Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones through Sequential One-Pot Suzuki-Miyaura Cross-Couplings

Article abstract of DOI:10.1002/ejoc.201301631

A practical synthesis of 7-chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)-one is described that starts from 2-chloro-4-(methylamino)nicotinaldehyde. The dihalo compound then undergoes sequential, site-selective Suzuki-Miyaura cross-coupling reactions to afford highly functionalized 1,6-naphthyridones in good yields.

Full text of DOI:10.1002/ejoc.201301631

FULL PAPER
DOI: 10.1002/ejoc.201301631
Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones through
Sequential One-Pot Suzuki–Miyaura Cross-Couplings
David Montoir,[a] Alain Tonnerre,[a] Muriel Duflos,[a] and Marc-Antoine Bazin*[a]
Keywords: Synthetic methods / C–C coupling / Cross-coupling / Nitrogen heterocycles / Palladium / Microwave chemistry
A
practical synthesis of 7-chloro-3-iodo-1-methyl-1,6-
pound then undergoes sequential, site-selective Suzuki–
Miyaura cross-coupling reactions to afford highly func-
tionalized 1,6-naphthyridones in good yields.
naphthyridin-2(1H)-one is described that starts from 2-
chloro-4-(methylamino)nicotinaldehyde. The dihalo com-
available to produce highly functionalized 3,7-disubstituted
1,6-naphthyridin-2(1H)-ones. Indeed, Thompson and co-
Introduction
Naphthyridones, which are privileged structures for drug workers have reported the selective inhibition of c-Src kin-
discovery, have received much attention as biologically ase in a nanomolar range for such compounds.[5a]
active compounds, and, specifically, 1,8-naphthyridin-
As part of our ongoing research of the functionalization
4(1H)-ones have been widely studied as aza analogues of of nitrogen heterocycles by employing Suzuki–Miyaura
antibacterial fluoroquinolones.[1] In addition, 1,6-naphthyr- cross-coupling reactions,[6] we disclose a new synthetic pro-
idin-2(1H)-one substrates have been established as tocol that involves the rapid preparation of 3,7-dihalo-1,6-
cardiotonic agents,[2] N-methyl-d-aspartate (NMDA)/glyc- naphthyridin-2(1H)-ones followed by sequential Suzuki–
ine site antagonists,[3] antibacterial agents,[4] and protein Miyaura cross-coupling reactions with a variety of boron
kinases inhibitors.[5] Because of this broad range of bio- reagents to provide complex 3,7-diaryl-1,6-naphthyridin-
logical activities, various strategies to provide function- 2(1H)-ones in one-pot. More precisely, 7-chloro-3-iodo-1-
alized 1,6-naphthyridin-2(1H)-ones efficiently are still methyl-1,6-naphthyridin-2(1H)-one was studied to highlight
needed.
7-Substituted
3-aryl-1,6-naphthyridin-2(1H)- the reactivity differences between the iodo and chloro sub-
ones[5a,5c–5g] are of particular value, but few methods are stituents. Indeed, sequential palladium-catalyzed cross-cou-
Scheme 1. Synthesis of 3,7-diarylnaphthyridin-2(1H)-ones.
pling reactions are powerful strategies that have been widely
developed to provide highly functionalized heterocyclic
scaffolds.[7]
The classical approach to synthesize 3-aryl-1,6-naphthyr-
idin-2(1H)-ones relies on a modified Friedländer synthesis[8]
that starts from a 4-aminonicotinaldehyde and an aryl
acetic ester under basic conditions (see Scheme 1). The
[a] Université de Nantes, Nantes Atlantique Universités,
Laboratoire de Chimie Thérapeutique, Cibles et Médicaments
des Infections et du Cancer, IICiMed EA 1155, UFR des
Sciences Pharmaceutiques et Biologiques,
1 rue Gaston Veil, 44035 Nantes, France
E-mail: marc-antoine.bazin@univ-nantes.fr
www.iicimed.univ-nantes.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301631.
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main drawback of this strategy is the multistep synthesis of ation, Roy’s procedure[11] was carried out, but it failed to
the aryl acetic ester from the corresponding benzoic acid provide any product (see Table 1, Entry 1). A slight im-
derivative. A method that involves a Suzuki–Miyaura cross- provement of the results was observed by increasing the
coupling reaction could overcome this problem. Indeed, Su- amount of NBS and water (see Table 1, Entry 2). We were
zuki cross-coupling reactions provide C–C linkages ef- pleased to find that the use of microwave-mediated heating
ficiently under mild conditions by using widely and com- efficiently promoted the bromodecarboxylation reaction
mercially available boron reagents.[9] Using this approach, (see Table 1, Entry 3). Hence, other solvent systems such as
the preparation of a 3-halo-1,6-naphthyridin-2(1H)-one anhydrous THF, THF/water (9:1),[12] and dimethoxyethane
would be required, and this could be obtained in two steps (DME)/water (9:1)[13] were examined under these condi-
from an ortho-amino carbaldehyde. Thus, the 3,7-dihalo- tions, but unfortunately to no avail (not shown in Table).
1,6-naphthyridin-2(1H)-one would undergo sequential Su- The increased quantities of NBS and LiOAc allowed for a
zuki reactions to efficiently provide the target compounds good conversion, which was observed by ultraperformance
(see Scheme 1) .
liquid chromatography–mass spectrometry (UPLC–MS; see
Table 1, Entries 4 and 5). Performing the reaction in a mix-
ture of DMF/water (9:1) led to a high conversion (see
Table 1, Entry 6) and allowed for a more convenient treat-
ment of the reaction mixture, as opposed to the acetonitrile/
water system. Increasing the temperature or reaction time
resulted in incomplete conversion and formation of byprod-
ucts (see Table 1, Entries 7 and 8). We then examined
whether the amount of LiOAc (3.2 equiv.) was justified. We
noticed that decreasing the amount of LiOAc to 1.2 equiv.
led to the desired product in a similar yield to that obtained
with 3.2 equiv. of this base (see Table 1, Entry 9). Gratify-
ingly, when NBS (increased to 4.2 equiv.) was treated with
1.2 equiv. of LiOAc, the bromodecarboxylation was suc-
cessful with a high conversion and a very good yield of 7a
(see Table 1, Entry 10). Next, we investigated the iodode-
carboxylation reaction to obtain the corresponding aryl
iodide, which is known to be significantly more reactive in
most Pd-catalyzed transformations. The replacement of
NBS with NIS (1.2 equiv.) along with the employment of
standard conditions led to a better reactivity (see Table 1,
Entry 11), and a quantitative conversion (93% isolated
yield) was observed when the amount of NIS was increased
to 3.2 equiv. (see Table 1, Entry 12). These experiments
identified an excess amount of the NXS along with LiOAc
(1.2 equiv.) in a mixture of DMF/water (9:1) as the optimal
combination of solvent and reagents to provide high yields
of product within a short period of microwave-assisted
heating (10 min).
