3-haloquinolines by Friedlaender reaction of α-haloketones

Article abstract of DOI:10.1021/jo2008252

A general approach to 3-fluoro-, 3-chloro-, and 3-bromoquinolines which relies on organosilane-promoted Friedlaender reaction of α-haloketones is described. The scope of the methylene component as well as influence of the organosilane component on the outcome of the reaction is studied. The method can be used under parallel synthesis conditions.

Full text of DOI:10.1021/jo2008252

ARTICLE
pubs.acs.org/joc
€
3-Haloquinolines by Friedlander Reaction of r-Haloketones
Sergey V. Ryabukhin,*,†,‡ Vasiliy S. Naumchik,†,§ Andrey S. Plaskon,†,§ Oleksandr O. Grygorenko,†,§
and Andrey A. Tolmachev†,§
†Kyiv National Taras Shevchenko University, 64 Volodymyrska str., Kyiv 01601, Ukraine
‡The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Kyiv 03187, Ukraine
§Enamine Ltd., 23 A. Matrosova str., Kyiv 01103, Ukraine
S Supporting Information
b
ABSTRACT: A general approach to 3-fluoro-, 3-chloro-, and
3-bromoquinolines which relies on organosilane-promoted
Friedl€ander reaction of R-haloketones is described. The scope
of the methylene component as well as influence of the
organosilane component on the outcome of the reaction is
studied. The method can be used under parallel synthesis
conditions.
’ INTRODUCTION
Friedl€ander reaction of ortho-aminocarbonyl compounds and R-
haloketones.
Quinoline derivatives fairly take a leading position among
other aromatic heterocycles in organic chemistry and related
areas. The quinoline scaffold has been identified among privi-
leged ones in drug discovery.1 In particular, quinoline derivatives
can be found among antimalarial, antibacterial, antiasthmatic,
antihypertensive, and anti-inflammatory agents.2ꢀ4 Aryl-substituted
quinolines act as ligands for 5-lipoxygenase,5 tyrosine kinase
(PDGF-RTK),6 leukotriene,7 LTD4,8 and other receptors.
Furthermore, polyquinolines were shown to undergo hierarch-
ical self-assembly into nanostructures with promising electronic
and photonic properties.9
3-Haloquinolines 1 are valuable building blocks for the pre-
paration of otherwise hardly accessible 3-substituted quinolines,
in particular, using palladium-catalyzed couplings. On the other
hand, 3-fluoroquinolines are of especial interest to medicinal
chemistry: introduction of a fluorine atom into organic molecules
is widely considered to improve their physicochemical para-
meters related to ADME properties.10
Most of the methods used for the preparation of 3-haloquin-
olines11 1 included either direct or indirect introduction of
halogen (e.g., by Sandmeyer reaction) into the quinoline core.12
Alternative approaches included dichlorocarbene-promoted in-
dole ring expansion,13 iodine-induced cyclization of N-propargyl-
anilines,14 cyclization of ortho-substituted difluorostyrenes,15 and
other methods.16 Noteworthy, classical condensations such as
DoebnerꢀMiller, Combes,17 Pfitzinger,12c or Friedl€ander reac-
tions were rarely used for the synthesis of 3-haloquinolines.
In this work, we wish to report a general method for the
synthesis of 3-haloquinolines 1 and their heteroanalogues using
’ RESULTS AND DISCUSSION
It has been shown previously that organosilanes can be used
as promoters for various reactions of carbonyl compounds.18
In particular, we have reported that chlorotrimethylsilane is an
effective promoter for the Friedl€ander reaction of ortho-amino-
carbonyl compounds and classical methylene components (i.e.,
β-dicarbonyl compounds, acetophenones, and their analogues,
cyclic ketones). The scope of the reaction was demonstrated by
variation of both carbonyl and methylene components of the
reaction.19,20
R-Haloketones are rarely encountered among methylene
components of the classical condensation reactions21 as the
presence of an additional electrophilic center results in further
transformations (e.g., formation of epoxides in Darzens reaction22).
In particular, apart from two isolated examples described by our
group (i.e., 4-chloroacetoacetate19 and 1,3-dichloroacetone23),
there have been no reports using R-haloketones as substrates for
the organosilane-promoted Friedl€ander reactions (Scheme 1).
To address the problem of selectivity in the latter transforma-
tions, first we studied condensation of 20-aminobenzophenone
2a and R-haloacetophenones 3aꢀd in the presence of various
organosilanes (Table 1, entries 1ꢀ16). It was found that, in the
case of R-fluoroacetophenone 3a, 3-fluoro-2,4-diarylquinoline
1aa is formed in 93ꢀ95% yields irrelevant to the organosilane
used as the reaction promoter. Analogously, 2,4-diarylquinoline 4
Received: April 29, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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Scheme 1. Organosilane-Promoted Friedl€ander Reaction of
ortho-Aminocarbonyl Compounds 2 and R-Haloketones 3
Scheme 2. Reaction of r-Haloketones 3 and Organosilanes
was the main product (80ꢀ93% yield) obtained in the reaction of
2a and R-iodoacetophenone 3d in all of the cases studied. As for
3b and 3c, the outcome of the reaction depended critically on the
organosilane used. In particular, quinolines 1ab and 1ac were
obtained from both these substrates in the case of Me3SiCl and
Me3SiBr, respectively. Hence the halogen atom in the final
3-haloquinoline arrived from the reaction promoter not from
the R-haloketone 3b or 3c. Moreover, the 3-unsubstituted
product 4 was obtained from 3b or 3c in the presence of Me3SiI.
