Applications of diethoxymethane as a versatile process solvent and unique reagent in organic synthesis

Article abstract of DOI:10.1021/op000288c

Diethoxymethane (DEM) has recently become available in commercial quantities. It has unique properties and is useful in a variety of applications in organic synthesis. It is low boiling (88 °C), azeotropes with water, and has a very low affinity for water. It is stable under basic conditions and as manufactured does not require drying for use as a solvent, even for organometallic reactions. DEM is useful as a process solvent especially for sodium hydride reactions, organolithium chemistry, copper-catalyzed conjugate additions, and phase-transfer reactions. As such, DEM is a potential replacement for tetrahydrofuran (THF), dichloromethane (CH₂Cl₂), glyme (1,2-dimethoxyethane), and methylal (1,1-dimethoxymethane). DEM is also useful as an ethoxymethylating agent, a formaldehyde equivalent, and a carbonylation substrate. Due to these unique properties and applications, DEM has exciting potential for widespread use both as a reagent and especially as a preferred solvent.

Full text of DOI:10.1021/op000288c

Organic Process Research & Development 2001, 5, 127−131
Applications of Diethoxymethane as a Versatile Process Solvent and Unique
Reagent in Organic Synthesis
Neil W. Boaz*,† and Bhaskar Venepalli‡
Research Laboratories, Eastman Chemical Company, P.O. Box 1972, Kingsport, Tennessee 37662, and
CiVentiChem, P.O. Box 12041, Research Triangle Park, North Carolina 27709, U.S.A.
Abstract:
cases, DEM and other formaldehyde acetals were used as
solvents and stabilizing agents since DEM can act a source
of formaldehyde. Because DEM is a protected form of
formaldehyde, it has been used as an attractive source of
formaldehyde (instead of an aqueous solution) due to its ease
of handling, safety, and nonaqueous nature. For example,
several novel 6-methylene-substituted steroid derivatives with
potential use as anticancer agents were prepared in good
yields using DEM as a methylenating agent in the presence
of phosphorus oxychloride.8 In addition, sterically hindered
di- and trialkylphenols upon condensation with formaldehyde
acetals such as DEM in the presence of an acid catalyst
afforded dimers (bisphenols) and oligomers (polyphenols)
useful as nontoxic, colorless, low volatility antioxidants for
rubbers and plastics.9 Bis(phenylcarbamate) esters were
prepared by the reaction of phenyl carbamates with DEM
in the presence of superacid catalysts.10 With two oxygens
and a reactive methylene group, DEM is a very good
substrate for carbonylation reactions. Thus, ethyl 2-ethoxy-
acetate was prepared by carbonylation of DEM using either
Amberlyst 1511 or Co2(CO)8/γ-picoline as catalyst.12 Several
phenylglycine derivatives and other amino acids were
prepared by reacting DEM with anilines in the presence of
carbon monoxide and a cobalt catalyst.13 In contrast to many
of these applications, we feel that DEM has its greatest
potential as a process solvent and reagent for organic
chemistry, and we wish to report our investigations along
those lines.
Diethoxymethane (DEM) has recently become available in
commercial quantities. It has unique properties and is useful
in a variety of applications in organic synthesis. It is low boiling
(88 °C), azeotropes with water, and has a very low affinity for
water. It is stable under basic conditions and as manufactured
does not require drying for use as a solvent, even for organo-
metallic reactions. DEM is useful as a process solvent especially
for sodium hydride reactions, organolithium chemistry, copper-
catalyzed conjugate additions, and phase-transfer reactions. As
such, DEM is a potential replacement for tetrahydrofuran
(THF), dichloromethane (CH2Cl2), glyme (1,2-dimethoxy-
ethane), and methylal (1,1-dimethoxymethane). DEM is also
useful as an ethoxymethylating agent, a formaldehyde equiva-
lent, and a carbonylation substrate. Due to these unique
properties and applications, DEM has exciting potential for
widespread use both as a reagent and especially as a preferred
solvent.
