Development of a practical and efficient synthesis of chloromethyl 2-ethoxy-2-methylpropanoate

Article abstract of DOI:10.1021/op1002038

An efficient synthesis of chloromethyl 2-ethoxy-2-methylpropanoate from 2-bromoisobutyric acid is reported. Four developments were key to this route: (i) a mild, base-mediated ethanolysis of a tertiary alkyl bromide, (ii) a sodium bisulfite purge of 2-methylacrylic acid, (iii) preparation of a thiomethyl ester via a formal Pummerer process with DMSO, and (iv) improved conversion of a thiomethyl ester to a chloromethyl ester through suppression of a competing chlorination pathway.

Full text of DOI:10.1021/op1002038

Organic Process Research & Development 2010, 14, 1402–1406
Development of a Practical and Efficient Synthesis of Chloromethyl
2-Ethoxy-2-methylpropanoate
John A. Ragan,* Nathan D. Ide,* Weiling Cai, James J. Cawley, Roberto Colon-Cruz, Rajesh Kumar, Zhihui Peng, and
Brian C. Vanderplas
Chemical Research & DeVelopment, Pfizer Worldwide Research & DeVelopment, Eastern Point Road, Groton,
Connecticut 06340, United States
Scheme 1. Original synthesis of chloromethyl
2-ethoxy-2-methylpropanoate (1)
Abstract:
An efficient synthesis of chloromethyl 2-ethoxy-2-methylpro-
panoate from 2-bromoisobutyric acid is reported. Four develop-
ments were key to this route: (i) a mild, base-mediated ethanolysis
of a tertiary alkyl bromide, (ii) a sodium bisulfite purge of
2-methylacrylic acid, (iii) preparation of a thiomethyl ester via a
formal Pummerer process with DMSO, and (iv) improved conver-
sion of a thiomethyl ester to a chloromethyl ester through
suppression of a competing chlorination pathway.
1. Introduction
We recently required multikilogram quantities of chloro-
methyl 2-ethoxy-2-methylpropanoate (1) for use in the prepara-
tion of a drug candidate. Several challenges were associated
with this target, including the reactivity/instability of chlorom-
ethyl esters and the fact that this material is a volatile oil.
The original preparation of 1 (Scheme 1) was conceptually
and operationally straightforward but suffered from a relatively
lengthy linear sequence of reactions.1 Three of these reactions
were required for the conversion of 2-hydroxyisobutyric acid
(2) to 2-ethoxyisobutyric acid (5). Additionally, this route made
use of the expensive and toxic reagent chloromethyl chloro-
sulfate (6), which is difficult and hazardous to handle.2 The route
shown in Scheme 1 provided access to 100 g quantities of 1,
but with modest purity (∼65%), confirming that further scale-
up would require a more efficient synthesis.
Scheme 2. Ethanolysis of 2-bromoisobutyric acid (7)
chloroform (1,1,1-trichloro-2-methylpropan-2-ol) to 5 using
potassium hydroxide in ethanol.4 This reaction displayed an
uncontrolled exotherm on small scale, consistent with the
original report.8 It appeared to us that developing a safe, dose-
controlled, and scaleable version of this transformation would
be challenging.
A key finding was identified in House’s report of the
preparation of 2-methoxyisobutyric acid from 2-bromoisobutyric
acid and sodium methoxide.9 This reaction is not the primary
focus of the original paper and receives no discussion beyond
the detailed experimental describing its execution. Mechanisti-
cally, the reaction is intriguing and is discussed further in section
2.2. We found that the conditions reported by House worked
equally well with sodium ethoxide in ethanol to provide our
target product (5). After 48 h at room temperature, ethoxy acid
5 was observed as the major product (70%) along with 15-20%
of the acrylate elimination product 8 (Scheme 2). Shorter
reaction times could be realized by heating the reaction, but
increased elimination product was observed.10
2. Discussion
2.1. A More Efficient Synthesis of 2-Ethoxyisobutyric
Acid (5). We initially focused our efforts on identifying a more
efficient synthesis of 2-ethoxyisobutyric acid (5). A review of
the literature showed numerous citations for acid 5.1,3-7 We did
pursue an intriguing report of the one-step conversion of acetone
* john.a.ragan@pfizer.com, nathan.d.ide@pfizer.com.
