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Oxathiazinone DioxidesЧA New Group of Sweetening Agents.

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Volume 12 - Number 11
November 1973
Pages 869 - 942
International Edition in English
Oxathiazinone Dioxides- A New Group of Sweetening Agents
By Karl Clauss and Harald Jensen[*l
Dedicated to Professor Werner Schultheis on the occusion of his 70th birthday
1,2,3-0xathiazin-4(3H)-one
2Jdioxides bearing lower alkyl substituents on C-5 and C-6
represent potential sweeteners. They are formed from chloro- or fluorosulfonyl isocyanate
and acetylenes, ketones, fl-diketones, 0-0x0 carboxylic esters, or benzyl vinyl ethers viu
N-halosulfonyl 0-0x0 carboxamides as common intermediates.
1. Introduction
Since time immemorial the sensation of sweetness of a
fruit, a plant secretion, or honey has provided man-and
probably also other animals-with
a principle for the
selection of suitable nourishment from the fullness of his
environment. In the course of cultural development, sweet
natural products were employed in the preparation of
food to intentionally modify its taste. Thus began the
checkered history of the development of sweeteners, starting with thedomestication of the honeybee and continuing
through to the migration of sugar cane from Indochina,
ria the Mediterranean, to America. Cane sugar was
unknown in Central Europe until the time of the Crusades.
Here the reader is reminded of the introduction of sugar
beet cultivation during the Continental Blockade. Cane
and beet sugar have remained the dominant sweetening
agents since the foundation of the sugar industry and
annual production now runs at some 75 million tonnes.
This figure testifies to man’s love of sweetness.
and nutritionalists. Thus the search for sweeteners which
d o not overtax the metabolism even on liberal comsumption, i. e. low-calorie sweeteners, has become more pressing
than ever. The sugar substitutes sorbitol or fructose long
used by diabetics are metabolized slowly but nevertheless
completely and therefore offer no solution to the problem
of low-calorie sweetening, especially since their sweetening
power is no greater than that of sugar.
Anybody having to live on a diet or wishing to consume
less sugar without foregoing sweetness must take recourse
to a “synthetic sweetener” in the narrow sense of the term.
Such agents cover a whole variety of compounds, the
only real limitation being that they should be several orders
of magnitude sweeter than saccharose. Many such compounds have been discovered largely by chance during
the past hundred years”’. For toxicological reasons, however, only two were permitted for general use as sweeteners
until quite recently: saccharin ( 1 ) and cyclamate (2) in
The high sugar consumption in developed countries whose
populations are plagued by such civilization diseases as
diabetes, hyperlipemia, obesity, cardiac infarction, caries,
or gout is attracting increasing attention from physicians
[*] Dr. K . Clauss and Dr. H. Jensen
Farbwerke Hoechs! AG
623 Frankfurt (Main) 80 (Germany)
A n g c w . Chrm. inrrmar. E d i t . ! Vo/. 12 f l y 7 3 1 i No. I 1
the form of their neutral sodium and calcium salts. Saccharin is 100 to 500 times as sweet as saccharose, and
cyclamate 30 times as sweet.
8 69
Like most synthetic sweeteners, the well-established saccharin, which was discovered in 1879, suffers from a bitter
metallic aftertaste. Only cyclamate, which was introduced
as a sweetener in 1950, is characterized by an almost
pure sweet taste and its triumphal conquest of the sweetener
market was therefore without parallel. Its success story
came to a grinding halt when it was found to be partially
metabolized to the carcinogen cyclohexylamine[2,3I in
humans and to cause bladder cancer in ratsi41. Its use
was finally banned in the USA and many other industrial
countries in 1970. Almost simultaneously it was discovered
that saccharin can also give rise to bladder cancer[']. The
Food and Drug Administration of the USA accordingly removed saccharin from their GRAS (Generally
Recognized as Safe) list, a collection of about 1000 chemicals generally considered to have no harmful action. The
toxicity of saccharin is now being studied on a world-wide
basis and the results obtained may also lead to its being
banned.
sponding increase with rising concentration. Thus saccharin
is 500 times sweeter than a 1.2% saccharose solution
but only 100times sweeter than a 8.5 YOsaccharose solution.
Apart from toxicological considerations, the organoleptic
properties mainly decide the usefulness of a sweetener.
2. The FSI Method
2.1. Acetylenes
The above situation in the field of sweeteners was responsible for our interest when we encountered a sweet-tasting
compound on reaction of 2-butyne with fluorosulfonyl
isocyanate (FSI). The reaction"'' proceeds according to
Scheme 1.
