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

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.

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 [22-2440-42]. 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.

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.

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 [22-2453] afforded triazinylpent-4-ynamides 6–9 in moderate to good yields (Scheme 3, Table 2).

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).

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.

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.

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.

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			22	74
2			23	80
3			24	73
4			25	79
5			26	91
6			27	94
7			28	78
8			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.

Experimental section.