N,N-dialkyl-N′-chlorosulfonyl chloroformamidines in heterocyclic synthesis. IV. 3-dialkylamino-1,1,8-trioxo-1H-1λ6-pyrano[3,4- e][1,4,3]oxathiazines

Article abstract of DOI:10.1071/CH06368

N,N-dialkyl-N?-chlorosulfonylchloroformamidines 1 reacted regioselectively with 4-hydroxy-2-pyrone derivatives 2 to give 3-dialkylamino-1,1,8-trioxo-1H-1? ⁶-pyrano[3,4-e][1,4,3]oxathiazines 3. Dichloride 1b reacted regioselectively with 1,3-dim

Full text of DOI:10.1071/CH06368

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 113–119
N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines
in Heterocyclic Synthesis. IV. 3-Dialkylamino-1,1,8-trioxo-
1H-1λ6-pyrano[3,4-e][1,4,3]oxathiazines
Teresa Cablewski,A Craig L. Francis,A,B and Andris J. LiepaA,B
ACSIRO Molecular and Health Technologies, Clayton VIC 3168, Australia.
BCorresponding authors. Email: craig.francis@csiro.au; andy.liepa@csiro.au
N,N-dialkyl-Nꢀ-chlorosulfonylchloroformamidines 1 reacted regioselectively with 4-hydroxy-2-pyrone derivatives 2
to give 3-dialkylamino-1,1,8-trioxo-1H-1λ6-pyrano[3,4-e][1,4,3]oxathiazines 3. Dichloride 1b reacted regioselectively
with 1,3-dimethylbarbituric acid 10 to give 3-diethylamino-5,7-dimethyl-1,1,6,8-tetraoxo-1H-1λ6-pyrimido[5,4-e]-
[1,4,3]oxathiazine 11. The compounds 3 and 11 are derivatives of new ring systems.
Manuscript received: 11 October 2006.
Final version: 27 November 2006.
Introduction
The reaction of dichlorides 1 with 4-hydroxy-2-pyrones 2 by
heating in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(dimethylpropylene urea, DMPU) provided 3-dialkylamino-
1,1,8-trioxo-1H-1λ6-pyrano[3,4-e][1,4,3]oxathiazines 3, a sta-
ble, hitherto unknown heterocyclic system (Scheme 2, Table 1).
The ease of work-up partly compensated for the modest
yields. Usually, the desired product was selectively precipitated
at the interface between the organic and aqueous phases after
addition of ethyl acetate and water. The mother liquor generally
consisted of a complex mixture of by-products, and in some
As part of our ongoing interest in the synthesis of
novel, low molecular weight heterocyclic compounds, we
have been exploiting the use of N,N-dialkylated Nꢀ-
chlorosulfonylchloroformamidines 1, which embody readily
available[1,2] but rarely used[3–5] 1,3-dielectrophiles. In Part I[6]
of this series we reported the regioselective reaction between 1
and either hydrazines or hydroxamic acids (1,2-dinucleophilic
species) which gave the uncommon 5-membered heterocyclic
products, [1,2,3,5]thiatriazole dioxides or [1,3,2,4]oxathiadia-
zole dioxides, respectively. In Parts II[7] and III[8] of this series,
we described reactions of dichlorides 1 with five classes of
2-amino-1-azaheterocycle (1,3-dinucleophilic species), where
these species were based on the readily available thiazole, thia-
diazole, oxadiazole, pyridine, and pyridazine systems. These
reactions provided syntheses of a variety of novel, fused
[1,2,4,6]thiatriazine dioxides.
R2
O
N
N
HO
O
R2
N
R1
S
O
DMPU
Cl
O
O
ϩ
O
R1
R3
NSO2Cl
O
1a–1d
2a–2c
We now report some results of reactions of 1 with a
1,3-dinucleophilic (:O–C–C:) system based on 4-hydroxy-2-
pyrones, as a representative class of cyclic 1,3-dicarbonyl
compounds.
R3
3a–3h
Scheme 2.
Table 1.
Results and Discussion
The dichlorides 1a–1d were readily prepared according to pro-
cedures in the literature[1,2,6] from sulfuryl chloride and the
corresponding dialkyl cyanamide (Scheme 1).
R1R2N
R3
Product
Yield [%]
Me2N (1a)
Et2N (1b)
Me (2a)
Me (2a)
Me (2a)
3a
3b
3c
20
10
8
(1c)
R1R2N
N
R1R2N
Cl
SO2Cl2
BnNMe (1d)
Me2N (1a)
Et2N (1b)
Me (2a)
3d
3e
3f
30
8
15
10
Me2N (1a)
R1R2N
N
PhCH2CH2 (2b)
PhCH2CH2 (2b)
PhCH2CH2 (2b)
Et2N
(1b)
NSO2Cl
(1c)
N
3g
1
(1c)
BnMeN (1d)
N
Et2N (1b)
Ph (2c)
3h
9
Scheme 1.
© CSIRO 2007
10.1071/CH06368
0004-9425/07/020113

114
T. Cablewski, C. L. Francis, and A. J. Liepa
cases more desired product could be obtained by chromato-
graphy. However, this was not normally undertaken since the
principal focus of the investigation was upon the discovery and
rapid acquisition of novel compounds for biological screening.
The reaction was successfully carried out in cases where
a second, carbocyclic ring was fused to the pyrone moiety.
4-Hydroxycoumarin 2d and 4-hydroxy-5,6,7,8-tetrahydro-
coumarin 2e[9] reacted with dichlorides 1a–1d in DMPU
to afford coumarino[3,4-e][1,4,3]oxathiazine dioxides 3i–3m
(Schemes 3 and 4).
