Rare Medium-Sized Rings Prepared via Hydrolytic Imidazoline Ring Expansion (HIRE)

Article abstract of DOI:10.1021/acs.joc.8b01210

The hydrolytic imidazoline ring expansion (HIRE) methodology was extended to readily available tetracyclic [1,4]thiazepines as well as sulfoxide and sulfone analogs thereof. The reactions resulted in the facile formation of a rare medium-sized [1,4,7]thia

Full text of DOI:10.1021/acs.joc.8b01210

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Article
Rare Medium-Sized Rings Prepared via
Hydrolytic Imidazoline Ring Expansion (HIRE)
Angelina Osipyan, Alexander Sapegin, Alexander S. Novikov, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01210 • Publication Date (Web): 13 Aug 2018
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Rare MediumꢀSized Rings Prepared via Hydrolytic Imidazoline Ring
Expansion (HIRE)
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Angelina Osipyan, Alexander Sapegin, Alexander S. Novikov and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
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ABSTRACT: The hydrolytic imidazoline ring expansion (HIRE) methodology was extended to
readily available tetracyclic [1,4]thiazepines as well as sulfoxide and sulfone analogs thereof.
The reactions resulted in the facile formation of a rare mediumꢀsized [1,4,7]thiazecine ring
system that has an emerging utility in bioactive compound design. Comparing the HIRE rates for
representative compounds in the three groups of substrates allowed drawing some
generalizations about the substituent effects on the course of the reaction.
Introduction
Smallꢀsized (particularly, 5ꢀ to 7ꢀmembered) rings are omnipresent in existing screening
collections for drug discovery.1 However, due to their reduced flexibility, such compounds can
adopt a limited number of conformations, which reduces the chances of finding among them a
molecule with an optimal fit for a particular protein target. Excessive conformational flexibility
(rotatable bond count) featured in linear scaffolds is also undesired due to impaired cell
membrane permeability and intestinal absorption of a future drug.2 Thus, mediumꢀsized (8ꢀ to
11ꢀmembered) rings appear to be an optimum scaffold choice for compounds intended for
interrogation of biological targets.3 On the one hand, the cyclic character of such frameworks
limits the range of lowerꢀenergy conformations the respective compounds can adopt. On the
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other hand, this range is sufficiently large for a single compound to optimally present its
molecular periphery for a tight and selective binding to a protein.4 Such multiꢀconformational
small molecule tools are particularly desired when poorly ‘druggable’ targets are concerned (e.
g., proteinꢀprotein interactions).5
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Unfortunately, the area of chemical space corresponding to mediumꢀsize rings is quite
underpopulated in terms of tangible compounds that can be screened for bioactivity.6 Most
likely, this situation has to do with the difficulty to obtain such compounds via synthesis (which
hinders their deposition in screening collections and progression through medicinal chemistry
optimization programs).7 Entropy constraints are the major contributing factor limiting the
applicability of ringꢀclosing strategies to construct mediumꢀsized rings; additionally, formation
of such rings can be associated with unfavorable enthalpy changes due to destabilizing
transannular interactions.8 An alternative – and significantly more prolific – approach lies in
exploring various ring expansion opportunities.9 The latter are normally recognized in polycyclic
systems with some degree of instability which is released via breaking of a central bond which
leads to energyꢀlowering transformations such aromatization or strain relief. Recent illustrative
examples include synthesis of 10ꢀmembered lactam 1 from readily available 2ꢀ
oxocyclohexancarboxylic acid by Unsworth and coꢀworkers3 and conformationally induced
Smiles ring expansion synthesis of dibenzodiazepine analogs 2 reported by Clayden and coꢀ
workers10 as well as other examples from these two groups.11 In recent years, we have been
involved12 in exploring Nꢀ(hetero)aryl 2ꢀimidazolines as privileged motifs for drug discovery as
well as versatile templates for scaffoldꢀoriented synthesis.13 This led us to an idea of considering
polycyclic 2ꢀimidazolines 3 as potential objects for ring expansion driven by hydrolysis and
resulting in the formation of lactams 4. This resulted in the development of an expedited and
atomꢀeconomical route to [1,4,7]oxadiazecinꢀ9(6H)ꢀones 5 from readily available14 tetracyclic
[1,4]oxazepines 6.15 Herein, we describe an extension of the hydrolytic imidazoline ring
expansion (HIRE) methodology to tetracyclic [1,4]thiazepines 7 as well as their sulfoxide (8)
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and sulfone (9) analogs) which offers more flexibility with the periphery group variation and
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provides some insights into substituent effects on the rate of the HIRE reaction (Figure 1).
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Figure 1. Recent examples of mediumꢀsized ring synthesis via ring expansion and the substrate
focus of the present study.
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Results and Discusssion
Preparation of [1,4]thiazepines fused to two aromatic rings and a 2ꢀimidazoline cycles (such as
7) has been described previously.16ꢀ17 Following a modified procedure for the synthesis of 2ꢀ(4,5ꢀ
dihydroꢀ1Hꢀimidazolꢀ2ꢀyl)benzenethiol (10) and its condensation with various bisꢀelectrophilic
(hetero)aromatic substrates 11aꢀk, a set of 2,3ꢀdihydroimidazo[1,2ꢀd][1,4]thiazepines 7aꢀk was
obtained. The regiochemistry of the double SNAr reaction leading to the formation of 7 is
governed by the intermittent Smiles rearrangement which was observed in all similar reactions
studies by us18 and others16ꢀ17 before and also confirmed in this case by a singleꢀcrystal Xꢀray
analysis (see Supporting Information) of representative compounds obtained in this work
(Scheme 1). The synthesis of tetracyclic compounds 7 was conducted overnight at variable
temperature depending on the electrophilicity of the respective aromatic substrate 11 and
resulted in good to excellent yields of the target products (Table 1).
Scheme 1. Preparation and the use of thiophenol 10 in the synthesis of 2,3ꢀdihydroimidazo[1,2ꢀ
d][1,4]thiazepines 7aꢀk.
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Table 1. 2,3ꢀDihydroimidazo[1,2ꢀd][1,4]thiazepines 7aꢀk prepared in this work.
Temperature
Entry Compound Bisꢀelectrophile 11
Product 7
Yield, %
89
(ºC)
1
2
3
4
5
6
7
50
7(11)a
50
75
75
r. t.
50
75
87
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66
91
95
72
7(11)b
7(11)c
7(11)d
7(11)e
7(11)f
7(11)g
7(11)h
7(11)i
8
9
50
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90
75
86
76
10
11
7(11)j
7(11)k
r. t.
As it was previously observed for the respective 2,3ꢀdihydroimidazo[1,2ꢀd][1,4]oxazepines,15
tetracycles 7 failed to undergo hydrolytic ring expansion, even on prolonged heating in basic or
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acidic aqueous acetonitrile. Activation of the 2ꢀimidazoline, via N3ꢀalkylation, towards the
nucleophilic attack of hydroxide anion made the respective imidazolinium species 12 quite
reactive in the subsequent HIRE reaction as shown in Scheme 2 and the complete conversion of
2,3ꢀdihydroimidazo[1,2ꢀd][1,4]thiazepines 7 to the respective [1,4,7]thiadiazecines (13aꢀr) was
achieved within 1 h at room temperature. The ringꢀenlarged products 13aꢀr were obtained in
moderate to good yields over two steps (Table 2, entries 1ꢀ18).
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Scheme 2. The HIRE reaction of tetracycles 7 towards [1,4,7]thiadiazecines 13.
[1,4,7]Thiadiazecines 13 are representatives of a rare mediumꢀsized ring system. However, its
utility as a peptide reverse turn mimic has been recently revealed by the HaskellꢀLuevano group
in the design of melanocortin receptor ligands.19ꢀ21 Constrained bicyclic versions featuring a
similar framework have been employed as a scaffold for CXCR4 antagonists22ꢀ23 and ROMK
potassium channel blockers24 (Figure 2).
Figure 2. Examples of bioactive compounds incorporating [1,4,7]thiadiazecine ring system.
One notable feature of compounds 13 compared to their oxygen counterparts 5 is the greater
diversity of substituents (Alk) on the lactam nitrogen atom that can be introduced via alkylation
of the 2ꢀimidazoline moiety in the tetracyclic precursors (7 and 6, respectively). With
compounds 6 as substrates, we did not succeed at introducing any substituents at the imidazoline
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N3 atom besides methyl or ethyl group. On the contrary, 2,3ꢀdihydroimidazo[1,2ꢀ
d][1,4]thiazepines 7 turned out to be quite reactive toward alkyl iodides and bromides – with
benzyl bromides reacting on conventional heating (or even ambient temperature – vide infra). A
general explanation could be in the greater nucleophilicity of the 2ꢀimidazoline moiety in 7
compared to the same in 6. The difference in electronꢀdonating properties of oxygen atom vs.
sulfur (6 vs. 7) is unlikely to be a significant factor: the oxygen atom is likely to be in a better
conjugation with the imidazoline’s amidine group and thus 6 should have been more
nucleophilic. Most likely, the observed higher reactivity of 2ꢀimidazoline moiety in 7 towards
alkylating agents has to do with the geometry differences introduced in the tetracyclic system by
the larger sulfur atom.
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We were also quite curious to see whether oxidation of the sulfur atom in 7 (to produce
sulfoxides 8 or sulfones 9) would have a noticeable effect on the HIRE reaction. To this end, we
prepared sulfoxides 8aꢀb by brief exposure of the respective sulfide precursors 7 to mꢀCPBA
(longer reaction times led to further oxidation to sulfone). Sulfones 9aꢀd were prepared using
sodium periodate – ruthenium(III) chloride system.25 Both sets of oxidized substrates for the
HIRE reaction were obtained in moderate to good yields (Scheme 3).
Scheme 3. Synthesis of sulfoxides 8aꢀb and sulfones 9aꢀd.
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All of the sulfoxide (8aꢀb) and sulfone (9aꢀd) substrates thus synthesized displayed good
reactivity in the HIRE reaction, upon activation with alkylating agents, under conditions
analogous to those shown in Scheme 2 for sulfide substrates 7aꢀk. The respective ringꢀexpanded
1,4,7ꢀthiadiazecineꢀ1ꢀoxides 14aꢀd and 1,4,7ꢀthiadiazecine 1,1ꢀdioxides 15aꢀd were obtained in
good yields over two steps (Table 2, entries 19ꢀ26).
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Table 2. [1,4,7]Thiadiazecines 13aꢀr, 14aꢀd and 15aꢀd prepared in this work.
