CA1077501A - Preparation of gamma-pyrones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Gamma-pyrones of the formula where R is lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms or benzyl are prepared from the corresponding where R' is C1-6 alkyl. Such an intermediate may be prepared from furfural via (a) the corresponding 1-(2-furyl)-1-alkanol, (b) 2-(1-hydroxy alkyl)2,5-dialkoxy, 2,5-dihydrofuran, and (c) the corresponding 2-alkyl-2H-pyran-3-(6H). The process is of particular use for preparing maltol, pyromeconic acid and ethyl maltol.
Certain of the intermediate and reactions for producing the inter-mediates are novel.

Description

The present invention relates to a process for preparing gamma-pyrones, for example maltol. Maltol is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production was from the destructive distillation of wood. ~ -Syn~hesis of maltol from 3-hydroxy-2~ piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J. Am.
~hem. Soc. 69, 2908 (1947). Schenck and Spielman, J. Am.
Chem. Soc. 67, 2276 (1945), obtained maltol by alkaline hydrolysis o streptomycin salts. Chawla and McGonigal, i J. Org. Chem. 39, 3281 ~1974), and Lichtenthaler and Heidel, Angew, Chem. 81, 999 ~1969), reported the synthesis of maltol from protected carbohydrate derivatives. ;
Synthe~es of gamma-pyrones ~uch as pyromeconic acid, maltol, ethyl maltol and other 2-substituted-3-hydroxy-gamma-pyrones are described in United States Pa~en~s 3,130,204, 3,133,089, 3,140,239, 3,15g,652, 3,376,317, 3,468,915, 3,440,183 and 3,446,6~9.
Maltol and ethyl maltol enhance the flavor and ; 20 aroma o~ a variety of food products. I~ addition, these makeria~s are used aq ingredients in perfumes and es~ence3.
The 2-alkenylpyromeconic acids reported in United States 3,644,635 and the 2-arylmethylpyromeconic aoids described in United 5tates 3,365,469 inhibit the growth of bacteria and fungi and are u~eful as flavor and aroma enhancers in '~ :

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foods and beverages and aroma enhancer~ in perfume~
According to the present invlention there is pro- :
vided a process for preparing gamma-pyrones of the formula~
` J~ , wherein R is hydrogen, lower alkyl of 1 to 6 carbon atoms, :~
lower alkenyl of ~ to 6 carbon atoms, phenyl or benzyl wherein a compound of the formula -~

I R'O
i wherein R is as defined above and R' is lower alkyl of 1 to 6 carbon atoms, is contacted with an acid to form the desired I gamma-pyrone.
: From further aspects there are provided novel compound~ of the ormulae ~ and ; R' ~ R R~O ~ *
wherein R i5 ethyl and R' is lower alkyl ~f 1 to 6 carbon -~
atom~.
Thi~ invention permits the preparakion of 2-eub-~tituted-3-hydroxy gamma pyrones utilizing furfural as the ~tarting materlal~ ~urfural i9 an inexpenslve raw ma~erial whi~h i9 prepared indu~trially ~rom pen~o~an~ which are contained in cereal stra~s and bran~.

As used throughout the specification and claims, the term "lower alkyl" and the lower alkyl portion of alkoxy embraces both straight and branched chai.n alkyl radical~ -containing from one to six carbon atoms; the term "lower 5 alkenyl" embraces straight and branched chain alkenyl groups containing from two to six carbon atoms; the term "aryl"
denotes a monocyclic aromatic hydrocarbon of six to eight carbon atoms; and the term 'laralkyl" emcompasses lower alkyl groups in which aryl as defined above i~ substituted for a hydrogen atom.
~ he reactions involved in the present invention when starting from furfural are ~utlined as follows~

~ RMg,X ~ ~ ~ ~.~ '' '' O ~ ~ ~OH or electrolyais - :;.
CHO ~ - H -:
1 R `

R' I~OH
: . 2 ~ .
~0~
11 11 ~ ~f ~ Bise/H20 ¦ ¦ -15 ~ R' ~ R H22 R'O
. 3 _ In~ermediates: R'= Cl_6 alkyl R - hydrogen, allyl, aryl, alkenyl r aralkyl ~, !

