Synthesis of 6-Bromo-3a,4-dihydrobenzo[f]isoindolinium Bromides and Their Aqueous-Alkaline Cleavage

Article abstract of DOI:10.1134/S1070428019080104

Cyclization of allyl[3-(4-bromophenyl)prop-2-ynyl]ammonium bromides under basic catalysis conditions, unlike their propargyl analogs, occurs under heating of the reaction mixture at 90–92°C. Cyclization, which is the main reaction route, is accompanied by

Full text of DOI:10.1134/S1070428019080104

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 8, pp. 1124–1130. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 8, pp. 1215–1222.
Synthesis of 6-Bromo-3a,4-dihydrobenzo[f]isoindolinium
Bromides and Their Aqueous-Alkaline Cleavage
a
a,
a
E. O. Chukhajian , L. V. Ayrapetyan *, H. S. Mkrtchyan ,
a
a
El. O. Chukhajian , and H. A. Panosyan
a
The Institute of Organic Chemistry of the Scientific Technological Centre of Organic and Pharmaceutical Chemistry of NAS
of Republic of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
*
e-mail: shhl@mail.ru
Received March 15, 2019; revised May 10, 2019; accepted May 15, 2019
Abstract—Cyclization of allyl[3-(4-bromophenyl)prop-2-ynyl]ammonium bromides under basic catalysis
conditions, unlike their propargyl analogs, occurs under heating of the reaction mixture at 90–92°C.
Cyclization, which is the main reaction route, is accompanied by rearrangement–cleavage to form 1-allyl-p-bromo-
cinnamaldehyde. A favorable effect of the substituents on the nitrogen atom and the presence of the bromine atom
in the 4 position of the aromatic ring on the cyclization and rearrangement–cleavage reactions is established.
Keywords: 1-allyl-p-bromocinnamaldehyde, allyl[3-(4-bromophenyl)prop-2-ynyl]ammonium bromides, 6-
bromo-3a,4-dyhydrobenzo[f]isoindolinium bromides, base-catalyzed intramolecular cyclization, isomeric 2-
dialkylaminomethyl-7-bromo-3-methylnaphthalenes, 3-dialkylaminomethyl-7-bromo- 2-methylnaphthalenes,
rearrangement–cleavage, aqueous-alkaline cleavage.
DOI: 10.1134/S1070428019080104
We earlier showed that propagyl[3-(4-bromo-
phenyl)prop-2-ynyl]ammonium bromides, except for
their dimethyl analog, in the presence of alkali
0.2 mol per mole salt) at room temperature undergo
cyclization accompanied by self-heating and form 6-
The obtained results give grounds to say that the
phenyl group in the 3 position of the allylic system
favors cyclization, like this is the case with bis-(3-
phenylprop-2-ynyl) salts [9]. This phenomenon is the
only precedent of the base-catalyzed intramolecular
cyclization of ammonium salts containing an allylic
group along with 3-arylprop-2-ynyl [3–6].
(
bromobenzo[f]isoindolinium bromides in high yields
1, 2].
[
These results provide evidence for the cyclization
mechanism proposed in [10, 11], as well as are
consistent with published data, according to which
diene synthesis involves nucleophilic addition of diene
to dienophile. Since the phenyl group in the 3 position
of the allylic system in comparison with hydrogen
atom increases the positive charge of the dienophile,
thereby facilitating nucleophilic addition.
As known, the cyclization of ammonium salts
containing an allylic-type group along with various 3-
arylprop-2-ynyl fragments in the presence of alkali
(
0.2 mol per mole salt) occurs under heating at 90–92°C
for 2 h [3–5]; along with cyclization, which is the main
reaction route, take place also rearrangement–cleavage
reaction. It should be noted that with [3-(naphthalene-
1
-yl)prop-2-ynyl] analogs take place only cyclization
under the above conditions [6]. In our recent
works [7, 8] we found that (3-phenylprop-2-enyl)(3-
arylprop-2-ynyl)ammonium bromides, unlike the
above salts [6], undergo base-catalyzed cyclization
under heating at 40–45°C for 6–15 min. Under
these conditions, the heterogeneous system
undergo homogenization followed by cyclization
with self-heating. The yields of cyclic products are
high.
Aimed at developing and extending the scope of the
base-catalyzed intramolecular cyclization, in the
present work we planned to study cyclization of allyl
[3-(4-bromophenyl)prop-2-ynyl]ammonium bromides.
If positive results were obtained, we could prepare
potentially biologically active 6-bromo-3а,4-dihydro-
benzo[f]isoindolinium bromides hardly accessible by
other synthetic routes. We also expected to reveal the
effect of substituents at the nitrogen atom and in the
1
124

SYNTHESIS OF 6-BROMO-3a,4-DIHYDROBENZO[f]ISOINDOLINIUM BROMIDES
1125
Scheme 1.
H
Br
+
OH–
Br
+
R N
2
+
R N
2
R N
Br
2
Br–
Br–
CH2
Br–
1
a–1e
2a–2e
OH–
HC
CH2
Br
R NH
2
+
HC
C
H
O
C
H
1
2 2 4 2 2 5 2 2 2 2 2
, 2 R = Me (а), R = Et (b), R = –(CH ) – (c), R = –(CH ) – (d), R = –(CH ) O(CH ) – (e).
aromatic ring on cyclization and rearrangement–
cleavage and to obtain further evidence for the
proposed cyclization mechanism. To achieve the above
goals, we performed by alkylation of dimethyl-,
diethylamines and pyrrolidine, piperidine and
morpholine with allyl bromide in acetonitrile medium
were synthesized test salts: bromides of dimethyl- (1а)
and diethyl(allyl)[3-(4-bromophenyl)prop-2-ynyl]am-
monium (1b), as well as allyl[3-(4-bromophenyl)prop-
kinetic study in [12], which showed that the rate of
cyclization of salt 1b is much higher compared to the
other salts. It should be noted that the reaction with
piperidinium salt 1d was performed by stepwise
adding 0.3 mol of alkali per 1 mol of the starting salt,
because alkali is consumed for rearrangement–
cleavage and, therefore, part of the starting salt does
not have time to undergo cyclization. Judging from the
yields of cyclic products, we can suggest that alkyl
substituents on the nitrogen atom favor cyclization [11]
(Scheme 1). The fairly low yields of cyclic products
from piperidinium 1d and morpholinium 1e salts can
be explained by that the bromine substituent favors
rearrangement–cleavage.
