CA1095921A

CA1095921A - Preparation of gamma-pyrones

Info

Publication number: CA1095921A
Application number: CA279,922A
Authority: CA
Inventors: Thomas M. Brennan; Donald E. Kuhla; Paul D. Weeks; Daniel P. Brannegan
Original assignee: Pfizer Inc
Current assignee: Danisco Finland Oy
Priority date: 1976-08-02
Filing date: 1977-06-06
Publication date: 1981-02-17
Also published as: FI72720C; JPS5436271A; IE45641L; SE452616B; FI831704L; JPS5436268A; HK30381A; PT66694B; MY8100267A; FI831702L; ES470744A1; YU40166B; YU42613B; GB1538374A; HU185686B; FI73424C; PH13926A; HU185687B; DE2728499A1; DK153483B

Abstract

ABSTRACT OF THE DISCLOSURE
Gamma-pyrones, particularly maltol (2-methyl-3-hydr-oxy-4H-pyran-4-one) and ethyl maltol (2-ethyl-3-hydroxy-4H-pyran-4-one) are prepared by hydrolyzing certain pyran inter-mediates prepared by reacting furfuryl alcohols, particularly 1(2-furyl)-1-ethanol, in aqueous solution with a halogen-con-taining oxidant. Novel 4-halo-dihydropyran intermediates and the preparation thereof are also disclosed.

Description

This invention rel~tes to the preparation o gamma-pyrones and particularly to the preparation of gammz-pyrones by the hydrolysis of certain intermediate compounds, some of `which are novel, which intermediates are prepared from appro-priate furfuryl alcohols by the use of halogen-containing oxidants. The invent-lon is also concerned with a one-pot process for preparing gamma-pyrones from furfuryl alcohols.
The invention is further concerned with novel 4- halo-dihydro-pyran intermPdiates and the preparation thareof.
Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) 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. The synthesis of maltol from 3-hydroxy-2-tl-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J. Am. Chem. Soc., 69 2908 (1947). Schenck and Spielman, J. AmO Chem. Soc., 67, 2276 (1945~, obtained maltol by alkaline hydrolysis of strep-tomycin salts. Chawla and McGonigal, J. Org. Chem., 39~ 3281 (1974) and Lichtenthaler and Heidel, Angew. Chem., 81, 998 (1969), reported the synthesis of maltol from protected carbo hydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), described a five step synthesis of maltol starting with methyl furfuryl alcohol.
The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one a~3 one of the characteristic sweet-aroma component~

. . .

.. ~ ' :. :

- ,.

~L~9s~
in refinery final molasses was reported by Hiroshi Ito in A~r. Biol. Chem., 40 t5), 827-832 (1976). This compound was previously synthesized by the process described in United States Patent Specification No. 3r468l915a Syntheses of gamma-pyrones such as pyromeconic acid, maltol, ethyl malto~ and other 2-substituted-3-hydroxy-gamma-pyrones are described in United S~ates Patents No. 3,130,204;
3,133,089; 3,140,239; 3,159,65~; 3,365,469; 3,376,317;
3,468,915; 3,440,183; and 3,~46,629.
Maltol and ethyl ma~tol enhance the flavor and aroma of a varlety of food products. In addition, these compounds are used as ingredients in perfumes and essences The 2-alkenylpyromeconic acids repor~ed in United States Patent No.
3,644,635 and the 2-arylmethyLpyromeconic acids described in United States Patent No. 3,365,469 inhibit the growth of bacteri and fungi and are useful as flavor and aroma enhancers in foods and be~erages and aroma enhancers in perfumes.
The present invention provides a process for pre-paring a gamma-pyrone of the formula:-o ~ H
~ ~ ~R ~I) R''' which comprises heating in acidic aqueous solution, preferably at a temperature within the range of 70 to 160C., until hydrolysis is substantially complete a 4-halo-dihydropyran of the formula (II) or a 6,6~-oxybis[4-halo-2H-pyran-3(6H)-one]
of the formul~l (V):-gz~
x x x R' ~ or ~ ~ ~
R'O O R R O R
(II) (V) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is methyl, ethyl or phenyl, R" ' is hydrogen or alkyl of 1 to 4 carbon atoms, and X is chlorine or bromine.
The acid required for the hydrolysis may be added to the reaction mixture, e.g. by dissolving the intermediate compound of formula (II) or formula (V) in an aqueous inorganic or organic acid before heating; or alternatively the acid may be generated in situ during the preparation of the intermediates as hereinafter described.
The intermediate compound of formula (II) above may be prepared by reacting a compound of the formula:-,~
R'' ~ ¦ (IV) R'O ~ O ~ R
wherein R, R' and R' ' ' are as defined above, in a solvent at atemperature of -50~ to 50C., preferably at room temperature, with at least one equivalent of a halogen-containing oxdiant selected from chlorine, bromine, bromine chloride, hypochlor-ous acid, hypobromous acid or mixtures thereof until the reaction is substantially complete.
Examples of suitable solvents for this reaction are water, an alkanol or diol of 1 to 4 carbon atoms, preferably methanol, an ether of 2 to 10 carbon atoms, preferably tetra-hydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, a low molecular weight nitrile, ester or _~_ ~'`' ' .
: ' :

