CA1040648A - Process for producing 2-thia substituted 1,4-diones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Process for producing 3-thia substituted alkane 1,4 diones comprising the steps of:
(i) Providing a 2-ene-1,4 dione having the structure:
(ii) Intimately admixing said 2-ene-1,4 dione with a sulfur compound having the formula:

thereby providing a substituted or unsubstituted 2-thia substituted alkane 1,4 dione having the structure:
(iii) Optionally (but only when R3 is acyl or aroyl) hydrolyzing said 2-thia substituted 1,4 dione (in the case where R3 is acyl or aroyl) thereby forming a 3-mercapto substituted alkane 1,4 dione having the structure:

wherein R3 is either acyl, aroyl, alkyl, tolyl, benzyl or phenyl;
wherein R1, R2, R4 and R6 are the same or different and represent hydrogen or lower alkyl. If either or R1 or R2 are hydrogen or both R1 and R2 are hydrogen, then step (ii) is performed in the presence of an organic base such as piperidine, pyridine, triethyl amine, quinoline or .alpha.-picoline.

Description

~040~48 BACKGROUND OF THE INVENTION
The present invention relates to novel processes for producing 3-thia substituted alkane 1,4-diones.
Artificial flavoring agents for foodstuffs have received increas-ing attention in recent years. In many areas, such food flavoring agents are preferred over natural flavoring agents at least in part because of the uniform flavor that may be so obtained. For example, natural food flavoring agents such as extracts, essences, concentrates and the like are often sub-ject to wide variation due to changes in the quality, type and treatment of the raw materials. Such variation can be reflected in the end product and results in unreliable flavor characteristics and uncertainity as to consumer acceptance and cost. Additionally, the presence of the natural product in the ultimate food may be undesirable because of increased tendency to spoil.
This is particularly troublesome in convenience and snack food usage where such products as dips, soups, chips, prepared dinners canned foods, sauces, ~-gravies and the like are apt to be stored by the consumer for some time prior to use.
i The fundamental problem in preparing artificial flavoring agents is that of achieving as nearly as possible a true flavor reproduction. This generally proves to be a difficult task since the magnetism for flavor development in many foods is not understood. This is noteable in products having meaty and roasted flavor characteristics. It is also noteable in products having vegetable-like and hydrolyzed vegetable protein-like and anise-like flavor characteristics.
Reproduction of roasted and meat flavors and aromas and vegetable-like and hydrolyzed vegetable protein-like and anise-like flavors and aromas has been the subject of the long and continuing search by those engaged in , the production of foodstuffs. The severe shortage of foods, especially protein foods, in many parts of the world has given rise to the need for utilizing non-meat sources of proteins and making such proteins as palatable and as meat-like as possible. Hence, materials which will closely simulate ~ or exactly reproduce the flavor and aroma of roasted meat products and liver -~; - 1 - ~

products and vegetable products are required.
Moreover, there are a great many meat containing or meat based foods presently distributed in a preserved form. Examples being condensed soups, dry-soup mixes, dry meat, freeze-dried or lyophilized meats, packages gravies and the like While these products contain meat or meat extracts, the fragrance, taste and other organoleptic factors are very often impaired by the processing operation and it is desirable to supplement or enhance the flavors of these preserved foods with versatile materials which have either roasted meat or gravy-like or vegetable-like or meat-like or ham-like nuances.
Swiss Patent 531,313 discloses the addition of hydrogen sulfide across a double bond, eliminating the double bond. Such a reaction, however, is not shown in conjunction with a chemical compound which has two ketone ~ -moieties. The mechanism of the addition of hydrogen sulfide across a double bond of an ~,~-unsaturated ketone is set forth at lines 40-67 of columns 3 -and 4 of Swiss Patent 531,559. Hydrolysis of a thio ester to a thiol is set forth at page 446 of chapter 36 of "Organic Sulfur Compounds" Volume 1, Editor: N. Kharash, Pergamon Press 1961 London. The formation of thio esters using thio acetic acid and unsaturated ketones is set forth at lines 15-20 of column 6 of Swiss Patent 531,559.
THE INVENTION
The processes of the present invention provide straight-forward methods for producing 3-thia substituted alkane 1,4 diones in good yields in i an economical manner.
~ . . .
Briefly, the processes of our invention comprise the steps of:
(i) Providing a 2-ene-alkane 1,4 dione having the structure:

l 2 (ii) Intimately admixing said 2-ene-alkane-1,4 dione with a sulfur .- . ~

. .
. . .
- . :. - , ., : , . :
.. . . . .

