Note: Descriptions are shown in the official language in which they were submitted.
~ ~ .
This is a divisional of Patent Application No.
279922, filed June 6, 1977~
Applioation No. 279922 describe3 and claims the
praparation of gamma-pyrones and partiaularly to the pre
S para~ion of gama-pyrones by the hydrolysis of certain inter-
mediate compounds, some of which are novel, which intermedi-
ates are prepared from appropriate ~urfuryl alcohols by the
u~e of halogen-contai~ing oxidant3. Appli~ation No. 27g922
al~o di3closes a one-pot process for preparing gamma-pyrone~
10 from furfuryl alc~hols. The pre~ent divisional is concern-
ed with novel 4-halo-dihydropyran intermediates and the
preparation thereof~
Maltol (2-methyl-3~hydroxy-4H-pyran-4-one) is a
naturally occurring ~ubstance found in the bark of young
15 larch treesl pine needles and chiaory. Early commercial
production was frcm the destructive di~tillation of wood.
The synthesi3 of maltol from 3-hydroxy-2-(1-piperidylmethyl)-
1,4-pyrone was reported by Spielman and Freifelder in ~. Am.
Chem. Soc., 69 2908 ~1947). Schenck ana Spielman, J. Am.
20 Chem. Soc., 67, 2276 (1945), ob~ained maltol by alkaline
hydrolysis of streptomycin salt3. Chawla and McGonigal,
J. Org. Chem., 39, 3281 (1974) and ~ichtenthaler and Heidel,
Angew. Chem., 81, 998 (1969), reported the synthe~is of
mal~ol from protecked caxbohydrate derivatives. Shono and
25 Matsumura. Tetrahedron Letter~ No, 17, 1363 (1976), describ-
ed a five step synthe~i~ o~ maltol starting with methyl
furfuryl alcohol.
~The i olation of 6-methyl-2-ethyl-3-hydroxy-4H-
., : .
~75~ ~
pyran-4-one as on~ of the charac~eristic sweet-aroma com-
ponents in refinery final mola~ses waq reported by Hiro~hi
I~o in Agr. siOl, Chem., 40 (5), 827-832 (1976). Thi~ com-
pound was previou~ly ~ynthesized by the proce~s de~cribed
5 in United State~ Patent Speciflcation No~ 3,468,915.
Synthese~ o~ gamrna-pyrones such as pyrorneconic
acid, maltol, ethyl maltol and o~her 2-~u~s~ituted-3-hydroxy-
gamma-pyrones are de~cribed in United States Patent~ No.
3,130,20~; 3,133,0a9; 3,140,239; 3,159,~52; 3,365,469;
10 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 o food products. In addition, these
compounds are u~ed as ingredientq in per~ume~ and essence~
The 2-alkenylpyromeconic acids reported in United States
15 Patent No. 3,644,63S and the 2-arylmethylpyromeconic acid
de~cribed in United States Patsnt No. 3,365,469 inhibit the
growth of baoteri and fungi and are useful a~ flavor and
aroma enhancers in foods and beverages and aroma enhancers
in perfumes.
Applica~ion No. 279922 provides a process for pre-
paring a gamma-pyr~ne of the formula:
o
~ OH
,,) \ O ~ \R ...(I)
which comprises heating i~l acidic aqueous solution, prefer-
ably at a temperatur2 within the range of 70 to 160C.,
25 until hydrolysi~ is ubstantially complete a 4-halo-dihydro-
pyran of the ormula (II) or a 6,6'~oxybis~4-halo-2H-pyran-
3(6H)-one] o~ the formula (V): .
X ~ X
B R~ O or ~\~
R'O O R R / ~ O ~ O O R
(II)
(V)
wherein R i~ hydrogen, alkyl of 1 to 4 carbon atoms, phenyl
or ben~yl, R' i8 hydroyen, alkyl of 1 to 4 carbon atoms or
-COR", wherein R" is methyl, ethyl or phenyl, R''' is hydro~
gen or alkyl of 1 ~o 4 carbon atom~, and X i~ chlorine or
S bromine.
The acid required for the hydroly~is may be added
to the reaction mixture, e.y. by di3~01ving the intermediate
compound of formula (II) or formula (V~ in an aqueous
inorganic or organic before heating; or alternatively the
acid may be generated in situ during the preparation of the
intermediates as hereinafter described.
In accordance with the present divi~ional thexe
is provided a process for preparing the intermediate com-
pound of formula (II) which comprises reacting a compound
of the formula:
,~
R' ~ ¦ I
R'O `O ~ R ~ IV)
wherein R, R' and R''' are a~ defined above, in a solvent
at a temperature of -50 to 50C., preferably at room
temperature, with at least one equivalent of a halogen-con-
taining oxidan~ selected from chlorine, bromine, brominechloride, hypochlorou~ acid, hypobromous acid or mixtures
thereof until the reaction is sub~tantially complet~r
~ xamples 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 tetrahydrofuran or isopropyl ether, a low
molecular weight ketone, preferably acetone, a low molecular
weight nitrile, ester or amide.