~5~;21 amide.
The intermadiate compound of formula ~V) above wherein R' i~ hydrogen may be prepared by reaGting a fur-furyl alcohol of the formula:-.~.IIIwherein R and R''' are as defined above, in aqueous solutlon with at least oneequivalent of a halogen-containing oxidant se-lected ~rom chloine, bromine,-~romine chloride, hypochlorous acid, hypobromous acid or mixtures khereof at a temperature of -50 to 50C., preferably room temperature, until the reaction is substantially complete. The reaction may be conducted in the presence of a co-solvent which suitably may be one of the sol-vents previously mentioned for the prepara~ion of the intermedi-ate compound of formula (II).
lS If desired, the intermediate 4-halo-dihydropyran compound of formula (II) wherein R' is hydrogen may be prepared direct from an appropriate furfuryl alcohol of formula (III) by reacting the latter in an aqueous solvent at a temperature of -50 to 50C,, with at least two equivalents of one of the afore-~0 mentioned halogen-containing oxidants until the reaction is sub-stantially complete.
In each of the above-described reactions the preferred halogen-containing oxidant is chlorine or bromine chloride.
The intermediate compound of ~rmula (V) may be pre-pared by dehydrating a compound of the formula:-HO ~ ~ R ~II") ~5-592~

The present invention further provides a novel and facile synthesis of gamma pyrones of formula (I) above, par-ticularly maltol ~2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds, by a one-pot process from a furfuryl al-cohol of formula (III)above.
In accordance with this one-pot process, a furfuryl alcohol in aqueous medium is reacted with two equivalents of a halogen-containing oxidant and the reaction mixture is then heated to hydrolyze the resulting intermediate. The one pot process may be represented by the following equation.

R~ ~ 2 XY _1~ ~ R
(III) (I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' " is hydrogen or alkyl of 1 to 4 carbon atoms:
and XY is C12, Br2, ClBr, HOCl, HOBr or mixtures thereof.
The full reaction pathway is shown in the follow ng scheme:-~ R Ox~ant ~ ~ Y ~ ~o R'' ~ ~
OH H2 R~ ~o~R R"' ~ O~ R

(III) OH ~ OH
R"' - C=O open ~H chain ~H tautomer C=O
H--COH

~s~
x o R''~ ~ R R''' ~ R

tl (II') (I) open chain tautomer Lefebvre and co-workers in J. Med. Chem., ~6, 1084 (1973) demonstrated that furfuryl alcohols could be directly converted to 6-hydroxy-2H-pyran-3(6H)ones when a peracid oxidant such as peracetic acid or m-chloroperbenzoic acid is employed.
The first step of the Lefebvre work uses a peracid in an organic solvent and probably leads to a 6-acetoxy or 6-m-chlorobenzoyl-oxy pyran derivative which is hydrolyzed to the 6-hydroxy com-pound during the aqueous work-up. Water is not used in the first step of the reaction, and would in fact ~e deleterious.
In any case, the process of Lefebvre and co-workers cannot lead directly to the conversion of a furfuryl alcohol ~ a gamma-pyrone.
Critical to the process for the preparation of the intermediates of the presant invention is the use of an aqueous solution of a halogen-contalning oxidant. A furfuryl alcohol may be cleanly oxidized to a 6-hydroxy-2H-pyran-3(6H)-one using one equivalent of a halogen-containing oxidant in water or water/organic co-solvent. It is a surprising and unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can be converted to gamma-pyrones A 6-hydroxy-2H-pyran-3~6H)-one may be regarded as a hemi-acetal of an a~dehyde and as such might be expected to undergo-numberous undesired side reactions such as over oxi-dation or an aldol-type condensations. By employing two ::~ , , :

~6~95~

equivalents of a halogen-containing oxidant in water or water and organic co-solvent, the reaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone. This novel one pot process offers the advantages of employinc3 low cost C12, Br2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant.
Isolation of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and may be removed in va~uo to afford crude gamma-pyrone directly in high yield by simple concentration.
The one pot process is operated by dissolving a furfuryl alcohol in water or water and a co-solvent. The co-solvent may be water-miscible or water-immiscible and may be -~
selected from a wide range of solvents such as Cl to C4 alkanols or diols, for example, methanol; C2 to Clo ethers, for example, tetrahydrofuran or isopropyl ether; low molecular weight ketones, for example, acetone; low molecular weight nitriles;
low molecular weight esters and low molecular weight amides.
The preferred co-solvents are Cl to C4 alkanols and C2 to Clo ethers, with methanol the choice of solvents because of cost.
The solution is kept at a temperature of -50 to 50C., pre-ferably -10 to 10C~ To this solution is charged a desired furfuryl alochol while simultanteously adding a halogen-containing oxidant (two equivalents3 to the reaction mixture.
The temperature of the reaction mixture is maintained at -50 to 50C., preferably -10 to 10C., during halogen addition.
If a low-boiling co-solvent is employed, it is removed by distillation after all additions are complete. The reaction mixture is then heated to a temperature at which the hydrolysis proceeds at a reasonable rate, for example, 70 to 160C. The generally employed hydrolysis temperature is 100 to 110C.