To confirm that the structure of the products was 3, rather than
the possible isomeric structure 4 (Fig. 1), X-ray crystallographic
studies were carried out on 3j and 3l (Fig. 2, Table 2).
The examples of the new heterocyclic system 3 described
above were all stable, colourless, crystalline solids which showed
no significant signs of decomposition after being stored for many
months at room temperature and they were unaffected by recrys-
tallization from methanol. The solubility of the compounds 3 in
chloroform ranged from poor to moderate, but solubility in either
diethyl ether or ethyl acetate was generally poor.
In the course of establishing preferred reaction conditions for
preparing the pyrano- and coumarino[3,4-e][1,4,3]oxathiazine
dioxides 3, we initially evaluated more conventional solvents
and bases. However, in no case were the conditions as effective
as when DMPU was used as the solvent. Attempted preparation
of the coumarino adduct 3i in refluxing acetonitrile gave the
desired product, but in lower yield and purity. Another attempt
at this reaction using potassium carbonate in acetonitrile at
room temperature afforded only the open-chain chloro com-
pound 5 (Scheme 5) which is unable to undergo ring closure
to oxathiazine 3i.
We confirmed the structure of 5 by X-ray crystallography of
the corresponding methyl ester 6a (Fig. 3, Table 3), prepared
by simply heating the chloride 5 in methanol and allowing the
solution to cool.
Due to the simplicity of the esterification process and unex-
pected stability of the product, we also prepared the ethyl and
isopropyl esters 6b and 6c (Scheme 5).
The possible isomeric product 7 (Fig. 4) was not isolated from
the original reaction mixture (which gave 5) under our workup
conditions.
Another attempted preparation of 3i was carried out using
Hünig’s base and dichloromethane as solvent and in this case a
very low yield of the chloride 5 was directly precipitated from
the reaction mixture. Chromatography of the residue from evap-
oration of the mother liquor provided a mixture of chloride 5 and
methyl ester 6a (methanol was a minor component of the mobile
phase). Further elution afforded a solid, whose spectroscopic
R2
O
N
N
R1
S
HO
O
O
DMPU
O
O
O
1a–1c
ϩ
O
2d
3i R1ϭR2ϭMe (24%)
3j R1ϭR2ϭEt (28%)
3k R1R2Nϭ
(11%)
N
Scheme 3.
R2
O
N
N
R1
S
HO
O
O
DMPU
O
O
O
1a, 1d
ϩ
O
2e
3l R1ϭR2ϭMe (11%)
3m R1ϭBn, R2ϭMe (26%)
Scheme 4.
R2
O
N
N
R1
O
S
O
O
O
R4
R3
4
Fig. 1.
C14
C13
O51
O41
O5
S1
C2
N11
C121
N1
O4
S11
C11
N21
C1
N2
C11
O31
C21
C31
O21
O3
O11
C12
O1
C111
C61
C51
C3
O2
C6
C5
C41
C71
C4
C7
C101
C91
C10
C9
C81
C8
3l
3j
Fig. 2. ORTEP diagrams of 3j and 3l.

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis
115
data, in particular the presence of two olefinic resonances and
signals corresponding to eight aromatic hydrogens in the 1H
NMR spectrum, were consistent with the dicoumarino structure
8 (Fig. 5). None of the desired product 3i was observed.
An attempted preparation of 3f was also carried out using
Hünig’s base and dichloromethane as solvent and a very low
yield of the desired product 3f was obtained after chromatogra-
phy. Further elution provided a solid, whose spectroscopic data,
in particular the presence of four olefinic resonances and sig-
nals corresponding to two phenethyl groups in the 1H NMR
spectrum, indicated the dipyrono structure 9 (Fig. 5).
the oxathiazine ring was observed. These effects may be a con-
sequence of relatively slow (on the NMR time scale) rotation of
this substituent and have been noted previously.[6] Variable tem-
perature 1H NMR studies on 6a supported this conclusion. The
1H NMR spectrum of 6a showed sharpening of the initially two
broad (CH3)2N signals (at 20◦C) to a single resonance at higher
temperatures (>45◦C) and resolution into two distinct and sharp
1
singlets upon cooling to 5◦C. In the H and 13C NMR spectra
of 3d, there were two separate resonances (of approximately
equal integration) attributable to each of the vinylic, benzylic,
pyrone-methyl, and N-methyl moieties. When the spectra were
recorded at 140◦C, all of these resonances coalesced to single
signals. Upon cooling to 20◦C, the resonances reverted to twin
signals(alongwithadditional, minorresonancesindicatingsome
thermal decomposition). Similar behaviour was observed in the
NMR spectra of 3m, which also possesses an N-methyl benzy-
lamino moiety. These observations indicate that the N-methyl
benzylamino compounds may exist as two conformers which
interconvert slowly (on the NMR timescale).
With a successful preparation of the pyrano[3,4-e][1,4,3]-
oxathiazine ring system 3 in hand, it became apparent that
this methodology might be extended to include reactions
with other 1,3-dicarbonyl systems. We briefly investigated one
other example of this type of synthon. Treatment of 1,3-
dimethylbarbituric acid 10 with the dichloro compound 1b
in DMPU provided a cyclic product, which by analogy with
compounds 3, was assigned the structure tetraoxopyrimido
[5,4-e][1,4,3]oxathiazine 11 (Scheme 6), thus affording another
new ring system.
