N,N-dialkyl-N′-chlorosulfonyl chloroformamidines in heterocyclic synthesis. Part VII 4-dialkylamino[1,2,3,5]benzoxathiadiazepine dioxides and 4-dialkylamino-[2,1,3,5]benzothiatriazepine dioxides

Article abstract of DOI:10.1071/CH08250

N,N-dialkyl-N′-chlorosulfonyl chloroformamidines 1 reacted with 2-aminophenols 2 to give 4-dialkylamino[1,2,3,5]benzoxathiadiazepine dioxides 3, which are examples of a new ring system. Reaction of 1 with 1,2-diaminobenzenes 7 afforded 4-dialkylamino[2,1,

Full text of DOI:10.1071/CH08250

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 785–796
N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in
Heterocyclic Synthesis. Part VII∗ 4-Dialkylamino[1,2,3,5]
Benzoxathiadiazepine Dioxides and 4-Dialkylamino
[2,1,3,5]Benzothiatriazepine Dioxides
Teresa Cablewski,A Craig M. Forsyth,B Craig L. Francis,A,C Andris J. Liepa,A
and Victor TranA
ACSIRO Molecular and Health Technologies, Clayton, Vic. 3168, Australia.
BSchool of Chemistry, Monash University, Clayton, Vic. 3800, Australia.
CCorresponding author. Email: craig.francis@csiro.au
N,N-dialkyl-Nꢀ-chlorosulfonyl chloroformamidines 1 reacted with 2-aminophenols 2 to give 4-dialkylamino[1,2,3,5]
benzoxathiadiazepine dioxides 3, which are examples of a new ring system. Reaction of 1 with 1,2-diaminobenzenes 7
afforded 4-dialkylamino[2,1,3,5]benzothiatriazepine dioxides 8 and 9, which are new derivatives of a rare ring system.
Some N-alkyl and N-acyl derivatives of 3 and 8 were prepared to demonstrate the potential of these compounds as novel
scaffolds for synthetic and medicinal chemistry.
Manuscript received: 10 June 2008.
Final version: 31 July 2008.
Introduction
(N,N-diisopropylethylamine) provided 4-dialkylamino[1,2,3,5]
benzoxathiadiazepine dioxides 3 (Scheme 2, Table 1), examples
of a new ring system.
The [1,2,3,5]benzoxathiadiazepines 3 were precipitated from
the DMPU-based reaction mixture in high purity by the addition
of ethyl acetate and water and acidification to pH 3.
The derivatives of the new [1,2,3,5]benzoxathiadiazepine
ring system described above were stable, colourless, crystalline
solids unaffected by recrystallization from alcohols.
Confirmation of the ring structure of [1,2,3,5]benzoxathia-
diazepines 3 was provided by X-ray crystallographic studies of
N-acylated and N-alkylated derivatives (see below). Ring for-
mation to produce compounds 3 proceeds so that the amino
group of 2 bonds with the amidine carbon atom of 1 and the
hydroxy group reacts with the sulfamoyl chloride moiety. This
mode of reaction confirms[3–8] the greater electrophilicity of
the amidinyl chloride moiety, relative to the sulfamoyl chloride
group, in dichlorides 1.
The possible regioisomeric products 4 (Scheme 2) were
not isolated. Upon chromatographic purification of the residue
from evaporation of the mother liquor from isolation of 3b,
the only clearly identifiable component was 2-piperidin-1-
ylbenzoxazole,[9,10] produced in low yield.
We have previously remarked upon the facility with which
readily available[1,2] N,N-dialkyl Nꢀ-chlorosulfonyl chlorofor-
mamidines 1 react with 1,2- and 1,3-bidentate nucleophiles
to generate uncommon or previously unknown five-[3] or six-
membered[4–8] heterocyclic ring systems, respectively.Whilethe
novelty of these products had much to commend them as candi-
dates for biological testing, further evaluation was constrained
by a lack of reactive sites where a diversity of substituents could
be readily introduced. In order to overcome this limitation as
well as to examine the feasibility of creating seven-membered
heterocyclic rings, the potential for 2-aminophenols and 1,2-
diaminobenzenes to condense with the dichloro compound 1,
was examined.
Results and Discussion
The dichlorides 1a–c were readily prepared[1,2] from sulfuryl
chloride and the corresponding dialkyl cyanamide (Scheme 1).
Reaction of
1 with 2-aminophenols 2 in DMPU
(dimethylpropylene urea, 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone) in the presence of Hünig’s base
The new heterocycle 3 contains an NH moiety and thus has
the potential for introduction of various substituents.The nucleo-
philic nature of the nitrogen atoms of the oxathiadiazepine ring
was confirmed by acylation and alkylation of 3b and 3d.
The reactions of 3b and 3d with acetic anhydride and the
reaction of 3b with benzoyl chloride all occurred selectively at
N5 to give the acylated products 5a–c (Scheme 3, Table 2).
R2N
R2N
Cl
SO2Cl2
1a
1b
Me2N
Et2N
R2N
N
NSO2Cl
1
1c
N
Scheme 1.
∗ Part VI, Aust. J. Chem. 2008, 61, 332.
© CSIRO 2008
10.1071/CH08250
0004-9425/08/100785

786
T. Cablewski et al.
R1
6
R4
R1
NR2
4
NR2
NR2
H
N
5
R3
R2
R2
R3
O
R2
R3
NH2
OH
7
8
Pri2NEt
DMPU
Cl
Cl
N3
N
O
ϩ
N
O
2S
S
1
O
S
N
H
9
R4
O
R1
R4
O
O
O
2
1
3
4
Scheme 2.
Table 1. Synthesis of the 4-dialkylamino[1,2,3,5]benzoxathiadiazepine dioxides 3
R2N
R1
H
R2
H
R3
H
R4
Product
3a
Yield [%]
Me2N (1a)
H (2a)
H (2a)
48
69
H
H
H
3b
N
(1c)
Me
H
H
H (2b)
3c
23
N
(1c)
Me2N (1a)
H
H
Me
Me
H
H
H (2c)
H (2c)
3d
3e
53
24
N
(1c)
Me2N (1a)
Et2N (1b)
Me2N (1a)
Et2N (1b)
Et2N (1b)
H
H
H
H
H
H
H
Cl
Cl
Me
Me
H
H
fused
H (2d)
H (2d)
Cl (2e)
Cl (2e)
H (2f)
3f
3g
3h
3i
71
53
31
48
54
Tetrahydrobenzo
3j
R2
NR2
NR2
R2
NR2
H
R1
R1
R1
N
N
N
O
ϩ
N
N
N
O
S
S
S
O
O
O
O
O
O
O
5
6
3
Scheme 3.
Table 2. Synthesis of the [1,2,3,5]benzoxathiadiazepine dioxides 5 and 6
R2N
R1
R2
Method
Product
Yield [%]
H
CH3
H
COCH3
COCH3
COPh
(CH3CO)2O, py, 120◦C
(CH3CO)2O, py, 120◦C
PhCOCl, py, room temp.
5a
5b
5c
77
77
50
N
Me2N
N
H
4-ClC6H4CH2
4-ClC6H4CH2Br, cat. Bun4NBr,
K2CO3, CH3CN, room temp.
5d + 6d
32 + 49
N
The structural assignments for 5a–c were based on X-
ray crystallographic analysis of the benzoylated product 5c
(Fig. 1).
Alkylation of 3b with 4-chlorobenzyl bromide was not selec-
tive and a mixture of benzylated products 5d and 6d was
obtained (Scheme 3, Table 2). The structure of compound 6d
was confirmed by X-ray crystallography (Fig. 1).
analogous reaction with 1,2-diaminobenzenes 7. Indeed, such
a reaction gave 4-dialkylamino[2,1,3,5]benzothiatriazepine 2,2-
dioxides 8 and, on occasion when R2 = H, the isomeric
compounds 9 as a minor product (Scheme 4, Table 3).
These compounds are new derivatives of a rare[11,12] ring
system.
Usually, the 2,1,3,5-benzothiatriazepines 8 were precipitated
from the reaction mixture in high purity by our favoured ethyl
acetate/water (pH 3) workup method.
Having constructed the 2,1,3,5-benzothiatriazepine ring
from dichlorides 1 and 2-aminophenols 2, we envisaged an