Starting
material 7
Alkylation
conditionsa
Entry
1
AlkHal
MeI
Product 13
Yield, %
64
A
A
A
A
A
A
7b
7a
7c
7h
7i
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MeI
MeI
MeI
MeI
EtI
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40
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EtI
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nꢀPrI
nꢀPrI
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A
7j
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11
MeO(CH2)2Br
A
A
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7e
7d
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B
B
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B
B
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B
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7h
7j
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7k
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B
B
55
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8a
8a
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A
B
A
B
38
62
46
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8b
8b
9a
9b
O
O
O2N
S
N
14d
N
H
EtI
25
26
MeI
A
B
33
50
9c
9d
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aConditions – A: AlkHal (1.05 equiv.), MeCN, ꢀW at 120 ºC, 5 h; B: AlkHal (1.05 equiv.),
3
4
MeCN, 60 ºC, 16 h.
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7
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9
Converting divalent sulfur in substrates 7 into electronꢀwithdrawing sulfoxide and sulfone
substituents (as in 8 and 9) can be expected to significantly influence the course of the HIRE
reaction due to the direct conjugation of these groups to the imidazolinium moiety and the
nitrogen atom of the ‘aniline’ leaving group formed as a result of the ring expansion. In order to
compare the HIRE rates for the sulfide, sulfoxide and sulfone variants of the tetracyclic HIRE
substrates, we prepared pure imidazolinium salts 16aꢀc (Scheme 4) and investigated their timeꢀ
dependent conversion under the HIRE conditions. The data obtained are shown in Figure 3.
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Scheme 4. Preparation of imidazolinium salts 16aꢀc.
Br
N
S
Ph
N
S
BnBr
N
N
MeCN, r. t.
overnight
(O)n
(O)n
CO2Me
CO2Me
7c 8a 9b
16a
, n = 0
,
or
16b, n = 1
16c, n = 2
Figure 3. Comparison of HIRE conversion rates for compounds 16aꢀc.
As was expected, sulfone 16c prove to be much more reactive compared to sulfide 16a, with
most of the starting material disappearing within 20 seconds from the reaction start. This is
justified both by the increased electrophilicity of the imidazolinium group toward the hydroxide
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anion (facilitating the formation of tetrahedral intermediate 17) and the pushꢀpull interaction
3
4
with the anilinic nitrogen in the HIRE product (Scheme 5).
5
6
7
Scheme 5. Plausible mechanistic pathway for the HIRE reaction of 16aꢀc.
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Br
Bn
Bn
Bn
N
S
N
S
N
S
H
O
O
HO
HO
N
HO
N
HN
H
(O)n
(O)n
(O)n
CO2Me
CO2Me
CO2Me
7h 8a 9b
or
,
16
17
However, the fact that sulfoxide 16b turned out to be even somewhat less reactive than sulfide
16a, was quite surprising. Such a reactivity pattern can, in principle, be justified by a possible
participation of the sulfur unshared electron pair in 16b in the conjugation with the
imidazolinium fragment, which would reduce the electrophilicity of the latter (Figure 4). The
lower value of dihedral angle between the imidazolinium ring and the nearby benzene ring in the
singleꢀcrystal Xꢀray structure of 16b compared to that in 16a (67º and 70º, respectively) argues
for the correctness of such an interpretation (see Supporting Information). Additionally, DFT
calculations of atomic charges on the amidine carbon atoms of compounds 16aꢀc confirmed a
lower positive charge in case of sulfoxide 16b compared to sulfide 16a (see Supporting
Information). This is also in line with the observed relative reactivity of the three substrates
under HIRE conditions.
Figure 4. Possible resonance structures in 16b.
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Conclusion
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In summary, we described an application of the hydrolytic imidazoline ring expansion (HIRE)
reaction to 2,3ꢀdihydroimidazo[1,2ꢀ ][1,4]thiazepines as well as their sulfoxide and sulfone
analogs activated by ꢀalkylation of the 2ꢀimidazoline moiety. The resulting tenꢀmembered
d
N
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lactams contain a rare mediumꢀsized ring system that has recently emerged as a versatile scaffold
in bioactive compound design.
EXPERIMENTAL SECTION
1
General. NMR spectroscopic data were recorded with a 400 spectrometer (400.13 MHz for H
and 100.61 MHz for 13C) in DMSOꢀd6 or in CDCl3 or in Acetoneꢀd6 and were referenced to
residual solvent proton signals (δH = 2.50, 7.26 and 2.05 ppm, respectively) and solvent carbon
signals (δC = 39.52, 77.00 and 206.26 ppm, respectively). For the HPLCꢀUV analysis was used
chromatograph MiLiChrom Aꢀ02 (Econova, Novosibirsk, Russia). Microwaveꢀassisted reactions
were performed in the Biotage® Initiator+ microwave synthesizer reactor using a sealed reaction
vessel. Mass spectra were recorded with a HRMSꢀESIꢀqTOF spectrometer (ESI ionization).
Melting points were determined with an automated heat block instrument and are uncorrected.
Single crystal Xꢀray data were obtained using an Agilent Technologies SuperNova Atlas and an
Agilent Technologies Xcalibur Eos diffractometers at a temperature of 100 K. Column
chromatography was carried out with silica gel grade 60 (0.040−0.063 mm) 230−400 mesh.
Chlorobenzene, dichloromethane and MeCN were distilled over P2O5 and stored over molecular
sieves 3 Å. THF and 1,4ꢀdioxane were distilled after refluxing with sodiumꢀbenzophenone and
stored over molecular sieves 3 Å.
Preparation of 2ꢀ(4,5ꢀDihydroꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀbenzenethiol 10
To a suspension of thiosalicylic acid (10.00 g, 0.065 mol) in 1,2ꢀdichlorobenzene (100 mL) was
added ethylenediamine (11 mL, 0.183 mol) and refluxed under nitrogen for 4 h then cooled to
60°C and methanol (15 mL) was added. The solution was stirred at room temperature overnight
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and the resulting yellow crystalline solid was collected and washed with methanol and ether to
give pure product.
5
6
7
8
9
1
Yield 8.5g, 74%; yellow solid, mp 247ꢀ248 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
11.57 (br.s,
= 1.3 Hz, 1H), 7.01 (ddd,
= 7.1 Hz, = 1.3 Hz, 1H), 3.89 (s,
166.7, 137.3, 129.7, 129.1, 129.1, 119.2,
2H), 7.59 (dd,
J
= 8.1 Hz,
J
= 1.3 Hz, 1H), 7.43 (dd,
J
= 8.2 Hz,
J
J =
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8.2 Hz,
J
=7.1 Hz,
J
= 1.5 Hz, 1H), 6.79 (ddd, = 8.1 Hz,
J
J
J
4H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
13
118.7, 43.9, 43.9 ppm. HRMS (ESI), m/z calcd for C9H11N2S+ [M+H]+ 179.0639, found
179.0637.
General procedure for preparation of 2,3ꢀdihydroimidazo[1,2ꢀd][1,4]thiazepines 7aꢀk
A solution of 10 (500 mg, 2.800 mmol) and bisꢀelectrophile 11 (1.867 mmol) in anhydrous DMF
(10 mL) containing anhydrous Cs2CO3 (1370 mg, 5.600 mmol) was heated at a given
temperature (Table 1) for overnight. DMF was removed in vacuo and water was added (10 mL).
This suspension was stirred 2 h at room temperature, the resulting solid was collected and
washed with water, recrystallized from propanolꢀ2/water to provide the analytically pure
product.
2,3ꢀDihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ5ꢀcarbonitrile (7a)
1
Yield 462 mg, 89%; light beige solid; mp 185ꢀ187 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
7.92
= 1.6 Hz, 1H), 7.71 – 7.62 (m, 1H),
= 7.8 Hz, 1H), 4.81 – 4.72 (m, 1H), 4.13 –
(dd,
J = 7.8 Hz, J = 1.6 Hz, 1HAr), 7.85 (dd, J = 7.8 Hz, J
7.61 – 7.55 (m, 1H), 7.49 – 7.45 (m, 2H), 7.26 (t,
J
3.81 (m, 3H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ 159.4, 144.7, 138.4, 135.5, 134.9,
134.7, 132.3, 131.5, 131.4, 130.8, 129.5, 125.3, 117.1, 107.3, 52.5, 52.4 ppm. HRMS (ESI), m/z
calcd for C16H12N3S+ [M+H]+ 278.0746, found 278.0751.
2,3ꢀDihydrodibenzo[b,f]imidazo[1,2ꢀ
d][1,4]thiazepineꢀ7ꢀcarbonitrile (7b)
Yield 451 mg, 87%; light beige solid; mp 152ꢀ154 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
7.98 (d,
J
= 2.1 Hz, 1H), 7.81 (dd, J = 8.5 Hz, J = 2.1 Hz, 1H), 7.69 (dd, J = 7.5 Hz, J = 1.6 Hz, 1H), 7.56
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3
4
5
6
7
8
(dd,
1.6 Hz, 1H), 7.34 (d,
(101 MHz, DMSOꢀd6
J
= 7.5 Hz,
J
= 1.6 Hz, 1H), 7.49 (td,
J
= 7.5 Hz,
J
= 1.6 Hz, 1H), 7.44 (dd,
J = 7.5 Hz, J =
J
= 8.5 Hz, 1H), 4.17 (s, 2H), 3.93 (t, J
= 9.2 Hz, 2H) ppm. 13C{1H} NMR
)
δ 159.5, 146.8, 137.0, 134.7, 134.6, 133.9, 132.3, 132.0, 132.0, 129.7,
126.3, 120.0, 118.6, 105.0, 52.8, 51.9 ppm. HRMS (ESI), m/z calcd for C16H12N3S+ [M+H]+
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
278.0746, found 278.0750.
Methyl 2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ7ꢀcarboxylate (7c)
1
Yield 459 mg, 79%; white solid; mp 182ꢀ184 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.04 (d,
= 1.6 Hz, 1H), 7.59
= 1.6 Hz, 1H), 7.41 (td, = 7.6 Hz,
= 9.3 Hz, 2H), 3.82 (s, 3H) ppm.
165.0, 159.3, 146.4, 134.3, 133.9, 133.8, 131.7, 131.5,
J =
2.1 Hz, 1H), 7.91 (dd,
J
= 8.5 Hz,
J
= 2.1 Hz, 1H), 7.69 (dd,
= 7.6 Hz,
J = 7.6 Hz, J
(dd, = 7.6 Hz, = 1.6 Hz, 1H), 7.47 (td,
J
J
J
J
J
J =
1.6 Hz, 1H), 7.32 (d,
J = 8.6 Hz, 1H), 4.17 (s, 2H), 3.93 (t, J
13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
131.4, 131.1, 129.0, 125.1, 123.5, 118.9, 52.2, 52.1, 51.4 ppm. HRMS (ESI), m/z calcd for
C17H15N2O2S+ [M+H]+ 311.0849, found 311.0851.