1~;)4~)69~8 compound having the formula:

thereby providing a substituted or unsubstituted 2-thia substituted 1,4 dione having the structure:

R4 ~ ~ 3 H ~ / ~ R6 ~ R
Rl 2 (iii) Optionally but only when R3 is acyl or aroyl, hydrolyzing said

2-thia substituted 1,4 dione in the case where R3 is acyl or aroyl to form a ~ -2-mercapto substituted alkane 1,4 dione having the structure:
4 \ H

Rl ~ , wherein R3 is either of acyl, aroyl, alkyl, tolyl, benzyl or phenyl; wherein Rl, R2, R4 and R6 are the same or different and are hydrogen or lower alkyl.
Thus, R3SH is either a thio acid or a thiol.
Rl or/and R2 may each be hydrogen in the event that in step (ii) the 2-ene-1,4 dione is admixed with the thiol or thio acid having the formula R3SH in the presence of an organic base such as piperidine, pyridine, triethyl amine, quinoline, a-picoline or a mixture thereof.
Examples of such thiols and thio acids are:
thioacetic acid thiopropionic acid thiobutyric acid thioisobutyric acid thio-n-pentenoic acid `^
methyl mercaptan ethyl mercaptan n-propyl mercaptan

3 --10~0648 isopropyl mercaptan n-butyl mercaptan isobutyl mercaptan n-hexyl mercaptan n-octyl mercaptan n-nonyl mercaptan :
benzyl mercaptan :-thiophenol p-tolyl mercaptan m-tolyl mercaptan ::
o-tolyl mercaptan thiocinnamic acid thiobenzoic acid :
2-methyl-thiobenzoic acid 3-methyl-thiobenzoic acid

4-methyl-thiobenzoic acid 2,4-dimethyl-thiobenzoic acid j 3,5-dimethyl-thiobenzoic acid ~:
~hether an organic baseis used or not in the re.action with the ~ 20 2-ene-1,4 dione with the thiol or thio acid having the formula R3SH, the :l 2-ene-1,4 dione can be exemplified as follows: 1~

Name Rl R2 ;~ :
3-Hexen-2,5 dione Methyl Methyl Hydrogen 3-Methyl-3-hexen-2,5 dione Methyl Methyl Methyl 3-Methyl-3-hepten-2,5 dione Methyl Ethyl Methyl `J~ 3-Ethyl-3-hepten-2,5 dione Methyl Ethyl Ethyl ~: :
3 4-Ethyl-4-octen-3,6-dione Ethyl Ethyl Ethyl -~
~, 3-Propyl-3-hepten-2,5 dione Methyl Ethyl Propyl 4-Methyl-3-hepten-2,5 dione Ethyl Methyl Methyl 4-Methyl-4-octen-3,6 dione E~hyl Ethyl Methyl 4-Methyl-4-nonen-3,6 dione Ethyl Propyl Methyl . , .

:

~040648 Compound R R R
Name 1 2 4 4-Propyl-3-hepten-3,6 dione Ethyl Methyl Propyl

5-Methyl-~-decene-4,7 dione Propyl Propyl Methyl 5-Methyl-4-nonen-3,6-dione Propyl Ethyl Methyl 4-Methyl-3-nonen-2,5 dione Butyl Methyl Methyl 4-Ethyl-3-nonen-2,5 dione Butyl Methyl Ethyl 3-Methyl-3-nonen-2,5 dione Methyl Butyl Methyl 3-Propyl-3-nonen-2,5 dione Methyl Butyl Propyl 3-Butyl-3-hexen-2,5 dione Methyl Methyl Butyl 4-Octen-3,6 dione Ethyl Ethyl Hydrogen As stated above, Rl and R2 can each be hydrogen for the purposes of these processes of our invention in the event that in the reaction of the 2-ene-1,4 dione with the thiol or thioacid of the formula R3SH, an organic base is used. Hence, in addition to the foregoing compounds, the following compounds can be utilized in the reaction with R3SH:
Compound Rl R2 3 Name 2-Buten-1,4 dial Hydrogen Hydrogen Hydrogen 2-Methyl-2-Buten-1,4 dial Hydrogen Hydrogen Methyl 2-Pentenal-4-one Methyl Hydrogen Hydrogen 9 20 2-Hexenal-4-one Ethyl Hydrogen Hydrogen ! :~
3-Methyl-2-Hexenal 4-one Ethyl Hydrogen Methyl Z-Methyl-2-pentenal 4-one Hydrogen Methyl Hydrogen 2-Methyl-2-heptenal 4-one Hydrogen Propyl Methyl 2-Methyl-2-octenal 4-one Hydrogen Butyl Methyl Examples of useful organic bases are piperidine, pyridine, quinoline, triethyl amine and a-picoline. In place of such organic bases, radical initiators may be used such as benzoyl peroxide or azobisisobutyl nitrile. The reaction may be carried out in a solvent such as water or an ether such as diethyl ether or a hydrocarbon such as benzene or hexane or cyclohexane. The reaction may also be carried out without the use of a sol-ven~. The reaction may be carried out under re~lux conditions although tem-., ~

.

