A novel, flexible strategy to construct privileged dibenzo[b,f][1,4,5]oxathiazepine 5,5-dioxides and their heterocyclic isosteres

Article abstract of DOI:10.1016/j.tet.2016.10.008

Secondary o-hydroxybenzene sulfonamides have been explored as bis-electrophilic partners in a practically simple, atom-economical approach to dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxides and their heterocyclic analogs, which is an underexplored version o

Full text of DOI:10.1016/j.tet.2016.10.008

Accepted Manuscript
A novel, flexible strategy to construct privileged dibenzo[b,f][1,4,5]oxathiazepine 5,5-
dioxides and their heterocyclic isosteres
Alexander Sapegin, Valeria Panova, Elena Reutskaya, Alexey V. Smirnov, Mikhail
Krasavin
PII:
S0040-4020(16)31018-3
10.1016/j.tet.2016.10.008
TET 28149
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 August 2016
Revised Date: 21 September 2016
Accepted Date: 4 October 2016
Please cite this article as: Sapegin A, Panova V, Reutskaya E, Smirnov AV, Krasavin M, A novel, flexible
strategy to construct privileged dibenzo[b,f][1,4,5]oxathiazepine 5,5-dioxides and their heterocyclic
isosteres, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.008.
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ACCEPTED MANUSCRIPT
A
novel,
flexible
strategy
to
construct
privileged
dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxides and their heterocyclic
isosteres
Alexander Sapegin, Valeria Panova, Elena Reutskaya, Alexey V. Smirnov, Mikhail Krasavin*
1

ACCEPTED MANUSCRIPT
A
novel,
flexible
strategy
to
construct
privileged
dibenzo[b,f][1,4,5]oxathiazepine 5,5-dioxides and their heterocyclic
isosteres
Alexander Sapegin,a Valeria Panova,b Elena Reutskaya,b Alexey V. Smirnov,b Mikhail
Krasavina,*
aInstitute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof,
198504 Russian Federation
bThe Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl,
150000, Russian Federation
* Corresponding Author; phone: + 7 931 3617872, fax: +7 812 428 6939.
E-mail: m.krasavin@spbu.ru
URL: http://krasavin-group.org
Keywords: privileged structures, tricyclic scaffolds, ring-forming process, bis-nucleophiles, bis-
electrophiles, aromatic nucleophilic substitution, Smiles rearrangement.
ABSTRACT
Secondary o-hydroxybenzene sulfonamides have been explored as bis-electrophilic partners in a
practically simple, atom-economical approach to dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxides
and their heterocyclic analogs, which is an underexplored version of privileged tricyclic
scaffolds for drug design. The reaction proceeds smoothly and regiospecifically under
conventional heating conditions and delivers the target compounds in good to excellent yields.
The
approach
represents
a
completely
new
disconnection
of
the
dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxide scaffolds and allows accessing a new chemical
space in terms of the substitution pattern. In particular, heterocycles can be conveniently varied
within the tricyclic frameworks by altering the nature of the bis-electrophilic aromatic partner in
the cyclization. This has been demonstrated by the synthesis of three hitherto uundescribed
heterotricyclic scaffolds. The cyclizations were shown to proceed via the Smiles rearrangement,
as had been observed by us for a range of similar ring-forming processes.
2

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1. Introduction
Tricyclic scaffolds (such as 1) consisting of a seven-membered heterocycle fused to two
aromatic or heteroaromatic groups are privileged1-2 from drug design perspective as they have
delivered numerous high-affinity ligands in the central nervous system3 target area as well of
other therapeutically relevant biotargets (Figure 1).4
Figure 1. Privileged tricycles for the drug design.
Recently, we have developed a general strategy to constructing such scaffolds that involves the
use of phenols 2 containing a second moderately acidic functionality in ortho-position, which
can react, under basic conditions with bis-electrophilic aromatic and heteroaromatic partners 3.
The process essentially consists of two SNAr events intermitted, without exception, by a Smiles
rearrangement.5-8 We have shown that the process is triggered by displacement of the most labile
leaving group in 3 by the phenoxide anion and cannot be completed before phenoxide anion is
liberated again, via the Smile rearrangement, for the substitution of the other less labile leaving
group. Thus, the intricate interplay of intramolecular events with nucleophile switch creates an
energetically favorable path for the reaction and enables efficient overall ring closing process, in
which some of the individual elementary steps would be impossible to realize in practice. The
strategy has been realized for such Y-ZH motifs as secondary amides,5 pyrazoles,6-7
imidazolines.8 In this work we investigated a possible involvement of secondary sulfonamide
groups that are isosteric to the secondary amides employed earlier (Scheme 1).
Scheme 1. Synthetic strategy toward tricycles 1 described by us earlier and pursued in this work.
3

