Chlorotrimethylsilane: A suitable reagent for the synthesis of chlorohydrin esters

Article abstract of DOI:10.1021/jo026020w

A new methodology for obtaining chlorohydrin esters using a one-pot esterification-chlorination reaction, in which one of the reagents, chlorotrimethylsilane, acts as solvent, is described. The reaction is stereospecific and its regioselectivity depends o

Full text of DOI:10.1021/jo026020w

Ch lor otr im eth ylsila n e: A Su ita ble Rea gen t for th e Syn th esis of
Ch lor oh yd r in Ester s
J ordi Eras,† J onh J airo Me´ndez,† Merce` Balcells,†,‡ and Ramon Canela*,†,‡
Chemistry Department and Centre UdL-IRTA, Universitat de Lleida,
Rovira Roure 191, 25198 Lleida, Spain
canela@quimica.udl.es
Received J une 6, 2002
A new methodology for obtaining chlorohydrin esters using a one-pot esterification-chlorination
reaction, in which one of the reagents, chlorotrimethylsilane, acts as solvent, is described. The
reaction is stereospecific and its regioselectivity depends on the number of carbons between the
hydroxyl groups present in the starting material. A mechanism is proposed.
In tr od u ction
epichlorohydrins.8 Methodologies for preparing these
esters include (a) esterification of either chloro alcohols
with different acylating agents6,9 or diols with acyl
chlorides,10 (b) reaction of diol monoesters with dry HCl,11
(c) cleavage of ethers and epoxides using different
reagents;12 (d) cleavage of cyclic ketal acids with phos-
phorus pentachloride,13 thionyl chloride14 or pivaloyl
chloride,15 and (e) cleavage of cyclic ortho esters with
either trityl chloride16 or CTMS.7 Whereas most of these
methodologies are only applicable for preparing â- or
γ-chlorohydrin esters, a few of them can be used to
prepare δ- or ꢀ-chlorohydrin esters.17 Moreover, only one
of these methodologies does not require a solvent to carry
out the reaction.12b
The selective transformation of diols is always a
challenging task for a chemist, and many chemical and
enzymatic methodologies have been developed to date.1
For instance, their transformation to monoesters has
been used as a strategy for preparing highly stereoiso-
merically pure compounds using lipase as a tool.2 Con-
sidering that in this approach the ee of the desired
stereoisomer is usually improved using long acyl chains,3
we planned to expand our previously described chlorot-
rimethylsilane (CTMS) method4 for the formation of fatty
monoesters of diols, as a previous step to studying their
lipase hydrolysis.
During our attempts using 2,3-butanediol and methyl
palmitate, we found a secondary compound that was
identified as 3-chloro-2-butyl palmitate. To the best of
our knowledge, this type of combined reaction in the
presence of CTMS, producing chlorohydrin esters is
unprecedented. Chlorohydrin esters have been used in
the preparation of drugs,5 surfactants,6 epoxides,7 and
All of the facts described above prompted us to inves-
tigate further the desymmetrization of 2,3-butanediol
using CTMS as a reagent and the scope of this methodol-
ogy for preparing different halohydrin esters (Scheme 1).
Resu lts a n d Discu ssion
Initially, the influence of the amount of commercial
diastereomeric mixture of 2,3-butanediol (1a -c) was
studied. As expected, the increase of diol concentration
from equimolar to 5-fold molar excess caused an increase
in 3-chloro-2-butyl palmitate formation (diastereomeric
* To whom correspondence should be addressed. Telephone: +34
973 702843. Fax: +34 973 238264.
† Chemistry Department.
‡ Centre UdL-IRTA.
(1) (a) Fujioka, H.; Nagatomi, Y.; Kotoku, N.; Kitagawa, H.; Kita,
Y. Tetrahedron 2000, 56, 10141-10151. (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2001, 40, 3726-3748. (c) Kasai, N.; Suzuki,
T.; Furukawa, Y. J . Mol. Catal. B: Enzymatic 1998, 4, 237-252. (d)
Suzuki, T.; Kasai, N.; Minamiura, N. Tetrahedron: Asymmetry 1994,
5, 239-246. (e) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483-2547.
(2) (a) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Tsujino, T.; Kita,
Y. J . Org. Chem. 2002, 67, 411-419. (b) Morgan, B.; Dodds, D. R.;
Zaks, A.; Andrews, D. R.; Klesse, R. J . Org. Chem. 1997, 62, 7736-
7743.
