Note: Descriptions are shown in the official language in which they were submitted.
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This is a divisional of Patent Application No.
279922 filed June 6th 1977.
Application No. 279922 describes and claims the
preparation of gamma-pyrones and particularly the prepara-
tion of gamma-pyrones by the hydrolysis of certain intermedi-
ate compounds, some of which are novel, which intermediates
are prepared from appropriate furfuryl alcohols by the use
of halogen-containing oxidants. The present divisional
is concerned with a one-pot process for preparing gamma-
pyrones from furfuryl alcohols.
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-~1-piperidylmethyl)-
1,4-pyrone was reported by Spielman and Freifelder in J.
Am. Chem. Soc., 69 2908 (1947). Schenck and Spielman, J.
Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkaline
hydrolysis of streptomycin salts. Chawla and McGonigal,
J. Org. Chem., 39, 3281 (1974) and Lichtenthaler and Heildel,
Angew. Chem., 81, 998 (1969), reported the synthesis of
maltol from protected carbohydrate derivatives. Shono and
Matsumura, Tetrahedron Letters No. 17, 1363 (1976), describ-
ed a five step synthesis of maltol starting with methyl
furfuryl alcohol.
The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-
pyran-4-one as one of the characteristic sweet-aroma compon-
ents in refinery final molasses was reported by Hiroshi Ito
in Agr. Biol. Chem., 40 (5), 827-832 (1976) This compound
was previously synthesized by the process described in
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United States Patent Specification No. 3,468,915.
Syntheses of gamma-pyrones such as pyromeconic
acid, maltol, e~hyl maltol and other 2-subs~ituted-3-
hydroxy-gamma-pyrones are described in United States Patents
No. 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,469;
3,376,317; 3,468,915; 3,440,183; and 3,446,629.
Maltol and ethyl maltol enhance the flavor and
aroma of a variety of food products. In addition, these
compounds are used as ingredients in perfumes and essences.
- 10 The 2-alkenylpyromeconic acids reported 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 beverages and aroma enhancers
in perfumes.
The present invention Provides a proaess for
preparing a gamma-pyrone of the formula:
~ OH
/\o ~~ R
R'''
wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl
or benzyl and R''' is hydrogen or alkyl of 1 to 4 carbon
atoms, which comprises reacting a compound of the formula:
~ ~ OH o~(III)
R''' R
wherein R and R''' are as defined above, in aqueous solution
at a temperature of -50 to 50C. with at least two equival-
ents of a halogen-containing oxidant selected from chlorine,
bromine, bromine chloride, hypochlorous acid, hypobromous
acid or mixtures thereof and heating the resulting 4-halo-
dihydropyran intermediate until hydrolysis is substantially
complete.
Thus, the present invention provides a novel and
25~
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facile synthesis of gamma-pyrones of formula (I) above, par-
ticularly maltol t2-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 reac-
tion mixture is then heated to hydrolyze the resulting inte~
mediate. The one pot process may be represented by the
following equation.
R ' ~ ~ ~R
R' "
(III) (I)
wherein R i9 hydrogen, alkyl of I 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 mixture~ thereof.
The full reaction pathway is shown in the following scheme:
R ' ' ' ~o
(III) R' ' ' (~=0 H
~H
~H op~n
~=O chain
H- ~OH tautomér
R " ~ R ' '~
~1
l~ (II') (I)
open
chain
tautomer
254
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Lefebvre and co-workers in J. Med. Chem., 16, 1084
(1973) demonstrated that furfuryl alcohols could be direat-
ly converted to 6-hydroxy-2H-pyran-3(6H)one6 when a peracid
oxidant such as peracetic acid or m-chloroperben~oic acid
is employed, The first step on the Lefebvre work uses a
peracid in an orqanic solvent and probably leads to a 6-
acetoxy or 6-m-chlorobenzoyloxy pyran derivative which is
hydrolyzed to the 6-hydroxy compound during the aqueous
work-up. Water is not used in the first step of the reac-
tion, and would in fact be deleterious. In any case, theprocess of Lefebvre and co-workers cannot lead directly to
the conversion of a furfuryl alcohol to a gamma-pyrone.
Critical to the process for the preparation of the
intermediates of the present invention is the use of an
15 aqueous solution of a halgen-containing 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
aldehyde and as such might be expected to undergo numerous
undesired si~e reactions such as over oxidation or an aldol-
type condensations. By employing two equivalents of a
25 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 employing low cost Cl2, Br2, BrCl, HOCl,
HOBr or mixtures thereof as the halogen-containing oxidant.
30 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 vacuo to afford crude gamma-
pyrone directly in high yield by simple concentration.
