Functiaonalization of 2-(1-Cyclohexen-1-yl)aniline Derivatives

Article abstract of DOI:10.1134/S1070363219040030

The reaction of 2-(1-cyclohexen-1-yl)aniline and -6-methylaniline with phthalic anhydride has afforded 2-(2-cyclohex-1-en-1-ylphenyl)- and 2-(2-cyclohex-1-en-1-ylphenyl)-6-methylphenyl)-1H-isoindole-1,3(2H)-diones. The reaction of the obtained isoindole-1,3-diones with bromine in dichloromethane in the presence of sodium bicarbonate has led to the formation of the product of pseudo-allylic halogenation. Replacement of the halogen atom by methoxy group has been performed by keeping 2-[2-(6-bromocyclohex-1-en-1-ylphenyl)-6-methylphenyl)]-1H-isoindole-1,3(2H)-dione in a methanolic solution in the presence of NaHCO₃. The reaction of 2-(2-cyclohex-1-en-1-yl-6-methylphenyl)-1H-isoindole-1,3(2H)-dione with molecular bromine in the presence of methanol has given a co-halogenation product, whereas the dibromination product has been obtained in the presence of octyl alcohol.

Full text of DOI:10.1134/S1070363219040030

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 653–662. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 4, pp. 511–521.
Functiaonalization of 2-(1-Cyclohexen-1-yl)aniline Derivatives
R. N. Khusnitdinova, R. M. Sultanovb, and R. R. Gataullina*
a Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Russia
*e-mail: gataullin@anrb.ru
b Ufa State Petroleum Technical University, Ufa, Russia
Received November 29, 2018; revised November 29, 2018; accepted December 6, 2018
Abstract—The reaction of 2-(1-cyclohexen-1-yl)aniline and -6-methylaniline with phthalic anhydride has
afforded 2-(2-cyclohex-1-en-1-ylphenyl)- and 2-(2-cyclohex-1-en-1-ylphenyl)-6-methylphenyl)-1H-isoindole-
1,3(2H)-diones. The reaction of the obtained isoindole-1,3-diones with bromine in dichloromethane in the
presence of sodium bicarbonate has led to the formation of the product of pseudo-allylic halogenation.
Replacement of the halogen atom by methoxy group has been performed by keeping 2-[2-(6-bromocyclohex-1-
en-1-ylphenyl)-6-methylphenyl)]-1H-isoindole-1,3(2H)-dione in a methanolic solution in the presence of
NaHCO3. The reaction of 2-(2-cyclohex-1-en-1-yl-6-methylphenyl)-1H-isoindole-1,3(2H)-dione with mole-
cular bromine in the presence of methanol has given a co-halogenation product, whereas the dibromination
product has been obtained in the presence of octyl alcohol.
Keywords: isoindolediones, methoxylation, bromination, phthalimides, atropisomer
DOI: 10.1134/S1070363219040030
Several approaches of preparative introduction of
allyl [1, 2], homoallyl [3], and vinyl [4‒6] substituents
in benzene core have been developed. For example,
many aminoaryl-substituted unsaturated hydrocarbons
[7] with ortho- [8, 9], meta- [10], and para-positions
[11] of amine, alkene and cycloalkene fragments in the
aromatic ring as well as theirs derivatives with amino
and oxy groups at alkene [12, 13] and N-alkenylaniline
[14, 15] have become available. Many of these com-
pounds have been applied in organic synthesis [16].
For example, biologically active arylamides [17], acidic
corrosion inhibitors [18], antiviral [19, 20] and anti-
tumoral drugs have been synthesized basing on these
substances [21].
different hydrogenation patterns. The drawback of
these schemes is the removal of protecting tosyl and
mesyl groups in aggressive media, which may be
accompanied by undesired transformation of other
functional groups. The use of protectors which can be
removed easier in comparison with aryl- and alkyl-
sulfonyl ones can lead to different results. In particular,
attempts to functionalize cycloalkene fragments of N-
acetyl- and N-alkoxycarbonyl-substituted analogs in a
similar way, via the interaction with bromine [26] or
peroxides [27], has led to the formation of ben-
zoxazines. In view of the above, the investigation of
protecting groups which allow convenient useful
functionalization of cycloalkene fragment yet can be
easily removed from the nitrogen atom has become an
emerging field of research.
Chemical transformations of several N-tosyl(mesyl)-
2-(1-cycloalkene-1-yl)aniline substituents via the inter-
action with conventional electrophilic reagents might
differ from the classical concepts. Such transforma-
tions occurs in the reactions of the said sulfonylamides
with molecular bromine in the presence of hydro-
carbonates or methanolic solution of copper di-
bromide, resulting in the formation of pseudo-allyl
bromination [22‒24] or methoxylation [25] products,
which can be used in the synthesis of carbazoles with
In this study, we synthesized phthalimide derivatives
of 2-(1-cyclohexene-1-yl)-phenyl-1,3-isoindoledione
and investigated theirs reactions with bromine under
different conditions. Phthalyl group [29] is among the
most commonly used ones for the amine protection in
the synthetic schemes involving amino acids [28].
Phthalyl group is applicable in the cases of relatively
thermally stable amines, since their interaction with
653

654
KHUSNITDINOV et al.
Scheme 1.
O
R
O
3
DMF, 180°C
N
+
O
1
NH2
O
O
R
1a, 1b
2a (92%), 2b (89%)
CH3
O
4
Br2
N
CH2Cl2
NaHCO3
MeOH
1''
OCH3
O
2''
Br
4 (36%)
R = H (a), CH3 (b).
phthalic anhydride occurs at high temperature [30, 31]
but this group can be removed via the treatment with
hydrazine under mild conditions [32]. Amines 1a, b
used in this study exhibited high thermal stability.
