Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines

Article abstract of DOI:10.1016/j.tetlet.2018.09.068

A simple and convenient sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6] naphthyridines has been developed. The reductive amination of 2-chloro-3-formylquinolines with various amines in the presence of sodium borohydride provided the corresponding secondary amines in high yields. Further, a sequential one-pot reaction involving N-allylation and intramolecular Heck type 6-exo-trig cyclization was performed on the secondary amines to afford a range of desired 1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine derivatives in good to high yields.

Full text of DOI:10.1016/j.tetlet.2018.09.068

Accepted Manuscript
Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-
tetrahydrobenzo[b][1,6]naphthyridines
P. Bharath Kumar Reddy, K. Ravi, K. Mahesh, P. Leelavathi
PII:
S0040-4039(18)31181-X
https://doi.org/10.1016/j.tetlet.2018.09.068
TETL 50307
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
25 June 2018
21 September 2018
27 September 2018
Please cite this article as: Bharath Kumar Reddy, P., Ravi, K., Mahesh, K., Leelavathi, P., Intramolecular Heck
reaction: A facile sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines, Tetrahedron
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Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-
tetrahydro benzo[b][1,6]naphthyridines
P. Bharath Kumar Reddy, K. Ravi, K. Mahesh and P. Leelavathi*

1
Tetrahedron Letters
Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-
tetrahydrobenzo[b][1,6]naphthyridines
P. Bharath Kumar Reddy, K. Ravi, K. Mahesh and P. Leelavathi*
Department of Chemistry, Osmania University, Hyderabad 500 007, India. E-mail: leelaou@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and convenient sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6]
naphthyridines has been developed. The reductive amination of 2-chloro-3-
formylquinolines with various amines in the presence of sodium borohydride provided the
corresponding secondary amines in high yields. Further, a sequential one-pot reaction
involving N-allylation and intramolecular Heck type 6-exo-trig cyclization was performed
on the secondary amines to afford a range of desired 1,2,3,4-tetrahydrobenzo[b][1,6]-
naphthyridine derivatives in good to high yields.
Available online
Keywords:
Keyword_1 1,6-Naphthyridines
Keyword_2 2-Chloro-3-formylquinolines
Keyword_3 Reductive amination
Keyword_4 Heck reaction
2009 Elsevier Ltd. All rights reserved.
Keyword_5 Sequential one-pot synthesis
Among various naphthyridines, 1,6-naphthyridines and their
fused analogues are of interest as they showed exceptionally
broad spectrum of
[1,6]naphthyridines by annulation of 2-alkynyl-quinoline-3-
carboxaldehydes17a,b with aqueous ammonia and also from 2-
chloroquinoline-3-carbonitriles using elemental sulfur and
amines as nucleophiles.17c The interesting pharmacological
properties of 1,6-naphthyridines, stimulated us to make
considerable efforts towards their synthesis. Not many methods18
appear in the literature for the synthesis of fused naphthyridines
as their pharmacological properties demand. With this pretext,
we felt that it is still desirable to explore efficient methods for the
synthesis of fused naphthyridines.
biological activities1 includinganti-
inflammatory,2 anticancer,3 anti-HIV,4 anti-HSV5 antimicrobial,6
cytotoxic7 and adrenoceptor blocking8 activities. Additionally,
these are also reported as allosteric inhibitors9 of Akt1 and Akt2,
and antagonists of 5-HT4 receptors.10 Lophocladine-A and
Aaptamine are the naphthyridine alkaloids11,12 found to be d-
opioid receptor antagonist and cytotoxic respectively. The
synthetic bronchodilator drugs,13a such as Benafentrine,
Tolafentrine are developed based on benzo[b][1,6]naphthyridine
derivatives, which are phosphopdiesterase inhibitors. As shown
in the Fig. 1, the other interesting benzene fused 1,6-
naphthyridines (A and B) displayed anti-proliferative activity13b
in human tumor cells, C exhibited in vitro cytotoxicity against
colon adenocarcinoma, ovarian carcinoma cell lines13c and D
showed anti HSV-1 activity.5
We envisioned that benzo[b]naphthyridines (4) can be
synthesized by intramolecular Heck-type 6-exo-cyclization of
corresponding N-allyl amines (3). The precursors (2) could be
prepared from 2-chloro-3-formylquinolines (1) by reductive
amination (Scheme 1). One-pot sequential or one-pot synthesis19
are one of the most powerful synthetic strategies in the modern
era of organic chemistry for being step-economy and
environmentally benign. They avoid the tedious work-up
procedure and purification of the intermediate, which would save
time, energy, minimize waste and increase the efficiency. Herein,
we wish to report a sequential one-pot synthesis of 1,2,3,4-
tetrahydrobenzo[b][1,6]naphthyridines via N-allylation followed
by intramolecular Heck-type cyclization.
Fig. 1 Bioactive compounds with 1,6-naphthyridine skeleton.
A number of synthetic strategies14 have been reported for
synthesis of 1,6-naphthyridines, however, their benzo-analogues
are little explored. Recently, the groups of Verma15 and
Nagarajan16 have reported independently the synthesis of
benzo[b][1,6]naphthyridines from 2-alkynyl-quinoline-3-carbox-
aldehydes via silver-catalyzed multicomponent reactions and
copper(II)triflate-catalyzed heteroannulation, respectively. Singh
and co-workers17 described the synthesis of benzo[b]-
Scheme 1: Retrosynthetic analysis of tetrahydronaphthyridines