Background Information
Diethoxymethane is an intriguing molecule with densely
packed functionality. That may be the reason that there are
over 300 citations for various uses of DEM, despite the fact
that it only recently became commercially available.1 The
documented uses are varied and will be briefly described to
indicate the versatility of this molecule.
DEM has found use as a solvent in a number of unusual
applications. For example, it has been reported to be a useful
solvent in lithium batteries with nonaqueous electrolytes.2,3
Several diethers including DEM were found to be useful fuel
additives to reduce carbon monoxide emissions and to
increase octane ratings.4 DEM was reported to be a useful
solvent for adhesives and other resins.5-7 In many of these
Synthesis and Properties
Diethoxymethane (DEM) is a colorless mobile liquid.
There are several methods for preparing DEM, but the most
economical route is by reacting formaldehyde and ethanol
in the presence of an acid catalyst (Figure 1).
The typical properties of commercial diethoxymethane
(DEM) are listed in Table 1.
† Eastman Chemical Company.
‡ CiVentiChem.
(1) DEM is available in drum or tank car quantities from Eastman Chemical
Company. Contact the author or call 1-800-EASTMAN for more details.
(2) Watanabe, H.; Yoshimura, S.; Takahashi, M.; Ooshita, R.; Furukawa, S.
Jpn. Kokai Tokkyo Koho JP 04206279, 1992; Chem. Abstr. 1992, 117,
237241b.
(3) Furukawa, S. Nishio, K.; Yoshinaga, N. Jpn. Kokai Tokkyo Koho JP
03074060, 1991; Chem. Abstr. 1991, 115, 53458e.
(4) (a) Mayerhof, H.; Scheider, W.; Muering, A.; Exner, W. Ger. Offen. 2,
216,880, 1972; Chem. Abstr. 1973, 78, 100200u. (b) Miklau, R. Austrian
321,440, 1975; Chem. Abstr. 1975, 83, 100665c.
(8) Buzzetti, F.; Di Salle, E.; Lombardo, P. Ger. Offen. DE 3,719,913, 1987;
Chem. Abstr. 1988, 109: 110743.
(9) (a) Michurov, Y. I.; Yansheskii, V. A.; Gusev, V. K.; Laikumovich, A. G.;
Styskin, E. L.; Gurvich, Y. A.; Kumok, S. T.; Starikova, O. F.; Rutman, G.
I. Fr. Demande 2,354,988, 1978; Chem. Abstr. 1978, 89, 179694s. (b)
Styskin, E. L.; Gurvich, Y. A.; Kumok, S. T.; Starikova, O. F.; Rutman, G.
I.; Michurov, Y. I.; Yansheskii, V. A.; Gusev, V. K.; Laikumovich, A. G.
Br. Patent 1,555,728, 1979; Chem. Abstr. 1980, 93, 46171e.
(10) Jpn. Kokai Tokkyo Koho JP 82 64,645, 1982; Chem. Abstr. 1982, 97,
127289j.
(5) Li, S.; Wei, L. Faming Zhuanli Shenqing Gongkai Shuomingshu CN 1,-
034,566, 1987; Chem. Abstr. 1990, 113, 80148u.
(11) Kumagai, K.; Koyano, T. Eur. Pat. Appl. EP 88,529, 1983; Chem. Abstr.
1983, 99, 212163z.
(6) Ito, A.; Nakase, Y.; Kojima, K.; Yoshida, M.; Iwai, T.; Hayshi, K.; Okamura,
S. Ger. Offen. 2,030,412, 1971; Chem. Abstr. 1971, 74, 65012c.
(7) Fr 1,574,971, 1969; Chem. Abstr. 1970, 72, 67696m.
(12) Murata, K.; Matsuda, A.; Masuda, T. Bull. Chem. Soc. Jpn. 1985, 58, 2141.
(13) Murata, K.; Matsuda, A.; Masuda, T. Jpn. Kokai Tokkyo Koho JP 01 63,-
557, 1989; Chem. Abstr. 1989, 111, 58344s.