(1) Brighty, K. E.; Marfat, A.; McLeod, D. G.; O’Donnell, J. P. (Pfizer
Products Inc., U.S.A.). Application: WO 2008, 29 pp, 2008. CAN
148:100428.
(2) Efforts to source this material from commercial vendors indicated that
it would not be possible to ship multikilogram quantities of this reagent
(6) via any practical means.
Fractional distillation did partially remove the acrylate
impurity, with the purest fractions containing 2-3% of 8. A
simpler and more efficient method for purification was realized
(3) Blaise, E. E.; Picard, L. Bull. Soc. Chim. Fr. 1912, 11, 587–90.
(4) Weizmann, C.; Sulzbacher, M.; Bergmann, E. J. Am. Chem. Soc. 1948,
70, 1153–8.
(8) “The violent reaction... was checked by energetic cooling.” (quote from
Experimental Section of ref 4).
(5) Wada, T.; Oda, J.; Inouye, Y. Agric. Biol. Chem. 1972, 36, 799–807.
(6) Mori, Y.; Fujiwara, S.; Miyachi, T.; Kitanishi, H.; Oya, M.; Yamamoto,
K.; Suzuki, M. Chem. Pharm. Bull. 1983, 31, 1505–17.
(7) Ishihara, S.; Kogen, H.; Koga, T.; Kitazawa, E.; Serizawa, N.; (Sankyo
Co., Ltd., Japan). Application: EP, 1994, p 173; CAN 122:213765.
(9) House, H. O.; Prabhu, A. V.; Wilkins, J. M.; Lee, L. F. J. Org. Chem.
1976, 41, 3067–76.
(10) The level of acrylate formation was based on integration of the well-
resolved vinyl proton signals in the 1H NMR. No correction for
relaxation times was applied, so this is an approximation.
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10.1021/op1002038  2010 American Chemical Society
Published on Web 10/27/2010

Scheme 3. Removal of acrylate 8 via bisulfite adduct
formation
Figure 1. Structure of chloromethyl 2-ethoxy-2-methylpro-
panoate (1).
Scheme 4. Biocatalytic approaches to acid 5
Figure 2. Possible reactive intermediates in the ethanolysis
of 7.
by treatment with aqueous sodium bisulfite, which resulted in
formation of the bisulfite conjugate addition derivative 9
(Scheme 3).11 The substantial water solubility of this derivative
allowed for easy removal by aqueous extraction. Control of pH
was found to be important for minimizing loss of acid 5 during
the aqueous wash. After the 16 h bisulfite treatment, the aqueous
phase was adjusted from pH ∼4 to ∼1 using 1 N HCl, which
minimized the loss of acid 5 to the aqueous phase (the increased
polarity of 9 as the free carboxylic acid relative to acid 5 allowed
for effective removal of 9 in the aqueous phase at pH 1).12
Distillation of the crude product provided acid 5 in >97%
chemical purity by GC and elemental analysis.
A significant improvement was realized when sodium
ethoxide was replaced with Hu¨nig’s base (i-Pr2NEt). With 2.1
equiv of this base in refluxing ethanol, starting material was
consumed in 2 h, and at 40 °C the reaction was complete in
12 h. These reaction times are comparable to those realized
with the significantly stronger base, sodium ethoxide. Impor-
tantly, under these conditions the formation of the acrylate
impurity was significantly reduced (<5%).
Biocatalytic approaches to 5 were also studied (Scheme 4).