They were obtained via heating of 2-(2-cyclohexen-1-
yl)aniline and its 6-methyl-substituted homolog,
respectively, with KOH at 300°С as reported elsewhere
[33]; physico-chemical parameters of the products
coincided with the reference values [22, 33, 34].
Isoindolones 2a, b were synthesized via boiling of the
corresponding cyclohexenylanilines 2a [33, 34], 2b
[22] with phthalic anhydride in DMF (Scheme 1). The
reaction products were isolated by chromatography on
silica gel.
the С1'' carbon atom (singlet with chemical shift δ
79.34 ppm) and the bromine-substituted carbon atom
С2 (doublet at δ 51.05 ppm) in 13C NMR spectrum.
According to the HSQC and HMBC data, the three-
proton singlet signal of the carbon atom of the OCH3
substituent (quartet at δ 55.01 ppm), corresponded to
the signal at δ 2.94 ppm. Mass spectrum of compound
4 showed the signals with m/z 428 and 430 (80% peak
intensity), which corresponded to the molecular ion
[M + H]+ decomposing with the loss of halogen atom
yielding the fragment with m/z 348 (100%), which was
subsequently degraded into the fragment with m/z 316
(I = 68%) (Scheme 2).
We have previously shown that N-tosyl- and N-
mesyl-substituted analogs 3a, b are transformed into
ethers 5c, d during the interaction with CuBr2 in
methanol (Scheme 3) [22, 25]. Unlike this, keeping
compounds 2a, b in copper dibromide solution in
MeOH did not lead to the transformations of those
imides. N-acetyl- (3e) [33] and N-ethoxycarbonyl-
substituted (3f) cyclohexenylanilines were not trans-
formed into the products of pseudoallyl methoxylation
5e, f under similar conditions as well (Scheme 3).
Comparison of the results of bromination of the
synthesized 2-[2-(1-cyclohexen-1-yl)]-6-methylphenyl-
1-indole-2,3-dione 2b (Scheme 1) and bromine
interaction with N-tosylate 3a [22, 25, 34, 35] or N-
mesylate 3b [22] (Scheme 2) under the same condi-
tions reported previously showed significant influence
of protecting group at the nitrogen atom on the
direction of the reaction. Unlike the reaction of tosylate
3a or mesylate 3b with halogen in the presence of
methanol [25], the interaction of compound 2 with
molecular bromine under the same conditions led to
the product of cohalogenation 4 with methoxy group at
the 1'' atom of the cyclohexane fragment (Scheme 1),
which was confirmed by the presence of the signals of
An attempt to obtain the compound analogous to
ether 4 and bearing the octyloxy group at the 1'' carbon
atom of cyclohexane ring led to the product of
dihalogenation. During the interaction of compound 2b
with molecular bromine in methylene chloride in the
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FUNCTIAONALIZATION OF 2-(1-CYCLOHEXEN-1-YL)ANILINE DERIVATIVES
Scheme 2.
+
+
Br
OCH3
OCH3
O
N
O
N
H+
4
−HBr
O
O
H3C
H+
H3C
H+
[M + H − HBr]+
[M + H]+
+
O
N
−CH3OH
O
H3C
H+
[M + H − HBr − CH3OH]+
presence of octyl alcohol, compound 6 with two
Compound 6 was unstable under the conditions of
chemical ionization under atmospheric pressure
(APCI) and decomposed with the formation of the
fragment 7 with m/z 316 [M – 2НBr + H]+ (60%) and
associate 8 composed of that fragment with water [M –
2НBr + H2O + H]+ (100%) with m/z 334 (Scheme 5).
bromine atoms at the cyclohexane ring (Scheme 4) was
1
formed; its structure was confirmed by Н and 13С
NMR spectroscopy. Aliphatic carbon atom range of
the 13С NMR spectrum was simple and easy to be
assigned: there were seven signals corresponding,
according to their multiplicity, to the СH3 group
(18.12 ppm), methylene chain (CH2)4 of the
cyclohexane ring (triplets at 19.76, 20.81, 30.53, and
32.72 ppm), C2'' carbon atom (doublet at 57.17 ppm),
and C1'' quaternary carbon atom (singlet at 74.90 ppm).
The signals assignment to the listed groups was made
on the basis of NMR HSQC and HMBC data.
The interaction of compounds 2a, b with molecular
bromine in CH2Cl2 in the presence of NaHCO3 gave
the products of monobromination 9a, b with high yield
(Scheme 6). Molecular ion [М + Н]+ of compound 9b
was unstable under the conditions of APCI experi-
ment, due the presence of labile allyl bromine atom,
Scheme 3.
H3CO
X
i, 20oC
CuBr2
×
MeOH
i: Br2, CH2Cl2, NaHCO3, X = Br
i: Br2, MeOH, CH2Cl2, NaHCO3, X = OCH3
i: CuBr2, MeOH, X = OCH3
NHR
NHR
5e, 5f
NH
SO2Ts(Ms)
5a−5d
3a, 3b, 3e, 3f
X= Br (5a, 5b), OCH3 (5c, 5d); R = Ts (3a), Ms (3b), Ac (3e, 5e), OCOEt (3f, 5f).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

656
KHUSNITDINOV et al.
Scheme 5.
Scheme 4.
4''
2''
+
Br
Br
O
N
O
O
1''
APCI
Br2
6
2b
N
−2HBr
CH2Cl2
NaHCO3
C8H17OH
H3C
H+
H3C
O
7, m/z 316 (60%) [M − 2HBr + H]+
6 (56%)
H2O
8, m/z 334 (100%)[M − 2HBr + H2O + H]+
and the peak of that ion was absent. In the mass spec-
trum, the [M – Br]+ fragment with m/z 316 (100%)
was observed, it formed the associate with water [M –
Br + H2O]+ with m/z 334 (10%).
