Ring expansion reactions of 4-amino-1,1-dioxo-[1,2,3,5]-thiatriazoles

Article abstract of DOI:10.1039/b615569c

An unusual ring-expansion reaction of 4-amino-1,1-dioxo-[1,2,3,5]- thiatriazoles 4 has been identified that produces the relatively rare 5-amino-1,1-dioxo-[1,2,4,6]-thiatriazines 6 and 9. Initial alkylation of the thiatriazole 4 with α-halo-esters at N-3

Full text of DOI:10.1039/b615569c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Ring expansion reactions of 4-amino-1,1-dioxo-[1,2,3,5]-thiatriazoles
Peter J. Duggan,* Andris J. Liepa, Laura K. O’Dea and C. Elisabet Tranberg
Received 26th October 2006, Accepted 27th November 2006
First published as an Advance Article on the web 13th December 2006
DOI: 10.1039/b615569c
An unusual ring-expansion reaction of 4-amino-1,1-dioxo-[1,2,3,5]-thiatriazoles 4 has been identified
that produces the relatively rare 5-amino-1,1-dioxo-[1,2,4,6]-thiatriazines 6 and 9. Initial alkylation of
the thiatriazole 4 with a-halo-esters at N-3 produces a-substituted esters which, under basic reaction
conditions, undergo opening of the thiatriazole ring and re-closure to a thiatriazine ring. Similar
alkylations of 4 with diethyl chloromalonate and ethyl dichloroacetate lead to the loss of SO2 and the
production of triazine 10a and triazole 14, apparently by an initial alkylation at N-5. The reaction of 4
with phenacyl bromides or a phenacyl dibromide forms fully unsaturated
5-amino-1,1-dioxo-[1,2,4,6]-thiatriazines 13.
the synthesis and properties of 4-dialkylamino-1,2,3,5-thiatriazole
Introduction
1,1-dioxides, such as 4,4 readily prepared by reaction between
Amino-substituted 1,2,4,6-thiatriazine-1,1-dioxides remain a rel-
atively unexplored class of heterocyclic compounds. During the
1970s and 1980s, there was interest in their synthesis because
of the potentially valuable biological activity of some members
of this class. The 3,5-diamino derivatives in particular, were
investigated for their histamine H2 antagonism and antiulcer
activity, as typified by Hoechst’s HUK 978 (1).1 The related 5-
dichloride 3 and hydrazines. In the course of these investigations,
we treated the thiatriazole 4b with methyl 2-bromopropanoate
in the presence of K2CO3, expecting to form the simple N-
alkylated product 5b (Scheme 2). Surprisingly, the major product
from this reaction was not 5b, but a ring-expanded compound.
X-Ray analysis confirmed that the product was a derivative of
the relatively rare 5-amino-1,2,4,6-thiatriazine 1,1-dioxide system,
6b.6 Herein we describe the results of an investigation of the scope
of this reaction, and show that variation of the electrophile can
result in additional reactions involving unsaturation or the loss of
SO2.
amino-2H-1,2,4,6-thiatriazin-3-ones received attention for their
herbicidal activity. The dimethylamino derivative 2 can be used
to control mildew and rust, and exhibits herbicidal action.2 The
key step in the syntheses of these compounds involves ring closure
by intramolecular attack of a sulfamide onto a cyanamide3 or
carbamate.2
As part of a programme aimed at the discovery of novel, low
molecular weight, heterocyclic compounds with potential biolog-
ical activity, we have been investigating the use of N,N-dialkyl-
(Nꢀ-chlorosulfonyl)chloroformamidines, such as 3 (Scheme 1), as
versatile intermediates for the preparation of a diverse range of
sulfur-containing heterocycles.4,5 This has included a study of
Scheme 2
Results and discussion
Having established the identity of the unexpected ring-expanded
product to be 6b, the effect of changing the substitution on the
phenyl substituent of 4 was investigated. The reactions of three
more thiatriazoles 4a, 4c and 4d with methyl 2-bromopropanoate
were studied and the results are shown in Table 1. It was found that
in these cases, if the reaction was performed at room temperature
(20 ◦C), significant quantities of simple N-alkylated products 5a,
5c and 5d were isolated, with 5a being the exclusive product formed
from 4a. No N-alkylated products were isolated if these reactions
were warmed to 50 ◦C; the major products in all three cases being
the ring-expanded compounds 6a, 6c and 6d.
