Sulfur Oxidation Increases the Rate of HIRE-Type [1.4]Thiazepinone Ring Expansion and Influences the Conformation of a Medium-Sized Heterocyclic Scaffold

Article abstract of DOI:10.1021/acs.joc.1c00236

The hydrated imidazoline ring expansion (HIRE-type) reaction was investigated for a series of di(hetero)arene-fused [1.4]thiazepinones in comparison with their sulfone counterparts. The sulfones were found to undergo ring expansion at a much higher rate compared to the thioethers, much in line with the current mechanistic understanding of the process. Moreover, the amide bond cis- and trans-isomers of the ring-expanded products were found, in the case of sulfones, to be stabilized through an intramolecular hydrogen bond. The latter phenomenon was studied in detail by NMR experiments and corroborated by X-ray crystallographic information.

Full text of DOI:10.1021/acs.joc.1c00236

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Article
Sulfur Oxidation Increases the Rate of HIRE-Type [1.4]Thiazepinone
Ring Expansion and Influences the Conformation of a Medium-Sized
Heterocyclic Scaffold
Elena Reutskaya, Alexander Sapegin, Stefan Peintner, Máté Erdélyi, and Mikhail Krasavin*
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ABSTRACT: The hydrated imidazoline ring expansion (HIRE-
type) reaction was investigated for a series of di(hetero)arene-fused
[1.4]thiazepinones in comparison with their sulfone counterparts.
The sulfones were found to undergo ring expansion at a much higher
rate compared to the thioethers, much in line with the current
mechanistic understanding of the process. Moreover, the amide
bond cis- and trans-isomers of the ring-expanded products were
found, in the case of sulfones, to be stabilized through an
intramolecular hydrogen bond. The latter phenomenon was studied
in detail by NMR experiments and corroborated by X-ray
crystallographic information.
a “hydrated imidazoline”. Hence, the entire approach to ring
expansion was dubbed the ‘hydrated imidazoline ring
expansion’ or HIRE. In intermediate 4, irreversible (due to
the lower nucleophilicity of the anilinic nitrogen atom in 3)
breaking of the central C−N bond (highlighted red),
presumably, leads to the formation of ring-expanded product
3. However, the hydrated imidazoline 4 could be in
equilibrium with 2-aminoethyl derivatives 5 which form
through an alternative leaving group elimination and breaking
of another C−N bond (highlighted blue). With this possibility
in mind, we achieved ring expansion of purposefully
synthesized seven-membered lactams 5 (X = O, S) via the
formal 2-aminoethyl side chain insertion into the amide bond
(or intramolecular N → N′ acyl migration).8 At the same time,
certain tetracyclic imidazolinium salts 2 (X = O,9 NAlk10),
when exposed to dilute aqueous basic solution, yielded only
the product of side chain expulsion (5) but no ring-expanded
product 3. Applying forcing conditions to some of lactams 5
did help transform them into 3, while for others the approach
failed.9 Aiming to understand the influence of electronic
factors on the rate of transformation 5 → 3, we established that
electron-withdrawing substituents both in the carbonyl-bound
INTRODUCTION
■
Medium-sized (8- to 14-membered) rings have gained
recognition as preferred scaffolds for lead generation in drug
discovery.1 A good balance of conformational rigidity and
flexibility allows compounds based on such scaffolds to adopt a
large number of energetically feasible conformations (com-
pared to flat heterocyclic cores historically employed in lead
generation libraries2) and still display a favorable absorption
and membrane permeability profile (in contrast to overly
flexible, linear scaffolds).3 Being essentially “fuzzy shape” small
molecule probes for protein binding sites, medium-sized rings
may be particularly useful for interrogation of targets
traditionally labeled undruggable (such as protein−protein
interactions).4 Unfortunately, medium-sized cyclic scaffolds are
notoriously difficult to synthesize via ring closure due to
unfavorable entropy associated with this process and trans-
annular interactions present in such rings, which raises their
enthalpy.5 As a result, the current scarcity of medium-sized
cyclic systems in current compound collections for drug
discovery has driven the alternative synthetic methodology
development which is based on expansion of smaller rings.6
In 2017, we described a ring expansion approach involving
tetracyclic imidazoline-fused [1.4]oxazepines 1 (X = O, Figure
1). The compounds themselves proved rather resistant to
hydrolysis. However, when activated by alkylation, the
respective imidazolinium salts 2 underwent a rapid hydrolytic
transformation into ring-expanded, 10-membered lactams 3 on
treatment with 0.1% solution of K2CO3 in aqueous acetonitrile
at room temperature.7 The formation of 3 is thought to involve
the formation of tetrahedral intermediate 4 which we viewed as
Received: January 30, 2021
Published: April 7, 2021
https://doi.org/10.1021/acs.joc.1c00236
© 2021 American Chemical Society
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Figure 1. Hydrated imidazoline ring expansion (HIRE): a unified mechanistic view.
Scheme 1. Preparation of Carboxylic Acids 8a−h via SNAr-Type Reaction
(hetero)aromatic ring and, to a much larger extent, in the
nitrogen-bound (hetero)aromatic ring promote the reaction.11
This prompted us to compare the rates of transformation 5 →
3 for [1,4]thiazepin-5-ones (X = S) and 1,4-thiazepin-5-one-
1,1-dioxides (X = SO2). In the latter, we reasoned the sulfone
group would increase the electrophilicity of the lactam
carbonyl carbon atom thus making the formation of 4 more
energetically favorable. However, even more pronounced
effects of the sulfone group were expected on the rate of
subsequent aromatic amine departure from the tetrahedral
carbon in 4 and the irreversible formation of 3 (Figure 1).
Besides evaluating the effect of S → SO2 oxidation on the rates
of the HIRE-type ring expansion, we aimed to verify if such a
perturbation of the electronic character of the [1,4]thiazepin-5-
one core would facilitate the insertion of ω-aminoalkyl side
chains longer than 2-aminoethyl (the process we designated as
homox-HIRE8). Previously, insertion of 3-aminopropyl (homo-
HIRE) and 4-aminobutyl (homo2-HIRE) side chains led to the
expansion of [1,4]thiazepin-5-one and [1,4]oxazepin-5-one
core into 11- and 12-membered lactams (unfortunately,
preparation of 13-membered lactams via homo3-HIRE reaction
failed).8 Herein, we present the results obtained in the course
of this investigation.
the target compounds starting from thiosalicylic (6a) or 2-
mercaptonicotinic (6b) acids. Thio compounds 6a−b were
reacted with o-nitro halo(hetero)arenes 7 in refluxing isopropyl
alcohol in the presence of DIPEA to afford good to excellent
yields of carboxylic acids 8a−h (Scheme 1).
Starting from carboxylic acids 8a−h, target [1,4]thiazepin-5-
ones 9a−m were synthesized using the following straightfor-
ward one-pot protocol. The carboxylic acid was activated with
CDI, and the resulting imidazolide was treated with mono-
Boc-protected ethylene diamine as well as α,ω-diaminoalkanes
of various chain lengths (C3−C5). Once the amidation was
complete, solid Cs2CO3 (3 equiv) was added to the reaction
mixture, the temperature was raised to 60−80 °C, and at that
temperature, the intramolecular SNAr reaction was conducted
over 18 h. As anticipated, it proceeded with an intermittent
Smiles rearrangement8 which defined the regiochemistry of
products 9a−m (Scheme 2).
In addition to the set of somewhat electronically biased
[1,4]thiazepin-5-ones 9a−m (all of which feature an electron-
deficient nitrogen-bound (hetero)aromatic ring, we synthe-
sized their electron-neutral analog 9n which was prepared via
alkylation of commercially available dibenzo[b,f ][1,4]-
thiazepin-11(10H)-one (10) (Scheme 3).
With a set of 14 Boc-protected [1,4]thiazepin-5-one starting
materials 9a−n for the HIRE-type ring expansion at hand, we
converted all of them into their sulfone counterparts 11a−n
using a 3-fold excess of sodium periodate in the presence of a
catalytic amount (5 mol %) of RuCl3.8 Reaction conducted in
the CCl4−MeCN−H2O 1:1:2 mixture gave, after chromato-
RESULTS AND DISCUSSION
■
To synthesize [1,4]thiazepin-5-ones for the present study, the
following route was developed which represents a modification
of the previously reported synthesis.8 We found the new
approach to offer significant advantage in the overall yield of
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Scheme 2. Preparation of [1,4]Thiazepin-5-ones 9a−m
Scheme 3. Synthesis of Compound 9n from the
Commercially Available Precursor
are comparable or higher than those for ring-expanded
thioethers 12. One notable exception is sulfone lactam 13i
which was obtained in only 15% yield in contrast to its
thioether analog 12i. The major competing process in this case
(as well as in other cases discussed below) was the hydrolysis
of the lactam ring in 11i. Competing lactam hydrolysis was also
the predominant process observed for lactams 9c−d and 11c−
d for which the desired homo2/3-HIRE8 side chain insertion
process was likely much slower for entropic reasons. In the
case of lactams 9d and 11c−d, the respective lactam hydrolysis
products 14a−c were isolated in high yields and characterized
by 1H and 13C NMR spectroscopy, high-resolution mass
spectrometry, and single-crystal X-ray crystallography (14b−c)
(Scheme 6).
In order to firmly establish that the rates of the HIRE (and
homox-HIRE) process are generally higher for sulfones 11 as
compared to thioethers 9, we performed a spectrophotometric
study of the reaction kinetics and calculated reaction rate
constants (kobs, s−1) for the room-temperature reactions in
which no competing substrate hydrolysis was observed, i.e. for
all substrates 9 and 11 except for 9(11)c−d and 9(11)i.
Substrates 9g and 9n were also excluded since they underwent
an appreciable conversion only at 60 °C (see Supporting
Information for details). These data are summarized in Table
1.
graphic purification or simple crystallization, generally good
yields of sulfones 11a−n throughout the set (Scheme 4).
At this point, we were set to involve [1,4]thiazepin-5-ones
9a−n and their sulfone counterparts 11a−n in the HIRE-type
ring expansion reactions. To this end, the Boc protecting group
was removed, and the resulting hydrochloride salt was
dissolved in 50% aqueous methanol and treated with 3 equiv
of 10% aqueous sodium hydroxide solution. For nearly all
substrates, conversion of the starting material was complete in
18 h at room temperature leading to the isolated yields of ring-
expanded thioethers 12 and sulfones 13 summarized in
Scheme 5. Notable exceptions were presented by substrates
9g and 9n carrying an electron-neutral nitrogen-bound
benzene ring. For these substrates, full conversion was only
achieved at 60 °C over 7 and 30 days, respectively, leading to
moderate yields of ring-expanded products 12g and 12n. This
observation, as well as the fact that respective sulfones 11g and
11n gave excellent yields of the ring-expanded products 13g
and 13n after 18 h at room temperature, is very much in line
with the expected manifestation of the electronic effects on the
HIRE rate11 and our initial expectations (vide supra).
As it is evident from comparing the reaction rates presented
in Table 1, sulfones 11 underwent the HIRE (homo-HIRE)
process at substantially higher rates as compared to thioethers
9. Homo-HIRE reactions (leading to 11-membered ring
formation) were generally markedly slower compared to
HIRE (cf. 9(11)a and 9(11)b, 9(11)j, and 9(11)k). However,
introduction of a nitrogen atom into the carbonyl-bound
aromatic ring seemed to make the difference in rates less
Besides the difference in HIRE rates (discussed below),
sulfones generally gave ring-expanded lactams 13 in yields that
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Scheme 4. S → SO2 Oxidation of [1,4]Thiazepin-5-ones 9a−n
pronounced (cf. 9(11)l and 9(11)m). At the same time, pyrido
compounds 9(11)l reacted at the same rates as their phenyl
analogs 9(11)f, thereby confirming, again, that the substitution
in the carbonyl-bound aromatic ring has a less pronounced
effect on the rate of the ring expansion.11
A significant difference between ring-expanded thioethers 12
and sulfones 13 that we noted was in the ratio of what we
presumed (and later confirmed) to be amide bond cis- and
trans-isomers observed in the 1H NMR spectra of these
compounds. For instance, while compound 12a displayed an
∼1:12 cis/trans ratio, for compound 13a the proportion of the
cis-isomer was markedly higher and thus the cis/trans ratio was
2:3 (Figure 2). We hypothesized that the apparent stabilization
of the cis-isomer in 13a could be due to the possible
involvement of the sulfone oxygen atoms in intramolecular
hydrogen bonding.12
We studied this phenomenon in detail for 13a (Figure 3).
Upon acquiring its EXSY spectrum in DMSO-d6, exchange
crosspeaks were observed (Figure 3A) suggesting the presence
of two isomers in slow exchange. Interproton distances were
deduced for each isomer based on NOE crosspeak intensities
(tmix: 500 ms at 400 MHz), using the ortho aromatic protons as
the internal reference (2.44 Å). We observed 2.9 and 3.3 Å
H11−H7 interatomic distances for the major and minor
isomers, respectively. In addition, no H11−H6a NOE cross-
peaks were observed for the major isomer, whereas strong
H11−H6a crosspeaks, corresponding to 3.1 Å, were detected for
the minor isomer. This suggested amide cis-trans isomerization
to be the likely cause of the signal doubling, which
corroborated the hypothesis by the large chemical shift
differences of the amide carbon and nitrogen atoms of the
isomers (ΔδCO 1.9 ppm in 13C and ΔδNH 4.1 ppm in 15N
NMR; Figure 3B and C). Monte Carlo conformational
searches using the OPLS3e force field with restrained C−
CO−N−C dihedral angles, 0° for cis and 180° for trans, were
performed to generate two ensembles, within a 42 kJ/mol
energy interval from the global minimum. The Boltzmann
weighted average H11−H7 distances differed 0.6 Å for the cis
(3.8 Å) and trans (3.2 Å) isomers and 1.6 Å for H11−H6a (cis
3.2 Å, trans 4.8 Å). This reveals that the major set of signals of
13a corresponds to the trans isomer.