Heating of compound 9b in MeOH gave methyl
ether 10 is formed (Schemes 4, 6). A distinct feature of
the 13С NMR spectra of compounds 9a, 9b and 10 was
the presence of a single set of the signals of the
symmetrical phthalimide moiety. Simulation of the
molecules of compounds 9a, 9b, and 10 using
Hyperchem software revealed almost parallel
orientation of isoindoledione and cyclohexene rings.
At the same time, each symmetrical group of the
phthalimide fragment was close to different carbon
atoms of the cyclohexene ring, resulting in the
nonequivalent magnetic surrounding. More detailed 1H
and 13C NMR signals assignment performed basing on
the HSQC experiment data and using compound 9b as
example showed that the chemical shifts of pairwise
symmetrical phthalimide carbon atoms С4,5,6,7 differed
insignificantly (≈0.09 ppm). After heating compound
9b in methanol, the signal of the H6'' proton (4.75 ppm)
disappeared, while a singlet signal of the H6'' proton
The latter compound should have been a racemate
of syn- and anti-isomers 9 (Scheme 6) due to steric
features caused by close bulky substituents at aromatic
and cyclohexene rings. Preliminary theoretical analysis
using Hyperchem [36] software allowed elucidation of
mutual orientation of phthalimide and aromatic cycles
which was almost perpendicular in the hypothetical
anti-isomer 9. In the case of syn-isomer, the dihedral
angle was smaller (≈40°). At the same time, the
aliphatic chain of cyclohexene fragment and aromatic
ring were not coplanar as well the С2''С1''С2'С1' dihedral
angle being >40° for both isomers. Yet, there was no
experimental confirmation of the presence of the
atropoisomers. Probably, the energy barrier of the
rotation about the carbon-carbon bond between the
sp2-hybridized atoms (С6'‒C1'') in monobromide 9 was
too low to manifest deceleration of the axial rotation
in the NMR spectra.
1
was present at 3.67 ppm in H NMR spectrum of the
only reaction product 10. The presence of the methoxy
group in the compound 10 was confirmed by the
presence of a three-proton singlet at 3.20 ppm in the
Scheme 6.
Br
6''
6''
6''
2''
2''
2''
2''
Br
+
H3CO
Br
H
CH2Cl2
1''
Br2
1a, 1b
2'
NPht
NPht
CH3
NPht
NPht
CH2Cl2
NaHCO3
MeOH
1'
NaHCO3
CH3
syn-9a, 9b
R
CH3
anti-9a, 9b
10, 86%
R = H (a), CH3 (b).
9a (90%), 9b (97%)
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FUNCTIAONALIZATION OF 2-(1-CYCLOHEXEN-1-YL)ANILINE DERIVATIVES
Scheme 7.
(CH2)n
(CH2)n
Br
(CH2)n
MeO
MeO
R2
Br
R2
CuBr2
+
Br
NH2
MeOH
20oC
NH2
NH2
R1
R1
R1
13a (80%)
13b (11%)
13c (80%)
12a (79%)
12b (85%)
1a, 1c, 11b
R1 = R2 = H, n = 2 (a), R1 = CH3, R2 = H, n = 1 (b), R1 = CH3, R2 = (Z)-CH3-CH-CH=CH-CH3, n = 2 (c).
1H NMR spectrum. 13C NMR spectrum (JMOD mode)
of compound 10 contained the signals of carbon atoms
of methoxy group and C6'' at 56.95 and 75.63 ppm,
respectively. The signals of carbon atoms of three
methylene groups appeared at δ 16.60, 25.46, and
26.56 ppm. The proton signals assignment to the
carbon groups was also confirmed by HSQC, HMBC,
and H–H correlation NMR data. The molecular ion
[M + H]+ of compound 10, formed under conditions of
the APCI experiment (m/z 348) was poorly stable. Low
intensity of that ion peak (about 10%) could be
explained by fast decay according to the [M ‒ CH3OH +
H]+ scheme yielding the fragment with m/z 316
(100%).
and 3445‒3460 cm–1 in the IR spectrum. The H2'
proton gave rise to a doublet of doublets of doublets at
5.05‒5.08 ppm with the spin-spin interaction constants
J1 = 1.2, J2 = 1.6, and J3 = 6.3 Hz in 1Н NMR spectrum
of compounds 12b and 13b. The double resonance
data revealed that the larger constant (J3 = 6.3 Hz) of
the proton H2' was due to the interaction with one of
the protons of the C3'H2 group, and the multiple signal
1
of that group was present in H NMR spectra of both
amino ethers 12b and 13b at 2.65‒2.82 ppm.
Replacement with halogen at the para-position was
determined by the presence of the doublet signals of
the H3 and Н5 protons of the aromatic ring of com-
pound 12a. The presence of heteroatoms (bromine,
methoxy group, etc.) between such aromatic protons
enhanced their interaction (the W-system effect) with
spin-spin interaction constant up to 3.0 Hz, as known
from numerous examples. The aliphatic carbon region
of the 13С NMR (JMOD) spectra of compounds 12b
and 13b contained 7 signals; those at 92.5 and
92.8 ppm corresponded to the С1' atom according to
multiplicity and chemical shift. The signals at 54.0 and
54.5 ppm were assigned to the methoxy group, the
signals of bromine-substituted carbon atom С2' of
compounds 12b and 13b were at 51.1 and 51.4 ppm,
respectively. Chemical shifts of three triplet signals of
the methylene groups in the cyclopentane unit
corresponded to the calculated values. 13С NMR
spectra of compounds 12a, 13a, and 13c contained the
signals of the methoxy carbon atoms at 54.0 ppm, and
the С1' carbon atoms adjacent to that group were
present at 81.0 ppm.
