The first synthesis of benzo[e]cycloalk[g]oxazocinone atropisomers via lactonization of N-mesyl- or N-arylsulfonyl-N-[2-(1-cycloalken-1-yl)-6-methylphenyl]glycines

Article abstract of DOI:10.1016/j.tet.2021.132388

The article describes an efficient access to cycloalkene-annulated benzoxazocines displaying both axial and central chiralities, via a domino halogenation-lactonization reaction of substituted glycine precursors. Upon interaction between N-[2-(1-cyclohexe

Full text of DOI:10.1016/j.tet.2021.132388

Tetrahedron 96 (2021) 132388
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The first synthesis of benzo[e]cycloalk[g]oxazocinone atropisomers
via lactonization of N-mesyl- or N-arylsulfonyl-N-[2-(1-cycloalken-1-
yl)-6-methylphenyl]glycines
Rail R. Gataullin
Russian Academy of Sciences Ufa Institute of Chemistry 71 Prosp, Oktyabrya, Ufa, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The article describes an efficient access to cycloalkene-annulated benzoxazocines displaying both axial
and central chiralities, via a domino halogenation-lactonization reaction of substituted glycine pre-
cursors. Upon interaction between N-[2-(1-cyclohexen-1-yl)-6-methylphenyl]-N-mesyl- or -N-arylsul-
fonylglycines and bromine an axially chiral mixture of (aR,R)- and (aS,S)-enantiomers of heterocycles
with benzo[e]cyclohexa[g][1,4]oxazocine core is formed as the main reaction product, which slowly
transforms into the corresponding mixture of (aS,R)- and (aR,S)-enantiomers. The reaction of N-tosyl
analog of these glycines with iodine under the same conditions leads to the heterocycle of spiro[4,1-
benzoxazepin-5,10-cyclohexane] structure. Upon treatment of the cyclopentenyl homologue N-tosylate
of these glycines with molecular bromine or iodine, in both cases, a compound with the benzox-
azocinone backbone is obtained as the only reaction product.
Received 31 May 2021
Received in revised form
2 August 2021
Accepted 6 August 2021
Available online 12 August 2021
Keywords:
Bromocyclization
Glycine
Atropisomerism
Axial chirality
Benzoxazepine
Benzoxazocine
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
fragment. There are known heterocycles of the benzoxazocine se-
ries, in whose molecules the signs of axial isomerism are absent,
In the some natural and synthetic aryl fused carbo- [1] and
heterocycles [2], axial chirality can also be present, which leads to
pronounced differences in their properties, but such compounds
are not so common. The appearance of axial chirality promotes the
existence of these molecules in the form of an equilibrium mixture
or one of the atropisomers, which is stable under normal condi-
tions. The configuration of a stereogenic element (center or axis)
may lead to differences in biological activities [2e,h]. There is only
scant information about such aryl fused representatives of the
oxazocine series and the heterocycles shown in Fig. 1 exist in the
form of an equilibrium mixture in the ratio 96e98 : 4-2 depending
on the solvent and have the low energy of mutual transition [2f].
Remarkably, enantiomers exhibit different antagonistic activity
towards NK1 receptors. The isomers with the predominant (aR,3S)-
configuration are 50e200 times more active than the (3R)-analogs,
where aS stereochemistry predominates. This could indicate that
axial chirality is important for receptor recognition. A necessary
condition for the existence of equilibrium atropisomerism in these
oxazocines is the presence of the phenyl substituent at the pyridine
but, nevertheless, these compounds also exhibit certain types of
biological activity. Some synthetic representatives have been
investigated as inhibitors of cellular receptors [3], efficient as
antithrombotic agents [4] or have analgesic properties [5]
(Fig. 2aec).
The heterocycle with the backbone of N-(2-hydroxyethyl)iso-
indolone (porritoxin), isolated from natural raw materials, was
initially mistakenly assigned the structure shown in Fig. 2 (d) [6a].
Ten years later, the same authors have corrected the formula [6b],
the heterocycle has phytotoxin properties.
The choice of the method for constructing the benzoxazocine
backbone is quite wide and depends on the mutual arrangement of
nitrogen and oxygen atoms in the heterocycle, regio localization
and stereochemistry of substituents [7]. For this purpose, ap-
proaches involving halogene source can also be used, among which
the results of studies on the synthesis of benzoxazocines from
aminoaryl-substituted alkenes also attract an attention [8]. It
should be noted that the set of compounds with the benzoxazocine
nucleus obtained by cohalogenation of such alkenes is still scarce.
Although approaches to the lactonization of unsaturated carboxylic
acid derivatives or their amides, intramolecular halogenamidation
E-mail address: gataullin@anrb.ru.
https://doi.org/10.1016/j.tet.2021.132388
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

R.R. Gataullin
Tetrahedron 96 (2021) 132388
sodium. For this goal, sulfonylamide 3a-d was stirred with methyl
bromoacetate in THF in the presence of KOH and triethylbenzy-
lammonium bromide (TEBAB). In this case, complete conversion of
the starting amide was achieved with the formation of methyl ester
4a-d as the only reaction product (see Scheme 1).
Next, we studied the interaction of glycines 5a-d with Br2 and
iodine. The dropwise addition of molecular bromine to a stirred
suspension of compound 5a and potassium carbonate in methylene
chloride or stirring with molecular iodine under analogous condi-
tions leads to cyclopenta[g]benzoxazocinone M*-6 in racemic form
(as a mixture of heterocycles aR,S-6 and aS,R-6) (Scheme 2). When
the compound M*-6 is kept at room temperature in the form of a
powder or in CHCl3 for 3 months, as well as when heated at 55 ꢀC in
CHCl3 for 30 h, no changes occur in the spectra.
Fig. 1. An atropisomeric aryl-fused oxazocinones, in which the aR isomer
predominates.
Below, using the example of cyclohexenyl homologues
(Schemes 3), we show the initial formation of a mixture of aR,R- and
aS,S-enantiomers, which at room temperature slowly isomerize
into a mixture of aS,R- and aR,S-analogs, respectively. Therefore,
and in the case of the cyclization of glycine 5a, one would expect
the appearance in the reaction mixture of the diastereomer P*-6
with aR,R- and aS,S-configuration of substituents. However, the
signals of this supposed compound were not detected in the NMR
spectra, or the P*-analogue almost instantly isomerized to give the
heterocycle M*-6.
Analysis of the structure of the M*-6 molecule using a ball-and-
stick model and programs built into the graphical editors of a set of
chemical schemes made it possible to establish that the Overhauser
effect can be observed between the protons of the tosyl aromatic
ring and the H-3a proton. At the same time, what is important,
these protons are located on one side of the oxazocine ring. The
simulation data are in good agreement with the previously ob-
tained parameters of X-ray diffraction studies of the diiodinated
heterocycle aR*,S*-7 [8a], whose tricyclic framework is identical to
the skeleton of compound M*-6 (Scheme 2). In these experiments it
was found that in the compound aR*,S*-7 the tosyl group and the
H-3a proton are located quite close to each other. And in the 1He1H
NOESY spectrum of this compound there is a noticeable cross-peak
of the spatial interaction between the tosyl aromatic ring protons
H-20,60 and the H-3a proton (a doublet signal, ESI, Page 43).
The 1He1H NOESY NMR spectrum of benzoxazocinone M*-6
also shows a similar cross-peak of the triplet signal of the H-3a
Fig. 2. Synthetic bioactive benzoxazoheterocycles.
of alkenyl-(thio)ureas under the action of halogens has proven itself
well in the preparation of five-, six-, or seven-membered hetero-
cyclic systems [9].
In this publication, we report on the first synthesis of axially
chiral representatives of benzoxazocinone heterocycles by the re-
action of N-[2-(1-cycloalken-1-yl)-6-methylphenyl]-N-mesyl- or
-N-arylsulfonylglycines with molecular iodine or bromine. In this
reaction, unexpectedly, a non-trivial direction of lactonization with
the formation of eight-membered heterocycles was realized, and
the halogen atom, which is its mediator, is absent in the esterifi-
cation product. In the cycloalkene fragment annulated with ben-
zoxazocinone, a double bond is induced during the reaction, with
the emergence of which the potential prerequisites for the subse-
quent easy functionalization of the obtained compounds are laid.
