Simple, rapid procedure for the synthesis of chloromethyl methyl ether and other chloro alkyl ethers

Article abstract of DOI:10.1021/jo051344g

Zinc(II) salts catalyze the reaction between acetals and acid halides to provide haloalkyl ethers in near-quantitative yield. Reactions from millimole to mole scale are typically complete in 1-4 h with 0.01 mol % catalyst. The solutions of haloalkyl ethers thus obtained can be utilized directly in reactions in which the presence of the ester byproduct does not interfere. Excess haloalkyl ether is destroyed on workup, thereby minimizing exposure to this class of carcinogenic compounds.

Full text of DOI:10.1021/jo051344g

SCHEME 1
Simple, Rapid Procedure for the Synthesis
of Chloromethyl Methyl Ether and Other
Chloro Alkyl Ethers1
Martin A. Berliner* and Katherine Belecki
Chemical Research and Development,
Pfizer Global Research and Development, Groton Labs,
Groton, Connecticut 06340
martin.a.berliner@pfizer.com
Received June 29, 2005
oxymethylation strategies that circumvent the use of 1
by employing Lewis acid catalyzed exchange reactions
between methoxymethyl donors and alcohols,7 carboxylic
acids,8 and carboxamides.9 As part of a project to develop
a scalable synthesis of methoxymethylated intermediates
(4) for a medicinal chemistry program,10 we had occasion
to look closely at one of these methods.8 Our findings,
which led to the development of a rapid and convenient
protocol for the synthesis of R-halo ethers from symmetric
acetals, are described in this note.
The methoxymethylation protocol employed by our
Discovery colleagues to prepare malonate derivatives 4
was first reported by Gaudemar.8 This process involves
initial deprotonation of the starting malonate ester (2)
by ethyl 2-bromozinc acetate in dimethoxymethane (DMM)
to give an intermediate zinc enolate (3), which is then
treated with acetyl chloride to furnish the methoxym-
ethylated product (Scheme 1).
It was difficult to obtain consistent results using this
procedure, with yields of 4 ranging between 0 and 60%.
Our initial efforts to improve this reaction focused on
determining the role of zinc in this process, since there
is some discrepancy in the literature about the reaction
of acetals with acetyl chloride in the presence of Zn(II)
Zinc(II) salts catalyze the reaction between acetals and acid
halides to provide haloalkyl ethers in near-quantitative
yield. Reactions from millimole to mole scale are typically
complete in 1-4 h with 0.01 mol % catalyst. The solutions
of haloalkyl ethers thus obtained can be utilized directly in
reactions in which the presence of the ester byproduct does
not interfere. Excess haloalkyl ether is destroyed on workup,
thereby minimizing exposure to this class of carcinogenic
compounds.
Chloromethyl methyl ether (MOMCl, 1) and other
haloalkyl ethers are useful reagents for the introduction
of acid-sensitive protecting groups for alcohols, phenols,
thiols, and carboxylic acids,2 and they participate in a
wide variety of carbon-carbon bond forming reactions
as electrophiles and carbene precursors.3 MOMCl is the
most-utilized of this class of reagents, but because its
commercial preparation involves the reaction between
formaldehyde, methanol, and hydrogen chloride,4 1 is
typically contaminated with the highly carcinogenic bis-
(chloromethyl) ether. As a consequence, a number of
procedures have been devised for the synthesis of 1 that
do not result in the formation of bis(chloromethyl) ether.5
It is often only casually acknowledged that MOMCl is
hazardous, but current evidence indicates that it is also
carcinogenic.6 In addition, 1 is listed as an extremely
hazardous substance by the EPA and European Com-
munity, and is subject to extensive regulations governing
its distribution, handling, and use. These characteristics
have prompted the development of alternative meth-
(5) The majority of these processes rely on halide exchange between
an acid chloride and dimethoxymethane, and typically employ elevated
temperature and/or protic acid catalysis to accelerate the reaction. With
HCl: (a) Weinstock, L. M.; Karady, S.; Sletzinger, M. U.S. Patent
3,972,947; Chem. Abstr. 1976, 85, 142633. (b) Amato, J. S.; Karady,
S.; Sletzinger, M.; Weinstock, L. M. Synthesis 1979, 970. (c) Linderman,
R. J.; Jaber, M.; Griedel, B. D. J. Org. Chem. 1994, 59, 6499. With
H2SO4: (d) Chong, J. M.; Shen, L. Synth. Commun. 1998, 28, 2801.