The intermediate compound of formula (IV) above
wherein R' is hydrogen may be prepared by reaoting a
furfuryl alcohol o~ the formula:
R'.'~ ~ OH
" O ~ ~ R .~o(III)
s~
wherein R and R'l' are as defined above, in aqueous solution
wlth at least one equival~nt of a halogen-containing
oxidant selected from chlorine, bromine, bromine chl~ride,
hypochlorous acid, hypobromous acid or mixttlres thereof at
a temperature of -50 to 50C , preferably room temperature,
until the reaction is substantially complete~ me reaction
may be conducted in the presence o a co-~olvent which
suitably may be one of the ~olvents previously mentioned
fox the preparation of the intarmediate compound of formula
(II).
If desired, the in~ermediate 4-halo-dihydropyran
compound of ormula (II) wherein R' i9 hydrogen may be pre-
pared dixect from an appropriate furfuryl alcohol of
fo~mula (III) by reacting the latter in an aqueous solvent
at a temperature of -50 to 50 C., with at lea~t two
equivalents of one of the aforementloned halogen-containing
oxidants until the reaction is ~b3tantially complete.
In each of the above-de~cribed reactions the pre-
ferred halogen-containing oxidant i9 chlorine or bromine
chloride.
The intermediate compound of formula (V) may be
prepared by dehydrating a compound of the formula:
X
L
H0 ~ 0 ~ \R ...~II")
As disclosed in Application No. 279922 a novel
and facile 6yn~hesis of gamma-pyrones of formula (I) above,
particularly maltol (2-methyl-3-hydroxy-4H-pyran-4-one)
and related compounds, may be provided by a one-pot process
from a fur~uryl alaohol of formula (III) above.
In accordance with thi~ one-pot process, a
furfuryl alcohol in a~ueous medium i~ reacted with two
equivalents of a halogen-containlng oxidant and the reaction
mixture is then heatad to hydrolyze the resulting inter-
medlate, The one pot proces~ may be represented by the
1 ~l75~1
--5--
:~ollowing equation.
Ll OH
o~
... (III) ,,.(I)
wherein R is hydrogen, alkyl of 1 to 4 carbon atoms,
phenyl or ben~yl; R" ' is hydrogen or alkyl of 1 to 4
S carbon atoms; and XY i9 C12, Br2, ClBr, HOCl, HOBr or mix-
tures thereof. The full reaction pathway i ~hown in the
following scheme:
~ Oxidant O Y 1
R''' ~ o ~ ~ ~ ~
OH ~ ~ ,
(III) R" ~ `t~ ' R R"'~ f l
R' " C-O
I open
CH chain
CH tautomer
C~O
H- COH
R
X o
R''' ~ O ~ R ''' ~ ~ R
OH ~II') (I)
open
chain
tautomer
Lefebvre and co-workers in J. M~d. Chem., 16,
1084 (1973) demonstrated that furfuryl alaohols could be
directly converted to 6-hydroxy-2H-pyran-3~6H)ones when a
peracid oxidant such a~ peracetic acid or m-chloroperbenzolc
acid is employed~ The first stap of the Lefebvre work uses
~7~ ~
a peracid in an organic solvent and probably leads to a
6-acetoxy or 6 m-chlorobenzoyloxy pyran derivative ,1hich i3
hydrolyzed ~o ~he 6-hydroxy compound during ~he a~ueous
work-up. water i~ not u3ed in the fir~t ~tep of the react-
ion, and would in Eact be deleterious~ In any case, theproces~ of Lefebvre and co-worker~ cannot lead directly
to the conver~ion of a furfuryl alcohol to A yamma-pyrone.
Critical to the process for the preparation of
the intermediate~ of the pre~ent invention i9 the use of an
aqueous solu~ion of a halogen-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
~e converted to gamma-pyrone~ A 6-hydroxy-2H-pyran-3~6H)-
one may be regarded as a hemi-aoetal of an aldehyde and as
such might be expected to undergo num~rous undeslred side
reactions such as over oxidation or an aldol-tvpe conden-
sations. By employing two equivalents of a halogen-contain-
ing oxidant in water or wa~er and organic co-solvent, khe
raaction proceeds smoothly from a furfuryl alcohol to a
gamma-pyrone This novel one pot process offer3 the advan-
tages of employing low cost C12, Br2, BrCl, HOCl, HOBr or
mixtures thereof as the halogen-containing oxidant. Isola
tion of the desired gamma-pyrone is greatly simplified
since solvent, oxidant and by-product mineral acid are all
volatile and may be removed i_ vacuo to afford crude gamma~
pyrone directly in high yield by simple concentration~
The one pot process i~ operated by dis olving a
furfuryl alcohol in water or water and a co-solvent. The
co-~olvent may be water-miscible or water-immiscible and
may be selected from a wide range of solvent~ such as Cl to
C4 alkanols or diols, for example, mathanol; C2 to C10
ethers, for example, tetrahydro~uran or isopxopyl ether;
low molecular weight ketones, for example, acet~ne; low
molecular weight ~itrile~; low molecular weight esters and
low moleaular weight amides. The preferred co-solvents are
Cl to C4 alkanols ~nd c2 to C10 ethers, ~.~ith methanol the
choice ~f ~olvents becau~e of C09t. The ~olution ls kept
at a temperature of -50 to 50C,, preferably -10 to 10C.