Results and Discussion
The stepwise synthesis of the desired 3,7-dihalonaphthyr-
idin-2(1H)-one required known nicotinaldehyde derivative
5, which could be prepared in multigram quantities in four
steps by following a reported procedure.[5d] Commercially
available diethyl 3-oxopentanedioate was treated with tri-
ethyl orthoformate and then underwent a cyclization by
treatment with ammonia to give compound 2 in a satisfac-
tory yield (72%, see Scheme 2). Chlorination with phos-
phorus oxychloride and a subsequent regioselective amin-
ation furnished ester 4 in high yields. The reduction of the
ester functional group by treatment with lithium aluminum
hydride (LAH) followed by a mild oxidation with manga-
nese(II) dioxide led to the desired 2-chloro-4-(methyl-
amino)nicotinaldehyde 5. By following a modified pro-
cedure of Garino et al.,[10] the treatment of 5 with Meld-
rum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) in the pres-
ence of substoichiometric amounts of piperidine and acetic
acid produced naphthyridone 6 in excellent yield.
Next, we envisaged a halodecarboxylation of acid 6 by
using either N-bromosuccinimide (NBS) or N-iodosuccin-
imide (NIS) to afford the target 3-halogenated derivatives
7a and 7b, respectively. Our initial efforts focused on the
optimization of the conditions of such a conversion (see
Table 1). In the first experiments for the bromodecarboxyl-
Scheme 2. Synthesis of 3,7-dihalonaphthyridin-2(1H)-ones 7a and 7b. Reagents and conditions: (i) HC(OEt)3, acetic anhydride, 120 °C,
3 h, then ammonia (30% water solution), 0 °C, 15 min, 72%; (ii) POCl3, 110 °C, 2 h, 95%; (iii) CH3NH2 (40% water solution), CH3CN,
0 °C, 30 min, then room temp., 3 h, 96%; (iv) (a) LAH, tetrahydrofuran (THF), –78 °C, 3 h, (b) MnO2, dichloromethane (DCM), room
temp., 2 h, 84%; (v) Meldrum’s acid, piperidine, acetic acid, EtOH, reflux, 2 h, 99%; (vi) NXS, LiOAc, N,N-dimethylformamide (DMF)/
H2O, microwave (MW), 110 °C, 10 min, X = Br, 74%, X = I, 93%.
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Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones
Table 1. Optimization of conditions for halodecarboxylation of withdrawing group were examined using identical reaction
carboxylic acid 6.
conditions (see Table 2, Entries 2 and 3). In both cases,
compound 9 was detected (UPLC-MS analysis) or isolated
(9b in 9% yield). Lowering the temperature to 80 °C led to
a significant reduction in the formation of the undesirable
compound 9a (see Table 2, Entry 4). We then performed
our coupling reaction with 3-iodo precursor 7b to compare
its reactivity with the aryl bromide. The reaction went to
completion at 80 °C without the formation of the biphenyl
byproduct to afford product 8a in good yield (see Table 2,
Entry 5). This protocol also occurred in the same manner,
but a shorter heating time (approximately 10 min), under
microwave irradiation (see Table 2, Entry 6). As expected,
the chemoselective control of the Suzuki–Miyaura reactions
was more efficient with the aryl iodide than the bromo de-
rivative. For this reason, 7-chloro-3-iodo-1-methyl-1,6-
naphthyridin-2(1H)-one (7b) was used as the starting mate-
rial for further studies of these Suzuki–Miyaura coupling
reactions.
Entry NXS LiOAc Solvent[a]
[equiv.] [equiv.]
Heating
Time Conv. Yield
[%][b] [%][c,d]
1
NBS
(1.2)
NBS
(2.2)
NBS
(2.2)
NBS
(2.2)
NBS
(3.2)
NBS
(3.2)
NBS
(3.2)
NBS
(3.2)
NBS
(3.2)
NBS
(4.2)
NIS
1.2
1.2
1.2
2.2
3.2
3.2
3.2
3.2
1.2
1.2
1.2
1.2
A
B
B
B
B
C
C
C
C
C
C
C
classical
(100 °C)
classical
(100 °C)
MW[e]
5 h
2 h
0
7
n.d.
n.d.
n.d.
n.d.
n.d.
64
2
3
10 min 59
(100 °C)
4
MW (100 °C) 10 min 65
MW (100 °C) 10 min 90
MW (100 °C) 20 min 85
MW (150 °C) 20 min 48
MW (110 °C) 30 min 64
MW (110 °C) 10 min 76
MW (110 °C) 10 min 91
MW (110 °C) 10 min 68
MW (110 °C) 10 min 100
5
6
7
n.d.
52
Table 2. Suzuki–Miyaura coupling of compounds 7a and 7b with
aryl boronic acids.[a]
8
9
63
10
11
12
74
n.d.
93
(1.2)
NIS
(3.2)
[a] Solvents are A (CH3CN/H2O, 97:3), B (CH3CN/H2O, 9:1), and
C (DMF/H2O, 9:1). [b] Conversion (conv.) percent as determined
by UPLC–MS analysis. [c] Isolated yield after purification. [d] Not
determined = n.d. [e] Microwave reactions were carried out in a
sealed vessel.
With aryl halides 7a and 7b in hand, we were able to
study the effectiveness of the Suzuki–Miyaura cross-cou-
pling reaction to yield the desired 3-aryl-1,6-naphthyridin-
2(1H)-ones. We decided to investigate N-methylated 1,6-
naphthyridones to overcome problems with regard to the
solubility or reactivity of free N-H-containing 1,6-naphth-
yridones.[7d] We then applied the same reaction conditions
that had been previously reported[12] for Suzuki reactions
of 3-bromopyridopyridazin-2(1H)-one. The results are sum-
marized in the Table 2. Hence, the coupling of phenyl-
boronic acid with aryl bromide 7a using Pd(PPh3)4 as the
catalyst and sodium carbonate as the base was carried out
in an aqueous mixture of 1,4-dioxane/water (4:1) that was
heated at 105 °C for 3 h in a sealed vessel to result in com-
plete conversion (see Table 2, Entry 1). The expected prod-
uct 8a was obtained in a satisfactory yield (67%) along with
the formation of biphenyl byproduct 9a, which was pro-
[a] Reagents and conditions: 7 (0.3 mmol), ArB(OH)2 (1.1 equiv.),
Pd(PPh3)4 (5 mol-%), Na2CO3 (2.5 equiv.), 1,4-dioxane/water (4:1,
5 mL), 80–105 °C, sealed vessel. [b] Isolated yield after purification.