The above results suggest that the presence of added base
promotes reaction of the hydroxyl group of 2 with one or both
of the electrophilic sites of dichlorides 1 to produce compounds
such as sulfamoyl chloride 5 (which is unable to undergo ring
closure to 3) or dipyrono derivatives such as 8 or 9. Formation of
the desired oxathiazine dioxides 3 requires initial reaction of the
carbon α to the carbonyl group of 2 with the sulfonyl chloride
moiety of 1 followed by reaction of the hydroxyl group with
the amidinyl chloride centre. This latter pathway appears to be
favoured in the absence of added base.
1
In H NMR spectra of many of the compounds described
above, a differentiation between, or significant broadening of,
the resonances attributable to the methyl or methylene groups
flanking the nitrogen atom of the dialkylamino substituent on
O
O
O
O
N
N
S
N
N
S
Cl
OR
K2CO3
ROH
O
O
O
O
1a ϩ 2d
CH3CN
O
O
O
O
N
N
S
O
O
Cl
O
6a RϭMe (72%)
6b RϭEt (70%)
6c RϭPri (28%)
5
7
Scheme 5.
Fig. 4.
C12
O
O
N
N
N
N
S
S
O
O
O6
N1
O
O
O
O
O
O
O
O
N2
C11
O
O
O
O
C10
S1
C13
8
9
O5
O3
O4
C2
C3
C1
Fig. 5.
O2
C4
C5
O
N
N
N
O1
O
O
S
O
C9
DMPU
C6
1b
ϩ
O
O
N
N
N
C8
O
10
C7
O
11
Fig. 3. ORTEP diagram of 6a.
Scheme 6.

116
T. Cablewski, C. L. Francis, and A. J. Liepa
Conclusions
154.9, 147.3, •103.5, 97.0, 43.5, 42.2, 20.2, 13.4, 11.7. m/z (EI+)
286 (2%, M+ ), 254 (8), 245 (31), 217 (100).
The dichloro compounds 1a–1d have been shown to react
regioselectively with some 4-hydroxy-2-pyrone derivatives 2
to form the novel pyrano[3,4-e][1,4,3]oxathiazine ring system
3. It should be possible to extend this methodology to not
only include reaction with 2-unsubstituted barbituric acids to
afford tetraoxopyrimido[5,4-e][1,4,3]oxathiazines, but to also
traverse other 1,3-dicarbonyl domains to produce related [1,4,3]
oxathiazines.
6-Methyl-3-piperidin-1-yl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3c
Recrystallized from methanol, 8% yield, mp 264–266◦C
(dec.) (Found: C 48.1, H 4.8, N 9.4. C12H14N2O5S requires
C 48.3, H 4.7, N 9.4%). δH ([D6]DMSO) 6.51 (1H, s, C=CH),
3.5–3.7 (4H, m, CH2NCH2), 2.30 (3H, s, CH3), 1.62 (6H, br
s, CH2CH2CH2). δC ([D6]DMSO) 167.1, 162.1, 155.4, 147.1,
102.9, 98.1, 45.5, 45.0, 25.0, 24.5, 23.2, 20.0. m/z (EI+) 298
Experimental
•
(57%, M+ ), 245 (33), 234 (35), 217 (100).
Materials
General experimental conditions have been described
previously.[7] Atmospheric pressure chemical ionization (APCI)
or electrospray ionization (ESI) mass spectra were recorded on
a Fisons InstrumentsVG Platform quadrupole using the positive
ion mode with cone voltage 30 eV for both APCI and ESI, using
either 1:1 acetonitrile/water or methanol as solvent. Samples
wereusuallyintroduceddissolvedinmethanol/dichloromethane.
Only the major fragments are given with their relative abun-
dances shown in parentheses.
3-(N-Benzyl)methylamino-6-methyl-1,1,8-trioxo-1H-
1λ6-pyrano[3,4-e][1,4,3]oxathiazine 3d
Precipitated in 30% yield. An analytical sample was recrys-
tallized from methanol, mp 245–246◦C (Found: C 53.7, H
4.1, N 8.4. C15H14N2O5S requires C 53.9, H 4.2, N 8.4%).
δH (200 MHz, CDCl3 + ∼10% [D6]DMSO) 7.16–6.98 (4H, m,
ArH), 6.98–6.88 (1H, m, ArH), 5.91 (1H, s, C=CH), 4.39 (2H,
s, CH2N), 2.81 and 2.78 (2 singlets) (3H, NCH3), 2.05 (3H,
s, CH3). When the spectrum was recorded at 200 MHz using
100% CDCl3, the singlets at δ 5.91, 4.39, and 2.05 each split
into two singlets (integrating approximately equally) at slightly
higherchemicalshiftsthantheabove. δH (500 MHz, [D6]DMSO,
20◦C) 7.41–7.29 (5H, m, ArH), 6.65 and 6.61 (1H, 2 singlets,
C=CH), 4.71 and 4.65 (2H, 2 singlets, CH2N), 3.07 and 3.00
(3H, 2 singlets, NCH3), 2.32 and 2.30 (3H, 2 singlets, CH3). δH
(500 MHz, [D6]DMSO, 140◦C) 7.41–7.31 (5H, m, ArH), 6.46
(1H, s, C=CH), 4.71 (2H, s, CH2N), 3.08 (3H, s, NCH3), 2.32
(3H, s, CH3). δC (125.75 MHz, [D6]DMSO, 20◦C) 168.4, 168.3,
162.2, 162.1, 155.42, 155.41, 149.0, 148.3, 135.6, 135.1, 128.8,
128.7, 128.0, 127.9, 127.8, 127.7, 102.9, 102.8, 98.1, 98.0, 52.5,
52.1, 35.8, 34.3, 20.01, 19.97. δC (125.75 MHz, [D6]DMSO,
140◦C) 167.5, 161.2, 154.2, 148.4, 134.6, 127.9, 127.1, 127.0,
4-Hydroxy-6-phenethyl-2-pyrone 2b,[10] 4-hydroxy-6-
phenyl-2-pyrone 2c,[11] 4-hydroxy-5,6,7,8-tetrahydrocoumarin
2e,[9] and benzylmethylcyanamide[12] were prepared according
to literature procedures. Other materials were obtained from
commercial sources.