2
-ynyl]-pyrrolidinium (1с), -piperidinium (1d), and –
morpholinium bromides (1е). Cyclization of salts 1а–
е occurred according to the mechanism proposed in
10, 11]. Actually, the IR spectral study undertaken to
1
[
establish the cyclization mechanism showed that the
enyne moiety was directly involved in intramolecular
4
Our study allowed to develop a practical method of
synthesis of potentially biologically active 2,2-dialkyl-
cyclization as a π -fragment [10], and alkali was a
driving force of this process [11].
6
3
-bromo-3а,4-dihydrobenzo[f]isoindolinium, 6-bromo-
а,4-dihydrobenzo[f]-pyrrolidinium and -piperidinium,
The yields of cyclic products 2a–2e were 70, 85,
8
0, 72, and 71%, respectively.
and 6-bromo-3а,4-dihydro[spirobenzo[f]isoindolin]-
2
,4'-morpholinium bromides.
Along with cyclization, we also observed rearran-
gement–cleavage to form 1-allyl-p-bromocynnam-
aldehyde in yields of 15, 20, 18, and 20% from salts
Salts 2а, 2b, 2d, and 2e underwent smooth 1,2- and
,6-cleavage in aqueous alkali to form a mixture of
isomeric 3-dialkylaminomethyl-2-methyl- and 2-
dialkylaminomethyl-3-methyl-7-bromonaphthalenes in
total yields of 57–60% (Scheme 2).
1
1
a, 1c, 1d, and 1e, respectively. In the case of salt 1b,
the yield of the rearrangement–cleavage product is as
low as 6%. The fact that the yields of cyclization
product from salt 1b is 85%, whereas the yield of the
rearrangement–cleavage product is 6% can be
considered as evidence showing that the ethyl
substituents on the nitrogen atom favor cyclization.
These data are consistent with the mechanism
proposed in [10, 11], as well as with the results of the
1
13
According to Н and С NMR, the estimated ratios
of the isomeric amines in the mixtures were as follows:
3а : 4а = 5.5 : 4.5; 3b : 4b = 4.4 : 5.6; 3d : 4d = 6 : 4;
and 3e : 4e = 6 : 4. Hydrochlorides of analogous dialkyl-
aminomethylnaphthalenes are known to show anti-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019

1
126
CHUKHAJIAN et al.
Scheme 2.
Me
Br
CH2
Br
1
,2-
H
R N
2
R N
2
Br
+
3
a, 3b, 3d, 3e
R N
2
Br–
1
,6-
Br
Br
R N
2
2a, 2b, 2d, 2e
R N
2
H
Me
a, 4b, 4d, 4e
CH2
4
3
, 4, R = Me (a), R = Et (b), R
2
2 5 2 2 2 2 2
= –(CH ) – (d), R = –(CH ) O(CH ) – (e).
acetylcholine, antihistamine, as well as papaverine-
and atropine-like activities [13]. It is not excluded that
the synthesized dialkylaminomethylnaphthalenes 3а,
Abramyan and Sargsyan method [14]. The melting
points were measured on a Wägetechnik Rapido
melting point apparatus. The purity of cyclic salts was
checked by TLC on Silufol UV-254 plates; eluent p-
3
b, 3d, 3e and 4а, 4b, 4d, 4e may, too, exhibit such
activities.
BuOH–EtOH–H O–AcOH, 10 : 2 : 1 : 5; visualization
2
by exposure to iodine vapor.
The structures of [3-(4-bromophenylprop-2-ynyl)]-
pyrrolidine, initial salts 1а–1e, cyclization products
а–2e, 1-allyl-p-bromocinnamaldehyde, and isomeric
amines 3а, 3b, 3d, 3e and 4а, 4b, 4d, 4e were
established by IR and Н and С NMR spectroscopy,
using 2D NMR techniques (DEPT, HMQC, NOESY)
for signals assignment.
The starting dialkyl[3-(4-bromophenyl)prop-2-
ynyl]amines were synthesized according to [2].
2
The previously unknown 1-[3-(4-bromophenyl-
prop-2-ynyl)]pyrrolidine was prepared by the
reaction of 2.8 g (4 mmol) of pyrrolidin-1-amine, 1.2 g
1
13
(
4 mmol) of Paraform, and 7 g (4 mmol) of p-bromo-
Thus, dialkyl(allyl)[3-(4-bromophenyl)prop-2-ynyl]
ammonium, as well as allyl[3-(4-bromophenyl)prop-2-
ynyl]-pyrrolidinium, -piperidinium, and -morpholi-
nium bromides undergo base-catalyzed cyclization to
form in high yields 6-bromo-3а,4-dihydrobenzo[f]-
isoindolinium bromides hardly accessible by other
synthetic routes. Alongside with cyclization, which is
the preferential reaction direction, take rearrangement–
cleavage reaction. The synthesized cyclic salts undergo
smooth 1,2- and 1,6-cleavage in an aqueous alkaline
medium.
phenylacetylene in 70 mL of dioxane in the presence
of 0.15 g of copper diacetate and 0.2 g of iron(III)
chloride. The reaction mixture was heated for 70 h at
90–95°С and then made acidic with 25% HCl. The
solvent was removed at reduced pressure, and the
residue was treated with ether (2 × 60 mL) to separate
unreacted (p-bromophenyl)acetylene, after which it
was made alkaline and treated with ether (3 × 70 mL).