Cycloalkenylanilines 1a [33, 34], 1c [37] and 11b
[38] formed haloethers 12, 13 in the reaction with
copper(II) bromide in methanol (Scheme 7). The use
of 4-(1-methylbut-2-en-1-yl)cyclohexenylaniline 1c
under those conditions led to the formation of the only
compound 13c with high yield. In the case of the
analogs 1a and 11b, the proton substitution with the
halogen atom at the para-position of the aromatic ring
was possible depending on the CuBr2 amount, on top
of the formation of the haloether. The interaction of
compound 11b with 2 eq. of CuBr2 in methanol gave
dibromide 12b and monobromide 13b. The interaction
of cyclohexenyl homolog 1a with 1 eq. of copper(II)
bromide gave haloether 13a with high yield, whereas
para-bromo-substituted ether 12a was also formed in
significant amount when using 2 eq. of CuBr2.
The structure of the obtained compounds was
elucidated by spectral methods, the composition was
confirmed by elemental analysis. For example, the
presence of the primary amino group in the structure of
compounds 12a, 12b and 13a–13c was evidenced by
the presence of the characteristic signal at 3360‒3370
In summary, 2-(2-cyclohex-1-en-1-ylphenyl)- and
2-(2-cyclohex-1-en-1-yl-6-methylphenyl)-1H-isoindole-
1,3(2H)-dione were synthesized via the interaction of
2-(2-cyclohex-1-en-1-yl)aniline and 2-(2-cyclohex-1-
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658
KHUSNITDINOV et al.
en-1-yl)-6-methylaniline with phthalic anhydride with
high yields. The reaction of the latter product with
bromine in the presence of MeOH led to the product of
cohalogenation, and vicinal dibromide was obtained in
the presence of octanol. An efficient approach to
obtain the product of pseudoallyl halogenation of both
imides via the interaction with bromine which could be
applicable to polyheterocycles synthesis was proposed.
Keeping 2-(1-cyclopenten-1-yl)-6-methyl-, 2-(1-cyclo-
hexen-1-yl)-4-(1-methylbut-2-en-1-yl)-6-methyl-, and
2-(1-cyclohexen-1-yl)aniline in a solution of CuBr2 in
MeOH gave the corresponding 2-(1-methoxy-2-bromo-
1-cycloalkyl)anilines and the products of their further
para-bromination. At the same time, the mentioned
phthalimides of cyclohexenyl derivatives were intact in
a methanolic solution of copper dibromide.
matography on silica gel (15 g, eluent: C6H6). The
obtained viscous substance was triturated with petro-
leum ether, the precipitate was filtered off and dried.
1
Yield 2.78 g (92%). Н NMR spectrum, δ, ppm: 1.41‒
1.48 m, 1.57‒1.63 m, 1.79‒1.87 m, 2.20‒2.29 m
(4×2H, 4CH2), 2.21 s (3H, CH3), 5.50 br. s (1H, H2''),
7.25 d (1Н, НAr, J = 7.9 Hz), 7.34‒7.46 m (2Н, НAr),
7.78 d. d (2Н, НAr, J = 3.0, J = 5.0 Hz), 7.94 d. d (2Н,
НAr, J = 3.0, J = 5.0 Hz).
2-(2-Cyclohex-1-en-1-yl-6-methylphenyl)-1H-
isoindole-1,3(2H)-dione (2b) was obtained similarly
from compound 1b (1.87 g, 10 mmol) and 1.48 g (10
mmol) of phthalic anhydride. Yield 2.82 g (89%),
colorless crystals, mp 99–102°С, Rf 0.77 (CHCl3). IR
spectrum, ν, cm–1: 1741, 1715, 1462, 1378, 721. UV
1
spectrum (CH3CN), λmax, nm: 268 (ε = 12000). Н
NMR spectrum, δ, ppm: 1.35‒1.45 m, 1.50‒1.60 m,
1.75‒1.85 m, 2.12‒2.20 m (4×2H, 4CH2), 2.21 s (3H,
CH3), 7.95 s (2H, H5,6), 7.89‒7.98 s and 7.74‒7.83 s
(2H, H4, H7), 7.27‒7.38 t (1H, H4', J = 15.2 Hz) 7.24 d
(2H, H3, H5, J = 7.3 Hz), 7.13 d (1Н, НAr, J = 7.3 Hz),
5.48 s (1H, H2''). 13С NMR spectrum, δС, ppm: 18.30
(CH3), 21.77, 23.01, 25.27, 29.52 (C3'', C4'', C5'', C6''),
123.52 (C4, C7), 126.10, 126.54, 129.01, 129.15 (C3',
C4', C5', C2''), 128.23, 132.04, 135.97, 137.13 (C3а, C7а,
C1'', C2', C6'), 134.08 (C5, C6), 144.38 (C1'), 167.65 (C1,
C3). Mass spectrum, m/z (Ir, %): 318 (100) [M + H]+.
EXPERIMENTAL
The experiments were performed using the equip-
ment of the Center for Collective Usage “Chemistry”
of Ufa Institute of Chemistry, RAS. IR spectra were
registered using an IR Presstige-21 spectrometer
(Shimadzu). Н and 13С-NMR spectra were registered
1
using a Bruker AM 300 spectrometer operating at
300.13 and 75.73 MHz, respectively, and a Bruker
Avance III instrument at (500.13 and 125.13 MHz,
respectively) in CDCl3 [internal reference: TMS). GLC
monitoring of the reaction products purity was
performed using a Chrom-5 chromatograph (carrier
gas: helium, 50 mL/min, flame ionization detector,
1200×3 mm columns, stationary phase: silicone liquid
SE-30 (5%) on Chromaton N-AW DMCS, operating
temperature 50‒300°С]. Elemental analysis were
performed using a CHNS Elemental Analyzer EURO
EA-3000 device. Halogen content was determined via
the Schoeniger method followed by potentiometric
titration. Elemental analysis data coincided with the
calculated values. Column chromatography was
performed on MN Kisielgel 60 silica gel (40‒100 μm).