(e) Williams, A. G. WO 02/059070 A1; Chem. Abstr. 2002, 137, 124930.
(f) Reggelin, M.; Doerr, S. Synlett 2004, 1117. By other methods: (g)
Stadlwieser, J. Synthesis 1984, 490. (h) Jones, M. Synth. Commun.
1984, 14, 727.
(6) For a summary of toxicological data and safety recommendations,
see: (a) Sax’s Dangerous Properties of Industrial Materials, 10th ed.;
Lewis, R. J., Sr., Ed.; John Wiley & Sons: New York, 2000; Vol. 2, p
854. (b) Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.;
Lenga, R. E., Ed.; Sigma-Aldrich: Milwaukee, WI, 1988; Vol. 1, p 804.
The carcinogenicity of MOMCl has been estimated to be greater than
that of vinyl chloride; see Van Duuren, B. L. Environ. Res. 1989, 49,
143.
(7) From dimethoxymethane using protic and/or Lewis acids: (a)
Karimi, B.; Ma’mani, L. Tetrahedron Lett. 2003, 44, 6051. (b) Patney,
H. K. Synlett 1992, 567. (c) Fuji, K.; Nakano, S.; Fujita, E. Synthesis
1975, 276. (d) Olah, G. A.; Husain, A.; Narang, S. C. Synthesis 1983,
896. (e) Gras, J.-L.; Kong Win Chang, Y.-Y.; Guerin, A. Synthesis 1985,
74. (f) Kantam, M. L.; Santhi, P. L. Synlett 1993, 429. (g) Dieter, R.
K.; Datar, R. Org. Prep. Proced. Int. 1990, 22, 63-70. Using other
reagents: (h) Marcune, B. F.; Karady, S.; Dolling, U.-H.; Novak, T. J.
J. Org. Chem. 1999, 64, 2446-2449.
(8) Dardoize, F.; Gaudemar, M.; Goasdoue, N. Synthesis 1977, 567.
(9) Ledneczki, I.; Ago´cs, P. M.; Molna´r, A. Synlett 2003, 14, 2255.
(10) Reiter, L. R.; Freeman-Cook, K. D. WO 03/090752A1; Chem.
Abstr. 2003, 139, 364949.
(1) A preliminary version of this work was presented at the 2003
National Organic Symposium, Bloomington, IN.
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Wuts, P.
G. M. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: New York, 1995.
(3) For a review, see: Benneche, T. Synthesis 1995, 1 and references
therein.
(4) For a representative lab-scale procedure, see: Marvel, C. S.;
Porter, P. K. Organic Syntheses; John Wiley & Sons: New York, 1941;
Collect. Vol. I, p 377.
10.1021/jo051344g CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/13/2005
9618
J. Org. Chem. 2005, 70, 9618-9621

TABLE 1. Survey of Lewis Acids that Catalyze the
Reaction between DMM and AcCla
TABLE 2. Solvent Effects on the Rate of Chloride
Exchange between DMM and AcCla
entry
catalyst
loading (mol %)
reaction timeb
entry
solvent
neat
CH2Cl2
toluene
ClCH2CH2Cl
EtOAc
Et2O
CH3CN
THF
reaction timeb (h)
1
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
Zn(OTf)2
ZnI2
10
<1 minc
<1 minc
<2 minc
15 min
1 h
2
1
1
2
3
4
5
6
7
8
0.25
4
3
0.1
4
0.01
0.001
0.01
0.01
0.01
0.01
0.1
4
5
4
6
15 mind
15 mind
15 mind
15 mind
30 min
48 h
4
7
12
8
ZnCl2
48
9
Zn(OAc)2
Sc(OTf)3
LiBr
MgBr2
none
c
10
11
12
13
a Reactions were conducted on a 50 mmol scale with 3 volumes
of solvent under the standard conditions (see Experimental
Section). b Time for the exchange reaction to proceed to >98%
consumption of DMM by 1H NMR analysis of an aliquot of the
reaction mixture. c THF reacts slowly to give 4-chlorobutyl acetate
(see ref 15).