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; Final Product (5): R=hydrogen, alkyl, alkenyl, aryl, aralkyl R~H, pyromeconic ac:id R=CH3, maltol R=CH2CH3, e~hyl maltol The reaction of furfural wikh the appropriate Grignard reagent is described in Chemical Abstracts 44, 1092d (1949).
The pr~paration of intermediate 2 (R = H) by electrolysis in methanol is described in United States

2,714,57~ and Ac~a. Chem. Scand. 6, 545 (1952). The ~ynthesis employing bromine in methanol i~ reported in Ann. 516, 231 (1935). The general concept of using chlorine in an alcoholic ~olvent i8 also well known (for example, British Patent 595,041). It has been found during the proces~ of this invention that the reaction of intermediate 1 with chlorine in an alcohslic solvent at a temperature between -70 and 50C. gives a clean oonversion to the desixed intermediate ~ ;
2 with the HCl by-product being neu~ralized by a base such a~ ammonia, sodium carbonate or other alkali metal bases.
Although the early literature involving this reaction cites yields o~ up to around 50~ the process of the present invention results in yields in excess of 90~
Intermediate 2 tR = CH3~ is described in Acta.
Chem. Scand. 9, 17 (1955); and Tetrahedron 27, lg73 (1971).
Inkermediate 2 (R = CH2CH3) is a new c~mpound which can be made by methods already described.
The treatment of intermediake 2 with a ~trong ; organic acid i5 novel and it produces the desired 6-alkoxy der~vative 3 directly in high yield and avoid~ the formatio~
o the corresponding hydroxy derivative which is very un-775~
stable to further reactions. Intermediate 2 is contacted with an acid which is preferably essentially anhydrou~, ` although the presence of a protic solvent such as an ; alcohol or a small amount of water is actually beneficial.
-, 5 Following this treatment, the product in a state of purity suitable for conversion to intermediate 3, is separated from the acid medium by conventional extraction techniques.
Although formic and trifluoroacetic acids are preferred, ; any acid with a pKa of approximately 4 or below will con vert intermediate 2 to the desired intermediate 3. Other suitable organic acids include p-toluenesulfonic acid, , methanesulfonic acid, citric acid, oxalic acid and chloro-acetic acid; suitable mineral acids include sulfuric acid, hydrochloric acid and phosphoric acid. Acidic resins such i 15 as Amberlite GC-120 and Dowex 50W may also be employed.
; ~"Amberlite" and "Dowex" are Trademarks~) The epoxidation of intermediate 3 to the epoxy ketone 4 is a new and novel process. Intermediate 3 is dis-~olved in a suitable solvent such as water or an alcohol such as isopropyl alcohol or methanol. A base such as sodium bi-carbonate or sodium hydroxide i.s added followed by the addi-tion of H2O2(30%). The desired intermediate 4 can be sepa-rated by conventional extraction techniques~ and is suitable for rearrangement to the desired pyrone 5 without further purification.
The final rearrangements o the epoxy ketones 4 to gamm~-pyrones 5 are novel and proceed in good yield and purity. The intermediate 4 is reacted in an acid medium and subsequsnt isolation of the desired gamma-pyrone 5 is sffected by conventional crystallization or extraction tech-niques. The pure gamma-pyrone may be recrystallized from ~ ! ~
`~ ,,) ~a77s~

an appropriate solvent such as isopropanol, methanol or water.
Although hot aqueous mineral acid such as sulfuric or hydro-chloric acid is ~he most oonvenient method of converting intermediate 4 to product 5, the desired gamma-pyrone can be produced by Lewis acids such as borontrifluoride etherate, zinc chloride and tin tetrachloride; by acidic ion resins such :
as"Amberli~e'GC-120 or"Dowex"50W; and by strong organic acids such as p-toluenesulfonic acid or formic acid.
Compounds related to intermediate 3 ~R = CH2OH
or R = CH2O~Alkyl) can be prepared from carbohydrate sources as described in Accounts of Chemical Research 8, }32 (1975).
By the process of the present invenkion~ these compounds can be converted to intermediate 4 and product 5 where R CH2OH or CH2O-Alkyl. Product 5 (R = CH2OH or CH2O-Alkyl) can be converted to maltol as described in United States

