A mild synthesis of substituted 1,8-naphthyridines

Article abstract of DOI:10.1039/c9gc00408d

A greener method for the synthesis of substituted 1,8-naphthyridines has been developed, which is supported by reaction metric analysis. Using 2-aminonicotinaldehyde as a starting material with a variety of carbonyl reaction partners, the Friedl?nder reac

Full text of DOI:10.1039/c9gc00408d

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DOI: 10.1039/C9GC00408D
Green Chemistry
PAPER
A Mild Synthesis of Substituted 1,8-Naphthyridines
a
b
a
Edward C. Anderson, Helen F. Sneddon, and Christopher J. Hayes*
Received 00th January 20xx,
Accepted 00th January 20xx
A greener method for the synthesis of substituted 1,8-naphthyridines has been developed, which is supported by reaction
metric analysis. Using 2-aminonicotinaldehyde as a starting material with a variety of carbonyl reaction partners, the
Friedländer reaction can be performed with high yield using water as the reaction solvent. Divergent reactivity was seen
when using acrolein, and an alternative method was developed to give access to 2-vinyl-1,8-naphthyridine in high yield, and
an assessment of addition reactions to 2-vinyl-1,8-naphthyridine was performed.
DOI: 10.1039/x0xx00000x
www.rsc.org/greenchem
functional groups that allow for the second pyridine to be
constructed via a Friedländer reaction with a suitable enolisable
Introduction
carbonyl (Scheme 1).3 From a green chemistry perspective,
2-aminonicotinaldehyde (11) is attractive as it can be synthesised
directly from the natural product nicotinamide (vitamin B3) (10).20
1
Since Koller’s first report in 1927, 1,8-naphthyridines (1, Chart 1)
2
–5
have emerged as important heterocycles, and interest in them has
grown rapidly. This recent growth of activity in 1,8-naphthyridine
6
chemistry is due to their presence in a wide variety of functional
molecules, with the first phase being stimulated by the discovery of
novel antibacterial agents (e.g. gemifloxacin 2).7–9 Partially reduced
O
N
O
1
,8-naphthyridines also occur in a number of natural products (e.g.
F
OH
eucophylline 3)10 and in drug candidates ( e.g. 4),11 where they can
act as arginine mimics. In addition to being a key structural element
of biologically active molecules, 1,8-naphthyridines find use as
ligands,12,13 as molecular sensors (e.g. 5), as molecular tweezers,15
self-assembly/host-guest systems,16 and in optoelectronic devices
such as dye-sensitized solar cells17 and light-emitting diodes.18 The
wide utility of 1,8-naphthyridine derivatives has led to a number of
key synthetic methods being developed for their preparation, with
focus now being placed on cleaner, more sustainable routes. A
recent review on quinolone synthesis highlighted opportunities to
N
N
N
O
N
N
1
2
NH2
14
1,8-naphthyridine
Gemifloxacin
HO
N
N
N
H
N
N
3
4
OH
Eucophylline
  antagonist
v
6
O
improve heterocycle synthesis (from
a
green chemistry
N
N
1
9
perspective ) by adopting alternative solvents (e.g. water), catalytic
transformations and less energy intensive processing, and stimulated
by this report, we now present our own work in this area that has
resulted in an improved (greener) synthesis of 1,8-naphthyridine
derivatives.
N
N
H
H
O
N
N
O
H
H
H
O
O
H
O
RO
At the inception of our studies, we chose 2-aminonicotinaldehyde
5
monosaccharide sensor
(11) as a key synthetic intermediate as it provides one of the required
pyridine rings, and it also incorporates adjacent amine and aldehyde
Chart 1. Examples of fully aromatic and partially reduced 1,8-naphthyridines.
aCentre for Sustainable Chemistry, School of Chemistry, University of Nottingham,
Nottingham, NG7 2RD, UK
Due to the commercial importance of the vitamin B3 complex,
numerous methods have been developed for its production using
E-mail: chris.hayes@nottingham.ac.uk
b
GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts. SG1 2NY,
2
1,22
and catalytic ammoxidation of 3-picoline.23–
biotransformations
UK.
E-mail: helen.f.sneddon@gsk.com
25
These routes use non-petrochemical feedstocks (e.g. glycerol,26
†Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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Green Chem., 2017, 00, 1-3 | 1
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PAPER
Green Chemistry
acrolein,27 tetrahydrofurfuryl alcohol (THFA)28,29) and they offer molecular weight alternative to proline, and this deVlieivweArretidclemOnulicnhe
sustainable access to 2-aminonicotinaldehyde (11) (Scheme 1).
shortened reaction times (10 mins to 1 h)DOanI:d10p.1r0o3v9id/Ce9dGeCx0c0e4l0le8nDt
yields at 100 mol% loading, with either ethanol or water as the
solvent (Table 1 entries 5-6). Furthermore, the reaction proceeded
well without heating using lithium hydroxide monohydrate in water,
and the reaction was high yielding at room temperature in only 45
mins. (Table 1 entry 7). Further to this, we found that the catalyst
loading could be lowered to 10 mol% when using lithium hydroxide
monohydrate, and the number of equivalents of acetone could also
be reduced (1.05 equiv.), without affecting yield (Table 1 entry 9). An
increase in concentration to 1 M afforded comparable yield and
more expedient reaction time (Table 1 entry 10). Sodium hydroxide,
potassium hydroxide, and pyrrolidine all perform in a comparable
manner at 10 mol% using water as solvent (Table 1 entries 11-13).
non-petrochemical feedstocks
OH
HO
OH
catalytic ammoxidation
O
6
NH2
glycerol
N
N
OH
O
9
10
nicotinamide
O
3
-picoline
7
8
THFA
acrolein
This Work - greener Friëdlander
O
R2
R2
R1
catalyst
These optimised reaction conditions represent
a
distinct
improvement over the original (Table 1 entry 1), and have delivered
shortened reaction time, lower reaction temperature, lower catalyst
loading, more efficient ketone usage in a benign reaction solvent.