Finally, the use of Me3SiOTf allowed the halogen atom from the
starting R-haloketone 3b or 3c to be retained in the correspond-
ing products 1ab and 1ac.
Scheme 3. Reaction of Aminoketones 2 and Intermediates
7 or 8 in the Presence of Organosilane (for X1 = F or X = OTf,
X2 = X1, Otherwise X2 = X)
The tendencies described in the above paragraph were
confirmed on a wide scope of the substrates. In particular,
3-chloroquinolines 1aeꢀ1cb were obtained by the reaction of
ortho-aminoketones 2aꢀ2c and R-chloroketones 3 (Table 1,
entries 17ꢀ24, 29ꢀ33). While in the case of 2a and 2c the
corresponding 3-chloroquinolines 1 were formed in good
yields (56ꢀ87%), the yields of the products prepared from
2b were moderate to good (47ꢀ76%), presumably due to the
self-condensation of 2b.
The method was successfully applied to the synthesis of
3-chlorothieno[2,3-b]pyridines. Hence thienopyridines 5aꢀ5c
were obtained in 79ꢀ83% yields starting from the thiophene 6
and R-chloroketones 3 (Table 1, entries 36ꢀ38).
R-Bromoketones 3n and 3o smoothly reacted with ketone 2a
in the presence of bromotrimethylsilane, leading to the forma-
tion of 3-bromoquinolines 1an and 1ao in good yields
(73ꢀ88%) (Table 1, entries 25 and 26).
Finally, 3-fluoroquinolines 1ap, 1ba, 1cp, and 1dp and
thienopyridines 5d and 5e were isolated in good yields (75ꢀ
89%, except 1ba) as the products of the Friedl€ander reactions
involving R-fluoroketones 3a and 3p (Table 1, entries 27, 28, 34,
35, 39, and 40). Again, the yield was moderate (39%) in the case
of 1ba obtained from o-aminoacetophenone 2b.
eliminated to give the 3-haloquinolines 1; otherwise, IX is
eliminated instead to yield 4.
’ CONCLUSIONS
The results obtained on the organosilane-promoted
Friedl€ander reaction can be explained by the transformations
shown in the Schemes 2 and 3. The reaction starts with
activation of R-haloketone 3 upon action of the organosilane
Me3SiX giving adducts 7aꢀ7c.18 7 can equilibrate with
intermediates 8 via the halogen exchange.24 Provided that
5-fold excess of the organosilane is used, these equilibriums
are shifted toward the formation of 8. The formation of 8 is
disfavored in the case of X1 = F due to the resistance to
substitution of the CꢀF bond and in the case of X = OTf due
to the low nucleophilicity of this counterion. Hence for X1 = F
or X = OTf, X2 in the Scheme 3 is the same as X1, otherwise
X2 = X.
Either 7 or 8 can react with N-silyl derivatives 9 of the
aminocarbonyl compounds 2, yielding imines 10. The latter
undergo an intramolecular aldol-type reaction, whose mechan-
ism is well-documented in the literature.18 Intermediate 11 then
can react with organosilane by two means. If X2 ¼ I, then HX is
Organosilane-promoted Friedl€ander reaction of R-haloke-
tones and ortho-aminocarbonyl compounds is a general and
efficient method for the synthesis of 3-fluoro-, 3-chloro-, and
3-bromoquinolines.
The combination of organosilane and R-haloketone used critically
influences the reaction outcome. In the case of R-fluoroketones,
3-fluoroquinolines are formed regardless the organosilane used. If
an R-iodoketone is introduced into the reaction, 3-unsubstituted
quinoline is obtained. In the case of R-chloro- and R-bromoke-
tones, the outcome of the reaction depends on the organosilane
used. If Me3SiCl or Me3SiBr are the reaction promoters,
3-haloquinoline formed contains the halogen atom from the
organosilane used. On the contrary, the halogen atom from R-
haloketone is retained in the case of Me3SiOTf. Finally, the use of
Me3SiI resulted in the formation of 3-unsubstituted quinolines.
As the operating procedure of the organosilane-promoted
Friedl€ander reaction is technically simple, the method can be
used under parallel synthesis conditions.
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Table 1. Friedl€ander Reaction of Aminoketones 2, 6, and R-Haloketones 3
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Table 1. Continued
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Table 1. Continued
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’ EXPERIMENTAL SECTION
3-Chloro-2-(chloromethyl)-4-phenylquinoline (1af): Yield
87%; mp 152 °C; 1H NMR (DMSO-d6) δ = 5.10 (s, 2H), 7.35ꢀ7.40 (m,
3JH,H = 8.5 Hz); 13C NMR (DMSO-d6) δ = 46.5, 126.2, 126.6, 128.0,
128.8, 129.2, 129.3, 129.5, 129.6, 130.7, 135.0, 145.6, 147.2, 153.8; APCI
MS (Mþ þ 1) = 288. Anal. Calcd for C16H11Cl2N: C, 66.69; H, 3.85; N,
4.86. Found: C, 66.72; H, 3.82; N, 4.81.
3
General Comments. All starting materials were commercially
available and were used without additional purification. All solvents
were purified by standard methods. All procedures were carried out
under open atmosphere with no precautions taken to exclude ambient
moisture. Melting points are uncorrected. 1H NMR spectra were
recorded on 400 and 500 MHz spectrometers with TMS as an internal
standard. 13C NMR (125 MHz) and NMR experiments were recorded
on a 500 MHz with TMS as internal standard. LC/MS spectra were
recorded using a chromatography/mass spectrometric system that
consists of high-performance liquid chromatograph equipped with a
diode-matrix and mass-selective detector. Ionization method, chemical
ionization under atmospheric pressure (APCI). Ionization mode,
simultaneous scanning of positive and negative ions in the mass range
of 80ꢀ1000 m/z. According to HPLC MS and 1H NMR spectra data, all
synthesized compounds have purity >95%.