0.5
0.1
120 h
e
a Reactions were conducted neat on a 50 mmol scale using the
standard conditions (see Experimental Section). b Time for the
exchange reaction to proceed to >98% consumption of DMM by
1H NMR analysis of an aliquot of the reaction mixture. c Very
exothermic reaction. d Displayed reactivity similar to that of ZnBr2.
e Less than 10% reaction after 24 h at 25 °C.
catalyst, with less than 10% conversion after 24 h at 25
°C (entry 13).
During our initial work on optimizing the exchange
reaction, we noted that for experiments on a preparative
scale, it was necessary to add the AcCl slowly to prevent
a vigorous exotherm and loss of material, even when
external cooling was utilized. Additional thermal control
is conferred by diluting the catalyst/DMM solution with
a non-acetal solvent prior to addition of the acid halide
(Table 2). Non-Lewis basic solvents (toluene, dichlo-
romethane, ethyl acetate, and 1,2-dichloroethane) result
in the best combination of reaction time and product
stability, but ether and acetonitrile can also be used with
longer reaction times (>12 h). The use of THF as a
dilution solvent during the exchange reaction is not
recommended because of the formation of significant
amounts of 4-chlorobutyl acetate from acetolysis of the
solvent, which is a reaction known to occur under these
conditions.15 Solutions of MOMCl in toluene prepared
using this procedure did not degrade after six months of
storage at ambient temperature,16 and were equally
effective as freshly prepared MOMCl in alkylation reac-
tions.
The scope of the exchange reaction extends beyond the
reaction of dimethoxymethane with acyl chlorides. Other
halogenating agents participate in the reaction (Table 3),
with relative reactivity in the order (COCl)2 > RCOCl ≈
SOCl2 > RCOBr . POCl3. Reactions between DMM and
oxalyl chloride are so vigorous that careful attention to
the addition rate is required to prevent uncontrollable
exotherms. At the other extreme, complete halogen
transfer from phosphorus oxychloride17 and chlorotrim-
ethylsilane is too sluggish to be of practical use. Acetyl
bromide readily participates in the exchange reaction to
salts. Gaudemar has noted that ZnBr2 catalyzes the
halide exchange reaction between DMM and AcCl to give
MOMCl and MeOAc.8 In a subsequent report by Yue and
co-workers, it was observed that these conditions failed
for the exchange reaction between AcCl and the arylac-
etaldehyde-derived acetal 4-MeOC6H4CH2CH(OMe)2, lead-
ing to the formation of an aldehyde instead of the
expected R-chloro ether.11 Bailey and co-workers12 have
developed a highly regioselective ZnCl2-catalyzed acetoly-
sis of cyclic formals, which proceeds via an intermediate
chloromethyl alkyl ether. Zinc(II) halides have also been
reported to be among a range of Lewis acids that catalyze
the formation of glycosyl halides from methyl glycopy-
ranosides and acid halides.13
Given these reports, our first experiments were con-
ducted to test Gaudemar’s claim of the catalytic activity
of ZnBr2 in the exchange reaction between DMM and
AcCl. Immediate and strongly exothermic reactions oc-
curred on addition of acetyl chloride to homogeneous
solutions of ZnBr2 (10, 1, and 0.1 mol %) in DMM (Table
1, entries 1-3). Within 1-2 min, all heat evolution
ceased, and analysis of the reaction mixture by 1H NMR
indicated an equimolar mixture of methyl acetate and
MOMCl. The use of less ZnBr2 results in a more control-
lable reaction, and for preparative purposes, we deter-
mined that 0.001-0.01 mol % ZnBr2 efficiently catalyzes
the exchange reaction between AcCl and DMM within 1
h (entries 4 and 5). A survey of other Lewis acids revealed
that several readily available Zn(II) salts catalyze the
reaction with an efficiency comparable to that of ZnBr2
(entries 6-9),14 and all are much more reactive than
selected Li, Mg, and Sc salts (entries 10-12). Finally, in
a control experiment, the exchange reaction between
DMM and AcCl was very slow in the absence of a
(14) These sources of Zn(II) are rapidly converted to ZnCl2 in situ
by halogen exchange between the Zn(II) salt and MOMCl. For example,
when 1 mol % ZnBr2 is employed, 2 mol % MOMBr is present in
solution. Under typical reaction conditions with 0.01 mol % or less
catalyst, R-halo ethers from the halogenation exchange process cannot
be detected.