2. Results and discussion
The required for this study amines 1a [10] and 1b (see ESI) were
obtained by heating of allylic regio isomers 2a,b with potassium
hydroxide. Upon interaction of these amines with tosyl-, mesyl- or
(2-nitrobenzene)sulfonylchloride sulfonylamides 3a [11], 3b-
d were synthesized. Heating tosylamides 3a,b with metallic sodium
gave their sodium salts, the addition of methyl bromoacetate to
which led to esters 4a,b. When esters 4a,b were prepared by this
method, a certain amount of starting tosylate 3a,b remained in the
reaction mixture. The presence of an impurity of the starting amide
does not interfere with the alkaline hydrolysis of the resulting es-
ters to give the corresponding acids 5a,b. During the subsequent
work-up of the reaction mixture, all water-insoluble organic im-
purities are removed by extraction. We have also discovered an
approach to the synthesis of esters 4a-d without the use of metallic
Scheme 1. Synthesis of starting carboxylic acids 5a-d. Reagents and conditions: i)
KOH, 305 ꢀC, 1 h (89e95%); ii) TsCl, Py, 20 ꢀC, 24 h (80%); iii) MsCl, Py, 20 ꢀC, 24 h (75%);
iv) NsCl, Py, 20 ꢀC, 48 h (94%); v) 1. Na, C6H6, reflux. 2. BrCH2CO2CH3, reflux (4b, 69%);
vi) KOH, TEBAB, THF, BrCH2CO2CH3, 20 ꢀC, 12 h (89e95%); vii) LiOH, THF-H2O, 3:1 v/v,
20 ꢀC, 4 h (40e79%)..
2

R.R. Gataullin
Tetrahedron 96 (2021) 132388
Fig. 3. An assignment of stereochemical descriptors to the corresponding atro-
pisomers of heterocycles 8b-d.
Scheme 2. Synthesis of benzoxazocinone M*-6 and the proposed mechanism of its
formation, as well as the formula of the previously synthesized heterocycle aR*,S*-7.
Reagents and conditions: i) Br2, K2CO3, 20 ꢀC, 3 h, 57%; ii) I2, K2CO3, 20 ꢀC, 24 h, 82%.
Probably, the tosyl derivative of 1,4-benzoxazocionone P*-8b is
more resistant to isomerization, since in the NMR spectra recorded
after z18 h, no signals of the M*-isomer 8b were detected. The
half-transformation time t1/2 of the supposed P*-isomer 8b into the
atropisomer M*-8b at room temperature, according to 1H NMR
spectra, is ca. 60 days. After boiling this compound in ethanol for
z9 h, the isomerization is almost complete, and upon cooling,
crystals of the M*-8b diastereomer precipitate.
In the case of bromination of analogs 5c,d, in the NMR spectra
recorded after z18 h, along with the signals of the main atro-
pisomer P*-8c,d, the signals of the axial isomer M*-8c,d are also
detected [a pairwise ratio of atropisomers P*-8c: M*-8c z 8:1
(Fig. 4, b) and P*-8d: M*-8d z 4:1 (Fig. 5, a)].
To obtain axial diastereomers M*-8c,d, solutions with these
ratios of atropisomers in deuterochloroform were kept at 55 ꢀC for
21 h. However, residual signals of protons of the initial P*-isomer
are recorded in the 1H NMR spectrum of the reaction mixture, even
with longer heating. After removal of CDCl3, the residue was crys-
tallized from ethanol, and pure M*-8c,d was isolated. Fig. 4 shows
the change in the ratio of integrals of the most clearly distinguished
signals of axial diastereomers M*-8c and P*-8c with time in the
spectral region from 3.8 to 7.0 ppm, using compound 8c as an
example. Fig. 5 shows, for comparison, the same spectral range for
compounds P*-8d (Fig. 5, a) and M*-8d (Fig. 5, b).
Hence, it can be seen that the general picture of changes in this
region of the spectra of these compounds is practically the same, if
we do not take into account the small differences in the values of
chemical shifts. The transformation of heterocycles P*-8b-d into
axial isomers M*-8b-d, as can be seen in Figs. 4 and 5, is accom-
panied by the disappearance of the signal attributed to the aromatic
Scheme 3. Formation of benzoxazocinones P*-8b-d or benzoxazepinone
interaction between glycines 5b-d and molecular bromine or iodine.
9 upon
proton (
d 5.96 ppm) with the doublet signal of the tosyl protons H-
20,60 (
d
7.60 ppm) (ESI, Page 42).
Upon interaction between cyclohexenyl homologues 5b-d and
molecular bromine, heterocycles P*-8b-d (Scheme 3) are initially
formed, which are a mixture of (aR,R)- and (aS,S)-enantiomers with
the stereogenic axis at the N8eC8a bond and the chirality center at
the C4a atom. At room temperature or with slight heating, P*-8b-
d heterocycles slowly transform into axial isomers M*-8b-d as a
mixture of (aS,R)- and (aR,S)-enantiomers. It is known [12] that in
such cyclizations, in some cases, the direction of conversion of N-
acyl-2-(1-alken-1-yl)anilines depends on the structure of the olefin
unit, the nature of substituent at the nitrogen atom, the halogen
used, and the reaction conditions. This development of trans-
formations was no exception and in this study. The interaction of
acid 5b with molecular iodine gave spirocyclic compound 9 with a
benzoxazepinone structure.
Fig. 3 shows the procedure for determining whether axial iso-
mers belong to M- or P-stereoisomers. The sulfonyl group is
considered the senior substituent. The line of the arrow from this
senior substituent is directed to the second most senior carbon
atom C-12a of benzoxazocinone (Fig. 3).
Comparison of the spectra of individual compounds 8b-d and
spectra recorded at certain time intervals after exposure at room
temperature and at 55ꢀС gives a visually beautiful picture of the
dynamics of changes in the peak intensity caused by axial trans-
formations in these compounds.
H-12 proton (d 6.85e6.97 ppm) from this segment of the spectrum
due to the shift to the weak field. A similar downfield shift is
observed for the H-1, H-4a, H-7A and He7B protons in the product
of axial isomerization M*-8b-d.
The structures of benzoxazocinones 8b-d by the example of
heterocycles P*-8c and M*-8c were analyzed using ball-and-stick
models as in the case of compound M*-6. From this, we assumed
that, first, in the P*-8c isomer, the protons of the O2SCH3 group and
the H-4a proton are located at a great distance from each other,
where the Overhauser effect is possible, but can be very weak.
Second, the discussed protons are located on opposite sides of the
osazocine cycle. After axial isomerization to the M*-8c diaste-
reomer, the protons of the O2SCH3 group and the H-4a proton are
located on one side of the oxazocine ring and approach significantly
to distances sufficient to record the manifestations of the Over-
hauser effect (Fig. 6). Ball-and-stick modeling of the structure of
3

R.R. Gataullin
Tetrahedron 96 (2021) 132388
Fig. 6. The assumed configurations of substituents of the oxazocine nucleus in
accordance with the ball-and-stick models of P*-8c and M*-8c molecules.
these atropisomers made it possible to reveal one more point that
deserves attention. In the atropisomer P*-8c, the olefin group C1¼C
[12b] is located almost perpendicular to the aromatic ring. Whereas
in the M*-8c diastereomer, this fragment and the aromatic ring
become planar, which, in general, can facilitate their p-conjugation.
Indeed, in the 1He1H NOESY NMR spectra of benzoxazocinones
in the case of the M*-8c isomer, a cross-peak between the protons
of the O2SCH3 group (
proton ( 5.95e5.92 ppm) was found (ESI, Page 59, a, b). In the
NOESY spectrum of the P*-8c isomer, such cross-peak between the
O2SCH3 protons ( 3.08 ppm) and the triplet signal of the H-4a
proton ( 4.96 ppm) is absent (ESI, Page 54, b). Based on these
d 3.04 ppm) and a multiplet signal of the H-4a
d
d
d
observations, with a high degree of probability, the structure of
these six benzoxazocinones was assigned to the corresponding
axial isomers P*-8b-d and M*-8b-d.
The mechanistic aspects of the formation of benzoxazocinones
M*-6, P*-8b-d are considered from the point of view of classical
concepts of halocyclization reactions. Probably, both in the case of
N-(2-cyclopentenyl)aryl substituted glycine 5a, and in the case of
cyclohexenyl homologues 5b-d, the heterocyclization proceeds
through the stage of generating halogenonium complexes A
(Scheme 2) or B (Scheme 3). When molecular bromine is involved
in the cyclization reaction, as shown in both Schemes 2 and 3, a
pseudoallyl bromination product 10a (Scheme 2) or 10b-d (Scheme
3) is formed. After substitution of a bromine atom for a carboxyl
group in these allyl halides, benzoxazocinones M*-6 (Scheme 2) or
P*-8 (Scheme 3) are formed.
Fig. 4. Changes in the ratio of atropisomers P*-8c and M*-8c with time and upon
heating. The most distinct signals of H-1, H-4a, H-7A, He7B, and H-12 protons are
shown in the range of 3.8e7.0 ppm in the spectra of compounds: a) P*-8c, purified by
сrystallization from MeOH; b) P*-8c after 18 h at 20 ꢀC; c) the same solution after 21 h
at 55 ꢀC; d) M*-8c, purified by crystallization from EtOH.