3H), 7.58ꢀ7.64 (m, 4H), 7.84 (t, 1H, JH,H = 7.55 Hz), 8.13 (d, 1H,
3-Chloro-2-(5-methyl-2-thienyl)-4-phenylquinoline (1ag):
Yield 67%; mp 124 °C; H NMR (DMSO-d6) δ = 2.53 (s, 3H), 6.92
1
(br s, 1H), 7.24 (d, 1H, 3JH,H = 8.4 Hz), 7.39 (d, 2H, 3JH,H = 7.6 Hz),
7.50 (t, 1H, 3JH,H = 7.6 Hz), 7.56ꢀ7.62 (m, 3H), 7.77 (t, 1H, 3JH,H
=
7.6 Hz), 8.00 (m, 2H); 13C NMR (DMSO-d6) δ = 15.6, 124.1, 126.2, 126.9,
127.1, 127.8, 129.1, 129.2, 129.6, 130.7, 131.0, 135.7, 140.5, 144.8, 145.7,
147.9, 149.2; APCI MS (Mþ þ 1) = 336. Anal. Calcd for C20H14ClNS: C,
71.53; H, 4.20; N, 4.17. Found: C, 71.51; H, 4.23; N, 4.19.
3-Chloro-4-phenyl-2-(1,2,5-trimethyl-1H-pyrrol-3-yl)quino-
line (1ah): Yield 85%; mp 136 °C; H NMR (DMSO-d6) δ = 2.22
1
3
€
GeneralProcedure for Organosilane-Promoted Friedlander
(s, 3H), 2.36 (s, 3H), 3.46 (s, 3H), 6.21 (s, 1H), 7.25 (d, 1H, JH,H
=
3
3
Reaction. ortho-Aminocarbonyl compounds 2aꢀd or 6 (1 mmol) and
R-haloketones 3aꢀp (1 mmol) were placed in an 8 mL pressure tube
and dissolved in DMF (2 mL). Organosilane (5 mmol) was added
dropwise to the solution at 0 °C. The tube was thoroughly sealed and
heated on a steam bath for 4ꢀ10 h (Me3SiCl) or allowed to stand for
24ꢀ48 h (other organosilanes). After cooling, the tube was opened
(CAUTION! Excessive pressure inside), and the reaction mixture was
poured into water (5 mL) and then sonicated at 20 °C for 1 h. The
precipitate formed was filtered and washed with small amount of
CH3CN. The crude product was recrystallized from 2-propanol or
CH3CN or purified by flash chromatography (hexanesꢀether (95:5 or
9:1) as an eluent) to yield the compounds 1, 4, or 5 (Table 1).
8.3 Hz), 7.40 (d, 2H, JH,H = 7.1 Hz), 7.47 (t, 1H, JH,H = 7.5 Hz),
7.53ꢀ7.61 (m, 3H), 7.73 (t, 1H, 3JH,H = 7.4 Hz), 7.98 (d, 1H, 3JH,H = 8.3
Hz); 13C NMR (DMSO-d6) δ = 12.0, 12.9, 30.5, 107.8, 117.8, 126.0,
126.6, 126.7, 126.9, 127.0, 128.8, 129.07, 129.11, 129.3, 129.7, 129.9,
136.3, 146.1, 146.3, 154.7; APCI MS (Mþ þ 1) = 347. Anal. Calcd for
C22H19ClN2: C, 76.18; H, 5.52; N, 8.08. Found: C, 76.20; H, 5.49;
N, 8.16.
3-Chloro-2-(4-ethoxyphenyl)-4-phenylquinoline (1ai):
Yield 81%; mp 106 °C; 1H NMR (DMSO-d6) δ = 1.37 (t, 3H, 3JH,H
=
7.1 Hz), 4.12 (q, 2H, 3JH,H = 7.1 Hz), 7.07 (d, 2H, 3JH,H = 8.8 Hz), 7.33
(d, 1H, 3JH,H = 8.3 Hz), 7.43 (d, 2H, 3JH,H = 7.4 Hz), 7.56ꢀ7.63 (m,
4H), 7.73 (d, 2H, 3JH,H = 8.8 Hz), 7.81 (t, 1H, 3JH,H = 7.4 Hz), 8.11 (d,
3
1H, JH,H = 8.3 Hz); 13C NMR (DMSO-d6) δ = 15.2, 63.7, 114.3,
2-(4-Chlorophenyl)-3-fluoro-4-phenylquinoline (1aa):
Yield 89%; mp 113 °C; H NMR (DMSO-d6) δ = 7.58ꢀ7.67 (m,
1
126.15, 126.23, 127.4, 128.1, 129.1, 129.2, 129.5, 129.7, 130.6, 131.4,
131.6, 135.8, 145.9, 147.3, 156.8, 159.6; APCI MS (Mþ þ 1) = 360.
