Note: Descriptions are shown in the official language in which they were submitted.
3L2L~L~3125
Description
5-~alo-4H-1,3-Dioxin ~-One Compoun~ n-~alo-
Acetoacetic Ester~ Pre~ared frsm Such Com~ounds
and Proces ~ n
Back~roun of the Invention
This invention relates to halogenated 4~-1,3-
dioxin-4-one compounds and their preparation and the
use of such halogenated 4~-1,3-dioxin-4-ones for the
10 pre~aration of ~-haloacetoacetic esters.
The preparation of acetoacetic esters by the
reaction of alcohols and diketene in the presence of
an acid catalyst has been described by A. ~. Boese in
Ind. ~. hem. 32, 16 (194~). The sodiuDI enolate
15 salt of ethyl acetoacetate has been reported by Chick
et al, Journal of American Chemical Society ~3, ~46
~lY08~ and 97, 197h (1910~ to be produced by reacting
diketene and sodium ethoxide in dry alcohol. The
desired ~-halogenated product may be obtained ~y
20 treating ~he ace~oacetic ester with a suitable
halogenating agent, e.g. ~02C12. [~ee Boehme,
org. ~X~ Cvll., Vol. 4, S~O ~1~63)~.
Reported by Blom~uist et al in Journal of American
S~ LL ~5Ea~ Vol- 70, page 29 (1948) is the
25 preparation of ethyl 2-bromoacetoacetate by first
treating ketene dimer in ~hloro~orm solution with
N-bromosuccinimide followed ~y reac~ion with ethyl
alcohol. The 2-chloro derivative was similarly
prepared by treating ketene dimer with N,2,4-
30 trichloroacetanilide ~ollowed by reaction with ethylalcohol. ~eported yields are 43~ and 35~,
respectively.
A new intermedia~e compound, halogenated 4~-1,3-
dioxin-4-one, has now been ~ound which provides an
~L2~8~5
alternate method for producing ~ aloacetoacetiG
esters.
It has been found that by reacting a halogenating
agent ti.e., X2 or S~X2 wherein X is Cl or Br)
with a 4~-1,3-dioxin-4-one compound the ~nono-
halogenated derivative, 5-halo-4~-1,3-dioxin-4-one, is
obtained.
The 5-halo-4H-1,3-dioxin-4-ones are o~tained in a
relatively short reaction time and excellent yield.
The unpurified product, for many uses, need not be
purified before being used in subsequent reactions.
In addition, halogenation is achieved without the use
of expensive halogenating agents. These 5-halo-4H-
1,3-dioxin-4-ones can then be reacted with alkali
metal alkoxides to give acetoacetic esters mono-
halogenated at the a-PositiOn.
Summary of the Invention
The present invention relates to 5-halo-4H-1~3-
dioxin-4-one compounds, a-haloacetoacetic esters
prepared from such compounds and to processes for tlle
preparation of such compounds. The 5-halo-4H-1,3-
dioxin-4-one compounds have the formula
3 /-lb ~
and are produced by treating a compound haviny the
formula
R
30 / ~ ~ 2
~3~H / ~ / ~ 1
with X2 or S02X2 an~ recovering tlle produc~
resulting therefrom.
ï2~8~L25
The 5-halo-4H-1,3-dioxin-4-ones are then reacted
with an alkali metal alkoxide at a temperature of
about -40C. to about 50C. to give an ~-haloaceto-
acetic ester. This reaction may be represented by ~he
following reaction
3 ,d~ R OM ~ > R3CH2 B ~ H ~ -o-R4 ~ Rl ~ R2
1~ (II) ~III~
The ~-haloacetoacetic esters obtained ~y this
process are useful intermediates for synthesizing a
wide variety of compounds including, for example,
pharlnaceuticals and dye in~ermedia~es as descri~ed in
U.S. Patent No. 3,876,647 (1~75); J. Am. Chem. ~oc.
57, 1876 (1935); J. r~. Chem. 43, 3821 ~1978); and
Chem. Ber. B8, 130 (1955). In the above formulae X is
~1 or Br; Rl and x2 are each inde~endently alkyl,
aryl, substituted aryl, or collectively alkylene; R3
is hy~rogen, Cl, Br, alkyl, alkoxy, aryl, substituted
aryl, or a hetero moiety. R4 can ~e alkyl or
aralkyl: and M is an alkali metal ion.
petaile~ DescriPtion o~ the Invention
The invention described herein relates ~o
2~ S-halo-4~-1,3-dioxin-4-one compounds, ~-haloaceto-
acetic esters prepared ~rom such compounds and
processes for their preparation.