[c] Reaction performed in a sealed vessel in a microwave reactor
(fixed temperature, variable pressure).
To investigate the scope of the Suzuki–Miyaura reaction
duced from a dual cross-coupling reaction.[14] To ensure at the 3-position of the naphthyridone core with various
that the formation of the 3,7-diaryl product did not origi- boronic acids, various 3-aryl-7-chloro-1-methyl-1,6-
nate because of the boron reagent, two other boronic acids naphthyridin-2(1H)-ones were synthesized under the reac-
that contained either an electron-donating or an electron- tion conditions previously described (see Table 3). In gene-
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ral, the introduction of substituents on the benzene ring was successful (68% yield; see Table 3, Entry 6), and, hence,
had no effect on the success of this Pd-catalyzed coupling. this result confirmed the problem of steric hindrance with
Indeed, electron-donating (i.e., methoxy and methyl) and regard to the coupling partner. The coupling reaction also
electron-withdrawing groups (i.e., halogens and cyano) did tolerated the use of heterocyclic 4-pyridylboronic acid pin-
not affect the reactivity of corresponding boronic acids, as acol ester to afford the corresponding 3-pyridylnaphthyr-
products 8 were obtained in good yields (approximately idone 8g in 55% yield, but this occurred over a prolonged
70%; see Table 3, Entries 2–4 and 6–7). However, the reac- reaction time (see Table 3, Entry 8). We also attempted to
tion that involved 2,6-dimethylphenylboronic acid failed, include a furan ring in the reaction, and, unfortunately to
even after 10 h (see Table 3, Entry 5). This result prompted no avail, this resulted in a complex reaction mixture (see
us to use another isomer of this boronic acid. Interestingly, Table 3, Entry 9). From these experiments, we concluded
the coupling reaction with 3,5-dimethylphenylboronic acid that our protocol to provide 3-aryl-7-chloro-1-methyl-1,6-
naphthyridin-2(1H)-ones appeared reliable and could toler-
ate a wide variety of boron reagents. Moreover, all of the
reactions proceeded to completion (see Table 3, except for
Entries 5 and 9), even if the isolated yields did not exceed
80%.
Table 3. Scope of Suzuki–Miyaura coupling of 7-chloro-3-iodo-1,6-
naphthyridin-2(1H)-one 7b.[a]
Our next task was to convert monoarylated compounds
8 into 3,7-diaryl-1,6-naphthyridin-2(1H)-ones 9. Because of
the observed lability of the chloro group of the starting aryl
bromide under the Suzuki conditions (vide supra), we con-
sidered that a subsequent Suzuki–Miyaura cross-coupling
reaction could be efficiently carried out with the 7-chloro
derivatives.
Treating
7-chloro-1-methyl-3-phenyl-1,6-
naphthyridin-2-(1H)-one 8a with our typical Suzuki condi-
tions [(het)ArB(OR)2 (1.1 equiv.), Na2CO3 (2.5 equiv.), and
Table 4. Suzuki–Miyaura coupling of 3-aryl-7-chloro-1,6-naphthyr-
idin-2(1H)-ones 8.[a]
[a] Reagents and conditions: 7b (0.3 mmol), (het)ArB(OR)2
(1.1 equiv.), Pd(PPh3)4 (5 mol-%), Na2CO3 (2.5 equiv.), 1,4-diox-
ane/water (4:1, 5 mL), 80 °C, sealed vessel. [b] Isolated yield after
purification. [c] No reaction occurred. [d] Formation of a complex
reaction mixture.
[a] Reagents and conditions:
8 (0.3 mmol), (het)ArЈB(OR)2
(1.1 equiv.), Pd(PPh3)4 (5 mol-%), Na2CO3 (2.5 equiv.), 1,4-diox-
ane/water (4:1, 5 mL), 105 °C, sealed vessel, microwave heating.
[b] Isolated yield after purification.
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Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones
Pd(PPh3)4 (5 mol-%) in 1,4-dioxane/water (4:1) at 105 °C in mixture along with Pd(PPh3)4 (5 mol-%) and base
a sealed vessel] resulted in incomplete conversion after 72 h. (Na2CO3, 2.5 equiv.). The mixture was subjected to micro-
Indeed, approximately 50% of the starting material (com- wave heating at 105 °C for 3 h to give diphenyl-1,6-naphth-
pound 8a) remained according to the UPLC–MS chroma- yridone 9a in 58% overall yield. The initial Suzuki coupling
togram (data not shown). The long reaction time required step that afforded the intermediate compound 8a was
for the full conversion of the aryl chloride prompted us to checked by using UPLC–MS analysis. The Pd/SPhos (palla-
explore the scope of the reaction under microwave heating dium/2-dicyclohexylphosphino-2Ј,6Ј-dimethoxybiphenyl)
(see Table 4). The reaction of 8a with phenylboronic acid catalyst/ligand system, which was reported by Cross and
smoothly afforded 3,7-diaryl derivative 9a in 2 h in good Manetsch,[7d] was used to shorten reaction time of the sec-
yield (see Table 4, Entry 1). The nature of the boron reagent ond step. Although the conditions were efficient for the first
was then investigated. Both electron-poor and electron-rich step, the arylation at the 7-position failed (data not shown).
phenylboronic acids behaved similarly to provide the de- The next attempt used 3-fluorophenylboronic acid and then
sired products in 1 h in good to very good yields (see 4-methoxyphenylboronic acid to provide 1,6-naphthyridone
Table 4, Entries 2, 3, and 5). Although 4-pyridylboronic 9h in good yield over two steps in one pot (see Table 5,
acid pinacol ester appeared less reactive towards a Suzuki Entry 2). Reactions that employed other heterocyclic boron
coupling at the 3-position (see Table 3), the reaction at the reagents such as 4-pyridylboronic acid pinacol ester or 2-
7-position of compound 8b provided 9f within the same thienylboronic acid afforded the desired products 9i and 9j
time as those of the substituted phenylboronic acids (ap- in 32 and 33% yield, respectively (see Table 5, Entries 3 and
proximately 1 h; see Table 4, Entry 4). Thus, this second 4). It is noteworthy that the incorporation of these hetero-
arylation at C-7 offers an original approach to a variety of cycles at C-3 in the first step required more than 1 h under
di(hetero)aryl derivatives.