Two substrates were evaluated: 2-ethoxy isobutyronitrile (10)
and ethyl 2-ethoxy-2-methylpropanoate (11). The former was
obtained by treatment of acetone cyanohydrin with ZnCl2 in
EtOH (the analogous reaction in methanol has been reported),13
and the latter was prepared by diethylation of 2-hydroxy
isobutyric acid. Several nitrilases were examined for the
hydrolysis of nitrile 10, and >95% conversion was observed
with nitrilase NIT 106 (Codexis). For the hydrolysis of ethyl
ester 11, five esterases were identified from screening (95
different hydrolases including lipases, proteases and esterases
from various sources) that provided >95% conversion, including
Candida antarctica lipase B, pig liver esterase, and esterase N
(Dow Pharma). It should be noted that chemical saponification
of this ester is extremely slow, due to steric hindrance, and
suffers from competitive elimination to the acrylate.
2.2. Mechanistic Considerations. The comparable rates
observed with NaOEt and i-Pr2NEt in the conversion of 7 to 5
are consistent with an SN1 mechanism wherein the bromide
departs in a rate-limiting step to generate a carbocation (and
suggest that ethoxide is not involved in the rate-determining
step). The adjacent carboxylate can stabilize the carbocation
via anchimeric assistance,14-17 with the extreme form of this
assistance resulting in the formation of an R-lactone (Figure
2).18 A report by Edwards supports this mechanism.19 Edwards’
work determined retention of configuration for chiral R-bromo
acids upon displacement with lithium azide (LiN3), a result
consistent with the intermediacy of R-lactone 12 or tight ion
pair 13, but not zwitterion 14. In contrast, clean inversion of
configuration was observed for R-bromo ketones, esters, and
lactones. Taken together, this data suggests that a free carboxy-
late provides anchimeric assistance in these systems.
The decreased formation of the acrylate side product 8 with
Hu¨nig’s base suggests that the elimination pathway is dependent
upon the strength of the base, which is consistent with an E2
mechanism. Fortunately for our application, the fact that base
was involved in the rate-determining step for formation of the
impurity, but not for formation of product, allowed us to modify
the base and achieve desirable results.
2.3. Conversion of Acid 5 to Chloromethyl Ester 1. The
cost, toxicity, and limited availability of chloromethyl chloro-
sulfate (6) led us to consider alternative approaches to 1. There
are numerous literature examples of converting carboxylic acids
directly into chloromethyl esters. These include direct reaction
with bis-alkylating reagents (e.g., XCH2X′) such as chlorom-
ethyl chlorosulfate,20,21 bromochloromethane,22 and chloroiodo-
ethane.23-25 Handling and toxicity issues are relevant for all of
these reagents; additionally, the use of bromochloromethane is
limited due to its ozone-depleting properties.26 Competitive
(14) Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1937,
1208–36.
(15) Winstein, S.; Lucas, H. J. J. Am. Chem. Soc. 1939, 61, 1576–81.
(16) Grunwald, E.; Winstein, S. J. Am. Chem. Soc. 1948, 70, 841–6.
(17) Bordwell, F. G.; Knipe, A. C. J. Org. Chem. 1970, 35, 2956–9.
(18) Chapman, O. L.; Wojtkowski, P. W.; Adam, W.; Rodriguez, O.;
Rucktaeschel, R. J. Am. Chem. Soc. 1972, 94, 1365–7.
(19) Edwards, O. E.; Grieco, C. Can. J. Chem. 1974, 52, 3561–2.
(20) Baltzer, B.; Binderup, E.; Von Daehne, W.; Godtfredsen, W. O.;
Hansen, K.; Nielsen, B.; Soerensen, H.; Vangedal, S. J. Antibiot. 1980,
33, 1183–92.
On the basis of these results we feel that an enzymatic
approach to acid 5 is viable. However, due to project timeline
constraints and the concurrent identification of the chemistry
described in Schemes 2-3, the biocatalytic approaches were
not pursued further.
(11) Hejchman, E.; Haugwitz, R. D.; Cushman, M. J. Med. Chem. 1995,
38, 3407–10.