Rl and R2 of the above formulae, are residues
of the aliphatic or cyclo~ llatic ketone from which
the ~-1,3-dioxin-~-one compounds are derived, can
each independently be alkyl, aryl, su~stituted aryl,
or collectively alkylene. The al~yl substituents fvr
Rl ~nd R2 generally can be lower ~lkyl (i.e.,
Cl-C6~, either branched or straight chain.
i24t~5
_ 4 _
~xamples of these include methyl, ethyl, propyl and
isobutyl. Tne aryl su~stituent generally can be
phenyl and the su~sti~uted aryl group may contain any
substituent which is not reactive with the halogenat-
ing agent or alkali metal alkoxide or does not oth~r-
wise interfere with the oourse of the reactions.
~xamples of su~stituted aryl groups include p-nitro-
phenyl and o-chlorophenyl. Examples of the alkylene
groups are tetramethylene and pen~amethylene [i.e.,
2(~2J2C~2- and -C~2~c~2J3c 2-]
Most com~only and preferably R and R2 are each
methyl.
The alkyl substituent for X3 of the a~ove
formulae may be satura~ed or unsaturated and s~raight
or branched chain alkyl of about Cl-C20 carbon
atoms. The alkoxy substituent generally can have 1-4
car~on atoms. ~xamples of the alkoxy ~ubstituent
include methoxy and ethoxy. The aryl su~stituent
generally is inten~ed to mean phenyl and substituted
aryl and inc}udes, for example, p-nitrophenyl.
Examples of the hetero su~s~ituen~s include phenyl-
thio, anilino and diethyl phosphonato li.e.,
( CH3CH20 ) 2PO ] -
The alkyl substituents o~ the alkyl and aralkyl
substituents for R4 ~re generally lower alkyl ti.e.,
Cl-C6). Examples include methyl, ethyl, iso-
propyl, isobutyl, and benzyl. Prefera~ly, R4 will
be methyl or ethyl.
The alkali metal ion, represented by M in the
a~ove formula, may be sodium, lit~ium ~r potassium
with sodium being preferred for reasons o~ economy.
~ he starting materials as shown ~y formula lI) are
known in the ar~ and/or are readily obtained by
methods known to one skilled in the art. ~For
example, see Boeckman, Journ. or~. Chem. 47, 2823-2824
~L24~3~25
(1982); Blomquist, Journ, Amer. Chem. Soc. 70, 29-30
(1948)].
q'he 5-halo compounds of formula II are prepared by
treating a 1,3-dioxin-4-one of the forlnula
tl ~ ~ I
R3C~2/ b' \~1
with X2 or S02X2, wherein X is Cl or Br.
Elemental chlorine or ~romine are the preferre~
halogenating agents. The conditions of the reaction
may be varied considerably, de~ending on the
halogenating agent used and whether the reaction is
carried out in a gaseous or liquid ~hase. In carrying
out the reaction, for example, using elemental
chlorine or bromine and in a liquid phase the reaction
is carried out at temperatures and ~ressure sufficient
to maintain chlorine or ~romine in liquid form, i.e.
at atmospheric pressure the temperature for chlorine
will be below -35C and below 59C for bromine. U~
course, higher temperatures may be used with the use
of elevated pressures. It was unex~ected that
haloyenation in this manner would give monohalogena-
tion at the 5-position of the dioxinone riny.
In carrying out tlle reaction in a liquid phase a
solvent is not required but one may be use~ if
desired. Typical solvents which may be used are, for
example, aliphatic or aromatic llydrocar~ons, or
chlorinated aliphatic or aromatic }~ydrocar~ons,
including, for example, methylene chloride, chloro-
form, benzene, chlorobenzene and the like. The amount
of solvent generally will be dictated ~y economy an~
convenience. A by-product of the halogena~ion
reaction is a hy~rogen halide. This by-product
generally may ~e removed by addi~ion of a ~ase to the
~2~125
product mixture such as an amine or carbonate salt,
including, for example, pyridine triethylamine, or
~odium carb~nate.