1040648 .
peratures varying from 0 up to 60C are suitable and will give rise to commercially suitable yieldsO When the reaction is carried ou~ with highly volatile reactants, e.g., methyl mercaptan, higher pressures than atmospheric pressure are preferred, e.g., three atmospheres pressure. Examples of reaction products, 3-thia-substituted-1,4-diones which are formed from the reaction of the 2-ene-1,4-diones with the thioacids and thiols having the ~ -formula R3SH are as follows:

2-ene-1,4 dione R3SH 3-Thia-Substituted Reactant Reactant 1,4-dione Reaction 3-Hexen-2,5-dione Thiacetic acid 3-Thioacetyl-2,5-hexane dione 3-Methyl-3-hexen- Thiopropionic 3-Thiopropionyl-4-methyl 2,5 dione acid hexane-2,5 dione 3-Methyl-3-heptene- Thiobenzoic acid 4-Thiobenzoyl-4-methyl -2,5-dione heptane-3,6-dione 3-Ethyl-3-heptene- Benzyl mercaptan 4-Benzyl-thio-5-ethyl-2,5-dione heptane-3,6-dione 4-Ethyl-4-octene- Thioacetic acid 4-Thioacetyl-5-ethyl-3,6-dione octane-3,6-dione 3-Propyl-3-heptene- Butyl mercaptan 4-Butylthio-5-propyl-2,5-dione heptane-3,6-dione 4-Methyl-3-heptene- o-tolyl 3(o-tolylthio~4~nethyl 2,5-dione mercaptan heptane-2,5-dione 2-Buten-1,4-dial Thioacetic acid 2-Thioacetyl-butane 1,4-dial 2-Methyl-2-buten- Butyl mercaptan 2-Butylthio-3-methyl-1,4-dial butane-1,4-dial 2~Pentenal-4-one 4-Methyl-thio 2-Thiobenzoyl-pentanal-benzoic acid 4-one The 2-thia-substituted-1,4-diones as exemplified above are useful for altering the organoleptic properties of consumable materials, more par-ticularly, foodstuffs. Thus, for example, 3-thioacetyl-2,5-hexanedione has a roasted meat aroma and a pot-roast and roasted meat flavor tested at levels of 5 ppm. Its flavor threshhold value is at 1 ppm. 3-Mercapto-2,5-hexane-dione has a roasted meat aroma and a roasted meat flavor at concentrations of 2 ppm with a threshhold value at 0.5 ppm. The compound 3-thiobenzoyl-2,5-he~anedione has a berry and a meat aroma, an alium, earthy and horseradish

6 - - -. . ., :

~04064~3 flavor at concentrations of approximately 0.5 ppm. Its threshold value is at 0.5 ppm. 3-Thiobenzoyl-2,5-hexanedione at 5 ppm evaluated in beef bouillon has a meaty note. 3-Mercapto-2,5-hexanedione evaluated at 12.5 ppm adds a slight sulphury note ~which indeed is desirable) to beef bouillon. 3-Thio-acetyl-2,5-hexanedione at 5 ppm adds a burnt meat note to beef bouillon. 3-Thiobenzoyl-2,5-hexanedione adds a slight green chicken meat note to chicken broth at 2.5 ppm. 3-Thioacetyl-2,5-hexanedione adds eggy chicken notes to chicken broth at 2.5 ppm. 3-Mercapto-2,5-hexanedione adds chicken sulphury notes to chicken broth at 2.5 ppm.
A number of the products of the process of our invention may be used as reaction intermediates and, when used as such, the thia-substituted 1,4 diones produced by the process of our invention are then cyclized to form substituted or unsubstituted 3-thiafurans according to the following reaction: -~ ~ 4 wherein Rl and R2 are the same or different and are each hydrogen or lower alkyl; wherein R3 is either acyl or aroyl and R4 is hydrogen or lower alkyl.
The resulting 3-thiafurans may be used as such for their organoleptic proper-ties or they may be hydrolyzed and then reacylated or aroylated to form other acyl thia or aroyl thia substituted furans which have still other organoleptic properties useful for flavoring foodstuffs.
Where R3 of the compound having the structure:

Rl/ O ~R2 ~ :

,: , . . . :

~040648 is acylor aroyl, such compounds may also be intermediates in that they may be hydrolyzed first using a weak base (e.g., 2-5% aqueous NaOH, LiOH or KOH) and then neutralizing with acid to a pH of 5-6 to form compounds having the structure:

4 \ / SH

R \ R

which have useful organoleptic propertiesO Thus, for example, 3-thioacetyl-2,5 hexanedione is hydrolyzed to 3-mercapto-2,5-hexanedione by treating the 3-thioacetyl compound first with 2% aqueous NaOH and then adjust-; ing the pH to about 5 using 10% HCl. Hydrolysis conditions are preferably atmospheric pressure and 20-50C with ambient temperature the most preferable being most convenient and economical.
Thus, the 3-thia alkane-1,4 dione derivatives and mixtures thereof produced according to the present invention can be used to alter, vary, fortify, modify, enhance, or otherwise improve the organoleptic properties, including flavor and/or aroma, of a wide variety of materials which are in-gested, consumed, or otherwise organoleptically sensed. The term "alter" in its various forms will be understood herein to mean the supplying or imparting a flavor character or note to an otherwise bland, rela*ively tasteless sub-stance, or augmenting an existing flavor characteristic where the natural flavor is deficient in some regard, or supplementing the existing flavor or aroma impression to modify the organoleptic character. The materials which are so altered are generally referred to herein as consumable materials.
Such 3-thia alkane-1,4 dione derivatives are accordingly useful in flavoring compositions. Flavoring compositions are herein taken to mean those which contribute a part of the overall flavor impression by supplementing ~ ;;
or fortifying a natural or artificial flavor in a material, as well as those which supply substantially all the flavor and/or aroma character to a consum- ;
' able article.
The term "foodstuff" as used herein includes both solid and liquid ~, .

