pressure [∼100 °C (air
(32) Truce, W. E.; Goralski, C. T. J . Org. Chem. 1969, 34, 3324-8.
(33) Truce, W. E.; Vrencur, D. J . J . Org. Chem. 1970, 35, 1226-7.
(34) Hosseini, M. W.; Comarmond, J .; Lehn, J . M. Helv. Chim. Acta
1989, 72, 1066-77.
(35) Rauhut, M. M.; Sheehan, D.; Clarke, R. A.; Roberts, B. G.;
Semsel, A. M. J . Org. Chem. 1965, 30, 3587-3592.
(36) Poduska, K.; Rudinger, J . Collect. Czech. Chem. Commun. 1957,
22, 1283-1291.

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5639
bath temperature), 0.5 mmHg] to afford the mesylate (37.3 g,
85%) as a clear oil: 1H NMR (CDCl3) δ 3.88 (2 H, s), 3.01 (3 H,
s), 1.00 (9 H, s); 13C NMR (CDCl3) δ 79.0 (1 C), 36.9 (1 C), 31.6
(1 C), 25.9 (3 C); ESI/MS m/z 184.0 (M + NH4)+.
Neop en tyl 3-Hyd r oxy-1-p r op a n esu lfon a te (10). A solu-
tion of n-butyllithium (44 mL, 110 mmol, 2.5 M) in hexanes was
added dropwise to the cooled (-80 °C, diethyl ether/dry ice bath),
stirred solution of neopentyl mesylate 9 (16.6 g, 100 mmol) and
tetramethylethylenediamine (30 mL, 200 mmol) in dry THF (220
mL) over 20 min under argon. Stirring was continued for an
additional 30 min; then a solution of ethylene oxide (22 mL, 110
mmol, 5.14 M) in dry THF was added dropwise over 15 min.
The reaction mixture was stirred at room temperature for 16 h,
9-[[[[4-(4-Eth oxy-4-oxobu tyl)p h en yl]su lfon yl][4-(2,2-d i-
m eth ylpr opoxy)-4-su lfobu tyl]am in o]car bon yl]-10-[4-(2,2-di-
m eth ylp r op oxy)-4-su lfobu tyl]a cr id in iu m Tr ifla te Sa lt (12).
To the stirred solution of compound 5 (12.0 g, 18 mmol) in dry
dichloromethane (180 mL) were added triflate 11 (8.0 g, 23.4
mmol) and 2,6-di-tert-butyl-4-methylpyridine (4.8 g, 23.4 mmol).
The reaction mixture was stirred at room temperature for 7 days.
The solvent was removed under diminished pressure on a rotary
evaporator, and the remaining material was purified by gravity
column chromatography (1 kg silica gel, 50% ethyl acetate in
hexanes to 2% methanol in dichloromethane to 5% methanol in
dichloromethane). Starting material (7.5 g, 63%) was recovered
from fractions in ethyl acetate/hexanes. The change from ethyl
acetate/hexanes to methanol/dichloromethane started after the
starting material was completely eluted. All fractions in metha-
nol/dichloromethane containing fluorescent material were col-
lected, combined, and evaporated in vacuo to give the acridinium
product 12 (6.28 g, 34%, 96% based on recovered 5): ESI/Ms
m/z 861.5 (M+); 1H NMR (300 MHz, CD3OD + TFA) δ 8.83 (2
H, m), 8.49 (2 H, m), 8.25 (1 H, d, J ) 9), 8.10 (1 H, br d, J ) 8),
8.02 (1 H, m), 7.82 (1 H, m), 7.81 (1 H, br d, J ) 9), 7.67 (1 H,
d, J ) 9), 7.27 (2 H, m), 5.66 (2 H, m), 4.14 (2 H, m, CH2 of ethyl
ester), 4.00 and 3.51 (4 H, m, CH2 of neopentyl sulfonate), 1.25
(3 H, m, CH3 of ethyl ester), 1.03, 1.00, 0.99 and 0.77 (18 H, s,
CH3 of neopentyl sulfonate); HPLC [3.9 × 300 mm µBondapak
C-18, 65:35:0.1 acetonitrile/water/trifluoroacetic acid, 1 mL/min,
254 nm] tR, 5.6 min, 94%.