(8) Hamaguchi, S.; Ohashi, T.; Watanabe, K. Agric. Biol. Chem.
1986, 50, 375-380.
(9) Cambou, B.; Klibanov, A. M. J . Am. Chem. Soc. 1984, 106, 2687-
2692.
(10) Berthe, M. C.; Fort, Y.; Caubere, P. Synth. Commun. 1992, 22,
617-628.
(11) Derbesy, M.; Naudet, M. Bull. Soc. Chim. Fr. 1968, 4531-4539.
(12) (a) Bhar, S.; Ranu, B. C. J . Org. Chem. 1995, 60, 745-747. (b)
(3) (a) Ladner, W. E.; Whitesides, G. M. J . Am. Chem. Soc. 1984,
106, 7250-7251. (b) Babali, B.; Aksoy, H. A.; Tuter, M.; Ustun, G. J .
Am. Oil Chem. Soc. 2001, 78, 53-56.
Kotsuki, H.; Shimanouchi, T.; Ohshima, R.; Fujiwara, S. Tetrahedron
1998, 54, 2709-2722.
(13) Newman, M. S.; Chen, C. H. J . Org. Chem. 1973, 38, 1173-
(4) Eras, J .; Llovera, M.; Ferran, X.; Canela, R. Synth. Commun.
1999, 29, 1129-1133.
1177.
(14) Newman, M. S.; Chen, C. H. J . Am. Chem. Soc. 1972, 94, 2149-
2150.
(5) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .; J ackson,
W. R.; Gountzos, H.; Matthews, B. R. Chem. Commun. 1990, 1018-
1019.
(15) Robins, M. J .; Mengel, R.; J ones, R. A. J . Am. Chem. Soc. 1973,
95, 4074-4076.
(6) Beger, J .; J acobi, R.; Rehbeil, U.; Knoll, E. Tenside, Surfactants,
Deterg. 1992, 29, 328-332.
(7) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-
10530.
(16) Newman, M. S.; Chen, C. H. J . Am. Chem. Soc. 1973, 95, 278-
279.
(17) Wilen, S. H.; Delguzzo, L.; Saferstein, R. Tetrahedron 1987, 43,
5089-5094.
10.1021/jo026020w CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
J . Org. Chem. 2002, 67, 8631-8634
8631

Eras et al.
TABLE 2.
SCHEME 1. Str a tegy for th e Syn th esis of
Ch lor oh yd r in Ester s
TABLE 1. In flu en ce of th e Am ou n t of Com m er cia l
Dia ster eom er ic Mixtu r e of 2,3-Bu ta n ed iol Wh en P a lm itic
Acid Wa s Used
a
Isolated yields after column chromatography purification. Only
one chromatographic peak was observed by GC in each experiment
on the crude product. tR ) 24.02 min for 10b and 24.16 min for
10c-d racemate. Reactions were carried out using a 2.5 molar
excess of the corresponding alcohol.
entry
1:3
10a -d (yield %)a
1
2
3
4
5
1
2
3
4
5
91 (71%)b
99
99 (51%)c
TABLE 3.
80
89
a
Determined by GC. Mixture of diastereomers tR ) 24.18 and
b
24.03 min. Isolated yield after column chromatography purifica-
tion. c Isolated yield after crystallization, mp 29-34 °C.
compd 4
products
R3 R4
mixture, 10a -d ) from 55 to 99% yields. No differences
were observed by GC between the area ratio of the two
chromatographic peaks, each corresponding to the ex-
pected racemates (results not shown).
4a -i
R1
R2
n
12:13a
yield (%)b
60 (12a )
60 (12b)
88 (12c)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
H
H
H
H
0
2
4
0
0
1
2
3
0
H
H
H
In our attempts to improve our yields for the diol, we
planned to use palmitic acid instead of the corresponding
methyl ester. Esterification of alcohols using carboxylic
acids and CTMS had previously been described by Nakao
et al.18 Moreover, palmitic acid could easily be separated
from the halohydrin ester by sodium bicarbonate wash-
ing. Table 1 shows the results obtained when palmitic
acid and different amounts of the diol were used. In this
case, a small spot was detected by TLC below the spot
corresponding to 10a -d . Its intensity decreases rapidly
from the 1:3 ratio onward. This byproduct was identified
by NMR as the diester, 11a -c.