.~ , ., ~ .

~040648 ingestible materials for man or animals, which materials usually do, but need not, have nutritional value. Thus, foodstuffs includes meats, gravies, soups, conveniencefoods, malt and other alcoholic or non-alcoholic beverages, milk and dairy products, nut butters such as peanut butter and other spreads, seafoods including fish, crustaceans, mollusks and the like, candies, break-fast foods, baked goods, vegetables, cereals, soft drinks, snack foods, dog -and cat foods, other veterinary products, and the like.
When the 3-thia alkane-1,4 dione derivatives produced according to the process of this invention are used in a food flavoring composition, they can be combined with conventional flavoring materials or adjuvants. Such co-ingredients or flavoring adjuvants are well known in the art for such use and have been extensively described in the literature. Apart from the require-ment that any such adjuvant material be ingestibly acceptable, and thus non-toxic or otherwise non-deleterious, conventional materials can be used and broadly include other flavor materials, vehicles, stabilizers, thickeners, surface active agents, conditioners, and flavor intensifiers.
Examples of preferred co-flavoring adjuvants are:
Methyl thiazole alcohol (4-methyl-5-~-hydroxyethyl thiazole);
2-Methyl butanethiol;
4-Mercapto-2-butanone;
3~Mercapto-4-pentanone;
l-Mercapto-2-propanone;
Benzaldehyde;
Furfural;
Furfural alcohol; ~ ~-2-Mercapto propionic acid;
2-Pentene;
Alkyl pyrazine;
Methyl pyrazine; ~ -2-Ethyl-3-methyl pyrazine;
Tetramethyl pyrazine;

Polysulfides;
_ g _ ... .: . , ~ : .

~040648 Dipropyl disulfide;
Methyl benzyl disulfide;
Alkyl thiophenes;
2-Butyl thiophene;
2,3-Dimethyl thiophene;
5-Methyl furfural Acetyl furan; ~ :
2,4-Decadienal;
Guiacol; .
i 10 Phenyl acetaldehyde;
~-Decalactone; ~ .
d-Limonene; :~
Acetoin;
Amyl acetate;
Maltol;
.
Ethyl butyrate;
Levulinic acid;
Piperonal;
Ethyl acetate;
n-Octanal;
, n-Pentanal;
` Hexanal; - .:
Diacetyl; ~ . -Monosodium glutamate;
Sulfur-containing amino acids;
Cysteine;
Hydrolyzed vegetable protein;
~ Hydrolyzed fish protein; and `jJ Tetramethyl pyrazine ., i 3Q The 3-thia alkane-1,4 dione derivatives, or the compositions in- ~ : :
corporating them, as mentioned above, can be combined ~ith one or more vehicles or carriers for adding them to the particular product. Vehicles can ~'' .. . .~ , .
. ~ , ~ , . . . .

~04(11648 be edible or otherwise suitable materials such as ethyl alcohol, propylene glycol, water, and the like. Carriers include materials such as gum arabic, carrageenan, other gums, and the like. The 3-thia alkane-1,4 dione compounds according to this invention can be incorporated with the carriers by conven-tional means such as spray-drying, drum-drying, and the like. Such carriers can also include materials for coacervating the 3-thia alkane-1,4 dione derivatives (and other flavoring ingredients, as present) to provide encap-sulated products. When the carrier is an emulsion, the flavoring composition can also contain emulsifi0rs such as mono- and diglycerides of fatty acids and the like. With these carriers or vehicles, the desired physical form of the composition can be prepared.
The quantity of 3-thia alkane-1,4 dione derivatives or mixtures thereof utilized should be sufficient to impart the desired flavor character-istic to the product, but on the other hand, the use of an excessive amount of the derivative is not only wasteful and uneconomical, but in some instances too large a quantity may unhalance the flavor or other organoleptic properties of the product consumed. The quantity used will vary depending upon the ultimate foodstuff; the amount and type of flavor initially present in the foodstuff; the further process or treatment steps to which the foodstuff will 2Q be subjected; regional and other preference factors; the type of storage, if ; any, to which the product will be subjected, and the preconsumption treatment, ~ such as baking, frying, and so on, given to the product by the ultimate J consumerO Accordingly, the terminology "effective amount" and "sufficient amount" is understood in the context of the present invention to be quantita-tively adequate to alter the flavor of the foodstuff.
It is accordingly preferred that the ultimate compositions contain from about 0.02 parts per million (ppm) to about 250 ppm of 3-thia alkane-1,4 I dione derivative or derivatives. More particularly, in food compositions it is desirable to use from about 0.05 ppm to 100 ppm for enhancing flavors and in certain preferred embodiments of the invention, from about 0.2 to 50 ppm of ~he derivatives are included to add positive flavors to the finished pro-duct. All parts, proportions, percentages, and ra~ios herein are by weight :' -: .
~ :, . .

