Silver-catalyzed tandem synthesis of naphthyridines and thienopyridines via three-component reaction

Article abstract of DOI:10.1021/jo400400c

An efficient approach for the silver-catalyzed regioselective tandem synthesis of highly functionalized 1,2-dihydrobenzo[1,6]naphthyridines 6a-z and 7a-e by the reaction of ortho-alkynylaldehydes 3a-n with amines 4a-d and ketones 5a-c/active methylene com

Full text of DOI:10.1021/jo400400c

Article
pubs.acs.org/joc
Silver-Catalyzed Tandem Synthesis of Naphthyridines and
Thienopyridines via Three-Component Reaction
Akhilesh K. Verma,*,† Siva K. Reddy Kotla,† Deepak Choudhary,† Monika Patel,† and Rakesh K. Tiwari‡
†Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
‡Department of Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
02881, United States
S
* Supporting Information
ABSTRACT: An efficient approach for the silver-catalyzed regioselective tandem synthesis of highly functionalized 1,2-
dihydrobenzo[1,6]naphthyridines 6a−z and 7a−e by the reaction of ortho-alkynylaldehydes 3a−n with amines 4a−d and
ketones 5a−c/active methylene compounds 5d−g, under mild reaction conditions, is described. The scope of the developed
chemistry was successfully extended for the direct synthesis of 1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines 8a−e, which is
known as the sulfur analogue of β-carbolines. Naphthyridines 6a−z and thienopyridines 8a−e were obtained via dual activation
concept using L-proline as organocatalyst; however, naphthyridines 7a−e were synthesized without using organocatalyst. The
reaction shows selective N−C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-
cyclized products. Reactivity behavior of electron-deficient and electron-rich ortho-alkynylaldehydes in the synthesis of
naphthyridines and thienopyridine by three-component reaction is supported by the control experiment.
benafentrine has been developed on the basis of the derivatives
of partially hydrogenated benzo[c][1,6]naphthyridines, which
are phosphodiesterase III/IV inhibitors.7 Benzothieno[2,3-
c]pyridines (S-analogues of β-carbolines) have been found as
appetite-depressants and anxiolytics (Figure 1iv).8 In contrast
to the naphthyridines, synthesis of benzothieno[2,3-c]pyridine
has not been explored. Despite the various synthetic protocols
available for the synthesis of naphthyridines9 and thieno[2,3-
c]pyridine,10 a need for atom-economic efficient methodologies
starting from inexpesive and readily available starting materials
for their synthesis attracts the interest of synthetic chemists.
In the past two decades, construction of small molecules,
heterocycles and natural-product-like compounds via tandem/
three-component reactions (TCRs) has attracted growing
interest in organic synthesis due to their high degree of atom
economy, convergence, productivity, selectivity, and broad
applications in combinatorial chemistry.11 The variation of two
or more reactants of the reaction can lead a large number of
INTRODUCTION
■
Rapid advances in medicinal chemistry continue to underscore
the need of practical routes for the synthesis of heterocycles, as
a majority of drug-like compounds and natural products
contains a heterocyclic nucleus at their core.1 In recent years,
transition-metal-catalyzed reactions provided a promising
algorithm to this urge, which enables the efficient conversion
of simple starting materials to complex molecules in an iterative
manner.2 Among the various transition metals, silver-catalyzed
tandem sequences have gained considerable attention because
of their ability to activate various π-systems in mild conditions
and at low-catalyst loading.3
Among various N-heterocycles, naphthyridines and thieno-
[2,3-c]pyridine occur widely among natural products and are
known to exert significant biological activity in many active
pharmaceutical ingredients.4 Marine sponges are proving to be
productive sources of many interesting series of naphthyridine
alkaloids (Figure 1ii,iii).5 Naphthyridines have attracted
considerable interest due to their interesting biological
activities, such as anti-HIV-1, anticancer, antimicrobial and
antifungal properties (Figure 1i).6 The bronchodilator drug
Received: February 23, 2013
Published: April 8, 2013
© 2013 American Chemical Society
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Figure 1. Significant examples of biologically active naphthyridines and thienopyridines.
Scheme 1. Designed Tandem Strategy for the Synthesis of Naphthyridines and Thienopyridines via Three-Component Reaction
Scheme 2. Preparation of o-Alkynylaldehydes
molecules and increase the chemical diversity. Considerable
progress has been made for the tandem synthesis of nitrogen
heterocycles from ortho-alkynylaldehydes using dual activation
concept. Dual-activation concept involves combination of two
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a
Table 1. Optimization of Reaction Conditions
entry
catalyst
organocatalyst
solvent
time (h)
yield (%)
1
AgOTf
AgOTf
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
EtOH
EtOH
EtOH
EtOH
EDC
6
50
52
58
57
42
45
68
68
70
65
50
69
70
10
68
nr
2
12
6
b
3
AgOTf
b
4
AgOTf
12
6
5
AgOTf
b
6
AgOTf
EDC
6
7
AgNO3
AgNO3
AgNO3
AgNO3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
H2O
6
8
3
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0.5
3
c
AgNO3
b
AgNO3
1
d
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgOAc
PdCl2
L-proline
−
1
10
1
L-proline
L-proline
L-proline
L-proline
L-proline
piperidine
L-proline
L-proline
L-proline
12
6
EDC
35
25
35
10
30
10
15
toluene
THF
12
12
6
EtOH
EtOH
EtOH
EtOH
6
6
Pd(OAc)2
6
a
b
Reaction was performed using 3a (70 mg, 1 equiv), 4a (1 equiv) and 5 equiv of 5a in 2 mL of EtOH at 60 °C, unless otherwise noted. 20 mol % of
c
d
catalyst was loaded. 5 mol % of catalyst was employed. 20 mol % L-proline was used.
separate catalysts in one catalytic system.12 Yamamoto
proposed a concept called “designer acids” to form a
combination of acids with higher reactivity, selectivity, and
versatility than the individual.13
standard Sonogashira coupling of o-haloarylaldehydes 1a−e
with commercially available terminal alkynes 2a−j (Scheme
2).17
To identify the optimal conditions for the reaction, we
examined the reaction of 2-(phenylethynyl)quinoline-3-carbal-
dehyde (3a) with aniline (4a) and acetone (5a) using 10 mol %
of AgOTf, 10 mol % of L-proline in 2 mL of EtOH at 60 °C for
6 h; the desired product 6a was obtained in 50% yield (entry
1). When the reaction was further allowed to run for 12 h, no
significant change in the yield of the product was observed
(entry 2). Increasing the catalyst loading from 10 to 20 mol %
made no significant improvement in the yield of the product 6a
(entries 3 and 4). When reaction was carried out in EDC, the
product 6a was obtained in 42 and 45% yields, respectively
(entries 5 and 6). Reaction using 10 mol % of AgNO3 in
ethanol at 60 °C for 6 h afforded the desired product 6a in 68%
(entry 7). Decreasing the reaction time from 6 to 3 h made no
significant change in the yield (entry 8). Further decreasing the
reaction time to 1 h and then to 30 min afforded the desired
product 6a in 70 and 65% yield, respectively (entries 9 and 10).
However, decreasing the catalyst loading from 10 to 5 mol %
afforded the product 6a in only 50% yield (entry 11), whereas
the increase of catalyst loading from 10 to 20 mol % made no
significant change in the yield (entry 12). Increase of the
loading of L-proline from 10 to 20 mol % made no
improvement in the yield of the product (entry 13). However,
in absence of L-proline, the desired product 6a was obtained in
Ding et al. reported the synthesis of isoquinolines by three-
component reaction from ortho-alkynylaldehydes, and later
Larock and co-workers reported the synthesis of a library of
isoquinolines using dual activation concept.14,15 Hecht and co-
workers have found that introduction of nitrogen in
camptothecin ring system made significant improvement in
antitumor activity.16 Recently, we have successfully synthesized
variety of nitrogen heterocycles using 2-(arylethynyl)quinoline-
3-carbaldehydes.17,18 Encouraged by the above observation of
Hecht and co-workers and our ongoing work on the synthesis
of heterocycles by tandem reactions/electrophilic cyclization of
alkynes,19 herein we report the synthesis of highly function-
alized 1,2-dihydrobenzo[1,6]naphthyridines 6a−z, 7a−e and
1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines 8a−e by the
reaction of ortho-alkynylaldehydes 3a−q with amines 4a−d
and ketones 5a−c /active methylene compounds 5d−g in
moderate to good yields, by three-component reaction under
mild reaction conditions (Scheme 1).
RESULTS AND DISCUSSION
■
Preparation of o-Alkynylaldehydes. Starting substrates
o-alkynylaldehydes 3a−q required for examining the scope and
generality of this chemistry were readily prepared by the
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a
Table 2. Synthesis of 1,2-Dihydrobenzo[1,6]naphthyridine
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Table 2. continued
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Table 2. continued
a
Reactions were performed using o-alkynylaldehyde 3 (70 mg, 1 equiv), amine 4 (1 equiv) and 5 equiv of 5, L-proline (10 mol %) and AgNO3 (10
b
c
d
mol %) in 2 mL of EtOH at 60 °C for 1 h. Yields. Reaction was run for 1−2 h. Inseparable complex mixtures.
only 10% yield (entry 14). After the optimization of reaction
time, we screened the effect of solvents. Different solvents like
EtOH, EDC, MeOH, H2O, toluene and THF were screened to
find out an appropriate solvent for the reaction (entries 15−
19). It is clear from Table 1 that EtOH and MeOH at 60 °C
were found to be suitable solvents for the reaction (entries 9
and 15). When piperidine was used instead of L-proline, the
product 6a was obtained in 20% yield (entry 20). Use of other
catalysts such as AgOAc, PdCl2 and Pd(OAc)2 were found
inferior and afforded the product 6a in lower yield (entries 21−
23), respectively.
Synthesis of 1,2-Dihydrobenzo[1,6]naphthyridine.