N,Nꢀdimethylꢀ2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ7ꢀsulfonamide (7d)
1
Yield 444 mg, 66%; light yellow solid; mp 211ꢀ213 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
7.80
= 7.6
= 8.6 Hz, 1H), 4.19 (s, 2H),
(d,
Hz,
3.94 (t,
J
= 2.2 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.61 (dd,
J
= 7.6 Hz,
J
= 1.5 Hz, 1H), 7.49 (td,
J
J
= 1.5 Hz, 1H), 7.43 (td,
J
= 7.6 Hz,
J
= 1.5 Hz, 1H), 7.41 (d,
J
J
= 9.2 Hz, 2H), 2.60 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
159.6, 146.7,
134.8, 134.0, 132.3, 132.3, 132.02, 132.0, 130.1, 129.7, 128.7, 126.2, 119.8, 52.9, 51.9, 38.0
(2С) ppm. HRMS (ESI), m/z calcd for C17H18N3O2S2 [M+H]+ 360.0835, found 360.0836.
+
7ꢀNitroꢀ2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d][1,4]thiazepine (7е)
Yield 505 mg, 91%; yellow solid; mp 214ꢀ216 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.32 (d,
J =
2.7 Hz, 1H), 8.22 (dd,
(dd, = 7.6 Hz, = 1.4 Hz, 1H), 7.52 (td,
1.4 Hz, 1H), 7.38 (d,
J
= 9.0 Hz,
J
= 2.7 Hz, 1H), 7.71 (dd,
J = 7.6 Hz, J = 1.6 Hz, 1H), 7.62
J
J
J
= 7.5 Hz,
J
= 1.7 Hz, 1H), 7.45 (td,
J = 7.5 Hz, J =
J
= 9.1 Hz, 1H), 4.22 (s, 2H), 3.98 (t, J
= 9.1 Hz, 2H) ppm. 13C{1H} NMR
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2
(101 MHz, DMSOꢀd6
)
δ
158.8, 148.0, 141.0, 134.2, 133.1, 131.9, 131.6, 131.6, 129.3, 128.1,
3
4
125.7, 125.0, 119.1, 52.6, 51.5 ppm. HRMS (ESI), m/z calcd for C15H12N3O2S+ [M+H]+
5
6
7
298.0645, found 298.0647.
8
9
7ꢀ(Trifluoromethyl)ꢀ2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀd][1,4]thiazepine (7f)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield 569 mg, 95%; white solid; mp 169ꢀ171 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
7.83 (d,
= 1.4 Hz, 1H), 7.48 (td,
= 9.3 Hz, 2H) ppm.
159.7, 146.3, 134.7, 134.2, 132.2, 132.0, 132.0, 130.1 (q,
= 271.9 Hz, CF3), 123.3 (q, = 32.7
J =
2.2 Hz, 1H), 7.70 (td, J = 7.8 Hz, J = 2.0 Hz, 2H), 7.58 (dd, J = 7.6 Hz, J
J
= 7.5 Hz,
J = 1.8 Hz, 1H), 7.37 – 7.45 (m, 2H), 4.18 (s, 2H), 3.93 (t, J
13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
J
= 3.3 Hz), 129.6, 127.6 (q,
J
= 3.5 Hz), 126.5, 124.2 (q,
J
J
Hz), 120.0, 52.7, 51.8 ppm. HRMS (ESI), m/z calcd for C16H12F3N2S+ [M+H]+ 321.0670, found
321.0668.
2,3ꢀDihydrobenzo[
f
]imidazo[1,2ꢀ
d
]pyrido[3,2ꢀ
b
][1,4]thiazepine (7g)
1
Yield 341 mg, 72%; light beige solid; mp 136ꢀ138 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.32
(dd,
J
= 4.8 Hz,
J
= 1.8 Hz, 1H), 7.92 (dd,
J
= 7.6 Hz,
J
= 1.8 Hz, 1H), 7.76 (dd,
= 7.5 Hz, = 1.7 Hz, 1H), 7.42 (td,
= 4.8 Hz, 1H), 4.23 (t,
J
= 7.6 Hz,
J
J
=
=
J
1.7 Hz, 1H), 7.57 (dd,
J
= 7.6 Hz, 1.4 Hz, 1H), 7.48 (td,
J
J
7.5 Hz,
J
= 1.5 Hz, 1H), 7.03 (dd,
J
= 7.6 Hz,
J
J
= 9.5 Hz, 2H), 3.90 (t,
13
= 9.5 Hz, 2H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
158.7, 153.9, 148.5, 141.2, 133.8,
133.5, 131.9, 131.7, 131.5, 128.9, 120.2, 118.7, 51.1, 51.0 ppm. HRMS (ESI), m/z calcd for
C14H12N3S+ [M+H]+ 254.0746, found 254.0750.
Methyl 2,3ꢀdihydrobenzo[
f
]imidazo[1,2ꢀ
d
]pyrido[3,2ꢀ
b
][1,4]thiazepineꢀ7ꢀcarboxylate (7h)
8.81 (d,
= 7.6 Hz,
= 1.6 Hz, 1H), 4.29 (t,
1
Yield 297 mg, 51%; white solid; mp 169ꢀ171 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
J =
2.2 Hz, 1H), 8.27 (d,
= 1.6 Hz, 1H), 7.53 (td,
= 9.2 Hz, 2H), 3.95 (t,
158.3, 144.5, 143.6, 140.3, 138.0, 133.2, 131.4, 131.3, 126.8, 123.0, 121.1, 119.1, 118.5,
J
= 2.1 Hz, 1H), 7.77 (dd,
J
= 7.6 Hz,
J
= 1.6 Hz, 1H), 7.62 (dd,
J
J
J
= 7.6 Hz, 1.6 Hz, 1H), 7.46 (td,
J
= 7.6 Hz,
J
J
J
= 9.2 Hz, 2H), 3.85 (s, 3H) ppm. 13C{1H} NMR (101 MHz, Chloroformꢀ
d) δ
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77.4, 51.8, 51.5 ppm. HRMS (ESI), m/z calcd for C16H14N3O2S+ [M+H]+ 312.0809, found
3
4
312.0807.
5
6
7
8
9
7ꢀNitroꢀ2,3ꢀdihydrobenzo[
Yield 502 mg, 90%; light yellow solid; mp 226ꢀ228 °C. H NMR (400 MHz, DMSOꢀd6
(d, = 2.8 Hz, 1H), 8.57 (d, = 2.8 Hz, 1H), 7.76 (d, = 7.6 Hz, 1H), 7.64 (d, = 7.6 Hz, 1H),
= 8.9 Hz, 2H), 3.98 (t,
157.0, 157.0, 144.3, 138.1, 135.2,
f]imidazo[1,2ꢀd]pyrido[3,2ꢀb][1,4]thiazepine (7i)
1
)
δ 9.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
J
J
7.55 (td,
J
= 7.6 Hz,
J
= 1.8 Hz, 1H), 7.52 – 7.44 (m, 1H), 4.32 (t,
J
J =
8.9 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
133.4, 131.8 (2С) 131.5, 131.2, 128.9, 118.3, 51.7, 51.1 ppm. HRMS (ESI), m/z calcd for
C14H11N4O2S+ [M+H]+ 299.0599, found 299.0597.
7ꢀ(Pyrrolidinꢀ1ꢀylsulfonyl)ꢀ2,3ꢀdihydrobenzo[
(7j)
f]imidazo[1,2ꢀd]pyrido[3,2ꢀb][1,4]thiazepine
Yield 607 mg, 86%; light yellow solid; mp 177ꢀ179 °C; 1H NMR (400 MHz, DMSOꢀd6
(d, = 2.3 Hz, 1H), 8.16 (d, = 2.3 Hz, 1H), 7.78 (dd, = 7.6 Hz, = 1.5 Hz, 1H), 7.63 (dd,
7.6 Hz, 1.5 Hz, 1H), 7.54 (td, = 7.6 Hz, = 1.5 Hz, 1H), 7.47 (td, = 7.6 Hz, = 1.5 Hz, 1H),
= 9.2 Hz, 2H), 3.14 – 3.20 (m, 4H), 1.73 – 1.66 (m, 4H) ppm.
) δ 8.68
J
J
J
J
J =
J
J
J
J
4.29 (t,
J = 9.2 Hz, 2H), 3.96 (t, J
13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ 157.8, 156.2, 147.3, 139.4, 133.7, 132.2 (2С), 132.1,
131.7, 129.3, 126.6, 119.4, 51.80, 51.2, 47.8, 47.8, 24.7, 24.7 ppm. HRMS (ESI), m/z calcd for
+
C18H19N4O2S2 [M+H]+ 387.0940, found 387.0944.
2,3ꢀDihydrobenzo[
f]imidazo[1,2ꢀd]pyrazino[2,3ꢀb][1,4]thiazepine (7k)
Yield 362 mg, 76%; light beige solid; mp 123ꢀ125 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.37 (d,
= 7.6 Hz, 1H), 7.53
= 9.3 Hz, 2H), 3.96 (t, = 9.2 Hz, 2H)
δ 158.3, 151.0, 142.8, 142.7, 138.0, 133.6, 132.7
J
= 2.6 Hz, 1H), 8.16 (d, J = 2.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.63 (d, J
(t,
J
= 7.6 Hz, 1H), 7.46 (t,
J
= 7.6 Hz, 1H), 4.23 (t,
J
J
ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
(2С), 132.5, 131.3, 129.7, 51.9, 51.8 ppm. HRMS (ESI), m/z calcd for C13H11N4S+ [M+H]+
255.0703, found 255.0699.