3,130,204 or Angew. Chem. 81, g98 ~1969).
The following Examples are illustrative of the process of the invention:

In a 3 neck-roundbottom flask equipped with a magnetic stirrlng bar, a jacketed addition funnel, a thermo-meter and a dry ice condensor was added 22.4 g. (0.2 mol) of intermediate 1 ~R = CH3), 100 ml of methanol and 21.1 g.
~0~2 mol) of sodium carbonate, and this mixture cooled to : 25 0C. using an ice-acetone bath~ To this rapidly stirred solution was then added dropwise a cold (-30) solution o~ chlorine (11.0 m7, 0.24 mol) in methanol. The addition o~ chIo~ine was oontrolled to keep the reaction temperature under 40C. The addition required about ~ hours. After the addition, the reaction mixture was stirred at ice ~ath ~775~
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temperature for 30 minutes, and then allowed to warm to room temperature. The resulting slurry was Eiltered, the methanol removed ln vacuo, the residue taken up :in benzene and passed through an alumina plug as a final filter. Removal o the benzene provided 31.~ g. ~91~) of the desired dimethoxy dihydrofuran 2 ~R = C~I3, R'= CH3). This material can be ; used without further purification or it can be distilled, b.p. 76-78/5mm ~104-107/10-llmm, Acta Chem. Scand. 9, 17 (1955)]. -Analysis~
Calc'd. for C8H14O4: C, 5S.22 H, 8.11 Found:C, 55.34 H, 8.04 The mathod of Example 1 was repeated with inter-15 mediate 1 (R - H) to yield intermediate 2 (R = H, R' = CH3), h.p. 80-82/5mm r71/l.Omm Tetrahedron 27, 1973 (1971)}.
' EXAMPLE 3 The method of Example 1 was repeated with inter-mediate 1 (R = H) to yield intermediate 2 (R = H, R' = CH3) b.p. 102/lOmm.
Analysis:
Calc'd. for CgH16O4: C, 57.50 H, 8.58 Found:C, S7.39 H, 8.59 ....
The method of Example 1 was repeated using intermediate 1 (R a CH3) replacing methanol with isopropanol 2 [R ~ CH3, R' ~ CH(CH3)2], b.p. 62-64/0.05 mm.
EX~MPLE 5 The method of Example 1 may be repeated using bromine instead of chlorine using in~ermediate 1 to yield `

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intermediate 2 where R is hydrogen, methyl, eth~l, hexyl, phenyl, vinyl, l-butenyl, allyl and l-hexenyl; and R' is methyl, ethyl, isopropyl and hexyl.

In a small glass elec~rolysis vessel having a carbon anode and nickel cathode was placed 50 ml of methanol, 0.5 ml of concentrated sulfur~c acid, and 1~12 g~ ~0~01 mol~
of the intermediate 2 (R = CH3, R' = CH3) and the solution cooled to -20C. An electrolysis was then carried out using a potentiostat/galvanostat Princeton Applied Research Corpora-tion Model 373 instrument set to deliver a constant current of 0.6 amperes. After a reaction time of 30 minutes, the reaction waq poured into water and the product 3 ~R = CH3, R' ~ CH3), isolated by a chloroform extraction procedure.
This procedure is similar to that described in United States ~,714,576 with sulfuric acid replacing ammonium bromide as the electrolyte.
EXAMPLE_7 The method of Example 6 may be repeated with inter-mediate 2 to yield intermediate 3 where R is hydrogen, ethyl, hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl and R' i~ eth~l, isopropyl and hexyl.

To a 2-liter, 3-neck roundbottom flask equipped with a magnetic stirrer, dropping funnel and a ~thermometer was added 400 ml of formic acid and 20 ml of methanol. To this solution was added a solution of intermediate 2 (R = CH3, R' - CH3) 104.4 g., 0.6 mol in 40 ml of methanol.
The dropwise addition required 15 minutes. The reaction was poured in a liter of wat~r and extracted 3 times with _g_ ~.