(21) Pop, E.; Wu, W. M.; Bodor, N. J. Med. Chem. 1989, 32, 1789–95.
(22) Gomes, P.; Santos, M. I.; Trigo, M. J.; Castanheiro, R.; Moreira, R.
Synth. Commun. 2003, 33, 1683–1693.
(12) With this pH adjustment, predistillation recoveries of 80-85% were
realized; absent the adjustment, the yield was reduced to 65-70%.
(13) Ramalingam, K. Org. Prep. Proced. Int. 1989, 21, 511–14.
(23) Chen, A.-j.; Han, Z.-s.; Huang, X.-y. Zhongguo Yaowu Huaxue Zazhi
2003, 13, 299–300.
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Scheme 5. Preparation of thiomethyl esters via alkylation
Scheme 6. Pummerer reaction to form 16 and conversion
to 1 with sulfuryl chloride
formation of the bis-condensation product (e.g., (RCO2)2CH2)
is also problematic with many of these methods. A method
involving condensation of a carboxylic acid with formaldehyde
in the presence of ZnCl2 has also been reported.27,28 While we
successfully utilized this method for the synthesis of simpler
chloromethyl esters, it was ineffective for the preparation of 1.
We next turned to an indirect approach from an aryl- or
alkylthiomethyl ester (Scheme 5). There is good precedent for
the conversion of thioaryl esters (15)29 and thiomethyl esters
(16)30 into the corresponding chloromethyl esters by treatment
with electrophilic chlorinating reagents such as chlorine gas or
sulfuryl chloride (SO2Cl2). The chlorination of methylthiomethyl
esters (e.g., 16) is typically less efficient due to competitive
chlorination of the methyl group (e.g., 19 in Scheme 6).30 Our
initial approach was based on alkylation with chloromethyl
phenyl sulfide or chloromethyl methyl sulfide to generate 15
and 16, respectively. While these alkylations were efficient, the
chloromethylsulfide reagents were expensive, corrosive, and
foul-smelling.
An approach based on Swern oxidation conditions (DMSO,
oxalyl chloride, triethylamine), as reported by Jadhav and
Ghosh,31 was then considered, as it offered cost and safety
advantages over the alkylation strategy (Scheme 6). This formal
Pummerer rearrangement is occasionally evidenced in standard
Swern oxidations by the formation of methyl thiomethyl ether
byproducts. While this approach provided practical access to
16 (from DMSO), 15 was not as readily accessible.32 Extensive
experimentation indicated that the reaction to form 16 proceeds
within a wide temperature range (-78-0 °C) with an optimal
temperature of -20 °C. The reaction was found to work in
either dichloromethane or ethyl acetate. The former provided a
cleaner reaction, but ethyl acetate allowed for better removal
of the triethylamine hydrochloride during aqueous workup.
While the Pummerer strategy provided an effective alterna-
tive to the alkylation strategy for the synthesis of 16, the
subsequent chlorination was problematic, as predicted by
literature precedent.30 The conversion of 16 to 1 was effected
by sulfuryl chloride in dichloromethane at -20 °C. Ascorbic
acid was added during the aqueous workup in order to scavenge
the methylsulfenyl chloride (ClSMe) generated during the
reaction. This resulted in the isolation of a 67% yield of a 2:1
mixture of the desired chloromethyl ester 1 and chlorinated side
product 19. The latter impurity was efficiently removed by
distillation, but this side reaction reduced the yield of the desired
product.
