Pd-Catalyzed One-Pot Stepwise Synthesis of Benzo[b][1,6]naphthyridines from 2-Chloroquinoline-3-carbonitriles Using Sulfur and Amines As Nucleophiles

Article abstract of DOI:10.1021/acs.joc.7b02147

A palladium-catalyzed one-pot stepwise coupling-annulation reaction of 2-chloroqunoline-3-carbonitriles enabled the direct synthesis of sulfur-substituted benzo[b][1,6]naphthyridines via multiple bond formation. The reaction provided an unusual mode for cyclization as sodium sulfide, a soft nucleophile, preferred to attack on the carbon of the nitrile group rather than on the C-C triple bond. The developed chemistry was extended with the secondary amines as nucleophiles to afford nitrogen-substituted benzo[b][1,6]naphythyridines while primary amines afforded hydroamination products. The hydromination products were transformed to benzo[b][1,6]naphthyridones via a base-mediated cyclization reaction. The developed protocol features inexpensive and easily synthesizable starting materials, easy operations, and a high efficiency and tolerance to a broad range of substrates.

Full text of DOI:10.1021/acs.joc.7b02147

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Article
Pd-catalyzed one-pot stepwise synthesis of benzo[b][1,6]naphthyridines from
2-chloroquinoline-3-carbonitriles using sulphur and amines as nucleophiles
Ritush Kumar, MRITYUNJAYA ASTHANA, and Radhey M. Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02147 • Publication Date (Web): 05 Oct 2017
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Pd-catalyzed one-pot stepwise synthesis of benzo[b][1,6]naphthyridines
from 2-chloroquinoline-3-carbonitriles using sulphur and amines as
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nucleophiles
Ritush Kumar,*,a,b Mrityunjaya Asthana,a and Radhey M. Singhb
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a Department of Chemistry, Indian Institute of Technology Guwahati, Assamꢀ781039, India.
b Department of Chemistry, Institute of Science, Centre of Advanced Study, Banaras Hindu University,
Varanasiꢀ221005
Eꢀmail: rk.singh1987.bhu@gmail.com
ABSTRACT: A palladiumꢀcatalyzed oneꢀpot stepwise couplingꢀannulation reaction of 2ꢀ
chloroqunolineꢀ3ꢀcarbonitriles enabled the direct synthesis of sulphurꢀsubstituted
benzo[b][1,6]naphthyridines via multiple bond formation. The reaction provided an unusual
mode for cyclization as sodium sulphide a soft nucleophile preferred to attack on carbon of
nitrile group rather than on carbonꢀcarbon triple bond. The developed chemistry was
extended with the secondary amines as nucleophile to afford nitrogenꢀsubstituted
benzo[b][1,6]naphythyridines while with primary amines hydroamination products were
obtained. The hydromination products were transformed to benzo[b][1,6]naphthyridones via
base mediated cyclization reaction. This developed protocol features inexpensive and easily
synthesizable starting materials, easy operations, high efficiency and tolerance to a broad
range of substrates.
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INTRODUCTION
The synthesis of polyheterocycles1 in oneꢀpot strategy starting from simple and unexplored
precursors has garnered interest due to prevalence in various natural products as well as in
functional material, photochemistry etc. Among them, nitrogenꢀcontaining heterocycles,
particularly naphythyridines and their benzo/heteroꢀfused analogoues represent an important
class of molecules. Naphythyridines are present in numerous marine alkaloids (Fig.1 a, b)2
and exhibit wide range of distinctive biological activities such as antitumor,3aꢀb antiꢀ
inflammatory,3c antiꢀHSV (Herps Simplex Virus) properties,4 anticancer and antiꢀHIVꢀ1 (Fig.
1c),5 adrenoceptor blocking activities6 along with AKt1 and AKt2 inhibitor properties.7
Besides, benzo[1,6]naphthyridines are found in synthetic drugs, such as Benafentrine and
Tolafentrine (Fig. 1d) as phosphodiesterase III/IV inhibitors8 and also exhibit luminescence
properties.9
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A number of synthetic strategies have been reported for [1,6]naphthyridines10 via
multicomponent reactions,11 transitionꢀmetal catalyzed reactions,12 cycloaddition reactions13
and other approaches.14 However, their benzoꢀanalogues have been less explored. Coscia et
al. have reported the first synthesis of parent compound from aniline and 1ꢀacetylꢀ3ꢀ
ethoxycarbonylꢀ4ꢀpiperidone by condensation and dehydrogenation reaction.15 Recently,
groups of Verma16 and Langer17 have reported silverꢀcatalyzed tricyclic/tetetracyclic
benzo[b][1,6]naphthyridines via multicomponent reactions from 2ꢀalkynylquinolineꢀ3ꢀ
carbaldehydes respectively. We have also reported synthesis of benzo[b][1,6]naphthyridines
from quinoline analogues using aqueous ammonia.18a
Stepwise reactions19 in oneꢀpot are one of the most powerful synthetic strategies in
the modern era of organic chemistry for being step economy. The practical utility of “oneꢀpot
stepwise” reactions avoids the tedious purification of the intermediate along with reduces the
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costs and effort for the synthesis of complex molecules.20 Over the past few decades,
transition metalꢀcatalyzed nucleophilic cyclization reactions have achieved substantial
progress. Particularly, palladiumꢀcatalyzed stepwise oneꢀpot reactions have attracted much
attention owing to activation of CꢀC triple bond towards a wide range of nucleophiles leading
to broad range of carbo21ꢀ/heterocycles.22
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Recently, we have demonstrated sodium sulphide as an ideal nucleophilic reagent for the
Pdꢀcatalyzed cyclization of 2ꢀalkynylquinolineꢀ3ꢀcarbaldehydes to cyclopenta[b]quinolinꢀ1ꢀ
ones (Scheme 1A).23 We proposed the reaction was initiated by nucleopalladation of alkynes
and quenched by 1,2ꢀaddition to carbonꢀheteroatom for synthesis of cyclopentenone
annulated quinolines. Inspired by this unusual finding and wellꢀdocumentation of the fact that
sulphide is a soft nucleophile and addition reaction would proceed via carbonꢀcarbon triple
bond, we further explored this nucleophilic cyclization reaction (i.e. sodium sulphide as
nucleophile) towards oꢀalkynylquinolinꢀ3ꢀcarbonitrile as cyano group has been considered as
an unreactive functional group; inert to organoꢀpalladium reagents and the nitriles are not
incorporated into the molecular structure of the products.24
Scheme 1. Mode of attack of sulphur
(A)Previous work
(B) Present work
Therefore, we envisioned that 2ꢀalkynylquinolineꢀ3ꢀcarbonitriles 2 would undergo
similar annulation reaction with sodium sulphide as a nucleophile and provide easy access to
sulphur substituted cyclopenta[b]quinolinꢀ1ꢀones 3’. Thus, when 2ꢀalkynylquinolinꢀ3ꢀ
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carbonitrile was treated under our previously reported condition, an unexpected product 1ꢀ
benzylsulfanylꢀ3ꢀphenylꢀbenzo[b][1,6]naphthyridine 3 was isolated instead of the expected
product cyclopenta[b]quinolinꢀ1ꢀone 3’ (Scheme 1B). In continuation of our efforts in metalꢀ
catalyzed sequential oneꢀpot reactions,18b,23,25 we report herein palladiumꢀcatalyzed oneꢀpot
synthesis of benzo[b][1,6]naphthyridines form 2ꢀalkynylquinolinꢀ3ꢀcarbonitriles using
sodium sulfide as nucleophile. The reaction was further extended with secondary and primary
amines as nucleophilic partners to afford amino substituted benzo[b][1,6]naphthyridines and
hydroamination products respectively.
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RESULTS AND DISCUSSION
Initially, 2ꢀphenylethynylquinolinꢀ3ꢀcarbonitrile 2a was reacted with sodium sulfide
using our previous standardized reaction condition,23 i.e. 2.5 mol% of Pd(OAc)2, 5 mol% of
PPh3,2 equiv Na2S in DMF at 80°C under an open atmosphere followed by quenching with
benzyl chloride (Table 1, entry 1). The isolated product was characterized as 1ꢀ
benzylsulfanylꢀ3ꢀphenylꢀbenzo[b][1,6]naphthyridine 3a instead of 3’ from spectral analytical
data and furthermore unambiguously confirmed by single crystal Xꢀray analysis (Figure S1).
The formation of this product revealed that the preferred attack of sulphide takes over
carbonitrile rather than the alkyne in contrast to our previous observation.
Table 1. Optimization reaction condition of annulations step (2a to 3a)a
Entry
No.
1
Catalyst
(mol%)
Ligand
(mol%)
Ph3P (5)
Solvent
Time
Yield
(%)b
86
Pd(OAc)2 (2.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
25 min
1 h
2c
3d
4
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
PdCl2 (2.5)
Ph3P (5)
Ph3P (5)
70
66
73
65
74
55
74
25 min
1h
Ph3P (5)
5
Pd(dba)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Ph3P (5)
55 min
1 h
6
Cy3P (5)
7
BINAP (2.5)
TMEDA (5)
1 h
8
1 h
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Pd(OAc)2 (2.5)
Ph3P (5)
MeOH
3.5 h
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Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
CuI (2.5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
THF
Dioxane
CH3CN
DMSO
DMF
3 h
3 h
67
66
68
72
40
nre
nre
nre
3 h
1.5 h
1 h
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FeCl3 (2.5)
DMF
1 h
Ag(OTf)3 (2.5)
DMF
1 h
RuCl3 (2.5)
DMF
1 h
aAll reactions were carried out using 0.5 mmol of 2a. bIsolated yield.c Reaction at 60 °C.
d Reaction at 100 °C. e nr= no reaction with 2a being recovered.