A similar mechanism of the lactonization reaction passing
through the stage of formation of allyl iodide 10a (X ¼ I) is repro-
duced in the case of glycine 5a when molecular iodine is used as a
cyclizing agent (Scheme 2). The formation of allyl iodide can be
confirmed by an example, where the generation of a similar in-
termediate iodide C was previously assumed [13] upon the inter-
action of ethanimidamide D with iodine. In this reaction, 2-ethyl-3-
methyleneindole E was unexpectedly obtained (Fig. 7).
The iodonium complex B generated from the cyclohexene de-
rivative 5b, in contrast to the cyclopentene homologue A, is
transformed via the 7-exo-cyclization route to form spiro-fused
benzoxazepinone 9 (Scheme 3). Probably, the latter direction in
this case is realized faster than the formation of allyl iodide. Dry
heterocycle 9, according to NMR spectra, practically did not un-
dergo any changes, when stored at temperatures up to 30 ꢀC for 2
years. When dissolved in CDCl3, benzoxazepinone 9 was rapidly
transformed into the starting acid 5b. The mechanism of this retro
transformation is unknown; apparently, water, which is present in
commercial deuterochloroform, participates in this process.
Assumptions about the mutual arrangement in space of the
RO2SeNeCH2CO2H fragment and the cyclohexene ring in glycines
5b-d before the interaction with bromine also remain controversial.
The segment of the aromatic ring C-1-C-2-C-6 in these glycines is
overloaded with substituents, and this tightness creates certain
Fig. 5. Spectrum region of atropisomers P*-8d and M*-8d after 18 h at 20ꢀС (a) and
pure compound M*-8d (b).
restrictions on their rotation along the axis
C
Ar(100)dN and
4

R.R. Gataullin
Tetrahedron 96 (2021) 132388
irreversible axial isomerization into the corresponding mixture of
(aS,R)- and (aR,S)-analogs.
3.1. Experimental section
All common reagents and solvents were used as obtained from
commercial suppliers without further purification. Preparative
chromatographic separations were performed on silica gel MN 60
Fig. 7. A known example of the supposed formation of allylic iodide C.
(35e75 mm) and reactions followed by TLC analysis using silica gel
plates Sorbfil ZAO Sorbpolimer, Krasnodar, Russia, the substances
were detected with iodine vapor. The spectral analyses were per-
formed on the equipment of the Center of joint usage of the Ufa
Institute of Chemistry, Russian Academy of Sciences. Melting points
were determined on a table Boetius and are uncorrected. The IR
spectra were recorded on a spectrophotometer with Fourier
transformer IR Prestige-21 Shimadzu. The 1H and 13C NMR spectra
were recorded on a Bruker Avance III instrument at 500.13 and
125.13 MHz, respectively. The internal standard - TMS. Spectra
methods of homo- and heteronuclear correlation COSY, HMBC were
used for correct assignment of signals in the NMR spectra. Chemical
shift in ppm is quoted relative to solvent signals calibrated as fol-
lows for CDCl3: dH (CHCl3) ¼ 7.26, dC (CDCl3) ¼ 77.2. Mass spectra
(APCI, 20 eV) were obtained on a Shimadzu LCMS-2010EV instru-
CAr(200)dCCyHex(1000). As is known [14], such axial isomerism can
contribute to the direction of cyclization reactions. For this reaction,
it can be assumed that for the initial formation of heterocycles P*-
8b-d, there must be an anti-arrangement of the olefin fragment of
the cyclohexene ring and the sulfonyl group. In other words, acids
5b-d in this reasoning should be designated as anti-5b-d, along the
NeC1” and C200dC1000 axes, of which P*,P*-axial isomerism exists
(Fig. 8). It was found that in the 1H NMR spectra of esters 4b-d and
acids 5b-d due to the magnetic nonequivalence of the methylene
protons of the glycine fragment, the chemical shifts of their doublet
signals differ significantly. We assume that the reason for this may
be the existence of these acids as a stable atropisomer of anti-5b-d,
caused by restriction of the rotation of fragments of this molecule
around the NeC1” and C200dC1000 axes.
ment, with Luna 5
m
С(18) 150 ꢁ 4.6 mm column and octadecylsilan
as sorbent. Elemental analysis was performed on the device CHNS
Elemental Analyzer EURO EA-3000. The iodine content was deter-
mined by the Schoeniger flask technique, followed by potentio-
metric titration.
3. Conclusions
In summary, we have proposed a simple approach to the syn-
thesis of benzo[e]cycloalk[g]oxazocinones via the one-pot haloge-
nation-lactonization reaction of N-mesylates or N-arylsulfonates of
N-[2-(1-cycloalken-1-yl)phenyl]glycines. In the case of the cyclo-
pentenyl homologue, the molecular bromine or iodine can be used
as a cyclizing agent. In this reaction a single atropisomer of ben-
zoxazocinone is formed, which does not undergo subsequent axial
transformations. In the case of cyclohexenyl analogs, the structure
of the reaction product depends on the nature of the halogen. Upon
interaction with bromine, a compound of the benzoxazocine
structure was obtained. While using molecular iodine in this re-
action, a heterocycle with a spiro[4,1-benzoxazepin-5,10-cyclo-
3.1.1. Methyl N-(2-cyclopent-1-en-1-yl-6-methylphenyl)-N-[(4-
methylphenyl)sulfonyl]glycinate (4a)
Compound 3a (0.99 g, 3 mmol), TEBAB (0.49 g, 0.6 mmol), and
KOH (0.171 g, 3.05 mmol) were intensively stirred in THF (10 mL)
for 10 min on a magnetic stirrer. Thereafter, methyl bromoacetate
(0.55 g, 3.6 mmol) was added to the mixture in one portion and
stirring was continued for 24 h. A light powdery precipitate of
potassium bromide is gradually formed. Then, t-BuOMe (90 mL)
and water (20 mL) were added to the reaction mixture, stirred until
homophase and transferred to a separatory funnel. The organic
layer was separated, washed with water (10 mL) and dried over
MgSO4. The solvent was evaporated in vacuo to obtain 1.2 g (100%)
of compound 4a in the form of a syrupy mass, practically pure ac-
cording to NMR spectra for the subsequent hydrolysis reaction. The
entire sample was purified on a silica gel column (20 g) from
possible resinous impurities. Yield: 1.12 g (93%), as viscous oil, Rf 0.5
hexane]
backbone
is
formed.
The
initially
formed
benzoxazocinones [g]-annulated with cyclohexene are a mixture of
(aR,R)- and (aS,S)-enantiomers, which undergo subsequent slow
(C6H6 e t-BuOMe, 200:1). 1H NMR:
d
7.72 (d, J ¼ 8.1 Hz, 2 Н, Н30,50),
7.30 (d, J ¼ 8.1 Hz, 2 H, H20,60), 7.19 (t, J ¼ 7.5 Hz, 1 H, Н400), 7.12e7.09
(m, 2 H, ArH), 5.78 (s, 1 Н, Н2000), 4.66 (d, J ¼ 17.6 Hz, 1 H, Н2A), 4.12
(d, J ¼ 17.6 Hz, 1 H, Н2B), 3.66 (s, 3 H, OCH3), 2.45 (s, 3 H, ArCH3),
2.18 (s, 3 H, ArCH3), 2.72e2.55, 1.98e1.89 (m, 6H, 3 CH2). 13C NMR:
d
169.34 (C1), 143.44, 141.17, 140.22, 139.90, 138.46, 136.92 (С10, С40,
С100, С200, C600, C1000), 130.97, 130.26, 128.16, 127.86 (C300, C400, C500,
C2000), 129.01, 128.14 (С20,60, С30,50), 53.81 (С2), 52.05 (OCH3), 37.68,
33.73, 23.72 (C3000, C4000, C5000), 21.58, 19.65 (2 ArСH3). MS (MeCN/
H2O, 83/17), (Irel., %): m/z ¼ 244.1 [M ꢂ H3CC6H4SO2]þ (65), 400.2
[M þ H]þ (100), 523.2 (25).
3.1.2. Methyl N-(2-cyclohex-1-en-1-yl-6-methylphenyl)-N-[(4-
methylphenyl)sulfonyl]glycinate (4b)
Metallic sodium (0.04 g, 1.74 mmol) was added to a solution of
tosylate 3b (0.59 g,1.74 mmol) in benzene (10 mL). The solution was
heated at reflux until the metal disappeared, then methyl-
bromoacetate (0.23 g, 1.74 mmol) was added to the flask and
heating was continued for additional 2 h. The reaction mixture was
cooled to room temperature, water (10 mL) was added and the
Fig. 8. The assumed mutual arrangement of the cyclohexene and N-tosylglycine
fragments in the molecule of the starting tosylates 5b-d and the subsequent stages of
bromination, formation of allyl bromide and intramolecular nucleophilic substitution,
resulting from this, leading to the formation of stereoisomeric heterocycles P*-8b-d.