To ~his ~olution i8 charged a desired furfuryl alcohol
whila simultaheously adding a halogen~containing oxidant
(two equivalents) to th8 reaction mixture. The temperature
of the reaction mixture is main~ained at -50 to 50C.,
preferably -10 to 1~C , during halogen addition. If a
low-boiling co-solvent is employed, it is removed by dis-
tillation after all additions are complete. The reactionmixture is then heated to a t~mperature at which the
hydrolysis proceeds at a reasonable rate, for example, 70
to 160C. The generally employed hydrolysis temperature iq
100 to 110C. The heating is continued until the
hydrolysis of the formed 4~halo-hydropyran intermediate is
sub~tantially complete ~usual~y 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
thP course o~ the reactionO Additional acid may be added
if desired
The halogen-containlng 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 in situ
by the addition of chlorine to a solution of sodium or
potassium bromine or by the addition of bromine to a
solution of sodium or potassium chloride. Hypochlorous and
hypobromou~ acid conveniently may be generated in itu by
the addition of aqueous a~id (HCl, H2SO4 or HBr) to a
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 on cost factors, are
chlorine and bromine chloride prepared in situ.
As de~cribed above, khe intermediate 6-hydroxy-
2H-pyran-3(6H)-one of formula (IV~ may be prepared by re-
acting the appropriate furfuryl alcohol with one equivalent
of a halogen-containing oxidant. The isolated intermediate
7~;;'1 ~
ls readily co~ve~ted to ~he desired gamma-pyrone by react-
in~ it with an additional equivalent of a halogen oxidant
and hydroly~ing the formed 4-halv-&-hydroxy-2H-pyran~3(6H)-
one of formula (II) as previously de~aribed.
Alte~natively, a furfuryl alcohol in aqueou3 801u-
tion with an optional co-~olvent may be reaated at -10
to 10C. with two equivalents o~ a halogen-containiny
oxidant. After stirring at room temperAture for 30 minutes,
the pH of ~he reac~ion mixtura i8 adju~ted to 2 with a
strong base and the reaction mixture i3 extracted with a
solvent ~uch as ethyl acetQte. ~emoval of the ~olvent
yields the 4-halo-6-hydroxy-2H-pyran-3~6H)-one of foxmula
(II') which may be hydrolyzed to the de~ired gamma-pyrone.
The 4-halo~dihydropyran may be dehydrated by heating under
vacuum to yield the 6,6~-oxybis ~4-halo-2~-pyran-3(6H)-one].
This dimer yields the desired gamma-pyrone on hydroly~is,
with added acid if desired.
Certain of th~ 4-halo-dihydropyran intermediate
compounds are novel compounds and, accordingly, the present
invention also provide~ a compound of the formula:
R' " ~ ~ ...(II')
HO O R
wherein R, R' " and X are as defined above, and a compound
of the formula:
R ' ~ ...(IV)
R C2~5
wherein R and X are a deined above and R4 is alkyl of
1 to 4 carbon atoms or -COR" wherein ~" i8 m~thyl, ~thyl
or phenyl, provided that when X is chlorin~ and R4 is
ethyl, R' " i~ not hydrogen
The 6,6'-oxybis [4-halo-2H-pyran-3(6H)~one]
intermediate compound o the formula:
31 ~3 7~
--3--
\X~ (V)
R o / o o R
wherein R and X are a~ defined above, is also a ~ovel com-
pound .
A 6-alkoxy-2H-pyxan-3(5H)-one may be prepared by
the method dascribed in Tetrahedron Letters No. 17, 1363-
1364 (1976). A furfuryl alcohol is anodically alkoxylatedto the 2~ hydroxyalkyl)~2,5-dialkoxy-dihydro-
furan. Treatment with a strong oryanic acid produces the
desired 6~alkoxy compound~ A 6-aayl compound may be pre-
pared by ~onventional treatment of the 6-hydroxy compound
with the appropriate anhydride in the presence of pvridine.
A 6-acyl or 6-alkoxy-2H-pyran-3(6H)-one i8 dis-
solved in a solvent select~d from acetic acid, formic acid,
trifluoroacetia aaid, halogenated solvents, ethexs, Cl to
C4 alkanols or diols, or low molecular weight ketones,
nitriles, esters or amide~. The preferred 601vent is
acetic a~id, formic açid or methanol. An equivalent of a
halogen-containing oxidant selected chlorine, bromine,
bromine chloride, hypochlorous acid, hypobromous acid or
mixtures thereof i8 added at room temperature and the
reac~ion mixture is heated ~o 70-160C., genexally 100-
110 C., until th~ conversion to the de~ired gamma-pyrone i9
substantially complete (approximately 1 to 3 hours)0 The
gamm~-pyrone may be obtained from the cooled, neutralized
reaction mixture on standing or by extracting the xeaction
mixture with a solvent ~uch as chlorQform which yields the
gamma-pyrone on concentration.