Anal. Calcd for C23H18ClNO: C, 76.77; H, 5.04; N, 3.89. Found: C,
76.75; H, 5.06; N, 3.86.
9H), 7.82 (t, 1H, 3JH,H = 7.5 Hz), 8.09 (d, 2H, 3JH,H = 8.0 Hz), 8.19 (d,
3
3
1H, JH,H = 8.5 Hz); 13C NMR (DMSO-d6) δ = 125.6 (d, JC,F
=
5.0 Hz), 127.7, 128.5, 129.1, 129.2, 129.50, 129.54, 129.9, 130.5, 131.0.
2
3
131.40, 131.44, 133.0 (d, JC,F = 14.5 Hz), 134.7 (d, JC,F = 5.0 Hz),
3-Chloro-2-[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrol-
3
2
1
135.2, 145.1 (d, JC,F = 3.5 Hz), 147.3 (d, JC,F = 15.9 Hz), 151.2 (d,
1JC,F = 257.8 Hz); 19F NMR (DMSO-d6) δ = ꢀ123.1; APCI MS
(Mþ þ 1) = 334. Anal. Calcd for C21H13ClFN: C, 75.57; H, 3.93;
N, 4.20. Found: C, 75.54; H, 3.92; N, 4.22.
3-yl]-4-phenylquinoline (1aj): Yield 76%; mp 168 °C; H NMR
(DMSO-d6) δ = 2.05 (s, 3H), 2.17 (s, 3H), 6.42 (s, 1H), 7.28 (m, 1H),
7.41ꢀ7.50 (m, 5H), 7.55ꢀ7.66 (m, 5H), 7.75 (m, 1H), 8.01 (m, 1H);
13C NMR (DMSO-d6) δ = 11.1, 11.3, 106.3, 116.5, 126.1, 126.7, 126.8,
127.1, 127.3, 128.1, 129.0, 129.14, 129.16, 129.25, 129.29, 129.6,
129.7, 130.1, 132.2, 133.0, 136.2, 146.1, 146.6, 154.1, 166.4; APCI MS
(Mþ þ 1) = 443. Anal. Calcd for C27H20Cl2N2: C, 73.14; H, 4.55; N,
6.32. Found: C, 73.16; H, 4.58; N, 6.33.
3-Chloro-2-(4-chlorophenyl)-4-phenylquinoline (1ab):
Yield 84%; mp 154 °C; 1H NMR (DMSO-d6) δ = 7.35 (d, 1H, 3JH,H
=
8.3 Hz), 7.42 (d, 2H, 3JH,H = 7.5 Hz), 7.54ꢀ7.62 (m, 6H), 7.77ꢀ7.84
(m, 3H), 8.12 (d, 1H, 3JH,H = 8.3 Hz); 13C NMR (DMSO-d6) δ = 125.9,
126.2, 127.6, 128.4, 128.5, 129.2, 129.7, 130.6, 131.8, 134.3, 135.6, 138.1,
146.1, 147.2, 156.0; APCI MS (Mþ þ 1) = 350. Anal. Calcd for
C21H13Cl2N: C, 72.02; H, 3.74; N, 4.00. Found: C, 72.04; H, 3.75; N, 4.03.
3-Bromo-2-(4-chlorophenyl)-4-phenylquinoline (1ac):
Yield 83%; mp 142 °C; 1H NMR (DMSO-d6) δ = 7.33 (d, 1H,
N-[3-(3-Chloro-4-phenylquinolin-2-yl)-2,5-dimethyl-1H-
pyrrol-1-yl]benzamide (1ak): Yield 73%; mp >300 °C; H NMR
1
(DMSO-d6) δ = 2.14 (s, 3H), 2.27 (s, 3H), 6.33 (s, 1H), 7.28 (d, 1H,
3JH,H = 8.3 Hz), 7.42 (d, 2H, 3JH,H = 8.0 Hz), 7.50 (t, 1H, 3JH,H = 7.7 Hz),
3
7.55ꢀ7.62 (m, 5H), 7.67 (m, 1H), 7.76 (t, 1H, JH,H = 7.7 Hz), 8.03
3
3JH,H = 8.3 Hz), 7.39 (d, 2H, JH,H = 7.8 Hz), 7.55ꢀ7.62 (m, 6H),
(m, 3H), 11.50 (s, 1H); 13C NMR (DMSO-d6) δ = 12.7, 13.1, 109.2,
119.1, 126.1, 126.7, 127.0, 127.3, 127.4, 128.9, 129.16, 129.21, 129.7,
130.0, 130.1, 130.6, 133.3, 136.2, 137.2, 146.1, 146.5, 154.2; APCI MS
(Mþ þ 1) = 452. Anal. Calcd for C28H22ClN3O: C, 74.41; H, 4.91;
N, 9.30. Found: C, 74.44; H, 4.89; N, 9.32.