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Dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxide scaffold 4, which was expected to result from
realization of such a methodology, is largely underrepresented in the medicinal chemistry
literature (except for a few isolated reports on its employment in the design of antiviral,9-10
antipsychotic,11-12 and histone deacetylase inhibitory13 compounds). Such a void in the
bioannotated chemistry space could be due to the absence of reliable and flexible methods to
construct 4. Besides some early reports on electrophilic aromatic cyclization of sulfonyl nitrenes
(where compounds containing scaffold 4 were only a part of the total product distribution),14-15
the literature examples of constructing 4 are limited to reactions of 2-halobenzenesulfonyl
chlorides with o-aminophenols which involves amino group acylation in the latter followed by
intramolecular diphenyl ether formation.16-18 The alternative disconnection pursued in this work
provides access to a vastly different chemical space, including heterocyclic version of the C ring
(Figure 2); herein, we present our results in this area.
Figure 2. Comparison of two alternative disconnections of scaffold 4.
2. Results and discussion
A set of four 2-hydroxybenzenesulfonamides 5a-d was prepared from 4-chloroanisol and 4-
fluoroanisol by regiospecific sulfochlorination at position 3 to deliver sulfonyl chlorides 6a-b
both of which are also available commercially. These reagents were reacted with a set of primary
amines (MeNH2, EtNH2, i-PrNH2, cyclo-PrNH2) to give sulfonamides 7a-d, all of which are
expensive commercially available compounds and one (7a) is described in the literature.19
Cleavage of the methyl ether group in 7a-d was achieved with BBr3 and the respective phenols
5a-d were obtained in good yields and purity after a simple reaction workup (Scheme 2).
Scheme 2. Preparation of 2-hydroxybenzenesulfonamides 5a-d.
4

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In order to test the applicability of synthons 5a-d in the formation of
dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxide scaffold 4, we investigated a model reaction of 5a
with 1-chloro-2,4-dinitrobenzene under different conditions including variation of the base,
solvent and time/temperature regimen (Table 1). In principle, for such a reactive substrate, a
reasonable yield of the resulting tricyclic adduct (8a) was obtained in all cases. However, the
o
best result was achieved with K2CO3 in DMF at 50 C which is in line with the previously
published reports from our group.5-8 Hence, these conditions were adopted for all combinations
of 5a-d with bis-electrophilic aromatic substrates 9 studied herein for the respective ring-forming
reactions leading to 8a-n, with occasional raising of the reaction time and temperature, as was
needed to promote full substrate-to-product conversion for less reactive substrates 9 (Scheme 3).
Table 1. Base, solvent and temperature screening for a model dibenzo[b,f][1,4,5]oxathiazepine-
5,5-dioxide formation.
Yield of
8a (%)
51
Experiment
Base
Solvent
T (oC)
Time, h
1
2
3
4
5
6
NaH
DMF
DMF
50
50
3
3
t-BuOK
Na2CO3
K2CO3
K2CO3
K2CO3
58
DMF
100
24
8
74
DMF
50
83
MeCN
Acetone
reflux
reflux
12
36
79
61
Scheme 3. General synthesis of dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxides and their
heterocyclic analogs 8a-n investigated in this work (for exact product and substrate structure see
Table 2).
The results presented in Table 3 lead to several generalizations. All the reactions clearly
represent an efficient way to construct medicinally important compounds 8 which allows
drawing from a broad pool of bis-electrophilic partners 9: 1-halo-2-nitroaromatic and
5

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heteroaromatic (8a-b, 8n), 1,2-dichloroaromatic and heteroaromatic (8c-e, 8g-i, 8k, 8m) and 1,2-
difluoroaromatic (8f, 8j, 8l). The reaction proceeds with a full regioselectivity as only one
positional isomer was obtained in each case. This selectivity was particularly striking for the
reaction leading 8j where the potentially labile fluorine atom in ortho-position of the benzonitrile
moiety is fully preserved and the cyclic product resulting only from the displacement of the
para-fluoro substituent formed.
Table 2. Compounds 8a-n prepared in this work.
Isolated
Time,
Compound
Structure of 8
T, ºC
yield,
%
5
h
8
50
83
76
8a
5a
16
80
8b
5a
14
10
7
75
50
45
73
81
85
8c
8d
8e
5a
5a
5b
24
14
100
75
63
75
8f
5b
5b
8g
6

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10
7
50
45
68
80
62
65
67
8h
8i
5b
5c
5c
5c
5d
16
16
24
80
8j
8k
8l
80
100
16
16
80
80
71
69
8m
8n
5d
5d
We urge the reader not to be surprised at the regioisomer which is formed in this case. One
would expect phenoxide anion formed from 5a-d under the basic reaction conditions to displace
the more labile leaving group in substrates 9 while the less reactive conjugate base of the
secondary sulfonamide would perhaps displace the less prone leaving group to complete the
cyclization. Yet, the regiochemistry of products was quite the opposite as shown in Table 2 and
as was demonstrated by cross-peaks in the NOESY spectra (see Supporting Information) of a
representative set of products (8a-c, Figure 3).
7

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Figure 3. Through-space interactions observed in the NOESY spectra of compounds 8a-c,
confirming their regiochemistry.
Secondary sulfonamide is, in principle, capable of reacting with some of these substrates directly
under similar reaction conditions, as was demonstrated in a control reaction of methyl ether 7a
with 1-chloro-2,4-dinitrobenzene which went to completion albeit under more forcing conditions
than the cyclization of the same substrate with 5a (see Table 1). However, the less reactive 3,4-
difluorobenzonitrile did not convert more than 15% of 7a at 100 ºC over 24 h, i.e. under the
conditions that led to a complete reaction toward product 8f (Scheme 4).
Scheme 4. Control reactions of methyl ether 7a with selected substrates 9.
Therefore, the presence of the free phenol in 5a-d creates a less demanding energy profile for the
reaction which results in an efficient displacement of both leaving groups in 9 (one of them
being in a non-activated position compared to the other) and a ring-forming process delivering
8a-n. As mentioned above, we have demonstrated on several occasions5-8 that such a lower
activation barrier reaction path is initiated by the displacement of the more labile leaving group
in compound 9 by the phenoxide anion derived from the bis-electrophilic phenol partner. The
resulting initial adduct evolved into another phenoxide via a Smiles rearrangement path b (as the
deprotonated sulfonamide is too weak a nucleophile to displace the less labile leaving group via
path a, even intramolecularly) and the phenoxide triggers the final ring-closing SNAr, as shown
for the formation of product 8c in Scheme 5.
8

