Atropisomeric N-acyl-N-(cyclopentenylphenyl)glycines in the synthesis of oxazolo[3,4-a]benzoxazocinones

Article abstract of DOI:10.1134/S1070428017050098

Intramolecular [3+2]-cycloaddition was studied of munchnones generated at heating syn- and anti-atropisomers of N-acyl-N-[6-methyl-2-(cyclopent-2-en-1-yl)phenyl]glycines with acetic anhydride. By spectral and X-ray diffraction analysis syn-isomers of acids and tetrahydro-1,4,7-methanetriyl[1,3]oxazolo[3,4-a][1]- bensazocin-3(3aH)-ones were identified.

Full text of DOI:10.1134/S1070428017050098

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 697–708. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © R.R. Gataullin, Z.A. Ibatullina, E.S. Meshcheryakova, A.A. Fatykhov, L.M. Khalilov, 2017, published in Zhurnal Organicheskoi
Khimii, 2017, Vol. 53, No. 5, pp. 688–698.
Atropisomeric N-Acyl-N-(cyclopentenylphenyl)glycines
in the Synthesis of Oxazolo[3,4-a]benzoxazocinones
R. R. Gataullina,* Z. A. Ibatullinab, E. S. Meshcheryakovac,
A. A. Fatykhova, and L. M. Khalilovc
a Ufa Institute of Chemistry, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Russia
*е-mail: gataullin@anrb.ru
b Ufa Institute of Biology, Russian Academy of Sciences, Ufa, Russia
c Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, Russia
Received March 1, 2017
Abstract—Intramolecular [3+2]-cycloaddition was studied of munchnones generated at heating syn- and anti-
atropisomers of N-acyl-N-[6-methyl-2-(cyclopent-2-en-1-yl)phenyl]glycines with acetic anhydride. By spectral
and X-ray diffraction analysis syn-isomers of acids and tetrahydro-1,4,7-methanetriyl[1,3]oxazolo[3,4-a][1]-
bensazocin-3(3aH)-ones were identified.
DOI: 10.1134/S1070428017050098
Synthesis and investigation of properties of aryl-
fused nitrogen heterocycles is a fast developing
research field in organic chemistry. The attention of a
wide number of scientists is focused on the
development of approaches to new scaffold structures
[1–7] in whose synthesis arylamines are utilized [7–9],
in particular, N-and ortho-allylanilines [10–18].
and at the ortho-carbon atom of the aromatic ring. It
provokes the formation of methanooxazoloquinolines
distinguished by the configuration of substituents at
the atom С5 in the course of cyclization of ortho-(1-
methylbut-2-en-1-yl)-phenylglycine deri-vatives [20].
Intramolecular cycloaddition of munchnones
generated from ortho-cycloalkenylphenylglycines was
not explored. Due to the presence of diverse
substituents at the atom С1 of the alkenyl fragment
derivatives of N-(alkenylphenyl)-N-acylglycine as well
as N-acyl-N-(cycloalkenyl)-2,6-disubstituted anilines
[21–25] or N-(2-hydroxyaryl)methylanilides [26] exist
as syn- and anti-atropisomers. In the case of
methylbutenyl derivative this isomerism does not
affect the ability of munchnone generated at heating
both isomers with carboxylic acids anhydrides to enter
One of poorly investigated application fields of ortho-
allylaniline derivatives is the synthesis of heterocycles
by intramolecular [3+2]-cycloaddition of munchnones
which are generated in situ from N-(2-alkenylphenyl)-
N-acylglycines, alanines, or 2-pheny-lglycine at heating
with carboxylic acids anhydrides. Subsequent transfor-
mations of these reactive compounds result in metha-
nooxazoloquinolines [12–17]. A special feature of this
reaction consists in the possibility to control the stereo-
chemistry of atoms С1, С3а, and С4 in the forming
heterocycles. The structure of munchnones cycloaddition
to dipolarophiles is known to depend on many factors
[19]. At the formation of methanooxazoloquinolines
the regio-isomerism of the cycloaddition is sensitive to
the nature of the substituent at the α-atom of glycine
and of acyl unit [11–13].
Scheme 1.
H
R
R
H
R
4
R
6
5
5
6
11
4
Me
Me
3a
8
O2
1
O3
8
N
N
10
10
3
2
The structure of heterocycles formed at heating
alkenylphenylglycines with carboxylic acids anhydrides
depends also on atropisomerism induced by diverse
substituents at the α-carbon atom of the allyl fragment
R
3a
1
R
O
O
H
H
A
B
R = H [15], Me [20].
697

GATAULLIN et al.
698
Scheme 2.