The ethereal extract was dried over MgSO , the solvent
4
was distilled off, and the product was isolated by
vacuum distillation. Yield 5 g (47%), bp 139–140°С
(
3–4 mm Hg), mp 172°С (picrate; from EtOH). IR
–
1
EXPERIMENTAL
spectrum, ν, cm : 2230 (disubstituted C≡C bond),
8
1
40–810 (para-substituted benzene ring). Н NMR
The IR spectra were registered on a Specord 75 IR
spectrum (300.09 MHz, DMSO-d + CCl ), δ, ppm (J,
6
4
1
13
spectrophotometer in CHCl . The Н and С NMR
Hz): 1.70–1.84 m (4H, β,β'-CH ), 2.52–2.64 m (4H,
3
2
spectra were obtained on a Varian Mercury 300 VX
spectrometer (300 and 75 MHz, respectively) in a 1 : 3
α,α'-CH ), 3.55 s (2H, CH –C≡C), 7.25–7.30 m
(2Harom), 7.42–7.46 m (2Harom). C NMR spectrum
2
2
1
3
DMSO-d –CCl4 mixture, internal reference TMS.
(75.47 MHz, DMSO-d + CCl ), δ, ppm: 23.3 (β-CH ),
6
6
4
2
Analysis for C, H, and N was performed on a Vario
Micro cube analyzer, and analysis for Br , by the
42.7 (CH –C≡C), 51.5 (α-CH ), 82.7 and 86.5 (C≡C),
121.2, 121.8, 130.9 (2-CH), 132.5 (2-СН). Found, %:
2 2
–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019

SYNTHESIS OF 6-BROMO-3a,4-DIHYDROBENZO[f]ISOINDOLINIUM BROMIDES
1127
С 59.39; H 5.44; N 5.15; Br 30.46. C H NBr.
C H Br N. Calculated, %: C 49.64; H 5.47; Br 41.28;
16 21 2
1
3
14
Calculated, %: С 59.11; H 5.34; N 5.30; Br 30.25.
N 3.62.
Synthesis of 2,2-dialkyl(allyl)[3-(4-bromophenyl)-
prop-2-ynyl]ammonium and allyl[3-(4-bromophe-
nyl)prop-2-ynyl]pyrrolidinium, -piperidinium, and
Allyl-[3-(4-bromophenyl)prop-2-ynyl]pyrrolidi-
nium bromide (1с). Yield 2.5 g (80%), white crystals,
–
1
mp 145–146°C (abs. EtOH). IR spectrum, ν, cm :
3020, 1580 (aromatic ring), 2230 (disubstituted C≡C
bond), 1640, 990, 925 (unconjugated C=C bond), 845–
-
morpholinium bromides (general procedure). To a
solution of 8 mmol of corresponding dialkyl[3-(4-
bromophenyl)prop-2-ynyl]amine in 5 mL of MeCN
and 10 mL of absolute ether (in the case of pyrroli-
dinium 1с and morpholinium 1e salts, in MeCN
exclusively) was added 1.45 g (12 mmol) 3-bromo-1-
phenylprop-1-ene [15], the mixture was left to stand
for 2–3 h at room temperature, and the white crystals
of salts 1а–1e were filtered off.
1
820 (p-substituted benzene ring). Н NMR spectrum
(300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz):
6
4
2.19–2.32 m (4H, β-CH ), 3.76–3.89 m (4H, α-CH ),
2
2
4.29–4.40 m (2H, CH2allyl), 4.74 s (2H, CH –C≡C),
2
5.67 d.d (1H, =CH , J 10.1, 1.7), 5.81 d.d.t (1H, =CH ,
2
2
J 16.8, 1.7, 1.0), 6.18 d.d.t (1H, =CH, J 16.8, 10.1, 7.2),
1
3
7.50–7.57 m (4Harom). C NMR spectrum (75.47 MHz,
DMSO-d6 + CCl ), δ, ppm: 21.7 (β-CH ), 50.9
4
2
Allyl(dimethyl)[3-(4-bromophenyl)-prop-2-ynyl]-
ammonium bromide (1a). Yield 2.9 g (98%), white
crystals, mp 185–187°C (abs. EtOH). IR spectrum, ν,
(
CH2allyl), 61.0 (α-CH ), 62.5 (CH –C≡C), 79.1 (C≡C),
2 2
8
8.3 (C≡C), 119.4, 123.1, 126.0 (=CH), 127.1 (=СН2),
–
1
131.2 (2-СНarom), 133.3 (2-СНarom). Found, %: C
9.85; H 5.58; Br 41.49; N 3.51. C H Br N.
cm : 3020, 3010, 1580 (aromatic ring), 2230 (disubs-
4
1
6
21
2
tituted C≡C bond), 1640, 995, 925 (unconjugated C=C
1
Calculated, %: C 49.64; H 5.47; Br 41.28; N 3.62.
bond), 840–810 (p-substituted benzene ring). Н NMR
spectrum (300.09 MHz, DMSO-d + CCl ), δ, ppm (J,
Allyl-[3-(4-bromophenyl)prop-2-ynyl]piperidi-
6
4
Hz): 3.31 s [6H, N(CH ) ], 4.34 d (2H, CH –CH=CH ,
nium bromide (1d). Yield 2.7 g (85%), white crystals,
3
2
2
2
–
1
J 7.4), 4.81 s (2H, CH –C≡C), 5.70 d.d (1H, =CH , J
mp 135–136°C (abs. EtOH). IR spectrum, ν, cm :
3010, 1610 (aromatic ring), 2230 (disubstituted C≡C
bond), 1630, 995, 925 (unconjugated C=C bond), 840,
2
2
1
0.0, 1.7), 5.79 d.d (1H, =CH , J 16.8, 1.6), 6.16 d.d.t
2
1
3
(
1H, =CH, J 16.8, 10.0, 7.4), 7.50–7.58 m (4Harom). C
1
NMR spectrum (75.47 MHz, DMSO-d + CCl ), δ,
825 (p-substituted benzene ring). Н NMR spectrum
6
4
ppm: 49.1 (CH ), 53.6 (CH ), 64.8 (CH ), 78.4 and
(300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz):
3
2
2
6
4
8
9.2 (C≡C), 119.4 (C H ), 123.1 (C H ), 125.3
1.69–1.80 m (2H, CH ), 1.90–2.06 m (4H, α-CH ),
6
4
6
4
2
2
(
=СН ), 127.8 (=CH), 131.2 (2-СН, C H ), 133.3 (2-
3.65–3.79 m [2H, N(CH ) ], 4.35 br.d (2H, CH –
2 2 2
2
6
4
СН, C H ). Found, %: C 47.04; H 4.89; Br 44.72; N
CН=CH , J 7.3), 4.79 s (2H, CH –C≡C), 5.68 br.d.d
6
4
2
2
3
4
.74. C H Br N. Calculated, %: C 46.83; H 4.77; Br
4.5; N 3.9.