After optimizing the reaction conditions, we then examined
the scope and generality of the reaction by employing variety of
ortho-alkynylaldehyde 3a−m with substituted amines 4a−f and
ketones 5a−c. A diverse library of 1,2-dihydrobenzo[1,6]-
naphthyridine 6a−z was synthesized in good yields (Table 2,
entries 1−29).
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Figure 2. Analogue of β-carbolines.
Scheme 3. Plausible Mechanistic Pathway by Dual Activation Using L-Proline
The reaction of 2-(phenylethynyl)quinoline-3-carbaldehyde
(3a) and anilines 4a−c with acetone (5a) afforded the desired
products 6a−c in 70, 75, and 69% yields, respectively (entries
1−3). Products 6d,e were obtained in lower yields when ketone
5a was replaced with unsymmetrical 2-butanone (5b) (entries 4
and 5). Reaction of 2-(p-tolylethynyl)quinoline-3-carbaldehyde
(3b) with amine 4c and cyclohexanone (5c) afforded the
desired product 6f in 50% yield (entry 6). The substrates 3c−e
bearing electron-donating substituent such as Et, OMe and
NMe2 para to the triple bond of the phenyl ring showed the
capability to trigger the 6-endo-dig cyclization and provided the
respective desired products 6g−m in good yields (entries 7−
13). 2-(Thiophen-3-ylethynyl)quinoline-3-carbaldehyde (3f)
bearing an electron-rich heterocycle thiophene on reaction
with amine 4c and ketone 5a proved to be favorable for the
reaction and afforded the desired product 6n in 76% yield
(entry 14). ortho-Alkynylaldehyde 3g, bearing substitution at
the meta position of the phenyl ring afforded the desired
products comparatively in lower yields (entries 15−16).
Substrates 3h,i bearing a cyclohexyl and n-butyl group provided
the desired products 6q−u in 68−70% yields (entries 17−21).
Reaction of 6-methoxy substituted o-alkynylaldehydes 3j,k with
anilines 4a,b and 5a afforded the desired product 6v−x in 71−
78% yields (entries 22−24). Further exploring the reaction of
2-(p-tolylethynyl)nicotinaldehyde (3l) with anilines 4b,c and
acetone 5a provided the desired products 6y and 6z in 79 and
74% yields, respectively (entries 25 and 26). However, reaction
of substrate 3a with cyclohexylamine (4e) and n-butylamine
(4f) provided an inseparable, unidentified complex mixture
(entries 27 and 28). Reaction of 2-((4-nitrophenyl)ethynyl)-
quinoline-3-carbaldehyde (3m) bearing an electron-withdraw-
ing nitro group at 4-position of the phenyl ring fails to afford
the desired product.
All the synthesized products 6a−z were fully characterized by
1H NMR, 13C NMR, HRMS and X-ray crystallographic
analysis20 (Figure 2). Products were obtained as racemic
mixtures, and chiral-HPLC analysis of products 6h, 6i, 6k and
6v supports the formation of racemic products.
The possible mechanism for the formation of 1,2-
dihydrobenzo[1,6]naphthyridines 6a−z and 1,2-dihydrobenzo-
[4,5]thieno[2,3-c]pyridines 8a−e via three-component reaction
is shown in Scheme 3. It is proposed that generation of key
intermediates imine D (generated by the reaction of o-
alkynylealdehyde 3 with aniline) and enamine C (generated
by the reaction of L-proline and ketone) takes place
simultaneously. Under silver catalysis imine D is susceptible
to attack by the nucleophile. Intermolecular attack of enamine
C on imine carbon of intermediate D and subsequent
intramolecular attack of nitrogen on alkyne form F (path a).
Intermediate F can also be obtained by the attack of C on
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Table 3. Synthesis of 1,2-Dihydrobenzo[1,6]naphthyridine Using Reactive Methylene Compounds and Cyclic 1,3-Diketones
a
and Ketoesters
a
Reactions were performed using o-alkynylaldehyde 3 (70 mg, 1 equiv), amine 4 (1 equiv), 5 equiv of 5, and AgNO3 (10 mol %) in 2 mL of EtOH
at 60 °C for 0.5 h.
possible isoquinolinium intermediate E (path b). F on
hydrolysis results in the formation of the products 6, 8 and
regenerates L-proline.
proline. Intermolecular attack of enolate on imine carbon of
intermediate D and subsequent intramolecular attack of
nitrogen on alkyne result in the formation of the products 7.
We further extended the scope of the developed chemistry
for the synhesis of another very important class of hetrocyclic
scaffold 1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines 8a−e,
which is known as sulfur analogue of the β-carbolines (Figure
2). Using the optimized reaction conditions (Table 1, entry 9),
reaction of 3-(arylethynyl)benzo[b]thiophene-2-carbaldehydes
3o−q with acetone (5a) and aniline 4a, 4d provided the
thienopyridines 8a−e, along with uncyclized imine 9a−e
(Table 4, entries 1−5).
With the above results, we investigated further structural
elaboration of the bromo-substituted naphthyridines via
palladium-catalyzed cross-coupling reactions. To this end,
compound 6j was functionalized by applying palladium-
catalyzed Suzuki21 and Heck21 coupling reactions using 2-(1-
benzotriazolyl)pyridine (BtPy) as a ligand to afford the
corresponding products 11 and 13 in 72 and 70% yields,
respectively (Scheme 5).
Encouraged by the above results, we further explored the
scope of the reaction with a wide range of readily accessible
reactive methylene compounds and “1,3-dione” substrates, by
replacing one of the reactants of the three-component reaction.
Under the optimized reaction conditions (Table 1, entry 9),
reaction of o-alkynylaldehydes 3a, 3c, 3l and 3n, arylamines
4b−c with dimedone (5d), diethylmalonate (5e), ethyl-
acetoacetate (5f), and meldrum’s acid (5g) afforded the
desired products 7a−e in 62−74% yields (Table 3, entries
1−5). We observed that reaction with reactive dicarbonyl
compounds/esters was faster and completed within 30 min
(compare reaction times of Table 2 and /table 3). It is
interesting to note that synthesis of naphthyridines 7a−e
proceeds without using organocatalyst L-proline.
The possible mechanism for the formation of naphthyridines
7a−e via three-component reaction is shown in Scheme 4. The
proposed mechanism for products 7a−e does not involve the
enamine formation, as this reaction proceeds without use of L-
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yields with high regioselectivity under mild reaction conditions.
Application of the developed chemistry has been successfully
extended for the another important class of hetrocyclic scaffold
1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines, which is known
as sulfur analogue of the β-carbolines. Naphthyridines 6a−z
and thienopyridines 8a−e were obtained via dual activation
concept using L-proline as organocatalyst; however, naphthyr-
idines 7a−e were synthesized via enolate chemistry (without
using organocatalyst). Reactivity behavior of the electron-
deficient and electron-rich ortho-alkynylaldehydes in the
synthesis of variety of heterocyclic compounds by three-
component reaction is described and validated by the control
experiment. From a synthetic point of view, the net
transformation involves a one-step conversion of simple,
inexpensive and readily available starting materials into an
interesting class of fused heterocyclic scaffolds. This chemistry
is expected to find application in organic synthesis in general
and in the construction of a variety of heterocyclic compounds.
Scheme 4. Plausible Mechanistic Pathway without Using L-
Proline
EXPERIMENTAL SECTION
General Information and Methods. H NMR (400 MHz) and
■
1
13C NMR (100 MHz) spectra were recorded in CDCl3. Chemical
shifts for carbons are reported in ppm from tetramethylsilane and are
referenced to the carbon resonance of the solvent. Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, dd = doublet of doublet), coupling
constants in Hertz, and integration. High-resolution mass spectra were
recorded with q-TOF electrospray mass spectrometer . TLC analysis
was performed on commercially prepared 60 F254 silica gel plates and
visualized by either UV irradiation or by staining with I2. All purchased
chemicals were used as received. All melting points are uncorrected.
The starting materials 3 were prepared by Sonogashira coupling
using the reported procedure.17 The structure and purity of known
starting materials 3a,b,d,f,h,17b and 3g,i,17a were confirmed by
comparison of their physical and spectral data (1H NMR and 13C
NMR) with those reported in literature.
Study of the Reactivity Behavior of the Electron-
Deficient and Electron-Rich ortho-Alkynylaldehydes.
Naphthyridines 6a−z and 7a−e synthesized from 2-
(arylethynyl)quinoline-3-carbaldehyde) 3a−n were obtained
in good yields and required less reaction time; however,
thienopyridines 8a−e synthesized by using 3-(arylethynyl)-
benzo[b]thiophene-2-carbaldehydes 3o−q were obtained in
lower yield and required longer reaction time in comparison to
naphthyridines (compare Tables 2, 3 with Table 4). The above
observation could be explained on the basis of reactivity
behavior of o-alkynylaldehydes. In case of 2-(arylethynyl)-
quinoline-3-carbaldehydes (3a−n), presence of electron-
deficient pyridine ring system (-I and -R effect) increases the
reactivity of the aldehydic group, which facilitates the formation
of the key intermediate imine, whereas in the case of 3-
(arylethynyl)benzo[b]thiophene-2-carbaldehydes (3o−q),
presence of electron-rich thiophene ring system (+R effect)
decreases the reactivity of the aldehydic group as well as
intramolecular attack of imine on alkyne (Figure 3).
To validate the reactivity behavior of the electron-deficient,
electron-rich ortho-alkynylaldehydes, we performed a control
experiment. We carried out the reaction of 3a (1 equiv), 3o (1
equiv), with amine 4a (1 equiv) and ketone 5a (5 equiv) using
10 mol % of AgNO3 and 10 mol % L-proline in 2 mL of EtOH
at 60 °C for 2 h (Scheme 6). The results demonstrate that the
product 6a was obtained in 63% yield, whereas product 9a was
formed only in 6% yield. This clearly reveals that o-
alkynylaldehydes 3a−n is more reactive because of the presence
of electron-withdrawing pyridine ring and afforded the products
in good yields. However, o-alkynylaldehydes 3o−q bearing an
electron-rich thiophene ring provided the products in lower
yields along with unreacted imines.