CH3
C2H5
CH3
CH3
CH3
OC(CH3)2
CH3
C2H5
CH3
CH3
CH3
H
H
H
H
H
0.10 92 (12d + 13d )
<0.04 94 (12e + 13e)
0.33 88 (12f + 13f)
1.08 69 (12g + 13g)
5.25 74 (12h + 13h )
69 (13i)c
CH2Cl
a
Primary position versus secondary one. Determined by
integration of the GC chromatogram of the crude products.
Isolated yields after column chromatography purification. Reac-
tions were carried out using methyl palmitate and a 5-fold molar
excess of the corresponding alcohol. c Yield after crystallization,
mp 32-33 °C.
b
Our interest was then focused on studying the ste-
reospecificity of this reaction. Thus, D-(-)-2,3-butanediol
(10b) and meso-2,3-butanediol (10c) were treated with
palmitic acid and CTMS (Table 2), and the corresponding
chlorohydrin esters were analyzed by NMR and GC prior
to SiO2 column purification. Both techniques showed that
each butanediol yielded one of the two possible race-
mates. Moreover, when the chlorohydrin ester from D-(-)
-2,3-butanediol was injected into an optical rotation (OR)
HPLC detector, the angle of rotation obtained was
clockwise. Both results, one chromatographic peak and
the presence of optical rotation, could indicate that D-(-)
-2,3-butanediol (10b) produced a single compound. This
result is in accordance with those described when either
a corresponding cyclic R-ketal acid was opened using
phosphorus pentachloride13 or its cyclic orthoacetate was
opened using trityl chloride.14
hydroxyl function were used (4d and 4e), halohydrin
esters with the chlorine atom in the primary position
(13d and 13e) were mainly obtained. The other regioi-
somers (12d and 12e) were present in amounts below
10%. 1,3-Butanediol (4f) produced halohydrin ester with
the chlorine atom in the primary position (13f) as the
major compound. The other regioisomer (12f) was present
now to the extent of about 25%. Subsequently, 1,4-
pentanediol (4g) produced both chlorohydrin ester re-
gioisomers (12g and 13g) in a 1:1 proportion and 1,5-
hexanediol (4h ) produced mainly the ester presenting the
chlorine atom in the secondary position (12h ). 1,2-
Ethanediol (4a ), 1,4-butanediol (4b), and 1,6-hexanediol
(4c) produced the corresponding halohydrin esters (12a -
c). Finally, 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane
(4i) produced 1,3-dichloro-2-propyl palmitate (13i). In this
case, neither the 2,3-dichloro isomer nor the dipalmitoyl
chloropropanes were detected.19
Finally, the developed methodology was applied to a
set of different substrates to determine its regioselectivity
and scope (Table 3). When 1,2-diols with a primary
(19) (a) Davidek, J .; Velisek, J .; Kubelka, V.; J anicek, G.; Simicova,
Z. Z. Lebensm.-Unters. Forsch. 1980, 171, 14-17. (b) Golendeev, V. P.
J . Gen. Chem. (USSR) 1940, 10, 1408-1414.
(18) Nakao, R.; Oka, K.; Fukumoto, T. Bull. Chem. Soc. J pn. 1981,
54, 1267-1268.
8632 J . Org. Chem., Vol. 67, No. 24, 2002

Chlorotrimethylsilane
SCHEME 2
To study some aspects of the mechanism of this
transformation, two different reactions were carried out
using methyl palmitate and either 2,3-butanediol or
4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane as reagents.
Their progress was followed by GC/MS. The formation
and then the gradual decline of the two chromatographic
peaks were observed in each case. These chromatographic
peaks were different from the ones corresponding to the
putative halohydrin esters, which arose as the reaction
time increased. When 2,3-butanediol was used, the two
chromatographic peaks produced an m/z of 284, corre-
sponding to the M+ of each diastereomeric monoester.
Two chromatographic peaks were also detected when
4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane was used.
Both showed an m/z of 355, which can be assigned to the
[M - 15]+ of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl palm-
itate or 2,2-dimethyl-1,3-dioxan-5-yl palmitate. The iden-
tity of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl palmitate
was confirmed by comparison with a sample obtained by
a literature method.20 Finally, 4-hydroxymethyl-2,2-dim-
ethyl-1,3-dioxolane was treated with CTMS without the
presence of either palmitic acid or methyl palmitate. After
72 h, the alcohol was recovered almost unaltered. The
putative chloro derivatives were only detected in a very
small amount by GC/MS, showing that CTMS alone can
only cause hydroxyl substitution and ring opening to a
very slight extent. Snyder21 has already demonstrated
that CTMS can only result in substitution of primary and
tertiary hydroxyls if DMSO is present. Secondary alco-
hols were not transformed to secondary chloro derivatives
under the same conditions. Thus, the assistance of the
ester seems necessary to produce the chlorohydrin esters.