1"
NO2C6H4COCl
or AcBr, K2CO3
H
O
BrCH2CO2CH3
MePh, reflux
CHCl3, 20oC
R
N
NH2
NCH2CO2Me
H
Me
Me
Me
CH2CO2Me
1
2
syn-3a, 3b
+
Ac2O, 20oC
H
N
O
Na
BrCH2CO2CH3
C6H6, 80oC
C6H6, 80oC
R
NCOR
H
NCOMe
Na
Me
Me
Me
CH2CO2Me
anti-3a, 3b
4a, 4b
5a, 5b
1. LiOH H2O,
THF_H2O, 3 : 1, 20oC
2. 1N HCl, 20oC
6
5
H
H
H
Ac2O, 120oC,
1"
4
3 h
H
H
O
7a
R
R
C
O
3a
H2O
R
N+
3
N
N
12
O
1
CH3
Me
CH3
2
CH2CO2H
O
5
_
H
O
syn-6a, 6b
10a, 10b
8a, 8b
6
+
5
H
H
11
8
H
7
Ac2O, 120oC
3 h
9
H
O
H
4
R
1
O
11a
2
C
10
2
3
R
3a
N+
1
O
N
11
N
3
12
Me
CH3
CH3
O
H
4
CH2CO2H
R
_
O
7a (51_66%), 7b (90%)
9a, 9b
anti-6a, 6b
R = 4-NO2C6H4 (a), CH3 (b).
into the intramolecular cycloaddition with the sp2-
hybridized carbon system of the contiguous ortho-
alkenyl fragment [20]. Formerly obtained data [15, 20]
make it possible to find certain regularity in the
heterocyclization of N-(2-alkenylphenyl)-N-acetylgly-
cines with unsubstituted allyl fragment, and also of
analogs having methyl groups at the α-carbon atom
and the terminal double bond of the allyl unit. In both
cases as the major regio-isomer 3a-methyl-substituted
cycloadduct was obtained: methanooxazoloquinoline
А with (1R*,3aR*,4R*)-configuration of nodal carbon
atoms. The fraction of 1-methyl-substituted isomer В
did not exceed 15%. The rigid structure of the cyclo-
alkane unit at the ortho-carbon atom of the aromatic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

ATROPISOMERIC N-ACYL-N-(CYCLOPENTENYLPHENYL)GLYCINES
699
ring of atropisomers, in contrast to open-chain analogs,
may affect the regioisomerism at the formation of the
heterocycles of scaffold structure (Scheme 1).
[29] with sodium in dimethoxyethane followed by
adding methyl bromoacetate to the obtained sodium
salt 5b (а) and by reaction of ester 2 with acetyl
bromide (b). The ratios of syn- and anti-isomers 3b
obtained by the first scheme (4b→5b→syn-/anti-3b)
and by the reaction of ester 2 with AcBr are practically
identic (~1 : 1).
We investigated [3+2]-cycloaddition of munchno-
nes generated in situ from N-[(cyclopent-2-en-1-yl)-
phenyl]glycines having at the carbonyl carbon atom of
the N-acyl unit substituents with an electron-acceptor
(4-NO2C6H4) and an electron-donor (Me) group, and in
the ortho-position of the aromatic ring a methyl group
was introduced in order to reliably prevent the
interconversion of atropisomers. As known, the
interconversion temperature of non-biaryl atropisomers
[27] with the occupied ortho-position in some cases
exceeded by over 100°С that of isomers where this
substituent was absent.
The alkaline hydrolysis of esters 3a and 3b by
stirring with a LiOH solution in a mixture THF–water
led to the formation of lithium salts 6a and 6b. The
successive treatment with hydrochloric acid of water
solutions of these salts resulted in a mixture of syn-
and anti-atropisomers 6a and 6b that we failed to
separate by chromatography or crystallization
(Scheme 2). The ratio of syn- and anti-isomers 6a, same
as syn- and anti-isomers of esters 3a, was ~2 : 1 (Fig. 1а);
in the case of compounds 3b and 6b it was ~1 : 1
(Fig. 2a).
To this end we synthesized from cycloalkenyltolui-
dine 1 [28] and methyl bromoacetate glycinate 2 whose
reaction with p-nitrobenzoic acid chloride afforded a
mixture of syn- and anti-apropisomers 3a in a ratio 1 : 2
(Scheme 2). We failed to prepare the mixture of syn-
and anti-isomers 3a by treating amide 4a with sodium
in dimethoxyethane followed by adding methyl
bromoacetate to the obtained homogenous solution.
At heating compounds 6a and 6b in acetic
anhydride at 120°С in both cases only the anti-
atropisomer reacted affording heterocycles 7a or 7b.
Apparently munchnones 8 and 9 formed both from
anti-, and syn-atropisomers of acids 6a and 6b. But the
intramolecular cycloaddition to the dipolar part of the
molecule at this temperature is possible only for
Compounds syn- and anti-3b were synthesized by
two procedures: by successive reactions of amide 4b
(a)
6.00
5.90
5.80
5.70
5.60
5.50
5.40
5.30
5.20
5.10
δ, ppm
(b)
0.02
0.02
5.0
6.0
5.9
5.8
5.7
5.6
5.5
5.4
5.3
5.2
5.1
4.9
4.8
δ, ppm
Fig. 1. The most characteristic region of protons at the double bond of the cyclopentene ring in the 1Н NMR spectrum
of a mixture of syn- and anti-isomers 6a in CDCl3 (а), the same region after heating the mixture in Ac2O (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

GATAULLIN et al.