104~)~;48 ~
unless otherwise indicated.
~ amount of 3-thia alkane-1,4 dione material or materials of our invention to be utilized in flavoring compositionscan be varied over a wide range depending upon the particular quality to be added to the foodstuff.
Thus, amounts of one or more derivatives according to the present invention of from about 2 ppm up to 80 or 90 percent of the total flavoring composition can be incorporated in such compositions. It is generally found to be desirable to include from about 10 ppm up to about 0.1 percent of the 3-thia alkane-1,4 dione derivatives in such compositions.
The following examples are given to illustrate embodiments of the invention as it is preferably preferred to practice it. It will be understood that these examples are illustrative and the invention is not to be considered as restricted thereto except as indicated in the appended claims.
EXAMPLE I
~Preparation of Cis-3-hexene-2,5-dione) .

In a 1000 ml round bottom flask fitted with condenser and magnetic stirrer are placed 200 g of 2,5-dimethoxy-2,5-dimethyl-2,5-dihydrofuran and :
200 ml of a 1% aqueous acetic acid solution. The resulting solution is heated to reflux, refluxed for 2 minutes, cooled with an ice bath to 25C and ~
625 ml of a 2% sodium bicarbonate solution is added. The solution is saturat- ~ , ed by addition of 23 g of sodium chloride and extracted with methylene chloride ~1 x 200 ml and 3 x 100 ml). After drying over sodium sulfate removal of the methylene chloride in vacuo gives 142 g of crude cis-3-hexene-2,5-dione which by GLC analysis is about 90% product having ~he structure:

~O 0~
EXAMPLE II
~Preparation of 3-Thioacetyl-2,5-hexanedione) In a lOOO ml round bottom flask fitted with magnetic stirrer, thermometer, addition funnel and reflux condenser are placed 142 g of crude cis-3-hexene-2,5-dione (ex Example I), 380 ml of ether and 5 drops of piperi-.: .
, . ~ . . .
' ., ~ ~' ` ' :

~V4~)648 dine. Thio acetic acid ~96.6g) is added over a period of one hour. When about 1/8 of the thio acetic acid is added the solution begins to reflux which continues during the remainder of the addition. After addition is complete the mixture is allowed to stand for 85 minutes. Ether is then removed in vacuo (water aspirator) to give 235 g of crude material containing about 91%
3-thioacetyl-2,5-hexanedione. Distillation of a 134 g portion of the crude gives 84.5 g of 3-thioacetyl-2,5-hexanedione boiling at 86 to 87C at 0.5 torr. MMR, IR and mass spectral analysis confirm the structure:
S y ~, O O O

; 10 EXAMPLE III
Preparation of 3-Propylthio-2,4-hexanedione) In a 500 ml flask fitted with thermometer, addition funnel, reflux condenser and magnetic stirrer are placed 95 ml of ether and one drop of piperidine. Addition of n-propanethiol is started and as the addition pro-gresses more piperidine is added (33 drops total). After standing 18 hours, the solution is washed succesively with 10% hydrochloric acid ~2 x 7.5 ml), saturated sodium chloride solution (10 ml), 5% sodium bicarbonate solution and saturated sodium chloride solution (2 x 10 ml). The ether solution is dried over sodium sulfate and concentrated to give 51.4 g of a dark yellow oil. Analysis by GLC shows the material to be essentially pure 3-thiopropyl-2,5-hexanedione. Mass spectral analysis shows molecular ion 188 then descend-ing order 43, 103, 41, 145, 71, 114 and 61 m/e units.
EXAMPLE IV
(~reparation of 3-Mercapto-2,5-hexanedione) ; To 150 ml of a 2% sodium hydroxide solution in a flask fitted for stirring is added 10 g of 3-thioacetyl-2,5-hexanedione. After stirring for ; one hour the pH of the mixture is adjusted to 5-6 by the addition of dilut0 ~10%) hydrochloric acid, the solution is saturated with sodium chloride solution and extracted with ether (4 x 25 ml). The ether extracts are com-- 13 ~

.

.

~040648 ~
bined, washed with saturated sodium chloride solution (15 ml), dried and con-centrated in vacuo to give 6.2 g of crude 3-mercapto-2,5-hexanedione. Vacuum distillation gives 2.5 g of 3-mercapto-2,5-hexanedione boiling at 57 - 59C
at 0.85 torr. NMR, IR and mass spectral analysis confirm the structure as 3- -mercapto-2,5-hexanedione.
EXAMPLE V
~Preparation of 2-Thioacetyl-1,4-butane-dial~
(A) Preparation of 2-Butene-1,4-dial A mixture of 2,5-dimethoxy-2,5-dihydrofuran (20 g), water (80 ml) and acetic acid (3 drops) is stirred for 105 minutes at room temperature, 22 minutes at 40C and 90 minutes between 60C and 75C. GLC analysis at this point indicates 15.7% starting material and 83.5% 2-butene-1,4-dial. The mix-ture is cooled to 25C and sodium bicarbonate (0.3 g) is added.
~B) Preparation of 3-Thioacetyl-1,4-butanedial : . ,: .
To the aqueous solution obtained in A, supra, is added 10 g of thioacetic acid during a 14 minute period. During the addition, the tempera-ture is kept below 30C by intermittent application of a cooling bath. After 110 minutes, the reaction mixture is extracted ~ith methylene chloride ~3 x 35 ml). The combined methylene chloride extracts are dried and then concentrat-ed in vacuo to give 17.3 g of yellow oil containing about 80% 2-thioacetyl-1,4-butanedial. The compound is identified through mass spectral, NMR and IR
analysis as having the structure:
~ S ~