The need for similar assistance has already been pro-
posed by several authors to explain similar processes.11,17,22
A feasible mechanism for this one-pot esterification-
chlorination is outlined in Scheme 2. Although we have
already noted that the esterification rate of primary
alcohols was higher than that of the secondary ones
under these conditions,4 diols could be transformed into
both monoesters (5a and 5b) followed by the formation
of a dioxygenated ring (6a and 6b), similar to those
proposed by several authors.7,14,16,17 These intermediates,
in equilibrium with the open hydroxyesters, can tau-
tomerize to 7. Compound 7 could produce 8, favored by
the presence in the medium of protons or CTMS. Then,
either the intermediate 8 (path I) or the resulting 1,3-
dioxo-2-ylium cation 9 (path II) could react with chloride
ions present in the medium through a nucleophilic
opening process similar to the one proposed by several
authors.7,14,16 This chloride attack would produce the
corresponding chlorohydrin ester (10, 12, or 13) bringing
the reaction to completion. This mechanism could explain
why an epimerization process was not observed when
D-(-)-2,3-butanediol (10b) was used as the substrate for
this reaction.
1-chloro-2-alkyl palmitates. However, 1,3-butanediol pro-
duced a 3:1 mixture of 4-chloro-2-butyl and 3-chlorobutyl
palmitate isomers. As the ring size increases, chloride
preference for the primary position decreases and, finally,
for 1,5-diols, chloride shows a clear preference for the
secondary position. Although steric hindrance phenom-
ena could be invoked to explain the differences observed
between 1,2-propanediol and 1,2-butanediol, this expla-
nation does not seem conceivable for the progressive
change found in the regioselectivity. We assume that
inductive and conformational effects are likely to be
present. Thus, the charge density of carbons supporting
oxygen atoms could hardly be influenced by the alkyl
group in 1,2-diols. This effect would tend to equalize as
the separation between the two hydroxyls increases.23
Moreover, as the ring size increases, both intermediates
8 and 9 become more flexible, so more conformational
states with similar energy could be present. Then, the
probability of the chloride ion approaching correctly to
Kolb and Sharpless7 have already shown that when
1,3-dioxolan-2-ylium intermediates are formed, chloride
ions will prefer primary carbons if they are present.
Indeed, 1,2-propanediol and 1,2-butanediol form mainly
(20) Rejzek, M.; Vacek, M.; Wimmer, Z. Helv. Chim. Acta 2000, 83,
2756-2760.
(21) Snyder, D. C. J . Org. Chem. 1995, 60, 2638-2639.
(22) Collier, P. D.; Cromie, D. D. O.; Davies, A. P. J . Am. Oil Chem.
Soc. 1991, 68, 785-790.
(23) Peterson, P. E.; Coffey, J . F. J . Am. Chem. Soc. 1971, 93, 5208-
5213.
J . Org. Chem, Vol. 67, No. 24, 2002 8633

Eras et al.
SCHEME 3
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in screw
cap vials with a Teflon-faced rubber liner under the pressure
generated by the system. The vials were heated using an
aluminum block. A 12-place carousel aluminum reaction
station with reflux head and a syringe pump were used when
CTMS was continuously added. All reagents were com-
mercially available and were used as received. Chromato-
graphic analyses (GLC) were carried out with a capillary
column (30 m × 0.25 mm diameter, 0.25 µm film thickness)
unless otherwise noted. Hydrogen (0.5 mL/min) was used as
carrier gas. Tinjector ) 275 °C, Tdetector ) 300 °C, Tcolumn ) 50 °C
(1 min), 50-250 °C (10 °C/min), and 250 °C (10 min); tR values
are given in min under these conditions, unless otherwise
noted.
Gen er a l P r oced u r e Usin g Meth yl P a lm ita te. Chlorot-
rimethylsilane (1.5 mL, 13.2 mmol) was continuously added
for 2 h to a stirred solution of methyl palmitate (420 mg, 1.56
mmol) and the corresponding alcohol (1.56 to 7.78 mmol) at
80 °C. The reaction mixture was stirred at 80 °C for 48 h,
quenched with saturated sodium bicarbonate solution, and
then extracted with hexane. The combined organic extracts
were washed with water, dried over MgSO4, and concentrated
in vacuo to give the chlorohydrin ester product. When indi-
cated, the residue was purified by column chromatography
(silica gel H60, hexane/ethyl acetate) or by crystallization (hot
ethanol 200 mg/mL) to yield the expected compounds. Yields
corresponding to compounds are included in Tables 1 and 4.