~9~

The heating is continued until the hydrolysis of the formed 4-halo-dihydropyran intermediate is substantially complete (usually 1 to 2 hours). The acid necessary to catalyze this final hydrolysis is generated in situ by loss of acid from the intermediates formed during the course of the reaction.
Additional acid may be added if desired.
The halogen-containing oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous or hypybrom-ous acid or mixtures thereof Bromine chloride is a com~cially available gas. It may be prepared in situ by the addition of chlorine to a solution of sodium or potassium bromine or by theaddition cf bromine to a solution of sodium or potassium chloride. Hypochlorous and hypobromous acid conveniently may be generated ln situ by the addition of aqueous acid (HCl, H2SO4 or HBr) to a solution of an alkali metal or alkaline earth metal hypohalite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred halogen-containing oxidants, based on cost factors, are chlorine and bromine chloride prepared in situ.
As described above, the intermediate 6-hydroxy-2H-pyran-3(6H)-one of formula (IV) may be prepared by reacting the appropriate furfuryl alcohol with one equivalent of a halogen-containing oxidant. The isolated intermediate is readily converted to the desired gamma-pyrone by reacting it with an additional equivalent of a halogen oxidant and hydro-25 lyzing the formed 4-halo-6-hydroxy-2H-pyran-3(6H)-one of formula (II) as previously described.
Alt:ernatively, a furfuryl alcohol in aqueous solu-tion with an optional co-solvent may be reacted at -10 to 10C.
with two equivalents of a halogen-containing oxidant. After stirring at room temperature for 30 minutes, the pH of the ~: _g_ ~. . . j ..
:: .
:.

reaction mixture is adjusted to 2 with a strong base and the reaction mixture is extracted with a solvent such as ethyl acetate. Removal of the solvent yields the 4-halo-6-hydroxy-2H-pyran-3(6H)-one of formula (II') which may be hydrolyzed to the desired gamma-pyrone. l'he 4-halo-dihydropyran may be dehydrated by heating under vacuum to yield the 6,6'~oxybis ~4-halo-2H-pyran-3~6H)-one]. This dimer yields the desired gamma-pyrone on hydrolysis, with added acid if desired.
Certain of the 4-halo-dihydropyran intermediate compounds and the 6,6'-oxybis ~4-halo-2H-pyran-3(6H)-one] in-termediate compounds are novel compounds and, accordingly, the present invention also provides compounds of th~ following formulae, some of which are novel:-~o R ~ ~ (II~) X

~4 ~ l l (VI) R40i o~c2H5 RX~o~ ~R tV) wherein R, R' " and X are as defined above and R4 i5 alkyl of l to 4 carbon atoms or -COR" wherein R" is methyl, ethyl or phenyl.
The gamma~pyrones of formula ~I) alsc may be pre-pared by reacting in acidic aqueous solution at least one ,~

~s~9~
!

equivalent of a halogen-containing oxidant with a compound of the formula:-R~l ~ (IV) R' o~ R
wherein R, R' and R' " are as defined above.
A 6-alkoxy-2H-pyran-3~6H)-one may be prepared by the method described in Tetrahadron Letters No. 17, 1363-1364 (1976) A furfuryl alcohol is anodically alkoxylated to the

2-(1-hydroxyalkyl~-2,5-dialkoxy-dihydrofuran> Treatment with a strong organic acid produces ~he desired 6-alkoxy compound.
A 6-acyl compound may be prepared by conventional treatment of the 6-hydroxy compound with the appropriate anhydride in khe presence of pyridine.
A 6-acyl or 6-alkoxy-2H-pyran-3(6H)-one is dissolved in a solvent selected from acetic acid~ formic acid, tri1uoro-acetic acid, halogenated solvents, e~hers, C1 to C~ alkanolsor diols, or low molecular weight ketones, nitriles, esters or amides. The preferred so1vent is acetic acid, formic acid or methanol. An equivalent of a halogen-containing oxidant selected chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof is added at room temperature and the reaction mixture is heated to 70-160C., generally 100-110C., until the conversion to the desired gamma-pyrone is substantialLy complete (approximately 1 to

3 hours). The gamma-pyrone may be obtained ~rom the cooled, neutralized reaction mixture on standing or by extracting the reaction mixture with a solvent such as chloroform which yields the gamma-pyrone on concentration.
With organic acids and other protic solvents such , :: ,: .