With organic acids and other protia solvents such
a formic acid, acetic acid, other organic a~ids and
alkanols that have not been vlgorously dried, no additional
water is added in the above described reaction. However,
with non-proti~ solvenks, water is nece~ary and is added
for the conver~ion of the intermediate 4-halo-6-sub~tituted-
2H-pyran-3(6H)-one to the pyrone. When a low-boiling ~ol-
'~ ~J~7 ~ ~
--10--
vent is employed in the reaction it is removed by distill-
ation just before the reaction mixture i~ heated to 100 to
110C. for the hydrolytic conversion of ~he intermediate
4-halo-dihydropyran to the gamma-py~o~e.
If desired, the 4-h~lo-dihydropyran may he pre-
pared and isolated by conduating the halogenation at a
temperature of -20 to 20C., pre~erably 5b~ 10C., in
the presence of an oxganic base such a~ triethylamide.
After about 30 minutes khe reaction mixture is allowed to
warm ~o room temperature, filtered to remove triethylamide
hydrochloride and ~he solven~ removed under vacuum to
yield the 4-halo-dihydropyran. This compound is readily
hydrolyzed to the gamma-pyrone by haating for about an
hour in aqueou~ solution, with added acid if desired, pre-
ferably at a tempera~ure within the range of 70 to 160C.,
more preferably 100 t~ 110C.
Thi~ process wherein the 6-acyl or 6-alkoxy-2H-
pyran-3(6~)-one is reacted in an organic ~olvent with one
equivalent of a halogen-containing oxidant and the inter-
mediate 4-halo-dihydropyran heated until the conversion to
the de3ired gamma-pyrone is sub~tantiall~ complete difers
from the multi-step process described by Shono and
Matsumura in Tetrahedron Letters 17, 1363 ~1976) wherein
the 6-alkoxy-2H-pyran-3(6H)-one i8 treated with a methanol-
ic solution of hydrogen peroxide with sodium hydroxidesolution to yield an epoxy keton~. The i~olated epvxy
ketone is then refluxed in water with "Dowex"* 50 ion
exchange resin to yield the desired gamma-pyrone.
The following Examples illustrate the preparation
of the gamma-pyrones according to tha proaess of the
invention and the preparation o~ the various intermediate
compound~,
In the Examples where spe~tral data are give,
NMR chemical shift data are reported by aonventional
literature symboli~m and all shifts are expre~sed as
units rom tetramethyl silane:
~a~--
~; a singlet
d = doublat
t = triplet
~ = quartet
m = multipl~t
br ~ broad
Example 1
In a 3-neck round bo~ton ~lask equipp~d with a
magnetic stirring barl a gas inlet tube, a thermometex and
an additional funnel was added 20 ml of tetrahydrofuran
and 50 ml of water. The 801ution was cooled to a tempera-
ture of 0 ~o 10C. The addition funnel was charged with
a solution of 1(2-furyl)-1-athanol (00~89 mole~) in 20 ml
of tetrahydrofuran and ~his was added dropwise to th~
stirred reaction flask while chlorine (0.30 mole) was
added via th~ gas inlet tube~ The rate of addition was
such that all the alcohol was added in the fir3t 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 re-
moved by distillation. When the re~ction mixture reached
a temperature o~ 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 wa~ cooled to 5C. Crystallization
and filtration yielded 3.43 grams of crude 3-hydroxy-2-
methyl-~-pyrone ~maltol). The aqueous filtrate was ex-
tracted with chloroform to ~btain a second crop of 2.58 g
of maltol. Distillation of the combined solids and re-
crystallization from methanol gave 5.5 g ~49%) of purewhite maltol, m.p. 159.5 to 160.5C.
~ 2
The procedure of Example 1 was repeated under
varying conditions as shown in Tablc I with furfu~yl
alcohol~ of the formula
7~
-12~
3 OEI
\O <
R
Table 1. One Pot Process u~.ing chlorine a~ the oxidant.
-
Temp. Temp.
(C) of ~C) o ~ield
~ osolvent oxldatlon_ hydrolysis ~
CH3 methanol 10 100 45
CH3 methanol 5 110 56
CH3 methanol -5 104 60
CH3 methanol ~10 104 77
CH3 methanol -20 106 62-67
CH3 THF 10 105 49
CH3 acetone -5 110 36
CH3 CH3CN -5 110 29
CH3 EtOAc 0 110 26
CH3 none 10 110 17-30
CH3 benzene 10 110 26
CH3 methyl
isobutyl
ketone S 110 44
CH isopropyl
3 alcohol 0 110 49
20 CH2-
CH3 methanol 5 110 49
CH2-
CH3 methanol -10 110 58
CH2-
CH3 THF 10 110 47
H methanol -10 110 57
CH3 methanol -30 110 50
THF = tetrahydrofuran
EtOAc - ethyl acetate
~.