(1H, =CH , J 10.0, 1.7), 5.82 br.d.d (1H, =CH , J 16.8,
2 2
1
4
17
2
1.7), 6.15 d.d.t (1H, =CH, J 16.8, 10.0, 7.3), 7.53 s
13
(
4Harom). C NMR spectrum (75.48 MHz, DMSO-d +
6
Allyl(diethyl)[3-(4-bromophenyl)-prop-2-ynyl]-
CCl ), δ, ppm: 19.1 (2-CH ), 20.3 (CH ), 49.6 (NCH ),
4
2
2
2
ammonium bromide (1b). Yield 2.7 g (89%), white
crystals, mp 155–157°C (abs. EtOH). IR spectrum, ν,
cm : 3010, 1600 (aromatic ring), 2230 (disubstituted
C≡C bond), 1640, 995, 920 (unconjugated C=C bond),
8
5
7.4 [N(CH ) ], 60.8 (NCH ), 78.1 (C≡C), 89.3 (C≡C),
2 2 2
–
1
119.5 (CBr), 123.1, 124.7 (=CH), 127.6 (=СН
2-СН), 133.3 (2-СН). Found, %: C 51.36; H 5.42; Br
40.24; N 3.43. C17 N. Calculated, %: C 51.15; H
.3; Br 40.03; N 3.51.
2
), 131.2
(
1
H21Br
2
45–825 (p-substituted benzene ring). Н NMR
5
spectrum (300.09 MHz, DMSO-d + CCl ), δ, ppm (J,
6
4
Hz): 1.42 t (6H, CH , J 7.2), 3.57 q (4H, CH –CH , J
Allyl-[3-(4-bromophenyl)prop-2-ynyl]morpholi-
nium bromide (1e). Yield 2.6 g (82%), white crystals,
3
2
3
7
.2), 4.21 br.d (2H, CH2allyl, J 7.2), 4.69 s (2H, CH2–
–
1
C≡C), 5.67 d.d (1H, =CH , J 10.1, 1.6), 5.81 d.d (1H,
mp 185–186°C (abs. EtOH). IR spec-trum, ν, cm :
3020, 1580 (aromatic ring), 2230 (di-substituted C≡C
bond), 1630, 990, 925 (unconjugated C=C bond), 840,
2
=
CH , J 16.8, 1.6), 6.15 d.d.t (1H, =CH, J 16.8, 10.1,
2
1
3
7
.2), 7.49–7.58 m (4Harom). C NMR spectrum
1
(
75.47 MHz, DMSO-d + CCl ), δ, ppm: 7.3 (CH ),
820 (p-substituted benzene ring). Н NMR spectrum
6
4
3
4
8.8 (CH2allyl), 53.7 (CH –CH ), 60.2 (CH –C≡C), 78.3
(300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz): 3.69–
2
3
2
6
4
(
(
C≡C), 88.9 (C≡C), 119.4 (CBr), 123.1 (Cipso), 125.1
=CHallyl), 127.1 (=СН2allyl), 131.2 (2-СН), 133.3 (2-
3.83 m [4H, O(CH ) ], 4.00–4.15 m [4H, N(CH ) ],
2 2 2 2
4.51 d (2H, CH –CН=CH , J 7.3), 4.95 s (2H, CH –
2
2
2
СН). Found, %: C 49.86; H 5.61; Br 41.48; N 3.51.
C≡C), 5.71 br.d.d (1H, =CH , J 9.9, 1.7), 5.86 br.d.d
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019

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128
CHUKHAJIAN et al.
(
9
(
5
(
1
1H, =CH , J 16.9, 1.7), 6.18 d.d.t (1H, =CH, J 16.9,
.9, 7.3), 7.51–7.59 m (4Harom). C NMR spectrum
6-Bromo-2,2-dimethyl-3а,4-dihydrobenzo[f]iso-
indolinium bromide (2а). Yield 1.5 g (70%), white
crystals, mp 247–250°C (abs. EtOH). IR spectrum, ν,
2
1
3
75.47 MHz, DMSO-d + CCl ), δ, ppm: 50.1 (CH ),
6 4 2
–
1
6.3 [N(CH ) ], 59.5 [O(CH ) ], 61.1 (CH ), 77.8
cm : 1610, 1580 (aromatic ring), 880–875, 825–805
2
2
2 2
2
1
C≡C), 89.7 (C≡C), 119.4 (CBr), 123.1, 124.4 (=CH),
28.1 (=СН ), 131.2 (2-СН), 133.4 (2-СН). Found, %:
(1,2,4-substituted benzene ring). Н NMR spectrum
(300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz): 2.68
2
6
4
C 48.12; H 4.89; Br 40.01; N 3.38. C H Br NO.
t (1H, CH , J 15.6, 15.2), 3.01 d.d (1H, CH , J 15.2,
1
6
19
2
2
2
Calculated, %: C 47.91; H 4.77; Br 39.84; N 3.49.