Qualitative TLC analysis was performed using Sorbfil
plates (Sorbpolimer, Krasnodar, Russia) developed
with iodine vapor.
Ethyl-(2-cyclohex-1-en-1-ylphenyl)carbamate
(3f). A solution of 2.72 g (25.0 mmol) of ethyl chloro-
formate in 10 mL of CH2Cl2 was added dropwise to a
suspension of 3.8 g (22.1 mmol) of amine 1a and
4.14 g K2CO3 in 20 mL CH2Cl2 at vigorous stirring,
the reaction course was monitored by TLC. 3 h after
the reaction was complete, 20 mL of H2O and 30 mL
of CH2Cl2 were added, the mixture was stirred for
10 min, the organic phase was separated and dried over
Na2SO4. The solvent was evaporated, the residue was
purified by column chromatography silica gel (150 g,
eluent: petroleum ether–C6H6, 1 : 1). Yield 4.75 g
(86%), Rf 0.3 (150 g, eluent: petroleum ether–C6H6,
1
1 : 1). IR spectrum ν, cm–1: 3320 (NH). Н NMR
spectrum, δ, ppm: 1.33 t (3H, CH3), 1.70‒1.75 m, 1.77‒
1.82 m, 2.18‒2.25 m (3×2H, CH2), 4.19 q (2H, OCH2,
J = 7.1 Hz), 5.70‒5.73 m (1H, H2’), 6.82 br. s (1H,
HAr), 6.95 d. t (1H, HAr, J = 1.0, J = 7.5 Hz), 7.01 d. d
(1H, HAr, J = 1.6, J = 7.5 Hz), 7.16 d. t (1H, HAr, J =
1.6, J = 7.5 Hz), 7.99 br. s (1H, NH). 13С NMR
spectrum, δС, ppm: 14.68 (CH3), 21.99, 23.00, 25.34,
29.95 (4 CH2), 60.76 (OCH2), 122.57, 127.49, 128.00,
128.11 (C3, C4, C5, C6), 134.43, 135.91 (C1, C2),
2-(2-Cyclohex-1-en-1-ylphenyl)-1H-isoindole-1,3(2H)-
dione (2a). A solution of compound 1a (1.73 g,
10 mmol) and phthalic anhydride (1.48 g, 10 mmol) in
5 mL of DMF was heated at 180°С for 12 h. The
solvent was evaporated under reduced pressure; then
5 mL of water was added to the reaction mixture, the
substance was triturated, and water was removed by
filtration. The residue was purified via column chro-
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FUNCTIAONALIZATION OF 2-(1-CYCLOHEXEN-1-YL)ANILINE DERIVATIVES
153.00 (NCO2). Mass spectrum, m/z (Irel, %): 246.0
(100) [M + H]+, 244.2 (100) [M ‒ H]–.
1.80 m, 1.83‒1.87 m, 2.15‒2.20 m, 2.75‒2.83 m
(4×2Н, 4CH2), 2.10 s (3H, CH3), 4.33 s (1H, H2''), 7.33
d (1H, HAr, J = 7.2 Hz), 7.38 t (1H, HAr, J = 7.2 Hz),
7.42 d. d (1H, HAr, J = 0.8, J = 7.2 Hz), 7.80–7.83 m,
7.93–7.96 m, 7.99–8.10 m (4H, HPht). 13С NMR spec-
trum, δ, ppm: 18.12 (CH3), 19.76, 20.81, 30.53, 32.72
(C3'', C4'', C5'', C6''), 57.17 (C2''), 74.90 (C1''), 123.82,
124.03, 127.45, 128.91, 130.77, 134.75 (C4, C5, C6, C7,
C3', C4', C5'), 131.97, 132.06, 138.43, 144.51 (C3a, C7a,
C1', C2', C6'), 168.32, 169.41 (C1, C3). Mass spectrum,
m/z (Irel, %): 316 (60) [M – Br2 + H]+, 334 (100) [M –
Br2 + H2O + H]+.
2-{2-[(1R*,2S*)-2-Bromo-1-methoxycyclohexyl]-
6-methylphenyl}-1H-isoindole-1,3(2H)-dione (4).
2 mL of MeOH and 0.42 g (5 mmol) of NaHCO3 were
added to a solution of 2b (0.317 g, 1.0 mmol) in 5 mL
of CH2Cl2. 0.16 g (0.052 mL, 1 mmol) of Br2 in 2 mL
of CH2Cl2 was slowly added to that mixture under
vigorous stirring. The reaction mixture were stirred
until the solution become colorless, then the solution
was diluted with 30 mL of H2O at stirring and
extracted with 70 mL of CH2Cl2. The organic phase
was dried over Na2SO4. The solvent was evaporated
under reduced pressure, the residue was chromato-
graphed on column with 10 g of silica gel (eluent:
benzene) and crystallized from EtOH. Total yield
0.115 g (36%), colorless crystals, mp 110–112°C
(EtOH), Rf 0.64. IR spectrum, ν, cm–1: 1747, 1463,
2-[2-(6-Bromo-1-cyclohexen-1-yl)phenyl]-1H-
isoindole-1,3(2H)-dione (9a). 0.32 g (0.11 mL,
2.0 mmol) of Br2 in 5 mL of CH2Cl2 was slowly added
to a suspension of 0.606 g (2.0 mmol) of compound 1a
and 0.98 g (12 mmol) NaHCO3 in 10 mL CH2Cl2
under vigorous stirring. The reaction mixture was
stirred until the solution became colorless, diluted with
30 mL of H2O, and extracted with 70 mL of CH2Cl2.