N
N
R1
low temp.
N
NH2
O
green solvent
1
1
Scheme 1. Synthesis of 1,8-naphthyridines from non-petrochemical feedstocks.
Table 1. Optimisation of the synthesis of 2-methyl-1,8-naphthyridine (13).
O
Results and discussion
O
conditions
An initial inspection of the literature highlighted three methods for
N
NH2
N
N
1
1
12
13
the synthesis of 2-methyl-1,8-naphthyridine 13 as starting points for
reaction
development.12,30,31
All
three
methods
used
Entry
Eq.
Catalyst (mol%)
(S)-proline (110)
(S)-proline (110)
(S)-proline (110)
(S)-proline (110)
Solventa
T
t
Yield
(%)
86
2
-aminonicotinaldehyde (11) and acetone as starting materials, with
Me
3
2
CO
variation being seen in the choice of solvent and base/catalyst. Bera
1
2
3
4
5
6
7
8
9
EtOH
(0.3 M)
Reflux
Reflux
80 °C
Reflux
Reflux
80 °C
rt
19 h
21 h
19 h
19 h
1 h
et al. used methanol and KOH at reflux,12 Campbell et al. used
ethanol and proline at reflux,30 and Matveeva et al. used piperidine
22.7
3
Me
2
CO
63
60
93
96
95
96
96
97
(0.6 M)
in acetone at 100 °C in a sealed tube.31 A reaction metric analysis
was performed on these methods for later comparison (vide infra,
Table 2), and our studies began by repeating Campbell’s conditions
using (S)-proline as catalyst as a benchmark (Table 1 entry 1). Thus,
treating 11 with an excess of acetone (3 equiv.) and super-
H O
2
(0.5 M)
EtOH
1.2
1.2
1.2
1.2
1.2
1.05
(
0.5 M)
EtOH
0.5 M)
LiOH•H
LiOH•H
LiOH•H
LiOH•H
LiOH•H
LiOH•H
2
2
2
2
2
2
O (100)
O (100)
O (100)
O (10)
(
stoichiometric proline (110 mol%) in refluxing ethanol gave the
desired product 13 in good yield.30 Whilst these reaction conditions
H
2
O
10 min
45 min
1 h
(0.5 M)
H O
2
contain some attractive features (i.e. use of proline as catalyst and
use of ethanol as solvent), the process does require an excess of both
the catalyst and starting ketone, along with heating at reflux for an
extended period (19 h) to reach completion. In an attempt to reduce
reaction time (and temperature), we next performed the reaction
using acetone as the solvent (Table 1 entry 2), but unfortunately, an
extended reaction time was still required and the overall yield was
reduced. In an effort to use a more benign solvent, water was used
instead of acetone and this gave a similar outcome (Table 1 entry 3),
with the reaction failing to reach full conversion (by TLC). Returning
to ethanol as the solvent, we sought to reduce the amount of
acetone used in the reaction, and found that the reaction performed
extremely well with only 1.2 equivalents of acetone (Table 1 entry 4).
Attempts to lower the loading of (S)-proline to 10 mol%, resulted in
very poor conversion, and we next explored alternative catalysts. We
first investigated the use of lithium hydroxide monohydrate as a low
(
0.5 M)
EtOH
0.5 M)
rt
(
O (10)
H
2
O
rt
5 h
(0.5 M)
1
1
0
1
1.05
1.05
O (10)
H
2
O
rt
rt
2 h
5 h
98
92
(1 M)
NaOH (10)
2
H O
(0.5 M)
12
1.05
1.05
1.05
KOH (10)
H O
2
rt
rt
rt
5 h
99
94
0
(0.5 M)
1
1
3
4
Pyrrolidine (10)
(S)-proline (10)
H
2
O
1.75 h
24 h
(0.5 M)
2
H O
(0.5 M)
aConcentrations quoted with respect to 11.
2
| Green Chem., 2017, 00, 1-3
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Green Chemistry
PAPER
In order to objectively assess the improvements made (from a green solvent, and both toxic and innocuous solvents are trVeieawteArdticelexOancltinlye
chemistry perspective), we performed a reaction metric analysis on the same. To illustrate this point, entry 4, wDhOiIc:h10u.1s0e3s9o/Cu9rGpCr0e0fe4r0r8eDd
our optimised method for comparison to the three previously reaction concentration of 0.5 M shows a significantly worse PMI
published routes12,30,31 to 13 (Table 2). As all four syntheses of 13 use value (i.e. 16) due to the extra use of water as solvent. In contrast,
the same starting materials (i.e. 11 and 12) the atom economy is the EMY does not show this same trend, and entries 4 and 5 (Table 2)
same (80%) for all methods, and hence this metric is not well suited give very similar (good) values, which reflects the fact that water
to highlighting improvements in the reaction methodology. (despite known problems when considering, for example, product
However, if the catalyst is included in the calculations, then our isolation, and disposal of contaminated waste water) is classed as a
method compares favourably, as lithium hydroxide has a lower benign solvent, and its use should be encouraged. Entry 3 (Table 2)
molecular weight than the other catalysts used in the previous gives the worse EMY value due to the fact that stoichiometric
work.32
amounts of piperidine (non-benign) are used. Both EcoScale and
GREEN MOTIONTM score our new method well.
In order to address the limitations associated with atom economy,
we selected Process Mass Intensity (PMI),33 effective mass yield
(
EMY),34 and also the two less commonly-used metrics: EcoScale,35 Table 3. Synthesis of substituted 1,8-naphthyridines.
and GREEN MOTIONTM (Table 2).36 These latter two metrics are
penalty point systems, where 100 is the ideal value, and points are
subtracted for every penalty (e.g. safety concerns, high energy costs,
origin & cost of starting materials/reagents, poor reaction efficiency).