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Scheme 5. The SNAr1-Smiles rearrangement-SNAr2 reaction path leading to 8c.
Compounds 8a, 8f, 8j, 8l contain privileged tricyclic dibenzo[b,f][1,4,5]oxathiazepine-5,5-
dioxide core 4 described earlier which was assembled following a completely novel
disconnection, alternative to the ones reported.16-18 In contrast, compounds 8b, 8e, 8i-k, 8m-n as
well as compounds 8c, 8g and 8d, 8h are examples of hitherto undescribed (according to the
results of SciFinder search19 summarized in Table 3) tricyclic scaffolds benzo[b]pyrido[2,3-
f][1,4,5]oxathiazepine-10,10-dioxide, benzo[b]pyridazino[4,5-f][1,4,5]oxathiazepin-1-one-6,6-
dioxide and benzo[b]pyrazino[2,3-f][1,4,5]oxathiazepine-6,6-dioxide, respectively.
Table 3. SciFinder novelty analysis for compounds 8a-n reported herein.
Scaffold
(substructure searched)
Representative
compounds
Hits in SciFinder®19
119
Novelty component
Novel substitution
pattern and ring
8a, 8f, 8j, 8l
system disconnection
8b, 8e, 8i-k, 8m-n
0
0
0
Novel ring system
Novel ring system
Novel ring system
8c, 8g
8d, 8h
9

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3. Conclusion
In summary,
we
have
described
a
fundamentally
new
approach
to
dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxides and their heterocyclic analogs which are
representative of a well-known cluster of privileged tricyclic scaffolds. The cyclization of
secondary o-hydroxybenzene sulfonamides with a range of (hetero)aromatic bis-electrophilic
substrates proceeded via a Smiles rearrangement that defined the product regiochemistry. The
approach allows for a flexible variation of substituents in both cyclization partners and for
streamlined
generation
of
hitherto
undescribed
heterocyclic
versions
of
dibenzo[b,f][1,4,5]oxathiazepine-5,5-dioxide scaffold in question. This significantly extends the
boundaries of the privileged tricyclic heterocycle chemistry space compared to the earlier
described approached. Unveiling the medicinal chemistry potential of the newly synthesized
tricycles is underway in our group; the results of these studies will be reported in due course.
4. Experimental
4.1 General considerations
All reactions were run in oven-dried glassware in atmosphere of nitrogen. Melting points were
measured with a Büchi В-520 melting point apparatus and were not corrected. Analytical thin-
layer chromatography was carried out on Silufol UV-254silica gel plates using an appropriate
mixtures of ethyl acetate and hexane. Compounds were visualized with short-wavelength UV
1
light. H NMR and 13C NMR spectra were recorded on Bruker MSL-300 spectrometers in
DMSO-d6 using TMS as an internal standard. Elemental analyses were obtained at Research
Institute for Chemical Crop Protection (Moscow, Russia) using Carlo ErbaStrumentazione 1106
analyzer. IR spectra were recorded on Perkin Elmer Spectrum RX1 FTIR spectrometer. All and
reagents were obtained from commercial sources and used without purification. DMF was dried
o
according to the standard procedure20 and potassium carbonate was dried at 200 C for 5 hours
prior to use.
4.2 General procedure for preparation of compound 6a,b
A solution of the respective anisole (175 mmol) in CH2Cl2 (50 mL) was added dropwise to a 0
ºC chlorosulfonic acid (100 mL) so as to maintain the reaction temperature below 5 ºC. After the
addition was complete, the reaction mixture was stirred for 3 h and poured over ice. The organic
phase was separated, washes with water, dried over anhydrous Na2SO4, filtered and concentrated
10