~ H ~ O O > ~ H
: .
M.S. - No molecular ion; remaining peaks in decreasing intensity - 43, 29, ~, 27, 45, 55, 60, 84, 100 and 142 m/e units.
NMR (CDC13) ~ 2.38 (s,3) 3.02 (multiplet 2,J=lOH~) 4.46 ~r,lJ=lOH~), 9 40 ~s,l) and 9.68 (s,l) ppm.
IR ~thin film) - 2850, 2750, 1720, 1700 (shoulder), 1388, 1352, 1132 and .

.~ , . .
.
- : - : ~ , . .
.

~04()648 958 cm EXAMPLE VI
(Preparation of 3-Thioacetyl-4-oxo-pentanal) (A) 4-Oxo-2-pentanal -Into a 5 liter, three-necked flask fitted with mechanical stirrer, thermometer and vacuum take-off are placed 600 g of 2-methyl-2,5-dimethoxy-2,5-dihydrofuran and 2400 ml of deionized water. After 20 minutes of stirring at room temperature, the mixture bPcomes homogeneous and has a pale yellow green color. Analysis of a sample of the reaction mixture by GLC after 3.25 hours shows 22% methanol, 67% 4-oxo-2-pentanal and 9% starting material.
Vacuum (26 torr.) is applied to the reaction mixture while maintaining the temperature of the reaction mixture between 25 and 30C. After 3.25 hours GLC analysis shows 13% methanol, 82% 4-oxo-2-pentenal and 3.2% starting ma- ~ -terial. The vacuum is removed and the reaction mixture is allowed to stand at room temperature overnight. Analysis after standing overnight shows 12.9%
methanol, 85% 4-oxo-2-pentanal and 2.1% starting material.
~B) 3-Thioacetyl-4-oxo-pentanal In a 5 liter, three-necked flask fitted with mechanical stirrer, thermometer and addition funnel are placed 2325 ml of the solution obtained in ~A) and 2 ml of piperidine diluted in 5 ml of water. To this solution is added a mixture of thiolacetic acid ~292.3 g) and piperidine ~13 ml) over a 20 minute period. After standing an additional 10 minutes, 20 ml of concentrat-ed hydrochloric acid is addedJ the resulting mixture poured into a separatory funnel and the oil layer removed. The aqueous layer is extracted with benzene (500 ml) and methylene chloride (2 x 500 ml). The benzene extract is combined with the oil layer and the mixture is dried over sodium sulfate. The methylene .j chloride extracts are combined and dried over sodium sulfate. Solvent removal in vacuo (40 - 45 & both at 15 torr.) gives 414.5 g of crude oil from the ben-zene extract and 172.5 g of crude oil from the methylene chloride extracts.
3Q The crude oil is distilled under vacuum to give a mixture of 3-thioacetyl-4-oxo-pentanal and 2-thioacetyl-4-oxo-pentanal boiling at 94 - 98 C at 0.3 -0.55 mm Hg.

: ~ .

:, ~ , : .

EXAMPLE VII
(Preparation of 3-Thiobenzoyl-2,5-hexanedione) In a 50 ml three-recked flask equipped with thermometer, 10 ml addi-tion funnel and magnetic stirrer is placed 6 gm of 2,5-dimethoxy-2,5-dimethyl-2,5-dihydrofuran, 24 ml H2O and 1 drop of glacial acetic acid. The mixture is stirred for one hour until homogeneous. Then 5.25 gm thiobenzoic acid is added over a five-minute period. The mixture is allowed to stand for eighteen more minutes and is then extracted with 35 ml of methylene dichloride. After drying over anhydrous sodium sulfate and subsequent solvent removal, 7.55 gm --of a crude 3-thiobenzoyl-2,5-hexanedione is recovered. The crude material is -purified by column chromatography on 108 gm silicic acid packed in ether~
hexane (1:9) mixture. Elution with 630 ml ether:hexane (1:9) solvent mixture;
followed by elution with 500 ml ether:hexane (1:4) solvent mixture; followed by elution with 850 ml ether:hexane (1:3) solvent mixture gives 6.2 gm of 3-thiobenzoyl-2,5-hexanedione, having the following analysis:
MS: Parent Ion, then decreasing order:
' 250, 105, 77, 43, 128, 106 NMR(CDC13): 7.96 (d,l,J=2Hz), ; 7.28 (d,l,J~2Hz),

7.48 (m,3), ~ 4.78 (q,l,J=5Hz), - 3.06 (m,2), 2.29 (s,3), , 2.14 (s,4) ppm f IR (KBr plate, thin film): 3060, 3000, 2960, 2910, ~ 1709, 1661, 1590, 1570, J 1445, 1355, 1204, 1172, j 1154, 900, 759, 681, 640 cm 1 ; EXA~P~E VIII
-~ 30 The ~ollowing formulatlon is prepared:

~' , .. . . ~ . ~ . . - . ~ ; - . .
. , . . , . ~ .
~ . ' . : , Ingredient Parts by Weight Liquid hydrolyzed vegetable protein 90.00 4-Methyl-5-beta-hydroxy-ethyl thiazole 5.00 Tetrahydro thiophene-3-one 1.00 -Furfuryl mercaptan 0.01 2-Nonenyl 0.50 Difurfuryl disulfide 0-49 Dimethyl sulfide 0.50 :~
Methyl mercaptan 0.50 -3-Thioacetyl-2,5-hexanedione 2.00 The 3-thioacetyl-2,5-hexanedione imparts a roasted mea~ taste to the above formula and ties in and rounds up the other meat-like chemicals in the formula. When 3-thioacetyl-2,5-hexanedione is replaced by any one of the following compounds, a similar effect is imparted to the over-all flavor and aroma pattern of the above formula: ~
3-Mercapto-2,5-hexanedione -3-Thiobenzoyl-2,5-hexanedione EXAMPLE IX
.
Preparation of 3-Thioisovaleryl-2,5-hexanedione In a 250 ml three-necked flask fitted with magnetic stirrer, reflux condenser and addition funnel are placed 10 g (0.068 moles) of 3-mercapto-2,5-hexanedione, 5.4 g ~0.068 moles) pyridine and 150 ml anhydrous diethyl ether. To this is added 8.3 g ~0.068 moles) of isovaleryl chloride during a four minute period. The resulting ether solution is then washed, in se-quence, with 150 ml of water, 50 ml of 4% HCl, 50 ml of saturated NaHCO3 solu-tion and dried over anhydrous sodium sulfate. Solvent removal in vacuo gives 13.2 g crude 3-thioisovaleryl-2,5-hexanedione:
Distillation of the crude gives 10.8 g product boiling at 108 -llo& at 0.8 - 0.9 mm Hg pressure and having the following analyses:
; 30 Mass Spectral Analysis - In decreasing order ~no parent ion):
43, 57, 85, 128 ` 104~648 NMR Spectrum (CDC13) ~ :
4.60 ~q,l) 2.95 (m,5~
..
2.32 (s,3) ~ -- 2.17 (s,3) 0.99 (d,6) ppm EXAMPLE X
Preparation of 2-Propyl-3-thioacetyl furan (A) Preparation of 2-propyl-2,5-dimethoxy-2,5-dihydro furen from 2-propyl furan ;
Reaction CH3CH ~ ~

' :
Into a 500 ml three-necked reaction flask equipped with mechanical stirrer, calcium carbonate drying tube and thermometer, the following materials - are placed:
~i) 2-Propyl furan 25.0 g ~0.227 moles) ~ii) Methanol, absolute 180 ml ~iii) Sodium carbonate 47.1 g (0.454 moles) The reaction mass is cooled to -10C using a dry-ice acetone bath. Over a period of 20 minutes,~a solution of 36.3 grams of bromine in 70 ml absolute methanol is added dropwise while maintaining the reaction mass at -12C to -13C. After the addition of the bromine solution, the reaction mass is stir-, red for 1.5 hours while maintaining same at -10C.
The reaction mass is then mixed with 450 ml of saturated sodium chloride solution. The resulting mixture is suction filtered and the filter cake is washed with 100 ml of methylene dichloride. The resultant filtrate and washings are placed in a separatory funnel and the lower organic phase is drawn off. The aqueous phase is extracted with two 100 ml portions of meth-lene dichloride and the organic solutions aTe combined. The organic solution 3Q ~ then dried over anhydrous sodium sulfate and filtered; and then concentrated -~

. . . ~ . .
.

104~648 in vacuo to a yellow liquid weighing 32.7 grams. The major peak of this material determined by GLC contains 2-propyl-2,5-dimethoxy-2,5-dihydro furan (GLC conditions: F ~ M 5750; 8' x 1/4"; SE-30; 130 225C per min., flow rate - 80 ml/minute, chart speed 0.25" per minute).
(B) Preparation of 4-oxo-2-heptenal Reaction .

--0~\ ~ C

Into a 250 ml three-necked reaction flask equipped with mechanical ~ -stirrer and th0rmometer the following materials are added:

(i) 2-Propyl-2,5-dimethoxy 32.7 g 2,5-dihydrofuran prepared (0.16 moles) according to the process of ; Part A
(ii) Water (distilled) 325 ml ; The reaction mass is stirred for a period of 4 hours at 24C. At the end of this period of time, the reaction mass exists in two phases: an aqueous upper phase, and an organic lower phase. The aqueous upper phase is decanted and placed in a one liter vessel for the following reaction C.
(C) ReactiOn of 4-Oxo-heptenal with thioacetic acid ~ ~R ~ ~

o I ~ ~ ~ \ H

' , - 19 - :

. ~ .

.
: . . . . . . .

