A facile and efficient synthesis of 1-trichloromethyl-1,2-dihydrobenzo [b] [1,6] naphthyridines via three-component reaction among 2-alkynylquinoline-3- carbaldehydes, primary amines, and chloroform

Article abstract of DOI:10.1515/hc-2011-0106

A three-component reaction among 2-alkynylquinoline-3-carbaldehydes, primary amines, and chloroform leading to novel 1-(trichloromethyl)-1,2- dihydrobenzo [b] [1,6] naphthyridines was developed using microwave initiation in an absence of any catalysts. Th

Full text of DOI:10.1515/hc-2011-0106

Heterocycl. Commun., Vol. 18(2), pp. 87–92, 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hc-2011-0106
A facile and efficient synthesis of 1-trichloromethyl-1,2-
dihydrobenzo[b][1,6]naphthyridines via three-component
reaction among 2-alkynylquinoline-3-carbaldehydes, primary
amines, and chloroform
ˇ
primary amines, and C-pronucleophiles and the use of this
method for the preparation of biologically important 1,2-
dihydrobenzo[b][1,6]naphthyridine scaffold. Herein, we pres-
ent the results of our investigations.
Rita Bukšnaitiene and Inga Cikotiene*
˙
˙
Department of Organic Chemistry, Faculty of Chemistry,
Vilnius University, Naugarduko 24, LT-03225 Vilnius,
Lithuania
*Corresponding author
e-mail: inga.cikotiene@chf.vu.lt
Results and discussion
For the synthesis of the starting compounds 1a–d, we fol-
lowed a classical Sonogashira coupling (Sonogashira et al.,
1975) between commercially available 2-chloroquinoline-3
-carbaldehyde and terminal acetylenes. First, we turned our
attention to the multicomponent reaction among the sub-
strates 1a–d, amines, and chloroform by the method devel-
oped earlier by Asao et al. (2006) and Iso et al. (2008) for
o-alkynylbenzenecarbaldehydes. However, upon the treat-
ment of compounds 1a–d with amines in chloroform in the
presence of 3-Å molecular sieves at room temperature, the
conversions of the starting compounds were incomplete and
mixtures of various products were formed. Heating under
reflux of aldehydes 1a,b with 1.2 equivalents of the cor-
responding amine in chloroform and in the presence of the
molecular sieves furnished the target compounds 2a–d,h,i in
16–60% yields (Scheme 1). It should be noted that refluxing
took 24–48 h, and the conversions of the starting compounds
were still incomplete. Moreover, the reaction between 1a and
bulky cyclopentylamine in chloroform was unsuccessful, as
no product was observed by thin-layer chromatography (TLC)
after 48 h of heating. On the other hand, 2-hexynylquinoline-
3-carbaldehyde 1d was completely inert toward benzylamine
and butylamine in refluxing chloroform.
To shorten the long reaction times, microwave-assisted
chemistry was used (Gedye et al., 1986; Caddick, 1995;
Strauss et al., 1995; Lew et al., 2002). When the mixtures
of the starting compounds 1a–d, amines, chloroform, and
molecular sieves in 1,2-dichloroethane were placed in closed
vessels and irradiated in a domestic microwave oven for 5–60
min, the target 1-(trichloromethyl)-1,2-dihydrobenzo[b][1,6]
naphthyridines formed. The method tolerates well aliphatic
amines. In the case of bulky cyclopentylamine, the reaction
time is longer and the yields are slightly lower. An attempted
reaction of the starting quinoline 1a with aniline was unsuc-
cessful, and the formation of a stable Schiff base 3a as a sole
reaction product was observed (Scheme 2). On the other
hand, the attempted reaction of 1b with aniline in chloroform
did not produce any isolable product.
Abstract
Athree-component reaction among 2-alkynylquinoline-3-car-
baldehydes, primary amines, and chloroform leading to novel
1-(trichloromethyl)-1,2-dihydrobenzo[b][1,6]naphthyridines
was developed using microwave initiation in an absence of
any catalysts. This method provides a facile approach to the
title compounds with moderate to higher yields.
Keywords: 2-alkynylquinoline-3-carbaldehydes;
benzo[b][1,6]naphthyridines; microwave chemistry;
three-component reaction.