2-((4-Ethylphenyl)ethynyl)quinoline-3-carbaldehyde (3c). This
compound was obtained as a light brown solid (1.04 g, 70%): mp
1
114−118 °C; H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.71 (s,
1H), 8.14 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.3
Hz, 1H), 7.61−7.57 (m, 3H), 7.25−7.21 (m, 2H), 2.67 (q, J = 7.3 Hz,
2H), 1.24 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 190.9,
150.1, 146.5, 144.1, 137.0, 132.9, 132.3, 129.6, 129.2, 128.7, 128.14,
128.06, 126.3, 118.4, 96.0, 85.0, 28.9, 15.2; HRMS (ESI) [M]+ Calcd
for [C20H15NO] 285.1154, found 285.1154.
2-((4-(Dimethylamino)phenyl)ethynyl)quinoline-3-carbaldehyde
(3e). This compound was obtained as dark brown solid (1.17 g, 75%):
mp 172−174 °C; 1H NMR (400 MHz, CDCl3) δ 10.8 (s, 1H), 8.68 (s,
1H), 8.13−8.10 (m, 1H), 7.92−7.90 (m, 1H), 7.81 (t, J = 8.0 Hz, 1H),
7.58−7.54 (m, 3H), 6.66 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 191.3, 151.0, 150.2, 144.8, 136.8, 133.7, 132.8,
129.6, 129.0, 128.4, 127.6, 126.0, 111.6, 107.3, 98.4, 84.6, 40.0; HRMS
(ESI) [M]+ Calcd for [C20H16N2O] 300.1263, found 300.1263.
6-Methoxy-2-((4-methoxyphenyl)ethynyl)quinoline-3-carbalde-
hyde (3j). This compound was obtained as a dark brown solid (1.10 g,
77%): mp 142−150 °C; 1H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H),
8.56 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.60−7.58 (m, 2H), 7.47−7.44
(m, 1H), 7.12 (d, J = 2.9, 1H), 6.90−6.88 (m, 2H), 3.92 (s, 3H), 3.82
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.2, 160.7, 158.8, 146.5,
141.8, 135.3, 133.8, 130.6, 128.9, 127.5, 126.2, 114.2, 113.5, 106.2,
95.2, 84.6, 55.7, 55.3; HRMS (ESI) [M]+ Calcd for [C20H15NO3]
317.1052, found 317.1052.
6-Methoxy-2-(m-tolylethynyl)quinoline-3-carbaldehyde (3k).
CONCLUSION
■
This compound was obtained as a yellow solid (0.97 g, 72%): mp
1
In conclusion, we have demonstrated a direct one pot approach
for the silver-catalyzed tandem synthesis of highly function-
alized 1,2-dihydrobenzo[1,6]naphthyridines via three-compo-
nent reaction using readily available starting materials in good
138−142 °C; H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.61 (s,
1H), 8.07 (d, J = 9.5 Hz, 1H), 7.51−7.47 (m, 3H), 7.30−7.24 (m,
2H), 7.16 (d, J = 2.2, 1H), 3.95 (s, 3H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 191.0, 159.5, 146.4, 141.5, 138.3, 135.4, 132.8, 130.6,
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a
Table 4. Synthesis of 1,2-Dihydrobenzo[4,5]thieno[2,3-c]pyridine
a
Reactions were performed using o-alkynylaldehyde 3 (70 mg, 1 equiv), amine 4 (1 equiv), 5 equiv of 5, L-proline (10 mol %) and AgNO3 (10 mol
%) in 2 mL of EtOH at 60 °C for 2 h.
129.3, 128.4, 127.8, 126.4, 121.1, 106.2, 85.1, 55.8, 21.2; HRMS (ESI)
[M]+ Calcd for [C20H15NO2] 301.1103, found 301.1103.
= 5.6 Hz, 1H), 7.69 (d, J = 5.1 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 6.93
(d, J = 8.8 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.1, 160.6, 154.5, 148.7, 140.2, 133.5, 121.9, 119.2, 114.5, 114.0,
113.6, 99.4, 80.9, 55.3; HRMS (ESI) [M]+ Calcd for [C15H11NO2]
237.0790, found 237.0790.
2-(p-Tolylethynyl)nicotinaldehyde (3l). This compound was
obtained as an orange solid (0.80 g, 68%): mp 96−100 °C; 1H
NMR (400 MHz, CDCl3) δ 10.67 (s, 1H), 8.82 (dd, J = 2.2, 5.1 Hz,
1H), 8.21 (dd, J = 1.4, 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.41−
7.38 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 191.0, 154.5, 146.4, 140.4, 134.8, 132.1, 131.7, 129.4,
123.0, 118.6, 96.9, 83.6, 21.7; HRMS (ESI) [M]+ Calcd for
[C15H11NO] 221.0841, found 221.0841.
3-(Phenylethynyl)benzo[b]thiophene-2-carbaldehyde (3o). This
compound was obtained as a yellow brown solid (0.38 g, 70%): mp
1
104−110 °C; H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.10−
8.08 (m, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.59−7.56 (m, 2H), 7.51−7.43
(m, 2H), 7.37−7.33 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 180.9,
139.9, 137.5, 135.8, 128.4, 126.0, 125.3, 125.1, 124.2, 122.1, 121.5,
119.8, 118.3, 95.5, 77.0; HRMS (ESI) [M]+ Calcd for [C17H10OS]
262.0452, found 262.0451.
2-((4-Nitrophenyl)ethynyl)quinoline-3-carbaldehyde (3m). The
product was obtained as a yellow solid (0.80 g, 65%): mp 164−166
1
°C; H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 8.76 (s, 1H), 8.26
3-(Thiophen-3-ylethynyl)benzo[b]thiophene-2-carbaldehyde
(d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H),
7.91−7.87 (m, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 189.9, 150.0, 147.9, 142.4, 137.9,
133.4, 133.1, 132.6, 129.6, 129.4, 128.9, 128.8, 128.1, 126.6, 123.8,
92.3, 89.8; HRMS (ESI) calcd for [C18H10N2O3] requires [M]+
302.0691, found 302.0692.
3-((4-Methoxyphenyl)ethynyl)isonicotinaldehyde (3n). This com-
pound was obtained as an orange solid (0.91 g, 72%): mp 55−60 °C;
1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.94 (s, 1H), 8.69 (d, J
(3p). This compound was obtained as yellow solid (0.41 g, 75%): mp
1
68−74 °C; H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.12−8.10
(m, 1H), 7.86−7.84 (m, 1H), 7.69−7.67 (m, 1H), 7.53−7.48 (m, 2H),
7.37−7.35 (m, 1H), 7.28−7.27 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 183.6, 143.0, 140.5, 138.9, 130.2, 129.3, 128.3, 127.0, 125.6,
125.1, 124.5, 122.8, 120.5, 93.6, 79.7; HRMS (ESI) [M]+ Calcd for
[C15H8OS2] 268.0017, found 268.0017.
3-((4-(Trifluoromethyl)phenyl)ethynyl)benzo[b]thiophene-2-car-
baldehyde (3q). This compound was obtained as a dark brown solid
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Scheme 5. Pd-Catalyzed Synthetic Elaboration
Figure 3. Reactivity behavior of the electron-deficient, electron-rich ortho-alkynylaldehydes.
MHz, CDCl3) δ 184.1, 144.2, 141.0, 139.2, 132.2, 129.0, 126.6, 125.8,
125.60, 125.57, 124.9, 123.4, 97.1, 82.6; HRMS (ESI) [M]+ Calcd for
[C18H9F3OS] 330.0326, found 330.0326.
Scheme 6. Experimental Support on the Reactivity of o-
Alkynylaldehydes
General Procedure for Synthesis of 1,2-Dihydrobenzo[1,6]-
naphthyridine. A solution of o-alkynylaldehyde 3a−m (70 mg, 1
equiv), amine 4a−f (1 equiv), ketones 5a−c (5 equiv), AgNO3 (10
mol %), L-proline (10 mol %) in C2H5OH (2 mL) was stirred at 60 °C
for a period of 1−2 h. After completion of the reaction as indicated by
TLC, the solvent was evaporated and then quenched with water (10
mL), extracted with EtOAc (3 × 10 mL), and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by purification on silica
gel provided the corresponding products 6a−z.
1-(2,3-Diphenyl-1,2-dihydrobenzo[b][1,6]naphthyridin-1-yl)-
propan-2-one (6a). This compound was obtained as a yellow solid
(74 mg, 70%): mp 120−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.97
(d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.64−7.56 (m, 2H), 7.53−7.51 (m,
2H), 7.33 (t, J = 7.1 Hz, 1H), 7.23−7.19 (m, 4H), 7.05−6.97 (m, 4H),
6.81 (t, J = 7.0 Hz, 1H), 5.70 (t, J= 6.9 Hz, 1H), 3.32 (dd, J = 7.3, 17.6
Hz, 1H), 2.81 (dd, J = 5.8, 16.8 Hz, 1H), 2.07 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 206.5, 151.5, 148.3, 147.8, 146.6, 137.7, 132.3, 129.5,
1
(0.42 g, 68%): mp 92−98 °C; H NMR (400 MHz, CDCl3) δ 10.40
(s, 1H), 8.09−8.07 (m, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 8.0
Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.53−7.45 (m, 2H);13C NMR (100
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129.1, 128.8, 128.6, 128.2, 127.8, 127.6, 127.5, 127.2, 125.3, 123.13,
123.09, 112.4, 61.0, 47.8, 31.6; HRMS (ESI) [M]+ Calcd for
[C27H22N2O] 390.1732, found 390.1731.
