Note: Descriptions are shown in the official language in which they were submitted.
This appl~cation is a divisional from copending Canadian Patent
Application Serial Number 215~57~ filed December 10, 1974. The aforesaid
patent application is directed to a novel process for the preparation of 3-
alkyl-cyclopentane-1,2-diones and in particular, to a novel process for the
preparation of 3-alkyl-cyclopentane-1,2-diones via the intermediates 2-alkoxy-
3,5-dicarboalkoxy-5-alkyl-cyclopent-2-ene-1-ones by thç condensation of esters
of glutaric acid and oxalic acid in a polar aprotic solvent in the presence
of an alkali metal alkoxide to form 3,5-dicarboalkoxy-cyclopentane-1,2-dione
dialkali metal salts, alkylating said salts with an alkylating agent to form
a 2-alkoxy-3,5-dicarboalkox~-5-alkyl-cyclopent-2-ene-1-one, removing said
solvent therefrom, and hydrolyzing the remainder to form a 3-alkyl-cyclopen-
tane-1,2-dione. The 3-methyl-cyclopentane-1,2-dione, is known as Maple
Lactone and finds immediate and practical utility as a flavoring agent in the
manufacture of synthetic maple syrup.
It is generally recognized that 3-alkyl-cyclopentane-1,2-diones are
materials having sweet characteristic flavors reminiscent of walnuts and have
been employed as flavoring additives in a variety of food products. In par-
ticular, 3-methyl-cyclopentane-1,2-dione is a white crystalline solid which
has been found to be useful as the primary flavoring agent in the preparation
of synthetic maple syrup and has come to be known as Maple Lactone.
Because of the well-accepted use of this product and its analogous
compounds, the art has been interested in developing economical and commercial
processes for the preparation of the 3-alkyl-cyclopentane-1,2-diones from
readily available starting materials. However, the processes known hereto-
fore in the patent and technical literature suffer serious technical deficien-
' cies which render them unsuitable for development into economical) commercial-
ly feasible processes.
One such patent, which relates to products of this type, is United
:, : ,
.: . : . . . . :
,: :: : : -
1~38~251
States Patent No. 2,865,962 which teaches the preparation of these compounds
by reaction of an alkyl acrylate with an alkali metal salt of an alkyl
alkoxalylpropionate and decarbox~lating the resulting cyclic compound. A
further method is provided for preparation of analogous products in United
States Patent No. 3,652,643, specifically the preparation of 2-hydroxy-3-
lower alkyl-cyclopent-2-ene-1-ones by cyclization of dialkyladipate to 2-
carbo-alkoxy-cyclopentan-l-one, alkylation thereof to 2-lower alkyl 2-carbo-
alkoxycyclopentan-l-one, introducing an appropriate halogen gas into an
anhy~rous reaction inert organic solvent solution of said 2-lower alkyl-2-
carboalkoxycyclopentan-l-one producing a product 2-lower alkyl-2-carbo-
methoxy-5,5-dibromo or dichloro cyclopentane-l-one, the acid hydrolysis of
the latter compound to yield the final product.
In addition, United States Patent No. 3,518,296 to Bucourt et al
teaches the preparation of 2-alkyl-cyclopentane-1,3-diones by the process of
reacting a beta-keto ester with an alkaline cyclizing agent, saponifying the
resultant 2-lower alkyl-4-carboxylate-cyclopentane-1,3-dione, decarboxylating
the resultant 2-lower alkyl-4-carboxy-cyclopentane-1,3-dione, and recovering
the 2-alkyl cyclopentane-1,3-diones.
Further, United States Patent No. 3,349,130 also to Bucourt teaches
a process for preparing the 2-alkyl-cyclopentane-1,3-diones which comprises
cyclizing a lower alkyl ester of 5-lower alkyl-levulinic acid in the presence
of an alkali metal tertiary alcoholate in an aprotic solvent to obtain a cor-
responding 2-lower alkyl cyclopentane-1,3-diones.
Another United States Patent, No. 3,671,589, teaches the prepara~
tion of 2-alkyl cyclopentane-1,3-dione by the reaction of succinic anhydride
with an appropriate carboxylic acid anhydride in the presence of aluminum
chloride and in an inert organic solvent. The acid hydrolysis of the latter
product yields the final product. In addition, each of the abovementioned
~, . .
'
.,.,~., ., ~ . .; .
... . , . . : . :-
. .
- ~ . .. :: . : :
: ~: : ', , :
: .: : , , . : . ~ ~ : ~
S~
United States patents also disclose various other prior art processes for
the preparation of compounds of this type.