2
Table 1. Optimization of the reaction conditions for the synthesis of 4a.a
Initially, we attempted the synthesis of tetrahydronaphthyridines
(4a) in a step-wise manner as described in Scheme 2. The
compound
(2a)
easily
obtained
from
2-chloro-3-
formylquinoline20 (1a) via reductive amination21 with benzyl
amine. The compound 2a was treated with allylbromide/K2CO3 in
DMF at room temperature for 15 h and the desired N-allyl
product (3a) was obtained in 86% yield. The N-allyl derivative
(3a) is then subjected to intramolecular Heck reaction with 5
mol% Pd(OAc)2, tripenylphosphine (10 mol%) and potassium
carbonate (2 eq.) in DMF at 130oC under nitrogen atmosphere.
The reaction is found clean and afforded the desired product in
70% yield. Exclusively one isomer of (4a) formed via 6-exo-trig
cyclization, which was confirmed from the appearance of
Entry
Pd(OAc)2
mol%
Base
Solvent
Temp
(oC)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
5
5
5
5
5
2.5
5
5
5
K2CO3
K2CO3
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
PhCH3
Dioxane
THF
100
130
130
100
130
130
120
100
70
3
2
3
2
2
3
5
5
60
66
51
75
84
61
45
46
63
65
1
characteristic signals for exo-cyclic methylene protons in H-
9
10
10
10
NMR spectrum as a pair of doublets at δ 5.2 and 6.6 with J= 1.5
Hz. To our surprise, the other possible isomer (4a') has not been
observed via 7-endo-trig cyclization.
5
CH3CN
85
a
Reaction conditions: All reactions were carried out on a 0.25 mmol of 2-
chloro-quinoline-3-ylmethyl)-aryl amines (2a, 1 eq.), allyl bromide (1 eq.),
base (1.5 eq.), in solvent (2.5 mL). After 15 h, added Pd(OAc)2, PPh3 (10
mol%), and base (2 eq.). b Isolated yields after column chromatography.
CHO
H2N
Ph
N
Ph
Br
H
NaBH4, MeOH, rt
92%
K2CO3/ DMF
86%
N
Cl
N
2a
Cl
1a
Ph
Table 2. Sequential one-pot operation for synthesis of tetrahydro-
naphthyridines (4).a,b
N
N
Ph
Pd (OAc)2
N
Ph
PPh3, K2CO3, DMF
N
Cl
N
N
70%
3a
4a' (not obsereved)
4a
Scheme 2: Synthesis of tetrahydronaphthyridine (4a).
Encouraged by the result, we next explored the
possibility of sequential one-pot synthesis of the compound (4a),
as both reactions that is allylation and cyclization are being done
in a common solvent and base. Our next investigation is to
optimize the reaction conditions (Table 1) for sequential one-pot
reaction. A mixture of 2a, allyl bromide and potassium carbonate
in DMF is stirred at room temperature for 15 h (till TLC
indicated completion). Without isolation of 3a, we performed the
reaction with 5mol% Pd(OAc)2, PPh3(10 mol%) and K2CO3(2eq)
in DMF at 100oC for 3 h. This procedure afforded the desired
product in 60 % yield (entry 1). Increasing the reaction
temperature from 100 to 130oC resulted in marginal increase in
the yield of the product (entry 2). Changing the base K2CO3 to
Et3N decreased the efficiency of the reaction (entry 3). However,
the use of Cs2CO3 provided a better yield of the product in less
N
N
N
N
N
N
F
N
OMe
4a: 82%
4b: 75%
4c: 83%
Me
Me
N
N
F
N
Me
N
N
4e: 74%
4f: 76%
4d: 71%
N
N
N
N
Me
N
F
Me
N
OMe
N
Me
4i: 68%
4g: 81%
4h: 73%
MeO
MeO
N
N
N
F
F
N
N
Me
4l: 76%
4k: 70%
4j: 82%
OMe
Me
Me
N
N
N
N
N
o
N
time (entries 4 and 5), the best result achieved at 130 C and the
4o: 50%
4n: 70%
4m: 75%
desired product in 82% yield (entry 5). On decreasing the catalyst
loading to 2.5% of Pd(OAc)2, the yield decreased (entry 6).
Keeping the catalyst loading to 5 mol%, changing the solvent to
toluene, 1,4-dioxane, THF and acetonitrile afforded the product
only in moderate yields (entries 6-10). Therefore, we have
continued with the sequential one-pot procedure for synthesis a
variety of tetrahydronaphthyridine derivatives under optimized
reaction conditions.
OMe
Me
N
N
Me
N
Me
N
4q: 75%
4p: 78%
Reaction conditions: aAll reactions were carried out on a 0.5 mmol of 2-
chloro-quinoline-3-ylmethyl)-aryl amines (1 eq.), allyl bromide (1 eq.),
Cs2CO3 (1.5 eq.) in DMF (5 mL). After 15 h, added Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), and Cs2CO3 (2 eq.);
chromatography.
b
Isolated yields after column
Having optimized the reaction conditions, we next
focused our attention on the exploration of the substrate scope
with sequential one-pot procedure. The results are summarized in
Table 2. A variety of N-benzyl-quinoline-3-carbaldehydes (2a-e)
were subjected N-allylation followed by intramolecular Heck-type
reaction under optimized reaction conditions. The reaction proceeded
smoothly with 2a-e afforded the desired products (4a-q) in good
to high yields. Substitution on the quinoline ring and benzyl
amines has not played any important role on the outcome.
Compared to benzyl amines, aniline were found to be less
efficient. However, the efficiency increased with anilines having
electron releasing groups like methyl and methoxy groups.
Overall, all the reactions proceeded smoothly to afford the
corresponding1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines in
moderate to high yields.
To demonstrate the efficiency and practicality, further we
explored the generality and scope of this approach (Table 3), by
extending our investigation to other allyl bromides such as
cinnamyl bromide, crotyl bromide and 3,3-dimethylallyl
bromide. A variety of N-benzyl-quinoline-3-carbaldehydes with
cinnamyl bromide afforded corresponding 1,6-naphthyridines
(5a-d) in moderate yields under optimized reaction conditions.
Disappointingly, we could get only 22% yield of 5e with 3,3-
dimethylallyl bromide and formed a trace amount of the product
5f with crotyl bromide. However, by loading another 5 mol%
Pd(OAc)2 after 1 h, the desired product 5f afford in 38% yield.