6.3), 3.17 s (3H, CH
3
), 3.21–3.44 m (1H, CH), 3.30 s
(
3H, CH ), 3.58 d.d (1Н, NCH CH, J 11.3, 10.5), 4.01
3 2
Intramolecular cyclization of salts 1a–1e (general
procedure). To a solution of 6 mmol of salt 1а–1e in
d.d (1H, NCH CH, J 11.3, 8.0), 4.37 d.t (1H,
NCH =CH, J 16.2, 2.3), 4.46 br.d (1H, NCH =CH, J
1
8
C H ). C NMR spectrum (75.47 MHz, DMSO-d +
CCl ), δ, ppm: 30.5 (CH ), 35.5 (CH), 51.8 (CH ), 52.4
2
2
2
3
.5 mL of water, 0.4 mL of 3 N KOН (salt : alkali
6.2), 6.63 q (1H, =CH, J 2.4), 7.13 d (1H, C H , J
6 3
molar ratio 5 : 1) was added. No self-heating was
observed. The reaction mixture was heated at 75–80°С
for 2.5 h and then treated with ether (2 × 35 mL) to
remove by-products. Cyclic salts 2а–2e were isolated
from the reaction mixture by filtration. Titration
revealed 10–20% of secondary amines in the ethereal
extract. The ethereal extract was made acidic with
HCl. The HCl solution was made basic and extracted
to isolate secondary amines: dimethylamine,
dimethylpyrro-lidine, dimethylpiperidine, and
dimethylmorpholine; their picrates melted at 154–155,
.0), 7.40 d.d (1H, C H , J 8.0, 1.9), 7.44 br.s (1H,
6
3
1
3
6
3
6
4
2
3
(CH ), 67.1 (NCH ), 68.8 (NCH ), 119.9, 120.3
3 2 2
(
=CH), 128.0 (CHarom), 129.7 (CHarom), 130.5 (CHarom),
1
4
4
32.6, 136.1, 137.1. Found, %: C 47.17; H 4.72; Br
4.84; N 3.79. C H Br N. Calculated, %: C 46.96; H
14
16
2
.5; Br 44.63; N 3.91.
6-Bromo-2,2-diethyl-3а,4-dihydrobenzo[f]iso-
indolinium bromide (2b). Yield 2.0 g (85%), white
crystals, mp 218–220°C (abs. EtOH). IR spectrum, ν,
cm : 3030, 1590 (aromatic ring), 820–805, 885–875
(1,2,4-substituted benzene ring). Н NMR spectrum
(300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz): 1.35
t (3H, CH , J 7.3), 1.38 t (3H, CH , J 7.3), 2.83 d.d
(1H, CH , J 15.2, 15.0), 2.98 d.d (1H, CH , J 15.2,
6.5), 3.26–3.42 m (1H, CH), 3.44–3.58 m (2H,
1
30, 145, and 140°С, respectively, and gave no
–
1
melting point depression with the authentic samples.
Diethylamine hydro-chloride melted at 223–224°С and
gave no melting point depression with the authentic
sample. The ethereal extract that contained a nonamine
product was washed with water and dried over CaCl2.
The ether was distilled off, and the residue was
1
6
4
3
3
2
2
distilled in
a
vacuum to isolate 1-allyl-p-
СН CH ), 3.66 q (2H, СН CH , J 7.3), 3.73 d.d (1H,
2
3
2
3
bromocinnamaldehyde. The yields of the latter from
NCH , J 11.6, 10.0), 4.21 d.d (1H, NCH , J 11.6, 8.4),
2
2
salts 2а–2e were 15, 6, 20, 18, and 20%, respectively.
4.57 d.t (1H, NCH
2
, J 16.5, 2.2), 4.60 d.t (1H, NCH , J
2
1
8
C
6.5, 2.0), 6.61 br.s (1H, =CH), 7.06 d (1H, C H , J
6 3
1
-Allyl-p-bromocinnamaldehyde, bp 88–94°С (2–
.0), 7.30 d.d (1H, C H , J 8.0, 1.8), 7.34 br.s (1H,
6 3
3
mmHg), mp 193–195°С (hydrazone). IR spectrum, ν,
1
3
–
1
6
H ). C NMR spectrum (75.47 MHz, DMSO-d +
3
6
cm : 3090, 1590 (aromatic ring), 1700 (carbonyl
group conjugated with the double bond), 1630, 840,
CCl ), δ, ppm: 8.2 and 8.4 (2-CH ), 31.0 (CH ), 34.9
4
3
2
(
CH), 53.4 (NCH ), 54.8 (NCH ), 63.9 (NCH ), 64.8
2 2 2
8
00 (terminal vinyl bond), 880, 840, 800 (p-substituted
benzene ring). According Н and С NMR, two stereo-
isomers were isolated in a 95 : 5 ratio. Н NMR spec-
trum (300.09 MHz, DMSO-d + CCl ), δ, ppm (J, Hz):
.21 d.t (2Н, CH , J 5.6, 1.8), 5.01 d.t.d (1H, =CH , J
7.2, 1.8, 1.6), 5.05 d.t.d (1H, =CH , J 10.3, 1.8, 1.6),
.87 d.t.d (1H, =CHallyl, J 17.2, 10.3, 5.6), 7.45 br.s (1H,
1
13
(NCH ), 120.0, 120.4 (CH), 127.5 (CH), 129.3 (CH),
130.3 (CH), 132.2, 135.7, 136.1. Found, %: C 49.97; H
5
4
2
1
.33; Br 41.59; N 3.41. C H Br N. Calculated, %: C
16 20 2
6
4
9.77; H 5.22; Br 41.38; N 3.63.