Whilst such metrics introduce an element of subjectivity, they do
give a good indication of the criteria that should be discussed when
designing reactions in a more green and sustainable manner. When
designing a “green & sustainable reaction”, there is a risk that
applying one metric in isolation can lead to a single reaction
parameter being over emphasised, which can result in oversight of
other important features such as whether the starting materials and
reagents are available from renewable sources; whether the
reagents are benign to the user and environment; or whether large
amounts of energy (e.g. for prolonged heating) are required in the
reaction process.
O
R2
R1
catalyst,
O
R2
N
NH2
R1
solvent, rt
N
N
1
1
1
4a-f
15a-i
(
1.05 eq.)
Entry
1
Active
methylene
Product
Base
Solventa
Yield
(%)
69
O
O
O
O
O
LiOH•H
O
O
2
H O
2
2
(0.5 M)
1
4a
N
N
1
5a
2
O
O
LiOH•H
H
2
O
70
t
OtBu
(0.5 M)
O Bu
14b
N
N
N
1
5b
3
4
LiOH•H
LiOH•H
2
2
O
O
H
2
O
96
83
(0.5 M)
Ph
N
Ph
Ph
1
4c
1
5c
Table 2. Metric analysis of 2-methyl-1,8-naphthyridine (13) synthesis.
O
2
H O
PMIa
b
Ph
(0.5 M)
Entry
Method
EMY (%)
EcoScale
GREEN
MOTIONTM
N
N
1
4d
KOH/MeOH13
(S)-Proline/EtOH30
15d
1
2
3
8
10
6
106 (73)
117 (79)c
54 (43)
56
61
66
58
79
68
5
O
Cl
LiOH•H
LiOH•H
2
2
O
O
H
2
O
18
Cl
(0.5 M)
Piperidine/sealed
tube31
N
N
N
N
N
N
1
4e
1
5e
4
LiOH/H
This work)
LiOH/H O (1 M)
This work)
PMI values calculated using the reaction step only; Acetone is used both as a solvent
2
O (0.5 M)
16
111 (75)
84
82
(
6
7
8
9
O
H
2
O
40
86
79
41
5
2
8
112 (75)
85
84
(0.5 M)
N
(
1
4f
4f
4f
a
b
15f
and a reagent in some examples, so the values in parentheses are EMY values that take
into account the acetone consumed in the reaction, and give a better reflection of the
EMY of the process when ‘non-benign’ ketones are used as reagents. The unedited EMY
calculations can be found in the supporting information; (S)-Proline was assumed benign
due to lack of hazardous SDS information.
O
OMe KOH
OEt KOH
OiPr KOH
MeOH
(0.25 M)
N
1
1
5g
c
O
EtOH
(0.25 M)
N
1
1
5h
O
iPrOH
(0.125 M)
Upon comparing the four processes that are run at similar
concentrations (0.8 M (entry 1), 0.76 M (entry 2), 1.5 M, (entry 3)
N
14f
1
5i
1
.0 M (entry 5), Table 2), the PMI values fall in a narrow range (6-10),
aConcentrations quoted with respect to 11.
which reflects the fact that solvent use is a dominant factor in this
metric. However, PMI doesn’t take into account the nature of the
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PAPER
Green Chemistry
Having developed excellent reaction conditions for the synthesis of In keeping with our goal to develop greener syntheVtiiecwrAorutictleesO,nwlinee
DOI: 10.1039/C9GC00408 3D 8
1
3, we explored the synthesis of a wider range of substituted performed a solvent screen to find an alternative to acetonitrile.
1
,8-naphthyridines (Table 3). Pleasingly, 1,3-dicarbonyls (Table 3 Initial experiments with ethanol as the solvent showed that
entries 1 and 2), aldehydes (entry 4) and a variety of ketones (entries conjugate addition to the electrophilic vinyl group of 15f was an
, 5-6) all provided the desired 1,8-naphthyridine product in modest issue, thus reducing the yield of desired product. A range of
3
to excellent yield. The use of -chloroacetone (entry 5) gave the alternative solvents was screened (Table 4), and we were pleased to
lowest yield, and although the reason for this is yet to be established, find that dimethylcarbonate was a more sustainable alternative to
a number of competitive decomposition pathways for the chloro acetonitrile, giving a comparable yield (74% vs 79%) (Table 4 entry
ketone can be imagined under the basic aqueous conditions. As an 8). This two-step route to 15f from 11, via 13 gives a significantly
extension to this study, we found that by reacting 11 and acrolein higher overall yield (>70%) than the 1 step alternative (Table 3 entry
(
14f) in simple alcohol solvents using KOH as base, a range of 6), and it avoids the divergent reactivity of acrolein described
disubstituted 1,8-naphthyridines 15g-i were obtained (Table 3 previously.
entries 7-9). The regioselective formation of 15g-i can be rationalised
Having developed a reliable route to 2-vinyl-1,8-naphthyridine
15f),39 we next performed a preliminary assessment of addition
reactions to the vinyl moiety, analogous to the recently published
study of additions to 2-vinylpyridine.40 In Williams’ work, a
by invoking conjugate addition of the alcohol to 14f, resulting in a
regiospecific enol/enolate. After addition of this to the carbonyl of
(
1
1, subsequent condensation of the amine and resulting ketone, and
elimination, the naphthyridines 15g-i are afforded. It should be
noted that when lithium hydroxide monohydrate was used as base
under these alcoholic conditions, inseparable mixtures of the mono-
and disubstituted 1,8-naphthyridine regioisomers were afforded.
substoichiometric amount of the Lewis acid Zn(NO
elevated temperatures were required to facilitate addition to
-vinylpyridine, but in our investigation (and with the exception of
diethylamine (Table entry 3)), we found that 2-vinyl-
3 2 2
) •6H O and
2
5
Given the divergent reactivity displayed during the reactions of 11 1,8-naphthyridine (15f) was a more reactive electrophile, generally
with acrolein 14f, we were keen to explore a complimentary route to needing no Lewis acid activation, nor elevated temperatures for
2
-vinyl-1,8-naphthyridine 15f as we could see the potential synthetic addition to occur.
utility of this previously unknown heterocycle, and developing a high
yielding (green) synthetic route is desirable. Having established a
new, near quantitative yielding route to 2-methyl-1,8-naphthyridine
Table 5. Preliminary addition reactions of 2-vinyl-1,8-naphthyridine (15f).