5.61−5.58 (m, 1H), 3.63 (s, 3H), 3.37 (dd, J = 8.1, 17.6 Hz, 1H), 2.75
(dd, J = 7.3, 18.3 Hz, 1H), 2.58 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.17
(t, J = 8.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.7, 155.8,
151.8, 148.9, 145.5, 140.4, 134.1, 132.1, 129.4, 128.2, 128.1, 128.0,
127.6, 127.4, 126.9, 125.1, 124.8, 114.1, 111.1, 61.7, 55.2, 47.8, 31.7,
28.5 15.2; HRMS (ESI) [M]+ Calcd for [C30H28N2O2] 448.2151,
found 448.2151.
1-(2-(4-Bromophenyl)-3-(4-ethylphenyl)-1,2-dihydrobenzo[b]-
[1,6]naphthyridin-1-yl)propan-2-one (6h). This compound was
obtained as a yellow solid (90 mg, 74%): mp 134−136 °C; 1H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H),
7.69−7.62 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H),
7.18 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H), 6.96
(d, J = 8.8 Hz, 2H), 5.68−5.65 (m, 1H), 3.40 (dd, J = 8.8, 17.6 Hz,
1H), 2.72 (dd, J = 5.8, 17.6 Hz, 1H), 2.60 (q, J = 8.0 Hz, 2H), 2.12 (s,
3H), 1.19 (t, J = 8.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.5,
151.5, 148.0, 147.6, 145.9, 145.8, 133.7, 131.9, 131.8, 129.6, 128.4,
128.3, 127.6, 127.4, 127.1, 125.4, 124.6, 115.9, 112.9, 61.0, 47.5, 31.5,
28.6 15.2; HRMS (ESI) [M]+ Calcd for [C29H25BrN2O] 496.1150,
found 496.1151.
1-(2-(4-Methoxyphenyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6b). This compound was obtained
as orange solid (85 mg, 75%): mp 136−140 °C; 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.69−7.62 (m, 2H),
7.58−7.55 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.27−7.24 (m, 4H),
7.00−6.96 (m, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.62 (t, J = 7.0 Hz, 1H),
3.63 (s, 3H), 3.36 (dd, J = 7.3, 16.8 Hz, 1H), 2.79 (dd, J = 7.3, 18.3
Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.6, 155.9,
151.6, 148.9, 147.7, 140.2, 136.8, 132.3, 129.5, 129.1, 128.5, 128.1,
128.0, 127.6, 127.5, 126.8, 125.2, 124.9, 114.1, 111.3, 61.6, 55.3, 47.9,
31.6; HRMS (ESI) [M]+ Calcd for [C28H24N2O2] 420.1838, found
420.1837.
1-(2-(4-Bromophenyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6c). This compound was obtained
1
as a yellow solid (87 mg, 69%): mp 178−184 °C; H NMR (400
MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.64−7.57 (m,
2H), 7.49−7.47 (m, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.23−7.22 (m, 3H),
7.13 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.90 (d, J = 8.0 Hz, 2H), 5.65−
5.61 (m, 1H), 3.35 (dd, J = 8.1, 17.6 Hz, 1H), 2.70 (dd, J = 5.8, 17.5
Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.4, 151.3,
147.5, 145.8, 139.1, 136.3, 132.8, 132.1, 132.0, 131.8, 131.0, 129.7,
129.3, 129.0, 128.8, 128.3, 127.7, 127.5, 127.0, 126.4, 125.6, 124.6,
116.1, 113.3, 61.0, 47.6, 31.5; HRMS (ESI) [M]+ Calcd for
[C27H21BrN2O] 468.0837, found 468.0837.
1-(2,3-Bis(4-methoxyphenyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6i). This compound was obtained
1
as a brown solid (86 mg, 79%): mp 136−144 °C; H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.59−7.53 (m,
2H), 7.44 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 6.91 (d, J = 9.5
Hz, 2H), 6.86 (s, 1H), 6.71 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz,
2H), 5.52−5.49 (m, 1H), 3.67 (s, 3H), 3.56 (s, 3H), 3.31 (dd, J = 8.8,
17.6 Hz, 1H), 2.66 (dd, J = 5.8, 16.9 Hz, 1H), 2.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 206.6, 160.2, 155.7, 151.8, 148.6, 147.7, 140.3,
133.7, 132.1, 129.3, 129.0, 127.9, 127.5, 127.3, 126.7, 124.9, 124.8,
114.1, 113.9, 110.0, 61.6, 55.13, 55.09, 47.7, 31.5; HRMS (ESI) [M]+
Calcd for [C29H26N2O3] 450.1943, found 450.1943.
1-(3-Phenyl-2-(p-tolyl)-1,2-dihydrobenzo[b][1,6]naphthyridin-1-
yl)butan-2-one (6d). This compound was obtained as a yellow solid
(62 mg, 55%): mp 80−84 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d,
J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.62−7.55 (m, 2H), 7.51−7.49 (m, 2H),
7.32 (t, J = 8.0 Hz, 1H), 7.21−7.18 (m, 3H), 6.94 (s, 1H), 6.85 (q, J =
8.8 Hz, 4H), 5.65 (t, J = 6.9 Hz, 1H), 3.28 (dd, J = 7.3, 16.1 Hz, 1H),
2.72 (dd, J = 5.8, 16.8 Hz, 1H), 2.37−2.26 (m, 1H), 2.24−2.19 (m,
1H), 2.09 (s, 3H), 0.96 (t, J = 7.3, 3H); 13C NMR (100 MHz, CDCl3)
δ 209.4, 151.8, 148.3, 147.9, 144.2, 136.9, 132.8, 132.0, 129.4, 129.3,
129.0, 128.6, 128.4, 127.8, 127.6, 127.5, 127.1 125.2, 123.1, 112.3, 61.5,
46.7, 37.7, 20.7, 7.5; HRMS (ESI) [M]+ Calcd for [C29H26N2O]
418.2045, found 418.2045.
1-(2-(4-Bromophenyl)-3-(4-methoxyphenyl)-1,2-dihydrobenzo-
[b][1,6]naphthyridin-1-yl)propan-2-one (6j). This compound was
1
obtained as a light brown solid (0.260 g, 75%): mp 140−142 °C; H
NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H),
7.63−7.56 (m, 2H), 7.43−7.40 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H),
7.14−7.12 (m, 2H), 6.94−6.89 (m, 3H), 6.75 (d, J = 8.8 Hz, 2H),
5.61−5.58 (m, 1H), 3.71 (s, 3H), 3.34 (dd, J = 8.0, 16.8 Hz, 1H), 2.67
(dd, J = 5.8, 17.6 Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 206.5, 160.5, 151.6, 148.0, 147.3, 146.0, 131.9, 131.8, 129.5, 129.1,
128.6, 128.3, 127.6, 127.3, 127.0, 125.3, 124.7, 116.0, 114.2, 112.0,
61.1, 55.3, 47.5, 31.5; HRMS (ESI) [M]+ Calcd for [C28H23BrN2O2]
498.0943, found 498.0943.
1-(2-(4-Methoxyphenyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)butan-2-one (6e). This compound was obtained as
1
an orange solid (70 mg, 60%): mp 68−72 °C; H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.63−7.58 (m, 2H),
7.51−7.49 (m, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.21−7.19 (m, 3H), 6.97
(s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 5.60−5.57
(m, 1H), 3.58 (s, 3H), 3.30 (dd, J = 8.0, 16.9 Hz, 1H), 2.69 (dd, J =
6.6, 17.6 Hz, 1H), 2.42−219 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 209.4, 155.9, 151.5, 140.2, 132.5, 129.6,
129.1, 128.5, 128.0, 127.8, 127.6, 127.5, 126.9, 125.2, 124.9, 114.1,
61.8, 55.3, 46.7, 37.7, 31.9; HRMS (ESI) [M]+ Calcd for
[C29H26N2O2] 434.1994, found 434.1994.
1-(3-(4-(Dimethylamino)phenyl)-2-(p-tolyl)-1,2-dihydrobenzo[b]-
[1,6]naphthyridin-1-yl)propan-2-one (6k). This compound was
obtained as a brown solid (81 mg, 78%): mp 128−134 °C; 1H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 10.6 Hz, 1H), 7.72 (s, 1H),
7.65−7.62 (m, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H),
7.33 (t, J = 9.5 Hz, 1H), 6.96−6.94 (m, 2 H), 6.92−6.87 (m, 3H), 6.57
(d, J = 9.5 Hz, 2H), 5.65−5.60 (m, 1H), 3.38 (dd, J = 8.8, 17.6 Hz,
1H), 2.92 (s, 6H), 2.73 (dd, J = 6.6, 17.6 Hz, 1H), 2.15 (s, 3H), 2.11
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 152.3, 150.8, 149.0,
147.9, 145.0, 132.4, 131.9, 129.4, 129.2, 129.0, 128.0, 127.5, 127.2,
124.7, 124.0, 123.2, 115.9, 111.7, 61.5, 47.6, 40.1, 31.7, 20.6; HRMS
(ESI) [M]+ Calcd for [C30H29N3O] 447.2311, found 447.2311.
1-(3-(4-(Dimethylamino)phenyl)-2-(4-methoxyphenyl)-1,2-
dihydrobenzo[b][1,6]naphthyridin-1-yl)propan-2-one (6l). This
2-(2-(4-Bromophenyl)-3-(p-tolyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)cyclohexanone (6f). This compound was obtained
1
as a brown solid (67 mg, 50%): mp 180−184 °C; H NMR (400
MHz, CDCl3) δ 7.70−7.64 (m, 4H), 7.43 (d, J = 8.1 Hz, 2H), 7.35 (d,
J = 8.8 Hz, 1H), 7.24 (s, 1H), 7.13−7.07 (m, 4H), 6.78 (d, J = 8.8 Hz,
1H), 6.35 (d, J = 8.8 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H), 3.24−3.17 (m,
1H), 2.51 (d, J = 13.2 Hz, 1H), 2.43−2.35(m, 1H), 2.32 (m, 1H), 2.29
(s, 3H), 2.08−2.02 (m, 1H), 1.70−1.60 (m, 3H), 1.46−1.39 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 212.1, 152.0, 149.6, 148.7, 147.9,
1
compound was obtained as an orange semisolid (85 mg, 79%): H
NMR (400 MHz, CDCl3) δ 7.95 (d, J = 10.1 Hz, 1H), 7.68 (s, 1H),
7.60−7.52 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H),
6.94 (d, J = 9.5 Hz, 2H), 6.86 (s, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.51
(d, J = 8.8 Hz, 2H), 5.52−5.48 (m, 1H), 3.58 (s, 3H), 3.34 (dd, J = 8.8,
17.6 Hz, 1H), 2.87 (s, 6H), 2.63 (dd, J = 5.9, 16.8 Hz, 1H), 2.06 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 155.6, 150.9, 140.9,
129.5, 129.2, 128.8, 127.6, 127.2, 127.0, 124.9, 124.8, 124.0, 123.9,
115.9, 114.1, 111.7, 61.8, 55.3, 47.7, 40.1, 31.8; HRMS (ESI) [M]+
Calcd for [C30H29N3O2] 463.2260, found 463.2260.