(a)
700
6.00
5.90
5.80
5.70
5.60
5.50
δ, ppm
(b)
6.00
5.90
5.80
5.70
5.60
5.50
δ, ppm
Fig. 2. The most characteristic region of protons at the double bond of the cyclopentene ring in the 1Н NMR spectrum of a mixture
of syn- and anti-isomers 6b (а), the same region after heating the mixture in Ac2O (b). Only signals of unreacted atropisomer syn-
6b remained in the 1Н NMR spectrum of the reaction mixture of compounds syn-6b and heterocycle 7b in CDCl3.
munchnone 9 generated from the anti-atropisomer 6
(Scheme 2).
were recovered without changes during the
experiment.
Munchnones 8 formed in these conditions from the
syn-isomers 6 do not enter into the cycloaddition. In
the course of subsequent workup of the reaction
mixture a water molecule adds to munchnone 8 leading
to the opening of the oxazolium ring with the
formation of the initial syn-isomers of acid 6 which
The monitoring of the reaction mixture composition
by the Н NMR spectra is the most convenient by
1
following the signals of the double bond protons of the
fragment HC2''=C3''H of the cyclopentene ring for in
this region sufficiently clear resolution of signals is
observed. As seen from Figs. 1, 2, the difference in the
chemical shifts of the protons of anti-atropisomers of
acid 6a and 6b is larger than for syn-isomers (Figs. 1а,
2а). The analysis of NMR spectra of the reaction
mixture shows the presence in the spectra of only the
proton signals of the olefin fragment HC2''=C3''H from
acid syn-6a and 6b (Figs. 1b, 2b), and the proton
signals of heterocycles 7a and 7b are absent in this
region.
We failed to separate by crystallization the mixture
of unreacted syn-atropisomer of acid 6a and the
formed heterocycle 7a since these compounds
crystallized together. Therefore the syn-atropisomer of
Fig. 3. Crystals obtained from the solution of compound
syn-6b. Prismatic, left, and bipyramidal, right.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

ATROPISOMERIC N-ACYL-N-(CYCLOPENTENYLPHENYL)GLYCINES
701
O2
O2
O1
O1
C15
C15
O3
O3
C14
N1
C14
C12
C13
C11
C12
C13
C7
C10
C11
N1
C1
C7
*
C10
*
C2
C1
C2
C8
C9
C8
C3
C9
C16
C16
C3
C6
C6
C4
C4
C5
C5
Fig. 4. Structure of compound syn-6b according to XRD data. Atoms are represented by thermal ellipsoids of 50% probability.
Chiral center is marked with an asterisk.
acid 6a was isolated by column chromatography on
silica gel. After the [3+2]-cycloaddition of the mixture
of atropisomers 6b (the ratio of syn- and anti-isomers
~39 : 46) the unreacted isomer syn-6b was easily
separated from its mixture with compound 7b by
crystallization from acetonitrile. Heterocycles 7a and
7b were purified by chromatography on silica gel. We
succeeded in growing crystals of both compounds
suitable for X-ray diffraction (XRD) analysis, and their
structures were established by XRD method and
confirmed by spectral data.
At the graphic representation when we look at these
molecules along the axis С4–С1–N and place the
aromatic ring vertically and the acetyl and carboxy-
methyl substituents at the nitrogen atom horizontally
we obtain PS- and MR-isomers of the acid syn-6b(S)
and syn-6b(R). We believe that this consideration of the
molecule has some advantages in describing the nomen-
clature of the chiral center at the cyclopentene fragment,
since in this case the junior substituent (proton H1ʺ)
takes from the start the position “off the observer”
which is required by the rules for determining the
configuration at a chiral center (Fig. 5). At the same
time if these molecules are regarded along the axis N–
С1–С4, in this case to obtain for the proton at the chiral
center the position “off the observer” the cyclopentene
ring must be rotated 180° around the axis С7–С2.
The XRD experiments revealed the existence of two
kinds of crystals of acid 6b syn-isomer: prismatic and
bipyramidal (Fig. 3). The prismatic crystals correspond to
isomer 6b with R-configuration of the chiral center at the
atom С7, and the bipyramidal ones are characteristic of
isomer 6b with S-configuration of the atom С7 (Fig. 4).
CH3
CH3
The planes of the five- and six-membered rings are
orthogonal to each other, the angle between the mean
planes of the S-epimer is –86.21(14)°, R-epimer,
87.03(7)°. Atom С11 deviates from the mean cyclopen-
tene plane by 0.392(13) and 0.225(12) Å in molecules
of S- and R-epimers, respectively; consequently, the
cycle conformation is envelop. In attempt to apply to
syn-(S)- and (R)-isomers of acid 6b a commonly used
with axially chiral biaryl atropisomers MP-
identification we encountered some difficulties.
O
R
O
R
CH2CO2H
H1''
S-
HCO2CH2
H1''
R-
P-
M-
syn-6b(S), P,S-isomer
Fig. 5. Graphic representation of PS- and MR-isomers of
acid syn-6b(S) and syn-6b(R).
syn-6b(R), M,R-isomer
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GATAULLIN et al.