7.72 (d, 2H, 3JH,H = 8.5 Hz), 7.83 (t, 1H, 3JH,H = 7.8 Hz), 8.10 (d, 1H,
3JH,H = 8.8 Hz); 13C NMR (DMSO-d6) δ = 118.2, 126.5, 127.8,
128.4, 128.5, 129.1, 129.2, 129.5, 129.7, 130.8, 131.8, 134.1, 137.9,
139.8, 146.3, 149.9, 157.5; APCI MS (Mþ þ 1) = 395. Anal. Calcd
for C21H13BrClN: C, 63.91; H, 3.32; N, 3.55. Found: C, 63.85; H,
3.35; N, 3.52.
2-tert-Butyl-3-chloro-4-phenylquinoline (1al): Yield 56%;
1
mp 115 °C; H NMR (DMSO-d6) δ = 1.61 (s, 9H), 7.21 (d, 1H,
3-Chloro-2-methyl-4-phenylquinoline (1ae): Yield 73%; mp
3JH,H = 8.5 Hz), 7.36 (d, 2H, 3JH,H = 7.1 Hz), 7.50ꢀ7.60 (m, 4H), 7.76
(t, 1H, 3JH,H = 7.6 Hz), 8.04 (d, 1H, 3JH,H = 8.3 Hz); 13C NMR (DMSO-
d6) δ = 29.4, 40.5, 125.9, 126.5, 127.24, 127.7, 128.8, 129.1, 129.63,
129.65, 130.0, 136.2, 144.6, 147.8, 163.3; APCI MS (Mþ þ 1) = 296.
Anal. Calcd for C19H18ClN: C, 77.15; H, 6.13; N, 4.73. Found: C, 77.18;
H, 6.11; N, 4.76.
108 °C; 1H NMR (DMSO-d6) δ = 2.79 (s, 3H), 7.29 (d, 1H, 3JH,H
=
3
3
8.4 Hz), 7.36 (d, 2H, JH,H = 7.4 Hz), 7.51 (t, 1H, JH,H = 7.6 Hz),
7.56ꢀ7.61 (m, 3H), 7.76 (t, 1H, 3JH,H = 7.6 Hz), 8.03 (d, 1H, 3JH,H = 8.4
Hz); 13C NMR (DMSO-d6) δ = 24.7, 126.0, 127.17, 127.24, 127.3,
128.97, 129.04, 129.6, 129.9, 135.5, 145.4, 145.8, 156.4; APCI MS
(Mþ þ 1) = 254. Anal. Calcd for C16H12ClN: C, 75.74; H, 4.77; N, 5.52.
Found: C, 75.71; H, 4.79; N, 5.54.
3-Bromo-2-(4-fluorophenyl)-4-phenylquinoline (1an):
Yield 88%; mp 140 °C; 1H NMR (DMSO-d6) δ = 7.33ꢀ7.38 (m, 3H),
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7.40 (d, 2H, 3JH,H = 7.1 Hz), 7.56ꢀ7.63 (m, 4H), 7.77 (m, 2H), 7.84 (t,
1H, 3JH,H = 7.7 Hz), 8.12 (d, 1H, 3JH,H = 8.5 Hz); 13C NMR (DMSO-d6)
δ = 115.2 (d, 2JC,F = 21.9 Hz), 118.4, 126.5, 127.8, 128.4, 129.1, 129.2,
129.5, 129.6, 130.8, 132.1 (d, 3JC,F = 8.5 Hz), 137.5 (d, 4JC,F = 3.0 Hz),
C16H12ClN: C, 75.74; H, 4.77; N, 5.52. Found: C, 75.76; H, 4.79;
N, 5.54.
3,6-Dichloro-2,4-diphenylquinoline (1cm): Yield 89%; mp
122 °C; 1H NMR (DMSO-d6) δ = 7.24 (br s, 1H), 7.44 (m, 2H), 7.51
(m, 3H), 7.60 (m, 3H), 7.72 (m, 2H), 7.82 (d, 1H, 3JH,H = 8.4 Hz), 8.13
(d, 1H, 3JH,H = 8.6 Hz); 13C NMR (DMSO-d6) δ = 124.6, 127.3, 128.2,
128.4, 129.3, 129.4, 129.4, 129.6, 129.9, 130.9, 131.9, 132.9, 135.0, 139.0,
144.5, 146.3, 157.6; APCI MS (Mþ þ 1) = 350. Anal. Calcd for
C21H13Cl2N: C, 72.02; H, 3.74; N, 4.00. Found: C, 72.05; H, 3.71;
N, 4.03.
1
137.9, 146.3, 149.8, 157.7, 162.7 (d, JC,F = 245.9 Hz); APCI MS
(Mþ þ 1) = 379. Anal. Calcd for C21H13BrFN: C, 66.69; H, 3.46; N,
3.70. Found: C, 66.63, H, 3.48; N, 3.73.
3-Bromo-2-cyclohexyl-4-phenylquinoline (1ao): Yield 73%;
1
mp 120 °C; H NMR (DMSO-d6) δ = 1.33(m, 1H), 1.43 (m, 2H),
1.73(m, 3H), 1.87 (m, 2H), 1.97 (m, 2H), 3.42 (m, 1H), 7.24 (d, 1H,
3JH,H = 8.0 Hz), 7.32 (d, 2H, 3JH,H = 7.4 Hz), 7.48 (t, 1H, 3JH,H = 8.0 Hz),
7.53ꢀ7.60 (m, 3H), 7.77 (t, 1H, 3JH,H = 7.6 Hz), 8.03 (d, 1H, 3JH,H = 8.3
Hz); 13C NMR (DMSO-d6) δ = 26.2, 26.6, 32.0, 45.3, 120.1, 126.3,
127.44, 127.47, 128.9, 129.1, 129.3, 129. 5, 130.2, 138.2, 146.2, 148.7,
163.2; APCI MS (Mþ þ 1) = 367. Anal. Calcd for C21H20BrN: C, 68.86;
H, 5.50; N, 3.82. Found: C, 68.88, H, 5.53; N, 3.85.