Scheme 1
This ring-expansion appears to be related to a reaction identified
by Bartholomew and Kay in 1977 (Scheme 3).7 Examination of
CSIRO Molecular and Health Technologies, Bag 10, Clayton South,
Victoria, 3169, Australia. E-mail: peter.duggan@csiro.au
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Table 1 Preparation of 5-dimethylamino-1,1-dioxo-1,2,4,6-thiatriazines
the acyclic intermediate 8 (Ar = 4-NO2–Ph) such that multiple
reaction pathways then become accessible.
Product
Ar
Temperature/◦C
Yielda (%)
To further investigate the scope of this unusual ring-expansion
reaction, 4a was treated with a number of other electrophiles.
Several of these, such as 3-chloropentan-2,4-dione, produced
complex mixtures, but two in particular, diethyl chloromalonate
and ethyl 2-chloroacetoacetate, produced identifiable products
when mild reaction conditions were used (Scheme 5).
6a
6b
6c
6d
Ph
50 b
20
37
20
31
37
3,5-Di-Cl–Ph
2,6-Di-Cl–Ph
4-CF3–Ph
50 c
50 c
a Isolated yields after purification by crystallization or trituration. b No
ring expansion at room temperature. c Mixture of N-alkylated and ring-
expanded products at room temperature.
Scheme 5
Scheme 3
the mechanism suggested by these workers for their reaction,
and the apparent promotion of the current reaction by electron
withdrawing groups present on the aromatic ring of 4, lead us to
propose the mechanism shown in Scheme 4. According to this
mechanism, the reaction begins by the removal of the proton on
the ring nitrogen in 4. This proton is known to be quite acidic,
as demonstrated by the solubility of 4a in aqueous NaHCO3.
Displacement of the bromide from methyl 2-bromopropanoate
by anion 7 gives the N-alkylated product 5, which ring-opens
in the presence of base to give the sulfonamide anion 8. Ring
closure at the imine-type carbon, followed by protonation gives the
ring expanded product 6. Support for this proposed mechanism
was found when the N-alkylated product 5a, which had been
isolated from the room temperature treatment of 4a with methyl 2-
bromopropanoate, was exposed to the same conditions that were
used to prepare 6a from 4a. The result was the isolation of 6a as
the sole product in 82% yield.
Compounds 9a and 9b appear to result from ring expansion
reactions analogous to those that produce 6a–d, but in the case
of the chloromalonate reaction, a second product was obtained.
Analytical data for this compound were consistent with it being
the triazine 10a, and its strong yellow colour was reminiscent of
related ring systems.8,9 The formation of 10a involves the expulsion
of SO2, and a suggested mechanism for this process is shown in
Scheme 6. A distinguishing feature of this mechanism is the initial
alkylation of N-5 rather than N-3 to give 11. The action of base on
this intermediate would lead to ring-opening and expulsion of SO2,
to give the highly delocalised anion 12. Ring closure by attack on
an ester functionality would lead to the observed triazinone 10a.
Scheme 6
The thiatriazole 4a was then treated with a third class of
electrophile, the phenacyl bromides, which led to ring expanded
products in moderate yields (Scheme 7). The analytical data for the
products of these reactions were consistent with their assignment
as 13a and 13b. It appears that the added conjugation possible
Scheme 4
Electron withdrawing chlorine or trifluoromethyl substituents
in 4b–d presumably facilitate the ring-opening of 5 to form the
intermediate 8, leading to the moderate to exclusive production of
the ring expanded products 6b–d at room temperature, something
that was not observed with 4a. Interestingly, when the more
strongly electron withdrawing 4-nitro substituent was present in
the starting material 4 (Ar = 4-NO2–Ph), the result was a complex
mixture. It is likely that the nitro group increases the lifetime of
Scheme 7
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with the attached phenacyl groups has promoted aerial oxidation
of the intermediate ring-expansion products to give the highly
conjugated compounds 13a and 13b. The structural assignment of
13b was confirmed by X-ray analysis.10
Experiments were also performed with 4a and other elec-
trophiles, including 2-chloroamides and 2-chlorosulfonamides,
and bromomethyl phenylsulfone, but none of these reactions
produced significant quantities of N-alkylated or ring-expanded
products. The electrophiles used in these reactions do not appear
to be sufficiently activated to participate in reactions with anion
7 under the conditions employed, and were generally recovered
from the reaction mixtures unchanged.
Bartholomew and Kay also identified a related ring-expansion
reaction in which the electrophile possessed two leaving groups so
that, after alkylation and ring-expansion, elimination occurred,
leading to an unsaturated product (Scheme 8).7 It was of interest
to learn if a similar process would occur in the current system, thus
4a was treated with ethyl dichloroacetate and K2CO3 under the
conditions described earlier. This reaction gave a major product
that, surprisingly, did not contain sulfur and was shown to be
the triazole 14 (Scheme 9). A mechanism that accounts for the
formation of 14 is shown in Scheme 9, and is related to that
proposed for the formation of 10a, involving initial alkylation
of N-5 and ring closure at the imine-type carbon rather than the
carbonyl carbon of the ester moiety.
