Efficient preparation of 2-methyl-1,3-dioxolane-2-ethanol and 2-(2-bromoethyl)-2-methyl-1,3-dioxolane from 4-hydroxy-2-butanone

Article abstract of DOI:10.1081/SCC-120002130

2-Methyl-1,3-dioxolane-2-ethanol was prepared in 90% isolated yield from 4-hydroxy-2-butanone and ethylene glycol using a weak acid catalyst and ethyl acetate as the reaction solvent. 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane was prepared in 75% isolated yield by bromination of 2-Methyl-1,3-dioxolane-2-ethanol with dibromotriphenylphosphorane. The reagent was prepared in situ by titrating triphenylphosphine with bromine at an ice-ethanol bath temperature. The target compounds are useful methyl vinyl ketone equivalents.

Full text of DOI:10.1081/SCC-120002130

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EFFICIENT PREPARATION OF 2-METHYL-1,3-
DIOXOLANE-2-ETHANOL AND 2-(2-BROMOETHYL)-2-
METHYL-1,3-DIOXOLANE FROM 4-HYDROXY-2-
BUTANONE
a
Richard J. Petroski*
a
Agricultural Research Service , National Center for Agricultural Utilization Research ,
Bioactive Agents Research Unit , USDA, REE , 1815 N. University Street, Peoria, IL,
61604, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Richard J. Petroski* (2002) EFFICIENT PREPARATION OF 2-METHYL-1,3-DIOXOLANE-2-ETHANOL AND 2-
(2-BROMOETHYL)-2- METHYL-1,3-DIOXOLANE FROM 4-HYDROXY-2-BUTANONE, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:3, 449-455
To link to this article: http://dx.doi.org/10.1081/SCC-120002130
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SYNTHETIC COMMUNICATIONS, 32(3), 449–455 (2002)
EFFICIENT PREPARATION OF
2
-METHYL-1,3-DIOXOLANE-2-ETHANOL
AND 2-(2-BROMOETHYL)-2-
METHYL-1,3-DIOXOLANE FROM
4
-HYDROXY-2-BUTANONE
RichardJ. Petroski
USDA, REE, Agricultural Research Service,*
National Center for Agricultural Utilization
Research, Bioactive Agents Research Unit,
1815 N. UniversityStreet, Peoria, IL 61604
Fax: (309) 681-6693; E-mail: petrosrj@mail.ncaur.usda.gov
ABSTRACT
2
-Methyl-1,3-dioxolane-2-ethanol was prepared in 90% iso-
lated yield from 4-hydroxy-2-butanone and ethylene glycol
using a weak acid catalyst and ethyl acetate as the reaction
solvent. 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane was pre-
pared in 75% isolated yield by bromination of 2-Methyl-
1,3-dioxolane-2-ethanol with dibromotriphenylphosphorane.
The reagent was prepared in situ bytitrating triphenly-
phosphine with bromine at an ice–ethanol bath temperature.
*
Names are necessaryto report factuallyon available data; however, the USDA
neither guarantees nor warrants the standard of the product, and the use of the name
byUSDA implies no approval of the product to the exclusion of others that mayalso
be suitable.
4
49
Copyright & 2002 byMarcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
4
50
PETROSKI
The target compounds are useful methyl vinyl ketone
equivalents.
Methyl vinyl ketone equivalents such as 2-methyl-1,3-dioxolane-2-
1
ethanol (1) and 2-(2-bromoethyl)-2-methyl-1,3-dioxolane (2) are vital for
2
3
use in the formation of rings via a Robinson annulation strategy. Com-
pound 1 has been used in the preparation of the sex pheromone of the
4
western pine beetle, Dendroctonus brevicomis Le Conte. Robinson annula-
5
tion in the presence of an acid has been reported using compound 1.
Compound 2 has also been used in the synthetic pathway leading to the
male-produced sex pheromone of the Mexican fruit fly, Anastrepha ludens
6
Loew, and the Caribbean fruit fly, Anastrepha suspensa Loew; and it has
3
also been used in annulation as well as Grignard chemistries. Preparation
7,8
of compounds 1 and 2, in high yield and purity, would be beneficial.
Compound 1 has been prepared directly from 4-hydroxy-2-butanone
9
with hydrous zirconium oxide, but the yield was only 28%. A com-
pound [2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane], similar to 2, has
been prepared from a solution of methyl vinyl ketone in benzene using gas-
eous HBr to afford 4-bromo-2-butanone, which was subsequentlyconverted
to the desired bromoketal using a mixture of neopentanediol, triethyl-
1
0
orthoformate, and p-toluenesulfonic acid. Fractional distillation was
1
0
required to purifythe product and the isolated yi eld was only54%. Com-
pound 2 was prepared from methyl vinyl ketone via 4-bromo-2-butanone,
using relativelyexpensive bromotrimet hl sy ilane as the brominating
1
agent. Although the isolated yield was good (82%), the solvent was
1
1
1
benzene. Unfortunately, either chromatography on basic alumina gel
Al O /basic Brockman II) or fractional distillation was required to purify
(
the product.
2
3
1
1
In this paper, we report the direct conversion of 4-hydroxy-2-butanone
9
to 1 in high yield (improved from 28 to 90%), using a weak acid catalyst in
ethyl acetate for the ketalization process. The facile conversion of 1 to 2 in
good yield with dibromotriphenylphosphorane (Ph PBr ) is also reported.
3
2
Neither column chromatographynor tedious fractional distillation are
required in the workup for the preparation of either 1 or 2.