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General procedure for oneꢀpot preparation of [1,4,7]ꢀthiadiazecines 13aꢀr
3
4
5
6
7
8
9
To a microwave reaction vial were added the solution of the respective imidazolineꢀfused
[1,4]thiazepine 7aꢀk (0.35 mmol) and AlkHal (0.368 mmol) in acetonitrile (10 mL). The
resulting mixture was stirred in the microwave for 5 h at 120°C. After cooling to RT, 0.2%
aqueous K2CO3 (10 mL) was added and stirred for 1 h at room temperature (the reaction was
monitored by TLC in THFꢀHexane (3:1) or EtOAc). Then CH2Cl2 (2x4 mL) were added and the
organic layer was separated using centrifuge, washed with water and dried over Na2SO4,
evaporated and purified by column chromatography eluting with EtOAc.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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52
53
54
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60
8ꢀMethylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5
H
ꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀcarbonitrile (13a)
°
Yield 69 mg, 64%; white solid; mp 195ꢀ197 C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.11 (d,
= 2.0 Hz, 1H), 7.37 (td,
= 1.3 Hz, 1H), 7.13 (dd, = 7.6 Hz, = 1.6
= 8.6 Hz, = 4.2 Hz, 1H), 3.57 (ddt, = 14.8 Hz,
J =
2.0 Hz, 1H), 7.67 (dd,
= 7.6 Hz, = 1.6 Hz, 1H), 7.31 (td,
Hz, 1H), 6.98 (d, = 8.6 Hz, 1H), 5.47 (dd,
J
= 7.6 Hz,
J
= 1.3 Hz, 1H), 7.58 (dd,
J = 8.6 Hz, J
J
J
J
= 7.6 Hz,
J
J
J
J
J
J
J
J
= 11.0 Hz,
DMSOꢀd6
J
δ
= 3.7 Hz, 1H), 3.31 – 3.13 (m, 3H), 2.91 (s, 3H) ppm. 13C{1H} NMR (101 MHz,
169.2, 154.7, 140.1, 139.5, 135.1, 134.5, 130.8, 130.2, 128.5, 127.6, 121.8, 119.6,
)
116.8, 100.2, 53.5, 42.8, 32.1 ppm. HRMS (ESI), m/z calcd for C17H16N3OS+ [M+H]+ 310.1008,
found 310.1009.
8ꢀMethylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5
Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ4ꢀcarbonitrile (13b)
Yield 63 mg, 58%; white solid; mp 207ꢀ209 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.17 (dd,
J =
7.7 Hz,
(m, 2H), 7.22 – 7.16 (m, 1H), 6.97 (t,
3.74 – 3.61 (m, 1H), 3.51 – 3.40 (m, 1H), 3.18 (ddd,
J
= 1.6 Hz, 1H), 7.80 – 7.74 (m, 1H), 7.68 (dd,
= 7.7 Hz, 1H), 5.41 (dd,
= 14.3 Hz,
J = 7.7 Hz, J = 1.6 Hz, 1H), 7.42 – 7.34
J
J
= 10.5 Hz,
J = 3.1 Hz,
J
J
= 1.8 Hz, 1H),
= 1.4 Hz, 1H),
J
3.11 – 3.04 (m, 1H), 3.03 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
) δ 169.0, 154.1,
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141.6, 141.0, 136.3, 135.1, 129.9, 129.7, 129.1, 126.5, 126.3, 121.1, 117.8, 102.2, 52.3, 44.2,
3
4
30.6 ppm. HRMS (ESI), m/z calcd for C17H16N3OS+ [M+H]+ 310.1005, found 310.1009.
5
6
7
Methyl 8ꢀmethylꢀ6,7,8,9ꢀtetrahydroꢀ5
H
ꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀcarboxylate (13c)
8
9
°
Yield 81 mg, 67%; white solid; mp 174ꢀ176 C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.17 (d,
= 1.4 Hz, 1H), 7.35
= 1.4 Hz, 1H), 7.11 (dd, = 7.5 Hz, J =
J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.1 Hz, 1H), 7.76 (dd,
(td, = 7.5 Hz, = 1.7 Hz, 1H), 7.29 (td,
1.7 Hz, 1H), 6.95 (d, = 8.6 Hz, 1H), 5.32 (dd,
(ddt, = 14.5 Hz, = 9.3 Hz,
NMR (101 MHz, DMSOꢀd6
J
= 8.6 Hz,
J
= 2.1 Hz, 1H), 7.57 (dd,
= 7.5 Hz,
= 8.3 Hz,
J = 7.5 Hz, J
J
J
J
J
J
J
J
J
= 4.5 Hz, 1H), 3.80 (s, 3H), 3.58
13
J
J
J
δ
= 5.2 Hz, 1H), 3.31 – 3.18 (m, 3H), 2.88 (s, 3H) ppm. C{1H}
)
168.7, 165.5, 154.6, 138.7, 137.0, 133.6, 132.1, 130.6, 129.7,
127.8, 127.2, 120.1, 119.3, 115.6, 53.0, 51.7, 42.6, 31.7 ppm. HRMS (ESI), m/z calcd for
C18H21N2O2S+ [M+H]+ 329.1328, found 329.1326.
Methyl
carboxylate (13d)
Yield 48 mg, 40%; white solid; mp 153ꢀ156 °C. H NMR (400 MHz, DMSOꢀd6
8ꢀmethylꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀbenzo[i]pyrido[3,2ꢀb][1,4,7]thiadiazecineꢀ2ꢀ
1
)
δ
8.60 (d,
J =
2.2 Hz, 1H), 8.21 (d,
J
= 2.2 Hz, 1H), 7.49 (dd,
J
= 7.6 Hz,
J
= 1.2 Hz, 1H), 7.36 (td, = 7.6 Hz,
J
1.5 Hz, 1H), 7.27 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.09 (dd,
J
= 7.7 Hz,
J
= 1.6 Hz, 1H), 6.02 (dd,
J
= 7.6 Hz,
J
= 5.0 Hz, 1H), 4.06 – 3.91 (m, 1H), 3.81 (s, 3H), 3.45 – 3.33 (m, 2H), 3.28 (dd,
J
=
13.7 Hz, 3.1 Hz, 1H), 2.72 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ 168.2, 164.8,
161.7, 150.8, 142.9, 142.9, 136.0, 131.3, 129.4, 129.3, 128.1, 126.7, 115.7, 112.8, 53.5, 51.8,
32.3 ppm. HRMS (ESI), m/z calcd for HRMS (ESI), m/z calcd for C17H20N3O2S+ [M+H]+
330.1271, found 330.1275.
8ꢀMethylꢀ2ꢀnitroꢀ5,6,7,8ꢀtetrahydroꢀ9
(13e)
Hꢀbenzo[i]pyrido[3,2ꢀb][1,4,7]thiadiazecinꢀ9ꢀone
Yield 80 mg, 65%; light yellow solid; mp 181ꢀ183°C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.94 (d,
= 7.7
J
= 2.6 Hz, 1H), 8.54 (d, = 2.6 Hz, 1H), 7.53 (dd, = 8.1 Hz, = 1.1 Hz, 1H), 7.38 (td,
J
J
J
J
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6
7
8
Hz,
6.64 (t,
NMR (101 MHz, DMSOꢀd6
J
= 1.6 Hz, 1H), 7.28 (td,
J
= 7.5 Hz,
J
= 1.2 Hz, 1H), 7.11 (dd,
J
= 7.7 Hz,
J
= 1.5 Hz, 1H),
13
J
= 6.1 Hz, 1H), 4.09 – 3.97 (m, 1H), 3.50 – 3.32 (m, 3H), 2.75 (s, 3H) ppm. C{1H}
)
δ 168.3, 161.7, 146.3, 137.1, 135.8, 135.3, 131.3, 129.4, 128.7,
128.2, 126.8, 113.0, 53.4, 40.6, 32.5 ppm. HRMS (ESI), m/z calcd for C15H14N4NaO3S+
9
[M+Na]+ 353.0679, found 353.0684.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
36
37
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42
43
44
45
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48
49
50
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54
55
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60
8ꢀEthylꢀ2ꢀ(trifluoromethyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9Hꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone
(13f)
1
Yield 55 mg, 43%; white solid; mp 140ꢀ142°C. H NMR (400 MHz, DMSOꢀd6
)
δ
7.97 (d,
= 2.3 Hz, 1H), 7.36
= 1.5 Hz, 1H), 7.08 (dd, = 7.3 Hz, J =
J =
2.2 Hz, 1H), 7.65 (dd,
(td, = 7.6 Hz, = 1.9 Hz, 1H), 7.31 (td,
1.8 Hz, 1H), 7.00 (d, = 8.6 Hz, 1H), 5.31 (dd,
J
= 7.8 Hz,
J
= 1.5 Hz, 1H), 7.50 (dd,
J = 8.5 Hz, J
J
J
J
= 7.4 Hz,
J
J
J
J
= 8.7 Hz,
J = 3.8 Hz, 1H), 3.67 – 3.50 (m, 2H),
3.31 – 3.21 (m, 2H), 3.14 – 3.05 (m, 2H), 1.18 (t,
J
= 7.0 Hz, 3H) ppm. 13C{1H} NMR (126
MHz, DMSOꢀd6 168.4, 153.9, 139.3, 134.0, 132.6 (d, J = 4.1 Hz), 130.1, 129.7, 128.1, 127.9
)
δ
(q,
J = 3.6 Hz), 127.1, 124.3 (q, J = 270.9 Hz), 121.0, 118.7 (q, J = 32.4 Hz), 116.5, 50.4, 43.1,
38.0, 12.7 ppm. HRMS (ESI), m/z calcd for C18H18F3N2OS [M+H]+ 367.1086, found 367.1084.
8ꢀEthylꢀ5,6,7,8ꢀtetrahydroꢀ9
Hꢀbenzo[i]pyrido[3,2ꢀb][1,4,7]thiadiazecinꢀ9ꢀone (13g)
Yield 49 mg, 47%; white solid; mp 128ꢀ130 °C. 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.07 (dd,
= 1.4 Hz, 1H), 7.34
= 7.6 Hz, = 1.7 Hz,
= 5.2 Hz, 1H), 3.70 (tdd, = 11.8,
= 7.1 Hz, 1H), 3.44 – 3.38 (m, 1H), 3.29 (dd, = 14.5,
= 7.1 Hz, 3H)
168.6, 160.7, 149.7, 143.9, 138.6, 136.8, 133.6,
J =
4.8,
(td,
J
J
= 1.8 Hz, 1H), 7.91 (dd,
= 7.6, = 1.7 Hz, 1H), 7.29 (td,
= 7.5, = 4.8 Hz, 1H), 5.47 (dd,
= 2.6 Hz, 1H), 3.53 (dq, = 14.0,
J
= 7.5,
J
= 1.8 Hz, 1H), 7.54 (dd,
= 7.6, = 1.4 Hz, 1H), 7.04 (dd,
= 7.1,
J = 7.6, J
J
J
J
J
J
1H), 6.66 (dd,
5.2,
J
J
J
J
J
J =
J
J
J
J
J
= 2.7 Hz, 1H), 3.20 – 3.11 (m, 1H), 2.94 (dq, J = 14.0, J = 7.1 Hz, 1H), 1.13 (t, J
13
ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
130.6, 129.9, 127.9 (2С), 115.3, 51.1, 41.3, 38.5, 13.2 ppm. HRMS (ESI), m/z calcd for
C16H18N3OS+ [M+H]+ 300.1165 found 300.1162.