Synthesis Method
A stirred mixture of the 4-hydroxy-2-pyrone (or coumarin) 2
(4.8 mmol) and the dichloro compound 1 (7.2 mmol) in DMPU
(3 mL) was heated at 80◦C for 40 h. The mixture was cooled and
ethyl acetate (10 mL) was stirred in, followed by water (20 mL).
The resulting mixture was stirred vigorously for 1 h.The aqueous
layer was carefully removed (without removing any precipitate)
and more water (10 mL) was added. The mixture was stirred
vigorously for a further 1 h and filtered. The solid was washed
with ethyl acetate and purified by radial chromatography and/or
recrystallization to afford the title compounds.
•
103.2, 97.0, 52.1, 34.4, 19.1. m/z (EI+) 334 (2%, M+ ), 245 (30),
217 (100).
3-Dimethylamino-6-phenethyl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3e
The following compounds were prepared by the above
procedure.
Purified by radial chromatography, eluting with 0–2%
methanol in dichloromethane, followed by recrystallization from
methanol, 8% yield, mp 229–230◦C (dec.) (Found: C 55.2, H 4.5,
3-Dimethylamino-6-methyl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3a
•
N 8.0; M+ 348.0771. C16H16N2O5S requires C 55.2, H 4.6, N
•
Precipitated in 20% yield. An analytical sample was puri-
fied by radial chromatography, eluting with 3% methanol in
dichloromethane, mp 278–279◦C (Found: C 41.6, H 3.8, N 10.7.
C9H10N2O5S requires C 41.9, H 3.9, N 10.9%). δH ([D6]DMSO)
6.57 (1H, s, C=CH), 3.10 (3H, s, NCH3), 3.01 (3H, s, NCH3),
2.30 (3H, s, CH3). δC ([D6]DMSO) 168.7, 162.5, 155.9,•149.0,
103.2, 98.4, 37.8, 36.6, 20.4. m/z (EI+) 258 (80%, M+ ), 194
(25), 70 (100).
8.0%; M+ 348.0774). δH 7.37–7.12 (5H, m, Ph), 5.91 (1H, s,
C=CH), 3.13 (6H, s, NMe2), 3.08–2.96 (2H, m, CH2), 2.92–
2.80 (2H, m, CH2). δC 170.3, 161.2, 155.3, 148.5, 138.9, 128.8,
128.3, 126.8, 104.2, 97.3, 38.1, 36.6, 36.2, 32.5. m/z (EI+) 348
•
(22%, M+ ), 214 (6), 91 (100).
3-Diethylamino-6-phenethyl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3f
Purified by radial chromatography, eluting with dichloro-
methane, followed by recrystallization from methanol, 15%
yield, mp 204–205◦C (Found: C 57.4, H 5.3, N 7.5.
C18H20N2O5S requires C 57.4, H 5.4, N 7.4%). δH 7.37–7.12
(5H, m, Ph), 5.90 (1H, s, C=CH), 3.50 (2H, q, J 7, NCH2),
3.44 (2H, q, J 7, NCH2), 3.08–2.96 (2H, m, CH2), 2.92–2.80
(2H, m, CH2), 1.25 (3H, t, J 7, CH3), 1.23 (3H, t, J 7, CH3).
δC 170.2, 161.4, 155.4, 147.7, 138.9, 128.7, 128.2, 126.7, 104.2,
97.4, 43.9, 42.6, 36.1, 32.4, 13.8, 12.1. m/z (EI+) 376 (73%,
3-Diethylamino-6-methyl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3b
Purified by radial chromatography, eluting with 5–10% ethyl
acetate in dichloromethane, followed by recrystallization from
ethyl acetate, 10% yield, mp 276–277◦C (dec.) (Found: C 46.2,
H 4.9, N 9.8. C11H14N2O5S requires C 46.2, H 4.9, N 9.8%). δH
(CDCl3 + [D6]DMSO) 5.96 (1H, s, C=CH), 3.31 (2H, q, J 7,
CH2N), 3.30 (2H, q, J 7, CH2N), 2.16 (3H, s, CH3), 1.06 (6H, t,
J 7, 2 × CH3N). δC (CDCl3 + ∼10% [D6]DMSO) 167.8, 161.1,
•
M+ ), 297 (12), 214 (17), 99 (68), 91 (100).

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis
117
6-Phenethyl-3-piperidin-1-yl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3g
2-Dimethylamino-4,4-dioxo-4H-4λ6-5,6,7,8-
tetrahydrocoumarino[3,4-e][1,4,3]oxathiazine 3l
Purified by radial chromatography, eluting with dichloro-
Purified by radial chromatography, eluting with 1%
methane, followed by recrystallization from methanol, 10%
yield, mp 239–240◦C (Found: C 58.5, H 5.1, N 7.2.
