Synthesis of 1,8-naphthyridines from 2-aminonicotinaldehydes and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2016.03.070

A copper(II) triflate-catalyzed diethylamine-assisted protocol for the reaction of 2-aminonicotinaldehydes and terminal alkynes leading to 1,8-naphthyridines is described. The overall process presumably involves a copper(II) triflate-catalyzed hydroaminat

Full text of DOI:10.1016/j.tetlet.2016.03.070

Accepted Manuscript
Synthesis of 1,8-naphthyridines from 2-aminonicotinaldehydes and terminal al-
kynes
Binbin Li, Steven Nguyen, Jianjun Huang, Gaigai Wang, Huiping Wei, Olga P.
Pereshivko, Vsevolod A. Peshkov
PII:
S0040-4039(16)30292-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.070
TETL 47458
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 January 2016
18 March 2016
22 March 2016
Please cite this article as: Li, B., Nguyen, S., Huang, J., Wang, G., Wei, H., Pereshivko, O.P., Peshkov, V.A.,
Synthesis of 1,8-naphthyridines from 2-aminonicotinaldehydes and terminal alkynes, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.070
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Synthesis of 1,8-naphthyridines from 2-aminonicotinaldehydes and terminal
alkynes
Binbin Li, Steven Nguyen,# Jianjun Huang, Gaigai Wang, Huiping Wei, Olga P. Pereshivko,*
Vsevolod A. Peshkov*
College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Dushu Lake Campus, Suzhou, 215123, China
# S.N. is a visiting COOP student from University of Waterloo, Canada.
Email: olga@suda.edu.cn, vsevolod@suda.edu.cn
ABSTRACT. A copper (II) triflate-catalyzed diethylamine-assisted protocol for the reaction of 2-
aminonicotinaldehydes and terminal alkynes leading to 1,8-naphthyridines is described. The overall process
presumably involves a copper (II) triflate-catalyzed hydroamination of the triple bond followed by the
Friedländer-type condensation of the resulting enamine with 2-aminonicotinaldehyde.
Keywords: 1,8-naphthyridines, 2-aminonicotinaldehydes, alkynes, copper catalysis, hydroamination,
Friedländer synthesis
1,8-Naphthyridine is important heterocyclic motif that is present in a large number of biologically active
compounds.1 In addition, 1,8-naphthyridines and their dimer derivatives have been investigated for the
applications in host-guest and self-assembling systems2 and in organic light-emitting diodes.3
The Friedländer synthesis4 is a classical way to access quinolines 45 and 1,8-naphthyridines 56 through the
condensation of aromatic 2-aminoaldehydes 1 or 2 with aldehydes or ketones 3 containing a methylene
group in the alpha position to the carbonyl moiety (Scheme 1a). In 2010, Patil and Raut described a
complimentary copper (I) iodide/pyrrolidine-co-catalyzed reaction of 2-aminobenzaldehydes 1 with terminal
alkynes 6 leading to 2-substituted quinolines 8 (Scheme 1b).7,8 Following the success of their procedure, we
decided to evaluate the reactivity of 2-aminonicotinaldehydes 2 in the analogous process. As a result of
these efforts we were able to establish a novel route towards 3-substituted 1,8-naphthyridines 9 (Scheme 1c)
that features different regioselectivity compared to the parent Patil and Raut’s transformation. Herein we
wish to outline the scope and limitations of our procedure.