Experimental
General experimental methods
The general methods used in this study were the same as
those previously reported.4 1H NMR spectra were recorded at
298 K unless otherwise stated. Electrospray ionization (ESI) and
atmospheric pressure chemical ionization (APCI) mass spectra
were recorded on a Fisons Instruments VG Platform quadrupole
mass spectrometer using positive (+) and negative (−) ion modes
with a cone voltage of 50 eV, and acetonitrile as the solvent,
unless otherwise stated. The preparation of 4c has been described
previously.4
Preparation of triazoles
Scheme 8
(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-1k6 -[1,2,3,5]thiatriazol-4-
yl)dimethylamine (4a). Phenylhydrazine (9.0 g, 83 mmol) in
CH2Cl2 (8 cm3) was added over 20 min to the dichloride 311,12
(17.0 g, 83 mmol) in CH2Cl2 (85 cm3) at 5 ◦C. After 25 min,
triethylamine (24 cm3, 174 mmol) was added over 80 min at
5
◦C. After 4 days at rt the reaction mixture was poured into
ice-cold HCl (2 M, 100 cm3) and enough diethyl ether was added
to float the organic phase. The whole was filtered and the residue
was washed with water, HCl (0.1 M) and water. The solid was
added to aqueous Na2CO3 (1 M, 150 cm3) and stirred until the
majority had dissolved. The resulting brown solution was washed
with CH2Cl2 (2 × 30 cm3) and the aqueous phase was cooled in
ice and acidified with conc. HCl. The mixture was filtered and the
residue washed thoroughly with water and dried to give the title
compound as a white solid (5.50 g, 28%). Mp 106–107 ◦C (dec.);
found: C, 45.1; H, 5.15; N, 23.4; S, 13.6. Calc. for C9H12N4O2S: C,
45.0; H, 5.0; N, 23.3; S, 13.3%); 1H NMR (400 MHz, DMSO-d6)
dH 3.04 (6H, s, 2 × CH3), 7.16–7.22 (3H, m, ArH), 7.36 (2H, m,
ArH), 10.53 (1H, br s, NH); 13C NMR (100.6 MHz, DMSO-d6):
dC 37.6 (br s), 120.2, 125.9, 129.3, 142.6, 160.2; m/z (ESI+) 263.1
(M + Na)+, 279.0 (M + K)+.
Scheme 9
[2-(3,5-Dichlorophenyl)-1,1-dioxo-2,3-dihydro-1H-1k6 -[1,2,3,5]-
thiatriazol-4-yl]dimethylamine (4b). The dichloride 3 (0.5 g,
3 mmol) was added to a stirred suspension of 3,5-dichlorophenyl-
hydrazine hydrochloride (0.42 g, 2 mmol) in CH2Cl2 (10 cm3) at
In contrast to the result obtained with ethyl dichloroacetate,
when a dihalide lacking an ester functionality, the phenacyl
dibromide 15, was allowed to react with 4a, the anticipated
unsaturated ring-expansion product 13c was produced in good
yield (Scheme 10).
◦
0 C followed by triethylamine (0.6 g, 6 mmol) added dropwise.
After 48 h at rt the solution was stirred into aqueous citric acid
(50 cm3, 10%) , the organic phase was separated and the solvent
removed under reduced pressure. The residue was stirred with a
mixture of diethyl ether (50 cm3) and aqueous NaOH (20 cm3,
5%), the aqueous phase was removed, extracted with a fresh
portion of diethyl ether and acidified by addition of an excess
of conc. HCl. After 3 h the precipitate was collected by filtration
to give the product as a cream powder (0.28 g, 45%). A sample
Scheme 10
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was recrystallized from ethyl acetate to give a white powder. Mp
118–120 C (dec.); found: C, 35.1; H, 3.3; N, 18.1; S, 10.4. Calc.