The intensive search for new low-calorie and toxicologically safe sweeteners can be readily appreciated against
this background.
This search is still confined to the heuristic principle. There
are general theories on the correlation of structure and
sweetness16-81 but they are hardly suited as a basis for
a directed search for new sweeteners. Consequently, a
checkered mixture of compounds whose sweet taste was
discovered by accident has accumulated in recent years['].
Their suitability as sweeteners has been studied in some
cases and one of them, L-aspartyl-L-phenylalaninemethyl
ester['*], developed jointly by G. D. Searle Co. and Ajinomoto Co. Inc., has good prospects of official acceptance.
No definite regulations exist as to which stipulations of
the licensing authorities must be fulfilled by a sweetener
in order to be released onto the market. The situation
differs from that of a pharmaceutical preparation in that
a sweetener is ingested regularly for long periods and
consequently requires more rigoSous toxicological testing.
In particular, long-term feeding experiments on several
animal species and studies on possible carcinogenic, mutagenic, and teratogenic effects and on its metabolism are
necessary. Moreover, a sweetener must be water-soluble
and within certain limits stable to hydrolysis, i. r. resistant
to boiling and baking, and be devoid of any aftertaste.
The human tongue is especially sensitive to fine differences
in the sweet regime, such as the differences in taste between
the isomeric hexoses and disaccharides, and to the presence
of aftertastes. Nevertheless, it is difficult to determine how
many times sweeter a sweetener is than the reference substance saccharose. Relative sweetness is measured by establishing which of a series of sugar solutions of various
concentrations is just as sweet as a sweetener solution
of known concentration. Since differing sensations of taste
are generally being compared in such tests a certain degree
of inaccuracy cannot be avoided. Moreover, the compli~ a t e d [ ~ *dependence
.~~'
of the intensity of a given taste
upon concentration permits recognition of only relatively
large concentration differences. However, tests on a large
number of human subjects and statistical evaluation of
the results do lead to reliable data["]. The measurements
show that the relative sweetness does not display a corre870
H3C
CH3
0 8 0
CH,
HSC
2 NaOH
f--
N~-~Ao,
o p o
(4)
NH-SO,F
H
Scheme I.
2-Butyne reacts with FSI to give bis(fluorosulfony1)uracil
( 3 ) , whose structure was confirmed by X-ray analysis[' 31.
Hydrolysis of this compound leads to N-fluorosulfonyl-rmethylacetoacetamide ( 4 ) which undergoes surprisingly
smooth ring closure to give the new heterocycle 5,6dimethyl- 1,2,3-oxathiazin-4(3H)-one2,2-dioxide ( 5 ) under
the action of sodium hydroxide solution. Other alkynes
such as 1-butyne or 1-hexyne undergo analogous reactions
uia uracil derivatives to the 6-alkyl derivatives (6 J and
(7) which also have a sweet taste (Table I).
Table I. Oxathiazinone dioxides from alkynes.
R' RZ
O F ?
(5)-(7)
N-S02
H
Cpd
(5)
(6)
(7)
R'
CH3
H
H
R2
CH3
C2HS
n-C4Hq
Starting
material
Yield
M.p
w1
I: C l
2-butyne
I-butyne
I-hexyne
15
108.5
80
63
8
14
N-Fluorosulfonyl p-0x0 carboxamides, e. y. ( 4 ) , proved
to be essential intermediates for the formation of the new
oxathiazinone system. A broader-based study of the sweeteners required development of a simpler preparation for
these intermediates that would also permit variation of
the substituents.
Anyew. Chrm. inrernur. Edrt. J Vol. 12 ( 1 9 7 3 ) J No. 11
2.3. fJ-Diketones
2.2. Ketones
Reaction of a-unsubstituted ketones with FSI was
recognized as an important general method of preparing
N-fluorosulfonyl 0-0x0 carboxamides["'. Ketones of this
kind generally react with halosulfonyl isocyanates with
replacement of an a hydrogen
In some cases
the resulting sulfonyl fluorides (8) are obtained in crystalline form (Table 2)[*].
The activated methylene group of 0-diketones is attacked
particularly readily by FSI to give N-fluorosulfonyl diacylacetamides (Z0)l' 51.
R'-CC-CH, I
R2-C0
+ O=C=N-SO~F
F SI
-
Table 2. N-Fluorosulfonyl p-0x0 carboxamides fH).
