Bromination of 2-phenyl-1,2,3,4-tetrahydroquinolines

Article abstract of DOI:10.1134/S1070428015050085

Bromination of 2-phenyltetrahydroquinolines derivatives was investigated. During the bromination of 2-phenyl-1,2,3,4-tetrahydroquinoline with bromine in chloroform or bromosuccinimide along with the formation of di- and tribrom derivatives the oxidation r

Full text of DOI:10.1134/S1070428015050085

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 5, pp. 636–639. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © M.N. Zemtsova, S.V. Kulemina, V.B. Rybakov, Yu.N. Klimochkin, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51,
No. 5, pp. 656–659.
Bromination of 2-Phenyl-1,2,3,4-tetrahydroquinolines
M. N. Zemtsovaa, S. V. Kuleminaa, V. B. Rybakovb, and Yu. N. Klimochkina
a Samara State Technical University, ul. Kuibysheva 153, Samara, 443010 Russia
e-mail: orgchem@samgtu.ru
b Lomonosov Moscow State University, Moscow, Russia
Received January 19, 2015
Abstract―Bromination of 2-phenyltetrahydroquinolines derivatives was investigated. During the bromination
of 2-phenyl-1,2,3,4-tetrahydroquinoline with bromine in chloroform or bromosuccinimide along with the
formation of di- and tribrom derivatives the oxidation reaction occurs with the generation of quinoline
structure. The interaction of 2-phenyl-1,2,3,4-tetrahydroquinoline with bromine in acetic acid leads to the
formation of 6,8-dibromoderivative preserving the 1,2,3,4-tetrahydroquinoline ring. At the same time N-
substituted 2-phenyl-1,2,3,4-tetrahydroquinoline is selectively brominated in various conditions with the
formation of 6-monobromoderivative. By the method of X-ray diffraction analysis the molecular structure of
3,6,8-tribromo-2-phenylquinoline single crystals was determined.
DOI: 10.1134/S1070428015050085
An important position belongs to tetrahydroquino-
lines in the synthetic organic chemistry. They possess
high reactivity, wide diversity of chemical properties,
and a large area of practical application [1]. 1,2,3,4-
Tetrahydroquinoline system underlies many bioactive
natural substances [2–8] and potential drugs [9–11]. The
development of medicinal chemistry is an important
initiator of the progress in new methods of synthesis of
tetrahydroquinoline derivatives, in particular, of mono-
and polyhalo derivatives. In the literature the halogena-
tion of 1,2,3,4-tetrahydroquinoline is described per-
formed with halogens, N-halosuccinimide, aqueous
solutions of sodium chlorate and bromoate affording
various halogen-substituted tetrahydroquinolines [12].
Previously we carried out the bromination of
methyl 2-methyl-1,2,3,4-tetrahydro-4-quinolinecarbo-
xylate 1 with molecular bromine, which led to the
formation of compound 2 at room temperature and to
compound 3 [13] at lower temperature (Scheme 1).
In extension of the investigation of 2-R-1,2,3,4-
tetrahydroquinoline derivatives [13–16] we studied the
bromination of 2-phenyl- and 2-phenyl-N-chloracetyl-
1,2,3,4-tetrahydroquinoline with N-bromosuccinimide
and bromine in different conditions.
Scheme 1.
At the bromination of 2-phenyl-1,2,3,4-tetrahydro-
quinoline 4 with bromine in chloroform at the
temperature of –20оС and with N-bromosuccinimide at
stirring for 3 h at room temperature in solvents mixture
(chloroform–tetrachloromethane) along with the
bromination the oxidation of the heterocyclic ring of
COOMe
Br
Br2
_20oC
N
CH3
COOMe
H
Br
3
Scheme 2.
COOMe
N
CH3
Br2
H
Br
Br
Br
_20oC
Br2
1
20oC
N
Ph
N
CHBr2
NBS
25oC
N
Ph
H
Br
Br
4
5
2
636