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part VII
787
NR2
R1
R1
NH2
Cl
Cl
ϩ
N
O
S
NH
R2
O
O(4)
7
1
N(4)
Pri2NEt
DMPU
C(6)
C(4)
N(5)
C(7)
N(3)
R2
N
NR2
NR2
H
O(3)
C(8)
6
9
R1
R1
R1
R1
N
4
7
8
S(2)
5
N3
N
O
C(9)
2S
S
1
O(1)
5c
N
N
H
O
O(2)
O
O
R2
8a–h
9
Cl(1)
Scheme 4.
Table 3. Synthesis of the 4-dialkylamino[2,1,3,5]benzothiatriazepine
2,2-dioxides 8 and 9
N(4)
C(6)
R2N
R1
R2
Product
Yield [%]
C(4)
N(5)
O(1)
C(7)
C(8)
N(3)
S(2)
Me2N (1a)
H
H
H (7a)
H (7a)
8a
8b
55
33
C(9)
N
O(3)
(1c)
O(2)
Me2N (1a)
Et2N (1b)
Me2N (1a)
Et2N (1b)
Me2N (1a)
Cl
Cl
Me
Me
H
H (7b)
H (7b)
H (7c)
8c
8d
8e
8f
66
14
52
52
48
6d
Fig. 1. ORTEP diagrams of 5c (above) and 6d (below). For 6d, only one
of two crystallographically independent, but virtually identical, molecules
is shown.
H (7c)
4-ClC6H4CH2 (7d)
8g
H
Me (7e)
8h + 9h
43 + 2
N
(1c)
The derivatives of the uncommon heterocyclic system
described above were all stable, colourless, crystalline solids
unaffected by recrystallization from alcohols. Compound 9h
was more soluble and more mobile during TLC than the major
isomer 8h.
Spectroscopic studies alone did not allow us to distinguish
between the two isomeric structures 8 and 9; therefore struc-
tural assignments for compounds listed in Table 3 were based
upon X-ray crystallographic analyses of compounds 8g and 8h
(Fig. 2).
C(6)
N(5)
N(1)
N(4)
C(4)
C(7)
C(8)
N(3)
S(2)
C(9)
O(2)
O(1)
Interestingly, in both crystal structures of 8g and 8h·H2O,
a single tautomeric form is clearly evident, with the hydrogen
atom residing on the (diaminobenzene-derived) nitrogen atom,
N5, rather than N3 (Fig. 2). The thiatriazepine heterocycle exists
in a pseudo boat conformation, for which there are two enantio-
morphic configurations (A and B, Fig. 3). In the solid state, 8g
crystallizes in the non-centrosymmetric space group P212121
and the crystal analyzed contained only one configuration (A),
whereas 8h·H2O has both configurations A and B due to the
inversion symmetry present in the centrosymmetric space group
P21/c.
The new heterocyclic products 8 (and 9) contain either one
or two NH moieties in the newly formed thiatriazepine ring and
thus have the desired potential for introduction of various sub-
stituents. The nucleophilic nature of the nitrogen atoms of the
thiatriazepine ring was confirmed by acylation and alkylation of
8a and 8h.
Cl(1)
8g
N(5)
C(6)
N(4)
C(4)
C(7)
N(3)
S(2)
C(8)
C(9)
N(1)
O(1)
O(2)
Acylation of 1-methyl thiatriazepine 8h with acetic anhydride
or benzoyl chloride occurred preferentially at N3 (Scheme 5,
Table 4) to afford the 3-acetyl and 3-benzoyl derivatives 10a and
10b, respectively. The structural assignments were confirmed
8h·H2O
Fig. 2. ORTEP diagrams of 8g (above) and 8h·H2O (below). For 8h·H2O,
the lattice water molecule is not shown.

788
T. Cablewski et al.
NR2
O
NMe2
H
NMe2
H
R
H
N
N
N5
N1
N
O
N
N3
S
O
S
S
O
N5
N1
N
N
H
N3
O
O
O
S
NR2
H
R
R
O
8a
O
8i–k
A
B
Scheme 6.
Fig. 3. Enantiomorphic forms of the thiatriazepine ring found in the solid
state.
Table 5. Synthesis of the acylated [2,1,3,5]benzothiatriazepine
2,2-dioxides 8i–k
R
Method
Product
Yield [%]
CH3
Ph
4-CH3C6H4NH
(CH3CO)2O, py, room temp.
PhCOCl, py, room temp.
4-CH3C6H4NCO, cat. NEt3,
CH2Cl2, room temp.
8i
8j
8k
69
49
76
R
N
N
N
N
N
N
8h
ϩ
R
S
S
N
N
O
O
O
O
Me
Me
10
11
C(6)
N(5)
N(4)
N(3)
Scheme 5.
C(7)
C(8)
Table 4. Synthesis of the [2,1,3,5]benzothiatriazepine 2,2-dioxides 10
and 11
S(2)
C(9)
N(1)
O(2)
O(1)
R
Method
Product
Yield [%]
COCH3
COPh
4-ClC6H4CH2
(CH3CO)2O, py, 90◦C
PhCOCl, py, room temp.
4-ClC6H4CH2Br, cat.
Bun4NBr, K2CO3,
10a
10b
10c + 11c
64
38
70 + 18
O(3)
8j
CH3CN, room temp.
N(5)
C(6)
N(4)
C(7)
C(8)
N(3)
S(2)
O(2)
C(9)
N(1)
N(4)
C(6)
N(5)
O(1)
O(3)
C(7)
C(8)
N(6)
N(3)
O(3)
O(2)
S(2)
C(9)
N(1)
O(1)
10b
Fig. 4. ORTEP diagram of 10b.
8k
Fig. 5. ORTEP diagrams of 8j (top) and 8k (bottom). In 8j, the lat-
tice MeCN has been omitted for clarity and only one conformation of the
disordered methyl group is shown.
by X-ray crystallography of the benzoyl derivative 10b
(Fig. 4).
Alkylation of 8h with 4-chlorobenzyl bromide also pro-
ceeded predominantly at N3 to give 10c as the major product, but
also occurred at N5, to afford 11c as a minor product (Scheme 5,
Table 4).
Evidence to support the structural assignments of 10c and
11c wasobtainedfrom 1HNMRexperiments. Duringa500 MHz
gradient-selected nuclear overhauser effect correlation spectro-
scopy (NOESY) two-dimensional 1H NMR experiment with