10.1021/op000288c CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 01/04/2001
Vol. 5, No. 2, 2001 / Organic Process Research & Development
•
127

H2O) at 75 °C and ethanol (58:42 DEM:ethanol) at 74 °C.14
These properties along with the immiscibility of DEM and
water allow simple drying of DEM to very low water levels
during recycling to afford good economics and a minimum
of waste. DEM’s freezing point (-66 °C) and boiling point
(88 °C) offer a useful operating temperature range for many
chemical sequences. Thus, DEM can potentially replace
commonly used solvents such as tetrahydrofuran, ethyl
acetate, dichloromethane, toluene, 1,4-dioxane, dimethoxy-
ethane, tert-butyl methyl ether, and others. Indeed, DEM is
currently used as a process solvent in various large-scale
manufacturing settings. It has been evaluated for safety and
handling properties and found to be suitable for industrial
use.15
Two important characteristics of DEM which differentiate
it from many other ethers are its water-immiscibility and its
nonhygroscopic nature. It is manufactured in very dry form,
with about 100-150 ppm water and includes 100 ppm
butylated hydroxytoluene (BHT) peroxide inhibitor. In
addition, it has very little propensity to absorb water. For
example, DEM from a container that had been open for over
a year performed superbly in our laboratories as a solvent
for several water-sensitive reactions. Indeed, this is one of
the most intriguing characteristic of DEMsit can readily be
used for numerous water-sensitive reactions (even organo-
metallic reactions) without any further drying. In addition,
the water-immiscibility of DEM should facilitate product
recovery as compared to solvents that are more water-
miscible. We have compared DEM as manufactured (no
further drying) with “anhydrous-grade” THF (stored under
argon) as solvents for several representative organometallic
reactions.
DEM has been compared with anhydrous THF for the
benzylation of 3-butyn-1-ol using sodium hydride as base.16
Similar product yields were obtained in both cases, with
product isolation much simpler with DEM due to its water-
immiscibility (Figure 2a).
The reaction of benzaldehyde with n-butyllithium pro-
ceeded to slightly higher conversion in DEM than THF. The
product isolation was again much simpler due to the water-
immiscibility of DEM (Figure 2b).
A Grignard reaction, modeled in this case by the reaction
of methylmagnesium chloride with benzaldehyde (Figure 2c),
proceeded equally well in DEM and THF, with product
isolation again being simpler from a DEM solution. However,
we have found in our laboratories that the preparation of
Grignard reagents appears to be more difficult in DEM than
in other ethereal solvents.
The copper-catalyzed addition of methylmagnesium chlo-
ride to isophorone17 (Figure 2d) proceeded with higher
selectivity (for the conjugate adduct) in DEM than in THF.
In addition, the yield of product was significantly higher
when the reaction was run in DEM.
Figure 1.
Table 1
molecular formula:
molecular weight:
appearance:
boiling point:
freezing point:
flash point:
viscosity at 20 °C:
solubility (%):
water in
in water
C5H12O2
104.15
clear, colorless liquid
88 °C (190 °F)
-66.5 °C (-88 °F)
-6 °C (21 °F)
0.405 cp
1.3
4.2
0.8305
3.6
100
specific gravity at 20°/20 °C:
vapor density (air ) 1):
inhibitor (BHT), ppm:
Stability of Diethoxymethane
The stability of DEM is crucial for its use in process
chemistry. Due to the nature and arrangement of functional-
ity, it was important to examine the stability of DEM under
basic, acidic, and oxidative conditions.
DEM is stable to numerous strong bases such as hydrox-
ide, sodium hydride, Grignard reagents, and organolithium
reagents (as will be described below). Being the diethyl acetal
of formaldehyde, DEM is not stable under homogeneous
acidic conditions for an extended period of time, and it is
not recommended for use with homogeneous acid species
as formaldehyde can be liberated under such conditions.