C19H20N2O5S requires C 58.8, H 5.2, N 7.2%). δH 7.34–7.14
(5H, m, Ph), 5.91(1H, s, C=CH), 3.68–3.54(4H, m, CH2NCH2),
3.01 (2H, t, J 7.5, CH2), 2.85 (2H, t, J 7.5, CH2), 1.67 (6H, br
s, CH2CH2CH2). δC 170.2, 161.4, 155.3, 147.0, 138.9, 128.7,
128.2, 126.7, 104.1, 97.4,•46.4, 45.5, 36.1, 32.4, 25.5, 24.8, 23.6.
m/z (EI+) 388 (56%, M+ ), 91 (100).
methanol in dichloromethane, followed by recrystallization from
methanol, 11% yield, mp 285–286◦C (dec.) (Found: C 48.3, H
4.6, N 9.4. C12H14N2O5S requires C 48.3, H 4.7, N 9.4%).
δH 3.17 (3H, s, NCH3), 3.13 (3H, s, NCH3), 2.58 (2H, t, J
5.5, C=CCH2), 2.46 (2H, t, J 5.5, C=CCH2), 1.83 (4H, m,
CH2CH2). δC 165.7, 160.9, 155.2, 148.9, 106.7, 103.6, 37.9,
•
36.6, 27.9, 20.9, 20.7, 20.2. m/z (EI+) 298 (87%, M+ ), 234
(12), 164 (25), 136 (60), 71 (100).
3-Diethylamino-6-phenyl-1,1,8-trioxo-1H-1λ6-
pyrano[3,4-e][1,4,3]oxathiazine 3h
2-(N-Benzyl)methylamino-4,4-dioxo-4H-4λ6-5,6,7,8-
tetrahydrocoumarino[3,4-e][1,4,3]oxathiazine 3m
Purified by radial chromatography, eluting with 1%
methanol in dichloromethane, followed by recrystallization from
methanol, 9% yield, mp 240–242◦C (dec.) (Found: C 55.0, H
4.5, N 8.1. C16H16N2O5S requires C 55.2, H 4.6, N 8.0%). δH
7.89–7.82 (2H, m, ArH), 7.62–7.45 (3H, m, ArH), 6.61 (1H, s,
C=CH), 3.53 (4H, q, J 7, NCH2), 1.30 (3H, t, J 7, CH3), 1.27
(3H, t, J 7, CH3). δC 165.0, 161.6, 154.7, 147.8, 133.0, 129.6,
129.4, 126.5, 104.7, 93.9, 44.1, 42.6, 14.0, 12.3. m/z (EI+) 348
Precipitated in 26% yield. An analytical sample was puri-
fied by radial chromatography, eluting with 0–3% methanol in
dichloromethane, followed by recrystallization from methanol,
mp 245–246◦C (Found: C 57.5, H 4.8, N 7.6. C18H18N2O5S
requires C 57.7, H 4.9, N 7.5%). δH 7.43–7.31 (4H, m, ArH),
7.20 (1H, d, J 6.5, ArH), 4.68 (2H, s, NCH2Ph), 3.10 and
3.05 (3H, 2 singlets, NCH3), 2.63–2.52 (2H, m, C=CCH), 2.45
(1H, m, C=CCH), 2.27 (1H, m, C=CCH), 1.91−1.68 (4H, m,
CH2CH2). δC (125.75 MHz, [D6]DMSO) 166.0, 165.8, 161.6,
161.5, 155.4, 149.6, 148.8, 136.0, 135.6, 129.3, 129.1, 128.34,
128.25, 128.1, 127.8, 107.1, 106.8, 103.6, 103.5, 53.0, 52.6, 36.4,
34.9, 27.7, 21.1, 21.0, 20.82, 20.75, 20.13, 20.10. m/z (EI+) 374
•
(4%, M+ ), 320 (7), 307 (16), 279 (15), 265 (13), 250 (15), 202
(51), 174 (61), 142 (58), 133 (50), 105 (100).
2-Dimethylamino-4,4-dioxo-4H-4λ6-coumarino-
[3,4-e][1,4,3]oxathiazine 3i
•
(4%, M+ ), 279 (5), 149 (46), 120 (30), 91 (100).
Recrystallized twice from DMF/methanol (5:2) and washed
with diethyl ether, 24% yield, mp 260–261◦C (dec.) (Found:
[Dimethylamino-(2-oxo-2H-chromen-4-yloxy)-
methylene]sulfamoyl Chloride 5
•
C 48.6, H 3.4, N 9.5; M+ 294.0308. C12H10N2O5S requires C
49.0, H 3.4, N 9.5%; M+• 294.0305). δH ([D6]DMSO) 8.00 (1H,
dd, J 8,1.5, ArH), 7.92–7.82 (1H, m, ArH), 7.60–7.48 (2H, m,
ArH), 3.30 (3H, s, NCH3), 3.10 (3H, s, NCH3). δC ([D6]DMSO)
157.7, 154.0, 153.0, 148.4, 135.6, 125.5, 124.5, 117.1, 111.6,
A mixture of 4-hydroxycoumarin (0.98 g, 6 mmol), dichloro
compound 1a (1.85 g, 9 mmol), andpotassiumcarbonate(2.48 g,
18 mmol) in dry acetonitrile (15 mL) was stirred at room tem-
perature for 44 h. Ethyl acetate (40 mL) was stirred in, followed
by water (80 mL). The resulting mixture was stirred vigor-
ously for 20 min and the resultant precipitate was collected by
suction filtration and air-dried to provide the title compound
5 (0.62 g, 31%) as an off-white solid. δH 7.93–7.90 (1H, m,
ArH), 7.73–7.63 (1H, m, ArH), 7.45–7.35 (2H, m, ArH), 5.78
(1H, s, C=CH), 3.38 (3H, s, NCH3), 3.18 (3H, s, NCH3).