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part VII
789
8a
11c, we observed a relatively strong NOE between the resonance
attributed to the benzylic methylene group and the resonance of
the ortho-hydrogen (relative to N5) of the benzo moiety.
1 to 1.1equiv.
4-ClC6H4CH2Br
Base
Two striking similarities were observed in the one-
dimensional 1H NMR spectrum of 10c and that of the analogous
N3-benzylated benzoxathiadiazepine 6d (Scheme 3, Table 2,
Fig. 1), the structure of which was determined by X-ray crystallo-
graphy. The splitting pattern for the signals due to the aromatic
R
N
NMe2
NMe2
H
N
ϩ
ϩ
N
N
S
S
1
N
N
H
O
O
hydrogen atoms in the H NMR spectrum of 10c was almost
O
O
identical to that for 6d, and the chemical shift of δ4.11 for
the benzylic methylene group in 10c was very similar to
that for the corresponding signal (δ4.21) in the spectrum of
6d. The benzylic methylene resonance for 10c was signifi-
cantly upfield from the corresponding signal for the isomeric
N5-benzylated compound 5d (δ4.72), which was very simi-
lar to that for 11c (δ4.66) and other N5-benzylated derivatives
(see below).
The reactions of 8a with acetic anhydride, benzoyl chloride,
and p-tolyl isocyanate all occurred selectively at N1 to give the
acylated products 8i–k shown in Scheme 6 and Table 5.
The structural assignments were based on X-ray crystallo-
graphicanalysesofthebenzoylatedproduct8jandtheisocyanate
adduct 8k (Fig. 5). A single tautomeric form is also clearly evi-
dent, with the hydrogen atom residing on the (diaminobenzene-
derived)nitrogenatomN5, ratherthanonN3.Aswith 8g (above),
R
9g
8g
R
N
NMe2
NMe2
N
ϩ
N
R
N
O
S
S
N
N
O
O
O
R
R
13
12
R ϭ H2C
Cl
Scheme 7.
8k crystallizes in a non-centrosymmetric space group P212121
and has only the one enantiomorph (A in Fig. 3) present in the
crystal.
Table 6. Alkylation products from the [2,1,3,5]benzothiatriazepine
2,2-dioxide 8a
Alkylation of 8a with 1 to 1.1 molar equivalents of 4-
chlorobenzyl bromide under basic conditions was not selec-
tive and mixtures of mono- and di-alkylated products were
obtained with a variety of reaction conditions (Scheme 7,
Table 6). Aqueous sodium hydroxide, dichloromethane, and a
phase transfer catalyst resulted in predominant formation of
the 1,3-bis(4-chlorobenzyl) product 12 along with minor pro-
portions of the 1,5-bis(4-chlorobenzyl) product 13 and the N1
monosubstituted derivative 8g. Potassium carbonate in N,N-
dimethylformamide (DMF) afforded a similar product mixture,
with an additional product, the N5-monosubstituted deriva-
tive 9g, being isolated in very low yield. Formation of an
N-anion with 1.1 molar equivalents of sodium hydride in tetrahy-
drofuran (THF)/DMF, followed by addition of 4-chlorobenzyl
bromide, resulted in the N1-monosubstituted derivative 8g
being the major product, along with a significant proportion
of the 1,3-bis-substituted product 12, and minor proportions of
9g and 13.
Method
Yield of product [%]
8g
9g
12
13
NaOH, cat. Bun4NBr, CH2Cl2,
H2O, room temp.
K2CO3, cat. Bun4NBr, DMF,
room temp.
NaH, THF/DMF (2:1),
room temp.
4
—
41
2
8
4
5
36
23
2
3
31
reaction of 1a with 2-aminothiophenol (Hünig’s base/DMPU)
afforded a complex mixture of products. The only compound
obtained from chromatographic purification was the known
2-(N,N-dimethylamino)benzothiazole.[10]
Conclusions
These results suggest that initial alkylation probably occurs
at N1 and that the resulting compound 8g is more susceptible to
alkylation than the starting material 8a.
The dichloro compounds 1, readily available 1,3-dielectrophiles,
have been shown to react with 2-aminophenols to afford dioxo
derivatives of the hitherto unreported [1,2,3,5]benzoxathiadi-
azepine ring system. Similar reaction of dichlorides 1 with
1,2-diaminobenzenes provides a convenient pathway to the
rare [2,1,3,5]benzothiatriazepine dioxides. Convenient alkyla-
tion and acylation reactions of representative derivatives of
both of the ring systems demonstrated the potential of these
compounds as novel scaffolds for synthetic and medicinal
chemistry.
The structural assignments for 9g, 12, and 13 were made on
1
the basis of their H NMR spectra and insights gained from
other alkylation experiments. The benzylic methylene group
of 9g resonated at δ4.71. If the compound had the isomeric
structure with N3 substitution, this resonance would have been
expected further upfield, as for 10c (δ4.11). Assignment of 1,3-
bis substitution for compound 12 and 1,5-bis substitution for
compound 13 was made on the basis of the benzylic methy-
lene resonances at δ4.68 and 4.12 for 12, and at δ4.68 and 4.43
for 13.
Successful construction of the [1,2,3,5]benzoxathiadiazepine
and[2,1,3,5]benzothiatriazepineringsfrom2-aminophenolsand
1,2-diaminobenzenes, respectively, encouraged us to investigate
the analogous reaction with 2-aminothiophenols. However,
Experimental
Methods and Materials
General experimental conditions have been described
previously.[4,6] N,N-Dialkyl-Nꢀ-chlorosulfonyl chloroforma-
midines 1a, 1b, and 1c were prepared by literature

790
T. Cablewski et al.
procedures[1,2] and used as crude products. Other materials were
obtained from commercial sources.
δH ([D6]DMSO) 9.73 (1H, s, NH), 7.11 (1H, m, ArH), 7.08
(2H, m, ArH), 3.15 (6H, s, NMe2), 2.29 (3H, s, ArCH3). δC
([D6]DMSO) 152.5, 141.9, 136.0, 130.4, 127.8, 124.8, 122.6,
38.9, 20.8. m/z (EI) 255 (48%, M+•), 175 (100).
General Synthesis Procedure for 4-Dialkylamino-
2,2-dioxo-2λ6-[1,2,3,5]benzoxathiadiazepines 3a–j
2,2-Dioxo-4-piperidin-1-yl-7-methyl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3e
N,N-Diisopropylethylamine (13 mmol) was added to an ice-
water cooled, stirred mixture of the 2-aminophenol 2 (5 mmol),
the dichloro compound 1 (6.5 mmol), and DMPU (4 mL). The
resulting mixture was stirred at room temperature for at least
4 h. Ethyl acetate (15 mL) was added, followed by water (30 mL)
and acidification to pH 3 with concentrated hydrochloric acid.
The mixture was stirred vigorously at room temperature for at
least 1 h. The precipitate was collected by filtration and washed
sequentially with water, ethyl acetate, and diethyl ether.
The following compounds were prepared by the above
procedure.
Precipitated as a beige solid in 24% yield. A sample was
recrystallized from ethanol to give off-white crystals, mp
261.5–262◦C. (Found: C 52.8, H 6.0, N 14.4; M+• 295.0983.
C13H17N3O3S requires C 52.9, H 5.8, N 14.2%; M+• 295.0985).
δH ([D6]DMSO) 9.88 (1H, s, NH), 7.11–7.06 (3H, m,ArH), 3.67
(4H, br, 2 × NCH2), 2.29(3H, s,ArCH3), 1.59(6H, br, 3 × CH2).
δC ([D6]DMSO) 151.2, 142.1, 136.1, 130.3, 127.9, 124.9, 122.5,
47.5, 25.9, 23.8, 20.7. m/z (EI) 295 (27%, M+•), 215 (95), 148
(86), 111 (95), 84 (100).
4-Dimethylamino-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 3a
4-Dimethylamino-2,2-dioxo-8-methyl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3f
Precipitated as a light beige solid in 48% yield. A sample was
recrystallized from ethyl acetate to give off-white+c•rystals, mp
231–232◦C. (Found: C 44.8, H 4.5, N 17.6; M 241.0511.
C9H11N3O3S requires C 44.8, H 4.6, N 17.4%; M+• 241.0516).
δH ([D6]DMSO) 9.84 (1H, s, NH), 7.33–7.25 (3H, m, ArH),
7.24–7.18 (1H, m, ArH), 3.16 (6H, s, NMe2). δC ([D6]DMSO)
152.6, 144.1, 130.8, 127.4, 126.6, 124.7, 122.9, 38.9. m/z (EI)
241 (14%, M+•), 161 (39), 134 (26), 71 (100).
Precipitated as a brilliant white solid in 71% yield. A sample
was recrystallized from ethanol to give colourless+c•rystals, mp
269–270◦C. (Found: C 47.0, H 5.2, N 16.7; M 255.0672.
C10H13N3O3S requires C 47.1, H 5.1, N 16.5%; M+• 255.0672).
δH ([D6]DMSO) 9.77 (1H, s, NH), 7.17 (1H, d, J 8, ArH), 7.09
(1H, d, J 8, ArH), 7.03 (1H, s, ArH), 3.15 (6H, s, NMe2), 2.30
(3H, s, ArCH3). δC ([D6]DMSO) 152.7, 143.9, 137.3, 128.1,
127.1, 124.4, 123.1, 38.8, 20.7. m/z (EI) 255 (22%, M+•), 175
(77), 148 (48), 93 (46), 71 (100).
2,2-Dioxo-4-piperidin-1-yl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3b
4-Diethylamino-2,2-dioxo-8-methyl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3g
Precipitated as a pale beige solid in 69% yield. A sample
was recrystallized from ethanol to give off-white crystals, mp
226.5–228.5◦C. (Found: C 51.1, H 5.4, N 15.1; M+• 281.0828.
C12H15N3O3S requires C 51.2, H 5.4, N 14.9%; M+• 281.0829).
δH ([D6]DMSO) 9.99 (1H, s, NH), 7.31–7.16 (4H, m,ArH), 3.68
(4H, br, 2 × NCH2), 1.61 (6H, br, 3 × CH2). δC ([D6]DMSO)
151.2, 144.3, 130.7, 127.5, 126.6, 124.7, 122.9, 47.5, 25.9, 23.8.
m/z (EI) 281 (5%, M+•), 201 (30), 134 (34), 111 (37), 84 (100).
The organic phase of the mother liquor was washed four
times with water, dried, and evaporated. The residue was
chromatographed over silica gel (0–3% methanol in dichloro-
methane) to afford 2-piperidin-1-ylbenzoxazole[9,10] (1%).
Precipitated as a white solid in 53% yield. A sample was
recrystallized from ethanol to give colourless crystals, mp
209–210◦C. (Found: C 50.8, H 6.2, N 15.0; M+• 283.0980.
C12H17N3O3S requires C 50.9, H 6.1, N 14.8%; M+• 283.0985).
δH ([D6]DMSO) 9.72 (1H, s, NH), 7.17 (1H, d, J 8, ArH), 7.10
(1H, d, J 8,ArH), 7.04 (1H, s,ArH), 3.54 (4H, q, J 7, 2 × NCH2),
2.30 (3H, s,ArCH3), 1.18 (6H, t, J 7, 2 × CH3). δC ([D6]DMSO)
151.9, 144.2, 137.5, 128.3, 127.1, 124.6, 123.1, 43.7, 20.7, 13.6.
m/z (EI) 283 (52%, M+•), 203 (70), 148 (91), 99 (100).
7,9-Dichloro-4-dimethylamino-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 3h
2,2-Dioxo-6-methyl-4-piperidin-1-yl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3c
Precipitated as a fawn solid in 31% yield. A sample was
recrystallized from ethanol to give off-white crystals, mp
263.5–264◦C. (Found: C 34.9, H 3.2, N 13.7; M+• 308.9727.
C9H9Cl2N3O3S requires C 34.9, H 2.9, N 13.6%; M+•
308.9736). δH ([D6]DMSO) 10.01 (1H, s, NH), 7.65 (1H, d,
J 2.3, ArH), 7.41 (1H, d, J 2.3, ArH), 3.18 (6H, s, NMe2). δC
([D6]DMSO) 152.1, 139.7, 133.4, 130.0, 128.2, 127.1, 123.5,
39.1. m/z (EI) 309/311/313 (21/14/3%, M+•), 229/231/233
(90/77/16), 202/204/206 (61/36/5), 112 (61), 71 (100).
Precipitated as a cream solid in 23% yield. A sample was
recrystallized from ethanol to give colourless crystals, mp
264–265◦C. (Found: C 52.7, H 6.0, N 14.4; M+• 295.0985.
C13H17N3O3S requires C 52.9, H 5.8, N 14.2%; M+• 295.0985).
δH ([D6]DMSO) 9.51 (1H, s, NH), 7.27–7.17 (2H, m, ArH),
7.11–7.06 (1H, m, ArH), 3.67 (4H, m, 2 × NCH2), 2.32 (3H,
s, CH3), 1.62 (6H, m, 3 × CH2). δC ([D6]DMSO) 151.8, 146.2,
134.6, 129.3, 128.4, 128.0, 120.5, 47.6, 25.9, 23.9, 17.8. m/z
(EI) 295 (23%, M+•), 215 (80), 186 (39), 148 (85), 111 (82),
84 (100).
7,9-Dichloro-4-diethylamino-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 3i
4-Dimethylamino-2,2-dioxo-7-methyl-2λ6-
[1,2,3,5]benzoxathiadiazepine 3d
Precipitated as a beige solid in 48% yield. A sample was
recrystallized from ethanol to give pale grey crystals, mp
262.5–263◦C. (Found: C 39.1, H 4.1, N 12.5; M+• 337.0040.
C11H13Cl2N3O3S requires C 39.1, H 3.9, N 12.4%; M+•
337.0049). δH ([D6]DMSO) 9.98 (1H, s, NH), 7.67 (1H,
Precipitated as a beige solid in 53% yield. A sample was
recrystallized from ethanol to give off-white crystals, mp
231–232◦C. (Found: C 47.0, H 5.2, N 16.6; M+• 255.0676.
C10H13N3O3S requires C 47.1, H 5.1, N 16.5%; M+• 255.0672).

