Synthesis of 4-haloquinolines and their fused polycyclic derivatives

Article abstract of DOI:10.1016/j.mencom.2008.03.020

A general method for the synthesis of 4-chloro- or 4-bromo-substituted quinolines and quinoline moieties of polycyclic compounds includes the addition of hydrogen halides to vic-amino(3-oxoalk-1-ynyl)arenes under mild conditions followed by the intramolecular cyclization of the adducts.

Full text of DOI:10.1016/j.mencom.2008.03.020

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 109–111
Synthesis of 4-haloquinolines and their fused polycyclic derivatives
Mark S. Shvartsberg* and Ekaterina A. Kolodina
Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
630090 Novosibirsk, Russian Federation. Fax: +7 383 330 7350; e-mail: shvarts@kinetics.nsc.ru
DOI: 10.1016/j.mencom.2008.03.020
A general method for the synthesis of 4-chloro- or 4-bromo-substituted quinolines and quinoline moieties of polycyclic
compounds includes the addition of hydrogen halides to vic-amino(3-oxoalk-1-ynyl)arenes under mild conditions followed by the
intramolecular cyclization of the adducts.
A variety of biologically active compounds and materials contain
a quinoline or quinoline-5,8-dione fragment, e.g. (20S)-campto-
thecin and its derivatives,1 cleistopholine,2 sampangin,2,3 ascidi-
demin and its analogues,4 arylquinolines5 and polymers incor-
porating them.6 A general approach to polynuclear condensed
heterocycles, which consists in the cyclization of functionalised
acetylenic precursors, is intensively developed.7 Previously we
applied this approach to the synthesis of a 4-dialkylamino-
quinoline moiety using vic-amino(3-oxoalk-1-ynyl)arenes as
key precursors.8 The method involved the addition of secondary
amines to the triple bond of acetylenic ketones and the subsequent
heterocyclization of the adducts in the presence of a mineral
acid or base. Marinelli et al.9 proposed rhodium-catalyzed
tandem hydroarylation (hydrovinylation)–cyclization reactions
for the preparation of arylated and arylvinylated quinolines.
The above acetylenic building blocks and arylboronic acids or
potassium aryltrifluoroborates and potassium arylvinyltrifluoro-
borates, respectively, were used as initial materials. Unfortu-
nately, both methods allow one to obtain quinolines only with
determinate substituent types in a pyridine ring, which cannot
usually be replaced by other functional groups. Furthermore,
the protection of functional groups in the acetylenic precursors,
which are sensitive to nucleophiles, is a problem. The precursors
and reaction intermediates can be unstable at elevated tem-
peratures (up to 100 °C). Here we report a new synthesis of
polycyclic compounds containing 4-haloquinoline and 4-halo-
quinoline-5,8-dione moieties on the basis of the above pre-
cursors. Alkyl ethynyl ketones add hydrogen halides to yield
regioselectively corresponding -halovinyl ketones.10 Z-Isomers
of the formed compounds can easily transform into E-isomers
under mild conditions. We suggested that vic-amino(3-oxoalk-1-
ynyl)arenes react with hydrogen halides in the same manner. If it
is true, the addition is followed by acid-catalysed isomeriza-
tion of Z-adducts into E-isomers and intramolecular cyclization
of the latter to close a pyridine ring. This assumption was
confirmed by the synthesis of 4-bromo-2-phenylquinoline 1 and
a series of condensed polycyclic compounds 2a,b, 3a,b and
4a,b containing a haloquinoline moiety (Table 1).†
†
General heterocyclization procedure: a solution of an acetylenic
precursor (1.0 mmol) in dry dioxane or CHCl3 (15 ml) under Ar was
mixed with a solution (4–5 ml) containing 2.5–3 equiv. of hydrogen
halide in the above solvent and stirred at 20 °C for 5–6 h. After the
neutralization of the hydrohalide formed, the product was isolated and
purified in a usual way.