146.7, 146.2, 139.5, 133.7, 133.2, 131.9, 131.6, 129.5, 128.3, 127.6,
127.1, 125.3, 124.9, 124.7, 121.2, 120.7, 115.8, 113.5, 64.1, 52.2, 43.2,
32.5, 28.7, 25.1, 21.2; HRMS (ESI) [M]+ Calcd for [C31H27BrN2O]
522.1307, found 522.1307.
1-(3-(4-Ethylphenyl)-2-(4-methoxyphenyl)-1,2-dihydrobenzo[b]-
[1,6]naphthyridin-1-yl)propan-2-one (6g). This compound was
obtained as a yellow solid (85 mg, 78%): mp 116−120 °C; 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H),
7.67−7.61 (m, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.37 (t, J = 6.6 Hz, 1H),
7.09 (d, J = 8.0 Hz, 2H), 6.99−6.97 (m, 3H), 6.62 (d, J = 8.8 Hz, 2H),
1-(2-(4-Bromophenyl)-3-(4-(dimethylamino)phenyl)-1,2-
dihydrobenzo[b][1,6]naphthyridin-1-yl)propan-2-one (6m). This
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compound was obtained as an orange solid (89 mg, 75%): mp 76−80
°C; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.74 (s,
1H), 7.66−7.60 (m, 2H), 7.42−7.34 (m, 3H), 7.18 (d, J = 8.8 Hz,
2H), 6.99−6.96 (m, 3H), 6.57 (d, J = 8.8 Hz, 2H), 5.65−5.61 (m,
1H), 3.41 (dd, J = 8.0, 17.6 Hz, 1H), 2.93 (s, 6H), 2.67 (dd, J = 5.9,
17.6 Hz, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.7,
151.8, 151.0, 148.5, 147.5, 146.4, 139.2, 132.0, 131.7, 129.6, 128.9,
127.8, 127.5, 127.2, 127.1, 125.1, 124.7, 123.2, 115.7, 111.8, 61.1, 47.3,
40.1, 31.6; HRMS (ESI) [M]+ Calcd for [C29H26BrN3O] 511.1259,
found 511.1259.
1-(3-Butyl-2-phenyl-1,2-dihydrobenzo[b][1,6]naphthyridin-1-yl)-
propan-2-one (6s). This compound was obtained as a brown liquid
1
(74 mg, 68%): H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz,
1H), 7.64 (s, 1H), 7.58−7.50 (m, 2H), 7.29−7.18 (m, 3H), 7.06−7.02
(m, 3H), 6.33 (s, 1H), 5.40−5.37 (m, 1H), 3.04 (dd, J = 5.8, 16.8 Hz,
1H), 2.93 (dd, J = 7.3, 16.8 Hz, 1H), 2.34−2.28 (m, 1H), 2.21−2.16
(m, 1H), 1.98 (s, 3H), 1.25−1.15 (m, 4H), 0.80−0.75 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 206.3, 152.2, 151.5, 147.5, 145.5, 132.2,
129.4, 129.1, 127.8, 127.6, 127.1, 125.7, 124.7, 124.6, 108.4, 61.0, 48.1,
33.3, 31.5, 30.4, 22.2, 13.8; HRMS (ESI) [M]+ Calcd for [C25H26N2O]
370.2045, found 370.2045.
1-(3-Butyl-2-(4-methoxyphenyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6t). This compound was obtained
as a brown liquid (82 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 7.91
(d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.55 (t, J =
7.4 Hz, 1H), 7.29 (t, J = 6.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.79 (d,
J = 8.8 Hz, 2H), 6.22 (s, 1H), 5.29 (t, J = 7.3 Hz, 1H), 3.74 (s, 3H),
3.05 (dd, J = 6.5, 17.5 Hz, 1H), 2.92 (dd, J = 7.3, 17.6 Hz, 1H), 2.24−
2.11 (m, 2H), 1.99 (s, 3H), 1.44−1.39 (m, 2H), 1.29−1.20 (m, 2H),
0.83−0.79 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 206.4, 157.2,
152.6, 151.9, 147.9, 138.7, 131.8, 129.6, 129.2, 128.8, 127.9, 127.5,
127.1, 126.8, 125.3, 124.3, 114.3, 106.6, 61.4, 55.0, 48.0, 33.3, 31.4,
30.3, 22.2, 13.8 ; HRMS (ESI) [M]+ Calcd for [C26H28N2O2]
400.2151, found 400.2151.
1-(2-(4-Bromophenyl)-3-(thiophen-3-yl)-1,2-dihydrobenzo[b]-
[1,6]naphthyridin-1-yl)propan-2-one (6n). This compound was
1
obtained as a pale white solid (95 mg, 76%): mp 168−172 °C; H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H),
7.70−7.63 (m, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 (s, 1H), 7.25−7.21
(m, 4H), 7.07 (s, 1H), 6.98−6.96 (m, 2H), 5.63−5.60 (m, 1H), 3.39
(dd, J = 8.0, 17.6 Hz, 1H), 2.72 (dd, J = 5.8, 17.5 Hz, 1H), 2.13 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 206.5, 151.2, 147.8, 146.1,
142.7, 138.5, 132.1, 131.9, 129.7, 128.3, 127.6, 127.4, 126.9, 126.4,
126.3, 125.6, 125.3, 124.4, 116.3, 112.4, 61.2, 47.6, 31.6; HRMS (ESI)
[M]+ Calcd for [C25H19BrN2OS] 474.0401, found 474.0402.
1-(2-(4-Methoxyphenyl)-3-m-tolyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6o). This compound was obtained
1
as orange solid (81 mg, 72%): mp 66−78 °C; H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.60−7.53 (m, 2H),
7.38 (s, 1H), 7.31−7.23 (m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.98 (d, J =
7.4 Hz, 1H), 6.92−6.90 (m, 3H), 6.55 (d, J = 8.8 Hz, 2H), 5.53 (t, J =
7.3 Hz, 1H), 3.55 (s, 3H), 3.30 (dd, J = 7.4, 16.9 Hz, 1H), 2.69 (dd, J
= 5.9, 17.6 Hz, 1H), 2.21 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.5, 155.8, 151.8, 149.0, 147.9, 140.3, 138.0, 136.8, 132.1,
129.8, 129.3, 128.6, 128.3, 128.2, 127.5, 126.8, 125.2, 125.0, 124.8,
114.0, 111.5, 61.7, 55.1, 47.8, 31.5, 22.5; HRMS (ESI) [M]+ Calcd for
[C29H26N2O2] 434.1994, found 434.1994.
1-(2-(4-Bromophenyl)-3-butyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6u). This compound was obtained
1
as a brownish liquid (89 mg, 68%): H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 8.8 Hz, 1H), 7.56−7.44 (m, 3H), 7.26−7.19 (m, 3H), 6.89
(d, J = 8.7 Hz, 2H), 6.36 (s, 1H), 5.28 (t, J = 6.6 Hz, 1H), 3.06 (dd, J =
6.6, 17.6 Hz, 1H), 2.70 (dd, J = 6.6 Hz, 17.5, 1H), 1.94 (s, 3H), 1.38−
1.25 (m, 3H), 1.18−1.10 (m, 3H), 0.76−0.70 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 206.0, 151.2, 151.1, 147.5, 144.7, 132.04, 131.97,
129.4, 127.9, 127.5, 127.1, 125.7, 125.6, 124.9, 117.4, 110.4, 60.9, 47.9,
33.1, 31.2, 30.4, 22.2, 13.7; HRMS (ESI) [M]+ Calcd for
[C25H25BrN2O] 448.1150, found 448.1150.
1-(8-Methoxy-3-(4-methoxyphenyl)-2-phenyl-1,2-dihydrobenzo-
[b][1,6]naphthyridin-1-yl)propan-2-one (6v). This compound was
obtained as an orange solid (77 mg, 78%): mp 170−174 °C; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 9.5 Hz, 1H), 7.63(s, 1H), 7.43 (d, J
= 8.0 Hz, 2H), 7.24−7.21 (m, 1H), 7.05−6.96 (m, 4H), 6.91−6.89 (m,
2H), 6.80 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 5.64 (t, J = 6.6
Hz, 1H), 3.81 (s, 3H), 3.69 (s, 3H), 3.29 (dd, J = 7.3, 16.8 Hz, 1H),
2.76 (dd, J = 5.8, 16.8 Hz, 1H), 2.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.8, 160.2, 156.9, 149.9, 146.9, 146.5, 143.8, 131.0, 129.6,
129.2, 129.0, 128.8, 128.2, 127.5, 123.0, 122.9, 121.9, 114.0, 111.5,
105.5, 61.1, 55.5, 55.2, 47.8, 31.6; HRMS (ESI) [M]+ Calcd for
[C29H26N2O3] 450.1943, found 450.1943.