6-Chloro-3-fluoro-2,4-diphenylquinoline (1cp): Yield 83%;
1
mp 137 °C; H NMR (DMSO-d6) δ = 7.49 (m, 1H), 7.56ꢀ7.65 (m,
8H), 7.80 (dd, 1H, 3JH,H = 9.0 Hz, 4JH,H = 2.2 Hz), 8.02 (m, 2H), 8.18 (d,
1H, 3JH,H = 9.0 Hz); 13C NMR (DMSO-d6) δ = 124.1 (d, 3JC,F = 5.4
Hz), 128.5, 129.0, 129.4, 129.67, 129.71, 129.8, 130.0, 130.4, 130.5,
132.1, 132.2 (d, 2JC,F = 15.2 Hz), 132.9, 135.5 (d, 3JC,F = 4.6 Hz), 143.6
(d, 3JC,F = 3.9 Hz), 149.3 (d, 2JC,F = 15.8 Hz), 151.8 (d, 1JC,F = 259.4
Hz); 19F NMR (DMSO-d6) δ = ꢀ126.2; APCI MS (Mþ þ 1) = 334.
Anal. Calcd for C21H13ClFN: C, 75.57; H, 3.93; N, 4.20. Found: C,
75.59, H, 3.96; N, 4.23.
3-Fluoro-2,4-diphenylquinoline (1ap): Yield 87%; mp 123 °C;
1H NMR (DMSO-d6) δ = 7.53ꢀ7.62 (m, 10H), 7.78 (t, 1H, 3JH,H = 7.5
3
3
Hz), 8.02 (d, 2H, JH,H = 7.7 Hz), 8.16 (d, 1H, JH,H = 8.5 Hz); 13C
3
NMR (DMSO-d6) δ = 125.5 (d, JC,F = 5.5 Hz), 127.5, 128.2, 129.0,
129.2, 129.4, 129.6, 129.7, 129.9, 130.2, 130.5, 131.1, 132.8 (d, 2JC,F
=
3-Fluoro-6-nitro-2,4-diphenylquinolinequinoline (1dp):
Yield 80%; mp 205 °C; 1H NMR (DMSO-d6) δ = 7.53ꢀ7.70 (m, 8H),
8.09 (m, 2H), 8.36 (m, 1H), 8.41 (m, 1H), 8.48 (m, 1H); 13C NMR
15.0 Hz), 135.9 (d, 3JC,F = 5.0 Hz), 145.2 (d, 3JC,F = 4.0 Hz), 148.7 (d,
2JC,F = 15.9 Hz), 151.2 (d, JC,F = 257.8 Hz); 19F NMR (DMSO-d6)
1
δ = ꢀ128.0; APCI MS (Mþ þ 1) = 300. Anal. Calcd for C21H14FN: C,
3
(DMSO-d6) δ = 122.4 (d, JC,F = 5.3 Hz), 122.8, 126.8, 128.5, 129.1,
129.5, 129.91, 129.95, 130.2, 130.7, 131.1, 131.9, 134.7 (d, 2JC,F = 16.0
Hz), 135.1 (d, 3JC,F = 4.6 Hz), 146.1, 147.0 (d, 3JC,F = 3.8 Hz), 152.1 (d,
1JC,F = 260.9 Hz), 152.3 (d, 2JC,F = 16.0 Hz); 19F NMR (DMSO-d6) δ =
ꢀ124.6; APCI MS (Mþ þ 1) = 345. Anal. Calcd for C21H13FN2O2: C,
73.25; H, 3.81; N, 8.14. Found: C, 73.27, H, 3.84; N, 8.17.
84.26; H, 4.71; N, 4.68. Found: C, 84.24, H, 4.74; N, 4.64.
2-(4-Chlorophenyl)-3-fluoro-4-methylquinoline (1ba):
Yield 39%; mp 116 °C; 1H NMR (DMSO-d6) δ = 2.64 (s, 3H), 7.63 (d,
2H, 3JH,H = 8.6 Hz), 7.69 (t, 1H, 3JH,H = 7.5 Hz), 7.77 (t, 1H, 3JH,H = 7.3
Hz), 8.02 (d, 2H, 3JH,H = 8.6 Hz), 8.08 (d, 1H, 3JH,H = 8.6 Hz), 8.10 (d,
1H, 3JH,H = 8.3 Hz); 13C NMR (DMSO-d6) δ = 10.2 (d, 3JC,F = 6.0 Hz),
124.6 (d, 3JC,F = 5.0 Hz), 127.9, 128.55 (d, 4JC,F = 3.0 Hz), 129.0, 129.1
3-Chloro-2-(4-chlorophenyl)-4-phenyl-5,6,7,8-tetrahydro-
[1]benzothieno[2,3-b]pyridine (5a): Yield 83%; mp 164 °C; H
1
(d, 2JC,F = 15.0 Hz), 129.4 (d, 4JC,F = 2.0 Hz), 130.0, 131.30 (d, 4JC,F
=
NMR (DMSO-d6) δ = 1.51 (m, 2H), 1.75 (m, 4H), 2.85 (m, 2H), 7.38
5.5 Hz), 134.8 (d, 3JC,F = 5.0 Hz), 135.0, 144.6 (d, 4JC,F = 3.0 Hz), 146.6
(d, 2JC,F = 15.9 Hz), 152.9 (d, 1JC,F = 255.3 Hz); 19F NMR (DMSO-d6)
δ = ꢀ128.0; APCI MS (Mþ þ 1) = 272. Anal. Calcd for C16H11ClFN:
C, 70.73; H, 4.08; N, 5.15. Found: C, 70.75, H, 4.11; N, 5.18.