•
105.9, 37.6, 36.6. m/z (EI+) 294 (30%, M+ ), 230 (35), 224
(30), 120 (100).
2-Diethylamino-4,4-dioxo-4H-4λ6-coumarino-
[3,4-e][1,4,3]oxathiazine 3j
Precipitated in 28% yield. An analytical sample was puri-
fied by radial chromatography, eluting with 1% methanol in
dichloromethane, followed by recrystallization from methanol,
•
m/z (EI+) 330 (1%, M+ ), 305 (1), 295 (9), 231 (52), 171
1
•
mp 240–241◦C (Found: C 52.1, H 4.2, N 8.8; M+ 322.0633.
(35), 169 (100). Attempts to record the H NMR spectrum in
C14H14N2O5S requires C 52.2, H 4.4, N 8.7%; M+• 322.0618).
δH 7.82–7.69 (2H, m, ArH), 7.50–7.39 (2H, m, ArH), 3.67 (2H,
q, J 7, NCH2), 3.59 (2H, q, J 7, NCH2), 1.41 (3H, t, J 7, CH3),
1.31 (3H, t, J 7, CH3). δC 157.2, 153.9, 153.4, 147.6, 135.5,
125.6, 123.3, 117.7, 111.4, 106.9, 44.3, 43.1, 13.8, 12.2. m/z
[D6]DMSO resulted in significant decomposition of the sam-
ple. The compound was fully characterized as its methyl ester,
using the following method.The chloride 5 (100 mg, 0.30 mmol)
was dissolved in methanol (8 mL) with heating. The resultant
solution was allowed to cool and stand at room temperature
overnight. Filtration of the mixture afforded [dimethylamino-(2-
oxo-2H-chromen-4-yloxy)-methylene]sulfamic acid methyl ester
6a (70 mg, 72%) as colourless crystals, mp 167–168◦C (Found:
C 48.0, H 4.3, N 8.5. C13H14N2O6S requires C 47.9, H 4.3, N
8.6%). δH 7.92–7.85 (1H, m, ArH), 7.70–7.60 (1H, m, ArH),
7.42–7.32 (2H, m, ArH), 5.77 (1H, s, C=CH), 3.87 (3H, s,
OCH3), 3.25 (3H, br s, NCH3), 3.09 (3H, br s, NCH3). δC 161.2,
161.0, 153.6, 152.5, 133.5, 124.7, 123.1, 117.0, 113.5, 95.0,
•
(EI+) 322 (6%, M+ ), 224 (17), 162 (34), 120 (100).
4,4-Dioxo-2-piperidin-1-yl-4H-4λ6-coumarino-
[3,4-e][1,4,3]oxathiazine 3k
Purified by radial chromatography, eluting with 0.5%
methanol in dichloromethane, followed by recrystallization from
methanol, 11% yield, mp 255–256◦C (Found: C 53.4, H 4.1,
•
N 8.3; M+ 334.0617. C15H14N2O5S requires C 53.9, H 4.2,
•
•
N 8.4%; M+ 334.0618). δH ([D6]DMSO) 8.03 (1H, dd, J
57.1, 39.2, 37.4. m/z (ESI+) 349 (14%, [M + Na]+ ), 344 (10,
•
•
8,1.5, ArH), 7.92–7.82 (1H, m, ArH), 7.59–7.47 (2H, m, ArH),
3.82 (2H, br s, NCH2), 3.61 (2H, br s, NCH2), 1.66 (6H, br
s, CH2CH2CH2). δC ([D6]DMSO) 157.8, 153.9, 152.9, 147.0,
135.5, 125.4, 124.6, 117.1, 111•.6, 106.0, 45.8, 45.4, 25.1, 24.5,
23.1. m/z (EI+) 334 (14%, M+ ), 270 (12), 242 (22), 120 (36),
110 (100).
[M + NH4]+ ), 327 (47, [M + H]+ ), 165 (100).
The following compounds were prepared by the above
procedure.
