Tertiary formylated amines by microwave irradiation of N,N-dimethyl-N′-(2-pyridyl)formamidines with methyl vinyl ketone

Introduction

The amidine functional group contains an amino nitrogen atom with a free electron pair conjugated with the π-electrons of the C=N double bond. This functional group has been often utilized in the synthesis of heterocycles. For example, N-monosubstituted formamidines readily react with ylidenemalononitriles to give useful pyrimidine intermediates [1]. Amidines have been used as a three- or two-unit synthon in the synthesis of 3- to 6-membered heterocycles [2]. Amidines have also been reacted with methyl-2-dimethoxymethyl-3-methoxypropionate to give dihydropyridopyrimidines [3]. They are also intermediates in the synthesis of [1,2,4]triazolo[1,5-a]pyridines [4]. Evaluation of biological activity of some amidine derivatives has also been reported [5]. Recently, we have utilized the core N,N-dimethyl-N′-heteroarylformamidine in the construction of heteroaryl-N-imidazoles [6].

Herein, we describe the results obtained from the reaction of N,N-dimethyl-N′-(2-pyridyl)formamidine with methyl vinyl ketone (MVK) under microwave irradiation.

Results and discussion

Pyridylformamidines 1 were readily prepared by condensation of a 2-aminopyridine with an excess of N,N-dimethylformamide dimethyl acetal [7]. Initially, we were interested in the possibility that pyridylformamidines 1 would undergo a hetero Diels-Alder type reaction with MVK 2 (Scheme 1), to give pyridopyrimidines 3 by analogy with the reaction of N¹,N¹-dimethyl-N²-[(1-phenyl-3-methyl)pyrazol-5-yl]formamidine, which undergoes a hetero Diels-Alder reaction with N-phenylmaleimide or N-4′-nitrophenyl maleimide under microwave irradiation to give a tricyclic cycloadduct [8]. First, the reaction was carried out on conventional heating using an excess of MVK in different solvents (DMF, MeCN) or without solvent. In most experiments, mixtures of substrate 1 and polymerized MVK were obtained. Experiments under microwave (mw) irradiation followed, until best conditions (160 W, 140°C) were found that did not cause MVK polymerization. However, the isolated product did not correspond to the expected cycloadduct 3; instead, the tertiary amine N-formyl-N-(3-oxobutyl)-2-pyridylamine (4) was isolated in good yield.

Scheme 1

This result, together with the finding that formamidines 1 can be transformed into N-arylimidazoles [6] in a related reaction, support the suggestion that the most nucleophilic nitrogen is the nitrogen of the moiety C=N². By contrast, in the reaction of these formamidines with phenacyl bromides, it is the endo pyridine nitrogen which reacts first [9]. The most probable mechanism of the synthesis of 4 involves the initial attack of the imine nitrogen C=N² (assisted by the functionality Me₂N¹) to the Michael acceptor MVK. Hydrolysis of the dimethyliminium intermediate leads to the N-formyl derivative 4.

Proper assignment of protons and carbons of molecules 4 was achieved with the aid of GHMBC and GHSQC NMR experiments (examples can be found in the supplementary material). The N-formyl proton was readily identified in the ¹H NMR spectra as a singlet at δ 8.93–9.07 and the formyl carbon atom in the ¹³C NMR spectra at δ 161.5–162.2.

Treatment of the N-formylated aminoketone 4 with acid causes deformylation to give the product of Michael addition of a 2-pyridylamine with MVK, which is exemplified by 5 in Scheme 2. This Michael addition reaction has been reported elsewhere [10]. The treatment of 4 with ammonium acetate causes a retro Michael addition giving the starting MVK and 2-aminopyridine. By contrast, the reaction of sodium borohydride in either neutral or acidic solution gives the deformylated product, such as 5. Interestingly, treatment of 5 with an excess of dimethylformamide dimethyl acetal under mw conditions gave the starting formamidine 1f in 90% yield (Scheme 2).

Scheme 2

It has been previously demonstrated that treatment of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (hydrochloride) 6 with potassium permanganate in hydrochloric acid solution leads to the open structure N-formyl-N-methyl-2-benzoylethylamine 7 (Scheme 3) [11]. Therefore, the reaction described here may be considered as a non- oxidative alternative approach to the preparation of the analogs 4.

Scheme 3

Experimental

Melting points were measured on an electrothermal melting point apparatus and are reported without correction. ¹H and ¹³C NMR spectral data were recorded in CDCl₃ at 300 and 75 MHz, respectively, using a Varian Mercury 300 MHz NMR spectrometer or at 500 and 125 MHz, respectively, using a Varian NMR System 500 MHz spectrometer. The microwave irradiation was performed in a Discovery microwave apparatus.

2-Aminopyridines, N,N-dimethylformamide dimethyl acetal and MVK were purchased from Aldrich Chemical Co.