Scheme 1. Approaches to quinolines 4 and 8 and 1,8-naphthyridines 5 and 9
We have started our investigation with a search for the optimal reaction parameters employing 2-
aminonicotinaldehyde 2a and phenyl acetylene 6a as model substrates (Table 1). The first trial was
performed under the conditions adopted from the Patil and Raut’s report utilizing slight access of phenyl
acetylene 6a, 10 mol% of copper (I) iodide as a catalyst, 0.25 equivalents of pyrrolidine 7a as a secondary
amine additive and 3.3 mL of MeCN as a solvent. However, conducting this reaction at 100 °C for 14 hours
resulted in only 50% conversion of 2a producing only very small amounts of two isomeric 1,8-naphthyridines
9a and 10a (Table 1, entry 1). Increasing the reaction time to 26 hours or decreasing the amount of solvent
did not affect the reaction outcome (Table 1, entries 2 and 3). Switching to the use of diethylamine 7b as an
additive slightly affected the regioselectivity but the yields remained poor (Table 1, entry 4). At this point,
we decided to switch to the use of stoichiometric amounts of the amine additive. Simultaneously, we have
opted to pre-treat 2a, 6a and a copper catalyst prior to the addition of the secondary amine. Conducting the
reaction with 5 mol% of copper (I) iodide and 1.2 equivalents of diethylamine 7b in 1 mL of MeCN led to
almost complete conversion of 2a producing 3-substituted 1,8-naphthyridine 9a in 32% yield (Table 1, entry
5). At the same time the yield for the isomeric 2-substituted 1,8-naphthyridine 10a remained poor directing
the focus of our optimization efforts towards the 3-substituted isomer 9a. Next we have found that the
copper (I) bromide is a less efficient catalyst compared to copper (I) iodide (Table 1, entry 6) whilst copper (II)
triflate demonstrated superior performance furnishing 9a in 47% yield (Table 1, entry 7) thus making it a
catalyst of choice for further screening. An attempt to lower the amount of diethylamine 7b met with failure
leading to diminished yield of 9a (Table 1, entry 8). Omitting the pretreatment step resulted in lower yield of
9a and an incomplete conversion of 2a despite the prolonged reaction time of 17 hours (Table 1, entry 9).9
Employing copper (II) triflate in a combination with other secondary amine additives such as pyrrolidine 7a,
piperidine 7c or morpholine 7d significantly decreased the regioselectivity of the process (Table 1, entries

10-12). The use of other solvents such as dioxane or toluene also proved to be disadvantageous leading to
diminished yield of 9a and incomplete conversion of 2a (Table 1, entries 13 and 14). Finally, some
improvements were made by decreasing the amount of acetonitrile solvent (Table 1, entry 15) and