R'
Cpd.
R2
CH3
(Xu)
Cff,
(ah)
-(CHJ-0-C,H,-(CH
( 8c)
2)2-
Starting
ketone
Yield
M.p
"41
[Cl
2-butanone
cyclohexanone
x-tetralone
I7
65
82
45
91
133
R2
These products are shown by their 'H-NMR spectrum
in solution to exist as the enols and to be strongly chelated
(6 = 13.5 and 16 ppm). The yields are very good, P . y. almost
quantitative for acetylacetone. The N-fluorosulfonyldiacylacetamides (10) lose an acyl group on heating with ethanol
or on stirring with 1 mol of aqueous alkali and thus furnish
N-fluorosulfonyl p-0x0 carboxamides [(11), 75 % yield]
especially smoothly :the latter then cyciize to oxathiazinone
dioxide with more alkali. There is no need to isolate the
intermediate since addition of 3 mol of alkali effects both
release of the acyl group and ring closure to give, r.y.
6-methyloxathiazinone dioxide ( 9 u ) in 80% yield.
O ~ O ( 9 )
N-SO,
H
Benzoylacetone and dibenzoylmethane react in a corresponding manner: mild deacylation readily yields the N -
N o isolation or purification of this precursor is necessary
since ring closure also occurs with the crude products
and the pronounced tendency of the oxathiazinone dioxides
( 9 ) to crystallize renders their purification simple. The
route afforded the products listed in Table 3.
R'-CH,-CO-R2
+ O=C=N-SOzF
F SI
0
8
NH-SO,F
-
R'
Table 3. Oxathiazinone dioxides ( 9 ) obtained from ketones.
cpd.
R'
Starting
ketone
Yield
w.3
M. p.
ICI
Sweetness
acetone
2-butanone
3-pentanone
2-pentanone
2-hexanone
4-methyl-2-pentanone
cyclohexanone
4-heptanone
acetophenone
5-nonanone
propiophenone
phenylacctonc
2-tetralone
2-undecdnone
6-undecanonc
13
45
60
55
50
3.5
60
43
9
49
63
61
76
50
43
123.5
108.5
94
102
965
I14
I23
86
181
47
123
I45
216
58
35
+
+
+
+
+
RZ
Homogeneous reaction products are obtained from symmetrical dialkyl ketones or from ketones bearing no a-hydrogen on one side. Ketones exhibiting sufficiently different
activation of the .*-hydrogens, r . y. methyl alkyl ketones
or methyl benzyl ketones, react regiospecifically.
Ketones offering only a methyl as point of attack by FSI,
r. y. acetone or acetophenone, react only with difficulty
and yield mainly side products. A more productive route
was therefore sought for preparing the 6-methyl derivative
(9u).
+
ClI,-co011
0
N I I-so, E'
(f O f f )
(11)
I
1
h-S,02
[*] N-Fluorosulfonyl-~,x-dimethylacetoacetamide
[151 can also readily
be obtained in crystalline form from methyl isopropyl ketone and FSI
but the absence of a proton necessary for enolizdtion prohibits its cyclization to oxathiazinone dioxide
AIIYCW.Chern. internot. E d i t .
+
/ Val. / Z ( I 9 7 3 1 / N o . / I
H
(9a)
fluorosulfonylbenzoylacetamide ( 1 2 ) whose ring closure
affords 6-phenyloxathiazinonedioxide( 9 h ) . A new variant
871
occurs if N-fluorosulfonyl-z-benzoylacetoacetamide
( 1Oh)
is cyclized directly with 3 mol ofsodium hydroxide solution.
In this case only partial removal of the acetyl group occurs
and the 5-acetyl-6-phenyl derivative ( 9 0 ) results (Table
4).
HCI,
HOOC
OY'
CH,
O F 9 (9Cl)
N- so,
H
+ CO, + H,C(CH,),
On standing at room temperature, or more rapidly on
to 40-70 C, compound ( 1 5 ) eliminates COz
and isobutene to give N-fluorosulfonylacetoacetamide
( I 1) in 85 O h yield.
Compound (16), which is accessible from N,N-diethylacetoacetamide and FSI, also undergoes preferential closure
ofthe oxathiazinone ring with alkali thus offering a preparative route to the amide ( 9 r ) in 54% yield (Table 5).