BROMINATION OF 2-PHENYL-1,2,3,4-TETRAHYDROQUINOLINES
637
Br7B
C8B
Scheme 3.
Br
C7B
C6B
C5B
C4B
Br2, CHCl3
20oC
N
Ph
N
Ph
C9B
H
Br
4
6
Br9B
C10B
N1B
Br7A
tetrahydroquinoline occurs with the formation of 3,6,8-
tribromo-2-phenyl-quinoline 5 (Scheme 2).
C2B
C2B
C7A
C8A
C9A
C10A
N1A
C21A
Br9A
C22B
C21B
C26B
C25B
The structure of 3,6,8-tribromo-2-phenylquinoline
5 is established by the X-ray diffraction (XRD)
method. Crystals for XRD experiment were obtained
by slow evaporation of the benzene solution. In this
structure two crystallographically independent
molecules are present, distinguished by the sign of the
turn of the phenyl substituents (see the figure).
C6A
C5A
Br3BA
C23B
C4A
C24B
C3A
C22A
C2A
C26A
C25A
C23A
C24A
At the formation of compound 5 evidently
successive processes occur of bromination and dehyd-
robromination of the quinoline heterocyclic ring.
Br3A
Molecular structure of the two crystallographically inde-
At the bromination of 2-phenyl-1,2,3,4-tetrahyd-
roquinoline 4 with bromine in chloroform at room tem-
perature the oxidation of heterocyclic ring also occurs,
but unlike the reaction at –20°С the 6,8-dibromo-2-
phenylquinoline 6 is generated (Scheme 3).
pendent molecules of 3,6,8-tribromo-2-phenylquinoline 5.
6-bromo-2-phenyl-N-chloracetyl-1,2,3,4-tetrahydro-
quinoline 9 is obtained (Scheme 5).
The bromination of compound 4 with bromine
in acetic acid at heating results in the formation
of 6,8-dibromo-2-phenyl-1,2,3,4-tetrahydroquinoline 7
(Scheme 4).
EXPERIMENTAL
Mass spectra were registered on chromato-mass-
spectrometer Thermo Finnigan Trace DSQ using a
capillary column BPX-5 (30 × 0.32 mm) under electron
impact conditions, ionized electrons energy 70 eV. 1H,
13C, DEPT, and HMQC NMR spectra were registered
on a Jeol JNM-ECX400 spectrometer [399.78 (1H),
100.53 (13C) MHz], solvent CDCl3. The signals of
deuterated solvent were used as internal references.
TLC was carried out on Sorbfil plates, development in
iodine vapor and under UV irradiation. For the column
chromatography silica gel Silica 60 was applied,
particles diameter 0.063–0.2 mm. Melting points were
determined by capillary method on a PTP-M device.
Elemental analysis was carried out on an automatic
CHNS-analyser Euro Vector EA-3000.
At the same time as a result of bromination of less
activated 2-phenyl-N-chloracetyl-1,2,3,4-tetrahydro-
quinoline 8 with N-bromosuccinimide in dimethyl-
formamide at room temperature and with bromine in
acetic acid at heating the monobromination occurs and
Scheme 4.
Br
Br2, CH3COOH
50oC
N
Ph
N
Ph
H
H
Br
4
7
Scheme 5.
Br2, CH3COOH
3,6,8-Tribromo-2-phenyl-1,2,3,4-tetrahydroqui-
noline (5). а. To a suspension of 1 g (0.0048 mol) of
compound 4 in 85 mL of a mixture tetrachlorometha-
ne–chloroform, 3 : 2, was added while stirring 10.1 g
(0.0576 mol) of N-bromosuccinimide. The mixture was
maintained at room temperature for 3 h, then cold 10%
solution of NaHCO3 was added till alkaline pH was
Br
50oC
N
Ph
N
Ph
O
O
NBS, DMF
25oC
Cl
Cl
8
9
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