[Dimethylamino-(2-oxo-2H-chromen-4-yloxy)-methylene]
sulfamic acid ethyl ester 6b (70%) as colourless crystals, mp
149.5–150◦C (Found: C 49.5, H 4.7, N 8.2. C14H16N2O6S

118
T. Cablewski, C. L. Francis, and A. J. Liepa
Table 2. Crystal data and structure refinement for 3j and 3l
Table 3. Crystal data and structure refinement for 6a
Parameter
3j
3l
Parameter
6a
CCDC deposition number
Empirical formula
Formula weight
Temperature [K]
Wavelength [Å]
Crystal system
Space group
Unit cell dimensions
a [Å]
b [Å]
c [Å]
β [◦]
Volume [Å3]
Z
622913
C14H14N2O5S
322.33
622912
C12H14N2O5S
298.31
CCDC deposition number
Empirical formula
Formula weight
Temperature [K]
Wavelength [Å]
Crystal system
Space group
Unit cell dimensions
a [Å]
b [Å]
622911
C13H14N2O6S
326.32
123(2)
123(2)
123(2)
0.71073
Monoclinic
P21/c
0.71073
Monoclinic
P2/c
0.71073
Monoclinic
P21/c
10.0656(2)
10.4563(2)
13.8854(3)
98.1809(9)
1446.55(5)
4
1.480
0.250
0.25 × 0.14 × 0.10
3.83 to 28.22
22711
15.3371(2)
8.7463(1)
19.2704(3)
99.2470(4)
2551.39(6)
8
1.553
0.276
0.25 × 0.25 × 0.19
3.56 to 28.19
35252
10.9073(2)
15.2525(2)
8.7159(1)
105.0416(6)
1400.33(4)
4
1.548
0.264
0.38 × 0.23 × 0.13
3.78 to 27.87
19815
c [Å]
β [◦]
Volume [Å3]
Z
Density (calc.) [Mg m−3
]
]
Density (calculated) [Mg m−3
Absorption coefficient [mm−1
Crystal size [mm3]
Theta range [◦]
Reflections collected
Independent reflections
R(int)
]
]
Absorption coeff. [mm−1
Crystal size [mm3]
Theta range [◦]
Reflections collected
Independent reflections
R(int)
3514
0.0827
6197
0.0359
3320
0.0491
No. reflections included in
refinement
Final R indices [I > 2σ(I)]
R1
3514
6197
No. reflections included
in refinement
Final R indices [I > 2σ(I)]
R1
3320
0.0561
0.1360
0.0374
0.0926
0.0404
0.0898
wR2
wR2
R indices (all data)
R1
R indices (all data)
R1
0.0987
0.1574
1.009
0.0498
0.0987
1.027
0.0625
0.0993
1.029
wR2
wR2
Goodness-of-fit on F2
Goodness-of-fit on F2
requires C 49.4, H 4.7, N 8.2%). δH 7.92–7.85 (1H, m, ArH),
7.69–7.59 (1H, m, ArH), 7.42–7.32 (2H, m, ArH), 5.76 (1H, s,
C=CH), 4.25 (2H, q, J 7, OCH2), 3.24 (3H, br s, NCH3), 3.08
(3H, br s, NCH3), 1.33 (3H, t, J 7, CH3). δC 161.2, 161.0, 153.6,
152.3, 133.5, 124.7, 123.1, 116.9, 113.5, 95.0, 67.4, 39.2, 37.3,
solution of the dichloro compound 1a (3.02 g, 14.7 mmol) in
dichloromethane (8 mL) was added dropwise via syringe. The
resultant mixture was allowed to warm to room temperature
and was then stirred at that temperature for 24 h. Ethyl acetate
(50 mL) was stirred in, followed by water (75 mL). The resulting
mixture was stirred vigorously for 1 h and the resultant precip-
itate was collected by suction filtration and air-dried to provide
the title compound 5 (0.27 g, 8%) as an off-white solid. The
organic phase of the mother liquor was dried and evaporated.
The residue was purified by radial chromatography. Elution with
0–1% methanol in dichloromethane gave a mixture of chloride 5
and corresponding methyl ester 6a (0.15 g). Further elution gave
a beige solid (0.18 g) which was tentatively identified as the title
compound 8. δH 7.88–7.80 (1H, m, ArH), 7.72–7.54 (3H, m,
ArH), 7.46–7.18 (4H, m, ArH), 6.58 (1H, s, C=CH), 5.80 (1H,
s, C=CH), 3.32 (3H, s, NCH3), 3.16 (3H, s, NCH3). m/z (ESI+)
•
•
14.6. m/z (ESI+) 363 (20%, [M + Na]+ ), 341 (82, [M + H]+ ),
163 (100).
[Dimethylamino-(2-oxo-2H-chromen-4-yloxy)-methylene]
sulfamic acid isopropyl ester 6c (28%) as colourless crystals,
mp 130–131◦C. (Found: C 50.9, H 5.1, N 7.9. C15H18N2O6S
requires C 50.8, H 5.1, N 7.9%). δH 7.92–7.86 (1H, m, ArH),
7.69–7.59 (1H, m, ArH), 7.42–7.32 (2H, m, ArH), 5.77 (1H,
s, C=CH), 4.84 (1H, septet, J 6, Me2CHO), 3.21 (3H, br s,
NCH3), 3.09 (3H, br s, NCH3), 1.35 (6H, d, J 6, Me2CH). δC
161.3, 161.1, 153.7, 152.2, 133.5, 124.7, 123.2, 117.0, 113.6,
•
95.1, 77.6, 38.8, 37.4, 22.7. m/z (ESI+) 377 (10%, [M + Na]+ ),
•
•
372 (22, [M + NH4]+ ), 355 (15, [M + H]+ ), 233 (100).
•
•
479 (100%, [M + Na]+ ), 457 (20, [M + H]+ ).