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2ꢀNitroꢀ8ꢀpropylꢀ5,6,7,8ꢀtetrahydroꢀ9
(13h)
Hꢀbenzo[i]pyrido[3,2ꢀb][1,4,7]thiadiazecinꢀ9ꢀone
5
6
7
8
Yield 48 mg, 38%; light beige solid; mp 197ꢀ199 °C.1H NMR (400 MHz, DMSOꢀd6
= 2.6 Hz, 1H), 8.52 (d, = 2.6 Hz, 1H), 7.52 (dd, = 7.7 Hz, = 1.0 Hz, 1H), 7.38 (td,
Hz, = 1.4 Hz, 1H), 7.28 (td, = 7.7 Hz, = 1.0 Hz, 1H), 7.04 (dd, = 7.7 Hz, = 1.4 Hz, 1H),
= 7.8
)
δ
8.94 (d,
J
J
J
J
J
= 7.7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
J
J
J
6.68 – 6.58 (m, 1H), 4.13 – 4.00 (m, 1H), 3.42 – 3.32 (m, 4H), 2.64 (ddd,
J = 13.6 Hz, J
Hz,
J = 5.8 Hz, 1H), 1.62 – 1.41 (m, 2H), 0.87 (t, J
= 7.4 Hz, 3H) ppm. 13C{1H} NMR (101
MHz, DMSOꢀd6) δ 168.0, 161.8, 146.2, 137.1, 135.7, 135.1, 131.0, 129.3, 128.4, 128.2, 126.7,
112.5, 50.8, 44.8, 41.0, 20.5, 11.1 ppm. HRMS (ESI), m/z calcd for C17H19N4O3S+ [M+H]+
359.1172 found 359.1172.
8ꢀPropylꢀ2ꢀ(pyrrolidinꢀ1ꢀylsulfonyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9
H
ꢀbenzo[i]pyrido[3,2ꢀ
b
][1,4,7]
thiadiazecinꢀ9ꢀone (13i)
1
Yield 78 mg, 50%; white solid; mp 167ꢀ170°C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.44 (d, J =
2.3 Hz, 1H), 8.03 (d,
Hz, = 7.6 Hz, = 1.6 Hz, 1H), 7.25 (td,
Hz, 1H), 6.03 (dd, = 9.0 Hz,
11.3 Hz, = 3.8 Hz, 1H), 3.31 – 3.18 (m, 3H), 3.14 (q,
= 5.8 Hz, 1H), 1.72 (q, = 7.0 Hz, 4H), 1.60 – 1.37 (m, 2H), 0.84 (t,
168.0, 161.6, 148.3, 141.6, 134.9, 130.0, 129.1,
J
= 2.3 Hz, 1H), 7.47 (dd,
J
= 8.2 Hz,
J
= 1.2 Hz, 1H), 7.36 (ddd,
= 7.6 Hz,
J
= 8.2
J
J
J
= 7.6,
J
= 1.2 Hz, 1H), 6.98 (dd,
J
J
= 1.6
J
J
= 4.1 Hz, 1H), 4.16 – 4.04 (m, 1H), 3.39 (ddd,
= 4.0 Hz, 4H), 2.59 (ddd,
J
= 14.9 Hz,
J
=
J
J
J
= 13.6 Hz,
J
= 8.2 Hz,
J
J
J = 7.4 Hz, 3H)
13
ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
128.7, 128.3, 126.2, 121.2, 112.1, 51.1, 47.8, 47.8, 44.9, 41.3, 24.6, 24.6, 20.5, 11.2 ppm. HRMS
+
(ESI), m/z calcd for C21H27N4O3S2 [M+H]+ 447.1519 found 447.1515.
8ꢀ(2ꢀMethoxyethyl)ꢀ2ꢀnitroꢀ5,6,7,8ꢀtetrahydroꢀ9
(13j)
Hꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone
Yield 43 mg, 33%; yellow solid; mp 146ꢀ148 °C. 1H NMR (400 MHz, DMSOꢀd6
2.8 Hz, 1H), 8.05 (dd, = 9.2 Hz, = 2.8 Hz, 1H), 7.58 (dd, = 7.6 Hz, = 1.3 Hz, 1H), 7.36 (td,
= 7.6 Hz, = 1.6 Hz, 1H), 7.31 (td, = 7.6 Hz, = 1.3 Hz, 1H), 7.04 (dd, = 7.6 Hz, = 1.6
) δ 8.42 (d, J =
J
J
J
J
J
J
J
J
J
J
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Hz, 1H), 6.98 (d,
J = 9.2 Hz, 1H), 5.84 (t, J = 6.5 Hz, 1H), 3.72 – 3.46 (m, 4H), 3.40 – 3.32 (m,
3
4
2H), 3.29 (s, 3H), 3.20 – 3.08 (m, 2H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ 168.5,
5
6
7
8
9
155.9, 137.4, 137.2, 132.6, 131.4, 129.6, 129.5, 127.6, 127.4, 126.8, 118.6, 114.2, 69.5, 58.2,
51.7, 43.2, 42.5 ppm. HRMS (ESI), m/z calcd for C18H20N3O4S+ [M+H]+ 374.1169 found
374.1171.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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47
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53
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57
58
59
60
N,Nꢀdimethylꢀ9ꢀoxoꢀ8ꢀ(propꢀ2ꢀynꢀ1ꢀyl)ꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]
thiadiazecineꢀ2ꢀsulfonamide (13k)
Yield 54 mg, 35%; light beige solid; mp 196ꢀ198 °C. 1H NMR (400 MHz, DMSOꢀd6
= 2.3 Hz, 1H), 7.60 (dd, = 7.7 Hz, = 1.4 Hz, 1H), 7.52 (dd, = 8.6 Hz, = 2.3 Hz, 1H), 7.38
(td, = 7.7 Hz, = 1.6 Hz, 1H), 7.32 (td, = 7.5 Hz, = 1.4 Hz, 1H), 7.07 (dd, = 7.5 Hz,
1.6 Hz, 1H), 7.05 (d, = 8.6 Hz, 1H), 5.46 (dd, = 8.1 Hz, = 5.0 Hz, 1H), 4.26 (dd, = 17.6
) δ 7.90 (d, J
J
J
J
J
J
J
J
J
J
J =
J
J
J
J
Hz,
J = 2.4 Hz, 1H), 4.04 (dd, J = 17.6 Hz, J = 2.5 Hz, 1H), 3.74 – 3.64 (m, 1H), 3.46 – 3.35 (m,
2H), 3.32 (s, 1H), 3.26 – 3.16 (m, 1H), 2.57 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
168.3, 154.3, 137.4, 135.5, 133.3, 130.5, 130.5, 129.9, 127.9, 127.1, 123.1, 120.1, 115.8, 79.6,
74.5, 51.3, 42.7, 37.7, 37,7, 33.2 ppm. HRMS (ESI), m/z calcd for C20H21N3NaO3S2 [M+Na]+
+
438.0917, found 438.0921.
General procedure for oneꢀpot preparation of [1,4,7]ꢀthiadiazecines 13lꢀr
To a solution of respective compound 7aꢀk (0.35 mmol) in acetonitrile (10 mL) 0.368 mmol of
BrCH2Ar was added. The resulting mixture was stirred overnight at 60°C (the reaction was
monitored by TLC in THFꢀHexane (3:1) or EtOAc). Then 0.2% aqueous K2CO3 (10 mL) was
added at room temperature. After 1 h, CH2Cl2 (2x4 mL) was added, the organic layer was
separated, washed with water, dried over Na2SO4, evaporated and purified by column
chromatography eluting with EtOAc.
8ꢀ(3ꢀFluorobenzyl)ꢀ2ꢀ(pyrrolidinꢀ1ꢀylsulfonyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9
][1,4,7]thiadiazecinꢀ9ꢀone (13l)
Hꢀbenzo[i]pyrido[3,2ꢀ
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Yield 108 mg, 60%; white solid; mp 206ꢀ208 °C. 1H NMR (400 MHz, DMSOꢀd6
) δ 8.50 (d, J =
3
4
5
6
7
8
9
2.3 Hz, 1H), 8.07 (d,
J
= 2.3 Hz, 1H), 7.50 (dd,
= 1.2 Hz, 1H), 7.19 – 7.07 (m, 3H), 7.04 (dd,
= 4.2 Hz, 1H), 4.51 (d, = 15.3 Hz, 1H), 4.26 – 4.12 (m, 1H), 3.88 (d, J =
J
= 8.1 Hz,
J
= 1.2 Hz, 1H), 7.44 – 7.36 (m, 2H),
7.28 (td,
6.19 (dd,
J
= 7.6 Hz,
= 8.8 Hz,
J
J
= 7.6 Hz, = 1.3 Hz, 1H),
J
J
J
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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37
38
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40
41
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44
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46
47
48
49
50
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53
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55
56
57
58
59
60
15.3 Hz, 1H), 3.51 – 3.40 (m, 1H), 3.29 – 3.20 (m, 2H), 3.18 – 3.11 (m, 4H), 1.75 – 1.60 (m, 4H)
ppm.13C{1H} NMR (101 MHz, DMSOꢀd6
) δ 168.4, 162.3 (d, J = 243.9 Hz), 161.5, 148.4, 141.7,
140.8 (d,
J
= 7.1 Hz), 134.2, 130.6 (d,
J
= 8.4 Hz), 130.2, 129.3, 129.0, 128.3, 126.3, 123.3 (d,
J
= 2.7 Hz), 121.3, 114.2 (d,
J
= 21.7 Hz), 114.0 (d,
J
= 21.2 Hz), 112.1, 51.3, 47.8, 47.8, 46.0,
40.8, 24.6 (2С) ppm. HRMS (ESI), m/z calcd for C25H26FN4O3S2 [M+H]+ 513.1425 found
+
513.1428.
8ꢀ(4ꢀMethylbenzyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9
(13m)
Hꢀbenzo[i]pyrido[3,2ꢀb][1,4,7]thiadiazecinꢀ9ꢀone
Yield 54 mg, 49%; white solid; mp 144ꢀ146 °C. 1H NMR (400 MHz, DMSOꢀd6
4.8 Hz, = 1.8 Hz, 1H), 7.91 (dd, = 7.5 Hz, = 1.8 Hz, 1H), 7.56 (dd, = 7.9 Hz,
1H), 7.36 (td, = 7.6 Hz, = 1.7 Hz, 1H), 7.32 – 7.29 (m, 1H), 7.27 (d, = 7.8 Hz, 2H), 7.18 (d,
= 7.8 Hz, 2H), 7.07 (dd, = 7.5 Hz, = 1.8 Hz, 1H), 6.67 (dd, = 7.5 Hz, = 4.8 Hz, 1H), 5.48
= 14.9 Hz, 1H), 3.99 (d, = 14.9 Hz, 1H), 3.79 (tdd, = 11.7 Hz,
= 14.2 Hz, 2.9
)
δ
8.10 (dd,
J =
J
J
J
J
J
= 1.3 Hz,
J
J
J
J
J
J
J
J
(t,
J
= 6.3 Hz, 1H), 4.80 (d,
J
J
J
J
= 5.9 Hz,
J
= 3.0 Hz, 1H), 3.42 – 3.34 (m, 1H), 3.27 – 3.18 (m, 1H), 3.10 (dd, J
13
Hz, 1H), 2.29 (s, 3H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
168.7, 160.1, 149.2, 143.4,
137.3, 136.4, 134.7, 132.8, 130.3, 129.5, 129.2 (2С), 127.7 (2С), 127.4 (2С), 114.8, 114.5, 50.7,
45.5, 40.3, 20.7 ppm. HRMS (ESI), m/z calcd for C22H22N3OS+ [M+H]+ 376.1478, found
376.1479.