None of the above processes, however, are considered to be particu-
larly pertinent to -the process of the instant invention.
Among the literature references which relate to the process of the
invention disclosed in the aforesaid Canadian Patent Application are articles
by Hesse et al, Liebig. Ann. 563, pp 31-53 (1949) and Gianturco et al,
Tetrahedron, 19, pp 2031-2049, ~1963). Aside from the fact that the starting
materials of the lnstant invention are mentioned by Gianturco et al, the
similarity between the process of the lnstant invention and the processes
mentioned b~ Hesse et al and Gianturco et al is remote.
As pointed out above, the aforesaid Canadian Patent application re-
lates to the preparation of 3-alkyl-cyclopentane-1,2-diones which may be
represented by the following general formula:
/ \ R
I. ;~
O ' ~
wherein R is alkyl of 1 to 5 carbon atoms but is preferably methyl.
It is to be understood, of course, that the compound of formula I
also exists as the l-hydroxy tautomer as illustrated by the following equa-
tion:
~ ~ OH
Thus the invention is inclusive of both products.
. . .
- 3 -
, . , . . , ~ .
These compounds are prepared by conde}lsing a dialkyl ester of
glutaric acid ~ith a dialkyl ester of oxalic acid, in a polar aprotic solvent,
in the presence of an alkali metal alkoxide and at temperatures sufficient to
effect condensation of said esters to form a first reaction mixture containing
3,5-dicarboalkoxy cyclopentane-1,2-dione dialkali metal salt, contacting said
first reaction mixture with at least an equimolar amount of an alkyl halide
under alkylating conditions to produce a second reaction mixture containing
2-alkoxy-3,5-dicarboalkoxy-5-alkyl-cyclopent-2-ene-1-one, removing said aprotic
solvent from said second reaction mixture and hydrolyzing said 2-alkoxy~3,5-
dicarboalkoxy-5-alkyl-cyclopent-2-ene-1-one by heating with a 10 to 30 percent
aqueous mineral acid solution to produce a 3-alkyl-cyclopentane-1,2-dione as
represented by formula I, above.
The present invention is directed to the preparation of the inter-
mediate 2-alkoxy-3,5-dicarboalkoxy-5-alkyl cyclopent-2-ene-1-one.
Accordingly the present invention provides a process for the prepara-
tion of a 2-alkoxy-3,5-dicarboalkoxy-5-alkyl-cyclopent-2-ene-1-one wherein
the alkyl and alkoxy radicals have from 1 to 5 carbon atoms and the carboalkoxy
radicals have from 2 to 6 carbon atoms, which comprises contacting a 3,5-
dicarboalkoxy-cyclopentane-1,2-dione dialkali metal salt wherein the carboal-
koxy radicals have from 2 to 6 carbon atoms with at least 2 moles of a Cl 5 .
alkyl halide per mole of 3,5,-dicarboalkoxy-cyclopentane-1,2-dione dialkali
metal salt under alkylating conditions.
While not wishing to be bound by any particular theory or mechanism
of reaction, it is believed that the reaction scheme of the present invention
is illustrated as follows:
i
.. . . , ~ ,~ ,, ~ :
~ .: ~' : ~, : .
Sl
2Na r~ COORl ~ CP~l
~RIOOC ~ ~ A
o OR
In the above equation R is alkyl of l to 5 carbon atoms, Rl is
lower alkyl of l - 7 carbon atoms, preferably methyl and X is halogen, prefer-
ably bromine or chlorine.
The 3,5-dicarboalkoxy cyclopentane-1,2~dione dialkali metal salt is
alkylated to $orm a 2-alkoxy-3,5-dicarboalkoxy-5-alkyl-cyclo-pent-2-ene-1-one.
According to the process of the invention, the 3,5-dicarboalkoxy-cyclopentane-
1,2-dione dialkali ~etal salt is reacted with at least an equimolar amount and
preferably a slight molar excess o an alkyl halide, preferably an alkyl halide
of the formula RX in which R is alkyl of 1 - 5 carbon atoms and X is bromine
or chlorine, with vigorous agitation while the alkyl halide i9 bubbled or
otherwise added to the crude slurry at as rapid a rate as possible except that `~`
no alkyl halide should be eluted from the reactor during the addition. The
alkylation reaction is carried out at about 70 - 120C, and a batch process
would require about 1 - 3 hours by use of external heat. If external heat is
not employed ~n~ the heat of reaction will cause the alkylation to proceed at
about 40 - 60C and require about 5 - 7 hours for completion. The alkylation
agents of choice are methyl, ethyl, n-propyl or n-butyl halides with the
halide being bromide or chloride. However, methyl bromide and ethyl bromide
are highly preferred.