Inspired by this new result, we next considered finding optimal conditions for the best
yield of 3a. The results are summarized in Table 1. Decreasing (60°C) or increasing (100°C)
the reaction temperature, product yields decreased substantially (entries 2ꢀ3). The reaction
with other Pdꢀcatalysts such as PdCl2 and Pd(dba)2 afforded the product 3a in low yields
(entries 4ꢀ5). Similarly, monodentate ligand Cy3P, bidentate ligand BINAP and nitrogen
based ligand TMEDA (entries 6ꢀ8) were found to be less effective than PPh3 (entry 1).
Various solvents such as MeOH, THF, Dioxane, CH3CN and DMSO (entries 9ꢀ 13) were also
found to be less effective than DMF (entry 1). CuI as a catalyst afforded 3a in 40% yield
(entry 14). Other metal salts such as FeCl3, Ag(OTf)3 and RuCl3 were totally ineffective
(entries 15ꢀ17). The high yield and less time could be attributed to the better electrophilic
character of the palladium complex. Thus, the combination of 0.5 mmol of 2a with 2.5 mol%
Pd(OAc)2 and 5 mol% Ph3P, 2 equiv. each of sodium sulphide and benzyl chloride in DMF
at 80°C in an open atmosphere was the best reaction condition (entry 1).
As both the Sonogashira coupling and annulation steps are Pd catalyzed, thus we next
examined oneꢀpot stepwise reactions from 2ꢀchloroquinolineꢀ3ꢀcarbonitrile 1a to save time,
solvents and avoid the column chromatography separation of 2a.
Scheme 2. Stepwise Sonogashira coupling and annulation
Thus, a mixture of 2ꢀchloroquinolineꢀ3ꢀcarbonitrile 1a (0.5 mmol) and phenylacetylene
(0.6 mmol) was treated with 5 mol % of Pd(OAc)2, 10 mol % of PPh3 and 2 equiv Et3N in
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acetonitrile at 80°C for 3 h under N2 atm for Sonogashira coupling reaction23. Subsequently
acetonitrile was removed under reduced pressure and DMF along with 2.5 mol % Pd(OAc)2,
5 mol % Ph3P, 2 equiv of Na2S were added to the reaction mixture and heated at 80 °C under
an open atm for 25 minutes. Quenching with 2 equiv of benzyl chloride, led to the formation
of 3a in 83% overall yield (Scheme 2). Thus, we considered the oneꢀpot stepwise reaction as
our optimized reaction condition (Scheme 2).
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With the oneꢀpot optimum conditions in hand, the generality of reaction with various
alkynes (Table 2) was undertaken. All reactions proceeded smoothly and completed in 15ꢀ40
min. The corresponding cyclized products 3(b-g) were obtained in 73ꢀ85% yields. No
significant variations in the yields were found with phenylacetylene ring bearing electron
donating 3(b-c) or electron withdrawing groups 3d. The cyclized products 3(e-f) were
obtained in good yields with alkyl alkynes such as octꢀ1ꢀyne and pentꢀ1ꢀyne. Similarly,
heterocyclic alkyne such as 3ꢀethynylthiophene afforded the cyclized product 3g in 73%
yield.
The generality of the reaction was further examined using various substituted 2ꢀ
chloroquinolineꢀ3ꢀcarbonitriles 1(h-k) with phenylacetylene. All reactions proceeded
smoothly and completed in 20ꢀ40 min affording the corresponding cyclized products 3(h-k)
in 75ꢀ78% yields (Table 2). Next, the reaction scope was explored with different alkyl
halides. Similarly, the reactions proceeded smoothly and afforded the products 3(l-q) in 75ꢀ
82% yields (Table 2). Further, the cyclization reaction was performed with sodium sulphide
followed by quenching with water. The reaction completed in 5 min and afforded the cyclized
product 3r in 78% yield. The reaction also worked well with pyridine derivative affording the
cyclized product 5a in 79%.
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Table
2.
Reaction
scope
for
the
synthesis
of
1,3-
disubstitutedbenzo[b][1,6]naphthyridinesa
SR"
Pd(OAc)2 (5 %)
N
N
Pd(OAc)2 (2.5 %)
Ph3P (5 %)
Na2S, R"X
DMF, 80°C
air
Ph3P (10 %)
N
Et3N,CH3CN
N
Cl
N
R'
R
N
R
R
R'
R'
1
80 °C, N2 atm
3
2
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Product no., yield,b Time (C/A)c
SCH2Ph
SCH2Ph
SR"
N
N
N
N
Ph
R
N
3a - 3g
R'
N
Ph
3l - 3q
3h - 3k
3a, R' = Ph, 83%, 3 h / 25 min
3h, R = 6ꢀMe, 78%, 3 h / 35 min
3i, R = 7ꢀMe, 78%, 4.5 h / 35 min
3j, R = 8ꢀMe, 76%, 5 h / 40 min
3l, R'' = Me, 83%, 3 h / 20 min
3m, R'' = Et, 80%, 3 h / 25 min
3n, R'' = nꢀpentyl, 78%, 3 h / 35 min
3o, R'' = nꢀhexyl, 77%, 3 h / 40 min
3p, R'' = Allyl, 80%, 3 h / 30 min
3q, R'' = Propargyl, 75 %, 3 h / 40 min
3b, R' = mꢀtolyl, 84 % , 3.5 h / 35 min
3c, R' = pꢀtolyl, 85 % , 3.5 h / 35 min
3d, R' = 4FꢀC6H4, 83% , 2.5 h / 20min 3k, R = 7ꢀCl, 75%, 3 h / 20min
3e, R' =C3H7, 80 % , 12hd / 15min
3f, R' =C6H13, 78 % , 12hd / 20min
SCH2Ph
Ph
SH
N
3g, R' = 3ꢀthiophene, 73 % , 3h/ 40 min
N
3r, 78%, 3 h/ 5 min
Ph
N
Ph
5a, 79%, 3 h/ 55 min
N
Conditions: a(i) Sonogashira coupling: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 2 equiv Et3N, CH3CN, 80 °C, N2 atm; (ii) Annulation: 2.5 mol
% Pd(OAc)2, 5 mol % Ph3P, 2 eq. each of Na2S and R”ꢀX, DMF, 80 °C, air. bOverall isolated yields over two steps. c[C/A] means coupling
time/annulation time. d Sonogashira coupling reaction condition for aliphatic alkynes: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 15% CuI, 2 equiv
Et3N, CH3CN, 80 °C, N2 atm .
Next, we explored the reaction with other sulphur nucleophiles such as ethanethiol
and thiophenol. Thus, 2ꢀphenylethynylquinolineꢀ3ꢀcarbonitrile 2a was treated with
ethanethiol (2 equiv) and K2CO3 (2 equiv) using the optimized reaction condition. The
reaction completed in 1 h, surprisingly addition product across carbonꢀcarbon triple bond 6a
was isolated rather than the anticipated cyclized product. Under similar conditions,
thiophenol also afforded the addition product 6b in 75% yield (Scheme 3).
Scheme 3. Addition of thiols across the triple bond
Pd(OAc)2 (2.5 %)
Ph3P (5 %)
R"SH (2 equiv)
N
N
SR"
Ph
K2CO3 (2 equiv)
DMF, 80 °C
time, air
N
N
6
2a
Ph
R"
6a Et
6b Ph
Time Yield (%)
1 h
2 h
80
75
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Scheme 4. Gram scale synthesis 3a.
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The robustness of chemistry was examined in largeꢀscale reactions. A largeꢀscale
experiment (1a, 6 mmol, 1.128 g) was carried out under the standard optimized condition.
The reaction proceeded smoothly, providing the desired 3a in 76% (1.723 g) (Scheme 4).
After establishing the reaction with sulphur nucleophiles, we became intrigued to
explore the scope of chemistry with nitrogen nucleophiles such as amines (primary and
secondary amines) due to their prevalence in medicinal chemistry.26 We selected morpholine
(a secondary amine) as nucleophile for the optimization of reaction conditions (Table 3).
Table 3. Optimization of the reaction conditions for synthesis of 7aa
Entry Catalyst
Ligand
(mol %)
Solvent
Morpholine
(equiv.)
Base
(equiv.) (h)
Time Yield
b
no.
(mol %)
(%)
1
Pd(OAc)2
(2.5)
Pd(OAc)2
(5)
Pd(OAc)2
(5)
Pd(OAc)2
(5)
Pd(OAc)2
(5)
Pd(OAc)2
(10)
Ph3P
(5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
2
3
4
5
4
4
4
4
4
4
4
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
K2CO3
24
15
2
Ph3P
(10)
Ph3P
(10)
Ph3P
(10)
Ph3P
(10)
Ph3P
(20)
Ph3P
(10)
Ph3P
(10)
Cy3P
(10)
24
24
13
13
13
18
15
20
15
13
24
20
30
80
80
70
40
60
50
60
75
25
3
4
(2)
5
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
K3PO4
(2)
Cs2CO3
6
7
PdCl2 (5)
8
Pd(dba)2
(5)
Pd(OAc)2
(5)
9
10
11
12
Pd(OAc)2 BINAP
(5)
Pd(OAc)2
(5)
(10)
Ph3P
(10)
Ph3P
Pd(OAc)2
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(5)
Pd(OAc)2
(5)
Pd(OAc)2
(5)
(10)
Ph3P
(10)
Ph3P
(10)
Ph3P
(10)
(2)
K2CO3
(2)
K2CO3
(2)
K2CO3
(2)
13
14
15c
DMF
4
4
4
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78
DMSO
Pd(OAc)2
(5)
CH3CN
a All the reactions performed in 0.5 mmol scale. Isolated yield. Oneꢀpot sequential reaction of Sonogashira
b
c
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coupling and intramolecular cyclization reactions.
Initially, 2ꢀphenylethynylquinolineꢀ3ꢀcarbonitrile 2a (0.5 mmol) was treated with 2.5 mol
% of Pd(OAc)2, 5 mol % of PPh3 and 2 equiv morpholine along with 2 equiv K2CO3 in
CH3CN at 80 °C under air atomophere. The starting material was not completely consumed
even after 24 h and isolated product 1ꢀ(morpholinꢀ4ꢀyl)ꢀ3ꢀphenylbenzo[b][1,6]naphthyridine
7a was obtained in 15 % yield (Table 3, entry 1). On increasing the mol % of Pd(OAc)2 to 5
% and Ph3P to 10 % , the reaction completed in 24 h with 7a isolated in 20 % yield (entry 2).