The amide temperature coefficients Δδ/ΔTNHcis −0.1 ppb/
K and Δδ/ΔTNHtrans −0.8 ppb/K (see Supporting Informa-
tion) indicated that the amide proton of both isomers were
solvent shielded, expectably by an intramolecular hydrogen
bond to a sulfonyl oxygen, which rigidifies the macrocycle and
thereby hinders amide bond isomerization.13 The sharper line
1
width of the H NMR signals of 13a as compared to 12a
(Figure 2) corroborates the formation of an intramolecular
aniline to sulphonyl hydrogen bond in 13a. The anilinic NH of
12a lacks such stabilization and therefore is in a faster exchange
(Figure 3E and F). The temperature dependence of the H11
and H16 chemical shifts of the cis and trans isomers of 13a
followed a classical slow exchange pattern (Figure 3D).14
Hence, we observed signal broadening at 55−65 °C,
compatible with intermediate exchange, whereas sharp signals
and a decrease of the intensity of the minor signal set above 85
°C.15 In agreement with the NMR observations an NH···O
intramolecular hydrogen bond (dHO 2.2 Å) was observed by X-
ray diffraction for 13a, which crystallized in its cis isomer
(Figure 3F). It should be noted that the observation of a single
solid state geometry despite the existence of an ensemble of
conformers in solution is not unusual.16,17
CONCLUSIONS
■
In summary, we have investigated HIRE-type ring expansion in
di(hetero)arene-fused [1.4]thiazepinones and in their S →
SO2 oxidized analogs. In accordance with the general
mechanistic understanding and the previously undertaken
mechanistic study of the electronic effects on the rate of the
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Scheme 5. HIRE Reaction of [1,4]Thiazepin-5-ones 9a−n and Their 1,1-Dioxide Counterparts 11a−n
a
b
c
X-ray crystallographic structure obtained. Lactam hydrolysis product isolated and characterized. Reaction conducted over 7 days at 60 °C.
d
e
Reaction conducted over 30 days at 60 °C. X-ray crystallographic structure of the lactam hydrolysis product obtained.
1
a 500 spectrometer (500.03 for H and 125 MHz for 13C{1H}) in
HIRE reaction, sulfones underwent the ring expansion at a
markedly faster rate compared to thioethers. Besides the effect
on the HIRE reaction rate, oxidation to sulfones was shown to
have a profound influence on the conformational behavior of
the ring-expanded products. Specifically, in contrast to
thioethers, sulfones were shown to exist as an equilibrium
mixture of amide-bond cis- and trans-isomers. The energy
barrier between these isomeric forms is heightened due to the
existence of an intramolecular hydrogen bond involving the
sulfone oxygen atom. These findings significantly expand our
knowledge base concerning the preparation as well as
conformational rigidity/flexibility of medium-sized rings as
scaffolds for drug discovery.
DMSO-d6 and in CDCl3 and were referenced to residual solvent
proton signals (δH = 2.50 and 7.26 ppm, respectively) and solvent
carbon signals (δC = 39.5 and 77.0 ppm, respectively). Mass spectra
were recorded with an HRMS-ESI-qTOF spectrometer (electrospray
ionization mode, positive ion detection). Single crystal X-ray data
were obtained using Agilent Technologies SuperNova Atlas and an
Agilent Technologies Xcalibur Eos diffractometers at a temperature of
100 K. Spectrophotometric measurements were performed on a UV-
1800 Shimadzu double beam spectrophotometer (Japan) using 10.00
mm quartz cells. Flash column chromatography on silica was
performed with a Biotage Isolera Prime instrument using Biotage
SNAP KP-Sil 25g cartridges. TLC was performed with Macherey-
Nagel ≪Alugram Sil G/UV254≫ plates. Melting points were
determined with a Stuart SMP50 instrument in open capillary tubes
and are uncorrected. All reactions were performed in air, unless
otherwise noted. Toluene was distilled from sodium and stored over
MS 4 Å. Ethyl acetate and DMSO were dried over MS 4 Å.
EXPERIMENTAL SECTION
■
General. NMR spectroscopic data were recorded with a 400
spectrometer (400.13 MHz for 1H and 100.61 MHz for 13C{1H}) and
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Scheme 6. Predominant Hydrolysis Observed in Attempted Homo2/3-HIRE Transformation of Lactams 9d and 10c−d
a
Structure confirmed by X-ray crystallography.
Table 1. Experimentally Determined Rate Constants (kobs·104 s−1) for the HIRE Reaction of Substrates 9 and 11
a
b
e
f
g
h
j
k
l
m
n
9
11
18
258
4.2
107
9
86
2.6
37
−
12
2.5
39
5
63
0.7
14
2.5
39
1.3
32
−
5
filter and washed with water. The solid residue was dried at 60 °C
overnight.
2-((2,4-Dinitrophenyl)thio)benzoic Acid (8a). Yield 3.01 g, 94%;
1
yellow solid; mp 179−181 °C. H NMR (400 MHz, DMSO-d6) δ
13.65−13.14 (br s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.35 (dd, J = 9.0,
2.6 Hz, 1H), 8.08−7.91 (m, 1H), 7.79−7.64 (m, 3H), 7.13 (d, J = 9.0
Hz, 1H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.7, 145.8,
145.3, 144.9, 137.2, 137.0, 133.4, 131.4, 131.3, 131.2, 129.6, 128.0,
121.5 ppm. HRMS (ESI), m/z calcd for C13H7N2O6S− [M−H]−
319.0019, found 319.0028.
2-((4-Cyano-2-nitrophenyl)thio)benzoic Acid (8b). Yield 2.73 g,
91%; yellow solid; mp 184−186 °C. 1H NMR (400 MHz, DMSO-d6)
δ 13.57−13.11 (br s, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.02−7.91 (m,
2H), 7.71−7.60 (m, 3H), 7.06 (d, J = 8.5 Hz, 1H) ppm. 13C{1H}
NMR (101 MHz, DMSO-d6) δ 167.8, 146.1, 143.5, 136.9 (2C),
136.7, 133.3, 131.3, 131.2, 131.0, 130.2, 129.9, 117.4, 109.1 ppm.
HRMS (ESI), m/z calcd for C14H7N2O4S− [M−H]− 299.0121, found
299.0133.
2-((3-Nitropyridin-2-yl)thio)benzoic Acid (8c). Yield 1.60 g, 58%;
light orange solid; mp 156−158 °C. 1H NMR (400 MHz, DMSO-d6)
δ 13.39−12.81 (br s, 1H), 8.57 (dd, J = 4.6, 1.6 Hz, 1H), 7.89 (dd, J =
6.6, 2.5 Hz, 1H), 7.73−7.51 (m, 4H), 7.43 (dd, J = 8.3, 4.6 Hz, 1H)
ppm. 13C{1H} NMR (101 MHz, DMSO) δ 167.9, 154.1, 142.3, 137.4,
136.6, 134.6, 133.7, 132.2, 130.8, 130.0, 126.5, 121.3 ppm. HRMS
(ESI), m/z calcd for C12H7N2O4S− [M−H]− 275.0121, found
275.0117.
2-((4-Chloro-2-nitrophenyl)thio)benzoic Acid (8d). Yield 1.95 g,
63%; yellow solid; mp 164−166 °C. 1H NMR (400 MHz, DMSO-d6)
δ 13.70−13.13 (br s, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 7.8,
1.7 Hz, 1H), 7.92 (dd, J = 7.6, 1.7 Hz, 1H), 7.73 (dd, J = 8.6, 2.4 Hz,
1H), 7.61−7.54 (m, 2H), 7.22 (d, J = 8.7 Hz, 1H) ppm. 13C{1H}
NMR (101 MHz, DMSO-d6) δ 167.9, 149.3, 139.4, 134.6, 134.2,
133.9, 133.8, 133.1, 132.5, 131.2, 129.1, 126.4, 125.3 ppm. HRMS
(ESI), m/z calcd for C13H7ClNO4S− [M−H]− 307.9790, found
307.9794.
Figure 2. 1H NMR spectra of compounds 12a and 13a show two sets
of signals with 1:12 and 2:3 ratios, respectively. This signal doubling is
shown to originate from the cis and trans amide isomers.
General Procedure for the Preparation of Carboxylic Acids
8a−h. To a solution of acid 6a,b (10.0 mmol) and o-nitro
halo(hetero)arenes 7 (10.0 mmol) in 50 mL of propan-2-ol DIPEA
(3.82 mL, 22.0 mmol) was added. The resulting mixture was heated
in an oil bath at reflux overnight. Then the solvent was evaporated.
The residue was diluted with H2O (100 mL) and acidified with
AcOH (5 mL). The precipitated product was filtered through a glass
2-((2-Nitro-4-(trifluoromethyl)phenyl)thio)benzoic Acid (8e).
1
Yield 2.81 g, 82%; yellow solid; mp 179−181 °C. H NMR (400
MHz, DMSO-d6) δ 13.43−13.30 (br s, 1H), 8.51 (d, J = 2.0 Hz, 1H),
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Figure 3. (A) EXSY spectrum of 13a showing exchange cross peaks (arrows) indicating both sets of signals originating from the same molecule.
(B) HMBC spectrum showing chemical shift difference of the carbonyl carbon of the cis and trans isomer. (C) 15N HSQC spectrum showing
chemical shift difference of the amide nitrogen of the cis and trans isomer. (D) Variable temperature NMR recorded in DMSO-d6 for 13a showing
peaks of the cis isomer decreasing with temperature and peak shape alternation of the trans peaks of H11. (E) Lowest energy transisomer as
calculated by a Monte Carlo conformational search. Intramolecular hydrogen bond indicated by a dashed line. (F) The overlaid geometries of cis-
13a observed by X-ray crystallography (green) in the solid state and by NMR in DMSO-d6 solution (red), with the isomer-stabilizing
intramolecular hydrogen bond being highlighted with a dashed line.
7.98−7.91 (m, 2H), 7.68−7.59 (m, 3H), 7.18 (d, J = 8.5 Hz, 1H)
ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.9, 146.5, 141.9,
136.5(2C), 133.2, 132.0, 131.2, 130.7(2C), 130.4 (q, J = 5.2 Hz),
127.1 (q, J = 33.8 Hz), 123.5 (q, J = 272.4 Hz), 123.1 (q, J = 4.4 Hz)
ppm. HRMS (ESI), m/z calcd for C14H7F3NO4S− [M−H]−
342.0053, found 342.0059.
2-((5-Cyano-2-nitrophenyl)thio)benzoic Acid (8f). Yield 2.69 g,
90%; yellow solid; mp 179−181 °C. 1H NMR (400 MHz, DMSO-d6)
δ 13.51−13.33 (br s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.04 (dd, J = 8.4,
1.8 Hz, 1H), 7.95 (dd, J = 7.6, 1.8 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H),
7.63−7.53 (m, 2H), 7.34 (dd, J = 7.6, 1.6 Hz, 1H) ppm. 13C{1H}
NMR (101 MHz, DMSO-d6) δ 167.9, 151.4, 137.1, 134.6, 133.7,
133.6, 133.5, 133.3, 132.3, 131.3, 129.3, 126.6, 117.3, 116.7 ppm.
HRMS (ESI), m/z calcd for C14H7N2O4S− [M−H]− 299.0132, found
299.0130.
1H), 8.47 (d, J = 1.8 Hz, 1H), 8.42 (dd, J = 4.7, 1.8 Hz, 1H), 8.31
(dd, J = 7.8, 1.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.8,
4.7 Hz, 1H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.8,
158.0, 152.6, 144.3, 139.9, 139.5, 139.0, 131.9, 130.5 (q, J = 33.6 Hz),
129.7 (q, J = 3.9 Hz), 129.3 (q, J = 3.7 Hz), 123.3 (q, J = 272.7 Hz),
115.5 ppm. HRMS (ESI), m/z calcd for C13H7F3N2O4SNa [M +
Na]+ 366.9971, found 366.9970.
General Procedure the Preparation of [1,4]Thiazepin-5-
ones 9a−m. To a solution of acid 8a−h (2.00 mmol) in 20 mL of
DMF CDI (360 mg, 2.20 mmol) was added. The mixture was stirred
at room temperature for 1.5−2 h. Afterward, the mixture was cooled
to 0 °C and mono-Boc-protected diaminoalkane (2.00 mmol) was
added. The resulting mixture was stirred at the same temperature for
1 h and then was stirred overnight at room temperature. Then
Cs2CO3 (1950 mg, 6.00 mmol) was added, and the mixture was
stirred at the corresponding temperature (60 °C for 9a−e, 9h, 9l−m;
80 °C for 9f−g, 9i−k) in an oil bath for 24 h. The reaction progress
was monitored by TLC analysis (toluene/acetone/hexane = 3/5/5).
Then the solvent was evaporated. The residue was diluted with water
(50 mL) and extracted with CH2Cl2 (60 mL). The organic layer was
separated, washed with 1% NaOH aqueous solution (3 × 30 mL) and
water (2 × 20 mL), and dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The resulting
compounds were purified by column chromatography at CH2Cl2/
EtOAc = 20/1.
2-((4-(N,N-Dimethylsulfamoyl)-2-nitrophenyl)thio)benzoic Acid
1
(8g). Yield 3.10 g, 81%; yellow solid; mp 171−173 °C. H NMR
(400 MHz, DMSO-d6) δ 13.40−13.28 (br s, 1H), 8.40 (d, J = 2.0 Hz,
1H), 7.98−7.93 (m, 1H), 7.89 (dd, J = 8.6, 2.1 Hz, 1H), 7.70−7.63
(m, 3H), 7.17 (d, J = 8.6 Hz, 1H), 2.67 (s, 6H) ppm. 13C{1H} NMR
(101 MHz, DMSO-d6) δ 167.8, 146.1, 142.7, 136.8, 136.7, 133.3,
133.2, 132.1, 131.6, 131.3, 130.9, 130.4, 125.0, 38.0(2C) ppm. HRMS
(ESI), m/z calcd for C15H14N2O6S2[M + H]+ 383.0366, found
383.0369.
2-((2-Nitro-4-(trifluoromethyl)phenyl)thio)nicotinic Acid (8h).
1
Yield 1.76 g, 51%; dark yellow solid; mp 166−168 °C. H NMR
tert-Butyl (2-(7-Nitro-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
yl)ethyl)carbamate (9a). Yield 548 mg, 66%; beige solid; Rf = 0.17
(400 MHz, DMSO-d6) δ 14.22−13.63 (br s, 1H), 8.55−8.50 (m,
5784
https://doi.org/10.1021/acs.joc.1c00236
J. Org. Chem. 2021, 86, 5778−5791

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Article
1
(CH2Cl2/EtOAc = 20/1); mp 120−122 °C. H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 2.7 Hz, 1H), 8.20 (dd, J = 8.9, 2.7 Hz, 1H),
7.75−7.68 (m, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.53−7.46 (m, 1H),
7.44−7.33 (m, 2H), 5.05−4.92 (br s, 1H), 4.66 (dt, J = 13.5, 5.1 Hz,
1H), 3.99 (dt, J = 13.5, 6.8 Hz, 1H), 3.58−3.38 (m, 2H), 1.32 (s, 9H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 155.7, 149.7, 144.7,
137.5, 137.2, 131.6(2C), 131.3, 129.4(2C), 128.2, 126.4, 125.0, 79.5,
51.5, 39.2, 28.3(3C) ppm. HRMS (ESI), m/z calcd for
C20H21N3O5SNa [M + Na]+ 438.1094, found 438.1081.