1
3 (Table 1 entry 9) we decided to explore the transformation of 13
into 15f by adapting conditions reported by Feng and co-workers for
the synthesis of 2-vinylquinolines from 2-methylquinolines.37 Thus,
condensation of 13 with paraformaldehyde under microwave
irradiation using diethylamine hydrochloride (20 mol%) as catalyst in
acetonitrile, gave the desired product 15f in good yield (79%, Table 4
entry 1).
MeCN (1 M), rt
+
Nucleophile (1 eq.)
6a-e
N
N
N
N
Nuc
1
15f
17a-e
Entry
1
Nucleophile
Time
2.5 h
Product
Yield (%)a
99
NH
N
N
N
1
6a
1
7a
7b
Table 4. Solvent screen for 2-vinyl-1,8-naphthyridine (15f) synthesis.
2
4 h
95
O
NH
EtNH HCl (20 mol%),
N
N
N
2
1
6b
O
paraformaldehyde (1.3 eq.),
solvent (0.5 M),
1
1
20 °C wave, 1 h
3b
4
22 h
87
NH
N
N
N
N
N
N
N
N
NEt2
SPh
1
6c
1
3
15f
1
7c
SH
10 min
26.5 h
87
Entry
Solvent
MeCN
DMSO
Heptane
Anisole
Methyl isobutyl ketone
Octyl acetate
Yield (%)
1
2
3
4
5
6
7
8
79
0
8
23
32
33
52
74
1
6d
17d
5
H
99 (4:1 dr)
H
N
N
Furfural
Dimethyl carbonate
16e
1
7e
a
b
3 2 2
Isolated yield; Zn(NO ) •6H O (2.5 mol%) added
4
| Green Chem., 2017, 00, 1-3
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Green Chemistry
PAPER
tert-Butyl 2-methyl-1,8-naphthyridine-3-carboxylate (15b)
Experimental
View Article Online
DOI: 10.1039/C9GC00408D
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg, 1.00
mmol) and LiOH•H O (4.20 mg, 100 μmol) in H O (2 mL) was added
tert-butyl acetoacetate (174 μL, 166 mg, 1.05 mmol) and the reaction
All reagents and solvents were obtained from commercial suppliers,
and were used without further purification unless otherwise stated.
All reactions were carried out using conventional glassware, or
Reacti-Vials™, at ambient temperature under an air atmosphere, and
with no special attention given to the exclusion of moisture, unless
otherwise stated. Thin layer chromatography was carried out using
Merck TLC silica gel 60 F254 aluminium sheets. These were analysed
under 254 nm UV light or developed using potassium permanganate
solution. Column chromatography was carried out using Fluorochem
Silicagel 60A 40-63μ. Fourier-transformed infrared (FTIR) spectra
2
2
mixture allowed to stir at ambient temperature for 23 h. The reaction
mixture was diluted with sat. aq. Na
EtOAc (3 x 10 mL). The combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with
4
SO )
2
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, EtOAc) to give 15b as a pale
-1
orange crystalline solid (157 mg, 70%). vmax/cm 3048, 2923, 2937,
1
1
721, 1609, 1554; H NMR (400 MHz, CDCl
3
) δ 9.12 (dd, J = 4.3, 2.0
Hz, 1H), 8.63 (s, 1H), 8.22 (dd, J = 8.1, 2.0 Hz, 1H), 7.47 (dd, J = 8.1,
4.3 Hz, 1H), 3.02 (s, 3H), 1.64 (s, 9H); 13C NMR (100 MHz, CDCl
) δ
65.4 (C), 162.2 (C), 156.1 (C), 155.2 (CH), 140.3 (CH), 137.5 (CH),
27.0 (C), 122.1 (CH), 120.3 (C), 82.7 (C), 28.3 (CH ), 26.2 (CH ); m/z
requires 245.1285).
were obtained using a Bruker ALPHA FTIR spectrometer with a single
reflection attenuated total reflectance (ATR) module. 1H and 13C
NMR spectra were obtained on a Bruker AV 400 at 400 MHz and 100
3
1
1
3
3
MHz respectively. Chemical shifts are reported in ppm, and coupling
+
+
1
17 2 2
(ESI) 245.1283 (M + H C14H N O
constants are reported in Hz, with CDCl
3
referenced at 7.2600 ( H)
1
3
and 77.160 ( C). High resolution mass spectra were obtained using
a Bruker MicroTOF machine using electrospray ionisation.