microwave irradiation. The one-pot procedure allowed the
Having established a convenient route for the differential preparation of 3,7-disubstituted derivatives in overall yields
functionalization of 3,7-dihalo-1,6-naphthyridin-2(1H)- comparable to those obtained in the stepwise synthesis.
ones to provide the corresponding diaryl derivatives, we re-
investigated sequential Suzuki–Miyaura couplings in a sin-
gle flask under microwave irradiation without isolating the
3-(hetero)aryl intermediate. Therefore, for step 1, 7b was
treated with phenylboronic acid under the established reac-
tion conditions (see Table 5, Entry 1), and thereafter, phen-
ylboronic acid (1 equiv.) was added to the crude reaction
Conclusions
We have developed a strategy for a rapid approach to
3,7-diaryl-1-methyl-1,6-naphthyridin-2(1H)-ones from 2-
chloro-4-(methylamino)nicotinaldehyde. The key intermedi-
ate 7-chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)-one,
which was prepared by a two-step process that involved a
Meldrum’s acid-mediated cyclization and a iododecarboxyl-
ation, was a suitable reagent to undergo one-pot, sequential
Suzuki–Miyaura cross-coupling reactions under microwave-
assisted heating. This practical approach provides highly
functionalized naphthyridin-2(1H)-ones of potential phar-
maceutical interest. Furthermore, the straightforward func-
tionalization at both C-3 and C-7 of this readily available
scaffold could be extended to other metal-catalyzed reac-
tions.
Table 5. Microwave-assisted one-pot sequential Suzuki–Miyaura
couplings of 7-chloro-3-iodo-1,6-naphthyridin-2(1H)-ones 7b.[a]
Experimental Section
General Methods: All commercial reagents were used without fur-
ther purification. All solvents were reagent or HPLC grade. THF
was distilled prior to use with a Na/benzophenone system. Analyti-
cal TLC was performed on silica gel 60 F254 plates. Flash column
chromatography was performed on silica gel 60 (70–230 mesh
ASTM), yields refer to chromatographically and spectroscopically
pure compounds. Melting points were measured with an Electro-
thermal melting point apparatus. The 1H and 13C NMR spectro-
scopic data were recorded using [D6]DMSO with a 400 MHz spec-
trometer. Chemical shifts are reported as δ values in parts per mil-
lion (ppm) relative to tetramethylsilane as the internal standard,
and coupling constants (J) are given in Hertz. Multiplicities are
reported as singlet (s), doublet (d), doublet of doublets (dd), doub-
[a] Reagents and conditions: step 1: 7b (0.3 mmol), (het)ArB(OR)2
(1 equiv.), Pd(PPh3)4 (5 mol-%), Na2CO3 (2.5 equiv.), 1,4-dioxane/
water (4:1, 5 mL), 80 °C, sealed vessel, microwave heating; step 2:
(het)ArЈB(OR)2 (1 equiv.), Pd(PPh3)4 (5 mol-%), Na2CO3
(2.5 equiv.), 105 °C, sealed vessel, microwave heating. [b] Isolated
yield after purification.
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let of doublet of doublets (ddd), triplet (t), multiplet (m), quartet
(q), and broad singlet (br. s). Low resolution mass spectra were
obtained by ESI, and high resolution mass spectra were obtained
by ESI-TOF. Microwave reactions were carried out in a CEM Dis-
cover microwave reactor in sealed vessels (monowave, maximum
power 300 W, temperature control by IR sensor, fixed temperature).
Compounds 2–5 were synthesized as previously reported in the lit-
erature.[5d]
8.64–8.54 (m, 1 H), 8.47 (s, 1 H), 6.83 (s, 1 H), 2.93 (d, J = 4.8 Hz,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 193.3, 158.2,
155.1 (2 C), 114.9, 104.5, 28.9 ppm. MS (ESI): m/z (%) = 171.0
(100) [M + H]+.
7-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic
Acid (6): To a stirred solution of compound 5 (200 mg, 1.17 mmol)
in EtOH (2 mL) were added Meldrum’s acid (169 mg, 1.17 mmol),
piperidine (17 μL, 0.12 mmol), and acetic acid (20 μL, 0.35 mmol).
The reaction mixture was stirred at room temperature for 20 min
and then heated at reflux for 2 h. After cooling to room tempera-
ture, the crystallized product was filtered, washed with EtOH (3ϫ),
and dried in vacuo to give 6 (279 mg, 99%) as a yellow powder;
m.p. 277–278 °C. Rf = 0.22 (DCM/EtOH, 98:2). 1H NMR
(400 MHz, [D6]DMSO): δ = 13.76 (s, 1 H), 9.06 (s, 1 H), 8.92 (s, 1
H), 7.87 (s, 1 H), 3.71 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 164.1, 161.7, 153.0, 152.7, 146.9, 142.1, 121.3, 114.8,
109.5, 30.0 ppm. HRMS (ESI): calcd. for C10H7ClN2O3 [M + H]+
239.0218; found 239.0208.
Ethyl 4,6-Dihydroxynicotinate (2): A mixture of diethyl 1,3-acetone-
dicarboxylate (1, 25.00 g, 0.12 mol), triethyl orthoformate
(21.96 mL, 0.13 mol), and acetic anhydride (22.64 mL, 0.24 mol)
was heated at 120 °C for 3 h. The light yellow oily solution was
cooled in an ice bath, and then ammonia (30% solution, 35.00 mL)
was added. The precipitate was collected by filtration and rinsed
with cold EtOH to afford 2 (16.19 g, 72% yield) as a yellow pow-
der; m.p. 220–221 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 11.83
(s, 1 H), 10.79 (s, 1 H), 8.05 (s, 1 H), 5.64 (s, 1 H), 4.29 (q, J =
7.2 Hz, 2 H), 1.32 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 166.6, 165.9, 163.6, 142.3, 100.7, 98.3, 60.6,
14.0 ppm. MS (ESI): m/z (%) = 184.1 (100) [M + H]+.