Introduction
Multicomponent reactions belong to the most efficient methods
for preparation of organic compounds, allowing the formation
of several bonds and the construction of complex molecular
architectures from simple precursors in a single synthetic oper-
ation without the need for isolation of intermediates (Ugi et al.,
1994;Armstrong et al., 1996; Bienayme et al., 2000; Doemling,
2000; Ramon andYus, 2005; Zhu and Bienayme, 2005; Ganem,
2009;ChenandWu, 2010;Wangetal., 2011). Recently, wehave
presented the straightforward synthesis of few 2-substituted
1-(trichloromethyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]naph-
thyridines from 2-phenylethynylquinoline-3-carbaldehyde,
primary amines, and chloroform and showed that these prod-
ucts induced considerably growth inhibition in some human
solid cancer cell lines (Rudys et al., 2010). There also are some
reports in the literature about notable antitumor activity of
1,2-dihydrobenzo[b][1,6]naphthyridine derivatives (Croisy-
DelceyandBisagni, 1983;Deadyetal., 2003, 2005). Continuing
our research on the use of ethynylazines in the synthesis of
ˇ
fused nitrogen nucleus-containing heterocycles (Cikotiene˙
ˇ
ˇ
et al., 2008, 2009, 2010, Cikotiene˙, 2009, Cikotiene˙ and
Morkunas, 2009), we decided to explore the scope of the three-
component reactions of 2-alkynylquinoline-3-carbaldehydes,
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ˇ
88 R. Bukšnaitiene˙ and I. Cikotiene˙
CCl3
(CH=N) and 4.98 ppm (N-CH2) were observed. These sig-
nals were attributed to the corresponding imine derivative 3
(Figure 1A). Upon heating the solution for 3 h, the gradual
appearance of new singlets at 5.27 and 6.49 ppm together
with the AB pattern at 4.54 and 4.86 ppm with a coupling
constant 15.9 Hz for the final compound 2a were observed
(Figure 1B). This reaction is highly regioselective in that only
the formation of 6-endo-dig cyclization products is observed.
As an extension of this work, similar three-component
reactions with other pronucleophiles, such as nitromethane,
diethyl malonate, phenylacetylene, and trimetoxymethane,
were attempted. In all cases, mixtures of various undefined
products were formed.
R′
O
i
N
or ii
N
N
R
R
2a-u
1a-d
R = Ph (1a), H (1b),
Bu (1c), c-Pr (1d).
PhNH2
1a
CHCl3
Ph
Ph
N
N
Conclusions
3a
An efficient microwave-assisted three-component reac-
tion among 2-alkynylquinoline-3-carbaldehydes, primary
amines, and chloroform leading to novel 1-(trichloromethyl)-
1,2-dihydrobenzo[b][1,6]naphthyridines was described. The
presented method opens the way to biologically important
1,2-dihydrobenzo[b][1,6]naphthyridine derivatives.
Scheme 1 (i) R′NH2 (1.2 equiv.), 3-Å molecular sieves, CHCl3,
reflux. (ii) R′NH2 (1.2 equiv.), 3-Å molecular sieves, CHCl3
(3 equiv.) in 1,2-dichloroethane, microwave irradiation, 600 W.
We believe that at the beginning, the formation of imi-
nes 3 from the starting substrates and amines takes place.
Nucleophilic attack of the imine nitrogen at the triple bond
would lead to the formation of zwitterion salt A. Abstraction
of proton from chloroform and subsequent attack of trichlo-
romethyl anion would produce the final compounds 2a–u
(Scheme 2). A similar mechanism was proposed by Asao
et al. (2006) for o-alkynylbenzenecarbaldehydes.
Experimental section
Melting points were determined in open capillaries and are uncor-
rected. Infrared spectra were run in Nujol mulls or in KBr discs
1
on a Perkin-Elmer FT spectrophotometer Spectrum BX II. H and
13C NMR spectra were recorded in CDCl3 at 300 and 75 MHz,
respectively, on a Varian Unity INOVAspectrometer (300 MHz). The
three-component reactions were carried out in closed 15-mL vessels
in the domestic microwave oven (model Daewoo KOR6305A). All
reactions and the purity of the synthesized compounds were moni-
tored by TLC using silica gel 60 F254 aluminum plates (Merck).
Visualization was accomplished by ultraviolet light.
The examination of the results suggests that there are
several factors affecting the successful cyclization. These
include steric factors (hindrance or geometrical alignment of
substituents on alkynyl and imine moieties), stability of the
intermediate products, and reaction conditions. The observed
failure of the attempted reaction of aniline can be explained
in two ways. First, the imine nitrogen in compound 3a is rela-
tively nonnucleophilic due to conjugation with the aromatic
ring. However, Asao et al. (2006) have found that the reac-
tion among o-ethynylbenzaldehyde, aniline, and chloroform
proceeded successfully. It can be suggested that, in our case,
there is a steric hindrance between two planar phenyl rings in
compound 3a, thus the formation of intermediate A becomes
impossible.
General procedure for the synthesis of
2,3-disubstituted 1-(trichloromethyl)-1,2-dihydro-
benzo[b][1,6]naphthyridines (2)
Method A (conventional heating) To a mixture of the corre-
sponding compound 1a,b (0.39 mmol) and 3-Å molecular sieves
(0.3 g) in chloroform (3 mL), the corresponding amine (0.39 mmol)
was added. The reaction mixture was heated under reflux for 24–48
h. After completion of the reaction, as observed by TLC, the solvent
was removed to leave the crude product that was purified by basic
silica gel column chromatography using a mixture of toluene and
ethyl acetate as an eluent to give 2a–d,h,i.