(15) Synerholm, M. E. J. Am. Chem. Soc. 1947, 69, 2581.
(16) Purity analysis was conducted by periodically analyzing aliquots
by 1H NMR spectroscopy.
(11) Chang, C.; Chu, K. C.; Yue, S. Synth. Commun. 1992, 22, 1217.
(12) Bailey, W. F.; Carson, M. W.; Zarcone, L. M. J. Org. Synth.
1998, 75, 177. (b) Bailey, W. F.; Zarcone, L. M. J.; Rivera, A. D. J.
Org. Chem. 1995, 60, 2532. (c) Bailey, W. F.; Rivera, A. D. J. Org.
Chem. 1984, 49, 4958.
(13) Grynkiewicz, G.; Konopka, M. Pol. J. Chem. 1987, 61, 149.
J. Org. Chem, Vol. 70, No. 23, 2005 9619

TABLE 3. Different Halide Sources in the
TABLE 4. Zn(II)-Catalyzed Synthesis of r-Halo Ethers
ZnBr2-Catalyzed Exchange Reaction with DMMa
entry
halide source
equiv
reaction timeb (min)
1
2
3
4
5
6
7
8
(COCl)2
SOCl2
0.5
0.5
1.0
1.0
0.33
1.0
1.0
0.5
<5c
30d
30
AcCl
n-C5H11COCl
POCl3
TMSCl
AcBr
SOBr2
30d
e
f
45
g
a Reactions were conducted neat on a 50 mmol scale using
standard conditions (see Experimental Section). b Time for the
exchange reaction to proceed to >98% consumption of DMM by
1H NMR analysis of an aliquot of the reaction mixture. c Very
rapid, exothermic reaction. d Reactivity is similar to that in AcCl.
e Reaction stalls at 66% conversion after 16 h. f Reaction stalls at
20% conversion after 1 h. g Reaction stalls at 50% conversion after
15 min.
provide MOMBr, but thionyl bromide is less effective as
a brominating agent (entries 7 and 8). For applications
requiring purified R-halo ethers, the products from the
exchange reaction can be conveniently separated by
distillation when a higher molecular weight acyl halide
is employed (entry 4).5c,d,f
Other acetals can be used in this reaction, and a
representative set of chloroalkyl ethers prepared via this
method is listed in Table 4. The best substrates for this
reaction are acyclic symmetric aliphatic and benzylic
acetals (entries 1-7), which are efficiently converted to
R-halo ethers in high yield. These solutions of R-haloalkyl
ethers can be utilized directly in reactions with alcohols,
acids, phenols, and stabilized enolates to give the ex-
pected products in high yields (Table 5). Upon completion
of the reaction, unreacted R-halo ether is decomposed
during aqueous workup by vigorously mixing the initial
biphasic mixture for 5-15 min before separating the
phases.18 The last four entries in Table 4 illustrate
current limitations of this method. Allylic acetals react
to form a complex mixture of products (entry 8). The
acyclic mixed acetal t-BuOCH2OMe19 halogenates to
provide a mixture of products favoring 1 (ratio 85:15,
entry 9). Reaction of a simple cyclic mixed acetal (2-
methoxytetrahydropyran, entry 10) proceeds regioselec-
tively, but the resulting R-halo ether slowly decomposes
under the reaction conditions. More-substituted acetals
such as methyl 2,3,4,6-tetraacetyl glucopyranoside (entry
11) are unreactive, even at elevated temperatures using
higher catalyst loadings.
a Conditions: A, AcCl; O, oxalyl chloride; B, ZnBr2; T, Zn(OTf)2.