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part VII
791
d, J 2.4, ArH), 7.41 (1H, d, J 2.4, ArH), 3.56 (4H, q, J
7, 2 × NCH2), 1.19 (6H, t, J 7, 2 × CH3). δC ([D6]DMSO)
151.3, 140.2, 133.5, 130.0, 128.2, 127.3, 123.8, 44.1, 13.5.
m/z (EI) 337/339/341 (14/10/2%, M+•), 257/259/261 (64/48/7),
202/204/206 (64/46/8), 72 (100).
washed thrice with water, dried, and evaporated. The residue
was triturated with cyclohexane/n-hexane (1:1) to give a pale
yellow solid, which was chromatographed over silica gel (0–
1% methanol in dichloromethane), followed by recrystallization
from ethanol (charcoal) to give the title compound (193 mg,
50%) as colourless crystals, mp 194–195◦C. (Found: C 59.2,
H 5.0, N 11.0; M+• 385.1087. C19H19N3O4S requires C 59.2,
H 5.0, N 10.9%; M+• 385.1091). δH 7.79–7.71 (2H, m, ArH),
7.55–7.35 (5H, m, ArH), 7.32–7.18 (2H, m, ArH), 3.81 (1H,
br, CHN), 3.56 (1H, br, CHN), 3.22 (2H, br, CH2N), 1.46 (6H,
br, CH2CH2CH2). δC 168.1, 151.6, 146.8, 132.5, 132.3, 131.0,
129.8, 129.3, 128.6, 128.4, 126.3, 122.5, 48.9, 48.0, 25.6, 24.4,
23.4. m/z (EI) 385 (38%, M+•), 280 (24), 105 (100).
4-Diethylamino-2,2-dioxo-2λ6-[5,6,7,8]
tetrahydronaphthaleno[2,3-f][1,2,3,5]
oxathiadiazepine 3j
Precipitated as a beige solid in 54% yield. A sample was
recrystallized from ethanol to give off-white crystals, mp
235.5–236◦C. (Found: C 55.4, H 6.7, N 13.1; M+• 323.1302.
C15H21N3O3S requires C 55.7, H 6.5, N 13.0%; M+• 323.1298).
δH ([D6]DMSO) 9.64 (1H, s, NH), 6.97 (1H, s, ArH), 6.90
(1H, s, ArH), 3.53 (4H, q, J 7, 2 × NCH2), 2.69 (4H, m,
2 × CH2Ar), 1.71 (4H, m, CH2CH2), 1.17 (6H, t, J 7, 2 × CH3).
δC ([D6]DMSO) 151.8, 142.1, 136.3, 135.0, 128.1, 124.6, 122.4,
43.7, 28.6, 22.8, 22.7, 13.6. m/z (EI) 323 (25%, M+•), 243 (93),
99 (100).
3-(4-Chlorobenzyl)-4-piperidin-1-yl-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 6d and
5-(4-Chlorobenzyl)-4-piperidin-1-yl-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 5d
A mixture of compound 3b (141 mg, 0.5 mmol), potas-
sium carbonate (76 mg, 0.55 mmol), 4-chlorobenzyl bromide
(113 mg, 0.55 mmol), tetrabutylammonium bromide (18 mg,
0.055 mmol), and acetonitrile (4 mL) was stirred at room tem-
perature overnight. The solvent was removed under vacuum and
the residue extracted with ethyl acetate (10 mL). The extract
was washed with water (3 × 5 mL), dried, and evaporated. The
residue was chromatographed over silica gel (0–1% methanol in
dichloromethane) to give two fractions. (i) The title compound
6d (100 mg, 49%). Recrystallized from methanol; colourless
crystals, mp 86.5–87.5◦C. (Found: C 56.1, H 5.0, N 10.2; M+•
405.0909. C19H20ClN3O3S requires C 56.2, H 5.0, N 10.4%;
M+• 405.0908). δH 7.23 (1H, d, J 8, ArH), 7.17 (1H, t, J 7.8,
ArH), 7.14 (2H, d, J 8.3,ArH), 7.05 (1H, t, J 7.4,ArH), 6.93 (2H,
d, J 8.3, ArH), 6.85 (1H, d, J 7.7, ArH), 4.21 (2H, s, CH2Ar),
3.49 (4H, br, 2 × NCH2), 1.9–1.1 (6H, br, 3 × CH2). δC 146.5,
140.8, 134.7, 132.3, 130.5, 128.7, 127.9, 125.5, 124.1, 122.0,
54.8, 47.1, 25.5, 24.2. m/z (EI) 405/407 (58/18%, M+•), 280
(22), 258 (62), 125 (100). (ii) The title compound 5d (64 mg,
32%). Recrystallized from dichloromethane/methanol; colour-
less crystals, mp 274–275◦C. (Found: C 56.3, H 5.0, N 10.4; M+•
405.0920. C19H20ClN3O3S requires C 56.2, H 5.0, N 10.4%;
5-Acetyl-4-piperidin-1-yl-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 5a
A stirred mixture of compound 3b (281 mg, 1.0 mmol), acetic
anhydride (1 mL), and pyridine (4 drops) was heated at 120◦C for
15 min. The mixture was cooled and diluted with water (10 mL)
and allowed to stand at room temperature for 1 h. The precipitate
was collected and washed with water followed by ether. Recrys-
tallization from ethanol (charcoal) gave the title compound
(250 mg, 77%) as colourless crystals, mp 165–166◦C. (Found:
C 52.0, H 5.2, N 13.2; M+• 323.0935. C14H17N3O4S requires
C 52.0, H 5.3, N 13.0%; M+• 323.0934). δH (200 MHz) 7.53–
7.43 (1H, m, ArH), 7.34–7.24 (3H, m, ArH), 3.97–3.70 (2H, m,
CH2N), 3.68–3.60 (2H, m, CH2N), 2.01 (3H, s, CH3CO), 1.97–
1.50 (6H, m, CH2CH2CH2). δC (50 MHz) 169.1, 151.9, 147.4,
131.6, 129.4, 127.5, 126.3, 122.4, 48.8, 47.9, 25.9, 24.9, 23.6,
22.2. m/z (EI) 323 (11%, M+•), 281 (65), 84 (100).
5-Acetyl-4-dimethylamino-2,2-dioxo-7-methyl-2λ6-
[1,2,3,5]benzoxathiadiazepine 5b
A stirred mixture of compound 3d (256 mg, 1.0 mmol), acetic
anhydride (1 mL), and pyridine (0.5 mL) was heated at 120◦C for
30 min. The mixture was cooled and allowed to stand at room
temperature for 1 h. The precipitate was collected and washed
with water followed by ether. Recrystallization from ethanol
(charcoal) gave the title compound (229 mg, 77%) as colour-
less crystals, mp 208.5–209◦C. (Found: C 48.6, H 5.1, N 14.3;
M
+• 405.0908). δH (CDCl3, 200 MHz) 7.24–7.09 (8H, m, ArH),
4.72 (2H, s, CH2Ar), 3.59 (4H, br m, 2 × NCH2), 1.73 (6H, br
s, 3 × CH2). δC (CDCl3 + 3 drops CD3OD, 100 MHz) 156.6,
147.2, 134.4, 133.7, 132.5, 130.0, 129.7, 128.7, 126.7, 126.2,
123.0, 57.9, 49.7, 25.5, 23.9. m/z (EI) 405/407 (9/4%, M+•),
325 (4), 280 (8), 258 (20), 125 (100).
M
+• 297.0773. C12H15N3O4S requires C 48.5, H 5.1, N 14.1%;
M+• 297.0778). δH ([D6]DMSO, 500 MHz, 50◦C) 7.59 (1H, br
s, ArH), 7.36 (1H, d, J 8.3, ArH), 7.24 (1H, d, J 8.3, ArH), 3.26
(3H, s, NCH3), 3.16 (3H, s, NCH3), 2.35 (3H, s, ArCH3), 1.97
(3H, br s, CH3CO). δC ([D6]DMSO, 125.75 MHz, 50◦C, NMe2
signals obscured by solvent at 20◦C) 168.4, 152.8, 144.1, 136.4,
131.8, 130.5, 127.4, 121.0, 38.8, 38.6, 21.7, 19.9. m/z (EI) 297
(10%, M+•), 255 (100).
1-N-(4-Chlorobenzyl)-1,2-diaminobenzene 7d
Prepared by modification of literature procedures.[13,14] Thus,
a mixture of 2-nitrochlorobenzene (3.15 g, 20 mmol) and
4-chlorobenzylamine (7.08 g, 50 mmol) was heated at 100◦C
for 19 h. Upon cooling, the mixture solidified. The solid was
pulverized and washed twice with 10% aqueous citric acid solu-
tion, and then washed copiously with water. The resulting solid
was dried to give N-(4-chlorobenzyl)-2-nitroaniline (3.82 g,
73%) as a bright orange solid, mp 109–111◦C (lit.[14] 110◦C). δH
8.41 (1H, br, NH), 8.20 (1H, dd, J 8.6, 1.3, ArH), 7.41–7.25 (5H,
m, ArH), 6.75 (1H, d, J 8.6, ArH), 6.68 (1H, m, ArH), 4.53 (2H,
s, CH2). A stirred mixture of N-(4-chlorobenzyl)-2-nitroaniline
(1.30 g, 4.98 mmol), iron powder (1.38 g, 24.7 mmol), ammo-
nium chloride (0.13 g), ethanol (34 mL), and water (17 mL) was
5-Benzoyl-4-piperidin-1-yl-2,2-dioxo-2λ6-
[1,2,3,5]benzoxathiadiazepine 5c
Benzoyl chloride (0.8 mL) was added slowly to a stirred solu-
tion of compound 3b (281 mg, 1 mmol) in pyridine (1.5 mL).
The resulting solution was stirred at room temperature for
90 min. Water (20 mL) was cautiously added and the mixture
was extracted with dichloromethane (20 mL). The extract was