However, DEM exhibits unexpected stability to aqueous acid,
such that <1% of DEM is decomposed upon ambient
temperature exposure to an equal volume of water at pH 2
over 24 h. This stability is attributed to the inherent
hydrophobicity of DEM, which limits its exposure to the
proton source. Thus, DEM is a useful solvent for reactions
involving a mildly acidic work up, although it is recom-
mended that the pH of an aqueous solution mixed with DEM
remain at 4 or above.
Even though DEM is an ether, its propensity to form
peroxides is very low compared to that of other ethers such
as THF. As added insurance, DEM is commercially supplied
with 100 ppm butylated hydroxytoluene (BHT) as a peroxide
inhibitor.
Applications of Diethoxymethane
The applications of DEM can be best classified into two
major categories: DEM as a solvent in organic processes
and DEM as a chemical intermediate. Most of our investiga-
tions focused on the use of DEM as a solvent, but we will
also present an example of its use as a reagent.
DEM as a Solvent
DEM has many properties that make it attractive as a
general cost-competitive process solvent for use as a reaction
medium and for operations such as extractions, dilutions,
and recrystallizations. Its low viscosity allows easy handling.
It forms a binary azeotrope with both water (90:10 DEM:
(14) Horsley, L. H. In Azeotropic Data; American Chemical Society: Wash-
ington, DC, 1952.
(15) An MSDS and other information for DEM can be found at http://
www.eastman.com.
(16) Burns, C. J.; Gill, M.; Saubern, S. Aust. J. Chem. 1997, 50, 1067.
(17) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
128
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development

Figure 4.
Alkylation of diethyl malonate with ethyl iodide18 pro-
ceeded significantly faster in DEM than in DCM, with similar
selectivities (Figure 3b).
The preparation of stilbene from benzaldehyde and benzyl
triphenylphosphonium chloride19 proceeded at approximately
the same rate and in similar yields in both DEM and DCM,
with similar E:Z isomer selectivities (Figure 3c). In all of
these cases product isolation was facilitated by the im-
miscibility of the aqueous and DEM layers.
DEM was an equivalent or superior solvent in all of the
cases examined and is thus an attractive replacement solvent
for DCM for phase-transfer-catalyzed reactions.
Figure 2.
DEM as a Reagent
Due to the presence of its two oxygens, DEM has been
found to be very useful in ethoxymethylation of alcohols,
phenols,20 and amines.21 Attaching an ethoxymethyl group
is typically done using hazardous chloromethyl ethyl ether
under basic conditions. DEM, however, can be used as an
innocuous ethoxymethylating agent in the presence of an
acidic catalysts. As an example, menthol was ethoxymethy-
lated in quantitative yield using a solid acid catalyst with
azeotropic removal of ethanol (Figure 4).
Conclusions
Diethoxymethane is finding wide acceptance as a reaction
process solvent and for other applications in the chemical
industry. In addition to its uses as a reagent, DEM shows
particular promise as a solvent for reactions that are water-
sensitive, mainly due to the low water content and non-
hygroscopic nature of this diether solvent. DEM is also
recommended as a solvent for phase-transfer-catalyzed
reactions and for general processing of organic materials.
The ease of handling, immiscibility with water, and ability
for recycle serve to increase the attractiveness of this useful
new solvent.
Figure 3.
These results indicate that in all of the organometallic
reactions investigated DEM was equivalent or superior to
anhydrous THF. We have also found DEM to be an attractive
solvent for lithium dialkylcuprate conjugate addition reac-
tions, palladium(0)-catalyzed allylation reactions, noble
metal-catalyzed hydrogenations, and enzymatic esterification
reactions.
DEM is also useful if a reaction warrants the presence of
some water since DEM does have limited water solubility.
Of particular interest were phase-transfer reactions. Although
dichloromethane (DCM) is a standard solvent for phase-
transfer-catalyzed reactions, concerns surround the use of
this halogenated solvent. Thus, DEM was examined as a
DCM replacement for phase-transfer reactions. Three dif-
ferent representative reactions were investigated: O-alkyla-
tion, C-alkylation, and a Wittig reaction (Figure 3). These
reactions described below all employed aqueous sodium
hydroxide as the base and, except for the Wittig reaction
(where the reagent is the catalyst), tetrabutylammonium
bromide was used as the catalyst.
