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Synthesis of 3,4-dihydro-1,8-naphthyridin-2(1H)-ones via microwave-activated inverse electron-demand Diels–Alder reactions

  1. 1,2 ,
  2. 1,2 ,
  3. 1 ,
  4. 3 ,
  5. 2 and
  6. 2
1Laboratoire de Chimie Organique et Analytique, Université Sultan Moulay Slimane, FST Béni-Mellal, BP 523, 23000 Béni-Mellal, Morocco
2Institut de Chimie Organique & Analytique, Université d’Orléans, UMR-CNRS 7311, BP 6759, 45067 Orléans Cedex 2, France
3Laboratoire de Biochimie, Environnement & Agroalimentaire, URAC 36, Université Hassan II, FST Mohammedia, BP 146, 20800 Mohammedia, Morocco
  1. Corresponding author email
Associate Editor: J. P. Wolfe
Beilstein J. Org. Chem. 2014, 10, 282–286. https://doi.org/10.3762/bjoc.10.24
Received 19 Oct 2013, Accepted 02 Jan 2014, Published 28 Jan 2014
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Abstract

Substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones have been synthesized with the inverse electron-demand Diels–Alder reaction from 1,2,4-triazines bearing an acylamino group with a terminal alkyne side chain. Alkynes were first subjected to the Sonogashira cross-coupling reaction with aryl halides, the product of which then underwent an intramolecular inverse electron-demand Diels–Alder reaction to yield 5-aryl-3,4-dihydro-1,8-naphthyridin-2(1H)-ones by an efficient synthetic route.

Keywords: inverse-electron-demand Diels–Alder reaction; microwave irradiation; naphthyridin-2(1H)-ones; Sonogashira cross-coupling; 1,2,4-triazine

Introduction

1,8-Naphthyridine derivatives are an important class of heterocyclic compounds and include many substances of both biological and chemical interest [1-4]. Prevention and treatment of angiogenic disorders and cancers were realized with this class of heterocyclic derivatives [5]. They show anti-allergic [6], anti-inflammatory [7], antibacterial [8] and gastric antisecretory activities [9]. Many other remarkable applications are reported in the literature [10-14], such as the selective inhibition of p38 mitogen-activated protein kinase [15] and the potent inhibition of protein kinase C isozymes [16]. Much attention has been devoted to the synthesis of 1,8-naphthyridin-2(1H)-ones because of their acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity [17] and their role as phosphodiesterase inhibitors [18,19]. To date, 1,8-naphthyridin-2(1H)-ones have been prepared mainly by the Knorr or the Friedländer reaction [20,21]. However, these methods cannot give access to various polysubstituted 1,8-naphthyridin-2-ones. Recently, we reported an efficient method for the synthesis of polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines from 1,2,4-triazines via an inverse electron-demand Diels–Alder reaction under microwave irradiation [22-24]. The use of 1,2,4-triazines in inverse electron-demand Diels–Alder reactions proved to be an efficient strategy for the construction of various heterocyclic compounds [25-27], such as azacarbazoles [28-33], polycyclic condensed pyrazines [34,35], dihydropyrrolopyridines [36,37], thienopyridines and thiopyranopyridines [38,39], as well as furo- and pyranopyridines [22-24,40-42]. Reactions with microwave irradiation are well-known for their ability to reduce reaction times, increase product yields, and reduce unwanted side reactions compared to conventional heating methods [43-49]. In the continuation of our studies on the synthesis of fused heterocyclic systems we decided to extend this methodology to the synthesis of substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones.

Results and Discussion

Synthesis of 1,7-disubstituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones

3-Methylsulfonyl-5-phenyl-1,2,4-triazine

Our strategy was first based on the 3-methylsulfonyl-1,2,4-triazine 1 (Scheme 1). This key triazine 1 was prepared according to the procedure described by Taylor and Paudler [34,50], i.e., the phenylglyoxal was condensed with the S-methylthiosemicarbazide followed by an oxidation reaction with MCPBA.

[1860-5397-10-24-i1]

Scheme 1: (a) MeI, EtOH, reflux, 3 h (87%); (b) phenylglyoxal, Na2CO3, H2O, 5 °C, 6 h (96%); (c) MCPBA, CH2Cl2, rt, 4 h (82%).

Synthesis of N-substituted pent-4-ynamides

N-Alkyl or N-aryl-pent-4-ynamides were prepared by amide coupling reactions between pent-4-ynoic acid and various amines in THF in the presence of EDCI and DMAP. The corresponding amides 2–5 were obtained in excellent yields (Scheme 2). The results are shown in Table 1.

[1860-5397-10-24-i2]

Scheme 2: Coupling of pent-4-ynoic acid with different amines. Conditions: (a) EDCI, DMAP, THF, rt, 36 h.

Table 1: Amide coupling reactions of pent-4-ynoic acid with different amines.

Entry Amine Product Yield (%)a
1 butylamine 2 96
2 prop-2-en-1-amine [51] 3 91
3 isopropylamine 4 84
4 aniline [52] 5 97

aYield of pure isolated product.