8ꢀ(3ꢀFluorobenzyl)ꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5
carbonitrile (13n)
Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
1
Yield 79 mg, 56%; white solid; mp 205ꢀ207 °C; H NMR (400 MHz, DMSOꢀd6
) δ 8.11 (d, J =
2.0 Hz, 1H), 7.67 (dd, = 7.9 Hz, = 1.3 Hz, 1H), 7.60 (dd, = 8.7 Hz, = 2.0 Hz, 1H), 7.48 –
J
J
J
J
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8
7.37 (m, 2H), 7.34 (td,
6.99 (d, = 8.7 Hz, 1H), 5.51 (dd,
= 15.2 Hz, 1H), 3.62 (tt,
(101 MHz, DMSOꢀd6 169.0, 162.3 (d,
= 8.3 Hz), 130.1, 129.8, 127.9, 127.2, 123.6 (d,
= 21.6 Hz), 114.1 (d, = 20.9 Hz), 99.6, 50.9, 45.6, 42.2 ppm.
J
= 7.5 Hz,
J
= 1.3 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.17 – 7.10 (m, 2H),
J
J
= 7.9 Hz, J = 4.8 Hz, 1H), 4.86 (d, J = 15.2 Hz, 1H), 4.23 (d,
J
J = 9.9 Hz, J
= 4.8 Hz, 1H), 3.30 – 3.14 (m, 3H) ppm. 13C{1H} NMR
= 243.8 Hz), 154.1, 140.7 (d, = 7.1 Hz), 139.6,
= 2.8 Hz),
)
δ
J
J
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
137.9, 134.6, 133.6, 130.6 (d,
120.5, 119.1, 115.9, 114.4 (d,
J
J
J
J
HRMS (ESI), m/z calcd for C23H19FN3OS+ [M+H]+ 404.1221, found 404.1227.
8ꢀ(4ꢀmethylbenzyl)ꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
carbonitrile (13o)
°
1
Yield 59 mg, 42%; white solid; mp 221ꢀ223 C; H NMR (400 MHz, DMSOꢀd6
2.0 Hz, 1H), 7.67 (dd, = 7.9 Hz, = 1.3 Hz, 1H), 7.60 (dd, = 8.6 Hz, 2.0 Hz, 1H), 7.38 (td,
= 7.6 Hz, = 1.7 Hz, 1H), 7.35 – 7.28 (m, 3H), 7.19 (d, = 7.9 Hz, 2H), 7.09 (dd, = 7.6 Hz,
1.7 Hz, 1H), 6.98 (d, = 8.6 Hz, 1H), 5.51 (dd, = 8.3 Hz, = 4.5 Hz, 1H), 4.86 (d,
)
δ
8.11 (d,
J
=
J
J
J
J
J
J
J
J
=
J
J
J
J
= 14.8 Hz,
1H), 4.16 (d,
J = 14.8 Hz, 1H), 3.65 – 3.54 (m, 1H), 3.27 – 3.12 (m, 3H), 2.30 (s, 3H) ppm.
13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ 169.3, 154.6, 140.1, 138.8, 136.9, 135.2, 135.2, 134.2,
130.6, 130.3, 129.7, 129.7, 128.5, 128.3, 128.3, 127.6, 121.2, 119.6, 116.6, 100.1, 51.1, 46.2,
42.7, 21.2 ppm. HRMS (ESI), m/z calcd for C24H22N3OS+ [M+H]+ 400.1483, found 400.1478.
Methyl
8ꢀbenzylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
carboxylate (13p)
1
Yield 82 mg, 53%; white solid; mp 183ꢀ186 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.16 (d,
= 1.3 Hz, 1H), 7.41 – 7.28
= 8.7 Hz, 1H), 5.38 (dd, = 7.5 Hz,
= 15.0 Hz, 1H), 3.80 (s, 3H), 3.69 – 3.58 (m,
168.9, 165.5, 154.5,
J =
2.0 Hz, 1H), 7.78 (dd,
(m, 7H), 7.11 (dd, = 7.5 Hz,
5.1 Hz, 1H), 4.87 (d,
J
= 8.7 Hz, 2.0 Hz, 1H), 7.57 (dd,
J = 7.9 Hz, J
J
J
= 1.6 Hz, 1H), 6.96 (d,
J
J
J =
J
= 15.0 Hz, 1H), 4.17 (d, J
1H), 3.28 – 3.10 (m, 3H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
13
137.9, 137.7, 137.0, 133.2, 132.1, 130.5, 129.7, 128.7 (2С), 127.7, 127.6 (2С), 127.3, 127.2,
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119.4, 119.2, 115.4, 51.7, 50.7, 45.9, 42.4 ppm. HRMS (ESI), m/z calcd for C24H22N2NaO3S+
3
4
[M+Na]+ 441.1243 found 441.1242.
5
6
7
8ꢀBenzylꢀ2ꢀnitroꢀ5,6,7,8ꢀtetrahydroꢀ9
Hꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone (13q)
8
9
Yield 72 mg, 51%; light yellow solid; mp 228ꢀ230°C. 1H NMR (400 MHz, DMSOꢀd6
) δ 8.45 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
= 2.7 Hz, 1H), 8.11 – 8.06 (m, 1H), 7.61 (dd,
J
= 7.9 Hz,
J = 1.3 Hz, 1H), 7.41 – 7.29 (m, 7H),
7.11 (dd, = 7.6 Hz, = 1.6 Hz, 1H), 7.03 (d,
J
J
J
= 9.2 Hz, 1H), 5.88 (t,
J
= 6.5 Hz, 1H), 4.86 (d,
J
= 15.1 Hz, 1H), 4.12 (d,
J
= 15.1 Hz, 1H), 3.81 – 3.68 (m, 1H), 3.33 – 3.25 (m, 2H), 3.19 (dd,
J
13
= 13.5 Hz,
J
= 3.2 Hz, 1H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
168.7, 155.8, 137.7,
137.3, 137.3, 132.9, 131.4, 129.8, 129.7, 129.7, 128.7, 128.7, 128.7, 127.6, 127.6, 127.4, 127.3,
126.8, 118.8, 50.7, 46.1, 42.1 ppm. HRMS (ESI), m/z calcd for C22H20N3O3S+ [M+H]+ 406.1228,
found 406.1225.
8ꢀ(2ꢀFluorobenzyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9
(13r)
Hꢀbenzo[i]pyrazino[2,3ꢀb][1,4,7]thiadiazecinꢀ9ꢀone
Yield 58 mg, 41%; light beige solid; mp 177ꢀ179 °C; 1H NMR (400 MHz, DMSOꢀd6
)
δ
8.08 (d,
= 8.0 Hz, 1.2 Hz, 1H), 7.42 – 7.37 (m, 2H),
= 7.6 Hz, = 1.6 Hz, 1H), 5.62 (dd, = 8.2
= 14.2 Hz, = 11.5 Hz, = 8.5 Hz,
J
= 2.6 Hz, 1H), 7.84 (d,
7.36 – 7.28 (m, 2H), 7.24 – 7.18 (m, 2H), 7.11 (dd,
Hz, 4.9 Hz, 1H), 4.69 (d,
J
= 2.6 Hz, 1H), 7.48 (dd,
J
J
J
J
J
= 15.4 Hz, 1H), 4.04 (dddd,
J
J
J
J
J
=
=
3.2 Hz, 1H), 3.94 (d,
J = 15.4 Hz, 1H), 3.39 – 3.35 (m, 1H), 3.27 – 3.21 (m, 1H), 3.18 (dd,
14.6 Hz,
J
= 3.2 Hz, 1H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
169.3, 160.9 (d,
J = 244.8
Hz), 155.7, 142.1, 137.3, 135.8, 134.2, 131.5, 130.2 (d,
J
= 4.3 Hz), 129.9, 129.8 (d, = 8.2 Hz),
J
129.2, 128.5, 127.3, 125.1 (d,
J = 3.4 Hz), 124.7 (d, J = 14.5 Hz), 115.8 (d, J = 21.2 Hz), 51.4,
41.1 (d,
J
= 3.8 Hz), 40.0 ppm. HRMS (ESI), m/z calcd for C20H17FN4NaOS+ [M+Na]+
403.0999, found 403.1005.
General procedure for preparation of sulfoxides 8aꢀb
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To a solution of 0.67 mmol of thiazepine in methanol was added a solution of
mꢀCPBA (289.4
3
4
5
6
7
8
9
mg, 1.68 mmol) in methanol at 0°C. This suspension was stirred for 2 h at room temperature and
the resulting solid was filtered off, washed with methanol. Crystallized from DMF to provide the
analytically pure product.
10
11
12
13
14
15
16
17
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19
20
21
22
23
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60
Methyl 2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ7ꢀcarboxylate 9ꢀoxide (8a)
1
Yield 131 mg, white solid; yield 60%; mp 281ꢀ283 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.12
(d,
J
= 2.1 Hz, 1H), 8.03 (dd,
J
= 8.4 Hz,
J
= 2.1 Hz, 1H), 7.85 – 7.70 (m, 3H), 7.59 (ddd,
J
= 8.7
Hz,
J
= 6.6 Hz,
J
= 2.3 Hz, 1H), 7.50 (d,
J
= 8.5 Hz, 1H), 4.47 – 4.36 (m, 1H), 4.10 – 3.98 (m,
165.7, 158.3, 144.2,
2H), 3.97 – 3.80 (m, 4H) ppm. C{1H} NMR (101 MHz, Chloroformꢀ
d
)
δ
13
139.5, 136.6, 132.7, 132.3, 130.8 (2С), 126.5, 124.3, 124.1, 120.7, 77.4, 52.4, 52.3, 51.4 ppm.
HRMS (ESI), m/z calcd for C17H15N2O3S+ [M+H]+ 327.0798, found 327.0801.