3.20 (6H, s, 2 × CH3–N), 3.59 (3H, br s, CH3–O), 4.31 (1H, q, J
6.95 Hz, CH–CH3), 7.20–7.36 (5H, m, ArH); 1H NMR (500 MHz,
368 K, DMSO-d6) dH 1.30 (3H, d, J 6.9 Hz, CH3–CH), 3.17 (6H, s,
2 × CH3–N), 3.48 (3H, s, CH3–O), 4.64 (1H, q, J 6.9 Hz, CH–
CH3), 7.17 (2H, d, J 7.3 Hz, ArH),7.23 (1H, t, J 6.9 Hz, ArH),
7.37 (2H, t, d, J 8.3 Hz, ArH); 13C NMR (100.6 MHz, DMSO-d6)
dC 13.3, 39.1 (br s), 51.2, 60.4, 121.3, 125,8, 128.1, 142.1, 164.6,
168.2; m/z (ESI+, MeOH–CH3CN–H2O, 2 : 1 : 1, ramped cone
voltage) 327.0 (M + H)+, 653.0 (2M + H)+.
◦
for C9H10Cl2N4O2S: C, 35.0; H, 3.3; N, 18.1; S, 10.4%; 1H NMR
(400 MHz, DMSO-d6) dH 3.05 (6H, s, 2 × CH3–N), 7.25 (2H, d, J
2.0 Hz, ArH), 7.41 (1H, t, J 2.0 Hz, ArH), 10.66 (1H, br s, NH);
13C NMR (100.6 MHz, DMSO-d6) dC 37.7, 118.3, 125.2, 134.8,
145.0, 159.8; m/z (ESI−, MeOH) 307.1 (M−H)−.
(1,1-Dioxo-2-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1k6-
[1,2,3,5]thiatriazol-4-yl)dimethylamine (4d). 4-Trifluoromethyl-
phenylhydrazine (0.88 g, 5 mmol) was stirred into a solution of
the dichloride 3 (1.02 g, 6 mmol) in DMF (2.5 cm3). After 30 min
N,N-diisopropylethylamine (1.55 g, 12 mmol) was added dropwise
over 5 min, the mixture was stirred overnight and poured into a
mixture of HCl (20 cm3, 2 M) and diethyl ether–cyclohexane (1 :
1, 10 cm3). After 1 h the mixture was filtered and the solid washed
with water and then diethyl ether–cyclohexane (1 : 1) to give the
product (0.53 g, 35%) as a colourless powder. Mp 121–124 ◦C;
found: C, 39.05; H, 3.7; N, 18.2; S, 10.4. Calc. for C10H11F3N4O2S:
C, 39.0; H, 3.6; N, 18.2; S, 10.4%; 1H NMR (400 MHz, CDCl3) dH
3.17 (6H, s, 2 × CH3–N), 7.33 (2H, d, J 8.4 Hz, ArH), 7.37 (1H,
br s, NH), 7.59 (2H, d, J 8.4 Hz, ArH); 13C NMR (125.8 MHz,
Methyl 5-dimethylamino-3-methyl-1,1-dioxo-2-phenyl-1,2,3,4-
tetrahydro-1k6-[1,2,4,6]thiatriazine-3-carboxylate (6a). The title
compound was prepared from the N-phenylthiatriazole dioxide
(4a) and methyl 2-bromopropanoate at 50 ◦C according to method
A—the product crystallized during work up. Yield (100 mg, 37%)
mp 197–199 ◦C; found: C, 47.9; H, 5.6; N, 17.2, S, 9.8. Calc.
1
for C13H18N4O4S: C, 47.8; H, 5.6; N, 17.2, S, 9.8%; H NMR
(400 MHz, CDCl3) dH 1.43 (3H, s, CH3), 3.06 (6H, s, 2 × CH3–
N), 3.81 (3H, s, CH3–O), 5.82 (1H, br s, NH), 7.35 (5H, s, ArH);
13C NMR (100.6 MHz, CDCl3) dC 24.6, 37.1, 53.46, 53.50, 128.5,
128.9, 130.8, 137.2, 153.9, 171.5. m/z (ESI−) 325.3 (M − H)−,
651.1 (2M − H)−, 977.2 (3M − H)−.
1
DMSO-d6) dC 37.2 (br s), 119.1, 124.2 (q, JCF = 272 Hz), 125.2
Methyl
2-(3,5-dichlorophenyl)-5-dimethylamino-3-methyl-1,
(q, 2JCF = 33 Hz), 126.1 (d, 3JCF = 3 Hz), 145.4, 159.3; 19F NMR
(376.5 MHz, DMSO-d6–CFCl3) dF −61.0; m/z (ESI−) 307.1 (M −
H)−, 615.0 (2M − H)−, 923.0 (3M − H)−.