as formic acid, acatic acid, other organic acids and alkanols that have not been vigorously dried, no additional water i5 added in the above described reaction. However, with non-protic solvents, water is necessary and is added for the con-version of the intermediate 4-halo-6-substituted-2H-pyran-3 (6H)-one to the pyrone. When a low-boiling solvent is employed in the reaction it is removed by distillation just before the reaction mixture is heated to 100 to 110C. for the hydrolytic conversion of the intermediate 4-halo-dihydropyran to the gamma-pyrone.
If desired, the 4-halo-dihydropyran may be prepared and isolated by conducting the halogenation at a temperature of -20 to 2~C., preferably 5 to 10C., in the presence of an organic base such as triethylamide. A~ter about 30 minu~es the reaction mixture is allowed to warm to room tempera~ure, filtered to remove triethylamide hydrochloride and the solvent removed under vacuum to yiel~d the 4-halo-dihydropyran. This compound is readily hydrolyzed to the gamma-pyrone by heating for about an hour in aqueous solution, with added acid if desired,preferably at a temperature within the range of 70 to 160C., more preferably 100 to 110C.
This process wherein the 6-acyl or 6-alkoxy-2H-pyran-3(6H)-one is reacted in an organic solvent with one equivalent of a halogen-containing oxidant and the intermed-~5 iate 4-halo-clihydropyran heated until the conversion o the desired gamma-pyrone is substantially complete differs from the multi-step procec~s described by Shono and Matsumura in Tetrahedron Letters 17, 1363 (1976) wherein the 6-alkoxy-2H-pyran-3(6H)-one is treated with a methanolic solution of hydrogen peroxide with sodium hydroxide solution to yield an ' 2~
epoxy ketone. The isolated epoxy ketone is then refluxed in water with "Dowex" 50 ion exchange resin to yield the de~sired gamma--pyrone .
The following Examples illustrate the preparatiOn of the gamma-pyrones according to the process of the invention .
and the preparation of the various intermediate compounds.
In the Examples where spectral ~ata are yiven, NMR
chemical shift data are reported by conventional literature symbolism and all shifts are expressed as~ units from tetra- , 10 methyl silane: li s = singlet ; d = doublet t = triplet q = quar~et !
m = multiplit br = broa Example 1 In a 3-neck round bottom flask equipped with a , magnetic stirring bar, a gas inlet tube, a therometer and an additional funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The solution was cooled to a temperature of ~
to 10C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.089 moles) in 20 ml of tetrahydrofuran and this was added dropwise to the stirred reaction flask while chlorine (0.30 mole) was added via the gas inlet tube. The rate of addition was such thatall the alcohol was added in the first 1.3 to 1.5 equivalents of chlorine (approximately ¦, 30 minutes) while maintaining the temperature below 10C.
The reaction mixture was heated to reflux and the tetrahydro-30 furan removed by distillation. When the reaction mixture, .
* Trade Mark -13-a~

..... ,. ;.

~9~9~
reached a temperature of about 105C., a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then flltered hot, cooled, the pH adjust~d to 2.2 and the reaction mixture was cooled to 5~C. Crystallization and filtxat.ion yielded 3343 grams of crude 3-hydroxy-2-methyl-'r-pyrone (maltol). The aqueous filtrate was extracted with chloroform to obtain a second crop of 2.58 g of maltol.
Distillation of the combined solids and recry~tallization from methanol gave 5,5 g (49%~ of pure white maltol, m,p. 159.5 to 1~ 160.5C-Example 2 The procedure of Example 1 was repeated under varying conditions as shown in Table I with furfur~l alcohols of the formula ~3~ OH

Table 1. One Pot Process using chlorine as the oxidant.

.
Temp. (C~ Temp. (C) Yield R Cosolvent of oxidation of hydrolysis ~%) .
CH3 methanol 10 100 45 20 CH3 methanol 5 110 56 CH3 methanol -5 l04 60 CH3 methanol -l0 104 77 CH3 methanol -20 106 62-67 25 CH3 acetonP -5 110 36 CH3 CH3CN ~5 110 29 CH3 Et OAc 0 110 26 CH3 none 10 110 17-30 .

, :~:

~Q959i2~

Temp. (C) Temp. (C) Yield .
RCosolvent of oxidation of h~drolysis (%) CH3benzene 10 110 26 CH3methyl isobutyl ketone 5 110 44 CH3isopropyl alcohol 0 110 49 CH2CH3 methanol 5 110 49 CH2CH3 methanol -10 110 58 Hmethanol -10 110 57 CH3methanol -30 110 50 THF = tetrahydrofuran EtOAc = ethyl acetate Example 3 The method of Example 2 was repeated with comparable results employing each of the following co-solvents:
ethanol n-propanol iso-butanol n-butanol t-butanol dioxane ethyl ether isopropyl ether dimethoxy ethane 2-methoxy ethanol 2-ethoxy ethanol ethylene glycol Example 4 In a 3-neck round bottom flask equipped with a ~s~

stirring bar, a yas inlet tube and an acldition funnel was added 20 ml of -tetrahydrofuran, 50 ml of water and sodium bromide (0.20 mole). The solution was cooled to a tempexature of 0 to 20C~ The addition ~unnel was charged with a solution of 1(2-furyl)-1-ethanol (0,18 mole) in 20 ml of tetrahydrofuran and this was added dropwise to l:he rapidly stirred reaction flask while gaseous chlorine (0.40 mole) was added via the gas-eous inlet tube. The rate of the alcohol addition was such that a yellow orange color wa~ maintained. The temperature was kept be~ow 20C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction 1ask, the temper-ature was raiséd to reflux to distill off the tetrahydrofuran, The isolation procedure of Example 1 was uRed to isolate 12.47 g of pure maltol (55% yield).
Substantially the same results were obtained ~ub8ti-tuting potassium bromide for sodium bromide.-The method of Example 4 wa~ repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula R

Table 2. One Pot Process using BrCl as the oxidant, generated by addition of chlor~ne in situ to NaBr.