7ꢀNitroꢀ2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepine 9ꢀoxide (8b)
1
Yield 149 mg, 71 %; yellow solid; mp 230ꢀ232 °C. H NMR (400 MHz, Chloroformꢀ
d
)
δ
8.66
= 1.2 Hz, 2H),
= 8.8 Hz,
(d,
J = 2.6 Hz, 1H), 8.29 (dd, J = 8.8 Hz, J = 2.7 Hz, 1H), 7.92 (td, J = 7.9 Hz, J
7.75 (td,
J
= 7.7 Hz,
J
= 1.2 Hz, 1H), 7.56 (td,
J
= 7.6 Hz,
J
= 1.3 Hz, 1H), 7.30 (d,
J
1H), 4.51 – 4.38 (m, 1H), 4.30 – 4.10 (m, 3H) ppm. 13C{1H} NMR (101 MHz, Chloroformꢀd)
δ
158.3, 144.5, 143.6, 140.3, 138.0, 133.2, 131.4, 131.2, 126.8, 123.0, 121.1, 119.1, 118.5, 51.8,
51.5. HRMS (ESI), m/z calcd for C15H12N3O3S+ [M+H]+ 314.0599, found 314.0594.
General procedure for preparation of sulfones 9aꢀd
To a stirred solution of 0.360 mmol of thiazepine, in 2 mL of carbon tetrachloride, 2 mL of
acetonitrile, and 4 mL of water was added 231 mg (1.080 mmol) of sodium periodate. Once all
of the sodium periodate had dissolved, 0.2 mg (0.018 mmol) of ruthenium trichloride hydrate
was added, and the reaction mixture was stirred vigorously overnight at room temperature. It was
then extracted with CH2Cl2; the combined organic extracts were dried over Na2SO4 and
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evaporated. The crude product was purified by column chromatography eluting with THFꢀ
Hexane (4:1).
5
6
7
2,3ꢀDihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ7ꢀcarbonitrile 9,9ꢀdioxide (9a)
8
9
1
Yield 58 mg, 52%; light beige solid; mp 226ꢀ228 °C. H NMR (400 MHz, DMSOꢀ
d
6) δ 8.24 (s,
= 8.7 Hz,
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
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41
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43
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46
47
48
49
50
51
52
53
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55
56
57
58
59
60
1H), 8.12 (d,
1H), 4.47 (dt,
J
= 9.0 Hz, 1H), 8.00 (d,
J
= 7.6 Hz, 1H), 7.95 – 7.81 (m, 3H), 7.49 (d,
J
J
= 11.1 Hz, J
= 11.3 Hz, 1H), 4.15 – 3.90 (m, 3H) ppm. 13C{1H} NMR (400 MHz,
Chloroformꢀd)
δ 120.9, 104.1, 101.6, 100.3, 97.3, 94.9, 94.5, 94.3, 93.2, 90.1, 87.6, 82.0, 79.8,
67.8, 15.0, 14.6, ppm. HRMS (ESI), m/z calcd for C16H12N3O2S+ [M+H]+ 310.0642, found
310.0645.
Methyl 2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀ
d
][1,4]thiazepineꢀ7ꢀcarboxylate 9,9ꢀdioxide (9b)
1
Yield 59 mg, 48%; white solid; mp 205ꢀ207 °С. H NMR (400 MHz, DMSOꢀd6
)
δ
8.40 (d,
= 1.5 Hz, 1H), 7.95
= 1.5 Hz, 1H), 7.82 (td, = 7.5 Hz,
= 10.7 Hz, 1H), 4.16 – 3.93 (m, 3H), 3.87 (s,
164.5, 157.7, 141.6, 138.6, 135.8, 135.1,
J =
2.1 Hz, 1H), 8.20 (dd,
J
= 8.7 Hz,
J
= 2.1 Hz, 1H), 8.02 (dd,
= 7.5 Hz,
J = 7.5 Hz, J
(dd, = 7.5 Hz, = 1.5 Hz, 1H), 7.88 (td,
J
J
J
J
J
J =
1.5 Hz, 1H), 7.49 (d,
J = 8.7 Hz, 1H), 4.51 (q, J
3H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
132.5, 132.2, 128.5, 127.6, 127.3, 124.2, 122.5, 120.2, 52.4, 52.1, 51.6 ppm. HRMS (ESI), m/z
calcd for C17H15N2O4S+ [M+H]+ 343.0744, found 343.0747.
Methyl 2,3ꢀdihydrobenzo[
dioxide (9c)
f]imidazo[1,2ꢀ
d
]pyrido[3,2ꢀb][1,4]thiazepineꢀ7ꢀcarboxylate 9,9ꢀ
1
Yield 61 mg, white solid; 49%; mp 199ꢀ201°C. H NMR (400 MHz, DMSOꢀd6
)
δ
9.07 (d,
= 1.4 Hz, 2H), 7.91
= 1.5 Hz, 1H), 4.53 – 4.27 (m, 1H), 4.06
164.1,
J =
2.2 Hz, 1H), 8.54 (d,
J = 2.2 Hz, 1H), 8.03 (ddd, J = 9.5 Hz, J = 7.6 Hz, J
(td, = 7.6 Hz, = 1.5 Hz, 1H), 7.86 (td,
J
J
J
= 7.6 Hz, J
(s, 2H), 4.12 – 3.92 (m, 3H), 3.88 (s, 3H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
13
156.7, 155.2, 151.2, 138.2, 136.9, 135.9, 133.5, 132.9, 127.6, 125.0, 122.9, 119.2, 53.0, 52.0
(2С). HRMS (ESI), m/z calcd for C16H14N3O4S+ [M+H]+ 344.0698, found 344.0700.
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7ꢀNitroꢀ2,3ꢀdihydrodibenzo[b,f]imidazo[1,2ꢀd][1,4]thiazepine 9,9ꢀdioxide (9d)
3
4
5
6
7
8
9
1
Yield 57 mg, 48%; yellow solid; mp 237ꢀ239 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.55 (d,
J
J
=
=
2.7 Hz, 1H), 8.45 (dd,
7.6 Hz, 1.5 Hz, 1H), 7.89 (td,
= 9.2 Hz, 1H), 4.49 (dt,
J
= 9.1 Hz, 2.8 Hz, 1H), 8.02 (dd,
J = 7.7 Hz, 1.4 Hz, 1H), 7.94 (dd,
J
= 7.5 Hz, 1.5 Hz, 1H), 7.83 (td,
J
= 7.5 Hz, 1.6 Hz, 1H), 7.51 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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33
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37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
= 12.3 Hz, 10.3 Hz, 1H), 4.17 (td, J = 9.7 Hz, 3.5 Hz, 1H), 4.13 –
13
4.05 (m, 1H), 4.03 – 3.92 (m, 1H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
157.4, 142.7,
140.2, 137.9, 135.4, 132.7, 132.3, 130.2, 128.0, 127.2, 124.4, 122.6, 120.7, 52.4, 51.8 ppm.
HRMS (ESI), m/z calcd for C15H12N3O4S+ [M+H]+ 330.0555, found 330.0553.
All the lactams 14aꢀd and 15aꢀd were prepared according to general procedures for preparation
of compounds 13aꢀr.
Methyl 8ꢀ(3ꢀfluorobenzyl)ꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
carboxylate 14ꢀoxide (14a)
1
Yield 87 mg, white solid; 55%; mp 180ꢀ182 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.30 (d,
= 1.7 Hz, 1H), 7.53 –
= 1.7 Hz, 1H), 7.19
= 3.5 Hz, 1H), 5.36 (d, = 15.3
= 5.0 Hz, 1H),
168.9, 165.4,
J =
2.1 Hz, 1H), 7.77 (dd,
J
= 8.5 Hz,
= 10.4 Hz,
= 8.5 Hz, 1H), 6.04 (dd,
J
= 2.1 Hz, 1H), 7.61 (dd,
= 4.7 Hz, 2H), 7.25 (dd,
= 9.6 Hz,
J
= 7.7 Hz,
J
7.43 (m, 3H), 7.29 (dd,
J
J
J
= 7.2 Hz, J
– 7.12 (m, 1H), 6.88 (d,
J
J
J
J
Hz, 1H), 4.18 (d,
J
= 15.3 Hz, 1H), 3.83 (s, 3H), 3.51 – 3.44 (m, 1H), 3.28 (d,
J
3.15 (dd,
162.3 (d,
J
= 9.0 Hz,
J
= 3.4 Hz, 2H) ppm. 13C NMR (101 MHz, DMSOꢀd6
) δ
J
= 243.7 Hz), 148.4, 143.0, 140.7 (d,
J = 7.2 Hz), 135.4, 135.3, 132.7, 131.2, 130.6 (d,
J
= 8.3 Hz), 130.3, 125.8, 124.6, 123.7 (d,
J
= 2.6 Hz), 123.0, 120.6 (2С), 115.7, 114.5 (d, J =
21.5 Hz), 114.0 (d,
J = 20.9 Hz), 51.8, 50.3, 45.7 ppm. HRMS (ESI), m/z calcd for
C24H22FN2O4S+ [M+H]+ 453.1277, found 453.1279.
Methyl
8ꢀbenzylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
carboxylate 14ꢀoxide (14b)
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1
Yield 52 mg, 34%; white solid; mp 193ꢀ195 °C. H NMR (400 MHz, DMSOꢀd6) δ 8.32 (d,
J =
3
4
5
6
7
8
9
2.0 Hz, 1H), 7.77 (dd,
7.39 (m, 6H), 7.35 – 7.30 (m, 1H), 7.22 (dd,
1H), 5.97 (dd, = 9.7 Hz, = 3.4 Hz, 1H), 5.40 (d,
J
= 8.5 Hz,
J
= 2.0 Hz, 1H), 7.63 (dd,
= 7.3 Hz, = 1.5 Hz, 1H), 6.86 (d,
= 15.1 Hz, 1H), 4.15 (d,
J
= 7.7 Hz,
J
= 1.5 Hz, 1H), 7.50 –
J
J
J
= 8.5 Hz,
J
J
J
J
= 15.1 Hz, 1H),
3.83 (s, 3H), 3.49 – 3.42 (m, 1H), 3.31 – 3.25 (m, 1H), 3.18 – 3.05 (m, 2H) ppm. C{1H} (101
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, DMSOꢀd6) δ 168.8, 165.5, 148.4, 143.0, 137.6, 135.6, 135.2, 132.7, 131.2, 130.2, 128.7
(2С), 127.7 (2С), 127.3, 125.8, 124.6, 123.1, 120.6, 115.8, 51.9, 50.1, 46.0, 39.9. HRMS (ESI),
m/z calcd for C24H23N2O4S+ [M+H]+ 435.1373, found 435.1379.