Further, using 3 equiv of morpholine under similar condition, the reaction completed in 24 h
with yield increased to 30% (entry 3). However, using 4 equiv of morpholine, the reaction
completed in 13 h and yield of 7a enhanced upto 80 % (entry 4). Further, increasing the
equivalency of morpholine did not improve the yield of 7a (entry 5). On the other hand,
increasing the mol% of Pd(OAc)2 to 10 % and Ph3P to 20 % along with 4 equiv morpholine
and 2 equiv K2CO3 did not improve the yield (entry 6). Other palladium catalysts such as
PdCl2 and Pd(dba)2 also did not improve the yield of 7a (entries 7ꢀ8). Similarly, other ligands
such as monodentate ligand Cy3P and bidentate ligand BINAP were found to be less effective
(entries 9ꢀ10) than Ph3P (entry 4). Other inorganic bases such as K3PO4 and Cs2CO3 were
also screened. K3PO4 was found equally effective (entry 11) as K2CO3 (entry 3). However,
Cs2CO3 was found to be less effective (entry 12). Similarly, solvents such as DMF and
DMSO were found to be less effective (entries 13ꢀ14) than CH3CN (entry 3). Thus, the
combination of 0.5 mmol of 2a with 5 mol % Pd(OAc)2, 10 mol % Ph3P, 4 equiv morpholine
and 2 equiv K2CO3 in acetonitrile at 80°C under aerobic atmosphere is an optimal reaction
condition for the best yield of 7a (entry 3). We next examined oneꢀpot stepwise reactions
from 2ꢀchloroquinolineꢀ3ꢀcarbonitrile 1a via Sonogashira coupling and annulation reaction
with a view to save time, solvents and avoid the column chromatography separation of 2a
(Table 3, entry 15). Thus, a mixture of 2ꢀchloroquinolineꢀ3ꢀcarbonitrile 1a (0.5 mmol) and
phenylacetylene (0.6 mmol) were treated with 5 mol % of Pd(OAc)2, 10 mol % of PPh3 and 2
equiv Et3N in acetonitrile at 80°C for 3 h under N2 for Sonogashira coupling and
subsequently added 5 mol % Pd(OAc)2, 10 mol % Ph3P and 4 equiv morpholine along with 2
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equiv K2CO3 in acetonitrile and heated at 80°C under aerobic atmosphere. The reaction was
completed in 13 h with 7a isolated in 78% overall yield (Scheme 5).
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7
Scheme 5. One-pot stepwise Sonogashira coupling and annulation using morpholine
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With the oneꢀpot stepwise optimum reaction condition in hand, the scope of reaction with
various alkynes was carried out. These results are summarized in Table 4. The reactions
proceeded smoothly and completed in 10ꢀ15 h affording the corresponding cyclized products
7(a-e) in 74ꢀ80 % yields (Table 4). The reaction with alkyl acetylenes such as octꢀ1ꢀyne
failed to provide the cyclized product 7f, as a complex TLC was observed. The scope of the
reaction was further examined with various quinoline derivatives. All the reactions proceeded
smoothly and completed in 9ꢀ18 h affording the products 7(g- k) in 65ꢀ74% yield. Various
secondary amines such as piperidine, pyrolidine and dimethyl amine were also examined as
nucleophiles for cyclization reaction. Cyclic secondary amines such as piperidine and
pyrolidine afforded the cyclized product in good yield7(l- m), however acyclic amine such as
dimethylamine failed to provide the product 7n with only coupling product 2ꢀ
phenylethynylquinolinꢀ3ꢀcarbonitrile 2a recovered even after prolonged heating which could
be due to steric effect. The reaction was also successful with pyridine analogue with the
cyclized product 8a obtained in 65% yield. The structure of cyclized product was further
confirmed by the single crystal Xꢀray analysis of compound 7i (Figure S2).
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Table
4.
Reaction
scope
for
the
synthesis
of
amino
substituted
benzo[b][1,6]naphthyridinesa
NR1R2
N
Pd(OAc)2 (5 %)
Ph3P (10 %)
NHR1R
N
N
Pd(OAc)2 (5 %)
Ph3P (10 %)
2 ( 4 equiv)
Et3N,CH3CN
R'
N
N
Cl
R
N
R'
R
R
K2CO3 (2 equiv)
CH3CN, 80 °C, air
R'
2
1
7
80 °C, N2 atm
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Product no., yield,b Time (C/A)c
O
N
O
N
NR1R2
N
N
7l - 7n
Ph
N
N
N
7a - 7f
R'
N
7g - 7k
Ph
R
7l, NR1R2 = Piperidine, 60 %, 3 h / 15 h
7m, NR1R2 = Pyrrolidine, 71 %, 3 h / 12 h
(CH ) NH
7a, R' = Ph, 78%, 3 h / 13 h
7g, R = 6ꢀMe, 74 %, 3 h / 16 h
7h, R = 7ꢀMe, 74 %, 4.5 h / 16 h
7i, R = 6ꢀMeO, 72 %, 5 h / 18 h
7j, R = 7ꢀMeO, 70 %, 5 h / 18 h
7k, R = 7ꢀCl, 75 %, 3 h / 9 h
7n, NR1R2 =
, 00%, 3 h / 24 h
3 2
7b, R' = mꢀtolyl, 75 % , 3.5 h / 15 h
7c, R' = pꢀtolyl, 74 % , 3.5 h / 15 h
7d, R' = 4MeOꢀC6H4, 80 % , 4 h / 17 h
7e, R' = 4FꢀC6H4, 83% , 2.5 h / 10 h
7f, R' =C6H13, 00 % , 12hd / 24 h
O
N
8a, 65%, 3 h/ 14 h
Ph
N
N
Ph
Conditions:a (i) Sonogashira coupling: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 2 equiv Et3N, CH3CN, 80 C, N2 atm; (ii)
°
Annulation: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 2°amine (4 equiv), K2CO3 (2 equiv), CH3CN, 80 C, air. b Overall isolated
°
yields over two steps. [C/A] = coupling time/annulation time. dSonogashira coupling reaction condition for aliphatic
c
alkynes: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 15% CuI, 2 equiv Et3N, CH3CN, 80 °C, N2 atm .
We next explored the scope of reaction with primary amines. Using the optimal
stepwise reaction condition of secondary amines, the reaction was attempted with 2 equiv of
benzyl amine (a primary amine). The reaction completed in 9 h, surprisingly isolating
hydroamination product 9a via addition across carbonꢀcarbon tripe bond (Scheme 6) and no
cyclization reaction occurred.
Scheme 6. One-pot stepwise Sonogashira coupling and annulation attempt using benzyl
amine
The reaction was also examined with other primary alkylamines such as nꢀbutyl, iꢀ
propyl and cyclohexyl as nucleophiles under similar reaction condition. But in all cases only
the hydroamination products 9b-d was isolated (Table 5). The structure of hydroamination
product was further confirmed by the single crystal Xꢀray analysis of compound 9c (Figure
S3).
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Table 5. Substrate scope for the hydroamination reactionsa
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a
°
Conditions: (i) Sonogashira coupling: 5 mol % Pd(OAc)2, 10 mol % Ph3P, 2 equiv Et3N, CH3CN, 80 C, N2 atm; (ii)
°
b
Hydramination: 2.5 mol % Pd(OAc)2, 5 mol % Ph3P, Primary amines (2 equiv), K2CO3 (2 equiv), CH3CN, 80 C, air.
[C/Ha] = coupling time/Hydroꢀamination time. c Overall isolated yields over two steps.
Next, we became interested to cyclize the hydroamination products 9 (Scheme 6).
Thus, hydroamination products 9 were treated with 2 equiv sodium hydride in THF at 600C
under aerobic condition. The reactions completed in 14ꢀ16
h
affording
benzo[b][1,6]naphthyridinꢀ1(2H)ꢀones 10a-b as a single product in 75ꢀ80% yields (Scheme
7).
Scheme 7. Base mediated synthesis of benzo[b][1,6]naphthyridin-1(2H)-ones
A plausible mechanism for Pdꢀcatalyzed cyclization is illustrated in Scheme 8. In this
reaction Pd(OAc)2 plays dual role22c: (1) as a Lewis acid which forms complex A with the
–
nitrogen atom of the cyano group, facilitating the nucleophilic attack of SNa ion on carbon
atom of cyano group; (2) as a transition metal catalyst which forms complex B with πꢀ
electrons of alkyne; (3) complex B undergoes cyclization to give organopalladium
intermediate C which on protonation gives 3r and exclusion of Pd0 which upon aerial
oxidation gets converted to Pd(II). Further, quenching with benzyl chloride gives cyclized
product 3a.
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Scheme 8. Proposed Mechanism for annulation process
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CONCLUSIONS
In summary, we have developed palladiumꢀcatalyzed oneꢀpot stepwise synthesis of
sulphur and nitrogen appended benzo[b][1,6]naphthyridines using sodium sulphide and
secondary amines as nucleophiles with 2ꢀchloroquinolineꢀ3ꢀcarbonitriles respectively. The
protocol involved making of four new bonds (CꢀC, SꢀC, NꢀC and SꢀC bonds) for sulphur
substituted and three bonds (one CꢀC and two NꢀC bonds) for nitrogen substituted
benzo[b][1,6]naphthyridines all in stepwise manner. With thiols and primary amines addition
products across CꢀC triple bond were obtained. The hydroamination products were
transformed into benzo[b][1,6]naphthyridinꢀ1(2H)ꢀones in good yields.