The one pot process is operated by dissolving
35 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
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C4 alkanols or diols, for example, methanol; C2 to C10
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 C10 ethers, with methanol
the choice of solvents because of cost. The solution is
kept at a temperature of -50 to 50C., preferably -10 to
10C To this solution is charged a desired furfuryl
alcohol while simultanteously adding a halogen-containing
oxidant (two equivalents) 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 temperatue at which the hydro-
lysis proceeds at a reasonable rate, for example, 70 to
160C, The generally employed hydrolysis temperature is
100 to 110C. 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
ln 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
hypobromous acid or mixtures thereof. Bromine chloride is
a commercially available gas, It may be prepared ln situ
by the addition of chlorine to a solution of sodium or
potassium bromine or by the addition of bromine to a solu-
tion of sodium or potassium chloride. Hypochlorous and
hypobromous acid conveniently may be generated in situ by
the addition of aqueous acid (HCl, H2SO4 or HBr) to a
- 35 solution of an alkali metal or alkaline earth metal hypo-
halite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred
halogen-containing oxidants, based ~n cost factors, are
chlorine and bromine chloride prepared in situ.
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The following Examples illustrate the preparation
of the gamma-pyrones according to the procegs of the inven-
tion.
In the Examples where spectral data are given,
5 NMR chemical shift data are reported by conventional liter-
ature symbolism and all shifts are expressed as ~ units fran
tetramethyl silane:
s = singlet
t = triplet
q = quartet
Example 1
In a 3-neck round bottom f lask equipped with a
magnetic stirring bar, a gas inlet tube, a thermometer and
an additional funnel was added 20 ml of tetrahydrofuran
15 and 50 ml of water. The solution was cooled to a temper-
ature of 0 to 10C. The addition funnel was charged with
a solution of 1(2-furyl) -l-ethanol ~0,089 moles~ in 20 ml
of tetrahydrofuran and this was added dropwise to the reac-
tion flask while chlorine (0.30 mole) was added via the
20 gas inlet tube. The rate of addition was such that all the
alcohol was added in the f irst 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 tetrahydrofuran removed by distillation.
25 When the reaction mixture reached a temperature of about
105C,, a condensor was added and the refluxing continued
for about 2 hours. The reaction mixture was then filtered
hot, cooled, the pH adjusted to 2.2 and the reaction mixture
was cooled to 5C. Crystallization and filtration yielded
30 3.43 grams of crude 3-hydroxy-2-methyl-~-pyrone ~maltol) .
The aqueous filtrate was extracted with chloroform to o~tain
a second crop of 2.58 g of maltol. Distillation of the
combined solids and recrystallization f~om methanol gave
5.5 g (49%) of pure white maltol, m.p. 159.5 to 160.5C.
Example 2
The procedure of Example 1 was repeated under
varying conditions as shown in Table I with furfuryl alco-
254
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hols of the formula
~ ~ ~ H
Table 1. One Pot Process using ~hlorine as the oxidant.
RCosolvent Temp. (C) Temp. ~C) Yield
of oxidation of hydrolysis ~%~
CH3methanol lO 100 45
CH3methanol 5 110 56
CH3methanol -5 104 60
CH3methanol -lO 104 77
10 CH3methanol -20 106 62-67
CH3 THF 10 105 49
CH3acetone -5 110 36
CH3CH3CN -5 110 29
CH3Et OAc O llO 26
15 CH3none 10 110 17-30
CH3 benzene lO llO 26
CH3 methyl isobutyl
ketone 5 llO 44
CH3 isopropyl alcohol O llO 49
20CH2CH3 methanol 5 llO 49
CH2CH3 methanol -lO 110 58
- CH2CH3 THF 10 110 47
H methanol -10 110 57
CH3 methanol -30 110 50
THF - tetrahydrofuran
EtOAc = ethyl acetate
Example 3
The method of Example 2 was repeated with compar-
able results employing each of the following co-solvents:
ethanol ethyl ether
n-propanol isopropyl ether
iso-butanol dimethoxy ethane
n-butanol 2-methoxy ethanol
t-butanol 2-ethoxy ethanol
dioxane ethylene glycol
111~254
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Example 4
In a 3-neck round bottom flask equipped with a
stirring bar, a gas inlet tube and an addition funnel was
added 20 ml of tetrahydrofuran, 50 ml of water and sodium
5 bromide (0.20 mole) . The solution was cooled to a tempera-
ture of 0 to 20C. The addition funnel 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 the rapid-
ly stirred reaction flask while gaseous chlorine (0.40 mole)
10 was added via the gaseous inlet tube. The rate of the
alcohol addition was such that a yellow orange color was
maintained. The temperature was kept bèlow 20C. with ice
bath cooling. After the alcohol and chlorine had both been
added to the reaction flask, the temperature was raised
15 to reflux to distill off the tetrahydrofuran. The isolation
procedure of Example 1 was used to isolate 12.47 g of pure
maltol (55% yield) . ~
Substantially the same results were obtained sub-
stituting potassium bromide for sodium bromide.