Equimolar amounts of acetal and halogen source were employed
with 0.01-0.025% catalyst. b Time for the exchange reaction to
proceed to no further conversion by 1H NMR analysis of an aliquot
of the reaction mixture. c Percent R-haloether in the reaction
mixture; remainder is unreacted acetal, as determined by 1H NMR
analysis of the reaction mixture. d Product is extremely susceptible
to hydrolysis, resulting in the formation of substantial amounts
of aldehyde when dissolved in the NMR solvent. e The acetal
decomposes under the reaction conditions. f Selectivity is 85:15
MOMCl:t-BuOCH2Cl. g The exchange reaction is initially regiose-
lective (after 1 h, 94:6 ratio of cyclic chloroether to acyclic
chloroether at 66% conversion), but the products are unstable and
decompose under the reaction conditions.
catalyzed exchange reaction between acyclic acetals and
acid halides. The solutions of haloalkyl ethers thus
obtained can be utilized without isolation in base-
mediated reactions in which the presence of the ester
byproduct does not interfere, including alkylations of
acids, alcohols, phenols, and stabilized enolates. The
present procedure offers a significant operational advance
over existing methods for preparing R-haloethers because
of its greater generality and rapidity. Because the
preparation and use of these reagents is conducted in one
vessel and excess reagent is decomposed on workup,
exposure issues arising from the handling of these
potential carcinogens can be minimized. Finally, the
results of this study suggest that methoxymethylation
reactions conducted under Gaudemar conditions proceed
via a stepwise process, consisting of rapid formation of
MOMCl in solution followed by reaction with the in situ
nucleophile.
In conclusion, we have described a useful method for
the rapid preparation of R-halo alkyl ethers by the Zn(II)-
(17) The reaction with POCl3 proceeds rapidly (less than 1 h) to 33%
conversion, and then slows substantially, with 66% conversion after
16 h at 45 °C. In this instance, reaction endpoint monitoring is
inaccurate because of the evaporative losses of the DMM and MOMCl
during the extended reflux.
(18) The initial aqueous quench is mildly exothermic, and typically
>98% of residual R-halo ether is decomposed when heat evolution has
ceased, which is 5 min or less for preparative scale experiments (100
mmol scale). See Supporting Information for additional details.
(19) Goff, D. A.; Harris, R. N., III; Bottaro, J. C.; Bedford, C. D. J.
Org. Chem. 1986, 51, 4711.
Experimental Section
Catalyst Considerations. For small- and medium-scale
reactions with DMM, such small amounts of catalyst are
required that we found it easiest to dispense the correct amount
9620 J. Org. Chem., Vol. 70, No. 23, 2005

TABLE 5. Alkoxyalkylation with In-Situ Generated
mL of solvent/mL of acetal) is added at this time if desired. A
halide source (1 equiv) is introduced to the flask portionwise so
that the reaction temperature remains below 45 °C, and the
reaction mixture is then allowed to cool to ambient temperature.
Reaction progress is monitored by removing aliquots from the
reaction mixture and analyzing them by NMR. These exchange
reactions can be very exothermic, so slow addition of the halide
source and dilution of the reaction mixture with an unreactive
cosolvent are recommended to prevent a runaway reaction and
unnecessary exposure. CAUTION: Due to the known carcino-
genicity of 1 and potential carcinogenicity of other R-halo ethers
described in this note, we recommend that exposure be mini-
mized by limiting the handling of solutions of R-halo ethers once
they have been formed.