shortening the pretreatment time (Table 1, entry 16) that allowed to upgrade the NMR yield of 9a up to 57%,
which corresponds to the isolated yield of 55%. The use of copper (II) triflate catalyst in the absence of
diethylamine 7b additive or visa versa gave no 1,8-naphthyridines 9a and 10a (Table 1, entries 17 and 18)
despite the partial consumption of starting 2a that, thus, could be ascribed to decomposition.
Table 1. Optimization of the reaction parametersa
Entry
x
Catalyst (mol %)
Amine 7
Solvent
Temp, °Cb
time, h
Yields (%)c
9a
2a
50
30
44
48
6
25
tr
tr
9
tr
tr
tr
49
24
tr
4
51
86
10a
4
6
5
3
4
4
4
3
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
CuI (10 mol%)
CuI (10 mol%)
CuI (10 mol%)
CuI (10 mol%)
7a; 0.25 equiv
7a; 0.25 equiv
7a; 0.25 equiv
7b; 0.25 equiv
7b; 1.2 equivd
7b; 1.2 equivd
7b; 1.2 equivd
7b; 0.5 equivd
7b; 1.2 equiv
7a; 1.2 equivd
7c; 1.2 equivd
7d; 1.2 equivd
7b; 1.2 equivd
7b; 1.2 equivd
7b; 1.2 equivd
7b; 1.2 equivd
-
MeCN (3.3 mL)
MeCN (3.3 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
MeCN (1 mL)
dioxane (1 mL)
toluene (1 mL)
MeCN (0.5 mL)
MeCN (0.5 mL)
MeCN (1 mL)
MeCN (1 mL)
100
100
100
100
110
110
110
110
110
110
110
110
110
110
110
110
110
110
14
26
14
3
4
3
4
32
27
47
27
43
21
33
14
CuI (5 mol%)
3e+12
3e+12
3e+12
3e+12
17
CuBr (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OTf)2 (5 mol%)
-
9
4
16
14
10
11
12
13
14
15
16
17
18
3e+12
3e+12
3e+12
3e+12
3e+12
3e+12
1e+12
12
35 (31)f 26 (19)f
22
22
4
5
4
4
-
53
57 (55)f
-
-
7b; 1.2 equiv
12
-
a The reactions were run on 0.5 mmol scale. b This refers to the oil bath temperature. c Yields are determined by 1H NMR using 3,4,5-
trimethoxybenzaldehyde as internal standard. d Added after the indicated pretreatment time. e Pretreatment time. f Isolated yield is
given in parentheses.
Having these results in hand, we moved to the substrate scope evaluation (Table 2).10 First, we tested
several 2-aminonicotinaldehydes 2a-e in a combination with phenyl acetylene 6a. All reactions proceeded
with comparable efficiency delivering 1,8-naphthyridines 9a-e with good isolated yields ranging from 47% to
55% (Table 2, entries 1-5). However, the analogous reaction of 3-aminopyrazine-2-carbaldehyde 2f gave only
poor yield of pyrido[2,3-b]pyrazine 9f (Table 2, entry 6) restricting the scope of our procedure. Next, we
reacted various (hetero)aromatic acetylenes 6b-i in a combination with 2-aminonicotinaldehyde 2a. The
acetylenes 6b-g bearing neutral or electron withdrawing substituents on the aromatic ring all gave good
results furnishing 1,8-naphthyridines 9g-l in up to 62% yield (Table 2, entries 7-12). The 4-methoxyphenyl