5.9 Hz, 1H), 4.73−4.62 (m, 1H), 3.90−3.77 (m, 1H), 3.58−3.33 (m,
2H), 1.35 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.7,
155.8, 142.6, 138.1, 137.8, 137.6, 132.7, 131.6, 131.4, 131.2, 131.1,
130.1, 129.0, 127.1, 79.3, 51.1, 39.2, 28.3(3C) ppm. HRMS (ESI), m/
z calcd for C20H21ClN2O3S [M + H]+ 405.1034, found 405.1026.
tert-Butyl (2-(11-Oxo-7-(trifluoromethyl)dibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (9h). Yield 544 mg, 62%;
white solid; Rf = 0.26 (CH2Cl2/EtOAc = 20/1); mp 143−145 °C. 1H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.1 Hz, 1H), 7.75−7.70 (m,
1H), 7.60 (dd, J = 8.5, 2.1 Hz, 1H), 7.53−7.46 (m, 2H), 7.41−7.32
(m, 2H), 5.04 (t, J = 6.2 Hz, 1H), 4.74−4.64 (m, 1H), 4.00−3.88 (m,
1H), 3.61−3.35 (m, 2H), 1.31 (s, 9H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 168.6, 155.7, 147.3, 137.9, 137.6, 136.7, 131.5, 131.3,
131.2, 130.2 (q, J = 3.6 Hz), 129.1, 128.5 (q, J = 32.5 Hz), 126.9 (q, J
= 3.1 Hz), 126.4, 123.2 (q, J = 272.7 Hz), 79.3, 51.4, 39.3, 28.2(3C)
ppm. HRMS (ESI), m/z calcd for C21H21F3N2O3SNa [M + Na]+
461.1117, found 461.1104.
tert-Butyl (3-(7-Nitro-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
yl)propyl)carbamate (9b). Yield 524 mg, 61%; light beige solid; Rf =
0.25 (CH2Cl2/EtOAc = 20/1); mp 110−112 °C. 1H NMR (400
MHz, CDCl3) δ 8.51 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 8.9, 2.6 Hz,
1H), 7.72−7.67 (m, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.52−7.46 (m,
1H), 7.42−7.33 (m, 2H), 5.06−4.95 (br s, 1H), 4.90−4.78 (m, 1H),
3.80−3.67 (m, 1H), 3.44−3.29 (m, 1H), 3.26−3.13 (m, 1H), 1.99−
1.86 (m, 1H), 1.79−1.69 (m, 1H), 1.43 (s, 9H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 168.5, 156.0, 149.0, 144.8, 137.9, 137.6, 137.4,
131.5, 131.4, 131.2, 129.3, 128.5, 126.2, 124.8, 79.2, 48.7, 37.5, 28.6,
28.4(3C) ppm. HRMS (ESI), m/z calcd for C21H23N3O5SNa [M +
Na]+ 452.1251, found 452.1262.
tert-Butyl (2-(8-Cyano-11-oxodibenzo[b,f ][1,4]thiazepin-10-
(11H)-yl)ethyl)carbamate (9i). Yield 269 mg, 34%; white solid; Rf
1
= 0.19 (CH2Cl2/EtOAc = 20/1); mp 203−205 °C. H NMR (400
MHz, CDCl3) δ 7.77−7.71 (m, 2H), 7.69−7.64 (m, 1H), 7.47 (dd, J
= 7.5, 1.6 Hz, 1H), 7.44−7.32 (m, 3H), 5.09−4.92 (br s, 1H), 4.71
(dt, J = 13.6, 5.3 Hz, 1H), 3.84 (dt, J = 13.7, 6.0 Hz, 1H), 3.58−3.34
(m, 2H), 1.35 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
168.4, 155.7, 144.9, 142.0, 137.4, 137.3, 134.0, 131.6, 131.4, 131.3,
129.6, 129.5, 129.3, 117.2, 113.9, 79.5, 51.6, 39.1, 28.3(3C) ppm.
HRMS (ESI), m/z calcd for C21H21N3O3SNa [M + Na]+ 418.1196,
found 418.1211.
tert-Butyl (4-(7-Nitro-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
yl)butyl)carbamate (9c). Yield 53 mg, 60%; brown oil; Rf = 0.22
(CH2Cl2/EtOAc = 20/1). H NMR (400 MHz, CDCl3) δ 8.51 (d, J
1
= 2.6 Hz, 1H), 8.19 (dd, J = 8.9, 2.6 Hz, 1H), 7.75−7.67 (m, 1H),
7.52 (d, J = 8.9 Hz, 1H), 7.50−7.44 (m, 1H), 7.40−7.33 (m, 2H),
4.82−4.68 (m, 1H), 4.65−4.47 (br s, 1H), 3.77−3.64 (m, 1H), 3.13
(q, J = 6.6 Hz, 2H), 1.80−1.66 (m, 2H), 1.64−1.53 (m, 2H), 1.43 (s,
9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 156.0, 149.3,
144.6, 137.7, 137.6, 137.4, 131.6, 131.4, 131.1, 129.2, 128.4, 126.1,
124.7, 79.2, 51.0, 39.9, 28.4(3C), 27.5, 25.5 ppm. HRMS (ESI), m/z
calcd for C22H25N3O5SNa [M + Na]+ 466.1407, found 466.1390.
tert-Butyl (5-(7-Nitro-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
yl)pentyl)carbamate (9d). Yield 448 mg, 49%; brown oil; Rf = 0.22
tert-Butyl (2-(7-(N,N-Dimethylsulfamoyl)-11-oxodibenzo[b,f ]-
[1,4]thiazepin-10(11H)-yl)ethyl)carbamate (9j). Yield 506 mg,
53%; beige solid; Rf = 0.15 (CH2Cl2/EtOAc = 20/1); mp 165−167
1
°C. H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.1 Hz, 1H), 7.76−
7.69 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.52−7.45 (m, 1H), 7.42−
7.33 (m, 2H), 5.09−5.01 (br s, 1H), 4.71−4.59 (m, 1H), 3.99−3.89
(m, 1H), 3.62−3.50 (m, 1H), 3.50−3.38 (m, 1H), 2.77 (s, 6H), 1.37
(s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 155.8,
147.8, 137.7, 137.5, 137.0, 134.1, 132.3, 131.6, 131.4, 131.3, 129.2,
129.1, 126.3, 79.5, 51.6, 39.1, 37.8(2C), 28.3(3C) ppm. HRMS (ESI),
m/z calcd for C22H27N3O5S2Na [M + Na]+ 500.1284, found
500.1280.
1
(CH2Cl2/EtOAc = 10/1). H NMR (400 MHz, CDCl3) δ 8.51 (d, J
= 2.6 Hz, 1H), 8.19 (dd, J = 8.9, 2.7 Hz, 1H), 7.75−7.67 (m, 1H),
7.52 (d, J = 9.0 Hz, 1H), 7.50−7.44 (m, 1H), 7.42−7.32 (m, 2H),
4.82−4.68 (m, 1H, CH), 4.63−4.46 (br s, 1H), 3.74−3.61 (m, 1H),
3.10 (q, J = 6.5 Hz, 2H), 1.81−1.60 (m, 2H), 1.57−1.35 (m, 13H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 156.0, 155.9, 149.3,
144.6, 137.7, 137.4, 131.7, 131.4, 131.1, 129.2, 128.5, 126.1, 124.7,
51.1, 40.3, 29.6, 28.4(3C), 27.8, 23.9, 22.5 ppm. HRMS (ESI), m/z
calcd for C23H27N3O5SNa [M + Na]+ 480.1564, found 480.1558.
tert-Butyl (2-(7-Cyano-11-oxodibenzo[b,f ][1,4]thiazepin-10-
(11H)-yl)ethyl)carbamate (9e). Yield546 mg, 69%; white solid; Rf
tert-Butyl(3-(7-(N,N-Dimethylsulfamoyl)-11-oxodibenzo[b,f ]-
[1,4]thiazepin-10(11H)-yl)propyl)carbamate (9k). Yield 600 mg,
61%; yellow solid; Rf = 0.16 (CH2Cl2/EtOAc = 20/1); mp 169−171
1
°C. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.1 Hz, 1H), 7.76−
7.68 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 6.7, 2.2 Hz, 1H),
7.41−7.32 (m, 2H), 5.15−4.93 (br s, 1H), 4.88−4.75 (m, 1H), 3.78−
3.65 (m, 1H), 3.43−3.29 (m, 1H), 3.26−3.13 (m, 1H), 2.77 (s, 6H),
1.98−1.82 (m, 1H), 1.80−1.66 (m, 1H), 1.45 (s, 9H) ppm. 13C{1H}
NMR (126 MHz, CDCl3) δ 168.8, 156.0, 147.0, 137.8, 137.7(2C),
133.9, 132.5, 131.4, 131.3, 131.2, 129.1, 128.9, 126.2, 79.2, 48.6, 41.0,
37.9(2C), 28.6, 28.4(3C) ppm. HRMS (ESI), m/z calcd for
C23H29N3O5S2Na [M + Na]+ 514.1441, found 514.1443.
1
= 0.21 (CH2Cl2/EtOAc = 20/1); mp 146−148 °C. H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 1.9 Hz, 1H), 7.74−7.68 (m, 1H), 7.63
(dd, J = 8.5, 2.0 Hz, 1H), 7.53−7.45 (m, 2H), 7.43−7.34 (m, 2H),
5.04−4.94 (br s, 1H), 4.69−4.59 (m, 1H), 4.01−3.88 (m, 1H), 3.61−
3.38 (m, 2H), 1.34 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3)
δ 168.4, 155.7, 148.2, 137.5, 137.3, 137.2, 136.7, 133.4, 131.6, 131.5,
131.2, 129.3, 126.7, 117.2, 110.2, 79.5, 51.4, 39.2, 28.3(3C) ppm.
HRMS (ESI), m/z calcd for C21H21N3O3SNa [M + Na]+ 418.1196,
found 418.1194.
tert-Butyl (2-(5-Oxo-9-(trifluoromethyl)benzo[b]pyrido[3,2-f ]-
[1,4]thiazepin-6(5H)-yl)ethyl)carbamate (9l). Yield 360 mg, 41%;
light beige solid; Rf = 0.11 (CH2Cl2/EtOAc = 20/1); mp 151−153
tert-Butyl (2-(10-Oxobenzo[f ]pyrido[3,2-b][1,4]thiazepin-11-
(10H)-yl)ethyl)carbamate (9f). Yield 394 mg, 53%; beige solid; Rf
= 0.16 (CH2Cl2/EtOAc = 10/1); mp 93−95 °C. 1H NMR (400
MHz, CDCl3) δ 8.43 (dd, J = 4.7, 1.9 Hz, 1H), 7.93 (dd, J = 7.7, 1.8
Hz, 1H), 7.74−7.68 (m, 1H), 7.50−7.43 (m, 1H), 7.40−7.32 (m,
2H), 7.10 (dd, J = 7.7, 4.7 Hz, 1H), 5.53−5.41 (br s, 1H), 4.58−4.47
(m, 1H), 4.47−4.35 (m, 1H), 3.62−3.42 (m, 2H), 1.39 (s, 9H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 155.9, 148.8, 141.8,
138.1, 137.1, 131.8(2C), 131.2, 130.7, 130.1, 129.0, 121.4, 78.9, 48.6,
39.6, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C19H21N3O3SNa
[M + Na]+ 394.1196, found 394.1199.
tert-Butyl (2-(7-Chloro-11-oxodibenzo[b,f ][1,4]thiazepin-10-
(11H)-yl)ethyl)carbamate (9g). Yield 308 mg, 38%; white solid; Rf
1
°C. H NMR (400 MHz, CDCl3) δ 8.51 (dd, J = 4.8, 1.9 Hz, 1H),
8.05−7.99 (m, 2H), 7.65 (dd, J = 8.5, 2.1 Hz, 1H), 7.54 (d, J = 8.5
Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 1H), 5.03−4.89 (br s, 1H), 4.74−
4.62 (m, 1H), 4.06−3.94 (m, 1H), 3.56−3.38 (m, 2H), 1.31 (s, 9H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.9, 157.7, 155.7, 151.1,
146.3, 140.0, 134.0, 133.8, 131.3 (q, J = 4.8 Hz), 129.0 (q, J = 33.4
Hz), 127.3 (q, J = 3.5 Hz), 126.3, 124.0, 123.0 (q, J = 272.6 Hz), 79.5,
51.2, 39.3, 28.8(3C) ppm. HRMS (ESI), m/z calcd for
C20H20F3N3O3SNa [M + Na]+ 462.1070, found 462.1071.
tert-Butyl (3-(5-Oxo-9-(trifluoromethyl)benzo[b]pyrido[3,2-f ]-
[1,4]thiazepin-6(5H)-yl)propyl)carbamate (9m). Yield 453 mg,
50%; beige solid; Rf = 0.15 (CH2Cl2/EtOAc = 20/1); mp 156−158
°C. 1H NMR (400 MHz, CDCl3) δ 8.52−8.47 (m, 1H), 8.01 (dd, J =
7.7, 1.9 Hz, 2H), 7.64 (dd, J = 8.6, 2.2 Hz, 1H), 7.53 (d, J = 8.5 Hz,
1H), 7.33 (dd, J = 7.8, 4.7 Hz, 1H), 5.03−4.89 (br s, 1H), 4.90−4.74
1
= 0.18 (CH2Cl2/EtOAc = 20/1); mp 118−120 °C. H NMR (400
MHz, CDCl3) δ 7.71 (dd, J = 7.1, 2.1 Hz, 1H), 7.62 (t, J = 1.3 Hz,
1H), 7.47 (dd, J = 7.2, 1.8 Hz, 1H), 7.40−7.29 (m, 4H), 5.06 (t, J =
5785
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J. Org. Chem. 2021, 86, 5778−5791

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Article
(m, 1H), 3.79−3.63 (m, 1H), 3.42−3.27 (m, 1H), 3.25−3.09 (m,
1H), 1.98−1.82 (m, 1H), 1.80−1.67 (m, 1H), 1.44 (s, 9H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 157.8, 156.0, 151.1,
145.4, 139.9, 134.8, 133.9, 131.5 (q, J = 3.7 Hz), 129.0 (q, J = 33.6
Hz), 127.1 (q, J = 3.4 Hz), 126.1, 123.9, 123.0 (q, J = 272.7 Hz), 79.3,
48.4, 37.6, 29.7, 28.4(3C) ppm. HRMS (ESI), m/z calcd for
C21H22F3N3O3SNa [M + Na]+ 476.1226, found 476.1217.