Temp.-(C) Temp. (C) Yield 25 R(os_lv ~ _ of hy~roly~is (~

1~9S92~L

Temp. (C) Temp. (C) Yield R Cosolvent of oxidation of hYdrolYsis (%) -- ~
CH3Isopropyl ether 25 110 46 CH3ethyl ether 20 110 43 CH3 acetone lS 105 47 CH3 CH30~ 15 110 32 THF = tetrahydrofuran Example 6 In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermcmeter and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-l-ethanol ~0.09 mole) was added dropwise. The temper-ature of the reaction mixture was not allowed to exceed 10C.
Bromine (0.10 mole) was then added and the-reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of maltol was obtain~d.
Example 7 .

To a 4-neck round bottom flask equipped with a thermo-meter, a condensor and two addition funnels was charged 50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10C. To this well stirred solution was added bogether in the two addition funnels bromine (0.20 mole) and 1(2-furyl)-l-ethanol (0.09 mole). The temperature of the mixture was maintained at 15C. throughout the double addition. The reaction mixture was then heated to 75C. for 10 hours. Maltol was iso-.
.:::

... . . ,~ .

lated by the procedure of Example 1 (53% yield).
~xample 8 The method of Example 7 was repeated under varying conditions shown in Table 3 with furfuryl alcohols of the formula ~OH
R
Table 3 _ _ ___ Temp. (C) Temp. (C) Yiald R Cosolvent of oxidation of ~olysis (%) CH3 CH30H 5o 105 47 CH3 none 15 100 30 Example 9 A 2.8 M sodium hypoohlorite solution wa~ prepared by passing chlorine gas ~42.6 g) into a olution of 48 g of sodi~m hydroxide in 150 ml of water at O~C. A solution of 1(2-furyl)-l-ethanol (0.05 mole) in 15 ml of tetrahydrofurAn and 15 ml of water was prepared in a 3-neck flask and oooled to 5C. While maintaining a pH from 1.0 to 0.8 with 6 N HCl, 21.7 ml of the hypochlorite solution was added dropwise to the reaction flask over a period of about 33 minutes while maintaining the temper-ature below 5C. A 15 ml portion of concentrated hydrochloric acid was then added to the reaction mixture which was then heated to remov~ the tetrahydrofuran by distillation. Heating - . , :

9~

was continued for an addition~1 hou~ Maltol was isolated as described in Example 1.
Substantially the same result~ are obtained when sodium hypobromite is used in placed of sodium hypochlorite.
Example 10 To a solution of 1~2-Euryl~-l-ethanol (0.05 mole~
in 15 ml of tetrahydrofuran and 15 ml of water at 5C. was added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) was added to the reaction flask via a gas inlet tube while maintaining the temperature below SC. The reaction mix-ture was then heated to reflux and the tetrahydrofuran removed by distillation. Heating was continued for an additional hour.
The reaction mixture was cooled and maltol was isolated by the procedure described in Example 1.
Example 11 To a 3-neck round bottom flask was charged a ~olu-tion of 50 ml of watex and 20 ml of tetrahydrofuran and the solution was cooled to 0C. An addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml -of tetrahydrofuran and this solution was added dropwise to thereaction flask while BrCl ~0.30 mole) was added via a gas inlet tube. The rate of add-~tion was such that all the fur-furyl alcohol was added in the first 1.3 to 1.5 equivalents of BrCl while maintaining the temperature below 30C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reached 105C., a condensor was attached and the reaction mixture heated under reflux for about 2 hours~, The reaction mixture was cooled and maltol iso-lated by the procedure of Example 1.

!~r -19--~9~;~2~
Exa~ple 12 In a 3-neck round bottom flask equipped wlth a magnetic bar, a thermometer and two addition funnels was charged 25 ml of tetrahydrofuran and 50 ml of water. To this solution was added 1(2-furyl)~ ethanol (0.89 mole) in 25 ml of tetrahydrofuran while bromine (0.16 mole) was added drop-wise while maintaining the temperature below 15C. After the additions were complete, chlorine (0.10 mole) was added via a gas inlet tube and the-reaction was heated to reflux. Maltol was isolated from the cooled solu~ion by the procedure of Example 1.
Exam~e 13 6-hy~roxy-2-methy~1-2H-pyran-3t6H)-one To a solution of 25 g of 1(2-furyl)-1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5C. wa~ added 1 equivalent of bromine. The temperature was maintained at 5 to lO~C. throughout the addition. The solution was adjusted to pH 2.1 and extracted with ethyl ac~tate (3 X 50 ml). Ths ethyl acetate extract was dried and evaporated to give a yellow oil. The oil was chromatographed on silica gel and eluted with chloroform-ethyl acetate (3:1) to give 4.8 g of clear oll which was shown by spectr~l data to be identlcal with 6-hydroxy-2-methyl-2H-pyran-3(6H)-ona prepared from 6-methoxy-2-methyl-2H-pyran-3(6H)-one by acid hydroly~is ~Tetrahedron 27, 1973(1971~].