702
C16a
C15a
O25b
C14a
C13a
C3a
N24b
O26b
C12a
C11a
C19b
C10a
O27a
C4a
C20b
C17b
C18b
C9a
C21b
C22b
O2b
O2a
C22a
C8b
C1a
C23b
C1b
C6a
C7b
N5a
N5b
C7a
C6b
C23a
C21a
C8a
C9b
C18a
C17a
C20a
C4b
C10b
C11b
C3b
C13b
O26a
O27b
C19a
C12b
N24a
C14b
C16b
O25a
C15b
Fig. 6. Molecular structure of compound 7а. Atoms are represented by thermal ellipsoids of 50% probability. Hydrogen atoms are
not shown for the sake of simplicity.
C15
C19
C14
C3
C5
C11
C2
C10
C1
N12
C4
C6
C3A
C7
C18
O3
C9
O2
C16
Fig. 7. Molecular structure of compound 7b. Atoms are represented by thermal ellipsoids of 50% probability.
The crystal structure of compound 7а contains two
independent molecules А and B (Fig. 6) which have
similar geometric parameters. The orientation of the
benzene ring С18С19С20С21С22С23 is characterized by a
torsion angle О2C1C23C22 80.90(4) and –84.09(4)° in
molecules А and В respectively. A significant
difference between the two molecules appears in the
geometry of rings in the composition of the
heterocyclic fragment. The cyclopentane ring
С12С13С14С15С1 possesses the envelop conformation as
shows the deviation of С16 atom from the mean ring
plane by 0.654(3) and 0.643(3) Å in molecules А and
В respectively. The conformation of the piperidine ring
is sofa [the deviation of atom С1 from the plane
С13С12С11С6N5 in molecules А and В 0.821(5) and
0.817(5) Å respectively]. The oxazolidine fragment is
present in the envelop conformation where the
deviation of the N5 from the ring plane is insignificant
(0.001 Å) in both molecules.
In the structure of compound 7b 5 chiral centers are
present of various configurations: С1(S), С5(R), С9(S),
С10(R), С14(S). Five-membered carbo- and heterocyclic
fragments possess the envelop conformation. The
cyclic fragment N12C9C10C5C2C6 has sofa
conformation, where the atom С9 deviates from the
plane of the ring by 0.815(7) Å (Fig. 7).
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ATROPISOMERIC N-ACYL-N-(CYCLOPENTENYLPHENYL)GLYCINES
703
δ, ppm
15
20
25
30
35
40
45
50
55
60
65
70
75
4.0
3.5
3.0
2.5
2.0
1.5
1.0 δ, ppm
Fig. 8. HSQC NMR spectrum of the heterocyclic region of compound 7а.
δ, ppm
30
40
50
60
70
80
90
100
110
120
130
140
4.0
3.5
3.0
2.5
2.0
1.5
1.0 δ, ppm
Fig. 9. Results of HMBC NMR experiment for heterocycle 7a (CDCl3).
The assignment of proton and carbon signals in the
NMR spectra of heterocycles 7а and 7b was performed
with the help of experiments HH-Cosy, HMBC,
HSQC. As known, the assignment of the proton
signals of cyclopentane ring basing on the vicinal spin-
spin coupling constants of protons is difficult. The
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GATAULLIN et al.
704
Crystallographic data and refinement parameters of compounds syn-6b, 7а, and 7b
Parameter value
Parameter
syn-6b(R)
1530824
C16H19NO3
273.32
293
syn-6b(S)
1530825
C16H19NO3
273.32
293
7a
1530822
C21H18N2O4
362.37
7b
1530823
C16H17NO2
255.31
293
CCDC
Empirical formula
М
T, K
250
Crystal system
Space group
a, Å
Monoclinic
P21/a
Orthorhombic
P212121
9.8156(7)
10.4201(8)
14.3297(10)
90
Triclinic
P-1
Monoclinic
P21
11.4635(6)
8.8688(3)
14.1138(6)
90
9.1214(5)
10.5036(5)
20.6638(10)
77.903(4)
79.014(4)
69.476(5)
1798.03(17)
4
7.2558(7)
9.1740(14)
10.0632(9)
90
b, Å
c, Å
α, deg
β, deg
94.462(4)
90
90
99.728(9)
90
angle, deg
V, Å3
90
1430.57(11)
4
1465.64(18)
4
660.22(13)
2
Z
Dcalc, g/cm3
μ, mm–1
F(000)
1.269
1.239
1.339
1.284
0.088
0.085
0.094
0.085
584
584
760
272
Θmax, deg
Reflections collected
31.13
31.08
31.13
30.99
8512
5941
17628
1548
Independent reflections
(Rint)
4162 (0.0148)
3718 (0.0122)
10260 (0.0170)
1282 (0.0064)
Quality factor
1.033
0.0466
0.1268
1.053
0.0425
0.1193
1.014
0.0744
0.2067
1.021
0.0346
0.0922
R1 [I=2σ(I)]
wR2 (for all reflections)
Residual peaks of electron
0.31/–0.19
0.23/–0.14
0.41/–0.38
0.08/–0.11
density, min/max, e·Å–3
carbon-proton couplings in the molecule of heterocycle
7а were established using the method HSQC and were
confirmed by HMBC experiments (Figs. 8, 9). Yet the
data of only HSQC experiment were insufficient for
the precise assignment of the methylene protons
signals of the cyclopentane ring of the molecule of
benzoxazocinone 7а.
group С5H2 has a cross-peak with the atom С4 (44.59
ppm) (Fig. 9). On the strength of these data we
ascribed the more downfield signal (δ 38.73 ppm) to
atom С6, and the peak at δ 26.56 ppm, to atom С5.