140.5, 138.7, 134.6, 132.2, 131.8, 131.3, 128.8, 127.1, 124.0, 122.9,
79.2, 51.5, 39.7, 28.4(3C), 27.6, 24.5 ppm. HRMS (ESI), m/z calcd
for C22H25N3O7SNa [M + Na]+ 498.1305, found 498.1303.
tert-Butyl (5-(7-Nitro-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)pentyl)carbamate (11d). Yield 133 mg, 68%;
1
beige oil; Rf = 0.29 (CH2Cl2/EtOAc = 20/1). H NMR (400 MHz,
CDCl3) δ 8.88 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.0, 2.7 Hz, 1H),
7.95 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.75−7.62 (m,
3H), 4.70−4.53 (m, 2H), 3.96−3.82 (m, 1H), 3.11 (q, J = 7.1 Hz,
2H), 1.97−1.72 (m, 2H), 1.64−1.34 (m, 13H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 166.0, 156.0, 144.9, 144.5, 140.5, 138.7, 134.5,
132.2, 131.8, 131.4, 128.8, 126.9, 124.0, 122.9, 79.1, 51.9, 40.1, 29.6,
28.4(3C), 27.0, 24.0 ppm. HRMS (ESI), m/z calcd for
C23H27N3O7SNa [M + Na]+ 512.1462, found 512.1463.
tert-Butyl (2-(7-Cyano-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (11e). Yield 137 mg, 79%;
white solid; mp 179−181 °C. 1H NMR (400 MHz, CDCl3) δ 8.34 (d,
J = 2.0 Hz, 1H), 7.97 (dd, J = 7.7, 1.3 Hz, 1H), 7.90 (dd, J = 7.6, 1.3
Hz, 1H), 7.86 (dd, J = 8.5, 2.1 Hz, 1H), 7.74 (td, J = 7.6, 1.4 Hz, 1H),
7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.67−7.61 (m, 1H), 5.22 (t, J = 6.1 Hz,
1H), 4.75 (dt, J = 13.6, 3.6 Hz, 1H), 4.17 (dt, J = 13.8, 6.9 Hz, 1H),
3.53 (td, J = 6.6, 3.7 Hz, 2H), 1.28 (s, 9H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 166.0, 155.8, 144.0, 140.5, 137.9, 137.5, 134.7, 132.1,
131.8, 131.2, 130.9, 127.5, 124.1, 116.3, 110.3, 79.2, 51.8, 39.7,
28.2(3C) ppm. HRMS (ESI), m/z calcd for C21H21N3O5SK [M + K]+
466.0833, found 466.0839.
Preparation of tert-Butyl (2-(11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (9n). Sodium hydride
(60% suspension in mineral oil, 0.451 g, 7.5 mmol) was added
slowly to a solution of dibenzo[b,f][1,4]thioazepin-11(10H)-one
(10) (1.136 g, 5.0 mmol) in DMF (8 mL) at 0 °C. The mixture was
stirred at the same temperature for 30 min. Then tert-butyl (2-
bromoethyl)carbamate (1.233 g, 5.5 mmol) was added. The resulting
mixture was stirred at 0 °C for 10 min. Then the mixture was stirred
at 80 °C in an oil bath for 72 h. The resulting mixture was cooled to
room temperature. Then the solvent was evaporated. The residue was
suspended in EtOAc and filtered. Then the filtrate was evaporated.
The product was crystallized from diethyl ether and filtered. The
resulting product was purified by column chromatography in CH2Cl2/
EtOAc = 20/1 (Rf = 0.17). The yield 1.037 g; white solid; mp 107−
1
109 °C. H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.2, 2.0 Hz,
1H), 7.64−7.59 (m, 1H), 7.47 (dd, J = 7.3, 1.7 Hz, 1H), 7.38−7.29
(m, 4H), 7.17−7.11 (m, 1H), 5.24−5.06 (br s, 1H), 4.77−4.66 (m,
1H), 3.91−3.78 (m, 1H), 3.61−3.47 (m, 1H), 3.44−3.29 (m, 1H),
1.34 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 169.0, 155.8,
143.9, 139.0, 138.0, 136.2, 133.1, 131.4, 131.0, 130.9, 129.9, 128.7,
126.6, 126.1, 79.2, 51.2, 39.2, 28.3(3C) ppm. HRMS (ESI), m/z calcd
for C20H22N2O3SNa [M + Na]+ 393.1243, found 393.1242.
tert-Butyl (2-(5,5-Dioxido-10-oxobenzo[f ]pyrido[3,2-b][1,4]-
thiazepin-11(10H)-yl)ethyl)carbamate (11f). Yield 82 mg, 51%;
1
white solid; mp 132−134 °C. H NMR (400 MHz, CDCl3) δ 8.68
(dd, J = 4.7, 1.9 Hz, 1H), 8.36 (dd, J = 7.8, 1.9 Hz, 1H), 7.94 (ddd, J
= 7.7, 6.2, 1.3 Hz, 2H), 7.73 (td, J = 7.6, 1.4 Hz, 1H), 7.66 (td, J = 7.6,
1.3 Hz, 1H), 7.33 (dd, J = 7.9, 4.7 Hz, 1H), 5.34 (t, J = 6.1 Hz, 1H),
4.88−4.74 (m, 1H), 4.64−4.49 (m, 1H), 3.59−3.49 (m, 2H), 1.29 (s,
9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 155.8, 153.2,
151.8, 140.5, 135.9, 134.4, 132.4, 131.8, 131.7, 131.5, 123.6, 121.0,
78.8, 49.0, 39.7, 28.3(3C) ppm. HRMS (ESI), m/z calcd for
C19H21N3O5SNa [M + Na]+ 426.1094, found 426.1093.
tert-Butyl (2-(7-Chloro-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (11g). Yield 79 mg, 45%;
white solid; mp 130−133 °C. 1H NMR (400 MHz, CDCl3) δ 8.02 (d,
J = 2.5 Hz, 1H), 7.95 (dd, J = 7.7, 1.3 Hz, 1H), 7.89 (dd, J = 7.7, 1.3
Hz, 1H), 7.71 (td, J = 7.6, 1.4 Hz, 1H), 7.64 (td, J = 7.6, 1.3 Hz, 1H),
7.55 (dd, J = 8.7, 2.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 5.33 (t, J =
6.2 Hz, 1H), 4.76 (dt, J = 13.6, 3.6 Hz, 1H), 4.11−3.97 (m, 1H),
3.61−3.41 (m, 2H), 1.28 (s, 9H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 166.1, 155.8, 141.1, 138.9, 138.3, 134.6, 134.4, 132.4, 132.0,
131.6, 131.4, 128.1, 126.6, 124.0, 79.0, 51.6, 39.6, 28.2(3C) ppm.
HRMS (ESI), m/z calcd for C20H21ClN2O5SNa [M + Na]+ 459.0752,
found 459.0758.
tert-Butyl (2-(5,5-Dioxido-11-oxo-7-(trifluoromethyl)dibenzo-
[b,f ][1,4]thiazepin-10(11H)-yl)ethyl)carbamate (11h). Yield 122
mg, 65%; white solid; mp 163−165 °C. 1H NMR (400 MHz,
CDCl3) δ 8.31 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 7.8, 1.3 Hz, 1H),
7.90 (dd, J = 7.6, 1.3 Hz, 1H), 7.85 (dd, J = 8.6, 2.2 Hz, 1H), 7.73 (td,
J = 7.6, 1.4 Hz, 1H), 7.69−7.61 (m, 2H), 5.28 (t, J = 6.2 Hz, 1H),
4.79 (dt, J = 13.7, 3.4 Hz, 1H), 4.22−4.10 (m, 1H), 3.57−3.47 (m,
2H), 1.23 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.1,
155.8, 143.6, 140.9, 137.5, 134.5, 132.1(2C), 131.7, 131.3 (q, J = 3.6
Hz), 128.6 (q, J = 34.2 Hz), 127.3, 124.4 (q, J = 3.6 Hz), 124.1, 122.7
(q, J = 272.6 Hz), 79.1, 51.8, 39.7, 28.1(3C) ppm. HRMS (ESI), m/z
calcd for C21H21F3N2O5SNa [M + Na]+ 493.1015, found 493.1017.
tert-Butyl (2-(8-Cyano-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (11i). Yield 154 mg, 89%;
white solid; mp 204−206 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d,
J = 8.1 Hz, 1H), 7.95 (dd, J = 7.8, 1.2 Hz, 1H), 7.90 (dd, J = 7.7, 1.2
Hz, 1H), 7.80 (s, 1H), 7.74 (td, J = 7.6, 1.3 Hz, 1H), 7.69−7.61 (m,
2H), 5.25 (t, J = 6.3 Hz, 1H), 4.78 (dt, J = 13.7, 3.7 Hz, 1H), 4.17−
4.03 (m, 1H), 3.61−3.46 (m, 2H), 1.28 (s, 9H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 166.0, 155.8, 141.4, 140.6, 140.5, 134.8, 132.2,
131.8, 131.3, 130.3, 129.4, 127.9, 124.2, 118.5, 116.1, 79.2, 52.1, 39.6,
General Procedure the Preparation of [1,4]Thiazepin 5,5-
Dioxides 11a−n. Sodium periodate (257 mg, 1.20 mmol, 3 equiv)
was added to a stirred solution of [1,4]thiazepin-5-ones 9a−n (0.40, 1
equiv) in a mixture of CCl4 (10 mL) and water (20 mL). Once all of
the NaIO4 had dissolved, a catalytic amount of RuCl3 (4.2 mg, 0.02
mmol) was added and the reaction mixture was stirred vigorously at
room temperature overnight. It was extracted with CH2Cl2 (50 mL).
The organic extract was dried over Na2SO4, filtered, and concentrated
in vacuo. The products 11a, 11e−j, 11l, and 11n were purified by
crystallization from methanol, and the products 11b−d, 11k, 11 were
purified by column chromatography in CH2Cl2/EtOAc = 20/1.
tert-Butyl (2-(7-Nitro-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)ethyl)carbamate (11a). Yield 157 mg, 88%;
white solid; mp 154−156 °C. 1H NMR (400 MHz, CDCl3) δ 8.90 (d,
J = 2.7 Hz, 1H), 8.42 (dd, J = 9.0, 2.7 Hz, 1H), 7.99 (dd, J = 7.7, 1.3
Hz, 1H), 7.90 (dd, J = 7.7, 1.3 Hz, 1H), 7.79−7.65 (m, 3H), 5.21 (t, J
= 6.3 Hz, 1H), 4.78 (dt, J = 13.7, 3.7 Hz, 1H), 4.21 (dt, J = 13.7, 6.9
Hz, 1H), 3.54 (td, J = 6.6, 3.7 Hz, 2H), 1.24 (s, 9H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 166.0, 155.8, 145.5, 144.6, 140.4, 137.8,
134.8, 132.1, 131.9, 131.2, 129.0, 127.6, 124.2, 122.7, 79.3, 51.9, 39.7,
28.2(3C) ppm. HRMS (ESI), m/z calcd for C20H21N3O7SNa [M +
Na]+ 470.0992, found 470.1000.
tert-Butyl (3-(7-Nitro-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)propyl)carbamate (11b). Yield 140 mg, 76%;
white solid; Rf = 0.26 (CH2Cl2/EtOAc = 20/1); mp 181−183 °C. 1H
NMR (400 MHz, CDCl3) δ 8.90 (d, J = 2.7 Hz, 1H), 8.43 (dd, J =
8.9, 2.7 Hz, 1H), 7.97 (dd, J = 7.7, 1.4 Hz, 1H), 7.89 (dd, J = 7.6, 1.4
Hz, 1H), 7.77−7.62 (m, 3H), 4.95−4.84 (br s, 1H), 4.84−4.72 (m,
1H), 3.99−3.86 (m, 1H), 3.35−3.14 (m, 2H), 2.05−1.94 (m, 2H),
1.44 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 156.1,
144.7, 144.6, 140.6, 138.8, 134.6, 132.2, 131.9, 131.2, 128.9, 127.0,
124.1, 123.0, 79.3, 49.5, 38.0, 28.4(3C), 28.1 ppm. HRMS (ESI), m/z
calcd for C21H23N3O7SNa [M + Na]+ 484.1149, found 484.1165.
tert-Butyl (4-(7-Nitro-5,5-dioxido-11-oxodibenzo[b,f ][1,4]-
thiazepin-10(11H)-yl)butyl)carbamate (11c). Yield 167 mg, 88%;
1
yellow oil; Rf = 0.20 (CH2Cl2/EtOAc = 20/1). H NMR (400 MHz,
CDCl3) δ 8.89 (d, J = 2.6 Hz, 1H), 8.43 (dd, J = 9.0, 2.7 Hz, 1H),
7.96 (dd, J = 7.8, 1.3 Hz, 1H), 7.89 (dd, J = 7.6, 1.2 Hz, 1H), 7.76−
7.61 (m, 3H), 4.75−4.58 (m, 2H), 3.99−3.84 (m, 1H), 3.23−3.08
(m, 2H), 1.94−1.73 (m, 2H), 1.65−1.52 (m, 2H), 1.43 (s, 9H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 156.1, 144.8, 144.5,
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https://doi.org/10.1021/acs.joc.1c00236
J. Org. Chem. 2021, 86, 5778−5791

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Article
28.2(3C) ppm. HRMS (ESI), m/z calcd for C21H21N3O5SNa [M +
Na]+ 450.1094, found 450.1096.
compound 9g at 60 °C for 7 days; compound 9n at 60 °C for 30 days.
The resulting mixture was concentrated in vacuo and treated with
water (1 mL). The precipitated product was filtered and washed with
MeOH (0.5 mL), except compound 12cthe compound was
extracted with CHCl3 (2 mL) and washed with water (3 × 0.5
mL). In addition, compounds 13a−b, 13e−h, and 13l−n were treated
with DMSO (0.2 mL) and filtered. The products were dried at 70 °C
in vacuum for 24 h.
tert-Butyl (2-(7-(N,N-Dimethylsulfamoyl)-5,5-dioxido-11-
oxodibenzo[b,f ][1,4]thiazepin-10(11H)-yl)ethyl)carbamate (11j).
1
Yield 179 mg, 88%; white solid; mp 194−196 °C. H NMR (400
MHz, CDCl3) δ 8.41 (d, J = 2.2 Hz, 1H), 8.01−7.94 (m, 2H), 7.91
(dd, J = 7.7, 1.3 Hz, 1H), 7.74 (td, J = 7.6, 1.5 Hz, 1H), 7.71−7.64
(m, 2H), 5.29 (t, J = 6.5 Hz, 1H), 4.81−4.68 (m, 1H), 4.19−4.03 (m,
1H), 3.66−3.45 (m, 2H), 2.81 (s, 6H), 1.31 (s, 9H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 166.2, 156.0, 143.7, 140.8, 137.7, 135.0,
134.6, 133.3, 132.2, 131.8, 131.2, 127.3, 126.3, 124.1, 79.2, 52.4, 39.5,
37.8(3C), 28.3(2C) ppm. HRMS (ESI), m/z calcd for
C22H27N3O7S2Na [M + Na]+ 532.1183, found 532.1191.