; 20 Example 5
The method of Example 4 was repeated under varying
conditions shown in Table 2 with furfuryl alcohols of the
formula
.
/~ ~OH
25 Table 2. One Pot Process using BrCl as the oxidant, generat-
ed by addition of chlorine in situ to NaBr,
R CosolventTemp, (C) Temp, (C) Yield
of oxidation of hydrolysis ~96)
CH3 THF 20 104 55
30CH3 THF 27 110 54
CH3 THF 15 110 52
CH3Isopropyl ether 25 110 ~ 46
CH3 ethyl ether 20 110 43
CH3 acetone 15 105 47
35CH3 CH30H 15 110 32
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R Co~olvent Temp. (C) Temp. (C) Yield
of oxidation of hvdrolvsis (%)
_
CH2CH3 THF 16 113 47
H THF 20 109 48
-
THF = tetrahydrofuran
- Example 6
In a 3-neck round bottom flask equipped with a
magnetic stirring bar, a gas inlet tube, a thermometer 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)-1-ethanol (0.09 mole) was added dropwise.
The temperature 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 isola-
tion procedure of Example 1, a yield of 5.7 g of maltol was
obtained.
Example 7
To a 4-neck round flask equipped with a thermo-
meter, a condensor and two addition funnels was charged50 ml of tetrahydrofuran and 50 ml of water and the solution
was cooled to 10C. To this well stirred solution was
added together in the two addition funnels bromine (0.20
mole~ and 1(2-furyl)-1-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 isolated by the procedure
of Example 1 (53~ yield).
Example 8
The method of Example 7 was repeated under varying
conditions shown in Table 3 with furfuryl alcohols of the
formula
~OH
O
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--10-
Table 3
R CosolventTemp. (C) Temp. ~C) Yield
of oxidation of hydrolysis (~)
CH3 THF 15 75 53
5 CH3 CH30H 50 105 47
CH3 none 15 100 30
CH2CH3 THF 25 105 47
H THF 15 100 45
CH3 THF 50 lO0 20
Example 9
A 2.8 M sodium hypochlorite solution was prepared
by passing chlorine gas (42.6 g) into a solution of 48 g
of sodium hydroxide in 150 ml of water at 0C. A solution
of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydro-
furan and 15 ml of water was prepared in a 3-neak flask
and cooled 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 temperature below 5C.
A 15 ml portion of concentrated hydrochloric acid was then
- added to the reaction mixture which was then heated to
remove the tetrahydrofuran by distillation. Heating was
continued for an additional hour, Maltol was isolated
as described in Example 1,
Substantially the same results are obtained when
sadium hypobromite is used in place of sodium hypochlorite.
Example 10
To a solution of 1(2-furyl)-1-ethanol (O.D5 mole)
in 15 ml of tetrahydrofuran and 15 ml of water at 5C. was
30 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 5C.
The reaction mixture was then heated to reflux and the
tetrahydrofuran removed by distillation. Heating was con-
tinued for an additional hour. The reaction mixture was
cooled and maltol was isolated by the procedure described
in Example 1.
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Example ll
To a 3-neck round bottom flask was charged a solu-
tion of 50 ml of water 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 the reaction flaskwhile BrCl ~0.30 mole~ was
added via a gas inlet tube. The rate of addition was such
that all the furfuryl 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 isolated by the
procedure of Example 1.
Example 12
In a 3-neck round bottom flask equipped with 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)-1-ethanol (0.89 mole)
in 25 ml of tetrahydrofuran while bromine (0.16 mole) was
added dropwise 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
solution by the procedure of Example 1.
Example 13
6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one
In a three necked round bottom flask were 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 (J. Org. Chem., 26, 1673, 1960) and 0.416
mole of chlorine were added simultaneously. During the
addition, the temperature was maintained between -16 and
-8C. When addition was completed, the solution was warmed
to 80C. and refluxed for about 3 hours. Upon cooling to
P254
-12-
room temperature, the pH was adjusted to 2 1 and the mixture
extracted with chloroform (3 x 100 ml.). The combined
organic layers were 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 solidO Sublimation yielded pure
product, m.p. 157 to 159C
Analysis
Calc'd for C8H103 C, 62-33; H~ 6.54
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 (lH, s).
Example 14
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 0.167 mole
of 5-methyl-2-(~-hydroxy-ethyl)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 chloro-
form (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 with methylene
chloride/ethyl acetate (95:5). The product, isolated by
evaporation, was recrystallized from methanol as a tan
solid (yield, 25%). Sublimation yielded white crystals,
m.p. 161 to 163C.
Analysis
Calc'd- for C7H82 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).