5

R.R. Gataullin
Tetrahedron 96 (2021) 132388
reaction mixture was stirred. The reaction product was extracted
with benzene (50 mL), dried over MgSO4, the solvent was evapo-
rated in vacuo. The residue was chromatographed on a silica gel
column (20 g, C6H6). Yield: 0.5 g (69%), as viscous oil, Rf 0.25 (C6H6).
was added, extracted with t-BuOMe (80 mL). The organic layer was
dried over MgSO4, solvent was evaporated in vacuo. Yield: 0.81 г
(79%), as viscous oil, Rf 0.15 (C6H6 e t-BuOMe, 50:1). 1H NMR:
d 9.68
(br. s, 1 Н, COOН), 7.65 (d, J ¼ 8.1 Hz, 2 Н, Н30,50), 7.25 (d, J ¼ 8.1 Hz,
2 H, H20,60), 7.15 (t, J ¼ 7.5 Hz, 1 H, Н400), 7.06e7.03 (m, 2 H, ArH),
5.73 (s, 1 Н, Н2000), 4.53 (d, J ¼ 17.9 Hz, 1 H, Н2A), 4.13 (d, J ¼ 17.9 Hz,
1 H, Н2B), 2.44 (s, 3 H, ArCH3), 2.06 (s, 3 H, ArCH3), 2.71e2.65,
IR (KBr): 1789, 1463, 1372, 1089, 1040. 1H NMR:
d
7.71 (d, J ¼ 7.9 Hz,
2 Н, Н30,50), 7.28 (d, J ¼ 7.9 Hz, 2 H, H20,60), 7.14 (t, J ¼ 7.6 Hz, 1 H,
Н400), 7.08 (d, J ¼ 7.6 Hz, 1 H, ArH), 6.96 (d, J ¼ 7.3 Hz, 1 H, ArH), 5.57
(s, 1 Н, Н2000), 4.59 (d, J ¼ 17.7 Hz, 1 H, Н2A), 4.14 (d, J ¼ 17.7 Hz, 1 H,
Н2B), 3.59 (s, 3 H, OCH3), 2.42 (s, 3 H, ArCH3), 2.27 (s, 3 H, ArCH3),
2.38e2.32, 2.12e2.05, 2.02e1.94, 1.72e1.55 (m, 8H, 4 CH2). 13C
2.58e2.51, 1.95e1.89 (m, 6H, 3 CH2). 13C NMR:
d 173.70 (C1), 143.33,
141.28, 140.61, 139.43, 137.71, 136.63 (С10, С40, С100, С200, C600, C1000),
130.99,130.26,129.16,128.25,128.20,127.85 (С20,60, С30,50, C300, C400,
C500, C2000), 53.87 (С2), 37.92, 33.71, 23.67 (C3000, C4000, C5000), 21.57,
19.54 (2 ArСH3). MS (MeOH/H2O, 100/0), (Irel., %): m/z ¼ 231.1
[M þ H e H3CC6H4SO2]þ (20), 386.1 [M þ H]þ (100); 326.1 [M ꢂ
CH2COOH] (20), 384.2 [M ꢂ H]ꢂ (100).
NMR:
d 169.33 (C1), 140.29, 143.42, 139.94, 137.70, 136.92, 136.04
(С10, С40, С100, С200, C600, C1000), 129.87, 129.83, 129.19, 128.09, 128.05,
127.86 (С20,60, С30,50, C300, C400, C500, C2000), 53.55 (С2), 52.00 (OCH3),
30.55, 25.28, 23.10, 21.76 (C3000, C4000, C5000, C6000), 21.55, 20.02 (2
ArСH3). MS (MeCN/H2O, 95/5), (Irel., %): m/z ¼ 428 (60), 414 [M þ
H]þ (100), 342 [M ꢂ CH2СO2СH3 þ H]þ (20), 273 (40), 259 [M ꢂ
CH3C6H4SO2 þ H]þ (90).
3.1.6. N-(2-cyclohex-1-en-1-yl-6-methylphenyl)-N-[(4-
methylphenyl)sulfonyl]glycine (5b)
Was synthesized according to a similar procedure for the
preparation of acid 5a from ester 4b (0.2 g, 0.48 mmol). Yield: 0.12 г
3.1.3. Methyl N-(2-cyclohex-1-en-1-yl-6-methylphenyl)-N-
(methylsulfonyl)glycinate (4c)
(62%), as viscous oil, Rf 0.2 (CHCl3eMeOH, 95:5). 1H NMR:
d 7.69 (d,
Was synthesized according to a similar procedure for the
preparation of compound 4a by stirring methanesulfonylamide 3c
(1.06 g, 4 mmol), TEBAB (1.08 g, 4 mmol), KOH (0.24 g, 4.2 mmol),
and methyl bromoacetate (0.68 g, 4.4 mmol) in THF (10 mL). The
yield of a crude viscous syrupy mass is 1.2 g (89%), which crystal-
J ¼ 8.3 Hz, 2 Н, Н30,50), 7.29 (d, J ¼ 8.3 Hz, 2 H, H20,60), 7.18 (t,
J ¼ 7.3 Hz, 1 H, Н400), 7.08 (d, J ¼ 7.3 Hz, 1 H, ArH), 6.99 (d, J ¼ 7.3 Hz,
1 H, ArH), 5.55 (s, 1 Н, Н2000), 4.41 (d, J ¼ 18.0 Hz, 1 H, Н2A), 4.25 (d,
J ¼ 18.0 Hz, 1 H, Н2B), 2.43 (s, 3 H, ArCH3), 2.09 (s, 3 H, ArCH3),
2.38e2.32, 2.00e1.94, 1.73e1.56 (m, 8H, 4 CH2). 13C NMR:
d 172.78
lizes upon standing, m. p. 76e77ꢀС (EtOH). IR, KBr,
n
, cmꢂ1: 1751
7.16e7.09
(C1), 145.86, 143.99,139.15,136.65,136.45, 136.19 (С10, С40, С100, С200,
C600, C1000), 130.02, 129.48, 128.33, 128.20, 128.15 (С20,60, С30,50, C300,
C400, C500, C2000), 53.71 (С2), 30.65, 25.21, 23.03, 21.72 (C3000, C4000, C5000,
C6000), 21.59, 19.74 (2 ArСH3). MS (MeCN/H2O, 95/5), (Irel., %): m/
z ¼ 400 [M þ H]þ (100), 245 [M ꢂ CH3C6H4SO2 þ H]þ (90); 398
[M ꢂ H] (100), 434 [M ꢂH þ 2H2O] (25).
(C]O), 1331, 1323, 1208, 1145, 876, 788, 771. 1H NMR:
d
(m, 2 Н, ArH), 6.96 (d, J ¼ 6.2 Hz, 1 H, ArH), 5.66 (s, 1 Н, Н200), 4.39
(dd, J ¼ 4.6 Hz, J ¼ 18.0 Hz,1 H, Н2A), 4.18 (dd, J ¼ 4.6 Hz, J ¼ 18.0 Hz,
1 H, Н2B), 3.73 (s, 3 H, OCH3), 3.28 (s, 3 H, SCH3), 2.48 (s, 3 H,
ArCH3), 2.32e2.30, 2.20e2.12, 1.69e1.63 (m, 8H, 4 CH2). 13C NMR:
d
169.73 (C1), 145.17, 138.84, 138.31, 136.85 (С10, С20, С60, С100),
129.97, 128.16, 128.02, 127.72 (С30, С40, C5’, C200), 53.67 (С2), 51.96
(OCH3), 42.92 (SCH3), 30.41, 25.28, 22.99, 21.89 (C300, C400, C500, C600),
19.75 (ArСH3). MS (MeCN/H2O, 100/0), (Irel., %): m/z ¼ 259 [M ꢂ
CH3SO2 þH]þ (100).