IR (CHC13) 3700, 3300, 1700 cm~l NMR (CDC13,~ ): 6,8-7.1 (lH, d of d); 6.0-6~2 (lH, d), 5.6 (lH, br. s, exchangeq with D20); 504-5.5 (lH, d);

4.8-5.0 (lH, q); 1.3-1.6t3H, t).
Exampl~ 14 The method of Example 13 was repea~ed with a ~915~
furfuryl alcohol of the formula ~ OH
R

to yield a compound of the formula ,~0 H R
wherein R is hydrogen ox ethyl.
Ethyl compound: IR ICRCl3) 3600, 3340, 1706 cm 1 Hydrogen compound: IR (CHC13) 3565, 3300, 1703 cm 1 Example 15 4-bromo-6-hydroxy-2-meth~1-2H-p~ran-3(6H)-one 10To a solu~ion,of 25 g of 1(2-f~ryl)-1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at ~ to 5C. was added dropwise 2.2 equivalents of bromine. Throughout the ad-dition the temperature was maintained at 5 to 10C. After the bromine addition the solution was stirred at room temperature 15for 30 minutes and the pH adjusted to 2.1 with 2 N NaO~ solutio~
The reaction mixture was extracted with ethyl acetate (3 X 100 ml). The ethyl acetate extracts wera combined, dried over MgSO4, filtered and taken to drynes~. ~he residue was chroma-tographed on silica gel and eluted with chloroformoethyl acetate ~95:5). The product was an orange oil whlch was rechromato-graphed on silica gel and eluted with chloroform-ethyl acatat~
(95:5).

NMR (CDCl~,~ ) 7.3 (lH, d); 5.6 (lH,d); 4.7-S.
(lH, q); I.1~1.5 (3H, m).
Example 16 The procedure of Example 15 was repeated with a fur-furyl alcoho'l of the formula ` -21-~, ;

~t2~
C3~H

to yield a compound of ~he formula HOlO~R
wherein R is hydrogen or ethyl.

Ethy1 compound 4-bromo-6-hydroxy-2-ethyl-2H-pyran-3(6H)-one NMR (CDC13,~ ) 7.4 (lH, d), 4.6-4.9 (lH,m);
1.8-2.2 (2H, m); 1.0~1.3 (3H, t) Hydrogen compound 4-bromo-6-hydroxy-2H-pyran-3(6H)-one NMR (CDC13,~ ) 7.4 (lH, d); 5.5 ~lH, d); 4 6 (2H, d of d).

Example 17 A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one was prepared by dissolving the compound in either an aqueous inorganic or aqueous organic acid. The solution was then heated to reflux, cooled to room temperature, the pH ad-justed to 2.1 with 6 N NaOH and the reaction mixture extracted with chloroform. Concentration yielded maltol. The acids, time of reaction and yields of maltol were as follows:
Acid Concentration(~) Reaction Time(Hrs) Yield(%) HCl 32 2 68 HCl 32 5 52 HCl 18 5 35 HCl 25 3 49 HBr 18 5 24 v~ CH3COOH -22- 2 69 ~ ~:
.

s~

Acid Concentration(%3 Reaction Time(Hrs) Yield(%) .
CF3COOH neat 3 36 CF3COOH neat 3 70 CH3COOH neat 3 77 ' HCOOH neat 3 24 Alternatively organic solvents such as benzene and toluene, together with acidic materials such as ~-toluene-10' sulfonic acid and "Amberlite" IR-120, may be used~
Example 18 The method of Example 15 wa- repeated employing chlorine in place of bromine and the appropriate furfuryl al-cohols to' produce the ~ollowing compounds:
Methyl: 4-chloro-6-hydroxy-2-methyl-2H-pyran-3(6H)-one NMR (CDC13,~ ): 7.1 (lH, d)~ 5.8'(1H,d);
4.6-5.0'(1H,m); 4.4~H,br.sO); 1.2-1.5(3H,m).
Ethyl: 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3(6H)-one NMR (CDC13, ~): 7.0-7.1 (lH, d); 5.6-6.0 (2H, m); 4.4-5.0 (lH, m); 1.6-2 1 (2H, m); 0.9-1.1 (3H, t).
Hydro~en: 4-chloro-6-hydroxy-2H-pyran-3(6H)-one NMR (CDC13,~ ): 7.1-7.2 (lH, d); 5.6 (lH, d); 4.4-4.9 (2H, d of d) (D2O added).
Example l The method of Example 15 was repeated to yield a compound of the formula -I
HO~O ~ R
wherein R is propyl, butyl, phenyl or benzyl; X is bromine or chlorine.
Example 20 4-Bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one was * Trade Mark ,' ~ : ~
' ~

:, :. , , :

5'13~

heated under vacuum for 16 hours at 40C. The resulting oily solid was crystallized from isopropyl alcohol to yield 6,6'-oxybis [4-bromo-2-methyl-2H-pyran-3(6H)-one], m.p. 125C.
Example 21 The method of Example 20 was repeated starting with a compound of the formula 1~
HO O R

to yield a compound of the formula 0~ o RJ~OJ~O ~R
wherein R iS hydrogen, ethyl, propyl, butyl, phenyl or benzyl;
X is bromine or chlorine~
R X M~Po (C~ ~
CH3 Cl 177 to 179 CH2CH3 Cl 132 to 135 Example 22 A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one (0.0025 mole)in 20 ml of 35% phosphoric acid was refluxed for about 5 hours. Maltol ~34%) was isolated by the procedure of Example 1.
Example 23 A compound of the formula X X