Experimental Section
General. Diethoxymethane (DEM) was commercial grade
obtained from Eastman Chemical Company and in all cases
was used as received. Other solvents and reagents were used
as received from J. T. Baker Chemical Company or Aldrich
1
Chemical Co. All H- and 13C spectra were obtained on a
Varian Gemini-300 spectrometer. Gas chromatography was
(18) Bra¨ndstro¨m, A.; Junggren, U. Tetrahedron Lett. 1972, 473.
(19) Dehmlow, E. V. Angew. Chem., Int. Ed. Engl. 1974, 13, 170.
(20) (a) Schreyer, R. C. J. Am. Chem. Soc. 1951, 73, 4404. (b) Schaper, U.
Synthesis 1981, 794. (c) Schouten, H. G. U.S. Patent 4,500,738, 1985.
(21) Ozaki, S.; Watanabe, Y.; Hoshiko, T.; Nagase, T.; Ogasawara, T.; Furukawa,
H.; Uemura, A.; Ishikawa, K.; Mori, H.; Hoshi, A.; Iigo, M.; Tokuzen, R.
Chem. Pharm. Bull 1986, 34, 150.
The O-benzylation of 3-butyn-1-ol afforded similar reac-
tion rates, yields, and product purities with either DCM or
DEM as organic solvent (Figure 3a).
Vol. 5, No. 2, 2001 / Organic Process Research & Development
•
129

performed on a Hewlett-Packard 5890 gas chromatograph
using a J&W DB-17 (30 m × 0.25 mm) capillary column.
1-Benzyloxy-3-butyne (1) Prepared in DEM. A 60 wt
% suspension of sodium hydride in mineral oil (1.00 g, 25
mmol, 1.0 equiv) was slurried in DEM (25 mL), and the
mixture was cooled to 0 °C. 3-Butyne-1-ol (1.89 mL, 25
mmol) was added slowly dropwise with a small amount of
frothing noted. The reaction mixture was warmed to ambient
temperature for 15 min and then cooled to 0 °C. Benzyl
bromide (2.82 mL, 23.75 mmol, 0.95 equiv) was added
dropwise, and tetrabutylammonium iodide (462 mg, 1.25
mmol, 0.05 equiv) was added. The reaction mixture was
allowed to warm to ambient temperature and stirred overnight
to afford a white slurry. The mixture was quenched by careful
addition of water (10 mL), and the layers were separated.
The organic layer was dried (Na2SO4) and concentrated to
afford 4.17 g of a 98:2 ratio of 1 and benzyl bromide,
respectively. The crude product was flash-chromatographed
and eluted with 2.5% ethyl acetate:heptane to afford 3.30 g
(87%) of 1. The analytical details were identical to those
reported.13
1-Benzyloxy-3-butyne Prepared in THF. A 60 wt %
suspension of sodium hydride in mineral oil (1.00 g, 25
mmol, 1.0 equiv) was slurried in THF (25 mL), and the
mixture was cooled to 0 °C. 3-Butyne-1-ol (1.89 mL; 25
mmol) was added slowly dropwise with significant frothing
noted. The reaction mixture was warmed to ambient tem-
perature for 15 min and then cooled to 0 °C. Benzyl bromide
(2.82 mL, 23.75 mmol, 0.95 equiv) was added dropwise,
and tetrabutylammonium iodide (462 mg, 1.25 mmol, 0.05
equiv) was added. The reaction mixture was allowed to warm
to ambient temperature and stirred overnight to afford a white
slurry. The mixture was quenched by careful addition of
water (10 mL), and the reaction mixture was diluted with a
1:1 mixture of ethyl acetate and heptane (50 mL). The layers
were separated, and the organic layer was dried (MgSO4)
and concentrated to afford 4.28 g of a 98:2 ratio of 1 and
benzyl bromide, respectively. The crude product was flash-
chromatographed and eluted with a gradient of 0-10% ethyl
acetate:heptane to afford 3.38 g (89%) of 1.