1-(2-(4-Bromophenyl)-3-m-tolyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6p). This compound was obtained
1
as yellow solid (89 mg, 72%): mp 54−60 °C; H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.57−7.50 (m, 2H),
7.32−7.25 (m, 2H), 7.16 (d, J = 7.3 Hz, 1H), 7.09−7.02 (m, 3H),
6.98−6.96 (m, 2H), 6.88−6.85 (d, J = 8.8 Hz, 2H), 5.59−5.56 (m,
1H), 3.29 (dd, J = 8.1, 17.6 Hz, 1H), 2.63 (dd, J = 5.1, 17.6 Hz, 1H),
2.19 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.3,
151.2, 147.8, 147.7, 145.8, 138.3, 136.2, 132.0, 131.7, 130.1, 129.5,
128.5, 128.2, 127.5, 127.4, 127.0, 125.4, 124.8, 124.5, 115.9, 113.8,
60.9, 47.4, 31.3, 21.3; HRMS (ESI) [M]+ Calcd for [C28H23BrN2O]
482.0994, found 482.0994.
1-(3-Cyclohexyl-2-(4-methoxyphenyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6q). This compound was obtained
as a yellowish semisolid (77 mg, 69%): 1H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz,
1H), 7.60−7.52 (m, 2H), 7.48(t, J = 7.3 Hz, 1H), 7.25 (t, J = 8.0 Hz,
1H), 6.94 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.35 (s, 1H),
5.26 (t, J = 6.6 Hz, 1H), 3.69 (s, 3H), 3.05 (dd, J = 6.6, 16.8 Hz, 1H),
2.73 (dd, J = 6.6, 17.5 Hz, 1H), 1.98 (s, 3H), 1.93−1.81 (m, 3H),
1.68−1.62 (m, 3H), 1.54−1.47 (m, 3H), 1.46−1.29 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 206.3, 151.7, 147.1, 141.5, 139.5, 137.4,
132.5, 132.1, 129.5, 129.2, 128.7, 127.7, 127.5, 127.2, 127.0, 126.0,
125.5, 124.5, 61.2, 55.4, 48.1, 31.3, 26.7, 26.2, 26.1, 25.7, 24.8; HRMS
(ESI) [M]+ Calcd for [C28H30N2O2] 426.2307, found 426.2307.
1-(2-(4-Bromophenyl)-3-cyclohexyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6r). This compound was obtained
as a dark brown liquid (85 mg, 68%): 1H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.59−7.49 (m, 2H), 7.32−7.28
(m, 3H), 6.93 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 5.36 (t, J = 6.6 Hz,
1H), 3.15 (dd, J = 7.4, 17.6 Hz, 1H), 2.65 (dd, J = 5.8, 17.6 Hz, 1H),
2.02 (s, 3H), 1.97−1.95 (m, 1H), 1.93−1.74 (m, 5H), 1.65−1.46 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 206.0, 152.8, 151.1, 145.6,
139.2, 135.3 132.1, 129.5, 127.9, 127.5, 127.3, 125.9, 125.3, 123.9,
123.3, 60.8, 48.0, 40.6, 31.6, 31.1, 30.3, 29.3, 26.7, 26.2, 26.1; HRMS
(ESI) [M]+ Calcd for [C27H27BrN2O] 474.1307, found 474.1307.
1-(8-Methoxy-2-phenyl-3-(m-tolyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one (6w). This compound was obtained
1
as a yellow solid (71 mg, 71%): mp 130−132 °C; H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.35 (s, 1H),
7.22−7.16 (m, 2H), 7.05−6.89 (m, 8H), 6.78−6.75 (m, 1H), 5.64 (t, J
= 6.6 Hz, 1H), 3.77 (s, 3H), 3.27 (dd, J = 7.3, 17.5 Hz, 1H), 2.77 (dd,
J = 6.5, 17.5 Hz, 1H), 2.20 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.7, 157.0, 149.4, 147.1, 146.8, 143.8, 138.1, 136.8, 131.0,
129.7, 129.6, 128.7, 128.3, 128.2, 127.5, 124.8, 122.8, 122.0, 112.6,
105.5, 60.9, 55.4, 47.7, 31.6, 21.3; HRMS (ESI) [M]+ Calcd for
[C29H26N2O2] 434.1994, found 434.1994.
1-(8-Methoxy-2-(4-methoxyphenyl)-3-(m-tolyl)-1,2-
dihydrobenzo[b][1,6]naphthyridin-1-yl)propan-2-one (6x). This
compound was obtained as an orange solid (79 mg, 74%): mp
136−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 9.5 Hz, 1H),
7.60 (s, 1H), 7.38 (s, 1H), 7.26−7.20 (m, 2H), 7.06 (t, J = 7.3 Hz,
1H), 6.99−6.96 (m, 1H), 6.92−6.89 (m, 4H), 6.55 (t, J = 9.5, 2H),
5.51 (t, J = 6.6, 1H), 3.79 (s, 3H), 3.56 (s, 3H), 3.29 (dd, J = 7.3, 16.8
Hz, 1H), 2.70 (dd, J = 5.8, 16.8 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 206.8, 156.9, 155.7, 149.6, 147.7,
143.8, 140.4, 138.0, 136.9, 129.7, 129.6, 128.4, 128.3, 127.1, 125.0,
124.6, 121.9, 114.0, 111.7, 105.5, 61.6, 55.5, 55.2, 47.9, 31.6, 21.4;
4398
dx.doi.org/10.1021/jo400400c | J. Org. Chem. 2013, 78, 4386−4401

The Journal of Organic Chemistry
Article
1
HRMS (ESI) [M]+ Calcd for [C30H28N2O3] 464.2100, found
464.2100.
pound was obtained as a yellow semisolid (105 mg, 72%): H NMR
(400 MHz, CDCl3) δ 14.84 (s, 1H), 8.54 (d, J = 4.4 Hz, 1H), 7.31−
7.26 (m, 3H), 7.11−7.06 (m, 5H), 6.71 (d, J = 8.8 Hz, 2H), 6.52 (d, J
= 8.8 Hz, 2H), 4.57 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 16.8 Hz, 1H),
3.65 (s, 3H), 2.46 (s, 2H), 2.30 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 13C
NMR (100 MHz, CDCl3) δ 200.1, 195.5, 169.7, 158.2, 151.6, 147.9,
139.3, 136.2, 135.8, 131.4, 129.9, 129.1, 126.7, 125.7, 115.9, 114.1,
114.0, 106.2, 55.2, 52.6, 52.1, 43.9, 31.6, 28.0, 24.6, 22.7; HRMS (ESI)
[M]+ Calcd for [C30H30N2O3 ]466.2256, found 466.2256.
1-(6-(4-Methoxyphenyl)-7-(p-tolyl)-5,6-dihydro-1,6-naphthyri-
din-5-yl)propan-2-one (6y). This compound was obtained as a yellow
solid (95 mg, 79%): mp 114−118 °C; 1H NMR (400 MHz, CDCl3) δ
8.35−8.34 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.32 Hz,
1H), 6.99−6.87 (m, 3H), 6.76 (s, 3H), 6.54 (d, J = 8.8 Hz, 2H), 5.38−
5.34 (m, 1H), 3.54 (s, 3H), 3.19 (dd, J = 8.1, 16.9 Hz, 1H), 2.59 (dd, J
= 5.9, 16.8 Hz, 1H), 2.19 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.8, 155.5, 151.1, 148.3, 146.1, 140.0, 138.7, 133.8, 133.1,
129.1, 127.6, 125.8, 124.5, 121.0, 113.9, 110.5, 61.2, 55.1, 47.1, 29.6,
21.1; HRMS (ESI) [M]+ Calcd for [C25H24N2O2 ] 384.1838, found
384.1838.
1-(6-(4-Bromophenyl)-7-(p-tolyl)-5,6-dihydro-1,6-naphthyridin-
5-yl)propan-2-one (6z). This compound was obtained as a yellow
solid (101 mg, 74%): mp 114−118 °C; 1H NMR (400 MHz, CDCl3)
δ 8.49 (d, J = 3.6 Hz, 1H), 7.44−7.39 (m, 3H), 7.23 (d, J = 8.0 Hz,
2H), 7.13−7.08 (m, 3H), 7.00−6.95 (m, 3H), 5.57−5.54 (m, 1H),
3.38−3.31 (m, 1H), 2.70 (dd, J = 5.8, 17.6 Hz, 1H), 2.34 (s, 3H), 2.18
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.5, 150.8, 148.5, 145.6,
145.0, 139.1, 133.3, 133.0, 131.6, 129.4, 127.4, 126.5, 124.4, 121.3,
115.7, 112.2, 60.4, 46.7, 29.5, 21.1; HRMS (ESI) [M]+ Calcd for
[C24H21BrN2O ] 432.0837, found 432.0837.
5-(2-(4-Methoxyphenyl)-3-phenyl-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7e). This
compound was obtained as a yellow solid (100 mg, 74%): mp 220−
226 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.72
(t, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.53 (t, J =
7.8 Hz, 1H), 7.28−7.26 (m, 4H), 6.77 (d, J = 8.8 Hz, 2H), 6.67 (s,
2H), 6.44 (d, J = 8.8 Hz, 2H), 4.89 (d, J = 16.8 Hz, 1H), 4.39 (d, J =
16.9 Hz, 1H), 3.53 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 199.8, 170.8, 167.3, 162.5, 158.2, 153.5, 151.6, 146.2,
139.3, 136.1, 134.5, 131.0, 130.3, 130.2, 129.5, 128.4, 127.8, 127.7,
126.8, 126.6, 126.3, 124.0, 123.5, 117.3, 114.8, 114.2, 103.3, 55.7, 55.2,
44.2, 26.8, 26.5; HRMS (ESI) [M]+ Calcd for [C31H26N2O5]
506.1842, found 506.1842.