6-Bromo-2,2-tetramethylene-3а,4-dihydrobenzo-
3
1
5
2
2
2
[f]isoindolinium bromide (2с). Yield 1.8 g (80%),
=
CH), 7.43–7.48 m (2Нarom); 7.55–7.60 m (2Нarom),
white crystals, mp 235–237°C (abs. EtOH). IR
1
3
–1
9.56 s (1Н, СНO). C NMR spectrum (75.47 MHz,
DMSO-d + CCl ), δ, ppm: 28.0 (CH ), 115.4 (=CH ),
spectrum, ν, cm : 3010, 1600 (aromatic ring), 885–
1
875, 825–805 (1,2,4-substituted benzene ring). Н
6
4
2
2
1
1
%
23.2, 130.9 (2-СН, С Н ), 131.3 (2-СН, С Н ), 133.1,
NMR spectrum (300.09 MHz, DMSO-d + CCl ), δ,
6
4
6
4
6
4
33.5 (=CH), 139.4, 148.5 (=CH), 193.2 (CHO). Found,
: C 57.61; H 4.61; Br 32.03; O 6.54. C H BrO.
ppm (J, Hz): 2.15–2.31 m (4H, β,β'-СН ), 2.79 br.t
2
(1H, CH , J 15.3), 3.00 d.d (1H, CH , J 15.3, 6.4),
1
2
11
2
2
Calculated, %: C 57.4; H 4.42; Br 31.82; O 6.37.
3.22–3.38 m (1H, CH), 3.63–3.75 m (2H, α-CH ),
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019

SYNTHESIS OF 6-BROMO-3a,4-DIHYDROBENZO[f]ISOINDOLINIUM BROMIDES
1129
3
.79–3.93 m (3H, α'-CH and NCH ), 4.24 d.d (1H,
2 2
C H Br NO. Calculated, %: C 48.03; H 4.53; Br
16 18
2
NCH , J 11.2, 7.9), 6.59 d.t (1H, =CH, J 2.5, 2.2), 7.06
39.94; N 3.50.
2
d (1H, C H , J 8.0), 7.30 d.d.d (1H, C H , J 8.0, 2.0,
6
3
6
3
13
Aquoeus-alkaline cleavage of salts 2a, 2b, 2d,
and 2e (general procedure). Potassium hydroxide, 0.3 g,
was added to a solution of 2 mmol of salt 2a, 2b, 2d, or
0
.8), 7.34 br.d (1Н, C H , J 2.0). C NMR spectrum
6 3
(
75.47 MHz, DMSO-d + CCl ), δ, ppm: 21.3 (β-CH ),
6 4 2
2
1
1.5 (β'-CH ), 30.7, 35.8, 62.4, 62.9, 64.3, 65.8, 119.9,
20.1, 127.5, 129.3, 130.3, 132.3, 135.6, 136.5. Found,
2
2e in 2–3 mL of water, and the mixture was heated at
1
10–120°С with simultaneous distillation of water
%
: C 50.25; H 4.93; Br 41.83; N 3.53. C H Br N.
16 18 2
(
10–15 mL of water was intermittently added to the
Calculated, %: C 50.03; H 4.72; Br 41.6; N 3.65.
-Bromo-2,2-pentamethylene-3а,4-dihydrobenzo-
f]isoindolinium bromide (2d). Yield 1.7 g (72%),
white crystals, mp 235–236°C (abs. EtOH). IR spec-
reaction mixture. To complete the cleavage, the reac-
tion mixture was heated at 140–145°С for 5–7 min.
The total reaction time was 1.5 h. Then the reaction
6
[
mixture and the distillate were treated with Et O
2
–
1
trum, ν, cm : 3040, 1600 (aromatic ring), 885–870,
(
3 × 50 mL). The extract was washed with water
1
8
25–805 (1,2,4-substituted benzene ring). Н NMR
and dried over MgSO . The ether was removed, and
4
spectrum (300.09 MHz, DMSO-d + CCl ), δ, ppm (J,
6
4
the residue was distilled in a vacuum to obtain a
mixture of isomeric amines 3a, 3b, 3d, 3e and 4a, 4b,
4d, 4e.
Hz): 1.54–1.66 m (2H, γ-СН ), 1.77–1.90 m (4H, β,β'-
2
СН ), 2.67 t (1H, CH , J 15.2), 3.00 d.d (1H, CH , J
2
2
2
1
5.2, 6.4), 3.22–3.37 m (1H, CH), 3.43 br.t (2H, CH2,
7
-Bromo-3-(dimethylaminomethyl)-2-methyl-
J 5.7), 3.51 d.d (1H, CH , J 11.5, 10.5), 3.54 br.t (2H,
2
naphthalene (3а) and 7-bromo-2-(dimethylamino-
methyl)-3-methylnaphthalene (4а) (isomer mixture,
CH , J 5.7), 4.14 br.d.d (1H, CH , J 11.5, 8.0), 4.36
2
2
+
+
br.d.t (1H, N CH , J 16.4, 2.2), 4.57 br.d (1H, N CH ,
2
2
3
3
1
a/4a 5.5 : 4.5). Yield 0.3 g (60%), bp 110–120°С (2–
mmHg), nD 1.5970. IR spectrum, ν, cm : 3040,
J 16.4), 6.60 br.q (1Н, =CH, J 2.3), 7.14 d (1H, C H ,
6
3
2
0
–1
J 8.0), 7.40 d.d.d (1H, C H , J 8.0, 2.0, 0.7), 7.46 br.s
6
3
13
600, 1570 (aromatic ring), 885–870, 825–805 (1,2,4-
(
1Н, C H ). C NMR spectrum (75.47 MHz, DMSO-
6 3
1
and 1,2,4,5-substituted benzene ring). Н NMR spec-
d + CCl ), δ, ppm: 20.4 (γ-CH ), 20.6 (β-CH ), 21.0
6
4
2
2
trum, δ, ppm: 2.23 s [6Н, (CH ) ], 2.50 d (1.65Н, CH ,
(
β'-CH ), 30.6 (СН ), 34.4 (СН), 59.3 (СН ), 61.3
3 2
3
2
2
2
J 0.9), 2.52 d (1.35Н, CH , J 0.9), 3.47 br.s (0.9Н,
(
СН ), 63.7 (СН ), 66.3 (СН ), 120.0, 120.1 (=CH),
3
2
2
2
CH ), 3.48 br.s (1.1Н, СН ), 7.43 d.d (0.45Н, =CH, J
1
1
28.0 (=CH), 129.7 (=CH), 130.5 (=CH), 132.6, 136.0,
36.6. Found, %: C 51.49; H 5.15; Br 40.37; N 3.39.
2
2
8
.7, 2.0) and 7.44 d.d (0.55Нarom, =CH, J 8.7, 2.0), 7.50
br.s (0.45H, =CH), 7.56 br.s (0.55Н, =CH), 7.58–7.67
m (2Harom), 7.88 d (0.45Нarom, J 2.0) and 7.91 d
C H Br N. Calculated, %: C 51.28; H 5.06; Br 40.14;
1
7
20
2
N 3.52.