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in vacuo. The residue was purified by short-path chromatography on silica gel using 10% ethyl
acetate in hexanes as eluent to provide the analytically pure target compound.
4.2.1 4-Chloro-2-methoxybenzene-1-sulfonyl chloride (6a). White solid, (26.9 g, 64%); m.p.
157-160 oC; δH (400 MHz, CDCl3) 7.95 (1H, d, J 2.7 Hz, HAr), 7.64 (1H, dd, J 2.7, 9.0 Hz, HAr),
7.09 (1H, d, J 9.0 Hz, HAr), 4.07 (3H, s, OCH3); δC (100.61 MHz, CDCl3) 155.9, 136.9, 132.5,
129.3, 125.5, 114.6, 57.0.
4.2.2 4-Fluoro-2-methoxybenzene-1-sulfonyl chloride (6b). White solid, (27.4 g, 70%); m.p. 76-
79 oC; δH (400 MHz, CDCl3) 7.66 (1H, dd, J 3.9, 7.3 Hz, HAr), 7.37-7.46 (1H, m, HAr), 7.15 (1H,
dd, J 3.9, 9.3 Hz, HAr), 4.04 (3H, s, OCH3); δC NMR (100.61 MHz, DMSO-d6) 155.1 (d, J 245.0
Hz), 153.7 (d, J 2.9 Hz), 131.9 (d, J 7.4 Hz), 124.0 (d, J 22.8 Hz), 116.5 (d, J 27.1 Hz), 114.6 (d,
J 7.3 Hz), 57.1.
4.3 General procedure for preparation of compounds 7a-d
To a solution of the respective sulfonyl chloride 6 (70 mmol) in c a mixture of the respective
primary amine (71 mmol) and trimethylamine (9.9 mL, 71 mmol) was added slowly as to
maintain the reaction temperature below 25 ºC. After the addition was complete, the reaction
mixture was stirred for 3 h and washed with water (3 x 25 mL). The organic phase was dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was crystallized
from ethyl acetate-hexanes to give analytically pure target compounds.
4.3.1 5-Chloro-2-methoxy-N-methylbenzenesulfonamide (7a). White solid, (14.37 g, 87%); m.p.
115-118 oC (C6H14/AcOEt); δH (400 MHz, DMSO-d6) 7.63-7.71 (2H, m, HAr), 7.27 (1H, d, J 8.7
Hz, HAr), 7.22 (1H, br s, NH), 3.90 (3H, s, OCH3), 2.42 (3H, d, J 5.2 Hz, NHCH3); δC (100.61
MHz, DMSO-d6) 155.7, 134.4, 129.5, 128.7, 124.2, 115.4, 57.1, 29.2; HRMS (ESI): MH+, found
237.0043. [C8H10ClNO3S]+ requires 237.0040.
4.3.2 5-Chloro-N-isopropyl-2-methoxybenzenesulfonamide (7b). White solid, (17.00 g, 92%);
m.p. 110-113 oC (C6H14/AcOEt); δH (400 MHz, DMSO-d6) 7.69-7.62 (2H, m, HAr), 7.36 (1H, d,
J 7.8 Hz, NH), 7.25 (1H, d, J 7.8 Hz, HAr), 3.91 (3H, s, OCH3), 3.23-3.32 (1H, m, CH(CH3)2),
0.95 (6H, d, J 6.5 Hz, CH(CH3)2); δC (100.61 MHz, DMSO-d6) 155.6, 134.1, 131.1, 128.9,
124.0, 115.3, 56.9, 45.9, 23.5 (2C); HRMS (ESI): MH+, found 265.0349. [C10H14ClNO3S]+
requires 265.0353.
4.3.3 N-Ethyl-5-fluoro-2-methoxybenzenesulfonamide
(7c). White solid, (12.07 g, 74%);
m.p. 111-114 oC (C6H14/AcOEt); δH (400 MHz, DMSO-d6) 7.44-7.51 (2H, m, HAr), 7.35 (1H, t, J
11.4 Hz, NH), 7.22-7.28 (1H, m, HAr), 3.89 (3H, s, OCH3), 2.79-2.88 (2H, m, CH2CH3), 0.94
(3H, t, J 14.4 Hz, CH2CH3); δC (100.61 MHz, DMSO-d6) 155.4 (d, J 240.0 Hz), 153.4, 130.0 (d,
11