General Procedure for the Synthesis of 1,2-Dihydrobenzo
[4,5]thieno[2,3-c]pyridines (Table 4). A solution of o-alkynylalde-
hyde 3o−q (70 mg, 1 equiv), amine 4a/4d (1 equiv), acetone 5a (5
equiv), AgNO3 (10 mol %), L-proline (10 mol %) in C2H5OH (2 mL)
was stirred at 60 °C for a period of 2 h. After completion of the
reaction as indicated by TLC, the solvent was evaporated and then
quenched with water (10 mL), extracted with EtOAc (3 × 10 mL),
and dried over anhydrous Na2SO4. Evaporation of the solvent followed
by purification on silica gel provided the corresponding products 8a−e
along with imines 9a−e, respectively (Table 4).
1-(2,3-Diphenyl-1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridin-1-yl)-
propan-2-one (8a). This compound was obtained as a brown solid
(68 mg, 65%): mp 114−119 °C; 1H NMR (400 MHz, CDCl3) δ 7.90
(d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7. 55−7.53 (m, 2H),
7.45−7.39 (m, 2H), 7.32−7.26 (m, 2H), 7.21−7.17 (m, 1H), 7.10−
7.04 (m, 4H), 7.00 (s, 1 H), 6.85−6.81 (m, 1H), 5.77−5.73 (m, 1H),
3.24 (dd, J = 8.1, 17.6 Hz, 1H), 2.83 (dd, J = 5.1, 16.8 Hz, 1H), 2.17
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.9, 147.0, 141.7, 139.7,
138.6, 137.3, 134.6, 131.8, 128.7, 128.6, 128.4, 127.3, 127.0, 124.3,
123.9, 122.9, 122.53, 122.47, 122.3, 120.8, 106.4, 57.5, 47.3, 31.6;
HRMS (ESI) [M]+ Calcd for [C26H21NOS] 395.1344, found
395.1344.
General Procedure for Synthesis of 1,2-Dihydrobenzo[1,6]-
naphthyridines (Table 3). A solution of o-alkynylaldehydes 3 (70
mg, 1 equiv), amine 4b,c (1 equiv), 5d−g (5 equiv) and AgNO3 (10
mol %), in C2H5OH (2 mL) was stirred at 60 °C for a period of 0.5 h.
After completion of the reaction as indicated by TLC, the solvent was
evaporated and then quenched with water (10 mL), extracted with
EtOAc (3 × 10 mL), and dried over anhydrous Na2SO4. Evaporation
of the solvent followed by purification on silica gel provided the
corresponding products 7a−e. (Table 3, entries 1−5).
Diethyl 2-(6-(4-bromophenyl)-7-(p-tolyl)-5,6-dihydro-1,6-naph-
thyridin-5-yl)malonate (7a). This compound was obtained as a
1
yellow solid (118 mg, 70%): mp 114−120 °C; H NMR (400 MHz,
CDCl3) δ 8.41 (d, J = 5.12 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.30 (d,
J = 8.0 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.01−6.96 (m, 4H), 6.92 (d,
J = 8.8 Hz, 2H), 5.59 (d, J = 11.0 Hz, 1H), 4.30−4.18 (m, 2H), 3.99−
3.87 (m, 3H), 2.22 (s, 3H), 1.22−1.14 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.7, 166.6, 151.0, 149.2, 145.2, 139.3, 134.7, 132.6, 131.7,
129.2, 127.5, 124.8, 123.1, 121.1, 116.4, 112.9, 64.2, 62.0, 61.6, 54.3,
21.2, 13.9, 13.8; HRMS (ESI) [M]+ Calcd for [C28H27BrN2O4]
534.1154, found 534.1154.
Ethyl 2-(2-(4-bromophenyl)-3-(4-ethylphenyl)-1,2-dihydrobenzo-
[b][1,6]naphthyridin-1-yl)-3-oxobutanoate (7b). This compound
1-(3-Phenyl-2-(p-tolyl)-1,2-dihydrobenzo[4,5]thieno[2,3-c]-
pyridin-1-yl)propan-2-one (8b). This compound was obtained as a
brown semisolid (65 mg, 60%): H NMR (400 MHz, CDCl3) δ 7.84
1
was obtained as a yellow solid (78 mg, 62%): mp 72−76 °C; H
1
NMR (400 MHz, CDCl3) δ 8.02 (t, J = 7.3 Hz, 1H), 7.86 (d, J = 15.4
Hz, 2H), 7.68−7.61 (m, 2H), 7.45−7.42 (m, 2H), 7.37 (t, J = 7.3 Hz,
1H), 7.26 (s, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.10 (d, J =
8.1 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 5.86 (d, J = 11 Hz, 1H), 5.23 (s,
1H), 4.46−4.41 (m, 2H), 2.60−2.54 (m, 2H), 2.30 (s, 3H), 1.28−1.22
(m, 3H), 1.16 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
201.8, 200.2, 167.1, 166.2, 151.1, 147.7, 146.0, 145.4, 134.6, 134.1,
132.8, 131.8, 130.0, 128.4, 128.1, 127.6, 127.0, 125.6, 124.8, 123.8,
116.7, 112.9, 63.8, 62.1, 60.4, 29.6, 28.5, 14.0, 13.7; HRMS (ESI) [M]+
Calcd for [C32H29BrN2O3]568.1362, found 568.1363.
(d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.50−7.47 (m, 2H),
7.38−7.34 (m, 1H), 7.26−7.14 (m, 5H), 6.91−6.88 (m, 3H), 6.81(d, J
= 8.8 Hz, 1H), 5.65−5.61 (m, 1H), 3.17 (dd, J = 8.0, 16.8 Hz, 1H),
2.75 (dd, J = 5.1, 16.8 Hz, 1H), 2.11 (s, 3H), 2.08 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.0, 145.0, 139.7, 138.7, 137.4, 135.6, 132.3,
129.5, 129.3, 128.5, 127.9, 127.0, 124.3, 124.2, 122.9, 122.4, 120.7,
113.7, 57.8, 47.4, 31.6, 20.6; HRMS (ESI) [M]+ Calcd for
[C27H23NOS] 409.1500, found 409.1501.
1-(2-Phenyl-3-(thiophen-3-yl)-1,2-dihydrobenzo[4,5]thieno[2,3-
c]pyridin-1-yl)propan-2-one (8c). This compound was obtained as
brown solid (68 mg, 65%): mp 92−100 °C; H NMR (400 MHz,
Diethyl 2-(2-(4-bromophenyl)-3-(4-methoxyphenyl)-1,2-dihydro-
1
2,6-naphthyridin-1-yl)malonate (7c). This compound was obtained
1
as a brown solid (119 mg, 74%): mp 150−156 °C; H NMR (400
CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.45−7.43
(m, 2H), 7.34−7.28 (m, 3H), 7.25−7.20 (m, 1H), 7.13−7.08 (m, 2H),
7.02 (s, 1H), 6.90 (t, J = 6.6 Hz, 1H), 6.70−6.61 (m, 1H), 5.71−5.67
(m, 1H), 3.26 (dd, J = 11.0, 18.3 Hz, 1H), 2.79 (dd, J = 6.6, 16.8 Hz,
1H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 147.3,
139.5, 135.6, 134.0, 129.9, 129.7, 128.8, 128.1, 126.0, 125.7, 124.4,
124.3, 122.9, 122.7, 122.1, 120.8, 114.1, 57.9, 47.2, 31.6; HRMS (ESI)
[M]+ Calcd for [C24H19NOS2] 401.0908, found 401.0908.
MHz, CDCl3) δ 8.56 (s, 1H), 8.34−8.32 (m, 1H), 7.36 (d, J = 8.1 Hz,
2H), 7.17 (d, J = 8.8 Hz, 2H), 7.06−7.05 (m, 1H), 6.94 (d, J = 8.8 Hz,
2H), 6.80−6.75 (m, 3H), 5.62 (d, J = 11.0 Hz, 1H), 4.36−4.20 (m,
2H), 4.07−3.94 (m, 2H), 3.88 (d, J=11.0 Hz, 1H), 3.75 (s, 3H), 1.24
(t, J = 7.32 Hz, 3H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.4, 166.5, 160.3, 146.7, 145.2, 145.0, 142.4, 135.8, 131.8,
128.7, 128.2, 127.9, 124.7, 121.8, 116.5, 114.0, 107.6, 63.2, 62.1, 61.9,
55.3, 53.9, 14.0, 13.8; HRMS (ESI) [M]+ Calcd for [C28H27BrN2O5]
550.1103, found 550.1102.
1-(3-(Thiophen-3-yl)-2-(p-tolyl)-1,2-dihydrobenzo[4,5]thieno[2,3-
c]pyridin-1-yl)propan-2-one (8d). This compound was obtained as
brown solid (65 mg, 60%): mp 68−70 °C; H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.35−7.33
1
3-Hydroxy-2-(6-(4-methoxyphenyl)-7-(p-tolyl)-5,6-dihydro-1,6-
naphthyridin-5-yl)-5,5-dimethylcyclohex-3-enone (7d). This com-
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(m, 1H), 7.26−7.18 (m, 3H), 7.16−7.12 (m, 2H), 6.91−6.83 (m, 4H),
5.56−5.52 (m, 1H), 3.17 (dd, J = 8.1, 16.1 Hz, 1H), 2.69 (dd, J = 5.8,
16.8 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 207.1, 145.0, 139.6, 132.4, 129.4, 128.2, 126.1, 125.6, 124.3,
124.2, 123.9, 122.9, 122.8, 122.2, 120.7, 105.3, 58.2, 47.3, 31.6, 20.7;
HRMS (ESI) [M]+ Calcd for [C25H21NOS2] 415.1065, found
415.1065.
mg, 2 equiv), in 2 mL of DMF:H2O (4:1) was purged under N2 for
15−20 min, and then catalyst Pd(OAc)2 (2.25 mg, 5 mol %) and L (2
mg, 5 mol %) were added under inert atmosphere and then heated to
80 °C for a period of 2 h. After completion of the reaction as indicated
by TLC, reaction mixture was quenched with water (10 mL), extracted
with EtOAc (3 × 10 mL), and dried over anhydrous Na2SO4.