2
-Phenyl-1,8-naphthyridine (15c)
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg, 1.00
mmol) and LiOH•H O (4.20 mg, 100 μmol) in H O (2 mL) was added
2
-Methyl-1,8-naphthyridine (13)
2
2
acetophenone (122 μL, 126 mg, 1.05 mmol) and the reaction mixture
allowed to stir at ambient temperature for 20.5 h. The reaction
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg, 1.00
mmol) and LiOH•H O (4.20 mg, 100 μmol) in H O (1 mL) was added
acetone (77.1 μL, 61.0 mg, 1.05 mmol) and the reaction mixture
2
2
mixture was diluted with sat. aq. Na
EtOAc (3 x 10 mL). The combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with
4
SO )
2
allowed to stir at ambient temperature for 2 h. The reaction mixture
and concentrated under reduced pressure. The residue was purified
was diluted with sat. aq. Na
x 10 mL). The combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with EtOAc (3
SO ) and
by column chromatography (silica gel, EtOAc) to give 15c as a
2
4
4
2
colourless solid (197 mg, 96%). mp 114-115 °C (lit., 115-116
°C),vmax/cm-1 3045, 3003, 1602, 1537, 1483; H NMR (400 MHz,
concentrated under reduced pressure to give 13 as a cream solid
1
141 mg, 98%). mp 99-100 °C (lit.,41 99-100 °C), vmax/cm 3043, 2998,
-1
(
1
CDCl
.5 Hz, 1H), 8.16 (dd, J = 8.1, 2.0 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.54-
7.46 (m, 3H), 7.44 (dd, J = 8.1, 4.3 Hz, 1H); 13
C NMR (100 MHz, CDCl
δ 160.3 (C), 156.2 (C), 153.9 (CH), 138.6 (C), 137.8 (CH), 136.8 (CH),
30.2 (CH), 128.9 (CH), 128.0 (CH), 121.8 (CH), 121.8 (C), 119.8 (CH);
3
) δ 9.11 (dd, J = 4.3, 2.0 Hz, 1H), 8.33-8.28 (m, 2H), 8.21 (d, J =
1
3
601, 1544, 1496; H NMR (400 MHz, CDCl ) δ 8.99 (dd, J = 4.3, 2.0
8
Hz, 1H), 8.06 (dd, J = 8.1, 2.0 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.35 (dd,
J = 8.1, 4.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 2.74 (s, 3H); 13C NMR (100
3
)
MHz, CDCl
3
) δ 163.0 (C), 155.9 (C), 153.3 (CH), 136.8 (CH), 136.6 (CH),
1
1
H+ C
23.0 (CH), 121.3 (CH), 120.7 (C), 25.7 (CH ); m/z (ESI) 145.0762 (M +
3
+
+
+
m/z (ESI) 207.0917 (M + H C14
11 2
H N requires 207.0917).
9 9 2
H N requires 145.0760).
3
-Phenyl-1,8-naphthyridine (15d)
1
-(2-Methyl-1,8-naphthyridin-3-yl)ethan-1-one (15a)
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg,
.00 mmol) and LiOH•H O (4.20 mg, 100 μmol) in H O (2 mL) was
added phenylacetaldehyde (122 μL, 126 mg, 1.05 mmol) and the
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg, 1.00
mmol) and LiOH•H O ( 4.20 mg, 100 μmol) in H O (2 mL) was added
acetylacetone (108 μL, 105 mg, 1.05 mmol) and the reaction mixture
1
2
2
2
2
reaction mixture allowed to stir at ambient temperature for 26 h. The
allowed to stir at ambient temperature for 1.5 h. The reaction
reaction mixture was diluted with sat. aq. Na
extracted with a mixture of EtOAc (10 mL) and CHCl
2
CO
3
(10 mL) and
(20 mL), then
mixture was diluted with sat. aq. Na
EtOAc (3 x 10 mL). The combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with
4
SO )
3
2
further extracted with CHCl
phases were dried (Na SO
3
(2 x 10 mL). The combined organic
4
) and concentrated under reduced
and concentrated under reduced pressure. The residue was purified
2
by column chromatography (silica gel, EtOAc) to give 15a as a
3
pressure. The residue was purified by column chromatography (silica
gel, EtOAc) to give 15d as a colourless solid (172 mg, 83%). mp 125-
colourless solid (129 mg, 69%). mp 144-145 °C (lit., 146-147 °C),
-
1
1
v
(
max/cm 3246, 3033, 2999, 2947, 1680, 1608, 1599, 1552; H NMR
400 MHz, CDCl ) δ 9.13 (dd, J = 4.3, 2.0 Hz, 1H), 8.46 (s, 1H), 8.22 (dd,
J = 8.1, 2.0 Hz, 1H), 7.49 (dd, J = 8.1, 4.3 Hz, 1H), 2.94 (s, 3H), 2.70 (s,
H); 13C NMR (100 MHz, CDCl
) δ 199.4 (C), 161.7 (C), 156.0 (C), 155.5
CH), 138.8 (CH), 137.5 (CH), 132.3 (C), 122.4 (CH), 120.1 (C), 29.6
3
-1
1
1
27 °C (lit., 126-127 °C),vmax/cm 3046, 3001, 1595, 1561, 1478; H
NMR (400 MHz, CDCl ) δ 9.38 (d, J = 2.6 Hz, 1H), 9.11 (dd, J = 4.2, 2.0
Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 8.23 (dd, J = 8.1, 2.0 Hz, 1H), 7.72-
.68 (m, 2H), 7.55-7.48 (m, 3H), 7.47-7.41 (m, 1H); 13C NMR (100
3
3
3
3
7
(
(
+
+
MHz, CDCl
3
) δ 155.6 (C), 153.5 (CH), 153.2 (CH), 137.3 (CH), 137.1 (C),
CH
3 3 11 2
), 26.0 (CH ); m/z (ESI) 187.0865 (M + H C11H N O requires
1
87.0866).
This journal is © The Royal Society of Chemistry 20xx
Green Chem., 2017, 00, 1-3 | 5
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Page 6 of 8
PAPER
Green Chemistry
1
35.0 (C), 134.0 (CH), 129.4 (CH), 128.6 (CH), 127.6 (CH), 122.6 (CH); allowed to stir at ambient temperature for 2.5 h.ViTewheArtriceleaOctniloinne
+
+
DOI: 10.1039/C9GC00408D
m/z (ESI) 207.0918 (M + H C14
11
H N
2
requires 207.0917).