ORDER
REPRINTS
PREPARATION OF 2-METHYL-1,3-DIOXOLANE-2-ETHANOL
RESULTS AND DISCUSSION
451
Direct preparation of compound 1 from 4-hydroxy-2-butanone
usually results in low yield because of acid-catalyzed dehydration to give
9
methyl vinyl ketone. It was reasoned that the yield of compound 1 could
be improved if a weak acid catalyst were used. The formation of 1,3-
dioxolanes from aldehydes has been reported to occur in high yield using
1
2
tartaric acid ( pK ¼ 2.93) as catalyst. Acetalization of aldehydes was con-
a
ducted in refluxing benzene with anhydrous MgSO present to remove the
4
water forming during the reaction and thus improve the isolated product
1
yield.
2
Less-toxic ethyl acetate could replace benzene as the solvent for ketal
formation. Acetylation of either 4-hydroxy-2-butanone or ethylene glycol
was not observed. Anhydrous MgSO was more finelydispersed in refluxing
4
ethyl acetate than in refluxing benzene; therefore, is less likely to cause
bumping. Magnetic stirring was used in this reported synthesis, but the
use of mechanical stirring would be recommended for larger batches.
It is necessaryto separate compound 1 from unreacted ethylene glycol
in the workup. The task is not trivial since both substances have high water
as well as ethyl acetate solubility. Ethyl acetate was removed by rotary
evaporation and the oilyresidue was dissolved in CH Cl . Ethylene glycol
2
2
1
3
is practicallyinsoluble in CH Cl ; so it could be washed awayusing a
2
2
small volume of a saturated aqueous NaHCO solution. Because of the
3
high water solubilityof compound 1, it was necessaryto back-extract the
aqueous wash with CH Cl . Removal of ethylene glycol by this method
eliminated the need for tedious fractional distillation.
2
2
The preparation of compound 2 from compound 1 required bromina-
tion of the alcohol moietyin the presence of the acid-labile ketal function. It
was reasoned that this could be accomplished with Ph PBr because this
3
2
reagent has been used to brominate cis-homoallylic alcohols containing a
1
ketal function. The hygroscopic reagent Ph PBr was verydifficult to
4
3
2
handle in the open air. When water comes in contact with the reagent,
HBr is formed, and direct use of commerciallyavailable Ph PBr resulted
in considerable cleavage of the ketal protecting group. To avoid these prob-
3
2
lems, Ph PBr was prepared in situ bytitrating triphen yl phosphine with
3
2
bromine in a vessel cooled in an ice–ethanol bath and provided an inert
atmosphere. This procedure resulted in a good yield of compound 2 with
verylittle loss of the ketal protecting group.
In summary, compounds 1 and 2 have been prepared in verygood
yield and high purity without the need for either column chromatography or
tedious fractional distillation. The preparative routes to these important
synthetic intermediates have been conducted on a multigram scale.