EXPERIMENTAL SECTION
General Methods
Unless otherwise stated, all reactions were performed under nitrogen atmosphere and air
successively. Solvents were purified following standard literature procedures. Melting points
were measured in an open capillary tube and are uncorrected. H (300 MHz) and 13C (75
1
MHz) NMR spectra were recorded on a 300 MHz spectrometer. Multiplicities are given as: s
(singlet), brs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets) or m (multiplet).
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The chemical shifts (δ ppm) and coupling constants (J Hz) are reported in the standard
1
fashion with reference to either internal tetramethylsilane (for H) or the central line (77.0
13
ppm) of CDCl3 (for C). Moisture and residual peak of CDCl3 appear at δ 1.5 and 7.2 ppm
7
respectively in 1H NMR. High resolution mass spectra (HRMS) were obtained on TOF/6500
SRIES QTOF B.05.00 (B5042.0). Thinꢀlayer chromatographies (TLC) were performed on
glass plates (7.5 x 2.5 and 7.5 x 5.0 cm) coated with silica gel GF 254 and various
combinations of ethyl acetate and hexane were used as eluent. Visualisation of spots was
accomplished by exposure to UV light. Silica gel (60ꢀ120 mesh) was used for column
chromatography (approximately 15ꢀ20 g per 1g of the crude product).
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Procedure for Palladium-catalyzed synthesis of 1-Benzylsulfanyl-3-phenyl-
benzo[b][1,6]naphthyridine (3a).
A mixture of 2ꢀphenylethynylquinolinꢀ3ꢀcarbonitrile 2a (0.50 mmol), 2.5 mol% of Pd(OAc)2,
5 mol% of PPh3 and 2 equiv Na2S.9H2O were added in 2 mL of DMF and reaction was
heated at 80°C under aerobic atmosphere. After completion of reaction, the reaction mixture
was quenched by benzyl chloride (2 equiv). The mixture was diluted with water, extracted
with ethyl acetate, washed with brine solution and dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was purified by column chromatography on silica gel using
EtOAc/hexane to afford 3a.
General
procedure
for
the
one-pot
synthesis
of
1,3-disubstituted
benzo[b][1,6]naphthyridines (3).
A mixture of substituted 2ꢀchloroquinolineꢀ3ꢀcarbonitrile (1a) (0.50 mmol), alkynes (1.2
equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %) and triethylamine (2 eq.) in CH3CN (2.0 mL)
were heated under N2 at 80°C. After completion of reaction (as monitored by TLC), solvent
was evaporated under reduced pressure and DMF (2.0 mL) was added followed by Pd(OAc)2
(2.5 mol %), PPh3 (5 mol %), and Na2S.9H2O (2 equiv) respectively and heated at 80 °C
under aerobic atmosphere. After completion of reaction, the reaction mixture was quenched
by appropriate alkyl halides (2 equiv). The mixture was diluted with water, extracted with
ethyl acetate, washed with brine solution and dried over anhydrous Na2SO4. The solvent was
evaporated and the residue was purified by column chromatography on silica gel using
EtOAc/hexane to afford the products 3a-q.
1-Benzylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine(3a)
Red solid; yield: 156.8 mg, 83%; mp 169ꢀ170 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H NMR
(300 MHz, CDCl3): δ= 4.85 (s, 2H), 7.27ꢀ7.39 (m, 2H), 7.45ꢀ7.59 (m, 7H), 7.87 (t, J =7.2 Hz,
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1H), 8.01 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 10.8 Hz, 2H), 8.28 (d, J = 7.5 Hz, 2H), 9.11 (s,
1H); 13C NMR (75 MHz, CDCl3): δ = 34.5, 112.1, 119.7, 126.0, 126.3, 127.0, 127.3, 128.1,
126.7, 128.7, 129.0, 129.2, 130.7, 132.8, 134.5, 137.2, 138.2, 149.8, 150.6, 152.2, 161.5 ppm;
IR (KBr, cmꢀ1): 1595, 2926; HRMS (ESI) m/e calcd for C25H19N2S [M+H]+ 379.1263, found
379.1281.
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1-Benzylsulfanyl-3-m-tolyl-benzo[b][1,6]naphthyridine (3b).
1
Yellow solid; yield: 164.6 mg, 84%; mp 185ꢀ186 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 2.47 (s, 3H), 4.84 (s, 2H), 7.27ꢀ7.44 (m, 5H), 7.55 (t, J = 8.4
Hz, 3H), 7.86 (t, J = 7.2 Hz, 1H), 8.02 (t, J = 8.4 Hz, 3H), 8.16 (t, J = 8.7 Hz, 2H), 9.10 (s,
1H); 13C NMR (75 MHz, CDCl3): δ = 21.6, 34.4, 113.0, 119.8, 124.1, 126.1, 127.3, 127.7,
128.6, 128.6, 128.8, 128.9, 129.0, 129.9, 132.3, 133.8, 137.4, 138.2, 138.8, 150.5, 151.5,
152.0, 161.2 ppm; IR (KBr, cmꢀ1): 1596, 2926; HRMS (ESI) m/e calcd for C26H21N2S
[M+H]+ 393.1420, found 393.1434.
1-Benzylsulfanyl-3-p-tolyl-benzo[b][1,6]naphthyridine (3c).
1
Yellow solid; yield: 166.6 mg, 85%; mp 140ꢀ141 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 2.44 (s, 3H), 4.85 (s, 2H), 7.27ꢀ7.40 (m, 5H), 7.54 (t, J = 11.7
Hz, 3H), 7.86 (t, J = 7.5 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 8.1 Hz, 4H), 9.09 (s,
1H); 13C NMR (75 MHz, CDCl3): δ = 21.3, 34.4, 112.3, 119.7, 126.1, 126.8, 127.3, 128.6,
129.0, 129.5, 130.7, 132.3, 133.8, 135.7, 137.4, 139.2, 150.5, 151.4, 151.9, 161.2 ppm; IR
(KBr, cmꢀ1) : 1593, 2926; HRMS (ESI) m/e calcd for C26H21N2S [M+H]+ 393.1420, found
393.1434.
1-Benzylsulfanyl-3-(4-fluoro-phenyl)-benzo[b][1,6]naphthyridine (3d).
Light yellow solid; yield: 164.3 mg, 83%; mp 159ꢀ160 °C; Rf = 0.35 (05:95 EtOAc/hexane);
1H NMR (300 MHz, CDCl3): δ= 4.83 (s, 2H), 7.20 (t, J = 8.7 Hz, 1H), 7.28ꢀ7.36 (m, 3H),
7.51ꢀ7.60 (m, 4H), 7.87 (t, J = 7.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.17ꢀ8.27
(m, 3H), 9.11 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 34.5, 112.5, 115.5, 115.8, 119.7,
126.2, 127.4, 128.6, 128.7, 128.8, 129.0, 130.0, 132.4, 133.8, 134.6, 134.6, 137.2, 150.3,
150.8, 151.5, 161.6 ppm; IR (KBr, cmꢀ1): 1599, 2924; HRMS (ESI) m/e calcd for
C25H18FN2S [M+H]+ 397.1169, found 397.1184.
1-Benzylsulfanyl-3-propyl-benzo[b][1,6]naphthyridine (3e).
1
Red solid; yield: 137.6 mg, 80%; mp 97ꢀ98 °C; Rf = 0.35 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3): δ= 1.04 (t, J= 7.2 Hz, 3H), 1.88ꢀ1.95 (m, 2H), 2.94 (t, J = 7.5 Hz, 2H),
4.70 (s, 2H), 7.27ꢀ7.36 (m, 4H), 7.48ꢀ7.56 (m, 3H), 7.83 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 8.4
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Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 9.06 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 22.0,
34.0, 40.2, 114.9, 119.2125.8, 125.9, 127.1, 128.4, 128.8, 128.9, 129.1, 132.1, 133.7, 150.3,
151.2, 157.5, 160.5 ppm; IR (KBr, cmꢀ1): 1603, 2956; HRMS (ESI) m/e calcd for C22H21N2S
[M+H]+ 345.1420, found 345.1426.
1-Benzylsulfanyl-3-hexyl-benzo[b][1,6]naphthyridine (3f).
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1
Yellow liquid; yield: 150.5 mg, 78%; mp Rf = 0.35 (05:95 EtOAc/hexane); H NMR (300
MHz, CDCl3): δ= 0.89 (t, J = 5.7 Hz, 3H), 1.32ꢀ1.43 (m, 6H), 1.92ꢀ1.92 (m, 2H), 2.96 (t, J =
7.5 Hz, 2H), 4.71 (s, 2H), 7.29ꢀ7.34 (m, 4H), 7.48ꢀ7.56 (m, 3H), 7.83 (t, J = 7.2 Hz, 1H),
7.99 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 9.06 (s, 1H); 13C NMR (75 MHz, CDCl3):
δ = 14.1, 22.6, 28.8, 28.9, 31.7, 34.0, 38.1, 114.8, 119.3, 125.8, 125.9, 127.1, 128.4, 128.8,
129.0, 129.1, 132.2, 133.9, 138.0, 150.4, 151.2, 157.8, 160.5 ppm; IR (KBr, cmꢀ1): 1621,
2945; HRMS (ESI) m/e calcd for C25H27N2S [M+H]+ 387.1889, found 387.1906.
1-Benzylsulfanyl-3-thiophen-3-yl-benzo[b][1,6]naphthyridine (3g).
Light green solid; yield: 140.1 mg, 73%; mp 82ꢀ83 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H
NMR (300 MHz, CDCl3): δ= 4.04 (s, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.41 (t, J = 7.5 Hz, 2H),
7.67ꢀ7.75 (m, 4H), 7.87 (d, J = 8.4 Hz, 2H), 8.03 (s, 1H), 8.06 (s, 1H), 8.86 (s, 1H); 13C NMR
(75 MHz, CDCl3): δ = 42.8, 108.9, 114.5, 124.2, 125.3, 125.4, 126.1, 128.5, 128.9, 129.0,
130.8, 131.9, 135.9, 135.9, 142.6, 147.9, 150.6, 153.7, 161.6, 162.1 ppm; IR (KBr, cmꢀ1):
1590, 2926; HRMS (ESI) m/e calcd for C23H17N2S2 [M+H]+ 385.0828, found 385.0841.