1-dioxo-1,2,3,4-tetrahydro-1k6-[1,2,4,6]thiatriazine-3-carboxylate
(6b). The title compound was prepared from the N-(3,5-
dichlorophenyl)thiatriazole dioxide (4b) and methyl 2-bromo-
propanoate at rt according to method A—the product crystallized
during work up (51 mg, 20%). A sample was recrystallized by slow
evaporation from ethanol–water (6 : 1) to give thick, colourless
needles. Mp 213–215 ◦C (dec.); found: C, 39.5; H, 4.3; N, 14.2, S,
7.9. Calc. for C13H16Cl2N4O4S: C, 39.5; H, 4.1; N, 14.2, S, 8.1%;
1H NMR (400 MHz, CDCl3) dH 1.50 (3H, s, CH3), 3.12 (6H, s,
2 × CH3–N), 3.85 (3H, s, CH3–O), 5.56 (1H, br s, NH), 7.31
(2H, s, ArH), 7.38 (1H, s, ArH); 13C NMR (100.6 MHz, CDCl3)
dC 24.9, 37.1, 53.9, 74.7, 129.2, 129.6, 135.0, 139.0, 153.7, 171.3;
m/z (APCI−, MeOH–CH3CN–H2O, 2 : 1 : 1) 393.1 (M − H)−.
Reactions of triazoles
Representative procedures for the reactions of the 4-amino-
[1,2,3,5]-thiatriazole dioxides with organohalides.
Method A. To a solution of the 4-amino-[1,2,3,5]-thiatriazole
dioxide (4) in DMF (0.3 M solution) was added K2CO3 (2 eq.)
and the halide (2 ◦eq.) and the resulting mixture stirred for 5 days
at either rt or 50 C. Water (5 × vol. of DMF) and diethyl ether
(2.5 × vol. of DMF) were added with stirring and the mixture left
to stand for several hours. Where the product crystallized at the
interface between the aqueous and organic layers, the whole was
filtered, the crystals were washed with diethyl ether and dried. In
all other cases the layers were separated, the aqueous layer was
extracted with CHCl3 (3×), the combined organic layers washed
with water and dried (MgSO4), filtered and concentrated to yield
the crude product as an oil.
Methyl 2-(2,6-dichlorophenyl)-5-dimethylamino-3-methyl-1,1-
dioxo-1,2,3,4-tetrahydro-1k6 -[1,2,4,6]thiatriazine-3-carboxylate
(6c). The title compound was prepared from the N-(2,6-
dichlorophenyl)thiatriazole dioxide (4c) and methyl 2-bromo-
◦
propanoate at 50 C according to method A with the extractive
work up. The product was recrystallized from chloroform to yield
◦
Method B. To a solution of the 4-amino-[1,2,3,5]-thiatriazole
dioxide (4) in DMF (0.3 M solution) was added NaHCO3 (1.2 eq.)
and the mixture was left to stir for 5–10 min. The halide (1.2 eq.)
was added and the resulting mixture was stirred at rt for 1–2 h.
K2CO3 (1.2 eq.) was then added and the mixture stirred for a
further 5 days. The workup was the same as in method A.
a white powder (79 mg, 31%). Mp 227–230 C (dec.); found: C,
39.6; H, 4.2; N, 14.5, S, 8.1. Calc. for C13H16Cl2N4O4S: C, 39.5; H,
4.1; N, 14.2, S, 8.1%; 1H NMR (400 MHz, CDCl3) dH 1.69 (3H, s,
CH3), 3.08 (6H, s, 2 × CH3–N), 3.75 (3H, s, CH3–O), 5.62 (1H,
br s, NH), 7.19 (1H, t, J 8.05 Hz, ArH), 7.36 (1H, d, J 8.05 Hz,
ArH), 7.40 (1H, d, J 8.05 Hz, ArH); 13C NMR (100.6 MHz,
DMSO-d6) dC 22.7, 37.3, 53.3, 73.9, 129.7, 129.8, 131.1, 133.7,
137.5, 140.2, 154.1, 170.7; m/z (ESI−, MeOH) 395.1 (M − H)−,
788.9 (2M − H)−.
Methyl 2-(4-dimethylamino-1,1-dioxo-2-phenyl-1,2-dihydro-1k6-
[1,2,3,5]thiatriazol-3-yl)propanoate (5a). The title compound
was prepared from the N-phenylthiatriazole dioxide 4a and
methyl 2-bromopropanoate at rt according to method A with
the extractive workup and the reaction time reduced to 70 min.