ORDER
REPRINTS
4
52
PETROSKI
EXPERIMENTAL
General Details
Ethyl acetate, acetonitrile and pyridine were sufficiently dried by sto-
rage over 4 angstrom molecular sieves prior to use. Kugelrohr boiling points
are given as the oven temperature at which the product begins to distil.
Organic chemicals were purchased from Aldrich (Milwaukee, WI) unless
otherwise stated.
Preparation of 2-Methyl-1,3-dioxolane-2-ethanol (1)
Over a period of 10 min, anhydrous ethylene glycol (12.4 g, 200 mmol)
was added to a 500 mL round-bottomed flask containing 4-hydroxy-
2-butanone (10.2 g, 116 mmol; Lancaster Synthesis, Windham, NH),
d-tartaric acid (90 mg, 0.6 mmol), and anhydrous MgSO (4.0 g, 33 mmol),
4
in dryet hl y acetate (150 mL). The flask was then equipped with
a Dean-Starke adapter and condenser, and a nitrogen atmosphere
was introduced. A small amount of anhydrous MgSO4 (1 g) was
placed into the bottom of the Dean-Starke adapter prior to use, in
order to further remove water (reaction byproduct) that azeotropes
with ethyl acetate. The mixture was heated to reflux for 16 h then
allowed to cool. Solid NaHCO (420 mg, 5 mmol) was added to neutralize
3
the acid, and the mixture was stirred for 30 min. The reaction mixture
was then filtered and the filter cake was washed with ethyl acetate
(
was dissolved in CH Cl (200 mL). The solution was washed with
10 mL Â 3). The solvent was evaporated in vacuo and the oilyresidue
2
2
saturated aqueous NaHCO3 solution (10 mL) to remove unreacted
ethylene glycol. The aqueous NaHCO3 solution was back-extracted
with CH Cl (20 mL Â 3) and the CH Cl phases were combined.
2
2
2
2
After drying over anhydrous MgSO and a small amount of anhydrous
4
NaHCO , the solvent was evaporated in vacuo to give a pale yellow
3
oil (14.1 g). The crude product was distilled (Kugelrohr), to afford a
clear, colorless liquid (13.7 g, 90% yield). Purity was checked by gas
chromatography(GC) and found to be >98% before distillation and
ꢀ
5
ꢀ
>
1
7
99% after distillation. b.p. 56 C @ 2.5 mmHg. Lit., b.p. 135–139 C @
þ
5 mmHg. MS m/z (% base) 131 (M -1, 2), 117 (20), 99 (14), 87 (100),
1
3 (6), 55 (4), 43 (56). H NMR d 1.34 (3H, s, -CH ), 1.93 (2H, t,
3
J ¼ 5.5, -CH -CH -OH), 3.68 (1H, s, -OH), 3.74 (2H, t, J ¼ 5.5, CH -CH -
2
2
2
2
1
3
OH), 3.97 (4H, s, -O-CH -CH -O-).
2
C NMR d 23.8 (-CH ), 40.2
2
3

ORDER
REPRINTS
PREPARATION OF 2-METHYL-1,3-DIOXOLANE-2-ETHANOL
453
(
(
-CH -CH -OH), 58.9 (-CH -CH -OH), 64.7 (-O-CH -CH -O-), 109.0
2
2
2
2
2
2
-C-(OR) -).
2
Preparation of 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane (2)
To a 500 mL round-bottomed flask containing 1 (10.5 g, 80 mmol),
triphenylphosphine (27.3 g, 104 mmol) and anhydrous pyridine (9.6 g,
1
ꢁ
21 mmol) in dryacetonitrile (185 mL) under a nitrogen atmosphere at
ꢀ
10 to 0 C (ice–ethanol bath), bromine (17.1 g, 107 mmol in 15 mL of dry
acetonitrile) was added dropwise until a pale yellow color persisted. (The
color turns to bright yellow if an excess amount of bromine is added in this
titration step). The addition funnel containing anyexcess bromine is quickly
removed and the inert atmosphere is restored. The reaction mixture is
allowed to warm to room temperature graduallyover the course of 1.5 h
under a nitrogen atmosphere. The light yellow color fades during this time
as the excess bromine dissipates. The solvent was evaporated in vacuo to give
a nearlysolid mass composed of mainlytriphen ly phosphine oxide. The
nearlysolid mass was extracted with hexane (80 mL Â 5) byadding the
solvent and stirring vigorouslyfor 30 min before collection of the solvent
bydecantation. In the course of acetonitrile evaporation in vacuo, some
(
approx. 2%) of the product 2 was also distilled over. This was recovered
byan evaporation in vacuo, of the collected acetonitrile. The recovered
product was added to the combined hexane extracts. The extracts were
washed with saturated aqueous NaCl solution (10 mL) then with a solution
of 0.1 M CuSO (10 mL Â 3); the aqueous copper solution no longer turned
4
deep blue due to a copper–pyridine complex during the final wash.
The combined aqueous copper wash was back-extracted with hexane
(
Na SO (neutral drying agent added first to remove most of the water) and
20 mL Â 2). The hexane solution was dried over a mixture of anhydrous
2
4
anhydrous MgSO (slightlyacidic, but more efficient, dr yi ng agent added
4
15 min later) and stored overnight in the freezer to precipitate most of the
remaining triphenylphosphine oxide byproduct of the reaction. After filtra-
tion, the solvent was evaporated in vacuo to give a pale yellow oil (12.8 g).
The crude product was distilled (Kugelrohr), to afford a clear, colorless
liquid (11.3 g, 75% yield). Purity was checked by gas chromatography (GC)
and found to be >95% before distillation of >99% after distillation. b.p.
ꢀ
11
ꢀ
5
1
(
2 C @ 2.6 mmHg; lit., b.p. 42–46 C @ 0.4 mmHg. MS m/z (% base)
81 (M -15, 17), 179 (M -15, 17), 137 (5), 135 (5), 109 (8), 87 (100), 55
þ
þ
1
11), 43 (49). H NMR d 1.32 (3H, s, -CH ), 2.27 (2H, t, J ¼ 8.3, -CH -CH -
3
2
2
Br), 3.40 (2H, t, J ¼ 8.3, -CH -CH -Br), 3.94 (4H, m, -O-CH -CH -O-).
2 2 2 2