1-Phenyl-1-butanol (2) Prepared in DEM. Benzalde-
hyde (1.06 g; 10 mmol) was dissolved in DEM (10 mL) in
a dry, nitrogen-flushed flask. The solution was cooled to 0
°C, and a solution of n-butyllithium in hexane (2.5 M, 4.2
mL, 10.5 mmol, 1.05 equiv) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h and then
quenched by the addition of water (10 mL). More DEM (20
mL) was added, and the layers were separated. The organic
solution was dried (MgSO4) and concentrated to afford 1.33
g of crude 2. Examination of this material by 1H NMR and
GC indicated a 90:10 ratio of 2:benzaldehyde. The 2 thus
prepared was identical to an authentic sample.
1-Phenyl-1-butanol (2) Prepared in THF. Benzaldehyde
(1.06 g, 10 mmol) was dissolved in THF (10 mL) in a dry,
nitrogen-flushed flask. The solution was cooled to 0 °C, and
a solution of n-butyllithium in hexane (2.5 M, 4.2 mL, 10.5
mmol, 1.05 equiv) was added dropwise. The reaction mixture
was stirred at 0 °C for 1 h and then quenched by the addition
of water (10 mL). Ethyl acetate (20 mL) was added, and the
layers were separated. The organic solution was dried
(MgSO4) and concentrated to afford a crude product which
still contained some water and salts. This material was
dissolved in 25 mL of 1:1 ethyl acetate:heptane, dried (Na2-
SO4), and concentrated to afford 1.28 g of crude 2.
Examination of this material by 1H NMR and GC indicated
a 85:15 ratio of 2:benzaldehyde.
1-Phenyl-1-ethanol (3) prepared in DEM: Benzalde-
hyde (1.06 g; 10 mmol) was dissolved in DEM (10 mL) in
a dry, nitrogen-flushed flask. The mixture was cooled to 0
°C, and a solution of methylmagnesium chloride in THF (3.0
M, 3.33 mL, 10 mmol, 1.0 equiv) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h and then warmed
to ambient temperature for 1 h. The reaction was quenched
by the addition of 3 N HCl (3.0 mL, 9.0 mmol, 0.9 equiv)
and water such that the pH was about 6. The layers were
separated, and the organic solution was dried (MgSO4) and
concentrated to afford 1.12 g (92%) of 3 which was identical
to an authentic sample.
1-Phenyl-1-ethanol (3) Prepared in THF. Benzaldehyde
(1.06 g, 10 mmol) was dissolved in THF (10 mL) in a dry,
nitrogen-flushed flask. The mixture was cooled to 0 °C, and
a solution of methylmagnesium chloride in THF (3.0 M, 3.33
mL, 10 mmol, 1.0 equiv) was added dropwise. The reaction
mixture was stirred at 0 °C for 1 h and then warmed to
ambient temperature for 1 h. The reaction was quenched by
the addition of 3 N HCl (3.0 mL, 9.0 mmol, 0.9 equiv) and
water such that the pH was about 6. The mixture was diluted
with ethyl acetate (20 mL), and the layers were separated.
The organic solution was dried (MgSO4) and concentrated
to afford 1.12 g (92%) of 3.
3,3,5,5-Tetramethylcyclohexanone (4) Prepared in DEM.
Copper bromide dimethyl sulfide complex (21 mg, 0.10
mmol, 0.1 equiv) was slurried in DEM (10 mL) and cooled
to 0 °C. A solution of methylmagnesium chloride in THF
(3.0 M, 4.0 mL, 12 mmol, 1.2 equiv) was added dropwise.
The resulting mixture was warmed to ambient temperature
for 15 min and then cooled to 0 °C. Isophorone (3,5,5-
trimethylcyclohex-2-en-1-one)(1.50 mL, 10 mmol) was
added dropwise to afford a gray suspension. The mixture
was stirred for 30 min at 0 °C and then warmed to ambient
temperature and allowed to stir overnight. The reaction
mixture was treated with water (1 mL) and 3 M HCl (4.0
mL,12 mmol; 1.2 equiv). The layers were separated, and the
organic solution was dried (MgSO4) and concentrated to
afford 1.31 g (85%) of crude 4 which was 95.9% pure
according to GC analysis (area %). The 4 thus produced was
identical to an authentic sample.