ACCEPTED MANUSCRIPT
J 6.4 Hz), 121.0 (d, J 22.7 Hz), 116.3 (d, J 25.4 Hz), 115.1 (d, J 7.3 Hz), 57.1, 38.1, 15.3; HRMS
(ESI): MH+, found 234.0558. [C9H12FNO3S]+ requires 234.0555.
4.3.4 N-Cyclopropyl-5-fluoro-2-methoxybenzenesulfonamide
(7d). White solid, (14.41 g,
o
84%); m.p. 132-134 C (C6H14/AcOEt); δH (400 MHz, DMSO-d6) 7.71 (1H, d, J 2.8 Hz, NH),
7.46-7.55 (2H, m, HAr), 7.26 (1H, dd, J 2.8, 8.8 Hz, HAr), 3.88 (3H, s, OCH3), 2.10-2.17 (1H, m,
CH(cyclopropyl)), 0.37-0.47 (4H, m, 2CH2 (cyclopropyl)); δC (100.61 MHz, CDCl3) 163.0 (d, J 239.5
Hz), 153.4 (d, J 1.8 Hz), 129.2 (d, J 6.2 Hz), 121.3 (d, J 22.74 Hz), 116.8 (d, J 26.0 Hz), 115.1
(d, J 7.7 Hz), 57.1, 24.4, 5.4 (2С); HRMS (ESI): MH+, found 246.0557. [C10H12FNO3S]+
requires 246.0555.
4.4 General procedure for preparation of compounds 5a-d
A solution of the respective sulfonamide 7 (25 mmol) in CH2Cl2 (50 mL) was cooled to 0 ºC and
treated dropwise with 1M solution of BBr3 in CH2Cl2 (30 mL, 30 mmol) so that the reaction
temperature remained below 5 ºC. After the addition was complete, the reaction mixture was
stirred at that temperature for 5 h. Methanol (2 mL) was added, the mixture stirred for 5 min,
washed with water (50 mL), dried over anhydrous Na2SO4, filtered, passed through a short plug
of silica gel and concentrated in vacuo. The residue was crystallized from the solvent indicated
to provide analytically pure target compound.
4.4.1 5-Chloro-2-hydroxy-N-methylbenzenesulfonamide (5a).19 White solid, (4,052 mg, 73%);
o
m.p. 94-97 C (C6H14/AcOEt); δH (400 MHz, DMSO-d6) 11.00 (1H, s, OH), 7.58 (1H, d, J 2.7
Hz, HAr), 7.48 (1H, dd, J 2.7, 8.7 Hz, HAr), 6.99-7.09 (2H, m, HAr + NH), 2.42 (3H, d, J 4.8 Hz,
CH3); δC (100.61 MHz, CDCl3) 154.5, 134.2, 129.1, 126.7, 122.5, 119.4, 29.2; HRMS (ESI):
MNa+, found 244.9708. [C7H7ClNNaO3S]+ requires 244.9703.
4.4.2 5-Chloro-2-hydroxy-N-isopropylbenzenesulfonamide (5b). Dark oil, (5,062 mg, 81%); δH
(400 MHz, DMSO-d6) 10.96 (s, 1H, OH), 7.59 (1H, d, J 2.7 Hz, HAr), 7.47 (1H, dd, J 2.7, 8.7
Hz, HAr), 7.18 (1H, d, J 7.6 Hz, NH), 7.01 (1H, d, J 8.7 Hz, HAr), 3.23-3.36 (1H, m, CH(CH3)2),
0.98 (6H, d, J 6.4 Hz, CH(CH3)2); δC (100.61 MHz, CDCl3) 154.5, 133.9, 129.1, 128.6, 122.4,
119.4, 45.9, 23.6 (2C); HRMS (ESI): MNa+, found 273.0021. [C9H11ClNNaO3S]+ requires
273.0016.
4.4.3 N-Ethyl-5-fluoro-2-hydroxybenzenesulfonamide
(5c). Yellow solid, (3,723 mg, 68%);
m.p. 54-57 oC (C6H14); δH (400 MHz, DMSO-d6) 10.63 (1H, s, OH), 7.38 (1H, dd, J 3.3, 8.6 Hz,
HAr), 7.27-7.33 (1H, m, HAr), 7.19 (1H, t, J 11.5 Hz, NH), 6.99 (1H, dd, J 4.3, 8.6 Hz, HAr), 2.79-
2.88 (2H, m, CH2CH3), 0.96 (3H, t, J 14.4 Hz, CH2CH3); δC (100.61 MHz, CDCl3) 154.5 (d, J
236.9 Hz), 151.9 (d, J 2.2 Hz), 127.4 (d, J 6.6 Hz), 121.1 (d, J 22.7 Hz), 118.9 (d, J 7.3 Hz),
12

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115.6 (d, J 25.7 Hz), 38.0, 15.3; HRMS (ESI): MNa+, found 242.0221. [C8H9FNNaO3S]+
requires 242.0218.
4.4.4 N-Cyclopropyl-5-fluoro-2-hydroxybenzenesulfonamide
(5d). Yellow solid, (4,042 mg,
70%); m.p. 118-121 oC (C6H14); δH (400 MHz, DMSO-d6) 10.63 (1H, s, OH), 7.57 (1H, d, J 2.7
Hz, NH), 7.41 (1H, dd, J 2.7, 8.7 Hz, HAr), 7.29-7.36 (1H, m, HAr), 7.01 (1H, dd, J 4.4, 8.7 Hz,
HAr), 2.10-2.17 (1H, m, CH(cyclopropyl)), 0.42 (4H, d, J 5.2 Hz, 2CH2 (cyclopropyl)); δC (100.61 MHz,
CDCl3) 154.2 (d, J 237.0 Hz), 152.0 (d, J 2.2 Hz), 126.7 (d, J 6.6 Hz), 121.5 (d, J 22.8 Hz),
118.9 (d, J 7.3 Hz), 116.1 (d, J 25.7 Hz), 24.4, 5.4 (2С); HRMS (ESI): MNa+, found 254.0225.
[C9H9FNNaO3S]+ requires 254.0218.
4.5 General procedure for preparation of compounds 8a-n
The respective 2-hydroxybenzene sulfonamide 5 (2 mmol) and 1,2-dihaloarene (1-halo-2-
nitroarene) partner 9 (2 mmol) were combined in anhydrous DMF (7 mL) with freshly calcinated
K2CO3 (829 mg, 6 mmol) and the mixture was kept, with stirring, at the temperature and for the
time period indicated in Table 2. DMF was removed in vacuo and the residue was treated with
water (10 mL), which caused a viscous oil to separate. It was extracted with CH2Cl2 (5 mL), the
organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel using an appropriate gradient
of CH2Cl2 in hexanes as eluent.
4.5.1 3-Chloro-6-methyl-9-nitro-6H-dibenzo[b,f][1,4,5]oxathiazepine 5,5-dioxide (8a). Yellow
o
solid, (564 mg, 83%); m.p. 181-184 C; [Found: C, 45.69; H, 2.67; N, 8.26; S, 9.43.
C13H9ClN2O5S requires C,45.82; H, 2.66; N, 8.22; S, 9.41]; δH (400 MHz, DMSO-d6) 8.25 (1H,
d, J 2.7 Hz, HAr), 8.11 (1H, dd, J 2.7, 8.7 Hz, HAr), 7.87 (1H, dd, J 2.7, 8.7 Hz, HAr), 7.83 (1H, d,
J 2.5 Hz, HAr), 7.76 (1H, d, J 8.7 Hz, HAr), 7.67 (1H, d, J 8.7 Hz, HAr), 3.26 (3H, s, CH3); δC
(100.61 MHz, CDCl3) 150.5, 149.4, 147.1, 138.0, 136.1, 132.4, 130.3, 129.9, 127.3, 125.5,
121.1, 118.4, 39.7.
4.5.2 Мethyl 8-chloro-11-methyl-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine-3-carboxylate
10,10-dioxide (8b). White solid, (540 mg 76%); m.p. 164-167 oC; [Found: C, 47.26; H, 3.13; N,
7.94; S, 9.05. C14H11ClN2O5S requires C, 47.40; H, 3.13; N, 7.90; S, 9.04]; δH (400 MHz,
DMSO-d6) 8.72 (1H, d, J 1.7 Hz, HPy), 8.23 (1H, d, J 1.7 Hz, HPy), 7.90 (1H, dd, J 2.6, 8.7 Hz,
HAr), 7.83 (1H, d, J 2.6 Hz, HAr), 7.68 (1H, d, J 8.7 Hz, HAr), 3.90 (3H, s, COOCH3), 3.39 (3H, s,
13