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500 ml portions of chloroform. The combined chloro~orm washings were washed with a sodium bicarbonate aqueous solution and with brme. The chloroform solution was evaporated to a crude yield of 76 g ~89~) of intermediate 3 (R = CH3, R' =
CH3) as a light brown product. The crucle material may be used as such or distilled at 2mm pressure, 50-52~C. ~82-85/-30mm, Tetrahedron 27, 1973 (1971)].

The method of Example 8 was repeated with analogous -intermediate 2 (R - H, Rl = CH3) to ~ield intermediate 3 (R ~ H, R' = CH3), b.p. 60-66/14mm ~76-81/23mm, ~etrahedron 27, 1973 (1971)].

The method of Example 8 was repeated with inter-mediate 2 (R = CH2CH3, Rl = CH3) to yield intermediate 3 (R = CH2CH3, R' = CH3), b.p. 79-80/14mm.

The method of Example 8 may be repeated with intermediate 2 to yield intermediate 3 where R is hexyl, phenyl, benzyl, vinyli allyl, l-butenyl and l-hexenyl; and R is isopropyl and hexyl.

The method of Example 8 may be repeated, with comparable results, replacing formic acid with an organic 2S selected from the group consisting o~ citric acid, oxalic acid, chloroacetic acid, p-toluenesulfonic acid, methan~
sulfonic acid and ~rifluoracetic acid.

In a 3-neck roundbottom equipped with an addition funnel, low temperatura thermome~er and stirring bar was --10-- :

:

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prepared a solution of 5.0 g. (00029 mol) of in~ermedia~e 2 ' (R = CH3~ X' ~ CH3) in diethyl ether ~10 ml) and the solution was cooled to -40C. To this solution was then added drop-wise 1.6 ml of concen~rated sulfuric acid and the black mixkure stirred for 5 minutes at -40C., poured into water and the desired intermediate 3 (R = CH3, R' = CH3) isolated by the method of Example 8.
Substantially the same results may be obtained replacing sulfuric acid with hydrochloric or phosphoric acids.

To a dry flask was added 1.05 grams (0.0074 mol) of intermediate 3 (R = CH3, R' ~ CH30) dissolved in 20 ml o~ iso-propyl alcohol and the flask cooled to O~C. Then 0.5 g.
(O.OOS9 mol) of sodium bicarbonate and 2.0 ml (0.023 mol) of 30~ hydrogen peroxide were added, and the reaction allowed to stir at room temperature for about 2 hours. The reaction mixture wa~ poured into 100 ml of water and the water ex~
tracted with chloroform, followed by concentration to yield oil which could be distilled at 70-sO/3mm. An analytic sample was purified by gas chromatography.
Analysis:
Calc'd. for C7H1004: C, 53-16 H~ 6-37 Found: C, 52.90 H, 6.27 The method of Example 14 was repeated with inter~
mediate 3 ~R = H, R' - CH3) to yield intermediate 4 ~R = H, R' = CH3)-Analysis:
Calc'd for C6H~04: C, 50~00 H, 5.S9 Found: C, 50.09 H, 5.81 7S~

~:;

The method of Example 14 was repeated with inter-mediate 3 (R - CH~CH3, R' = CH3) to yield intermediate 4 (R ~ CH2CH3, R' ~ C~3).
Analysis:
Calc'd for ~gH12O4: C, 55.~1 H, 7.02 Found: C, S5.95 H, 7.04 The method of Example 14 may be repeated with inter-mediate 3 ~o yield inkermediate 4 where R is hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl; and R' is isopropyl and hexyl.

To a 75 ml flask was added 2.84 g. (0.02 mol) of intermediate 3 (R ~ CH3, R' = CH3), 10 ml of water and 10 ~ -ml of isopropanol. The solution was cooled to 0-5C., and the pH adjusted to 7.0-9.0 with 1 N NaOH. Then 2.1 ml of 30% hydrogen peroxide was added dropwise, with NaOH also aaded as necessary to maintain constan~ pH. Cooling was necessary to keep the pot temperature below 10~C. After the addition of peroxide, the reaction was stirred at 8~10C.
for about one hour, poured in water and the solution extracted with chloroform. Solvent removal yielded 2.99 g. (94.5~ of the intermediate 4 (R = CH3, R' = CH3) as a clear oilO Re-action temperature above 15C. and a pH above 9O5 or below 6.5 result in lower yields of ~ntermediate 4.
Substantially the same results are obtained replacing isopropanol with water.