Therefore we obtained additional data evidencing
the effect of the structure of the alkenyl fragment on
the direction of the intramolecular cycloaddition of
munchnone generated from syn- or anti-atropisomers
of N-[2-(alken-2-en-1-yl)phenyl]-N-acylglycines. When
in the ortho-position of the alkenylphenyl fragment a
cyclopentene unit is present this influence is
HMBC experiment demonstrated that the protons
of the cyclopentane methylene group С6H2 are
involved in the distant coupling with the aromatic
atom С7a (134.31 ppm), and the proton H5A of the
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ATROPISOMERIC N-ACYL-N-(CYCLOPENTENYLPHENYL)GLYCINES
705
significant. In this case in the reaction of [3+2]-
cycloaddition only munchnone is involved generated at
heating the anti-atropisomers of N-(4-nitrobenzoyl)- or
N-acetyl-N-[6-methyl-2-(cyclopent-2-en-1-yl)phenyl]-
glycine with acetic anhydride at 120°С, whereas syn-
isomers are recovered intact. The known trend [15, 20]
of heterocyclization of N-[2-(alken-2-en-1-yl)phenyl]-
N-acylglycines at heating with carboxylic acids
anhydrides with prevailing formation of new carbon-
carbon bonds between pairs of atoms С4 of oxazolium,
С3" of alkene and С2 of oxazolium, С2" of alkene
fragments is retained also in the formation of
compounds 7 from cycloalkenyl-substituted analogs.
EA-3000, the obtained data were consistent with the
calculated values. Melting points were measured on a
Boёtius heating block. For column chromatography
silica gel MN Kieselgel 60 (40–100 µm) was utilized.
Qualitative analysis was carried out by TLC on Sorbfil
plates (Sorbpolymer, Krasnodar, Russia) with
development in iodine vapor.
Methyl N-[2-methyl-6-(cyclopent-2-en-1-yl)-phe-
nyl]glycinate (2). To a slurry of 5.1 g (30 mmol) of 6-
methyl-2-(cyclopent-2-en-1-yl)aniline 1 and 4.2 g
(30 mmol) of K2CO3 in 20 mL of dimethoxyethane
was added 4.5 g (30 mmol) of methyl bromoacetate.
The reaction mixture was heated at boiling while
stirring for 36 h. As show GLC data, the reaction
virtually stops at the ratio amine 1–ester 2 ~1 : 1. On the
TLC plates the spots of these compounds were prac-
tically inseparable. To separate the products 2.3 mL of
Ac2O was added to the reaction mixture. Ester 2 did
not react with acetic anhydride, amine 1 reacted giving
amide 4b. Chromatographic spot of amide 4b
remained practically on the start and strongly differed
by Rf from ester 2. Saturated solution of NaHCO3 was
added to the reaction mixture, the mixture was stirred
for 30 min, diluted with CH2Cl2, shaken in a
separatory funnel, the organic layer was separated,
dried with MgSO4. The solvent was evaporated in a
vacuum, the residue was chromatographed on a
column packed with silica gel. Yield 3.0 g (40%). IR
spectrum, ν, cm–1: 3390 (N–H), 1738 (C=O). 1H NMR
spectrum, δ, ppm: 0.83–0.91 m, 1.57–1.72 m, 2.42–
2.67 m (4Н, C4''H2C5''H2), 2.33 s, 3.76 s (3H each, CH3,
OCH3), 3.74–4.02 m (3Н, H1', NCH2), 4.21 br.s (1H,
NH), 5.72–5.76 m, 5.93–5.997 m (1H each, C2''H=C3''H),
6.87–7.02 m (3Harom). Mass spectrum, m/z (Irel, %):
246 [M + H]+ (100), 244 [M – H]– (33).
EXPERIMENTAL
X-ray diffraction experiments were carried out on
the equipment of the Institute of Petrochemistry and
Catalysis of the Russian Academy of Sciences. The
array of reflections was collected at room temperature
using a diffractometer Xcalibur Е, equipped with
spatial detector EOS CCD and a monochromatic
source of MoKα-radiation (graphite monochromator, λ
0.71073 Å, w-scanning, 2θmax 62°). Collection and
processing of results were carried out using program
CrysAlisPro Oxford Diffraction Ltd [29]. The structure
was solved by the direct method and refined by the full
-matrix least-squares method in the anisotropic
approximation for nonhydrogen atoms. Hydrogen
atoms were placed in the geometrically calculated
positions and were refined in the rider model. The
calculations were performed using SHELX software
[30]. The main crystallographic characteristics,
parameters of registering and refining are compiled in
the table and are available at the address http://
www.ccdc.cam.ac.uk/products/csd/request/.