1: mp 90–91 °C (EtOH).11
2a: mp 194–195 °C (Et2O). H NMR (200 MHz, CDCl3) d: 1.30 (d,
1
6H, Me, J 6.9 Hz), 3.35 (sept., 1H, CH, J 6.9 Hz), 7.64 (s, 1H, H3),
7.75–7.90 (m, 2H, H8,9), 8.25–8.40 (m, 2H, H7,10), 9.18 (s, 1H, H5).
Found (%): C, 64.91; H, 3.67; Cl, 19.02. Calc. for C20H13Cl2NO2 (%):
C, 64.88; H, 3.54; Cl, 19.15.
Table 1 Synthesis of haloquinoline structures.
1
2b: mp 198–199 °C (toluene–hexane). H NMR, d: 1.45 (d, 6H, Me,
X–
R1
R1
J 6.9 Hz), 3.34 (sept., 1H, CH, J 6.9 Hz), 7.70–7.90 (m, 2H, H8,9), 7.84
(s, 1H, H3), 8.25–8.45 (m, 2H, H7,10), 9.14 (s, 1H, H5). Found (%): C,
58.20; H, 3.03; Br, 19.02; Cl, 8.44. Calc. for C20H13BrClNO2 (%): C, 57.93;
H, 3.16; Br, 19.27; Cl, 8.55.
H
N
R2
R3
NH2
R2
R3
R
HX
R
3a: mp 252–253 °C (toluene–hexane). 1H NMR, d: 7.50–7.70 (m, 3H,
X
Ph), 7.70–7.90 (m, 2H, H9,10), 8.16 (s, 1H, H3), 8.2–8.5 (m, 4H, H8,11
,
5–8
O
Ph), 8.52 (d, 1H, H5(6), J 8.7 Hz), 8.63 (d, 1H, H6(5), J 8.7 Hz). Found
(%): C, 74.95; H, 3.37; Cl, 9.77. Calc. for C23H12ClNO2 (%): C, 74.70;
H, 3.27; Cl, 9.59.
R1
R2
R3
N
X
R
aq. NaHCO3
3b: mp 237–238 °C (toluene–hexane). 1H NMR, d: 7.50–7.70 (m, 3H,
Ph), 7.70–7.90 (m, 2H, H9,10), 8.38 (s, 1H, H3), 8.20–8.45 (m, 2H,
H8,11), 8.51 (d, 1H, H5(6), J 8.7 Hz), 8.60 (d, 1H, H6(5), J 8.7 Hz). Found
(%): C, 66.78; H, 2.98; Br, 19.40. Calc. for C23H12BrNO2 (%): C, 66.69;
H, 2.92; Br, 19.29.
1–4
1
4a: mp 194–195 °C (toluene–hexane). H NMR, d: 1.55 (s, 9H, Me),
Sub-
strate
Yield
(%)
R
R1
R2
H
R3
H
X
Product
7.75 (s, 1H, H3), 7.70–7.90 (m, 2H, H9,10), 8.20–8.40 (m, 2H, H8,11), 8.48
(d, 1H, H5(6), J 8.6 Hz), 8.58 (d, 1H, H6(5), J 8.6 Hz). Found (%): C, 71.92;
H, 4.56; Cl, 10.39. Calc. for C21H16ClNO2 (%): C, 72.10; H, 4.61; Cl, 10.13.
5
6
6
7
7
8
8
Ph
H
Br
1
73
77
70
65
90
82
69
Pri Cl
Pri Cl
ortho-CO–C6H4–CO– Cl 2a
ortho-CO–C6H4–CO– Br 2b
1
4b: mp 188–189 °C (toluene–hexane). H NMR, d: 1.54 (s, 9H, Me),
7.70–7.90 (m, 2H, H9,10), 7.95 (s, 1H, H3), 8.20–8.40 (m, 2H, H8,11),
8.47 (d, 1H, H5(6), J 8.8 Hz), 8.54 (d, 1H, H6(5), J 8.8 Hz). Found (%): C,
64.24; H, 4.28; Br, 20.00. Calc. for C21H16BrNO2 (%): C, 63.97; H, 4.09;
Br, 20.27.