To a flask with a condenser was adcled 3.7 g. t0.023 775~L
.
.

mol) o~ intermediate 4 (R = CH3, R' - C~3) and 50 ml of 2M
H2SO4. After heating this two phase solution for 1.5 hours at reflux, the reaction mixture was cooled, adjusted to pH
2.2 with 6 N NaOH, extracted 3 times wi~h 100 ml volumes of chloroform and the combined solvent extract concentrated to yield product 5 ~R = CH3, maltol).

The method of Example 19 may be repeated with inter-mediate 4 where R is hydrogen, ethyl, hexyl, phenyl, benzyl, allyl, vinyl, l-butenyl and l-hexenyl; and R' is methyl, ethyl, isopropyl and hexyl to yield product 5 where R is hydrogen, ethyl, hexyl, phenyl, benzyl, allyl, vinyl, 1-butenyl and l-hexenyl.
EXAMPLE 21 ~ ;
To a 250 cc Wheaton pressure bot~le was added 3.16 g. t0.02 mol) of intermediate 4 (R = CH3, R' = C~I3) and S0 cc of 2 M H2SO~. The vessel was sealed and heated to 140-160 for 1-2 hours. After cooling, the reaction was processed as in Example 19 to yield maltol (R = CH3). :
EXaMPLE 22 The method of Example 19 and 20 may be repeated, with comparable results, replacing sulfuric acid with hydrochloric :~
acid,UDowex 50W and Amberlite GC-120.

To a small flask was added 1.58 g. (0.01 mol~ of intermediate 4 ~R = CH3, R' - CH3) and 25 ml of benzene followed by 3.1 ml of boron trifluoride etherate. After ~tirring for 24 hours at 25C., the solvent was removed, the residue extracted with chloroform, and the chloroform removed to yield maltol (R = CH3).
' ~

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Substantially the same results are obtained when boron trifluoride etherate is replaced with p-toluene~ulfonic acid, formic acid, zino chloride or tin tetrachloride.
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Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing gamma-pyrones of the formula:

wherein R is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, phenyl or benzyl wherein a compound of the formula:

wherein R is as defined above and R' is lower alkyl of 1 to 6 carbon atoms, is contacted with an acid to form the desired gamma-pyrone.

2. A process according to claim 1, wherein said acid is selected from sulphuric acid, hydrochloric acid, boron trifluoride etherate, zinc chloride, tin tetrachlor-ide, p-toluene sulfonic acid and formic acid.

3. A process according to claim 1, wherein the com-pound of the formula:

is prepared by:
(a) contacting a compound of the formula:

wherein R is as defined in claim 1, with an alcoholic (R'OH) solution of chlorine or bromine to form a compound of the formula:

wherein R and R' are as defined in claim 1;
(b) contacting the compound obtained in step (a) with an acid to form a compound of the formula:

wherein R and R' are as defined in claim 1;
(c) contacting the compound obtained in step (b) with hydrogen peroxide to form a compound of the formula:

wherein R and R' are as defined in claim 1.

4, A process according to claim 3, wherein the con-version of the compound of formula:

to the former is first dissolved in water, methanol or iso-propanal and is successively treated with a base and aqueous hydrogen peroxide.

5. A process according to claim 3, wherein the com-pound of the formula:

is prepared by treatment of a compound of the formula:

with an acid which is substantially anhydrous.

6. A process according to claim 5, wherein there is also present a protic solvent or a small amount of water.

7. A process according to either of claims 5 and 6, wherein the acid employed is selected from formic acid, trifluoroacetic acid, p-toluene sulfonic acid, methane sulfonic acid, citric acid, oxalic acid, chloroacetic acid, sulfuric acid, hydrochloric acid, phosphoric acid.