(
0.55Нarom, J 2.0). Found, %: С 60.69; Н 5.91; N 5.15;
Spiro[6-bromo-3а,4-dihydrobenzo[f]isoindolin-
,4']morpholinium bromide (2e). Yield 1.7 g (71%),
Br 28.91. C H NBr. Calculated, %: С 60.45; Н 5.8;
1
4
16
2
N 5.03; Br 28.72.
white crystals, mp 275–276°C (abs. EtOH). IR
–
1
spectrum, ν, cm : 3040, 1580 (aromatic ring), 885–
7-Bromo-3-(dimethylaminomethyl)-2-ethylnaph-
thalene (3b) and 7-bromo-2-(dimethylaminome-
thyl)-3-ethylnaphthalene (4b) (isomer mixture, 3b/4b
4.4 : 5.6). Yield 0.35 g (57%), bp 142–143°С (2–
1
8
70, 825–805 (1,2,4-substituted benzene ring). Н
NMR spectrum (300.09 MHz, DMSO-d + CCl ),
6
4
δ, ppm (J, Hz): 2.69 t (1H, CH , J 15.3), 3.01 d.d
2
2
D
0
–1
(
1H, CH , J 15.3, 6.5), 3.23–3.39 m (1H, CH), 3.51–
3 mmHg), n
1.5670. IR spectrum, ν, cm : 3020,
2
3
4
4
.56 m (2H, NCH ), 3.59–3.67 m (3H, CH ), 3.86–
1610, 1580 (aromatic ring), 880–875, 825–805 (1,2,4-
and 1,2,4,5-substituted benzene ring). Н NMR spec-
2
2
1
.01 m [4H, O(CH ) ], 4.27 d.d (1H, CH , J 11.5, 8.1),
2
2
2
.47 d.t (1H, CH , J 16.4, 2.3), 4.74 br.d (1H, CH ,
trum, δ, ppm: 1.04 t (6H, 2-CH
(3Н, СН ), 2.53 q [4Н, N(CH
s (2Н, NCH
d.d (0.56Н, C
7.54 br.s (0.56Н, =CH), 7.61 d (0.56H, CH
7.65 d (0.44H, CH , J 8.7), 7.65 br.s (0.56Н, =CH),
7.69 br.s (0.44Н, =CH), 7.87 d (0.44H, C , J 1.8),
, J 1.8). C NMR spectrum
+ CCl ), δ, ppm: 11.4 (2-CH ),
3
, J 7.1), 2.50 and 2.52 s
, J 7.1], 3.62 and 3.63
, J 8.7, 1.8), 7.4
, J 8.7, 1.8), 7.48 br.s (0.44H, =CH),
, J 8.7),
2
2
J 16.4), 6.62 br.q (1Н, =CH, J 2.3), 7.15 d (1H, C H ,
J 8.1), 7.40 d.d.d (1H, C H , J 8.1, 2.0, 0.8), 7.46
br.s (1Н, C H ). C NMR spectrum (75.47 MHz,
DMSO-d + CCl ), δ, ppm: 30.4 (CH ), 34.3 (CH),
5
6
3
2
)
2
6
3
), 7.42 d.d (0.44Н, C H
2 6 3
6
3
1
3
H
6 3
6
3
6
4
2
3
8.3 (СН ), 59.8 (СН ), 61.0 (OСН ), 61.5 (OСН ),
3
2
2
2
2
3.6 (СН ), 66.8 (СН ), 120.0, 120.3 (=CH), 128.0
H
6 3
2
2
1
3
(
1
=CH), 129.7 (=CH), 130.5 (=CH), 132.5, 135.9,
36.0. Found, %: C 48.25; H 4.73; Br 40.16; N 3.38.
7.91 d.d (0.56Н, C
H
6 3
(75.47 MHz, DMSO-d
6
4
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019

1
130
CHUKHAJIAN et al.
1
5
1
1
1
2
4
8.95 and 18.99 (CH ), 46.2 [N(CH СН ) ], 55.89 and
REFERENCES
3
2
3 2
5.96 (NCH ), 117.84, 118.37, 126.30, 126.52, 127.16,
2
1
. Gevorgyan, H.R., Chukhajian, E.O., Shahkhatuni, K.G.,
and Chukhajian El.O. 4th International Scientific
Conference “Advances in Synthesis and Complexing”,
April 24–28, 2017, Moscow, RUDN University, p. 64.
. Chukhadzhyan, Em.O., Gevorgyan, H.R., Shahkhatu-
ni, K.G., Chukhadzhyan, El.O., Ayrapetyan, L.V., and
Khachatryan, A.A., Russ. J. Org. Chem., 2018, vol. 54,
p. 517. doi 10.1134/S1070428018040012
3. Babayan, A.T., Chukhadzhyan, E.O., Babayan, G.T.,
Chukhadzhyan, El.O., and Kinoyan, F.S., Arm. Khim.
Zh., 1970, vol. 23, p.149.
. Chukhadzhyan, El.O., Chukhadzhyan, E.O., and
Babayan, A.T., Zh. Org. Khim., 1974, vol. 10, p. 46.
. Babayan, A.T., Chukhadzhyan, El.O., and Manasyan, L.A.,
Arm. Khim. Zh., 1978, vol. 31, p. 489.