1
The reaction was studied by H NMR experiments. Upon
dissolution of 1a and benzylamine in CDCl3 and before the
heating, the immediate disappearance of aldehyde signal at
10.81 ppm and the appearance of new singlets at 9.11 ppm
CCl3
R
R
′
R
′
R′NH2
R
′
N
N
N
2a-u
1a-d
N
N
N
R
R
B
3
A
H-CCl3
Scheme 2 The plausible mechanism of the three-component reaction.
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Synthesis of 1-trichloromethyl-1,2-dihydrobenzo[b][1,6]naphthyridines 89
B
A
9.0
8.0
7.0
6.0
5.0
Figure 1 Fragments of 1H NMR spectra.
(A) Immediately after mixing of 1a with excess of benzylamine in CDCl3. (B) After 3 h of heating.
Method B (microwave irradiation) A mixture of the corre-
sponding compound 1a–d (0.39 mmol), the corresponding amine
(0.39 mmol), chloroform (1 mL), and 3-Å molecular sieves (0.3 g) in
1,2-dichloroethane (3 mL) was irradiated in a closed 15-mL vessel in
the domestic microwave oven (model Daewoo KOR6305A) at 600
W for 10–25 min. After completion of the reaction, as observed by
TLC, the solvent was removed to leave the crude product that was
purified by basic silica gel column chromatography using a mixture
of toluene and ethyl acetate as an eluent to give 2a–u.
(m, 1H, CH2CH = CH2); 13C NMR: δ 152.2, 148.3, 137.9, 136.6,
133.2, 130.3, 129.3, 128.8, 128.6, 128.0, 127.9, 127.8, 126.6, 124.9,
118.9, 117.9, 109.4, 104.5, 74.3, 58.1. Anal. Calcd for C22H17Cl3N2:
C, 63.56; H, 4.12; N, 6.74. Found: C, 63.68; H, 4.05; N, 6.80.
2-Butyl-1-(trichloromethyl)-3-phenyl-1,2-dihydrobenzo[b]
[1,6]naphthyridine (2d) Yield 39% (method A), 70% (method
B); yellow solid; mp 103–104°C; 1H NMR: δ 8.27 [s, 1H, C(10)H],
8.10 (d, 1H, J = 8.1 Hz, ArH), 7.87 (dd, 1H, J = 8.1, 1.2 Hz, ArH),
7.75–7.78 (m, 3H,ArH), 7.47–7.52 (m, 4H,ArH), 6.47 [s, 1H, C(4)H],
5.26 [s, 1H, C(1)H], 3.65–3.72 (m, 1H, CH2CH2CH2CH3), 3.27–3.36
(m, 1H, CH2CH2CH2CH3), 2.30–2.39 (m, 2H, CH2CH2CH2CH3),
0.99–1.10 (m, 2H, CH2CH2CH2CH3), 0.68 (t, 3H, J = 7.5 Hz,
CH2CH2CH2CH3); 13C NMR: δ 152.9, 137.9, 136.9, 130.4, 129.4,
129.0, 128.7, 128.2, 127.9, 126.7, 125.9, 125.0, 109.4, 109.3, 104.9,
99.9, 75.9, 55.9, 31.1, 19.7, 13.7. Anal. Calcd for C23H21Cl3N2: C,
63.98; H, 4.90; N, 6.49. Found: C, 64.03; H, 4.89; N, 6.55.
1-(Trichloromethyl)-3-phenyl-2-(phenylmethyl)-1,2-
dihydrobenzo[b][1,6]naphthyridine (2a) Yield 48% (method
A), 81% (method B); yellow solid; mp 146–148°C; 1H NMR: δ 8.04
(d, 1H, J = 8.4 Hz, ArH), 7.97 [s, 1H, C(10)H], 7.69–7.81 (m, 4H,
ArH), 7.41–7.51 (m, 4H, ArH), 7.08–7.10 (m, 3H, ArH), 6.98–6.99
(m, 2H, ArH), 6.49 [s, 1H, C(4)H], 5.27 [s, 1H, C(1)H], 4.86 (d, 1H,
J2 = 15.9 Hz, PhCH), 4.54 (d, 1H, J2 = 15.9 Hz, PhCH); 13C NMR: δ
152.8, 148.7, 137.9, 137.5, 136.9, 130.3, 129.5, 128.8, 128.6, 128.4,
128.0, 127.6, 127.3, 126.6, 124.9, 119.0, 109.2, 104.9, 74.9, 59.2.
Anal. Calcd for C26H19Cl3N2: C, 67.04; H, 4.11; N, 6.01. Found: C,
67.01; H, 4.25; N, 5.97.