mixture was concentrated under reduced pressure. The residue was
diluted with sat. aq. Na CO (10 mL) and extracted with EtOAc (3 x 10
mL). The combined organic phases were dried (Na SO ) and
2
3
3
-Chloro-2-methyl-1,8-naphthyridine (15e)
2
4
concentrated under reduced pressure. The crude product was
purified by column chromatography (silica gel, EtOAc/EtOH (4:1)) to
give 15g as a yellow solid (162 mg, 86%). vmax/cm 3031, 2981, 2925,
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg,
.00 mmol) and LiOH•H O (4.20 mg, 100 μmol) in H O (2 mL) was
added chloroacetone (83.6 μL, 97.1 mg, 1.05 mmol), and the reaction
1
2
2
-1
1
2
8
4
866, 2826; H NMR (400 MHz, CDCl
3
) δ 9.00 (dd, J = 4.3, 2.0 Hz, 1H),
mixture allowed to stir at ambient temperature for 20.5 h. The
.10 (dd, J = 8.0, 2.0 Hz, 1H), 8.06 (d, J = 1.1 Hz, 1H), 7.38 (dd, J = 8.0,
.3 Hz, 1H), 4.58 (d, J = 1.1 Hz, 2H), 3.48 (s, 3H), 2.72 (s, 3H); 13C NMR
reaction mixture was diluted with sat. aq. Na
aqueous phase extracted with EtOAc (3 x 10 mL). The combined
organic phases were dried (Na SO ) and concentrated under reduced
2 3
CO (10 mL), and the
(
(
(
100 MHz, CDCl
CH), 131.5 (C), 121.6 (CH), 121.2 (C), 71.7 (CH
3
) δ 161.4 (C), 155.4 (C), 153.1 (CH), 136.6 (CH), 134.9
), 58.8 (CH ), 23.0
3 13 2
CH ); m/z (ESI) 189.1026 (M + H C11H N O requires 189.1022).
2
4
2
3
pressure to give a brown oil. The residue was purified by column
+
+
chromatography (silica gel, EtOAc) to give 15e (32.2 mg, 18%) as a
-1
1
tan-coloured solid. vmax/cm 3036, 2988, 2922, 1595, 1544; H NMR
400 MHz, CDCl ) δ 9.06 (dd, J = 4.2, 2.0 Hz, 1H), 8.12 (s, 1H), 8.09 (dd,
J = 8.2, 2.0 Hz, 1H), 7.46 (dd, J = 8.2, 4.2 Hz, 1H), 2.87 (s, 3H); 13C NMR To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg,
3
-(Ethoxymethyl)-2-methyl-1,8-naphthyridine (15h)
(
3
(
(
(
100 MHz, CDCl
3
) δ 160.8 (C), 154.2 (C), 153.6 (CH), 135.9 (CH), 135.4 1.00 mmol) and KOH (112 mg, 2.00 mmol) in EtOH (4 mL) was added
CH), 130.0 (C), 122.3 (CH), 122.1 (C), 24.2 (CH
3
); m/z (ESI) 179.0369 MVK (14f) (μL, mg, 1.05 mmol) and the reaction mixture allowed to
stir at ambient temperature for 45 min. The reaction mixture was
+
+
M + H C
9 8 2
H ClN requires 179.0371).
concentrated under reduced pressure. The residue was diluted with
2
-Vinyl-1,8-naphthyridine (15f)
sat. aq. Na
combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with EtOAc (3 x 10 mL). The
SO ) and concentrated
2
4
Method A: To a stirred mixture of 2-aminonicotinaldehyde (122 mg,
.00 mmol) in H O (2 mL) was added LiOH•H O (4.20 mg, 100 μmol),
under reduced pressure. The crude product was purified by column
chromatography (silica gel, EtOAc) to give 15h as a light brown oil
1
2
2
then methyl vinyl ketone (85.0 μL, 73.6 mg, 1.05 mmol), and the
reaction mixture allowed to stir at room temperature for 4.5 h. The
1
(
(
159 mg, 79%). vmax/cm-1 2984, 2972, 2873, 1618, 1600; H NMR
3
400 MHz, CDCl ) δ 9.02 (dd, J = 4.3, 2.0 Hz, 1H), 8.13 (dd, J = 8.1, 2.0
reaction mixture was diluted with sat. aq. Na
aqueous extracted with EtOAc (3 x 10 mL). The combined organic
phases were dried (Na SO ) and concentrated under reduced
pressure to give a dark yellow oil. The residue was purified by column
chromatography (silica gel, petroleum ether/EtOAc (1:1) – 5% iso-
propyl alcohol in EtOAc) to give 15f (62.8 mg, 40%) as a yellow-brown
oil.
2 3
CO (10 mL), and the
Hz, 1H), 8.10 (s, 1H), 7.40 (dd, J = 8.1 4.3 Hz, 1H), 4.64 (d, J = 1.0 Hz,
H), 3.66 (q, J = 7.0 Hz, 2H), 2.75 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13
NMR (100 MHz, CDCl ) 161.5 (C), 155.4 (C), 153.1 (CH), 136.7 (CH),
2
C
2
4
3
1
2
2
34.9 (CH), 131.9 (C), 121.6 (CH), 121.3 (C), 69.8 (CH
2
), 66.7 (CH
2
),
+
+
3.1 (CH
3
), 15.3 (CH
3
); m/z (ESI) 203.1179 (M + H C12
H
15
N
2
O requires
03.1179).
3
-(iso-Propoxymethyl)-2-methyl-1,8-naphthyridine (15i)
Method B: A mixture of 2-methyl-1,8-naphthyridine (13) (144 mg,
1
(
1
.00 mmol), Et
39.0 mg, 1.30 mmol) in dimethyl carbonate ( 2 mL) was heated to
20 °C (μwave) for 1 h. The reaction mixture was concentrated under
2
NH•HCl (21.9 mg, 200 μmol), and paraformaldehyde
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg,
i
1
.00 mmol) and KOH (112 mg, 2.00 mmol) in PrOH (8 mL) was added
MVK (14f) (109 μL, 94.6 mg, 1.05 mmol) and the reaction mixture
allowed to stir at ambient temperature for 17 h. The reaction mixture
was concentrated under reduced pressure. The residue was diluted
reduced pressure, and the residue purified by column
chromatography (silica gel, EtOAc) to give 15f as a light brown solid
115 mg, 74%). vmax/cm-1 3043, 2995, 1596, 1539, 1494; H NMR
400 MHz, CDCl
1
(
(
with sat. aq. Na
The combined organic phases were dried (Na
2
CO
3
(10 mL) and extracted with EtOAc (3 x 10 mL).