The method of Example 2 wa~ repeated with ~om-
parable results employing each of the following co-solvents:
ethanol
n-propanol
iso-bu~anol
n-butanol
t-butanol
dioxane
ethyl ether
i~opropyl ether
dimethoxy ethane
2-methoxy ethanol
2-ethoxy ethanol
ethylene ylycol
~,.
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 ~f water and sodium
bromide (0.20 mole). The solution was cooled to a tempera-
ture of 0~ to 20C. The addi~ion funnel wa~ charged with
a solution o~ 1~2-furyl)-1-ethanol (0~18 mole) in 20 ml of
tetrahydro~uran and thi8 was added dropwi~e ko the rapidly
stirred reaction flask while gaseous chlorine ~0~40 mole)
was added via the gaseous inlet tube. The xate of the
alcohol addition was such that a yellow orange color was
maintained, The tempexature wa~ kept below 20C. with
ice bath oooling. After the alaohol and chlorine had
both been added to the rea~kion ~lask, the temperature
was ra~ed to reflux to distill off the tetrahydrofuran.
me i901ation procedure of Example 1 was used to isolate
12.47 g of pure maltol (55% yield).
Substantially the same re~ults were obtained
substituting potassium bromide for sodium bromide.
Example 5
The method of Example 4 was repeated under
varying conditions shown in Table 2 with furfuryl alcohols
of the formula
OH
o~
7~
-14-
Table 2. One Pot Process u~ng ~Cl a~ the oxidant, genera~-
ed by addltion of chlorlne in ~itu t~ NaBr~
Tamp~ Temp,
(C) of ~C) ofYield
R Coiolvent oxidationhvdrolvsi~ (%)
CH3 THF 20 o 104 55
CH3 THF 27 110 54
CEl3 THF 15 110 52
CH3 Isopropyl
ether 25 llO 46
lO CH3 ethyl
eth~r 20 110 43
CH3 acetone 15 105 47
CH3 CH30H 15 110 3 2
CH2-
15 CH3 ~HF 16 113 47
H THF 20 109 48
.
THF = ~etrahydrofuran
Exam~e 6
In a 3-neck round bottom fla~k e~uipped with a
magnetic s~irring bar, a gas inlet tuhe, 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
25 while 1(2-furyl)~l-ethanol (0~09 mole) was added dropwise.
The temperature of the rea~tion 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 mal~ol was
30 obtained.
~.
To a 4-neck round bottom flask e~uipped with a
thermometer, a aonden30r and two addition funnel3 was
charged 50 ml of tetrahydrofuran and 50 ml o~ water and the
35 solution was cooled to 10C. To this well stirred solution
was added together in the ~wo addi~ion funnels bromine
(0.20 mole) and 1~2-furYl~ ethanol (Q.Og mola). The
~7~1
-15-
temperature of the mixtur~ was maintained at 15C. throuyh-
out the double addition. The xeaction mixture was then
heated to 75C. for 10 hour.~, Maltol was i~olated by the
procedure o ~xample 1 (53~ yield),
~
The me~hod of Example 7 was repeated under vary-
ing conditions shown in Table 3 with fururyl alcohols of
the formula
10Table 3
Temp, Temp.
(C) of ~,C) of Yield
R _ Cosolv~nt _ oxidation _ hydrolysis ~%) _
CH3 THF lS~ 75 53
lS CH3 CH30H 5 lOS 47
CH3 none 15 100 30
CH2-
CH3 THF 25 105 47
H THF 15 100 45
20 CH3 THF 50 100 20
Exam~le 9
A 2.8 M sodium hypochlorite solution was prepared
by passing chl~rine ga3 ~42.6 g) into a solution of 48 g
of sodium hydroxide in lS0 ml of water at 0C. A solution
25 of 1~2 furyl)-l-ethanol ~O.OS mole) in lS ml of tetrahydro-
furan and 15 ml of water was prepared in a 3-neck flask
and cooled to 5C. While maintaining a pH from 1.O to 0.8
with 6 N HCl, 21.7 ml o~ ~he hypochlorite solution was added
dropwi~e to the reaction fla~k over a period of about 33
30 minutes while maintaining the temperature below 5C. A
15 ml portion of concentr~ted hydrochloric acid was then
added to the reaction mixture which was then heated to rqmove
the tetrahydrofuran by distillation. Heating was continued
for an additional hour. Maltol was isolated as described
35 in Example 1.
~7~
-16-
Sub~tan~ially the same xesults are obtained when
sodium hypobromite is used in place of sodium hypochlorite.
To a solution of 1~2~furyl)-1-ethanol ~0.05 mole~
5 in 15 ml of tetrahydrofuran and 15 ml of water at 5C. wa~
added 21.7 ml of 2.8 M sodium hypochlorite ~olution.