. As this reaction proceeds and alkylation occurs, the contents of
the reactor gradually become less viscous and dark brown with crystals of
:'. '`'`~.
~ ~ 5 - ~ ~
'; :
., . .. , . , : : , : ~ . : . :
::.. :: .: :: . :. . , . . . . ,, . , ~ ~-.. . .
2Sl
alkali metal ~alid~ settling out when agitation ceases. At this point, the
aprotic solvent is stripped from the reaction at temperatures below about
120C and preferably under vacuum.
Preferably the 3,5-dicarboalkoxy cyclopentane-1,2-dione dialkali
metal salt is prepared by condensing a dialkyl ester of glutaric acid with
a dialkyl ester of oxalic acid, in a polar aprotic solvent, in the presence
of an alkali metal alkoxide and at temperatures sufficient to effect conden-
sation of said esters.
While not wishing to be bound by any particular theory or mechanism
of reaction it is believed that the ollowing illustrates the reaction
A. _ _
~ COORl =
I I COORI ~ 2~a R100~ ~ 0 ~ ~
COORl
_ ._ :` .
In the above equation Rl is as defined above.
The reaction is a condensation of approximately equimolar amounts
of the simple dibasic acid esters of oxalic acid and glutaric acid in the
presence of a polar aprotic solvent. The reaction may be carried out at a
temperature ranging from room temperature up to 120C, and preferably from
50 - 120C and in the presence of an alkali metal alkoxide which is present
in a molar excess and preferably with about 2 moles of the alkali metal
alkoxide for each mole of reactants. It should also be conducted free of
oxygen or in the presence of an inert gas such as nitrogen. After the reac-
tion is completed, the product is stirred vigorously, and any alcohol formed
in the reaction is allowed to distill, but it is not necessary to remove all
, - 6 -
, ~.. ,
: ; - ~ - .
5~
th~ alcohol formcd. Without the addition of external heat, it wi~l be ound
that the r0action is complete in about thr~e hours.
In the reaction the alkali metal alkoxide used is preferably alkali
metal methoxide, but other materials may be used with the same results, in-
cluding alkali-metal n-butoxides, ethoxides, n-propoxide or mixtures thereof.
The preferred alkali metal is sodium, but potassium or lithium may also be
used. Sodium methoxide and sodium ethoxide are highly preferred reagents.
One of the main features of the process of this invention is the
use of the aprotic solvent. As the aprotic solvent there may be used such
solvents as dimethylformamide, dimcthylsulfoxide, dimethylacetamide, sulfolane
and the like, or mixtures thereof. The highly preferred process of this in-
vention uses an aprotic solvent which has a high dipole moment, that is a di-
pole moment exceeding 1.5, and the above listed solvents fall within this
range. Dimethylformamide is the aprotic solvent of choice.
While it is possible to isolate intermediate products from step A
of the process, according to the scheme of this invention it is not necessary
or economical to do so. Thus, the final mixture from the initial reaction,
which is a thick light-brown solution that becomes a slurry after distilla-
tion or other removal of the alcohol formed, may be reacted as is without -
removal of aprotic solvent or purification of the intermediate in the second
step, alkylation step ~B).
The following examples will serve to illustrate the practice of the
invention.
EXAMPL~
3-Methyl Cyclopentane-1,2-Dione
2-Hydroxy-3-methyl cyclopent-2-ene-1-one)
A 5-liter three-necked round bottom flask is fitted with a thermo-
meter and nitrogen inlet tube, a mechanical stirrer, and a ten-tray Oldershaw
- 7 -
' :
~:. . , - : , - : ~ . ' . : ' - ' ; : ~
- , . ,: ; : , , - -:
.: ~ . . . ~ - . .
-
s~
column ~ith a condenser and ~ake-off head. The flask is purged with dry
nitrogen and charged with two liters of dry dimethylformamide, 292 grams
t2 moles) diethyl oxalate, 320 grams (2 moles) dimethyl glutarate, and 240
grams ~4.44 moles) of sodium methoxide. With the addition o sodium methoxide,
the temperature rose to approximately 50C. Continuing the nitrogen purge and --
while stirring, the pot temperature is taken to about 110C. During this time
the thick, light-brown solution is stirred vigorously and the methanol and
ethanol formed during the reaction is allowed to distill. It was not neces-
sary to remove all of the alcohol formed during the reaction. The reaction
ls complete at 110C pot temperature in about 30 minutes. The pot contains
the condensation products:
3,5-dicarbomethoxy cyclopentane-1,2-dione disodium salt,
3,5-dicarboethoxy cyclopentane-1,2-dione disodium salt,
3-carbomethoxy-5-carboethoxy cyclopentane-1,2-dione disodium salts,
hereafter referred to as 3,5-dicarboalkoxy cyclopentane-1,2-dione disodium
salt in Example 1.