3.1.7. N-(2-cyclohex-1-en-1-yl-6-methylphenyl)-N-
(methylsulfonyl)glycine (5c)
Was synthesized according to a similar procedure for the
preparation of acid 5a from ester 4c (0.94 g, 2.79 mmol). Yield:
0.36 g (40%) as colorless crystals, m. p. 169e174 ꢀC, Rf 0.2
3.1.4. Methyl N-(2-cyclohex-1-en-1-yl-6-methylphenyl)-N-[(2-
nitrophenyl)sulfonyl]glycinate (4d)
(CHCl3eMeOH, 95:5). IR, Vaseline oil,
n
, cmꢂ1: 1787, 1729, 1329,
1314, 1247, 1183, 1146, 1120, 1072, 964, 881, 789, 622, 557, 519. 1H
Was synthesized by a similar procedure for the preparation of
compound 4a by stirring sulfonylamide 3d (1.36 g, 3.64 mmol),
TEBAB (0.98 g, 3.64 mmol), KOH (0.23 g, 4.0 mmol) and
BrCH2CO2CH3 (0.62 g, 4.04 mmol). Yield 1.59 g (95%) of crude ether
NMR: d 7.96 (br. s, 1 H, COOH), 7.20e7.15 (m, 2 Н, ArH), 7.01 (d,
J ¼ 6.1 Hz, 1 H, ArH), 5.69 (s, 1 Н, Н200), 4.55 (d, J ¼ 18.6 Hz, 1 H, Н2A),
4.25 (d, J ¼ 18.6 Hz, 1 H, Н2B), 3.28 (s, 3 H, O2SCH3), 2.48 (s, 3 H,
ArCH3), 2.33e1.66 (m, 8H, 4 CH2). 13C NMR:
d 174.47 (C1), 145.12,
in the form of a viscous yellowish mass. Rf 0.24 (C6H6). IR, KBr,
cmꢂ1: 1761 (C]O), 1546, 1437, 1371, 1360, 1199, 1163, 1126, 1085,
875, 852, 785, 774, 752, 598, 569. 1H NMR:
n,
138.97, 137.80, 136.71 (С10, С20, С60, С100), 130.17, 128.47, 128.20,
128.08 (С30, С40, C5’, C200), 53.47 (С2), 42.83 (SCH3), 30.45, 25.25,
22.94, 21.79 (C300, C400, C500, C600), 19.77 (ArСH3). MS (MeCN/H2O,
100/0), (Irel., %): m/z ¼ 324.1 [M þ H]þ (100), 245.1 [M ꢂ
CH3SO2 þ H]þ (90), 198.1 (80); 322.2 [M ꢂ H]e (100).
d
7.98 (dd, J ¼ 1.2 Hz,
J ¼ 7.6 Hz, 1 Н, ArН), 7.68e7.60 (m, 2 Н, ArН), 7.55 (dd, J ¼ 1.2 Hz,
J ¼ 7.6 Hz, 1 Н, ArН), 7.17 (t, J ¼ 7.6 Hz, 1 H, H400), 7.08 (d, J ¼ 7.6 Hz,
1 H, ArН), 6.96 (d, J ¼ 7.6 Hz, 1 H, ArH), 5.52 (s, 1 Н, Н2000), 4.77 (d,
J ¼ 18.3 Hz, 1 H, Н2A), 4.16 (d, J ¼ 18.3 Hz, 1 H, Н2B), 3.66 (s, 3 H,
3.1.8. N-(2-Nitrobenzenesulfonyl)-N-[6-(1-cyclohexen-1-yl)-2-
methylphenyl]glycine (5d)
OCH3), 2.28 (s, 3 H, ArCH3), 2.16e2.02, 1.75e1.61 (m, 8H, 4 CH2). 13
C
NMR:
d
168.85 (C1), 148.64, 145.74, 139.32, 136.58, 136.04, 134.52
Was synthesized according to a similar procedure for the
preparation of acid 5a from ester 4d (1.52 g, 3.42 mmol). Yield:
0.76 g (52%). Amorphous mass in the form of foam. Rf 0.2
(С10, С20, С100, С200, C600, C1000), 133.23, 131.93, 1300.095, 130.07, 128.41,
128.32, 127.99, 123.79 (С30, C4’, С50, C6’, C300, C4 , C500, C2000), 54.22
(С2), 51.86 (OCH3), 30.84, 25.36, 23.09, 21.79 (C3000, C4000, C5000, C6000),
20.10 (ArСH3). MS (MeCN/H2O, 100/0), (Irel., %): m/z ¼ 445.1 [M þ
H]þ (100), 259.1 [M þ H e NO2C6H4SO2]þ (30).
(CHCl3eMeOH, 95:5). IR, Vaseline oil,
1296, 1268, 1240, 1197, 1162, 1126, 1117, 1085, 1067, 876, 851, 776,
752, 738, 597. 1H NMR:
n
, cmꢂ1: 1732, 1589, 1546,
d
8.23 (br s, 1 H, COOH), 7.91 (d, J ¼ 7.6 Hz, 1
Н, ArН), 7.69 (t, J ¼ 7.6 Hz, 1 Н, ArН), 7.62 (t, J ¼ 7.6 Hz, 1 Н, ArН), 7.59
(d, J ¼ 7.6 Hz, 1 Н, ArН), 7.20 (t, J ¼ 7.6 Hz, 1 H, H400), 7.10 (d,
J ¼ 7.6 Hz, 1 H, ArН), 6.99 (d, J ¼ 7.6 Hz, 1 H, ArH), 5.49 (s, 1 Н, Н2000),
4.76 (d, J ¼ 18.3 Hz, 1 H, Н2A), 4.29 (d, J ¼ 18.3 Hz, 1 H, Н2B), 2.24 (s,
3 H, ArCH3), 2.30e2.27, 2.15e1.97, 1.72e1.58 (m, 8H, 4 CH2). 13C
3.1.5. N-(2-cyclopent-1-en-1-yl-6-methylphenyl)-N-[(4-
methylphenyl)sulfonyl]glycine (5a)
To the stirring solution of 4a (1.06 g, 2.65 mmol) in THF e Н2О
(3:1, 80 mL) at 20 ꢀC the LiOH$H2O (0.34 g, 8.0 mmol) was added.
After 3 h t-BuOMe (70 mL) and water (60 mL) were added. The
aqueous phase was separated and extracted with t-BuOMe
(2 ꢁ 15 mL). To the aqueous phase hydrochloric acid (10 mL, 1 N)
NMR:
d 173.67 (C1), 148.38, 145.81, 139.28, 136.23, 135.97, 133.90
(С10, С20, С100, С200, C600, C1000), 133.79, 131.75, 131.38, 130.23, 128.67,
128.47, 128.28, 124.01 (С30, C4’, С50, C6’, C300, C400, C500, C2000), 54.14
6

R.R. Gataullin
Tetrahedron 96 (2021) 132388
(С2), 30.80, 25.31, 23.04, 21.69 (C3000, C4000, C5000, C6000), 20.03 (ArСH3).
MS (MeCN/H2O, 100/0), (Irel., %): m/z ¼ 431.1 [M þ H]þ (100), 472.1
[M þ H þ CH3CN]þ (50); 429.5 [M ꢂ H]e (100), 372.6 (90).
colorless crystals of the isomer M*-8b were filtered off. Yield: 0.2 g
(50%), m. p. 171e174 ꢀC (EtOH). 1H NMR:
d
7.67 (d, 2H, J ¼ 7.8 Hz,
ArH), 7.30 (d, 2H, J ¼ 7.8 Hz, ArH), 7.26 (t,1H, J ¼ 7.6 Hz, ArH), 7.17 (d,
1H, J ¼ 7.6 Hz, ArH), 7.12 (d,1H, J ¼ 7.6 Hz, ArH), 5.98 (s,1H, H1), 5.20
(br. s,1H, H4a), 5.01 (d,1H, J ¼ 15.7 Hz, H7A), 4.42 (d,1H, J ¼ 15.7 Hz,
H7B), 2.45 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.20e1.16 (m, 6H, 3CH2).
3.1.9. 8-Methyl-7-[(4-methylphenyl)sulfonyl]-3,3a,6,7-
tetrahydrobenzo[e]cyclopenta[g][1,4]oxazocin-5-(2H)-one (M*-6)
A) To the stirring suspension of 5a 0.193 g (0.5 mmol) and K2CO3
(0.8 g, 5.8 mmol) in CH2Cl2 (10 mL) molecular bromine (0.08 g,
0.5 mmol) in CCl4 (2 mL) was added. The reaction mixture was
stirred for 24 h, sodium thiosulfate (5%, 5 mL) solution was added
and stirred for additional 10 min. The product was extracted with
CH2Cl2 (40 mL), washed with water (10 mL), dried over MgSO4.
Solvent was evaporated in vacuo. The residue (0.15 g) was purified
on silica gel column (3 g, C6H6). Yield: 0.11 g (57%), m. p.125e130 ꢀC
13C NMR:
d 167.08 (C6), 144.21, 140.60, 139.83, 138.46, 136.94,
132.80 (C8a, C9, C12a, C12b, C1’, C4’), 131.09 (C1), 130.95, 127.95
(C10, C12), 130.23 (C11), 129.66, 127.61 (C30,50, C20,60), 76.31 (C4a),
52.44 (C7), 29.78, 25.33, 19.61 (C2, C3, C4), 21.57, 18.09 (2 CH3). MS
(MeCN/H2O, 95/5), (Irel., %): m/z ¼ 398.3 [M þ H]þ (100), 242.2 [M ꢂ
CH3C6H4SO2]þ (50).