ORDER
REPRINTS
4
54
PETROSKI
1
3
C NMR d 23.9 (-CH ), 26.7 (-CH -CH -Br), 42.8 (-CH -CH -Br), 64.5
3
2
2
2
2
(
-O-CH -CH -O-), 110.0 (-C-(OR) -).
2 2 2
Analysis of Reaction Products
All reactions were monitored byGC using a Hewlett-Packard (HP)
890 Series II instrument equipped with flame ionization detector and inter-
faced to a HP ChemStation data system. The oven temperature was pro-
5
ꢀ
ꢀ
grammed from 50 to 250 C at 10 C/min; the programmable cool on-column
ꢀ
inlet temperature was always 3 C hotter than the oven temperature and the
ꢀ
detector temperature was 250 C. A DB-1 capillarycolumn (15 m  0.25 mm,
0.25-mm film thickness, J&W Scientific, Folsom, CA) was used with 1 mL
sample injections.
Electron impact mass spectra (70 eV) were obtained with an HP 5973
MSD instrument, equipped with a splitless injector. The oven temperature
ꢀ
ꢀ
was programmed from 50 to 250 C at 10 C/min; the injection temperature
ꢀ
ꢀ
was 250 C and the detector temperature was 250 C. An EC-1 capillary
GC column (30 m  0.25 mm, 0.25-mm film thickness. Alltech, Deerfield,
IL) was used with 0.3 mL sample injections. Proton NMR spectra (CDCl )
3
were obtained on a Bruker (Bellerica, MA) Advance 400 spectrometer
at 400 MHz. Chemical shifts are referenced to tetramethylsilane; coupling
constants (J ) are in hertz.
ACKNOWLEDGMENTS
We thank Bruce W. Zilkowski and Dr. Robert J. Bartelt for acquiring
mass spectral data, David Weisleder for acquiring NMR spectra, and
Dr. Robert J. Bartelt for helpful discussions.
REFERENCES
1
2
. 2-Methyl-1,3-dioxolane-2-ethanol has also been named 4-Hydroxy-2-
butanone ethylene ketal. Registry Number 5754-32-5.
. 2-(2-Bromoethyl)-2-methyl-1,3-dioxolane has also been named 1,3-
Dioxolane, 2-(2-bromoethyl-2-methyl, 1-Bromobutan-3-one ethylene
acetal, and 4-Bromo-2-butanone ethylene ketal. Registry Number
37865-96-6.
3. Jung, E.J. Tetrahedron 1976, 32, 3.
4. Meyer, H.H. Justus Liebigs Ann. Chem. 1977, 5, 732.

ORDER
REPRINTS
PREPARATION OF 2-METHYL-1,3-DIOXOLANE-2-ETHANOL
455
5
. Zoretic, P.A.; Branchaud, B.; Maestrone, T. Org. Prep. Proc. Int. 1975,
(1), 51.
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Soc. Jpn. 1990, 63, 1258.
9
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0. Stowell, J.C.; Keith, D.R.; King, B.T. In Organic Synthesis Vol. 62,
Semelhach, Ed. John Wiley& Sons, Inc., 1984, 140.
1. Hsung, H. Synth. Commun. 1990, 20(8), 1175.
2. Lu, T.J.; Yang, J.F.; Sheu, L.J. J. Org. Chem. 1995, 60, 2931.
3. Budavari, S. The Merck Index, 11th Ed. Merck & Co., Inc. 1989, 3759.
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1
1
1
1
Received in the USA March 19, 2001

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