1-Benzylsulfanyl-8-methyl-3-phenyl-benzo[b][1,6]naphthyridine (3h).
1
Orange solid; yield 152.8 mg, 78%; mp 158ꢀ159 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 2.57 (s, 3H), 4.84 (s, 2H), 7.27ꢀ7.36 (m, 4H), 7.41ꢀ7.54 (m,
13
4H), 7.68ꢀ7.81 (m, 3H), 8.10 (t, J =13.5 Hz, 2H), 8.27 (d, J = 7.5 Hz, 1H), 8.98 (s, 1H); C
NMR (75 MHz, CDCl3): δ = 21.6, 34.4, 112.3, 119.8, 121.2, 126.2, 126.9, 127.3, 128.6,
128.7, 129.0, 129.8, 133.2, 135.2, 135.6, 136.4, 137.4, 138.4, 149.3, 149.6, 151.7, 161.2 ppm;
IR (KBr, cmꢀ1): 1614, 2925; HRMS (ESI) m/e calcd for C26H21N2S [M+H]+ 393.1420, found
393.1433.
1-Benzylsulfanyl-7-methyl-3-phenyl-benzo[b][1,6]naphthyridine (3i).
Light yellow solid; yield: 152.8 mg, 78%; mp 145ꢀ146 °C; Rf = 0.35 (05:95 EtOAc/hexane);
1H NMR (300 MHz, CDCl3): δ= 22.58 (s, 3H), 4.84 (s, 2H), 7.27ꢀ7.36 (m, 3H), 7.44ꢀ7.54 (m,
13
5H), 7.69ꢀ7.81 (m, 3H), 8.04ꢀ8.16 (m, 2H), 8.27 (d, J = 7.2 Hz, 1H), 8.99 (s, 1H); C NMR
(75 MHz, CDCl3): δ = 21.6, 34.4, 113.0, 120.0, 126.5, 126.7, 127.0, 127.4, 128.7, 128.8,
129.1, 129.2, 130.0, 133.0, 135.5, 136.4, 137.6, 138.7, 150.0, 150.5, 151.7, 161.3 ppm; IR
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(KBr, cmꢀ1): 1613, 2924; HRMS (ESI) m/e calcd for C26H21N2S [M+H]+ 393.1420, found
393.1424.
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1-Benzylsulfanyl-6-methyl-3-phenyl-benzo[b][1,6]naphthyridine (3j).
Light yellow solid; yield: 148.9 mg, 76%; mp 95ꢀ98 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H
NMR (300 MHz, CDCl3): δ= 2.92 (s, 3H), 4.85 (s, 2H), 7.29ꢀ7.35 (m, 3H), 7.45ꢀ7.55 (m,
5H), 7.68 (t, J =6.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H),
9.04 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 18.2, 34.4, 113.7, 119.7, 126.1, 126.9, 127.0,
127.3, 128.5, 128.6, 128.7, 128.9, 129.0, 131.6, 132.3, 133.6, 138.7, 142.8, 149.8, 151.1,
151.4, 161.0 ppm; IR (KBr, cmꢀ1): 1610, 2926; HRMS (ESI) m/e calcd for C26H21N2S
[M+H]+ 393.1420, found 393.1428.
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1-Benzylsulfanyl-7-chloro-3-phenyl-benzo[b][1,6]naphthyridine (3k).
Yellow solid; yield: 154.5 mg, 75%; mp 92ꢀ93 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H NMR
(300 MHz, CDCl3): δ= 4.85 (s, 2H), 7.05 (s, 1H), 7.31ꢀ7.36 (m, 2H), 7.44ꢀ7.53 (m, 6H), 7.95
(d, J =9.0 Hz, 1H), 8.10 (d, J = 17.7 Hz, 2H), 8.27 (d, J = 7.5 Hz, 2H), 9.08 (s, 1H); 13C NMR
(75 MHz, CDCl3): δ = 34.5, 112.7, 119.7, 121.4, 124.4, 127.0, 128.6, 128.8, 129.0, 129.4,
130.2, 133.9, 137.2, 138.3, 138.7, 139.5, 141.8, 148.3, 151.4, 152.4, 161.6 ppm; IR (KBr, cmꢀ
1): 1610, 2926; HRMS (ESI) m/e calcd for C25H18ClN2S [M+H]+ 413.0874, found 413.0872.
1-Methylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine (3l).
1
Yellow solid; yield: 125.3 mg, 83%; mp 133ꢀ134 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 2.91 (s, 3H), 7.45ꢀ7.61 (m, 4H), 7.88 (t, J = 7.2 Hz, 1H), 8.06
(d, J = 8.4 Hz, 1H), 8.18 (t, J = 8.7 Hz, 2H), 8.31 (d, J = 7.2 Hz, 2H), 9.13 (s, 1H); 13C NMR
(75 MHz, CDCl3): δ =13.1, 112.3, 120.0, 126.1, 126.9, 127.9, 128.7, 128.8, 129.0, 129.1,
132.3, 133.7, 138.5, 150.3, 151.3, 151.7, 162.2 ppm; IR (KBr, cmꢀ1): 1604, 2926; HRMS
(ESI) m/e calcd for C19H15N2S [M+H]+ 303.0950, found 303.0960.
1-Ethylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine (3m).
Light yellow solid; yield: 126.4 mg, 80%; mp 107ꢀ108 °C; Rf = 0.35 (05:95 EtOAc/hexane);
1H NMR (300 MHz, CDCl3): δ= 1.58 (t, J = 7.5, 3H), 3.58 (q, J = 7.2, 2H), 7.45ꢀ7.57 (m,
4H), 7.87 (t, J = 7.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 8.7 Hz, 2H), 8.28 (d, J =
7.2 Hz, 2H), 9.12 (s, 1H); 13C NMR (75 MHz, CDCl3): δ =14.3, 24.5, 112.4, 120.1, 126.0,
126.8, 127.8, 128.6, 128.8, 129.0, 129.0, 132.2, 133.7, 138.6, 150.4, 151.4, 151.7, 161.8 ppm;
IR (KBr, cmꢀ1) : 1603, 2926; HRMS (ESI) m/e calcd for C20H17N2S [M+H]+ 317.1107, found
317.1123.
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1-Pentylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine (3n).
Light green solid; yield: 139.6 mg, 78%; mp 82ꢀ83 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H
NMR (300 MHz, CDCl3): δ= 0.95 (t, J = 7.2, 3H), 1.39ꢀ1.59 (m, 4H), 1.88ꢀ1.98 (m, 2H),
3.55 (t, J = 7.2, 2H), 7.42ꢀ7.59 (m, 4H), 7.86 (t, J= 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.16
(t, J = 8.7 Hz, 2H), 8.27 (d, J = 7.2 Hz, 2H), 9.12 (s, 1H); 13C NMR (75 MHz, CDCl3): δ =
14.0, 22.3, 28.8, 30.1, 31.3, 112.3, 120.1, 126.0, 126.1, 126.8, 128.6, 128.8, 129.0, 129.0,
132.2, 133.8, 138.5, 150.4, 151.3, 151.7, 162.0 ppm; IR (KBr, cmꢀ1): 1597, 2926; HRMS
(ESI) m/e calcd for C23H23N2S [M+H]+ 359.1576, found 359.1584.
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1-Hexylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine (3o).
Light yellow solid; yield: 143.2 mg, 77%; mp 77ꢀ78 °C; Rf = 0.35 (05:95 EtOAc/hexane); 1H
NMR (300 MHz, CDCl3): δ= 0.91 (t, J = 6.6, 3H), 1.30ꢀ1.42 (m, 4H), 1.54ꢀ1.63 (m, 2H),
1.87ꢀ1.97 (m, 2H), 3.56 (t, J = 7.5, 2H), 7.44ꢀ7.59 (m, 4H), 7.86 (t, J = 6.9 Hz, 1H), 8.04 (d, J
13
= 8.4 Hz, 1H), 8.18 (t, J = 8.7 Hz, 2H), 8.28 (d, J = 7.5 Hz, 2H), 9.13 (s, 1H); C NMR (75
MHz, CDCl3): δ = 14.0, 22.5, 28.9, 29.2, 30.2, 31.4, 112.1, 120.2, 126.1, 126.4, 126.9, 128.7,
129.0, 129.1, 130.2, 132.4, 134.1, 138.5, 150.3, 151.1, 151.9 ppm; IR (KBr, cmꢀ1): 1601,
2926; HRMS (ESI) m/e calcd for C24H25N2S [M+H]+ 373.1733, found 373.1745.
1-Allylsulfanyl-3-phenyl-benzo[b][1,6]naphthyridine (3p).
1
Yellow solid; yield: 131.2 mg, 80%; mp 123ꢀ124 °C; Rf = 0.35 (05:95 EtOAc/hexane) ; H
NMR (300 MHz, CDCl3): δ= 4.25 (d, J = 6.6, 3H), 5.21 (d, J = 9.9, 1H), 5.45 (d, J = 17.4,
1H), 6.12ꢀ6.21 (m, 1H), 7.45ꢀ7.61 (m, 5H), 7.87 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H),
8.18 (t, J = 8.7 Hz, 1H), 8.28 (d, J = 7.2 Hz, 2H), 9.13 (s, 1H); 13C NMR (75 MHz, CDCl3): δ
= 32.8, 112.7, 118.0, 119.9, 126.1, 126.8, 128.6, 128.7, 128.8, 129.0, 129.1, 132.2, 133.4,
133.7, 138.4, 150.3, 151.4, 151.6, 161.0 ppm; IR (KBr, cmꢀ1) : 1590, 2926; HRMS (ESI) m/e
calcd for C21H17N2S [M+H]+ 329.1107, found 329.1116.