Table 4. Oxathiazinone dioxides from P-diketones
Cpd
R1
R*
Starting
material
(Yai
H
(Yh)
H
CH3
ChH5
190)
CO-CH3
C6H5
acetylacetone
benzoylacetone.
d tbenzoylmethane
benzoylacetone
M P
I CI
123.5
1x1
Table 5. Oxathiazinone dioxides from &ox0 acid derivatives.
164
Cpd.
R'
R2
Starting
material
Yield
"GI
~
2.4. p-0x0 Carboxylic Acid Derivatives
Free p-0x0 carboxylic acids such as acetoacetic acid react
with FSI with elimination of CO, to give N-fluorosulfonylamides (11). Owing to the well-known lability of p-0x0
acids this reaction has no practical importance.
The 3-substitution productsf"] of acetoacetic esters and
FSI react in various ways on treatment with alkalis. Several
parallel reactions occur and lead:
a) to malonic ester derivatives (13) by deacetylation ;
b) to amides ( 1 4 ) by elimination of the SOzF group;
c) to ring closure in the case of the tert-butyl ester.
C H,-CO-C
IT-COOR
I
C 0-N H-SO, F
+
bl
.COOR
C H,-CO-CH-COOR
I
CD-NHz
114)
rert-Butyl acetoacetate reacts with FSI to give a thermolabile x-substitution product ( 1 5 ) , m. p. 53 C, 97 O/O yield,
from which a 37% yield of the oxathiazinone ( 9 p ) can
be obtained by ring closure. Acid cleavage of the ester
group with hydrogen chloride furnishes oxodihydrooxathiazine-5-carboxylic acid dioxide (9 4 ) .
872
(Yui
H
CH,
(Ypl
COOC(CH3)n
CH,
(Yy)
lYr1
COOH
CON(C2H5)r
CH3
CH3
acetoacetic acid
~~
55
31
trrt-butyl
acetoacetate
(YP)
N,N-diethylacetoacetamide
M.p.
I Cl
123.5
66
90
104
54
162
2.5. The Benzyl Ether Method[' '1
In spite of the versatility of the synthetic routes discussed
so far, none can provide oxathiazinone dioxides having
particular combinations of substituents in positions 5 and
6. Such compounds include the benzo derivative ( 9 c ) ,
which is interesting as a homolog of saccharin, and the
unsubstituted parent compound ( 9 s ) (Table 6). The N fluorosulfonylsalicylamide ( 1 8 ) , m. p. 156.5 C, required
for synthesis of the benzoxathiazinone ( 9 c ) cannot be
obtained directly from salicylic acid and FSI since the
reactivity of the phenolic hydroxyl group proves
dominant['8][*].However, (18) i s readily prepared in 88 %
yield from 0-benzylsalicylic acid'"] by reaction with FSI
to give ( I 7), m. p. I 15 'C, and subsequent hydrogenation
in acetic acid solution to remove the benzyl group. If
hydrogenolysis is conducted in the presence of sodium
hydroxide solution then the desired benz- 1,2,3-oxathiazin4(3H)-one 2,2-dioxide ( 9 c ) is obtained (Table 6).
[*] Our own experiments with FSI led to O-(N-fluorosulfonylcarbamoyI)salicylic acid having m.p. I I I C.
A I I ~ C WChrm.
.
inrrrnar. Edit. J V d . 12 (19731 1 Nu. 11
The ease of removal of the fluoride ion is surprising in
view of the strength of the S-F bond. We assume that
ring closure proceeds cia nucleophilic attack by the ketonic
oxygen on the fluorosulfonyl group in the dianion ( 2 1 ) .
(18) 0
( 9 \*I 0
An apparently obvious step would be to carry out the
cyclization reactions with the analogous chlorosulfonyl
derivatives from which the chloride ion is much more
easily removed. Such attempts fail because the chlorosulfonyl group is rapidly hydrolyzed under the conditions
used for the fluorides.
Ifthe protective group is hydrogenolyzed off in the alkaline
medium then the amount of hydrogen taken up must
be restricted to 1 mol since hydrogenolysis of the oxathiazinone ring will occur with more hydrogen.
The derivatives of N-fluorosulfonyl-p-hydroxyacrylamide
( 2 0 ) needed for preparation of 5-alkyloxathiazinone dioxides and the unsubstituted compound are produced by
The
reaction of vinyl benzyl ethers with FSI in
reaction yields N-fluorosulfonyl-p-benzyloxyacrylamides
( 19) which suffer ring closure on catalytic hydrogenation
in the presence of sodium hydroxide solution. The uptake
of hydrogen must be limited to l m o l here too (Table
6).