1-(Trichloromethyl)-2-cyclopentyl-3-phenyl-1, 2-
dihydrobenzo[b][1,6]naphthyridine (2e) Yield 45% (method
B); yellow solid; mp 110–112°C; 1H NMR: δ 8.27 [s, 1H, C(10)H],
8.08 (1H, d, J = 8.7 Hz, ArH), 7.83–7.87 (m, 3H, ArH), 7.69–7.75
(m, 1H, ArH), 7.44–7.49 (m, 4H, ArH), 6.71 [s, 1H, C(4)H], 5.23
[s, 1H, C(1)H], 3.74–3.85 [m, 1H, CH(CH2CH2)2], 1.97–2.04 [m, 2H,
CH(CH2CH2)2], 1.64–1.68 [m, 2H, CH(CH2CH2)2], 1.41–1.47
[m, 2H, CH(CH2CH2)2], 1.25–1.28 [m, 2H, CH(CH2CH2)2]; 13C
NMR: δ 153.3, 152.8, 148.4, 137.6, 130.2, 129.2, 128.7, 128.5,
128.2, 127.8, 127.6, 126.8, 125.1, 120.7, 112.2, 104.1, 69.5, 64.7,
29.7, 29.1, 22.6, 22.2. Anal. Calcd for C24H21Cl3N2: C, 64.95; H,
4.77; N, 6.31. Found: C, 65.01; H, 4.80; N, 6.27.
1-(Trichloromethyl)-3-phenyl-2-(phenylethyl)-1,2-
dihydrobenzo[b][1,6]naphthyridine (2b) Yield 56% (method A),
84% (method B); yellow solid; mp 139–140°C; 1H NMR: δ 8.04 (d,
1H, J = 8.7 Hz, ArH), 7.79 [s, 1H, C(10)H], 7.74–7.78 (m, 4H, ArH),
7.47–7.51 (m, 4H, ArH), 6.89–6.92 (m, 3H, ArH), 6.79–6.82 (m, 2H,
ArH), 6.45 [s, 1H, C(4)H], 4.93 [s, 1H, C(1)H], 4.09–4.18 (m, 1H,
PhCH2CH2N), 3.48–3.58 (m, 1H, PhCH2CH2N), 2.50–2.57 (m, 2H,
PhCH2 CH2N); 13C NMR: δ 152.8, 151.3, 148.7, 138.0, 137.5, 136.8,
130.2, 129.4, 128.8, 128.4, 128.2, 127.9, 126.9, 126.7, 126.3, 124.9,
119.2, 110.5, 104.8, 77.2, 58.1, 35.8. Anal. Calcd for C27H21Cl3N2: C,
67.58; H, 4.41; N, 5.84. Found: C, 67.61; H, 4.33; N, 5.90.
1-(Trichloromethyl)-2-(phenylmethyl)-1,2-dihydrobenzo[b]
[1,6]naphthyridine (2f) Yield 71% (method B); yellow solid; mp
1
125–128°C; H NMR (300 MHz, CDCl3) δ 8.06 [s, 1H, C(10)H],
2-Allyl-1-(trichloromethyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]
naphthyridine (2c) Yield 60% (method A), 89% (method B); yel-
low solid; mp 127–128°C; 1H NMR: δ 8.23 [s, 1H, C(10)H], 8.09 (d,
1H, J = 8.4 Hz, ArH), 7.86 (dd, 1H, J = 7.95, 1.2 Hz, ArH), 7.74–
7.79 (m, 3H, ArH), 7.46–7.51 (m, 4H, ArH), 5.47–5.61 (m, 1H, CH2
CH = CH2), 6.52 [s, 1H, C(4)H], 5.28 [s, 1H, C(1)H], 4.97–5.07 (m,
2H, CH2CH = CH2), 4.19–4.26 (m, 1H, CH2CH = CH2), 3.88–3.96
8.03 (br. s., 1H, ArH), 7.78 (dd, 1H, J = 8.1, 1.2 Hz, ArH), 7.68–7.74
(m, 1H, ArH), 7.40–7.45 (m, 1H, ArH), 7.25–7.28 (m, 3H, ArH),
7.13–7.16 (m, 3H, ArH), 6.85 [dd, 1H, J = 7.8, 1.5 Hz, C(3)H], 6.09
[dd, 1H, J = 7.8, 0.6 Hz, C(4)H], 5.30 [dd, 1H, J = 1.5, 0.6 Hz,
C(1)H], 5.04 (d, 1H, J2 = 15.9 Hz, PhCH), 4.82 (d, 1H, J2 = 15.9
Hz, PhCH); 13C NMR: δ 152.3, 148.4, 141.9, 138.2, 137.4, 130.4,
128.9, 128.1, 127.9, 127.8, 126.9, 126.4, 124.7, 117.3, 103.1, 84.1,
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ˇ
90 R. Bukšnaitiene˙ and I. Cikotiene˙
75.0, 62.3. Anal. Calcd for C20H15Cl3N2: C, 61.64; H, 3.88; N, 7.19.