Yield 111 mg (41%). A sample was recrystallized from chloroform–
diethyl ether (10 : 1) then precipitated from DMSO with water to
afford a white solid. Mp 126–128 ◦C; found: C, 47.85; H, 5.7; N,
17.0, S, 9.6. Calc. for C13H18N4O4S: C, 47.8; H, 5.6; N, 17.2, S,
9.8%; 1H NMR (400 MHz, CDCl3) dH 1.44 (3H, br s, CH3–CH),
Methyl
5-dimethylamino-3-methyl-1,1-dioxo-2-(4-trifluoro-
methylphenyl)-1,2,3,4-tetrahydro-1k6 -[1,2,4,6]thiatriazine-3-car-
boxylate (6d). The title compound was prepared from the
N-(4-trifluoromethylphenyl)thiatriazole dioxide (4d) and methyl
2-bromopropanoate at 50 ◦C according to method A with the
extractive work up. Trituration of the product with diethyl ether
gave a beige powder (46 mg, 37%). A sample was recrystallized
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from chloroform to give colourless crystals. Mp 182–184 ◦C;
found: C, 42.5; H, 4.4; N, 14.1, S, 7.9. Calc. for C14H17F3N4O4S:
C, 42.6; H, 4.3; N, 14.2, S, 8.1%; 1H NMR (400 MHz, CDCl3) dH
1.40 (3H, s, CH3), 3.04 (6H, s, 2 × CH3–N), 3.80 (3H, s, CH3–O),
6.11 (1H, br s, NH), 7.49 (2H, d, J 8.05 Hz, ArH), 7.61 (2H, d, J
8.05 Hz, ArH); 13C NMR (100.6 MHz, CDCl3) dC 24.8, 37.1, 53.7,
74.8, 123.6 (q, JCF = 272 Hz), 126.1 (q, JCF = 4 Hz), 130.6 (d,
2JCF = 33 Hz), 131.3, 140.6, 153.9, 171.2; 19F NMR (376.5 MHz,
CDCl3–CFCl3) dF −63.2; m/z (ESI−, MeOH) 393.1 (M − H)−,
787.0 (2M − H)−.
m, ArH); 13C NMR (100.6 MHz, CDCl3) dC 13.9, 22.0, 38.2, 39.6,
63.0, 70.8, 127.2, 128.0, 128.4, 129.0, 129.5, 138.5, 156.6, 167.0,
168.5; m/z (ESI+) 369.1 (M + H)+, 391.0 (M + Na)+, 759.1 (2M +
Na)+.
(5-Dimethylamino-1,1-dioxo-2-phenyl-1,2-dihydro-1k6-[1,2,4,6]-
thiatriazin-3-yl)phenylmethanone (13a). The title compound was
prepared from the N-phenylthiatriazole dioxide (4a) and phenacyl
bromide according to method B—the product crystallized as
a cream coloured solid during work up. Yield (67 mg, 47%).
Mp 211–213 ◦C; found: C, 57.4; H, 4.6; N, 15.7; S, 8.9. Calc.
1
3
1
Treatment of N-phenylthiatriazole dioxide (4a) with diethyl
chloromalonate. The N-phenylthiatriazole dioxide (4a) was
treated with diethyl chloromalonate according to method B with
the extractive work up. The crude product was crystallized from
chloroform to yield the triazine (10a) as a yellow solid. The con-
centrated mother liquors were purified by radial chromatography
using a hexane–ethyl acetate solvent gradient to yield more of the
triazine (combined yield 100 mg, 24%) and the thiatriazine (9a) as
a brown oil (71 mg, 12%).
for C17H16N4O3S: C, 57.3; H, 4.5; N, 15.7; S, 9.0%; H NMR
(400 MHz, CDCl3) dH 3.24 (3H, s, CH3–N), 3.25 (3H, s, CH3–N),
7.25–7.37 (5H, m, ArH), 7.45 (2H, t, J 7.6 Hz, ArH), 7.62
(1H, t, J 7.7 Hz, ArH); 7.83 (2H, d, J 8.0 Hz, ArH); 13C
NMR (100.6 MHz, CDCl3) dC 37.5, 37.7, 129.0, 129.39, 129.44,
129.6, 130.2, 132.3, 133.0, 135.2, 157.5, 159.4, 185.3; m/z (ESI+,
MeOH) 357.1 (M + H)+, 379.0 (M + Na)+, 713.0 (2M + H)+, 735.1
(2M + Na)+.
(4-Bromophenyl)-(5-dimethylamino-1,1-dioxo-2-phenyl-1,2-di-
hydro-1k6-[1,2,4,6]thiatriazin-3-yl)methanone (13b). The title
compound was prepared as an orange foam from the N-
phenylthiatriazole dioxide (4a) and 4-bromophenacyl bromide
according to method B using the extractive work up. Yield (102 mg,
56%). A sample was further purified by radial chromatography
using a hexane–ethyl acetate solvent gradient then recrystallized
from CH2Cl2–ethyl acetate to yield the title compound as a white
solid. Mp 154–156 ◦C; found: C, 47.2; H, 3.5; N, 12.9; S, 7.1.