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 tetra-
10 hydrofuran removed by distillation. Heating wa~ continuedfor an additional hour. The reaction mixture was cooled
and maltol wa~ i~olated by the pro~edure desaribed in
Example 1.
To a 3-neck round bottom flask was charged a solu~
tion of 50 ml o~ water and 20 ml of tetrahydrofuran and the
solution was cooled to 0C. An addition funnel wa~ charged
with a solution of 1~2-furyl)-l~ethanol ~0.89 mole) in 25 ml
of tetrahydrofuran and this ~olution was added dropwise ts
20 the reaction ~la~k while BrCl ~0~30 mole~ was added via a
gas inlet tube. The rate of addi~ion was ~uch that all the
furfuryl alcohol wa~ added in the first 1.3 to 1.5 equival-
ents of BrCl while maintaining the temperature below 30C.
The reaction mixture was heated to reflux and the tetrahydro-
25 furan removed by distilla~ion. When the temperature reached105C., ~ condensor was attached and the reaction mixture
heated under r~flux for about 2 hour~. The reaction mixture
was cooled and maltol isolated hy the procedure of ~ .
In a 3-nec~s round bottom flask equipped with a
magnetic bar, a thermometer and two addition funnels was
charged 25 ml o~ tetrahydrofuran and 50 ml of water. To
this solution wa3 added 1(2-furyl)-1-ethanol ~0.89 mole) in
25 ml of tetrahydrouran while bromine ~0.16 mole) was added
35 dropwise while maintaining the tamper~ture below 15C. After
the addition~ were complete, chlorine, chlorine ~0.10 mola)
was added via a gas inlet tube and the reaction was heated
~75;~ ~
17-
to reflux. Maltol was i~olated ~rom the cooled solution by
the procedure of Example 1.
3(6H)-one
_.
S To a solution of 25 g of 1(2 furyl)-l-ethanol in
125 ml of tetrahydrofuran and 125 ml of water at 5C. was
added 1 equivalent of bromine. The temperatur~ was main-
tained at 5 to 10~C. throughout the addition. The solu-
tion was adjusted to pH 2.1 and extracted with ethyl acetate
t3 X 50 ml). The ethyl acetate extract was dried and evapo-
rated to give a yellow oil. The oil was chromatographed on
a silica gel and eluted with chloroform-ethyl acetate ~3:1)
to give 4.8 g of clear oil which was shown by spectral data
to be identical with 6-hydroxy 2-methyl-2H-pyran-3(6H)-one
lS prepared from 6-methoxy-2-methyl-2H~pyran-3(6H)-one by acid
hydrolysis [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, exchanges with D2O); 5.4-5.5 ~lH, d);
4.8-5.0 (lH, q); 1.3-1~6~3H, t).
The method of Example 13 was repeated with a
furfuryl alcohol of khe formula
~ OH
O ~
R
to yield a compound of the formula
~0
HO o R
wherein R is hydrogen or ethyl.
Eth~l compound: IR ~CHC13) 3600, 3340, 1706 cm 1
30 Hydro ~ : IR (CHC13) 3565,3300, 1703 cm 1
~7~
Exd~ 15
4-Br o ~ -2-meth~ ~H~ ~
To a solutiorl of 25 g o~ 1(2-furyl)-1-ethanol in
125 ml of tetrahydrofuran and 125 ~1 of water at 0 to 5C.
was added dropwise 2.2 equivalent--3 of bromine. Throughout
the addi'cion the temperakure was maintained at 5 to 10C.
After the bromine addition the solution ~as stirred at room
temperature for 30 minutes and the pH adjusted to 2.1 with
2N NaOH solution. The reaction mixture was extracted with
ethyl acetate (3 X 100 ml3. The ethyl acetate extracts
were combined, dried over MgSO~, filtered and taken to dry-
ness. The residue was chromatographed on silica gel and
eluted with chloroform~ethyl acetate ~95:5). The product
was an orange oil which was rechromatographed on silica gel
and eluted with chloroform-ethyl acetate (95:5).
NMR ~CDC13,~) 7.3 (lH, d); 5.6 (lH,d); 4.7-5.0
~ lH, q~; 1.1-1.5 (3H, m).
The procadure of Example 15 was repeated with a
furfuryl alcohol of the formula
r--
to yield a compound of the formula
",[~
HO O R
wherein R is hydrogen or ethyl.
4-bromo-6-hydroxy-2-ethyl-2H-pyran-
3~H)-one NMR (CDC13,~) 7.4 (lH, d); 4.6-4.9 ~lH,
m); 1.3-2.2 (2H, m); 1.0-1.3 (3H, t).