(81
(21j
L
3. The Phenoxide Method['']
.ZO2lowH
r
NH-SOZF
e
(9)
;-so2
A leaving group exhibiting sufficient resistance to hydrolysis and favoring cyclization is the phenoxide group.
Ketones[ ''I, 0-diketones, and p-0x0 carboxylic esters are
attacked analogously by the aryloxysulfonyl isocyanates["] and lead to N-aryloxysulfonyl f3-0x0 carboxamides, e.g. in the case of 2-butanone to the amides (22)
and in that of rut-butyl acetoacetate to the tricarbonylmethane compound (231, m.p. 92 C (dec.), 95% yield.
Table 6. Oxathiazinone dioxides prepared by the benzyl ether method.
cpd
R'
R'
Starting material
Yield
M. p.
Sweerness
107
81
13
170
+
+
+
[*A]
(9%)
(911
H
CH.?
H
H
(YUi
(91')
<'211<
tj
-(CH=CH)>-
benzyl vinyl ether [a]
benzyl propenyl ether [b]
benzyl butcnyl ether [c]
0-benzyl salicylic acid [I91
39
22
25
85
+
[a] Prepared by pressureless vinylation of bcnzyl alcohol at 130 -150 C in the presence of potassium hydroxide.
[b] Prepared by catalytic isomerization from ally1 benzyl ether with potassium rw-butoxide in dimethyl sulfoxide
at 25- 40 C in 8 3 % yield according t o C. C. Price and W H. Sn).drr. J. Amer. Chem. SOC. 83, 1773 (1961).
[c] Obtained from crotyl benzyl ether by catalytic isomerization with pentacarbonyliron and U V irradiation
according to P. W Jollj, F . G . A Stone, and K . Mackrnzie, J. Chem Soc. 1Y6.5. 6416.
2.6. Ring Closure
Cyclization of the intermediates prepared by the above
methods is usually carried out in aqueous solution or
suspension by slow addition of the necessary amount of
caustic alkali, 2 mol being required for N-fluorosulfonyl
B-0x0 amides ( 8 ) and 3mol for the tricarbonylmethane
derivatives ( 1 0 ) accessible from 0-dicarbonyl compounds
if an acyl group has to be removed. As salts, the oxathiazinone dioxides are mostly readily soluble in water and
are isolated from their solutions by acidification and extraction with organic solvents.
Aiigew. Chum.
inrrrriar. Edit. 1 Vof. I 2 ( 1 9 7 3 ) / No. I f
On warming, (23) readily loses COz and isobutene to
give N-phenoxysulfonylacetoacetamide ( 2 4 ) , m. p. 82 C,
in 56% yield.
873
0
#
+
CH3-CO-CHz
I
F0
O-C(CH,),
-+
CH3-CO-C H-CO-NH
(CH3)SC-O
S02*-C6H5
(9a)
I
70
-
OC&5
51
( 2 7 0 ) . R = H [ 2 5 ] , m.p. 174 C, yield 10%
(24)
Removal of phenols or fluoride ions from the reaction
products is difficult and, with regard to the use of oxathiazinone dioxides as sweeteners, gives rise to toxicological
problems. It therefore appeared desirable to develop a
synthesis starting from N-chlorosulfonyl p-0x0 carboxamides. Such a route would also be attractive since all
previous methods required fluorosulfonyl isocyanate which
is difficultly accessible and exceptionally toxic.
Whereas
d o not react in just a single direction
with chlorosulfonyl isocyanate (CSI), the more active pdicarbonyl derivatives react very smoothly. For instance,
tert-butyl acetoacetate in ether at 0-20 C readily affords
tert-butyl
s(-(N-chlorosulfonylcarbamoyl)acetoacetate
( 2 5 ) , m.p. 78 'C (dec.) in 91 YOyield~'51.On melting, this
adduct liberatesCO, and isobuteneand furnishes N-chlorosulfonylacetoacetamide (26), m.p. 86 "C, in 85% yield.