Preparation of N-substituted N-triazinylpent-4-ynamides

The nucleophilic substitution of the methylsulfonyl leaving group from 1 by the lithium salt of ynamides 2–5 [22-24,53] afforded triazinylpent-4-ynamides 6–9 in moderate to good yields (Scheme 3, Table 2).

[1860-5397-10-24-i3]

Scheme 3: Reaction of triazine 1 with different pent-4-ynamides. Conditions: n-BuLi, THF, −30 °C, 2 h.

Table 2: Substitution of 1,2,4-triazine 1 by different amides 2–5.

Entry R Product Yield (%)a
1 butyl 6 74
2 propenyl 7 56
3 isopropyl 8 24
4 phenyl 9 79

aYield of pure isolated product.

Intramolecular inverse electron-demand Diels–Alder reactions

With the tethered triazines 6–9 in hand, we were able to study the cycloaddition reaction under microwave heating following the optimal experimental conditions already reported with triazines [22-24]. In chlorobenzene at 220 °C (optimal reaction temperature for six-membered-ring formation), the corresponding cycloadducts 10–13 were obtained in high yields (Scheme 4, Table 3).

[1860-5397-10-24-i4]

Scheme 4: Reaction of triazines 6–9 under microwave irradiation. Conditions: Chorobenzene, 220 °C, 1 h.

Table 3: Intramolecular inverse electron-demand Diels–Alder reactions under microwave irradiation.

Entry R Product Yield (%)a
1 butyl 10 97
2 propenyl 11 96
3 isopropyl 12 93
4 phenyl 13 98

aYield of pure isolated product.

We therefore developed an efficient method for the synthesis of 1-substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones by using 1,2,4-triazine and alkyne tethered together by an amide linker.

Synthesis of 1,5,7-trisubstituted-3,4-dihydro-1,8-naphthyridin-2(1H)-ones

In order to functionalize the 4-position of the pyridine ring and to extend diversity, we envisaged to evaluate the reactivity of internal alkynes towards the inverse electron-demand Diels–Alder reaction. To reach this goal, we decided to functionalize the alkynes 6–9 employing the Sonogashira cross-coupling reaction.

Preparation of aryl-N-triazinylpentynamides

The terminal alkynes 6–9 were then subjected to a Sonogashira cross-coupling reaction. Thus, treating compounds 6–9 in DME with Pd(PPh3)2Cl2 (5 mol %), CuI, Et3N and aryl iodide, gave the cross-coupling products 14–21 in very good yields (Scheme 5). The results are summarized in Table 4.

[1860-5397-10-24-i5]

Scheme 5: Preparation of aryl-N-triazinylpentynamides. Conditions: CuI (10 mol %), Pd(PPh3)2Cl2 (5 mol %), DME, Et3N, rt, 3 h.

Table 4: Sonogashira cross-coupling reactions from alkynes 6–9.

Entry R Aryl Product Yield (%)a
1 butyl 2-thienyl 14 95
2 4-methoxyphenyl 15 95
3 propenyl 2-thienyl 16 95
4 4-methoxyphenyl 17 89
5 isopropyl 2-thienyl 18 91
6 4-methoxyphenyl 19 85
7 phenyl 2-thienyl 20 86
8 4-methoxyphenyl 21 82

aYield of pure isolated product.

Intramolecular inverse electron-demand Diels–Alder reactions

Finally, the inverse electron-demand Diels–Alder reaction with tethered triazine 14–21 was carried out under microwave irradiation in a sealed tube at 220 °C (Scheme 6) as previously mentioned [22-24]. The corresponding substituted naphthyridin-2(1H)-ones 22–29 were obtained in excellent yields. The results are given in Table 5.

[1860-5397-10-24-i6]

Scheme 6: Preparation of 3,4-dihydro-1,8-naphthridin-2(1H)-ones. Conditions: Chlorobenzene, 220 °C, 1 h.

Table 5: Intramolecular inverse electron-demand Diels–Alder reactions of substituted alkynes 14–21.

Entry R Ar Product Yield (%)a
1 [Graphic 1] [Graphic 2] 22 74
2 [Graphic 3] [Graphic 4] 23 80
3 [Graphic 5] [Graphic 6] 24 73
4 [Graphic 7] [Graphic 8] 25 79
5 [Graphic 9] [Graphic 10] 26 91
6 [Graphic 11] [Graphic 12] 27 94
7 [Graphic 13] [Graphic 14] 28 78
8 [Graphic 15] [Graphic 16] 29 84

aYield of pure isolated product.

Conclusion

In this article, we report the successful application of a new synthesis strategy leading to 1-substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones by inverse electron-demand Diels–Alder reactions under microwave activation. We also synthesized 5-substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones via the Sonogashira cross-coupling reaction followed by intramolecular inverse electron-demand Diels–Alder reactions. The developed approaches allow a high diversity of substituents on the bicyclic scaffold.

Supporting Information

Supporting Information File 1: Experimental section.
Format: PDF Size: 346.3 KB Download

Acknowledgements

The authors thank the Volubilis Hubert Curien Program for financial support.

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