ACCEPTED MANUSCRIPT
NCH3); δC (100.61 MHz, DMSO-d6) 164.3, 149.4, 146.6, 144.9, 142.7, 136.8, 133.8, 131.8,
130.2, 126.1, 125.6, 124.4, 53.1, 35.8.
4.5.3 8-Chloro-2,5-dimethyl-2,5-dihydro-1H-benzo[b]pyridazino[4,5-f][1,4,5]oxathiazepin-1-
o
one 6,6-dioxide (8c). White solid, (479 mg 73%); m.p. 189-192 C; [Found: C, 43.84; H, 3.08;
N, 12.89; S, 9.80. C12H10ClN3O4S requires C, 43.98; H, 3.08; N, 12.82; S, 9.78]; δH (400 MHz,
DMSO-d6) 8.00 (1H, s, Hpyridazine), 7.87 (1H, dd, J 2.7, 8.6 Hz, HAr), 7.82 (1H, d, J 2.7 Hz, HAr),
7.50 (1H, d, J 8.6 Hz, HAr), 3.68 (3H, s, CH3pyridazine), 3.12 (3H, s, NCH3); δC (100.61 MHz,
DMSO-d6) 148.5, 145.8, 143.7, 139.5, 136.4, 133.8, 129.8, 126.8, 126.4, 125.2, 55.9, 22.3.
4.5.4 8-Chloro-5-methyl-5H-benzo[b]pyrazino[2,3-f][1,4,5]oxathiazepine 6,6-dioxide (8d).
o
White solid, (423 mg, 71%); m.p. 132-135 C; [Found: C, 44.24; H, 2.71; N, 14.18; S, 10.79.
C11H8ClN3O3S requires C, 44.38; H, 2.71; N, 14.11; S, 10.77]; δH (400 MHz, DMSO-d6) 8.38
(1H, d, J 2.2 Hz, Hpyrazine), 8.28 (1H, d, J 2.2 Hz, Hpyrazine), 7.87 (1H, dd, J 2.7, 8.6 Hz, HAr), 7.83
(1H, d, J 2.7 Hz, HAr), 7.59 (1H, d, J 8.6 Hz, HAr), 3.32 (s, 3H, NCH3); δC (100.61 MHz, DMSO-
d6) 149.1, 148.3, 139.8, 139.7, 139.5, 136.5, 132.9, 129.9, 126.2, 125.6, 36.0.
4.5.5 8-Сhloro-11-isopropyl-3-nitro-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine 10,10-
dioxide (8e). Yellow solid, (629 mg, 85%); m.p. 144-147 oC; [Found: C, 48.71; H, 3.56; N, 7.63;
S, 8.71. C14H12ClN3O5S requires C,48.85; H, 3.55; N, 7.60; S, 8.69]; δH (400 MHz, DMSO-d6)
9.10 (1H, d, J 2.5 Hz, HPy), 8.60 (1H, d, J 2.5 Hz, HPy), 7.85-7.93 (2H, m, 2HAr), 7.61 (1H, d, J
8.7 Hz, HAr), 4.32-4.44 (1H, m, CH(CH3)2), 1.21 (6H, d, J 6.9 Hz, CH(CH3)2); δC (100.61 MHz,
DMSO-d6) 155.9, 148.4, 142.3 (2C), 136.8, 135.7, 131.4, 129.9, 127.8, 127.7, 125.5, 40.1, 39.2
(2C).
4.5.6 3-Chloro-6-isopropyl-6H-dibenzo[b,f][1,4,5]oxathiazepine-9-carbonitrile 5,5-dioxide (8f).
o
White solid, (438 mg, 63%); m.p. 147-150 C; [Found: C, 54.93; H, 3.76; N, 8.07; S, 9.21.
C16H13ClN2O3S requires C, 55.09; H, 3.76; N, 8.03; S, 9.19]; δH (400 MHz, DMSO-d6) 8.05 (1H,
d, J 1.7 Hz, HAr), 7.77-7.87 (3H, m, 3HAr), 7.68 (1H, d, J 8.5 Hz, HAr), 7.51 (1H, d, J 8.5 Hz,
HAr), 4.26-4.38 (1H, m, CH(CH3)2), 1.11 (6H, d, J 6.6 Hz, CH(CH3)2); δC (100.61 MHz, DMSO-
d6) 154.9, 149.8, 135.3, 134.5, 133.2, 132.0, 130.5, 129.2, 127.2, 127.1, 124.8, 117.7, 113.7,
54.7, 22.0 (2C).
4.5.7
8-Chloro-5-isopropyl-2-methyl-2,5-dihydro-1H-benzo[b]pyridazino[4,5-
o
f][1,4,5]oxathiazepin-1-one 6,6-dioxide (8g). White solid, (533 mg, 75%); m.p. 159-162 C;
[Found: C, 47.12; H, 3.97; N, 11.87; S, 9.03. C14H14ClN3O4S requires C, 47.26; H, 3.97; N,
11.81; S, 9.01]; δH (400 MHz, DMSO-d6) δ 7.87 (1H, d, J 2.6 Hz, HAr), 7.59 (1H, s, Hpyridazine),
7.56 (1H, dd, J 2.6, 8.8 Hz, HAr), 7.46 (1H, d, J 8.8 Hz, HAr), 4.15-4.27 (1H, m, CH(CH3)2), 3.85
(3H, s, CH3 pyridazine), 1.17 (6H, d, J 6.7, CH(CH3)2); δC (100.61 MHz, DMSO-d6) δ 155.9, 148.1,
146.7, 137.7, 136.3, 132.7, 129.5, 127.6, 124.8, 123.6, 55.1, 40.6, 21.8 (2C).
14

