US 2188874 A
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Patented Jan. 30, 1940 UNITED STATES PATENT OFFICE SECONDARY Ar-ALKENYL MALONIC ESTERS AND PROCESS OF PRODUCING SAME Arthur 0. Gone, Bryn Mawr, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Application October 15, 1936, Serial No. 105,820
3 ooom in which R. is a secondary Ai-alkenyl radical and R1 is an alkyl radical or an aralkyl radical, and in which either the secondary alkenyl radical has more than three carbon atoms, or the alkyl or aralkyl radical is higher than methyl, I and R2 is an alkyl radical, or the like. The secondary alkenyl radical, represented by R, in general has the following structure: I
in which R3, R4 and Rs'may be alkyl groups,
saturated or unsaturated, aralkyl groups, aryl groups, or other hydrocarbon or substituted hydrocarbon residues, and may be alike or different,
in which R4 or R5, or both, may be hydrogen. The new products are advantageously prepared by the alkylation of the corresponding secondary alkylidene malonic esters, inthe course of which the double bond uniting the alkylidene group and the malonic ester group is shifted to the A1 position, so that the alkylidene group is changed, by isomerization or other means, to the corresponding secondary alkenyl group with the double bond in the A1 position, as shown in the equation:
(or ma. R. OOOEt (oinm, R. CODE OOOEt Rd 000m In general, the'secondary Ai-alknyl group in the alkenyl malonic esters can vary widely, as all of the secondary alkylidene malonic esters can be transformed into corresponding secondary A1- alkenyl malonic esters by the novel processes of this invention, and the range ofsecondary A1- ,alkenyl esters which may be produced is limited onlylb'y the availability of the corresponding' alkylidene malonic esters. v
, Thenew products are useful as intermediates for the'production of secondary Ai-alkenyl barbituric acids and thiobarbituric acids, which may readilybe produced by the condensation of urea or thiourea with the corresponding malonic esters, and'are also useful for the production of unsaturated acids, by the de-carboxylation of the malonic esters.
In accordance with the process of the invention, the secondary alkylidene malonic esters may be subjected, in solution, to alkylation with a suitable alkyl halide, sulfate, or other alkyl salt, in the presence of a sodium alkoxide, such as sodium methoxide or sodium ethoxide," or in the presence of metallicv sodium, in an inert solvent. In this latter process, the sodium reacts first with the alkylidene malonic ester to give an intermediate sodio-derivative, which in turn reacts with the alkyl salt. In the course of the reaction which takes place, the double bond of the alkylidene malonic ester shiftsto the A1 position in the alkenyl group, and the alkyl group of the halide, sulfate or other salt becomes attached to the methylene carbon of the malonic ester.
The invention will be further illustrated by the following specific examples, with particular reference to the production of new secondary A1- alkenyl alkyl malonic esters, but it is not limited thereto T Example 1 .Preparation of isopropenyl' allyl malonic ester oHF' ooo'Et T I oHl=o'HoH= ooonzfl Into a suitable reaction vessel, equipped with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer are placed 300 parts of anhydrous alcohol in which are dissolved 11.5 parts of sodium. The solution is cooled below 0 C. by means of an ice-salt mixture and parts of isopropylidene' malonic ester are slowly added, with agitation, at such a rate that the temperature of the mixture does not rise above 0 C. After'all' of the ester has been'added, the stirringis continued-for'several minutes and 93 partsof allyl bromide are added in one portion. The molar ratio of allyl bromide and isopropylidene malonic ester used is 3 to 2. After the allyl bromide is added, the cooling bath is removed and the reaction mixture is rapidly warmed to the refluxing temperature, at which time a noticeable reaction takes place. The reaction should not be allowed to proceed too vigorously. When the reaction starts, sodium bromide precipitates from the solution, The refluxing and stirring are continued for about ,8 to 'l l'hours, and the mixture is allowed to stand overnight. It is then diluted with .about2. volumes of water, the organic layer r CHFC 'ooont 0111920151 COOEt 'l1.5 parts of sodium are powdered under xylene and rinsed into a reaction vessel equipped with a stirrer, a reflux condenser and a dropping funnel with about 400 parts of dry ether. The vessel is cooled in an ice bath while parts of isopropylidene malonic ester are added, with stirring, over a period of 10 minutes. The stirred suspension (the sodio-derivative is relatively insoluble) is then refluxed for about 10 hours, after which parts of diphenyl-methyl bromide is added over a period of 10 minutes, and the refluxing is continued for another 2l hours. Dilute hydrochloric acid is added, the ethereal layer is removed, and the aqueous layer is extracted with ether. The ether is removed from the combined ethereal layer andextract at reduced pressure, and the residue is shaken with ammonia to remove unalkylated material. The ester is extracted from the ammonia with ether, washed with water, and purified by distillation and recrystallization. It melts at 89.5-90.5 0.
Sodamide may be used in place of rnetallic sodium in the process of the preceding example; but if sodamide is used, it must be handled with due precautions, as, if not properly handled, it is explosive. safely involves dissolving it in liquid ammonia, admixing the solution with an inert solvent such as benzene, ether or the like, and removing. the liquid ammonia by vaporization. The inert solvent, containingthe sodamide, may then be used in the process. Almost any solvent inert to sodium, such as ether, benzene, toluene, etc., may be used in carrying out the process of the foregoing example. I
Example 3.Preparation of isopropenyl ethyl malonic ester,
CH; CHFJ} 000E:
c (3235 COOEl Diethyl sulfate, isopropylidene malonic ester, and sodium ethoxide are reacted under substantially the same conditions, and in the same molar ratio, as in Example 1, .except that ether is used as the solvent, and the resulting isopropenyl ethyl malonic ester is separated and purified by distillation. It boils at 128-129 C./24 mm.