The organic phase was dried over Na2SO4. The solvent
was evaporated under reduced pressure, the residue
was chromatographed through a layer of silica gel (5 g,
eluent: CHCl3). Yield 0.69 g (90%), white amorphous
1
1372, 1089, 1040. Н NMR spectrum, δ, ppm: 1.50‒
2.00 m (6H, CH2), 2.46 s (3H, CH3), 2.94 s (3H,
OCH3), 3.82 s (1H, H2''’’), 7.21 d (1H, HAr, J = 7.8 Hz),
7.24 d. t (1H, HAr, J = 1.6, J 7.8 Hz), 7.29 d. d (1H,
HAr, J = 1.0, J = 7.8 Hz), 7.58 d. t (1H, HAr, J = 2.0,
J = 7.4 Hz), 7.65–7.80 m (2H, HAr), 7.91 d. t (1H, HAr,
J = 1.0, J = 7.6 Hz). 13С NMR spectrum, δС, ppm:
18.82 (CH3), 19.15, 20.41, 29.95, 30.32 (C3'', C4'', C5'',
C6''), 51.05 (C2''), 55.01 (OCH3), 79.34 (C1''), 121.95,
124.56, 124.96, 126.07, 130.35, 131.13, 133.09 (C4,
C5, C6, C7, C3', C4', C5'), 106.88, 129.95, 130.29,
133.10, 139.19, 143.77 (C3a, C7a, C1', C2', C6'), 163.99
(C1, C3). Mass spectrum, m/z (Irel, %): 428 (100) [M + H]+.
1
powder, Rf 0.33 (CHCl3). Н NMR spectrum, δ, ppm:
1.51‒2.19 m (3×2H, 3CH2), 4.72 br. s (1H, H6''), 5.62
d. d (1H, H2''), 7.12 d. d (1H, HAr, J = 1.3, J = 7.6 Hz),
7.32‒7.38 m (1H, HAr), 7.62 d. d (1H, HAr, J = 1.6, J =
7.6 Hz), 7.68 d. d (2H, HAr, J = 3.0, J = 5.0 Hz), 7.82
d. d (2H, HAr, J = 3.0, J = 5.0 Hz). 13С NMR spectrum,
δС, ppm: 16.70, 25.18, 33.01 (C3'', C4'', C5''), 50.81
(C6''), 123.43, 123.60, 128.26, 129.02, 129.10, 130.73,
131.90, 134.04, 134.08 (C4, C5, C6, C7, C2', C3', C4', C5',
C2''), 129.63, 131.96, 135.93, 141.03 (C3а, C7а, C1', C2',
C1'', C6'), 166.93, 167.13 (C1, C3).
2-{2-[(1R*,2S*)-1,2-Dibromocyclohexyl]-6-methyl-
phenyl}-1H-isoindole-1,3(2H)-dione (6).
1
mL
(5.0 mmol) of С8H17OH and 0.42 g (5 mmol) of
NaHCO3 were added to a solution of 2b (0.317 g,
1.0 mmol) in 5 mL of CH2Cl2. Solution of 0.16 g
(0.052 mL, 1 mmol) of Br2 in 2 mL of CH2Cl2 was
slowly added dropwise to that mixture under vigorous
stirring. The reaction mixture was stirred until the
solution became colorless, diluted with 30 mL of H2O
at stirring, and extracted with 70 ml CH2Cl2. The
organic phase was dried over Na2SO4. The solvent was
evaporated under reduced pressure, the residue was
chromatographed on a column with silica gel (10 g,
eluent: С6H6). The obtained viscous substance was
triturated with petroleum ether, the white precipitate
was filtered off and dried. Yield 0.27 g (56%), mp 135–
140°С (petroleum ether), Rf 0.33 (CHCl3). IR spec-
2-[2-(6-Bromo-1-cyclohexen-1-yl]-6-methylphenyl]-
1H-isoindole-1,3(2H)-dione (9b) was obtained similarly
from 0.634 g (2.0 mmol) of compound 2b and 0.32 g
(2.0 mmol) Br2 in the presence of 0.98 g (12 mmol) of
NaHCO3. 0.55 g (70%) of purified sample was ob-
tained via column chromatography on silica gel (10 g,
eluent: benzene), mp 145–155°С (C6H6), Rf 0.34
(CHCl3). IR spectrum, ν, cm–1: 719, 1380, 1461, 1699.
1Н NMR spectrum, δ, ppm: 1.54‒1.61 m (2H, CH2),
1.86‒2.16 m (2×2H, 2CH2), 2.18 s (3H, CH3), 4.75 br. s
(1H, H6''), 5.71 d. d (1H, H2'', J = 2.4, J = 4.6 Hz), 7.29
d (1H, HAr, J = 7.6 Hz), 7.33–7.39 m (1H, HAr), 7.45 d
(1H, HAr, J = 7.6 Hz), 7.79‒7.82 m (2H, HAr), 7.91‒
7.94 m (2H, HAr). 13С NMR spectrum, δС, ppm: 16.72,
25.15, 32.97 (C3'', C4'', C5''), 18.22 (CH3), 51.29 (C6''),
1
trum, ν, cm–1: 1699, 1460, 1380, 1148, 886. Н NMR
spectrum, δ, ppm: 1.45‒1.51 m, 1.65‒1.69 m, 1.71‒
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

660
KHUSNITDINOV et al.
123.63, 123.72, 134.31, 134.37 (C4, C5, C6, C7), 128.50,
130.03 (C3', C5'), 129.18 (C4'), 131.81 (C2''), 123.77,
128.89, 131.91, 136.31, 137.03, 141.59 (C3а, C7а, C1',
C2', C1'', C6'), 167.07, 167.62 (C1, C3). Mass spectrum, m/z
(Irel, %): 316 (60) [M – Br + H]+, 334 (100) [M – Br +
H2O + H]+.