ZEMTSOVA et al.
638
reached. The organic layer was separated, the aqueous
phase was extracted twice with chloroform. The
combined organic phases were washed with water and
dried with Na2SO4. The solvent was distilled off in a
vacuum, the residue was recrystallized from ethanol.
Yield 1.3 g (61%), colorless crystals, mp 167–168ºC.
6,8-Dibromo-2-phenylquinoline (6). To a solution
of 1 g (0.0048 mol) of compound 4 in 13 mL of
chloroform at room temperature was added dropwise
1.64 g (0.53 mL, 0.010 mol) of bromine in 7 mL of
chloroform. The mixture was stirred during 2 h, then
35 mL of chloroform was added, the reaction mixture
was washed with 5% solution of NaHCO3 and dried
with Na2SO4. The solvent was distilled off in a vacuum,
the reaction product was purified by column chromato-
graphy (eluent tetrachloromethane). Yield 0.7 g (40%),
colorless crystals, mp 95–97ºC (mp 95–97ºC [17]).
b. To a solution of 1 g (0.0048 mol) of compound 4
in 13 mL of chloroform at –20ºC in the darkness was
added dropwise 1.64 g (0.53 mL, 0.010 mol) of bromine
in 7 mL of chloroform. The mixture was stirred during
2 h, then 35 mL of chloroform was added, the reaction
mixture was washed with 5% solution of NaHCO3 and
dried with Na2SO4. The solvent was distilled off, the
precipitate was recrystallized from ethanol. Yield 1.25 g
6,8-Dibromo-2-phenyl-1,2,3,4-tetrahydroquino-
line (7). To solution of 1 g (0.0048 mol) of compound
4 in 10 mL of glacial acetic acid was added dropwise
while stirring the solution of 0.5 mL (0.0096 mol) of
bromine in 5 mL of glacial acetic acid. The mixture
was stirred during 3 h at 50ºС, after cooling it was
poured in water, alkalinized till рН10, and extracted
with chloroform. The extract was dried with Na2SO4,
the solvent was distilled off in a vacuum, the residue
was recrystallized from ethanol. Yield 0.8 g (46%),
1
(59%), colorless crystals, mp 167–168ºC. Н NMR
spectrum, δ, ppm: 7.47–7.49 m (3Н, Ph), 7.85–7.86 m
(3Н, Ph, Н7aryl), 8.11 d (1Н, Н5aryl,4JHH 1.8 Hz), 8.35 s
(1Н, Н4aryl). 13С NMR spectrum, δ, ppm: 119.0, 120.8,
126.4 (С3,6,8), 128.1, 128.3, 129.5, 129.6, 130.1, 136.4,
138.9, 139.6, 142.6 (Ph, С4,4а,5,7,8а), 158.8 (C2). Mass-
spectrum, m/z (Irel, %): 442 [M]+ (38), 363 (80), 282
(56), 208 (90), 176 (25), 141 (25), 101 (40), 73 (100).
Found, %: C 48.98; H 1.91; N 3.29. C15H8Br2N.
Calculated, %: C 48.42; H 2.01; N 3.76. M 441.95.
1
colorless crystals, mp 78–80ºС. Н NMR spectrum, δ,
ppm: 1.92–1.94 m (1Н, Н3), 2.09–2.13 m (1Н, Н3),
2.67–2.71 m (1Н, Н4), 2.83–2.86 m (1Н, Н4), 4.52 d.d
3
(1Н, Н2, JHH 5.0, 8.5 Hz), 4.52 br.s (1Н, NH), 7.06 s
X-ray diffraction study of compound (5).
Crystals were grown from benzene solution by a slow
evaporation at room temperature. A single crystal with
linear size of 0.20 × 0.20 × 0.20 mm was chosen for the
experiment. The XRD experiment was run at 295(2) K
using the Stoe Stadi Vari Pilatus-100K diffractometer.
Prismatic crystals belong to monoclinic crystal system,
space group P21/n, а 4.09000(10) Å, b 42.3172(3) Å,
c 15.9411(3) Å, β 95.1690(10)º, V 2747.82(10) Å3,
ρcalc 1.868 mg/cm3, Z 8, F(000) 1680, µ 10.751 mm–1,
final divergence factors: R1 0.0473, ωR2 0.1067 [I > 2σ(I)];
R1 0.0604, ωR2 0.1111 for all reflections.
(1Н, Н5aryl), 7.37 s (1Н, Н7aryl), 7.36–7.41 m (5Н, Ph).
13С NMR spectrum, δ, ppm: 26.4 (С3), 30.2 (С4), 56.2
(С2), 107.6 (С8aryl), 108.7 (С6aryl), 124.0 (C4а), 126.4,
127.8, 128.8, 130.9, 132.1, 140.9 (Ph, C5aryl , С7aryl),
143.9 (C8а). Found, %: C 49.33; H 3.61; N 3.71.
C15H13Br2N. Calculated, %: C 49.08; H 3.57; N 3.82.
6-Bromo-2-phenyl-N-chloracetyl-1,2,3,4-tetra-
hydroquinoline (9). а. To a solution of 0.78 g
(0.0027 mol) of compound 8 in 10 mL of DMF while
stirring was added by portions 1.22 g (0.0068 mol) of
N-bromosuccinimide. The mixture was stirred during
10 h at room temperature, then the solution was poured
in water, the precipitate was filtered off, the mother
liquor was extracted with methylene chloride, dried
with Na2SO4. The solvent was distilled in a vacuum,
the precipitate was recrystallized from ethanol. Yield
0.2 g (20%), yellow crystals, mp 127–128ºС.
Diffraction data were collected in the range 4.18º ≤
θ ≤ 71.53º; spherical segment –3 ≤ h ≤ 4, –51 ≤ k ≤ 50,
–19 ≤ l ≤ 19. 4793 independent reflections were
registered, 3465 of them with I > 2σ(I). The structure
was solved with the direct method and refined in the
full-matrix least-squares approximation in the
anisotropic approach. All hydrogen atoms were placed
basing on geometric considerations and refined in the
rider model. The solution and refining of the structure
was realized using the program complex SHELX-97.
Crystallographic information on structure 5 and the
refining parameters were deposited in the Cambridge
Crystallographic Data Center (CCDC 1033987).
b. To a solution of 0.9 g (0.0031 mol) of compound
8 in 10 mL of glacial acetic acid was added dropwise
while stirring a solution of 0.33 mL (0.0062 mol) of
bromine. The mixture was stirred during 3 h at 50°С,
after cooling the reaction mixture was poured in water,
alkalinized till рН10, and extracted with chloroform.
The extract was dried with Na2SO4. The solvent was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