792
T. Cablewski et al.
heated at 90–100◦C for 40 min. The mixture was cooled and fil-
tered, and the collected solids were washed with ethyl acetate.
The filtrates were combined and concentrated. The residue was
extracted with dichloromethane and the extract was washed with
brine, dried, and evaporated. The residue was chromatographed
over silica gel. Elution with dichloromethane afforded the title
compound (1.04 g, 90%) as a fawn solid, which was used without
further purification. δH 7.35–7.25 (4H, m, ArH), 6.84–6.72 (3H,
m, ArH), 6.65 (1H, d, J 7.6, ArH), 4.31 (2H, s, CH2) 3.94 (3H,
br, NH2 + NH). m/z (ES−) 231/233 (10/4%, M − H), 125/127
(36/12), 106 (100).
244/246/248 (78/50/9), 229/231/233 (73/47/8), 201/203/205
(100/64/10).
7,8-Dichloro-4-diethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8d
Precipitated as a light grey solid in 14% yield. A sample was
recrystallized from ethanol (charcoal) to give white crystals, mp
232–233◦C. (Found: C 39.4, H 4.2, N 16.5; M+• 336.0202.
C11H14Cl2N4O2S requires C 39.2, H 4.2, N 16.6%; M+•
336.0209). δH ([D6]DMSO) 9.32 (1H, s, NH), 9.25 (1H, s, NH),
7.47 (1H, s,ArH), 7.20 (1H, s,ArH), 3.50 (4H, q, J 7, 2 × NCH2),
1.16 (6H, t, J 7, 2 × CH3). δC ([D6]DMSO) 151.6, 134.3, 132.0,
127.9, 126.0, 125.6, 123.9, 43.5, 13.7. m/z (EI) 336/338/340
(38/25/6%, M+•), 272/274/276 (10/6/1), 257/259/261 (12/8/1),
243/245/247 (22/14/3), 228/230/232 (14/9/3), 214/216/218
(15/10/2), 201/203/205 (80/50/8), 72 (100).
General Synthesis Procedure for 4-Dialkylamino-2,2-dioxo-
2λ6-[2,1,3,5]benzothiatriazepines 8a–h and 9h
N,N-Diisopropylethylamine (13 mmol) was added to an ice-
water cooled, stirred mixture of the 1,2-diaminobenzene 7
(5 mmol), the dichloro compound 1 (6.5 mmol), and DMPU
(4 mL). The mixture was stirred at room temperature for at
least 4 h. Ethyl acetate (15 mL) was added, followed by water
(30 mL), and the mixture stirred vigorously for a few minutes.
The whole was acidified to pH 3 with concentrated hydrochlo-
ric acid and the resulting mixture stirred vigorously at room
temperature for at least 1 h. The precipitate was collected by fil-
tration and washed sequentially with water, ethyl acetate, and
diethyl ether.
7,8-Dimethyl-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8e
Precipitated as an off-white solid in 52% yield. A sample was
recrystallized from methanol to give colourless crystals, mp
247–249◦C (dec.). (Found: C 49.2, H 6.0, N 21.1; M+• 268.0991.
C11H16N4O2S requires C 49.2, H 6.0, N 20.9%; M+• 268.0988).
δH ([D6]DMSO) 9.11 (1H, s, NH), 8.75 (1H, s, NH), 6.91 (1H, s,
ArH), 6.77 (1H, s,ArH), 3.06 (6H, s, NMe2), 2.143 (3H, s, CH3),
2.137 (3H, s, CH3). δC ([D6]DMSO) 152.5, 134.2, 132.8, 131.1,
129.8, 124.74, 124.68, 38.6, 19.2, 19.1. m/z (EI) 268 (100%,
The following compounds were prepared by the above
procedure.
M
+•).
4-Dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8a
4-Diethylamino-7,8-dimethyl-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8f
Precipitated as a white solid in 55% yield. A sample was
recrystallized from methanol to give colourless +c•rystals, mp
239–240◦C. (Found: C 45.3, H 5.0, N 23.5; M 240.0673.
C9H12N4O2S requires C 45.0, H 5.0, N 23.3%; M+• 240.0675).
δH ([D6]DMSO) 9.25 (1H, s, NH), 8.96 (1H, s, NH), 7.16–7.06
(3H, m,ArH), 7.01 (1H, dd, J 7.5, 1.8,ArH), 3.09 (6H, s, NMe2).
δC ([D6]DMSO) 152.7, 133.7, 132.2, 126.2, 124.8, 124.0, 123.7,
38.7. m/z (EI) 240 (100%, M+•).
Precipitated as a beige solid in 52% yield after addition of diethyl
ether (5 mL). A sample was recrystallized from ethyl acetate to
givecolourlesscrystals, mp226–228.5◦C. (Found:C52.7, H7.1,
N 19.2; M+• 296.1297. C13H20N4O2S requires C 52.7, H 6.8,
N 18.9%; M+• 296.1301). δH ([D6]DMSO) 9.09 (1H, s, NH),
8.70 (1H, s, NH), 6.92 (1H, s, ArH), 6.80 (1H, s, ArH), 3.48
(4H, q, J 7, 2 × NCH2), 2.16 (3H, s, CH3), 2.15 (3H, s, CH3),
1.15 (6H, t, J 7, 2 × CH3). δC ([D6]DMSO) 151.6, 134.5, 132.8,
131.6, 130.1, 124.89, 124.85, 43.2, 19.2, 19.1, 13.8. m/z (EI) 296
(97%, M+•), 232 (31), 217 (34), 203 (54), 188 (28), 174 (26),
161 (100).
2,2-Dioxo-4-piperidin-1-yl-2λ6-
[2,1,3,5]benzothiatriazepine 8b
Precipitated as an off-white solid in 33% yield. A sample
was recrystallized from ethanol to give colourless crystals, mp
233.5–234.5◦C. (Found: C 51.6, H 5.8, N 20.1; M+• 280.0980.
C12H16N4O2S requires C 51.4, H 5.8, N 20.0%; M+• 280.0988).
δH ([D6]DMSO) 9.41 (1H, s, NH), 8.99 (1H, s, NH), 7.15–7.05
(3H, m,ArH), 7.03–6.99 (1H, m,ArH), 3.59 (4H, m, 2 × NCH2),
1.65–1.50 (6H, m, 3 × CH2). δC ([D6]DMSO) 151.7, 133.8,
132.0, 126.3, 124.7, 123.9, 123.6, 47.3, 25.9, 24.1. m/z (EI) 280
(36%, M+•), 216 (16), 201 (14), 133 (100).
1-(4-Chlorobenzyl)-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8g
Precipitated as a brilliant white solid in 48% yield. A sample
was recrystallized from ethanol to give colourless prisms, mp
205–207◦C. (Found: C 52.9, H 4.8, N 15.5; M+• 364.0751.
C16H17ClN4O2S requires C 52.7, H 4.7, N 15.4%; M+•
364.0755). δH 7.46 (1H, br, NH), 7.19–6.99 (7H, m, ArH), 6.92
(1H, m, ArH), 4.70 (2H, s, CH2), 2.93 (6H, s, NMe2). δC 150.7,
135.3, 134.8, 133.4, 131.4, 130.3, 128.2, 127.8, 127.5, 125.4,
121.8, 54.5, 38.7. m/z (EI) 364/366 (93/57%, M+•), 71 (100).
7,8-Dichloro-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8c
2,2-Dioxo-1-methyl-4-piperidin-1-yl-2λ6-
[2,1,3,5]benzothiatriazepine 8h and
2,2-Dioxo-5-methyl-4-piperidin-1-yl-2λ6-
[2,1,3,5]benzothiatriazepine 9h
Precipitated as an off-white solid in 66% yield. A sample was
recrystallized from methanol/DMF (1:1) to give small, white,
woolly needles, mp 265–267◦C (dec.). (Found: C 35.0, H 3.3,
N 18.2; M+• 307.9894. C9H10Cl2N4O2S requires C 35.0, H 3.3,
N 18.1%; M+• 307.9896). δH ([D6]DMSO) 9.34 (1H, s, NH),
9.31 (1H, s, NH), 7.47 (1H, s,ArH), 7.16 (1H, s,ArH), 3.09 (6H,
s, NMe2). δC ([D6]DMSO) 151.9, 133.1, 131.3, 126.9, 125.4,
124.6, 123.2, 38.4. m/z (EI) 308/310/312 (90/62/13%, M+•),
No precipitate was obtained initially. The aqueous layer was
replaced with fresh water and the resulting mixture stirred vig-
orously for a further hour, and left to stand overnight. The
resultant crystals were collected and washed with water and