3-Phenyl-1-prop-2-ynylsulfanyl-benzo[b][1,6]naphthyridine (3q).
1
Red solid; yield: 122.2 mg, 75%; mp 88ꢀ89 °C; Rf = 0.35 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3): δ= 2.57 (s, 1H), 4.35 (d, J = 2.1 Hz, 2H), 7.19(s, 1H), 7.43ꢀ7.62 (m, 4H),
7.88 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.30 (d, J = 7.5 Hz, 2H), 9.07
13
(s, 1H); C NMR (75 MHz, CDCl3): δ = 18.6, 70.8, 79.5, 113.2, 119.7, 126.2, 126.4, 127.0,
128.8, 129.0, 129.0, 129.2, 132.5, 133.6, 138.4, 143.1, 150.4, 151.9, 159.6 ppm; IR (KBr, cmꢀ
1): 1612, 2926; HRMS (ESI) m/e calcd for C21H15N2S [M+H]+ 327.0950, found 327.0954.
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5-Benzylsulfanyl-3,7-diphenyl-[1,6]naphthyridine (5a).
1
White solid; yield: 159.5 mg, 79%; mp 179ꢀ180 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 4.81 (s, 2H), 7.28ꢀ7.34 (m, 2H), 7.42ꢀ7.55 (m, 9H), , 7.70 (d, J
= 7.2 Hz, 2H), 8.10 (s, 1H), 8.23 (d, J = 7.5 Hz, 2H), 8.59 (s, 1H), 9.29 (s, 1H); 13C NMR
(75 MHz, CDCl3): δ= 34.4, 113.8, 120.9, 126.8, 127.2, 128.4, 128.4, 128.5, 128.7, 128.9,
129.0, 129.1, 129.2, 129.6, 134.2, 136.9, 137.5, 138.0, 138.4, 150.3, 152.9, 154.0, 159.7 ppm;
IR (KBr, cmꢀ1): 1581, 2923; HRMS (ESI) m/e calcd for C27H21N2S [M+H]+ 405.1420, found
405.1423.
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Procedure for one-pot synthesis of 3-Phenyl-benzo[b][1,6]naphthyridine-1-thiol 3r.
A mixture of substituted 2ꢀchloroquinolineꢀ3ꢀcarbonitrile (1a) (0.50 mmol), alkynes (1.2
equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %) and triethylamine (2 eq.) in CH3CN (2.0 mL)
were heated under N2 at 80°C. After completion of reaction (as monitored by TLC), solvent
was evaporated under reduced pressure and DMF (2.0 mL) was added followed by Pd(OAc)2
(2.5 mol %), PPh3 (5 mol %), and Na2S.9H2O (2 equiv) and heated at 80 °C under aerobic
atmosphere. After completion of reaction, the reaction mixture was quenched by addition of
water, extracted with ethyl acetate, washed with brine solution and dried over anhydrous
Na2SO4. The solvent was evaporated and the residue was purified by column chromatography
on silica gel using EtOAc/hexane to afford the products 3r.
3-Phenyl-benzo[b][1,6]naphthyridine-1-thiol (3r).
1
Red solid; yield: 112.3 mg, 78%; mp 80ꢀ81 °C; Rf = 0.35 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3): δ= 2.91 (s, 3H), 7.45ꢀ7.61 (m, 4H), 7.88 (t, J = 7.2 Hz, 1H), 8.06 (d, J =
8.4 Hz, 1H), 8.18 (t, J = 8.7 Hz, 2H), 8.31 (d, J = 7.2 Hz, 2H), 9.13 (s, 1H); 13C NMR (75
MHz, CDCl3): δ =13.1, 112.3, 120.0, 126.1, 126.9, 127.9, 128.7, 128.8, 129.0, 129.1, 132.3,
133.7, 138.5, 150.3, 151.3, 151.7, 162.2 ppm; IR (KBr, cmꢀ1): 1591, 2926; HRMS (ESI) m/e
calcd for C18H13N2S [M+H]+ 289.0794, found 289.0805.
Procedure for palladium-catalyzed synthesis of addition products 6.
To a solution 2ꢀphenylethynylquinolinꢀ3ꢀcarbonitrile 2a (0.50 mmol) in DMF (2 mL) under
aerobic atmosphere were added thiols (2 equiv), Pd(OAc)2 (2.5 mol %), PPh3 (5 mol %),
K2CO3 (2 equiv) and the reaction mixture heated at 80 °C for 1ꢀ2 h. After completion of the
reaction cold water was poured into the reaction mixture and extracted with ethyl acetate,
dried over anhydrous sodium sulphate (Na2SO4), concentrated under vacuum and the residue
was purified by column chromatography to afford products 6a-b.
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2-(2-ethylsulfanyl-2-phenyl-vinyl)-quinoline-3-carbonitrile (6a).
1
White solid; yield: 124.4 mg, 80%; mp 119ꢀ120 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ= 1.07 (t, J = 7.2 Hz, 3H), 2.45 (q, J = 7.5 Hz, 2H), 7.09 (s, 1H),
7.39 (t, J = 10.8 Hz, 3H), 7.52ꢀ7.61 (m, 3H), 7.83 (q, J = 5.4 Hz, 2H), 8.23 (d, J = 8.4 Hz,
1H), 8.48 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.4, 27.7, 106.3, 107.1, 121.9, 123.9,
127.3, 127.7, 128.4, 128.4, 129.2, 129.2, 132.5, 139.6, 142.2, 148.1, 152.6, 154.0 ppm; IR
(KBr, cmꢀ1): 1548, 2221, 2924; HRMS (ESI) m/e calcd for C20H16N2NaS [M+Na]+ 339.0926,
found 339.0921.
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2-(2-Phenyl-2-phenylsulfanyl-vinyl)-quinoline-3-carbonitrile (6b).
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White solid; yield: 136.5 mg, 75 %; mp 127ꢀ128 °C; Rf = 0.35 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3): δ = 7.04 (s, 3H), 7.14ꢀ7.22 (m, 5H), 7.39 (d, J = 3.6 Hz, 2H), 7.61
(t, J = 7.5 Hz, 1H), 7.82ꢀ7.89 (m, 2H), 8.28 (d, J = 8.1 Hz, 1H), 8.51 (s, 1H); 13C NMR (75
MHz, CDCl3): δ = 100.3, 106.3, 117.0, 122.4, 124.0, 127.2, 127.5, 127.7, 128.0, 128.2,
129.1, 129.2, 132.7, 133.3, 139.3, 142.3, 148.0, 151.3, 153.7 ppm; IR (KBr, cmꢀ1): 1582,
2222, 2956; HRMS (ESI) m/e calcd for C24H17N2S [M+H]+ 365.1107, found 365.1104.
Procedure for Palladium-catalyzed synthesis of 7a.
A mixture of 2ꢀphenylethynylquinolinꢀ3ꢀcarbonitrile 2a (0.50 mmol), Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), morpholine (2 equiv) and K2CO3 (2 equiv) in CH3CN (4 mL) were stirred
under aerobic condition at 80°C. After completion of the reaction (as monitored by TLC),
cold water was added into the reaction mixture and extracted with ethyl acetate, dried over
anhydrous sodium sulphate (Na2SO4), concentrated under vacuum. The residue was purified
by column chromatography to afford product 7a.
General
procedure
for
one-pot
synthesis
of
1,3-disubstituted
benzo[b][1,6]naphthyridines (7) from secondary amines.
A mixture of substituted 2ꢀchloroquinolineꢀ3ꢀcarbonitrile (1) (0.50 mmol), alkynes (1.2
equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %) and triethylamine (2 equiv.) in CH3CN (2 mL)
were heated under N2 at 80°C. After completion of reaction (as monitored by TLC),
subsequently added Pd(OAc)2 (5 mol %), Ph3P (10 mol %) and morpholine (4 equiv) along
with K2CO3 (2 equiv) in acetonitrile and heated at 80°C under aerobic atmosphere. After
completion of reaction, the reaction mixture was diluted with water, extracted with ethyl
acetate, washed with brine solution and dried over anhydrous Na2SO4. The solvent was
evaporated and the residue was purified by column chromatography on silica gel using
EtOAc/hexane to afford the products 7a-m.
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1-Morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7a).
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Yellow solid; yield: 132.9 mg, 78%; mp 120ꢀ121 °C; Rf = 0.30 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 3.69 (t, J = 4.5 Hz, 4H), 4.06 (t, J = 4.8 Hz, 4H), 7.42ꢀ7.58
(m, 4H), 7.85 (t, J = 7.8 Hz, 1H), 8.03 (t, J = 8.4 Hz, 2H), 8.18ꢀ8.27 (m, 3H), 8.95 (s, 1H);
13C NMR (75 MHz, CDCl3): δ = 51.9, 66.9, 111.3, 114.7, 125.8, 125.9, 126.9, 128.7, 128.8,
129.0, 129.0, 132.2, 135.0, 138.9, 151.0, 151.3, 153.2, 161.3 ppm; IR (KBr, cmꢀ1): 1600,
2850, 2919, 2955; HRMS (ESI) m/e calcd for C22H20N3O [M+H]+ 342.1601, found
342.1604.
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1-Morpholin-4-yl-3-m-tolylbenzo[b][1,6]naphthyridine (7b).
Light green solid; yield: 133.1 mg, 75%; mp 135ꢀ136 °C; Rf = 0.25 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3H), 3.68 (t, J = 3.0 Hz, 4H), 4.05 (t, J = 3.3 Hz,
4H), 7.30 (t, J = 8.1 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 8.00 (t, J =
8.4 Hz, 2H), 8.15 (t, J = 7.8 Hz, 3H), 8.92 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 21.2,
51.8, 66.7, 110.4, 110.5, 114.4, 125.5, 126.7, 128.8, 129.3, 131.9, 134.7, 134.8, 136.0,
138.9, 150.8, 151.2, 153.0, 161.0 ppm; IR (KBr, cmꢀ1): 1605, 2932, 2958; HRMS (ESI) m/e
calcd for C23H22N3O [M+H]+ 356.1757, found 356.1748.