Ethyl
3-dimethylamino-6-oxo-1-phenyl-1,6-dihydro-[1,2,4]tri-
azine-5-carboxylate (10a). A sample of the above mentioned
yellow solid was recrystallized from CH2Cl2–hexane to give the
title compound as yellow crystals. Mp 207–209 ◦C; found: C,
58.4; H, 5.6; N, 19.5. Calc. for C14H16N4O3: C, 58.3; H, 5.6; N,
1
19.4%; H NMR (400 MHz, CDCl3) dH 1.00 (3H, t, J 6.8 Hz,
CH3–CH2), 3.15 (6H, br s, 2 × CH3–N), 4.15 (2H, q, J 6.9 Hz,
CH2–CH3), 7.54 (4H, m, ArH), 7.57–7.63 (1H, m, ArH); 13C
NMR (100.6 MHz, CDCl3) dC 13.5, 36.9, 63.0, 123.7, 123.9,
129.6, 129.7, 131.6, 132.7, 142.8, 160.6, 162.6, 162.7; m/z (ESI+)
289.0 (M + H)+, 311.1 (M + Na)+, 599.0 (2M + Na)+.
1
Calc. for C17H15BrN4O3S: C, 46.9; H, 3.5; N, 12.9; S, 7.4%; H
NMR (400 MHz, CDCl3) dH 3.23 (3H, s, CH3–N), 3.24 (3H, s,
CH3–N), 7.27–7.36 (5H, m, ArH), 7.60 (2H, d, J 8.8 Hz, ArH),
7.70 (2H, d, J 8.8 Hz, ArH); 13C NMR (100.6 MHz, CDCl3) dC
37.5, 37.7, 129.2, 129.6, 130.3, 130.9, 131.0, 131.8, 132.2, 132.4,
157.3, 158.8, 184.3; m/z (APCI+, MeOH–CH3CN–H2O, 2 : 1 : 1,
ramped cone voltage) 436.9 (M + H (81Br))+, 434.9 (M + H (79Br))+,
373.0 (M + H − SO2(81Br))+, 371.0 (M + H − SO2(79Br))+, 355.0
(M − Br)+.
Diethyl 5-dimethylamino-1,1-dioxo-2-phenyl-1,4-dihydro-2H-
1k6-[1,2,4,6]thiatriazine-3,3-dicarboxylate (9a).
A sample of
the above mentioned brown oil was crystallized from ethyl
acetate–hexane to give the title compound as a pale purple solid.
Mp 130–132 ◦C; found: C, 48.4; H, 5.7; N, 14.1, S, 7.9. Calc.
1
for C16H22N4O6S: C, 48.2; H, 5.6; N, 14.1, S, 8.05%; H NMR
(400 MHz, CDCl3) dH 1.07 (6H, t, J 7.0 Hz, 2 × CH3), 3.16 (6H, s,
2 × CH3–N), 4.14 (4H, q, J 7.0 Hz, 2 × CH2–O), 6.50 (1H, br s,
NH), 7.27–7.33 (5H, m, ArH); 13C NMR (100.6 MHz, CDCl3): dC
13.4, 36.8, 64.2, 79.9, 128.16, 128.18, 128.9, 140.1, 152.9, 165.1;
m/z (ESI+, MeOH) 399.1 (M + H)+, 421.0 (M + Na)+, 819.1
(2M + Na)+.