r-Halo Alkyl Ethersa
Chloromethyl Methyl Ether (1) as a Solution in Tolu-
ene. A three-neck 500 mL flask fitted with a thermocouple
thermometer, reflux condenser, and addition funnel was charged
with dimethoxymethane (44.25 mL, 0.50 mol, 1 equiv), toluene
(133 mL, 3 volumes), and Zn(OAc)2 (9.2 mg, 0.01%). Acetyl
chloride (35.5 mL, 0.50 mol, 1 equiv) was placed in the addition
funnel, and was then introduced into the reaction mixture at a
constant rate over 5 min. The Zn(OAc)2 dissolved shortly after
addition of the AcCl was started. During the next 15 min, the
reaction mixture warmed slowly to 45 °C, and then cooled to
ambient temperature over 3 h, at which time analysis of an
aliquot of the reaction mixture by NMR indicated complete
consumption of DMM. Solutions of MOMCl in toluene prepared
using this stoichiometry have a density of 0.91 g/mL, are
approximately 2.1 M (18% w/w), and are stable for months if
adequately sealed. 1H NMR (CDCl3): δ 5.44 (s, 2H, MOMCl),
3.64 (s, 3H, MeOAc), 3.49 (s, 3H, MOMCl), 2.03 (s, 3H, MeOAc).
Methoxymethylation of an Alcohol: 1-Methoxymethyl-
1-phenylethane (10). R-Phenethyl alcohol (5 mL, 41.5 mmol,
1 equiv) and diisopropylethylamine (9.0 mL, 1.25 equiv) were
added sequentially to a toluene solution of MOMCl (2.1 M, 40
mL, 83 mmol, 2 equiv), prepared following the general procedure.
The reaction mixture was maintained at ambient temperature
for 16 h, at which time HPLC analysis indicated that the starting
material had been consumed (starting material tR ) 4.46 min,
product tR ) 7.25 min). The light yellow solution was partitioned
between EtOAc and a saturated aqueous NH4Cl solution, and
the biphasic mixture was stirred vigorously for a minimum of 5
min to ensure all residual 1 had been decomposed. The resulting
clear, colorless organic layer was removed, washed with a
saturated aqueous NaHCO3 solution and then with brine, dried
with MgSO4, and concentrated under reduced pressure. Purifi-
cation by distillation (Kugelrohr, OT 106 °C, 5 mmHg) provided
the title compound as a clear, colorless oil (6.32 g, 38.0 mmol,
a Reactions were typically conducted at ambient temperature
with 1.2-1.5 equiv of i-Pr2NEt in toluene. Products were isolated
using a standard aqueous workup; see Supporting Information.
b Isolated yield of purified products. c Reaction was conducted in
THF using NaH as base.
1
92% yield). Rf ) 0.5 (5:1 hexanes:EtOAc). H NMR (CDCl3): δ
7.31 (m, 4H), 7.27 (m, 1H), 4.75 (q, J ) 6.5 Hz, 1H), 4.57 (d, A
of AB, J ) 6.8 Hz, 1H), 4.54 (d, B of AB, J ) 6.8 Hz, 1H), 3.37
(s, 3H), 1.47 (d, J ) 6.5 Hz, 1H). 13C NMR (CDCl3): δ 143.2,
128.4, 127.5, 126.3, 94.0, 73.9, 55.3, 23.6. IR (neat, cm-1): 2976,
2931, 2887, 1451, 1153, 1098, 1026, 917, 758, 699, 544. Anal.
Calcd for C10H14O2: C, 72.26; H, 8.49. Found: C, 72.52; H, 8.73.
of catalyst from standard solutions of ZnBr2 in DMM (10-20
mg/mL). These standard solutions retain all catalytic activity
for at least one month if well-sealed. The solubility of zinc halides
is poor in more-substituted acetals, so Zn(OTf)2, which has
improved solubility, has proven easiest to utilize in these cases.
For large-scale reactions, Zn(OAc)2 is an excellent catalyst
because it is easy to manipulate and not hygroscopic.
General Procedure for Exchange Reactions. Catalyst
(0.001-0.01 mol %) and acetal (1 equiv) are mixed in a flask
fitted with a reflux condenser and an internal thermocouple
thermometer. For temperature control, the flask is immersed
in an ambient-temperature water bath. An inert cosolvent (3
Acknowledgment. We thank Mark Mitton-Fry and
Russ Linderman for proofreading the manuscript.
Supporting Information Available: Experimental pro-
cedures and characterization data for R-halo ethers in Table
4 and alkoxylalkylated products in Table 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO051344G
J. Org. Chem, Vol. 70, No. 23, 2005 9621