3.1.12. 9-Methyl-8-methylsulfonyl-2,3,4,4a,7,8-hexahydro-6H-
dibenzo[e,g][1,4]oxazocin-6-one (as a mixture of (aR,R)- and (aS,S)-
enantiomers) (P*-8c)
(EtOH), Rf 0.15 (C6H6 - PhCH3, 20:1). IR, Vaseline oil, n
, cmꢂ1: 1739,
1345, 1302, 1162, 1116, 1092, 1052, 901, 814, 796, 784, 735, 706, 664,
573, 544, 536. 1H NMR:
d
7.60 (d, J ¼ 8.2 Hz, 2 Н, Н20,60), 7.31e7.24
Was synthesized in a similar way according to procedure A for
the preparation of the previous heterocycle M*-6 from glycine 5c
(0.285 g, 0.88 mmol) and molecular bromine (0.14 g, 0.88 mmol) in
the presence of K2CO3 (0.4 g, 2.9 mmol) in CH2Cl2 (10 mL). The
residue (0.27 g) was purified on silica gel column (2 g, CHCl3). The
heterocycle P*-8c 0.203 g (72%) was obtained containing ca. 15%
(according to 1H NMR data) impurity of the isomer M*-8c. Crys-
tallization from ethanol gave 0.13 g of pure (according to NMR data)
compound P*-8c, m. p. 165e170 ꢀC (EtOH). Rf 0.2 (CHCl3). IR,
(m, 4 Н, ArН), 7.15 (d, J ¼ 7.3 Hz, 1 Н, Н11), 6.25 (t, J ¼ 1.3 Hz, 1 Н, Н1),
5.96 (dt, J ¼ 7.6 Hz, J ¼ 1.5 Hz, 1 H, Н3a), 5.18 (d, J ¼ 16.6 Hz, 1 Н,
Н6A), 4.38 (d, J ¼ 16.6 Hz, 1 Н, Н6B), 2.44 (s, 3 H, ArCH3), 2.43e2.40,
2.34e2.28, 2.23e2.18, 1.96e1.87 (m, 4H, CH2CH2), 2.03 (s, 3 H,
ArCH3). 13C NMR:
d 167.40 (C5), 144.28 (C4’), 142.72 (С11b), 139.91
(С8), 136.69 (C1’), 136.13, 133.09 (C1), 132.62 (С7a, С11a), 131.30
(C9), 130.07, 127.90 (C10, C11), 129.83, 127.47 (С20,60, С30,50), 83.95
(C3a), 52.52 (С6), 31.91, 29.35 (C2, C3), 21.60, 17.67 (2 ArСH3). MS
(MeCN/H2O, 99/1), (Irel., %): m/z ¼ 767.1 [2 M þ H]þ (100), 612.2
[2 M þ H e CH3C6H4SO2]þ (25), 384.1 [M þ H]þ (50), 228.0 [M ꢂ
CH3C6H4SO2]þ (25); 382.1 [M ꢂ H]ꢂ (100).
Vaseline oil,
n
, cmꢂ1: 1727, 1351, 1313, 1239, 1201, 1151, 974, 885,
7.28e7.20 (m, 2H, ArH), 6.97 (dd,
804, 773, 750, 582, 517. 1H NMR:
d
1H, J ¼ 2.0 Hz, J ¼ 7.0 Hz, ArH), 6.11 (t, 1H, J ¼ 3.9 Hz, H1), 4.95 (t, 1H,
J ¼ 3.7 Hz, H4a), 4.74 (d, 1H, J ¼ 15.9 Hz, H7A), 3.94 (d, 1H,
J ¼ 15.9 Hz, H7B), 3.08 (s, 3H, O2SCH3), 2.43 (s, 3H, CH3), 2.35e2.17,
B) A suspension of glycine 5a (0.73 g, 1.9 mmol), K2CO3 (0.42 g,
3 mmol) and molecular iodine (0.56 g, 2.2 mmol) in CH2Cl2 (15 mL)
was stirred on a magnetic stirrer for 24 h, then sodium thiosulfate
(5%, 20 mL) was added and stirred for additional 10 min. The
product was extracted with CH2Cl2 (50 mL), washed with water
(2 ꢁ 10 mL), dried over MgSO4. Solvent was evaporated in vacuo.
The yield of practically pure crude product M*-6 is 0.65 g (86%).
After clarification by chromatography on a silica gel column (1 g),
0.6 g (82%) of the heterocycle M*-6 was isolated as a white powder.
The NMR characteristics of the compound obtained by this method
are identical to the data given at point A.
1.95e1.65 (m, 6H, 3CH2). 13C NMR:
d 172.75 (C6), 142.97 (C12a),
140.56, 137.42, 135.60 (C8a, C9, C12b), 134.54 (C1), 131.47, 129.77,
129.74 (C10, С11, C12), 76.94 (C4a), 55.02 (C7), 42.00 (SCH3), 29.41,
25.36, 16.71 (C2, C3, C4), 19.02 (CH3). MS (MeCN/H2O, 100/0), (Irel.
,
%): m/z ¼ 322.1 [M þ H]þ (70), 243.1 [M þ H e CH3SO2]þ (100).
3.1.13. 9-Methyl-8-methylsulfonyl-2,3,4,4a,7,8-hexahydro-6H-
dibenzo[e,g][1,4]oxazocin-6-one (as a mixture of (aS,R)- and (aR,S)-
enantiomers) (M*-8c)
A solution of compound P*-8c (30 mg) in deuterochloroform
(1.0 mL) in an ampoule for taking the NMR spectra of the NORELL®
508 UP brand was kept at 55 ꢀC for 21 h. After this time, according
to the measured integrals in the 1H NMR spectra, the signal ratio
M*-8c:P*-8c z 22:1 is achieved. The solution was transferred to a
flask, the solvent was evaporated in vacuo, the residue in the form
of a white powder was dissolved in boiling ethanol (5 mL), very fine
colorless crystals of the M*-8c isomer precipitated after cooling
were filtered off and dried in air. Yield: 25 mg (83%), m. p.
3.1.10. 9-Methyl-8-[(4-methylphenyl)sulfonyl]-2,3,4,4a,7,8-
hexahydro-6H-dibenzo[e,g][1,4]oxazocin-6-one (as a mixture of
(aR,R)- and (aS,S)-enantiomers) (P*-8b)
Was synthesized in a similar way according to procedure A for
the preparation of the previous heterocycle M*-6. Molecular
bromine (0.32 g, 2 mmol) in CCl4 (2 mL) was added to the sus-
pension of glycine 5b (0.8 g, 2 mmol) and K2CO3 (0.7 g, 5 mmol)
under stirring. Yield of the crude residue 0.8 g (100%). Crystalliza-
tion from ethanol gives 0.64 g (81%) colorless crystals of the het-
190e193ꢀС (EtOH). IR, Vaseline oil,
n
, cmꢂ1: 1725, 1351, 1335, 1308,
erocycle P*-8b, m. p. 137e139 ꢀC (EtOH). 1H NMR:
d 7.58 (d, 2H,
1259, 1159, 1113, 1031, 960, 909, 802, 774, 562, 537, 516. 1H NMR:
J ¼ 7.6 Hz, ArH), 7.26e7.21 (m, 4H, ArH), 6.85 (d, 1H, J ¼ 7.0 Hz, ArH),
5.70 (s, 1H, H1), 4.93 (d, 1H, J ¼ 15.8 Hz, H7A), 4.57 (br. s, 1H, H4a),
4.00 (d, 1H, J ¼ 15.8 Hz, H7B), 2.45 (s, 3H, CH3), 2.41 (s, 3H, CH3),
d
7.29 (dt,1H, J ¼ 0.9 Hz, J ¼ 7.6 Hz, ArH), 7.21 (d, 2H, J ¼ 7.6 Hz, ArH),
6.19 (s, 1H, H1), 5.95e5.92 (m, 1H, H4a), 5.14 (d, 1H, J ¼ 15.9 Hz,
H7A), 4.39 (d, 1H, J ¼ 15.9 Hz, H7B), 3.04 (s, 3H, O2SCH3), 2.40 (s, 3H,
CH3), 2.39e2.27, 2.01e1.98, 1.83e1.72 (m, 6H, 3CH2). 13C NMR:
2.00e1.22 (m, 6H, 3CH2). 13C NMR:
d 171.77 (C6), 144.30, 143.40,
140.60, 137.05, 136.49, 135.47 (C8a, C9, C12a, C12b, C10, C40), 134.73,
131.11, 129.48, 129.43 (C1, C10, C11, C12), 129.04, 128.21 (C30,50,
C20,60), 75.77 (C4a), 54.90 (C7), 29.60, 25.38, 15.21 (C2, C3, C4),
21.56, 19.21 (2 CH3). MS (MeCN/H2O, 95/5), (Irel., %): m/z ¼ 398.2
[M þ H]þ (100), 242.0 [M ꢂ CH3C6H4SO2]þ (78).
d 167.06 (C6), 141.07, 138.63, 138.47, 132.18 (C8a, C9, C12a, C12b),
131.84, 131.14, 130.49, 128.36 (C1, C10, С11, C12), 76.43 (C4a), 52.33
(C7), 40.71 (O2SCH3), 30.04, 25.61, 20.48 (C2, C3, C4), 18.27 (ArCH3).