General Procedure for Halodecarboxylation of Compound 6 with
NBS or NIS: In a microwave vial (10 mL) that contained a solution
of compound 6 (100 mg, 0.42 mmol) in a mixture of DMF/water
(9:1, 5 mL) were added NXS (1.76 mmol for NBS, 1.35 mmol for
NIS) and LiOAc (33 mg, 0.50 mmol). The vial was sealed and then
heated under microwave heating at 110 °C for 10 min. After cool-
ing, water was added, and the mixture was extracted with DCM.
The organic layer was washed with brine, dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. Trituration with
diisopropyl ether afforded the desired products 7.
Ethyl 4,6-Dichloronicotinate (3): A mixture of compound 2 (5.00 g,
0.03 mol) and POCl3 (30 mL) was heated at reflux for 2 h. After
cooling, the mixture was poured into ice water, and the resulting
mixture was neutralized with K2CO3 (approximately 100 g). The
organic layer was extracted with DCM. The combined organic ex-
tracts were dried with Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography (DCM) to give 3 (5.72 g, 95% yield) as a white
powder; m.p. 71–72 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.87
(s, 1 H), 8.03 (s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 1.37 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.7, 153.5,
151.7, 144.5, 125.8, 125.3, 62.0, 13.9 ppm. MS (ESI): m/z (%) =
220.0 (100) [M + H]+.
3-Bromo-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (7a): Pale
yellow powder (74% yield); m.p. 264–265 °C. Rf = 0.24 (petroleum
1
ether/EtOAc, 8:2). H NMR (400 MHz, [D6]DMSO): δ = 8.76 (s,
1 H), 8.67 (s, 1 H), 7.72 (s, 1 H), 3.68 (s, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 157.5, 150.8, 149.5, 145.8, 138.7,
117.5, 115.7, 109.1, 30.9 ppm. HRMS (ESI): calcd. for
C9H6BrClN2O [M + H]+ 272.9425; found 272.9418.
Ethyl 6-Chloro-4-(methylamino)nicotinate (4): Compound 3 (5.72 g,
0.03 mol) was dissolved in acetonitrile (80 mL). The solution was
cooled to 0 °C, and methylamine (40% water solution, 18.00 mL)
was slowly added. The reaction was stirred at 0 °C for 30 min and
then warmed to room temperature for 3 h. The solvent was re-
moved under reduced pressure, and the crude product was purified
by silica gel chromatography (cyclohexane/EtOAc, 8:2) to provide
7-Chloro-3-iodo-1-methyl-1,6-naphthyridin-2(1H)-one (7b): Brown
powder (93% yield); m.p. 227–228 °C; Rf = 0.24 (petroleum ether/
1
EtOAc, 8:2). H NMR (400 MHz, [D6]DMSO): δ = 8.82 (s, 1 H),
8.71 (s, 1 H), 7.66 (s, 1 H), 3.65 (s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 158.3, 150.7, 149.1, 146.4, 145.7, 116.8, 109.0,
96.0, 31.1 ppm. HRMS (ESI): calcd. for C9H6ClIN2O [M + H]+
320.9286; found 320.9279.
1
4 (5.37 g, 96% yield) as a white powder; m.p. 34–36 °C. H NMR
(400 MHz, [D6]DMSO): δ = 8.54 (s, 1 H), 8.16–8.04 (m, 1 H), 6.77
(s, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 2.91 (d, J = 4.4 Hz, 3 H), 1.34
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
166.3, 156.0, 154.5, 152.0, 106.7, 104.6, 60.6, 29.1, 14.0 ppm. MS
(ESI): m/z (%) = 215.1 (100) [M + H]+.
General Procedure for Suzuki–Miyaura Cross-Coupling of 7b: To a
10 mL vessel were added compound 7b (100 mg, 0.32 mmol) in 1,4-
dioxane/water (4:1, 5 mL), the appropriate boron reagent
(0.34 mmol), Na2CO3 (83 mg, 0.78 mmol), and Pd(PPh3)4 (18 mg,
5 mol-%). The tube was sealed, and the reaction was heated in an
oil bath at 80 °C from 1.5 to 11 h (as indicated in Table 3). After
cooling, water was added, and the mixture was extracted with
DCM. The organic layer was washed with brine, dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography to provide
8a–8g (see Table 3).
6-Chloro-4-(methylamino)pyridine-3-carbaldehyde (5): To a mixture
of LAH (1.95 g, 51.5 mmol) in anhydrous THF (81 mL) at –78 °C
was added dropwise compound 4 (5.26 g, 24.5 mmol) in anhydrous
THF (72 mL). The reaction mixture was stirred at –78 °C for 3 h
and then gradually warmed to room temperature. A mixture of
MeOH/EtOAc (1:1, 20 mL) was slowly added to destroy the excess
amount of LAH. The resulting mixture was filtered through Celite,
and the filtrate was evaporated to dryness. The crude alcohol was
dissolved in DCM (120 mL), and MnO2 (21.31 g, 245 mmol) was
added. The reaction was stirred at room temperature for 2 h. The
resulting mixture was filtered through Celite to remove the MnO2,
and the filter cake was washed thoroughly with DCM. The filtrate
was concentrated under reduced pressure, and the crude residue
was purified by silica gel chromatography (cyclohexane/EtOAc, 7:3)
to provide 5 (3.51 g, 84% yield over two steps) as a white powder;
m.p. 81–82 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 9.90 (s, 1 H),
7-Chloro-1-methyl-3-phenyl-1,6-naphthyridin-2(1H)-one (8a): Purifi-
cation by silica gel chromatography (mixtures of DCM/EtOH of
increasing polarity) afforded 8a (74% yield) as a yellow powder;
m.p. 146–147 °C. Rf = 0.18 (DCM). 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.82 (s, 1 H), 8.24 (s, 1 H), 7.73 (dd, J = 8.4, 1.6 Hz,
2 H), 7.69 (s, 1 H), 7.52–7.45 (m, 3 H), 3.69 (s, 3 H) ppm. 13C
1492
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1487–1495

Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones
NMR (100 MHz, [D6]DMSO): δ = 160.5, 150.5, 150.3, 145.9, General Procedure for Microwave-Promoted Suzuki–Miyaura Cross-
135.8, 134.3, 132.4, 128.7 (2 C), 128.4, 128.0 (2 C), 115.8, 108.5, Coupling of 8a, 8b, and 8f: To a vessel (40 mL) were added com-
29.8 ppm. HRMS (ESI): calcd. for C15H11ClN2O [M + H]+
271.0633; found 271.0624.
pound 8 (0.55 mmol) in 1,4-dioxane/water (4:1, 10 mL), the appro-
priate boron reagent (0.61 mmol), Na2CO3 (147 mg, 1.39 mmol),
and Pd(PPh3)4 (32 mg, 5 mol-%). The tube was sealed, and the re-
action mixture was heated under microwave irradiation at 105 °C
for 1 or 2 h (as indicated in Table 4). After cooling, water was
added, and the mixture was extracted with DCM. The organic layer
was washed with brine, dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
silica gel chromatography to provide 9a and 9d–9g (see Table 4).