SO ) and concentrated
3
) δ 9.07 (dd, J = 4.2, 2.0 Hz, 1H), 8.12 (d J = 8.1 Hz,
H), 8.11 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.1,
.2 Hz, 1H), 7.06 (dd, J = 17.6, 10.8 Hz, 1H), 6.46 (dd, J = 17.6, 1.0 Hz,
H), 5.71 (dd, J = 10.8, 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl
) δ 159.2
2
4
1
4
1
under reduced pressure. The crude product was purified by column
chromatography (silica gel, EtOAc/EtOH (4:1)) to give 15i as an
3
orange oil (87.7 mg, 41%). vmax/cm 2970, 2929, 2870, 1619, 1560,
-1
(C), 156.2 (C), 153.9 (CH), 137.5 (CH), 137.4 (CH), 136.7 (CH), 121.8
1
1
555; H NMR (400 MHz, CDCl
3
) δ 9.00 (dd, J = 4.3, 2.0 Hz, 1H), 8.12
+
+
9 2
(C), 121.8 (CH), 120.0 (CH); m/z (ESI) 157.0759 (M + H C10H N
(d, J = 8.1, 2.0 Hz, 1H), 8.11 (d, J =1.1 Hz, 1H), 7.39 (dd, J = 8.1, 4.3 Hz,
requires 157.0760).
1
1
H), 4.63 (d, J = 1.1 Hz, 2H), 3.77 (hept, J = 6.1 Hz, 1H), 2.74 (s, 3H),
.27 (d, J = 6.1 Hz, 6H); 13C NMR (100 MHz, CDCl
) δ 161.5 (C), 155.3
3
3
-(Methoxymethyl)-2-methyl-1,8-naphthyridine (15g)
(
(
(
C), 153.0 (CH), 136.7 (CH), 134.9 (CH), 132.4 (C), 121.6 (CH), 121.3
C), 72.2 (CH), 67.3 (CH ), 23.1 (CH ), 22.2 (CH ); m/z (ESI) 217.1335
O requires 217.1335).
2
3
3
To a stirred mixture of 2-aminonicotinaldehyde (11) (122 mg,
.00 mmol) and KOH (112 mg, 2.00 mmol) in MeOH (4 mL) was added
MVK (14f) (109 μL, 94.6 mg, 1.05 mmol) and the reaction mixture
+
+
17 2
M + H C13H N
1
6
| Green Chem., 2017, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 8
Please Gd roe en no tC ha ed mj u iss tt r my argins
Green Chemistry
PAPER
2
-(2-(Piperidin-1-yl)ethyl)-1,8-naphthyridine (17a)
To a stirred mixture of 2-vinyl-1,8-naphthyridine (1V5iefw) A(r5ti0cl.e0Onmlinge,
3
3
20 μmol) in MeCN (320 μL) was added thiopDhOeI:n1o0l.1(03329.9/Cμ9LG,C3050.340m8gD,
20 μmol) and the reaction mixture allowed to stir at ambient
To a stirred mixture of 2-vinyl-1,8-naphthyridine (15f) (50.0 mg,
3
3
20 μmol) in MeCN (320 μL) was added piperidine (31.6 μL, 27.2 mg,
20 μmol), and the reaction mixture allowed to stir at ambient
temperature for 10 min. The resulting solution was concentrated
under reduced pressure and purified by column chromatography to
give 17d as a cloudy pale yellow oil with BHT present (73.8 mg, 87%).
temperature for 2.5 h. The reaction mixture was concentrated under
reduced pressure to give 17a as a pale orange solid (76.7 mg, 99%).
-1
1
v
9
8
max/cm 3051, 2923, 1604, 1582, 1554; H NMR (400 MHz; CDCl
3
): δ
.08 (dd, J = 4.5, 2.0 Hz, 1H), 8.14 (dd, J = 8.0, 2.0 Hz, 1H), 8.08 (d, J =
.5 Hz, 1H), 7.44 (dd, J = 8.0., 4.5 Hz, 1H), 7.41-7.36 (m, 2H), 7.35 (d,
-1
v
max/cm 3045, 3003, 2928, 2855, 2805, 1602, 1548, 1498, 1446,
1
1
434; H NMR (400 MHz, CDCl
3
) δ 9.05 (dd, J = 4.5, 2.0 Hz, 1H), 8.12
(dd, J = 8.0, 2.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz,
J = 8.5 Hz, 1H), 7.29-7.23 (m, 2H), 7.18-7.13 (m, 1H), 3.57-3.51 (m,
H), 3.38-3.32 (m, 2H); 13C NMR (100 MHz; CDCl
): δ 164.2 (C), 156.0
C), 153.5 (CH), 137.2 (CH), 136.9 (CH), 136.1 (C), 129.5 (CH), 129.0
1
2
H), 7.40 (d, J = 8.5 Hz, 1H), 3.28-3.19 (m, 2H), 2.94-2.85 (m, 2H),
.57-2.39 (m, 4H), 1.58 (tt, J = 5.5, 5.5 Hz, 4H), 1.47-1.38 (m, 2H); 13
) δ 165.4 (C), 156.0 (C), 153.4 (CH), 137.0 (CH),
36.8 (CH), 123.0 (CH), 121.5 (CH), 121.1 (CH), 58.6 (CH ), 54.6 (CH ),
6.7 (CH ), 26.2 (CH ), 24.5 (CH
); m/z (ESI) 242.1660 (M + H+
requires 242.1652).
2
3
C
(
(
(
NMR (100 MHz, CDCl
3
2
CH), 126.1 (CH), 123.0 (CH), 121.8 (CH), 121.4 (C), 38.6 (CH ), 32.5
2 15 2
CH ); m/z (ESI) 267.0957 (M + H C16H N
1
3
C
2
2
+
S+ requires 267.0950).