BROMINATION OF 2-PHENYL-1,2,3,4-TETRAHYDROQUINOLINES
639
5. Perry, N.B., Blunt, J.W., and Munro, M.N.G.,
Tetrahedron, 1988, vol. 44, p. 1727.
6. Katritzky, A.R., Rachwal, S., and Rachwal, B.,
Tetrahedron, 1996, vol. 52, p. 15031.
7. Ueda, M., Kawai, S., Hayashi, M., Naito, T., and
distilled off in a vacuum, the residue
was
recrystallized from ethanol. Yield 0.5 g (44%), yellow
1
crystals, mp 127–128ºС. Н NMR spectrum, δ, ppm:
1.81–1.83 m (1Н, Н3), 2.63–2.64 m (3Н, Н3, С4Н2),
2
4.09 d (1Н, СНСl, JHH 12.6 Hz), 4.17 d (1H, CHCl,
2JHH 12.6 Hz), 5.61 br.s (1Н, Н2), 7.13–7.37 m (5Н,
Ph), 7.37 s (1Н, Н5aryl), 7.40 d (1Н, Н8aryl, 3JHH 2.1 Hz),
7.42 d (1Н, Н7aryl, 3JHH 2.1 Hz). 13С NMR spectrum, δ,
ppm: 26.5 (С4), 33.5 (С3), 42.2 (СН2Сl). 58.0 (С2),
126.3, 126.4, 127.4, 128.8, 130.2, 130.9, 136.6, 142.0
(Ph, С4а,5,7,8,8а), 166.2 (С=О). Mass-spectrum, m/z (Irel,
%): 366 [M]+ (80), 329 (100), 287 (45), 208 (38), 77
(10). Found, %: C 56.13; H 4.22; N 3.95.
C17H15BrClNO. Calculated, %: C 55.99; H 4.15; N
3.84.
Miyata, O., J. Org. Chem., 2010, vol. 75, p. 914.
8. Ahmed, N., Brahmbhatt, K.G., Sabde, S., Mitra, D.,
Singh, I.P., and Bhutani, K.K., Bioorg. Med. Chem.,
2010, vol. 18, p. 2872.
9. Ramesh, E., Manian, R.D.R.S., Raghunathan, R.,
Sainath, S., and Raghunathan, M., Bioorg. Med. Chem.,
2009, vol. 17, p. 660.
10. Balint, J., Egri, G., Fogassy, E., Bocskei, Z., Simon, K.,
Gajary, A., and Friesz, A., Tetrahedron: Asymm., 1999,
vol. 10, p. 1079.
11. Ikeda, S., Shibuya, M., and Iwabuchi, Y., Chem.
Commun., 2007, p. 504.
This study was performed in frame of project part
of the State contract of the Ministry of Education and
Science of the Russian Federation (no. 4.1440.2014/k)
and in the frame of the Moscow State University
development program.
12. Sahin, A., Cakmak, O., Demirtas, I., Okten, S., and
Tutar, A., Tetrahedron., 2008, vol. 64, p. 10068.
13. Zhuravleva, Yu.A., Zimichev, A.V., Zemtsova, M.N.,
and Klimochkin, Yu.N., Russ. J. Org. Chem., 2011,
vol. 47, p. 306.
14. Zhuravleva, Y.A., Zimichev, A.V., Zemtsova, M.N.,
Rybakov, V.B., and Klimochkin, Y.N., Acta Cryst.,
2009, vol. E65, p. 2059.
REFERENCES
1. Sridharan, V., Suryavanshi, P.A., and Menéndez, J.C.,
Chem. Rev., 2011, vol. 111, p. 7157.
2. Morimoto, Y., J. Heterocycl. Chem., 1998, vol. 35, p. 279.
3. Witherup, K.M., Ransom, R.W., Graham, A.C.,
Bernard, A.M., Salvatore, M.J., Lumma, W.C.,
Andersen, P.S., Pitzenberger, S.M., and Varga, S.L.,
J. Am. Chem. Soc., 1995, vol. 117, p. 6682.
15. Zhuravleva, Yu.A., Zimichev, A.V., Zemtsova, M.N.,
and Klimochkin, Yu.N., Russ. J. Org. Chem., 2008,
vol. 44, p. 776.
16. Zhuravleva, Yu.A., Zimichev, A.V., Zemtsova, M.N.,
and Klimochkin, Yu.N., Russ. J. Org. Chem., 2009,
vol. 45, p. 609.
4. Williamson, N.M., March, D.R., and Ward, A.D.,
17. Yu, J., Li, Z., and Su, W., Synth. Commun., 2013,
Tetrahedron Lett., 1995, vol. 36, p. 7721.
vol. 43, p. 361.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015