Attempted Preparation of 3i using Hünig’s Base/
Dichloromethane
Preparation of 3-Diethylamino-6-phenethyl-1,1,8-trioxo-
1H-1λ6-pyrano[3,4-e][1,4,3]oxathiazine 3f and
(Z)-2-oxo-6-phenethyl-2H-pyran-4-yl(diethylamino)(2-
oxo-6-phenethyl-2H-pyran-4-yloxy)methylenesulfamate
9 using Hünig’s Base/Dichloromethane
[Dimethylamino-(2-oxo-2H-chromen-4-
yloxy)methylene]sulfamoyl Chloride 5,
[Dimethylamino-(2-oxo-2H-chromen-4-
A mixture of 4-hydroxy-6-phenethyl-2-pyrone 2b[10] (0.65 g,
3 mmol), dichloro compound 1b (1.05 g, 4.5 mmol), and
N,N-diisopropylethylamine (1.16 g, 1.57 mL, 9 mmol) in dry
dichloromethane (15 mL) was stirred at room temperature for
2.5 h. The mixture was diluted with more dichloromethane and
washed with aqueous sodium carbonate solution. The aqueous
layer was extracted with dichloromethane and the organic phases
yloxy)methylene]sulfamic Acid Methyl Ester 6a, and
(Z)-2-oxo-2H-chromen-4-yl(dimethylamino)(2-oxo-2H-
chromen-4-yloxy)methylenesulfamate 8
N,N-Diisopropylethylamine (3.88 g, 5.23 mL, 30 mmol) was
added to a stirred suspension of 4-hydroxycoumarin 2d (1.59 g,
9.8 mmol) in dry dichloromethane (10 mL) under a nitrogen
atmosphere. The resultant solution was cooled in ice and a

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis
119
•
were combined, washed with brine, dried, and evaporated. The
residue was purified by radial chromatography. Elution with
0–1% methanol in dichloromethane gave a fraction (0.26 g)
containing compound 3f and another component. Trituration
of this pale yellow solid with ethyl acetate and then decanting
the supernatant afforded 3f (72 mg, 6%) as a white solid. The
supernatant was evaporated and the residue was further purified
by radial chromatography. Elution with 40–50% ethyl acetate in
dichloromethane gave a pale yellow, viscous gum (0.12 g) which
was tentatively identified as the title compound 9. δH 7.35–7.13
(10H, m, ArH), 6.11 (1H, d, J 2, C=CH), 5.97 (1H, d, J 2,
C=CH), 5.86 (1H, d, J 2, C=CH), 5.49 (1H, d, J 2, C=CH),
3.51 (2H, q, J 7, CH2N), 3.26 (2H, q, J 7, CH2N), 3.06–2.91
(4H, m, 2 × CH2), 2.88–2.74 (4H, m, 2 × CH2), 1.26 (6H, t, J
27.8, 13.2, 11.6. m/z (EI+) 316 (7%, M+ ), 98 (64), 83 (57),
55 (100).
Acknowledgments
We thank Roger Mulder for assistance with NMR spectroscopy, Gary Fal-
lon and Craig Forsyth (Monash University) for X-ray crystallography, and
E. I. DuPont de Nemours and Co., Agricultural Products Department, for
biological screening of these compounds.
References
[1] N. Schindler, Chem. Ber. 1973, 106, 56.
[2] L. N. Markovskii,Y. G. Shermolovich,V. I. Shevchenko, J. Org. Chem.
USSR [Engl. Transl.] 1973, 9, 644.
[3] L. N. Markovskii,Y. G. Shermolovich,V. I. Shevchenko, J. Org. Chem.
USSR [Engl. Transl.] 1974, 10, 492.
[4] M. Knollmüller, P. Kosma, Monatsh. Chem. 1985, 116, 1321.
doi:10.1007/BF00811103
[5] H. Schröder, E. Fischer, M. Michalik, J. Prakt. Chem. 1988, 330, 900.
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Aust. J. Chem. 2007, 60, 105. doi:10.1071/CH06367
•
7, 2 × CH3). m/z (APCI+) 593 ([M + H]+ ).
3-Diethylamino-5,7-dimethyl-1,1,6,8-tetraoxo-1H-1λ6-
pyrimido[5,4-e][1,4,3]oxathiazine 11
A stirred mixture of 1,3-dimethylbarbituric acid 10 (1.11 g,
7.11 mmol) and the dichloro compound 1b (2.48 g, 10.64 mmol)
in DMPU (4 mL) was heated at 80◦C for 23 h. The mixture
was cooled and ethyl acetate (15 mL) was stirred in, followed
by water (30 mL). The resulting mixture was stirred vigorously
overnight. The aqueous layer was carefully removed (without
removing any precipitate) and more water (10 mL) was added.
The mixture was stirred vigorously for a further 1 h and suc-
tion filtered. The collected solid was washed with ethyl acetate
to give the title compound (0.43 g, 19%). An analytical sam-
ple was recrystallized (using a little decolourizing charcoal)
from methanol/dichloromet•hane, mp 240–241◦C (dec.) (Found:
C 41.9, H 5.0, N 17.9; M+ 316.0834. C11H16N4O5S requires
[9] F. Effenberger, T. Ziegler, K. H. Schoenwaelder, T. Kesmarszky,
B. Bauer, Chem. Ber. 1986, 119, 3394.
[10] S. Thaisrivongs, K. D. Watenpaugh, W. J. Howe, P. K. Tomich,
L. A. Dolak, K. T. Chong, C. S. C. Tomich, A. G. Tomasselli,
S. R. Turner, J. W. Strohbach, A. M. Mulichak, M. N. Janakiraman,
J. B. Moon, J. C. Lynn, M. M. Horng, R. R. Hinshaw, K.A. Curry, D. J.
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3945. doi:10.1021/JO00170A012
•
C 41.8, H 5.1, N 17.7%; M+ 316.0836). δH 3.51 (4H, q, J
7, 2 × NCH2), 3.49 (3H, s, NCH3), 3.34 (3H, s, NCH3), 1.32
(3H, t, J 7, CH3), 1.26 (3H, t, J 7, CH3). δC (CDCl3 + ∼10%
[D6]DMSO) 155.5, 153.2, 148.4, 144.9, 94.7, 43.8, 42.4, 29.2,
[12] W. L. Garbrecht, R. M. Herbst, J. Org. Chem. 1953, 18, 1003.
doi:10.1021/JO50014A015