Hydrogen compound 4-bromo-6-hydroxy-2H=pyran-3(6H)
7.4 (lH, d); 5.5 (lH, d); 406
~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 acidO
The solution was then heated to re~lux, cooled to room
temperat~re, khe pH adjusted to 2.1 with 6 N NaOH and the
75~ ~
--19--
reaction mixture extracted with chloroform. Concentration
yielded mal~ol. The aclds, time of reaction and yields of
maltol were as follows:
Acid concentration~%l P~eac~ion Time ~Ers.) Yield~%~
5 HCl i~
EICl 32 S S2
HCl 18 5 35
HCl 25 3 49
HBr 18 5 24
H2SO4 35 2 26
H3PO4 35 2 29
CH3COOH 35 2 69
CF3COO~ neat 3 36
~NO3 35 3 0'4
15 CF3COO~ neat 3 70
CH3COOH neat 3 77
HCOOH neat 3 24
H SO 35 5 48
2 4 Alternatively organic solvent3 such as benzene and
toluene, together with acidic materials such as p-toluenesulfon-
ic acid and "Am~erlite"* IR-12~, may be used.
Example 18
Tha method of Example lS was repeated employing
chlorine in place of bromine and the appropria~e furfuryl alco-
hols to produce the following compounds:
M ~ : 4-chloro-6-hydroXy.-2-methyl~ pyran-3(6H~-
one NMR ~CDCl ,~1: 7.1 ~lH,d~: 5.8 ~lH,d):
4.6-5.0 (lH,m~; 4.4 ~lH, br.s.~; 1.2-1.5 ~3H,m).
~ : 4-chloro-6~hydroxy-2-ethyl-2H-pyran-3(6H)-
3Q one NMR ~CDC13,~): 7.~7.1 ~lH,d); 5.6-
6.0 ~2H,~); 4.4-5.0 ~l~,m~; 1.6-2.1 ~2H,
m); Q.9~ 3H,t).
4-chloro~6~hydr~xy-2H-pyran-3(6~)-one NMR
~CDC13,~): 7.1~7.2 ~lH,d); 5.6 (lH,d); 4.4-
4.9 ~2H,d o~ d) ~D2O added).
The method of Example lS wa~ repeated to yield a
compound of the formula
* Trade Mark
~7~
-2~-
X
HO ~ O ~ R
wherein R is propyl, butyl, phenyl or benzyl; X is bromine
or chlorine.
4-Bromo-6-hydroxy-2-methyl-2H-pyran-3~6H)-ona was
heated under vacuum for 16 hours at 40C. The resulting
oily solid was crystallized from isopropyl alcohol ~o yiald
6,6'-oxybis [4-bromo-2-methyl-2~-pyran-3(6~)-one], m~p. .
125C.
~
The method of Example 20 was repeated starting
with a compound o~ the formula
X
_~i~'
HO o~R
to yield a compound of the Eormula
X X
R o O R
wheréin R is hydrogen, ethyl, propyl~ butyl, phenyl or
benzyl; X is bromine or chlorine.
R X M,P. ~C.)
CH3 Cl 177 to 179
CH2CH3 Cl 132 to 135
Exa ~
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.
7~
-21
E~
A compound of the formula
X X
Oq~ ~0
RJ~o ~o~O~'R
wherein R is hydrogen, methyl, ethyl, propyl, butyl/ phenyl
or benzyl; and X is bromine or chlorine is treated by the
method of Example 22 ~o yield a compound of the formula
~OH
O R
wherein R is as defined above.
~,
A solution of 6~methoxy-2-methyl-2H-pyran-3(6H)-
one ~0.01 mole) in 20 ml of acetic acid was treated with
gaseous chlorine ~0.01 mole~ at room temperature. The
reaction mixtuxe was then heated to reflux for about.one
hour, cooled to room temperature, diluted with 20 ml of
water, khe p~I adjusted with 50% NaOH solution to 7.0 and the
reaction mixture extracted with chloroform~ The chloroform
extrac~ was concentrated to yield maltol w~ich was recrystal-
lized ~rom methanol to give the pure product 156%), m.p.
2~ 159.5 to 160.5C.
ThP procedure of Example 24 was repeated starting
with a compound of the formula
~0
R'O ~ O ~ R
wherein R is hydroge~, alXyl of 2 to 4 carbon atoms, phenyl
or benzyl; Rl is alkyl of 2 to 4 carbon atoms or -COR"
where R" is methyl, ethyl or phenyl to yield a gamma-pyrone
~7~
-22-
of the formula
o
¢~OH
wherain R is hydrogen, alkyl of 2 to 4 carbon atorn~, phenyl
or benzyl.
Example 26
The procedure of Example 24 was repeated with com-
parable results replacing acetic acid with each of the fol
lowing solvents:
formic acid
methanol
ethanol
tetrahydrofuran'
benæene
ethylene glycol
trifluoracetic 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 chlor-
~0 ide or bromine chloride prepared in situ by the addition of
chlorine to a solution containing sodium bromide or bromine
to a solution of sodium chloride.