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part VII
793
ethyl acetate to afford the title compound 8h (43%) as light
grey crystals, mp 127–130◦C. (Found: C 50.2, H 6.5, N 18.2;
M+• 294.1145. C13H18N4O2S.H2O requires C 50.0, H 6.5,
N 17.9%; M+• 294.1145). δH 8.66 (1H, br, NH), 7.22–7.03
(4H, m, ArH), 3.56 (4H, m, 2 × NCH2), 3.18 (3H, s, NCH3),
1.56 (6H, m, 3 CH2). δC ([D6]DMSO) 152.3, 138.5, 133.3,
126.9, 125.3, 124.1, 122.5, 47.3, 35.2, 25.9, 23.9. m/z (EI) 294
(56%, M+•), 230 (42), 215 (86), 147 (100). The organic phase
of the mother liquor was washed with brine, dried, and evapo-
rated. The residue was chromatographed over silica gel. Elution
with 0–5% methanol in dichloromethane, followed by recrystal-
lization from chloroform afforded the title compound 9h (2%)
as white crystals, mp 173.5–174.5◦C. (Found: C 52.4, H 6.1,
N 19.1; M+• 294.1142. C13H18N4O2S requires C 53.0, H 6.2,
N 19.0%; M+• 294.1145). δH 7.31–7.26 (1H, m,ArH), 7.21–7.15
(3H, m, ArH), 6.50 (1H, br, NH), 3.53 (4H, m, 2 × NCH2), 3.30
(3H, s, NCH3), 1.69 (6H, m, 3 CH2). δC 158.0, 137.3, 135.4,
129.0, 126.3, 126.1, 124.5, 49.3, 43.1, 25.6, 24.1. m/z (EI) 294
(5%, M+•), 215 (90), 186 (100).
3-(4-Chlorobenzyl)-4-piperidin-1-yl-2,2-dioxo-1-methyl-
2λ6-[2,1,3,5]benzothiatriazepine 10c and
5-(4-Chlorobenzyl)-4-piperidin-1-yl-2,2-dioxo-1-methyl-
2λ6-[2,1,3,5]benzothiatriazepine 11c
A mixture of compound 8h (294 mg, 1.0 mmol), potassium car-
bonate (152 mg, 1.1 mmol), 4-chlorobenzyl bromide (226 mg,
1.1 mmol), tetrabutylammonium bromide (35 mg, 0.11 mmol),
and acetonitrile (2 mL) was stirred at room temperature for
20 h. The mixture was partitioned between dichloromethane
(12 mL) and water (6 mL). The aqueous phase was extracted
with dichloromethane (10 mL). The extracts were combined,
washed with brine, dried, and evaporated. The residual gum
was chromatographed over silica gel (0–2% methanol in
dichloromethane) to give two fractions. (i) The title compound
10c (293 mg, 70%) as a viscous, colourless gum. (Found: C 57.1,
H 5.4, N 13.4; M+• 418.1223. C20H23ClN4O2S requires C 57.3,
H 5.5, N 13.4%; M+• 418.1225). δH 7.30 (1H, d, J 7.8, ArH),
7.17 (1H, t, J 7.6, ArH), 7.10 (2H, d, J 8.2, ArH), 7.06 (1H, t,
J 7.6, ArH), 6.90 (2H, d, J 8.2, ArH), 6.83 (1H, d, J 7.8, ArH),
4.11 (2H, s, CH2Ar), 3.47 (4H, br m, 2 × NCH2), 3.22 (3H, s,
NCH3), 1.64–1.34 (6H, br m, 3 × CH2). δC 147.0, 144.5, 134.1,
133.1, 131.5, 130.4, 128.4, 128.1, 125.6, 124.8, 123.6, 53.3, 46.9,
37.2, 25.7, 24.3. m/z (EI) 418/420 (34/12%, M+•), 293 (17), 270
(44), 229 (76), 200 (60), 125 (100). (ii) The title compound 11c
(77 mg, 18%). A sample was recrystallized from ethanol to give
colourless crystals, mp 226–227◦C. (Found: C 57.4, H 5.6, N
13.2; M+• 418.1219. C20H23ClN4O2S requires C 57.3, H 5.5, N
13.4%; M+• 418.1225). δH 7.27–7.19 (2H, m, ArH), 7.16–7.10
(3H, m, ArH), 7.07 (1H, d, J 8, ArH), 7.02 (2H, d, J 8, ArH),
4.66 (2H, br s, CH2Ar), 3.61 (4H, br s, 2 × NCH2), 2.86 (3H, s,
NCH3), 1.71 (6H, br s, 3 × CH2). δC 157.2, 141.4, 136.0, 134.1,
133.1, 130.4, 129.2, 128.1, 126.2, 125.6, 122.2, 58.0, 49.6, 34.2,
25.7, 24.1. m/z (EI) 418 (2%, M+•), 340 (3), 293 (5), 270 (6),
235/237 (49/14), 229 (6), 200 (30), 125 (100).
3-Acetyl-4-piperidin-1-yl-2,2-dioxo-1-methyl-2λ6-
[2,1,3,5]benzothiatriazepine 10a
A stirred mixture of compound 8h (235 mg, 0.8 mmol), acetic
anhydride (1 mL), and pyridine (4 drops) was heated at 90◦C for
4 h. More pyridine (0.2 mL) was added and the mixture heated at
90◦C for a further 3 h. The mixture was cooled, allowed to stand
at room temperature overnight, and then diluted with diethyl
ether (4 mL) and water (4 mL) and stirred vigorously for 10 min.
The white precipitate was collected and washed with water fol-
lowed by ether to give the title compound (171 mg, 64%) as
a white solid. A sample was recrystallized from methanol to
give colourless crystals, mp 219–221◦C. (Found: C 53.2, H 6.1,
N 16.6; M+• 336.1244. C15H20N4O3S requires C 53.5, H 6.0,
N 16.7%; M+• 336.1251). δH (500 MHz) 7.51–7.45 (1H, m,
ArH), 7.31 (1H, dd, J 8, 0.7,ArH), 7.23–7.17 (2H, m,ArH), 3.96–
3.90 (1H, m, CHN), 3.75–3.57 (3H, m, CHN, CH2N), 3.38 (3H,
s, NMe), 1.96–1.84 (1H, m, CH), 1.92 (3H, s, CH3CO), 1.77–
1.52 (5H, m, CH2CH2CH). δC (125 MHz) 169.1, 151.0, 140.8,
131.7, 131.1, 128.9, 125.2, 121.8, 48.5, 47.7, 35.4, 26.0, 24.9,
23.8, 22.2. m/z (EI) 336 (17%, M+•), 294 (28), 230 (34), 215
(36), 147 (100).
1-Acetyl-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8i
Acetic anhydride (0.1 mL) was added to a stirred mixture of
compound 8a (240 mg, 1 mmol) in pyridine (2 mL). The resul-
tant mixture was stirred at room temperature for 19 h. More
acetic anhydride (0.1 mL) was added and the mixture stirred for
a further 4 h. The mixture was evaporated and the residue stirred
vigorously in a mixture of diethyl ether (4 mL) and water (4 mL).
The resultant white solid was collected and washed with water
followed by ether and dried to give the title compound (194 mg,
69%). A sample was recrystallized from methanol; colourless
crystals, mp 238–240◦C. (Found: C 46.9, H 5.1, N 19.8; M+•
282.0781. C11H14N4O3S requires C 46.8, H 5.0, N 19.9%;
M+• 282.0781). δH ([D6]DMSO) 10.00 (1H, s, NH), 7.39–7.19
(4H, m, ArH), 3.18 (6H, s, NMe2), 2.30 (3H, s, CH3CO). δC
([D6]DMSO) 170.7, 153.9, 135.2, 132.9, 130.5, 128.5, 126.7,
124.8, 39.0, 25.2. m/z (EI) 282 (11%, M+•), 240 (100).
3-Benzoyl-4-piperidin-1-yl-2,2-dioxo-1-methyl-2λ6-
[2,1,3,5]benzothiatriazepine 10b
Benzoyl chloride (0.8 mL) was added slowly to a stirred solu-
tion of compound 8h (295 mg, 1 mmol) in pyridine (1.5 mL).
The resulting solution was stirred at room temperature for
45 min. Water (20 mL) was added cautiously and the mixture
was extracted with dichloromethane (20 mL). The extract was
washed twice with water, dried, and evaporated. The residue was
triturated with cyclohexane/n-hexane (1:1) to give a white solid,
which was chromatographed over silica gel (0–1% methanol in
dichloromethane) to give the title compound (150 mg, 38%).
A sample was recrystallized from dichloromethane/methanol to
give colourless crystals, mp 144–145◦C. (Found: C 60.4, H 5.6,
N 14.1; M+• 398.1404. C20H22N4O3S requires C 60.3, H 5.6,
N 14.1%; M+• 398.1407). δH 7.54–7.48 (3H, m,ArH), 7.46–7.41
(2H, m, ArH), 7.40–7.34 (2H, m, ArH), 7.27 (1H, d, J 8.8, ArH),
7.16 (1H, t, J 7.5, ArH), 3.66 (4H, br, 2 × CH2N), 3.21 (3H,
s, NMe), 1.52 (6H, br, CH2CH2CH2). δC 168.5, 144.8, 144.4,
132.9, 131.0, 130.4, 129.0, 128.3, 128.2, 124.7, 124.2, 47.2,
39.0, 25.6, 24.1. m/z (EI) 398 (22%, M+•), 293 (10), 105 (100).
1-Benzoyl-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8j
Benzoyl chloride (1.6 mL) was added slowly to a stirred solution
of compound 8a (240 mg, 1 mmol) in pyridine (3 mL). The solu-
tion was stirred at room temperature for 45 min. Water (20 mL)
was cautiously added and the mixture was extracted twice with
dichloromethane. The extracts were combined, washed with
saturated, aqueous sodium bicarbonate solution, followed by
water, dried, and evaporated. The residue was chromatographed