Found: C, 61.55; H, 4.00; N, 7.23.
CH(CH2)2], 0.83–0.91 [m, 2H, CH(CH2)2], 0.52–0.58 [m, 1H,
CH(CH2)2]; 13C NMR: δ 152.8, 148.1, 138.3, 137.4, 130.3, 128.6,
127.8, 127.6, 127.2, 126.0, 125.9, 124.4, 117.9, 104.7, 101.8, 76.4,
57.1, 14.2, 8.6, 4.5. Anal. Calcd for C23H19Cl3N2: C, 64.28; H, 4.46;
N, 6.52. Found: C, 64.16; H, 4.49; N, 6.88.
1-(Trichloromethyl)-2-(phenylethyl)-1,2-dihydrobenzo[b][1,6]
naphthyridine (2g) Yield 76% (method B); yellow solid; mp
110–112°C; 1H NMR (300 MHz, CDCl3) δ8.07 (1H, d, J= 8.4 Hz,ArH),
7.70–7.77 (3H, m, ArH), 7.42–7.48 (1H, m, ArH), 6.98–7.05 (5H, m,
ArH), 6.79 [1H, dd, J = 7.3, 0.9 Hz, C(3)H], 6.14 [1H, d, J = 7.3 Hz, C(4)
H], 4.78 [1H, d, J = 0.9 Hz, C(1)H], 3.91–3.99 (2H, m, PhCH2CH2N),
2.73–2.92 (2H, m, PhCH2CH2N); 13C NMR: δ 152.4, 141.1, 138.7,
138.2, 130.8, 129.2, 128.8, 128.2, 126.8, 126.5, 125.8, 125.1, 124.2,
117.8, 104.7, 103.7, 76.7, 60.1, 37.7. Anal. Calcd for C21H17Cl3N2: C,
62.47; H, 4.24; N, 6.94. Found: C, 62.55; H, 4.15; N, 7.09.
3-Cyclopropyl-1-(trichloromethyl)-2-(phenylethyl)-1,2-di-
hydrobenzo[b][1,6]-naphthyridine (2l) Yield 71% (method
1
B); yellow oil; H NMR: δ 8.02 (dd, 1H, J = 8.25, 1.2 Hz, ArH),
7.65–7.73 (m, 3H, ArH), 7.37–7.43 (m, 1H, ArH), 6.95–7.05 (m, 5H,
ArH), 6.05 [s, 1H, C(4)H], 4.80 [s, 1H, C(1)H], 4.58–4.67 (m, 1H,
PhCH2CH2N), 3.67–3.77 [m, 1H, PhCH2CH2N], 2.76–2.80 (m, 2H,
PhCH2CH2N), 1.72–1.79 [m, 1H, CH(CH2)2], 1.05–1.10 [m, 1H,
CH(CH2)2], 0.89–0.94 [m, 2H, CH(CH2)2], 0.78–0.82 [m, 1H,
CH(CH2)2]; 13C NMR: δ 153.1, 152.9, 148.2, 137.9, 137.2, 130.0,
128.7, 128.3, 127.8, 127.7, 126.3, 124.3, 118.1, 104.6, 102.7, 77.1,
56.5, 36.1, 13.8, 9.3, 4.9. Anal. Calcd for C24H21Cl3N2: C, 64.95; H,
4.77; N, 6.31. Found: C, 65.09; H, 4.96; N, 6.49.
2-Allyl-1-(trichloromethyl)-1,2-dihydrobenzo[b][1,6]naph-
thyridine (2h) Yield 16% (method A), 75% (method B); yellow
solid; mp 124–126°C; 1H NMR: δ 8.13 [s, 1H, C(10)H], 8.00 (d, 1H,
J = 8.25 Hz, ArH), 7.78 (dd, 1H, J = 8.1, 1.2 Hz, ArH), 7.65–7.71
(m, 1H, ArH), 7.38–7.43 (m, 1H, ArH), 6.72 [dd, 1H, J = 7.5, 1.2
Hz, C(3)H], 6.02 [d, 1H, J = 7.5 Hz, C(4)H], 5.71–5.83 (m, 1H,
CH2CH = CH2), 5.23 [d, 1H, J = 1.2 Hz, C(1)H], 5.07–5.16 (m, 2H,
CH2CH = CH2), 4.28–4.36 (m, 1H, CH2CH = CH2), 4.11–4.19
(m, 1H, CH2CH = CH2); 13C NMR: δ 152.4, 148.3, 141.3, 138.3,
133.5, 130.5, 128.0, 127.9, 126.4, 124.7, 118.4, 117.3, 104.7, 103.2,
74.9, 60.2. Anal. Calcd for C16H13Cl3N2: C, 56.58; H, 3.86; N, 8.25.
