One-pot synthesis of 2-amino-3-cyanopyridine derivatives under microwave irradiation without solvent

A series of 2-amino-3-cyanopyridine derivatives have been prepared by one-pot condensation from malononitrile, aromatic aldehyde, methyl ketone and ammonium acetate under microwave irradiation without solvent. This method has the advantage of short routine, high yields and being environmentally-friendly.


Introduction
Many natural occurring and synthetic compounds containing the pyridine scaffold possess interesting pharmacological properties. 1 Among them, 2-amino-3-cyanopyridines have been identified as IKK-βinhibitors. 2 Besides, they are important and useful intermediates in preparing variety of heterocyclic compounds. 3Therefore, the synthesis of 2-amino-3-cyanopyridine derivatives continues to attract much interest in organic chemistry.
It has been reported that the 2-amino-6-aryl-3-cyano-4-piperidinylpyridine core structure can be constructed using a one-pot coupling reaction of acetophenone, piperidine, malononitrile and ammonium acetate in conventional heating mode. 4Nevertheless, the protocol gives comparatively lower yields and longer reaction time.
6][7][8] Not long ago, Satya et al has prepared 2-amino-3-cyanopyridines from arylidenemalanonitrile, ketone and ammonium acetate under microwave irradiation. 9However, arylidenemalanonitriles as one of the starting materials must be synthesized from malononitrile and aromatic aldehyde, which results in longer routine.
It goes without saying that the most efficient synthesis of functionalized organic compounds would be one-pot reaction from commercially available and inexpensive starting materials 10 .In our previous study, [11][12][13][14][15][16] we have synthesized large amounts of heterocyclic compounds by one-pot under microwave irradiation.Through further investigation, we found that one-pot synthesis of the target compounds from malononitrile, aromatic aldehyde, methyl ketone and ammonium acetate under microwave irradiation without solvent can be successfully achieved in excellent yields and short reaction time.
Herein, we wish to report this convenient and efficient method, which is, to the best of our knowledge, the 1st one-pot synthesis of 2-amino-3-cyanopyridines from cheap reagents under microwave irradiation and solvent-free.

Results and Discussion
When a mixture of aromatic aldehyde 1, methyl ketone 2, malononitrile 3 and ammonium acetate was irradiated in a microwave oven (Scheme 1), the reactions were almost completed in 7-9 min.The reaction mixtures were then washed with a small amount of ethanol.The crude products were purified by recrystallization from 95% ethanol to afford products with good yields (72-86%).The main results for the synthesis of these compounds are given in Table 1.It is seen that this procedure has the advantage of short routine, good yields, convenient workup and being environmentally friendly.The reaction may proceed via imine 5 formed from aldehyde and ammonium acetate, imine 5 reacts with alkylidenemalononitrile 6(from condensation of aromatic aldehyde with malononitrile) to give 7, followed by cycloaddition, isomerization, aromatization to afford the 2-amino-3-cyanopyridine 4(Scheme 2).
Scheme 2. Mechanisms of the reaction.
All the products were characterized by IR and 1 H NMR analysis.Furthermore, the structure of 4a was established by the X-ray crystallographic analysis (Figure 1).

Conclusions
We have synthesized a series of 2-amino-3-cyanopyridine derivatives by one-pot method under microwave irradiation and solvent-free conditions, thus providing a facile, rapid, efficient and environmentally friendly method.

Experimental Section
General Procedures.Melting points were determined in a capillary tube and were uncorrected.
The 1 H NMR spectra were recorded on a DPX 400 MHz spectrometer with TMS as internal standard.The IR spectra were obtained with SE-1730 instrument as potassium bromide pellets.Elemental analyses were determined by using a Perkin-Elmer 240c elemental analysis instrument.