acetylene 6h showed inferior reactivity producing 1,8-naphthyridine 9m in only 22% yield along with 9% of
isomeric 10m (Table 2, entry 11). The heteroaromatic 3-ethynylthiophene 6i reacted well allowing to isolate
1,8-naphthyridines 9n and 10n in 53% and 9% yields, respectively (Table 2, entry 12).
Table 2. Scope of the processa
Entry
1
2
6
Product
Yieldsb
10
9
a
b
55
4c
2d
6a
53
-
3e
4f
5f
6d
6a
6a
6a
6a
c
d
e
f
49
51
47
10
-
5
5
-
7
2a
2a
2a
2a
g
h
i
52
42
62
62
-
-
-
-
8d,g
9
10d
j
11
12
2a
2a
k
l
61
58
-
-
13
14
2a
2a
m
n
22
53
9
9
a
The reactions were run on 0.5 mmol scale (based on 2) using 1.5 equiv excess of 6 in 0.5 mL of MeCN for 1+12 hours unless
otherwise stated. b Isolated yields. c Determined by 1H NMR using 3,4,5-trimethoxybenzaldehyde as internal standard. d The reaction

was run in 0.8 mL of MeCN. e The reaction was run in 1 mL of MeCN. f The reaction was run on 0.75 mmol scale. g The reaction was
run for 1+20 hours.
The reaction of aliphatic 1-octyne 6j and 2-aminonicotinaldehyde 2a under the standard conditions
proceeded completely unselectively yielding monosubstituted 1,8-naphthyridines 9o and 10o in comparable
yields of 13% and 14%, respectively along with the trace amounts of disubstituted 1,8-naphthyridine 11
(Table 3, entry 1). Interestingly, changing the amine additive from diethylamine 7b to morpholine 7d
allowed to upgrade the selectivity at the same time diverging it towards 2-substituted 1,8-naphthyridine 10o
that in this case was obtained in 49% yield (Table3, entry 2).
Table 3. Reaction of 2-aminonicotinaldehyde 1a with octyne 2ja
Entry
7
Yieldsb
9o
13
10o
14
49
11
tr
1
2
7b
7d
10c
5c
a The reactions were run on 0.5 mmol scale (based on 2a) using 1.5 equiv excess of 6j in 0.5 mL of MeCN for 1+12 hours. b Isolated
yields. c For this entry 9m and 11 were obtained as a mixture. The individual yields are estimated based on 1H NMR.
A tentative mechanistic pathway for the formation of 3-substituted 1,8-naphthyridines 9 is depicted on Scheme 2. 11
The copper catalyst activates the alkyne 6 towards the nucleophilic attack by the amine 7b resulting in the enamine A
formation. Such copper-catalyzed alkyne hydroaminations are well known12,13 and typically are accompanied by the
addition of the second alkyne molecule to the generated enamine A yielding propargylamines as final products. In our
case, the enamine A chooses to react with 2-aminonicotinaldehyde 2a through the Friedländer-type sequence
that starts from the nucleophilic attack onto the carbonyl group of 2a and follows by the cyclization into the
aminal B. Finally, B converts into naphthyridine 9 with concomitant elimination of water and amine 7b.
Following the above considerations, it is reasonable to assume that the regioselectivity of the overall process arises
from the regioselectivity of the alkyne hydroamination step where the anti-Markovnikov pathway seems to be
predominant leading to the formation of 3-substituted 1,8-naphthyridine 9 as a major product. Thus, the minor
2-substituted 1,8-naphthyridine 10 should result from the following the Markovnikov pathway during the
hydroamination.

Scheme 2. Tentative mechanism
In conclusion, we have discovered and documented a novel copper (II) triflate-catalyzed reaction of 2-
aminonicotinaldehydes with terminal alkynes providing access to 1,8-naphthyridine core. The reaction
requires the presence of secondary amine and presumably involves a copper (II) triflate-catalyzed
hydroamination of alkyne followed by the Friedländer-type condensation of resulting enamine with 2-
aminonicotinaldehyde. The scope and limitation of the process have been briefly assessed resulting in a
generation of a mini library of 1,8-naphthyridines.
Acknowledgements
This work was supported by the start-up fund from Soochow University (grant Q410900714), Natural
Science Foundation of Jiangsu Province of China (grant BK20150317) and the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
Supplementary data
Full experimental procedures as well as copies of 1H and 13C NMR spectra of the compounds associated with
this article can be found, in the online version, at http://dx.doi.org/.
References and notes
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10 Representative procedure exemplified by the synthesis of 3-phenyl-1,8-naphthyridine (9a). 2-Aminonicotinaldehyde
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acetonitrile (0.5 ml) and phenyl acetylene 6a (77 mg, 0.75 mmol). The resulting mixture was flushed with argon,
submerged in the oil bath preheated at 110 °C and kept with a stirring for 1 hour. Upon completion of this time, the
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resulting mixture was diluted with EtOAc and evaporated with silica gel. Column chromatography with PE-EtOAc
(40ꢀ50 %) followed by washing with diethyl ether delivered pure 9a (57 mg, 55 %). 1H NMR (400 MHz, CDCl3): δ 9.38
(bs, 1H), 9.10 (bs, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.23 (dd, J = 8.1, 1.4 Hz, 1H), 7.76–7.64 (m, 2H), 7.58-7.47 (m, 3H), 7.47-
7.38 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 155.5, 153.4, 153.2, 137.3, 137.0, 135.0, 134.0, 129.4, 128.6, 127.5, 122.6;
HRMS (ESI, [M+H]+) for C14H10N2 calcd. 207.0917, found 207.0918.
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*Highlights
- 1,8-Naphthyridine core can be assembled from 2-aminonicotinaldehydes and terminal
alkynes.
- The developed procedure utilizes copper (II) triflate catalyst in the presence of
diethylamine.
- The developed procedure selectively yields 3-substituted 1,8-naphthyridines.