1-Morpholin-4-yl-3-p-tolylbenzo[b][1,6]naphthyridine (7c).
Light yellow solid; yield: 131.3 mg, 74%; mp 112ꢀ113 °C; Rf = 0.25 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3H), 3.68 (t, J = 4.2Hz, 4H), 4.06 (t, J = 4.5 Hz,
4H), 7.31 (t, J = 8.1 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 8.00 (t, J =
10.8 Hz, 2H), 8.16 (t, J = 8.4 Hz, 3H), 8.94 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 21.2,
51.9, 66.8, 110.7, 114.5, 125.6, 125.7, 126.8 128.7, 128.9, 129.4, 132.0, 134.8, 136.1, 139.0,
151.0, 151.3, 153.2, 161.2 ppm; IR (KBr, cmꢀ1): 1595, 2933; HRMS (ESI) m/e calcd for
C23H22N3O [M+H]+ 356.1757, found 356.1758.
3-(4-Methoxy-phenyl)-1-morpholin-4-yl-benzo[b][1,6]naphthyridine (7d).
Light green solid; yield: 148.4 mg, 80%; mp 145ꢀ146 °C; Rf = 0.20 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3); δ = 3.68 (t, J = 4.5Hz, 4H), 3.89 (s, 3H), 4.05 (t, J = 4.8 Hz,
4H), 7.03 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 8.00 (t, J =
10.8 Hz, 2H), 8.20 (t, J = 8.4 Hz, 3H), 8.93 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 51.9,
55.2, 66.8, 109.8, 114.0, 114.3, 125.5, 125.6, 128.2, 128.6, 128.9, 131.4, 131.9, 132.1,
134.8, 150.9, 153.2, 160.4, 161.1 ppm; IR (KBr, cmꢀ1): 1522, 2922, 2957; HRMS (ESI) m/e
calcd for C23H22N3O2 [M+H]+ 372.1707, found 372.1707.
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3-(4-Fluoro-phenyl)-1-morpholin-4-yl-benzo[b][1,6]naphthyridine (7e).
1
Yellow solid; yield: 148.9 mg, 83%; mp 151ꢀ152 °C; Rf = 0.25 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 3.68 (t, J = 4.5 Hz, 4H), 4.05 (t, J = 4.2 Hz, 4H), 7.18 (t, J =
8.7 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.85 (t, J =7.8 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 8.16ꢀ
8.25 (m, 3H), 8.94 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 51.9, 66.8, 110.8, 111.0, 114.5,
115.4, 115.7, 125.9, 128.5, 128.7, 128.8, 128.9, 129.0, 132.2, 134.9, 135.0, 150.3, 151.0,
153.1, 161.3, 161.8, 165.1 ppm; IR (KBr, cmꢀ1): 1595, 2942, 2959; HRMS (ESI) m/e calcd
for C22H19FN3O [M+H]+ 360.1507, found 360.1503.
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8-Methyl-1-morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7g).
1
Yellow solid; yield: 131.3 mg, 74%; mp 128ꢀ129 °C; Rf = 0.35 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3); δ = 2.58 (s, 3H), 3.66 (t, J = 4.2 Hz, 4H), 4.04 (t, J = 4.2 Hz, 4H),
7.39ꢀ7.52 (m, 3H), 7.68 (d, J = 8.7 Hz, 1H), 7.76 (s, 1H), 8.06 (d, J =11.7 Hz, 2H), 8.24 (d, J
= 7.5 Hz, 2H), 8.83 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 21.5, 51.8, 66.8, 111.2, 111.4,
114.6, 125.8, 126.6, 126.7, 128.5, 128.7, 133.5, 134.7, 135.5, 138.9, 149.8, 150.5, 152.4,
161.0 ppm; IR (KBr, cmꢀ1):1598, 2914, 2956; HRMS (ESI) m/e calcd for C23H22N3O
[M+H]+ 356.1757, found 356.1748.
7-Methyl-1-morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7h).
Light yellow solid; yield: 131.3 mg, 74%; mp 118ꢀ119 °C; Rf = 0.35 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3): δ = 2.62 (s, 3H), 3.67 (t, J = 4.5 Hz, 4H), 4.05 (t, J = 4.2 Hz,
4H), 7.37ꢀ7.53 (m, 4H), 7.91 (t, J = 8.4 Hz, 2H), 8.04 (s, 1H), 8.25 (d, J = 7.2 Hz, 2H), 8.88
(s, 1H); 13C NMR (75 MHz, CDCl3): δ = 22.3, 51.9, 66.8, 111.3, 114.2, 124.2, 126.8, 127.1,
128.5, 128.8, 134.3, 138.9, 142.8, 151.0, 151.2, 153.1, 161.2 ppm; IR (KBr, cmꢀ1): 1602,
2908, 2962; HRMS (ESI) m/e calcd for C23H22N3O [M+H]+ 356.1757,found 356.1749.
8-Methoxy-1-morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7i).
Light green solid; yield: 133.5 mg, 72%; mp 141ꢀ142 °C; Rf = 0.35 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3): δ = 3.66 (t, J = 4.2 Hz, 4H), 4.00 (s, 3H), 4.07 (t, J = 4.5 Hz,
4H), 7.19 (d, J = 2.4 Hz, 1H), 7.41ꢀ7.55 (m, 4H), 8.07 (d, J = 10.2 Hz, 2H), 8.24 (d, J = 7.5
Hz, 2H), 8.80 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 51.9, 66.9, 104.1, 111.7, 115.0,
126.8, 127.0, 128.6, 130.4, 132.3, 132.4, 139.0, 148.1, 150.2, 151.6, 157.2, 160.9 ppm; IR
(KBr, cmꢀ1): 1603, 2922, 2945; HRMS (ESI) m/e calcd for C23H22N3O2 [M+H]+ 372.1707,
found 372.1700.
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7-Methoxy-1-morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7j).
Light green solid; yield: 124.2 mg, 70%; mp 141ꢀ142 °C; Rf = 0.25 (05:95 EtOAc/hexane):
1H NMR (300 MHz, CDCl3): δ = 3.59 (t, J = 3.6 Hz, 4H), 3.92 (s, 3H), 3.99 (t, J = 4.2 Hz,
4H), 7.10 (d, J = 1.8 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.40ꢀ7.48 (m, 3H), 8.00 (d, J = 11.4
Hz, 2H), 8.16 (d, J = 7.8 Hz, 2H), 8.72 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 51.9, 55.6,
66.9, 104.1, 111.6, 114.9, 126.7, 126.9, 127.0, 128.6, 128.7130.3, 132.4, 139.0, 148.1,
150.1, 151.5, 157.1, 160.8 ppm; IR (KBr, cmꢀ1): 1603, 2922, 2945; HRMS (ESI) m/e calcd
for C23H22N3O2 [M+H]+ 372.1707, found 372.1703.
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7-Chloro-1-morpholin-4-yl-3-phenylbenzo[b][1,6]naphthyridine (7k).
1
Red solid; yield: 121.8 mg, 65%; mp 95ꢀ96 °C; Rf = 0.35 (05:95 EtOAc/hexane): H NMR
(300 MHz, CDCl3): δ= 3.69 (t, J = 3.9 Hz, 4H), 4.05 (t, J = 4.5 Hz, 4H), 7.41ꢀ7.54 (m, 4H),
7.95 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 8.23 (t, J = 9.0 Hz, 3H), 8.93 (s, 1H); 13C NMR (75
MHz, CDCl3): δ = 51.9, 66.8, 110.8, 114.6, 124.1, 127.0, 128.3, 128.7, 129.2, 130.2, 135.2,
138.5, 138.6, 150.8, 152.0, 153.7, 161.2 ppm; IR (KBr, cmꢀ1): 1600, 1628, 2924, 2955;
HRMS (ESI) m/e calcd for C22H19ClN3O [M+H]+ 376.1211, found 376.1210.
3-Phenyl-1-piperidin-1-yl-benzo[b][1,6]naphthyridine (7l).
1
Light red solid; yield: 101.7 mg, 60%; mp 80ꢀ81 °C; Rf = 0.40 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 1.75ꢀ1.82 (m, 2H), 1.89ꢀ196 (m, 4H), 3.65 (t, J = 4.8 Hz,
4H), 7.41ꢀ7.55 (m, 4H), 7.83 (t, J = 7.8 Hz, 1H), 8.00 (d, J = 6.9 Hz, 2H), 8.16 (d, J = 8.7
Hz, 1H), 8.26 (d, J = 7.2 Hz, 2H), 8.93 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 24.9, 26.1,
52.7, 110.0, 115.1, 125.5, 125.8, 126.9, 127.0, 128.3, 128.6, 128.9, 132.1, 135.7, 139.2,
150.5, 151.7, 153.2, 162.3 ppm; IR (KBr, cmꢀ1): 1640, 2852, 2937; HRMS (ESI) m/e calcd
for C23H22N3 [M+H]+ 340.1808, found 340.1815.
3-Phenyl-1-pyrrolidin-1-yl-benzo[b][1,6]naphthyridine (7m).
Light red solid; yield: 115.3 mg, 71%; mp 105ꢀ106 °C; Rf = 0.40 (05:95 EtOAc/hexane): 1H
NMR (300 MHz, CDCl3): δ = 2.12 (t, J = 3.0 Hz, 4H), 4.10 (t, J = 6.3 Hz, 4H), 7.40ꢀ7.50
(m, 4H), 7.81 (t, J = 7.5 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.27 (d,
J = 7.2 Hz, 2H), 9.11 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 25.8, 51.4, 106.4, 104.5,
124.6, 125.0, 126.8, 128.1, 128.4, 128.7, 129.0, 131.7, 135.7, 139.5, 150.1, 152.1, 154.0,
156.8 ppm; IR (KBr, cmꢀ1): 1582, 1610, 2932; HRMS (ESI) m/e calcd for C22H20N3 [M+H]+
326.1652, found 326.1654.