2-Nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-9-
1
one (12a). Yield 39 mg, 82%; yellow solid; mp 206−208 °C. H
NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H, Hminor), 8.30 (s, 1H,
Hmajor), 8.19−8.03 (m, 3H, 2Hmajor + Hminor), 7.98−7.83 (m, 2H,
Hmajor + Hminor), 7.73 (d, J = 7.0 Hz, 1H, Hminor), 7.52−7.33 (m, 4H,
2Hmajor + 2Hminor), 7.26 (d, J = 7.1 Hz, 1H, Hmajor), 7.18 (d, J = 6.8
Hz, 1H, Hminor), 7.07 (d, J = 9.2 Hz, 1H, Hmajor), 6.95 (d, J = 9.2 Hz,
1H, Hminor), 6.22−6.08 (m, 2H, Hmajor + Hminor), 3.79−3.52 (m, 3H,
3Hmajor), 3.52−3.36 (m, 1H, Hmajor), 3.27−3.14 (m, 3H, 3Hminor),
3.05−2.96 (m, 1H, Hminor) ppm. 13C{1H} NMR (101 MHz, DMSO-
d6) δ 169.6 (Cmajor), 158.8 (Cmajor), 138.5 (Cmajor), 133.1 (2Cmajor),
131.8 (Cmajor), 130.4 (2Cmajor), 129.5 (Cmajor), 127.4 (2Cmajor), 121.2
(Cmajor), 115.8 (Cmajor), 45.0 (Cmajor), 37.4 (Cmajor) ppm. HRMS
(ESI), m/z calcd for C15H13N3O3SNa [M + Na]+ 338.0570, found
338.0567.
tert-Butyl (3-(7-(N,N-Dimethylsulfamoyl)-5,5-dioxido-11-
oxodibenzo[b,f][1,4]thiazepin-10(11H)-yl)propyl)carbamate (11k).
Yield 161 mg, 77%; white solid; Rf = 0.13 (CH2Cl2/EtOAc = 20/1);
mp 136−138 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.0 Hz,
1H), 7.98 (dd, J = 8.5, 2.2 Hz, 1H), 7.94 (dd, J = 7.7, 1.3 Hz, 1H),
7.88 (dd, J = 7.6, 1.2 Hz, 1H), 7.75−7.68 (m, 1H), 7.69−7.62 (m,
2H), 5.01−4.82 (br s, 1H), 4.78−4.64 (m, 1H), 3.99−3.81 (m, 1H),
3.33−3.15 (m, 2H), 2.82 (s, 6H), 2.07−1.93 (m, 2H), 1.45 (s, 9H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 156.1, 143.0, 140.8,
138.6, 134.8, 134.5, 133.2, 132.1, 131.8, 131.3, 126.9, 126.4, 124.1,
79.2, 49.4, 38.0, 37.8(2C), 28.4(3C), 28.1 ppm. HRMS (ESI), m/z
calcd for C23H29N3O7S2Na [M + Na]+ 546.1339, found 546.1344.
tert-butyl (2-(11,11-Dioxido-5-oxo-9-(trifluoromethyl)benzo[b]-
pyrido[3,2-f ][1,4]thiazepin-6(5H)-yl)ethyl)carbamate (11l). Yield
2-Nitro-6,7,8,9-tetrahydrodibenzo[b,j][1]thia[4,8]diazacyclo-
undecin-10(5H)-one (12b). Yield 80 mg, 81%; yellow solid; mp more
1
than 250 °C. H NMR (400 MHz, DMSO-d6) δ 8.41 (t, J = 6.0 Hz,
1H), 8.27 (d, J = 2.7 Hz, 1H), 8.07−7.96 (m, 2H), 7.52−7.41 (m,
2H), 7.29 (dd, J = 6.7, 2.3 Hz, 1H), 7.21 (t, J = 7.0 Hz, 1H), 6.85 (d, J
= 9.3 Hz, 1H), 4.00−3.83 (m, 1H), 3.83−3.67 (m, 1H), 3.56−3.41
(m, 1H), 3.11−2.94 (m, 1H), 1.98−1.78 (m, 1H), 1.66−1.49 (m,
1H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 169.4, 155.1,
142.9, 137.1, 136.3, 133.6, 132.9, 130.8, 130.1, 128.1, 127.5, 119.4,
111.0, 43.3, 39.0, 25.3 ppm. HRMS (ESI), m/z calcd for
C16H16N3O3S [M + H]+ 330.0907, found 330.0898.
1
141 mg, 75%; white solid; mp 198−200 °C. H NMR (400 MHz,
CDCl3) δ 8.80 (d, J = 4.5 Hz, 1H), 8.44 (s, 1H), 8.31−8.25 (m, 1H),
7.93−7.86 (m, 1H), 7.74−7.64 (m, 2H), 5.21 (t, J = 6.1 Hz, 1H),
4.79 (dt, J = 13.7, 3.5 Hz, 1H), 4.29−4.15 (m, 1H), 3.59−3.46 (m,
2H), 1.23 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 164.3,
155.7, 151.6, 143.5, 141.0(2C), 135.9, 131.9 (q, J = 3.5 Hz), 129.3 (q,
J = 34.0 Hz), 128.7, 128.2, 127.4, 125.9 (q, J = 3.5 Hz), 122.6 (q, J =
272.9 Hz), 79.2, 51.8, 39.7, 28.1(3C) ppm. HRMS (ESI), m/z calcd
for C20H20F3N3O5SNa [M + Na]+ 494.0968, found 494.0973.
tert-Butyl (3-(11,11-Dioxido-5-oxo-9-(trifluoromethyl)benzo[b]-
pyrido[3,2-f ][1,4]thiazepin-6(5H)-yl)propyl)carbamate (11m).
Yield 146 mg, 75%; white solid; Rf = 0.16 (CH2Cl2/EtOAc = 20/
2-Nitro-5,6,7,8,9,10-hexahydro-11H-dibenzo[b,k][1]thia[4,9]-
1
diazacyclododecin-11-one (12c). Yield 16 mg, 6%; yellow oil. H
NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.7 Hz, 1H), 8.21−8.13 (m,
2H), 7.72−7.66 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.49−7.42 (m,
1H), 7.40−7.30 (m, 2H), 4.81−4.66 (m, 1H), 4.59−4.44 (br s, 1H),
3.75−3.59 (m, 1H), 2.73 (t, J = 6.7 Hz, 2H), 1.84−1.62 (m, 2H),
1.55 (p, J = 7.3 Hz, 2H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6)
δ 167.7, 161.4, 148.9, 144.7, 138.0, 137.3, 132.0, 131.8, 131.6, 129.9,
128.2, 127.7, 125.6, 56.5, 50.2, 27.8, 25.3 ppm. HRMS (ESI), m/z
calcd for C17H18N3O3S [M + H]+ 344.1063, found 344.1071.
9-Oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]thiadiazecine-2-
carbonitrile (12e). Yield 35 mg, 79%; beige solid; mp 216−218 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H, Hminor), 8.08 (t, J =
5.7 Hz, 1H, Hmajor), 8.02−7.77 (m, 4H, 2Hmajor + 2Hminor), 7.77−7.69
(m, 1H, Hminor), 7.61 (d, J = 8.6 Hz, 1H, Hmajor), 7.51−7.34 (m, 4H,
2Hmajor + 2Hminor), 7.25 (d, J = 7.1 Hz, 1H, Hmajor), 7.18 (d, J = 6.3
Hz, 1H, Hminor), 7.02 (d, J = 8.7 Hz, 1H, Hmajor), 6.95 (d, J = 8.4 Hz,
1H, Hminor), 5.93−5.75 (m, 2H, Hmajor + Hminor), 3.74−3.45 (m, 3H,
3Hmajor), 3.45−3.35 (m, 1H, Hmajor), 3.27−3.12 (m, 3H, 3Hminor),
2.70−2.59 (m, 1H, Hminor) ppm. 13C{1H} NMR (126 MHz, DMSO-
d6) δ 171.4 (Cminor), 169.5 (Cmajor), 156.8 (Cmajor), 154.9 (Cminor),
141.3 (Cmajor + Cminor), 140.5 (Cminor), 140.3 (Cmajor), 136.3 (Cminor),
135.4 (Cminor), 135.1(Cmajor + Cminor), 132.1 (Cmajor), 130.6 (Cmajor),
130.2 (Cmajor + Cminor), 129.4 (Cminor), 129.3 (Cmajor), 127.7 (Cmajor),
127.2 (Cminor), 123.8 (Cminor), 121.9 (Cmajor), 119.6 (Cminor), 119.5
(Cmajor), 117.1 (Cminor), 117.0 (Cmajor), 100.6 (Cminor), 100.5 (Cmajor),
46.2 (Cminor), 45.3 (Cmajor), 40.9 (Cminor), 37.4 (Cmajor) ppm. HRMS
(ESI), m/z calcd for C16H13N3OSNa [M + Na]+ 318.0672, found
318.0669.
1
1); mp 177−179 °C. H NMR (400 MHz, CDCl3) δ 8.78 (dd, J =
4.7, 1.5 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 7.8, 1.7 Hz,
1H), 7.90 (dd, J = 8.5, 2.2 Hz, 1H), 7.77−7.61 (m, 2H), 4.98−4.67
(m, 2H), 3.94−3.80 (m, 1H), 3.32−3.12 (m, 2H), 2.10−1.90 (m,
2H), 1.44 (s, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 164.5,
156.1, 155.9, 151.5, 142.5, 141.1, 137.0, 131.7 (q, J = 3.5 Hz), 129.4
(q, J = 34.6 Hz), 128.9, 128.2, 127.0, 126.0 (q, J = 3.8 Hz), 122.6 (q, J
= 273.0 Hz), 82.8, 49.4, 47.7, 38.0, 28.4(3C) ppm. HRMS (ESI), m/z
calcd for C21H22F3N3O5SNa [M + Na]+ 508.1124, found 508.1115.
tert-Butyl (2-(5,5-Dioxido-11-oxodibenzo[b,f ][1,4]thiazepin-10-
(11H)-yl)ethyl)carbamate (11n). Yield 95 mg, 59%; white solid;
1
mp 157−159 °C. H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 7.9,
1.5 Hz, 1H), 7.94 (dd, J = 7.8, 1.3 Hz, 1H), 7.89 (dd, J = 7.6, 1.3 Hz,
1H), 7.68 (td, J = 7.6, 1.3 Hz, 1H), 7.64−7.57 (m, 2H), 7.48 (d, J =
8.1 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 5.49−5.40 (br s, 1H), 4.83−
4.74 (m, 1H), 4.12−4.01 (m, 1H), 3.62−3.41 (m, 2H), 1.25 (s, 9H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 155.9, 141.7, 140.5,
137.3, 134.6, 134.0, 132.0, 131.7, 131.3, 126.9, 126.7, 126.5, 123.8,
78.8, 52.0, 39.5, 28.2(3C) ppm. HRMS (ESI), m/z calcd for
C20H22N2O5SNa [M + Na]+ 425.1142, found 425.1145.
General Procedure for the Preparation of Diarene-fused
Medium-size Cycles 12a−n, 13a−n. Boc-protected amine 9a−n or
11a−n (0.15 mmol) was dissolved in DCM (5 mL) and 4 M solution
of HCl in 1,4-dioxane (0.188 mL). The mixture was stirred at room
temperature overnight. Volatiles were removed in vacuo, and the
residue was treated with diethyl ether (1 mL). The solid formed was
filtered off and washed with diethyl ether (0.5 mL). The ammonium
hydrochloride salt thus obtained was dissolved in a H2O/MeOH
(1:1) mixture (5 mL). Then 10% aq. NaOH (0.45 mmol) was added,
and the resulting mixture was stirred under the following conditions:
compounds 9a−f, 9h−m, 11a−n at room temperature overnight;
5,6,7,8-Tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]thiadiazecin-
1
9-one (12f). Yield 22 mg, 54%; white solid; mp 172−174 °C. H
NMR (400 MHz, DMSO-d6) δ 8.20−8.08 (m, 2H, 2Hmajor), 8.09−
8.02 (m, 2H, 2Hminor), 8.00−7.93 (m, 1H, Hminor), 7.85−7.76 (m, 1H,
2Hmajor), 7.71−7.65 (m, 1H, Hminor), 7.64−7.53 (m, 1H, Hminor),
7.49−7.31 (m, 3H, 2Hmajor + Hminor), 7.30−7.19 (m, 1H, Hmajor),
7.20−7.14 (m, 1H, Hminor), 6.73−6.66 (m, 1H, Hminor), 6.66−6.57 (m,
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Article
1H, Hmajor), 6.04−5.85 (m, 2H, Hmajor + Hminor), 4.07−3.84 (m, 1H,
2Hmajor + 2Hminor), 7.23 (d, J = 7.3 Hz, 1H, Hmajor), 7.15 (d, J = 8.9
Hz, 1H, Hmajor), 7.02 (d, J = 8.8 Hz, 1H, Hminor), 5.94−5.73 (m, 2H,
Hmajor + Hminor), 3.79−3.37 (m, 4H, 3Hmajor + Hminor), 3.31−3.12 (m,
1H, Hmajor), 2.76−2.61 (m, 3H, 3Hminor), 2.58 (s, 6H, 6Hminor), 2.45
(s, 6H, 6Hmajor) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.8
(Cmajor), 156.7 (Cmajor), 136.6 (Cmajor), 133.4 (Cmajor), 132.9 (Cmajor),
130.8 (Cmajor), 130.1 (Cmajor), 128.8 (2Cmajor), 124.4 (Cmajor), 121.7
(Cmajor), 117.3 (Cmajor), 45.3 (Cmajor), 37.9 (2C), 37.0 (Cmajor) ppm.
HRMS (ESI), m/z calcd for C17H19N3O3S2Na [M + Na]+ 400.0760,
found 400.0759.
Hmajor), 3.78−3.38 (m, 2H, 2Hmajor), 3.28−3.07 (m, 3H, Hmajor
+
2Hminor), 2.73−2.55 (m, 2H, 2Hminor) ppm. 13C{1H} NMR (101
MHz, DMSO-d6) δ 171.5 (Cminor), 169.9 (Cmajor), 163.0 (Cmajor),
161.1 (Cminor), 150.2 (Cmajor), 150.0 (Cminor), 145.7 (Cmajor), 144.3
(Cminor), 142.7 (Cminor), 136.2 (Cminor), 134.8 (Cminor), 133.8 (Cmajor),
133.6 (Cmajor), 132.5 (Cmajor), 130.1 (Cmajor), 129.5 (Cminor), 129.3
(Cmajor), 129.2 (Cmajor), 127.5 (Cminor), 127.4 (Cminor), 118.4 (Cminor),
116.6 (Cmajor), 115.8 (Cminor), 115.5 (Cmajor), 46.3 (Cminor), 44.1
(Cminor), 43.7 (Cmajor), 37.5 (Cmajor) ppm. HRMS (ESI), m/z calcd for
C14H13N3OSNa [M + Na]+ 294.0672, found 294.0676.