R ~J~XR

~ 9~2~

wherein R is hydrogen, methyl, ethyl, propyl, butyl, phenyl or benzyl; and x is bromin~ or chlorine is treated by the method of Example 22 to yield a compound of the formula OH

O~--~ R
wherein R is as defined above.
Example 24 A solution of 6-methoxy-2-methyl-2H-pyran-3(6~)-one (0.01 mole) in 20 ml of acetic acid was treated with gaseou~
chlorine (0.01 mole) at room temperature. The reactlon mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform. The chloroform extract was concentrated to yield maltol which was recrystallized from methanol to give the pure product (56%), m.p. 159.5 to 160.5C.
Example 25 The procedure of Example 24 was repeated starting with a compound of ~he formula ~ O
1~
R'O R
wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl; R' is al~yl of 2 to 4 carbon atom~ or -COR" where R"
is methyl, ethyl or phenyl to yield a gamma-pyrone of the formula O
. ¢~0~

R

-25-, , ~:
. -wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl.
Exam~le 26 The procedure of Example 24 was repeated with com-parable results replacing acetic acid with each of the followingsolvents:

formic acicl methanol e~hanol tetrahydrofuran benzene ethylene glycol trifluoroacetic acid acetone acetonitrile Example 27 The procedure of Example 24 was repeated with com-parable results replacing chlorine with bromine, sodium or potassium hypochlorite or hypobromite, gaseous bromine chloride or bromine chloride prepared in situ by the addition of chlorine to a solution containing sodium bromide or bromine to a solu-tion of sodium chloride.
Example 28 4-chloro-6-methoxy-2-methyl-2H-Eyran-3~6H)-one To a solution of 6-methoxy-2-methyl-2H-pyran-3 (6H)-one (0.05 mole) in 70 ml of dichloromethane at -lO~C.
was added chlorine (0.05 mole) via a gas inlet tube. Following this addition, triethylamine (0.05 mole) was added slowly while maintaining the temperature at -10C. After 30 minutes of stirring the reaction mixture was allowed to warm to room temperature, Xiltered to remove triethylamine hydrochloride and tha solvent removed under vacuum. Redissolving the crude product in ether-benæane and filtration removed the last trace~ of triethylamine hydrochloride. Removal of the solvent ; ~

~.

~9~
gave 4-chloro-6-methoxy-2-methyl-2H- pyran-3(6H)-one (yield, 99%).
NMR analysis of the signals at 5.05 to 5.25 clearly showed two doublets in a 3 to 1 ratio corresponaing to the proton at C-6 of the two possible isomers of the compound. Both optical forms of the trans isomer had been synthesized from a carbo-hydrate precursor by Paulsen, Eberstein and Koebernick, Tetra-hedron Letters 4377 ~1974).
Example 29 4-bromo-6-methoxy-2-methyl-2H-pyran-3(6H)-one The p~ocedure of Example 28 was repeated replacing chlorine with bromine to obtain 4-bromo-6-methoxy-2-methyl-2H-pyran-3(6H)-one in 93% yield. The two optical orms of the tran_ isomer had been synthesized by Paulsen and co-workers, Tetrahedron Letters 4377 (1974).
Example 30 The procedure of Examples 28 and 29, respectively, was repeate~ ,tarting with a compound of the formula:

R'O "q~`O "D~`R
wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl; and R' is alkyl of 2 to 4 carbon atoms to yield a com-pound of the formula X

R'O ~ " ~``R
wherein R and R' are as defined above; and X is chlorine or bromine.

Example 31 4-bromo-6-acetyl-2H-pyran-3(6H)-one ~' . .

~9~

A solution i.n dichloromethane of 6-acetyl-2H-pyran-3(6H)-one, prepaxed by t.he me~hod described in Tetra-hedron 27, 1973 ~1971), was brominated by the procedure of Example 6 to yield 4-bromo-6-acetyl-2H-pyran-3(6H)-one, m.p.
5 78 to 80C. The mass spectrum of the compound ~howed the expected parent peaks at 234 ancl 236 mass units.
Example 32 4-bromo-6-acetyl-2-methyl-2H-3(6H)-one The procedure of Example 31 was repeated with 6-acetyl-2-methyl-2H-pyran-3(6H)-one to yield 4-bromo-6-acetyl-2-methyl-2H-3(6H)-one which showed parent masses of 249.96 and 247.96 by mass spectroscopy and the following NMR spectrum:
(~ , CDC13): 7.3(lH~ d); 6.4(lH, d of d); 4.7~lH, Q); 2.2 (3H, S); 1.4(3H, S).
Example 33 The procedure of Example 28 was repeated employing chlorine in place of bromine and starting with a compound of the formula:-R'O O R

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl orbenzyl, R' is alkyl of 1 to 4 carbon atoms or -COR" where R' is methyl, ethyl or phenyl to yield a compound of the formula .

R'O ~ O ~ R
wherein R and R' are as defined above and X is chlorine.