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5-Morpholin-4-yl-3,7-diphenyl-[1,6]naphthyridine (8a).
1
Green solid; yield: 119.2 mg, 65%; mp 101ꢀ102 °C; Rf = 0.30 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 3.53 (t, J = 3.9 Hz, 4H), 3.94 (t, J = 4.2 Hz, 4H), 7.36ꢀ7.51
(m, 6H), 7.62 (d, J = 7.2 Hz, 2H), 7.96 (s, 1H), 8.14 (d, J = 7.5 Hz, 2H), 8.41 (s, 1H), 9.17
(s, 1H); 13C NMR (75 MHz, CDCl3): δ = 51.9, 66.8, 112.1, 115.3, 126.8, 127.2, 128.3,
128.7, 129.0, 129.3, 130.7, 133.5, 137.4, 138.8, 152.0, 152.9, 153.1, 160.8 ppm; IR (KBr,
cmꢀ1): 1601, 2912, 2960; HRMS (ESI) m/e calcd for C24H22N3O [M+H]+ 368.1757, found
368.1756.
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General procedure for palladium-catalyzed hydroamination reaction.
A mixture of substituted 2ꢀchloroquinolineꢀ3ꢀcarbonitrile (1a) (0.50 mmol), alkynes (1.2
equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %) and triethylamine (2 equiv) in CH3CN (2 mL)
were heated under N2 at 80°C. After completion of reaction (as monitored by TLC)
subsequently added Pd(OAc)2 (5 mol %), Ph3P (10 mol %), different alkyl amines (2 equiv)
along with K2CO3 (2 equiv) in acetonitrile and heated at 80°C under aerobic atmosphere.
After final completion of reaction, the reaction mixture was diluted with water, extracted with
ethyl acetate, washed with brine solution and dried over anhydrous Na2SO4. The solvent was
evaporated and the residue was purified by column chromatography on silica gel using
EtOAc/hexane to afford pure products 9a-d.
2-(2-Benzylamino-2-phenylvinyl)-quinoline-3-carbonitrile (9a).
1
Yellow solid; yield: 144.4 mg, 80%; mp 110ꢀ111 °C; Rf = 0.40 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 4.46 (d, J = 5.1 Hz, 2H), 5.70 (s, 1H), 7.28ꢀ7.37 (m, 4H),
7.41ꢀ7.49 (m, 5H), 7.58ꢀ7.64 (m, 4H), 8.27 (s, 1H), 11.26 (bs, D2O exchangeable, 1H); 13C
NMR (75 MHz, CDCl3): δ = 48.9, 92.9, 104.9, 117.5, 122.4, 124.7, 126.8, 127.1, 127.7,
128.1, 128.4, 128.6, 129.0, 132.2, 136.5, 139.4, 142.2, 142.3, 147.8, 157.2, 159.8 ppm; IR
(KBr, cmꢀ1):1582, 2216, 2968; HRMS (ESI) m/e calcd for C25H20N3 [M+H]+ 362.1652,
found 362.1658.
2-(2-Butylamino-2-phenylvinyl)-quinoline-3-carbonitrile (9b).
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Yellow solid; yield: 135.7 mg, 83%; mp 95ꢀ96 °C; Rf = 0.30 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3H), 1.37ꢀ1.56 (m, 4H), 3.19 (t, J = 6.3
Hz, 2H), 5.52 (s, 1H), 7.18ꢀ7.40 (m, 6H), 7.54ꢀ7.69 (m, 3H), 8.17 (s, 1H), 10.83 (bs, D2O
exchangeable, 1H); 13C NMR (75 MHz, CDCl3): δ = 13.7, 19.9, 33.0, 44.5, 92.0, 104.9,
117.6, 122.4, 124.5, 126.8, 127.9, 128.1, 128.3, 128.8, 132.2, 136.9, 142.2, 148.1, 157.4,
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160.2 ppm; IR (KBr, cmꢀ1): 1582, 2223, 2926; HRMS (ESI) m/e calcd for C22H22N3 [M+H]+
328.1808, found 328.1820.
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-(2-Isopropylamino-2-phenylvinyl)-quinoline-3-carbonitrile (9c).
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Yellow solid; yield: 122.0 mg, 78%; mp 105ꢀ106 °C; Rf = 0.35 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 1.24 (s, 6H), 3.36 (s, 1H), 5.57 (s, 1H), 7.36ꢀ7.50 (m, 6H),
7.62ꢀ7.77 (m, 3H), 8.24 (s, 1H), 10.85 (bs, D2O exchangeable, 1H); 13C NMR (75 MHz,
CDCl3): δ = 24.6, 46.1, 92.6, 104.9, 117.6, 122.4, 124.6, 126.9, 127.8, 128.0, 128.3, 128.8,
132.2, 137.3, 142.3, 148.0, 157.3, 159.4 ppm; IR (KBr, cmꢀ1): 1580, 2228, 2956; HRMS
(ESI) m/e calcd for C21H20N3 [M+H]+ 314.1652, found 314.1661.
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2-(2-Cyclohexylamino-2-phenylvinyl)-quinoline-3-carbonitrile (9d).
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Yellow solid; yield: 134.1 mg, 76%; mp 113ꢀ114 °C; Rf = 0.30 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 1.28ꢀ1.55 (m, 4H), 1.72ꢀ1.82 (m, 4H), 3.39 (d, J = 9.3 2H),
5.57 (s, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.41ꢀ7.48 (m, 4H), 7.61ꢀ7.71 (m, 3H), 7.77 (d, J = 8.4
Hz, 3H), 8.24 (s, 1H), 11.04 (bs, D2O exchangeable, 1H); 13C NMR (75 MHz, CDCl3): δ =
23.9, 25.5, 34.3, 52.1, 92.5, 104.9, 117.6, 122.3, 124.5, 126.7, 127.8, 128.3, 128.8, 132.2,
137.2, 142.2, 148.0, 157.3, 159.3 ppm; IR (KBr, cmꢀ1):1596, 2213, 2932; HRMS (ESI) m/e
calcd for C24H23NaN3 [M+Na]+ 376.1784, found 376.1790.
General procedure for synthesis of N-alkyl-3-phenyl-2H-benzo[b][1,6]naphthyridin-1-
ones 10.
To a solution of compound 9a/9b (0.20 mmol) in THF was added sodium hydride (2 equiv)
and heated at 600C under aerobic condition. After completion of the reactions, cold water was
added into the reaction mixture and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over anhydrous sodium sulphate (Na2SO4). The solvent
was evaporated under vacuum to give crude product, which was purified by column
chromatography on silica gel using EtOAc and hexane as eluent to afford pure products 10a-
b.
N-benzyl-3-phenyl-2H-benzo[b][1,6]naphthyridin-1-one (10a).
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Green solid; yield: 57.9 mg, 80%; mp 121ꢀ122 °C; Rf = 0.25 (05:95 EtOAc/hexane): H
NMR (300 MHz, CDCl3): δ = 5.26 (s, 2H), 6.81 (s, 1H), 6.92 (d, J = 3.3 Hz, 2H), 7.17 (d, J
= 2.1 Hz, 3H), 7.27 (d, J = 7.2 Hz, 2H), 7.34ꢀ7.43 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.85 (t,
J = 7.5 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4Hz, 1H), 9.34 (s, 1H); 13C NMR
(75 MHz, CDCl3): δ = 48.5, 110.4, 119.7, 126.2, 126.6, 126.8, 127.1, 128.3, 128.4, 128.7,
128.8, 129.2, 129.4, 132.4, 135.4, 137.2, 138.9, 148.2, 151.2, 151.7, 163.7 ppm; IR (KBr,
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cmꢀ1): 1659, 2923, 3056; HRMS (ESI) m/e calcd for C25H19N2O [M+H]+ 363.1492, found
363.1496.
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N-butyl-3-phenyl-2H-benzo[b][1,6]naphthyridin-1-one (10b).
Light green solid; yield: 49.2 mg, 75%; mp 90ꢀ91 °C; Rf = 0.25 (05:95 EtOAc/hexane): 1H
NMR (300 MHz, CDCl3): δ = 0.74 (t, J = 7.2 Hz, 3H), 1.12ꢀ1.19 (m, 4H), 3.97 (t, J = 8.1 Hz,
2H), 6.77 (s, 1H), 7.49ꢀ7.59 (m, 6H), 7.84 (t, J = 8.1 Hz, 1H), 8.04 (t, J = 8.1 Hz, 1H), 8.12
(d, J = 8.7 Hz, 1H), 9.30 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 13.4, 19.8, 30.7, 45.2,
109.5, 109.5, 119.8, 126.0, 126.6, 128.5, 128.7, 129.1, 129.4, 132.2, 135.7, 138.5, 148.1,
151.1, 151.6, 163.3 ppm; IR (KBr, cmꢀ1): 1661, 2913, 3012; HRMS (ESI) m/e calcd for
C22H21N2O [M+H]+ 329.1648 found 329.1646.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:.
Crystal structure and data of compounds 3a, 7i and 9c.
1H and 13C NMR spectra’s of all the new compounds.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rk.singh1987.bhu@gmail.com
ORCID
Ritush Kumar: 0000ꢀ0002ꢀ8384ꢀ3868
Mrityunjaya Asthana: 0000ꢀ0001ꢀ8249ꢀ2747
Notes
The authors declare no competing financial interest. This work is a part of doctoral thesis submitted
by Ritush Kumar at Department of Chemistry, Banaras Hindu University, Varanasi, India.
ACKNOWLEDGMENTS
RK acknowledges Department of Chemistry, Banaras Hindu University for laboratory
facility. MA acknowledges SERB (PDF/2015/000565), New Delhi. The authors thank Dr.
Ajit Pathak, NIFFT Ranchi for Xꢀray crystallographic analysis.
REFERENCES
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