=O
+
-
C H,-CO-C
(CH,),C+-C
H-CO-NH
=O
SO2Cl
I
CH3
C
I
(25)
o=c=N-SO,Cl
c SI
O
O
( 9 0 ) N-SO,
H
(C2H,),N
c-CH3-C@CH,-C0-NH-SO2C1
(26)
Unlike the fluoro- or phenoxy compound, N-chlorosulfonylacetoacetamide(26) rapidly reacts with water or alcohol at room temperature to give the sulfonic acid or its
esters. In aprotic solvents such as ethyl acetate the oxathiazinone ring is readily closed with elimination of HCl on
treatment with bases such as tertiary amines. This reaction
is fast and gives good yields at -78 to O'C, possibly
providing some indication of the intermediacy of the sulfonylamine (azasuIfene)1241.
This cyclization is also possible with other amines. However, primary amines and ammonia also lead in part to
formation of thiadiazinone dioxides (27).
874
127h), R=CH3, m.p. 162 C,yield 7 %
CH3-CO-CHz-CO-NH-S0,-OC6H5
4. The CSI Method[231
CH3-CO-CH,
h-R
N-602
H
(23)
Treatment of (22) or ( 2 4 ) with caustic alkaline solutions
removes the phenoxide ion to yield the oxathiazinone
dioxides. The reaction conditions are strongly dependent
upon the phenoxide group: whereas trichlorophenoxide
departseasily like the fluoride ion, unsubstituted phenoxide
requires considerably more stringent conditions.
(CH3),C-O-k
05
I
702
Since the oxathiazinone dioxides are formed in a basic
medium they are obtained as salts owing to the acidic
nature of the -CO-NH-S02
group. Isolation of the
acids is best performed by acidifying the aqueous salt
solutions with mineral acids and extracting the oxathiazinone with ethyl acetate.
5. Properties and Reactionsof
OxathiazinoneDioxides
The oxathiazinone dioxides accessible by one of the above
procedures are thermally and chemically stable crystalline
substances that dissolve in the common organic solvents
and, when only slightly substituted, also in water. As strong
monobasic acids they are practically completely dissociated
in water and form stable neutral salts having melting points
above 2 0 0 T with alkali metals and calcium (Table 7).
Table 7. Melting points and solubilities of some salts of 6-methyloxathiazinone dioxide ( 9 0 ) in water.
Cation
Na'
K'
Ca2+
220
250
>310
23 C 340
25
105 C 5 8 0
135
_-__
M.P. [ Cl
[(C2Hs)3NH]'
~
_________
~
Solubility
[g/IOO ml H 2 0 ]
_
_
_
68
120-130
830
180-190
~3
___
__
__
~
__
The steep temperature gradient of the solubility of the
potassium salt in water makes it particularly suitable for
purification of 6-methyloxathiazinone dioxide (9 a). 5,6Dimethyl- ( 5 ) and the two ethylmethyloxathiazinone dioxides ( 9 h ) and (9c) exhibit such a high thermal stability
that they can be distilled in a good vacuum or subjected
to gas chromatography. The intense UV absorption at
228 nm (log&;=.4.0)can be used to advantage for concentration determination.
The calcium salt of 6-methyloxathiazinone dioxide survives
eight hours' heating at 120+2 'C of a 0.2 % aqueous solution at pH 7 without measurable decomposition. The free
6-methyloxathiazinone dioxide (9a) decomposes when an
aqueous solution is boiled to give 90% acetone alongside
C 0 2 ,ammonium sulfate, and sulfuricacid. These fragments
suggest that cleavage proceeds viu acetoacetic acid.
1
1
NH4HS04
Angrx,. Chvm. internat. Edit
I
1
Vol. I2 (1973)
I No. I I
As already mentioned in Section 2.6, benzoxathiazinone
dioxide ( 9 r ) undergoes ring cleavage in alkaline media
on attack by catalytically activated (palladium) hydrogen
( 1 mol). The N-sulfonic acid can be precipitated in crystal-
line form and fragmented to benzamide and sulfuric acid
by brief boiling in acid solution.
In aqueous solution, bromine cleaves the oxathiazine ring
of the dimethyl compound (5) to form a-bromo-cr-methylacetoacetamide (33), m.p. 68"C, 53% yield. The same
compound also results on bromination of a-methylacetoacetamide.
(33)
6. Relative Sweetness and Structure
of Oxathiazinone Dioxides
5,6-Dimethyl- and 6-methyloxathiazinone dioxide undergo
a corresponding reaction with 2 mol of hydrogen. However,
the N-sulfonic acids could not be detected in these cases:
after hydrolytic release of the S 0 3 H
'H-NMR
spectra revealed mixtures of the amides with the free carboxylic acids.