~he halogenating agent will yenerally be employed
in stoichiometric amounts and preferably in sliyht
excess, up to about 1.2 moles per mole of (I).
Advantageously, monohalogenation of (I~ is achieved
rapi~ly, giving 5-halo-4~-1,3-~ioxin-4-ones in
excellent yield and of sufficient purity as not to
o require purification ~rior to the use thereof in
subsequent reactions. Of course, when ~3 is Cl or
Br the dihalogenated compoun~ will be the resultin~
~roduct. When a product of even higher purity is
desired the crude 5-halo-~-1,3-dioxin-4-ones l,lay ~e
purified, for example, by column chromatograpl~y or
distillation with wi~ed-film eYaporation.
The S-halo-4N-1,3-dioxin-4-ones can then be use~
in the preparation of ~-haloacetoacetic esters.
~epending on the acetoacetic ester desired, these
2~ compounds ~ay be reacte~ with a phenol compound or an
alkali metal alkoxi~e to obt~in ~-haloacetoacetic
esters of the formula
R CH2~ ~ H ~ -~ III
In the above formula X is Cl or ~r, ~4 is the
residue of the phenol reactant or the alkali metal
alkoxide reactant, and R3 is as previously de~ined.
~ he phenol reactant Rnd the alkali metal alkoxide
r~aotant may be re~resented by ~he ~ormula ~4V~i
wherein R4 i-~ alkyl, aryl or aralkyl and M is an
alkali metal ion when ~4 is alkyl or M is hydroyen~
when ~4 is aryl. The alkyl ~ubstikuents are
generally lower alkyl having 1 to 6 carbon atoms such
as methyl, ethyl, isopropyl or aryl such as benzyl,
~Z~ 2~
preferably methyl or ethyl. The alkali metal ion,
represented by M in t~e above formula, a~ noted
heretofore, may be sodium, lithium or potas~ium witb
~odium being preferred ~or reason6 of economy. The
5 mole ratio of alkali metal alkoxide to dioxene
generally may be in tAe range of a~ least l.0 up to
about 2.0 with best results being obtained wi~h a mole
ratio of about l.0 to about 1.2.
The mole ratio of compound (III) to compound (II)
10 generally may be in the range of at least about 1.0 up
to about 2.0 wi~h best result6 being obtained with a
mole ratio of about 1.0 to about 1.2.
The temperatures at wbicb tbe reaction can be
carried ou~ will depend on tbe particular acetoacetic
15 ester prepared, i.e. depending in part on ~hether
compound (III) i6 a pbenol or an alkali metal
alkoxide. Temperatures in the range of about -400 to
about 50C and preferably ambient temperatures, i.e.
0-25C, will generally be u6ed with an alkali metal
20 alkoxide. With a phenol compound, the reaction
temperature may range Prom about 100 to about 200C
and preferably about 120 to about 145C. Thus, the
range of temperature6 at which the a-haloacetoacetic
e6~er~ can be prepared can vary from about -40C up to
25 about 2000C.
A solvent may be used in preparing the a-halo-
acetoacetic esters if desired. When an alkali metal
alkoxide is used the solYent desirably i~ an al~anol
baving tbe 6ame number of carbon atoms dS the al~oxide
30 reactant. When compound (III~ i6 a pbenol the solvent
can be, for example, toluene, xylene, and ~he like.
The amount of ~olvent is not crit~cal to the reaction
and generally will be dictated by economy and
convenience.
:~Z48~L25
The a-haloacetoacetic ester which i6 initially
formed as an enolate 6alt can be reacted further to
produce otber derivative6 or converted to the free
ester by acidification.
S The following examples are given ~o further
illustrate the invention, bu~ it i6 to be under6tood
~hat the invention i6 not to be limited in any way by
the details described therein.
XAMPLE 1 - Preparation of 5-Bromo-2,2,~-Trimethyl-4H-
1,3-Dioxin-4-One
Bromine (0.105 mol, 5.38 ml) was added dropwise to
a 20C 601ution of 2,2,6-trimethyl-4H~1,3-dioxin-4-one
(T~D, 0.1 mol, 14.2 9~ in 100 ml CH2C12 over fiYe
minute6. The reaction ~olution wa6 rapidly
15 decolorized and ~ydrogen bromide e~olved. After 15
minute~, the solvent wa6 removed in vacuo to provide
22 g (99~, ~95~ pure by NMR) of a pale yellow oil
which solidified upon refrigeration. Flash chromato-
graphy (10~ ~ther/hexane on æilica) afforded 16.5 g
20 (753) of t~e title compound a~ colorless plates.