1a and 0.45 g (2 mmol) of CuBr2. The product was
isolated via silica gel column chromatography. Yield
0.45 g (80%), Rf 0.47 (C6H6). IR spectrum, ν, cm–1:
1
3360, 3465 (NH2). Н NMR spectrum, δ, ppm: 1.50‒
2.59 m (8H, CH2), 3.15 s (3H, OCH3), 5.25 q (1Н,
C2'H, J = 3.0 Hz), 5.30 br. s (2Н, NH2), 7.00–7.60 m
(4H, НAr). 13С NMR spectrum, δС, ppm: 19.70, 20.6,
24.7, 30.3 (4СН2), 50.8 (ОСН3), 53.4 (C2'), 81.3 (C1'),
109.6, 144.0 (C1, C2), 118.0, 126.7, 131.3, 132.7 (C3,
C4, C5, C6). Found, %: С 54.82; Н 6.19; Br 27.91; N
4.78. C13H18BrNO. Calculated, %: С 54.94; Н 6.38; Br
28.12; N 4.93.
2-[2-(6-Methoxycyclohex-1-en-1-yl)-6-methylphenyl]-
1H-isoindole-1,3(2H)-dione (10). A solution of 0.08 g
(0.2 mmol) of compound 9b in 3 mL of MeOH was
refluxed for 1 h and then kept at room temperature for
24 h. The solvent was evaporated under reduced
pressure, and the residue was chromatographed on a
column with silica gel (2 g, eluent: CHCl3). Yield 0.06 g
(86%), mp 110–114°С, Rf 0.75 (CHCl3). IR spectrum,
4-Bromo-2-(1-methoxy-2-bromo-1-cyclopentyl)-
6-methylaniline (12b) was obtained similarly from
0.35 g (2 mmol) of aniline 11b and 0.9 g (4 mmol) of
CuBr2. The product was isolated via silica gel column
chromatography. Yield 0.61 g (85%), Rf 0.67 (C6H6).
1
ν, cm–1: 1699, 1460, 1380, 1148, 886. Н NMR spec-
trum, δ, ppm: 1.20‒2.09 m (6Н, CH2), 2.20 s (3H,
CH3), 3.20 s (3H, OCH3), 3.62 s (1H, H6''), 5.65 d. d
(1H, H2'', J = 1.4, J = 2.9 Hz), 7.24 d (1H, HAr, J =
7.0 Hz), 7.28‒7.37 m (2H, HAr), 7.74‒7.79 m (2H,
HPht), 7.85‒7.94 m (2H, HPht). 13С NMR spectrum, δС,
ppm: 18.12 (CH3), 16.60, 25.46, 26.56 (C3'', C4'', C5''),
56.99 (ОCH3), 75.66 (C6''), 123.33, 123.55, 127.91,
129.02, 129.34, 130.84, 133.98, 134.05 (C4, C5, C6, C7,
C3', C4', C5', C2''), 128.69, 132.08, 135.79, 136.76,
142.77, 144.51 (C3a, C7a, C1', C2', C6', C1''), 167.20,
167.46 (C1, C3). Mass spectrum, m/z (Irel, %): 348 [M +
H]+ (10), 316 [M ‒ CH3OH + H]+ (100).
1
IR spectrum, ν, cm–1: 3370, 3460 (NH2). Н NMR
spectrum, δ, ppm: 1.70‒2.05 m (2H, C4'H2), 2.16 s
(3H, CH3), 2.19‒2.37 m (2H, C5'H, C3'H), 2.59 d. t
(1Н, C5'H, J = 10.0, J = 13.8 Hz), 2.68‒2.82 m (1Н,
C3'H), 3.09 s (3Н, OСН3), 4.51 br. s (2Н, NH2), 5.08 d.
d. d (1Н, Н2', J = 1.2, J = 1.6, J = 6.3 Hz), 7.13 d (1H,
13
НAr, J = 2.2,), 7.17 d (1H, НAr, J = 2.2 Hz). С NMR
spectrum, δС, ppm: 17.50 (CH3), 19.3, 27.6, 34.8,
(3СН2), 51.4 (C2'), 54.5 (ОСН3), 92.8 (C1'), 106.4,
124.2, 124.4, 143.4 (C1, C2, C4, C6), 130.1, 132.7 (C3,
C5). Found, %: С 42.79; Н 4.58; Br 43.82; N 3.68.
C13H17Br2NO. Calculated, %: С 43.00; Н 4.72; Br
44.01; N 3.86.
4-Bromo-2-(1-methoxy-2-bromo-1-cyclohexyl)-
aniline (12a). 0.9 g (4 mmol) CuBr2 was added to a
solution of 0.35 g (2 mmol) aniline 1a in 10 mL of
MeOH. The reaction mixture was kept at room
temperature for 24 h, then it was diluted with 50 mL of
H2O under vigorous stirring, and the product was
extracted with 70 ml of CH2Cl2. The organic phase
was dried over Na2SO4, the solvent was evaporated
under reduced pressure, the residue was chromato-
graphed on a silica gel column (40 g, eluent: C6H6).
Yield 0.57 g (79%), Rf 0.66 (C6H6). IR spectrum, ν, cm–1:
2-(1-Methoxy-2-bromo-1-cyclopentyl)-6-methyl-
aniline (13b) was obtained by further eluting from the
chromatography column (cf. the previous experiment).
Yield 0.06 g (11%), Rf 0.45 (C6H6). IR spectrum, ν, cm–1:
1
3370, 3460 (NH2). Н NMR spectrum, δ, ppm: 1.70‒
2.05 m (2H, C4H2), 2.14 s (3H, CH3), 2.15‒2.35 m
(2H, C5'H, C3'H), 2.55 d. t (1Н, C5’H, J = 10.0, J =
13.8 Hz), 2.65‒2.78 m (1Н, C3'H), 3.10 s (3Н, OСН3),
4.45 br. s (2Н, NH2), 5.05 d. d. d (1Н, Н2', J = 1.2, J =
1.6, J = 6.3 Hz), 7.15‒7.39 m (3H, НAr). 13С NMR
spectrum, δС, ppm: 17.50 (CH3), 19.1, 27.3, 34.7
(3СН2), 51.1 (C2'), 54.0 (ОСН3), 92.50 (C1'), 106.2,
124.3, 143.6 (C1, C2, C6), 124.3, 130.2, 132.7 (C3, C4,
C5). Found, %: С 54.75; Н 6.34; Br 27.86; N 4.81;
C13H18BrNO. Calculated, %: С 54.94; Н 6.38; Br
28.12; N 4.93.