3,3,5,5-Tetramethylcyclohexanone (4) Prepared in THF.
Copper bromide dimethyl sulfide complex (21 mg, 0.10
mmol, 0.1 equiv) was slurried in THF (10 mL) and cooled
to 0 °C. A solution of methylmagnesium chloride in THF
(3.0 M, 4.0 mL, 12 mmol, 1.2 equiv) was added dropwise.
The resulting mixture was warmed to ambient temperature
for 15 min and then cooled to 0 °C. Isophorone (3,5,5-
trimethylcyclohex-2-en-1-one)(1.50 mL, 10 mmol) was
added dropwise to afford a gray solution. The mixture was
130
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development

stirred for 30 min at 0 °C and then warmed to ambient
temperature and allowed to stir overnight. The reaction
mixture was treated with water (1 mL) and 3 M HCl (4.0
mL, 12 mmol, 1.2 equiv). Ethyl acetate was added, and the
layers were separated. The organic solution was dried
(MgSO4) and concentrated to afford 1.18 g (77%) of crude
4 which was 91.2% pure according to GC analysis (area %).
1-Benzyloxy-3-butyne (1) via Phase-Transfer Catalysis
in DEM. 3-Butyn-1-ol (0.91 mL, 12 mmol, 1.2 equiv) was
dissolved in 5 mL of DEM. Benzyl bromide (1.19 mL, 10
mmol) was added followed by tetrabutylammonium bromide
(161 mg, 0.50 mmol, 0.05 equiv). Water (1 mL) was added
followed by sodium hydroxide (2.00 g, 25 mmol, 2.5 equiv).
The resulting mixture was stirred for 1.5 days at ambient
temperature to completely consume benzyl bromide accord-
ing to GC analysis. The reaction mixture was diluted with
DEM, and the layers were separated. The resulting organic
solution was washed with water (5 mL), dried (MgSO4), and
concentrated to afford 1.60 g (99%) of 1 with no detectable
impurities (1H NMR analysis).
1-Benzyloxy-3-butyne (1) via Phase-Transfer Catalysis
in DCM. 3-Butyn-1-ol (0.91 mL, 12 mmol, 1.2 equiv) was
dissolved in 5 mL of dichloromethane. Benzyl bromide (1.19
mL, 10 mmol) was added followed by tetrabutylammonium
bromide (161 mg, 0.50 mmol, 0.05 equiv). Water (1 mL)
was added followed by sodium hydroxide (2.00 g, 25 mmol,
2.5 equiv). The resulting mixture was stirred for 1.5 days at
ambient temperature to completely consume benzyl bromide
according to GC analysis. The reaction mixture was diluted
with ethyl acetate, and the layers were separated. The
resulting organic solution was washed with water (5 mL),
dried (MgSO4), and concentrated to afford 1.63 g (99%) of
1 with no detectable impurities (1H NMR analysis).
Diethyl 2-Ethylmalonate (5) via Phase-Transfer Ca-
talysis in DEM. Diethyl malonate (1.52 mL, 10 mmol) was
dissolved in DEM (5 mL). Iodoethane (1.6 mL, 20 mmol,
2.0 equiv) was added followed by tetrabutylammonium
bromide (161 mg, 0.50 mmol, 0.05 equiv). Water (1 mL)
was added followed by 50% sodium hydroxide (1.60 g, 20
mmol, 2.0 equiv). The reaction mixture was stirred at ambient
temperature and assayed by GC. After 1 h, 94% consumption
of diethyl malonate was observed with a 99:1 ratio of 5 to
dialkylated malonate. After the mixture stirred overnight at
ambient temperature, complete consumption of diethyl
malonate was observed with a ratio of 5 to dialkylated
material of 94:6. The mixture was neutralized to pH 7 by
the addition of aqueous HCl. The layers were separated, and
the organic layer was dried (MgSO4) and concentrated to
afford 5 which was contaminated with dialkylated material.