~C)40648 To the stirred aqueous solution produced in Part B, supra, of 4-oxo-2-heptenal is added 0.4 ml piperidine. After the piperidine addition, 12.4 grams of thioacetic acid is added to the reaction mass over a period of 4 minutes while maintaining the reaction mass at a temperature in the range of 27 - 32C. After the thioacetic acid addition is complete, the reaction mass is stirred for 1.5 hours. The reaction mass is then placed in a separatory funnel and extracted with 100 ml of methylene dichloride. The methylene di-chloride solution is then separated, dried over anhydrous sodium sulfate and concentrated to an orange oil weighing 23.8 grams. This orange oil is analyzed using GLC and determined to contain two isomers having the above structures.
Mass Spectral Analysis of Trap I:
Molecular Ion, then in decreasing intensity:
202, 43, 28, 71, 55, 41, 97, 83 m/e Mass Spectral Analysis of Trap II:
Molecular Ion, then in decreasing intensity:
202, 28, 43, 71, 99 m/e (D) Preparation of 2-Propyl-3-thioacetyl furan Reaction O ':

Into a 500 ml flask, equipped with reflux condenser, calcium chloride drying tube, mechanical stirrer, thermometer and addition funnel, the following materials are placed:

~; - ' ' ' ` ' ' ' 1040~4~
(i) Isopropenyl acetate 175 ml ~ii) Concentrated sulfuric acid 0.5 ml The mass is heated to reflux ~93C) and, over a period of 20 min-utes, while maintaining the reaction mass temperature at 91 - 93C, a solu-tion of 23.0 grams of the reaction product of Part C in 25 ml of isopropenyl acetate is added from the addition funnel to the reaction mass with stirring.
The reaction mass is then stirred and maintained at 91C for a period of 30 minutes at which point 5.0 grams of sodium bicarbonate is added to the mass.
The isopropenyl acetate cyclization agent is then distilled off at a pot temperature of 80C and a head temperature of 50C at 60 mm Hg pressure.

The resulting residue is admixed with 50 ml benzene and 50 ml water. The resulting mixture is placed into a separatory funnel and the layers are sepa-rated. The benzene layer is filtered through anhydrous sodium sulfate and is then concentrated in vacuo to a brown liquid weighing 5.0 grams. This liquid is distilled through a short path microdistillation apparatus at 100 -103C and 0.3 mm Hg pressure, yielding 2-propyl-3-thioacetyl furan as confirmed by mass spectral and NMR analysis.
Mass Spectral Analysis:
Molecular Ion, then in decreasing intensity:
184, 113, 43, 142, 27, 184 ;' "':

`. :
., ' :

' ~
~ ' :
~ .

:. ~ , , , i, . , ~. , : , .... .
.: - , . . . , . : .
. . .
,: - .

10~ 8 : ~
NMR Analysis (CDC13) Signal Interpretation 1.01 (t,3) CH2C_3 1.65 (m,2) CH2CH2CH3 2.36 (s,3) - C - C~3 -2.59 ~t,2) ~ CH-2 ~ CH2 . .
6.32 (d,l) 7.35 ppm (d,l) .
, - . .

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing substituted and unsubstituted 3-thia alkane-1,4 diones comprising the steps of:
(i) Providing a 2-ene-1,4 dione having the structure:

(ii) Intimately admixing said 2-ene-1,4 dione with a sulfur compound having the formula:

thereby providing a substituted or unsubstituted 2-thia substituted alkane 1,4 dione having the structure:

wherein R3 is selected from the group consisting of acyl, aroyl, alkyl, tolyl, benzyl and phenyl; and wherein R1, R2, R4 and R6 are the same or different and are selected from the group consisting of hydrogen and lower alkyl.

2. The process of Claim 1 wherein at least one of R1 and R2 is hydrogen and the reaction is carried out in the presence of an organic base.

3. The process of Claim 2 wherein the organic base is selected from the group consisting of piperidine, pyridine, triethyl amine, quinoline and .alpha.-picoline.

4. The process for producing 3-mercapto-alkane-1,4 diones comprising the steps of:
(i) Providing a 2-ene-1,4 dione having the structure:

(ii) Intimately admixing said 2-ene-1,4 dione with a sulfur compound having the formula:

thereby providing a substituted or unsubstituted 2-thia substituted 1,4 dione having the structure:

(iii) Hydrolyzing said 2-thia substituted 1,4 dione thereby providing a compound having the structure:

wherein R3 is acyl or aroyl and R1, R2, R4 and R6 is selected from the group consisting of hydrogen, and lower alkyl.

5. The process of claim 4 wherein R1 or R2 is hydrogen and the reaction is carried out in the presence of an organic base.

6. The process of claim 5 wherein the organic base is selected from the group consisting of piperidine, pyridine, triethyl amine, quinoline and .alpha.-picoline.

7. The process of claim 1 wherein R6 is hydrogen and R1 and R2 are each methyl.

8. The process of claim 7 wherein R3 is benzoyl.

9. The process of claim 7 wherein R3 is acetyl.

10. The process of claim 7 wherein R4 is hydrogen.

11. The process of claim 7 wherein R4 and R6 are each hydrogen, R1 and R2 are each methyl; and R3 is selected from the group consisting of benzoyl, and acetyl.

12. The process of claim 2 wherein R1 is hyrogen, R2 is methyl, R3 is methyl, R4 is hydrogen and R6 is hydrogen.