Methyl N-[2-methyl-6-(cyclopent-2-en-1-yl)-phe-
nyl]-N-(4-nitrobenzoyl)glycinate (3a), a mixture of syn-
and anti-atropisomers. To a slurry of 1.72 g (7 mmol) of
methyl ester 2 and 4 g (29 mmol) of K2CO3 in 15 mL
of anhydrous CHCl3 was added at stirring 1.65 g
(8.4 mmol) of 4-nitrobenzoyl chloride. The reaction
was stirred for 4 h, diluted with 10 mL of H2O, stirred
for 30 min, the reaction product was extracted with
150 mL of CHCl3. The organic phase was dried with
MgSO4, the solvent was evaporated in a vacuum. Yield
2.69 g (97%), amorphous powder, mp 178–180°C
(C6H6).
The spectral analyses were performed on the
equipment of the Center of joint usage of the Ufa
Institute of Chemistry, Russian Academy of Sciences.
IR spectra were taken on a Fourier spectrometer IR
Prestige 21 (Shimadzu). 1Н and 13С NMR spectra were
registered on spectrometers Bruker AM 300 (300 and
75 МHz respectively) and Bruker Avance III (500.13
and 125.13 MHz respectively) in CDCl3, internal
reference TMS. 13С NMR spectra of all synthesized
compounds were registered applying the method of J-
modulated spin-echo. Mass spectra were recorded on a
LC-MS instrument LCMS-2010EV (Shimadzu), liquid
phase acetonitrile–water, 95 : 5. Elemental analysis
was carried out on a CHNS Elemental Analyzer EURO
Methyl N-acetyl-N-[2-methyl-6-(cyclopent-2-en-
1-yl)phenyl]glycinate (3b), a mixture of syn- and anti-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

GATAULLIN et al.
706
atropisomers. а. In a one-neck round-bottom flask (V
50 mL) equipped with a reflux condenser and a
calcium chloride tube was charged a solution of 4.66 g
(21.7 mmol) of amide 4b in 38 mL of anhydrous
benzene and 0.5 g (21.7 mmol) of metal sodium was
added. The reaction mixture was boiled for 3 h, 3.31 g
(21.7 mmol) of methyl bromoacetate was added, and
the mixture was heated at boiling for 2 h. On cooling
to room temperature 50 mL of benzene and 20 mL of
H2O was added. The reaction mixture was stirred, the
organic phase was separated, dried with MgSO4, the
solvent was evaporated in a vacuum. Yield 5.82 g
(93%) of crude product containing according to NMR
data an impurity of inseparable initial amide 4. The
sample was hydrolyzed without purification.
syn-Isomer 6a. A mixture of syn- and anti-atrop-
isomers of acid 6a (3.63 g, 9.49 mmol) was heated at
120°С in 21 mL of Ac2O for 3 h. The reaction mixture
was cooled to 20°С, 10 mL of H2O was added, the
mixture was stirred for 40 min, shaken with saturated
solution of NaHCO3 till the end of CO2 liberation. The
reaction products were extracted with 150 mL of
СH2Cl2, the organic phase was washed with 50 mL of
H2O, and dried with MgSO4. The solvent was
evaporated in a vacuum. We obtained 1.7 g of a
mixture of compounds syn-6a and 7a that was
subjected to chromatography on a column packed with
20 g of silica gel (eluent С6H6). Yield of compound 7a
0.76 g (66% recalculated to the ratio of syn- and anti-
isomers of initial acid 6a, ~2 : 1), mp 193–195°C
(petroleum ether). After eluate containing compound
7a was collected the eluent was changed to С6H6‒
EtOAc mixture, 7 : 3, and 0.69 g (19%) of syn-isomer
of acid 6a was isolated. The main part of the acid was
lost at the treatment of the reaction mixture with
sodium hydrogen carbonate solution. mp 195–198°С
(C6H6). IR spectrum, ν, cm–1: 1733 (С=O), 1622, 1597,
b. To a slurry of 1.51 g (6.18 mmol) of compound 2
and 1.7 g (12.4 mmol) of K2CO3 in 10 mL of anhyd-
rous CH2Cl2 was added at stirring 1.52 g (12.4 mmol)
of acetyl bromide. The reaction mixture slightly self-
heated. The mixture was stirred for 4 h, within this
interval initial compound 2 disappeared. The reaction
mixture was diluted with 20 mL of water, vigorously
stirred for 10 min, 1 g of NaHCO3 was added, and the
mixture was stirred for 5 min. The content of the flask
was removed to a separatory funnel, the flask was
rinsed with 100 mL of CH2Cl2, the washings were
added to the separatory funnel, and the funnel was
shaken. The organic phase was separated, washed with
20 mL of H2O, separated, dried with MgSO4, the
solvent was evaporated in a vacuum. Yield 1.65 g
(100%) of crude product containing according to TLC
1
1521, 1345, 1224, 788. H NMR spectrum, δ, ppm:
1.51–1.63 m, 2.35–2.55 m (4Н, C4''H2, C5''H2), 2.34 s
(3H, CH3), 4.45–4.50 m (1Н, H1'), 4.24 d (1H, H2A, J
16.8 Hz), 4.53 d (1H, H2B, J 16.8 Hz), 5.19–5.27 m,
5.92–5.95 m (1H each, C2''H=C3''H), 6.94 d (1Harom, J
7.5 Hz), 7.05 d (1Harom, J 7.5 Hz), 7.17 t (1Harom, J 7.5 Hz),
7.54 d (2Harom, J 8.7 Hz), 8.11 d (2Harom, J 8.7 Hz). 13C
NMR spectrum, δ, ppm: 18.37, 21.39 (2CH3), 32.42,
34.48 (C4'', C5''), 45.39 (C1''), 52.58 (CH2), 126.76,
129.28, 132.81, 133.47 (C3′, C4′, C5′, C2′′, C3′′), 135.83,
139.82, 144.59 (C1′, C2′, C6′), 171.76, 173.41 (CO2H,
NC=O). Mass spectrum, m/z (Irel, %): 379 [M – H]–
(100).