N,N-Dimethyl-10-oxo-5,6,7,8,9,10-hexahydrodibenzo[b,j][1]thia-
[4,8]diazacycloundecine-2-sulfonamide (12k). Yield 23 mg, 39%;
2-Chloro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-
1
1
9-one (12g). Yield 18 mg, 38%; white solid; mp 154−156 °C. H
white solid; mp 196−198 °C. H NMR (400 MHz, DMSO-d6) δ
NMR (400 MHz, DMSO-d6) δ 8.05 (t, J = 5.0 Hz, 1H, Hmajor), 7.81−
7.75 (m, 1H, Hminor), 7.73−7.65 (m, 2H, Hmajor + Hminor), 7.59 (d, J =
2.5 Hz, 1H, Hmajor), 7.56 (dd, J = 7.6, 1.5 Hz, 1H, Hmajor), 7.51−7.35
(m, 7H, 3Hmajor + 4Hminor), 7.28 (d, J = 8.9 Hz, 1H, Hmajor), 7.25−
7.20 (m, 2H, 2Hminor), 6.97 (d, J = 8.8 Hz, 1H, Hminor), 5.39−5.31 (m,
1H, Hmajor), 4.27−3.98 (m, 3H, Hmajor + 2Hminor), 3.96−3.81 (m, 2H,
2Hmajor), 3.58−3.37 (m, 3H, Hmajor + 2Hminor) ppm. 13C{1H} NMR
(101 MHz, DMSO-d6) δ 173.6 (Cminor), 164.8 (Cmajor), 156.5
(Cminor), 146.7 (Cmajor), 140.6 (Cminor), 139.5 (Cmajor), 139.2 (Cmajor),
138.5 (Cminor), 137.5 (Cminor), 137.2 (Cmajor), 136.8 (2Cmajor+Cminor),
136.6 (Cmajor), 136.1 (Cminor), 135.1 (Cmajor), 134.9 (Cminor), 134.3
(Cmajor), 133.6 (Cminor), 133.2 (Cminor), 133.0 (Cminor), 131.5 (Cmajor),
127.3 (Cmajor), 126.0 (Cmajor+Cminor), 124.0 (Cminor), 57.3 (Cmajor),
56.5 (Cmajor), 50.5 (Cminor), 42.0 (Cminor) ppm. HRMS (ESI), m/z
calcd for C15H13ClN2OSNa [M + Na]+ 327.0329, found 327.0331.
2-(Trifluoromethyl)-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]-
thiadiazecin-9-one (12h). Yield 37 mg, 73%; white solid; mp 214−
216 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.15−8.06 (m, 2H, Hmajor
+ Hminor), 8.06−8.01 (m, 1H, Hminor), 7.87 (d, J = 7.3 Hz, 1H, Hmajor),
7.82−7.77 (m, 1H, Hminor), 7.76−7.71 (m, 1H, Hmajor), 7.53 (dd, J =
8.7, 2.3 Hz, 1H, Hmajor) 7.49−7.35 (m, 5H, 2Hmajor + 3Hminor), 7.25
(dd, J = 7.1, 1.9 Hz, 1H, Hmajor), 7.19 (dd, J = 6.5, 2.5 Hz, 1H, Hminor),
7.07 (d, J = 8.7 Hz, 1H, Hmajor), 7.02 (d, J = 8.6 Hz, 1H, Hminor),
7.95−7.82 (m, 2H), 7.77 (dd, J = 8.5, 2.2 Hz, 1H), 7.65−7.60 (m,
1H), 7.58−7.51 (m, 1H), 7.48−7.40 (m, 3H), 4.75−4.58 (m, 1H),
3.85−3.69 (m, 1H), 2.63 (s, 6H), 2.61−2.54 (m, 2H), 1.73−1.52 (m,
2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.7, 147.3,
138.2, 137.7, 137.0, 132.9, 132.0, 131.9, 131.8, 131.4, 129.7, 129.6,
127.7, 48.5, 39.4, 38.0 (2C), 32.0 ppm. HRMS (ESI), m/z calcd for
C18H22N3O3S2[M + H]+ 392.1097, found 392.1087.
12-(Trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[b]pyrido[3,2-
i][1,4,7]thiadiazecin-5-one (12l). Yield 27 mg, 54%; white solid; mp
1
222−224 °C. H NMR (400 MHz, DMSO-d6) δ 8.56−8.49 (m, 2H,
Hmajor + Hminor), 8.12 (d, J = 8.2 Hz, 1H, Hmajor), 7.75 (d, J = 2.2 Hz,
1H, Hminor), 7.64−7.56 (m, 4H, 3Hmajor + Hminor), 7.53 (dd, J = 8.8,
2.2 Hz, 1H, Hminor), 7.48 (dd, J = 7.7, 1.9 Hz, 1H, Hminor), 7.34 (dd, J
= 7.6, 4.7 Hz, 1H, Hmajor), 7.29−7.26 (m, 1H, Hminor), 7.23 (d, J = 8.5
Hz, 1H, Hmajor), 7.00 (d, J = 8.8 Hz, 1H, Hminor), 5.86−5.76 (m, 1H,
Hmajor), 5.34−5.26 (m, 1H, Hminor), 3.84−3.65 (m, 2H, 2Hmajor),
3.50−3.36 (m, 2H, Hmajor + Hminor), 3.28−3.19 (m, 1H, Hminor), 3.16−
3.09 (m, 1H, Hminor), 3.04−2.83 (m, 2H, Hmajor + Hminor) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 169.0 (Cminor), 166.8
(Cmajor), 156.0 (Cmajor), 155.6 (Cminor), 150.2 (Cminor), 149.8 (Cmajor),
137.8 (Cmajor), 136.9 (Cminor), 134.7 (q, J = 3.0 Hz, Cmajor), 133.2 (q, J
= 4.3 Hz, Cminor), 132.1 (Cminor), 129.1 (q, J = 3.7 Hz, Cmajor), 128.5
(q, J = 3.1 Hz, Cminor), 127.9 (Cminor), 125.7 (Cmajor), 123.5 (Cmajor),
122.3 (Cmajor), 121.4 (Cminor), 121.3 (Cminor), 120.4 (q, J = 30.1 Hz,
Cmajor), 119.7 (q, J = 36.6 Hz, Cminor), 118.9 (Cmajor), 118.8 (Cmajor),
117.6 (q, J = 264.4 Hz, Cmajor), 117.2 (q, J = 270.2 Hz, Cminor), 116.5
(Cminor), 47.0 (Cminor), 46.9 (Cminor), 45.1 (Cmajor), 36.5 (Cmajor) ppm.
HRMS (ESI), m/z calcd for C15H12F3N3OSNa [M + Na]+ 362.0545,
found 362.0549.
5.76−5.65 (m, 2H, Hmajor + Hminor), 3.66−3.35 (m, 5H, 4Hmajor
+
H
minor), 3.29−3.12 (m, 2H, 2Hminor), 2.69−2.54 (m, 1H, Hminor) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.5 (Cminor), 169.3
(Cmajor), 156.2 (Cmajor), 154.6 (Cminor), 142.3 (Cminor), 140.8 (Cminor),
136.2 (Cminor), 134.1 (q, J = 3.7 Hz, Cmajor), 133.3 (q, J = 3.4 Hz,
Cminor), 132.3 (Cmajor), 130.8, (Cminor), 130.6 (Cminor), 130.2 (2Cmajor),
129.2, 128.5 (q, J = 3.7 Hz, Cminor), 128.4 (q, J = 3.2 Hz, Cmajor), 127.9
(Cminor), 126.1 (Cmajor), 125.4 (q, J = 305.8 Hz, Cminor), 123.4 (Cmajor),
122.2 (q, J = 302.2 Hz, Cmajor), 121.3 (Cmajor), 119.4 (q, J = 33.2 Hz,
Cmajor), 119.3 (q, J = 32.7 Hz, Cminor), 119.4 (Cmajor), 117.6 (Cminor),
13-(Trifluoromethyl)-7,8,9,10-tetrahydrobenzo[b]pyrido[3,2-j]-
[1]thia[4,8]diazacycloundecin-5(6H)-one (12m). Yield 25 mg, 48%;
white solid; mp 253−255 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.59
(dd, J = 4.8, 1.9 Hz, 1H), 8.40 (t, J = 5.9 Hz, 1H), 7.69 (dd, J = 7.6,
1.9 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.50−7.40 (m, 2H), 6.92 (d, J
= 8.7 Hz, 1H), 6.43 (t, J = 7.0 Hz, 1H), 3.80−3.56 (m, 2H), 3.47−
3.36 (m, 1H), 3.20−3.05 (m, 1H), 2.05−1.89 (m, 1H), 1.59−1.46
(m, 1H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.9, 154.1,
152.6, 150.5, 138.1, 137.2, 134.0 (q, J = 3.9 Hz), 128.2 (q, J = 3.4
Hz), 124.9 (q, J = 270.5 Hz), 124.0, 117.2, 116.9 (q, J = 32.3 Hz),
112.8, 43.3, 39.3, 24.6 ppm. HRMS (ESI), m/z calcd for
C16H14F3N3OSNa [M + Na]+ 376.0702, found 376.0702.
117.1 (Cmajor), 46.9 (Cminor), 46.1 (Cminor), 45.6 (Cmajor), 37.4 (Cmajor
)
ppm. HRMS (ESI), m/z calcd for C16H13F3N2OSNa [M + Na]+
361.0593, found 361.0593.
9-Oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]thiadiazecine-3-
carbonitrile (12i). Yield 36 mg, 81%; white solid; mp 233−235 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.06 (t, J = 5.5 Hz, 1H, Hmajor),
8.01−7.93 (m, 2H, 2Hminor), 7.83−7.73 (m, 2H, Hmajor + Hminor), 7.55
(d, J = 8.0 Hz, 1H, Hmajor), 7.48−7.32 (m, 6H, 3Hmajor + 3Hminor),
7.23 (d, J = 7.2 Hz, 1H, Hmajor), 7.21−7.16 (m, 1H, Hminor), 7.14 (d, J
= 7.9 Hz, 1H, Hminor), 7.04 (d, J = 7.9 Hz, 1H, Hmajor), 5.61−5.51 (m,
1H, Hmajor), 5.50−5.43 (m, 1H, Hminor), 3.81−3.36 (m, 4H, 4Hmajor),
3.25−3.08 (m, 2H, 2Hminor), 2.65−2.54 (m, 2H, 2Hminor) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 168.8 (Cmajor), 153.3
(Cmajor), 138.2 (Cmajor), 134.0 (Cmajor), 133.9 (Cmajor), 132.3 (Cmajor),
130.2 (Cmajor), 129.1 (Cmajor), 128.5 (Cmajor), 127.0 (Cmajor), 122.7
(Cmajor), 120.8 (Cmajor), 119.2 (Cmajor), 113.7 (Cmajor), 45.5 (Cmajor),
37.1 (Cmajor) ppm. HRMS (ESI), m/z calcd for C16H13N3OSNa [M +
Na]+ 318.0672, found 318.0670.
5,6,7,8-Tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-9-one
1
(12n). Yield 15 mg, 37%; white solid; mp 175−177 °C. H NMR
(400 MHz, DMSO-d6) δ 8.07−7.96 (m, 2H, Hmajor + Hminor), 7.86−
7.78 (m, 2H, 2Hminor), 7.74 (dd, J = 7.7, 1.3 Hz, 1H, Hmajor), 7.44−
7.32 (m, 5H, 3Hmajor + 2Hminor), 7.27−7.19 (m, 3H, 2Hmajor + Hminor),
7.20−7.15 (m, 1H, Hminor), 6.94 (dd, J = 8.3, 1.3 Hz, 1H, Hmajor),
6.93−6.87 (m, 1H, Hminor), 6.82−6.76 (m, 1H, Hminor), 6.69−6.62 (m,
1H, Hmajor), 5.37−5.30 (m, 2H, Hmajor + Hminor), 3.58−3.35 (m, 4H,
3Hmajor + Hminor), 3.30−3.19 (m, 2H, Hmajor + Hminor), 3.20−3.12 (m,
1H, Hminor), 3.10−3.02 (m, 1H, Hminor) ppm. 13C{1H} NMR (126
MHz, DMSO-d6) δ 171.7 (Cminor), 168.9 (Cmajor), 152.6 (Cmajor),
151.8 (Cminor), 141.4 (Cminor), 141.3 (Cminor), 137.3 (Cmajor), 136.7
(Cminor), 136.5 (Cminor), 133.7 (Cmajor), 133.5 (Cmajor), 131.7 (Cminor),
131.6 (Cminor), 131.4 (Cmajor), 130.4 (Cminor), 129.9 (Cmajor), 129.5
(Cminor), 128.5 (Cmajor), 128.4 (Cmajor), 126.8 (Cmajor), 124.6 (Cminor),
121.1 (Cmajor), 120.8 (Cminor), 120.0 (Cmajor), 119.2 (Cminor), 117.9
N,N-Dimethyl-9-oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]-
thiadiazecine-2-sulfonamide (12j). Yield 39 mg, 69%; beige solid;
1
mp 179−181 °C. H NMR (400 MHz, DMSO-d6) δ 8.13−7.99 (m,
2H, Hmajor + Hminor), 7.94 (d, J = 11.6 Hz, 1H, Hminor), 7.86−7.72 (m,
2H, Hmajor + Hminor), 7.69 (d, J = 6.9 Hz, 1H, Hminor), 7.62 (s, 1H,
Hmajor), 7.58−7.49 (m, 2H, Hmajor + Hminor), 7.47−7.31 (m, 4H,
5788
https://doi.org/10.1021/acs.joc.1c00236
J. Org. Chem. 2021, 86, 5778−5791

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(Cmajor), 48.3 (Cminor), 46.0 (Cmajor), 45.5 (Cminor), 37.4 (Cmajor) ppm.
HRMS (ESI), m/z calcd for C15H14N2OSNa [M + Na]+ 293.0719,
found 293.0718.
(Cmajor), 46.6 (Cminor), 43.2 (Cminor), 41.4 (Cmajor), 36.8 (Cmajor) ppm.
HRMS (ESI), m/z calcd for C14H13N3O3SNa [M + Na]+ 326.0570,
found 326.0576.
2-Nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-9-
2-Chloro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-
9-one 14,14-Dioxide (13g). Yield 45 mg, 89%; brown solid; mp 138−
140 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.31−8.07 (m, 3H,
2Hmajor + Hminor), 7.99 (d, J = 8.1 Hz, 1H, Hminor), 7.87 (d, J = 2.6 Hz,
1H, Hminor), 7.81−7.67 (m, 3H, 2Hmajor + Hminor), 7.67−7.56 (m, 2H,
Hmajor + Hminor), 7.54−7.40 (m, 3H, 2Hmajor + Hminor), 7.36 (d, J = 7.6
Hz, 1H, Hminor), 7.11 (d, J = 9.5 Hz, 2H, Hmajor + Hminor), 6.58 (d, J =
11.5 Hz, 1H, Hminor), 6.53−6.34 (m, 1H, Hmajor), 4.02−3.79 (m, 1H,
Hmajor), 3.63−3.42 (m, 3H, 2Hmajor + Hminor), 3.25−3.10 (m, 2H,
2Hminor), 3.06−2.90 (m, 1H, Hmajor), 2.76−2.56 (m, 1H, Hminor) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 169.2 (Cmajor), 167.0
(Cminor), 150.5 (Cmajor + Cminor), 147.9 (Cmajor), 147.6 (Cminor), 138.8
(Cminor), 137.1 (Cminor), 137.0 (Cminor), 136.2 (Cmajor), 135.9 (Cmajor),
134.6 (Cmajor), 134.5 (Cminor), 131.0 (Cmajor), 130.9 (Cmajor), 130.3
(2Cmajor), 129.5 (Cminor), 129.2 (Cminor), 129.0 (Cmajor), 128.6 (Cminor),
128.3 (Cmajor), 127.8 (Cminor), 123.0 (Cminor), 122.5 (Cmajor), 122.4
(Cminor), 47.2 (Cminor), 46.6 (Cminor), 40.9 (Cmajor), 37.4 (Cmajor) ppm.