We suspected that impurity 19 was being generated Via a
chloro-Pummerer rearrangement (Scheme 7).33 We hypoth-
esized that the chloro-Pummerer reaction might proceed Via a
rate-determining elimination of HCl, followed by rapid addition
of chloride to quench the reactive sulfocarbenium ion 18. In
contrast, we expected the desired reaction to proceed Via an
SN2 displacement of methylsulfenyl chloride (ClSMe) with
chloride ion. If this mechanistic hypothesis was correct, then
chloride ion would be involved in the rate-determining step for
the desired pathway, but not for the undesired pathway. For
this reason, we added an external chloride source (2.0 equiv of
tetrabutylammonium chloride) to the reaction and found that
this completely suppressed the formation of 19. The use of tri-
ethylamine hydrochloride provided the same benefit at a lower
cost. Having shown that triethylamine hydrochloride was
beneficial for the chlorination reaction, the removal of this
byproduct during the workup of 16 was no longer necessary or
desirable. Because dichloromethane provided a cleaner forma-
tion of 16, whereas the main benefit of ethyl acetate had been
that it allowed for the removal of triethylamine hydrochloride,
this observation allowed us to use a single solvent (dichlo-
romethane) for both steps (5 to 16 and 16 to 1).
(24) Andrianjara, C.; Chantel-Barvian, N.; Gaudilliere, B.; Jacobelli, H.;
Ortwine, D. F.; Patt, W. C.; Pham, L.; Kostlan, C. R.; Wilson, M. W.
(Warner-Lambert Company, U.S.A.). Application: WO 2002, 264 pp.
CAN 137:185501.
(25) Chen, A. Q.; Willis, C. L. Chin. Chem. Lett. 2001, 12, 397–398.
(26) http://www.epa.gov/EPA-AIR/2003/July/Day-18/a18154.htm.
(27) Baudy, R. B.; Butera, J. A.; Abou-Gharbia, M. A.; Chen, H.; Harrison,
B.; Jain, U.; Magolda, R.; Sze, J. Y.; Brandt, M. R.; Cummons, T. A.;
Kowal, D.; Pangalos, M. N.; Zupan, B.; Hoffmann, M.; May, M.;
Mugford, C.; Kennedy, J.; Childers, W. E., Jr. J. Med. Chem. 2009,
52, 771–778.
The optimized synthesis of 1 from 2-bromoisobutyric acid
(7) is shown in Scheme 8. The Experimental Section describes
a laboratory-scale preparation starting with 75 g of 2-bro-
moisobutyric acid. The overall yield for this three-step sequence
was 44%. Scale-up to multikilogram scale was successfully
realized at an outside vendor with comparable yields and purity.
Purity was controlled by distillation of acid 5 and final product
(28) Brunin, T.; Legentil, L.; Henichart, J.-P.; Rigo, B. Tetrahedron 2006,
62, 3959–3968.
(29) Hageman, D. L.; Crawford, T. C. (Pfizer Inc., U.S.A.). Application:
EP, 1982, 27 pp, CAN 97:182105.
(30) Benneche, T.; Strande, P.; Wiggen, U. Acta Chem. Scand. 1989, 43,
74–7.
(31) Jadhav, S. B.; Ghosh, U. Tetrahedron Lett. 2007, 48, 2485–2487.
(32) While DMSO was chosen to provide the methylthiomethyl ester 15,
use of methyl phenyl sulfoxide would provide access to phenylthi-
omethyl ester 14. However, the cost of this sulfoxide discouraged us
from pursuing this strategy.
(33) Bordwell, F. G.; Pitt, B. M. J. Am. Chem. Soc. 1955, 77, 572–7.
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Scheme 7. Competing SN2 and sulfocarbenium pathways
diisopropylethylamine (164 mL, 0.943 mol, 2.10 equiv) was
added at 0 ( 2 °C over 30 min. Upon complete addition the
clear reaction mixture was allowed to warm to room temperature
over 15 min. The reaction was then warmed to 40 °C for 12 h.