Evaporation of the solvent followed by purification on silica gel
provided the corresponding product 11. This compound was obtained
as an orange solid (73 mg, 72%): mp 50−60 °C; 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.69−7.61 (m, 2H),
7.52 (d, J = 6.6 Hz, 2H), 7.38 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz,
4H), 7.14 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 9.9 Hz, 2H), 7.02 (s, 1H),
6.81 (d, J = 8.8 Hz, 2H), 5.76 (t, J = 7.0 Hz, 1H), 3.76 (s, 3H), 3.39
(dd, J = 7.3, 17.6 Hz, 1H), 2.86 (dd, J = 6.6, 18.3 Hz, 1H), 2.31 (s,
3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.6, 160.4,
151.6, 148.2, 147.4, 145.8, 139.2, 137.4, 136.6, 135.7, 132.5, 130.0,
129.6, 129.4, 129.2, 129.0, 127.8, 127.6, 127.3, 127.2, 126.5, 125.2,
123.4, 115.4, 114.1, 110.7, 61.0, 55.2, 47.6, 30.3, 21.0; HRMS (ESI)
[M]+ Calcd for [C35H30N2O2] 510.2307, found 510.2308.
1-(2-Phenyl-3-(4-(trifluoromethyl)phenyl)-1,2-dihydrobenzo[4,5]-
thieno[2,3-c]pyridin-1-yl)propan-2-one (8e). This compound was
1
obtained as a brown semisolid (29 mg, 30%): H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61−7.57
(m, 2H), 7.45−7.43 (m, 2H), 7.39−7.36 (m, 1H), 7.28−7.25 (m, 1H),
7.06−6.98 (m, 5H), 6.82 (t, J = 6.6 Hz, 1H), 5.71−5.68 (m, 1H), 3.16
(dd, J = 8.0, 17.6 Hz, 1H), 2.76 (dd, J = 5.8, 17.6 Hz, 1H), 2.11 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 206.6, 146.7, 142.7, 140.9,
139.6, 137.2, 135.5, 131.9, 130.9, 128.9, 128.0, 127.0, 125.5, 124.6,
124.5, 123.02, 122.99, 122.3, 120.8, 116.0, 114.0, 107.9, 57.6, 47.4,
31.6; HRMS (ESI) [M]+ Calcd for [C27H20F3NOS] 463.1218, found
463.1218.
(E)-Methyl 3-(4-(3-(4-methoxyphenyl)-1-(2-oxopropyl)benzo[b]-
[1,6]naphthyridin-2(1H)-yl)phenyl)acrylate (13). A solution of 1-(2-
(4-bromophenyl)-3-(4-methoxyphenyl)-1,2-dihydrobenzo[b][1,6]-
naphthyridin-1-yl)propan-2-one 6j (100 mg, 1 equiv), methyl acrylate
12 (18 mg, 1.1 equiv) and K2CO3 (60 mg, 2 equiv), in 2 mL of DMF
was purged under N2 for 15−20 min, and then catalyst Pd(OAc)2
(2.25 mg, 5 mol %) and L (2 mg, 5 mol %) were added under inert
atmosphere and then heated to 120 °C for a period of 8 h. After
completion of the reaction as indicated by TLC, reaction mixture was
quenched with water (10 mL), extracted with EtOAc (3 × 10 mL),
and dried over anhydrous Na2SO4. Evaporation of the solvent followed
by purification on silica gel provided the corresponding product 13.
This compound was obtained as a yellow solid (70 mg, 70%): mp
148−166 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1H),
7.78 (s, 1H), 7.64−7.56 (m, 2H), 7.47−7.41 (m, 3H), 7.34 (t, J = 8.8
Hz, 1H), 7.22−7.19 (m, 2H), 7.00 (d, J = 8.8 Hz, 3H), 6.76 (d, J = 8.8
Hz, 2H), 6.15 (d, J = 16.1 Hz, 1H), 5.73 (t, J = 7.3 Hz, 1H), 3.71 (s,
3H), 3.67 (s, 3H), 3.33 (dd, J = 7.3, 16.8 Hz, 1H), 2.77 (dd, J = 5.9,
17.6 Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.4,
167.6, 160.6, 151.5, 148.5, 147.8, 147.6, 147.3, 147.1, 144.2, 139.3,
132.2, 129.7, 129.0, 128.8, 128.7, 128.6, 128.1, 127.6, 127.4, 127.3,
125.5, 123.9, 123.4, 122.7, 116.0, 114.2, 114.0, 112.0, 60.5, 55.3, 51.6,
47.4, 31.5; HRMS (ESI) [M]+ Calcd for [C32H28N2O4] 504.2049,
found 504.2050.
(E)-N-((3-(Phenylethynyl)benzo[b]thiophen-2-yl)methylene)-
aniline (9a). This compound was obtained as a yellow solid (14 mg,
15%): mp 116−122 °C; 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H),
8.00−7.98 (m, 1H), 7.82−7.77 (m, 1H), 7.58−7.54 (m, 3H), 7.47−
7.32 (m, 8H), 7.28−7.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
152.8, 151.0, 139.74, 139.67, 131.9, 131.8, 129.2, 128.6, 127.3, 126.7,
125.6, 125.1, 123.9, 123.7, 123.2, 122.6, 122.5, 121.3, 97.9, 81.5;
HRMS (ESI) [M]+ Calcd for [C23H15NS] 337.0925, found 337.0925.
(E)-4-Methyl-N-((3-(phenylethynyl)benzo[b]thiophen-2-yl)-
methylene)aniline (9b). This compound was obtained as a yellow
solid (19 mg, 20%): mp 146−154 °C; 1H NMR (400 MHz, CDCl3) δ
8.96 (s, 1H), 7.98−7.95 (m, 1H), 7.77−7.75 (m, 1H), 7.56−7.53 (m,
2H), 7.40−7.35 (m, 2H), 7.33−7.31 (m, 3H), 7.19−7.13 (m, 4H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9, 148.5, 144.9,
139.8, 139.5, 136.7, 131.9, 131.7, 129.8, 129.0, 128.9, 128.6, 128.5,
127.2, 125.0, 123.8, 122.8, 122.52, 122.45, 121.2, 97.7, 81.6, 21.1;
HRMS (ESI) [M]+ Calcd for [C24H17NS] 351.1082, found 351.1082.
(E)-N-((3-(Thiophen-3-ylethynyl)benzo[b]thiophen-2-yl)-
methylene)aniline (9c). This compound was obtained as a brown
1
solid (18 mg, 20%): mp 99−103 °C; H NMR (400 MHz, CDCl3) δ
8.93 (s, 1H), 7.95−7.92 (m, 1H), 7.78−7.73 (m, 1H), 7.56−7.55 (m,
1H), 7.47−7.41 (m, 1H), 7.37−7.35 (m, 2H), 7.30−7.25 (m, 1H),
7.21−7.18 (m, 1H), 7.16−7.12 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 184.5, 151.9, 148.4, 144.8, 139.7, 139.5, 136.7, 130.5, 129.8,
128.8, 127.2, 126.0, 125.8, 125.0, 123.8, 122.8, 121.2, 115.9, 92.7, 81.2
; HRMS (ESI) [M]+ Calcd for [C21H13NS2] 343.0489, found
343.0490.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of H NMR, 13C NMR,
1
(E)-4-Methyl-N-((3-(thiophen-3-ylethynyl)benzo[b]thiophen-2-
yl)methylene)aniline (9d). This compound was obtained as a brown
solid (21 mg, 22%): mp 100−104 °C; 1H NMR (400 MHz, CDCl3) δ
8.93 (s, 1H), 7.95−7.92 (m, 1H), 7.78−7.73 (m, 1H), 7.56−7.55 (m,
1H), 7.47−7.41 (m, 1H), 7.37−7.35 (m, 2H), 7.30−7.25 (m, 1H),
7.21−7.18 (m, 1H), 7.16−7.12 (m, 3H), 2.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 184.5, 151.9, 148.4, 144.8, 139.7, 139.5, 136.7, 130.5,
129.8, 128.8, 127.2, 126.0, 125.8, 125.0, 123.8, 122.8, 121.2, 115.9,
92.7, 81.2, 21.1; HRMS (ESI) [M]+ Calcd for [C22H15NS2] 357.0645,
found 357.0646.
HRMS and Chiral-HPLC (6h, 6i, 6k, and 6v) spectra for all
new compounds. CIF for compound 6z (CCDC 886742). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: averma@acbr.du.ac.in.
■
(E)-N-((3-((4-(Trifluoromethyl)phenyl)ethynyl)benzo[b]thiophen-
2-yl)methylene)aniline (9e). This compound was obtained as a yellow
solid (42 mg, 50%): mp 124−128 °C; 1H NMR (400 MHz, CDCl3) δ
8.94 (s, 1H), 7.97−7.95 (m, 1H), 7.80−7.77 (m, 1H), 7.65−7.57 (m,
5H), 7.45−7.33 (m, 3H), 7.26−7.17 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.4, 150.9, 145.7, 139.6, 132.2, 132.0, 129.3, 128.9, 127.4,
126.9, 126.2, 125.49, 125.45, 125.2, 123.7, 123.4, 122.9, 121.9, 121.3,
96.1, 83.8; HRMS (ESI) [M]+ Calcd for [C24H14F3NS] 405.0799,
found 405.0798.
1-(3-(4-Methoxyphenyl)-2-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2-
dihydrobenzo[b][1,6] naphthyridin-1-yl)propan-2-one (11). A sol-
ution of 1-(2-(4-bromophenyl)-3-(4-methoxyphenyl)-1,2-
dihydrobenzo[b][1,6]naphthyridin-1-yl)propan-2-one 6j (100 mg, 1
equiv), p-tolylboronic acid 10 (30 mg, 1.1 equiv) and Cs2CO3 (130
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Department of Science and
Technology (SR/S1/OC-66/2010) for financial support and
USIC, University of Delhi, for providing instrumentation
facilities. S.K.R.K., D.C., and M.P. are thankful to CSIR, DST
for a fellowship.
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