Exarnple 28
4-chloro-6-methox~2~methyl-_~ Ey~--3(6H)-one
To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-
one ~0.05 mol ) in 70 ml of dichloromethane at -10C. was
added chlorine ~0.05 mole) via a gas inlet tube. Following
this addition, triethylamine (0.05 mole) was added slowly
while maintaining the tempe~ature at -10C. after 30 minutes
of stirring the reaction mixture was allowed to warm to
room temperature, filtered to remove tri~thylamin~ hydro-
chloride and the solvent removed under vacuum. Redissolving
the crude product in ether-benæene and filtration removed
the last traces of triethylamine hydrochloride. Removal
~7~5~1
of the solvent gave 4-chloro-6-methoxy-2-meth~1-2H-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 cor~e~ponding
to the proton at C-6 of the two possible isomers of the com-
pound. Both optic~l forms of the krans isomer had beensynthesized from ~ carbohydrate precursor by Paulsen,
Eberstein and Koebernick, Tetrahedron Letters ~377 (1974~.
Exam~le 29
4-Bromo-6-metho~y-2-meth~-2H-~yran-3(6H)-one
The procedure of Example 28 was repeated replacing
chlorine with bromine to obtain 4-bromo-6-methoxy-2-methyl-
2H-pyran~3t6H)-one in 93% yield. The two optical forms of
the trans isomer had been synthesized by Paulsen and co-
workers, Tetrahedron Letters 4377 (1974).
~
The procedure of Examples 28 and 29, respeotively,
was repeated starting with a compound of the formula:
~0
R'~o j~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 compound o the formula
X
~0
RlO~\o~ - R
wherein R and R' are as defined above; and X is chlorine or
bromine.
~
4-B~omo-6-acetyl-2H-~Yran-3~6H)-one
A solution in dichloromethane of 6-acetyl-2H~
pyran-3~6H)-one, prepared by the method described in Tetra-
hedron 27, 1973 ~1971), was hromina~ed by the procedure of
Example 6 to yield 4-bromo-6-acetyl-2~-pyran-3~6H)-one, m.p,
-2~-
78 to 80C. The mass spactru~ of the compound showed the
expected parent peaks at 234 and 236 mass units.
~559~e=~ 3~0o~Y~ one
The procedure of Example 31 was repeated with 6-
acetyl~2-methyl-2M-pyran-3(6H)~one to yield 4-bromo-6-acetyl-
2-methyl-2H-3~6~-one which showed parent masses of 249.96
and 247.96 by mass spectroscopy and the following NMR
spectrum: ~, CDC13); 7.3(1H, d); 6.4(1H, d of d); 4.7(1H,
Q); 2.2 ~3H, S~; 1.4(3H, S).
Exam~le 33
The procedure of Example 28 was repeated employ-
ing chlorine in place of bxomine and starting with a com-
pound of the formula:
lS f ~
R O O ~ ~
wherein R is hydrogen, alkyl of 1 to 4 carbon atom~, phenyl
or benzyl, R' is alkyl of 1 to 4 carbon atoms or -COR"
where Rl is methyl, ethyl or phenyl to yield a compound of
the formula:
X
2~ ,O
R'O O R
wherein R and R' are as defined aboye and X is chlorine.
Ex~ e 34
To a round bottom flask equipped with a stirring
bar and a aondenser was added 4-chloro-6-methoxy~2-methyl-
2H-pyran-3~6H)-one and ac~ti~ acid and the reaction mixture
heated to reflux for an hour. Maltol (65%) was obtained on
cooling.
The procedure of Example 34 was repeated with com~
par~bla resul~s using formic acid in place af acetic acid
7~1
The proc~dure of Example 34 was repeated starting
with a compound of the formula:
X
R ~ o~\ o/l--R
S 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 phenyli and X is bromine or
chlorine to yield a compound of the formula:
o
OH
O
lQ wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl
or ben~yl.
Example 37
6-~thyl-2-ethyl-3-h~~g~y~ y~----4 one
In a three necked round bottom flask were added
lS 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 addi~ion,
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 room temp-
erature, the p~ was adjusted to 2.1 and the mixture extract-
ed with chloroform (3 x 100 ml). The combined oryanic
layers were washed with water, brine and dried over rnagn~-
sium sulfate. The organic solution was filtered and evapor~ated to give a thick dark solid. The solid was recrystallized
~wice from methanol to give 8006 grams (30% yield) of white
solid. Sublimation yielded pur~ product, m.p. 157 to 159Co
Analysis
Calc'd. for C8H1003: C, 62.33; H, 6.54
-~6~
Found: C, 62.U5; H, 6.44
NMR ~CDC13,~; 6-CH , 2~33 (3H, 5); 2~CH3, 1.30 ~3H, t);
2-CH2-, 2.75 (2H, q~artet), 5H, 6.23 ~lH, s).
2,6-~imet~yl-3~hydrox~y 4~I~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 (~. 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 tempexature 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 ~ater 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 163~C.
Analysis
Calc d. for C7H8O2: C, .99; H, 5.75
Found; C, 59.83; H, 5.82
NMR ~CDCl3,~); 5-CH3, 2.33 (3H, s); 2-CH3, 2~26 (3H, s);
5-H, 6.10 ~lH, s).