Example 4.Preparation of n-butyl isopropenyl malonic ester,
CH: OOOEt 1 CH2: -o v CHSCHQCHICfii OOOEt 11.5 parts of sodium, 100 parts of isopropylidene malonic ester, and 88.parts of n-butyl iodide are reacted under substantially thev same conditions asin Example 2 using benzene as the solvent,
with the production of' the above product, which may be purified by distillation. It boils at 136 One way in which it may be used.
132 C./20 mm.
In the processes of the foregoing examples,
various alkyl salts, such as the sulfates, halides, 7
etc, may be used for the conversion of the alkylidene malonic esters, to the corresponding secondary Ai-alkenyl malonic Jesters, presence of sodium methoxide or sodium ethoxide or other alkoxides. When the halides are used as alkylating agents, it is preferable to use the more reactive bromides and iodides, as they give somewhat better yields, but the chlorides i may be used if desired.
The groups which may be so introduced include; not only the primary alkyl groups, but
in the also the secondary alkyl groups, such as the isopropyl or secondary butyl groups, as well as the unsaturated alkyl groups, such as the allyl, crotyl and citronellyl groups, aralkyl groups, such as berizyl and the like, cyclic groups, such as the cyclohexyl or cyclopentyl groups, etc.
Among the compounds which may be somepared, and which are new products, useful as intermediates in the production of other products, are the isopropenyl derivatives, in which.
the bond of the methylene carbon of the malonic ester not attached to the isopropenyl group may be attached to one of the following radicals:
secondary) and others. Other secondary alkenyl malonic esters, inwhich one-bond of themethylene car;- bon is attached to one of the above radicals, or T methyl, and which have in" place of 'the" iso--.
propenyl group oneof the following radicals are "also included in the invention as new products:-
1-methyl-A1+n-.propenyl l-methyl-Ai-butenyl (normal oriso') l-methyl-Air-pentenyl (normal oriso') l-methvl-Ai-hexenyl (normal or-iso) lemethyl-Ai-heptenyl. (normal or iso) l-ethyl-Ai-propenyl 'I-rn-prQpyl-Ar-butenyI l-butyl-Ai-pentenyl and others.
The secondary alkylidene malonic esters, used for the production of the secondary Ai-alkenyl malonic esters, maybe produced in any suitable manner; but they areadvantageously produced by the condensation'ofa ketone with malonic ester inthe presence of zinc chloride, zinc chloride' and acetic anhydride, or other condensing agents.
The new products of the present invention may be prepared by other processes than those described above, but the process'in which the secondary alkylidene malonic esters and the alkylating salts are reacted inan inert solvent in the presence of metallic sodium is of particularadvantage.
g h I I r 2,188,874 1. As new products, compounds of the formula 1 31 ooom p in which R is a secondary A1-alkenyl group, R1
is a radical selected from the class consisting of alkyl and aralkyl radicals having at least two carbon atoms, and R2 is alkyl.
2. Compounds of the formula I n coon,-
in which R is a secondary Ai-alkenyl group hav- 'ing more than three carbon atoms, R1 is an lonic acid has more than one carbon atom.
4. Alkyl esters of secondary Ai-alkenyl alkyl malonic acids, in which the alkenyl group has more than three carbon atoms. v p 5. Alkyl esters of allyl isopropenyl malonic acid. i
6. Alkyl esters of butyl isopropenyl malonic acid.
7. Alkyl esters'of ethyl isopropenyl malonic. acid. v
8. The process of producing alkyl esters of secondary A1-alkenyl malonic acids which comprises reacting an'alkyl ester of a secondary alkylidene malonic acid with an alkyl salt in the presence of an alkali metal alkoxide.
v9. The process of producing alkyl esters or secondary Ai-alkenyl malonic acids which comprises reactingan alkyl ester of .a' secondary alkylidene malonic acid with an alkyl salt in the presence of a sodium alkoxide.
10. The process oi producing alkyl esters of secondary A1-alkeny1 malonic acids which comprises reacting an alkyl ester of a secondary alkyl-idene malonic acid withan alkyl salt in the presence of a substance of thegroup consisting of alkali metals, alkali metal amides, and alkali metal alkoxides in an inert solvent.
11. The process of producing alkyl esters of secondary Ai alkenyl malonic acids which comprises reacting an alkyl ester, of a secondary alkylidene malonic acid with an alkyl salt in the presence of metallic sodium in an inert solvent. 12. The process of producing alkyl esters of prises reacting an alkyl ester of a secondary alkylidene malonic acid with an alkyl salt in the presence of metallic sodium in ether.
13. The process of preparing alkyl esters of secondary Ai-alkenyl malonic acids which comprises formingan alkali metal derivative of an alkyl ester ofa secondar'y'alkylidene malonic acid and reacting said derivative with an alkyl salt.
14;. The process of preparing alkyl esters of secondary A1a1kenyl malonic acids which comprises forming an alkali metal derivative of an 1 secondary A1-a1kenyl malonic acids which c'omalkyl ester of a secondary alkylidene malonic acid and reacting said derivative'with an alkyl halide. 15. The process of preparing alkyl esters of secondary A1-alkenyl malonic acids which comprises forming an alkali metal derivative of an alkyl ester of a secondary alkylidene malonic acid and reacting said derivative with an alkyl sulfate.
AR'I'HUR C. COPE. I