1
3360, 3465 (NH2). Н NMR spectrum, δ, ppm: 1.50‒
2.55 m (8H, CH2), 3.12 s (3H, OCH3), 5.18 q (1Н,
C2'H, J = 3.0 Hz), 5.22 br. s (2Н, NH2), 7.10 d (1H,
НAr, J = 2.2), 7.37 d. t (1H, НAr, J = 2.2, J = 7.6 Hz),
7.52 d (1H, НAr, J = 7.6 Hz). 13С NMR spectrum, δС,
ppm: 19.70, 20.4, 24.9, 29.9 (4СН2), 50.6 (ОСН3),
52.9 (C2'), 81.2 (C1'), 109.3, 127.0, 144.3 (C1, C2, C4),
118.1, 131.1, 132.5 (C3, C5, C6). Found, %: С 42.85; Н
4.59; Br 43.75; N 4.28. C13H17Br2NO. Calculated, %:
С 43.00; Н 4.72; Br 44.01; N 4.41.
2-(1-Methoxy-2-bromo-1-cyclohexyl)-4-(1-methyl-
but-2-en-1-yl)-6-methylaniline (13c) was obtained
via the reaction of 0.69 g (2.7 mmol) of amine 1c [37]
and 1.22 g (5.5 mmol) of CuBr2 in 10 mL of MeOH.
2-(1-Methoxy-2-bromo1-cyclohexyl)aniline (13a)
was obtained similarly from 0.35 g (2 mmol) of aniline
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

661
FUNCTIAONALIZATION OF 2-(1-CYCLOHEXEN-1-YL)ANILINE DERIVATIVES
10. Xu, G., Wei, H., Ren, Y., Yin, J., Wang, A., Zhang, T.,
Green Chem., 2016, vol. 18, p. 1332. doi 10.1039/
c5gc01914a
11. Chainikova, E.M., Pankratyev, E.Yu., Teregulova, A.N.,
Gataullin, R.R., and Safiullin, R.L., J. Phys. Chem. (A),
2013, vol. 117, no. 13, p. 2728. doi 10.1021/jp401038g
The product was isolated via silica gel column chro-
matography (25 g, eluent: C6H6). Yield 0.79 g (80%),
Rf 0.66 (C6H6). IR spectrum, ν, cm–1: 3370, 3465
(NH2). 1Н NMR spectrum, δ, ppm: 1.29 d. d (3H, CH3,
J = 1.0, J = 7.0 Hz), 1.69 d. d (3H, CH3, J = 1.0, J =
6.2 Hz), 1.50‒2.59 m (8H, 4CH2), 2.16 s (3H, CH3),
3.10 s (3H, OCH3), 3.27 q (1H, H1'', J = 7.0 Hz), 4.50
br. s (2Н, NH2), 5.30 d. d (1Н, Н2', J = 1.2, J = 6.2 Hz),
5.35‒5.65 m (2Н, HC=CH), 6.75 s (1H, НAr), 6.85 s
(1H, НAr). 13С NMR spectrum, δС, ppm: 17.90, 17.95,
21.37 (3CH3), 19.9, 20.5, 25.2, 30.0 (4СН2), 41.41
(CH1'''), 50.4 (C2'), 54.1 (ОСН3), 81.7 (C1'), 122.2,
124.0, 133.7, 141.3 (C1, C2, C4, C6), 122.8, 126.7,
128.5, 136.9 (C3, C5, C2''', C3''''). Found, %: С 62.08; Н
7.57; Br 21.54; N 3.72. C19H28BrNO. Calculated, %: С
62.29; Н 7.70; Br 21.81; N 3.82.
12. Brucelle, F. and Renaud, P., J. Org. Chem., 2013,
vol. 78, no. 12, p. 6245. doi 10.1021/jo4009904
13. Reding, M.T., Kabaragi, Y., Tokuyama, H., and
Fukuyama, T., Heterocycles, 2002, vol. 55, nos. 1–2,
p. 313. doi 10.3987/COM-01-S(K)42
14. Xu, H.-D., Jia, Z.-H., Xu, K., Zhou, H., and Shen, M.-H.,
Org. Lett., 2015, vol. 17, no. 1, p. 66. doi 10.1021/
ol503247t
15. Xiao, Y.-C. and Moberg, C., Org. Lett., 2016, vol. 18,
no. 2, p. 308. doi 10.1021/acs.orglett.5b03479
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Tetrahedron Lett., 2001, vol. 42, no. 22, p. 3737. doi
10.1016/S0040-4039(01)00552-4
FUNDING
17. Gataullin, R.R., Kazhanova, T.V., Karachurina, L.T.,
Il’yasova, L.T., Davydova, V.A., Sapozhnikova, T.A.,
Zarudii, F.S., and Abdrakhmanov, I.B., Pharm. Chem.
J., 2001, vol. 35, no. 9, p. 493. doi 10.1023/
A:1014094709169
18. Gataullin, R.R., Khaziev, E.V., Khusnutdinov, R.N.,
Borisov, I.M., and Abdrakhmanov, I.B., Russ. J. Appl.
Chem., 2001, vol. 74, no. 11, p. 1910. doi 10.1023/
A:1014809214971
This study was performed in the scope of the govern-
mental task (topic no. AAAA-A19-119011790021-4).
CONFLICT OF INTEREST
No conflict of interest was declared by authors.
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