794
T. Cablewski et al.
over silica gel (2–3% methanol in dichloromethane) to give
the title compound (164 mg, 49%) as a white solid, mp
265–266◦C. (Found: C 55.8, H 4.7, N 16.3; M+• 344.0939.
C16H16N4O3S requires C 55.8, H 4.7, N 16.3%; M+• 344.0938).
δH ([D6]DMSO) 10.46 (1H, s, NH), 7.41–7.19 (7H, m, ArH),
7.11–7.01 (1H, m, ArH), 6.99–6.91 (1H, m, ArH), 3.27 (6H,
s, NMe2). δC ([D6]DMSO) 169.7, 154.6, 135.7, 135.0, 134.3,
131.9, 129.7, 129.0, 128.53, 128.47, 127.1, 124.8 (NMe2 signal
obscured by solvent resonances). δC (CD3OD + 3 drops CDCl3)
172.0, 156.4, 136.3, 135.8, 135.4, 132.9, 130.7, 130.1, 129.8,
129.2, 128.3, 125.3, 39.4. m/z (EI) 344 (9%, M+•), 105 (100).
Recrystallization from acetonitrile provided solvated crystals
suitable for X-ray crystallographic analysis.
130.4, 129.6, 129.0, 128.9, 128.61, 128.57, 127.7, 124.92, 123.9,
54.2, 53.7, 38.4. m/z (EI) 488/490/492 (100/88/17%, M+•).
(ii) The title compound 13 (5 mg, 2%) as a colourless gum. δH
7.25–7.21 (2H, m, ArH), 7.19–7.12 (5H, m, ArH), 7.11–7.02
(5H, m, ArH), 4.68 (2H, s, CH2), 4.43 (2H, br s, CH2), 3.11
(6H, s, NMe2). m/z (APCI+) 511/513 (22/17%, [M + Na]+•),
489/491/493 (100/75/16%, [M + H]+•). (iii)The title compound
8g (8 mg, 4%).
Method B
A mixture of compound 8a (120 mg, 0.5 mmol), potas-
sium carbonate (76 mg, 0.55 mmol), 4-chlorobenzyl bromide
(113 mg, 0.55 mmol), tetrabutylammonium bromide (18 mg,
0.055 mmol), and DMF (3 mL) was stirred at room tempera-
ture for 26 h. The mixture was partitioned between ethyl acetate
(10 mL) and water (5 mL). The organic layer was washed four
times with water, followed by brine, dried, and evaporated. The
residual was chromatographed over silica gel as for Method
A above, to afford four fractions. (i) The title compound 12
(88 mg, 36%); (ii) the title compound 13 (5 mg, 2%); (iii) the
title compound 9g (7 mg, 4%), recrystallized from methanol
to give white crystals, mp 176–177◦C. (Found: M+• 364.0752.
C16H17ClN4O2S requires M+• 364.0755). δH 7.23–7.13 (7H, m,
ArH), 7.02–6.99 (1H, m, ArH), 5.94 (1H, br, NH), 4.71 (2H, s,
CH2), 3.14 (6H, s, NMe2). δC 157.9, 136.2, 135.7, 134.4, 133.1,
130.3, 129.2, 128.6, 126.7, 126.3, 124.9, 58.1, 40.0. m/z (EI)
364/366 (1/0.5%, M+•), 285/287 (32/9), 160 (100). (iv) The title
compound 8g (15 mg, 8%).
4-Dimethylamino-2,2-dioxo-2λ6-[2,1,3,5]
benzothiatriazepine-1-carboxylic Acid p-Tolylamide 8k
A mixture of compound 8a (240 mg, 1 mmol), p-tolyl iso-
cyanate (0.14 mL, 1.1 mmol), triethylamine (2 drops), and
dichloromethane (3 mL) was stirred at room temperature for
2 days. More p-tolyl isocyanate (0.1 mL) and triethylamine
(1 drop) were added and the mixture was stirred at room tempera-
ture for 7 days.The mixture was partitioned between chloroform
and water. The aqueous phase was extracted with chloroform.
The organic phases were combined, washed with saturated, aque-
ous sodium chloride solution, dried, and evaporated. The residue
was recrystallized from methanol to give the title compound
(284 mg, 76%) as colourless crystals, mp 205–206◦C. (Found:
C 54.8, H 5.1, N 18.8; M+• 373.1201. C17H19N5O3S requires
C 54.7, H 5.1, N 18.8%; M+• 373.1203). δH 9.74 (1H, s, NH),
8.09 (1H, s, NH), 7.45–7.37 (3H, m, ArH), 7.28–7.23 (1H, m,
ArH), 7.19–7.13 (3H, m, ArH), 6.81 (1H, d, J 7.6, ArH), 2.99
(6H, s, NMe2), 2.34 (3H, s, CH3). δC 152.2, 152.0, 135.4, 134.8,
134.2, 130.4, 129.6, 128.8, 126.3, 123.3, 120.6, 38.8, 20.8. m/z
(EI) 373 (2%, M+•), 240 (42), 133 (100).
Method C
A suspension of compound 8a (240 mg, 1.0 mmol) in THF
(4 mL) and DMF (1 mL) was added to a stirred suspension of
sodium hydride (60% dispersion in oil, 44 mg, 1.1 mmol) in
THF (2 mL) under a nitrogen atmosphere. After the evolution
of hydrogen gas had ceased, 4-chlorobenzyl bromide (210 mg,
1.0 mmol) in THF (2 mL) was added and the mixture stirred at
room temperature for 21 h. A little water was added carefully
and the mixture was neutralized with dilute hydrochloric acid.
The whole was extracted twice with ethyl acetate. The extracts
were combined and washed with water (twice) followed by brine,
dried, and evaporated. The residual gum was chromatographed
over silica gel (0–2% methanol in dichloromethane), to afford
four fractions. (i) The title compound 12 (110 mg, 23%); (ii) the
title compound 13 (11 mg, 3%); (iii) the title compound 9g
(19 mg, 5%); and (iv) the title compound 8g (111 mg, 31%).
1-(4-Chlorobenzyl)-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 8g,
5-(4-Chlorobenzyl)-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 9g,
1,3-Bis(4-Chlorobenzyl)-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 12, and
1,5-Bis(4-Chlorobenzyl)-4-dimethylamino-2,2-dioxo-2λ6-
[2,1,3,5]benzothiatriazepine 13
Method A
A solution of 4-chlorobenzyl bromide (113 mg, 0.55 mmol)
in dichloromethane (1.5 mL) was added to a stirred solution
of compound 8a (120 mg, 0.5 mmol) and sodium hydro-
xide (30 mg) in water (0.8 mL). Tetrabutylammonium bromide
(18 mg, 0.055 mmol) was added and the mixture was stirred
vigorously at room temperature for 21 h. The mixture was
partitioned between ethyl acetate (10 mL) and water (5 mL)
and filtered. The organic phase of the filtrate was washed with
water, followed by brine, dried, and evaporated. The residue
was chromatographed over silica gel (0–10% methanol in
dichloromethane) to give three fractions. (i) The title compound
12 (100 mg, 41%) as a colourless solid. A sample was recrys-
tallized from methanol, mp 151–153◦C. (Found: C 56.2, H 4.8,
N 11.3; M+• 488.0814. C23H22Cl2N4O2S requires C 56.4, H 4.5,
N 11.5%; M+• 488.0835). δH 7.20–7.09 (6H, m, ArH), 7.06–
7.02 (2H, m, ArH), 7.00–6.94 (1H, m, ArH), 6.94–6.90 (2H, m,
ArH), 6.85–6.81 (1H, m,ArH), 4.68 (2H, s, CH2), 4.12 (2H, br s,
CH2), 2.95 (6H, s, NMe2). δC 148.1, 134.6, 134.4, 133.7, 132.9,
X-Ray Crystallography
Single crystals suitable for X-ray analysis were covered in vis-
cous oil and mounted on a glass fibre. Data (2θmax 55◦) were
collected at 123(1) K using a Nonius KAPPA CCD system and
MoKα (λ 0.71073 Å) radiation. After integration and scaling,
datasets (Ntotal) were merged to N unique reflections (Rint as
quoted) with Nobs considered ‘observed’ with I > 2σ(I). The
structures were solved using conventional methods and refined
by full matrix least-squares using the SHELX-97 software,[15] in
conjunction with the X-Seed interface.[16] Non-hydrogen atoms
were refined with anisotropic thermal parameters and hydrogen
atoms were placed in calculated positions. Data were corrected
for absorption using SORTAV.[17] Crystals of 6d have two inde-
pendent molecules in the unit cell. Both molecules are essentially
identical, differing only in the relative rotation of the pendant
piperidinyl ring. For structures 8g and 8k, the Flack parameter