3-Chloro-2-(4-chlorophenyl)-4-methylquinoline (1bb):
Yield 69%; mp 158 °C; 1H NMR (DMSO-d6) δ = 2.81 (s, 3H), 7.58 (d,
2H, 3JH,H = 8.5 Hz), 7.71 (m, 3H), 7.81 (t, 1H, 3JH,H = 7.5 Hz), 8.03 (d,
1H, 3JH,H = 8.3 Hz), 8.20 (d, 1H, 3JH,H = 8.5 Hz); 13C NMR (DMSO-d6)
δ = 16.2, 125.0, 126. 9, 127.8, 128.2, 128.5, 130.0, 130.4, 131.7, 134.1,
138.5, 143.3, 145.5, 155.7; APCI MS (Mþ þ 1) = 288. Anal. Calcd for
C16H11Cl2N: C, 66.69; H, 3.85; N, 4.86. Found: C, 66.72; H, 3.81;
N, 4.89.
(m, 2H), 7.53 (m, 3H), 7.57 (d, 2H, 3JH,H = 8.3 Hz), 7.74 (d, 2H, 3JH,H
=
8.3 Hz); 13C NMR (DMSO-d6) δ = 22.4, 25.7, 26.2, 34.6, 126.0, 128.1,
128.5, 128.6, 129.1, 129.5, 131.7, 131.9, 134.0, 136.3, 137.7, 140.8, 144.1,
150.8, 158.4; APCI MS (Mþ þ 1) = 410. Anal. Calcd for C23H17Cl2NS:
C, 67.32; H, 4.18; N, 3.41. Found: C, 67.35; H, 4.16; N, 3.44.
3-Chloro-5,6,7,8-tetrahydro-2,4-diphenyl[1]benzothieno-
[2,3-b]pyridine (5b): Yield 79%; mp 158 °C; 1H NMR (DMSO-d6)
δ = 1.51 (m, 2H), 1.74 (m, 4H), 2.84 (m, 2H), 7.38 (m, 2H), 7.48ꢀ7.53
(m, 6H), 7.70 (d, 2H, 3JH,H = 7.6 Hz); 13C NMR (DMSO-d6) δ = 22.4,
25.8, 26.2, 34.6, 126.0, 128.0, 128.4, 128.6, 129.0, 129.5, 129.9, 131.4,
136.5, 139.0, 140.4, 144.0, 152.1, 158.4; APCI MS (Mþ þ 1) = 376.
Anal. Calcd for C23H18ClNS: C, 73.49; H, 4.83; N, 3.73. Found: C,
73.47; H, 4.86; N, 3.76.
3-Chloro-2,4-dimethylquinoline (1be): Yield 47%; mp 102 °C;
1H NMR (DMSO-d6) δ = 2.74 (s, 3H), 2.76 (s, 3H), 7.64 (t, 1H, 3JH,H
=
3-Chloro-2-(chloromethyl)-5,6,7,8-tetrahydro-4-phenyl-
1
7.6 Hz), 7.76 (t, 1H, 3JH,H = 7.2 Hz), 7.96 (d, 1H, 3JH,H = 8.4 Hz), 8.13 (d,
1H, 3JH,H = 8.8 Hz); 13C NMR (DMSO-d6) δ = 15.8, 24.8, 124.9, 127.1,
127.4, 128.5, 129.2, 129.8, 141.4, 145.3, 156.0; APCI MS (Mþ þ 1) = 192.
Anal. Calcd for C11H10ClN: C, 68.94; H, 5.26; N, 7.31. Found: C, 68.96;
H, 5.29; N, 7.28.
[1]benzothieno[2,3-b]pyridine (5c): Yield 83%; mp 124 °C; H
NMR (DMSO-d6) δ = 1.49 (m, 2H), 1.74 (m, 4H), 2.84 (m, 2H), 5.01
(s, 1H), 7.33 (m, 2H), 7.53 (m, 3H); 13C NMR (DMSO-d6) δ =22.3,
22.4, 25.8, 26.3, 46.3, 127.4, 128.2, 128.6, 129.2, 129.4, 132.5, 135.8,
141.4, 144.0, 148.8, 157.9; APCI MS (Mþ þ 1) = 348. Anal. Calcd for
C18H15Cl2NS: C, 62.07; H, 4.34; N, 4.02. Found: C, 62.09, H, 4.37;
N, 4.06.