. Chukhajian, E.O., Chukhajian, El.O., Shahkhatuni K.G.,
and Babayan, A.T., Chem. Heterocycl. Compd., 1989,
vol. 25, p. 512. doi 10.1007/BF00482495
. Ayrapetyan, L.V., Chukhajian, E.O., Shahkhatuni, K.G.,
and Chukhajian, El.O., V Nauchnaya Konferentsiya
Armyanskogo Khimicheskogo Obshchestva (s mezh-
dunarodnym uchastiyem) “Aktual'nyye zadachi
fundamental'noy i prikladnoy khimii” (V Scientific
Conference of the Armenian Chemical Society (with
international participation) “Actual problems of
fundamental and applied chemistry”), October 3–7,
27.37, 127.48, 127.87, 128.04, 128.08, 128.60,
28.68, 129.71, 130.51, 132.46, 133.28, 135.56, 136.32,
36.83, 137.50. Found, %: С 62.96; Н 6.79; N 4.43; Br
6.31. C H NBr. Calculated, %: С 62.75; Н 6.58; N
1
6
20
2
.57; Br 26.09.
7
-Bromo-2-methyl-3-(piperidinomethyl)naph-
thalene (3d) and 7-bromo-3-methyl-2-(piperidinome-
thyl)naphthalene (4d) (isomer mixture, 3d/4d 4 : 6).
Yield 0.4 g (59%), honey-like substance. IR spectrum,
–
1
ν, cm : 3040, 1620, 1580 (aromatic ring), 885–875,
20–805 (1,2,4- and 1,2,4,5-substituted benzene ring).
4
5
6
8
1
Н NMR spectrum, δ, ppm: 1.41–1.59 m (6Н, 3-СН3),
.37–2.43 m (4Н, α,α'-СН ), 2.50 s (1.7Н, CH ), 2.52 s
2
2
3
(
1.3Н, СН ), 3.49 s (0.8Н, CH ), 3.50 s (1.2Н, СН ),
3 2 2
7
.42 d.d (0.4Н, C H , J 8.7, 2.0), 7.43 d.d (0.6Н, C H ,
6 3 6 3
J 8.7, 2.0), 7.49 br.s (0.4Н, =CH, C H ), 7.54 br.s
6
2
(
0.6Н, =CH, C H ), 7.57 br.s (0.6H, =CH, C H ), 7.62
6 2 6 2
7
br.s (0.4Н, =CH, C H ), 7.61 d (0.4Н, C H , J 8.7), 7.64
d (0.4Н, C H , J 8.7), 7.86 d (0.4Н, C H , J 2.0), 7.91
d (0.6Н, C H , J 2.0). Found, %: С 64.38; Н 6.45; N
4
6
6
2
6
3
6
3
6
3
6
3
.28; Br 25.32. C H NBr. Calculated, %: С 64.16; Н
17 20
.33; N 4.4; Br 25.1.
-Bromo-2-methyl-3-(morpholinomethyl)naph-
7
thalene (3e) and 7-bromo-3-methyl-2-(morpholino-
methyl)naphthalene (4e) (isomer mixture, 3e/4e 4 : 6).
Yield 0.4 g (58%), honey-like substance. IR spectrum,
2
017, Yerevan, p. 63.
8
. Chukhajian, E.O., Ayrapetyan, L.V., Chukhajian, El.O.,
and Panosyan, H.A., Chem. Heterocycl. Compd., 2013,
vol. 49, 1274. doi 10.1007/s10593-013-1375-1
. Babayan, A.T., Chukhadzhyan, E.O., and Chukhad-
zhyan, El.O., Zh. Org. Khim., 1973, vol. 9, p. 467.
0. Chukhadzhyan, E.O., Nalbandyan, M.K., Gevorkyan, A.R.,
and Kinoyan, F.S., Arm. Khim. Zh., 2007, vol. 60, p. 83.
1. Chukhajian, E.O., Nalbandyan, M.K., Gevorkyan, H.R.,
–
1
ν, cm : 3060 (CHarom), 1640, 1580 (aromatic ring),
85–870, 825–805 (1,2,4- and 1,2,4,5-substituted
8
9
1
benzene ring). Н NMR spectrum, δ, ppm: 2.41–2.46
m (4Н, NCH2morph), 2.52 d (1.8Н, CH , J 0.8), 2.54 d
3
1
(
1.2Н, CH , J 0.8), 3.56 s (0.8Н, CH ), 3.57 s (1.2Н,
3
2
СН ), 3.57–3.61 m (4Н, OСН2morph), 7.43 d.d (0.4Н,
C H , J 8.7, 2.0), 7.45 d.d (0.6Н, C H , J 8.7, 2.0),
7
2
1
6
3
6
3
Chukhajian, El.O., Panosyan, H.A., Ayvazyan, A.G., and
Tamazyan R.A., J. Heterocycl.Chem., 2008, vol. 45,
p. 687. doi 10.1002/jhet.5570450309
.51 br.s (0.4Н, =CH, C H ), 7.57 br.s (0.6Н, =CH,
6 2
С Н ), 7.60 br.s (0.6Н, =CH, C H ), 7.63 br.s (0.4Н,
6
2
6
2
=
CH, С Н ), 7.62 d (0.6Н, C H , J 8.7), 7.65 d (0.4Н,
6 2 6 3
12. Abramyan-Babayan, I.A. and Babayan, A.T., Arm.
Khim. Zh., 1972, vol. 25, p. 19.
C H , J 8.7), 7.88 d (0.4Н, C H , J 2.0), 7.92 d (0.6Н,
6
3
6
3
C H , J 2.0). Found, %: С 60.23; Н 5.88; N 4.26; Br
6
3
13. Ohta, K., Yakugaku Zasshi, 1965, vol. 85, p. 14. doi
2
5.16. C H NOBr. Calculated, %: С 60.01; Н 5.67;
10.1248/yakushi1947.85.1_14
16
18
N 4.37; Br 24.95.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
1
1
4. Abramyan, A.A., Quantitative Trace Element Analysis
of Organic Compounds (in Armen.), Yerevan:
Haypethrat, 1963.
5. Gredy, M., Bull. Soc. Chim. Fr., Mem., 1936, vol. 3,
p. 1098.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 8 2019