Spectroscopic and analytical data are included as Supporting
Information.
Gen er a l P r oced u r e Usin g P a lm itic Acid . Chlorotrim-
ethylsilane (1.5 mL, 13.2 mmol) was added by aliquots to a
stirred solution of palmitic acid (400 mg, 1.56 mmol) and the
corresponding alcohol (1.56 to 7.78 mmol). First, 100 µL of
CTMS was added in four equivalent portions over a 2-h period.
During this period the reaction mixture was stirred at 80 °C,
and cooled each time CTMS was added. The remaining CTMS
was then added as a single aliquot. The reaction mixture was
stirred at 80 °C for 24 h, quenched with saturated sodium
bicarbonate solution, and then extracted with hexane. The
organic extract was washed with water, dried over MgSO4, and
concentrated in vacuo to give the chlorohydrin ester product.
When indicated, the residue was purified either by column
chromatography (silica gel H60, hexane/ethyl acetate) or by
crystallization (hot ethanol 200 mg/mL) to yield the expected
compounds. Yields corresponding to compounds are shown in
Tables 2 and 3. Spectroscopic and analytical data are included
as Supporting Information.
P r oced u r e for Deter m in in g th e Ca p a bility of CTMS
To Rea ct w ith Alcoh ols. Chlorotrimethylsilane (2 mL, 17.6
mmol) was added by aliquots to the 4-hydroxymethyl-2,2-
dimethyl-1,3-dioxolane (264 mg, 2.0 mmol). First, 100 µL of
CTMS was added in four equivalent portions over 2 h. During
this period, the reaction mixture was stirred at 80 °C and
cooled each time CTMS was added. The remaining CTMS was
then added as a single aliquot. The reaction mixture was
stirred at 80 °C for 72 h, quenched with saturated sodium
bicarbonate solution, and then extracted with ethyl acetate.
The organic extract was dried over MgSO4 and analyzed by
GC/MS.
the secondary position could increase. Consequently, the
primary ester would be predominant for 1,5-diols. In our
opinion, the alternative direct palmitoyloxy substitution
by chloride ion24 does not seem conceivable. If it were so,
the excess of CTMS should always cause equivalent
substitutions whatever the initial substrate was.
When 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane is
used, the formation of 1,3-dichloro-2-propyl palmitate
(13i) could be explained by a similar mechanism involv-
ing a double dioxolane formation. Ketal opening would
be favored by the presence of protons in the medium and
the methoxide group, either free or bonded to trimeth-
ylsilane (Scheme 3). The presence of 14b detected by GC/
MS could be due to the tautomerization of 18a to 18b.
Then, 18b could produce 14b through successive equi-
libria (Scheme 3).
In summary, we have developed a promising method-
ology for obtaining chlorohydrin esters from commercial
substances using a one-pot esterification-chlorination
reaction, in which one of the reagents, chlorotrimethyl-
silane, acts as a solvent. The reaction is stereospecific
and its regioselectivity depends on the distance between
the two hydroxyl groups. We have shown that the
described reaction can be carried out with diols separated
by up to six carbons. The influence of the alcohol
concentration has also been studied. The application of
this methodology as the starting step in the synthesis of
chiral chlorohydrins to be used as building blocks is
underway. The usefulness of other trimethylsilane de-
rivatives in similar reactions is also underway. Both
studies will be reported in due course.
Ack n ow led gm en t . Financial support by the
Secretar´ıa de Estado de Pol´ıtica Cient´ıfica y Tecnolo´gica
of the Spanish Ministerio de Ciencia y Tecnolog´ıa
(PPQ2001-1687-C02-02) is gratefully acknowledged. We
thank Paquita Vilaro´ and Montserrat Llovera for OR
and GC/MS measurements, respectively.
Su p p or tin g In for m a tion Ava ila ble: Analytical and spec-
troscopic data for synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Colvin, E. W. Silicon Reagents in Organic Synthesis, 2nd ed.;
Academic Press: London, UK, 1990.
J O026020W
8634 J . Org. Chem., Vol. 67, No. 24, 2002