Found: C, 56.71; H, 4.00; N, 8.33.
2-Allyl-1-(trichloromethyl)-3-cyclopropyl-1,2-dihydrobenzo[b]
1
[1,6]naphthyridine (2m) Yield 64% (method B); yellow oil; H
NMR: δ 8.13 [s, 1H, C(10)H], 8.03 (d, 1H, J = 8.4 Hz, ArH), 7.79
(dd, 1H, J = 8.1, 1.2 Hz, ArH), 7.66–7.71 (m, 1H, ArH), 7.38–7.44
(m, 1H, ArH), 6.04 [s, 1H, C(4)H], 5.64–5.76 (m, 1H, CH2CH =
CH2), 5.19 [s, 1H, C(1)H], 4.92–5.05 (m, 3H, CH2CH = CH2 and
CH2CH = CH2), 4.18 (ddt, 1H, J = 18, 4.8, 1.2 Hz, CH2CH = CH2),
1.63–1.73 [m, 1H, CH(CH2)2], 0.84–1.06 [m, 3H, CH(CH2)2], 0.64–
0.72 [m, 1H, CH(CH2)2]; 13C NMR: δ 154.1, 152.9, 148.0, 137.7,
133.8, 130.4, 127.9, 127.6, 124.6, 118.2, 116.6, 104.7, 101.9, 75.6,
56.0, 14.2, 8.7, 4.4. Anal. Calcd for C19H17Cl3N2: C, 60.10; H, 4.51;
N, 7.38. Found: C, 59.87; H, 4.45; N, 7.40.
2-Butyl-1-(trichloromethyl)-1,2-dihydrobenzo[b][1,6]naph-
thyridine (2i) Yield 45% (method A), 85% (method B); yellow
solid; mp 102–104°C; 1H NMR: δ 8.14 [s, 1H, C(10)H], 8.02 (d, 1H,
J = 8.4 Hz, ArH), 7.78 (dd, 1H, J = 8.1, 0.9 Hz, ArH), 7.64–7.70 (m,
1H, ArH), 7.37–7.43 (m, 1H, ArH), 6.73 [dd, 1H, J = 7.5, 1.2 Hz,
C(3)H], 6.03 [d, 1H, J = 7.5 Hz, C(4)H], 5.21 [d, 1H, J = 1.2 Hz,
C(1)H], 3.53–3.73 (m, 2H, CH2CH2CH2CH3), 1.47–1.57 (m, 2H,
CH2CH2CH2CH3), 1.16–1.28 (m, 2H, CH2CH2CH2 CH3), 0.85 (t, 3H,
J = 7.5 Hz, CH2CH2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 152.4,
147.9, 141.5, 138.3, 130.6, 127.9, 127.7, 126.3, 124.7, 117.5, 104.7,
102.5, 75.7, 57.8, 32.4, 19.8, 13.7. Anal. Calcd for C17H17Cl3N2:
C, 57.40; H, 4.82; N, 7.88. Found: C, 57.66; H, 4.75; N, 7.99.
2-Butyl-1-(trichloromethyl)-3-cyclopropyl-1,2-dihydro-
benzo[b][1,6]naphthyridine (2n) Yield 57% (method B); yel-
1
low solid; mp 112–114°C; H NMR: δ 8.17 [s, 1H, C(10)H], 8.04
(d, 1H, J = 8.4 Hz, ArH), 7.80 (dd, 1H, J = 7.8, 1.2 Hz, ArH),
7.67–7.72 (m, 1H,ArH), 7.39–7.45 (m, 4H,ArH), 6.03 [s, 1H, C(4)H],
5.19 [s, 1H, C(1)H], 4.26–4.36 (m, 1H, CH2CH2CH2CH3), 3.45–3.55
(m, 1H, CH2CH2CH2CH3), 1.68–1.77 [m, 1H, CH(CH2)2], 1.40–1.50
(m, 2H, CH2CH2CH2CH3), 1.22–1.29 (m, 2H, CH2CH2CH2CH3),
1.01–1.08 [m, 2H, CH(CH2)2], 0.89–0.93 [m, 1H, CH(CH2)2], 0.87
(t, 3H, J = 7.5 Hz, CH2CH2CH2CH3), 0.72–0.84 [m, 1H, CH(CH2)2];
13C NMR: δ 152.9, 147.6, 137.9, 130.6, 127.9, 127.2, 126.1, 124.6,
118.3, 104.6, 101.3, 76.2, 54.4, 31.5, 19.9, 14.1, 13.8, 9.3, 5.0. Anal.
Calcd for C20H21Cl3N2: C, 60.70; H, 5.35; N, 7.08. Found: C, 60.64;
H, 5.48; N, 6.99.