~XAMPLE 2 - Preparation of 5-Chloro-2,2,6-Trimethyl-
1,3-~ioxin-4-One
A ~olution of 2,2,6-trimethyl-1,3-dioxin-4-one
(0.2 mol, 28.~ g) in 100 ml of ~H2C12 wa~ cooled
25 to -50C a~d liguid chlorine tO.25 mol) was added
dropwi6e over ~ive minutes. The solution was allowed
to warm to 20C over 30 minutes, and the solvent was
then removed in vacuo, leaving 35.8 g tlOO% yield, 92%
as6ay) of a pale yellow oil. A portion of ~i6
30 mixture wa6 purified by flash chromatography (10
Et20/~exanes on silica) to provide the title
compound as white crystal6.
~48~
XAMPLE 3 - Preparation of 4-Nitrophenyl 2-Chloroaceto-
acetate
A 601ution of 5-chloro-2,2,6-trimethyl-4H-1,3-
dioxin-9-one (8.8 g, 50 mmol) and 4-nitropbenol
5 (7.65 g, 55 mmol) in 5 ml of xylene u~der continuous
nitrogen purge was immersed in an oil batb preheated
to 110C. The reaction was then beated to 135C and
then stirred an addiSional 15 minute~. The pale brown
reaction was cooled to 20C and the precipitated
lQ product washed with ether~hexanes to afford 10.9 9
(89%) of the title compound as flaky, white cry~tals.
EXAMPLE 4 - Preparation of Methyl-a-Chloroaceto-
acetate
A solution of 25~ sodium methoxide in methanol
15 (5 ml, 21.6 mmol) wa6 added to a ~olution of 5-chloro-
2,2,6-trimethyl-4H-1,3-dioxin-4-one (3.24 g, 18.q
mmol) in 10 ml of methanol at 20C. The resulting
yellow solution wa~ stirred for 10 minutes, acidified
with 10% HCl, and extracted with ether. Evapora~ion
20 Of the ether provided 2.35 g ~gga yield, NMR assay
~90%~ of a pale yellow oil, which wa~ di~tilled to
provide 1.~ g (66%) of pure title compound as a
colorles6 liguid.
EXAMPLE 5 - Preparation of Etbyl-a-Chloroacetoacetate
.
Sodium metal ~0.3 9, 12 mmol) was added to 10 ml
of ethanol, ~nd tben 5-~hloro-2,Z,6-trimet~yl-~H-1,3-
dioxin-4-one (1.76 g, 10 mmol) was added. The
reaction was tirred one bour at 20C, during whicb
time ~he 60diu~ di~solved. Tbe reaction partitioned
30 between et~er and saturated ammonium chloride whicb
had been a~idified to pH ~2 wit~ HCl. Evaporation
of the ethereal layer, followed by distillation
~;~4~
- 10 -
afforded 1.15 g (70%) of the title compound a6 a
colorle6s liquid.
EXAMPLE 6 - Preparation of Ethyl-a-Bromoacetoacetate
Sodium metal (13.7 g, 0.59 mol) was di6solved in
5 500 ml of ab601ute ethanol, and the re6ulting ethoxide
solution was cooled to 0C. Crude 5-bromo-2,2,6-tri-
methyl-4H-1,3-dioxin-4-one (115.5 g, 0.5 mole at 95
purity) wa6 then added, dropwise, to the chilled
ethoxide solution over 30 minute6 and the dark orange
10 reaction mixture was 6tirred an additional 30 minutes
at 0C. The reaction WdS poured into 500 ml of ether
and 550 ml of lN HCl, and the organic layer was washed
repeatedly with water (4 x 250 ml) and then dried over
Na2S04. Removal of solvent in vacuo (30C, 2
5 Torr), followed by di~tillation on a 2-inch wiped-film
molecular 6till (120~C jacket, 0.2 Torrl afforded
68.7 g (7}~) of a pale yellow oil (98% pure by gc~.
The invention has been described in detail with
particular reference to preferred embodiments therevf.
20 but it will be under6tood that variation6 and
modification6 can be effected within the 6pirit aDd
6cope of the invention.