N,N-Dialkyl-Nꢀ-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part VII
795

796
T. Cablewski et al.
xabs was refined (see Table 7). CCDC 689972–689978 con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.CCDC.cam.ac.uk/data_
request/cif.
[7] T. Cablewski, C. L. Francis, A. J. Liepa, Aust. J. Chem. 2008, 61, 332.
doi:10.1071/CH08059
[8] T. Cablewski, C. L. Francis, A. J. Liepa, Aust. J. Chem. 2007, 60, 113.
doi:10.1071/CH06368
[9] Y. Sato, M. Yamada, S. Yoshida, T. Soneda, M. Ishikawa, T. Nizato,
K. Suzuki, F. Konno, J. Med. Chem. 1998, 41, 3015. doi:10.1021/
JM9801004
[10] A. I. Khalaf, R. G. Alvarez, C. J. Suckling, R. D. Waigh, Tetrahedron
2000, 56, 8567. doi:10.1016/S0040-4020(00)00802-4
[11] E. Otto, W. Dürckheimer, R. Muschaweck, (Hoechst A. G.), German
Pat. DE 2409355 1975 [Chem. Abstr. 1976, 84, 59606q].
[12] N. Murai, M. Komatsu, Y. Ohshiro, T. Agawa, Chem. Lett. 1976, 5,
1379. doi:10.1246/CL.1976.1379
[13] C. Kus¸, H. Göker, G.Ayhan, R. Ertan, N.Altanlar,A.Akin, Il Farmaco
1996, 51, 413.
[14] A. G. Schering, British Pat. GB 1954, 703, 272 [Chem. Abstr. 1955,
49, 1816].
[15] G. M. Sheldrick, SHELX-97: Program for Crystal Structure Solution
and Refinement 1997 (Universität Göttingen: Göttingen).
[16] L. J. Barbour, J. Supramol. Chem. 2001, 1, 189. doi:10.1016/S1472-
7862(02)00030-8
[17] R. H. Blessing, J. Appl. Cryst. 1997, 30, 421. doi:10.1107/
S0021889896014628
Acknowledgements
We thank Dr Roger Mulder and Dr Jo Cosgriff for assistance with NMR
spectroscopy, and Mr Carl Braybrook for assistance with mass spectrometry.
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