2
2
2
+
15 20
H N
3
2-(1,4,5,6,7-Pentamethylbicyclo[2.2.1]hept-5-en-2-yl)-1,8-
naphthyridine (17e)
4
-(2-(1,8-Naphthyridin-2-yl)ethyl)morpholine (17b)
To a stirred mixture of 2-vinyl-1,8-naphthyridine (15f) (50.0 mg,
To a stirred mixture of 2-vinyl-1,8-naphthyridine (15f) (50.0 mg,
3
20 μmol) in MeCN (320 μL) was added 1,2,3,4,5-
3
3
20 μmol) in MeCN (320 μL) was added morpholine (27.6 μL,
20 μmol), and the reaction mixture allowed to stir at ambient
pentamethylcyclopentadiene (50.1 μL, 43.6 mg, 320 μmol) and the
reaction mixture allowed to stir at ambient temperature for 26.5 h.
The reaction mixture was concentrated under reduced pressure and
temperature for 21 h. The reaction mixture was concentrated under
reduced pressure to give 17b as a pale orange solid (73.9 mg, 95%).
the residue purified by column chromatography (silica gel, Et
2
O) to
max/cm-1 2974, 2959, 2854, 2790, 2759, 1600; H NMR (400 MHz,
1
v
give a mixture of diastereoisomers (4:1 dr) of 17e as a colourless oil
CDCl
.08 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.0, 4.5 Hz, 1H), 7.41 (d, J = 8.5
Hz, 1H), 3.75-3.65 (m, 4H), 3.27-3.19 (m, 2H), 2.98-2.90 (m, 2H), 2.61-
.47 (m, 4H); 13C NMR (100 MHz, CDCl
) δ 164.8 (C), 156.0 (C), 153.4
CH), 137.1 (CH), 136.8 (CH), 122.9 (CH), 121.6 (CH), 121.2 (C), 67.1
3
) δ 9.05 (dd, J = 4.5, 2.0 Hz, 1H), 8.13 (dd, J = 8.0, 2.0 Hz, 1H),
92.3 mg, 99%). (Major isomer) vmax/cm-1 2951, 2926, 2868, 1604,
(
8
1
1
3
546, 1496, 1444, 1423, 1376; H NMR (400 MHz, CDCl ) δ 9.06 (dd,
J = 4.5, 2.0 Hz, 1H), 8.11 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.96 (d, J = 8.5 Hz,
H), 7.40 (dd, J = 8.0 Hz, 4.5 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 3.56 (dd,
J = 9.0, 4.5 Hz, 1H), 1.99 (dd, J = 12.0 Hz, 9.0 Hz, 1H), 1.76 (dd, J =
2.0, 4.5 Hz, 1H), 1.69 (d, J = 1.0 Hz, 3H), 1.57 (q, J = 6.5 Hz, 1H), 1.14
s, 3H), 1.10 (s, 3H), 0.96 (d, J = 1.0 Hz, 3H), 0.61 (d, J = 6.5 Hz, 3H);
13C NMR (100 MHz, CDCl
) δ 168.2 (C), 153.1 (CH), 136.6 (CH), 135.7
CH), 121.5 (CH), 121.2 (CH), 62.8 (CH), 61.1 (CH), 57.0 (C), 53.5 (C),
2
3
1
(
(
CH
2
), 58.1 (CH
2
), 53.7 (CH
2
), 36.4 (CH
2
); m/z (ESI) 244.1451 (M + H+
1
(
+
C
14
18
H N
3
O requires 244.1444).
3
N,N-Diethyl-2-(1,8-naphthyridin-2-yl)ethan-1-amine (17c)
(
4
1.4 (CH
2
), 15.5 (CH
3
), 14.4 (CH
3
), 12.2 (CH
3
), 10.1 (CH
3
), 8.2 (CH
3
);
To a stirred solution of 2-vinyl-1,8-naphthyridine (15f) (50.0 mg,
+
+
m/z (ESI) 293.2011 (M + H C20
H
25
N
2
requires 293.2012).
3
2
20 μmol) in MeCN (320 μL) was added diethylamine (33.1 μL,
3.4 mg, 320 μmol), then Zn(NO •6H O (2.3 mg, 8.00 μmol) and the
3
)
2
2
reaction mixture allowed to stir at ambient temperature for 22 h. The
reaction mixture was concentrated under reduced pressure, the
Conclusions
residue diluted with sat. aq. Na
phase extracted with EtOAc (3 x 1 mL). The combined organic phases
were dried (Na SO ), concentrated under reduced pressure to give
7c as a brown oil (63.8 mg, 87%). vmax/cm 3377, 3053, 2971, 2933,
2 3
CO solution (1 mL) and the aqueous
We have reported conditions for a mild, greener synthesis of
substituted 1,8-naphthyridines from 2-aminonicotinaldehyde (11),
which can be ultimately sourced from sustainable starting materials,
with accompanying analysis using green chemistry metrics.
Furthermore, we have shown two routes to 2-vinyl-1,8-
naphthyridine (15f), a previously unreported heterocycle. In
addition, we have shown that 2-vinyl-1,8-naphthyridine (15f)
displays good electrophilic character with various nucleophiles, and
proves to be more reactive than the analogous pyridine species when
used in this manner.
2
4
-
1
1
1
1
3
603, 1553, 1497; H NMR (400 MHz, CDCl ) δ 9.02 (dd, J = 4.5, 2.0
Hz, 1H), 8.10 (dd, J = 8.0, 2.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.41-
7
4
1
5
.35 (m, 2H), 3.18-3.11 (m, 2H), 3.03-2.97 (m, 2H), 2.59 (q, J = 7.0 Hz,
H), 1.02 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl
) δ 165.4 (C),
56.0 (C), 153.2 (CH), 136.8 (CH), 122.9 (CH), 121.4 (CH), 121.0 (C),
3
2.3 (CH
2
), 46.9 (CH
2
), 36 (CH
2 3
), 12.0 (CH ); m/z (ESI) 230.1660 (M +
H+ C14
+
requires 230.1652).
20
H N
3
2
-(2-(Phenylthio)ethyl)-1,8-naphthyridine (17d)
Conflicts of interest
There are no conflicts to declare.
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