(5-Dimethylamino-1,1-dioxo-2-phenyl-1,2-dihydro-1k6-[1,2,4,6]-
thiatriazin-3-yl)(4-methoxyphenyl)methanone (13c). The title
compound was prepared from the N-phenylthiatriazole dioxide
(4a) and 4-methoxyphenacyl dibromide (15)13 according to
method B—the product crystallized as a pastel-orange coloured
solid during work up. Yield (130 mg, 81%). A sample was further
purified with radial chromatography using a hexane–ethyl acetate
solvent gradient then recrystallized from CH2Cl2–ethyl acetate to
yield the title compound as a white solid. Mp 180–182 ◦C; found:
C, 55.9; H, 4.9; N, 14.3; S, 8.1. Calc. for C18H18N4O4S: C, 55.95;
Ethyl
3-acetyl-5-dimethylamino-1,1-dioxo-2-phenyl-1,2,3,4-
tetrahydro-1k6-[1,2,4,6]thiatriazine-3-carboxylate (9b). The title
compound was prepared from the N-phenylthiatriazole dioxide
(4a) and ethyl 3-chloroacetoacetate according to method B and
the extractive work up. The crude product was purified by radial
chromatography using a hexane–ethyl acetate solvent gradient
to give the ring-expanded compound in a partially crystalline
state (165 mg, 36%). A sample was recrystallized from ethyl
1
H, 4.7; N, 14.5; S, 8.3%; H NMR (400 MHz, CDCl3) dH 3.23
(3H, s, CH3–N), 3.24 (3H, s, CH3–N), 3.88 (3H, s, CH3–O), 6.91
(2H, d, J 8.8 Hz, ArH), 7.28–7.34 (3H, m, ArH), 7.37 (2H, d, J
8.8, ArH), 7.81 (2H, d, J 8.8 Hz, ArH); 13C NMR (100.6 MHz,
CDCl3) dC 37.5, 37.6, 55.7, 114.3, 126.0, 129.4, 130.1, 132.3,
132.4, 157.6, 159.8, 165.2, 183.8; m/z (ESI+, MeOH) 387.1, (M +
H)+, 409.1 (M + Na)+, 394.9 (2M + Na)+.
◦
acetate–hexane to give a white solid. Mp 143–145 C; found: C,
49.0; H, 5.6; N, 15.25, S, 8.7. Calc. for C15H20N4O5S: C, 48.9; H,
5.5; N, 15.2, S, 8.7%; 1H NMR (400 MHz, CDCl3) dH 1.25 (3H, t,
J 7.3 Hz, CH3), 2.33 (3H, s, CH3CO), 3.26 (3H, s, CH3–N), 3.28
(3H, s, CH3–N), 4.19 (1H, q, J 7.0 Hz, 0.5 × CH2–O), 4.26 (1H,
q, J 7.3 Hz, 0.5 × CH2–O), 6.51 (1H, br s, NH), 7.31–7.54 (5H,
Ethyl 5-dimethylamino-2-phenyl-2H-[1,2,4]triazole-3-carboxy-
late (14). The title compound was prepared from the N-
phenylthiatriazole dioxide (4a) and ethyl dichloroacetate at 50 ◦C
476 | Org. Biomol. Chem., 2007, 5, 472–477
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according to method A. The product partially crystallized during
work up and the remainder was recovered using the extractive
procedure. Yield (68 mg, 24%). A sample was further purified
by radial chromatography using a hexane–ethyl acetate solvent
gradient then recrystallized from CH2Cl2–hexane to yield the title
Acknowledgements
Dr Saba Jahangiri is thanked for providing N-(2,6-
dichlorophenyl)thiatriazole dioxide (4c) and Dr Craig Francis is
acknowledged for his helpful advice during the preparation of this
manuscript.
◦
compound as a white solid. Mp 111–113 C; found: C, 60.0; H,
6.4; N, 21.6. Calc. for C13H16N4O2: C, 60.0; H, 6.2; N, 21.5%; 1H
NMR (400 MHz, CDCl3) dH 1.26 (3H, t, J 7.2 Hz, CH3), 3.08
(6H, s, 2 × CH3–N), 4.32 (2H, q, J 7.2 Hz, CH2), 7.41–7.49 (5H,
m, ArH); 13C NMR (100.6 MHz, CDCl3) dC 13.9, 38.5, 62.3, 125.8,
128.8, 129.1, 138.3, 143.4, 157.6, 165.8; m/z (ESI+, MeOH) m/z
261.2 (M + H)+, 283.1 (M + Na)+.
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rare 5-dialkylamino-1,1-dioxo-1,2,4,6-thiatriazines,14 in three sim-
ple steps from commercially available starting materials. The by-
products generally partition into the aqueous phase on work-
up, thus readily providing the ring-expanded products in high
purity. When the 1,1-dioxo-1,2,3,5-thiatriazole 4a is treated with
phenacyl bromides or a phenacyl dibromide, fully unsaturated 1,1-
dioxo-1,2,4,6-thiatriazines are produced in good yield and high
purity.
12 L. N. Markovskii, Y. G. Shermolovich and V. I. Shevchenko, Zh. Org.
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14 Only one example of the synthesis of a 3-amino-1,2,4,6-thiatriazine
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been described. Its preparation involves four steps starting from
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The reactions that produce the 1,1-dioxo-1,2,4,6-thiatriazines
involve initial alkylation at N-3 of the starting thiatriazole, but
apparently initial alkylation at N-5 can also occur, leading to loss
of SO2 and formation of triazoles or triazines.
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