ACCEPTED MANUSCRIPT
4.5.8 8-Chloro-5-isopropyl-5H-benzo[b]pyrazino[2,3-f][1,4,5]oxathiazepine 6,6-dioxide (8h).
o
White solid, (442 mg, 68%); m.p. 182-185 C; [Found: C, 47.79; H, 3.72; N, 12.96; S, 9.86.
C13H12ClN3O3S requires C, 47.93; H, 3.71; N, 12.90; S, 9.84]; δH (400 MHz, DMSO-d6) δ 8.49
(1H, d, J 2.5 Hz, Hpyrazine), 8.45 (1H, d, J 2.5 Hz, Hpyrazine), 7.84-7.90 (2H, m, HAr), 7.60 (1H, d, J
9.0 Hz, HAr), 4.18-4.30 (1H, m, CH(CH3)2), 1.16 (6H, d, J 6.8 Hz, CH(CH3)2); δC (75 MHz,
DMSO-d6) 152.2, 148.3, 142.2, 140.2, 137.0, 136.2, 132.9, 129.4, 126.6, 125.0, 55.2, 22.3 (2C).
4.5.9 11-Ethyl-8-fluoro-3-nitro-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine 10,10-dioxide
o
(8i). Yellow solid, (542 mg, 80%); m.p. 149-152 C; [Found: C, 45.88; H, 2.97; N, 12.45; S,
9.47. C13H10FN3O5S requires C, 46.02; H, 2.97; N, 12.38; S, 9.45]; δH (400 MHz, DMSO-d6)
9.05 (1H, d, J 2.2 Hz, HPy), 8.64 (1H, d, J 2.2 Hz, HPy), 7.71-7.80 (3H, m, HAr), 4.09 (2H, dd, J
7.0, 13.9 Hz, CH2CH3), 1.16 (3H, t, J 7.0 Hz, CH2CH3); δC (75 MHz, DMSO-d6) 158.8 (d, J
248.0 Hz), 147.4, 146.5 (d, J 2.9 Hz), 141.8 (d, J 11.7 Hz), 140.1, 134.8 (d, J 8.1 Hz), 127.2
(2С), 125.9 (d, J 8.1 Hz), 124.0 (d, J 23.5 Hz), 113.6 (d, J 27.1 Hz), 45.1, 15.2.
4.5.10 6-Ethyl-3,8-difluoro-6H-dibenzo[b,f][1,4,5]oxathiazepine-9-carbonitrile 5,5-dioxide (8j).
o
White solid, (416 mg, 62%); m.p. 143-146 C; [Found: C, 53.41; H, 3.00; N, 8.37; S, 9.55.
C15H10F2N2O3S requires C, 53.57; H, 3.00; N, 8.33; S, 9.53]; δH (400 MHz, DMSO-d6) 8.13 (1H,
d, J 6.4 Hz, HAr), 7.84 (1H, d, J 9.5 Hz, HAr), 7.62-7.74 (2H, m, HAr), 7.54-7.60 (1H, dd, J 4.4,
9.5 Hz, HAr), 3.76 (2H, dd, J 7.1, 13.9 Hz, CH2CH3), 0.99 (3H, t, J 7.1 Hz, CH2CH3); δC (75
MHz, DMSO-d6) 160.4 (d, J 133.5 Hz), 157.9 (d, J 125.4 Hz), 148.8 (d, J 2.9 Hz), 147.1 (d, J
2.9 Hz), 136.0 (d, J 11.0 Hz), 133.7 (d, J 6.6 Hz), 127.9, 125.3 (d, J 8.1 Hz), 123.1 (d, J 22.7
Hz), 118.0 (d, J 22.7 Hz), 114.5 (d, J 26.4 Hz), 113.2, 101.0 (d, J 16.9 Hz), 47.4, 13.8.
4.5.11
11-Ethyl-8-fluoro-3-(trifluoromethyl)-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine
o
10,10-dioxide (8k). Yellow solid, (470 mg, 65%); m.p. 156-159 C; [Found: C, 46.88; H, 2.77;
N, 7.45; S, 8.47. C14H10F4N2O3S requires C, 46.41; H, 2.78; N, 7.73; S, 8.85]; δH (400 MHz,
DMSO-d6) 8.65 (1H, d, J 1.2 Hz, HPy), 8.28 (1H, d, J 1.2 Hz, HPy), 7.64-7.75 (3H, m, HAr), 4.03
(2H, dd, J 7.0, 14.0 Hz, CH2CH3), 1.12 (3H, t, J 7.0 Hz, CH2CH3); δC (75 MHz, DMSO-d6)
156.2 (d, J 247.9 Hz), 146,4 (d, J 2.9 Hz), 146.1, 143.0, 141.2 (m), 135.0 (d, J 8.0 Hz), 129.3
(m), 125.7 (d, J 8.0 Hz), 123.8 (d, J 23.5 Hz), 123.3 (d, J 272.9 Hz), 123.4, 113.4 (d, J 27.2 Hz),
45.1, 15.0.
4.5.12 6-Cyclopropyl-3-fluoro-6H-dibenzo[b,f][1,4,5]oxathiazipine-7-carbonitrile 5,5-dioxide
o
(8l). White solid, (442 mg, 67%); m.p. 195-197 C; [Found: C, 58.00; H, 3.36; N, 8.52; S, 9.72.
C16H11FN2O3S requires C, 58.18; H, 3.36; N, 8.48; S, 9.71]; δH (400 MHz, DMSO-d6) 7.60-7.67
(2H, m, 2HAr), 7.47-7.57 (2H, m, 2HAr), 7.34-7.40 (1H, m, HAr), 7.25-7.32 (1H, m, HAr), 3.08-
3.16 (1H, m, CHcyclopropyl), 1.31-1.40 (1H, m, CH2 cyclopropyl), 0.87-1.04 (2H, m, CH2 cyclopropyl),
0.61-0.71 (1H, m, CH2 cyclopropyl); δC (75 MHz, DMSO-d6) 158.6 (d, J 246.5 Hz), 155.8, 147.7 (d,
15