1-(Trichloromethyl)-2-cyclopentyl-1,2-dihydrobenzo[b][1,6]
naphthyridine (2j) Yield 75% (method B); yellow solid; mp
137–138°C; 1H NMR (300 MHz, CDCl3) δ 8.18 [s, 1H, C(10)
H], 8.05 (d, 1H, J = 8.7 Hz, ArH), 7.79 (dd, 1H, J = 7.95, 0.9 Hz,
ArH), 7.68–7.74 (m, 1H, ArH), 7.41–7.47 (m, 1H, ArH), 6.90
[dd, 1H, J = 7.8, 1.2 C(3)H], 6.12 [d, 1H, J = 7.8 Hz, C(4)H],
5.31 [d, 1H, J = 1.2 Hz, C(1)H], 4.09 [pent., 1H, J = 7.8 Hz,
CH(CH2CH2)2], 2.21–2.30 [m, 1H, CH(CH2CH2)2], 1.91–2.00 [m,
2H, CH(CH2CH2)2], 1.69–1.85 [m, 4H, CH(CH2CH2)2], 1.36–1.46
[m, 1H, CH(CH2CH2)2]; 13C NMR: δ 152.3, 147.4, 138.8, 137.6,
130.7, 127.9, 127.3, 126.3, 124.7, 117.6, 104.3, 102.9, 77.3, 68.7,
33.5, 29.7, 24.0, 23.9. Anal. Calcd for C18H17Cl3N2: C, 58.80; H,
4.66; N, 7.62. Found: C, 59.01; H, 4.75; N, 7.49.
1-(Trichloromethyl)-2-cyclopentyl-3-cyclopropyl-1,2-dihyd-
robenzo[b][1,6]naphthyridine (2o) Yield 72% (method B); yel-
low oil; 1H NMR: δ 8.17 [s, 1H, C(10)H], 8.00 (dd, 1H, J = 8.4, 0.6
Hz, ArH), 7.80 (dd, 1H, J = 8.1, 1.2 Hz, ArH), 7.64–7.68 (m, 1H,
ArH), 7.39–7.44 (m, 1H, ArH), 6.14 [s, 1H, C(4)H], 5.18 [s, 1H,
C(1)H], 4.51–4.62 [m, 1H, CH(CH2CH2)2], 2.12–2.16 [m, 1H,
CH(CH2)2], 1.45–1.74(m, 6H), 1.92–2.00(m, 1H), 0.96–1.17(m, 3H)
[CH(CH2)2, and CH(CH2CH2)2], 0.83–0.92 [m, 1H, CH(CH2)2],
0.64–0.73 [m, 1H, CH(CH2)2]; 13C NMR: δ 155.7, 153.2, 148.3,
136.9, 130.0, 128.0, 127.8, 126.5, 124.6, 119.9, 105.8, 70.3, 62.9,
30.2, 30.0, 23.1, 22.5, 14.5, 10.0, 5.0. Anal. Calcd for C21H21Cl3N2:
C, 61.86; H, 5.19; N, 6.87. Found: C, 62.00; H, 5.22; N, 6.90.
3-Cyclopropyl-1-(trichloromethyl)-2-(phenylmethyl)-1,2-
dihydrobenzo[b][1,6]-naphthyridine (2k) Yield 65% (method
1
B); yellow solid; mp 146–148°C; H NMR: δ 8.05 (d, 1H, J = 8.4
Hz, ArH), 8.04 [s, 1H, C(10)H], 7.76 (dd, 1H, J = 8.25, 1.2 Hz, ArH),
7.67–7.71 (m, 1H, ArH), 7.38–7.44 (m, 1H, ArH), 7.17–7.20 (m, 3H,
ArH), 6.97–7.00 (m, 2H, ArH), 6.08 [s, 1H, C(4)H], 5.64 (d, 1H,
J2 = 17.4 Hz, PhCH), 5.25 [s, 1H, C(1)H], 4.88 (d, 1H, J2 = 17.4
Hz, PhCH), 1.62–1.73 [m, 1H, CH(CH2)2], 1.02–1.09 [m, 1H,
3-Butyl-1-(trichloromethyl)-2-(phenylmethyl)-1,2-dihydro-
benzo[b][1,6]naphthyridine (2p) Yield 64% (method B); yellow
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Synthesis of 1-trichloromethyl-1,2-dihydrobenzo[b][1,6]naphthyridines 91
solid; mp 150–152°C; 1H NMR: δ 8.08 [s, 1H, C(10)H], 8.07
[m, 1H, CH(CH2CH2)2], 2.61–2.72 (m, 1H, CH2CH2CH2CH3),
2.34–2.44 (m, 1H, CH2CH2CH2CH3), 1.94–1.98 and 2.10–2.14
[2m, 2H, CH(CH2CH2)2], 1.45–1.78 [m, 10H, CH2CH2CH2CH3,
CH2CH2CH2CH3, CH(CH2CH2)2], 0.99 (t, 3H, J = 7.5 Hz,
CH2CH2CH2CH3); 13C NMR: δ 154.4, 152.8, 148.1, 137.1, 130.1,
127.9, 127.8, 126.6, 124.7, 119.7, 109.7, 104.6, 70.3, 62.3, 34.2, 30.6,
30.1, 30.0, 23.2, 22.6, 22.5, 13.8. Anal. Calcd for C22H25Cl3N2: C,
62.35; H, 5.95; N, 6.61. Found: C, 62.66; H, 6.02; N, 6.67.