Into the thick, light-brown slurry of 3,5-dicarboalkoxy cyclopen-
tane-1,2-dione disodium salt formed by the condensation reaction of the alkyl
esters of oxalic acid and glutaric acid as described in the above paragraph,
is bubbled 422 grams (4.44 moles) of methyl bromide with vigorous stirring
at as rapid a rate as possible, provided no methyl bromide is eluted from the
pot. This alkylation step is conducted at a temperature of about 70 - lO0 C
in 2 hours, using external heat. Without external heat, and the condensed
esters at room temperature, alkylation will proceed at a temperature of
45 - 55C. When about one liter of dimethylformamide is removed, the pot
! contents are filtered to remove the majority of the sodium bromide formed
;' during the alk~lation step. When all ~he dimethylformamide is removed, the
crude dark bro~n mixture (100 grams) contains mostly:
_ 8 -
.
,:- . ;:: : . :: : : . ::
5~
2-methoxy-3,5-dicarbomethoxy-5-methyl cyclopent-2-ene-l-one,
2-methoxy-3,5-dicarboethoxy-5-methylcyclopent-2-ene-1-one,
2-methoxy-3-carbomethoxy-5-carboethoxy-5-methylcyclopent-2-ene-1-one,
2-methoxy-S-carbomethoxy-3-carboethoxy-5-methylcyclopent-2-ene-1-one ;
(referred to hereafte~ in Example l as 2-methoxy-3,5-dicarboalkoxy-5-methyl
cyclopent-2-ene-l-one) and a small amount of sodium bromide.
The crude dark brown mixture of 2-methoxy-3,5-dicarbo-alkoxy-5-
methyl cyclopent-2-ene-1-one is mixed with 2 liters of 10% sulfuric acid and
heated at reflux with vigorous stirring for 3 hours. The resulting brown
solution is cooled to about 50C and filtered to remove small amounts of
black tars. The filtrate is cooled to room temperature and crystals ~about
90 grams) of 3-methyl cyclopentane-1,2-dione removed by filtr~tion. The
filtrate is extracted with three 300-ml portions of ethyl acetate to remove
the soluble product. The product crystals removed by filtration are added
to ~he ethyl acetate extracts and washed with a saturated sodlum bicarbonate
solution, then distilled water. The ethyl acetate phase is heated on a
steam bath to remove ethyl acetate, leaving the crude 3-methyl cyclopentane-
1,2-dione. Yields overall are 160-165 grams or 70-75% of theoretical from
the esters. The crude crystals of the product are recrystallized from ethyl -
acetate to give a material of M.P. 102-105C whose molecular weight is 112.
EXAMPLE 2
The condensation reaction of dimethyl glutarate and diethyl oxa- `;
late with sodium methylate, being exothermic, is repeated without adding ;
external heat. The time required for condensation is about three hours
during which time the pot temperature is 40C, when using sodium methylate.
In this example, no methanol is removed from the reaction mixture. Complete
condensation is indicated by a very thick, light-brown reaction mixture and
confirmed by gas chromatographic analysis showing the absence of the starting
;~ esters of glutaric and oxalic acid.
, ~ ~ - 9 - '.:'
J `:
s~
EX~MPLE 3
3-Methyl Cyclopentane-1,2-Dione
(2-Hydroxy-3-methyl cyclopent-2-ene-1-one)
The condensation reaction of equimolar amounts of dimethyl glutarate
and dimethyl oxalate with sodium methylate is repeated according to the pro-
cedure of Example 1.
Alkylation of the 3,5-dicarbomethoxy cyclopentane-1,2-dione di-
sodium salt with methyl bromide is accomplished also by the same procedure
bf Example 1.
10 Removal of the solvent dimethylformamide is accomplished in the
same manner as described in Example 1, leaving a dark brown mixture and con-
taining mostly 2-methoxy-3,5-dicarbomethoxy~s~cyclopent-2-ene-1-one which may
b- purified by first washing with water to remove the sodium bromide and
'
~, .
:,
:,
:; - 9a -
-: . , . . . - . ~ .
.. : . , .:
. . ~ . . .
vacuum distilling the organic phase at a temperatllre of 135 - 139C using a
20-tray Oldershaw column
EXAMPLE 4
The proc0dures of Example 1 and Example 2 are repeated using the
followin~ esters of oxalic acid and glutaric acid and mixtures thereof.