.
- -~L~9~

xample 3 4 To a rouna bot~orn I lask ~c~uip~d with a stlrringbar and a condens~r was a~ded 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H)-one and acetic acid and the reaction mixture heated to reflux for an hour. Maltol ~65~) was obtained on cooling.
Example 35 The procedure of Example 34 was repeated with com-parable results using formic acid in place of acetic acid.
Example 36 ._ The procedure oi Example 34 was repeated starting with a compound o~ the formula X
~,0 R'O - ~ R
~wherein R is hydrogen,,alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' is alkyl of 1 to 4 carbon atoms or -COR" where R"
is methyl, ethyl or phenyl; and X is bromine or chlorine to yield a compound of the formula o ¢~OH

O
wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl.
Exam~e 37

6-methyl-2-ethyl-3-hydroxy-4H-E~_an-4-one In a three necked round bottom flask wPre added 28 ml of methanol and 38 ml of water. The solution was cooled to -15C. and 0.166 mole of 5-methyl-2-(2-hydroxy~propyl)furan ~ ~5 (J. Or~. Chem., 26, 1673, 1960) and 0.416 mole of chlorine .h~ ' 29 ;~

*~5~

wer~ added simultaneously. During the additio~, the temperature was maintained between -16 and -8~C. When addition was com-pleted, the solution was warmed to 80C. and refluxed Eor about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and the mixture extracted ~ith chloroorm (3 x 100 ml).
The combined organic layers wer~ washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30~ yield) of white solid. Sublimation yielded pure product, m.p. 157 to 159C.
Analysis Calc'd. for C8~103: C, ~2.33; H, 6054 Found: C, 62.05; H, 6.44 NMR (CDC13,~ ); 6-CH3, 2.33 (3H, s); 2-CH3, 1.30 (3H, t);
2-CH2-, 2.75 ~2H, quartet), 5H, 6.23 tlH, s).
Example 38 2,6-dimethyl-3-hydroxy-4H-pyran-4-one In a three necked round bottom flask were added 28 ml of water and 32 ml of methanol and the mixture was cooled to -15C. The solution was treated with 0~16~ mol~ of 5-methyl-2-~-hydroxy-èthyl)furan (J. Org. Chem., 26, 1673,1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10C. during addition. The mixture was allowed to warm to room temperature over 30 minutes and heated to reflux for 3 hours. The cooled solution was adjusted to pH 2.1 and extracted with chloroform (3 X 100 ml). The chloroform extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue, a dark oil, was chromatographed on silica gel developed : . ' .-- 1 ~ ' ' ~ "' .
.
~ .
" :

~5~

with methylene chloride~ethyl acetate (95:5), The product, isolated by evaporation, was recrystalli~ed from methanol as a tan solid (yield, 25~. Sublimation yielded white cry-stals, m.p. 161 ~0 163Co Analysis Calc'd. for C7H802: C, 59.99; H, 5.75 Found: C, 59.83; H, 5.82 NMR (CDC13,~ ); 6-CH3, 2.33 (3H, s); 2-CH3, 2.26 (3H, s);
5-H, 6.10 (lH, s).

, ,:

Claims

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

1. A process for preparing a gamma-pyrone of the ormula:- (I) which comprises heating in acidic aqueous solution until hydrolysis is substantially complete a 4-halo-dihydropyran of the formula (II) or a 6,6'-oxybis [4-halo-2H-pyran-3(6H)-one] of the formula (V):- (II) (V) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is methyl, ethyl or phenyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms, and X is chlorine or bromine.

2. A process according to claim 1, wherein the acid re-quired for the hydrolysis is provided by dissolving the compound of formula (II) or (V) in aqueous inorganic or organic acid before heating.

3. A process according to claim 1, wherein the temperature at which the hydrolysis is conducted is within the range of 70°
to 160°C.

4. A process according to claim 1, wherein the gamma-pyrone is 2-methyl-3-hydroxy-4H-pyran-4-one or 2-ethyl-3-hydroxy-4H-pyran-4-one.

5. A process according to claim 1, wherein the gamma-pyrone is 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one or 2,6-dimethyl-3-hydroxy-4H-pyran-4-one.

6. A process according to claim 1, wherein the intermediate 4-halo-dihydropyran of formula (II) is prepared by reacting a compouna of the formula:- (IV) wherein R, R' and R''' are as defined in claim 1, in a solvent at a temperature of -50° to 50°C. with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof until the reaction is substantially complete.

7. A process according to claim 6, wherein the solvent is water, an alkanol or diol of 1 to 4 carbon atoms, an ether of 2 to 10 carbon atoms, a low molecular weight ketone, nitrile, ester or amide.

8. A process according to claim 7, wherein the solvent is methanol, tetrahydrofuran, isopropyl ether or acetone.

9. A process according to claim 6, wherein the halogen-containing oxidant is chlorine or bromine chloride.

10. A process according to claim 6, wherein the acid re-quired for the subsequent hydrolysis of the compound of formula (II) is generated in situ by loss of acid from the intermediates formed during the course of the reaction with the halogen-containing oxidant.

11. A process according to claim 1, wherein the intermediate compound of formula (V) is prepared by dehydrating a compound of the formula:- (II') wherein R and X are as defined in claim 1.