9-[[[[4-(3-Ca r b oxyp r op yl)p h en yl]su lfon yl][3-su lfop r o-
p yl]a m in o]ca r bon yl]-10-(3-su lfop r op yl)a cr id in iu m In n er
Sa lt (13). Acridinium compound 12 (4.26 g, 4.2 mmol) was
heated to reflux in 1 N HCl (200 mL) for 8 h. After being cooled
to room temperature, the yellow solution was decanted and
lyophilized to give 13 (2.9 g, 4.2 mmol, 100%) as an amorphous
deliquescent solid after drying over P2O5: 1H NMR (pyridine-
d5) δ 9.41 (2 H, d, J ) 9), 8.57 (2 H, d, J ) 8), 8.35 (2 H, m), 8.02
(2 H, d, J ) 8), 7.85 (2 H, m), 7.65 (2 H, d, J ) 8), 6.19 (2 H, m),
4.29 (2 H, m), 3.66 (2 H, m), 2.58 (2 H, m), 3.30 to 2.40 (8 H, m),
2.15 (4 H, m); ESI/MS m/z 711.4 (M + NH4)+; HPLC [3.9 × 300
mm µBondapak C-18, 25:75:0.1 acetonitrile/water/formic acid,
1 mL/min, 254 nm] tR, 6.29 min, 94%.
diluted with diethyl ether (300 mL), and washed with
a
saturated sodium chloride solution (600 mL). The organic layer
was separated, dried over anhydrous magnesium sulfate, fil-
tered, and evaporated in vacuo. The resulting oil was purified
by bulb-to-bulb distillation under diminished pressure [Kugel-
rohr apparatus, ∼100 °C (air bath temperature), 0.1 mmHg] to
afford pure product 10 (16.0 g, 76%): 1H NMR (CDCl3) δ 3.89
(2 H, s), 3.81 (2 H, t, J ) 6), 3.28 (2 H, m), 2.11 (2 H, m), 1.80 (1
H, broad s), 1.00 (9 H, s); 13C NMR (CDCl3) δ 78.7 (1 C), 60.1 (1
C), 46.8 (1 C), 31.6 (1 C), 26.4 (1 C), 25.9 (3 C). Anal. Calcd for
C8H18O4S: C, 45.69; H, 8.62; S, 15.25. Found: C, 45.46; H, 8.58;
S, 15.13.
Neop en tyl 3-Tr iflyloxy-1-p r op a n esu lfon a te (11). Triflic
anhydride (10 mL, 0.060 mol) was added dropwise over 15 min
to the stirred, cooled (0 °C) solution of 10 (12.54 g, 0.060 mol)
and pyridine (5.4 mL, 0.066 mol) in dry dichloromethane (360
mL) under argon. After the addition was complete, the reaction
mixture was stirred at 0 °C for 2 h. The reaction mixture was
then washed with ice cold 5% aqueous sodium bisulfate (2 ×
250 mL), 10% aqueous sodium bicarbonate (2 × 250 mL), and
saturated aqueous sodium chloride (500 mL). The organic phase
was dried over anhydrous sodium sulfate, filtered, and then
evaporated under reduced pressure to give 11 (15 g, 0.049 mol,
82%) as a tan solid. This material was used in subsequent
reactions without further purification. In
a separate run,
analytically pure material was obtained after flash column
chromatography (500 silica gel, 20% ethyl acetate in hexanes)
to afford 11 (8.0 g, 39%) as a white crystalline solid: mp 44-45
°C; 1H NMR (CDCl3) δ 4.70 (2 H, t, J ) 6), 3.91 (2 H, s), 3.26 (2
H, t, J ) 7), 2.40 (2 H, m), 0.99 (9 H, s); 13C NMR (CDCl3) δ 79.3
(1 C), 74.1 (1 C), 45.7 (1 C), 31.7 (1 C), 25.9 (3 C), 24.0 (1 C).
Anal. Calcd for C9H17F3O6S2: C, 31.58; H, 5.00; F, 16.65; S,
18.73. Found: C, 31.73; H, 5.11; F, 16.73; S, 18.56.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of compounds 2 and 5 are included as Sup-
porting Information (8 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
An NMR sample was kept at room temperature for 13 days.
No significant decomposition of the material was observed.
J O980047R