Oxalic Acid Esters Glut~rlc Acid Esters
Dimethyl oxalate Dimethyl glutarate
Diethyl oxalate Di0thyl glutarate
Di-n-propyl oxalate Di-n-propyl glutarate
Di-n-butyl oxalate Di-n-butyl glutarate
~.XAMPLE 5
3-Methyl Cyclopentane-1,2-Dione
~ ~.
The procedure of Example 1 is repeated using dimethyl acetamide in
place of dimethylformamide as the polar aprotic solvent. Subsequent hydrolysis
of the 2-methoxy-3,5-dicarboalkoxy-5-methyl cyclopent-2-ene-1-one yields
3-methyl cyclopentane-1,2-dione
EXAMPLE 6
3~Methyl Cyclopentane-1,2-Dione
~ e ~ ~ c ~ ent~2-ene l-one)
The procedure of Example 1 is repeated using dimethyl sulfoxide in
place of dimethylformamide as the polar aprotic solvent. Subsequent hydrolysis
of the 2_methoxy_3,5-dicarboalkoxy-5-methyl cyclopent-2-ene-1-one yields
3-methyl cyclopentane-1,2-dione.
EXAMPLE 7
The condensation products of dimethyl glutarate and diethyl oxalate,
referred to and prepared by the procedure in Example 1 as 3,5_dicarboalkoxy
cyclopent-2-ene-l-one disodium salts, are alkylated with ethyl bromide by
~.
- 10- ~
s~
mixing with 4.44 moles o~ the ethyl bromide at an alkylation temperature of
40 - lO0 C under alkylating conditions. The pot contents gradually became
less viscous and dark brown with crystals of sodium bromide settling out when
stirring ceased. The solvent dimethylformamide is stripped at 20 mm Hg and a
temperature of 70 - 80 C by the procedures of F.xample 1. The crude dark brown
mixture contains the four 2-ethoxy-3~5-dicarbo alkoxy-5-ethyl cyclopent-2-ene-
l-one compounds referred to in Example 1.
EXAMPLE 8
3-Butyl-Cyclopentane-1,2-Dione
(2-Hydroxy-3-butyl cyclopent-2-ene-1-one)
The condensation products of dimethyl glutarate and diethyl oxalate,
referred to and prepared by the procedure in Example l as 3J5-dicarboalkoxy
cyclopent-2-ene-l-one disodium salts, are alkylated with butyl bromide by
mixing with 4.44 moles of the butyl bromide at an alkylation temperature of
75 100C under alkylating conditions.
Subsequent removal of dimethylformamide solvent by the procedure of
Example 1 and acid hydrolysis yields the 3-butyl-cyclopentane-1,2-dione com-
pound.
EXAMPLE 9
3-Methyl Cyclopentane-1,2-Dione
~2-Hydroxy-3-methyl_cyclopent-2-ene-1-one)
The condensation products of dimethyl glutarate and diethyl oxalate,
referred to and prepared by the procedure in Example l as 3,5-dicarboalkoxy
cyclopent-2-ene-1-one disodium salts, are alkylated with dimethyl sulfate by
mixing with 4.44 moles of the dimethyl sulfate at an alkylation temperature of
40 - 100C under alkylating conditions. Subsequent removal of dimethylforma-
; mide and acid hydrolysis yields 3-methyl-cyclopentane-1,2-dione.
1 1
., . . : - . :
::, ' : . , ,:, ; : ' ~ ' : '
:~ .
':.- ' ' . ' ~ , .
. , , . , ~ . . . . .
~38~
XAMPLE 1 0
3-Methyl-Cyclopentane-1,2-Dione
(2-Hydroxy-3-methyl-cyclopent-2-ene-1-one)
The condensation products of dimethyl glutarate and diethyl oxalate,
referred to and prepared by the procedure in Example 1 as 3,5-dicarboalkoxy
cyclopent-2-ene-1-one disodium salts, are alkylated with methyl chloride at
an alkylation temperature of 40 - 100C under alkylating conditions. Subse-
quent removal of dimethylformamide and acid hydrolysis yields 3-methyl-cyclo- .
pentane-1,2-dione.
While the invention has been described by way of specific examples
it is not to be limited thereby and it is manifestly obvious that numerous
modifications and variations of the invention will occur to those skilled in
the art without departing from the spirit and scope of the invention. Thus,
the invention is not to be limi~ed excrpt by the scope of the sppended claims.
.
,:
.'i .;
~ 12 _ ~