After cooling to room temperature, the reaction mixture was
concentrated on a rotary evaporator to remove the majority of
ethanol (20-35 mbar, 30-35 °C), leaving ∼200 mL of a thick,
white slurry. Methyl tert-butyl ether (MTBE, 300 mL) and water
(100 mL) were added, the mixture was cooled to 0 °C, and
then acidified with 10% aqueous HCl (130-140 mL, final pH
1.0 ( 0.5). The contents of the flask were diluted with MTBE
(450 mL) and brine (100 mL), the aqueous phase was removed,
and the organic phase was washed with a second portion of
brine (250 mL). The organic phase was stirred vigorously with
10% aqueous NaHSO3 (75 mL) for 6 h. The biphasic mixture
was acidified with 10% aqueous HCl (ca. 30 mL) to a final pH
of 1.0 ( 0.5. The solution was extracted with brine (2 × 100
mL), dried over sodium sulfate, filtered, and concentrated to
provide 52 g of product as a clear, colorless oil (15 mbar, 30
°C). A majority portion of this material (50.3 g) was purified
by vacuum distillation (17 mbar). A small fore-run (1.7 g) was
collected, with the major fraction collected at 103-106 °C,
providing 43.3 g of 5 as a colorless oil (73% yield).
for formation of 1 and 19
Scheme 8. Optimized synthesis of chloromethyl
2-ethoxy-2-methylpropanoate (1)
Data: IR (thin film): 3250-2950 (br), 2982, 2938, 1711,
1
1471, 1395, 1164, 1107, 1066, 974, 773 cm-1; H NMR
(CDCl3): δ 3.49 (q, 2H, J ) 7.0 Hz), 1.44 (s, 6H), 1.21 (t, 3H,
J ) 7.0 Hz); 13C NMR (CDCl3): δ 179.6, 77.2, 60.0, 24.1, 15.7;
HRMS Calcd for C6H11O3 (M - H): 131.07137. Found:
131.07138; Anal. Calcd for C10H9Cl3N4: C, 54.53; H, 9.15.
Found: C, 54.20; H, 8.82.
1. The final potency was 95% based on GC analysis, which
compares favorably with typical potencies realized using the
route shown in Scheme 1 (∼65%). As noted in the introduction,
chloro methyl esters are reactive alkylating agents, and thus
we have avoided prolonged storage of the title compound,
whose purity is further limited by its lack of crystallinity.
However, we have observed that higher-purity samples (e.g.
>90%, per Scheme 8) are more stable than their less pure
counterparts (e.g. ∼65%, per Scheme 1). In general we
recommend that these reagents be prepared near the time that
they are needed for their use in downstream operations.
In conclusion, we have developed a three step synthesis of
chloromethyl ester 1 from 2-bromoisobutyric acid. Key devel-
opments include (i) a mild, base-mediated ethanolysis of a
tertiary alkyl bromide (7 to 5), (ii) a sodium bisulfite purge of
the byproduct acrylic acid (8), (iii) preparation of thiomethyl
ester 16 via a formal Pummerer process with DMSO, and (iv)
conversion of thiomethyl ester 16 to chloromethyl ester 1 and
suppression of a competing chlorination pathway by addition
of an external chloride source.
3.2. Preparation of Thiomethyl 2-ethoxy-2-methylpro-
panoate (16). A solution of DMSO (30.1 mL, 0.424 mol, 2.24
equiv) and dichloromethane (100 mL) was cooled to an internal
temperature of -20 °C, and oxalyl chloride (26.0 mL, 0.300
mol, 1.58 equiv) was added over 20 min, during which the
internal temperature remained <0 °C. The reaction mixture was
then stirred for an additional hour at -10 ( 5 °C. 2-Ethoxy-
isobutyric acid (5) (25.0 g, 0.189 mol, 1.00 equiv) was added
over 10 min, rinsing with dichloromethane (25 mL). The
reaction mixture was cooled to -20 °C, and triethylamine (103
mL, 0.739 mol, 3.91 equiv) was added at -15 ( 5 °C. The
reaction was then stirred for an additional hour at 0 ( 5 °C.
The reaction was quenched with water (175 mL), the phases
were separated, and the organic phase was concentrated (15
mbar, 40 °C) to provide the crude product as a clear, yellow
1
oil (37.0 g). Purity was estimated at 85% by H NMR, with
3. Experimental Section
the primary impurity being triethylamine hydrochloride. This
material was used directly in the next reaction. On larger scale,
the final concentration from dichloromethane was omitted, and
the solution was carried directly into the next reaction.