2ꢀNitroꢀ8ꢀ(propꢀ2ꢀynꢀ1ꢀyl)ꢀ5,6,7,8ꢀtetrahydroꢀ9
oxide (14c)
H
ꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone 14ꢀ
1
Yield 54 mg, 38%; yellow solid; mp 208ꢀ210 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.48 (d,
= 1.5 Hz, 1H), 7.51
= 1.5 Hz, 1H), 6.95 (d, = 9.0 Hz, 1H),
= 2.5 Hz, 1H), 4.08 (dd, = 17.7 Hz,
J =
2.7 Hz, 1H), 8.07 (dd,
(pd, = 7.3 Hz, = 1.5 Hz, 2H), 7.21 (dd,
6.41 (dd, = 9.9 Hz, 3.5 Hz, 1H), 4.78 (dd,
J
= 9.0 Hz,
J
= 2.7 Hz, 1H), 7.66 (dd,
= 7.3 Hz,
= 17.7 Hz,
= 14.1 Hz, J = 2.5 Hz, 1H), 3.31 – 3.27 (m, 1H),
J = 7.7 Hz, J
J
J
J
J
J
J
J
J
J
J
= 2.5 Hz, 1H), 3.68 – 3.56 (m, 1H), 3.49 (dd,
J
3.19 (ddd,
J
= 15.1 Hz,
J
= 11.6 Hz,
J
= 3.5 Hz, 1H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
168.1, 149.8, 142.5, 139.5, 135.5, 135.1, 131.6, 130.7, 127.6, 125.8, 124.8, 118.1, 115.3, 79.2,
75.3, 50.1, 39.4, 33.3 ppm. HRMS (ESI), m/z calcd for C18H15N3KO4S+ [M+K]+ 408.0428, found
408.0430.
8ꢀBenzylꢀ2ꢀnitroꢀ5,6,7,8ꢀtetrahydroꢀ9
Hꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone 14ꢀoxide (14d)
Yield 64 mg, 43%; light yellow solid; mp 234ꢀ236 °C. 1H NMR (400 MHz, DMSOꢀd6
) δ 8.49 (d,
J
= 2.7 Hz, 1H), 8.06 (dd,
J
= 9.0 Hz,
J
= 2.7 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.52 – 7.40 (m, 6H),
= 9.0 Hz, 1H), 6.68 (dd, = 9.5 Hz, = 2.8
7.36 – 7.31 (m, 1H), 7.26 – 7.22 (m, 1H), 6.93 (d,
J
J
J
Hz, 1H), 5.41 (d,
14.4, = 8.9 Hz,
d6
J
J
= 15.2 Hz, 1H), 4.14 (d,
J = 15.2 Hz, 1H), 3.60 – 3.51 (m, 1H), 3.38 (ddd, J =
J
= 3.5 Hz, 1H), 3.23 – 3.11 (m, 2H) ppm. 13C{1H} NMR (101 MHz, DMSOꢀ
)
δ
168.6, 149.9, 142.4, 139.4, 137.6, 135.7, 135.5, 131.5, 130.5, 128.7, 128.7, 127.7 (3C),
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127.3, 125.9, 124.8, 118.1, 115.1, 50.0, 46.0, 39.6 ppm. HRMS (ESI), m/z calcd for
3
4
C22H20N3O4S+ [M+H]+ 422.1166, found 422.1169.
5
6
7
8ꢀEthylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀcarbonitrile 14,14ꢀ
8
9
dioxide (15a)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield 57 mg, 46%; white solid; mp 181ꢀ183 °C; 1H NMR (400 MHz, DMSOꢀd6
2.0 Hz, 1HAr), 7.97 (dd, = 8.2 Hz, = 1.3 Hz, 1H), 7.80 (dd, = 8.8 Hz, = 2.1 Hz, 1H), 7.70
(td, = 7.5 Hz, = 1.3 Hz, 1H), 7.60 (ddd, = 8.5 Hz, = 7.4 Hz, = 1.4 Hz, 1H), 7.30 (dd,
7.6 Hz, = 1.3 Hz, 1H), 7.16 (d, = 8.8 Hz, 1H), 6.78 (d, = 7.7 Hz, 1H), 3.70 (dq, = 14.1 Hz,
= 7.0
) δ 8.25 (d, J =
J
J
J
J
J
J
J
J
J
J =
J
J
J
J
J
= 6.7 Hz, 1H), 3.58 – 3.47 (m, 2H), 3.41 – 3.32 (m, 2H), 3.08 – 2.99 (m, 1H), 1.23 (t,
J
Hz, 3H) ppm. 13C NMR (101 MHz, DMSOꢀd6
) δ 166.8, 150.9, 138.2, 136.4, 136.0, 134.1, 133.9,
131.0, 130.3, 128.3, 125.5, 118.8, 118.3, 99.7, 51.4, 42.4, 40.2, 12.5 ppm. HRMS (ESI), m/z
calcd for C18H17N3NaO3S+ [M+Na]+ 378.0883, found 378.0885.
Methyl
carboxylate 14,14ꢀdioxide (15b)
Yield 52 mg, 42%; white solid; mp 202ꢀ205 °C. H NMR (400 MHz, DMSOꢀd6
8ꢀbenzylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀdibenzo[b,i][1,4,7]thiadiazecineꢀ2ꢀ
1
)
δ
8.39 (d,
J =
2.1 Hz, 1H), 7.92 (dd,
= 7.5 Hz, = 1.2 Hz, 1H), 7.64 – 7.58 (m, 1H), 7.50 (d,
2H), 7.36 – 7.30 (m, 2H), 7.08 (d, = 8.8 Hz, 1H), 6.64 (d,
J
= 8.8 Hz,
J
= 2.1 Hz, 1H), 7.85 (dd,
J
J
= 8.2 Hz,
J
= 1.2 Hz, 1H), 7.71 (td,
J
J
= 7.5 Hz, 2H), 7.41 (t, = 7.5 Hz,
J
J
J
= 8.2 Hz, 1H), 5.03 (d, J = 15.0 Hz,
1H), 4.58 (d,
J
= 15.0 Hz, 1H), 3.83 (s, 3H), 3.52 – 3.37 (m, 2H), 3.28 – 3.22 (m, 1H), 3.18 –
13
3.10 (m, 1H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
167.6, 164.9, 151.2, 137.7, 136.5,
135.7, 134.0, 130.7, 130.5, 130.5, 128.7, 128.7, 128.2, 127.9, 127.9, 127.4, 126.4, 124.7, 118.9,
118.0, 52.1, 51.5, 46.5, 41.9. HRMS (ESI), m/z calcd for C24H22N2KO5S+ [M+K]+ 489.0881
found 489.0883.
Methyl 8ꢀmethylꢀ9ꢀoxoꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀbenzo[
carboxylate 14,14ꢀdioxide (15с)
i]pyrido[3,2ꢀb][1,4,7]thiadiazecineꢀ2ꢀ
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The Journal of Organic Chemistry
1
2
1
Yield 43 mg, 33%; white solid; mp 175ꢀ177 °C. H NMR (400 MHz, DMSOꢀd6
)
δ
8.79 (d,
J =
3
4
2.3 Hz, 1H), 8.48 (d,
J
= 2.3 Hz, 1H), 7.92 (d,
J
= 8.1 Hz, 1H), 7.70 (td,
J
= 7.6 Hz,
J
= 1.3 Hz,
5
6
7
8
9
1H), 7.61 (td, = 7.6 Hz,
J
J
= 1.4 Hz, 1H), 7.35 (dd,
J
= 7.6 Hz,
J
= 1.3 Hz, 1H), 7.17 (s, 1H),
3.85 (s, 4H), 3.67 (s, 1H), 3.37 – 3.32 (m, 1H), 3.24 – 3.15 (m, 1H), 3.02 (s, 3H). C{1H} NMR
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(101 MHz, DMSOꢀd6) δ 166.9, 164.1, 158.0, 155.2, 138.9, 136.3, 134.1, 130.5 (2С), 130.4,
128.4, 119.2, 116.1, 53.4, 52.2, 40.0 ppm. HRMS (ESI), m/z calcd for C17H18N3O5S+ [M+H]+
376.0960, found 376.0962.
8ꢀ(2ꢀFluorobenzyl)ꢀ2ꢀnitroꢀ5,6,7,8ꢀtetrahydroꢀ9Hꢀdibenzo[b,i][1,4,7]thiadiazecinꢀ9ꢀone
14,14ꢀdioxide (15d)
1
Yield 80 mg, 50%; light yellow solid; mp 252ꢀ254 °C. H NMR (400 MHz, DMSOꢀd6) δ 8.61
(d,
Hz,
7.40 (dtd,
9.3 Hz, 1H), 7.01 (d,
(t,
160.4 (d,
Hz), 129.6 (d,
117.7, 115.5 (d,
J
= 2.8 Hz, 1H), 8.22 (dd,
= 1.3 Hz, 1H), 7.62 (td,
= 7.6 Hz,
J
J
= 9.3 Hz,
= 7.8 Hz,
J
J
= 2.8 Hz, 1H), 8.02 – 7.92 (m, 1H), 7.74 (td,
= 1.3 Hz, 1H), 7.56 (td, = 7.8 Hz, = 1.8 Hz, 1H),
= 1.9 Hz, 1H), 7.35 – 7.22 (m, 3H), 7.18 (d, J =
J = 7.5
J
J
J
J
J
= 6.3 Hz,
J
= 5.4 Hz,
J
J
= 8.1 Hz, 1H), 5.18 (d,
J
= 15.4 Hz, 1H), 4.52 (d,
J
= 15.4 Hz, 1H), 3.59
167.3,
= 4.1
J = 3.2 Hz), 124.1, 123.9 (d, J = 14.6 Hz),
13
J
= 6.8 Hz, 2H), 3.30 – 3.18 (m, 2H) ppm. C{1H} NMR (101 MHz, DMSOꢀd6
)
δ
J
= 244.9 Hz), 152.1, 137.5, 135.9, 135.8, 134.4, 131.2, 130.7, 130.3, 130.0 (d, J
J
= 8.2 Hz), 128.2, 125.7, 124.8 (d,
= 21.4 Hz), 51.3, 41.6, 40.6 ppm. HRMS (ESI), m/z calcd for C22H19FN3O5S+
J
[M+H]+ 456.1029, found 456.1027.
Preparation of imidazolinium salts 16aꢀc
Compound 7c, 8a, 9b (0.322 mmol) and BnBr (58 mg, 0.38 mmol) were combined in dry
acetonitrile in a glass test tube with a screw cap. The resulting mixture was stirred overnight at
60°C, then the reaction was monitored by TLC (ethyl acetate/hexane 8:2). After completion of
the reaction, the mixture was concentrated in vacuo, diluted with 3 mL of Et2O, filtered and airꢀ
dried.
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