The strongly acidic proton of the oxathiazinone dioxides
can be smoothly methylated by ethereal diazomethane,
the product mixture containing N-methyl compounds with
minor amounts of the 0-methyl representative, as in the
case of 5,6-dimethyloxathiazinone dioxide ( 5 ) [ ( 2 8 ) , b. p.
66 C/O.Ol torr, 6 8 % yield; (29), b.p. 110 C/O.Ol torr,
m. p. 63 C, 16 YOyield].
(5)
CHZN,
H3C
CH,
O E O
+
Unsubstituted oxathiazinone dioxide (9s) and a number
of slightly substituted derivatives exhibit varying degrees
of sweetness. Since they also have an acidity comparable
with that of mineral acids, taste comparisons are feasible
only with the neutral alkali or alkaline earth metal salts.
Table 8 lists those of the derivatives we have prepared
which have a sweet taste, together with their relative
sweetnesses. The parent compound proves to be the least
sweet, and the 5-ethyl-6-methyl derivative the most sweet.
Exchange of the two alkyl groups or shortening of the
ethyl chain lowers the sweetness to half its original value.
H3C
CH3
H 3 C - O F p
N-SOz
N-SOz
Table 8. Relative sweetness and LDso of salts of oxathiazinone dioxides.
R1
M
R2
Methylation can also be accomplished by the action of
dimethyl sulfate on the alkali metal salts of oxathiazinone
dioxide, K. y. with the 6-methyl derivative ( 9 0 ) . Reaction
furnishes (301, b.p. 85 C/I torr, m. p. 40 'C, in 40% yield.
Relative
sweetness [ d ]
I0
130
I30
130
20
130
I50
LDso
[gjkg rat]
10.4
7.4
6.5
8.7
20
130
250
30
30
CH3
ca.
A chIorine atom can be introduced at C-4 by phosphorus
pentachloride in carbon tetrachloride solution. The resulting oxathiazine dioxide (31 ), b. p. 98'C/10-3 torr, 80%
yield, is capable of further exchange reactions. For example,
aniline gives the derivative (32). m.p. 221 C, in 48%
yield.
[ a ] Relative to cane sugar
1n
9.9
50
50
70
4% aqueo~issolution
Our attention has become focused mainly on the 6-methyl
derivative (9a) whose potassium or calcium salt is about
four times sweeter than cyclamate and stands out from
the others in the purity of its sweet taste. Tests with various
preparations and juices show the taste of these salts to
fit in particularly well for use as a sweetening agent. Their
high solubility in water (see Table 7) also offers advantages
in use since most syntheticsweetenersdisplay an unsatisfactory solubility.
The salts of (90) also prove sufficiently stable to hydrolysis
for practical purposes. Even in highly acidic beverages
A n y r w Chrm. inleinut. Edit. 1 Voi. 12 ( 1 9 7 3 )
!No. I 1
875
they remain unchanged for months and no deterioration
in their purity of taste can be registered.
The acute toxicity was determined in various cases and
is likewise given in Table 8. The substances tested can
thus be regarded as practically nontoxic. Meanwhile, a
95-day feeding test on rats has been carried out with
the calcium salt of the 6-methyl compound (9a), with
up to 5 % of ( 9 a ) in the feed. N o evidence was found
that ingestion of compound ( 9 a ) had an influence on
the increase in body weight, food consumption, blood
count, serum enzyme values, urinalysis, the findings of
macroscopic post mortem examinations, and organ
weights. No deviations from control animals could be
detected during animal growth or on histological examination of their organs. As already mentioned, these animal
experiments represent only partial results and any toxicological assessment of the salts of ( 9 a ) with regard to their
suitability as sweeteners will have to await their completion.
the salts of 6-methyloxathiazinone dioxides ;they are derivatives of acetoacetic acid.
As found with other sweeteners”. ’I, any functional change
of the system leads to complete loss of the sweet taste.
Scheme 2 shows some derivatives completely devoid of
any sweet taste.
Scheme 3 shows a number of benzo heterocyclic compounds some of which are sweet while others have no
sweet taste. It accordingly still appears difficult to predict
the property of sweetness for a given compound.
Application of Hansch a n a l y ~ i s ”to~the
~ problems of sweetening action may possibly provide a further insight into
the underlying principles.
We are grateful to Dr. H . Bestian for his actire interest
and nitmerous caluahfe discussions.