MS (MeCN/H2O, 100/0), (Irel., %): m/z ¼ 322.1 [M þ H]þ (100), 243.1
[M þ H e CH3SO2]þ (100), 242.1 [M ꢂ CH3SO2]þ (50).
3.1.11. 9-Methyl-8-[(4-methylphenyl)sulfonyl]-2,3,4,4a,7,8-
hexahydro-6H-dibenzo[e,g][1,4]oxazocin-6-one (as a mixture of
(aS,R)- and (aR,S)-enantiomers) (M*-8b)
3.1.14. 9-Methyl-8-(2-Nitrobenzenesulfonyl)-2,3,4,4a,7,8-
hexahydro-6H-dibenzo[e,g][1,4]oxazocin-6-one (as a mixture of
(aR,R)- and (aS,S)-enantiomers) (P*-8d)
A solution of the heterocycle P*-8b (0.4 g, 1 mmol) in EtOH
(5 mL) was heated at reflux for 9 h; after cooling, very small
Was synthesized in a similar way according to procedure A for
the preparation of the previous heterocycle M*-6 from glycine 5d
7

R.R. Gataullin
Tetrahedron 96 (2021) 132388
(0.43 g, 1.0 mmol) and molecular bromine (0.16 g, 1.0 mmol) in the
presence of K2CO3 (0.84 g, 5.8 mmol) in CH2Cl2 (10 mL). The residue
(0.38 g), along with the heterocycle P*-8d, contains ca. 20% (ac-
cording to 1H NMR data after 18 h) impurity of the M*-8d isomer.
This residue was chromatographed on a silica gel column (11 g,
CHCl3), yielding 0.31 g (72%) pure heterocycle P*-8d as a white
e CH3C6H4SO2 þ H]þ (45).
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
foam. Rf 0.35 (CHCl3 e t-BuOMe, 50:1). IR, Vaseline oil,
1731, 1546, 1166, 1127, 1087, 1034, 972, 888, 777, 755, 746, 606, 604,
573. 1H NMR:
n :
, cmꢂ1
d
7.85 (d, J ¼ 8.0 Hz, 1 Н, ArН), 7.67 (t, J ¼ 7.3 Hz, 1 Н,
Acknowledgements
ArН), 7.60 (t, J ¼ 7.3 Hz,1 Н, ArН), 7.55 (d, J ¼ 7.6 Hz,1 Н, ArН), 7.27 (t,
J ¼ 7.6 Hz, 1 H, H400), 7.21 (d, J ¼ 7.3 Hz, 1 H, ArН), 6.95 (d, J ¼ 7.3 Hz,
1 H, ArH), 5.83 (t, 1 H, J ¼ 3.7 Hz, H1), 5.14 (d, 1H, J ¼ 15.6 Hz, H7A),
4.80 (t, 1 H, J ¼ 3.7 Hz, H4a), 3.94 (d, 1 H, J ¼ 15.6 Hz, H7B), 2.19 (s,
This study was performed in the scope of the “Design, directed
synthesis and study of biological activity of functionalized benzo
fused heterocycles, polyheteromono-, bicyclic N,N-, N,O-, S,O-
containing systems and uracil derivatives” governmental task
(topic no. AAAA-A19-119011790021-4).
3 H, CH3), 2.03e1.68, 1.58e1.43 (m, 6 H, 3 CH2). 13C NMR:
d 172.82
(C6), 148.40, 144.17, 139.73, 136.26, 134.65, 133.72 (C8a, C9, C12a,
C12b, C1’, C2’), 135.04 (C1), 133.66, 131.72, 131.44, 131.28, 130.41,
130.09, 123.66 (C10, С11, C12, C3’, C4’, C5’, C6’), 76.26 (C4a), 55.51
(C7), 29.44, 25.52, 16.58 (C2, C3, C4), 18.58 (CH3). MS (MeCN/H2O,
100/0), (Irel., %): m/z ¼ 429.1 [M þ H]þ (50), 242.1 [M ꢂ
O2NC6H4SO2]þ (95), 196.1 (40), 83.0 (100).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132388.
3.1.15. 9-Methyl-8-(2-Nitrobenzenesulfonyl)-2,3,4,4a,7,8-
hexahydro-6H-dibenzo[e,g][1,4]oxazocin-6-one (as mixture of
(aS,R)- and (aR,S)-enantiomers) (M*-8d)
References
[1] a) E.S. Shchegravina, E.V. Svirshchevskaya, H.-G. Schmalz, A. Fedorov, Yu.
Synthesis. 51 (2019) 1611e1622;
A solution of compound P*-8d (55 mg) in deuterochloroform in
a NORELL® 508 UP ampoule was kept at 55 ꢀC for 21 h. After this
time, the signals of the P*-isomer were practically absent in the
NMR spectra. Crystallization from ethanol gives pure compound
b) D.J. Paymode, C.V. Ramana, ACS Omega 2 (2017) 5591e5600;
c) A.V. Vorogushin, W.D. Wulff, H.-J. Hansen, J. Am. Chem. Soc. 124 (2002)
6512e6513.
[2] a) H. Tabata, T. Yoneda, T. Oshitari, H. Takahashi, H. Natsugari, J. Org. Chem. 78
(2013) 6264e6270;
M*-8d, 43 mg (78%), m. p. 162e165ꢀС (EtOH). IR, Vaseline oil,
n,
b) E.W.D. Burke, G.A. Morris, M.A. Vincent, I.H. Hilliera, J. Clayden, Org. Biomol.
Chem. 10 (2012) 716e719;
c) H. Tabata, N. Wada, Y. Takada, T. Oshitari, H. Takahashi, H. Natsugari, J. Org.
Chem. 76 (2011) 5123e5131;
d) H. Tabata, K. Akiba, S. Lee, H. Takahashi, H. Natsugari, Org. Lett. 10 (2008)
4871e4874;
e) S. Seto, J. Asano, Bioorg. Med. Chem. 15 (2007) 5083e5089;
f) Y. Ishichi, Y. Ikeura, H. Natsugari, Tetrahedron 60 (2004) 4481e4490;
g) J.S. Albert, C. Ohnmacht, P.R. Bernstein, W.L. Rumsey, D. Aharony,
B.B. Masek, B.T. Dembofsky, G.M. Koether, W. Potts, J.L. Evenden, Tetrahedron
60 (2004) 4337e4347;
cmꢂ1: 1737, 1541, 1314, 1292, 1193, 1166, 1088, 1030, 942, 912, 799,
611, 567. 1H NMR:
d
7.73 (t, J ¼ 7.9 Hz, 1 Н, ArН), 7.65 (d, J ¼ 7.9 Hz, 1
Н, ArН), 7.64 (d, J ¼ 7.9 Hz,1 Н, ArН), 7.55 (t, J ¼ 7.9 Hz,1 Н, ArН), 7.30
(t, J ¼ 7.9 Hz,1 H, H400), 7.18 (d, J ¼ 7.9 Hz,1 H, ArН), 7.15 (d, J ¼ 7.9 Hz,
1 H, ArH), 6.02 (s, 1 H, J ¼ 3.7 Hz, H1), 5.79e5.75 (m, 1 H, H4a), 5.39
(d, 1 H, J ¼ 16.5 Hz, H7A), 4.57 (d, 1H, J ¼ 16.5 Hz, H7B), 2.10 (s, 3H,
ArCH3), 2.17e2.12, 2.00e1.65 (m, 6H, 3CH2). 13C NMR:
d 167.13 (C6),
147.88, 140.63, 139.25, 138.29, 133.30, 131.96 (C8a, C9, C12a, C12b,
C10, C20), 134.17 (C1), 132.21, 131.67, 131.69, 131.09, 130.60, 128.20,
123.77 (C10, С11, C12, C30, C40, C50, C6’), 76.24 (C4a), 53.70 (C7),
29.81, 25.41, 20.010 (C2, C3, C4), 17.61 (CH3). MS (MeCN/H2O, 95/5),
(Irel., %): m/z ¼ 429.1 [M þ H]þ (70), 242.1 [M ꢂ O2NC6H4SO2]þ
(100), 196.1 (30), 83.0 (100).
h) H. Natsugari, Y. Ikeura, I. Kamo, T. Ishimaru, Y. Ishichi, A. Fujishima,
T. Tanaka, F. Kasahara, M. Kawada, T. Doi, J. Med. Chem. 42 (1999) 3982e3993.
[3] C. Dockendorff, P.W. Faloon, J. Pu, M. Yu, S. Johnston, M. Bennion, M. Penman,
T.J.F. Nieland, S. Dandapani, J.R. Perez, B. Munoz, M.A. Palmer, S.L. Schreiber,
M. Krieger, Bioorg. Med. Chem. Lett 25 (2015) 2100e2105.
[4] J.K. Mishra, K. Samanta, M. Jain, M. Dikshit, G. Panda, Bioorg, Med. Chem. Lett.
20 (2010) 244e247.