7-Chloro-3-(4-methoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one
(8b): Purification by silica gel chromatography (petroleum ether/
EtOAc, 4:1) afforded 8b (70% yield) as a white powder; m.p. 171–
1
172 °C. Rf = 0.09 (DCM). H NMR (400 MHz, [D6]DMSO): δ =
8.80 (s, 1 H), 8.19 (s, 1 H), 7.73 (d, J = 9.0 Hz, 2 H), 7.67 (s, 1 H),
7.06 (d, J = 9.0 Hz, 2 H), 3.85 (s, 3 H), 3.68 (s, 3 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 160.7, 159.4, 150.1, 150.0,
145.6, 133.0, 131.9, 130.0 (2 C), 128.0, 115.9, 113.5 (2 C), 108.4,
55.2, 29.8 ppm. HRMS (ESI): calcd. for C16H13ClN2O2 [M + H]+
301.0738; found 301.0735.
1-Methyl-3,7-diphenyl-1,6-naphthyridin-2(1H)-one (9a): Purification
by silica gel chromatography (DCM) afforded 9a (69% yield) as a
white powder; m.p. 155–156 °C. Rf = 0.22 (DCM). 1H NMR
(400 MHz, [D6]DMSO): δ = 9.03 (s, 1 H), 8.28 (dd, J = 8.4, 1.6 Hz,
2 H), 8.24 (s, 1 H), 7.96 (s, 1 H), 7.75 (dd, J = 8.4, 1.6 Hz, 2 H),
7.57–7.40 (m, 6 H), 3.80 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 160.8, 156.0, 150.5, 144.8, 138.4, 136.2, 134.8, 131.8,
129.5, 128.8 (2 C), 128.7 (2 C), 128.1, 128.0 (2 C), 127.1 (2 C),
115.4, 104.8, 29.6 ppm. HRMS (ESI): calcd. for C21H16N2O [M +
H]+ 313.1335; found 313.1322.
7-Chloro-3-(4-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one
(8c): Purification by silica gel chromatography (DCM) afforded 8c
(68 % yield) as a yellow powder; m.p. 229–230 °C. Rf = 0.20
1
(DCM). H NMR (400 MHz, [D6]DMSO): δ = 8.82 (s, 1 H), 8.29
(s, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.70 (s, 1 H), 7.56 (d, J = 8.4 Hz,
2 H), 3.68 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
160.4, 150.6, 150.4, 145.9, 134.6 (2 C), 133.1, 131.0, 130.5 (2 C),
128.1 (2 C), 115.7, 108.6, 29.8 ppm. HRMS (ESI): calcd. for
C15H10Cl2N2O [M + H]+ 305.0243; found 305.0235.
7-(4-Methoxyphenyl)-1-methyl-3-phenyl-1,6-naphthyridin-2(1H)-one
(9d): Purification by silica gel chromatography (DCM) afforded 9d
(61% yield) as a white powder; m.p. 198–199 °C. Rf = 0.22 (DCM/
MeOH, 99:1). 1H NMR (400 MHz, [D6]DMSO): δ = 9.01 (s, 1 H),
8.29 (d, J = 9.0 Hz, 2 H), 8.24 (s, 1 H), 7.91 (s, 1 H), 7.77 (dd, J =
6.8, 1.6 Hz, 2 H), 7.52–7.42 (m, 3 H), 7.13 (d, J = 9.0 Hz, 2 H),
3.89 (s, 3 H), 3.82 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 160.9, 160.6, 155.9, 150.4, 144.8, 136.3, 134.9, 131.3, 130.8,
128.7 (2 C), 128.6 (2 C), 128.1, 128.0 (2 C), 114.9, 114.1 (2 C),
103.6, 55.3, 29.6 ppm. HRMS (ESI): calcd. for C22H18N2O2 [M +
H]+ 343.1441; found 343.1432.
7-Chloro-3-(4-cyanophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one
(8d): Purification by silica gel chromatography (DCM) afforded 8d
(70% yield) as a beige powder; m.p. 330–331 °C. Rf = 0.13 (DCM).
1H NMR (400 MHz, [D6]DMSO): δ = 8.84 (s, 1 H), 8.40 (s, 1 H),
7.99 (d, J = 8.4 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.74 (s, 1 H),
3.70 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.2,
151.1, 150.7, 146.2, 140.5, 135.9, 132.0 (2 C), 130.6, 129.6 (2 C),
118.7, 115.5, 110.8, 108.7, 29.9 ppm. HRMS (ESI): calcd. for
C16H10ClN3O [M + H]+ 296.0585; found 296.0582.
7-(4-Cyanophenyl)-1-methyl-3-phenyl-1,6-naphthyridin-2(1H)-one
(9e): Purification by silica gel chromatography (DCM) and tritura-
tion with diisopropyl ether afforded 9e (81% yield) as a white pow-
der; m.p. 235–236 °C. Rf = 0.13 (DCM). 1H NMR (400 MHz, [D6]-
DMSO): δ = 9.11 (s, 1 H), 8.53 (d, J = 8.4 Hz, 2 H), 8.29 (s, 1 H),
8.14 (s, 1 H), 8.06 (d, J = 8.4 Hz, 2 H), 7.78 (dd, J = 8.4, 1.6 Hz,
2 H), 7.53–7.45 (m, 3 H), 3.84 (s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 160.8, 153.8, 150.7, 144.9, 142.6, 136.0, 134.6,
132.7 (2 C), 132.6, 128.8 (2 C), 128.3, 128.0 (2 C), 127.8 (2 C),
118.8, 116.0, 111.7, 106.1, 29.8 ppm. HRMS (ESI): calcd. for
C22H15N3O [M + H]+ 338.1288; found 338.1290.