3
Table 3. Sequential one-pot operation for synthesis of tetrahydro-
naphthyridines (5).a,b
Reaction conditions: aAll reactions were carried out on a 0.5 mmol of 2-
chloro-quinoline-3-ylmethyl)aryl amines (1 eq.), corresponding allylbromides
(1 eq.), Cs2CO3 (1.5 eq.) in DMF (5 mL). After 15 h, added Pd(OAc)2 (5
Scheme 4: Plausible mechanism
b
Conclusions
mol%), PPh3(10 mol%), and Cs2CO3 (2 eq.); Isolated yields after column
chromatography. c After 1 h added further 5 mol% of Pd(OAc)2.
In summary, we have successfully developed a sequential one-
pot approach for the synthesis of benzo[b][1,6]naphthyridine
derivatives from the 2-chloro-3-formyl quinolines via reductive
amination followed by N-allylation and intramolecular Heck-type
cyclization. The developed methodology is operationally simple,
step-economical and efficient for synthesis of 1,6-naphthyridine
derivatives. The generality and ready availability of the starting
materials should make this an attractive method for the synthesis
of biologically important benzo-naphthyridine motifs.
With a view to understand the generality, we next explored
reaction of 2a with acryloyl chloride for the synthesis of
benzo[b][1,6]naphthyrid-3-one (6). Unfortunately, desired
product (6) did not formed under the standard reaction
conditions (Scheme 3). Further, we have also tried to get (6)
in step-wise manner, but we could not succeed in getting the
amide itself. We also extended the reaction to methallyl
bromide to get the corresponding cyclised product (7) via 7-
endo-trig cyclisation, but at the end of the sequential one pot
reaction we could recover only the corresponding N-
allylated product.
Acknowledgments
We thank UPE-FAR and OUDST-PURSE program for the
financial assistance. PBKR thanks CSIR, New Delhi and KR and
KM thank UGC, New Delhi for their fellowship. We also thank
Department of Chemistry, OU for laboratory infrastructure under
SAP (DRS-I) and DST-FIST programmes.
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5
Highlights
Sequential one-pot approach for synthesis
of benzo[b][1,6]naphthyridines is developed.
A variety of naphthyridines have been
accessed via N-allylation and Heck-type
cyclization.
This method is a simple, straightforward
and broad substrate scope compatibility.