[5] M. Sanga, J. Banach, A. Ledvina, N.B. Modi, A. Mittur, Xenobiotica 46 (2016)
1001e1016.
[6] a) R. Suemitsu, K. Ohnishi, M. Horiuchi, A. Kitaguchi, K. Odamura, Phyto-
chemistry 31 (1992) 2325e2326;
b) M. Horiuchi, T. Maoka, N. Iwase, K. Ohnishi, J. Nat. Prod. 65 (2002)
1204e1205.
[7] a) T. Afrough, H. Eshghi, Monatsh. Chem. 152 (2021) 475e479;
b) M.R. Baimuratov, M.V. Leonova, Y.N. Klimochkin, Chem. Heterocycl. Compd.
57 (2021) 298e304;
3.1.16. (20R*,5S*)-20-Iodo-9-methyl-1-[(4-methylphenyl)sulfonyl]-
1,2-dihydro-3H-spiro[4,1-benzoxazepine-5,10-cyclohexan]-3-one
(9)
To stirring suspension of glycine 5b (0.12 г, 0.3 mmol) and K2CO3
(0.138 g, 1 mmol) in CH2Cl2 (10 mL) molecular iodine (0.18 g,
0.7 mmol) was added. The reaction mixture was stirred for 24 h,
sodium thiosulfate (5%, 20 mL) was added and stirred for additional
10 min. The product was extracted with CH2Cl2 (40 mL), washed
with water (10 mL), dried over MgSO4. The solvent was evaporated
in vacuo. The reaction product was isolated by chromatography on
silica gel column (2 g, С6H6). Yield: 0.11 г (70%), Rf 0.42 (CHCl3 e t-
BuOMe, 99:1). Сolorless crystals from MeOH, m.p. 122e125 ꢀC
c) R.R. Gataullin, Z.A. Ibatullina, E.S. Meshcheryakova, A.A. Fatykhov,
L.M. Khalilov, Russ. J. Org. Chem. 53 (2017) 697e708;
d) M.N. El-Haddad, K.M. Elattar, Inter. J. Ind. Chem. 6 (2015) 105e117;
e) L.K. Ransborg, M. Overgaard, J. Hejmanowska, S. Barfüsser, K.A. Jørgensen,
Ł. Albrecht, Org. Lett. 16 (2014) 4182e4185;
ꢀ
ꢀꢁ
ꢁ
f) L. Hradilova, M. Grepl, J. Hlavac, A. Lycka, P.J. Hradil, Heterocyclic Chem 50
(2013) 528e533;
g) G.I. Schaefer, J.R. Perez, J.R. Duvall, A.F. Shamji, S.L. Schreiber, J. Am. Chem.
Soc. 135 (2013) 9675e9680;
h) A. Taher, B.A. Aderibigbe, G.L. Morgans, L.G. Madeley, S.D. Khanye, L. van
der Westhuizen, M.A. Fernandes, V.J. Smith, J.P. Michael, I.R. Green, W.A.L. van
Otterlo, Tetrahedron 69 (2013) 2038e2047;
i) F.M. Moghaddam, Z. Mirjafary, H. Saeidian, B.K. Foroushani, S. Nourian,
Synth. Commun. 42 (2012) 1941e1949;
j) V.K. Tandon, A.K. Awasthi, Y.K. Maurya, P. Mishra, J. Heterocycl. Chem. 49
(2012) 424e427;
(decomp.). 1H NMR:
d
7.89 (d, J ¼ 8.2 Hz, 2 Н, Н300,500), 7.37 (d,
J ¼ 8.2 Hz, 2 H, H200,600), 7.33e7.28 (m, 3 H, ArН), 5.07 (s, 1 H, H2’),
4.97 (d, J ¼ 18.4 Hz,1 H, Н2A), 3.94 (d, J ¼ 18.4 Hz,1 H, Н2B), 2.86 (dt,
J ¼ 3.5 Hz, J ¼ 14.0 Hz, 1 H, H30A), 2.45 (s, 3 H, ArCH3), 2.31 (s, 3 H,
ArCH3), 2.11e2.04, 1.75e1.45 (m, 7H, H30B, CH2CH2CH2). 13C NMR:
d
167.90 (C3), 144.64, 139.64, 138.83, 137.15, 136.83 (С5a, С9, С9a,
С100, C400), 133.21, 130.03, 128.17, 127.48, 127.41 (C6, C7, C8, С200,600,
С300,500), 87.34 (C5,10), 52.35 (С2), 38.15 (C2’), 33.18, 31.21, 21.19,
20.84 (C3’, C4’, C5’, C6’), 21.60, 20.34 (2 ArСH3). MS (MeCN/H2O, 95/
5), (Irel., %): m/z ¼ 526 [M þ H]þ (60), 398 [M ꢂ I]þ (100), 244 [M ꢂ I
k) M.N. El-Haddad, K.M. Elattar, Res. Chem. Intermed. 39 (2013) 3135e3149;
l) H.A. Khan, K.G.M. Kou, V.M. Dong, Chem. Sci. 2 (2011) 407e410;
m) S. Mitra, T.S. Banerjee, S.K. Hota, D. Bhattacharya, S. Das, P. Chattopadhyay,
Eur. J. Med. Chem. 46 (2011) 1713e1720;
n) J. Rujirawanich, T. Gallagher, Org. Lett. 11 (2009) 5494e5496;
8

R.R. Gataullin
o) A. Neogi, T.P. Majhi, R. Mukhopadhyay, P. Chattopadhyay, J. Org. Chem. 71
Tetrahedron 96 (2021) 132388
140 (2018) 8675e8680;
(2006) 3291e3294;
p) Bilokin Belokon, Y. V, S.N. Kovalenko, V.P. Chernykh, Heterocycl. Commun.
4 (1998) 169e170;
r) K. Nagarajan, A. Nagana Goud, V. Ranga Rao, R.K. Shah, S.J. Shenoy, Proc.
Indian Acad. Sci. 104 (1992) 549e568.
d) A. Andries-Ulmer, C. Brunner, J. Rehbein, T. Gulder, J. Am. Chem. Soc. 140
(2018) 13034e13041;
e) T.V. Frolova, D.G. Kim, P.A. Slepukhin, Russ. J. Org. Chem. 52 (2016)
1344e1347;
f) T. Yan, B. Zhou, X.-S. Xue, J.-P. Cheng, J. Org. Chem. 81 (2016) 9006e9011;
g) S. Robin, G. Rousseau, Tetrahedron 54 (1998) 13681e13736.
[10] R.R. Gataullin, I.S. Afon’kin, I.V. Pavlova, I.B. Abdrakhmanov, G.A. Tolstikov,
Russ. Chem. Bull. 48 (1999) 396e397.
[8] a) R.R. Gataullin, E.S. Mescheryakova, R.M. Sultanov, A.A. Fatykhov,
L.M. Khalilov, Synthesis 51 (2019) 3485e3490;
~
b) W.R. Martínez, G.C.G. Militao, T.G. da Silva, R.O. Silva, P.H. Menezes, RSC
Adv. 4 (2014) 14715e14718;
[11] I.А. Kirillova,
М.M. Zalimova, R.V. Mulyukova, YuV. Vakhitova,
c) G.G. Mazgarova, K. Yu Suponitskii, R.R. Gataullin, Russ. J. Org. Chem. 50
(2014) 1472e1479;
R.N. Khusnitdinov, R.R. Gataullin, Russ. J. Gen. Chem. 88 (2018) 418e424.
[12] a) L. Liu, Z. Wang, Green Chem. 19 (2017) 2076e2079;
b) S. Ortgies, A. Breder, Org. Lett. 17 (2015) 2748e2751.
[13] R.R. Gataullin, I.S. Afon’kin, A.A. Fatykhov, L.V. Spirikhin, I.B. Abdrakhmanov,
Mendeleev Commun. 11 (2001) 201e203.
[14] a) P. Renzi, Org. Biomol. Chem. 15 (2017) 4506e4516;
b) R.R. Gataullin, Russ. J. Org. Chem. 55 (2019) 1247e1274;
c) A.R. Gataullina, R.R. Gataullin, Russ. J. Gen. Chem. 90 (2020) 1255e1284.
d) R.R. Gataullin, R.R. Ishberdina, T.V. Kazhanova, O.V. Shitikova, L.V. Spirikhin,
I.B. Abdrakhmanov, Mendeleev Commun. 14 (2004) 219e221.
[9] a) N. Korol, M. Slivka, M. Fizer, V. Baumer, V. Lendel, Monatsh. Chem. 151
(2020) 191e198;
ꢂ
b) G. Broggini, S. Giofre, R. Sala, E.M. Beccalli, L. Lo Presti, Helv. Chim. Acta 102
(2019), e1900088;
c) N. Hartrampf, N. Winter, G. Pupo, B.M. Stoltz, D. Trauner, J. Am. Chem. Soc.
9