HRMS (ESI), m/z calcd for C15H13ClN2O3SNa [M + Na]+ 359.0228,
found 359.0227.
one 14,14-Dioxide (13a). Yield 41 mg, 78%; yellow solid; mp 197−
1
198 °C. H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.7 Hz, 1H,
H
minor), 8.42 (d, J = 2.7 Hz, 1H, Hmajor), 8.36−8.28 (m, 1H, Hmajor),
8.28−8.17 (m, 3H, 2Hmajor + Hminor), 7.96 (dd, J = 8.1, 1.2 Hz, 1H,
H
H
minor), 7.83−7.69 (m, 3H 2Hmajor + 2Hminor), 7.64−7.58 (m, 1H,
minor), 7.47 (dd, J = 7.4, 1.4 Hz, 2H, Hmajor), 7.38 (dd, J = 7.7, 1.3
Hz, 1H, Hminor), 7.31−7.20 (m, 4H, 3Hmajor + Hminor), 7.17 (d, J = 9.3
Hz, 1H, Hminor), 3.97−3.86 (m, 1H, Hmajor), 3.84−3.64 (m, 3H, Hmajor
+ 2Hminor), 3.29−3.20 (m, 2H, Hmajor + Hminor), 3.13−3.02 (m, 1H,
Hmajor), 2.79−2.66 (m, 1H, Hminor) ppm. 13C{1H} NMR (126 MHz,
DMSO-d6) δ 169.1 (Cminor), 167.2 (Cmajor), 155.7 (Cminor), 152.8
(Cmajor), 138.2 (Cmajor), 138.0 (Cminor), 137.8 (Cmajor), 137.7 (Cminor),
136.3 (Cminor), 136.1 (Cmajor), 134.9 (Cmajor + Cminor), 131.6 (Cminor),
131.0 (Cmajor), 130.8 (Cminor), 130.7 (Cmajor), 130.5 (Cminor), 129.1
(Cmajor), 129.0 (Cmajor), 128.7 (Cminor), 127.7 (Cmajor), 126.2 (Cminor),
124.8 (Cminor), 123.9 (Cmajor), 119.2 (Cmajor), 118.2 (Cminor),46.4
(Cmajor), 45.3 (Cminor), 43.1 (Cmajor), 36.6 (Cminor) ppm. HRMS (ESI),
m/z calcd for C15H13N3O5SNa [M + Na]+ 370.0468, found 370.0462.
2-Nitro-6,7,8,9-tetrahydrodibenzo[b,j][1]thia[4,8]diazacyclo-
undecin-10(5H)-one 15,15-Dioxide (13b). Yield 40 mg, 74%; yellow
solid; mp 254−256 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J
= 2.7 Hz, 1H), 8.31−8.21 (m, 2H), 8.18 (dd, J = 9.6, 2.7 Hz, 1H),
8.02 (dd, J = 8.4, 4.7 Hz, 1H), 7.79−7.69 (m, 2H), 7.46 (dd, J = 6.5,
2.2 Hz, 1H), 7.11 (d, J = 9.6 Hz, 1H), 3.97−3.74 (m, 2H), 3.61−3.47
(m, 1H), 3.14−3.01 (m, 1H), 2.06−1.89 (m, 1H), 1.72−1.60 (m,
1H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.2, 152.5,
139.4, 138.0, 136.2, 134.5, 130.5, 130.2, 129.9, 128.7(2C), 120.8,
115.6, 43.6, 39.4, 25.6 ppm. HRMS (ESI), m/z calcd for
C16H15N3O5SNa [M + Na]+ 384.0625, found 384.0623.
2-(Trifluoromethyl)-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]-
thiadiazecin-9-one 14,14-Dioxide (13h). Yield 50 mg, 90%; gray
solid; mp 201−202 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.37−8.16
(m, 3H, 2Hmajor + Hminor), 8.10 (s, 1H, Hminor), 7.94 (d, J = 8.1 Hz,
1H, Hminor), 7.89 (s, 1H, Hmajor), 7.84−7.66 (m, 5H, 3Hmajor
+
+
2Hminor), 7.65−7.56 (m, 1H, Hminor), 7.53−7.32 (m, 2H, Hmajor
H
H
minor), 7.30−7.15 (m, 2H, Hmajor + Hminor), 6.94 (d, J = 11.1 Hz, 1H,
minor), 6.88−6.75 (m, 1H, Hmajor), 4.01−3.82 (m, 1H, Hmajor), 3.75−
3.53 (m, 3H, 2Hmajor + Hminor), 3.30−3.14 (m, 2H, 2Hminor), 3.11−
2.95 (m, 1H, Hmajor), 2.66 (q, J = 11.2 Hz, 1H, Hminor) ppm. 13C{1H}
NMR (101 MHz, DMSO-d6) δ 169.3 (Cmajor), 167.2 (Cminor), 154.1
(Cminor), 151.5 (Cmajor), 138.7 (Cmajor), 138.0 (Cminor), 136.7 (Cmajor),
136.3 (Cminor), 134.7 (Cmajor), 134.6 (Cminor), 132.5 (q, J = 3.1 Hz,
9-Oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]thiadiazecine-2-
carbonitrile 14,14-Dioxide (13e). Yield 29 mg, 60%; white solid; mp
1
232−233 °C. H NMR (400 MHz, DMSO-d6) δ 8.31−8.18 (m, 3H,
C
minor), 132.3 (Cminor), 131.1 (Cmajor), 130.9 (Cmajor), 130.4 (Cmajor),
2Hmajor + Hminor), 8.13 (s, 1H, Hmajor), 8.01 (d, J = 8.1 Hz, 1H, Hminor),
7.95−7.84 (m, 1H, Hminor), 7.83−7.67 (m, 5H, 3Hmajor + 2Hminor),
7.61 (t, J = 7.6 Hz, 1H, Hminor), 7.49−7.31 (m, 2H, Hmajor + Hminor),
7.23−7.12 (m, 2H, Hmajor + Hminor), 7.12−7.04 (m, 1H, Hminor), 7.02−
6.92 (m, 1H, Hmajor), 3.99−3.83 (m, 1H, Hmajor), 3.74−3.56 (m, 3H,
2Hmajor + Hminor), 3.30−3.14 (m, 2H, 2Hminor), 3.09−2.93 (m, 1H,
Hmajor), 2.72−2.58 (m, 1H, Hminor) ppm. 13C{1H} NMR (101 MHz,
DMSO-d6) δ 169.2 (Cmajor), 167.2 (Cminor), 154.2 (Cminor), 151.4-
(Cmajor), 138.7 (Cmajor), 138.6 (Cminor), 138.4 (Cmajor), 137.9 (Cminor),
136.5 (Cminor), 136.2 (Cminor), 136.1 (Cmajor), 134.7 (Cmajor), 134.7
(Cminor), 134.5 (Cmajor), 131.5 (Cminor), 130.9 (Cmajor), 130.3 (2Cmajor),
129.4 (Cminor), 128.9 (Cmajor), 128.5 (Cminor), 126.2 (Cminor), 125.2
(Cminor), 120.1 (Cmajor), 119.3 (Cmajor), 118.8 (Cminor), 100.3 (Cmajor),
129.1 (Cminor), 129.0 (Cmajor), 128.6 (Cminor), 128.2 (q, J = 2.7 Hz,
Cmajor), 126.7 (q, J = 3.7 Hz, Cminor), 125.8 (Cminor), 125.5 (q, J =
275.5 Hz, Cminor), 124.4 (q, J = 2.2 Hz, Cmajor), 124.3 (q, J = 269.6 Hz,
Cmajor), 120.3 (Cminor), 119.9 (Cmajor), 118.9 (q, J = 32.6 Hz, Cmajor),
118.5 (q, J = 33.0 Hz, Cminor), 46.6 (Cminor), 46.0 (Cminor), 43.8
(Cmajor), 37.1 (Cmajor) ppm. HRMS (ESI), m/z calcd for
C16H13F3N2O3SNa [M + Na]+ 393.0491, found 393.0494.
9-Oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]thiadiazecine-3-
carbonitrile 14,14-Dioxide (13i). Yield 7 mg, 15%; white oil. 1H
NMR (400 MHz, DMSO-d6) δ 8.26−8.13 (m, 3H, 2Hmajor + Hminor),
8.03 (d, J = 8.2 Hz, 1H, Hminor), 7.90 (dd, J = 8.1, 1.2 Hz, 1H, Hminor),
7.84−7.67 (m, 5H, 3Hmajor + 2Hminor), 7.65−7.57 (m, 2H, Hmajor
+
H
H
minor), 7.45 (d, J = 7.4 Hz, 1H, Hmajor), 7.37 (dd, J = 7.7, 1.3 Hz, 1H,
minor), 7.27 (dd, J = 8.2, 1.5 Hz, 1H, Hminor), 7.17 (dd, J = 8.4, 1.5
100.1 (Cminor), 46.6 (Cminor), 45.6 (Cminor), 43.6 (Cmajor), 36.9 (Cmajor
)
ppm. HRMS (ESI), m/z calcd for C16H13N3O3SNa [M + Na]+
350.0570, found 350.0574.
Hz, 1H, Hmajor), 6.76−6.68 (m, 1H, Hminor), 6.68−6.58 (m, 1H,
Hmajor), 4.01−3.79 (m, 1H, Hmajor), 3.72−3.49 (m, 3H, 2Hmajor
minor), 3.23−3.09 (m, 1H, Hmajor), 3.09−3.00 (m, 2H, 2Hminor),
+
5,6,7,8-Tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]thiadiazecin-
9-one 14,14-Dioxide (13f). Yield 27 mg, 59%; white solid; mp 165−
168 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.42−8.33 (m, 1H,
Hmajor), 8.33−8.21 (m, 3H, Hmajor + 2Hminor), 8.19 (dd, J = 7.8, 1.8
Hz, 1H, Hminor), 8.14 (d, J = 7.9 Hz, 1H, Hmajor), 8.00 (d, J = 7.9 Hz,
1H, Hmajor), 7.85 (dd, J = 8.2, 1.2 Hz, 1H, Hminor), 7.78−7.65 (m, 3H,
2Hmajor + Hminor), 7.64−7.56 (m, 1H, Hminor), 7.43 (d, J = 7.3 Hz, 1H,
Hmajor), 7.36 (dd, J = 7.6, 1.3 Hz, 1H, Hminor), 7.17−7.09 (m, 1H,
H
2.68−2.56 (m, 1H, Hminor) ppm. 13C{1H} NMR (126 MHz, DMSO-
d6) δ 169.1 (Cmajor), 167.0 (Cminor), 151.5 (Cminor), 148.9 (Cmajor),
138.5 (Cminor), 138.1 (Cminor), 136.5 (Cminor), 136.4 (Cminor), 134.8
(Cmajor + Cminor), 132.2 (Cmajor), 131.1 (Cmajor), 130.9 (Cmajor), 130.7
(Cmajor), 130.4 (2Cmajor), 130.0 (Cminor), 129.2 (Cminor), 129.1 (Cmajor),
128.6 (Cminor), 128.3 (Cminor), 124.1 (Cminor), 123.9 (Cmajor), 121.7
(Cmajor), 121.1 (Cminor), 118.3 (Cmajor), 118.1 (Cmajor + Cminor), 46.7
(Cmajor), 44.1 (Cminor), 40.9 (Cmajor), 37.2 (Cminor) ppm. HRMS (ESI),
m/z calcd for C16H13N3O3SNa [M + Na]+ 350.0570, found 350.0577.
N,N-Dimethyl-9-oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]-
thiadiazecine-2-sulfonamide 14,14-Dioxide (13j). Yield 44 mg,
72%; white solid; mp 212−214 °C. 1H NMR (400 MHz, DMSO-d6)
δ 8.34−8.26 (m, 1H, Hmajor), 8.26−8.13 (m, 2H, Hmajor + Hminor), 8.08
(d, J = 2.3 Hz, 1H, Hminor), 7.93−7.82 (m, 2H, Hmajor + Hminor), 7.81−
7.66 (m, 5H, 3Hmajor + 2Hminor), 7.67−7.58 (m, 1H, Hminor), 7.53−
7.32 (m, 2H, Hmajor + Hminor), 7.29−7.16 (m, 2H, Hmajor + Hminor),
7.06−6.89 (m, 2H, Hmajor + Hminor), 4.00−3.79 (m, 1H, Hmajor), 3.78−
H
minor), 6.94−6.85 (m, 2H, Hmajor + Hminor), 6.83 (dd, J = 7.9, 4.7 Hz,
1H, Hmajor), 4.17 (q, J = 11.2, 8.9 Hz, 1H, Hmajor), 4.05−3.87 (m, 2H,
Hmajor + Hminor), 3.47−3.36 (m, 1H, Hmajor), 3.28−3.21 (m, 1H,
H
minor), 3.13−3.03 (m, 1H, Hminor), 3.04−2.93 (m, 1H, Hmajor), 2.70−
2.54 (m, 1H, Hminor) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ
169.3 (Cmajor), 167.4 (Cminor), 158.7 (Cmajor), 156.7 (Cminor), 155.0
(Cmajor), 154.8 (Cminor), 140.3 (Cmajor), 138.9 (Cminor), 138.8 (Cmajor),
137.9 (Cminor), 137.0 (Cminor), 136.1 (Cminor), 134.5 (Cminor), 130.9
(Cminor), 130.8 (Cmajor), 130.2 (2Cmajor), 129.1 (Cmajor), 128.8 (Cminor),
128.6 (Cmajor), 121.1 (Cmajor), 120.2 (Cminor), 115.4 (Cminor), 114.9
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3.56 (m, 3H, 2Hmajor + Hminor), 3.28−3.15 (m, 2H, 2Hminor), 3.11−
3.00 (m, 2H, Hmajor), 2.76−2.63 (m, 1H, Hminor), 2.59 (s, 6H,
6Hminor), 2.51 (s, 6H, 6Hmajor) ppm. 13C{1H} NMR (126 MHz,
DMSO-d6) δ 169.2 (Cmajor), 167.2 (Cminor), 154.2 (Cmajor), 151.7
(Cminor), 138.6 (Cmajor), 137.8 (Cminor), 134.7 (Cmajor), 134.6 (Cminor),
134.5 (Cmajor + Cminor), 131.2 (Cmajor), 130.9 (Cmajor), 130.8 (Cminor),
130.4 (Cmajor + Cminor), 129.4 (Cminor), 129.1 (Cmajor), 128.9 (Cminor),
128.7 (Cmajor), 125.5 (Cminor), 125.3 (Cminor), 124.2 (Cmajor), 123.8
(Cminor), 123.4 (Cmajor), 119.7 (Cmajor), 119.3 (Cminor), 46.6 (Cminor),
45.7 (Cminor), 43.3 (Cmajor), 38.1 (2Cmajor), 38.0 (2Cminor), 36.8
(Cmajor) ppm. HRMS (ESI), m/z calcd for C17H19N3O5S2Na [M +
Na]+ 432.0658, found 432.0654.