Ph ortho-CO–C6H4–CO–
Ph ortho-CO–C6H4–CO–
But ortho-CO–C6H4–CO–
But ortho-CO–C6H4–CO–
H
H
H
H
Cl 3a
Br 3b
Cl 4a
Br 4b
– 109 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 109–111
Pri
Pri
O
O
,
O
O
O
O
N
N
Pri
N
NH
OH
OH
Br
10
CuI, Et3N
Pd(PPh3)2Cl2,
DMSO–CHCl3
O
O
Me
11
12
14
15
Pri
Scheme 2
O
O
OH
tional hydrocarbon and heteroatomic groups. Some examples
are presented here as an illustration.§
Chlorazaanthraquinone 10 reacted readily with piperidine at
20 °C to give almost quantitatively 2-isopropyl-4-N-piperidino-
benzo[g]quinoline-5,10-dione 14 (Scheme 2). Compound 14 is
an amino analogue of alkaloid cleistopholine 15.
aq. NH3
dioxane
CrO3·2Py
CH2Cl2
NH2
13
Pri
The X-ray structure of 14 is shown in Figure 1.¶ In the
molecule of this compound, benzene and pyridine rings are
planar. In the quinone ring, the carbon C(4A) deviates from
the plane of other atoms by 0.386 Å. Both substituents are
turned relatively to the pyridine plane so that the torsion angles
O
O
O
Cl
N
O
HCl
CHCl3
NH2
Pri
O
9
10
‡
13: yield 47%, mp 143–144 °C (toluene). 1H NMR, d: 1.08, 1.11 (2d,
Scheme 1
6H, Me2C, J 6.7 Hz), 1.90–2.15 (m, 1H, CH), 2.94 (br. s, 1H, OH), 4.53
(d, 1H, HCO, J 5.6 Hz), 5.81 (br. s, 2H, NH2), 7.55–7.80 (m, 2H, H6,7),
7.95–8.15 (m, 2H, H5,8). IR (CHCl3, n/cm–1): 1645, 1677 (C=O), 2212
(CºC), 3384, 3500 (NH2), 3604 (OH). Found (%): C, 71.29; H, 5.77;
N, 5.13. Calc. for C16H15NO3 (%): C, 71.36; H, 5.61; N, 5.20.
9: yield 65%, mp 145–146 °C (toluene–hexane). 1H NMR, d: 1.31 (d,
6H, Me, J 6.9 Hz), 2.81 (sept., 1H, CH, J 6.9 Hz), 6.27, 6.46 (2br. s, 2H,
NH2), 7.60–7.85 (m, 2H, H6,7), 8.00–8.20 (m, 2H, H5,8). IR (n/cm–1):
1649, 1662, 1682 (C=O), 2181 (CºC), 3375, 3492 (NH2). Found (%):
C, 71.70; H, 4.75; N, 5.19. Calc. for C16H13NO3 (%): C, 71.90; H, 4.90;
N, 5.24.
The generality of the method consists in its applicability to
the synthesis of both haloquinolines and haloquinoline moieties
in condensed polycyclic structures. Table 1 summarises the
preparation of both a substituted quinoline and linear and angular
fused tetracycles. The successful syntheses of polycyclic com-
pounds 2–4 having a quinoid ring out of a quinoline fragment
showed that electron-withdrawing substituents in the precursors
do not influence the regioselectivity of the addition of hydrogen
halides.
1
Note that, in the H NMR spectra of compounds 2–4, the
1
10: yield 68%, mp 122–123 °C (Et2O–hexane). H NMR, d: 1.38 (d,
disposition of the H3 proton singlet depends on the nature of a
halogen atom at the 4-position and a substituent at the 2-position.
In the spectra of bromides 2b, 3b and 4b, this singlet is shifted
downfield relatively to the chemical shift of the H3 proton in the
spectra of chlorides 2a, 3a and 4a ( d » 0.2 ppm). The replace-
ment of the alkyl group by an aryl (compounds 3a,b and 4a,b)
provokes a considerable downfield shift of the H3 singlet as well.