Data: IR (thin film): 2159, 1738 (CdO), 1469, 1439, 1381,
Reactions were monitored primarily by 1H NMR. HPLC was
not utilized due to the absence of UV-active chromophores.
GC/MS analysis was also used to monitor the ethanolysis
reaction to generate acid 5 (Hewlett-Packard 5890, HP-1
column, 12 m × 0.2 mm × 0.33 µm, 1.5 mL/min, injector
temp 280 °C, oven temp 60-300 at 20 °C/min; bromoisobutyric
acid RT ) 5.47 min, ethoxyisobutyric acid RT ) 5.07 min).
3.1. Preparation of 2-Ethoxyisobutyric Acid (5). A solu-
tion of 2-bromoisobutyric acid (75.0 g, 0.449 mol, 1.00 equiv)
and anhydrous ethanol (600 mL) was cooled to -5-0 °C and
1
1262, 1188, 1125, 1103, 1071, 977, 942, 918, 895 cm-1; H
NMR (CDCl3): δ 5.23 (s, 1H), 3.42 (q, 2H, J ) 7 Hz), 2.29 (s,
3H), 1.44 (s, 6H), 1.18 (t, 3H, J ) 7 Hz); 13C NMR (CDCl3):
δ 174.3, 77.0, 68.5, 60.1, 24.4, 15.6, 15.2; MS (EI): (M + Na)+
215; GC purity (FID): 89%.
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3.3. Preparation of Chloromethyl 2-ethoxy-2-methylpro-
Data: IR (thin film): 2160, 1759, 1395, 1383, 1363, 1260,
1
panoate (1). The methylthiomethyl ester (16) prepared in the
1190, 1154, 1106, 1092, 1070, 1018, 974 cm-1; H NMR
1
preceding procedure (37.0 g, 0.16 mol based on H NMR
(CDCl3): δ 5.77 (s, 2H), 3.42 (q, 2H, J ) 7 Hz), 1.44 (s, 6H),
1.22 (t, 3H, J ) 7 Hz); 13C NMR (CDCl3): δ 178.5, 77.4, 68.9,
60.5. 24.4, 15.7; GC purity (FID): 95%; (Combustion analysis
failed to meet purity specifications, consistent with the GC purity
assessment of just 95%): Anal. Calcd for C7H13ClO C: 46.55,
H: 7.25, Cl: 19.63 Found: C, 45.83, H: 6.34, Cl: 18.53.
assessment of 85% potency) was dissolved in dichloromethane
(148 mL). Triethylamine hydrochloride (27.5 g, 0.200 mol, 1.25
equiv) was added, and the mixture was cooled to -30 °C.
Sulfuryl chloride (16.2 mL, 0.200 mol, 1.25 equiv) was added
over 10 min at -20 to -30 °C. The solution was stirred at
-20 °C for 1 h, then warmed to 0 °C and stirred for 2 h. The
cooling bath was removed, and L-ascorbic acid (33.8 g, 0.192
mol, 1.2 equiv) was added, followed by water (185 mL). The
two-phase system was stirred for 30 min and the phases were
separated. The organic phase was washed with 10% aq NaHCO3
(400 mL) and water (185 mL), then concentrated on a rotary
evaporator (15 mbar, 20 °C) to provide 30 g of a clear, yellow
oil. This material was purified by fractional distillation (15
mbar), collecting the main fraction at bp 66-68 °C (20.5 g,
0.114 mol, 60% overall yield from acid 5). The product was a
clear, colorless oil.
Acknowledgment
We gratefully acknowledge Jade Nelson and Ste´phane Caron
for helpful discussions, Jerry Salan and Tom Ljubicic for
assistance with Multi-Max IR real-time reaction monitoring in
the conversion of 5 to 1, and Kris Jones for proof-reading of
the manuscript.
Received for review July 26, 2010.
OP1002038
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