1
and Н NMR data no impurity of initial compound 2.
IR spectrum, ν, cm–1: 1738 (С=O). Mass spectrum, m/z
(Irel, %): 288 [M + H]+ (100). The sample was
hydrolyzed without purification.
N-Acetyl-N-[2-methyl-6-(cyclopent-2-en-1-yl)-
phenyl]glycine (6b), a mixture of syn- and anti-atrop-
isomers, 1 : 1, was similarly obtained by hydrolysis of
5.82 g of a mixture of syn- and anti-isomers of ester 3b
in 204 mL THF–H2O, 3 : 1, with 1.7 g (40.5 mmol) of
LiOH·H2O. After removal of the solvent in a vacuum
the residue was crystallized from acetonitrile. The
precipitate (2.97 g, 47% with respect to initial amide
4b) was filtered off. At crystallization from ethanol the
ratio of atropisomers did not change. White crystals,
mp 165–169°C (MeCN). Mass spectrum, m/z (Irel, %):
288 [M + H]+ (100).
N-[2-Methyl-6-(cyclopent-2-en-1-yl)phenyl]-N-(4
-nitrobenzoyl)glycine (6a), a mixture of syn- and anti-
atropisomers, 2 : 1. In an Erlenmeyer flask was
charged a solution of 1.69 g (4.3 mmol) of a mixture of
syn- and anti-atropisomers of ester 3a in 60 mL of
THF–H2O, 3 : 1, 0.36 g (8.6 mmol) of LiOH·H2O was
added, After 3 h 50 mL of Me3COMe and 150 mL of
H2O was added. The water layer was separated,
washed with 10 mL of Me3COMe, and shaken with
60 mL of 1N HCl. The reaction product was extracted
with 100 mL of Me3COMe, the organic layer was
dried with MgSO4. After removing the solvent in a
vacuum the residue was crystallized from acetonitrile.
Yield 0.86 g (52%), yellowish crystals, mp 216–218°C
(MeCN).
syn-Isomer 6b. A solution of 0.5 g (1.83 mmol) of a
mixture of syn- and anti-isomers of acid 6b in 3 mL of
Ac2O was heated at 120°С for 3 h. The reaction
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

ATROPISOMERIC N-ACYL-N-(CYCLOPENTENYLPHENYL)GLYCINES
707
mixture was cooled to 20°С, 10 mL of H2O, was
added, the mixture was stirred for 30 min, then 1.8 g
(21 mmol) of NaHCO3 and 50 mL of СHCl3 was
added. The organic layer was separated, washed with
10 mL of H2O, and dried with MgSO4. The solvent
was evaporated in a vacuum, the residue was dissolved
at boiling in 3 mL of MeCN, colorless crystals preci-
pitated at cooling were filtered off, washed with 2 mL
of MeCN, and dried in air. Yield 0.092 g (37% recal-
culated to the mixture of syn- and anti-isomers of initial
acid 6b, ~1 : 1) of syn-isomer 6b, mp 166–167°С
t (1H, H7, J 5.0 Hz), 3.61 t (1H, H11, J 7.0 Hz), 4.00 s
(1H, H3a), 6.72 d (1H, H8, J 7.2 Hz), 6.87 t (1H, H9, J
7.2 Hz), 6.91 t (1H, H10, J 7.2 Hz), 7.65 d (2H, H2′,6′, J
8.7 Hz), 8.05 d (2H, H3′,5′, J 8.7 Hz). 13C NMR
spectrum, δ, ppm: 17.22 (CH3), 26.56 (C5), 38.73 (C6),
44.35 (C7), 44.59 (C4), 52.17 (C11), 70.56 (C3a), 101.21
(C1), 123.61 (C3′,5′), 124.75 (C8), 127.13 (C9), 128.74
(C10), 129.52 (C2′,6′), 134.31 (C7a), 134.52 (C11), 139.00
(C4′), 139.83 (C11a), 148.66 (C1′), 171.33 (C3).