It was interesting to test the applicability of the method to the
construction of a 4-haloquinoline-5,8-dione structural fragment
as a new route to alkaloid cleistopholine derivatives and the
antibiotic sampangin.2(b),3 However, in this case, key acetylenic
compounds should contain reactive amino and oxoalkynyl
groups in a nonaromatic quinoid ring.
6H, Me, J 6.9 Hz), 3.34 (sept., 1H, CH, J 6.9 Hz), 7.60 (s, 1H, H3),
7.70–7.90 (m, 2H, H7,8), 8.20–8.40 (m, 2H, H6,9). Found (%): C, 67.40;
H, 3.99; Cl, 12.40. Calc. for C16H12ClNO2 (%): C, 67.26; H, 4.23; Cl, 12.41.
§
14: yield 95%, mp 123–124 °C (Et2O–hexane). 1H NMR, d: 1.34 (d, 6H,
Me, J 6.9 Hz), 1.60–1.90 [m, 6H, (CH2)3], 3.21 (sept., 1H, CH, J 6.9 Hz),
3.25–3.40 (m, 4H, CH2–N–CH2), 6.93 (s, 1H, H3), 7.65–7.85 (m, 2H,
H7,8), 8.15–8.30 (m, 2H, H6,9). Found (%): C, 71.29; H, 6.21; N, 8.25.
Calc. for C20H20N2O3 (%): C, 71.41; H, 5.99; N, 8.33.
1
16: yield 81%. H NMR, d: 0.98 (d, 6H, Me, J 6.8 Hz), 2.85 (sept.,
1H, CH, J 6.8 Hz), 6.52 (s, 1H, H3), 6.85–7.05 (m, 3H, OPh), 7.15–7.40
(m, 5H, OPh), 7.45–7.60 (m, 2H, OPh), 7.70–7.85 (m, 2H, H8,9), 8.25–8.40
(m, 2H, H7,10), 9.27 (s, 1H, H5). UV [hexane, lmax/nm (e)]: 291 (30020),
486 (5770).
1
17: yield 80%, mp 244 °C (decomp., CH2Cl2). H NMR, d: 1.53 (s,
The direction and stereochemistry of hydrogen halides addition
to such conjugated complex systems are not clearly understood.
Nevertheless, we attempted to prepare 2-amino-3-(4-methyl-
3-oxopentynyl)-1,4-naphthoquinone 9 and to use it as a key
precursor for 4-chloro-2-isopropylbenzo[g]quinoline-5,10-dione
10 (Scheme 1).‡
A procedure for introducing several acetylenic substituents into
the quinone ring was described.12 We succeeded in applying
it to the preparation of secondary acetylenic alcohol 12 from
2-bromo-1,4-naphthoquinone 11. Because of its lability, alcohol
12 without isolation was aminated into the 3-position to give
more stable aminoacetylenic alcohol 13. Selective oxidation of
13 by an excess of the Collins reagent (8:1 by weight) at 0–2 °C
afforded desired key ketone 9. Ketone 9 reacts, like amino-
arylynones 5–8, with hydrogen chloride under conditions of the
method giving heterocyclic quinone 10. This example shows
that the method can be applied to the synthesis of 4-halo-
quinoline-5,8-dione structures.
6H, Me), 2.16 (s, 1H, OH), 7.50–7.70 (m, 3H, Ph), 7.70–7.90 (m, 2H,
H9,10), 8.15 (s, 1H, H3), 8.20–8.50 (m, 2H, H8,11, Ph), 8.48 (d, 1H, H5(6)
,
J 8.7 Hz), 8.59 (d, 1H, H6(5), J 8.7 Hz). IR (n/cm–1): 1660, 1673 (C=O),
2220 (CºC), 3392 (OH). Found (%): C, 80.30; H, 4.42; N, 3.51. Calc.
for C28H19NO3 (%): C, 80.56; H, 4.59; N, 3.35.