The 5 thus produced was identical to an authentic sample.
Diethyl 2-Ethylmalonate (5) via Phase-Transfer Ca-
talysis in Dichloromethane. Diethyl malonate (1.52 mL,
10 mmol) was dissolved in dichloromethane (5 mL). Iodo-
ethane (1.6 mL, 20 mmol, 2.0 equiv) was added followed
by tetrabutylammonium bromide (161 mg, 0.50 mmol, 0.05
equiv). Water (1 mL) was added followed by 50% sodium
hydroxide (1.60 g, 20 mmol, 2.0 equiv). The reaction mixture
was stirred at ambient temperature and assayed by GC. After
1 h, 71% consumption of diethyl malonate was observed
with a >99:1 ratio of 5 to dialkylated malonate. After the
mixture stirred overnight at ambient temperature, complete
consumption of diethyl malonate was observed with a ratio
of 5 to dialkylated material of 99:1.
1,2-Diphenylethylene (6) in DEM. Benzyl triphenylphos-
phonium chloride (7.78 g, 20 mmol, 1.0 equiv) and benzal-
dehyde (2.03 mL, 20 mmol) were combined in 10 mL of
DEM. Aqueous sodium hydroxide (50%, 10 mL, excess) was
added, and the resulting mixture was stirred vigorously at
ambient temperature for 3 h. The reaction mixture was
diluted with DEM and washed with water, dried over
magnesium sulfate, and concentrated. The crude product
(6.76 g) was filtered through a pad of flash silica gel and
eluted with 1:4 ethyl acetate:heptane to afford 3.40 g (94%)
of 6 as a 55:45 E:Z ratio of isomers. E- and Z-6 were identical
to authentic samples.
1,2-Diphenylethylene (6) in Dichloromethane. Benzyl
triphenylphosphonium chloride (7.78 g, 20 mmol, 1.0 equiv)
and benzaldehyde (2.03 mL, 20 mmol) were combined in
10 mL of DEM. Aqueous sodium hydroxide (50%, 10 mL,
excess) was added, and the resulting mixture was stirred
vigorously at ambient temperature for 3 h. The reaction
mixture was diluted with DEM and washed with water, dried
over magnesium sulfate, and concentrated. The crude product
(8.90 g) was filtered through a pad of flash silica gel and
eluted with 1:4 ethyl acetate:heptane to afford 3.49 g (97%)
of 6 as a 46:54 E:Z ratio of isomers.
Ethyoxymethylmenthol (7). Menthol (3.91 g, 25 mmol)
was dissolved in DEM (25 mL). Amberlyst 15 acidic resin
(196 mg, 5 wt %) was added, and the reaction mixture was
heated to reflux for 2 h to consume about 80% of the menthol
(GC analysis). Most of the volatiles were removed between
65 and 85 °C to afford a 95:5 mixture of 7:menthol. DEM
(10 mL) was added, and the volatiles were azeotropically
distilled for 1 h at which point GC analysis indicated >99%
conversion. The reaction mixture was filtered, and solvent
was removed to afford 5.38 g (99%) of 7 which was >99%
pure by GC analysis. 1H NMR (CDCl3) δ 4.827 (d, 1H, J )
7.14 Hz); 4.639 (d, 1H, J ) 7.14 Hz); 3.7-3.5 (m, 2H);
3.366 (dt, 1H, J ) 4.21, 10.50 Hz); 2.2 (m, 1H); 2.083 (br
d, 1 H, J ) 12.09 Hz); 1.7-1.6 (m, 2H); 1.4 (m, 1H); 1.216
(t, 3H; 7.08 Hz); 0.911 (d, 6H, J ) 6.78 Hz); 1.1-0.8 (m,
4H); 0.779 (d, 3H, J ) 7.08 Hz).
OP000288C
Vol. 5, No. 2, 2001 / Organic Process Research & Development
•
131