7-Chloro-3-(3,5-dimethylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-
one (8e): Purification by silica gel chromatography (DCM) afforded
8e (68% yield) as a pale yellow powder; m.p. 165–166 °C. Rf = 0.18
1
(DCM). H NMR (400 MHz, [D6]DMSO): δ = 8.80 (s, 1 H), 8.19
(s, 1 H), 7.67 (s, 1 H), 7.33 (s, 2 H), 7.08 (s, 1 H), 3.67 (s, 3 H),
2.36 (s, 6 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.5,
150.4, 150.2, 145.8, 136.9 (2 C), 135.7, 134.0, 132.6, 129.7, 126.4 (2
C), 115.8, 108.4, 29.7, 20.9 (2 C) ppm. HRMS (ESI): calcd. for
C17H15ClN2O [M + H]+ 299.0946; found 299.0940.
7-Chloro-3-(3-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one
(8f): Purification by silica gel chromatography (DCM) afforded 8f
(71% yield) as a white powder; m.p. 160–161 °C. Rf = 0.27 (DCM).
1H NMR (400 MHz, [D6]DMSO): δ = 8.82 (s, 1 H), 8.34 (s, 1 H),
7.71 (s, 1 H), 7.63–7.52 (m, 3 H), 7.33–7.28 (m, 1 H), 3.69 (s, 3
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 161.7 (d, J =
241 Hz), 160.3, 150.8, 150.5, 146.0, 138.0 (d, J = 8 Hz), 135.1, 130.8
(d, J = 2 Hz), 130.0 (d, J = 8 Hz), 124.8 (d, J = 3 Hz), 115.6, 115.5
(d, J = 23 Hz), 115.1 (d, J = 20 Hz), 108.6, 29.8 ppm. HRMS (ESI):
calcd. for C15H10ClFN2O [M + H]+ 289.0538; found 289.0532.
3-(4-Methoxyphenyl)-1-methyl-7-(pyridin-4-yl)-1,6-naphthyridin-
2(1H)-one (9f): Purification by silica gel chromatography (mixtures
of DCM/MeOH of increasing polarity) and trituration with di-
isopropyl ether afforded 9f (78% yield) as a yellow powder; m.p.
1
252–253 °C. Rf = 0.10 (DCM/MeOH, 98:2). H NMR (400 MHz,
[D6]DMSO): δ = 9.09 (s, 1 H), 8.78 (dd, J = 5.2, 1.6 Hz, 2 H), 8.27
(dd, J = 5.2, 1.6 Hz, 2 H), 8.25 (s, 1 H), 8.14 (s, 1 H), 7.78 (d, J =
8.8 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H), 3.83 (s, 3
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.9, 159.4,
152.9, 150.5, 150.3 (2 C), 145.4, 144.6, 133.3, 132.2, 130.1 (2 C),
128.2, 121.1 (2 C), 116.6, 113.5 (2 C), 106.0, 55.2, 29.8 ppm. HRMS
(ESI): calcd. for C21H17N3O2 [M + H]+ 344.1394; found 344.1394.
7-Chloro-1-methyl-3-(pyridin-4-yl)-1,6-naphthyridin-2(1H)-one (8g):
Purification by silica gel chromatography (mixtures of DCM/
MeOH of increasing polarity) afforded 8g (55% yield) as a white
1
powder; m.p. Ͼ400 °C. Rf = 0.07 (DCM/MeOH, 99:1). H NMR
(400 MHz, [D6]DMSO): δ = 8.86 (s, 1 H), 8.71 (dd, J = 4.6, 1.6 Hz,
3-(3-Fluorophenyl)-1-methyl-7-(3,5-dimethylphenyl)-1,6-naphthyr-
2 H), 8.46 (s, 1 H), 7.78 (dd, J = 4.6, 1.6 Hz, 2 H), 7.74 (s, 1 H), idin-2(1H)-one (9g): Purification by silica gel chromatography
3.70 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.0, (DCM) afforded 9g (92 % yield) as a white powder; m.p. 225–
1
151.2, 150.8, 149.6 (2 C), 146.3, 143.1, 136.1, 129.6, 123.1 (2 C), 226 °C. Rf = 0.16 (DCM). H NMR (400 MHz, [D6]DMSO): δ =
115.4, 108.7, 29.8 ppm. HRMS (ESI): calcd. for C14H10ClN3O [M
9.04 (s, 1 H), 8.36 (s, 1 H), 7.95 (s, 1 H), 7.94 (s, 2 H), 7.68–7.64
(m, 2 H), 7.58–7.52 (m, 1 H), 7.29 (ddd, J = 8.5, 8.5, 2.1 Hz, 1 H),
+ H]+ 272.0585; found 272.0581.
Eur. J. Org. Chem. 2014, 1487–1495
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1493

D. Montoir, A. Tonnerre, M. Duflos, M.-A. Bazin
FULL PAPER
7.16 (s, 1 H), 3.83 (s, 3 H), 2.43 (s, 6 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 161.8 (d, J = 240 Hz), 160.6, 156.5, 150.6, 144.9,
138.4 (d, J = 8 Hz), 138.2, 137.7 (2 C), 135.5, 131.0, 130.0 (d, J =
1 Hz), 129.9 (d, J = 12 Hz), 124.9 (2 C), 124.8 (d, J = 2 Hz), 115.5
(d, J = 22 Hz), 115.1, 114.9 (d, J = 20 Hz), 104.6, 29.7, 21.0 (2
C) ppm. HRMS (ESI): calcd. for C23H19FN2O [M + H]+ 359.1554;
found 359.1550.
150.6, 150.3 (2 C), 145.3, 143.8, 136.1, 129.9, 129.4, 126.8, 126.2,
125.7, 121.1 (2 C), 116.5, 106.2, 30.0 ppm. HRMS (ESI): calcd. for
C18H13N3OS [M + H]+ 320.0852; found 320.0847.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details, characterization data, and 1H and
13C NMR spectra for new products.