¶
The X-ray analysis of compound 14 was performed on a Bruker P4
diffractometer using MoK radiation with a graphite monochromator.
The crystals are orthorhombic: a = 15.998(1), b = 12.864(1) and c =
= 17.093(2) Å, V = 3517.8(6) Å3, space group Pbca, Z = 8, C21H22N2O2,
M = 334.41, F(000) = 1424, m = 0.082 cm–1, dcalc = 1.263 g cm–3, T = 293 K,
crystal size, 0.48×0.38×0.24 mm. The intensities of 3453 independent
reflections with 2q < 52° were measured using the q/2q scanning technique.
The structure was solved by a direct method using the SHELX-97
programs (S-97 and L-97) and refined by the least squares method in a
full-matrix anisotropic–isotropic (for hydrogen atoms) approximation to
wR2 = 0.1699, S = 1.005 for all reflections [R1 = 0.0567 for 2037 reflec-
tions with I ³ 2s(I)]. The positions of hydrogen atoms were obtained
from calculated geometrical and refined in riding model.
CCDC 645254 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
A halogen atom at the 4-position of a quinoline or quinoline-
dione moiety is labile and easily substituted by various func-
– 110 –

Mendeleev Commun., 2008, 18, 109–111
References
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C(14)
1
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C(3)
3
4
C(4A)
C(6)
C(4)
C(2)
C(5A)
C(7)
C(5)
C(13)
C(10A)
O(2)
C(11)
5
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N(1)
C(9A)
C(10)
C(12)
C(8)
C(9)
6
7
Figure 1 X-ray structure of 14.
C(3)–C(4)–N(2)–C(18) and C(3)–C(2)–C(11)–C(13) are 11.74°
and 31.14°, respectively.
O
O
OPh
N
Pri
PhOH, K2CO3
DMF
2a
8
9
(a) M. S. Shvartsberg, A. V. Piskunov, M. A. Mzhel’skaya and A. A.
Moroz, Izv. Akad. Nauk, Ser. Khim., 1993, 1423 (Russ. Chem. Bull.,
1993, 42, 1357); (b) E. A. Yakovleva, I. D. Ivanchikova and M. S.
Shvartsberg, Izv. Akad. Nauk, Ser. Khim., 2005, 412 (Russ. Chem. Bull.,
Int. Ed., 2005, 54, 421).
OPh
16
Scheme 3
In compound 2a, both chlorine atoms are replaced by phenoxy
groups under the action of phenol in the presence of K2CO3 in
DMF at 120 °C (Scheme 3). 2-Isopropyl-4,12-diphenoxynaphtho-
[2,3-g]quinoline-6,11-dione 16 is a heterocyclic analogue of the
known photochrome phenoxynaphthacenequinone.13
The cross-coupling of bromide 3b with 2-methylbut-3-yn-2-ol
demonstrates the possibility of introducing reactive acetylenic
groups into prepared heterocyclic compounds (Scheme 4).
G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi and M. Verdecchia, Synlett,
2006, 3218.
10 B. Cavalchi, D. Landini and F. Montanari, J. Chem. Soc. C, 1969,
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Izv. Akad. Nauk, Ser. Khim., 2005, 1636 (Russ. Chem. Bull., Int. Ed.,
2005, 54, 1686).
12 C. E. Kaslow and W. R. Lawton, J. Am. Chem. Soc., 1950, 72, 1723.
13 F. Buchholts, A. Zelichenok and V. Krongaus, Macromolecules, 1993,
26, 906.
Ph
O
N
, NaHCO3
OH
3b
Pd(PPh3)2Cl2, CuI
aq. dioxane
OH
O
17
Scheme 4
Thus, vic-3-oxoalk-1-ynyl substituted aromatic amines react
with hydrogen halides under mild conditions to close the
halopyridine ring. This tandem hydrohalogenation–cyclization
process is a general method for the formation of 4-haloquinoline
and 4-haloquinoline-5,8-dione moieties in polycyclic compounds.
Received: 31st August 2007; Com. 07/3004
– 111 –