Received: July 27, 1973 [A 969 IE]
German version: Angew. Chem. 85.965 ( 1973)
[ I ] For reviews, see: C . Runt;, Bull. Soc. Pharm. Bordeaux 101, 197
(1962): R. J . Wicker, Chem. Ind. (London) 1966, 1708.
[2] S. Kojima and H . Ichihagasr, Chem. Pharm. Bull. 14, 961 (1966).
[3] L. Golhury, C Pore/&, A. Patti, and K . S o i k ~Toxicol.
,
Appl. Pharmacol. 14, 654 (1969).
G. I: Bryan and E. Ertiirk, Science 167. 996 ( 1970).
G. I: Brgun. E. Erriirk, and 0 Yoshid~,Science 168, 1238 (1970).
R . S. Sha//enheryrr and I: E. Arrre, Nature 216, 4x0 (1967).
B. Untrrhalt, Deut. Apoth.-Ztg 110, 289 (1970)
L. B. Kier, J. Pharm. Sci. 61. 1394 (1972).
[9] For a survey, see A. run Eijk, Gordian 73, 44 (1973).
[lo] R. H . M a x r . J . M . Schlarrer, and A. H Goldkamp, J. Amer. Chem.
Soc. 91. 2684 (1969).
[ I I ] S. Yumug~rchr.I: Yoshikawa, S Ikedu, and I: Ninoniiya, Agr. Biol.
Chem. 34, 181, 187 (1970).
[I21 K . Clairss and H . J e n s m . Tetrahedron Lett. 1970, 119.
[I31 D. Kohdt, E. F . Paulus, and K . Clarr.sa, Tetrahedron Lett 1971,
3627.
[I41 K . Clauss and H . Jmsrn, DOS 2001 017 (1970).Farbwerke Hoechst:
Chem. Abstr. 75. 129843e (1971).
[I51 K . Clauss, H.-J. Friedrrrh, and H . Jensm, Liebigs Ann. Chem.,
in press.
[I61 K . C l a i m and H . J u n s m , German Pat. Appl. No. P 2264235.9
(1972), Farbwerke Hoechst.
[I71 K . Clauss, H . Jensen, and E. Luck, German Pat. Appl. No
P 2228423.7 (1972), Farhwerke Hoechst.
[4]
[5]
[6]
[7]
[8]
The question of their metabolism will also have to be
elucidated. If a hydrolytic route is followed, i. e. metabolism
commences with ring cleavage to give acetoacetamide-Nsulfonic acid, further degradation should yield physiological substances. This is yet another reason why we prefer
[IX] H . Vorhruygrn, Tetrahedron Lett.
196X. 1631
[I91 J . 6. CoJwii and H . W. Dudltzy. J. Chem. SOC. 97, 1745 (19LO).
sweet
+ bitter
not sweet
[‘I
sweet “1
not sweet‘22’
(I) 0
sweet
Scheme 3
876
OH
not sweet [ I ’
sweet
+ bitter“]
1201 Cf. F . Effnhuryer, Angew. Chcm. H I , 374 (1969): Angew. Chem.
internat. Edit. H , 295 11969).
[21] K . Claussand G. Lohaus. DOS 2024694 (1970), Farbwerke Hoechst:
Chcm. Abstr. 76. 72565e (1972).
[22] G. Lohuur, Chem. Ber. 105. 2791 (1972): DBP 1230017 (196%
Farbwerke Hoechst: Chem. Abstr. 68. 6 8 7 1 4 ~(1968).
[23] K. Cfauss, H . Jensen, and H. Schnabel, German Pat. Appl No.
P 2327804.8 (1973), Farbwerke Hoechst.
[24] G. M A t k i n s j r . and E. M . Buryrss. J . Amer. Chem. Soc. Y4, 6135
( I 972).
[25] R. Die et ul., J. Heterocycl. Chem. Y, 973 (1972).
1261 R. Gruf. Liebigs Ann. Chem. 661, 118 (1963).
[27] E. J. Moriconr and Y. Shbira~oM?a,J. Org. Chem. 37. 196 (1972).
[28] E . C o l ~ and
i
B. Clurhrry, J. Amer. Chem. Soc. X4. 1994 (1962).
1291 Advan. Drug Res. 6 (1971)
[30] L. M . Beidler. Advan. Chem. Ser. 56. I (1966).
[31] J Hrrrrnann, Lebensm.-lnd. 20, 13 (1973).
Angew Chum. internat. Edit. / Vol.
12 f 1973) / No. 1 1
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