(Cminor), 46.6 (Cminor), 40.9 (Cmajor), 37.6 (Cmajor) ppm. HRMS (ESI),
m/z calcd for C15H14N2O3SNa [M + Na]+ 325.0617, found 325.0629.
Hydrolysis Products 14a−c. 2-((2-((5-Aminopentyl)amino)-5-
nitrophenyl)thio)benzoic Acid (14a). Yield 38 mg, 68%; yellow solid;
mp more than 250 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.70−8.60
(br s, 1H), 8.42 (d, J = 2.7 Hz, 1H), 8.10 (dd, J = 9.3, 2.8 Hz, 1H),
7.43 (d, J = 7.6 Hz, 1H), 7.28−7.11 (m, 3H), 6.65 (d, J = 9.3 Hz,
1H), 3.17 (q, J = 5.1 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H), 1.70−1.53 (m,
4H), 1.55−1.39 (m, 2H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6)
δ 171.7, 157.8, 155.1, 144.5, 135.0, 133.2, 130.7, 128.6, 128.2, 128.0,
127.1, 117.9, 109.1, 42.9, 31.2, 28.4, 27.5, 27.0 ppm. HRMS (ESI), m/
z calcd for C18H22N3O4S [M + H]+ 376.1326, found 376.1331.
2-((2-((4-Aminobutyl)amino)-5-nitrophenyl)sulfonyl)benzoic
Acid (14b). Yield 47 mg, 79%; yellow solid; mp more than 250 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.8 Hz, 1H), 8.13 (dd, J =
9.5, 2.8 Hz, 1H), 7.58−7.50 (m, 2H), 7.36−7.26 (m, 2H), 6.83 (d, J =
9.6 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.43
(p, J = 7.1 Hz, 2H), 1.16−1.04 (m, 2H) ppm. 13C{1H} NMR (126
MHz, DMSO-d6) δ 171.0, 151.0, 146.4, 134.6, 133.8, 133.6, 130.0,
129.2, 128.5, 127.3, 127.1, 122.7, 112.5, 43.1, 41.6, 30.5, 25.7 ppm.
HRMS (ESI), m/z calcd for C17H19N3O6SNa [M + Na]+ 416.0887,
found 416.0886.
2-((2-((5-Aminopentyl)amino)-5-nitrophenyl)sulfonyl)benzoic
Acid (14c). Yield 57 mg, 94%; yellow solid; mp more than 250 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.8 Hz, 1H), 8.13 (dd, J =
9.4, 2.8 Hz, 1H), 7.57−7.46 (m, 2H), 7.33−7.23 (m, 2H), 6.82 (d, J =
9.5 Hz, 1H), 3.26 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.39
(p, J = 7.0 Hz, 2H), 1.24 (p, J = 7.1 Hz, 2H), 1.09−0.97 (m, 2H)
ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.9, 150.8, 146.5,
134.1, 133.8, 133.0, 130.2, 129.4, 128.3, 127.2, 127.1, 122.2, 112.5,
42.9, 41.7, 33.0, 27.8, 23.7 ppm. HRMS (ESI), m/z calcd for
C18H21N3O6SNa [M + Na]+ 430.1043, found 430.1040.
Spectrophotometric Monitoring of the Conversion Rates in
the HIRE Reaction. The conversion was monitored using a UV-1800
Shimadzu double-beam spectrophotometer using 10.00 mm quartz
cells. Measurements were performed at room temperature (23 °C).
The solutions of ammonium hydrochloride salts obtained by
deprotection of 9a−n or 11a−n were prepared by dissolving 0.01
mmol of the respective compound in 1:1 H2O/MeOH (10 mL) and
making up the total volume to 100 mL. The calibration curves were
generated at four concentrations: 0.1, 0.05, 0.025, and 0.0125 mM. To
start the measurements, the starting solution prepared as described
above (3 mL) was placed in a 10.00 mm quartz cell. Then 10% aq
NaOH solution (100 μL) was added, and the monitoring was started.
The UV spectra were run at equal time intervals. The conversion of
the starting materials was evaluated using calibration curves. The first-
order reaction rate constants were calculated graphically.
N,N-Dimethyl-10-oxo-5,6,7,8,9,10-hexahydrodibenzo[b,j][1]thia-
[4,8]diazacycloundecine-2-sulfonamide 15,15-Dioxide (13k). Yield
1
32 mg, 50%; white solid; mp 246−248 °C. H NMR (400 MHz,
DMSO-d6) δ 8.25−8.13 (m, 2H), 7.78−7.59 (m, 5H), 7.46 (dd, J =
6.5, 2.2 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 3.91−3.68 (m, 2H), 3.54−
3.41 (m, 1H), 3.32 (s, 6H), 3.15−3.01 (m, 1H), 2.09−1.91 (m, 1H),
1.68−1.53 (m, 1H) ppm. 13C{1H} NMR (126 MHz, DMSO- d6) δ
166.1, 151.1, 139.8, 137.9, 134.2, 133.9, 132.1, 130.3, 129.8, 128.3,
120.9, 120.8, 115.7, 43.3, 39.4, 37.9(2C), 25.4 ppm. HRMS (ESI), m/
z calcd for C18H21N3O5S2Na [M + Na]+ 446.0815, found 446.0818.
12-(Trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[b]pyrido[3,2-
i][1,4,7]thiadiazecin-5-one 14,14-Dioxide (13l). Yield 45 mg, 80%;
white solid; mp 243−245 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.85
(d, J = 4.7 Hz, 1H, Hminor), 8.79 (d, J = 4.6 Hz, 1H, Hmajor), 8.41−8.29
(m, 1H, Hmajor), 8.30−8.16 (m, 1H, Hminor), 8.10−7.62 (m, 8H,
4Hmajor + 4Hminor), 7.27−7.15 (m, 2H, Hmajor + Hminor), 7.08−6.89 (m,
1H, Hmajor), 6.85−6.73 (m, 1H, Hminor), 4.09−3.92 (m, 1H, Hminor),
3.69−3.47 (m, 2H, 2Hmajor), 3.29−3.11 (m, 3H, Hmajor + 2Hminor),
3.10−2.96 (m, 1H, Hminor), 2.66−2.53 (m, 1H, Hmajor) ppm. 13C{1H}
NMR (126 MHz, DMSO-d6) δ 167.7 (Cmajor), 165.7 (Cminor), 154.5
(Cminor), 154.1 (Cminor), 152.0 (Cminor), 151.6 (Cminor), 151.5 (Cmajor),
150.3 (Cmajor), 138.5 (Cmajor), 137.9 (Cminor), 134.7 (Cminor), 132.9 (q,
J = 3.3 Hz, Cmajor), 132.8 (q, J = 3.2 Hz, Cminor), 128.6 (q, J = 2.9 Hz,
(Cminor)), 128.5 (Cmajor + Cminor), 128.4 (Cmajor), 128.2 (q, J = 3.9 Hz,
Cmajor), 124.4 (q, J = 270.9 Hz, Cmajor), 124.3 (q, J = 269.1 Hz, Cminor),
122.6 (Cminor), 122.5 (Cmajor), 121.1 (Cmajor), 119.9 (Cmajor), 118.5 (q,
J = 33.4 Hz, Cminor), 118.4 (q, J = 33.6 Hz, Cmajor), 46.8 (Cmajor), 46.0
(Cmajor), 45.0 (Cminor), 37.5 (Cminor) ppm. HRMS (ESI), m/z calcd for
C15H12F3N3O3SNa [M + Na]+ 394.0444, found 394.0447.
13-(Trifluoromethyl)-7,8,9,10-tetrahydrobenzo[b]pyrido[3,2-j]-
[1]thia[4,8]diazacycloundecin-5(6H)-one 15,15-Dioxide (13m).
1
Yield 34 mg, 59%; white solid; mp 215−217 °C. H NMR (400
MHz, DMSO-d6) δ 8.85 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 (d, J = 8.3 Hz,
1H), 8.00 (dd, J = 7.7, 1.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.76
(dd, J = 7.7, 4.6 Hz, 1H), 7.70 (dd, J = 9.1, 2.3 Hz, 1H), 7.64 (dd, J =
9.0, 4.4 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 3.95−3.81 (m, 1H), 3.82−
3.68 (m, 1H), 3.51−3.38 (m, 1H), 3.11−3.00 (m, 1H), 2.01−1.86
(m, 1H), 1.72−1.60 (m, 1H) ppm. 13C{1H} NMR (101 MHz,
DMSO-d6) δ 164.5, 154.8, 150.8, 150.2, 138.9, 134.3, 132.2 (q, J = 3.3
Hz), 129.4 (q, J = 4.3 Hz), 128.1, 124.6 (q, J = 270.4 Hz), 118.6,
116.1 (q, J = 33.0 Hz), 115.9, 42.9, 39.4, 26.0 ppm. HRMS (ESI), m/
z calcd for C16H14F3N3O3SNa [M + Na]+ 408.0600, found 408.0604.
5,6,7,8-Tetrahydro-9H-dibenzo[b,i][1,4,7]thiadiazecin-9-one
Sample Preparation for the Crystal Growth. The solutions of
the compounds 12a, 12e, 12n, 13a, 13b, 13e, 13f, 13h, 13l, 13n, 14b,
and 14c in DMSO-d6 after NMR experiments were filtered through a
syringe filter and left in open vials until crystals grew.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00236.
14,14-Dioxide (13n). Yield 39 mg, 87%; white solid; mp 216−218
1
°C. H NMR (400 MHz, DMSO-d6) δ 8.30−8.04 (m, 3H, Hmajor
+
X-ray crystallographic information for compounds 12a,
12e, 12n, 13a, 13b, 13e, 13f, 13h, 13l, 13n, 14b, and
14c; example of kobs calculation for compound 9a;
copies of 1H and 13C NMR spectra; NMR assignment of
compound 13a; EXSY/NOESY spectra; results of
variable temperature NMR; NOE-based distance calcu-
lations; Monte Carlo conformational search; ensemble
atom coordinates (PDF)
2Hminor), 7.98−7.81 (m, 2H, Hmajor + Hminor), 7.78−7.52 (m, 5H,
3Hmajor + 2Hminor), 7.52−7.26 (m, 4H, 3Hmajor + Hminor), 7.15−6.97
(m, 2H, Hmajor + Hminor), 6.92 (t, J = 7.7 Hz, 1H, Hminor), 6.81 (t, J =
7.8 Hz, 1H, Hmajor), 6.60 (d, J = 11.5 Hz, 1H, Hminor), 6.44 (s, 1H,
H
minor), 4.06−3.76 (m, 1H, Hmajor), 3.73−3.40 (m, 4H, 2Hmajor
2Hminor), 3.27−3.09 (m, 2H, Hmajor + Hminor), 3.09−2.86 (m, 1H,
minor) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.4 (Cmajor),
+
H
151.6 (Cminor), 149.1 (Cmajor), 137.8 (Cminor), 136.1 (Cmajor + Cminor),
136.0 (Cmajor), 134.2 (Cmajor + Cminor), 134.0 (Cminor), 131.0 (Cminor),
130.7 (Cmajor + Cminor), 130.6 (Cmajor), 130.2 (Cmajor + Cminor), 129.6
(Cmajor), 128.9 (Cmajor + Cminor), 128.6 (Cminor), 126.9 (Cmajor), 120.5
(Cmajor + Cminor), 120.2 (Cminor), 119.7 (Cmajor), 118.9 (Cminor), 47.3
Accession Codes
CCDC 2046962−2046963, 2046965, 2046967−2046972, and
2046974−2046976 contain the supplementary crystallographic
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data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Mikhail Krasavin − Institute of Chemistry, Saint Petersburg
State University, Saint Petersburg 199034, Russia;
orcid.org/0000-0002-0200-4772; Email: m.krasavin@
spbu.ru
Authors
Elena Reutskaya − Institute of Chemistry, Saint Petersburg
State University, Saint Petersburg 199034, Russia
Alexander Sapegin − Institute of Chemistry, Saint Petersburg
State University, Saint Petersburg 199034, Russia
Stefan Peintner − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden
Máté Erdélyi − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden; orcid.org/0000-
0003-0359-5970
(13) Kessler, H. Conformation and Biological Activity of Cyclic
Peptides. Angew. Chem., Int. Ed. Engl. 1982, 21, 512−523.
(14) Anthis, N. J.; Clore, G. M. Visualizing transient dark states by
NMR spectroscopy. Q. Rev. Biophys. 2015, 48, 35−116.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00236
Notes
̂
(15) Saito, H., Chapter One - Dynamic Pictures of Proteins by
The authors declare no competing financial interest.
NMR. In Annual Reports on NMR Spectroscopy; Webb, G. A., Ed.;
Academic Press: 2014; Vol. 83, pp 1−66.
(16) Schweiger, M.; Seidel, S. R.; Arif, A. M.; Stang, P. J. Solution
and Solid State Studies of a Triangle-Square Equilibrium: Anion-
Induced Selective Crystallization in Supramolecular Self-Assembly.
Inorg. Chem. 2002, 41, 2556−2559.
ACKNOWLEDGMENTS
■
This research was supported by the Russian Foundation for
Basic Research (Project Grant 19-33-90010). We are grateful
to the Research Centre for Magnetic Resonance, the Centre
for Chemical Analysis and Materials Research, and the Centre
for X-ray Diffraction Methods of Saint Petersburg State
University Research Park for the analytical data. The project
made use of the NMR Uppsala infrastructure, which is funded
by the Department of Chemistry - BMC and the Disciplinary
Domain of Medicine and Pharmacy. The Monte Carlo
simulations were enabled by resources provided by the
Swedish National Infrastructure for Computing (SNIC) at
NSC, partially funded by the Swedish Research Council,
through the Project 2020/5-435. The Swedish Research
Council is acknowledged for funding (Grant 2019-03715).
(17) Thompson, H. P. G.; Day, G. M. Which conformations make
stable crystal structures? Mapping crystalline molecular geometries to
the conformational energy landscape. Chem. Sci. 2014, 5, 3173−3182.
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