3-Chloro-2-(chloromethyl)-4-methylquinoline (1bf): Yield
76%; mp 98 °C; 1H NMR (DMSO-d6) δ = 2.79 (s, 3H), 5.03 (s, 2H),
7.73 (t, 1H, 3JH,H = 7.2 Hz), 7.83 (t, 1H, 3JH,H = 7.4 Hz), 8.04 (d, 1H,
3JH,H = 8.3 Hz), 8.18 (d, 1H, 3JH,H = 8.6 Hz); 13C NMR (DMSO-d6) δ =
15.8, 46.6, 124.8, 127.4, 128.0, 128.4, 129.7, 130.4, 143.2, 145.0, 153.2;
APCI MS (Mþ þ 1) = 226. Anal. Calcd for C11H9Cl2N: C, 58.43; H,
4.01; N, 6.19. Found: C, 58.46; H, 4.03; N, 6.16.
2-(4-Chlorophenyl)-3-fluoro-5,6,7,8-tetrahydro-4-phenyl-
[1]benzothieno[2,3-b]pyridine (5d): Yield 79%; mp 143 °C; 1H
NMR (DMSO-d6) δ = 1.54 (m, 2H), 1.76 (m, 2H), 1.88 (m, 2H), 2.86
(m, 2H), 7.48 (m, 2H), 7.55 (m, 3H), 7.59 (d, 2H, 3JH,H = 8.6 Hz), 7.99
(d, 2H, 3JH,H = 7.8 Hz); 13C NMR (DMSO-d6) δ = 22.4, 22.5, 26.0, 26.3,
128.3 (d, 3JC,F = 3.5 Hz), 128.5, 129.0, 129.3, 130.1, 130.8 (d, 3JC,F = 6.4
Hz), 131.8, 132.6 (d, 2JC,F = 19.4 Hz), 134.3 (d, 3JC,F = 5.0 Hz), 134.5,
140.2 (d, 2JC,F = 16.4 Hz), 141.5, 152.9 (d, 1JC,F = 250.3 Hz), 155.8 (d,
4JC,F = 3 Hz); 19F NMR (DMSO-d6) δ = ꢀ129.8; APCI MS (Mþ þ 1) =
394. Anal. Calcd for C23H17ClFNS: C, 70.13; H, 4.35; N, 3.56. Found:
C, 70.16, H, 4.38; N, 3.58.
3-Chloro-4-methyl-2-phenylquinoline (1bm): Yield 63%;
1
mp 108 °C; H NMR (DMSO-d6) δ = 2.82 (s, 3H), 7.51 (m, 3H),
3
7.65ꢀ7.72 (m, 3H), 7.80 (t, 1H, JH,H = 7.7 Hz), 8.03 (d, 1H,
3JH,H = 8.3 Hz), 8.20 (d, 1H, 3JH,H = 8.6 Hz); 13C NMR (DMSO-d6)
δ = 16.3, 125.0, 127.1, 127.7, 128.0, 128.4, 129.2, 129.7, 130.0, 130.4,
139.7, 143.1, 145.5, 156.9; APCI MS (Mþ þ 1) = 254. Anal. Calcd for
5780
dx.doi.org/10.1021/jo2008252 |J. Org. Chem. 2011, 76, 5774–5781

The Journal of Organic Chemistry
ARTICLE
3-Fluoro-5,6,7,8-tetrahydro-2,4-diphenyl[1]benzothieno-
[2,3-b]pyridine (5e): Yield 75%; mp 118 °C; 1H NMR (DMSO-d6)
δ = 1.51 (m, 2H), 1.73 (m, 2H), 1.85 (m, 2H), 2.83 (m, 2H), 7.46ꢀ7.51
(m, 8H), 7.93 (d, 2H, 3JH,H = 7.1 Hz); 13C NMR (DMSO-d6) δ = 22.4,
22.5, 26.1, 26.3, 128.4 (d, 3JC,F = 3.5 Hz), 128.5, 129.0, 129.2 (d, 3JC,F = 6
Hz), 129.3, 129.6, 130.1, 131.5, 132.0, 132.6 (d, 2JC,F = 18.9 Hz), 135.5
(d, 3JC,F = 5 Hz), 141.2, 141.7 (d, 2JC,F = 16.5 Hz), 152.5 (d, 1JC,F = 249.3
Hz), 155.7 (d, 4JC,F = 3 Hz); 19F NMR (DMSO-d6) δ = ꢀ134.9; APCI
MS (Mþ þ 1) = 360. Anal. Calcd for C23H18FNS: C, 76.78; H, 5.04; N,
3.90. Found: C, 76.23, H, 5.05; N, 3.86.
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’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data of pro-
b
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
(16) (a) Hosokawa, T.; Matsumura, A.; Katagiri, T.; Uneyama, K.
J. Org. Chem. 2008, 73, 1468–1474. (b) Campos, P. J.; Tan, C.-Q.;
Rodriguez, M. A.; Anon, E. J. Org. Chem. 1996, 61, 7195–7197.
(c) Campos, P. J.; Anon, E.; Malo, M. C.; Tan, C.-Q.; Rodriguez,
M. A. Tetrahedron 1998, 54, 6929–6938.
Corresponding Author
*E-mail: s.v.ryabukhin@gmail.com. Fax: þ380 44 5373253.
’ ACKNOWLEDGMENT
(17) Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine Chem.
The authors thank Mr. Vitaliy V. Polovinko for NMR mea-
surements, and Mrs. Olga V. Manoylenko for chromatographic
separations.
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