General Procedure for Microwave-Promoted One-Pot Sequential
Suzuki–Miyaura Cross-Coupling of 7b: To a vessel (40 mL) were
added compound 7b (0.47 mmol) in 1,4-dioxane/water (4:1,
10 mL), the appropriate boron reagent (0.47 mmol), Na2CO3
(124 mg, 1.17 mmol), and Pd(PPh3)4 (27 mg, 5 mol-%). The tube
was sealed, and the reaction was heated under microwave irradia-
tion at 80 °C from 10 min to 1.5 h (as indicated in Table 5). After
completion of the reaction (monitored by UPLC–MS), the second
boron reagent (0.47 mmol) was added to the crude reaction mixture
along with Pd(PPh3)4 (27 mg, 5 mol-%) and Na2CO3 (124 mg,
1.17 mmol). The tube was sealed, and the mixture was subjected to
microwave irradiation at 105 °C from 1.5 h to 3.5 h (as indicated
in Table 5). After cooling, water was added, and the mixture was
extracted with DCM. The organic layer was washed with brine,
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by silica gel chromatography
to provide 9a and 9h–9j (see Table 5).
Acknowledgments
Dr. Catherine Roullier is gratefully acknowledged for the HRMS
measurements.
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1-Methyl-3,7-diphenyl-1,6-naphthyridin-2(1H)-one (9a): Purification
by silica gel chromatography (mixtures of DCM/MeOH of increas-
ing polarity) afforded 9a (58% Yield). Analytical data agree with
previous characterization.
3-(3-Fluorophenyl)-7-(4-methoxyphenyl)-1-methyl-1,6-naphthyridin-
2(1H)-one (9h): Purification by silica gel chromatography (DCM)
afforded 9h (55% yield) as a beige powder; m.p. 160–161 °C. Rf =
1
0.19 (DCM). H NMR (400 MHz, [D6]DMSO): δ = 9.01 (s, 1 H),
8.34 (s, 1 H), 8.29 (d, J = 9.0 Hz, 2 H), 7.91 (s, 1 H), 7.67–7.63 (m,
2 H), 7.57–7.52 (m, 1 H), 7.29 (ddd, J = 8.6, 8.6, 2.1 Hz, 1 H), 7.13
(d, J = 9.0 Hz, 2 H), 3.89 (s, 3 H), 3.82 (s, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 161.8 (d, J = 240 Hz), 160.6 (2 C),
156.1, 150.7, 144.9, 138.5 (d, J = 8 Hz), 135.6, 130.7, 129.9 (d, J =
9 Hz), 129.6 (d, J = 3 Hz), 128.6 (2 C), 124.7 (d, J = 3 Hz), 115.5
(d, J = 23 Hz), 114.8 (d, J = 20 Hz), 114.7, 114.1 (2 C), 103.6,
55.3, 29.6 ppm. HRMS (ESI): calcd. for C22H17FN2O2 [M + H]+
361.1347; found 361.1341.
7-(3,5-Dimethylphenyl)-1-methyl-3-(pyridin-4-yl)-1,6-naphthyridin-
2(1H)-one (9i): Purification by silica gel chromatography (DCM/
MeOH, 98:2) and trituration with diisopropyl ether afforded 9i
(32% yield) as a beige powder; m.p. 233–234 °C. Rf = 0.10 (DCM/
MeOH, 98:2). 1H NMR (400 MHz, [D6]DMSO): δ = 9.05 (s, 1 H),
8.70 (d, J = 5.4 Hz, 2 H), 8.46 (s, 1 H), 7.95 (s, 1 H), 7.93 (s, 2 H),
7.82 (d, J = 5.4 Hz, 2 H), 7.16 (s, 1 H), 3.82 (s, 3 H), 2.42 (s, 6
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.3, 156.9,
150.9, 149.5 (2 C), 145.2, 143.5, 138.1, 137.8 (2 C), 136.5, 131.1,
128.7, 125.0 (2 C), 123.1 (2 C), 114.9, 104.7, 29.7, 21.0 (2 C) ppm.
HRMS (ESI): calcd. for C22H19N3O [M + H]+ 342.1601; found
342.1598.
1-Methyl-7-(pyridin-4-yl)-3-(thien-2-yl)-1,6-naphthyridin-2(1H)-one
(9j): Purification by silica gel chromatography (mixtures of DCM/
MeOH of increasing polarity) and trituration with diisopropyl
ether afforded 9j (33% yield) as a yellow powder; m.p. 261–262 °C.
[8] a) C.-C. Cheng, S.-J. Yan, The Friedländer Synthesis of Quinol-
ines, in: Organic Reactions (Ed.: W. G. Dauben), Wiley, New
York, 1982, vol. 28, p. 37–201; b) D. J. Brown (Ed.), Primary
Syntheses of 1,6-Naphthyridines, in: Chemistry of Heterocyclic
Compounds: The Naphthyridines, John Wiley & Sons, Inc., Ho-
boken, NJ, 2008, vol. 63, p. 67–89.
1
Rf = 0.15 (DCM/MeOH, 98:2). H NMR (400 MHz, [D6]DMSO):
δ = 9.12 (s, 1 H), 8.78–8.74 (m, 3 H), 8.28 (br. s, 2 H), 8.16 (s, 1
H), 7.99 (s, 1 H), 7.73 (d, J = 2.5 Hz, 1 H), 7.25 (s, 1 H), 3.87 (s,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 159.8, 152.8,
[9] A. Suzuki, J. Organomet. Chem. 1999, 576, 147–168.
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Eur. J. Org. Chem. 2014, 1487–1495

Differential Functionalization of 1,6-Naphthyridin-2(1H)-ones
[10] C. Garino, T. Tomita, N. Pietrancosta, Y. Laras, R. Rosas, G.
Herbette, B. Maigret, G. Quéléver, T. Iwatsubo, J.-L. Kraus, J.
Med. Chem. 2006, 49, 4275–4285.
[11] S. Chowdhury, S. Roy, J. Org. Chem. 1997, 62, 199–200.
[12] B. Wu, H.-L. Wang, L. Pettus, R. P. Wurz, E. M. Doherty, B.
Henkle, H. J. McBride, C. J. M. Saris, L. M. Wong, M. H.
Plant, L. Sherman, M. R. Lee, F. Hsieh, A. S. Tasker, J. Med.
Chem. 2010, 53, 6398–6411.
[13] M.-A. Bazin, L. El Kihel, J.-C. Lancelot, S. Rault, Tetrahedron
Lett. 2007, 48, 4347–4351.
[14] It is noteworthy that the mixture of products 8 and 9 was diffi-
cult to purify on a silica gel chromatography column. Reversed-
phase chromatography using water/acetonitrile was required to
isolate each product.
Received: October 30, 2013
Published Online: January 8, 2014
Eur. J. Org. Chem. 2014, 1487–1495
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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