(1S*,3aR*,4S*,7S*,13S*)-1,11-Dimethyl-4,5,6,7-
tetrahydro-1,4,7-methanetriyl[1,3]oxazolo[3,4-a][1]-
bensazocin-3(3aH)-one (7b). Mother liquor after
separation of compound syn-6b and the liquid obtained
by washing it on the filter were combined and eva-
porated at a reduced pressure. The residue was chroma-
tographed on a column packed with silica gel, eluent
benzene. Yield 0.226 g (90% recalculated to the mixture
of syn- and anti-isomers of initial acid 6b, ~1 : 1),
transparent viscous fluid that in 24 h solidified to a
white amorphous mass, mp 104–105°С (petroleum
ether), Rf 0.27 (С6H6). IR spectrum, ν, cm–1: 1791
(C=O), 1464, 1460, 1450, 1388. 1H NMR spectrum, δ,
ppm: 1.05 d.d (2Н, H5A, J 6.3, 10.0 Hz), 1.49 s (3H,
CH3), 1.66–1.72 m (1H, H6A), 1.84–2.04 m (2H, H5B,
H6B), 2.31 s (3H, CH3), 2.71 d.q (1H, H4, J 7.6 Hz),
2.99 d.d (1H, H7, J 6.2, J 7.3 Hz), 3.50 d.d (1H, H11, J
4.7, J 5.3 Hz), 3.82 s (1H, H3a), 6.99–7.09 m (3H, H8,
H9, H10). 13C NMR spectrum, δ, ppm: 15.18 (CH3),
17.01 (CH3), 26.54 (C5), 38.46 (C6), 43.98 (C7), 44.46
(C4), 53.83 (C11), 70.67 (C3a), 101.32 (C1), 124.51 (C8),
126.55 (C9), 128.31 (C10), 134.57 (C7a), 135.35 (C11),
140.48 (C11a), 172.95 (C3). Mass spectrum, m/z (Irel,
%): 256 [M + H]+ (100), 297 [M + H + CH3CN]+ (23).
1
(MeCN). H NMR spectrum, δ, ppm: 1.47–1.60 m,
2.24–2.49 m (4Н, C4''H2, C5''H2), 1.77 s, 2.21 s (3H
each, 2CH3), 3.94–4.01 m (1Н, H1'), 4.12 d (1H, H2A, J
15.8 Hz), 4.18 d (1H, H2B, J 15.8 Hz), 5.35 br.s (1H,
COOH), 5.48–5.51 m, 5.90–5.94 m (1H each,
C2''H=C3''H), 7.05 d.d (1H, H4', J 7.5, 8.6 Hz), 7.17 d
(1H, Harom, J 8.6 Hz), 7.20 d (1H, Harom, J 7.5 Hz). 13C
NMR spectrum, δ, ppm: 18.37, 21.39 (2CH3), 32.42,
34.48 (C4'', C5''), 45.39 (C1''), 52.58 (CH2), 126.76,
129.28, 132.81, 133.47 (C3′, C4′, C5′, C2′′, C3′′), 135.83,
139.82, 144.59 (C1′, C2′, C6′), 171.76, 173.41 (CO2H,
NC=O). Mass spectrum, m/z (Irel, %): 274 [M + H]+
(100), 272 [M – H ]– (100).
anti-Isomer 6b. 13C NMR spectrum was obtained
by subtracting the signals of compound syn-6b from
the spectrum of the mixture. 13C NMR spectrum, δ,
ppm: 18.22, 21.27 (2CH3), 32.30, 33.41 (C4'', C5''),
45.27 (C1''), 52.10 (CH2), 126.64, 129.19, 131.91,
133.89 (C3′, C4′, C5′, C2′′, C3′′), 135.63, 139.76, 144.74
(C1′, C2′, C6′), 171.82, 173.20 (CO2H, NC=O).
(1S*,3aR*,4S*,7S*,13S*)-11-Methyl-1-(4-nitro-
phenyl)-4,5,6,7-tetrahydro-1,4,7-methanetriyl[1,3]-
oxazolo[3,4-a][1]bensazocin-3(3aH)-one (7a). In 6 mL
of Ac2O 0.87 g (2.28 mmol) of a mixture of syn- and
anti-6a was heated at 120°С for 3 h. The reaction
mixture was cooled to 20°С, 10 mL of H2O, was
added, the mixture was stirred for 40 min, shaken with
saturated solution of NaHCO3 till the end of CO2
liberation. The reaction products were extracted with
60 mL of Me3CCOMe, the organic phase was washed
with 10 mL of H2O and dried with MgSO4. The solvent
was evaporated in a vacuum. The residue was chroma-
tographed on a column packed with silica gel (eluent
С6H6). Yield 0.14 g (51% recalculated to the mixture
of syn- and anti-isomers of initial acid 6a, 2 : 1), mp
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