(d, 1H, J = 8.7 Hz, ArH), 7.78 (dd, 1H, J = 8.1, 1.2 Hz, ArH),
7.69–7.72 (m, 1H, ArH), 7.41–7.46 (m, 1H, ArH), 7.19–7.22
(m, 3H, ArH), 6.99–7.01 (m, 2H, ArH), 6.15 [s, 1H, C(4)H], 5.24
[s, 1H, C(1)H], 5.14 (d, 1H, J2 = 17.4 Hz, PhCH), 4.79 (d, 1H,
J2 = 17.4Hz, PhCH), 2.50–2.60(m, 1H, CH2 CH2CH2CH3), 2.27–2.38
(m, 1H, CH2CH2CH2CH3), 1.70–1.83 (m, 2H, CH2CH2CH2CH3),
1.38–1.50 (m, 2H, CH2CH2CH2CH3), 0.99 (t, 3H, J = 7.5 Hz,
CH2CH2CH2CH3); 13C NMR: δ 152.8, 149.4, 148.3, 138.2, 137.6,
130.5, 128.9, 127.9, 127.8, 127.5, 126.3, 125.9, 124.6, 118.1, 104.9,
76.8, 57.3, 33.7, 29.8, 22.4, 13.8. Anal. Calcd for C24H23Cl3N2: C,
64.66; H, 5.20; N, 6.28. Found: C, 64.77; H, 5.12; N, 6.44.
Acknowledgments
This research was funded by the European Social Fund under the
Global Grant measure (grant VP1-3.1-ŠMM-07-K-01-002).
3-Butyl-1-(trichloromethyl)-2-(phenylethyl)-1,2-dihydro-
benzo[b][1,6]naphthyridine (2r) Yield 62% (method B); yellow
1
solid; mp 116–118°C; H NMR: δ 8.00 (dd, 1H, J = 8.4, 0.6 Hz,
ArH), 7.67 (d, 1H, J = 7.8 Hz, ArH), 7.58 (s, 1H, CH), 7.35–7.40 (m,
1H, ArH), 6.90–6.98 (m, 6H, ArH), 6.13 (s, 1H, CH), 4.65 (s, 1H,
CH), 4.14–4.23 (m, 1H, PhCH2CH), 3.53–3.63 (m, 1H, PhCH2CH),
2.55–2.78 (2m, 3H, CH2CH2CH2CH3, and PhCH), 2.32–2.42 (m, 1H,
PhCH), 1.66–1.80 (m, 2H, CH2CH2CH2CH3), 1.40–1.56 (m, 2H,
CH2CH2CH2CH3), 0.98 (t, 3H, J = 7.5 Hz, CH2CH2CH2CH3); 13C
NMR: δ 152.8, 151.8, 148.0, 137.8, 137.2, 130.1, 128.8, 128.3, 127.7,
126.3, 126.1, 124.4, 118.2, 106.2, 104.6, 77.6, 56.5, 36.4, 33.6, 29.9,
22.5, 13.8. Anal. Calcd for C25H25Cl3N2: C, 65.30; H, 5.48; N, 6.09.
Found: C, 65.40; H, 5.35; N, 5.98.
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[s, 1H, C(10)H], 8.02 (d, 1H, J = 8.4 Hz,ArH), 7.79 (dd, 1H, J = 8.1, 0.9
Hz,ArH), 7.65–7.71 (m, 1H,ArH), 7.38–7.44 (m, 1H,ArH), 6.09 [s, 1H,
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3.32–3.42 (m, 1H, NCH2CH2CH2CH3), 2.52–2.62 (m, 1H,
CH2CH2CH2CH3), 2.28–2.39 (m, 1H, CH2CH2CH2CH3), 1.68–1.80
(m, 2H, CH2CH2CH2CH3), 1.40–1.55 (m, 4H, CH2CH2CH2CH3, and
CH2CH2CH2CH3), 1.16–1.29 (m, 2H, CH2CH2CH2CH3), 1.00 (t, 3H,
J =7.5Hz,CH2CH2CH2CH3),0.85(t,3H,J=7.5Hz,CH2CH2CH2CH3);
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124.4, 118.4, 105.4, 104.9, 76.7, 54.3, 33.6, 31.8, 29.9, 22.4, 19.9, 13.9,
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Received November 4, 2011; accepted January 24, 2012; previously
published online March 28, 2012
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