ACCEPTED MANUSCRIPT
J 2.9 Hz), 134.4, 132.3 (d, J 52.8 Hz), 131.6 (d, J 7.0 Hz), 128.6, 125.4 (d, J 8.1 Hz), 123.0 (d, J
23.5 Hz), 115.9, 115.3 (2С), 115.0, 32.7, 9.5, 5.6.
4.5.13
11-Cyclopropyl-8-fluoro-3-(trifluoromethyl)-11H-benzo[b]pyrido[2,3-
o
f][1,4,5]oxathiazepine 10,10-dioxide (8m). White solid, (531 mg, 71%); m.p 180-183 C;
[Found: C, 47.99; H, 2.70; N, 7.52; S, 8.58. C15H10F4N2O3S requires C, 48.13; H, 2.69; N, 7.48;
S, 8.56]; δH (400 MHz, DMSO-d6) δ 8.73 (1H, s, HPy), 8.28 (1H, s, HPy), 7.65-7.76 (2H, m, HAr),
7.58 (1H, dd, J 4.3, 8.9 Hz, HAr), 3.03-3.10 (1H, m, CHcyclopropyl), 0.83-0.91 (2H, m, CH2
cyclopropyl), 0.58-0.66 (2H, m, CH2 cyclopropyl); δC (75 MHz, DMSO-d6) 161.9, 158.6 (d, J 248.7 Hz),
152.4, 146.1, 145,3 (d, J 2.9 Hz), 144.6, 138.2 (m), 135.0 (d, J 8.1 Hz), 125.3 (d, J 8.1 Hz),
123.9 (d, J 23.2 Hz), 123.3 (d, J 272.9 Hz), 113.4 (d, J 27.2 Hz), 30.4, 9.4 (2С).
4.5.14 Methyl 11-cyclopropyl-8-fluoro-11H-benzo[b]pyriddo[2,3-f][1,4,5]oxathiazepine-3-
carboxylate 10,10-dioxide (8n). White solid, (502 mg, 69%); m.p. 174-176 oC; [Found: C, 52.59;
H, 3.60; N, 7.73; S, 8.82. C16H13FN2O5S requires C, 52.74; H, 3.60; N, 7.69; S, 8.80]; δH (400
MHz, DMSO-d6) 8.85 (1H, d, J 2.0 Hz, HPy), 8.44 (1H, d, J 2.0 Hz, HPy), 7.38-7.46 (2H, m, HAr),
7.02 (1H, dd, J 4.3, 9.9 Hz, HAr), 3.90 (3H, s, COOCH3), 2.87-2.94 (1H, m, CHcyclopropyl), 0.57-
0.79 (4H, m, CH2 cyclopropyl); δC (75 MHz, DMSO-d6) 162.7, 160.0 (d, J 249.1 Hz), 151.5, 146.1
(d, J 2.9 Hz), 145.9 (d, J 33.4 Hz), 136.6, 134.9 (d, J 8.1 Hz), 125.1 (d, J 8.4 Hz), 124.2 (d, J
23.5 Hz), 122.5, 119.7, 113.9 (d, J 27.5 Hz), 44.6, 25.3, 15.1.
Acknowledgement
We gratefully acknowledge support from the Russian Scientific Fund (Project Grant 14-50-
00069). NMR studies were performed at the Research Centre for Magnetic Resonance of Saint
Petersburg State University Research Park.
Supplementary data
1
Supplementary data contains copies of H and 13C NMR spectra and can be found at
http://dx.doi.org/xxx.
Referenced and notes
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